[18107-18-1]  · C4H10N2Si  · Trimethylsilyldiazomethane  · (MW 114.25)

(one-carbon homologation reagent; stable, safe substitute for diazomethane; [C-N-N] 1,3-dipole for the preparation of azoles1)

Physical Data: bp 96 °C/775 mmHg; n25D 1.4362.2

Solubility: sol most organic solvents; insol H2O.

Form Supplied in: commercially available as 2 M and 10 w/w% solutions in hexane, and 10 w/w% solution in CH2Cl2.

Analysis of Reagent Purity: concentration in hexane is determined by 1H NMR.3

Preparative Method: prepared by the diazo-transfer reaction of Trimethylsilylmethylmagnesium Chloride with Diphenyl Phosphorazidate (DPPA) (eq 1).3

Handling, Storage, and Precautions: should be protected from light.

One-Carbon Homologation.

Along with its lithium salt, which is easily prepared by lithiation of trimethylsilyldiazomethane (TMSCHN2) with n-Butyllithium, TMSCHN2 behaves in a similar way to Diazomethane as a one-carbon homologation reagent. TMSCHN2 is acylated with aromatic acid chlorides in the presence of Triethylamine to give a-trimethylsilyl diazo ketones. In the acylation with aliphatic acid chlorides, the use of 2 equiv of TMSCHN2 without triethylamine is recommended. The crude diazo ketones undergo thermal Wolff rearrangement to give the homologated carboxylic acid derivatives (eqs 2 and 3).4

Various ketones react with TMSCHN2 in the presence of Boron Trifluoride Etherate to give the chain or ring homologated ketones (eqs 4-6).5 The bulky trimethylsilyl group of TMSCHN2 allows for regioselective methylene insertion (eq 5). Homologation of aliphatic and alicyclic aldehydes with TMSCHN2 in the presence of Magnesium Bromide smoothly gives methyl ketones after acidic hydrolysis of the initially formed b-keto silanes (eq 7).6

O-Methylation of carboxylic acids, phenols, enols, and alcohols can be accomplished with TMSCHN2 under different reaction conditions. TMSCHN2 instantaneously reacts with carboxylic acids in benzene in the presence of methanol at room temperature to give methyl esters in nearly quantitative yields (eq 8).7 This method is useful for quantitative gas chromatographic analysis of fatty acids. Similarly, O-methylation of phenols and enols with TMSCHN2 can be accomplished, but requires the use of Diisopropylethylamine (eqs 9 and 10).8 Although methanol is recommended in these O-methylation reactions, methanol is not the methylating agent. Various alcohols also undergo O-methylation with TMSCHN2 in the presence of 42% aq. Tetrafluoroboric Acid, smoothly giving methyl ethers (eq 11).9

Alkylation of the lithium salt of TMSCHN2 (TMSC(Li)N2) gives a-trimethylsilyl diazoalkanes which are useful for the preparation of vinylsilanes and acylsilanes. Decomposition of a-trimethylsilyl diazoalkanes in the presence of a catalytic amount of Copper(I) Chloride gives mainly (E)-vinylsilanes (eq 12),10 while replacement of CuCl with rhodium(II) pivalate affords (Z)-vinylsilanes as the major products (eq 12).11 Oxidation of a-trimethylsilyl diazoalkanes with m-Chloroperbenzoic Acid in a two-phase system of benzene and phosphate buffer (pH 7.6) affords acylsilanes (a-keto silanes) (eq 12).12

(E)-b-Trimethylsilylstyrenes are formed by reaction of alkanesulfonyl chlorides with TMSCHN2 in the presence of triethylamine (eq 13).13 TMSC(Li)N2 reacts with carbonyl compounds to give a-diazo-b-hydroxy silanes which readily decompose to give a,b-epoxy silanes (eq 14).14 However, benzophenone gives diphenylacetylene under similar reaction conditions (eq 15).15

Silylcyclopropanes are formed by reaction of alkenes with TMSCHN2 in the presence of either Palladium(II) Chloride or CuCl depending upon the substrate (eqs 16 and 17).16 Silylcyclopropanones are also formed by reaction with trialkylsilyl and germyl ketenes (eq 18).17

[C-N-N] Azole Synthon.

