Rh(II)-catalyzed isomerization of 2-aryl-2H-azirines to 2,3-disubstituted indoles

Article abstract of DOI:10.1246/cl.2007.52

Various 2,3-disubstituted indoles are synthesized by Rh ₂(OCOCF₃)₄-catalyzed isomerization of 2-aryl-2H-azirines. Copyright

Full text of DOI:10.1246/cl.2007.52

52
Chemistry Letters Vol.36, No.1 (2007)
Rh(II)-catalyzed Isomerization of 2-Aryl-2H-azirines to 2,3-Disubstituted Indoles
Shunsuke Chiba, Gaku Hattori, and Koichi Narasakaꢀ
Department of Chemistry, Graduate School of Science, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033
(Received October 6, 2006; CL-061169; E-mail: narasaka@chem.s.u-tokyo.ac.jp)
R1
Various 2,3-disubstituted indoles are synthesized by
Rh2(OCOCF3)4-catalyzed isomerization of 2-aryl-2H-azirines.
R1
R1
R2
Transition metal
[M]
R2
R2
N
N
N
− [M]
H
[M]
2H-Azirine
Introduction of an amino group to organic molecules by di-
rect amination of C–H bonds would be an extremely attractive
tool for the synthesis of amino compounds. Recently, consider-
able advances have been made in C–H amination by the use of
transition-metal catalysts, where various amide derivatives are
used as the nitrogen donors.1 In this communication, we present
an intramolecular C–H amination (aromatic substitution) reac-
tion to prepare 2,3-disubstituted indoles2 by a catalytic isomeri-
zation of 2-aryl-2H-azirines with Rh2(OCOCF3)4.
The Neber reaction of O-sulfonyloximes has been recog-
nized as one of the preparative methods for ꢀ-amino ketones
via 2H-azirines as intermediates (Scheme 1).3 One of the plausi-
ble reaction pathways of the formation of 2H-azirines from O-
sulfonyloximes involves initial removal of an ꢀ-proton followed
by loss of the sulfonate to afford vinyl nitrenes, which are con-
verted into 2H-azirines via the insertion to the C–C double
bond.4 It is also known that 2-aryl-2H-azirines can be converted
to indoles by the aryl C–H amination through the formation of
vinyl nitrene intermediates by pyrolysis, whereas the application
is quite limited.5 Accordingly, we intended to develop a metal-
catalyzed method for the transformation of 2-aryl-2H-azirines
to indoles.
It was expected that the treatment of 2H-azirines with appro-
priate transition-metals would form vinyl nitrene–metal com-
plexes, which in turn might undergo intramolecular C–H amina-
tion to furnish the corresponding azaheterocyclic compounds.6
On the basis of the above considerations, we assumed that the
vinyl nitrene–metal complexes generated from 2-aryl-2H-azir-
ines would undergo the successive aromatic substitution to give
