Chapter 16 Nitriles and Isonitriles

Transcription

1 hapter 16 itriles and Isonitriles I. Introduction II. Isonitriles A. Reactions Group Replacement Elimination Reactions Addition Reactions B. Synthesis III. itriles A. Synthesis B. Reactions IV. Summary V. References I. Introduction Radical reactions of carbohydrate nitriles and isonitriles are not widespread. Isonitrile reactions are rare because these compounds themselves are not common. Their primary reaction is replacement of the isocyano group with a hydrogen atom. itriles are more plentiful than isonitriles but less reactive in radical reactions. They typically are involved in radical cyclization. Both nitriles and isonitriles can be synthesized by radical reaction. H 2 Ac Ac Ac Ac AIB 6 H o H 3 H 2 Ac Ac Ac Ac ( 1 ) 89% II. Isonitriles A. Reactions 1. Group Replacement a. Isocyano Groups Reaction of tri-n-butyltin hydride with carbohydrates containing isocyano groups replaces each of these groups with a hydrogen atom. Such replacement is known to occur when isocyano groups are attached to anomeric, 1,2 secondary, 3 9 and primary 7 9 carbon atoms. An example of

2 337 hapter 16 replacement at an anomeric carbon atom is shown in eq 1, 5 while both primary and secondary groups are replaced in the reaction described in Scheme 1. 7,9 Scheme 1 Ac H 2 = Ac 1 R 1 AIB 6 H 6 70 o Ac H 2 = Ac 63% R 2 AIB 80 o 6 H 6 R 1 = Ac R 2 = Ac Ac H 3 Ac 81% Ac Ac R 2 Isocyano group replacement is remarkably temperature sensitive. Reaction of the secondary groups in 1 takes place at 70 o, but the primary isocyano group is unreactive (Scheme 1). 7,9 When the temperature of the reaction mixture is raised to 80 o, both groups are replaced. This temperature dependence provides a basis for regioselective reaction. propagation steps Scheme 2 + R R 2 R 2 + R R + RH + A mechanism for isocyano group replacement with a hydrogen atom is pictured in Scheme In the first step of this process the tri-n-butyltin radical adds to the carbon atom of the isocyano group to produce an imidoyl radical (2). Fragmentation of this radical (2) then generates the carbon-centered radical R, which abstracts a hydrogen atom from to complete the reaction sequence. If R represents a phenyl or substituted-phenyl group, fragmentation to give an aryl radical does not occur; rather, an addition reaction takes place. 11 When tris(trimethylsilyl)silane

3 itriles and Isonitriles 338 replaces tri-n-butyltin hydride in reduction of isonitriles, compounds containing primary, secondary, or tertiary isocyano groups all are reactive. 12 initiation phase Scheme 3 H 2 Ac SH H 2 Ac S Ac + In Ac Ac Ac Ac Ac 3 In = an initiating radical 4 + InH propagation phase H 2 Ac H 2 Ac S S Ac + (H 3 ) 3 Ac Ac Ac Ac Ac 4 5 (H 3 ) 3 H 2 Ac 5 S==(H 3 ) 2 + Ac Ac Ac H 2 Ac H Ac Ac H Ac b. Sulfhydryl Groups An isonitrile can participate in replacement of a sulfhydryl group by a hydrogen atom. 13 Such a reaction is pictured in Scheme 3, where replacement begins when the sulfur-centered radical 4 forms from the thiol 3 by hydrogen-atom abstraction. Addition of 4 to t-butyl isocyanide gives the adduct radical 5, which then fragments to produce the pyranos-1-yl radical 6. Hydrogen-atom abstraction by 6 from another molecule of the starting thiol (3) completes the cycle and begins a

