Mechanistic studies on the enantioselective BINOLAM/titanium(IV)-catalyzed cyanobenzoylation of aldehydes: Part 1

Article abstract of DOI:10.1016/j.tetasy.2011.07.006

The enantioselective titanium(IV)-catalyzed cyanobenzoylation of aldehydes using 1:1 BINOLAM/Ti(OiPr)₄ mixtures as a precatalyst gave O-aroyl cyanohydrins 4 with good enantiomeric excesses. The standard optimization set carried out on the assumption of Curtin-Hammett behavior, led to no amelioration. Extensive experimental and computational studies were carried out with the purpose of identifying the key mechanistic aspects governing enantioselectivity. HCN and isopropyl benzoate were detected in the reacting mixtures. This as well as the reaction response to the presence of an exogenous base, and the failure to react in the presence of Binol/Ti(OiPr)₄ mixtures, led us to propose, not a direct but an indirect process involving an enantioselective hydrocyanation step followed by O-benzoylation. Computational work carried out with mononuclear monomeric M_M and dinuclear mixed dimer D_lMD as catalysts support this mechanistic proposal. On the other hand, cyanobenzoylations carried out with 1:2 or higher 1:n (up to 1:5) BINOLAM/Ti(OiPr)₄ mixtures appear to involve a reversal of the enantioselection. This, together with the fact that the benzoylation of the ligated iPrOH is a slow reaction, has led us to conclude that these cyanobenzoylations do not fit within the standard Curtin-Hammett kinetic scheme. Instead, such BINOLAM/Ti(OiPr)₄ -catalyzed cyanobenzoylations of aldehydes rather behave as non-Curtin-Hammett kinetic schemes. Further computational analysis is needed in order to make a clear distinction between Curtin-Hammett and non-Curtin-Hammett kinetic frameworks.

Full text of DOI:10.1016/j.tetasy.2011.07.006

Tetrahedron: Asymmetry 22 (2011) 1282–1291
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Mechanistic studies on the enantioselective BINOLAM/titanium(IV)-catalyzed
cyanobenzoylation of aldehydes: Part 1
Alejandro Baeza a, Carmen Nájera a, , José M. Sansano a, , José M. Saá b,à
⇑
a Departamento de Química Orgánica e Instituto de Síntesis Orgánica (ISO), Universidad de Alicante, Aptdo. 99, 03080 Alicante, Spain
b Departamento de Química, Universidad de las Islas Baleares, 07122 Palma de Mallorca, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
The enantioselective titanium(IV)-catalyzed cyanobenzoylation of aldehydes using 1:1 BINOLAM/
Ti(OiPr)4 mixtures as a precatalyst gave O-aroyl cyanohydrins 4 with good enantiomeric excesses. The
standard optimization set carried out on the assumption of Curtin–Hammett behavior, led to no amelio-
ration.
Received 11 May 2011
Accepted 7 July 2011
Available online 10 August 2011
Extensive experimental and computational studies were carried out with the purpose of identifying the
key mechanistic aspects governing enantioselectivity. HCN and isopropyl benzoate were detected in the
reacting mixtures. This as well as the reaction response to the presence of an exogenous base, and the
failure to react in the presence of Binol/Ti(OiPr)4 mixtures, led us to propose, not a direct but an indirect
process involving an enantioselective hydrocyanation step by O-benzoylation. Computational work car-
ried out with mononuclear monomeric MM and dinuclear mixed dimer DlMD as catalysts support this
mechanistic proposal.
On the other hand, cyanobenzoylations carried out with 1:2 or higher 1:n (up to 1:5) BINOLAM/
Ti(OiPr)4 mixtures appear to involve a reversal of the enantioselection. This, together with the fact that
the benzoylation of the ligated iPrOH is a slow reaction, has led us to conclude that these cyanobenzoy-
lations do not fit within the standard Curtin–Hammett kinetic scheme. Instead, such BINOLAM/Ti(OiPr)4
-
catalyzed cyanobenzoylations of aldehydes rather behave as non-Curtin–Hammett kinetic schemes.
Further computational analysis is needed in order to make a clear distinction between Curtin–Hammett
and non-Curtin–Hammett kinetic frameworks.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
However, most of the above cyanating reagents are moisture
sensitive and, therefore, their use for large scale enantioselective
Accessing enantiomerically enriched cyanohydrins and their
O-functionalized derivatives is a goal of major synthetic interest.1
For this purpose both chiral Lewis acids, chiral Lewis bases, and
dual catalysts have been successfully employed.2 In particular,
we have explored the use of metal complexes of the bifunctional
ligand BINOLAM (R)-1a and (S)-1a [(R)- or (S)-3,30-bis(diethylami-
nomethyl)-1,10-binaphthol] as catalysts for the enantioselective
cyanation of aldehydes.3 These studies revealed that aluminium-
derived catalysts generated in situ by reacting BINOLAM with
Me2AlCl, and generally represented as ‘BINOLAM–AlCl’, work as
efficient catalysts for the direct enantioselective cyanosilylations,4
cyanophosphorylations,5 and cyanoalkoxycarbonylations of alde-
hydes.6
cyanations should be avoided. The less hydrolizable acyl cyanides
seemed to be a good choice in light of their well-known capacity
to promote the cyanoacylation of aldehydes.7 Accordingly, we
decided to explore the enantioselective cyanoacylations of alde-
hydes using acyl cyanides as the reagents of choice. However,
our previously successful ‘BINOLAM–AlCl’ complexes were of no
use for the cyanoacetylations or cyanobenzoylations as neither
one of these reactions took place, even in the presence of a substo-
ichiometric amount of water, ethyl alcohol, water-containing
molecular sieves 4 Å or triphenylphosphane oxide. Instead, we
explored ‘BINOLAM–TiX2’ complexes resulting from a 1:1 mixture
of BINOLAM 1a and Ti(OiPr)4 as catalysts for the cyanoacylation of
aldehydes (3-phenylpropanal and benzaldehyde were initially
employed as representative substrates). The results of this investi-
gation have already been reported.8 At the time of this preliminary
communication, the detailed mechanism of the action of ‘BINO-
LAM–TiX2’ complexes as catalysts was lacking, because the struc-
ture of titanium(IV) complexes was not well-known,9 in spite of
recent advances in the field.10 Herein we fully describe the
⇑
Corresponding author. Tel./fax: +34 965903549.
E-mail addresses: cnajera@ua.es (C. Nájera), jmsansano@ua.es (J.M. Sansano),
jmsaa@uib.es (J.M. Saá).
Tel./fax: +34 965903549.
Tel.: +34 971173262; fax: +34 971173426.
à
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.07.006

A. Baeza et al. / Tetrahedron: Asymmetry 22 (2011) 1282–1291
1283
‘BINOLAM–TiX2’ catalyzed cyanobenzoylations and illustrate some
mechanistic aspects that we believe are of general validity for
other catalyzed reactions. In particular, we claim that the great dif-
ficulty in optimizing some catalytic reactions might be related to
the fact that they do not fit within the usual Curtin–Hammett ki-
netic construction. More specifically, we will illustrate by means
of combined experimental and computational studies that ‘BINO-
LAM–TiX2’ catalyzed cyanobenzoylations actually take place by
means of an indirect process involving an enantioselective hydro-
cyanation, by O-benzoylation, which appear to behave as a non-
Curtin–Hammett kinetic system.11
heteroatoms in the substrate led to a decrease in enantioselectivity
(Table 1, entries 10 and 18). In all cases the absolute configuration
of the O-benzoylcyanohydrins 4 was determined by comparing
their specific rotations with those of samples prepared by the O-
benzoylation of enantiopure cyanohydrins. In addition, we showed
that the chiral ligand could be easily recovered after workup and
successfully reused (Table 1, entry 3).
