A new route to nitrile oxides from primary alkylhalides for in situ dipolar cycloadditions

Article abstract of DOI:10.1055/s-1998-1669

A new route to nitrile oxide preparation from primary alkylbromide, chloride, nitrite and their cycloadditions with olefins to form isoxazolines in a single pot are described.

Full text of DOI:10.1055/s-1998-1669

April 1998
SYNLETT
385
A New Route to Nitrile Oxides from Primary Alkylhalides for in situ Dipolar Cycloadditions
Dilipkumar Maiti and Pranab K. Bhattacharya*
Medicinal Chemistry Division, Indian Institute of Chemical Biology, 4, Raja S.C. Mullick Road, Calcutta 700 032, INDIA
Fax 91-33-4730284/4735197; Email: IICHBIO@GIASCIL 01. VSNL.NET.IN
Received 26 November 1997
Abstract: A new route to nitrile oxide preparation from primary
alkylbromide, chloride, nitrite and their cycloadditions with olefins to
form isoxazolines in a single pot are described.
Conversion of organic functionalities in organic synthesis is still a focal
point of thinking. Halogens are widely used in aliphatic systems to
introduce various other functionalities. For example, treatment of
alkylhalides with sodium nitrite gives rise to alkylnitro compounds
1
-3
along with nitrite esters. We report herein the formation of nitrile
oxides from alkylbromide, chloride and nitrite when treated with
2
4
sodium nitrite and acetic acid in dimethyl sulfoxide (DMSO) medium.
The nitrile oxides thus formed by this easy methodology, were made to
react in situ with various olefins; both electron deficient and electron
rich, such as acrylate, vinylacetate, vinyl pyridine and styrene (Table) to
form respective isoxazolines (I, Scheme 1). Only one regioisomer (I)
was formed in these cycloaddition reactions.
References and Notes
1. (a) Kornblum, N. Organic Reactions: Cope, A.C., Ed.; John
Scheme 1
Wiley: London, 1962, vol.12, pp. 101-56. (b) Coombes, R.G.
Comprehensive Organic Chemistry: The Synthesis and Reactions
of Organic Compounds: Barton, D.H.R.; Ollis, W.D., Eds.;
Pergamon Press: Oxford, 1979, vol 2, 305-381.
The importance of nitrile oxides in organic chemistry is well
documented, particularly for the use in 1,3 dipolar cycloaddition by
both the intra- and intermolecular pathway. Both of the well known
oxidative and dehydrative methods of nitrile oxide preparation are
multistep processes.5a So far there is only one route known for the
5
2
.
McCullough, K.J. Encyclopedia of Reagents for Organic
Synthesis: Paquette, L.A., Ed., John Wily & Sons: New York,
1
995, vol 7, pp 4604-09.
formation of carbethoxy fulmide (carbethoxy foromonitrile oxide,
6
CEFNO) in the literature and our route is the second one.
3.
4.
(a) Kornblum, N.; Weaver, W.M. J. Am. Chem. Soc. 1958, 80,
4
1
333-37. (b) Matt, C.; Wagner, A.; Mioskowski, C. J. Org. Chem.
997, 62, 234-35.
We have prepared nitrile oxides from alkylhalides and it clearly reveals
that the only possible pathway of the reaction is through the nitro and
then nitrolic acid intermediate (Scheme 2) which was rightly assumed
General Procedure : The alkylhalide (0.01 mole), DMSO (50 ml)
and acetic acid (10ml) were taken together and cooled to 0°C.
Sodium nitrite (2.1g, 0.03mole) was added to it and the
suspension was stirred vigorously. The substituted olefin (0.03
mole) was added and stirred at room temperature for about 15-25
hr. The reaction mixture was diluted with cold water. The product
was extracted with ether (4x50ml) and the combined ether layer
was washed with brine (3x10ml) and dried passing through
anhydrous sodium sulfate. The crude products were separated by
silica gel column chromatography. In some cases the products
were purified by crystallization in appropriate solvent or by
evaporative distillation at low pressure. Always, small amounts of
nitrile oxide hydrolysed product and HNO2 addition product to
olefin were also found as byproducts.
3
b
3a
by Mioskowski and Kornblum et al. We also confirmed the
hypothesis by using two nitro compounds for the preparation of nitrile
oxides. It is interesting to note that if the reactions are studied at low
temperature (-20°C) in DMF, only the corresponding nitro compounds
were formed not the nitrile oxides.
Scheme 2
Comp. No. 1. : Colorless needle shaped solid(ether). m.p. 74°C
-
1
(
1
γ max / cm , KBr): 3084, 2932, 1736, 1656, 1589, 1516, 1462,
Acknowledgement
1
438, 1345, 1259, 1153, 1106, 1016, 900. HNMR (CDCl , 100
MHz): δ 1.32 (3H, t, J=7Hz), 3.64 (1H, d, J=2Hz), 3.74 (1H, s),
.30 (2H, q, J=7Hz), 5.28 (1H, dd, J=8Hz), 7.88 (2H, d, J=8Hz),
.32 (2H, d, J=8Hz).
CNMR (CDCl3, 25MHz):
3
Thanks are due to CSIR and UGC , India for financial assistance as well
as a research fellowship to one of the authors (DKM). Thanks are also
due to the Director, IICB for various help.
4
8
1
3
δ 14.0(q), 38.05(t), 62.22(t),
78.85(d), 123.97(d), 127.59(d), 134.52(s), 154.47(s), 169.46(s).

