Asymmetric Mannich reaction between (S)-N-(tert-butanesulfinyl)-3,3,3- trifluoroacetaldimine and malonic acid derivatives. Stereodivergent synthesis of (R)- and (S)-3-amino-4,4,4-trifluorobutanoic acids

Article abstract of DOI:10.1039/c3ob42425a

Inorganic as well as organic base catalysis was found to be effective for diastereoselective Mannich additions of malonic acid derivatives to (S _S)-N-(tert-butanesulfinyl)-3,3,3-trifluoroacetaldimine. In the presence of catalytic amounts of ino

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ARTICLE TYPE
Asymmetric Mannich reaction between (S)-N-(tert-butanesulfinyl)-3,3,3-
trifluoroacetaldimine and malonic acid derivatives. Stereodivergent
synthesis of (R)- and (S)-3-amino-4,4,4-trifluorobutanoic acids
Norio Shibata,*a Takayuki Nishimine,a Naoyuki Shibata,a Etsuko Tokunaga,a Kosuke Kawada,b Takumi
Kagawa,b José Luis Aceña,c Alexander E. Sorochinskyc,d,e and Vadim A. Soloshonok*c,d
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Inorganic as well as organic base catalysis was found to be effective for diastereoselective Mannich
additions of malonic acid derivatives to (SS)-N-(tert-butanesulfinyl)-3,3,3-trifluoroacetaldimine. In the
10 presence of catalytic amounts of inorganic bases, n-BuLi or DMAP, the reaction gives the corresponding
(R,SS)-β-aminomalonates in good yield and with diastereoselectivity up to 9/1 dr. On the contrary,
phosphazene bases favour the formation of the (S,SS)-diastereomer with selectivities as high as 99/1.
Simple choosing of appropriate base catalyst for the Mannich addition reaction allowed to obtain
enantiomerically pure either (R)- or (S)-configured 3-amino-4,4,4-trifluorobutanoic acids after hydrolysis
15 and decarboxylation of the corresponding β-aminomalonates.
acetate to the enantiomerically pure N-p-toluenesulfinyl imine of
ethyl trifluoropyruvate was applied by Zanda et al. to the
asymmetric synthesis of (S)- and (R)-α-(trifluoromethyl)aspartic
acids in good yield and excellent diastereoselectivity.6 Addition
50 of a Reformatsky reagent to α-aryl(alkyl)-α-(trifluoromethyl)-N-
tert-butanesulfinyl amino acetals as stable precursors of the
corresponding trifluoromethyl ketimines was further utilized by
Introduction
The diastereoselective Mannich reaction of chiral ester enolates
or chiral imines and related compounds with the corresponding
achiral counterparts has become an efficient and powerful
20 strategy allowing access to chemically and biologically important
β-amino acids and their derivatives.1 Since chiral trifluoromethyl
imines are good electrophiles owing to the electron-withdrawing
effect of the CF3 group, there are several reports on their Mannich
reactions with ester enolate nucleophiles.2 According to this
25 strategy, LiCl/Et3N-assisted Mannich reaction of chiral Ni(II)
complex of glycine Schiff base with N-p-methoxyphenyl imine
derived from trifluoroacetaldehyde has been used by Soloshonok
Grellepois
for
the
elaboration
of
β-alkyl(aryl)-β-
(trifluoromethyl)-β-amino acid derivatives in good yields and
55 high diastereoselectivities.7 Nitro-Mannich reaction, which
involves the nucleophilic addition of nitroalkanes to
trifluoromethyl α,β-unsaturated N-tert-butanesulfinyl ketimines
was carried out readily in the presence of catalytic amounts of
anhydrous potassium carbonate by Liu et al. to give the
60 corresponding adducts diastereoselectively in high yields.8
Conversions of the resulting trifluoromethyl β-nitroamines to α-
(trifluoromethyl)-α,β-diamino acids was also demonstrated.
et
al.
for
the
synthesis
of
α,β-diamino-β-
(trifluoromethyl)carboxylic acid in high yield and with excellent
30 diastereoselectivity.3 Additionally, the Mannich reaction of the
chlorotitanium enolate of (α-benzyloxy)acetyl 2-oxazolidinone
with the N-Cbz imine of trifluoropyruvate was explored by Zanda
et al. in asymmetric preparation of α-(trifluoromethyl)-β-
hydroxyaspartic acid.4 The Mannich reaction of diastereomeric
35 mixtures of oxazolidines derived from trifluoroacetaldehyde and
(R)-phenylglycinol with ethyl trimethylsilyl ketene acetal, studied
by Huguenot and Brigaud, was shown to afford the corresponding
β-amino ester derivatives with moderate diastereoselectivity.5
After chromatographic separation and removal of the chiral
40 auxiliary, the major isomer gave rise to enantiopure (R)-3-amino-
4,4,4-trifluorobutanoic acid. Lately, examples of highly
diastereoselective Mannich reactions were represented by
addition of ester enolates to trifluoromethyl imines bearing an N-
sulfinyl group as the chiral auxiliary. An efficient procedure
45 involving the addition of the chlorotitanium enolate of tert-butyl
Recently,
(SS)-N-(tert-butanesulfinyl)-3,3,3-
trifluoroacetaldimine (SS)-1 was introduced as a multifunctional
65 chiral synthon for the potencial preparation of a great variety of
organic compounds containing the biologically important α-
(trifluoromethyl)amino moiety.9 In particular, (SS)-1 has been
successfully employed for the asymmetric Reformatsky reaction10
as well as reactions with enolates to give adducts with good to
70 high level of diastereoselectivity.11 Subsequent deprotection of
the addition adducts under acidic conditions produced the free α-
trifluoromethyl amino derivatives without any sign of
racemization. Importantly, the synthesis of (SS)-1 as a pure E-
isomer can be performed on industrial scale, thus providing a
75 significant incentive for systematic study of its chemistry and
synthetic applications.10 To continue developing practical
methods for constructing fluorinated β-amino acids we have
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DOI: 10.1039/C3OB42425A
Table 1 Mannich reaction between dialkyl malonates 2 and imine (SS)-1 using inorganic bases or n-BuLi as catalystsa
O
S
O
O
S
F3C
H
F3C
H
R1O2C
R1O2C
S
Base (10 mol %)
+
N
N
+
CHR2(CO2R1)2
F3C
N
R2
R1O2C
R2
Solvent, Temp., Time
H
H
(SS)-1
R1O2C
2a-g
(1.0 equiv)
(1.0 equiv)
(R,SS)-3a-g
(S,SS)-4a-g
R1 = Et, R2 = H (a), R1 = Me, R2 = H (b), R1 = i-Pr, R2 = H (c), R = t-Bu, R2 = H (d),
R1 = Bn, R2 = H (e), R1 = Et, R2 = F (f), R1= Et, R2 = Me (g)
Entry
malonate
2a
2a
base
K2CO3
Cs2CO3
KOt-Bu
NaOt-Bu
K2CO3
n-BuLi
n-BuLi
n-BuLi
LiHMDS
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
Solvent (0.3 M)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
Temp. (oC)
rt
Time (h)
12
12
Yield (%)b
84
80
dr (R,SS)/(S,SS)c
1
2
3
75/25
71/29
76/24
75/25
48/52
86/14
89/11
89/11
88/12
80/20
88/12
87/13
89/11
87/13
89/11
90/10
92/8
rt
rt
rt
rt
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
12
12
24
3
2
2
2
3
2
5
87
96
83
85
88
88
95
82
78
85
83
61
94
98
99
98
4
5d
6
rt
7
8e
9
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
10
11
12f
13g
14
15
16h
17
18
19
20
21
22
Et2O
toluene
toluene
toluene (0.2 M)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1
3
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
86/14
58/42
95/5
79/21
84/16
2d
2e
2f
2g
99
99
84
80
a The reactions of (SS)-1 (1 equiv) with dialkyl malonates 2 (1 equiv) were performed in the corresponding solvent (0.3 M) in the presence of base (10 mol
b
c
d
e
5
%). Isolated total yield of both diastereomers. Determined by 19F NMR analysis. 20 mol % of 18-crown-6 was added to the reaction mixture. 1.2
equiv of LiCl was added to the reaction mixture. f 5 mol % of n-BuLi was used. g 20 mol % of n-BuLi was used. h 1.2 equiv of imine (SS)-1 were used.
