Mul icomponen Ca aly ic
Reac ions
Theo e ical and Expe imen al S udies
Ma in Pauze
Ma in Pauze Mul icomponen Ca aly ic Reac ions
Doc o al Thesis in O ganic Chemis y a S ockholm Uni e si y, Sweden 2021
Depa men o O ganic Chemis y
ISBN 978-91-7911-544-9
(cc)2021 MARTIN PAUZE (cc by-nc-nd 4.0)
Mul icomponen Ca aly ic Reac ions
Theo e ical and Expe imen al S udies
Ma in Pauze
Academic disse a ion o he Deg ee o Doc o o Philosophy in O ganic Chemis y a
S ockholm Uni e si y o be publicly de ended on Tuesday 28 Sep embe 2021 a 10.00 in online
ia Zoom, public link is a ailable a he depa men websi e.
Abs ac
In his hesis, Densi y Func ional Theo y (DFT) me hods ha e been applied o s udy he mechanisms o h ee di e en
mul icomponen o ganic eac ions. Also, a new syn he ic p ocedu e o he p epa a ion o quinolinium sal s is p esen ed,
and i s mechanism also s udied by DFT calcula ions. The hesis summa izes he wo k ealized in wo uni e si ies, and
is di ided in he ollowing way: The i s pa o he hesis conce ns he de elopmen o an expe imen ally simple, bu
mechanis ically complex, eac ion o he o ma ion o qua e na y quinolinium sal s ca alyzed by palladium sal s. This
mul icomponen p ocess uses eadily a ailable p opylamine and i s de i a i es as s a ing ma e ials. Th ough DFT s udies
a mechanism h ough he ac i a ion o wo alipha ic C-H bonds is p oposed. The second pa ocuses on he mechanis ic
in es iga ion o a h ee-componen s eac ion, namely e minal alkynes, CO2 and allylic chlo ides, media ed by an N-
he e ocyclic ca bene ca alys ha yields p opa gylic es e s. By DFT calcula ions, he a e-limi ing s ep was iden i ied o
be he eac ion be ween he ca boxyla ed ca alys and he allylic chlo ide. Th ough DFT modelling, we we e also able
o unde s and he limi a ions o his eac ion. The mechanism o a mul icomponen eac ion in which allylic alcohols
a e ans o med in o α- unc ionalized ca bonyls was also in es iga ed. The eac ion elies on an umpolung s a egy ha
enables o eac enol in e media es wi h di e en nucleophiles. By DFT s udies, a mechanism ia enolonium in e media es
is p oposed, which p o ides an unde s anding o he selec i i y o he eac ion. The inal chap e o he hesis deals
wi h ano he mul icomponen sol en - ee eac ion o syn hesizing p opa gylamines ca alyzed by manganese ia a KA2
coupling. DFT s udies we e unde aken and a mechanism ia manganese phenylace ylide species is p oposed.
Keywo ds: C-H Ac i a ion, Qua e na y Quinolinium, O ganoca alys , T ansi ion Me al Ca alys , Umpolung S a egy,
Mul i-s ep Reac ions, Mechanis ic In es iga ion, Densi y Func ional Theo y.
S ockholm 2021
h p://u n.kb.se/ esol e?u n=u n:nbn:se:su:di a-195122
ISBN 978-91-7911-544-9
ISBN 978-91-7911-545-6
Depa men o O ganic Chemis y
S ockholm Uni e si y, 106 91 S ockholm
MULTICOMPONENT CATALYTIC REACTIONS
Ma in Pauze
Mul icomponen Ca aly ic
Reac ions
Theo e ical and Expe imen al S udies
Ma in Pauze
©Ma in Pauze, S ockholm Uni e si y 2021
ISBN p in 978-91-7911-544-9
ISBN PDF 978-91-7911-545-6
P in ed in Sweden by Uni e si e sse ice US-AB, S ockholm 2021
“I am among hose who
hink ha science has
g ea beau y”
Ma ie Cu ie
ii
Table o Con en s
Abs ac ..................................................................................................................... i
Populä e enskaplig samman a ning ...................................................................... ii
Lis o abb e ia ions ............................................................................................... iii
Lis o publica ions ................................................................................................. i
Rep in Pe missions .................................................................................................
O he documen s based on his wo k ...................................................................... i
I In oduc ion ........................................................................................................... 1
I.1 Ca alysis in o ganic chemis y ........................................................................ 1
I.1.1 Ca alysis and ca aly ic eac ions .............................................................. 1
I.1.2 T ansi ion me al ca alysis ........................................................................ 1
I.1.3 NHC ca alysis .......................................................................................... 2
I.2 Umpolung eac i i y ....................................................................................... 4
I.2.1 Hype alen Iodine .................................................................................. 5
I.2.2 CO2 Ac i a ion by NHC .......................................................................... 6
I.3 Csp² and Csp³H ac i a ions by ansi ion me als ....................................... 7
I.3.1 Mechanisms o CH bond ac i a ions .................................................... 7
I.3.2 Di ec ing g oups o CH ac i a ion ....................................................... 8
I.3.3 Csp³H ac i a ion o alipha ic amines .................................................... 10
I.4 A3 coupling and KA2 coupling eac ions ...................................................... 11
I.5 Densi y unc ional heo y o mechanis ic in es iga ions ............................ 13
I.5.1 P inciples o densi y unc ional heo y and unc ionals cons uc ion ... 13
I.5.2 Basis se s ............................................................................................... 14
I.5.3 Sol a ion model ..................................................................................... 14
I.5.4 Func ionals and basis se s selec ed in he hesis .................................... 15
I.6 Objec i e o he hesis .................................................................................. 16
II Syn hesis o subs i u ed alkyl quinoliniums om p opylamine and i s de i a i es
(Pape I) ...................................................................................................................... 17
II.1 In oduc ion ................................................................................................. 17
II.2 P elimina y wo k and s uc u e de e mina ion ............................................ 19
II.3 Op imiza ion o he eac ion condi ions ...................................................... 23
II.4 Scope ........................................................................................................... 26
II.4.1 Subs a e scope: .................................................................................... 26
II.4.2 Scope o he eac ion ............................................................................ 26
II.4.3 P opylamine subs a e scope: ............................................................... 28
II.5 Mechanis ic in es iga ion ............................................................................ 30
II.6 Conclusion ................................................................................................... 37
iii
III NHC-ca alyzed syn hesis o p opa gylic es e s wi h CO2 cap u e (Pape II) ... 38
III.1 In oduc ion ................................................................................................ 38
III.2 Expe imen al esul s and scope o he eac ion ......................................... 39
III.3 Mechanis ic s udies .................................................................................... 41
III.3.1 P oposed mechanism .......................................................................... 41
III.3.2 Me hodology o compu a ional in es iga ions .................................. 41
III.3.3 Resul s and discussion ........................................................................ 42
III.4 Conclusion ................................................................................................. 45
IV Reac ion o Ca aly ic Enols wi h Nucleophiles (Pape III) .............................. 46
IV.1 In oduc ion ............................................................................................... 46
IV.2 Expe imen al esul s and scope o he eac ion ......................................... 47
IV.3 Mechanis ic s udies .................................................................................... 49
IV.3.1 Me hod and model selec ion ............................................................... 49
IV.3.2 In e molecula eac i i y mechanism ................................................. 50
IV.3.3 In amolecula eac i i y mechanism ................................................. 51
IV.4 Conclusion ................................................................................................. 52
V Theo e ical s udy o manganese-ca alyzed syn hesis o p opa gylamines (Pape
IV) ............................................................................................................................... 53
V.1 In oduc ion ................................................................................................. 53
V.2 Scope o eac ion ......................................................................................... 54
V.3 Mechanism s udy ........................................................................................ 55
V.4 Conclusion .................................................................................................. 56
VI Concluding ema ks .......................................................................................... 57
Appendix A. Au ho con ibu ion: ......................................................................... 58
Acknowledgemen s ................................................................................................ 59
Re e ences .............................................................................................................. 60
1
I In oduc ion
I.1 Ca alysis in o ganic chemis y
I.1.1 Ca alysis and ca aly ic eac ions
The a e o a eac ion depends on a ious chemical and physical ac o s (p essu e,
sol en , s i ing condi ions, e c.). When hose ac o s a e ixed, he a e o eac ion elies
on he concen a ion o he eac an s and on he ene gy gi en o he sys em,
expe imen ally e alua ed by he empe a u e. E e y eac ion has an ac i a ion ene gy,
which ep esen s a ba ie ha needs o be o e come in o de o he eac ion o happen,
and o ob ain he p oduc . A ca aly ic eac ion is cha ac e ized by a lowe ene gy o
ac i a ion compa ed o ha o he eac ion in he absence o he ca alys . A ca alys is a
species ha inc eases he eac ion a e by lowe ing he ac i a ion ene gy.1 Because he
ene gy o ac i a ion is lowe wi h ca alys and he en i ies in ol ed can be di e en ,
ca aly ic eac ions may ollow pa hways ha a e e y di e en om hose o hei
unca alyzed eac ions. O he cha ac e is ic is ha he ca alys is no consumed du ing he
eac ion.
Ca alysis can be di ided in o h ee main ca ego ies, homogeneous, he e ogeneous
and bio-ca alysis. In homogeneous ca alysis, all he componen s a e soluble in he
eac ion media. One o he main sub-g oups in his ca ego y is he ca alysis media ed by
ansi ion me al complexes, whe e he me al is usually coo dina ed by anions o neu al
ligands.2 An example can be he Ho eyda-G ubbs ca alys o me a hesis eac ions.3
Ano he impo an sub-g oup in homogeneous ca alysis is ha in ol ing o ganoca alys s,
which a e small o ganic molecules used in p ocesses.4 An example could be he seconda y
amines used in Knoe enagel eac ion.5 He e ogeneous ca alys s a e no soluble in he
eac ion media (e.g. liquid media) and he physical in e ac ions (adso p ion, di usion,
e c…) be ween he eagen s and he ca alys play a key ole. The las ype o ca alys s, a
he on ie be ween o ganic chemis y and biochemis y, a e he enzymes, which ca alyse
a majo pa o he eac ions needed o li e and a e becoming o common use in he
chemical indus y.6
I.1.2 T ansi ion me al ca alysis
T ansi ion me als a e elemen s ha o m one o mo e s able ca ions wi h incomple e d
o bi als.1 These elemen s o m he d-block o he pe iodic able, including g oups 3 o 12
(Figu e 1). In e es ingly, one o he main pa icula i ies o he ansi ion me als is he
abili y o exhibi a ange o possible oxida ion s a es. All o hem ha e a leas wo
di e en posi i e s a es o oxida ion.
2
Figu e 1. T ansi ion me als (in yellow) on he pe iodic able
In ecen yea s, ansi ion me als ha e ul illed an impo an ole in he syn hesis o
o ganic compounds. Nume ous o ganic ans o ma ions need ansi ion me als, as i
happens o example in he amily o c oss-coupling and ela ed eac ions. Mizo oki-
Heck,7 Suzuki-Miyau a8 o Buchwald-Ha wig9 coupling eac ions a e widely used in
academia and in indus y.
The e a e wo majo d awbacks o he gene al use o ansi ion me als in syn he ic
chemis y. The i s one is ela ed o he supply chain. Noble me als a e no abundan and
o he s, like cobal , a e p oduced in socially and poli ically uns able coun ies. The second
p oblem is oxici y, which can be o g ea conce n o an indus ial use.
I.1.3 NHC ca alysis
N-He e ocyclic ca benes (NHCs) a e o ganic molecules used in a wide ange o
applica ions, and hey can also unc ion as o ganoca alys s. The i s e idence o he
exis ence o N-he e ocyclic ca benes was p o ided du ing he 50’s, bu he i s s able and
isolable ones we e de eloped by A duengo and co-wo ke s in 1991.10 NHCs se e as
ligands o o ganome allic complexes11 as well as ca alys s in hei own igh , mo e
p ominen ly as nucleophilic species in umpolung chemis y,12 bu also as B øns ed bases
in o ganic ans o ma ions.13
Many NHCs a e eadily accessible and e en comme cially a ailable, mainly om
imidazolonium sal s upon dep o ona ion wi h a base (Scheme 1).14,15 They allow a apid
de elopmen o new syn he ic me hodologies, gi ing access o a wide ange o s uc u es.
The in oduc ion o chi ali y in he ca benes has also been exploi ed o he asymme ic
cons uc ion o o ganic molecules.16
3
Scheme 1. Two di e en s a egies o syn hesize NHCs
An example o a eac ion in ol ing an NHC ca alys is he benzoin condensa ion
eac ion, whe e wo aldehydes eac oge he o o m -hyd oxy ke ones (Scheme 2),
impo an in e media es in he syn hesis o bioac i e molecules. These p ocesses show in
gene al high yields and high enan iome ic excess.17
Scheme 2. Syn hesis o -hyd oxy ke ones in high yields and wi h enan iome ic
excess.18
In addi ion, he use o ca benes has been expanded o o he ela ed eac ions, like c oss
benzoin condensa ions, c oss aza-benzoin eac ions, and he S e e eac ion.19 I has o
be no iced ha a base is necessa y o in si u gene a e he ca alys and ini ia e he eac ion.
The base is used in he same amoun as he ca alys , and i s s eng h can a y om mild
4
bases (such as ca bona e sal s and e ia y amines) o s onge ones, such as po assium
e -bu oxide. Fo he las case, he scope can be limi ed due o he absence o
o hogonali y o eac ion be ween he base and ce ain subs i uen s, especially p o ec ing
g oups.
The N-he e ocyclic ca bene amily includes a sub-g oup called “non-classical
ca benes”. Thei main cha ac e is ic is ha hey ha e a signi ican ly lowe he e oa om
s abiliza ion by adjacen he e oa oms (Figu e 2).20 Those non-classical ca benes ecen ly
disco e ed ha e been used mainly o complexa ion wi h me als (palladium, nickel,
hodium), wi h implica ions o CC o ma ion,21 hyd ogena ion22 and me a hesis
eac ions.23 A cha ac e is ic o non-classical NHCs is ha hey ha e less dono abili y.
Thei complexes a e less s able han hose o classical NHC, widening he scope o
ca aly ic species.
Figu e 2. Examples o classical and non-classical ca benes
I.2 Umpolung eac i i y
The p inciple o umpolung is he in e sion o he na u al eac i i y o a syn hon.24 A
majo pa o he eac i i y in o ganic chemis y is based on he eac ion be ween an
elec ophile and a nucleophile. Acco ding o his model, wo en i ies wi h he same
pola i y (nucleophile-nucleophile, o elec ophile-elec ophile) would no eac oge he .
Umpolung is a p ocess ha allows his kind o eac i i y o happen, by swi ching he
pola i y o one o he eagen s. An example could be he eac ion be ween an aldehyde
and an alkyl b omide, which a e bo h elec ophilic by na u e. Howe e , eac ing he
aldehyde wi h 1,3-p opanedi hiol yields a hioke al, which can o m a nucleophilic
o ganoli hium eagen . This species can hen eac wi h he elec ophilic alkyl b omide,
and a e emo al o he 1,3-p opanedi hiol, he ke one is ob ained (Scheme 3).25
Scheme 3. Umpolung s a egy o make aldehydes nucleophilic species.
5
I.2.1 Hype alen Iodine
Poly alen iodine compounds o e pass he oc e ule, p o iding speci ic eac i i y.
Those compounds a e buil a ound iodine a oms wi h an oxida ion s a e o III o V, and
hey can be cyclic. They ha e h ee main ypes o applica ions. The i s one is as
oxida ion eagen s, such as he Dess-Ma in pe iodinane (Scheme 4a), used o he mild
oxida ion o alcohols, o (diace oxyiodo)benzene (PIDA) commonly used o eoxidizing
ansi ion me al ca alys s.26 A second usage is as eagen s o o ganic syn hesis.27 Fo
example, hey a e p ecu so s o benzyne, which can be p oduced in-si u wi h luo ine
dono eagen s (Scheme 4b).28 Finally, hype alen iodine eagen s can also wo k as
umpolung eagen s. The elec ophilici y o he iodine a om allows access o elec ophilic
syn hons s a ing om nucleophiles,29,30 due o hei capaci y o induce ligand exchange,
educ i e elimina ions o ligand couplings.31 Fo example, Ochiai’s g oup epo ed he -
ace yla ion o ke ones wi h iodobenzene diace a e.32 A e o ma ion o he enola e, a
ligand exchange happens wi h he hype alen iodine eagen , ollowed by ei he a SN2
eac ion wi h he ace a e anion o ei he an in amolecula ligands exchange o o m he
desi ed p oduc and iodobenzene, which could be hen eoxidized and used in ca aly ic
amoun (Scheme 4c).
