Synlett 2004(7): 1321-1322  
DOI: 10.1055/s-2004-825600
SPOTLIGHT
© Georg Thieme Verlag Stuttgart · New York

Dimethyl(methylene)ammonium Salts: Mannich Reagents

Heedong Yun*
Department of Chemistry, Havemeyer Hall MC 3135, Columbia University, 3000 Broadway, New York, NY 10027, USA
e-Mail: hy2013@columbia.edu;

Further Information

Publication History

Publication Date:
10 May 2004 (online)

Biographical Sketches

Heedong Yun was born in Kumi, Korea, in 1975. He received a B.S. in 1999 from Seoul National University in Seoul, Korea. He obtained an M.A. from Columbia University in 2003 and he is currently pursuing a Ph.D. on the total synthesis of biologically active marine natural products under the guidance of Prof. Samuel J. ­Danishefsky.

Introduction

These reagents comprise a family of preformed iminium salts which have been extensively utilized in condensation reactions with carbonyl and aromatic compounds in a variant of the Mannich reaction. Böhme prepared the first dimethyl(methylene)ammonium chloride (1), [1] and the ­iodide salt 2 was later developed by Eschenmoser. [2] Preformed iminium salts are sufficiently soluble in many aprotic solvents, enabling the use of highly reactive nucleophiles which ordinarily would decompose under the protic conditions of the classical Mannich reaction. A comparison study of these salts favors the trifluoroacetate salt (3) because it is the most soluble and can be transferred by syringe, although it is more tedious to prepare. [3]

Salt 1 is prepared by cleavage of N,N,N¢,N¢-tetramethylmethanediamine by AcCl [4] or cleavage of methyl dimethylaminomethyl ether by TMSCl. [5] Salt 2 is prepared by thermolysis of (iodomethyl)trimethylammonium iodide2 or cleavage of N,N,N¢,N¢-tetramethylmethanediamine by TMSI. [6] Salt 3 is prepared by Polonovski reaction of tri­methylamine oxide with TFAA or cleavage of N,N,N¢,N¢-tetramethylmethanediamine with TFA. [7]

Abstracts

(A) Trimethylsilyl enol ethers derived from ketones and aldehydes add to salts 1-3 and the reaction proceeds via a silyloxonium ion which hydrolyzes on aqueous workup. This method has been used for the synthesis of the two regioselective Mannich bases of 2-methylcyclohexanone. [8]

(B) Enolates generated by the decomposition of a-diazo ketones in the presence of trialkylborane provide Mannich bases in excellent regioselectivity from simple unsymmetrical ketones. [9]

(C) Salts 1-3 serve as excellent one-carbon equivalents for an a-methylene group. The dimethylamino group can be easily eliminated by quaternization with iodomethane followed by treatment with base or direct purification on silica-gel chromatography. This method was successfully applied to an elegant synthetic approach toward Xestocyclamine A. [10]

(D) Electron-rich aromatic and heteroaromatic compounds have been shown to undergo condensation reactions with salts 1-3 with excellent regiocontrol. Monosubstituted phenols, which usually ­afford mixtures of ortho, para and diaminomethylated products under conventional methods, react with 1 or 2 to afford the ortho-product in excellent yield, presumably because of ion pair inter­action between the phenoxide anion and the iminium salt. [11]

(E) Aryl and heteroaryl stannanes react with salt 1 to afford an ipso-substitution product of the stannyl group. The directing effect of tin allows for the preparation of Mannich bases with an ipso substitution pattern which is not ordinarily obtained under traditional procedures. [12]

(F) Analogous to the enolate additions, organometallic reagents such as Grignards, [13] cuprates [14] and lithium reagents [15] add to salt 2 to produce N,N-dimethylamine. Similarly, the salts have been added to hydrazines [16] and oximes. [17]