4 339 hapter 16 new reaction sequence. Sulfhydryl group replacement represents another pathway for generating carbon-centered, carbohydrate radicals. Scheme 4 6 H 5 MeS Me - 6 H 5 MeS Me S - SSMe S 7 - MeSS 6 H 5-6 H 5 Me Me 8 Scheme 5 6 H 5 HH 6 H 5 6 H 5 HH 6 H 5-6 H 5 H H 6 H H 5 H 2 H 6 H 5-6 H 5 H 2 H 2 6 H 5 55% 2. Elimination Reactions Reaction of tri-n-butyltin hydride with a carbohydrate that has adjacent isocyano and -thiocarbonyl groups generates a product with a double bond (Scheme 4). 4 In this reaction radicals 7 and 8 are both possible intermediates. Study of the diisonitrile 9 provides information helpful in choosing between 7 and 8. Reaction of 9 with produces a carbon-centered radical (10) with an isocyano group attached to the carbon atom adjacent to the radical center (Scheme 5). 8 The intermediate 10 does not expel a cyano radical to form a multiple bond but rather abstracts a hydrogen atom from tri-n-butyltin hydride. Extrapolating the behavior of 10 to the reaction

5 itriles and Isonitriles 340 shown in Scheme 4 leads to the conclusion that the radical 8 is an unlikely intermediate in this process. initiation Scheme 6 RTe 7 H 17 h R + Te 7 H 17 propagation R + =Ar R=Ar R + R Te 7 H 17 R=Ar + RTe 7 H 17 R=Ar + R Ar = 6 H 3 (H 3 ) 2 (2,4) R = a carbohydrate radical H 2 Ac H 2 Ac TeTol Ac + =Ar h Ac ( 2 ) Ac Ac Ar Ac Ac TeTol Ar = 6 H 3 (H 3 ) 2 (2,4) Tol = 6 H 4 H 3 (p) 3. Addition Reactions As a part of the replacement process shown in Scheme 2, an isonitrile reacts with to produce an intermediate, carbon-centered radical R. ormal completion of this reaction involves hydrogen-atom abstraction by R from ; however, if R is formed without a hydrogen-atom donor present, it will add to a molecule of isonitrile (Scheme 6). A specific example of this type of reaction is found in eq 2, which describes the α addition of a pyranos-1-yl radical, formed from a carbohydrate telluride, to an aromatic isonitrile. 14 B. Synthesis It is possible to produce isonitriles from isothiocyanates by radical reaction (eq 3). 2 A proposed mechanism for such a structural change is shown in Scheme 7. Isonitrile formation results when reaction is conducted at room temperature (eq 3), but if the reaction temperature is raised to 110 o, the isonitrile is not isolated because it undergoes isocyano group replacement by a hydrogen atom (eq 4). 2,15

6 341 hapter 16 Ac H 2 Ac Ac Ac S Et 2 25 o H 2 Ac Ac Ac Ac 76% ( 3 ) Scheme 7 R S + R SSnBu 3 R SSnBu 3 R + S S + SH + H 2 Ac Ac Ac Ac S AIB Bu3 SnH 6 H 5 H o H 2 Ac Ac Ac Ac 89% ( 4 ) H 2 Ac H 2 Ac AIB Ac R (H 3 ) 3 SiH + 3 Ac + - R 3 SiBr Ac Br 80 o Ac H(H 3 ) 3 Ac 6 H 6 Ac R = (H 3 ) 3 Si 89% ( 5 ) III. itriles A. Synthesis When t-butyl isonitrile reacts with a carbon-centered radical, an addition-elimination process takes place that results in the formation of a nitrile (Scheme 8) This type of nitrile synthesis is illustrated by the reaction shown in eq (Scheme 10 in hapter 2 describes another example of this type of reaction. 22 )

7 itriles and Isonitriles 342 Scheme 8 R + (H 3 ) 3 R (H 3 ) 3 R (H 3 ) 3 R + (H 3 ) 3 (H 3 ) 3 + (Me 3 ) 3 SiH H(H 3 ) 3 + (Me 3 ) 3 Si (Me 3 ) 3 Si + RX R + (Me 3 ) 3 SiX Scheme 9 Br Ac HAc Ac - Br Ac HAc 11 Ac Ac HAc Ac - Ac HAc Ac H 2 - H 3 H Ac HAc Ac B. Reactions 1. Addition to a yano Group Radical reactions of carbohydrate nitriles usually involve internal addition in which a carbon-centered radical generated in close proximity to a cyano group forms a new ring system An example is shown in Scheme 9, where the radical centered on -6 in 11 adds to the cyano group as a part of this sequential process. 24 arbohydrate radical formation in this type of reaction typically begins with the tri-n-butyltin radical abstracting a halogen atom or an -thiocarbonyl group. After cyclization, the radical abstracts a hydrogen atom from to produce an imine, which in some cases is isolated and in others is hydrolyzed to the corresponding carbonyl compound before isolation.