Within the framework of a Curtin–Hammett catalytic cycle the
optimization of a specific enantioselective catalytic procedure is, in
general, a self-consistent adjustment of operational variables (re-
agents, temperature, solvent, time, additives, and so on). Initially
we took for granted the Curtin–Hammett behavior of our Ti(IV)-
catalyzed methodology.13 However, the difficulties in further
improving the encouraging, although nevertheless insuperable,
(84:16) enantiomeric ratio reached in the above titanium(IV)-cat-
alyzed cyanobenzoylations drove us to carry out both experimen-
tal and, eventually, computational mechanistic studies upon the
‘BINOLAM–TiX2’-catalyzed cyanobenzoylation,11 with the aim of
understanding those mechanistic intricacies that could help us im-
prove their efficiency and perhaps the related reactions as well.14
Kinetic studies on titanium(IV) alkoxide catalysis are difficult to
carry out due to their tendency to form aggregates. Accordingly, we
focused our attention on evaluating the competing catalytic routes
with the purpose of undergoing a rational, Curtin–Hammett-based
optimization of ‘BINOLAM–TiX2’-catalyzed cyanobenzoylations.
2. Results and discussion
We previously explored some time ago the enantioselective
synthesis of O-acylcyanohydrins 4 promoted by a ‘BINOLAM–
TiX2’ species. In particular, extensive experimentation was carried
out using enantiomerically pure ligands 1–3, different titanium(IV)
sources [either Ti(OiPr)4, Ti(OiPr)2Cl2 or Ti(OMe)4], different acylat-
ing reagents (acetyl cyanide, benzoyl cyanide and related aroyl
cyanides), solvents (THF, toluene or CH2Cl2), additives (MS 4 Å,
iPrOH, Ph3PO), and eventual fine-tuning of the common reaction
variables, as well as the ligand:titanium ratio. The best results were
obtained when operating in THF at room temperature with tita-
nium-derived catalysts prepared in situ from 1:1 BINOLAM 1a/
Ti(OiPr)4 mixtures in the presence of aroyl cyanides (incomplete
conversions were observed when acetyl cyanide was employed).
It is worth noting that these reactions responded to the ligand-
accelerated catalysis concept as only trace amounts of the product
could be observed when using Ti(OiPr)4 (10 mol %) alone.12 The de-
sired O-aroyl (for the most part O-benzoyl) cyanohydrins 4 were
thus obtained in good yield and with an encouraging 84:16 enan-
tiomeric ratio (for the case of benzaldehyde) or 83:17 for the case
of 3-phenylpropanal.8 These results were considered worthy of
further study for improvement (Scheme 1) and thus we became in-
volved in a careful, Curtin–Hammett based optimization process.
As illustrated in Table 1, the scope of the reaction was shown to
2.1. Mechanistic studies: the competing catalytic routes
As illustrated in Scheme 2, four possible competing routes were
considered feasible for the observed cyanobenzoylations, the first
being the organocatalytic route A. Since BINOLAMs 1 are bis ter-
tiary amines, we envisioned them as plausible organocatalysts
capable of promoting enantioselective cyanations by means of a
Lewis base mechanism.15 However, this mechanistic alternative
was soon rejected because BINOLAM 1a in the absence of a metallic
cocatalyst was found to be unable to promoting the benzoylcyana-
tion of benzaldehyde (Table 2, entry 1). Instead, we judged it
probable that the observed asymmetric cyanobenzoylation of alde-
hydes promoted by BINOLAM/Ti(OiPr)4 mixtures could be the re-
sult of a Ti(IV)-catalyzed asymmetric process, either through a
direct cyanobenzoylation (route B) or, perhaps, through an indirect
process involving hydrocyanation by the action of HCN followed by
be wide (applicable to aromatic, heteroaromatic,
and aliphatic aldehydes), although with some limitations. Particu-
larly relevant is the case of -substituted aldehydes (cyclohexane-
a,b-unsaturated
a
carbaldehyde), which yielded an almost racemic product (Table 1,
entry 16). Also worthy of note is that the presence of basic
NR2
NR2
NR
OH
OH
NR
OH
OH
OH
OH
NR2
NR2
(S)-Binolams 1
(S)-3
(S)-OctahydroBinolams 2
2a R = Et
1a, R = Et
1b, R = iPr
1c, R = N(Me)CH2CH2NMe2
O
(S)-ligand (10 mol%)
O
O
Ar
CN
co-catalyst (10 mol%)
RCHO
+
NC
Ar
R
solvent, T (ºC)
(R)-O-aroylcyanohydrins 4
4a Ar = Ph
4a' Ar = p-OMe-C6H4
4a'' Ar = p-Cl-C6H4
Scheme 1. Catalytic systems employed for the enantioselective cyanobenzoylation of aldehydes

1284
A. Baeza et al. / Tetrahedron: Asymmetry 22 (2011) 1282–1291
Table 1
Enantioselective synthesis of O-aroylcyanohydrins 4 by reaction of aroyl cyanides ArCOCN with aldehydes RCHO in the presence of a 1:1 BINOLAM 1a:Ti(OiPr)4 mixture
Entry
R
Ar
t (h)
4
Yield (%)a/erb
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
6
6
6
(R)-4a
(S)-4a
(R)-4a
(R)-4a0
(R)-4a00
(R)-4b
(R)-4c
(R)-4d
(S)-4e
(R)-4f
(R)-4g
(R)-4h
(R)-4i
(R)-4j
(R)-4k
(R)-4l
(R)-4m
(R)-4n
91/84:16c
90/16:84c
90/84:16c
75/78:22c
87/79:21c
76/79:21
85/79:21
92/83:17
89/78:22
93/64:36f
78/83:17
87/84:16g
75/92:8
Phd
Phe
Ph
Ph
4-(MeO)C6H4
4-ClC6H4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
24
72
21
18
22
7
22
17
6
24
60
12
8
4-(MeO)-C6H4
4-Cl-C6H4
3-(PhO)-C6H4
2-Furyl
3-Pyridyl
(E)-MeCH@CH
(E)-C5H11CH@CH
(E)-PhCH@CH
(E)-4-(MeO)-C6H4CH@CH
n-C6H13
9
10
11
12
13
14
15
16
17
18
71/88:12
80/78:22h
83/56:44
93/83:17f
85/69:31
Cyclohexyl
PhCH2CH2
PhCH2OCH2
3
2
a
b
c
Isolated yields after flash chromatography.
Determined by HPLC using chiral columns (Daicel, Chiralpack AS).
Determined by HPLC using chiral columns (Daicel, Chiralpack AS).
(R)-BINOLAM (R)-1a was used.
Recovered ligand (S)-1a after one batch was employed.
Determined by HPLC using chiral columns (Daicel, Chiralcel OD-H).
Determined by HPLC using chiral columns (Daicel, Chiralcel OJ).
d
e
f
g
h
Determined by GC using a chiral column (c-cyclodextrin).
O
O
O
organocatalysis
(route A)
direct cyanobenzoylation
(route B)
Φ
Φ
O
R
CN
R
CN
O
O-aroylcyanohydrins 4
O-aroylcyanohydrins 4
RCHO
+
Φ
NC
+ Ti(OiPr)4 + Binolam
O
O
FCOOiPr
FCOOiPr
+ HCN
Φ
Φ
O
O
+ HCN
R
CN
R
CN
O-aroylcyanohydrins 4
O-aroylcyanohydrins 4
indirect cyanobenzoylation
(route C)
dynamic kinetic resolution
(route D)
Scheme 2. Plausible catalytic routes for the BINOLAM/Ti(OiPr)4 enantioselective cyanobenzoylation of aldehydes.
O-benzoylation (route C). Alternatively, enantiomerically enriched
O-benzoylcyanohydrins 4 could result from a dynamic kinetic res-
olution (route D) of racemic cyanohydrins involving ‘BINOLAM–
TiX2’-catalyzed O-benzoylation. However, the attempted kinetic
resolution of a racemic sample of mandelonitrile under the above
optimized conditions led to racemic 4a. Consequently, the
titanium(IV)-catalyzed kinetic resolution (route D) was also
disregarded as an operating route in these cyanobenzoylations.
