Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of Aldehydes: A Mechanistic Study

Article abstract of DOI:10.1002/chem.201503782

A mechanistic investigation, which included a Hammett correlation analysis, evaluation of the effect of variation of catalyst composition, and low-temperature NMR spectroscopy studies, of the Lewis acid-Lewis base catalyzed addition of acetyl cyanide to prochiral aldehydes provides support for a reaction route that involves Lewis base activation of the acyl cyanide with formation of a potent acylating agent and cyanide ion. The cyanide ion adds to the carbonyl group of the Lewis acid activated aldehyde. O-Acylation by the acylated Lewis base to form the final cyanohydrin ester occurs prior to decomplexation from titanium. For less reactive aldehydes, the addition of cyanide is the rate-determining step, whereas, for more reactive, electron-deficient aldehydes, cyanide addition is rapid and reversible and is followed by rate-limiting acylation. The resting state of the catalyst lies outside the catalytic cycle and is believed to be a monomeric titanium complex with two alcoholate ligands, which only slowly converts into the product.

Full text of DOI:10.1002/chem.201503782

DOI: 10.1002/chem.201503782
Full Paper
&
Dual Catalysis
Dual Lewis Acid/Lewis Base Catalyzed Acylcyanation of
Aldehydes: A Mechanistic Study
Anna Laurell Nash,[a] Robin Hertzberg,[a] Ye-Qian Wen,[a] Bjçrn Dahlgren,[b] Tore Brinck,[b] and
Christina Moberg*[a]
Abstract:
A
mechanistic investigation, which included
the acylated Lewis base to form the final cyanohydrin ester
occurs prior to decomplexation from titanium. For less reac-
tive aldehydes, the addition of cyanide is the rate-determin-
ing step, whereas, for more reactive, electron-deficient alde-
hydes, cyanide addition is rapid and reversible and is fol-
lowed by rate-limiting acylation. The resting state of the cat-
alyst lies outside the catalytic cycle and is believed to be
a monomeric titanium complex with two alcoholate ligands,
which only slowly converts into the product.
a Hammett correlation analysis, evaluation of the effect of
variation of catalyst composition, and low-temperature NMR
spectroscopy studies, of the Lewis acid–Lewis base catalyzed
addition of acetyl cyanide to prochiral aldehydes provides
support for a reaction route that involves Lewis base activa-
tion of the acyl cyanide with formation of a potent acylating
agent and cyanide ion. The cyanide ion adds to the carbonyl
group of the Lewis acid activated aldehyde. O-Acylation by
Introduction
anide sources, such as KCN, trimethylsilyl cyanide (TMSCN), or
acetone cyanohydrin.
Enantioselective additions of acyl cyanides to prochiral carbon-
yl compounds constitute highly versatile processes, which pro-
vide access to enantioenriched O-acylated cyanohydrins. The
products are useful synthetic building blocks[1] and valuable
target compounds with important applications.[2] The addition
of acyl cyanides to aldehydes and ketones is catalyzed by
bases/nucleophiles and is accelerated by Lewis acids (LAs). It
was shown already in 1949 that benzoyl cyanide added to al-
dehydes in the presence of base to yield cyanohydrin ben-
zoates.[3] Other more recent examples include 1,4-diazabicy-
clo[2.2.2]octane (DABCO)[4] and N-heterocyclic carbene-mediat-
ed[5] acylcyanation of aldehydes, 1,5-diazabicyclo[5.4.0]undec-5-
ene (DBU)-catalyzed additions to ketones,[6] and additions cata-
lyzed by Bu3SnCN.[7] Activation of the acyl cyanide by DMSO[8]
or aqueous carbonate[9] has also been shown to lead to cyano-
hydrin esters, in the absence of any additional catalyst. The
same compounds, in racemic[10] or enantioenriched[11] forms,
have also been prepared by one-pot, two-step procedures that
involve acylation of cyanohydrins obtained by use of other cy-
By use of a chiral LA in combination with an achiral tertiary
amine, we were able to prepare highly enantioenriched acylat-
ed cyanohydrins from aromatic and aliphatic aldehydes and
acyl cyanides derived from aliphatic acid chlorides or bro-
mides.[12] For cases in which insufficient enantioselectivity was
observed, a method incorporating in situ recycling of the
minor enantiomer led to improved results.[13] Baeza et al. re-
ported analogous products derived from aromatic acyl cya-
nides by employing a binol derivative equipped with tertiary
amine substituents; the conditions employed did, however,
not allow reaction with acetyl cyanide (2).[14]
In contrast to the detailed studies performed concerning the
mechanism of LA-catalyzed additions of silyl cyanides[15] and
cyanoformates,[16] little information is available on the acylcya-
nations of carbonyl compounds. Benzoylcyanation, employing
the TiIV catalyst used by Baeza et al.,[14] prepared in situ from
3,3’-bis(diethylaminomethyl)-1,1’-binaphthol (binolam) and
Ti(OiPr)4, was suggested to be a two-step process that pro-
ceeded through the addition of HCN to the aldehyde followed
by benzoylation.[17] We and others[4–6] have suggested a differ-
ent mechanism, in which the nucleophile is liberated from the
acyl cyanide through activation by the Lewis base (LB); the
[a] Dr. A. Laurell Nash, Dr. R. Hertzberg, Dr. Y.-Q. Wen, Prof. C. Moberg
KTH Royal Institute of Technology, Department of Chemistry
Organic Chemistry 10044 Stockholm (Sweden)
same mode of activation has been suggested for reactions
18]
with cyanoformate.[5,
To obtain further information on the
details of the catalytic reaction, a mechanistic study has now
been performed, and the results are presented herein.