Scheme 4. a) Hype alen eagen s used as oxidan s. b) P ecu so o a yne. c)
Example o an umpolung eac ion media ed by PIDA.
6
I.2.2 CO2 Ac i a ion by NHC
As p e iously shown, NHCs a e nucleophilic en i ies, and a e able o eac wi h ca bon
dioxide o o m imidazole-2-ca boxyla es. The i s example o his adduc was epo ed
by he Kuhn g oup, om a p e o med NHC.33 The NHCCO2 adduc has a ela i e low
s abili y, because CO2 can be eleased i he adduc is hea ed abo e 100 °C. The NHC-
CO2 adduc can be used as a p ecu so o NHCs, o i can be used as a empo a y ca ie
o CO2 (Scheme 5).
Scheme 5. Syn hesis o NHC-CO2 adduc .
The NHC-CO2 adduc is a neu al zwi e ionic species, whe e he ca boxyla e holds a
o mal nega i e cha ge. CO2 is no mally a kine ically s able, weak elec ophile; i can
eac only wi h s ong nucleophiles, like phenylmagnesium b omide, o ming benzoic
acid in his case. A e o ma ion o he NHC-CO2 adduc , due o he nega i e cha ge a
he oxygen a om, he CO2 molecule can ac as a nucleophile. This ac en iches and
expands eno mously he eac i i y o ca bon dioxide, like in he o ma ion o cyclic
ca bona es by eac ion be ween NHC-CO2 adduc s and p opa gylic alcohols.34 The
ca boxyla e g oup o he adduc a acks he alkyne, and he ca banion hen dep o ona es
he alcohol. The ca aly ic cycle is closed a e a cycliza ion s ep, eleasing he NHC
ca alys (Scheme 6).
Scheme 6. Mechanism o he syn hesis o cyclic ca bona es ia NHC-CO2 adduc s.35
7
I.3 Csp² and Csp³H ac i a ions by ansi ion me als
I.3.1 Mechanisms o C
H bond ac i a ions
Un ela ed o any unc ional g oups, CH bonds ha e low in insic eac i i y.36 The
ene gy ba ie o clea e hem is so high ha , wi hou ha sh chemical condi ions (high
empe a u e, s ong bases o acids), unca alyzed eac ions a e unlikely o happen.
Howe e , some eac ions as di icul as he CH bond ac i a ion o me hane o o m
me hanol ha e been achie ed, like in he pla inum ca alyzed p ocess epo ed by Shilo .37
And, in pas decades, an abundan li e a u e has been de eloped.38 Due o he po en ial
o a om economy and sho e syn he ic pa hs, impo an esea ch e o s ha e been
dedica ed o seek ca alys s and po en ial subs a es o a ainable CH ac i a ion
p ocesses.
In he case o ansi ion me al ca alyzed CH ac i a ions, di e en mechanisms ha e
been p oposed. Among hem, one o he undamen al a ian s is he oxida i e addi ion o
he CH bond, o ming a me al hyd ide and inc easing he oxida ion s a e o he me al
a om (Scheme 8a); o he mechanisms in ol e elec ophilic a oma ic subs i u ion (SEA )
(Scheme 7b); -bond me a hesis (Scheme 7c); o single-elec on ans e (SET) wi h
adical in e media es (Scheme 7e).
Mo e closely ela ed o ou wo k, wo o he app oaches ha e ecen ly appea ed. Fi s ,
he conce ed me ala ion dep o ona ion (CMD), whe e he o ma ion o he ca bon-me al
bond and he clea age o he CH bond a e conce ed. The p o on depa u e is assis ed
by a base, in a single elemen a y s ep. The elec oposi i i y o he me al, while
app oaching he ca bon, inc eases he acidi y o he p o on. CMD is one o he mos
p oposed mechanisms o palladium CH ac i a ion (Scheme 7e). On he o he hand, he
base-assis ed in amolecula elec ophilic subs i u ion (BIES), is a mechanism wi h wo
elemen a y s eps, whe e he me al i s coo dina es wi h he ca bon and hen he p o on is
emo ed by he base (Scheme 7 ). The bases in ol ed in bo h mechanism a e commonly
ca boxyla es, ca bona e, amide o phosphine oxide.39,40
8
Scheme 7. Mechanisms o CH ac i a ions by ansi ion me als.
I.3.2 Di ec ing g oups o C
H ac i a ion
A g ea in e es o C-H ac i a ion is he possibili y o con olling he egioselec i i y.
This is achie ed by he in oduc ion o di ec ing g oups (DG). When using Pd complexes,
once he CH bond is clea ed, a palladacycle is o med. The size o he cycle may a y
om h ee o en a oms, al hough he mos s able ones a e he i e- and six-membe ed
ings.41 Many o hese me allacycles ha e been isola ed.42–44 Thus, he posi ion o he
di ec ing g oup on he molecule dic a es he posi ion o he CH bond ha will be
ac i a ed. Fo palladium, nume ous ypes o unc ional g oups can di ec he ac i a ion.
Those based on oxygen as he coo dina ing a om commonly include ca boxylic acids
(ca boxyla e o m in he palladacycle), es e s o alkoxides.45 Among he amily based on
ni ogen as he coo dina ing g oup, amines, imines, oximes, amides, N-oxides and
sul amides ha e been epo ed.46 A classi ica ion o he s eng h o hose di ec ing g oups
has been epo ed by No by and co-wo ke s (Figu e 3).47
15
Wi h ∆𝐺𝑐𝑎𝑣 is he ca i a ion ene gy, i is he ene gy di e ence wi h and wi hou he
ca i y in he con inuum. ∆𝐺𝑑𝑖𝑠𝑝 is he dispe sion ene gy be ween solu e and sol en ,
∆𝐺𝑟𝑒𝑝 ep esen s he epulsion be ween solu e and sol en and ∆𝐺𝑒𝑙𝑒𝑐 is he e m o he
elec os a ic pola iza ion caused by he cha ge dis ibu ion o he solu e molecules in he
sol en , o he opposi e.
I.5.4 Func ionals and basis se s selec ed in he hesis
In he second chap e , he B97D unc ional was used o op imiza ion o he di e en
s uc u es. I is an adequa e me hod o he calcula ion o s uc u es con aining
palladium.72 Also, he 6-311G(d,p) basis se was used, known o be cos e ec i e and
p o iding accu a e geome ies. M06/De 2TZVPP we e used oge he o ene gy
e inemen . Conside ing he physical in e ac ions be ween a oms, he accu acy is much
highe wi h De 2TZVPP,73 se al hough p esen ing he d awback o an inc ease in he
calcula ion ime, becoming no applicable o i e a i e geome y op imiza ions. Iodine
and palladium a e no de ined in he Pople basis se 6-311G, bu an app op ia e al e na i e
exis , known as he SDD basis se . Bo h a oms a e de ined wi hin he De 2TZVPP basis
se .
In he hi d chap e , M06-2X and 6-31G(d,p) we e used o geome y op imiza ion as
unc ional and basis se , espec i ely. Recen li e a u e examples also use his pai o he
s udy o pu e o ganic eac ions,74 and in addi ion, i has been demons a ed ha hey
pe o m well in cases in ol ing zwi e ionic species and halogen-ions.75
In he ou h chap e , he s udy was done wi h using he B97D unc ional o he
s uc u e op imiza ions, oge he wi h he 6-31G(d,p) basis se s o all he a oms.
16
I.6 Objec i e o he hesis
The aims o he hesis a e he de elopmen o e icien me hods o he o ma ion o
complex molecules om simple and easily accessible ma e ials. The hesis is di ided in o
ou independen p ojec s wi h di e en inhe en objec i es.
The i s p ojec (Chap e II) epo s a new syn he ic me hod o p oduce alkyla ed
quinoliniums, as molecules o high alue, which a e p epa ed om simple p opylamine
and i s de i a i es. In addi ion, he ocus was pu on he comp ehension o he mechanism
o u he de elopmen .
The second p ojec (Chap e III) ocuses on he comp ehension o an o ganoca aly ic
eac ion ha yields p opa gylic es e s om simple eagen s, as alcohols, ca bon dioxide
and p opa gyl halides. The s udy by DFT aims o gi e a clea iew o he mechanism,
and o y o explain ce ain in iguing eac i i y in some cases. Also, he aim was o
unde s and he limi a ion o he scope and highligh he possible incompa ibili ies
be ween he di e en eagen s.
The hi d p ojec (Chap e IV) has o objec i e o unde s and how hype alen iodine
enables he eac ion o wo nucleophiles, an enola e and an alcohol, ia an umpolung
eac ion. The enola e is gene a ed unde he eac ion condi ions om allylic alcohols ia
an i idium-ca alyzed isome iza ion. A second objec i e is o unde s and he selec i i y
ob ained when he e exis wo di e en nucleophiles ha may eac wi h he enola e
p oduced ia isome iza ion.
The las p ojec (Chap e V), used he expe imen al esul o a KA2 coupling eac ion,
in o de o unde s and he mechanism. Fo he i s ime, manganese is used as a ca alys
o his eac ion, he e o e, i is in e es ing o s udy his ole. To p oceed, DFT calcula ions
we e used.
17
II Syn hesis o subs i u ed alkyl quinoliniums om
p opylamine and i s de i a i es (Pape I)
II.1 In oduc ion
Quinoliniums and quinolines ep esen an impo an class o molecules wi h s a egic
applica ions in many ields o chemis y. Looking o hei bioac i i y, hey a e ound in
an i i al, an ibac e ial, analgesic, and an idep essan d ugs.76 Well-known molecules such
as quinine a e emblema ic in o ganic chemis y, and i s de i a i es a e essen ial o an i-
mala ial ea men s. Quinoliniums a e used as ools in biology as DNA dyes and
in e calan s. They a e essen ial o s udies o cells and hei en i onmen , and in low
cy ome y he main known dye is hiazole o ange. O he applica ions in ch oma og aphy
ha e been epo ed (Figu e 4).77
Figu e 4. Examples o high- alue molecules wi h quinoline sca olds.
New me hods o he syn hesis o quinolines a e con inuously epo ed, and some o
hem a e pa o he mos well-known eac ions in o ganic chemis y. Howe e , hose
syn heses, wi h ew excep ions, need Csp²-N bond con aining s a ing ma e ial, in he o m
o subs i u ed anilines o ni obenzenes. Fo example, he Combes syn hesis needs
anilines wi h 1,3-dike one and acid as ca alys o ende he quinoline.78 The d awback o
his simplici y is he di icul y o each egioselec i i y. Regioselec i i y can be achie ed
by using s e ic e ec s and kine ics, bu he scope is meanwhile educed.
To ob ain he desi ed s uc u e o quinoline, he de elopmen o me hodologies has
been p oli ic du ing he las decades.79 Howe e , he complexi y o he s a ing ma e ials
needed o hose ans o ma ions may be high, and incompa ibili ies may exis wi h he
desi ed subs i uen s on he inal molecule (Scheme 14).
18
Scheme 14. Classical syn he ic ou es o o m quinolines om aniline
Mos o he qua e na y quinolinium species a e syn he ized om quinolines h ough
alkyla ion wi h halogena ed building blocks. Fo he di ec p epa a ion o quinolinium
sal s, only ew examples a e epo ed. One me hod was de eloped by L. Cheng e al.,80
using N-subs i u ed anilines, aldehydes and alkynes, in a eac ion ca alyzed by coppe
(scheme 15).
Scheme 15. Th ee componen s eac ion o he syn hesis o subs i u ed quinolinium
sal s.
In addi ion o he men ioned applica ions o he quinolinium compounds, hey can be
used also as in e media es o he syn hesis o complex molecules. Fo example, posi ions
2 and 4 become elec ophilic, and can eac wi h s ong nucleophiles such as G igna d
eagen s.81
Quinolinium sal s can also be hyd ogena ed o yield he e ahyd oquinoline skele on.
Fu he , me hods ha e been ecen ly de eloped o he o ma ion o unc ionalized
e ahyd o/dihyd o-quinolines (Scheme 16).82,83
19
Scheme 16. Examples o possible eac ions om quinolinium sal s.
The aim o his p ojec is o access o quinoline sca olds om a ylp opylamines, in
one s ep. As he majo i y o syn he ic ou es o quinolines use aniline as s a ing ma e ial,
ou me hod o e s an al e na i e app oach o access hei cyclic s uc u e, o ming he key
A -N bond om open alipha ic amines. In addi ion, he con ol o he subs i u ion pa e n
is impo an o p o ide a eliable ans o ma ion. The in oduc ion o an alkyl quinolinium
moie y o e s di e se possibili ies o u he ans o ma ions.
II.2 P elimina y wo k and s uc u e de e mina ion
Ini ially we eac ed 3-phenylp opylamine wi h iodobenzene (2a) in he p esence o a
ca aly ic amoun o palladium ace a e and sil e i luo oace a e in ace ic acid a 110 °C,
wi h he in en ion o p epa ing dia ylp opylamine de i a i es (4). Howe e , he o ma ion
o an unknown compound was obse ed (3a). A simila ou come was ob ained when he
eac ion was un wi h iodo oluene (2b), ob aining a complex adduc (3b). In ei he case
he a yla ed p oduc 4 was no o med (Scheme 17).
Scheme 17. Ea ly a emp s on he a yla ion o alipha ic amines ia CH ac i a ion.
20
P oduc s 3a and 3b we e hen isola ed by p epa a i e TLC and cha ac e ized.
Acco ding o he s a ing ma e ials used, he assump ion was made ha a limi ed numbe
o ni ogen and oxygen a oms can be p esen on p oduc s 3a and 3b. The exac masses
we e undamen al o know he molecula o mula o 3a and 3b, which, as expec ed, di e
in one me hyl g oup. Wi h a measu e o 324.1745 m/z o 3a, i s molecula o mula was
p elimina y p oposed o be C24H22N. Fo 3b, a mass o 338.1900 m/z was measu ed,
co esponding o C25H24N (Figu e 5). The e o o he exac masses was below 3 ppm in
bo h ins ances.
These o mulas p o ided e y use ul pieces o in o ma ion. Fo example, bo h 3a and
3b con ained 14.5 unsa u a ions, so hey con ained po en ially a polycyclic s uc u e. The
unsa u a ion igu e is no an in ege (14.5 unsa u a ions), and his could come om ha ing
he M+H de ec ion. Howe e , by 1H NMR spec oscopy, 22 + 3 p o ons we e ob ained
a e in eg a ion o he signals, and a highly pola compound was de ec ed by TLC. These
da a sugges ed he p esence o a posi i e cha ge on he molecule, accompanied by an
ace a e moie y, possibly coming om he sol en . This is suppo ed by a signal a a ound
1.9 ppm on he 1H NMR spec um, and a 181 ppm on he 13C NMR spec um.
The di e ence o mass and o mula be ween 3a and 3b was equi alen o a me hyl
g oup, being he same di e ence be ween phenyl and olyl s a ing ma e ials, so i can be
deduced ha only one a yl g oup is in ol ed in he eac ion, as men ioned be o e.
Figu e 5. a) Exac mass o 3a, b) Exac mass o 3b.
F om he 1H NMR and COSY NMR spec a o compound 3a independen coupling
sys ems could be iden i ied. A i s one, wi h h ee signals om 2.5 o 5.0 ppm, each
signal in eg a ing o 2H, which can be assigned o a chain R-CH2-CH2-CH2-R’,
associa ed wi h he p opylamine moie y. A ound 7.0 ppm, a mul iple signal o 5H,
ypical o a benzene ing wi h single subs i u ion can be no iced. The same sys em o 5H,
a ound 7.5 ppm, is also associa ed wi h a benzene ing, linked o a di e en pa o he
molecule. The nex sys em con ains wo p o ons, one a 7.6 ppm, di ec ly coupled wi h
ano he a 9 ppm. The las coupling sys em bea s ou p o ons sys em, one o hem a 7.8
ppm, coupled wi h wo H a 8.1 ppm, which a e coupled hemsel es wi h one p o on a
8.3 ppm (Figu es 6 and 7).
a)
b)
21
Figu e 6. 1H NMR in CDCl3 o 3a
a)
22
Figu e 7. a) COSY 1H NMR in CDCl3 o 3a, b) Enla gemen o he COSY NMR.
