Kaolin-assisted Aromatic Chlorination and Bromination$ Masao Hirano,* Hiroyuki Monobe, Shigetaka Yakabe and Takashi Morimoto Department of Applied Chemistry, Faculty of Technology, Tokyo University of Agriculture and Technology, Koganei, Tokyo 184-8588, Japan Moist kaolin catalyses the regioselective and high-yielding chlorination and bromination of C6H5OR (R a C1�}C8 alkyl, But, allyl, cyclohexyl, benzyl) to 4-XC6H4OR (X a Cl and Br, respectively) with NaClO2 and Mn(acac)3 in CH2Cl2 in the absence and presence of NaBr, respectively, under mild and neutral conditions.Use of supported reagents and catalysts for organic synthesis has gained general acceptance as a new, environ- mentally benign protocol.1 Aluminosilicate clays are well characterised by their surface acidities, which render them ecient, versatile supports or catalysts.1c,2 Somewhat sur- prisingly, while montmorillonites (bentonites) have achieved very wide use, kaolin-based reagents or kaolin-assisted reac- tions appear to be extremely limited.2 We felt from our own experiments on the oxidation of sulRdes to sulfones3a and to sulfoxides3b that kaolin is slightly inferior as a catalyst to bentonite.However, a marked catalysis of natural kaolins has recently been observed upon the protection reaction of carbonyl compounds4a and the alkylation of benzene.4b It might therefore be of considerable interest to Rnd further use of kaolin as a solid catalyst in a variety of organic reactions.We chose the electrophilic halogenation5 of aromatic ethers as a target, since certain alkyl 4-halogenophenyl ethers exhibit bioactivity and are useful intermediates en route to many Rne chemicals; for example, 4-chlorophenyl octyl ether 2h is a very active plant growth regulator.6 Thus, treatment of anisole 1a with a combination of sodium chlorite (NaClO2) and a catalytic amount of Mn(acac)3 (1 mole % with respect to 1a)7 in CH2Cl2 at 25 8C in the presence of kaolin preloaded with a small amount of water (moist kaolin)% a€orded monochloroanisoles with high selectivity to p-isomer 2a (System A in Scheme 1).System A can successfully be used for the selective chlorin- ation of a series of alkyl phenyl ethers 1b�}1k, irrespective of chain length or steric bulk of the alkyl groups. During this study, we have fortunately found that nuclear bromination is readily achieved by simple addition of NaBr to System A (System B), giving good to quantitative yield of alkyl p-bromophenyl ethers 3a�}3k, along with minor amounts of p-chloro derivatives 2 (<4%).GLC analyses of reaction mixtures showed that Systems A, B achieved 100% regio- speciRcity, except for halogenations of 1a where o-chloro- anisole 4a (4.9%) and o-bromoanisole 5a (1.0%) were formed. Moreover, Systems A, B have proved to be appli- cable to gram scale halogenation of 1a with the use of the same quantity of Mn(acac)3 (0.1 mole % in this case) as that in the small scale experiment (see Table 1).An independent experiment with compound 1a carried out in the absence of moist kaolin brought about no halo- genation even after a prolonged period (1a recovery 99% by GLC), clearly indicating that the clay eciently catalyses the halogenation. Comparative halogenations of 1a using a common acidic clay, Montmorillonite K10, and a mildly acidic support, silica gel, in place of kaolin, revealed that kaolin is superior to the others in its catalytic activity, selectivity or yield of the product (see Table 1).Another set of experiments showed that neither NaClO2/NaBr/moist kaolin nor Mn(acac)3/NaBr/moist kaolin can halogenate 1a, and also that 2a does not change to 3a under bromination conditions. Consequently, it could be likely that a positive chlorine