[50-00-0]  · CH2O  · Formaldehyde-Dimethylamine  · (MW 30.03) ((CH2O)n)

[30525-89-4]  · (CH2O)n  · Formaldehyde-Dimethylamine (R1 = Me, R2 = Me)

[124-40-3]  · C2H7N  · Formaldehyde-Dimethylamine  · (MW 45.10) (R1 = Me, R2 = Me; HCl salt)

[506-59-2]  · C2H8ClN  · Formaldehyde-Dimethylamine  · (MW 81.56) (R1 = Bn, R2 = H)

[100-46-9]  · C7H9N  · Formaldehyde-Benzylamine  · (MW 107.17) (R1 = Bn, R2 = H; HCl salt)

[3287-99-8]  · C7H10ClN  · Formaldehyde-Dimethylamine  · (MW 143.63)

(reagent for aminomethylation of active methylenes,1a-c aromatic compounds,1d and nucleophilic alkenes,1e,f reagent for generation of methyleneiminium species capable of participating in [4 + 2]2 and [3 + 2]3 cycloadditions)

Physical Data: Me2NH, bp 7 °C (also supplied as a 40 wt % solution in water); Me2NH.HCl, mp 170-173 °C; BnNH2, bp 184-185 °C, d 0.981 g cm-3; BnNH2.HCl, mp 262 °C.

Form Supplied in: amine HCl salts are widely available as white solids; HCHO is available as 37 wt % soln in water; paraformaldehyde (CH2O)n is available as a white solid

Handling, Storage, and Precautions: amines are irritants and corrosive; HCHO is highly toxic and a cancer suspect agent; paraformaldehyde is a moisture-sensitive irritant which can be expected to give off HCHO. Use in a fume hood.

Mannich Aminomethylation.

The generation of reactive methyleneiminium salts (eq 1) from formaldehyde and primary or secondary amines (usually as HCl salts) defines the classical Mannich conditions under which a wide variety of nucleophilic species can be aminomethylated. Historically, the most common nucleophiles have been active methylene compounds1a-c with a pKa of 20 or less (e.g. ketones, aldehydes, and malonates) and nucleophilic aromatic compounds.1d Recent examples of each include the aminomethylation of a ketone in the synthesis of the alkaloid (±)-glaucine (eq 2)4 and the aminomethylation of a phenol, which occurs regioselectively ortho to the hydroxyl group (eq 3).5

Aminomethylation of active methylene compounds is often accompanied by elimination of the amine, comprising one of the most useful syntheses of a-methylene carbonyl compounds.1a-c This methylenation procedure was recently incorporated into a cephalosporin synthesis (eq 4).6 Formation of the double bond is also often accomplished separately by quaternization and base-induced elimination.

Methyleneiminium species are sufficiently reactive to be attacked by moderately nucleophilic alkenes.1f,7-10 In most cases, this reaction is terminated by addition of an external nucleophile, such as halide or water, to the opposite terminus of the alkene.9,10 However, the addition of an alkene to the methyleneiminium ion can also occur in the context of a pericyclic reaction. The elegant stereoselective pyrrolidine synthesis reported by Overman proceeds via a tandem aza-Cope rearrangement/Mannich condensation and has been incorporated into a number of alkaloid total syntheses.1f The method is exemplified in eq 5.11 An unprecedented aza-ene reaction was also recently observed during an intramolecular reaction of an alkene with a methyleneiminium ion (eq 6).12

Terminal alkynes will condense with secondary amines and HCHO in the presence of Cu+ or Zn2+ catalysts to afford aminomethylalkynes13 or allenes.14 Overman has exploited the intramolecular trapping of methyleneiminium ions with alkynes coupled with nucleophilic addition to the incipient vinyl cations to effect the syntheses of pyrrolidines and piperidines possessing exocyclic substituted methylenes of defined stereochemistry (eq 7).15 Apparently the success of this cyclization depends on the presence of an external nucleophile.

The enhanced nucleophilicity of allyl and vinyl silanes relative to alkenes renders them particularly susceptible to reaction with methyleneiminium ions. Grieco has demonstrated that allylsilanes and -stannanes react readily, both inter- and intramolecularly.16 The resulting homoallyl amines may react further with formaldehyde, affording 4-hydroxypiperidines via the subsequent intramolecular addition of the terminal alkene to the methyleneiminium ion (eq 8).16a Vinylsilanes are particularly valuable nucleophiles in that they add intramolecularly in a stereospecific fashion to methyleneiminium ions (eq 9).1f,17


Böhme first demonstrated that dimethylmethyleneiminium ion is reactive enough to participate as a dienophile in Diels-Alder reactions with 1,3-dienes.18 More recently it has been reported that methyleneiminium ions generated in situ from primary amines and HCHO undergo this reaction as well (eq 10).2 Diastereoselectivity has been noted when amines bearing asymmetrical groups are employed (eq 11).2a,19

When HCHO is combined with a primary amine bearing an electron-withdrawing group (e.g. ester or nitrile) in the a-position, the resultant methyleneiminium ion can deprotonate at the a-carbon, generating an azomethine ylide capable of undergoing [3 + 2] cycloadditions with alkenic dipolarophiles.3,20 A typical example is presented in eq 12.20 This method suffers from a lack of regio- and stereoselectivity.