explored a new asymmetric approach via the Mannich-type
reactions between (SS)-1 and derivatives of malonic acid followed
by decarboxylation of one of the carboxylic groups.12 Operational
and NaOt-Bu resulted in similar level of diastereoselectivity as
compared to K2CO3 (entries 3 and 4). However, in both cases the
yields were higher than 87%. Interestingly, the use of 18-crown-6
ether in conjunction with catalytic amounts of K2CO3 provided
10 simplicity of this approach would render it a highly attractive
alternative to the existing methods toward enantiomerically pure 35 the opposite ratio of diastereomers, however low dr was observed
3-amino-4,4,4-trifluorobutanoic acids. We report herein a full
account of our study concerning the asymmetric base-catalyzed
malonates addition to (SS)-1 giving access to β-amino acid
15 precursors.
(entry 5). Changing the counterion from potassium and sodium to
lithium by using malonate enolate prepared in advance with 10
mol % of n-BuLi allowed to improve the result of the Mannich
reaction. After stirring the reaction mixture for 3 h at room
40 temperature the addition product was isolated in 85% yield with
significant increase in diastereoselectivity to 86/14 dr (entry 6).
Results and Discussion
Temperature
control
experiments
showed
that
the
Mannich addition of dialkyl malonates
2 to N-(tert-
diastereoselectivity was sensitive to temperature and the highest
89/11 dr and chemical yield of 88% could be obtained at –78 ºC
45 (entry 7). The addition of LiCl as additive to the reaction
catalyzed by n-BuLi did not modify the result (entry 8). If a
catalytic amount of LiHMDS was employed as base for
pregeneration of lithium malonate enolate the mixture of
diastereomers was formed with improving yield without affecting
50 the diastereoselectivity significantly (entry 9). THF and Et2O
were also examined as solvents for this reaction, but lower yield
and diastereoselectivity were observed in both cases (entries 10
and 11). Further optimization of the reaction conditions focused
on several factors such as amount of catalyst, concentration of
55 reagents and reaction time, to reveal that using 10 mol % of n-
BuLi for pregeneration of malonate-derived enolate was required
butanesulfinyl)-3,3,3-trifluoroacetaldimine (SS)-1 in the
presence of inorganic bases or n-BuLi as catalysts
20 Our investigation of the asymmetric direct Mannich reaction was
begun with the addition of diethyl malonate 2a to the imine (SS)-1
in toluene in the presence of 10 mol % of K2CO3 or Cs2CO3.
These reactions required 12 h at room temperature to go to
completion giving rise to the desired addition product as a
25 mixture of (R,SS)-3a and (S,SS)-4a diastereomers. While K2CO3
afforded the addition product in 84% yield and 75/25 dr in favor
of the (R,SS)-3 isomer, the use of the Cs2CO3 lowered the
stereoselectivity of the reaction to 71/29 dr (Table 1, entries 1 and
2). The shown effect may be related to the size of the cation in
30 the solution. Other bases tested in the reaction such as KOt-Bu
2
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O
O
RO
OR
2
n-BuLi (10 mol %)
H
O
F3C
O
S
O
O
OLi
OR
RO
N
H
S
F3C
N
RO
RO
O
A
(S)-1
(R,SS)-3
Autocatalysis
O
O
S
F3C
H
O
O
RO
N
Li
RO
OR
2
RO
O
B
Scheme 1 Autocatalytic reaction of dialkyl malonates 2 with imine (SS)-1 in the presence of catalytic amount of n-BuLi
to ensure the best yields and selectivities in toluene at –78 ºC
within 0.25 h (entries 12-15). Under these optimized conditions,
the addition adduct was obtained in 98% isolated yield and 90/10
transition state TS 1 (Fig. 1) similar to proposed by Davis et al.
and Ellman et al., were both the sulfinyl oxygen and imine
nitrogen are coordinated to the metal.14 The suggestion of four-
5
dr (entry 16). Increasing the amount of base did not improve 45 membered chelate ring presented in transition state TS 1 is in
either yield or diastereoselectivity (entry 13). Interestingly, the
alkyl group of dialkyl malonates was found to have a substantial
accord with previously published crystal structure of lithium
azaenolates derived from carboxylic acid amides.15 Due to
chelation of the metal with the sulfinyl oxygen, enolate approach
occurs from opposite to the bulky tert-butyl group Re face of the
10 effect on the stereoselectivity. Excellent yield and a slightly
improved diastereoselectivity was observed for the addition of
dimethyl and dibenzyl malonates 2b,e when compared to the 50 imine delivering (R,SS) addition product. It should be emphasized
diethyl malonate 2a (entries 17 and 20). When diisopropyl and
di-tert-butyl malonates 2c,d were employed for the reaction,
15 excellent yield could still be obtained, however a significant drop
in diastereoselectivity to 86/14 and 58/42 dr was observed
that this mechanism is different from addition of organometallic
and Reformatsky reagents as well as enolates to imine (SS)-1
which proceeded via a non-chelated transition state model
affording predominantly (S,SS) diastereomers.9b,c,10 The crucial
(entries 18 and 19). The diethyl malonates 2f,g having fluorine or 55 role of the metal ion for realization of high stereoselectivity has
methyl substituent at the α-position also reacted with imine (SS)-1
giving the Mannich adducts in satisfying yield and
20 diastereoselectivity ranging from 79/21 to 84/16 (entries 21 and
22).
