Lewis acid-lewis base-catalysed enantioselective addition of α-ketonitriles to aldehydes

Article abstract of DOI:10.1002/adsc.200600365

Additions of structurally diverse α-ketonitriles to aromatic and aliphatic prochiral aldehydes yielding highly enantioenriched acylated cyanohydrins were achieved using a combination of a titanium salen dimer and an achiral or chiral Lewis base. In most cases high yields and high enantioselectivities were observed. The ee was moderate in the initial part of the reaction but increased over time. This could be avoided, and higher ees obtained, by keeping the titanium complex, in the presence or absence of aldehyde and ketonitrile, at -40°C prior to the addition of the Lewis base. A mechanism initiated by nucleophilic attack of the tertiary amine at the carbonyl carbon atom of the ketonitile is supported by ¹³C labelling experiments.

Full text of DOI:10.1002/adsc.200600365

FULL PAPERS
DOI: 10.1002/adsc.200600365
Lewis Acid–Lewis Base-Catalysed Enantioselective Addition of
a-Ketonitriles to Aldehydes
Stina Lundgren,a Erica Wingstrand,a and Christina Moberga,*
a
KTH School of Chemical Science and Engineering, Organic Chemistry, SE 100 44 Stockholm, Sweden
Fax : (+46)-8-791-2333; e-mail: kimo@kth.se
Received: July 19, 2006; Published online: January 8, 2007
Abstract: Additions of structurally diverse a-ketoni- ing the titanium complex, in the presence or absence
triles to aromatic and aliphatic prochiral aldehydes of aldehyde and ketonitrile, at À408C prior to the
yielding highly enantioenriched acylated cyanohy- addition of the Lewis base. A mechanism initiated
drins were achieved using a combination of a titani- by nucleophilic attack of the tertiary amine at the
um salen dimer and an achiral or chiral Lewis base. carbonyl carbon atom of the ketonitile is supported
In most cases high yields and high enantioselectivi- by 13C labelling experiments.
ties were observed. The ee was moderate in the ini-
tial part of the reaction but increased over time. This Keywords: O-acylcyanohydrins; Lewis acids; Lewis
could be avoided, and higher ees obtained, by keep- bases; salen; titanium
Introduction
ence of an acylating agent, led to slow formation of
enantioenriched cyanohydrin esters.[9]
Chiral enantiomerically pure cyanohydrins serve as
Procedures for direct additions of a-ketonitriles to
versatile synthetic building blocks, and enantioselec- prochiral aldehydes, avoiding the formation of accom-
tive cyanantions of prochiral carbonyl compounds are panying products, are attractive due to their simplicity
therefore currently being extensively studied.[1] Proce- and atom economy. This has been achieved in several
dures allowing direct access to O-protected non-race- non-selective processes yielding racemic products.
mic cyanohydrins are essential in order to avoid re- Thus, addition of benzoyl cyanide to benzaldehyde in
versibility of the cyanide addition, which may lead to the presence of catalytic amounts of potassium hy-
decreasing enantioselectivity. Several procedures af- droxide was shown already in 1949 to afford the ben-
fording O-silylated,[2] O-phosphorylated,[3] and O-for- zoate of the cyanohydrin,[10] and later aqueous aceto-
mylated[4] products from both aldehydes and ketones nitrile together with potassium carbonate[11] and even
are now well established. Acylated cyanohydrins (1) DMSO without any base[12] were employed for the
constitute other important synthetic intermediates, same purpose. Tributyltin cyanide was also shown to
which can undergo further transformations without catalyse the addition of acetyl cyanide to several alde-
loss of enantiomeric purity.[5] They are also in them- hydes.[13] More general conditions, allowing the prepa-
selves important synthetic targets, which have found ration of cyanohydrin esters from a variety of alde-
commercial applications as potent insecticides.[6]
hydes and keto esters, were found using DABCO[14]
Enantioenriched acylated cyanohydrins have been or DBU[15] as a Lewis base catalyst.
obtained via several indirect methods. Esterification
We were recently able to demonstrate that, using a
without stereochemical deterioration of non-racemic safe and convenient catalytic system capable of a dual
preformed O-trimethylsilylated cyanohydrins was ach- Lewis acid-Lewis base activation,[16] highly enantioen-
ieved using acid chlorides or anhydrides in the pres- riched acetylated cyanohydrins (1) were formed in
ence of catalytic amounts of Sc
(OTf)3.[7] A more con- high yields from acetyl cyanide (2a) and aromatic as
G
venient one-pot procedure which, however, required well as aliphatic aldehydes (3, Scheme 1).[17] Our work
large excess of reagents, was described, whereby was followed by the first enantioselective cyanoben-
enantioselective cyanation of aldehydes using KCN zoylation, reported by Sansano, Najera, and co-work-
was performed in the presence of acetic anhydride.[8] ers.[18] We also developed an enzymatic method for
Another one-pot procedure based on dynamic kinetic the rapid determination of conversion of starting ma-
resolution of in situ obtained racemic cyanohydrins terial and enantiomeric excess of the product.[19]
using lipase B from Candida antarctica in the pres- Direct access to other O-acylated cyanohydrins is of
364
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 364 – 372

Enantioselective Addition of a-Ketonitriles to Aldehydes
FULL PAPERS
These methods offer a facile synthesis of ketonitriles
from primary, secondary and tertiary alkyl and olefin-
ic acid halides. No by-products, such as acyl cyanide
dimers, were observed.
Scheme 2.
Asymmetric Synthesis of Cyanohydrin Esters
Scheme 1.
