Phenyl Isocyanate1

PhNCO

[103-71-9]  · C7H5NO  · Phenyl Isocyanate  · (MW 119.13)

(organic heterocumulene capable of forming heterocycles via cycloaddition to dipolarophiles;1a-e adds nucleophiles producing polyfunctional compounds;1a,b,f,g readily inserts into metal-element bonds providing metal-mediated construction of new C-C bond;1g,h used as dehydrating agent)

Physical Data: mp -30 °C; bp 55 °C/13 mmHg; d19.64 1.10 g cm-3; n20D 1.5350.

Solubility: sol ether, alcohol, benzene, toluene, xylene, DMF, MeCN.

Form Supplied in: liquid with acrid odor; purity about 98%.

Analysis of Reagent Purity: GLC.

Purification: addition of Grignard reagent solution and rapid distillation.

Handling, Storage, and Precautions: moisture sensitive; corrosive; highly toxic; irritating to eyes; lachrymator. Use in a fume hood.

Nucleophilic Addition.

Oxygen, nitrogen, sulfur, phosphorus, and carbon nucleophiles add across the C=N bond of phenyl isocyanate (1). Due to a high affinity to water, (1) is used in Triethylamine-promoted dehydration of primary nitroalkanes to nitrile oxides (Mukaiyama reaction) (eq 1),2 and of aldoximes3 and a-hydroximino acids4 to nitriles. The phenylcarbamic acid formed from (1) immediately decomposes with CO2 evolution. In a similar way, (1) reacts with alcohols to produce N-phenylurethanes.1a,b,5 N-Phenyl-O-arylurethanes can be hydrogenolyzed to give arenes.5b Hydroxamic acid azides behave as oxygen nucleophiles toward (1) and give 5-phenyloxadiazoles.6

Nitrogen nucleophiles of high basicity (N,N-acetals, hexahydro-s-triazine, iminophosphoranes) are especially active in additions to (1),1a,f,7 while aminoalkylphosphoramidates react regioselectively at the nitrogen of the P-N bond giving carbodiimides (eq 2).8 Even carboxamides readily react with (1) to form uracils after cyclization.9a To compensate for the low basicity of tosylamides, their reactions with (1), yielding N-tosylureas, are carried out in the presence of Copper(I) Chloride.9b

a,o-Alkanedithiols react with (1) to give biscarbamothioates in good yields.10 Comparatively weak P-nucleophiles are not very active in additions to (1). However, trialkylphosphine-induced dimerization and trimerization of (1) does involve intermediate betaine formation due to addition of the phosphorus nucleophile to the isocyano group.11 Hydride-ion or enolate addition to the isocyanate carbon provides N-functionalized N-phenylformamido compounds12 and highly substituted b-keto amides (eq 3),13 respectively.

Aziridines react with (1) with ring expansion (eq 4).14,1f,1g This is formally a 1,3-dipolar cycloaddition reaction (see below). With more complex bifunctional nucleophiles (silylamines,15 aminoboranes, and organoboranes16) the reactions of (1) provide a facile route to polyfunctional organosilicon and organoboron compounds.

Cycloaddition.

Phenyl isocyanate undergoes polar cycloaddition reactions with unsaturated substrates to give both heterocycles and functionalized open-chain compounds. Although both the C=N and C=O double bonds can participate in cycloadditions, usually the process takes place with high regioselectivity across the C=N bond. The structure of cycloadducts and the cycloaddition mode are defined by the nature of the unsaturated substrate and also by the substrate:phenyl isocyanate ratio. Nucleophilic alkenes react with (1) to afford unstable [2 + 2] cycloadducts (2-azetidinones), which are readily cleaved to give polyfunctional aliphatic compounds (eq 5).17

Reactions of (1) with C=N-containing substrates1d are sensitive to the nucleophilicity of the C=N double bond. N-Alkyl-N-arylcarbodiimides add to (1) exclusively at the N-alkyl-substituted C=N bond to give 4-arylimino-1,3-diazetidin-2-ones.18 Six-membered heterocycles can be synthesized from unsaturated substrates and phenyl isocyanate via [2 + 2 + 2], [2 + 2 + 2], or [4 + 2] dipolar cycloaddition reactions. The first two modes are realized due to low stability [2 + 2] adducts which react further (especially at elevated temperature) with an excess of phenyl isocyanate. In a [2 + 2 + 2] reaction, ketene S,N-acetals react with (1) (2 equiv reflux in toluene) to afford 1,3-diphenyl-2-pyrimidinones,19 whereas the [2 + 2 + 2] route occurs in the reaction with 3H-indole (eq 6).20

[4 + 2] Cycloaddition reactions are based on a condensation of (1) with a suitable 1,4-dipolar synthon (4-amino-1-azabutadienes,21 1,3-diazabutadienes,22 2-aza-1,3-dienes,23 1-(triphenylphosphinimido)dienes24) and give the corresponding heterocycles (2-imino-1,2-dihydropyrimidines,21 5,6-dihydro-1,3,5-triazine-2,4(1H,3H)-diones,22 1,2-dihydropyrimidin-4(3H)-ones (eq 7),23 2-phenylaminopyridines,24a or condensed quinazolines.24b,c). Phenyl isocyanate also enters 1,3-dipolar [3 + 2] cycloaddition reactions (with N-oxides, 1,2-diimines, 2-imino ketones, azides) to produce five-membered ring heterocycles.1a,c,e,25

Metal-Promoted C-C Bond Forming Reactions.

