Copper-catalyzed arylation of heterocycle C-H bonds

Article abstract of DOI:10.1021/ja075802+

A new method for the direct, copper-catalyzed arylation of heterocycle C-H bonds by aryl halides has been developed. In addition to electron-rich five-membered heterocycles, electron-poor pyridine oxides can also be arylated. The best results are obtained by using a combination of lithium tert-butoxide base, aryl iodide coupling partner, and copper iodide catalyst. Copyright

Full text of DOI:10.1021/ja075802+

Published on Web 09/22/2007
Copper-Catalyzed Arylation of Heterocycle C-H Bonds
Hien-Quang Do and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
Received August 2, 2007; E-mail: olafs@uh.edu
Table 1. Optimization of the Arylation Conditionsa
Because many pharmaceuticals contain heterocycle-aryl linkages,
arylation of heterocycles has received significant attention in the
recent years.1 The shortest and most efficient routes to these
compounds involve direct functionalization of heterocycle C-H
bonds.2 In general, most efforts in cross-coupling methodologies
currently are geared toward the replacement of aryl iodides with
cheaper aryl chlorides.3 However, for realistic catalyst loadings it
is more cost-efficient to replace the expensive transition metal
catalyst, usually palladium or rhodium, with a cheaper one.4 Use
of copper catalysts for the amination and Stille- or Suzuki-type
couplings has been demonstrated.5 Copper-catalyzed direct
heterocycle C-H arylation reactions are unknown.6,7 We report
here a general method for the copper-catalyzed heterocycle
arylation by aryl iodides. In addition to electron-rich five-
membered heterocycles, electron-deficient pyridine oxides can also
be arylated. Preliminary mechanistic studies of the arylation are
also reported.
entry
base
PhX
yield, %
1
KOtBu
KOtBu
KOtBu
KOtBu
LiOtBu
LiOtBu
PhF or PhOTs
no arylation
40
51
61
no arylation
93
2b
3
PhCl
PhBr
PhI
4
5
6
PhCl, PhBr, or PhOTs
PhI
a Substrate (1 equiv), aryl halide (3 equiv), base (2 equiv). Yields are
isolated yields. b PhCl (4 equiv), base (3 equiv).
Table 2. Arylation Scope with Respect to Aryl Iodidesa
Our attention was drawn to the observation that copper salts can
affect the regioselectivity of palladium-catalyzed electron-rich
heterocycle arylation. Pioneering work in this field was performed
by Miura and co-workers who demonstrated that N-methylimidazole
is arylated in the 2-position if a combination of catalytic Pd and
stoichiometric Cu is used, and in the 5-position if catalytic Pd is
used.7 This effect may arise from the involvement of organocopper
intermediates in the reaction. If the presumed intermediate could
be generated without a palladium cocatalyst, a cheap and efficient
method for the heterocycle arylation would be achieved. The
organocopper species could be generated by using a stronger
base instead of the commonly used cesium or potassium
carbonates. Several amide and alkoxide bases were screened in the
phenylation of benzoxazole. The best results were obtained by using
lithium or potassium tert-butoxides (Table 1), with LiOtBu/aryl
iodide combination affording the highest yields. Equally good
results can be obtained in DMF, DMA, DMPU, or toluene-DMF
mixtures. Commercial, non-anhydrous DMF can be used in all
reactions.
The scope with respect to aryl iodide is presented in Table 2.
The arylation of benzoxazole shows that electron-deficient (entries
1 and 2) as well as electron-rich (entries 3-7) aryl iodides are
reactive. Substantial steric hindrance is tolerated on the aryl iodide
(entries 5 and 6). Heteroaryl iodides are also reactive (entry 8).
Yields are uniformly excellent, with the exception of mesityl iodide
(entry 6).
The scope with respect to the heterocycles is presented in Table
3. Oxazole can be monoarylated in 59% yield, with 7% of the
diarylated product isolated (entry 1). 1,3-Thiazole is diarylated in
59% yield (entry 2). 4,5-Dimethylthiazole and benzothiazole are
also reactive (entries 3 and 4). 1,2,4-Triazole, benzimidazole, and
caffeine are arylated in good yields (entries 5-7). Interestingly,
electron-deficient 2-phenylpyridine oxide is arylated in the
