Efficient and general synthesis of oxazino[4,3-a]indoles by cascade addition-cyclization reactions of (1H-indol-2-yl)methanols and vinyl sulfonium salts

Article abstract of DOI:10.1039/c0cc03823g

An efficient and general approach to oxazino[4,3-a]indole architectures is described. The addition-cyclization cascade of (1H-indol-2-yl)methanols with vinyl sulfonium salts affords oxazino[4,3-a]indole derivatives in high yields.

Full text of DOI:10.1039/c0cc03823g

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Efficient and general synthesis of oxazino[4,3-a]indoles by cascade
addition-cyclization reactions of (1H-indol-2-yl)methanols and vinyl
sulfonium saltsw
Jing An, Ning-Jie Chang, Li-Dong Song, Yu-Qin Jin, Ying Ma, Jia-Rong Chen* and
Wen-Jing Xiao*
Received 13th September 2010, Accepted 16th November 2010
DOI: 10.1039/c0cc03823g
An efficient and general approach to oxazino[4,3-a]indole
architectures is described. The addition-cyclization cascade of
(1H-indol-2-yl)methanols with vinyl sulfonium salts affords
oxazino[4,3-a]indole derivatives in high yields.
to low yields. Thus, it is necessary to develop more efficient
and straightforward approaches to oxazino[4,3-a] indoles.
In terms of reaction efficiency, cascade or tandem reactions have
been established as powerful tools for the rapid assembly of
complex polycyclic architectures.9 Notably, vinyl sulfonium salts10
have been identified as valuable and versatile intermediates. For
instance, Aggarwal and co-workers11 described an excellent epoxy-
annulation cascade, affording five-, six-, and seven-membered
epoxide-fused heterocycles from diphenyl vinyl sulfonium salts
and amido aldehydes/ketones.11a–c In addition, they further
developed a concise strategy for the synthesis of morpholines,
thiomorpholines, and piperazines from readily available amino
alcohols/thiols/amines and vinyl sulfonium salts.11d,e
Fused indole moieties are widely present as important structural
units in diverse naturally occurring alkaloids, pharmaceuticals
and agrochemicals.1 N-Fused indoles are particularly important
because of their remarkable biological properties across a broad
spectrum of pharmacological screens. For example, 1,2,3,4-tetra-
hydropyrazino[1,2-a]indoles 1 have been shown to be powerful
5-HT2C receptor ligands and 5-HT4 receptor antagonists.2 It has
also been found that 3,4-dihydro-1H-[1,4]oxazino[4,3-a]indoles 2
exhibit potent antidepressant activity,3a and notably antitumor
activities (Scheme 1).3b
As part of our ongoing program on carbo- and heterocycle
oriented methodology development,12 we herein describe an
efficient synthesis of oxazino[4,3-a]indoles by means of a cascade
addition-cyclization reaction of (1H-indol-2-yl)methanols and
vinyl sulfonium salts.
Despite their remarkable biological importance, the synthesis of
this type of N-fused indole remains a significant challenge in
organic chemistry.1c,4 Methodology based on ring closure
including intramolecular alkylations, radical cyclizations and
trans-annulation reactions, has been the most prevalent over the
past decades.5 Recently, Bandini and Umani-Ronchi6 have
elegantly disclosed a novel catalytic strategy for the preparation
of 3,4-dihydropyrazino[1,2-a]indol-1(2H)-ones by means of
aza-Michael reactions of a,b-unsaturated esters. Akiyama and
co-workers7 have developed a direct catalytic C–H carbenoid
insertion approach to generate various N-fused indoles with a
range of cyclic amino sub-structures. However, in contrast to
numerous publications concerning the synthesis of pyrazino[1,2-a]-
indoles,2,6 the development of efficient methods to construct
oxazino[4,3-a] indoles has been the subject of relatively few
investigations.3,8 Conventional synthesis of oxazino[4,3-a]-
indoles usually requires several synthetic steps, in moderate
We began our investigation by examining the reaction of
(1H-indol-2-yl)methanol 3a and diphenyl vinyl sulfonium
triflate 4. As shown in Table 1, the choice of base was
important to this cascade process, and the reaction did not
take place in the absence of base (Table 1, entry 1). After
screening several organic and inorganic bases, potassium
hydroxide was found to give the best results (Table 1, entries
2–5). A simple survey of solvents revealed that the reaction
media had a significant effect on the reaction efficiency. The
variation of solvent from CH2Cl2 to ClCH2CH2Cl or CH3CN
led to decreased yields (Table 1, entries 5–7). The reaction
Table 1 Optimization of the reaction conditionsa
Entry
Base
Equiv.
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
9
10
—
—
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
ClCH2CH2Cl
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
—
39
71
63
83
77
58
93
84
64
Scheme 1 Examples of N-fused indole derivatives.
DBU
NaH
tBuOK
KOH
KOH
KOH
KOH
KOH
KOH
3.0
3.0
3.0
3.0
3.0
3.0
2.5
2.0
1.0
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University,
152 Luoyu Road, Wuhan, Hubei 430079, China.
E-mail: wxiao@mail.ccnu.edu.cn; Fax: +86 27 67862041;
Tel: +86 27 67862041
w Electronic supplementary information (ESI) available: Experimental
procedures and compound characterization data. CCDC 800928. For
ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c0cc03823g
a
Conditions: 3a (0.30 mmol), 4 (0.36 mmol), base (1.0–3.0 equiv.),
b
solvent (30 mL). Yield of isolated product.
c
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Chem. Commun., 2011, 47, 1869–1871 1869

