are well-known to share the common deficiencies of Ullmann
chemistry (e.g., stoichiometric amount of Cu complex, high
reaction temperature, polar solvent (e.g., DMSO, pyridine),
poor reproducibility, good yields are usually obtained for
highly activated aryl halides).11 An improved process was
subsequently reported in 1993 employing a catalytic amount
of CuI and K2CO3 in DMSO at 120 °C for the R-arylation
of activated methylene compounds.12 Under these reaction
conditions, the products were readily decomposed, and thus
good yields were only obtained in particular cases. A milder
protocol in accessing a variety of arylated malonates from
aryl iodides was reported by Buchwald and Hennessy in
2002.9a In the presence of 5 mol % of CuI and 10 mol % of
2-phenylphenol monodentate ligand at 70 °C, a number of
corresponding arylated malonates were afforded in good
yield. This investigation indicated the importance of the
supporting ligand in achieving milder reaction conditions.
In 2005, Ma and co-workers reported a catalytic system with
20 mol % of CuI and 40 mol % of L-proline ligand, which
could be efficiently applied in the coupling of aryl halides
with diethyl malonate in DMSO solvent.9e Although im-
provements have been made, a general Ullmann protocol for
C-C bond construction, which can be carried out at ambient
temperature with relatively nontoxic solvent and low catalyst
loading, remains challenging. We were intrigued by the
notable success in the recent Cu-catalyzed C-N coupling
reaction that can be efficiently performed at room temper-
ature.13 Herein, we report our explicit use of supporting
ligand in achieveing an unexplored room-temperature Ull-
mann-type C-C bond formation.
We initially tested the feasibility of using monodentate
oxygen donor ligands for the arylation of diethyl malonate
(Table 1). However, significant catalyst deactivation was
Table 1. An Investigation on the Ligand Effect in
Cu-Catalyzed Arylation of Malonatea
(6) For recent selected references, see: (a) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. (b) Ma,
D.; Xia, C. Org. Lett. 2001, 3, 2583. (c) Gujadhur, R. K.; Bates, C. G.;
Venkataraman, D. Org. Lett. 2001, 3, 4315. (d) Antilla, J. C.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. (e) Kwong, F. Y.;
Klapars, A.; Buchwald, S. L. Org. Lett. 2002, 4, 581. (f) Kwong, F. Y.;
Buchwald, S. L. Org. Lett. 2003, 5, 793. (g) Shen, R.; Lin, C. T.; Bowman,
E. J.; Bowman, B. J.; Porco, J. A., Jr. J. Am. Chem. Soc. 2003, 125, 7889.
(h) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J.
2004, 10, 5607. (i) Ma, D.; Cai, Q. Synlett 2004, 128. (j) Pan, X.; Cai, Q.;
Ma, D. Org. Lett. 2004, 6, 1809. (k) Zhu, W.; Ma, D. Chem. Commun.
2004, 888. (l) Deng, W.; Wang, Y.; Zou, W.; Liu, L.; Guo, Q. Tetrahedron
Lett. 2004, 45, 2311. (m) Zhang, H.; Cai, Q.; Ma, D. J. Org. Chem. 2005,
70, 5164. (n) Altman, R. A.; Buchwald, S. L. Org. Lett. 2007, 9, 643. (o)
Rivero, M. R.; Buchwald, S. L. Org. Lett. 2007, 9, 973.
(7) For recent selected references, see: (a) Buck, E.; Song, Z. J.; Tschaen,
D.; Dormer, P. G.; Volante, R. P.; Reider, P. J. Org. Lett. 2002, 4, 1623.
(b) Ma, D.; Cai, Q. Org. Lett. 2003, 5, 3799. (c) Nordmann, G.; Buchwald,
S. L. J. Am. Chem. Soc. 2003, 125, 4978. (d) Wan, Z.; Jones, C. D.; Koenig,
T. M.; Pu, Y. J.; Mitchell, D. Tetrahedron Lett. 2003, 44, 8257. (e) Cristau,
H.-J.; Cellier, P. P.; Hamada, S.; Spindler, J.-F.; Taillefer, M. Org. Lett.
2004, 6, 913. (f) Ma, D.; Cai, Q.; Xie, X. Synlett 2005, 1767. (g) Nonappa,
P. D.; Pandurangan, K.; Maitra, U.; Wailes, S. Org. Lett. 2007, 9, ASAP.
(8) For recent selected references, see: (a) Kwong, F. Y.; Buchwald, S.
L. Org. Lett. 2002, 4, 3517. (b) Baskin, J. M.; Wang, Z. Org. Lett. 2002,
4, 4423. (c) Bates, C. G.; Saejueng, P.; Doherty, M. Q.; Venkataraman, D.
Org. Lett. 2004, 6, 5005. (d) Deng, W.; Zou, Y.; Wang, Y. F.; Liu, F.;
Guo, Q. X. Synlett 2004, 1254. (e) Zhu, W.; Ma, D. J. Org. Chem. 2005,
70, 2696.
(9) (a) Hennessy, E. J.; Buchwald, S. L. Org. Lett. 2002, 4, 269. (b)
Zanon, J.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 2890.
(c) Ma, D.; Liu, F. Chem. Commun. 2004, 1934. (d) Bates, C. G.; Saejueng,
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D. Org. Lett. 2005, 7, 4693.
(10) (a) Hurtley, W. R. H. J. Chem. Soc. 1929, 1870. For canonical
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(11) (a) Setsune, J.; Matsukawa, K.; Wakemoto, H.; Kaito, T. Chem.
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a Reaction conditions: ArI (1.0 mmol), malonate (2.0 mmol), CuI (0.05
mmol), L (0.1-0.2 mmol), Cs2CO3 (3.0 mmol), and dioxane (1.0 mL) at
rt to 70 °C under N2 atm for 20 h. b Calibrated GC yields in average of
two independent runs (dodecane as internal standard).
observed through competitive O-arylation of the ligand (L1-
L3).14 In general, the more the phenolic ligand is sterically
hindered, the less the tendency to be subjected to O-arylation.
A 4-fold excess of L to CuI was necessary to compensate
for this undesirable ligand arylation (Table 1, entries 4 vs
5). Although hindered phenolic ligands showed better
catalytic activity, the extremely congested phenol L6 was
not effective (Table 1, entry 6).
Since the monodentate ligands were not satisfactory, we
turned to investigating the applicability of the bidentate
ligands (L7-L10). To our delight, benzoic acid L7 provided
good catalytic activity in this transformation. On the basis
of this ligand prototype, we examined the bidentate O,S and
O,N ligands (Table 1, entries 8-10). Commercially available
2-picolinic acid L10 showed significant rate acceleration in
the arylation of malonate (Table 1, entry 11). The efficiency
of the ligand L10 can be further demonstrated by its catalytic
activity at room-temperature conditions (Table 1, entry 13).
(13) For the first general Ullmann-type C-N coupling at room temper-
ature see: Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742.
(14) The observations of ligand O-arylation were judged by GC-MS
analysis.
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