Assembly of substituted 3-methyleneisoindolin-1-ones via a cul/l-proline-catalyzed domino reaction process of 2-bromobenzamides and terminal alkynes

Article abstract of DOI:10.1021/ol9000922

Cul/L-proline catalyzed coupling of 2-bromobenzamides and terminal alkynes in i-Pr0H (or DMF and DMSO) at 85-110 °C and subsequent additive cyclization produces substituted 3-methyleneisoindolin-1-ones. Variation of N-substituents, aromatic ring, and meth

Full text of DOI:10.1021/ol9000922

ORGANIC
LETTERS
2009
Vol. 11, No. 6
1309-1312
Assembly of Substituted
3-Methyleneisoindolin-1-ones via a
CuI/L-Proline-Catalyzed Domino Reaction
Process of 2-Bromobenzamides and
Terminal Alkynes
Li Li,† Miao Wang,† Xiaojing Zhang,† Yongwen Jiang,*,‡ and Dawei Ma*,‡
Shenyang Pharmaceutical UniVersity, 103 Wenhua Lu, Shenyang 110016, China, and
State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Lu,
Shanghai 200032, China
madw@mail.sioc.ac.cn
Received January 16, 2009
ABSTRACT
CuI/L-proline catalyzed coupling of 2-bromobenzamides and terminal alkynes in i-PrOH (or DMF and DMSO) at 85-110 °C and subsequent
additive cyclization produces substituted 3-methyleneisoindolin-1-ones. Variation of N-substituents, aromatic ring, and methylene part is possible
by using suitable starting materials.
The 3-methyleneisoindolin-1-one is a core structure of
numerous natural products or designed pharmaceutical mol-
ecules.1 These compounds include fumaridine (Figure 1) that
was extracted from vegetable sources,1a compound 1 that
has local anesthetic activity superior to that of procaine,1b
compound 2 that exhibited sedative activity,1hand muscaric
receptor ligand 3.1f In addition, 3-methyleneisoindolin-1-ones
have been found to be useful intermediates for the total
synthesis of alkaloids such as lennoxamine.2
The classical methods to 3-methyleneisoindolin-1-ones are
based on using phthalimides as starting materials, which
undergo Wittig reaction3 or addition of organometallic reagents
and subsequent dehydration2a,4 to give the target molecules.
This approach suffers from poor regioselectivity in the cases
of unsymmetrical substrates. To avoid this problem, a new
method based on condensation of phosphorylated 4-alkoxy-
† Shenyang Pharmaceutical University.
‡ Shanghai Institute of Organic Chemistry.
(1) (a) Blasko´, G.; Gula, D. J.; Shamma, M. J. Nat. Prod. 1982, 45,
105. (b) Laboratori Baldacci S. p. A. JP 59046268, Chem. Abstr. 1984,
101, 54922. (c) Kato, Y.; Ebiike, H.; Achiwa, K.; Ashizawa, N.; Kurihara,
T.; Kobayashi, F. Chem. Pharm. Bull. 1990, 38, 2060. (d) Kato, Y.;
Takemoto, M.; Achiwa, K. Chem. Pharm. Bull. 1999, 47, 529. (e) Chia,
Y.-C.; Chang, F.-R.; Teng, C.-M.; Wu, Y.-C. J. Nat. Prod. 2000, 63, 1160.
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S.; Pfeiffer, B.; Renard, P. Bioorg. Med. Chem. Lett. 2002, 12, 3557. (h)
Hulin, B.; Parker, J. C.; Piotrowski, D. W. US2005234065. (i) Toyooka,
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(2) (a) Pigeon, P.; Decroix, B. Tetrahedron Lett. 1996, 37, 7707. (b)
Moreau, A.; Couture, A.; Deniau, E.; Grandclaudon, P. J. Org. Chem. 2004,
69, 4527. (c) Rys, V.; Couture, A.; Deniau, E.; Lebrun, S.; Grandclaudon,
P. Tetrahedron 2005, 61, 665. (d) Couty, S.; Meyer, C.; Cossy, J.
Tetrahedron Lett. 2006, 47, 767. (e) Lamblin, M.; Couture, A.; Deniau, E.;
Grandclaudon, P. Org. Biomol. Chem. 2007, 5, 1466.
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P. Tetrahedron 2006, 62, 706
.
10.1021/ol9000922 CCC: $40.75
Published on Web 02/18/2009
2009 American Chemical Society

