2-METHYLBENZOTHIAZOLE 1

2-Methylbenzothiazole1

S

N

[120-75-2] C8H7NS (MW 149.23)InChI = 1/C8H7NS/c1-6-9-7-4-2-3-5-8(7)10-6/h2-5H,1H3InChIKey = DXYYSGDWQCSKKO-UHFFFAOYAE

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

Physical Data: mp 14 ◦C; bp 238 ◦C/765 mmHg; bp 151 ◦C/15mmHg; 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 withskin, and if swallowed. Use in a fume hood.

Introduction. 2-Methylbenzothiazole (1) has been used4 inbase- and acid-mediated condensations with aldehydes to giveproducts which normally undergo dehydration in situ to givealkenes (2) (eq 1).

S

N

S

NRCHO RHO

(1)S

N R

(1)

(2)

base oracid

ααα-Lithio-2-methylbenzothiazole.1 This reagent is readilysavailable by lithiation of 2-methylbenzothiazole (1) withButyllithium at −78 ◦C (eq 2),1,3 which gives rise to a yellowprecipitate (indicating the formation of the organometallic com-pound) when diethyl ether is used as a solvent or to a clear light-brown solution in THF or 1,2-dimethoxyethane.

S

N BuLi(2)

(1)

S

N Li

(3)

–78 °C

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

(3)S

N

R1 R2

O R1R2 OH1. (3)

2. H2O

93–99%

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

(4)

S

NO 1. methylation

2. reduction3. hydrolysis

(3), HF–78 °C to rt

Cl

O

O CHO

80%76%

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, bisacy-lated compounds are obtained (eq 7).

(5)S

N(3) R1O

R1

O

OR2

(6)S

N(3) RH2N

R N

S

N(3) R1O

OR1

(7)2R1

O

Cl

2-(Trimethylsilylmethyl)benzothiazole. α-Lithio-2-methyl-benzothiazole (3) is quantitatively silylated with Chlorotrimethyl-silane to give reagent (4), which can be further metalated andcondensed with carbonyl compounds to give the correspondingalkenes (eq 8).3 This two-carbon homologation sequence corre-sponds to a Peterson alkenation, i.e. it is an alternative to the Wittigand Horner–Emmons reactions.6 Endocyclic analogs such as2-(1-cyclohexenyl)- and 2-(1-cyclopentenyl)benzothiazolesare accessible via addition of 2-lithiobenzothiazole (seeBenzothiazole) to corresponding cyclic ketones and subsequentdehydration.3

1. BuLi

S

N TMS(3)

S

N

(4)

R2R1

(8)

TMSCl

2. R1R2CO

The vinylbenzothiazole (5), derived from cyclohexanonethrough (4), undergoes efficient conjugate addition reactions witha variety of alkyllithium reagents (alkyl, vinyl, phenyl, and allyl)as well as with acetone and acetaldehyde N,N-dimethylhydrazoneanions.7a The resulting adduct carbanions may be protonated(MeOH) or alkylated in situ with methyl, allyl, and propargylhalides. The double bond of (5) can be hydrogenated (H2, Pd/C,EtOH) smoothly without catalyst poisoning. Conversion of thebenzothiazole moiety to the formyl group is accomplished by

Avoid Skin Contact with All Reagents

2 2-METHYLBENZOTHIAZOLE

N-methylation (MeOSO2F, CH2Cl2), reduction (NaBH4, EtOH),and hydrolysis (AgNO3, aq. MeCN, pH 7). Aldol cyclization of theliberated aldehyde onto the α- or β-acetonyl substituents provideeffective methods for fused and spiro annulation of cyclohexenoneor cyclopentenone rings (e.g. eq 9).7b

S

N

O

O

O

NLi NMe2

1.

BT

O

(9)

1. MeO3SF2. NaBH4

(5)

TsOH

3. AgNO3 H2O

2. CuCl2 H2O

Other 2-Alkylbenzothiazoles. Florio et al.8 have reportedthe metalation of 2-alkylbenzothiazoles (2-ethyl, 2-propyl, and2-phenyl) to give the corresponding α-lithioalkylbenzothiazoleswhich undergo aldol condensations with carbonyl compounds(eq 10).

S

N R

S

N

R

R1

R2OH

S

N

R

HOR2

R1

1. BuLi

(10)+

2. R1R2CO

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

S

N Cl

S

N1. LDA

(6)

O

R2R1

(11)2. R1R2CO

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

1. For an extensive study on the metalation of 2-methylbenzothiazole withseveral reagents, see: Costa, M. V.; Lochon, P., J. Organomet. Chem. 1985,293, 265.

2. Chikashita, H.; Ikegami, S.; Okumura, T.; Itoh, K., Synthesis 1986,375.

3. Corey, E. J.; Boger, D. L., Tetrahedron Lett. 1978, 5.

4. Dryanska, V.; Ivanov, C., Synthesis 1976, 37.

5. Costa, M. V.; Brembilla, A.; Roizard, D.; Lochon, P., J. Heterocycl. Chem.1991, 28, 1541.

6. Knott, E. B., J. Chem. Soc. 1965, 3793.

7. (a) Corey, E. J.; Boger, D. L., Tetrahedron Lett. 1978, 9. (b) Corey, E. J.;Boger, D. L., Tetrahedron Lett. 1978, 13.

8. (a) Epifani, E.; Florio, S.; Ingrosso, G., Tetrahedron Lett. 1987, 28,6385. (b) Epifani, E.; Florio, S.; Ingrosso, G., Tetrahedron 1987, 43,1937.

9. Florio, S.; Troisi, L., Tetrahedron Lett. 1992, 33, 7953.

Alessandro DondoniUniversity of Ferrara, Ferrara, Italy

Pedro MerinoUniversity of Zaragoza, Zaragoza, Spain

A list of General Abbreviations appears on the front Endpapers