LETTER 885
S udies on he Syn hesis o 2-Alkyl-5-a yl-1,3,4-oxadiazolines om
N-Acylhyd azones
Syn hesis o 2-Alkyl-5-a yl-1,3,4-oxadiazolines
Eugenia Ma qués-López,a,1, Elena Díez,a Eloísa Ma ín-Zamo a,a Eleu e io Ál a ez,b Rosa io Fe nández,*a
José M. Lassale a*b
aDepa amen o de Química O gánica, Uni e sidad de Se illa, Apdo. de Co eos N° 1203, 41071 Se ille, Spain
E-mail: [email p o ec ed]s
bIns i u o de In es igaciones Químicas (CSIC-US), Amé ico Vespucio 49, 41092 Se ille, Spain
Fax +34(95)4460565; E-mail: jmla[email p o ec ed]sic.es
Recei ed 24 No embe 2011
SYNLETT 2012, 23, 885–888
xx.xx.2012
Ad anced online publica ion: 15.03.2012
DOI: 10.1055/s-0031-1290609; A ID: D71011ST
© Geo g Thieme Ve lag S u ga · New Yo k
Abs ac : Reac ion o N-acylhyd azones wi h benzyloxyace yl
chlo ide in he p esence o i-P 2E N a o ds new 1,3,4-oxadiazo-
lines in excellen yields (72–95%), unde mild eac ion condi ions
and in sho eac ion imes. The s uc u es o he p oduc s we e con-
i med by single-c ys al X- ay di ac ome y. A plausible eac ion
mechanism is p oposed.
Key wo ds: N-acylhyd azones, oxadiazolines, benzyloxyace yl
chlo ide, acyla ion, he e ocycles
Among i e-membe ed he e ocycles, 1,3,4-oxadiazolines
and de i a i es ha e been he subjec o chemical and bi-
ological s udies on accoun o hei in e es ing pha maco-
logical p ope ies, including an imic obial,2 an i-
in lamma o y,3 an i i al,4 and an i umo ac i i ies.5 Se-
lec ed s uc u es 1–3, a e ou lined in Figu e 1. As a conse-
quence o he signi ican biological ac i i y, he syn hesis
o new and easily accessible 1,3,4-oxadiazolines seems an
aim o g ea in e es .
P e ious syn he ic me hods epo ed o hese compounds
in ol e cycliza ion o anionic N-acylhyd azones unde
acyla ion condi ions using ace ic anhyd ide6 o ace yl
chlo ide.7 O he me hods include oxida i e cycliza ion o
aldazines using Pb(OAc)4.8 On he o he hand, he o ma-
ion o simila s uc u es is desc ibed o eac ions in ol -
ing ke enes (gene a ed in si u) and N-acylhyd azones o
2,3-diaza-1,3-dienes (azines) ei he wi h mode a e o
good yields o as by-p oduc s.9 The absence o epo s o
he syn hesis o simple 2-alkyl-5-a ylde i a i es is no e-
wo hy.
Du ing he las ew yea s, ou esea ch g oup has been in-
e es ed in he asymme ic syn hesis o b-lac ams by a
S audinge -like eac ion be ween aldehyde N,N-dialkyl-
hyd azones and unc ionalized benzyloxyke ene10 (gene -
a ed in si u om benzyloxyace yl chlo ide 4 wi h a base)
o amino ke enes.11 Recen ly, we decided o explo e he
beha io o mo e eac i e N-acylhyd azones 5 as he imi-
ne componen in he [2+2] cycloaddi ion. Taking ad an-
age o he high ela i e s abili y o hyd azones owa d
enoliza ion, we decided o ocus on alipha ic de i a i es.
Thus, he eac ion o iso ale aldehyde benzoyl hyd azone
(5a) as a model subs a e and benzyloxyace yl chlo ide (4)
as he eagen , was chosen o p elimina y expe imen s.
Howe e , unde ou p e iously op imized condi ions (2
equi o 4, 4 equi o E 3N in anhyd ous oluene),10 he e-
ac ion a o ded no ace o he co esponding b-lac am 6,
ins ead, o ma ion o oxadiazoline 7a in 80% yield was
obse ed a e 24 hou s a oom empe a u e (Scheme 1).
