Improved method for the preparation of oxadiazoles from diacyl hydrazines

Article abstract of DOI:10.1080/00397910903353721

N-methylimidazole (NMI) is used as the base in the triflic anhydride (Tf₂O)-mediated formation of oxadiazoles from diacyl hydrazines. This reagent is superior to pyridine-derived bases in terms of cost and reaction profile. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910903353721

Synthetic Communications1, 40: 3021–3026, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903353721
IMPROVED METHOD FOR THE PREPARATION OF
OXADIAZOLES FROM DIACYL HYDRAZINES
David Ellis, Patrick S. Johnson, Andrew Nortcliffe,
and Simon Wheeler
Sandwich Chemistry, Pfizer Global Research and Development, Sandwich,
Kent, UK
N-methylimidazole (NMI) is used as the base in the triflic anhydride (Tf2O)–mediated for-
mation of oxadiazoles from diacyl hydrazines. This reagent is superior to pyridine-derived
bases in terms of cost and reaction profile.
Keywords: Cyclization; dehydration; oxadiazoles
The oxadiazole ring is a frequently occurring motif in medicinal chemistry, exempli-
fied by zibotentan (1, an Astra-Zeneca agent in phase 3 development for the treat-
ment of prostate cancer)[1] and raltegravir (2, an HIV integrase inhibitor
discovered by Merck) (Fig. 1).[2]
2,5-Disubstituted oxadiazoles are typically prepared from diacyl hydrazines by
a cyclodehydration reaction. Traditionally, this has been carried out using powerful
reagents such as POCl3 or SOCl2; however, it is possible to use a variety of other
reagents: inorganic[3] and organic[4] acids and strong dehydrating agents such as
P2O5,[5] P2S5,[6] and PCl5.[7] The functional group tolerance of most of these reagents
is often low, which has lead to efforts to identify milder conditions for this cycliza-
tion. Triphenylphosphine has been used in combination with a selection of other
[8]
=
reagents to accomplish this transformation: CX4 (X Cl, Br, I), hexachlor-
oethane,[9] iodine,[10] diethylazodicarboxylate (DEAD),[11] and trichloroacetoni-
trile.[12] However, such successes must be qualified by the generation of large
quantities of triphenylphosphine oxide as a by-product, while attempts to circum-
vent this problem by using a polymer-supported reagent must be limited to small
scales because of the high cost of immobilized phosphine. Similar considerations
undermine the otherwise attractive use of TsCl and 5 equivalents of polymer-
supported phosphazene base t-butylimino-2-diethylamino-1,3-dimethylperhydro-
1,3,2-diazaphosphorine (BEMP).[13] The Burgess reagent has been reported as an
alternative,[14] but it is also limited because of its high cost. Other reported reagents
(ZrCl4[15] and Pd(PPh3)4[16]) are disadvantaged by low substrate scope and very high
Received August 4, 2009.
Address correspondence to Simon Wheeler, Sandwich Chemistry, Pfizer Global Research and
Development, Ramsgate Roaed, Sandwich, Kent CT13 9NJ, UK. E-mail: simon.wheeler@pfizer.com
3021

3022
D. ELLIS ET AL.
Figure 1. Drugs containing oxadiazole rings.
reaction temperatures, respectively. Hence, the search for mild, general conditions
for this important cyclisation has continued. The use of hexamethyldisalazane
(HMDS) and tetrabutyl ammonium fluoride (TBAF)[17] and an imidazolinium
salt[18] has received scant further attention and were capricious in our hands. Perhaps
the most promising approach to a general solution to the problem of preparing oxa-
diazoles of this nature is the combination of triflic anhydride (Tf2O) and pyridine.[19]
However, this reagent combination is not without its disadvantages. Most parti-
cularly, the highly electrophilic nature of the Tf2O prompts attack by the pyridine
base, which is then itself activated to nucleophilic attack at the 2- and 4-positions.
Indeed, attempts in our laboratories to obtain oxadiazole 4a from diacyl hydrazine
3a led to only 50% isolated yield from a messy reaction mixture from which com-
pound 5 could also readily be isolated (Scheme 1).
Such problems are commonplace with Tf2O, which has caused many research-
ers to replace pyridine with alkyl-substituted derivatives, most commonly 2,6-di-t-
butyl-4-methylpyridine. We were not attracted to this approach because of the high
cost of this base and instead searched for a cheaper alternative. We postulated that
N-methylimidazole (NMI) would provide similar nucleophilcity to pyridine but in an
electron-rich ring, which would not be subject to mechanistic pathways leading to
products analogous to 5. We were gratified to find that this base was successful in
the cyclodehydrative preparation of oxadiazoles, giving clean reaction profiles in
every case. (Cheapest prices, derived from the 2009–2010 Aldrich catalogue, are
shown in Scheme 2; from the same source the cheapest price of Tf2O is £0.83 gꢀ1.)
The broad scope of these reaction conditions is demonstrated with the
examples listed in Table 1. A range of functional and protecting groups survive
Scheme 1. Product and by-product from the reaction of 3a with Tf2O=pyridine.

