Temhcdmn Letters. Vol. 34, No. 41. pp. 6525X08.1993 Priikd in Great Britain

0@404039/93 56.00 + .OO Pergamon Press Ltd

Preparation of &Fluorobmieofhiazobs &a Regbeebcfive Nucleophilk Arometk Substifufbn Reacfbn

David M. Fink’ and Joseph T. Strupczewski

Chemical Research Department, Neuroscience Strategic Business Unii

Hoechst-Roussel Pharmaceuticals Inc. P.O. Box 2500 Somerville, NJ 08676

Abstract: An efficient three step procedure for the preparation of &flwm- 1,24enzisothiazoles is described. The key step is a regioselecfive nucleopMic amah substitution reactkm in which the carbony/ group of a ketone or aldehyde directs nudeophi/lEc displacement to the orlho posibbn in preferme to the para positkm

HP-873 W is a potential atypical antipsychotic currently in clinical trials for the treatment of schizophrenia.’ In our exploration of anafogues of this compound, we were prompted to prepare benzisothiazole analogues 2 and 3. Although

F

a number of methodologies for the preparation of 1,2benzisothiazoles exisr2 many of these methods are not generally

useful, and none appeared to be suited to the synthesis of the desired 6-fluoro isomers. For example, treatment of ortho halo ketones or aldehydes with elemental sulfur and ammonia at elevated temperatures provides l,P-benziiothiazoles in

fair to good yields.3 Application of thii methodology to the present case would be expected to result in a mixture of products, since the starting material would have leaving groups in both the 2 and 4 positions. However, this tvpe of starting material (e.g. 2,4difluorophenyl ketones) is readily avallable,4 and we became interested in the posslbkty of selectively displacing the ortho fluorine with a sulfide in an aromatic substitution reaction. We thought that a ketone or aldehyde might direct subetftution to the ortho position through chelation, or via addition of the nucleophile to the carbonyl, followed by an internal delivery to the ortho position. While the selective displacement of the ortho halogen in 2,4- dihalonitrobenzenes has been reported,6 we are unaware of any examples of nucleophilic aromatic substftution reactions in which the carbonyl of a ketone or aldehyde has a directing effect. In this communication, we report an efficient process for the preparation of 6-fluoro benzisothiazoles in which the key step is a carbonyf directed nucleophilic aromatic substitution reaction.

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The choice of sulfide nucleophile was based on the possibility of transforming the product into a sulfenamide, which would then spontaneously cyclize to provide the desired 1,2_benzisothiazole (Scheme I). Sulfenamides are readily prepared from sulfenyl halides,8 and so a sulfids which could be readily converted into a sulfenyl halide was ideal.

Karasch and Langford reported that treatment of benzyl sulfides with sulfuryl chloride cleaves the benzyl group and gives the desired halide under mild conditions.7

Treatment of the tropaneg8with the potassium anion of benzyl mercaptan (K-0-t-Bu, PhCH&H) in THF at OoC provided the ortho substituted product 3 in 49% yields. Analysis of the NMR of the crude material indicated that it was contaminated with ca. 10% of the para isomer and/or the 2,4diiulfide. The identity of the ma@ product 5 was confirmed by its further transformation into the desired 1,2 benzisothiazole 6. Addition of sulfuryl chloride to the sulfide5

4 I B

in dichloroethane at room temperature, followed by treatment of the resulting sulfenyl chloride with ammonia in ethanol provided the desired benzisothiazolefi in 60% yield.10 Use of this method for the preparation of the benzisothiazole

analogue of HP 873 is outlined in Scheme II. In this case the amine functionality was protected as a formamide.

Z

scheme II B

Addition of potassium benzyt mercaptide to this substrate gave the expected ortho substituted productZ in 63% yield. Sulfenamide formation and cyclization as above gave the benzisothiazole 8 in 42% yield. The generality of the transformation was briefly explored using several simple 2,4difluorophenyl carbonyl compounds as substrates. As shown in Table 1, benzyl mercaptan selectively displaced the ortho fluorine substituent in 2,4difluorobenzaldehyde, 2’Jdifluoroacetophenone and 2,4difluorobenzophenone. Treatment of these benzykuWides with SOfi12 in dichlomethane followed by ammonia in ethanol as described above provided the expected benzisothiazoles in 570% yield.