Scheme 1 Fo ma ion o oxadiazoline 7a
Figu e 1 Selec ed bioac i e 1,3,4-oxadiazolines: 1 (an i ungal),2 2
(an i-in lamma o y),3 and 3a and 3b (an i umo )5a,c
N
O
N
MeO
MeO
O
2
3a: X = NMe2
3b: X = OMe
N
O
N
O
H
1
MeO
F
O
O2N
N
O
N
O
HO
O
X
BnO Cl
O
N
O
N
O
BnO
Ph
NNH
H
5a
4
7a
N
ONH
BnO
6
+
OPh
E 3N
Ph
O
. .
oluene
80%
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886 E. Ma quéz-López e al. LETTER
Synle 2012,23, 885–888 © Thieme S u ga · New Yo k
Using he same model eac ion, u he expe imen s we e
pe o med o in es iga e he in luence o he base and/o
he eac ion empe a u e on he p oduc dis ibu ion. To
his end, eac ions pe o med a oom empe a u e using
diisop opyle hylamine and ibenzylamine we e analyzed
a e 24 hou s and compa ed wi h he ie hylamine-p o-
mo ed eac ion. The esul s, collec ed in Table 1 (en ies
1–3), indica e a sligh imp o emen wi h diisop opyle hy-
lamine and a signi ican d op o yield in he case o he
less basic ibenzylamine.12 Finally, pe o ming he eac-
ions a 80 °C no only p o ided a sligh ly be e yield, bu
also led o a signi ican a e accele a ion, leading o i u-
ally comple e eac ions in only i e hou s (en ies 4 and
5).
These op imized condi ions [hyd azone (2 equi ), i-
P 2E N (4 equi ), anhyd ous oluene, 80 °C] we e hen ap-
plied o he eac ion o di e en N-acylhyd azones 5a–g
wi h benzyloxyace yl chlo ide (4) o he syn hesis o ad-
duc s 7a–g. The esul s, collec ed in Table 2, indica e he
e iciency o he eac ion o p ima y (en ies 1, 3, 6, and
7), seconda y (en ies 2 and 5), and e en e ia y (en y 4)
alipha ic de i a i es, al hough highe eac ion empe a-
u es and longe eac ion imes we e equi ed in he la e
case. Examples ha illus a e he compa ibili y wi h elec-
on-wi hd awing (en ies 4–6) o elec on-dona ing (en-
y 7) g oups a e included.
In addi ion o he usual spec oscopic cha ac e iza ion
(see he Suppo ing In o ma ion), single-c ys al X- ay di -
ac ion analysis o adduc 7e (Figu e 2)13 unequi ocally
con i med he p oposed s uc u e.
Two plausible eac ion pa hs can be a p io i p oposed o
his eac ion. As is he case in eac ions wi h N,N-dialkyl-
hyd azones, benzyloxyace yl chlo ide 4 could possibly e-
ac i s wi h he base o o m he co esponding
benzyloxy ke ene 8 a e hyd ogen chlo ide b-elimina-
ion. Ensuing nucleophilic addi ion o he sp2 imine ni o-
gen o 5 o he elec on-de icien ke ene cen al ca bon
and spon aneous cycliza ion o he esul ing zwi e ionic
in e media e 10 would ende he p oduc 7 (Scheme 2,
blue pa h). A second possible pa h s a s wi h he acyla-
ion o he imino ni ogen o he subs a e by 4 o o m
acyl immonium in e media e 9 om which dep o ona ion
by he base ende s he inal p oduc 7 h ough he same
zwi e ionic in e media e 10.
Se e al pieces o e idence sugges ha he mechanism in-
ol ing ke ene 8 can be dis ega ded. Fi s , p e ious
s udies11b indica e ha he a e o ke ene o ma ion de-
c eases in he o de E 3N > i-P 2E N >> Bn3N, wi h he la -
e being much slowe han he obse ed eac ion a e.
Such a dependence on he base is no consis en wi h he
obse ed end. Fu he e idence o 9 as a eac ion in e -
media e was ob ained om he eac ion o 5g wi h 4 in he
Table 1 Sc eening o Reac ion Condi ionsa
En y Base Temp (°C) Time (h) Yield (%)b
1E
3N . . 2480
2i-P 2E N . . 24 84
3Bn
3N . . 24 51
4i-P 2E N 80 5 88
5Bn
3N80 5 64
a Reac ions pe o med a 0.5 mmol scale using 4 (2 equi ) and base (4
equi ).
b Isola ed yield a e column ch oma og aphy.
