Copper-catalyzed direct arylation of cyclic enamides using diaryliodonium salts

Article abstract of DOI:10.1021/ol303400s

A convenient method for the copper(II)-catalyzed direct arylation of cyclic and nonaromatic enamides using diaryliodonium salts has been developed. The reaction demonstrates large functional group tolerance, good yields, and total regioselectivity with a

Full text of DOI:10.1021/ol303400s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Copper-Catalyzed Direct Arylation
of Cyclic Enamides Using
Diaryliodonium Salts
†
†
‡,§
€
Nicolas Gigant, Laetitia Chausset-Boissarie, Marie-Charlotte Belhomme,
Thomas Poisson,‡,§ Xavier Pannecoucke,*,‡,§ and Isabelle Gillaizeau*,†
Institut de Chimie Organique et Analytique, UMR 7311 CNRS, rue de Chartres,
ꢀ
ꢀ
ꢀ
Universite d’Orleans, F-45067 Orleans Cedex 2, France, INSA de Rouen avenue de
l’Universite, 76800 Saint Etienne du Rouvray, France, and Laboratory COBRA UMR
ꢀ
ꢀ
6014 & FR 3038, IRCOF, Universite de Rouen, 1 Rue Tesniere, 76821 Mont St Aignan
ꢁ
Cedex, Rouen, France
isabelle.gillaizeau@univ-orleans.fr; xavier.pannecoucke@insa-rouen.fr
Received November 13, 2012
ABSTRACT
A convenient method for the copper(II)-catalyzed direct arylation of cyclic and nonaromatic enamides using diaryliodonium salts has been
developed. The reaction demonstrates large functional group tolerance, good yields, and total regioselectivity with a C(3)-functionalization. The
synthetic potential of this coupling was explored by using a range of readily accessible diaryliodonium salts and enamides.
CarbonÀcarbon bond-forming reactions mediated by
direct carbonÀhydrogen bond functionalization remain a
crucial challenge in organic chemistry and currently repre-
sent a powerful tool for the formation of complex building
blocks.1 Addressing this issue will thus not only improve
atom economy but also increase the overall efficiency of
multistep synthetic sequences.
starting materials.2d,3 Among some recent significant stu-
dies, a major contribution was made by Gaunt’s research
group who reported the selective copper-catalyzed aryla-
tion of indoles,2k aromatic compounds,2hÀj and alkenes.2c
Independently, MacMillan and co-workers described an
elegant enantioselective R-arylation2g or R-vinylation2d of
carbonyl groups.
Consequently, the direct copper-catalyzed functionali-
zation of various derivatives by using iodonium salts has
been recently extensively studied.2 Iodonium salts are indeed
extremely appealing as they are air- and moisture-stable and
can be easily prepared in one step from commercially available
In our quest to generate libraries of nitrogen-containing
derivatives for biological screening,4 we sought to apply
(2) For recent or significant examples: (a) Liu, C.; Zhang, W.; Dai,
L.-X.; You, S.-L Org. Lett. 2012, 14, 4525–4527. (b) Jui, N. T.; Garber,
J. A. O.; Finelli, F. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012,
134, 10815–10818. (c) Phipps, R. J.; McMurray, L.; Ritter, S.; Duong,
H. A.; Gaunt, M. J. J. Am. Chem. Soc. 2012, 134, 10773–10776. (d)
Skucas, E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2012, 134, 9090–
9093. (e) Harvey, J. S.; Simonovich, S. P.; Jamison, C. R.; MacMillan,
D. W. C. J. Am. Chem. Soc. 2011, 133, 13782–13785. (f) Bigot, A.;
Williamson, A. E.; Gaunt, M. J. J. Am. Chem. Soc. 2011, 133, 13778–
13781. (g) Allen, A.; MacMillan, D. W. C. J. Am. Chem. Soc. 2011, 133,
4260–4263. (h) Duong, H. A.; Gilligan, R. E.; Cooke, M. L.; Phipps,
R. J.; Gaunt, M. J. Angew. Chem., Int. Ed. 2011, 50, 463–466. (i) Ciana,
C.-L.; Phipps, R. J.; Brandt, J. R.; Meyer, F.-M.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2011, 50, 458–462. (j) Phipps, R. J.; Gaunt, M. J. Science
2009, 323, 1593–1597. (k) Phipps, R. J.; Grimster, N. P.; Gaunt, M. J.
J. Am. Chem. Soc. 2008, 130, 8172–8174. (l) Jalalian, N.; Petersen, T. B.;
Olofsson, B. Chem.;Eur. J. 2012, 18, 14140–14149.
