Reductive elimination of alkylamines from low-valent, alkylpalladium(II) amido complexes

Article abstract of DOI:10.1021/ja307558x

A series of three-coordinate norbornylpalladium amido complexes ligated by bulky N-heterocyclic carbene (NHC) ligands were prepared that undergo reductive eliminations to form the alkyl-nitrogen bond of alkylamine products. The rates of reductive elimination reveal that complexes containing more-electron-donating amido groups react faster than those with less-electron-donating amido groups, and complexes containing more-sterically bulky amido groups undergo reductive elimination more slowly than complexes containing less-sterically bulky amido groups. Complexes ligated by more-electron-donating ancillary NHC ligands undergo reductive elimination faster than complexes ligated by less-electron-donating NHC ligands. In contrast to the reductive elimination of benzylamines from bisphosphine-ligated palladium amides, these reactions occur with retention of configuration at the alkyl group, indicating that these reductive eliminations proceed by a concerted pathway. The experimentally determined free energy barrier of 26 kcal/mol is close to the computed free energy barrier of 23.9 kcal/mol (363 K) for a concerted reductive elimination from the isolated, three-coordinate NHC-ligated palladium anilido complex.

Full text of DOI:10.1021/ja307558x

Communication
pubs.acs.org/JACS
Reductive Elimination of Alkylamines from Low-Valent,
Alkylpalladium(II) Amido Complexes
Patrick S. Hanley,‡ Seth L. Marquard,‡ Thomas R. Cundari,† and John F. Hartwig*,‡,§
‡Department of Chemistry, University of Illinois at Urbana−Champaign, Urbana, Illinois 61801, United States
§Department of Chemistry, University of California, Berkeley, California 94720, United States
†Department of Chemistry and Center for Advanced Scientific Computing and Modeling, University of North Texas, Denton, Texas
76203, United States
S
* Supporting Information
Pd intermediate that would be prone to C−N bond-forming
ABSTRACT: A series of three-coordinate norbornylpalla-
dium amido complexes ligated by bulky N-heterocyclic
carbene (NHC) ligands were prepared that undergo
reductive eliminations to form the alkyl−nitrogen bond of
alkylamine products. The rates of reductive elimination
reveal that complexes containing more-electron-donating
amido groups react faster than those with less-electron-
donating amido groups, and complexes containing more-
sterically bulky amido groups undergo reductive elimi-
nation more slowly than complexes containing less-
sterically bulky amido groups. Complexes ligated by
more-electron-donating ancillary NHC ligands undergo
reductive elimination faster than complexes ligated by less-
electron-donating NHC ligands. In contrast to the
reductive elimination of benzylamines from bisphos-
phine-ligated palladium amides, these reactions occur
with retention of configuration at the alkyl group,
indicating that these reductive eliminations proceed by a
concerted pathway. The experimentally determined free
energy barrier of 26 kcal/mol is close to the computed free
energy barrier of 23.9 kcal/mol (363 K) for a concerted
reductive elimination from the isolated, three-coordinate
NHC-ligated palladium anilido complex.
reductive elimination. In addition, several Pd-catalyzed
reactions that form C(sp3)−N bonds without external oxidant
have been reported, including the Pd-catalyzed formation of
norbornylindoline10,11 and an intermolecular amination of C−
H bonds.12 The species that undergoes the reductive
elimination step has not been observed directly in these
systems.
Recently, our group reported examples of C(sp3)−N and
C(sp3)−O bond-forming reductive elimination of benzylamines
and benzyl ethers from isolated benzylpalladium(II) amido and
phenoxide complexes ligated by a chelating phosphine ligand,
as shown in eq 1.13,14 Kinetic and stereochemical studies
implied that these reactions proceed by a stepwise pathway that
involves dissociation of the diarylamido ligand, followed by
nucleophilic attack of the amide onto a proposed η3-
benzylpalladium intermediate. However, reductive elimination
to form an alkyl−nitrogen bond from an isolated Pd complex
has not been reported, despite significant effort.15,16 Thermol-
ysis of 1,1'-Bis(diphenylphosphino)ferrocene (DPPF) ligated
alkylpalladium amido complexes that are analogues of the
benzylpalladium amido complexes did not generate products
from reductive elimination (eq 2).17
Here, we report a series of isolated and fully characterized
three-coordinate Pd-alkylamido complexes ligated by bulky,
monodentate N-heterocyclic carbene (NHC) ligands that
undergo direct thermal reductive eliminations of N-alkylamines.
