Direct site-selective arylation of enamides via a decarboxylative cross-coupling reaction

Article abstract of DOI:10.1021/ol303497q

An efficient Pd-catalyzed decarboxylative cross-coupling reaction of simple enamides was achieved. Depending on the choice of the nitrogen-protecting group, a site-selective synthesis of mono- or diarylated framework(s) was performed under mild conditions

Full text of DOI:10.1021/ol303497q

ORGANIC
LETTERS
2013
Vol. 15, No. 4
816–819
Direct Site-Selective Arylation of
Enamides via a Decarboxylative
Cross-Coupling Reaction
€
Nicolas Gigant, Laetitia Chausset-Boissarie, and Isabelle Gillaizeau*
Institut de Chimie Organique et Analytique, UMR 7311 CNRS, rue de Chartres,
ꢀ
Universite d’Orleans, F-45067 Orleans Cedex 2, France
ꢀ
ꢀ
isabelle.gillaizeau@univ-orleans.fr
Received December 20, 2012
ABSTRACT
An efficient Pd-catalyzed decarboxylative cross-coupling reaction of simple enamides was achieved. Depending on the choice of the nitrogen-
protecting group, a site-selective synthesis of mono- or diarylated framework(s) was performed under mild conditions. This unprecedented
reactivity could be applied to the synthesis of a range of 2- or 2,4-diarylated nitrogen-containing bioactive derivatives.
The screening of libraries of small organic molecules to
discover new potential drugs or to detect an interaction
with proteins for instance has become one of the most
important challenges for the organic chemist.1 “Diversity-
Oriented Synthesis” (DOS) first introduced by Schreiber
and co-workers in 20002 is perhaps the most promising
strategy to improve the number of compounds in order to
find a lead for medicinal chemistry programs,3 as it enables
considerable molecular diversity to be generated in only a
few steps starting from simple materials. At the heart of
DOS are the synthetic methods required for the efficient
generation of complex molecular scaffolds. This diversity
can be rapidly obtained by carbonꢀcarbon bond-forming
reactions. Indeed, catalyzed cross-coupling is currently
one of the most powerful methods in the construction of
carbon frameworks, and during the past decade in particular,
benzoic acids have emerged as viable coupling partners
toward oxidative decarboxylative couplings.4 These spe-
cies can be considered as the synthetic equivalents of aryl
halides and have several advantages, principally their
availability, low cost, and stability. In 2002, Myers et al.
reported the first palladium-catalyzed coupling of arene
carboxylic acids with olefinic substrates in a decarboxyla-
tive Heck-type reaction.5 This concept was further ex-
panded by Goossen6 and others,7 and more especially for
the arylation of a range of substrates. Despite significant
advances in this chemistry, some limitations emerge when
the process combines both decarboxylative cross-coupling
and carbonꢀhydrogen bond activation.4a
(5) Myers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc.
2002, 124, 11250–11251.
(6) For selected papers, see: (a) Bhadra, S.; Dzik, W. I.; Goossen,
L. J. J. Am. Chem. Soc. 2012, 134, 9938–9941. (b) Goossen, L. J.;
Rodriguez, N.; Lange, P. P.; Linder, C. Angew. Chem., Int. Ed. 2010, 49,
1111–1114. (c) Goossen, L. J.; Rodriguez, N.; Linder, C. M. J. Am.
Chem. Soc. 2008, 130, 15248–15249. (d) Goossen, L. J.; Rodriguez, N.;
Melzer, B.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007,
129, 4824–4833. (e) Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006,
313, 662–664.
