Base-Catalyzed Selective Synthesis of 2-Azabicyclo[3.2.0]hept-2-enes and Sulfonyl Vinyl-Substituted Pyrroles from 3-Aza-1,5-enynes

Article abstract of DOI:10.1021/acs.orglett.5b01474

A base-catalyzed selective cycloisomerization of 3-aza-1,5-enynes is developed. This transformation provides a facile access to highly functionalized 2-azabicyclo[3.2.0]hept-2-enes and sulfonyl vinyl-substituted pyrroles. The chemoselectivity was controll

Full text of DOI:10.1021/acs.orglett.5b01474

Letter
pubs.acs.org/OrgLett
Base-Catalyzed Selective Synthesis of 2‑Azabicyclo[3.2.0]hept-2-enes
and Sulfonyl Vinyl-Substituted Pyrroles from 3‑Aza-1,5-enynes
Xiaoyi Xin, Haolong Wang, Xincheng Li, Dongping Wang, and Boshun Wan*
Dalian Institute of Chemical Physics, Chinese Academy of Sciences, 457 Zhongshan Road, Dalian 116023, China
S
* Supporting Information
ABSTRACT: A base-catalyzed selective cycloisomerization of 3-aza-1,5-enynes is developed. This transformation provides a
facile access to highly functionalized 2-azabicyclo[3.2.0]hept-2-enes and sulfonyl vinyl-substituted pyrroles. The chemoselectivity
was controlled by the substituent pattern of the substrates.
Scheme 2. Summary for Approaches
ycloisomerization of enynes has emerged as a powerful
1
Cstrategy for the synthesis of heterocycles and carbocycles.
Higher levels of molecular complexity and better functional
group compatibilities can be achieved from relatively simple
and readily accessible starting materials. In most cases,
transition-metal catalysts were usually essential. In terms of
the product patterns, five- or six-membered monocyclic and
cyclopropane-bridged bicyclic compounds were the most
common products.1 Herein, we report a transition-metal-free
synthesis of densely functionalized 2-azabicyclo[3.2.0]hept-2-
enes and sulfonyl vinyl-substituted pyrroles from 3-aza-1,5-
enynes (Scheme 1).
Scheme 1. Cycloisomerization of 3-Aza-1,5-enynes
2-Azabicyclo[3.2.0]hept-2-ene is a unique kind of bicyclic
heterocycle.2 The limited reports on their synthesis are divided
into the following five methods: (1) thermal decomposition of
1-azido-4-methylcubane in CD3OD (Scheme 2a);3 (2) [2 + 2]
cycloaddition of dioxopyrroline with alkenes (Scheme 2b);4 (3)
Cu-catalyzed cycloisomerization of alkynyl imines (Scheme
2c);5 (4) thermal cyclization of aza-trienes at 220 °C (Scheme
2d);6 and (5) reaction of vinyl aziridines with dimethyl
acetylenedicarboxylate (DMAD) (Scheme 2e).7 Meanwhile,
vinyl sulfones are important sulfur-containing functional groups
and have found widespread applications in biological research
and drug design.8 The synthetic procedures for the
construction of vinyl sulfones often require toxic or unstable
starting materials and several steps.9 The method in this work
provides a straightforward strategy where α-substituted vinyl
sulfone functional groups and pyrrole rings10 are built
simultaneously in one step.
In the course of our continuous transformation of the six-
atom skeleton of 3-aza-1,5-enynes to diverse heterocycles and
carbocycles,11 we reasoned that if one additional exploitable
CH2 group (C7 in substrates 1 and 3, Scheme 1) existed in the
previous framework then the newly added carbon atom may be
Received: May 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01474
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Letter
incorporated into the product skeleton, thus leading to more
complex heterocycles. We initiated our study with aza-enyne 1a
(see Table 1 for structure) as model substrate to test its
We also carried out the experiment on a larger scale (eq 1).
Besides the major product 2a, its stereoisomer 2a′ (two groups
a
Table 1. Substrate Scope and Limitations
at the C6 and C7 position are in a syn relationship; see the
Supporting Information) was also obtained albeit in very low
yield (4%).
