Intramolecular carbocupration of N-aryl-ynamides: A modular indole synthesis

Article abstract of DOI:10.1021/ol4013298

A modular indole synthesis based on an intramolecular 5-endo-dig carbocupration starting from readily available N-aryl-ynamides is reported. A variety of ynamides are converted to indoles in moderate to good yields and with varying substitution pattern on the indole ring. This further extends the synthetic utility of ynamides in organic synthesis and provides additional insights on the use of intramolecular carbometalation reactions.

Full text of DOI:10.1021/ol4013298

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Intramolecular Carbocupration of
N‑Aryl-ynamides: A Modular Indole Synthesis
Wafa Gati,†,‡ Franc-ois Couty,† Taoufik Boubaker,‡ Mohamed M. Rammah,‡
Mohamed B. Rammah,‡ and Gwilherm Evano*,§
ꢀ
Institut Lavoisier de Versailles, UMR CNRS 8180, Universite de Versailles
Saint-Quentin en Yvelines, 45, avenue des Etats-Unis, 78035 Versailles Cedex, France,
ꢀ ꢀ
ꢀ
ꢀ
ꢀ
Laboratoire de Chimie Heterocyclique, Produits Naturels et Reactivite, Departement de
ꢀ
ꢀ
Chimie, Faculte des Sciences de Monastir, Universite de Monastir, avenue de
l’environnement, 5019 Monastir, Tunisia, and Laboratoire de Chimie Organique,
ꢀ
Service de Chimie et PhysicoChimie Organiques, Universite Libre de Bruxelles,
Avenue F. D. Roosevelt 50, CP160/06, 1050 Brussels, Belgium
gevano@ulb.ac.be
Received May 13, 2013
ABSTRACT
A modular indole synthesis based on an intramolecular 5-endo-dig carbocupration starting from readily available N-aryl-ynamides is reported.
A variety of ynamides are converted to indoles in moderate to good yields and with varying substitution pattern on the indole ring. This further extends
the synthetic utility of ynamides in organic synthesis and provides additional insights on the use of intramolecular carbometalation reactions.
Due to the development of efficient methods for their
synthesis,1 ynamides have emerged as one of the most
efficient building blocks in organic synthesis over the past
decade.2 They have been used for the development of an
impressive and ever-increasing number of transformations,
the presence of the nitrogen atom attached to the alkyne
being responsible for a strong differentiation of the two sp
carbon atoms, which typically allows for high levels of regio-
and stereoselectivities. This polarization of the triple bond
combined with the presence of the electron-withdrawing
group, which can act as a remarkably efficient directing
group, makes them ideal candidates for the development of
metal-mediated transformations. Indeed, they have been
used, for example, in palladium-catalyzed hydrostannyla-
tions,3 carbopalladations,4 silaborations,5 hydroacyloxyla-
tions,6 chloroallylations,7 gold-catalyzed hydroamina-
tions,8 or nickel-catalyzed hydrophosphorylations9 and
were also found to be excellent substrates for intermolecular
(3) Buissonneaud, D.; Cintrat, J.-C. Tetrahedron Lett. 2006, 47, 3139.
(4) (a) Witulski, B.; Alayrac, C.; Tevzadze-Saeftel, L. Angew. Chem.,
†
ꢀ
Universite de Versailles Saint-Quentin en Yvelines.
‡
§
ꢀ
Int. Ed. 2003, 42, 4257. (b) Couty, S.; Liegault, B.; Meyer, C.; Cossy, J.
ꢀ
Universite de Monastir.
Org. Lett. 2004, 6, 2511. (c) Greenaway, R. L.; Campbell, C. D.; Holton,
O. T.; Russel, C. A.; Anderson, E. A. Chem.;Eur. J. 2011, 17, 14366. (d)
Cao, J.; Xu, Y.; Kong, Y.; Cui, Y.; Hu, Z.; Wang, G.; Deng, Y.; Lai, G.
Org. Lett. 2012, 14, 38. (e) Greenaway, R. L.; Campbell, C. D.; Chapman,
H. A.; Anderson, E. A. Adv. Synth. Catal. 2012, 354, 3187.
(5) Saito, N.; Saito, K.; Sato, H.; Sato, Y. Adv. Synth. Catal. 2013,
355, 853.
