DIPARTIMENTO DI SCIENZE PURE E APPLICATE
CORSO DI DOTTORATO DI RICERCA IN SCIENZE DI BASE E APPLICAZIONI
Cu iculum – SCIENZE CHIMICHE E SCIENZE FARMACEUTICHE
CICLO XXX
SYNTHESIS OF VARIOUS AND INTERESTING HETEROCYCLES
INCLUDED BERBERINO DERIVATIVES
Se o e scien i ico disciplina e: CHIM/06
RELATORE DOTTORANDO
Chia .ma p o . De C escen ini Lucia Do . Ma i Giacomo
ANNO ACCADEMICO 2016/2017
- 1 -
- 2 -
SUMMARY
1. GENERAL INTRODUCTION - 4 -
1.1 The impo ance o he e ocyclic compounds - 5 -
1.2 1,2-Diaza-1,3-dienes as use ul building blocks - 7 -
1.2.1 1,2-Diaza-1,3-dienes as accep o s in 1,4-conjuga e addi ions - 10 -
1.2.2 1,2-Diaza-1,3-dienes as dienes in IEDDA - 12 -
1.3 Resul s - 14 -
2. FACILE ODOURLESS QUANTITATIVE SYNTHESIS OF 3-HYDROXY-3,4-
DIHYDRO-2H-1,4-THIAZINES - 18 -
2.1 In oduc ion - 19 -
2.2 Resul s and Discussion - 21 -
2.3 Conclusions - 24 -
3. UNEXPECTED SYNTHESIS OF 2,3,5,6-TETRAHYDRO-1H-PYRROLO[3,4-
C]PYRIDINE-1,3,6-TRIONES - 25 -
3.1 In oduc ion - 26 -
3.2 Resul s and Discussion - 28 -
3.2 Conclusions - 35 -
4. SEQUENTIAL ONE POT SYNTHESIS OF 2,5-DIHYDROTHIOPHENES AND
THIOPHENES - 36 -
4.1 In oduc ion - 37 -
4.2 Resul s and Discussion - 38 -
4.3 Conclusion - 53 -
5. N-ACYLIMINIUM IONS AS NOVEL MANNICH-TYPE ACCEPTORS IN 1,4
ADDITIONS OF NUCLEOPHILES - 54 -
5.1 In oduc ion - 55 -
5.2 Resul s and discussion - 56 -
5.3 Conclusion - 60 -
- 3 -
6. SINTHESYS AND BIOLOGICAL EVALUATION OF NEW BERBERINO
DERIVATIVES - 61 -
6.1 In oduc ion - 62 -
6.2 Resul s and Discussion - 64 -
6.3 An ioxidan p ope ies: - 68 -
6.4 Conclusion - 71 -
7. GENERAL CONCLUSION - 72 -
8. EXPERIMENTAL SESSION - 74 -
CHAPTER 2 - 75 -
CHAPTER 3 - 80 -
CHAPTER 4 - 92 -
CHAPTER 5 - 129 -
CHAPTER 6 - 139 -
9. BIBLIOGRAPHY - 156 -
10. AKNOWLEGMENT - 164 -
- 4 -
1. GENERAL INTRODUCTION
CHAPTER 1
- 5 -
1.1 The impo ance o he e ocyclic compounds
Li e a u e su ey e ealed ha he his o y o he e ocyclic chemis y began in he 1800's,
consequen ially o he i s no ewo hy de elopmen s like he wo ks o B ugna elli, Dobe eine ,
Runge… A e Wo ld Wa II, he e was an eno mous inc ease o he esea ch in he ield o
he e ocycles. Abou one hal o o e six million compounds eco ded in Chemical Abs ac s
a e he e ocyclic. He e ocyclic chemis y is one o he mos complex and in iguing b anch o
o ganic chemis y and he e ocyclic compounds cons i u e he la ges and mos a ied amily o
o ganic compounds.1
He e ocyclic compounds a e he cyclic o ganic compounds which con ain a leas one he e o
a om; he mos common he e oa oms he ni ogen, oxygen and sulphu bu he e ocyclic ings
con aining o he he e o a oms a e also widely known. He e ocyclic compounds a e conside ed
one o he i al classes o o ganic compounds, which a e used in many biological ields, due
hei ac i i y in mul iple illnesses. He e ocyclic compounds played an impo an ole in
biological p ocesses and a e wide sp ead as na u al p oduc s. They a e widely ound in na u e
pa icula ly in nucleic acids, plan alkaloids, an hocyanins and la ones as well as in
chlo ophyll. Addi ionally some i amins, p o eins, ho mones con ain a oma ic he e ocyclic
sys em (Figu e 1).
He e ocyclic compounds ha e a wide ange o applica ion: hey a e p edominan among he
ype o compounds used as pha maceu icals, as ag ochemicals and as e e ina y p oduc s.
He e ocycles a e he key o biological ac i i y in many small molecule d ugs due o hei abili y
o hyd ogen bond, al e pola i y and modula e lipophilici y a speci ic si es in he pa hogen o
hos wi h he o e all e ec o inhibi ing he biological p ocesses ha lead o p og ammed
p og ession o diseases. These subuni s hus ha e he abili y o imp o e pha macological,
pha macokine ic, oxicological and physicochemical p ope ies o compounds, making hem
mo e e ec i e in alle ia ing a a ie y o a lic ions. In ac mo e han 90% o new d ugs con ain
he e ocycles and he in e ace be ween chemis y and biology, a which so much new scien i ic
insigh s, disco e ies and applica ions a e aking place, is c ossed by he e ocyclic compound
(Figu e 2).2
- 6 -
N
S
N
O
O
O
HN N
NNO
N
S
O
HO
O
N
H
O
OH
NH2
N
N
N
N
CH3Cl
Figu e 1: Na u al compounds con ain he e ocycles: a-Thymine b-Adenine c-Guanine d-Cy osine
e-Be be ine -Ca eine g-T yp ophan h-Thiamine i-Vi amin C
Figu e 2: Syn he ic compounds con ain he e ocycles: j-Amoxicillin k-Sildena il l-Alp azolam
a
b
c
d
e
g
i
h
j
k
l
Figu e 1
Figu e 2
- 7 -
1.2 1,2-Diaza-1,3-dienes as use ul building blocks
1,2-Diaza-1,3-dienes (DDs) a e cha ac e ized by a ca bon-ca bon, ni ogen-ni ogen conjuga e
double bond sys em. Those compounds a e ex emely e sa ile: in ac , o o e hi y yea s,
hey we e used as building blocks o he syn hesis o se e al i e-, six- and se en-membe ed
he e o ing sys ems. The chemical p ope ies o DD a e s ic ly ela ed o he elec on-
wi hd awing e ec o he azo g oup in he he e odiene sys em, as showed om he esonance
s uc u es in Scheme 1 ha make hese compounds good Michael accep o s.
R1
CC
R2
N
R3
NR4R1
CC
R2
N
R3
NR4
Scheme 1: Resonance s uc u es o DDs
DDs ea u e an umpolung o he classical ca bonyl eac i i y, since hese neu al compounds
enable nucleophilic addi ions a he e minal ca bon a om o he azoene sys em (Scheme 2).
This a om is o iginally loca ed in he α-posi ion o he ke one unc ion om which DDs a e
p epa ed. I is well known ha such a ca bon a om is a nucleophilic a he han an elec ophilic
si e. The e o e, he eac i i y o DD p oceeds con a y o he na u al pola i y o he pa en
ca bonyl de i a i es and hei employmen ep esen s a alid app oach o e e se he no mal
pola i y o ca bon a om in he α-posi ion o he ca bonyl g oup.
C
R1
R3
O
R2
R1
CC
R2
N
R3
NR4
Scheme 2: DDs as umpolung o he classic ca bonyl eac i i y
1
2
3
2
- 8 -
DDs a e usually p epa ed by means o 1,4-elimina ion o a good lea ing g oup X ( equen ly
chlo ide o b omide) in he α-posi ion wi h espec o an hyd azone unc ion. The lea ing g oup
can be p esen in he s a ing ca bonyl de i a i es (Scheme 3, Pa h A) o in oduced la e in he
hyd azone compounds (Scheme 3’, Pa h B). Bo h cyclic and acyclic ke ones can be used in he
p epa a ion o DDs.
O
R3R2
n
H
NR4NH2
O
R3R2
nX
N
R3R2
n
N H
R4
X
HX N
R3R2
n
N
R4
O
R3R2
n
N
R3R2
n
N H
R4
X
HX N
R3R2
n
N
R4
H
NR1NH2N
R3R2
n
N H
R4
Scheme 3: Syn he ic pa hways o p epa e DDs
Subs i uen s in luence he physical and chemical p ope ies o DD. Elec on-wi hd awing
g oups (e.g. es e s o amides) on he e minal ca bon and/o ni ogen a om a o hei s abili y
and enhance he elec ophilic cha ac e o he he e odiene sys em (Figu e 3).3 In addi ion he
yellow, o ange, ed o ama an h colo o DDs, due o hei conjuga ion, is a con enien and
use ul “in e nal li mus” o check he p og ess o he eac ion. In ac , he ans o ma ion o hese
compounds is accompanied wi h he change o he ini ial colo o he eac ion mix u e o he
inal colo less o pale-yellow s a e.
pa h A
pa h B
4
5
6
7
4
8
6
7
- 15 -
In o g aphic 1: Rep esen a i e examples o ou g oup wo ks
- 16 -
In o g aphic 2: Rep esen a i e examples o ou g oup wo ks
- 17 -
In o g aphic 3: Rep esen a i e examples o ou g oup wo ks
- 18 -
2. FACILE ODOURLESS QUANTITATIVE SYNTHESIS
OF 3-HYDROXY-3,4-DIHYDRO-2H-1,4-THIAZINES
CHAPTER 2
G. Ma i, G. Fa i, L. De C escen ini, S. San eusanio, O. A. A anasi, F. Man ellini
Asian J. O g. Chem., 2016, 5, 705709
- 19 -
2.1 In oduc ion
One o he main objec i es o he mode n o ganic chemis y is he easy ans o ma ion o
eadily a ailable p ecu so s in o a ge - ele an p oduc s in a apid, economical, e icien and
eco- iendly manne . In pa icula , in he las ime, he en i onmen al p o ec ion and was e
p e en ion ha e inc eased in e es and ele ance in an o e c owded wo ld whe e demand
becomes mo e p essing. The e iciency in a om economy combined wi h quan i a i e eac ion
can play a key ole in he en i onmen al ield. In ac , was e- ee syn hesis ( o al a om economy)
yielding single p oduc in pu e o m ha does no equi e sol en -consuming pu i ica ion s eps,
a oiding u he p ocedu es such as ch oma og aphy, ex ac ion o ec ys alliza ion
co esponds o a undamen al bene i bo h om he en i onmen al and he economical poin o
iew.9
The 1,4- hiazine co e ( hiomo pholine) ep esen s a ecu en s uc u e in o ganic chemis y
because i is p esen in some nume ous compounds ha ound applica ion bo h in
medicinal/pha maceu ical chemis y, as well as in chemical manu ac u ing.
In ac , he biological p ope ies shown by hese aza-sulphu he e ocycles ange om
an ibac e ial10 o an imic obial11 o an i-in lamma o ies cha ac e is ic,12 om hepa op o ec i e
ea u es13 o calcium an agonis ic,14 om asop essin ecep o an agonis ic15 o an icance
ac i i ies,16 om an ioxidan o hypolipidemic agen s.17
Besides, he 1,4- hiazine de i a i es a e commonly used as s abilize o inhibi o , 18 and i is
well known how his he e ocyclic nucleus plays an impo an ole in nume ous pigmen s19 and
dyes u s.20
The hiomo pholine co e con ibu es o cons i u e also he skele on o di e en na u al p oduc s
(Figu e 8): o example, i is p esen in he s uc u e o Adaciaquinones B,21 a compound
ex ac ed om ma ine sponge Pe osia al iani ha showed an i umo ac i i ies, o in a
me aboli e p oduced by endophy ic ungus Pa aphaeosphae ia neglec a FT462 isola ed om
he Hawaiian plan Lycopodiella ce nua,22 o in cy o oxic e pene de i ed Conicaquinones A
o B isola ed om Medi e anean ascidian Aplidium conicum.23
By i ue o hese nume ous applica ions, di e en me hods ha e been de eloped o he
p epa a ion o hiomo pholine co es.11,24 Usually, hese app oaches equi e ha sh condi ions,
elabo a ed wo k up p ocedu es and he hiols employed as s a ing ma e ials a e lammable,
ha m ul, and s ong smelly eagen s, which can lead o se ious en i onmen al and sa e y
p oblems. The mos common syn he ic ou e ha in ol es 1,2-dihalode i a i es as s a ing
ma e ials u nishes low yields due o side- eac ions such as elimina ion, equi ing di e en
pu i ica ion p ocedu e.25
- 20 -
N
H
S
O
O
S
H
N
O
O
O O
O O
Conicaquinones A Conicaquinones B
N
S
H
HO
( )3
O
OO
COOH
N
H
S
O
O
OO
O
O
Adaciaquinones B Pa aphaeosphae ide A
Figu e 8: Rep esen a i e examples o na u al p oduc s con aining a 1,4- hiazine co e.
Awa e o his in e es , in he las yea s, we ha e p oposed a syn he ic ou e o ob ain dihyd o-
o benzo-1,4- hiazine de i a i es employing 1,2-diaza-1,3-dienes and 1,2-me cap oamines as
s a ing ma e ials. In his case, he desi ed he e ocycles we e ob ained in good yields h ough a
o mal [4+2] cycliza ion, in which he DDs con ibu e wi h 2 ca bon a oms.26
Also, he syn hesis o con aining 1,4- hiazine co e bis-he e ocycles such as 2-
oxo[1,2,4] iazolo[5,1-c][1,4] hiazines was de eloped by ou g oup using DDs and
me cap oke ones in acidic medium.27 Some limi s a ec his me hodology: he o e all yields
we e mode a e, he 1,4- hiazine in e media es canno be isola ed, and, employing phosphonyl-
subs i u ed-DDs, he a ge he e ocycles we e no ob ained.
Fu he mo e, despi e o he a ie y o syn he ic me hodologies which a e a ailable o he
cons uc ion o hiazine ing, dihyd o hiazines bea ing a qua e na y ca bon cen e such as
emiheminal ha e been di icul o ob ain. Un il now, only one example o 3-hyd oxy-dihyd o-
1,4-benzo hiazine has been epo ed.28
Fo hese easons, we decided o ind ou new eagen s able o eac wi h DDs29 o o e come
hese issues. The ai s able, and odo less 1,4-di hiane-2,5-diol ha has shown o be an use ul
syn hon o he p epa a ion o a ious sulphu con aining he e ocycles such as
e ahyd o hiophenes,30 1,3-oxa hiolanes,31 hiazoles,32 e ahyd o hiopy anols33 should be a
alid candida e.
- 21 -
2.2 Resul s and Discussion
Ini ially, we se ou o iden i y he possible mild condi ions unde which he eac ion o DDs
wi h di hiane-2,5-diol 19 would p oceed choosing DD 1a as ep esen a i e compound.
MeO2CNNCO2 -Bu N
SMeO2C
OH
HN CO2 -Bu
S S
OH
HO
+2
Scheme 8: Used eagen o he op imiza ion o he syn hesis o 3-hyd oxy-3,4-dihyd o-2H-1,4- hiazine
En y
Base
Equi alen o base
Sol en
Vol. sol en (mL)
Time (h)
Yield (%) o 21a[b]
1
DIPEA
0.1
CH2Cl2
10.0
0.15
37
2
TEA
0.1
CH2Cl2
10.0
0.15
68
3
DABCO
0.1
CH2Cl2
10.0
0.15
66
4
K2CO3
0.1
CH2Cl2
10.0
0.15
21
5
TEA
0.2
CH2Cl2
10.0
0.15
75
6
TEA
0.3
CH2Cl2
10.0
0.15
73
7
TEA
0.2
MeCN
10.0
0.15
51
8
TEA
0.2
E OAc
10.0
0.15
49
9
TEA
0.2
E OH
10.0
0.15
36
10
TEA
0.2
THF
10.0
0.15
81
11
TEA
0.2
E 2O
10.0
2.15
93
12
TEA
0.2
E 2O
25.0
3.50
86
13
TEA
0.2
E 2O
5.0
1.50
95
14
TEA
0.2
E 2O
2.0
1.15
Quan .
15
TEA
0.2
SFC
0
5.00
31[c]
16
TEA
0.2
SFC
0
5.00
34[d]
17
Resin[e]
0.2
E 2O
2.0
1.00
38
18
Resin[e]
1.0
E 2O
2.0
1,00
42
19
DMEA
0.2
E 2O
2.0
1.50
Quan .
Table 1: Op imiza ion o eac ion condi ions o he syn hesis o 3-hyd oxy-3,4-dihyd o-2H-1,4- hiazine.
All he eac ions we e ca ied ou unde he ollowing condi ions: 1,4-di hiane-2,5-diol 19 (0.5
mmol), DD 1a (1.0 mmol), oom empe a u e. [b] The yields we e de e mined by 1H NMR
spec oscopy o he c ude (4-ni o oluene as in e nal s anda d).34 [c] DD 1a was employed as
sol en - eagen in he mola a io o 1:0.5 e e ed o 1. [d] DD 1a was employed as sol en -
eagen in he mola a io o 3:0.5 e e ed o 19. [e] Me ck Millipo e 104767 Ion exchange
III.
Ou in es iga ion began e alua ing di e en bases, necessa y o gene a e in si u he 2-
me cap oe hanal 19’ (Scheme 8, Table 1, en ies 1-5). The desi ed 3-hyd oxy-3,4-dihyd o-2H-
1,4- hiazine 21a was ob ained wi h highe yields using 1,4-diazabicyclo[2.2.2]oc ane
(DABCO) and ie hylamine (TEA) in dichlo ome hane (en ies 2,3, Table 1). Be ween hese
wo bases, he cheapes TEA has been chosen. We ha e obse ed ha p oduc 21a du ing he
ch oma og aphic p ocedu e spon aneously ga e decomposi ion eac ions. Fo his eason, he
yield o he hiazine 21a was de e mined di ec ly on he c ude mix u e by 1H-NMR analisys.34
By inc easing he amoun o TEA o 0.2 eq, he yield o he p oduc 21a was enhanced o 75%
(en y 5, Table 1). No u he imp o emen in he yield was obse ed when TEA was
19
1a
21a
- 22 -
inc emen ed o 0.3 eq. (en y 6, Table 1). Then we p oceeded es ing di e en sol en s such as
ace oni ile, e hyl ace a e, e hanol, e ahyd o u an and die hyl e he (en ies 7-11, Table 1).
The bes ou come was in die hyl e he (en y 11, Table 1). An inc emen o he sol en amoun
gene a es lowe yields wi h longe eac ion ime (en y 12, Table 1), while mo e concen a ed
solu ions p o ide be e yields and as e eac ions (en ies 13, 14, Table 1). Encou aged by
hese indings, we ha e ca ied ou he eac ion in sol en ee condi ions (SFC), in which DD
1a ac s as sol en - eagen (mp o 1a < 15 °C). The desi ed hiomo pholine de i a i e 19a was
o med only in poo yields, employing ei he 1 o 3 equi . o 1a (en ies 15, 16, Table 1).
These la e esul s p obably a e due o he low solubili y o 1,4-di hiane-2,5-diol 19 in hese
condi ions. Wi h ou deligh , we ha e ound ha , a oom empe a u e, in 2 mL o die hyl e he
and in he p esence o 0.2 equi . o TEA, he eac ion be ween 1,4-di hiane-2,5-diol 19 (0.5
mmol) and DD 1a (1.0 mmol) u nished quan i a i ely he desi ed 3-hyd oxy-3,4-dihyd o-2H-
1,4- hiazine 21a (en y 14, Table 1). Taking ad ance o his ac , o acili a e he sepa a ion o
he desi ed hiomo pholine 21a om he p omo e , we ha e es ed o he bases easily emo able
om he c ude such as a basic esin, eadily u ned away by il a ion, o N,N-
dime hyle hylamine (DMEA) (bp 36-38 °C) easily and ully e apo able unde acuum. While
he use o he esin bo h in a ca aly ic (0.2 equi .) o in s oichiome ic amoun p o ided he
desi ed 21a only in mode a e yields (en ies 17, 18, Table 1), he employ o he DMEA
p oduced 21a in quan i a i e manne wi hou o ma ion o any by-p oduc (en y 19, Table 1).
I is ema kable ha in his la e case, o ob ain he c ude and pu e desi ed p oduc 21a, solely
he e apo a ion o he sol en and DMEA was necessa y. A oiding he ch oma og aphic
sepa a ion, he deg ada ion p ocesses p e iously obse ed du ing he de elopmen o he
p ocedu e did no ake place. In ac , he di ec 1H- and 13C-NMR analyses o he c ude showed
exclusi ely he signals ela ed o he p oposed s uc u e o compound 21a con i ming ha he
yields a e quan i a i e.
The g adual disappea ance o he ed colou impa ed o DDs by hei in e nal conjuga ion
pe mi s he isual check o he eac ion p og ess. The e o e, his occu ence con ibu es o make
his me hodology e y acile, e en ually equi ing only he e apo a ion s ep a he end o he
eac ion shown by a colou change o he solu ion. Iden i ied he op imal condi ions, eac ions
o 1,4-di hiane-2,5-diol 19 wi h a ange o di e en DDs 1ak we e e alua ed (Table 2). In all
cases, p oduc s 21ak we e quan i a i ely ob ained simply by unde acuum e apo a ion a
oom empe a u e o he sol en and DMEA wi hou any o he pu i ica ion s ep. No ably, he
syn hesis o 3b was scaled up o he g am-scale wi hou any no iceable d awback (Table 2).
- 23 -
N
S
OH
P
HN
O
O
O
O
O
N
S
OH
HN
O
O
O
O
N
S
OH
HN
O
O
O
O
N
S
OH
HN
O
O
O
O
N
S
OH
HN
O
O
O
O
N
S
OH
HN
O
O
O
O
N
S
OH
HN
O
O
O
O
N
S
OH
HN
O
O
O
O
N
S
OH
C
HN
O
O
O
O
N
S
OH
HN
O
O
O
O
N
S
OH
HN
O
O
O
O
Table 2: The yields we e de e mined by 1H NMR spec oscopy o he c ude pu e p oduc s.34
Reac ion was ca ied ou on g am scale wi h 1.0 g o 1b
Employing 4-phosphonyl-DD 1k, he co esponding phospho yla ed 1,4 hiazine 21k was
achie ed. I is no ewo hy ha he in oduc ion o o ganophospho us moie ies in simple
syn hons may p o ide alid subs a es o he p epa a ion o biologically ac i e compounds.
21a quan i a i e yeld
21b quan i a i e yeld
21c quan i a i e yeld
21d quan i a i e yeld
21e quan i a i e yeld
21 quan i a i e yeld
21g quan i a i e yeld
21h quan i a i e yeld
21i quan i a i e yeld
21j quan i a i e yeld
21k quan i a i e yeld
- 24 -
The plausible mechanism con empla es he in si u gene a ion o 2-me cap oe hanal 19’ ha is
eadily cap u ed om he e minal ca bon a om o he azo-ene sys em o DDs 1. This ini ial
sulpha-Michael addi ion leads o he o ma ion o he odou less -sulpha- unc ionalized
hyd azone in e media es 20. In amolecula ni ogen nucleophilic a ack on ca bonyl g oup
u nishes he inal 21ak h ough a o mal [3+3] cycloaddi ion. In his way, he eac ion comes
o comple ion wi hou any o ma ion o unpleasan s ench.
S
SHO
OH
HSH
O
R1
NNCOOR3
R2
R1
N
H
NCOOR3
R2
S
O
H
H
S
N
OH
H
NCOOR3
R2
R1
H
2
Scheme 9: Plausible mechanism o he syn hesis o 3-hyd oxy-3,4-dihyd o-2H-1,4- hiazines 21a
k.
2.3 Conclusions
In conclusion, he e we epo a new simple and con enien me hodology o easy access o a
se ies o 3-hyd oxy-3,4-dihyd o-2H-1,4- hiazines. This p ocedu e p oceeds apidly o
comple ion, p oduces only he desi ed compounds wi hou o ma ion o by-p oduc s, and o e s
he inal pu e p oduc s wi hou any ch oma og aphy p ocess. The in si u gene a ion o 2-
me cap oe hanal using odou less, and ino ensi e di hiane-2,5-diol 19 is an app op ia e solu ion
o se ious en i onmen al and sa e y p oblems due o he u iliza ion o ola ile and unpleasan
smelling hiols.Then, quan i a i e yields, absence o edious sepa a ion p ocedu es, o al a om
e iciency, mild eac ion condi ions, eadily a ailable and inexpensi e s a ing ma e ials,
ope a ional simplici y, clean eac ion p o iles as well as ene gy e iciency, a e he key
ad an ages o he p esen me hod.
19
19’
1
20
21
- 31 -
En y
1
R1
R2
R3
22
R4
1
1a
E
CO2Me
Me
22a
E
3
1b
Me
CO2 Bu
Me
22a
E
4
1a
E
CO2Me
Me
22b
Ph
5
1c
Me
CO2E
Me
22b
Ph
6
1d
E
CO2 -Bu
Me
22b
Ph
7
1e
Me
CO2E
Bu
22b
Ph
8
1
E
CO2Bn
Me
2b
Ph
9
1g
Me
CO2Me
Me
22c
4-Cl-Ph
10
1b
Me
CO2 -Bu
Me
22c
4-Cl-Ph
11
1c
Me
CO2E
Me
22c
4-Cl-Ph
12
1c
Me
CO2E
Me
22d
4-OMe-Ph
13
1d
E
CO2 -Bu
Me
22d
4-OMe-Ph
Table 4 Subs a es used o he syn hesis o bis-hyd azone unc ionalized hodanine 24d and o he
syn hesis o 2,3,5,6- e ahyd o-1H-py olo[3,4-c]py idine-1,3,6- ione 26e
In pa icula , ollowing he Pa h A, by eac ing DDs 1a,ce wi h hodanines 22ad, in THF,
wi h 2 equi alen s o K2CO3, a oom empe a u e, bis-hyd azone- unc ionalized hodanines
24a we e ob ained in good o excellen yields (79-93%) and he eac ions we e comple ed in
0.10.5 h (Scheme 12, Pa h A, Table 5).
Thei basic ea men wi h 5 equi alen s o K2CO3 in THF a 55 °C in open lask u nished he
co esponding 2,3,5,6- e ahyd o-1H-py olo[3,4-c]py idine-1,3,6- iones 26a,ce,j,l, in
2.05.0 h in accep able yields (3961%) (Scheme 12, Pa h A, Table 5).
Mo e con enien ly, he 2,3,5,6- e ahyd o-1H-py olo[3,4-c]py idine-1,3,6- iones 26al we e
ob ained in good yields (4366%) by means o one po p ocedu e, ca ying ou he eac ion
be ween DDs 1ag and hodanines 22ad, in THF, wi h 5 equi alen s o K2CO3, a 55 °C in
open lask. Unde hese condi ions he eac ions we e comple ed in 1.05.0 h (Scheme 12, Pa h
B, Table 5).
- 32 -
S
N
O
S
O
O
N
N
H
O
N
N
H
O
O
OO
O
S
N
O
S
O
O
NN
H
O
N
N
H
O
O
OO
O
S
N
O
S
O
O
N
N
H
O
N
N
H
O
O
OO
O
S
N
O
S
O
O
NN
H
O
N
N
H
O
O
OO
O
S
N
O
S
O
O
NN
H
O
N
N
H
O
O
OO
O
Cl
S
N
O
S
O
O
N
N
H
O
N
N
H
O
O
OO
O
O
Table 5: Yields o pu e isola ed p oduc s e e ed o hodaines 22a
d.
Any a emp o isola e he mono-adduc 23, de i ing om he Michael- ype addi ion o he
hodanine 22 o one equi alen o DD 1 ailed (Scheme 12); in ac , in all he es s ca ied ou
in di e en condi ions and in he DD/ hodanine equimola a io, only bis adduc s 24 we e
o med. Ha ing in hand he p oduc s 23 would ha e gi en us he oppo uni y o add hem o
DDs molecules di e en om he s a ing ones.
The plausible mechanism o his cascade eac ion in ol es he p elimina y double a ack
(Michael- ype) o he ca bon a om in 5 posi ion o he hodanine 22 o he e minal ca bon a om
o he azo-ene sys em o wo molecules o he DD 1, wi h he o ma ion o he bis-hyd azonic
in e media e 24. The key s ep in he cons uc ion o he e ahyd o-1H-py olo[3,4-c]py idine-
1,3,6 ione sys em is he opening o he 2- hioxo hiazolidin-4-one ing which esul s in he loss
24a 79%
24b 85%
24c 92%
24d 93%
24e 88%
24 93%
- 33 -
o CS2. This p ocess is igge ed by he emo al om he base o he acidic p o on o iginally
loca ed in posi ion 4 o he i s azo-ene molecule, wi h he consequen ac i a ion o he ni ogen
de i ing om hodanine co e. I s nucleophilic a ack on he es e unc ion de i ed om he
second DD molecule p omo es he o ma ion o he py olidine-2,5-dione co e o he non-
isolable in e media e 25. The u he cycliza ion o ob ain py idin-2(1H)-one nucleus occu s as
a esul o he basic emo al o he analogous p o on de i ing om he second molecule o DD
ha p omo es he nucleophilic a ack o he sp2 ni ogen a he es e ca bonyl unc ion o iginally
loca ed in he i s DD (Scheme 12).
