Pd-catalyzed N-arylation of secondary acyclic amides: Catalyst development, scope, and computational study

Article abstract of DOI:10.1021/ja9044357

We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was found to be uniquely effective for this amidation. The critical aspects of the ligand were explored through synthetic, mechanistic, and computational studies. Systematic variation of the ligand revealed the importance of (1) a methoxy group on the aromatic carbon of the "top ring" ortho to the phosphorus and (2) two highly electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups. Computational studies suggest the electron-deficient nature of the ligand is important in facilitating amide binding to the LPd(II)(Ph)(X) intermediate.

Full text of DOI:10.1021/ja9044357

Published on Web 11/03/2009
Pd-Catalyzed N-Arylation of Secondary Acyclic Amides:
Catalyst Development, Scope, and Computational Study
Jacqueline D. Hicks, Alan M. Hyde,* Alberto Martinez Cuezva,† and
Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, 77 Massachusetts AVenue,
Cambridge, Massachusetts 02139
Received June 1, 2009; E-mail: sbuchwal@mit.edu; ahyde@fas.harvard.edu
Abstract: We report the efficient N-arylation of acyclic secondary amides and related nucleophiles with
aryl nonaflates, triflates, and chlorides. This method allows for easy variation of the aromatic component
in tertiary aryl amides. A new biaryl phosphine with P-bound 3,5-(bis)trifluoromethylphenyl groups was
found to be uniquely effective for this amidation. The critical aspects of the ligand were explored through
synthetic, mechanistic, and computational studies. Systematic variation of the ligand revealed the importance
of (1) a methoxy group on the aromatic carbon of the “top ring” ortho to the phosphorus and (2) two highly
electron-withdrawing P-bound 3,5-(bis)trifluoromethylphenyl groups. Computational studies suggest the
electron-deficient nature of the ligand is important in facilitating amide binding to the LPd(II)(Ph)(X)
intermediate.
mides) with aryl bromides3 and aryl or vinyl sulfonates4 has
largely been accomplished by the use of xantphos or XPhos as
Introduction
Methods for the cross-coupling of amides with aryl halides
and pseudohalides have matured to a point that they may be
used to reliably prepare a wide variety of substances.1 Advances
in this area are due, in large part, to the identification of
improved supporting ligands. The classic copper-mediated
coupling of an amide with an aryl iodide (the Goldberg reaction)
proceeds catalytically and at lower temperatures when diamine
ligands are employed.2 Efficient Pd-catalyzed coupling of
amides and related nucleophiles (ureas, carbamates, sulfona-
the supporting ligand. Most recently, the use of monodentate
biarylphosphines bearing a methyl or methoxy group ortho to
the phosphorus (L3) has enabled the coupling of amides with
heteroaryl and aryl chlorides.5,6 A prominent limitation of all
amidation methods is they are mostly restricted to primary
amides or lactams; a general method for the intermolecular
cross-coupling of acyclic secondary amides with aryl halides
and/or pseudohalides has not yet been reported.7-9 The large
size of acyclic secondary amides,3a combined with their
relatively low nucleophilicity (compared to amines), has made
secondary amides a particularly challenging substrate class for
cross-coupling.
† Present address: Universidad de Burgos, Burgos, Spain.
(1) For reviews, see: Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed.
2003, 42, 5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett 2003,
2428. (c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (d) Jiang,
L.; Buchwald, S. L. In Metal-Catalyzed Cross-Coupling Reactions,
2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-VCH: Weinheim,
Germany, 2004. (e) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int.
Ed. 2008, 47, 6338.
(4) For the use of xantphos, see: refs 3a,b and. (a) Wallace, D. J.; Klauber,
D. J.; Chen, C.; Volante, R. P. Org. Lett. 2003, 5, 4749. (b) Imbriglio,
J. E.; DiRocco, D.; Raghavan, S.; Ball, R. G.; Tsou, N.; Mosley, R. T.;
Tata, T. R.; Collitti, S. L. Tetrahedron Lett. 2008, 49, 4897. For the
use of XPhos, see: (c) Huang, X.; Anderson, K. W.; Zim, D.; Jiang,
L.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2003, 125, 6653.
(d) Bhagwanth, S.; Waterson, A. G.; Adjabeng, G. M.; Hornberger,
K. R. J. Org. Chem. 2009, 74, 4634. For the use of other ligands, see:
(e) Klapars, A.; Campos, K. R.; Chen, C.; Volant, R. P. Org. Lett.
2005, 7, 1185. (f) Willis, M. C.; Brace, G. N.; Holmes, I. P. Synthesis
2005, 3229.
(2) For Cu-catalyzed reactions, see: (a) Shen, R.; Porco, J. A. Org. Lett.
2000, 2, 1333. (b) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald,
S. L. J. Am. Chem. Soc. 2001, 123, 7727. (c) Klapars, A.; Huang, X.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 7421. (d) Jiang, L.;
Job, G. E.; Klapars, A.; Buchwald, S. L. Org. Lett. 2003, 5, 3667. (e)
Klapars, A.; Parris, S.; Anderson, K. W.; Buchwald, S. L. J. Am. Chem.
Soc. 2004, 126, 3529. (f) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6,
1809. (g) Strieter, E. R.; Blackmond, D. G.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4120. (h) Strieter, E. R.; Bhayana, B.;
Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78.
(5) (a) Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2007, 129, 13001. (b) Fors, B. P.; Krattiger, P.; Strieter,
E.; Buchwald, S. L. Org. Lett. 2008, 10, 3505. (c) Fors, B. P.;
Dooleweerdt, K.; Zeng, Q.; Buchwald, S. L. Tetrahedron 2009, 65,
6576.
(3) For the use of xantphos, see: (a) Yin, J.; Buchwald, S. L. Org. Lett.
2000, 2, 1101. (b) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 6043. (c) Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2007, 129,
7734. (d) Huang, J.; Chen, Y.; King, A. O.; Dilmeghani, M.; Larsen,
R. D.; Faul, M. M. Org. Lett. 2008, 10, 2609. (e) Manley, P. J.;
Bilodeau, M. T. Org. Lett. 2004, 6, 2433. (f) Audisio, D.; Messaoudi,
S.; Peyrat, J.-F.; Brion, J.-D.; Alami, M. Tetrahedron Lett. 2007, 48,
6928. (g) Messaoudi, S.; Audisio, D.; Brion, J.-D.; Alami, M.
Tetrahedron 2007, 63, 10202. (h) Artamkina, G. A.; Sergeev, A. G.;
Beletskaya, I. P. Tetrahedron Lett. 2001, 42, 4381. (i) For the use of
P(t-Bu)3, see: Hartwig, J. F.; Kawatsura, M.; Hauck, S. I.; Shaughnessy,
K. H.; Alcazar-Roman, L. M. J. Org. Chem. 1999, 64, 5575.
(6) For additional examples of amidations with aryl chlorides, see: (a)
Ghosh, A.; Sieser, J. E.; Riou, M.; Cai, W.; Rivera-Ruiz, L. Org. Lett.
2003, 5, 2207. (b) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig,
J. F. Angew. Chem., Int. Ed. 2005, 44, 1371. (c) Ligthart, G. B. W. L.;
Ohkawa, H.; Sijbesma, R. P.; Meijer, E. W. J. Org. Chem. 2006, 71,
375. (d) Piguel, S.; Legraverend, M. J. Org. Chem. 2007, 72, 7026.
(e) McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8,
3311. For an example of amidation with gem-dichloroolefins, see: (f)
Ye, W.; Mo, J.; Zhao, T.; Xu, B. Chem. Commun. 2009, 3246.
9
16720 J. AM. CHEM. SOC. 2009, 131, 16720–16734
10.1021/ja9044357 CCC: $40.75  2009 American Chemical Society

Pd-Catalyzed N-Arylation of Secondary Acyclic Amides
A R T I C L E S
Chart 1. Ligand Optimization for the Coupling of 4-tert-Butylphenyl
Nonaflate and N-Butyl Acetamidea
Figure 1. Representative biologically active tertiary aryl amides and
sulfonamides.
