Stabilized Sulfur Ylide Mediated Cyclopropanations and Formal [4+1] Cycloadditions of 3-Acyl-2H-chromenones and Their Imines

Article abstract of DOI:10.1002/ejoc.201600759

Stabilized sulfur ylide mediated cyclopropanation and formal [4+1] cycloaddition of 3-acyl-2H-chromenones and their imines were explored. The transformations could be performed under mild conditions and were shown to have wide substrate scopes and signifi

Full text of DOI:10.1002/ejoc.201600759

A Journal of
Accepted Article
Title: Stabilized Sulfur Ylide-Mediated Cyclopropanations and Formal [4+1] Cyclo-
additions of 3-Acyl-2H-chromenones and its imines
Authors: Xiang-Suo Meng; Shan Jiang; Xiao-Yun Xu; Qiang-Xian Wu; Yu-Cheng Gu;
De-Qing SHI
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600759
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600759
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European Journal of Organic Chemistry
10.1002/ejoc.201600759
Communications
Stabilized Sulfur Ylide-Mediated Cyclopropanations and Formal [4+1]
Cycloadditions of 3-Acyl-2H-chromenones and its imines
Xiang-Suo Meng,[a] Shan Jiang,[a] Xiao-Yun Xu,[a] Qiang-Xian Wu, [a] Yu-Cheng Gu, [b] De-Qing Shi*[a]
Keywords: Formal [4+1] Cycloaddition / Cyclopropanation / Stabilized Sulfur Ylide / 3-Acyl-2H-chromenone / Imine
A
convenient and efficient stabilized sulfur ylide-mediated
as excellent regio-selectivity, which makes this method powerful
for one-pot synthesis of highly functionalized cyclopropane- and
dihydropyrrole-fused chromen-2-one derivatives.
cyclopropanation and formal [4+1] cycloadditions of 3-acyl-2H-
chromenones and its imines are developed. This transformation
takes advantages of mild condition, wide substrate scope and
significant functional group tolerance as well
derivatives are yielded when unstable or semi-stabilized sulfur
ylides were adopted[10]. To the best of our knowledge, there is only
a few report in the formal [4+1] cycloaddition of α,β-unsaturated
Introduction
imines with stabilized sulfur ylides[7b]
.
Coumarin derivatives received continuing attention due to their
versatile pharmaceutical activities,[1] such as anti-cancer,[1a,1b]
antimicrobial,[1c,1d] antiinflammatory,[1e] selective human dopamine
As mentioned above, due to their versatile annulation routes and
different regio-selectivities, sulfur ylides mediated [2+1] and [4+1]
annulations of α,β-unsaturated ketones or imines can be applied in
the synthesis of potential biologically active compounds. As part of
our ongoing interest in developing concise, convenient and
environmentally benign methods for the synthesis of important
biologically active heterocycles,[11]
D4 antagonists,[1f] lipid peroxidation,[1g] aromatase,[1i] monoamine
1l]
oxidases,[1j] and acetylcholinesterase inhibitors.[1k,
Moreover,
some of coumarin-fused heterocycles possess a variety of
biological activities, which can be used as antiviral agents[2a]
modules of protein tyrosine phosphatases[2b]
modulators of
MetAP2[2c] and flavorants[2d]
So, the methodology for the
,
,
.
1) ¦Á,¦Â-unsaturated ketone substrates
synthesis of novel coumarin-fused heterocyclic compounds attracts
more attention of chemists.
