A highly active catalyst system for the heteroarylation of acetone

Article abstract of DOI:10.1016/j.tetlet.2003.09.176

A highly active catalyst system for the heteroarylation of acetone has been identified. The coupling between the in situ generated tributyltin enolate of acetone and a variety of heteroaromatic bromides, chlorides, and triflates in the presence of this catalyst system provided arylacetones in good yields.

Full text of DOI:10.1016/j.tetlet.2003.09.176

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8869–8871
A highly active catalyst system for the heteroarylation of
acetone
Ping Liu,* Thomas J. Lanza, Jr., James P. Jewell, Carrie P. Jones, William K. Hagmann and
Linus S. Lin
Department of Medicinal Chemistry, Merck Research Laboratories, Merck & Co., Inc., PO Box 2000, Rahway, NJ 07065, USA
Received 4 September 2003; revised 18 September 2003; accepted 19 September 2003
Abstract—A highly active catalyst system for the heteroarylation of acetone has been identified. The coupling between the in situ
generated tributyltin enolate of acetone and a variety of heteroaromatic bromides, chlorides, and triflates in the presence of this
catalyst system provided arylacetones in good yields.
© 2003 Elsevier Ltd. All rights reserved.
The palladium-catalyzed coupling of aryl halides with
ketone enolates to form sp2-sp3 CꢀC bonds has
emerged as an extremely useful method for the synthe-
sis of a-aryl ketones.1 Buchwald, Hartwig, and others
have developed new catalyst systems that rendered this
reaction quite general for a wide range of carbonyl
substrates.2 Recently, the enantioselective construction
of quaternary centers by a-arylation of ketone enolates
has also been realized.3 Although a lot of advances
have been made in this area, to the best of our know-
ledge there has been only one report of a-arylation
reaction of acetone.4,5 Herein, we report a highly active
catalyst system for the palladium-catalyzed heteroaryla-
tion of acetone that provides an array of a-heteroaryl
acetones.
Table 1. Effects of phosphine on the palladium-catalyzed
heteroarylation of acetone
During our research we required a convenient prepara-
tion of a-heteroaryl acetones from commercially avail-
able heteroaromatic halides. The attempt to convert
5-bromopyridine-3-carbonitrile to the corresponding
methyl ketone using the literature procedure (PdCl2(o-
Tol3P)2 as the catalyst)4 did not provide synthetically
useful yields (<10%). The effect of phosphine ligands on
this palladium-catalyzed heteroarylation of acetone was
then investigated and the results are summarized in
Table 1. Little or no product in the presence of
triphenylphosphine and tri(o-tolyl)phosphine (entries 1
and 2) was observed; but modest yields of products in
the presence of DPPF and Xantphos (entries 3 and
4), and much improved yields in the presence of
* Corresponding author. Tel.: +1-732-594-0321; fax: +1-732-594-2210;
e-mail: ping liu2@merck.com
–
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.176

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P. Liu et al. / Tetrahedron Letters 44 (2003) 8869–8871
Table 2. Scope of the palladium-catalyzed heteroarylation of acetone
Buchwald’s o-biphenyl phosphines (entries 5–7) were
obtained.6 2-Dimethylamino-2%-diphenylphosphino-1,1%-
biphenyl (1) was found to be the best among the
phosphines surveyed thus far, which provided the
desired a-pyridyl acetone in 81% yield.
reaction is also quite general. Thiophenes, imidazoles,
pyridines, as well as other heterocycles are all suitable
substrates.9
This palladium-catalyzed arylation of acetone also
works quite well on phenyl halide substrates (Eqs. (1)
and (2)).6 Interestingly, with an electron-donating
group (CH3S) on the phenyl ring, biphenyl ligand 1
gave optimal results; while with an electron-withdraw-
ing group (CN) on the phenyl ring, biphenyl 2 gave the
optimal results.
A wide array of electronically and structurally diverse
heteroaromatic substrates were converted to the corre-
sponding methyl ketones using this catalyst system
(Table 2).7 This reaction tolerates electron-donating
groups on the aromatic ring (entry 1) as well as elec-
tron-withdrawing groups (entries 2 and 3). Yields for a
few substrates including 3-bromo-6-methoxy pyridine
(entry 6) remain low (<10%) for unknown reasons.
Heteroaromatic bromide, chloride, and triflate8 are all
suitable substrates for this synthetically useful transfor-
mation. In terms of the scope of the heterocycles, this
(1)

