Preparation of substituted indolines via anionic cyclization

Full text of DOI:10.1021/jo960305p

2596
J . Org. Chem. 1996, 61, 2596 2597
Sch em e 1
P r ep a r a tion of Su bstitu ted In d olin es via
An ion ic Cycliza tion
William F. Bailey* and Xing-Long J iang
Department of Chemistry, The University of Connecticut,
Storrs, Connecticut 06269-3060
Received February 14, 1996
The 5-exo cyclization of substituted 5-hexenyllithiums
provides a convenient route five-membered-ring-contain-
ing carbocycles.1 Much less information is available on
the potential utility of such “anionic” cyclizations2 for the
preparation of heterocycles.3 Herein we report that
cycloisomerization of the organolithium derived from a
2-bromo-N-allylaniline by lithium bromine exchange
provides a novel and experimentally simple route to
substituted indolines (2,3-dihydro-1H-indoles) bearing a
variety of functionalities at the C(3) position. Classical
approaches to such materials, which typically involve
reduction of the corresponding indole, have been exten-
sively reviewed.4
tion of a 2-bromoaniline (allyl bromide/Na2CO3 in DMF),
were used in this exploratory study. Treatment of an
approximately 0.1 M solution of 1 in dry n-pentane
diethyl ether (9:1 by vol) at 78 °C with 2.2 molar equiv
of tert-butyllithium (t-BuLi) following our general protocol
for lithium halogen exchange5 cleanly generates the
corresponding aryllithium 2 as demonstrated by the fact
that quench of such a reaction mixture with MeOH at
78 °C affords the N,N-diallylaniline in essentially
quantitative yield. Cyclization of 2 to give a (1-allyl-3-
indolinyl)methyllithium (3) was easily effected, as il-
lustrated in Scheme 1, by addition of 2.2 equiv of dry,
oxygen-free N,N,N′,N′-tetramethylethylenediamine (TME-
DA) to the 78 °C solution and allowing the resulting
mixture to stand under an atmosphere of argon at 0 °C
for 40 min. As demonstrated by the results presented
in Table 1, the [(1-allyl-3-indolinyl)methyl]lithium (3)
may be trapped by addition of any of a variety of
electrophiles (Scheme 1, 3 f 4) to give 70 90% isolated
yields of 3-substituted indolines6 (4). As a practical
matter, isolation of pure product (Table 1) is a fairly
simple matter since the only byproduct is a small
quantity of the unfunctionalized N,N-diallylaniline de-
rived, as detailed elsewhere,5 from formal reduction of 1
during the exchange reaction.
It should be noted that the 5-exo cyclization of 2 is a
facile process that does not require the presence of
TMEDA. Indeed, substituted indolines may be prepared
in the absence of the additive, albeit with some loss of
yield, by allowing solutions of 2 in n-pentane diethyl
ether to warm and stand at room temperature for 1 h
prior to the addition of the electrophile. The use of
TMEDA to facilitate the isomerization of 2 to 3 is,
however, the recommended procedure: exploratory ex-
periments revealed that a portion of the organolithium
product 3 is inadvertently quenched by proton abstrac-
tion from the solvent at the elevated temperatures
needed to effect cyclization of 2 in the absence of the
additive.
In the interest of synthetic simplicity, 2-bromo-N,N-
diallylanilines 1, which are readily prepared by diallya-
(1) (a) Bailey, W. F.; Ovaska, T. V. In Advances in Detailed Reaction
Mechanisms; Coxon, J . M., Ed.; J AI Press: Greenwich, CT, 1994; Vol.
3, Mechanisms of Importance in Synthesis, pp 251 273. (b) Bailey,
W. F.; Patricia, J . J .; DelGobbo, V. C.; J arret, R. M.; Okarma, P. J . J .
Org. Chem. 1985, 50, 1999. (c) Ross, G. A.; Koppang, M. D.; Bartak,
D. E.; Woolsey, N. F. J . Am. Chem. Soc. 1985, 107, 6742. (d)
Chamberlin, A. R.; Bloom, S. H Tetrahedron Lett. 1986, 27, 551. (e)
Bailey, W. F.; Nurmi, T. T.; Patricia, J . J .; Wang, W. J . Am. Chem.
