Palladium-Catalyzed, Enantioselective Formal Cycloaddition between Benzyltriflamides and Allenes: Straightforward Access to Enantioenriched Isoquinolines

Palladium-Ca alyzed, Enan ioselec i e Fo mal Cycloaddi ion
be ween Benzyl iflamides and Allenes: S aigh o wa d Access o
Enan ioen iched Isoquinolines
Xand o Vidal, JoseL. Masca enas,*and Moise
s Gulías*
Cen o Singula de In es igacion en Química Bioloxica e Ma e iais Molecula es (CIQUS) and Depa amen o de Química O ga
nica,
Uni e sidade de San iago de Compos ela, 15782 San iago de Compos ela, Spain
*
SSuppo ing In o ma ion
ABSTRACT: Benzyl and allyl iflamides can engage in
Pd-ca alyzed oxida i e (4+2) annula ions wi h allenes, o
p oduce highly aluable e ahyd oisoquinoline o dihy-
d opy idine skele ons. The eac ion is especially efficien
when ca ied ou in he p esence o designed N-p o ec ed
amino acids as me al ligands. Mo e impo an ly, using his
ype o chi al ligands, i is possible o pe o m
desymme izing, annula i e C−H ac i a ions o p ochi al
dia ylme hylphenyl amides, and hus ob ain he co e-
sponding isoquinolines wi h high enan iome ic a ios.
The me al-ca alyzed unc ionaliza ion o nonac i a ed C−
H bonds has eme ged as an ex emely powe ul syn he ic
ool.
1
Mo eo e , i he C−H ac i a ion is app op ia ely
ha nessed o encompass a concomi an annula ion eac ion,
he me hodology allows a di ec assembly o cyclic skele ons
om simple, non unc ionalized acyclic s a ing ma e ials.
2
In
his con ex , we ha e epo ed se e al Rh and Pd-ca alyzed
annula ions o alkenylphenols and alkenylanilides wi h diffe -
en unsa u a ed pa ne s. These s a egies allow o build a
a ie y o he e ocyclic p oduc s in a s aigh o wa d manne .
3
The use o allenes as annula ion pa ne s is pa icula ly
a ac i e owing o hei inhe en eac i i y, and because hey
a o educ i e elimina ion e sus β-hyd ide elimina ion s eps
in key me allacyclic in e media es.
4
Owing o his special eac i i y, we wonde ed i allenes could
engage in annula i e C−H unc ionaliza ions o benzyl- o
allylamines, as his would allow o build highly aluable
e ahyd oisoquinoline and e ahyd opy idine skele ons om
simple p ecu so s. Achie ing hese ans o ma ions is a om
ob ious, no only because o he difficul ies associa ed wi h he
C−H ac i a ion and allene inse ion s eps bu also because o
compe ing benzylic o allylic oxida ion eac ions. Indeed, he
only p eceden in his ype o annula ions in ol es he use o
α,α-disubs i u ed benzylamines (which can be oxidized) and
monosubs i u ed allenes, and p o ides mix u es o isome ic
adduc s.
5,6
He ein, we epo he disco e y o condi ions ha allow o
ca y ou efficien Pd-ca alyzed annula ions be ween benzyla-
mides and allenes. The eac ion wo ks o α-unsubs i u ed and
monosubs i u ed benzyl iflamides, and diffe en ypes o
allene pa ne s, and akes place wi h excellen egio- and
s e eoselec i i ies. The annula ion can be ex ended o allyl and
e en homoallylamines, he eby allowing o build dihyd opy -
idine and azepine skele ons. Mo e impo an ly, we demon-
s a e ha he e ahyd oisoquinoline p oduc s can be
assembled in an efficien and highly enan ioselec i e manne
ia desymme iza ion o p ochi al s a ing ma e ials (Scheme
1A). While se e al desymme izing C−H ac i a ion/ unc ion-
aliza ion p ocesses ha e been desc ibed, especially unde Pd-
ca alysis,
7−9
o he bes o ou knowledge, palladium-ca alyzed
enan ioselec i e o mal cycloaddi ions elying on C−H
ac i a ions a e unknown.
10
Mo eo e , he numbe o epo s
on any desymme izing me al-media ed annula ions in ol ing
C−H ac i a ions is ma ginal.
11
Finally, i is impo an o no e ha e ahyd oisoquinoline
skele ons a e p i ileged scaffolds p esen in a as amoun o
bioac i e na u al p oduc s and d ugs (Scheme 1B), and
he e o e he de elopmen o enan ioselec i e app oaches o
hese cyclic skele ons is o majo significance.