(7) For some other selected examples: (a) Cornella, J.; Righi, M.;
Larrosa, I. Angew. Chem., Int. Ed. 2011, 50, 9429–9432. (b) Zhou, J.; Hu,
P.; Zhang, M.; Huang, S.; Wang, M.; Su, W. Chem.;Eur. J. 2010, 16,
5876–5881. (c) Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010,
49, 2768–2771. (d) Shang, R.; Fu, Y.; Li, J.-B.; Zhang, S.-L.; Guo, Q.-X.;
Liu, L. J. Am. Chem. Soc. 2009, 131, 5738–5739. (e) Forgione, P.;
Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; (f) Bilodeau,
F. J. Am. Chem. Soc. 2006, 128, 11350–11351.
(1) For reviews, see: (a) O’Connor, C. J.; Beckmann, H. S. G.;
Spring, D. R. Chem. Soc. Rev. 2012, 41, 4444–4456. (b) Galloway, W. R.
J. D.; Isidro-Llobet, A.; Spring, D. R. Nat. Commun. 2010, 1, 80. (c)
Schreiber, S. L. Nature 2009, 457, 153–154. (d) Burke, M. D.; Schreiber,
S. L. Angew. Chem., Int. Ed. 2004, 43, 46–58.
(2) Schreiber, S. L. Science 2000, 287, 1964–1969.
(3) Galloway, W. R. J. D.; Spring, D. R. Nature 2011, 470, 43.
(4) For reviews, see: (a) Cornella, J.; Larrosa, I. Synthesis 2012, 653–
676. (b) Dzik, W. I.; Lange, P. P.; Goossen, L. J. Chem. Sci. 2012, 3,
2671–2678. (c) Rodriguez, N.; Goossen, L. J. Chem. Soc. Rev. 2011, 40,
5030–5048. (d) Goossen, L. J.; Rodriguez, N.; Goossen, K. Angew.
Chem., Int. Ed. 2008, 47, 3100–3120.
r
10.1021/ol303497q
Published on Web 01/31/2013
2013 American Chemical Society

intermediateled toa mixture of the expected monoarylated
product 3a in combination with the diarylated product 4a
(as a 3a:4a 30:70 ratio) in a promising global yield of 47%
(entry 2). This result showed that the second cross-coupling
reaction proceeds faster than the first one. It is noticeable
that this diarylated framework is the key scaffold of some
bioactive substances such as the β-carboline alkaloids
tadalafil or quillifoline (Figure 1). As the choice of solvent
is known to control the decarboxylation rate,4b,7b,7f,16c our
next attempt was to use TMSO in place of DMSO (entry 3)
asa cosolvent;anincreasein the yield of product 3ato21%
and 4a to 51% was thus observed.
Figure 1. Representative examples of 2-aryl- or 2,4-diaryl-
piperidines.
Enamides are stable enamine surrogates and are im-
portant key intermediates for the synthesis of small but
complex nitrogen containing compounds; recently, they
have been involved in several metal catalyzed reactions.8
Among these reactions, direct C3 dehydrogenative func-
tionalization of nonaromatic enamides was recently de-
scribed with alkenes9 or arenes10 and direct C2 function-
alization was extensively reported by Xiao’s team starting
from aryl chlorides11 and Park with pinacol arylboronates.12
Recently, we have been engaged in the development of a
regioselective oxidative CꢀH bond functionalization pro-
gram starting from nonaromatic enamides.9,13 In pursuit
of this goal, we wish herein to report our results in this area
involving the decarboxylative cross-coupling reaction of
aryl carboxylic acids, for the synthesis of arylated nitrogen
containing frameworks. We expect this new method to be
broadly applicable to the synthesis of natural products and
medicinal agents (Figure 1).14
Guided by recent advances in this area, our representa-
tive attempts are summarized in Table 1. We first selected
the simple cyclic enamide 1a and 2,6-dimethoxybenzoic
acid as a coupling partner, in the presence of Ag2CO3, a
catalytic amount of Pd(OAc)2, PPh3 asa phosphine ligand,
and DMSO as a cosolvent in DMF at 80 °C for 24 h
(Table 1, entry 1). By applying these conditions at the
outset of our study, only a trace amount of the attempted
product was identified. Surprisingly, adding propionic
acid to enhance the electrophilic ability of the palladium
Table 1. Optimization of Direct Mono- or Diarylation onto
Enamide 1aa
yield yield
2a
3a
4a
entry (equiv)
catalyst
Pd(OAc)2
cosolvent additive (%)b (%)b
1
3
3
3
3
3
3
3
5
1
5
5
DMSO none
trace trace
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
DMSO EtCO2H 14
TMSO EtCO2H 21
33
51
34
3
4
TMSO none
19
5
TMSO tBuCO2H trace trace
6c
7d
8
TMSO EtCO2H
TMSO EtCO2H
0
0
0
0
TMSO EtCO2H trace 65
TMSO EtCO2H trace trace
TMSO EtCO2H trace 26
9e
10
11
Pd(MeCN)2Cl2 TMSO EtCO2H trace trace
a Reaction conditions unless otherwise specified: 1a (1 equiv), 2a,
Ag2CO3 (2 equiv), Pd(II) catalyst (10 mol %), PPh3 (0.5 equiv),
cosolvent (2.4 equiv), additive (0.5 equiv) in DMF at 80 °C for 24 h.