indoles (Scheme 2). There has been only one report on a metal-
catalyzed transformation of 2,2-diphenyl-2H-azirines to indoles
by the use of a catalytic amount of PdCl2(PhCN)2.7 This reaction
was carried out under high dilution conditions (0.003 M) in
benzene, and the application was not investigated. We, therefore,
started to screen metal-catalysts for the transformation of 2-
aryl-2H-azirines to indoles.
Vinyl nitrene
−metal complex
Indole
Scheme 2. Metal-catalyzed indole formation.
Firstly, 2,20-diphenyl-3-methyl-2H-azirine (3a)8 was treated
with various metal complexes, and dirhodium(II) carboxylates
were found to catalyze the isomerization to indole 6a
(Table 1).9 When 2H-azirine 3a was treated with a catalytic
amount of Rh2(OCOCH3)4 in 1,2-dichloroethane (0.2 M) at
60 ꢁC for 9 h, the reaction proceeded as expected to give 2-meth-
yl-3-phenylindole (6a) in 12% yield with 82% recovery of 3a
(Entry 1). 2H-Azirine 3a was not transformed to indole 6a at
all in the absence of the rhodium catalyst in refluxing 1,2-di-
chloroethane (Entry 2). Rh2(OCOCF3)4 was found to catalyze
this reaction efficiently to give indole 6a in 85% yield at 60 ꢁC
for 1 h (Entry 4). Furthermore, Rh2(OCOCF3)4-catalyzed reac-
tion proceed even at room temperature (Entry 5), and the catalyst
loading was reduced to a 0.02 molar amount to afford indole 6a
in 90% yield (Entry 6).
We turned our attention to the scope of this catalytic indole
formation with a diverse array of 2-aryl-2H-azirines (Table 2).
3-Alkenyl- and 3-alkynyl-2,2-diphenyl-2H-azirines 3b and 3c
could isomerize to the corresponding indoles 6b and 6c in good
yields without affecting the alkenyl and alkynyl moieties
(Entries 1 and 2). From C2-monosubstituted 2H-azirine 3d,
however, the desired indole did not obtained at all (Entry 3).
Table 1. Rh(II)-catalyzed isomerization of 2H-azirine 3a to
indole 6a
catalyst
Me
Me
ClCH2CH2Cl
conditions
N
N
H
3a
6a
Catalyst
(mol amt.)
Yieldb/%
Conditionsa
Entry
O
OSO2R
R2
base
N
R1
N
HCl aq.
R2
1
2
3
4
5
6
12 (82)c
0 (99)c
2 (89)c
60 °C, 9 h
reflux, 8 h
60 °C, 9 h
Rh2(OCOCH3)4 (0.05)
none
R1
R1
R2
•
NH2 HCl
-amino ketone
2H-azirine
α
Rh2(OCOCPh3)4 (0.05)
•
Formation of 2H-azirines from O-sulfonyloximes via vinyl nitrene.
Rh2(OCOCF3)4 (0.05)
60 °C, 1h
rt, 17 h
85
85
90
OSO2R
N
N
Rh2(OCOCF3)4 (0.05)
Rh2(OCOCF3)4 (0.02)
base
N
insertion
R1
R1
R2
R1
R2
60 °C, 2h
R2
vinyl nitrene
2H-azirine
aAll reactions were performed under 0.2 M concentration.
Scheme 1. Neber reaction.
bIsolated yield. cRecovery yield of 3a.
Copyright Ó 2007 The Chemical Society of Japan

