Dimethyl(methylene)ammonium Iodide1

(1; X = I-)

[36627-00-6]  · C3H8IN  · Dimethyl(methylene)ammonium Iodide  · (MW 185.02) (2; X = Cl-)

[30438-74-5]  · C3H8ClN  · Dimethyl(methylene)ammonium Chloride  · (MW 93.57) (3; X = CF3CO2-)

[85413-84-9]  · C5H8F3NO2  · Dimethyl(methylene)ammonium Trifluoroacetate  · (MW 171.14)

(electrophilic aminomethylation (Mannich reaction) agent which condenses with active methylene compounds,1 organometallic reagents,2 and electron-rich aromatics and heteroaromatics3 to produce tertiary amines; useful for the synthesis of a,b-unsaturated carbonyl compounds by elimination of the dimethylamino group1)

Alternate Names: (1) Eschenmoser's salt; (2) Böhme's salt.

Physical Data: (1) mp 219 °C (dec). (2) mp 116 °C. (3) bp 100 °C/14 mmHg.

Solubility: sol DMF; partially sol4 MeCN, CH2Cl2, THF (reactions in these solvents occur even though the reagent is not completely soluble).

Form Supplied in: salts (1) and (2) are widely available as solids.

Preparative Methods: salt (1) is prepared by thermolysis of (iodomethyl)trimethylammonium iodide5 or cleavage of N,N,N,N-tetramethylmethanediamine by TMSI.6 It is purified by recrystallization from tetrahydrothiophene dioxide or by sublimation at 120 °C/0.05 mmHg.5 Salt (2) is prepared by cleavage of N,N,N,N-tetramethylmethanediamine by AcCl7 or cleavage of methyl dimethylaminomethyl ether by TMSCl.8 Salt (3), a liquid, is prepared by Polonovksi reaction of trimethylamine oxide with TFAA or cleavage of N,N,N,N-tetramethylmethanediamine with TFA. It is purified by distillation.9

Handling, Storage, and Precautions: salts (1)-(3) are very hygroscopic and must be used under anhydrous conditions to preserve their reactivity.

Dimethyl(methylene)ammonium Salts.

These reagents comprise a special family of preformed iminium salts which have been widely utilized in condensation reactions with active methylene compounds and arenes in a variant of the Mannich reaction. They have their origins in the work of Böhme,10 who prepared the first dimethyl(methylene)ammonium salt (2).11 Higher concentrations of iminium salts are achieved using salts such as (1)-(3) than under the conditions of the classical Mannich reaction in which the iminium salt is generated reversibly; hence reactions are faster, proceed under milder conditions, and are more compatible with sensitive functionality. Preformed iminium salts are sufficiently soluble in many aprotic solvents, enabling the use of highly reactive nucleophiles which would ordinarily decompose under the protic conditions of the classical Mannich reaction. Moreover, salts (1)-(3) have special applications as one-carbon synthons for an exo methylene group, owing to the leaving group ability of the dimethylamino group on subsequent quaternization. In addition to the iodide salt (1), the chloride (2) and trifluoroacetate (3) have been increasingly utilized in recent years and are essentially equivalent Mannich reagents. In choosing a particular counterion form, factors such as solubility, ease of preparation and purification, and moisture sensitivity should be considered. A comparison study of the three reagents12a favors the trifluoroacetate (3) because it is the most soluble and can be transferred by syringe, although it is more tedious to prepare. Several other counterion forms have been prepared by anion exchange of the chloride but have had minimal synthetic applications.10,13

Reactions with Active Methylene Compounds and their Derivatives.