When emo ing he numbe o ca bons and p o ons, and he unsa u a ions ela ed o
he p opyl chain and he wo benzene ings om he o mula o 3a, he emainde coun s
o 9C, 6H, 1N and 7 unsa u a ions. This is ypical o a subs i u ed quinoline sca old.
Thus, i was p oposed ha he s uc u e o 3a ag ees wi h ha o qua e na y quinolinium
sal , wi h a 3-phenylp opyl alkyl chain, and a phenyl subs i uen on posi ion 4 o he
quinoline moie y (Figu e 8). A NOE expe imen was done on he signal a 5.1 ppm. This
demons a ed an expec ed special p oximi y wi h he wo o he signals a 2.7 and 2.5 ppm,
bu also wi h hose a 9.0 ppm and 8.4 ppm (Figu e 9).
Figu e 8. P oposed s uc u e o 3a.
b)
23
Figu e 9. NOE expe imen on he signal a 5.1 ppm o compound 3a.
II.3 Op imiza ion o he eac ion condi ions
Wi h he s uc u e iden i ied, he op imiza ion o he eac ion condi ions was ca ied
ou . By looking i s o o he ac i e ca alys s, di e en ansi ion me al sal s we e es ed
(Table 1, en y 1). None o hem, excep palladium ace a e (Table 1, en y 3), could a o d
he p oduc . O he palladium sou ces like e akis( iphenylphosphine)palladium did no
yield he p oduc ei he (Table 1, en y 2). On he side o he oxidan , only sil e sal s
such as sil e oxide wo ked e icien ly (Table 1, en ies 3-4). O he oxidan s84 commonly
used in connec ion wi h palladium-media ed ans o ma ion did no a o d he p oduc ,
such as ni ic acid, oxygena ed wa e o coppe ace a e (Table 1, en ies 5-7). As epo ed
by Bo,44 sil e could play a double ole, as oxidan and also o cap u e he iodine a om
du ing he oxida i e addi ion / educ i e elimina ion s eps. Nex , he ocus was pu on he
possible sol en s o he eac ion (Table 1, en ies 8-10). I was no iced om he
beginning o ou s udy ha he p esence o ace ic acid is essen ial o he eac ion o occu .
The e o e, we decided o con inue wi h pu e ace ic acid (Table 1, en y 4).
24
Table 1. Op imiza ion o he eac ion condi ions.
En y
Ca alys (10 mol%)
oxidan
Sol en
Yield (%)a
1b
M(OAc)2
CF3CO2Ag (1.5 equi .)
AcOH
0
2
Pd(PPh3)4
CF3CO2Ag (1.5 equi .)
AcOH
0
3
Pd(OAc)2
CF3CO2Ag (1.5 equi .)
AcOH
16
4
Pd(OAc)2
Ag2O (2 equi .)
AcOH
21
5
Pd(OAc)2
HNO3 (2 equi .)
AcOH
0
6
Pd(OAc)2
H2O2 (2 equi .)
AcOH
0
7
Pd(OAc)2
CuOAc2 (2 equi .)
AcOH
0
8
Pd(OAc)2
Ag2O (2 equi .)
DMF
0
9
Pd(OAc)2
Ag2O (2 equi .)
MeOH
0
10
Pd(OAc)2
Ag2O (2 equi .)
Toluene
0
All eac ions we e pe o med wi h 2 equi . o iodobenzene (2a), a 110 °C, o e nigh . aYields by 1H NMR
spec oscopy wi h ime hoxybenzene as in e nal s anda d. bM: Cu, Mn, Co and Zn.
Du ing he eac ion, a by-p oduc , ace amide 5, was de ec ed in he 1H NMR spec um
o he c ude mix u es. The nex objec i e was he e o e o educe he amoun o his
undesi ed p oduc . Fi s , la ge amoun s o sil e and iodobenzene (2a) subs a es we e
es ed in o de o inc ease he a e o o ma ion o he desi ed p oduc 3a, howe e , hese
changes did no succeed and no signi ican imp o emen o yields was obse ed (Table
2, en ies 1-3). Inc easing he empe a u e did no ha e he expec ed posi i e e ec (Table
2, en y 4). The solu ion came wi h he idea ha educing he amoun o ace ic acid could
dec ease he speed o o ma ion o amide 5 by-p oduc . This can be done by using a
mix u e o ace ic acid and wa e as he sol en mix u e, as wa e was he only o he
compa ible sol en . Di e en / a ios o AcOH and H2O we e in es iga ed, and a 1:1
( / ) a io was ound o gi e he bes con e sion in o quinolinium p oduc 3a wi h a
d as ic educ ion o amide 5 in he c ude mix u e. Howe e , he eac ion was incomple e
a he s anda d imes, so he eac ion had o be p olonged o up o 60 h. Those condi ions
p o ided he bes yields ob ained so a (Table 2, en y 7). The numbe o equi alen s o
he di e en s a ing ma e ials we e also op imized, inding ha dec easing sil e o
palladium quan i ies had a nega i e impac on he yield (Table 2, en ies 8-9), whe eas no
impac was no ed in he case o highe palladium and sil e loadings (Table 2, en y 10).
Reduc ion o empe a u e o ime wen oge he wi h a d op in he yields (Table 2).
31
Scheme 19. P oposed mechanism o he eac ion.
The di e en pa s o he p oposed mechanism we e s udied by DFT,89–92 using
B97D/6-311g**+SDD (Pd and I) o geome y op imiza ion and M06/DEF2TZVPP o
he ene gy e inemen s.93 The inal ee ene gies we e he esul o he he mal co ec ion
om B97D/6-311g**/SDD added o he elec onic ene gy om he single poin
e inemen wi h M06/DEF2TZVPP. As he eac ion also wo ks wi h he palladium
complex alone, in d y ace ic acid, his sol en has been used o he calcula ions, and
he e o e sil e was no conside ed.
The oxida ion s udy s a s wi h he coo dina ion o he palladium o he amine and
o ma ion o an N-Pd bond by H ans e o one o he ace a es (I o II), wi h a downhill
ene gy o 14.4 kcal/mol (Figu e 10). Then, he amine / imine ans o ma ion occu s
h ough a classical -hyd ide elimina ion eac ion, like in TS1, wi h an o e all ac i a ion
ene gy o 10.2 kcal/mol. I he e e ence o he ene gy is he complex II (ob ained om
IRC calcula ion o he TS), he ene gy ba ie is 24.6 kcal/mol. The ene gies in ol ed in
his ans o ma ion, a e easonable and in ag eemen wi h he empe a u e o he
expe imen al condi ions. The o ma ion o he imine is uphill om he amide N-Pd
complex, bu a ou able om he sepa a e eac an s (amine + Pd(OAc)2), showing an
ene gy o -6.5 kcal/mol o III, a complex ha e ol es by elease o he ee imine, Pd(0)
and wo molecules o ace ic acid.
The abili y o he amine in I o unc ion as di ec ing g oup o he C-H ac i a ion was
also compu ed. F om I o TS1’, an ac i a ion o 11.0 kcal/mol was ound o he C-H
clea age, 1.0 kcal/mol highe han he oxida ion s ep in TS1, and he e o e, he amine
32
oxida ion o imine is sligh ly a ou ed. In any case, hese da a do no allow us o
comple ely disca d ha he C-H ac i a ion occu s i s , ollowed by he amine/imine
oxida ion. On he o he hand, Pd(0) is o med a he end o Figu e 1, which has o be e-
oxidized o Pd(II) o con inue he p ocess.
Figu e 10. Ene ge ic p o ile o he oxida ion ans o ma ion and compa ison wi h
amine as di ec ing g oup o he C-H ac i a ion.
Nex , he p e iously o med p opylimine coo dina es wi h Pd(OAc)2 in V. As his
complex is in a di e en oxida ion s a e om he inal adduc s in Figu e 10, we ook V
as ela i e G=0 o s udy he nex s eps o he eac ion. F om complex V, he ollowing
elemen a y s ep is he CH ac i a ion in posi ion 3 o he p opyl chain, p omo ed by one
o he ace a e ligands (Figu e 11). The compu ed ene gy o TS2 is 8.7 kcal/mol highe
han he palladacycle, while he p oduc VI is a 10.0 kcal/mol. A e a sligh dec ease
o ene gy due o he ligand exchange and ace a e elease om VI o VII, he oxida i e
addi ion o PhI happens wi h a ba ie o 17.4 kcal/mol, a o ding Pd(IV) complex VIII.
Then, an easy educ i e elimina ion was compu ed in TS4 wi h only 5.5 kcal/mol o e
VIII kcal/mol ac i a ion ba ie o p o ide he o ma ion o he Ph-C bond. P opylimine
IX is a ou ed compa ed o he s a ing ma e ials, being a an ene gy o -34.1 kcal/mol.
33
Figu e 11. DFT compu ed ene gy p o ile o he a yla ion o p opylamine.
34
We also s udied he easibili y o a second C-H ac i a ion and o ma ion o ano he
Ph-C bond in he same posi ion (Figu e 12). This s ep is especially impo an in he case
o subs a e 1a, which al eady con ains a phenyl g oup, as in IX, and mus be able o
inco po a e he second one. Ini ially, he iodide p esen in IX mus be eplaced by an
ace a e ligand. Ace ic acid and/o e en ually sil e sal s can pa icipa e in his anion
exchange, which is di icul o be accu a ely desc ibed. In any case, complex X is p one
o su e a simila p ocess as men ioned be o e o V, and in p inciple Figu es 12 and 11
should show simila esul s. The main di e ence ela ed o he absence/p esence o he
phenyl g oup a C-3 is he gene al inc ease o he ac i a ion ene gies due o he la ge
s e ic hind ance. Fo example, he ba ie o he C-H ac i a ion is qui e la ge in he
p esence o he phenyl g oup (19.3 kcal/mol in TS5 s 8.7 kcal/mol in TS2). A simila
end occu s also du ing he oxida i e addi ion o PhI (30.0 kcal/mol in TS6 s 17.4
kcal/mol in TS3), and o he inal educ i e elimina ion (10.0 kcal/mol in TS7 s 5.5
kcal/mol in TS4). Howe e , he o e all pic u es s ays unal e ed, poin ing o he oxida i e
addi ion o o m he Pd(IV) complex as he slowes s ep.
The las s eps o he mechanism we e also assessed, al hough we could no loca e all
s uc u es in ol ed, because o he exis ing unce ain ies abou he coo dina ion pa e n
a ound palladium in mos species. Howe e , we can o e some hin s abou a ew
indi idual s eps ha migh happen o comple e he p ocess. Fo example, a e o ma ion
o a XV- ype complex, one o he a oma ic ings has o be ac i a ed by palladium h ough
a C-H clea age / A -Pd bond o ma ion, like in TS8 (Figu e 13). Ou calcula ion shows
Figu e 12. DFT compu ed ene gy p o ile o he a yla ion o 3-phenyl subs i u ed subs a e.
35
ha his p ocess is comple ely easible, spi e he ac ha he esul ing complex XVI is a
7-membe ed ing palladacycle. La e , he o ma ion o an amide-Pd bond in XVII migh
igge a Buchwald-Ha wig a yl amina ion. The compu ed ansi ion s a e TS9 p esen s
a low ene gy alue, leading o an amine-imine adduc XVIII, which con ains all he a oms
and disposi ion needed o he o ma ion o he inal adduc s. The hypo he ical sequence
could p obably occu h ough cycliza ion o XIX and a oma iza ion o XX, s eps which
do no eally need he aid o palladium.
Figu e 13. Las s eps o he eac ion, including calcula ed a yl CH-ac i a ion and
a yl amina ion
O e all, he compu ed ene gies o he s eps o he p ocess a e compa ible wi h he
empe a u e o he eac ion, usually a 130 °C. All ene gies a e below 30 kcal/mol, wi h
he maximum a he oxida i e addi ion o XII in TS6. No ewo hy, we did no loca e any
in e media e wi h a signi ican ly lowe ene gy han he es , and hus, none o hem
ep esen a global minimum in he ene gy su ace ha could be expe imen ally isolable.
Those DFT esul s can explained ha he o ma ion o 4 is no obse ed, as he amine
is oxidized o imine quickly. On he o he hand, he imine becomes a good di ec ing g oup
o u he ans o ma ions.
These calcula ions o e one o he possible pa hways ha explains some o he
expe imen al obse a ions, and a leas shed some ligh on pa o he ansi ion s a es and
in e media es ha ake place in his in ica e ans o ma ion. Ob iously, mo e
expe imen al e idence is needed o con i m he di e en pa s o he mechanism. The
necessi y o he ace ic acid as sol en is no ully explained. KIE measu emen s on
deu e a ed p opylamine could con i m ha CH ac i a ion is no he a e limi ing s ep.
Since wo equi alen s o amine a e needed o comple e he eac ion, a well designed
expe imen wi h 15N labelled amines could be use ul o asce ain he amine sou ce o he
quinolinium ni ogen. Also, he ole o he sil e is no aken in o accoun in hese
mechanis ic s udies. A ecen wo k94 shows he impo an ole o he me al o he CH
36
ac i a ion, he e o e, in es iga ion o po en ial ease o he eac ion by sil e is
in e es ing.44
37
II.6 Conclusion
In his chap e , a success ul and inno a i e syn hesis o qua ena y quinolinium sal s
om p opylamines and i s de i a es is epo ed, ca alyzed by palladium ace a e. A yl-
p oylamines ha e been ans o med in o he desi ed p oduc s, wi h mode a e o good
yields. Mo eo e , he me hod can be used wi h p opylamine, in a p ocess ha in ol es
he ac i a ion o wo alipha ic CH bonds.
The mechanism o he eac ion has been s udied by compu a ional means, and
compa ed wi h he expe imen al esul s and li e a u e p eceden s. In he case o
p opylamine, he p oposed mechanism s a s wi h he oxida ion o imine, hen a double
Csp³H ac i a ion/a yla ion. Then a Csp²H bond is ac i a ed, ollowed by a CN bond
o ma ion. The in e media e is cyclized and oxidized o yield he inal p oduc s.
The in e es s o he me hod a e, he possibili y o e ed o o m quinolines sca old om
simple s a ing ma e ial and o ha e mul iple CH ac i a ions, and c ea ing mul iple CC
bonds and a CN bond, in a single eac ion.
38
III NHC-ca alyzed syn hesis o p opa gylic es e s wi h
CO2 cap u e (Pape II)
III.1 In oduc ion
P opa gylic es e s a e p esen in wide ange o compounds. F om in e media es o
o al syn hesis o na u al p oduc s, Diphylin, Jus icine B o Tawainin C,95 o bioac i e
compounds such as Oxybu ynin o he ea men o bladde cance .96 Thei syn hesis can
be achie ed ia he es e i ica ion o he co esponding ca boxylic acid,97,98 which needs
o be p epa ed be o e. The g oup o P o . Vougioukalakis de eloped he me hodology o
he syn hesis o he p opa gylic es e s, and he expe imen al esul s used o he DFT
s udies we e pe o med by his g oup. They epo ed a me hod ha uses comme cially
a ailable s a ing ma e ials and CO2 o a one-s ep syn hesis o p opa gylic es e s.
Because CO2 is one o he majo g eenhouse gases and a he same ime a cheap and sa e
eagen , me hods using CO2 as eagen ha e in gene al a g ea in e es economically and
o he socie y. A simila eac ion o his wo k has been de eloped, showing he in e es
o new ou es o syn hesis using CO2.99
In he ecen li e a u e o CO2 ixa ion on e minal alkyls, o ganoca alyzed by NHC,
wo me hods o syn hesis we e epo ed by wo di e en g oups.
The i s one, by Liu e al.,100 we e able o eac e minal alkynes wi h CO2 o o m
he p opa gyl ca boxylic acid. Then, he ea men wi h HCl in he p esence o alkyl
halides led o he co esponding es e s.The eac ion is ca ied u a 60ºC in DMSO,
ca alyzed by in si u gene a ed NHC (Scheme 20). The mechanism p oposed is simila o
ou p oposal101 and ely on he o ma ion o he NHC-CO2 adduc .
Scheme 20. Syn hesis o p opa gylic acid and es e s ca alyzed by NHC.
39
III.2 Expe imen al esul s and scope o he eac ion
Fo he syn hesis o p opa gylic es e s, h ee common eagen s a e in ol ed: e minal
alkynes (15), allylic chlo ides (16) and CO2. The eac ion is ca alyzed by NHC 18
(Scheme 21). The expe imen al esul s p esen ed in his sec ion (II.2) ha e been
pe o med by he g oup o P o . Vougioukalakis.
