Preparation of the isomeric azaindoline family by intramolecular carbolithiation

Article abstract of DOI:10.1021/ol702862d

An operationally convenient, one-pot, three-step sequence has been developed that provides access to 3-substituted 4-, 5-, 6-, and 7-azaindolines (2,3-dihydro-1H-pyrollopyridines) via intramolecular carbolithiation of the aryllithium derived from an appro

Full text of DOI:10.1021/ol702862d

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1071-1074
Preparation of the Isomeric Azaindoline
Family by Intramolecular Carbolithiation
William F. Bailey,* Paresh D. Salgaonkar, Jason D. Brubaker, and
Vijayata Sharma
Department of Chemistry, UniVersity of Connecticut, Storrs, Connecticut 06269-3060
William.Bailey@uconn.edu
Received November 27, 2007
ABSTRACT
An operationally convenient, one-pot, three-step sequence has been developed that provides access to 3-substituted 4-, 5-, 6-, and 7-azaindolines
(2,3-dihydro-1H-pyrollopyridines) via intramolecular carbolithiation of the aryllithium derived from an appropriate (N,N-diallylamino)bromopyridine.
Whereas cyclization proceeds as expected to give 1-allyl-3-methyl-4-azaindoline and 1-allyl-3-methyl-6-azaindoline following protonation of the
3-CH2Li group of the azaindoline, the isomeric 3-methyl-5-azaindoline and 3-methyl-7-azaindoline are generated as 3-methyl-N-allyl anions
prior to quench with MeOH.
The 5-exo cyclization of unsaturated organolithiums has been
rather widely used for the preparation of carbocyclic
products,1 but the synthesis of heterocyclic compounds using
this methodology is less well developed.2 In light of the fact
that indolines are readily prepared by cyclization of the aryl-
lithium derived from a 2-bromo-N-allylaniline,3 it occurred
to us that it might be possible to access all four isomeric
azaindolines4 from aminobromopyridines by analogous routes
provided that the cyclization is more rapid than are potential
anion-consuming reactions, such as the well-precedented
intermolecular addition of organolithiums to the azomethine
moiety of the pyridine.5
The azaindolines are attractive targets: there is no general
synthetic route to these simple heterocycles. Indeed, whereas
a variety of 7-azaindolines have been prepared and charac-
terized,6 synthetic routes to 5-azaindolines7 and 6-azaindo-
lines8 are limited, and to the best of our knowledge, only