I is no ewo hy ha a double in e ac ion be ween he wo agmen s de i ed om he wo DDs
occu s and in he one po p ocedu e, his cascade eac ion u nishes wo new single ca bon-
ni ogen bonds as well as a single and a double ca bon-ca bon bonds.
The wo ac i a ed p o ons play a c ucial ole by p omo ing he double ni ogen nucleophilic
a ack on o he es e unc ion o he o he agmen s.
To he bes o ou knowledge, jus one example o ing-opening/ ing-closing p ocess o he
hodanine co e is epo ed in li e a u e.44 Di e en ly om his, ou sequence occu s wi h he
loss o a molecule o ca bon disulphide so ac i a ing he subs i u ed ni ogen o he hodanine
as nucleophile in he i s cycliza ion e en .
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
26a 44%a 42%b
26b 58%a
26c 60%a
26d 55%a 53%b
- 34 -
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
Cl
N
O
O N
NH
O
NNH
O
O
O
O
Cl
N
O
O N
NH
O
NNH
O
O
O
O
Cl
N
O
O N
NH
O
NNH
O
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
O
Table 5:. [a] Yields o pu e isola ed p oduc s e e ed o hodanines 22a
d, in he one-po p ocedu e
(Pa h B o Scheme 2) [b] Yields o pu e isola ed p oduc s e e ed o bis-hyd azones 24a
(Pa h A o Scheme 2).
26e 66%a 61%b
26 63%
26g 43%
26h 46%
26i 51%
26j 58%a 39%b
26k 59%
26l 64%a 64%b
- 35 -
The s uc u e o compounds 24 and 26 was con i med by mono and bidimensional NMR
measu emen s and he da a a e pe ec ly compa able o hose epo ed in he li e a u e o
simila compounds.42,45
Fu he e idence o he p oposed s uc u e o compounds 26 was u nished by he hyd oly ic
clea age o he hyd azone moie y in posi ion 27 o he py idine ing o compound 26e, chosen
as an example, ha was ob ained unde he e ogeneous condi ions, using ace one/wa e (9:1)
and Ambe lys 15H.46 In hese acidic condi ions also he loss o he e -bu oxyca bonyl moie y
occu ed o gi e he co esponding 7-ace yl-5-amino-4-me hyl-2-phenyl-1H-py olo[3,4-
c]py idine-1,3,6(2H,5H)- ione 27a in e y good yield (83%) (Scheme 13).
N
O
O N
HN
O
NHN
O
O
O
O
(CH3)2CO/H2O 9:1
AMBERLYST 15H
N
O
O O
O
NH2N
Scheme 13: Hyd oly ic clea age o 2,3,5,6- e ahyd o-1H-py olo[3,4-c]py idine-1,3,6- ione 26e o 7-
ace yl-5-amino-4-me hyl-2-phenyl-1H-py olo[3,4-c]py idine-1,3,6(2H,5H)- ione 27a
3.2 Conclusions
In conclusion, s a ing om 1,2-diaza-1,3-dienes and hodanine de i a i es, we ha e de eloped
a syn he ic s a egy o ha e access o 2,3,5,6- e ahyd o-1H-py olo[3,4-c]py idine-1,3,6-
iones ia double Michael addi ion/CS2 ex usion/double cycliza ion sequence. To he bes o
ou knowledge, his wo k ep esen s he i s example o ing-opening/ ing-closing p ocess wi h
concomi an ex usion o ca bon disul ide om he hodanine co e. The easy a ailabili y o he
s a ing ma e ials, he simplici y o he expe imen al me hod, as well as he po en ial biological
ac i i ies and u ili ies o p oduc s can inc ease he syn he ic use ulness o his no el p ocedu e.
Fu he mo e, employing he s ep by s ep app oach, also highly unc ionalized hodanines could
be easily ob ained in sa is ac o y yields
26e
27a
- 36 -
4. SEQUENTIAL ONE POT SYNTHESIS OF 2,5-
DIHYDROTHIOPHENES AND THIOPHENES
CHAPTER 4
- 37 -
4.1 In oduc ion
One o he main aim o a syn he ic chemis s is he de elopmen o highly e icien p ocedu es
o assemble aluable compounds wi h high s uc u al complexi y eso ing o simple a ailable
ma e ials.47 This eques can be mee by exploi ing he mul icomponen eac ions (MCRs) ha
allows inco po a ion in o he inal p oduc s o h ee o mo e eac an s. MCRs lead o wide
molecula di e si y, minimizing he wo k-up p ocedu es and consequen ly sa ing bo h ime
and sol en s.48 A class o MCR is he sequen ial eac ions, whe e he eagen s a e added
consecu i ely in a de ined o de in he same eac ion en i onmen unde cons an condi ions In
his way, i is possible o s op he syn he ic sequence a e e y s ep, and so he in e media es can
be isolable. The eby, he in e media es can be isolable by s opping he sequence a he igh
momen .49 Thiophene is he key s uc u al uni o nume ous pha macopho es such as Pla ix,
(adenosine diphospha e P2Y12 ecep o an agonis ),50 Raloxi ene (selec i e es ogen ecep o
modula o ),51 PaT in 2 (MGMT inac i a ing d ug),52 a icaine (local anaes he ic),53 Cymbal a
(selec i e se o onin no epineph ine eup ake inhibi o ).54
Fu he mo e, i s peculia elec onic p ope ies and he ele an s uc u al igidi y make he
hiophenes de i a i es in e es ing co es in he p oduc ion o inno a i e o ganic ma e ials like
o ganic semiconduc o s, o ganic ligh emi ing diodes (OLED), o ganic pho o ol aics (OPV),
o ganic ield e ec ansis o s (OFET), sola cells, liquid c ys als.55
Abou he p epa a ion o hiophenes, a ple ho a o syn he ic app oaches ha e been epo ed,
some o which can be ela ed o classical Gewald, Fiesselmann, Paal-Kno , and Hinsbe g
eac ions,56 and many o he s examples.57 Howe e , mos o hese p ocedu es equi e mul is ep
p o ocols wi h consequen labo ious isola ion ope a ion.
Also he dihyd o hiophene compounds ep esen a common s uc u al mo i o nume ous
bioac i e de i a i es and hey has shown o be e sa ile in e media es o syn he ic
applica ions.58 consequen ly, no able a en ion has been di ec ed owa d new and con enien
syn he ic p ocedu es o p epa e bo h dihyd o hiophenes and hiophenes.
Du ing ou ongoing s udies37,59 on he e sa ili y o 1,2-diaza-1,3-dienes,38 as syn he ic s a ing
ma e ials, inspi ed by he wo k o Alizadeh,60 we ha e in es iga ed he eac ion be ween DDs
1 and 3-alkylamino-2-(ca bamo hioyl)bu -2-enoa es 28 (ACTs) o en a i ely ob ain
hiazepines A by means o a o mal [4+3] cycliza ion (Scheme 1, pa h A), in analogy o he
esul s p e iously ob ained.60 Su p isingly, he eac ion u nish 5-(phenylimino)-2,5-
dihyd o hiophenes (DHTs) 29 h ough an unusual o mal [4+1] cycliza ion,61 whe e he DDs
con ibu es in he inal he e ocyclic s uc u e only wi h one ca bon a om (Scheme 14, pa h B).
- 38 -
4.2 Resul s and Discussion
In o de o ealize a one-po eac ion by subsequen addi ion o eagen s, we began ou
in es iga ion on he p epa a ion o ACTs 28. The me hodology equi es he p elimina y
o ma ion o enamino es e in e media es,62 ha successi ely eac wi h a yl-iso hiocyana es o
p oduce he desi ed ACTs 28. Among all he p oposed p ocedu es,63 Alizadeh desc ibes he
mos con enien way, whe e all he s eps a e pe o med unde sol en ee condi ions (SFC).60
Scheme 14: Expec ed and obse ed beha iou o he eac ion be ween DDs 1 and ACTs 28
We ha e obse ed ha conduc ing he addi ion o he enamino es e 32 o he a yl
iso hiocyana es 34ac in me hanol, he desi ed ACTs 28 di ec ly p ecipi a e om he eac ion
medium as pu e p oduc s wi h be e yields, a oiding any o he pu i ica ion p ocedu es.
R4O
O O
R5Alk NH2
+
N
HOR5
Alk
R4O
R4
O
OR5Alk NH2
+
MeOH, . .
N
C
R6
S N
HOR5
Alk
R4O
SNH
R6
SFC
Scheme 15: Syn hesis o 3-alkylamino-2-(ca bamo hioyl)bu -2-enoa es 28.
1
28
29
30a-i
31a,b
32
31b
33a
34a-c
28a-m
- 39 -
H
N
OO
S
HN
H
N
OO
S
HN
O
H
N
OO
S
HN
H
N
OO
S
HN
H
N
OO
S
HN
Cl
H
N
O O
S
HN
H
N
O O
S
HN
H
N
O O
S
HN
H
N
OO
S
HN
Cl
H
N
OO
S
HN
H
N
OO
S
HN
H
N
O O
S
HN
H
N
OO
S
HN
Cl
Table 7: Yields o isola ed ACT 28 based on alkyl amines 31
Based on ou p e ious expe ience,64 we ha e es ed also he eac ion be ween alkynoa es and
p ima y amines o p epa e enamino es e de i a i es. Only in his case o aza-Michael eac ion
be ween e hyl 3-phenylp opiola e 33a and benzyl amine 31b conduc ed in SFC a oom
empe a u e, we ha e quan i a i ely ob ained a waxy solid ha was iden i ied as he desi ed
28a 72%
28b 49%
28c 58%
28d 35%
28e 51%
28 55%
28h 40%
28g 75%
28j 33%
28k 45%
28i 50%
28l 34%
28m 27%
- 40 -
enamine es e 32a. The subsequen addi ion o he phenyl iso hiocyana es 34a o he eac ion
mix u e in SFC p oduces ACT 28l only in poo yield, p obably because he sca ce solubili y.
Then, a ious sol en s such as dichlo ome hane (DCM), e ahyd o u an (THF), e hanol,
ace oni ile (ACN), dime hyl o mamide (DMF), and empe a u es we e e alua ed in he second
s ep (Table 8). The bes esul was ob ained in me hanol, a oom empe a u e, bu un o una ely
e en in his case he yield was only o 37%.
33
R4
R5
31
Alk
34
R6
2
Sol en a
Yield (%)b
Sol en c
Yield (%)b
a
Ph
Me
b
Bn
a
Ph
m
SFC
13
SFC/MeOH
37
a
Ph
Me
b
Bn
a
Ph
m
SFC/THF
15
a
Ph
Me
b
Bn
a
Ph
m
SFC/ACN
17
a
Ph
Me
b
Bn
a
Ph
m
SFC/DCM
21
a
Ph
Me
b
Bn
a
Ph
m
SFC/DMF
6
a
Ph
Me
b
Bn
a
Ph
m
SFC/MeOH
22d
a
Ph
Me
b
Bn
a
Ph
m
SFC/MeOH
18e
Table 8: aReac ion condi ions: alkyl amines 31 (0.5 mmol) we e added o e hyl phenylp opiola e 33a (0.55
mmol) unde sol en - ee condi ions a oom empe a u e. A e 0.5 h a yl iso hiocyana es 34a-
c (0.5 mmol) we e added and he eac ions we e s i ed un il he disappea ance o he enamino
es e s 32 (moni o ed by TLC). b Yields o isola ed ACT 2 based on alkyl amines 31. cReac ion
condi ions: alkyl amines 31 (0.5 mmol) we e added o e hyl phenylp opiola e 33a (0.55 mmol)
unde sol en - ee condi ions a oom empe a u e. A e 0.5 h a yl iso hiocyana es 34a-c (0.5
mmol) in MeOH (1.5 mL) we e added and he eac ions we e s i ed un il he disappea ance o
he enamino es e s 32 (moni o ed by TLC). dReac ion conduc ed a 0 °C. eReac ion conduc ed a
50 °C.
Thus, a p elimina y s udy o he nex s ep o his sequen ial eac ion was conduc ed using DD
1a and ACT 28b chosen as examples (Table 9, Scheme 16). In SFC he low solubili y a ec s
he eac ion; in ac he main spo was isola ed wi h unsa is ac o y yield. Spec oscopic s udies
ha e e ealed ha he main p oduc was he co esponding 2,5-dihyd o hiophene 29b. In
pa icula , he signal a 75.4 ppm in he 13C NMR spec a o he qua e na y ca bon in posi ion
wo o he hiophene ing is diagnos ic. So, di e en sol en s such as DCM, THF, ACN,
me hanol we e es ed. Despi e he low solubili y o he ACTs 28 in MeOH, his sol en has
u nished he bes esul in e m o yield. P obably he g adual dissolu ion and he consequen
lowe concen a ion o ACTs 28 a ou a be e selec i i y and p omo e g ea e selec i i y.
While he empe a u e does no a ec he eac ion, on he con a y, o an inc emen o DDs
equi alen s co espond an app eciable imp o emen in he inal yield. In ac , he p ima y
amine eleased in he cycliza ion p ocess gi es a nucleophilic a ack o he azo-ene sys em
sub ac ing he DDs 1 om he eac ion medium.65
- 47 -
mo e elec ophile wi h espec o he es e unc ion. In basic medium, ins ead, he hyd olysis
in ol es he es e unc ion in posi ion 2 o DHT, p omo ing a di e en a oma iza ion p ocess.
S
O
NR6
N
R2
NH
R3OC
OR5
R4
R1OO
S
O
NR6
N
R2
NH
R3OC
OR5
R4
-OO
S
O
HN R6
N
R2
NH
R3OC OR5
R4
THF
NaH -CO2
,
Scheme 20: Syn hesis o 2-a ylamino 5-hyd azono hiophene-3 ca boxyla es (AHTs) 41a
g by basic
ea men o DHT 29
S
OO
NH
N
NH
O
O
S
OO
NH
N
NH
O
O
S
O
O
NH
N
NH
O
O
S
OO
NH
N
NH
O
O
S
OO
NH
N
NH
O
O
Cl
S
OO
NH
N
NH
O
O
Cl
S
OO
NH
N
NH
O
O
Table 12: Yields o isola ed AHTs 41a
g based on DHT 29
29a,b,d- ,h,i,m,n
40
40ag
41a 71%
41b 78%
41c 77%
41g 68%
41d 73%
41e 78%
41 78%
- 48 -
S
O
NR6
N
R2
NH
R3OC
OR5
R4
R1OO
S
O
NR6
O
R2
OR5
R4
R1OO
HOH
S
O
NR6
-O
R2
OR5
R4
R1OO
S
O
HN R6
OR5
R4
R1O
O
S
O
NR6
N
R2
NH
R3OC
OR5
R4
-OO
S
O
HN R6
N
R2
NH
R3OC OR5
R4
THF
NaH
Ambe lys
15H
Ace one/H2O
HO
-CO2
Scheme 21: Di e en ways in he ea men o DHTs 29
F om he con e sion o DHTs 29 in o ATDs 35 o in o AHTs 41 i eme ges ha he elimina ion
o one subs i uen in posi ion wo igge s an a oma iza ion p ocess. To ealize he di ec
syn hesis o a oma ic 2-amino hiophenes h ough a sequen ial mul i componen syn hesis,
simila o ha desc ibed abo e, we ha e planned o inse an easily emo able hyd ogen in
posi ion 2 o he DHTs 29. The ca bon in posi ion wo o DHT 29 de i es om he DDs, 1 and
o iginally is loca ed in posi ion ou o he azo-ene sys em. Then, employing 4-unsubs i u ed
DDs we should achie e he p oposed a ge . As hese subs a es showed poo s abili y, hey a e
usually gene a ed in si u by basic ea men o he co esponding -alo hyd azones 15ag.38,68
This ci cums ance equi es an adjus men o he eac ion condi ions p e iously employed. As
29
39
40
38
35aj
41ag
- 49 -
abo e desc ibed, ini ially we p epa ed he enamino es e in e media es 32 unde sol en ee
condi ions and successi ely he a yl iso hiocyana es 33ac was added u nishing he desi ed 3-
alkylamino-2-(ca bamo hioyl)bu -2-enoa es (ACTs) 28am. To he eac ion mix u e we e
added he -halo hyd azones 14 we e added and ou equi alen s o po assium ca bona e we e
needed o he con e sion o he hyd azones in he 4-unsubs i u ed DDs. The me hanol,
p e iously used as sol en , eac s wi h de i a i es 14 gi ing he subs i u ion o he halogens.
Some o he sol en s we e hen es ed, and he bes esul s we e ob ained using dichlo ome hane
(Scheme 22).
R4OR5
AlkHN O
S
N
R6
H
N
N
R3OC
R2
R4OR5
AlkHN O
SN R6
C
H
H
N
R2
H
N
R3OC
C
S
AlkHN
O-
N R6
N
R2
NH
R3OC
OR5
HR4
S
O
NR6
N
R2
NH
R3OC
OR5
R4
-AlkNH2
H
R4OR5
AlkHN O
C
S
NR6
R4OR5
AlkHN
O
O
+
DCM
N
N
R3OC
R2
SFC
H
X
B-
DCM, K2CO3
S
O
HN R6
N
R2
NH
R3OC OR5
R4
Scheme 22: One po sequen ial syn hesis o 2-a ylamino 5-hyd azono hiophene-3 ca boxyla es (AHTs)
41h
s a ing om in si u gene a ed 4-unsubs ui ed DDs.
31
32
30
34
15
28
16
42
43
44
31
41h
- 50 -
S
O
O
NH
N
NH
O
O
S
O
O
NH
N
NH
O
O
S
O
O
NH
N
NH
O
S
O
O
NH
N
NH
O
O
S
O
O
NH
N
NH
O
O
S
O
O
NH
N
NH
O
O
S
O
O
NH
N
NH
O
O
B
N
O2N
S
O
O
NH
N
NH
O
S
O
O
NH
N
NH
O
O
S
O
O
NH
N
NH
O
O
B
S
O
O
NH
N
NH
O
N
Table 13: Yields o isola ed AHTs 41h
based on
-ke oes e s 32a.
41h 80%
41i 82%
41j 87%
41q 91%
41k 53%
41m 80%
41l 58%
41n 85%
41p 87%
4o 62%
41 74%
- 51 -
On he basis o his e idence a plausible mechanism can in ol e a sulphu nucleophilic a ack
o ACTs 28 o he e minal ca bon a om o he azo-ene sys em o he 4-unsubs i ued DDs 15.
The basic medium a o s he loss o he i s acid p o on ac i a ing he ca bon nucleophilic
inylogous a ack a he conjuga ed sys em de i ing om he s a ing ACT 28. By means o
his annula ion, he i s sulphu -he e ocyclic s uc u e o he e ahyd o hiophene in e media es
was c ea ed. The conjuga ed elimina ion o he amino moie ies a o ds he co esponding 2,5-
dihyd o hiophene in e media es. The loss o he second p o on p omo es he a oma iza ion o
he ing. In summa y, when he e a e wo hyd ogens a he e minal ca bon a om o he azo-ene
o 4-unsubs i u ed DDs 15, he a oma iza ion p ocess can be easily inco po a ed in he syn he ic
sequence, ob aining di ec ly he 2-a ylamino 5-hyd azono hiophene-3 ca boxyla es 41h . On
he o he hand, employing 4-subs y u ed DDs 1aj, lacking an easily emo able g oup, he inal
a oma iza ion is no possible, and he sequence s ops a he o ma ion o DHTs 29ax (Table
13).
S
O
O
NH
N
N
S
S
OO
NH
N
N
S
S
OO
NH
N
N
S
S
O
O
NH
N
N
S
Cl
S
O
O
NH
N
N
S
Cl
S
OO
NH
N
N
S
Cl
S
OO
NH
N
N
S
Cl
S
OO
NH
N
N
S
Cl
Cl
Table 14: Yields o isola ed AHTs 43a-g based on AHT 41.
43g 62%
43a 63%
43c 61%
43b 57%
43d 63%
43 58%
43e 56%
43h 64%
- 52 -
2-A ylamino 5-hyd azono hiophene-3 ca boxyla es (AHT) 41 a e aluable s a ing ma e ials
o c ea e a second sulphu -con aining-he e ocycle di ec linked o he hiophene ing. In ac ,
he ea men o AHTs 41ag con aining a me hyl subs i u ed hyd azone moie y wi h hionyl
chlo ide, acco ding o a ypical Hu d-Mo i condi ions, p oduces new 2-(phenylamino)-5-(1,2,3-
hiadiazol-4-yl) hiophene-3-ca boxyla es (ATTs) 43ad.
S
O
HN R6
N
NH
R3OC OR5S
O
HN R6
OR5
N
N
S
S
O
HN R6
OR5
N
N
SCl
SOCl2
(10 equi .)
CH2Cl2, . .
1.0-1.5 h 15.0-18 h
Scheme 23: P og ess o he Hu d-Mo i eac ion.
Ini ially, he eac ions we e conduc ed on AHTs 41a (0.5 mmol) chosen as ep esen a i e
compound a oom empe a u e in dichlo ome hane (2.0 mL) es ing di e en mola a ios o
hionyl chlo ide. Wi h one o wo equi alen s he eac ions do no come o comple eness, while
wi h i e equi . he eac ion p oceeds slowly (36 h, moni o ed by TLC) and oge he wi h he
desi ed ATT 43a (26% yield) also he co esponding me hyl 4-(chlo ome hyl)-2-
(phenylamino)-5-(1,2,3- hiadiazol-4-yl) hiophene-3-ca boxyla e 43e (17% yield) was
p oduced.
The bes esul was achie ed employing en equi alen s o SOCl2. In ac , unde his condi ion
he desi ed ATT 43a was o med in 63% yield in 1.5 h oge he wi h aces o he co esponding
4-chlo ome hyl ATT 43e (moni o ed by TLC). On he o he hand, he in oduc ion o an
halogen makes his la e compound 43e in e es ing eac ion in e media e ha can be u he
unc ionalized h ough simple nucleophilic subs i u ion eac ions. Fo his eason, we ha e also
de eloped a me hod o i s p epa a ion. P olonging he eac ion ime o 15 hou s, unde he
same eac ion condi ions p e iously employed, he 4-chlo ome hyl ATT 43e was p oduced in
56%yield, and no aces o he co esponding ATT 43a we e de ec ed. On he basis o hese
e idences, i can be deduced ha he chlo ina ion p oceeds slowly, and p olonging he eac ion
ime he 4-chlo ome hyl ATT 43e becomes p edominan . Using 5.0 equi . o hionyl chlo ide,
he Hu d-Mo i eac ion p oceeds slowly and he chlo ina ion eac ion also occu s, while
employing 10.0 equi . Hu d-Mo i eac ion is as e minimizing he o ma ion o he compound
43e.
43ad
43eh
41
- 53 -
4.3 Conclusion
In conclusion, we ha e de eloped wi h success a sequen ial MCR ha p oduces 2,5-
dihyd o hiophene de i a i es by eac ion o DDs and ACTs. Impo an ly, his p o ocol p o ides
wide and lexible subs i u ion pa e ns in he 2,5-dihyd o hiophenes allowing he planning “ab
ini io” o six di e en subs i uen s by app op ia ely selec ing he s a ing -ke oes e s,
iso hiocyana es o DDs. This oppo uni y, oge he wi h mild and simple eac ion condi ions
(no ca alys s, o d y sol en s, o ine a mosphe e), make his sequen ial MCR well sui able o
he easy c ea ion o b oad lib a ies.
A ca e ul selec ion o he s a ing ma e ials enables he choice up o six di e en a ia ion in
he a chi ec u e o he inal p oduc s. Employing he in si u gene a ed 4-unsubs i u ed DDs he
same me hodology p oduces di ec ly he 2-a ylamino 5-hyd azono hiophene-3 ca boxyla es,
inco po a ing he a oma iza ion p ocess in he sequence. Also he 2,5-dihyd o hiophenes a e
aluable in e media es p oducing in u n egioselec i ely he co esponding 5-amino hiophene-
2,4-dica boxyla es o 2-a ylamino 5-hyd azono hiophene-3 ca boxyla es simply by acid o
basic ea men . All hese aspec s highligh he e sa ili y o his sequen ial mul icomponen
eac ion ha unde mild condi ions can p oduce a b oad a ie y o hiophene de i a i es. And
las bu no leas , he syn hesis o unknown new 2-(phenylamino)-5-(1,2,3- hiadiazol-4-
yl) hiophene-3-ca boxyla es u he en iches he ange o sul u ic he e ocycles ob ainable,
combining in his la e case he p ope ies o bo h hiophene and 1,2,3- hiazoles.
- 54 -
5. N-ACYLIMINIUM IONS AS NOVEL MANNICH-TYPE
ACCEPTORS IN 1,4 ADDITIONS OF NUCLEOPHILES
CHAPTER 5
G. Ma i, L. De C escen ini, F. Man ellini, S. San eusanio, G. Fa i
O g. Chem. F on ., 2018, accep ed manusc ip
- 55 -
5.1 In oduc ion
Iminium ions play a signi ican ole in a ange o enzyme-ca alyzed p ocesses69 and syn he ic
ans o ma ions as key ( eac i e) in e media es70 o he cons uc ion o C-C and C-He bonds.
Fo example, na u e u ilizes ype I aldolase enzymes o ca alyze an aldol p ocess ha ope a es
ia an iminium ca ion unde physiological condi ions.
In he ield o o ganoca alysis71 and in he eme ging pho o edox ca alysis,72 a ple ho a o s e eo-
and enan ioselec i e me hods ha e been achie ed ha ely on he use o chi al iminium ions.73
Wi hin he iminium species, N-acyliminium ions74 (NAIs) a e ecognized o be much mo e
eac i e as elec ophiles han N-alkyliminium coun e pa s due o he elec on-a ac ing
p ope ies o he ca bonyl g oup on ni ogen. Among di e en named eac ions in ol ing NAIs,
he wo mos -s udied ypes, Mannich75 and Pic e −Spengle 76 eac ions, ha e been ex ensi ely
employed o he assembly o alkaloids, na u al-p oduc -like compounds, and biologically
ac i e molecules. The gene a ion o hese highly uns able (e ec i e eac i e o ansien
elec ophilic) species, which ypically equi e acidic condi ions, is ollowed by in si u apping
by nucleophiles o dienes in bo h addi ion and cycloaddi ion eac ions, espec i ely.
Despi e signi ican ad ances in he nucleophilic addi ion o NAIs,77 eac ions ha in ol e he
in e molecula addi ion o conjuga ed N-acyliminium accep o s s ill emain elusi e due o he
challenging issue o egioselec i i y (Figu e 10). To da e, ( o he bes o ou knowledge) only
a e examples ha e demons a ed he easibili y o he γ-selec i e addi ion o nucleophiles o
cyclic conjuga ed N-acyliminium ions.78 Al hough hese p ocedu e can u nish he γ-adduc in
a 1,4-addi ion ashion, hey a e o en complica ed by he o ma ion o mix u e o α- and γ-
egioisome s as well as limi ed o a ew dica bonyl nucleophiles only. In addi ion, hese
eac ions p o ide unc ionaliza ion a he C4-posi ion o he azahe e ocyclic (e.g. pipe idine)
skele on since an endocyclic double bond esul s in ole in N-acyliminium ion s uc u es o ype
A. On he o he hand, he e ocyclic a chi ec u es ea u ing an iminium ca ion lanked by an
exocyclic double bond o ype B (e.g. 5-me hylene N-acyl dihyd opy idazinium ions) ha e no
ye epo ed. This is su p ising, because hey could be used o e ec di ec unc ionaliza ion a
he γ’ posi ion, a ans o ma ion ha would pe mi o in oduce nucleophiles on o exo me hylene
g oup o he ing (ole in e minus).
- 56 -
N
O R
'
He
Nu
and/o
N
O R
He
N
O R
He
Nu
N
O
He
Nu
addi ion addi ion
R
his wo k
Nu
N
O R
He Nu
A
B'addi ion
'
selec i e
'
p e ious wo ks
Figu e 10: Nucleophilic Addi ion o Conjuga ed Cyclic N-Acyliminium ions.
The challenge and oppo uni y o con olling egioselec i i y as well as he possibili y o adding
a a ie y o nucleophiles ha e p omp ed us o in es iga e he eac i i y o hese in iguing
accep o s in addi ion eac ions. Along hese lines, ou in e es in he chemis y o he
azahe e ocycles led us o conside 5-me hylene-6-me hoxy-1,4,5,6- e ahyd opy idazines
(N,O-ace als) easily p epa ed ia a egioselec i e in e se-elec on-demand he e o-Diels-Alde
eac ion o in si u gene a ed 1,2-diaza-1,3-dienes wi h me hoxyallene.8 Fo his pu pose, he
mos widely applied me hod o NAI o ma ion ha in ol es he elease o a lea ing g oup
om he α-posi ion o he acyl ni ogen unde acidic eac ion condi ions has been used o assis
he o ma ion o ansien elec ophilic species. Following his s a egy, a a ied epe oi e o
adduc s ea u ing non adi ional dihyd opy idazine-based skele on connec ions molecules o
di icul - o-access 5-me hylenyl-subs i u ed 1,4-dihyd opy idazines can be assembled in high
yield and excellen egioselec i i y in he i s example o a di ec , Michael- ype addi ion
eac ion o nucleophiles o in si u gene a ed cyclic 5-me hylene N-acyl dihyd opy idazinium
ions (β-me hylene N-acyliminium ions o exocyclic ene conjuga ed iminium ions).
