1,1,3,3-Tetramethylbutyl Isocyanide1

[14542-93-9]  · C9H10N  · 1,1,3,3-Tetramethylbutyl Isocyanide  · (MW 139.26)

(adds organometallic reagents to give a-metalloaldimines; synthetically useful acyl anion equivalent2)

Alternate Name: isooctyl isocyanide; 2-isocyano-2,4,4-trimethylpentane; TMBI.

Physical Data: bp 55-57 °C/11 mmHg; n20D 1.4220; d 0.794 g cm-3.

Solubility: insol water; sol common organic solvents.

Form Supplied in: colorless liquid, commercially available.

Analysis of Reagent Purity: IR n = 2130 cm-1; 1H NMR (neat) d 1.08 (s, 9H), 1.43 (t, J14N-H = 2 Hz, 6H) 1.58 (t, J14N-H = 2.3 Hz, 2H).

Preparative Methods: readily available in two steps from 1,1,3,3-tetramethylbutylamine, which is formylated with Formic Acid (86-90%) followed by dehydration with Dimethylchloromethyleneammonium Chloride (Vilsmeier reagent).3

Purification: distillation under reduced pressure.

Handling, Storage, and Precautions: unlike other isocyanides 1,1,3,3-tetramethylbutyl isocyanide is not malodorous, though its sweetish pine odor may become unpleasant after continued inhalation. Since some isocyanides are presumed to be toxic,4 appropriate precautions are recommended.

Addition of Organometallic Reagents.

Organolithium, Grignard, organocopper, and organozinc reagents add to the NC function of isocyanides that do not possess a-hydrogen atoms to give a-addition products. The a-metalloaldimines formed are useful synthetic equivalents5 for acyl anions, which are notoriously difficult to prepare.6 Reaction of a-metalloaldimines with electrophiles followed by hydrolysis of the imine introduces the acyl moiety into the product (eq 1).

1,1,3,3-Tetramethylbutyl isocyanide has several advantages over other isocyanides without a-hydrogens.7 It is easy to prepare from inexpensive starting materials and is not malodorous. Aromatic isocyanides, which could also be considered as precursors to a-metalloaldimines, tend to oligomerize and arylalkyl isocyanides do not form sufficiently stable a-metalloaldimines.

a-Lithioaldimines are generally prepared by addition of organolithium reagents to a solution of 1,1,3,3-tetramethylbutyl isocyanide in ether at 0 °C.2,7 Aliphatic organolithium reagents add rapidly to produce excellent yields of the products. Aromatic organolithiums usually give lower yields. Grignard reagents also tend to give somewhat lower yields,2,7 but their use may sometimes be more expedient when organolithiums are not readily available. Anions generated from C-H acids of pKa < 30 do not add to 1,1,3,3-tetramethylbutyl isocyanide. Reaction with the substituted cyclopropyllithium shown leads to a substituted cyclobutanone as the main product (eq 2).8

Preparation of Aldehydes and 1-Deuterio Aldehydes.

While simple protonation of metalloaldimines followed by hydrolysis of the imine provides a facile procedure for the preparation of aldehydes,2,7 from a synthetic point of view it is much more interesting to utilize this reaction to prepare 1-deuterioaldehydes by using D2O as a quenching agent (eq 3).2,3,7

Yields and deuterium incorporation are higher with organolithiums than with Grignard reagents (Table 1). The products are conveniently isolated by steam distillation from oxalic acid solution.

Reactions with Other Electrophiles.

a-Metalloaldimines react smoothly with Carbon Dioxide to give, after hydrolysis, a-keto acids (eq 4).2,7 Similar reaction with Ethyl Chloroformate leads to a-keto esters.2

Alkylation can be performed with primary halides, which leads to unsymmetrical ketones (eq 5).7b Benzylic and allylic halides do not give synthetically useful reactions, whereas secondary halides undergo elimination. In the latter case, dialkylchloroboranes were successfully used to overcome this difficulty (demonstrated for t-butyl isocyanide).9

