COMMUNICATION
Robust preparation of novel imidazo[5,1-b][1,3,4]oxadiazoles†
Tuan P. Tran, Nandini Patel, Brian Samas and Jacob B. Schwarz*‡
Received 7th August 2009, Accepted 2nd October 2009
First published as an Advance Article on the web 15th October 2009
DOI: 10.1039/b916188k
Cyclodehydration of amino acid-derived acyl hydrazide
amides 2 to the corresponding oxadiazoles was followed by
a second dehydration event, smoothly furnishing the novel
imidazo[5,1-b][1,3,4]oxadiazole motif 1.
Recently, analysis of a large set of pharmaceutical data supported a
general view that lower molecular weight and lipophilicity resulted
in a trend toward improved ADME properties.1 Similarly, it was
reported that an increased likelihood of in vivo toxic events could
be expected from drug candidates with high lipophilicity.2
A
common strategy for decreasing the lipophilicity in lead structures
involves replacing a phenyl ring with a heteroaromatic nucleus. As
part of a medicinal chemistry program, we sought to transform
a series of N-benzyl amides into [1,3,4]oxadiazoles 3. During the
course of the investigation we discovered a facile preparation of a
novel heterocyclic motif, which is reported herein.3–5
Scheme 1 Preparation of dibenzoyl hydrazide amide 2a.
which we considered to be either compound 1a or 7, based on
LC/MS which suggested that a second dehydration event had
taken place.
Two mechanistic possibilities for double dehydration of 2a
were considered (Fig. 1). In scenario A, cyclodehydration to an
hydrazido-oxazole 6 would be followed by attack on the carbonyl
and dehydration to afford 1H-pyrazolo[4,3-d]oxazole 7. In fact,
oxazolylamine formation in this manner is precedented, however
the amines employed were not contained within a hydrazine
motif.16 Scenario B would proceed as initially envisioned, namely
through formation of the oxadiazole amide 3a which could then
proceed to form a novel imidazo-oxadiazole 1a. Scenario A
We envisioned that the desired oxadiazolyl amides 3 could be
obtained by cyclodehydration of acyl hydrazides 2. A straightfor-
ward preparation of Boc-protected Gly and Ala oxadiazoles had
been previously reported.6 Using a slightly modified procedure, we
were able to access the requisite acyl hydrazides (Scheme 1). Hence,
conversion of CBz-protected glycine 4 to the benzoyl hydrazide 57,8
using EDCI was followed by deblocking of the carbamate and a
second peptide coupling with benzoic acid to furnish the requisite
acyl hydrazide 2a.9 Boc protection of the amino acid subunit was
similarly successful for obtaining acyl hydrazides 2, obviating the
need for hydrogenation (see ESI†).
Cyclodehydration of amino acid-derived acyl hydrazides has
been effected with various reagents including thionyl chloride10
and the Burgess reagent.11–13 Alternatively, the oxadiazole amides
could be obtained from the hydrazide and carboxylic acid partners
in one pot with CDI followed by CBr4/PPh3,14 or alternatively
in one step using POCl3.15 However, when POCl3 in refluxing
acetonitrile was employed to effect cyclodehydration of 2a, we
observed smooth conversion to a new heteroaromatic product
was ruled out by exposing valine-derived hydrazide 2b (R2
=
isopropyl), which would be prohibited from undergoing the
second dehydration, to POCl3 providing exclusively imidazo[5,1-
b][1,3,4]oxadiazole 1b in 73% isolated yield. In addition, when
2-methylalanine was employed as the core subunit in acyclic
precursor 8, only the oxadiazole amide 9 was obtained in 65% yield
as cyclodehydration to the imidazo-oxadiazole was precluded by
the presence of a quaternary carbon atom (Scheme 2). Similarly,
Pfizer Global Research and Development, Eastern Point Road, Groton, CT
06340, USA
† Electronic supplementary information (ESI) available: Full experimental
and characterization data for 1a–n, 2a–n, and 8–11. CCDC reference
numbers 743852 and 743853. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/b916188k
‡ Current address: Genentech, Inc., 1 DNA Way, S. San Francisco,
CA 94080, USA. Fax: +1 650-742-4943; Tel: +1 650-225-7732; E-mail:
Scheme 2 Substrates designed to stop at oxadiazole amide.
Org. Biomol. Chem., 2009, 7, 5063–5066 | 5063
This journal is
The Royal Society of Chemistry 2009
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