Scheme 21. Th ee-componen eac ion o he syn hesis o p opa gylic es e s.
A e op imiza ion o he eac ion condi ions, he subs a e scope was ex ended.
A oma ic p opa gylic eagen s, wi h di e en subs i uen s on he a oma ic ing, ga e
good esul s (Scheme 22). I was also possible o use di e en allylic chlo ide eagen s,
wi h a ious unc ional g oups, such as es e , cinnamyl, benzyl, ca bona e o e en ole ins
(Scheme 22). On he o he hand, when using 2-picolyl chlo ide he expec ed p oduc was
no o med (19m).
40
Scheme 22. Scope and limi a ions o he eac ion s udied by he g oup o P o .
Vougioukalakis.
47
A ecen me hodology was de eloped by Kiel and Gulde ,119 o - unc ionaliza ion
by nucleophiles o -py idyl-ke ones wi h hype alen eagen . Wi h he same umpolung
s a egy, hey succeeded o o m, egioselec i ely, CO, CN and CS bonds wi h no
enol e he p e- o ma ion needed. The selec i i y is d i en by he py idyl g oup,
coo dina ing weakly bu su icien ly wi h iodine a om. The e o e, he nucleophile eac s
only on one side o he ke one (Scheme 25).
Scheme 25. Func ionaliza ion o py idyl ke one wi h hype alen iodine.
IV.2 Expe imen al esul s and scope o he eac ion
The expe imen al p o ocol uses he i idium dime [Cp*I Cl2]2 as he ca alys s o he
isome iza ion o he allylic alcohol. A small excess o he hype alen iodine eagen 23
is needed (1.2 equi .), o p o ide good yields. Impo an ly, he yields we e imp o ed in
he p esence o 80 mol% o KBF4 as an addi i e. Me hanol is one o he sol en s in he
mix u e used (TFE, 1:3, TFE/MeOH / ), as well as being he sou ce o he me hoxy
g oup (nucleophile). The bes yields we e ob ained a 35 °C.
The me hod was success ully applied o a wide ange o allylic alcohols (Scheme 26).
Fi s , allylic alcohols wi h e minal double bonds ga e mode a e o quan i a i e yields o
me hoxy ke ones 25a-25h. The eac ion a o ded he p oduc s wi hou any de ec able
byp oduc when he allylic alcohols con ained unc ional g oups such as ni ile, ke one,
halogen, o e en azide (25e-25h). I was possible o ob ain he e hoxy p oduc using
e hanol as he sol en (25b), al hough in lowe yields. Allylic alcohols wi h in e nal
double bonds also a o ded he co esponding -me hoxy ke ones (25i-25l) in good
yields, anging om 60 o 79%.
48
Scheme 26. Scope o he syn hesis o -me hoxy ke ones om allylic
alcohols.Isola ed yields*
Fo he case o allylic alcohol wi h a ke one in posi ion, di e en p oduc s we e
ob ained. The eac ion yielded i e membe ed- ings, 3- u anones, 27a-27c in yields
anging om 46% o 91%. In e es ingly, 5-amino-3- u anone 27d was ob ained om he
co esponding amide.
*Expe imen al esul s we e ob ained by D . A. Sanz-Ma co and D . S. Ma inez-E o.
49
Scheme 27. Scope o he eac ion a o ding 3- u anones.
*
IV.3 Mechanis ic s udies
IV.3.1 Me hod and model selec ion
To s udy he mechanism we pe o med DFT calcula ions wi h he help o Gaussian 16
so wa e sui and wi h M06102 as unc ional and 6-31G(d,p)120 as basis se (SDD o
I).121,122 Di e en mechanis ic pa hways we e conside ed. Fi s , we conside ed a
mechanism occu ing in wo independen s ages; i s he i idium-media ed isome iza ion
o he allylic alcohol o an enol o enola e, ollowed by i s eac ion wi h he hype alen
iodine eagen 23 and me hanol, o yield he p oduc . A mo e complex mechanism, whe e
all pa s (i idium complex, iodine(III) eagen 23 and MeOH) eac in a conce ed ashion
could also be en isioned. The second p oposal was e alua ed, bu he ene gies ob ained
we e much highe han hose expec ed om he expe imen al condi ions.
An expe imen wi h an isola ed silyl enola e eac ing unde he same condi ions o he
me hod yielded he expec ed p oduc . This esul poin s in he di ec ion o he i s
mechanism conside ed. In addi ion, he possible p esence o adical in e media es was
es ed wi h adical sca enge s such as TEMPO o 2-diphenyle hylene and p oduc 27a
was ob ained in high yields. Thus, he eac ion does no seem o pass h ough adical
in e media es.
F om hese esul s, we can hypo hesize ha he isome iza ion by i idium and he
eac ion o he esul ing enola e wi h iodine(III) eagen 23 and me hanol a e wo
independen pa s o he mechanism. We ocused ou s udy he e on he second pa o he
eac ion. The mechanism o he isome iza ion o he allylic alcohol ca alyzed by i idium
has been in s udied in de ail by ou g oup ecen ly.123 The mechanism goes h ough
complex mul iple s eps, s a ing wi h coo dina ion, ollowed by oxida ion o he alcohol,
and inse ion o an i idium hyd ide o o m an i idium enola e moie y.
*Expe imen al esul s we e ob ained by D . A. Sanz-Ma co and D . S. Ma inez-E o.
50
IV.3.2 In e molecula eac i i y mechanism
Fi s , we in es iga ed he mechanism o he eac ion using MeOH as he nucleophile
(i.e. he in e molecula eac ion). The p oposed mechanism (Scheme 28) s a s wi h he
eac ion o enola e A and he iodine(III) species 23 o o m an enolonium in e media e
(B). This one eac s wi h MeOH o ende in e media e C. A educ i e ligand coupling
o ms he inal p oduc 28. A ansi ion s a e (TS1) was ound, showing an ac i a ion
ene gy o 16.2 kcal/mol, which is a alue ha i s well wi h he expe imen al condi ions.
Scheme 28. P oposed mechanism o in e molecula eac i i y.
Du ing he calcula ions, we hypo hesized ha he addi ion o a molecule o TFE
would ac i a e he ca bonyl g oup o he enolonium h ough hyd ogen bonding. Wi hou
his molecule o TFE, he TS1’ had an ac i a ion ene gy o 21.8 kcal/mol. These indings
illus a e he posi i e e ec o TFE by educing he elec on densi y o in e media e C,
wha acili a es he ligand coupling. A model wi h wo molecules o TFE was also
compu ed, a o ding highe ac i a ion ene gy (20 kcal/mol). This e ec can be explained
by a less signi ican educ ion o he elec on densi y o he complex by he second TFE
molecule and an inc ease o he en opic e ec as he s uc u e con ains mul iple “ ee”
molecules.
Di e en au ome s ha e been conside ed, like he enolonium B’ and C’ wi h I-O
bonding. Simila enoloniums ha e been conside ed be o e in he eac ion o enola es wi h
non-cyclic iodine(III) eagen s.115 Bo h s uc u es ha e signi ican ly highe ene gies han
hose o B and C. Speci ically, ΔG = 14.1 kcal/mol highe o B’ compa ed o B, and ΔG
= 5.3 kcal/mol highe o C’ compa ed o C. A TS s a ing om C’ could no be ound.
Fo hose easons, B’ and C’ ha e no been conside ed as possible in e media es o he
eac ion (Scheme 29).
51
Scheme 29. P oposed mechanism o in e molecula eac i i y
IV.3.3 In amolecula eac i i y mechanism
We hen u ned ou a en ion o he mechanism o he in amolecula eac ion, whe e
he nucleophile is he oxygen o a ca bonyl o o a ca boxylic acid de i a i e. Simila o
he p e ious pa , enolonium D ende s he mos s able species (E, ΔGǂ = 11.7 kcal/mol,
Scheme 30). This in amolecula ea angemen co esponds o a nucleophilic-
addi ion/ au ome iza ion. As in he in e molecula eac ion, he p oduc is ob ained ia a
educ i e ligand coupling. The ene gy o ac i a ion o TS2 is 8.0 kcal/mol, esul ing in a
much as e eac ion han he in e molecula eac ion.
Scheme 30. P oposed mechanism o in amolecula eac i i y.
52
IV.3.4 Compe i i e eac ions
In o de o explain why only he cyclic p oduc was ob ained when bo h eac ions can
happen, we compu ed bo h TSs o he same subs a e. In he case o he i s eac ion,
wi h he molecule o me hanol eac ing, he ene gy o ac i a ion is ΔGǂ = 18.3 kcal/mol
(TS3). In addi ion, o he cycliza ion, only ΔGǂ = 8 kcal/mol we e p edic ed (TS2). Wi h
a di e ence o 10 Kcal/mol, we can easily explain he absence o he p oduc de i ed
om he in e molecula eac ion wi h MeOH.
Scheme 31. Key elemen a y s eps o compe i i e eac ions om ca bonyl-
unc ionalized allylic alcohols.
IV.4 Conclusion
The mechanism o he syn hesis o -me hoxyke ones and o 3(2H)- u anones
om allylic alcohols has been s udied by compu a ional means. The i idium ca alys
seems o be in ol ed only in he isome iza ion o he allylic alcohol. The esul ing enola e
eac s hen wi h he hype alen iodine eagen . The key s ep is a ligand coupling,
p omo ed by i luo me hyl e hanol, which allows he o ma ion o a new CO bond ia
an o e all umpolung s a egy. Fu he , we ha e also concluded ha he selec i i y o he
eac ion esul ing in o ma ion o 3(2H)- u anones as sole p oduc s om ca bonyl-
unc ionalized allylic alcohols is due o a lowe ac i a ion ene gy o he cycliza ion s ep
han ha o he al e na i e in e molecula eac ion wi h he sol en MeOH.
53
V Theo e ical s udy o manganese-ca alyzed syn hesis
o p opa gylamines (Pape IV)
V.1 In oduc ion
P opa gylamines a e common building blocks o he syn hesis o N-con aining
o ganic molecules.124 The ac ha p opa gylamines con ain mul iple unc ional g oup
allows o use a a ie y o syn he ic ools o ans o m hem. Examples include he
syn hesis o di e en he e ocycles, such as py idine,125 quinoline,126 hyd oquinoline o
e en oxazolidinones.127 Fo example, Yu and cowo ke s,126 epo ed he syn hesis o
hyd oquinolines om N-subs i u ed p opa gyl amines and aldehyde ace als media ed by
i on halides sal s (Scheme 32a).126
The iple bond in p opa gyl amines can unde go click eac ions upon eac ion wi h
azides.128 Cai and cowo ke s de eloped a mul icomponen one-po eac ion o quickly
gene a e nume ous bioac i es compounds om a se o azides (Scheme 32b). They used
i s a me al ee iazole syn hesis om azide, ke ene and he p opa gylanime, wi h DBU
as base, ollow by a classical, coppe ca alyzed click eac ion wi h a second azide.
Scheme 32. a) Hyd oquinoline syn hesis om p opa gylamine. b) Sequen ial
iazoles o ma ion wi h p opa gylamines as in e media e.
Chi al p opa gylamines can be used o he syn hesis o op ically ac i e compounds.
Innocen i and co-wo ke s used enan ioen iched p opa gylamines o syn he ize bicyclic
compounds as a single dias e eoisome h ough a cobal -media ed Pauson-Khand eac ion
(Scheme 33).129
Scheme 33. Pauson-Khand eac ion om chi al p opa gylamines.
In his chap e , he KA2 eac ion has been media ed by manganese ca alys s.130 As an
abundan me al, he de elopmen o new ca aly ic me hods media ed by manganese a e
o in e es o he indus y.131 Manganese complexes has been used o ca alyzed CH
ac i a ion eac ions wi h concomi an CC bond o ma ions,132 c oss-coupling
eac ions133 o hyd ogena ion.134
54
V.2 Scope o eac ion
The KA2 eac ion s udied in his chap e was expe imen ally de eloped by ou
collabo a o s, he g oup o P o . Vougioukalakis.101 In his eac ion, p ima y o seconda y
amines (30), e minal alkynes (31), and ke ones (29) a e eac ed using manganese
b omide as ca alys . The eac ions a e un nea , a 130 °C o 20 h (Scheme 34).
Cyclic amines such as pipe idine 30a, py oline 30b, mo pholine 30d o no nico ine
30i ga e he co esponding p opa gyl amines (32a, 32b, 32d, 32i) in excellen yields.
Wi h he la e amine, 32i was ob ained as a single dias e eoisome . In addi ion, alipha ic,
p ima y o seconda y amines a o ded hei co esponding p oduc s, 32g and 32h,
espec i ely, in good yields. Rega ding he scope o he ke ones (29), cyclopen anone,
cyclohexanone and cyclohep anone could be used success ully, as well as non-cyclic
alipha ic ke ones. Phenylace ylene de i a i es we e used in all ins ances. The eac ion
was no success ul when using 1,2-cyclohexanedione no wi h benzophenone.
Scheme 34. Scope o he MnB 2-ca alyzed KA2 coupling. a enan iome ic a io
de e mined by 1H NMR spec oscopy.
55
V.3 Mechanism s udy
Lee and co-wo ke s p oposed a mechanism o he A3 eac ion ha we ook as he
s a ing poin o he mechanis ic in es iga ions o he KA2 coupling.135 We selec ed
cyclohexyl amine (30e), phenyl ace ylene (31e) and cyclohexanone (29e) as he eagen s.
Condensa ion o 30e wi h 29e o ms iminium III. In pa allel, ace ylene 31e is
dep o ona ed in si u by pipe idine 30e, wi h he assis ance o he manganese sal I,
o ming Mn phenyl ace ylide II. This in e media e eac s hen wi h iminium III a o ding
p opa gylic amine 32e, and eleasing MnB 2 (Scheme 35).
Scheme 35. P oposed mechanism o he KA2 eac ion ca alyzed by MnB 2.
The e only exis a ew compu a ional s udies on he mechanism KA2 eac ions.56 We
he e o e s a ed he DFT calcula ions on he model subs a es. The expe imen al eac ion
is pe o med in nea condi ions, and as sol a ion is impo an o accu a e calcula ions,
cyclohexanone was used o sol a ion model o he DFT s udies. Since iminium sal s
can be o med a empe a u es lowe han 130 °C, hei o ma ion was no calcula ed. We
used he B97-D unc ional o he s uc u e op imiza ions, oge he wi h he 6-31G(d,p)
basis se s o all he a oms.
A i s , we no iced ha he manganese species in ol ed in he ca aly ic eac ion we e
lowe in ene gy a qua e s a e ins ead o double s a e, wi h an a e age di e ence o 10
kcal/mol. This means ha he me al complex holds h ee unpai ed elec ons du ing he
eac ion pa hway. As he p oposal o he mechanism, phenylace ylene is i s
dep o ona ed by a base, being he s onges one in he sys em pipe idine. The iple bond
coo dina es o MnB 2, leading o an inc ease acidi y o he ace ylenic p o on. This p o on
is hen emo ed by pipe idine (30e), yielding o an ionic pai . The p oduc was ound less
s able ha he s a ing ma e ials (4.2 kcal/mol highe ). This means ha he concen a ion
o his species is low in he eac ion media (Figu e 16a).
The second pa o he mechanism is he o ma ion o he imminium sal III, by
eac ion o he ke one and he amine. III eac s hen wi h he manganese phenyl ace ylide
(II), gene a ing he p oduc . The ene gy in ol ed in he ansi ion s a e, TS1, is 23.9
kcal/mol. This ene gy needs o be added o he ene gy o he p e ious complex, leading
o a ansi ion s a e a 28.9 kcal/mol, a easonable numbe aking in o accoun he
expe imen al condi ions, i.e. a empe a u e o 130 °C. The p oduc consis s hen o he
expec ed p oduc (32e) coo dina ed o manganese. The ene gy o his complex is 1.7
56
kcal/mol compa ed o ha o he s a ing ma e ials. Thus, he eac ion is d i en by he
s abili y o his inal compound (IV, Figu e 16b).
Figu e 16. DFT esul s o : a) he dep o ona ion o he ace ylene, b) Nucleophilic
a ack o he manganese complex on o he ke amine.