Tertiary aryl amides and sulfonamides, the primary products
described in this paper, are found in a variety of biologically
active molecules (Figure 1).10 Access to this class of compounds
by arylation of the secondary amides would have advantages
over traditional acylation strategies because it would allow for
easy variation of the aromatic component, facilitating the
generation of analogues for SAR studies. Additionally, second-
ary amides and carbamates are often intermediates in synthetic
sequences,11 and the ability to arylate these directly would
improve the efficiency of synthetic routes.
a ArONf (1 equiv), amide (2.5 equiv), [(allyl)PdCl]2 (1 mol %), ligand
(5 mol %), base (2.0 equiv), 3 Å mol sieves (50 mg/mL), solvent (0.25 M),
110 °C, 18 h.
Herein, we describe the rational development of a new biaryl
phosphine (JackiePhos, L6) with P-bound 3,5-(bis)trifluoro-
methylphenyl groups that facilitates amide binding by creating
a more electrophilic Pd(II) intermediate. We have examined
aspects of this catalyst system by synthetic, mechanistic, and
computational investigations. The synthetic investigations will
focus on (1) substrate scope for the cross-coupling of secondary
amides with aryl triflates and nonaflates, (2) cross-coupling of
related nucleophiles (ureas, carbamates, sulfonamides), (3)
extension of this method to include aryl chlorides, and (4)
development of a diarylation process. The mechanistic inves-
tigations will focus on (1) the correlation of ligand structure to
catalyst stability and (2) trends in aryl halide reactivity and the
mechanistic implications. Finally, a computational study will
examine each catalytic step for a series of related ligands to
understand the effect of structural substitutions.
Results
In designing a new ligand for the N-arylation of secondary
amides, we took into account existing knowledge of ligand
effects and the mechanism of amidation. Xantphos, the standard
ligand for the amidation of aryl iodides, bromides, and triflates,
was ineffective as a ligand for the reaction in Chart 1. Instead
we chose to focus our efforts on ligands derived from the
BrettPhos biaryl motif12 (Chart 1), which contains two methoxy
groups on the upper ring of the biaryl. This scaffold imparts
properties that give catalysts superior performance in a number
of C-N bond-forming transformations. Reactions employing
BrettPhos13 (L2) and t-Bu2BrettPhos5c (L3) provided unsatisfac-
tory yields of the desired product (27% and 21%, respectively).
Based on our knowledge that “transmetalation” was rate-limiting
for primary amides5a (and this step would likely be even more
difficult for the larger secondary amides), we undertook the
development of ligands that would facilitate this step. We
hypothesized that a more electrophilic and less sterically
demanding Pd(II) intermediate was necessary to facilitate amide
binding. Moreover, a similar strategy was employed by Be-
letskaya for the N-arylation of ureas in which an electron-
deficient xantphos ligand possessing P-bound 3,5-(bis)trifluo-
romethylphenyl groups was shown to give the most active
catalyst.13 Toward this goal we prepared ligands L4-L6, in
which the P-bound alkyl groups in L2 and L3 were replaced
with aryl groups. The strongly electron-withdrawing 3,5-
(bis)trifluoromethylphenyl substituent in ligand L6 provided the
most efficient ligand, and the catalyst derived from L6 provided
the desired product in 87% yield. Consistent with our supposi-
(7) For intramolecular examples, see: (a) Wolfe, J. P.; Rennels, R. A.;
Buchwald, S. L. Tetrahedron 1996, 52, 7525. (b) Wagaw, S.; Rennels,
R. A.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 8451. (c) Yang,
B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35. (d) Yamada, K.; Kubo,
T.; Tokuyama, H.; Fukuyama, T. Synlett 2002, 231. (e) Ooi, T.;
Kameda, M.; Maruoka, K. J. Am. Chem. Soc. 2003, 125, 5139. (f)
Poondra, R. R.; Turner, N. J. Org. Lett. 2005, 7, 863. (g) Bonnaterre,
F.; Bois-Choussy, M.; Zhu, J. Org. Lett. 2006, 8, 4351. (h) Hoogen-
brand, A.; Lange, J. H. M.; Iwema-Bakker, W. I.; Hartog, J. A. J.;
Schaik, J.; Feenstra, R. W.; Terpstra, J. W. Tetrahedron Lett. 2006,
47, 4361. (i) Feng, G.; Wu, J.; Dai, W. Tetrahedron Lett. 2007, 48,
401. (j) Hoogenbrand, A.; Lange, J. H. M.; Hartog, J. A. J.; Henzen,
R.; Terpstra, J. W. Tetrahedron Lett. 2007, 48, 4461. (k) Furuta, T.;
Kitamura, Y.; Hashimoto, A.; Fujii, S.; Tanaka, K.; Kan, T. Org. Lett.
2007, 9, 183. (l) Kalinski, C.; Umkehrer, M.; Ross, G.; Kolb, J.;
Burdack, C.; Hiller, W. Tetrahedron Lett. 2006, 47, 3423.
(8) For isolated intermolecular examples, see: refs 2c, 3a, 3b, 5a and Deng,
W.; Wang, Y.-F.; Zou, Y.; Liu, L.; Guo, Q.-X. Tetrahedron Lett. 2004,
45, 2311.
(9) For secondary formamides, see: refs 2c, 3a, 3b, 4c, and 5a.
(10) (a) Wagner, J.; Wagner, M. L.; Hening, W. A. Ann. Pharmacother.
1998, 36, 680. (b) VanBever, W. F. M.; Niemegeers, C. J. E.; Janssen,
P. A. J. J. Med. Chem. 1974, 17, 1047. (c) Anderson, R.; Hokama,
T.; Lee, S.-F.; Oey, R.; Elich, T.; Breazeale, S. Preparation of
modulators of acetyl coenzyme A carboxylase as fungicides and
pharmaceuticals. U.S. Patent 20080200461, 2008.
(11) Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic
Chemistry, 3rd ed.; John Wiley & Sons: New York, 1999; pp 503-
564.
(12) Fors, B. P.; Watson, D. A.; Biscoe, M. R.; Buchwald, S. L. J. Am.
Chem. Soc. 2008, 130, 13552.
(13) Sergeev, A. G.; Artamkina, G. A.; Beletskaya, I. P. Tetrahedron Lett.
2003, 44, 4719.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16721

A R T I C L E S
Hicks et al.
Table 1. Pd-Catalyzed Coupling of Aryl Nonaflates and Triflates
tion, the conversion and product yields increased as the ligand
became more electron-deficient (R ) 3,5-CF3Ph > 4-CF3Ph >
Ph).
with Secondary Amidesa
Several other aspects of the reaction conditions utilized for
the N-arylation of secondary amides deserve comment.14 Aryl
nonaflates (ArONf ) ArOSO2(CF2)3CF3)15 were chosen as a
cross-coupling partner because they are less susceptible to
hydrolysis than aryl triflates, while still providing a similar,
highly electrophilic, Pd(II) intermediate.16,17 The use of a
nonpolar solvent such as toluene was found to be critical in
obtaining high yields, whereas reactions in polar solvents (e.g.,
t-BuOH, DME) were less efficient. Additionally, the inclusion
of molecular sieves in the reaction mixture improved the yields
by inhibiting the formation of phenols and related side prod-
ucts.18 The [(allyl)PdCl]2 precatalyst was chosen due to its ease
of use and lack of coordinating ligands (such as dba).19
However, Pd(OAc)2 could also be used if a preactivation step
was employed to ensure formation of the Pd(0) complex.5b
Synthetic Investigations. With optimized reaction conditions
in hand, we examined the scope of the method. Secondary
amides coupled efficiently with a variety of electron-deficient,
electron-neutral, and moderately electron-rich aryl nonaflates,
with electron-deficient aryl nonaflates typically giving the
highest yields (Table 1, entries 1-3). R-Branched amides reacted
smoothly (entries 5 and 6), but branched alkyl substitution on
the nitrogen was not tolerated. In addition to nonaflates, aryl
triflates were also successfully converted to product (entries 7
and 8). In difunctionalized substrates, it was found (unsurpris-
ingly) that the nonaflate group reacted in preference to a chloride
substituent (entries 9 and 10). A relatively small group at the
ortho position of the aryl sulfonate such as Cl was tolerated,
but larger substituents were not. Acetanilide and other N-aryl
amides are traditionally difficult substrates for Pd-catalyzed
cross-coupling reactions, but by using a slight modification of
our general protocol, employing K3PO4 as the base, acetanilide
could be N-arylated in 78% yield (entry 11).20 We note that
attempts to realize the same product from the aryl bromide using
xantphos as the supporting ligand gave a very low yield of the
product.21
Given the successful coupling of secondary amides, we next
examined the reaction of carbamates, ureas, and sulfonamides.
