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DOI:10.15227/orgsyn.068.0001

Organic Syntheses, Coll. Vol. 8, p.612 (1993); Vol. 68, p.1 (1990).

TRIMETHYLSILYLDIAZOMETHANE[Silane, (diazomethyl)trimethyl-]

Submitted by Takayuki Shioiri, Toyohiko Aoyama, and Shigehiro Mori1 .
Checked by George Maynard and Leo A. Paquette.

1. Procedure
Caution! Trimethylsilyldiazomethane should be regarded as extremely toxic and should only behandled by individuals trained in its proper and safe use. All operations must be carried out in awell-ventilated fume hood and all skin contact should be avoided.
A. Trimethylsilylmethylmagnesium chloride. Magnesium turnings (10.7 g, 0.44 g-atom) are placed ina dry, 300-mL, four-necked, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar, a
200-mL pressure-equalizing dropping funnel capped with a rubber septum, a thermometer, anotherrubber septum, and a reflux condenser connected to an argon flow line. The apparatus is flushed withargon, and an argon atmosphere is maintained throughout the reaction. Anhydrous diethyl ether (40 mL)(Note 1) and 0.1 mL of 1,2-dibromoethane are placed in the reaction flask with a syringe, and themixture is stirred at room temperature for 15 min. The dropping funnel is charged with a solution of 45.4
g (0.37 mol) of chloromethyltrimethylsilane (Note 2) in 100 mL of anhydrous diethyl ether with asyringe. With stirring, about 10 mL of this solution is added at once. When the reaction has started (Note3), the remaining solution is added dropwise at such a rate that a gentle reflux is maintained throughout
the addition (addition time ca. 2 hr). After the exothermic reaction subsides, the resulting solution isstirred at reflux by heating for an additional 1 hr. The reaction mixture is cooled to room temperature,and is used in step B.
B. Trimethylsilyldiazomethane. (See (Note 4).) A dry, 1-L, four-necked, round-bottomed flask isequipped with a liquid paraffin-sealed mechanical stirrer (Note 5), a rubber septum, 200-mL pressureequalizing dropping funnel capped with another rubber septum, and a reflux condenser connected to anargon flow line. The apparatus is flushed with argon, and an argon atmosphere is maintained throughout
the reaction. A solution of 91.2 g (0.33 mol) of diphenyl phosphorazidate (Note 6) in 350 mL ofanhydrous diethyl ether is placed in the flask with a syringe. The rubber septum is quickly replaced by a
low-temperature thermometer. The Grignard reagent prepared in Step A is transferred to the dropping
funnel with a syringe. The flask is cooled with an ice–sodium chloride bath, and the stirring is started.
When the internal temperature reaches −10°C, the Grignard reagent is added dropwise at such a rate thatthe internal temperature is maintained below 0°C (addition time ca. 1.5 hr) (Note 7). After the addition iscomplete, the ice–salt bath is replaced with an ice bath and the mixture is stirred for 2 hr, then allowed tostand in the ice bath for 14–16 hr. The reaction mixture is cooled again to −15°C with an ice–sodium
chloride bath. With vigorous stirring, 35 mL of cold water is carefully added dropwise at such a rate thatthe internal temperature is maintained below 0°C (addition time about 1 hr), and the stirring is continued
for 0.5 hr (Note 8). The reaction mixture is then filtered by suction using a glass filter. The white solid isthoroughly washed with three 100-mL portions of diethyl ether. The combined filtrate is washed with two100-mL portions of cold water and dried over anhydrous sodium sulfate. After the sodium sulfate isremoved by filtration, the filtrate is placed in a 1-L, round-bottomed flask equipped with a Teflon-coatedmagnetic stirring bar and a 30-cm Vigreux column (15-mm diameter). With constant stirring by amagnetic stirring bar and a 30-cm Vigreux column (15-mm diameter). With constant stirring by amagnetic stirrer, the solution is slowly concentrated to a volume of about 200 mL by distillation at
atmospheric pressure with the bath temperature below 45°C. The concentration time requires about 6 hr(Note 9) and (Note 10). The remaining deep-yellow solution is distilled through the same apparatus
under reduced pressure between 100 mm at 0°C (bath temperature) and 15 mm at 40°C (bathtemperature) until no more volatile material comes over, and the distillate is collected in a receivercooled in a dry ice–acetone bath. The distillate is dried again over anhydrous sodium sulfate. The drying
agent is removed by filtration, and 100 mL of hexane (Note 11) is added to the filtrate. In a manner
similar to that described above, this solution is slowly concentrated by distillation at atmospheric pressure
through a 30-cm Vigreux column (15-mm diameter). The color of the distillate gradually becomesyellow. Concentration is continued until the temperature of the vapor reaches 68°C (final oil-bathtemperature 87°C). The concentration requires about 3 hr (Note 9). Approximately 80–110 mL of theremaining yellow hexane solution contains 220–230 mmol of trimethylsilyldiazomethane (67–70% yield
based on diphenyl phosphorazidate) (Note 12) and (Note 13). This hexane solution can be stored without
decomposition for periods exceeding 6 months at 0°C with protection from light.