12
Conside ing ou p e ious wo k on he annula ion o
alkenylanilides and allenes unde palladium ca alysis,
3e
we
Recei ed: No embe 25, 2018
Published: Janua y 13, 2019
Scheme 1. Asymme ic C−H Ac i a ion/Annula ion
App oach o Isoquinoline Skele ons
Communica ion
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Ci e This: J. Am. Chem. Soc. 2019, 141, 1862−1866
© 2019 Ame ican Chemical Socie y 1862 DOI: 10.1021/jacs.8b12636
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began ou esea ch by explo ing he eac ion be ween
benzyl iflamide 1a and inylidenecyclohexane (2a) in he
p esence o 1.5 equi o Cs2CO3, and using Pd (OAc)2as
ca alys , and Cu(OAc)2as eoxidan . Wi h e -amyl alcohol as
sol en , he desi ed (4+2) cycloadduc was isola ed in a
modes 15% yield. The use o o he sol en s, a he same
empe a u e (80 °C), allowed o li le imp o emen s (up o
23−25% yield, Table 1, en ies 1−5). Al hough he p esence o
he iflyl subs i uen in he amine slows down he benzylic
oxida ion, he o ma ion o undesi ed benzylaldehyde was s ill
significan (obse ed a e he wo k-up). While he addi ion o
DMSO in oluene allowed a sligh inc ease in he yield o 34%,
we ound ha adding p o ec ed amino acids (en ies 6−10),
and especially 2,6-F,F-Bz-Leu-OH (L, 40 mol %), boos s he
yield up o 85% (en y 11). This could be u he imp o ed by
adding 15 equi o DMSO o he eac ion mix u e (95% yield,
en y 12), wi h he eac ion being comple e a e only 40 min.
The ole o he DMSO is unclea , bu i may help o s abilize
Pd(0) in e media es and a o a mo e effec i e eoxida ion o
Pd(II). Finally, he amoun o Cu(OAc)2can be dec eased o
50 mol % wi hou significan ly affec ing he yield (en y 13).
Using he op imized condi ions, we ound ha he eac ion
can be ex ended o diffe en ypes o allenes (see Table 2).
Thus, o he 1,1-dibsubs i u ed allenes like 5- inylidenenonane
(2b) o (4-me hylpen a-1,2-dien-3-yl)benzene (2c) led o he
co esponding isoquinolines 3ab and 3ac in 85 and 86% yield.
1,3-Disubs i u ed allenes 2d and 2e p o ided he co espond-
ing adduc s 3ad and 3ae, as only one s e eo- and egioisome
(80 and 74% yield, espec i ely). Monosubs i u ed allenes like
p opa-1,2-dien-1-ylcyclohexane also wo k, o gi e 3a as 1.1:1
mix u e o E:Zisome s. Mo e imp essi ely, isubs i u ed
allenes led o only one cycloadduc in a e y efficien manne
(3ag and 3ah, 80 and 90% yield, espec i ely). I is impo an
o no e ha diphenylace ylene o s y ene ailed o eac wi h 1a
unde he s anda d eac ion condi ions, which suppo s he
special eac i i y o allenes in his ype o palladium ca alyzed
annula ions.
The eac ion is no limi ed o unsubs i u ed benzyl i-
flamides, and he eby α-alkyl benzyl iflamides can pa icipa e
in he annula ions, p o iding o efficien kine ic esolu ions.
The e o e, ea men o 2 equi o (1-phenylp opyl) iflamide
(1b) wi h allene 2a, using s anda d condi ions, p oduced a
91% yield o cycloadduc 3ba (45% yield based on he
iflamide 1b,Table 2) wi h a e y good 93:7 enan iome ic
a io (e ). We also isola ed a 40% yield o enan ioen iched
s a ing amide (e = 86:14).
Nex , we wonde ed i he annula ion could be ex ended o
mo e challenging iflamides bea ing alkenyl ins ead o benzyl
pendan s. Palladium-ca alyzed ac i a ions o olefinic C(sp2)−
H bonds has been much less de eloped han ha o hei
a oma ic coun e pa s, in pa because o compe ing alkene
addi ion eac ions. G a i yingly, using he abo e condi ions,
allene 2a eac ed efficien ly wi h allylamines 1c and 1d o
p oduce he expec ed e ahyd opy idines 3ca and 3da in 71
and 88% yield (Table 3).
13
This eac ion is gene al o o he
allenes as exemplified wi h isubs i u ed de i a i e 2g ha led
o he o ma ion o 3cg in an excellen 90% yield.
