Benzonitrile Oxide1

[873-67-6]  · C7H5NO  · Benzonitrile Oxide  · (MW 119.12)

(versatile reagent for regio- and stereoselective construction of heterocycles; synthesis of polyfunctionalized acyclic and cyclic compounds1)

Physical Data: mp 18-19 °C; bp 113 °C/15 mmHg; d224 1.10 g cm-3; n22D 1.6172.

Solubility: sol ether, benzene, CCl4.

Form Supplied in: prepared as described below; not commercially available.

Preparative Methods: the most widely employed methods of benzonitrile oxide (1) generation involve triethylamine-mediated dehydrohalogenation of benzhydroxamoyl chloride (2) (or bromide), readily accessible through chlorination of benzaldoxime,2a or dehydration of a-nitrotoluene with PhCNO2b,c or PhSO2Cl or ClCO2Et and a catalytic amount of Et3N (Mukaiyama reaction).2d A reaction of (2) with alkali metal fluorides also provides a facile quantitative generation of (1).2e Although (1) has been obtained as a crystalline solid,2f it is commonly generated in situ.1 Et3N almost immediately reacts with (2),3 and should be added very slowly to an ice-cooled solution of (2) to maintain a low stationary concentration of (1) and thereby suppress its dimerization into 3,4-diphenylfuroxan (3).2a Benzonitrile oxide can also be generated photochemically by irradiation of (2) and Hexabutyldistannane,4a or via electrochemical oxidation of benzaldoxime.4b

Handling, Storage, and Precautions: usually prepared in situ; readily undergoes dimerization on storage; use in a fume hood.


To simplify the representation of (1) as an organic dipole (dipole moment 4.00 D at 15 °C),1a the nitrilium betaine formula PhC&tbond;+N-O- is most commonly used. As implied by this structure, reactions with nucleophiles at the positively charged N atom or with dipolarophiles across the C-N-O system are common with (1).

Reactions with Nucleophiles.

Benzonitrile oxide reacts with O-, C-, N-,5a-c and S-nucleophiles5d to give benzhydroxamic acid derivatives (eq 1).5d

Nitrogen nucleophiles catalyze dimerization of (1),6a which may be also promoted under specific acidic conditions (eq 2).6b In DMSO, (1) undergoes Me3N-induced polymerization to produce cyclic oligomers.6c

1,3-Dipolar Cycloaddition.

Benzonitrile oxide demonstrates high reactivity towards numerous dipolarophiles containing multiple carbon-carbon and carbon-heteroatom bonds. It is these [p4s + p2s] dipolar cycloadditions (DCA) that are responsible for the considerable synthetic potential of (1). DCA of (1) with alkenes commonly delivers a mixture of isomeric 5- and 4-substituted 3-phenyl-D2-isoxazolines. Regioselectivity depends on dipolarophile structure. From monosubstituted alkenes, 5-substituted heterocycles are predominantly formed1a,b,7 and in some cases almost complete regiospecificity is achieved (eq 3).2e

Ratios of regioisomers produced from disubstituted alkenes are defined by a combination of polar, steric, and hydrogen-bonding factors.8 Nevertheless, conformational features, substituent effects, and additives can all affect the regiochemistry of 1,3-DCA reactions (eq 4).9

1,3-DCA of alkenes bearing a chiral residue at the double bond proceed with asymmetric induction.10 The nature of a substituent in the allylic position of the dipolarophile can affect the ratio of erythro:threo products, as shown in eq (5).10b The best theoretical model proposed to rationalize such diastereoselectivity assumes conformational control in the transition state of DCA.10c,e However, charge transfer and electrostatic effects should not be neglected.10f

Diastereoselective DCA of (1) to chiral acrylic dipolarophiles offers an approach to optically active 2-isoxazolines. Initial studies with chiral sulfonamide (4) proceed with 56% de and showed attack of (1) to occur on the re face of (4). This suggested that the major diastereomer resulted from the s-cis conformer of (4) (eq 6).11 It is worth noting that generally 1,3-DCA of (1) with substrates of type (4) takes place with lower selectivity than the corresponding Diels-Alder reactions,11,12 and Lewis acids retard the 1,3-DCA and decrease yields with no improvement in diastereoselectivity. Higher diastereoselectivity (80-90% de) is observed if bornyl crotonates,13 chiral imides,14 alkenes containing a chiral imidazolidine controller,15 or carbohydrates16 are employed in DCA with (1).

Acryloylsultams such as (5)17a and (S)- and (R)-(6)17b are the best auxiliaries for almost complete asymmetric induction yielding, after reduction, enantiomerically pure isoxazolines (eq 7).