Active methylene compounds with acidity comparable to or greater than that of a simple ketone or aldehyde condense directly and without prior activation with salts (1)-(3) in aprotic solvents to produce Mannich bases. Reaction conditions vary depending on the acidity of the substrate and may employ elevated temperatures and base additives to promote enolization. A comparison study finds that ketone Mannich bases are obtained in generally higher yields using salt (2) than under the conditions of the classical Mannich reaction, especially in the case of sterically crowded and a,b-unsaturated ketones.7 For example, a-methylpropiophenone reacts with (2) to produce the corresponding Mannich base in 53% yield (eq 1), whereas under the classical conditions the yield is only 6%. Other ketone substrates reported to react with salts (1)-(3) in a superior manner to the classical Mannich reaction include chromanones,14 thiochromanones,14 and 1H-pyrido[3,2,1-k]phenothiazin-3(2H)-ones.15 The regiochemistry of the reactions of unsymmetrical methyl ketones with salt (3) in TFA has been studied.16 Under kinetic control, attack at the more substituted enol predominates in parallel to the classical Mannich reaction17 to give the more substituted Mannich base, while under thermodynamic control reversibility favors the less substituted Mannich base (eq 2).18 In addition to simple ketones and aldehydes, other classes of active methylene compounds known to react in this variant of the Mannich reaction include 2H-benzo[b]furan-3-ones,19 2H-benzo[b]thiophen-3-ones,19 1,3-dithian-5-ones,20 a-methylene-b-diketones,21 b-diketones,22 malonates,6,23-25 a-diazo ketones,26 and N,N-diphenylglycinate esters.27 These reactions have been used in the modification of natural products such as steroids,9 hydrocodone,28 oxycodone,28 and spectinomycin.26

Preformed kinetic enolates undergo alkylation with salts (1)-(3), extending the scope of the Mannich reaction to weakly acidic active methylene components such as esters (eq 3),12b,29,30 lactones,12b,29,31-34 unsaturated lactones,35 carboxylic acids,12b and nitriles.36 Because of their enhanced nucleophilicity, enolates are able to add under extremely mild conditions (-78 °C to rt). Moreover, in the case of unsymmetrical ketones, predictable regiocontrol can be achieved if the enolate is prepared regiospecifically. Enolates used in these reactions have generally been prepared by deprotonation with strong bases such as Lithium Diisopropylamide29-35 or Potassium Hydride,12,29 cleavage of silyl enol ethers12b or enol carbonates37 with Methyllithium, or by decomposition of a-diazo ketones in the presence of trialkylboranes to generate the corresponding boron enolate.38 The latter method, which reliably generates ketone enolates regiospecifically, is excellent for the regiospecific synthesis of Mannich bases derived from simple unsymmetrical ketones (eq 4). Also, ester enolates generated by cleavage of cyclopropyl esters in the presence of Trimethylsilyl Trifluoromethanesulfonate add to salt (2).39

Trimethylsilyl enol ethers derived from ketones and aldehydes add to salts (1)-(3) in a complementary fashion to enolates.12a,32 The reaction proceeds via a silyloxonium ion which hydrolyzes on aqueous workup (eq 5). This method has been used for the synthesis of the two regioisomeric Mannich bases of 2-methylcyclohexanone starting from the individual silyl enol ethers40 and for the synthesis of the exo Mannich base of (+)-camphor,41 which does not undergo aminomethylation under the conditions of the classical Mannich reaction. Chromanone42 and enone40,43 trimethylsilyl enol ethers also react. In situ methods for the generation of salt (1), involving cleavage of N,N,N,N-tetramethylmethanediamine by Chloroiodomethane44 or cleavage of n-butyldimethylaminomethyl ether45 by Iodotrimethylsilane, are also compatible with these reactions and avoid handling the moisture-sensitive reagent (eq 6). In a minor variant of this reaction employing more stable t-butyldimethyl silyl enol ethers, the product retains the silyl enol ether following workup with retention or migration of the original position of the enol ether double bond, depending on the substrate (eq 7).46

Reactions with Organometallic Reagents.

In analogy to enolate anion additions, organometallic reagents such as alkyl bromomagnesium and lithium reagents,2 vinyl and aromatic bromomagnesium reagents,6 vinylcuprates,47 and cyclopropyllithiums48 add to salt (1) to produce N,N-dimethylamines (eq 8). Salt (1) is also capable of condensing directly with less nucleophilic organometallic reagents such as 1,4-bis(trimethylstannyl)-2-butyne to afford 2,3-bis(dimethylamino)methyl-1,3-butadiene.49

Synthesis of a,b-Unsaturated Carbonyl Compounds and Terminal Alkenes.