In e es ingly, in a a e example o a o mal (5+2) annula ion,
he ans o ma ion can be ex ended o homoallylic amines, as
demons a ed wi h he assembly azepine 3ea (83%). This
p elimina y esul p oposes a i ial and p ac ical en y o
se en-membe ed azahe e ocycles, and wa an s u he u u e
esea ch o explo e he scope o he p ocess.
While he abo e examples demons a e ha using N- iflyl
p o ec ed amines and allenes i is possible o achie e e y
appealing annula i e C−H ac i a ions, he efficiency o he
kine ic esolu ion o gi e op ically ac i e isoquinoline 3ba,
called o explo ing asymme ic a ian s based on desymme -
iza ion s a egies. G a i yingly, ea men o he diphenylme-
hylamide 1 wi h allene 2a, unde s anda d condi ions a 90
°C, ga e he expec ed cycloadduc 3 a wi h an excellen 85%
yield and a e y good 94:6 enan iome ic a io. Simila esul s
we e ob ained wi h o he disubs i u ed allenes such 2b and 2c,
Table 1. Op imiza ion o he Reac ion Condi ions
a
En y Sol en TLigand
b
Yield
c
1 -AmyOH 80 °C−15%
2 Dioxane 80 °C−23%
3 DCE 80 °C−24%
4CH
3CN 80 °C−9%
5 Toluene 90 °C−25%
6
d
Toluene 90 °C−34%
7 Toluene 90 °C Boc-Leu-NHOMe 37%
8 Toluene 90 °C Boc-Phe-NHOMe 31%
9 Toluene 90 °C Boc-Ala-OH 58%
10 Toluene 90 °C Boc-Val-OH 69%
11 Toluene 90 °C 2,6-F,F-Bz-Leu-OH 85%
12
d
Toluene 90 °C 2,6-F,F-Bz-Leu-OH 95%
e
13
d
Toluene 90 °C 2,6-F,F-Bz-Leu-OH 86%
e
,
a
Condi ions: 0.333 mmol 1a, 0.167 mmol o allene 2a, 2 mL o
sol en , unde ai , 16 h.
b
40% o ligand.
c
Yields based on 2a,
calcula ed by using an in e nal s anda d.
d
15 equi o DMSO added.
e
Isola ed yield based on 2a.
0.5 equi o Cu(OAc)2·H2O
Table 2. Pd(II)-Ca alyzed Annula ion o N-
Benzyl iflimides wi h Allenes
a
a
Isola ed yield based on allenes, a e 16 h.
b
E:Zand egioisome ic
a ios a e >20:1, unless o he wise no ed.
c
Insepa able isome s.
Regioisome ic a io de e mined by c ude 1H NMR.
Jou nal o he Ame ican Chemical Socie y Communica ion
DOI: 10.1021/jacs.8b12636
J. Am. Chem. Soc. 2019, 141, 1862−1866
1863
which ga e he p oduc s 3 b and 3 c wi h yields be ween 66
and 95%, and 95:5 e a ios. Rema kably, using a
monosubs i u ed allene (p opa-1,2-dien-1-ylcyclohexane, 2 ),
we ob ained an excellen yield (81%) and e (93:7) o he
adduc 3ffand, con a y o he eac ion wi h he unsubs i u ed
benzyl iflamide (Table 2), we only obse ed he Zisome .
O he p ochi al subs a es ea u ing diffe en subs i uen s a
he a yl moie y also pa icipa ed in he annula ion. The e o e,
p oduc s like 3ga o 3g , in which he phenyl g oups ha e o ho
me hyl subs i uen s, we e p oduced in excellen yields and wi h
enan iome ic a ios o 97:3 and 98:2. A c ys al s uc u e o 3ga
allowed o s ablish he absolu e configu a ion o he chi al
cen e (Table 4). Fo he case o pa a subs i u ed a oma ic
ings, he eac ion was also e y efficien , and p oduc s 3ha,
3hb,3ia and 3ib, we e isola ed in yields o 86−95% yields, and
enan iome ic a ios o up o 95:5. Finally, cycloadduc s wi h
me hoxy subs i uen s in pa a o me a posi ions o he a oma ic
ings we e also efficien ly o med (3ja and 3ka), al hough he
enan iome ic a io sligh ly d opped o 90:10 o he la e .
A hypo he ical ca aly ic cycle depic ed in Scheme 2 allows o
in e key elemen s ha a e c i ical o he success o he abo e
annula ions. The iflyl g oup should a o dep o ona ion a
he ni ogen, and he o ma ion o in e media es like I,in
which elimina ions o benzylic hyd ogens migh be no
especially easy.
