Cooperative thiourea-Bronsted acid organocatalysis: Enantioselective cyanosilylation of aldehydes with TMSCN

Article abstract of DOI:10.1021/jo201864e

We report a new thiourea - Bronsted acid cooperative catalytic system for the enantioselective cyanosilylation of aldehydes with yields up to 90% and enantioselectivities up to 88%. The addition of an achiral acid was found to be crucial for high asymmetric induction. Mechanistic investigations using a combination of NMR, ESI-MS, and density functional theory computations (including solvent corrections) at the M06/6-31G(d,p) level of theory suggest that the key catalytic species results from the cooperative interaction of bifunctional thioureas and an achiral acid that form well-defined chiral hydrogen-bonding environments.

Full text of DOI:10.1021/jo201864e

Article
pubs.acs.org/joc
Cooperative Thiourea−Brønsted Acid Organocatalysis:
Enantioselective Cyanosilylation of Aldehydes with TMSCN
Zhiguo Zhang, Katharina M. Lippert, Heike Hausmann, Mike Kotke, and Peter R. Schreiner*
Institute of Organic Chemistry, Justus-Liebig University, Heinrich-Buff-Ring 58, 35392 Giessen, Germany
S
* Supporting Information
ABSTRACT: We report a new thiourea−Brønsted acid cooperative catalytic system for
the enantioselective cyanosilylation of aldehydes with yields up to 90% and
enantioselectivities up to 88%. The addition of an achiral acid was found to be crucial
for high asymmetric induction. Mechanistic investigations using a combination of NMR,
ESI-MS, and density functional theory computations (including solvent corrections) at
the M06/6-31G(d,p) level of theory suggest that the key catalytic species results from the
cooperative interaction of bifunctional thioureas and an achiral acid that form well-defined
chiral hydrogen-bonding environments.
mode can be applied advantageously to the enantioselective
cyanosilylation of various aldehydes.
INTRODUCTION
■
Optically active cyanohydrins are of high synthetic utility, as
they can be converted into a number of key functional groups,
including α-hydroxy acids, β-hydroxy alcohols, and other
valuable building blocks.1 The asymmetric addition of a cyanide
source to carbonyl compounds with a chiral catalyst represents
one of the most appealing approaches to enantiomerically
enriched cyanohydrins. Among others, trimethylsilyl cyanide
(TMSCN) has been the most widely used cyanide source2
since the first reports by the groups of Evans3 and Lidy,4
allowing the desired cyanohydrin to be prepared directly as the
corresponding trimethylsilyl ether.5 As a consequence, a
multitude of catalysts have been reported for the enantiose-
lective addition of TMSCN to aldehydes and ketones, including
Lewis acids, Lewis bases, peptides, and enzymes;6 however,
there are only a few organocatalytic approaches to this
asymmetric transformation.7
RESULTS AND DISCUSSION
■
Early on, we demonstrated that low-molecular-weight hydro-
gen-bonding catalysts such as 1 are highly active for a variety of
organic transformations;18,19 indeed, the 3,5-bis(trifluoro-
methyl)phenyl motif can now be found in the majority of
(thio)urea-derived organocatalysts.20 Our initial experiments
showed that 1 catalyzes the addition of TMSCN to aldehydes
under solvent-free conditions, and our catalyst design principle
builds on the bifunctional concept by combining the privileged
3,5-bis(trifluoromethyl)phenyl thiourea motif with an addi-
tional Lewis basic functionality. On the basis of these con-
siderations, we synthesized chiral thiourea derivatives 2a−g, 3a,
and 4a,b and several known thiourea catalysts 3b,c, 5, and 6
(Figure 1).
The past decade has seen an explosion of interest in the use
of thiourea derivatives as catalysts in asymmetric synthesis, in
large part due to their hydrogen-bonding interactions with
partially developing negatively charged atoms in the sub-
strates.8,9 In this context, the development of bifunctional
catalysts by incorporating a Lewis basic functionality and a
thiourea moiety in one chiral scaffold is the most active
research area and has found widespread applications.10−13
Recently, in contrast to asymmetric counteranion-directed
catalysis (ACDC) developed by the List group,14 we15 as well
as others16,17 advanced a novel mechanistic feature in which the
cooperative interaction of a hydrogen-bonding catalyst with a
Brønsted acid gives rise to improvement in terms of reactivity
and enantioselectivity. Herein, we report that this interaction
In a first set of experiments, the catalytic efficacy of the
prepared thiourea derivatives was tested for the direct addition
of TMSCN to benzaldehyde 7a (Table 1). While 1 catalyzes
this transformation with low conversion, the oxazoline
thioureas 2a−g displayunfortunatelyno catalytic activity
in the test reaction.21 Schiff base−thiourea derivatives 3a,b and
the pyrrole thiourea derivative 3c also do not promote this
transformation. Thiourea derivatives 4a,b, 5, and 6 give the
product in moderate to high conversion but with poor
enantioselectivities (Table 1, entries 1, 3, 5, and 7).
Received: September 12, 2011
Published: October 19, 2011
© 2011 American Chemical Society
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Figure 1. The 15 compounds prepared as potential catalysts for the title reaction.
Indeed, we recently documented a case where catalytic
activity of thiourea (the parent compound) itself was ascribed
in the reductive amination of aldehydes. After careful
examination, we found that thiourea is ineffective and that
catalysis was achieved through small amounts of benzoic acid
derivatives from oxidation.22 At the same time, it is clear that
two Brønsted acids indeed can operate cooperatively, so that
these effects need to be examined very carefully.15 Inspired by
the recent developments on anion recognition with (thio)urea
derivatives9,23 and cooperative Brønsted acid catalysis,15,17,24 we
added 10 mol % of benzoic acid to the reaction mixture. To our
delight, our novel imidazole-derived thiourea 4a in combination
with benzoic acid drastically improves the enantioselectivity
(Table 1, entry 2). Unexpectedly, urea catalyst 4b with or
without benzoic acid 9 gives high conversion but virtually no ee
(Table 1, entries 3 and 4), presumably owing to the propensity
for self-assembly of ureas in solution.19 The addition of benzoic
acid has little influence on the efficiency of Takemoto’s catalyst
5 and quinine-derived catalyst 6 (Table 1, entries 5−8). As a
consequence, we envisaged that the cooperative species formed
by thiourea 4a and benzoic acid is the active catalyst for the
asymmetric addition of TMSCN to benzaldehyde.
The finding that the enantioselectivity increases with the
addition of substoichiometric amounts of benzoic acid 9
encouraged us to investigate the effect of a number of acids and
alcohols on the catalytic efficiency of 4a (Table 2). In the
absence of an additive, the cyanosilylation product with freshly
distilled benzaldehyde 7a forms in high conversion but gives no
ee in the presence of 10 mol % of 4a, implying the key role of
Brønsted acid additives in the stereocontrolled cyanosilylation
addition step (Table 2, entry 1). HCN generated in situ from
TMSCN with CF3CH2OH, utilized in Jacobsen’s tertiary
amine−thiourea promoted cyanosilylation of ketones, gives
rise to comparable conversion but a nearly racemic product
(Table 2, entry 3).12
Substituted benzoic acid derivatives give the cyanosilylation
products with comparable conversions but slightly inferior
enantioselectivities (Table 2, entries 5−9 and 12), with the
exception of p-methoxybenzoic acid and 3,5-dichlorobenzoic
acid, owing to their poor solubility in toluene (Table 2, entries
10 and 11). Some other Brønsted acids led to significant
decreases in enantioselectivities, suggesting that aqueous acidity
(pKa) may be limited to a specific range (in this case around 4),
which agrees with our previous observations (Table 2, entries
13−18).15 Chiral acids as cocatalysts do not improve the ee
Table 1. Catalyst Screening in the Asymmetric Addition of
a
TMSCN to Freshly Distilled Benzaldehyde
b
c
entry
cat.
cocat. (amt (mol %))
conversn (%)
ee (%)
1
2
3
4
5
6
7
8
4a
4a
4b
4b
5
92
98
96
97
81
89
47
54
0
74
0
benzoic acid (10)
benzoic acid (10)
benzoic acid (10)
benzoic acid (10)
3
30
30
5
d
6
−32
−33
d
6
a
Under an argon atmosphere, the reaction was carried out on 0.2
mmol scale with 10 mol % catalyst in 1 mL of anhydrous toluene and
b
with 1.5 equiv of TMSCN. Determined by GC using n-dodecane as
c
d
internal standard. Determined by chiral GC analysis. The minus
indicates opposite enantioselectivity relative to that of the product with
catalyst 4a.
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Table 2. Acid Screening in the Asymmetric Addition of
TMSCN to Benzaldehyde with 4a
Table 3. Solvent, Concentration, Temperature and Catalyst
Loading Effects for the Test Reaction
a
a
b
c
entry
1
7a (M)
solvent
C
(%)
98
ee (%)
b
c
entry
cocat. (10 mol %)
PhCOOH
pKa
C
(%)
ee (%)
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.2
0.1
0.04
0.4
1.0
toluene
toluene
toluene
CH2Cl2
CHCl3
THF
74
43
54
0
d
1
92
98
85
76
95
87
93
90
96
84
86
90
96
56
94
94
96
54
0
74
−9
−4
71
69
68
71
72
22
54
62
52
57
15
36
38
−6
49
73
67
68
73
2
2
87
93
30
36
90
87
96
92
73
90
89
91
98
e
2
4.2
11.4
15.5
n.a.
3.8
3
3
CF3CH2OH
4
4
MeOH
5
0
5
p-t-Bu-PhCOOH
m-Cl-PhCOOH
p-Me-PhCOOH
p-n-octyl-PhCOOH
m-Br-PhCOOH
p-OMe-PhCOOH
3,5-Cl2PhCOOH
2,6-Me2PhCOOH
p-NO2-PhOH
6
0
6
7
Et2O
57
65
0
7
n.a.
n.a.
4.0
8
xylenes
8
9
chlorobenzene
cyclopentyl methyl ether
toluene
9
10
11
12
13
14
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
4.5
71
72
57
23
n.a.
