Studies on the ɑ-lithiation-in situ intramolecular nucleophilic addition reactions of 2-acyl-N-sulfonylpyrroles

Article abstract of DOI:10.1016/j.tetlet.2021.152907

Treatment of 2-acyl-N-sulfonylpyrroles with LDA resulted in the formation of benzo[e]pyrrolo[1,2-b][1,2]thiazine 5,5-dioxides in moderate to good isolated yields.

Full text of DOI:10.1016/j.tetlet.2021.152907

Tetrahedron Letters 68 (2021) 152907
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Tetrahedron Letters
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Studies on the ɑ-lithiation-in situ intramolecular nucleophilic addition
reactions of 2-acyl-N-sulfonylpyrroles
⇑
Cui Zhao, Chuanjun Song
College of Chemistry, and Green Catalysis Center, Zhengzhou University, Zhengzhou 450001, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Treatment of 2-acyl-N-sulfonylpyrroles with LDA resulted in the formation of benzo[e]pyrrolo[1,2-b][1,2]
thiazine 5,5-dioxides in moderate to good isolated yields.
Received 29 December 2020
Revised 31 January 2021
Accepted 2 February 2021
Available online 9 February 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
ɑ-lithiation
2-acyl-N-sulfonylpyrrole
Sultam
Enolizable ketone
The ɑ-lithiation of N-sulfonylpyrroles followed by trapping with
electrophiles is a reliable way to obtain 2-substituted pyrroles [1].
As part of our continued interest toward the synthesis of polycyclic
ring systems embedding pyrroles [2], we need to get access to sub-
stituted pyrrole-2-carboxylate. To this end, we treated N-tosylpyr-
role 1 with LDA, followed by reaction with dimethyl carbonate
(Scheme 1). The reaction yielded pyrrole-2-carboxylate 2 and pyr-
role-2,5-dicarboxylate 3 in 27% and 31% isolated yields, respec-
tively. Besides, a small amount of compound 4 was also obtained.
Literature search indicated that such structural motifs possess
appreciable antitumor activity [3], which are also potential 5-HT6
receptor ligands [4]. Evidently, 4 was formed via ɑ-lithiation of
the benzene ring of 2 and subsequent intramolecular nucleophilic
addition to the ester functionality [5–7]. Indeed, treatment of 2
with LDA resulted in the formation of 4 in 44% isolated yield
(Scheme 2). Inspired by the results, we then decided to explore
the details of the ɑ-lithiation-in situ intramolecular nucleophilic
addition reactions of 2-acyl-N-arylsulfonylpyrrole derivatives.
We commenced our study using 2-benzoyl-1-tosylpyrrole 5a as
substrate, and the results for the optimization of reaction condi-
tions were listed in Table 1. The desired product 6a was obtained
in 73% isolated yield by treatment of 5a with 2 equiv. of LDA
at À78 °C in THF (Entry 1). No reaction occurred in the presence
of NaH or LiH (Entries 2, 3), and only trace amount of 5a was
obtained when LiHMDS was applied (Entry 4). iPrMgCl as base gave
a mixture of products, and no trace of 6a was evident on TLC plate
(Entry 5). With LDA as base, neither variation of its equivalents
(Entries 6, 7) nor raising the reaction temperature (Entries 8, 9)
could give a better result. The reaction could not be driven to com-
pletion in the presence of 1.5 equiv. of LDA, while de-tosylation of
5a began to take place in the presence of 2.5 equiv. of LDA.
With the optimal conditions in hand, the ɑ-lithiation-in situ
intramolecular nucleophilic addition reaction of a variety of 2-
acyl-N-arylsulfonylpyrroles and analogues was investigated. The
results were summarized in Table 2 and Scheme 3. Reaction of 2-
acyl-N-tosylpyrroles 5b-e proceeded smoothly to give the corre-
sponding products 6b-e in moderate to good isolated yields. It is
noteworthy that no products resulting from aldol condensation
were obtained for substrates 5c-e with an enolizable ketone moi-
ety. Next, 2-benzoylpyrroles bearing different N-arylsulfonyl moi-
ety were investigated. While 2-benzoyl-N-phenylsulfonylpyrrole
5f reacted smoothly to provide 6f in moderate isolated yield, reac-
tion of substrate 5g with an electron-withdrawing nitro group sub-
stituted benzene ring was less satisfactory and gave a mixture of
products from which 6g was isolated in 20% yield only. Reaction
of 2-benzoyl-N-(3-fluorophenylsulfonyl)pyrrole 5h was governed
by regioselective lithiation under the joint effect of the sulfonyl
and the fluoro group [8] to provide 6h in 46% isolated yield. The
alternative product resulting from 6-lithiation of 5h and subse-
quent intramolecular nucleophilic addition was not observed.
When 2-benzoyl-N-(o-tosyl)pyrrole 5i was used as substrate, 6i
with a seven-membered ring was obtained solely in good isolated
yield. Under the conditions, imidazole and pyridine derivatives 6j
and 6k (Scheme 3) could also be obtained, albeit in low yield.
⇑
Corresponding author.
E-mail address: chjsong@zzu.edu.cn (C. Song).
https://doi.org/10.1016/j.tetlet.2021.152907
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