been proved by addition of diethyl malonate 2a in the presence of
18-crown-6 ether effectively breaking up the chelation (Table 1,
entry 5). Under these conditions (R,SS)-3a and (S,SS)-4a
diastereomers were formed in almost 1:1 ratio. Considering the
Taking into account the experimental results, the behavior of 60 sterically congested structure of the bicyclic chelated TS 1, the
n-BuLi as a catalyst in the Mannich addition reaction could be
explained by an autocatalytic process (Scheme 1). The first step
25 involves deprotonation of dialkyl malonate 2 with n-BuLi. The
resulting malonate-derived enolate A then reacts with the imine
(SS)-1 to form the lithium sulfinamide intermediate B. The latter
is sufficiently basic to deprotonate a new molecule of dialkyl
size of the chelating metal might be of great importance in its
stabilization. One may assume that Li could be a better fit in both
six- and four-membered chelated rings leading to more stable TS
1 and higher stereochemical outcome.
Re-attack
malonate
2 thus providing the sulfinamide (R,SS)-3 and
30 regenerating the malonate-derived enolate A to re-enter the
catalytic cycle.
S
N
H
H
O
M
(R,SS)-3
Assignment of the configuration of the major diastereomer
(R,SS)-3a was done after hydrolysis to the corresponding known
β-(trifluoromethyl)-β-alanine of (R) absolute configuration which
35 had (+)-sign of rotation.5,13 The resulting stereochemistry
revealed that the asymmetric induction in the Mannich-type
reaction of imine (SS)-1 with dialkyl malonates 2 catalyzed by
inorganic bases or n-BuLi matches to that of the reactions of non-
fluorinated N-tert-butanesulfinyl and N-p-toluenesulfinyl imines
40 with ester and malonate enolates.1b-e Thus, this stereoselectivity
could be rationalized by the six/four-membered bicyclic chelated
RO2C
O
CF3
RO
Chelated transition
state TS 1
65
Fig. 1 Transition state model for the Mannich reaction between imine
(SS)-1 and dialkyl malonates 2 catalyzed by inorganic bases or n-BuLi.
Mannich addition of dialkyl malonates
butanesulfinyl)-3,3,3-trifluoroacetaldimine (SS)-1 in the
70 presence of organic bases as catalysts
2 to N-(tert-
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N
The success in achieving high level of diastereoselectivity in the
NH
N
n-BuLi-catalyzed asymmetric Mannich reaction between dialkyl
malonates 2 and imine (SS)-1 led us to explore organic bases as
catalysts with the goal of inverting the stereochemical outcome of
these reactions. In this case no preformation of malonate enolate
would be required for preparation of addition adducts. We have
found that the reaction of imine (SS)-1 with diethyl malonate 2a
in the presence of 10 mol % of Et3N took place at a relatively
slow rate at room temperature to give, however, the desired
Me2N
NMe2
N
N
DABCO
(18.3)
DBU
(24.3)
TMG
(23.3)
5
t-Bu
t-Bu
Me
t-Bu
N
P
N
N
P
N
P
N
NEt2
Me
Me2N
NM2
Me2N
NM2
10 addition products as a mixture of (R,SS)-3a and (S,SS)-4a
diastereomers in 69/31 dr and 14% combined yield within 12 h
(Table 2, entry 1). With the aim to improve the yield and ratio of
diastereomers we revisited the reaction catalyzed by Et3N with
other organic bases. We found that synthetically meaningful
15 chemical yield (87%) and diastereomeric ratio (88/12) can be
obtained in the reactions catalyzed by DMAP at room
temperature for 48 h (entry 2). The ester group of malonate also
affected the asymmetric induction under DMAP-catalyzed
reaction. While dimethyl malonate 2b provided yield and
20 diastereoselectivity comparable to that observed for the diethyl
ester 2a, the use of more sterically demanding di-tert-butyl
malonate 2c produced noticeably lower yield and
diastereoselectivity (entries 3 and 4). The addition reaction with
diethyl malonate 2a catalyzed by sterically hindered, non-
25 nucleophilic N,N-diisopropylethylamine (Hünig’s base) occurred
at higher rate within 24 h but, most surprisingly, gave the ratio of
diastereomers (R,SS)-3a and (S,SS)-4a, which was opposite to that
we observed in the Et3N and DMAP-catalyzed reactions (entry
5). Inversion of the diastereoselectivity by simply changing of
30 base implied the involvement of two competitive reaction
pathways. With these results in hand, we set for ourselves a goal
of preparing the diastereomer (S,SS)-4a as the major product in a
synthetically meaningful yield by reasonable choice of the
catalyst. Taking advantage of commercial availability of
35 numerous quite strong and non-nucleophilic bases (Fig. 2) we
were in position to study their effect on rate and
diastereoselectivity of the reactions between imine (SS)-1 and
dialkyl malonates 2.
