A variety of reagents have been employed for thiosemicar-
bazide cyclization, including I2/NaOH,2g carbodiimides,7
tosyl chloride,8 and stoichiometric mercury salts.2c,i,9 Al-
though these procedures are often effective, they are usually
performed above room temperature, and they do not provide
ready access to N,N-disubstituted 2-amino-1,3,4-oxadiazoles.
preparing 2-amino-1,3,4-oxadiazoles through C2-N bond
formation. The procedure avoids the use of iso[thio]cyanates
and toxic metal salts. Furthermore, secondary amine nucleo-
philes generate products difficult to access through cyclo-
dehydration (i.e., in Scheme 1, when R2, R3 * H). In this
report, we discuss the results of our preliminary investigation.
By comparison, there are relatively few strategies analo-
gous to method B (Scheme 1). The key steps are: (1)
activation of an oxadiazol-2-one (X ) O) or 2-thione (X )
S) at C2; (2) addition of a nitrogen nucleophile to generate
the C2-N bond. A typical procedure for oxadiazole-2-thione
activation requires two steps: sulfur alkylation, then oxidation
to the sulfone.4,10,11 Oxadiazole-2-one chlorination using
PCl5/POCl3 has been reported, though yields were poor (ca.
8-10%).10
Scheme 2. Model System for Reaction Optimization
a See Table 1 for list of bases and coupling reagents. b Internal standard
for HPLC analysis.
Previously, we developed12 an efficient procedure for
direct amination of cyclic amides and ureas using BOP,13
a
well-known peptide coupling reagent.14 We envisioned that
activation of cyclic carbamates, like 1,3,4-oxadiazol-2-ones,
could be achieved by a similar approach. 1,3,4-Oxadiazol-
2-ones, readily prepared from acid hydrazides using phosgene
or milder phosgene equivalents,15 are vulnerable to ring
opening by nitrogen nucleophiles, particularly at high tem-
perature.15b,d,16 We discovered that phosphonium reagents
(e.g., BOP) promote a different reaction path: SNAr substitu-
tion at C2 by primary and secondary amine nucleophiles,
allowing synthesis of 2-amino-1,3,4-oxadiazoles in good to
excellent yields. This provides a convenient method for
We began by optimizing the reaction conditions. 1,3,4-
Oxadiazol-2-one 2a (from 3-bromobenzoic acid hydrazide,
1a) was selected for screening (Scheme 2). BnNH2 was
coupled to 2a in DMF at room temperature with BOP and
one of seven bases; conversion to product 3 was determined
by HPLC-MS analysis of each reaction mixture (Table 1,
entries 1-7).17 Proton sponge, DMAP, and diisopropylethy-
lamine (DIPEA) all performed well under these conditions.
Nearly quantitative conversion to 3 was achieved using
DIPEA with BOP (entry 7).
(5) Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J. Tetrahedron Lett.
1999, 40, 3275–3278.
(6) (a) Appel, R. Angew. Chem., Int. Ed. Engl. 1975, 14, 801–811. (b)
Kosˇmrlj, J.; Kocˇevar, M.; Polanc, S. Synlett 1996, 652–654. (c) Mazurk-
iewicz, R.; Grymel, M. Pol. J. Chem. 1997, 71, 77–82. (d) Dumcˇiujte˙, J.;
Table 1. Results of Reaction Condition Screening
entry
base
TMGb
reagent
hours
yield, 3a
ˇ
Martynaitis, V.; Holzer, W.; Mangelinckx, S.; De Kimpe, N.; Sacˇkus, A.
Tetrahedron 2006, 62, 3309–3319.
1
2
3
4
5
6
7
8
BOP
BOP
BOP
BOP
BOP
BOP
BOP
BOP
18.5
18.5
18.5
18.5
18.5
18.5
18.5
1
30%
72%
76%
82%
94%
95%
>99%
96%
92%
76%
74%
0%
(7) (a) AboulWafa, O. M.; Omar, A. M. M. E. Sulfur Lett. 1992, 14,
181–188. (b) Coppo, F. T.; Evans, K. A.; Graybill, T. L.; Burton, G.
