[18162-48-6]  · C6H15ClSi  · t-Butyldimethylchlorosilane  · (MW 150.72)

(widely used reagent for the protection of alcohols, amines, carboxylic acids, ketones, amides, thiols, and phenols;1 useful for regioselective silyl enol ether formation2 and stereoselective silyl ketene acetal formation3)

Alternate Names: t-butyldimethylsilyl chloride; TBDMSCl; TBSCl.

Physical Data: mp 86-89 °C; bp 125 °C.

Solubility: very sol nearly all common organic solvents such as THF, methylene chloride, and DMF.

Form Supplied in: moist white crystals, commonly available.

Handling, Storage, and Precautions: hygroscopic, store under N2; harmful if inhaled, swallowed, or absorbed through skin; should be used and weighed out in a fume hood.

Protecting Group.

The reactions of TBDMSCl closely parallel those of Chlorotrimethylsilane (TMSCl). However, TBDMS ethers are about 104 more stable toward hydrolysis than the corresponding TMS ethers.1,4 The hydrolytic stability of the TBDMS group has made it very valuable for the isolation of many silicon-containing molecules. Since its introduction in 1972, the TBDMS protecting group has undoubtedly become the most widely used silicon protecting group in organic chemistry.1 Alcohols are most commonly protected as their TBDMS ethers by treatment of the alcohol in DMF (2 mL g-1) at rt with 2.5 equiv of Imidazole (Im) and 1.2 equiv of TBDMSCl. Alcohol protection in the presence of 4-Dimethylaminopyridine (DMAP) allows a greater range of solvents to be used (protection of alcohols in solvents other than DMF using TBDMSCl alone are sluggish) and distinguishes a kinetic preference for protection of primary alcohols in the presence of secondary alcohols.5 Table 1 outlines conditions for the selective protection of primary and secondary alcohols using TBDMSCl and DMAP as catalyst.

Table 26 compares the rate of hydrolysis of several bulky silicon ethers with acid, base, and fluoride; TBDMS ethers are less resistant to hydrolysis than the corresponding TIPS (triisopropylsilyl) and TBDPS (t-butyldiphenylsilyl) ethers.

The TBDMS group is also suitable for the protection of amines, including heterocycles, carboxylic acids, and phenols. Other more reactive reagents are also available for introduction of the TBDMS group including t-Butyldimethylsilyl Trifluoromethanesulfonate, MTBSA, and TBDMS-imidazole.1,7

Anion Trap.

TBDMSCl is useful as an anion trapping reagent. For example, TBDMSCl was found to be an efficient trap of the lithio a-phenylthiocyclopropane anion.8 When dichlorothiophene was treated with 2 equiv of n-Butyllithium followed by 2 equiv of TBDMSCl the di-TBDMS-thiophene was isolated.9 The lithium anions of primary (eq 1) and secondary (eq 2) nitriles were trapped with TBDMSCl to give C,N-disilyl- and N-silylketenimines in excellent yields.10

Silyl stannanes have been prepared by trapping tin anions with TBDMSCl or other silyl chlorides. Alkynes treated with with silyl stannanes and catalytic Tetrakis(triphenylphosphine)palladium(0) give cis-silyl stannylalkenes in good yields.11

Silyl Ketene Acetals.

The lithium enolates of esters may be trapped with TBDMSCl to prepare the corresponding ketene silyl acetals.3 The resulting TBDMS ketene acetals are more stable than the corresponding TMS ketene acetals and have a greater preference for O- vs. C-silylation products. When TMSCl was used to trap the enolate of methyl acetate, a 65:35 ratio of O- to C-silated products was obtained. In addition, O-(TMS) silyl ketene acetals are thermally and hydrolytically unstable. However, similar treatment of lithium enolates with TBDMSCl provided the corresponding O-(TBDMS) silyl ketene acetals exclusively (eq 3). The O-TBDMS ketene acetals generally survive extraction from cold aqueous acid. Lithium Diisopropylamide was found to be satisfactory for the preparation of the ester enolates. The lower reactivity of TBDMSCl requires that the enol silation be performed at 0 °C with added HMPA.12

A detailed study of the formation of (E)- and (Z)-silyl ketene acetals was recently published.3d It was found that the formation of silyl enolates does not correspond to simple kinetic vs. thermodynamic formation of the enolates. Formation of the ester enolates occurred under kinetic control and a kinetic resolution accounted for selective formation of (E)- and (Z)-silyl ketene acetals. Table 3 summarizes some of these results.