5.2 Resul s and discussion
I well-known ha a ious B øns ed o Lewis acids such as TiCl4, BF3·OE 2, SnCl4, InCl3,
NbCl5, Zn(OT )2, HNT 2, Zn(NT 2)2, TMSOT 74,75 a e e ec i e o he Mannich- ype addi ions
o N-acyliminium ions. Among he di e en Lewis acids es ed in ou p elimina y expe imen s
(BF3·OE 2, CuI, Cu(OT )2, ZnB 2, Zn(OT )2, Y(OT )3, InB 3, LiClO4), only indium ib omide
(40%) and bo on i luo ide e he a e (73%) we e ound o be p oduc i e. The supe io i y o
- 63 -
Addi ionally, THB has also been obse ed o block ATP-sensi i e K+ ion channels in ol ed in
he pa hogenesis o Pa kinson’s disease,89c indica ing an impo an neu op o ec i e ole.
As pa o ou p og am aimed a ocusing new s a egies o he cons uc ion o po en ial
biologically ac i e compounds, we de ised a s a egy aiming a he syn hesis o s uc u ally
complex e ahyd obe be ine analogues con aining he py olo[2,3-b]py idine sys em. The
py olo[2,3-b]py idine co e is s uc u ally impo an because, o example, i is ela ed o he
alkaloids o he chae ominine and kapakahine amilies (Figu e 13)82,90 and i has been ound in
se e al pha maceu ical ac i e molecules and d ug candida es.91 The same nucleus can be ound
in isoschizogamine and isoschizogaline (Figu e 13), belonging o he amily o schizozygane
alkaloids, ha exhibi an imic obial and an i ungal ac i i ies a low mic omola
concen a ions.83
N
N
O
py olo[2,3-b]py idine co e
o chae ominines and kapakahines py olo[2,3-b]py idine co e o
isoschizogamine (R1, R2= OMe) and
isoschizogaline (R1= H, R2= OMe)
R1
R2N
H
N
O
H
Figu e 13: Py olo[2,3-b]py idine co e o chae ominines and kapakahines and o isoschizogamine and
isoschizogaline.
The e osyn he ic analysis o his used-bicyclic s uc u e emphasizes wo s a egic
disconnec ions o he py ole ing: he i s one is along he N(1)-C(7a) and he second one
along C(3)-C(3a) bonds. This e eals wo subuni s ha ace he le hal back o he zwi e ionic
amine A and he igh hal o he pe inen he e ocyclic zwi e ion B (Scheme 26). F agmen A
can be co ela ed o he azo-ene sys em o 1,2-diaza-1,3-dienes, ha ep esen he main ield o
ou esea ch o he pas se e al yea s.92 The agmen B can be ela ed o he pe inen dihyd o-
py idine D, ha is con ained in he s uc u e o 7,8-dihyd obe be ine (7,8-DHB), he pa ially
educed o m o be be ine (Figu e 12, Scheme 26).
In ac , 7,8-DHB con ains an enamine moie y ha could eac wi h he azoene sys em o DDs,
as p e iously epo ed in li e a u e by se e al au ho s93 and also by some o ou g oup.94
- 64 -
O
O
N
O
O
1
2
3
5
7a
3a
7
4
6
N
N
HN
N
N
N
N
N
N
R3R2
A
B
CD
R1
R4
Figu e 14: Re osyn he ic analysis o py olo[2,3-b]py idine sys ems.
6.2 Resul s and Discussion
Following known p ocedu es, we p epa ed 7,8-dihyd obe be ine 4795 and 8-ace onyl-7,8-
dihyd obe be ine 47’96 (Scheme 26). Bo h 7,8-dihyd obe be ines 47 and 47’ possess he
enamino unc ion, equi ed o he nucleophilic a ack on he DDs.
O
ON+
O
O
O
ON
O
O
O
O
ON
O
NaBH4
Cl-
O
N
ONaOH
Scheme 26: Syn hesis o 7,8-dihyd obe be ine 47 95 and o 8-ace onyl-7,8-dihyd obe be ine 47’,96 s a ing
om comme cial be be ine chlo ide 46.
47
46
47’
- 65 -
By choosing DD 1e and 7,8-DHB 47 as ep esen a i e examples, we in es iga ed he eac ion
in di e en condi ions o sol en s (dichlo ome hane, e ahyd o u an, die hyl e he , e hyl
ace a e and ace oni ile) and empe a u es ( . ., 0 °C and -15 °C) (Scheme 27). In all he
condi ions es ed, he eac ion ook place wi h he o ma ion o he co esponding used
py olino-THB de i a i e 49e in good yields. By using ace oni ile, he eac ion p oceeds a
oom empe a u e and 49e di ec ly p ecipi a es in 87% yield om he eac ion medium.
Ha ing op imized he condi ions, we explo ed he eac ions o a ious DDs 1an wi h 7,8-
DHB de i a i es 47 and 47’. The be be be ino de i a i es 49an we e ob ained in good o
excellen yields (4992%), wi h he excep ion o 49g (22%), and all he eac ions we e
comple ed in 0.25 h (Table 16).
NN
Me
E OOC
O
ON
O
O
N
N
Me COOE
H
CH3CN
O
ON
O
O
ON
O
O
N
E OOC
Me
NH
+
O
COO -Bu
-BuOOC
-
-BuOOC
. .
Scheme 27: Mechanism o he syn hesis be be ino de i a i es 49a
n.
O
ON
O
O
N
HN
O
O
O
O
O
ON
O
O
N
HN
O
O
O
O
O
ON
O
O
N
HN
O
O
O
O
O
ON
O
O
N
HN
O
O
O
O
R
47
1
48
49
49a 61%
49b 83%
49c 92%
49d R=H 60%
49d’ R=CH3COCH3 49%
- 66 -
O
ON
O
O
N
P
HN
O
O
OO
O
O
ON
O
O
N
H
N
O
O
O
O
O
ON
O
O
N
H
N
O
O
H
N
O
O
ON
O
O
N
H
N
O
O
O
O
O
ON
O
O
N
H
N
O
O
H
N
HN
O
ON
O
O
N
H
N
O
O
O
O
O
ON
O
O
N
H
N
O
O
O
N
O
ON
O
O
N
NH
O
O
O
O
O
ON
O
O
N
HN
O
O
O
O
O
ON
O
O
N
HN
O
O
O
O
R
Table 15: Yields o he syn hesis o be be ino de i a i es 49a
n e e ed o 1
49e R=H 87%
49e’ R=CH3COCH3 72%
49 96%
49g 22%
49h 73%
49i 62%
49i 61%
49k 55%
49l 61%
49m 85%
49n 61%
- 67 -
Compounds 49 possess an in iguing used esacyclic new sys em and h ee o he ings a e
a ayed a ound he aminal ca bon. Thei o ma ion occu s h ough a o mal [3+2] cycloaddi ion
and he plausible mechanism could in ol e a p elimina y egioselec i e Michael ype addi ion
o he -ca bon a om o he enamino unc ion in posi ion 13 o 7,8-DHBs 47,47’ o he
elec ophilic e minal ca bon o he azo-ene sys em o DDs 1 p oducing he non-isolable
zwi e ionic hyd azone in e media es 48. The loss o he hyd ogen in -posi ion o he
hyd azine moie y o 48 could p omo e he ni ogen in amolecula nucleophilic a ack on o he
iminium unc ion, de e mining he o ma ion o he dihyd opy ole ing o 49 (Scheme 27). To
he bes o ou knowledge, only one o he example o Michael- ype addi ion in ol ing DHB
de i a i es was epo ed.97
The s uc u es o compounds 49 we e de e mined by mono and bidimensional NMR
measu emen s. Addi ionally, X- ay di ac ion s udies o 49e, de i ed om DD 1e and 7,8-
DHB 47, and o 49e’, de i ed om he same DD 1e and 8-ace onyl-7,8-DHB 47’, we e
pe o med and hey unequi ocally con i med he p oposed s uc u es (Figu es 15 and 16).98
Figu e 15: X- ay s uc u e o compound 49e
Figu e 16: X- ay s uc u e o compound 49e’
- 68 -
6.3 An ioxidan p ope ies:
The no el THB de i a i es 49an we e ound o exhibi an ioxidan p ope ies a a ious
deg ees, by using he ORAC (Oxygen adical abso bance capaci y) me hod.100 (Table 16 and
G aphic 1). In pa icula , ORAC alues o 49a, 49b and 49e we e compa able o hose o THB.
A sligh ORAC decay (10%) was obse ed o he compounds 49d and 49h, ollowed by 49
(20%). Ins ead, compounds 49g, 49i and 49l showed 30% an ioxidan capaci y decay as
compa ed o ha o THB. The analogues 49c, 49j, 49k, 49m and 49n showed he lowes ORAC
alues.
G aphic 1: An ioxidan capaci y o THB and i s analogues 49a
n de ec ed by he ORAC
me hod. (p<0.05, one-way ANOVA).
SAMPLES
ORAC alues (μmol TE/mmol)
THB
1577±72
49a
1629±42
49e
1565±56
49b
1504±18
49d
1474±60
49h
1440±49
49
1255±9
49j
1164±51
49g
1133±57
49i
955±15
49m
855±71
49c
512±19
49k
206±7
49l
185±46
49n
87±3
Table 16: An ioxidan capaci y alue o THB and i s analogues 49a
n
0
200
400
600
800
1000
1200
1400
1600
1800
49a 49b 49c 49d 49e 49 49g 49h 49i 49j 49k 49l 49m 49n THB
μmol T olox eq
/mmol
- 69 -
Based on syn hesis p ocedu es and ORAC alues, 7 ou o 14 THB de i a i es we e selec ed
o u he in i o an ioxidan assays: 2 wi h high ORAC alues (49d and 49e), 2 wi h
medium/high alues (49g and 49j), 2 wi h medium alues (49i and 49m) and 1 wi h a low
ORAC alue (49l).
Re e ing o he DCFH-DA assay, expe imen s we e conduc ed in NCTC-2544 cells bo h in he
absence (basal condi ion) and in p esence (oxida i e condi ion) o he oxidan molecule H2O2.
In basal condi ions, cells we e incuba ed wi h he selec ed THB de i a i es up o 3h, and hen
he in acellula oxida ion le els we e e alua ed by eco ding DCFH-DA luo escence
emission. As epo ed in G aphic 2, NCTC-2544 cells incuba ed o 1h wi h compounds 49e
and 49i p esen ed signi ican ly lowe oxida ion le els as compa ed o un ea ed con ol cells
(p<0.05 s. CTR). The same end was obse ed o 49e e en a e 3 h o cell incuba ion wi h
he es molecule.
G aphic 2: Rela i e in acellula oxida ion le els in NCTC-2544 cells incuba ed o 1 and
3h wi h THB de i a i es (30 µM) o ehicle (0.1% DMSO, CTR). Da a a e
exp essed as mean ± SD (n=3). *p<0.05 s. un ea ed cells (CTR).
0,00
0,20
0,40
0,60
0,80
1,00
1,20
1,40
Rela i e oxida ion ( s. CTR)
1H 3H
*
**
CTR THB 49d 49e 49g 49i 49j 49l 49m
- 70 -
In oxida i e condi ions, NCTC-2544 cells we e p e-incuba ed wi h he selec ed THB
de i a i es up o 3 h and hen oxidized wi h H2O2. DCFH-DA luo escence emission was
eco ded o 30 min a e H2O2 adminis a ion. As shown in g aphic 3, bo h THB and i s
de i a i es signi ican ly educed H2O2-induced in acellula oxida ion (p<0.05 s CTR+).
Among THB de i a i es, 49e and 49i p esen ed he highes an ioxidan p o ec ion agains H2O2.
In pa icula , 49e exhibi ed an an ioxidan capaci y signi ican ly di e en om THB as well as
om he nega i e con ol (non-oxidized cells).
G aphic 3: Rela i e in acellula oxida ion le els a e H2O2 adminis a ion (100 µM) o NCTC-2544 cells
p e-incuba ed o 1 and 3 h wi h THB de i a i es (30 µM). CTR-: non-oxidized cells (nega i e
con ol, e e ence alue). CTR+: H2O2- ea ed cells (posi i e con ol, maximum oxida ion).
Da a a e exp essed as mean ± SD (n=3). *p<0.05 s. CTR-. #p<0.05 s. THB.
The e ec s o he selec ed THB de i a i es on cell iabili y we e also explo ed. As epo ed in
G aphic 3, compounds 49d, 49e, 49i and 49j had no signi ican e ec s on NCTC-2544 cell
g ow h when compa ed o un ea ed cells (CTR). Compounds 49l and 49m showed a bland
s imula o y e ec on cell g ow h (p>0.05 s. CTR), while 49g, a e an ini ial s imula o y e ec
(p<0.05 s. CTR), exhibi ed a la e inhibi o y ac ion (cell g ow h dec emen by 35% a 72h as
compa ed o CTR, p<0.05).
0,00
0,50
1,00
1,50
2,00
2,50
3,00
3,50
Rela i e oxida ion ( s. CTR-)
1h 3h
*
#
#
*
CTR- CTR+ THB 49d 49e 49g 49i 49j 49l 49m
- 71 -
G aphic 4: E ec o THB de i a i es (30 µM) on NCTC-2544 cell g ow h a e 24, 48, and 72 h o
incuba ion. Da a a e exp essed as mean ± SD (n=3). *p<0.05 s. un ea ed cells (CTR).
6.4 Conclusion
In conclusion, s a ing om easily a ailable s a ing ma e ials, such as DDs and
dihyd obe be ines, we de eloped a acile p ocedu e o he syn hesis o no el unp eceden ed
py olino- e ahyd obe be ine de i a i es h ough a o mal [3+2] cycloaddi ion. These
compounds a e ascina ing in i ue o he ac ha hey possess a complex used esacyclic new
sys em and h ee o hese ings a e a ayed a ound an aminal ca bon. Besides, he py olino-
e ahyd obe be ines syn hesized ha e shown a p omising an ioxidan ac i i y, as a s udy
ca ied ou wi h he ORAC me hod and NCTC-2544 cell line ex ha e been demons a ed.
0,0
20,0
40,0
60,0
80,0
100,0
120,0
140,0
Cell g ow h (%)
24h 48h 72h
*
*
CTR THB 49d 49e 49g 49i 49j 49l 49m
- 72 -
7. GENERAL CONCLUSION
CHAPTER 7
- 79 -
Dime hyl {4-[( e -bu oxyca bonyl)amino]-3-hyd oxy-5-
me hyl-3,4-dihyd o-2H-1,4- hiazin-6-yl}phosphona e 21k.
Whi e oam; 1H NMR (400 MHz, CDCl3): δ = 1.36 (s, 9H), 2.15 (s,
3H), 2.68 (b s, 1H), 3.60 (s, 3H), 3.63 (s, 3H), 4.25 (b s, 1H), 3.66-
3.77 (m, 2H), 5.06 (s, 1H), 8.06 (b s, 1H); 13C NMR (100 MHz,
CDCl3) δ = 17.2 (q), 28.1 (q), 32.4 ( ), 52.6 (q, 2JCP = 5.4 Hz), 52.8 (q, 2JCP = 5.1 Hz),81.0 (d),
81.4 (s), 100.5 (s, 1JCP = 130.8 Hz), 153.1 (s), 154.8 (s); IR (nujol): max = 3478, 3281, 1762
cm-1; MS m/z (%): 354 (M+) (5), 281 (17), 253 (34), 245 (23), 144 (85),; anal. calcd. o
C12H23N2O6PS (354.3607): C 40.67, H 6.54, N 7.91; ound: C 40.86, H 6.59, N 7.65.
N
S
OH
P
HN
O
O
O
O
O
- 80 -
CHAPTER 3
Gene al in o ma ion
All chemicals and sol en s we e pu chased om comme cial supplie s and used as ecei ed.
Rhodanines 22ad we e ob ained as ollows, acco ding o he p ocedu e epo ed in
li e a u e:43a a mix u e o hioglycolic acid (0.92 g, 10 mmol) and e hyl, phenyl, 4-chlo ophenyl
o 4-me hoxyphenyl iso hiocyana es (12 mmol) in me hanol (8 ml) and wa e (100 ml) was
hea ed in an oil ba h o 4 h a 100 °C. 1,2-Diaza-1,3-dienes 1ag we e p epa ed as epo ed99
and used as EE/EZ isome s mix u es. Mel ing poin s we e de e mined in open capilla y ubes
and a e unco ec ed. FTIR spec a we e ob ained as Nujol mulls. All 1H NMR and 13C NMR
spec a we e eco ded a 400 and 100 MHz, espec i ely. P o on and ca bon spec a we e
e e enced in e nally o sol en signals, using alues o = 2.50 ppm o p o on (middle peak)
and = 39.50 ppm o ca bon (middle peak) in DMSOd6 and = 7.27 ppm o p o on and =
77.00 ppm o ca bon (middle peak) in CDCl3. All coupling cons an s (J) a e gi en in Hz. All
he NH exchanged wi h D2O. P ecoa ed aluminium oxide pla es 0.25 mm we e employed o
analy ical hin laye ch oma og aphy. All new compounds showed sa is ac o y elemen al
analysis. Mass spec a we e eco ded in he ESI mode. The nomencla u e was gene a ed using
ACD/IUPAC Name ( e sion 3.50, 5 Ap . 1998), Ad anced Chemis y De elopmen Inc.,
To on o, ON (Canada).
Gene al p ocedu e o syn hesis o dialkyl 2,2’-((3-subs i u ed-4-oxo-2-
hioxo hiazolidine-5,5-diyl)bis(4-alkoxy-4-oxobu an-3-yl-2-ylidene))bis(hyd azine-
ca boxyla es) (24a ).
To a magne ically s i ed solu ion o 1,2-diaza-1,3-dienes 1a,c,d (4.2 mmol) and 3-e hyl o 3-
phenyl o 3-(4-chlo ophenyl) o 3-(4-me hoxyphenyl)-2- hioxo hiazolidin-4-ones 22ad (2.0
mmol) in THF (10 mL) a oom empe a u e, po assium ca bona e (2.0 mmol) was added. A e
he disappea ance o he eagen s (0.10.5 h) (TLC moni o ing), K2CO3 was il e ed, he
eac ion sol en was e apo a ed unde educed p essu e and he c ude mix u e was pu i ied by
column ch oma og aphy on silica gel (cyclohexane : e hyl ace a e mix u es) o a o d he
co esponding bis-hyd azone- unc ionalized hodanines 24a , ha we e c ys allized om
die hyl e he -pe oleum e he (b.p. 4060 °C).
- 81 -
Dime hyl 2,2’-((3-e hyl-4-oxo-2- hioxo hiazolidine-
5,5-diyl)bis(4-e hoxy-4-oxobu an-3-yl-2-
ylidene))bis(hyd azineca -boxyla e) (24a).
Whi e powde (887.2 mg, 79% yield); mp: 141
143
°C;
1
H NMR (400 MHz, CDCl
3
, 25 °C): δ =
1.13
1.23 (m, 9H, 2OCH
2
CH
3
, NCH
2
CH
3
), 1.87 (s,
3H, CH
3
), 1.99 (s, 3H, CH
3
), 3.76 (s, 3H, OCH
3
), 3.79 (s, 3H, OCH
3
), 4.02
4.12 (m, 7H,
CH, 2OCH
2
CH
3
, NCH
2
CH
3
), 4.51 (b s, 1H, CH), 8.24 (b s, 2H, 2NH);
13
C NMR (100
MHz, CDCl
3
, 25 °C): δ = 11.0 (q), 13.8 (q), 13.9 (q), 14.8 (q), 17.2 (q), 39.6 ( ), 52.8
(q), 58.2 (s), 58.7 (d),61.0 (d), 61.8 ( ), 62.1 ( ), 146.0 (s), 146.3 (s), 154.1 (s), 154.7 (s),
167.5 (s), 168.5 (s), 177.0 (s), 203.4 (s);
);
IR (nujol):
max
= 3239, 1737, 1715, 1666 cm
-
1
; MS m/z (ESI): 562.70 (M + H
+
); anal. calcd. o C
21
H
31
N
5
O
9
S
2
(561.6289): C 44.91,
H 5.56, N 12.47; ound: C 45.04, H 5.59, N 12.35.
Dime hyl 2,2’-((4-oxo-3-phenyl-2- hioxo hiazolidine-
5,5-diyl)bis(4-e hoxy-4-oxobu an-3-yl-2-
ylidene))bis(hyd azineca -boxyla e) (24b).
Whi e powde (1.03 g, 85% yield); mp: 145
147 °C;
1
H NMR (400 MHz, CDCl
3
, 25 °C): δ = 1.23
1.36 (m,
6H, 2OCH
2
CH
3
), 1.84 (s, 3H, CH
3
), 2.08 (s, 3H, CH
3
),
3.73 (b s, 3H, CH
3
), 3.73 (s, 3H, OCH
3
), 4.18 (s, 1H, CH), 4.19
4.30 (m, 4H,
2OCH
2
CH
3
), 4.67 (b s, 1H, CH), 7.43
7.55 (m, 5H, A ), 7.98 (b s, 1H, NH), 8.17 (b s,
1H, NH);
13
C NMR (100 MHz, CDCl
3
, 25 °C): δ = 14.4 (q), 14.4 (q), 14.6 (q), 17.5 (q),
52.7 (q), 52.8 (q), 53.0 (q), 53.1 (q), 58.1 (s), 58.9 (d), 59.0 (d), 62.1 ( ), 128.2 (d), 128.3
(d), 129.3 (d), 136.0 (d), 145.4(s), 146.0 (s), 153.3 (s), 153.4 (s), 154.1 (s),168.4 (s),
169.4 (s), 171.1 (s), 204.0 (s); IR (nujol):
max
=
3241, 3160, 1741, 1720, 1690
cm
-1
; MS
m/z (ESI): 608.72 (M - H
+
); anal. calcd. o C
25
H
31
N
5
O
9
S
2
(609.6717): C 49.25, H 5.13,
N 11.49; ound: C 49.14, H 5.10, N 11.65.
S
N
O
S
O
O
N
N
H
O
N
N
H
O
O
OO
O
S
N
O
S
O
O
N
N
H
O
N
N
H
O
O
OO
O
- 82 -
Die hyl 2,2’-((4-oxo-3-pheny-2- hioxo hiazolidine-
5,5-diyl)bis(4-me hoxy-4-oxobu an-3-yl-2-
ylidene))bis(hyd azineca boxyla e) (24c).
Whi e powde (1.12 g, 92% yield); mp: 135137 °C;
1
H
NMR (400 MHz, CDCl
3
, 25 °C): δ = 1.28
1.37 (m,
6H, 2OCH
2
CH
3
), 1.85 (s, 3H, CH
3
), 2.08 (s, 3H,
CH
3
), 3.74 (s, 3H, OCH
3
), 3.74 (s, 3H, OCH
3
), 4.18
(s, 1H, CH), 4.19
4.31 (m, 4H, 2OCH
2
CH
3
), 4.69 (b s, 1H, CH), 7.44
7.56 (m, 5H, A ),
7.80 (b s, 1H, NH), 7.95 (b s, H, NH);
13
C NMR (100 MHz, CDCl
3
, 25 °C): δ = 14.4
(q), 14.6 (q), 15.2 (q), 17.5 (q), 52.8 (q), 53.1 (q), 58.2 (s), 62.1 ( ), 62.3 (d), 65.8 (d),
128.3 (d), 129.3 (d), 129.4 (d), 136.0 (s), 146.0(s), 153.1 (s), 153.9 (s), 168.4 (s), 169.4
(s), 171.2 (s), 204.0 (s); IR (nujol):
max
=
3234, 3159, 3127, 1741, 1701
cm
-1
; HRMS (ESI)
m/z [M+H]
+
calcd. o C
25
H
32
N
5
O
9
S
2
: 610.1641; ound: 610.1641; MS m/z (ESI): 610.55
(M + H
+
); anal. calcd. o C
25
H
31
N
5
O
9
S
2
(609.6717): C 49.25, H 5.13, N 11.49; ound:
C 49.12, H 5.11, N 11.62.
Di- e -bu yl 2,2’-((4-oxo-3-pheny-2-
hioxo hiazolidine-5,5-diyl)bis(4-e hoxy-4-
oxobu an-3-yl-2-ylidene))bis(hyd azineca -
boxyla e) (24d).
Whi e powde (1.29 g, 93% yield) mp: 138141 °C
1
H NMR (400 MHz, CDCl
3
, 25 °C): δ =
1.23
1.27 (m, 6H, 2OCH
2
CH
3
), 1.51 (s, 9H,
(CH
3
)
3
), 1.56 (s, 9H, (CH
3
)
3
), 1.84 (s, 3H, CH
3
), 2.09 (s, 3H, CH
3
), 4.11 (s, 1H, CH),
4.17
4.23 (m, 4H, 2OCH
2
CH
3
), 4.67 (b s, 1H, CH), 7.45
7.56 (m, 5H, A ), 7.65 (b s,
1H, NH), 7.77 (b s, 1H, NH);
13
C NMR (100 MHz, CDCl
3
, 25 °C): δ = 13.9 (q), 14.0
(q), 14.5 (q), 17.6 (q), 28.2 (q), 28.4 (q), 58.2 (s), 59.1 (d), 59.2 (d), 61.9 ( ), 62.1 ( ),
62.2 ( ), 81.5 (s), 81.7 (s), 128.4 (d), 129.3 (d), 136.2 (s), 145.3(s), 151.9 (s), 152.6 (s),
168.0 (s), 169.0 (s), 177.4 (s), 204.4 (s); IR (nujol):
max
=
3328, 3225, 1724, 1746, 1700
cm
-1
; MS m/z (ESI): 694.00 (M + H
+
); anal. calcd. o C
31
H
43
N
5
O
9
S
2
(693.8312): C
53.66, H 6.25, N 10.09; ound: C 53.78, H 6.29, N 10.02.
S
N
O
S
O
O
NN
H
O
N
N
H
O
O
OO
O
S
N
O
S
O
O
NN
H
O
N
N
H
O
O
OO
O
- 83 -
Die hyl 2,2’-((3-(4-chlo ophenyl)-4-oxo-2-
hioxo hiazolidine-5,5-diyl)bis(4-me hoxy-4-
oxobu an-3-yl-2-ylidene))bis(hyd a-zineca boxla e)
(24e).
Whi e powde (1.13 g, 88% yield); mp: 182184 °C;
1
H
NMR (400 MHz, CDCl
3
, 25 °C): δ = 1.29
1.37 (m,
6H, 2OCH
2
CH
3
), 1.83 (s, 3H, CH
3
), 2.09 (s, 3H,
CH
3
), 3.73 (s, 3H, OCH
3
), 3.74 (s, 3H, OCH
3
), 4.17 (s, 1H, CH), 4.20
4.33 (m, 4H,
2OCH
2
CH
3
), 4.68 (s, 1H, CH), 7.40 (d, 2H, J = 8.4 Hz, A ), 7.51 (d, 2H, J = 9.2 Hz, A ),
7.84 (b s, 1H, NH), 7.98 (b s, 1H, NH);
13
C NMR (100 MHz, CDCl
3
, 25 °C): δ = 14.4
(q), 14.4 (q), 14.5 (q), 15.2 (q), 17.6 (q), 52.9 (q), 53.2 (q), 58.2 (s), 59.0 (d), 62.1 ( ),
65.8 (d), 129.7 (d), 129.8 (d), 134.5 (s), 135.4 (s), 145.8(s), 153.1 (s), 155.8 (s), 168.5
(s), 169.5 (s), 177.1 (s), 203.7 (s); IR (nujol):
max
=
3332, 3209, 1718, 1752, 1698
cm
-1
;
MS m/z (ESI): 643.31 (M - H
+
); anal. calcd. o C
25
H
30
ClN
5
O
9
S
2
(644.1168): C 46.62,
H 4.69, N 10.87; ound: C 46.75, H 4.71, N 10.73.
Di- e -bu yl 2,2’-((3-(4-me hoxypheny)-4-oxo 2-
hioxo hiazolidine-5,5-diyl)bis(4-e hoxy-4-
oxobu an-3-yl-2-ylidene))bis(hyd azineca -
boxyla e) (24 ).
Whi e powde (1.34 g, 93% yield) mp: 169171 °C
(dec.)