Salts (1)-(3) serve as excellent one-carbon units for an a-methylene group, since the dimethylamino group of the derived Mannich base can be easily eliminated by quaternization with Iodomethane followed by treatment with base (eq 9). Active methylene compounds that have been converted to their a-methylene derivatives by this method include esters,27,29,30,39 lactones,29,32-34,50 and ketones.37,51 Similarly, g-methylene enones,40 and g-methylene butenolides35 have been prepared from their respective Mannich bases. Quaternary ammonium salts from Mannich bases of a-alkoxymalonates23,52 and a-alkoxy-a-methoxycarbonyl lactones24 undergo base or thermal fragmentation to provide enolpyruvates for the synthesis of chorismic acid and related natural products (eq 10). Mannich base hydrochlorides derived from b-diketones and salt (2) undergo spontaneous elimination by addition of water to give enediones.22 Tertiary amines derived from the addition of organometallic reagents to salts (1)-(3) can also be converted to terminal alkenes by thermolysis of the corresponding N-oxides.2

Reactions with Aromatic Compounds.

Several electron-rich aromatic and heteroaromatic systems have been shown to undergo condensation reactions with salts (1)-(3) with improved yields and regiocontrol over the conventional method. Monosubstituted phenols, which typically give mixtures of ortho, para, and diaminomethylated products under conventional conditions, react with salt (1) or (2) in the presence of Potassium Carbonate to afford the corresponding ortho-substituted Mannich base in high yield (eq 11).53 An ion pair interaction between the phenoxide anion and the iminium salt is believed to be responsible for the directing effect. This reaction is also successful with deactivating groups in the para position. 2,3-Dimethylphenol,54 1-naphthol,55 and 2-methyl-1-naphthol56 also react in a superior manner with respect to yield and regiospecificity by simple treatment with salts (1) or (2) in aprotic solvents. In the case of 1-naphthol derivatives, 4-substituted Mannich bases mainly result. The reaction has been exploited for the preparation of aminomethylated derivatives of papulacandin A, a resorcinol-containing antibiotic,57 and 4,4- and 3,3-dihydroxy-a,b-diethylstilbenes.58 Among heterocyclic systems, salt (2) has been used to effect aminomethylation at the 2-position of furan59 and thiophene,60 the 3-position of 4-substituted indoles,61-63 the 8-position of a 2,3-dihydro-5(1H)-indolizinone derivative,64 and the 5-position of a 1,4-dihydropyridine derivative.65 The cases of furan and thiophene are noteworthy, since they fail or condense poorly in the classical Mannich reaction. In situ methods for the generation of dimethyl(methylene)ammonium species involving cleavage of N,N,N,N-tetramethylmethanediamine by Sulfur Dioxide66 and by chlorosilanes67 has been investigated in the Mannich reactions of N-methylpyrrole, indole, and N-methylindole (eq 12). Evidence suggests, however, that free iminium species are not involved in these reactions. An unusual out-of-ring aminomethylation reaction catalyzed by Acetyl Chloride occurs at the 1-methyl of a 1-methyl-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine derivative using salt (2), generated in situ by cleavage of N,N,N,N-tetramethylmethanediamine with excess AcCl.68 In an interesting variant of the Mannich reaction, aryl- and heteroarylstannanes react with salt (2) to produce Mannich bases obtained by ipso-substitution of the stannyl group.69 The directing effect of tin allows for the preparation of Mannich bases with substitution patterns not ordinarily obtained in the Mannich reaction, as in the case of 3-(N,N-dimethylaminomethyl)thiophene (eq 13).

Heteroatom Addition.

Salt (2) undergoes heteroatom addition to amides,70 phosphoramides,71 hydrazines,72 oximes,73 and secondary phosphines and arsines.4

Related Reagents.