3.25
7.1
toluene
toluene
toluene
a
PhCOCOOH
4.2
Under an Ar atmosphere on a 0.2 mmol scale with 10 mol % of 4a,
b
PhCH2COOH
CH3COOH
4.3
10 mol % of 9, and 1.5 equiv of TMSCN. Determined by GC using
c
4.8
n-dodecane as internal standard. Determined by chiral GC analysis.
d
e
At −50 °C. With 5 mol % of 4a and benzoic acid 9.
(CH3)3COOH
CF3COOH
n.a.
−0.3
3.5
Performing the reaction in THF led to racemic product,
suggesting that nonpolar solvents are critical for the formation
of hydrogen-bonded complexes (Table 3, entry 6). Chlorinated
solvents generally give lower conversions and no enantiose-
lectivities, in agreement with the observation of ion pair
formation via thiourea−chloride anion binding observed by the
Jacobsen group (Table 3, entries 4, 5, and 9).25 The potential
binding with partially negatively charged chloride in chlorinated
solvents might compete with the formation of a thiourea−
benzoic acid complex, leading to poor results. Lowering the
temperature reduces the reaction rate but does not increase the
ee (Table 3, entry 2). A reduction of the catalyst loadings
results in a decrease of ee values (Table 3, entry 3). While
reactions run at lower concentrations give comparable
conversions and enantioselectivities, higher concentrations
lead to inferior results (Table 3, entries 11−14).
aspirin
100
vitamin C
4.2
100
84
Boc-L-Pro-OH
Boc-L-Phe-OH
Boc-L-Val-OH
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
n.a.
3.4
93
100
100
100
89
Boc-L-Cha-OH
Boc-D-Asp(OBzl)-OH
(R)-Mosher’s acid
(S)-Mosher’s acid
(R)-mandelic acid
(S)-mandelic acid
O-methyl-D-mandelic acid
O-methyl-L-mandelic acid
64
73
53
46
74
30
71
62
84
3.4
91
3.1
83
3.1
95
a
Under an argon atmosphere, the reactions were carried out on a 0.2
mmol scale with 10 mol % of catalyst 4a and cocatalyst (10 mol %) in
1 mL of anhydrous toluene, with 1.5 equiv of TMSCN. Determined
by GC using n-dodecane as internal standard. Determined by chiral
b
c
Using 10 mol % of 4a and 10 mol % of benzoic acid 9 as the
cooperative catalyst pair, a wide range of aldehydes was
investigated in toluene at −30 °C (Table 4). Benzaldehydes
bearing either electron-donating or -withdrawing substituents at
ortho, meta, and para positions are well tolerated, giving the
corresponding cyanohydrin acetates in moderate to good yields.
Benzaldehydes with electron-donating substituents at the para
position react much more slowly than benzaldehydes bearing
electron-withdrawing groups (Table 4, entries 6 and 13).
Generally, substituents at the para position of benzaldehyde
give higher enantioselectivities (Table 4, entries 3, 6, 8, 10, and
13) than substituents at ortho and meta positions of
benzaldehyde, probably due to steric hindrance (Table 4,
entries 2, 4, 5, 7, and 9). The substrate scope was further
extended to α,β-unsaturated aldehyde and aliphatic aldehydes,
affording the corresponding products in good yields (Table 4,
entries 14−16). However, aliphatic aldehydes give poor
enantioselectivities, which strongly suggests that π−π stacking
interactions between the aromatic aldehydes and 4a are
important in the enantiodifferentiating step (Table 4, entries
15 and 16).
GC analysis.
values (Table 2, entries 21−31), but there are noticeable
matching and mismatching effects: the addition of (R)-
Mosher’s acid, (S)-mandelic acid, and O-methyl-L-mandelic
acid exhibited results superior to those of their enantiomers for
the 4a-catalyzed cyanosilylation product in terms of reactivities
and enantioselectivities (Table 2, entries 26−31). Interestingly,
vitamin C is also a good cocatalyst, giving the product with
quantitative conversion and good enantioselectivity (Table 2,
entry 20). These studies established the necessity of adding a
Brønsted acid for obtaining significant enantioselectivity. In
view of the efficiency, cost, and adaptability of the Brønsted
acids, we chose benzoic acid as the ideal cocatalyst.
We next examined the influence of solvents, temperature,
concentrations, and catalyst loadings on the reaction in the
presence of 4a as the catalyst and benzoic acid 9 as the
cocatalyst (Table 3). The reaction in toluene gives the best
result in terms of conversion and ee (Table 3, entry 1); as
expected, the reaction in xylenes is similar (Table 3, entry 8).
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entry 3). To devise a plausible mechanism, we then focused on
mechanistic investigations by means of NMR and ESI-MS, as
well as computations.
Table 4. Asymmetric Cyanosilylation of Aldehydes Catalyzed
by Thiourea 4a
a
NMR Studies of the Binary Bifunctional Thiourea Catalyst/
Benzoic Acid Complex. To establish the presence of a
hydrogen-bonded complex of catalyst 4a and benzoic acid,
1H NMR, 2D NMR, NOESY, ROESY, and H DOSY spectra
1
b
c
entry
aldehyde
benzaldehyde (7a)
yield (%)
ee (%)
were measured. Initial NMR studies in d6-benzene on the
association of catalyst 4a and benzoic acid 9 through hydrogen
bonding did not provide insights into the structure of the
1
2
3
4
5
73
74
80
69
72
57
83
79
66
78
87
80
88
67
90
72
73
46
84
8
3-methylbenzaldehyde (7b)
4-methylbenzadehyde (7c)
2-methoxybenzaldehyde (7d)
3-methoxybenzaldehyde (7e)
4-methoxybenzaldehyde (7f)
2-fluorobenzaldehyde (7g)
4-fluorobenzaldehyde (7h)
3-chlorobenzaldehyde (7i)
4-bromobenzaldehyde (7j)
4-(trifluoromethyl)benzaldehyde (7k)
4-acetoxybenzaldehyde (7l)
4-(allyloxy)benzaldehyde (7m)
trans-cinnamaldehyde (7n)
cyclohexanecarboxaldehyde (7o)
octanal (7p)
1
complex, as the H NMR spectra are rather crowded in the
aromatic region and no unique interpretation was possible.
Therefore, 2,6-dimethylbenzoic acid (11) was chosen as an
alternative acid, providing the methyl group signal as a unique
reporter.27 The low-field shifts of the NH protons by the
addition of 11 clearly show the presence of the H-bonding
complexation of 4a with 11. Further evidence for the
58
68
42
82
65
85
82
77
83
88
18
51
d
6
7
8
9
1
10
11
12
interaction of 4a with 11 was provided by H NMR titration
studies, in which various ratios of 4a to 11 in d6-benzene
resulted in interpretable chemical shift changes for the two
different NH signals (shown in Figure 2 as dark and light blue
at Δδ 0.48 and 0.95 ppm, respectively). Additionally, the ortho
proton (gray) of the catalyst and one of the imidazole’s methine
protons (red) shift downfield, while the second imidazole
methine proton (light green) shifts upfield. The strong
dependence of the chemical shifts on increasing the amount
of acid confirms the strong interaction of 11 and 4a.
To elucidate the detailed geometric arrangement of the
components in the complex, we next measured NOE effects
with 2D NMR NOESY and ROESY experiments in d6-benzene.
Unfortunately, all cross signals have the same sign as the
diagonal signals, and negative NOEs indicate slowly tumbling
molecules (see the Supporting Information). To avoid
undesirable overlaps in the aromatic region arising from d6-
benzene, CD2Cl2 was chosen as the solvent. To our delight, all
the proton signals of 4a and 11 were sufficiently well separated
so that all ROESY cross-peaks could be assigned unambigu-
ously and an intermolecular NOE contact from the methyl
group at 2.23 ppm can be seen for the aromatic ortho H's at
8.14 ppm (Figure 3). This is further corroborated by the NOE
e
13
f
14
15
16
a
Under an argon atmosphere, the reactions were carried out on a
0.2 mmol scale in the presence of 10 mol % of 4a and 10 mol %
of benzoic acid with 1.5 equiv of TMSCN in anhydrous toluene at
−30 °C for 16 h, unless otherwise stated. Yield of isolated product
after the conversion to cyanohydrin acetate. Determined by chiral GC
or chiral HPLC analysis for the corresponding acetate. Reaction time
b
c
d
e
f
60 h. Reaction time 60 h. Reaction time 48 h.
Mechanistic Considerations. Jacobsen et al. has proposed
a pathway for tertiary amine−thiourea promoted cyanosilylation
of ketones and aldehydes, in which the tertiary amine activates in
situ generated HCN toward the addition of thiourea-bound
ketones or aldehydes.26 In our reaction system, the addition of
CF3CH2OH gives rise to comparable conversion but a nearly
racemic product, suggesting the different roles that 9 and
CF3CH2OH play in thiourea-catalyzed cyanosilylations (Table 2,
1
Figure 2. H NMR spectra of thiourea catalyst 4a and 2,6-dimethylbenzoic acid 11 in various ratios.
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Figure 3. Section of the H 2D ROESY spectrum for 4a and 2,6-dimethylbenzoic acid (1:1 mixture of 4a (0.01 mmol) and 11 (0.01 mmol) in
CD2Cl2), showing the cross peaks arising from the interactions between the CH3 groups of 11 with the catalyst.
of the methyl group with the NH (light blue) at 9.16 ppm and
the imidazole protons at 7.87 and 6.51 ppm. Since the signal of
the methyl group further displays an NOE contact to the
aromatic phenyl ring protons at 7.34 ppm, the phenyl ring of 4a
and 11 must be also in close proximity.
intermolecular hydrogen bond with the carbonyl oxygen of 11,
and the proposed complex structure is depicted in Figure 4.
There is no signal for a third NH function, confirming that 11
is not deprotonated.