1
H NMR (400 MHz, CDCl
3
, 25 °C): δ =
1.21
1.77 (m, 6H, 2OCH
2
CH
3
), 1.51 (s, 9H,
(CH
3
)
3
), 1.55 (s, 9H, (CH
3
)
3
), 1.83 (s, 3H, CH
3
),
2.08 (s, 3H, CH
3
), 3.84 (s, 3H, OCH
3
), 4.09 (s, 1H, CH), 4.16
4.23 (m, 4H, 2OCH
2
CH
3
),
4.66 (s, 1H, CH), 7.03 (d, 2H, J = 9.2 Hz, A ), 7.37 (d, 2H, J = 8.4 Hz, A ), 7.64 (b s,
1H, NH), 7.75 (b s, 1H, NH);
13
C NMR (100 MHz, CDCl
3
, 25 °C): δ = 14.0 (q), 14.0
(q), 14.5 (q), 17.6 (q), 28.2 (q), 28.4 (q), 55.4 (q), 58.2 (s), 59.2 (d), 61.9 ( ), 61.9 ( ),
62.2 ( ), 65.8 (d), 81.5 (s), 81.7 (s), 114.6 (d), 128.7 (s), 129.4 (d), 145.4 (s), 151.8 (s),
160.0 (s), 168.0 (s), 169.0 (s), 177.5 (s), 204.7 (s); IR (nujol):
max
=
3246, 3150, 3109,
1754, 1693
cm
-1
; MS m/z (ESI): 724.67 (M + H
+
); anal. calcd. o C
32
H
45
N
5
O
10
S
2
(723.8572): C 53.10, H 6.27, N 9.68; ound: C 53.01, H 6.26, N 9.78.
S
N
O
S
O
O
NN
H
O
N
N
H
O
O
OO
O
Cl
S
N
O
S
O
O
N
N
H
O
N
N
H
O
O
OO
O
O
- 84 -
Gene al p ocedu e o syn hesis o 2,3,5,6- e ahyd o-1
H
-py olo[3,4-c]py idine-
1,3,6- iones (26a,c
e,j,l) s a ing om 24a
(Pa h A).
To a magne ically s i ed solu ion o bis-hyd azone- unc ionalized hodanines
4a
(1.0
mmol) in THF (5 mL) hea ed a 55 °C in an oil ba h, po assium ca bona e (5.0 mmol)
was added. The lask was kep open in o de o emo e CS
2
by e apo a ion (b.p. 49.3
°C). A e he disappea ance o he p oduc s
24
(2.0
5.0 h) (TLC moni o ing), K
2
CO
3
was il e ed, he eac ion sol en was e apo a ed unde educed p essu e and he c ude
mix u e was pu i ied by column ch oma og aphy on silica gel (cyclohexane : e hyl
ace a e mix u es) o a o d he co esponding 2,3,5,6- e ahyd o-1H-py olo[3,4-
c]py idine-1,3,6- iones
(26a,c
e,j,l)
, ha we e c ys allized om die hyl e he -
pe oleum e he (b.p. 40
60 °C).
Gene al p ocedu e o syn hesis o 2,3,5,6- e ahyd o-1
H
-py olo[3,4-c]py idine-
1,3,6- iones (26a
l) in one-po p ocedu e (Pa h B).
To a magne ically s i ed solu ion
o 1,2-diaza-1,3-dienes
1a
g
(2.1 mmol) and 3-e hyl o 3-phenyl o 3-(4-chlo ophenyl)
o 3-(4-me hoxyphenyl)-2- hioxo hiazolidin-4-ones
22a
d
(1.0 mmol) in THF (5 mL)
hea ed a 55 °C in an oil ba h, po assium ca bona e (5.0 mmol) was added. The lask was
kep open in o de o emo e CS
2
by e apo a ion. A e he disappea ance o he eagen s
(1.0
5.0 h) (TLC moni o ing), K
2
CO
3
was il e ed, he eac ion sol en was e apo a ed
unde educed p essu e and he c ude mix u e was pu i ied by column ch oma og aphy
on silica gel (cyclohexane : e hyl ace a e mix u es) o a o d he co esponding 2,3,5,6-
e ahyd o-1H-py olo[3,4-c]py idine-1,3,6- iones (
6a
l
), ha we e c ys allized om
die hyl e he -pe oleum e he (b.p. 4
60 °C).
Me hyl 2-(1-(2e hyl-5-((me hoxyca bonyl)amino)-4-
me hyl-1,3,6- ioxo-2,3,5,6- e ahyd o-1H-py olo[3,4-
c]py idin-7-yl)e hylidene)-hyd azineca boxyla e (26a).
Pale yellow powde (149.7 mg, 38% yield, pa h A; 239.8,
61% yield, pa h B); mp: 235−237 °C (dec.); 1H NMR (400
MHz, CDCl3, 25 °C): δ = 1.22 ( , J = 7.2 Hz, 3H, NCH2CH3),
2.16 (s, 3H, CH3), 2.79 (s, 3H, CH3), 3.68 (q, J = 7.2 Hz, 2H, NCH2CH3), 3.83 (s, 6H, 2 OCH3),
7.60 (b s, 1H, NH), 8.16 (b s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.4 (q), 14.4
(q), 15.6 (q), 33.4 ( ), 53.2 (q), 54.2 (q), 105.7 (s), 125.4 (s), 137.2 (s), 142.5 (s), 152.2 (s), 156.2
(s), 161.0 (s), 164.0 (s), 165.5 (s); IR (nujol): max = 3331, 3239, 1753, 1721, 1672 cm-1;
HRMS
(ESI) m/z [M+H]
+
calcd. o C
16
H
20
N
5
O
7
: 394.1363; ound: 394.1363;
MS m/z (ESI):
N
O
O N
NH
O
NNH
O
O
O
O
A
- 85 -
394.11 (M + H+); anal. calcd. o C16H19N5O7 (393.1284): C 48.85, H 4.87, N 17.80; ound: C
48.94, H 4.85, N 17.68.
Te -bu yl 2-(1-(5-(( e -bu oxyca bonyl)amino)-2e hyl-
4-me hyl-1,3,6- ioxo-2,3,5,6- e ahyd o-1H-
py olo[3,4-c]py idin-7-yl)e hy-
lidene)hyd azineca boxyla e (26b).
Pale yellow powde (277.7, 58% yield, pa h B); mp:
218220 °C (dec.); 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 1.22 ( , J = 7.2 Hz, 3H, NCH2CH3), 1.50 (s, 18H, 2 C(CH3)3), 2.13 (s, 3H, CH3), 2.76 (s, 3H,
CH3), 3.67 (q, J = 7.2 Hz, 2H, NCH2CH3), 7.38 (b s, 1H, NH), 7.89 (s, 1H, NH); 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 13.4 (q), 14.4 (q), 15.6 (q), 28.0 (q), 28.2 (q), 33.3 ( ), 81.4 (s),
83.8 (s), 105.1 (s), 125.6 (s), 136.7 (s), 141.4 (s), 152.1 (s), 154.5 (s), 160.9 (s), 164.2 (s), 165.7
(s); IR (nujol): max = 3358, 3190, 1735, 1718, 1678 cm-1; MS m/z (ESI): 476.38 (M - H+); anal.
calcd. o C22H31N5O7 (477.5108): C 55.34, H 6.54, N 14.67; ound: C 55.22, H 6.50, N 14.78.
Me hyl 2-(1-(5-((me hoxyca bonyl)amino)-4-me hyl-1,3,6-
ioxo-2-phenyl-2,3,5,6- e ahyd o-1H-py olo[3,4-
c]py idin-7-yl)e hyli-dene)hyd azineca boxyla e (26c)
Pale yellow powde (209.3 mg, 37% yield, pa h A; 340.2,
60% yield, pa h B); mp: 169172 °C; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 2.16 (s, 3H, CH3), 2.83 (s, 3H, CH3), 3.82
and 3.85 (2s, 6H, 2 OCH3), 7.347.37 (m, 2H, Ph), 7.397.43 (m, 1H, Ph), 7.477.51 (m, 2H,
Ph), 7.80 (b s, 1H, NH), 8.20 (s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.5 (q),
14.6 (q), 15.5 (q), 15.6 (q), 53.3 (q), 54.1 (q), 54.2 (q), 105.1 (s), 125.8 (s), 126.5 (d), 126.6 (d),
129.1 (d), 131.2 (s), 136.7 (s), 142.5 (s), 153.5 (s), 156.2 (s), 161.0 (s), 163.3 (s), 164.7 (s); δ =
IR (nujol): max = 3352, 3195, 1738, 1722, 1681 cm-1; MS m/z (ESI): 442.27 (M + H+); anal.
calcd. o C20H19N5O7 (441.3942): C 54.42, H 4.34, N 15.87; ound: C 54.57, H 4.38, N 15.76.
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
- 86 -
E hyl 2-(1-(5-((e hoxyca bonyl)amino)-4-me hyl-1,3,6-
ioxo-2-phenyl-2,3,5,6- e ahyd o-1H-py olo[3,4-
c]py idin-7-yl)e hylide-ne)hyd azineca boxyla e (26d).
Pale yellow powde (165.2 mg, 35% yield, pa h A; 258.6,
55% yield, pa h B); mp: 182184 °C; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.281.34 (m, 6H, 2 OCH2CH3), 2.16
(s, 3H, CH3), 2.84 (s, 3H, CH3), 4.254.33 (m, 4H, 2 OCH2CH3), 7.347.37 (m, 2H, Ph),
7.397.42 (m, 1H, Ph), 7.477.51 (m, 2H, Ph), 7.58 (b s, 1H, NH), 8.04 (s, 1H, NH); 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 14.3 (q), 14.5 (q), 14.6 (q), 15.6 (q), 62.1 ( ), 63.6 ( ), 105.1 (s),
125.8 (s), 126.5 (d), 128.5 (d), 129.1 (d), 131.2 (s), 136.7 (s), 142.4 (s), 153.6 (s), 155.8 (s),
161.0 (s), 163.4 (s), 164.7 (s); IR (nujol): max = 3343, 3239, 1722, 1675, 1631 cm-1; MS m/z
(ESI): 470.15 (M + H+); anal. calcd. o C22H23N5O7 (469.4473): C 56.29, H 4.94, N 14.92;
ound: C 56.36, H 4.96, N 14.81.
Te -bu yl 2-(1-(5-(( e -bu oxyca bonyl)amino)-4-
me hyl-1,3,6- ioxo-2-phenyl-2,3,5,6- e ahyd o-1H-
py olo[3,4-c]py idin-7-
yl)e hylidene)hyd azineca boxyla e (26e).
Pale yellow powde (216.2 mg, 41% yield, pa h A; 346.1,
66% yield, pa h B); mp: 220222 °C (dec.); 1H NMR (400
MHz, DMSOd6, 25 °C): δ = 1.45 and 1.48 (2s, 18H, 2
C(CH3)3), 2.06 (s, 3H, CH3), 2.66 (s, 3H, CH3), 7.387.40 (m, 2H, Ph), 7.447.46 (m, 1H, Ph),
7.497.53 (m, 2H, Ph), 9.93 (b s, 1H, NH), 10.23 (s, 1H, NH); 13C NMR (100 MHz, DMSOd6,
25 °C): δ = 14.0 (q), 16.9 (q), 27.8 (q), 28.0 (q), 79.4 (s), 81.4 (s), 104.2 (s), 125.9 (s), 127.4
(d), 128.3 (d), 128.7 (d), 131.7 (s), 135.6 (s), 142.7 (s), 152.4 (s), 152.7 (s), 154.2 (s), 160.0 (s),
163.3 (s), 164.7; (s); IR (nujol): max = 3314, 3253, 1725, 1712, 1677 cm-1;
HRMS (ESI) m/z
[M+H]
+
calcd. o C
26
H
32
N
5
O
7
: 526.2302; ound: 526.2302;
MS m/z (ESI): 524.38 (M -
H+); anal. calcd. o C26H31N5O7 (525.5536): C 59.42, H 5.95, N 13.33; ound: C 59.49, H 5.99,
N 13.20.
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
- 87 -
E hyl 2-(1-(4-bu yl-5-((e oxyca bonyl)amino)-1,3,6-
ioxo-2-phenyl-2,3,5,6- e ahyd o-1H-py olo[3,4-
c]py idin-7-yl)pen yli-dene)hyd azineca boxyla e
(26 ).
Pale yellow powde ; (350.8, 63% yield, pa h B); mp:
194196 °C (dec.); 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 0.850.98 (m, 8H, alkyl), 1.241.39 (m, 8H, alkyl),
1.561.74 (m, 4H, alkyl), 2.482.63 (m, 2H, alkyl), 2.713.09 (m, 2H, alkyl), 4.214.32 (m,
4H, 2 OCH2CH3), 7.08 (b s, 1H, NH), 7.377.41 (m, 3H, Ph), 7.477.50 (m, 2H, Ph), 8.06 and
8.27 (2b s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.6 (q), 13.7 (q), 14.3 (q), 14.5
(q), 22.7 ( ), 23.0 ( ), 27.0 ( ), 27.9 ( ), 29.7 ( ), 30.7 ( ), 63.6 ( ), 104.7 (s), 126.4 (s), 126.5 (d),
128.5 (d), 129.1 (d), 131.2 (s), 137.5 (s), 139.3 (s), 156.0 (s), 157.6 (s), 161.5 (s), 163.4 (s),
164.5 (s), 165.3; IR (nujol): max = 3348, 3192, 1729, 1721, 1680 cm-1; MS m/z (ESI): 552.37
(M - H+); anal. calcd. o C28H35N5O7 (553.6068): C 60.75, H 6.37, N 12.65; ound: C 60.62, H
6.33, N 12.79.
Benzyl 2-(1-(5-
(((benzyloxy)ca bonyl)amino)-4-me hyl-
1,3,6- ioxo-2-phenyl-2,3,5,6- e ahyd o-
1H-py olo[3,4-c]py idin-7-yl)
e hylidene)hyd azineca boxyla e (26g).
Pale yellow powde (253.8, 43% yield, pa h
B); mp: 199201 °C (dec.); 1H NMR (400
MHz, CDCl3, 25 °C): δ = 2.12 (s, 3H, CH3), 2.80 (s, 3H, CH3), 5.22 and 5.25 (2s, 4H, 2
OCH2Ph), 7.347.51 (m, 15H, 3 Ph), 7.64 (s, 1H, NH), 8.12 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 14.6 (q), 14.8 (q), 27.8 (q), 67.8 (T), 69.1 (s), 105.1 (s), 126.4 (s), 126.5 (d),
128.3 (d), 128.5 (d), 128.6 (d), 128.6 (d), 128.7 (d), 128.8 (d), 129.1 (d), 129.2 (s), 131.2 (s),
134.7 (s), 136.8 (s), 142.5 (s), 153.5 (s), 153.5 (s), 155.5 (s), 160.9 (s), 163.3 (s), 164.6 (s); IR
(nujol): max = 3331, 3240, 1738, 1725, 1670; MS m/z (ESI): 592.12 (M + H+); anal. calcd. o
C32H27N5O7 (593.5861): C 64.75, H 4.58, N 11.80; ound: C 64.66, H 4.54, N 11.88.
N
O
O N
NH
O
NNH
O
O
O
O
N
O
O N
NH
O
NNH
O
O
O
O
- 88 -
Me hyl 2-(1-(2-(4-chlo ophenyl)-5-
((me oxyca bonyl)amino)-4-me hyl-1,3,6- ioxo-
2,3,5,6- e ahyd o-1H-py olo[3,4-c]py- idin-7-
yl)e hylidene)hyd azineca boxyla e (26h).
Pale yellow powde (220.2, 46% yield, pa h B); mp:
221222 °C (dec.); 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 2.13 (s, 3H, CH3), 2.80 (s, 3H, CH3), 3.79 and 3.83 (2s, 6H, 2 OCH3), 7.32 (d, J = 8.8 Hz,
2H, Ph), 7.45 (d, J = 8.8 Hz, 2H, Ph), 8.34 (s, 1H, NH), 8.61 (b s, 1H, NH); 13C NMR (100
MHz, CDCl3, 25 °C): δ = 14.6 (q), 14.7 (q), 15.5 (q), 15.6 (q), 53.1 (q), 53.3 (q), 54.1 (q), 54.3
(q), 104.9 (s), 126.0 (s), 127.6 (d), 129.3 (d), 129.6 (s), 134.4 (s), 136.5 (s), 142.2 (s), 153.8 (s),
156.2 (s), 160.9 (s), 163.0 (s), 164.4 (s); IR (nujol): max = 3325, 3239, 1752, 1735, 1718, 1670
cm-1;
HRMS (ESI) m/z [M+H]
+
calcd. o
C20H19ClN5O7
: 476.0973; ound: 476.0973;
MS
m/z (ESI): 476.10 (M + H+); anal. calcd. o C20H18ClN5O7 (475.8392): C 50.48, H 3.81, N
14.72; ound: C 50.59, H 3.82, N 14.65.
Te -bu yl 2-(1-(5-(( e -bu oxyca bonyl)amino)-2-(4-
chlo ophenyl)-4-me hyl-1,3,6- ioxo-2,3,5,6-
e ahyd o1H-py - olo[3,4-c]py idin-7-
yl)e hylidene)hyd azineca boxyla e (26i).
Pale yellow solid; (284.8, 51% yield, pa h B); mp:
171173 °C (dec.); 1H NMR (400 MHz, CDCl3, 25 °C): δ
= 1.49 (s, 18H, 2 C(CH3)3), 2.13 (s, 3H, CH3), 2.82 (s, 3H,
CH3), 7.33 (d, J = 8.8 Hz, 2H, Ph), 7.45 (d, J = 8.8 Hz, 2H, Ph), 7.48 (b s, 1H, NH), 7.86 (s,
1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.5 (q), 14.7 (q), 15.5 (q), 15.7 (q), 27.9
(q), 28.0 (q), 28.2 (q), 28.3 (q), 81.5 (s), 83.9 (s), 104.4 (s), 126.1 (s), 127.8 (d), 127.8 (d), 129.2
(d), 129.3 (d), 129.8 (d), 134.2 (s), 136.1 (s), 141.7 (s), 152.1 (s), 153.7 (s), 154.4 (s), 160.9 (s),
163.2 (s), 164.6 (s); IR (nujol): max = 3328, 3205, 1732, 1718, 1685 cm-1; MS m/z (ESI): 558.30
(M - H+); anal. calcd. o C26H30ClN5O7 (559.9987): C 55.76, H 5.40, N 12.51; ound: C 55.84,
H 5.44, N 12.53.
N
O
O N
NH
O
NNH
O
O
O
O
Cl
N
O
O N
NH
O
NNH
O
O
O
O
Cl
- 95 -
E hyl 3-(bu ylamino)-2-((4-
chlo ophenyl)ca bamo hioyl)bu -2-enoa e 28e.
28e was isola ed by p ecipi a ion in me hanol in 51%
yield. Ligh yellow solid; mp: 8992 °C; 1H NMR (400
MHz, CDCl3, 25 °C): δ = 0.96 ( , 3H, J=7,2 Hz, n-Bu ),
1.31 ( , 3H, J=7,2 Hz, OCH2CH3),1.43-1.70 (m, 4H, n-Bu ), 2.26 (s, 3H, CH3), 3.36 (q, 2H,
J=5,6 Hz, n-Bu ), 4.22 (q, 2H, OCH2CH3), 7.32 (d, 2H, J=8.4 Hz, Ph), 7.49 (d, 2H, J=8.4 Hz,
Ph), 10.86, (b s, 1H, NH), 12.49 (b s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.6
(q), 13.7 (q), 14.2 (q), 14.6 (q), 19.3 ( ), 20.0 ( ), 20.2 ( ), 31.2 (q), 32.4 (q), 42.7 ( ), 43.8 ( ),
58.2 ( ), 60.2 ( ), 81.6 (s), 99.9 (s), 126.5 (d), 126.9 (d), 128.7 (d), 130.0 (d), 131.2 (s), 132.9
(s), 138.0 (s), 161.9 (s), 166.7 (s), 169.9 (s), 170.6 (s), 195.9 (s), 206.9 (s); IR (nujol): max =
3257, 3187, 1632, 1602 cm-1; MS m/z (ESI): 355.03 (M + H+); anal. calcd. o C17H23ClN2O2S
(354.8947): C 57.53, H 6.53, N 7.89; ound: C 57.62, H 6.52, N 7.83.
Isop opyl 3-(bu ylamino)-2-(phenylca bamo hioyl)bu -2-enoa e 28 .
28 was isola ed 1by p ecipi a ion in me hanol in 55% yield.
Ligh yellow solid; mp: 9799 °C; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.75, 1.12, 1.28 (3d, 6H, J=5,2 Hz, J=6,0
Hz, J=6,4 Hz, OCH(CH3)2), 0.94 ( , 3H, J=7,2 Hz, n-Bu ),
1.37-1.69 (m, 4H, n-Bu ), 2.22 and 2.25 (2s, 3H, CH3), 3.23,
3.33 (2q, 2H, J=6,0 Hz, J=6,8 Hz, n-Bu ), 4.75 and 5.09 (2ep,
2H, J=6,4 Hz, J=6,4 Hz, OCH(CH3)2), 7.03-7.54 (m, 5H, Ph), 9.61, 9.69, 10.70, 12.27 (4b s,
2H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.6 (q), 19.7 ( ), 20.2 ( ), 21.9 (q), 31.2 (q),
31.9 (q), 43.1 ( ), 43.7 ( ), 66.4 (d), 67.6 (d), 98.1 (s), 100.4 (s), 121.6 (d), 125.1 (d), 125.5 (d),
126.0 (d), 128.5 (d), 129.0 (d), 139.5 (s), 161.7 (s), 165.5 (s), 165.9 (s), 169.2 (s), 191.2 (s),
201.4 (s); IR (nujol): max = 3255, 3167, 1622, 1612 cm-1; MS m/z (ESI): 344.23 (M + H+);
anal. calcd. o C18H26N2O2S (343.4762): C 64.64, H 7.84, N 8.38; ound: C 64.73, H 7.86, N
8.32.
H
N
OO
S
HN
Cl
H
N
O O
S
HN
- 96 -
Te -bu yl 3-(bu ylamino)-2-((4-
chlo ophenyl)ca bamo hioyl)bu -2-enoa e 28g.
28g was isola ed by p ecipi a ion in me hanol in 75%
yield. Ligh yellow solid; mp: 9294 °C; 1H NMR (400
MHz, CDCl3, 25 °C): δ = 0.94 ( , 3H, J=7,2 Hz, n-Bu ),
1.42-1.70 (m, 4H, n-Bu ), 1.51 (s, 9H, C(CH3) 3), 2.24 (s,
3H, CH3), 3.33 (q, 2H, J=6,8 Hz, n-Bu ), 7.30 (d, 2H,
J=8.4 Hz, Ph), 7.45 (d, 2H, J=8.4 Hz, Ph), 9.47, 9.61, 10.97, (3b s, 2H, NH); 13C NMR (100
MHz, CDCl3, 25 °C): δ = 13.6 (q), 20.2 ( ), 28.4 (q), 31.2 ( ), 43.8 ( ), 81.0 (s), 101.2 (s), 124.4
(s), 124.5 (s), 126.6 (d), 128.6 (d), 131.0 (s), 132.9 (s), 138.1 (s), 166.3 (s), 169.6 (s), 190.0 (s),
(s); IR (nujol): max = 3257, 3191, 1624, 1615 cm-1; MS m/z (ESI): 383.59 (M + H+); anal.
calcd. o C19H27ClN2O2S (382.9479): C 59.59, H 7.11, N 7.32; ound: C 59.67, H 7.08, N 7.37.
Allyl 3-(bu ylamino)-2-(phenylca bamo hioyl)bu -2-
enoa e 28h.
28h was isola ed by p ecipi a ion in me hanol in 40% yield.
Ligh yellow solid; mp: 8890 °C; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.95 ( , 3H, J=7,6 Hz, n-Bu ), 1.37-1.68
(m, 4H, n-Bu ), 2.22 and 2.26 (2s, 3H, CH3), 3.18-3.26, 3.33
(m, q, 2H, J=6,0 Hz, n-Bu ), 4.28-4.67 (m, 2H,
OCH2CH=CH2), 5.06-5.37 (m, 2H, OCH2CH=CH2), 5.62-6.00 (m, 1H, OCH2CH=CH2), 7.02-
7.58 (m, 5H, Ph), 8.54, 9.58, 10.42, 11.88 (4b s, 2H, NH); 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 13.6 ( ), 13.7 (q), 19.3 ( ), 19.4 ( ), 19.9 ( ), 20.2 ( ), 31.3 (q), 32.4 (q), 42.7 ( ), 43.7 ( ), 63.1
( ), 64.7 (d), 81.3 (s), 97.4 (s), 100.2 (s), 116.8 ( ), 118.1 ( ), 122.3 (d), 124.9 (d), 125.7 (d),
126.2 (d), 127.2 (d), 128.6 (d), 129.0 (d), 129.5 (d), 132.4 (s), 133.6 (s), 139.4 (s), 162.0 (s),
162.3 (s), 165.7 (s), 165.7 (s), 168.8 (s), 170.1 (s), 192.2 (s), 192.3 (s),201.5 (s); IR (nujol): max
= 3240, 3141, 1654, 1626 cm-1; MS m/z (ESI): 333.12 (M + H+); anal. calcd. o C18H24N2O2S
(332.4604): C 65, H 7.28, N 8.43; ound: C 64.86, H 7.24, N 8.52.
H
N
O O
S
HN
Cl
H
N
O O
S
HN
- 97 -
Me hyl 3-(bu ylamino)-2-((4-
chlo ophenyl)ca bamo hioyl)pen -2-enoa e 28i.
28i was isola ed by p ecipi a ion in me hanol in 50% yield.
Ligh yellow solid; mp: 102105 °C; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.95 ( , 3H, J=7,2 Hz, n-Bu ), 1.27 ( ,
3H, J=7,2 Hz, CH2CH3),1.47 (sex, 2H, J=7,6 Hz, n-Bu ),1.63-1.70 (m, 2H, n-Bu ), 2.55 (q, 2H,
J=7,2 Hz, CH2CH3), 3.37 (q, 2H, J=6,4 Hz, n-Bu ), 3.74 (s, 3H, OCH3), 7.33 (d, 2H, J=8.4 Hz,
Ph), 7.53 (d, 2H, J=8.4 Hz, Ph), 9.58, 9.63, 10.48, 11.90 (4b s, 2H, NH); 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 12.6 (q), 13.6 (q), 20.0 ( ), 20.1 ( ), 25.2 ( ), 30.8 (q), 31.6 (q), 43.2 ( ), 51.1
(q), 51.2 (q), 99.8 (s), 123.4 (d), 126.1 (d), 126.3 (d), 128.6 (d), 130.0 (s), 131.2 (s), 137.9 (s),
166.6 (s), 169.7 (s), 170.0 (s), 180.5 (s), 199.2 (s), 199.2 (s), 201.5 (s); IR (nujol): max = 3289,
3267, 1654, 1632 cm-1; MS m/z (ESI): 355.58 (M + H+); anal. calcd. o C17H23ClN2O2S
(354.8947): C 57.53, H 6.53, N 7.89; ound: C 57.39, H 6.49, N 8.01.
E hyl 3-(bu ylamino)-2-(phenylca bamo hioyl)pen -2-enoa e 28j (E hyl 3-(bu ylimino)-2-
(phenylca bamo hioyl)pen anoa e 28j’).
28j is in au ome ic equilib ium be ween he enamino j (51%) and he imino j’ o ms. g was
isola ed by p ecipi a ion in me hanol in 76% yield. Ligh yellow solid; mp: 9495 °C; 1H NMR
(400 MHz, CDCl3, 25 °C): δ = 0.92-0.98 (m, 3.3 H), 1.14 ( , 1.4 H, J=7,6 Hz), 1.24-1.33 (m,
4.3 H), 1.39-1.68 (m, 4.4 H), 2.22 (q, 1.0 H, J=7,6 Hz), 2.59 (q, 1.0 H, J=7,6 Hz), 3.20 (q, 0.9
H, J=6,4 Hz), 3.37 (q, 1.1 H, J=6,4 Hz), 4.09 (q, 0.9 H, J=7,2 Hz), 4.21 (q, 0.9 H, J=7,2 Hz),
4.45 (s, 0.4 H), 7.06 (b s, 0.34 H), 7.21-7.57 (m, 4.9 H), 8.57 (b s, 0.34 H), 9.51, 9.67 (b s, 0.18
H), 10.36 (b s, 0.37 H), 11.79 (b s, 0.37 H); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 12.2,
13.7, 13.7, 14.6, 20.0, 20.2, 25.3, 32.4, 42.3, 43.2, 58.2, 60.1, 79.8, 100.2, 124.9, 125.6, 125.7,
125.7, 126.2, 127.2, 128.6, 129.5, 129.5, 129.5, 139.5, 167.1, 171.0, 192.5, 201.7; IR (nujol):
max = 3248, 3135, 1625, 1598 cm-1; MS m/z (ESI): 335.20 (M + H+); anal. calcd. o
C18H26N2O2S (334.4762): C 64.64, H 7.84, N 8.38; ound: C 64.76, H 7.82, N 8.45.
H
N
OO
S
HN
Cl
H
N
OO
S
HN
N
OO
S
HN
- 98 -
E hyl 3-(bu ylamino)-2-(phenylca bamo hioyl)hex-2-
enoa e 28k.
28k was isola ed by p ecipi a ion in me hanol in 45% yield.