†
ꢀ
ꢀ
Universite d'Orleans.
‡
§
ꢀ
INSA de Rouen avenue de l'Universite.
ꢀ
Universite de Rouen.
(1) For recent reviews of transition-metal-catalyzed CÀH activation:
(a) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F. Angew.
Chem., Int. Ed. 2012, 51, 10236–10254. (b) Arockiam, P. B.; Bruneau, C.;
Dixneuf, P. H. Chem. Rev. 2012, 112, 5879–5918. (c) Cho, S. H.; Kim,
J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068–5083. (d)
Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40, 1976–1991. (e)
McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011, 40,
1885–1898. (f) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147–
1169.
r
10.1021/ol303400s
XXXX American Chemical Society

this powerful copper-catalyzed direct arylation to cyclic
nonaromatic enamides. Despite their poor reactivity in
comparison to enamine species, they have seen much recent
use notably as nucleophiles in various processes.5 While
the direct C-2 arylation of enamides has been extensively
explored,6 only a few examples of their C-3 arylation have
been reported. For instance, Rutjes developed a two-step
sequence involving halogenation followed by a subsequent
Pd(0) catalyzed cross-coupling reaction;7 Loh and co-
workers also described the first palladium-catalyzed direct
C-3 arylation of acyclic enamides with simple arenes.8
Inspired by these pioneering studies, we envisioned that a
copper-catalyzed direct arylation reaction of nonaromatic
enamides in the presence of diaryliodonium salts would
afford 3-arylpiperidine backbones prevalent in a wide
range of bioactive compounds (Figure 1).9
At the outset of the study, six-membered cyclic enamide
1a and diphenyliodonium triflate 2a were chosen as model
substrates to establish the best reaction conditions (Table 1).
In light of recent advances in this area, the feasibility of the
direct coupling reaction was first examined using 20 mol %
Cu(OAc)2 as a catalyst and 2 equiv of 2,6-di-tert- butyl-
pyridine (DTBP) as a base in dioxane at 80 °C (entry 1).
Under these conditions, the attempted C3-arylated enam-
ide 3a was isolated albeit in 19% yield. Modifying the
nature of the copper source identified Cu(OTf)2 as the
most efficient catalyst (entries 1À3). It is noteworthy to
mention that the reaction is not effective in the absence of
copper triflate (entry 4).
Table 1. Optimization of Direct Arylation onto Enamide 1aa
Cu catalyst
(20 mol %)
base
yield 3a
(%)b
entry
X
(2 equiv)
solvent
1
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
PF6
BF4
OTs
Br
Cu(OAc)2
CuCl
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
pyridine
Et3N
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
19
34
67
12
41
41
32
30
0
2
3
Cu(OTf)2
none
4
5c
6d
7e
8f
9
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
10
11
12
13
14
15
16
0
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
43
76
73
80
0
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
a Reaction conditions: 1a (1 equiv), 2a (2 equiv), copper catalyst, and
base in solvent at 80 °C for 24 h. b Yield of pure product after purification
by column chromatography. c The reaction was conducted for 12 h.
d Cu(OTf)2 (10 mol %) was used. e Base (1 equiv) was used. f 2a (1 equiv)
was used.
Considering that processes havetobecarried outrapidly
with high atom economy and using inexpensive reagents,
we next explored different parameters such as reaction time
and loadings of base, diaryliodonium salt, or catalyst
(entries 5À8). Unfortunately, despite all our attempts the
yield of CÀH arylation was not improved. Further studies
highlighted the crucial role of DTBP as a base in our
catalytic system (entries 9À10).10 Pleasingly, a study of the
nature of the solvent revealed that good results were
obtained by using CH2Cl2 (entry 12); the desired adduct
3a was thus isolated in 76% yield. Diaryliodonium salts 2
bearing different counteranions (entries 13À16) were next
examined. Among all the tested reagents, triflate, hexa-
fluorophosphate, and tetrafluoroborate diaryliodonium
salts showed similar behavior, while either p-toluenesulfonate
or bromide diaryliodonium salt was unreactive in our reac-
tion conditions, as decomposition was observed.2l To our
Figure 1. Representive examples of 3-arylpiperidine.
(3) For recent reviews, see: (a) Merritt, E. A.; Olofsson, B. Angew.
Chem., Int. Ed. 2009, 48, 9052–9070. (b) Deprez, N. R.; Sanford, M. S.