NMe2
NMe2
P1-t-Oct
P1-t-Bu
BEMP
(27.6)
(26.5)
(27.0)
Me2N
-Bu
t
NMe2
N
P
N
P
NMe2
Et
N
P
N
N
P
NMe2
NMe2
NMe2
NMe2
Me2N
NMe2
Me2N
P
N
P
NMe2
NMe2 NMe2
NMe2
P2-Et
P4-t-Bu
(32.9)
(42.7)
40 Fig. 2 Structures of strong, non-nucleophilic organic bases (pKBH values
in acetonitrile in parentheses16)
The reactions in the presence of the catalytic strong organic
nitrogen bases DBU and TMG allowed complete conversion of
the starting materials in 12 h. However, the observed ratio of
45 diastereomers still favoring product (S,SS)-4a was lower than in
the Hünig’s base-catalyzed reaction (Table 2, entries 7 and 8). In
the presence of 10 mol % of DABCO, which is less basic than
DBU and TMG, the reaction was sluggish and low yield of
Mannich adduct was obtained (entry 6). This finding showed that
50 DBU and TMG facilitated the nucleophilic attack, but did not
affect the structure of the transition state essentially. In an attempt
to improve these results, highly reactive “naked” enolates were
generated by deprotonation of 2a using a catalytic amount of
phosphazene bases.17 A series of reactions in the presence of 10
55 mol % of P1, P2, and P4 phosphazene bases in toluene at room
temperature showed a noticeable increase in the ratio of
diastereomers (S,SS)-4a and (R,SS)-3a to synthetically meaningful
94/6 in the case of P1-t-Oct (entries 9-13). The solvent effect was
also examined for the P1-t-Oct-catalyzed reaction. In DMF,
60 (S,SS)-4a was produced as the major product in a similar
diastereoselectivity and yield (entry 14). Using THF and CH2Cl2
as solvents gave comparable diastereoselectivity but low
chemical yields (entries 15 and 16). Furthermore, when the
reaction was performed in MeOH the diastereoselectivity was
65 decreased substantially (entry 17). The impact of temperature on
diastereoselectivity and yield of phosphazene bases-catalyzed
Mannich reactions was examined next. Lowering the temperature
to –78 oC led to an improvement in diastereoselectivity up to
98/2–99/1 dr (entries 18-22). The best result was observed with
70 P2-Et which was found to promote the addition of
diethylmalonate 2a in 84% yield and with 99/1 dr. To verify the
efficacy of the optimization procedure, the Mannich addition was
performed on various malonate esters 2b-g using the best
experimental conditions. Dialkyl malonates 2b-e cleanly reacted
75 with imine (SS)-1 to afford the desired Mannich products
generally with good yield and excellent diastereoselectivity
4
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(≥98/2 dr) (entries 23-26). A sole exception was dibenzyl
malonate 2e which gave the product in lower diastereoselectivity
could be purified by column chromatography. Further one-step
hydrolysis and decarboxylation under reflux in 6N HCl was
but without deteriorating yield. It should be mention that diethyl 15 performed on Mannich products to furnish the corresponding β-
2-fluoromalonate 2f was also tolerated under relatively basic
reaction conditions affording the Mannich product in excellent
yield and diastereoselectivity (entry 27). In fact, a single
diastereoisomer was observed for these cases by crude 19F NMR
amino acids (R)-5 and (S)-5 in enantiomerically pure form. Yield
of 95-96% was obtained under these convenient conditions. The
absolute stereochemistry of the products (R)-5 and (S)-5 has been
determined by comparison of their chiroptical properties with the
5
analysis. Methyl-substituted diethyl malonate 3g gave the 20 literature data.5,13 The configurations of the major diastereomers
Mannich adduct with a quaternary carbon atom in excellent 99/1 and were therefore assigned as (R,SS) and (S,SS)
correspondingly.
3
4
10 dr (entry 28). However, the yield of Mannich adduct was
diminished to 22% probably because of steric hindrance.
It is noteworthy that major diastereomers (R,SS)-3 and (S,SS)-4
25 Table 2 Mannich-type reaction between dialkyl malonates 2 and imine (SS)-1 in the presence of organic bases as catalysisa
O
S
O
S
O
S
F3C
H
F3C
H
R1O2C
R1O2C
Base (10 mol %)
+
N
N
+
CHR2(CO2R1)2
F3C
N
R2
R1O2C
R2
Solvent, Temp., Time
H
H
(SS)-1
R1O2C
2a-g
(1.0 equiv)
(1.0 equiv)
(R,SS)-3a-g
(S,SS)-4a-g
1) 6N HCl
2)
For (R,SS)-3a
For (S,SS)-4a
O
R1 = Et, R2 = H (a), R1 = Me, R2 = H (b), R1 = i-Pr, R2 = H (c),
R = t-Bu, R2 = H (d), R1 = Bn, R2 = H (e), R1 = Et, R2 = F (f),
R1= Et, R2 = Me (g)
NH2
NH2
CO2H
CO2H
F3C
F3C
(R)-5
(S)-5
95%
96%
Entry
1
2
3
4
5
6
7
8
Malonate
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
Base
Et3N
Solvent (0.3 M)
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DMF
Temp. (oC)
Time (h)
12
48
48
48
24
12
12
12
12
12
12
12
12
12
12
12
12
25
24
22
24
24
24
24
24
24
24
24
Yield (%)b
dr (R,SS)/(S,SS)c
69/31
88/12
88/12
80/20
20/80
34/66
25/75
39/61
6/94
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
–78
14
87
85
67
47
33
62
82
71
73
76
80
65
70
43
61
67
59
70
32
72
84
85
89
73
78
98
22
DMAP
DMAP
DMAP
i-Pr2EtN
DABCO
DBU
TMG
9
P1-t-Oct
P1-t-Bu
BEMP
P2-Et
P4-t-Bu
P1-t-Oct
P1-t-Oct
P1-t-Oct
P1-t-Oct
BEMP
P1-t-Oct
P1-t-Bu
P2-Et
P2-Et
P2-Et
P2-Et
P2-Et
P2-Et
P2-Et
P2-Et
10
11
12
13
14
15
16
17
18
19
20
21
22d
23
24
25
26
27
28
9/91
12/88
7/93
7/93
6/94
9/91
THF
CH2Cl2
MeOH
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
9/91
13/87
2/98
2/98
2/98
1/99
1/99
2/98
>1/99
>1/99
8/92
2d
2e
2f
2g
>1/99
1/99
a The reactions of (SS)-1 (1 equiv) with dialkyl malonates 2 (1 equiv) were performed in the corresponding solvent (0.3 M) in the presence of base (10 mol
%). b Isolated total yield of both diastereomers. c Determined by 19F NMR analysis. d 1.2 equiv of imine (SS)-1 were used.
To determine whether the (R,SS)-3a and (S,SS)-4a products
DMAP or phosphazene P2-Et in toluene at room temperature
30 were formed under kinetic or thermodynamic control, they were 35 failed and it was recovered in 90-95% yield (Scheme 2). Retro-
subjected to treatment with DMAP and phosphazene P2-Et under
the reaction conditions. However, attempts to isomerize
diastereomer (R,SS)-3a in the presence of 10 or 100 mol % of
Mannich products were not also observed either by NMR
analysis of the reaction mixtures or following separation of the
product. Similar results were noted for (S,SS)-4a with the same
This journal is © The Royal Society of Chemistry [year]
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DOI: 10.1039/C3OB42425A
bases combinations. These data indicated a kinetically controlled
addition of dialkyl malonates to imine (SS)-1 leading
preferentially to (R,SS)-3 or (S,SS)-4 depending on the organic
base employed.
highly stereoselective synthesis of either (R,SS)- or (S,SS)-β-
aminomalonates in good yield. Especially high
diastereoselectivity was attained using “naked”-enolates
40 generated with phosphazene bases. The β-aminomalonates
obtained were further applied in the synthesis of valuable 3-
amino-4,4,4-trifluorobutanoic acids 5 in both (R)- and (S)-
configurations. The described base-catalyzed asymmetric
synthesis is the shortest and most direct approach to 3-amino-
45 4,4,4-trifluorobutanoic acids.