Chemistry Letters Vol.36, No.1 (2007)
53
Table 2. Rh(OCOCF3)4-catalyzed isomerization of 2-aryl-2H-
azirines 3 to indoles 6a
of alkenyl and alkynyl 2H-azirines 3b and 3c with the same pal-
ladium catalyst in 1,2-dichloroethane (0.2 M) gave the desired
indoles 6b and 6c only in 14 and 7% yields, respectively, under
the reaction conditions shown in Table 2, Entries 1 and 2.10
Thus Rh2(OCOCF3)4 is found to be the effective catalyst for
the isomerization of 2H-azirines 3 to indoles 6.
Indoles 6b
Entry
2H-Azirines 3
Conditions
R1
R1
This work was supported by the Grants-in-Aid for Scientific
Research (A) (No. 16205012) and for The 21st Century COE
program for Frontiers in Fundamental Chemistry from Ministry
of Education, Culture, Sports, Science and Technology, Japan.
N
N
H
3b R1 =
3c R1 =
60 °C, 5 h
6b 80%
6c 83%
H
1
2
reflux, 3 h
H
This paper is dedicated to Professor Teruaki Mukaiyama on
the occasion of his 80th birthday.
3c
reflux, 8 h
N
N
H
3d
6d 0%
References and Notes
1
For example, see: a) C. G. Espino, K. W. Fiori, M. Kim, J. Du
Bois, J. Am. Chem. Soc. 2004, 126, 15378. b) C. G. Espino,
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Int. Ed. 2004, 43, 4210. f) X.-Q. Yu, J.-S. Huang, X.-G. Zhou,
C.-M. Che, Org. Lett. 2000, 2, 2233.
Me
N
Me
4d
reflux, 11 h
N
H
6e 34%
3e
R2
R2
Me
Me
N
2
For reviews on synthetic methods of indoles, see: a) G.
Battistuzzi, S. Cacchi, G. Fabrizi, Eur. J. Org. Chem. 2002,
2671. b) H. Tokuyama, T. Fukuyama, Chem. Rec. 2002, 2,
37. c) G. W. Gribble, J. Chem. Soc., Perkin Trans. 1 2000,
1045. d) Y. Kobayashi, T. Fukuyama, J. Heterocycl. Chem.
1998, 35, 1043.
N
H
O
3f R2 =
3g R2 =
reflux, 3 h
reflux. 9 h
6f 91%
6g 84%
5
6
N
O
CN
R4
3
4
5
a) P. W. Neber, A. Friedolsheim, Justus Liebigs Ann. Chem.
1926, 449, 109. b) For a review, see: C. O’Brien, Chem. Rev.
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Chem. Soc. 2002, 124, 7640.
CF3
Me
60 °C, 5 h
7
Me
R3
N
H
N
a) D. F. Taber, W. Tian, J. Am. Chem. Soc. 2006, 128, 1058. b)
D. Knittel, Synthesis 1985, 186. c) L. Henn, D. M. B. Hickey,
C. J. Moody, C. W. Rees, J. Chem. Soc., Perkin Trans. 1
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For intramolecular C–H insertion and aromatic substitution of
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The details of the synthetic procedures of 2H-azirines were
depicted in the Supporting Information, which is available
electronically on the CSJ-Journal web site, http://www.csj.jp/
journals/chem-lett/index.html.
The isomerization of 2H-azirine 3a to indole 6a with other
transition metals did not gave satisfactory results. For example,
PtCl2 (8%), Cu(acac)2 (0%), Pd(OAc)2 (10%), and Pd(BF4)2-
(CH3CN)2 (0%).
88% (6h:6h' = 2:1)e
6h (R3 = H, R4 = CF3)
6h' (R3 = CF3, R4 = H)
3h
aAll reactions were performed with 0.05 mol amt. of Rh2-
(OCOCF3)4 in ClCH2CH2Cl (0.2 M). bIsolated yields. cBenzene
was used as a sovent. d2H-Azirine 3e was recorved in 14% yield.
eThe ratio was judged from H NMR spectroscopy.
1
6
2,3-Dialkyl-substituted indole 6e was obtained in 34% yield due
to the product instability under these reaction conditions (Entry
4). This method was applied successfully to the synthesis of
indoles bearing an electron-withdrawing group at C2 such as
aminocarbonyl and cyano groups (Entries 5 and 6). The rhodium
catalyst was vital for this conversion, because pyrolysis of 3g
in refluxing 1,2-dichloroethane in the absence of the rhodium
catalyst gave a complex mixture without formation of indole
6g. Electronic effect of aryl groups did not exhibit a significant
influence in the cyclization. That is, the isomerization of 2H-
azirine 3h having a trifluoromethyl group on one of the phenyl
rings proceeded smoothly to give a mixture of indoles 6h and
6h0 in 88% yield in 2:1 ratio (Entry 7).
7
8
9
The isomerization of 3a with a 0.05 molar amount of
PdCl2(PhCN)2 proceeded slowly to give indole 6a in 84% yield
for 23 h under 0.2 M concentration in benzene, presumably
owing to low solubility of the palladium catalyst. The reaction
10 The starting materials, 2H-azirine 3b and 3c were recovered
in 55 and 31%, respectively along with some unidentified side
products.
Published on the web (Advance View) December 16, 2006; doi:10.1246/cl.2007.52