(Methylene)ammonium salts containing different N-alkyl substitution have been synthesized and undergo similar reactions to those of dimethyl(methylene)ammonium salts.1,3,10


1. Kleinman, E. F. COS 1991, 2, 899.
2. Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. TL 1977, 1299.
3. Heany, H. COS 1991, 2, 953.
4. Kellner, K.; Seidel, B.; Tzschach, A. JOM 1978, 149, 167.
5. Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A AG(E) 1971, 10, 330.
6. Bryson, T. A.; Bonitz, G. H.; Reichel, C. J.; Dardis, R. E. JOC 1980, 45, 524.
7. Kinast, G.; Tietze, L.-F. AG(E) 1976, 15, 239.
8. Rochin, C.; Babot, O.; Dunogues, J.; Duboudin, F. S 1986, 228.
9. Ahond, A.; Cavé, A.; Kan-Fan, C.; Potier, P. BSF(2) 1970, 2707.
10. For a comprehensive review of his work, see: Böhme, H.; Haake, M. In Advances in Organic Chemistry: Methods and Results; Taylor, E. C., Ed.; Wiley: New York, 1976; Vol. 9, Part 1, pp 107-213.
11. Böhme, H.; Mundlos, E.; Herboth, O.-E. CB 1957, 90, 2003.
12. (a) Holy, N.; Fowler, R.; Burnett, E.; Lorenz, R. T 1979, 35, 613. (b) Holy, N. L.; Wang, Y. F. JACS 1977, 99, 944.
13. Knoll, F.; Krumm, U. CB 1971, 104, 31.
14. Eiden, F.; Schmidt, M. AP 1987, 320, 1099.
15. Grol, C. J.; Dijkstra, D.; Schunselaar, W.; Westerink, B. H. C.; Martin, A. R. JMC 1982, 25, 5.
16. Jasor, Y.; Gaudry, M.; Luche, M. J.; Marquet, A. T 1977, 33, 295.
17. House, H. O.; Trost, B. M. JOC 1964, 29, 1339.
18. Gaudry, M.; Jasor, Y.; Bui Khac, T. OSC 1988, 6, 474.
19. Schaefer, M.; Weber, J.; Faller, P. BSF(2) 1978, 241.
20. Mitsudera, H.; Uneme, H.; Okada, Y.; Numata, M.; Kato, A. JHC 1990, 27, 1361.
21. Dimmock, J. R.; Raghavan, S. K.; Logan, B. M.; Bigam, G. E. Eur. J. Med. Chem. 1983, 18, 248.
22. Möhrle, H.; Schaltenbrand, R. Pharmazie 1985, 40, 697.
23. Hoare, J. H.; Policastro, P. P.; Berchtold, G. A. JACS 1983, 105, 6264.
24. Ganem, B.; Ikota, N.; Muralidharan, V. B.; Wade, W. S.; Young, S. D.; Yukimoto, Y. JACS 1982, 104, 6787.
25. Landsbury, P. T.; Mojica, C. A. TL 1986, 27, 3967.
26. Thomas, R. C.; Fritzen, E. L. J. Antibiotics 1985, 38, 208.
27. Tarzia, G.; Balsamini, C.; Spadoni, G.; Duranti, E. S 1988, 514.
28. Görlitzer, K.; Meyer, E. AP 1993, 326, 181.
29. Roberts, J. L.; Borromeo, P. S.; Poulter, C. D. TL 1977, 1621.
30. Snider, B. B.; Phillips, G. P. JOC 1984, 49, 183.
31. Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. JACS 1983, 105, 5390.
32. Danishefsky, S.; Kitahara, T.; McKee, R.; Schuda, P. F. JACS 1976, 98, 6715.
33. Rigby, J. H.; Wilson, J. Z. JACS 1984, 106, 8217.
34. Hanessian, S.; Liak, T. J.; Dixit, D. M. Carbohydr. Res. 1981, 88, C4.