8 343 hapter 16 Scheme 10 Scheme 11 I Bn Bn - I R Bn Bn R ArH 2 Bn Bn R - ArH 2 Bn H 3 Bn R 76% R = H 3 H 3 Ar = Me 2 2. yano Group Migration When a cyclic imino radical forms during carbon-centered radical addition to a cyano group, the possibility exists that ring opening will lead to cyano group migration (Scheme 10) Such a reaction is shown in Scheme 11, where migration accompanies ring opening of a benzylidene acetal. 32

9 itriles and Isonitriles 344 IV. Summary When compared to reactions of halogenated carbohydrates or -thiocarbonyl compounds, radical reactions of nitriles and isonitriles are few in number. The primary reaction for isonitriles is isocyano group replacement by a hydrogen atom. For nitriles the only reaction of significance is internal addition of a carbon-centered radical to a cyano group to form a cyclic imino radical. Radical reactions can be involved in nitrile and isonitrile synthesis. Isonitriles are formed from reaction of isothiocyanates with tri-n-butyltin hydride. itriles are produced by addition of a carbon-centered radical to t-butyl isonitrile and subsequent elimination of the t-butyl radical. V. References 1. Hiebl, J; Zbiral, E. Monatsh. hem. 1990, 121, Witczak, Z. J. Tetrahedron Lett. 1986, 27, Tavecchia, P.; Trumtel, M.; Veyrières, A.; Sinaÿ, P. Tetrahedron Lett. 1989, 30, Barton, D. H. R.; Bringmann, G.; Lamotte, G.; Motherwell, W. B.; Motherwell, R. S. H.; Porter, A. E. A. J. hem. Soc., Perkin Trans. I 1980, Barton, D. H. R.; Bringmann, G.; Lamotte, G.; Motherwell, R. S. H.; Motherwell, W. B. Tetrahedron Lett. 1979, Trumtel, M.; Tavecchia, P.; Veyrières, A.; Sinaÿ, P. arbohydr. Res. 1989, 191, Barton, D. H. R.; Hartwig, W.; Motherwell, W. B. J. hem. Soc., hem. ommun. 1982, Barton, D. H. R.; Motherwell, W. B. Pure Appl. hem. 1981, 53, Barton, D. H. R.; Bringmann, G.; Motherwell, W. B. J. hem. Soc., Perkin Trans. I 1980, Saegusa, T.; Kobayashi, S.; Ito, Y.; Yasuda,. J. Am. hem. Soc. 1968, 90, a) Yamago, S. Synlett 2004, 1875; b) Yamago, S.; Miyazoe, H.; Goto, R.; Yoshida, J. Tetrahedron Lett. 1999, 40, Ballestri, M.; hatgilialoglu,.; lark, K. B.; Griller, D.; Giese, B.; Kopping, B. J. rg. hem. 1991, 56, Benati, L.; Leardini, R.; Miozzi, M.; anni, D.; Scialpi, R.; Spagnolo, P.; Stazzari, S.; Zanardi, G. Angew. hem. Int. Ed. 2004, 43, Yamago, S.; Miyazoe, H.; Goto, R.; Hashidume, M.; Sawazaki, T.; Yoshida, J. J. Am. hem. Soc. 2001, 123, rich, D.; Quintero, L. hem. Rev. 1989, 89, Stork, G.; Sher, P. M. J. Am. hem. Soc. 1983, 105, Stork, G.; Sher, P. M. J. Am. hem. Soc. 1986, 108, López, J..; Gómez, A. M.; Fraser-Reid, B. J. rg. hem. 1995, 60, López, J..; Fraser-Reid, B. hem. ommun. 1997, 2251.

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