BnO Cl
O
N
O
N
O
BnO
Ph
5a
4
7a
H
N
H
NPh
OR3N (4 equi ), oluene
Table 2 Syn hesis o Oxadiazolines 7a–g om N-Acylhyd azones
5a–g
En y 5A R Time
(h)
7Yield
(%)a
15a Ph i-Bu 5 7a 88
25b Ph i-P 5 7b 86
35c Ph CH2CH2Ph 5 7c 89
4b5d 4-O2NC6H4 -Bu 16 7d 72
55e 4-O2NC6H4i-P 5 7e 93
65 4-O2NC6H4i-Bu 4 7 95
75g 4-MeOC6H4i-Bu 4 7g 89
a Isola ed yields a e column ch oma og aphy.
b Reac ion pe o med a 100 °C.
BnO
Cl
O
oluene
i
-P 2E N
N
O
N
O
BnO
RA
N
H
N
HR
A
O
5a
–
g
4
7a
–
g
+
80 °C
Figu e 2 X- ay c ys al s uc u e o oxadiazoline 7e. Hyd ogen
a oms omi ed o cla i y. The mal ellipsoids d awn a he 50% p oba-
bili y le el.
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LETTER Syn hesis o 2-Alkyl-5-a yl-1,3,4-oxadiazolines 887
© Thieme S u ga · New Yo k Synle 2012,23,885–888
p esence o a la ge excess o ibenzylamine (8 equi ) as
he base. Unde hese condi ions, a mode a e (50% yield)
amoun o p oduc 7g was ob ained, along wi h a small
amoun (22%) o enhyd azine by-p oduc 11 (Scheme 3),
which is p esumed o o m by compe i i e dep o ona ion
o he acidic a-me hylene om he same in e media e 9.
Scheme 3
In summa y, use o diisop opyle hylamine as he base en-
ables a mild and e icien syn hesis o 5-alkyl-1,3,4-oxa-
diazolines 7a–g om N-acylhyd azones 5a–g and
benzyloxyace yl chlo ide 4. Expe imen al e idence sug-
ges s ha he eac ion p oceeds h ough N-acyliminium
in e media es esul ing om di ec acyla ion o he hyd a-
zone N(sp2) a om by acyl chlo ide 4.
Suppo ing In o ma ion o his a icle is a ailable online a
h p://www. hieme-connec .com/ejou nals/ oc/synle .
Acknowledgmen
We hank he Spanish Minis e io de Ciencia e Inno ación (g an
numbe s CTQ2010-15297 and CTQ2010-14974), he Eu opean
FEDER unds, and he Jun a de Andalucía (g an numbe s 2008/
FQM-3833 and 2009/FQM-4537) o inancial suppo .
Re e ences and No es
(1) P esen add ess: Labo a o io de Sín esis Asimé ica,
Depa amen o de Química O gánica, Ins i u o de Sín esis
Química y Ca álisis Homogénea, Uni e sidad de Za agoza-
CSIC, 50009 Za agoza, Spain
(2) Rollas, S.; Gule man, N.; E deniz, H. Il Fa maco 2002, 57,
171.
(3) Rajak, H.; Kha ya, M. D.; Mish a, P. Yakugazu Zasshi 2007,
127, 1757.
(4) Ali, O. M.; Ame , H. H.; Abdel-Rahman, A. A.-H. Syn hesis
2007, 2823.
(5) (a) Tahi , S. K.; Han, E. K.-H.; C edo, B.; Jae, H.-S.;
Pie enpol, J. A.; Sca ena, C. D.; Wu-Wong, J. R.; F os , D.;
Sham, H.; Rosenbe g, S. H.; Ng, S.-C. Cance Res. 2001, 61,
5480. (b) Hans, J.; Wallace, E. M.; Zhao, Q.; Lyssika os, J.
P.; Aiche , T. D.; Robinson, J.; Allen, S. PCT In . Appl. WO
2006044825, 2006. (c) Lee, L.; Robb, L. M.; Lee, M.; Da is,
R.; Mackay, H.; Cha da, S.; Babu, B.; O’B ien, E. L.;
Risinge , A. L.; Moobe y, S. L.; Lee, M. J. Med. Chem.