Accordingly, we were left with routes B and C, only.
The so-called indirect cyanobenzoylation (route C) calls for the
intervention of a substoichiometric amount of HCN in the stereo-
chemically relevant hydrocyanation step, which should then be
followed by O-acylation of the resulting chiral cyanohydrin, there-
by regenerating the HCN required for a subsequent cycle. For the
hydrocyanation step, one could conceive of catalysis taking place
either through an LABB type mechanism or through a titanium cya-
nate or isocyanate intermediate. As reported by Spencer et al., trace
amounts of Brønsted acids derived from the hydrolysis of Lewis
acids are in many cases the actual catalysts for many so-called
‘Lewis acid-catalyzed reactions’.16 By analogy, the cyanide deriva-
tives used as reagents in cyanation reactions could well be the
source of HCN due to inevitable partial, or trace, hydrolysis under-
gone during manipulation. In the previous work we,17–19 and other
groups,20,21 reported positive proof of the presence of HCN in
the solution mixtures employed for titanium-catalyzed and
aluminium-catalyzed cyanosilylations (110.5 ppm in CDCl3),18 cya-
nophosphorylations (112.3 ppm in CDCl3),17 and cyanoalkoxycarb-
onylations (109.8 ppm in CDCl3).19 An additional, indirect proof for
the implication of HCN in the enantioselective processes catalyzed
by ‘BINOLAM–AlCl’ is the dramatic loss of ee when the reactions
were carried out in the presence of an exogenous base, such as
Et3N, as in this case the LABB dual role of the catalyst should be se-
verely disabled due to the competing action of an external
Brønsted base .
On the other hand, the direct cyanobenzoylation (route B) is
generally assumed to involve a highly reactive chiral, N-acylium

A. Baeza et al. / Tetrahedron: Asymmetry 22 (2011) 1282–1291
1285
Table 2
vided that the presence of HCN could be demonstrated, we planed
to confront both the direct and indirect routes (B and C,
respectively) by means of a computational study, aimed at identi-
fying the actual mechanism of our cyanobenzoylations.
Optimization of the reaction conditions for cyanoaroylation of aldehydes RCHO with
aroyl cyanides catalyzed by 1:1 BINOLAM/Ti(OiPr)4 mixtures
Entrya
R
ligand/additive/co-catalyst/solvent/time Yield (%)b/ erc
In fact, the 13C NMR spectrum of the solution mixture employed
for cyanobenzoylations [i.e., a 1:1 mixture of BINOLAM and
Ti(OiPr)4 in the presence of an equivalent amount of commercial
benzoyl cyanide] in deuterated chloroform showed a very small
signal at 111.8 ppm, which was shown to correspond to HCN (as
expected, a somewhat larger signal was observed when CD3CN
was used as solvent, as this solvent is usually contaminated with
water). Since commercial benzoyl cyanide does not contain dis-
solved HCN according to 13C NMR measurements, the above obser-
vation must be the consequence of the reaction of iPrOH (either
free or ligated to titanium) with benzoylcyanide. The O-benzoylcy-
anides 4 were obtained in high chemical yield under these condi-
tions (Table 2, entries 3 and 4). In agreement with this, when the
experimental conditions were modified so as to incorporate vac-
uum removal of iPrOH prior to addition of benzoyl cyanide, we
found the reaction to be inefficient (50% yield) even after 45 h reac-
tion time (Table 2, entry 6). Moreover, attempted cyanobenzoyla-
tions carried out with a 1:1 BINOLAM/Ti(OiPr)2Cl2 mixture ended
up with no reaction taking place (Table 2, entry 7), a result consis-
tent with the irreversible protonation of the amino groups by the
HCl produced during complexation. It thus became inevitable to
consider the likely implication of HCN in the above ‘BINOLAM–
TiX2’-catalyzed cyanobenzoylation reactions, a scenario in which
the amino arms of our ‘BINOLAM–TiX2’ catalyst ought to play a rel-
evant role.
1
2
3
4
5
6
7
8
Ph
Ph
Ph
1a/none/none/THF/5 h
none/none/Ti(OiPr)4/THF/ 24 h
1a/none/Ti(OiPr)4/THF/5 h
(0)/__
(<5d)/__
(>95)/84:16
(>95)/83:15
(>70)/64:36
(50e)/84:16
(0)/__
Ph(CH2)2 1a/none/Ti(OiPr)4/THF/5 h
Ph
Ph
Ph
Ph
Ph
Ph
Ph
1a/iPrOH(10 mol %)/Ti(OiPr)4/THF/7 h
1a/none/Ti(OiPr)4/THF/45 h
1a/none/TiCl2(OiPr)2/CH2Cl2/48 h
Binol/none/Ti(OiPr)4/THF/72 h
1a/Et3N(10 mol %)/Ti(OiPr)4/THF/5 h
1a/Et3N(50 mol %)/Ti(OiPr)4/THF/5 h
1a/Et3N(100 mol %)/Ti(OiPr)4/THF/
45 min
(0)/__
(>95)/63:37
(>95)/54:46
(>95)/50:50
9
10
11
a
The general procedure for the cyanoaroylation of aldehydes involved the
treatment of a THF(dry) solution of aldehyde, at room temperature, under argon,
with 3 equiv of aroyl cyanide in the presence of 10 mol % of Ti(OiPr)4 and 10 mol %
of (R)- or (S)-BINOLAM 1a.
b
Crude yields of O-aroyl cyanohydrins were determined by 1H NMR
spectroscopy.
c
Determined by HPLC using chiral columns (Daicel, Chiralpack AS).
10 mol % of Ti(OiPr)4
iPrOH was removed under vacuum.
d
e
N
Ti
N
N
iPr
OiPr
O
O
O
OiPr
OiPr
O
O
OiPr
(R)
Ti
(R)
Ti
OiPr
OiPr
O
To further elucidate the role, if any, of the catalyst amino arms
we carried out an experiment using Binol instead of BINOLAM,
under otherwise identical conditions; no reaction was observed
(Table 2, entry 8), thus suggesting a key role for those amino
groups.8 Furthermore, the addition of exogenous triethylamine to
the 1:1 BINOLAM/Ti(OiPr)4 mixture employed for the cyanobenzoy-
lation of aldehydes gave rise to a significant lowering of the er va-
lue. The addition of 0, 10, 50 or 100 mol % of Et3N, led to a
straightforward decline of the enantiomeric ratio (84:16, 63:37,
54:46 and 50:50, respectively), again pointing to hydrocyanation
by HCN (Table 2, entries 3, 9, 10, 11) as the major event (route C)
in our Ti(IV)-catalyzed cyanobenzoylations. This decrease in the
er promoted by the addition of an external tertiary amine is in line
with a significant rise of the background reaction, as supported by
the observed rate acceleration after addition of 100 mol % Et3N
(reaction was over in ca. 45 min, as shown in Table 2, entry 11).