14
The amino acid ligand likely plays a key
ole in acili a ing he C−H ac i a ion o gi e palladacycle IIb,
which a e coo dina ion o he allene would o m in e media e
III. This in e media e e ol es by mig a o y inse ion o gi e a
π-allylic palladacycle (IV), which unde goes a N−Csp
2
educ i eelimina ion, a o edby hep esenceo he
coo dina ing exoalkene g oup. Pd(0) is eoxidized o he
ac i e Pd(II) ca alys h ough a combina ion o Cu(OAc)2and
ai .
In he case o he desymme iza ion p ocess, he palladacycle
in e media e o ype II is chi al, and he p e e ed o ma ion o
one o he enan iome o e he o he mus be a ibu ed o
s e ic clashing effec s in he C−H ac i a ion s ep (I o II), as
p oposed o simple unc ionaliza ion eac ions.
14
In conclusion, we ha e de eloped a s aigh o wa d access o
highly aluable e ahyd oisoquinoline and e ahyd opy idine
skele ons h ough a palladium-ca alyzed o mal (4+2) cyclo-
addi ion o benzyl and allylamines o allenes. The eac ion
elies on a Pd-ca alyzed Csp2−H ac i a ion, and p esen s
excellen le els o chemo- and egioselec i i y; being also
highly appealing in e ms o a om economy. Mo e impo an ,
he annula ion can be pe o med in an enan ioselec i e ashion
using p ochi al dia ylme hylamines, leading o enan iome ic
Table 3. Pd(II)-Ca alyzed Annula ion be ween N-Allyl (and
Homoallyl iflamides) and Allenes
a
a
Isola ed yields based on allenes 2a e 16 h.
b
105 °C.
c
An equimola
amoun o 1e and 2a was used.
Table 4. Enan ioselec i e Pd(II)-Desymme iza ion o
Dia ylme hyl iflamide
a
,
b
a
Condi ions: 0.333 mmol o amides 1, 0.167 mmol o allenes 2, unde
ai , 16 h. Isola ed yields based on 2.
b
S uc u e o he majo p oduc
shown.
c
70 °C, 3 days.
d
0.167 mmol o iflamide 1g, 0.333 mmol o
allenes 2a and 2d. Yield based on 1g.
e
Hyd ogens omi ed o cla i y.
No e: A ep esen s he same a oma ic ing han ha unde going he
ans o ma ion, as co esponds o a symme ic subs a e.
Scheme 2. Mechanis ic P oposal
Jou nal o he Ame ican Chemical Socie y Communica ion
DOI: 10.1021/jacs.8b12636
J. Am. Chem. Soc. 2019, 141, 1862−1866
1864
a ios up o 98:2. This ype o palladium-ca alyzed annula i e
C−H ac i a ion/desymme iza ion p ocesses, which had no
been p e iously epo ed, ep esen s an impo an new
addi ion o he a mo y o ca aly ic asymme ic me hods.
■ASSOCIATED CONTENT
*
SSuppo ing In o ma ion
The Suppo ing In o ma ion is a ailable ee o cha ge on he
ACS Publica ions websi e a DOI: 10.1021/jacs.8b12636.
Expe imen al p ocedu es and spec oscopic da a o new
compounds (PDF)
CIF file o compound 3ba (CIF)
CIF file o compound 3ga (CIF)
■AUTHOR INFORMATION
Co esponding Au ho s
*[email p o ec ed]
*[email p o ec ed]
ORCID
JoseL. Masca enas: 0000-0002-7789-700X
Moise
s Gulías: 0000-0001-8093-2454
No es
The au ho s decla e no compe ing financial in e es .
■ACKNOWLEDGMENTS
This wo k has ecei ed financial suppo om Spanish g an s
(SAF2016-76689-R, CTQ2016-77047-P and FPU ellowship
o X.V.), he Conselle i

a de Cul u a, Educacion e O denacion
Uni e si a ia (ED431C 2017/19, 2015-CP082 and Cen o
Singula de In es igacion de Galicia acc edi a ion 2016-2019,
ED431G/09), he Eu opean Regional De elopmen Fund
(ERDF), and he Eu opean Resea ch Council (Ad anced
G an No. 340055). The o eo-cinqa ne wo k CTQ2016-
81797-REDC is also kindly acknowledged.
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( )Shi,H.;He on,A.N.;Shao,Y.;Shao,Q.;Yu,J.-Q.
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