(5) Wakefield, B. J. The Chemistry of Organolithium Compounds;
Pergamon Press: New York, 1974.
(6) (a) Kruber, O. Chem. Ber. 1943, 76, 128. (b) Clemo, G. R.; Swan,
G. A. J. Chem. Soc. 1945, 603. (c) Robison, M. M.; Robison, B. L. J. Am.
Chem. Soc. 1955, 77, 457. (d) Willette, R. E. Monoazaindolines: The
Pyrrolopyridines. In AdV. In Heterocyclic Chemistry; Katritzky, A. R.,
Boulton, A. J., Eds.; Academic Press: New York 1968; Vol. 9, pp 27-
105. (e) Taylor, E. C.; Pont, J. L. Tetrahedron Lett. 1987, 28, 379. (f) Taylor,
E. C.; Macor, J. E.; Pont, J. L. Tetrahedron 1987, 43, 5145. (g) Frissen, A.
E.; Marcelis, A. T. M.; van der Plas, H. C. Tetrahedron Lett. 1987, 28,
1589. (h) Taylor, E. C; Warner, J. C.; Pont, J. L. J. Org. Chem. 1988, 53,
800. (i) Frissen, A. E.; Marcelis, A. T. M.; van der Plas, H. C Tetrahedron
1989, 45, 803. (j) Marcelis, A. T. M.; van der Plas, H. C. Tetrahedron
1989, 45, 2693. (k) Ciganek, E. J. Org. Chem. 1992, 57, 4521. (l) Ly, T.;
Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron Lett. 1999, 40, 2533.
(m) Johnston, J. N.; Plotkin, M A.; Viswanathan, R.; Prabhakaran, E. N.
Org. Lett. 2001, 3, 1009. (n) Viswanathan, R.; Mutnick, D.; Johnston, J.
N. J. Am. Chem. Soc. 2003, 125, 7266. (o) Bacque´, E.; Qacemi, M. E.;
Zard, S. Z. Org. Lett. 2004, 6, 3671. (p) Davies, A. J.; Brands, K. M.;
Cowden, C. J.; Dolling, U. H.; Liebermann, D. R. Tetrahedron Lett. 2004,
45, 1721. (q) Sanders, W. J.; Zhang, X.; Wanger, R. Org. Lett. 2004, 6,
4527-4530.
(1) For reviews, see: (a) Bailey, W. F.; Ovaska, T. V. In AdVances in
Detailed Reaction Mechanisms; Coxon, J. M., Ed.; Vol. 3, Mechanisms of
Importance in Synthesis; JAI Press: Greenwich, CT, 1994; pp 251-273.
(b) Clayden, J. Organolithiums: SelectiVity for Synthesis; Pergamon
Press: New York, 2002; pp 293-335.
(2) For, a review, see: Bailey, W. F.; Mealy, M. J. J. Organomet. Chem.
2002, 646, 59.
(3) (a) Bailey, W. F.; Jiang, X.-L. J. Org. Chem. 1996, 61, 2596. (b)
Zhang, D.; Liebeskind, L. S. J. Org. Chem. 1996, 61, 2594.
(4) Azaindoline is used here to describe the pyrrolopyridine system; thus,
4-azaindoline is 2,3-dihydro-1H-pyrrolo[3,2-b]pyridine, 5-azaindoline is 2,3-
dihydro-1H-pyrrolo[3,2-c]pyridine, 6-azaindoline is 2,3-dihydro-1H-pyrrolo-
[2,3-c]pyridine, and 7-azaindoline is 2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.
10.1021/ol702862d CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/14/2008