The NH proton adjacent to the cyclohexyl ring is a singlet
through the coupling with 14N, which has a spin of 1. The
relative amount of 15N is too low (<0.4%) to split the NH
signal (light blue). For further support of our proposed
complex structure in Figure 4 through a hydrogen-bonded
complex with the acid-protonated function, we measured
To explore the roles of the two thiourea NH protons in the
1
complex, a H, 15N HSQC experiment in CD2Cl2 was carried
out (Figure 4). The NH signal at δ(15N) −253.5 ppm (dark
1
1D and 2D NOESY NMR and H, 15N HSQC spectra of
N-methylimidazole with an excess of 11. The secondary
nitrogen of the N-methylimidazole ring is not protonated
(see the Supporting Information).
The interaction between 4a and 11 can also be derived from
the 1H DOSY spectrum (Figure 5). The presence of the
hydrogen-bonded complex was followed by concomitant
changes observed in the diffusion coefficient D of 11 as it
changes from D = 4.92 × 10−10 m2 s−1 in the free state to D =
4.32 × 10−10 m2 s−1 after the addition of the bifunctional
catalyst. The changes of D are affected through the complex-
ation of the 4a with 11 through hydrogen bonding. Structure
11 diffuses more slowly, owing to its effectively larger solvated
radius upon complexation with 4a.
ESI/MS-Studies of the Binary Bifunctional Thiourea
Catalyst/Benzoic Acid Complex. The proposed chiral struc-
ture ensuing from complexation of 4a and 9 was further
confirmed by means of mass spectrometry (MS). The ESI-MS
spectrum in negative mode shows the presence of [4a +
PhCOO]− at m/z 633.18, which is consistent with its isotopic
pattern (for details see the Supporting Information).
Computational Studies of the Binary Bifunctional
Thiourea Catalyst/Benzoic Acid Complex. First we searched
for the energetically favored conformers of 4a; the results are
summarized in the Supporting Information. When ΔG298 values
are compared, 4a_4 is favored in the gas phase but the energy
differences are small. The PCM model28 computations in
benzene differ somewhat from those in the gas phase: while
Figure 4. Section of the 1H, 15N HSQC spectrum in CD2Cl2 for 4a and
11 (1:1 at 0.01 mmol), showing the NH signals, especially the one NH
signal arising from the interaction between the NH protons and of 11.
blue) appears as a weak cross peak in the correlation spectrum,
due to the broad NH proton signal. The NH signal at δ(15N)
−251.0 ppm (light blue) appears as an intense peak, indicating
that the exchange of this NH proton slowed down due to an
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Figure 5. H DOSY NMR of (left) 11 (0.01 mmol in d6-benzene) and (right) 11 + 4a (equimolar mixture of 0.01 mmol of each component in
d6-benzene).
Figure 6. Lowest lying conformer of 4a at the M06/6-31G(d,p) level, including solvent inclusion via SCRF (benzene) according to relative ΔG298
.
4a_4 is the lowest-lying structure at 0 K, inclusion of entropy
and thermal effects at higher temperatures eventually favor
4a_1 (Figure 6). However, the relative energy differences are
only within ca. 1.0 kcal mol−1. It is clear that no single structure
can be identified as the most favorable minimum structure and
the uncomplexed thiourea catalyst is conformationally flexible.
Equally it is currently entirely unfeasible to optimize transition
structures for such a large and highly flexible system. A
simplified model system would not take into account the fine
yet important details of the manifold weak interactions.
Figure 7 shows a selection of two low-lying complexes of 4a
with 9. Both complexes include hydrogen bonding due to a
N−H···OC interaction of the thiourea with the acid and an
additional interaction of the benzoic acid proton with the
nitrogen of the imidazole ring. The conformation of 4a in
complex 4a·9_7 displays a Z,Z orientation of the thiourea NH
bond and offers double hydrogen bonding. Additionally, the
acidified ortho protons of the 3,5-bis(trifluoromethyl)phenyl
groups coordinate to the acid. The presence of three
complexation sites should favor this complex. Structure
Figure 7. Lowest lying complex of 4a with 9 at M06/6-31G(d,p),
including solvent modeling at SCRF (benzene). Distances of 4a·9_7:
NH1···O1 d = 2.111 Å (2.368 Å), NH2···O1 d = 2.000 Å (2.052 Å),
Hortho···O1 d = 3.379 Å (3.459 Å), Nimidazole···OH2 d = 1.725 Å (1.744
Å). Distances of 4a·9_8: NH1···O1 d = 2.021 Å (2.220 Å),
Nimidazole···OH2 d = 1.712 Å (1.746 Å).
4a·9_8 prefers an E,Z orientation of the NH protons but
offers only one N−H···OC hydrogen bond. When the
relative energies are compared at room temperature (ΔG298
)
and at 0 K (ΔH0), the energetically preferred complex in the
gas phase and in solution is 4a·9_8 (Table 5). The dissociation
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Table 5. Overview of the Lowest Lying Conformers of 4a and Complexes 4a·9, Computed at the M06/6-31G(d,p) level in the
Gas Phase and in Solution (SCRF for Benzene)
ΔH0 (kcal mol−1
)
D0 (kcal mol−1
)
ΔG298 (kcal mol−1
)
D298 (kcal mol−1
)
4a_1
2.4 (0.7)
0.3 (−0.5)
−12.8 (−4.4)
−14.8 (−9.3)
−1.5 (−3.5)
−0.8 (−2.2)
−10.7 (−2.2)
−9.3 (−4.4)
4a _4
4a·9_7
4a·9_8
22.2 (12.7)
24.2 (17.6)
8.6 (−1.6)
7.2 (0.6)
Figure 8. Lowest lying complex of catalyst 4a·9·7a_7 at the M06/6-31G(d,p) level and solvent model SCRF (benzene) according to relative D0 and
ΔG298. Distances: NH1···O1 d = 2.044 Å (2.420 Å), NH2···O3C d = 2.080 Å (2.167 Å), Nimidazole···H−O2 d = 1.708 Å (1.743 Å), Hortho···phenyl
ring d = 2.626 Å (2.585 Å).
energies (D298) underline the stabilities of 4a·9_7 in the gas
phase and 4a·9_8 in solution. Both NMR and computational
studies favor the presence of 4a·9_8 in solution at room
temperature. Analogous computations were performed with
2,6-dimethylbenzoic acid 11 (see the Supporting Information);
the results are comparable.
CONCLUSIONS
■
We have developed the enantioselective addition of TMSCN to
aldehydes promoted by a cooperative catalyst system comprised
of the novel chiral bifunctional imidazole−thiourea catalyst 4a
and benzoic acid as the cocatalyst. A range of optically active
cyanohydrin acetates were obtained in good yields. Aromatic
aldehydes generally gave good enantioselectivities with this
protocol. Mechanistic investigations using a combination of
NMR and ESI-MS techniques reveal the presence of a
hydrogen-bonded complex of thiourea 4a with benzoic acid,
which is consistent with our computational studies.
The new mechanistic feature is that the key catalytic species
results from the synergistic interplay of a bifunctional thiourea
catalyst and an achiral acid that forms a well-defined chiral
hydrogen-bonding environment. The addition of an achiral acid
is critical for the conformational fixation of the flexible “free”
catalyst. The computations of the ternary complex of the
catalysts with the substrate show that one of the thiourea NH
protons interacts with the CO group of the acid while the
other binds to the CO function of benzaldehyde. Addition-
ally, there is a strong fixation of the aromatic aldehyde via a T-
shaped π−π stacking interactions of the acidified ortho proton
of the 3,5-bis(trifluoromethyl)phenyl moiety with the phenyl
ring. This interplay of hydrogen-bonding and π−π-stacking
Computational Studies of the Ternary Bifunctional Thio-
urea Catalyst/Benzoic Acid/Benzaldehyde Complex. The
computations for the ternary bifunctional thiourea−benzoic
acid−benzaldehyde complex 4a·9·7a_7 show a clear preference
for the E,Z orientation of the NH protons and for the associa-
tion depicted in Figure 8, whereby the free second thiourea NH
proton coordinates the CO bond of the benzaldehyde. This
interaction is additionally aided by a T-shaped π−π interac-
tion of the thiourea’s ortho proton to the phenyl ring of
benzaldehyde;29 this interaction increases with π electron
donors such as Cl substituents. The Si face is shielded by the
thiourea’s phenyl ring, and the Re face of this complex is
therefore preferentially attacked by TMSCN. This is consistent
with our cyanosilylation protocol, because S enantiomers are
preferred. The T-shaped stabilizing interaction is strong when
π-electron-withdrawing substituents are involved. The enantio-
selectivities for aliphatic aldehydes are low (Table 4, entries 17
and 18), because these π−π interactions are absent.30
9770
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Article
CDCl3): δ 7.24 (s, 1 H), 7.10 (s, 1 H), 5.57 (br, 2 H, NH), 4.41 (dd,
J = 9.1, 7.6, 1 H), 4.10−4.21 (m, 2 H), 1.83−1.91 (m, 1 H), 1.04 (d,
J = 6.7, 3 H), 0.97 (d, J = 6.9, 3 H). 13C NMR (100 MHz, CDCl3): δ
160.9, 148.3, 133.2, 132.9, 132.6, 132.3, 132.2, 131.9, 131.6, 131.2,
127.2, 124.5, 121.8, 115.7, 112.0, 72.8, 70.0, 32.7, 18.8, 18.4. HRMS:
m/z calcd for C14H14N2OF6 340.1010, found 340.1004. Anal. Calcd
for C14H14F6N2O (340.26): C, 49.42; H, 4.15; N, 8.23. Found: C,
49.38; H, 4.03; N, 8.56.
interactions supports the formation of a chiral complex
preferring Re facial nucleophilic attack of TMSCN.
EXPERIMENTAL SECTION
■
General Procedures for the Synthesis of Thiourea Deriva-
tives 2a−g. 2-(4,5-Dihydro-1,3-oxazol-2-yl)aniline. An oven-
dried 50 mL two-neck round-bottom flask was fitted with a magnetic
stirring bar and a reflux condenser. Under an argon atmosphere, the
flask was charged with anthranilonitrile (2.95 g, 25 mmol) and
2-aminoethanol (75 mmol), in anhydrous PhCl (40 mL), using ZnCl2
(0.51 g, 3.75 mmol) as a catalyst. The mixture was refluxed about 36 h
to give a red solution. The solvent was removed, and the crude product
was dissolved in CH2Cl2. After washing with H2O, the organic layer was
dried over Na2SO4 and the solvent was removed in vacuo. The residue
was purified by column chromatography on silica gel using hexane/
EtOAc (19/1) as eluent to yield the corresponding oxazoline.