DMAP
(10 mol % or 100 mol %)
O
S
O
S
toluene, rt, 36 h
F3C
H
F3C
H
EtO2C
EtO2C
(R,SS)-3a
EtO2C
EtO2C
(S,SS)-4a
N
N
H
H
or
P2-Et
Experimental
(10 mol % or 100 mol %)
toluene, rt, 18 h
General methods
5
Scheme 2 Stability of diastereomers (R,SS)-3a and (S,SS)-4a under basic
reaction conditions.
All reactions were performed in oven-dried glassware under a
positive pressure of nitrogen. Solvents were transferred via
50 syringe and were introduced into the reaction vessels through a
rubber septum. All reactions were monitored by TLC on 0.25 mm
Merck aluminum plates, silica gel 60, F254. The TLC plates were
visualized with UV light and 7% phosphomolybdic acid or
KMnO4 in water followed by brief heating. Column
55 chromatography was carried out on a column packed with silica
gel 60N spherical neutral size 63-210 ꢀm. The 1H-NMR (300
MHz), 13C-NMR (75.5 MHz) and 19F-NMR (282 MHz) spectra
for solution in CDCl3 or CD3OD were recorded on a Varian
Mercury 300. Chemical shifts (δ) are expressed in ppm and
60 referenced to the internal TMS (1H) and CFCl3 (19F). Mass
spectra were recorded on a SHIMAZU LCMS-2010EV (ESI-
MS). Optical rotations were measured on a HORIBA SEPA-300.
IR spectra were recorded on a JASCO FT/IR-4100 spectrometer.
To explain the observed results one can reasonably suggest
that diastereoselectivity of organic base-catalyzed Mannich
10 reactions of dialkyl malonates 2 with imine (SS)-1 is determined
by the competing of two transition states. Apparently, in the
presence of DMAP addition of dialkyl malonates in their enol
forms occurred via a proton-mediated six/four-membered bicyclic
chelated transition state TS 2 (Fig. 3) similar to transition state
15 TS 1 (Fig. 1) proposed for the Mannich reaction catalyzed by
inorganic bases or n-BuLi affording predominantly (R,SS)
diastereomers. The opposite sense of stereoinduction observed for
phosphazene-catalyzed addition of dialkyl malonates 2 was
attributed to the formation of “naked” enolates due to the
20 noncoordinating phosphazene counterion. Thus, the “naked”
caracter of phosphazene enolates precludes the formation of the
chelated transition state and addition was suggested to proceed
via a non-chelated transition state TS 3 (Fig. 3). In transition state
TS 3 enolates preferably added to the imine from the less
25 hindered Si-face to afford (S,SS) major diastereomer. Previously,
steric arguments were already used to explain stereochemical
preference for addition of organometallic reagents and ketone-
derivative enolates to weakly coordinating imine (SS)-1.
(R)-Diethyl 2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
65 trifluoroethyl]malonate (3a). General Procedure.
(a) To a solution of diethyl malonate 2a (0.30 mmol; 45.5 ꢀl) in
dry toluene (1.0 ml), n-BuLi (1.15 M in Hexane, 0.03 mmol; 26.1
ꢀl) was added with stirring at –78 ºC. After 10 min at –78 ºC
imine (SS)-1 (0.36 mmol; 72.4 mg) was added dropwise. Stirring
70 was continued at –78 ºC for 15 min, then the reaction was
quenched with saturated NH4Cl (3.0 ml), followed by H2O (10.0
ml) and the mixture was brought to room temperature. The
organic layer was taken and the aqueous layer was extracted with
diethyl ether (3 × 10 ml). The combined organic layers were
75 washed with brine (15 ml), dried over anhydrous Na2SO4 and the
solvent was removed under reduced pressure. After purification
by chromatography on silica-gel (Hexane/EtOAc = 4/1), 3a
(106.5 mg, 98.2%) was obtained as a colorless oil; [α]D25 +71.9 (c
Re-face attack
Si-face attack
RO
O BH
H
CF3
O
S
N
H
H
O
H
RO2C
H
N
RO2C
O
CF3
RO
1
1.48, CHCl3). H NMR (300 MHz, CDCl3): δ 1.24 (s, 9H), 1.29
Chelated transition
state TS 2
Open transition
state TS 3
80 (t, J = 6.9 Hz, 3H), 1.31 (t, J = 7.2 Hz, 3H), 3.81 (d, J = 3.0 Hz,
1H), 4.21 (q, J = 6.9 Hz, 2H), 4.27 (q, J = 7.2 Hz, 2H), 4.47 (dqd,
J = 3.0, 6.6, 9.3 Hz, 1H), 5.59 (d, J = 9.3 Hz, 1H); 13C NMR
(75.5 MHz, CDCl3): δ 13.6, 22.2, 49.5, 56.8, 58.6 (q, J = 31.6
Hz), 62.2, 63.1, 124.1 (q, J = 282.1 Hz), 165.1, 167.4; 19F NMR
85 (282 MHz, CDCl3): δ –75.6 (d, J = 6.6 Hz); IR (NaCl): 3328,
2984, 1747, 1469, 1263, 1182, 1130, 1092, 878, 461 cm-1; MS
(R,SS)
(S,SS)
30
Fig. 3 Transition state models for the Mannich-type reaction between
imine (S)-1 and dialkyl malonates 2 catalyzed by organic bases.
(ESI): m/z
=
384.1 [M+Na]+; HRMS (ESI) Calcd for
Conclusions
C13H22F3NNaO5S: (M+Na+): 384.1068, found: 384.1068.
(b) To a solution of diethyl malonate 2a (0.3 mmol; 45.5 ꢀl)
90 and DMAP (0.03 mmol; 3.7 mg) in dry toluene (1.0 ml), imine
(S)-1 (0.30 mmol; 60.4 mg) was added with stirring at room
temperature. After 48 h the solvent was removed under reduced
Inorganic as well as organic bases promote the catalytic
asymmetric Mannich addition of dialkyl malonates to (SS)-N-
35 (tert-butanesulfinyl)-3,3,3-trifluoroacetaldimine. These reactions
can be applied to a wide range of dialkyl malonates and lead to
6
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DOI: 10.1039/C3OB42425A
pressure. Purification by chromatography on silica-gel
(Hexane/EtOAc = 4/1) gave 3a (94.6 mg, 87.3%) as colorless oil; 60 [M+Na]+; HRMS (ESI) Calcd for C13H21F4NNaO5S: (M+Na+):
[α]D25 +68.5 (c 1.13, CHCl3).
