Rapid route to 3,4-substituted indoles via a directed ortho metalation-retro-Mannich sequence.

Article abstract of DOI:10.1021/ol017310m

[reaction: see text] In the presence of NXS (X = Br, I, Cl), gramine derivatives 1, derived by combined directed ortho metalation (DoM)-cross-coupling sequences, rapidly undergo retro-Mannich fragmentation (2) to afford 3-halo indoles 3 in 37-88% yields.

Full text of DOI:10.1021/ol017310m

ORGANIC
LETTERS
2002
Vol. 4, No. 5
815-817
Rapid Route to 3,4-Substituted Indoles
via a Directed Ortho
Metalation−Retro-Mannich Sequence
Brian Chauder, Andrew Larkin, and Victor Snieckus*
Department of Chemistry, Queen's UniVersity, Kingston, ON, K7L 3N6, Canada
snieckus@chem.queensu.ca
Received December 30, 2001
ABSTRACT
In the presence of NXS (X ) Br, I, Cl), gramine derivatives 1, derived by combined directed ortho metalation (DoM)−cross-coupling sequences,
rapidly undergo retro-Mannich fragmentation (2) to afford 3-halo indoles 3 in 37−88% yields. A conceptually new methodology to diverse
3,4-substituted indoles (10, 11, 13) is thereby introduced.
We report a new and unique route to 3,4-substituted indoles
3 based on a combined metalation and retro-Mannich
sequence, 1f 3. This route proceeds via a highly regiose-
lective C-4 lithiation of gramine discovered by Iwao1 and
our finding,2 of some vintage, concerning the interconversion
of tetrahydro-γ-carboline 4 and tetrahydropyrimidoindole 5
ring systems that involves, in part, a Br+-initiated retro-
Mannich fragmentation (Scheme 1).
specifically polyfunctionalized benzenes.3 Among the few
methods for direct C-4 substitution, the Iwao procedure1 is
exceptional in its brevity and scope. The DoM-retro-
Mannich protocol delineated herein demonstrates rapid access
to 3,4-differentially halogenated (Table 2, entries 1 and 2),
4-substituted 3-haloindoles (entries 4 and 5) and, via transi-
tion metal catalyzed coupling processes, interesting C-C
bond construction motifs (Scheme 2 and Table 3). In view
of the considerable effort needed to obtain valuable 4-sub-
stituted indoles,4 the present methodology provides a short
and general route with potential application for the prepara-
tion of less accessible bioactive indoles and tryptamines and
new conceptual tools for viewing indole natural product
synthetic targets.
Scheme 1
(3) Gribble, G. W. J. Chem. Soc., Perkin Trans. 1 2000, 1045 and refs
cited therein. For Pd-catalyzed heteroannulation methods, see: Soederberg,
B. C.; Schriver, J. A. J. Org. Chem. 1997, 62, 5838 and a comprehensive
list of refs therein.
(4) (a) Kozikowski, A. P. Heterocycles 1981, 16, 267. (b) Hollins, R.
A.; Colnago, L. A.; Salim, V. M.; Seidl, M. C. J. Heterocycl. Chem. 1979,
16, 993. (c) Tidwell, J. H.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
11797 and refs cited therein. (d) Somei, M.; Amari, H.; Makita, Y. Chem.
Pharm. Bull. Jpn. 1986, 34, 3971 and refs cited therein. (e) Hegedus, L.
Angew. Chem., Int. Ed. Engl. 1988, 27, 1113. (f) Brown, M. A.; Kerr, M.
A. Tetrahedron Lett. 2001, 42, 983.
Methods for de novo C-4-substituted indole ring construc-
tion (inter alia, Fischer, Madelung, and Reissert) suffer from
regioisomer production or dependency on synthesis of
(1) Iwao, M. Heterocycles 1993, 36, 29.
(2) Bhandari, K. S.; Snieckus, V. Synthesis 1971, 327.
10.1021/ol017310m CCC: $22.00 © 2002 American Chemical Society
Published on Web 02/05/2002