Addition to nonenolizable aldehydes proceeds smoothly to give, after hydrolysis, a-hydroxy ketones (eq 6), whereas Propylene Oxide yields b-hydroxy ketones (eq 7) virtually without dehydration.2,7b

The mechanism of the reaction with aldehydes has been studied in more detail.10 It was found that, whereas a-metalloaldimines add to acrolein in a 1,2 fashion, a 1,4-Michael-type addition occurs with Methyl Acrylate.10

Reaction of metalloaldimines with Chlorotrimethylsilane constitutes a simple route to acylsilanes, though the yield is somewhat low due to the difficulties with selective hydrolysis of the intermediate imine (eq 8).2,7b

Coupling of Lithium Aldimines with Aryl, Vinyl, and Alkynyl Halides.

In a reaction unique among acyl anion equivalents, lithium aldimine generated from 1,1,3,3-tetramethylbutyl isocyanide and t-Butyllithium2 couples with aryl, vinyl, and alkynyl halides to give, after hydrolysis, the corresponding ketones (eqs 9-11).11

Aryl halides like iodo- or bromobenzene (but not chlorobenzene) give excellent yields of ketones. This interesting reaction is believed to proceed by halogen-metal exchange to give imidoyl halides and organolithium reagents, which in turn couple to give the product.11

Dissociation of Metalloaldimines.

Lithium aldimines are relatively stable; very little dissociation is observed in their reactions. However, their conversion to copper derivatives accelerates the dissociation.12 Good yields of nitriles are found only when tertiary alkyllithium reagents are used to generate the lithium aldimine (eq 12).


1. (a) Isonitrile Chemistry; Ugi, L., Ed.; Academic: New York, 1971. (b) Hoffmann, P.; Marquarding, D.; Kliimann, H.; Ugi, I. In The Chemistry of the Cyano Group; Rappoport, Z., Ed.; Wiley: New York, 1970. (c) Periasamy, M.; Walborsky, H. M. OPP 1979, 11, 293. (d) Walborsky, H. M.; Periasamy, M. P. In The Chemistry of Functional Groups, Supplement C; Patai, S.; Rappoport, Z., Eds.; Wiley: New York, 1983.
2. Niznik, G. E.; Morrison, W. H.; Walborsky, H. M. JOC 1974, 39, 600.
3. (a) Niznik, G. E.; Morrison, W. H.; Walborsky, H. M. OS 1971, 51, 31. (b) Walborsky, H. M.; Niznik, G. E. JOC 1972, 37, 187.
4. (a) Olson, J. S.; Gibson, Q. H. JBC 1972, 247, 1713. (b) Reichmann, L. M.; Annaev, B.; Belova, V. S.; Rozantzev, E. G. Nature New Biology 1972, 237, 31.
5. Ager, D. J. In Umpolung Synthons; Hase, T. A., Ed.; Wiley: New York 1987; Chapter 2 and references cited therein.
6. (a) Hiiro, T.; Morita, Y.; Inoue, T.; Kambe, N.; Ogawa, A.; Ryu, I.; Sonoda, N. JACS 1990, 112, 455. (b) Narayana, C.; Periasamy, M. S 1985, 253. (c) Shiner, C. S.; Berks, A. H.; Fisher, A. M. JACS 1988, 110, 957.
7. (a) Walborsky, H. M.; Niznik, G. E. JACS 1969, 91, 7778. (b) Walborsky, H. M.; Morrison, W. H.; Niznik, G. E. JACS 1970, 92, 6675.
8. Niznik, G. E.; Walborsky, H. M. JOC 1974, 39, 608.
9. (a) Yamamoto, Y.; Kondo, K.; Moritani, I. TL 1974, 793. (b) Yamamoto, Y.; Kondo, K.; Moritani, I. BCJ 1975, 48, 3682.
10. Marks, M. J.; Walborsky, H. M. JOC 1981, 46, 5405.
11. Marks, M. J.; Walborsky, H. M. JOC 1982, 47, 52.
12. Periasamy, M. P.; Walborsky, H. M. JOC 1974, 39, 611.

Harry M. Walborsky & Marek Topolski

Florida State University, Tallahassee, FL, USA



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