Substituted ureas proved to be difficult substrates and could only
(14) For a more complete ligand examination and condition optimization,
see Supporting Information.
(15) Aryl nonaflates can be easily prepared from the corresponding phenols
and nonafluorobutanesulfonyl fluoride. For their preparation and use
in C-N coupling, see: (a) Anderson, K. W.; Mendez-Perez, M.; Priego,
J.; Buchwald, S. L. J. Org. Chem. 2003, 68, 9563. (b) Tundel, R. E.;
Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2006, 71, 430.
(16) For the use of ArONf substrates in Heck reactions, see: (a) Beletskaya,
I. P.; Cheprakov, A. V. Chem. ReV. 2000, 100, 3009. (b) Lyapkalo,
I. M.; Webel, M.; Reibig, H.-U. Eur. J. Org. Chem. 2002, 3646.
(17) Aryl nonaflates are generally more resistant to hydrolysis than the
corresponding triflates. For an example, see: (a) Zhang, X.; Sui, Z.
Tetrahedron Lett. 2003, 44, 3071.
a Reaction conditions: ArONf/ArOTf (1 equiv), amide (2.5 equiv),
[(allyl)PdCl]2 (1 mol %), JackiePhos (5 mol %), K2CO3 (2.0 equiv), 3 Å
mol sieves (200 mg/mmol), toluene (0.25 M), 110 °C, 17 h. b Yields
reported are an average of at least two runs determined to be >95% pure
by elemental analysis or H NMR. c Pd(OAc)2 (3 mol %), JackiePhos (7
1
mol %), H2O activation. d K3PO4 was used instead of K2CO3.
(18) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J. Am.
Chem. Soc. 2006, 128, 10694.
be coupled with electron-deficient nonaflates, and then only in
moderate yields (Table 2, entries 1 and 2). In contrast, secondary
carbamates, which are less sterically demanding, were excellent
substrates. The coupling of Boc- and Cbz-protected amines
proceeded in 87% and 90% yield, respectively (entries 3 and
6). The use of secondary sulfonamides also provided good yields
of coupled products (entries 7-9). These examples are signifi-
cant because there are only isolated examples of the successful
(19) Coordination of dba can result in diminished reactivity. See: (a)
Fairlamb, I. J. S.; Kapdi, A. R.; Lee, A. F.; McGlacken, G. P.;
Weissburger, F.; de Vries, A. H. M.; Vondervoort, L. S. Chem.sEur.
J. 2006, 12, 8750. (b) Mace, Y.; Kapdi, A. R.; Fairlamb, I. J. S.; Jutand,
A. Organometallics 2006, 25, 1795. (c) Amatore, C.; Jutand, A. Coord.
Chem. ReV. 1998, 178, 511.
(20) For Cu-catalyzed arylations of N-aryl amides with aryl iodides and
bromides: refs 2b, 2c, 2f and Freeman, H. S.; Butler, J. R.; Freedman,
L. D. J. Org. Chem. 1978, 43, 4975.
(21) Yin, J.; Buchwald, S. L., unpublished results.
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Pd-Catalyzed N-Arylation of Secondary Acyclic Amides
A R T I C L E S
Table 2. Pd-Catalyzed Coupling of Aryl Nonaflates and Triflates
Table 3. Pd-Catalyzed Coupling of Aryl Chlorides with Secondary
with Secondary Ureas, Carbamates, and Sulfonamidesa
Amides, Carbamates, and Sulfonamidesa
a Reaction conditions: ArCl (1 equiv), amide (2.5 equiv), [(allyl)-
PdCl]2 (1 mol %), JackiePhos (5 mol %), base (2.0 equiv), 3 Å mol
sieves (200 mg/mmol), solvent (0.25 M), 110 °C, 18 h. b Yields reported
are an average of at least two runs determined to be >95% pure by
elemental analysis or H NMR. c K3PO4 was used instead of Cs2CO3.
1
cross-coupling of N-alkyl carbamates22 and, to the best of our
knowledge, the intermolecular coupling of N-alkyl acyclic
sulfonamides or N-alkyl, N′,N′-dialkyl ureas has not yet been
reported.
To expand the utility of this method, we sought to develop
conditions that would allow for the coupling of secondary
amides with aryl chlorides. Many aryl chlorides are com-
mercially available, and the ability to utilize these substrates
would improve the generality of this method.23 Increasing the
reaction temperature and utilizing Cs2CO3 as the base provided
good yields of amidation products. The substrate scope of the
aryl chloride coupling was briefly examined as shown in Table
3. A variety of aryl chlorides were successfully coupled with
secondary amides as well as with a secondary carbamate (entry
4) and a secondary sulfonamide (entry 5). The reaction of more
hindered amides proved to be difficult with aryl chlorides; for
those substrates in particular, aryl triflates/nonaflates are recom-
mended as the coupling partners.
Given our success in coupling N-aryl amides with aryl
nonaflates and chlorides, we examined the diarylation of a
a Reaction conditions: ArONf/ArOTf (1 equiv), urea or carbamate
(2.5 equiv), [(allyl)PdCl]2 (1 mol %), JackiePhos (5 mol %), K2CO3 (2.0
equiv), 3 Å mol sieves (50 mg/mL), toluene (0.25 M), 110 °C, 17 h.
b Yields reported are an average of at least two runs determined to be
(22) For isolated examples of N-arylation with secondary carbamates, see:
refs 3a, 3c, and Tasler, S.; Mies, J.; Lang, M. AdV. Synth. Catal. 2007,
349, 2286.
(23) (a) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(b) Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047.
1
>95% pure by elemental analysis or H NMR.
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J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16723

A R T I C L E S
Hicks et al.
Table 5. Variation of the Upper Ring of the Biaryl Backbone
Table 4. Diarylation of Primary Amides and Synthesis of a Nuclear
Receptor Binding Agent and Related Analoguesa b
,
catalyst derived from ligand L9, containing only one methoxy
substituent ortho to the phosphorus, led to successful amidation.
Yields for amidation reactions using L9 were similar to those
obtained with JackiePhos, and monitoring the amidation with
in situ IR indicated that the reaction profiles were nearly
identical. However, the catalyst derived from ligand L7, lacking
both of the methoxy groups, provided only 5% of the desired
product and quickly degraded to palladium black. This indicates
that the upper methoxy ortho to the phosphorus is of critical
importance to catalyst stability. To determine if this was simply
a steric effect, ligand L8 containing an ortho methyl group was
synthesized. Interestingly, L8 was not a useful ligand for
amidation reactions despite NMR experiments showing it
undergoes oxidative addition to PhCl. Thus, the methoxy group
ortho to the phosphorus of JackiePhos cannot be substituted
with a slightly larger, noncoordinating group.
To better understand the relative reactivity of the aryl halide
or pseudohalide in these amidation reactions, we compared the
reaction profiles of phenyl triflate, iodobenzene, bromobenzene,
and chlorobenzene with N-butyl acetamide. The reactions were
monitored for product formation by in situ IR spectroscopy
(Chart 2). The reaction of N-butyl acetamide with phenyl triflate
proceeded to completion in just over 5 h. In contrast, the reaction
of aryl halides did not reach completion in 22 h. We observed
some unexpected trends in the reactions of the aryl halides; the
reaction of chlorobenzene was significantly faster than that of
bromobenzene, which in turn was much faster than iodobenzene,
which produced essentially no product. The general trend of
ArOTf/ArONf > ArCl > ArBr > ArI was also observed for the
other substituted aryl halides/pseudohalides examined.