Because the D2-isoxazoline ring can be readily cleaved, this chemistry provides a powerful approach to the synthesis of polyfunctional compounds from alkenes. Upon base-initiated ring-opening, a,b-unsaturated ketones are obtained (eq 8),18 whereas reductive cleavage offers an approach to b-hydroxy ketones (eq 9),19 b,g-enones,20 b-diketones, and 3(2H)-furanones.21 While the primary products of reduction with Raney Nickel19,20 are 3-imino alcohols, precursors of b-hydroxy ketones19 and pyridines,22 reductive cleavage with Lithium Aluminum Hydride gives 1,3-amino alcohols.23 This has been used in the stereoselective synthesis of amino sugars.23a

Methodology involving cycloaddition of nitrile oxides to C=C bonds and subsequent cleavage of the resulting D2-isoxazolines has been widely used in natural product synthesis24 and other synthetic ventures.25

1,3-DCA of (1) with dipolarophiles containing multiple bonds other than C=C provides a route to various heterocyclic systems.1a,b,d Alkynes add (1) to produce 3-phenylisoxazoles.1a,b Metalated alkynes serve as a handle for introducing a variety of functional groups into the 2-position (eq 10).26 Alternatively, isoxazoles can be synthesized via DCA of (1) with nitroalkenes and subsequent 1,2-elimination of HNO2.27

Compounds containing C=N bonds react with (1) to produce 1,3,5-oxadiazepines,28a D2-1,2,4-oxadiazolines,28b and fused 1,2,4-oxadiazolines.28c-f In substrates with both C=C and C=N bonds, the 1,3-DCA takes place across the C=N bond.28b,c Nitriles react with (1) yielding 3-phenyl-1,2,4-oxadiazoles,29,30 and the C&tbond;N bond successfully competes with C=C in dipolarophile activity.30b Dimerization of (1) to furoxan (3), a common process under 1,3-DCA conditions, can be considered as a particular case of 1,3-DCA of (1) to a C&tbond;N bond.31

Benzonitrile oxide also reacts with carbonyl groups to produce 1,4,2-dioxazolines. Uncatalyzed DCA is possible with aromatic carbonyl compounds,2a,32 while aliphatic substrates react only in the presence of Boron Trifluoride Etherate.33 Upon treatment with Potassium t-Butoxide, 1,4,2-dioxazolines obtained from arenecarbaldehydes lose PhCN to produce the corresponding arenecarboxylic acids (eq 11).29 Site-specific or site-selective addition to the C=O group is observed in reactions of (1) with quinones34a or tropone.34b

The C=S bond exhibits high dipolarophilic activity in reactions with (1) affording 1,4,2-oxathiazolines.1a,b,35 Although 3,5-diphenyl-l3-phosphinin is inert to (1), DCA reaction takes place selectively at the P=C bond after complexation with tungsten pentacarbonyl (eq 12).36