V.4 Conclusion
The mechanism o a manganese-ca alyzed KA2 coupling has been in es iga ed by
DFT. I was shown ha upon coo dina ion o MnB 2 o he e minal alkyne subs a e, a
acile dep o ona ion akes place, o ming an anionic manganese phenylace ylide
complex. This species eac s wi h he iminium species. The mode a e ac i a ion ene gy
o he CC bond- o ming s ep, oge he wi h he low concen a ion o he manganese
phenylace ylide makes his s ep a e-limi ing, and ag ees wi h he need o high
empe a u es in he expe imen s. Wi h app op ia e ligands on Mn ha enables
s abiliza ion o he gene a ed anionic Mn ace ylide species, i s concen a ion may be
inc eased, which may esul in easonable eac ion a es a lowe empe a u es.
63
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I
FULL PAPER
1
Syn hesis o subs i u ed alkyl quinoliniums om p opylamine
and i s de i a i es
Ma in Pauze[a] and En ique Gómez-Bengoa*[a]
[a] Depa men o O ganic Chemis y I, Facul y o Chemis y
Uni e si y o he Basque Coun y
UPV/EHU, 20018 Donos ia-San Sebas ián, Spain
Suppo ing in o ma ion o his a icle con aining copies o he 1H and 13C NMR spec a, as well as he Ca esian coo dina es o which he p esen
manusc ip e e s, is gi en ia a link a he end o he documen .
Abs ac : The syn hesis o a g oup o quinolinium s uc u es has been
achie ed s a ing om alipha ic p ima y amines, h ough a palladium
ca alyzed p ocess. The app op ia e combina ion o he palladium
ca alys , sil e oxidan and ace ic acid / wa e sol en mix u e gi es
ise o mode a e yields o a he complex he e ocyclic s uc u es in a
single s ep. Two uni s o he amine and one o wo uni s o he a yl
iodide a e inco po a ed in his mul icomponen eac ion. In gene al,
unp o ec ed alipha ic p ima y amines a e no sui able subs a es o
palladium ca alyzed p ocesses, due o undesi able side eac ions.
Howe e , in ou case, hey can be sa ely used, gi ing ise o a
ema kable inc ease in complexi y. Some o he elemen a y s eps o
he mechanism ha e also been s udied by DFT means.
In oduc ion
Azahe e ocycles a e p edominan in he chemical s uc u e o
many app o ed d ugs.[1] The subca ego y ep esen ed by
quinoline sca old (quinolines, quinolones, e ahyd oquinolines),
is a signi ican pa o he pha macopho es, o e ing ou s anding
bioac i i ies om an i i al o an icance and h ough an i-
in lamma o y o an ibac e ial d ugs.[2] Fu he mo e, qua e na y
quinoliniums a e key in e media es o he syn hesis o many o
hose d ugs, as hei ich eac i i y allows o access a wide ange
o di e en sca olds, leading o high s uc u al di e si y.[3] In
gene al, quinolinium sal s a e bes p epa ed by alkyla ion o
quinoline p ecu so s, which is a p ocedu e a he limi ed by he
a ailabili y o he co esponding quinolines, depending inally on
he me hods o hei p epa a ion. Thus, a di ec access o
quinoliniums om simple and inexpensi e ma e ials would be e
i wi h he idea o e icien and concise syn hesis. Howe e ,
alkyla ion emains nowadays he bes app oach as quinoline
syn hesis ha e been in ensi ely s udied and, a e s ill he objec o
new syn he ic me hodologies.[4] The as majo i y o hose
me hods imply s a ing ma e ials wi h p e o med A ylN bond, as
aniline o ni obenzene, and in ol e he o ma ion o he py idine
ing by eac ion wi h mode a e o high complex eac an s. Only
ew examples epo he syn hesis o quinolines wi h cons uc ion
o he c i ical A ylN bond om a C(sp2)H one.[5]
The C-H ac i a ion o sp2 and sp3 ca bons is an ins umen al new
ool o he la e s age modi ica ion o p e-exis ing d ugs.[6] Mo e
speci ically, he ac i a ion o alipha ic amines has become a
aluable ool, due o he inhe en di icul y o ac i a ing ine
C(sp3)-H bonds, and o he p eponde an p esence o subs i u ed
amines in bioac i e molecules p esen in he d ug ma ke .
T ansi ion me al ca alyzed C-H ac i a ions allow si e selec i e
unc ionaliza ion o molecules, e en i he selec i i y is highly
dependen on he p esence o di ec ing g oups. Any kind o
amines can ac in gene al as in amolecula di ec ing g oups,
howe e , p ima y amines a e he mos challenging subs a es o
di e en easons, among hem, he i e e sible o ma ion o he
s ong co alen C-N bond, o he easy oxida ion o he amine o
he imine moie y. In bo h cases, he u he eac i i y o he amine
is in e up ed. Seminal wo k by Dauglis g oup used a picolinamide
ins alled in he subs a e as di ec ing g oup (Scheme 1a), yielding
-a yla ion o he p o ec ed amine.[7] As d awback, he amide had
o be p epa ed ini ially and clea ed a e he unc ionaliza ion o
he subs a e. Mo e ecen ly, Ge’s g oup[8] p oposed he in si u
o ma ion o a ca boxy-imine, a ansien di ec ing g oup, o med
be ween he ee p ima y amine and ca aly ic amoun s o glyoxylic
acid, which is eleased a e he - unc ionalisa ion (Scheme 1b).
These me hods mee some essen ial c i e ia in la e s age
unc ionaliza ion, like high si e selec i i y and compa ibili y wi h
he co e s uc u e o he subs a es. In pa allel, C-H ac i a ion
p ocesses also o e simple ans o ma ion o complex molecules
om inexpensi e, economically and en i onmen ally iendly
s a ing ma e ials. In ou g oup, by a modi ica ion o he exis ing
me hods, we ha e used he - unc ionaliza ion o he alipha ic
amines in a di e en way, de eloping a di e en app oach,
consis ing in he poly unc ionaliza ion o alipha ic amines, leading
o a ema kable inc ease o he complexi y o he subs a es
(Scheme 1c). Ini ially, he me hod also uses a cascade C-H
a yla ion o he alipha ic amine in he gamma posi ion, and
subsequen cycliza ion, oxida ion s eps o he o ma ion o
quinolinium ings. The subs a es a e no p e unc ionalized, and
he me hod does no equi e he p esence o ansien di ec ing
g oups.
FULL PAPER
2
Scheme 1. Palladium ca alyzed C-H ac i a ion and unc ionaliza ion o
p opylamine chains. a) Picolamide di ec ed -CH a yla ion o p o ec ed alkyl
amines. b) Si e-selec i e -CH a yla ion o p ima y amines wi h glycoxylic acid
as ansien di ec ing g oup. c) In his wo k, non-di ec ed syn hesis o subs i u ed
qua e na y quinolinium sal s om unp o ec ed p ima y amines.
Resul s and Discussion
Reac ion de elopmen and op imiza ion. We began his wo k
by e alua ing he sui abili y o unp o ec ed 3-phenylp opylamine
1a o he palladium ca alysed C-H ac i a ion condi ions, using
iodobenzene 2a as model a yla ing agen . We conside ed ha he
amine could unde go mul iple C-H ac i a ion, C-C and C-N bonds
o ma ion and oxida ion in he p esence o palladium ace a e
ca alys , as his ansi ion me al has demons a ed i s abili y o
pa icipa e in such ans o ma ions.[9,10] Thus, in he p esence o
10 mol% palladium ace a e, a s oichiome ic amoun o sil e
i luo oace a e, one equi alen o iodobenzene 2a, a e luxing
condi ions in ace ic acid, a e y pola luo escen compound was
de ec ed. The ca e ul analysis o i s NMR and HRMS spec a
iden i ied complex he ca ionic quinolinium s uc u e o 3a, o med
in a 16% yield (en y 2, Table 1). In he s uc u e, wo subuni s o
phenyl-p opylamine can be dis inguished, one o hem o ming
he py idine ing o he he e ocycle and he o he one as he side
chain subs i uen o he N (highligh ed in ed in 3). The second
a oma ic ing comes om he phenyl iodide eagen . Al hough
o he me al ace a es we e ini ially e alua ed, like coppe , zinc,
manganese and cobal , we did no obse ed he o ma ion o any
p oduc . Changing he s oichiome ic oxidan o a less expensi e
sil e oxide imp o ed he yield o 21%, al hough he highe
eac i i y o Ag2O could a ise om i s highe solubili y o om he
use o a highe load (2 equi .) o he oxidan , which can also be
ans o med in si u o sil e ace a e in he eac ion medium. The
sol en sc eening showed ha only ace ic acid, wi h o wi hou
wa e , can be used o he eac ion (en ies 7-9, Table 1). The use
o he acidic condi ions can be explained by he need o
des abilize any un eac i e amine/palladium complexes. Howe e ,
he acidi y o he medium has o be con olled, as i luo oace ic
acid did no yield he desi ed compound (en y 10).
Table 1. In es iga ion o he possible ca alys , oxidan s and sol en s o he
eac ion.
En y
Ca alys
10 mol%
Addi i es
2 eq.
Sol en
Yield (%)[a]
1[b]
M(OAc)2
CF3CO2Ag[c]
AcOH
0
2
Pd(OAc)2
CF3CO2Ag[c]
AcOH
16
3
Pd(OAc)2
Ag2O
AcOH
21
4
Pd(OAc)2
HNO3
AcOH
0
5
Pd(OAc)2
H2O2
AcOH
0
6
Pd(OAc)2
CuOAc2
AcOH
0
7
Pd(OAc)2
Ag2O
DMF
0
8
Pd(OAc)2
Ag2O
MeOH
0
9
Pd(OAc)2
Ag2O
Toluene
0
10
Pd(OAc)2
Ag2O
TFA
0
All he eac ion we e done wi h 2 eq o iodobenzene, a 110°C o e nigh . [a]
Yields by NMR wi h ime hoxybenzene as in e nal s anda d. [b] Me als ied:
Cu, Mn, Co and Zn. [c] 1.5 eq o CF3CO2Ag used.
An undesi ed side e ec o he use o AcOH is he o ma ion o
amide 4a, which appea s in he eac ion in a iable amoun s,
which we e di icul o con ol ini ially. The a io be ween wa e and
ace ic acid (Table 2) was ound o ha e a big impac in he
eac ion ou come, and a signi ican educ ion o he amoun o he
amide by-p oduc was accomplished. The op imal a io was ound
o be 1:1 (en y 5), a which no mo e amide o ma ion was no iced.
Howe e , he yield emained low (21%), bu inc easing he
empe a u e o 130°C ende ed he p oduc 3a in 35% yield (en y
6). Finally, he yield was imp o ed o 77% a e p olonged eac ion
imes (60 h, en y 7).
Table 2. Op imiza ion o he sol en .
En y
Ag2O
PhI (eq.)
Sol en
Temp.
(°C)
Yield
(3/4,%)[a]
1
2
2
AcOH
110
26/47
2
3
2
AcOH
110
31/46
3
2
3
AcOH
110
30/42
FULL PAPER
3
4
2
2
AcOH
130
28/49
5
2
2
AcOH/H2O[b]
110
21/0
6
2
2
AcOH/H2O[b]
130
35/2
7[c]
2
2
AcOH/H2O[b]
130
77/4
[a] Yields by NMR wi h ime hoxybenzene as in e nal s anda d. [b] / 1:1. [c]
eac ion ime o 60 h.
To be e unde s and he main ea u es o he p ocess, some
con ol expe imen s we e conduc ed. Fo example, in he
absence o any palladium ca alys (bu in he p esence o
s oichiome ic sil e oxide, en y 1, Table 3), he eac ion did no
p oceed. Howe e , in he opposi e combina ion, absence o sil e
and p esence o 10 mol% palladium ca alys (en y 2), a 7% yield
o he p oduc was obse ed, indica ing ha he palladium is only
able o un one u n o he ca aly ic cycle, he sil e oxidan being
necessa y o e-oxidize he palladium species o i s ac i e o m.
To con i m his idea, a s oichiome ic amoun o palladium was
used in he absence again o sil e co-oxidan (en y 3), and in
his occasion a 42% yield o he p oduc was ob ained. I appea s,
hus, ha he ole o he sil e is no di ec ly linked o he C-H
ac i a ion o cycliza ion s eps. Finally, as expec ed, he a yl iodide
is manda o y o he eac ion o occu . Phenyl p opylamine alone
did no cyclize o ende any o he ype o compound, bu ins ead,
i decomposed o a complex mix u e o ma e ials.
Table 3. Con ol expe imen s o he eac ion.
En y
Pd(OAc)2
(mol%)
Ag2O
(equi .)
IPh (equi .)
Yield (%)[a]
1
0
2
2
0
2
10
0
2
7
3
100
0
2
42
4
10
2
0
0
[a] Yields by NMR wi h ime hoxybenzene as in e nal s anda d.
Scope. Wi h he op imal condi ions in hands, we nex explo ed
he scope o possible a yl iodide eagen s, and hei
egioselec i i y in eac ions wi h 3-phenylp opylamine. In p inciple,
i R1 and R2 in 1 and 2 a e he same subs i uen , he inal ings in
3 a e in e con e ible (R3 = R4) and a single isome is o med. This
is he case in compounds o en ies 1-4 (Table 4), when applying
he eac ion o me hyl, chlo o and me hoxy g oups in bo h
a oma ic subs a es. Meanwhile, wo possible isome s can a ise
om mixing di e en ly subs i u ed p opylamines and iodides,
since he o ma ion o he key C-N bond and cycliza ion o he
ini ial 3,3-diphenyl p opylamine in e media e can happen wi h
ei he a oma ic ing ( ide in a). Fo his eason, mixing
unsubs i u ed 1a (R1=H) wi h p-iodo oluene (R2=Me) (3e), he wo
possible isome s a ose in 1:4.3 a io, wi h he me hyl g oup in he
he e ocycle o in he pe iphe al phenyl ing. Seemingly, o-
iodo oluene also p o ided he desi ed p oduc s, 3 , in 40% yield
by NMR, ( he p oduc s could no be isola ed in his case). The
si ua ion becomes a bi mo e complex in he case o he m-
iodo oluene (3k), as he cycliza ion can happen in wo
egioisome ic a oma ic posi ions (o ho and pa a o he me hyl
g oup), gi ing ise o h ee possible egioisome s in 47% yield.
Elec on wi hd awing g oups a e also ole a ed in he eac ion, as
pa a luo o-, chlo o- and b omo- oluene de i a i es ga e he
expec ed mix u e o isome s in accep able yields (54, 43 and 39%
espec). In he case o luo ine, 3h, a a io o 1:1.2 was de e mined
by 19F NMR. A s onge elec on wi hd awing g oup in
i luome hyl iodobenzene was also employed wi h success. No
su p isingly, wo isome s we e ob ained in a 1:1.2 a io wi h he
pa a isome (3g), and a mix u e o h ee ismoe s o he me a
analogue (1:6:4, 3l).
FULL PAPER
4
Scheme 2. Scope o he eac ion wi h di e en 3-a ylp opylamine and a yl-
iodines. [a] a io: 1:4.3 by 1H NMR. [b] 40% yields by 1H NMR wi h
ime hoxybenzene as in e nal s anda d. [c] a io: 1:1.2 by 19F NMR. [d] a io:
1:1.2 by 19F NMR. [e] a io: 6:4:1 by 19F NMR.
A his poin , we wonde ed abou he i s elemen a y s eps o his
in ica e ans o ma ion. Indeed, a e o ma ion o he amine-Pd
complex I, a be a-hyd ide elimina ion, ollowed by oxida ion o he
Pd(0) species, would lead o imine complex II (Scheme 2). This
s ep is lowe in ene gy han he di ec C-H ac i a ion o he amine
a he gamma posi ion (see SI). A his poin , he compu ed
ac i a ion ene gy o he C-H ac i a ion (TS1) is a o dable in he
eac ion condi ions (G‡ = 19.3 kcal/mol) o ende III, which
ollows he logical s eps o oxida i e addi ion o iodobenzene and
educ i e elimina ion o in oduce he bia yl sys em in he gamma
posi ion o he imine. We hypo hesized ha a simila p ocess
could also ake place in he unsubs i u ed p opyl imine sys em IV,
an in ac , he ac i a ion ene gy o TS2 is much lowe (8.7
kcal/mol) han in he p e ious subs i u ed sys em II. Fo his
eason, i seemed wo h o check he sui abili y o simple,
unsubs i u ed p opylamine as a subs a e o he eac ion, which
could su e a double a yla ion p ocess en ou e o he desi ed
quinolinium sal s.