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TABLE 1

R 8uni&Ybkf,% ulho&terarew BedwhmbW%

CH3 63 8.6:l

H 52 11:l :

Fvl 66 >10:1 70

a. Ratios were detenirmd by analysis of MO MHz lH NMR of the cwde products

b. The aldeh@? was nol puriied ptior to benzisothiiole forma&m in this case

Several experiments were performed to explore the origin of the observed selectivity. As outlined below, there are three possible products which could be formed in these reactions. Treatment of 2Jdifluoroacetophenone with two

equivalents of the lithium anion of benzyl mercaptan (UOH, PhCHfiH) in DMF at room temperature provided an authentic sample of the bis sulfide in 88% yield. The use of one equivalent of the liiium mercaptide provided a mixture of all three of the possible products in an ortho:para:bis ratio of 4:8.8:1 (ortho:para=l :17). However, using THF (n-BuLi, PhCHfiH) as the solvent in place of DMF afforded the ortho isomer in 80% yield with an orthdpara ratio of greater than 20/l. In addition, none of the bis sulfide could be detected in the NMR of the crude product. The solvent and counter-ion effects observed in this reaction support a chelation controlled addition.

GENERAL PROCEDURES:

Benzyl mercaptan (1.59 g, 12.8 mmol) in IO mL of tetrahydrofuran was added dropwise to a solution of potassium t-butoxide (1.4 g, 12.8 mmol) in 55 mL of tetrahydrofuran. The resulting suspension was stirred at ambient temperature for 5 min., and then 2,4difluoroacetophenone (2.0 g, 12.8 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hr, then saturated ammonium chloride solution was added, and the product was extracted into ethyl

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acetate. The combined organic layers were washed with brine, dried over MgS04, filtered and concentrated to leave 3.2 g of crude product. Recrystallization from methanol gave 2.1 g (63%) of product as white solid, m.p.=l 1 l-l 12oC.

Sulfuryl chloride (0.52 g, 3.6 mmd) was added dropwise to a suspension of 4-fluoro-2-(phenylmethylthio)acetophenone (1 .O g, 3.8 mmol) in 12 mL of dichloroethane at room temperature. The resulfng yellow solution was stirred for 0.5 hr, and then the solvent was removed in vacua, and the residue was suspended in 12 mL of tetrahydrofuran and treated at room temperature with 12 mL of ethanol saturated with ammonia. The resultant mixture was stirred for 0.5 hr; water was added, and the product was extracted into ethyl acetate. The combined organic layers were washed with brine, dried over MgSO,, filtered and concentrated to leave 0.6 g of crude product. Purification by radially-accelerated preparative thin layer chromatography (Chromatotronm , elution with ethyl acetate-hexanes) provided 0.37 g (58%) of a pale yellow solid,

m.p.=5&51.5oC.

REFERENCES

1.

2.

3. 4.

5. 6. 7.

8.

9.

10.

11.

Strupczewski, J.T. ; Bordeau, K. J.; Chiang, Y.; Glamkowski, E. J.; Dunn, R. W. Szewczak, M. R.; Wtlmot, C. A. and Helsey, G. C. Abstracfs of the 2001h American Chemical So&y Meeting, Washington DC. 1990. (a) Davis, M. A&. Heterocyd. Chem. 1972, 14,43 . (b) Davis, M. Adv. Heterocycf. Cftem. 1985,38,105 and references cited therein.

Markert, J.; Hagen, H. Liebigsh. Chem. 1980,768. Larock, R.C. Comprehensive Organic Transformations, VHC Publishers, Inc. , New York,1 989, pp. 587-818. Bunnett, J.F.; Morath, R.J. J. Amer. C&m. Sot. 1955, 77,505l. For a review see: Kuhle, E. Synmesis, 1971,617.

Kharasch, N.; Langford, R.B. J. Org. Chem. 1963,28,1903. The substrate was prepared via a Friedl-Crafts acylation of 2,4difluoroberuene with tropane-3-carbonyl chloriiet 1, followed by demethylation with cyanogen bromide.

All new compounds exhibited satisfactory spectral data (IH-NMR, MS and IR).

The exo stereochemistry of the product was assigned by analysis of the proton NMR spectrum. The eppearence of the aproton as a septet with a large coupling constant is consistent an axial position on the ring,

US patent 4,350,691.

(Received in USA 27 July 1993; accepted 16 August 1993)