2-Methylbenzothiazole1

[120-75-2]  · C8H7NS  · 2-Methylbenzothiazole  · (MW 149.23)

(the a-lithio derivative represents a masked enolate;2 the a-trimethylsilyl derivative is used for Peterson alkenations3)

Physical Data: mp 14 °C; bp 238 °C/765 mmHg; bp 151 °C/15 mmHg; d 1.1763 g cm-3; nD 1.6092.

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

Form Supplied in: liquid; widely available.

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

Purification: distillation under reduced pressure.

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

Introduction.

2-Methylbenzothiazole (1) has been used4 in base- and acid-mediated condensations with aldehydes to give products which normally undergo dehydration in situ to give alkenes (2) (eq 1).

a-Lithio-2-methylbenzothiazole.1

This reagent is readily available by lithiation of 2-methylbenzothiazole (1) with n-Butyllithium at -78 °C (eq 2),1,3 which gives rise to a yellow precipitate (indicating the formation of the organometallic compound) when diethyl ether is used as a solvent or to a clear light-brown solution in THF or 1,2-dimethoxyethane.

a-Lithio-2-methylbenzothiazole (3) reacts with various electrophiles such as aldehydes and ketones2 to afford 2-(2-hydroxyalkyl)benzothiazoles in high yields (eq 3).

Chikashita et al.2 have demonstrated the synthetic equivalence of (3) to a masked enolate anion through the liberation of the aldehyde by cleavage of the Benzothiazole ring (eq 4).

More recently, Lochon et al.5 have reported the reaction of (3) with other electrophiles such as esters (eq 5) and nitriles (eq 6). When the same reaction is carried out with acyl chlorides, bisacylated compounds are obtained (eq 7).

2-(Trimethylsilylmethyl)benzothiazole.

a-Lithio-2-methylbenzothiazole (3) is quantitatively silylated with Chlorotrimethylsilane to give reagent (4), which can be further metalated and condensed with carbonyl compounds to give the corresponding alkenes (eq 8).3 This two-carbon homologation sequence corresponds to a Peterson alkenation, i.e. it is an alternative to the Wittig and Horner-Emmons reactions.6 Endocyclic analogs such as 2-(1-cyclohexenyl)- and 2-(1-cyclopentenyl)benzothiazoles are accessible via addition of 2-lithiobenzothiazole (see Benzothiazole) to corresponding cyclic ketones and subsequent dehydration.3

The vinylbenzothiazole (5), derived from cyclohexanone through (4), undergoes efficient conjugate addition reactions with a variety of alkyllithium reagents (alkyl, vinyl, phenyl, and allyl) as well as with acetone and acetaldehyde N,N-dimethylhydrazone anions.7a The resulting adduct carbanions may be protonated (MeOH) or alkylated in situ with methyl, allyl, and propargyl halides. The double bond of (5) can be hydrogenated (H2, Pd/C, EtOH) smoothly without catalyst poisoning. Conversion of the benzothiazole moiety to the formyl group is accomplished by N-methylation (MeOSO2F, CH2Cl2), reduction (NaBH4, EtOH), and hydrolysis (AgNO3, aq. MeCN, pH 7). Aldol cyclization of the liberated aldehyde onto the a- or b-acetonyl substituents provide effective methods for fused and spiro annulation of cyclohexenone or cyclopentenone rings (e.g. eq 9).7b

Other 2-Alkylbenzothiazoles.

Florio et al.8 have reported the metalation of 2-alkylbenzothiazoles (2-ethyl, 2-propyl, and 2-phenyl) to give the corresponding a-lithioalkylbenzothiazoles which undergo aldol condensations with carbonyl compounds (eq 10).

More recently,9 the Darzens reaction between the lithio derivative of 2-chloromethylbenzothiazole (6) and carbonyl compounds to furnish epoxides has been described (eq 11).

Related Reagents.

Benzothiazole; 2-Methyl-2-thiazoline; 5,6-Dihydro-2,4,4,6-tetramethyl-1,3(4H)-oxazine; 2,4,4-Trimethyl-2-oxazoline; 2-(Trimethylsilyl)thiazole.


1. For an extensive study on the metalation of 2-methylbenzothiazole with several reagents, see: Costa, M. V.; Lochon, P. JOM 1985, 293, 265.
2. Chikashita, H.; Ikegami, S.; Okumura, T.; Itoh, K. S 1986, 375.
3. Corey, E. J.; Boger, D. L. TL 1978, 5.
4. Dryanska, V.; Ivanov, C. S 1976, 37.
5. Costa, M. V.; Brembilla, A.; Roizard, D.; Lochon, P. JHC 1991, 28, 1541.
6. Knott, E. B. JCS 1965, 3793.
7. (a) Corey, E. J.; Boger, D. L. TL 1978, 9. (b) Corey, E. J.; Boger, D. L. TL 1978, 13.
8. (a) Epifani, E.; Florio, S.; Ingrosso, G. TL 1987, 28, 6385. (b) Epifani, E.; Florio, S.; Ingrosso, G. T 1987, 43, 1937.
9. Florio, S.; Troisi, L. TL 1992, 33, 7953.

Alessandro Dondoni

University of Ferrara, Italy

Pedro Merino

University of Zaragoza, Spain



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