    References

  • 1 Böhme H. Mundlos E. Herboth O.-E. Chem. Ber.  1957,  90:  2003 
  • 2 Schreiber J. Maag H. Hashimoto N. Eschenmoser A. Angew. Chem., Int. Ed. Engl.  1971,  10:  330 
  • 3 Holy N. Fowler R. Burnett E. Lorenz R. Tetrahedron  1979,  35:  613 
  • 4 Kinast . Tietze L.-F. Angew. Chem., Int. Ed. Engl.  1976,  15:  239 
  • 5 Robin C. Babot O. Dunogues J. Duboudin F. Synthesis  1986,  228 
  • 6 Bryson TA. Bonitz GH. Reichel CJ. Dardis RE. J. Org. Chem.  1980,  45:  524 
  • 7 Ahond A. Cave A. Kan-Fan C. Husson H.-P.
    de Rostolan
    J. Potier P. J. Am. Chem. Soc.  1968,  90:  5622 
  • 8 Danishefsky S. Prisbylla M. Lipisko B. Tetrahedron Lett.  1980,  805 
  • 9 Hooz J. Bridson JN. J. Am. Chem. Soc.  1973,  95:  602 
  • 10 Gagnon A. Danishefsky SJ. Angew. Chem. Int. Ed.  2002,  41:  1581 
  • 11 Pochini A. Puglia G. Ungaro R. Synthesis  1983,  906 
  • 12 Cooper MS. Fairhurst RA. Heaney H. Papageorgiou G. Wilkins RF. Tetrahedron  1989,  45:  1155 
  • 13 Holy NL. Synth. Commun.  1976,  539 
  • 14 Germon C. Alexakis A. Normant JF. Bull. Soc. Chim. France  1984,  II-377 
  • 15 Poulter CD. Roberts JL. Borromeo PS. Tetrahedron Lett.  1977,  1299 
  • 16 Böhme H. Martin F. Chem. Ber.  1973,  106:  3540 
  • 17 Unterhalt B. Koehler H. Synthesis  1977,  265 

    References

  • 1 Böhme H. Mundlos E. Herboth O.-E. Chem. Ber.  1957,  90:  2003 
  • 2 Schreiber J. Maag H. Hashimoto N. Eschenmoser A. Angew. Chem., Int. Ed. Engl.  1971,  10:  330 
  • 3 Holy N. Fowler R. Burnett E. Lorenz R. Tetrahedron  1979,  35:  613 
  • 4 Kinast . Tietze L.-F. Angew. Chem., Int. Ed. Engl.  1976,  15:  239 
  • 5 Robin C. Babot O. Dunogues J. Duboudin F. Synthesis  1986,  228 
  • 6 Bryson TA. Bonitz GH. Reichel CJ. Dardis RE. J. Org. Chem.  1980,  45:  524 
  • 7 Ahond A. Cave A. Kan-Fan C. Husson H.-P.
    de Rostolan
    J. Potier P. J. Am. Chem. Soc.  1968,  90:  5622 
  • 8 Danishefsky S. Prisbylla M. Lipisko B. Tetrahedron Lett.  1980,  805 
  • 9 Hooz J. Bridson JN. J. Am. Chem. Soc.  1973,  95:  602 
  • 10 Gagnon A. Danishefsky SJ. Angew. Chem. Int. Ed.  2002,  41:  1581 
  • 11 Pochini A. Puglia G. Ungaro R. Synthesis  1983,  906 
  • 12 Cooper MS. Fairhurst RA. Heaney H. Papageorgiou G. Wilkins RF. Tetrahedron  1989,  45:  1155 
  • 13 Holy NL. Synth. Commun.  1976,  539 
  • 14 Germon C. Alexakis A. Normant JF. Bull. Soc. Chim. France  1984,  II-377 
  • 15 Poulter CD. Roberts JL. Borromeo PS. Tetrahedron Lett.  1977,  1299 
  • 16 Böhme H. Martin F. Chem. Ber.  1973,  106:  3540 
  • 17 Unterhalt B. Koehler H. Synthesis  1977,  265