402.0974, found: 402.0989.
1472, 1256, 1166, 1094, 1046, 882, 644; MS (ESI): m/z = 402.7
(R)-Dimethyl
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
(R)-Diethyl
2-methyl-2-[(S)-1-(tert-butanesulfinamido)-
5
trifluoroethyl]malonate (3b). Colorless oil; [α]D25 +78.9 (c 1.18,
2,2,2-trifluoroethyl]malonate (3g). Colorless oil; [α]D25 +82.1 (c
1
CHCl3); H NMR (300 MHz, CDCl3): δ 1.25 (s, 9H), 3.83 (s,
1.04, CHCl3); 1H NMR (300 MHz, CDCl3): δ 1.23 (s, 9H), 1.30
3H), 3.86 (d, J = 3.9 Hz, 1H), 3.88 (s, 3H), 4.53–4.41 (m, 1H), 65 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 6.9 Hz, 3H), 1.60 (s, 3H), 4.26-
5.55 (d, J = 9.3 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): δ 22.3,
49.4, 53.1, 53.8, 56.9, 58.8 (q, J = 31.6 Hz), 124.1 (q, J = 282.1
10 Hz), 165.6, 167.9; 19F NMR (282 MHz, CDCl3): δ –75.7 (d, J =
7.9 Hz); IR (NaCl): 3479, 3298, 2960, 1738, 1438, 1360, 1264,
1174, 1130, 1090, 929, 472 cm-1; MS (ESI): m/z = 356.6 70 Hz); IR (NaCl): 3312, 2984, 1742, 1470, 1245, 1180, 1097, 1018,
[M+Na]+; HRMS (ESI) Calcd for C11H18F3NNaO5S: (M+Na+):
4.33 (m, 4H), 4.48 (dq, J = 9.6, 7.5 Hz, 1H), 5.06 (d, J = 9.0 Hz,
1H); 13C NMR (75.5 MHz, CDCl3): δ 13.6, 18.3, 18.4, 22.3, 55.9,
57.2, 62.5, 62.7 (q, J = 29.9 Hz), 62.8, 124.4 (q, J = 283.8 Hz),
168.8, 169.0; 19F NMR (282 MHz, CDCl3): δ –69.0 (d, J = 6.8
863, 417; MS (ESI): m/z = 398.4 [M+Na]+; HRMS (ESI) Calcd
for C14H24F3NNaO5S: (M+Na+): 398.1225, found: 398.1249.
356.0755, found: 356.0770.
15
(R)-Diisopropyl
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
(S)-Diethyl
trifluoroethyl]malonate (4a). General Procedure.
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
trifluoroethyl]malonate (3c). Colorless oil; [α]D25 +65.4 (c 0.89,
CHCl3); 1H NMR (300 MHz, CDCl3): δ 1.24 (s, 9H), 1.29 (d, J =
6.0, 6H), 1.33 (d, J = 6.0 Hz, 6H), 3.75 (d, J = 2.7 Hz, 1H), 4.48
(dqd, J = 2.7, 7.8, 7.8 Hz, 1H), 5.15 (sept, J = 6.3 Hz, 1H), 5.16
75 To a solution of diethyl malonate 2a (0.30 mmol; 45.5 ꢀl) in dry
toluene (1.0 ml), P2-Et (0.03 mmol; 10.0 ꢀl) was added with
stiring at –78 ºC. After 10 min at –78 ºC imine (SS)-1 (0.36 mmol;
72.4 mg) was added dropwise. Stirring was continued at –78 ºC
for 24 h, then the reaction was quenched with saturated NH4Cl
80 (3.0 ml), followed by H2O (10.0 ml) and the mixture was brought
to room temperature. The organic layer was taken and the
aqueous layer was extracted with diethyl ether (3 × 10 ml). The
combined organic layers were washed with brine (15 ml), dried
over anhydrous Na2SO4 and the solvent was removed under
85 reduced pressure. After purification by chromatography on silica-
gel (Hexane/EtOAc = 4/1), 4a (91.1 mg, 84.0%) was obtained as
a colorless oil; [α]D25 +20.1 (c 1.52, CHCl3); 1H NMR (300 MHz,
CDCl3): δ 1.21 (s, 9H), 1.29 (t, J = 7.2 Hz, 3H), 1.31 (t, J = 7.2
Hz, 3H), 3.81 (d, J = 3.6 Hz, 1H), 4.22 (q, J = 7.2 Hz, 2H), 4.27
90 (q, J = 7.2 Hz, 2H), 4.47 (dqd, J = 3.6, 7.2, 10.8 Hz, 1H), 5.08 (d,
J = 10.8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): δ 13.7, 13.7,
22.3, 50.2, 57.2, 58.3 (q, J = 32.1 Hz), 62.1, 62.6, 123.9 (q, J =
284.3 Hz), 165.5, 166.7; 19F NMR (282 MHz, CDCl3): δ –74.0
(d, J = 7.2 Hz); IR (NaCl): 3294, 2984, 1733, 1471, 1263, 1181,
95 1130, 1092, 882, 493 cm-1; MS (ESI): m/z = 384.5 [M+Na]+;
HRMS (ESI) Calcd for C13H22F3NNaO5S: (M+Na+): 384.1068,
found: 384.1052.
20 (sept, J = 6.3 Hz, 1H), 5.62 (d, J = 8.7 Hz, 1H); 13C NMR (75.5
MHz, CDCl3): δ 21.3, 21.3, 21.4, 21.6, 22.3, 49.7, 56.8, 58.4 (q, J
= 31.5 Hz), 70.1, 71.4, 124.3(q, J = 282.1 Hz), 164.7, 167.0; 19F
NMR (282 MHz, CDCl3): δ –75.6 (d, J = 7.1 Hz); IR (NaCl):
3289, 2984, 1730, 1469, 1375, 1263, 1181, 1101, 920, 489; MS
25 (ESI): m/z
C15H26F3NNaO5S: (M+Na+): 412.1381, found: 412.1394.