b Yield of pure product after purification by column chromatography.
c The reaction was conducted without PPh3. d The reaction was carried
out in a sealed tube. e Ag2CO3 (1 equiv) was used.
(8) (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.
(9) (a) Gigant, N.; Gillaizeau, I. Org. Lett. 2012, 14, 3304–3307. (b)
Xu, Y.-H.; Chok, Y. K.; Loh, T.-K. Chem. Sci. 2011, 2, 1822–1825.
(10) Pankajakshan, S.; Xu, Y.-H.; Cheng, J. K.; Low, M. T.; Loh,
T.-P. Angew. Chem., Int. Ed. 2012, 51, 5701–5705.
(11) (a) Ruan, J.; Iggo, J. A.; Berry, N. G.; Xiao, J. J. Am. Chem. Soc.
2010, 132, 16689–16699. (b) Hyder, Z.; Ruan, J.; Xiao, J. Chem.;Eur. J.
2008, 14, 5555–5566. (c) Mo, J.; Xiao, J. Angew. Chem., Int. Ed. 2006, 45,
4152–4157. (d) Mo, J.; Xu, L.; Xiao, J. J. Am. Chem. Soc. 2005, 127, 751–
760.
(12) Liu, Y.; Li, D.; Park, C.-M. Angew. Chem., Int. Ed. 2011, 50,
7333–7336.
(13) (a) Gigant, N.; Gillaizeau, I. Org. Lett. 2012, 14, 4622–4625. (b)
Gigant, N.; Claveau, E.; Bouyssou, P.; Gillaizeau, I. Org. Lett. 2012, 14,
844–847. (c) Gigant, N.; Dequirez, G.; Retailleau, P.; Gillaizeau, I.;
Dauban, P. Chem.;Eur. J. 2012, 18, 90–94.
Modifications of both the additive and of the phosphine
ligand were unsuccessful (entries 4ꢀ6). The low yields
observed in these cases resulted from a degradation reac-
tion in addition to the formation of side products arising
from degradation and/or homocoupling.15 Degradation
also occurred when the process was carried out under
pressure (entry 7). With selective transformations noted
as a key challenge in organic chemistry, in order to favor
the formation of diarylated scaffolds 4a, the amount of
carboxylic acid was increased. The use of 5 equiv of 2a
led gratifyingly to the corresponding piperidine core 4a,
(14) (a) Seabrook, G. R.; Shepheard, S. L.; Williamson, D. J.; Tyrer,
P.; Rigby, M.; Cascieri, M. A.; Harrison, T.; Hargreaves, R. J.; Hill,
R. G. Eur. J. Pharmacol. 1996, 317, 129–135. (b) Pansare, S. V.; Paul,
E. K. Org. Biomol. Chem. 2012, 10, 2119–2125.
(15) Hu, P.; Shang, Y.; Su, W. Angew. Chem., Int. Ed. 2012, 51, 5945–
5949.
Org. Lett., Vol. 15, No. 4, 2013
817

isolated as the sole compound in 65% yield (entry 8).
Unfortunately, by using only 1 equiv of 2a, no selectivity
was observed and the monoarylated product 3a was not
isolated due to a lack of conversion (entry 9). Other
palladium sources were also tested but with no overall
improvement (entries 10ꢀ11).
occurred with enamides 1e, 1f, and 1g in fair to good yields.
For the five-membered ring, a low yield was associated
with a degradation reaction. Surprisingly, we were pleased
to find that, starting from enamide 1h bearing a Boc pro-
tecting group, the corresponding 2-arylpipiridine core 3h
was isolated as the sole compound in 70% yield. The same
behavior was also observed with enamide 1i bearing a
phenyl carbamate group. With this strategy, we were now
able to perfectly control the mono- or difunctionalization
of the enamides thanks to the electronic density of the pro-
tecting group on the nitrogen atom. Performing the reac-
tion with strong electroattractive protecting groups fa-
vored the double direct cross-coupling process while less
electroattractive protecting groups such as carbamates
favored the mono-cross-coupling reaction.
Scheme 1. Influence of the Protecting Group for the Direct
Mono- or Diarylation of Enamides 1a
Moreover, we examined the direct arylation for the syn-
thesis of various arylpiperidine skeletons (Scheme 2). The
reaction tolerates a range of polyfonctionalized electron-
rich ortho-methoxy-substituted benzoic acids in good to
excellent yields (3kꢀm). Naphtalen derivative 3n is also
compatible under these conditions. Moreover, other ben-
zoic acids bearing ortho-electron donating groups gave us
the desired frameworks 3oꢀq in high yields. Different aryl
carboxylic acids were then tested under optimized condi-
tions on enamide 1h bearing a Boc-nitrogen protective
group (Scheme 2). The reaction tolerated a range of poly-
functionalized electron-rich alkoxy-substituted or weak
electron-donating alkyl-substituted benzoic acids in good
to excellent yields (3jꢀq). The particular substitution
pattern of the phenyl ring of these carboxylic acids affected
the yield (3m versus 3l, 3j versus 3h).16 It is noteworthy that
attempts to test the reaction with meta- or para-alkoxy
substituted benzoic acid derivatives were not satisfactory.
Naphtalen derivative 3n is also compatible in these condi-
tions. Electron-defficientarylcarboxylicacids underwenta
cross-coupling reaction to afford the corresponding ary-
lated product 3r, albeit in low yield. When the electronic
density decreased on the aromatic core, the direct cross-
coupling arylation was less efficient. Finally, we focused
our last efforts on the synthesis of 2,4-diarylpiperidines
with success. Frameworks 4sꢀw were isolated with mod-
erate to good yields for a double direct C2,C4 dehydro-
genative functionalization. It is interesting to note that
with specific enamide 1c we can control the monoaddition
with the use of more hindered substituents to afford 3x in
moderate yield. Beyond this elegant method, the obtained
products could be easily further functionalized for the
synthesis of small but more complex heterocyclic systems.
Given that the exact mechanism of decarboxylative cou-
pling is still not clear, a plausible catalytic cycle is proposed in
Scheme 3. After generation of a Pd(II) species and formation
of a Pd(II)-carboxylate complex, an aryl Pd(II) intermedi-
ate was created via extrusion of CO2. Subsequent carbo-
palladation of enamide 1a, followedbyβ-hydride elimination,
gave both compound 2a and the Pd-hydride species. Thanks
a Reaction conditions: 1 (1 equiv), 2a (5 equiv), Pd(OAc)2 (10 mol %),
Ag2CO3 (2 equiv), PPh3 (0.5 equiv), TMSO (2.4 equiv) and propionic
acid (0.5 equiv) in DMF at 80 °C for 24 h. Yield of pure product after
purification by column chromatography in parentheses.