The most widely exploited route to new C-C bond formation at the isocyanate carbon is based on insertion of (1) into main-group metal-carbon bonds26 or transition metal-carbon bonds.27 Samarium(II) Iodide-promoted self-coupling of (1) affords N,N-diphenyloxamide.28

Regiospecific C-(N-phenylcarbamoylation) reactions of copper and nickel b-keto imine complexes,29a phenols (in the ortho-position in the presence of Boron Trichloride),29b and 5H-azepino[1,2-a]benzimidazol-7(8H)-one at C-629c are examples of electrophilic substitution reactions in which the acidic proton of the substrate or ligand is transferred to the nitrogen atom of phenyl isocyanate.

Numerous coupling reactions of (1) with unsaturated substrates are catalyzed by nickel(0) complexes.1h These serve as templates providing intermediate formation of nickel azaheterocycles stabilized by strong Ni-N coordination. These heterocycles decompose with formation of unsaturated amides and liberation of coordinated Ni0 that enables one to employ only a catalytic amount of the Ni0 source.1h

In contrast to 1,1-difluoroalkenes, which produce saturated b,b-difluorocarboxamides with (1),30 alkenes and arylalkenes undergo substitutive N-phenylcarbamoylation at the terminal or allylic carbon, yielding the corresponding alkenic carboxamides.1h,31 1,3-Pentadiene reacts analogously to form sorbanilide in 250% yield (based on Ni0) (eq 8).32 Both acyclic and five-membered carbocyclic amides are formed from 1,5-hexadiene and 1,6-heptadiene (eq 9).33

Nickel(0) complexes1h as well as low-valent tantalum complexes34 promote reductive carbamoylation of alkynes with (1) to produce 2-alkenyl- and 2,4-alkadienylcarboxamides (eq 10).34 [2 + 2 + 2] Cycloaddition occurs in the presence of basic phosphine ligands under very mild conditions to give 2-pyridones.1h,35 On the contrary, in Pentacarbonyliron-mediated reactions, [2 + 2 + 2] cycloaddition occurs to afford hydantoins (eq 11).36

Strained rings readily undergo ring expansion upon metal-mediated reactions with (1). For example, Pd0 complexes catalyze condensation of (1) with vinylcyclopropanes to give 5-vinyl-4-phenylpyrrolidin-2-ones.37 The direction of ring cleavage of oxiranes with (1) depends on the catalyst employed. For example, SbV and Pd0 compounds,38,39 as well as trialkyltin reagents coordinated by HMPA,40 affect a-cleavage yielding 4-substituted 3-phenyloxazolidin-2-ones (eq 12), while other organotin reagents afford also the 5-substituted isomers.41 These heterocycles are masked b-amino alcohols, which are readily liberated on hydrolysis.

Related tin-mediated cleavage of four-membered oxetanes, g-bromo-b-lactones, or b-lactams has been used in facile one-pot syntheses of tetrahydro-1,3-oxazin-2-ones,42a 5-(methoxycarbonyl)methyl-3-phenyloxazolidin-2-ones, and 1,3-imidazolidin-2-ones.42b Tetrakis(triphenylphosphine)palladium(0)-promoted reaction of propylene carbonates with (1)43 also effectively leads to tetrahydro-1,3-oxazin-2-ones which hydrolyze to the corresponding g-amino alcohols.