Our previously reported conditions for the synthesis
interest due to their usefulness as both synthetic tar- of a variety of cyanohydrin esters from different alde-
gets and intermediates. We have now extended the hydes and acetyl cyanide used a combination of Ti-
scope of the catalytic reaction to include a further va- salen dimer (4) and triethylamine. These conditions
riety of combinations of aldehydes and a-ketonitriles were applicable to a large varity of combinations of
and performed experiments which cast light on the aldehydes and ketonitriles (Table 1). Good yields (72–
mechanism of the reaction.
93%) and enantioselectivities (85–96% ee) were ach-
ieved using aromatic aldehydes and acetyl cyanide
(entries 1–8), the only exception being 2-pyridinecar-
boxaldehyde, which gave lower enantioselectivity
(20% ee, entry 8). The position of the aldehyde sub-
stituent thus seems to be crucial for the selectivity
since 3-pyridinecarboxaldehyde gave significantly
Results and Discussion
Preparation of a-Ketonitriles
a-Ketonitriles[20] were first described as early as 1832 higher ee (86%, entry 7). m-Phenoxybenzaldehyde
when Wçhler and Liebig prepared benzoyl cyanide was less reactive and required longer reaction time
from benzoyl chloride and HgCN.[21] Other metal (48 h instead of 8–12 h) probably because of steric
salts, such as AgCN[22] and Bu3SnCN,[23] HCN in com- hindrance by the phenoxy group (entry 6). Unsaturat-
bination with pyridine,[24] phase-transfer catalysis,[25] ed and aliphatic aldehydes gave high enantiomeric ex-
Me3SiCN,[26] and KCN together with ZnI2 and cesses and isolated yields (entries 9–11).
PEG400[27] have later been used in place of HgCN to-
Benzaldehyde was selected for reactions with keto-
gether with acid chlorides or bromides. Acetyl cya- nitriles 2b–h (Table 2). The reactivity was shown to be
nide was prepared from acetyl bromide and CuCN in influenced by the structure of the ketonitrile and de-
1944,[28] but due to the propensity of enolisable acyl creased with increased size of the alkyl group. Linear
cyanides to be converted to their acylated enols in the aliphatic ketonitriles reacted smoothly to afford high
presence of base, satisfactory and more general meth- yields (85–90%) of highly enantioenriched (92–93%
ods for the preparation of aliphatic acyl cyanides ap- ee) products (entries 1–4). While 3-methyl-2-oxobut-
peared only later.[20] Normant found that high yields anenitrile 2e exhibited equally high reactivity as the
of aliphatic as well as aromatic ketonitriles were ob- linear compounds (entry 5), 3,3-dimethyl-2-oxobut-
tained from acid chlorides and CuCN in the presence anenitrile (2f) was unreactive at À408C. Increasing
of LiI or using acetonitrile as solvent.[29]
the temperature to room temperature gave a product
We prepared a-ketonitriles 2b–g by reacting acyl with 79% ee in 81% isolated yield (entry 6). Cinna-
chlorides or bromides with CuCN (Scheme 2). We moyl cyanide (2g) was the most reactive ketonitrile
found heterogenous conditions, without solvent, to be and gave the acetylated product in high isolated yield
optimal for low-boiling products which could be distil- with excellent ee after only four hours (entry 7). Ben-
led directly from the reaction mixture, whereas aceto- zoyl cyanide (2h) provided the product with high iso-
nitrile was used as solvent for less volatile products. lated yield and good ee (76% yield and 75% ee
Adv. Synth. Catal. 2007, 349, 364 – 372
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
365

Stina Lundgren et al.
FULL PAPERS
Table 1. Cyanation of aldehydes by acetyl cyanide (2a).[a]
Entry
Aldehyde [R1]
Product
Time (h)
Yield [%][b]
94 (
ee [%][c] (abs. conf.)[d]
1[17]
2[17]
3[17]
4[17]
5
3a [C6H5]
1a
1b
1c
1d
1e
1f
1g
1h
1i
1089
1090 96 (
12
8
12
48
12
12
12
6
S)
S)
94(S)
95 (S)
89 (R)
85 (S)
86 (n.d.)
20(n.d.)
93 (S)
76 (S)
3b [4-CH3-C6H4]
3c [4-CH3O-C6H4]
3d [4-Cl-C6H4]
3e [2-furyl]
3f [3-PhO-C6H4]
3g [3-Pyridyl]
3h [2-Pyridyl]
3i [(E)-CH=CHPh]
72
89
93
84
91
87
64
84
89
6
7
8
9[17]
10[17]
11[17]
3j [C
A
1j
1k
3k [(CH2)4CH3]
6
90 S)
(
[a]
Reactions were carried out in dichloromethane at À408C using 1 equiv. of aldehyde, 2 equivs. of ketonitrile, 5 mol% 4
and 10mol% Et N.
3
[b]
[c]
[d]
Isolated yield.
Determined by chiral GC or chiral HPLC.
Assigned by comparison with literature value.
Table 2. Cyanation of benzaldehyde by a-ketonitriles.[a]
Entry
a-Ketonitrile [R2]
Product
Time [h]
Yield [%][b]
ee [%][c] (abs. conf.)[d]
1[17]
2
3
2a [CH3]
1a
1l
1089
1089
1090 92 (
1085
1086
1081
4
94 (
93 (
S)
S)
S)
S)
S)
2b [CH2CH3]
2c [(CH2)2CH3]
2d [(CH2)3CH3]
1m
1n
1o
1p
1q
1r
4
93 (
92 (
79 (
5
2e [CH
A
6[e]
7
2f [C(CH3)3]
A
S)
2g [(E)-CH=CHPh]
2h [C6H5]
89
76
94 (S)
75 (S)
8
26
[a]
Reactions were carried out in dichloromethane at À408C using 1 equiv. of aldehyde, 2 equivs. of ketonitrile, 5 mol% 4
and 10mol% Et N.
