Facile one-Pot synthesis of 2,3,5-substituted 1,2,4-oxadiazolines from nitriles in aqueous solution

Article abstract of DOI:10.1021/ol0502073

(Chemical Equation Presented) Alkyl/aryl amidoximes, prepared from the corresponding nitriles and N-alkylhydroxylamines, have readily undergone consecutive Michael additions to electron-deficient alkynes and provided highly substituted 1,2,4-oxadiazolines

Full text of DOI:10.1021/ol0502073

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1391-1393
Facile One-Pot Synthesis of
2,3,5-Substituted 1,2,4-Oxadiazolines
from Nitriles in Aqueous Solution
B. Narasimhulu Naidu* and Margaret E. Sorenson
The Bristol-Myers Squibb Pharmaceutical Research Institute, 5 Research Parkway,
Wallingford, Connecticut 06422
narasimhulu.naidu@bms.com
Received February 1, 2005
ABSTRACT
Alkyl/aryl amidoximes, prepared from the corresponding nitriles and N-alkylhydroxylamines, have readily undergone consecutive Michael
additions to electron-deficient alkynes and provided highly substituted 1,2,4-oxadiazolines in good yields in homogeneous aqueous solution.
Oxadiazolines represent a class of heterocycle that, although
known for over a century, is rather limited in number. These
are partially reduced forms of well-known oxadiazoles.
Recently, these heterocycles have been receiving increased
attention due to their promising biological activity1 and
usefulness as synthetic intermediates.2 For example, oxa-
diazolines are reported to possess antitumor,1a anti-HIV,1b
antifungal,1c antiinflammatory,1d and anticonvulsant1e proper-
ties.
In 1889, Tiemann reported the first synthesis of a 1,2,4-
oxadiazoline derivative via cyclocondensation of benz-
amidoxime with acetaldehyde.3 This route is one of the most
robust and direct approaches to the synthesis of 1,2,4-
oxadiazolines. Many groups have used this or a slightly
modified route for the synthesis of these compounds.4
Furthermore, 1,2,4-oxadiazolines have also been prepared
by cycloaddition reactions. For example, Ibata and co-
workers employed a formal [2 + 3]-cycloaddition of oxazoles
and nitrosobenzenes to prepare 1,2,4-oxadiazolines.5a,b
Recently, Wagner et al. disclosed platinum(IV)-assisted
[2 + 3]-cycloaddition of nitrones to organonitriles to provide
1,2,4-oxadiazolines and then extended this methodology to
the first asymmetric synthesis of oxadiazolines using a chiral
sulfoxide ligand.5c,d Eguchi and co-workers synthesized 1,2,4-
oxadiazolines by the 1,3-dipolar cycloaddition of alkyl or
arylnitriles with nitrones under high-pressure conditions.6a,b
More recently, Wang and colleagues described an efficient
route suitable for the rapid synthesis of 1,2,4-oxadiazolines
via the 1,3-dipolar cycloaddition of in situ-generated nitrile
(4) (a) Lessel, J.; Herfs, G. Pharmazie 2000, 55, 22-26. (b) Lessel, J.
Arch. Pharm. (Weinheim) 1993, 326, 383-389. (c) Srivastava, R. M.; Freire,
M. V. S.; Chaves, A. S. S. C.; Beltrao, T. M.; Carpenter, G. B. J. Heterocycl.
Chem. 1987, 24, 101-105. (d) Malavaud, C.; Boisdon, M.-T.; Barrans, J.
Bull. Soc. Chim. France 1973, 2996-3000.
(5) (a) Suga, H.; Ibata, T. Chem. Lett. 1991, 1221-1224. (b) Suga, H.;
Shi, X.; Ibata, T. Bull. Chem. Soc. Jpn. 1998, 71, 1231-1236. (c) Wagner,
G.; Pombeiro, A. J. L.; Kukushkin, V. Y. J. Am. Chem. Soc. 2000, 122,
3106-3111. (d) Wagner, G.; Haukka, M. J Chem. Soc., Dalton Trans. 2001,
2690-2697.
(6) (a) Yu, Y.; Fujita, H.; Ohno, M.; Eguchi, S. Synthesis 1995, 498-
500. (b) Yu, Y.; Ohno, M.; Eguchi, S. J. Chem. Soc., Chem. Commun.
1994, 331-332. (c) Lin, X.-F.; Cui, S.-L.; Wang, Y.-G. Chem. Lett. 2003,
32, 842-843. (d) Shang, Y.-J.; Shou, W.-G.; Wang, Y.-G. Synlett 2003,
1064-1066. (e) Lin, X.-F.; Zhang, J.; Cui, S.-L.; Wang, Y.-G. Synthesis
2003, 1569-1573.
(1) (a) Chimirri, A.; Grasso, S.; Montforte, A.-M.; Rao, A.; Zappala,
M. Farmaco 1996, 51, 125-129. (b) Chimirri, A.; Grasso, S.; Montforte,
A.-M.; Montforte, P.; Zappala, M.; Carotti, A. Farmaco 1994, 49, 509-
511. (c) Singh, C. P.; Hasan, H. J. Indian Council Chem. 2002, 19, 46-49.
(d) Tinperciuc, B.; Parvu, A.; Palage, M.; Oniga, O.; Ghiran, D. Farmacia
(Bucharest) 1999, 47, 77-84. (e) Dogan, H. N.; Duran, A.; Rollas, S.; Sener,
G.; Armutak, Y.; Keyer-Uysal, M. Med. Sci. Res. 1998, 26, 755-758.
(2) (a) Charmier, M. A. J.; Haukka, M.; Pombeiro, A. J. L. J. Chem.
Soc., Dalton Trans. 2004, 2741-2745. (b) Moustafa, A. H. Synthesis 2003,
837-840. (c) Srivastava, R. M.; Rosa, M. F.; Carvalho, C. E. M.; Portugal,
S. G. M.; Brinn, I. M.; Pereira, M. C.; Antunes, O. A. C. Heterocycles
2000, 53, 191-195. (d) Burger, K.; Einhellig, K.; Roth, W.-D.; Daltrozzo,
E. Chem. Ber. 1977, 110, 605-610.
(3) Tiemann, F. Ber. 1889, 22, 2412-2417.
10.1021/ol0502073 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/26/2005

