[80-70-6]  · C5H13N3  · 1,1,3,3-Tetramethylguanidine  · (MW 115.21)

(strong base used to generate diazo compounds, protected 3b-substituted steroids, amino acid derivatives without racemization, a-nitroalkyl anions, b-glycosylated phenols, amides from acid chlorides; for the selective cleavage of Cbz groups; for cleavage of peptides from a resin; for the catalysis of conjugate addition reactions, as an azide counterion in asymmetric synthesis; for the catalysis of silylation reactions; for the conversion of ketone hydrazones to vinyl iodides)

Alternate Name: TMG.

Physical Data: bp 165 °C, 52-54 °C/11 mmHg; mp 60 °C; d 0.918 g cm-3.

Solubility: freely sol most organic solvents; sol water.

Purification: distillation in vacuo.

Handling, Storage, and Precautions: this liquid is corrosive. It is harmful if swallowed, inhaled, or absorbed through the skin. It should be handled in a fume hood; the handler should wear chemical safety goggles, rubber gloves, and a respirator. Bottles of the liquid should be flushed with an inert atmosphere such as nitrogen or argon to minimize exposure to carbon dioxide.

Diazodiphenylmethane Preparation.

1,1,3,3-Tetramethylguanidine is the base of choice for use in the preparation of Diphenyldiazomethane from the corresponding ketone hydrazone (eq 1).1

Protected 3b-Substituted Steroids.

Protection of 3b-substituted steroids by conversion to 6-oxo-3a,5-cyclo-5a-steroid derivatives is facile with TMG (eq 2).2

Amino Acid Derivatives without Racemization.

TMG readily forms soluble salts with numerous amino acids, thus facilitating many reactions. The variety of amino acid derivatives prepared without racemization include N-Boc from t-Butyl Azidoformate3 or from t-butyl phenyl carbonate,4 N-trifluoroacetyl,5 and peptide coupling products (eq 3).6,7

Insoluble amino acids such as taurine are converted to g-L-glutamyl taurine with TMG as base (eq 4).8

a-Nitroalkyl Anion Formation.

TMG is often chosen as the basic catalyst for conjugate additions of nitromethane. An early report9 cited isolation of monomeric addition products to unsaturated esters as a key result (eq 5). Highly selective additions of nitromethane to levoglucosenone afford excellent yields of condensation products (eq 6).10

Addition of nitromethane to 4-oxygenated 2-substituted cyclopent-2-enones provides a facile entry to prostaglandin intermediates (eq 7).11 Precursors of g-aminobutyric acid analogs are readily available in good yield from nitromethane additions to 2-alkenoic esters (eq 8).12

With more hindered nitroalkanes, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) is required as base for high yields of Michael products (eq 9).13

Nitroalkane addition to 3-methylene-2,3-dihydrothiophene S,S-dioxide furnishes a new route to 1,3-dienes, including a precursor to ipsenol (eq 10).14

b-Glycosylated Phenol Formation.

While inorganic bases (CsF, K2CO3) or weaker bases such as 2,6-lutidine inhibit the reaction, TMG is especially effective at enhancing b-selectivity in glycosidation of phenols (eq 11).15

Amides from Acid Chlorides.

For the preparation of chiral, nonracemic C2-symmetrical pyrrolidine-derived auxiliaries, TMG is the base of choice (eq 12).16

Selective Cleavage of Z Groups.

Selective removal of a primary benzyloxycarbonyl (Cbz, Z) group in the presence of both primary t-butoxycarbonyl (Boc) and secondary Z groups gives primary amines by TMG-catalyzed methanolysis (eq 13).17,18

Cleavage of Peptides from a Resin.

TMG-catalyzed elimination effects removal of protected peptides from a 2-[4-(hydroxymethyl)phenylacetoxy]propionyl resin (eq 14).19

Catalysis of Conjugate Addition Reactions.

Thiol addition to a,b-unsaturated nitroalkenes, in the presence of Formaldehyde, leads to precursors of allyl alcohols in high yields (88-97%) (eq 15).20 Conjugate addition of hydroxylamine to b-alkoxy acrylonitrile derivatives provides an entry to 4-thiocarbamoyl-5-aminoisoxazoles (eq 16).21 Conjugate addition of benzyl alcohol catalyzed by TMG provides an adduct with no racemization noted at the initial stereocenter (eq 17).22

A practical synthesis of (-)-huperzine A utilizes TMG as the base in a key step involving the assemblage of the tricyclic intermediate (eq 18).23,24 Enantioselective synthesis of a-allokainoic acid uses tandem conjugate additions catalyzed by TMG (eq 19).25

Azide Counterion in Asymmetric Synthesis.