(6) Smith, D. L.; Goundry, W. R. F.; Lam, H. W. Chem. Commun.
2012, 48, 1505.
(7) Lu, Z.; Kong, W.; Yuan, Z.; Zhao, X.; Zhu, G. J. Org. Chem.
ꢀ
Universite Libre de Bruxelles.
(1) For general methods for the synthesis of ynamides, see: (a)
Dunetz, J. R.; Danheiser, R. L. Org. Lett. 2003, 5, 4011. (b) Zhang,
Y.; Hsung, R. P.; Tracey, M. R.; Kurtz, K. C. M.; Vera, E. L. Org. Lett.
2004, 6, 1151. (c) Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc.
2008, 130, 833. (d) Coste, A.; Karthikeyan, G.; Couty, F.; Evano, G.
Angew. Chem., Int. Ed. 2009, 48, 4381. (e) Jouvin, K.; Couty, F.; Evano,
G. Org. Lett. 2010, 12, 3272. (f) Jia, W.; Jiao, N. Org. Lett. 2010, 12,
2000. (g) Sueda, T.; Oshima, A.; Teno, N. Org. Lett. 2011, 13, 3996. (h)
Jouvin, K.; Heimburger, J.; Evano, G. Chem. Sci. 2012, 3, 756.
(2) For current leading reviews on ynamides, see: (a) Evano, G.;
Coste, A.; Jouvin, K. Angew. Chem., Int. Ed. 2010, 49, 2840. (b)
DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang,
Y.; Hsung, R. P. Chem. Rev. 2010, 110, 5064. (c) Evano, G.; Jouvin, K.;
Coste, A. Synthesis 2013, 45, 17.
2011, 76, 8524.
(8) Kramer, S.; Dooleweerdt, K.; Lindhardt, A. T.; Rottlander, M.;
€
Skrydstrup, T. Org. Lett. 2009, 11, 4208.
(9) Fadel, A.; Legrand, F.; Evano, G.; Rabasso, N. Adv. Synth.
Catal. 2011, 353, 263.
r
10.1021/ol4013298
XXXX American Chemical Society

carbomagnesiation,10 carbozincation,11 and carbocupra-
tion12 reactions.
copper-catalyzed cross-coupling between the correspond-
ing bromoalkyne and Boc-protected aniline,1b was chosen
as a model substrate. A variety of conditions and metals,
including lithium, magnesium, zinc, palladium, and cop-
per, were screened to promote the intramolecular carbo-
metalation: selected results from these studies are collected
in Table 1.
In this context, we have recently reported a straightfor-
ward synthesis of 1,4-dihydropyridines 4 relying on a highly
efficient intramolecular carbolithiation starting from
N-allyl-ynamides 1 (Scheme 1).13 To further exploit both
this strategy and the use of ynamides in heterocyclic synthesis,
we decided to investigate the possibility of an intramolecular
carbometalation from N-(2-bromoaryl)ynamides such as 5.
Provided that a clean bromineÀmetal exchange could be
achieved in the presence of the reactive ynamide in 5, we
anticipated that a 5-endo-dig carbometalation14 would afford
polysubstituted indoles 8. The indole skeleton being a privi-
leged molecular scaffold at the core of an impressive number
of natural and/or biologically relevant molecules, the devel-
opment of new routes to indoles is still a highly active area of
research.15 Indeed, while the Fischer indole synthesis has been
one of the most popular routes to indoles since its discovery
130 years ago,16 there is still a strong demand for versatile,
efficient, and regioselective indole synthesis. Herein, we pre-
sent the development of a new and modular method for the
synthesis of polysubstituted indoles 8 from readily available
N-(2-bromoaryl)ynamides 5.
