Heck - Suzuki - Miyaura domino reactions involving ynamides. An efficient access to 3-(arylmethylene)isoindolinones

Article abstract of DOI:10.1021/ol049302m

(Matrix Presented) Substituted 3-(arylmethylene)isoindolin-1-ones can be efficiently synthesized in a stereoselective manner from various ynamides and boronic acids by palladium-catalyzed Heck-Suzuki-Miyaura domino reactions.

Full text of DOI:10.1021/ol049302m

ORGANIC
LETTERS
2004
Vol. 6, No. 15
2511-2514
Heck−Suzuki−Miyaura Domino
Reactions Involving Ynamides.
An Efficient Access to
3-(Arylmethylene)isoindolinones
Sylvain Couty, Benoˆıt Lie´gault, Christophe Meyer, and Janine Cossy*
Laboratoire de Chimie Organique, associe´ au CNRS, ESPCI, 10 rue Vauquelin,
75231 Paris Cedex 05, France
janine.cossy@espci.fr
Received April 16, 2004
ABSTRACT
Substituted 3-(arylmethylene)isoindolin-1-ones can be efficiently synthesized in a stereoselective manner from various ynamides and boronic
acids by palladium-catalyzed Heck−Suzuki−Miyaura domino reactions.
Substituted 3-methyleneisoindolin-1-ones of type
A
alkynes,1a,5 and the Horner condensation of 3-(diphenylphos-
phinoyl)isoindolin-1-ones with aldehydes.1b,6
(Figure 1) are present in a number of naturally occurring
and biologically active compounds.1,2 Existing methods for
their preparation often rely on nucleophilic additions to
phthalimides of type B followed by dehydration, but this
can produce mixtures of regioisomers in the case of unsym-
metrical substrates.1-3
Several recent synthetic developments that have improved
the situation include some Pd-catalyzed three-component
processes that exploit a carbonylation reaction,4 Pd-catalyzed
heteroannulations involving 2-iodobenzamides and terminal
In recent years, the synthetic application of ynamides has
expanded enormously,7 these stable electron-deficient vari-
ants of ynamines having been demonstrated to undergo
several transformations usually carried out with alkynes such
as metal-catalyzed cycloadditions,7,8 metathesis,9 sigmatropic
rearrangements,10 and addition reactions11,12 eventually fol-
lowed by cross-couplings.13,14 However, to our knowledge,
reports dealing with palladium-catalyzed reactions directly
involving ynamides appear to be restricted, so far, to
hydrostannation.14
(1) (a) Kundu, N. G.; Khan, M. W. Tetrahedron 2000, 56, 4777-4792.
(b) Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron 1997, 53,
10313-10330 and references therein.
(2) Dihydroanalogues (3-alkylisoindolin-1-ones) also constitute an im-
portant class of biologically active products; see: Chen, M.-D.; Zhou, X.;
He, M.-Z.; Ruan, Y.-P.; Huang, P.-Q. Tetrahedron 2004, 60, 1651-1657
and references therein.
Herein, we would like to report an alternative synthetic
strategy toward a variety of (E)-3-(arylmethylene)isoindolin-
(3) For some examples, see: (a) Pigeon, P.; Decroix, B. Tetrahedron
Lett. 1996, 37, 7707-7710. (b) Ha, D.-C.; Yuun, C.-S.; Yu, E. Tetrahedron
Lett. 1996, 37, 2577-2580. (c) Kato, Y.; Takemoto, M.; Achiwa, K. Chem.
Pharm. Bull. 1993, 41, 2003-2006. (d) Kato, Y.; Ebiike, H.; Achiwa, K.;
Ashizawa, N.; Kurihara, T.; Kobayashi, F. Chem. Pharm. Bull. 1990, 38,
2060-2062. (e) Islam, A. M.; El-Sharief, A. M. S.; Bedair, A. H.; Hammad,
N. E. Egypt. J. Chem. 1983, 25, 251-261. (f) Islam, A. M.; El-Sharief, A.
M. S.; El-Maghraby, A. A.; Bedear, A. H. Indian J. Chem., Sect. B 1978,
16, 301-304. (g) Marsili, A.; Scartoni, V. Gazz. Chim. Ital. 1972, 102,
806-817. (h) Marsili, A.; Scartoni, V. Tetrahedron Lett. 1968, 2511-2516.
Figure 1.
10.1021/ol049302m CCC: $27.50 © 2004 American Chemical Society
Published on Web 06/24/2004