Inorg. Chem. 2007, 46, 1924–1935. See also: (c) Bielawski, M.; Aili, D.;
Olofsson, B. J. Org. Chem. 2008, 73, 4602–4607. (d) Bielawski, M.; Zhu,
M.; Olofsson, B. Adv. Synth. Catal. 2007, 349, 2610–2618.
(4) (a) Gigant, N.; Gillaizeau, I. Org. Lett. 2012, 14, 4622–4625. (b)
Gigant, N.; Gillaizeau, I. Org. Lett. 2012, 14, 3304–3307. (c) Gigant, N.;
Claveau, E.; Bouyssou, P.; Gillaizeau, I. Org. Lett. 2012, 14, 844–847. (d)
Gigant, N.; Dequirez, G.; Retailleau, P.; Gillaizeau, I.; Dauban, P.
Chem.;Eur. J. 2012, 18, 90–94.
(5) For recent reviews: (a) Gopalaiah, K.; Kagan, H. B. Chem. Rev.
2011, 111, 4599–4657. (b) Matsubara, R.; Kobayashi, S. Acc. Chem. Res.
2008, 41, 292–301. (c) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455–
3460.
(6) (a) Liu, Y.; Li, D.; Park, C.-M. Angew. Chem., Int. Ed. 2011, 50,
7333–7336. (b) Ruan, J.; Iggo, J. A.; Berry, N. G.; Xiao, J. J. Am. Chem.
Soc. 2010, 132, 16689–16699. (c) Hyder, Z.; Ruan, J.; Xiao, J. Chem.;
Eur. J. 2008, 14, 5555–5566. (d) Mo, J.; Xiao, J. Angew. Chem., Int. Ed.
2006, 45, 4152–4157. (e) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005,
127, 751–760.
(7) van den Broek, S. B. A. M. W.; Rensen, P. G. W.; van Delft, F. L.;
Rutjes, F. P. J. T. Eur. J. Org. Chem. 2010, 5906–5912.
(8) Pankajakshan, S.; Xu, Y.-H.; Cheng, J. K.; Low, M. T.; Loh,
T.-P. Angew. Chem., Int. Ed. 2012, 51, 5701–5705.
(9) (a) Wallace, D. J.; Baxter, C. A.; Brands, K. J. M.; Bremeyer, N.;
Brewer, S. E.; Desmond, R.; Emerson, K. M.; Foley, J.; Fernandez, P.;
Hu, W.; Keen, S. P.; Mullens, P.; Muzzio, D.; Sajonz, P.; Tan, L.;
Wilson, R. D.; Zhou, G.; Zhou, G. Org. Process Res. Dev. 2011, 15, 831–
840. (b) Michael, J. P. Nat. Prod. Rep. 2005, 22, 603–626. (c) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893–930.
(10) Presumably a less hindered base might poison the copper
catalyst and inhibit the reaction.
B
Org. Lett., Vol. XX, No. XX, XXXX

knowledge, this is the first report on the copper-catalyzed
direct regioselective C-3 arylation of nonaromatic enam-
ides using diaryliodonium salts.
were well-tolerated under these conditions, demonstrating
the potential of this process (3fÀi). Interestingly the sub-
stituent on the aryl group could then be further func-
tionalized, a critical consideration for the elaboration of
more complex derivatives. Noteworthy, the transforma-
tion is also compatible with meta-substituted diaryliodo-
nium salt 3j; unfortunately the sterically more hindered
enamide 3k could not be isolated. A heteroaromatic
aryliodonium salt afforded the desired enamide 3l albeit
with moderate yield. It is noticeable that a competing
substrate decomposition was observed prior to the com-
plete consumption of the starting material.
Scheme 1. Direct Coupling of Enamide 1a with Various Diary-
liodonium Saltsa
Scheme 2. Direct Coupling of Diaryliodonium Salt 2a with
Various Enamidesa
a Reaction conditions: 1a (1 equiv), 2a (2 equiv), Cu(OTf)2 (20 mol %),
and DTBP (2 equiv) in CH2Cl2 at 80 °C for 24 h. Yield of pure prod-
uct after purification by column chromatography. b 5 equiv of 2a were
used.