Table 1. Optimization of the Intramolecular Carbometalation
NMR
entry
1
conditions
yielda
b
sBuLi (1.2 equiv), TMEDA (1.2 equiv),
THF, À78 °C, 14 h
À
b
2
3
tBuLi (2.2 equiv), Et2O, À78 to À50 °C, 14 h
À
tBuLi (2.2 equiv), MgBr2 OEt2 (1.2 equiv),
À
b
3
Et2O, À78 to À50 °C, 14 h
b
4
5
6
7
tBuLi (2.2 equiv), ZnCl2 (1.2 equiv),
Et2O, À78 to À50 °C, 14 h
À
tBuLi (2.2 equiv), CuCN 2LiCl (1.0 equiv),
62%
37%
45%
3
Et2O, À78 to À50 °C, 14 h
Scheme 1. Strategy for the Synthesis of Indoles by
Intramolecular Carbometalation from Ynamides
sBuLi (2.2 equiv), CuCN 2LiCl (1.0 equiv),
3
Et2O, À78 to À50 °C, 14 h
sBuLi (2.2 equiv), TMEDA (2.2 equiv),
CuCN 2LiCl (1.0 equiv),
3
Et2O, À78 to À50 °C, 14 h
8
nBuLi (2.2 equiv), CuCN 2LiCl (1.0 equiv),
55%
3
Et2O, À78 to À50 °C, 14 h
c
9
iPrMgCl LiCl (1.1 equiv), CuCN 2LiCl
À
3
3
(0.3 equiv), THF, rt, 14 h
10
11
12
13
14
15
tBuLi (2.2 equiv), CuCN 2LiCl (1.0 equiv),
20%
14%
48%
54%
15%
62%
3
THF, À78 to À50 °C, 14 h
tBuLi (2.2 equiv), CuBr SMe2 (1.0 equiv),
3
THF, À78 to À50 °C, 14 h
tBuLi (2.2 equiv), CuI P(OEt)3 (1.0 equiv),
3
Et2O, À78 to À50 °C, 14 h
tBuLi (2.2 equiv), CuCN 2LiCl (0.2 equiv),
3
To test our hypothesis and optimize the reaction condi-
tions, ynamide 5a, readily prepared through Hsung’s
Et2O, À78 to À50 °C, 14 h
tBuLi (2.2 equiv), CuCN 2LiCl (1.0 equiv),
3
Et2O, À78 °C, 14 h
tBuLi (1.5 equiv), CuCN 2LiCl (1.0 equiv),
3
(10) (a) Yasui, H.; Yorimitsu, H.; Oshima, K. Chem. Lett. 2007, 36,
32. (b) Yasui, H.; Yorimitsu, H.; Oshima, H. Bull. Chem. Soc. Jpn. 2008,
81, 373.
Et2O, À78 to rt, 14 h
b
16
17
Bu3SnH, AIBN, benzene, reflux, 48 h
Pd(OAc)2 (5 mol %), PPh3 (10 mol %), HCO2NH4
(1.5 equiv), DMF, 80 °C, 14 h
À
d
(11) Gourdet, B.; Lam, H. W. J. Am. Chem. Soc. 2009, 131, 3802.
(12) (a) Chechik-Lankin, H.; Livshin, S.; Marek, I. Synlett 2005,
2098. (b) Das, J. P.; Chechik, H.; Marek, I. Nat. Chem. 2009, 1, 128. (c)
Minko, Y.; Pasco, M.; Lercher, L.; Botoshansky, M.; Marek, I. Nature
2012, 490, 522. (d) Minko, Y.; Pasco, M.; Chechik, H.; Marek, I.
Beilstein J. Org. Chem. 2013, 9, 526.
(13) (a) Gati, W.; Rammah, M. M.; Rammah, M. B.; Couty, F.;
Evano, G. J. Am. Chem. Soc. 2012, 134, 9078. (b) Gati, W.; Rammah,
M. M.; Rammah, M. B.; Evano, G. Beilstein J. Org. Chem. 2012, 8, 2214.
(14) For a comprehensive review on Baldwin’s rules for the cycliza-
tion of alkynes, see: Gilmore, K.; Alabugin, I. V. Chem. Rev. 2011, 111,
6513. For related examples of anionic 5-endo-dig carbometalation
reactions from heterosubtituted alkynes, see: (a) Funk, R. L.; Bolton,
G. L.; Brummond, K. M.; Ellestad, K E.; Stallman, J. B. J. Am. Chem.
Soc. 1993, 115, 7023. (b) Johnson, F.; Subramanian, R. J. Org. Chem.