[b] B. Dahlgren, Prof. T. Brinck
KTH Royal Institute of Technology, Department of Chemistry
Applied Physical Chemistry, 10044 Stockholm (Sweden)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201503782.
Results and Discussion
Part of a Special Issue “Women in Chemistry” to celebrate International
Women’s Day 2016. To view the complete issue, visit: http://dx.doi.org/
chem.v22.11.
As previously demonstrated, acyl cyanides react with prochiral
aldehydes in the presence of titanium salen dimer 1 and a terti-
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ary amine, such as triethylamine, 4-dimethylaminopyridine
(DMAP), or DABCO, to give highly enantioenriched O-acylated
cyanohydrins.[12] Based on a preliminary mechanistic study,[19]
we proposed a mechanism for the reaction that consisted of
nucleophilic attack on the LA-coordinated aldehyde by cya-
nide, generated by reaction of the tertiary amine with 2, lead-
ing to a titanium alcoholate; the acetyl ammonium ion (3)
formed along with cyanide serves as a highly efficient acylating
reagent. The suggested mechanism is illustrated in Scheme 1
for the reaction of benzaldehyde (4a) with 2 to give acylated
cyanohydrin 5.
Hammett analysis
Our present investigation included a Hammett correlation
study. Determination of the initial rates was nontrivial due to
induction periods of different lengths for different substrates.
Instead, the relative rates of the reaction of 4a and 10 different
3- and 4-substituted arylaldehydes were determined from com-
petition experiments.[24] The aldehydes were present in equi-
molar amounts and in excess relative to 2 to prevent the reac-
tions from going to completion (Scheme 2). The experiments
were performed by mixing 1 and triethylamine with 4a and
a competing aldehyde in dichloromethane. The mixtures were
kept at À358C for 90 min before the addition of 2 to allow the
formation of dimer 1 from the mixture of mono- and dimer
In the presence of only triethylamine, rapid product forma-
tion is observed at room temperature, whereas for an efficient
reaction at À408C the presence of both LA and LB is re-
quired.[20,21] The mechanism proposed is in accord-
ance with that previously suggested for the synthesis
of racemic cyanohydrin esters.[4] Support for initial
nucleophilic attack by the tertiary amine is available
from studies of the reactivity of 2,[22] which is known
to yield substitution products with replacement of
cyanide upon reaction with N-, O-, and S-nucleo-
philes.[23]
Scheme 2. Reaction of a substoichiometric amount of 2 with competing aldehydes.
present at ambient temperature (see below). The relative rates
of the reaction of the competing aldehydes were determined
1
as the ratio of the products formed, as analyzed by H NMR
spectroscopy.[25] A plot of log(kR/kH) against s[26] resulted in
a plot that exhibited a rate maximum, which was indicative of
a change in the rate-determining step (Figure 1). A straight
line with 1=1.81 was found for 6 of the 10 substrates. The re-
sults show that a negative charge is built up during the course
of the reaction for these aldehydes, in line with rate-limiting
nucleophilic attack. For the silylcyanation of aldehydes cata-
lyzed by titanium dimer 1, a reaction constant 1=2.4 was pre-
viously reported, whereas lower values were observed for reac-
tions dominated by LB catalysis.[27]
Scheme 1. Suggested mechanism for the addition of 2 to 4a.