To probe the reaction mechanism, deuterium-labeling
experiments were carried out (Scheme 3). Substrate deuterated
b
entry
1
R1
R2
R3
2, yield (%)
1
1a
1b
1c
1d
1e
1f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
4-MeC6H4
Ph
2a, 56
2b, 41
2
4-MeC6H4
2-MeOC6H4
4-FC6H4
2-ClC6H4
3-ClC6H4
4-BrC6H4
2-CF3C6H4
2-naphthyl
Ph
c
Scheme 3. Mechanistic Studies
3
2c, −
4
2d, 44
2e, 35
2f, 45
2g, 54
5
6
7
1g
1h
1i
d
8
2h, 13
9
2i, 54
2j, 45
2k, 56
2l, 40
10
11
12
13
14
15
16
17
18
19
20
21
1j
4-MeC6H4
1k
1l
Ph
4-MeOC6H4
Ph
nBu
nBu
4-FC6H4
e
1m
1n
1o
1p
1q
1r
1s
1t
Ph
2m, -
e
nPr
Et
nPr
2n, -
f
Ph
2o, 52
Ph
2p, 51
2q, 34
Ph
Bn
c
Ph
Cl
2r, -
4-FC6H4
2-ClC6H4
Ph
Ph
2s, 50
2t, 43
2u, 25
Ph
Ph
at the C4-position (1a-D1) was subjected to the standard
reaction conditions, and the D atom was incorporated
completely into the C6-position of the product (2a-D1)
(Scheme 3a). One of the two D atoms at the C7 position (1a-
D2) appeared at C7 position of the product (2a-D2) with no
deuterium scrambling, and another D atom at C7 position was
incorporated at the C5 position of 2a-D2 with scrambling of
the D atom (Scheme 3b). Substrate deuterated at the C1-
position (1o-D) was also subjected to the standard reaction
conditions, and the D atom was incooporated into the C1-
position of the product (2o-D) without any scrambling
(Scheme 3c).
A plausible reaction mechanism for the formation of 2-
azabicyclo[3.2.0]hept-2-enes based on the deuterium-labeling
experiments is depicted in Scheme 4. The base (Cs2CO3)
abstracts one of the two protons (marked as Hb) at C7-position
of reactant 1 to form the allene intermediate B. It is competitive
that abstraction of a proton of reactant 1 by the base at C4- and
C7-position. The proton at C4-position is more acidic but has
more steric hindrance. In contrast, the proton at C7-position is
less acidic yet has less steric hindrance. The proton abstraction
occurs at the C7-position is favorable probably because steric
hindrance factor is dominant. The [2 + 2] cycloaddition
between the akene and one of the double bonds in the allene
moiety of B gives the heterocyclic itermediate C. Then [1,3]-
shift of the H atom at C4-position (marked as Ha) to form the
intermediate D (Ha appears at C6-position in D). Finally, [1,3]-
sulfonyl migration generates the 2-azabicyclo[3.2.0]hept-2-ene
2. The overall outcome is that Ha at C4-position of the starting
material appears at the C6-position of the product, Hb connects
1u
Ph
4-NO2C6H4
a
Reaction conditions: 1 (0.4 mmol), Cs2CO3 (20 mol %), DMSO (8
b
c
mL), argon atmosphere, 100 °C, 24 h. Isolated yields. Very
complicated mixtures; the desired product was not successfully
d
e
f
isolated. 0.8 mmol scale. No reaction. 1.0 mmol scale.
reactivity. To our delight, 2-azabicyclo[3.2.0]hept-2-ene 2a was
obtained. The structure of 2a was unambiguously confirmed by
X-ray crystal diffraction analysis (see the Supporting
Information). Sulfonyl group migration11a,12 was observed in
this reaction. After screening of catalysts, solvents, and reaction
temperatures, the following reaction conditions were chose as
the optimized reaction conditions: 20 mol % of Cs2CO3 as
catalyst, DMSO as solvent, under 100 °C for 24 h (see Table
S1 in the Supporting Information for details).
With the optimized reaction conditions in hand, we then
directly investigated the scope of this transformation (Table 1).
Both electron-deficient and electron-rich groups on aromatic
groups (R1) were tolerated in this reaction, giving low to
moderate yields (13%−56%, entries 1−8). Unfortunately, 2-
MeO-substituted substrate 1c gave very complicated mixtures,
and the desired products were not successfully isolated (entry
3). 2-CF3-substituted 1h gave very low yield (entry 8). A fused
ring was also suitable in this reaction (entry 9). The alkyl (R1)
substrates did not react under the standard condations with
recovery of the starting materials 1m and 1n (entries 13 and
14). Aryl and alkyl groups (R2) were both tolerated (entries
10−12 and 15−17). The Cl-substituted 1r also yielded a very
complicated mixture (entry 18). When R3 was 4-NO2C6H4, a
relatively lower yield was obtained (entry 21 versus entry 1).
B
DOI: 10.1021/acs.orglett.5b01474
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Letter
withdrawing groups (entries 4−8) were well tolerated, and the
desired products were isolated with moderate to high yields. A
fused ring was also suitable for this process (entry 9). The
electronic properties of the sulfonyl group (R3) had a relatively
small impact on the yield (entries 4, 10, and 11).