Claisen Rearrangement.

The first silyl ketene acetal Claisen rearrangement was introduced in 1972 using TMS ketene acetals. Since then, the silyl Claisen rearrangement using TBDMS ketene acetals has found widespread use in organic synthesis.13,14 One advantage of the silyl ketene acetal Claisen rearrangement is that the ketene acetal geometry may be predictably controlled (see above). Two components of the reaction contribute to stereocontrol: the geometry of the silyl ketene acetal and the contribution of boat vs. chair transition state. A useful variant of the Claisen rearrangement involves the use of an enantiomerically pure a-silyl secondary alcohol prepared by Brook rearrangement of a TBDMS-protected primary alcohol. In this reaction the stereochemistry at the silicon-bearing center is transferred to the Claisen product.15 The (E)-enolate was prepared by treatment of the ester with Lithium Hexamethyldisilazide (eq 4); the (Z)-enolate was prepared by treatment of the ester wit h LDA (eq 5).15b As expected, the (Z)- and (E)-silyl ketene acetals gave the corresponding syn and anti Claisen products in good selectivity. The vinylsilane was hydrolyzed to the alkene using 50% HBF4 in acetonitrile at 55 °C.

The silyl ketene acetals of methyl a-(allyloxy)acetates were found to undergo [3,3]-sigmatropic rearrangement, whereas the corresponding lithium enolates undergo [2,3]-sigmatropic rearrangement.16 An interesting ring contraction based on the TBDMS silyl ketene acetal Claisen rearrangement has also been reported.17

TBDMS Enol Ethers.18

Enolates trapped with TBDMSCl to prepare the corresponding enol ethers are more stable than the corresponding TMS enol ethers.19 The potassium enolate of 2-methylcyclohexanone, prepared by addition of Potassium Hydride to a solution of the ketone and TBDMSCl in THF at -78 °C followed by warming to rt, gave the thermodynamic enol ether in a 56:44 ratio. In the presence of HMPA, the ratio improves to 98:2 (eq 6). This method works especially well with ketones with a propensity for self-condensation.20

Potassium enolates derived from acylfulvalenes were trapped with TBDMSCl but not TMSCl or diphenylmethylsilyl chloride.21 Interestingly, TBDMSCl was found to be compatible with CpK anion at -78 °C. TBDMS enol ethers have also been used as b-acyl anion equivalents.22 The TBDMS-silyl enol ethers of diketones (eq 7) and b-keto esters (eq 8) may be prepared by mixing them with TBDMSCl in THF with imidazole.23 Alcohols may be protected under acidic conditions as their TBDMS ethers by treatment with b-silyl enol ethers in polar sovents.

Aldol Reaction.

The catalyst system TBDMSCl/InCl3 selectively activates aldehydes over acetals for aldol reactions with TBDMS enol ethers.24 Acetals and aldehydes are activated towards aldol reactions using TMSCl/InCl3 or Et3SiCl/InCl3 as catalysts (eq 9).

TBDMSCl as Cl- Source.

TBDMSCl was used as a source of chloride ion in the Lewis acid-assisted opening of an epoxide.25 The epoxide was treated with TBDMSCl and Triethylamine followed by Titanium Tetraisopropoxide and additional TBDMSCl to give the trans chloride as the major product in 67% yield (eq 10).

TBDMSCl-Assisted Reactions.