If the electron-withdrawing group is carboxyl, spontaneous decarboxylation occurs, comprising a remarkably mild and convenient generation of nonstabilized azomethine ylides.21 Cycloaddition with various alkenes is stereospecific, providing 2,5-unsubstituted pyrrolidines (eq 13).21b

Related Reagents.

Dimethyl(methylene)ammonium Iodide; Dimethyl(phenylthiomethyl)amine; Formaldehyde; N-(Methylthiomethyl)piperidine.

1. (a) Tramontini, M. S 1973, 703. (b) Tramontini, M.; Angiolini, L. T 1990, 46, 1791. (c) Kleinman, E. F. COS 1991, 2, 893. (d) Heaney, H. COS 1991, 2, 953. (e) Kleinman, E. F.; Volkmann, R. A. COS 1991, 2 975. (f) Overman, L. E.; Ricca, D. J. COS 1991, 2, 1007.
2. (a) Larsen, S. D.; Grieco, P. A. JACS 1985, 107, 1768. (b) Grieco, P. A.; Larsen, S. D. OS 1990, 68, 206; OSC 1993, 8, 31. (c) Cortes, D. A. U.S. Patent 4 946 993, 1990. (d) Skvarchenko, V. R.; Lapteva, V. L.; Gorbunova, M. A. JOU 1990, 26, 2244.
3. Tsuge, O.; Kanemasa, S. Adv. Heterocycl. Chem. 1989, 45, 231.
4. Ozaki, Y.; Kim, S.-W. CPB 1991, 39, 1349.
5. Hartman, G. D.; Halczenko, W. JHC 1990, 27, 127.
6. Gunda, T. E. LA 1990, 311.
7. Barnett, C. J.; Copley-Merriman, C. R.; Maki, J. JOC 1989, 54, 4795.
8. Tolstikov, G. A.; Shul'ts, É. É.; Baikova, I. P.; Spirikhin, L. V. JOU 1991, 27, 357.
9. Schmidle, C. J.; Mansfield, R. C. JACS 1956, 78, 1702.
10. (a) Grewe, R.; Hamann, R.; Jacobsen, G.; Nolte, E.; Riecke, K. LA 1953, 581, 85. (b) Grob, C. A.; Wohl, R. A. HCA 1966, 49, 2175. (c) Cope, A. C.; Burrows, W. D. JOC 1966, 31, 3099.
11. Overman, L. E.; Jacobsen, E. J.; Doedens, R. J. JOC 1983, 48, 3393.
12. Shishido, K.; Hiroya, K.; Fukumoto, K.; Kametani, T. TL 1986, 27, 1167.
13. (a) Amstutz, R.; Ringdahl, B.; Karlén, B.; Roch, M.; Jenden, D. J. JMC 1985, 28, 1760. (b) Stütz, A.; Georgopoulos, A.; Granitzer, W.; Petranyi, G.; Berney, D. JMC 1986, 29, 112.
14. (a) Crabbe, P.; Fillion, H.; André, D.; Luche, J.-L. CC 1979, 859. (b) Yasukouchi, T.; Kanematsu, K. TL 1989, 30, 6559.
15. (a) Overman, L. E.; Sharp, M. J. JACS 1988, 110, 612. (b) Overman, L. E.; Sharp, M. J. TL 1988, 29, 901. (c) Arnold, H.; Overman, L. E.; Sharp, M. J.; Witschel, M. C. OS 1992, 70, 111.
16. (a) Larsen, S. D.; Grieco, P. A.; Fobare, W. F. JACS 1986, 108, 3512. (b) Grieco, P. A.; Fobare, W. F. TL 1986, 27, 5067. (c) Grieco, P. A.; Fobare, W. F. CC 1987, 185. (d) Grieco, P. A.; Bahsas, A. JOC 1987, 52, 1378.
17. (a) Overman, L. E.; Malone, T. C. JOC 1982, 47, 5297. (b) Overman, L. E.; Bell, K. L.; Ito, F. JACS 1984, 106, 4192. (c) Daly, J. W.; McNeal, E. T.; Overman, L. E.; Ellison, D. H. JMC 1985, 28, 482.
18. Böhme, H.; Harke, K.; Müller, A. CB 1963, 96, 607.
19. (a) Grieco, P. A.; Bahsas, A. JOC 1987, 52, 5746. (b) Waldman, H. AG(E) 1988, 27, 274. (c) Waldman, H. LA 1989, 231.
20. Tsuge, O.; Kanemasa, S.; Ohe, M.; Yorozu, K.; Takenaka, S.; Ueno, K. BCJ 1987, 60, 4067.
21. (a) Joucla, M.; Mortier, J. CC 1985, 1566. (b) Tsuge, O.; Kanemasa, S.; Ohe, M.; Takenaka, S. CL 1986, 973.

Scott D. Larsen

The Upjohn Co., Kalamazoo, MI, USA

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