Highly selective R,S-coordination of non racemic (1R,2R)-(1,2-dialkyl)-1,2- diamine cyclohexane derivatives to palladium dichloride

Article abstract of DOI:10.1039/b613961b

In non-racemic (1R,2R)-(1,2-dialkyl)-1,2-diaminocyclohexane palladium dichloride complexes the C₂ symmetry of the diamine ligand is broken, resulting in selective R,S-coordination. The Royal Society of Chemistry.

Full text of DOI:10.1039/b613961b

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Highly selective R,S-coordination of non racemic (1R,2R)-(1,2-
dialkyl)-1,2-diamine cyclohexane derivatives to palladium dichloride{
Esfandiar Rafii, Benjamin Dassonneville and Andreas Heumann*
Received (in Cambridge, UK) 26th September 2006, Accepted 15th December 2006
First published as an Advance Article on the web 12th January 2007
DOI: 10.1039/b613961b
Among the current methods to introduce selectively one organic
group into a secondary amine the reductive amination of carbonyl
compounds seemed to us the most appropriate one. The palladium
chloride complexes 3a may be obtained via ligand exchange from
L2PdCl2 (L = MeCN, Me2S; L2 = 1,5-COD). Accordingly,
dialkyldiaminocyclohexanes 2a–2k are readily prepared in this
way. As a first example the bisbenzyl amine (R,R)-2a was
coordinated to PdCl2 (Scheme 1, Scheme 2).
In non-racemic (1R,2R)-(1,2-dialkyl)-1,2-diaminocyclohexane
palladium dichloride complexes the C2 symmetry of the
diamine ligand is broken, resulting in selective
R,S-coordination.
The role of nitrogen donor ligands in controlling the reactivity, but
also the selectivity, in metal-catalysed transformations has become
increasingly important for organic synthesis.1 Indeed, a great
variety of amines are known and, generally, are easily available by
simple organic reactions.2 This is particularly true for chiral amines
and their use for asymmetric transformations. One point that
merits major attention is the possibility of making use of
stereogenic nitrogen atoms upon coordination of the metal to a
disymmetrically substituted amine. Such persistent N-chirality has
recently been demonstrated with achiral 1,2-diamines in LPdCl2
metal complexes.3
Vicinal diamines,4 and especially enantiomerically pure trans-
1,2-diaminocyclohexanes,5 are convenient starting materials for
highly discriminating derivatives and their metal complexes.
Jacobsen’s salicylidene Co(III) complexes for kinetic resolution of
terminal epoxides6 or Trost’s phosphinobenzoylamides7 for
palladium catalysed allylic substitution reactions are two extremely
efficient systems among others. Though numerous chiral non
racemic palladium amine coordination compounds are known and
are frequently applied in asymmetric catalysis, trans-1,2-diamino-
cyclohexane and derivatives are only rarely used in combination
with palladium as such in NHC (N-heterocyclic carbene),8,9 or
hybrid imine–NHC10 complexes. PdCl2(1R,2R)-1,2-diaminocyclo-
hexane gave good results as a reagent in the determination of the
enantiomeric ratio of unprotected amino acids.11 The enantiose-
lective Claisen rearrangement of allyl ethers,12 and allylic
alkylation of acetates13 are catalysed, with good to excellent
selectivities, by palladium complexes with these types of C2-
symmetrical ligands. Given the ready access to chiral diamines
from 15 and the great interest in Pd–amine complexes as catalysts
(oxidation of alcohols,14 allylic substitution reactions,15 etc.), we
decided to prepare optically active PdCl2–diaminocyclohexane
complexes that contain variable, but identical organic groups at
each nitrogen atom. In this paper we report on the synthesis of a
series of trans-1,2-diaminocyclohexanes, their coordination to
PdCl2 and a structural study of these new complexes.
The coordination of a metal to trans-1,2-diaminocyclohexanes
leads to a 5-membered metallaheterocyclic ring that blocks the
nitrogen in a tetrahedral position, increases the N-inversion
barrier, and thus induces chirality provided there is non-
equivalence of the nitrogen substituents.
In the case of 3 with identical substituents at each nitrogen we
can consider three possibilities: first, the dl pair R,R- and S,S-
(R,R)-3 with the substituents at nitrogen in a pseudo equatorial or
pseudo axial position, respectively, and second, the isomeric
structure with two different nitrogen atoms, the R,S-(R,R)-3 with
the substituents at nitrogen in both a pseudo equatorial and a
pseudo axial configuration (Scheme 3). The latter situation
corresponds to the meso compound in the case of achiral amines.
The bright yellow complex (R,R)-3a that we obtained from
(R,R)-2a exhibited NMR spectra that were quite different from the
picture of the free ligand.16 All data that we obtained from the
proton and carbon spectra17 led to the conclusion that upon
coordination to PdCl2 the original C2 symmetry of the diamine
ligand disappeared. The aromatic signals were much more split
from a quite narrow multiplet at 7.6 (less than 0.5 ppm broad) in
(R,R)-2a to a pattern of at least three complex signals between
7.1 and 8.0 ppm in (R,R)-3a. Two broad NH resonances at 5.41
and 5.56 ppm in (R,R)-3a indicate that the two nitrogen atoms are
no more equivalent compared to the C2 symmetrical diamine
(R,R)-2a. We also observe two well separated signals for the ring
junction protons at, respectively, 2.44 and 4.14 ppm (Dd 1.7 ppm),
as well as two pairs of signals for the benzylic CH2 group (3.36 and
4.22; 3.78 and 4.36 ppm). The C1H or C2H proton resonance at
4.14 ppm is hidden by the signal of one of the four benzylic
Universite´ Paul Ce´zanne, UMR CNRS 6180 ‘Chirotechnologies:
Catalyse et Biocatalyse’, Faculte´ Saint-Je´roˆme, Case A 62, 13397
Marseille Cedex 20, France. E-mail: andreas.heumann@univ-cezanne.fr;
Fax: 33 49128 8278; Tel: 33 49128 8278
Scheme 1 (i) C6H5CHO, CH2Cl2, 40 uC, 15 min; (ii) NaBH4, MeOH,
4 h; (iii) (MeCN)2PdCl2, CH2Cl2, 25 uC, 1 h, or (finely powdered)
PdCl2,MeCN, 25 uC, 2–3 days.
{ Electronic supplementary information (ESI) available: Experimental
1
details, H, 13C and 19F NMR spectra. See DOI: 10.1039/b613961b
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Chem. Commun., 2007, 583–585 | 583

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Scheme 2
Scheme 3 dl- and R,S-coordination mode of Pd(II) to trans-1,2-
diaminocyclohexanes.
hydrogens. This attribution was confirmed by 2D experiments,
and furthermore a HMQC sequence made it possible to clearly
show the relationship of the proton signal at 4.14 ppm with a
tertiary carbon at 66.8 ppm. The ‘loss of symmetry’ was also
apparent in the 13C NMR spectra which showed 17 different
carbon resonances corresponding to roughly one signal for every
carbon atom. Upon variation of the substitutents at nitrogen a
similar picture could be observed for all comparable groups in
compounds 3a–3k. Different substitution patterns at the aromatic
core but also the position (ortho, meta, and para) of the functional
groups such as CH3, F, CF3 and NO2 are compatible with the
coordination mode in (1R,2R)-3.18 Also a longer aliphatic chain in
(1R,2R)-3k gave similar NMR patterns.
Fig. 1 X-ray structure representation (ORTEP) of (1R,2R)-3b. Selected
˚
˚
structural parameters: Bond distances (A), atom distances (A), and angles
(u) for one of the two monomers include N1–Pd = 2.059(6), N2–Pd
2.073(7), Cl1–Pd = 2.322(2), Cl2–Pd 2.324(2), H1–Pd = 3.23, H2–Pd 3.07,
H7b–Pd = 3.17, H8b–Pd 3.26, H1n–Pd = 2.46, H2n–Pd 2.44, N1–Pd–N2
= 84.88, Cl1–Pd–Cl2 = 92.95. Only one of the two molecules 3b is shown.
The geometrical parameters of the second monomer are very similar to
those presented for the first monomer.
bisaryl(1R,2R)-diaminocyclohexane derivatives coordinated to
palladium(II). The bond lengths and angles do not vary from
known values (Fig. 1).3 In the square planar Pd(II) complex the
palladaheterocyclopentane ring adopts a twist conformation that is
slightly out of the plane of the cyclohexane plane (C1–C2–C4–C5).
As Fig. 1 shows, each substituent at nitrogen is visibly pseudo axial
at one and pseudo equatorial at the other nitrogen in the
coordinated (R,R)-2. This orientation places both benzyl groups at
the same side of the cyclohexane plane and opposite to the metal.
The bridgehead protons are fairly close to the palladium atom
It is clear from the NMR data that we do not have in solution
all the different structures depicted in Scheme 3. However, either
we have two different species or, on the other hand, only one
compound that has lost C2-symmetry. The possible mixture of the
dl isomers R,R- and S,S-(1R,2R)-3a is discarded with the following
argument. In all compounds studied the integration of the different
hydrogens accounts for 1 unit per hydrogen. When fluorine atoms
are present two resonances appear with a 1 : 1 ratio. The dl isomers
R,R- and S,S-(1R,2R)-3a are diastereomers and thus have different
physical properties. It seems to us highly improbable that the
coordination of all substrates 2 to PdCl2 would give an exactly
equimolar mixture of the R,R- and S,S-isomers. The resulting
structure that we retain is R,S-(1R,2R)-3a with two nitrogen atoms
showing opposite (R and S) configuration, respectively. To our
delight, an unequivocal structure determination was obtained with
the crystal structure of (1R,2R)-3b.
˚
(3.231 and 3.067 A). They now have completely different magnetic
neighbourhoods: one proton is quite close to a phenyl group and
consequently high-field shifted proton resonances (2.44 ppm)
appear. The second CH under the cyclohexane plane is completely
unaffected by the N-benzyl substituents and exhibits ‘normal’
magnetic behaviour. The high Dd value of 1.69 ppm in (1R,2R)-3b
reflects nicely this magnetic non-equivalence.19 The proximity (Pd–
˚
H2 = 3.067 A) of the Pd atom to the ‘anti’ hydrogen (with respect
to the benzyl groups) most probably enlarges this effect.
The reason for the selective R,S-coordination of (1R,2R)-
dialkyl-diaminocyclohexane derivatives to palladium chloride is
not clear. Normally, in square planar d8 complexes the ligand
substitution is an associative process.20 It is reasonable to assume
that coordination will occur in a stepwise manner. Thus if the first
nitrogen coordinates via the N directing the benzyl group into an
equatorial position after which the approach of the second
N-benzyl to the metal should occur in a position distant to the
metal, that means into the pseudo-axial configuration. The size of
the substituents at nitrogen might be decisive for this exclusive
coordination mode, in other words: would the presence of a
tertiary amine favour the dl isomers? The amine required for this
On slowly evaporating a dichloromethane solution of (1R,2R)-
3b we obtained bright orange crystals that were suitable for an
X-ray structure analysis.{ The asymmetric unit consists of two
monomers of (1R,2R)-3b related by a pseudo centre of symmetry.
The absolute configuration was previously known since we started
from enantiomerically pure diamine 2a and it was then confirmed
experimentally by the anomalous scattering of the Pd and Cl
atoms and the refinement of 3506 Friedel pairs. A view of the
molecule is given in Fig. 1.
This X-ray structure is consistent with the interpretation of the
NMR spectra and confirms the loss of C2 symmetry of the
584 | Chem. Commun., 2007, 583–585
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refined on F2 to final indices R[F2 . 4sF2: 6291 reflections] = 0.048,
wR[7681 reflections] = 0.1094 [w = 1/[s2(Fo2) + (0. 027P)2 + 2.3231P] where
P = (Fo2 + 2Fc2)/3]. The final residual Fourier positive and negative peaks
were equal to 0.785 and 20.757, respectively. Absorption correction was
applied to the data before the final stage of refinements. CCDC 629162 (3b)
contains the supplementary crystallographic data for this structure. For
crystallographic data in CIF or other electronic format see DOI: 10.1039/
b613961b
purpose, (R,R)-4, could be obtained after methylation (MeI, LiOH
in CH2Cl2)21 of 2b. On reacting the tertiary amine (1R,2R)-4 with
PdCl2 or (MeCN)2PdCl2 under the usual conditions a mixture of
three inseparable isomeric complexes (1R,2R)-5 was observed by
NMR. The NMR resonances of the fluorine atom in the ligand
part of (1R,2R)-5 allows convenient estimation of the ratios of dl
and R,S isomers in the new complex (1R,2R)-5.22 The ratios of
the three components may vary depending on the reaction
conditions; however, the complex R,S-(1R,2R)-5 (see Scheme 1)
is predominant together with 2 dl isomers of (1R,2R)-5 (ratio e.g.
of 5 : 2 : 2).23
1 A. Togni and L. Venanzi, Angew. Chem., Int. Ed. Engl., 1994, 33, 497;
F. Fache, E. Schulz, M. L. Tommasino and M. Lemaire, Chem. Rev.,
2000, 100, 2159; Enantioselective catalysis (thematic issue), Chem. Rev.,
2003, 103, 2763.
2 R. C. Larock, Comprehensive Organic Transformations, VCH, New
York, 1989.
It is interesting to note that exhaustive N-substitution gives rise
to quite unselective R,S and dl coordination. This behaviour has
already been observed in more flexible 1,2-diamines, such as
disubstituted amines from 1,2-diaminoethane with PdCl2 (e.g. 6a)
leading to the mixture of (R,R), (S,S) and (R,S) compounds in a
ratio of about 1 : 1 : 1.3 We also wanted to evaluate the influence
of the cyclic chiral backbone upon coordination in these systems.
A palladium complex without the constraint of the diequatorial
position of the nitrogen atoms in the trans 1,2-cyclohexane and
secondary nitrogen atoms (6b) was synthesized The bright orange
compound formed easily in MeCN and the 19F NMR showed two
peaks in a ratio of 2 : 1.24 Though, for the present, we cannot
attribute the major compound to either the (R,R) or the dl series
this result compares to the reactions with tertiary 1,2-diami-
noethanes3 as well with aliphatic but also with alicyclic compounds
5 and (1R,2R)-3.
3 K. A. Pelz, P. S. White and M. R. Gagne´, Organometallics, 2004, 23,
3210.
4 D. Lucet, T. Le Gall and C. Mioskowski, Angew. Chem., Int. Ed., 1998,
37, 2580.
5 T. A. Whitney, J. Org. Chem., 1980, 45, 4214. For an interesting
synthetic procedure, see: J. F. Larrow, E. N. Jacobsen, Y. Gao,
Y. Hong, X. Nie and C. M. Zepp, J. Org. Chem., 1994, 59, 1939.
6 E. N. Jacobsen, Acc. Chem. Res., 2000, 33, 421; S. E. Schaus, B. D.
Brandes, J. F. Larrow, M. Tokunaga, K. B. Hansen, A. E. Gould,
M. E. Furrow and E. N. Jacobsen, J. Am. Chem. Soc., 2002, 124, 1307.
7 B. M. Trost and D. L. van Vranken, Chem. Rev., 1996, 96, 395. Recent
application: B. M. Trost and M. U. Frederiksen, Angew. Chem., Int.
Ed., 2005, 44, 308.
8 A. Fu¨rstner, G. Seidel, D. Kremzow and C. W. Lehmann,
Organometallics, 2003, 22, 907.
9 L. G. Bonnet, R. E. Douthwaite and R. Hodgson, Organometallics,
2003, 22, 4384.
10 L. G. Bonnet, R. E. Douthwaite, R. Hodgson, J. Houghton,
B. M. Kariuki and S. Simonovic, Dalton Trans., 2004, 3528.
11 B. Staubach and J. Buddrus, Angew. Chem., Int. Ed. Engl., 1996, 35,
1344.
12 K. Akiyama and K. Mikami, Tetrahedron Lett., 2004, 45, 7217.
13 S.-H. Kim, E.-K. Lee and G.-J. Kim, Bull. Korean Chem. Soc., 2004, 25,
754.
14 J. Muzart, Tetrahedron, 2003, 59, 5789.
15 B. M. Trost, J. Org. Chem., 2004, 69, 5813.
16 S. E. Denmark, H. Stadler, R. L. Dorow and J.-H. Kim, J. Org. Chem.,
1991, 56, 5063; Y. L. Bennani and S. Hanessian, Tetrahedron, 1996, 52,
13837.
17 See electronic supplementary material for the complete NMR data.
18 The presence of fluorine as a spectator atom in the ligand is a valuable
aid in the NMR detection of the composition of the complex structure
and the reaction mixtures.
19 In the complexes studied, the Dd values vary from 1.28 to 1.71 ppm (see
Table 1 in the supplementary material).
20 R. J. Cross, Adv. Inorg. Chem., 1989, 34, 219.
21 E. Boyd, G. S. Coumbarides, J. Eames, R. V. H. Jones, M. Motevalli,
R. A. Stenson and M. J. Suggate, Tetrahedron Lett., 2005, 46, 3473.
22 19F NMR d: 2111.2 (21%, dl-1), 2111.7 and 2112.0 (55%, R,S),
2111.8 (20%, dl-2), 2114.5 (3%, unknown). The predominance of the
R,S isomer is recognized by the presence of the two fluorine resonances
with a ratio of 1 : 1. The analysis of the proton spectra of the mixture is
also diagnostic. Theoretically we are expecting eight doublets for the
benzylic protons. In reality we visualize (and attribute) seven doublets:
dl-1 (1R,2R)-5 d: 4.47, 3.26; dl-2 (1R,2R)-5: 4.96, 2.96 (partially hidden);
R,S (1R,2R)-5c: 4.23, 3.54, and 4.74, 3.67. It was possible to obtain
mixtures with variable dl and R,S proportions via chromatography on
silica (eluent: dichloromethane–methanol 95 : 5).
23 Conditions: (MeCN)2PdCl2, CH2Cl2, 25 uC, 1 h.
24 Complex 6b is insoluble in most common solvents and we could only
obtain the proton and fluorine NMR spectra in D6-DMSO. Except for
the visibility of the presence of two compounds, confirmed by proton
resonances, too, we are unable for the moment to analyze completely the
NMR data.
In conclusion, we have shown that easily accessible enantiomeric
1,2-diamines with cyclohexane as the chiral backbone and the
nitrogens of secondary amines as the coordinating heteroatoms
react with PdCl2 to form stable and easily isolated metal
complexes.25 Without any exception the coordination mode
corresponds to an R,S-stereochemistry, which means that the
chiral nitrogens blocked in a five-membered diaza-palladacycle
ring system show opposite
R and S configuration. This
phenomenon is, for the moment, limited to systems with square-
planar ligand fields (Pd, Pt) since in the octahedral nickel complex
Ni-bis[(R,R)-N,N9-dibenzylcyclohexane-1,2-diamine]Br2 7 recently
described by Evans et al.26 the (1R,2R)-dialkyl-diaminocyclohex-
ane coordinates in the homochiral (S,S) fashion with both benzyl
groups blocked in the pseudo-diequatorial configuration. This
coordination behaviour, apart from its fundamental interest for
the relation between ligand structure and coordination mode, may
occur in metal catalysed transformations. As we have shown in
this study, small structural changes may modify the coordination
mode and the selectivity of the coordination.
We thank Dr Michel Giorgi from the Laboratoire de
Cristallochimie, Universite´ Paul Ce´zanne Aix-Marseille III (F. S.
T. Saint-Je´roˆme, Service 432) for the X-ray structure determina-
tion. We are also grateful to Dr Nicolas Vanthuyne for kindly
having measured some optical rotation values and Deborah
Schour for valuable preparative work.
Notes and references
25 In preliminary experiments we have obtained complexes from PtCl2
with the same R,S structure comparable to R,S-(1R,2R)-3 according to
the NMR spectra.
26 D. A. Evans and D. Seidel, J. Am. Chem. Soc., 2005, 127, 9958. This
complex is a highly enantioselective catalyst for the addition of malonate
to nitroalkenes (95% ee).
{ Single-crystal X-ray diffraction data for (1R,2R)-3b: C20H24Cl2F2N2Pd,
Mw = 507.73, monoclinic, orange crystal (0.3 6 0.2 6 0.05 mm3), a =
3
˚
˚
14.214(5), b = 9.039(1), c = 16.311(3) A, b = 100.552(8)u, V = 2060.2(9) A ,
space group P21, Z = 4, r = 1.637 g cm23, m(MoKa) = 11.89 cm21, 14477
reflections measured at 293 K to hmax = 25.97u, 7681 unique, 487 parameters
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Chem. Commun., 2007, 583–585 | 585