While the results presented above represent a significant
improvement over those previously reported, the substrate
scope of the amidation of unactivated aryl halides still has
only a moderate level of generality. To date, the amidations
of unactivated aryl chlorides (e.g., p-chlorotoluene), o-
substituted electronically neutral aryl halides (e.g., 2-bro-
motoluene), and electron-rich aryl halides (e.g., 4-bromoani-
sole) are not efficient. Additionally, secondary acyclic amides
(e.g., N-methylacetamide, N-methylbenzamide) other than
N-methylformamide react sluggishly with unactivated aryl
halides. We have also been unsuccessful in our attempts to
effect the coupling of sulfonamides with electron-neutral or
electron-rich aryl halides.
In this work, we found that amidations involving less
nucleophilic amides (e.g., sulfonamides and acetanilide) and
less electrophilic aryl halides (e.g., unactivated aryl halides)
were generally slower, requiring higher temperatures, longer
reaction times, and/or higher quantities of catalysts and
sometimes resulted in low conversions.13 For example, both
benzamide and 4-methoxybenzamide reacted efficiently with
4-tert-butylbromobenzene at 100 °C in 16 h (Table 2, entries
3 and 4). In contrast, under the same conditions as those
used for the reaction of benzamide, 4-trifluoromethylben-
zamide gave only 50% conversion to product. Amidation of
unactivated aryl halides was only effective with primary
amides, N-methylformamide, and lactams. The relatively
higher reactivity of these amides might be explained by the
configuration of the deprotonated amide (Figure 1). Binding
H, this is less important. Additionally, when R ) H (i.e.,
for primary amides), the Pd moiety can position itself away
from the bulk of R′ with little cost in energy. Consistent
with these hypotheses is that when neither R nor R′ is H,
the reactions fail to proceed in an efficient manner.
In addition to the desired C-N coupling products, small
amounts (2%-8%) of N-phenylated amides were also detected
in crude reaction mixtures by GC and GC-MS analyses when
less reactive aryl halides were used (Table 1, entry 12; Table
2, entries 1-8 and 13). These byproducts, which were
removed by flash chromatography, are possibly formed via
aryl group exchange between the aryl group bound to Pd-
(II) and the phenyl group bound to the phosphine ligand14
followed by C-N bond formation between the amide and
the phenyl group. Work is underway to overcome this
problem.
In conclusion, use of Xantphos as the ligand, THF or 1,4-
dioxane as the solvent, and Cs2CO3 as the base allows for
the first general intermolecular C-N bond-forming reactions
between aryl halides and amides. The amidations proceed
at 45-110 °C with 1-4 mol % of Pd catalyst in good to
excellent yields, and various functional groups are well
tolerated. In addition, aryl triflates, carbamates, and sulfona-
mides also participate in this process. Further investigations
to expand the scope of this and related reactions are currently
underway.
Acknowledgment. We thank NIH (Grant GM58160) for
support of this work. We are also grateful to Pfizer and
Merck for additional unrestricted support.
Supporting Information Available: Experimental pro-
cedures and characterization data for amidation products
(Tables 1 and 2). This material is available free of charge
OL005654R
(13) A substantial influence of the temperature of the reaction or the
mol % of catalyst employed on the efficiency of some reactions involving
unactivated aryl halides or triflate was also observed. For example, when
1 mol % of Pd catalyst was used, the reactions in entries 1-3 and 7 of
Table 2 gave low conversions (<15%). When the reaction in entry 3 of
Table 2 was carried out at 120 °C with 5 mol % of Pd catalyst, a product/
ArBr ratio of 0.20 was obtained after 19 h. The use of 2 mol % of Pd at the
same temperature gave a product/ArBr ratio of 1.1 after 16 h; no further
conversion was noted after an additional 26 h. However, when the
temperature was lowered to 100 °C, complete conversion was achieved
using 2.5 mol % of catalyst after 16 h (Table 2, entry 3). These results
suggest that unknown competitive processes leading to decomposition of
the catalyst can occur and that changes in reaction parameters may change
the relative rates of the desired and unwanted reactions.
(14) Hartwig observed similar aryl group exchange processes in pal-
ladium-catalyzed aminations: (a) Hamann, B. C.; Hartwig, J. F. J. Am.
Chem. Soc. 1998, 120, 3694-3703. See also: (b) Kong, K.-C.; Cheng,
C.-H. J. Am. Chem. Soc. 1991, 113, 6313-6315. (c) Segelstein, B. E.;
Butler, T. W.; Chenard, B. L. J. Org. Chem. 1995, 60, 12-13. (d) Herrmann,
W. A.; Broâmer, C.; O¨ fele, K.; Beller, M.; Fischer, H. J. Organomet. Chem.
1995, 491, C1-C4.
Figure 1.
of the deprotonated amide to the Pd(II) intermediate can
occur either via I or II. In most instances, the steric repulsion
between R and R′ would destabilize I; in the reactions of
lactams, only I is possible. Intermediate II would be expected
to suffer, in most cases, from severe steric interactions
between R′ and the Pd complex. For substrates with R′ )
1104
Org. Lett., Vol. 2, No. 8, 2000