1. (a) Grundmann, C.; Grünanger, P. The Nitrile Oxides; Springer: New York, 1971. (b) Caramella, P.; Grünanger, P. 1,3-Dipolar Cycloaddition Chemistry; Padwa, A., Ed.; Wiley: New York, 1984; Vol. 1, pp 291-392. (c) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. G 1989, 119, 253. (d) Kanemasa, S.; Tsuge, O. H 1990, 30, 719.
2. (a) Huisgen, R.; Mack, W. CB 1972, 105, 2805. (b) Mukaiyama, T.; Hoshino, T. JACS 1960, 82, 5339. (c) Le Gall, T.; Lellouche, J.-P.; Toupet, L.; Beaucourt, J.-P. TL 1989, 30, 6517. (d) Shimizu, T.; Hayashi, Y.; Shibafuchi, H.; Teramura, K. BCJ 1986, 59, 2827. (e) Kim, J. N.; Chung, K. H.; Ryu, E. K. H 1991, 32, 477. (f) Wieland, H. CB 1907, 40, 1667.
3. Beltrame, P.; Dondoni, A.; Barbaro, G.; Gelli, G.; Loi, A.; Steffe, S. JCS(P2) 1978, 607.
4. (a) Kim, B. H. SC 1987, 17, 1199. (b) Shono, T.; Matsumura, Y.; Tsubata, K.; Kamada, T.; Kishi, K. JOC 1989, 54, 2249.
5. (a) Dignam, K. J.; Hegarty, A. F.; Quain, P. L. JOC 1978, 43, 388. (b) Hegarty, A. F. ACR 1980, 13, 448. (c) El-Abadelah, M. M.; Hussein, A. Q.; Awadallah, A. M. H 1989, 29, 1957. (d) Saito, S.; Uzawa, H.; Nagatsugi, F. CPB 1989, 37, 2519.
6. (a) De Sarlo, F.; Guarna, A. JCS(P2) 1976, 626. (b) Morrocchi, S.; Ricca, A.; Selva, A.; Zanarotti, A. G 1969, 99, 165. (c) De Sarlo, F.; Guarna, A. JCS(P1) 1979, 2793.
7. Christl, M.; Huisgen, R. CB 1973, 106, 3345.
8. (a) Caramella, P.; Cellerino, G. TL 1974, 229. (b) Curran, D. P.; Choi, S. M.; Gothe, S. A.; Lin, F. JOC 1990, 55, 3710. (c) Brandi, A.; Carli, S.; Guarna, A.; De Sarlo, F. TL 1987, 33, 3845.
9. (a) Fray, M. J.; Thomas, E. J.; Williams, D. J. JCS(P1) 1985, 2763. (b) Blake, A. J.; Cook, T. A.; Forsyth, A. C.; Gould, R. O.; Paton, R. M. T 1992, 48, 8053. (c) Kanemasa, S.; Nishiuchi, M.; Wada, E. TL 1992, 33, 1357.
10. (a) Jäger, V.; Schohe, R.; Paulus, E. F. TL 1983, 24, 5501. (b) Houk, K. N.; Moses, S. R.; Wu, Y.-D.; Rondan, N. G.; Jäger, V.; Schohe, R.; Fronczek, F. R. JACS 1984, 106, 3880. (c) Curran, D. P.; Gothe, S. A. T 1988, 44, 3945. (d) Annunziata, R.; Cinquini, M.; Cozzi, F.; Raimondi, L. T 1988, 44, 4645. (e) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y.-D.; Brown, F. K.; Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J. Science 1986, 231, 1108. (f) Burdisso, M.; Gandolfi, R.; Lucchi, M.; Rastelli, A. JOC 1988, 53, 2123.
11. Curran, D. P.; Kim, B. H.; Piyasena, H. P.; Loncharich, R. J.; Houk, K. N. JOC 1987, 52, 2137.
12. Oppolzer, W. A. AG(E) 1984, 23, 876.
13. Olsson, T.; Stern, K.; Sundell, S. JOC 1988, 53, 2468.
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15. (a) Kanemasa, S.; Hayashi, T.; Yamamoto, H.; Wada, E.; Sakurai, T. BCJ 1991, 64, 3274. (b) Kanemasa, S.; Onimura, K.; Wada, E.; Tanaka, J. TA 1991, 2, 1185.
16. Blake, A. J.; Gould, R. O.; McGhie, K. E.; Paton, R. M.; Reed, D.; Sadler, I. H.; Young, A. A. Carbohydr. Res. 1991, 216, 461.
17. (a) Curran, D. P.; Kim, B. H.; Daugherty, J.; Heffner, T. A. TL 1988, 29, 3555. (b) Oppolzer, W.; Kingma, A. J.; Pillai, S. K. TL 1991, 32, 4893.
18. Grund, H.; Jäger, V. LA 1980, 80.
19. Curran, D. P. JACS 1983, 105, 5826.
20. (a) Jäger, V.; Grund, H.; Schwab, W. AG(E) 1979, 18, 78. (b) Curran, D. P.; Kim, B. H. S 1986, 312.
21. Curran, D. P.; Singleton, D. H. TL 1983, 24, 2079.
22. Kanemasa, S.; Asai, Y.; Tanaka, J. BCJ 1991, 64, 375.
23. (a) Jäger, V.; Schohe, R. T 1984, 40, 2199. (b) Lathbury, D. C.; Parsons, P. J. CC 1982, 291.
24. Kozikowski, A. P. ACR 1984, 17, 410.
25. Goti, A.; Brandi, A.; De Sarlo, F.; Guarna, A. T 1992, 48, 5283.
26. Kondo, Y.; Uchiama, D.; Sakamoto, T.; Yamanaka, H. TL 1989, 30, 4249.
27. Baranski, A.; Kelarev, V. I. KGS 1990, 435.
28. (a) Rees, C. W.; Somanathan, R.; Storr, R. C.; Woolhouse, A. D. CC 1975, 740. (b) Singh, N.; Sandhu, J. C.; Mohan, S. TL 1968, 4453. (c) Streith, J.; Wolff, G.; Fritz, H. T 1977, 33, 1349. (d) Stajer, G.; Bernath, G.; Szabo, A. E.; Sohar, P.; Argay, G.; Kalman, A. T 1987, 43, 5461. (e) Szabo, J.; Fodor, L.; Bernath, G.; Talpas, G. S.; Bani-Akoto, E.; Sohar, P. JHC 1991, 28, 481. (f) Eddaif, A.; Kitane, S.; Soufiaoui, M.; Mison, P. TL 1991, 30, 3709.
29. Aitken, R. A.; Raut, S. V. SL 1991, 189.
30. (a) van Leusen, A. M.; Jagt, J. C. TL 1970, 971. (b) Corsaro, A.; Chiacchio, U.; Purrello, G. JCS(P1) 1977, 2154. (c) Ried, W.; Fulde, M. HCA 1988, 71, 1681.
31. Huisgen, R. AG(E) 1963, 2, 633.
32. Huisgen, R.; Mack, W. CB 1972, 105, 2815.
33. Morrocchi, S.; Ricca, A.; Velo, L. TL 1967, 331.
34. (a) Shiraishi, S.; Ikeuchi, S.; Seno, M.; Asahara, T. BCJ 1977, 50, 910. (b) De Micheli, C.; Gandolfi, R.; Grünanger, P. T 1974, 30, 3765.
35. Katada, T.; Eguchi, S.; Sasaki, T. JCS(P1) 1984, 2641.
36. Märkl, G.; Beckh, H.-J. TL 1987, 28, 3475.

Emmanuil I. Troyansky

Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russia

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