3
[b]
[c]
[d]
[e]
Isolated yield.
Determined by chiral GC or chiral HPLC.
Assigned by comparison with literature value.
The reaction was carried out at room temperature.
366
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 364 – 372

Enantioselective Addition of a-Ketonitriles to Aldehydes
FULL PAPERS
(entry 8), as compared to 68% ee using the catalytic tions gave reactions with low selectivity (entries 19–
system of Sansano, Najera, and co-workers[18]).
21).
Influence of the Lewis Base
Mechanistic Aspects
The Ti dimer 4 did not catalyse the addition of keto- The proximity of the CO and CN groups in a-ketoni-
nitriles to benzaldehyde at À408C in the absence of a triles enhances the electrophilicity of both functions.
Lewis base (Table 3, entry 1). Best results for the ad- Propionyl cyanide was already in 1880shown to yield
dition of acetyl cyanide were obtained with triethyl- a dimer in the presence of cyanide ions.[30] The dimer-
amine (entry 2). While a range of other tertiary Lewis isation was shown to occur by initial attack of cyanide
bases afforded acceptable results (entries 3–5), a sec- on the carbonyl group, followed by acetylation of the
ondary amine provided a catalytic system with inferi- alcoholate.[31] Although nucleophiles as a rule add to
or properties (entry 6). DBU exhibited high reactivity, the carbonyl group of ketonitriles,[32] attack at the ni-
but at the expense of the enantioselectivity (entry 7, trile carbon atom by soft nucleophiles such as H2S[33]
vide infra). In contrast to DMAP, pyridine did not and azides[34] has been observed. Whereas strongly
catalyse the reaction (entry 8). Chiral bases influ- basic nucleophiles like diethylamine and piperidine
enced the enantioselectivity only to a minor extent, as were shown to react instantaneously with acetyl cya-
seen from results using 4 and ent-4 (entries 9 and 10). nide at 245 K to yield an amide and hydrogen cya-
Results similar to those obtained using acetyl cya- nide, tetrahedral intermediates were observed by
nide were obtained from reactions with 2-oxobutane- 13C NMR spectroscopy from a variety of more weakly
nitrile (2b, entries 11–14) whereas 3,3-dimethyl-2-oxo- basic nucleophiles.[35]
butanenitrile (2f) exhibited lower reactivity and/or se-
Acetyl cyanide has also been employed for the ace-
lectivity (entries 15–18). As expected, higher reactivi- tylation of alcohols. In the presence of DMAP an
ty and reasonable selectivity were observed at room active acylating agent was obtained. The counterion
temperature, except for DBU which under all condi- affected the rate and selectivity, as shown by a com-
Table 3. Influence of different bases on the cyanation of benzaldehyde by a-ketonitriles.[a]
Entry
Lewis base
a-Ketonitrile [R2]
Time [h]
Conv. [%][b]
ee [%]{c] (abs. conf.)[d]
1[17]
2[17]
3[17]
4[17]
5[17]
6
-
2a [CH3]
2a [CH3]
2a [CH3]
2a [CH3]
2a [CH3]
2a [CH3]
2a [CH3]
2a [CH3]
2a [CH3]
2a [CH3]
2b [CH2CH3]
2b [CH2CH3]
2b [CH2CH3]
2b [CH2CH3]
24
8
6
9
8
8
2
24
9
9
1094
9
0.5
8
24
24
5
24
4
0
-
-
Et3N
96
57
67
97
41
99
0
94 (S)
94 (S)
92 (S)
81 (S)
81 (S)
20( S)
DMAP
DABCO
DIEA
Diethylamine
DBU
Pyridine
Cinchonidine
Cinchonidine
Et3N
DABCO
DBU
DIEA
Et3N
DABCO
DBU
DIEA
7
8
9[17]
10[17],[e]
11
78
75
93 (
53
99
98
0
0
62
0
96 (S)
92 (R)
S)
92 (S)
12 (S)
78 (S)
12
13
14
15
16
17
2f [C
2f [C
2f [C
2f [C
2f [C
2f [C
2f [C
C
-
-
0
18
-
19[f]
20[f]
21[f]
DABCO
DBU
DIEA
49
10
56
79 (S)
S)
76 (S)
4
4
0
6 (
[a]
Reactions were carried out in dichloromethane at À408C using 1 equiv. of aldehyde, 2 equivs. of ketonitrile, 5 mol% 4
and 10mol% Lewis base.
[b]
[c]
[d]
[e]
[f]
Determined by GC/MS.
Determined by chiral GC.
Assigned by comparison with literature value.
ent-4 was used.
The reaction was carried out at room temperature.
Adv. Synth. Catal. 2007, 349, 364 – 372
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
367

Stina Lundgren et al.
FULL PAPERS
parison with reagents obtained from acetyl cyanide,
acetyl chloride and acetic anhydride.[36] Selective ace-
tylation of a primary alcohol in the presence of a sec-
ondary alcohol was recently achieved employing
acetyl cyanide and triethylamine.[37]
On the basis of the known reactivity of ketonitriles,
it seems reasonable that the first step in the catalytic
reaction is the attack of the Lewis base on the carbon-
yl group of the acyl cyanide with formation of cyanide
ion and a potent acylating agent, which both can react
with the aldehyde to form the observed product
(Scheme 3). This mechanism has previously been sug-
Figure 1. a) Normal conditions, b) Ti-salen complex kept at
À408C for 3 h before the addition of aldehyde, ketonitrile,
and Lewis base, c) Ti-salen complex kept at room tempera-
ture for 3 h before cooling to À408C and addition of alde-
hyde, ketonitrile, and Lewis base.
