Palladium catalysed mono-N-arylation of enantiopure diamines

Article abstract of DOI:10.1016/S0957-4166(99)00158-5

The palladium catalysed arylation of amines is employed to prepare selectively a range of new, mono-N-arylated, enantiopure diamine ligands. The ligands were tested in the catalytic asymmetric transfer hydrogenation of acetophenone.

Full text of DOI:10.1016/S0957-4166(99)00158-5

Pergamon
Tetrahedron: Asymmetry 10 (1999) 1831–1834
Palladium catalysed mono-N-arylation of enantiopure diamines
Christopher G. Frost ∗ and Paul Mendonça
Department of Chemistry, University of Bath, Claverton Down, Bath, BA2 7AY, UK
Received 31 March 1999; accepted 23 April 1999
Abstract
The palladium catalysed arylation of amines is employed to prepare selectively a range of new, mono-N-
arylated, enantiopure diamine ligands. The ligands were tested in the catalytic asymmetric transfer hydrogenation
of acetophenone. © 1999 Elsevier Science Ltd. All rights reserved.
The effectiveness of enantiopure amine-based transition metal complexes in asymmetric catalysis
is well established.1 In particular, ligands derived from certain C2-symmetric enantiopure diamines
have been successfully employed in a wide range of asymmetric catalytic transformations including
epoxidation,2 allylic substitution3 and hydrogenation.4 As part of an ongoing research programme in the
development of new enantiopure ligands for asymmetric catalysis, we required the efficient preparation of
mono-N-arylated, enantiopure diamines 1. A flexible protocol that allowed us to incorporate aryl groups
with different steric and electronic properties was desired.
A general aromatic carbon–nitrogen bond forming reaction employing primary amines and aryl
bromides as coupling partners was realised independently by the research groups of both Buchwald
and Hartwig.5 We have previously applied this protocol to the iterative coupling of enantiopure
amines and aryl bromides in the assembly of new peptidomimetics.6 Previous studies have reveal-
ed that for the reaction to proceed without racemisation the choice of ligand was crucial.7 The cat-
∗
Corresponding author. E-mail: c.g.frost@bath.ac.uk
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00158-5

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alytic cross-coupling of aryl bromides and enantiopure amines employing Pd(0)/dppf (dppf=1,10-
bis(diphenylphosphino)ferrocene) or Pd(0)/BINAP combinations affords products in good yields with no
erosion of enantiopurity. We now wish to report the use of this strategy in the catalytic mono-N-arylation
of enantiopure diamines.8
For the cross-coupling of (1R,2R)-(−)-1,2-diaminocyclohexane 2 with a range of aryl bromides, we
employed the combination of Pd2(dba)3 and dppf as catalyst. For a typical experiment the aryl halide
(1 equiv.) then the diamine (1.4 equiv.) were added to a mixture of t-BuONa (1.8 equiv.), Pd2(dba)3 (6
mol%) and ligand (18 mol%). The mixture was heated to reflux in THF in a sealed tube for approximately
24 hours.
Table 1
Palladium catalysed mono-N-arylation
The mono-N-arylated products 3a–c were obtained in moderate yields as indicated in Table 1. For the
cross-coupling of 2 with 2-bromopyridine the major product was the bis-N-arylated diamine. In each case
we observed significant amounts of the reduced product and, in some cases, the starting aryl bromide was
not totally consumed. Attempts to optimise the yields by changing reaction parameters such as catalyst
loadings, solvent and temperature were largely unsuccessful. However, the use of BINAP as a ligand
resulted in a notable increase in efficiency (entries 5 and 6).9
Having established that the palladium catalysed arylation protocol could be applied to the mono-N-
arylation of 2, we extended this strategy to (1S,2S)-(−)-1,2-diphenyl-1,2-ethanediamine 4 (Table 2).
Table 2
Palladium catalysed mono-N-arylation
With a synthesis of mono-N-arylated enantiopure diamines in hand, it was decided to explore their
suitability as ligands for asymmetric catalysis. The catalytic, enantioselective transfer hydrogenation of

C. G. Frost, P. Mendonça / Tetrahedron: Asymmetry 10 (1999) 1831–1834
1833
ketones provides a useful method for obtaining enantiomerically enriched secondary alcohols. Noyori
noted a significant rate enhancement in the transfer hydrogenation of acetophenone when ethanolamine
was added to a mixture of 2-propanol, potassium hydroxide and catalytic [RuCl2(η6-benzene)]2.10 This
led to the testing of enantiopure β-amino alcohols as ligands for the enantioselective transformation,
and eventually to the development of the enantiopure mono-N-tosylated diamine ligands 6 and 7 which
allow the highly efficient enantioselective transfer hydrogenation of a wide range of ketones and imines.
Knochel has reported that the enantiopure mono-N-tosylated diaminocyclohexane 8 is similarly efficient
in the same reaction.11
Initial results employing the enantiopure mono-N-arylated diamines as ligands in the ruthenium
catalysed transfer hydrogenation of acetophenone are presented in Table 3.12 The levels of asym-
metric induction obtained were low compared with the enantiopure mono-N-tosylated diamine ligand 8.
However, the effect of the electron-withdrawing sulfonamide moiety was significant in terms of activity
and enantioselectivity (entries 4 and 7). The enantiomeric bias of the asymmetric reduction is consistent
with the Noyori system.13
Table 3
Enantioselective transfer hydrogenation of acetophenone
The ligand 5c was also effective when used in combination with [Ir(cod)Cl]2 to give the product 2-
phenylethanol in 67% yield but with lower enantioselectivity (16% ee).
In conclusion, we have shown that the palladium catalysed arylation reaction is effective for the mono-
N-arylation of enantiopure diamines. This class of compounds has previously been unavailable due to the
lack of efficient hetero-aromatic coupling protocols. The compounds are expected to be versatile scaffolds
for the assembly of new ligands for asymmetric catalysis, and in this context we have demonstrated a
remote electronic effect in the ruthenium catalysed transfer hydrogenation of acetophenone. This has
implications in the future design of new ligands for this transformation.

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Acknowledgements
We are grateful to the University of Bath for funding a studentship (PM) and to Johnson Matthey for
the generous donation of transition metal salts.
References
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