1. (a) Patai, S. The Chemistry of Cyanates and Their Derivatives; Wiley: Chichester 1977; Parts 1 and 2. (b) Ozaki, S. CR 1972, 72, 457. (c) Ulrich, H. Cycloaddition Reactions of Heterocumulenes; Academic: New York, 1967. (d) Ulrich, H. ACR 1969, 2, 186. (e) Noack, R.; Schwetlick, K. ZC 1986, 26, 117. (f) Noack, R.; Schwetlick, K. ZC 1987, 27, 77. (g) Braunstein, P.; Nobel, D. CR 1989, 89, 1927. (h) Hoberg, H. JOM 1988, 358, 507.
2. Mukaiyama, T.; Hoshino, T. JACS 1960, 82, 5339.
3. Mukaiyama, T.; Nohira, H. JOC 1961, 26, 782.
4. Ahmad, A. S 1976, 418.
5. (a) Sivakamasundari, S.; Ganesan, R. JOC 1984, 49, 729. (b) Weaver, J. D.; Eisenbraun, E. J.; Harris, L. E. CI(L) 1973, 187.
6. Molina, P.; Alajarin, M.; Ferao, A. S 1986, 843.
7. Saito, T.; Nakane, M.; Endo, M.; Yamashita, H.; Oyamada, Y.; Motoki, S. CL 1986, 135.
8. Jászay, Z. M.; Petneházy, I.; Tóke, L.; Szajáni, B. S 1988, 397.
9. (a) Naim, A.; Shevlin, P. B. SC 1990, 20, 3439. (b) Cervello, J.; Sastre, T. S 1990, 221.
10. Hanefeld, W.; Shulze-Weisschu, P. AP 1986, 319, 310.
11. Buckles, R. E., McGrew, L. A. JACS 1966, 88, 3582.
12. Corriu, R. J. P.; Lanneau, G. F.; Perrot-Petta, M.; Mehta, V. D. TL 1990, 31, 2585.
13. Hendi, S. B.; Hendi, M. S.; Wolfe, J. F. SC 1987, 17, 13.
14. Benhaona, H.; Texier, F.; Guenot, P.; Martelli, J.; Carrie, R. T 1978, 34, 1153.
15. Kaufmann, K.-D., Bormann, H.; Rühlmann, K.; Engelhardt, G.; Kriegsmann, H. CB 1968, 101, 984.
16. (a) Cragg, R. H.; Miller, T. J. JOM 1985, 294, 1. (b) Singaram, A.; Molander, G. A. H 1981, 15, 231.
17. Graziano, M. L.; Cimminiello, G. S 1989, 54.
18. Ulrich, H.; Richter, R.; Tucker, B. JHC 1987, 24, 1121.
19. Gelbin, M.; Martin, D. JPR 1987, 329, 753.
20. Huisgen, R.; Herbig, K.; Morikawa, M. CB 1967, 100, 1107.
21. Barluenga, J.; Tomás, M.; Ballesteros, A.; Gotor, V. S 1987, 489.
22. Barluenga, J.; Tomás, M.; Ballesteros, A.; Lopez, L. A. S 1989, 228.
23. Barluenga, J.; Gonzalez, F. J.; Gotor, V.; Fustero, S. JCS(P1) 1988, 1739.
24. (a) Molina, P.; Fresneda, P. M.; Alarcon, P. TL 1988, 29, 379. (b) Bruche, L.; Garanti, L.; Zecchi, G. JCS(P1) 1986, 2177. (c) Molina, P.; Alajarin, M.; Vidal, A. JOC 1992, 57, 6703.
25. Huisgen, R. PAC 1980, 52, 2283.
26. (a) Lappert, F. M.; Prokai, B. JCS 1963, 4223. (b) Lappert, F. M.; Prokai, B. Adv. Org. Chem. 1967, 5, 225.
27. (a) Wilkins, J. D. JOM 1974, 67, 269. (b) Gambarotta, S.; Strologo, S.; Floriani, C.; Chiesi-Villa, A.; Guastini, C. IC 1985, 24, 654.
28. Liu, Y.-S.; Bei, M.-Z.; Zhou, Z.-H.; Takaki, K.; Fujiwara, Y. CL 1992, 1143.
29. (a) Kenney, J. W.; Nelson, J. H.; Henry, R. A. CC 1973, 690. (b) Piccolo, O.; Filipini, L.; Tinucci, L.; Valoti, E.; Citterio, A. T 1986, 43, 885. (c) Ohta, S.; Narita, Y.; Yuasa, T.; Hatakeyama, S.; Kobayashi, M.; Kaibe, K.; Kawasaki, I.; Yamashita, M. CPB 1991, 39, 2787.
30. Hoberg, H.; Guhl, D. JOM 1989, 378, 279.
31. Hoberg, H.; Nohlen, M. JOM 1990, 382, C6.
32. Hoberg, H.; Hernandez, E. AG(E) 1985, 24, 961.
33. Hernandez, E.; Hoberg, H. JOM 1987, 328, 403.
34. Kataoka, Y.; Oguchi, Y.; Yoshizumi, K.; Mitwatashi, S.; Takai, K.; Utimoto, K. BCJ 1992, 65, 1543.
35. Hoberg, H.; Oster, B. W. JOM 1983, 252, 359.
36. Ohshiro, Y.; Kinugasa, K.; Minami, T.; Agawa, T.; JOC 1970, 35, 2136.
37. Yamamoto, K.; Ishida, T.; Tsuji, J. CL 1987, 1157.
38. Fujiwara, M.; Baba, A.; Matsuda, H. JHC 1988, 25, 1351.
39. (a) Trost, B. M.; Sudhakar, A. R. JACS 1987, 109, 3792. (b) Hayashi, T.; Yamamoto, A.; Ito, Y. TL 1988, 29, 99.
40. Yano, K.; Amishiro, N.; Baba, A.; Matsuda, H. BCJ 1991, 64, 2661.
41. Shibata, I.; Baba, A.; Iwasaki, H.; Matsuda, H. JOC 1986, 51, 2177.
42. (a) Shibata, I.; Imoto, T.; Baba, A.; Matsuda, H. JHC 1987, 24, 361. (b) Shibata, I.; Toyota, M.; Baba, A.; Matsuda, H. JOC 1990, 55, 2487.
43. Tamaru, Y.; Bando, T.; Kawamura, Y.; Okamura, K.; Yoshida, Z.; Shiro, M. CC 1992, 1498.

Emmanuil I. Troyansky

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



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