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Table 2 Synthesis of oxazino[4,3-a]indoles using diphenyl vinyl
sulfonium salt 4a
With the optimal conditions in hand, the scope of the
(1H-indol-2-yl)methanol compounds was explored. As high-
lighted in Table 2, significant structural variations in the
(1H-indol-2-yl)methanol components were well tolerated and
furnished the corresponding N-fused indoles in moderate to
good yields. As revealed in entries 2 and 3, the substrates with
electron-rich substituents at the C(5)-indole position could be
successfully utilized in this transformation. Moreover, the
electron-deficient substrates in the context of 5-halogen- and
5-nitro-substituted indoles also exhibited high reaction
activities (Table 2, entries 4–7). These results clearly indicated
that the electronic modification of the indole ring can be
accomplished with little influence on the outcome of the
reaction. Importantly, these halogenated oxazino[4,3-a]indoles
(e.g. 5e and 5f) can be further functionalized with the use of
organometallic technologies,13 and in doing so generate diverse
polycyclic indoles with more molecular complexity (Table 2,
entries 4–6, and 9). When disubstituted (1H-indol-2-yl)methanol
substrates were employed, cyclization products were obtained
in slightly lower yields (Table 2, entries 8–9). Furthermore, the
substrate with a methyl at the 3-position of indole was
applicable as well (Table 2, entry 10), and the secondary
alcohol substrate 3k also smoothly cyclized to afford the
corresponding product in moderate yield (Table 2, entry 11).
Significantly, N-methyl-1H-indole-2-carboxamide 3l and 1H-
indole-2-carboxamide 3m could also successfully participate in
this cyclization and afforded the corresponding products 5l14
and 5m in 80% and 90% yield respectively, both of
which are precusors of the bioactive pyrazino[1,2-a]indoles
(Table 2, entries 12 and 13).
Entry Substrate
Product
Yield (%)b
1
2
3
3a
3b
3c
5a 93
5b 73
5c 75
5d 81
5e 74
5f 76
5g 74
5h 60
4
5
6
7
8
3d
3e
3f
3g
3h
In order to clarify the mechanism, (1H-indol-2-yl)methanol
substrates 3c and 3g were tested with dimethyl[(E)-2-phenyl-1-
ethenyl]sulfonium trifluoromethane-sulfonate
6 under the
optimized conditions. As illustrated in eqns (1) and (2), the fact
that only the olefin products 7 and 815 were isolated in high yields
indicated that the cascade reaction was initiated by the addition
of the nitrogen anion of the indole ring to the sulfonium salt.
9
3i
5i 61
5j 74
5k 62
10
3j
ð1Þ
ð2Þ
11
12
3k
3l
5l 80
5m 90
13
3m
As shown in Scheme 2, the conjugated addition of the
nitrogen anion to the electrophilic sulfonium salt affords an
intermediate sulfur ylide I. Intra- or intermolecular proton
shift followed by SN2 substitution gave the cyclization
product.11d,e
a
Conditions: 3 (0.50 mmol), 4 (0.60 mmol), KOH (1.25 mmol),
b
CH2Cl2 (50 mL). Yield of isolated product.
conditions were further optimized by adjusting the amount of
the base; for example, 2.5 equivalents of KOH produced 5a in
93% yield (Table 1, entries 5, 8–10).
Finally, the synthetic utility of this transformation was high-
lighted in the synthesis of 3,4-dihydro-7,8-dimethoxy-10-(4-
methoxyphenyl)-1H-[1,4]oxazino[4,3-a]indole 10, a drug candidate
c
1870 Chem. Commun., 2011, 47, 1869–1871
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ð3Þ
In summary, we have developed an addition-cyclization
reaction of (1H-indole-2-yl)methanols and vinyl sulfonium
salts, providing biologically and pharmaceutically important
oxazino[4,3-a]indoles in good to excellent yields. This methodology
can also be used in the preparation of pyrazino[1,2-a] indole
derivatives.
We are grateful to the National Science Foundation of
China (20872043) for support of this research.
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Chem. Commun., 2011, 47, 1869–1871 1871