Nitro aldol (Henry) reactions have been reported to be promoted by TBDMSCl.26 To a THF solution of Tetra-n-butylammonium Fluoride is added sequentially equimolar amounts of the nitro compound, aldehyde, and Et3N, followed by an excess of TBDMSCl (eq 11). Substitution of TMSCl for TBDMSCl reduces the yield of nitro aldol product. The authors speculate that TBDMSCl is responsible for activation of the aldehyde while n-Bu4NF activates the nitro compound. In a related method, primary and secondary nitro alkanes were treated with LDA in THF followed by addition of TBDMSCl to give the corresponding silyl nitronates. The silyl nitronates reacted with a variety of aliphatic and aromatic aldehydes which gave vicinal nitro TBDMS aldol products.27

Reaction with Nucleophiles.

TBDMSCl is the reagent of choice for the preparation of other TBDMS-containing reagents. For example, t-Butyldimethylsilyl Cyanide may be prepared by the reaction of TBDMSCl and Potassium Cyanide in acetonitrile containing a catalytic amount of Zinc Iodide.28 TBDMSCN has also been prepared by treatment of TBDMSCl with KCN and 18-Crown-6 in CH2Cl2 at reflux and by treatment of TBDMSCl with Lithium Cyanide prepared in situ.29 t-Butyldimethylsilyl Trifluoromethanesulfonate is prepared by treatment of TBDMSCl with Trifluoromethanesulfonic Acid at 60 °C.30 Other nucleophiles, such as thiolates, also react with TBDMSCl.31 t-Butyldimethylsilyl Iodide was prepared by treatment of TBDMSCl with Sodium Iodide in acetonitrile.32 In contrast to THF cleavage reactions using TMSI, the more stable TBDMS-protected primary alcohol may be isolated from the reaction in eq 12.

Mannich Reaction.

The Mannich reaction of N-methyl-1,3-oxazolidine with 2-methylfuran was shown to proceed smoothly in the presence of TBDMSCl and catalytic 1,2,4-Triazole in 61% yield. Interestingly, this reaction failed with TBDMSOTf due to the destruction of 2-methylfuran. The reaction proceeds with decreased yield (31%) in the absence of triazole. These reaction conditions allowed for the isolation of the TBDMS-protected alcohol (eq 13).33

Acid Chlorides.

TBDMS esters, when treated with DMF and Oxalyl Chloride in methylene chloride at 0 °C, give the corresponding acid chlorides in excellent yields under neutral conditions (eq 14).34 Similarly, N-carboxyamino acid anhydrides were prepared via the intermediacy of an acid chloride prepared from a TBDMS ester (eq 15).35

Conjugate Additions.

When a mixture of TBDMSCl and a b-aryl enone (2:1) was added to Bu2CuCNLi2 at -78 °C, the TBDMS group added 1,4 to the enone to give b-silyl carbonyl compounds (eq 16).36 N-TBDMS silyliminocuprates also add to a,b-unsaturated carbonyl compounds.37

a-Silyl Aldehydes.

Initial attempts to isolate TMS a-silyl aldehydes were unsuccessful due to the lability of the TMS group. However, the a-silyl aldehyde was prepared from the cyclohexyl imine of acetaldehyde by treatment with LDA followed by TBDMSCl (eq 17). Typical of TBDMSCl trapping reactions of imines and hydrazones, C-silylation was observed. The imine was hydrolyzed with HOAc in CH2Cl2 which gave the a-silyl aldehyde. These compounds, after treatment with organometallic reagents such as Ethylmagnesium Bromide or Ethyllithium, may be eliminated in a Peterson-like manner to give either cis or trans alkenes (eq 18).38

a-Silyl Ketones.

When SAMP or RAMP hydrazones were treated with LDA followed by TBDMSCl, the corresponding a-silyl hydrazones were isolated. Ozonolysis of the hydrazone gave the enantiomerically enriched a-silyl ketones (eq 19).39 Yields for the overall process are 52-79% for the preparation of a-silyl ketones and 22-42% for the preparation of a-silyl aldehydes. TBDMSOTf may also be used for quench of the SAMP/RAMP hydrazone enolate.

Acyl Silanes.

Although acyl trimethylsilanes are known, they are usually unstable and lead to poor diastereoselectivity in aldol reactions.40 TBDMS acyl silanes, however, were prepared in 50% yield from 1-methoxy-1-lithiopropene in the presence of TMEDA at rt (eq 20). The lithium enolates of TBDMS acyl silanes were treated with aldehydes to give the corresponding aldol products in reasonable yields.