Scheme 3.
gested for cyanoacylations in the presence of
DABCO[14] and recently also DBU,[15] which indeed in the solution, as that would lead to 13C exchange be-
can serve as a potent nucleophile.[38]
tween H13CN and CNÀ.
An alternative mechanism was proposed for cyano-
It has previously been observed that, in cyanations
benzoylation of aldehydes.[18] It was suggested that using the Ti-salen dimer 4, the enantioselectivity in-
the reaction is initiated by cyanide ions obtained by creases with time.[39] The same phenomenon was ob-
deprotonation of the small amount of HCN present in served in the present cyanations. Thus, the addition of
the ketonitrile. However, knowing that amines readily aldehyde and acetyl cyanide to dimer 4 and triethyla-
attack the carbonyl function of a-ketonitriles and that mine resulted in immediate product formation. After
a superior acylating agent thereby is obtained, we 45 min, merely 70% ee was observed, whereas the
favour the route proposed above. In addition, depro- final ee was 91% (Figure 1). However, when the reac-
tonation is highly inefficient in dichloromethane; the tion mixture was kept at À408C for 3 h in the absence
1H NMR spectrum of a mixture of HCN and triethyl- of Lewis base, no product was formed. Upon subse-
amine in CD2Cl2 shows no trietylammonium ion. This quent addition of Lewis base, the reaction started,
fact is, however, no strict proof against the suggested giving product with a constant and somewhat higher
mechanism, as a low concentration of cyanide may be ee value than that observed under normal conditions
sufficient to initiate the process. Therefore, in order (95%). The same result was obtained when only the
to further study the possibility that the reaction is ini- Ti-salen complex was kept at À408C for 3 h before
tiated by HCN, two equivalents of 13C-labeled HCN the addition of aldehyde, ketonitrile, and Lewis base
were bubbled through the reaction solution before ad- (Figure 1). When the reaction mixture was stirred at
dition of the reactants (Scheme 4). A mass spectrum room temperature for 3 h prior to cooling to À408C
recorded after 5% conversion showed no 13C incorpo- and the aldehyde, ketonitrile, and Lewis base added
ration in the product, demonstrating that HCN does at that temperature, the ee was again lower in the ini-
not serve as a source of cyanide ion. This experiment tial part of the reaction and increased with time.
also shows that free cyanide is probably not present
In order to gain some information about this effect,
1H NMR spectra of the Ti complex were recorded at
intervals at À408C. At room temperature the dimer
to monomer ratio was 4:1 as shown by the integration
of the aromatic protons [d=7.55 ppm (s, 1H, ArH)
for the monomer and d=7.41 ppm (s, 1H, ArH) for
the dimer]. Spectra taken immediately after cooling
the solution showed a ratio of dimer to monomer of
90:10. This increased over time and was found to be
95:5 after 90min and then constant. No other change
Scheme 4.
368
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 364 – 372

Enantioselective Addition of a-Ketonitriles to Aldehydes
FULL PAPERS
um compound required for reaction with the Lewis
acid activated aldehyde.
Experimental Section
General Remarks
Figure 2. Proposed mechanism for addition of ketonitriles to
aldehydes.
Benzaldehyde, CH2Cl2 and Et3N were distilled over CaH2.
All bases were distilled before use. Aldehydes, pyruvonitrile
and benzoyl cyanide were purchased from Aldrich, stored
under N2, and used without further purification. The Ti-
salen catalyst (4) was prepared by following the published
procedure.[2a,8b] All reactions were performed under N2.
Conversions were determined by GC/MS and the enantio-
meric excesses by GC analysis using a chiral column [Chiral-
dex, G-TA (gamma cyclodextrin trifluoroacetyl), 30m”
0.25 mm] or by HPLC using a chiral column (Daicel Chiral-
cel OD-H, 0.46 cm ؔ25 cm). 1H NMR spectra were re-
corded at 500 or 400 MHz, 13C spectra at 125 or 100 MHz.
in the spectrum was observed. Heating the sample to
room temperature restored the original 4:1 ratio.[40]
It thus seems as if high ee values are obtained in re-
actions catalysed by the dimeric Ti complex. Belo-
kon’, North and co-workers used two different alde-
hydes in order to study the variation of ee.[39] A sacri-
ficial aldehyde was assumed to convert the precatalyst
to the catalytically active species. Using this species in
the reaction of the second aldehyde afforded the
product with an ee which was constant over time, but
somewhat lower than that observed under normal
conditions.
Deterioration of ee, seemingly caused by the pres-
ence of the Ti-salen monomer, was expected to be
most serious for highly reactive systems, since a large
part of the catalytic reaction occurs before the mono-
mer to dimer equilibrium is established. In order to
test this assumption, the reaction of benzaldehyde
with acetyl cyanide using DBU as the Lewis base was
run at À408C and the reactants stirred at this temper-
ature for 3 h before addition of the base. This proce-
dure did indeed result in a product with higher ee,
69% as compared to 20% under normal conditions.
Considering the results reported here, it seems rea-
sonable that the two carbonyl species, the aldehyde
and the ketonitrile, are coordinated to the two Ti
atoms of the dimeric Ti-salen complex. The 13C NMR
signal from the carbonyl carbon atom of acetyl cya-
nide was indeed found to be shifted in the presence
of the Ti complex, corroborating this assumption. Cy-
anide delivery within the catalytic complex would ex-
plain the lack of isotope scrambling between labelled
cyanide from the ketonitrile and non-labelled HCN
(Figure 2).
1
The H and 13C chemical shifts are reported in ppm relative
to the solvent as internal standard.
General Procedure for Synthesis of Liquid a-
Ketonitriles (2b–f)[41]
The acid bromide (22 mmol) was added to CuCN
(26.6 mmol, 1.2 equivs.) under N2 and the heterogeneous
mixture was stirred for 2 h at 908C before distilled to yield
the a-ketonitrile.
1
2-Oxobutanenitrile (2b): Yield: 74%; H NMR (CDCl3):
d=0.79 (q, d=7.3 Hz, 2H, CH2), 1.24 (t, J=7.3 Hz, 3H,
CH3); 13C NMR (CDCl3): d=177.4, 113.2, 38.8, 6.8; MS
(EI): m/z:=83.0[ M+]. Other spectral data were in accord-
ance with those previously published.[26b]
2-Oxopentanenitrile (2c): Yield: 71%; 1H NMR
(400 MHz, CDCl3): d=2.72 (t, J=7.3 Hz, 2H, CH2), 1.78
(tq, 7.3 Hz, 2H, CH2), 1.00 (t, J=7.3, 3H, CH3); 13C NMR
(CDCl3): d=176.9, 113.3, 46.8, 16.4, 13.1; MS (EI): m/z=
97.10[ M+]. Other spectral data were in accordance with
those previously published.[26b,29]
1
2-Oxohexanenitrile (2d): Yield: 75%; H NMR (CDCl3):
d=2.74 (t, J=7.6 Hz, 2H, CH2), 1.69–1.76 (tt, J=7.6 Hz,
2H, CH2), 1.34–1.44 (tq, J=7.6 Hz, 2H, CH2), 0.95 (t, J=
7.6 Hz, 3H, CH3); 13C NMR (CDCl3): d=177.1, 113.3, 44.8,
24.8, 21.8, 13.6; MS (EI): m/z=111.10[ M+]. Other spectral
data were in accordance with those previously published.[29]
3-Methyl-2-oxobutanenitrile (2e): Yield: 79%; 1H NMR
(CDCl3): d=2.79 (hept, J=6.9 Hz, 2H), 1.30(d, J=6.9 Hz,
6H, CH3); 13C NMR (CDCl3): d=181.1, 112.9, 43.1,
16.7 ppm; MS (EI): m/z=97.05 [M+]. Other spectral data
were in accordance with those previously published.[42]
Conclusions
3,3-Dimethyl-2-oxobutanenitrile
(2f):
Yield:
63%;
An efficient catalytic system consisting of a chiral
Lewis acid and an achiral or chiral Lewis base was
found for the 100% atom economic addition of keto-
nitriles to aldehydes affording highly enantioenriched
synthetically important O-acylated cyanohydrins in
high yields. Experimental data support a mechanism
involving attack of the Lewis base on the carbonyl
carbon atom of the ketonitrile coordinated to Ti,
1H NMR (CDCl3): d=1.29 (s, 9H, CH3); 13C NMR (CDCl3):
d=183.1, 112.1, 45.0, 24.5; MS (EI): m/z=111.10[ M+].
Other spectral data were in accordance with those previous-
ly published.[26b]
(3E)-2-Oxo-4-phenylbutenenitrile (2g)[29]
A solution of trans-cinnamic acid (1.0g, 6.7 mmol), oxalyl
thereby providing the cyanide and acylated ammoni- chloride (0.71 mL, 8.1 mmol) and DMF (10 mL, 0.13 mmol)
Adv. Synth. Catal. 2007, 349, 364 – 372
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
369

Stina Lundgren et al.
FULL PAPERS
in CH2Cl2 (40mL) was refluxed for 2 h under N 2. The sol-
vent was removed under vacuum and CuCN (1.2 g,
13.5 mmol) was added followed by dry acetonitrile (6 mL).
The suspension was refluxed for 40min under N 2 and the re-
sulting clear solution was cooled to ambient temperature
before the solvent was removed under vacuum. Dry Et2O
(100 mL) was added and the mixture was heated to reflux
and filtered under N2 while still hot. The solvent was re-
moved from the filtrate to give the product; yield: 81%;
1H NMR (CDCl3): d=8.01 (d, J=16.1 Hz, 1H, CH), 7.65
(m, 2H, Ph), 7.55 (m, 1H, Ph), 7.49 (m, 2H, Ph), 6.87 (d,
J=16.1 Hz, 1H, CH); 13C NMR (CDCl3): d=167.5, 155.0,
133,1, 132.8, 129.5, 129.4, 125,3, 112.4; MS (EI): m/z=157.0
[M+]. Spectral data were in accordance with those previous-
ly published.[43]
24.8 min (minor), 28.6 min (major). Spectral data were in ac-
cordance with those previously published.[44] The absolute
configuration was determined from the sign of optical rota-
tion.[44]
O-Pentyryl-(S)-2-hydroxy-2-phenylacetonitrile (1n): The
crude product was purified by column chromatography on
silica gel (eluent: EtOAc in hexanes). Yield: 85%, [a]2D0:
À3.6 (c 1.0, CHCl3); 1H NMR (CDCl3): d=7.52 (m, 2H,
Ph), 7.45 (m, 3H, Ph), 6.43 (s, 1H, CHCN), 2.43 (dt, J=
7.6 Hz, 1H, COCH2), 2.44 (dt, J=7.3 Hz, 2H, COCH2), 1.64
(ddt, J=7.3, 7.6, 8.1 Hz, 2H, CH2CH2CH2), 1.35 (tq, J=8.1,
7.30Hz, 2H, C H2CH3), 0.91 (t, J=7.3 Hz, 3H, CH3);
13C NMR (CDCl3): d=171.8, 131.9, 130.3, 129.2, 127.8,
116.2, 62.7, 33.4, 26.6, 22.1, 13.6; MS (EI): m/z=217 .10
[M+]; anal. calcd. (%) for C13H15NO2 (217.26): C 71.87, H
6.96, N 6.45; found: C 72.06, H 7.06, N 6.44; Chiral GC,
pressure 25 psi; injection temp. 2258C; initial column temp.
