[3 + 2]-Annulation of Prop-2-ynylsulfonium Salts: Access to Hydroindol-5-ones Containing a Methylthio Group

Article abstract of DOI:10.1021/acs.orglett.6b03667

An unprecedented [3 + 2]-annulation of prop-2-ynylsulfonium salts and p-quinamines was developed, affording a series of hydroindol-5-ones with a methylthio group in moderate to good yields under mild conditions. In this reaction, the prop-2-ynylsulfonium

Full text of DOI:10.1021/acs.orglett.6b03667

Letter
pubs.acs.org/OrgLett
[3 + 2]-Annulation of Prop-2-ynylsulfonium Salts: Access to
Hydroindol-5-ones Containing a Methylthio Group
Penghao Jia,† Qinglong Zhang,† Hongxing Jin,† and You Huang*,†,‡
†State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai University, Tianjin 30071, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 30071, China
S
* Supporting Information
ABSTRACT: An unprecedented [3 + 2]-annulation of prop-2-
ynylsulfonium salts and p-quinamines was developed, affording a
series of hydroindol-5-ones with a methylthio group in moderate
to good yields under mild conditions. In this reaction, the prop-2-
ynylsulfonium salt acts as a novel C2 synthon and sulfide does not
serve as a leaving group, which provides facile access to
organosulfur compouds.
ydroindol-5-one scaffolds exist widely in the polycyclic
Scheme 2. Application of Vinylsulfonium Salts as C2
Synthons
H
alkaloids isolated from medicinal herbs. Hasubanan and
acutumine alkaloids are representative examples (Scheme 1).1
Scheme 1. Representative Polycyclic Alkaloids Containing
Hydroindol-5-one Scaffolds
heterocycles containing nitrogen and oxygen atoms can be
constructed (Scheme 2, eq 3).7 For all the reactions mentioned
above, vinylsulfonium salts are directly used or generated in
situ. Therefore, the development of new kinds of sulfur ylides
as C2 synthons and their applications in more reaction types are
underexplored.
It has been reported that prop-2-ynylsulfonium salts could
transform into allenic sulfonium salts and react with enolate
anions of β-diketones to afford substituted furans (Scheme 3).8
Inspired by their previous work and on the basis of our
continuous interest in exploring new reactions of sulfur ylides,9
we developed a novel [3 + 2]-annulation reaction10 of prop-2-
ynylsulfonium salts and p-quinamines11 to generate S-
containing hydroindol-5-ones. In this reaction, sulfide does
not serve as leaving group compared with traditional reactions
of sulfur ylides, which provides the possibility for the
These densely functionalized small molecules exhibit promising
biological properties. For example, acutumine alkaloid has
selective T-cell cytotoxicity and antiamnesic activity.2 There-
fore, the synthesis of such structures has been of interest to the
chemical community for many years.3
As C1 synthons, sulfur ylides have been widely used as
methylene-transfer reagents in the construction of three-
membered ring compounds with C = X (X = C, N, O, etc.)
double bonds.4 In recent years, Aggarwal’s, Xiao’s, and other
groups have reported the significant application of sulfur ylides
as C2 synthons. According to their research, vinylsulfonium
salts could react with active methylene compounds containing
electron-withdrawing groups to give substituted cyclopropane
derivatives (Scheme 2, eq 1).5 Upon reaction with α-, β-, and γ-
aminoaldehydes, hydroxyaldehydes, or similar olefins or imines,
epoxide-, cyclopropane-, or aziridine-fused heterocycles can be
obtained, which also provides a key strategy for the total
synthesis (Scheme 2, eq 2).6 When amino alcohols or diamines
are used in the reaction with vinylsulfonium salts, a series of
Received: December 9, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03667
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Organic Letters
Letter
products, among which DCE gave the best yield of 72% of 3a
with a trace amount of 4a (Table 1, entry 10). Lowering the
reaction temperature to 10 °C gave a lower yield of 69% (Table
1, entry 13). Changing the loading of prop-2-ynylsulfonium salt
2a and bases did not give better yields (Table 1, entries 14−
17).
Scheme 3. Reactions of Prop-2-ynylsulfonium Salts
The generality of this prop-2-ynylsulfonium salts involved [3
+ 2]-cycloaddition reaction was examined. As summarized in
Scheme 4, a wide range of p-quinamines can be employed in
a,b
Scheme 4. Scope of the Reactions
construction of organosulfur compounds with biological and
chemical properties.12
At the outset of this investigation, we employed p-quinamine
1a with prop-2-ynylsulfonium salt 2a in the presence of
Cs2CO3 (2 equiv) in CH3CN at room temperature. The
reaction gave the [3 + 2]-annulation product 3a in 41% yield as
well as N-methyl product 4a in 17% yield after 3 h (Table 1,
entry 1). When the reaction time was extended to 24 h,
pleasingly, the yield of 3a improved to 53% (Table 1, entry 2).
Subsequent screening of bases showed that K2CO3 could give a
better yield of 58% (Table 1, entries 3−8). Solvents such as