Cyclopropanation routes
O
O
Diam ine (20m ol%)
PhCO2 (20mol% )
O
O
H
R2
R2
+
S
R1
Feng's work
°
CHCl3
,
5A MS
R1
Ref. 9a
COR2
Sulfur ylides have been identified as a versatile one-carbon
synthons and are widely used in epoxidation,[3] cyclopropanation,[4]
and aziridination [5]and other rearrangements for the preparation of
three-membered carbo- and heterocycles. In all cases, the sulfur
ylide initially attacks at an electrophilic carbon center (i.e.,
aldehyde, imine, or Michael acceptor) to form a zwitterionic
intermediates, which undergoes an intramolecular nucleophilic
t-BuOK/THF
-78
CO2Me
R1
C
°
O
CO2M e
S
OH
+
MeO2
C
C
H
Br
R1
R2
Cs2CO3, BTF
O
Ref. 9c
Tang's work
L
10
H2O, 0
°
R1
R2
Ref. 7a
[4+1] annulation route by Tang
R
COMe
COMe
S
CO2Et
Cs2CO3/DMF
displacement to generate an epoxide, an aziridine, or
a
R
+
OH
Br
COMe
EtO2
C
O
cyclopropane, respectively. Recently, sulfur ylides mediated the
domino reactions such as [4+1] and [3+3] cycloadditions were
developed.[6-8] When α,β-unsaturated ketones were used as the
substrates, in some cases, cyclopropane or cyclohexadiene epoxide
derivatives are yielded[9]; However, in other cases, the formal [4+1]
adducts are formed,[7a] which is depicted by Sun and Tang[6e], the
success of these [4+1] routes over competitive [2+1] routes can be
largely attributed to the steric hindrance at the reactive centers. As
for α,β-unsaturated imine substrates, the aziridine or cyclopropane
2) ¦Á,¦Â-unsaturated im ine substrates
Ref. 10
[2+1] annulation routes
Ph
N
Ph
R
R
R'
PG
or
S
+
Ph
N
PG
N
PG
R'
R'
PG=Ts
PG=Ph
Ref. 7b
[4+1] annulation route by Xiao
R2
O
TIPBS
CO2R3
N
COPh
S
PhC
CO2R3
N
+
R2
TIPBS
3) This w ork
O
[a] X. -S. Meng, S. Jiang, X. -Y. Xu, Prof. Q. -X. Wu, Prof. Dr. D.-Q. Shi
Key Laboratory of Pesticide & Chemical Biology
Ministry of Education, College of Chemistry
Central China Normal University
NTs
R2
R2
R3
R1
R3
O
R1
O
O
O
S
R2
4
O
O
NTs
R3
1
152 Luoyu Road, Wuhan, Hubei 430079 (China)
Fax: (+) 86-27-67862041
E-mail: chshidq@mail.ccnu.edu.cn
R1
R2
Cs2CO3(1.0 equ.)
DMF, Room Tem p.
O
O
Cs2CO3(1.0 equ.)
DMF, Room Tem p.
R1
O
O
Br
O
O
2
5
3
[b] Prof. Dr. Y. -C. Gu
Syngenta Jealott’s Hill International Research Centre, Bracknell,
Berkshire RG42 6EY, U.K.
Supporting information for this article is available.
Scheme 1. Sulfur ylides mediated cyclopropanation and [4+1]
annulation of α,β-unsaturated ketones and imines
Submitted to the European Journal of Organic Chemistry
1

European Journal of Organic Chemistry
10.1002/ejoc.201600759
salts 2 (Table 2). Firstly, it was found that a variety of R1
substituted coumarin imine 1 bearing electron-donating (CH3, t-Bu)
or electron-withdrawing groups (Cl, CO2Et) or different substituted
pattern were found to be suitable substrates for the formal [4+1]
annulation, gave the desired products 3a~3f in good to excellent
yields (Table 2, 81%~95% yields). It is worth noting that different
R2 substituted coumarin imines 1 are tolerated and gave the
desired products 3g~3j in 85~95% yields, irrespective of electron-
donating (OCH3, 3j) or electron-withdrawing group substituted
benzene ring (Cl, 3i), or naphthyl or heteroaryl substituted (2-furyl)
ones (3g, 3h).
In this paper, we wish to report a highly regio-selective annulation
between stabilized sulfur ylide with 3-acyl-2H-chromenones and
its imines to structurally diverse cyclopropane- and dihydropyrrole-
fused chromenone derivatives under mild conditions.
Results and Discussion
We began our study by subjecting coumarin imine 1a to
sulfonium salt 2a in the presence of 1.0 equiv. KOH at room
temperature. To our delight, the reaction proceeded smoothly and
gave [4+1] annulation product 3a (yield: 34%) in 15 min. (Table 1,
entry 1). Encouraged by this result, a variety of bases (K2CO3,
Cs2CO3, Et3N, DBU and t-BuOK) were screened (Table 1, entries
2-6), the results indicate that Cs2CO3 is the most suitable base for
the [4+1] annulation. Lowering the amount of Cs2CO3 to 0.5 equiv.
resulted in reducing the yield of 3a (Table 1, entry 7).
