Robust preparation of novel imidazo[5,1-b][1,3,4]oxadiazoles

Article abstract of 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.

Full text of DOI:10.1039/b916188k

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www.rsc.org/obc | Organic & Biomolecular Chemistry
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:
schwarz.jacob@gene.com
Scheme 2 Substrates designed to stop at oxadiazole amide.
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Fig. 1 Possible routes for double dehydration of diacyl hydrazide amides 2.
methylation of the amide nitrogen as in 10 afforded a substrate
unable to participate in the second dehydration event, resulting in
exclusive formation of 11.
Several examples of hydrazides being converted to imidazo-
oxadiazole products 1a–k are shown in Table 1. Gly, Ala, Val,
Phg, and Phe at a minimum were tolerated in the core hydrazide.
Aromatic or aliphatic functionality could be incorporated at either
the 2- or 5-positions of the heterocyclic nucleus. In all cases the
process provided >50% isolated yield of the desired imidazo-
oxadiazole products. Unambiguous confirmation of the structure
was achieved through X-ray crystallographic analysis of 1a and 1f
(Fig. 2).
Scheme 3 Dehydration of 2b and 2k under alternate conditions.
isolation, the pure amides 3b and 3k were completely converted
to imidazo-oxadiazoles 1b and 1k on treatment with phosphorus
oxychloride.
Next, we examined the bimolecular coupling process promoted
by POCl3 that was reported to provide the oxadiazole amide as the
major product.7 Hence, hippuric acid 12 and benzhydrazide hy-
drochloride 13 were combined and refluxed in POCl3 (Scheme 4).
After 8 hours, as reported, oxadiazole amide 3a was determined
to be the major product by LC/MS, although we did in fact
observe initial formation of the imidazo-oxadiazole 1a (<10%). In
an effort to maximize the amount of 1a formed, the mixture was
refluxed for 2 days resulting in an isolated yield for 1a of only 19%.
Clearly, stepwise formation of diacyl hydrazides 2 was important
for obtaining efficient conversion to imidazo-oxadiazoles 1.
Fig. 2 ORTEP plot of imidazo[5,1-b][1,3,4]oxadiazole 1f with ellipsoids
drawn at 50% probability.17
To address the fact that others had previously reported the
preparation of oxadiazole amides 3 without mention of a second
dehydration event, we first examined the reaction of 2b under
alternate conditions (Scheme 3). Treatment with the Burgess
reagent (THF, reflux, 3 h) resulted in ca. 25% conversion to
amide 3b, with starting 2b comprising the balance of material.
Extending the time of reaction to 16 h led to complete conversion
to amide 3b. Next, when 2b or 2k were reacted under the
CBr4/PPh3 conditions reported in ref. 8 (with the exception of
added CDI), as expected oxadiazole amides 3b and 3k were
obtained in moderate yield (32% and 48%, respectively). Following
Scheme 4 Examination of bimolecular process to form 1a.
Finally, we examined whether the carbon substituent at the
individual N-termini of diacyl hydrazides 2 could be replaced by
hydrogen, resulting in lower substitution at positions 2- or 5- of
the heterocycle 1 (Scheme 5). Hence, valine-derived formamide
2m (prepared from 5 as outlined in Fig. 1 using formic acid in
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Table 1 Formation of imidazo[5,1-b][1,3,4]oxadiazoles 1a
Hydrazide 2
Imidazo-oxadiazole 1
Product (Yield%)b
1a (76)
1b (73)
1c (80)
Scheme 5 Reaction of formamide variants 2m and 2n.
place of benzoic) was converted in moderate yield to the desired
5-hydro-imidazo-oxadiazole product 1m.
To prepare the 2-hydro variant, hippuric acid 13 was coupled
with formic hydrazide (EDCI, CH2Cl2, 58%) affording formamide
2n. Double dehydration as before furnished imidazo-oxadiazole 1n
in 23% isolated yield.
1d (65)
1e (76)
In conclusion, as part of an effort to reduce the lipophilicity of a
series of N-benzyl amides, we targeted oxadiazole amides of type
3. Formation of the hydrazide of an amino acid such as glycine or
valine, and subsequent acylation of both termini allowed for con-
venient access to the prerequisite cyclodehydration substrates 2.
We were surprised to find that the desired oxadiazole amides were
smoothly converted to a novel imidazo[5,1-b][1,3,4]oxadiazole
motif 1. Of the previous methods used to prepare oxadiazole
amides 2, in our hands only the bimolecular variant promoted
by POCl3 furnished motif 1, albeit in low yield. Efforts to further
elucidate the scope and limitations of this process are currently in
progress.
1f (50)
1g (80)
1h (62)
Notes and references
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3 The isomeric imidazo[2,1-b][1,3,4]oxadiazoles are known: H. Beyer and
A. Hetzheim, Zeitschrift fur Chemie, 1962, 2, 153, see also Ref. 4.
4 G. Westphal and P. Henklein, Zeitschrift fur Chemie, 1969, 9, 25–
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5 Recently, an analysis was performed that showed the rate of publication
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a Conditions: POCl3, CH3CN, reflux. b Isolated yield.
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12 Polymer-supported: C. T. Brain, J. M. Paul, Y. Loong and P. J. Oakley,
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13 C. T. Brain and S. A. Brunton, Synlett, 2001, 382–384.
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17 C14H12N4O3 1f: M = 284.28, Triclinic, a = 7.0096(2), b = 7.1705(3),
˚
˚
c = 13.7650(5) A, U = 659.38(4) A3, T = 298K, space group P-1,
Z = 2, 2224 reflections measured, 1519 unique (Rint = 0.0140)
which were used in all calculations. The final R1 = 0.0422 with
wR2 = 0.1275.
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