2. Notes
1. Diethyl ether was distilled from lithium aluminum hydride under argon before use.
2. Chloromethyltrimethylsilane, obtained from Petrarch Systems Inc., was purified by distillation at 97°C
under atmospheric pressure.
3. If the reaction does not start, the flask is gently heated by a heat gun.
4. Trimethylsilyldiazomethane is both nonexplosive and nonmutagenic.2 Therefore, the very careful
operations 3 used for the preparation of diazomethane are not necessary. Note added September, 2009: theprevious statement refers to precautions associated with the explosivity of diazomethane. TMS-diazomethane
should be regarded as having similar toxicity to diazomethane and must be handled with all precautions
appropriate for work with highly toxic substances.

5. A glass or Teflon stirring rod should be used.
6. Diphenyl phosphorazidate, obtained from either Daiichi Pure Chemicals Co., Ltd. or Aldrich Chemical
Company, Inc., was purified by distillation under reduced pressure; bp 134–136°C at 0.2 mm. It can beeasily prepared according to Org. Synth., Coll. Vol. VII 1990, 206.
7. After approximately two-thirds of the Grignard reagent is added, a large amount of white precipitate
appears.
8. The mixture becomes yellow, which is the color of trimethylsilyldiazomethane.
9. The color of the distillate is pale yellow because of codistillation of trimethylsilyldiazomethane.
Therefore, the rate of concentration is very important. If the rate of concentration is more rapid, the yieldof trimethylsilyldiazomethane will decrease.
10. The submitters report that when a 30-cm Widmer column is used, the concentration time required isshorter (ca. 4 hr).
11. Hexane was purified by distillation.
12. The infrared spectrum (hexane) has absorptions at 2075, 1260, and 885 cm −1. The 1 H NMR spectrum
is as follows (hexane) δ: 0.16 (s, 9 H), 2.58 (s, 1 H) (internal chloroform standard).
13. The 1 H NMR of the hexane solution showed the presence of a trace of diethyl ether. The
concentration of trimethylsilyldiazomethane was determined by the 1 H NMR analysis as follows: Ninetyone milligrams of dibenzyl was dissolved in 1 mL of a hexane solution of trimethylsilyldiazomethane,
and its 1 H NMR spectrum was determined. The concentration (x mmol/mL) of
trimethylsilyldiazomethane was calculated as follows: x = 2b/a (mmol/mL) where a = integral value(mm) of methylene protons (δ: 2.99) of dibenzyl b = integral value (mm) of the methine proton (δ: 2.58)
of trimethylsilyldiazomethane