To further evaluate this mechanistic proposal (route C) we carefully
examined the NMR spectrum of a 1:1 mixture of BINOLAM and
iPr
N
DlMD
MM
Scheme 3. Monomeric M and dimeric titanium(IV) D derivatives computationally
evaluated as benzoylcyanation catalysts.
cyanide intermediate species capable of adding to the carbonyl
group, thereby giving rise to the final O-functionalized
cyanohydrin either in a single step, or stepwise. In this case, catal-
ysis should be of the LALB type. A recent report by Moberg et al.
regarding a specific Ti(IV)-catalyzed acylcyanation of aldehydes
called for a direct acylcyanation,22 as there were no Brønsted acids
(ROH, H2O, etc.) available either on the catalyst, or in the reaction
media. The main support for this proposal was the lack of incorpo-
ration of 13C when H13CN was bubbled through the reaction solu-
tion prior to introduction of the reagents. We rejected, however,
carrying out such an experiment as the literature clearly points
out that the H13CN carefully prepared from K13CN and 85%
H3PO4 and eventually distilled under extremely careful conditions
is in fact a solution of H13CN in water in a 1:2 molar ratio.23 Under
these conditions our catalytic reaction would be quenched, thus
leading to meaningless conclusions.
benzoyl cyanide, and also of
a 1:1:1 mixture of BINOLAM/
Ti(OiPr)4:benzoyl cyanide, at room temperature. Our conclusion
from this first set of experiments was simple: there was no obser-
vable interaction between BINOLAM and benzoyl cyanide, as re-
vealed by a 1H NMR spectrum taken after a short period of time,
in agreement with the fact that BINOLAM 1a itself does not promote
the benzoylcyanation of benzaldehyde (Table 1, entry 1). As afore-
mentioned, when Ti(OiPr)4 was added to this mixture, we immedi-
ately noticed the formation of a very small amount of HCN (broad
With this in mind, we decided to look first for the direct
detection of HCN in ‘BINOLAM–TiX2’-catalyzed benzoylcyanation
reactions under the experimental conditions of the operation. Pro-
Table 3
Evaluation of direct (route B) vs. indirect cyanobenzoylation (route C) by DFT (B3LYP/6-31G⁄) calculations.
Entry
Reactants
Relative energies in kcal/mol and
absolute energies in hartrees (in italics)
1
2
3
4
MlMDPhCOꢀCN-tsSi + Biphelam + 2PhCOOiPr + 2HCN
2Biphelam + 2Ti(OiPr)4 + 3PhCOCN + CH3CHO
MlMD-tsSi + Biphelam + 2PhCOOiPr + HCN + COCN
MM-tsSi + 8.2(iPrOH) + HCN + 2PhCOOiPr
+10.04ꢁ6637,273770
0ꢁ6637,289775
ꢁ14.39ꢁ6637,312699
ꢁ20.91ꢁ6637,323097

1286
A. Baeza et al. / Tetrahedron: Asymmetry 22 (2011) 1282–1291
Table 4
by GC-MS analysis. This is consistent with the idea that the initial
complexes formed in a 1:1 BINOLAM/Ti(OiPr)4 mixture slowly react
with benzoyl cyanide, thereby giving rise to the actual catalysts and
HCN. As expected, the reaction of a 1:1 BINOLAM/Ti(OiPr)4 mixture
with benzoyl chloride took place much faster.
Thus, conditions for indirect benzoylcyanations (route C) indeed
exist in our reaction mixture. Nevertheless, the existence of HCN
does not invalidate the occurrence of the N-benzoyl ammonium
cyanide species required for a direct benzoylcyanation (route B).
To discriminate between them, we looked for computational evi-
dence, for which purpose we examined prototype mononuclear
MM and dinuclear DMD Ti(IV) complexes, as illustrated in Scheme 3.
The absence of non-linear effects in the cyanobenzoylations carried
Dependence of benzoylcyanation enantioselectivity upon BINOLAM/Ti(OiPr)4 ratios
BINOLAM/
Ti(OiPr)4 ratio
Reaction
time (h)
Conversion er
(%)
Configuration of major
enantiomer of 6a
1:1
1:2
1:3
1:5
5
6
5
7
95
98
90
90
84:16
(R)
(R)
(R)
(S)
69:31
48:52
42:58
peak centred at 111.8 ppm) and of isopropyl benzoate (relevant sig-
nals appearing at 21.0, 68.0, 175.8 ppm) in the 13C NMR spectrum of
the mixture. Isopropyl benzoate was also detected in this mixture
Figure 1. HPLC chromatograms of O-benzoylcyanohydrin 4a resulting from cyanobenzoylation reactions catalyzed by 1:1 rac-BINOLAM/Ti(OiPr)4 and 1:n (S)-BINOLAM/
Ti(OiPr)4 mixtures (n = 1, 2, 3, 5).

A. Baeza et al. / Tetrahedron: Asymmetry 22 (2011) 1282–1291
1287
out with 1:1 BINOLAM/Ti(OiPr)4 mixtures (see Experimental)
3. Conclusion
indicate that only mononuclear monomeric MM and dinuclear
mixed dimers DMD can actually intervene as catalysts. Accordingly,
we chose mononuclear titanium derivative MM.2iPrOH and
DlMD.2iPrOH for this computational test.11 Ion pair MMCOPh+NCꢁ
(resulting from the reaction of MMꢀ2iPrOH with 3 equiv of PhCOCN)
and the corresponding aldehyde complex MMCOPh+NCꢁꢀCH3CHO
were found to be stationary points at the B3LYP/6-31G⁄ level of
calculation. However, we were unable to find (at both the HF ab
initio and DFT levels of calculations) the transition structures cor-
responding to the direct benzoylcyanation (route B). We also ex-
plored the dinuclear mixed dimer DlMD as a catalyst for the
direct benzoylcyanation reactions (route B). Eventually, we found
the transition structure for the direct benzoylcyanation, namely
DlMDCOPh+NC-ts. This transition structure was computed to lie
30.95 kcal/mol higher than that corresponding to the indirect ben-
zoylcyanation, namely MM-ts (relevant energy data are given in Ta-
ble 3). We can thus conclude that the most favorable route for the
enantioselective ‘BINOLAM–TiX2’ catalyzed cyanobenzoylations
should be that of the indirect process (route C), which requires
the intervention of an enantioselective hydrocyanation by means
of HCN followed by an stereochemically inert O-benzoylation.
Since, as shown above, HCN is generated in situ by the reaction of
the aroyl cyanide with iPrOH (either free or ligated), and most
importantly, this appeared to be a slow process, at this point we
realized that our experimental conditions might not be leading us
to a Curtin–Hammett kinetic scheme. Instead, cyanobenzoylations
could be taking place under a non-Curtin–Hammett framework
where the precatalytic BINOLAM–titanium complexes initially
formed should be converted to the actual catalysts by reacting with
benzoyl cyanide. The most relevant consequence derived from this
new set of conditions is the striking differences one could find in
optimizing a non-Curtin–Hammett instead of a Curtin–Hammett
system. Thus, whereas optimization of the latter generally involves
a self-consistent adjustment of operational variables (temperature,
solvent, concentration of reagents, time, etc), that of a non-Curtin–
Hammett mechanism may be quite hard to achieve due to the fact
that a kinetic quench of the active catalytic routes occur in this case.
Accordingly, optimization of a non-Curtin–Hammett mechanism
may require the modification of structural variables namely ligand
modification, change of metal derivative, and so on.11
It was thus of major importance to find out whether or not
these Ti(IV)-catalyzed cyanobenzoylations could be definitely
categorized as Curtin–Hammett or non-Curtin–Hammett kinetic
systems. A straightforward comparative analysis (Table 4) of the
cyanobenzoylations carried out with 1:1 BINOLAM/Ti(OiPr)4 mix-
tures,8 with those employing 1:2 or higher (1:n) ratios, provided
evidence indicative of the existence of, at the very least, two com-
peting routes leading to opposite enantioselectivities.24 A reversal
of enantioselection is apparent in going from 1:1 to 1:5 BINOLAM/
Ti(OiPr)4 ratios as illustrated in the HPLC chromatograms provided
in Figure 1. One can expect some erosion of enantioselectivity by
the background reaction that takes place when using excess
Ti(OiPr)4, but definitely not a reversal of enantioselectivity. In fact,
only trace amounts (<5%) of racemic O-benzoylcyanohydrin 4a
were obtained when benzaldehyde was submitted to benzoylcya-
nation in the presence of 10 mol %ar Ti(OiPr)4 (Table 2, entry 2)
as the sole catalyst. We therefore conclude that at the very least,
two competitive routes with opposite enantioselectivities operate
in our cyanobenzoylations. With the final objective of finding the
appropriate conditions for an efficient enantioselective cya-
nobenzoylation, we considered it of prime importance to properly
identify these competing routes. Due to the difficulty in carrying
out kinetic studies upon Ti(IV)-catalyzed reactions, we plan to car-
ry out a detailed computational study as the most reliable plan to
reach our goal.11
The exploration of the enantioselective benzoylcyanation of
aldehydes using less reactive cyanide derivatives such as aroyl cya-
nides, catalyzed by BINOLAM/Ti(OiPr)4 mixtures, turned out to be
difficult because the optimization armory employed on the
assumption of a Curtin–Hammett kinetic framework, did not work
properly. We thus planned to carry out a mechanistic study.