(R)-Di-tert-butyl
=
412.6 [M+Na]+; HRMS (ESI) Calcd for
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
trifluoroethyl]malonate (3d). Colorless oil; [α]D25 +61.0 (c 2.13,
1
CHCl3); H NMR (300 MHz, CDCl3): δ 1.24 (s, 9H), 1.50 (s,
30 9H), 1.53 (s, 9H), 3.64 (d, J = 2.4 Hz, 1H), 4.43 (dqd, J = 2.4,
7.9, 8.7 Hz, 1H), 5.56 (d, J = 8.7 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3): δ 22.4, 27.7, 27.8, 50.8, 56.9, 58.1 (q, J = 30.4 Hz), 83.4,
84.5, 124.5 (q, J = 282.7 Hz), 164.3, 166.7; 19F NMR (282 MHz,
CDCl3): δ –75.5 (d, J = 7.9 Hz); IR (NaCl): 3288, 2980, 1724,
35 1459, 1370, 1263, 1175, 1094, 845, 488 cm-1; MS (ESI): m/z =
440.5 [M+Na]+; HRMS (ESI) Calcd for C17H30F3NNaO5S:
(M+Na+): 440.1694, found: 440.1693.
(R)-Dibenzyl
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
trifluoroethyl]malonate (3e). Colorless oil; [α]D25 +49.1 (c 1.39,
40 CHCl3); 1H NMR (300 MHz, CDCl3): δ 1.22 (s, 9H), 3.93 (d, J =
2.7 Hz, 1H), 4.52 (dqd, J = 3.0, 7.8, 9.3 Hz, 1H), 5.14-5.27 (m,
4H), 5.54 (d, J = 9.0 Hz, 1H), 7.26-7.41 (m, 10H); 13C NMR
(75.5 MHz, CDCl3): δ 22.3, 50.0, 56.9, 58.8 (q, J = 31.6 Hz),
68.1, 68.9, 124.1 (q, J = 282.1 Hz), 128.5, 128.5, 128.5, 128.6,
45 128.6, 128.8, 134.3, 134.6, 164.9, 167.1; 19F NMR (282 MHz,
CDCl3): δ –75.4 (d, J = 7.9 Hz); IR (NaCl): 3296, 2960, 1751,
1457, 1345, 1263, 1173, 1089, 698, 467; MS (ESI): m/z = 508.3
[M+Na]+; HRMS (ESI) Calcd for C23H26F3NNaO5S: (M+Na+):
508.1381, found: 508.1394.
(S)-Dimethyl
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
trifluoroethyl]malonate (4b). Colorless oil; [α]D25 +18.5 (c 0.90,
1
100 CHCl3); H NMR (300 MHz, CDCl3): δ 1.21 (s, 9H), 3.78 (s,
3H), 3.81 (s, 3H), 3.87 (d, J = 3.9 Hz, 1H), 4.48 (dqd, J = 3.9,
7.2, 10.8 Hz, 1H), 5.03 (d, J = 10.8 Hz, 1H); 13C NMR (75.5
MHz, CDCl3): δ 22.3, 50.0, 53.1, 53.3, 57.3, 58.4 (q, J = 31.5
Hz), 123.9 (q, J = 283.8 Hz), 166.0, 167.1; 19F NMR (282 MHz,
105 CDCl3): δ –74.0 (d, J = 7.2 Hz); IR (NaCl): 3472, 3331, 2959,
1749, 1438, 1365, 1263, 1173, 1131, 1086, 424 cm-1; MS (ESI):
m/z = 356.5 [M+Na]+; HRMS (ESI) Calcd for C11H18F3NNaO5S:
(M+Na+): 356.0755, found: 356.0757.
50
(R)-Diethyl
2-fluoro-2-[(S)-1-(tert-butanesulfinamido)-
2,2,2-trifluoroethyl]malonate (3f). Colorless oil; [α]D25 +79.4 (c
1
(S)-Diisopropyl
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
1.62, CHCl3); H NMR (300 MHz, CDCl3): δ 1.23 (s, 9H), 1.35
(t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H), 4.15 (d, J = 10.2 Hz,
110 trifluoroethyl]malonate (4c). Colorless oil; [α]D25 +14.5 (c 0.97,
1
1H), 4.31-4.48 (m, 4H), 4.81-4.94 (m, 1H); 13C NMR (75.5 MHz,
CHCl3); H NMR (300 MHz, CDCl3): δ 1.22 (s, 9H), 1.25-1.31
(m, 12H), 3.75 (d, J = 3.3 Hz, 1H), 4.46 (dqd, J = 3.3, 7.2, 10.8
Hz, 1H), 5.04 (sept, J = 6.3 Hz, 1H), 5.12 (sept, J = 6.3 Hz, 1H),
5.14 (d, J = 10.8 Hz, 1H); 13C NMR (75.5 MHz, CDCl3): δ 21.3,
115 21.3, 21.4, 21.4, 22.4, 50.5, 57.3, 58.2 (q, J = 32.1 Hz), 70.0,
70.7, 124.1 (q, J = 283.0 Hz), 165.1, 166.3; 19F NMR (282 MHz,
55 CDCl3): δ 13.6, 13.7, 22.2, 57.6, 61.5 (dq, J = 20.5, 30.6 Hz),
63.7, 64.4, 93.3 (d, J = 208.5 Hz), 123.0 (q, J = 283.2 Hz), 162.3,
162.7; 19F NMR (282 MHz, CDCl3): δ –71.3 (dd, J = 7.1, 9.9
Hz), –179.0 (dq, J = 9.9, 22.3 Hz); IR (NaCl): 3304, 2985, 1780,
This journal is © The Royal Society of Chemistry [year]
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CDCl3): δ –74.0 (d, J = 7.2 Hz); IR (NaCl): 3324, 2983, 1742,
propylene oxide (3.0 ml) and stirred for 1 h at room temperature.
1469, 1375, 1264, 1183, 1130, 908, 496 cm-1; MS (ESI): m/z = 60 Precipitate was filtered off and washed with hexane (2 × 3.0 ml)
412.6 [M+Na]+; HRMS (ESI) Calcd for C15H26F3NNaO5S:
(M+Na+): 412.1381, found: 412.1386.
to provide (R)-5 (149.4 mg, 95%) as a white solid: mp 174–175
ºC; [α]D25 +24.4 (c 1.05, 6N HCl); 1H NMR (300 MHz, CD3OD):
δ 2.49 (dd, J = 9.6, 16.5 Hz, 1H), 2.71 (dd, J = 3.6, 16.5 Hz, 1H),
3.81-3.91 (m, 1H); 13C NMR (75.5 MHz, CD3OD): δ 35.2, 51.8
5
(S)-Di-tert-butyl
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
trifluoroethyl]malonate (4d). White solid, Mp = 93–94 ºC;
[α]D25 +7.5 (c 1.04, CHCl3); 1H NMR (300 MHz, CDCl3): δ 1.24 65 (q, J = 30.4 Hz), 127.0 (q, J = 280.5 Hz), 173.7; 19F NMR (282
(s, 9H), 1.47 (s, 9H), 1.49 (s, 9H), 3.65 (d, J = 3.3 Hz, 1H), 4.36-
4.41 (m, 1H), 5.13 (d, J = 10.5 Hz, 1H); 13C NMR (75.5 MHz,
MHz, CD3OD): δ –77.1 (d, J = 7.1 Hz); IR (KBr): 2894, 2724,
2132, 1620, 1526, 1381, 1133, 902, 655; MS (ESI): m/z = 158.0
[M+H]+; HRMS (ESI) Calcd for C4H7F3NO2: (M+H+): 158.0429,
found: 158.0427.