1986, 51, 5040. (c) Kunz, T.; Knochel, P. Angew. Chem., Int. Ed. 2012,
51, 1958. For a review on the carbocupration of heterosubstituted
alkynes, see: Basheer, A.; Marek, I. Beilstein J. Org. Chem. 2010, 6,
No. 77.
À
a Determined using p-anisaldehyde as an internal standard. b Com-
plete reduction of the starting material was observed. c Competitive
intermolecular carbomagnesiation was observed. d A mixture of N-(2-
bromophenyl)-oxazolone and N-phenyl-oxazolone was formed.
While an intramolecular 6-endo-dig carbolithiation from
anallylicsp3 organolithiumintermediate2wasremarkably
efficient in the case of the formation of a dihydropyridine
ring system 4 (Scheme 1),13 the related carbolithiation
involving an aryllithium intermediate and a 5-endo-dig
carbolithiation was disappointingly inefficient, the reduc-
tion of the starting N-(2-bromophenyl)ynamide 5a being
B
Org. Lett., Vol. XX, No. XX, XXXX

the only reaction observed under similar reaction condi-
tions (Table 1, entries 1 and 2). While transmetalation to
magnesium or zinc after bromine/lithium exchange in
order to promote an intramolecular carbomagnesiation
or carbozincation was equally inefficient (Table 1, entries 3
collected in Figure 1. The reaction proceeded smoothly in
most cases, with indoles 8aÀl being obtained in moderate
to good yields regardless of the substituent of the ynamide.
Indeed, aryl-substituted ynamides 5aÀ5h were found to
smoothly undergo intramolecular 5-endo-dig carbocupra-
tion regardless of the substitution pattern or the electronic
properties of the aromatic substituent. The corresponding
3-aryl-indoles 8aÀ8h were predominantly formed in all
cases along with minor amounts of debrominated starting
materials. The produced compounds are very useful build-
ing blocks, with many biologically active indoles posses-
sing an aromatic group at C-3 and no substituent at C-2.19
The reaction worked equally well with a styryl group,
affording the corresponding indole 8i in 54% yield; with
alkyl groups, no competitive propargylic deprotonation or
proton transfer was observed during the preparation of
propyl-substituted indole 8k. Finally, a TIPS-substituted
indole (8l) could also be obtained using the metalation/
intramolecular carbocupration sequence, although with
less efficiency.
and 4), the addition of 1 equiv of CuCN 2LiCl17 was
3
found to have a dramatic effect on the outcome of the
intramolecular carbometalation reaction, the desired in-
dole 8a being formed in 62% yield (Table 1, entry 5). The
use of other reagents for the metalation step was then
briefly evaluated but with little success, with n-butyl- and
s-butyllithium (with or without additional TMEDA) giving
lower yields (Table 1, entries 6À8) and competitive inter-
molecular carbomagnesiation being observed with Knochel’s
iPrMgCl LiCl,18 which was found to be remarkably efficient
3
for the intramolecular copper-catalyzed carbomagnesiation
of alkynyl(2-bromoaryl)thioethers (Table 1, entry 9).14c
Switching from diethyl ether to THF or changing the
copper source to CuBr SMe2 or CuI P(OEt)3 was found
3
3
to be detrimental for the yield (Table 1, entries 10À13). We
next looked at the possibility of using a catalytic amount of
CuCN 2LiCl: if the copper-catalyzed intramolecular car-
3
bolithiation was still operative, the yield was however
lower. The effect of the temperature was finally evaluated,
and it was found that the cyclization was too slow when
the reaction temperature was kept at À78 °C (Table 1,
entry 14) while slowly warming the reaction mixture
from À78 °C to room temperature gave the desired indole
8a in 62% yield (Table 1, entry 15), conditions that we kept
for the intramolecular carbocupration. Of note, radical
(Table 1, entry 16) and palladium-catalyzed (Table 1, entry 17)
cyclizations were also evaluated but failed to give the
desired indole, as reduction or cyclization to oxazolones
by nucleophilic attack of the Boc group to the activated
alkyne was the major respective reaction pathway in these
cases.