TMSCHN2, mainly as its lithium salt, TMSC(Li)N2, behaves like a 1,3-dipole for the preparation of [C-N-N] azoles. The reaction mode is similar to that of diazomethane but not in the same fashion. TMSC(Li)N2 (2 equiv) reacts with carboxylic esters to give 2-substituted 5-trimethylsilyltetrazoles (eq 19).18 Treatment of thiono and dithio esters with TMSC(Li)N2 followed by direct workup with aqueous methanol gives 5-substituted 1,2,3-thiadiazoles (eq 20).19 While reaction of di-t-butyl thioketone with TMSCHN2 produces the episulfide with evolution of nitrogen (eq 21),20 its reaction with TMSC(Li)N2 leads to removal of one t-butyl group to give the 1,2,3-thiadiazole (eq 21).20

TMSCHN2 reacts with activated nitriles only, such as cyanogen halides, to give 1,2,3-triazoles.21 In contrast with this, TMSC(Li)N2 smoothly reacts with various nitriles including aromatic, heteroaromatic, and aliphatic nitriles, giving 4-substituted 5-trimethylsilyl-1,2,3-triazoles (eq 22).22 However, reaction of a,b-unsaturated nitriles with TMSC(Li)N2 in Et2O affords 3(or 5)-trimethylsilylpyrazoles, in which the nitrile group acts as a leaving group (eq 23).23 Although a,b-unsaturated nitriles bearing bulky substituents at the a- and/or b-positions of the nitrile group undergo reaction with TMSC(Li)N2 to give pyrazoles, significant amounts of 1,2,3-triazoles are also formed. Changing the reaction solvent from Et2O to THF allows for predominant formation of pyrazoles (eq 24).23 Complete exclusion of the formation of 1,2,3-triazoles can be achieved when the nitrile group is replaced by a phenylsulfonyl species.24 Thus reaction of a,b-unsaturated sulfones with TMSC(Li)N2 affords pyrazoles in excellent yields (eq 25). The geometry of the double bond of a,b-unsaturated sulfones is not critical in the reaction. When both a cyano and a sulfonyl group are present as a leaving group, elimination of the sulfonyl group occurs preferentially (eq 26).24 The trimethylsilyl group attached to the heteroaromatic products is easily removed with 10% aq. KOH in EtOH or HCl-KF.

Various 1,2,3-triazoles can be prepared by reaction of TMSC(Li)N2 with various heterocumulenes. Reaction of isocyanates with TMSC(Li)N2 gives 5-hydroxy-1,2,3-triazoles (eq 27).25 It has been clearly demonstrated that the reaction proceeds by a stepwise process and not by a concerted 1,3-dipolar cycloaddition mechanism. Isothiocyanates also react with TMSC(Li)N2 in THF to give lithium 1,2,3-triazole-5-thiolates which are treated in situ with alkyl halides to furnish 1-substituted 4-trimethylsilyl-5-alkylthio-1,2,3-triazoles in excellent yields (eq 28).26 However, changing the reaction solvent from THF to Et2O causes a dramatic solvent effect. Thus treatment of isothiocyanates with TMSC(Li)N2 in Et2O affords 2-amino-1,3,4-thiadiazoles in good yields (eq 28).27 Reaction of ketenimines with TMSC(Li)N2 smoothly proceeds to give 1,5-disubstituted 4-trimethylsilyl-1,2,3-triazoles in high yields (eq 29).28 Ketenimines bearing an electron-withdrawing group at one position of the carbon-carbon double bond react with TMSC(Li)N2 to give 4-aminopyrazoles as the major products (eq 30).29

Pyrazoles are formed by reaction of TMSCHN2 or TMSC(Li)N2 with some alkynes (eqs 31 and 32)24,30 and quinones (eq 33).31 Some miscellaneous examples of the reactivity of TMSCHN2 or its lithium salt are shown in eqs 34-36.20,31,32