6-position in a 66% yield.8 2-Phenylpyridine and N-methylindole
were found to be unreactive under these reaction conditions. In
a Substrate (1 equiv), aryl iodide (3 equiv), base (2 equiv). Yields are
isolated yields.
most cases, LiOtBu affords the best yields. However, in the case
of imidazole or triazole derivatives (entries 5-7) use of KOtBu or
KOtBu/LiOtBu mixture as a base afforded higher yields.
9
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10.1021/ja075802+ CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 3. Arylation Scope with Respect to Heterocyclesa
KOtBu base; PhI) was obtained if CuI was omitted from the reaction
of Scheme 1.
In conclusion, a new method for the direct, copper-catalyzed
arylation of heterocycle C-H bonds by aryl halides has been
developed. In addition to electron-rich five-membered heterocycles,
electron-poor pyridine oxides can also be arylated. The best results
are obtained by using a combination of lithium t-butoxide base and
aryl iodide coupling partner. The generality and ready availability
of stating materials should make this method useful for organic
synthesis.
Acknowledgment. We thank the Welch Foundation (Grant No.
E-1571) and the National Institute of General Medical Sciences
(Grant No. R01GM077635) for supporting this research.
Supporting Information Available: Detailed experimental pro-
cedures and characterization data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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a Substrate (1 equiv), iodobenzene (3 equiv), base (2 equiv). Yields are
isolated yields. b 2,5-Diphenyloxazole also isolated (7%). c 2-Phenylthiazole
d
also isolated (37%). KOtBu base. e LiOtBu/KOtBu base (1:1).
Scheme 1. Mechanistic Investigations
(3) Review: Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
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equiv of aryl halide and 5 mol % of palladium acetate or 10 mol % of
copper iodide catalyst. The cost of the palladium-catalyzed reaction is
$11 (chlorobenzene) + $403 (Pd(OAc)2). The cost of the copper-catalyzed
reaction is $150 (iodobenzene) + $3 (CuI; Aldrich prices). An expensive
ligand is usually used for palladium-catalyzed reactions.
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We have carried out preliminary mechanistic investigations of
the coupling process (Scheme 1). The arylation employing KOtBu
base is successful for aryl iodides, bromides, and chlorides, although
the yields are moderate. If 4,5-dimethylthiazole is reacted with
iodo- or bromobenzene-d5 using KOtBu as a base (Scheme 1A),
tetradeuterated product 1-1 is obtained. A single hydrogen is
introduced at the ortho position of the phenyl group. This
observation can be explained by assuming that the reaction proceeds
via a copper-assisted benzyne-type mechanism.9,10 No H-D
exchange is observed if pentadeuterated 1-2 is submitted to the
reaction conditions of Scheme 1A. If LiOtBu is used as a base,
hydrogen incorporation is not observed (Scheme 1B, 1-2).
Involvement of benzyne intermediate is unlikely in this case.
Presumably, heterocycle deprotonation by tert-butoxide (perhaps
assisted by copper precoordination to the heterocycle)2h followed
by lithium-copper transmetallation and reaction of the organo-
copper species with aryl iodide leads to the arylation product. No
product (LiOtBu base; PhI) or only a trace of the product (<2%;
(7) Heterocycle arylation under Pd, by Pd/Cu catalysis, or by using several
equivalents of Cu: Pivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.;
Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467.
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S.; Fagnou, K. J. Am. Chem. Soc. 2005, 127, 18020.
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701. Benzyne reactions with Pd species: (d) Liu, Z.; Larock, R. C. J.
Org. Chem. 2007, 72, 223.
(10) Arylation of 4,5-dimethylthiazole by p-tolyl bromide under conditions of
Scheme 1A affords a mixture of m-tolyl- and p-tolylderivatives. See
Supporting Information for details.
JA075802+
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