Table 1. Synthesis of Highly Substituted 1,2,4-Oxadiazolines from Nitrilesa
a Unless otherwise mentioned, reactions were conducted in 1:1 EtOH/H2O as the solvent. b Isolated yields. c This reaction was conducted in 1:1 CH3CN/
H2O as solvent. d This reaction was carried out using purified benzamidoxime 3g.
oxides with imines.6c-e Furthermore, 1,2,4-oxadiazolines
have been prepared by the addition of alkyllithiums to 1,2,4-
oxadiazoles2c and diborane reduction of 1,2,4-oxadiazoles.7
However, the methods described above suffer from several
limitations, including expensive starting materials, harsh
reaction conditions, and multiple steps. Herein, we disclose
a simple and efficient one-pot synthetic protocol for the
synthesis of highly substituted 1,2,4-oxadiazolines from the
corresponding nitriles.
hydroxylamines 2 in 1:1 ethanol/water, with diethyl acet-
ylenedicarboxylate (DEAD) provided exclusively 1,2,4-
oxadiazolines 6 (Scheme 1).8 The addition of amidoximes
to DEAD is exothermic, extremely fast, and complete within
a few minutes.9 The formation of oxadiazolines in this
process involves a sequential double Michael addition of
amidoximes to the electron-deficient alkyne. In the first step,
Michael addition of the amidoxime hydroxyl group to DEAD
generates the transient intermediate 5. Subsequently, the
During the course of our drug discovery efforts, we
discovered that the treatment of alkyl or arylamidoximes 3,
which were prepared by reacting nitriles 1 and N-alkyl-
(7) Yale, H. L.; Spitzmiller, E. R. J. Heterocycl. Chem. 1978, 15, 1373-
1378.
1392
Org. Lett., Vol. 7, No. 7, 2005