1. (a) Shioiri, T.; Aoyama, T. J. Synth. Org. Chem. Jpn 1986, 44, 149 (CA 1986, 104, 168 525q). (b) Aoyama, T. YZ 1991, 111, 570 (CA 1992, 116, 58 332q). (c) Anderson, R.; Anderson, S. B. In Advances in Silicon Chemistry; Larson, G. L., Ed.; JAI: Greenwich, CT, 1991; Vol. 1, pp 303-325. (d) Shioiri, T.; Aoyama, T. In Advances in the Use of Synthons in Organic Chemistry; Dondoni, A., Ed.; JAI: London, 1993; Vol. 1, pp 51-101.
2. Seyferth, D.; Menzel, H.; Dow, A. W.; Flood, T. C. JOM 1972, 44, 279.
3. Shioiri, T.; Aoyama, T.; Mori, S. OS 1990, 68, 1.
4. Aoyama, T.; Shioiri, T. CPB 1981, 29, 3249.
5. Hashimoto, N.; Aoyama, T.; Shioiri, T. CPB 1982, 30, 119.
6. Aoyama, T.; Shioiri, T. S 1988, 228.
7. Hashimoto, N.; Aoyama, T.; Shioiri, T. CPB 1981, 29, 1475.
8. Aoyama, T.; Terasawa, S.; Sudo, K.; Shioiri, T. CPB 1984, 32, 3759.
9. Aoyama, T.; Shioiri, T. TL 1990, 31, 5507.
10. Aoyama, T.; Shioiri, T. TL 1988, 29, 6295.
11. Aoyama, T.; Shioiri, T. CPB 1989, 37, 2261.
12. Aoyama, T.; Shioiri, T. TL 1986, 27, 2005.
13. Aoyama, T.; Toyama, S.; Tamaki, N.; Shioiri, T. CPB 1983, 31, 2957.
14. Schöllkopf, U.; Scholz, H.-U. S 1976, 271.
15. Colvin, E. W.; Hamill, B. J. JCS(P1) 1977, 869.
16. Aoyama, T.; Iwamoto, Y.; Nishigaki, S.; Shioiri, T. CPB 1989, 37, 253.
17. Zaitseva, G. S.; Lutsenko, I. F.; Kisin, A. V.; Baukov, Y. I.; Lorberth, J. JOM 1988, 345, 253.
18. Aoyama, T.; Shioiri, T. CPB 1982, 30, 3450.
19. Aoyama, T.; Iwamoto, Y.; Shioiri, T. H 1986, 24, 589.
20. Shioiri, T.; Iwamoto, Y.; Aoyama, T. H 1987, 26, 1467.
21. Crossman, J. M.; Haszeldine, R. N.; Tipping, A. E. JCS(D) 1973, 483.
22. Aoyama, T.; Sudo, K.; Shioiri, T. CPB 1982, 30, 3849.
23. Aoyama, T,; Inoue, S.; Shioiri, T. TL 1984, 25, 433.
24. Asaki, T.; Aoyama, T.; Shioiri, T. H 1988, 27, 343.
25. Aoyama, T.; Kabeya, M.; Fukushima, A.; Shioiri, T. H 1985, 23, 2363.
26. Aoyama, T.; Kabeya, M.; Shioiri, T. H 1985, 23, 2371.
27. Aoyama, T.; Kabeya, M.; Fukushima, A.; Shioiri, T. H 1985, 23, 2367.
28. Aoyama, T.; Katsuta, S.; Shioiri, T. H 1989, 28, 133.
29. Aoyama, T.; Nakano, T.; Marumo, K.; Uno, Y.; Shioiri, T. S 1991, 1163.
30. Chan, K. S.; Wulff, W. D. JACS 1986, 108, 5229.
31. Aoyama, T.; Nakano, T.; Nishigaki, S.; Shioiri, T. H 1990, 30, 375.
32. Rösch, W.; Hees, U.; Regitz, M. CB 1987, 120, 1645.

Takayuki Shioiri & Toyohiko Aoyama

Nagoya City University, Japan

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