Lewis acid acceleration of C-N bond-forming reductive elimination from heteroarylpalladium complexes and catalytic amidation of heteroaryl bromides

Article abstract of DOI:10.1021/ja0722473

A large acceleration of carbon-nitrogen bond-forming reductive elimination from heteroarylpalladium amido complexes by addition of Lewis acids is described. Several lines of data imply that this effect arises from coordination of the Lewis acid to the nitrogen of the heteroaryl group. The presence of this coordination was confirmed by isolation of a Lewis acid base complex with a borane coordinated to the pyridyl nitrogen. This adduct underwent reductive elimination faster than the complex lacking the Lewis acid, and it occurred in high yield. Control experiments showed that this acceleration of reductive elimination was not observed for the reactions of arylpalladium amide complexes. This effect of Lewis acids translated to catalytic C-N bond-forming coupling processes. The binding of Lewis acids to the pyridyl nitrogen led to an acceleration of the amidation of unactivated heteroaryl bromides catalyzed by palladium complexes of Xantphos. The rates were faster and the yields were higher for reactions of BEt₃ adducts of basic heteroaryl bromides than for the free heteroaryl bromides. This phenomenon draws parallels to the beneficial effect of Lewis acids on the reductive elimination of nitriles from arylmetal cyanide complexes and the catalytic hydrocyanation of olefins. Copyright

Full text of DOI:10.1021/ja0722473

Published on Web 06/02/2007
Lewis Acid Acceleration of C-N Bond-Forming Reductive Elimination from
Heteroarylpalladium Complexes and Catalytic Amidation of Heteroaryl Bromides
Qilong Shen and John F. Hartwig*
Department of Chemistry, UniVersity of Illinois, 600 South Mathews AVenue, Urbana, Illinois 61801, and
Department of Chemistry, Yale UniVersity, P.O. Box 208107, New HaVen, Connecticut 06520-8107
Received March 30, 2007; E-mail: jhartwig@uiuc.edu
Catalytic reactions of basic heteroaromatic reagents can be
challenging because the ligating ability of the heteroatom can lead
to catalyst deactivation and because the electronic properties of
certain ring positions can be unfavorable for the elementary
reactions required for the catalytic processes. These factors have
particularly complicated the palladium-catalyzed coupling of amines1
with heteroaryl halides.2 We report a strategy to address these
challenges. We show that the coordination of Lewis acids to the
nitrogen of pyridylpalladium complexes leads to an acceleration
of the rate of reductive elimination by more than 3 orders of
magnitude and that this coordination can facilitate palladium-
catalyzed coupling of amides with unactivated heteroaryl halides.3
We and others have observed that the coupling of heteroaryl
halides with zinc and alkali metal reagents can be different.4 This
observation led us to probe the potential effect of Lewis acids on
the reactivity of isolated heteroarylpalladium amido complexes and
on the catalytic coupling of heteroaryl halides with nitrogen
nucleophiles. To do so, we compared the rates and yields of
reductive elimination from pyridylpalladium amido complexes in
the presence and absence of added Lewis acids.
heating of 6 with PPh3 and suspended ZnCl2 in toluene solvent
formed over 90% yield of 4-N,N-diarylaminopyridine after 10 min at
90 °C (eq 2). Because of the lack of solubility of ZnCl2, we could
not study the effect of this Lewis acid quantitatively. Thus, to obtain
more quantitative data, we studied the reductive elimination of
4-pyridyl complex 6 in the presence of soluble boron Lewis acids.
Like ZnCl2, BEt3 accelerated the reductive elimination of
heteroarylamines from 4-pyridyl complex 6 (eq 2). Mixing of 6
with 1 equiv of BEt3, followed by addition of PPh3, led to reductive
elimination at room temperature within 30 min to give the pyridyl
di(tert-butylphenyl)amine in >90% yield. A similar effect of the
Lewis acid on reductive elimination from the pyridylpalladium
amidate complexes 10 and 11 was observed. Heating of 10 or 11
with BEt3 at 110 °C for 30-60 min formed the N-pyridyl
sulfonamide in 80 and 81% yields. In the absence of Lewis acid,
little reaction occurred after 1 h; after 24 h at 110 °C, the complex
was consumed but <10% yield of coupled product was observed.
Boron Lewis acids also accelerated reductive elimination from
3-pyridylpalladium amide 7, but the magnitude of this effect was
smaller than that for reductive elimination from 4-pyridyl complex
6. Heating a toluene solution of 7 with 1 equiv of BPh3 and excess
PPh3 at 90 °C for 2 h formed the corresponding triarylamine in
70% yield instead of the 38% yield that was observed after 5 h in
the absence of Lewis acid (eq 2).
