A versatile synthesis of 3-substituted indolines and indoles

Full text of DOI:10.1021/jo960304x

2594
J . Org. Chem. 1996, 61, 2594-2595
symmetry about the Csp2-N bond, ease of deprotection
of the resulting N-allylindoline), we undertook a brief
study of this cyclolithiation process. Bailey and others
have described a variety of related intramolecular car-
bolithiations of alkenes and alkynes.19-26
A Ver sa tile Syn th esis of 3-Su bstitu ted
In d olin es a n d In d oles
Dawei Zhang and Lanny S. Liebeskind*
Results of the study are depicted in Table 1 and
demonstrate that N-allylindolines and N-allylindoles
possessing a variety of substitution patterns can be
rapidly constructed. Readily available o-bromo-N,N-
diallylanilines 1a ,17 1b,17 1c,17 and 1d (see the supporting
information) were treated with 2 equiv of t-BuLi in tert-
butyl methyl ether (TBME) at -78 °C, and then the
lithiation reaction mixtures were allowed to warm to
room temperature. Protonation of the intermediate
3-(lithiomethyl)indolines thus formed provided a variety
of 3-methylindolines in good to high yields (2a - 2d ,
61%-95%). The indolines 2a - 2c were carried forward
to their respective 3-methylindoles 6a - 6c by treatment
with 1 equiv of o-chloranil in TBME at room temperature.
By quenching the intermediate 3-(lithiomethyl)indolines
formed on cyclolithiation of 1a and 1c with prochiral
carbonyl compounds (3-methoxy-4-(benzyloxy)benzalde-
hyde27 and 3,4-diisopropylsquarate28), the 3-substituted
indolines 3a , 3c, 4a , and 4c were produced as mixtures
of the diastereomers (3a , 2:1; 3c, 1:1; 4a , 1:1; 4c, 1:1) in
yields between 55% and 78%. Each of the diastereomeric
mixtures converged to a single 3-substituted indole (7a ,
7c, 8a , 8c, respectively) on oxidation with o-chloranil in
TBME at room temperature.
Sanford S. Atwood Chemistry Center, Emory University,
1515 Pierce Drive, Atlanta, Georgia 30322
Received February 14, 1996
Indolines and their oxidized counterparts, indoles, are
very important pharmacophores that appear in numerous
biologically active compounds, most notably those affect-
ing the central nervous system.1,2 In addition to classical
methods for the construction of the heteroatom ring of
these molecules,3-5 newer procedures mediated by transi-
tion metal species have been documented.6-18 Herein is
reported a new method for the synthesis of 3-substituted
indolines and indoles whose operational simplicity and
generality should find favor in many applications.
During an attempt to lithiate 2-bromo-4-methoxy-N,N-
diallylaniline with t-BuLi for use in another project, a
surprisingly facile cyclolithiation to N-allyl-3-(lithiometh-
yl)-5-methoxyindoline occurred, as judged by isolation of
N-allyl-3-(deuteriomethyl)-5-methoxyindoline in 86% yield
after quenching of the reaction with D2O (eq 1). Recog-
3-Substituted indoles bearing a basic alkylamino side
chain were easily constructed using this cyclolithiation
protocol. The indolines 5a and 5b were obtained in 57%
and 62% yields, respectively, upon reaction of N-meth-
ylenepiperidinium chloride29 with the 3-(lithiomethyl)-
indolines formed by cyclolithiation of o-bromoanilines 1a
and 1b. Oxidation to the corresponding indoles 9a and
9b proceeded uneventfully with 1 equiv of o-chloranil in
TBME at room temperature (64% and 53%, respectively).
On the basis of analysis of the ratios of indoline to
uncyclized products, the cyclolithiation process began
slowly at 0 °C and was complete after 2 h at room
temperature in tert-butyl methyl ether. Both n-BuLi and
t-BuLi were used to effect the cyclolithiation in either
diethyl ether or tert-butyl methyl ether, the latter orga-
nolithium reagent and solvent pair proving the superior
combination.
nizing the potential of this transformation as a versatile
construction of 3-substituted indolines and indoles, and
noting the inherent advantages that accrued from the
use of a symmetrically substituted N,N-diallylaniline
group in the chemistry (ease of synthesis, conformational
* To whom correspondence should be addressed: Tel: (404) 727-
6604. Fax: (404) 727-0845. E-mail: CHEMLL1@emory.edu.
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An inherent benefit of the intramolecular carbolithia-
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N-allyl-protected indolines, which should be susceptible
to deprotection by a variety of known N-deallylation
protocols.17,30,31 To assess the feasibility of N-allylindoline
deprotection, N-allylindolines 2a and 2b were treated
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0022-3263/96/1961-2594$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 8, 1996 2595
Ta ble 1. Cyclolith ia tion of o-Br om o-N,N-d ia llyla n ilin es to In d olin es a n d Th eir Oxid a tion to In d oles
electrophile:
product:
H2O
compd/yield (%)
compd/yield (%)
compd/yield (%)
compd/yield (%)
indoline
indolea
5a /57 9a /64
5b/62 9b/53
aniline
R1
R2
indoline
indolea
indoline
indolea
indoline
indolea
1a
1b
1c
1d
H
Me
MeO
(allyl)2N
H
H
H
MeO
2a /85
2b/87
2c/95
2d /61
6a /82
6b/82
6c/70
3a /67
3c/85
7a /87
4a /78
4c/72
8a /65
7c/74
8c/ 57
a
The indicated yield is that obtained on oxidation of the indoline to the indole.
with catalytic Pd2(dba)3/1,4-bis(diphenylphosphino)bu-
tane and 2-mercaptobenzoic acid in THF at reflux ac-
cording to a recently disclosed procedure.31 This pro-
duced moderate isolated yields of the air-sensitive
indolines 10a (56%)32 and 10b (66%), the latter as a 1:1
mixture of diastereomers (eq 2).
N-allylanilines to indoles, studied by Ban and Hegedus,6-10
but differs significantly in the range of functionalized
indolines and indoles that can be easily obtained from
the 3-(lithiomethyl)indoline intermediate. This new
procedure should provide the synthetic chemist with the
ability to construct a wide variety of substituted indolines
and indoles rapidly and with minimal effort.
Ack n ow led gm en t . This investigation was sup-
ported by Grant No. CA40157, awarded by the National
Cancer Institute, DHHS. We acknowledge the use of a
VG 70-S mass spectrometer purchased through funding
from the National Institutes of Health, S10-RR-02478,
and 300 and 360 MHz NMRs purchased through fund-
ing from the National Science Foundation, NSF CHE-
85-16614 and NSF CHE-8206103, respectively. We are
grateful to Professor William Bailey of the University
of Connecticut for sharing his results with us and for
agreeing to simultaneous publication (see the following
paper in this issue). We also gratefully acknowledge
Drs. J ohn Sofranko and Sujuan Ba of ARCO Chemical
Co. for providing a generous sample of tert-butyl methyl
ether and for encouraging our exploration of this solvent
as a safe and effective replacement for diethyl ether and
tetrahydrofuran.
In conclusion, a concise and technically simple proce-
dure for the construction of 3-substituted indolines and
indoles has been uncovered. It bears a resemblance to
the nickel- and palladium-catalyzed cyclization of o-halo-
Su p p or tin g In for m a tion Ava ila ble: A complete descrip-
tion of the synthesis and characterization of all compounds in
this paper (16 pages).
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M. Tetrahedron Lett. 1995, 36, 1267.
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J O960304X