Rearrangement of 3,3-disubstituted indolenines and synthesis of 2,3-substituted indoles

Article abstract of DOI:10.1021/ol0623567

(Diagram presented) Synthesis of 2,3-substituted indoles from phenylhydrazine and α-branched aldehydes via rearrangement of 3,3-disubstituted indolenine intermediates is reported.

Full text of DOI:10.1021/ol0623567

ORGANIC
LETTERS
2006
Vol. 8, No. 25
5769-5771
Rearrangement of 3,3-Disubstituted
Indolenines and Synthesis of
2,3-Substituted Indoles
Kevin G. Liu,* Albert J. Robichaud, Jennifer R. Lo, James F. Mattes, and
Yanxuan Cai
Chemical & Screening Sciences, Wyeth Research, CN 8000,
Princeton, New Jersey 08543
liuk1@wyeth.com
Received September 25, 2006
ABSTRACT
Synthesis of 2,3-substituted indoles from phenylhydrazine and
intermediates is reported.
r
-branched aldehydes via rearrangement of 3,3-disubstituted indolenine
In our efforts to synthesize 3,3-disubstituted oxindoles from
arylhydrazines (1) and R-branched aldehydes (2),1 we found
the intermediate indolenines (3) rearrange to afford 2,3-
disubstituted indoles (4) when heated to elevated reaction
temperatures for prolonged periods (Scheme 1). Although
rearrangement in greater detail in the hopes of expanding
the scope. Herein, we report the results of our studies on
this rearrangement and its application to the synthesis of 2,3-
disubstituted indoles.
During the course of our investigation, we first explored
the effect of solvents and catalysts on a typical reaction of
phenylhydrazine (1) with cyclohexanecarboxaldehyde (2a).
We were interested in the potential effects on the rearrange-
ment of the indolenine intermediate (3a) and the subsequent
formation of indole product 4a (Table 1). A typical experi-
ment was performed by heating a mixture of 1 and 2a in a
solvent at 60 °C for 30 min followed by elevating the
temperature to 110 °C for 6 h in the presence of a catalyst.
Close monitoring of the reaction showed that with all solvents
studied, the hydrazone intermediate was formed rapidly at
room temperature. In most cases, Fischer indole reaction was
complete or proceeded to a great extent to give indolenine
3a after 30 min at 60 °C. Running this reaction under mildly
acidic conditions (AcOH), a typical procedure for facile
Fischer indole reactions,4,5 afforded clean formation of
indolenine 3a, although the rearrangement was sluggish
(entry 1, Table 1). Stronger acids, such as TFA and HCl,
were utilized as catalysts to potentially accelerate the
Scheme 1
Rodriguez2,3 reported many years ago that rearrangement of
spiroindolenines of type 3 can occur with an acid catalyst to
give cycloalkanoindoles, detailed studies on this rearrange-
ment and examination of the acyclic variant have not been
reported. Our initial results prompted us to investigate the
(1) Liu, K. G.; Robichaud, A. J. Manuscript in preparation.
(2) Benito, Y.; Canoira, L.; Martinez-Lopez, N.; Rodriguez, J. G.;
Temprano, F. J. Heterocycl. Chem. 1987, 24, 623-628.
(3) Rodriguez, J. G.; Benito, Y.; Temprano, F. J. Heterocycl. Chem. 1985,
22, 1207-1210.
(4) Robinson, B. Chem. ReV. 1963, 63, 373-401.
(5) Robinson, B. Chem. ReV. 1969, 69, 227-50.
10.1021/ol0623567 CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/15/2006