species responsible for the chlorination oxidises bromide ion quickly to generate an electrophilic Bra species. The kaolin-based biphasic systems favorably aided the regiospeciRc halogenation of multisubstituted benzenes 6�}10 (Scheme 2).Although highly activated arenes such as veratrole 8 and pyrogallol trimethyl ether 10 are vulnerable to polyhalogenations,8 the present procedures can be con- trolled to stop at the monohalogenation stage. Like halogenations of simple alkyl phenyl ethers, the tendency that hydrogens attached to the more nucleophilic carbon atoms on the benzene rings5a are preferentially displaced by chlorine and bromine is quite general. J.Chem. Research (S), 1998, 662�}663$ Scheme 1 Scheme 2 $This is a Short Paper as deRned in the Instructions for Authors, Section 5.0 [see J. Chem. Research (S), 1998, Issue 1]; there is there- fore no corresponding material in J. Chem. Research (M). %The e€ect of water on surface-mediated reactions has been described elsewhere.7 *To receive any correspondence. 662 J. CHEM. RESEARCH (S), 1998Surface-mediated reactions a€ord excellent product yield and selectivity often unattainable by solution phase counterparts.9 For fascinating instances, CuCl2/alumina (100 8C, 2�}3 h),9b ButOCl/zeolite (25 8C, 1 h�}2 weeks),9c and Br2/zeolite (ambient, 1�}5 h)9d systems have elegantly achieved high-yielding, regio-controlled nuclear chlorina- tion9b,c and bromination9d of a number of arenes.Simple, inexpensive procedures demonstrated here accomplish e- cient halogenations under mild conditions and their regio- speciRcities are impressive.In addition, NaBr is more attractive as the bromine source than Br2. They could therefore be added to a list of synthetically useful halogena- tion methodologies.9 In view of the easy accessibility and excellent reaction performance of the new biphasic system, we are now looking for another synthetic target to make use of the remarkable catalysis by kaolin. Experimental Sodium chlorite (available chlorine ca. 82% by iodometry), Mn(acac)3, and substrates 1a, b, d, j, k, 6�}10 were used as received from commercial sources.Ethers 1c, 1e�}1h10 and 1i11 were prepared by known methods. Moist kaolin (H2O content, 13 wt. %) was prepared by adding deionised water (0.15 g) in portions to commer- cial kaolin (Kukita; 1.0 g), followed by vigorous shaking of the mixture after every addition for a few minutes until a free-�Powing powder was obtained. Montmorillonite K10 (Aldrich) and predried silica gel (Merck silica gel 60) were treated with deionised water as above.Chlorination Procedure.DA representative procedure was as follows. A 30 ml, two-necked, round bottom �Pask, equipped with a Te�Pon-coated stirrer bar and re�Pux condenser, was charged with anisole 1a (1 mmol), freshly prepared moist kaolin (1 g), Mn(acac)3 (0.01 mmol) and dried (molecular sieves) CH2Cl2 (10 ml), and the mixture stirred for a few minutes. Sodium chlorite (1.7 mmol as available chlorine) was then added in one portion with stirring.The cloudy suspension was kept at 25 8C while ecient stirring was continued in order to ensure smooth reaction and to attain re- producible results. After 100 min (agitation periods after complete addition of NaClO2 are indicated in Table 1) the whole material was transferred to a sintered glass funnel and the Rlter cake washed thoroughly with portions of dry diethyl ether (ca. 100 ml). Rotary evaporation of the solvent, followed by chromatography on a silica gel column (Merck silica gel 60, hexane�}AcOEt), gave p-chloroanisole 2a in 94% yield.Bromination Procedure.DThe bromination was carried out by adding NaClO2 and NaBr both in one portion to a stirred mixture