Ethyl Isocyanoacetate1

(R = Et)

[2999-46-4]  · C5H8NO2  · Ethyl Isocyanoacetate  · (MW 113.14) (R = Me)

[39687-95-1]  · C4H6NO2  · Methyl Isocyanoacetate  · (MW 99.11)

(heterocycle formation accompanied by cyclization onto the isocyano group;1 forms stabilized carbanion for alkylations in amino acid synthesis;1 a,a-additions to isocyano group and Passerini reactions2)

Physical Data: ethyl ester, bp 89-91 °C/11 mmHg; methyl ester, bp 59-60 °C/3 mmHg.

Solubility: slightly sol H2O; sol organic solvents.

Form Supplied in: yellow oils.

Preparative Methods: a-isocyanoacetate esters are most conveniently prepared by dehydration of the corresponding N-formylamino acid esters using Phosphorus Oxychloride in the presence of Triethylamine in CH2Cl2.3

Purification: by distillation.

Handling, Storage, and Precautions: isocyano compounds are generally quite sensitive to acids and immediately decompose to amine or formamide derivatives. They must be stored under N2 at 0 to -20 °C. All operations should be performed in a well-ventilated fume hood because of the strong, disagreeable odor, and the equipment should be washed with acid after use.

Heterocycle Formation by Electrophiles.

Isocyanoacetates having hydrogen at the carbon flanked with two activating groups can easily form the carbanion. a-Metalated (anionic) isocyanoacetates, which are obtained by means of the usual bases in carbanion chemistry such as NaH, t-BuOK, n-BuLi, DBU, and Et3N, permit attack of various electrophiles. The ambivalent nature of the isocyanide carbon atom allows nucleophilic cyclization to form heterocycles after addition to polar multiple bonds such as carbonyl, imino, thioxo, nitrile, active alkene, etc. (eq 1).

Reaction of a-anions from isocyanoacetate with acylating agents gives oxazole-4-carboxylates via cyclization of the enol form onto the isocyano group (eq 2).4 3-Amino-4-hydroxycoumarins and 2(1H)-quinolinones are synthesized by reactions with acetyl or salicyloyl chlorides5 and benzooxazinones6 followed by acid hydrolysis in a straightforward reaction. The addition of an arylsulfenyl chloride to the carbenoid carbon of ethyl isocyanoacetate followed by treatment with Triethylamine affords 2-arylthio-5-ethoxyoxazoles in situ (eq 3).7 Reaction with nitriles in the presence of Potassium Hydride in diglyme affords 5-substituted imidazole-4-carboxylates8 and reactions with Schiff bases (imino compounds) form imidazolines.9

Ethyl isocyanoacetate reacts with Carbon Disulfide to give thiazolethiolates in the presence of Potassium t-Butoxide, which provide 5-(methylthio)thiazole-4-carboxylates with Iodomethane (eq 4).10

The coupling reactions with arenediazonium ions give 1-aryl-1H-1,2,4-triazole-3-carboxylates via cyclization of hydrazone compounds in the presence of sodium acetate in aq MeOH.11 Condensation with heteroallenes such as isocyanates and isothiocyanates generates oxazole and thiazole skeletons, but the reactions give complicated products under various reaction conditions.12 Michael addition proceeds easily with C-C bond formation, while a,b-unsaturated carbonyl compounds on heating to 70-80 °C provide pyrrolines accompanying further cyclization by insertion of the anion into the isocyano group.13 When a nitroalkene is the Michael acceptor, 3,4-disubstituted pyrrole-2-carboxylates are obtained by cyclization and elimination of the nitro group (eq 5).14

Reactions with Aldehydes and Ketones.

Reactions with carbonyl compounds as electrophiles afford many valuable products. For example, formylaminoacrylates are obtained in the presence of t-BuOK or NaH via isomerization of the oxazolinyl anion by proton shift from C-4 to C-2 followed by elimination (eq 6).15 In the presence of NaCN in EtOH, trans-2-oxazoline-4-carboxylates are produced by protonation of the oxazolinyl anion.16 The use of metal catalysts such as NiCl and Cu2O also gives the oxazoline products. Especially, in the presence of a gold(I) complex (1) coordinated to a chiral ferrocenylphosphine ligand (2), oxazoline-4-carboxylates are formed with high enantio- and diastereoselectivity (eq 7).17

Formamidine derivatives are also formed using pyrrolidine or piperidine as bases in MeOH by insertion of the bases into the isocyano group of a-isocyanoacrylate, which is proposed as an intermediate (eq 8).18 The reaction with aldehydes in the presence of 1,8-Diazabicyclo[5.4.0]undec-7-ene in THF affords pyrrole-2,4-dicarboxylates via Michael addition by another equivalent of methyl isocyanoacetate to the proposed intermediate, i.e. methyl isocyanoacrylates (eq 8).19 Reaction with acetaldehyde in the presence of Et3N in benzene affords methyl a-isocyano-b-hydroxybutyrate (eq 8).20

a-Activating Group for Amino Acids Synthesis.