To assess the effectiveness of our reaction, different
enamides were then screened by focusing on six-membered
ring systems found in the 3-arylpiperidine framework
(Scheme2). Theefficiencyofthe processwasdemonstrated
whatever the nitrogen-protecting group employed, afford-
ing arylated enamides 3a and 3mÀn in good yields.12 The
protocol was also amenable to endo-enamide (3o). Unfor-
tunately, the five-membered enamide 3p could not be
delivered; the constrained structure is presumably respon-
sible for the lack of reactivity. Seven-membered cyclic
enamides 1q afforded an inseparable mixture of mono-
and diarylated products. However, performing the reac-
tion with 5 equiv of diaryliodonium salt 2a led to the
diarylated enamide 3q isolated as a sole compound in only
24% yield. In addition, we were pleased to isolate with a
good yield the same difunctionalized enamide 3q starting
from the corresponding ramified substrate (R = Ph).
a Reaction conditions: 1a (1 equiv), 2a (2 equiv), Cu(OTf)2 (20 mol
%), and DTBP (2 equiv) in CH2Cl2 at 80 °C for 24 h. Yield of pure
product after purification by column chromatography.
Having established the optimal conditions, we next exa-
mined the scope of the transformation (Scheme 1). Gratify-
ingly, symmetrical diaryliodonium salts were successfully
employed, and either electron-rich or -deficient arenes
were found to be suitable coupling partners in this proto-
col, affording C3-arylated enamides 3aÀe in good yields.
Furthermore, unsymmetrical diaryliodonium salts, con-
taining the desired aryl group and a more voluminous
second aryl unit that would not transfer in the catalytic
process,11 were tested. In this case despite moderate yields,
either halogen or other electron-withdrawing substituents
(11) (a) Deprez, N. R.; Kalyani, D.; Krause, A.; Sanford, M. S.
J. Am. Chem. Soc. 2006, 128, 4972–4973. (b) Deprez, N. R.; Sanford,
M. S. Inorg. Chem. 2007, 46, 1924–1935.
(12) The use of the N-Boc protecting group was unsuccessful.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Direct Coupling of Enamides with Various Iodonium
Saltsa
Figure 2. Proposed catalytic cycle for the direct arylation of
enamide 1.
Regarding the mechanism of the reaction, we assume, in
agreement with previous reports by Gaunt and co-work-
ers, that an oxidative insertion of Cu(OTf) into the diary-
liodonium salt will afford an electrophilic Cu(III)-aryl
intermediate (Figure 2).2 The latter Cu(III)-aryl species
undergoes electrophilic addition at the electron-rich C3
position of the enamide 1. Then a reductive elimination,
followed by regeneration of the enamide moiety, affords
the desired framework 3. Although this mechanism is
commonly admitted, we cannot rule out the possibility
that the copper catalyst might induce dissociation of the
triflate anion to form an activated aryliodonium species.
Then a new λ3 iodane is generated after attack by the
enamide 1 and undergoes a rapid reductive elimination to
deliver the corresponding intermediate.13 Theformation of
the diarylated enamide 3q can be rationalized by a first
regioselective arylation sequence at the C3 position accom-
panied by a second one at the C2 position. As previously
described by Gaunt,2k a C3 to C2 migration of the CÀCu
bond promoted by the N-benzoyl group of the seven-
membered intermediate iminium ion could be envisaged.
Finally, we were delighted to find that this methodology
is amenable to the more complex enamide 1r leading to the sub-
stitutedconjugated diene3r in moderate yield (Scheme 3).14
In addition, vinylphenyliodonium salts2a,d also appeared to
be interesting partners for this direct CH functionalization,
a Reaction conditions: 1a (1 equiv), 2a (2 equiv), Cu(OTf)2 (20 mol %),
and DTBP (2 equiv) in CH2Cl2 at 80 °C for 24 h. Yield of pure product after
purification by column chromatography.
albeit with low yields (3s). These results again highlight
the potential of this process in combination with further
conventional transformations.
In summary, we described herein a straightforward
method for the direct copper-catalyzed C-3 arylation of
cyclic and nonaromatic enamides using diaryliodonium
salts as a coupling partner. The transformation is both
general and efficient with respect to a broad range of
substrates. To the best of our knowledge, this is the first
direct strategy involving nonaromatic enamides and iodo-
nium salts. Further studies focusing on extending the scope
of the reaction to synthesize 3-arylpiperidine scaffolds as
potential medicinal products will be reported in due course.
Acknowledgment. Financial support from the MESR
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(Ministere de l’Enseignement Superieur et de la Recherche)
is gratefully acknowledged for the doctoral fellowships
to N.G. and M.-C.B. We thank the LABEX SynOrg for
financial support.
Supporting Information Available. Full characteriza-
1
tion details including H and 13C NMR, IR, MS, and
HRMS. This material is available free of charge via the
Internet at http://pubs.acs.org.
(13) (a) Allen, A. E.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010,
132, 4986–4987. (b) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.;
Niedermann, K.; Togni, A. Angew. Chem., Int. Ed. 2009, 48, 4332–4336.
(14) 56% of the starting material was recovered.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX