C(sp3)-N bond-forming reductive elimination of amines: Reactions of bisphosphine-ligated benzylpalladium(II) diarylamido complexes

Article abstract of DOI:10.1002/anie.200904032

(Chemical Equation Presented) A rare event: The benzylpalladium amido complex 1 (Ar= napthyl) was used to study the mechanism of an unusual reductive elimination of amines (see scheme). The observed inversion of configuration is proposed to result from dissociation of the amido ligand, followed by nucleophilic attack on the benzylic carbon atom. binap = 2,2′- bis(diphenylphosphanyl)-1,1′-binaphthyl, dppf=1,1′- bis(diphenylphosphanyl)ferrocene.

Full text of DOI:10.1002/anie.200904032

Angewandte
Chemie
DOI: 10.1002/anie.200904032
Palladium Amido Complexes
C(sp3)–N Bond-Forming Reductive Elimination of Amines: Reactions
of Bisphosphine-Ligated Benzylpalladium(II) Diarylamido
Complexes**
Seth L. Marquard, Devon C. Rosenfeld, and John F. Hartwig*
Reductive elimination is a common organometallic trans-
formation that is the key product-forming step in many
catalytic cycles.[1] Although many examples of reductive
tivity, and synthetic accessibility. Dppf-ligated benzylpalla-
dium amido complexes 1–7 were synthesized by treatment of
the known complex [(cod)Pd(Bn)Cl][9] (Bn = benzyl) with
dppf followed by the appropriate potassium diarylamide in
THF (Scheme 1). Complexes 8 and 9, which contain naph-
elimination from aryl palladium amido complexes to form
2
À
C(sp ) N bonds have been reported as part of catalytic
processes and as stoichiometric reactions,[2,3] reductive elim-
ination to form a bond between an amide ligand and an sp3-
hybridized carbon atom is less common. Reductive elimina-
tion from methylplatinum(IV) sulfonamido complexes by
dissociation of the sulfonamide has been reported,[4] as has
reductive elimination from alkyl nickel amido complexes
after the addition of an oxidant.[5,6] Reactions of free amines
with allyl- and benzylpalladium complexes are also known.[7–9]
However, despite several attempts,[10,11] reductive elimination
to form an C(sp ) N bond of any type through the simple
thermal reaction of an isolated organometallic amido com-
plex has not been reported.
3
À
Herein, we report a purely thermal reductive elimination
3
À
to form a C(sp ) N bond in an amine from a benzylpalladium
amido complex. An assessment of the stereochemical course
of this process showed that it occurs by a stepwise pathway
that is distinct from the accepted concerted pathway for the
reductive elimination of aromatic amines from aryl palladiu-
m(II) species, and an assessment of the effect of the electronic
properties of the amido group on the reaction rate showed
that this effect is distinct from that observed for reductive
À
elimination to form C O bonds from methylplatinum(IV)
carboxylate and phenoxide complexes.
We prepared a series of benzylpalladium amido com-
plexes to investigate their ability to undergo reductive
Scheme 1. Synthesis of palladium amido complexes. cod=1,5-cyclo-
octadiene.
3
À
elimination to form C(sp ) N bonds without competing b-
hydrogen elimination. We chose complexes containing che-
lating ligands to enforce a cis configuration of the benzyl and
the amido ligands for reductive elimination; complexes
containing a 1,1’-bis(diphenylphosphanyl)ferrocene (dppf)
ligand displayed the appropriate balance of stability, reac-
thylmethyl and mesitylmethyl groups, respectively, were
synthesized by the treatment of [CpPd(h3-allyl)][12] with
dppf followed by naphthylmethyl or mesitylmethyl bromide.
The resulting bromide complexes were then converted into
the diarylamido complexes by treatment with the appropriate
potassium diarylamide. The benzylpalladium arylamido com-
plex 10 and methylpalladium diarylamido complex 11 were
synthesized by analogous methods involving the treatment of
[(cod)Pd(Bn)Cl] with dppf followed by the potassium anilide,
and the treatment of [(cod)Pd(Me)Cl][13] with dppf followed
by the potassium diarylamide. These compounds were
characterized by conventional one- and two-dimensional
NMR spectroscopic methods and elemental analysis.
[*] S. L. Marquard, Dr. D. C. Rosenfeld, Prof. Dr. J. F. Hartwig
Department of Chemistry
University of Illinois Urbana-Champaign
Urbana, IL 61801 (USA)
Fax: (+1)217-244-8024
E-mail: jhartwig@illinois.edu
[**] This research was supported by the NSF as part of the Center for
Enabling New Technologies through Catalysis (CENTC), CHE-
0650456. We thank Luc Boisvert and Karen Goldberg at the
University of Washington for helpful discussions.
To assess the ability of complexes 1–11 to undergo
reductive elimination, we heated solutions of these complexes
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200904032.
Angew. Chem. Int. Ed. 2010, 49, 793 –796
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
793

Communications
in benzene at 758C. The reactions were conducted with added
differences were not large. Complex 2 and the diphenylamido
complex 3 reacted at nearly identical rates. The p-chloroa-
mido complex 4 reacted somewhat faster than the ditolyla-
mido complex 2, which suggests that p donation from the aryl
groups may be important. From this assessment, the rate of
reductive elimination is moderately influenced by the elec-
tronic properties of the amido group, and the complexes
containing more electron rich amido groups react faster.
The substitution pattern of the amido group had a
substantial influence on the rate of reductive elimination.
Amido complexes containing substituents at the 3- and 5-
positions of the amido aryl groups reacted more slowly than
those containing a substituent at the 4-position: the di-m-
xylylamide complex 7 underwent reductive elimination more
slowly than di-p-tolylamido complex 2, and complex 6, which
contains trifluoromethyl substituents in the 3- and 5-positions
of the aryl groups on the amido ligand, underwent reductive
elimination by far the most slowly. We do not have a firm
explanation for the difference in the reaction rates of the
complexes containing 3,5-disubstituted and 4-substituted
diarylamido ligands.
dppf to trap the Pd0 product. The benzyl complexes 1–7 and
naphthylmethyl complex 8 underwent reductive elimination
in high yields (Table 1). The mesitylmethyl complex 9 also
3
À
Table 1: C(sp ) N bond-forming reductive elimination.
Complex
R1
R2,R3
Yield [%][a]
t1/2 [min][b]
1
2
3
4
5
6
7
8
9
Ph
Ph
Ph
Ph
Ph
Ph
Ph
naphthyl
mesityl
Ph
p-OMe
p-tolyl
Ph
p-Cl
62[c]
83
88
87
93[e]
83
63
83
25[g]
0
33[c]
73[d]
72
43
79
p-CF3
3,5-(CF3)2C6H3
3,5-(CH3)2C6H3
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
H, p-tolyl
p-tolyl
>1400[f]
97
<10[f]
12[f,h]
–
10
11
H
0
–
The observation that complexes containing more electron
rich amido groups underwent reductive elimination more
rapidly than those containing less electron rich amido groups
with the same substitution pattern contrasts with the relative
rates found by Goldberg and co-workers[15] for the reductive
elimination of aryl methyl ethers from methylplatinum(IV)
phenoxide complexes. Given these electronic effects on the
rate of the reaction, it is surprising that the anilido complex 10
does not undergo reductive elimination. Apparently, the
steric properties of the amido ligand have a large impact on
the rate of reductive elimination.
[a] The yield was determined by 1H NMR spectroscopy relative to
trimethoxybenzene as an internal standard. [b] Reactions to determine
rate constants and half-lives were conducted in [D6]benzene at 558C,
unless otherwise noted. The t1/2 values were determined from kobs values
over three half-lives, unless otherwise noted. [c] The reaction was
conducted at 558C in THF. [d] When conducted in THF at 558C, this
reaction occurred with a half-life of 65 min. [e] The reaction was
conducted at 558C. [f] The t1/2 value was estimated by monitoring the
reactions, by 1H NMR spectroscopy with an internal standard, to
approximately 50% conversion. [g] The (2,3,5-trimethylbenzyl)diaryl-
amine was also formed in 26% yield. [h] The reaction was conducted
at 308C.
The effect of the benzyl group on the rate of reductive
elimination was revealed by comparing the reaction of
complex 6 to those of the naphthylmethyl complex 8 and
the more hindered mesitylmethyl complex 9. The naphthyl-
methyl complex 8 and the mesitylmethyl complex 9 reacted
faster than the analogous benzyl complex 6. The rate constant
for reductive elimination from the naphthylmethyl complex 8
was at least 140 times larger than the rate constant for the
underwent reductive elimination, in this case to form a
mixture of the (mesitylmethyl)diarylamine (25%), the (2,3,5-
trimethylbenzyl)diarylamine (26%), and the free diarylamine
by an unknown protonolysis (46%). We presume the (2,3,5-
trimethylbenzyl)diarylamine product forms by rearrange-
ment of the hindered mesitylmethyl complex to the less
hindered 2,3,5-trimethylbenzyl species during the reductive-
elimination process.[14]
In contrast, the less hindered anilide complex 10 and the
methyl complex 11 did not form products of reductive
elimination at 758C. Free H2N(p-tolyl) and bibenzyl formed
upon the heating of anilide complex 10, as determined by GC/
MS, and HN(p-tolyl)2 formed when the diarylamido complex
11 was heated. The proton source in these reactions is
unknown.
Several experiments provided information on the effect of
the electronic properties of the amide ligand on the rate of
this reductive elimination. The half-lives for reactions of the
various amido complexes are included in Table 1. Reductive
elimination from complex 5, which contains an electron-
withdrawing p-CF3 group, was slower than that from the di-p-
tolylamido complex 2, and reductive elimination from com-
plex 1, which contains an electron-donating p-OMe group,
was faster than that from complex 2, although the rate
À
overall C N bond-forming process from 6, and the rate
constant for reductive elimination from the mesitylmethyl
complex 9 (at 308C) was 40–50 times larger than that for
reductive elimination from 6 (at 558C).
The reductive-elimination reactions reported herein could
occur by a concerted, an ionic, or a radical pathway. The
configuration at the benzylic carbon atom can be used to
distinguish these mechanisms. A concerted reductive elimi-
nation would lead to retention of configuration, sequential
dissociation of the amide and backside attack on the benzyl
group would cause inversion of configuration, and reaction
via a benzyl radical would cause racemization at this carbon
atom.
Previously, the stereochemical course of reactions of
metal–benzyl complexes was determined by measurements of
optical rotation or the use of a chiral shift reagent to assess the
configuration of organic products.[16,17] Stille and co-workers
determined that the oxidative addition of benzyl halides to
[Pd(PPh3)4] occurred with inversion of configuration by
794
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 793 –796

Angewandte
Chemie
cleaving the benzyl group from the addition product with CO
and methanol and analyzing the alcohol formed by reduction
of the resulting ester. The stereochemical course of reactions
of alkyl complexes has also been determined with deuterated,
diastereomeric tert-butylethyl derivatives, but the use of such
complexes is limited by their propensity to undergo b-
hydrogen elimination when an open coordination site is
present. Thus, we devised a new, more direct, strategy to
determine the stereochemical course of reactions of metal–
benzyl complexes that does not rely on optical rotation or
require an interaction of the product with a chiral shift
reagent.
Our strategy involves the use of a chiral, nonracemic
phosphine, a chiral, nonracemic amido group, and an
enantiomerically enriched monodeuterobenzyl group. The
chiral ligand enables determination of the relative ratio of
benzylpalladium halide precursors with an R or S config-
uration at the benzylic position, and the chiral amido group
enables determination of the configuration of the benzylic
carbon atom in a diastereomeric amine product. We tested
several ligands and chiral auxiliaries and found that the
1H NMR spectra of the starting complexes and products
Complex 14 underwent reductive elimination of the N-
benzylbinaphthylamine 15 in 80% yield in 60 minutes at
1
room temperature, as determined by H NMR spectroscopy
1
with an internal standard [Eq. (1)]. H NMR spectroscopy
indicated that the same 85:15 ratio of diastereomers was
formed as was present in the intermediate 12. Comparison of
the 1H NMR spectrum of the amine product 15 to that of the
same amine prepared independently indicated that the
reductive elimination occurred with inversion of configura-
tion to form predominately (Ra,Sc)-15 (see the Supporting
Information). We envision that this configuration results from
dissociation of the diarylamide, followed by nucleophilic
attack on the benzylic carbon atom. Reactions that occur by
the dissociation of amide ligands to form ionic intermediates
during organometallic processes are unusual.[5]
containing
2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl
(binap) as the dative ligand and a binaphthyl group on the
amide ligand displayed well-resolved benzylic signals.
The monodeuterated benzylpalladium chloride complex
12 was synthesized in an 85:15 diastereomeric ratio in favor of
the Ra,Rc isomer from [CpPd(h3-allyl)], (R)-binap, and (S)-
monodeuteriobenzyl chloride (Scheme 2).[18] The configura-
This mechanistic proposal was corroborated by additional
experiments. First, the reductive elimination from complex 2
in [D6]benzene at 558C occurred with
73 minutes, whereas the same reaction of 2 in more polar
[D5]nitrobenzene occurred with shorter half-life of
a half-life of
a
26 minutes at 558C. Second, a first-order decay of 2 was
observed, and this result is inconsistent with a potential attack
of an intact amido complex on the benzyl group. Although
proton donors are known to assist the dissociation of anionic
ligands,[4,15,19] the reductive elimination from 2 was not
affected greatly by the addition of an amine. The rate
constant for reductive elimination from 2 was (11 Æ 1 ꢀ
10À4) sÀ1 for reactions conducted with an added amine, the
concentration of which ranged from (3.0 ꢀ 10À3) to (9.1 ꢀ
10À2)m (see the Supporting Information).
These results show that the factors that control the rate
and scope of this reductive elimination are unique. First, the
stepwise process contrasts with the concerted reductive
elimination from aryl palladium amide complexes. Second,
the reaction occurs without initial oxidation to a higher-valent
metal. Third, the ionic mechanism for this reductive elimi-
nation from palladium(II) occurs with amido ligands that
form less stabilized anions than the tosylamido groups that
have been observed to undergo reductive elimination from
platinum(IV) or nickel(II) (HNPh2, pKa = 25; PhS(O)2NH2,
pKa = 16 in dimethyl sulfoxide), and the reaction is faster
from complexes containing more electron donating diary-
lamido ligands than from complexes containing less electron
donating diarylamido ligands. Fourth, the reaction is not
strongly affected by an added amine that could promote
dissociation of the amide. Fifth, this reaction begins with an
amido ligand bound to palladium, rather than the free amine
used in allylic substitution reactions. Reactions that occur by
Scheme 2. Synthesis of the complexes used for stereochemical deter-
mination.
tion at the benzylic carbon atom was deduced by comparing
the 1H NMR spectrum of complex 12 generated by this route
to that of the complex generated from the known product of
oxidative addition of monodeuteriobenzyl chloride to [Pd-
(PPh3)4].[17,18] Complex 12 was converted into the correspond-
ing Ra,Ra,RC benzylpalladium binaphthylamido complex 14
by the addition of the potassium Ra binaphthylamide 13 at
À508C in [D8]THF. Complex 14 was unstable at room
temperature (see below) and was therefore characterized at
À508C by one- and two-dimensional NMR spectroscopic
methods. The characteristic benzylic peaks of complex 14
were identified by HMQC, COSY, and selective 1H{31P} NMR
spectroscopy.
Angew. Chem. Int. Ed. 2010, 49, 793 –796
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
795

Communications
the dissociation of an amide ligand, let alone the dissociation
of an amide ligand in hydrocarbon solvents to form an ionic
intermediate, have not been reported previously. Finally,
Experimental Section
Typical procedure for the synthesis of the bisphosphine benzylpalla-
dium amido complexes: In a 20 mL scintillation vial, [(cod)Pd(Bn)Cl]
(107 mg, 0.313 mmol) was dissolved in THF (5 mL). Dppf (174 mg,
0.313 mmol) was dissolved in THF (5 mL) in another vial, and the
resulting solution was added to the stirred solution of
À
these results suggest that the functionalization of C H bonds
via palladium(II) species to form carbon–heteroatom bonds
occurs by dissociation of the anionic ligand rather than by
likely direct reductive elimination.
[(cod)Pd(Bn)Cl] in
a nitrogen-filled glove box. After 10 min,
KN(Ar)2 (0.345 mmol) dissolved in THF (5 mL) was added to the
orange solution, and the resulting mixture was stirred for 10 min. The
THF was then evaporated in vacuo, and the residue was dissolved in
toluene. The toluene solution was filtered through a plug of Celite,
which was then rinsed with toluene until the color had dissipated. The
filtrate was reduced in volume to about 3 mL under reduced pressure,
layered with pentane, and cooled to À358C for 12 h to complete
precipitation. The solid was filtered from the solution, washed with
pentanes (3 ꢀ 10 mL), and then dried in vacuo.
The greater propensity for reductive elimination to occur
from benzyl complexes than from methyl complexes could
result from a greater electrophilicity of the benzyl group
relative to the methyl ligand, an ability of the benzyl group to
stabilize the cationic intermediate by an h3 interaction and
promote dissociation of the amide anion, or the greater steric
bulk of the benzyl group. Further studies are needed to define
the role of the organic ligand in these reactions, but these
preliminary results imply that the rate of reductive elimina-
tion is affected by more than one of these factors. Faster
reductive elimination from the naphthylmethyl complex,
which would form a more stable cationic h3-benzylic inter-
mediate than that derived from the parent benzyl complex,
suggests that the intermediacy of h3-benzyl complexes can
explain the difference in reactivity between benzyl complexes
1–9 and the methyl complex 11. However, the fast reaction of
the mesitylmethyl complex 9, which would form a less stable
h3-benzyl structure but possesses a more crowded coordina-
tion sphere, implies that steric congestion significantly
increases the rate of reductive elimination and also contrib-
utes to the difference in reactivity between complexes 1–7 and
the arylamido complex 10. Such steric factors are also likely to
contribute to the higher yield of reductive elimination from
diarylamido complexes 1–7 than from arylamido complex 10,
despite the seemingly more favorable electronic properties of
the arylamido ligand for this type of reductive elimination.
Received: July 21, 2009
Revised: November 10, 2009
Published online: December 18, 2009
À
Keywords: amido complexes · C N bond formation ·
.
dissociation · palladium · reductive elimination
[1] J. F. Hartwig, Organotransition Metal Chemistry: From Bonding
to Catalysis, University Science Books, 2009, chap. 8.
[2] A. S. Surry, S. L. Buchwald, Angew. Chem. 2008, 120, 6438;
Angew. Chem. Int. Ed. 2008, 47, 6338.
[3] J. F. Hartwig, Acc. Chem. Res. 2008, 41, 1534.
[4] A. V. Pawlikowski, A. D. Getty, K. I. Goldberg, J. Am. Chem.
Soc. 2007, 129, 10382.
[5] K. Koo, G. L. Hillhouse, Organometallics 1995, 14, 4421.
[6] B. L. Lin, C. R. Clough, G. L. Hillhouse, J. Am. Chem. Soc. 2002,
124, 2890.
[7] U. Nettekoven, J. F. Hartwig, J. Am. Chem. Soc. 2002, 124, 1166.
[8] A. M. Johns, J. W. Tye, J. F. Hartwig, J. Am. Chem. Soc. 2006,
128, 16010.
[9] A. M. Johns, M. Utsunomiya, C. D. Incarvito, J. F. Hartwig, J.
Am. Chem. Soc. 2006, 128, 1828.
In summary, we have described the first direct reductive
3
À
elimination to form an C(sp ) N bond in an amine from an
organometallic amido complex. This reaction occurs from a
low-valent Group 10 metal center without oxidation. A
combination of kinetic and stereochemical studies indicate
that this reaction occurs by a stepwise pathway that most
likely involves dissociation of a diarylamide anion, followed
by nucleophilic attack of the amide onto the resulting cationic
benzylpalladium complex. This pathway contrasts with the
concerted pathway for the coupling of aryl and amido
ligands[20] or the coupling of two alkyl ligands,[21] and the
electronic effects of the diarylamido ligand contrast with
those of the anionic ligand during reductive elimination from
platinum(IV). Studies to probe the origins of these differ-
ences and to extend these reactions to reductive elimination
from purely alkyl complexes are in progress.
[10] O. Esposito, A. K. de K. Lewis, P. B. Hitchcock, S. Caddick,
F. G. N. Cloke, Chem. Commun. 2007, 1157.
[11] O. Esposito, P. M. P. Gois, A. K. de K. Lewis, S. Caddick, F. G. N.
Cloke, P. B. Hitchcock, Organometallics 2008, 27, 6411.
[12] T. Yoshitaka, Y. Toshikatsu, O. Sei, Inorg. Syn. 1990, 28, 342.
[13] E. V. Salo, Z. Guan, Organometallics 2003, 22, 5033.
[14] No isomerization of the starting diarylamido complex was
observed during the reaction.
[15] B. S. Williams, K. I. Goldberg, J. Am. Chem. Soc. 2001, 123, 2576.
[16] Y. Becker, J. K. Stille, J. Am. Chem. Soc. 1978, 100, 838.
[17] K. S. Y. Lau, P. K. Wong, J. K. Stille, J. Am. Chem. Soc. 1976, 98,
5832.
[18] See the Supporting Information for 1H NMR spectra.
[19] N. A. Smythe, K. A. Grice, B. S. Williams, K. I. Goldberg,
Organometallics 2009, 28, 277.
[20] M. S. Driver, J. F. Hartwig, J. Am. Chem. Soc. 1997, 119, 8232.
[21] D. Milstein, J. K. Stille, J. Am. Chem. Soc. 1979, 101, 4981.
796
www.angewandte.org
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2010, 49, 793 –796