2-[(4S)-4-Methyl-4,5-dihydro-1,3-oxazol-2-yl]aniline. This com-
pound was prepared from anthranilonitrile (2.96 g, 25.0 mmol) and
L-alaninol (5.6 g, 74.5 mmol) by the general procedure described
above. The crude product was purified by column chromatography on
silica gel using hexane/EtOAc (9/1) as eluent to yield the
1
corresponding oxazoline (2.4 g, 54.5%) as a yellow solid. H NMR
(400 MHz, CDCl3): δ 7.67 (dd, J = 7.9, 1.5, 1 H), 7.15−7.20 (m,
1 H), 6.61−6.66 (m, 2 H), 6.06 (br, 2 H, NH), 4.33−4.43 (m, 2 H),
3.78−3.82 (m, 1 H), 1.31 (d, J = 6.4, 3 H). 13C NMR (100 MHz,
CDCl3): δ 163.4, 148.4, 131.8, 129.5, 115.9, 115.5, 109.0, 72.1, 62.0,
21.6.
2-[(4S)-4-Benzyl-4,5-dihydro-1,3-oxazol-2-yl]aniline. This com-
pound was prepared from anthranilonitrile (3.0 g, 25.0 mmol) and
L-phenylalanol (11.2 g, 74.1 mmol) by the general procedure described
above. The crude product was purified by column chromatography on
silica gel using hexane/EtOAc (10/1) as eluent to yield the
corresponding oxazoline (1.5 g, 23.8%) as a white solid. IR (KBr):
2-[(4S)-4-(sec-Butyl)-4,5-dihydro-1,3-oxazol-2-yl]-3,5-bis-
(trifluoromethyl)aniline. This compound was prepared from
2-amino-4,6-bis(trifluoromethyl)benzonitrile (2.0 g, 7.87 mmol) and
L-leucinol (2.76 g, 23.61 mmol) by the general procedure described
above. The crude product was purified by column chromatography on
silica gel using hexane/EtOAc (9:1) as eluent to yield the
corresponding oxazoline (1.34 g, 48.0%) as a white solid. IR (KBr):
1
3395, 3273, 2909, 1630, 751 cm−1. H NMR (400 MHz, CDCl3): δ
7.65 (dd, J = 7.9, 1.7, 1 H), 7.17−7.32 (m, 6 H), 6.61−6.69 (m, 2 H),
6.08 (br, 2 H, NH), 4.57−4.64 (m, 1 H), 4.25−4.30 (m, 1 H), 4.01−
4.04 (m, 1 H), 3.12 (dd, J = 13.7, 6.2, 1 H), 2.75 (dd, J = 13.7, 7.9,
1 H). 13C NMR (100 MHz, CDCl3): δ 164.3, 148.9, 138.6, 132.3,
129.8, 129.4, 128.7, 126.6, 116.2, 115.9, 109.2, 70.4, 68.3, 42.4. HRMS:
m/z calcd for C16H16N2O 252.1257, found 252.1226. Anal. Calcd for
C16H16N2O (252.32): C, 76.16; H, 6.39; N, 11.10. Found: C, 76.16;
H, 6.32; N, 11.07.
3432, 3321, 3199, 2979, 1668, 874 cm−1 1H NMR (400 MHz,
.
CDCl3): δ 7.21 (s, 1 H), 7.07 (s, 1 H), 5.54 (br, 2 H, NH), 4.37−4.41
(m, 1 H), 4.26−4.32 (m, 1 H), 4.10−4.14 (m, 1 H), 1.67−1.75 (m, 1
H), 1.56−1.65 (m, 1 H), 1.20−1.30 (m, 1 H), 0.94 (t, J = 7.5, 3 H),
0.88 (d, J = 6.8, 3 H). 13C NMR (100 MHz, CDCl3): δ 160.8, 148.3,
133.2, 132.9, 132.6, 132.23, 132.19, 131.9, 131.5, 131.2, 127.2, 127.1,
124.5, 124.4, 121.8, 121.7, 119.0, 115.7, 112.0, 111.7, 71.3, 69.5, 39.0,
26.1, 14.5, 11.4. HRMS: m/z calcd for C15H16F6N2O 354.1161, found
354.1165. Anal. Calcd for C15H16F6N2O (354.30): C, 50.85; H, 4.55;
N, 7.91. Found: C, 50.90; H, 4.44; N, 7.62.
2-[(4S)-4-Isobutyl-4,5-dihydro-1,3-oxazol-2-yl]aniline. This com-
pound was prepared from anthranilonitrile (2.95 g, 25.0 mmol) and
L-isoleucinol (8.78 g, 75.0 mmol) by the general procedure described
above. The crude product was purified by column chromatography on
silica gel using hexane/EtOAc (9/1) as eluent to yield the
corresponding oxazoline (0.9 g, 16.5%) as a white solid. IR (KBr):
2-[(4S)-4-Isobutyl-4,5-dihydro-1,3-oxazol-2-yl]-3,5-bis-
(trifluoromethyl)aniline. This compound was prepared from 2-
amino-4,6-bis(trifluoromethyl)benzonitrile (2.0 g, 7.87 mmol) and L-
isoleucinol (2.76 g, 23.61 mmol) by the general procedure described
above. The crude product was purified by column chromatography on
silica gel using hexane/EtOAc (9/1) as eluent to yield the
corresponding oxazoline (1.8 g, 64.5%) as a white solid. IR (KBr):
1
3416, 3278, 2953, 1640, 746 cm−1. H NMR (400 MHz, CDCl3): δ
7.68 (dd, J = 7.9, 1.6, 1 H), 7.17−7.21 (m, 1 H), 6.63−6.70 (m, 2 H),
6.10 (br s, 2 H, NH), 4.33−4.42 (m, 2 H), 3.82−3.89 (m, 1 H), 1.80−
1.91 (m, 1 H), 1.61−1.68 (m, 1 H), 1.35−1.42 (m, 1 H), 0.98 (t, J =
4.7, 3 H). 13C NMR (100 MHz, CDCl3): δ 163.4, 148.5, 131.8, 129.5,
116.0, 115.6, 109.3, 71.4, 65.2, 45.8, 25.7, 22.9, 22.6. HRMS: m/z calcd
for C13H18N2O 218.1414, found 218.1421. Anal. Calcd for C13H18N2O
(218.30): C, 71.53; H, 8.31; N, 12.83. Found: C, 71.65; H, 8.29; N,
12.75.
1
3440, 3325, 3201, 2967, 1668, 1642, 696 cm−1. H NMR (400 MHz,
CDCl3): δ 7.22 (s, 1 H), 7.08 (s, 1 H), 5.46 (br, 2 H, NH), 4.46 (dd,
J = 9.4, 7.9, 1 H), 4.36−4.39 (m, 1 H), 3.96 (t, J = 7.9, 1 H), 1.78−
1.88 (m, 1 H), 1.66−1.72 (m, 1 H), 1.39−1.46 (m, 1 H), 0.96 (t, J =
6.9, 6 H). 13C NMR (100 MHz, CDCl3): δ 160.7, 148.2, 132.9, 132.6,
131.9, 131.5, 124.5, 124.4, 121.8, 121.7, 115.74, 115.71, 112.1, 112.0,
111.9, 72.8, 65.1, 45.4, 25.6, 22.8, 22.6. HRMS: m/z calcd for
C15H16F6N2O 354.1161, found 354.1165. Anal. Calcd for
C15H16F6N2O (354.30): C, 50.85; H, 4.55; N, 7.91. Found: C,
51.03; H, 4.48; N, 7.65.
General Procedure for Oxazoline Thiourea Formation. An
oven-dried two-neck round-bottom flask was fitted with a magnetic
stirring bar and an additional funnel. Under an argon atmosphere, the
flask was charged with 3,5-bis(trifluoromethyl)phenylisothiocyanate
(1.08 g, 4.0 mmol) and anhydrous THF (5 mL), followed by dropwise
addition of a solution of oxazoline (1.0 equiv) in anhydrous THF
(15 mL) under 0 °C. The resulting mixture was stirred overnight at
room temperature. The solvent was removed by rotary evaporation,
and the residue was purified by column chromatography on silica gel
using hexane/EtOAc (5/1) as eluent to yield the corresponding
product.
2-[(4S)-4-(sec-Butyl)-4,5-dihydro-1,3-oxazol-2-yl]aniline. This
compound was prepared from anthranilonitrile (2.95 g, 25.0 mmol)
and L-leucinol (8.78 g, 75.0 mmol) by the general procedure described
above. The crude product was purified by column chromatography on
silica gel using hexane/EtOAc (9/1) as eluent to yield the
corresponding oxazoline (2.3 g, 42.1%) as a white solid. IR (KBr):
1
3464, 3287, 2962, 1638, 749 cm−1. H NMR (400 MHz, CDCl3): δ
7.66 (dd, J = 7.8, 1.5, 1 H), 7.15−7.19 (m, 1 H), 6.61−6.67 (m, 2 H),
6.10 (br, 2 H, NH), 4.26−4.30 (m, 2 H), 4.17−4.23 (m, 1 H), 3.96−
4.00 (m, 1 H), 1.57−1.70 (m, 2 H), 1.17−1.28 (m, 1 H), 0.93 (t, J =
7.4, 3 H), 0.86 (d, J = 6.7, 3 H). 13C NMR (100 MHz, CDCl3): δ
163.4, 148.5, 131.8, 129.5, 115.9, 115.5, 109.1, 71.5, 68.3, 39.5, 26.0,
14.7, 11.4. HRMS: m/z calcd for C13H18N2O 218.1414, found
218.1421. Anal. Calcd for C13H18N2O (218.30): C, 71.53; H, 8.31; N,
12.83. Found: C, 71.07; H, 8.31; N, 12.83.
2-[(4S)-4-Isopropyl-4,5-dihydro-1,3-oxazol-2-yl]-3,5-bis-
(trifluoromethyl)aniline. This compound was prepared from
2-amino-4,6-bis(trifluoromethyl)benzonitrile (2.54 g, 10.0 mmol)
and L-valinol (3.09 g, 30.0 mmol) by the general procedure described
above. The crude product was purified by column chromatography
on silica gel using hexane/EtOAc (9/1) as eluent to yield the
corresponding oxazoline (1.5 g, 44.2%) as a white solid. IR (KBr):
3,5-Bis(trifluoromethyl)anilino-2-[(4S)-4-methyl-4,5-dihydro-1,3-
oxazol-2-yl]anilinomethanethione (2a). This compound was pre-
pared from 2-[(4S)-4-methyl-4,5-dihydro-1,3-oxazol-2-yl]aniline
(1.76 g, 10.0 mmol) and 3,5-bis(trifluoromethyl)phenylisothiocyanate
(1.0 equiv) by the general procedure described above. The crude
product was purified by column chromatography on silica gel using
3452, 3324, 3203, 2974, 1667, 698 cm−1 1H NMR (400 MHz,
.
9771
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The Journal of Organic Chemistry
Article
hexane/EtOAc (5/1) as eluent to yield 2a (2.08 g, 46.5%) as a white
purified by column chromatography on silica gel using hexane/EtOAc
solid. IR (KBr): 3198, 3042, 2976, 2898, 1639, 1618, 891, 683 cm−1
.
(5/1) as eluent to yield 2e (0.22 g, 14.8%) as a white solid. IR (KBr):
1H NMR (600 MHz, CDCl3): δ 12.96 (br, 1 H, NH), 8.94 (d, J = 8.3,
3418, 2971, 1377, 1279, 1131, 683 cm−1. H NMR (400 MHz, d6-
1
DMSO): δ 10.79 (s, 1 H, NH), 10.05 (s, 1 H, NH), 8.41 (s, 1 H), 8.26
(s, 2 H), 8.08 (s, 1 H), 7.89 (s, 1 H), 4.46−4.50 (m, 1 H), 4.14−4.18
(m, 1 H), 4.06−4.12 (m, 1 H), 1.71−1.80 (m, 1 H), 0.90 (t, J = 6.6, 3
H), 0.86 (d, J = 6.8, 3 H). 13C NMR (100 MHz, d6-DMSO): δ 180.7,
157.3, 140.9, 140.1, 130.6, 130.5, 130.3, 130.2, 130.0, 129.8, 129.7,
127.3, 124.4, 123.7, 121.7, 120.8, 117.8, 72.7, 70.6, 31.8, 18.4, 18.1.
HRMS: m/z calcd for C23H17F12N3OS 611.0895, found 611.0936.
Anal. Calcd for C23H17F12N3OS (611.45): C, 45.18; H, 2.80; N, 7.07.
Found: C, 45.33; H, 2.67; N, 6.75.
1 H), 8.69 (br, 1 H, NH), 7.86 (s, 2 H), 7.80 (dd, J = 7.9, 1.5, 1 H),
7.72 (s, 1 H), 7.49−7.52 (m, 1 H), 7.14−7.17 (m, 1 H), 4.36 (t, J =
8.8, 1 H), 3.96−4.02 (m, 1 H), 3.79 (t, J = 8.0, 1 H), 0.90 (d, J = 6.7, 3
H). 13C NMR (150 MHz, CDCl3): δ 179.0, 163.1, 139.6, 139.1, 133.1,
132.9, 132.7, 132.5, 131.7, 124.7, 123.8, 121.8, 119.4, 115.3, 72.9, 61.4,
20.9. HRMS: m/z calcd for C19H15F6N3OS 447.0834, found 447.0816.
Anal. Calcd for C19H15F6N3OS (447.40): C, 51.01; H, 3.38; N, 9.39.
Found: C, 50.80; H, 3.23; N, 9.62.
2-[(4S)-4-Benzyl-4,5-dihydro-1,3-oxazol-2-yl]anilino-3,5-bis-
(trifluoromethyl)anilinomethanethione (2b). This compound was
prepared from 2-[(4S)-4-benzyl-4,5-dihydro-1,3-oxazol-2-yl]aniline
(1.16 g, 4.6 mmol) and 3,5-bis(trifluoromethyl)phenylisothiocyanate
(1.0 equiv) by the general procedure described above. The crude
product was purified by column chromatography on silica gel using
hexane/EtOAc (5/1) as eluent to yield 2b (0.9 g, 43.0%) as a white
3,5-Bis(trifluoromethyl)anilino-2-[(4S)-4-(sec-butyl)-4,5-dihydro-
1,3-oxazol-2-yl]-3,5-bis(trifluoromethyl)anilinomethanethione
(2f). This compound was prepared from 2-[(4S)-4-(sec-butyl)-4,5-
dihydro-1,3-oxazol-2-yl]-3,5-bis(trifluoromethyl)aniline (0.77 g, 2.17
mmol) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (1.1 equiv)
by the general procedure described above. The crude product was
purified by column chromatography on silica gel using hexane/EtOAc
(5/1) as eluent to yield 2f (0.69 g, 51.0%) as a white solid. IR (KBr):
1
solid. IR (KBr): 3345, 2909, 2791, 1634, 1276, 1120, 699 cm−1. H
NMR (400 MHz, CDCl3): δ 13.03 (s, 1 H, NH), 9.06 (d, J = 8.5, 1 H,
NH), 7.83−7.87 (m, 2 H), 7.71 (s, 1 H), 7.50−7.55 (m, 1 H), 7.10−
7.32 (m, 8 H), 4.45−4.53 (m, 1 H), 4.38−4.44 (m, 1 H), 4.07−4.13
(m, 1 H), 2.75−2.81 (m, 1 H), 2.63−2.70 (m, 1 H). 13C NMR (100
MHz, CDCl3): δ 178.9, 164.0, 140.1, 137.8, 132.0, 129.4, 129.0, 128.6,
126.8, 124.6, 123.4, 121.0, 114.5, 71.1, 67.4, 41.9. HRMS: m/z calcd
for C25H19F6N3OS 523.1148, found 523.1122. Anal. Calcd for
C25H19F6N3OS (523.49): C, 57.36; H, 3.66; N, 8.03. Found: C,
57.47; H, 3.53; N, 7.98.
3,5-Bis(trifluoromethyl)anilino-2-[(4S)-4-(sec-butyl)-4,5-dihydro-
1,3-oxazol-2-yl]anilinomethanethione (2c). This compound was
prepared from 2-[(4S)-4-(sec-butyl)-4,5-dihydro-1,3-oxazol-2-yl]-
aniline (0.87 g, 4.0 mmol) and 3,5-bis(trifluoromethyl)-
phenylisothiocyanate (1.0 equiv) by the general procedure described
above. The crude product was purified by column chromatography on
silica gel using hexane/EtOAc (5/1) as eluent to yield 2c (1.08 g,
55.6%) as a white solid. IR (KBr): 3169, 2966, 1637, 1377, 1277, 682
cm−1. 1H NMR (400 MHz, CDCl3): δ 13.10 (s, 1 H, NH), 8.89 (d, J =
8.3, 1 H, NH), 8.12 (s, 1 H), 7.80−7.82 (m, 3 H), 7.66 (s, 1 H), 7.50−
7.54 (m, 1 H), 7.15−7.19 (m, 1 H), 4.24−4.29 (m, 1 H), 3.98−4.02 (t,
J = 8.3, 1 H), 3.87−3.93 (m, 1 H), 1.15−1.28 (m, 2 H), 0.84−0.97 (m,
1 H), 0.78−0.82 (m, 3 H), 0.62−0.64 (m, 3 H). 13C NMR (100 MHz,
CDCl3): δ 178.9, 163.1, 139.7, 139.4, 133.0, 132.7, 131.7, 129.3, 123.7,
123.4, 121.5, 118.8, 115.2, 70.8, 68.6, 38.8, 25.7, 14.0, 11.2. HRMS:
m/z calcd for C22H21F6N3OS 489.1304, found 489.1315. Anal. Calcd
for C22H21F6N3OS (489.48): C, 53.98; H, 4.32; N, 8.58. Found: C,
54.00; H, 4.25; N, 8.59.
1
3427, 3179, 2972, 1375, 1279, 683 cm−1. H NMR (600 MHz, d6-
DMSO): δ 10.84 (br, 1 H, NH), 10.12 (br, 1 H, NH), 8.44 (s, 1 H),
8.26 (s, 2 H), 8.10 (s, 1 H), 7.91 (s, 1 H), 4.47−4.50 (m, 1 H), 4.16−
4.23 (m, 1 H), 1.52−1.59 (m, 2 H), 1.10−1.15 (m, 1 H), 0.79−0.81
(m, 6 H). 13C NMR (150 MHz, d6-DMSO): δ 180.7, 157.3, 140.9,
140.1, 130.7, 130.6, 130.4, 130.2, 130.0, 129.9, 129.7, 127.1, 125.8,
124.0, 123.6, 123.4, 122.2, 121.8, 121.5, 120.9, 120.4, 117.8, 71.3, 70.2,
38.2, 25.2, 14.2, 11.1. HRMS: m/z calcd for C24H19F12N3OS 625.1054,
found 625.1018. Anal. Calcd for C24H19F12N3OS (625.47): C, 46.09;
H, 3.06; N, 6.72. Found: C, 46.08; H, 2.82; N, 6.70.
