General synthesis of tetrasubstituted alkenyl-1,3,4-oxadiazoles

Article abstract of DOI:10.1016/j.tetlet.2005.11.057

Tetrasubstituted alkenyl-1,3,4-oxadiazoles were synthesized in moderate to excellent yield, under mild conditions and in the presence of sensitive functional groups, via the cyclization of diacylhydrazides using PPh₃ and hexachloroethane in the

Full text of DOI:10.1016/j.tetlet.2005.11.057

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 511–514
General synthesis of tetrasubstituted alkenyl-1,3,4-oxadiazoles
*
´
Clint A. James, Brigitte Poirier, Christiane Grise, Alain Martel and Edward H. Ruediger
Bristol-Myers Squibb Pharmaceutical Research Institute, 100 boulevard de l’Industrie, Candiac, Quebec, Canada J5R 1J1
Received 3 November 2005; accepted 10 November 2005
Available online 28 November 2005
Abstract—Tetrasubstituted alkenyl-1,3,4-oxadiazoles were synthesized in moderate to excellent yield, under mild conditions and in
the presence of sensitive functional groups, via the cyclization of diacylhydrazides using PPh3 and hexachloroethane in the presence
of Hunigꢀs base. An efficient one-pot acylation/cyclization approach for the conversion of acylhydrazides to 1,3,4-oxadiazoles is also
¨
described. The complexity of our substrate as well as the wide range of functional groups incorporated substantially broadens the
scope of this methodology.
ꢀ 2005 Elsevier Ltd. All rights reserved.
The replacement of acid and ester functionality in
medicinal chemistry continues to be a popular strategy
in the search for compounds with superior pharmaco-
kinetic profiles. In particular, the 1,3,4-oxadiazole ring
is increasingly used and has found application in several
areas.1 Consequently, the synthesis of this heterocycle
has attracted considerable attention and a wide variety
of methods have been used for its assembly.2 By far
the most common strategy involves the dehydrative
cyclization of diacylhydrazides, usually with strongly
acidic reagents such as POCl3,3 SOCl2,4 P2O5,5
H2SO4,6 or PPA.7 More recently, however, several
methods have been developed using essentially neutral
conditions and cyclization mediators such as Tf2O8
and HMDS/TBAF,9 as well as solid supported cycliza-
tion reagents.10
R
N
N
O
Ph
BocN
1
We reasoned that given the success of the PPh3/X2 com-
bination in such processes as halogenation of alcohols,12
these conditions, when properly buffered, might result in
efficient amide dehydration and subsequent cyclization.
In fact, a further survey of the literature showed that
for a limited number of cases similar conditions had
been used to effect this transformation. Mazurkiewicz
and Grymel13 showed that N-benzoyl-N0-acetylhydr-
azine and N,N0-dibenzoylhydrazine were converted to
the corresponding oxadiazoles in good to excellent
yields with PPh3ÆBr2, PPh3ÆCBr4, and PPh3ÆCCl4 in
refluxing CH2Cl2 in the presence of NEt3. A limited
number of N-acylsemicarbazides are also converted
smoothly to the corresponding 2-aminooxadiazoles
under these conditions. We were similarly encouraged
by a report by Polanc14 who effected similar chemistry
making use of PPh3/(BrCl2C)2. While the conditions
reported would be ideal for our purposes, the scope of
the reaction was not investigated. Only a limited number
of examples were reported starting only from 1,4-disubsti-
tuted semicarbazides to give 2-amino-1,3,4-oxadiazoles.
Recently, we required a convenient synthesis of vinyl-
1,3,4-oxadiazoles of type 1. A search of the literature
revealed that 1,3,4-oxadiazoles as substituents on
tetrasubstituted olefins are rare.11 In addition to the
complex nature of our substrate, we also required very
mild conditions, which would allow the incorporation
of sensitive functional groups, while leaving our protect-
ing group intact. Unfortunately, we found that several
of the standard conditions for diacylhydrazide cycliza-
tion, gave only complex mixtures of products (Scheme
1).
In our study, we were delighted to observe that when
a solution of diacylhydrazide 2 was treated with
*
Corresponding author. Tel.: +1 450 444 6133; fax: +1 450 444
4166; e-mail: clint.james@bms.com
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.057

512
C. A. James et al. / Tetrahedron Letters 47 (2006) 511–514
O
O
Me
N
N
HN
NH
Me
HN
NH
Me
O
O
a or b
c
O
Ph
Ph
Ph
BocN
BocN
BocN
2
1h
2
Scheme 1. Reagents and conditions: (a) POCl3/CH3CN/NEt3; (b) Tf2O/CH2Cl2/NEt3; (c) PPh3/Cl3CCCl3/i-Pr2NEt/CH3CN (75%).
hexachloroethane in acetonitrile in the presence of Hu-
¨
be unsuitable for this conversion in acetonitrile. How-
nigꢀs base and PPh3, a very fast cyclization occurred at
room temperature. Subsequent routine aqueous workup
afforded the desired oxadiazole in good yield (Scheme
1). Under these conditions, a series of diacylhydrazides15
2a–j were smoothly cyclized to give oxadiazoles 1a–j in
moderate to excellent yields (Table 1).16
ever, when 3 was treated with acetic anhydride in aceto-
nitrile containing Hunigꢀs base, clean conversion to the
¨
diacylhydrazide was effected (based on LCMS and
TLC analyses). Subsequent addition of PPh3, followed
by hexachloroethane, resulted in complete cyclization
to the oxadiazole after about 15 min at room tempera-
ture. Standard workup and purification afforded the
1,3,4-oxadiazole 1h, which was identical with the previ-
ously prepared material. A number of acylating agents
was used in an analogous manner to afford oxadiazoles
1k–p (Table 2).
These conditions are very mild and the olefin functional-
ity does not seem to interfere with the course of the reac-
tion. A wide variety of functional groups are tolerated,
for example, bromomethyl (entry 2) and silyloxymethyl
(entry 4). Additionally, heteroatom functionality (e.g.,
OMe, entry 3) and the versatile ester group (entry 5)
may also be incorporated into the 2-position of the
oxadiazole ring. Moreover, the base-sensitive Fmoc-
protected azetidine (entry 9) was well tolerated under
these conditions, as was the trityl protected aziridine
(entry 10).
As can be seen in Table 2, the yields of the one-pot pro-
cedure are generally good and again a variety of func-
tional groups are tolerated.18 For example, the use of
trifluoroacetic anhydride furnishes a 2-trifluoromethyl-
oxadiazole (entry 3), while a nitrogen functional group
can be installed using N,N-dimethylcarbamoyl chloride
(entry 4). Interestingly, the latter was found to react
smoothly with 3, in contrast to simple acid chlorides,
which gave complex mixtures.
Having established the conditions of the cyclization
step, we hoped that the synthesis could be made more
efficient by carrying out a one-pot procedure17 directly
from the monoacylhydrazide 3, thus eliminating one
purification step. Disappointingly, treatment of 3 with
In conclusion, we have demonstrated that PPh3/
Cl3CCCl3/i-Pr2NEt are efficient conditions for the
cyclization of diacylhydrazides to give a series tetrasub-
stituted alkenyl-1,3,4-oxadiazoles, where standard meth-
ods failed. We have also significantly expanded the
scope of this reaction, demonstrating that a wide variety
of functionality is tolerated, including the tetrasubsti-
tuted olefin of the core structure. An efficient one-pot
acetyl chloride in the presence of Hunigs base gave only
¨
a complex mixture, suggesting that acid chlorides may
Table 1. Synthesis of 1,3,4-oxadiazoles from diacylhydrazides
O
R
N
N
HN
NH
R
PPh3 / Cl3CCCl3
O
O
Table 2. One-pot synthesis of 1,3,4-oxadiazoles
iPr2NEt / CH3CN
rt
Ph
Ph
R
N
BocN
BocN
CONHNH2
1) acylating agent
N
O
2a-j
1a-j
MeCN / iPr2NEt
Ph
BocN
Ph
Entry
SM
R
Product
Yield (%)
2) PPh3 / Cl3CCCl3
BocN
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
c-Pr
1a
1b
1c
1d
1e
1f
95
53
85
74
54
70
98
75
3
1m, k-p
CH2Br
OMe
CH2OTBS
CO2Et
H
Entry Acylating agent
R
Product Yield (%)
1
2
3
4
5
6
Ac2O
(CH3CH2CO)2O
TFAA
ClCONMe2
(t-BuCO)2O
(PhCO)2O
Me
Et
CF3
1h
1k
1l
88
68
77
81
95
78
2g
2h
c-Bu
Me
1g
1h
NMe2 1m
t-Bu
Ph
1n
1o
9
2i
2j
1i
1j
75
68
NFmoc
NTrt
10
7
Methacrylic anhydride
1p
56

C. A. James et al. / Tetrahedron Letters 47 (2006) 511–514
513
11. A Chemical Abstracts search found only five com-
pounds; (a) Suda, Y.; Onikubo, S. Jpn. Kokai Tokkyo
Koho, JP 2002060742 A2, 2002; Chem. Abstr. 2002, 136,
207495; (b) Okutsu, S.; Onikubo, S.; Tamano, M.;
Enokida, T.; Jpn. Kokai Tokkyo Koho, JP 10152676
A2, 1998; Chem. Abstr. 1998, 129, 47261; (c) Yumoto, M.;
Yagihara, N.; Fujimori, J.; Jpn. Kokai Tokkyo Koho, JP
10020495 A2, 1998; Chem. Abstr. 1998, 128, 174182; (d)
Abdel-Hamid, A. A.; Fahmy, A. F. A.; Shiba, S. A.; El-
Hawary, N. A. Egypt. J. Chem. 1995, 36, 363; Chem.
Abstr. 1995, 124, 117240.
procedure for the conversion of acylhydrazides to 1,3,4-
oxadiazoles has also been demonstrated. The latter
approach is potentially amenable to parallel synthesis
strategies for the production of a wide variety of func-
tionalized 1,3,4-oxadiazoles, given the large number of
monoacylhydrazides, which are commercially available
and the mild conditions used for effecting the key cycli-
zation step.
12. (a) Nair, V.; Nair, J. S.; Vinod, A. U. Synthesis 2000, 1713;
(b) Valentine, D. H., Jr.; Hillhouse, J. H. Synthesis 2003,
317; (c) Yang, Y.-H.; Shi, M. J. Org. Chem. 2005, 70, 8645.
13. Mazurkiewicz, R.; Grymel, M. Polish J. Chem. 1997, 71,
77; For one example using similar conditions, see: Brown,
P.; Best, D. J.; Broom, N. J. P.; Cassels, R.; OꢀHanlon, P.
J.; Mitchell, T. J.; Osborne, N. F.; Wilson, J. M. J. Med.
Chem. 1997, 40, 2563.
References and notes
1. For example, see: (a) Tully, W. R.; Gardner, C. R.;
Gillespie, R. J.; Westwood, R. J. J. Med. Chem. 1991, 34,
2060; (b) Chen, C.; Senanayake, C. H.; Bill, T. J.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J. J. Org. Chem. 1994,
59, 3738; (c) Saunders, J.; Cassidy, M.; Freedmen, S. B.;
Harley, E. A.; Iversen, L. L.; Kneen, C.; MacLeod, A. M.;
Merchant, K. J.; Snow, R. J.; Baker, R. J. Med. Chem.
1990, 33, 1128; (d) Omar, F. A.; Mahfouz, N. M.;
Rahman, M. A. Eur. J. Med. Chem. 1996, 37, 2421.
2. For examples of 1,3,4-oxadiazole synthesis from silylated
diacylhydrazines, see: (a) Rigo, B.; Fassuer, D.; Cauliez,
P.; Couturier, D. Synth. Commun. 1989, 19, 2321; (b)
Rigo, B.; Cauliez, P.; Fasseur, D.; Couturier, D. Synth.
Commun. 1988, 18, 1247; For cyclizations using chlor-
amine T, see: (c) Singh, S. P.; Naithani, R.; Batra, H.;
Prakash, O.; Sharma, D. Indian J. Heterocycl. Chem. 1998,
8, 103; (d) Jedlovska, E.; Lesko, J. Synth. Commun. 1994,
24, 1879; For an example using the aza-Wittig reaction,
see: (e) Froeyen, P. Phosphorus, Sulfur Silicon Relat. Elem.
1991, 57, 11; For an example using PbO2, see: (f) Milcent,
R.; Barbier, G. J. Heterocycl. Chem. 1983, 20, 77; For
iodosobenzene diacetate-mediated synthesis of diacylhydr-
azines, see: (g) Singh, S. P.; Batra, H.; Sharma, P. K. J.
Chem. Res. Syn. 1997, 12, 468; For palladium (0)-
catalyzed cyclization, see: (h) Lutun, S.; Hasiak, B.;
Couturier, D. Synth. Commun. 1999, 29, 111; For a
method using 2-chloro-1,3-dimethylimidazolinium chlo-
ride, see: (i) Isobe, T.; Ishikawa, T. J. Org. Chem. 1999, 64,
6989; For a method using BF3ÆEt2O see: (j) Tandon, V. K.;
Chhor, R. B. Synth. Commun. 1999, 31, 1727; For a
method using microwave assistance see: (k) Natero, R.;
Koltun, D. O.; Zablocki, J. A. Synth. Commun. 2004, 34,
2523; For ZrCl4 catalyzed cyclization see: (l) Sharma, G.
V. M.; Begum, A.; Krishna, P. R. Synth. Commun. 2004,
34, 2387; For the synthesis of haloalkyl-1,3,4-oxadiazoles
from cyclopropyldiacylhydrazides see: (m) Yang, Y.-H.;
Shi, M. Tetrahedron Lett. 2005, 46, 6285.
3. (a) Hamad, A.-S. S.; Hashem, H. I. J. Heterocycl. Chem.
2002, 39, 1325; (b) Kerr, V. N.; Ott, D. G.; Hayes, F. N. J.
Am. Chem. Soc. 1960, 82, 186.
4. (a) Borg, S.; Vollinga, R. C.; Labarre, M.; Payza, K.;
Terenius, L.; Luthman, K. J. Med. Chem. 1999, 42, 4331;
(b) Klingsberg, E. J. Am. Chem. Soc. 1958, 80, 5786.
5. Carlsen, P. H. J.; Jorgensen, K. B. J. Heterocycl. Chem.
1994, 31, 805.
6. Short, F. W.; Long, L. N. J. Heterocycl. Chem. 1969, 6, 7.
7. Reddy, C. K.; Reddy, P. S. N.; Ratnam, C. V. Synthesis
1983, 842.
8. Spiros, L.; Allen, M. P.; Segelstein, B. E. Synth. Commun.
2000, 30, 437.
9. Rigo, B.; Cauliez, P. Synth. Commun. 1986, 16, 1665.
10. (a) Brain, C. T.; Paul, J. M.; Loong, Y.; Oakley, P. J.
Tetrahedron Lett. 1999, 40, 3275; (b) Brain, C. T.;
Brunton, S. A. Synlett 2001, 382; (c) Brown, B.; Clemens,
I.; Neesom, J. K. Synlett 2000, 131; (d) Huang, X.; Zhu,
Q. J. Chem. Res. Syn. 2000, 300.
14. Kosˇmrlj, J.; Kocˇevar, M.; Polanc, S. Synlett 1996, 7,
652.
15. The diacylhydrazides were prepared either by coupling of
the acid corresponding to 3, with an excess of the
appropriate hydrazide (AcNHNH2, HCONHNH2, or
MeOCONHNH2) in the presence of EDCI/HOBt in
DMF, or by acylation of 3 with the corresponding acid
chloride in H2O/dioxane (1:1) and Na2CO3 as base. The
latter procedure is exemplified by the preparation of 2b:
To a solution of 3 (0.220 g, 0.66 mmol) in dioxane/water
(1:1, 4 mL) was added Na2CO3 (0.07 g, 0.66 mmol) and
the solution was cooled to 0 ꢁC. Bromoacetyl bromide
(0.055 mL, 0.63 mmol) was added slowly. The mixture was
allowed to stir at 0 ꢁC for 1 h and was then quenched with
satd NH4Cl and extracted with EtOAc (·3). The combined
organic layers were washed (H2O, brine), dried (Na2SO4),
and concentrated in vacuo to afford diacyl hydrazide 2b
(0.209 mg, 70%), which was of sufficient purity for use in
1
the following step. H NMR (400 MHz, CDCl3) d 7.33–
7.40 (m, 3H), 7.21–7.24 (m, 2H), 4.09 (s, 2H), 3.16 (t,
J = 5.7 Hz, 2H), 3.38 (t, J = 5.7 Hz, 2H), 2.87 (t,
J = 5.7 Hz, 2H), 2.17 (t, J = 5.7 Hz, 2H), 1.45 (s, 9H).
LCMS m/e 452 (M+H)+. Monoacylhydrazide 3 was
prepared by EDCI/HOBt coupling of the corresponding
acid with an excess of hydrazine monohydrate.
16. Representative procedure for the cyclization of diacylhyd-
razides: To a suspension of diacylhydrazide 2f (0.106 g,
0.294 mmol) in CH3CN (2 mL) was added i-Pr2NEt
(0.30 mL, 1.7 mmol) and PPh3 (0.137 g, 0.523 mmol),
followed after 5 min by hexachloroethane (0.092 mg,
0.389 mmol). After stirring the mixture at room temper-
ature for 4 h the solvent was removed in vacuo and the
residue partitioned with H2O/EtOAc. The organic phase
was separated and the aqueous phase was re-extracted
with EtOAc. The combined organic phases were washed
(H2O, brine), dried (Na2SO4) and evaporated, and the
residue was purified by preparative HPLC to give 1f
1
(0.0504 g, 50%) as a colorless solid: H NMR (400 MHz,
CDCl3) d 8.28 (s, 1H), 7.41–7.36 (m, 3H), 7.18–7.16 (m,
2H), 3.59 (dd, J = 5.6, 5.8 Hz, 2H), 3.43 (dd, J = 5.5,
5.9 Hz, 2H), 2.91 (dd, J = 6.1, 5.5 Hz, 2H), 2.31 (dd,
J = 5.8, 5.5 Hz, 2H), 1.45 (s, 9H). LCMS: m/e 342
(M+H)+.
17. Polanc has demonstrated a similar one-pot protocol for a
limited number of substrates starting from monoacylhyd-
razides and isocyanates to give 2-amino-1,3,4-oxadiazoles
(see Ref. 14).
18. Representative procedure for the one-pot acylation/cycli-
zation: To a solution of hydrazide 3 (1.00 g, 3.02 mmol)
and i-Pr2NEt (3.62 mL, 20.8 mmol) in CH3CN (20 mL)

514
C. A. James et al. / Tetrahedron Letters 47 (2006) 511–514
was added acetic anhydride (0.357 mL, 3.78 mmol) and
the mixture was allowed to stir for 1 h at room temper-
ature. To this mixture was added PPh3 (3.25 g,
12.39 mmol), followed by hexachloroethane (1.65 g,
6.95 mmol). The mixture was allowed to stir for 30 min
and then it was worked up and purified as above (cf. Ref.
16) to afford 1h (0.946 mg, 88%) as a colorless solid: H
NMR (400 MHz, CDCl3) d 7.44–7.34 (m, 3H), 7.39–7.23
(m, 2H), 3.56 (m, 3H), 3.40 (m, 3H), 2.85 (br m, 2H), 2.33
(s, 3H), 2.20 (m, 2H). LCMS: m/e 356 (M+H)+.
1