Journal of the American Chemical Society
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aStandard condition as table 1, entry 6, except for LiNCy2 used as
base instead of LiHMDS. Isolated yield.
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(1) For reviews, see (a) Miura, M.; Nomura, M. Direct Arylation via
Cleavage of Activated and Unactivated C-H Bonds. Top. Curr. Chem. 2002,
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Esters: Ideal New Methodology for Discovery Chemistry. Angew. Chem.,
Int. Ed. 2002, 41, 953. (c) Culkin, D. A.; Hartwig, J. F. Palladium-Catalyzed
α-Arylation of Carbonyl Compounds and Nitriles. Acc. Chem. Res. 2003,
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of Carbonyl and Related Molecules: Novel Trends in C-C Bond Formation
by C-H Bond Functionalization. Angew. Chem., Int. Ed. 2010, 49, 676. (e)
Bellina, F.; Rossi, R. Transition Metal-Catalyzed Direct Arylation of
Substrates with Activated sp3-Hybridized C-H Bonds and Some of Their
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11108. (g) Hamann, B. C.; Hartwig, J. F. Palladium-Catalyzed Direct α-
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Complex. J. Am. Chem. Soc. 1997, 119, 12382. (h) Satoh, T.; Kawamura,
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Diarylation Reactions of 2-Phenylphenols and Naphthols with Aryl
Halides. Angew. Chem., Int. Ed. 1997, 36, 1740.
(2) Selected examples on palladium-catalyzed α-arylation of esters: (a)
Carfagna, C.; Musco, A.; Sallese, G.; Santi, R.; Fiorani, T. Palladium-
Catalyzed Coupling Reactions of Aryl Triflates or Halides with Ketene
Trimethylsilyl Acetals. A New Route to Alkyl 2-Arylalkanoates. J. Org.
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Lee, S.; Beare, N. A.; Hartwig, J. F. Palladium-Catalyzed α-Arylation of
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Jørgensen, M.; Liu, X.; Wolkowski, J. P.; Hartwig, J. F. Efficient Synthesis
of α-Aryl Esters by Room-Temperature Palladium-Catalyzed Coupling of
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Liu, X.; Hartwig, J. F. Palladium-Catalyzed Arylation of Trimethylsilyl
Enolates of Esters and Imides. High Functional Group Tolerance and
Stereoselective Synthesis of α-Aryl Carboxylic Acid. J. Am. Chem. Soc.
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Catalyzed α-Arylation of Zinc Enolates of Esters: Reaction Conditions and
Substrate Scope. J. Org. Chem. 2013, 78, 8250. (g) Martin, A.; Vors, J.-P.;
Baudoin, O. Synthesis of Conformationally Constrained Esters and Amines
by Pd-Catalyzed α‑Arylation of Hindered Substrates. ACS Catal. 2016, 6,
3941.
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Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. Palladium-Catalyzed
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Intramolecular Amide Arylation to the Synthesis of Oxindoles. J. Org.
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Catalyzed Intermolecular α-Arylation of Zinc Amide Enolates under Mild
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Drinkel, E.; Grant, S.; Linden, A.; Cavallo, L.; Dorta, R. Synthesis of
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(4) (a) Peter J. Harrington, P.; Lodewijk, E. Twenty Years of Naproxen
hrer, A.; Beller, M. An Efficient and Practical Sequential One-Pot Synthesis
of Suprofen, Ketoprofen and Other 2-Arylpropionic Acids. Adv. Synth.
McKillop, A. Thallium in Organic Synthesis. 65. A Novel Synthesis of
Naruto, S.; Wachi, K.; Tanaka, S.; Iizuka, Y.; Misaka, E. J. Synthesis and
Antiinflammatory Activity of [(Cycloalky lmethyl)phenyl]acetic Acids and
Related Compounds. J. Med. Chem. 1984, 27, 212. (e) Imai, M.; Ishikura,
M. Preparation of Pranoprofen. Jpn. Kokai Tokkyo Koho, 62258382, 1987.
(f) Takeda, H.; Morifuji, N.; Takahashi, T. Preparation of 2-(10,11-
The approach to the α-arylation of acids also was applicable to
the α-arylation of amides containing NH-bonds with minor
modification of the base. The reaction of N-benzyl butyramide (6a)
was chosen as the model substrate. Under the standard conditions
described for the reactions of carboxylic acids (vide supra), only
14% of α-aryl amide 7a formed from amide 6a (See SI for details).
Evaluation of the effect of temperatures and base showed that 7a
formed from 6a in 88% yield with LiNCy2 as the base instead of
LiHMDS.
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The scope of the α-arylation of secondary amides is illustrated
by the examples in Table 5. Both electron-poor (7b-7c) and
electron-rich aryl bromides (7d-7e) reacted in high yield (75-90%).
Heteroaryl bromides, such as a bromo pyridine, benzothiophene
and benzothiazole reacted in a good 70%, 79% and 89% yield,
respectively (7f-7h). Like the α-arylation of carboxylic acids, the
α-arylation of amides occurred with aryl bromides containing base-
sensitive functional groups, such as acyl, alkoxycarbonyl and nitro
groups, to give the product in 73-91% yield (7i-7l).
Studies on the scope of amides showed that a range of secondary
amides underwent the α-arylation reaction. Amides derived from
alkyl-, alkoxy- or aryl-substituted carboxylic acids and alkyl or aryl
amines reacted to give the coupled product in 70-93% yield (7m-
7n, 7p-7q). Reaction of an amide containing an α-branched amino
group occurred in a moderate 55% yield (7o). In this case, the
installation of the traceless protection occurred in approximately
84% yield, which is lower than for the less hindered amides,
presumably due to the steric properties of the amino group. Like
carboxylic acids, amides containing an N-H bonds and two alkyl
groups on the alpha carbon did not react.
In summary, we have designed and implemented a strategy for
the α-arylation of free carboxylic acids and secondary amides
involving a traceless protecting strategy with a broad range of aryl
and heteroaryl bromides in up to 99% yield. This coupling tolerates
aryl bromides containing base-sensitive groups, such as acyl,
alkoxycarbonyl, nitro, cyano and even hydroxyl groups. The value
of this coupling was further illustrated by one-step syntheses of the
five commercial profen drugs Ibuprofen, Naproxen, Flurbiprofen,
Fenoprofen and Ketoprofen in over 80% yield. Gram-scale
preparations of a group of arylated carboxylic acids, including
Naproxen and Flurbiprofen with 1-2 mol % palladium loading were
achieved in one step in 72-87% yield. We hope that this method
will be widely used for the direct synthesis of both synthetic
intermediates and final products.
ASSOCIATED CONTENT
Supporting Information
This material is available free of charge via the Internet at
Experimental details and procedures, spectra for all unknown
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*jhartwig@berkeley.edu
Dihydro-10-oxodibenzo[b,f]thiepin-2-yl)propionic
Acid
as
An
Notes
Inflammation Inhibitor and Analgesic. Jpn. Kokai Tokkyo Koho, 62292780,
1987.
The authors declare no competing financial interest.
(5) (a) Bala, T.; Prasad, B. L. V.; Sastry, M.; Kahaly, M. U.; Waghmare,
U. V. Interaction of Different Metal Ions with Carboxylic Acid Group: a
Quantitative Study. J. Phys. Chem. A 2007, 111, 6183. (b) Pichette Drapeua,
M.; Gooßen, L. J. Carboxylic Acids as Directing Groups for C−H Bond
Functionalization. Chem. Eur. J. 2016, 22, 18654. (c) Sigel, H.; Martin, R.
ACKNOWLEDGMENT
We thank Dow Chemicals for support of this work.
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