3,5-Bis(trifluoromethyl)anilino-2-[(4S)-4-isobutyl-4,5-dihydro-1,3-
oxazol-2-yl]-3,5-bis(trifluoromethyl)anilinomethanethione (2g). This
compound was prepared from 2-[(4S)-4-isobutyl-4,5-dihydro-1,3-
oxazol-2-yl]-3,5-bis(trifluoromethyl)aniline (1.06 g, 3.0 mmol) and
3,5-bis(trifluoromethyl)phenyl isothiocyanate (1.1 equiv) by the
general procedure described above. The crude product was purified
by column chromatography on silica gel using hexane/EtOAc (5/1) as
eluent to yield 2g (0.93 g, 42.1%) as a white solid. IR (KBr): 3428,
3177, 2972, 1375, 683 cm−1. 1H NMR (400 MHz, d6-DMSO): δ 10.71
(s, 1 H, NH), 10.03 (br, 1 H, NH), 8.35 (s, 1 H), 8.27 (s, 2 H), 8.03
(s, 1 H), 7.83 (s, 1 H), 4.50 (t, J = 8.8, 1 H), 4.30−4.38 (m, 1 H), 3.99
(t, J = 7.9, 1 H), 1.70−1.81 (m, 1 H), 1.51−1.58 (m, 1 H), 1.33−1.40
(m, 1 H), 0.83 (d, J = 6.5, 3 H), 0.86 (d, J = 6.6, 3 H). 13C NMR (100
MHz, d6-DMSO): δ 177.3, 159.1, 158.6, 156.2, 150.4, 150.2, 149.3,
141.5, 140.6, 131.3, 131.0, 130.6, 130.3, 124.9, 124.5, 124.0, 122.2,
121.8, 118.6, 118.0, 116.4, 115.2, 112.8, 107.0, 72.4, 64.8, 62.2, 60.9,
25.0, 22.7. HRMS: m/z calcd for C24H19F12N3OS 625.1054, found
625.1024. Anal. Calcd for C24H19F12N3OS (625.47): C, 46.09; H, 3.06;
N, 6.72. Found: C, 46.16; H, 2.86; N, 6.78.
3,5-Bis(trifluoromethyl)anilino-2-[(4S)-4-isobutyl-4,5-dihydro-1,3-
oxazol-2-yl]anilinomethanethione (2d). This compound was pre-
pared from 2-[(4S)-4-isobutyl-4,5-dihydro-1,3-oxazol-2-yl]aniline
(0.87 g, 4.0 mmol) and 3,5-bis(trifluoromethyl)phenylisothiocyanate
(1.0 equiv) by the general procedure described above. The crude
product was purified by column chromatography on silica gel using
hexane/EtOAc (5/1) as eluent to yield 2d (0.6 g, 30.6%) as a white
Synthesis of 2-Amino-4,6-bis(trifluoromethyl)benzonitrile.31 Under
an argon atmosphere, in a three-neck round-bottom flask equipped
with a magnetic stirbar and thermometer were added 1-nitro-3,5-
bistrifluoromethylbenzene (10.36 g, 0.04 mol), ethyl cyanoacetate
(13.84 g, 0.12 mol, 98%), anhydrous powdered KOH (2.60 g, 0.04
mol), and dry DMF (120 mL). The resulting mixture was stirred
vigorously at room temperature and then was cooled to 0 °C and
stirred for 60 min. The solvent was removed in vacuo. The residue was
mixed with 80 mL of 5% NaOH solution and refluxed for 60 min. The
reaction mixture was cooled to room temperature, and chloroform
(180 mL) was added. After separation of the organic phase, the
aqueous phase was extracted with chloroform (2 × 100 mL). The
combined organic phase was dried over Na2SO4, filtered, and
evaporated to afford the crude product as a brown solid, which was
purified by column chromatography on silica gel using chloroform as
eluent, yielding the product (4.89 g, 48.1%) as a yellow solid. IR
1
solid. IR (KBr): 3190, 2965, 2929, 1640, 1275, 682 cm−1. H NMR
(400 MHz, CDCl3): δ 13.16 (s, 1 H, NH), 8.94 (d, J = 8.4, 1 H, NH),
8.07 (s, 1 H), 7.83−7.85 (m, 3 H), 7.64−7.68 (m, 1 H), 7.50−7.54
(m, 1 H), 7.15−7.19 (m, 1 H), 4.36−4.40 (m, 1 H), 3.99−4.07 (m, 1
H), 3.83−3.87 (m, 1 H), 1.32−1.42 (m, 1 H), 1.04−1.17 (m, 2 H),
0.78−0.81 (m, 6 H). 13C NMR (100 MHz, CDCl3): δ 178.8, 163.0,
139.7, 139.3, 133.0, 131.7, 129.3, 123.7, 123.2, 121.4, 118.8, 118.76,
118.7, 115.2, 71.8, 64.6, 45.0, 25.3, 22.5, 22.3. HRMS: m/z calcd for
C22H21F6N3OS 489.1304, found 489.1327. Anal. Calcd for
C22H21F6N3OS (489.48): C, 53.98; H, 4.32; N, 8.58. Found: C,
54.15; H, 4.29; N, 8.54.
3,5-Bis(trifluoromethyl)anilino-2-[(4S)-4-isopropyl-4,5-dihydro-
1,3-oxazol-2-yl]-3,5-bis(trifluoromethyl)anilinomethanethione
(2e). This compound was prepared from 2-[(4S)-4-isopropyl-4,5-
dihydro-1,3-oxazol-2-yl]-3,5-bis(trifluoromethyl)aniline (1.02 g, 3.0
mmol) and 3,5-bis(trifluoromethyl)phenylisothiocyanate (1.0 equiv)
by the general procedure described above. The crude product was
1
(KBr): 3509, 3359, 3247, 2234, 1647, 1584 cm−1. H NMR (400
MHz, CDCl3): δ 7.26 (s, 1 H), 7.21 (s, 1 H), 5.02 (br, 2 H, NH). 13C
NMR (100 MHz, CDCl3): δ 151.6, 136.0, 135.7, 135.4, 135.0, 134.8,
134.4, 134.1, 133.8, 126.5, 126.0, 115.3, 113.3, 111.6, 94.6.
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Synthesis of Schiff Base Thiourea 3a. Preparation of
Monoammonium Salts of (R,R)-1,2-Diaminocyclohexane.32 (R,R)-
1,2-Diaminocyclohexane (810 mg, 7.1 mmol) was dissolved in ether
(25 mL). The solution was stirred vigorously while anhydrous HCl in
ether (2.35 mL, 2.9 M, 7.1 mmol, 1.0 equiv) was added dropwise over
15 min. An exothermic reaction was observed upon the addition of
the acid, and a precipitate was formed. After complete addition of the
acid, the mixture was stirred at room temperature for 10 h. The
precipitation was collected by vacuum filtration, washed with excess
ether, and dried in vacuo to give the product (900 mg, 84%) as a white
solid. 1H NMR (400 MHz, D2O): δ 2.29 (br, 2 H), 1.67 (d, J = 10.4, 2
H), 1.40 (br, 2 H), 0.96 (m, 4 H). 13C NMR (100 MHz, D2O): δ 54.5,
32.2, 24.2.
23.8. HRMS: m/z calcd for C30H37F6N3OS 601.2561, found 601.2550.
Anal. Calcd for C30H37F6N3OS (601.69): C, 59.88; H, 6.20; N, 6.98.
Found: C, 59.87; H, 6.18; N, 7.18.
The synthesis of catalysts 3b,c was carried out according to known
protocols.33
Synthesis of Thiourea Derivatives 4a,b. N,N′-Bis-
(benzylidiene)-(R,R)-1,2-diaminocyclohexane. Method 1.34 (R,R)-
1,2-Diaminocyclohexane (786 mg, 6.88 mmol) and benzaldehyde
(1.40 mL, 13.76 mmol) were dissolved in anhydrous methanol
(20 mL) and stirred under reflux for 5 h to produce a precipitate. The
reaction mixture was cooled to room temperature and the Schiff base
isolated by filtration and purified by recrystallization from a solvent
mixture of dichloromethane and hexane to give the product as white
platelike crystals (1.0 g, 50%).
1-((1R,2R)-2-Aminocyclohexyl)-3-(3,5-bis(trifluoromethyl)-
phenyl)thiourea Hydrochloride. (R,R)-1,2-Diaminohexane hydrogen
chloride (453 mg, 3.0 mmol) was dissolved in a mixture of methanol
and ethanol (50/50, v/v, 25 mL). 3,5-Bis(trifluoromethyl)phenyl
isothiocyanate (814 mg, 3.0 mmol, 1.0 equiv) was added to the
reaction mixture, and it was stirred at room temperature for 40 h. The
solvents were evaporated under reduced pressure, and the residue was
purified by column chromatography on silica gel (CH2Cl2/CH3OH
10/1−4/1) to give the corresponding product (739 mg, 71%) as a
Method 2 (Modified from Literature Procedure).35 A 500 mL,
three-necked flask equipped with a magnetic stirring bar, a reflux
condenser, and an addition funnel was charged with (R,R)-1,2-
diammoniumcyclohexane (+)-tartrate salt (7.9 g, 30.0 mmol), K2CO3
(8.3 g, 60.0 mmol), and distilled water (60 mL). The mixture was
stirred until dissolution was achieved, and then ethanol (150 mL) was
added. The resulting mixture was heated to reflux (70−80 °C), and a
solution of benzaldehyde (6.09 mL, 60 mmol) was added in a steady
stream over 30 min. The yellow mixture was stirred at reflux for 2 h
before heating was discontinued. The solution was rotary evaporated,
and the residue was suspended in dichloromethane (200 mL) and
washed with water (60 mL) and brine (60 mL). The organic phase
was dried over Na2SO4, filtered, and evaporated to give the crude
product as a yellow solid, which was further purified by
recrystallization from a solvent mixture of dichloromethane and
hexane to yield the product as yellow crystals (8.0 g, 83%).
1H NMR (400 MHz, CDCl3): δ 8.21 (s, 2H), 7.60−7.57 (m, 4H),
7.33−7.28 (m, 6H), 3.45−3.39 (m, 2H), 1.88−1.80 (m, 6H), (m, 2H),
1.52−1.48 (m, 2H). 13C NMR (100 MHz, CDCl3): δ 161.0, 136.4,
130.2, 128.4, 127.9, 73.9, 33.0, 24.6.
