Microwave-assisted one-step synthesis of substituted 2-chloromethyl-1,3,4- oxadiazoles

Article abstract of DOI:10.1081/SCC-200025582

We have developed a simple one-step synthesis of 2-chloromethyl-1,3,4- oxadiazoles from commercially available acylhydrazides using 1-chloro-2,2,2-trimethoxyethane as a solvent under microwave irradiation.

Full text of DOI:10.1081/SCC-200025582

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Microwave‐Assisted One‐Step
Synthesis of Substituted
2‐Chloromethyl‐1,3,4‐oxadiazoles
Reina Natero a , Dmitry O. Koltun a & Jeffery A.
Zablocki a
a Department of Bioorganic Chemistry , CV
Therapeutics , 3172 Porter Drive, Palo Alto,
California, 94304, USA
Published online: 10 Jan 2011.
To cite this article: Reina Natero , Dmitry O. Koltun & Jeffery A.
Zablocki (2004) Microwave‐Assisted One‐Step Synthesis of Substituted
2‐Chloromethyl‐1,3,4‐oxadiazoles, Synthetic Communications: An International
Journal for Rapid Communication of Synthetic Organic Chemistry, 34:14, 2523-2529,
DOI: 10.1081/SCC-200025582
To link to this article: http://dx.doi.org/10.1081/SCC-200025582
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 14, pp. 2523–2529, 2004
Microwave-Assisted One-Step Synthesis of
Substituted 2-Chloromethyl-1,3,4-
oxadiazoles
*
Reina Natero, Dmitry O. Koltun, and Jeffery A. Zablocki
Department of Bioorganic Chemistry, CV Therapeutics, Palo Alto,
California, USA
ABSTRACT
We have developed a simple one-step synthesis of 2-chloromethyl-1,3,4-
oxadiazoles from commercially available acylhydrazides using 1-chloro-
2,2,2-trimethoxyethane as a solvent under microwave irradiation.
INTRODUCTION
Numerous compounds containing 1,3,4-oxadiazoles have been evaluated
for their antibacterial, fungicidal, and insecticidal activity.[1–3] Furthermore,
1,3,4-oxadiazoles have been used as peptide mimetics due to their particular
geometric and electrostatic properties,[4] exemplified by the nonpeptidic
*
Correspondence: Reina Natero, Department of Bioorganic Chemistry, CV Thera-
peutics, 3172 Porter Drive, Palo Alto, CA 94304, USA; E-mail: reina.natero@cvt.com.
2523
DOI: 10.1080/SCC-200025582
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2524
Natero, Koltun, and Zablocki
inhibitors of human neutrophil elastase that also have favorable pharmaco-
kinetic and safety profiles.[5] Many of these compounds can be prepared
by a simple alkylation using the corresponding 2-chloromethyl-1,3,4-
oxadiazoles.[1,3,6] Synthetic approaches to obtaining these electrophilic build-
ing blocks include multi-step procedures that require a conventional aqueous
workup.[7–10]
We were interested in developing a synthesis of 2-chloromethyl-l,3,4-
oxadiazoles that could simplify the parallel production of these peptide
mimetic building blocks. The desired synthesis should be carried out in
one-step from inexpensive commercially available starting materials, and
could be further simplified by the exclusion of an aqueous workup prior
to purification. Herein, we report that benzoic hydrazide readily converts
into 2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole (1) using 1-chloro-2,2,2-
trimethoxyethane as a solvent under microwave irradiation (mW, Sch. 1),
and that this reaction is then directly purified by chromatography. After opti-
mization of this reaction, we explored the effect of substituted phenyl acyl
hydrazides on this one-step synthesis.
During the optimization of this reaction (mW, Sch. 1), we kept the time
constant at 300 sec while increasing the temperature in 208C increments,
and observed that microwave irradiation at a temperature of 1608C gave
the highest yield of 68% (Table 1, compare entries 1–8). Doubling and
tripling the reaction time to 600 and 900 sec while maintaining the tempera-
ture at 1608C, did not affect the yield significantly (Table 1, entries 9 and
10), and lead to the formation of by-products. In addition, we sought to
improve the yield of this reaction by removal of methanol with the use
of
a known adsorbent such as molecular sieves of the relevant
pore size.[11] However, the addition of 5 A molecular sieves while
keeping the temperature at 1608C for 300 sec, only increased the yield by
5% (Table 1, entry 11).
˚
We then applied automated microwave irradiation to many substituted
phenyl hydrazides using the conditions found in Table 1, entry 6. During this
parallel synthesis, we observed that different substituents affected the yield
for the formation of chloromethyl-l,3,4-oxadiazoles (Table 2, entries 2–15).
Scheme 1.

