Microwave assisted copper-free Sonogashira coupling/5-exo-dig cycloisomerization domino reaction: Access to 3-(phenylmethylene)isoindolin-1- ones and related heterocycles

Article abstract of DOI:10.1016/j.tetlet.2011.08.070

An efficient microwave assisted one-pot synthesis of substituted 3-(phenylmethylene)isoindolin-1-ones is reported via a copper-free Sonogashira coupling and a regioselective 5-exo-dig cycloisomerization. This domino reaction was also extended to other related heterocycles.

Full text of DOI:10.1016/j.tetlet.2011.08.070

Tetrahedron Letters 52 (2011) 5508–5511
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave assisted copper-free Sonogashira coupling/5-exo-dig
cycloisomerization domino reaction: access to
3-(phenylmethylene)isoindolin-1-ones and related heterocycles
⇑
Malik Hellal, Gregory D. Cuny
Laboratory for Drug Discovery in Neurodegeneration, Harvard NeuroDiscovery Center, Brigham & Women’s Hospital and Harvard Medical School,
65 Landsdowne Street, Cambridge, MA 02139, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient microwave assisted one-pot synthesis of substituted 3-(phenylmethylene)isoindolin-1-ones
is reported via a copper-free Sonogashira coupling and a regioselective 5-exo-dig cycloisomerization. This
domino reaction was also extended to other related heterocycles.
Received 20 July 2011
Revised 9 August 2011
Accepted 11 August 2011
Available online 19 August 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Isoindoline
Domino reaction
Cycloisomerization
Sonogashira coupling
Microwave
Considerable attention has been devoted to heterocyclic ring for-
mation by intramolecular annulations of carboxylic acids,1 esters,2
ketones,3 alcohols,4 amines5 and amides6 to alkynes. In particular,
various synthetic methods for the preparation of substituted
3-(phenylmethylene)isoindolin-1-ones and related systems have
been developed7 due to their presence in a wide variety of bioactive
natural products, such as fumaridine8 and lennoxamine.9 This struc-
tural motif is also found in a number of molecules demonstrating
interesting pharmaceutical properties, such as the local anesthetic
In order to investigate the feasibility of a copper-free Sonogash-
ira coupling-cycloisomerization domino strategy, different reac-
tion variables such as Pd source, ligand, base and solvent were
investigated using microwave (MW) heating at 120 °C for
30 min.17 As indicated in Table 1, the reaction was performed on
2-bromobenzamide 1, and phenylacetylene in DMF. The choice of
OMe
O
O
NEt2
MeO
N
A
10 and the AChE inhibitor B11 (Fig. 1).
NH
O
Included among the various strategies for preparing 3-(arylm-
ethylene)isoindolin-1-ones are different metal-catalyzed reactions,
such as Heck–Suzuki–Miyaura domino reactions involving
ynamides and arylboronic acids,12 Sonogashira coupling-carbonyl
ation–hydroamination one-pot reactions of dihalides,13 intramolec-
ular Heck reactions of enamides,14 and one-pot elimination–cycliza
tion-Suzuki coupling of o-[gem-dihalovinyl]benzamides and aryl-
boronic acids.15 Recently, Ma and coworkers reported an Ullman
coupling-heteroannulation of 2-bromobenzamides and terminal al-
kynes.16 Herein, we report the development of a microwave assisted
Sonogashira coupling/5-exo-dig cycloisomerization domino reac-
tion for the synthesis of 3-(phenylmethylene)isoindolin-1-ones
and related heterocycles.
O
Me2N
AcO
fumaridine
OMe
A
O
O
N
MeO
N
O
N
N
O
Bn
O
lennoxamine
B
⇑
Corresponding author. Tel.: +1 617 768 8640; fax: +1 617 768 8606.
E-mail address: gcuny@rics.bwh.harvard.edu (G.D. Cuny).
Figure 1. Structure of natural products and biologically active compounds
containing isoindolinones.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.08.070