Scheme 4. Proposed Mechanism for the Formation of 2
The proposed mechanism for the formation of pyrrole 4 is
described in Scheme 5. The propargyl moiety of 3 is
Scheme 5. Proposed Mechanism for the Formation of 4
to the C5, and Hc and Hd remain connected to the same carbon
atoms, C7 and C1, respectively. This illustrates well the D-
incorporated experiments (Scheme 3).
Along with the study went through, we found that phenoxy-
substituted aza-enyne 3 could generate a new kind of
heterocycle, 4-(1-sulfonylvinyl)-2-(trifluoromethyl)-1H-pyrrole
4, which contains a vinyl sulfone functional group (see Table 2
a
Table 2. Scope of the Synthesis of Pyrrole 4
transformed into allene F first. Cyclization of F generates
intermediate G. An ion pair H is formed through N−S bond
cleavege. The recombination of the cation and the anion of H
results in the formation of the C−S bond of I, and then I
aromatized to pyrroles J.11a Finally, pyrrole J eliminates phenol
to afford the double bond of product 4.
In summary, we have developed diverse transition-metal-free
methods to transform the aza-enyne building blocks to 2-
azabicyclo[3.2.0]hept-2-enes and sulfonyl vinyl functionalized
pyrroles under mild conditions. The chemoselectivity was
controlled by the substituent pattern of the substrates. These
distinctive reaction pathways and the structural novel products
maybe will bring new opportunities to the chemistry of enyne
cycloisomerization. Further mechanism research on the
formation of 2-azabicyclo[3.2.0]hept-2-enes and sulfonyl vinyl
functionalized pyrroles is currently underway.
b
entry
3
R1
R3
4
yield (%)
1
3a
3b
3c
3d
3e
3f
Ph
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
C6H5
4a
4b
4c
4d
4e
4f
88
69
53
86
85
78
62
86
79
85
83
2
4-CH3C6H4
2-CH3OC6H4
4-FC6H4
3
4
5
2-ClC6H4
4-BrC6H4
4-IC6H4
6
7
3g
3h
3i
4g
4h
4i
8
2-CF3C6H4
1-naphthyl
4-FC6H4
9
ASSOCIATED CONTENT
■
10
11
3j
4j
S
* Supporting Information
3k
4-FC6H4
4-ClC6H4
4k
a
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01474.
Reaction conditions: 3 (0.4 mmol), Cs2CO3 (20 mol %), DMF (4
b
mL), argon atmosphere, 100 °C, 4 h. Isolated yields.
X-ray crystallographic data for 2a (CIF)
X-ray crystallographic data for 2a′ (CIF)
X-ray crystallographic data for 2o (CIF)
X-ray crystallographic data for 3a (CIF)
X-ray crystallographic data for 4a (CIF)
Experimental procedures, characterization data, copies of
NMR spectra (PDF)
for structures). The structure of 4a was also unambiguously
confirmed by X-ray crystal diffraction analysis (see the
Supporting Information). And sulfonyl group migration11a,12
also occurred in this reaction. After screening of solvents and
reaction temperaturs using Cs2CO3 (20 mol %) as catalyst and
3a as model substrate, the optimal conditions were chose as
following: DMF as solvent, under 100 °C for 4 h (see Table S2
in the Supporting Information for details).
AUTHOR INFORMATION
Corresponding Author
■
We directly investigated the scope of this reaction (Table 2).
Aryl R1 groups bearing electron-neutral groups (entry 1),
electron-donating groups (entries 2 and 3), and electron-
* bswan@dicp.ac.cn
C
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Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(b) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.; Gevorgyan, V. Chem.
Rev. 2013, 113, 3084. (c) Joshi, S. D.; More, U. A.; Kulkarni, V. H.;
Aminabhavi, T. M. Curr. Org. Chem. 2013, 17, 2279. (d) Liu, T.; Fu,
Notes
The authors declare no competing financial interest.
H. Synthesis 2012, 44, 2805. (e) Estev
́
ez, V.; Villacampa, M.;
ACKNOWLEDGMENTS
This work was supported by NSFC (21172218).
Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402.
́
■
(11) (a) Xin, X.; Wang, D.; Li, X.; Wan, B. Angew. Chem., Int. Ed.
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Chem. 2013, 78, 4065. (c) Xin, X.; Wang, D.; Wu, F.; Wang, C.; Wang,
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D
DOI: 10.1021/acs.orglett.5b01474
Org. Lett. XXXX, XXX, XXX−XXX