To gain a more thorough understanding of the origin of these
trends, we carried out several competition experiments. In Table
6 a comparison of the yields for the cross-coupling of N-butyl
acetamide with aryl electrophiles under the optimal reaction
conditions developed for aryl chlorides is shown. The yields
given in this table are consistent with the relative reactivity of
this series of substrates. Given that aryl chlorides react faster
under these conditions than the corresponding aryl bromides,
we performed a competition experiment between 1-n-butyl-4-
chlorobenzene and 4-bromotoluene (eq 1). As expected, exclu-
sive cross-coupling with the 4-bromotoluene was observed,
consistent with a mechanism in which oxidative addition occurs
preferentially with 4-bromotoluene. A similar competition
a Reaction conditions: ArX (2.2 equiv), amide (1.0 equiv),
[(allyl)PdCl]2 (1 mol %), JackiePhos (5 mol %), K3PO4 (3.0 equiv), 3 Å
mol sieves (200 mg/mmol), toluene (0.25 M), 110 °C, 17 h.b Yields
reported are an average of at least two runs determined to be >95% pure
by elemental analysis or 1H NMR.c Runs conducted with [(allyl)PdCl]2
(1.5 mol %), JackiePhos (7 mol %), 42 h.
primary amide.24 By combining a primary amide with 2.2 equiv
of aryl halide or pseudohalide and 3 equiv of base under
otherwise identical reaction conditions to that described above,
good yields of the desired N,N-diaryl amides could be obtained
(Table 4). This diarylation method allows for the rapid synthesis
of diaryl benzamide derivatives. These compounds exhibit
interesting biological activity as nuclear receptor binding
agents.25 An example is 3-hydroxy-N,N-diphenylbenzamide,
which alters pS2/TFF1 expression levels. (pS2/TFF1 is impor-
tant in maintaining gastric mucosal integrity and may act as a
tumor suppressor signal in the stomach.26) Through the diary-
lation of 3-methoxybenzamide (entries 4-6), a series of
3-hydroxy-N,N-diphenylbenzamide analogues were readily
available.
Mechanistic Investigation. Our recent studies on C-N bond
formation have shown that ligands containing methoxy groups
on the upper ring of the biaryl backbone provide significantly
better results than those without the substituents. To probe the
importance of the methoxy groups, a series of JackiePhos
analogues were prepared and tested. Ligands L7-L9 (Table
5), containing variable substitution on the upper biaryl ring, were
examined under standard reaction conditions for the coupling
of N-butylacetamide and of 4-tert-butylphenyl nonaflate. The
(24) For Cu-catalyzed diarylations with aryl bromides and iodides, see:
(a) Hisayuki, K.; Hiroyuki, M.; Koji, H. Method for Producing
Aromatic Diamine Derivative. EP 1593665, 2005. (b) Yabunouchi,
N.; Kawamura, M. Aromatic Amine Derivative and Organic Elec-
troluminescent Device Using the Same. WO2006073054, 2006. (c)
Kawamura, H.; Yabunouchi, N. Aromatic Triamine Compound and
Organic Electroluminescent Device Using the Same. WO2006114921,
2006.
(25) Dalton, J.; Barrett, C.; He, Y.; Hong, S.; Miller, D. D.; Mohler, M. L.;
Narayanan, R.; Wu, Z. Nuclear Receptor Binding Agents. WO 2007/
062230 A2, 2007.
(26) Fujii, Y.; Shimada, T.; Koike, T.; Hosaka, K.; Tabei, K.; Namatame,
T.; Tajima, A.; Yoneda, M.; Terano, A.; Hiraishi, H. Aliment
Pharmacol. Ther. Symp. Ser. 2006, 2, 285.
9
16724 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Pd-Catalyzed N-Arylation of Secondary Acyclic Amides
A R T I C L E S
Chart 2. Comparison of Reaction Profiles for PhOTf, PhCl, and
PhBr
by the trend in rates of associative ligand exchange of [Pt(di-
en)X]n+ complexes, following the order Cl > Br > I.27
Computational Studies
Future advances in the design of biarylmonophosphine ligands
would benefit from a firm understanding of the effects bestowed
by substituents appended to the biaryl backbone. Although we
were pleased with the superior performance of JackiePhos in
comparison to other biarylmonophosphine ligands, we sought
further mechanistic support for our original hypothesis that its
electron-withdrawing nature allows for faster transmetalation;
this prompted us to investigate the role of the structural features
present in this ligand. For these studies, we chose to focus on
two points: (1) determination of the effect of substitution of
different P-bound R groups (i.e., 3,5-CF3Ph, t-Bu, Cy, Ph) and
(2) the development of an understanding of the role of the
methoxy group bound to the upper ring ortho to the phosphorus.
Since we were unable to measure the relative rates of each
mechanistic step due to difficulties in isolating catalytic
intermediates, we turned instead to a computational approach
using DFT methods. Computational investigations of Pd-
catalyzed cross-coupling reactions have become increasingly
routine, but an examination of the literature reveals that the
majority of these analyses are limited to catalysts containing
small phosphines (e.g., PH3, PMe3, H2PCH2CH2PH2) that serve
as models for larger ligands (e.g., PPh3, P(t-Bu)3, Ph2PCH2-
CH2PPh2).28 While the conclusions from these studies have
provided much insight into the operative mechanism of these
processes, many difficult cross-coupling reactions do not proceed
with these simple ligands. Therefore, caution should be exercised
when applying approximations to ligands when examining such
reactions.29
Table 6. Competition Experiments
With the rapid increases in computational power and concur-
rent decrease in cost, we favor a more rigorous approach, which
entails modeling the complete catalyst with all-atom DFT. We
believe that studying the subtle structural features of the ligand
is critical for a thorough mechanistic understanding. Further-
more, in the following discussion we compare several related
biaryl monophosphines that behave markedly different in
promoting catalysis. The direct comparison of ancillary phos-
phine ligands by computational methods represents an infre-
(27) Richens, D. T. Chem. ReV. 2005, 105, 1961.
(28) For representative examples, see: (a) Ariafard, A.; Lin, Z. Organo-
metallics 2006, 25, 4030. (b) Legault, C. Y.; Garcia, Y.; Merlic, C. A.;
Houk, K. N. J. Am. Chem. Soc. 2007, 129, 12664. (c) Nova, A.;
Ujaque, G.; Maseras, F.; Lledo´s, A.; Espinet, P. J. Am. Chem. Soc.
´
2006, 128, 14571. (d) Alvarez, R.; Faza, O. N.; Lo´pez, C. S.; de Lera,
A. R. Org. Lett. 2006, 8, 35. (e) Braga, A. A. C.; Ujaque, G.; Maseras,
F. Organometallics 2006, 25, 3647. (f) Ananikov, V. P.; Musaev,
D. G.; Morokuma, K. Organometallics 2005, 24, 715. (g) Zuidema,
E.; van Leeuwen, P. W. N. M.; Bo, C. Organometallics 2005, 24,
3703.
experiment between 1-n-butyl-4-chlorobenzene and 4-iodotolu-
ene provided no cross-coupled product (eq 2), demonstrating
that oxidative addition occurred with 4-iodotoluene in preference
to 1-n-butyl-4-chlorobenzene. These results strongly disfavor a
mechanism in which oxidative addition affects the observed rate
but instead are consistent with the idea that the “transmetalation”
step is responsible for the observed trend in reactivity. In our
previous kinetic studies on amidation, the faster rate of
“transmetalation” for aryl triflates was attributed to a more labile
LPd(Ph)OTf complex compared to LPd(Ph)halide complexes.5a
Analogously, the rate of amide/amidate attack on LPd(Ph)Cl
may be faster than the attack on LPd(Ph)Br due to the more
electrophilic nature of palladium in LPd(Ph)Cl. This is supported
(29) For examples that illustrate the importance of calculating the full ligand
structure in Pd-catalyzed cross-coupling reactions, see: (a) Li, Z.; Fu,
Y.; Guo, Q.; Liu, L. Organometallics 2008, 27, 4043. (b) Barder, T. E.;
Biscoe, M. R.; Buchwald, S. L. Organometallics 2007, 26, 2183.
