Synthesis and reactivity of alkylpalladium N-heterocyclic carbene complexes

Article abstract of DOI:10.1039/b700671c

The transamination of alkylpalladium halide N-heterocyclic carbene complexes has enabled the isolation of products that reveal interesting insights into the factors which might be barriers to the development of a palladium-catalysed alkyl-amination reaction. The Royal Society of Chemistry.

Full text of DOI:10.1039/b700671c

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Synthesis and reactivity of alkylpalladium N-heterocyclic carbene
complexes{
Oriana Esposito,a Alexandra K. de K. Lewis,b Peter B. Hitchcock,b Stephen Caddick*b and
F. Geoffrey N. Cloke*a
Received (in Cambridge, UK) 16th January 2007, Accepted 29th January 2007
First published as an Advance Article on the web 14th February 2007
DOI: 10.1039/b700671c
the formation of N-neopentyl morpholine from neopentyl chloride
and morpholine requires heating to 200 uC and a reaction time of
3 days in a sealed bomb.9 Thus, a palladium-catalysed version of
such a class of reaction might offer considerable advantages.
However, as with all palladium-catalysed transformations invol-
ving alkyl halides, one of the largest barriers to be overcome is
competitive b-hydride elimination (Scheme 1).10,11
The transamination of alkylpalladium halide N-heterocyclic
carbene complexes has enabled the isolation of products that
reveal interesting insights into the factors which might be
barriers to the development of a palladium-catalysed alkyl–
amination reaction.
In recent years palladium-catalysed cross-coupling reactions have
become an indispensable tool to the organic chemist.1 Advances in
electron rich ligands (alkyl phosphines and N-heterocyclic carbenes
(NHCs)) have extended the scope of aryl halide cross-coupling
reactions, to include aryl chlorides (previously unreactive).2 Whilst
Suzuki,3 Negishi,4 Heck,5 Kumada,6 and Buchwald–Hartwig
amination7 reactions have been successfully employed using aryl
halides, alkyl halides have proved much more challenging. In fact,
Pd-catalysed alkyl–amination cross-couplings (Scheme 1) have not
been previously explored to any great extent, and to date only
theoretical studies have been reported.8
In order to start to develop a palladium-catalysed amination of
alkyl halides, it is important to understand the mechanism of the
processes that would be involved. We believe that combined
structural and mechanistic studies can generate useful information
for the development of new organometallic protocols for organic
synthesis. Herein, we report our efforts towards the isolation of
alkyl halide oxidative addition (OA) and transamination products
of Pd–NHC complexes. Although these preliminary studies have
not yet allowed us to identify a palladium-catalysed amination of
alkyl halides, a number of important new patterns of organome-
tallic reactivity have been identified.
Whilst displacement of halides by amines can occur without the
requirement of Pd, these reactions can often be troublesome e.g.
Studies were undertaken using alkyl halides containing no
b-hydrogens, such that oxidative addition could be thoroughly
examined. Therefore, the oxidative addition of neopentyl halide
1
(halide = I/Br/Cl) to Pd(ItBu)2 in d6-benzene was followed by H
NMR spectroscopy at room temperature. In the case of neopentyl
iodide, the formation of 2,5-dimethylhexane was observed after
10 minutes, with concomitant formation of PdI2(ItBu)2, presum-
ably the result of intermolecular exchange, as previously described
by Cavell and McGuinness.12 Addition of neopentyl bromide to
Pd(ItBu)2 at room temperature led to no observable reaction.
However, at 75 uC the unexpected activation of one C–H bond of
tBu in ItBu occurred, followed by reductive elimination to yield
neopentane.13 This indicates that oxidative addition occurred but
that the resulting four-coordinate complex is thermally unstable.
On the other hand, when neopentyl chloride was reacted with
Pd(ItBu)2 at 75 uC only degradation of the starting palladium
complex was observed (no reaction occurs at room temperature).
As a consequence of these initial findings, an alternative route,
illustrated in Scheme 2 (reaction A), was developed to form an
alkylpalladium halide NHC complex, for use in further elabora-
tion of the alkyl–amination cross-coupling catalytic cycle. To this
end, the novel [(neopentyl)Pd(Cl)(1,5-COD)] 1 was synthesised and
used in the formation of Pd–NHC complexes (Scheme 2).
Addition of one equivalent of ItBu to 1 formed exclusively the
dimeric complex trans-[(neopentyl)Pd(Cl)(ItBu)]2, 2 (Scheme 2
reaction A). Crystals of 2, suitable for single X-ray crystallographic
analysis, were grown from Et2O at 220 uC. The structure is shown
in Fig. 1, together with selected bond lengths and angles, and
Scheme 1 Proposed mechanism for alkyl–amine cross-coupling reac-
tions. (a) Oxidative addition (b) b-hydride elimination (c) transamination
(d) reductive elimination.
aDepartment of Chemistry, School of Life Sciences, University of
Sussex, Falmer, Brighton, UK BN1 9QJ.
E-mail: f.g.cloke@sussex.ac.uk; Fax: +44 1273 677 196;
Tel: +44 1273 678735
bChristopher Ingold Laboratories, Department of Chemistry, University
College London, 20 Gordon Street, London, UK WC1H 0AJ.
E-mail: s.caddick@ucl.ac.uk; Fax: +44 207 679 7463;
Tel: +44 207 679 4694
{ Electronic supplementary information (ESI) available: Complete crystal-
lographic details for 2, 3 and 6, experimental procedures and full
characterising data for all new compounds. See DOI: 10.1039/b700671c
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 1157–1159 | 1157

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Fig. 2 Molecular structure of 3. (thermal ellipsoids at 30%). * indicates
that these atoms are at an equivalent position (2x, y, K 2 z). The
compound has crystallographically imposed twofold symmetry, with the
˚
two chlorine atoms on the twofold axis. Selected bond distances (A) and
angles (u) (iPr groups and H omitted for clarity): Pd–C(1) 1.977(4), Pd–
C(28) 2.053(4), Pd–Cl(2) 2.3932(9), Pd–Cl(1) 2.4887(9), N(1)–C(1)
1.369(4), N(1)–C(2) 1.383(5), N(2)–C(1) 1.373(5). C(1)–Pd–C(28)
89.81(14), C(1)–Pd–Cl(2) 168.82(10), C(28)–Pd–Cl(2) 94.03(11), C(1)–
Pd–Cl(1) 93.65(10), C(28)–Pd–Cl(1) 176.49(10), Cl(2)–Pd–Cl(1) 82.46(3),
Pd–Cl(1)–Pd* 94.71(4), Pd–Cl(2)–Pd* 100.37(5), N(1)–C(1)–N(2)
103.2(3).§1
NMR studies at 85 uC revealed that 3, in solution, undergoes a fast
cis–trans isomerisation process, which does not occur with 2.
Furthermore, at low temperature (210 uC) the C–H of the
isopropyl groups in 3 separate into two distinct multiplets, while
the CH3 split into four doublets, indicative of either a retardation
of the cis–trans isomerisation or the cessation of the carbene
rotation around the Pd–Ccarbene bond. Overall, this implies that IPr
imposes less steric constraints than ItBu, which is in contrast to the
widely accepted belief that IPr is bulkier than ItBu. However, a
DFT study by Cavallo et al. gives credence to these findings.14 In
fact, Cavallo et al. quantified the steric factors of the NHC ligands
by examining the volume of a sphere centred on the metal, covered
by overlap with atoms to various NHC ligands, measured as
%VBur (buried volume). The volume of this sphere represents the
space around the metal atom that must be shared by the different
ligands upon coordination. The bulkier the ligand, the larger the
Scheme 2 Synthesis and reactivity of dimers 1 and 2 (a) Et2O; 275 uC
(b) ItBu; rt; Et2O (c) Et2O; 275 uC (d) IPr; toluene; rt (e) C6D6; rt (f) ITMe;
toluene; rt (g) PPh3; toluene; rt (h) morpholine or hexylamine; toluene; rt.
confirms the expected square planar geometry around the metal
centres.
Intriguingly, in the 1,3-bis(2,6-diisopropylphenyl)imidazol-2-
ylidene (IPr) analogue of 2 (cis-[(neopentyl)Pd(Cl)(IPr)]2, 3
(Scheme 2, reaction B), the neopentyl substituents no longer
adopt the trans geometry in the solid state but prefer the cis
orientation as confirmed by X-ray crystallography (Fig. 2). 1H
amount of that sphere will be occupied, and the greater the %VBur
.
