Direct synthesis of pyrrolo[2,1-a]isoquinolines by 1,3-dipolar cycloaddition of stabilized isoquinolinium N-ylides with vinyl sulfonium salts

Article abstract of DOI:10.1016/j.tetlet.2013.05.053

A direct and efficient synthesis of 2,3-unsubstituted 1-acylpyrrolo[2,1-a] isoquinolines is described. The 1,3-dipolar cycloaddition of stabilized isoquinolinium N-ylides with vinyl sulfonium salts features simple experimental procedures, mild conditions, and moderate to good yields.

Full text of DOI:10.1016/j.tetlet.2013.05.053

Accepted Manuscript
Direct synthesis of pyrrolo[2,1-a]isoquinolines by 1,3-dipolar cycloaddition of
stabilized isoquinolinium N-ylides with vinyl sulfonium salts
Jing An, Qing-Qing Yang, Qiang Wang, Wen-Jing Xiao
PII:
S0040-4039(13)00810-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.05.053
TETL 42953
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
26 February 2013
24 April 2013
10 May 2013
Please cite this article as: An, J., Yang, Q-Q., Wang, Q., Xiao, W-J., Direct synthesis of pyrrolo[2,1-a]isoquinolines
by 1,3-dipolar cycloaddition of stabilized isoquinolinium N-ylides with vinyl sulfonium salts, Tetrahedron Letters
(2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.05.053
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Direct synthesis of pyrrolo[2,1-
Leave this area blank for abstract info.
a]isoquinolines by 1,3-dipolar cycloaddition
of stabilized isoquinolinium N-ylides with
vinyl sulfonium salts
Jing An, Qing-Qing Yang, Qiang Wang and Wen-Jing Xiao*
Ph
DABCO ( 2.5 equiv)
+
S
N
R
N
DMF, rt
24 h
Ph
OTf
R
Br
14 examples
48-88% yield

1
Tetrahedron Letters
journal homepage: www.elsevier.com
Direct synthesis of pyrrolo[2,1-a]isoquinolines by 1,3-dipolar cycloaddition of
stabilized isoquinolinium N-ylides with vinyl sulfonium salts
Jing Ana, Qing-Qing Yanga, Qiang Wanga and Wen-Jing Xiaoa, *
a Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University, 152 Luoyu Road, Wuhan,
Hubei 430079, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A direct and efficient synthesis of 2,3-unsubstituted 1-acylpyrrolo[2,1-a]isoquinolines is
described. The 1,3-dipolar cycloaddition of stabilized isoquinolinium N-ylides with vinyl
sulfonium salts features simple experimental procedures, mild conditions and moderate to good
yields.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
pyrrolo[2,1-a]isoquinoline
1,3-dipolar cycloaddition
isoquinolinium N-ylides
vinyl sulfonium salts
Pyrrolo[2,1-a]isoquinolines constitute the backbone of the
Lamellarin class of marine alkaloids1 which have exhibited
anticancer and antiviral activity2 and are considered as privileged
heterocycles broadly used in pharmaceutical and material
science3 (Scheme 1). Therefore, these important frameworks
have become targets of interest in the organic synthetic
community. Over the past decades, various synthetic methods for
the construction of pyrrolo[2,1-a]isoquinolines4-7 have been
developed, including the [3+2] cycloaddition of isoquinolinium
N-ylides with electron-deficient alkynes or alkenes,4 1,5-
electrocyclization5 and several transition metal catalyzed C-N
bond formation reactions.6
1-acylpyrrolo[2,1-a]isoquinolines
by
the
reaction
of
isoquinolinium ylide with maleic anhydride in the presence of the
oxidant tetrakispyridinecobalt(II) dichromate.8 However, this
elegant method required an excess of oxidant and high
temperature. Thus, the further development of more efficient and
mild approaches to synthesize 2,3-unsubstituted pyrrolo[2,1-
a]isoquinolines remains a worthwhile goal.
In the past few years, vinyl sulfonium salts9 have been
established as valuable and versatile intermediates for organic
synthesis. For instance, Aggarwal and co-workers10 have
developed
a series of reaction pathways involving vinyl
sulfonium salts resulting in the synthesis of morpholines,
oxazepines and imidazolinium salts. On the other hand, this
reagent can also be used for the synthesis of ꢀ-imidostyrenes by
michael addition, 1,2-H shift and an elimination sequence.9l,9m
Scheme 1. Structures of lamellarins and scaffold 3.
Among them, only a few examples are related to the direct
construction of 2,3-unsubstituted pyrrolo[2,1-a]isoquinolines 3,
which are important precursors3b for the synthesis of potent
cytotoxic analogues of the marine alkaloid Lamellarin D.
Conventional methods for the synthesis of 2,3-unsubstituted
pyrrolo[2,1-a]isoquinolines required multiple steps or using
special alkene substrates such as nitroketene dithioacetals
followed by desulfurization with raney-nickel.4g,4h Very recently,
Xu developed a method to generate a variety of 2,3-unsubstituted
Scheme 2. Reaction design.