To define the origin of the effect of the Lewis acid more
explicitly, the product from interaction of BEt3 with a heteroarylpal-
ladium complex was isolated. Because the amide complexes are
unstable after coordination of the Lewis acid, we were unable to
isolate the BEt3 adduct of the 4-pyridylpalladium amide complex.
However, addition of BEt3 to a THF solution of sulfonamidate 10
formed a stable complex 12 containing borane coordinated at the
nitrogen of the pyridyl group (eq 3). Complex 12 was characterized
by 1H NMR, 31P NMR, and 11B NMR spectroscopy. The 11B NMR
resonance at δ 1.0, which lies in the range of chemical shifts that
are characteristic of R3B‚Py complexes,8 indicated that the boron
was bound to nitrogen. This assignment was confirmed by X-ray
diffraction, although the quality of the data was not high enough
to obtain detailed structural information. Heating of this adduct in
Equation 1 summarizes the synthesis of pyridylpalladium
complexes in this study. Addition of KN(p-t-BuC6H4)2 to DPPBz-
ligated pyridyl- and p-tolylpalladium complexes 1-5 formed the
diarylamido complexes 6-9.5 Likewise, addition of KNMe(SO2-
Ar) formed the sulfonamidates 10 and 11. Complexes 6-11 were
stable at room temperature and were characterized by conventional
spectroscopic and microanalytical methods.
Reductive eliminations of the pyridyl- and arylpalladium amido
complexes are summarized in eq 2. In the absence of Lewis acids,
reductive elimination from 3-pyridyl- and 4-pyridylpalladium
diarylamido complexes occurred in lower yields than from arylpal-
ladium diarylamido complexes. Warming 4-pyridyl complex 6 at
90 °C in toluene for 10 h with added PPh3 did not form the pyridyl
diarylamine. Instead, free amine and biaryl products derived from
the palladium-bound pyridyl and the phosphine phenyl groups
formed. Likewise, reaction of the 3-pyridyl complex 7 required
heating in toluene at 110 °C for 5 h and formed the triarylamine in
a low 38% yield. Although reductive elimination from the DPPBz-
ligated arylpalladium amido complexes is less favorable than that
from complexes containing other phosphines,6,7 heating of p-
tolylpalladium complex 9 in the presence of PPh3 did form
triarylamine in 50% yield after 8 h at 90 °C.
In contrast to the slow rates and low yields for formation of
heteroarylamines from reactions of 6 and 7 with phosphine alone,
9
7734
J. AM. CHEM. SOC. 2007, 129, 7734-7735
10.1021/ja0722473 CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Rate Constants for Reductive Eliminations from
Pyridylpalladium Sulfonamidate 11 in the Presence of Different
Lewis Acids
1
4
entry
Lewis acid
temp (
°
C)
k (s-
×
10-
)
t1 2 (min)
/
1
2
3
4
BEt3
BEt3
BPh3
B(C6F5)3
90
70
70
40
7.7 (0.8)
15
∼170
14
toluene for 2 h at 90 °C formed the N-methyl-N-4-pyridyl
sulfonamide in 80% yield.
8.3 (0.2)
6.8 (0.5)
17
Although the most stable adduct contains the Lewis acid at the
pyridyl nitrogen, reductive elimination need not occur through this
species. To distinguish an effect of the Lewis acid by coordination
to the pyridyl nitrogen from an effect from coordination to the
amido nitrogen or the metal center, we heated the p-tolylpalladium
complex 9 in the presence of the Lewis acid. Acceleration of C-N
reductive elimination by the Lewis acid was not observed. Warming
of 9 with 1 equiv of BEt3 in the presence of PPh3 at 90 °C for 2 h
formed 4-ethyltoluene in 72% yield from exchange of the amido
and Lewis acid groups (eq 4). Warming of 9 with 1 equiv of BEt3
in the absence of PPh3 at 110 °C for 2 h formed 4-ethyltoluene in
57% yield. Thus, the accelerating effect of the Lewis acid on the
reductive eliminations from the 4-pyridyl complex 6 appears to
result from coordination of the Lewis acid to the pyridyl nitrogen.
Table 2. Palladium-Catalyzed Amidation of Heteroaryl Halides in
the Presence of Lewis Acids
a Isolated yield from an average of at least two runs; the borane is
removed during chromatography. b Yield by GC with an internal standard.
c 48 h. d BEt3 (20 mol %) was used.
binding to the cyanide ligand.11 The origin of the effect of Lewis
acids on the C-N reductive elimination is likely to result from the
creation of an electron-poor aryl group by Lewis acid binding;
reductive elimination of arylamines is known to be faster from
arylpalladium complexes containing more electron-poor aryl groups.6
Studies to define the origin and scope of this effect are ongoing.
Acknowledgment. We thank the NIH (GM-55382) for support
of this work, and Johnson Matthey for a gift of palladium catalysts.