In the test experiment of the retro-Mannich fragmentation,
N-TIPS gramine, when subjected to NBS, afforded, within
minutes, the 3-bromo derivative in essentially quantitative
yield (Table 1, entry 1). Similarly, the corresponding
N-SO2Ph (entry 4) derivatives in high yields. This route uses
inexpensive gramine as a starting material, requires no special
precautions, tolerating moisture and oxygen, and compares
favorably with established routes to 3-haloindoles.6 In an
unexpected but potentially useful observation, treatment of
N-Boc gramine with NBS or NIS yielded the 3-formyl indole
as the sole product, presumably via a radical mechanism
(entry 5).7 Reaction of 6a with other electrophilic reagents,
including TMSOTf, Tf2O, selectfluor, ICl, Br2, I2, Ph-
(OCOCF3)2/I2, and AlCl3/AcCl, gave either no reaction or a
complex mixture of products.
Table 1. 3-Haloindoles 7 by Retro-Mannich Fragmentation of
Gramine 6
Scheme 2a
entry
6
PG1 conditionsa
7
X
PG2
yield (%)b
1
2
3
4
5
6a TIPS
6a TIPS
a
b
c, d
c, e
f
7a Br
7b Cl
TIPS
TIPS
Boc
98
73
83-90
78
76
6b
6b
H
H
7c
7d
I
I
SO2Ph
6c Boc
7e CHO Boc
a (a) NBS/CH2Cl2/MeOH/rt/2 min; (b) NCS/CH2Cl2/MeOH/rt/15 min;
(c) NIS/MeOH/0 °C/5 min; (d) (Boc)2O/Et3N/catalytic DMAP/CH2Cl2/rt/
15 min; (e) PhSO2Cl/NaOH/catalytic Bu4NBr/PhMe/rt/30 min; (f) 2 equiv
NBS/catalytic AIBN/py/CH2Cl2/reflux/10 min. b Isolated yields after chro-
matography or crystallization.
a Key: (a) (1) NBS/MeOH/CH2Cl2/rt/2 min; (2) TBAF/THF/rt/
10 min; (3) (Boc)2O/catalytic DMAP/Et3N/CH2Cl2/rt/30 min. (b)
Bu3SnCH2CHdCH2/Pd(PPh3)4/PhMe/reflux/2 h. (c) PhB(OH)2/
DME/aqueous Ba(OH)2/Pd(PPh3)4/reflux/15 min.
3-chloroindole was prepared via reaction with NCS (entry
2). Reaction of N-TIPS gramine with NIS, however, resulted
only in decomposition products. This is not entirely surpris-
ing since 3-iodoindoles are reported to be unstable.5
To connect the retro-Mannich process to the DoM reaction,
a series of gramines 8 with C-4 carbon, silicon, oxygen, and
halogen functional groups were prepared from 6a as de-
scribed by Iwao (Table 2).1 These were subjected to
bromination and iodination conditions to afford, with one
exception (entry 3), 3,4-disubstituted indoles 3a and 3b in
good overall yields.
Table 2. Synthesis of 3,4-Disubstituted Indoles 3 via
DoM-Retro-Mannich Sequence
For the development of new C-3 and C-4 C-C bond
constructs, 4-bromogramine derivative 8b was treated with
3, yield (%)b
Table 3. Synthesis of 3,4-disubstituted Indoles 13 via Negishi
- Retro-Mannich Sequence
yield 3a , X ) Br 3b, X ) I
(%)b PG ) TIPS PG ) Boc
entry
8
E+
8a Cl3C-CCl3
8b BrCH2CH2Br Br
E
1
2
3
4
5
Cl
64
56
66
51
62
80
84
decomp
79
83
37
88
decomp
42
63
8c (TMSO)2
8d DMF
8e TMSCl
OH
CHO
TMS
a Bromination: NBS/CH2Cl2/MeOH/rt/2 min. Iodination: (1) TBAF
THF/rt/10 min; (2) NIS/MeOH/0 °C/5 min; (3) (Boc)2O/Et3N/catalytic
DMAP/CH2Cl2/rt/15 min. b Isolated yields after chromatography.
13, yield (%)b
13a , X ) Br
PG ) TIPS
13b, X ) I
PG ) Boc
entry
12
Ar
yield (%)b
1
2
3
12a
12b
12c
o-tol
Ph
3-py
22
53
34
81
68
24
Nevertheless, treatment of unprotected gramine with NIS
at 0 °C resulted in smooth conversion to 3-iodoindole, which,
upon immediate N-protection, gave the N-Boc (entry 3) and
81
a Bromination: NBS/CH2Cl2/MeOH/rt/2 min. Iodination: (1) TBAF/
THF/rt/10 min; (2) NIS/MeOH/0 °C/5 min; (3) (Boc)2O/Et3N/catalytic
DMAP/CH2Cl2/rt/15 min. b Isolated yields after chromatography.
(5) (a) Saulnier, M. G.; Gribble, G. W. J. Org. Chem. 1982, 47, 757. (b)
Saulnier, M. G.; Gribble, G. W. J. Org. Chem. 1983, 48, 2690.
816
Org. Lett., Vol. 4, No. 5, 2002