(30) For the calculated effect of ligand structure on the barrier to oxidative
addition of aryl halides with LnPd(0), see ref 28a and(a) Kozuch, S.;
Amatore, C.; Jutand, A.; Shaik, S. Organometallics 2005, 24, 2319.
For the effect on the overall cycle of a Pd-catalyzed Suzuki-Miyuara
coupling, see: (b) Huang, Y.; Weng, C.; Hong, F. Chem.sEur. J. 2008,
14, 4426. For the effect on the barrier to reductive elimination of
LnPd(II)ArX complexes, see: ref 28g and (c) Ananikov, V. P.; Musaev,
D. G.; Morokuma, K. Eur. J. Inorg. Chem. 2007, 5390. (d) Ariafard,
A.; Yates, B. F. J. Organomet. Chem. 2009, 694, 2075. For the effect
on the overall cycle of Cu-catalyzed amide arylations, see: (e) Zhang,
S.; Liu, L.; Fu, Y.; Guo, Q. Organometallics 2007, 26, 4546.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16725

A R T I C L E S
Hicks et al.
Scheme 1. Processes Examined in Our Computational Studies
quently used but powerful approach to understanding intricate
details of critical mechanistic processes.28a,30
algorithm using all-atom DFT (B3LYP/6-31(d)) and the
LANL2DZ basis set with the Hay-Wadt33 effective core
potential (ECP) for all Pd and Br atoms. Frequency calculations
were performed on all optimized structures to confirm that the
minima had no negative frequencies and transition states had a
single imaginary frequency. The Gibbs free energies were
calculated at 298.15 K and 1 atm. Single-point calculations were
then performed with the 6-311+g(2d,p) basis set to obtain higher
accuracy electronic energies. Solvation effects were calculated
at the 6-311+g(2d,p) level with the CPCM method34 in
conjunction with the UAKS cavity and employing a dielectric
constant of ε ) 2.374 for toluene. Basis set superposition error
(BSSE) was corrected for by use of the counterpoise method
of Boys and Bernardi.35 Although BSSE is a general phenom-
enon when using incomplete basis sets, correcting for it is critical
when constructing potential energy diagrams.36
Our strategy to unraveling the structure/activity relationship
of these ligands was to systematically change one portion of
the ligand and calculate the effect on each step of the catalytic
cycle. Scheme 1 shows the general outline of the possible steps
in the catalytic cycle we would examine: oxidative addition (eq
1), associative ligand exchange (eq 2), dissociative ligand
exchange (eq 3), formation of the κ2-bound amidate (eq 4), and
reductive elimination (eq 5). The ligands we opted to focus on
were L1 (xantphos), L6 (JackiePhos), L2 (BrettPhos), L3 (t-
Bu2BrettPhos), L4 (Ph2BrettPhos), and L10 (a simplified version
of L8), which are shown in Scheme 1. Xantphos was included
in this comparison since it is a very effective ligand for many
amidation reactions3a-h,4a,b and its role in Pd-catalyzed cross-
couplings has never been studied computationally.31 It also
serves as a benchmark for comparison to our biarylmonophos-
phine ligands and to validate our computational results by further
correlation with experiment. Our justification for modeling L10
instead of L8 rests on previous studies that demonstrate only
the methyl group ortho to the phosphorus influences the
properties of these ligands in amidation reactions.5a
Oxidative Addition. As stated earlier, it is unlikely that
oxidative addition is the rate-limiting step in most Pd-catalyzed
amide arylation reactions based on previous work performed
in our group.5a Nevertheless, the barriers for this step were
calculated (Table 7), as the rate-limiting step could change for
some ligands. We began by finding the barrier of oxidative
addition to bromobenzene (1-TS, entry 1) and chlorobenzene
(2-TS, entry 2) with xantphos ·Pd (1). Interestingly, the geometry
of these transitions states were pseudotetrahedral about the Pd
center as opposed to the more common square planar conforma-
Methods. All calculations were performed using the Gaussian
′03 suite of programs,32 primarily with Dell PowerEdge 1950
servers containing two quad-core Intel Xeon processors or Sun
servers containing dual-core Opteron processors, running the
sun grid engine (SGE) queuing program. We also made use of
supercomputing resources for potential energy scans. Ground-
state geometry optimizations were performed with the Berny
(33) Hay, P. J.; Wadt, W. R. J. Chem. Phys. 1985, 82, 299.
(34) Cossi, M.; Rega, N.; Scalmani, G.; Barone, V. J. Comput. Chem. 2003,
24, 669.
(31) For computational studies on Rh/xantphos complexes and their
behavior in hydroformylation reactions, see: (a) Landis, C. R.; Uddin,
J. Dalton Trans. 2002, 729. (b) 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.
(32) Frisch, M. J.; et al. Gaussian 03, revision D.01; Gaussian, Inc.:
Wallingford, CT, 2004.
(35) Boys, S. F.; Bernardi, F. Mol. Phys. 1970, 19, 553.
(36) For instances where the correction of BSSE is important in theoretical
studies of Pd-catalyzed processes, see: (a) Frankcombe, K. E.; Cavell,
K. J.; Yates, B. F.; Knott, R. B. J. Phys. Chem. 1996, 100, 18363. (b)
Delbecq, F.; Lapouge, C. Organometallics 2000, 19, 2716. (c) de Jong,
G. T.; Sola, M.; Visscher, L.; Bickelhaupt, F. M. J. Chem. Phys. 2004,
121, 9982.
9
16726 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Pd-Catalyzed N-Arylation of Secondary Acyclic Amides
A R T I C L E S
Table 7. Calculated Reaction Barriers for the Oxidative Addition of
PhX with Xantphos ·Pd
the relative importance of steric and electronic factors on the
rates of cross-coupling reactions.40
Associative Transmetalation. The step following oxidative
addition is “transmetalation”, in which ligand exchange of an
amide for a halide probably occurs by either an associative or
dissociative mechanism. Given the pKa difference between
amides (15.1 for N-H) and carbonate (10.3), we believe that
deprotonation occurs following amide binding to the Lewis
acidic Pd(II) center. If an associative mechanism is operative,
then the amide must first bind to Pd, giving rise to a
five-coordinate intermediate in the case of xantphos and a four-
coordinate intermediate in the case of monophosphines, followed
by deprotonation and halide dissociation. An examination of
the literature reveals very few mechanistic details concerning
ligand substitution with amides either experimentally or
theoretically.
The amide included in our calculations was N-methyl
acetamide, which was chosen to be representative of secondary,
acyclic, alkyl amides. The calculated geometry of the four-
coordinate trans-xantphos·Pd(Ph)(Br) complex 2b and five-
coordinate square pyramidal complex 8 with an O-bound amide
are shown in Scheme 2. This binding is endothermic by 28.7
kcal/mol of energy and results in a fairly weak Pd-Br
interaction in the axial position with a bond length of 3.22 Å.
A similar structure with a triflate counterion could not be located.
The binding energies of N-methyl acetamide to each biaryl
monophosphine·Pd(Ph)(Cl) complex were next determined
(Table 10). We first calculated the energy of amide binding to
the JackiePhos ·Pd(Ph)(Cl) complex in cases where the Pd center
is pointed away from the lower biaryl ring (complexes 9b-d).
The most favorable interaction, being endothermic by 18.2 kcal/
mol,41 occurred when the amide was bound to Pd through its
oxygen atom and oriented cis to the phosphorus (9b). The energy
of amide binding with the Pd but centered over the bottom ring
was also calculated and was significantly higher in energy in
both possible configurations (9f, 26.4 kcal/mol and 9g, 25.1 kcal/
mol). The energies of the other L ·Pd(Ph)(Cl)(amide) adducts
in configuration b were next calculated. We also verified that
the lowest energy configuration for JackiePhos held for other
ligands, and they did with the exception of isomer f. For
BrettPhos and t-Bu2BrettPhos, this isomer was not a stationary
state, but we found that isomer g oriented with the amide trans
to the phosphorus did represent a stable minimum. Larger
energies for amide binding were calculated for BrettPhos- (23.0
kcal/mol, 10b) and t-Bu2BrettPhos- (23.5 kcal/mol, 11b) ligated
complexes. In contrast, with Ph2BrettPhos, a significantly lower
energy for this step (19.8 kcal/mol, 12b) was calculated. As in
the oxidative addition step, L10 is calculated to behave similarly
to JackiePhos; its oxidative addition complex requires only 17.5
kcal/mol for amide binding.