terminal alkynes.8e,10 We were pleased to find after the
reaction that substituted 3-methyleneisoindolin-1-ones were
isolated exclusively. Both aromatic and aliphatic alkynes are
compatible with this process, thereby giving an inexpensive,
diverse, and convenient approach to assemble these hetero-
cycles. Herein, we disclose our results.
As indicated in Table 1, we initiated our studies by
conducting a coupling reaction of N-benzyl-2-bromobenza-
Table 1. Coupling of N-Benzyl-2-bromobenzamide with
Phenylacetylene under Different Conditionsa
entry
ligandb
base
solvent
yieldc (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
A
A
A
A
A
A
A
B
C
D
E
F
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K3PO4
Cs2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
85
86
83
50
<10
82
82
37
70
47
17
30
0
i-PrOH
DMSO
dioxane
toluene
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
Figure 1. Structures of some biologically important 3-methyl-
eneisoindolin-1-ones and their derivatives.
isoindolinones and aldehydes was developed. However, this
method required additional steps to prepare phosphorylated
reagents.2b,5 The lack of an efficient approach to 3-methyl-
eneisoindolin-1-ones has stimulated intensive studies for
assembly of these heterocycles via metal-catalyzed reactions.6
The successful examples include a Sonogashira reaction of
2-iodobenzamides with terminal alkynes followed by NaOEt-
mediated cyclization,6c Heck-Suzuki-Miyaura domino
reactions involving ynamides,6d and a Sonogashira reaction-
carbonylation-hydroamination of 2-bromoiodobenzene.6f
Among them, Kundu’s method is quite attractive because
both 2-halobenzamides and terminal alkynes are conveniently
available.6c In Kundu’s report, (Ph3P)2PdCl2 and CuI were
utilized for promoting the cross-coupling reaction, leading
to a mixture of open-chain condensation products and
heteroannulation products in most cases.6c The pure 3-me-
thyleneisoindolin-1-ones had to be obtained by treatment of
the mixture with NaOEt. In addition, when aliphatic alkynes
were employed a mixture of 3-methyleneisoindolin-1-ones
and isoquinolinones was formed.6c These shortcomings
limited its application in organic synthesis.
no
a Reaction conditions: 4a (1 mmol), 5a (1.5 mmol), CuI (0.1 mmol),
ligand (0.3 mmol), solvent (2 mL), 85 °C, 24 h. b Key: (A) L-proline; (B)
N,N-dimethylglycine; (C) pipecolinic acid; (D) 2-picolinic acid; (E) ethyl
2-cyclohexanonecarboxylate; (F) N,N-dimethylethylenediamine. c Isolated
yield.
mide with phenylacetylene. It was found that under the
catalysis of CuI/L-proline and heating at 85 °C for 24 h in
DMF, 3-methyleneisoindolin-1-one 6a was isolated as a
single product in 85% yield (entry 1). Similar results were
observed when the solvent was changed to i-PrOH and
DMSO (entries 2 and 3). However, poor yields were obtained
if the reaction was carried out in dioxane or toluene (entries
4 and 5). Switching base to K3PO4 and Cs2CO3 had little
influence to this reaction (entries 6 and 7). Further investiga-
tion revealed that ligand is essential for this process, as
evident from the unsatisfactory yields that were observed
when N,N-dimethylglycine, pipecolinic acid, 2-picolinic acid,
ethyl 2-cyclohexanonecarboxylate, and N,N-dimethylethyl-
enediamine were used (entries 8-12) and the fact that no
In connection with our project to develop new heterocycle
synthesis via amino acid-promoted Ullmann-type reac-
tions,7-9 we became interested in using CuI/amino acid to
catalyze the coupling reaction of 2-bromobenzamides and
(7) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450.
(5) Couture, A.; Deniau, E.; Grandclaudon, P.; Lebrun, S. Synlett 1997,
1475.
(8) (a) Lu, B.; Ma, D. Org. Lett. 2006, 8, 6115. (b) Lu, B.; Wang, B.;
Zhang, Y.; Ma, D. J. Org. Chem. 2007, 72, 5337. (c) Zou, B.; Yuan, Q.;
Ma, D. Angew. Chem., Int. Ed. 2007, 46, 2598. (d) Zou, B.; Yuan, Q.; Ma,
D. Org. Lett. 2007, 9, 4291. (e) Liu, F.; Ma, D. J. Org. Chem. 2007, 72,
4844. (f) Chen, Y.; Xie, X.; Ma, D. J. Org. Chem. 2007, 72, 9329. (g)
Chen, Y.; Wang, Y.; Sun, Z.; Ma, D. Org. Lett. 2008, 10, 625. (h) Wang,
B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008, 10, 2761. (i)
Yuan, Q.; Ma, D. J. Org. Chem. 2008, 73, 5159. (j) Guo, L.; Li, B.; Huang,
W.; Pei, G.; Ma, D. Synlett 2008, 1833.
(6) (a) Uozumi, Y.; Kawasaki, N.; Mori, E.; Mori, M.; Shibasaki, M.
J. Am. Chem. Soc. 1989, 111, 3725. (b) Wu, M.-J.; Chang, L.-J.; Wei, L.-
M.; Lin, C.-F. Tetrahedron 1999, 55, 13193. (c) Kundu, N. G.; Khan, M. W.
Tetrahedron 2000, 56, 4777. (d) Couty, S.; Liegault, B.; Meyer, C.; Cossy,
J. Org. Lett. 2004, 6, 2511. (e) Yao, T.; Larock, R. C. J. Org. Chem. 2005,
70, 1432. (f) Cao, H.; McNamee, L.; Alper, H. Org. Lett. 2008, 10, 5281.
(g) Sun, C.; Xu, B. J. Org. Chem. 2008, 73, 7361.
1310
Org. Lett., Vol. 11, No. 6, 2009