Scheme 3. Mechanism o he o ma ion o he imines as di ec ing g oup, ollow
by C-H ac i a ion and a yla ion o he subs a e, suppo ed by DFT calcula ion.
Thus, p opylamine was ea ed wi h 2 equi alen s o iodobenzene
in o he wise simila condi ions o hose desc ibed in Table 3, and
o ou deligh , a e 60 h a 130 ºC, compound 5a was ob ained as
a single p oduc . Al hough he isola ed yield was a low 32%, i can
be conside ed adequa e o a p ocess wi h such a ema kable
inc ease o complexi y. As expec ed, he side alkyl chain a he
ni ogen is a p opyl g oup, and since wo equal a yl g oups a e
inco po a ed in he molecule, a single isome o he inal adduc is
o med. Simila ou comes we e ob ained wi h o he a yl iodides,
namely p- olyl (5b), p-chlo o (5c) and me a-me hyl (5d). In he
la e case, he wo possible egioisome s is ob ained, con aining
he CH3 g oup a he 6 and 8 posi ions o he he e ocyclic wi h a
a ion o 3:1. The o he posi ion (C8) is p obably blocked by s e ic
impedimen . The yields o he h ee compounds ange om 32 o
38%, which a e alues ha ha e o be pu again in pe spec i e,
aking in o accoun he simplici y o he me hod and he s a ing
ma e ials and he complexi y o he inal adduc s.
Scheme 4. Scope o he eac ion wi h p opylamine and a yl-iodines. [a] P oduc
no isola ed. [b] a io: 3:1
Al hough he speci ic na u e o all he s eps in ol ed in such a
complex mul icomponen p ocess a e impossible o de ail a his
s age, we ha e en a i ely compu ed some o he key ansi ion
s uc u es ha a leas a e able o explain he key bond o ma ions
(Scheme 3). Fo example, we hypo hesize ha a e he C-H
ac i a ion p e iously men ioned, an easy oxida i e addi ion in TS3
would a o d Pd(IV) complex VII wi h an ac i a ion ba ie o 19.5
kcal/mol. The subsequen educ i e elimina ion p esen s only 9.9
kcal/mol ene gy in TS4 o yield bis-a yla ed imine VIII. A e iodide
/amine ligand exchange, he C-N bond o ma ion is also
ene ge ically accessible (TS5¸ 14.8 kcal/mol). The pa icipa ion o
he palladium me al is p obably no needed in he inal s eps,
in ol ing cycliza ion h ough a ach o he amine o he imine
unc ional g oup, and p oduc yielding oxida i e a oma iza ion.
Scheme 5. Mechanism o he C-H ac i a ion/a yla ion o he 3-
phenylp opylimine, C-N bond o ma ion and cycliza ion.
Finally, an in e es ing esul was ob ained when p- luo o oluene
was used as a yla ing agen o he eac ion wi h p opylamine o
3
3-(4-me hoxyphenyl)p opan-1-amine (1d):
P epa ed om 4-me hoxybenzaldehyde wi h he desc ibed me hod, isola ed as an o -
whi e solid, 65% yield a e bo h s eps. 1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 8.5
Hz, 2H), 6.86 (d, J = 8.5 Hz, 2H), 3.82 (s, 3H), 2.75 ( , J = 7.0 Hz, 2H), 2.63 ( , J = 7.0
Hz, 2H), 1.77 (p, J = 7.5 Hz, 2H). Resul in ag eemen wi h he li e a u e.
1
3-(4- luo ophenyl)p opan-1-amine (6b):
P epa ed om 4- lu o obenzaldehyde wi h he desc ibed me hod, isola ed as an o -whi e
solid, 68% yield a e bo h s eps. 1H NMR (400 MHz, CDCl3) δ 7.16 (dd, J = 8.5, 5.5 Hz,
2H), 7.07 – 6.89 (m, 2H), 2.75 ( , J = 7.0 Hz, 2H), 2.72 – 2.58 (m, 2H), 1.89 – 1.66 (m,
2H). 19F NMR (376 MHz, CDCl3) δ -117.91. 13C NMR (101 MHz, CDCl3) δ 161.2 (d, J
= 243Hz), 129.6 13 (d, J = 7.5 Hz), 115.0 13 (d, J = 21.0 Hz), 41.66, 35.49, 32.42. HRMS
m/z [M+H]+ calcd o C9H12FN+ 153.0954; Found 153.0950.
3-(2,6-di luo ophenyl)p opan-1-amine:
P epa ed om 4-me hoxybenzaldehyde wi h he desc ibed me hod, isola ed as an oil,
71% yield a e bo h s eps. 1H NMR (400 MHz, CDCl3) δ 7.25 – 7.06 (m, 1H), 6.87 ( , J
= 8.0 Hz, 2H), 2.77 (d , J = 12.0, 7.5 Hz, 4H), 1.81 (p, J = 7.5 Hz, 2H). 19F NMR (376
MHz, CDCl3) δ -116.1. 13C NMR (101 MHz, CDCl3) δ 127.4 ( , J = 8.5 Hz), 111.0 (d, J
= 8.0 Hz), 41.2, 32.5, 19.5. HRMS m/z [M+H]+ calcd o C9H11F2N+ 171.0860; Found
171.0853.
1
William F. McCalmon , Jaclyn R. Pa e son, Michael A. Lindenmu h, Ti any N. Heady, Do is M.
Ha e s ick, Lloyd S. G ay, Timo hy L. Macdonald. Bioo ganic & Medicinal Chemis y, 13, 11, 2005, 3821-
3839,
4
4-phenyl-1-(3-phenylp opyl)quinolin-1-ium ace a e (3a):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 55 % yield (32
mg, 0.82 mmol). 1H NMR (500 MHz, CD3CN) δ 9.09 (d, 4.4 Hz, 1H), 8.39 (d, J = 8.9
Hz, 1H), 8.27 (d, J = 8.5 Hz, 1H), 8.23 ( , J = 8.0 Hz, 1H), 8.00 – 7.93 ( , J = 7.5 Hz, 1H),
7.89 (d, J = 4.5 Hz, 1H), 7.74 – 7.68 (m, 3H), 7.64 (m, 2H), 7.24 (d, J = 7.5 Hz, 5H), 5.03
( , J = 7.0 Hz, 2H), 2.87 ( , J = 8.0 Hz, 2H), 2.47 – 2.43 (m, 2H), 1.97 (s, 3H). 13C NMR
(126 MHz, CD3CN) δ 180.0, 160.3, 148.6, 140.9, 136.2, 136.1, 131.5, 130.9, 130.6,
130.2, 130.0, 130.0, 129.3, 129.0, 129.0, 127.1, 122.9, 119.6, 58.5, 32.8, 31.3. HRMS
m/z [M-OAc-]+ calcd o C24H22N+ 324.1700; Found 324.1745.
7-me hyl-4-(p- olyl)-1-(3-(p- olyl)p opyl)quinolin-1-ium ace a e (3b):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 45 % yield (28.7
mg, 6.75 mmol). 1H NMR (400 MHz, CD3CN) δ 9.10 (d, J = 6.0 Hz, 1H), 8.16 (d, J =
9.0 Hz, 1H), 8.01 (s, 1H), 7.80 – 7.71 (m, 2H), 7.51 (s, 4H), 7.12 (d, J = 5.0 Hz, 2H), 7.03
(d, J = 8.0 Hz, 2H), 4.93 ( , J = 7.5 Hz, 2H), 2.80 ( , J = 7.5 Hz, 2H), 2.69 (s, 3H), 2.51
(s, 3H), 2.44 – 2.31 (m, 2H), 2.28 (s, 3H). 13C NMR (126 MHz, CD3CN) δ 175.4, 159.5,
148.4, 148.0, 142.0, 139.3, 137.8, 136.4, 135.4, 132.9, 132.5, 130.5, 130.4, 129.9, 129.7,
129.6, 129.3, 129.1, 128.8, 121.7, 57.7, 32.1, 31.1, 22.2, 21.0, 20.6, 20.60. HRMS m/z
[M-OAc-]+ calcd o C27H28N+ 366,2222; Found 366.2231.
7-chlo o-4-(4-chlo ophenyl)-1-(3-(4-chlo ophenyl)p opyl)quinolin-1-ium ace a e
(3c):
5
P epa ed acco ding o he gene al p ocedu e, p oduc no isola ed. HRMS m/z [M-OAc-
]+ calcd o C24H19Cl3N+ 426.0583 Found 426.0588.
7-me hoxy-4-(4-me hoxyphenyl)-1-(3-(4-me hoxyphenyl)p opyl)quinolin-1-ium
hyd oxyde (3d):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 29 % yield (19.1
mg, 0.044 mmol). 1H NMR (400 MHz, ) δ 10.13 (d, J = 6.2 Hz, 1H), 8.14 (d, J = 9.4 Hz,
1H), 7.72 (d, J = 6.1 Hz, 1H), 7.49 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 9.5 Hz, 2H), 7.29 (s,
1H), 7.21 – 7.16 (m, 3H), 7.12 (dd, J = 14.5, 8.5 Hz, 1H), 7.04 (s, 2H), 6.83 ( , J = 7.5
Hz, 6H), 5.30 – 5.07 (m, 2H), 4.15 – 3.64 (m, 3H), 2.80 – 2.50 (m, 3H), 2.00 (s, 3H), 1.90
– 1.77 (m, 2H). 13C NMR (126 MHz, CD3CN) δ 159.1, 151.6, 147.2, 132.5, 131.9, 122.6,
120.2, 116.5, 115.5, 115.5, 99.2, 57.5, 56.2, 56.0, 22.9. HRMS m/z [M-OH-]+ calcd o
C27H28NO3+ 414.2069; Found 414.2048.
7-me hyl-4-phenyl-1-(3-phenylp opyl)quinolin-1-ium ace a e (3e):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 72 % yield (47.5
mg, 0.108 mmol). 1H NMR (400 MHz, CDCl3) δ 10.32 (d, J = 5.5 Hz, 1H), 8.29 (d, J =
8.5 Hz, 1H), 7.98 – 7.91 (m, 2H), 7.91 – 7.79 (m, 1H), 7.46 (s, 3H), 7.30 (d, J = 4.9 Hz,
6
5H), 7.27 – 7.04 (m, 6H), 5.35 – 5.26 (m, 2H), 2.95 ( , J = 7.0 Hz, 2H), 2.51 (d, J = 19.0
Hz, 5H), 2.30 (s, 1H), 2.09 (s, 3H). 13C NMR (126 MHz, CDCl3) δ 161.8, 158.7, 151.2,
151.0, 141.5, 141.2, 139.9, 139.4, 138.6, 137.9, 134.8, 134.6, 134.2, 131.9, 131.5, 130.7,
130.5, 130.0, 129.7, 129.6, 129.4, 129.3, 129.2, 129.2, 128.8, 128.7, 128.6, 128.6, 128.8,
128.4, 128.4, 128.1, 128.1, 127.9, 126.6, 126.4, 126.09, 122.9, 121.6, 121.1, 120.8, 118.1,
117.1, 114.3, 56.6, 41.7, 33.2, 32.41 31.2, 29.7, 28.8, 21.5, 21.3, 20.9. HRMS m/z [M-
OAc-]+ calcd o C25H24N+ 338.1909; Found 338.1924.
1-(3-phenylp opyl)-4-(4-( i luo ome hyl)phenyl)quinolin-1-ium ace a e and 4-
phenyl-1-(3-phenylp opyl)-7-( i luo ome hyl)quinolin-1-ium ace a e (3g):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 31 % yield (21.0
mg, 0.047 mmol). Mix u e o 1:0.8. 1H NMR (400 MHz, CDCl3) δ 10.38 (d, J = 5.0 Hz,
1H), 8.10 (d, J = 8.5 Hz, 1H), 8.07 – 8.02 (m, 1H), 7.98 (d, J = 5.0 Hz, 1H), 7.90 ( d, J =
13.4, 8.5 Hz, 4H), 7.67 (d, J = 8.0 Hz, 2H), 7.42 (q, J = 8.5 Hz, 4H), 7.34 – 7.17 (m, 8H),
5.29 – 5.21 (m, 2H), 2.90 ( , J = 7.0 Hz, 2H), 2.50 – 2.38 (m, 2H), 2.03 (s, 3H). 19F NMR
(376 MHz, CDCl3) -62.29, -62.94. 13C NMR (100 MHz, CDCl3) δ 156.7, 151.3, 141.9,
139.6, 138.0, 137.7, 135.0, 132.9, 132.5, 130.9, 130.6, 130.0, 129.8, 129.8, 129.3, 128.8,
128.6, 128.5, 128.5, 128.4, 127.8, 127.5, 126.5, 126.2, 125.6, 124.7, 123.2, 122.9, 122.1,
122.0, 121.5, 118.3, 114.5, 57.1, 41.9, 33.2, 32.3, 31.0, 29.8. HRMS m/z [M-OAc-]+ calcd
o C25H21F3N+ 392.1626; Found 392.1638.
4-(4- luo ophenyl)-1-(3-phenylp opyl)quinolin-1-ium ace a e and 7- luo o-4-
phenyl-1-(3-phenylp opyl)quinolin-1-ium ace a e (3h):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 54 % yield (32.5
mg, 0.081 mmol). Mix u e o 1:1. 1H NMR (400 MHz, CDCl3) δ 9.95 (d, J = 6.0 Hz, 1H),
8.19 (d, J = 8.5 Hz, 1H), 8.09 – 7.90 (m, 4H), 7.89 – 7.81 (m, 1H), 7.58 (dd, J = 8.5, 5.0
7
Hz, 2H), 7.40 – 7.12 (m, 2H), 6.91 ( , J = 8.7 Hz, 2H), 5.27 – 5.02 (m, 2H), 2.89 ( , J =
7.2 Hz, 2H), 2.49 – 2.37 (m, 2H), 2.03 (s, 3H). 19F NMR (376 MHz, CDCl3) -108.47, -
116.60. 13C NMR (100 MHz, CDCl3) δ 176.8, 165.5, 163.0, 162.8, 160.4, 157.6, 1504.,
139.7, 137.9, 134.8, 131.9, 131.8, 131.3, 130.9, 130.8, 129.6, 129.2, 129.0, 128.9, 128.6,
128.4, 128.1, 126.51, 123.1, 118.4, 116.7, 116.5, 115.1, 114.9, 57.2, 32.4, 31.0, 29.7,
21.7. HRMS m/z [M-OAc-]+ calcd o C24H21FN+ 342.1658; Found 342.1668.
4-(4-chlo ophenyl)-1-(3-phenylp opyl)quinolin-1-ium ace a e and 7-chlo o-4-
phenyl-1-(3-phenylp opyl)quinolin-1-ium ace a e (3i):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 43 % yield (26.9
mg, 0.065 mmol). 1H NMR (400 MHz, CDCl3) δ 10.04 (s, 1H), 8.16 (d, J = 8.5 Hz, 1H),
8.02 (d, J = 7.5 Hz, 1H), 7.87 (m, 4H), 7.62 (d, J = 8.5 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H),
7.33 – 6.86 (m, 8H), 5.17 – 5.08 (m, 2H), 2.85 ( , J = 7.0 Hz, 2H), 2.45 – 2.35 (m, 2H),
2.03 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 157.3, 150.8, 139.7, 137.8, 137.5, 134.8,
133.0, 132.1, 131.0, 130.9, 129.6, 128.8, 128.7, 128.4, 128.2, 128.0, 126.5, 123.1, 118.3,
57.2, 32.4, 31.0, 29.7. HRMS m/z [M-OAc-]+ calcd o C24H21ClN+ 358.1363; Found
358.1371.
4-(4-b omophenyl)-1-(3-phenylp opyl)quinolin-1-ium ace a e and 7-b omo-4-
phenyl-1-(3-phenylp opyl)quinolin-1-ium ace a e (3j):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 39 % yield
(23.5 mg, 0.059 mmol). 1H NMR (400 MHz, CDCl3) δ 10.06 – 10.00 (m, 1H), 8.17 (d, J
= 8.5 Hz, 1H), 8.03 (d, J = 7.5 Hz, 1H), 7.98 – 7.57 (m, 3H), 7.43 (d, J = 8.5 Hz, 1H),
7.38 – 7.17 (m, 3H), 7.13 (d, J = 8.0 Hz, 2H), 5.18 – 5.10 (m, 2H), 2.87 ( , J = 7.0 Hz,
2H), 2.46 – 2.34 (m, 2H), 2.02 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 207.1, 176.2,
157.3, 150.7, 139.7, 137.8, 135.4, 134.9, 133.5, 132.6, 131.2, 131.1, 129.6, 129.4, 128.8,
8
128.7, 128.4, 127.9, 126.5, 125.8, 123.0, 120.1, 118.3, 57.2, 32.4, 31.0, 30.9. HRMS m/z
[M-OAc-]+ calcd o C24H21B N+ 402.0857; Found 402.0873.
