should add to chloroacetyl chloride in a copper-catalyzed
reaction.7 Herein, we report the direct synthesis of a variety
of substituted acetophenones in one step from the corre-
sponding aryl precursor.
Table 1. Acylation with Chloroacetyl Chloride
It was found that ortholithiation of 1,2-difluorobenzene
was possible using n-hexyllithium at -65 °C; however, rapid
decomposition was observed at temperatures above -50 °C.11
Direct acylation of the aryllithium species at -65 °C did
not yield any significant amount of product, and reverse
addition was unfeasible due to warming during transfer.
Transmetalation using zinc chloride did proceed cleanly
at -65 °C, and the corresponding aryl zinc species was found
to be stable even at room temperature. When treated directly
with chloroacetyl chloride, no reaction was observed due to
the weak nucleophilic character of the aryl zinc moiety, and
upon warming, extensive decomposition occurred with
minimal product formation. Catalytic cuprous(I) cyanide (10
mol %) was added in hopes of activating the acyl chloride,
and indeed, this successfully effected clean acylation. Further
optimization revealed the same loading of CuCl as a suitable
substitute for CuCN.12
This general procedure was applied to a variety of
substrates (Table 1). Typical assay yields were ∼70%, and
most of the products could be isolated by crystallization from
heptane at -30 °C without chromatography.13
It is interesting to note the positional contrast of several
of these products relative to their Friedel-Crafts product.
In the case of 1a, the 4-fluoro acetophenone is the product
of Friedel-Crafts acylation,14 as opposed to the 2-fluoro
isomer 2a. Similarly, as previously noted, 1b yields the 3,4-
difluoro acetophenone instead of the desired 2,3-difluoro
(2) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260-
11261.
(3) (a) Tillyer, R.; Frey, L. F.; Tschaen, D. M.; Dolling, U. H. Synlett
1996, 225-226. (b) Peese, K. M.; Gin, D. Y. J. Am. Chem. Soc. 2006,
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(4) (a) Gooâen, L. J.; Winkel, L.; Do¨hring, A.; Ghosh, K.; Paetzold, J.
Synlett 2002, 1237-1240. (b) Haddach, M.; McCarthy, J. R. Tetrahedron
Lett. 1999, 40, 3109-3112. (c) Bumagin, N. A.; Korolev, D. N. Tetrahedron
Lett. 1999, 40, 3057-3060. (d) Urawa, Y.; Ogura, K. Tetrahedron Lett.
2003, 44, 271-273. (e) Chen, H.; Den, M. Org. Lett. 2000, 2, 1649-1651.
(5) (a) Faul, M. M.; Winneroski, L. L. Tetrahedron Lett. 1997, 38, 4749-
4752. (b) Grey, R. A. J. Org. Chem. 1984, 49, 2288-2289.
(6) (a) Scheiper, B.; Bonnekessel, M.; Krause, H.; Fu¨rstner, A. J. Org.
Chem. 2004, 69, 3943-3949. (b) Fiandanese, V.; Marchese, G.; Martina,
V.; Ronzini, L. Tetrahedron Lett. 1984, 25, 4805-4808.
(7) (a) Sapountzis, I.; Dube, H.; Lewis, R.; Gommermann, N.; Knochel,
P. J. Org. Chem. 2005, 70, 2445-2454. (b) Dieter, R. K.; Sharma, R. R.;
Yu, H.; Gore, V. K. Tetrahedron 2003, 59, 1083-1094.
(8) Fillon, H.; Gosmini, C.; Pe´richon, J. Tetrahedron 2003, 59, 8199-
8202.
a HPLC assay yield based on comparison to purified reference standard.
(9) Frost, C. G.; Wadsworth, K. J. Chem. Commun. 2001, 2316-2317.
(10) Hirao, T.; Misu, D.; Yao, K.; Agawa, T. Tetrahedron Lett. 1986,
27, 929-932.
b sec-Butyllithium substituted for n-hexyllithium.
(11) Thermal stability of 2,5-difluorophenyl lithium: Scott, J. P.; Brewer,
S. E.; Davies, A. J.; Brands, K. M. J. Synlett 2004, 1646-1648.
(12) Control experiments indicate that stoichiometric CuI can be
substituted for ZnCl2 and 10 mol % of CuCl. For ease of processing, workup,
waste disposal, and reaction robustness, especially on a large scale, we have
developed this methodology using stoichiometric zinc and catalytic copper.
Further experiments will be required to determine if the CuCl is activating
the acid chloride or if transmetalation from zinc to copper is in fact taking
place. Substituting catalytic CuI for ZnCl2 yields almost no product by
HPLC.
(13) The use of commercially available PhZnBr as well as transmetalation
with PhMgCl/ZnCl2 gave the product in 40-45% assay yield.
(14) Joshi, K. C.; Dubey, K.; Dandia, A. Heterocycles 1981, 16, 71-
76.
isomer. The acylation of 1c using aluminum chloride has
been shown to form the 2,4-difluoro isomer.15 Attempts at
forming 2,6-difluoro acetophenones such as 2c have all
involved multistep sequences,16 whereas our method can
accomplish this in one step.
(15) (a) Konovalov, V. V.; Laev, S. S.; Beregovaya, I. V.; Shchegoleva,
L. N.; Shteingarts, V. D.; Tsvetkov, Y. D.; Bilkis, I. J. Phys. Chem. A 2000,
104, 352-361. (b) Belsham, M. G.; Muir, A. R.; Kinns, M.; Phillips, L.;
Twanmoh, L.-M. J. Chem. Soc., Perkin Trans. 2 1974, 119-125.
668
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