7664
J . Org. Chem. 1996, 61, 7664-7665
Bir ch Red u ction of Electr on -Deficien t
P yr r oles
Timothy J . Donohoe* and Paul M. Guyo
F igu r e 1.
Department of Chemistry, The University of Manchester,
Oxford Road, Manchester M13 9PL, U.K.
Sch em e 1
Received September 4, 1996
The partial reduction of aromatic compounds using
group I metals, ammonia solvent, and a proton source
(usually tert-butyl alcohol) has become a powerful method
for the preparation of complex organic molecules.1 The
scope of this reaction (the Birch reduction) has been
extended beyond carbocyclic aromatics and onto many
heteroaromatic systems.2 However, the Birch reduction
of pyrrole and its derivatives appears to have met with
failure3 and, to the best of our knowlege, is unknown in
the literature. By analogy with both furan and thiophene,
Birch reduction of the pyrrole nucleus should give the
3-pyrroline skeleton,4 which is a useful and versatile
synthetic intermediate (Figure 1).5 This paper concerns
extension of the Birch reduction to pyrroles.
Ta ble 1
entry
RX
MeI
BnBr
EtI
R
yield (%)
compd
1
2
3
4
5
6
Me
Bn
Et
Bu
iBu
H
85
72
81
86
73
71
6
7
8
9
10
11
BuI
iBuI
We speculated that, in general terms, the pyrrole
nucleus was too electron-rich to accept electrons and be
reduced. Moreover, the presence of an acidic hydrogen
atom on the pyrrole nitrogen presents the possibility of
deprotonation under Birch-type conditions, and the re-
sulting anion would be extremely resistant to reduction.
Initial studies began on the N-methylated pyrrole 2
(Scheme 1), which was readily prepared in two steps from
commercially available 2-(trichloroacetyl)pyrrole.6 Com-
pound 2 was designed to overcome both of the barriers
to reduction that are outlined above. The amide group
at C-2 was specifically chosen not only as an electron-
withdrawing group but also as a “handle” by which we
could introduce substituents at C-2 by reductive alkyla-
tion. Accordingly, Birch reduction/alkylation of 2 with
sodium in liquid ammonia (using 1 equiv of tert-butyl
alcohol and quenching with methyl iodide) gave the
pyrroline 3 (albeit in modest yield) (Scheme 1).7 In this
reaction, starting material was completely consumed, and
the major product was the volatile aldehyde 4, which had
resulted from amide reduction rather than pyrrole reduc-
tion.8
NH4Cl
Sch em e 2
A solution to this problem was sought in the form of
N-BOC amide 5, which we suspected was sufficiently
electron deficient to encourage reduction of the aromatic
portion of the molecule. After an efficient synthesis of
5, a versatile and high-yielding protocol for reductive
alkylation was found by employing sodium metal (3
equiv) and omitting tert-butyl alcohol (Scheme 2). The
results presented in Table 1 show that the enolate species
that is quenched in the final step of the reaction is very
reactive toward a series of primary alkyl halides, even
those with branching at the â-position (entry 5, Table
1).7 The 3,4-dehydroproline derivative 11 could be ob-
tained by quenching the reaction with ammonium chlo-
ride (entry 6, Table 1).7 Quenching of the enolate with
secondary alkyl iodides also gave compound 11, presum-
ably formed via an E2-type elimination from the alkyl
halide: despite this limitation, the reactivity of the amide
enolate is certainly great enough to open many op-
portunities for synthesis.
We propose that, under the conditions outlined above,
compound 5 is able to accept two electrons and form a
dianion:1b this would be protonated by ammonia at C-5,
leaving an anion (enolate) at C-2 that can be quenched
by addition of an electrophile.
Both the amide and BOC protecting groups should be
removable if this chemistry is to become synthetically
useful. Therefore, compound 6 was selected as a model
and was subjected to the conditions outlined in Scheme
3. Removal of the BOC group was straightforward and
proceeded under standard conditions to yield the free
amine 12 (Scheme 3). Treatment of 6 with concentrated
(1) For general reviews of the Birch reduction see: (a) Mander, L.
N. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon: New York, 1991; Volume 8. (b) Rabideau, P. W.; Marcinow,
Z. Org. React. 1992, 42, 1. (c) Rabideau, P. W. Tetrahedron 1989, 45,
1579.
(2) (a) Siegel, S. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Volume 8. (b) Gribble,
G. W. In Comprehensive Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon: New York, 1991; Volume 8. (c) Donohoe, T. J .; Garg
R.; Stevenson, C. A. Tetrahedron: Asymmetry 1996, 7, 317.
(3) Birch, A. J .; Slobbe, J . Heterocycles 1976, 5, 905.
(4) Reduction of the pyrrole nucleus to 3-pyrrolines under acidic
conditions is well documented. (a) Evans, G. G. J . Am. Chem. Soc. 1951,
73, 5230. Schumacher, D. P.; Hall, S. S. J . Am. Chem. Soc. 1982, 104,
6076. Cornforth, J .; Du, M. J . Chem. Soc., Perkin Trans. 1 1990, 1463.
(b) Ketcha, D. M.; Carpenter, K. P.; Zhou, Q. J . Org. Chem. 1991, 56,
1318. (c) Scott, J . W.; Focella, A.; Hengartner, U. O.; Parrish, D. R.;
Valentine, D., J r. Synth. Commun. 1980, 10, 529. (d) Robertson, A.
V.; Witkop, B. J . Am. Chem. Soc. 1962, 84, 1697.
(5) Ding, Z.; Turafiello, J . J . Synth. Commun. 1990, 20, 227.
(6) Compound 1 can be prepared conveniently from pyrrole and
trichloroacetylchloride: Harbuck, J . W.; Rapoport, H. J . Org. Chem.
1972, 37, 3618.
(7) All new compounds have been fully characterized. Compound 6
has been further characterized by X-ray crystallography. Donohoe, T.
J .; Guyo, P. M. Unpublished work.
(8) See Kaiser, E. M. Synthesis 1972, 391.
S0022-3263(96)01688-X CCC: $12.00 © 1996 American Chemical Society
Donohoe, Timothy J.