∆G‡
(kcal/mol)
entry
TS
X
1
2
1-TS
2-TS
Br
Cl
26.8
36.6
tion, probably a result of the large bite angle of xantphos.37
Alternative transition states with cis or O-bound geometries
could not be located. A moderate barrier of 26.8 kcal/mol was
calculated for 1-TS, but a high barrier of 36.6 kcal/mol was
calculated for 2-TS. This is consistent with the experimental
observation that the use of xantphos does not allow for the Pd-
catalyzed cross-coupling of unactivated aryl chlorides.5a,38
We found four energy minimized oxidative addition com-
plexes for xantphos · Pd(Ph)(Br), shown in Table 8. The
tetrahedral transition state 1-TS initially leads to the highest
energy tetrahedral isomer 2a (confirmed by an IRC calculation),
which then can isomerize to the lower energy trans39 (2b),
O-bound (2c), or cis (2d) complexes. The bond angles and bond
lengths about the Pd center are listed and illustrate the large
range of conformations the xantphos catalyst can adopt,
underscoring the dynamic nature of this ligand. The O5-Pd-P3
bond angle of 2c is only 76.0° while the P1-Pd-P2 bond angle
ranges from 104.9° in 2d to 113.3° in 2a to 146.2° in 2b.
Although aryl chlorides, triflates, and nonaflates are all
capable coupling partners when using JackiePhos, we chose to
focus on modeling oxidative addition with chlorobenzene as it
would simplify the calculations and corresponds to the most
difficult case in the series that we studied. In Table 9, the
calculated barriers for oxidative addition to chlorobenzene with
Pd(0) complexes of JackiePhos (entry 1), BrettPhos (entry 2),
t-Bu2BrettPhos (entry 3), Ph2BrettPhos (entry 4), and L10 (entry
5) are listed. They are quite low, even for electron-deficient
ligands, ranging between 10.8 and 20.4 kcal/mol, and are in
agreement with our previous computational study29b on the
reactivity of SPhos ·Pd and XPhos ·Pd. The low barrier calcu-
lated for JackiePhos (20.1 kcal/mol, entry 1) supports our
assertion that this step is not rate-limiting. It is interesting that
even though JackiePhos is significantly more electron-deficient
than xantphos, the barrier to oxidative addition of chlorobenzene
with the former is over 16 kcal/mol lower in energy. This is
consistent with previous findings from our laboratory concerning
Further information on the mechanism of this step would be
gained from examining transition states for amide attack and
amide deprotonation. However, our efforts to locate such
structures were unsuccessful, and at this point we can only
qualitatively say that they will be higher in energy than the
corresponding ground states.
(37) (a) Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N. M. Chem.
Soc. ReV. 2009, 38, 1099. (b) Kamer, P. C. J.; van Leeuwen,
P. W. N. M.; Reek, J. N. H. Acc. Chem. Res. 2001, 34, 895.
(38) For the cross coupling of activated aryl chlorides using a Pd/xantphos
catalyst, see: refs 6c, d and (a) Itoh, T.; Mase, T. Org. Lett. 2004, 6,
4587. (b) Patriciu, O.-I.; Finaru, A.-L.; Massip, S.; Le´ger, J.-M.; Jarry,
C.; Guillaumet, G. Eur. J. Org. Chem. 2009, 3753.
The accessibility of isomer b in Table 10 relies on the
free rotation about the Caryl-P bond, which has been shown
(39) Xantphos-Pd(II) complexes are often most stable as the trans isomer;
see: ref 3b and (a) Zuideveld, M. A.; Swennenhuis, B. H. G.; Boele,
M. D. K.; Guari, Y.; van Strijdonck, G. P. F.; Reek, J. N. H.; Kamer,
P. C. J.; Goubitz, K.; Fraanje, J.; Lutz, M.; Spek, A. L.; van Leeuwen,
P. W. N. M. Dalton Trans. 2002, 2308. (b) Fujita, K.; Yamashita,
M.; Puschmann, F.; Alvarez-Falcon, M. M.; Incarvito, C. D.; Hartwig,
J. F. J. Am. Chem. Soc. 2006, 128, 9044.
(40) Barder, T. E.; Walker, S. D.; Martinelli, J. M; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 4685.
(41) For experimentally determined binding energies of amines and anilines
with dimeric SPhos ·Pd(II)(Ar)(Cl) complexes, see: Biscoe, M. R.;
Barder, T. E.; Buchwald, S. L. Angew. Chem., Int. Ed. 2007, 46, 7232.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16727

A R T I C L E S
Hicks et al.
Table 8. Xantphos·Pd(Ph)(Br) Isomers with Selected Bond Angles and Bond Lengths
Table 9. Calculated Reaction Barriers for the Oxidative Addition of
PhCl with L1Pd
than the chloride complex, would be the more difficult case.
The maximum of the resulting energy curve, shown in Figure
2, corresponds to a barrier of rotation of 19.8 kcal/mol, an
amount of energy that is readily overcome even at room
temperature.
We next performed potential energy scans about the
C2-P3 bond with analogous complexes containing the other
ligands, and very similar curves were obtained (not shown).
However, the maximum for the BrettPhos complex lies at a
dihedral angle of 90° while all of the other ligands gave
maxima at 80°. The barrier heights for these complexes are
listed in Table 11: JackiePhos (entry 1), BrettPhos (entry 2),
and Ph2BrettPhos (entry 4) give barriers of very similar
energies (19.2, 20.5, and 19.1 kcal/mol, respectively). Of note
is that switching the methoxy group of the upper ring to a
methyl group in JackiePhos increases the barrier significantly
to 23.3 kcal/mol (entry 5), presumably because of its larger
size. We also found that the barrier to rotation for the most
sterically congested ligand, t-Bu2BrettPhos (entry 3), is only
27.7 kcal/mol (compared to 33 kcal/mol for Me4t-
Bu2XPhos5a). It follows from the Eyring equation that this
barrier corresponds to a half-life of only 9.16 min at 110 °C
assuming a first-order rate law. Based on these data, we
conclude that under the reaction conditions (110-130 °C)
all the ligands including t-Bu2BrettPhos can freely rotate with
the Pd moiety being either over or away from the lower biaryl
ring.
∆G‡
(kcal/mol)
entry
GS
TS
R1
R2
1
2
3
4
5
3
4
5
6
7
3-TS
4-TS
5-TS
6-TS
7-TS
2,5-OMe
2,5-OMe
2,5-OMe
2,5-OMe
2-Me
3,5-CF3Ph
Cy
t-Bu
20.1
10.8
20.1
16.5
20.4
Ph
3,5-CF3Ph
in previous computational studies to be quite difficult for
Me4t-Bu2XPhos · Pd(Ph)(amidate).5a The JackiePhos · Pd(Ph)-
(amidate) complex is likely to have a lower barrier of rotation
for two reasons: first, the methoxy group ortho to phosphorus
is smaller than the methyl group in Me4t-Bu2XPhos, and
second, the P-bound arenes of JackiePhos are much smaller
than the bulky t-Bu groups of Me4t-Bu2XPhos. To support
this assertion, we performed a potential energy scan about
the Caryl-P bond in which a restricted structure optimization
was executed at every 10°. We chose to calculate this with
the JackiePhos · Pd(Ph)(amidate) complex because it, too,
would need to freely rotate once formed and, being larger
Dissociative Transmetalation. The loss of a halide/pseudoha-
lide to form cationic Pd(II) intermediates is quite common
9
16728 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Pd-Catalyzed N-Arylation of Secondary Acyclic Amides
A R T I C L E S
Scheme 2. Calculated Binding Energy of N-Methyl Acetamide to Xantphos ·Pd(Ph)(Br)
Table 10. Calculated Binding Energies of N-Methyl Acetamide to L1 ·Pd(Ph)(Cl)a
a ∆Grel is in reference to isomer a of each complex and N-methyl acetamide.
