t-Butyl Isocyanide1,2


[7188-38-7]  · C5H9N  · t-Butyl Isocyanide  · (MW 83.13)

(reactive amphiphilic reagent for 1,1-additions to form various heterocyclic N-t-butylimines; asymmetric amino acid synthesis; fragment condensation of peptides; mild carboxylic acid esterifications; metal-catalyzed cyanation of acetals, a,b-enones, and 1-alkenes; other applications involving various iminyl 1,1-addition reactions1,2)

Physical Data: bp 91 °C/38 mmHg; d 0.74 g cm-3.

Solubility: sol most organic solvents, including methanol, ethanol, ether, toluene, dichloromethane.

Form Supplied in: pure liquid; commercially available.

Analysis of Reagent Purity: by gas chromatography.

Preparative Methods: dehydration of N-t-Butylformamide with Phosphorus Oxychloride3 and by the Hofmann carbylamine reaction.4

Handling, Storage, and Precautions: awful smelling liquid: should be stored and used in a fume hood; contaminated equipment should be washed with 5% methanolic sulfuric acid.

Heterocyclic Synthesis.

Silver(I) Cyanide catalyzes the formyl transfer from t-butyl isocyanide to 1,n-amino alcohols, diamines, and amino thiols.5 An example is the conversion of g-aminopropanol to 5,6-dihydro-4H-1,3-oxazine (eq 1). The reaction can be extended to o-aminophenol, o-phenylenediamine, and o-aminothiophenol, affording benzoxazole (54%), benzimidazole (64%), and benzothiazole (93%), respectively.

Four-membered ring formation of 2,3-bis(alkylimino)oxetanes can be performed in high yields from ketones and 2 equiv of t-butyl isocyanide (eq 2).6 Iminodioxolane derivatives are available in excellent yield from t-butyl cyanoketene (eq 3).7

A spiro 1,4-dioxan-2-one is formed in a Lewis-acid catalyzed reaction in reasonable yields from cycloalkyl ethylene acetals, which are easily prepared from the ketone and ethylene glycol (eq 4).8 [4 + 1] Cycloaddition of kinetically stabilized azetes with t-butyl isocyanide affords sterically hindered pyrrole imines (eq 5).9 An intermediate ketenimine built from 3-aminoacrylamide reacts with t-butyl isocyanide, forming the diiminopyrroline system (eq 6).10

[4 + 1] Cycloaddition of 1,3-diaza-2-methylthiobutadienes with t-butyl isocyanide affords 4-imino-2-thioimidazolines (eq 7).11 Isocyanides react with thiazolines, causing a ring transformation to imidazolines (eq 8).12 In the presence of Boron Trifluoride Etherate, t-butyl isocyanide dimerizes, forming pivalonitrile N-t-butylimine which reacts with o-phenylenediamine to afford 2-t-butylbenzimidazole (eq 9).13

A structurally interesting boron heterocycle, namely a borapyrrole derivative, can be made by [4 + 1] cycloaddition plus alkyl tautomerization (eq 10).14

Asymmetric Synthesis of a-Amino Acids and Peptide Coupling.

Enantioselective formation of a-amino acids can be performed by asymmetrically induced Ugi reaction (eqs 11 and 12).15,16

The chiral auxiliaries in eqs 11 and 12 are aminopyranoses with protected hydroxy functions, derived from glucose and galactose respectively. Another effective auxiliary is (R)-a-ferrocenylisobutylamine.17 In eq 13 chiral induction is nearly quantitative.

A method for fragment condensation of peptides involves using t-butyl isocyanide as coupling reagent (eq 14).18

Mild Esterification.

In the chemistry of b-lactam antibiotics, especially of penicillins and cephalosporins, introduction of the ester group is often difficult. This problem can be solved by using the Passerini reaction with a-geminal polyhalogenated aldehydes and t-butyl isocyanide (eq 15).19 The cleavage of b-haloalkyl esters can be performed under very mild conditions and regioselectively by cobalt(I) phthalocyanine anion without attack of the penicillin moiety.

Esterification of carboxylic acids with absolute alcohols can be achieved under mild conditions using t-butyl isocyanide. Exceptionally high yields are achieved in forming dicarboxylic monoalkyl esters (eq 16).20

Cyanation Reactions.

a-Imino nitriles are accessible in excellent yield from aldehyde acetals and t-butyl isocyanide (eq 17).21 t-Butyl isocyanide serves as a cyanide source for cyanohydrin ether formation (eq 18).8

t-Butyl isocyanide undergoes formal [4 + 1] cycloaddition to a,b-enones in the presence of Diethylaluminum Chloride to give N-t-butylimines of b,g-butenolides (~65%). Catalytic hydrogenation and hydrolysis afford g-butyrolactones.22a This tertiary isocyanide donates cyanide for conjugate hydrocyanation of a,b-enones, producing b-cyano ketones (eq 19).22b

Regioselective hydrocyanation of terminal alkenes can be accomplished by hydrozirconation with Schwartz's reagent (Chlorobis(cyclopentadienyl)hydridozirconium), followed by imine insertion with t-butyl isocyanide and iodinolysis (eq 20).23

Other Applications.