M. Hellal, G. D. Cuny / Tetrahedron Letters 52 (2011) 5508–5511
5509
Table 1
Table 2
Optimization of the reaction conditions
Substrate scope of the reactiona
Yieldb (%)
O
Entry
Amide
Product
O
Ph
O
O
NH
Ph
+
NH2
Bn
NH
N
Bn
Ph
Br
1
87
Br
1
2
3a
Entry
[Pd]
Ligand
Base
Solvent
Yielda (%)
4a
O
O
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
Pd(OAc)2
Pd2(dba)3
PdCl2(PPh3)2
Pd(PPh3)4
BINAP
BINAP
BINAP
BINAP
BINAP
XantPhos
dppf
XPhos
PPh3
—
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
BINAP
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Cs2CO3
K2CO3
NEt3
NaOtBu
DBU
DBU
DBU
DBU
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
dioxane
i-PrOH
Toluene
MeCN
39
12
15
23
89
75
41
30
68
16
49
38
0
n-Bu
NH
N
n-Bu
Ph
2
3
4
5
6
94c
93d
89
Br
3b
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
4b
O
O
Ph
Ph
NH
N
Br
3c
Ph
4c
O
0
0
0
24
51
O
Ph
NH
N
Ph
Br
3d
Ph
Reaction conditions: 2-bromobenzamide (0.5 mmol), phenylacetylene (0.75 mmol),
[Pd] (5 mol %), Ligand (5–10 mol %), Base (1 mmol), DMF (2 mL), MW 120 °C,
30 min.
4d
O
O
a
Isolated yield.
NH
O
N
63e
Br
3e
catalyst (Pd source and ligand) was critical for the reaction. The
combination of PdCl2(MeCN)2 and BINAP was found to be the opti-
mal catalyst for the reaction by furnishing (Z)-isomer 2 in 89% yield
(Table 1, entry 5). The yields decreased dramatically when
Pd(OAc)2, Pd2(dba)3, PdCl2(PPh3)2 or Pd(PPh3)4 were used (entries
1–4). Further investigation revealed that the reaction was also
dependent on the presence and choice of ligand. For example, low-
er yields were observed when Xantphos, dppf, Xphos, and PPh3
were used (entries 6–9) or in the absence of a ligand (entry 10).
Next, the base and solvent were further investigated. Replacing
DBU with K2CO3 or Cs2CO3 (entries 11 and 12) resulted in poorer
yields, whereas no desired product was isolated in the presence
of NEt3 or NaOt-Bu (entries 13 and 14). Performing the reaction
in a variety of other solvents also proved detrimental. For example,
no reactions were observed in either 1,4-dioxane or i-PrOH, and
significant decreases in yields were observed in toluene and aceto-
nitrile, due to the lack of solubility of 1 (entries 15–18).
Finally, the influences of temperature and heating source on the
reaction were examined. Reducing the reaction temperature to 80 or
100 °C resulted in decreased yields of 31% and 45%, respectively. In
addition, the desired product was obtained in only 13% yield using
conventional heating at 120 °C for 30 min. The yield could be im-
proved to 80% when the conventional heating was extended to
24 h. Overall, the optimized reactions conditions were: 2-bromo-
benzamide 1 (1 equiv), phenylacetylene (1.5 equiv), PdCl2(MeCN)2
(5 mol %), BINAP (5 mol %), DBU (2 equiv) in DMF under microwave
irradiation at 120 °C for 30 min.
Ph
O
4e
Cl
Cl
Bn
NH
N
Bn
Ph
73
Br
3f
4f
O
O
MeO
MeO
Bn
NH
N
Bn
Ph
7
53f
Br
4g
3g
3h
O
O
Bn
NH
N
Bn
Ph
8
9
51
Cl
Cl
Br
4h
O
O
NH2
NH
Ph
42g
Cl
3i
2
a
Reaction conditions: 3a–i (0.5 mmol), phenylacetylene (0.75 mmol),
With the optimized conditions identified, the scope of this pal-
ladium-catalyzed reaction was extended to a series of 2-haloben-
PdCl2(MeCN)2 (5 mol %), BINAP (5 mol %), DBU (1 mmol), DMF (2 mL), MW 120 °C,
30 min.
b
Isolated yield.
Ratio Z:E = 88:12.
Ratio Z:E = 93:7.
Ratio Z:E = 80:20.
140 °C, ratio Z:E = 82:18.
140 °C.
zamides
3 (Table 2). A wide range of N-substituents were
c
tolerated, including benzyl, allyl, phenyl, and alkyl groups (entries
1–5). Furthermore, this one-pot reaction was highly stereoselec-
tive, and gave the Z-isomer as the main product. These results
are consistent with a based-mediated cyclization process. As
d
e
f
g