6g-p in very good yields. When pure benzamidoxime 3g
was used, quantitative formation of 6g (cf. entries 7 and 8)
indicates that the addition of amidoximes to DEAD is a very
efficient and high-yielding process. Consequently, reduced
yields in some cases are presumably due to the poor
formation of amidoximes in the first step.
Scheme 1. Oxadiazolines from Diethyl
Acetylenedicarboxylate
As exemplified in Scheme 2, 1,2,4-oxadiazolines can also
be prepared by conjugative addition of amidoximes to other
Scheme 2. Oxadiazolines from Monoactivated Alkynes
amidoxime NH in 5 regioselectively undergoes an intra-
molecular Michael addition at the most electron-deficient
carbon, producing the five-membered 1,2,4-oxadiazoline
heterocycle 6.10
As shown in Table 1, the amidoximes derived from a
variety of nitriles, including alkyl, cycloalkyl, aryl, and
heteroaryl and N-methyl, N-isopropyl, N-cyclohexyl, or
N-benzylhydroxylamine, reacted with DEAD very smoothly
to provide 1,2,4-oxadiazolines 6a-p in good isolated yields.
From entries 1-6, it is clear that the yields of some products
are significantly reduced as the steric bulkiness of the
amidoxime substituents increases. For example, amidoximes
3b,c, derived from sterically hindered N-isopropyl and
N-cyclohexyl hydroxylamines and benzylnitrile, provided
products in reduced yields. Similarly, amidoximes 3e,f,
derived from isobutyronitrile and cyclopentanecarbonitrile
and N-methylhydroxylamine, also furnished products in low
yields. Amidoximes 3g-p, derived from aryl- or heteroaryl-
nitriles and N-methylhydroxylamine, reacted with DEAD
uneventfully and provided the corresponding oxadiazolines
electron-deficient alkynes. As expected, addition of amid-
oxime 3a to alkynes 7a-c was slower compared with the
more electron-deficient DEAD. Reaction of amidoxime 3a
with ethyl propiolate 7a was complete in 2 h and furnished
8a in 33% yield. The addition of 3a to 7b was significantly
slower, furnishing oxadiazoline 8b in 53% yield after 58 h.
Coupling of 3a and ketone 7c was complete in 6 h and
provided oxadiazoline 8c in 61% isolated yield.
In summary, we have described an easy and practical one-
pot approach to the synthesis of 1,2,4-oxadiazolines from
nitriles. This method works well with a variety of amid-
oximes derived from the combination of different alkyl or
aryl nitriles and N-alkylhydroxylamines and provided highly
substituted 1,2,4-oxadiazolines in good yield. One of the most
important advantages with this methodology is that there is
no need to isolate the amidoxime intermediates. This process
therefore constitutes a short and practical protocol for the
formation of such heterocycles. In addition, these reactions
are carried out in an environmentally benign solvent system.
(8) Typical Procedure for the Synthesis 1,2,4-Oxadiazolines. A
mixture of benzylnitrile (2.343 g, 20 mmol), N-methylhydroxylamine
hydrochloride (0.835 g, 10 mmol), and Na2CO3 (0.64 g, 6 mmol) in 1:1
EtOH/H2O (20 mL) was heated at 80 °C for 2 h. Then, the reaction mixture
was cooled to ambient temperature, and diethyl acetylenedicarboxylate (1.76
mL, 11 mmol) was added via syringe over 5 min. After 30 min, the reaction
mixture was taken up into EtOAc (100 mL), washed with brine (2 × 20
mL), dried (Na2SO4), filtered, and concentrated, and the resulting yellow
residue was purified by flash chromatography on silica gel column using a
3:7 EtOAc/hexanes mixture to afford the desired product 6a as a yellow
oil (2.61 g, 78%). 1H NMR (500 MHz, CDCl3) δ: 7.32-7.23 (5H, m),
4.33-4.20 (2H, m), 4.13 (2H, q, J ) 7.0 Hz), 3.67 (2H, s), 3.31 (1H, d,
JAB ) 16.2 Hz), 3.00 (3H, s), 2.96 (1H, d, JAB ) 16.2 Hz), 1.29 (3H, t, J
) 7.0 Hz), 1.23 (3H, t, J ) 7.0 Hz). 13C NMR (125 MHz, CDCl3) δ: 168.8,
168.4, 165.6, 134.0, 128.9, 128.7, 127.4, 103.7, 62.1, 60.8, 42.3, 40.1, 32.8,
14.2, 14.1. HRMS (M + H): calcd for C17H23N2O5, 335.1607; found,
335.1607. Anal. Calcd for C17H22N2O5: C, 61.06; H, 6.63; N, 8.37.
Found: C, 60.80; H, 6.66; N, 8.30.
Acknowledgment. We thank Drs. Nicholas A. Meanwell
and Michael A. Walker for their support of this work.
Supporting Information Available: General experimen-
tal conditions, representative procedure, and analytical data
for all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(9) Caution: We highly recommend cooling the reaction flask in an ice-
water bath before adding DEAD when carrying out these reactions on a
larger scale (>10 mmol of amidoxime).
(10) In cases where R2 ) H, 5 is stable and isolated as a mixture of
cis/trans isomers. See: Culbertson, T. P. J. Heterocycl. Chem. 1979, 16,
1423-1424 and references therein.
OL0502073
Org. Lett., Vol. 7, No. 7, 2005
1393