Subsequently, the effect of solvents on the [4+1] annulation was
investigated (Table 1, entries 8-12), DMF was proved to be the
best solvent and gave the desired product 3a in the highest yield
(Table 1, entry 11). However, raising or lowering the reaction
temperature could not result in a higher yield of 3a (Table 1,
entries 13-15).
Encouraged by these results, we then evaluated the scope of
sulfonium salts 2 in the formal [4+1] annulation. A series of
sulfonium salts 2 bearing electron-donating (OCH3, Ph) or
electron-withdrawing groups substituted benzoyl (F，Cl, Br, CF3,
NO2) are also suitable candidates for this annulation, affording the
desired products 3k~3q in good to excellent yields (71-90% yield).
Table 2. Substrate scope of sulphur ylide-mediated the formal
[4+1] cycloaddition for the synthesis of 3 [a, b]
R3
NTs
Cs2CO3(1.0 equiv.)
O
S
NTs
R2
+
R3
R1
R2
DMF, Room Temp.
O
Table 1. Optimization of the reaction conditions for regio-selective
synthesis of 3a[a]
R1
O
O
Br
O
O
1
2
3
Ph
NTs
Base (x mol%)
Solvent, Temp.
O
S
NTs
O
+
Ph
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
NTs
O
O
O
NTs
O
NTs
O
NTs
Br
2a
Ph
EtO2
C
Ph
Ph
Ph
O
1a
3a
O
O
O
O
O
3d: 83%
3c: 81%
Entry
Base (equiv.)
Solvent
Temp
(°C)
Time
Yield
Cl
3b: 93%
3a: 95%
(min.)
15
(%)[b]
34
Ph
O
Ph
O
Ph
Ph
O
NTs
O
1
KOH (1.0)
K2CO3 (1.0)
Cs2CO3 (1.0)
Et3N (1.0)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Room
Temp.
Room
Temp.
Room
Temp.
NTs
NTs
O
O
NTs
Ph
Ph
2
30
15
30
30
15
30
15
15
15
15
15
73
92
67
trace
82
85
72
86
78
95
23
O
O
F
O
O
O
Cl
O
O
3h: 92%
3e: 87%
3g: 90%
3f: 83%
3
Ph
Ph
O
O
NTs
O
NTs
4
Room
Temp.
Room
Temp.
Room
Temp.
Room
Temp.
Room
Temp.
Room
Temp.
Room
Temp.
Room
Temp.
Room
Temp.
-15°C
0°C
O
O
NTs
O
NTs
OCH3
Cl
Ph
Ph
5
DBU (1.0)
O
O
O
O
3j: 85%
O
O
3i: 95%
3l: 87%
3k: 88%
6
t-BuOK (1.0) CH2Cl2
Ph
CF3
Br
NO2
OCH3
7
Cs2CO3 (0.5)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
CH2Cl2
toluene
CH3CN
THF
O
O
O
O
O
NTs
NTs
8
NTs
O
NTs
NTs
O
Ph
Ph
Ph
Ph
Ph
9
O
O
O
O
O
O
O
O
3o: 90%
3q: 73%
3p: 82%
3n: 71%
3m: 80%
10
11
12
DMF
Ethanol
aUnless otherwise noted, reactions were carried out with 1 (0.50
mmol), 2 (0.55 mmol), Cs2CO3(0.5 mmol) in DMF (4.0 mL) at
room temperature under N2 atmosphere. bIsolated yield based on 1.
13
14
15
Cs2CO3 (1.0)
Cs2CO3 (1.0)
Cs2CO3 (1.0)
DMF
DMF
DMF
30
30
15
75
81
88
40°C
Next, we turn our attention to the annulation of sulfonium salt 2a
and 3-benzoyl-2H-chromenone 4a, to our surprise, the
cyclopropanation products 5a was obtained in 93% yield in the
optimized reaction condition. Experiments that probed the
generality of the cyclopropanations were also performed. As
summarized in Table 2, the reaction displays a broad scope for
sulfonium salts 2 and 3-acyl-2H-chromenones 4, and excellent
[a] Unless otherwise noted, the reaction condition is: under a N2
atmosphere, 1a (0.5 mmol), 2a (0.55 mmol), an amount of base in the
solvent (4.0 mL). [b] Isolated yield based on 1a.