Table 2. Synthesis of Substituted 3-Methyleneisoindolin-1-ones via a Domino Coupling/Additive Cyclization Process from
2-Bromobenzamides and Terminal Alkynesa
entry
X
Y
R
R′
time (h)
product
yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
H
H
H
H
H
H
H
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Bn
Bn
Bn
Bn
Bn
Bn
Bn
Bn
4-MeC6H4
4-MeOC6H4
3-FC6H4
BnOCH2
n-C5H11
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-HOC6H4
24
36
24
36
24
48
24
36
48
48
48
36
36
36
36
48
48
48
6b
6c
6d
6e
6f
6g
6h
6i
6j
6k
6l
6m
6n
6o
6p
6q
6r
6s
78
81
80
74
H
55c
57d
78
NO2
OMe
H
H
H
70
90
88
4-ClC6H4CH2
4-MeOC6H4CH2
allyl
allyl
allyl
C6H5
H
n-C4H9
TBSO(CH2)2
Et2N(CH2)2
H
88
NO2
OMe
H
H
H
61d,e
93
92
70
83
H
H
82
58f,g,h
a Reaction conditions: aryl bromide (0.5 mmol), 1-alkyne (0.75 mmol), CuI (0.05 mmol), L-proline (0.15 mmol), i-PrOH (1 mL), 85 °C. b Isolated yield.
c The reaction was carried out in DMSO at 100 °C. d A mixture of E- and Z-isomers was determined in a ratio of 5:1. e The reaction was carried out in
DMSO at 85 °C. f The reaction was carried out in DMF at 100 °C. g 4-Ethynylphenyl acetate was used as a coupling partner. h A mixture of E- and
Z-isomers was determined in a ratio of 14:1.
desired product was isolated in the absence of a ligand (entry
13). Based on these results, we chose L-proline as the ligand,
K2CO3 as the base, and i-PrOH as the solvent in the
subsequent studies.
The reaction scope and limitations were then examined
under the optimized conditions, and the results are sum-
marized in Table 2. Some functionalized arylacetylenes also
worked well, giving the corresponding products in good
yields (entries 1-3). Gratifyingly, when aliphatic alkynes
were employed, only 3-methyleneisoindolin-1-ones 6e and
6f were isolated (entries 4 and 5). This result indicated that
the CuI-mediated additive cyclization of the amide moiety
to the triple bond took place in a 5-exo manner exclusively,
which is different with base or Lewis acid-mediated additive
cyclization (both 5-exo and 6-endo attacks were observed).6c
In cases of 1-heptyne as a substrates, the reaction was
sluggish at 85 °C, and good conversion was obtained by
increasing the reaction temperature and using DMSO as a
solvent (entry 5). This result illustrated that aliphatic alkynes
are less reactive substrates for this transformation.
We next explored the possibility of changing the substit-
uents at the aromatic ring of aryl bromides and were pleased
to find that both electron-rich and electron-deficient aryl
bromides were compatible with these conditions (entries
6-8). It seemed that electron-rich aryl bromides are more
reactive than electron-deficient ones, as longer reaction times
were required for nitro- and chloro-substituted aryl bromides.
(9) For related studies from other groups, see: (a) Cuny, G.; Bois-
Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004, 126, 14475. (b) Klapars, A.;
Parris, S.; Andersom, K. W.; Buchwald, S. L. J. Am. Chem. Soc. 2004,
126, 3529. (c) Altenhoff, G.; Glorius, F. AdV. Synth. Catal. 2004, 346, 1661.
(d) Yang, T.; Lin, C.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2005, 7, 4781.
(e) Hu, H.; Li, C. Org. Lett. 2006, 8, 5365. (f) Martin, R.; Rodrı´guez, R.;
Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 7079. (g) Rivero, M. R.;
Buchwald, S. L. Org. Lett. 2007, 9, 973. (h) Zheng, N.; Buchwald, S. L.
Org. Lett. 2007, 9, 4749. (i) Jiang, B.; Tian, H.; Huang, Z.-G.; Xu, M.
Org. Lett. 2008, 10, 2737. (j) Bao, W.; Liu, Y.; Lv, X.; Qian, W. Org. Lett.
2008, 10, 3899. (k) Coste, A.; Toumi, M.; Wright, K.; Razafimahaleo, V.;
Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841. (l) Yao, P.-Y.;
Zhang, Y.; Hsung, R. P.; Zhao, K. Org. Lett. 2008, 10, 4275. (m) Chen,
L.; Shi, M.; Li, C. Org. Lett. 2008, 10, 5285. (n) Hasegawa, K.; Kimura,
N.; Arai, S.; Nishida, A. J. Org. Chem. 2008, 73, 6363. (o) Viirre, R. D.;
Evindar, G.; Batey, R. A. J. Org. Chem. 2008, 73, 3452. (p) Li, Z.; Sun,
H.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 3263. (q) Ohta, Y.; Chiba, H.;
Oishi, S.; Fujii, N.; Ohno, H. Org. Lett. 2008, 10, 3535. (r) Liu, X.; Fu, H.;
Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009, 48, 348. (s) Martins, A.;
Lemouzy, S.; Lautens, M. Org. Lett. 2009, 11, 181.
Further investigations demonstrated that a wide range of
N-substituents were tolerated in this process, which include
functionalized benzyl groups, allyl, phenyl, proton, and
simple and functionalized alkyl groups (entries 9-18). These
additional functional groups would allow further conversion
to more useful heterocycles. For example, 6r could be
transformed into a known tetracyclic intermediate for alkaloid
(10) Ma, D.; Liu, F. Chem. Commun. 2004, 1934.
Org. Lett., Vol. 11, No. 6, 2009
1311

