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ORGANIC
LETTERS
2001
Vol. 3, No. 26
4145-4148
Selective Cleavage of Cbz-Protected
Amines
Bruce H. Lipshutz,* Steven S. Pfeiffer, and Anthony B. Reed
Department of Chemistry and Biochemistry, UniVersity of California,
Santa Barbara, California 93106
Received September 4, 2001
ABSTRACT
Under conditions of catalytic Ni(0) and in most cases just over 1 equiv of Me2NH‚BH /K2CO or Cs2CO , a Cbz-protected nitrogen, which is part
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3
3
of a heteroaromatic ring, can be chemospecifically cleaved without affecting a Cbz group on an originally basic amine.
Among the myriad of protecting groups for nitrogen,1 the
Cbz moiety is regarded as one of the most useful in
synthesis.2 Installation of this residue follows from a standard
protocol involving treatment of an amine with Cbz-Cl or the
equivalent. The value of this blocking group lies in its
susceptibility to removal under conditions that are orthogonal
to those normally utilized to unmask alternative carbamate
derivatives, in particular the BOC and FMOC groups. Typical
conditions include those associated with catalytic hydrogena-
tion, strong acid, Na/NH3, and Lewis acids, although other
less commonly employed methods exist as well.1 None, to
the best of our knowledge, offer opportunities for generally
selective removal of a multiply Cbz-protected polyamine,3
thus necessitating use of at least two distinct protecting
groups. In this Letter, we describe a novel set of conditions
for the exclusive removal of a Cbz group attached to a
nonbasic nitrogen contained within a heteroaromatic ring
(Figure 1).
7-chloroindole 1 that dechlorinated and deprotected indole
was obtained if the reaction was allowed to proceed beyond
the time required for initial chloride removal (Scheme 1).
We surmised that the sequence leading to Cbz unraveling is
akin to that which takes place with the analogous allyloxy-
carbonyl unit.5 That is, with zerovalent palladium or in this
case nickel as nucleophile, a π-allylmetal intermediate is
likely that is subsequently trapped in situ (e.g., by hydride),
along with release of the free amine (Scheme 2). Such a
scenario does not distinguish between types of amines,
however, and thus we were surprised to find that several
Cbz derivatives of originally basic amines were untouched
under otherwise identical conditions. This may be attributed
to the availability of the nitrogen lone pair, which in the
former substrate type is minimized as a result of its
In the course of developing a highly functional group-
tolerant method for reductions of aryl chlorides based on
catalytic Ni(0), in combination with Me2NH‚BH3 and K2-
CO3 (1:1),4 it was observed in the case of Cbz-protected
(1) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Synthesis, 3rd ed.; John Wiley & Sons: New York, 1999.
(2) Bergmann, M.; Zervas, L. Ber. 1932, 65, 1192.
(3) Kohda, J.; Shinozuka, K.; Sawai, H. Tetrahedron Lett. 1995, 36(31),
5575. Sakaitani, M.; Ohfune, Y. J. Org. Chem. 1990, 55, 870.
(4) (a) Lipshutz, B. H.; Tomioka, T.; Pfeiffer, S. S. Tetrahedron Lett. In
press. (b) Lipshutz, B. H.; Tomioka, T.; Sato, K. Synlett 2001, 970.
Figure 1.
10.1021/ol016693l CCC: $20.00 © 2001 American Chemical Society
Published on Web 11/30/2001