Asymmetric synthesis of O-benzoyl cyanohydrins by reaction of aldehydes with benzoyl cyanide catalysed by BINOLAM-Ti(IV) complexes

Article abstract of DOI:10.1016/j.tetasy.2005.05.031

The asymmetric cyanobenzoylation of aldehydes has been carried out for the first time, by reaction with benzoyl cyanide in a process catalysed by either (R)- or (S)-3,3′-bis(diethylaminomethyl)-1,1′-binaphthol BINOLAM-Ti(IV) complexes at room temperature and without additives. The reaction can be described as an overall cyano-O-benzoylation of aldehydes where a Lewis acid-Broensted base (LABB) dual role for the catalyst induced firstly the key enantioselective hydrocyanation, which is then followed by O-benzoylation furnishing enantioenriched O-benzoyl cyanohydrins.

Full text of DOI:10.1016/j.tetasy.2005.05.031

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 2385–2389
Asymmetric synthesis of O-benzoyl cyanohydrins by reaction
of aldehydes with benzoyl cyanide catalysed by
BINOLAM–Ti(IV) complexes
a
Alejandro Baeza, Carmen Najera, Jose M. Sansano and Jose M. Saa
a
a,
b
*
´
´
´
´
a
´ ´ ´
Departamento de Quımica Organica, Facultad de Ciencias and Instituto de Sıntesis Organica (ISO),
Universidad de Alicante Apartado 99, 03080 Alicante, Spain
´
b
´
Departament de Quımica, Universitat de les Illes Balears, 07071 Palma de Mallorca, Spain
Received 19 May 2005; accepted 20 May 2005
Abstract—The asymmetric cyanobenzoylation of aldehydes has been carried out for the first time, by reaction with benzoyl cyanide
in a process catalysed by either (R)- or (S)-3,30-bis(diethylaminomethyl)-1,10-binaphthol BINOLAM–Ti(IV) complexes at room
temperature and without additives. The reaction can be described as an overall cyano-O-benzoylation of aldehydes where a Lewis
acid–Bro¨nsted base (LABB) dual role for the catalyst induced firstly the key enantioselective hydrocyanation, which is then followed
by O-benzoylation furnishing enantioenriched O-benzoyl cyanohydrins.
ꢀ 2005 Elsevier Ltd. All rights reserved.
1. Introduction
loid-derived tertiary amines,3 whilst the aldehydes
reacted with ethyl cyanoformate and chiral bimetallic
BINOL-derived yttrium(III) (YLB)4 or titanium(IV)–
salen complexes5 and with methyl cyanoformate in the
presence of a chiral 3,30-bis(diethylaminomethyl)-1,10-
binaphthol (BINOLAM)-derived aluminium com-
plexes.6 These last complexes7 and the above mentioned
chiral bimetallic YLB-complex8 were also involved in the
enantioselective synthesis of the cyanohydrin O-phos-
phates, from aldehydes and diethylcyanophosphonate
at room temperature and at ꢀ78 ꢁC, respectively.
Homochiral cyanohydrins are of synthetic interest as
they can be transformed into a number of relevant func-
tional groups such as b-amino alcohols, a-hydroxyacids,
a-hydroxyesters, a-sulfonyloxynitriles, a-aminonitriles,
a-fluoronitriles, 3-amino-2-alkenoates and substituted
azacycloalkanes.1 Many of them are key chiral building
blocks in the synthesis of both biologically active natural
products and therapeutically important molecules. The
synthesis of nonracemic cyanohydrins and their O-pro-
tected derivatives can be accomplished by enzymes,1b,c,2
organocatalysts1 and metal complexes,1 the latter being
the most widely used over the last decade.1c A serious
drawback of cyanohydrins and O-trimethylsilyl cyano-
hydrins is their instability due to the reversibility of the
cyanohydrin formation. In addition, they are frequently
prepared at very low temperatures while using highly
toxic hydrogen cyanide or trimethylsilyl cyanide.1 So, it
is advantageous, from the synthetic point of view, to
obtain chemically O-protected nonracemic cyanohydrins
under very mild reaction conditions. In this sense, the
O-alkoxycarbonyl cyanohydrins have been obtained
from ketones and cyanoformates using Cinchona alka-
Recently, nonracemic O-acetyl cyanohydrins have been
prepared with high enantioselection by employing chiral
salen complexes of titanium(IV) 19 and vanadium(V) 2,9
together with acetic anhydride and potassium cyanide as
the cyanide source. The reaction of aldehydes, per-
formed at ꢀ42 ꢁC with the dinuclear titanium(IV) com-
plex 1, gave the O-acetyl cyanohydrins in good chemical
yields and high enantiomeric excesses, whereas mono-
nuclear vanadium(V)–salen complex 2 gave the same
products with slightly lower ees.9,10 A recyclable
–titanium complex, based on structure 1, was also eval-
uated in the same reaction obtaining O-acetyl cyano-
hydrins in very good yield and good enantioselection
(up to 95.5:4.5 er) at ꢀ20 ꢁC.11,12 However, the
asymmetric direct cyanobenzoylation of carbonyl com-
pounds with acyl cyanides have not been described yet.
*
Corresponding author. Tel.: +34 965903728; fax: +34 965903549;
e-mail: jmsansano@ua.es
0957-4166/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2005.05.031