of ether, Mn(acac)3, and moist kaolin CH2Cl2. After a given time, work-up and chromatographic isolation as above gave the pure bromination product. Halogenoethers thus obtained were fully characterised by MS and NMR spectroscopies. Received, 29th May 1998; Accepted, 30th June 1998 Paper E/8/04043E References 1 (a) J.H. Clark, A. P. Kybett and D. J. Macquarrie, Supported Reagents. Preparation, Analysis, and Applications, VCH, New York, 1992; (b) J. H. Clark, Catalysis of Organic Reactions by Supported Inorganic Reagents, VCH, New York, 1994; (c) M. Balogh and P. Laszlo, Organic Chemistry Using Clays, Springer, Berlin, 1993; (d) Preparative Chemistry Using Supported Reagents, ed. P. Laszlo, Academic Press, San Diego, 1987; (e) Solid Supports ands, ed.K. Smith, Ellis Horwood, Chichester, 1992; ( f ) Supported Reagents and Catalysts in Chemistry, ed. B. K. Hodnett, A. P. Kybett, J. H. Clark and K. Smith, The Royal Society of Chemistry, Cambridge, 1998. 2 Ref. 1(d), Part VIII; J. A. Ballantine, in ref. 1(e), ch. 4; P. Laszlo, Acc. Chem. Res., 1986, 19, 121; A. Cornelis and P. Laszlo, Synthesis, 1985, 909. 3 (a) M. Hirano, J. Tomaru and T. Morimoto, Chem. Lett., 1991, 523; Bull. Chem. Soc. Jpn., 1991, 64, 3752; (b) M.Hirano, H. Kudo and T. Morimoto, Bull. Chem. Soc. Jpn., 1992, 65, 1744. 4 (a) D. Ponde, H. B. Borate, A. Sudalai, T. Ravindranathan and V. H. Deshpande, Tetrahedron Lett., 1996, 37, 4605; (b) K. R. Sabu, R. Sukumar and M. Lalithambika, Bull. Chem. Soc. Jpn., 1993, 66, 3535. 5 (a) R. Taylor, Electrophilic Aromatic Substitution, Wiley, Chichester, 1990, ch. 9; (b) J. March, Advanced Organic Chemistry. Reactions, Mechanisms, and Structure, 4th edn., Wiley, New York, 1992, pp. 531�}534. 6 S. R. McLane, E. W. Dean, J. W. Brown, C. R. Connell, W. H. Howard and C. E. Minarik, Weeds, 1953, 2, 288. 7 M. Hirano, S. Yakabe, J. H. Clark and T. Morimoto, J. Chem. Soc., Perkin Trans. 1, 1996, 2693; M. Hirano, S. Yakabe, H. Monobe, J. H. Clark and T. Morimoto, J. Chem. Soc., Perkin Trans. 1, 1997, 3081. 8 S. Kajigaeshi, Y. Shinmasu, S. Fujisaki and T. Kakinami, Chem. Lett., 1989, 415; D. Friedman and D. Ginsburg, J. Org. Chem., 1958, 23, 16. 9 (a) L.Delaude, P. 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Table 1 Aromatic mono-chlorination and -bromination of aromatic ethersa Chlorination Bromination Ether NaClO2 (mmol) t/min Product (%)b NaClO2 (mmol) NaBr (mmol) t/min Product (%)b 1a 1.7 100 2a (94), 4a (4.9) 1.2 3.0 110 3a (98), 5a (1.0) 1ac 2.1 60 2a (67), 4a (7.5)d 1.4 3.0 60 3a (99) 1ae 2.1 60 2a (72), 4a (13)f 1.4 3.0 120 3a (90)g 1a 14h 50 2a (94) 12h 30 130 3a (95) 1b 1.5 60 2b (96) 1.2 3.0 100 3b (95) 1c 1.6 80 2c (98) 1.2 3.0 160 3c (97) 1d 1.7 100 2d (quant.) 1.2 3.0 100 3d (96) 1e 1.5 70 2e (93) 1.2 3.0 140 3e (92) 1f 1.6 80 2f (99) 1.2 3.0 130 3f (97) 1g 1.6 100 2g (quant.) 1.2 3.0 110 3g (97) 1h 1.5 70 2h (99) 1.2 3.0 90 3h (95) 1i 1.5 60 2i (96) 1.2 3.0 90 3i (98) 1j 1.9 60 2j (99) 1.2 4.0 80 3j (98) 1k 2.2 120 2k (60)i 1.5 4.5 150 3k (66)j 6 1.5 110 11a (93) 1.0 4.5 120 11b (95) 7 2.0 70 12a (96) 1.3 4.5 60 12b (quant.) 8 1.5 60 13a (94) 1.0 3.5 120 13b (quant.) 9 1.2 80 14a (95) 1.1 4.5 90 14b (92) 10 1.3 80 15a (98) 1.0 3.5 120 15b (97) aAt 25 8C; 1 mmol ether, 0.01 mmol Mn(acac)3, 1 g moist kaolin, 10 ml CH2Cl2.bYield of chromatographically purified product based on the starting ether. cMoist montmorillonite K10 used as support. dca. 20% of 1a remained. eSilica gel as support. fca. 13% (GLC area ratio) of a unknown product was formed. gca. 3% of 2a was formed. hAt 30 8C; 10 mmol 1a, 0.01 mmol Mn(acac)3, 3 g moist kaolin, 30 ml CH2Cl2. iGLC yield. jGLC yield; 2.4% of 1k remained. J. CHEM. RESEARCH (S), 1998 6