Ligh yellow solid; mp: 8891 °C; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.95 ( , 3H, J=7,2 Hz, n-Bu ), 1.01 ( , 3H,
J=7,2 Hz, p op), 1.31 ( , 3H, J=7,2 Hz, OCH2CH3), 1.42-1.52 (m, 2H, p op), 1.56-1.74 (m, 4H,
n-Bu ), 2.51-2.55 (m, 2H, p op), 3.34 (q, 2H, J= 5.6 Hz, n-Bu ), 3.81-3.84, 4.20 (m, and q, 2H,
J=6,8 Hz, OCH2CH3), 7.04-7.57 (m, 5H, Ph), 9.57, 9.71, 10.27, 11.71 (4b s, 2H, NH); 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 13.7 (q), 14.3 (q), 20.2 (q), 21.9 ( ), 31.8 ( ), 33.7 ( ), 43.2 ( ),
60.1 ( ), 97.1 (s), 100.4 (s), 121.6 (s), 124.9 (d), 126.2 (s), 128.6 (d), 129.0 (s), 139.4 (s), 165.7
(s), 166.3 (s), 168.0 (s), 169.5 (s), 192.6 (s), 192.7 (s), 192.8 (s), 201.4 (s); IR (nujol): max =
3282, 3214, 1649, 1616 cm-1; MS m/z (ESI): 349.09 (M + H+); anal. calcd. o C19H28N2O2S
(348.5028): C 65.48, H 8.10, N 8.04; ound: C 65.39, H 8.06, N 8.11.
Benzyl 3-(bu ylamino)-2-(phenylca bamo hioyl)bu -2-
enoa e 28l.
28lwas isola ed by p ecipi a ion in me hanol in 34% yield.
Ligh yellow solid; mp: 120123 °C; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 2.23 and 2.24 (2s, 3H, CH3), 4.42, 4.48 (2d,
2H, J=6,4 Hz, J=6,0 Hz, NCH2Ph), 5.20 (d, 2H, J=4,4 Hz,
OCH2Ph), 7.32-7.40 (m, 14H, Ph), 7.58 (d, 1H, J=7,6 Hz, Ph),
9.87, 9.94, 10.10, 11.50 (4b s, 2H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.8 (q), 18.5
( ), 47.3 ( ), 49.8 ( ), 65.6 ( ), 66.9 ( ), 82.7 (s), 98.5 (s), 101.8 (s), 126.6 (d), 124.3 (d), 126.2
(d), 126.3 (d), 126.9 (d), 127.4 (d), 127.5 (d), 127.8(d), 128.2(d), 128.2(d), 128.3(d), 128.3(d),
128.4(d), 128.5(d), 128.7(d), 128.8(d), 135.1 (s), 136.1 (s), 136.5 (s), 136.7 (s), 137.5 (s), 138.9
(s), 139.1 (s), 161.0 (s), 164.4 (s), 165.9 (s), 166.8 (s), 168.1 (s), 193.7 (s), 200.3 (s), 201.2(s);
IR (nujol): max = 3319, 3193, 1634, 1611 cm-1; MS m/z (ESI): 417.27 (M + H+); anal. calcd.
o C25H24N2O2S (416.5353): C 72.09, H 5.81, N 6.73; ound: C 72.21, H 5.79, N 6.78.
H
N
OO
S
HN
H
N
O O
S
HN
- 99 -
Me hyl 3-(benzylamino)-3-phenyl-2-
(phenylca bamo hioyl)ac yla e 28m.
28m was isola ed by p ecipi a ion in me hanol in 27% yield.
Ligh yellow solid; mp: 110113 °C; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 0.58-0.68, 1.17-1.36 (2m, 3H, OCH2CH3),
3.55-3.68, 4.14-4.20 (2m, 2H, OCH2CH3), 4.22-4.29 (m, 2H, CH2Ph), 7.17-7.99, (m, 15H, Ph,
NHPh, Bn), 11.73 (b s, H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.0 (q), 14.0 (q),
14.5 (q), 45.8 ( ), 48.2 ( ), 48.7 ( ), 60.0 ( ), 60.1 ( ), 61.3 ( ), 100.8 (s), 100.9 (s), 125.4 (d),
125.9 (d), 126.7 (d), 127.0 (d), 127.0 (d), 127.0 (d), 127.3 (d), 127.3 (d), 127.7 (d), 128.2 (d),
128.3 (d), 128.5 (d), 128.9 (d), 129.2 (d), 133.6 (s), 136.3 (s), 137.2 (s), 139.1 (s), 167.3 (s),
168.3 (s), 170.1 (s), 170.8 (s), 188.4 (s), 192.3 (s), 199.7 (s); IR (nujol): max = 3317, 3298,
1679, 1645 cm-1; MS m/z (ESI): 403.28 (M + H+); anal. calcd. o C24H22N2O2S (402.5087): C
71.62, H 5.51, N 6.96; ound: C 71.51, H 5.48, N 7.04.
One-po p ocedu e o syn hesis o 2,5-dihyd o hiophenes 29a-x.
Alkyl amines 31a,b (0.5 mmol) we e added o -ke oes e s 30a-i (0.55 mmol) o o e hyl
phenylp opiola e 33a (0.55mmol) unde sol en - ee condi ions a oom empe a u e and
igo ously s i ed a oom empe a u e. A e 0.5 h a yl iso hiocyana es 34a-c (0.5mmol) in
MeOH (1.5 mL) we e added and he eac ions we e s i ed un il he disappea ance o he
enamino es e s 32 (6-18h moni o ed by TLC). DDs 1a-j (1.0 mmol) in MeOH (1.5mL) we e
added o he eac ion medium and magne ically s i ed un il he comple e disappea ance o he
ACTs 28a-m (3.0-5.0 h moni o ed by TLC). Then, he eac ion sol en was e apo a ed unde
educed p essu e and he desi ed 2,5-dihyd o hiophenes 29a-x we e pu i ied by
ch oma og aphy on silica gel column (elu ion mix u e: cyclohexane: e hyl ace a e).
H
N
OO
S
HN
- 100 -
Dime hyl 2-(1-(2- e bu oxyca bonyl)hyd azono)e hyl)-3-
me hyl-5-(phenylimino)-2,5-dihyd o hiophene-2,4-
dica boxyla e 29a.
29a was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 78% yield. Pale yellow solid; mp:
151153 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.50 (s, 9H, C(CH3)3), 1.83 (s, 3H, CH3),
2.24 (s, 3H, CH3), 3.80 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 7.04(d, 2H, J = 8.0 Hz, Ph), 7.15 ( ,
1H, J = 7.2 Hz, Ph), 7.35 ( , 2H, J = 7.6 Hz, Ph), 7.85 (s, 1H, NH); 13C NMR (100 MHz, CDCl3,
25 °C): δ = 12.3 (q), 16.2 (q), 28.2 (q), 52.7 (q), 64.4 (q), 75.1 (s), 81.7 (s), 120.1 (d), 125.2 (d),
129.1 (d), 136.0 (s), 144.6 (s), 150.7 (s), 152.2 (s), 157.7 (s), 163.8 (s), 164.2 (s), 168.1 (s); IR
(nujol): max = 3231, 1740, 1698, 1629 cm-1; MS m/z (ESI): 462.30 (M + H+); anal. calcd. o
C22H27N3O6S (461.5313): C 57.25, H 5.90, N 9.10; ound: C 57.16, H 5.87, N 9.16.
4-E hyl-2-me hyl 2-(1-(2-
e bu oxyca bonyl)hyd azono)e hyl)-3-me hyl-5-
(phenylimino)-2,5-dihyd o hiophene-2,4-dica boxyla e
29b.
29b was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 83% yield. Pale yellow solid; mp: 136139 °C; 1H NMR (400 MHz,
DMSOd6, 25 °C): δ = 1.30 ( , 3H, J = 7.2 Hz OCH2CH3), 1.45 (s, 9H, C(CH3)3), 1.84 (s, 3H,
CH3), 2.13 (s, 3H, CH3), 3.73 (s, 3H, OCH3), 4.33 (q, 2H, J = 7.2 Hz, OCH2CH3), 6.97 (d, 2H,
J = 7.2 Hz, Ph), 7.18 ( , 1H, J = 7.6 Hz, Ph), 7.40 ( , 2H, J = 7.6 Hz, Ph), 9.88 (s, 1H, NH); 13C
NMR (100 MHz, DMSOd6, 25 °C): δ = 13.4 (q), 13.9 (q), 15.4 (q), 27.9 (q), 53.4 (q), 61.4 ( ),
75.4 (s), 79.7 (s), 119.6 (d), 125.2 (d), 129.3 (d), 135.7 (s), 145.9 (s), 150.2 (s), 152.6 (s), 156.5
(s), 163.1 (s), 163.2 (s), 167.8 (s); IR (nujol): max = 3227, 1739, 1695, 1636 cm-1; MS m/z
(ESI): 476.29 (M + H+); anal. calcd. o C23H29N3O6S (475.5579): C 58.09, H 6.15, N 8.84;
ound: C 58.21, H 6.17, N 8.70.
S
O
O
N
O
O
N
NH
O
O
S
O
O
N
O
O
N
NH
O
O
- 101 -
4-E hyl-2-me hyl 2-(1-(2-
e bu oxyca bonyl)hyd azono)e hyl)-5-(phenylimino)-3-
p opyl--2,5-dihyd o hiophene-2,4-dica boxyla e 29c.
29c was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 58% yield. Pale yellow solid; mp:
142144 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ = 0.95 ( ,
3H, J = 7.2 Hz CH2CH2CH3), 1.39 ( , 3H, J = 7.2 Hz OCH2CH3), 1.51 (s, 9H, C(CH3)3), 1.46-
1.60 (m, 2H, CH2CH2CH3), 1.83 (s, 3H, CH3), 2.54-2.68 (m, 2H, CH2CH2CH3), 3.80 (s, 3H,
OCH3), 4.41 (q, 2H, J = 7.2 Hz, OCH2CH3), 7.04 (dd, 2H, J = 8.8 Hz, J = 1.2 Hz, Ph), 7.14 ( ,
1H, J = 7.2 Hz, Ph), 7.35 ( , 2H, J = 7.6 Hz, Ph), 7.72 (s, 1H, NH); 13C NMR (100 MHz,
DMSOd6, 25 °C): δ = 12.7 (q), 14.1 (q), 14.7 (q), 22.2 ( ), 28.2 (q), 32.1 ( ), 53.3 (q), 53.4 (q),
61.8 ( ), 75.4 (s), 81.7 (s), 120.2 (d), 125.1 (d), 129.1 (d), 136.7 (s), 145.0 (s), 150.9 (s), 152.3
(s), 160.1 (s), 164.0 (s), 164.2 (s), 168.4 (s); IR (nujol): max = 3237, 1745, 1695, 1636 cm-1;
MS m/z (ESI): 504.45 (M + H+); anal. calcd. o C25H33N3O6S (503.6110): C 59.62, H 6.60, N
8.34; ound: C 59.49, H 6.56, N 8.48.
2-E hyl-4-me hyl 2-(1-(2( e -
bu oxyca bonyl)hyd azono)e hyl)-3-me hyl-5-
(phenylimino)-2,5-dihyd o hiophene-2,4-dica boxyla e 29d.
29d was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 88 % yield. Pale yellow solid; mp:
152156 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.27 ( ,
3H, J = 7.2 Hz OCH2CH3), 1.47 (s, 9H, C(CH3)3), 1.82 (s, 3H, CH3), 2.22 (s, 3H, CH3), 3.89
(s, 3H, OCH3), 4.23 (q, 2H, J = 7.2 Hz, OCH2CH3), 7.01 (dd, 2H, J = 8.4 Hz, J = 1.2 Hz, Ph),
7.11 ( , 1H, J = 7.6 Hz Ph), 7.32 ( , 2H, J = 8.4 Hz, Ph), 8.35 (b s, 1H, NH); 13C NMR (100
MHz, CDCl3, 25 °C): δ = 12.5 (q), 12.6 (q), 13.8 (q), 16.1 (q), 16.1 (q), 28.0 (q), 52.4 (q), .52.5
(q), 62.6 ( ), 75.1 (s), 81.3 (s), 119.9 (d), 125.0 (d), 129.0 (d), 135.7 (s), 135.7 (s), 144.8 (s),
150.8 (s), 152.8 (s), 157.8 (s), 157.9 (s), 163.8 (s), 163.9 (s), 164.1 (s), 167.5 (s); IR (nujol):
max = 3254, 1713, 1676, 1628 cm-1; MS m/z (ESI): 476.38 (M + H+); anal. calcd. o
C23H29N3O6S (475.5579): C 58.09, H 6.15, N 8.84; ound: C 57.95, H 6.11, N 8.98.
SO
O
N
O
O
N
NH
O
O
S
O
O
N
O
O
N
NH
O
O
- 102 -
Die hyl 2-(1-(2( e -bu oxyca bonyl)hyd azono)e hyl)-3-
me hyl-5-(phenylimino)-2,5-dihyd o hiophene-2,4-
dica boxyla e 29e.
29e was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 79 % yield. Pale yellow solid; mp:
136139 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.31 ( ,
3H, J = 7.2 Hz OCH2CH3), 1.39 ( , 3H, J = 7.2 Hz OCH2CH3), 1.51 (s, 9H, C(CH3)3), 1.83 (s,
3H, CH3), 2.25 (s, 3H, CH3), 4.27 (q, 2H, J = 7.2 Hz, OCH2CH3), 4.42 (q, 2H, J = 7.2 Hz,
OCH2CH3), 7.06 (d, 2H, J = 8.4 Hz, Ph), 7.15 ( , 1H, J = 7.6 Hz Ph), 7.36 ( , 2H, J = 8.0 Hz,
Ph), 7.64 (b s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 12.4 (q), 14.0 (q), 14.2 (q),
16.0 (q), 28.2 (q), 61.7 ( ), .62.7 ( ), 75.2 (s), 81.6 (s), 120.19 (d), 125.1 (d), 129.1 (d), 136.3
(s), 144.9 (s), 150.9 (s), 152.5 (s), 156.9 (s), 163.7 (s), 163.9 (s), 167.6 (s); IR (nujol): max =
3230,1731,1693,1622 cm-1; MS m/z (ESI): 490.29 (M + H+); anal. calcd. o C24H31N3O6S
(489.5844): C 58.88, H 6.38, N 8.58; ound: C 58.76, H 6.35, N 8.61.
2-E hyl-4-me hyl 2-(1-(2( e -
bu oxyca bonyl)hyd azono)e hyl)-5-((4-
chlo ophenyl)imino)-3-e hyl-2,5-dihyd o hiophene-2,4-
dica boxyla e 29 .
29 was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 63 % yield. Pale yellow solid; mp:
107109 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.10 ( , 3H, J = 7.6 Hz CH2CH3), 1.30 ( ,
3H, J = 7.2 Hz OCH2CH3), 1.49 (s, 9H, C(CH3)3), 1.84 (s, 3H, CH3), 2.63-2.70 (m, 2H,
CH2CH3), 3.92 (s, 3H, OCH3), 4.22-4.29 (m, 2H, OCH2CH3), 6.97 (d, 2H, J = 8.8 Hz, Ph), 7.30
(d, 2H, J = 8.8 Hz Ph), 8.01 (b s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 12.9 (q),
13.0 (q), 13.9 (q), 22.4 ( ), 28.2 (q), 52.7 (q), 62.8 ( ), 75.8 (s), 81.6 (s), 121.6 (d), 129.2 (d),
130.3 (s), 135.8 (s), 144.8 (s), 149.3 (s), 152.6 (s), 162.9 (s), 164.5 (s), 165.2 (s), 167.6 (s); IR
(nujol): max = 3223,1717,1684,1621 cm-1; MS m/z (ESI): 524.81 (M + H+); anal. calcd. o
C24H30ClN3O6S (524.0295): C 55.01, H 6.77, N 8.02; ound: C 54.95, H 6.79, N 8.15.
S
O
O
N
O
O
N
NH
O
O
S
O
O
N
O
O
NNH
OO
Cl
- 103 -
4-Te -bu yl 2-e hyl 2-((1-(2( e -
bu oxyca bonyl)hyd azono)e hyl)-5-((4-
chlo ophenyl)imino)--3-me hyl-2,5-dihyd o hiophene-
2,4-dica boxyla e 29g.
29g was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 81 % yield. Pale yellow solid; mp:
120124 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.28 ( , 3H, J = 7.2 Hz OCH2CH3), 1.47
(s, 9H, C(CH3)3), 1.56 (s, 9H, C(CH3)3), 1.81 (s, 3H, CH3), 2.20 (s, 3H, CH3), 4.23 (q, 2H, J =
7.2 Hz OCH2CH3), 6.96 (d, 2H, J = 8.8 Hz, Ph), 7.27 (d, 2H, J = 8.8 Hz Ph), 8.46 (b s, 1H,
NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 12.4 (q), 13.9 (q), 15.8 (q), 28.1 (q), 62.6 ( ),
75.4 (s), 81.4 (s), 83.0 (s), 121.4 (d), 129.9 (d), 130.1 (d), 137.1 (s), 144.8 (s), 149.3 (s), 152.7
(s), 155.9 (s), 162.8 (s), 164.4 (s), 167.5 (s); IR (nujol): max = 3255,1736,1685,1624 cm-1; MS
m/z (ESI): 553.04 (M + H+); anal. calcd. o C26H34ClN3O6S (552.1890): C 56.56, H 6.21, N
7.61; ound: C 56.68, H 6.24, N 7.51.
4-Benzyl-2-e hyl 2-(1-(2-
e bu oxyca bonyl)hyd azono)e hyl)-3-me hyl-5-
(phenylimino)-2,5-dihyd o hiophene-2,4-
dica boxyla e 29h.
29h was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 65% yield. Pale yellow solid;
mp: 109113 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.30 ( , 3H, J = 7.2 Hz OCH2CH3),
1.49 (s, 9H, C(CH3)3), 1.82 (s, 3H, CH3), 2.21 (s, 3H, CH3), 4.26 (q, 2H, J = 7.2 Hz, OCH2CH3),
5.39 (s, 2H, OCH2Ph), 7.06 (dd, 2H, J = 8.4 Hz, J = 1.2 Hz, Ph), 7.16 ( , 1H, J = 7.6 Hz, Ph),
7.34-7.39 (m, 5H, Ph), 7.48 (dd, 2H, J = 8.0 Hz, J = 1.6 Hz, Ph), 7.88 (s, 1H, NH); 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 12.4 (q), 14.0 (q), 16.1 (q), 28.2 (q), 62.7 ( ), 67.4 ( ), 75.3 (s),
81.6 (s), 120.1 (d), 125.1 (d), 128.3 (d), 128.3 (d), 128.5 (d), 129.1 (d), 135.3 (s), 135.9 (s),
144.7 (s), 150.7 (s), 152.3 (s), 157.6 (s), 163.5 (s), 163.7 (s), 167.55 (s); IR (nujol): max =
3255,1751,1681,1643 cm-1; MS m/z (ESI): 552.37 (M + H+); anal. calcd. o C29H33N3O6S
(551.6538): C 63.14, H 6.03, N 7.62; ound: C 63.02, H 6.00, N 7.74.
S
O
O
N
O
O
NNH
O
O
Cl
S
O
O
N
O
O
N
NH
O
O
- 104 -
Die hyl-2-me hyl 2-(1-(2( e -
bu oxyca bonyl)hyd azono)e hyl)-3-phenyl-5-
(phenylimino)-2,5-dihyd o hiophene-2,4-dica boxyla e 29i.
29i was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 58 % yield. Pale yellow solid; mp:
105110 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.00 ( ,
3H, J = 7.2 Hz OCH2CH3), 1.14 ( , 3H, J = 7.2 Hz OCH2CH3), 1.49 (s, 9H, C(CH3)3), 1.88 (s,
3H, CH3), 4.10-4.18 (m, 4H, 2 OCH2CH3), 7.01-7.18 (m, 3H, Ph), 7.30-7.39 (m, 5H, Ph), 7.42-
7.44 (m, 2H, Ph), 7.92 (b s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.6 (q), 13.7
(q), 13.8 (q), 28.1 (q), 28.2 (q), 61.6 ( ), 62.7 ( ), 76.1 (s), 81.6 (s), 120.2 (d), 120.3 (d), 125.3
(d), 125.4 (d), 127.9 (d), 129.1 (d), 129.1 (d), 133.4 (s), 139.0 (s), 144.7 (s), 150.7 (s), 152.5
(s), 156.0 (s), 163.3 (s), 163.7 (s), 167.5 (s); IR (nujol): max = 3236,1747,1698,1623 cm-1; MS
m/z (ESI): 552.42 (M + H+); anal. calcd. o C29H33N3O6S (551.6538): C 63.14, H 6.03, N 7.62;
ound: C 63.01, H 5.99, N 7.78.
Dime hyl 2-(1-(2- e bu oxyca bonyl)hyd azono)p opyl)-3-
me hyl-5-(phenylimino)-2,5-dihyd o hiophene-2,4-
dica boxyla e 29j.
29j was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 78% yield. Pale yellow solid; mp:
120124 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ = 0.96 ( , 3H, J = 7.6 Hz OCH2CH3),
1.45 (s, 9H, C(CH3)3), 2.11 (s, 3H, CH3), 2.44 (q, 2H, J = 7.6 Hz OCH2CH3), 3.71 (s, 3H,
OCH3), 3.85 (s, 3H, OCH3), 6.97(dd, 2H, J = 8.4 Hz, J = 0.8 Hz, Ph), 7.19 ( , 1H, J = 7.2 Hz,
Ph), 7.41 ( , 2H, J = 7.6 Hz, Ph), 10.09 (s, 1H, NH); 13C NMR (100 MHz, DMSOd6, 25 °C): δ
= 10.5 (q), 15.8 (q), 19.8 ( ), 28.0 (q), 52.7 (q), 53.4 (q), 75.3 (s), 79.9 (s), 119.6 (d), 125.3 (d),
129.5 (d), 135.6 (s), 140.8 (s), 150.4 (s), 152.6 (s), 157.2 (s), 163.4 (s), 163.7 (s), 167.9 (s); IR
(nujol): max = 3220,1749,1715,1654 cm-1; MS m/z (ESI): 476.29 (M + H+); anal. calcd. o
C22H27N3O6S (475.5579): C 58.09, H 6.15, N 8.84; ound: C 57.96, H 6.12, N 8.96.
S
O
O
N
O
O
N
NH
O
O
S
O
O
N
O
O
N
NH
O
O
- 111 -
4-E hyl 2-me hyl 5-((4-me hoxyphenyl)imino)-3me hyl-
1-(2-(phenylca bamoyl)hyd azono)e hyl)-2,5-
dihyd o hiophene-2,4-dica boxyla e 29w.
29w was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 60 % yield. Pale yellow solid; mp:
133139 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.34
( , 3H, J = 7.2 Hz OCH2CH3), 2.01 (s, 3H, CH3), 2.23 (s,
3H, CH3), 3.81 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 4.26-4.39 (q, 2H, J = 7.2 Hz OCH2CH3),
6.91 (d, 2H, J = 8.8 Hz, Ph), 7.06-7.11 (m, 3H, Ph), 7.33 ( , 2H, J = 7.6 Hz, Ph), 7.45 (dd, 2H,
J = 8.8 Hz, J = 1.2 Hz, Ph), 7.98 (s, 1H, NH), 9.29 (s, 1H, NH); 13C NMR (100 MHz, CDCl3,
25 °C): δ = 13.2 (q), 14.1 (q), 15.8 (q), 52.8 (q), 55.4 (q), 62.8 ( ), 75.4 (s), 114.3 (d), 119.1 (d),
121.9 (d), 123.6 (d), 129.1 (d), 136.8 (s), 137.7 (d), 143.5 (s), 144.6 (s), 153.4 (s), 155.4 (s),
157.4 (s), 162.0 (s), 164.3 (s), 167.8 (s); IR (nujol): max = 3349, 3208, 1733, 1675, 1649 cm-
1; MS m/z (ESI): 524.79 (M + H+); anal. calcd. o C26H28N4O6S (524.1730): C 59.53, H 5.38,
N 10.68; ound: C 59.38, H 5.34, N 10.79.
E hyl 5-(dime hylca bamoyl)-4-me hyl-5-(-1-
(2(phenylca bamoyl)hyd azono)e hyl)-2-(phenylimino)-
2,5-dihyd o hiophene-3-ca boxyla e 29x
29x was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 77 % yield. Pale yellow solid; mp:
125131 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.39 ( ,
3H, J = 7.2 Hz, OCH2CH3), 2.04 (s, 3H, CH3), 2.23 (s, 3H, CH3), 2.81 (s, 3H, NCH3), 3.05 (s,
3H, NCH3), 4.42 (q, 2H, J = 7.2 Hz, OCH2CH3),7.05 (d, 2H, J = 7.6 Hz, Ph), 7.10 ( , 1H, J =
7.2 Hz, Ph), 7.17 ( , 1H, J = 7.2 Hz, Ph), 7.32-7.40 (m, 4H, Ph), 7.43 (d, 2H, J = 7.6 Hz, Ph),
8.01 (s, 1H, NH), 9.48 (s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.3 (q), 14.2 (q),
16.6 (q), 36.8 (q), .39.0 (q), 61.9 ( ), 73.8 (s), 119.0 (d), 120.1 (d), 123.7 (d), 125.3 (d), 129.2
(d), 129.2 (d), 135.6 (s), 137.5 (s), 144.7 (s), 150.8 (s), 153.4 (s), 159.2 (s), 163.0 (s), 163.8 (s),
167.2 (s); IR (nujol): max = 3374, 3239, 1754, 1636, 1625 cm-1; MS m/z (ESI): 507.72 (M +
H+); anal. calcd. o C26H29N5O4S (507.1940): C 61.52, H 5.76, N 13.80; ound: C 61.64, H
5.79, N 13.72.
SO
O
N
O
O
N
NH
O
N
H
O
SO
O
N
O
N
NNH
O
N
H
- 112 -
Gene al p ocedu e o syn hesis o 5-amino hiophene-2,4-dica boxyla es 9a-i.
To a solu ion o 2,5-dihyd o hiophenes 29a-c,e-g,l,m, , (0.5 mmol) in ace one/wa e (90/10,
5.0mL) we e added Ambe lys 15 H (4 equi ) and he eac ion mix u e was so ly s i ed a
oom empe a u e. A he disappea ance o he s a ing 2,5-dihyd o hiophenes 29 (2.0-4.0 h
moni o ed by TLC) he eac ion sol en was e apo a ed unde educed p essu e and he desi ed
2,5-5-amino hiophene-2,4-dica boxyla es 35a-j we e pu i ied by ch oma og aphy on silica gel
column (elu ion mix u e: cyclohexane: e hyl ace a e).
Dime hyl 3-me hyl-5-(phenylamino) hiophene-2,4-dica boxyla e
35a.
35a was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 82% yield. Whi e solid; mp: 135137 °C; 1H
NMR (400 MHz, CDCl3, 25 °C): δ = 2.75 (s, 3H, CH3), 3.81 (s, 3H,
OCH3), 3.90 (s, 3H, OCH3), 7.15 ( , 1H, J = 7.2 Hz, Ph), 7.34 (d, 2H,
J = 7.6 Hz, Ph), 7.40 ( , 2H, J = 7.2 Hz, Ph), 10.58 (s, 1H, NH); 13C NMR (100 MHz, CDCl3,
25 °C): δ = 15.9 (q), 51.3 (q), 51.5 (q), 108.2 (s), 109.0 (s), 120.0 (d), 124.4 (d), 129.6 (d), 139.8
(s), 147.7 (s), 162.6 (s), 163.1 (s), 167.3 (s); IR (nujol): max = 3225, 1700, 1662 cm-1; MS m/z
(ESI): 306.09 (M + H+); anal. calcd. o C15H15NO4S (305.3489): C 59.00, H 4.95, N 4.95;
ound: C 58.88, H 4.92, N 4.99.
4-E hyl-2-me hyl 3-me hyl-5-(phenylamino) hiophene-2,4-
dica boxyla e 35b.
35b was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 80% yield. Whi e solid; mp: 136139 °C;
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.42 ( , 3H, J = 7.2 Hz
OCH2CH3), 2.77 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 4.36 (q, 2H, J =
7.2 Hz, OCH2CH3), 7.15 ( , 1H, J = 7.2 Hz, Ph), 7.33-7.42 (m, 4H, Ph), 10.62 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 14.3 (q), 16.0 (q), 51.5 (q), 60.4 ( ), 108.1 (s), 109.2 (s),
119.9 (d), 124.3 (d), 129.6 (d), 139.8 (s), 147.8 (s), 162.4 (s), 163.2 (s), 166.9 (s); IR (nujol):
max = 3217, 1714, 1650 cm-1; MS m/z (ESI): 320.04 (M + H+); anal. calcd. o C16H17NO4S
(319.3755): C 60.17, H 5.37, N 4.39; ound: C 60.26, H 5.39, N 4.32.
S
O
O
O
ONH
S
O
O
O
O
NH
- 113 -
4-E hyl 2-me hyl 5-((4-chlo ophenyl)amino) 3-
me hyl hiophene-2,4-dica boxyla e 35c.
