Pd-Catalyzed Carbonylation Reactions of Aryl Bromides
TABLE 1. Ligand Optimization for the Synthesis of Weinreb
Amides via Pd-Catalyzed Aminocarbonylationa
Xantphos, a bidentate ligand developed by van Leeuwen for
the hydroformylation reaction,10 has been used extensively for
Pd-catalyzed C-N bond forming processes.11 The wide bite
angle (110°)12 and flexibility range (97-133°)12 characteristic
of Xantphos are believed to impart a dynamic coordination
environment that may be important for catalyst activity and
stability in Pd- and other transition-metal-catalyzed processes.13
Unlike other ligands examined, Xantphos provided a highly
active catalyst, delivering significant amounts of product after
only 2 h under our screening conditions (Table 1, entry 8). This
result is notable as both DPEphos and dppf, which are also
bidentate ligands and have similar bite angles to Xantphos,14
did not produce active catalysts and highlights the importance
of the flexible coordination environment of the Xantphos
backbone.
These initial screening experiments with Xantphos were
conducted with a 1:1 ratio of ligand to Pd(OAc)2, as the literature
indicated that excess Xantphos can inhibit Pd-catalyzed C-N
bond forming reactions.15 Optimization of the reaction condi-
tions using this Pd:L ratio revealed that the reaction was best
conducted at 80 °C. At 100 °C, incomplete conversion of the
starting material was observed. We attribute this unusual result
to increased catalyst stability at the lower temperatures.
Thus, under our optimized conditions [Pd(OAc)2 (2 mol %),
Xantphos (2 mol %), Na2CO3 (3 equiv), and N,O-dimethylhy-
droxylamine hydrochloride (1.5 equiv) in toluene at 80 °C under
esters: (g) Couve-Bonnaire, S.; Carpentier, J.-F.; Mortreux, A.; Castanet, Y. AdV.
Synth. Catal. 2001, 343, 289. Ketones: (h) Goure, W. F.; Wright, M. E.; Davis,
P. D.; Labadie, S. S.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 6417. Aldehydes
(from ArCl): (i) Ben-David, Y.; Portnoy, M.; Milstein, D. Chem. Commun. 1989,
1816. Aldehydes (from ArBr): (j) Klaus, S.; Neumann, H.; Zapf, A.; Stru¨bing,
D.; Hu¨bner, S.; Almena, J.; Riermeier, T.; Bross, P.; Sarich, M.; Krahnert, W.-
R.; Rossen, K.; Beller, M. Angew. Chem., Int. Ed. 2006, 45, 154. Carboxylic
acids: (k) Pri-Bar, I.; Buchman, O. J. J. Org. Chem. 1988, 53, 624. Phenyl
esters: (l) Kubota, Y.; Hanaoka, T.-a.; Takeuchi, K.; Sugi, Y. Synlett 1994, 515.
Benzo-fused azoles: (m) Perry, R. J.; Wilson, B. D.; Miller, R. J. J. Org. Chem.
1992, 57, 2883. Coumarins: (n) Kadnikov, D. V.; Larock, R. C. J. Org. Chem.
2003, 68, 9423. Chromones: (o) Kalinin, V. N.; Shastakovsky, M. V.; Pono-
maryov, A. B. Tetrahedron Lett. 1990, 13, 4073. R,ꢀ-Alkynyl ketones: (p)
Ahmed, M. S. M.; Mori, A. Org. Lett. 2003, 5, 3057. Lactones: (q) Cowell, A.;
Stille, J. K. J. Am. Chem. Soc. 1980, 102, 4193. R-Imino esters: (r) Watanabe,
H.; Hashizume, Y.; Uneyama, K. Tetrahedron Lett. 1992, 33, 4333. ꢀ-Keto
esters: (s) Raju, P. V. K.; Adapa, S. R. Indian J. Chem., Sect. B 1992, 31B,
363. Naphthyridines: (t) Addiati, G.; Arcadi, A.; Canevari, V.; Capezzuto, L.;
Rossi, E. J. Org. Chem. 2005, 70, 6454. Phthalimides: (u) Perry, R. J.; Turner,
S. R. J. Org. Chem. 1991, 56, 6573. Pyrazoles and isoxazoles: (v) Ahmed,
M. S. M.; Kebayashi, K.; Mori, A. Org. Lett. 2005, 7, 4487. ꢀ-Lactams: (w)
Dhawan, R.; Dghaym, R. D.; St. Cyr, D. J.; Arndtsen, B. A. Org. Lett. 2006, 8,
3927. Quinolones: (x) Kalinin, V. N.; Shostakovsky, M. V.; Panomaryov, A. B.
Tetrahedron Lett. 1992, 33, 373.