in Heck-type processes42 but is not necessary for most cross-
coupling reactions in which an organometallic component
participates as the nucleophile. However, this pathway should
be considered for reactions involving weakly nucleophilic,
nonmetallic partners, such as hindered amides. Furthermore,
dissociative ligand exchange through a cationic Pd(II)
intermediate has been suggested by van Leeuwen to occur
for xantphos-Pd(II) complexes undergoing cis/trans isomeriza-
tion39a and in the amination of aryl triflates.43
For the following calculations, we deemed it important to
model both the bromide and triflate, as the latter are so much
more effective as leaving groups.44 It was critical for the
inclusion of solvation effects for this step as dissociation was
highly endothermic in the gas phase. As depicted in Table
12, the energy differences between cationic complex 14 and
both the trans-xantphos · Pd(Ph)(Br) (2b) and trans-xantphos ·
Pd(Ph)(OTf) (15) complexes were determined. The loss of
the bromide is endothermic by 17.5 kcal/mol, but loss of
triflate is endothermic by only 0.8 kcal/mol. It should be
pointed out that correction for BSSE was critical for Br
dissociation as it was originally in error by 16.5 kcal/mol,
while triflate dissociation was only in error by 3.2 kcal/mol
(a more typical value). The unusually large error in the first
case is likely a result of the use of the approximations implicit
in the LANL2DZ basis set for an entire fragment.45
The ionization energy requirement for the bromide complex
could be low enough to outcompete the associative pathway.
For aryl triflates, the nearly equal energies of 14 and 15, our
inability to locate a five-coordinate amide-bound Pd-triflate
complex, and structural characterization by van Leeuwen39a of
a cationic xantphos ·Pd(Ar)(OTf) complex are good evidence
(42) (a) Deeth, R. J.; Smith, A.; Brown, J. M. J. Am. Chem. Soc. 2004,
126, 7144, references cited therein. (b) Tanaka, D.; Romeril, S. P.;
Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323.
(43) Guari, Y.; van Strijdonck, G. P. F.; Boele, M. D. K.; Reek, J. N. H.;
Kamer, P. C. J.; van Leeuwen, P. W. N. M. Chem.sEur. J. 2001, 7,
475.
(44) Howells, R. D.; McCown, J. D. Chem. ReV. 1977, 77, 69.
(45) Wadt, W. R.; Hay, J. J. Chem. Phys. 1985, 82, 284.
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16729

A R T I C L E S
Hicks et al.
K2-Binding of the Amide to Pd. Previous work has demon-
strated that Pd-catalyzed amidation reactions are complicated by
the formation of κ2-amidate complexes in which the amide is
simultaneously bound to the palladium center at both the nitrogen
and oxygen atoms.39b In these studies, it was shown that κ2-amidate
complexes do not undergo reductive elimination as readily as κ1-
amidate complexes. While some monophosphine ligands may not
be effective ligands for amidation as they allow κ2-amidate
formation, we have previously shown that bulky monodentate
biaryl phosphines can form effective catalysts for amidation.4c,5
In light of the experimental evidence presented,39b suggesting
that catalyst inhibition and inactivation results from κ2-binding,
we calculated the relative energies of κ1- and κ2-bound isomers
of both xantphos · Pd(Ph)(amidate) and JackiePhos · Pd(Ph)-
(amidate) complexes. Quite unexpectedly, the κ2-bound xantphos
structure (20) is calculated to be lower in energy than the cis-
κ1-bound structure (19) by 9.3 kcal/mol (Scheme 3). This energy
is seemingly in disagreement with the previously reported IR
and NMR data obtained for xantphos ·(Ph)(N-phenylacetamide)
complexes that support κ1-bound structures as being more
stable.39b However, the amide-bound complexes in this study
were prepared by the addition of potassium amides to
xantphos·Pd(Ph)(Br) at room temperature, and the thermody-
namically more stable isomer may have not been kinetically
accessible. Similarly, JackiePhos · Pd(Ph)(amidate) favors κ2-
bound structures, pointed both toward (22, -2.3 kcal/mol) and
away (23, -3.7 kcal/mol) from the lower biaryl ring (Scheme
4). In contrast to the xantphos system, the barrier to reach these
structures is probably not as high since there is an open
coordination site on Pd. Based on these results, we believe κ2-
binding does not necessarily lead to decomposition or inhibit
catalysis (i.e., it can form reversibly), but rather, it may lie on
the path to catalyst decomposition for unhindered monodentate
ligands.
Figure 2. Potential energy scan for rotation about the C2-P3 bond.
Table 11. Barriers to Rotation About the C2-P3 Bond for each
L1Pd(Ph)(amidate) Complex
maxima
(deg)
∆Ga
(kcal/mol)
entry
ligand
1
2
3
4
5
JackiePhos
BrettPhos
t-Bu2BrettPhos
Ph2BrettPhos
L10
80
90
80
80
80
19.2
20.5
27.7
19.1
23.3
Reductive Elimination. Reductive elimination is often the
most difficult step for the arylation of weaker nucleophiles such
as amides.46 We first calculated the barrier for C-N bond
formation from the xantphos ·Pd(Ph)(amidate) complex and
found it was 20.4 kcal/mol (8-TS, Scheme 5). In contrast to
the tetrahedral geometry in the transition state for oxidative
addition, this geometry is square planar, proceeding from cis-
complex 19. We believe that a tetrahedral transition state similar
in geometry to those found for oxidative addition (Table 7) is
no longer accessible due to the larger size of the amide compared
to bromide.
Next, we compared the barrier to C-N bond formation for
each of the biaryl monophosphine ligands (Table 14).47 The
ligands that allowed for the lowest barriers of reductive
elimination (16.6 kcal/mol for both) were t-Bu2BrettPhos (11-
TS, entry 2) and L10 (13-TS, entry 5), while the barrier for
this step was slightly higher with JackiePhos (17.7 kcal/mol,
entry 1). Both BrettPhos and Ph2BrettPhos were predicted to
be less effective at promoting this step, with barriers of 19.7
(entry 2) and 20.0 kcal/mol (entry 4), respectively.
a The electronic energies of structures corresponding to the indicated
dihedral angle were recalculated at 6-311+g(2d,p) with CPCM solvation
correction and zero-point energy correction.
that ligand exchange occurs by a dissociative pathway. However,
based on the experimental results that more hindered amides
(e.g., those that are the focus of this paper) are not readily
arylated with a xantphos/Pd catalyst and reductive elimination
should not be difficult (Vide infra), we must conclude that there
is also a significant energy cost to the approach of the amide
and/or isomerization from O- to N-bound isomers.
With a handle on the difference in energy for ionization in
xantphos·Pd(Ph)(OTf/Br) complexes, we were prompted to
perform similar calculations on the JackiePhos ·Pd(Ph)(OTf/Cl)
complexes (Table 13). The empty coordination site in the
cationic product may be cis or trans to the phosphorus, but
structures in which the empty site is trans to the phosphorus
were much lower in energy and are the only ones considered
here. Additionally, the Pd may be pointed away from the bottom
ring, in which it has a dative bond with the oxygen, or toward
the lower ring, in which it interacts with the π-electrons of the
arene. Surprisingly, C-bound isomer 18 is significantly lower
in energy than O-bound isomer 17. Unlike the xantphos system,
however, ionization of both the chloride (42.9 kcal/mol to reach
18) and triflate (34.9 kcal/mol to reach 18) were prohibitively
high in energy. The resistance to ionization of the JackiePhos
system is probably a consequence of the Pd being both
coordinatively unsaturated and electron poor.
Five-membered cyclic transition states were also found in
which an O-bound amidate pivots back toward the reactive Ph
group to form a C-N bond (Figure 3). In both the case of
xantphos (14-TS, 23.0 kcal/mol) and JackiePhos (15-TS, 22.0
kcal/mol), this transition state was higher in energy, leading us
(46) Hartwig, J. F. Inorg. Chem. 2007, 46, 1936.
