Unsymmetrical Diaryl Ketones from Arenes

Full text of DOI:10.1021/jo991055q

254
J . Org. Chem. 2000, 65, 254-255
bromobenzene, the chlorocarbonylation required longer
Un sym m etr ica l Dia r yl Keton es fr om
Ar en es
time and higher temperatures. The optimized conditions
are summarized in Table 1. In each case, 1.2 equiv of
oxalyl chloride were employed. It should be emphasized
that the yields reported are for reactions using 1.0 equiv
of each arene, not the severalfold excess of one or the
other often previously employed.8
Douglass F. Taber*
Department of Chemistry and Biochemistry, University of
Delaware, Newark, Delaware 19716
We have developed what appears to be an efficient
approach to both symmetrical and unsymmetrical diaryl
ketones. It is especially noteworthy that the conditions
of the second Friedel-Crafts reaction are mild enough
that even an o-methoxy ketone, 17, often demethylated
under Friedel-Crafts conditions,10 was prepared in
satisfactory yield.
Maya R. Sethuraman
Stine-Haskell Research Center, DuPont Agricultural
Products, Newark, Delaware 19714
Received J uly 1, 1999
Diaryl ketones serve as valuable intermediates in the
synthesis of biologically active compounds. The diaryl-
methane residue has been seen as a component of such
medicinal agents as tolcapone, an inhibitor of catechola-
mine-O-methyl transferase,1 and the GABA-delivering
agent progabide.2 Usually, such diaryl ketones have been
prepared by the aroylation of aryl organometallics (e.g.,
X ) B(OH)2, Y ) (CdO)PdI).3-5 We report here what
appears to be a general procedure for a much less
expensive approach, the coupling of two arenes (X, Y )
H) to make the diaryl ketone 3.
Exp er im en ta l Section
1
Gen er a l P r oced u r es. H NMR (at 300 MHz) and 13C NMR
(at 75 MHz) spectra were obtained as solutions in deuteriochlo-
roform (CDCl3). The infrared (IR) spectra were determined neat
or as KBr pellets using a FTIR. Rf values indicated refer to thin-
layer chromatography (TLC) on 5.0 × 10 cm, 250 µm analytical
plates coated with silica gel 60 F254 developed in the solvent
system indicated. Elemental analysis was carried out by Quan-
titative Technologies Inc., P.O. Box 470, Salem Industrial Park,
Bldg 5, Whitehouse, NJ 08888. Column chromatography was
carried out on an Isco mplc using silica gel 60 particle size
0.015-0.040 µm. The solvent mixtures used are volume/volume
mixtures. All reactions were carried out under a flow of nitrogen.
Dichloromethane was from EM Science. All reaction mixtures
were stirred magnetically, unless otherwise noted. The times
and temperatures for the chlorocarbonylations and for the
subsequent acylations are summarized in Table 1.
P r ep a r a tion of Dia r yl Keton es. Keton e 6. In a 100 mL
side arm round-bottom flask, oxalyl chloride (1.05 mL, 12 mmol)
was added dropwise over 5 min to a solution of p-xylene (1.23
mL, 10 mmol) in dichloromethane (50 mL) at 5 °C. Aluminum
chloride (1.33 g, 10 mmol) was added portionwise over 5 min to
give a yellow suspension. The reaction mixture was warmed to
room temperature and stirred for 1 h, during which time
dissolution of the solid and gas evolution were observed. A second
equivalent of p-xylene (1.23 mL, 10 mmol) was added dropwise
over 5 min, and the reaction mixture was allowed to stir for 13
h at room temperature. The reaction mixture was chilled in an
ice/water bath, and 25 mL of H2O was added dropwise over 10
min. The layers were separated, and the aqueous layer was
extracted twice with CH2Cl2. The combined organic extracts were
dried over Na2SO4 and concentrated. The residue was chromato-
graphed to give 611 as a clear oil (1.84 g, 77% yield): TLC Rf
(10% ethyl acetate/hexanes) ) 0.49; 1H NMR δ 7.21-7.14 (m,
4H), 7.11 (s, 2H), 2.37 (s, 6H), 2.29 (s, 6H); 13C NMR δ (CH3)
19.7, 18.5; (CH) 130.3, 129.4, 129.1; (C) 199.7, 137.6, 133.5, 133.4;
IR 1665 cm-1. Anal. Calcd for C17H18O: C, 85.67; H, 7.61.
Found: C, 85.34; H, 7.28.
The AlCl3-mediated chlorocarbonylation of arenes (4
f 5) has been known for many years.6,7 There were a
few reports7c,8,9 of the in situ coupling of the intermediate
complexed aroyl chloride with additional arene to prepare
the symmetrical benzophenone (e.g., 4 f 6). We have
optimized this procedure (Table 1, entry 1), and have
shown that it is easily extended to unsymmetrical ben-
zophenones (Table 1, entries 2-6).
Keton e 8: 1.78 g, 74% yield; mp 88-89 °C (lit.12 mp 88 °C);
As this procedure was optimized, it was found that the
best results were obtained when the less activated
substrate was used in the initial acylation and the more
activated arene was used as the subsequent acceptor.
With the less activated substrates, such as chloro- and
1
TLC Rf (10% ethyl acetate/hexanes) ) 0.21; H NMR δ 7.79 (d,
2H, J ) 8.9 Hz), 7.15 (m, 2H), 7.08 (s, 1H), 6.91 (d, 2H, J ) 8.9
(7) (a) Olah, G. Friedel-Crafts and Related Reactions; Interscience
Publishers: New York, 1964; Vol. III, p 1259. (b) Neubert, M. E.; Fishel,
D. L. Mol Cryst. Liq. Cryst. 1979, 53, 101. (c) Osman, M. Helv. Chim.
Acta 1982, 65, 2448.
(8) Zimmerman, H. E.; Paskovich, D. H. J . Am. Chem. Soc. 1964,
86, 2149.
(9) For intramolecular coupling of diarenes with oxalyl chloride to
prepare cyclized diaryl ketones, see: (a) Granoth, I.; Pownall, H. J . J .
Org. Chem. 1975, 40, 2088. (b) Heitzler, F. R.; Hopf, H.; J ones, P. G.;
Bubenitschek, P.; Lehne, V. J . Org. Chem. 1993, 58, 2781.
(10) Ucar, H.; Van derpoorten, K.; Poupaert, J . H. Heterocycles 1997,
45, 805.
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10.1021/jo991055q CCC: $19.00 © 2000 American Chemical Society
Published on Web 12/16/1999