Amongst the various mechanistic schemes examined as plausible
routes, only the direct (route B) and indirect (route C) cyanobenzoy-
lations were found to be real possibilities according to the experi-
mental results. A short term computational analysis carried out
upon mononuclear MM and dinuclear DlMD models allowed us to
establish that the so-called indirect cyanobenzoylation route
should be faster than the direct cyanobenzoylation route, at least
for our reaction conditions. Therefore, cyanobenzoylations pro-
moted by BINOLAM/Ti(OiPr)4 mixtures can be described as indirect
processes (route C) taking place by means of an enantioselective
hydrocyanation followed by O-benzoylation. Interestingly, exami-
nation of the results of cyanobenzoylations carried out with 1:1,
1:2 or higher 1:n BINOLAM/Ti(OiPr)4 ratios led us to observe a
reversal of enantioselection. This, together with the fact that the
benzoylation of ligated iPrOH is a slow reaction, has led us to con-
clude that our cyanobenzoylations might not fit within the classical
Curtin–Hammett kinetic scheme. We plan to carry out to a detailed
computational study to clearly identify Curtin–Hammett and non-
Curtin–Hammett frameworks,11,25 with the goal of finding an effi-
cient enantioselective method for the cyanoacylation of aldehydes.
4. Experimental section
4.1. General methods
All reactions were carried out under argon, including the transfer
of solid reagents to the reaction vessel. Anhydrous solvents were
freshly distilled under an argon atmosphere and commercial alde-
hydes were also distilled prior to use. Melting points were deter-
mined with a Reichert Thermovar hot plate apparatus and are
uncorrected. IR spectra were recorded on a Nicolet 510 P-FT and
only the structurally most relevant peaks are listed. NMR spectra
were performed on a Bruker AC-300 using CDCl3 as solvent and
TMS as the internal standard unless otherwise stated. Optical rota-
tions were measured on a Perkin Elmer 341 polarimeter. HPLC anal-
yses were performed on a Shimadzu LC-10AD and Jasco PU2000 Plus
series equipped with the corresponding chiral column (Chiralcel OD,
and OD-H and Chiralpack AD and AS) described for each compound,
using mixtures of n-hexane/isopropyl alcohol as the mobile phase.
Chiral GC analysis was performed on a HP-5890 using a WCOT c-
cyclodextrin column. Retention times of the major enantiomer are
given in boldface. Low-resolution electron impact (EI) mass spectra
were obtained at 70 eV on a Shimadzu QP-5000 and high resolution
mass spectra were obtained on a Finnigan VG Platform. HRMS (EI)
were recorded on a Finnigan MAT 95S. Microanalyses were per-
formed on a Perkin Elmer 2400 and a Carlo Erba EA1108. Analytical
TLC was performed on Schleicher & Schuell F1400/LS silica gel plates
and the spots visualized with UV light at 254 nm. Flash chromatog-
raphy employed Merck Silica Gel 60 (0.040–0.063 mm).
4.2. General procedure for the cyanobenzoylation of aldehydes
catalyzed by 1:1 BINOLAM/Ti(OiPr)4 mixtures
To a solution of (R)- or (S)-BINOLAM (0.025 mmol, 11.4 mg), in
dry THF (1 mL), under a dried atmosphere of argon, titanium tetra-
isopropoxide (0.025 mmol, 9
lL) was added, and the resulting sus-
pension being stirred for 1 h at room temperature. Freshly distilled

1288
A. Baeza et al. / Tetrahedron: Asymmetry 22 (2011) 1282–1291
aldehyde (0.25 mmol) and the aroyl cyanide (0.75 mmol, 90
l
L)
HRMS calcd for C21H15O3N: 329.1052, found: 329.1051; HPLC:
DAICEL CHIRACEL OD-H, k = 254 nm, n-hexane/2-propanol, 95:5,
1 mL/min, tr = 12,1 and 13.5 min.
were then added. The reaction was monitored by 1H NMR or GC.
When it was judged complete, HCl 2 M (2 mL) and ethyl acetate
(2 mL) were added, and the mixture was stirred for an additional
10 minutes. The organic layer was separated, dried over anhydrous
MgSO4, evaporated under vacuum, and the remaining crude mate-
rial was purified by flash chromatography to yield pure benzoyl-O-
cyanohydrin 4 in yields reported in the main text and Table 1. The
aqueous layer was treated with a 1 M NH3/1 M NH4Cl buffer solu-
tion and then extracted with ethyl acetate (2 ꢂ 10 mL). The organic
layers were dried (MgSO4) and after filtration evaporated under
vacuum to yield (S)-BINOLAM in 96% (11 mg). When using p-
methoxybenzoyl cyanide and p-chlorobenzoyl cyanide, under
otherwise identical conditions, compounds 4a0 and 4a00 were ob-
tained. The enantiomeric purity of the enantiomerically enriched
4 was then determined by HPLC or GC using chiral columns. Their
physical and analytical data are given below.
4.2.5. (R)-2-(Benzoyloxy)-2-furylacetonitrile 4e
Colorless oil; ½a D25
¼ þ2:9 (c 1.0, CHCl3) (55% ee); TLC: Rf 0.39
ꢃ
(n-hexane/ethyl acetate, 4:1); IR (neat): mmax 2339, 1731, 1255,
1085, 1600, 1585, 1496, 1452, 1315, 1026 cmꢁ1
;
1H NMR
(300 MHz, CDCl3): dH 6.46–6.48 (m, 1H, CH@CHO), 6.75 (s, 1H,
CHCN), 6.77 (d, J = 3.4 Hz, 1H, CH@C), 7.47 (t, J = 7.6 Hz, 2H, ArH),
7.54 (m, 1H, C@CHO), 7.60–7.65 (m, 1H, ArH), 8.07 (d, J = 7.2 Hz,
2H, Hz, ArH); 13C NMR (75 MHz, CDCl3): dC 61.6 (CHCN), 111.1
(CH@C), 112.8 (CH@CHO), 114.2 (CN), 127.8, 128.6, 130.1, 134.2
(ArC), 144.2 (CCHCN), 145.1 (C@CO), 164.4 (CO); MS (EI): m/z
227 (M+, 15%), 182 (42), 106 (60), 105 (100); HRMS calcd. for
C13H9NO3: 227.0582, found: 227.0588; HPLC: DAICEL CHIRALPAK
AS, k = 254 nm, n-hexane/2-propanol, 99:1, 1 mL/min, tr = 12.3
and 14.7 min.
