Steric Course of Deprotonation/Substitution of Chelating/Dipole-Stabilizing-Group-Substituted α-Amino- and α-Oxynitriles

Article abstract of DOI:10.1002/ejoc.201800484

The stereochemical course of electrophilic substitutions of α-nitrile metallocarbanions was investigated through the deprotonation of enantioenriched α-amino- and α-oxynitriles bearing a carbamoyl or methoxycarbonyl group in the presence of an electrophil

Full text of DOI:10.1002/ejoc.201800484

A Journal of
Accepted Article
Title: Steric Course of Deprotonation/Substitution of Chelating/Dipole-
Stabilizing Group-Substituted αꢀ-Amino- and αꢀ-Oxynitriles
Authors: Michiko Sasaki, Rumiko Shimabara, Tomo Takegawa, Yuri
Kotomori, Yuko Otani, Tomohiko Ohwada, and Kei Takeda
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800484
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10.1002/ejoc.201800484
European Journal of Organic Chemistry
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Steric Course of Deprotonation/Substitution of Chelating/Dipole-
a
a
Stabilizing Group-Substituted -Amino- and -Oxynitriles
Michiko Sasaki,*[a],[ ] Rumiko Shimabara,[a] Tomo Takegawa,[a] Yuri Kotomori,[a] Yuko Otani,*[b]
‡
Tomohiko Ohwada,[b] Kei Takeda[a],[ ]
‡‡
Abstract: The stereochemical course of electrophilic substitutions of
a-nitrile metallocarbanions was investigated using deprotonation of
enantioenriched a-amino- and a-oxynitriles bearing a carbamoyl or a
methoxycarbonyl group in the presence of an electrophile. The results
suggested that the dipole-stabilizing substituents can not only affect
the configurational stability and chemical reactivity of a-nitrile
metallocarbanions but also can change the steric course of the
electrophilic substitution (retention vs inversion). While the reaction of
a-aminonitrile bearing a dimethylaminocarbonyl group on the nitrogen
atom with LiHMDS in the presence of PhCOCl resulted in the
formation of a retention product (93:7), the case with that bearing a
methoxycarbonyl group was reversed in favor of the inversion product
(37:63). Thus, a methoxycarbonylamino group increases the degree
of planarization of the anionic center with maintenance of the planar
chirality more than does a ureido group, leading to preferable attack
of an electrophile from the rear face.
substitutions is understood, the foundations for a dramatic
breakthrough in asymmetric synthesis would be provided.5
We recently reported that chiral acyclic a-nitrile
metallocarbanions adjacent to a carbamoyloxy or ureido group
have sufficient configurational stability to be trapped by a carbon
electrophile with almost no loss of enantiopurity (Scheme 1).6
Obviously, the success of this methodology relies on the
capability of the chelating/dipole-stabilizing groups7,8 to fix the
configuration of chiral a-nitrile carbanions 3 and on in situ rapid
trapping of the carbanion by an electrophile present in the system.
Particularly noteworthy is base-dependent enantiodivergence
observed in the ureido cases. Thus, LDA and MHMDS (M = Li,
Na, K9) lead to the opposite enantioselectivity.6c For the
stereochemical outcome, we have proposed a mechanistic
rationale that involves participation of an electrophile through
precomplexation to the counter cation of MHMDS during
deprotonation.
NMe2
Introduction
NMe2
Y
LDA (3.0 equiv)
NCCO2Et (3.0 equiv)
O
O
O
CO2Et
O
O
X
R
M
Electrophilic substitution reactions of a-heteroatom-substituted
lithiocarbanions may proceed with retention or inversion of
configuration depending on a variety of factors, including the
nature of an electrophile and the presence or absence of a dipole-
stabilizing group on the heteroatom.1,2 Since the organolithiums
used in these studies should be required to retain their
configuration on the timescale of the reaction with an electrophile,
benzyl-type, allyl-type, or benzyl-allyl type lithiocarbanions appear
to be at the upper end of the range of applicability.1a-d More
synthetically useful but much more configurationally labile
lithiocarbanions next to a conjugative electron-withdrawing group
have not been explored with a few exceptions.3,4 If generation and
enantioselective trapping of these kinds of lithiocarbanions
become possible and the steric course of the electrophilic
H
THF–Et2O
–114 °C
92%, er = 90:10
Ph
Ph
CN
CN
Ph
CN
(R)-2a
3
(S)-1a
NMe2
LDA, ArCOCl
THF, –100 ˚C
MeN
O
COAr
inversion
er = up to 96:4
CN
NMe2
(R)-2b
MeN
O
H
Ph
NMe2
MHMDS, ArCOCl
THF, –100 ˚C
M = Li, Na, K
CN
MeN
O
COAr
(S)-1b
Ph
retention
er = up to 2:98
CN
(S)-2b
Scheme 1. Generation and Trapping of Chiral a-Nitrile Carbanions by Carbon
Electrophiles.