2
Tetrahedron Letters
In pursuing our ongoing program on carbon- and heterocycle
oriented methodology development,11 we envisioned that the
electrophilic vinylsulfonium salt should react with
Table 2. Synthesis of 2,3-unsubstituted 1-acylpyrrolo[2,1-
a]isoquinolinesa
5
isoquinolium ylides derived from the isoquinolium salts 4, to
form intermediate II under basic conditions. Then intermediate
III would be expected to be formed with another equivalent of
base. Subsequent elimination of Ph2S and dehydroaromatization
could afford 2,3-unsubstituted pyrrolo[2,1-a]isoquinolines 6. We
herein report the realization of this strategy for the direct
synthesis of 2,3-unsubstituted 1-acylpyrrolo[2,1-a]isoquinolines.
Yieldb
(%)
Entry
1
Substrate
Product
We initially studied the reaction of 2-(2-oxo-2-
62
phenylethyl)isoquinolin-2-ium
bromide
4a
and
the
4a
4b
6a
6b
vinylsulfonium salt 5 in CH3CN, in the presence of t-BuOK (2.5
equiv) at room temperature for 24 h. As highlighted in Table 1,
the base had a dramatic impact on the reaction efficiency. After
screening several organic and inorganic bases, DABCO (1, 4-
diazabicyclo[2.2.2]octane) was identified as the ideal choice
(Table 1, entries 1-6). A survey of solvents revealed that DMF
was optimal (Table 1, entries 6-10). The reaction conditions were
further optimized by adjusting the amount of the base. As
expected, there was nearly no conversion when 1.0 equiv of
DABCO was used (Table 1, entry 11). On the other hand,
increasing the amount of the base did not lead to improvement of
the reaction efficiency (Table 1, entry 13).
2
3
4
5
6
63
61
65
63
58
4c
4d
4e
4f
6c
O
N
F
Table 1. Optimization of the reaction conditionsa
6d
6e
Entry
Base
X
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
t-BuOK
NaH
Cs2CO3
KOH
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.0
2.0
3.0
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
DMF
CH3OH
DMF
DMF
DMF
39
36
39
45
20
52
33
59
62
6f
6g
6h
6i
7
8
9
88
64
73
4g
4h
4i
Et3N
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
9
10
11
12
13
15
trace
50
63
a Reaction conditions: 4a (0.30 mmol), 5 (0.36 mmol), base (1.0-3.0 equiv),
10
66
solvent (4.0 mL). DABCO = 1, 4-diazabicyclo[2.2.2]octane.
b Yield of isolated product.
4j
6j
With the optimal conditions established, the scope of the
isoquinolium ylides derived from the isoquinolium salts was
explored. As summarized in Table 2, this cyclization process
appeared to be tolerant with respect to significant structural
variations in the isoquinolium salts and furnished the
11
12
63
65
4k
4l
6k
corresponding
2,3-unsubstituted
1-acylpyrrolo[2,1-
6l
a]isoquinolines in moderate to good yield. The acyl group with
electron-rich substitutents could be successfully utilized for this
O
N
13
14
63
48
transformation (Table 2, entries
2
and 3). Moreover,
CF3
4m
4n
6m
incorporation of halogen groups at various positions of the acyl
benzene ring indicated that steric modification of the acyl group
could be accomplished without compromising reaction efficiency
(Table 2, entries 4-10). Furthermore, it was found that the aryl
framework could be extended to heterocycle-derived substrates,
affording products 6k and 6l in 63% and 65% yield, respectively
(Table 2, entries 11-12). It is well known that the trifluoromethyl
6n
a Reaction conditions: 4 (0.30 mmol), 5 (0.36 mmol), DABCO (0.75 mmol),
CH3CN (4.0 mL). DABCO = 1, 4-diazabicyclo[2.2.2]octane.
b Yield of isolated product.

3
7. (a) Yavari, I.; Piltan, M.; Moradi, L. Tetrahedron 2009, 65, 2067;
group could affect the biological activity of compounds. The
trifluoromethylacyl ylides could also be successfully employed in
this process and afforded the product in 63% yield (Table 2, entry
13). The cyano-derived ylide was tolerated for this cycloaddition
to produce the corresponding product which should be valuable
for further chemical transformations.
(b) Alizadeh, A.; Zohreh, N. Synthesis 2008, 429; (c) Ploypradith,
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In summary, we have developed a direct and efficient
synthesis of 2,3-unsubstituted 1-acylpyrrolo[2,1-a]isoquinolines
by 1,3-dipolar cycloaddition of stabilized isoquinolinium N-
ylides with vinyl sulfonium salts. This process features simple
experimental procedures, under mild conditions. Application of
this reaction to the preparation of biologically relevant
compounds is currently underway in our laboratory.
8. Liu, Y.; Zhang, Y.; Shen, Y.-M.; Hua, H.-W. Xu, J.-H. Org.
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Acknowledgments
We are grateful to the National Basic Research Program of
China (2011CB808600) and the National Science Foundation
of China (20872043 and 21002036), and Excellent Doctorial
Dissertation Cultivation Grant from CCNU for support of this
research.
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