1
white solid. IR (KBr): 3247, 3051, 2948, 2869, 1553, 1277, 681. H
NMR (200 MHz, d6-DMSO): δ 8.93 (br, 1 H), 8.41 (s, 2 H), 7.78 (s,
1 H), 4.38 (br, 1 H), 3.06−3.18 (m, 1 H), 2.54−2.58 (m, 1 H), 1.96−
2.15 (m, 2 H), 1.75−1.78 (m, 2 H), 1.15−1.59 (m, 4 H). 13C NMR
(50 MHz, d6-DMSO): δ 180.8, 142.1, 131.0, 130.3, 130.0, 129.7,
129.0, 125.9, 121.7, 120.5, 115.9, 54.8, 53.0, 30.4, 29.3, 23.8, 23.1.
(1R,2R)-2-(E)-1-[3,5-Di-tert-butyl-2-hydroxyphenyl]-
methylideneaminocyclohexylamino-3,5-bis(trifluoromethyl)-
anilinomethanethione (3a). A 50 mL two-necked flask equipped
with a reflux condenser and an addition funnel was charged with
(R,R)-1,2-diaminohexane hydrogen chloride thiourea (168.7 mg, 0.4
mmol), K2CO3 (55.2 mg, 0.4 mmol), and distilled water (8.0 mL).
The mixture was stirred until dissolution was achieved, and then
ethanol (8.0 mL) was added. The resulting colorless solution was
heated to reflux (75−80 °C), and a solution of 3,5-di-tert-butyl-2-
hydroxybenzaldehyde in ethanol (4.0 mL) was added dropwise over
15 min. The yellow solution was stirred at reflux 2.5 h before heating
was discontinued. Distilled water (8.0 mL) was added, and the stirred
mixture was cooled to less than 5 °C under an ice bath and maintained
at that temperature overnight. The product was collected by vacuum
filtration and dried under vacuum to give 3a (168 mg, 70%) as a
yellow solid. Mp: 153 °C. IR (KBr): 3274, 2968, 2865, 1628, 1539,
1-[(1R,2R)-2-(Benzylideneamino)cyclohexyl]-4-phenylimida-
zole.36 Under an argon atmosphere, anhydrous potassium carbonate
(2.7 g, 17.0 mmol), TosMIC (1.7 g, 8.7 mmol), and (1R,2R)-
diaminocyclohexane-N,N′-dibenzylidene (2.5 g, 8.6 mmol), activated
́
molecular sieves 4 Å (5.0 g), and anhydrous acetonitrile (25 mL) were
mixed, and the mixture was stirred at 70 °C for 72 h. The brown
mixture was filtered, and the solvent was removed from the filtrate
under reduced pressure to afford a brown oil (3.1 g), which was
extracted with diethyl ether (200 mL), and the solution was then
concentrated to 20 mL and added dropwise to pentane (200 mL); a
pale yellow solid and brown oil appeared. The organic solvent was
decanted, and the crude brown oil (730 mg, 26%) was confirmed as
the corresponding product and was used without further purification
for the next step.
1
1279, 1138 cm−1. H NMR (400 MHz, CDCl3): δ 13.04 (br, 1 H,
OH), 8.45 (s, 1 H), 7.69 (s, 1 H), 7.61 (s, 1 H), 7.52 (s, 2 H), 7.39 (d,
J = 2.4, 1 H), 7.13 (d, J = 2.4, 1 H), 6.23 (br, 1 H), 3.96 (br, 1 H),
3.09−3.12 (m, 1 H), 2.26−2.28 (m, 1 H), 1.73−1.95 (m, 4 H), 1.22−
1.59 (m, 22 H). 13C NMR (100 MHz, CDCl3): δ 181.4, 167.2, 157.5,
141.0, 139.6, 136.7, 132.3, 128.2, 126.9, 126.4, 125.5, 124.1, 121.4,
119.7, 117.4, 59.1, 34.8, 34.2, 33.5, 31.7, 31.4, 29.4, 29.3, 29.1, 24.6,
(1R,2R)-2-(5-Phenyl-1H-imidazol-1-yl)cyclohexanamine.37
A
mixture of 1R-(benzylideneamino)-2R-(5-phenylimidazolyl)-
cyclohexane (730 mg, 2.2 mmol) and hydrochloric acid (15 mL,
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1 M) was stirred at 25 °C for 2 h and filtered, and the filtrate was
washed with dichloromethane (2 × 15 mL). The aqueous solution was
cooled to 5 °C, and an aqueous solution of sodium hydroxide (17 mL,
1 M) was added dropwise to pH 9−11. The resulting cloudy
precipitate was extracted with diethyl ether (2 × 15 mL), and the
combined ether layers were washed with water (15 mL), dried over
MgSO4, and filtered. Removal of the volatiles under reduced pressure
gave (1R,2R)-2-(5-phenyl-1H-imidazol-1-yl)cyclohexanamine (224 mg,
42%) as a yellow oil.
was dissolved in CH2Cl2 (1.0 mL) and converted to the acetate by
reaction with pyridine (2 equiv) and Ac2O (2 equiv) from −30 °C to
room temperature for 30 min and diluted with 1 M HCl (5.0 mL) and
ethyl acetate (10.0 mL). The organic layer was separated, and the
aqueous phase was extracted with ethyl acetate (10.0 mL). The
combined organic phase was washed with saturated NaHCO3 solution
(5.0 mL) and brine (5.0 mL), dried over Na2SO4, and evaporated to
give the crude cyanohydrin acetate, which was purified by flash column
chromatography on silica gel (n-hexane/ethyl acetate (10/1)),
affording the desired product.
1-(3,5-Bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(5-phenyl-1H-imi-
dazol-1-yl)cyclohexyl)thiourea (4a). In a 50 mL round-bottom flask,
(1R,2R)-2-(5-phenyl-1H-imidazol-1-yl)cyclohexanamine (217 mg, 0.9
mmol) was dissolved in dry THF (5.0 mL) and 3,5-bis-
(trifluoromethyl)phenyl isothiocyanate (243.9 mg, 0.9 mmol) was
added dropwise. After the reaction mixture was stirred for 48 h at
room temperature, it was concentrated and purified by flash column
chromatography on silica gel (n-hexane/ethyl acetate (1/2)), yielding
the product as a yellow solid (316 mg, 68%). Mp: 177−178 °C.
IR (KBr): 3313, 3052, 2945, 2865, 1542, 1474, 1386, 1277, 1178,
1133 cm−1. 1H NMR (400 MHz, CDCl3 + d6-DMSO): δ 9.76 (s, 1H,
NH), 8.20 (s, 2H), 8.04 (s, 1H), 7.83 (d, 1H, J = 8.6), 7.43−7.52 (m,
5H), 7.03 (s, 1H, imidazoleNCHC), 5.04 (s, 1H, NH), 4.09−4.17 (m,
2H, c‑hexCHN), 2.32 (d, 1H, J = 12.6, c‑hexCH2), 2.07 (d, 1H, J = 12.6,
c‑hexCH2), 1.81 (br, 2H, c‑hexCH2), 1.61−1.71 (m, 1H, c‑hexCH2), 1.44−
Cyano(3-methylphenyl)methyl Acetate (10b).39,40 1H NMR (400
MHz, CDCl3): δ 7.29−7.18 (m, 4H), 6.30 (s, 1H), 2.32 (s, 3H), 2.10
(s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.0, 139.3, 131.6, 131.2,
129.2, 128.5, 125.0, 116.2, 62.9, 21.3, 20.5. The enantiomeric excess
was determined to be 46% by chiral GC analysis (Chiraldex γ-TA,
100−180 °C, 2 °C/min, 11.5 psi): tR(minor) = 24.92 min, tR(major) =
26.96 min.
Cyano(p-tolyl)methyl Acetate (10c).39 1H NMR (400 MHz,
CDCl3): δ 7.41 (d, J = 8.0, 2H), 7.26 (d, J = 8.0, 2H), 6.38 (s,
1H), 2.21 (s, 3H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
169.0, 140.7, 129.9, 128.9, 127.9, 116.3, 62.8, 21.3, 20.5. The
enantiomeric excess was determined to be 84% by chiral GC analysis
(Chiraldex γ-TA, 100−180 °C, 2 °C/min, 11.5 psi): tR(minor) = 26.37
min, tR(major) = 29.34 min.
Cyano(2-methoxyphenyl)methyl Acetate (10d).39 1H NMR (400
MHz, CDCl3): δ 7.56 (dd, J = 7.6, 1.6, 1H), 7.43 (td, J = 8.0, 1.6, 1H),
7.04 (td, J = 7.6, 0.9, 1H), 6.94 (d, J = 8.3, 1H), 6.71 (s, 1H), 3.88 (s,
3H), 2.16 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.0, 156.7,
131.8, 128.8, 121.0, 119.9, 116.3, 111.1, 58.2, 55.8, 20.5. The
enantiomeric excess was determined to be 8% by chiral GC analysis
(Chiraldex γ-TA, 100−180 °C, 2 °C/min, 11.5 psi): tR(minor) = 32.62
min, tR(major) = 33.40 min.
1.55 (m, 1H, c‑hexCH2), 1.21−1.35 (m, 2H, c‑hexCH2). 13C NMR (100
MHz, CDCl3 + d6-DMSO): δ 180.1, 140.9, 135.5, 132.6, 130.6 (q,
1
2JCF = 33.3), 129.1, 128.8, 128.4, 127.9, 126.1, 122.7 (q, JCF = 272.9),
121.8, 116.2, 58.2, 55.0, 34.6, 32.1, 24.4, 24.0. Anal. Calcd for
C24H22F6N4S (512.15): C, 56.24; H, 4.33; N, 10.93. Found: C, 56.58;
H, 4.41; N, 10.72.
1-(3,5-bis(trifluoromethyl)phenyl)-3-((1R,2R)-2-(5-phenyl-1H-imi-
dazol-1-yl)cyclohexyl)urea (4b). In a 25 mL round-bottom flask,
(1R,2R)-2-(5-phenyl-1H-imidazol-1-yl)cyclohexanamine (154.0 mg,
0.64 mmol) was dissolved in dry THF (5.0 mL) and 3,5-
bis(trifluoromethyl)phenyl isocyanate (179.5 mg, 0.70 mmol) was
added dropwise. After the reaction mixture was stirred overnight, it
was concentrated and purified by flash column chromatography on
silica gel (ethyl acetate as eluent), yielding the product as a pale yellow
solid (195 mg, 61%). Mp: 133−134 °C.