Carbon-carbon bond formation at the a-carbon of a-isocyanoacetates by alkylation with carbon electrophiles provides a useful preparative method for the synthesis of various amino acid derivatives, since the isocyano group is easily converted to the amino group by acidification. Hence, isocyanoacetates are regarded as synthetic equivalents for a-activated amino acids (eq 9).1

Reactions of a-metalated a-isocyanopropionate with alkyl halides and Michael acceptors followed by hydrolysis give a-methyldopa,21 a-methylhistidine,21 and a-methylglutamic acid.22 Palladium-catalyzed allylation of ethyl a-isocyanopropionate with allyl acetate in the presence of Tetrakis(triphenylphosphine)palladium(0) affords a-allylalanine ethyl ester after acidification.23 Furthermore, 2-oxazoline-4-carboxylates, which are accessed readily by reaction with aldehydes and ketones as described in the above section, are easily converted to b-hydroxy-a-amino acid derivatives by acid hydrolysis.1 In the same way, oxazole-4-carboxylates obtained by reaction with acylating agents are hydrolyzed to give C-acylamino acid esters.4

Insertion into the Isocyano Group.

a,a-Additions to the isocyano group are well known reactions in catalytic chemistry.24 Furthermore, the Passerini reaction, which provides a-acyloxycarboxamide from isocyano compounds, ketones, and carboxylic acids,25 and the Ugi reaction (four-component condensation: 4CC)26 are unique peptide synthetic methods. As an application of the 4CC, the reaction of 3-aryloxy-4,5-dihydroxypyrrole, which is an intramolecular condensation product of the aldehyde and amine components, with ethyl isocyanoacetate and benzoic acid affords N-benzoyl-b-aryloxyprolylglycinate (eq 10).27

Related Reagents.

(2S,4S)-3-Benzoyl-2-t-butyl-4-methyl-1,3-oxazolidin-5-one; t-Butyl Isocyanide; Diethyl Isocyanomethylphosphonate; Ethyl N-(Diphenylmethylene)glycinate; Phenyl Isocyanide; 1,1,3,3-Tetramethylbutyl Isocyanide; p-Tolylthiomethyl Isocyanide; p-Tolylsulfonylmethyl Isocyanide.

1. (a) Hoppe, D. AG(E) 1974, 13, 789. (b) Schöllkopf, U. AG(E) 1977, 16, 339. (c) Matsumoto, K.; Moriya, T.; Suzuki, M. J. Synth. Org. Chem. Jpn. 1985, 43, 764.
2. Ugi, I. Isonitrile Chemistry; Academic: New York, 1971.
3. Haytman, G. D.; Weinstock, L. M. OSC 1988, 6, 620.
4. Suzuki, M.; Iwasaki, T.; Miyoshi, M.; Okumura, K.; Matsumoto, K. JOC 1973, 38, 3571.
5. Matsumoto, K.; Suzuki, M.; Miyoshi, M.; Okumura, K. S 1974, 500.
6. (a) Matsumoto, K.; Suzuki, M.; Yoneda, N.; Miyoshi, M. S 1976, 805. (b) Suzuki, M.; Matsumoto, K.; Miyoshi, M.; Yoneda, N.; Ishida, R. CPB 1977, 25, 2602.
7. Bossio, R.; Marcaccini, S.; Pepino, R. H 1986, 24, 2003.
8. Murakami, T.; Otsuka, M.; Ohno, M. TL 1982, 23, 4729.
9. Meyer, R.; Schöllkopf, U.; Böhme, P. LA 1977, 1183.
10. (a) Schöllkopf, U.; Porsch, P. H.; Blume, E. LA 1976, 2122. (b) Fleischmann, K.; Scheunemann, K. H.; Schorlemmer, H. U.; Dickneite, G.; Blumbach, J.; Fischer, G.; Dürckheimer, W.; Sedlacek, H. H. AF 1989, 39, 743.
11. Matsumoto, K.; Suzuki, M.; Tomie, M.; Yoneda, N.; Miyoshi, M. S 1975, 609.
12. (a) Schröder, R.; Schöllkopf, U.; Blume, E.; Hoppe, I. LA 1975, 533. (b) Suzuki, M.; Moriya, T.; Matsumoto, K.; Miyoshi, M. S 1982, 874. (c) Solomon, D. M.; Rizvi, R. K.; Kaminski, J. J. H 1987, 26, 651.
13. (a) Schöllkopf, U.; Hantke, K. LA 1973, 1571. (b) Saegusa, T.; Ito, Y.; Kinoshita, H.; Tomita, S. JOC 1971, 36, 3316.
14. (a) Barton, D. H. R.; Zard, S. Z. CC 1985, 1098. (b) Ono, N.; Kawamura, H.; Bougauchi, M.; Maruyama, K. T 1990, 46, 7483.
15. Schöllkopf, U.; Gerhart, F.; Schroder, R.; Hoppe, D. LA 1972, 766, 116.
16. Hoppe, D.; Schöllkopf, U. LA 1972, 763, 1.
17. (a) Ito, Y.; Sawamura, M.; Hayashi, T. JACS 1986, 108, 6405. (b) Ito, Y.; Sawahara, M.; Shirakawa, E.; Hayashizaki, K.; Hayashi, T. T 1988, 44, 5253.
18. Suzuki, M.; Nunami, K.; Moriya, T.; Matsumoto, K.; Yoneda, N. JOC 1978, 43, 4933.
19. Suzuki, M.; Miyoshi, M.; Matsumoto, K. JOC 1974, 39, 1980.
20. Matsumoto, K.; Ozaki, Y.; Suzuki, M.; Miyoshi, M. ABC 1976, 40, 2045.
21. Suzuki, M.; Miyahara, T.; Yoshioka, R.; Miyoshi, M.; Matsumoto, K. ABC 1974, 38, 1709.
22. Schöllkopf, U.; Hantke, K. LA 1973, 1571.
23. Ito, Y.; Sawamura, M.; Matsuoka, M.; Matsumoto, Y.; Hayashi, T. TL 1987, 28, 4849.
24. Saegusa, T.; Ito, Y. S 1975, 291.
25. Passerini, M. G 1971, 51, 126.
26. Ugi, I. AG(E) 1982, 21, 810.
27. Bowers, M. M.; Carroll, P.; Joullie, M. M. JCS(P1) 1989, 857.

Kazuo Matsumoto & Mamoru Suzuki

Tanabe Seiyaku Co., Osaka, Japan

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