2386
A. Baeza et al. / Tetrahedron: Asymmetry 16 (2005) 2385–2389
Continuing with the general study of chiral BINOLAM
ligands 3,13 as part of the different bifunctional14 metal
complexes, and paying attention to the capability of
BINOLAM–AlCl complex 4 to perform enantioselective
addition of species containing a cyanide source onto
aldehydes, such as TMSCN,15 MeO2CCN6 and (EtO)2-
POCN,7 we herein, report the cyanobenzoylation of
aldehydes catalysed by the BINOLAM–Ti(IV)
complexes.
of (S)-BINOLAM and dimethylaluminium chloride,
did not give any reaction product, using toluene as
solvent, when benzaldehyde or 3-phenylpropanal were
employed as substrates. However, the complex derived
from (S)-BINOLAM and titanium tetraisopropoxide
furnished, at room temperature and in THF, quantita-
tive yields and good enantioselection of products 6
(Scheme 1 and Table 1). Cyanohydrin derivative 6a
(R = Ph) was obtained in an 84:16 enantiomeric ratio
But
But
But
But
But
But
N
N
O
O
N
N
N
N
O
O
O
V
Ti
O
Ti
O
O
O
But
But
But
But
But
But
2
1
NEt2
Et2N
OH
OH
HO
HO
NEt2
Et2N
3 (R)-BINOLAM
3 (S)-BINOLAM
Lewis Base
Lewis Acid
Et2N
O
NEt2
O
Cl Al
Al Cl
O
O
Et2N
NEt2
4 (R)-BINOLAM-AlCl
4 (S)-BINOLAM-AlCl
NEt2
O
Et2N
O
Lewis Base
Lewis Acid
Ti(OPri)2
(PriO)2Ti
O
O
NEt2
5 (S)-BINOLAM-Ti(OPri)2
Et2N
5 (R)-BINOLAM-Ti(OPri)2
2. Results and discussion
whilst 6h was isolated in an 83:17 enantiomeric ratio
(Scheme 1 and Table 1, entries 1 and 10, respectively).
The optimisation of the reaction conditions of the enan-
tioselective synthesis of O-acyl cyanohydrins was done
simultaneously for benzaldehyde and 3-phenylpropanal.
Benzoyl cyanide was selected as the cyanide source
because acetyl cyanide did not promote the reaction,
giving very low chemical yields of the corresponding
O-acetyl cyanohydrins. Following the previous enantio-
selective cyanation reaction conditions described for
BINOLAM–AlCl complexes 4,6,7,15 we first studied the
effect of the aluminium species in this reaction. Thus,
complex (S)-4, obtained by mixing equimolar amounts
The presumed monometallic (S)-BINOLAM–tita-
nium(IV) 5 (10mol %) was used as a catalyst for the
enantioselective preparation of O-benzoyl cyanohydrins
6 from different series of aldehydes using THF as solvent
at room temperature, under a nitrogen atmosphere
(Scheme 1 and Table 1). The aromatic aldehydes (Table
1, entries 1–5) gave good chemical yields of the titled
products 6 with good enantiomeric ratios (up to
84:16). Heteroaromatic aldehydes (Table 1, entries 6
and 7) behaved as in previous cyanation reactions pro-