Cyano(3-methoxyphenyl)methyl Acetate (10e).39,40 1H NMR
(400 MHz, CDCl3): δ 7.36 (t, J = 8.0, 1H), 7.09 (d, J = 7.8, 1H),
7.02−7.04 (m, 1H), 7.00−6.97 (m, 1H), 6.38 (s, 1H), 3.84 (s, 3H),
2.17 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 168.9, 160.1, 133.0,
130.4, 120.0, 116.1, 116.0, 113.2, 62.7, 55.4, 20.5. The enantiomeric
excess was determined to be 58% by chiral GC analysis (Chiraldex γ-
TA, 100−180 °C, 2 °C/min, 11.5 psi): tR(minor) = 32.85 min,
tR(major) = 34.35 min.
IR (KBr): 3357, 3082, 2942, 2864, 1708, 1564, 1475, 1389, 1278,
1130 cm−1. 1H NMR (400 MHz, CDCl3): δ 9.06 (s, 1H, NH), 7.75 (s,
2H), 7.67 (s, 1H), 7.41−7.30 (m, 6H), 6.86 (s, 1H, imidazoleNCHC),
6.45 (d, J = 7.1, 1H), 4.24−4.29 (m, 1H, c‑hexCHN), 3.71−3.73 (m,
1H, c‑hexCHN), 3.06 (br, 2H), 2.15−2.04 (m, 2H, c‑hexCH2), 1.74−1.76
(m, 3H, c‑hexCH2), 1.49−1.58 (m, 1H, c‑hexCH2). 13C NMR (100 MHz,
Cyano(4-methoxyphenyl)methyl Acetate (10f).39,41 1H NMR
(400 MHz, CDCl3): δ 7.53−7.56 (m, 2H), 7.17−7.20 (m, 2H),
6.35 (s, 1H), 3.76 (s, 3H), 2.14 (s, 3H). 13C NMR (100 MHz,
CDCl3): δ 169.0, 161.2, 129.7, 123.8, 116.4, 114.6, 62.6, 55.4, 20.6.
The enantiomeric excess was determined to be 68% by chiral GC
analysis (Chiraldex γ-TA, 100−180 °C, 2 °C/min, 11.5 psi): tR(minor)
= 35.75 min, tR(major) = 38.05 min.
2
CDCl3): δ 171.2, 154.7, 141.4, 135.7, 134.6, 131.8 (q, JCF = 33.0),
1
129.7, 129.0, 128.9, 128.8, 125.6, 123.2 (q, JCF = 272.9), 117.7, 114.8,
Cyano(2-fluorophenyl)methyl Acetate (10g).42 1H NMR (400
MHz, CDCl3): δ 7.62−7.66 (m, 2H), 7.50−7.45 (m, 1H), 7.28−7.24
(m, 1H), 7.18−7.13 (m, 1H), 6.63 (s, 1H), 2.18 (s, 3H). 13C NMR
(100 MHz, CDCl3): δ 168.7, 160.1 (d, J = 252.1), 132.6 (d. J = 8.7),
129.6 (d, J = 2.2), 124.9 (d, J = 3.7), 119.3 (d, J = 13.3), 116.2 (d, J =
20.6), 115.3, 57.4, 20.3. HRMS: m/z calcd for C10H8FNO2 193.053 36,
found 193.055 05. The enantiomeric excess was determined to be 42%
by chiral GC analysis (Chiraldex γ-TA, 100−180 °C, 2 °C/min, 11.5
psi): tR(minor) = 23.23 min, tR(major) = 24.88 min.
77.3, 54.8, 34.4, 32.5, 25.0, 24.9. HRMS: m/z calcd for C24H22F6N4O
496.1692, found 496.1719. Anal. Calcd for C24H22F6N4O (496.17): C,
58.06; H, 4.47; N, 11.28. Found: C, 57.94; H, 4.39; N, 11.69.
Catalysts 510,38 and 613 were prepared according to published
protocols.
General Procedures for Enantioselective Aldehyde Cyano-
silylations. Under anargon atmosphere, an oven-dried 10 mL
Schlenk flask equipped with a magnetic stir bar was charged with
the aldehyde (0.2 mmol), catalyst 4a (10 mol %), acid cocatalyst 9 (10
mol %), and anhydrous toluene (1.0 mL). The flask was sealed with a
rubber septum and cooled to −30 °C. TMSCN (40.2 μL, 0.3 mmol)
was added dropwise, and the reaction progress was monitored with
GC/MS. After the indication of a complete conversion (some
substrates cannot be completely converted), the respective TMS-
protected cyanohydrins were converted in situ to the corresponding
cyanohydrin acetate products by the following procedure, which allows
convenient determination of ee values by chiral GC. The reaction
mixture was quenched with 1 M HCl (2.0 mL) and ethyl acetate (5.0
mL). After the mixture was stirred for 3 h at room temperature, the
organic phase was separated and the aqueous layer was extracted with
ethyl acetate (2 × 5.0 mL). The organic extracts were combined,
washed with brine (5.0 mL), and dried over Na2SO4. The evaporation
of the solvent afforded the corresponding crude cyanohydrin, which
Cyano(4-fluorophenyl)methyl Acetate (10h).43 1H NMR (400
MHz, CDCl3): δ 7.54−7.50 (m, 2H), 7.16−7.12 (m, 2H), 6.38 (s,
1H), 2.16 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 168.9, 163.8 (d,
J = 252.2), 130.1 (d. J = 9.0), 127.8 (d, J = 3.0), 116.4 (d, J = 22.0),
116.0, 62.2, 20.5. The enantiomeric excess was determined to be 82%
by chiral GC analysis (Chiraldex γ-TA, 100−180 °C, 2 °C/min, 11.5
psi): tR(minor) = 21.97 min, tR(major) = 26.22 min.
(3-Chlorophenyl)(cyano)methyl Acetate (10i).39,40 1H NMR (400
MHz, CDCl3): δ 7.51−7.53 (m, 1H), 7.46−7.38 (m, 3H), 6.39 (s,
1H), 2.20 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 168.8, 135.3,
133.5, 130.7, 130.6, 128.0, 126.0, 115.6, 62.1, 20.4. The enantiomeric
excess was determined to be 65% by chiral GC analysis (Chiraldex
γ-TA, 100−180 °C, 2 °C/min, 11.5 psi): tR(minor) = 29.88 min,
tR(major) = 32.56 min.
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Cyano(4-bromophenyl)methyl Acetate (10j).40 1H NMR (400
MHz, CDCl3): δ 7.58−7.61 (m, 2H), 7.38−7.39 (m, 2H), 6.36 (s,
1H), 2.17 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 168.8, 132.5,
130.8, 129.5, 124.9, 115.6, 62.2, 20.4. The enantiomeric excess was
determined to be 85% by chiral GC analysis (Chiraldex γ-TA, 100−
180 °C, 2 °C/min, 11.5 psi): tR(minor) = 36.44 min, tR(major) =
39.66 min.
of the catalyst and complexes with benzoic acid and
benzaldehyde, respectively, Cartesian coordinates, and NMR
spectra of new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Cyano[4-(trifluoromethyl)phenyl]methyl Acetate (10k).40 1H
NMR (400 MHz, CDCl3): δ 7.73 (d, J = 8.2, 2H), 7.66 (d, J = 8.2,
2H), 6.46 (s, 1H), 2.19 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
168.7, 135.5, 132.6 (q, J = 32.8), 128.3, 126.3 (q, J = 3.6), 123.5 (q, J =
272.2), 115.5, 62.1, 20.4. The enantiomeric excess was determined to
be 82% by chiral GC analysis (Chiraldex γ-TA, 100−180 °C, 2 °C/
min, 11.5 psi): tR(minor) = 22.73 min, tR(major) = 29.08 min.
Cyano(4-acetyloxyphenyl)methyl Acetate (10l). 1H NMR (400
MHz, CDCl3): δ 8.02−8.04 (m, 2H), 7.61−7.63 (m, 2H), 6.41 (s,
1H), 2.63 (s, 3H), 2.19 (s, 3H). 13C NMR (100 MHz, CDCl3): δ
169.1, 168.9, 152.1, 129.4, 129.3, 122.6, 116.0, 62.2, 21.1, 20.5. Anal.
Calcd for C12H11NO4 (233.22): C, 61.80; H, 4.75; N, 6.00. Found: C,
61.45; H, 4.64; N, 6.10. The enantiomeric excess was determined to be
77% by chiral GC analysis (Hydrodex-β-6-TBDM, 100−250 °C, 2 °C/
min, 11.5 psi): tR(minor) = 44.76 min, tR(major) = 46.63 min.
Cyano(4-allyloxyphenyl)methyl Acetate (10m). 1H NMR (400
MHz, CDCl3): δ 7.42−7.46 (m, 2H), 6.94−6.98 (m, 2H), 6.35 (s,
1H), 6.09−5.99 (m, 1H), 5.45−5.39 (m, 1H), 5.33−5.30 (m, 1H),
4.56 (m, 2H), 2.14 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 169.0,
160.2, 132.6, 129.7, 124.0, 118.1, 116.3, 115.3, 68.9, 62.6, 20.6. Anal.
Calcd for C13H13NO3 (231.25): C, 67.52; H, 5.67; N, 6.06. Found: C,
67.61; H, 5.61; N, 5.61. The enantiomeric excess was determined to be
83% by chiral GC analysis (Chiraldex γ-TA, 100−180 °C, 2 °C/min,
11.5 psi): tR(minor) = 43.71 min, tR(major) = 46.22 min.
Corresponding Author
*E-mail: prs@org.chemie.uni-giessen.de.
ACKNOWLEDGMENTS
■
Generous financial support by the Deutsche Forschungsge-
meinschaft (SPP 1179) is gratefully acknowledged. Z.Z. thanks
the Justus-Liebig University for a fellowship (Junior Science
and Teaching Units, No. 60000434). We thank Dr. Mario
́
́
Benassi and Dr. Julia Denes for MS analyses and Christian
Kleiner for the resolution of cis-/trans-1,2-diaminocyclohexane.
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