An aromatic glaser-hay reaction

Article abstract of DOI:10.1021/ja907479j

(Chemical Equation Presented) A general method for copper-catalyzed deprotonative dimerization of arenes by employing oxygen as the terminal oxidant has been developed. Electron-rich and electron-poor heterocycles as well as electron-poor arenes are react

Full text of DOI:10.1021/ja907479j

Published on Web 11/09/2009
An Aromatic Glaser-Hay Reaction
Hien-Quang Do and Olafs Daugulis*
Department of Chemistry, UniVersity of Houston, Houston, Texas 77204-5003
Received September 9, 2009; E-mail: olafs@uh.edu
Scheme 3. Phenol Byproduct Formation
Direct functionalization of C-H bonds allows synthetic schemes
to be shortened by allowing transformations to be carried out in
fewer steps compared with traditional cross-coupling methods.1 In
most cases ruthenium, rhodium, platinum, iridium, or palladium
catalysts are employed.1g It would be advantageous to employ less
exotic metals such as copper or iron for C-H bond functionaliza-
tion. Even though copper is one of the first transition metals shown
to promote functionalization of C-H bonds,2 methods that utilize
copper catalysis for conversion of C-H bonds to C-C bonds are
rare.3 A notable example of such catalysis is the Glaser-Hay alkyne
dimerization that has been known since 1869 (Scheme 1).4
Interestingly, oxygen is used as the terminal oxidant. Copper-
catalyzed conversion of C-H to C-heteroatom bonds has been
described, and in some cases oxygen was employed as the terminal
oxidant.5 Copper-promoted 2-arylpyridine dimerization has been
recently described.6
Phenol can be formed either by the direct reaction of ArLi
intermediate with oxygen or by reaction of a high-valent ArCu
with hydroxide derived from water.9 A metal that binds
hydroxide removing it from the reaction mixture is required to
avoid phenol formation. A less polarized C-metal bond in the
intermediate should also decrease the reactivity of arylmetal with
oxygen. Magnesium tert-butoxide was inefficient, and a stronger
base was required. Fortunately, hindered zinc and magnesium
amide bases that have been extensively investigated by Knochel
worked well.10 The exact composition of the base needs to be
optimized for each substrate. The synthesis of bases used in
dimerizations is presented in Scheme 4. The best results are
obtained by employing tetramethylpiperidides.
Scheme 1. Glaser-Hay Reaction
While palladium-catalyzed arene dimerization by employing
oxygen as the terminal oxidant is known, the corresponding copper-
catalyzed reaction has not been reported for substrates other than
phenols.7 We report here a deprotonative, copper catalyzed arene
dimerization by employing oxygen as the terminal oxidant.
We have recently demonstrated that acidic sp2 C-H bonds can
be arylated by aryl halides under copper catalysis (Scheme 2).8
The reaction involves generation of an organocopper intermediate
followed by the reaction with aryl iodide affording a biaryl product.
We speculated that, under an oxygen atmosphere, the intermediate
Scheme 4. Bases Employed in Dimerization
Scheme 2. Copper-Catalyzed Arylation of Arene C-H Bonds
The results of the dimerization reactions are shown in Table
1. Reactions are run in THF solvent under an oxygen atmosphere
at 0-50 °C, typically at RT, and 1-3 mol % of CuCl2 catalyst
is employed. Electron-rich heterocycles such as thiazole, ben-
zofuran, 2-chlorothiophene, N-butylimidazole, and triazole are
dimerized in good yields (entries 1-5). Electron-poor hetero-
cycles 2-methoxypyrazine and 3,5-dichloropyridine were also
dimerized successfully (entries 6 and 7). Polyfluorinated arenes
are reactive, and tetrafluoroanisole was dimerized in 91% yield
(entry 8). 1,3-Difluorobenzene afforded tetrafluorobiphenyl in
71% yield (entry 10). The reaction is tolerant to functional groups
such as amino (entry 9), nitro (entry 11), cyano (entry 12), and
ester (entry 13). For dimerization of 2-chlorothiophene and
tetrafluoroanisole, cheaper dicyclohexylamide bases can be
employed. In other cases, tetramethylpiperidides afford better
results.
arylcopper species is expected to form biaryl and a low-valent
copper complex. Regeneration of arylcopper by reaction of aryl-
metal with the low-valent Cu species would close the catalytic cycle.
The initial experiments focused on the use of tBuOLi base that
was earlier shown to be successful for copper-catalyzed deproto-
native arylation. However, major amounts of phenol byproduct were
formed upon reacting methoxytetrafluorobenzene with tBuOLi and
catalytic CuCl2 under an O2 atmosphere (Scheme 3). Formation of