The optimized reaction conditions [imine (0.5 mmol), sulfonium
salt (0.55 mmol), 1.0 equiv. of Cs2CO3 in 4 mL of DMF at room
temperature under a N2 atmosphere] were applicable to the formal
[4+1] annulation of coumarin imine derivatives 1 with sulfonium
regio-selectivity are achieved. Firstly,
various 3-acyl-2H-
chromenones 4 having electron-rich (Table 3, 5c, 5e, 5f), electron-
neutral (Table 3, 5a and 5g) and electron-deficient (Table 3, 5b,
5d, 5h and 5i) R1 substituents or different substituted pattern were
Submitted to the European Journal of Organic Chemistry
2

European Journal of Organic Chemistry
10.1002/ejoc.201600759
explored, the results indicated that the electronic nature of
substituents have not remarkably affected the yields of the desired
cyclopropanation products (Table 3, 5a~5i, 85%~93% yields).
Subsequently, substrates 4 with different R2 substituents are also
compatible for this annulations (Table 3, 5j~5n), it is also worth
noting that introduction of 2-furyl or naphthyl substitutents (Table
3, 5k and 5m) also furnish the desired products in excellent yields.
Additionally, a variety of sulfonium salts were also investigated to
be suitable substrates for this reaction. For instance, sulfonium salts
with either an electron-donating or -withdrawing substituent at the
para-position of the benzene ring react well in this process,
affording products with 86-90% yields (Table 3, 5o, 5p, 5q, 5s). It
is also worth noting that sulfonium salts bearing substituents at the
ortho- or meta-position on the benzene ring were also well
tolerated (Table 3, 5r and 5t).
Michel addition, keto-enol tautomerism, followed by the carbon
SN2 attack and the release of dimethyl sulfide.
NTs
Ph
Ph
Ph
S
S
O
O
Br
Ph
O
NTs
Ph
O
NTs
Ph
Base
S
1a
S
Ph
O
Michael addition
O
O
O
O
O
2a
Ph
SN2 attack
A
B
O
O
Me2S
O
NTs
O
Ph
Ph
O
4a
O
Ph
3a
Ph
O
S
S
Ph
O
O
O
O
O
O
O
O
SN2 attack
Ph
Ph
Ph
Table 3. Substrate scope of sulphur ylide-mediated
cyclopropanation for the synthesis of 5 [a, b]
O
O
O
Me2S
D
C
5a
R3
O
O
R2
Scheme 2. The plausible mechanism for the sulfur ylide-mediated
cyclopropanation and formal [4+1] annulation
Cs2CO3(1.0 equiv.)
DMF, Room Temp.
S
R2
R3
+
R1
R1
Br
O
O
O
O
O
O
4
2
5
Conclusions
Ph
O
Ph
Ph
Ph
O
O
O
In summary, we developed a convenient and efficient method for
one-pot synthesis of highly functionalized cyclopropane- and
dihydropyrrole-fused chromen-2-one derivatives via a stabilized
sulfur ylide-mediated cyclopropanation and formal [4+1]
cycloaddition with 3-acyl-2H-chromenones and its imine
derivatives in moderate to excellent yields, respectively. A possible
mechanism was suggested based on our experimental results and
the related literature.
Ph
Ph
Ph
Ph
Cl
O
O
O
O
O
O
O
O
O
O
O
O
Cl
5d: 85%
Cl
5b: 88%
5c: 89%
5a: 93%
Ph
Ph
Ph
Ph
O
O
O
O
Ph
Ph
Ph
Ph
H3CO
Cl
O
O
O
O
O
O
O
O
O
O
O
O
5e: 87%
5g: 88%
5f: 90%
5h: 92%
Supporting Information (see footnote on the first page of this article):
General Remarks, General procedure and Copies of 1H, 13C NMR spectra of
all new products 3 and 5.