2010, 53, 325.
(6) Fo selec ed examples, see: (a) Somogyi, L. Liebigs Ann.
Chem. 1994, 623. (b) Somogyi, L. Bull. Chem. Soc. Jpn.
2001, 74, 873. (c) El Ash y, E. S. H.; Rashed, N.; Awad, L.
F.; Abdel-Rahman, A. A. H.; Rasheed, H. A. J. Chem. Res.,
Minip in 2001, 440.
(7) (a) A mes o, D.; Gallego, M. G.; Ho spool, W. M.; Ramos,
A. Te ahed on Le . 1988, 29, 3581. (b) Somogyi, L.
Te ahed on 1985, 41, 5187.
(8) Gillis, B. T.; Lamon agne, M. P. J. O g. Chem. 1967, 32,
3318.
(9) (a) Alcaide, B.; Mi anda, M.; Pé ez-Cas ells, J.; Polanco, C.;
Sie a, M. A. J. O g. Chem. 1994, 59, 8003. (b) Singh, G.
S.; Shang, M.; Iba a, T. Indian J. Chem., Sec . B: O g. Chem.
Incl. Med. Chem. 2000, 39, 554. (c) Singh, G. S.
J. He e ocycl. Chem. 2006, 43, 1653. (d) Kaspen akis, G.
C.; Tsole idis, C. A.; S ephanidou-S ephana ou, J.
J. He e ocycl. Chem. 2007, 44, 425.
(10) (a) Fe nández, R.; Fe e e, A.; Lassale a, J. M.; Lle a, J. M.;
Monge, A. Angew. Chem. In . Ed. 2000, 39, 2893.
(b) Fe nández, R.; Fe e e, A.; Lassale a, J. M.; Lle a, J. M.;
Ma ín-Zamo a, E. Angew. Chem. In . Ed. 2002, 41, 831.
(c) Ma ín-Zamo a, E.; Fe e e, A.; Lle a, J. M.; Muñoz, J.
M.; Pappala do, R. R.; Fe nández, R.; Lassale a, J. M.
Chem. Eu . J. 2004, 10, 6111.
(11) (a) Díez, E.; Fe nández, R.; Ma qués-López, E.; Ma ín-
Zamo a, E.; Lassale a, J. M. O g. Le . 2004, 6, 2749.
(b) Ma qués-López, E.; Ma ín-Zamo a, E.; Díez, E.;
Fe nández, R.; Lassale a, J. M. Eu . J. O g. Chem. 2008,
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(12) (a) G a on, J.; Besseau, F.; Be helo , M.; Raczynska, E. D.;
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(13) C ys al da a o 7e (CCDC 850772): C20H21N3O5;
M= 383.40; monoclinic; a= 33.9831 (8) Å, b= 6.14820
Scheme 2 Plausible eac ion mechanisms
N
H
N
RN
ON
BnO
OCl
BnO A
O
A
O
H
R
+
4
5
8
+
Cl–
O
BnO
H
H
R3N
– R3NH+Cl–
– R3NH+Cl–
9
R3N
N
ON
BnO
A
O
R
+-
10
N
H
N
R
A
O
5
+
7
N
ON
BnO
A
O
R
+
–H
Bn3N
N
O
N
O
BnO A
N
H
N
H
A
O
5g
4
7g
(50%)
11
(22%)
A =
p
-anisyl
N
ON
BnO
A
O
H
H
N
OH
N
BnO
A
O
+
+
PhMe
. .
Bn3N
9
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888 E. Ma quéz-López e al. LETTER
Synle 2012,23, 885–888 © Thieme S u ga · New Yo k
(10) Å, c= 20.2932 (5) Å, a= 90.00°, b= 118.3420 (10)°,
g= 90.00°; V= 3731.71 (14) Å3; T= 100 (2) K; space g oup
C2/c; Z=8; m(MoKa) = 0.100 mm–1; 34754 e lec ions
measu ed, 5690 independen e lec ions (Rin = 0.0436). The
inal R1 alues we e 0.0474 (I > 2s(I)). The inal wR(F2)
alues we e 0.1106 (I > 2s(I)). The inal R1 alues we e
0.0941 (all da a). The inal wR(F2) alues we e 0.1314 (all
da a); goodness-o - i : 1.030.
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