The stereochemical outcome of the norbornylamine products
from the reductive elimination step implies that these reactions
occur by a concerted reductive elimination.
eductive elimination is a fundamental organometallic
R
transformation that is proposed to be the product-forming
step in numerous catalytic cycles.1 Although C−N bond-
forming reductive eliminations of arylamines from a variety of
transition metal amido complexes are known, reductive
elimination of an alkylamine from an isolated metal amido
complex has only been observed in a few cases. Hillhouse has
reported the intramolecular reductive elimination of an indoline
from a nickel amide in the presence of an oxidant,2,3 and
Goldberg has reported the reductive elimination of a
sulfonamide from a methylplatinum(IV) sulfonamido complex
by dissociation of the sulfonamide ligand.4 However, the direct,
thermal reductive elimination of an alkylamine from an isolated,
low-valent metal amido complex is not well documented.5
Several palladium-catalyzed reactions have been proposed to
occur by reductive elimination from a palladium amido
complex to form new C(sp3)−N bonds. Several C(sp3)−H
amidation reactions with added oxidants have been re-
ported.6−9 These reactions presumably generate a high-valent
Received: August 1, 2012
Published: August 30, 2012
© 2012 American Chemical Society
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Synthesis of the Pd-amido complexes in this study is
summarized in Scheme 1. To isolate Pd-alkylamido complexes
complexes ligated by tri-tert-butylphosphine possessed C−Pd−
N angles between 88.75 and 93.46° and P−Pd−N angles
between 166.00 and 170.66°.22 Complex 2b is more distorted
from a true T-shaped geometry than these previous complexes.
The C(norbornyl)−Pd−N angle is 109.15°, and the C-
(NHC)−Pd−C(norbornyl) angle is 161.28°. The Pd−N
distance is ∼0.041 Å shorter and the Pd−C(alkyl) distance is
∼0.057 Å longer than those of (P(t-Bu)3)Pd(Ar)NAr′2
complexes (2.078 and 1.987 Å).
Scheme 1. Preparation of SIPr-Ligated Norbornylpalladium
Amido Complexes 2a−f
Warming of the SIPr-ligated Pd-norbornyl complexes 2a−f
resulted in the reductive elimination of norbornylamines in
good yields. The yields and rate constants for these reactions
are shown in Table 1. The decomposition of Pd-amide 2a at 90
Table 1. Reductive Elimination of Norbornylamines from
Pd-Amides 2a−f
that are stable to β-hydrogen elimination, norbornylpalladium
complexes were prepared. The β-hydrogen atoms in the
norbornyl ligand are known to be resistant to β-hydrogen
elimination.18 The SIPr-ligated palladium chloride complex 1
was prepared by ligand substitution of (COD)Pd(2-CH3-
norbornyl)Cl18 with 1,3-bis(2,6-diisopropylphenyl)-
imidazolidin-2-ylidene (SIPr) in THF at room temperature.
X-ray crystallographic analysis showed that complex 1 exists as
a stable, three-coordinate chloride complex in the solid state.
Palladium anilido complexes 2a−f were synthesized in good
yields from the reaction of chloride 1 with KNHAr salts in
benzene over 2−4 h at room temperature. In solution, the SIPr
ligand of each Pd-amido complex rotates freely about the Pd−C
bond, as evidenced by two doublet resonances and one triplet
b
entry
complex
yield (%)
kobs (×10−4 s−1
11
18
)
1
2
3
4
5
6
2a; Ar = 4-CH3C6H4
2b; Ar = 4-OCH3C6H4
2c; Ar = 3-CF3C6H
85
77
70
79
84
95
1
1.2 0.1
2.4 0.2
7.2 0.5
4.8
2d; Ar = 2-CH3C6H4
2e; Ar = 2,6-(CH3)2C6H3
2f; Ar = 2,4-(CH3)2C6H3
1
resonance observed in the H NMR spectrum between δ 7.32
and 7.03, each integrating to two hydrogen atoms.
The solid-state structure of 2b was determined by single-
crystal X-ray diffraction, and an ORTEP drawing is shown in
Figure 1. Complex 2b is a stable, three-coordinate palladium
a
Reactions were conducted in NMR tubes with 0.013 mmol of Pd-
amide, 0.013 mmol of SIPr, and 0.013 mmol of trimethoxybenzene
(TMB) in 0.4 mL of toluene-d8 at 90 °C. Yields determined by
comparison of the integrated aryl reasonances of norbornylamine and
TMB standard.
b
°C formed 3-methyl-2-(4-methylanilino)norbornane product in
85% yield. The reductive elimination of 2a was conducted in
both THF and toluene. The reaction was slightly faster in THF-
d8 than in toluene-d8 at 50 °C, but by less than a factor of 2. In
the presence of 1 equiv of SIPr, the reaction generated
(SIPr)2Pd0 as the metal product in 89% yield.