Soc. 1987, 109, 2442. (f) Chamberlin, A. R.; Bloom, S. H.; Cervini, L.
A.; Fotsch, C. H. J . Am. Chem. Soc. 1988, 110, 4788. (g) Bailey, W. F.;
Rossi, K. J . Am. Chem. Soc. 1989, 111, 765. (h) Bailey, W. F.;
Khanolkar, A. D. J . Org. Chem. 1990, 55, 6058. (i) Krief, A.; Barbeaux,
P. Synlett 1990, 511. (j) Krief, A.; Barbeaux, P. Tetrahedron Lett. 1991,
32, 417. (k) Bailey, W. F.; Khanolkar, A. D. Tetrahedron Lett. 1990,
31, 5993. (l) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K.; Ovaska, T.
V.; Rossi, K.; Thiel, Y.; Wiberg, K. B. J . Am. Chem. Soc. 1991, 113,
5720. (m) Bailey, W. F.; Khanolkar, A. D.; Gavaskar, K. V. J . Am.
Chem. Soc. 1992, 114, 8053. (n) Cooke, M. P., J r. J . Org. Chem. 1992,
57, 1495. (o) Bailey, W. F.; Khanolkar, A. D. Organometallics 1993,
12, 239. (p) Bailey, W. F.; Gavaskar, K. V. Tetrahedron 1994, 50, 5957.
(2) While the cyclization of 5-hexenyllithium and related species may
be viewed as a formally anionic process, it should be noted that the
lithium atom is intimately involved in the rearrangement. Indeed,
5-hexenyllithium is unique among the 5-hexenylalkalis in it ability to
undergo facile cyclization. See: Bailey, W. F.; Punzalan, E. R. J . Am.
Chem. Soc. 1994, 116, 6577.
(3) To date, the only published investigations of heteroatom-contain-
ing 5-hexenyllithiums involve (2-oxa-5-hexenyl)-, (3-oxa-5-hexenyl)-,
and (4-oxa-5-hexenyl)lithiums. For the 2-oxa system, which undergoes
5-exo closure on warming to give [(3-tetrahydrofuranyl)methyl]lithiums
in good yield, see: (a) Broka, C. A.; Lee, W. J .; Shen, T. J . Org. Chem.
1988, 53, 1336. (b) Broka, C. A.; Shen, T. J . Am. Chem. Soc. 1989,
111, 2981. (3-Oxa-5-hexenyl)lithium is inherently unstable and frag-
ments at low temperature via â-elimination: Bailey, W. F.; Punzalan,
E. R.; Zarcone, L. M. J . Heteroat. Chem. 1992, 3, 55. The 4-oxa system
isomerizes on warming to give the lithium salt of a 4-alken-1-ol in the
formal equivalent of a [1,4]-Wittig rearrangement: Bailey, W. F.;
Zarcone, L. M. J . Tetrahedron Lett. 1991, 32, 4425.
As a consequence of employing 2-bromo-N,N-diallyl-
anilines to generate 2, the 3-substituted indoline products
4 depicted in Table 1 bear an N-allyl substituent. The
allyl protecting group may be conveniently removed, as
shown below, using catalytic Pd2(dba)3 and 1,4-bis-
(4) (a) Preobrazhenskaya, M. N. Russ. Chem. Rev. 1967, 36, 753.
(b) Sundberg, R. J . Chemistry of Indoles; Academic Press: New York,
1970. (c) Houlihan, W. J ., Ed. Indoles; Wiley-Interscience: New York,
1972; Parts 1 and 2; 1979; Part 3. (d) Sakamoto, T.; Kondo, Y.;
Yamanaka, H. Heterocycles 1988, 27, 2225. (e) Pindur, U.; Adam, R.
J . Heterocycl. Chem. 1988, 25, 1. (f) Hegedus, L. S. Angew. Chem., Int.
Ed. Engl. 1988, 27, 1113. (g) J oule, J . A.; Mills, K.; Smith, G. F.
Heterocyclic Chemistry, 3rd ed.; Chapman and Hall: New York, 1995;
pp 305 349.
(5) Bailey, W. F.; Punzalan, E. R. J . Org. Chem. 1990, 55, 5404.
(6) All products were homogeneous by both TLC and capillary GC.
