side products.4,5 Ammonia surrogates have long been uti-
lized in the synthesis of primary arylamines,7 but their use is
significantly less atom-economical than the use of NH3.
A number of research groups including our own5 have
reported the selective Pd-catalyzed arylation of NH3 to
produce primary arylamines with minimal formation of
diarylamine side products. In the case of results from our
group, we demonstrated that a Pd catalyst supported by
the biarylphosphine ligand, tBuDavePhos (L1, Scheme 1),
is reasonably effective for the selective production of the
primary arylamines.5c
Table 1. Ligand Optimization for the Selective Pd-Catalyzed
Arylation of NH3
a
conv
(%)b
yield of
1 (%)b
yield of
2 (%)b
entry
ligand
1
2c
3
4
5
6
7
8
9
L1
L2
L3
L4
L5
L6
L7
L8
L9
100
100
100
100
100
100
100
54
72
80
89d
87
80
92d
76
22
28
15
3
4d
3
4
2d
16
20
7
Scheme 1. Pd-Catalyzed Selective Arylation of NH3
43
a Conditions: PhCl (0.5 mmol), NH3 (1.5 mmol), NaOtBu (0.7 equiv),
Pd2(dba)3 (1 mol %), ligand (5 mol %), dioxane (4 mL, 0.125 M), 80 °C,
5 h. b Determined by GC. c 13 h. d Average of two runs.
Despite the considerable advances, limitations remain.
These include: (1) the coupling of aryl halides bearing base-
sensitive (e.g., cyano and carbonyl) groups is typically
problematic or provide anilines in lower yields when
utilizing NaOtBu as the base.5 While one report detailing
the use of K3PO4 has appeared,5b it necessitates the use of a
high pressure of NH3. (2) The substrate scope with respect
to heteroaryl halides is generally limited to pyridines and
(iso)quinolines,5 and the Pd-catalyzed coupling of NH3
with more challenging heterocylic substrates, such as
diazines and five-membered heterocycles, is still unprece-
dented. Herein, we report the use of bulky biarylphosphine
ligands and their corresponding palladium precatalysts
that allow the highly selective arylation of NH3 to generate
a wide range of anilines and heteroarylamines in moderate
to excellent yields under mild reaction conditions.
Initial experiments focused on identifying optimal con-
ditions for the Pd-catalyzed coupling of chlorobenzene
with ammonia, utilizing 3 equiv of NH3 and Pd2(dba)3 as
the Pd source in a minimal amount of solvent (0.125 M)
(Table 1). Although L1 was previously reported to be an
excellent ligand for this transformation when 5 equiv of
NH3 and additional solvents were used (Scheme 1), the
ratio of aniline (1) to diphenylamine (2) decreased signifi-
cantly under these conditions (Table 1, entry 1). We pro-
posed that the appropriate ancillary ligand could decrease
the amount of 2; thus we proceeded to examine the effects
of biarylphosphine ligands on the selectivity of arylation.
We recently reported the use of sterically demanding ligands,
Me4 BuXPhos (L2),8a tBuBrettPhos (L3),8b,c AdBrettPhos
t
(L4),8d and RockPhos (L5),8e for the efficient cross-coupling
of smaller nucleophiles (hydroxide,8a fluoride,8b,e chloride,8c
and bromide8c) and five-membered heterocyclic electro-
philes.8d As depicted in Table 1 (entries 2ꢀ5), ligands
L2ꢀL5 provided higher yields of 1 while concomitantly
decreasing the formation of 2. To maximize the ratio of 1:2
further, we prepared and examined the effectiveness of new
Me3(OMe)XPhos-type ligands L6ꢀL9,9 which, like L2,
contain a more conformationally rigid biaryl backbone as
a result of the 3- and 6-methyl groups. We found that the
(5) For Pd chemistry, see: (a) Shen, Q.; Hartwig, J. F. J. Am. Chem.
Soc. 2006, 128, 10028. (b) Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc.
2009, 131, 11049. (c) Surry, D. S.; Buchwald, S. L. J. Am. Chem. Soc.
€
2007, 129, 10354. (d) Schulz, T.; Torborg, C.; Enthaler, S.; Schaffner, B.;
€
Dumrath, A.; Spannenberg, A.; Neumann, H.; Borner, A.; Beller, M.
€
Chem.;Eur. J. 2009, 15, 4528. (e) Dumrath, A.; Lubbe, C.; Neumann,
H.; Jackstell, R.; Beller, M. Chem.;Eur. J. 2011, 17, 9599. (f) Lundgren,
R. J.; Sappong-Kumankumah, A.; Stradiotto, M. Chem.;Eur. J. 2010,
16, 1983. (g) Lundgren, R. J.; Peters, B. D.; Alsabeh, P. G.; Stradiotto,
M. Angew. Chem., Int. Ed. 2010, 49, 4071. (h) Alsabeh, P. G.; Lundgren,
R. J.; McDonald, R.; Johansson Seechurn, C. C. C.; Colacot, T. J.;
Stradiotto, M. Chem.;Eur. J. 2013, 19, 2131.
(6) For recent examples of Cu chemistry, see: (a) Ji, P.; Atherton,
J. H.; Page, M. I. J. Org. Chem. 2012, 77, 7471. (b) Liao, B.-S.; Liu, S.-T.
J. Org. Chem. 2012, 77, 6653. (c) Huang, M.; Wang, L.; Zhu, X.; Mao,
Z.; Kuang, D.; Wan, Y. Eur. J. Org. Chem. 2012, 4897. (d) Fantasia, S.;
Windisch, J.; Scalone, M. Adv. Synth. Catal. 2013, 355, 627.
(8) (a) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L. J.
Am. Chem. Soc. 2006, 128, 10694. (b) Watson, D. A.; Su, M.; Teverovskiy,
G.; Zhang, Y.; Garcıa-Fortanet, J.; Kinzel, T.; Buchwald, S. L. Science
2009, 325, 1661. (c) Pan, J.; Wang, X.; Zhang, Y.; Buchwald, S. L. Org. Lett.
2011, 13, 4974. (d) Su, M.; Buchwald, S. L. Angew. Chem., Int. Ed. 2012, 51,
4710. (e) Maimone, T. J.;Miner, P. J.;Kinzel, T.; Zhang, Y.; Takase, M. K.;
Buchwald, S. L. J. Am. Chem. Soc. 2011, 133, 18106.
(9) We have reported the synthesis of Me3(OMe)tBuXPhos from
inexpensive 2,3,6-trimethylphenol; see: Ueda, S.; Ali, S.; Fors, B. P.;
Buchwald, S. L. J. Org. Chem. 2012, 77, 2543. See SI for details of the
synthesis of L6ꢀL9.
(7) For examples, see: (a) Lee, S.; Jørgensen, M.; Hartwig, J. F. Org.
Lett. 2001, 3, 2729. (b) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3,
3417. (c) Lee, D.-Y.; Hartwig, J. F. Org. Lett. 2005, 7, 1169.
B
Org. Lett., Vol. XX, No. XX, XXXX