Scheme 1
Scheme 2. Preparation of Ynamides of Type Ca
1-ones of type A′ that proceeds from ynamides of type C
and arylboronic acids, which relies on Pd(0)-catalyzed
Heck-Suzuki-Miyaura domino reactions for success
(Scheme 1).
To investigate the feasibility of this Pd(0)-catalyzed
process, several ynamides of type C were prepared from
2-iodobenzoic acid 1. Thus, coupling with benzylamine,
2-bromobenzylamine, and allylamine afforded the corre-
sponding 2-iodobenzamides 2a (60%), 2b (81%), 2c (73%),
respectively. Their conversion to ynamides was achieved by
formation of the potassium amides (KHMDS, toluene, rt)
and condensation with alkynyliodonium salt 315 to afford
compounds 4a (48%), 4b (72%), and 4c (63%), respectively,
in acceptable yields.16 Subsequent desilylation using TBAF
in THF finally provided 5a (96%), 5b (79%), and 5c (85%),
respectively. A structurally related ynamide 5d possessing
a Reagents and conditions: (a) R1NH2, EDCI, cat. DMAP, Et3N,
CH2Cl2, rt; (b) KHMDS, 3, toluene, rt; (c) TBAF, THF, rt.
a pyridine ring was also prepared from the readily available
2-bromonicotinic acid 617 and allylamine according to a
similar strategy (28% overall yield) (Scheme 2).
Since the planned strategy toward 3-(arylmethylene)-
isoindolin-1-ones of type A′ involved two different Pd(0)-
catalyzed steps, it was of interest to initially examine the
feasibility of the Heck reaction. Thus, ynamides 5b and 5c
(Scheme 3) were treated with a catalytic amount of Pd(OAc)2
(4) (a) Gai, X.; Grigg, R.; Khamnaen, T.; Rajviroongit, S.; Sridharan,
V.; Zhang, L.; Collard, S.; Keep, A. Tetrahedron Lett. 2003, 44, 7441-
7443. (b) Cho, C. S.; Shim, H. S.; Choi, H.-J.; Kim, T.-J.; Shim, S. C.
Synth. Commun. 2002, 32, 1821-1827.
(5) (a) Kundu, N. G.; Khan, M. W.; Mukhopadhyay, R. Tetrahedron
1999, 55, 12361-12376. (b) Sashida, H.; Kawamukai, A. Synthesis 1999,
1145-1148. (c) Kundu, N. G.; Khan, M. W. Tetrahedron Lett. 1997, 38,
6937-6940. (d) Khan, M. W.; Kundu, N. G. Synlett 1997, 1435-1437.
(6) (a) Rys, V.; Couture, A.; Deniau, E.; Grandclaudon, P. Tetrahedron
2003, 59, 6615-6619. (b) Couture, A.; Deniau, E.; Grandclaudon, P.;
Hoarau, C.; Rys, V. Tetrahedron Lett. 2002, 43, 2207-2210. (c) Couture,
A.; Deniau, E.; Grandclaudon, P.; Rybalko-Rosen, H.; Le´once, S.; Pfeiffer,
B.; Renard, P. Bioorg. Med. Chem. Lett. 2002, 12, 3557-3559. (d) Couture,
A.; Deniau, E.; Grandclaudon, P.; Hoarau, C. Tetrahedron 2000, 56, 1491-
1499.
Scheme 3
(7) For a review, see: Zificsak, C. A.; Mulder, J. A.; Hsung, R. P.;
Rameshkumar, C.; Wei, L.-L. Tetrahedron 2001, 57, 7575-7606.
(8) (a) Marion, F.; Coulomb, J.; Courillon, C.; Fensterbank, L.; Malacria,
M. Org. Lett. 2004, 6, 1151-1153. (b) Shen, L.; Hsung, R. P. Tetrahedron
