Cyanative self-condensation of aromatic aldehydes promoted by VO(O iPr)3-Lewis base as a cooperative catalyst

Article abstract of DOI:10.1039/c2ob26811f

Self-condensation of aromatic aldehydes with trimethylsilyl cyanide proceeded by the cooperative catalytic effect of VO(OⁱPr)₃ and a Lewis base to give the corresponding O-acylated cyanohydrins. The reaction conversion and selectivity were strongly dependent on the solvent used, the Lewis base, and the presence of oxygen. All the nine kinds of aromatic aldehydes considered herein afforded the O-acylated cyanohydrins with excellent selectivity under an O₂ atmosphere.

Full text of DOI:10.1039/c2ob26811f

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PAPER
Cyanative self-condensation of aromatic aldehydes promoted by
VO(OiPr)3–Lewis base as a cooperative catalyst†
Koichi Kodama, Hiroaki Kawamata, Naoya Takahashi and Takuji Hirose*
Received 15th September 2012, Accepted 16th October 2012
DOI: 10.1039/c2ob26811f
Self-condensation of aromatic aldehydes with trimethylsilyl cyanide proceeded by the cooperative
catalytic effect of VO(OiPr)3 and a Lewis base to give the corresponding O-acylated cyanohydrins. The
reaction conversion and selectivity were strongly dependent on the solvent used, the Lewis base, and the
presence of oxygen. All the nine kinds of aromatic aldehydes considered herein afforded the O-acylated
cyanohydrins with excellent selectivity under an O2 atmosphere.
Introduction
Cyanation of carbonyl compounds is one of the most important
carbon–carbon bond formation reactions in organic synthesis1
because the resulting cyanohydrins are versatile synthetic inter-
mediates that can be converted into a wide range of useful com-
Scheme 1
pounds such as α-hydroxy acids, α-hydroxy esters, β-amino
alcohols, and α-amino acids.2 Trimethylsilyl cyanide (TMSCN)
has recently been identified as a safe and easy-to-handle cyana-
tion reagent and is widely used in conjunction with Lewis acid/
synthetic targets and 2a has been synthesized by several
base catalysts.3 In particular, dual-catalysts that equip both Lewis
acid and Lewis base moieties have been reported to show excel-
lent results.4 A variety of titanium and aluminium-based metal
complexes have been developed as the Lewis acid catalysts,5 on
the other hand, there are only a few reports on the use of
vanadium-based catalysts in cyanohydrin synthesis.6 It has been
reported that vanadium compounds, which have numerous
configurations and coordination numbers resulting from the mul-
tiple oxidation states of vanadium, catalyze various organic reac-
tions by controlling the redox potential.7 Since vanadium-based
catalysts have been shown to be powerful tools in the develop-
ment of novel organic reactions, we carried out the preliminary
experiments of TMSCN addition to benzaldehyde 1a in the pres-
ence of vanadium compounds (VOCl3, VOSO4, VO(OiPr)3) and
a Lewis base (LB) as dual-functionalized catalysts. To our sur-
prise, the reaction of TMSCN with 1a in the presence of
VO(OiPr)3 and triethylamine (Et3N) afforded not only corres-
ponding cyanohydrin 3a but also O-benzoyl cyanohydrin 2a
(Scheme 1). O-Acylated cyanohydrins such as 2a are important
methods: catalytic addition reaction of benzoyl cyanide to benz-
aldehydes,8a–e catalytic addition of potassium cyanide in the
presence of benzoic anhydride,8f reductive coupling of benzoyl
cyanide9 and so on. However, to the best of our knowledge, a
catalytic self-condensation reaction that allows direct access to 2
from aldehydes 1 has never been reported. This method could be
a powerful alternative to conveniently obtain O-acylated cyano-
hydrins because structurally diverse aldehydes are commercially
available. Herein, we report the cyanative self-condensation of
aromatic aldehydes with TMSCN by the cooperative effect of
VO(OiPr)3 and a LB as a catalyst.
Results and discussion
As an initial reaction condition, aromatic aldehyde 1 was
allowed to react with 0.5 equiv. of TMSCN in the presence of
10 mol% each of VO(OiPr)3 and LB at 25 °C for 48 h. The
solvent effect on the reaction was investigated using 4-chloro-
benzaldehyde 1d and Et3N; the results are summarized in
Table 1. The conversion of the reaction was determined by the
Graduate School of Science and Engineering, Saitama University, 255,
Shimo-Okubo, Sakura-ku, Saitama, 338-8570, Japan.
E-mail: hirose@apc.saitama-u.ac.jp; Fax: +81-48-858-9548;
Tel: +81-48-858-9548
1
following equation on the basis of the H NMR spectrum of the
resultant mixture after aqueous workup:
†Electronic supplementary information (ESI) available: Copies of
1H and 13C NMR spectra of reported compounds. See DOI:
10.1039/c2ob26811f
H2 ꢀ 2 þ H3
conversion ð%Þ ¼
ꢀ 100
H1 þ H2 ꢀ 2 þ H3
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Table 1 The solvent effect on catalytic cyanoacylation of an aromatic
aldehyde 1d with TMSCN by the cooperative effect of a VO(OiPr)3–LB
mixturea
Table 3 The effect of the Lewis base on cyanoacylation of 1da
Conversionc
(%)
Product ratioc
2d : 3d
Entry
Dry solvent
Conversionb (%)
Product ratiob 2d : 3d
Entry
Lewis baseb (pKaH value)
N2
O2
N2
O2
1
2
3
4
5
6
7
CH3CN
DMF
Toluene
CH2Cl2
CHCl3
THF
82.9
80.3
71.0
72.0
64.4
68.1
77.7
70 : 30
59 : 41
40 : 60
26 : 74
26 : 74
39 : 61
40 : 60
1
2
3
4
5
6
7
8
DBU (12.5)
75.9
74.4
79.9
21.9
34.2
85.6
4.3
68.8
78.1
49.2
42.0
—
72.7
71.0
76.8
21.6
25.2
73.3
—
75.8
75.2
11.5
35.2
31.9
60.5
23 : 77
31 : 69
34 : 66
8 : 92
20 : 80
71 : 29
10 : 90
72 : 28
31 : 69
22 : 78
30 : 70
—
92 : 8
97 : 3
99 : 1
10 : 90
55 : 45
95 : 5
—
98 : 2
86 : 14
63 : 37
57 : 43
10 : 90
99 : 1d
iPr2NEt (11.4)
iPr2NH (11.1)
Et2NH (11.0)
nPr2NH (11.0)
Et3N (10.8)
Et2O
PhCH2NH2 (9.3)
DMAP (9.2)
DABCO (8.8)
2,6-Lutidine (6.8)
Pyridine (5.2)
(R)-PhCH(Me)NHMe
(R)-PhCH(Me)NMe2
a Reaction conditions: 1d (1.0 mmol), TMSCN (0.5 mmol), VO(OiPr)3
(0.1 mmol), Et3N (0.1 mmol), and dry solvent (5 mL). b Determined by
1H NMR measurement.
9
10
11
12
13
—
—
Table 2 The effects of the vanadyl complex and Lewis base on
cyanoacylation of an aromatic aldehyde 1da
a Reaction conditions: 1d (1.0 mmol), TMSCN (0.5 mmol), VO(OiPr)3
(0.1 mmol), base (0.1 mmol), and dry CH3CN (5 mL). b Figures in the
parentheses mean pKa values of the corresponding conjugated acid.
c Determined by 1H NMR measurement. d 8% ee (S) of 2d was obtained.
The ee value was determined by chiral HPLC.
VO(OiPr)3 Et3N
Entry Atmosphere (mol%) (mol%) (%)
Conversionb Product ratiob
sole product (entry 1), while the reaction hardly proceeded
without Et3N (entry 2), indicating that both VO(OiPr)3 and LB
are necessary for cyanoacylation. A combination of 10 mol%
VO(OiPr)3 and Et3N (1 : 1) afforded 2d with good selectivity
(entry 3). When the reaction was conducted under an O2 atmos-
phere, the conversion did not change, but the selectivity of 2d
increased markedly (entry 4), thus indicating that the cyanative
self-condensation of 1 was enhanced by molecular oxygen
(vide infra). However, when the amount of the catalysts was
reduced to 5 mol%, the conversion and selectivity reduced under
N2 as well as O2 atmospheres (entries 5 and 6).
2d : 3d
1
2
3
4
5
6
N2
N2
N2
O2
N2
O2
—
10
10
10
5
10
—
10
10
5
48
6
79
73
44
54
0 : 100
8 : 92
70 : 30
95 : 5
65 : 35
68 : 32
5
5
a Reaction conditions: 1d (1.0 mmol), TMSCN (0.5 mmol), and dry
CH3CN (5 mL). b Determined by 1H NMR measurement.
The influence of the LB was investigated by using a variety of
acyclic and cyclic amines and pyridine derivatives; the results
are summarized in Table 3. When the reactions were carried out
under a N2 atmosphere, the conversion was comparatively high
in the presence of strongly basic and/or bulky LBs (entries 1–3,
6, 8, 9) but low in the presence of weak and less hindered bases
(entries 10, 11). Primary and secondary amines without any
bulky substituents gave a significantly low conversion, probably
because they behaved as nucleophiles to form imines or iminium
ions with 1d, thereby becoming inactive as basic catalysts
(entries 4, 5 and 7). Surprisingly, even a subtle structural differ-
ence between the secondary amines caused a drastic change in
where H1 is the integration of the formyl proton of 1, while H2
and H3 are the integrations of the benzyl protons of 2 and 3,
respectively.
The reaction conversion and selectivity for 2d were good
when the reaction was carried out in CH3CN (entry 1), but the
selectivity was lower in DMF (entry 2), and 2d was obtained as
the minor product in other solvents. These results suggested that
cyanoacylation of 1d is accelerated in polar solvents with a high
dielectric constant. Denmark et al. have reported that the LB-cat-
alyzed addition of TMSCN to aldehydes proceeds more rapidly
in CH3CN than in CH2Cl2, toluene and THF.10 Cyanoacylation
of 1d did not proceed efficiently in THF and Et2O (entries 6 and
7), probably because these solvents strongly coordinated with
the vanadyl complex, thus preventing efficient product
conversion.
i
the results: Pr2NH gave a much higher conversion than did
n
Et2NH and Pr2NH, although the basicity is similar in the three
cases (entries 3–5). When the reactions were conducted under an
O2 atmosphere, the reaction conversions were almost unchanged
for all the LBs, which indicates that the rate-determining step of
the reaction is independent of the presence of O2.
Next, the influence of the amount of VO(OiPr)3 and Et3N was
studied under an N2 atmosphere; the results are summarized in
Table 2. Cyanation in the presence of Et3N alone gave 3d as the
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Table 4 The effect of reaction time on cyanoacylation of 1da
Table 5 Cyanoacylation of various substituted benzaldehydes (1)
using VO(OiPr)3 and DMAPa
Conversionb (%) Product ratiob,c 2 : 3
Lewis
base
Conversionb
(%)
Product ratiob
2d : 3d
Entry
Conditions
Entry Ar–
N2
O2 N2
O2
1
2
3
4
5
6
DMAP
DMAP
DMAP
iPr2NEt
iPr2NEt
iPr2NEt
N2, 24 h
N2, 48 h
N2, 72 h
O2, 24 h
O2, 48 h
O2, 72 h
57.0
68.8
74.0
61.4
71.0
80.4
76 : 24
72 : 28
75 : 25
93 : 7
97 : 3
96 : 4
1
2
3
4
5
6
7
8
9
C6H5– (1a)
69
59
60
69
61
54
58 71(45) : 29(19) 97 : 3
60 20(9) : 80(43) 98 : 2
56 40(22) : 60(32) 98 : 2
81 72(48) : 28(18) 98 : 2
68 61(35) : 39(21) 99 : 1
53 34(16) : 66(33) 93 : 7
28 18(4) : 82(25) 97 : 3
24 28(5) : 72(17) 99 : 1
28 35(9) : 65(17) 99 : 1
o-ClC6H4– (1b)
m-ClC6H4– (1c)
p-ClC6H4– (1d)
p-BrC6H4– (1e)
p-MeC6H4– (1f)
o-MeOC6H4– (1g) 34
m-MeOC6H4– (1h) 30
p-MeOC6H4– (1i) 29
a Reaction conditions: 1d (1.0 mmol), TMSCN (0.5 mmol), VO(OiPr)3
(0.1 mmol), base (0.1 mmol), and dry CH3CN (5 mL). b Determined by
1H NMR measurement.
a Reaction conditions: 1 (1.0 mmol), TMSCN (0.5 mmol), VO(OiPr)3
(0.1 mmol), DMAP (0.1 mmol), and dry CH3CN (5 mL). b Determined
by 1H NMR measurement. c Isolated yields of
2 and O-acetyl
cyanohydrins 4 are shown in the parentheses.
A similar tendency was observed for the product ratio: small
primary and secondary amines afforded 3d with high selectivity
(entries 4, 5 and 7), while high 2d selectivity was obtained when
Et3N and DMAP were used (entries 6 and 8). When the reactions
were conducted under an O2 atmosphere, cyanoacylation was
enhanced and very high selectivity for 2d was obtained when
using tertiary amines and bulky secondary amines (entries 1–3,
6, 8, 9). Toward an application to asymmetric synthesis, we
examined the possibility of an enantioselective reaction by using
chiral secondary and tertiary amines as the LB. A small degree
of chiral induction to 2d (S; 8% ee) was observed when N,N-
dimethyl-(R)-1-phenylethylamine was used (entry 13), although
no chiral induction was observed for N-methyl-(R)-1-pheny-
lethylamine (entry 12). This result is not satisfactory, however, it
shows the potential for the enantioselective synthesis of O-acy-
lated cyanohydrins by further investigation of chiral tertiary
amines as the LB.
Next, time-course studies of the reactions were conducted by
varying reaction times under N2 and O2 atmospheres (Table 4).
By increasing reaction times, the product ratio was almost
unchanged while the conversion was gradually increased both
under N2 and O2 atmospheres. This result suggests that the con-
version reaction from 3d to 2d may not take place and they are
formed via separate reaction pathways.
Fig. 1 Plausible mechanism I for cyanoacylation of 1.
Cyanoacylation of a variety of substituted benzaldehydes 1
was performed under a N2 or O2 atmosphere using DMAP as the
optimized LB catalyst (Table 5). In order to determine the iso-
lated yields of the reactions conducted under a N2 atmosphere,
acetic anhydride and pyridine were added to the mixture to deri-
vatize 3 to the corresponding O-acetyl cyanohydrins 4, and then,
2 and 4 were isolated. Benzaldehydes with an electron-withdraw-
ing group (entries 2–5) gave moderate-to-good conversions,
while those with an electron-donating group (entries 6–9) gave
poor conversions, irrespective of whether the reaction was per-
formed under a N2 or O2 atmosphere. Comparison of substrates
with similar steric demands suggested that the electrophilicity of
the carbonyl carbon of 1 affects the reaction conversion. It was
confirmed that the isolated yields of 2 and 4 were close to those
expected from the conversion and selectivity determined from
1H NMR measurement.
Next, the steric effect was studied for the positional isomers of
chloro- and methoxybenzaldehyde: under a N2 atmosphere, the
substituent position in 1 had a greater effect on the selectivity
rather than on the conversion. Highly selective cyanoacylation
was observed for unsubstituted benzaldehyde 1a, while the
selectivity for 2 gradually decreased in the order para > meta >
ortho when the substituent was brought closer to the formyl
group. In addition, an electron-donating substituent clearly
lowered the selectivity for 2 (entries 4 and 5 vs. 6 and 9). Under
an O2 atmosphere, however, cyanoacylation of all the nine sub-
strates considered proceeded selectively to afford 2.
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On the basis of the present results and the mechanisms pro-
posed previously, a plausible mechanism for the formation of 2
is proposed (mechanism I in Fig. 1).10
Conclusions
In summary, cyanative self-condensation of aromatic aldehydes
with TMSCN to afford O-acylated cyanohydrins was catalyzed
by the cooperation of VO(OiPr)3 and a Lewis base. The catalyst
system seemed to allow for acylation by the aldehyde after cya-
nation of the aromatic aldehyde. Strong and bulky Lewis bases
were effective for this reaction and O-acylated cyanohydrins
were selectively obtained in the presence of O2. Two tentative
catalytic mechanisms could be identified. To the best of our
knowledge, this is the first example of the direct cyanative self-
condensation of aromatic aldehydes. In order to further extend
the utility of this reaction, studies for selective crossed conden-
sation reactions of two different aldehydes as well as asymmetric
synthesis of O-acylated cyanohydrins are under investigation.
First, the LB reacts with TMSCN to form Me3Si–LB+·CN−
complex A, which then reacts with 1 to generate the correspond-
ing cyanohydrin alkoxide. When a bulky LB is used, this cyano-
hydrin alkoxide cannot approach Me3Si–LB+ easily and hence
interacts with VO(OiPr)3 to give complex B. The alkoxide in the
vanadium complex B reacts with another molecule of 1 to gener-
ate a hemiacetal alkoxide, which forms a coordination bond with
the vanadium reagent to afford complex C. Finally, a hydride
migrates to Me3Si–LB+ to release 2, and VO(OiPr)3 is regener-
ated. While trimethylsilane is expected to be produced, its fate is
still under investigation. Because no benzyl alcohol was
observed in our experiments, we speculated that the hydride
acceptor was not 1 but a silicide species. On the other hand, the
alkoxide can easily gain access to Me3Si–LB+ generated from a
small LB to give the silylether of cyanohydrin 5. When a
vanadium reagent is coordinated by a solvent such as THF, the
interaction with an alkoxide is weakened and Me3Si–LB+ is
expected to react to afford 5.
Experimental
Materials and general methods
All 1H and 13C NMR spectra were recorded on a 300 or a
500 MHz spectrometer and chemical shifts were recorded as δ
values in ppm downfield using tetramethylsilane as an internal
standard. IR spectra were measured using KBr pellets. Mass
spectra were recorded using electrospray ionization mass spec-
trometry. Optical rotations were measured using a polarimeter.
Enantiomeric excess determination was conducted by HPLC
analysis equipped with a Daicel Chiralcel OD-H or OD-3
column (4.6 × 250 mm) and detection at 254 nm. Melting points
were reported uncorrected. Acetonitrile, THF, toluene, hexane
and dichloromethane were dried and distilled prior to use. The
two chiral amines, N-methyl-(R)-1-phenylethylamine and N,N-
dimethyl-(R)-1-phenylethylamine, were prepared from (R)-1-
phenylethylamine according to the literature.13,14 All the other
reagents and solvents were purchased and used as received.
On the basis of mechanism I, we state that substituents located
close to the carbonyl group of 1 can hinder the coordination to VO
(OiPr)3. In ortho- and meta-substituted 1, the steric bulk around
the carbonyl group prevents the cyanohydrin alkoxide from
approaching VO(OiPr)3, thereby resulting in poor selectivity for 2.
Benzoyl cyanide, a cyanoacylation reagent, can be formed by
the oxidation of cyanohydrin alkoxide.11 In the present system,
oxidation of cyanohydrin alkoxide can be caused by the vanadyl
complex; therefore, another plausible mechanism II is presented
(Fig. 2). Accordingly, the in situ formation of acyl cyanide is
accompanied by the reduction of V(V) compounds to V(III)
species. Upon oxidation of the V(III) compound by oxygen mo-
lecules, a pentavalent vanadyl complex is regenerated, and the
catalytic cycle involves acyl cyanide.11,12 Mechanism II can
clearly explain the effect of oxygen for the higher selectivity of
2. (Both mechanisms I and II seem to be possible from our
present results and further studies are necessary to elucidate the
reaction.)
Synthesis and characterization
Typical procedure for catalytic cyanoacylation reaction. To a
solution of vanadyl triisopropoxide (24 μL, 0.1 mmol) and
Lewis base (0.1 mmol) in dry acetonitrile (5 mL) under a N2 or
O2 atmosphere, trimethylsilyl cyanide (65 μL, 0.5 mmol) and 1
(1.0 mmol) were added and the mixture was stirred at 25 °C for
2 days. The reaction mixture was quenched by 1 N HCl aq. and
acetonitrile was removed under reduced pressure. The mixture
was extracted with ethyl acetate several times and the combined
organic layer was washed with saturated NaHCO3 aq. and brine,
then dried over anhydrous Na2SO4. The solution was concen-
trated under reduced pressure to give a mixture of 1, 2 and 3.
The conversion and product ratio were determined by measure-
ment of the 1H NMR spectra of the mixture.
The mixture was dissolved in THF (3 mL) and acetic anhy-
dride (190 μL, 1.96 mmol) and pyridine (1.60 μL, 1.98 mmol)
were added, then the solution was stirred at room temperature for
a day. The reaction mixture was quenched by 1 N HCl aq. and
the solvent was removed under reduced pressure. The mixture
was extracted with ethyl acetate and the combined organic layer
was washed with saturated NaHCO3 aq. and brine, and then
dried over anhydrous Na2SO4. The solvent was removed under
Fig. 2 Plausible mechanism II for cyanoacylation of 1.
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reduced pressure and the residue was purified by silica gel PTLC
to give 2 and O-acetyl cyanohydrins (4).
ESI-MS: m/z calcd for C15H9Cl2NO2Na: 327.991, 329.988
[C15H9Cl2NO2
+
Na]+; found: 327.979, 329.982; m.p.
81.2–82.7 °C. The enantiomeric ratio of the product 2d was
determined by chiral HPLC analysis (Chiralcel OD-3, 1.0%
(v/v) 2-PrOH in hexane, 1.0 mL min−1, 254 nm UV detector).
The retention time of the two enantiomers: tr = 23.1 min for
(R)-2d and tr = 25.2 min for (S)-2d.
2-Benzoyloxy-2-phenylacetonitrile (2a).9 Compound 2a was
obtained in 45.0% yield as a colorless oil. H NMR (500 MHz,
CDCl3)/ppm: δ 8.08 (m, 2H), 7.63–7.60 (m, 3H), 7.49–7.45 (m,
5H), 6.68 (s, 1H); IR(KBr)/cm−1: 3066, 3036, 2943, 1732,
1601, 1585, 1495, 1454, 1316, 1258, 1193, 1178, 1087, 1067,
1026, 760, 712; ESI-MS: m/z calcd for C15H11NO2Na: 260.069
[C15H11NO2 + Na]+; found: 260.099.
1
2-Acetoxy-2-(4-chlorophenyl)acetonitrile (4d).6f Compound
4d was obtained in 17.5% yield as a colorless oil. 1H NMR
(500 MHz, CDCl3)/ppm: δ 7.48–7.43 (m, 4H), 6.39 (s, 1H),
2.17 (s, 3H); IR(KBr)/cm−1: 3094, 3072, 3039, 2943, 1758,
1599, 1494, 1413, 1372, 1218, 1092, 1027, 1016, 965, 822,
570; ESI-MS: m/z calcd for C10H8ClNO2Na: 232.014, 234.011
[C10H8ClNO2 + Na]+; found: 232.070, 234.075.
2-Acetoxy-2-phenylacetonitrile (4a).6f Compound 4a was
1
obtained in 18.7% yield as a colorless oil. H NMR (500 MHz,
CDCl3)/ppm: δ 7.53 (dd, J1 = 5.4 Hz, J2 = 2.2 Hz, 2H),
7.47–7.45 (m, 3H), 6.42 (s, 1H), 2.17 (s, 3H); IR(KBr)/cm−1
:
3068, 3038, 2946, 1757, 1496, 1457, 1373, 1219, 1026, 760,
698; ESI-MS: m/z calcd for C10H9NO2Na: 198.053 [C10H9NO2
+ Na]+; found: 198.108.
2-(4′-Bromobenzoyloxy)-2-(4-bromophenyl)acetonitrile (2e).
1
Compound 2e was obtained in 34.8% yield as a white solid. H
NMR (500 MHz, CDCl3)/ppm: δ 7.92–7.89 (m, 2H), 7.63–7.61
(m, 4H), 7.50–7.48 (m, 2H), 6.61 (s, 1H); 13C NMR (125 MHz,
CDCl3)/ppm: δ 163.9, 132.6, 132.2, 131.5, 130.7, 129.7, 129.6,
126.8, 125.1, 115.6, 63.0; IR(KBr)/cm−1: 3093, 3043, 2953,
2916, 1730, 1589, 1486, 1400, 1252, 1084, 1011, 751; ESI-MS:
m/z calcd for C15H9Br2NO2Na: 415.890, 417.888, 419.886
[C15H9Br2NO2 + Na]+; found: 415.883, 417.878, 419.876; m.p.
110.7–113.1 °C.
2-(2′-Chlorobenzoyloxy)-2-(2-chlorophenyl)acetonitrile (2b).9
Compound 2b was obtained in 9.4% yield as a colorless oil. H
1
NMR (500 MHz, CDCl3)/ppm: δ 7.92–7.90 (m, 1H), 7.83–7.81
(m, 1H), 7.50–7.48 (m, 3H), 7.47–7.40 (m, 2H), 7.36–7.33 (m,
1H), 6.95 (s, 1H); IR(KBr)/cm−1: 3072, 2943, 1747, 1592,
1577, 1475, 1439, 1278, 1239, 1103, 1039, 747; ESI-MS: m/z
calcd for C15H9Cl2NO2Na: 327.991, 329.988 [C15H9Cl2NO2 +
Na]+; found: 328.021, 330.004.
2-Acetoxy-2-(4-bromophenyl)acetonitrile (4e).6f Compound
4e was obtained in 21.1% yield as a colorless oil. 1H NMR
(500 MHz, CDCl3)/ppm: δ 7.61–7.58 (m, 2H), 7.41–7.39 (m,
2H), 6.37 (s, 1H), 2.17 (s, 3H); IR(KBr)/cm−1: 3090, 3068,
2943, 1757, 1593, 1490, 1410, 1371, 1217, 1073, 1026, 1012,
964, 817; ESI-MS: m/z calcd for C10H8BrNO2Na: 235.964,
277.962 [C10H8BrNO2 + Na]+; found: 276.014, 278.020.
2-Acetoxy-2-(2-chlorophenyl)acetonitrile (4b).4d Compound
4b was obtained in 43.1% yield as a colorless oil. 1H NMR
(500 MHz, CDCl3)/ppm: δ 7.76–7.75 (m, 1H), 7.51–7.47 (m,
1H), 7.47–7.41 (m, 2H), 6.74 (s, 1H), 2.23 (s, 3H); IR(KBr)/
cm−1: 3070, 2942, 1760, 1594, 1577, 1476, 1443, 1372, 1213,
1059, 1025, 967, 758; ESI-MS: m/z calcd for C10H8ClNO2Na:
232.014, 234.011 [C10H8ClNO2 + Na]+; found: 232.068,
234.071.
2-(4′-Methylbenzoyloxy)-2-(4-methylphenyl)acetonitrile (2f).9
1
2-(3′-Chlorobenzoyloxy)-2-(3-chlorophenyl)acetonitrile (2c).9b
Compound 2c was obtained in 21.6% yield as a colorless oil. 1H
NMR (500 MHz, CDCl3)/ppm: δ 8.04–8.03 (m, 1H), 7.97–7.95
(m, 1H), 7.62–7.60 (m, 2H), 7.52–7.50 (m, 1H), 7.49–7.47 (m,
1H), 7.45–7.42 (m, 2H), 6.63 (s, 1H); IR(KBr) cm−1: 3072,
2925, 2852, 1739, 1599, 1577, 1477, 1429, 1303, 1283, 1244,
1121, 1103, 1085, 1068, 789, 746; ESI-MS: m/z calcd for
C15H9Cl2NO2Na: 327.991, 329.988 [C15H9Cl2NO2 + Na]+;
found: 328.001, 329.992.
Compound 2f was obtained in 15.7% yield as a colorless oil. H
NMR (500 MHz, CD3OD)/ppm: δ 7.91 (d, J = 6.4 Hz, 2H),
7.52 (d, J = 6.4 Hz, 2H), 7.31 (d, J = 6.4 Hz, 4H), 6.71 (s, 1H),
2.41 (s, 3H), 2.38 (s, 3H); IR(KBr)/cm−1: 3034, 3007, 2951,
2925, 2862, 1731, 1612, 1514, 1311, 1257, 1178, 1085, 1020,
814, 750; ESI-MS: m/z calcd for C17H15NO2Na: 288.100
[C17H15NO2 + Na]+; found: 288.132.
2-Acetoxy-2-(4-methylphenyl)acetonitrile (4f).6f Compound
4f was obtained in 33.1% yield as a colorless oil. 1H NMR
(500 MHz, CD3OD)/ppm: δ 7.43 (d, J = 6.4 Hz, 2H), 7.23 (d, J
= 6.4 Hz, 2H), 6.48 (s, 1H), 2.38 (s, 3H), 2.14 (s, 3H); IR(KBr)/
cm−1: 3033, 2949, 2927, 2867, 1757, 1615, 1516, 1372, 1221,
1021, 964, 814; ESI-MS: m/z calcd for C11H11NO2Na: 212.069
[C11H11NO2 + Na]+; found: 212.123.
2-Acetoxy-2-(3-chlorophenyl)acetonitrile (4c).4d Compound
4c was obtained in 31.7% yield as a colorless oil. 1H NMR
(500 MHz, CDCl3)/ppm: δ 7.52 (d, J = 1.6 Hz, 1H), 7.46 (dt, J1
= 5.4 Hz, J2 = 1.6 Hz, 1H), 7.42–7.38 (m, 2H), 6.39 (s, 1H),
2.19 (s, 3H); IR(KBr)/cm−1: 3068, 2944, 1760, 1600, 1579,
1478, 1434, 1372, 1215; ESI-MS: m/z calcd for
2-(2′-Methoxybenzoyloxy)-2-(2-methoxyphenyl)acetonitrile (2g).
C10H8ClNO2Na: 232.014, 234.011 [C10H8ClNO2
found: 232.083, 234.083.
+
Na]+;
1
Compound 2g was obtained in 4.4% yield as a white solid. H
NMR (500 MHz, CDCl3)/ppm: δ 7.88–7.86 (m, 1H), 7.67–7.66
(m, 1H), 7.54–7.51 (m, 1H), 7.44–7.40 (m, 1H), 7.06–7.03 (m,
1H), 7.01–6.97 (m, 2H), 6.96–6.95 (m, 1H), 6.93 (s, 1H), 3.92
(s, 3H), 3.90 (s, 3H); 13C NMR (125 MHz, CDCl3)/ppm: δ
163.7, 160.0, 156.8, 134.7, 132.3, 131.5, 128.6, 120.9, 120.5,
120.2, 117.8, 116.5, 112.2, 111.0, 58.4, 56.0, 55.8; IR(KBr)/
cm−1: 3078, 3012, 2975, 2946, 2843, 1741, 1712, 1601, 1581,
2-(4′-Chlorobenzoyloxy)-2-(4-chlorophenyl)acetonitrile (2d).9
Compound 2d was obtained in 47.5% yield as a white solid. H
NMR (500 MHz, CDCl3)/ppm: δ 7.99 (d, J = 7.2 Hz, 2H), 7.56
(d, J = 6.8 Hz, 2H), 7.47–7.44 (m, 4H), 6.63 (s, 1H); IR(KBr)/
cm−1: 3091, 3075, 2935, 1729, 1593, 1493, 1413, 1403, 1327,
1313, 1296, 1252, 1094, 1085, 1014, 993, 942, 822, 759;
1
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1493, 1465, 1438, 1331, 1290, 1256, 1236, 1069, 1023, 755;
ESI-MS: m/z calcd for C17H15NO4Na: 320.090 [C17H15NO4 +
Na]+; found: 320.059; m.p. 104.1–105.6 °C.
added to the solution and the mixture was stirred for 8 h at room
temperature. After completion of the reaction monitored by TLC,
the reaction was quenched by addition of 1 N HCl aq. The
resulting cloudy aqueous solution was extracted with CH2Cl2 (2
× 15 mL) and washed with saturated NaHCO3 aq. The organic
layer was dried over anhydrous Na2SO4 and concentrated in
vacuo. Purification of the crude product by the Kugelrohr distil-
lation apparatus (<5 mmHg, 90 °C) afforded (R)-ethyl-N-(1-phe-
nylethyl)carbamate (1.75 g, 9.05 mmol, 90.5%) as a colorless
oil.
To a suspension of LiAlH4 (895 mg, 23.3 mmol) in dry THF
(5 mL), a solution of (R)-ethyl-N-(1-phenylethyl)carbamate
(1.74 g, 9.00 mmol) in dry THF (5 mL) was added dropwise at
0 °C under a N2 atmosphere. After completion of addition, the
reaction mixture was refluxed for 8 h. The reaction was quenched
by addition of ion-exchanged water (900 μL), 15% NaOH aq.
(900 μL), and ion-exchanged water (2.4 mL) again at 0 °C, and
then the cloudy reaction mixture was filtered through celite. The
resulting cloudy aqueous solution was extracted with CH2Cl2
(10 mL × 3) and the combined organic layer was dried over
anhydrous Na2SO4. The solvent was removed under
reduced pressure. Purification of the crude product by the
Kugelrohr distillation apparatus (<5 mmHg, 70 °C) afforded N-
methyl-(R)-1-phenylethylamine (1.07 g, 7.93 mmol, 88.1%) as a
colorless oil. 1H NMR (300 MHz, CDCl3)/ppm: δ 7.28–7.18
(m, 5H), 3.58 (q, J = 6.6 Hz, 1H), 2.25 (s, 3H), 1.44 (s, 1H),
1.31 (d, J = 6.6 Hz, 3H). IR(KBr)/cm−1: 3302, 2966, 1651,
1493, 1451, 1371, 1219, 1134, 760. [α]D = +73.4 (c 1.02,
CHCl3).
2-Acetoxy-2-(2-methoxyphenyl)acetonitrile (4g).6f Compound
1
4g was obtained in 24.9% yield as a pale yellow solid. H NMR
(500 MHz, CDCl3)/ppm: δ 7.58–7.56 (m, 1H), 7.45–7.41 (m,
1H), 7.06–7.03 (m, 1H), 6.95 (d, J = 6.3 Hz, 1H), 6.71 (s, 1H),
3.89 (s, 3H), 2.17 (s, 3H); IR(KBr)/cm−1: 3012, 2945, 2843,
1757, 1604, 1496, 1467, 1441, 1372, 1291, 1258, 1217,
1047, 1025, 962, 759; ESI-MS: m/z calcd for C11H11NO3Na:
228.064 [C11H11NO3 + Na]+; found: 228.128; m.p. 61.1–
63.2 °C.
2-(3′-Methoxybenzoyloxy)-2-(3-methoxyphenyl)acetonitrile (2h).
1
Compound 2h was obtained in 5.3% yield as a colorless oil. H
NMR (500 MHz, CDCl3)/ppm: δ 7.67–7.65 (m, 1H), 7.57–7.56
(m, 1H), 7.40–7.36 (m, 2H), 7.19–7.18 (m, 1H), 7.17–7.14 (m,
1H), 7.13–7.12 (m, 1H), 7.01–6.99 (m, 1H), 6.64 (s, 1H), 3.853
(s, 3H), 3.849 (s, 3H); 13C NMR (125 MHz, CDCl3)/ppm: δ
164.5, 160.2, 159.7, 133.1, 130.4, 129.7, 129.3, 122.5, 120.5,
120.0, 116.1, 116.0, 114.6, 113.4, 63.3, 55.5, 55.4; IR(KBr)/
cm−1: 3006, 2943, 2838, 1734, 1603, 1588, 1490, 1456, 1435,
1324, 1290, 1270, 1217, 1095, 1043, 753; ESI-MS: m/z calcd
for C17H15NO4Na: 320.090 [C17H15NO4
320.094.
+
Na]+; found:
2-Acetoxy-2-(3-methoxyphenyl)acetonitrile (4h).6f Compound
4h was obtained in 17.4% yield as a colorless oil. 1H NMR
(500 MHz, CDCl3)/ppm: δ 7.36 (t, J = 6.4 Hz, 1H), 7.09 (d, J =
6.4 Hz, 1H), 7.03 (t, J = 1.8 Hz, 1H), 7.00–6.97 (m, 1H), 6.38
(s, 1H), 3.84 (s, 3H), 2.17 (s, 3H); IR(KBr)/cm−1: 3063, 3007,
2944, 2840, 1754, 1604, 1590, 1493, 1372, 1290, 1251, 1216,
1038, 789, 695; ESI-MS: m/z calcd for C11H11NO3Na: 228.064
[C11H11NO3 + Na]+; found: 228.087.
Synthesis of N,N-dimethyl-(R)-1-phenylethylamine.14 (R)-
(+)-1-Phenylethylamine (2.42 g, 20 mmol) was added to formic
acid (4.6 g, 100 mmol) at 0 °C and then 40% aqueous formal-
dehyde (4.3 mL, 50 mmol) was added under a N2 atmosphere.
After completion of addition, the reaction mixture was refluxed
for 8 h and the reaction was quenched by addition of 1 N HCl
aq. at 0 °C. After the cloudy reaction mixture was basified by
addition of K2CO3, the resulting cloudy aqueous solution was
extracted with CH2Cl2 (10 mL × 3) and the combined organic
layer was dried over anhydrous Na2SO4. The solvent was
removed under reduced pressure. Purification of the crude
product by the Kugelrohr distillation apparatus (<5 mmHg,
130–140 °C) afforded N,N-dimethyl-(R)-1-phenylethylamine
(1.92 g, 12.9 mmol, 64.3%, >99% ee) as a colorless oil. The ee
value was determined by chiral HPLC analysis (Chiralcel OD-H,
0.2% (v/v) 2-PrOH in hexane, 1.0 mL min−1, 254 nm UV detec-
tor). The retention times of the two enantiomers: tr = 5.4 min for
2-(4′-Methoxybenzoyloxy)-2-(4-methoxyphenyl)acetonitrile (2i).9a
1
Compound 2i was obtained in 8.9% yield as a colorless oil. H
NMR (500 MHz, CDCl3)/ppm: δ 8.00 (dd, J1 = 5.6 Hz, J2 =
1.6 Hz, 2H), 7.54 (dd, J1 = 5.6 Hz, J2 = 1.6 Hz, 2H), 6.97 (dd,
J1 = 5.6 Hz, J2 = 1.6 Hz, 2H), 6.92 (dd, J1 = 5.6 Hz, J2
=
1.6 Hz, 2H), 6.60 (s, 1H), 3.86 (s, 3H), 3.84 (s, 3H); IR(KBr)/
cm−1: 3007, 2961, 2937, 2840, 1725, 1606, 1582, 1514, 1463,
1318, 1308, 1253, 1169, 1085, 1030, 847, 833, 768; ESI-MS:
m/z calcd for C17H15NO4Na: 320.090 [C17H15NO4 + Na]+;
found: 320.143.
2-Acetoxy-2-(4-methoxyphenyl)acetonitrile (4i).6f Compound
4i was obtained in 16.7% yield as a colorless oil. 1H NMR
(500 MHz, CDCl3)/ppm: δ 7.45 (d, J = 6.8 Hz, 2H), 6.95 (d, J =
6.8 Hz, 2H), 6.36 (s, 1H), 3.83 (s, 3H), 2.14 (s, 3H); IR(KBr)/
cm−1: 3007, 2960, 2939, 2842, 1754, 1612, 1587, 1516,
1465, 1371, 1256, 1218, 1178, 1029, 962, 831; ESI-MS: m/z
calcd for C11H11NO3Na: 228.064 [C11H11NO3 + Na]+; found:
228.145.
1
(R)-isomer and tr = 6.2 min for (S)-isomer. H NMR (300 MHz,
CDCl3)/ppm: δ 7.28–7.18 (m, 5H), 3.20 (q, J = 6.6 Hz, 1H),
2.17 (s, 6H), 1.34 (d, J = 6.6 Hz, 3H). IR(KBr)/cm−1: 3316,
2969, 2339, 1454, 1193, 956, 817, 700.
Synthesis of N-methyl-(R)-1-phenylethylamine.13 Under a N2
atmosphere, triethylamine (1.5 mL, 11.0 mmol) was added to a
solution of (+)-(R)-1-phenylethylamine (1.21 g, 10.0 mmol) in
dry CH2Cl2 (8 mL) at room temperature and then the solution
was cooled to −30 °C. Chloroethylformate (1.1 mL) was slowly
Acknowledgements
We thank Prof. Akira Nagasawa (Saitama University) for helpful
discussions concerning the structure of the vanadyl complex and
the reaction mechanism.
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This journal is © The Royal Society of Chemistry 2012