In Cavallo et al.’s study the %VBur occupied by [(IPr)Pd(allyl)Cl]
was found to be smaller than [(ItBu)Pd(allyl)Cl].14
Further addition of 1,3-bis(tert-butyl)imidazol-2-ylidene (ItBu)
to 2, surprisingly led to reductive elimination of neopentyl chloride
and formation of Pd(ItBu)2 (Scheme 2, reaction C), and similarly
reaction of 3 with IPr affords Pd(IPr)2. However, through
judicious choice of ligand, the monomeric heteroleptic compounds
[(neopentyl)Pd(ItBu)(ITMe)(Cl)], 4, and [(neopentyl)Pd(ItBu)
(PPh3)(Cl)], 5 were successfully obtained by addition of two
equivalents of 1,3,4,5-tetramethylimidazol-2-ylidene (ITMe) or
two equivalents of PPh3 to 3, respectively (Scheme 2, reactions
D and E). The formation of 4 and 5 further demonstrates that the
dimer 2 is readily cleaved, yielding monomeric species in the
presence of ligands with smaller cone angles/%VBur, e.g. PPh3
Fig. 1 Molecular structure of 2 (thermal ellipsoids at 30%). * indicates
atoms at an equivalent position (1 2 x, 1 2 y, 1 2 z), and that the
˚
compound lies about an inversion centre. Selected bond distances (A) and
angles (u): Pd–Cl 2.3975(7), Pd–Cl* 2.5252(7); Pd–C(12) 2.075(3), Pd–C(1)
1.980(3), C(1)–N(1) 1.364(4), C(1)–N(2) 1.371(3). C(1)–Pd–C(12)
86.14(11), C(1)–Pd–Cl 172.76(8), C(12)–Pd–Cl 100.36(8), C(1)–Pd–Cl*
89.64(8), C(12)–Pd–Cl 175.28(9), Cl–Pd–Cl* 83.98(2), Pd–Cl–Pd* 96.02(2),
N(1)–C(1)–N(2) 105.0(2).{1
(%VBur = 22%) than either ItBu (%VBur = 37%) or IPr (%VBur
=
29%).14 With this in mind, it appeared reasonable that the
transamination products could form stable intermediates and thus
be isolated.
1158 | Chem. Commun., 2007, 1157–1159
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mechanistic and structural studies to catalytic applications. These
results further suggest that alkyl–amine cross-coupling reactions
may not only be complicated by b-hydride elimination, but also by
the formation of a surprisingly stable transamination product.
We thank EPSRC for financial support of this project.
Notes and references
{ Selected crystal data for 2: empirical formula = C32H62Cl2N4Pd2, Mr =
786.56, T = 173(2) K, crystal system = monoclinic, space group = P21/c
(No. 14), unit cell dimensions a = 11.1540(3), b = 9.7982(2), c =
3
17.5999(4) A, V = 1833.85(7) A , Z = 2, m = 1.15 mm21, reflections
collected = 26967, independent reflections = 3596 [Rint = 0.066], final R
indices [I . 2s(I)] R1 = 0.031, wR2 = 0.061, R indices (all data) R1 = 0.041,
wR2 = 0.064. CCDC 633696. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b700671c
˚
˚
Fig. 3 Molecular structure of 6 (thermal ellipsoids at 30%). The
§ Selected crystal data for 3?2(Et2O), empirical formula
C64H94Cl2N4Pd2?2(C4H10O), Mr = 1351.37, crystal system = monoclinic,
=
neopentyl group is unequally disordered over two sites (0.757/0.243) and
˚
only the major one is shown. Selected bond distances (A) and angles (u):
space group = C2/c (No. 15), unit cell dimensions a = 22.4708(6), b =
21
,
Pd–C(1) 1.988(5), Pd–C(16) 2.072(16), Pd–C(16) 2.109(18), Pd–N(3)
2.126(4), Pd–Cl 2.4821(13), N(1)–C(1) 1.373(6), N(1)–C(2) 1.393(7).
C(1)–Pd–C(16) 90.0(5), C(1)–Pd–N(3) 176.70(18), C(16)–Pd–N(3)
87.6(9), C(1)–Pd–Cl 90.03(14), C(16)–Pd–Cl 162.41(18), N(3)–Pd–Cl
91.45(11), C(1)–N(1)–C(2) 109.8(4), C(3)–N(2)–C(1) 110.0(5), N(1)–C(1)–
N(2) 104.2(4), N(1)–C(1)–Pd 128.7(4), C(3)–C(2)–N(1) 107.6(5), C(2)–
C(3)–N(2) 108.3(5)."