A. Baeza et al. / Tetrahedron: Asymmetry 16 (2005) 2385–2389
2387
as a precursor of various cyanogenic glycosides isolated
from the leaves and roots of Phyllagatis rotundifolia;17
6b is a useful starting material in the synthesis of the nat-
ural products (ꢀ)-tembamide and (ꢀ)-aegeline7,18 and 6f
can be employed in the elaboration of sphingosines19
and coriolic acid.20
O
(S)-3 (10 mol%)
Ti(OPri)4 (10 mol%)
O
O
Ph
CN
(R)-6
RCHO
+
NC
Ph
THF, rt, N2
R
Scheme 1.
The mechanism of this reaction involves either a direct
cyanobenzoylation or a cyanation followed by benzoyl-
ation, the latter being the most consistent hypothesis as
it has been proven in other cyanation reactions catalysed
by complexes 4.15 We propose the formation of a possi-
ble catalytically active species 5, which would coordinate
strongly the aldehyde by the Lewis acid centre and
weakly the aldehydic hydrogen to an oxygen atom of
a isoproxide moiety to afford species 7 (Scheme 2).
The small amount of hydrogen cyanide, contained in
the commercial benzoyl cyanide, is enough to give com-
plex 8, in which both reagents are simultaneously acti-
moted by BINOLAM–AlCl complexes.6,7,15 Only nico-
tinaldehyde offered a lower enantioselection, possibly
because the heteroatom activates the benzoyl cyanide
and consequently the racemic catalytic cycle. a,b-Unsat-
urated (Table 1, entry 8) and aliphatic aldehydes (Table
1, entries 9 and 10) also gave good enantiomeric ratios
and chemical yields. The (R)-cyanohydrin O-benzoates
could be obtained by using the (R)-BINOLAM–Ti(O-
Pri)2 complex 5 furnishing (S)-6 in similar yield and
enantiomeric ratio (Table 1, entry 2). The (S)-5 complex
always gave O-benzoyl cyanohydrin 6 with an (R)-con-
figuration except in the example of furfural where (S)-
6d was obtained due to a change in the priority of the
substituents around the stereogenic centre. As previ-
ously described, ligand 3 could be recovered in an
almost quantitative yield (92%) under extractive work-
up6,7,15,16 and reused without any loss of activity in the
same transformation, for instance, compound (R)-6a
was prepared in good yield and in an 84/16 er in the
same reaction time (Table 1, entry 3). The reaction
was monitored by GC and when judged complete was
quenched with a 2 M aqueous solution of hydrochloric
acid.16 The enantiomeric ratios of products 6 were deter-
mined by chiral HPLC or chiral GC analysis while the
absolute configuration was established according to
the comparison of their specific rotations with the corre-
sponding ones obtained from enantiomerically pure
samples.
vated completing
a
real bifunctional catalysis
activating both nucleophilic and electrophilic species.
The role of the diethylaminomethyl arm as a Bro¨nsted
base seems to be crucial because, when using chiral
BINOL as ligand, the reaction failed. Finally, and after
the cyanide ion addition, the alcoholate in intermediate
9 would be benzoylated by an equivalent of benzoyl cya-
nide regenerating the catalytic amount of hydrogen cya-
nide and yielding the final O-benzoyl cyanohydrin 6.
3. Conclusions
This work reports, for the first time, the enantioselective
cyanobenzoylation of aldehydes using benzoyl cyanide
and the BINOLAM–Ti(IV) complex as a catalyst, in
good chemical yields, and easily recovering the chiral
ligand BINOLAM 3. In only one step, under mild reac-
tion conditions (room temperature), enantiomerically
enriched O-benzoylated cyanohydrins can be easily
obtained. A bifunctional mechanism has been proposed
based on a hydrogen cyanide addition followed by the
Many derivatives of these types of cyanohydrins have
been employed for multiple purposes in various scien-
tific areas. For instance, compound 6a can be considered
Table 1. Enantioselective synthesis of O-benzoyl cyanohydrins 6
Entry
R
Time (h)
6
Yielda (%)
erb
ee
1
Ph
Phd
6
6
(R)-6a
(S)-6a
(R)-6a
(R)-6b
(R)-6c
(S)-6d
(R)-6e
(R)-6f
(R)-6g
(R)-6h
91
84:16c
68
68
68
58
58
56
38
68
56
66
c
2
9016:84
9084:16
76
c
3
Phe
6
4
4-(MeO)C6H4
4-ClC6H4
2-Furyl
3-Pyridyl
E-C5H11CH@CH
C6H13
21
18
7
79:21
79:21
78:22
64:26f
5
85
89
6
7
22
6
93
87
8
84:16g
h
9
10PhCH
12
3
8078:22
93
2CH2
83:17f
a Isolated yields after flash chromatography.
b Determined by chiral HPLC (Daicel, Chiralpak AS).
c Determined by chiral HPLC (Daicel, Chiralpak AD).
d (R)-BINOLAM (R)-3 was used.
e Recovered ligand (S)-3 was employed.
f
Determined by chiral HPLC (Daicel, Chiralcel OD-H).
g Determined by chiral HPLC (Daicel, Chiralcel OJ).
h Determined by chiral GC (c-cyclodextrin).