OXADIAZOLES FROM DIACYL HYDRAZINES
3023
Scheme 2. Price comparison of bases used in the Tf2O cyclization of diacyl hydrazines.
Table 1. Substrate scope and yields
Product
Starting material
Time (h)
Yielda
68
3
1
3
72
61b
16
16
65
85
5
50
38
1.5
aRefers to isolated yield of pure material.
bCompound 3c was a 1:1 mixture of (2S, 4 R)- and (2S, 4S)-diastereomers. Stereochemistry at C-2 was
not affected by the reaction.

3024
D. ELLIS ET AL.
Figure 2. Diacyl hydrazines unreactive under our conditions.
the reaction unscathed. As well as the usual dialkyl (3a, 3c, 3d, and 3g) and diaryl (3e
and 3f) examples, it is possible to accommodate aromatic (3a and 3f) and aliphatic
(3c and 3g) heterocycles. Primary alkyl chlorides are stable to the reaction conditions
(3b), as are nitrogen and oxygen atoms protected as the t-butyl carbamate (3a and
3c) and benzyl ether (3b) respectively. We were particularly pleased to discover that
diacyl hydrazine 3a, which had been problematic with pyridine as base, reacted
cleanly under these new conditions, giving an improved yield after only minor
purification.
The reaction usually proceeds in a few hours at 0 ꢁC or slightly below. It gen-
erally requires 1.5 equivalents of Tf2O and 3 equivalents of NMI. Dichloromethane
(DCM) was the solvent in all cases, though we have not yet attempted to change this
for a more environmentally benign alternative. We have employed this protocol as
successfully on scales of <100 mg and up to >100 g (compound 4a).
This is not a general solution to the problem of finding mild conditions for
oxadiazole formation, however. In addition to the poor yield obtained on cyclizing
3 g, we were disappointed to find that diacyl hydrazines 3h and 3i proved unreactive
under our conditions even when adding multiple equivalents of Tf2O (Fig. 2).
REPRESENTATIVE EXPERIMENTAL PROCEDURE
Tf2O (0.353 ml, 1.5 equivalents) was added to a solution of diacyl hydrazine 3b
(500 mg, 1.43 mmol) in DCM (5 ml) and NMI (0.365 ml, 3.2 equivalents) cooled in
an ice-water bath, keeping the reaction temperature ꢂ0 ꢁC. After 1 h, thin-layer chro-
matography suggested completion. The reaction mixture was washed with 2M HCl
(10 ml) and then with saturated aqueous NaHCO3 (10 ml). The organic layer was
washed with brine, dried over MgSO4, and evaporated. The oily residue was tritu-
rated with Et2O to give the oxadiazole 4b (339 mg, 71%) as a cream-colored solid.
1H NMR (CDCl3, 400 MHz) d ¼ 3.98 (s, 3H), 4.76 (s, 2H), 5.23 (s, 2H), 6.98 (d,
J ¼ 8.2 Hz, 1H), 7.33 (d, J ¼ 7.0 Hz, 1H), 7.38 (t, J ¼ 7.4 Hz, 2H), 7.45 (d, J ¼ 7.4 Hz,
2H), 7.57 (dd, J ¼ 8.2, 2 Hz, 1H), 7.60 (d, J ¼ 2 Hz, 1H). LRMS (ESI) m=z 331=333
[M þ 1]þ.
CONCLUSION
In conclusion, we have demonstrated an improved procedure for the
preparation of oxadiazoles from diacyl hydrazines under mild conditions. This
method is characterized by simple procedures, ease of isolation, good yields, and
high tolerance of functional and protecting groups. We anticipate that the ability

OXADIAZOLES FROM DIACYL HYDRAZINES
3025
of our protocol easily to install an oxadiazole ring in the center of a molecule will
increase the popularity of this moiety in medicinal chemistry. Further research is
necessary to identify a truly general set of conditions for this cyclization. It is also
to be hoped the N-methylimidazole may serve as a cheap and effective alternative
to 2,6-di-t-butyl-4-methylpyridine in other processes involving triflic anhydride,
such as the preparation of triflates from lactams. Preliminary results from our
laboratories suggest that this is indeed the case.
ACKNOWLEDGMENT
Thanks go to Mike Kinns for spectroscopic studies elucidating the structure of
compound 5.
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