DCM, DCE, DBM, and CHCl3 all proceeded with the desired
a
Table 1. Screening of the Reaction Conditions
b
yield (%)
entry
base
solvent
time (h) 1a/2a/base
3a
4a
17
1
Cs2CO3
Cs2CO3
K2CO3
Et3N
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
3
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:1.5:2
1:3:2
1:2:1.5
1:2:3
41
53
58
52
26
49
41
43
68
72
59
52
69
68
67
68
73
2
18
3
13
4
NP
5
DABCO
K3PO4
NaOH
KOH
trace
28
6
7
15
a
Reactions of 1 (0.20 mmol) and 2a (0.40 mmol) were carried out in
8
22
the presence of K2CO3 (0.40 mmol) in 2 mL of 1,2-dichloroethane.
9
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
trace
trace
trace
trace
NP
b
Isolated yields are shown.
10
11
12
DCE
DBM
CHCl3
DCE
this transformation. p-Quinamines bearing either electron-rich
or electron-deficient substituents at the para and meta position
of the benzene ring were well-tolerated, producing the desired
products in good to high yields (3b−i). However, when p-
quinamine with Me at the ortho position of the benzene ring
was employed in the reaction, a reduced yield of 26% was
obtained, probably because of steric hindrance (3j). Substrates
1 with a 3,5-bis(trifluoromethyl)-substituted phenyl ring could
also be transformed into the corresponding product in 67%
c
13
14
15
16
17
DCE
trace
trace
trace
trace
DCE
DCE
DCE
a
Unless otherwise noted, reactions of 1a (0.20 mmol) and 2a were
b
c
carried out in 2 mL of the solvent at 20 °C. Isolated yields. The
reaction temperature was 10 °C.
B
DOI: 10.1021/acs.orglett.6b03667
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Letter
yield (3k). Further investigation showed that p-quinamines
bearing naphthyl groups or a biphenyl group (3l−n) were also
efficient for the transformation. Different alkyl groups were also
introduced into substrates 1. The yields decreased with the
increase of the chain R1 length because of steric hindrance
(3o−q). The protecting group of the sulfamide functional
group could also be changed and worked well in the reaction
(3r−t). p-Quinamine with R3 = Cl was also a suitable substrate
for this conversion, producing the corresponding cycloaddition
product in moderate yield (3u).
Scheme 6. Gram-Scale Synthesis and Further
Transformation of 3f
To further broaden the scope of the reaction, tetrahydro-
thiophene sulfonium salt 2b was employed in the reaction in
the presence of K2CO3 in dichloromethane at room temper-
ature. Ring-opened product 3v with a Br atom at the terminal
of the chain was obtained in 59% yield (Scheme 5). The
structure and stereochemistry of 3v were characterized by a
combination of NMR, HRMS, and single-crystal X-ray
analysis.13
Scheme 5. Reaction of 1a and 1-(Prop-2-yn-1-yl)tetrahydro-
1H-thiophene-1-ium Bromide
Scheme 7. Plausible Reaction Mechanism
To investigate the synthetic utility of this reaction, a gram-
scale version of the reaction using substrates 1f and 2a was
carried out, and compound 3f was obtained in 70% yield
(Scheme 6). Some transformations were conducted using
product 3f. Upon treatment of 3f with LiAlH4 in Et2O,
reduction product 5 was generated in 83% yield with 5:1
diastereoselectivity. Moreover, product 3n could also be
obtained from 3f via a Suzuki cross-coupling reaction in 85%
yield.
A possible mechanism is depicted in Scheme 7. Prop-2-
ynylsulfonium salt 2a first isomerizes into allenic sulfonium salt
2a′. Conjugate addition of the N anion to 2a′ generates
intermediate A, which then undergoes intramolecular nucleo-
philic addition to form intermediate B. Subsequent protonation
of B give intermediate C. The methyl group of the Me2S
sulfonium would be attacked by Br− to yield intermediate D,14
which then undergoes double-bond isomerization to afford the
final product 3. The Br− of MeBr proceeds via nucleophilic
substitution by the N anion to generate N-methyl product 4.
In conclusion, we have developed a method to construct
hydroindol-5-ones containing a methylthio group via [3 + 2]
annulation of prop-2-ynylsulfonium salts and p-quinamines.
Prop-2-ynylsulfonium salts can isomerize into allenic sulfonium
salts and act as a novel C2 sython in the reaction, which
broadens the chemistry of sulfur ylides. Moreover, sulfides do
not serve as leaving groups compared with traditional reactions,
which provides access to organosulfur compounds. Further
studies applying this method to the synthesis of molecules with
biological activity are underway in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03667.
C
DOI: 10.1021/acs.orglett.6b03667
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Experimental details, characterization data for new
Letter
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Crystallographic data for 3v (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hyou@nankai.edu.cn.
ORCID
You Huang: 0000-0002-9430-4034
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(21472097 and 21672109) and the Natural Science Foundation
of Tianjin (15JCYBJC20000).
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