35c was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 82% yield. Whi e solid; mp: 140141 °C;
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.42 ( , 3H, J = 7.6 Hz
OCH2CH3), 2.77 (s, 3H, CH3), 3.82 (s, 3H, O CH3), 4.37 (q, 2H, J =
7.6 Hz, OCH2CH3), 7.28 (d, 2H, J = 9.6 Hz, Ph), 7.36 (d, 2H, J = 9.6
Hz, Ph), 10.62 (s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.3 (q), 16.0 (q), 51.6
(q), 60.6 ( ), 108.6 (s), 109.6 (s), 121.2 (d), 129.4 (s), 129.6 (d), 138.4 (s), 147.8 (s), 162.0 (s),
163.1 (s), 166.9 (s); IR (nujol): max = 3160, 1704, 1652 cm-1; MS m/z (ESI): 354.55 (M + H+);
anal. calcd. o C16H16ClNO4S (353.8205): C 54.31, H 4.56, N 3.96; ound: C 54.42, H 4.58, N
3.88.
2-E hyl-4-me hyl 3-me hyl-5-(phenylamino) hiophene-2,4-
dica boxyla e 35d.
35d was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 78% yield. Whi e solid; mp: 128131
°C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.35 ( , 3H, J = 7.2
Hz OCH2CH3), 2.76 (s, 3H, CH3), 3.91 (s, 3H, OCH3), 4.29 (q, 2H, J = 7.2 Hz, OCH2CH3),
7.16 ( , 1H, J = 7.2 Hz, Ph), 7.35-7.44 (m, 4H, Ph), 10.55 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 14.4 (q), 15.9 (q), 51.3 (q), 60.5 ( ), 108.8 (s), 109.1 (s), 120.1 (d), 124.5
(d), 129.6 (d), 139.9 (s), 147.4 (s), 162.6 (s), 162.8 (s), 167.4 (s); IR (nujol): max = 3163, 1698,
1667 cm-1; MS m/z (ESI): 320.05 (M + H+); anal. calcd. o C16H17NO4S (319.3755): C 60.17,
H 5.37, N 4.39; ound: C 60.05, H 5.34, N 4.43.
Die hyl 3-me hyl-5-(phenylamino) hiophene-2,4-
dica boxyla e 35e.
35e was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 78% yield. Whi e solid; mp: 106111
°C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.34 ( , 3H, J = 7.2
Hz OCH2CH3), 1.41 ( , 3H, J = 7.2 Hz OCH2CH3), 2.76 (s, 3H, CH3), 4.28 (q, 2H, J = 7.2 Hz,
OCH2CH3), 4.35 (q, 2H, J = 7.2 Hz, OCH2CH3), 7.12-7.41 (m, 5H, Ph), 10.62 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 14.0 (q), 14.2 (q), 15.7 (q), 60.2 ( ), 108.4 (s), 108.9 (s),
119.6 (d), 124.0 (d), 129.3 (d), 139.6 (s), 147.2 (s), 162.0 (s), 162.6 (s), 166.1 (s); IR (nujol):
max = 3224, 1693, 1655 cm-1; MS m/z (ESI): 334.07 (M + H+); anal. calcd. o C17H19NO4S
(333.4021): C 61.24, H 5.74, N 4.20; ound: C 61.39, H 5.79, N 4.12.
S
O
O
O
O
NH
Cl
S
OO
O
O
NH
S
OO
O
O
NH
- 114 -
2-E hyl 4-me hyl 5-((4-chlo ophenyl)amino) 3-e hyl hiophene-
2,4-dica boxyla e 35 .
35 was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 78% yield. Whi e solid; mp: 149151 °C;
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.19 ( , 3H, J = 7.6 Hz
CH2CH3), 1.35 ( , 3H, J = 7.2 Hz OCH2CH3), 3.31 (q, 2H, J = 7.2
Hz, CH2CH3), 3.91 (s, 3H, O CH3), 4.30 (q, 2H, J = 7.2 Hz, OCH2CH3), 7.30 (d, 2H, J = 8.8
Hz, Ph), 7.37 (d, 2H, J = 8.8 Hz, Ph), 10.58 (s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C):
δ = 14.4 (q), 14.8 (q), 22.3 ( ), 51.5 (q), 60.6 ( ), 108.5 (s), 108.8 (s), 121.4 (d), 129.5 (s), 129.7
(d), 138.5 (s), 153.7 (s), 162.3 (s), 162.6 (s), 167.1 (s); IR (nujol): max = 3223, 1696, 1664 cm-
1; MS m/z (ESI): 368.42 (M + H+); anal. calcd. o C17H18ClNO4S (367.8471): C 55.51, H 4.93,
N 3.81; ound: C 55.40, H 4.95, N 3.86.
4-Benzyl 2-E hyl 3-me hyl-5-(phenylamino) hiophene-2,4-
dica boxyla e 35g.
35g was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 81% yield. Whi e solid; mp: 117119
°C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.34 ( , 3H, J =
7.2 Hz OCH2CH3), 2.77 (s, 3H, CH3), 4.28 (q, 2H, J = 7.2 Hz,
OCH2CH3), 5.38 (s, 2H, OCH2Ph), 7.16 ( , 1H, J = 7.2 Hz, Ph), 7.33-7.46 (m, 9H, Ph), 10.54
(s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.4 (q), 16.2 (q), 60.5 ( ), 66.2 ( ), 108.8
(s), 108.9 (s), 120.2 (d), 124.5 (d), 128.1 (d), 128.3 (d), 128.7 (d), 129.6 (d), 135.9 (s), 139.8
(s), 147.4 (s), 162.8 (s), 166.6 (s); IR (nujol): max = 3242, 1701, 1648 cm-1; MS m/z (ESI):
395.98 (M + H+); anal. calcd. o C22H21NO4S (395.4714): C 66.82, H 5.35, N 3.54; ound: C
66.95, H 5.38, N 3.59.
4-Allyl 2- e -bu yl 3-me hyl-5-(phenylamino) hiophene-2,4-
dica boxyla e 35h.
35h was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 70% yield. Whi e solid; mp: 7779 °C;
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.56 (s, 9H, OC(CH3)3),
2.75 (s, 3H, CH3), 4.82 (d, 2H, J = 5.2 Hz, OCH2CH=CH2), 5.31 (dd, 1H, J = 10.4 Hz, J = 0.8
Hz, OCH2CH=CH2), 5.42 (dd, 1H, J = 17.2 Hz, J = 1.2 Hz, OCH2CH=CH2), 6.00-6.10 (m, 1H,
OCH2CH=CH2), 7.15 ( , 1H, J = 7.2 Hz, Ph), 7.34-7.42 (m, 4H, Ph), 10.54 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 15.9 (q), 28.4 (q), 65.0 (s), 81.3 (s), 108.9 (s), 110.6 (s),
118.2 ( ), 120.0 (d), 124.3 (d), 129.6 (d), 132. 2 (s), 139.9 (s), 146.2 (s), 162.3 (s), 162.3 (s),
S
OO
O
O
NH
Cl
S
O
O
O
O
NH
S
OO
O
O
NH
- 115 -
166.6 (s); IR (nujol): max = 3188, 1704, 1664 cm-1; MS m/z (ESI): 374.08 (M + H+); anal. calcd.
o C20H23NO4S (373.4659): C 64.32, H 6.21, N 3.75; ound: C 64.39, H 6.22, N 3.75.
2-Benzyl 4-me hyl 3-me hyl-5-
(phenylamino) hiophene-2,4-dica boxyla e 35i.
35i was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 81% yield. Whi e solid; mp:
116118 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 2.78
(s, 3H, CH3), 3.91 (s, 3H, OCH3), 5.29 (s, 2H, OCH2Ph), 7.16 ( , 1H, J = 7.2 Hz, Ph), 7.34-7.43
(m, 9H, Ph), 10.59 (s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.0 (q), 51.4 (q),
66.0 ( ), 108.2 (s), 109.2 (s), 120.1 (d), 124.5 (d), 128.0 (d), 128.1 (d), 128.5 (d), 129.6 (d),
136.2 (s), 139.8 (s), 148.1 (s), 162.6 (s), 162.8 (s), 167.3 (s); IR (nujol): max = 3221, 1695,
1666 cm-1; MS m/z (ESI): 382.04 (M + H+); anal. calcd. o C21H19NO4S (381.4449): C 66.12,
H 5.02, N 3.67; ound: C 65.98, H 4.98, N 3.72.
4-Allyl 2-e hyl 3-me hyl-5-(phenylamino) hiophene-2,4-
dica boxyla e 35j.
35j was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 67% yield. Whi e solid; mp: 7073 °C;
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.35 ( , 3H, J = 7.2 Hz
OCH2CH3), 2.79 (s, 3H, CH3), 4.29 (q, 2H, J = 7.2 Hz,
OCH2CH3), 4.83 (d , 2H, J = 5.6 Hz, J = 1.2 Hz, OCH2CH=CH2), 5.31 (dd, 1H, J = 10.4 Hz, J
= 1.2 Hz, OCH2CH=CH2), 5.46 (dd, 1H, J = 17.2 Hz, J = 1.2 Hz, OCH2CH=CH2), 6.00-6.10
(m, 1H, OCH2CH=CH2), 7.16 ( , 1H, J = 7.2 Hz, Ph), 7.34-7.43 (m, 4H, Ph), 10.56(s, 1H, NH);
13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.4 (q), 16.1 (q), 60.5 ( ), 65.1 ( ), 108.8 (s), 108.9
(s), 118.4 ( ), 120.1 (d), 124.5 (d), 129.6 (d), 132.2 (d), 139.8 (s), 147.4 (s), 162.7 (s), 162.8 (s),
166.5 (s); IR (nujol): max = 3283, 1708, 1663 cm-1; MS m/z (ESI): 346.11 (M + H+); anal. calcd.
o C18H19NO4S (345.4128): C 62.59, H 5.54, N 4.06; ound: C 62.46, H 5.51, N 4.12.
S
OO
O
O
NH
S
O
O
O
O
NH
- 116 -
Gene al p ocedu e o he syn hesis o
2-a ylamino 5-hyd azono hiophene-3
ca boxyla es 41a-g by basic ea men o DHT 29.
To a solu ion o 2,5-dihyd o hiophenes
29a,b,d- ,h,j,m,n
(0.5 mmol) in THF (5.0mL)
NaH ( 2.0 equi .) we e added and he eac ion mix u e was so ly s i ed a oom
empe a u e. A he disappea ance o he s a ing 2,5-dihyd o hiophenes
29
(3.0-5.0 h
moni o ed by TLC) he eac ion sol en was e apo a ed unde educed p essu e and he desi ed
2-a ylamino 5-hyd azono hiophene-3 ca boxyla es 41a-g
we e pu i ied by ch oma og aphy on
silica gel column (elu ion mix u e: cyclohexane: e hyl ace a e).
Te -bu yl 2-(1-(4-(me hoxyca bonyl)-3-me hyl-5-
(phenylamino) hiophen-2-
yl)e hylidene)hyd azineca boxyla e 41a.
41a was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 71% yield. Pale yellow solid; mp:
123125 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.49 and
1.52 (b s and s, 9H, OC(CH3) 3), 2.16 and 2.48 (2s, 3H, CH3), 2.19 and 2.23 (2s, 3H, CH3), 3.86
and 3.88 (2s, 3H, OCH3), 7.04-7.14 (m, 1H, Ph), 7.27-7.39 (m, 4H, Ph), 7.73 and 7.83 (2b s,
1H, NH), 10.28 and 10.35 (2s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 16.6 (q), 16.8
(q), 25.4 (q), 28.2 (s), 28.3 (s), 51.1 (q), 51.3 (q), 81.2 (s), 107.0 (s), 108.6 (s), 109.7 (s), 119.4
(s), 119.5 (d), 119.6 (d), 123.5 (d), 124.1 (d), 129.5 (d), 129.6 (d), 135.2 (s), 135.2 (s), 140.2
(s), 140.3 (s), 142.9 (s), 152.5 (s), 159.9 (s), 161.5 (s), 167.0(s), 167.2 (s); IR (nujol): max =
3288, 3167, 1743, 1653 cm-1; MS m/z (ESI): 403.68 (M + H+); anal. calcd. o C20H25N3O4S
(403.1566): C 59.53, H 6.25, N 10.41; ound: C 59.68, H 6.28, N 10.31.
S
OO
NH
N
NH
O
O
- 117 -
Te -bu yl 2-(1-(4-(e hoxyca bonyl)-3-me hyl-5-
(phenylamino) hiophen-2-
yl)e hylidene)hyd azineca boxyla e 41b.
41b was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 78% yield. Pale yellow solid; mp:
170172 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ = 1.31 ( ,
3H, J = 7.2 Hz OCH2CH3), 1.41 and 1.45 (2s, 9H, OC(CH3) 3), 2.05 and 2.43 (2s, 3H, CH3),
2.10 and 2.18 (2s, 3H, CH3), 4.29 (q, 2H, J = 7.2 Hz, OCH2CH3), 7.12 ( , 1H, J = 7.2 Hz, Ph),
7.35-7.43 (m, 4H, Ph), 9.16 and 9.77 (2s, 1H, NH), 10.00 (s, 1H, NH); 13C NMR (100 MHz,
DMSOd6, 25 °C): δ = 14.2 (q), 14.2 (q), 16.4 (q), 16.4 (q), 17.5 (q), 25.2 (q), 28.0 (s), 28.1 (s),
59.9 ( ), 79.3 (s), 79.4 (s), 107.6 (s), 108.9 (s), 111.6 (s), 119.5 (d), 119.7 (d), 120.4 (s), 123.7
(d), 123.8 (d), 129.6 (d), 129.6 (d), 134.1 (s), 134.3(s), 140.4 (s), 140.7 (s), 147.2 (s), 152.6 (s),
152.8 (s), 158.4 (s), 159.9 (s), 165.4(s), 165.4 (s); IR (nujol): max = 3281, 3221, 1740, 1653
cm-1; MS m/z (ESI): 418.13 (M + H+); anal. calcd. o C21H27N3O4S (417.5288): C 60.41, H
6.52, N 10.06; ound: C 60.28, H 6.47, N 10.22.
Te -bu yl 2-(1-(5-((4-chlo ophenyl)amino)-3-e hyl--4-
(me hoxyca bonyl) hiophen-2-
yl)e hylidene)hyd azineca boxyla e 41c.
41c was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 77% yield. Pale yellow solid; mp:
150152 °C; 1H NMR (400 MHz, CDCl3,, 25 °C): δ = 1.09 and
1.21 (2 , 3H, J = 7.6 Hz, J = 7.2 Hz, CH2CH3), 1,48 and 1.53
(2s, 9H, OC(CH3) 3), 2.20 and 2.24 (2s, 3H, CH3), 2.58 and 2.96 (2q, 2H, J = 7.2 Hz, J = 7.2
Hz, CH2CH3), 3.88 and 3.90 (2s, 3H, OCH3), 4.29-4.37 (m, 2H, OCH2CH3), 7.22-7.34 (m, 4H,
Ph), 7.68 and 7.82 (2b s, 1H, NH), 10.31 and 10.41 (2s, 1H, NH); 13C NMR (100 MHz, CDCl3,,
25 °C): δ = 15.0 (q), 15.3 (q), 16.2 (q), 22.7 ( ), 23.1 ( ), 25.8 (q), 28.2 (s), 28.2 (s), 51.1 (q),
51.4 (q), 81.3 (s), 106.5 (s), 108.0 (s), 109.1 (s), 119.4 (s), 120.7 (d), 120.8 (d), 128.4 (s), 129.0
(s), 129.4 (d), 129.6 (d), 138.8 (s), 139.0 (s), 141.4 (s), 141.7 (s), 142.8 (s), 152.2 (s), 152.3 ( s),
159.7 (s), 161.4 (s), 166.6(s), 167.0 (s); IR (nujol): max = 3291, 3210, 1746, 1702 cm-1; MS
m/z (ESI): 452.57 (M + H+); anal. calcd. o C21H26ClN3O4S (451.9668): C 55.81, H 5.80, N
9.30; ound: C 55.73, H 5.78, N 9.37.
S
OO
NH
N
NH
O
O
S
OO
NH
N
NH
O
O
Cl
- 118 -
Te -bu yl 2-(1-(4-((benzyloxy)ca bonyl)-3-me hyl-5-
(phenylamino) hiophen-2-
yl)e hylidene)hyd azineca boxyla e 41d.
41d was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 73% yield. Pale yellow solid; mp:
126128 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.50
and 1.53 (2s, 9H, OC(CH3) 3), 2.18 and 2.52 (2s, 3H, CH3), 2.20 and 2.23 (2s, 3H, CH3), 5.35and
5.37 (2s, 2H, J = 7.2 Hz, OCH2Ph), 7.08-7.14 (m, 1H, J = 7.2 Hz, Ph), 7.30-7.45 (m, 9H, Ph),
7.63 and 7.81 (2b s, 1H, NH), 10.28 and 10.36 (2s, 1H, NH); 13C NMR (100 MHz, CDCl3,,
25 °C): δ = 16.6 (q), 16.8 (q), 17.2 (q), 25.5 (q), 28.2 (s), 28.3 (s), 66.0 ( ), 66.2 ( ), 81.3 (s),
106.8 (s), 108.5 (s), 109.6 (s), 119.6 (d), 119.7 (d), 120.4 (s), 123.7 (d), 124.2 (d), 128.1 (d),
128.2 (d), 128.2 (d), 128.3 (d), 128.6 (d), 128.7 (d), 129.5 (d), 129.6 (d), 135.2 (s), 135.9(s),
136.1 (s), 140.2 (s), 140.2 (s), 152.5 (s), 152.5 (s), 160.3 (s), 161.8 (s), 166.2(s), 166.4 (s); IR
(nujol): max = 3296, 3145, 1745, 1624 cm-1; MS m/z (ESI): 480.13 (M + H+); anal. calcd. o
C26H29N3O4S (479.5912): C 65.11, H 6.09, N 8.76; ound: C 65.24, H 6.11, N 8.71.
Te -bu yl 2-(1-(4-(me hoxyca bonyl)-3-me hyl-5-
(phenylamino) hiophen-2-
yl)p opylidene)hyd azineca boxyla e 41e.
41e was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 78% yield. Pale yellow solid; mp:
136138 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.08 ( ,
3H, J = 7.6 Hz, CH2CH3), 2.16 (s, 3H, CH3), 2.54 (q, 2H, J = 7.6 Hz, CH2CH3), 3.90 (s, 3H,
OCH3), 7.13 ( , 1H, J = 7.2 Hz, J = 8.4 Hz, J = 0.8 Hz, Ph), 7.39 ( , 2H, J = 7.6 Hz, Ph), 7.82
(b s, 1H, NH), 10.30 (s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 11.0 (q), 16.6 (q),
28.2 (q), 32.3 ( ), 25.7 (q), 51.3 (q), 81.2 (s), 107.0 (s), 108.5 (s), 119.6 (d), 124.1 (d), 129.6 (d),
135.8 (s), 140.2 (s), 144.5 (s), 147.6 (s), 152.6 (s), 161.5 (s), 167.0 (s); IR (nujol): max = 3296,
3220, 1745, 1653 cm-1; MS m/z (ESI): 417.85 (M + H+); anal. calcd. o C21H27N3O4S
(417.1722): C 60.41, H 6.52, N 10.06; ound: C 60.33, H 6.50, N 10.12.
S
OO
NH
N
NH
O
O
S
OO
NH
N
NH
O
O
- 119 -
Me hyl 2-(1-(5-((4-chlo ophenyl)amino)-4-
(e hoxyca bonyl)-3-me hyl hiophen-2-
yl)e hylidene)hyd azineca boxyla e 41 .
41 was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 69% yield. Pale yellow solid; mp:
136139 °C; 1H NMR (400 MHz, CDCl3,, 25 °C): δ = 1.36-1.40
(m, 3H, OCH2CH3), 2.17 and 2.46 (2s, 3H, CH3), 2.22 and 2.24 (2s, 3H, CH3), 3.80 and 3.83
(b s and s, 3H, OCH3), 4.29-4.37 (m, 2H, OCH2CH3), 7.20-7.33 (m, 4H, Ph), 7.97 (b s, 1H,
NH), 10.32 and 10.38 (2s, 1H, NH); 13C NMR (100 MHz, CDCl3,, 25 °C): δ = 14.3 (q), 16.7
(q), 16.7 (q), 16.9 (q), 25.3 (q), 53.0 (q), 60.2 ( ), 60.4 ( ), 107.5 (s), 109.1 (s), 109.5 (s), 119.1
(s), 120.5 (d), 120.7 (d), 128.3 (s), 129.0 (s), 129.4 (d), 129.6 (d), 135.5 (s), 135.6 (s), 138.7 (s),
138.9 (s), 143.9 (s), 153.9 (s), 154.2 ( s), 159.1 (s), 160.8 (s), 166.4(s), 166.7 (s); IR (nujol):
max = 3293, 3191, 1736, 1653 cm-1; MS m/z (ESI): 410.47 (M + H+); anal. calcd. o
C18H20ClN3O4S (409.8871): C 52.74, H 4.92, N 10.25; ound: C 52.58, H 4.89, N 10.34.
(Me hyl 2-(1-(4-(e hoxyca bonyl)-3-e hyl-5-
(phenylamino) hiophen-2-
yl)e hylidene)hyd azineca boxyla e 41g.
41g was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 68% yield. Pale yellow solid; mp:
128130 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.03 and 1.16 ( 2 , 3H, J = 7.2 Hz, J =
7.2 Hz, CH2CH3), 1.33 ( , 3H, J = 7.2 Hz OCH2CH3), 2.14 and 2.18 (2s, 3H, CH3), 2.51 and
2.90 ( 2q, 2H, J = 7.2 Hz, J = 7.2 Hz, CH2CH3), 3.73 and 3.76 (b s and s, 3H, OCH3), 4.29 (q,
2H, J = 7.2 Hz, OCH2CH3), 6.99-7.07 (m, 1H, Ph), 7.19-7.33 (m, 4H, Ph), 7.89 and 7.96 (b s
and s, 1H, NH), 10.27 and 10.38 (2s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.2
(q), 15.2 (q), 15.4 (q), 16.4 (q), 17.5 (q), 22.8 ( ), 23.3 (q), 25.7 (q), 53.3 (q), 60.2 ( ), 60.4 ( ),
79.3 (s), 106.1 (s), 107.8 (s), 108.2 (s), 118.4 (s), 119.6 (d), 119.8 (d), 123.6 (d), 124.2 (d),
129.5 (d), 129.6 (d), 140.3 (s), 140.4 (s), 141.7(s), 142.3 (s), 144.5 (s), 144.6 (s), 153.8 (s),
153.9 (s), 160.4 (s), 162.1 (s), 166.2 (s), 166.6 (s); IR (nujol): max = 3288, 3120, 1756, 1654
cm-1; MS m/z (ESI): 390.03 (M + H+); anal. calcd. o C19H23N3O4S (389.4686): C 58.59, H
5.95, N 10.79; ound: C 58.71, H 5.99, N 10.67.
S
OO
NH
N
NH
O
O
Cl
S
OO
NH
N
NH
O
O
- 120 -
One po sequen ial syn hesis o 2-a ylamino 5-hyd azono hiophene-3-ca boxyla es
(AHTs) 41h- s a ing om in si u gene a ed 4-unsubs i u ed DDs.
Alkyl amines 31a,b (0.5 mmol) we e added o -ke oes e s 30a,b,i (0.55 mmol) unde sol en -
ee condi ions a oom empe a u e and igo ously s i ed a oom empe a u e. A e 0.5 h a yl
iso hiocyana es 34a (0.5mmol) in CH2Cl2 (1.5 mL) we e added and he eac ions we e s i ed
un il he disappea ance o he enamino es e s 32 (5-20h moni o ed by TLC). -Halo hyd azones
15a-g (1.0 mmol) in CH2Cl2 (2.0 mL) and po assium ca bona e (4.0 mmol) we e added o he
eac ion medium and magne ically s i ed un il he comple e disappea ance o he ACTs 28a,c,i
(5.0-7.0 h moni o ed by TLC). Then, he eac ion sol en was e apo a ed unde educed
p essu e and he desi ed 2-a ylamino 5-hyd azono hiophene-3-ca boxyla es (AHTs) 41h-
we e pu i ied by ch oma og aphy on silica gel column (elu ion mix u e: cyclohexane: e hyl
ace a e).
Me hyl 2-((4-(me hoxyca bonyl)-3-me hyl-5-
(phenylamino) hiophen-2-
yl)(phenyl)me hylene)hyd azineca boxyla e (41h).
41h
was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane 20:80) in 80% yield. Whi e solid; mp:
169
172 °C;
1
H NMR (400 MHz, CDCl
3
, 25 °C): δ = 2.17 (s,
3H, CH
3
), 3.87 (b s, 3H, OCH
3
), 3.92 (s, 3H, OCH
3
), 7.11 ( ,
1H, J = 7.2 Hz, Ph), 7.29-7.38 (m, 7H, Ph), 7.63-7.68 (m, 2H, Ph), 8.22 (b s, 1H, NH),
10.39 (s, 1H, NH);
13
C NMR (100 MHz, CDCl
3
, 25 °C): δ = 16.5 (q), 51.3 (q), 53.1 (q),
106.0 (s), 106.9 (s), 119.6 (d), 124.1 (d), 127.3 (d), 128.4 (d), 129.6 (d), 129.7 (s), 136.6
(s), 137.8 (s), 140.1 (s), 144.1 (s), 153.6 (s), 162.2 (s), 166.9 (s); IR (nujol):
max =
3218, 3113, 1699, 1660 cm-1; MS m/z (ESI): 424.05 (M + H
+
); anal. calcd. o
C
22
H
21
N
3
O
4
S (423.4848): C 62.40, H 5.00, N 9.92; ound: C 62.34, H 4.98, N 9.96.
Te -bu yl 2-((4-(me hoxyca bonyl)-3-me hyl-5-
(phenylamino) hiophen-2-
yl)(phenyl)me hylene)hyd azineca boxyla e (41i).
41i
was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane 20:80) in 81% yield. Whi e solid; mp:
162
166 °C;
1
H NMR (400 MHz, CDCl
3
, 25 °C): δ = 1.55 (s,
9H, OC(CH
3
)
3
), 2.18 (s, 3H, CH
3
), 3.93 (s, 3H, OCH
3
), 7.11
( , 1H, J = 7.2 Hz, A ), 730-7.38 (m, 7H, Ph), 7.67-7.69 (m, 2H, Ph), 8.07 (b s, 1H, NH),
10.42 (s, 1H, NH);
13
C NMR (100 MHz, CDCl
3
, 25 °C): δ = 16.4 (q), 28.2 (q), 51.3 (q),
81.7 (s), 106.3 (s), 107.0 (s), 119.5 (d), 124.0 (d), 127.1 (d), 128.3 (d), 129.4 (d), 129.6
(d), 136.9 (s), 137.5 (s), 140.2 (s), 142.8 (s), 152.3 (s), 162.0 (s), 167.0 (s); IR (nujol):
max = 3287, 3178, 1751, 1663 cm-1; MS m/z (ESI): 466.18 (M + H
+
); anal. calcd. o
C
25
H
27
N
3
O
4
S (465.5646): C 64.50, H 5.85, N 9.03; ound: C 64.44, H 5.86, N 9.09.
S
O
O
NH
N
NH
O
O
S
O
O
NH
N
NH
O
O
- 127 -
Gene al P ocedu e o he syn hesis o 2-(phenylamino)-5-(1,2,3- hiadiazol-4-
yl) hiophene-3-ca boxyla es (ATTs) 43e-h s a ing om 2-a ylamino 5-hyd azono
hiophene-3-ca boxyla es (AHTs) 41a,b,d, .
To a solu ion o 2-a ylamino 5-hyd azono hiophene-3-ca boxyla es (AHTs)
41a,b,d,
.
(0.5 mmol) in CH
2
Cl
2
(4.0 mL) hionyl chlo ide (5.0 mmol) we e added and he eac ion
mix u e was so ly s i ed a oom empe a u e. A he disappea ance o he s a ing 2-
a ylamino 5-hyd azono hiophene-3-ca boxyla es (AHTs)
41
(15 h – 18h moni o ed by
TLC). Then, he c ude was neu alized by adding sa u a ed aqueous solu ion o sodium
hyd ogen ca bona e un il pH ~ 7 and hen ex ac ed wi h esh
CH
2
Cl
2
(
5.0 mL x 3). The
o ganic laye was washed wi h wa e and d ied on sodium sulpha e. The eac ion sol en was
e apo a ed unde educed p essu e and he desi ed 2-(phenylamino)-5-(1,2,3- hiadiazol-4-
yl) hiophene-3-ca boxyla es (ATTs) 43e-h we e pu i ied by ch oma og aphy on silica gel
column (elu ion mix u e: cyclohexane: e hyl ace a e).
E hyl 4-(chlo ome hyl)-2-(phenylamino)-5-(1,2,3- hiadiazol-4-
yl) hiophene-3-ca boxyla e 43e.