[a] Department of Synthetic Organic Chemistry, Institute of Biomedical &
Health Science, Hiroshima University
1-2-3 Kasumi, Minami-Ku, Hiroshima 734-8553, Japan
[b] Graduate School of Pharmaceutical Sciences
The University of Tokyo
7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
E-mail: otani@mol.f.u-tokyo.ac.jp
[‡] Current address: Faculty of Pharmaceutical Sciences, The University
of Tokyo, 7-3-1 Hongo, Bunkyo-Ku, Tokyo 113-0033, Japan
E-mail: fmisasaki@mail.ecc.u-tokyo.ac.jp
In this paper, we report the stereochemical results of
deprotonation/benzoylation of a-amino- and a-oxynitriles 1a-1d
bearing a chelating/dipole-stabilizing group on the a-heteroatoms
(Figure 1). Although it has been shown that carbamate-type
dipole-stabilizing groups increase the configurational stability of
a-heteroatom-substituted lithiocarbanions,10 very little is known
about the difference in the extents of stabilization among the
groups. Furthermore, because of the unique structural feature of
metalated nitriles, which can exist in several types involving N-
and C-coordinated structures depending on the metal, the solvent,
[‡‡] Professor Emeritus
Supporting information and ORCID(s) from the author(s) for this article
is.available on the WWW under
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10.1002/ejoc.201800484
European Journal of Organic Chemistry
FULL PAPER
and the temperature,11 a change in the counter cation from Li
through Na to K12 should influence both the configurational
stability of the corresponding carbanions and the steric course. 13
together with recovery of the starting material (23%). The er was
almost the same as the case using 5.0 equiv each of the reagents.
Table 1. In situ Deprotonation/Benzoylation of 1a-d by Amide Bases.
NMe2
NMe2
OMe
OMe
Y
Y
Y
PhCOCl (Z equiv)
base (Z equiv)
O
O
H
MeN
O
H
O
O
H
MeN
O
H
X
O
1a, 1c; R = CH2CH2Ph
1b, 1d; R = CH2Ph
X
O
X
O
Ph
Ph
COPh
H
+
COPh
Ph
CN
CN
Ph
CN
CN
THF
–100 °C, 10 min
R
CN
R
CN
R
CN
1a
1b
1c
1d
LDA: Z = 3
MHMDS: Z = 5
(S)-1a–d
(S)-2a–d
(R)-2a–d
Figure 1. Chelating/Dipole-Stabilizing Group-Substituted a-Amino- and a-
Oxynitriles.
entry
1
1
X
O
O
O
O
Y
base
yield (%)
S:R
40:60
–
1a
1a
1a
1a
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
NMe2
OMe
OMe
OMe
OMe
LDA
86
0
2
LiHMDS
NaHMDS
KHMDS
LDA
Results and Discussion
3
92
92
88
10
97
81
92
29
99
95
54:46
53:47
1:99
O-Methoxycarbonyl derivative (1c) and N-methoxycarbonyl
derivative (1d) were prepared from (S)-2-hydroxy-4-
4
phenylbutanenitrile
(Scheme 2).
4
and L-phenylalanine 5, respectively
5[a]
6[a]
7[a]
8[a]
9
1b NMe
1b NMe
1b NMe
1b NMe
LiHMDS
NaHMDS
KHMDS
LDA
93:7
OMe
99:1
ClCO2Me
NEt3
OH
H
CN
O
O
H
99:1
Ph
Ph
THF
79%
Ph
CN
4
1c
1c
1c
1c
1c
O
O
O
O
50:50
50:50
50:50
50:50
OMe
OMe
1. ClCO2Me, NaHCO3, H2O
2. ClCO2Et, NMM
then NH3 aq.
NH2
NaH
MeI
10
11
12
LiHMDS
NaHMDS
KHMDS
H
HN
O
H
MeN
O
H
OH
Ph
Ph
DMF
95%
CN
CN
3. cyanuric chloride, DMF
59% (3 steps)
O
5
6
1d
Scheme 2. Preparation of 1c and 1d.
13
14
15
16
1d NMe
1d NMe
1d NMe
1d NMe
OMe
OMe
OMe
OMe
LDA
70
49
92
92
4:96
37:63
80:20
91:9
LiHMDS
NaHMDS
KHMDS
Deprotonation/benzoylation was carried out by adding an amide
base to a cooled (–100 °C) THF solution of 1a–d and benzoyl
chloride. Although we reported the reactions of 1a with LDA in the
presence of NCCO2Et in THF-Et2O (2:1) at –114 °C, in which
90:10 er was obtained (Scheme 1),6a the reactions were
performed to secure comparability to results for 1b–d. The results
are shown in Table 1. The enantioselectivities observed varied
from 50:50 to 1:99. Carbamoyl derivatives provided better
enantioselectivity than did methoxycarbonyl derivatives (1a vs 1c
and 1b vs 1d). This observation is consistent with that by Pearson
for a-aminocarbanions lacking an a-cyano group.10 The results
obtained with the reactions of 1b and 1d bring up an interesting
point regarding the relation between enantioselectivity and a
dipole-stabilizing group. Thus, while the use of 1d in reactions
with LDA resulted in high inversion selectivity (entry 13) like in the
case with 1b, reactions with MHMDS (M = Li, Na, and K) (entries
14-16) showed countercation-dependency of the ratio of retention
products. Especially noteworthy is the fact that in the case of
LiHMDS, the enantioselectivity (37:63) was reversed in favor of
the (R)-isomer, an inversion product (entries 14 and 6). To obtain
information about the effect of inorganic salts, which accumulate
progressively in the reaction medium, we conducted the
experiment on 1d using 1.0 equiv of NaHMDS and 5.0 equiv of
PhCOCl, providing (S)-2d and (R)-2d in 51% yield and 81:19 er,
[a] updated data from previously reported6c
The major factors that determine the stereochemical outcome in
the reaction of 1 should be (1) the configurational stability of a
chiral metallocarbanion 3 (k2) (Scheme 3), (2) the relative rates
between reactions of 3 with an electrophile and racemization (k3-
ret, and k3-inv vs k2), and (3) the steric course (retention or
inversion) of the electrophilic substitution (k3-ret vs k3-inv). Thus, the
apparent enantioselectivity becomes lower when benzoyl chloride
can react by competing retention and inversion pathways even if
metallocarbanions 3 are configurationally stable on the time scale
of the electrophilic quenching.
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10.1002/ejoc.201800484
European Journal of Organic Chemistry
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Y
Table 2. Competition Experiment of 1b and 1d.
X
O
COPh
CN
k3-ret
NMe2
Y
NMe2
NMe2
Y
R
R
MeN
O
COPh
O
k1
2
X
O
H
CN
MeN
O
H
MeN
O
M
MNR'2
+
PhCOCl
Ph
X
R
M
Y
CN
Ph
Ph
Ph
base (X eq)
CN
CN
R
CN
2b
*
3
1b
+
3b
PhCOCl (1.0 eq)
1
X
O
COPh
CN
+
k3-inv
OMe
+
OMe
OMe
THF, –100 ºC
2 min
THF
MeN
O
COPh
MeN
O
H
MeN
O
M
k2
ent-2
Ph
Ph
CN
CN
CN
k3-ret
ent-2
1d
3d
LDA: X = 2.4, –85 °C
NaHMDS: X = 2.2, –90 °C
2d
Y
O
PhCOCl
X
R
M
2b (1b)
2d (1d)
CN
ent-3
base
2
k3-inv
yield (%)
34 (57)
12 (74)
yield (%)
65 (27)
79 (0)
Scheme 3. Stereochemical Pathway of In Situ Deprotonation/Benzoylation of 1.
LDA
NaHMDS
Because in this reaction deprotonation is conducted in the
presence of benzoyl chloride, regarding the above second item, a
difference in the reactivity of the metallocarbanions toward
benzoyl chloride, reflected by the rate constants k3, should be
considered. If metallocarbanions 3b and 3d are quenched by
benzoyl chloride at different rates due to the different steric
environments and electronic nature, the stereochemical outcome
should be different even if 3b and 3d have the same
configurational stability. Therefore, we decided to conduct
competition experiments using 3b and 3d. When a mixture of 1b
(1.0 equiv) and 1d (1.0 equiv) was treated with LDA (2.4 equiv) at
–85 °C for 3 min followed by addition of 1.0 equivalent of PhCOCl,
benzoylated products 2b and 2d were obtained in 34% and 65%
yields together with recovery of the starting materials in 57% and
27% yields, respectively, indicating that 3d–Li is more reactive
than 3b–Li (Table 2). Reaching completion of deprotonation
before addition of PhCOCl was confirmed by the fact that the
products and the starting materials recovered were completely
racemic. A competition experiment using NaHMDS resulted in the
formation of 2b and 2d in 12% and 79% yields along with 74%
and 0% recoveries of the starting materials, respectively,
indicating higher reactivity of 3d–Na relative to 3b–Na.
Consequently, the decreased enantioselectivity in the reaction of
1d cannot be attributed to an increased racemization originating
from the lower reactivity of the carbanions 3d.
It is difficult to experimentally determine whether the lower
enantioselectivity observed in 1d than in 1b is due to the lesser
configurational stability of 3d or the lowering of the
stereoselectivity (k3-ret vs k3-inv). In a previous paper,6c we
proposed that the preference of a retention product observed in
1b with MHMDS results from participation of PhCOCl through
precomplexation to the counter cation (M+) of less basic
MHMDS14 during deprotonation.15,16 Thus, in the case of MHMDS,
the transition state structures for electrophile-assisted
deprotonation, which were obtained by DFT calculations for the
model compound 7b (Table 3), are more favorable than non-
assisted ones. In sharp contrast to the results, both processes
with LDA have almost the same energy barriers, which are very
low. In order to gain insights into the difference in
enantioselectivity between 1b and 1d, energetics for
deprotonation with and without benzoyl chloride were examined
using 7d as model compounds and LDA, LiHMDS, and NaHMDS
as a base (Table 3, results6c with 7b are also shown for
comparison). Contrary to expectations based on the observed
reversal of enantioselectivity, in the case of 7d with LiHMDS, the
benzoyl chloride-assisted transition structures were more
favorable than non-assisted ones (entries 3 and 4). The results
obtained by using two different DFT hybrid functionals (B3PW91
and B3LYP) showed the same tendency. This discrepancy led us
to focus on the structural differences between the metallo anionic
species 8b and 8d that were obtained as products of
deprotonation of 7b and 7d from the calculations (Table 3).
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10.1002/ejoc.201800484
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Table 3. Free energies of activation for PhCOCl-Assisted Deprotonation and
Non-Assisted Deprotonation of 7b and 7d.
Table 4. DFT-Optimized Structures of the Metallo Anionic Species (B3LYP/6-
31G(d)).
Ph
R2N
R2N
Y
Y
d
O
M
M
Cl
MNR2
MeN
Me
O
MeN
O
+
+
HNR2 (PhCOCl)
H
M
NR2: NiPr2, N(SiMe3)2
(PhCOCl)
C
N
C
N
CN
Me
CN
R'N
R'N
α: pyramidalization angle
α
α
CH3
PhCOCl (+)
CH3
PhCOCl (‒)
7b: Y = NMe2
7d: Y = OMe
8b: Y = NMe2
8d: Y = OMe
8b, 8d
entry
base PhCOCl 7d (kcal/mol) [a]
7b (kcal/mol) [a]
entry
8
base
PhCOCl
a (°)
38.4
18.1
43.9
21.2
28.0
29.2
5.7
d (Å)
2.195
–
1
2
3
4
5
6
LDA
+
–
+
–
+
–
2.5 (4.4)
0.6 (2.2)
–0.4 (0.5)
1.8 (3.6)
1
2
8b
8b
8b
8b
8b
8b
8d
8d
8d
8d
8d
8d
LDA
LDA
+
–
+
–
+
–
+
–
+
–
+
–
LDA
LiHMDS
LiHMDS
NaHMDS
NaHMDS
9.0 (11.1)
12.0 (11.4)
8.8 (10.6)
9.7 (12.0)
10.6 (12.9)
14.3 (16.6)
10.0 (12.2)
11.5 (14.0)
3
LiHMDS
LiHMDS
NaHMDS
NaHMDS
LDA
4.826
–
4
5
2.438
–
6
7
5.176
–
[a] DG‡
C) at the level of IEFPCM (THF)-B3PW91/6-311++G(d,p)//B3LYP/6-
‡
(-100
°
31G(d). DG
at the level of IEFPCM (THF)-B3LYP/6-
(-100
C)
°
8
LDA
6.1
311++G(d,p)//B3LYP/6-31G(d) are shown in parentheses.
9
LiHMDS
LiHMDS
NaHMDS
NaHMDS
43.4
–9.0
12.5
–6.5
5.190
–
10
11
12
There are several intriguing structural aspects of a comparison of
the intermediates with and without benzoyl chloride. Noteworthy
is the deviation of the structure of the stereogenic carbon atom
from a pyramidal geometry and the variations in the distances
between the metal cation and the carbonyl oxygen atom of
benzoyl chloride. Most striking is the case of 8d-LiHMDS (without
PhCOCl), where the pyramidalization angle (deformation angle)17,
11c is –9.0 °, which is in sharp contrast to the corresponding case
of 8b-LiHMDS (21.2 °) (Table 4, entries 10 and 4, Figure 2). This
means that in the former, the anionic species has a slightly
puckered geometry towards the lithium cation side and a
considerable electron density at the rear face. Although the same
trend was also found in the case of 8d-NaHMDS (without
PhCOCl) (–6.5 °) (entry 12), a remarkable difference in the
distance between the metallo cation and the carbonyl oxygen
(5.190 Å vs 2.425 Å) was observed in the corresponding PhCOCl-
complexed intermediates 8d-LiHMDS-PhCOCl and 8d-NaHMDS-
PhCOCl (entries 9 and 11, Figure 2). Consequently, an inversion
product may be formed via planarization of the complexed
intermediate (8d-LiHMDS-PhCOCl ® 8d-LiHMDS) followed by
electrophilic quenching, probably because of the longer distance
between the metallo cation and the carbonyl oxygen atom of the
complexed benzoyl chloride and because of the lower reactivity
of lithioanion than that of the corresponding sodio counterpart.
2.425
–
NH(SiMe3)2
THF
NH(SiMe3)
O
2 THF
MeO
NMe
Li
Li
O
2.155
3.276
2.048
Me2N
2.884
–9.0°
N
MeN
H3C
C
N
C
H3C
21.2°
8d-LiHMDS
(Table 4, entry 10)
8b-LiHMDS
(Table 4, entry 4)
Ph
Cl
Cl
O
Ph
NH(SiMe3)2
O
5.19
THF
3.620
C
NH(SiMe3)2
2.425
Li
O
THF
O
Na
N
2.214
THF
MeO
MeN
3.438
MeO
2.437
MeN
N
H3C
C
12.5°
43.4°
CH3
8d-LiHMDS-PhCOCl
(Table 4, entry 9)
8d-NaHMDS-PhCOCl
(Table 4, entry 11)
Figure 2. DFT-Optimized Structures of the metallo anionic species.
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10.1002/ejoc.201800484
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Since the above results suggested that the degree of participation
of complexation of the electrophile with the metal can change
depending on a base used, we performed reactions of 1d with p-
methoxybenzoyl chloride and o-chlorobenzoyl chloride, which
have a stronger complexing but less electrophilic character and a
weaker complexing but more electrophilic character,
respectively.18 The enantiomeric ratios with LDA and LiHMDS
were hardly influenced by the electronic nature of the
electrophiles (Table 5, entries 1-6). On the other hand, in
reactions with NaHMDS, an obvious electrophile-dependent
enantioselectivity was observed (entries 7-9). Thus, the ratio of
retention versus inversion increases as the complexation ability of
an electrophile increases from o-chlorobenzoyl chloride through
benzoyl chloride to p-methoxybenzoyl chloride. The
independency of the steric course on the complexation ability of
an electrophile and the reversal of enantioselectivity observed
with LiHMDS suggest that the precomplexation plays no
important role in determining the selectivity.
determining
the
stereochemical
outcome
in
the
deporotonation/substitution of a-nitrile carbanions as well as
racemization associated with the configurational stability of the
anionic center. The findings not only offer a potential for
manipulating chiral a-nitrile carbanions in an enantioselective
carbon-carbon bond formation but also open up new perspectives
in asymmetric synthesis.
Experimental Section
General: All moisture-sensitive reactions were performed under
a positive pressure of nitrogen. Anhydrous MgSO4 was used for
drying all organic solvent extracts in workup unless otherwise
indicated, and removal of the solvents was performed with a
rotary evaporator. Dry solvents and reagents were obtained by
using standard procedures. Thin-layer chromatography was
performed on precoated glass-backed silica gel 60 F-254 plates.
For routine chromatography, the following adsorbents were used:
silica gel 60N of particle size 63-210 µm or 40-50 µm. Liquid
chromatography under medium pressures (MPLC) was carried
out using prepacked columns (22 mm x 100 mm (5 µm silica gel)
Table 5. In Situ Deprotonation/Acylation of 1d with Aroyl Chlorides.
OMe
OMe
OMe
1
1. ArCOCl (X equiv)
or 22 mm x 300 mm (10 µm silica gel)). H NMR spectra (500
MeN
O
COAr
MeN
O
COAr
MeN
O
H
+
MHz) were taken in CDCl3 with internal standards as follows:
CDCl3 (d 7.26). 13C NMR spectra (125 MHz) were taken in CDCl3
with internal standards as follows: CDCl3 (d 77.2). The
assignment of 1H and 13C NMR spectra was based on H-H
decoupling and HMQC experiments.
2. base (X equiv)
–100 °C, 10 min
Ph
Ph
Ph
CN
CN
(S)-2d
CN
1d
(R)-2d
LDA: X = 3
MHMDS: X = 5
entry
base
Ar-
2d
yield (%)
82
S:R
6:94
4:96
5:95
1
2
3
4
5
6
7
8
9
LDA
LDA
LDA
p-MeOC6H4-
C6H5-
2d’
2d
Preparation of (S)-1-cyano-3-phenylpropyl methyl carbonate
(1c): To a solution (25 °C) of (S)-2-hydroxy-4-phenylbutanenitrile
46a (600 mg, 3.72 mmol) and triethylamine (623 µL, 4.47 mmol) in
THF (15 mL) was added methyl chloroformate (343 µL, 4.47
mmol). After being stirred at the same temperature for 1.5 h, the
mixture was diluted with H2O (20 mL) and AcOEt (20 mL). The
aqueous phase was extracted with AcOEt (20 mL x 2). The
combined organic phases were dried, filtered, and concentrated.
The residual oil was subjected to column chromatography (silica
gel (40–50 µm) 35 g, elution with n-hexane/AcOEt = 4:1) to give
1c (645 mg, 79%, (98:2 er)) as a colorless oil. Rf = 0.34 (n-
70
o-ClC6H4-
p-MeOC6H4-
C6H5-
2d”
2d’
2d
58
LiHMDS
LiHMDS
LiHMDS
NaHMDS
NaHMDS
NaHMDS
50
54:46
37:63
44:56
90:10
80:20
71:29
49
o-ClC6H4-
p-MeOC6H4-
C6H5-
2d”
2d’
2d
49
97
hexane:AcOEt = 4:1); [a]24 –40.8 (c 1.05, CHCl3) (98:2 er);
92
D
CHIRALPAK® AD-H (4.8 x 250 mm), n-hexane/EtOH = 100:3, flow
rate 1.0 mL/min, detection at 220 nm, tr = 12.9 min (minor) and
16.5 min (major); IR (NaCl) 3029, 2960, 1762, 1445 cm-1; 1H NMR
(500 MHz, CDCl3): d = 2.20–2.36 (m, 2H), 2.85 (t, J = 7.8 Hz, 2H),
3.87 (s, 3H), 5.14 (t, J = 6.9 Hz, 1H), 7.19 (d, J = 7.1 Hz, 2H), 7.25
(t, J = 7.5 Hz, 1H), 7.30-7.35 (m, 2H); 13C NMR (125 MHz, CDCl3)
d = 30.6, 34.0, 56.0, 64.3, 116.5, 126.9, 128.5, 129.0, 138.9,
154.3; HRMS-ESI-LTQ Orbitrap (m/z): [M + Na]+ calcd for
C12H13NO3Na 242.0788, found 242.0786.
o-ClC6H4-
2d”
86
Conclusions
We
have
investigated
the
steric
course
of
deprotonation/benzoylation of acyclic a-amino- and a-oxynitriles
bearing a carbamoyl or a methoxycarbonyl group on the a-
heteroatoms. The most relevant finding is that the steric course of
deprotonation/substitution of (S)-1, retention or inversion, is
variable depending on a subtle change in the carbonyl substituent
on the a-nitrogen atom as well as the strength of the base used
for deprotonation. These results indicate the importance of the
Preparation of (S)-1-cyano-3-phenylpropyl methyl carbonate
(1d): To a solution (25 °C) of L-phenylalanine (2.0 g, 12.1 mmol)
and NaHCO3 (4.5 g, 53.3 mmol) in H2O (16 mL) was added methyl
chloroformate (1.4 mL, 18.2 mmol). After being stirred at the same
temperature for 22.7 h, the mixture was diluted with CH2Cl2 (40
mL) and H2O (10 mL), and the aqueous phase was extracted with
stereochemical course, SE2ret and SE2inv, as
a
factor
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10.1002/ejoc.201800484
European Journal of Organic Chemistry
FULL PAPER
CH2Cl2 (20 mL x 2). The aqueous phase was acidified to pH 1
with 2 N HCl and extracted with AcOEt (20 mL x 3). The combined
organic phases were washed with brine (10 mL), dried, filtered,
and concentrated. The product was used in the following step
without further purification. To a cooled (in an ice-salt bath)
solution of the above crude product in THF (54 mL) was added N-
methylmorpholine (1.30 mL, 11.8 mmol) and ethyl chloroformate
(1.13 mL, 11.8 mmol). After being stirred at the same temperature
for 30 min, aqueous NH3 solution (4.7 mL) was added over a
period of 7 min. After being stirred stirred for 1 h, CH2Cl2 (40 mL)
was added and the phases were separated. The organic phase
was successively washed with water (40 mL) and brine (40 mL),
dried over Na2SO4, and concentrated. n-hexane was added to the
product and the heterogeneous solution was filtered and
concentrated. The product was used in the following step without
further purification. To a cooled (–30 °C) solution of the above
crude product (2.1 g) in DMF (47 mL) was added cyanuric chloride
(3.3 g, 17.7 mmol). After being stirred at the same temperature for
3 h, the mixture was diluted with cooled 0.5 M NaOH aqueous
solution (60 mL) and extracted with AcOEt (30 mL x 3). The
combined organic phases were successively washed with water
(50 mL x 2) and brine (40 mL), dried over Na2SO4, and
concentrated. The residual oil was subjected to column
chromatography (silica gel (63–210 µm) 70 g, elution with n-
hexane/AcOEt = 2:1) to give nitrile 6 (1.46 g, 59%, 3 steps) as a
white solid. Recrystallization (n-hexane/AcOEt) gave colorless
General Procedure for Acylation: Reaction of (S)-1d with
NaHMDS and benzoyl chloride (Table 1, entry 15): To a cooled
(–100 °C) solution of (S)-1d (13:87 er, 32.1 mg, 0.147 mmol) and
benzoyl chloride (85 µL, 0.735 mmol) in THF (2.10 mL) was added
dropwise a solution of NaHMDS (0.99 M in THF, 747 µL, 0.735
mmol) over a period of 6 min. The mixture was stirred at the same
temperature for 10 min before addition of CH3COOH (1.0 M in
THF, 735 µL, 0.735 mmol). The mixture was diluted with Et2O (10
mL) and saturated aq NaHCO3 (10 mL), and the phases were
separated. The aqueous phase was extracted with Et2O (10 mL x
2). The combined organic phases were washed with water (10
mL) and brine (10 mL), dried, filtered, and concentrated. The
residual oil was subjected to column chromatography (silica gel
(40–50 µm) 13 g, elution with n-hexane/CH2Cl2/Et2O = 10:10:1) to
give 2d (43.5 mg, 92%, 28:72 er) as a white solid.
2-Cyano-1-oxo-1,4-diphenylbutan-2-yl methyl carbonate (2c):
2c was obtained from 1c (33.1 mg) using NaHMDS and benzoyl
chloride in 99% yield (48.3 mg, 50:50 er) as a colorless oil. Rf =
0.31 (n-hexane:AcOEt = 4:1); CHIRALPAK® AD-H (4.8 x 250 mm),
n-hexane/EtOH = 20:1, flow rate 1.0 mL/min, detection at 254 nm,
tr = 13.1 min and 17.7 min; IR (NaCl) 3029, 2961, 1768, 1700 cm-
1
1; H NMR (500 MHz, CDCl3): d = 2.48–2.66 (m, 2H), 2.97–3.10
(m, 2H), 3.82 (s, 3H), 7.18–7.25 (m, 3H), 7.27-7.32 (m, 2H), 7.49-
7.53 (m, 2H), 7.62-7.67 (m, 1H), 8.08-8.12 (m, 2H); 13C NMR (125
MHz, CDCl3): d = 30.3, 39.1, 56.3, 80.8, 115.9, 126.9, 128.5,
128.9, 129.2, 129.3, 131.9, 134.6, 139.0, 153.5, 188.8; HRMS-
ESI-LTQ Orbitrap (m/z): [M + Na]+ calcd for C19H17NO4Na
346.1050, found 346.1053.
needles. Rf = 0.28 (n-hexane:AcOEt = 2:1); mp 104–105 °C; [a]27
D
–42.9 (c 0.52, CHCl3); IR (KBr) 3317, 3062，3035，2971，2936，
1
1695 cm-1; H NMR (500 MHz, CDCl3, 50 °C) d = 3.08 (dd, J =
13.9, 6.9 Hz, 1H), 3.13 (dd, J = 13.9, 5.8 Hz, 1H), 3.72 (brs, 3H),
4.86 (brs, 1H), 4.90 (brs, 1H), 7.28 (d, J = 6.9 Hz, 2H), 7.30–7.40
(m, 3H); 13C NMR (125 MHz, CDCl3) d = 39.2, 43.9, 53.2, 118.2,
128.2, 129.3, 129.7, 133.8, 155.7; HRMS-ESI-LTQ Orbitrap
(m/z): [M + Na]+ calcd for C11H12N2O2Na 227.0791, found
227.0788.
Methyl
(S)-(2-cyano-1-oxo-1,3-diphenylpropan-2-
yl)(methyl)carbamate (2d): 2d was obtained from (S)-1d (13:87
er, 32.1 mg) using NaHMDS and benzoyl chloride in 92% yield
(43.5 mg, 28:72 er). Recrystallization (n-hexane/AcOEt) gave
colorless prisms. Rf = 0.35 (n-hexane:CH2Cl2:Et2O = 1:1:0.1); mp
151 °C; [a]27D 86.2 (c 0.36, CHCl3) (28:72 er); CHIRALPAK® AD-
H (4.8 x 250 mm), n-hexane/EtOH = 20:1, flow rate 1.0 mL/min,
detection at 254 nm, tr = 10.9 min (minor) and 14.5 min (major);
IR (KBr) 3060, 3031, 3002, 2957, 1710, 1692 cm-1; 1H NMR (500
MHz, CDCl3): d = 2.71 (s, 3H), 3.51 (brs, 3H), 3.58 (d, J = 14.0 Hz,
1H), 3.78 (brd, J = 14.0 Hz, 1H), 7.25–7.40 (m, 5H), 7.42-7.48 (m,
2H), 7.56 (t, J = 7.5 Hz, 1H), 7.88 (d, J = 7.3 Hz, 2H); 13C NMR
(125 MHz, CDCl3): d = 34.8, 40.6, 53.5, 67.6, 116.1, 128.1, 128.5,
128.7, 129.0, 130.7, 133.5, 133.8, 155.0, 189.1; HRMS-ESI-LTQ
Orbitrap (m/z): [M + Na]+ calcd for C19H18N2O3Na 345.1210, found
345.1211.
To a cooled (0 °C) solution of 6 (1.00 g) and methyl iodide (2.45
mL, 39.2 mmol) in DMF (9.8 mL) was added NaH (60% dispersion
in mineral oil, 196 mg, 4.90 mmol). The mixture was stirred at 0 °C
for 30 min and then saturated NH4Cl (30 mL) and AcOEt (30 mL)
were added. The aqueous phase was extracted with AcOEt (30
mL x 3). The combined organic phases were successively
washed with water (30 mL x 3) and brine (20 mL), dried, and
concentrated. The residual oil was subjected to column
chromatography (silica gel (40-50 µm) 60 g, elution with n-
hexane/AcOEt = 2:1) to give 1d (1.02 g, 95%, >99:1 er) as a
colorless oil. Rf = 0.23 (n-hexane:CH2Cl2:Et2O = 10:10:1); [a]25
–
D
47.3 (c 1.06, CHCl3) (>1:99 er); CHIRALPAK® AD-H (4.8 x 250
mm), n-hexane/EtOH = 20:1, flow rate 1.0 mL/min, detection at
220 nm, tr = 14.8 min (minor) and 17.2 min (major); IR (NaCl)
General Procedure for Competition Experiment: To a cooled
(–85 °C) solution of 1b (23.4 mg, 0.10 mmol) and 1d (22.1 mg,
0.10 mmol) in THF (1.70 mL) was added dropwise a solution of
LDA (1.2 M in THF, 200 µL, 0.24 mmol) over a period of 5 min.
The mixture was stirred at the same temperature for 3 min. The
mixture was cooled to –100 °C before addition of a solution of
benzoyl chloride (1.0 M in THF, 100 µL, 0.10 mmol). After being
stirred at the same temperature for 2 min, CH3COOH (1.0 M in
1
3031, 2956, 1716 cm-1; H NMR (500 MHz, CDCl3, 50 °C): d =
2.96 (s, 3H), 3.05 (dd, J = 13.8, 7.6 Hz, 1H), 3.14 (dd, J = 13.8,
8.0 Hz, 1H), 3.68 (brs, 3H), 5.32 (brs, 1H), 7.21–7.36 (m, 5H); 13
C
NMR (125 MHz, CDCl3): d = 30.8 and 31.1, 37.7 and 38.1, 49.9,
53.6, 117.2, 127.9, 129.0, 129.3, 134.3, 155.3 and 156.4; HRMS-
ESI-LTQ Orbitrap (m/z): [M + Na]+ calcd for C12H14N2O2Na
241.0948, found 241.0948.
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10.1002/ejoc.201800484
European Journal of Organic Chemistry
FULL PAPER
THF, 240 µL, 0.24 mmol) was added. The mixture was diluted
with Et2O (10 mL) and saturated aq NaHCO3 (10 mL). The
aqueous phase was extracted with Et2O (10 mL x 2). The
combined organic phases were washed with water (10 mL) and
brine (10 mL), dried, and concentrated. The residual mixture of
yellow solid and oil was subjected to column chromatography
(silica gel (40–50 µm) 13 g, elution with n-hexane/CH2Cl2/Et2O =
10:10:1) to give 2b (11.5 mg, 34%) as a white solid and 2d (21.1
mg, 65%) as a white solid. 1b (13.3 mg, 57%) and 1d (5.9 mg,
27%) were recovered.
coordination of the base metal to the urea carbonyl oxygen atom
of the reactant and simultaneously to the carbonyl oxygen atom
of a model electrophile, i.e., benzoyl chloride PhCOCl. All of the
stationary points in the paper were located at the level of
B3LYP/6-31G(d), and frequency calculations were then
performed at those geometries to confirm one or zero imaginary
frequency and to determine the free energy correction to
electronic energy at -100 °C. The zero-point vibrational energy
corrections were done without scaling. Intrinsic reaction
coordinate (IRC) computations of the transition structures verified
the reactants, intermediates, and products on the potential energy
surface (PES). Then single point energies were calculated at the
levels of B3PW91/6-311++G(d,p) and B3LYP/6-311++G(d,p) on
the basis of the B3LYP/6-31G(d) optimized structures. Bulk
solvation effects (self-consistent reaction field, SCRF) in THF
were simulated implicitly during single point energy calculations
through the integral equation formalism polarizable continuum
model (IEFPCM). 20 Here we present the activation free energies
obtained by single point calculations at the levels of IEFPCM
(THF) - B3PW91/6-311++G(d,p) and IEFPCM (THF) - B3LYP/6-
311++G(d,p) on the basis of B3LYP/6-31G(d) optimized
structures.
Methyl
(S)-(2-cyano-1-(4-methoxyphenyl)-1-oxo-3-
phenylpropan-2-yl)(methyl)carbamate (2d’): 2d’ was obtained
from 1d (33.7 mg) using NaHMDS and p-methoxybenzoyl
chloride in 97% yield (52.9 mg, 10:90 er). Purification by MPLC
(elution with n-hexane/CH2Cl2/Et2O = 1:1:0.1) gave 2d’ (Ar = 4-
MeOC6H4) as a white solid. Rf = 0.23 (n-hexane:CH2Cl2:Et2O =
1:1:0.1); mp 113–114 °C; [a]28D 118.3 (c 1.00, CHCl3) (10:90 er);
CHIRALPAK® AD-H (4.8 x 250 mm), n-hexane/EtOH = 10:1, flow
rate 1.0 mL/min, detection at 254 nm, tr = 14.8 min (minor) and
28.3 min (major); IR (KBr) 2998, 2966, 1704 cm-1; 1H NMR (500
MHz, CDCl3): d = 2.71 (s, 3H), 3.49-5.57 (m, 4H), 3.77 (brd, J =
14.0 Hz, 1H), 3.86 (s, 3H), 6.92 (d, J = 9.0 Hz, 2H), 7.25–7.39 (m,
5H), 7.89 (d, J = 9.0 Hz, 2H); 13C NMR (125 MHz, CDCl3): d =
34.7, 40.5, 53.4, 55.6, 67.5, 114.0, 116.3, 126.1, 128.0, 128.9,
130.7, 130.9, 133.9, 155.0, 163.8, 187.3; HRMS-ESI-LTQ
Orbitrap (m/z): [M + Na]+ calcd for C20H20N2O4Na 375.1315, found
375.1318.
Acknowledgements
This research was partially supported by a Grant-in-Aid for
Challenging Exploratory Research 16K08165 (M.S.), 15K14929
(K.T.) from the Ministry of Education, Culture, Sports, Science and
Technology (MEXT), the Hoan Sha Foundation (M.S.), the
Takeda Science Foundation (M.S.) and the Naito Foundation
Natural Science Scholarship (M.S.). We thank the staff of the
Natural Science Center for Basic Research and Development (N-
BARD), Hiroshima University, for the use of their facilities. The
computations were performed at the Research Center for
Computational Science, Okazaki (Japan)
Methyl
(S)-(1-(2-chlorophenyl)-2-cyano-1-oxo-3-
phenylpropan-2-yl)(methyl)carbamate (2d”): 2d” (Ar = 2-
ClC6H4) was obtained from 1d (33.6 mg, 0.154 mmol) using LDA
and o-chlorobenzoyl chloride in 58% yield (31.6 mg, 95:5 er).
Purification by MPLC (elution with n-hexane/CH2Cl2/Et2O =
1:1:0.05) gave 2d” (Ar = 2-ClC6H4) as a white solid. Rf = 0.38 (n-
hexane:CH2Cl2:Et2O = 1:1:0.1); mp 124–125 °C; [a]27D –202.6 (c
0.90, CHCl3) (92:8 er); CHIRALCEL® OD-H (4.8 x 250 mm), n-
hexane/iPrOH = 20:1, flow rate 1.0 mL/min, detection at 254 nm,
tr = 8.9 min (major) and 15.0 min (minor); IR (KBr) 3033, 2963,
Keywords: chiral carbanion • electrophilic substitution • nitrile
1
1723, 1691 cm-1; H NMR (500 MHz, CDCl3): d = 2.66 (s, 3H),
[1]
a) R. E. Gawley in Stereochemical Aspects of Organolithium Compounds,
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126.0, 128.2, 128.6, 129.0, 130.6, 131.8, 132.5, 133.6, 155.8,
190.1; HRMS-ESI-LTQ Orbitrap (m/z): [M + Na]+ calcd for
C19H17ClN2O3Na 379.0820, found 379.0825.
Computational Methods: We carried out computational studies
by using the Gaussian 09 suites of programs.19 The geometries
of the reactants, reactant complexes, intermediates, transition
states, and products for deprotonation reaction and SE2 reaction
were fully optimized using the B3LYP/6-31G(d) level. Two
coordination structures of a base and a reactant were considered:
(i) coordination of the base metal (Li+ in the case of LDA and
LHMDS or Na+ in the case of NaHMDS) to the urea carbonyl
oxygen atom of the reactant (Coordination of the metal to the
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10.1002/ejoc.201800484
European Journal of Organic Chemistry
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201800484
European Journal of Organic Chemistry
FULL PAPER
FULL PAPER
Chiral -Nitrile Carbanion *
a
Y
Y
Y
Y
base
ArC(O)Cl
Michiko Sasaki,* Rumiko Shimabara,
Tomo Takegawa, Yuri Kotomori, Yuko
Otani,* Tomohiko Ohwada, Kei Takeda
O
X
O
COAr
X
O
COAr
X
O
or
X
R
M
H
R
CN
CN
R
CN
inversion
R
CN
retention
X = O, NMe
Y = OMe, NMe2
Page No. – Page No.
The stereochemistry of electrophilic substitutions of a-nitrile metallocarbanions was
investigated using deprotonation of enantioenriched a-amino- and a-oxynitriles
bearing a carbamoyl or a methoxycarbonyl group in the presence of an electrophile.
The most relevant finding is that the dipole-stabilizing substituents can not only
affect the configurational stability and reactivity of a-nitrile metallocarbanions but
also can change the steric course (retention vs inversion).
Steric Course of
Deprotonation/Substitution of
Chelating/Dipole-Stabilizing Group-
Substituted -Amino- and
a
a
-
Oxynitriles
This article is protected by copyright. All rights reserved.