synthesis,4b while acylation of 6s would provide compound
1 that has local anesthetic activity superior to that of
procaine.1b
Scheme 2
For stereochemistry of the present transformation, it was
found that in most cases only Z-isomers were determined.
However, in cases of two nitro-substituted aryl bromides
(entries 6 and 12) and N,N-diethylethylene-substituted aryl
bromide (entry 18) as substrates, E-isomers were isolated
as a major product. Their geometry was established via
NOESY studies and comparison of the analytical data with
the known compounds. The reason for this difference is not
clear yet, but this result indicated that some substituents have
strong influence to the transition state in additive cyclization
step.
For reaction process, we envisaged that coupling of aryl
bromides with 1-alkynes should occur first as indicated in
Scheme 1. The coupling products A might undergo depro-
Scheme 1
none 10 in quantitative yield. This intermediate has been
converted into lennoxamine in two steps by Cossy and co-
workers.2d
In conclusion, we have developed a CuI/L-proline-
catalyzed coupling/additive cyclization domino reaction
process for assembling substituted 3-methyleneisoindolin-
1-ones from 2-bromobenzamides and terminal alkynes.
Variation of N-substituents, aromatic ring, and methylene
part was proven possible. Thus, this process gives a
straightforward access to substituted 3-methyleneisoindolin-
1-ones and may find applications in the synthesis of complex
natural products or designed bioactive compounds.
tonation of the amide moiety and subsequent addition to
C-C triple bond under the action of the copper complex
(as intermediates B) to afford substituted 3-methyleneisoin-
dolin-1-ones. Indeed, in some cases the simple Sonogashira
reaction products A could be isolated if the reaction time
was shortened.
To further illustrate the synthetic usage of the present
method, we developed a formal synthesis of lennoxamine
as depicted in Scheme 2. Aryl bromide 7 was prepared from
2,3-dimethoxybenzoic acid in two steps based on known
procedure, which was coupled with 1-alkyne 8 under the
catalysis of CuI/L-proline in DMF at 110 °C to afford
heteroannulation product 9 in 57% yield as a mixture of Z-
and E-isomers (about 5.5:1 determined by 1H NMR). Upon
hydrogenation, this mixture was transformed into isoindoli-
Acknowledgment. We are grateful to the Chinese Acad-
emy of Sciences, National Natural Science Foundation of
China (Grant Nos. 20621062 and 20572119) and Ministry
of Science & Technology (Grant No. 2009CB940900) for
their financial support.
Supporting Information Available: Experimental pro-
cedures and copies of 1H NMR and 13C NMR spectra for all
new products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL9000922
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Org. Lett., Vol. 11, No. 6, 2009