NBS followed by desilylation and N-Boc protection to give
the 3,4-dibromo indole 9 in good overall yield (Scheme 2).
Subjection of 9 to prototype Stille and Suzuki-Miyaura
reactions led to the diallyl 10 and diphenyl 118 derivatives,
respectively, in modest yields.
indoles 13a and 13b, substrates for potential further cross-
coupling chemistry.
In conclusion, a rapid entry into 3,4-difunctionalized
indoles 3, especially dihalogenated systems, via a DoM-
retro-Mannich protocol has been established. Combination
with cross-coupling regimens allows ready access to new
indoles 10, 11, and 13a,b. The overall methodology may
suggest new strategies for bioactive molecule and alkaloid
construction.
The Negishi cross-coupling protocol may also be linked
to the indole retro-Mannich reaction (Table 3). Thus, C-4
metalation of N-TIPS gramine 6a with t-BuLi followed by
treatment with anhydrous zinc bromide or zinc chloride and
aryl halides under Pd-catalysis afforded 4-aryl derivatives
12 in low yields. Attempts to improve the yields by
vigorously degassing the system were not successful. None-
theless, treatment of 12 according to the retro-Mannich-
bromination and -iodination protocols provided 3-halo-4-aryl
Acknowledgment. We are grateful to NSERC Canada
for support under the Research Grant program. B.C. is a
recipient of a Queen’s Graduate Fellowship (QGF), 1999-
2000.
Supporting Information Available: Experimental pro-
cedures for the metalation of 6a and for the preparation of
3, 7, and 10-13 and characterization data for 7, 8a, 3a,b
(Table 2, entry 1), 10, 11, 12c, and 13a (Table 3, entry 3).
This material is available free of charge via the Internet at
http://pubs.acs.org.
(6) For 3-bromoindoles, see: Amat, M.; Sathyanarayana, S.; Hadida, S.;
Bosch, J. Heterocycles 1996, 43, 1713 and refs cited therein. For
3-iodoindoles, see: Benhida, R.; Blanchard, P.; Fourrey, J.-L. Tetrahedron
Lett. 1998, 39, 6849 and refs cited therein.
(7) For examples of debenzylation of amides using NBS/AIBN, see:
Baker, S. R.; Parsons, A. F.; Wilson, M. Tetrahedron Lett. 1998, 39, 331.
(8) Structurally reminiscent of stereochemically interesting 1,8-substituted
naphthalenes, see: Lunazzi, L.; Mazzanti, A.; Alvarez, A. M. J. Org. Chem.
2000, 65, 3200.
OL017310M
Org. Lett., Vol. 4, No. 5, 2002
817