Lett. 2003, 44, 9353-9358. (c) Witulski, B.; Lumtscher, J.; Bergstra¨âer,
U. Synlett 2003, 708-710. (d) Witulski, B.; Alayrac, C. Angew. Chem.,
Int. Ed. 2002, 41, 3281-3284.
(5 mol %) and PPh3 (10 mol %) in DMF at 80 °C, and to
regenerate the Pd(0) catalyst from the intermediate σ-vinyl-
palladium complexes of type D, the reaction was carried out
in the presence of ammonium formate (1.5 equiv).18 Under
these conditions, the desired 3-methyleneisoindolin-1-ones
7 and 84b were cleanly generated in 56% and 62%
yields, respectively. Worthy of note is the fact that the
presence of an arylbromide in substrate 5b did not alter the
(9) (a) Huang, J.; Xiong, H.; Hsung, R. P.; Rameshkumar, C.; Mulder,
J. A.; Grebe, T. P. Org. Lett. 2002, 4, 2417-2420. (b) Saito, N.; Sato, Y.;
Mori, M. Org. Lett. 2002, 4, 803-805.
(10) (a) Frederick, M. O.; Hsung, R. P.; Lambeth, R. H.; Mulder, J. A.;
Tracey, M. R. Org. Lett. 2003, 5, 2663-2666. (b) Mulder, J. A.; Hsung,
R. P.; Frederick, M. O.; Tracey, M. R.; Zificsak, C. Org. Lett. 2002, 4,
1383-1386.
(11) (a) Hirano, S.; Tanaka, R.; Urabe, H.; Sato, F. Org. Lett. 2004, 6,
727-729. (b) Tanaka, R.; Hirano, S.; Urabe, H.; Sato, F. Org. Lett. 2003,
5, 67-70.
(12) Ynamides have been used as partners in radical cascades leading
to nitrogen heterocycles: Marion, F.; Courillon, C.; Malacria, M. Org. Lett.
2003, 5, 5095-5097.
(13) (a) Mulder, J. A.; Kurtz, K. C. M.; Hsung, R. P.; Coverdale, H.;
Frederick, M. O.; Shen, L.; Zificsak, C. A. Org. Lett. 2003, 5, 1547-1550.
(b) Witulski, B.; Buschmann, N.; Bergstra¨âer, U. Tetrahedron 2000, 56,
8473-8480.
(14) (a) Naud, S.; Cintrat, J.-C. Synthesis 2003, 1391-1397. (b) Minie`re,
S.; Cintrat, J.-C. Synthesis 2001, 705-707.
(15) Kitamura, T.; Kotani, M.; Fujiwara, Y. Synthesis 1998, 1416-1418.
(16) For an account on the synthesis of ynamides, see: Mulder, J. A.;
Kurtz, K. C. M.; Hsung, R. P. Synlett 2003, 1379-1390 and references
therein.
(17) Meier, P.; Legraverant, S.; Mu¨ller, S.; Schaub, J. Synthesis 2003,
551-554.
(18) For related Heck-cross-coupling domino reactions with alkynes,
see: (a) Min, S.-H.; Pang, S.-J.; Cho, C.-G. Tetrahedron Lett. 2003, 44,
4439-4442. (b) Oh, C. H.; Lim, Y. M. Tetrahedron Lett. 2003, 44, 267-
270. (c) Wang, R.-T.; Chou, F.-L.; Luo, F.-T. J. Org. Chem. 1990, 55,
4846-4849. (d) Grigg, R. J. Heterocycl. Chem. 1994, 31, 631-639 and
references therein. (e) Negishi, E.-I.; Noda, Y.; Lamaty, F.; Vawter, E. J.
Tetrahedron Lett. 1990, 31, 4393-4396. (f) Grigg, R.; Santhakumar, V.;
Sridharan, V.; Stevenson, P.; Teasdale, A.; Thornton-Pett, M.; Worakun,
T. Tetrahedron 1991, 47, 9703-9720. (g) Burns, B.; Grigg, R.; Sridharan,
V.; Stevenson, P.; Sukirthalingam, S.; Worakun, T. Tetrahedron Lett. 1989,
30, 1135-1138.
2512
Org. Lett., Vol. 6, No. 15, 2004

