Unexpected formation of (Z)-3-(halomethylene)isoindolinones from gem-dihalovinylbenzonitriles: Efficient synthesis of enyne-containing isoindolinones

Article abstract of DOI:10.1016/j.tetlet.2011.03.143

An efficient one-pot procedure for the regioselective synthesis of (Z)-3-(halomethylene)-isoindolin-1-ones was developed from easily accessible 2-(2,2-dihalovinyl)benzonitriles. From this key intermediate, a variety of isoindolinones containing an enyne moiety were synthesized in good to excellent yields via palladium-catalyzed Sonogashira reaction. The generated enyne-containing isoindolinones could be further manipulated by iodide induced cyclization reaction to afford a versatile synthetic intermediate 5H-pyrrolo[2,1-a]isoindolol-5-one in high yield and could be further elaborated.

Full text of DOI:10.1016/j.tetlet.2011.03.143

Tetrahedron Letters 52 (2011) 2984–2989
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected formation of (Z)-3-(halomethylene)isoindolinones from
gem-dihalovinylbenzonitriles: efficient synthesis of enyne-containing
isoindolinones
Chengming Wang a, Caiyun Sun a, Fei Weng a, Mingchun Gao a, Bingxin Liu a, , Bin Xu a,b,
⇑
⇑
a Department of Chemistry, College of Sciences, Shanghai University, Shanghai 200444, China
b Shanghai Key Laboratory of Green Chemistry and Chemical Processes, Department of Chemistry, East China Normal University, Shanghai 200062, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient one-pot procedure for the regioselective synthesis of (Z)-3-(halomethylene)-isoindolin-1-
ones was developed from easily accessible 2-(2,2-dihalovinyl)benzonitriles. From this key intermediate,
a variety of isoindolinones containing an enyne moiety were synthesized in good to excellent yields via
palladium-catalyzed Sonogashira reaction. The generated enyne-containing isoindolinones could be fur-
ther manipulated by iodide induced cyclization reaction to afford a versatile synthetic intermediate 5H-
pyrrolo[2,1-a]isoindolol-5-one in high yield and could be further elaborated.
Received 18 January 2011
Revised 17 March 2011
Accepted 30 March 2011
Available online 5 April 2011
Keywords:
Cross-coupling
Enyne
Ó 2011 Elsevier Ltd. All rights reserved.
Isoindolinones
Nitrogen heterocycles
Palladium-catalyzed
In the past few decades, the conjugated enyne- or enediyne- con-
taining antitumor antibiotics have aroused lots of attention.1 These
molecules act as natural antibiotics destroying the DNA of bacteria
and viruses and resulting in the cleavage of DNA,2 intriguing mode
of action,2b,3 and having extremely potent cytotoxicity to a wide
range of tumor cells.4 In addition to their biological activity, these
O
O
O
Me
O
COOH
HO
O
OH
OH
O
O
HN
H
N
O
O
MeSSS
sugar
OMe
O
ArCO2
sugar-O
Neocarzinostatin
H
O
OH
Dynemicin A
Calicheamicin
N
AcO
O
Br
trans-Kumausyne
Lamisil
Scheme 1. Bioactive products with enyne or enediyne moiety.
⇑
Corresponding authors. Tel.: +86 21 66132065; fax: +86 21 66132065 (B.X.).
E-mail address: xubin@shu.edu.cn (B. Xu).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.03.143

C. Wang et al. / Tetrahedron Letters 52 (2011) 2984–2989
2985
H
X
R3
H
X
X
H
1) NaOH,
Sonogashira
reaction
EtOH
R1
NH
R1
R1
NH
2) H2O2
CN
O
O
Scheme 2. Synthesis of enyne-containing isoindolinones.
Special chemical or physical properties have been reported
when heterocycles are assembled with enyne pharmacophore.7
For example, the enyne-containing porphyrinoids present as a
new photosensitizer with much better properties which could be
widely used in photodynamic therapy (PDT).7f When chlorophylls
were attached by enyne moiety, they may act as finer donors and
acceptors for both energy and charge.7e For benzothiophene bear-
ing with a enyne fragment, it becomes a representative allylamine
antimycotics, known to act by selective inhibition of the fungal
squalnen epoxidase.7h,i This discovery sparks a great deal of excite-
ment in the research areas of pharmacology,7f,g,8 diagnostics,9
molecular assembly,10 materials science,7d,11 artificial photosyn-
thesis,12 and for the preparation of novel macrocycles.10
Br
Br
1) H2O2, EtOH
H
previous work
2) NaOH (6 N)
77%
NH2
Br
Br
H
O
H
CN
Br
1a
1) NaOH (6 N)
EtOH
NH
this work
2) H2O2
90%
O
2a
Isoindolinone derivatives are an important class of heterocycles
which could be widely found in both natural products and syn-
thetic pharmaceuticals with fine biological activity.8,13 They have
exhibited a variety of biological activities,14–16 such as antihyper-
tension,14g antipsychotics,15 antiinflammation,14f anesthetic,16
antiulcer,14h and vasodilatory.14e In addition, antiviral,17 antileuke-
mic,18 and platelet aggregation inhibitory19 properties have also
been observed in this class of structures, as well as acting as useful
synthetic building blocks and intermediates in organic synthe-
sis.13a–e
Br
Br
NaOH
H2O2
NH2
CN
O
A
B
Scheme 3. One-pot synthesis of (Z)-3-(bromomethylene)isoindolin-1-one 2a.
Recently, we have developed a novel and efficient one-pot reg-
ioselective elimination-cyclization-Suzuki approach to afford (Z)-
3-arylmethyleneisoindolin-1-ones in good to excellent yields from
easily accessible ortho-gem-dihalovinylbenzamides and organobo-
ron reagents.20 (Z)-3-(bromomethylene)isoindolin-1-one was pro-
posed as the in situ generated key intermediate in this tandem
process. During our research program concerning effective con-
struction and functionalization of nitrogen-containing molecules
and biochemical validation of various heterocycles,21 we intended
to prepare the enyne-containing isoindolinones based on the con-
sideration of their potential biological activity. Herein, we reported
an efficient synthesis of isoindolinones bearing an enyne scaffold
from unusually formed (Z)-3-(halomethylene)isoindolin-1-ones
which could be derived from ortho-gem-dihalovinylbenzonitriles
(Scheme 2).
X
X
H
R1
R2
CHO
CN
R1
R2
CX4, PPh3, CH2Cl2
R.T. or reflux
CN
R1, R2 = H, X = Br, 1a, 72%
R1 = H, R2 = F, X = Br, 1b, 89%
R1 = OMe, R2 = H, X = Br, 1c, 92%
R1, R2 = H, X = Cl, 1d, 66%
H
X
H
X
1) NaOH (6 N)
EtOH, 30 oC
R1
R2
R1
CH3I, NaH
DMF, R.T.
NH
N
CH3
2) H2O2, R.T.
R2
O
O
The ortho-gem-dihalovinylbenzamides have been prepared by
adding aqueous sodium hydroxide into the ethanol solution of 2-
(2,2-dihalovinyl)benzonitrile 1a and hydrogen peroxide (Scheme
3).20,22 However, when we changed the addition sequence by add-
ing hydrogen peroxide into the ethanol solution of 2-(2,2-dibromo-
vinyl)benzonitrile and sodium hydroxide, the cyclized (Z)-3-
(bromomethylene)isoindolin-1-one 2a was predominantly affor-
ded in 90% yield, instead of the previously reported 2-(2,2-dib-
romovinyl)benzamide (Scheme 3). The formation of this unusual
product 2a was envisioned to assign through dehydrobromination
of 1a under NaOH and furnish the alkynyl bromide A,23 which
could be further transferred into intermediate B by reacting with
hydrogen peroxide.24 The generated benzamide intermediate B
will undergo cyclization reaction and lead to (Z)-3-(bromomethyl-
ene)isoindolin-1-one 2a sequentially (Scheme 3).8,20
R1, R2 = H, X = Br, 2a, 90%
R1, R1 = H, X = Br, 2e, 95%
R
1 = H, R2 = F, X = Br, 2b, 71%
R
1 = OMe, R2 = H, X = Br, 2c, 59%
R1, R2 = H, X = Cl, 2d, 46%
Scheme 4. Synthesis of starting materials.
compounds are also of interest because of their unique structure fea-
ture of 1,5-diyne-3-ene or (Z)-enediyne which could be used as
important synthetic intermediates for chemical transformation.4
Typical representatives accounting for these characteristics are
some nature products, such as Calicheamicin,5d Dynemicin A,5d
trans-Kumausyne,5b and Neocarzinostatin,5a,c and could be exempli-
fied by marketingdrugs such as Lamisilthat is used for the treatment
of onychomycosis of the toenail or fingernail (Scheme 1). Such char-
acteristics have made the molecules significant synthetic targets6
and, therefore, have resulted in sustained interest in developing
new methods for the preparation of this valuable structural unit.1b
To explore the scope of this method, a variety of 2-(2,2-dihalo-
vinyl)benzonitriles 1a–d were firstly prepared from commercial or
readily available substituted 2-formyl-benzonitriles25 by treating
with carbon tetrahalides in the presence of PPh3 in CH2Cl2. The

2986
C. Wang et al. / Tetrahedron Letters 52 (2011) 2984–2989
Table 1
Synthesis of enyne-containing isoindolinone from vinyl halides and alkynesa
R3
H
H
X
PdCl2(PPh3)2,CuI
Et3N,reflux
R2
+
R1
R1
R3
H
N
R2
N
O
O
Entry
Substrate
R3
Product
Yieldb (%)
H
Br
NH
H
1
C6H5
91
NH
O
O
4a
2a
CH3
H
2
3
4
5
6
7
8
9
p-CH3-C6H4
p-C5H11-C6H4
p-F-C6H4
92
91
90
86
80
81
77
96
NH
O
4b
C5H11
H
H
H
H
H
NH
O
4c
F
NH
O
4d
Cl
p-Cl-C6H4
NH
O
4e
NO2
p-NO2-C6H4
NH
O
4f
OMe
MeO
NH
O
4g
H
Br
NH
H
C6H5
NH
F
F
O
2b
O
4h
H
Br
NH
H
MeO
MeO
C6H5
NH
O
2c
O
4i

C. Wang et al. / Tetrahedron Letters 52 (2011) 2984–2989
2987
Table 1 (continued)
Entry
Substrate
R3
Product
Yieldb (%)
H
Cl
NH
H
10
11
12
13
C6H5
71
93
92
90
93
NH
O
O
4a
4j
2d
H
Br
CH3
H
H
H
H
N
C6H5
N
CH3
CH3
CH3
CH3
O
2e
O
CH3
p-CH3-C6H4
p-C5H11-C6H4
p-F-C6H4
N
O
4k
C5H11
N
O
4l
F
14
N
O
4m
a
All reactions were performed on a 0.3 mmol scale, using vinyl halides (1 equiv), alkynes (1.1 equiv), PdCl2(PPh3)2 (4 mol %) and CuI (5 mol %) in Et3N (6 mL), 0.5–3.0 h.
Isolated yield.
b
formed benzonitriles 1a–d could readily react with sodium
in 77% and 96% yields, respectively (Table 1, entries 8–9). In partic-
ular, the employment of vinyl chloride 2d could also afford 4a in
moderate yields when reacted with phenyl acetylene (Table 1, en-
try 10). The N-methyl substituted isoindolinone could also react
with alkynes in excellent yields with good functional group com-
patibility (Table 1, entries 11–14). However, aliphatic alkynes such
as 1-hexyne failed to react under the same condition.
hydroxide and hydrogen peroxide, and afford (Z)-3-(bromomethyl-
ene)isoindolin-1-ones 2a–d in good to high yields. The yield for 2d
with chloro substitution is a little bit lower than corresponding vi-
nyl bromide 2a and compound 2e could be produced smoothly via
N-methylation reaction of 2a. The results are summarized in
Scheme 4.
Next, we tried to conduct the Sonogashira reaction from 2a–d.
The optimized conditions were performed using 4 mol % of
PdCl2(PPh3)2 and 5 mol % of CuI to execute the cross-coupling reac-
tion of 2a by phenyl acetylene under reflux and afforded the corre-
sponding enyne 4a in 91% yield (Table 1, entry 1).26 With these
conditions in hand, we started to explore the reaction scope using
a variety of terminal alkynes.
As illustrated in Table 1, the reaction proceeded smoothly in
high yields in the presence of a variety of functional groups at-
tached to phenyl ring of aryl acetylenes, including methyl, n-pen-
tyl, nitro, and halogen groups (Table 1, entries 2–6). Normally,
slightly longer reaction time was needed for alkynes with electron
deficient property. Alkynes with electron-donating groups, which
are usually extreme active substrates in Sonogashira reaction,
show better results than those alkynes with electron-withdrawing
groups (Table 1, entries 2–3 vs entry 6). Aryl acetylenes could be
expanded to naphthalene-containing alkyne and gave 4g in 81%
yield under the employed conditions (Table 1, entry 7). For
substrates having a fluoro and methoxy substitution, (Z)-3-(bro-
momethylene)-6-fluoroisoindolin-1-one 2b and (Z)-3-(bromom-
ethylene)-5-methoxyisoindolin-1-one 2c were also proved to be
good partners in this procedure and gave corresponding enynes
5H-pyrrolo[2,1-a]isoindolol-5-ones derivatives have occurred
widely in natural products and have different and important bio-
logical activities as well as used as versatile synthetic intermedi-
ates.27 However, few examples have been reported to synthesize
functionalized or substituted 5H-pyrrolo[2,1-a]-isoindolol-5-
ones.28 To expand the synthetic utility of our produced enyne com-
pounds, intramolecular cyclization reaction of these isoindolinones
was investigated. The (Z)-3-(3-phenyl-prop-2-ynylidene)isoindo-
lin-1-one 4a can be easily cyclized to afford 2-iodo-3-phenyl-5H-
pyrrolo[2,1-a]isoindolol-5-one 5 in 97% yield,8,29 which shall be a
useful synthetic intermediate and could be further elaborated
through metal-catalyzed cross-coupling reactions to give substi-
tuted products (Scheme 5).
In conclusion, we have developed a general and efficient two-
step procedure for the regioselective synthesis of enyne-containing
isoindolinones 4a–m in good to excellent yields from easily acces-
sible 2-(2,2-dihalovinyl)benzonitrile 1a–c. During the procedure,
an unusual one-pot formation of (Z)-3-(halomethylene)-isoindo-
lin-1-ones 2a–e was involved. The generated products could be
further manipulated by the iodide induced cyclization reaction to
afford a versatile synthetic intermediate 5H-pyrrolo[2,1-a]isoindo-
lol-5-one in high yield. Further investigation concerning the bioac-

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4a
5
Scheme 5. Iodide induced cyclization reaction of 4a.
tive property of generated products and the synthetic application
of compounds 2, 4, and 5 in the synthesis of bioactive compounds
are currently under investigation in our laboratory and will be re-
ported in due course.
Acknowledgments
We thank the National Natural Science Foundation of China
(No. 20972093), Shanghai Municipal Education Commission (No.
J50102 and 10YZ06), and Shanghai University (B.L.) for financial
support. The authors thank Professor Hongmei Deng for spectral
support.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.03.143.
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