4.2.1. (R)-2-(Benzoyloxy)-2-phenylacetonitrile 4a
Colorless oil; ½a D25
ꢃ
¼ þ7:7 (c 2.0, CHCl3) (68% ee); TLC: Rf 0.51 (n-
4.2.6. (R)-2-(Benzoyloxy)-2-(3-pyridyl)acetonitrile 4f
hexane/ethyl acetate, 4:1); IR (neat): mmax 2343, 1731, 1246,
White powdered solid;
acetate); TLC: Rf 0.31 (n-hexane/ethyl acetate, 3:2); IR (KBr): mmax
2244, 1724, 1258, 1091, 1600 cmꢁ1 1H NMR (300 MHz, CDCl3):
m p: 66 °C (from n-hexane/ethyl
1088 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 6.7 (s, 1H, CHO), 7.44–
;
7.49 (m, 5H, ArH), 7.60–7.64 (m, 3H, ArH), 8.06–8.08 (m, 2H,
ArH); 13C NMR (75 MHz, CHCl3): dC 63.3 (CH), 116.2 (CN), 127.8,
128.1, 128.6, 129.3, 130.1, 130.4, 131.8, 134.1 (ArC), 164.6 (CO);
MS (EI): m/z 237 (M+, 15%), 116 (41), 105 (100); HRMS calcd. for
;
dH 6.74 (s, 1H, CHCN), 7.46–7.51 (m, 3H, ArH), 7.59–7.67 (m, 1H,
ArH), 8.01–8.13 (m, 3H, ArH), 8.78 (br s, 1H, ArH), 8.92 (b s, 1H,
ArH); 13C NMR (75 MHz, CDCl3): dC 61.2 (CHCN), 115.3 (CN),
127.6, 128.3, 128.7, 130.1, 133.1, 134.4, 135.8, 148.8, 151.3 (ArC),
164.3 (CO); MS (EI): m/z 238 (M+, 3.4%), 183 (35), 117 (35), 105
(100). Anal. Calcd for C14H10N2O2: C, 70.6; H, 4.2; N, 11.8. Found:
C, 70.3; H, 4.3; N, 11.4. HPLC: DAICEL CHIRALCEL OD-H,
k = 254 nm, n-hexane/2-propanol, 96:4, 1 mL/min, tr = 26.7 and
30.5 min.
C
15H12NO2: 237.0790, found: 237.0800; HPLC: DAICEL CHIRALPAK
AS, k = 254 nm, hexane/2-propanol, 99:1, 1.0 mL/min, tr = 11.6 and
14.3 min.
4.2.2. (R)-2-(Benzoyloxy)-2-(4-methoxyphenyl)acetonitrile 4b
Colorless oil; ½a D25
¼ þ10:9 (c 1.0, CHCl3) (56% ee); TLC: Rf 0.67
ꢃ
(n-hexane/ethyl acetate, 4:1); IR (neat): mmax 2351, 1731, 1246,
1088 cmꢁ1
;
1H NMR (300 MHz, CDCl3): dH 3.84 (s, 3H, OCH3),
4.2.7. (2R,3E)-2-(Benzoyloxy)pent-3-enenitrile 4g
6.62 (s, 1H, CHCN), 6.98 (d, J = 8.8 Hz, 2H, ArH), 7.45 (t, J = 7.6,
1H, ArH), 7.55 (d, J = 8.8 Hz, 2H, ArH), 7.60–7.65 (m, 1H, ArH),
8.04 (m, 3H, ArH); 13C NMR (75 MHz): dC 55.4 (CH3), 63.1 (CHCN),
114.6 (ArC), 116.4 (CN), 123.9, 128.6, 129.7, 130.0, 132.0, 134.0,
161.1 (ArC), 164.7 (CO); MS (EI): m/z 267 (M+, 14.3%), 146 (51),
147 (51), 136 (54), 135 (100), 105 (43); HRMS calcd for
16H13NO2: 267.0895; found: 267.0889; HPLC: DAICEL CHIRALPAK
AD, k = 254 nm, n-hexane/2-propanol, 99:1, 1 mL/min, tr = 25.7 and
29.1 min.
Colorless oil; ½a D25
¼ ꢁ4:5 (c 1.3, CHCl3) (65% ee); TLC: Rf 0.55 (n-
ꢃ
hexane/ethyl acetate, 4:1); IR (neat): mmax 2240, 1732 1259, 1090,
1600 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 1.79 (d, J = 6.2 Hz, 3H,
;
CH3), 6.10 (dd, J = 6.6, 1.6. Hz, 1H, C@CHCO), 6.18 (d, J = 6.7 Hz,
1H, CHCN), 6.20–6.32 (m, 1H, CH3CH@C), 7.47 (t, J = 7.6 Hz, 2H,
ArH), 7.60–7.65 (m, 1H, ArH), 8.06 (d, J = 7.2 Hz, 2H, ArH); 13C
NMR (75 MHz, CDCl3): dC 17.7 (CH3), 61.9 (CHCN), 115.8 (CN),
121.4 (C@CHCO), 128.2, 128.6, 130.0, 133.9 (ArC), 135.9
(CH2CH@CH), 164.6 (CO); MS (EI): m/z 201 (M+, 2.3%), 105 (100),
77 (27); HRMS calcd for C12H11NO2: 201.0790, found: 201.0790;
HPLC: DAICEL CHIRALPAK AS, k = 254 nm, n-hexane/2-propanol,
99.5:0.5, 1 mL/min, tr = 7.1 and 8.1 min.
C
4.2.3. (R)-2-(Benzoyloxy)-2-(4-chlorophenyl)acetonitrile 4c
Colorless oil; ½a D25
¼ þ9:6 (c 1.0, CHCl3) (58% ee); TLC: Rf 0.45
ꢃ
(n-hexane/ethyl acetate, 4:1); IR (neat): mmax 2346, 1732, 1257
and 1088 cmꢁ1
;
1H NMR (300 MHz, CDCl3): dH 6.60 (s, 1H, CHO),
4.2.8. (R)-2-(Benzoyloxy)non-3-enenitrile 4h
7.37–7.43 (m, 4H, ArH), 7.51–7.56 (m, 3H, ArH), 7.98 (d,
J = 7.2 Hz, 2H, ArH); 13C NMR (75 MHz, CDCl3): dC 62.6 (CH),
115.8 (CN), 128.4, 128.7, 129.3, 129.6, 130.1, 130.4, 134.2, 136.7
(ArC), 164.5 (CO); MS (EI): m/z 271 (M+, 12%), 150 (34), 105
(100); HRMS calcd for C15H10ClNO2: 271.0400; found: 271.0401;
HPLC: DAICEL CHIRALPAK AS, k = 254 nm, n-hexane/2-propanol,
99.5:0.5, 0.5 mL/min, tr = 44.7 and 47.4 min.
Colorless oil; ½a D25
¼ ꢁ4:3 (c 0.5, CHCl3) (68% ee); TLC: Rf 0.65 (n-
ꢃ
hexane/ethyl acetate, 4:1); IR (neat): mmaxmmax 2339, 1732, 1258,
1089, 1600 cmꢁ1
;
1H NMR (300 MHz, CDCl3): dH 0.89 (t,
J = 6.9 Hz, 3H, CH3), 1.28–1.47 (m, 6H, 3xCH2), 2.12–2.19 (m, 2H,
CH2CH@CH), 5.67 (dd, J = 15.4, 6.6 Hz, 1H, C@CHCHO), 6.07 (d,
J = 6.6 Hz, 1H, CHCN), 6.20–6.29 (m, 1H, C@CHCH2), 7.47 (t,
J = 7.6 Hz, 2H, ArH), 7.60–7.65 (m, 1H, ArH), 8.06 (d, J = 7.2 Hz,
2H, ArH); 13C NMR (75 MHz, CDCl3): dC 14.0 (CH3), 22.4, 29.7,
31.3, 32.0 (CH2), 62.0 (CHCN), 115.9 (CN), 120.0 (C@CHCO),
128.1, 128.6, 130.0, 133.9 (ArC), 141.0 (CH2CH@CH), 164.6 (CO);
MS (EI): m/z 257 (M+, 0.3%), 125 (7), 105 (100), 77 (18); HRMS calcd
for C16H19NO2: 257.1416, found: 257.1411; HPLC: DAICEL CHIRAL-
CEL OJ, k = 254 nm, n-hexane/2-propanol, 93:7, 1 mL/min, tr = 6.5
and 7.4 min.