1-(3-phenylp opyl)-4-(p- olyl)quinolin-1-ium ace a e, 6-me hyl-4-phenyl-1-(3-
phenylp opyl)quinolin-1-ium ace a e and 8-me hyl-4-phenyl-1-(3-
phenylp opyl)quinolin-1-ium ace a e (3k):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 47 % yield (28.0
mg, 0.071 mmol). 1H NMR (400 MHz, CDCl3) δ 10.34 (s, 1H), 8.24 (d, J = 8.5 Hz, 1H),
8.06 – 7.95 (m, 1H), 7.92 (dd, J = 9.5, 6.0 Hz, 3H), 7.82 ( , J = 7.5 Hz, 1H), 7.67 – 7.60
(m, 1H), 7.56 – 7.40 (m, 3H), 7.40 – 6.98 (m, 6H), 6.91 (d, J = 7.0 Hz, 1H), 5.30 – 5.21
(m, 2H), 3.80 (s, 0.6H), 3.59 (s, 1.1H), 2.91 ( , J = 7.0 Hz, 2H), 2.51 (s, 2.3H), 2.44 (m,
2H), 2.03 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 175.9, 158.9, 150.9, 139.9, 139.3, 137.8,
137.5, 137.0, 134.7, 134.6, 131.5, 130.6, 130.3, 130.2, 129.5, 129.3, 129.3, 129.1, 128.6,
128.5, 128.2, 127.9, 126.8, 126.7, 126.5, 123.0, 118.1, 92.9, 56.8, 55.3, 32.4, 31.2, 29.7,
22.7, 21.4, 21.3. HRMS m/z [M-OAc-]+ calcd o C25H24N+ 338.1909; Found 338.1918.
1-(3-phenylp opyl)-4-(3-( i luo ome hyl)phenyl)quinolin-1-ium ace a e, 4-phenyl-
1-(3-phenylp opyl)-6-( i luo ome hyl)quinolin-1-ium ace a e and 4-phenyl-1-(3-
phenylp opyl)-8-( i luo ome hyl)quinolin-1-ium ace a e (3l):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 26 % yield (15.3
mg, 0.039 mmol). 1H NMR (400 MHz, CDCl3) δ 10.24 – 10.18 (m, 1H), 8.04 (m, 2H),
7.95 – 7.68 (m, 4H), 7.64 – 6.98 (m, 5H), 5.23 – 5.14 (m, 2H), 2.84 ( , J = 6.9 Hz, 2H),
2.46 – 2.34 (m, 2H), 1.99 (s, 3H). 19F NMR (376 MHz, CDCl3) -62.43, -62.48, -62.70.
13C NMR (101 MHz, CDCl3) δ 156.59, 151.17, 139.52, 137.85, 137.68, 135.33, 134.91,
133.01, 132.84, 131.83, 130.09, 129.85, 128.60, 128.41, 128.34, 127.86, 127.38, 126.50,
126.12, 123.24, 122.81, 118.26, 57.16, 43.28, 32.27, 30.82, 29.68. HRMS m/z [M-OAc-
]+ calcd o C25H21F3N+ 392.1626; Found 392.1635.
4-phenyl-1-p opylquinolin-1-ium hyd oxyde (5a):
9
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 32 % yield
(14.7 mg, 0.048 mmol). 1H NMR (500 MHz, CD3CN) δ 9.15 (d, J = 6.0 Hz, 1H), 8.49 (d,
J = 9.0 Hz, 1H), 8.31 (dd, J = 8.6, 1.0 Hz, 1H), 8.26 (ddd, J = 8.8, 7.0, 1.4 Hz, 1H), 8.03
– 7.93 (m, 2H), 7.75 – 7.63 (m, 5H), 5.03 – 4.90 ( , J = 7.7 Hz, 2H), 2.15 (sex, J = 7.4
Hz, 2H), 1.10 ( , J = 7.4 Hz, 3H). 13C NMR (126 MHz, CD3CN) δ 160.16, 148.30, 136.06,
135.96, 131.34, 130.72, 130.40, 129.80, 129.73, 122.77, 119.52, 59.97, 23.52, 10.60.
HRMS m/z [M-OH-]+ calcd o C18H18N+ 248.1439; Found 248.1450.
7-me hyl-1-p opyl-4-(p- olyl)quinolin-1-ium ace a e (5b):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 38 % yield (19.1
mg, 0.057 mmol). 1H NMR (500 MHz, CD3CN) δ 8.99 (d, J = 6.0 Hz, 1H), 8.25 (s, 1H),
8.23 (d, J = 9.0 Hz, 1H), 7.85 (d, J = 6.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.60 – 7.49
(m, 3H), 4.93 – 4.85 ( , 7.5 Hz, 2H), 2.76 (s, 3H), 2.52 (s, 3H), 2.13 (m, 2H), 1.09 ( , J =
7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 158.4, 150.2, 146.8, 141.5, 138.3, 132.0,
131.4, 130.0, 129.7, 129.3, 129.0, 128.6, 126.4, 121.9, 117.3, 58.5, 29.7, 23.3, 22.8, 21.4,
10.9. HRMS m/z [M-OAc-]+ calcd o C20H22N+ 276.1752; Found 276.1768.
7-chlo o-4-(4-chlo ophenyl)-1-p opylquinolin-1-ium ace a e (5c):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 16% (9.0 mg,
0.024 mmol). 1H NMR (500 MHz, CD3CN) δ 9.21 (s, 1H), 8.56 (s, 1H), 8.24 (d, J = 9.0
Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.5 Hz, 2H), 4.93
( , J = 7.5 Hz, 2H), 2.16 – 2.09 (m, 2H), 1.09 ( , J = 7.5 Hz, 3H). 13C NMR (126 MHz,
CD3CN) δ 158.8, 138.3, 137.7, 133.9, 132.1, 131.7, 131.3, 131.2, 130.0, 128.5, 128.0,
10
123.1, 60.1, 23.5, 10.5. HRMS m/z [M-OAc-]+ calcd o C18H16Cl2N+ 316.0660; Found
316.0679.
6-me hyl-1-p opyl-4-(m- olyl)quinolin-1-ium ace a e and 8-me hyl-1-p opyl-4-(m-
olyl)quinolin-1-ium ace a e (5d):
P epa ed acco ding o he gene al p ocedu e no isola ed. HRMS m/z [M-OAc-]+ calcd
o C20H22N+ 276.1752; Found 276.1768.
4-(4- luo ophenyl)-1-p opylquinolin-1-ium-7-ola e (8a):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 21 % yield (8.9
mg, 0.032 mmol). 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 7.82 (d, J = 9.5 Hz, 1H),
7.63 (s, 1H), 7.51 (dd, J = 8.5, 5.2 Hz, 2H), 7.36 (d, J = 9.5 Hz, 1H), 7.33 – 7.26 (m, 2H),
7.23 (s, 1H), 4.66 (s, 2H), 2.11 (d, J = 6.0 Hz, 2H), 1.08 ( , J = 7.0 Hz, 3H). 19F NMR
(471 MHz, CDCl3) δ -109.49. 13C NMR (126 MHz, CDCl3) δ 163.9 (d, J = 250 Hz),
155.2, 143.4, 142.1, 131.8, 131.5 (d, J = 9 Hz), 129.8, 126.7, 121.8, 116.4 (d, J = 22 Hz),
115.6, 101.1, 58.7, 29.7, 22.1, 11.0. HRMS m/z [M+H]+ calcd o C18H17FON+ 282.1294;
Found 282.1308.
4-(4- luo ophenyl)-1-(3-(4- luo ophenyl)p opyl)quinolin-1-ium-7-ola e (8b):
P epa ed acco ding o he gene al p ocedu e and ob ained as b own oil in 67 % yield
(37.7 mg, 0.101 mmol). 1H NMR (500 MHz, CDCl3) δ 8.45 (s, 1H), 7.72 (d, J = 10.0 Hz,
1H), 7.49 – 7.41 (m, 2H), 7.31 – 7.23 (m, 5H), 7.15 (dd, J = 8.5, 5.5 Hz, 2H), 7.00 (d, J
= 6.0 Hz, 1H), 6.92 ( , J = 8.5 Hz, 2H), 4.60 ( , J = 7.0 Hz, 3H), 2.80 ( , J = 7.5 Hz, 2H),
2.35 (p, J = 8.0 Hz, 3H). 19F NMR (471 MHz, CDCl3) δ -109.95, -116.40. 13C NMR (126
MHz, CDCl3) δ 174.8, 163.8 (d, J = 250Hz), 161.7 (d, J = 242Hz), 154.3, 142.8, 142.6,
11
135.5, 135.5, 132.3, 131.5 (d, J = 8 Hz), 130.0 (d, J = 8 Hz), 128.5, 121.4, 116.5 (d, J =
21 Hz), 115.7 (d, J = 21 Hz), 114.5, 101.0, 77.5, 77.3, 77.0, 56.3, 32.0, 29.8. HRMS m/z
[M+H]+ calcd o C25H19F2ON+ 376.1512; Found 376.1527.
3-(p- olyl)p opan-1-amine (1b):
12
3-(4-chlo ophenyl)p opan-1-amine (1c):
19
20
7-me hyl-4-(p- olyl)-1-(3-(p- olyl)p opyl)quinolin-1-ium ace a e (3b):
21
22
23
7-me hoxy-4-(4-me hoxyphenyl)-1-(3-(4-me hoxyphenyl)p opyl)quinolin-1-ium
hyd oxyde (3d):
24
7-me hyl-4-phenyl-1-(3-phenylp opyl)quinolin-1-ium ace a e and 1-(3-
phenylp opyl)-4-(p- olyl)quinolin-1-ium ace a e (3e):
25
26
1-(3-phenylp opyl)-4-(4-( i luo ome hyl)phenyl)quinolin-1-ium ace a e and 4-
phenyl-1-(3-phenylp opyl)-7-( i luo ome hyl)quinolin-1-ium ace a e (3g):
27
28
35
36
1-(3-phenylp opyl)-4-(3-( i luo ome hyl)phenyl)quinolin-1-ium ace a e, 4-phenyl-
1-(3-phenylp opyl)-6-( i luo ome hyl)quinolin-1-ium ace a e and 4-phenyl-1-(3-
phenylp opyl)-8-( i luo ome hyl)quinolin-1-ium ace a e (3l):
37
38
39
4-phenyl-1-p opylquinolin-1-ium ace a e (5a):
40
41
7-me hyl-1-p opyl-4-(p- olyl)quinolin-1-ium ace a e (5b):
42
7-chlo o-4-(4-chlo ophenyl)-1-p opylquinolin-1-ium ace a e (5c):
43
44
4-(4- luo ophenyl)-1-p opylquinolin-1-ium-7-ola e (8a):
51
C -1.078803 -1.304121 2.343882
H -2.020386 -1.855711 2.496527
H -0.817066 -0.870262 3.323497
C 0.027145 -2.233543 1.965723
H 0.164284 -3.209105 2.445001
N 0.845025 -1.818468 1.064855
H 1.670561 -2.353154 0.745584
Pd 0.563006 -0.044832 0.216194
H -1.410263 0.800022 1.783052
O 0.160937 1.965372 -0.498955
C 0.362743 2.944926 0.231833
C 0.080591 4.354104 -0.196743
H 1.004239 4.943762 -0.134075
H -0.307294 4.361575 -1.217833
H -0.647096 4.802586 0.492325
O 0.842794 2.839097 1.471830
H 0.995792 1.879222 1.653272
O 2.399233 -0.026065 -0.938158
C 3.242615 -1.006800 -1.005895
C 4.450563 -0.714011 -1.910230
H 4.975013 0.181495 -1.548781
H 5.139068 -1.566449 -1.925032
H 4.104061 -0.499855 -2.930884
O 3.159125 -2.111832 -0.428408
C -2.242551 -0.395820 0.223000
C -2.959137 0.693725 -0.320818
C -2.492919 -1.683029 -0.305588
C -3.884001 0.507972 -1.353120
H -2.778327 1.692125 0.076140
C -3.420433 -1.870543 -1.334794
H -1.945425 -2.538849 0.085797
C -4.119906 -0.776122 -1.867076
H -4.425652 1.363955 -1.754635
H -3.595782 -2.871929 -1.726754
H -4.840350 -0.923090 -2.670380
IV
SCF = -758.0970982
The mal co ec ion o Gibbs F ee Ene gy = 0.147708
C 1.458007 2.292404 -0.481816
C 0.522978 3.354844 0.118384
H 0.564146 4.279875 -0.475258
H 0.855106 3.636283 1.131560
C -0.901523 2.908315 0.227269
H -1.679056 3.655381 0.418105
N -1.233798 1.672647 0.130050
H -2.220552 1.383112 0.226556
Pd 0.055366 0.156874 -0.145974
H 2.510384 2.598075 -0.439327
O 1.389096 -1.367638 -0.468706
C 2.511230 -1.324514 0.212650
C 3.410548 -2.530168 -0.061622
52
H 2.952774 -3.427154 0.378317
H 3.506079 -2.701869 -1.141254
H 4.396502 -2.366597 0.386436
O 2.828954 -0.431985 1.008028
H 1.506732 1.358956 0.173675
O -1.342846 -1.339225 -0.087991
C -2.637754 -1.201512 0.076646
C -3.336432 -2.566041 0.077301
H -3.022426 -3.132876 0.963889
H -4.421341 -2.418906 0.095778
H -3.043747 -3.142469 -0.808890
O -3.274168 -0.152245 0.225219
H 1.214559 2.082227 -1.530403
TS2
SCF = -758.0794011
The mal co ec ion o Gibbs F ee Ene gy = 0.143856
C 1.500726 1.809621 -0.541215
C 0.905356 3.026760 0.200104
H 1.181696 3.972447 -0.292336
H 1.305634 3.090952 1.225945
C -0.579495 2.906785 0.307022
H -1.213384 3.773235 0.519954
N -1.099837 1.743154 0.161425
H -2.115317 1.560259 0.238701
Pd 0.040137 0.142419 -0.175084
H 2.596226 1.892442 -0.560800
O 1.300687 -1.540301 -0.393507
C 2.447811 -1.367026 0.139238
C 3.385286 -2.553078 0.220148
H 3.464219 -2.861460 1.271714
H 3.011706 -3.389527 -0.377233
H 4.384773 -2.252587 -0.116243
O 2.835449 -0.250634 0.616926
H 1.895972 0.645338 0.190260
O -1.522035 -1.227717 -0.057981
C -2.793088 -0.968844 0.088041
C -3.642721 -2.244178 0.111842
H -3.319645 -2.888144 0.940700
H -4.701063 -1.988078 0.228623
H -3.493253 -2.806080 -0.819771
O -3.325304 0.148382 0.199703
H 1.201368 1.799786 -1.597839
V
SCF = -758.1092181
The mal co ec ion o Gibbs F ee Ene gy = 0.148277
C 1.158581 2.005780 -0.450460
C 0.401265 3.200154 0.203417
H 0.551304 4.150727 -0.334929
H 0.765260 3.376884 1.230420
C -1.050800 2.872854 0.309720
53
H -1.816408 3.627048 0.521577
N -1.370947 1.633586 0.173005
H -2.337598 1.272618 0.256339
Pd 0.020921 0.291550 -0.243303
H 2.172983 1.899648 -0.042438
O 1.667609 -1.029730 -0.674416
C 2.574354 -1.218772 0.149950
C 3.728313 -2.141185 -0.106905
H 3.715865 -2.946364 0.639489
H 3.655245 -2.558672 -1.113625
H 4.669679 -1.590108 0.014694
O 2.608293 -0.623640 1.341722
H 1.812985 -0.042342 1.409824
O -1.269404 -1.444158 -0.083203
C -2.550913 -1.406113 0.096658
C -3.207889 -2.794994 0.137550
H -2.719067 -3.417406 0.899670
H -4.278920 -2.711687 0.354372
H -3.066409 -3.294384 -0.831479
O -3.261893 -0.385805 0.225591
H 1.235059 2.147951 -1.540137
VI
SCF = -989.063791
The mal co ec ion o Gibbs F ee Ene gy = 0.223427
C 1.158581 2.005780 -0.450460
C 0.401265 3.200154 0.203417
H 0.551304 4.150727 -0.334929
H 0.765260 3.376884 1.230420
C -1.050800 2.872854 0.309720
H -1.816408 3.627048 0.521577
N -1.370947 1.633586 0.173005
H -2.337598 1.272618 0.256339
Pd 0.020921 0.291550 -0.243303
H 2.172983 1.899648 -0.042438
O 1.667609 -1.029730 -0.674416
C 2.574354 -1.218772 0.149950
C 3.728313 -2.141185 -0.106905
H 3.715865 -2.946364 0.639489
H 3.655245 -2.558672 -1.113625
H 4.669679 -1.590108 0.014694
O 2.608293 -0.623640 1.341722
H 1.812985 -0.042342 1.409824
O -1.269404 -1.444158 -0.083203
C -2.550913 -1.406113 0.096658