O CH3
Br
O
Ph
O
O
Ph
Ph
Ph
O
O
O
Ph
EtO2
C
O
O
O
O
O
O
O
O
O
O
O
5l: 87%
5k: 88%
5i: 87%
5j: 85%
Acknowledgments
Cl
O
O
O
H3CO
O
F3
C
Ph
Ph
We are grateful to the National Natural Science Foundation of China (No.
21342004 and 51573066), and the Syngenta Ph.D. (postgraduate) program
for support of this research.
Ph
O
Ph
O
O
O
O
O
O
5p:89%
O
O
O
O
O
5m : 85%
5n: 91%
F
____________
5o: 90%
O2N
F
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O
Ph
O
O
Ph
O
Ph
Ph
O
Ph
O
O
O
O
O
O
O
O
O
O
5q: 86%
5r: 84%
5t: 79%
5s: 86%
aUnless otherwise noted, reactions were carried out with 4 (0.50
mmol), 2 (0.55 mmol), Cs2CO3(0.5 mmol) in DMF (4.0 mL) at
room temperature under N2 atmosphere. bIsolated yield based on 4.
Based on our experimental results and the related literature, [12]
a
plausible reaction mechanism has been proposed (Scheme 2). For
the formal [4+2] annulation, firstly, Michael addition of coumarin
imine 1a with Sulfur ylide, which formed from the deprotonation
of the corresponding sulfonium salt, generated intermediate A,
which could isomerize to B via a keto-enol tautomerism. Then, the
formal [4+1] annulation product 3a was obtained by the
intramolecular nitrogen SN2 attack with the release of dimethyl
sulfide. Meanwhile, the cyclopropanation route also involves the
Submitted to the European Journal of Organic Chemistry
3

European Journal of Organic Chemistry
10.1002/ejoc.201600759
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[5] For selected examples, a) X.-F. Yang, M.-J. Zhang, X.-L. Hou, L.-X.
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11951-11966
[6] For the reviews about sulfur Ylide-mediated cascade reactions, see: a)
a) B. M. Trost, L. S. Melvin, sulfur Ylides; Academic Press: New York,
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Huang, R.-Y. Chen, J. Org. Chem. 2011, 76, 7699-7705.
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[9] a) J. Wang, X. Liu, S. Dong, L. Lin, X. Feng, J. Org. Chem. 2013, 78,
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867; e) D. Morton, D. Pearson, R. A. Field, R. A. Stockman, Org. Lett.
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D.-Q. Shi, Eur. J. Org. Chem. 2014, 583–591
Submitted to the European Journal of Organic Chemistry
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European Journal of Organic Chemistry
10.1002/ejoc.201600759
Entry for the Table of Contents ((Please choose one layout.))
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((Key Topic))
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NTs
Xiang-Suo Meng, Shan Jiang, Xiao-
Yun Xu, Qiang-Xian Wu, Yu-Cheng
Gu, De-Qing Shi*
R2
R3
R1
R2
R3
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R2
R1
O
O
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S
4
O
O
NTs
O
R3
1
R1
R2
Cs2CO3(1.0 equ.)
DMF, Room Temp.
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Cs2CO3(1.0 equ.)
DMF, Room Temp.
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3
Stabilized
Cyclopropanations and Formal [4+1]
Cycloadditions of 3-Acyl-2H-
chromenones and its imines
Sulfur
Ylide-Mediated
A convenient and efficient stabilized
sulfur ylide-mediated cyclopropanation
and formal [4+1] cycloadditions of 3-
acyl-2H-chromenones and its imines are
developed. This transformation takes
advantages of mild condition, group
tolerance as wide substrate scope and
significant functional well as excellent
regioselectivity, which makes this
method powerful for one-pot synthesis of
highly functionalized cyclopropane- and
Keywords: Formal [4+1] cycloaddition
/ Cyclopropanation / Stabilized Sulfur
Ylide / 3-Acyl-2H-chromenone / imine
dihydropyrrole-fused
derivatives.
chromen-2-one
Submitted to the European Journal of Organic Chemistry
5

European Journal of Organic Chemistry
10.1002/ejoc.201600759
Submitted to the European Journal of Organic Chemistry
6