35. Ley, S. V.; Trudell, M. L.; Wadsworth, D. J. T 1991, 47, 8285.
36. Böhme, H.; Hitzel, E. AP 1990, 306, 948.
37. Danishefsky, S.; Chackalamannil, S.; Harrison, P.; Silvestri, M.; Cole, P. JACS 1985, 107, 2474.
38. Hooz, J.; Bridson, J. N. JACS 1973, 95, 602.
39. Reissig, H. U.; Lorey, H. LA 1986, 1914.
40. Danishefsky, S.; Prisbylla, M.; Lipisko, B. TL 1980, 21, 805.
41. McClure, N. L.; Dai, G.-Y.; Mosher, H. S. JOC 1988, 53, 2617.
42. Iwasaki, H.; Kume, T.; Yamamoto, Y.; Akiba, K. TL 1987, 28, 6355.
43. Trost, B. M.; Curran, D. P. JACS 1981, 103, 7380.
44. Miyano, S.; Hokari, H.; Hashimoto, H. BCJ 1982, 55, 534.
45. Hosomi, A.; Iijima, S.; Sakurai, H. TL 1982, 23, 547.
46. Wada, M.; Nishihara, Y.; Akiba, K. TL 1984, 25, 5405.
47. Germon, C.; Alexakis, A.; Normant, J. F. BSF2 1984, 377.
48. Saimoto, H.; Nishio, K.; Yamamoto, H.; Shinoda, M.; Hiyama, T.; Nozaki, H. BCJ 1983, 56, 3093.
49. Reich, H. J.; Yelm, K. E.; Reich, I. L. JOC 1984, 49, 3440.
50. Marshall, J. A.; Flynn, G. A. JOC 1979, 44, 1391.
51. Greengrass, C. W.; Hughman, J. A.; Parsons, P. J. CC 1985, 889.
52. Chouinard, P. M.; Bartlett, P. A. JOC 1986, 51, 75.
53. Pochini, A.; Puglia, G.; Ungaro, R. S 1983, 906.
54. Möhrle, H.; Scharf, U. AP 1980, 313, 435.
55. Möhrle, H.; Tröster, K. AP 1982, 315, 397.
56. Möhrle, H.; Tröster, K. AP 1982, 315, 222.
57. Traxler, P.; Tosch, W.; Zak, O. J. Antibiot. 1987, XL, 1146.
58. Schönenberger, H; Adam, D.; Alonso, G.; Adam, A. AP 1972, 305, 300.
59. Heaney, H.; Papegeorgiou, G.; Wilkins, R. F. TL 1988, 29, 2377.
60. Dowle, M. D.; Hayes, R.; Judd, D. B.; Williams, C. N. S 1983, 73.
61. Kozikowski, A. P.; Ishida, H. H 1980, 14, 55.
62. Barrett, A. G. M.; Dauzonne, D.; O'Neil, I. A.; Renaud, A. JOC 1984, 49, 4409.
63. Matsumoto, M.; Kobayashi, H.; Watanabe, N. H 1987, 26, 1197.
64. Earl, R. A.; Vollhardt, K. P. C. JOC 1984, 49, 4786.
65. Bennasar, M.-L.; Vidal, B.; Bosch, J. JACS 1993, 115, 5340.
66. Eyley, S. C.; Heaney, H.; Papageorgiou, G.; Wilkins, R. F. TL 1988, 29, 2997.
67. Heany, H.; Papageorgiou, G.; Wilkins, R. F. CC 1988, 1161.
68. Hester, J. B., Jr. JOC 1979, 44, 4165.
69. Cooper, M. S.; Fairhurst, R. A.; Heaney, H.; Papageorgiou, G.; Wilkins, R. F. T 1989, 45, 1155.
70. Abou-Gharbia, M.; Freed, M. E.; McCaully, R. J.; Silver, P. J.; Wendt, R. L. JMC 1984, 27, 1743.
71. Freeman, S.; Harger, M. J. P. CC 1985, 241.
72. Böhme, H.; Martin, F. CB 1973, 106, 3540.
73. Unterhalt, B.; Koehler, H. S 1977, 265.

Edward F. Kleinman

Pfizer Central Research, Groton, CT, USA



Copyright 1995-2000 by John Wiley & Sons, Ltd. All rights reserved.