3
17.9840(7), c = 19.0590(5) A, V = 7392.9(4) A , Z = 4, m = 0.60 mm
˚
˚
reflections collected = 24839, independent reflections = 7207 [Rint = 0.070],
final R indices [I . 2s(I)] R1 = 0.043, wR2 = 0.104, R indices (all data) R1 =
0.068, wR2 = 0.124. CCDC 633697.
" Selected crystal data for 6: empirical formula = C20H40ClN3OPd, Mr =
480.40, T = 173(2) K, crystal system = monoclinic, space group = P21/n
(No. 14), unit cell dimensions a = 9.6642(3), b = 23.1895(5), c =
3
10.4673(3) A, V = 2335.69(11) A , Z = 4, m = 0.92 mm21, reflections
collected = 21525, independent reflections = 4570 [Rint = 0.073], final R
indices [I . 2s(I)] R1 = 0.046, wR2 = 0.108, R indices (all data) R1 = 0.077,
wR2 = 0.129. CCDC 633698.
˚
˚
The transamination products, [(neopentyl)Pd(ItBu)(morpholine)Cl],
6, and [(neopentyl)Pd(ItBu)(hexylamine)Cl], 7, were success-
fully isolated by addition of hexylamine or morpholine to 2, in
toluene, at room temperature (Scheme 2, reaction F). These
are the first examples of transamination Pd–NHC complexes
derived from an alkylpalladium NHC complex. Crystals of 6,
suitable for X-ray analysis were grown from toluene at
ambient temperature revealing cis geometry between the
neopentyl and morpholine groups (Fig. 3), ideal for reductive
elimination. Rather surprisingly, subsequent attempted depro-
tonation of the coordinated amines in either 6 or 7 by a variety
of bases (KOtBu, NaOCEt3, LHMDS, and NaH) failed to
yield either the palladium amide complex or any alkylamine
product (in the absence of Pd the previously described bases
are not capable of deprotonating the free amine). Instead
morpholine is liberated, with concurrent formation of neo-
pentane, the CH-activated complex (vide supra) and Pd(ItBu)2.
These findings raise interesting questions as to why reductive
elimination does not occur in the presence of base. One
possibility is that the electron donating effect of the alkyl
substituent, combined with the strong s-donation of ItBu,
must increase the electron density on the metal centre
sufficiently to require only a weak interaction with the amine
lone pair. It may therefore be that the pKa of the –NH is
not significantly lowered to allow for deprotonation by
the standard bases used in aryl–amination cross-coupling
reactions.
1 F. Diedrich and P. J. Stang, Metal-Catalysed Cross-Coupling Reactions,
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T. Weskamp, V. P. W. Bo¨hm and W. A. Herrmann, J. Organomet.
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3 N. Miyaura and A. Suzuki, Chem. Rev., 1995, 2457.
4 E. I. Negishi, Acc. Chem. Res., 1982, 15, 340.
5 I. P. Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009.
6 Organopalladium Chemistry for Organic Synthesis, Wiley-Interscience,
New York, 2002, vol. 311.
7 S. Caddick, F. G. N. Cloke, P. B. Hitchcock, J. Leonard, A. K. de
K. Lewis, D. McKerrecher and L. R. Titcomb, Organometallics, 2002,
21, 4318; K. Arentsen, S. Caddick and F. G. N. Cloke, Tetrahedron,
2005, 61, 9710.
8 J. C. Green, B. J. Herbert and R. J. Lonsdale, J. Organomet. Chem.,
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9 T. S. Eckert and R. L. Rominger, J. Org. Chem., 1987, 52(24), 5474.
10 T. Ishiyama, S. Abe, N. Miyaura and A. Suzuki, Chem. Lett., 1992, 691;
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13 Manuscript in preparation. Nolan et al. have observed similar,
intramolecular C–H activation at Rh(I) and Ir(I) centres: N. M. Scott,
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In summary, a range of novel alkyl–Pd–NHC complexes have
been described, including the surprisingly stable transamination
products 6 and 7. These studies have revealed significant steric
sensitivity surrounding the Pd–NHC centre. It has become
apparent that relatively minor variations in steric bulk lead to
either success or failure of the synthesis of the desired complex, an
important consideration when attempting to translate these
14 L. Cavallo, A. Correa, C. Costabile and H. Jacobsen, J. Organomet.
Chem., 2005, 690, 5407; R. Dorta, E. D. Stevens, N. M. Scott,
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This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 1157–1159 | 1159