3
228
J . Org. Chem. 1996, 61, 3228-3229
Syn th esis a n d Use of
-Vin yl-1,2,4-oxa d ia zoles a s Mich a el
Accep tor s. A Ra p id Syn th esis of th e P oten t
Mu sca r in ic Agon ist L-670,548
pound indeed rapidly decomposed to a single product, and
the half-life (t1/2) of 4 in pH 7.4 water was found to be
only 45 min. Intrigued by this decomposition process,
we purposefully subjected the salt (4) to decomposition
5
2 3 2 2
conditions (Na CO in water/CH Cl ) and were able to
isolate 5 in >90% yield (Scheme 1). This compound (5)
was a low-boiling liquid making both isolation and
characterization difficult.
J ohn E. Macor,* Timothy Ordway, Robert L. Smith,
Patrick R. Verhoest, and Robert A. Mack
The ease of elimination of trimethylamine from 4 was
reminiscent of the ease of elimination of water and other
leaving groups from â-substituted carbonyl compounds,
and this premise led us to examine the Michael accepting
character of the olefin found in 5. Examination of the
reaction of the 5-vinyl-1,2,4-oxadiazole (5) with nucleo-
Department of Chemistry, Astra Arcus USA,
P.O. Box 20890, Rochester, New York 14602
Received February 20, 1996
The 1,2,4-oxadiazole heterocycle has been identified
and utilized as a metabolically stable analog of an ester
or amide functionality in pharmacologically important
molecules.1 Recent examples of the use of 1,2,4-oxadia-
zoles as ester bioisosteres include the potent serotonin
agonist (1)2 for the treatment of migraine and the
philes under basic conditions is summarized in Scheme
4
1
.
The olefin in 5 was found to be electrophilic in nature
with a range of nucleophiles able to add into the electron-
deficient olefin. Because of the volatility of 5, its forma-
tion was carried out in situ with an appropriate base in
methylene chloride/methanol (10:1). Methanol was needed
to help solublize the quaternary salt. As shown by TLC,
formation of the 5-vinyl-1,2,4-oxadiazole (5) was rapid
using any base. Dimethylamine was both base and
nucleophile in the formation of 6a . Likewise, ammonia
was both the base and nucleophile in the formation of
3
muscarinic receptor “super agonist” (2) for the treatment
of Alzheimer’s disease. Oxadiazoles have been typically
made as the last step in the synthesis of the biologically
relevant molecule under study via the reaction of an ester
or activated ester with an amide oxime. Convergent
methods of synthesis of 1,2,4-oxadiazoles with other
functional groups have not yet been exploited.
6
f. Only a catalytic amount of diisopropylethylamine
(
DIEA) was needed for the reaction of 3-hydroxypyrro-
lidine with the oxadiazole (example e), since trimethyl-
amine was the elimination product. In cases where the
nucleophile was formed by deprotonation of its conjugate
acid, stronger bases were needed to, at least, partially
deprotonate the acids. Accordingly, while DIEA was
adequate for benzyl mercaptan (example b), a stronger
base (DBU) was needed for deprotonation of malononi-
trile (example d). In the case of addition of methanol,
we found that excess methoxide anion was required for
reaction. The reaction of 5 with amines (dimethylamine,
During the course of a general study of muscarinic
agonists, we examined the efforts of Street and co-
3
workers, which had been focused on the discovery of the
muscarinic “super agonists” (i.e., 2). They reported that
their efforts to synthesize the simplest, acyclic analog (3)
of their azabicyclo[2.2.1]heptane (2)3b were unsuccessful.
However, upon examination of the reaction between
methyl 3-(dimethylamino)propionate and acetamide oxime
3
-hydroxypyrrolidine, and ammonia) was rapid at room
temperature, and high yields of the desired products (6a ,
e, and 6f, respectively, Scheme 1) were isolated. Reac-
6
tion of 5 with benzyl mercaptan was slower than the
reaction with amines and required heating, but the
thioether (6b) was also obtained in high yield. Use of
NaH in MeOH with heating formed the methyl ether (6c),
and the isolation of 6c was complicated by its volatility.