C -3.207889 -2.794994 0.137550
H -2.719067 -3.417406 0.899670
H -4.278920 -2.711687 0.354372
H -3.066409 -3.294384 -0.831479
O -3.261893 -0.385805 0.225591
H 1.235059 2.147951 -1.540137
54
TS3
SCF = 0.245198
The mal co ec ion o Gibbs F ee Ene gy = -1289.283792
C 1.226123 -0.995649 1.391125
C 1.087530 -2.427837 1.990489
H 1.589442 -2.492494 2.969378
H 1.583979 -3.169945 1.344114
C -0.352301 -2.811573 2.070596
H -0.717459 -3.596163 2.742388
N -1.143279 -2.194244 1.273953
H -2.154837 -2.392220 1.174514
Pd -0.404399 -0.766037 0.033888
O -2.136865 -0.902919 -1.336412
C -3.280810 -1.423928 -1.031978
C -4.348390 -1.249988 -2.123316
H -3.913027 -1.385772 -3.121223
H -5.176126 -1.951668 -1.967904
H -4.740736 -0.223191 -2.068733
O -3.588277 -1.998950 0.035130
H 1.012683 -0.260312 2.173899
C -2.217783 2.869734 2.489690
C -0.829565 2.704394 2.596868
C -0.111383 2.042256 1.591180
C -0.819058 1.515996 0.506270
C -2.195130 1.713514 0.343049
C -2.891830 2.378959 1.362705
H -2.767536 3.390516 3.271422
H -0.290132 3.097666 3.457654
H 0.965300 1.929794 1.659679
H -2.704355 1.322037 -0.530390
H -3.968389 2.510442 1.262328
I 0.503153 1.288970 -1.520195
C 2.526369 -0.724668 0.731773
C 3.292679 0.407398 1.078171
C 3.002151 -1.566033 -0.298558
C 4.486108 0.700853 0.408641
H 2.950025 1.053703 1.885440
C 4.189569 -1.273792 -0.971215
H 2.409240 -2.431486 -0.592613
C 4.935988 -0.134891 -0.623019
H 5.064347 1.579592 0.691114
H 4.534202 -1.926517 -1.772193
H 5.861123 0.094526 -1.149617
VII
SCF = 0.246677
The mal co ec ion o Gibbs F ee Ene gy = -1289.29682
C 1.076221 -0.255836 -1.631177
C 0.532306 0.532789 -2.850242
55
H -0.249216 -0.063559 -3.348572
H 1.320610 0.710448 -3.597078
C -0.117574 1.813108 -2.435591
H -0.323808 2.614135 -3.153112
N -0.462833 1.920918 -1.209459
H -1.007050 2.699775 -0.788795
Pd -0.127229 0.328088 0.029863
O -1.019968 1.332400 1.780707
C -1.670792 2.449077 1.750960
C -2.188692 2.898485 3.121359
H -2.568989 3.924896 3.073454
H -3.000508 2.224206 3.429799
H -1.392847 2.819995 3.872842
O -1.924114 3.141185 0.736702
H 0.974220 -1.333349 -1.768815
C -4.122695 -1.575922 -1.890790
C -2.933355 -2.311821 -1.956555
C -1.744744 -1.802303 -1.404303
C -1.780951 -0.547507 -0.793560
C -2.951766 0.208693 -0.714194
C -4.130037 -0.321019 -1.269360
H -5.038778 -1.979144 -2.319223
H -2.915770 -3.294272 -2.426905
H -0.835713 -2.393244 -1.437415
H -2.954439 1.191663 -0.250555
H -5.047446 0.263683 -1.212654
I 0.391833 -1.809095 1.573595
C 2.431439 0.106493 -1.147168
C 3.284906 -0.909823 -0.658526
C 2.899213 1.441172 -1.131897
C 4.561569 -0.606687 -0.185003
H 2.927465 -1.937279 -0.652750
C 4.176300 1.744770 -0.649275
H 2.263701 2.245816 -1.492719
C 5.011255 0.723920 -0.173610
H 5.207113 -1.404215 0.179165
H 4.519133 2.778096 -0.643767
H 6.004618 0.961672 0.203386
TS4
SCF = 0.247048
The mal co ec ion o Gibbs F ee Ene gy = -1289.281401
C -1.103945 -0.874337 -1.241416
C -0.989200 -2.360035 -1.559801
H -1.356761 -2.517007 -2.588004
H -1.628748 -2.977900 -0.913118
C 0.413884 -2.866522 -1.451633
H 0.668846 -3.838442 -1.886657
N 1.299814 -2.181072 -0.837997
H 2.284506 -2.495294 -0.752381
56
Pd 1.003104 -0.287432 -0.113137
O 3.049700 0.153107 -0.462938
C 4.033812 -0.702153 -0.437702
C 5.399055 -0.019953 -0.572495
H 5.626743 0.501899 0.367586
H 6.173691 -0.768793 -0.770227
H 5.377040 0.730923 -1.371748
O 3.955783 -1.936562 -0.303723
C -2.197841 -1.439476 3.282548
C -2.329548 -0.185588 2.666727
C -1.647608 0.094105 1.481519
C -0.782883 -0.860034 0.903714
C -0.671040 -2.127023 1.519391
C -1.370349 -2.407692 2.701213
H -2.744583 -1.662497 4.197354
H -2.981435 0.573478 3.096549
H -1.811810 1.045482 0.988275
H -0.024916 -2.894299 1.108130
H -1.257911 -3.387344 3.163676
I 0.789404 2.375162 0.445172
H -0.421965 -0.298041 -1.875022
C -2.434418 -0.245779 -1.258853
C -3.603589 -0.947745 -0.895216
C -2.538800 1.106440 -1.646899
C -4.846348 -0.315279 -0.938478
H -3.536027 -1.981591 -0.563684
C -3.783319 1.742051 -1.678666
H -1.632365 1.654881 -1.898437
C -4.940066 1.032429 -1.325634
H -5.743716 -0.865710 -0.661322
H -3.850794 2.787345 -1.974614
H -5.910356 1.525859 -1.346834
VIII
SCF = 0.249876
The mal co ec ion o Gibbs F ee Ene gy = -1289.348197
C -2.039162 -0.967353 -0.177005
C -1.996950 -2.227489 0.716572
H -2.655581 -2.989054 0.275259
H -2.442272 -2.006810 1.701495
C -0.669889 -2.871038 0.955040
H -0.681270 -3.895223 1.346170
N 0.458241 -2.307751 0.749347
H 1.305617 -2.845123 0.976744
Pd 1.018272 -0.424025 0.155052
O 2.638544 -1.307377 -0.826220
C 3.415365 -2.173986 -0.229700
C 4.607624 -2.577823 -1.101844
H 5.413186 -1.847956 -0.937143
57
H 4.962175 -3.569917 -0.800756
H 4.348858 -2.564367 -2.166533
O 3.268774 -2.634230 0.912063
C -0.662579 2.750197 1.587674
C -1.224665 2.707200 0.288870
C -1.515038 1.497879 -0.315599
C -1.290725 0.262599 0.363792
C -0.673783 0.318078 1.652149
C -0.372862 1.572829 2.253372
H -0.447697 3.710181 2.052367
H -1.431792 3.635997 -0.238900
H -1.979119 1.473142 -1.298980
H -0.652888 -0.563374 2.287342
H 0.067721 1.586420 3.247647
I 2.174364 1.918854 -0.534224
H -1.594138 -1.226281 -1.147925
C -3.509902 -0.622624 -0.415747
C -4.286949 -0.066995 0.615977
C -4.107584 -0.885563 -1.656797
C -5.640754 0.218646 0.408818
H -3.824700 0.154563 1.577749
C -5.464443 -0.599617 -1.867653
H -3.506028 -1.310892 -2.459916
C -6.233599 -0.047438 -0.835232
H -6.232134 0.652533 1.213872
H -5.916312 -0.804229 -2.837210
H -7.286329 0.178359 -0.998092
IX
SCF = 0.298171
The mal co ec ion o Gibbs F ee Ene gy = -936.2500241
C -0.958551 -1.330962 2.151059
C -0.456930 -0.866211 0.922782
C 0.892070 -0.463534 0.809298
C 1.713551 -0.559449 1.949699
C 1.217989 -1.034967 3.170379
C -0.121352 -1.425844 3.273505
H -2.004201 -1.626319 2.232403
H 2.754594 -0.249912 1.878779
H 1.877411 -1.092835 4.035382
H -0.521881 -1.795844 4.217087
C 2.824854 0.627165 -0.463926
C 3.997983 -0.143705 -0.539393
C 5.258433 0.457331 -0.419710
C 5.362788 1.840688 -0.218625
C 4.198620 2.618398 -0.138678
C 2.941590 2.012649 -0.259515
H 3.927260 -1.219946 -0.688589
H 6.157418 -0.154684 -0.482535
H 6.341955 2.308693 -0.127092
H 4.269697 3.694544 0.014746
H 2.036011 2.616251 -0.193797
58
C 1.443352 0.000283 -0.543706
H 0.753230 0.771690 -0.918067
C 1.372054 -1.195823 -1.550676
H 1.720009 -2.118657 -1.067700
H 2.032156 -0.979506 -2.403639
C -0.026466 -1.381877 -2.085207
H -0.315592 -0.659461 -2.861522
N -0.798193 -2.459602 -1.962027
H -0.341610 -3.139245 -1.341020
N -2.982217 0.239428 0.329994
H -2.787197 0.294416 1.333564
C -3.085059 1.626004 -0.154437
H -2.189564 2.228447 0.094418
H -3.175802 1.613964 -1.251736
C -4.323135 2.329021 0.439455
H -4.242032 2.313382 1.538175
H -5.220472 1.750601 0.174309
C -4.452601 3.778513 -0.056971
H -3.564866 4.367035 0.218492
H -4.549952 3.807604 -1.152513
H -5.335112 4.269733 0.376122
Pd -1.694646 -0.930105 -0.650284
TS5
SCF = -936.2287843
The mal co ec ion o Gibbs F ee Ene gy = 0.300464
C -1.700761 -0.434812 2.273402
C -1.073697 -0.255403 1.019793
C 0.316110 -0.496373 0.876844
C 1.033309 -0.913351 2.015670
C 0.414679 -1.089613 3.257907
C -0.964831 -0.860994 3.381998
H -2.766977 -0.228832 2.370034
H 2.099358 -1.112416 1.915071
H 1.002648 -1.401640 4.119620
H -1.466006 -0.996678 4.340243
C 2.470079 -0.260699 -0.463876
C 3.400979 -1.312210 -0.418666
C 4.776132 -1.048864 -0.335677
C 5.239090 0.272868 -0.295728
C 4.317953 1.330266 -0.339663
C 2.946595 1.061922 -0.420950
H 3.052449 -2.343296 -0.446731
H 5.483619 -1.876613 -0.302341
H 6.306916 0.478122 -0.233575
H 4.668249 2.361534 -0.313262
H 2.230207 1.882848 -0.450362
C 0.968621 -0.498121 -0.510217
H 0.532178 0.328505 -1.083295
C 0.564677 -1.817757 -1.262444
H 0.613732 -2.672861 -0.574410
H 1.282811 -1.988156 -2.078491
59
C -0.820207 -1.718703 -1.870100
H -0.865863 -1.145267 -2.806965
N -1.872552 -2.502348 -1.601430
H -1.631510 -3.136746 -0.830182
N -1.961050 1.340328 0.137478
H -2.428280 1.609023 0.999889
C -0.907055 2.300519 -0.185387
H -0.016646 2.166421 0.461650
H -0.580346 2.133764 -1.221748
C -1.405920 3.747509 -0.041734
H -1.761292 3.897351 0.990515
H -2.268808 3.899847 -0.706608
C -0.294581 4.760261 -0.364545
H 0.565584 4.622231 0.306945
H 0.059404 4.632722 -1.398240
H -0.653687 5.792408 -0.252446
Pd -2.224121 -0.551452 -0.662118
X
SCF = -936.2857884
The mal co ec ion o Gibbs F ee Ene gy = 0.301818
C -1.465800 -1.018233 1.642226
C -0.748290 0.003068 0.907623
C 0.651054 -0.233478 0.591691
C 1.283575 -1.352451 1.134964
C 0.601413 -2.296651 1.932184
C -0.763661 -2.146030 2.161510
H -2.454748 -0.794303 2.037002
H 2.336236 -1.513760 0.911636
H 1.140460 -3.148059 2.344509
H -1.313061 -2.872934 2.758498
C 2.859431 0.710566 -0.221595
C 3.762932 -0.157709 -0.857122
C 5.137906 -0.082124 -0.589144
C 5.628526 0.864017 0.319514
C 4.734339 1.735417 0.959963
C 3.363440 1.655020 0.690649
H 3.395318 -0.900182 -1.562627
H 5.823092 -0.764353 -1.091041
H 6.696166 0.924230 0.526279
H 5.105227 2.477009 1.666581
H 2.668035 2.327622 1.193406
C 1.352375 0.638569 -0.442903
H 1.000869 1.675844 -0.360992
C 0.997218 0.129286 -1.911920
H 1.090306 -0.964399 -1.916750
H 1.747742 0.560649 -2.589415
C -0.357264 0.509705 -2.409853
H -0.470551 1.511399 -2.845988
N -1.388042 -0.283492 -2.308787
H -2.220187 0.156952 -2.708352
N -1.275327 1.306142 0.779073
60
H -0.899477 1.778404 -0.036332
C -2.730314 1.492052 0.823240
H -3.231346 0.761086 0.155023
H -3.085368 1.293354 1.844536
C -3.103613 2.919579 0.415426
H -2.733309 3.104182 -0.606708
H -2.587009 3.629986 1.077861
C -4.621697 3.148268 0.467838
H -5.145169 2.453009 -0.204578
H -5.003938 2.985629 1.486102
H -4.878010 4.173025 0.167101
Pd -1.691894 -1.415786 -0.548337
XI
SCF = -980.8603258
The mal co ec ion o Gibbs F ee Ene gy = 0.326588
C -1.511212 2.266862 0.408815
C -0.812214 1.189890 -0.219201
C 0.621376 1.107323 -0.093320
C 1.305241 2.067774 0.684083
C 0.604479 3.123296 1.323989
C -0.799189 3.222134 1.171273
H -2.603786 2.352302 0.302934
H 2.403616 1.998189 0.773542
H 1.154864 3.868191 1.924454
H -1.352722 4.046892 1.655664
C 2.815354 -0.230056 -0.525875
C 3.174991 -0.605034 0.800046
C 4.530766 -0.818819 1.144826
C 5.546684 -0.661912 0.166503
C 5.198503 -0.289082 -1.155564
C 3.839580 -0.074160 -1.498354
H 2.382993 -0.719745 1.561623
H 4.797539 -1.107081 2.177887
H 6.605415 -0.828682 0.435323
H 5.985618 -0.164419 -1.921351
H 3.566702 0.217997 -2.528731
C 1.329137 -0.011680 -0.905869
H 1.279474 0.266624 -1.985489
C 0.528970 -1.356007 -0.726970
H 0.618074 -1.682484 0.328256
H 0.961089 -2.145153 -1.376114
C -1.005217 -1.193140 -1.090430
H -1.207468 -1.588604 -2.121158
N -1.462933 0.231618 -1.081772
C -2.888858 0.457872 -1.509602
H -2.987319 1.539430 -1.754327
H -3.042289 -0.128959 -2.444965
C -3.999787 0.055904 -0.465087
H -3.737038 0.469502 0.530461
H -4.027298 -1.049256 -0.377480
C -5.393481 0.592730 -0.917582