43e was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 56% yield. Da k g een solid; mp:
9898 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.49 ( , 3H, J =
7.2 Hz, OCH2CH3), 4.46 (q, 2H, J = 7.2 Hz, OCH2CH3), 5.06 (s, 2H, CH2Cl), 7.16 ( , 1H, J =
7.2 Hz, Ph), 7.36-7.44 (m, 4H, Ph), 8.79 (s, 1H, SCH), 10.40 (s, 1H, NH); 13C NMR (100 MHz,
CDCl3, 25 °C): δ = 14.2 (q), 39.6 ( ), 60.8 ( ), 106.0 (s), 114.5 (s), 120.0 (d), 124.5 (d), 129.7
(d), 130.9 (d), 133.5 (s), 140.0 (s), 155.0 (s), 161.2 (s), 165.9 (s); IR (nujol): max = 3193, 1661
cm-1; MS m/z (ESI): 380.49 (M + H+); anal. calcd. o C16H14ClN3O2S2 (379.8843): C 50.59, H
3.71, N 11.06; ound: C 50.72, H 3.76, N 10.92.
Me hyl 4-(chlo ome hyl)-2-(phenylamino)-5-(1,2,3- hiadiazol-4-yl) hiophene-3-
ca boxyla e 43 .
43 was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 58% yield. Da k g een solid; mp:
9798 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.00 (s, 3H,
OCH3), 5.00 (s, 2H, CH2Cl), 7.18 ( , 1H, J = 6.8 Hz, Ph), 7.37-7.44
(m, 4H, Ph), 8.79 (s, 1H, SCH), 10.34 (s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ =
14.2 (q), 14.4 (q), 38.9 ( ), 39.4 ( ), 60.9 ( ), 61.0 ( ), 106.5 (s), 106.6 (s), 113.9 (s), 114.9 (s),
121.0 (d), 121.0 (d), 129.3 (s),
S
OO
NH
N
N
S
Cl
S
OO
NH
N
N
S
Cl
- 128 -
129.4 (s), 129.7 (d), 129.7 (d), 131.0 (d), 131.6 (d), 132.0 (s), 133.5 (s), 138.6 (s), 154.8 (s),
154.9(s), 160.6 (s), 160.7 (s), 165.8 (s), 165.8 (s) IR (nujol): max = 3154, 1675 cm-1; MS m/z
(ESI): 366.26 (M + H+); anal. calcd. o C15H12ClN3O2S2 (365.8577): C 49.24, H 3.31, N 11.49;
ound: C 49.11, H 3.27, N 11.57.
Benzyl 4-(chlo ome hyl)-2-(phenylamino)-5-(1,2,3-
hiadiazol-4-yl) hiophene-3-ca boxyla e 43g.
43g was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 62% yield. Da k g een solid; mp:
116121 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 4.97 (s,
2H, OCH2Ph), 5.44 (s, 2H, CH2Cl), 7.17 ( , 1H, J = 7.2 Hz, Ph),
7.34-7.45 (m, 7H, Ph),7.55 (d, 2H, J = 6.8 Hz, Ph), 8.78 (s, 1H, SCH), 10.35 (s, 1H, NH); 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 39.5 ( ), 66.7 ( ), 105.6 (s), 114.6 (s), 120.1 (d), 124.6 (d),
128.4 (d), 128.4 (d), 128.7 (d), 129.7 (d), 130.9 (d), 133.5 (s), 135.7 (s), 139.9 (s), 154.9 (s),
161.5 (s), 165.5 (s); IR (nujol): max = 3128, 1654 cm-1; MS m/z (ESI): 442.58 (M + H+); anal.
calcd. o C21H16ClN3O2S2 (441.9536): C 57.07, H 3.65, N 9.51; ound: C 57.21, H 3.68, N
9.42.
E hyl 4-(chlo ome hyl)-2-((4-chlo ophenyl)amino)-5-(1,2,3-
hiadiazol-4-yl) hiophene-3-ca boxyla e 43h.
43h was isola ed by column ch oma og aphy on silica gel
(ace a e/cyclohexane) in 64% yield. Da k g een solid; mp:
101103 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.46-1.50 (m,
3H, OCH2CH3), 4.42-4.47 (m, 2H, OCH2CH3), 4.72 and 4.98 (2s,
2H, CH2Cl), 7.28-7.31 (m, 2H, Ph), 7.34-7.37 (m, 2H, Ph), 8.79 and 8.84 (2s, 1H, SCH), 10.42
(s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.2 (q), 14.4 (q), 38.9 ( ), 39.4 ( ), 60.9
( ), 61.0 ( ), 106.5 (s), 106.6 (s), 113.9 (s), 114.9 (s), 121.0 (d), 121.0 (d), 129.3 (s), 129.4 (s),
129.7 (d), 129.7 (d), 131.0 (d), 131.6 (d), 132.0 (s), 133.5 (s), 138.6 (s), 154.8 (s), 154.9(s),
160.6 (s), 160.7 (s), 165.8 (s), 165.8 (s) IR (nujol): max = 3119, 1657 cm-1; MS m/z (ESI):
415.88 (M + H+); anal. calcd. o C16H13Cl2N3O2S2 (414.3293): C 46.38, H 3.16, N 10.14;
ound: C 46.25, H 3.19, N 10.05.
S
OO
NH
N
N
S
Cl
S
OO
NH
N
N
S
Cl
Cl
- 129 -
CHAPTER 5
Expe imen al Sec ion
All chemicals and sol en s we e pu chased om comme cial supplie s and used as ecei ed.
1,2-Diaza-1,3-dienes we e p epa ed as epo ed[99] and used as EE/EZ isome mix u es. Mel ing
poin s we e de e mined in open capilla y ubes and a e unco ec ed. FTIR spec a we e ob ained
as Nujol mulls. All 1H NMR and 13C NMR spec a we e eco ded a 400 and 100 MHz,
espec i ely. P o on and ca bon spec a we e e e enced in e nally o sol en signals, using
alues o = 7.26 ppm o p o on and = 77.00 ppm o ca bon (middle peak) in CDCl3.
P ecoa ed silica gel pla es 0.25 mm we e employed o analy ical hin laye ch oma og aphy.
All new compounds showed sa is ac o y elemen al analysis. Mass spec a we e eco ded in he
EI mode (70eV). The nomencla u e was gene a ed using ACD/IUPAC Name ( e sion 3.50, 5
Ap . 1998), Ad anced Chemis y De elopmen Inc., To on o, ON (Canada).
Gene al P ocedu e o he Syn hesis o he γ-adduc 3as.
To a magne ically s i ed solu ion o e ahyd opy idazine 18 (0.1 mmol 1.0 eq) in DCM (2 mL)
a oom empe a u e, a nucleophile 44a-i (0.1 eq), and BF3(OE )2 (1.2 eq) as p omo e , was
added consequen ially. A e he disappea ance o he eagen s (0.10.5 h) (TLC moni o ing),
he eac ion sol en was e apo a ed unde educed p essu e and he c ude mix u e was pu i ied
by column ch oma og aphy on silica gel (e hyl ace a e/cyclohexane mix u es) o a o d he
co esponding adduc .
hyl 5-(bu -3-enyl)-3-phenylpy idazine-1(4H)-ca boxyla e (45a):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 80% yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.40 ( , 3H, OCH2CH3), 2.172.21 (m, 2H
CH2CH2CH=CH2), 2.252.31 (m, 2H CH2CH2CH=CH2), 3.17 (s, 2H,
CCH2C), 4.344.40 (q, 2H, OCH2CH3), 4.995.10 (m, 2H, CH2CH2CH=CH2), 5.785.88 (m,
1H, CH2CH2CH=CH2), 6.99 (s, 1H, NCH), 7.407.42 (m, 3H, Ph), 7.827.84 (m, 2H, Ph); 13C
NMR (100 MHz, CDCl3, 25 °C): δ = 14.5 (q), 26.3 ( ), 30.7 ( ), 33.3 ( ), 62.9 ( ), 113.7 (s),
116.0 ( ), 117.6 (s), 125.9 (d), 128.3 (d), 129.8 (d), 136.4 (s), 137.4 (d), 146.5 (s), 152.6 (s); IR
(nujol): max = 1697 cm-1; MS m/z (ESI): 285.03 (M + H+); anal. calcd. o C17H20N2O2 (284,35):
C 71.81, H 7.09, N 9.85; ound: C 71.68, H 5.05, N 9.96.
NN
O O
345
6
- 130 -
Me hyl 5-(bu -3-en-1-yl)-3-phenylpy idazine-1(4H)-ca boxyla e
(45b):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 69% yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C δ = 2.172.21 (m, 2H CH2CH2CH=CH2), 2.252.31 (m,
2H CH2CH2CH=CH2), 3.17 (s, 2H, CCH2C), 3.92 (s, 3H, OCH3), 4.995.10 (4m, 2H,
CH2CH2CH=CH2), 5.775.87 (m, 1H, CH2CH2CH=CH2), 7.00 (s, 1H, NCH), 7.407.41 (m,
3H, Ph), 7.817.83 (m, 2H, Ph); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 26.5 ( ), 30.7 ( ), 33.3
( ), 53.8 (q), 113.9 (s), 115.4 ( ), 117.6 (s), 126.0 (d), 128.4 (d), 129.9 (d), 136.4 (s), 137.4 (d),
146.4 (s), 152.6 (s); IR (nujol): max = 1717 cm-1; MS m/z (ESI): 271.01 (M + H+); anal. calcd.
o C16H18N2O2 (270,33): C, 71.09; H, 6.71; N, 10.36; ound: C, 71.22; H, 6.64; N, 10.25;
E hyl 3-(4-b omophenyl)-5-(bu -3-en-1-yl)py idazine-1(4H)-
ca boxyla e (45c):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 75% yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.38 ( , 3H, OCH2CH3), 2.162.20 (m, 2H
CH2CH2CH=CH2), 2.242.28 (m, 2H CH2CH2CH=CH2), 3.13 (s, 2H, CCH2C), 4.344.40 (q,
2H, OCH2CH3), 5.005.09 (4m, 2H, CH2CH2CH=CH2), 5.785.84 (m, 1H, CH2CH2CH=CH2),
6.98 (s, 1H, NCH), 7.54 (d, 2H, PhB ), 7.70 (d, 2H, PhB ); 13C NMR (100 MHz, CDCl3, 25
°C): δ = 14.5 (q), 26.2 ( ), 30.6 ( ), 33.3 ( ), 63.0 ( ), 113.6 (s), 115.4 ( ), 117.6 (s), 124.1 (d),
127.5 (d), 131.5 (s), 135.3 (s), 137.4 (d), 144.8 (s), 152.6 (s); IR (nujol): max = 1723 cm-1; MS
m/z (ESI): 363.89 (M + H+); anal. calcd. o C17H19B N2O2 (363,25): C, 56.21; H, 5.27; B ,
22.00; N, 7.71; ound: C, 56.36; H, 5.19; B , 22.05; N, 7.63
NN
O O
345
6
- 131 -
E hyl 5-(bu -3-enyl)-3-(4-ni ophenyl)py idazine-1(4H)-
ca boxyla e (45d):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 79% yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.40 ( , 3H, OCH2CH3), 2.182.22 (m, 2H
CH2CH2CH=CH2), 2.262.35 (m, 2H CH2CH2CH=CH2), 3.19 (s, 2H, CCH2C), 4.364.40 (q,
2H, OCH2CH3), 5.015.10 (4m, 2H, CH2CH2CH=CH2), 5.815.83 (m, 1H, CH2CH2CH=CH2),
6.99 (s, 1H, NCH), 7.98 (d, 2H, PhNO2), 8.25 (d, 2H, Ph NO2); 13C NMR (100 MHz, CDCl3,
25 °C): δ = 14.5 (q), 26.2 ( ), 30.5 ( ), 33.2 ( ), 63.3 ( ), 114.0 (s), 115.6 ( ), 117.5 (s), 123.6 (d),
126.7 (d), 136.4 (s), 137.2 (d), 142.3 (s), 148.3 (s), 152.0 (s); IR (nujol): max = 1689cm-1; MS
m/z (ESI): 330.96 (M + H+); anal. calcd. o C17H19N3O4 (329,35): C, 62.00; H, 5.81; N, 12.76;
ound: C, 62.14; H, 5.85; N, 12.66
3-E hyl 1-me hyl 5-(bu -3-en-1-yl)py idazine-1,3(4H)-dica boxyla e
(45e):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 26% yield. oil; 1H NMR (400 MHz, CDCl3,
25 °C δ = 1.38 ( , 3H OCH2CH3), 2.102.14 (m, 2H CH2CH2CH=CH2),
2.202.23 (m, 2H CH2CH2CH=CH2), 3.04 (s, 2H, CCH2C), 3.91 (s, 3H, OCH3), 4.334.37 (q,
2H OCH2CH3) 5.015.07 (4m, 2H, CH2CH2CH=CH2), 5.745.81 (m, 1H, CH2CH2CH=CH2),
6.85 (s, 1H, NCH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.1 (q), 25.3 ( ), 30.3 ( ), 33.0 ( ),
54.4 (q), 62.2 ( ), 115.6 (s), 116.1 ( ), 117.0 (s), 137.4 (d), 139.8 (s), 152.4 (s) 164.0 (s); IR
(nujol): max = 1756, 1723 cm-1; MS m/z (ESI): 266.91 (M + H+); anal. calcd. o C13H18N2O4
(266,29): C, 58.63; H, 6.81; N, 10.52; ound: C, 58.74; H, 6.75; N, 10.59;
NN
O O
O
O
345
6
- 132 -
E hyl 5-(bu -3-enyl)-1-(phenylca bamoyl)-1,4-
dihyd opy idazine-3-ca boxyla e (45 ):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 31% yield. oil; 1H NMR (400
MHz, CDCl3, 25 °C δ = 1.39 ( , 3H OCH2CH3), 2.122.16 (m,
2H CH2CH2CH=CH2), 2.222.27 (m, 2H CH2CH2CH=CH2), 3.11 (s, 2H, CCH2C), 4..38
(q, 2H OCH2CH3) 4.995.09 (4m, 2H, CH2CH2CH=CH2), 5.795.80 (m, 1H,
CH2CH2CH=CH2), 7.087.12 (m, 2H, NCH and NHph), 7.317.35 (m, 2H, NHph), 7.517.53
(m, 2H, NHph), 8.62 (s, H, NHph);13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.2 (q), 25.5 ( ),
30.2 ( ), 33.2 ( ), 61.9 ( ), 114.9 (s), 115.4 ( ), 115.5 (s), 119.7 (d), 123.8 (s), 129.0 (d), 136.6
(s), 137.2 (d), 137.5 (s), 149.6 (s) 163.7 (s); IR (nujol): max = 3266, 1669, 1624 cm-1; MS m/z
(ESI): 328.01 (M + H+); anal. calcd. o C18H21N3O3 (327,38): C, 66.04; H, 6.47; N, 12.84;
ound: C, 66.19; H, 6.41; N, 12.76
E hyl 3-(4-b omophenyl)-5-(2,2-dime hyl-3-
oxop opyl)py idazine-1(4H)-ca boxyla e (45g):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 65% yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.12 (s, 6H CH2C(CH3)2COH) 1.39 ( , 3H,
OCH2CH3), 2.32 (s, 2H CH2C(CH3)2COH), 3.01 (s, 2H, CCH2C), 4.344.39 (q, 2H,
OCH2CH3), 6.98 (s, 1H, NCH), 7.52 (d, 2H, PhB ), 7.64 (d, 2H, PhB ), 9.58 (s, 1H
CH2C(CH3)2COH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.5 (q), 22.1 (q), 27.6 ( ), 41.6
( ), 46.2 (s), 63.2 ( ), 110.2 (s), 120.4 (s), 120.7 (d), 124.4 (s), 127.6 (d), 131.6 (d), 135.0 (s),
139.4 (s), 144.9 (s), 205.6 (d); IR (nujol): max = 1742, 1620 cm-1; MS m/z (ESI): 538.69 (M +
H+); anal. calcd. o C18H21B N2O3 (393,27): C, 54.97; H, 5.38; B , 20.32; N, 7.12; ound: C,
54.82; H,
- 133 -
E hyl 5-(2-benzoyl-3-oxobu yl)-3-phenylpy idazine-1(4H)-
ca boxyla e (45h):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 95% yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.37 ( , 3H, OCH2CH3), 2.17 (s, 3H CH3CO),
2.81 (d, 2H CCH2CH), 3.15 (s, 2H, CCH2C), 4.314.39 (q, 2H,
OCH2CH3), 4.70 ( , 1H, CCH2CH), 7.01 (s, 1H, NCH), 7.49 (5m, 10H, Ph and COPh);
13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.5 (q), 26.4 (q), 28.0 ( ), 33.0 ( ), 61.0 (d), 63.0 ( ),
110.5 (d), 119.4 (s), 126.0 (d), 128.4 (d), 128.7 (d), 129.0 (d), 130.0 (d), 134.0 (d), 136.0 (s),
136.1 (s), 145.9 (s), 153.9 (s), 195.4 (s), 203.0 (s); IR (nujol): max = 1751, 1744, 1692 cm-1;
MS m/z (ESI): 405.12 (M + H+); anal. calcd. o C24H24N2O4 (404,46): C, 71.27; H, 5.98; N,
6.93; ound: C, 71.10; H, 5.92; N, 6.8575.
E hyl 5-(2-benzoyl-3-oxobu yl)-3-(4-
b omophenyl)py idazine-1(4H)-ca boxyla e (45i):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 86% yield. oil; 1H NMR (400
MHz, CDCl3, 25 °C): δ = 1.36 ( , 3H, OCH2CH3), 2.17 (s,
3H CH3CO), 2.80 (d, 2H CCH2CH), 3.10 (s, 2H, CCH2C),
4.304.38 (q, 2H, OCH2CH3), 4.69 ( , 1H, CCH2CH), 6.99 (s, 1H, NCH), 7.49 (3m, 9H,
PhB and COPh); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 14.5 (q), 26.2 (q), 28.0 ( ), 32.9 ( ),
61.0 (d), 63.1 ( ), 110.5 (d), 119.4 (s), 124.3 (d), 127.5 (d), 128.7 (d), 129.0 (d), 131.5 (d), 134.0
(s), 134.9 (s), 136.1 (s), 144.7 (s), 152.2 (s), 195.3 (s), 202.9 (s); IR (nujol): max = 1741, 1733,
1679 cm-1; MS m/z (ESI): 538.69 (M + H+); anal. calcd. o C24H23B N2O4 (483,35): C, 59.64;
H, 4.80; B , 16.53; N, 5.80; ound: C, 59.51; H, 4.75; B , 16.62; N, 5.89.
- 134 -
Me hyl 5-(2-ace yl-3-oxobu yl)-3-phenylpy idazine-
1(4H)-ca boxyla e (45j):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:9) in 42% yield. oil; 1H NMR (400
MHz, CDCl3, 25 °C): δ = 2.14 (2s, 6H, COCH3 enol o m),
and 2.22 (2s, 6H, COCH3), 2.64 (d 2H CCH2CH ) 2.99 (s 2H
CCH2C= enol o m), 3.14 (2s, 2H, CCH2C), 3.19 (2s, 2H, CCH2C enol o m), 3.92 (s, 3H,
OCH3), 3.953.99 (m, 1H, CCH2CH), 6.89 (2s, 1H, NCH enol o m) 7.01 (2s, 1H, NCH),
7.40 and 7.80 (2m, 5H, Ph); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 23.07 (q),
26.4 ( ) 26.8 ( , enol o m), 29.1 ( , enol o m) 29.7 ( ), 32.0 ( ), 54.0 ( ), 66.1 (s), 104.9 (s, enol
o m) 112.7 (d, enol o m), 117.8 (s) 119.4 (s), 125.9 and 126.0 (d), 128.4 (d), 136.0 and 136.1
(s), 145.9 (s), 153.0 (s), 191.8 (s), 202.9 (s); IR (nujol): max = 1736, 1672, 1657 cm-1; MS m/z
(ESI): 328.88 (M + H+); anal. calcd. o C18H20N2O4 (328,36): C, 65.84; H, 6.14; N, 8.53; ound:
C, 65.71; H, 6.19; N, 8.47.
E hyl 5-( u an-2-ylme hyl)-3-phenylpy idazine-1(4H)-
ca boxyla e (45k):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:4) in 58% yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.40 ( , 3H, OCH2CH3), 3.15 (s, 2H, CCH2C),
3.43 (s, 2H, CCH2C4H4O), 4.354.40 (q, 2H, OCH2CH3), 6.12
(dd, 1H, CCHCHCHO), 6.31 (dd, 1H, CCHCHCHO), 7.11 (s, 1H, NCH), 7.34 (dd, 1H,
CCHCHCHO), 7.347.40 and 7.797.81 (2m, 5H, Ph); 13C NMR (100 MHz, CDCl3, 25 °C): δ
= 14.5 (q), 26.0 ( ), 32.9 ( ), 63.0 ( ), 106.9 (d), 110.4(d), 110.8 (s), 118.9 (d), 126.0 (d), 128.3
(d), 129.8 (d), 136.4 (s), 141.8 (d), 146.5 (s), 151.6 (s), 152.6 (s); IR (nujol): max = 1673 cm-1;
MS m/z (ESI): 311.03 (M + H+); anal. calcd. o C18H18N2O3 (310,35): C, 69.66; H, 5.85; N,
9.03; ound: C, 69.73; H, 5.81; N, 9.09.
- 135 -
Die hyl 5,5'-[ u an-2,5-
diylbis(me hylene)]bis(3-phenylpy idazine-
1(4H)-ca boxyla e) (45l):
Isola ed by column ch oma og aphy on silica gel
(e hyl ace a e/cyclohexane, 2:3) in 39% yield. oil;
1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.39 ( ,
6H, OCH2CH3), 3.15 (s, 4H, CCH2C), 3.38 (s, 4H, CCH2C4H4O), 4.334.38 (q, 4H, OCH2CH3),
6.03 (s, 2H, -CCHCHC), 7.09 (s, 2H, NCH), 7.377.40 and 7.777.80 (2m, 10H, Ph); 13C NMR
(100 MHz, CDCl3, 25 °C): δ = 14.5 (q), 26.0 ( ), 32.9 ( ), 63.0 ( ), 106.9 (d), 110.4(d), 110.8
(s), 118.9 (d), 126.0 (d), 128.3 (d), 129.8 (d), 136.4 (s), 141.8 (d), 146.5 (s), 151.6 (s), 152.6
(s); IR (nujol): max = 1710, 1688 cm-1; MS m/z (ESI): 553.27 (M + H+); anal. calcd. o
C32H32N4O5 (552,62): C, 69.55; H, 5.84; N, 10.14; ound: C, 69.49; H, 5.91; N, 10.08.
E hyl 5-((5-me hyl u an-2-yl)me hyl)-1-(phenylca bamoyl)-
1,4-dihyd opy idazine-3-ca boxyla e (45m):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:4) in 30 % yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.38 ( , 3H, OCH2CH3), 2.25 (s, 3H, CCH3),
3.09 (s, 2H, CCH2C), 3.31 (s, 2H, CCH2C4H3O), 4.314.36 (q, 2H, OCH2CH3), 5.87 (d, 1H,
CCHCHCOCH3), 5.98 (d, 1H, CCHCHCOCH3), 7.10 ( , 1H NHph),7.17 (s, 1H, NCH),
7.34and 7.52 ( ,d, 4H, NHPh), 8.61 (s, 1H NHph); 13C NMR (100 MHz, CDCl3, 25 °C): δ =
13.6 (q),14.5 (q), 25.3 ( ), 32.9 ( ), 61.9 ( ), 106.2 (d), 107.9 (d), 112.6 (s), 116.5 (d), 119.7 (d),
123.9 (d), 129.0 (d), 137.0 (s), 137.4 (s), 148.7 (s), 149.6 (s), 151.5 (s), 163.6 (s); IR (nujol):
max = 3265, 1733, 1645 cm-1; MS m/z (ESI): 368.06 (M + H+); anal. calcd. o C20H21N3O4
(367,40): C, 65.38; H, 5.76; N, 11.44; ound: C, 65.25; H, 5.74; N, 11.54.
- 136 -
E hyl 5-((5-me hyl u an-2-yl)me hyl)-3-phenylpy idazine-
1(4H)-ca boxyla e (45n):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 1:4) in 94% yield. oil; 1H NMR (400 MHz,
CDCl3, 25 °C): δ = 1.40 ( , 3H, OCH2CH3), 2.26 (s, 3H, CCH3),
3.15 (s, 2H, CCH2C), 3.37 (s, 2H, CCH2C4H3O), 4.354.40 (q, 2H, OCH2CH3), 5.87 (d, 1H,
CCHCHCOCH3), 5.98 (d, 1H, CCHCHCOCH3), 7.10 (s, 1H, NCH), 7.397.40 and 7.797.82
(2m, 5H, Ph); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.5 (q) 14.5 (q), 25.9 ( ), 33.0 ( ), 63.0
( ), 106.1 (d), 107.6 (d), 111.1 (s), 118.8 (d), 126.0 (d), 128.3 (d), 129.8 (d), 136.3 (s), 146.2
(d), 149.5 (s), 151.3 (s), 152.4 (s); IR (nujol): max = 1716 cm-1; MS m/z (ESI): 324.89 (M +
H+); anal. calcd. o C19H20N2O3 (324,37): C, 70.35; H, 6.21; N, 8.64; ound: C, 70.20; H, 6.25;
N, 8.58.
Me hyl 5-[(1H-indol-3-yl)me hyl]-3-phenylpy idazine-
1(4H)-ca boxyla e (45o):
Isola ed by column ch oma og aphy on silica gel (e hyl
ace a e/cyclohexane, 2:3) in 50% yield. oil; 1H NMR (400
MHz, CDCl3, 25 °C): δ = 3.15 (s, 2H, CCH2C), 3.57 (s, 2H,
CCH2C8H7N), 3.94 (s, 3H, OCH3), 7.03 (d, 1H, Indole), 7.137.21, (m, 3H, NCH, Indole)
7.357.37 (m, 4H, Ph, Indole) 7.64(d, 1H, Indole) 7.737.75 (m, 2H, Ph) 8.14 (s, 1H NH
Indole); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 26.2 ( ), 30.1 ( ), 53.8 (q), 111.2 (d), 111.4
(s), 114.0 (s), 117.8 (d), 118.8 (d), 119.5 (d), 122.1 (d), 122.5 (d), 126.0 (d), 127.5 (s), 128.3
(d), 129.8 (d), 136.3 (s), 136.4 (s), 146.9 (s), 153.3 (s); IR (nujol): max = 3241, 1698 cm-1; MS
m/z (ESI): 346.01 (M + H+); anal. calcd. o C21H19N3O2 (345,39): C, 73.03; H, 5.54; N, 12.17;
ound: C, 73.17; H, 5.58; N, 12.10.
- 143 -
Me hyl 15-[( e -bu oxyca bonyl)amino]-9,10-
dime hoxy-14-me hyl-5,6,12b,15- e ahyd o-8H-
[1,3]dioxo[4,5-g]py olo[2’,3’:3,4]isoquino[3,2-
a]isoquinoline-13-ca boxyla e (49d).
49d was isola ed by column ch oma og aphy on
aluminum oxide (ace a e/cyclohexane 40:60) in 60%
yield. Whi e solid; mp: 186188 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ = 1.20, 1.40 and
1.46 (3s, 9H, OC(CH3)3), 2.032.26 and 2.542.67 (2m, 2H, C(5)H2), 2.12 and 2.15 (2s, 3H,
CH3), 2.322.44 and 2.682.80 (2m, 2H, C(6)H2), 3.48 and 3.53 (2s, 3H, CO2CH3), 3.69 (s,
3H, OCH3), 3.76 (s, 3H, OCH3), 3.813.88 and 4.444.48 (2m, 2H, C(8)H2), 4.12 and 4.18 (2s,
1H, C(12b)H), 5.915.99 (m, 2H, OC(2)H2O), 6.50 and 6.61 (b s and s, 1H, C(16)H), 6.65 and
6.76 (s and b s, 1H, C(4)H), 6.786.84 (m, 1H, C(11)H), 7.037.11 (m, 1H, C(12)H), 7.95,
8.20 and 8.53 (3s, 1H, NH); 13C NMR (100 MHz, DMSOd6, 25 °C): δ = 11.4 and 11.6 (CH3),
28.0 (OC(CH3)3), 28.6 and 28.6 (C(5)), 45.7 (C(8)), 46.6 (C(6)), 49.0 and 49.6 (C(12b)), 55.4
and 55.4 (OCH3), 60.3 (CO2CH3), 60.5 (OCH3), 79.4 (OC(CH3)3), 86.2 (C(15a)), 95.2 and 97.8
(C(13)), 100.7 and 100.8 (C(2)), 105.4 and 105.4 (C(16)), 107.2 (C(4)), 109.9 (C(11)), 125.2
and 125.7 (C(12)), 127.8 (C(8a)), 128.4 (C(12a)), 128.8 (C(15b)), 131.8 (C(4a)), 145.0 (C(9)),
146.2 (C(16a)), 146.5 and 146.7 (C(3a)), 150.0 (C(10)), 155.0 (NCOO), 160.3 (C(14)), 165.5
and 165.6 (CCOO); IR (nujol): max = 3234, 1718, 1673 cm-1; MS m/z (ESI): 566.29 (M + H+);
anal. calcd. o C30H35N3O8 (565.6143): C 63.70, H 6.24, N 7.43; ound: C 63.58, H 6.19, N
7.52.
