Asymmetric Strecker reactions of ketimines catalysed by titanium-based complexes

Article abstract of DOI:10.1016/S0040-4039(99)02215-7

The asymmetric addition of TMSCN to a ketimine has been achieved by use of catalytic quantities of chiral titanium(IV) complexes. Fast conversions together with enantiomeric excesses as high as 59% have been achieved. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(99)02215-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 873–876
Asymmetric Strecker reactions of ketimines catalysed by
titanium-based complexes
Janice J. Byrne, Murielle Chavarot, Pierre-Yves Chavant and Yannick Vallée ∗
L.E.D.S.S., associé au CNRS, Université Joseph Fourier, B.P. 53X, 38041 Grenoble, France
Received 15 July 1999; accepted 23 November 1999
Abstract
The asymmetric addition of TMSCN to a ketimine has been achieved by use of catalytic quantities of chiral
titanium(IV) complexes. Fast conversions together with enantiomeric excesses as high as 59% have been achieved.
© 2000 Elsevier Science Ltd. All rights reserved.
The classical Strecker synthesis1 is one of the most convenient methods for the preparation of α-amino
acids. Enantioselective approaches to the reaction generally involve the use of preformed imines whereby
the nitrogen atom bears a chiral inductor.2 Recently, enantioselective additions of HCN to imines have
been reported, involving either metallic complexes3 or organic molecules4 as catalysts. Nevertheless,
all the reported data involve additions to aldimines, not ketimines. We focused on the obtention of α-
alkylated α-aminonitriles5 from ketimines and report here our results using titanium based catalysts for
this purpose.
As a first approach to this problem we tested several complexes which were known to catalyse
asymmetric synthesis of cyanohydrins. We examined the reaction of the N-benzyl-phenyl-methyl-imine
1 with cyanotrimethylsilane (TMSCN) in the presence of 0.1 equivalent of the chiral alkoxytitanium(IV)
2 prepared from dichlorodiisopropoxytitanium and (R,R)-TADDOL.6 When 1 is treated with TMSCN
in the presence of the chiral titanium reagent 2 in dichloromethane at −40°C (Run 1, Scheme 1), the
corresponding α-aminonitrile is formed with poor enantioselectivity and a low rate of conversion.
Replacing the chloride ligands by phenoxy based ligands leads to catalysts which show higher rates of
conversion (Table 1). In the simplest case where 2,20-biphenol (BIPOL) replaces the chlorine atoms the
reaction rate doubles but the enantioselectivity drops to less than 10%. This may be rationalised by the
formation of the complex Ti(BIPOL)2 as a side product, which catalyses the addition reaction without
selectivity. We then used chiral 2,20-binaphtol (BINOL) ligands to replace the halide groups. The pre-
sence of either (R) or (S)-BINOL achieves high conversion rates. The orientation of the enantioselection
was found to be still governed by the TADDOL ligand. The complex Ti((S)-TADDOL)((R)-BINOL)
∗
Corresponding author. E-mail: yannick.vallee@ujf-grenoble.fr (Y. Vallée)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02215-7
tetl 16143

874
Scheme 1.
catalyses addition of TMSCN to imine 1 with a 31% e.e. Increasing the steric congestion about the metal
by replacing TADDOL by its β-napthyl homolog leads to higher enantiomeric excesses. However, further
steric congestion about titanium by use of the α-napthyl derivative of TADDOL does not improve the
result.
Table 1
Asymmetric hydrocyanation of 1 catalysed by titanium-TADDOL complexes7
These results led us to study the use of BINOLTi(OiPr)2 3 as a catalyst for TMSCN additions3a
to imines (Scheme 2). The reaction at −40°C in dichloromethane gives poor conversions and no
enantioselection. However, in toluene at −20°C the addition proceeds smoothly with 12% e.e. Activation
of the catalyst by a second BINOL ligand9 leads to a similar effect as that noted in the case of the
TADDOL based complex. We then studied the effect9b of achiral 2,20-biphenol (BIPOL) and substituted
BIPOL ligands on the e.e. (Table 2, runs 7–14). It is worth noting that all BINOLs activate the titanium
complex 3. In the case of the highly sterically hindered 3,5,30,50-tetratBu-2,20-biphenol (Run 14) the
enantioselectivity of the TMSCN addition is greatly increased, while conversions are still rapid.
Some studies9a on biphenolate species of titanium(IV) have suggested that when 3 is activated by a
second BINOL, the latter coordinates to the metal without removal of the isopropoxy ligands. We became
curious to know the effect of replacement of one of the phenolic ligands by its bis-O-methyl derivative on
conversions and e.e. (Table 2). The best results were obtained when the bis-methyl ether of BIPOL was
combined with the BINOL-titanium catalyst 3. The combination of (R)-BINOL with this (S)-bismethyl
ether also gave the same enantiomeric excess as those obtained with the (R)-BINOL-(R)-bismethyl ether
pair. Thus, the orientation of enantioselection is always governed by the BINOL group and the chirality
of the ether ligand does not play a role in the asymmetric induction.

875
Scheme 2.
Table 2
Asymmetric hydrocyanation of 1 catalysed by titanium-(R)-BINOL complexes (0.1 equiv./imine), in
the presence of additives6
We also checked the effect of simple non-chiral ethers or amines additives.10 Excesses as high as 59%
were achieved when Et3N was present in catalytic quantities. The use of tertiary amines led to higher e.e.s
than secondary amines and pyridine, although increasing the bulkiness of the amine (run 24) appeared to
be unsatisfactory.
In conclusion, we have achieved enantioselective additions of TMSCN to a ketimine. Many species
containing a mixture of chiral and/or achiral ligands bound to the central metal atom have been tested.
In the case of titanium–TADDOL complexes, adding BIPOL lowers the e.e. while raising the rate of
conversion. In the case of addition of a BINOL ligand to the titanium–TADDOL complex the match pair

876
corresponds to the system where all possible catalytic species present in equilibrium direct additions
towards the same enantiomer. The steric demand of the β-napthylTADDOL derivative may inhibit
equilibration with (TADDOL)2Ti species and therefore limit the number of possible sub-catalysts present
in solution; thus, one catalyst which is of moderate enantioselectivity is present. Table 2 supports a
similar theory. The (BINOL)(BIPOL)Ti species shows higher stereoselectivity when a bulky substituent
is present on the BIPOL unit. The best results were achieved in the presence of TMEDA. Although the
exact nature of the amine-activated complexes is unknown, we propose the formation of a TMEDA-
chelated, monomeric metal species.
Acknowledgements
We gratefully thank the Rhône-Poulenc Agro Company for financial support, and Dr. V. Henryon for
fruitful discussions.
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7. Typical experimental procedure: Imine 1 (105 mg, 0.5 mMol) was added to a mixture of TMSCN (0.13 mL, 1.0 mMol) and
the particular catalyst (0.05 mMol) in dichloromethane (5 mL) at −40°C (runs 1–6) or in toluene (5 mL) at −20°C (runs
7–26). The resulting mixture was stirred for the given time and the reaction quenched by addition of a saturated solution of
Na2CO3, extracted with ether, dried and concentrated. Conversions were measured from 1H NMR and enantiomeric excesses
measured by HPLC analysis (Daicel Chiralpak AD, 25 cm; eluant cyclohexane:iPrOH, 99:1; 1 mL/min; retention times 12
min and 13.5 min). In all runs described, the latter enantiomer is in excess.
8. Evolution of the reaction had practically stopped after 2 h.
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