3
86
LETTERS
SYNLETT
+
1440, 1380, 1255, 1132. 1019, 920,820, 782, 746. 1HNMR
EIMS (m/z, 70 ev): 264(M ), 233, 232, 218, 204, 190(bp), 174,
63, 144, 132.
1
(CDCl , 100MHz): δ 1.40 (3H, t, J=7.2Hz), 3.52 (1H, d,
3
J=2.4Hz), 3.58 (1H,s), 3.86 (3H,s), 4.20 (2H, q, J=7.2Hz), 5.26
Comp. No. 2. : Colorless solid (ether) m.p. 66°C
I.R. (γ max / cm , KBr): 3104, 2988, 2944, 1740, 1597, 1557,
(1H, dd J=2.4,8.4Hz) 13CNMR (CDCl , 75MHz): δ 13.79, 37.38,
3
-1
52.56, 62.17, 68.27, 151.76, 158.78, 169.33, 173.11. EIMS (m/z,
1
+
1490, 1436, 1399, 1374, 1345, 1249, 1222, 1093, 1027. HNMR
70 ev): 201(M ), 189,185, 175, 170, 163, 151, 148, 120, 101, 95,
(
CDCl , 100MHz): δ 1.34 (3H, t, J=7Hz), 3.60 (1H, d, J=2Hz),
85, 69.
3
3
.68 (1H,s), 4.30 (2H, q, J=7Hz), 5.22 (1H, dd, J=8Hz), 7.44 (2H,
1
3
d, J=8Hz) 7.68 (2H, d, J=8Hz). CNMR (CDCl , 25 MHz): δ
Comp. No. 8. : Brown colored solid(methanol) m.p. 88°C
3
-
1
1
1
1
3.9(q), 38.4(t), 61.8(t), 78.2 (d), 127(s), 128(d), 128.8(d),
36.2(s), 154.9(s), 169.7(s). EIMS (m/z, 70 ev): 254(M ), 222,
94, 193, 182, 180(bp), 154, 152, 137, 126.
I.R. (γmax / cm , KBr): 2924, 1588, 1466, 1436, 1354, 1323,
+
1
1145, 995, 953. HNMR (CDCl 100MHz): δ 3.68 (1H,d,J=2Hz),
3
3.8(1H, d, J=4Hz), 5.86 (1H, dd, J=8Hz), 7.12-7.88 (8H, m), 8.6
1H, d, J=5 Hz). 13CNMR (CDCl , 75MHz): δ 41.35, 82.34,
120.52, 122.87, 126.76, 128.62, 129.14, 130.13, 136.98, 149.26,
156.43, 159.78. EIMS (m/z, 70 ev): 224(M ), 207, 194, 193(bp),
(
3
o
Comp. No.3 : Colorless solid(methanol). m.p. 53 C
I.R. (γ max / cm , KBr): 3088, 2982, 2928, 1747, 1532, 1479,
-1
+
1
1441, 1353, 1300, 1246, 1210, 1092, 1021, 968, 915. HNMR
167, 165, 146, 144, 131, 121, 105, 91.
(
CDCl , 100MHz): δ 1.34 (3H, t, J=7Hz), 3.66 (1H, d, J=2Hz),