1158C; detection temp. 2258C; retention time (tR) of
42.1 min (minor), 46.9 min (major).
General Procedure for Enantioselective Addition of
a-Ketonitrile to Aldehydes
O-2-Methylbutyryl-(S)-2-hydroxy-2-phenylacetonitrile
(1o): The crude product was purified by column chromatog-
raphy on silica gel (eluent: EtOAc in hexanes). Yield: 86%,
[a]2D0: À5.2 (c 1.0CHCl 3); 1H NMR (CDCl3): d=7.52 (m,
2H, Ph), 7.45 (m, 3H, Ph), 6.43 (s, 1H, CHCN), 2.66 [dq,
Aldehyde (1 equiv.) was added to a solution of 4 (132 mg, 5
mol%) and base (10mol%) in dichloromethane (10mL).
The solution was cooled to À408C before a-ketonitrile
(2 equivs.) was added in one portion and the reaction was
monitored with GC/MS. After dilution with Et2O, the reac-
tion mixture was filtered through silica and the solvent was
evaporated under vacuum. The residue was purified by dis-
tillation or by column chromatography to give the pure
product.
O-Acetyl-(R)-2-hydroxy-(2-furyl)acetonitrile (1e): Chiral
GC, pressure 23 psi; injection temp. 2258C; initial column
temp. 1108C; detection temp. 2258C; retention time (tR) of
8.3 min (minor), 22.2 min (major). Spectral data were in ac-
cordance with those previously published.[9] The absolute
configuration was determined from the sign of optical rota-
tion.[9]
J=7.1, 6.8 Hz, 1H, CH(CH3)2], 1.23 (d, J=6.8 Hz, 3H,
A
CH3), 1.19 (d, J=7.1 Hz, 3H, CH3); 13C NMR (CDCl3): d=
175.0, 132.0, 130.3, 129.2, 127.7, 116.2, 62.7, 33.7, 18.6; MS
(EI): m/z=203.10 [M+]; anal. calcd. (%) for C12H13NO2
(203.24): C 70.92, H 6.45, N 6.89; found: C 70.75, H 6.38, N
6.84; Chiral GC, pressure 25 psi; injection temp. 2258C; ini-
tial column temp. 1158C; detection temp. 2258C; retention
time (tR) of 18.9 min (minor), 21.0min (major).
O-2,2-Dimethylbuturyl-(-(S)-2-hydroxy-2-phenylacetoni-
trile (1p): Chiral GC, pressure 25 psi; injection temp. 2258C;
initial column temp.1158C; detection temp. 2258C; retention
time (tR) of 15.0min (minor), 16.1 min (major). Spectral
data were in accordance with those previously published.[39]
The absolute configuration was determined from the sign of
optical rotation.[39]
O-Cinnamoyl (S)-2-hydroxy-2-phenylacetonitrile (1q):
The crude product was purified by column chromatography
on silica gel (eluent: EtOAc in hexanes). Yield: 89%, [a]2D0:
À41.1 (c 1.0, CHCl3); 1H NMR (CDCl3): d=7.8 (d, J=
15.9 Hz, 1H, CH), 7.60–7.40 (m, 10H, Ph), 6.58 (s, 1H,
CHCN), 6.47 (d, J=15.9 Hz, 1H, CH); 13C NMR (CDCl3):
d=164.7, 147.6, 133.6, 131.9, 131.0, 130.3, 129.2, 128.9, 128.3,
127.8, 116.2, 115.5, 62.8; MS (EI): m/z=263 .05 [M+]; anal.
calcd. (%) for C17H13NO2 (263.29): C 77.55, H 4.98, N 5.32;
found C 76.98, H 4.64, N 4.96;[45] Chiral HPLC, 2-propanol/
hexane, 1/9, flow: 0.7 mLminÀ1, detection 212 nm retention
time (tR) of 19.5 min (major), 27.7 min (minor).
O-Acetyl-(S)-2-hydroxy-2-(3-phenoxyphenyl)acetonitrile
(1f): Chiral HPLC, 2-propanol/hexane, 1/9. Flow:
0.8 mLminÀ1
; detection 212 nm; retention time (tR) of
15.1 min (major), 19.4 min (minor). Spectral data were in ac-
cordance with those previously published.[44] The absolute
configuration was determined from the sign of optical rota-
tion.[44]
O-Acetyl-(S)-2-hydroxy-2-(3-pyridyl)acetonitrile
(1g):
Chiral GC, pressure 25 psi; injection temp. 2258C; initial
column temp. 1208C; detection temp. 2258C; retention time
(tR) of 25.0min (minor), 42.1 min (major). Spectral data
were in accordance with those previously published.[14]
O-Acetyl-(S)-2-hydroxy-(2-pyridyl)acetonitrile
(1h):
Chiral GC, pressure 25 psi; injection temp. 2258C; initial
column temp. 1208C; detection temp. 2258C; retention time
(tR) of 27.3 min (minor), 52.6 min (major). Spectral data
were in accordance with those previously published.[45]
O-Benzoyl (S)-2-hydroxy-2-phenylacetonitrile (1r): Chiral
HPLC, 2-propanol/hexane 1.5/98.5, flow: 0.7 mLminÀ1; de-
tection 212 nm; retention time (tR) of 16.8 min (major),
85.6 min (minor). Spectral data were in accordance with
those previously published.[39] The absolute configuration
was determined from the sign of optical rotation.[39]
O-Propionyl-(S)-2-hydroxy-2-phenylacetonitrile
(1l):
Chiral GC, pressure 25 psi; injection temp. 2258C; initial
column temp. 1158C; detection temp. 2258C; retention time
(tR) of 16.4 min (minor), 21.8 min (major). Spectral data
were in accordance with those previously published.[39] The
absolute configuration was determined from the sign of opti-
cal rotation.[39]
O-Butyryl-(S)-2-hydroxy-2-phenylacetonitrile (1m): Chiral
GC, pressure 25 psi; injection temp. 2258C; initial column
temp. 1158C; detection temp. 2258C; retention time (tR) of
370
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 364 – 372

Enantioselective Addition of a-Ketonitriles to Aldehydes
FULL PAPERS
[11] M. Okimoto, T. Chiba, Synthesis 1996, 1188–1190.
