[79265-30-8]  · C6H11NSSi  · 2-(Trimethylsilyl)thiazole  · (MW 157.34)

(useful formyl anion equivalent;1 effective one-carbon homologating reagent of alkoxy aldehydes, amino aldehydes, and dialdoses2)

Physical Data: bp 51-53 °C/10 mmHg; d 0.992 g cm-3; nD 1.4980.

Solubility: insol H2O; very sol CH2Cl2, diethyl ether, THF.

Form Supplied in: liquid; widely available.

Analysis of Reagent Purity: 1H and 13C NMR.

Purification: distillation under reduced pressure.

Preparative Method: although 2-(trimethylsilyl)thiazole (1) is commercially available, it can be easily prepared on a multigram scale from 2-bromothiazole, n-Butyllithium, and Chlorotrimethylsilane as shown in eq 1.3

Handling, Storage, and Precautions: is stable upon storage under an inert atmosphere in a refrigerator. Nevertheless, it should be freshly distilled for best results. Irritating to the eyes, respiratory system, and skin. Wear suitable protective clothing, gloves and eye/face protection. Use in a fume hood.

General Discussion.

2-(Trimethylsilyl)thiazole (1) reacts with various C-electrophiles such as azolium halides (eq 2),4 ketenes (eq 3),5,6 acyl chlorides (eq 4),6,7 ketones, and aldehydes (eq 5)6-8 under mild conditions to give the corresponding 2-substituted thiazoles in very good isolated yields. No catalysts are required in these carbodesilylation reactions.

The general mechanism via an N-thiazolium-2-ylide, earlier proposed for all these reactions,6,7 has found substantial support in the identification of spirodioxolane intermediates in the reaction of (1) with aldehydes.9

The reaction of (1) with chiral alkoxy aldehydes led to the discovery of a new methodology for the one-carbon chain elongation of these compounds.2a,b The methodology proved to be capable of iteration and therefore suitable for the stereoselective synthesis of polyalkoxy aldehydes (carbohydrate-like materials).

The homologation of D-glyceraldehyde acetonide (2) serves to illustrate the method.3 This consists of two sequential operations: first, addition of 2-(trimethylsilyl)thiazole (1) to the aldehyde (2) followed by in situ desilylation and protection as the O-benzyl derivative (3) (eq 6); secondly, aldehyde release in the resultant adduct10 by a three-step sequence involving methylation of the thiazole ring to the N-methylthiazolium salt; reduction to thiazolidine; hydrolysis to a-benzyloxy aldehyde (4) (eq 7).

Hence, (1) serves as a synthetic equivalent for the formyl anion synthon which adds to the aldehyde in a stereoselective manner, creating a new chiral hydroxymethylene center. The repetition of the first and second operational sequences above over six consecutive cycles with high levels of diastereoselectivity and chemical yields in each cycle provided a series of protected D-aldoses2c having up to nine carbons in the chain (eq 8).

The utility of this approach to long-chain sugars (thiazole route to carbohydrates) is illustrated by the conversion of protected L-threose (5) and dialdogalactopyranose (6) into higher homologs (eqs 9 and 10).2c,d The extension of this methodology to other dialdoses has been reported.11

This technique, in combination with an inversion of configuration of the carbon adjacent to the thiazole ring, has been employed2e for the chain extension of D-glyceraldehyde acetonide (2) into all possible tetrose and pentose homologs (eq 11).

The 2-(trimethylsilyl)thiazole-based one-carbon extension strategy was also used for the construction of amino tetroses as well as amino pentoses12 using a-amino aldehydes as chiral educts. An interesting finding was that the reactions of (1) with the N-diprotected a-amino aldehydes were anti selective (eq 12), whereas those with the N-monoprotected a-amino aldehydes were syn selective (eq 13).

These opposite diastereoselectivities were explained by assuming a Felkin-Anh-Houk model (anti addition) and a proton-bridged Cram cyclic model (syn addition) for the case of differentially protected a-amino aldehydes (7) and (8). The resulting 1,2-amino alcohols proved to be convenient precursors to L-amino sugars and sphingosines.12

This strategy has been also employed for the synthesis of a dipeptide mimic,13 as illustrated in eq 14.

In summary, 2-(trimethylsilyl)thiazole (1) appears to be a useful formyl anion equivalent.14 The advantages over other precursors to the formyl anion (see Benzothiazole) can be found in the stability of the thiazole ring to a wide range of reaction conditions and its ready conversion into the formyl group under mild and neutral conditions. Few of the many formyl anion equivalents14 have been demonstrated to be capable of producing labile a-alkoxy aldehydes without racemization.

Related Reagents.

(4aR)-(4aa,7a,8ab)-Hexahydro-4,4,7-trimethyl-4H-1,3-benzoxathiin; 2-Lithio-1,3-dithiane; 1,1,3,3-Tetramethylbutyl Isocyanide.

1. For some leading references on the use of 2-(trimethylsilyl)thiazole, see: (a) Dondoni, A. PAC 1990, 62, 643. (b) Dondoni, A. In Modern Synthetic Methods; Scheffold, R., Ed.; Helvetica Chimica Acta: Basel, 1992. (c) Dondoni, A. In New Aspects of Organic Chemistry II; Yoshida, Z.; Ohshino, Y., Eds.; VCH: Weinheim, 1992.
2. (a) Dondoni, A.; Fogagnolo, M.; Medici, A.; Pedrini, P. TL 1985, 26, 5477. (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A. AG(E) 1986, 25, 835. (c) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. JOC 1989, 54, 693. (d) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A. T 1987, 43, 3533. (e) Dondoni, A.; Orduna, J.; Merino, P. S 1992, 201.
3. Dondoni, A.; Merino, P. OS 1993, 72, 21.
4. Dondoni, A.; Dall'Occo, T.; Galliani, G.; Mastellari, A.; Medici, A. TL 1984, 25, 3637.
5. Medici, A.; Pedrini, P.; Dondoni, A. CC 1981, 655.
6. Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A.; Pedrini, P. JOC 1988, 53, 1748.
7. Medici, A.; Fantin, G.; Fogagnolo, M.; Dondoni, A. TL 1983, 24, 2901.
8. Dondoni, A.; Boscarato, A.; Formaglio, P.; Bégué, J.-P.; Benayoud, F. S 1995, 654.
9. Dondoni, A.; Douglas, A. W.; Shinkai, I. JOC 1993, 58, 3196.
10. For a modification of the original procedure, see: Dondoni, A.; Marra, A.; Perrone, D. JOC 1993, 58, 275.
11. (a) Maillard, Ph.; Huel, C.; Momenteau, M. TL 1992, 33, 8081. (b) Khare, N. K.; Sood, R. K.; Aspinall, G. O. CJC 1994, 72, 237.
12. (a) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Medici, A. CC 1988, 10. (b) Dondoni, A.; Fantin, G.; Fogagnolo, M.; Pedrini, P. JOC 1990, 55, 1439.
13. Wagner, A.; Mollath, M. TL 1993, 34, 619.
14. (a) Dondoni, A.; Colombo, L. In Advances in the Use of Synthons in Organic Chemistry; Dondoni A., Ed.; JAI Press: London, 1993: (b) Ager, D. J. In Umpoled Synthons; Hase, T. A.; Ed.; Wiley: New York, 1987; Chapter 2.

Alessandro Dondoni

University of Ferrara, Italy

Pedro Merino

University of Zaragoza, Spain

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