Benzothiazole1

[95-16-9]  · C7H5NS  · Benzothiazole  · (MW 135.18)

(formyl and acyl anion equivalent;2 one-carbon homologation of aldehydes via the 2-trimethylsilyl derivative;3 the N-methylbenzothiazolium ring system has been used as a leaving group4)

Physical Data: mp 2 °C; bp 231 °C/765 mmHg; bp 131 °C/34 mmHg; d 1.246 g cm-3; nD 1.6379.

Solubility: slightly sol H2O; sol acetone; very sol ethanol, diethyl ether, THF, CS2.

Form Supplied in: liquid; widely available.

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

Purification: distillation under reduced pressure.

Handling, Storage, and Precautions: use in a fume hood. Benzothiazole should be used freshly distilled for best results. Toxic by inhalation, in contact with skin, and if swallowed.

2-Lithiobenzothiazole.5

Benzothiazole (1) is easily metallated at the 2-position by employing 1.0 equiv of n-Butyllithium at -78 °C in diethyl ether as solvent.2a,6 Chikashita et al.2b have found that better results can be achieved by adding a 10% excess of n-butyllithium and carrying out the reaction in THF as a solvent (eq 1). In fact, when diethyl ether is used as solvent or less than 2 mL THF/mmol benzothiazole, the lithium compound should precipitate and the corresponding suspension becomes very thick, making stirring difficult.

2-Lithiobenzothiazole (2) is stable only below -50 °C. A solution of 2-Lithiobenzothiazole in THF gives rise to a clear orange-colored solution. At temperatures higher than -50 °C a dark-brown solution indicating decomposition of the organolithium compound is observed. Consequently, reactions with this reagent have to be carried out at temperatures lower than -50 °C. 2-Lithiobenzothiazole (2) reacts with various electrophiles7 such as esters or nitriles (eq 2), a-halo ketones (eq 3), and carbonyl compounds4 to give the intermediate carbinols which can be easily dehydrated to the corresponding alkenes (3) as described (eq 4).2

On the other hand, Chikashita et al.7 suggest that 2-lithiobenzothiazole (2) does not react with alkyl halides.

The synthetic utility of the benzothiazole nucleus is demonstrated through the unmasking to the carbonyl function.2 The methodology involves three steps: (a) methylation of 2-substituted benzothiazoles (4), (b) reduction of the resulting salts (5), and (c) hydrolysis under mild and neutral conditions to afford the aldehydes (6) (eq 5).2,4 In several cases, however, the efficiency of this unmasking protocol and its compatibility with other protecting groups were not demonstrated.

The N-methylbenzothiazolium salts (5) also react with organometallic reagents to give 2,2-disubstituted N-methylbenzothiazolines which after hydrolysis afford the corresponding ketones (7) (eq 6).2,4

Corey and Boger have utilized this homologating methodology to devise new carbon-carbon bond-forming reactions8 and annulation processes for fused and spiro rings.9 Another application of benzothiazole chemistry involves the use of the heterocyclic ring as a leaving group. The synthesis of carboxylic acid derivatives via the N-methylbenzothiazolium salts (8) and (9), as outlined in eq 7, takes advantage of this property.4b

2-(Trimethylsilyl)benzothiazole.

This reagent can be prepared in high yield by addition of Chlorotrimethylsilane to 2-lithiobenzothiazole (2) at -78 °C with subsequent gradual warming to room temperature over a 4-5 h period (eq 8).10

2-(Trimethylsilyl)benzothiazole (10) reacts with several electrophiles such as acid derivatives and carbonyl compounds in the absence3a,10 (eq 9) or in the presence of Potassium t-Butoxide as catalyst3b (eq 10).

Only one addition of 2-(trimethylsilyl)benzothiazole (10) to a chiral aldehyde has been reported3c and significant diastereoselection was observed, in contrast to 2-lithiobenzothiazole (2) which showed a complete lack of stereoselectivity in the reaction with the same aldehyde (11) (eq 11).

Since benzothiazole has been shown to be a formyl anion equivalent,11 this reaction could represent a stereoselective homologation process. However, for this purpose 2-(Trimethylsilyl)thiazole is a more convenient synthetic equivalent since higher stereoselectivity is obtained with this reagent, and the aldehyde release is easier with thiazole than benzothiazole.

2-(Trimethylsilyl)benzothiazole (10) has been also used in the synthesis of heteroaromatic phosphines12 and mesomeric betaines.13


1. (a) Metzger, J. V. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R.; Rees, C. W., Eds.; Pergamon: Oxford, 1984; Vol. 6. (b) Sainsbury, M. In Rodd's Chemistry of Carbon Compounds, 2nd ed.; Coffey, S.; Ansell, M. F., Eds.; Elsevier: Amsterdam, 1986; Vol. IVc.
2. (a) Corey, E. J.; Boger, D. L. TL 1978, 5. (b) Chikashita, H.; Ishibaba, M.; Ori, K.; Itoh, K. BCJ 1988, 61, 3637. It has been reported for benzothiazole a value of pKa = 28-29. See: Fraser, R. R.; Mansour, T. S.; Savard, S. CJC 1985, 63, 3505.
3. (a) Ricci, A.; Fiorenza, M.; Grifagni, M. A.; Bartolini, G. TL 1982, 23, 5079. (b) Effenberger, F.; Spiegler, W. CB 1985, 118, 3872. (c) Dondoni, A.; Fogagnolo, M.; Medici, A.; Pedrini, P. TL 1985, 26, 5477.
4. (a) Chikashita, H.; Tame, S.; Yamada, S.; Itoh, K. BCJ 1990, 63, 497. (b) Chikashita, H.; Ishihara, M.; Takigawa, K.; Itoh, K. BCJ 1991, 64, 3256.
5. FF 1980, 8, 274.
6. Gilman, H.; Beel, J. A. JACS 1949, 71, 2328.
7. Chikashita, H.; Itoh, K. H 1985, 23, 295.
8. Corey, E. J.; Boger, D. L. TL 1978, 9.
9. Corey, E. J.; Boger, D. L. TL 1978, 13.
10. (a) Pinkerton, F. H.; Thames, S. F. JHC 1971, 8, 257. (b) Jutzi, P.; Hoffmann, H. J. CB 1973, 106, 594.
11. Dondoni, A.; Colombo, L. In Advances in the Use of Synthons in Organic Chemistry; Dondoni, A., Ed.; JAI: London, 1993.
12. Moore, S. S.; Whitesides, G. M. JOC 1982, 47, 1489.
13. Potts, K. T.; Murphy, P. M.; Kuehnling, W. R. JOC 1988, 53, 2889.

Alessandro Dondoni

University of Ferrara, Italy

Pedro Merino

University of Zaragoza, Spain



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