5901
J . Org. Chem. 1994,59, 5901-5904
Cation-ExchangedMontmorillonite-Catalyzed Facile Friedel-Crafts Alkylation of Hydroxy and Methoxy Aromatics with 4-Hydroxybutan-2-oneTo Produce Raspberry Ketone and Some Pharmaceutically Active Compounds Jun-ichi Tateiwa,t Hiroki Horiuchi,? Keiji €jashimoto,f Takayoshi Yamauchi,@and Sakae Uemura*,t Division of Energy and Hydrocarbon Chemistry, Graduate School of Engineering, Kyoto University, Sakyo-ku, Kyoto 606-01, Japan, Osaka Municipal Technical Research Institute, 1-6-5Morinomiya, Joto-ku, Osaka 536, Japan, and Nissei Chemical Znc., 2-18-110 Jyuhachgyo, Yodogawa-ku, Osaka 532, Japan Received May 2, 1994@
The Friedel-Crafts alkylation of hydroxy and methoxy aromatics with 4-hydroxybutan-2-one ( y KB) in the presence of a cation-exchanged montmorillonite (Mn+-mont;Mn+= Z++, N3+, Fe3+,and Zn2+)was investigated. Phenol was C-alkylated regiospecifically with y - K B in the presence of Z1A+-, A13+-, or Fe3+-montto produce 4-(4-hydroxyphenyl)butan-2-one (raspberry ketone) in 31-35% GLC yield. Anisole, 2-methoxynaphthalene, and 1-methoxynaphthalene were regiospecifically Calkylated to produce 4-(4-methoxyphenyl)butan-2-one, 4-(2-methoxy-l-naphthyl)butan-2-one (pharmaceutically active), and 4-(4-methoxy-l-naphthyl)butan-2-one, respectively. N3+and Fe3+-mont were the most effective catalysts in these cases (13-58% isolated yield). y - K B could be used as an alkylating agent instead of the highly toxic 3-buten-2-one (MVK) which also polymerizes easily.
Introduction Friedel-Crafts alkylations of aromatic substrates with alkenes, alcohols, and alkyl halides are catalyzed by various clays, both natural and acid-activated.l However, many of these reactions require relatively high temperature and pressure and the products are often isomeric mixtures. The results have usually been published in patents such that some of the detailed experimental procedures are not readily a ~ a i l a b l e . ~We , ~ are interested in the catalytic applications of cation-exchanged montmorillonite (Mn+-mont),a modified natural clay, to organic synthesis under mild conditions. These catalysts have attractive features such as ease of handling, noncorrosiveness, low cost, regeneration, and easy modification of acidity by exchange of cations in the interlayer They are environmentally-friendly catalysts, in that they circumvent the production of aluminum waste.3 We have attempted the alkylation of phenol with commercially-available, inexpensive 4-hydroxybutan-2one ( y - K B ) using various Mn+-mont as catalysts to produce the target 4-(4-hydroxyphenyl)butan-2-one (la). This compound is the odor source of raspberry and is called raspberry ketone. Until now, this ketone has been prepared industrially by the use of an acid catalyst such +
Kyoto University.
* Osaka Municipal Technical Research Institute.