5510
M. Hellal, G. D. Cuny / Tetrahedron Letters 52 (2011) 5508–5511
O
isoindolinones 4 were obtained in moderate to good yields (entries
O
R
6–8). However, with the electron-donating methoxy group a mix-
ture of (Z) and (E)-isomers in a ratio 82:18 were obtained (entry 7).
The domino reaction was also effective with 2-chlorobenzamide.
However, a higher temperature (140 °C) was required to afford 2
in 42% yield (entry 9).
R
N
H
N
PhB(OH)2
[Pd]
+
N
N
Br
Ph
Base
The methodology was next extended to substrates in which the
benzene ring was replaced with a pyridine in order to generate
pyrrolopyridines. Several methods have previously been reported
for the synthesis of pyrrolopyridine 5, as outlined in Scheme 1.
For example, cyclization of 2-alkynyl-3-cyanopyridines under ba-
sic conditions19 or by exposure of hydroxyl lactams to acidic con-
ditions has been used.20 More recently, Cossy et al. described two
different routes involving ynamides or 2-alkynylnicotinamides.18
Using the copper-free Sonogashira coupling/regioselective 5-
exo-dig cycloisomerization domino reaction process, various pyri-
dine substrates were converted to pyrrolopyridines with excellent
regioselectivity (Scheme 2). In all three cases, 5-exo-dig cycloiso-
merization was the only reaction observed. 2-Chloronicotinamide
6 afforded the pyrrolopyridine 7 in 53% yield following microwave
irradiation at 140 °C for 30 min.21 Pyridines 8 and 9 gave pyrrolo-
pyridines 9 and 11 in 73% and 79%, respectively. Compounds 7, 9
and 11 were produced as (Z)-isomers.
Finally, to further study the scope of the copper-free Sonogashira
coupling/regioselective 5-exo-dig cycloisomerization domino reac-
tion, the replacement of the amide with an amidine and a sulfon-
amide was briefly investigated (Scheme 3). Gratifyingly, coupling
of 2-bromobenzamidine 12 with phenylacetylene gave 13 in 83%
yield. However, coupling of sulfonamide 14 with phenylacetylene
resulted in a ꢀ1:1.7 mixture of isomers 15 (Z:E = 14:86) and 16 in
86% yield, with 16 as the major product.22 The alkene geometry of
15was establishedviaNOESYNMRstudies. Tomorefullyinvestigate
the cyclization of the sulfonamide, the alkyne intermediate was pre-
pared from compound 14 using classical Sonogashira reaction con-
ditions.23 Treatment of the alkyne with DBU (2 equiv) in DMF at
120 °C for 30 min under MW irradiation gave similar results to the
one-pot process (88% yield; ratio 15:16 = 41:59; Z:E of 15 = 20:80).
Interestingly, when the cyclization reaction of the alkyne intermedi-
ate was performed in EtOH with either DBU or NaOEt 16 was ob-
tained exclusively in 82% yield. Moreover, no cyclization was
observed without base. The reason for the difference between the
carboxamide and sulfonamide substrates is not readily clear. How-
ever, these results indicated that a based-mediated process is simi-
larly involved in the sulfonamide cyclization, with both the solvent
and the functional group (i.e., carboxamide vs sulfonamide) having
a significant influence during the cycloisomerization step.
O
N
R
N
Ph
5
Acid
Base
O
CN
NR
OH
Ph
N
N
Ph
Scheme 1. Representative synthetic strategies of pyrrolopyridine 5.
O
PdCl2(MeCN)2
BINAP, DBU, DMF
O
Ph
Ph
NH
Ph
+
+
NH2
MW: 140oC, 30 min
53%
N
N
Cl
6
7
9
O
PdCl2(MeCN)2
BINAP, DBU, DMF
O
Bn
N
Bn
Ph
N
H
N
MW: 120oC, 30 min
73%
N
Br
8
O
PdCl2(MeCN)2
BINAP, DBU, DMF
O
N
N
Bn
Ph
N
Bn
Ph
+
N
H
MW: 120oC, 30 min
79%
Br
10
11
Scheme 2. Synthesis of pyrrolopyridines.
previously reported, carbopalladation induces an E-geometry
whereas a based-mediated cycloisomerization affords the Z-iso-
mer.18 The effect of substitution on the aromatic ring of the
benzamide was examined. Both electron-donating and electron-
withdrawing substituents were compatible with this process, and
In summary, an efficient approach for the synthesis of 3-(phe-
nylmethylene)isoindolin-1-ones has been developed using a dom-
ino reaction involving a copper-free Sonogashira coupling and
NH2
PdCl2(MeCN)2
BINAP, DBU, DMF
NH
NH2
Ph
Ph
N
+
+
MW:
120°C, 30 min
83%
Br
12
Ph
13
Bn
NH
PdCl2(MeCN)2
BINAP, DBU, DMF
O
O O
S
O
O
S
S
Bn
Ph
N
N Bn
+
MW: 120oC, 30 min
86%
O
Br
Ph
ratio 15:16
37:63
14
15
16
Z:E = 14:86
Scheme 3. Extension of the method to amidines and sulfonamides.