(6) Rahman, O.; Kihlberg, T.; Langstrom, B. J. Org. Chem. 2003, 68, 3558.
(7) Calo, V.; Giannoccaro, P.; Nacci, A.; Monopoli, A. J. Organomet. Chem.
2002, 645, 152.
(8) (a) Morimoto, T.; Kakiuchi, K. Angew. Chem., Int. Ed. 2004, 43, 5589.
(b) Wan, Y.; Alterman, M.; Larhed, M.; Hallberg, A. J. Org. Chem. 2002, 67,
6232. (c) Wu, X.; Ronn, R.; Gossas, T.; Larhed, M. J. Org. Chem. 2005, 70,
3094.
(9) (a) Hidai, M.; Kokura, K.; Uchida, Y. J. Organomet. Chem. 1973, 52,
431. (b) Stromnova, T. A.; Moiseev, I. I. Russ. Chem. ReV. 1998, 67, 485.
(10) Kranenburg, M.; van der Burgt, Y. E.; Kamer, P. C. J.; van Leeuwen,
P. W. N. M. Organometallics 1995, 14, 3081.
(11) (a) Guari, Y.; van Es, D. S.; Reek, J. N. H.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M. Tetrahedron Lett. 1999, 40, 3789. (b) Wagaw, S.; Yang,
B. H.; Buchwald, S. L. J. Am. Chem. Soc. 1999, 121, 10251.
a Reaction conditions: 2 mol % of Pd(OAc)2, n mol % of ligand, 1
mmol para-bromoanisole, 1.5 mmol amine, 3 mmol base in toluene (2
mL) at 100 °C. b Determined by GC, average of two runs. c Cone
angles. d See ref 14. e Reaction was run at 80 °C for 5 h. f Isolated yield,
average of two runs.
derived from para-bromoanisole and dimethylhydroxylamine
hydrochloride (Table 1). Although numerous variables associ-
ated with the reaction conditions were examined (including Pd
precatalyst, base, and solvent), the most influential proved to
be the choice of ligand. Previous studies have shown that ligands
employed in carbonylation chemistry must be electron-donating
enough to promote oxidative addition and prevent precipitation
of Pd-black or formation of Pd-carbonyl clusters.9 Additionally,
bidentate ligands are often superior to monodentate ligands in
these processes,5a-e a fact that has been ascribed to their greater
ability to prevent catalyst poisoning via ligation of multiple CO
ligands. Despite these guidelines, our initial efforts in this area,
which examined a wide range of electron-rich mono- and
bidentate phosphine ligands, failed to provide detectable amounts
of product (Table 1, entries 1-7).
(5) Representative examples describing the preparation of the following
species via Pd-catalyzed carbonylation. Benzamides: (a) Martinelli, J. R.; Clark,
T. P.; Watson, D. A.; Munday, R. H.; Buchwald, S. L. Angew. Chem., Int. Ed.
2007, 46, 8460. Esters (from ArBr and HetArCl): (b) Albaneze-Walker, J.;
Bazaral, C.; Leavey, T.; Dormer, P. G.; Murry, J. A. Org. Lett. 2004, 6, 2097.
Esters (from ArOMs/Ts): (c) Munday, R. H.; Martinelli, J. R.; Buchwald, S. L.
J. Am. Chem. Soc. 2008, 130, 2754. Weinreb amides: (d) Martinelli, J. R.;
Freckmann, D. M. M.; Buchwald, S. L. Org. Lett. 2006, 8, 4843. Heterocyclic
Weinreb amides: (e) Deagostino, A.; Larini, P.; Occhiato, E. G.; Pizzuto, L.;
Prandi, C.; Venturello, P. J. Org. Chem. 2008, 73, 1941. R-Keto amides: (f)
Uozumi, Y.; Arii, T.; Watanabe, T. J. Org. Chem. 2001, 66, 5272. R-Keto
(12) Van der Veen, L. A.; Keeven, P. H.; Schoemaker, G. C.; Reek, J. N. H.;
Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Lutz, M.; Spek, A. L.
Organometallics 2000, 19, 872.
(13) Leeuwen, P. W. N. M.; Kamer, P. C. J.; Reek, J. N. H.; Dierkes, P.
Chem. ReV. 2000, 100, 2741.
(14) van Leeuwen, P. W. N. M.; Zuideveld, M. A.; Swennenhuis, B. H. G.;
Freixa, Z.; Kamer, P. C. J.; Goubitz, K.; Fraanje, J.; Lutz, M.; Spek, A. L. J. Am.
Chem. Soc. 2003, 125, 5523.
(15) Klingensmith, L. M.; Strieter, E. R.; Barder, T. E.; Buchwald, S. L.
Organometallics 2006, 25, 82.
J. Org. Chem. Vol. 73, No. 18, 2008 7103