C. Zhao and C. Song
Tetrahedron Letters 68 (2021) 152907
O
1. LDA, -78 oC, THF
2. dimethyl carbonate
N
S
O
+
MeO2C
CO2Me
+ O
CO2Me
N
N
N
Ts
Ts
Ts
1
2
3
4
, 5%
, 27%
, 31%
Scheme 1. Results for the ɑ-lithiation of N-tosylpyrrole 1 and subsequent reaction with dimethyl carbonate.
Having established the methodology, further transformations of
O
the products were then explored. Thus, treatment of 6i with conc.
HCl in acetone resulted in the formation of pyrrolo[1,2-b]benzoth-
iazepine derivative 7 in 97% isolated yield (Scheme 4). Similarly, 6c
could be converted into the elimination product 8, subsequent
Diels À Alder reaction of which with benzyne afforded benzoindole
derivative 9 in excellent isolated yield.
N
S
O
LDA ( 2eq )
O
CO2Me
N
THF -78 o
6 h, 44%
C
Ts
2
4
Scheme 2. Synthesis of
addition reaction of 2.
4 via ɑ-lithiation-in situ intramolecular nucleophilic
In summary, we have described an efficient ɑ-lithiation-in situ
intramolecular nucleophilic addition reaction sequence toward
the synthesis of annulated sultam derivatives. The reaction can tol-
erate a range of functional groups including enolizable ketones.
Table 1
Optimization of reaction conditions.
OH
Ph
N
S
O
Ph
base
THF
N
O
Ts
O
5a
6a
Entry
Base
Equiv.
Temp. (oC)
Yielda (%)
1
2
3
4
5
6
7
8
9
LDA
NaH
LiH
LiHMDS
iPrMgCl
LDA
LDA
LDA
2.0
2.0
2.0
2.0
2.0
1.5
2.5
2.0
2.0
À78
À78
À78
À78
À78
À78
À78
À60
À40
73
0b
0b
trace
0c
32
41
51
17
LDA
a
b
c
Isolated yield. No reaction occurred. Starting material recovered. Mixture of products. No desired product 6a was obtained.
Table 2
Substrate scope.
X
R1
X
OH
R1
N
S
N
S
O
O
LDA ( 2eq )
THF -78 oC
O
O
O
R2
R2
X = CH, N
5
6
OH
OH
OH
OH
OH
Ph
N
S
O
N
S
O
O
N
S
O
N
S
O
N
S
O
O
O
O
O
O
O
6c
6d
, 51%
6b
, 79%
6e
, 78%
, 47%
OH
6a
, 73%
OH
Ph
N
OH
OH
Ph
OH
Ph
Ph
F
N
S
N
S
N
S
N
S
O
Ph
N
S
O
O
O
O
O
O
O
NO2
, 20%
6h
, 46%
6f
6g
6j
, 32%
, 52%
6i
, 62%
2

C. Zhao and C. Song
Tetrahedron Letters 68 (2021) 152907
HO Ph
S
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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Acknowledgement
We are grateful to Postgraduate Education Reform and Quality
Improvement Project of Henan Province (YJS2021KC03) for finan-
cial support.
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