Exact mass spectroscopic molecular weights have been determined for
all previously unreported compounds, and their IR and 1H NMR and
13C NMR spectra are fully in accord with the assigned structures.
0022-3263/96/1961-2596$12.00/0 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 8, 1996 2597
Sch em e 2
Ta ble 1. P r ep a r a tion of 3-Su bstitu ted In d olin esa
remainder of the product mixture was unfunctionalized
4-methyl-N,N-diallylaniline). Significantly, the major
product of the reaction sequence, 7 (64% isolated yield),
was functionalized at both the C(3) methylene as well
as at the aromatic C(7) position. These results, which
demonstrate that cyclization of 9 is much less facile than
is ring closure of 6, suggest that easily prepared 2,6-
dibromo-N,N-diallylanilines may serve as precursors for
the one-pot synthesis of indolines bearing functionality
at both C(3) and C(7).
entry
R
E
E
yield,b %
1
2
3
4
5
6
7
8
9
H
CH3OH
CH3OD
H
D
90
76c
82
83
78
74d
90
80c
80
75
70
76
(CH3)3SiCl
(n-Bu)3SnCl
(CH3)2NCHO
(CH3)3CCHO
CH3OH
Si(CH3)3
Sn(n-Bu)3
CHO
(CH3)3CCH(OH)
H
CH3
CH3OD
D
(CH3)3SiCl
Br(CH2)2Br
ClCO2C2H5
(CH2O)n
Si(CH3)3
Br
CO2C2H5
CH2OH
10
11
12
a
The chemistry described above, and summarized in
Schemes 1 and 2, constitutes a novel route to substituted
indolines from readily available starting materials. It
should be noted that the indoline products generated by
this methodology (Table 1) may be easily oxidized to the
corresponding indoles. While a variety of oxidants have
been employed for this purpose,4 the use of 1 molar equiv
of o-chloranil at room temperature is a particularly
attractive, mild technique;8 representative examples are
presented below. A variety of protocols are available for
N-deallylation of the resulting N-allylindoles.7,9
[2-(N,N-Diallylamino)phenyl]lithium (2) was generated at 78
°C by addition of 2.2 equiv of t-BuLi to a solution of 1 in
n-pentane diethyl ether (9:1 by vol), 2.2 equiv of TMEDA were
then added, the cooling bath was removed, and the mixture was
allowed to stand at 0 °C for 40 min before the addition of an excess
b
of the electrophile. Isolated yield of chromatographically pure
product. c Determined by GC/MS analysis of the product. Product
d
was an approximately 1:1 mixture of diastereoisomers.
(diphenylphosphino)butane (DPPB) in the presence of
2-mercaptobenzoic acid following the procedure of Geneˆt.7
The methodology described above may also be used for
the preparation of indolines functionalized at both the
C(3) and C(7) positions. Treatment of 2,6-dibromo-4-
methyl-N,N-diallylaniline (5) in n-pentane diethyl ether
(9:1 by vol) at 78 °C with 4.4 equiv of t-BuLi effects
exchange of both bromines and generates the dilithio-
aryllithium 6: as illustrated in Scheme 2, quenching a
solution of 6 at 78 °C delivers 4-methyl-N,N-diallyl-
aniline in 85% isolated yield. It might be anticipated that
6 would undergo a dual 5-exo cyclization when warmed.
However, as summarized in Scheme 2, allowing a solu-
tion of 6 to stand at 0 °C for 40 min in the presence of
4.4 equiv of TMEDA followed by addition of an excess of
TMS-Cl afforded only monocyclized adducts 7 and 8 (the
Ack n ow led gm en t. This work was supported by the
Connecticut Department of Economic Development. We
thank Professor Lanny S. Liebeskind of Emory Univer-
sity for a helpful exchange of information prior to
publication of a related investigation (see the preceding
paper in this issue).
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and spectroscopic data for all compounds are available
(43 pages).
J O960305P
(8) Zhang, D.; Liebeskind, L. S. J . Org. Chem. 1996, 61, xxxx.
(9) Tidwell, J . H.; Buchwald, S. L. J . Am. Chem. Soc. 1994, 116,
11797 and references therein.
(7) Lemaire-Audoire, S.; Savignac, M.; Geneˆt, J . P.; Bernard, J .-M.
Tetrahedron Lett. 1995, 36, 1267.