(47) For a computational study on the reductive elimination of aryl amines
from biaryl monophosphine arylpalladium amido complexes, see:
Barder, T. E.; Buchwald, S. L. J. Am. Chem. Soc. 2007, 129, 12003.
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16730 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Pd-Catalyzed N-Arylation of Secondary Acyclic Amides
A R T I C L E S
Table 12. Dissociative Mechanism for Xantphos ·Pd(Ph)(X)
Table 13. Dissociative Mechanism for JackiePhos ·Pd(Ph)(X)
Scheme 3. Calculated Energy for κ2-Binding of
Xantphos·Pd(Ph)(Amidate)
metalation as well as the energy change for salt precipitation
and dissolution, as this is a heterogeneous reaction.
First, in Figure 4, the potential energy diagram for the
xantphos-Pd catalyst is depicted. Although aryl triflates likely
react through a dissociative pathway, we will examine the
energy pathway for the aryl bromide case because it will be
more comparable to the mechanism involving the biaryl-
monophosphine-derived catalysts. In the catalytic cycle with
bromobenzene, oxidative addition is slightly endothermic by
+3.3 kcal/mol based on the difference between 1 with
bromobenzene and the most stable trans-xantphos-Pd(II)
isomer (2b). Assuming transmetalation operates by associa-
tive ligand exchange, amide binding (8) brings the total
energy needed to 32.0 kcal/mol.
The information contained in the potential energy diagram
of the biarylmonophosphine-Pd catalysts in Figure 5 is not as
readily apparent as in Figure 4. First, the thermodynamics of
oxidative addition to reach C is drastically different for each
catalyst, all being exothermic but with an energy change ranging
between -0.2 and -13.8 kcal/mol. As a consequence, the more
exothermic this step becomes, the more energy that will be
required to scale the subsequent reaction barriers. In this
scenario, the energy requirement for catalysis will not be the
energy change from starting materials to the highest barrier but
the difference between the lowest point (C) and the highest
barrier. In the cases of t-Bu2BrettPhos and L10, the energy for
bond rotation (D) is the highest peak in Figure 5, but we believe
to believe that it constitutes a minor pathway for this reaction.
However, it may be more important in the arylation of other
less hindered amides or if O to N isomerization proves difficult.
Catalytic Cycle. Without an analysis of a continuous
potential energy diagram for the catalytic cycle, the relative
contributions from each mechanistic step are not entirely
clear. Accordingly, the relative energies of each step through
the amide binding event were connected in Figures 4 and 5
so that such an analysis could be performed. We did not
construct a potential energy diagram for the entire catalytic
cycle because of the uncertainties in the barriers to trans-
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J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16731

A R T I C L E S
Hicks et al.
Scheme 4. Calculated Energies of κ2-Binding of JackiePhos ·Pd(Ph)(Amidate)
Scheme 5. Calculated Barrier for Reductive Elimination of
cis-Xantphos·Pd(Ph)(Amidate)
under the reaction conditions, degrading by an as yet undeter-
mined pathway.
Conclusions
In summary, we have reported an efficient method for the
N-arylation of acyclic secondary amides with aryl nonaflates,
triflates, and chlorides. The catalyst system is also useful for
the N-arylation secondary carbamates, ureas, and sulfonamides
and the diarylation of primary amides. A ligand for this
transformation, JackiePhos (L6), was designed based on the
knowledge that “transmetalation” was rate-limiting for the
arylation of primary amides and the hypothesis that a more
electrophilic and less sterically demanding Pd(II) intermediate
would facilitate the “transmetalation” of secondary amides. Our
synthetic, mechanistic, and computational studies showed the
success of JackiePhos is due to (1) the methoxy group ortho to
the phosphorus and (2) the strongly electron-withdrawing
P-bound 3,5-(bis)trifluoromethylphenyl groups.
Table 14. Calculated Barriers for Reductive Elimination of
L1 ·Pd(Ph)(Amidate)
Theoretical studies have provided insight into the mechanism
of “transmetalation” and show that the lowest energy conforma-
tion for amide binding occurs while Pd is pointed away from
the lower biaryl ring. A potential energy scan about the Caryl-P
bond indicates that this conformation, in which Pd interacts with
the methoxy group ortho to the phosphorus, is quite accessible.
Our synthetic studies show that the ortho methoxy group is
critical for catalyst stability and cannot be removed or substituted
with a methyl group. Additionally, computational studies predict
the most favorable energies of amide binding for ligands
containing the highly electron-withdrawing P-bound 3,5-(bis)-
trifluoromethylphenyl groups. Overall, it seems the “transmeta-
lation” of secondary amides is facilitated by the ability of the
ligand to access a highly electrophilic Pd(II) intermediate where
∆G‡
(kcal/mol)
entry
GS
TS
R1
R2
1
2
3
4
5
21
24
25
26
27
9-TS
2,5-OMe
2,5-OMe
2,5-OMe
2,5-OMe
2-Me
3,5-CF3Ph
Cy
t-Bu
17.7
19.7
16.6
20.0
16.6
10-TS
11-TS
12-TS
13-TS
Ph
3,5-CF3Ph
that with consideration of the barriers for transmetalation and
reductive elimination it will not be rate-limiting.
Although we lack the information to give predicted energy
requirements and overall rates for each catalyst, we find that
the energy differences from the lowest energy point and the
amide-bound complex correlate well with ligand performance
in most cases. These energies are listed in Table 15, and the
smallest energy requirement is associated with JackiePhos (18.2
kcal/mol) and L10 (17.5 kcal/mol). We feel that the trends
shown here will be consistent but amplified when considering
the barriers for amide attack and deprotonation. Since L10 is
calculated to perform equally well or better than JackiePhos in
each mechanistic step but is completely ineffective in promoting
the reaction, we believe the catalyst formed from it is not stable
Figure 3. Five-membered cyclic transition states for reductive elimina-
tion.
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16732 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009

Pd-Catalyzed N-Arylation of Secondary Acyclic Amides
A R T I C L E S
Figure 4. Partial potential energy diagram of the catalytic cycle with the xantphos-Pd catalyst.
Figure 5. Partial potential energy diagram of the catalytic cycle with biarylmonophosphine-Pd catalysts.
the Pd is oriented away from the bottom ring of the biaryl
backbone and stabilized by the ortho methoxy group. Addition-
ally, the barrier to reductive elimination was lower for the
electron-deficient JackiePhos compared to other sterically similar
ligands (Ph2BrettPhos, L4). However, there remain many
questions on the precise mechanism and energetic requirements
of the transmetalation step, preventing the construction of a full
potential energy diagram. Overall, these studies further expand
9
J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009 16733

A R T I C L E S
Hicks et al.
Table 15. Calculated Energy Required for Catalytic Cycle through
Amide Binding (Not Including Deprotonation or Reductive
Elimination)
Acknowledgment. We thank the National Institutes of Health
(NIH) for funding this project (Grant GM-58160). We thank Merck,
Boehringer Ingelheim, BASF (Pd compounds), Chemetall (Cs2CO3),
and Nippon Chemical for additional support and the National
Science Foundation through the National Center for Supercomput-
ing Applications (NCSA), which provided supercomputing re-
sources. We are grateful to B. P. Fors for carrying out additional
experiments to address reviewer comments.
∆G
(kcal/mol)
ligand
xantphos
32.0a
18.2b
23.0b
23.5b
19.8b
17.5b
JackiePhos
BrettPhos
t-Bu2BrettPhos
Ph2BrettPhos
L10
Supporting Information Available: Experimental procedures
and spectral data for all compounds, computational data, kinetic
plots, and complete ref 32. This material is available free of
charge via the Internet at http://pubs.acs.org.
a Difference in energy from lowest energy state (1) and amide
binding (8) in Figure 4. b Difference in energy from lowest energy state
(C) and amide binding (E) in Figure 5.
our understanding of structural features of biarylmonophosphine
ligands and how each of these contributes to the catalysts derived
from them.
JA9044357
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16734 J. AM. CHEM. SOC. VOL. 131, NO. 46, 2009