Nissei Chemical Inc. Abstract published in Advance ACS Abstracts, September 1,1994. (1)For recent reviews on the reactions in the presence of clays, see: Balogh, M.; Laszlo, P. In Organic Chemistry Using Clays; SpringerVerlag: New York, 1993. Kellendonk, F. J. A.; Heinerman, J . J. L.; van Santen, R. A.; McKillop, A.; Clissold, D. W.; Pinnavaia, T. J.; Foucaud, A.; Adams, J. M. In Preparative Chemistry Using Supported Reagents; Laszlo, P., Ed.; Academic Press: New York, 1987; Part 8, pp 453-528. (2) Laszlo, P.; Mathy, A. Helu. Chim. Acta 1987, 70, 577. (3)Clark, J. H.; Kybett, A. P.; Macquarrie, D. J.; Barlow, S. J.; Landon, P. J . Chem. Soc., Chem. Commun. 1989,1353. Barlow, S. J.; Clark, J. H.; Darby, M. R.; Kybett, A. P.; Landon, P.; Martin, K. J . Chem. Res. (S) 1991, 74. (4) Technical Information Bulletin AL-143, Aldrich Chemical Co., Inc., 1987. @
as concentrated HzS04, H3P04, aqueous HCl,5 or the cation-exchange resin D0wex-50W.~We report here the successful result of a highly para-selective alkylation of phenol with a facile workup procedure. The application of this method to anisole and 2-methoxy- and l-methoxynaphthalene is also reported. Some of the products of this alkylation are pharmaceutically active compounds. For example, 4-(4-methoxyphenyl)butan-2-one (lb)is the insect attractant for the scarabaeid subfamily, Rutelinae? and 4-(2-methoxyphenyl)butan-2-one (2b)is a key intermediate en route to the bronchospasmolytically active (aralkylamino)(hydroxyphenyl)ethanols.8 442-Methoxyl-naphthyl)butan-2-0ne (4) is known to be pharmaceutically active, though slightly less effective than 4-(2methoxy-6-naphthyl)butan-2-one (Nabumeton), a nonsteroidal antiinflammatory c o m p ~ u n d . ~
Results and Discussion Friedel-Crafts Alkylation of Phenol with 4-Hydroxybutan-%one(yKB). In the presence of Z F - m o n t or Fe3+-mont as an acid catalyst, 4-(4-hydroxyphenyl)butan-2-one (la) was obtained regioselectively in 35% GLC yield by alkylation of phenol, which served as the reactant as well as the solvent, with 4-hydroxybutan-2one ( y - K B ) a t 100 "C for 48 h (Scheme 1;Table 1,runs 1 and 3). The formation of a small amount of 4-phenoxybutan-2-one (3) was observed, but no ortho-alkylation products, 4-(2-hydroxyphenyl)butan-2-one(2a),or polyalkylated compounds were produced. The time course of this reaction is illustrated in Figure 1. (5) Badische Anilin- und Soda-Fabrik A.-G. Ger. Offen. Patent 2,145,308, 1973; Chem. Abstr. 1973, 78, 14756611. (6) Chisso Corp. Jpn. Kokai Tokkyo Koho 55,151,530, 1980; Chem. Abstr. 1981, 94, 15653213. (7) Donaldson, J. M. I.; McGovern, T. P.; Ladd, T. L., Jr. J . Econ. Entomol. 1990, 83, 1298; Chem. Abstr. 1991, 114, 2225y. (8) Olsson, 0. A. T.; Persson, N. H. A.; Svensson, L. A.; Waldeck, C. B.; Wetterlin, K. I. L. Eur. Patent 4,835,1979; Chem. Abstr. 1980,92, 76103f. (9)Goudie, A. C.; Gaster, L. M.; Lake, A. W.; Rose, C. J.;Freeman, Miller, D. J. Med. Chem. 1978,21, 1260. P. C.; Hughes, B. 0.;
0022-3263/94/1959-5901$04.50/00 1994 American Chemical Society
5902 J . Org. Chem., Vol. 59,No. 20, 1994
Tateiwa et al.
Scheme 1
g
L
o
H
or
(rW
g
,L (MW
c
M"+-mont
la, b
Table 1. Mn+-Mont-CatalyzedAlkylation of Phenol or Anisole with 4-Hydroxybutan-2-one( y - K B ) O
product and GLC yield (%)b
reactant phenol phenol phenol phenol phenol phenol phenol phenol phenol
10 11 12 13 14 15 16 17
anisole anisole anisole anisole anisole anisole anisole anisole
catalyst Z++-mont AP+-mont Fe3+-mont Znz+-mont Z++-montd
la 35 (28)" 31 35 4 16 34 27 11g 3
3 l(0.4)" 1