Supporting Information Available: All experimental procedures
and spectroscopic data of new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
The Lewis acids did not affect the rate or yield of reductive
elimination of 2-pyridylpalladium amides. Reductive elimination
from the 2-pyridylpalladium complex 8 is relatively fast in the
absence of Lewis acids (heating of 8 at 70 °C for 5 h gave the
2-pyridyl diarylamine in 95% yield), and the nitrogen is sterically
hindered. Further, the Pd-C-N bond angle in the solid-state
structure of 8 is only 115.3°, which suggests the presence of a weak
interaction of the pyridyl nitrogen with the palladium.
The rate of reductive elimination increased with increasing
strength of the Lewis acids. Table 1 summarizes rates of reaction
of the heteroarylpalladium amidate 11 in the presence of BEt3, BPh3,
and B(C6F5)3. The complex containing BPh3 reacted nearly 12 times
faster than the complex containing BEt3, and the complex containing
B(C6F5)3 reacted even faster.
References
(1) (a) Hartwig, J. F. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E. I., Ed.; Wiley-Interscience: New York, 2002; Vol.
1, p 1051. (b) Hartwig, J. F. In Modern Arene Chemistry; Astruc, C.,
Ed.; Wiley-VCH: Weinheim, Germany, 2002; p 107. (c) Hartwig, J. F.
In Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH: Weinheim,
Germany, 2000, p 195. (d) Yang, B. H.; Buchwald, S. L. J. Organomet.
Chem. 1999, 576, 125. (e) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem.
2002, 219, 131.
To probe whether this acceleration of reductive elimination could
affect catalytic processes, we studied the effect of Lewis acids on
the amidation of aryl halides. In principle, this effect could be used
to improve these reactions conducted with any ligand. Data on
couplings in the presence and absence of added BEt3 for reactions
conducted with the Xantphos ligand commonly used for the
amidation of haloarenes9 are shown in Table 2. The reactions of
heteroaryl bromides with amides in the presence of K3PO4 as base
and Pd(dba)2/Xantphos as catalyst in toluene solvent occurred to
full conversion. The reactions formed the coupled product in 57-
91% yields in the presence of 1.0 equiv of BEt3 and in similar
yields with substoichiometric BEt3 in the example tested. Reactions
under the same conditions but without Lewis acid occurred to lower
conversions and formed the products in 5-63% yield.10 Products
from ethyl group transfer were formed in less than 10% yield when
BEt3 was used. Further investigation of the scope of C-N coupling
in the presence of Lewis acids will be part of future studies.
In summary, we report the promotion of reductive elimination
from several heteroarylpalladium amido complexes by Lewis acids.
This effect is most similar to the Lewis acid acceleration of the
reductive elimination of nitriles during catalytic hydrocyanation by
(2) (a) Shen, Q.; Shekhar, S.; Stambuli, J. P.; Hartwig, J. F. Angew. Chem.,
Int. Ed. 2004, 44, 1371. (b) Anderson, K. W.; Tundel, R. E.; Ikawa, T.;
Altman, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 6523.
(3) (a) Burton, G.; Cao, P.; Li, G.; Rivero, R. Org. Lett. 2003, 5, 4373. (b)
Alcaraz, L.; Bennion, C.; Morris, J.; Meghani, P.; Thom, S. M. Org. Lett.
2004, 6, 2705. (c) Ji, J.; Li, T.; Bunnelle, W. H. Org. Lett. 2003, 5, 4611.
(d) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421.
(4) (a) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
4976. (b) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979. (c) Ghosh,
I.; Jacobi, P. A. J. Org. Chem. 2002, 67, 9304.
(5) (a) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852. (b) Hooper, M. W.;
Hartwig, J. F. Organometallics 2003, 22, 3394.
(6) Driver, M. S.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 8232.
(7) Yamashita, M.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 5344.
(8) (a) Noth, H.; Wrackmeyer, B. Chem. Ber. 1974, 107, 3070. (b) Weisman,
A.; Gozin, M.; Kraatz, H.; Milstein, D. Inorg. Chem. 1996, 35, 1792.
(9) (a) Yin, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 6043. (b) Yin,
J.; Buchwald, S. L. Org. Lett. 2000, 2, 1101. (c) Yin, J.; Zhao, M. M.;
Huffman, M. A.; McNamara, J. M. Org. Lett. 2002, 4, 3481.
(10) The rate of the catalytic reactions was affected by whether the catalyst or
reagents were added first. Further study is needed to optimize conditions,
but the Lewis acid accelerated reactions conducted with either order.
(11) (a) Tolman, C. A.; Seidel, W. C.; Druliner, J. D.; Domaille, P. J.
Organometallics 1984, 3, 33. (b) Huang, J. K.; Haar, C. M.; Nolan, S. P.;
Marcone, J. E.; Moloy, K. G. Organometallics 1999, 18, 297.
JA0722473
9
J. AM. CHEM. SOC. VOL. 129, NO. 25, 2007 7735