TBDMS acyl enones were prepared by treatment of an ethoxyethyl (EE)-protected alkoxyallene with n-BuLi at -85 °C followed by treatment of resulting anion with TBDMSCl (eq 21). Acid hydrolysis of the OEE group led to the TBDMS acyl enones in good yield.41

Modified Amine Base.

The regioselectivity of ketone deprotonation was improved by the use of lithium t-butyldimethylsilylamide as base.42 The base was prepared by deprotonation of isopropylamine with n-BuLi in THF (eq 22). The resulting anion was quenched with TBDMSCl to give the amine in 70% yield after distillation. Deprotonation of various ketones using this amide base was found to be equally or more selective than LDA. For example, the TBDMS-modified base gave a 62:38 ratio of kinetic to thermodynamic enolate, whereas LDA gave a 34:66 ratio with phenyl acetone.


When secondary amines were treated with TBDMSCl, DMAP, and Et3N in DMF the corresponding N-formyl derivatives were formed (eq 23).43 It was found that the reaction proceeds through a Vilsmeier type reagent formed by the reaction of TBDMSCl and DMF. It is possible that other TBDMS alkylation reactions, such as protection of alcohols in DMF, may proceed through a similar DMF-derived Vilsmeier reagent.

N-Silyl Imines.

When aldehydes were treated first with tris(trimethylstannyl)amine followed by TBDMSCl, the corresponding N-TBDMS imines were isolated in good yields.44 These silyl imines reacted with ester enolates to give b-lactams (eq 24).