Notes
J . Org. Chem., Vol. 65, No. 1, 2000 255
Ta ble 1. P r ep a r a tion of Dia r yl Keton es
a
b
The time and temperature for the initial chlorocarbonylation. The time and temperature for the acylation. c The yield given is for
a reaction using 1.5 equiv of oxalyl chloride.
(d, 2H, J ) 8.5 Hz), 7.41 (d, 2H, J ) 8.5 Hz), 6.90 (s, 2H), 2.33
Hz), 3.86 (s, 3H), 2.32 (s, 3H), 2.23 (s, 3H); 13C NMR δ (CH3)
(s, 3H), 2.07 (s, 6H); 13C NMR δ (CH3) 19.6, 17.8; (CH) 129.2,
54.0, 19.4, 17.8; (CH) 133.5, 130.9, 129.2, 129.0, 112.2; (C) 196.2,
127.6, 126.9; (C) 197.9, 138.5, 137.2, 134.8, 134.2, 132.6; IR 1671
162.2, 133.3, 131.4, 129.1, 126.8; IR 1657 cm-1. Anal. Calcd for
cm-1
.
C
16H16O2: C, 79.97; H, 6.71. Found: C, 79.84; H, 6.78.
Keton e 10: 1.72 g, 68% yield; mp 74-75 °C (lit.13 mp 77-78
Keton e 17: 1.65 g, 54% yield; mp 66-69 °C; TLC Rf (10%
ethyl acetate/hexanes) 0.21; 1H NMR δ 7.67 (d, 2H, J ) 8.6 Hz),
7.57 (d, 2H, J ) 8.6 Hz), 7.25 (dd, 1H, J ) 8.44, 2.06 Hz), 7.17
(d, 1H, J ) 2.06 Hz), 6.89 (d, 1H, J ) 8.44 Hz); 13C NMR δ (CH3)
54.2, 18.8; (CH) 131.2, 130.0, 129.7, 128.5, 110.0; (C) 194.1, 153.8,
°C); TLC Rf (10% ethyl acetate/hexanes) 0.47; 1H NMR δ 7.24-
7.15 (m, 3H), 6.86 (m, 2H), 2.60 (s, 6H), 2.32 (s, 3H), 2.23 (s,
3H), 2.09 (s, 3H); 13C NMR δ (CH3) 19.8, 19.7, 19.3, 18.0; (CH)
131.5, 130.5, 130.2, 127.0; (C) 201.3, 137.1, 136.9, 135.6, 135.2,
133.9, 132.9; IR 1669 cm-1. Anal. Calcd for C18H20O: C, 85.67;
H, 7.99. Found: C, 85.39; H, 7.97.
135.3, 128.6, 126.5, 126.4; IR 1666 cm-1
.
Ack n ow led gm en t. We thank Bruce Finkelstein for
helpful discussions and Gina Blankenship for obtaining
the NMR spectra. We also thank the reviewers for their
helpful suggestions.
Keton e 12: 1.53 g, 72% yield, using 1.5 equiv of oxalyl
chloride; mp 62-64 °C (lit.14 mp 57 °C); TLC Rf (10% ethyl
acetate/hexanes) ) 0.16; 1H NMR δ 7.85 (d, 2H, J ) 8.9 Hz),
7.82 (m, 2H), 7.58-7.47 (m, 3H), 6.98 (d, 2H, J ) 8.9 Hz), 3.89
(s, 3H); 13C NMR δ (CH3) 54.0; (CH) 131.0, 130.4, 128.2, 126.7,
112.0; (C) 194.0, 161.7, 136.8, 128.6; IR 1659 cm-1. Anal. Calcd
for C14H12O2: C, 79.23; H, 5.70. Found: C, 78.99; H, 5.85.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
of 6, 8, 10, 12, 14, and 17. This material is available free of
charge via the Internet at http://pubs.acs.org.
Keton e 14: 1.80 g, 70% yield; mp 66-68 °C (lit.15 mp 68-69
°C; TLC Rf (10% ethyl acetate/hexanes) 0.40; 1H NMR δ 7.75
J O991055Q
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