1
The decay of the Pd-amides was monitored by H NMR
spectroscopy over time in the presence of 1 equiv of the NHC.
The decay curves fit well to a first-order exponential from
which the rate constants for reductive elimination were
determined. The reductive elimination was found to be zero-
order in the concentration of added NHC.23
The data in Table 1 reveal the electronic and steric effects of
the anilido ligand on the rate of reductive elimination:
complexes containing more-electron-donating anilido ligands
reacted faster than complexes containing less electron-donating
anilide ligands. Complex 2b, containing the most-electron-
donating p-anisylamido ligand, reacted approximately 2 times
faster than complex 2a, containing the p-tolylamido ligand, and
an order of magnitude faster than complex 2c, containing the
less-electron-donating m-trifluoromethylamido ligand. The
magnitude of the observed electronic effect on the rate of
reductive elimination of alkylamines is similar to that observed
on the reductive elimination of benzylamines13 and N-
methyldiarylamines24 from isolated benzyl- and arylpalladium
amido complexes.
Figure 1. ORTEP drawing of 2b with 35% probability ellipsoids.
Hydrogen atoms are omitted for clarity. Selected bond angles
(degrees) and lengths (Å): C(16)−Pd(1)−N(1), 161.28(12);
C(16)−Pd(1)−C(1), 89.35(12); N(1)−Pd(1)−C(1), 109.15(13);
Pd−C(16), 1.974(3); Pd−N, 2.037(3); Pd−C(1), 2.044(3).
amide that possesses a distorted T-shaped geometry and does
not form an N-bridged dimeric Pd-amido structure, which is
common among metal anilido complexes.19−21 The carbene
ligand is oriented cis to the open coordination site, and the 2-
methylnorbornyl ligand has the syn-exo configuration. Pre-
viously prepared three-coordinate arylpalladium diarylamido
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Complexes ligated by more-hindered anilido ligands reacted
more slowly than complexes containing less-sterically hindered
anilido ligands; however, the overall steric effect imparted by
the anilido ligand on the rate of reductive elimination was small.
The reductive elimination of complex 2d, containing an o-tolyl
substituent, was almost an order of magnitude slower than that
of complex 2a, containing a p-tolyl group, but the reductive
eliminations of complexes 2e and 2f, containing 2,6- and 2,4-
dimethylanilido ligands, respectively, were faster than that of
complex 2d and slower than that of complex 2a. We propose
that compensating steric and electronic effects of the
substituents of the anilido ligand of 2e and 2f result in
intermediate rate constants for the reductive elimination of the
corresponding N-arylnorbornylamines.
times smaller than the rate constant for the analogous reductive
elimination from complex 2a. In contrast to reductive
eliminations of benzylamines from four-coordinate benzylpalla-
dium amido complexes,13 this result indicates that the reductive
elimination of alkylamine is faster from complexes ligated by
more-electron-donating ancillary NHC ligands.
To examine the effects of the ancillary NHC ligand on the
rate of reductive elimination, we prepared a norbornylamido
complex (4) ligated by the unsaturated NHC, 1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene (IPr). Like that of 1, the
synthesis of the chloride complex 3 for conversion to the
anilide was accomplished by the reaction of 1 equiv of IPr with
(COD)Pd(2-CH3-norbornyl)Cl in THF. X-ray crystallography
showed that 3 exists as a dimeric Pd complex, with the two Pd
centers bridging through the chloride ligands. In solution, two
sets of resonances in the 1H NMR spectra suggest that 3 exists
as a mixture of cis and trans diastereomers at room temperature.
At 90 °C, a single set of resonances is observed that likely
indicates rapid interconversion between the cis and trans
diastereomers. Signer molecular weight analysis in benzene
confirmed that the 3 adopts a dimeric structure at room
temperature.
The stable stereochemical configuration of the norbornyl
ligand of the alkylpalladium amido complexes provides a means
to assess the mechanism of the reductive elimination step. The
reductive elimination of the norbornylamines could proceed by
one of the three pathways depicted in Scheme 2. A concerted
Scheme 2. Possible Mechanisms for the Reductive
Elimination of Norbornylamines from (SIPr)Pd(2-
CH3C7H10)NHAr Complexes
IPr-ligated complex 4 was isolated in 41% yield from the
reaction of 3 with 1 equiv of KNH(4-CH3C6H5) in benzene
(eq 3). Solid-state structural analysis confirmed that the IPr-
reductive elimination would lead to retention of the
configuration of the norbornyl ligand in Pd-amide 2a and
form the syn-exo-3-methyl-exo-2-(4-methylanilino)norbornane.