[12] T. Watahiki, S. Ohba, T. Oriyama, Org. Lett. 2003, 5,
2679–2681.
[13] M. Scholl, C.-K. Lim, G. C. Fu , J. Org. Chem. 1995, 60,
6229–6231.
Acknowledgements
This work was supported by the Swedish Foundation for
Strategic Research.
[14] H. M. R. Hoffmann, Z. M. Ismail, R. Hollweg, A. R.
Zein, Bull. Chem. Soc. Jpn. 1990, 63, 1807–1810.
[15] W. Zhang, M. Shi, Org. Biomol. Chem. 2006, 4, 1671–
1674.
[16] a) M. Shibasaki, M. Kanai, Chem. Pharm. Bull. 2001,
49, 511–525; b) S. Kanemasa, K. Ito, Eur. J. Org.
Chem. 2004, 4741–4753; c) J.-A. Ma, D. Cahard,
Angew. Chem. Int. Ed. 2004, 43, 4566–4583; d) M.
Kanai, N. Kato, E. Ichikawa, M. Shibasaki, Synlett
2005, 1491–1508.
[17] a) S. Lundgren, E. Wingstrand, M. Penhoat, C.
Moberg, J. Am. Chem. Soc. 2005, 127, 11592–11593;
b) E. Wingstrand, S. Lundgren, M. Penhoat, C.
Moberg, Pure Appl. Chem. 2006, 78, 409–414.
[18] A. Baeza, C. Nµjera, J. M. Sansano, J. M. Saµ, Tetrahe-
dron: Asymmetry 2005, 16, 2385–2389; An analogous
mechanism was suggested for cyanoalkoxycarbonyla-
tions of aldehydes: A. Baeza, J. Casas, C. Nµjera, J. M.
Sansano, J. M. Saµ, Eur. J. Org. Chem. 2006, 1949–
1958.
[19] A. Hamberg, S. Lundgren, M. Penhoat, C. Moberg, K.
Hult, J. Am. Chem. Soc. 2006, 128, 2234–2235.
[20] a) J. Thesing, D. Witzel, A. Brehm, Angew. Chem.
1956, 68, 425–448; b) S. Hünig, R. Schaller, Angew.
Chem. Int. Ed. Engl. 1982, 21, 36–49.
References
[1] a) J.-M. Brunel, I. P. Holmes, Angew. Chem. Int. Ed.
2004, 43, 2752–2778; b) M. North, Tetrahedron: Asym-
metry 2003, 14, 147–176; c) H. Griengl, H. Schwab, M.
Fechter, Trends Biotechnol. 2000, 18, 252–256; d) F. Ef-
fenberger, Angew. Chem. Int. Ed. Engl. 1994, 33, 1555–
1564.
[2] a) Y. N. Belokon’, S. Caveda-Cepas, B. Green, N. S.
Ikonnikov, V. N. Khrustalev, V. S. Larichev, M. A. Mo-
scalenko, M. North, C. Orizu, V. I. Tararov, M. Tasinaz-
zo, G. I. Timofeeva, L. V. Yashkina, J. Am. Chem. Soc.
1999, 121, 3968–3973; b) J. Casas, C. Nµjera, J. M. San-
sano, J. M. Saµ, Tetrahedron 2004, 60, 10487–10496;
c) D. H. Ryu, E. J. Corey, J. Am. Chem. Soc. 2004, 126,
8106–8107.
[3] a) A. Baeza, J. Casas, C. Nµjera, J. M. Sansano, J. M.
Saa, Angew. Chem. Angew. Chem. Int. Ed. 2003, 42,
3143–3146; b) Y. Abiko, N. Yamagiwa, M. Sugita, J.
Tian, S. Matsunaga, M. Shibasaki, Synlett 2004, 2434–
2436.
[4] a) Y. N. Belokon’, A. J. Blacker, L. A. Clutterbuck, M.
North, Org. Lett. 2003, 5, 4505–4507; b) J. Casas, A.
Baeza, J. M. Sansano, C. Nµjera, J. M. Saµ, Tetrahe-
dron: Asymmetry 2003, 14, 197–200; c) N. Yamagiwa,
J. Tian, S. Matsunaga, M. Shibasaki , J. Am. Chem. Soc.
2005, 127, 3413–3422.
[21] F. Wçhler, J. Liebig, Justus Liebigs Ann. Chem. 1832, 3,
249–282.
[22] a) G. Hausknecht, Ber. dtsch. chem. Ges. 1889, 22, 324–
330; b) W. Tschelnizeff, W. Schmidt, Ber. dtsch. chem.
Ges. 1929, 62, 2210–2214.
[23] M. Tanaka, Tetrahedron. Lett. 1980, 21, 2959–2962.
[24] L. Claisen, Ber. dtsch. chem. Ges. 1898, 31, 1023–1024.
[25] K. E. Koenig, W. P. Weber, Tetrahedon Lett. 1974,
2275–2278.
[5] a-Acetoxy amides: M. North, A. W. Parkins, A. N.