M. Hellal, G. D. Cuny / Tetrahedron Letters 52 (2011) 5508–5511
5511
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for this reaction are commercially available or can be easily pre-
pared. This methodology also provided access to pyrrolopyridines
in good yields. Finally, the method was also extended to an ami-
dine and a sulfonamide substrate. The compounds prepared
employing this methodology can be used for various applications,
including screening for biological activities.
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Acknowledgment
The authors appreciate financial support from the Harvard Neu-
roDiscovery Center.
Supplementary data
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Supplementary data (experimental details, characterization
data, and copies of 1H, 13C, and 2D NMR spectra for each com-
pound) associated with this article can be found, in the online ver-
sion, at doi:10.1016/j.tetlet.2011.08.070.
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21. General procedure for the synthesis of 3-(phenylmethylene)- isoindolinones and
related heterocycles: A microwave reaction tube was charged with an amide
(1 equiv), PdCl2(MeCN)2 (5 mol %) and BINAP (5 mol %), The tube was
evacuated and backfilled with argon (3 times), and then dry DMF (4 mL/
1 mmol of starting material), phenylacetylene (1.5 equiv), and DBU (2 equiv)
were added. The mixture was sparged with argon for 5 min and then irradiated
under microwaves at 120 °C for 30 min. After cooling to room temperature, the
solvent was partially removed in vacuo, then the mixture was diluted in EtOAc
(10 mL), washed with water (5 mL) and brine (5 mL). The organic layer was
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(Z)-6,7-Dihydro-7-(phenylmethylene)-5H-pyrrolo[3,4-b]pyridin-5-one
(7):
Purification by column chromatography (silica gel, 10–50% EtOAc in
cyclohexane) afforded 7 as a yellow solid in 53% yield. 1H NMR (500 MHz,
CDCl3): d 7.10 (s, 1H); 7.33–7.37 (m, 1H); 7.43–7.51 (m, 5H); 8.13 (br, 1H); 8.18
(dd, 1H, J = 1.5 and 8.0 Hz); 8.85 (dd, 1H, J = 1.5 and 5.0 Hz). 13C NMR
(125 MHz, DMSO-d6): d 107.06, 122.20, 124.61, 128.30, 129.25, 130.00, 131.90,
132.23, 134.37, 154.01, 157.01, 167.38. HRMS (MALDI-TOF) calcd for CHNO
[M+]: 223.0867; found: 223.0866.
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