two 4-azaindolines have been reported in the literature.9
Herein we report that cyclization of the aryllithium derived
from the appropriate (N,N-diallylamino)bromopyridine pro-
vides a general and expedient route to all four isomeric
azaindolines.
The aminobromopyridines used in this exploratory study
were readily prepared following literature procedures.10,11
However, the seemingly simple conversion of these materials
to their N,N-diallyl derivatives proved problematic; in short,
the pyridine nitrogen is more nucleophilic than is the NH2
group and activation of the amino nitrogen via deprotonation
may lead to a Chichibabin reaction (viz., intermolecular,
nucleophilic addition of aryl-NH- to the pyridine). After
considerable experimentation, a somewhat unorthodox, one-
pot route to N,N-diallyl derivatives, illustrated in Scheme 1,
ether (9:1 by vol) at -78 °C with 2.2 molar equiv of t-BuLi
in heptane following our general protocol for lithium-
halogen exchange12 cleanly generates the corresponding
aryllithium as demonstrated by the fact that quench of
such a reaction mixture with MeOH at -78 °C affords
3-(N,N-diallylamino)pyridine in essentially quantitative yield.
Allowing a solution of the aryllithium derived from 1 to stand
under an atmosphere of argon at 0 °C for 2 h before quench
with MeOH delivered the novel 1-allyl-3-methyl-4-azain-
doline (5) in 80% isolated yield (Scheme 2); quench with
Scheme 2
Scheme 1
MeOD gave a comparable yield of the 3-CH2D product
having a deuterium content of 95%. As illustrated in Scheme
2, the aryllithium derived from 4-bromo-3-(N,N-diallyl-
amino)pyridine (3), which was generated by lithium-
bromine exchange in n-pentane-diethyl ether (4:1 by vol)
due to the limited solubility of 3 in a more pentane-rich
solvent system, behaves similarly: 1-allyl-3-methyl-6-aza-
indoline (6) was isolated in 56% yield.
The cyclization of the aryllithium derived from 3-bromo-
2-(N,N-diallylamino)pyridine (4) followed an unanticipated
course. As illustrated in Scheme 3, two isomeric 7-azain-
Scheme 3
was developed that delivers substrates 1-4 in reproducible
yields of 70-90%.
Treatment of an approximately 0.1 M solution of 2-bromo-
3-(N,N-diallylamino)pyridine (1) in dry n-pentane-diethyl
(7) (a) Yakhontov, L. N.; Azimov, V. A.; Lapan, E. I. Tetrahedron Lett.
1969, 24, 1909. (b) Kauffmann, T.; Fischer, H. Chem. Ber. 1973, 106, 220.
(c) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.;
Wright, S. H. Synthesis 1996, 877. (d) Spivey, A. C.; Fekner, T.; Spey, S.
E.; Adams, H. J. Org. Chem. 1999, 64, 9430.
(8) (a) Dekhane, M.; Potier, P.; Dodd. R. H. Tetrahedron 1993, 49, 8139.
(b) Hands, D.; Bishop, B.; Cameron, M.; Edwards, J. S.; Cottrell, I. F.;
Wright, S. H. Synthesis 1996, 877. (c) De Bie, D. A.; Ostrowicz. A.;
Geurtsen, G.; Van Der Plas, H. C. Tetrahedron 1998, 44, 2977. (d) Fayol,
A.; Zhu, J. Org. Lett. 2005, 7, 239.
(9) (a) Donati, D.; Fusi, S.; Ponticelli, F. Eur. J. Org. Chem. 2002, 4211.
(b) Leroi, C.; Bertin, D.; Dufils, P. E.; Gigmes, D.; Marque, S.; Tordo, P.;
Couturier, J. L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003, 5, 4943.
(10) 2-Amino-3-bromopyridine, 3-amino-4-bromopyridine and 4-amino-
3-bromopyridine, see: Iwaki, T.; Yasuhara, A.; Sakamoto, T. J. Chem. Soc.,
Perkin Trans. 1999, 1, 1505.
(11) 3-Amino-2-bromopyridine, see: Can˜ibano, V.; Rodr´ıguez, J. F.;
Santos, M.; Sanz-Tejedor, M. A.; Carren˜o, M. C.; Gonza´lez, G.; Garc´ıa-
Ruano, J. L. Synthesis 2001, 14, 2175.
dolines were isolated: the expected 1-allyl-3-methyl-7-
azaindoline (7) was the minor product and enamine 8, largely
1
the Z-isomer (Z/E ∼30/1 by H NMR; the product rapidly
isomerizes to the apparently more stable E isomer upon
(12) Bailey, W. F.; Punzalan, E. R. J. Org. Chem. 1990, 55, 5404.
Org. Lett., Vol. 10, No. 6, 2008
1072