A stepwise pathway involving dissociation of the amido ligand
and backside nucleophilic attack onto the endo face of the
norboryl ligand would result in inversion of the configuration,
forming only the anti-exo-3-methyl-endo-2-(4-methylanilino)-
norbornane. Finally, a radical pathway would result in an
erosion of the configuration and the formation of multiple
isomers of the norbornylamine product.
To assess whether the stereochemical outcome of the
reaction would be biased by the relative stabilities of the
diastereomeric products, we computed the energies of the
different stereoisomers. Energy minimizations by DFT indicate
that the ground-state free energy of the syn-exo-3-methyl-exo-2-
anilinonorbornane isomer 8 is higher than that of either anti
diastereomer 6 or 7 by about 1.4 and 1.7 kcal/mol (Figure 2).
Thus, the product that would be formed by a concerted
pathway is the least stable of the diastereomers.
ligated norbornylamido complex is a stable three-coordinate
monomer. Pd-amide 3 crystallized as two distinct molecules
within the unit cell, both of which are less distorted from a true
T-shape than the SIPr-ligated Pd-amide 2a. Complex 4
contains C(NHC)−Pd−N angles of 163.42 and 163.83°,
C(norbornyl)−Pd−N angles of 91.05 and 92.05°, and C−
Pd−C angles of 105.06 and 103.67°.
The preparation of analogous norbornylpalladium amido
complexes ligated by 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-
ylidene (IMes) did not lead to an isolable amido complex. The
reaction of (IMes)Pd(2-CH3-norbornyl)Cl with KNHAr
generated a mixture of products that we were unable to
1
identify by H NMR spectroscopy. The IMes ligand lacks the
bulky isopropyl groups of SIPr and IPr that are likely necessary
for the formation of stable, three-coordinate amido complexes.
Warming of IPr-ligated 4 in toluene at 90 °C in the presence
of 1 equiv of IPr resulted in the reductive elimination of the
norbornylamine product in 80% yield and (IPr)2Pd0 in 92%
yield (eq 4). The rate constant for the reductive elimination of
Reductive eliminations from Pd-amides 2a−f and 4 formed a
single diastereomer. Independent preparation of syn- and anti-
norbornylamine isomers revealed that the syn-exo,exo diaster-
eomer 8 is formed.25 Thus, this reaction occurs with retention
of configuration at the palladium-bound carbon. This stereo-
N-norbornyltoluidine from 4, (5.7
0.1) × 10−4 s−1, was 5
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AUTHOR INFORMATION
Corresponding Author
jhartwig@berkeley.edu
■
Notes
The authors declare no competing financial interest.
Figure 2. Computed relative ground-state free energies (ΔG) of three
diastereomers of 3-methyl-2-anilinonorbornane.
ACKNOWLEDGMENTS
■
We thank the NSF for financial support through the Center for
Enabling New Technologies Through Catalysis (CENTC) and
Danielle Gray for collection of X-ray data.
chemical outcome implies that reductive elimination of the
norbornylamine from the three-coordinate (SIPr)Pd(2-
CH3C7H10)NHAr complexes occurs by a concerted pathway.
Because a direct, concerted reductive elimination from an
alkylpalladium amide has not been documented previously, we
sought to determine if the barrier we measured for such a
process is consistent with that computed for a concerted
reductive elimination. Hybrid quantum mechanics/molecular
mechanics (QM/MM) calculations were performed on a full
chemical model of 2f. The transition-state structure computed
for a concerted reductive elimination is illustrated in Figure 3.
REFERENCES
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In conclusion, we report discrete, low-valent Pd complexes
that undergo reductive elimination of alkylamines. The steric
bulk of the SIPr and IPr ligands leads to the formation of stable
three-coordinate palladium amido complexes, which undergo
reductive elimination of alkylamine upon heating without an
external oxidant to create a higher-valent intermediate. The
stereochemical configuration of the norbornylamine products
implies that these reductive eliminations occur by a concerted
mechanism. This mechanism contrasts the stepwise mechanism
for the reductive elimination of benzylamines from four-
coordinate DPPF-ligated benzylpalladium complexes. Future
work will examine the reductive elimination of alkylamines
from complexes ligated with a range of ancillary ligands and the
development of new catalytic reactions involving this class of
reductive elimination.
(17) Marquard, S. L. Ph.D. Thesis, University of Illinois at Urbana−
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(23) The rate constant for the reaction of 2a at 90 °C in the presence
of excess (10 equiv) SIPr was 1.0 × 10−3 s−1.
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(25) Detailed procedures for the synthesis of the syn-exo,exo-
norbornylamine products from the reductive eliminations in this
report are described in the Supporting Information.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization of complexes and
reductive elimination products, including CIF files, and
computational details. This material is available free of charge
via the Internet at http://pubs.acs.org.
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