4.2.4. (R)-2-(Benzoyloxy)-4-(3-phenoxyphenyl)acetonitrile 4d
Colorless oil; ½a D25
¼ þ17:5 (c 1.5, CHCl3) (66% ee); TLC: Rf 0.47
ꢃ
(n-hexane/ethyl acetate, 4:1); IR (neat): mmax 2245, 1733, 1247,
1088 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 6.62 (s, 1H, CHCN),
;
7.06 (m, 3H, ArH), 7.16 (t, J = 6,9 Hz, 1H, ArH), 7.32–7.39 (m, 4H,
ArH), 7.46 (m, 3H, ArH), 7.62 (t, J = J = 7.5 Hz, 1H, ArH), 8.06 (d,
J = 7.8 Hz, 2H, ArH); 13C NMR (75 MHz, CDCl3): dC 62.8 (CHCN),
115.9 (CN), 117.6, 119.4, 120.0, 122.0, 124.1, 128.0, 128.6, 129.9,
130.1, 130.6, 133.6, 134.1, 156.1, 158.2 (ArC), 164.5 (CO); MS
(EI): m/z 329 (M+, 12,4%), 181 (9), 114 (8), 106 (9), 105 (100);
4.2.9. (2R,3E)-2-(Benzoyloxy)-4-phenylbut-3-enenitrile 4i
Colorless oil; ½a D20
ꢃ
¼ þ7:5 (c 1.4, CHCl3) (82% ee); TLC: Rf 0.49 (n-
hexane/ethyl acetate, 4:1); IR (neat):
m
max 2226, 1732, 1246, 1089,

A. Baeza et al. / Tetrahedron: Asymmetry 22 (2011) 1282–1291
1289
1601 cmꢁ1; 1H NMR (300 MHz, CDCl3): dH 6.28–6.37 (m, 2H, CHCN,
CH@CHCO), 7.07 (m, 1H, CHPh), 7.35–7.65 (m, 8H, ArH), 8.08 (de-
form. d, J = 8.1 Hz, 2H, ArH); 13C NMR (75 MHz, CDCl3): 13C NMR
(75 MHz, CDCl3): dC 62.0 (CH), 115.5 (CN), 118.4, 127.2, 128.3,
128.6, 128.8, 129.4, 130.2, 134.1, 134.4, 138.0 (ArC), 164.6 (CO);
MS (EI): m/z 263 (M+, 9%), 141 (28), 140 (21), 115 (30), 105
(100); HRMS calcd for C17H13O2N: 263.0946, found: 263.0971.
HPLC: DAICEL CHIRACEL OJ, k = 254 nm, n-hexano/2-propanol,
93:7, 1 mL/min, tr = 29.7 and 42.5 min.
61.0 (CH), 116.7 (CN), 126.7, 128.1, 128.3, 128.6, 129.8, 130.0,
134.0, 139.0, (ArC), 164.7 (CO); MS (EI): m/z 266 (M++1, 0.05%),
143 (100), 116 (20), 105 (32); HRMS calcd for C17H16NO2 (M++1):
266.2181, found: 266.2183; HPLC: DAICEL CHIRACEL OD-H,
k = 254 nm, n-hexane/2-propanol, 95:5, 1.0 mL/min, tr = 14.1 and
16.0 min.
4.2.14. (R)-2-(Benzoyloxy)-3-benzyloxypropanenitrile 4n
Colorles oil; ½a D25
¼ þ10:1 (c 1.0, CHCl3) (38% ee); TLC: Rf 0.27 (n-
ꢃ
hexane/ethyl acetate, 4:1); IR (neat): mmax 2247, 1732, 1262,
4.2.10. (2R,3E)-2-(Benzoyloxy)-4-(4-methoxyphenyl)but-3-
1092 cmꢁ1 1H NMR (300 MHz, CDCl3): dY 3.91 (d, J = 5.5 Hz, 2H,
;
enenitrile 4j
CH2CH), 4,66 (d, J = 3.0 Hz, 2H, CH2O), 5.75 (t, J = 5.5 Hz, 1H, CHCN),
7.29–7.35 (m, 5H, ArH), 7.47 (t, J = 7.6 Hz, 2H, ArH), 7.60 (t,
J = 7.5 Hz, 1H, ArH), 8.04 (d, J = 7,2 Hz, 2H, ArH); 13C NMR
(75 MHz, CDCl3): dC 60.8 (CHCN), 68.2 (CH2CH), 73.7 (CH2OPh),
115.3 (CN), 127.8, 127.9, 128.1, 128.5, 128.6, 130.0, 134.1, 136.7
(ArC), 164.5 (CO); MS (EI): m/z 281 (M+, 0.4%), 174 (10), 106 (37),
105 (75), 91 (100), 77 (37); HRMS calcd for C17H15O3N: 281.1052,
found: 281.1063; HPLC: DAICEL CHIRACEL OD-H, k = 254 nm, n-
hexane/2-propanol, 97:3, 1 mL/min, tr = 23.3 and 25.1 min.
Colorless oil; ½a D25
ꢃ
¼ þ3:9 (c 1.0, CHCl3) (76% ee); TLC: Rf 0.46 (n-
max 2238, 1730, 1606, 1252,
hexane/ethyl acetate, 4:1); IR (neat):
m
1088 cmꢁ1; 1H NMR (300 MHz, CDCl3): dH 3.83 (s, 3H, OCH3), 6.18
(dd, J = 15.4, 6.9, Hz, 1H, CHCHCN), 6.24 (d, J = 6.9 Hz, 2H, CHCN),
6.90 (d, J = 8.6 Hz, 2H, ArH), 7.01 (d, J = 15.4 Hz, 1H, PhCH@CH),
7.39 (t, J = 8.6 Hz, 1H, ArH), 7.48 (t, J = 7.8 Hz, 2H, ArH), 7.63 (t,
J = 7.8 Hz, 1H, ArH), 8.07 (m, 2H, ArH); 13C NMR (75 MHz, CDCl3):
dC 55.3 (CH3), 62.3 (CHCN), 114.2 (ArC), 115.8 (CN), 116.0
(CHCHCN), 127.1 (ArC), 128.3 (PhCH@CH), 128.5, 128.6, 130.0,
134.0, 137.8, 160.1 (ArC), 164.7 (CO); MS (EI): m/z 293 (M+, 34%),
188 (18), 171 (60), 156 (20), 128 (18), 122 (24), 105 (100); HRMS
calcd for C18H15O3N: 293.1052, found: 293.1075; HPLC: DAICEL
CHIRALPAK AS, k = 260 nm, n-hexane/2-propanol, 98:2, 1 mL/min,
tr = 30.4 and 38.0 min.
4.2.15. (R)-2-(4-Methoxybenzoyloxy)-2-phenylacetonitrile 4a0
Colorless oil; ½a D25
¼ þ12:1 (c 1.0, CHCl3) (55% ee); TLC: Rf 0.70
ꢃ
(n-hexane/ethyl acetate, 3:2); IR (neat): mmax 2225, 1734, 1258,
1086 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 3.87 (s, 3H, OCH3),
;
6.66 (s, 1H, CHCN), 6.93 (d, J = 8.9 Hz, 2H, ArH), 7.47 (m, 3H,
ArH), 7.60 (m, 2H, ArH), 8.02 (d, J = 8.9 Hz, 2H, ArH); 13C NMR
(75 MHz, CDCl3): dC 55.5 (CH3), 63.0 (CHCN), 114.0 (ArC), 116.4
(CN), 113.9, 120.3, 127.8, 129.2, 130.3, 132.1, 161.4 (ArC), 164.3
(CO); MS (EI): m/z 267 (M+, 7%), 135 (100), 116 (32); HRMS calcd
for C16H13NO3: 267.0895; found: 267.0886; HPLC: DAICEL CHIR-
ALPAK AS, k = 254 nm, n-hexane/2-propanol, 98:2, 1 mL/min,
tr = 22.2 and 24.8 min.