Shariff, Tetrahedron Lett. 2004, 45, 7625–7627; allylic
transformations: H. Abe, H. Nitta, A. Mori, S. Inoue,
Chem. Lett. 1992, 2443–2446; N-acyl-b-amino alcohols:
L. Veum, S. R. M. Pereira, J. C. van der Waal, U. Hane-
feld, Eur. J. Org. Chem. 2006, 1664–1671.
[6] a) H. Huang, J. E. Stok, D. W. Stoutamire, S. J. Gee,
B. D. Hammock, Chem. Res. Toxicol. 2005, 18, 516–
527; b) G. Shan, B. D. Hammock, Anal. Biochem. 2001,
299, 54–62; c) C. E. Wheelock, Š. M. Wheelock, R.
Zhang, J. E. Stok, C. Morisseau, S. E. Le Valley, C. E.
Green, B. D. Hammock, Anal. Biochem. 2003, 315,
208–222; d) C. J. Peterson, R. Tsao, A. L. Eggler, J. R.
Coats, Molecules, 2000, 5, 648–654.
[26] a) G. A. Olah, M. Arvanaghi, G. K. Surya Prakash,
Synthesis 1983, 8, 636–637; b) K. Herrmann, G. Sim-
chen, Synthesis 1979, 204–205.
[27] Y-Q. Cao, Y.-F. Du, B.-H. Chen, J.-T. Li, Synth.
Commun. 2004, 34, 2951–2957.
[28] C. D. Hurd, O. E. Edwards, J. R. Roach . J. Am. Chem.
Soc. 1944, 66, 2013–2014.
[29] J. F. Normant, C. Peichucki, Bull. Soc. Chim. Fr. 1972,
2402–2403.
[30] L. Claisen, E. Moritz, Ber. dtsch. chem. Ges. 1880, 13,
2121–2123.
[7] S. Norsikian, I. Holmes, F. Lagasse, H. B. Kagan, Tetra-
hedron Lett. 2002, 43, 5715–5717.
[8] a) Y. N. Belokon’, A. G. Gutnov, M. A. Moskalenko,
L. V. Yashkina, D. E. Lesovoy, N. S. Ikonnikov, V. S.
Larichev, M. North, Chem. Commun. 2002, 244–245;
b) Y. N. Belokon’, P. Carta, A. V. Gutnov, V. Maleev,
M. A. Moskalenko, L. V. Yashkina, N. S. Ikonnikov,
N. V. Voskoboev, V. N. Khrustalev, M. North, Helv.
Chim. Acta 2002, 85, 3301–3312.
[9] a) L. Veum, L. T. Kanerva, P. J. Halling, T. Maschmey-
er, U. Hanefeld, Adv. Synth. Catal. 2005, 347, 1015–
1021; b) L. Veum, U. Hanefeld, Synlett 2005, 2382–
2384.
[31] B. E. Tate, P. D. Bartlett, J. Am. Chem. Soc. 1956, 78,
5575–5580.
[32] A. C. Veronese, R. Callegari, M. Basato, G. Valle, J.
Chem. Soc., Perkin Trans. 1994, 1779–1785.
[33] F. Asinger, F. Gentz, Angew. Chem. 1963, 75, 577.
[34] Z. P. Demko, K. B. Sharpless, Angew. Chem. Int. Ed.
2002, 41, 2113–2116.
[35] A. M. Lobo, M. M. Marques, S. Prabhakar, H. S.
Rzepa, J. Chem. Soc., Chem. Commun. 1985, 1113–
1115.
[10] C. S. Marvel, N. O. Brace, F. A. Miller, A. R. Johnson,
J. Am. Chem. Soc. 1949, 71, 34–36.
[36] E. Kattnig, M. Albert, Org. Lett. 2004, 6, 945–948.
Adv. Synth. Catal. 2007, 349, 364 – 372
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.asc.wiley-vch.de
371

Stina Lundgren et al.
FULL PAPERS
[37] A. Loukaci, O. Kayser, K.-U. Bindseil, K. Siems, J. Fre-
vert, P. M. Abreu, J. Nat. Prod. 2000, 63, 52–56.
[38] N. Ghosh, Synlett 2004, 574–575.
[39] Y. N. Belokon’, A. J. Blacker, P. Carta, L. A. Clutter-
buck, M. North, Tetrahedron 2004, 60, 10433–10448.
[40] That the monomer to dimer ratio varies with the tem-
perature has also been previously observed. It was also
shown to depend on the concentration of the Ti-salen
complex, see ref.[39].
[42] B. A. Clement, R. L. Soulen, J. Org. Chem. 1974, 39,
97–98.
[43] a) H. M. R. Hoffman, K. Haase, Z. M. Ismail, S. Preftit-
si, A. Weber, Ber. dtsch. chem. Ges. 1982, 115, 3880–
3885; b) M. Santelli, D. El Abed, A. Jellal, J. Org.
Chem. 1986, 51, 1199–1206.
[44] L. Veum, M. Kuster, S. Telalovic, U. Hanefeld, T.
Maschmeyer, Eur. J. Org. Chem. 2002,1516–1522.
[45] a) W. Mathes, W. Sauermilch, Chem. Ber. 1956, 89,
1515–1521; b) W. Huang, Y. Song, J. Wang, G. Cao, Z.
Zheng, Tetrahedron 2004, 60, 10469–10477.
[41] Procedure partly taken from P. Roth, A. Hꢁdener, C.
Tamm, Helv. Chim. Acta 1990, 73, 476–482.
[46] F. Francis, O. Minty, J. Chem. Soc 1909, 95, 1403–1407.
372
www.asc.wiley-vch.de
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2007, 349, 364 – 372