Methoxyacetonitrile

MeOCH2CN

[1738-36-9]  · C3H5NO  · Methoxyacetonitrile  · (MW 71.09)

(a protected formaldehyde equivalent that undergoes metalation and addition to various electrophiles and that intercepts various nucleophiles at the cyano group)

Physical Data: bp 49 °C/60 mmHg,1 111 °C/624 mmHg,2 120-121 °C/759 mmHg;3 d 0.956 g cm-3.

Solubility: sol ethyl ether, chloroform, acetone, most common organic solvents.

Form Supplied in: liquid. Drying: distillation from phosphorus pentoxide.

Preparative Method: from Formaldehyde, Sodium Cyanide, and Dimethyl Sulfate.4

Handling, Storage, and Precautions: an organic cyanide; should be handled with due care in a fume hood.

Metalation.

The deprotonation of methoxyacetonitrile with various bases (e.g. n-Butyllithium, Lithium Diisopropylamide, Sodium Hydride) produces the corresponding nitrile-stabilized anion. Self-condensation of lithiomethoxyacetonitrile [69521-26-2] occurs in some cases.5

Additions to Carbonyl Electrophiles.

The addition of the nitrile-stabilized anion of methoxyacetonitrile to aldehydes and ketones gives b-hydroxy-a-methoxy nitriles (eq 1)6 or a-methoxyacrylonitriles (eq 2)6,7 depending on the reaction conditions. In the latter case the a-methoxyacrylonitriles are protected acyl cyanides, and demethylation using benzyl thiol in the presence of an amine provides acetamides (eq 2).6 Bromination5,8 of methoxyacetonitrile and an Arbuzov reaction provides 2-(diethoxyphosphono)-2-methoxyacetonitrile,5 a useful reagent for the conversion of carbonyl compounds to a-methoxyacrylonitriles (Horner-Emmons-Wittig reaction) that complements the direct condensation of methoxyacetonitrile with carbonyl compounds (eq 2). The addition of methoxyacetonitrile to a putative iminium salt, derived from isopropoxy- or t-butoxybis(dimethylamino)methane, provides an avenue to b-dimethylamino-a-methoxyacrylonitriles.9,10

Additions to the Cyano Group.

The nucleophilic addition of Grignard11-16 or organolithium reagents17 as well as the acid-catalyzed addition (Hoesch reaction) of activated arenes18 to the cyano group of methoxyacetonitrile leads to a-methoxy ketones. These products are useful intermediates for the synthesis of heterocycles (e.g. coumarins,18 flavanones,18-22 quinolinones,14 pyrazoles12) or the synthesis of carbocycles.15 Nucleophilic additions to methoxyacetonitrile followed by an intramolecular N-alkylation provides a one-step construction of 3,4-dihydroquinolines, albeit in modest yield.23 The sequential addition of a Grignard reagent and an organolithium reagent to methoxyacetonitrile permits the addition of two alkyl groups to afford b-methoxy primary amines MeOCH2CR2NH2, having an adjoining quaternary carbon.24

Other Reactions.

The acid-catalyzed addition of alcohols with methoxyacetonitrile (Pinner reaction) produces a-methoxy orthoesters25,26 and the cyano group of methoxyacetonitrile intercepts carbocations (Ritter reaction) leading to decalins27 or heterocycles.28,29 A cobalt-catalyzed cycloaddition of methoxyacetonitrile to a,o-diynes leads to tetrahydroisoquinolines30 and a [3 + 2] cycloaddition of the anion of p-Tolylthiomethyl Isocyanide to methoxyacetonitrile provides a substituted imidazole.31

Related Reagents.

Acetonitrile; N,N-Diethylaminoacetonitrile; Lithioacetonitrile; p-Tolylthiomethyl Isocyanide; p-Tolylsulfonylmethyl Isocyanide.