Cyclohexenimines are accessible from Allyl Chloride, Acrylonitrile, and t-butyl isocyanide via N-t-butyl vinylketenimine in a [4 + 2] cycloaddition (eq 21).24

By a cross-coupling reaction of octyl-9-BBN, t-butyl isocyanide, and iodobenzene, an alkylarene ketimine is formed, which hydrolyzes by acid catalysis to the corresponding ketone (eq 22).25 Unsymmetrical ketones may also be obtained by 1,1-addition of an alkyllithium reagent to t-butyl isocyanide, lithium-boron exchange with R2BCl, thioglycolic acid-induced migration of one R group from boron to carbon, and alkaline oxidation (H2O2, OH-)26

Arylimino esters are available by a palladium-catalyzed reaction of aryl halides with t-butyl isocyanide and Tri-n-butyl(methoxy)stannane. The reaction conditions have been developed with great care (eq 23).27 Cyclic imino esters are also formed by formal substitution of carbon monoxide with t-butyl isocyanide and 5-aryl-2,3-dihydro-1,3-furandiones via a ketene intermediate (eq 24).28

Radical carbon-carbon linkage of acrylonitrile and t-butyl isocyanide can be performed in acceptable yields by using Azobisisobutyronitrile as radical initiator and Tris(trimethylsilyl)silane (eq 25).29

Isocyanides can insert at a benzylic carbon between a carbon-sulfur and a methoxycarbonyl bond to form a ketene S,N-acetal containing the isocyanide carbon (eq 26).30

Polymerization of isocyanides under the action of NiII catalysis leads to helical polymethylenimines (eq 27).31

Oxidation of t-butyl isocyanide by elemental Sulfur with Tellurium as catalyst gives the corresponding isothiocyanate in reasonable yield (eq 28).32 Direct oxidative addition to t-butyl isocyanide by elemental Selenium affords t-butyl isoselenocyanate.33

Related Reagents.

Copper(I) Oxide-t-Butyl Isocyanide; Cyclohexyl Isocyanide; Ethyl Isocyanoacetate; Methyl Isocyanide; Phenyl Isocyanide; 1,1,3,3-Tetramethylbutyl Isocyanide; p-Tolylthiomethyl Isocyanide; Triphenylmethyl Isocyanide.

1. For general reviews on isonitrile chemistry see (a) Ugi, I. Isonitrile Chemistry; Academic: New York, 1971. (b) Periasamy, M. P.; Walborsky, H. M. OPP 1979, 11, 295.
2. For applications of isonitriles in heterocyclic synthesis, see: Maraccini, S.; Torroba, T. OPP 1993, 25, 141.
3. Ugi, I.; Meyer, M.; Lipinski, M.; Bodensheim, F.; Rosendahl, F. OS 1961, 41, 13.
4. Ref. 1(a), Chapter II.
5. Ito, Y.; Inubushi, Y.; Zenbayashi, M.; Tomita, S.; Saegusa, T. JACS 1973, 95, 4447.
6. Kabbe, H. J. CB 1969, 102, 1404.
7. Moore, H. W.; Yu, C.-C. JOC 1981, 46, 4935.
8. Ito, Y.; Saegusa, T. CL 1984, 937.
9. Hees, U.; Regitz, M. S 1990, 834.
10. Capuano, L.; Dahm, B. CB 1988, 121, 271.
11. Morel, G.; Foucaud, A. JOC 1989, 54, 1185.
12. L'abbé, G.; Meutermanns, W. BSB 1986, 95, 1129.
13. Kabbe, H. J. CB 1969, 102, 1447.
14. Dorokhov, V.; Boldyreva, O. H 1982, 18, 87.
15. Goebel, M.; Ugi, I. S 1991, 1095.
16. Kunz, H.; Pfrengle, W. JACS 1988, 110, 651.
17. Urban, R.; Ugi, I. AG(E) 1975, 14, 61.
18. Wackerle, L. S 1979, 197.
19. (a) Eckert, H. ZN(B) 1990, 45b, 1715. (b) Eckert, H. S 1977, 332.
20. Rehn, D.; Ugi, I. JCR(S) 1977, 119.
21. (a) Pellissier, H.; Gil, G. TL 1989, 30, 171. (b) Ito, Y.; Kato, H.; Imai, H.; Saegusa, T. JACS 1982, 104, 6449.
22. (a) Ito, Y.; Kato, H.; Saegusa, T. JOC 1982, 47, 741. (b) Pellissier, H.; Gil, G. T 1989, 45, 3415.
23. Buchwald, S. L.; LaMaire, S. J. TL 1987, 28, 295.
24. (a) Ito, Y.; Saegusa, T. SC 1980, 10, 233. (b) Roesch, L.; Altnau, G. AG(E) 1979, 18, 60.
25. Ishiyama, T.; Oh-e, T. TL 1992, 33, 4465.
26. Yamamoto, Y.; Kondo, K.; Moritani, I. TL 1978, 793.
27. Kosugi, M.; Migita, T. CL 1986, 1197.
28. Andreichikov, Y.; Shurov, S. JOU 1986, 22, 766.
29. Chatgilialoglu, C.; Giese, B. TL 1990, 31, 6013.
30. Morel, G.; Foucaud, A. T 1984, 40, 1075.
31. Kamer, P. C.; Nolte, R. J. M. JACS 1988, 110, 6818.
32. Fujiwara, S.; Sonoda, N. TL 1992, 33, 7021.
33. Fujiwara, S.; Tsutomu, S. TL 1991, 32, 3503.

Heiner Eckert, Alfons Nestl & Ivar Ugi

Technische Universität München, Garching, Germany

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