Scheme 4
Table 1. Heck-Suzuki-Miyaura Domino Reactions
reaction. The use of Pd(dba)2 led to a slightly increased yield
of 9 (59%), but the optimal result (70%) was obtained when
Pd(OAc)2 (5 mol %) and PPh3 (10 mol %) in THF were
used to catalyze the process. Interestingly, Pd on C was also
an effective catalyst for this reaction, although 9 was obtained
in slightly diminished yield (56%).
The Pd(0)-catalyzed Heck-Suzuki-Miyaura domino re-
actions were applied to ynamides 5b-d in the presence of
various boronic acids under optimized conditions [Pd(OAc)2
(5 mol %), PPh3 (10 mol %), aqueous NaOH, THF, reflux],
and the resulting 3-(arylmethylene)isoindolin-1-ones 10
(51%) and 11 (67%), as well as the pyrrolopyridinones 12
(52%) and 13 (68%), were obtained in moderate to good
yields, as single geometric isomers.19 It is worth mentioning
that the use of the heterogeneous catalyst Pd on C was
unsatisfactory in the case of ynamide 5d, presumably due
to poisoning of the catalyst by the nitrogen atom of the
pyridine ring.
The (E)-configuration of the 3-benzylideneisoindolin-1-
1
one 9 was assigned by H NMR and comparison with the
literature data.1,3,5 The (E)-configurations of the isoindolinone
10 and the pyrrolopyridinone 12 were also unambiguously
confirmed by an independent preparation of authentic
samples of their corresponding (Z)-isomers.20 The configura-
tions of the other 3-(arylmethylene)isoindolin-1-ones were
determined on the basis of these results, which were in
agreement with the fact that carbopalladation of alkynes
involves a syn addition process, whereas the cross-coupling
with σ-vinylpalladium complexes proceeds with net retention
of the olefinic configuration.18
As the Suzuki-Miyaura cross-coupling reactions require
the presence of a base,21 and because alkynylsilanes are
known to be deprotected under these conditions, it was
envisaged that we could advantageously carry out a one-pot
transformation starting from the trimethylsilylynamide 4a.
Thus, treatment of 4a with aqueous NaOH in THF at reflux
generated the terminal ynamide 5a in situ, which underwent
the subsequent Heck-Suzuki-Miyaura domino reactions by
addition of benzeneboronic acid or 3,4-dichlorobenzene-
course of the reaction, it remaining intact in the final product
7 (Scheme 3).
Having demonstrated that ynamides were viable substrates
for the carbopalladation process, we investigated the achieve-
ment of the Heck-Suzuki-Miyaura domino reactions
(Table 1).18 When ynamide 5a was treated with benzene-
boronic acid in the presence of aqueous sodium hydroxide
as a base and a catalytic amount of Pd(PPh3)4 (5 mol %) in
refluxing 1,2-dimethoxyethane (DME), the corresponding
3-benzylideneisoindolin-1-one 9 was obtained in acceptable
yield (48%) and as a single stereoisomer.19 Additional
experiments indicated that other palladium catalysts could
also be used and that THF was a suitable solvent for this
(19) Apparently, the Heck-Suzuki-Miyaura domino reactions afforded
the 3-(arylmethylene)isoindolin-1-ones described herein as single geometric
isomers. However, we cannot rule out that for some substrates of this class,
depending on the aryl group and the nitrogen substituent, equilibration may
further occur especially by acid-catalyzed, hydration-dehydration, or
photochemical processes.
(20) Authentic samples of the (Z)-isomers of compounds 10 and 12 were
prepared from amides 2b and 2d, respectively, by Sonogashira coupling
with phenylacetylene and subsequent base-induced ring-closure (EtONa/
EtOH). The stereochemical outcome of this literature procedure has been
unambiguously established (see ref 1a).
(21) Miyaura, N.; Suzuki, A. Chem. ReV. 1995, 95, 2457-2483.
Org. Lett., Vol. 6, No. 15, 2004
2513

boronic acid and the palladium catalyst. Under these con-
ditions, the 3-(arylmethylene)isoindolinones 9 and 14
were respectively obtained in 65% and 45% overall yields
(Scheme 4).
In conclusion, we have reported an efficient stereoselective
access to (E)-3-(arylmethylene)isoindolin-1-ones by using
Pd(0)-catalyzed Heck-Suzuki-Miyaura domino reactions
involving ynamides and arylboronic acids. This process,
which further expands the synthetic utility of ynamides, will
be applied to the preparation of natural and/or biologically
active products.
Acknowledgment. We thank Johnson & Johnson for
financial support (Focused Giving Award to J.C.).
Supporting Information Available: Characterization
data for compounds 5a-d, 7-14, and the (Z)-isomers of
1
10 and 12, copies of the H NMR spectra of new com-
pounds, and representative experimental procedures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL049302M
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Org. Lett., Vol. 6, No. 15, 2004