3
3
.76 (1H, s), 4.31 (2H, q, J=7Hz), 5.28 (1H, dd, J=8Hz), 7.66 (1H
Comp.No. 9. : Colorless liquid.
I.R. (γmax / cm , neat): 3080, 2954, 2892, 1753, 1710, 1564,
1354, 1257, 1216. 1019, 933, 887. HNMR (CDCl , 100MHz): δ
-
1
,
t) 8.05-8.52 (3H, m).
3
1
1
CNMR (CDCl , 25MHz): δ 13.8(q), 38.0(t), 61.8(t), 78.5(d),
3
3
1
1
1
21.2(d), 124.4(d), 129.7(d), 130.2(s), 132.2(d), 148.1(s),
54.3(s), 169.3(s). EIMS (m/z, 70 ev): 264(M ), 233, 232, 191,
90(bp), 175, 163, 153, 136.
1.40 (3H, t, J=7Hz), 2.10 (3H, s), 3.32 (1H, d, J=2Hz), 3.40 (1H,
d, J=7.5Hz), 4.40 (2H, q, J=7Hz), 6.84 (1H, dd J=1.5Hz)
CNMR (CDCl , 75MHz): δ 13.98(q), 20.77(q), 39.77(t),
3
+
13
6
2.48(t), 96.34(d), 151.85(s), 161.2(s), 169.09(s). EIMS (m/z, 70
+
Comp. No. 4. : Colorless liquid.
ev): 201 (M ), 172, 159, 158(bp), 141, 129, 104, 103, 95, 83.
-
1
I.R. (γ max / cm , neat): 3062, 3015, 2982, 2932 1741, 1603,
1
557, 1494, 1451, 1375, 1326, 1274, 1206, 1032, 853, 809, 743.
5
.
.
(a) Basel, Y.; Hassner, A.; Synthesis, 1997, 309-12. (b) Kanemasa,
S.; Tsuge, O. Heterocycles, 1990, 30, 719-36 and references cited
therein. (c) de Blas, J.; Carretero, J. C.; Domingucz, E.
Tetrahedron Asym. 1995, 6, 1035-38. (d) Xiang, Y.; Schinazi, R.
F.; Zhao, K. J. Org. Chem. 1997, 62, 88-92.
1
HNMR (CDCl , 300MHz): δ 1.27 (3H, t, J=7.9Hz), 3.08 (2H, d,
J=8.4Hz) 3.32 (1H, d, J=2Hz), 3.69 (2H, s), 4.16 (2H, q, J=7.9Hz),
3
1
3
4.93 (1H, dd, J=1.5,8.4Hz), 7.32 (5H, m). CNMR (CDCl3,
75MHz): δ 13.97, 33.43, 40.23, 61.71, 77.34, 127.17, 128.68,
128.89, 135.09, 157.24, 170.21.
6
Kozikowski, A.P.; Adamczyk, M. J. Org. Chem. 1983, 48, 366-
3
72.
Comp. No. 5. : Colorless liquid.
I.R. (γ max / cm , neat): 3060, 2954, 2850, 1745, 1600, 1485,
-
1