The reaction of 5 with malononitrile afforded the disub-
stituted malononitrile (6d ) in which two molecules of the
olefin (5) were added to the active methylene of malono-
nitrile. In that example, 2 equiv of (4) was required.
(
Scheme 1), we found that we were able to isolate
consistently 30-45% yield of the desired 1,2,4-ozadiazole
3). Since our original interest in this compound was its
(
muscarinic receptor activity, we converted the N,N-
dimethylamine free base in 3 to its N,N,N-trimethyl
quaternary ammonium salt (4). We believed that 4
would be the most analogous compound to acetylcholine,
the natural substrate for muscarinic receptors which
itself is a N,N,N-trimethyl quaternary ammonium salt.
Accordingly, the reaction of 3 with methyl iodide in
acetone afforded the quaternary salt 4 (95%) as a
crystalline solid which was directly filtered from the
reaction mixture (Scheme 1).
During the pharmacological examination of 4, it was
suspected that significant biological activity was masked
by decomposition of the salt, likely to trimethylamine and
the 5-vinyl-1,2,4-oxadiazole (5). Careful examination of
a pH 7.4 aqueous solution of 4 revealed that the com-
These results demonstrate that 5-(2-(N,N-dimethy-
lamino)ethyl)-1,2,4-oxadiazoles (i.e., 3) can be easily used
as synthons for NUC-CH
CH -1,2,4-oxadiazoles, where
2 2
NUC is an appropriate nucleophile which contains other
functional groups. The utility of this concept can be
demonstrated by the retrosynthetic analysis shown in
Scheme 2. Disconnection of the muscarinic agonist
L-670,548 (2) at the carbon-carbon bond between the
azabicyclic bridgehead carbon and the carbon R to C5 of
(
4) A typical procedure is as follows: To a stirred mixture of 4 (2.00
(
1) Watjen, F.; Baker, R.; Engelstoff, M.; Herbert, R.; MacLeod, A.;
mmol) in methylene chloride/methanol (10:1, 11 mL) was added the
appropriate base (DIEA and DBU were used catalytically (10 mol %),
NaH was used in excess) as shown in Scheme 1, followed by the
appropriate nucleophile (amines were used in 3-fold excess, methanol
was used as solvent, and only 0.5 equiv of malononitrile was used).
The resulting reaction solution was stirred for the time and temper-
ature shown in Scheme 1. The resulting reaction solution was then
evaporated under reduced pressure. Purification of the residue could
be accomplished via removal of insoluble solids through trituration
using diethyl ether (or methylene chloride)/hexanes followed by
evaporation of the filtrate or via chromatography using silica gel and
an appropriate solvent system.
Knight, A.; Merchant, K.; Moseley, J .; Saunders, J .; Swain, C. J .; Wong,
E.; Springer, J . P. J . Med. Chem. 1989, 32, 2282-2291.
(2) Street, L. J .; Baker, R.; Castro, J . L.; Chambers, M. S.; Guiblin,
A. R.; Hobbs, S. C.; Matassa, V. G.; Reeve, A. J .; Beer, M. S.;
Middlemiss, D. N.; Noble, A. J .; Stanton, J . A.; Scholey, K.; Hargreaves,
R. J . J . Med. Chem. 1993, 36, 1529-1538.
(3) (a) Saunders, J . and Freedman, S. B. Trends Pharmacol. Sci.
1
989, Dec Suppl., 70-75. (b) Street, L. J .; Baker, R.; Book, T.; Kneen,
C. O.; MacLeod, A. M.; Merchant, K. J .; Showell, G. A.; Saunders, J .;
Herbert, R. H.; Freedman, S. B.; Harley, E. A. J . Med. Chem. 1990,
3, 2690-2697.
3
S0022-3263(96)00334-9 CCC: $12.00 © 1996 American Chemical Society
Macor, John E.