Synthesis of 2-Chloromethyl-1,3,4-oxadiazoles
2525
Table 1. Optimization of the reaction of benzoic hydrazide with
1-chloro-2,2,2-trimethoxyethane.
Temperature
(8C)
Time of mW,
irradiation (sec)
Yield
(%)
Entry
1
2
60
80
300
300
300
300
300
300
300
300
600
900
300
0a
27a
3
100
120
140
160
180
200
160
160
160
47a, 47b
56a
4
5
67a
6
68a
7
59a
8
47a
9
71a
10
11
74a
73a,c
aYield determined by HPLC analysis with external standard
calibration curve at 254 nm.
bIsolated yield.
c
˚
5 A molecular sieves.
The methoxy, fluoro, and chloro substituents were fully explored (o, m, and p,
Table 2, entries 2–10) demonstrating a trend of markedly lower yields for the
2-substitution (Table 2, entries 4, 7, and 10) as compared to their 4- and 3-sub-
stituted counterparts (Table 2, entries 2, 3, 5, 6, 8, and 9). This trend is not con-
sistent with a pronounced electronic effect, but rather with steric bulk, and is
further supported by the lower yield observed for 2-trifluoromethyl substituted
oxadiazole (Table 2, entry 11). Although all substitution patterns afforded useful
yields, the 4-substituted phenyl derivatives were further explored (Table 2,
entries 12–15). These 4-substituted derivatives are favorable from a medicinal
chemistry perspective, because hydrogen replacements at this position remove a
known site of metabolism (e.g. phase I hydroxylation), and therefore can
enhance oral bioavailability. We observed that a few substituted oxadiazoles
with lipophilic groups, crystallized upon cooling allowing for a simple isolation
by filtration (Table 2, entries 14 and 15).
In conclusion, we have developed a rapid and simple one-step method for
the preparation of substituted 2-chloromethyl-1,3,4-oxadiazoles from the cor-
responding commercially available acyl hydrazides. The short reaction times,
availability of reagents, and absence of aqueous workup provide an attractive
protocol for rapidly generating these building blocks.

2526
Natero, Koltun, and Zablocki
d

Synthesis of 2-Chloromethyl-1,3,4-oxadiazoles
2527

2528
Natero, Koltun, and Zablocki
EXPERIMENTAL
Typical Experimental Procedure for the
Microwave-Assisted Synthesis
Benzoic hydrazide (0.214g, 1.57mmol) was placed in a Smith Process
Viala (3 mL glass vessel) followed by the addition of 1-chloro-2,2,2-
trimethoxyethane (1mL). The vial was sealed and the mixture was heated in
the Emrys Optimizer [11] microwave at 1608C for 300 sec, fixed hold time on,
absorption level normal, pre-stirring 10sec. It was then cooled to room tempera-
ture, diluted with 2 mL of methanol and purified by semi-prep HPLC. The
HPLC fractions were evaporated under reduced pressure to furnish 2-(chloro-
methyl)-5-phenyl-1,3,4-oxadiazole as a white solid (0.170g, 55%)
ACKNOWLEDGMENTS
We would like to thank Dr. David Lustig and Mr. Irving Fong for their
help with liquid chromatography and mass-spectrometry, and Dr. Brent
Blackburn for helpful discussions.
REFERENCES
1. Yamamoto, H.; Terasawa, T.; Nakamura, A.; Kawabata, K.; Takasugi, H.;
Tanaka, H.; Matsumoto, S.; Matsumoto, Y.; Tawara, S. Bioorg. Med.
Chem. Lett. 2001, 9, 465–475.
2. Chen, H.; Li, Z.; Han, Y. J. Agric. Food Chem. 2000, 48, 5312–5315.
3. Cao, S.; Qian, X.; Song, G.; Huang, Q. J. Fluorine Chem. 2002, 117,
63–66.
¨
4. (a) Borg, S.; Estenne-Bouhtou, G.; Luthman, K.; Csoregh, I.; Hesselink, W.;
Hacksell, U. J. Org. Chem. 1995, 60, 3112–3120; (b) Borg, S.; Vollinga, R.;
Labarre, M.; Payza, K.; Terenius, L.; Luthman, K. J. Med. Chem. 1999, 42,
4331–4342.
5. Ohmoto, K.; Yamamoto, T.; Okuma, M.; Toshihide, H.; Imanishi, H.;
Odagaki, Y.; Kawabata, K.; Sekioka, T.; Hirota, Y.; Matsuoka, S.;
Nakai, H.; Toda, M. J. Med. Chem. 2001, 44, 1268–1285.
aSmith Process Vial and Emrys Optimizer are registered trademarks of Personal
Chemistry, Inc., Uppsala.

Synthesis of 2-Chloromethyl-1,3,4-oxadiazoles
2529
6. Kelarev, V.; Silin, M.; Grigor’eva, N.; Koshelev, V. Chem. Heterocyclic.
Comp. 2000, 36, 207–213.
7. Lancelot, J.; Maume, D.; Robba, M. J. Heterocyclic Chem. 1980, 17,
625–629.
8. Hogale, M.; Shelar, A.; Kachare, D.; Salunkhe, V. J. Ind. Chem. Soc.
1987, 64, 314–316.
9. Cao, S.; Qian, X.; Song, G.; Chai, B.; Jiang, Z. J. Agric. Food Chem.
2003, 51, 152–155.
10. El-Abadelah, M.; Nazer, M.; Hussein, A.; Awadallah, A. J. Heterocyclic
Chem. 1991, 28, 1229–1234.
11. Furniss, B.; Hannaford, J.; Smith, P.; Tatchell, A.R. Solvent and reagents.
In Vogel’s Texbook of Practical Organic Chemistry, 5th Ed.; Addison-
Wesley Publishing Company: Boston, 1996; 396–397.
Received in the USA March 2, 2004