3. Discussion
Trimethylsilyldiazomethane, as a stable and safe substitute for hazardous diazomethane, is usefulboth as a reagent for introducing a C 1 unit and as a C-N-N synthon for the preparation of azoles. 4 Many
methods are described in the literature for the preparation of trimethylsilyldiazomethane, including thetrimethylsilylation of diazomethane (7–74%),5 the alkaline decomposition of N-nitroso-N(trimethylsilylmethyl)amides (25–61%),2,6
and thediazogroup transfer reaction of
7trimethylsilylmethyllithium with p-toluenesulfonyl azide (38%). The present modified diazo grouptransfer method appears to be the most practical, high-yield, and large-scale procedure for the preparationof trimethylsilyldiazomethane.8
Diphenyl phosphorazidate can be replaced with diethyl phosphorazidate in the above procedure. Useof other azides such as p-toluenesulfonyl azide, p-methoxybenzyloxycarbonyl azide, diphenylphosphinicazide, or diphenylthiophosphinic azide is less satisfactory. No reaction occurs when trimethylsilyl azide,dimethylthiophosphinic azide, or alkaline azides are used, while decomposition of formed
trimethylsilyldiazomethane seems to occur when methanesulfonyl azide is used. 9The present procedure affords a general method for preparing silyldiazomethanes from thecorresponding chloromethylsilyl compounds. Typical examples are as follows:

1011

References and Notes
1. Faculty of Pharmaceutical Sciences, Nagoya City University, Tanabe-dori, Mizuho-ku, Nagoya
467, Japan.
2. Aoyama, T.; Shiori, T. Chem. Pharm. Bull. 1981, 29, 3249.
3. Moore, J. A.; Reed, D. E. Org. Synth., Coll. Vol. V 1973, 352.
4. Shioiri, T.; Aoyama, T. Yuki Gosei Kagaku Kyokaishi 1986, 44, 149; Chem. Abstr. 1986, 104,168525q.
5. Lappert, M. F.; Lorberth, J.; Poland, J. S. J. Chem. Soc. (A) 1970, 2954; Martin, M. Synth.
Commun. 1983, 13, 809.
6. Seyferth, D.; Menzel, H.; Dow, A. W.; Flood, T. C. J. Organomet. Chem. 1972, 44, 279;
Crossman, J. M.; Haszeldine, R. N.; Tipping, A. E. J. Chem. Soc., Dalton Trans. 1973, 483;
Sheludyakov, V. D.; Khatuntsev, G. D.; Mironov, V. F. Zh. Obshch. Khim. 1969, 39, 2785; Chem.
Abstr. 1970, 72 111553p; Schöllkopf, U.; Scholz, H.-U. Synthesis 1976, 271.
7. Barton, T. J.; Hoekman, S. K. Synth. React. Inorg. Met.-Org. Chem. 1979, 9, 297.
8. Mori, S.; Sakai, I.; Aoyama, T.; Shioiri, T. Chem. Pharm. Bull. 1982, 30, 3380.
9. Unpublished observations, these laboratories.
10. Sekiguchi, A.; Ando, W. Chem. Lett. 1983, 871.
11. Ando, W.; Tanikawa, H.; Sekiguchi, A. Tetrahedron Lett. 1983, 24, 4245.

Appendix
Chemical Abstracts Nomenclature (Collective Index Number);(Registry Number)dibenzyl
diethyl ether (60-29-7)

magnesium turnings (7439-95-4)
sodium sulfate (7757-82-6)
1,2-dibromoethane (106-93-4)
Diazomethane (334-88-3)
lithium aluminum hydride (16853-85-3)
hexane (110-54-3)
argon (7440-37-1)
Trimethylsilylmethylmagnesium chloride (13170-43-9)
p-toluenesulfonyl azide (941-55-9)
TRIMETHYLSILYL AZIDE (4648-54-8)
Diphenyl phosphorazidate (26386-88-9)
chloromethyltrimethylsilane (2344-80-1)
Trimethylsilyldiazomethane,
Silane, (diazomethyl)trimethyl- (18107-18-1)
trimethylsilylmethyllithium
diethyl phosphorazidate
diphenylphosphinic azide
diphenylthiophosphinic azide
dimethylthiophosphinic azide
methanesulfonyl azide
p-methoxybenzyloxycarbonyl azide (25474-85-5)
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