1. Kobler, H.; Schuster, K.-H.; Simchen, G. LA 1978, 1946 (CA 1979, 90, 151 545r).
2. Argabright, P. A.; Hall, D. W. CI(L) 1964, 1365.
3. Henze, H. R.; Rigler, N. E. JACS 1934, 56, 1351.
4. Scarrow, J. A.; Allen, C. F. H. OSC 1943, 2, 387.
5. Dinizo, S. E.; Freerksen, R. W.; Pabst, W. E.; Watt, D. S. JOC 1976, 41, 2846.
6. (a) Barton, D. H. R.; Bracho, R. D.; Widdowson, D. A. CC 1973, 781. (b) Barton, D. H. R.; Bracho, R. D.; Gunatilaka, A. A. L.; Widdowson, D. A. JCS(P1) 1975, 579.
7. Cariou, M.; Mabon, G.; Le Guillanton, G.; Simonet, J. T 1983, 39, 1551 (CA 1983, 99, 87 769y).
8. Sakurai, H.; Kyushin, S.; Nakadaira, Y. CL 1987, 297.
9. Bredereck, H.; Simchen, G.; Griebenow, W. CB 1974, 107, 1545 (CA 1974, 81, 49 645a).
10. Kantlehner, W.; Jaus, H.; Kienitz, L.; Bredereck, H. LA 1979, 2096 (CA 1980, 92, 128 373r).
11. Ogawa, M.; Matsuda, H.; Eto, H.; Asaoka, T.; Kuraishi, T.; Iwasa, A.; Nakashima, T.; Yamaguchi, K. CPB 1991, 39, 2301.
12. Yates, P.; Mayfield, R. J. CJC 1977, 55, 145.
13. Capillon, J.; Guetté, J. P. T 1979, 35, 1807 (CA 1980, 93, 7787r).
14. Nakatsu, T.; Johns, T.; Kubo, I.; Milton, K.; Sakai, M.; Chatani, K.; Saito, K.; Yamagiwa, Y.; Kamikawa, T. J. Nat. Prod. 1990, 53, 1508.
15. Gadwood, R. C.; Lett, R. M.; Wissinger, J. E. JACS 1986, 108, 6343.
16. Moffett, R. B.; Shriner, R. L. OSC 1955, 3, 562.
17. Fustero, S.; Díaz, M. D.; Barluenga, J.; Aguilar, E. TL 1992, 33, 3801.
18. Ahluwalia, V. K.; Prakash, C.; Singh, R. P. CI(L) 1980, 464.
19. Ferreira, D.; Van der Merwe, J. P.; Roux, D. G. JCS(P1) 1974, 1492.
20. Gaydou, E. M.; Bianchini, J.-P. Ann. Chim. (Paris) 1977, 2, 303 (CA 1978, 88, 136 410h).
21. Patwardhan, S. A.; Gupta, A. S. JCR(S) 1984, 395.
22. Dutta, P. K.; Bagchi, D.; Pakrashi, S. C. IJC(B) 1982, 21B, 1037.
23. Parham, W. E.; Bradsher, C. K.; Hunt, D. A. JOC 1978, 43, 1606.
24. (a) Chastrette, M.; Axiotis, G.; Gauthier, R. TL 1977, 18, 23 (CA 1977, 87, 5316p). (b) Gauthier, R.; Axiotis, G. P.; Chastrette, M. JOM 1977, 140, 245 (CA 1978, 88, 136 060u).
25. Ueno, H.; Maruyama, A.; Miyake, M.; Nakao, E.; Nakao, K.; Umezu, K.; Nitta, I. JMC 1991, 34, 2468.
26. Bakker, C. G.; Scheeren, J. W.; Nivard, R. J. F. RTC 1981, 100, 13.
27. Stevens, R. V.; Albizati, K. F. JOC 1985, 50, 632.
28. Maguet, M.; Poirier, Y.; Guglielmetti, R. BSF 1978, 561 (CA 1979, 91, 20 420u).
29. Noort, D.; Van der Marel, G. A.; Mulder, G. J.; Van Boom, J. H. SL 1992, 224.
30. Naiman, A.; Vollhardt, K. P. C. AG(E) 1977, 16, 708.
31. Van Leusen, A. M.; Schut, J. TL 1976, 17, 285.

David Watt & Miroslaw Golinski

University of Kentucky, Lexington, KY, USA



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