P. Liu et al. / Tetrahedron Letters 44 (2003) 8869–8871
8871
(d) Kawatsura, M.; Hartwig, J. F. J. Am. Chem. Soc. 1999,
121, 1473–1478; (e) Terao, Y.; Fukuoka, Y.; Satoh, T.;
Miura, M.; Nomura, M. Tetrahedron Lett. 2002, 43, 101–
104.
3. (a) Spielvogel, D. J.; Buchwald, S. L. J. Am. Chem. Soc.
2002, 124, 3500–3501; (b) Hamada, T.; Chieffi, A.;
Ahman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124,
1261–1268; (c) Ahman, J.; Wolfe, J. P.; Troutman, M. V.;
Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1998, 120,
1918–1919.
(2)
The mechanistic details of the arylation reaction are not
yet fully understood. Presumably, in a pathway similar
to that described by Buchwald and Palucki, a tin
enolate is generated in situ from tributyltin methoxide
and isopropenyl acetate, which undergoes transmetalla-
tion and coupling to the aryl partner to deliver the
a-aryl acetone.1a Since the reaction conditions are
essentially neutral, polyarylation and enolate mediated
condensation are not significant pathways. In compari-
son, both side reactions were observed in the presence
of a base.2a
4. Kosugi, M.; Suzuki, M.; Hagiwara, I.; Goto, K.; Saitoh,
K.; Migita, T. Chem. Lett. 1982, 939–940.
5. Hartwig observed the a-arylation of acetone during studies
of catalytic amination in acetone solvent but no yields
were reported, see: Culkin, D. A.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234–245. Direct heteroarylation of
acetone with the Buchwald protocol2a as well as the
Hartwig protocol2d was attempted, but in our hands none
of them gave the synthetically useful yield of the desired
products.
In summary, we have identified a highly active catalyst
system for heteroarylation of acetone that converts
various heteroaromatic bromides, chlorides, and trifl-
ates to the corresponding a-aryl acetones in good
yields.
6. The o-biphenyl phosphines were purchased from Strem
Chemical Co.
7. General experimental conditions: ArX (0.5 mmol),
Bu3SnOMe (173 mL, 0.6 mmol), isopropenyl acetate (66
mL, 0.6 mmol), and the biphenyl ligand (1, 2, or 3, 0.02
mmol), were dissolved in PhMe (1.5 mL), to which was
added Pd2(dba)3 (5 mg, 0.05 mmol). The reaction mixture
was heated at 100°C and monitored by TLC (2–14 h
depending on substrates). Then the reaction mixture was
subjected to column chromatography to obtain the a-aryl
acetones.
References
1. (a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997,
119, 11108–11109; (b) Hamann, B. C.; Hartwig, J. F. J.
Am. Chem. Soc. 1997, 119, 12382–12383; (c) Satoh, T.;
Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem.,
Int. Ed. Engl. 1997, 36, 1740–1742.
8. All the starting materials in Table 2 are commercially
available except for entry 7 where the triflate was prepared
from 5-fluoro-3-pyridinol.
9. For a new substrate, a quick screen of the catalyst using
biphenyl phosphines 1, 2, or 3 might be needed.
2. For leading references, see: (a) Fox, J. M.; Huang, X.;
Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122,
1360–1370; (b) Gaertzen, O.; Buchwald, S. L. J. Org.
Chem. 2002, 67, 465–475; (c) Lee, S.; Beare, N. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410–8411;