Figure 1. Hammett plot from competition experiments with 4a and substituted benzaldehydes by using relative rates and standard s constants. The solid
straight line (y=1.8075”À0.081; R2 =0.9734) refers to experiments with 4a in combination with p-MeO-, p-Me-, m-MeO-, p-Br-, p-Cl-, and p-CF3-benzaldehyde.
Average values from four experiments with each substrate are reported.
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For aldehydes with strongly electron-withdrawing substitu-
ents, decreasing overall reactivity was observed with increasing
s values. Adjustment to a straight line was less clear for these
aldehydes than for those with lower reactivity (Figure 1), but
the results suggested a transition state with an opposite elec-
tron flow in the rate-limiting step. This result is consistent with
a mechanism in which acylation is rate determining instead.
The Hammett study thus indicates a change in mechanism
upon going from aldehydes of low reactivity to highly reactive
aldehydes. The results are consistent with two-step processes
in which nucleophilic attack by cyanide is rate determining for
the less reactive aldehydes and acylation for those that are
highly electrophilic. For aldehydes of the latter type, attack by
cyanide is accordingly a rapid, reversible step and acylation is
the slow step. The suggestion is also in line with the mecha-
nisms proposed for cyanocarbonylation of aliphatic ketones,[28]
as well as acylcyanation of a-ketoesters,[29] which are based on
dynamic kinetic resolution of the initially formed racemic cya-
noalkoxides. The a-ketoesters were found to undergo rapid, re-
versible cyanation followed by slow, enantiodetermining acyla-
tion.
1H NMR spectroscopy, in accordance with the known higher
stability of the homodimer,[30] and therefore no heterodimers
were assumed to be involved in the catalytic reactions. Use of
the analogous achiral ligand derived from diaminoethane was
considered to be less appropriate because this complex has
been shown to adopt the heterochiral DL-configuration and
to be less reactive than (S,S)-1, which has the homochiral DD-
or LL-configuration (Figure 2).[31] The results from the experi-
ments are shown in Table 1.
Figure 2. The syn-LL-configuration of C2-symmetric homochiral dimer (S,S)-
1 (A) and S2-symmetric achiral dimer (B).
As expected from the results of the Hammett study, the LA
was found to be responsible for chirality transfer in reactions
with p-methoxy-, p-chloro-, and p-(trifluoromethyl)benzalde-
hyde as well as in that with the parent compound (Table 1, en-
tries 1a–4a). In reactions with these substrates, the chiral LB
had only a minor influence on ee (Table 1, entries 1b–4b) and
close to racemic product was obtained in the presence of race-
mic LA and chiral LB (Table 1, entries 1c–4c). In contrast, in the
reaction with 4-cyanobenzaldehyde, the presence of both
enantiopure LA and chiral LB was required to obtain an enan-
tioenriched product (Table 1, entry 5). As shown in Table 1 and
Scheme 4, cinchonidine forms mismatched and matched pairs
with (R,R)- and (S,S)-1, respectively. Although the enantiopure
LA in combination with triethylamine resulted in essentially
racemic product (5% ee; Table 1, entry 5a, and Scheme 4A),
the absolute configuration of the product from reactions with
triethylamine instead of cinchonidine was determined by the
LA, as shown by the formation of products with the opposite
absolute configuration in reactions with the two catalyst com-
binations (Table 1, entries 5b and c, and Scheme 4B and C).
The different results of the two reactions, 41 (S) and 61% ee
(R), respectively, demonstrate that the titanium complex has
a role in chirality transfer.
Three different aroyl cyanides, p-methoxy-, p-methyl, and p-
chlorobenzoyl cyanide, were also allowed to compete with
benzoyl cyanide in reactions with 4a (Scheme 3). Although
acylation is not rate determining in reactions that employ 4a
as the substrate, the reactivity of the acylating agents towards
the titanium-bound alcoholate and towards the LB is reflected
in the product mixture. As expected, the reactivity increased
with the electrophilicity of the reagents; the ratios of kOMe/kH,
kMe/kH, and kCl/kH were 0.09, 0.30, and 4.44, respectively (see
the Supporting Information).
Effect of variation of catalyst composition
If the first step constitutes a rapid, reversible cyanation, chiral
LAs are expected to result in only minor enantioselection,
whereas chiral LBs may lead to enantioenriched products, pro-
vided the acylating reagent contains the chiral amine. Con-
versely, if the first step is rate determining, chirality transfer
from the LA should be more important. To test these assump-
tions, a series of reactions were performed by using catalytic
systems composed of chiral enantiopure or racemic LAs in
combination with achiral or chiral LBs. A racemic mixture of
the dimeric titanium complex could, in principle, result in the
formation of both homo- and heterochiral dimers. However,
after stirring a 1:1 mixture of (R,R)-1 and (S,S)-1 in dichlorome-
thane for 10 h, only the homochiral dimers were detected by
If free cyanohydrin were an intermediate, as suggested by
Nµjera and co-workers for studies on benzoylcyanations,[17]
products with the same absolute configuration and with the
same ee would be expected in the two cases because essen-
tially racemic product, and therefore, probably also close to
Scheme 3. Reaction of 4a with competing aroyl cyanides.
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racemic cyanohydrin, was obtained in the presence of enantio-
pure LA (compare the reaction with (R,R)-1 and Et3N; Table 1,
entry 5a, and Scheme 4A). Furthermore, if decomplexation
from titanium would take place prior to acylation, the product
would be expected to form with the same ee irrespective of
whether racemic (Table 1, entry 5d, and Scheme 4D) or enan-
tiopure LA was used. The results obtained show that this is not
the case, but that instead enantiopure LA is required for the
formation of enantioenriched product.
Table 1. Enantiomeric excess (ee) of products from acetylcyanation cata-
lyzed by combinations of enantiopure LA–achiral LB, enantiopure LA–
chiral LB, and racemic LA–chiral LB in CH2Cl2 at À408C.
Entry
X
LA
LB
ee [%]
s
(absolute
configuration)
The results observed for the two remaining aldehydes
(Table 1, entries 6 and 7) suggest similar rates for the two
steps. The conclusion from this study is that acylation occurs
while the cyanohydrin is bound to titanium and that the acy-
lating reagent is obtained by the reaction of 2 with the chiral
base.
1[a]
2[a]
3[a]
4[b]
5[b]
a
b
c
4-OCH3 (R,R)-1
(R,R)-1
NEt3
79 (S)
cinchonidine 83 (S)
(S,S)+(R,R)-1 cinchonidine 6 (S)
À0.27
0
a
b
b
a
b
c
4-H
(R,R)-1
(R,R)-1
NEt3
82 (S)
cinchonidine 84 (S)
(S,S)+(R,R)-1 cinchonidine 6 (S)
4-Cl
(R,R)-1
(R,R)-1
NEt3
79 (S)
Low-temperature NMR spectroscopy studies
cinchonidine 81 (S)
0.23
0.54
(S,S)+(R,R)-1 cinchonidine 4 (S)
To further explore the course of the catalytic process and to
a
b
c
4-CF3
4-CN
(R,R)-1
(R,R)-1
NEt3
43 (S)
detect possible intermediates, the reactions of both 4a and 4-
cinchonidine 42 (S)
(S,S)+(R,R)-1 cinchonidine 7 (S)
cyanobenzaldehyde with
2 in the presence of catalytic
a
b
c
d
a
b
c
(R,R)-1
(R,R)-1
(S,S)-1
NEt3
5 (S)
amounts of 1 and triethylamine were followed over time by
cinchonidine 41 (S)
cinchonidine 61 (R)
1
0.66
0.71
0.74
low-temperature H NMR spectroscopy. The reaction with 4-cy-
anobenzaldehyde was studied at À40 and À508C and that
with less reactive 4a at À408C. In reactions with both alde-
hydes, evolution of acylated cyanohydrin was observed, ac-
(S,S)+(R,R)-1 cinchonidine 2 (S)
6[b,c]
3-NO2
3,5-Cl2
(S,S)-1
(S,S)-1
NEt3
14 (R)
cinchonidine 40 (R)
(S,S)+(R,R)-1 cinchonidine 13 (R)
companied by
a decrease in the amount of aldehyde
7[d]
a
b
c
(R,R)-1
(R,R)-1
(S,S)-1
NEt3
27 (S)
(Figure 3). After a short induction period a new compound ap-
peared. Because this compound started to form after the prod-
uct (see the Supporting Information), it was not an intermedi-
ate, but instead a compound off the catalytic cycle. The
amount of this compound was constant until most of the alde-
hyde was consumed; thereafter it was transformed into prod-
uct. In the reaction with 4a, this occurred after about 9–10 h,
whereas in the reaction with 4-cyanobenzaldehyde at À408C
the amount of this compound increased during the first
25 min and then decreased. The NMR spectrum of the com-
pound formed from 4-cyanobenzaldehyde showed three sig-
nals of unequal intensity (ratio ca. 1:0.6:0.07), a major signal at
d=5.57 ppm and smaller signals at dꢀ5.50–5.53 ppm. These
shifts are characteristic of benzylic cyanohydrin protons, albeit
different from that of the free cyanohydrin, which appears at
d=5.68 ppm, and therefore is most likely to originate from
diastereomeric titanium–cyanohydrin complexes. Other signals
that appeared and disappeared together with those at d
ꢀ5.5 ppm were found at d=8.25, 7.24, 7.15, and 6.66 ppm (in-
tensity 0.3:0.5:1:0.8); additional signals may be hidden by
other signals in the aromatic region. In the reaction with 4a,
a signal appeared at d=5.48 ppm, which is close to that of
free cyanohydrin, but, whereas free cyanohydrin undergoes in-
stantaneous acylation under the reaction conditions, the com-
pound formed in the reaction converted to product slowly.
The signal at d=5.48 ppm was flanked by only minor signals,
which is consistent with the high selectivity of the first step in
the reaction with this aldehyde. The yield of the compound
observed reached, in both cases, close to 20% based on the al-
dehyde, which indicated that two molar equivalents of cyano-
cinchonidine 74 (S)
cinchonidine 69 (R)
d
(S,S)+(R,R)-1 cinchonidine 10 (S)
[a] Determined by chiral GC. [b] Determined by chiral HPLC. [c] Poor peak
separation. [d] Determined by HPLC; the absolute configuration is un-
known, but assumed to be those indicated in analogy to products from
other aldehydes.
Scheme 4. Effect of catalyst variation in the reactions of 4-cyanobenzalde-
hyde. A) Enantiopure LA and achiral LB; B) and C) enantiopure LA and chiral
LB; D) racemic LA and chiral LB. DYKAT=dynamic kinetic asymmetric trans-
formation.
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~
&
Figure 3. Formation of the titanium–cyanohydrin complex ( ) and acylated product (”) and disappearance of aldehyde ( ) over time in reactions with 4a
(top) and 4-cyanobenzaldehyde (bottom) at À408C.
hydrin were bound to each titanium (5 mol% of dimer 1 was
used in the reaction).
Influence of the order of addition of the reagents
Complex 1 is known to be in equilibrium with monomer 1a.
The dimer is favored by high concentrations and low tempera-
tures.[16] North and co-workers demonstrated that the forma-
tion of an active catalyst was required before high ee could be
achieved.[16] We previously found that the ee of the product of
acylcyanation was lower in the initial phase of the reaction and
then increased to a constant value.[19] We also found that a con-
stant and higher ee was observed when a mixture of the titani-
um salen complex, aldehyde, and 2 was kept at À408C for 3 h
prior to the addition of the LB; this was likely to result from
the formation of the active catalyst.[19]
used as the substrate. When 2 was added to a mixture of alde-
hyde, 1, and triethylamine, which had been stirred at À408C
for 2 h, product formation was preceded by an induction
period. When triethylamine was added last, only a short induc-
tion period was observed, and when the aldehyde was added
last the reaction started almost immediately (Figure 4). These
observations suggest that an active catalyst is formed prior to
the reaction, and that 2 is involved in the formation of this
species. Attempts to gain information about the interactions of
To further study the conditions under which the catalytic re-
action was favored, reactions in which the reagents were
added in a different order were followed by taking aliquots
from the reaction mixture and analyzing the samples by GC.
For this purpose, slower reacting 4-methoxybenzaldehyde was
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tained as previously suggested,[16] but through the replace-
ment of ethyl cyanoformate with 2. Thus, compound 2 or,
more probably, the product obtained by the addition of the
LB, 3, reacts with 1 to give 8, which disproportionates into 9
and 10; bis-acetate 10 has previously been identified as a prod-
uct from the reaction of 1 with acetic anhydride.[11c] The alde-
hyde reacts in a [2+2] cycloaddition with monomeric complex
1a to provide metallacycle 11; although no interaction could
be detected between 4a and 1a, the corresponding metallacy-
cle was observed when 4a was replaced with hexafluoroace-
tone.[15] Addition of cyanide to the carbonyl function in 7 af-
fords the neutral complex 12, which undergoes acylation by
the LB-activated acetyl cyanide (3) to afford the observed
product 5 and 13, which reacts with the aldehyde to complete
the catalytic cycle. Complex 12 and bis-acetate 10, obtained
along with 9 during the formation of the active catalyst, are
suggested to be in equilibrium with 14, which is the off-cycle
resting state of the catalyst, and complex 15, which can be
converted back into 1 and 2. After complete consumption of
the aldehyde, complex 14 is slowly converted into the product
by reacting with 3. The relative rates of attack by cyanide and
acylation are a function of the reactivity of the aldehyde.
According to the mechanism shown in Scheme 5, the addi-
tion of 2 is crucial for the formation of the active catalyst. This
is in agreement with the induction period observed when 2 is
added after the other reagents.
Figure 4. Kinetic experiments following the development of product from 4-
methoxybenzaldehyde and 2 over time at À408C with different orders of
&
*
addition of amine, aldehyde, and 2. : NEt3 added last, : aldehyde added
last, and : 2 added last; ~: water (2.5 equiv) present.
^
1 and 2 by low-temperature NMR spectroscopy studies were
unfortunately hampered by the dimerization of 2, which result-
ed in its complete consumption over 90 min. Compound 2
also undergoes base-catalyzed dimerization,[32] which is reversi-
ble, as shown by isotope scrambling when doubly 13C-labeled
2 was mixed with unlabeled 2 in the presence of a catalytic
amount of triethylamine.[33] When acylcyanation was per-
formed in the presence of water (0.24–2.5 equiv), a slower re-
action was observed. In contrast, water, as well as tert-butanol
and imidazole, resulted in acceleration of the rate in acylcyana-
tions with KCN and acetic anhydride.[10c]
The fact that most of the catalyst is transformed to 14,
serves to explain the requirement of a rather high catalyst
loading, 5 mol%, for the reaction to proceed at an acceptable
rate. The same high catalyst loading was also needed in cyano-
formate addition, whereas silylcyanation of 4a proceeded rap-
idly in the presence of merely 0.1 mol% catalyst, which sug-
gests that the formation of an off-cycle resting state might
occur also in the addition of cyanoformate.[34]
Suggested mechanism
From the results presented herein, a mechanism with several
features analogous to that suggested by Belokon et al. for the
addition of cyanoformate to aldehydes, catalyzed by the same
titanium salen dimer,[16] is proposed for the acylcyanation of
prochiral aldehydes in the presence of a LB (6) and complex
1 (Scheme 5). The active catalyst is suggested to be 7, ob-
Scheme 5. Tentative mechanism suggested for LA/LB-catalyzed acylcyanation of aldehydes. RDS=rate-determining step.
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In the addition of cyanocarbonate to 4a catalyzed by titani-
um complex 1, a considerably higher rate was observed when
potassium cyanide was added as a cocatalyst.[35] In contrast,
when the acetylcyanation of 4a was performed in the pres-
ence of potassium cyanide, only a marginal effect on the reac-
tion rate was observed.
the acylating agent, but that instead the acyl group is bound
to the tertiary amine. These conflicting results of our studies
and those by Nµjera and co-workers[17] probably imply that the
course of the reaction is sensitive to the reaction conditions,
and that different reaction routes are followed under different
conditions.
The viability of Scheme 5 was investigated by numerical
modeling. Although the reaction system (Table 2) has too
many parameters for any fitting to be meaningful, in Figure 5
we show that the model is capable of qualitatively reproduc-
ing the data presented in Figure 3.
Conclusion
The results presented herein provide strong support for
a mechanism for the LA–LB-catalyzed addition of acyl cyanides
to prochiral aldehydes, which is analogous to that previously
suggested for the addition of cyanoformate to aldehydes. The
active titanium catalyst is suggested to be formed through
acylation of titanium dimer 1, either by the acyl cyanide or by
the LB-activated acyl cyanide, and activation of the prochiral
aldehyde by monomer 1a. The liberated cyanide ion then
adds to the LA-coordinated aldehyde. In the next step, the LA-
coordinated cyanohydrin is acylated by the LB-activated acyl
group. The high catalyst loading required is explained by the
abundant formation of a stable titanium complex, which lies
off the catalytic cycle.
Table 2. Reduced reaction system corresponding to Scheme 5 (com-
pounds 8, 12, and 15 are not included explicitly).
Ti2 (1)
2AcCN (2)+Ti2 (1)
Ti (1a)+A (4)
TiA (11)+TiCN2 (9)
2B (7)+TiOAc2 (10)
AcCN (2)+LB (6)
AcLB (3)+B (7)
TiCNTiCN (13)+A (4)
2AcLB (3)+C (14)
2Ti (1a)
TiCN2 (9)+TiOAc2 (10)
TiA (11)
$
!
$
!
$
!
!
!
!
B (7)
C (14)+2Ti2 (1)+2AcCN (2)
AcLB (3)
P (5)+TiCNTiCN (13)+LB (6)
B (7)
2P (5)+TiCN2 (9)+2LB (6)
Experimental Section
General
Glassware were oven-dried overnight before use. Solvents were
collected from a Glass Contour solvent-dispensing system. Benzal-
dehyde, 4-methoxybenzaldehyde, 3-methoxybenzaldehyde, and
triethylamine were distilled over CaH2 prior to use. 4-Cyanobenzal-
dehyde, 4-bromobenzaldehyde, 4-chlorobenzaldehyde, and 3,5-di-
chlorobenzaldehyde were recrystallized from ethanol. Recrystallized
aldehydes, Ti complex, and cinchonidine were dried over CaCl2
under vacuum prior to use. 1-Methoxynaphtalene and 4-(trifluoro-
methyl)benzaldehyde were purchased and used without further
purification. Compounds (S,S)- and (R,R)-[{(salen)Ti-(m-O)}2][11c,30] and
2[37] were prepared by following previously published procedures.
1H NMR spectra were recorded at 500 or 400 MHz and 13C NMR
spectra at 100 MHz. CD2Cl2 used in low-temperature NMR spectros-
copy studies on the evolution of product was filtered through
K2CO3 and MgSO4. Yields and enantiomeric ratios of the products
were determined by GC/flame ionization detector (FID; Agilent
6850) by using the chiral column CYCLOSIL-B (30 m, 0.25 mm,
0.12 mm) and n-undecane as an internal standard, or by HPLC (Shi-
madzu LC-10AD detector SPD-10 A) with the chiral columns CHIRA-
CEL OD-H or CHIRALPAK IC and 1-methoxynapthalene as an inter-
nal standard.
Figure 5. Modeled time evolution (1H NMR spectroscopy) of the concentra-
tions of ArCHO 4 (c), product 5 (g) and resting state 14 (b) for elec-
tron-poor (left) and -rich (right) aldehyde. In both models, the product is
formed before the resting state.
In contrast, a different mechanism involving HCN was pro-
posed by Nµjera and co-workers for the reaction of aroyl cya-
nides with aldehydes.[17] The catalyst used was prepared in situ
from the ligand and titanium tetra(isopropoxide), resulting in
liberation of isopropanol. As a consequence, HCN and isopro-
pyl benzoate were detected in the reaction mixture. The initial
formation of cyanohydrin was consistent with the presence of
HCN in the reaction mixture. The role of the tertiary amine was
suggested to be that of a Brønsted base, thus generating free
cyanide ions. This mechanism is not compatible with the re-
sults presented herein, and thus cannot be valid under our
conditions. Additional evidence against a mechanism involving
HCN is the lack of incorporation of 13C-labeled HCN into the
product.[19,36] HCN has also been ruled out as a reagent in the
acetylcyanation of aldehydes by KCN and acetic anhydride cat-
alyzed by 1.[11a] Our results also show that 2 does not serve as
General procedure for the kinetic experiments
4-Methoxybenzaldehyde (58 mL, 0.48 mmol, 1 equiv) was added to
a
solution consisting of (S,S)-[{(salen)Ti-(m-O)}2] (14.6 mg,
0.0120 mmol 0.025 equiv), triethylamine (3.3 mL, 0.024 mmol
0.05 equiv), and n-undecane (10 mL as an internal standard) in di-
chloromethane (2 mL). The vial was closed with an aluminum cap
with a septum. The reaction mixture was cooled to À408C for 2 h
before cold 2 (68 mL, 0.96 mmol, 2 equiv) was added. Samples
were taken every 3 min during 1.5 h and analyzed by GC/FID.
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The same experimental procedure was followed for experiments
with a different addition order, except that the last component
was varied (aldehyde/triethylamine/2).