phenol byproducts has been reported in the copper-catalyzed
reaction of arylboronic acids with various nucleophiles under
oxygen.9
Control experiments were run to determine if a trace of another
transition metal catalyzes the dimerization (Scheme 5).11 With
reagent grade or ultrapure CuCl2, similar results were obtained
showing that reactivity by contaminants is unlikely. If copper salt
was omitted, no product was obtained.
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17052 J. AM. CHEM. SOC. 2009, 131, 17052–17053
10.1021/ja907479j  2009 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Arene Dimerizationa
Scheme 5. Control Experiments
In conclusion, we have developed a general method for copper-
catalyzed, deprotonative dimerization of arenes by employing
oxygen as the terminal oxidant. Electron-rich and electron-poor
heterocycles as well as electron-poor arenes are reactive. The
method is tolerant to functionalities such as nitro, cyano, amino,
and ester groups.
Acknowledgment. We thank the Welch Foundation (Grant
No. E-1571), National Institute of General Medical Sciences
(Grant No. R01GM077635), A. P. Sloan Foundation, Camille
and Henry Dreyfus Foundation, and Norman Hackerman Ad-
vanced Research Program for supporting this research.
Supporting Information Available: Experimental procedures and
characterization data for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
(1) (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2008, 41,
1013. (b) Campeau, L.-C.; Fagnou, K. Chem. Commun. 2006, 1253. (c)
Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094. (d) Seregin, I. V.; Gevorgyan, V. Chem. Soc. ReV. 2007,
36, 1173. (e) Dick, A. R.; Sanford, M. S. Tetrahedron 2006, 62, 2439. (f)
Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074.
(g) Alberico, D.; Scott, M. E.; Lautens, M. Chem. ReV. 2007, 107, 174.
(2) Steinkopf, W.; Leitsmann, R.; Hofmann, K. H. Liebigs Ann. Chem. 1941,
546, 180.
(3) (a) Phipps, R. J.; Gaunt, M. J. Science 2009, 323, 1593. (b) Yoshizumi,
T.; Tsurugi, H.; Satoh, T.; Miura, M. Tetrahedron Lett. 2008, 49, 1598.
(c) Besselie`vre, F.; Piguel, S.; Mahuteau-Betzer, F.; Grierson, D. S. Org.
Lett. 2008, 10, 4029. (d) Ackermann, L.; Potukuchi, H. K.; Landsberg, D.;
Vicente, R. Org. Lett. 2008, 10, 3081. (e) Li, Z.; Li, C.-J. J. Am. Chem.
Soc. 2005, 127, 6968. (f) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org.
Lett. 2009, 11, 1511.
(4) (a) Glaser, C. Ber. Dtsch. Chem. Ges. 1869, 2, 422. (b) Hay, A. S. J. Org.
Chem. 1962, 27, 3320.
(5) (a) Basle, O.; Li, C.-J. Chem. Commun. 2009, 4124. (b) Chen, X.; Hao,
X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc. 2006, 128, 6790. (c)
Hamada, T.; Ye, X.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 833. (d)
Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A. Org. Lett. 2009, 11,
1607. (e) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932.
(6) Chen, X.; Dobereiner, G.; Hao, X.-S.; Giri, R.; Maugel, N.; Yu, J.-Q.
Tetrahedron 2009, 65, 3085.
(7) Pd-Catalyzed arene intermolecular homo/heterodimerization: (a) Okamoto,
M.; Yamaji, T. Chem. Lett. 2001, 212. (b) Brasche, G.; Garc´ıa-Fortanet,
J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207. (c) Hagelin, H.; Oslob, J. D.;
Åkermark, B. Chem.sEur. J. 1999, 5, 2413. Grignard homodimerization
under O2: (d) Cahiez, G.; Moyeux, A.; Buendia, J.; Duplais, C. J. Am.
Chem. Soc. 2007, 129, 13788. (e) Maji, M. S.; Pfeifer, T.; Studer, A. Angew.
Chem., Int. Ed. 2008, 47, 9547. Phenol dimerization under Cu/O2: (f)
Sakamoto, T.; Yonehara, H.; Pac, C. J. Org. Chem. 1994, 59, 6859. Enolate
homocoupling: (g) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem.
Soc. 2008, 130, 11546.
(8) (a) Do, H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2007, 129, 12404. (b) Do,
H.-Q.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 1128. (c) Do, H.-Q.;
Khan, R. M. K.; Daugulis, O. J. Am. Chem. Soc. 2008, 130, 15185.
(9) (a) King, A. E.; Brunold, T. C.; Stahl, S. S. J. Am. Chem. Soc. 2009, 131,
5044. (b) Lam, P. Y. S.; Bonne, D.; Vincent, G.; Clark, C. G.; Combs,
¨
A. P. Tetrahedron Lett. 2003, 44, 1691. (c) Demir, A. S.; Reis, O.;
Emruallahoglu, M. J. Org. Chem. 2003, 68, 10130.
(10) (a) Mosrin, M.; Knochel, P. Org. Lett. 2009, 11, 1837. (b) Dubbaka, S. R.;
Kienle, M.; Mayr, H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 9093.
(c) Wunderlich, S. H.; Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7685.
(11) Buchwald, S. L.; Bolm, C. Angew. Chem., Int. Ed. 2009, 48, 5586.
a Substrate (1 equiv), base (1.2-1.5 equiv). Yields are isolated yields.
See Supporting Information for details.
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