4.2.11. (R)-2-(Benzoyloxy)octanenitrile 4k
Colorless oil; ½a D25
¼ þ10:1 (c 0.7, CHCl3) (58% ee); TLC: Rf 0.29
ꢃ
(n-hexane/ethyl acetate, 4:1); IR (neat): mmax 2345, 1739, 1266,
1093 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 0.90 (t, J = 6.7 Hz, 3H,
;
CH3), 1.26–1.45 (m, 6H, 3 ꢂ CH2), 1.53–1.63 (m, 2H, CH2), 2.04
(dd, J = 15.6, 6.7 Hz, 2H, CH2CH), 5.58 (t, J = 6.7 Hz, 1H, CHO),
7.48 (t, J = 7.4 Hz, 2H, ArH), 7.63 (t, J = 7.4 Hz, 1H, ArH), 8.06 (d,
J = 7.2 Hz, 2H, ArH); 13C NMR (75 MHz, CDCl3): dC 14 (CH3), 22.4,
24.6, 28.5, 31.4, 32.4 (CH2), 61.6 (CH), 117.0 (CN), 128.3, 128.6,
130.0, 134.0 (ArC), 164.8 (CO); MS (EI): m/z 246 (M++1, 0.1%),
123 (36), 122 (34), 105 (100); HRMS calcd for
245.1416; found: 245.1417; CG: WCOT -CD (stationary phase
FS-Lipodex-E, 0.25 m), Tinjector = 250 °C, Tdetector = 260 °C,
4.2.16. (R)-2-(4-Chlorobenzoyloxy)-2-phenylacetonitrile 4a00
White powdered solid; mp 143–144 °C (from n-hexane/ethyl
acetate); ½a 2D5
¼ þ6:9 (c 1.0, CHCl3) (58% ee); TLC: Rf 0.76 (n-hex-
ꢃ
C
19H14NO2:
ane/ethyl acetate, 3:2); IR (CHCl3): mmax 2334, 1735, 1254 and
c
1092 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 6.66 (s, 1H, CHCN),
;
l
7.46 (m, 5H, ArH), 7.59 (m, 2H, ArH), 7.94 (d, J = 8.7 Hz, 2H, ArH);
13C NMR (75 MHz, CDCl3): dC 63.5 (CHCN), 116.0 (CN), 127.8,
128.0, 129.1, 129.3, 129.4, 130.5, 131.5, 141.4 (ArC), 163.8 (CO);
MS (EI): m/z 271 (M+ 29%), 141 (33), 139 (100), 116 (70), 105
(27); HRMS calcd for C15H10ClNO2: 271.0400; found: 271.0400;
HPLC: DAICEL CHIRALPAK AD, k = 254 nm, n-hexane/2-propanol,
99:1, 0.7 mL/min, tr = 24.6 and 26.8 min.
Tcolumn = 90 °C (5 min) to 180 °C (0.6 °C/min), P = 120 KPa,
tr = 152.5 and 152.9 min.
4.2.12. (R)-2-(Benzoyloxy)-2-cyclohexylacetonitrile 4l
Colorless prisms; m p: 101 °C (from n-hexane/ethyl acetate);
TLC: Rf 0.56 (n-hexane/ethyl acetate, 4:1); IR (KBr): mmax 2243,
1720, 1262, 1114 cmꢁ1 1H NMR (300 MHz, CDCl3): dH 1.19–1.33
;
(m, 6H, CH2), 1.72–2.01 (m, 5H, CH2
+
CHCH2), 5.44 (d,
4.3. NLE studies for the cyanobenzoylation of benzaldehyde
J = 5.8 Hz, 1H, CH-CN), 7.48 (t, J = 7.6 Hz, 2H, ArH), 7.63 (t,
J = 7.6 Hz, 1H, ArH), 8.05 (d, J = 7.2 Hz, 2H, ArH); 13C NMR
(75 MHz, CDCl3): dC 25.3, 25.4, 25.7, 28.0, 28.2 (CH2), 40.3
(CHCHCN), 66.0 (CHCN), 116.2 (CN), 128.4, 128.6, 129.9, 133.9
(ArC), 164.8 (CO); MS (EI): m/z 244 (M+, 0.1%), 161 (15), 123 (20),
121 (31), 105 (100). Anal. Calcd for C15H17NO2: C, 74.1; H, 7.0; N,
5.8. Found: C, 73.8; H, 6.8; N, 5.8. HPLC: DAICEL CHIRALPAK AS,
k = 254 nm, n-hexane/2-propanol, 99.5:0.5, 0.7 mL/min, tr = 11.3
and 13.1 min.
catalyzed by 1:1 BINOLAM/Ti(OiPr)4
The general procedure illustrated above for the cyanobenzoyla-
tion of benzaldehyde was followed. Four experiments were carried
using a) racemic BINOLAM; b) partially enriched (S)-BINOLAM
(33% ee); c) partially enriched (S)-BINOLAM (66% ee); d) (S)-BINO-
LAM (99% ee). After the usual work-up the crude material 4a was
examined by HPLC as shown in the general procedure. The follow-
ing results for 4a were obtained: (a) 0% ee; (b) 18% ee; (c) 35% ee;
(d) 68% ee.
4.2.13. (R)-2-(Benzoyloxy)-4-phenylbutanenitrile 4m
Colorless oil; ½a D25
ꢃ
¼ þ13:9 (c 2.0, CHCl3) (65% ee); TLC: Rf 0.40
4.4. Computational details
(n-hexane/ethyl acetate, 4:1); IR (neat): mmax 2333, 1731, 1263,
1104 cmꢁ1
;
1H NMR (300 MHz, CDCl3): dH 2.35–2.43 (m, 2H,
For the computational work, we used a closed-shell DFT (B3LYP)
treatment,26 as implemented in the Gaussian 03 package,27 with
the 6-31G⁄ basis set for all atoms.28 The original input molecular
skeletons were the optimized structures resulting from prior semi-
empirical work (not shown) carried out with PM3 as implemented
CH2CHO), 2.93 (t, J = 7.6 Hz, 2H, CH2Ph), 5.53 (d, J = 6.7 Hz, 1H,
CHO), 7.19–7.25 (m, 3H, ArH), 7.31–7.34 (m, 2H, ArH), 7.47 (t,
J = 7.5, 2H, ArH), 7.60–7.65 (m, 1H, ArH), 8.01 (d, J = 7.2, 2H,
ArH); 13C NMR (75 MHz, CDCl3): dC 30.8 (CH2CHO), 33.9 (CH2Ar),

1290
A. Baeza et al. / Tetrahedron: Asymmetry 22 (2011) 1282–1291
in the Spartan package.29 Electron correlation was incorporated, in
part, to our studies by means of density functional theory (DFT),30
by using the non-local hybrid three-parameter functional devel-
oped by Becke and denoted B3LYP exchange-correlation func-
tional.31,32 It should be noted that optimizations have been
carried out with keywords for tight convergence criteria as well
as for using the ultrafine integration grid of the program. Vibra-
tional analysis was applied to all B3LYP/6-31G⁄ stationary points
by diagonalization of their Hessian matrices (vibrational analy-
sis).33 Ground state equilibrium geometries on the potential energy
surface were recognized as having real frequencies only, whereas
transition structures were recognized as having only one negative
eigenvalue (visualized with the help of an appropriate application).
Unless otherwise noted only electronic energies are given in the
text. In all cases, the zero-point vibrational energies (ZPVE) were
computed at the same level, though were not scaled. Cartesian
coordinates of the stationary points found in this study are avail-
able upon request.
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Acknowledgments
This work is supported by MICINN (Spain) through projects
CTQ2007-62952/BQU, CTQ2007-62771/BQU, CTQ 2010-17339,
CTQ2010-20387, and Consolider INGENIO 2010 CSD2007-00006.
We also thank the computing facilities generously provided by
the UIB, CESCA, CESGA and CIEMAT.
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