With a set of optimized conditions in hand, we next
examined various simple enamides in the Pd-decarboxyla-
tive cross-coupling reaction with electron-rich 2,6-di-
methoxybenzoic acid as the coupling partner (Scheme 1).
It is important to mention that to date and to the best of
our knowledge, direct arylation cross-coupling has not
been reported in the literature on nonaromatic enamides.
We found that the endoenamide 1b or 1c was converted to
the corresponding diarylated compound 4b or 4c with
good yields via a one-pot double cross-coupling process.
Starting from the latter, further functionalization could be
envisaged by introducing diversity via the lactam function.
It should also be noted that the electronic density on the
benzyl protecting group had no influence on the reaction
selectivity. Unfortunately, the reaction was not selective
with enamide 1d; an inseparable mixture of mono- and
diarylated products (respectively 3d and 4d) was obtained
in moderate yield. Diversification was alsointroduced with
five- or seven-membered ring systems. Double cross-coupling
(16) For selected examples: (a) Xiang, S.; Cai, S.; Zeng, J.; Liu, X.-W.
Org. Lett. 2011, 13, 4608–4611. (b) Cornella, J.; Lu, P.; Larrosa, I. Org.
Lett. 2009, 11, 5506–5509. (c) Cornella, J.; Sanchez, C.; Banawa, D.;
Larrosa, I. Chem. Commun. 2009, 7176–7178.
818
Org. Lett., Vol. 15, No. 4, 2013

4a was thus isolated in 41% yield accompanied by some
impurities. Without a palladium source, the use of Ag2CO3
alone was not effective for the coupling, showing that this
salt is not the key reagent in the decarboxylation step. In
this case, starting material was recovered accompanied by
a small amount of decarboxylated derivative which led us
to suggest that the decarboxylation is mediated by palla-
dium on electron-rich carboxylic acids.5
Scheme 2. Direct Arylation with Various Aryl Carboxylic
Acidsa
Scheme 3. Proposed Catalytic Cycle for the Direct
Monoarylation of Enamides l
In conclusion, this report describes an original direct
mono- or diarylation reaction of cyclic enamides via a
Pd-catalyzed decarboxylative cross-coupling process un-
der mild conditions. We have developed a new site-selec-
tive arylation that can control the number of function-
alizations at either the C2 or C2ꢀC4 positions by involving
an electronic strategy thanks to nitrogen protecting groups.
This approach also represents a simple and convenient
one-pot route for the synthesis of polyarylated piperidinic
systems, and the synthesis of potential biological products
is currently being explored in our laboratory. An enantio-
selective approach using a chiral ligand and/or a chiral
catalyst could also be envisaged.
a Reaction conditions: 1 (1 equiv), 2 (5 equiv), Pd(OAc)2 (10 mol %),
Ag2CO3 (2 equiv), PPh3 (0.5 equiv), TMSO (2.4 equiv) and propionic
acid (0.5 equiv) in DMF at 80 °C for 24 h. Yield of pure product after
purification by column chromatography in parentheses.
Acknowledgment. Financial support from the MESR
0
ꢁ
ꢀ
(Ministerede l Enseignement SuperieuretdelaRecherche)
is gratefully acknowledged for the doctoral fellowship
to N.G.
to elimination of acetic acid and oxidation by silver carbo-
nate, the latter was converted to the reactive Pd(II) form.
We conjecture that a second catalytic cycle is involved in
the formation of the diarylated product 4a. In order to
evaluate the role of silver salt in this process, we carried out
the reaction in the absence of Ag2CO3 and by using
stoichiometric amounts of Pd(OAc)2.17 The desired scaffold
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.
(17) The use of other sources of oxidant such as Cu(OAc)2, CuCl2, or
benzoquinone was not successful.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 4, 2013
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