standing in CDCl3 solution), was produced in 70% yield.
The enamine was not stable on silica gel, but the compound
could be purified by careful chromatography over neutral
alumina and isolated in 54% yield. Repetition of the
cyclization, followed by reduction of the crude product as
shown in Scheme 3, delivered 3-methyl-1-propyl-7-azain-
doline (9) in 85% yield. In light of the unexpected generation
of the enamine product (8), a series of exploratory cycliza-
tions were conducted under a variety of conditions. The
results of these experiments, summarized in Table 1,
that deuterium had been incorporated in the N-allyl and
N-propenyl groups of 7 and 8, respectively. The methylene
hydrogens of the allyl group in 7 are diastereotopic, and the
2H NMR of the deuterated material displays two multiplets
(δ ) 4.12 and 3.89) corresponding to deuteration at these
positions; the 2H NMR of 8 is a clean doublet of triplets (δ
) 1.82, J ) 2.3 Hz, J ) 1.8 Hz) as appropriate for the
CHdCH-CH2D group in this compound.
Apparently, both 7 and 8 derive from a common precursor,
and the most reasonable candidate is a Z-configured allylic
anion (10), shown in Scheme 4, generated from the initial
cyclization product, 9, via proton transfer.13
In retrospect, it may appear somewhat surprising that
analogous deprotonation of the N-allyl group was not
observed in cyclizations leading to 4-azaindoline or 6-aza-
indoline (Scheme 2). Evidently, the etiology of the enhanced
acidity resides in the 7-azaindoline framework. As a working
hypothesis, the partial positive character of the N(1) position
in a 7-azaindoline, rationalized by the resonance structures
displayed below, may be invoked to account for the effect.
Table 1. Exploratory Cyclizations of Aryllithium Derived
from 4
products, % yielda
entry temp (°C) time (h)
ligand
none
7
8
1
2
3
4
5
5
7
-40
-20
0
20
-20
0
1.0
6
9
23
25
22
22
19
19
33
55
70
68
76
74
1.5
TMEDA
Clearly, comparable structures may be drawn for 5-aza-
indoline in which the nitrogens bear a 1,4 relationship.
Indeed, cyclization of the aryllithium derived from 3-bromo-
4-(N,N-diallylamino)pyridine (2) proceeds, as shown in
Scheme 5, to give a mixture consisting of 27% 1-allyl-3-
20
a Product yield determined by capillary GC analysis; in each case, 2-(N,N-
diallylamino)pyridine accounted for the remainder of the product mixture.
demonstrate that, although the ring closure of the aryllithium
derived from 4 is accelerated in the presence of TMEDA,
the enamine (8) was invariably the major product under all
conditions.
Scheme 5
The origin of the enamine product (8) became apparent
from analysis of a product mixture that had been quenched
with D2O; both isomeric azaindoline products, 7 and 8, were
found by GC/MS analysis to have a high a deuterium content
(>90%) but neither product contained appreciable deuterium
2
at the 3-methyl position. Indeed, H NMR analysis of the
crude product mixture revealed, as illustrated in Scheme 4,
methyl-5-azaindoline (11) and 43% of enamine 12 following
quench of the reaction mixture; 4-(N,N-diallylamino)pyridine
constituted the balance of the product mixture. An analytical
sample of 11 was isolated in low yield by column chroma-
tography, but it was not possible to purify the labile enamine.
Reduction of a crude product mixture subsequent to cycliza-
tion and quench with MeOH delivered pure 3-methyl-1-
propyl-5-azaindoline (13) in 40% yield over four steps.
Scheme 4
(13) It is likely that the proton transfer is an intermolecular process
catalyzed by a small quanity of 1-allyl-3-methyl-7-azaindoline peresent in
the reaction mixture as a consequence of inadvertent quench of 9 by solvent
or adventitious acid. Thus: 9 + 1-allyl-3-methyl-7-azaindoline f 1-allyl-
3-methyl-7-azaindoline + 10.
Org. Lett., Vol. 10, No. 6, 2008
1073

In summary, intramolecular carbolithiation of the aryl-
lithium derived from an appropriate (N,N-diallylamino)-
bromopyridine provides the first general route to all four
isomeric azaindolines. Ring-closure to give 1-allyl-3-methyl-
4-azaindoline (5) and 1-allyl-3-methyl-6-azaindoline (6)
proceeds in the normal way,3 but 3-methyl-5-azaindolines
and 3-methyl-7-azaindolines are generated as 3-methyl-N-
allyl anions prior to quench with MeOH.
thanks Pfizer, Inc., Groton, CT for an Undergraduate Summer
Research Fellowship. We are grateful to Dr. Christopher
Wolterman of FMC, Lithium Division, for a generous gift
of t-BuLi in heptane.
Supporting Information Available: Detailed experi-
mental procedures and NMR spectra of products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. This work was supported by a grant
from Procter & Gamble Pharmaceuticals, Mason, OH. J.D.B.
OL702862D
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