Table 1. Effects of Solvents and Acid Catalysts on
Rearrangement of 3,3-Disubstituted Indoleninea
Table 2. Rearrangement of a Variety of 3,3-Disubstituted
Indolenines to Yield 2,3-substituted Indolesa
entry
solvent
AcOH
catalyst
equiv
ratio (3a:4a)b
30:70
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
EtOH
TFA
HCl
HCl
ZnCl2
H2SO4
MsOH
HCl
HCl
TFA
ZnCl2
H2SO4
MsOH
MsOH
HCl
HCl
HCl
HCl
HCl
1.0
1.0
2.0
1.0
1.0
1.0
1.0
2.0
1.0
2.0
0.5
1.0
2.0
1.0
1.0
1.0
1.0
1.0
15:85
0:100
0:100
100:0
multiple products
0:100
87:13
0:100
97:3
hydrazone
multiple products
63:37
100:0
95:5
1,4-dioxane
n-BuOH
DMA
95:5
multiple products
multiple products
multiple products
HO(CH2)2OH
a Reaction conditions: 1 (1.68 mmol), 2a (1.68 mmol), solvent (16.8
mL), 110 °C, 6 h. b Ratio (3a:4a) determined by LC-MS based on peak
integration at 254 nm.
a Reaction conditions: 1 (1.68 mmol), 2 (1.68 mmol), 4 N HCl in dioxane
(1.68 mmol, 0.42 mL), HOAc (16.8 mL), 110 °C, 6 h. b Yields are isolated
yields after chromatography. c Only one isomer was obtained, and structures
were determined by 2-D NMR. d Combined yield of ester and hydrolyzed
acid products.
reaction. While TFA had a modest effect on the reaction
rate, addition of 1-2 equiv of HCl greatly facilitated the
transformation of 3a to 4a at 110 °C (entries 2-4, Table 1).
Several other acid catalysts including ZnCl2, H2SO4, and
methanesulfonic acid were also explored with AcOH as the
solvent, and only methanesulfonic acid proved equal to the
effects of HCl (entries 5-7, Table 1). Our investigation of
alternate solvents looked at the effects of nonacidic solvents
with addition of the various acid catalysts as before (entries
8-19, Table 1). In all instances these conditions were inferior
to the AcOH protocol and gave either reduced reaction rates
or mixtures containing a multitude of undesired products.
With the optimal reaction protocol in place we then sought
to investigate and possibly expand the scope of the re-
arrangement. A variety of aldehyde substrates including
acyclic and unsymmetrical R-branchedaldehydes were ex-
amined and are listed in Table 2. The rearrangement
proceeded well with both cyclic and acylic aldehyde
substrates (entries 4a-4d) affording products in moderate
to good yields. Somewhat to our surprise, in the cases of
2-phenylpropionaldehyde and 2-formylpropionic acid ethyl
ester (entries 4e and 4f, Table 2), the respective phenyl or
carbonyl moieties migrated exclusively to provide a single
regioisomer. The proposed mechanism for the rearrangement
is depicted in Scheme 2. In this hypothesis, the rearrangement
occurs through a cationic intermediate that upon aromatiza-
tion provides the indole product. The exclusive and somewhat
unanticipated migration of the phenyl group, rather than the
methyl group (entry 4e, Table 2), suggests that stabilization
of the carbocation is not the determining factor in deciding
the migratory aptitude in this instance. This regiospecific
migration may be facilitated by formation of a π-π
electronic interaction between these groups and the imine
CdN bond.
In summary, we have studied the rearrangement of 3,3-
disubstituted indolenines by exploring a number of catalysts
and solvents and further examined the scope of the re-
arrangement by expanding it to include acyclic systems. This
rearrangement provides an alternative method to the tradi-
tional Fischer indole synthesis and can afford products in a
Scheme 2
5770
Org. Lett., Vol. 8, No. 25, 2006

more regiospecific manner. The application of this re-
arrangement to the syntheses of pharmaceutically interesting
compounds is currently under investigation.
Supporting Information Available: Spectral data for all
final compounds along with detailed experimental proce-
dures. This material is available free of charge via the Internet
at http://pubs.acs.org.
Acknowledgment. We thank Bill Marathias and Alvin
Bach for their analytical support. We also thank Professor
Michael Jung of UCLA for providing valuable discussions.
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