In the asymmetric synthesis of a-amino acids via the electrophilic azidation of chiral nonracemic imide enolates, stereospecific bromide displacement by tetramethylguanidinium azide was a high yielding step (eq 20).26,27

Catalysis of Silylation Reactions.

While Triethylamine is typically used as the HCl scavenger in the formation of t-butyldimethylsilyl ethers, TMG as a catalyst tends to accelerate the reaction (eq 21).28

Conversion of Ketone Hydrazones to Vinyl Iodides.

Oxidation of ketone hydrazones by iodine in the presence of TMG occurs in high yields (eq 22).29

Related Reagents.

t-Butyltetramethylguanidine; 1,1,2,3,3-Pentaisopropylguanidine.

1. Adamson, J. R.; Bywood, R.; Eastlick, D. T.; Gallagher, G.; Walker, D.; Wilson, E. M. JCS(P1) 1975, 2030.
2. Anastasia, M.; Allevi, P.; Ciuffreda, P.; Fiecchi, A. S 1983, 123.
3. Ali, A.; Fahrenholz, F.; Weinstein, B. AG(E) 1972, 11, 289.
4. Ragnarsson, U.; Karlsson, S. M.; Sandberg, B. E.; Larsson, L.-E. OS 1973, 53, 25; OSC 1988, 6, 203.
5. Steglich, W.; Hinze, S. S 1976, 399.
6. Kemp, D. S.; Wrobel, S. J., Jr.; Wang, S.-W.; Bernstein, Z.; Rebek, J., Jr. T 1974, 30, 3969.
7. Kemp, D. S.; Wang, S.-W.; Rebek, J., Jr.; Mollan, R. C.; Banquer, C.; Subramanyam, G. T 1974, 30, 3955.
8. Gulyas, J.; Sebestyen, F.; Hercsel-Szepespataky, J.; Furka, A. OPP 1987, 19, 64.
9. Pollini, G. P.; Barco, A.; De Giuli, G. S 1972, 44.
10. Forsyth, A. C.; Paton, R. M.; Watt, I. TL 1989, 30, 993.
11. Baraldi, P. G.; Barco, A.; Benetti, S.; Pollini, G. P.; Simoni, D.; Zanirato, V. T 1987, 43, 4669.
12. Andruszkiewicz, R.; Silverman, R. B. S 1989, 953.
13. Ono, N.; Kamimura, A.; Miyake, H.; Hamamoto, I.; Kaji, A. JOC 1985, 50, 3692.
14. Nomoto, T.; Takayama, H. CC 1989, 295.
15. Yamaguchi, M.; Horiguchi, A.; Fukuda, A.; Minami, T. JCS(P1) 1990, 1079.
16. Veit, A.; Lenz, R.; Seiler, M. E.; Neuburger, M.; Zehnder, M.; Giese, B. HCA 1993, 76, 441.
17. Almeida, L. M. S.; Grehn, L.; Ragnarsson, U. CC 1987, 1250.
18. Almeida, L. M. S.; Grehn, L.; Ragnarsson, U. JCS(P1) 1988, 1905.
19. Whitney, D. B.; Tam, J. P.; Merrifield, R. B. T 1984, 40, 4237.
20. Ono, N.; Kamimura, A.; Kaji, A. TL 1984, 25, 5319.
21. Vicentini, C. B.; Veronese, A. C.; Poli, T.; Guarneri, M.; Giori, P.; Ferretti, V. JHC 1990, 27, 1481.
22. Fehr, C.; Guntern, O. HCA 1992, 75, 1023.
23. Yamada, F.; Kozikowski, A. P.; Reddy, E. R.; Pang, Y.-P.; Miller, J. H.; McKinney, M. JACS 1991, 113, 4695.
24. Xia, Y.; Kozikowski, A. P. JACS 1989, 111, 4116.
25. Barco, A.; Benetti, S.; Casolari, A.; Pollini, G. P.; Spalluto, G. TL 1990, 31, 4917.
26. Evans, D. A.; Ellman, J. A.; Dorow, R. L. TL 1987, 28, 1123.
27. Evans, D. A.; Britton, T. C.; Ellman, J. A.; Dorow, R. L. JACS 1990, 112, 4011.
28. Kim, S.; Chang, H. SC 1984, 14, 899.
29. Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. TL 1983, 24, 1605.

Cynthia A. Maryanoff

The R. W. Johnson Pharmaceutical Research Institute, Spring House, PA, USA

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