O
ON
O
O
N
HN
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15 15a
15b
16
16a
- 144 -
Me hyl 15-[( e -bu oxyca bonyl)amino]-9,10-
dime hoxy-14-me hyl-8-(2-oxop opyl)-5,6,12b,15-
e ahyd o-8H-[1,3]dioxo[4,5-
g]py olo[2’,3’:3,4]isoquino[3,2-a]isoquinoline-13-
ca boxyla e (49d’).
49d’ was isola ed by p ecipi a ion in 49% yield. Whi e
solid; mp: 166168 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ = 1.50 (3s, 9H, OC(CH3)3),
1.59 (s, 3H, CH2COCH3), 1.98 and 2.00 (2s, 3H, CH3), 2.36 (dd, 1H, J = 15.6 Hz, J = 3.2 Hz,
CH2COCH3), 2.672.69 (m, 2H, C(5)H2), 3.06 (dd, 1H, J = 15.6 Hz, J = 8.0 Hz, CH2COCH3),
3.273.41 (m, 2H, C(6)H2), 3.72 (s, 3H, CO2CH3), 3.84 (s, 3H, OCH3), 3.88 (s, 3H, OCH3),
5.13 (s, 1H, C(12b)H), 5.30 (dd, 1H, J = 8.0 Hz, J = 3.2 Hz, C(8)H2), 5.945.96 (m, 2H,
OC(2)H2O), 6.64 (s, 1H, C(16)H), 6.77 (d, 1H, J = 9.2 Hz, C(11)H), 7.00 (s, 1H, C(4)H), 7.17
(d, 1H, J = 8.8 Hz, C(12)H), 7.44 (s, 1H, NH); 13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.8
(CH2COCH3), 28.2 and 28.3 (OC(CH3)3), 30.9 and 31.0 (CH3), 31.7 (C(5)), 46.9 and 47.0
(CH2COCH3), 49.9 (C(6)), 51.9 and 52.0 (CO2CH3), 53.5 and 53.6 (C(8)), 55.0 and 55.1
(C(12b)), 55.7 and 55.8 (OCH3), 60.6 and 60.7 (OCH3), 80.8 (OC(CH3)3), 86.6 (C(15a)), 101.0
and 101.1 (C(2)), 102.2 (C(13)), 107.8 (C(16)), 108.8 and 108.9 (C(4)), 110.0 (C(11)), 119.3
and 119.4 (C(12)), 125.5 (C(8a)), 125.8 (C(12a)), 126.9 (C(15b)), 132.7 (C(4a)), 139.9 (C(9)),
142.2 (C(16a)), 145.5 (C(3a)), 147.1 (C(10)), 150.2 (NCOO), 150.8 and 152.3 (C(14)), 171.8
(CCOO), 207.9 (CH2COCH3); IR (nujol): max = 3300, 1716, 1685 cm-1; MS (EI) m/z (%): 621
(M+) (3), 564 (100), 508 (55), 432 (71); anal. calcd. o C33H39N3O9 (621.6776): C 63.76, H
6.32, N 6.76; ound: C 63.67, H 6.29, N 6.79.
O
ON
O
O
N
HN
O
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15
15a
15b
16
16a
- 145 -
E hyl 15-[( e -bu oxyca bonyl)amino]-9,10-
dime hoxy-14-me hyl-5,6,12b,15- e ahyd o-8H-
[1,3]dioxo[4,5-g]py olo[2’,3’:3,4]isoquino[3,2-
a]isoquinoline-13-ca boxyla e (49e).
49e was isola ed by p ecipi a ion in 87% yield. Whi e
solid; mp: 170172 °C; 1H NMR (400 MHz, DMSOd6, 25
°C): δ = 1.16 ( , J = 6.8 Hz, 3H, OCH2CH3), 1.20, 1.40 and 1.46 (3s, 9H, OC(CH3)3), 2.14 and
2.18 (2s, 3H, CH3), 2.252.29 and 2.592.70 (2m, 2H, C(5)H2), 2.352.45 and 2.702.81 (2m,
2H, C(6)H2), 3.70 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.813.89 and 4.444.48 (2m, 2H,
C(8)H2), 3.914.04 (m, 2H, OCH2CH3), 4.13 and 4.19 (2s, 1H, C(12b)H), 5.94, 5.97 and 5.99
(3s, 2H, ,OC(2)H2O), 6.52 and 6.60 (b s and s, 1H, C(16)H), 6.66 and 6.84 (s and b s, 1H,
C(4)H), 6.786.81 (m, 1H, C(11)H), 7.06 and 7.10 (2d, 1H, J = 8.0 Hz, J = 8.4 Hz, C(12)H),
7.87, 8.11 and 8.46 (3s, 1H, NH); 13C NMR (100 MHz, DMSOd6, 25 °C): δ = 11.4 and 11.5
(CH3), 14.1 and 14.2 (OCH2CH3), 27.4 and 27.9 (OC(CH3)3), 28.5 and 28.6 (C(5)), 44.8 and
45.7 (C(8)), 46.6 and 46.9 (C(6)), 49.0 (C(12b)), 55.4 (OCH3), 58.0 and 58.1 (OCH2CH3), 60.2
and 60.4 (OCH3), 79.3 (OC(CH3)3), 86.2 (C(15a)), 95.2 and 97.7 (C(13)), 100.8 (C(2)), 105.4
(C(16)), 107.1 (C(4)), 109.8 and 109.8 (C(11)), 125.4 and 126.0 (C(12)), 127.6 and 127.8
(C(8a)), 128.4 and 128.4 (C(12a)), 128.8 (C(15b)), 131.8 (C(4a)), 145.0 and 145.2 (C(9)),
145.4 and 146.2 (C(16a)), 146.5 and 146.7 (C(3a)), 150.0 and 150.1 (C(10)), 155.0 and 155.7
(NCOO), 159.9 and 160.2 (C(14)), 165.2 and 165.2 (CCOO); IR (nujol): max = 3226, 1713,
1667 cm-1; MS m/z (ESI): 580.21 (M + H+); anal. calcd. o C31H37N3O8 (579.6409): C 64.23,
H 6.43, N 7.25; ound: C 64.38, H 6.56, N 7.13.
O
ON
O
O
N
HN
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15 15a
15b
16
16a
- 146 -
E hyl 15-[( e -bu oxyca bonyl)amino]-9,10-
dime hoxy-14-me hyl-8-(2-oxop opyl)-5,6,12b,15-
e ahyd o-8H-[1,3]dioxo[4,5-
g]py olo[2’,3’:3,4]isoquino[3,2-a]isoquinoline-13-
ca boxyla e (49e’).
49e’ was isola ed by p ecipi a ion in 72% yield. Whi e
solid; mp: 168170 °C; 1H NMR (400 MHz, CDCl3, 25 °C): δ = 1.25 ( , J = 6.4 Hz, 3H,
OCH2CH3), 1.50 (s, 9H, OC(CH3)3), 1.61 (s, 3H, CH2COCH3), 1.99 and 2.01 (2s, 3H, CH3),
2.242.25 (m, 1H, CH2COCH3), 2.672.69 (m, 2H, C(5)H2), 3.073.11 (m, 1H, CH2COCH3),
3.303.40 (m, 2H, C(6)H2), 3.84 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 4.154.20 (m, 2H,
OCH2CH3), 5.09 (s, 1H, C(12b)H), 5.295.31 (m, H, C(8)H2), 5.95 and 5.96 (2s, 2H,
,OC(2)H2O), 6.64 (s, 1H, C(16)H), 6.76 (d, 1H, J = 9.2 Hz, C(11)H), 7.03 (s, 1H, C(4)H), 7.19
(d, 1H, J = 8.8 Hz, C(12)H), 7.40 (s, 1H, NH); 1H NMR (400 MHz, DMSOd6, 25 °C): δ = 1.06
( , J = 6.8 Hz, 3H, OCH2CH3), 1.37, 1.41 and 1.43 (3s, 9H, OC(CH3)3), 1.77 and 1.81 (2s, 3H,
CH2COCH3), 1.99 and 2.07 (2s, 3H, CH3), 2.252.29 (m, 1H, CH2COCH3), 2.542.58 and
2.672.72 2(m, 2H, C(5)H2), 3.063.11 (m, 1H, CH2COCH3), 3.283.30 (m, 2H, C(6)H2), 3.75
(s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.80CH2CH3), 4.82 (s, 1H, C(12b)H),
5.105.20 (m, 1H, C(8)H2), 5.936.04 (m, 2H, ,OC(2)H2O), 6.80 (d, 1H, J = 8.8 Hz, C(11)H),
6.84 (s, 1H, C(16)H), 6.91 (b s, 1H, C(4)H), 7.03 (d, 1H, J = 8.8 Hz, C(12)H), 9.61 (s, 1H, NH);
13C NMR (100 MHz, CDCl3, 25 °C): δ = 13.9 (OCH2CH3), 14.2 (CH2COCH3), 28.2
(OC(CH3)3), 30.9 (CH3), 31.6 (C(5)), 47.0 (CH2COCH3), 49.8 (C(6)), 53.4 and 53.5 (C(8)),
55.1 and 55.2 (C(12b)), 55.7 and 55.8 (OCH3), 60.0 (OCH3), 60.8 (OCH2CH3), 80.8
(OC(CH3)3), 86.0 (C(15a)), 100.1 (C(2)), 101.1 (C(13)), 107.7 (C(16)), 108.8 and 108.9 (C(4)),
110.9 (C(11)), 119.7 (C(12)), 125.6 (C(8a)), 125.8 (C(12a)), 126.9 (C(15b)), 132.6 (C(4a)),
139.7 (C(9)), 142.2 (C(16a)), 145.5 (C(3a)), 147.1 (C(10)), 150.1 (NCOO), 150.8 and 152.5
(C(14)), 171.2 (CCOO), 207.9 (CH2COCH3); IR (nujol): max = 3312, 1718 cm-1; MS (EI) m/z
(%): 635 (M+) (4), 578 (100), 522 (62), 432 (75); anal. calcd. o C34H41N3O9 (635.7042): C
64.24, H 6.50, N 6.61; ound: C 64.38, H 6.54, N 6.54.
O
ON
O
O
N
HN
O
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15
15a
15b
16
16a
- 147 -
Te -bu yl 15-[( e -bu oxyca bonyl)amino]-9,10-dime hoxy-14-me hyl -5,6,12b,15-
e ahyd o-8H-[1,3]dioxo[4,5-
g]py olo[2’,3’:3,4]isoquino[3,2-a]isoquinoline-13-
ca boxyla e (49 ).
49 was isola ed by column ch oma og aphy on alumina
oxide (ace a e/cyclohexane 20:80) in 96% yield. Whi e
solid; mp: 98100 °C; 1H NMR (400 MHz, DMSOd6, 25
°C): δ = 1.21, 1,35, 1.39, 1.40 and 1,46 (5s, 18H, 2
OC(CH3)3), 2.09 and 2.11 (2s, 3H, CH3), 2.202.33 and 2.532.60 (2m, 2H, C(5)H2), 2.372.44
and 2.672.75 (2m, 2H, C(6)H2), 3.70 and 3.70 (2s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.793.86
and 4.274.52 (2m, 2H, C(8)H2), 4.07 and 4.14 (2s, 1H, C(12b)H), 5.906.00 (m, 2H,
,OC(2)H2O), 6.486.76 (m, 2H, C(16)H and C(4)H), 6.797.16 (m, 2H, C(11)H and C(12)H),
7.87, 8.09 and 8.46 (3s, 1H, NH); 13C NMR (100 MHz, DMSOd6, 25 °C): δ = 11.4 and 11,5
(CH3), 27.4, 27.7, 28.0 and 28.3 (2 OC(CH3)3), 28.7 (C(5)), 45.0 and 45.9 (C(8)), 46.6 and 47.0
(C(6)), 49.0 (C(12b)), 55.4 (OCH3), 60.2 and 60.4 (OCH3), 78.1 (OC(CH3)3), 79.3 (OC(CH3)3),
86.0 (C(15a)), 96.8 and 99.7 (C(13)), 100.9 (C(2)), 105.3 (C(16)), 107.2 (C(4)), 109.6 (C(11)),
125.4 (C(12)), 126.1 (C(8a)), 127.8 (C(12a)), 128.6 and 128.8 (C(15b)), 132.0 (C(4a)), 145.0
and 145.4 (C(9)), 146.2 (C(16a)), 146.5 and 146.7 (C(3a)), 150.1 and 150.2 (C(10)), 155.1 and
155.8 (NCOO), 159.3 and 159.4 (C(14)), 165.0 (CCOO); IR (nujol): max = 3237, 1756, 1679
cm-1; MS m/z (ESI): 608.24 (M + H+); anal. calcd. o C33H41N3O8 (607.6941): C 65.22, H 6.80,
N 6.91; ound: C 65.04, H 6.76, N 7.03.
O
ON
O
O
N
HN
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15 15a
15b
16
16a
- 148 -
Dime hyl {15-[( e -bu oxyca bonyl)amino]-9,10-
dime hoxy-14-me hyl-5,6,12b,15- e ahyd o-8H-
[1,3]dioxo[4,5-g]py olo[2’,3’:3,4]isoquino[3,2-
a]isoquinolin-13-yl}phosphona e (49g).
49g was isola ed by column ch oma og aphy on
aluminum oxide (ace a e/cyclohexane 40:60) in 22%
yield. Whi e solid; mp: 101104 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ = 1.16 ( , J = 6.8
Hz, 3H, OCH2CH3), 1.20, 1,40 and 1.44 (3s, 9H, OC(CH3)3), 2.06 and 2.08 (s and b s, 3H,
CH3), 2.132.23 and 2.542.64 (2m, 2H, C(5)H2), 2.312.45 and 2.652.79 (2m, 2H, C(4)H2),
2.92 and 2.96 (2d, 3H, J = 11.2 Hz, J = 11.6 Hz, POCH3), 3.70, (s, 3H, OCH3), 3.44 and 3.46
(2d, 3H, J = 11.2 Hz, J = 11.2 Hz, POCH3), 3.68, (s, 3H, OCH3),3.76 (s, 3H, OCH3), 3.783.90
and 4.414.45 (2m, 2H, C(8)H2), 3.984.07 (m, 1H, C(12b)H), 5.956.02, (m, 2H,
,OC(2)H2O), 6.48, 6.55, 6.60 and 6.67 (2b s and 2s, 2H, C(16)H and C(4)H), 6.766.88 (m,
2H, C(11)H and C(12)H), 7.08, 8.41 and 9.54 (b s, s, b s 1H, NH); 13C NMR (100 MHz,
DMSOd6, 25 °C): δ = 11.9 and 12,1 (CH3), 28.0 and 28.1 (OC(CH3)3), 28.6 and 28.6 (C(5)),
45.1 and 45.8 (C(8)), 46.7 and 47.2 (C(6)), 50.1 (2JCP = 3.9 Hz (C(12b)), 50.7 (2JCP = 5.2 Hz
POCH3), 50.8 (2JCP = 4.9 Hz POCH3) 55.5 (OCH3), 60.4 and 60.6 (OCH3), 79.3 and 79.3
(OC(CH3)3), 85.7 (C(15a)), 100.8 (C(13)), 105.6 (C(2)), 107.0 (C(16)), 109.9 (C(4)), 110.1
(C(11)), 124.8 and 124.9 (C(12)), 127.8 (C(8a)), 128.1 and 128.1 (C(12a)), 129.1 (C(15b)),
132.2 (C(4a)), 145.3 (C(9)), 145.7 (C(16a)), 146.3 (C(3a)), 146.5 and 146.6 (C(10)), 150.3 and
150.4 (NCOO) 155.2 and 156.0 (C(14)); IR (nujol): max = 3268, 1751, 1698 cm-1; MS m/z
(ESI): 616.13 (M + H+); anal. calcd. o C30H38N3O9P (615.6113): C 58.53, H 6.22, N 6.83;
ound: C 58.33, H 6.17, N 6.94.
O
ON
O
O
N
P
HN
O
O
OO
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15 15a
15b
16
16a
- 149 -
Me hyl 15-[( e -bu oxyca bonyl)amino]-9,10-
dime hoxy-14-p opyl-5,6,12b,15- e ahyd o-8H-
[1,3]dioxo[4,5-g]py olo[2’,3’:3,4]isoquino[3,2-
a]isoquinoline-13-ca boxyla e (49h).
49h was isola ed by column ch oma og aphy on
aluminum oxide (ace a e/cyclohexane 40:60) in 73%
yield. Whi e solid; mp: 98100 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ = 0.87 ( , J = 7.2
Hz, 3H, CH2CH2CH3), 1.101.16 (m, 2H, CH2CH2CH3), 1.20, 1.39, 1.40 and 1.47 (4s, 9H,
OC(CH3)3), 2.082.42 and 2.492.78 (2m, 6H, C(5)H2, C(6)H2 and CH2CH2CH3 ), 3.47 and
3.52 (2s, 3H, CO2CH3), 3.69 and 3.69 (2s, 3H, OCH3), 3.75 (s, 3H, OCH3), 3.793.94 and
4.454.49 (2m, 2H, C(8)H2), 4.11 and 4.19 (2s, 1H, C(12b)H), 5.916.00 (m, 2H, OC(2)H2O),
6.486.68 (m, 2H, C(16)H and C(4)H), 6.777.10 (m, 2H, C(11)H and C(12)H), 7.89, 8.22,
8.55 and 8.60 (4s, 1H, NH); 13C NMR (100 MHz, DMSOd6, 25 °C): δ = 14.0 (CH2CH2CH3),
14.1 (CH2CH2CH3), 20.5 (CH2CH2CH3), 27.3 and 28.0 (OC(CH3)3), 28.7 (C(5)), 44.8 (C(8)),
46.6 (C(6)), 49.1 (C(12b)), 49.6 and 49.7 (CO2CH3), 55.4 (OCH3), 60.3 and 60.5 (OCH3), 79.3
(OC(CH3)3), 86.4 (C(15a)), 97.5 (C(13)), 100.9 (C(2)), 105.3 (C(16)), 107.1 (C(4)), 109.8
(C(11)), 125.4 (C(12)), 125.7 (C(8a)), 128.4 (C(12a)), 128.9 (C(15b)), 132.0 (C(4a)), 145.1
(C(9)), 146.3 (C(16a)), 146.8 (C(3a)), 150.1 (C(10)), 155.7 (NCOO), 164.1 and 160.8 (C(14)),
165.3 and 165.4 (CCOO); IR (nujol): max = 3271, 1749, 1732 cm-1; MS m/z (ESI): 594.22 (M
+ H+); anal. calcd. o C32H39N3O8 (593.6675): C 64.74, H 6.62, N 7.08; ound: C 64.90, H
6.67, N 6.96.
O
ON
O
O
N
NH
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15 15a
15b
16
16a
- 150 -
E hyl 15-[(e hoxyca bonyl)amino]-9,10-dime hoxy-
14-me hyl-5,6,12b,15- e ahyd o-8H-[1,3]dioxo[4,5-
g]py olo[2’,3’:3,4]isoquino[3,2-a]isoquinoline-13-
ca boxyla e (49i).
49i was isola ed by column ch oma og aphy on aluminum
oxide (ace a e/cyclohexane 30:70) in 62% yield. Whi e
solid; mp: 134136 °C; 1H NMR (400 MHz, DMSOd6, 25
°C): δ = 1.19 ( , J = 6.8 Hz, 3H, OCH2CH3), 2.13 and 2.16 (2s, 3H, CH3), 2.182.24 and
2.562.64 (2m, 2H, C(5)H2), 2.332.41 and 2.682.75 (2m, 2H, C(6)H2), 3.61 (s, 3H,
CO2CH3), 3.69 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 3.813.88 and 4.414.46 (2m, 2H, C(8)H2),
3.924.02 (m, 2H, OCH2CH3), 4.13 and 4.17 (2s, 1H, C(12b)H), 5.92, 5.97 and 5.99 (3s, 2H,
OC(2)H2O), 6.50 and 6.60 (b s and s, 1H, C(16)H), 6.65 and 6.84 (s and b s, 1H, C(4)H), 6.78-
6.80 (m, 1H, C(11)H), 7.05 and 7.12 (2d, 1H, J = 8.4 Hz, J = 8.4 Hz, C(12)H), 8.37, 8.88 and
9.05 (3s, 1H, NH); 13C NMR (100 MHz, DMSOd6, 25 °C): δ = 11.5 (CH3), 14.3 (OCH2CH3),
28.5 (C(5)), 45.7 (C(8)), 46.1 (C(6)), 49.0 (C(12b)), 52.1 (CO2CH3), 55.4 (OCH3), 58.2 and
58.3 (OCH2CH3), 60.3 and 60.5 (OCH3), 86.3 (C(15a)), 97.9 (C(13)), 100.9 (C(2)), 105.3
(C(16)), 107.1 (C(4)), 109.8 (C(11)), 125.6 and 126.0 (C(12)), 127.7 (C(8a)), 128.2 (C(12a)),
128.9 (C(15b)), 131.8 (C(4a)), 145.2 and 145.4 (C(9)), 146.3 (C(16a)), 146.5 and 146.8
(C(3a)), 150.2 (C(10)), 155.2 (NCOO), 160.0 (C(14)), 165.3 (CCOO); IR (nujol): max = 3279,
1756, 1720, cm-1; MS m/z (ESI): 538.19 (M + H+); anal. calcd. o C28H31N3O8 (537.5612): C
62.56, H 5.81, N 7.82; ound: C 62.80, H 5.87, N 7.67.
O
ON
O
O
N
H
N
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15
15a
15b
16
16a
- 151 -
Me hyl 15-[(anilinoca bonyl)amino]-9,10-
dime hoxy-14-me hyl-5,6,12b,15- e ahyd o-8H-
[1,3]dioxo[4,5-g]py olo[2’,3’:3,4]isoquino[3,2-
a]isoquinoline-13-ca boxyla e (49j).
49j was isola ed by column ch oma og aphy on
aluminum oxide (ace a e/cyclohexane 50:50) in 61%
yield. Whi e solid; mp: 130134 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ =, 2.20 and 2.24
(2s, 3H, CH3), 2.322.36 and 2.552.66 (2m, 2H, C(5)H2), 2.442.48 and 2.682.77 (2m, 2H,
C(6)H2), 3.49 and 3.54 (2s, 3H, CO2CH3), 3.69 and 3. 71 (2s, 3H, OCH3), 3.77 and 3.78 (2s,
3H, OCH3), 3.813.88 and 4.484.51 (2m, 2H, C(8)H2), 4.15 and 4.26 (2s, 1H, C(12b)H), 5.92,
6.02,6.04 and 5.42 (4s, 2H, OC(2)H2O), 6.677.40 (C(16)H), C(4)H), C(11)H, C(12)H NHph)
7.73 (s, 1H, NHph) 8.86 (s, 1H, NH); IR (nujol): max = 3312, 3245, 1746, 1682, cm-1; MS m/z
(ESI): 585.27 (M + H+); anal. calcd. o C32H32N4O7 (584.62): C, 65.74; H, 5.52; N, 9.58; ound:
C, 65.59; H, 5.56; N, 9.5851.
Men hol 15-[(me hoxyca bonyl)amino]-9,10-dime hoxy-
14-me hyl-5,6,12b,15- e ahyd o-8H-[1,3]dioxo[4,5-
g]py olo[2’,3’:3,4]isoquino[3,2-a]isoquinoline-13-
ca boxyla e (49k).
49k was isola ed by column ch oma og aphy on aluminum
oxide (ace a e/cyclohexane 70:30) in 55% yield. Whi e solid;
mp: 112116 °C; 1H NMR (400 MHz, DMSOd6, 25 °C): δ =
0.511.12(m, 14H, Men hol), 1.581.77(2m, 4H, Men hol),
2.10, 2.15 and 2.18 (2s, 3H, CH3), 2.272.30 and 2.562.64 (2m, 2H, C(5)H2), 2.352.43 and
2.662.75 (2m, 2H, C(6)H2), 3.61 (s, 3H, CO2CH3), 3.69 (s, 3H, OCH3), 3.74 (2s, 3H,
OCH3), 4.13 and 4.17 (2s, 1H, C(12b)H), 4.364.68 (2m, 2H, C(8)H2), 5.91, 5.97 and 5.99 (3s,
2H, OC(2)H2O), 6.48 (m 4H, C(16)H), C(4)H), C(11)H), C(12)H), 8.38, 8.87, 8.89 and
9.06 (4s, 1H, NH); IR (nujol): max = 3289, 1732, 1698, cm-1; MS m/z (ESI): 648.39 (M + H+);
anal. calcd. o C36H45N3O8 (647.76): C, 66.75; H, 7.00; N, 6.49; ound: C, 66.89; H, 7.07; N,
6.43
O
ON
O
O
N
H
N
O
O
H
N
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15
15a
15b
16
16a
O
ON
O
O
N
H
N
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15
15a
15b
16
16a
- 152 -
Anilino 15-[(anilinoca bonyl)amino]-9,10-
dime hoxy-14-me hyl-5,6,12b,15- e ahyd o-8H-
[1,3]dioxo[4,5-g]py olo[2’,3’:3,4]isoquino[3,2-
a]isoquinoline-13-ca boxyla e (49l).
49l was isola ed by column ch oma og aphy on
aluminum oxide (ace a e/cyclohexane 50:50) in
61% yield. Whi e solid; mp: 173137 °C; 1H NMR
(400 MHz, DMSOd6, 25 °C): δ = 2.07 and 2.12 (2s,
3H, CH3), 2.172.21 and 2.552.61 (2m, 2H, C(5)H2), 2.292.38 and 2.632.69 (2m, 2H,
C(6)H2), 3.61 (s, 3H, CO2CH3), 3.76 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 4.024.13 (m, 2H,
C(8)H2), 4.45 and 4.47 (2s, 1H, C(12b)H), 5.67 and 5.97 (2s, 2H, OC(2)H2O), 6.46 7.60 (s
and m 16H, C(16)H), C(4)H, C(11)H, C(12)H, 2NHph), 8.57 9.97 (2s, 1H, NH); IR (nujol):
max = 3313, 3289,3279, 1731, 1719, cm-1; MS m/z (ESI): 646.27 (M + H+); anal. calcd. o
C37H35N5O6 (645.70): C, 68.82; H, 5.46; N, 10.85; ound: C, 68.75; H, 5.42; N, 10.91.
Me hyl 15-[(me hoxyca bonyl)amino]-9,10-dime hoxy-
14-me hyl-5,6,12b,15- e ahyd o-8H-[1,3]dioxo[4,5-
g]py olo[2’,3’:3,4]isoquino[3,2-a]isoquinoline-13-
ca boxyla e (49m).
49m was isola ed by column ch oma og aphy on aluminum
oxide (ace a e/cyclohexane 70:30) in 85% yield. Whi e solid;
mp: 107111 °C; 1H NMR (400 MHz, DMSOd6, 25 °C):, 2.12 and 2.15 (2s, 3H, CH3),
2.182.25 and 2.562.63 (2m, 2H, C(5)H2), 2.342.45 and 2.642.76 (2m, 2H, C(6)H2), 3.48
and 3.53 (2s, 3H, CO2CH3), 3.60 (2s, 3H, CO2CH3), 3.69 (s, 3H, OCH3), 3.76 (s, 3H, OCH3),
3.823.88 and 4.414.46 (2m, 2H, C(8)H2), 4.12 (b s, 1H, C(12b)H), 5.97 and 6.00 (3s, 2H,
OC(2)H2O), 6.50 and 6.60 (b s and s, 1H, C(16)H), 6.64 and 6.83 (s and b s, 1H, C(4)H), 6.78-
6.80 (m, 1H, C(11)H), 7.04 and 7.10 (2d, 1H, J = 8.4 Hz, J = 8.4 Hz, C(12)H), 8.89 and 9.07
(3s, 1H, NH); 13C NMR (100 MHz, DMSOd6, 25 °C): δ = 11.5 (CH3), 28.5 (C(5)), 45.7 (C(8)),
46.6 (C(6)), 48.9 (C(12b)), 49.8 (CO2CH3), 52.1 (CO2CH3), 55.4 (OCH3), 60.3 (OCH3), 86.3
(C(15a)), 97.8 (C(13)), 100.9 (C(2)), 105.2 (C(16)), 107.2 (C(4)), 110.0 (C(11)), 125.3 and
125.6 (C(12)), 127.7 (C(8a)), 128.2 (C(12a)), 128.9 (C(15b)), 131.7 (C(4a)), 145.2 (C(9)),
146.3 (C(16a)), 146.8 (C(3a)), 150.2 (C(10)), 157.2 (NCOO), 160.0 (C(14)), 165.6 (CCOO);
IR (nujol): max = 3288, 1750, 1736, cm-1; MS m/z (ESI): 524.11 (M + H+); anal. calcd. o
C27H29N3O8 (523.53): C, 61.94; H, 5.58; N, 8.03; ound: C, 61.78; H, 5.53; N, 8.10
O
ON
O
O
N
H
N
O
O
H
N
HN
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33a 44a 5
6
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8a 9
10
11
12
12a
12b
13
14
15
15a
15b
16
16a
O
ON
O
O
N
H
N
O
O
O
O
1
2
33a 44a 5
6
8
8a 9
10
11
12
12a
12b
13
14
15
15a
15b
16
16a