10 CDCl3): δ 22.6, 27.6, 27.7, 51.5, 57.3, 58.0 (q, J = 31.0 Hz), 83.2,
83.7, 124.3 (q, J = 284.4 Hz), 164.7, 166.2; 19F NMR (282 MHz,
CDCl3): δ –74.0 (d, J = 7.9 Hz); IR (KBr): 3324, 2987, 1733,
1458, 1368, 1265, 1151, 1082, 985, 619 cm-1; MS (ESI): m/z =
440.6 [M+Na]+; HRMS (ESI) Calcd for C17H30F3NNaO5S:
15 (M+Na+): 440.1694, found: 440.1681.
70
(S)-3-Amino-4,4,4-trifluorobutanoic
acid
(5).
This
compound was synthesized according to procedure for (R)-5
starting from 4a on 2.50 mmol scale; yield 376.9 mg (96%);
white solid; [α]D25 –25.9 (c 1.02, 6N HCl).
(S)-Dibenzyl
2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
25
trifluoroethyl]malonate (4e). Colorless oil; [α]D +3.3 (c 1.06,
CHCl3); 1H NMR (300 MHz, CDCl3): δ 1.09 (s, 9H), 3.93 (d, J =
3.3 Hz, 1H), 4.49 (dqd, J = 3.3, 7.2, 10.8 Hz, 1H), 4.97 (d, J =
20 10.8 Hz, 1H), 5.10-5.25 (m, 4H), 7.21-7.37 (m, 10H); 13C NMR
(75.5 MHz, CDCl3): δ 22.3, 50.5, 57.3, 58.4 (q, J = 32.1 Hz),
68.1, 68.3, 123.9 (q, J = 284.3 Hz), 128.3, 128.5, 128.6, 128.7,
128.7, 128.8, 134.2, 134.3, 165.3, 166.4; 19F NMR (282 MHz,
CDCl3): δ –73.9 (d, J = 7.2 Hz); IR (NaCl): 3337, 2960, 1746,
25 1457, 1344, 1263, 1220, 1170, 1129, 1088, 698, 465 cm-1; MS
Acknowledgements
75 We thank IKERBASQUE, Basque Foundation for Science, and
the Basque Government (SAIOTEK S-PE12UN044) for generous
financial support.
Notes and references
a Department of Frontier Materials, Graduate School of Engineering,
80 Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555,
Japan. Fax: +81-52-735-5442; Tel: +81-52-735-7543; E-mail:
nozshiba@nitech.ac.jp
b Research Laboratory, TOSOH F-TECH, Inc., 4988 Kaisei-cho, Shunan,
Yamaguchi 746-0006, Japan.
85 c Department of Organic Chemistry I, Faculty of Chemistry, University of
the Basque Country UPV/EHU, 20018 San Sebastián, Spain. Fax: +34
943-015270; Tel: +34 943-015177; E-mail: vadym.soloshonok@ehu.es
d IKERBASQUE, Basque Foundation for Science, 48011 Bilbao, Spain
e Institute of Bioorganic Chemistry & Petrochemistry, National Academy
90 of Sciences of Ukraine, Murmanska 5, 02094 Kyiv, Ukraine.
† Electronic Supplementary Information (ESI) available: Copies of NMR
spectra for all compounds obtained. See DOI: 10.1039/b000000x/
(ESI): m/z
C23H26F3NNaO5S: (M+Na+): 508.1381, found: 508.1378.
(S)-Diethyl 2-[(S)-1-(tert-butanesulfinamido)-2,2,2-
=
508.4 [M+Na]+; HRMS (ESI) Calcd for
25
trifluoroethyl]-2-fluoromalonate (4f). Colorless oil; [α]D +0.9
1
30 (c 1.12, CHCl3); H NMR (300 MHz, CDCl3): δ 1.21 (s, 9H),
1.33 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 3H), 3.99 (d, J = 11.1
Hz, 1H), 4.19-4.40 (m, 4H), 4.79-4.97 (m, 1H); 13C NMR (75.5
MHz, CDCl3): δ 13.7, 13.7, 22.3, 57.4, 61.3 (dq, J = 19.9, 31.0
Hz), 63.5, 63.7, 93.7 (d, J = 211.3 Hz), 123.0 (q, J = 284.9 Hz),
35 162.5 (d, J = 24.9 Hz), 162.8 (d, J = 24.9 Hz); 19F NMR (282
MHz, CDCl3): δ –69.7 (dd, J = 6.9, 8.7 Hz), –179.8 (dq, J = 8.7,
23.7 Hz); IR (NaCl): 3286, 2985, 1771, 1472, 1254, 1166, 1094,
1046, 881, 492 cm-1; MS (ESI): m/z = 402.5 [M+Na]+; HRMS
(ESI) Calcd for C13H21F4NNaO5S: (M+Na+): 402.0974, found:
40 402.0988.
1
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(S)-Diethyl
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trifluoroethyl]-2-methylmalonate (4g). Colorless oil; [α]D
+6.2 (c 0.57, CHCl3); H NMR (300 MHz, CDCl3): δ 1.20 (s,
1
9H), 1.28 (t, J = 7.2 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 1.56 (d, J =
45 1.5 Hz, 3H), 4.17-4.30 (m, 4H), 4.57-4.59 (m, 2H); 13C NMR
(75.5 MHz, CDCl3): δ 13.7, 13.7, 17.2, 22.5, 56.6, 57.1, 62.2,
62.3, 62.6 (q, J = 29.9 Hz), 124.3 (q, J = 285.5 Hz), 168.5, 168.7;
19F NMR (282 MHz, CDCl3): δ –67.4 (d, J = 7.2 Hz); IR (NaCl):
3470, 3286, 2984, 1740, 1469, 1252, 1184, 1155, 1097, 734, 417
50 cm-1; MS (ESI): m/z = 398.6 [M+Na]+; HRMS (ESI) Calcd for
C14H24F3NNaO5S: (M+Na+): 398.1225, found: 398.1217.
2
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