With the optimized conditions, consisting of a bromine/
lithium exchange with tert-butyllithium in ether at À78 °C
followed by transmetalation with CuCN 2LiCl and intra-
3
molecular carbocupration upon warming the reaction to
room temperature, we next evaluated the scope of this
reaction. Tothisaim, a set of N-(2-bromophenyl)ynamides
5aÀl possessing various representative substituents on the
alkyne were submitted to the metalation/transmetalation/
carbocupration sequence: results from those studies are
Figure 1. Scope of the intramolecular carbocupration for the
synthesis of 3-substituted indoles.
(15) For recent reviews on the synthesis of indoles, see: (a) Gribble,
G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045. (b) Alonso, F.;
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Catal. 2008, 350, 2153. (g) Vincente, R. Org. Biomol. Chem. 2011, 9,
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Cacchi, S.; Fabrizi, G. Chem. Rev. 2011, 111, PR215. (j) Platon, M.;
Amardeil, R.; Djakovitchb, L.; Hierso, J.-C. Chem. Soc. Rev. 2012, 41,
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(16) (a) Fischer, E.; Jourdan, F. Ber. Dtsch. Chem. Ges. 1883, 16,
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(17) Knochel, P.; Yeh, M. C. P.; Berk, S. C.; Talbert, J. J. Org. Chem.
1988, 53, 2390.
This intramolecular carbometalation from readily avail-
able ynamides therefore provides an efficient and selective
(19) For selected examples, see: (a) Andersen, K.; Perregaard, J.;
Arn, J.; Nielsen, J. B.; Begtrup, M. J. Med. Chem. 1992, 35, 4823. (b)
Leboho, T. C.; Michael, J. P.; van Otterlo, W. A. L.; de Koning, C. B.;
van Vuuren, S. F. Bioorg. Med. Chem. Lett. 2009, 19, 4948. (c)
Richardson, T. I.; Clarke, C. A.; Yu, K.-L.; Yee, Y. K.; Bleisch, T. J.;
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Moore, T. L.; Shetler, P. K.; Zink, R. W.; Osborne, J. J.; Montrose-
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Org. Lett., Vol. XX, No. XX, XXXX
C

through this reaction, we finally examined the reactivity of
a small set of ynamides 5mÀq possessing additional sub-
stituents on the aniline core (Scheme 2). The presence of
this additional substituent had virtually no impact on the
outcome of the reaction, 1,3,5-, 1,3,6-, and 1,3,7-trisubsti-
tuted indoles 8mÀq, compounds that can be challenging to
prepare using other routes, being readily formed using the
reaction conditions.
Scheme 2. Synthesis of Polysubstituted Indoles by
Intramolecular Carbocupration
In conclusion, we have developed an efficient and
modular synthesis of polysubstituted indoles from readily
available N-aryl-ynamides. A variety of ynamides are
converted to 3-substituted indoles in moderate to good
yields and with varying substitution patterns on the indole
ring. This should further extend the synthetic utility of
ynamides in organic synthesis and provides additional
insight to the use of intramolecular carbometalation reac-
tions. The extension of this reaction to other heterosub-
stituted alkynes is under study and will be reported in due
time.
Acknowledgment. The authors thank the CNRS, the
Universities of Brussels, Versailles and Monastir, the ANR
(project DYNAMITE ANR-2010-BLAN-704), and the
CMCU/PHC Utique (grant 10G1025) for support. We are
ꢀ
grateful to Mr. Guillaume Boissonnat (Universite Libre de
Bruxelles and Ecole Polytechnique ParisTech) for techni-
cal assistance.
route to 3-substituted indoles and is therefore complemen-
tary to other routes to indoles such as, for example, the
intramolecular hydroamination from 2-ethynylanilines
yielding to 2-substituted indoles.15
Supporting Information Available. Experimental pro-
cedures, characterization, and copies of 1H and 13C NMR
spectra for all new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
To further evaluate the scope of our indole synthesis and
test the possibility of preparing polysubstituted indoles
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX