Highly efficient electrophilic cyclization of N′-(2-alkynylbenzylidene)hydrazides

Article abstract of DOI:10.1016/j.tetlet.2008.11.006

Electrophilic cyclization of N′-(2-alkynylbenzylidene)hydrazides with I₂, Br₂, or ICl under mild conditions is described. This reaction proceeds smoothly in dichloromethane at room temperature, which provides a useful method for the

Full text of DOI:10.1016/j.tetlet.2008.11.006

Tetrahedron Letters 50 (2009) 340–342
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Tetrahedron Letters
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Highly efficient electrophilic cyclization of N0-(2-alkynylbenzylidene)hydrazides
a,c,
Qiuping Ding b, Zhiyuan Chen a, Xingxin Yu a, Yiyuan Peng b, , Jie Wu
*
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330027, China
c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
a r t i c l e i n f o
a b s t r a c t
Electrophilic cyclization of N0-(2-alkynylbenzylidene)hydrazides with I2, Br2, or ICl under mild conditions
is described. This reaction proceeds smoothly in dichloromethane at room temperature, which provides a
useful method for the synthesis of functionalized isoquinolinium-2-yl amide.
Ó 2008 Elsevier Ltd. All rights reserved.
Article history:
Received 30 September 2008
Revised 31 October 2008
Accepted 4 November 2008
Available online 7 November 2008
Keywords:
N0-(2-Alkynylbenzylidene)hydrazide
Electrophilic cyclization
Iodine
Bromine
Isoquinolinium-2-yl amide
In pursuit of identifying small molecule ligands for studying
biological function as well as potential candidates as a lead com-
pound,1 we have explored efficient methodologies for the synthesis
of natural product-like molecules.2 Since the isoquinoline skeleton
is an important substructure in both natural products and thera-
peutic agents, as well as the wide application of isoquinolines in
pharmaceutical research,3 the development of efficient methods
for isoquinoline and related derivatives synthesis has continuously
attracted the attentions of many chemists. Recently, we have
developed efficient methods for synthesis of diverse 1,2-dihydro-
isoquinolines via multi-component tandem reactions starting from
2-alkynylbenzaldehyde or 2-alkynylbenzaldoxime.2 With a hope of
finding more active hits or leads for our particular biological
assays, it is still highly desired to construct the new isoquinoline-
based structures. Herein, we present our recent efforts for the syn-
thesis of functionalized isoquinolinium-2-yl amide via electro-
philic cyclization of N0-(2-alkynylbenzylidene)hydrazides with I2,
Br2, or ICl under mild conditions.
The electrophilic cyclization of heteroatomic nucleophiles such
as oxygen, nitrogen, sulfur, and phosphorus with tethered alkynes
has proven to be an effective method for preparing a large variety
of heterocyclic ring systems.4,5 The electrophiles such as iodine,
bromine, and ICl were commonly used in the reaction since the
resulting iodine- or bromo-containing products are readily elabo-
rated to more complex products by using known organopalladium
chemistry. Recently, we and others discovered that in the presence
of electrophiles (such as iodine or bromine) or Lewis acid, 2-alkyn-
ylbenzaldoxime would be transferred to isoquinoline-N-oxide
via electrophilic cyclization.6 Prompted by the results, we envi-
sioned that N0-(2-alkynylbenzylidene)hydrazide might be utilized
as starting material for synthesis of new isoquinoline-based
compounds due to the structural similarity with 2-alkynylbenzal-
doxime. We reasoned that in the presence of electrophiles such
as iodine or bromine, N0-(2-alkynylbenzylidene)hydrazide would
undergo electrophilic cyclization, leading to isoquinolinium-2-yl
amides. Thus, we started to investigate the possibility of this
electrophilic cyclization reaction of N0-(2-alkynylbenzylidene)-
hydrazide.
The reaction was initially studied with N0-(2-alkynylbenzylid-
ene)hydrazide 1a and iodine, which were selected as model sub-
strates (Scheme 1). As expected, the reaction proceeded smoothly
H
N
N
N
Ts
N
Ts
solvent
rt
+
I2
Ph
Ph
I
2a
82%
1a
DCM
DCE
Et2O
99%
94%
88%
THF
MeCN 97%
MeNO2 98%
toluene 96%
Scheme 1.
* Corresponding authors. Tel.: +86 21 5566 4619; fax: +86 21 6510 2412.
E-mail address: jie_wu@fudan.edu.cn (J. Wu).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.006

Q. Ding et al. / Tetrahedron Letters 50 (2009) 340–342
341
Table 1 (continued)
Table 1
Electrophilic cyclization reaction of N0-(2-alkynylbenzylidene)hydrazidesa,7
Entry
11
Substrate
E
Product
H
H
N
N
N
R3
N
R3
N
N
R1
R1
N
N
Ts
Electrophile
CH2Cl2, rt
N
Ts
R2
Br2
Ph
R2
X
2k, 86%
Br
Br
Ph
2
1
X = I, Br
1a
Electrophile: I2, ICl, or Br2
H
N
N
Entry
1
Substrate
E
Product
SO2Ph
N
N
SO2Ph
12
13
Br2
Br2
ICl
H
N
Ph
N
N
Ts
N
Ts
2l, 83%
1g
Ph
I2
Ph
I
H
N
2a, 99%
Ph
1a
N
Ts
Ts
N
N
Ts
H
N
N
O
O
O
O
N
Ts
N
Ts
Br
2m, 99%
2
3
4
5
6
7
I2
I2
I2
I2
I2
I2
1f
Ph
I
2b, 93%
Ph
H
N
1b
N
Ts
N
14
H
Ph
F
F
N
F
F
N
N
N
Ts
N
N
Ts
I
2a, 99%
Ph
1a
Ph
a
Isolated yield based on N0-(2-alkynylbenzylidene)hydrazide 1.
I
Ph
2c, 86%
1c
H
N
N
in dichloromethane at room temperature to afford the desired
product 2a in 99% yield. Similar results were observed when other
solvents were screened. From these results, it was found that this
reaction was highly efficient under extremely mild conditions.
With this preliminary optimized conditions in hand, the scope
of this reaction was then investigated (CH2Cl2, rt), and the results
are summarized in Table 1. We rapidly noticed the broad field of
application of the process and its remarkable functional group
compatibility. For all cases, N0-(2-alkynylbenzylidene)hydrazide 1
reacted with various electrophiles leading to the corresponding
products 2 in good to excellent yields. Usually, only 5 min to 2 h
was needed for completion of reaction. For instance, reaction of
N0-(2-alkynylbenzylidene)hydrazide 1b with iodine under the
standard conditions gave rise to the desired product 2b in 93%
yield (Table 1, entry 2). An 86% yield was obtained when fluoro-
substituted N0-(2-alkynylbenzylidene)-hydrazide 1c was utilized
as substrate (Table 1, entry 3). No difference was observed when
the group attached on the triple bond was changed. For example,
reaction of N0-(2-alkynylbenzylidene)hydrazide 1d and iodine
afforded the corresponding isoquinolinium-2-yl amide 2d in al-
most quantitative yield (Table 1, entry 4, 99% yield). When the aryl
group attached on the triple bond was replaced by n-butyl or
cyclopropyl group, similar yield was isolated (Table 1, entries 5
and 6). The reactions also worked well when tosyl group on the
nitrogen in N0-(2-alkynylbenzylidene)hydrazide 1 was changed to
other groups, such as benzoyl group (Table 1, entries 8–10). Reac-
tions of N0-(2-alkynylbenzylidene)hydrazides 1 with other electro-
philes were also examined. For example, 86% yield of product 2k
was generated when N0-(2-alkynylbenzylidene)hydrazide 1a was
employed in the reaction of bromine (Table 1, entry 11), while
83% yield of product 2l was isolated when substrate 1g was used
under the conditions shown in (Table 1, entry 12). Reaction of
N0-(2-alkynylbenzylidene)hydrazide 1f or 1a with bromine or ICl
also proceeded well to give rise to the corresponding products in
quantitative yields (Table 1, entries 13 and 14).
Ts
Ts
PMP
I
PMP
2d, 99%
1d
H
N
N
N
Ts
N
N
Ts
1e
Ts
Bu
I
I
I
I
Bu
2e, 94%
H
N
N
N
N
Ts
2f, 92%
1f
H
N
N
SO2Ph
N
N
SO2Ph
Ph
Ph
2g, 84%
1g
H
N
N
N
COPh
COPh
8
I2
Ph
Ph
N
2h, 70%
1h
F
N
H
N
N
COPh
F
COPh
PMP
9
I2
I
2i,
PMP
85%
1i
H
N
N
O
O
N
COPh
O
O
N
COPh
In summary, we have described a highly efficient electrophilic
cyclization of N0-(2-alkynylbenzylidene)-hydrazide with I2, Br2, or
ICl in dichloromethane at room temperature. This reaction pro-
ceeds smoothly under extremely mild conditions, which provides
Ph
10
I2
2j,
I
Ph
1j
82%

342
Q. Ding et al. / Tetrahedron Letters 50 (2009) 340–342
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Acknowledgments
Financial support from National Natural Science Foundation of
China (20772018), Shanghai Pujiang Program, and Program for
New Century Excellent Talents in University (NCET-07-0208) is
gratefully acknowledged.
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7. General procedure for electrophilic cyclization reaction of N0-(2-alkynylbenzyli-
dene)hydrazides: An electrophile (2.0 equiv of I2 or 1.0 equiv of Br2, ICl) in 2.0 mL
of CH2Cl2 was added dropwise to
a
mixture of N0-(2-alkynylbenzyli-
dene)hydrazide 1 (0.30 mmol) in CH2Cl2 (4.0 mL). The reaction mixture was
stirred at room temperature. After completion of reaction as indicated by TLC,
the reaction mixture was then diluted with CH2Cl2 (25 mL), washed with
saturated aqueous Na2S2O3 (25 mL), dried (Na2SO4) and filtered. Evaporation of
the solvent followed by purification on silica gel provided the corresponding
product 2.