2388
A. Baeza et al. / Tetrahedron: Asymmetry 16 (2005) 2385–2389
O
R
H
NEt2
NEt2
OPri
O
OPri
O
O
Ti
Ti
O
OPri
OPri
O
NEt2
H
5
R
Et2N
HCN
HCN
(traces)
(traces)
7
Ph
O
H
O
R
CN
6
NEt2
NCCOPh
O
O
OPri
OPri
Ti
NEt2
O
R
H
OPri
OPri
O
Ti
O
Et2N
H
+
_
O
CN
8
H
R
CN
+
Et2N
H
9
Scheme 2.
Jacobsen, E. N. In Comprehensive Asymmetric Catalysis.
Jacobsen, E. N.; Pfaltz, A.; Yamamoto H., Eds.; Supple-
ment 1, pp 117–129; (e) Gregory, R. J. H. Chem. Rev.
1999, 99, 3649–3682; (f) Effenberger, F. Angew. Chem.
1994, 106, 1609–1619; (g) North, M. Synlett 1993, 807–
820.
O-benzoylation. Ab initio and DFT calculations, as well
as NMR experiments, are in progress and will be
reported in due course with the aim of supporting these
hypotheses.
2. (a) Purkarthofer, T.; Skranc, W.; Weber, H.; Griengl, H.;
Wubbolts, M.; Scholz, G.; Po¨chlauer, P. Tetrahedron
2004, 60, 735–739; (b) Seoane, G. Curr. Org. Chem. 2000,
4, 283–304; (c) Schmidt, M.; Griengl, H. Top. Curr. Chem.
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Acknowledgements
This work has been supported by the DGES of the Span-
´
ish Ministerio de Educacion
y Cultura (MEC)
(BQU2001-0724, CTQ2004-02375/BQU and CTQ 2004-
00808/BQU) and Generalitat Valenciana (CTIOIB/
2002/320 and GRUPOS03/134) and by the University
of Alicante. A. Baeza also thanks Generalitat Valenciana
for a pre-doctoral fellowship (CTBPRB/2002/107).
3. Tian, S.-K.; Deng, L. J. Am. Chem. Soc. 2001, 123, 6195–
6196.
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(2 mL) and ethyl acetate (2 mL) were added and the
mixture stirred for 10min. The organic layer was sepa-
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vacuo, and the crude purified by flash chromatography to
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Table 1. The aqueous layer was treated with a 1 M NH3/
1 M NH4Cl buffer solution and then extracted with ethyl
acetate (2 · 10mL); the organic layers were dried over
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(11 mg).
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