1. (a) Corey, E. J.; Venkateswarlu, A. JACS 1972, 94, 6190. (b) Lalonde, M.; Chan, T. H. S 1985, 817. (c) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic Synthesis; Wiley: New York, 1991. (d) Colvin, E. Silicon in Organic Synthesis; Butterworths: London, 1981.
2. Stork, G.; Hudrlik, P. F. JACS 1968, 90, 4462.
3. (a) Rathke, M. W.; Sullivan, D. F. SC 1973, 3, 67. (b) Rathke, M. W.; Sullivan, D. F. TL 1973, 1297. (c) An interesting application of TBS silyl ketene acetals as homo-Reformatsky reagents may be found in: Oshino, H.; Nakamura, E.; Kuwajima, I. JOC 1985, 50, 2802. (d) Ireland, R. E.; Wipf, P.; Armstrong, J. D., III JOC 1991, 56, 650.
4. For general papers comparing the stability of silanes containing various alkyl groups on Si see: (a) Sommer, L. H.; Tyler, L. J. JACS 1954, 76, 1030. (b) Ackerman, E. ACS 1956, 10, 298; ACS 1957, 11, 373.
5. Hernandez, O.; Chaudhary, S. K. TL 1979, 99.
6. Cunico, R. F.; Bedell, L. JOC 1980, 45, 4797.
7. Mawhinney, T. P.; Madson, M. A. JOC 1982, 47, 3336.
8. Wells, G. J.; Yan, T.-H.; Paquette, L. A. JOC 1984, 49, 3604.
9. Okuda, Y.; Lakshmikantham, M. V.; Cava, M. P. JOC 1991, 56, 6024.
10. Watt, D. S. SC 1974, 4, 127.
11. Chenard, B. L.; Van Zyl, C. M. JOC 1986, 3561.
12. Ireland, R. E.; Mueller, R. H. JACS 1972, 94, 5897.
13. Ireland, R. E.; Mueller, R. H.; Willard, A. K. JACS 1976, 98, 2868.
14. For other examples see (a) Mohammed, A. Y.; Clive, D. L. J. CC 1986, 588. (b) Kita, Y.; Shibata, N.; Miki, T.; Takemura, Y.; Tamura, O. CC 1990, 727. (c) Metz, P.; Mues, C. SL 1990, 97.
15. (a) Ireland, R. E.; Varney, M. D. JACS 1984, 106, 3668. (b) Ireland, R. E.; Daub, J. P. JOC 1981, 46, 479.
16. Raucher, S.; Gustavson, L. M. TL 1986, 27, 1557.
17. (a) Abelman, M. M.; Funk, R. L.; Munger, J. D., Jr. JACS 1982, 104, 4030. (b) Funk, R. L.; Munger, J. D., Jr. JOC 1984, 49, 4320.
18. For a review see: Brownbridge, P. S 1983, 1; S 1983, 29.
19. (a) Ireland, R. E.; Courtney, L.; Fitzsimmons, B. J. JOC 1983, 48, 5186. (b) Piers, E.; Burmeister, M. S.; Reissig, H.-U. CJC 1986, 64, 180.
20. (a) Orban, J.; Turner, J. V.; Twitchin, B. TL 1984, 25, 5099. (b) Orban, J.; Turner, J. V. TL 1983, 24, 2697. (c) Ireland, R. E.; Thompson, W. J.; Mandel, N. S.; Mandel, G. S. JOC 1979, 44, 3583.
21. McLoughlin, J. I.; Little, R. D. JOC 1988, 53, 3624.
22. Trimitsis, G.; Beers, S.; Ridella, J.; Carlon, M.; Cullin, D.; High, J.; Brutts, D. CC 1984, 1088.
23. Veysoglu, T.; Mitscher, L. A. TL 1981, 22, 1299.
24. Mukaiyama, T.; Ohno, T.; Han, J. S.; Kobayashi, S. CL 1991, 949.
25. Hudlicky, T.; Luna, H.; Olivo, H. F.; Andersen, C.; Nugent, T.; Price, J. D. JCS(P1) 1991, 2907.
26. Fernández, R.; Gasch, C.; Gómez-Sánchez, A.; Vílchez, J. E. TL 1991, 32, 3225.
27. Colvin, E. W.; Beck, A. K.; Seebach, D. HCA 1981, 64, 2264.
28. Rawal, V. H.; Rao, J. A.; Cava, M. P. TL 1985, 26, 4275.
29. (a) Gassman, P. G.; Haberman, L. M. JOC 1986, 51, 5010. (b) Mai, K.; Patil, G. JOC 1986, 51, 3545.
30. Corey, E. J.; Cho, H.; Rücker, C.; Hua, D. H. TL 1981, 22, 3455.
31. Aizpurua, J. M.; Paloma, C. TL 1985, 26, 475.
32. (a) Nyström, J.-E.; McCanna, T. D.; Helquist, P.; Amouroux, R. S 1988, 56. (b) Detty, M. R.; Seidler, J. D. JOC 1981, 46, 1283.
33. Fairhurst, R. A.; Heaney, H.; Papageorgiou, G.; Wilkins, R. F.; Eyley, S. C. TL 1989, 30, 1433.
34. Wissner, A.; Grudzinskas, C. V. JOC 1978, 43, 3972.
35. Mobashery, S.; Johnston, M. JOC 1985, 50, 2200.
36. Amberg, W.; Seebach, D. AG(E) 1988, 1718.
37. (a) Murakami, M.; Matsuura, T.; Ito, Y. TL 1988, 29, 355. (b) Ager, D. J.; Fleming, I.; Patel, S. K. JCS(P1) 1981, 2520.
38. Hudrlik, P. F.; Kulkarni, A. K. JACS 1981, 103, 6251.
39. (a) Lohray, B. B.; Enders, D. HCA 1989, 72, 980. (b) Enders, D.; Lohray, B. B. AG(E) 1987, 26, 351.
40. Schinzer, D. S 1989, 179.
41. Reich, H. J.; Kelly, M. J.; Olsen, R. E.; Holtan, R. C. T 1983, 39, 949.
42. Prieto, J. A.; Suarez, J.; Larson, G. L. SC 1988, 18, 253.
43. Djuric, S. W. JOC 1984, 49, 1311.
44. Busato, S.; Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta, G. SL 1991, 243.

Bret E. Huff

Lilly Research Laboratories, Indianapolis, IN, USA

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