General procedure for experiments combining enantiopure
LA and chiral LB
The reactions were performed as described above by using a cata-
lyst prepared from (R,R)-[{(salen)Ti-(m-O)}2] (14.6 mg, 0.0120 mmol,
0.05 equiv) and cinchonidine (7.0 mg, 0.024 mmol, 0.1 equiv).
General procedure for experiments combining racemic LA
and chiral LB
General procedure for competitive Hammett correlation ex-
periments
The reactions were performed as described above by using a cata-
Variation of the aldehyde: The experiments were performed in
lyst prepared from (R,R)-[{(salen)Ti-(m-O)}2] (7.3 mg, 0.0060 mmol,
a
glove box. (S,S)-[{(salen)Ti-(m-O)}2] (6.0 mg, 0.0049 mmol,
0.025 equiv),
(S,S)-[{(salen)Ti-(m-O)}2]
(7.3 mg,
0.0060 mmol,
0.05 equiv) was dissolved in dichloromethane (0.5 mL). Compound
4a (10 mL, 0.098 mmol, 1 equiv) and the competing aldehyde
(0.098 mmol, 1 equiv) were added to the solution followed by trie-
thylamine (1.4 mL, 0.0099 mmol, 0.1 equiv). The reaction mixture
was cooled to À358C for 60 min before cold 2 (3.4 mL, 0.049 mmol,
0.5 equiv) was added. The reaction mixture was kept at that tem-
perature for 18 h before the reaction was quenched by filtering
the cold reaction mixture through silica, followed by elution with
diethyl ether. After evaporation of the solvents, the crude mixture
0.025 equiv), and cinchonidine (7.0 mg, 0.024 mmol, 0.1 equiv).
Low-temperature NMR spectroscopy studies
(S,S)-[{(salen)Ti-(m-O)}2] (6.0 mg, 0.0049 mmol, 0.05 equiv) was dis-
solved in CD2Cl2 (0.5 mL) and cooled to À408C for 2 h. The alde-
hyde (0.10 mmol, 1 equiv), triethylamine (1.4 mL, 0.010 mmol,
0.1 equiv), 1-methoxynapthalene (10 mL, used as an internal stan-
dard), and 2 (14 mL, 0.20 mmol, 2 equiv) were added at À788C.
1H NMR spectra were recorded every 13 min at À408C (see the
Supporting Information).
1
was analyzed by H NMR spectroscopy. The relative rates of the re-
actions were determined as the ratio of products formed. When
possible, the ee value of the products in the crude mixture was de-
termined by chiral GC (see the Supporting Information).
Numerical modeling
Variation of the aroyl cyanide: The experiments were performed
Numerical modeling was performed by using the COPASI (a com-
plex pathway simulator)[38] 4.15 program. All rate laws were as-
sumed to follow the law of mass action.
in
a glove box. (S,S)-[{(salen)Ti-(m-O)}2] (6.0 mg, 0.0049 mmol,
0.05 equiv) was dissolved in dichloromethane (0.2 mL) in a small
vial. Compound 4a (5 mL, 0.05 mmol, 0.5 equiv) and triethylamine
(1.4 mL, 0.0099 mmol, 0.1 equiv) were added and the solution was
cooled to À358C for 60 min. A precooled mixture of benzoyl cya-
nide (13 mg, 0.1 mmol, 1 equiv) and the competing aroyl cyanide
(0.1 mmol, 1 equiv) in dichloromethane (0.3 mL) was added to the
reaction vial. The reaction mixtures were kept at À358C for 18 h.
The reaction was quenched by filtering the cold reaction mixture
through a short silica plug followed by elution with diethyl ether.
The organic mixture was washed twice with an aqueous solution
of NaHCO3 to remove the excess aryl acids formed. The two
phases were separated and the organic phase was dried over
MgSO4, filtered, and concentrated under vacuum. The crude mix-
ture was analyzed by 1H NMR spectroscopy. The relative rates of
the reactions were determined as the ratio of products formed.
Acknowledgements
This work was financed by the Swedish Research Council
(grant 621-2012-3391) and by the Wenner-Gren Foundations.
We are grateful to Dr. Zoltµn Szabó, Department of Chemistry,
KTH, for skillful help with NMR spectroscopy and to Professor
Anny Jutand, ENS, Paris, and Professor Mal Penhoat, Univer-
sitØ de Lille, for valuable discussions.
Keywords: asymmetric catalysis · Lewis acids · Lewis bases ·
reaction mechanisms · titanium
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Published online on November 23, 2015
Chem. Eur. J. 2016, 22, 3821 – 3829
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