Tetrahedron Lett. 2004, 45, 3257–3260. (c) Baxendale, I. R.; Ley, S. V.;
Martinelli, M. Tetrahedron 2005, 61, 5323–5349. (d) Severinsen, R.;
Kilburn, J. P.; Lau, J. F. Tetrahedron 2005, 61, 5565–5575.
(8) Dolman, S. J.; Gosselin, F.; O’Shea, P. D.; Davies, I. W. J. Org.
Chem. 2006, 71, 9548–9551.
DBU
Barton’s basec
2,6-lutidine
proton sponge
DMAP
DIPEA
DIPEA
(9) Wang, X.; Li, Z.; Wei, B.; Yang, J. Synth. Commun. 2002, 32, 1097–
1103
.
9
DIPEA
DIPEA
DIPEA
DIPEA
BrOPd
PyBOPe
PyAOPf
HATUg
EDCIh
1
1
1
16
(10) (a) Madhavan, R.; Srinivasan, V. R. Ind. J. Chem. 1969, 7, 760–
765. (b) Alternate route to 2-chloro-1,3,4-oxadiazoles: Deshukh, M. B.;
10
11
12
13
Shelar, M. A.; Mulik, A. R. Ind. J. Heterocycl. Chem. 2000, 10, 13–16
.
(11) (a) Hoggarth, E. J. Chem. Soc. 1949, 1918–1923. (b) Direct
amination of oxadiazole-2-thiones has been reported : Laddi, U. V.; Desai,
S. R.; Bennur, R. S.; Bennur, S. C. Ind. J. Heterocycl. Chem. 2002, 11,
319–322. (c) Honnalli, S. S.; Ronad, P. M.; Vijaybhasker, K.; Jukkeri, V. I.;
DIPEA
16
0%
a Chromatographic yield of 3 relative to Ph2O internal standard.
b Tetramethylguanidine. c N-t-butyl-N′,N′,N′′,N′′-tetramethylguanidine.
d Bromotris(dimethylamino) phosphonium·PF6.18a e (Benzotriazol-1-yloxy)
tripyrrolidinophosphonium·PF6.18b f (7-Azabenzotriazol-1-yloxy) tripyrroli-
dinophosphonium·PF6.18cg O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyl-
uronium·PF6. h N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide·HCl.
Kumar, R. Heterocycl. Commun. 2005, 11, 505–508
.
(12) (a) Wan, Z.-K.; Binnun, E.; Wilson, D. P.; Lee, J. Org. Lett. 2005,
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Levins, C. G.; Lin, M.; Tabei, K.; Mansour, T. S. J. Org. Chem. 2007, 72,
10194–10210.
-
(13) Benzotriazol-1-yloxytris(dimethylamino)-phosphonium·PF6
.
(14) Castro, B.; Dormoy, J. R.; Evin, G.; Selve, C. Tetrahedron Lett.
1975, 14, 1219–1222.
(15) (a) Smith, A. E. W. Science 1954, 119, 514. (b) Stempel, A.;
Zelauskas, J.; Aeschlimann, J. A. J. Org. Chem. 1955, 20, 412–418. (c)
Rosen, G. M.; Popp, F. D.; Gemmill, F. Q., Jr. J. Heterocycl. Chem. 1971,
8, 659–662. (d) Thompson, S. K.; Smith, W. W.; Zhao, B.; Halbert, S. M.;
Tomaszek, T. A.; Tew, D. G.; Levy, M. A.; Janson, C. A.; D’Alessio, K. J.;
McQueney, M. S.; Kurdyla, J.; Jones, C. S.; DesJarlais, R. L.; Abdel-
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(16) Grzyb, J. A.; Dekeyser, M. A.; Batey, R. A. Synthesis 2005, 2384–
A selection of coupling reagents were screened with the
same model system using DIPEA as base (Table 1, entries
8-13). There was >90% conversion to product 3 within 1 h
with phosphonium reagents BOP and BrOP. Neither PyBOP
(17) A sample containing a known concentration of 3 and Ph2O was
used to calibrate LCMS analysis.
2392
.
1756
Org. Lett., Vol. 10, No. 9, 2008