Catalytic syntheses of γ-functionalized α-keto esters from thioacetals and N,O-acetals

Article abstract of DOI:10.1016/j.tet.2011.04.013

Ethyl 2-(trimethylsilyloxy)acrylic ester (1a) reacts with thioacetals providing the corresponding α-keto-γ-thio esters in good to satisfactory yields. Whereas aminals do not react, N,O-acetals lead to γ-amino-α-keto esters in good to excellent yields. All reactions proceed under mild reaction conditions, and no additional work up is required. Subsequent transformations of the obtained products to the corresponding α-oximes have been demonstrated.

Full text of DOI:10.1016/j.tet.2011.04.013

Tetrahedron 67 (2011) 4055e4060
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Catalytic syntheses of g-functionalized a-keto esters from thioacetals
and N,O-acetals
*
Anke Krebs, Carsten Bolm
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Ethyl 2-(trimethylsilyloxy)acrylic ester (1a) reacts with thioacetals providing the corresponding
a
-keto-
-amino- -keto
esters in good to excellent yields. All reactions proceed under mild reaction conditions, and no additional
g-
Received 15 February 2011
Received in revised form 31 March 2011
Accepted 6 April 2011
thio esters in good to satisfactory yields. Whereas aminals do not react, N,O-acetals lead to
g
a
work up is required. Subsequent transformations of the obtained products to the corresponding
have been demonstrated.
a-oximes
Available online 11 April 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Dedicated to Professor Dr. Dieter Enders on
the occasion of his 65th birthday
Keywords:
Acetals
Acrylic esters
Catalysis
a
-Keto esters
Thioacetals
1. Introduction
synthetic applications of such compounds can be found in the lit-
erature. Those include the use of 1 in radical polymerization re-
actions2 and applications as dienophiles in DielseAlder reactions.3
Baltas reacted 1 with epoxyaldehydes in Mukaiyama-aldol type
reactions furnishing ulosonic and heptulosonic esters and ana-
logues thereof.4 Photocycloaddition reactions with 1 were studied
by Bach, who prepared tetrahydrocyclobuta[c]-quinolin-3(4H)-
ones as part of his (þ)-meloscine synthesis.5 Finally, the majority of
applications stem from Sugimura, who reported reactions, such as
the one between ethyl 2-(trimethylsilyloxy)acrylate (1a) and
Synthesizing densely functionalized molecules by easy means
will always be a major challenge in organic chemistry. Key to suc-
cess is the choice of appropriate starting materials. (Tri-
alkylsilyloxy)acrylic esters 1 possess unique properties due to the
captodative 1,1-substitution of the double bond bearing an
electron-donating trialkylsilyloxy and an electron-withdrawing
carbonyl group. Generally, syntheses of such unsaturated esters
are straightforward and involve reactions between the corre-
sponding pyruvates and trialkylsilyl chloride (Scheme 1).1
(dimethoxymethyl)benzene (2a), which provided g-alkoxy-a-keto
ester 3a in good yield when performed in the presence of an excess
of borontrifluoride etherate.6 The product could then be reduced to
b,g-unsaturated a
-keto ester 4,7 which itself proved valuable for
synthetic organic chemistry (Scheme 2).8
OR
OSiMe3
OR
O
Lewis acid
OEt
OEt
+
OR
Scheme 1. (Trialkylsilyloxy)acrylic esters and their access from pyruvates and tri-
alkylsilyl chloride.
O
O
1a
a: R = Me
2
3
Despite the interesting structural features of (trialkylsilyloxy)
acrylic esters, only a rather limited number of reports dealing with
O
OEt
SiO2
3a
O
4
* Corresponding author. Tel.: þ49 241 8094675; fax: þ49 241 8092391; e-mail
Scheme 2. Synthesis of b,g-unsaturated a-keto ester 4.
address: carsten.bolm@oc.rwth-aachen.de (C. Bolm).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.04.013

4056
A. Krebs, C. Bolm / Tetrahedron 67 (2011) 4055e4060
Recently, we improved Sugimura’s protocol by developing
arylthioacetals 5b and 5c gave the corresponding products in only
49% and 53% yield, respectively (entries 2 and 3). Also the thio-
acetals derived from p-bromobenzaldehyde and 2-naph-
thylcarbaldehyde (5d and 5e, respectively) reacted with 1a, but the
a catalytic version of this synthetically useful CeC-bond forming
process.9 With Cu(OTf)2 as Lewis acid, side reactions resulting from
the acid sensitivity of the starting materials and products were
avoided, and a simple room temperature work up afforded
g-alk-
yields of the resulting a-keto-g-thio esters 6d and 6e were low (14%
oxy- -keto esters 3 in yields up to 99%. Various functional groups
were tolerated under these mild reaction conditions allowing
a broadening of the reaction scope.
With the goal to extend the product portfolio, we turned our
attention to reactions between ethyl 2-(trimethylsilyloxy)acrylate
(1a) and other electrophiles. Starting from thioacetals and aminal-
a
and 35%, entries 4 and 5). To our disappointment, several com-
pounds did not react at all. For example, no product was found in
attempts to use p-nitro- and p-dimethylamino-substituted thio-
acetals 5f and 5g, respectively, as electrophiles (entries 6 and 7).
The same was true for thioacetal 5h (entry 8), which was easily
prepared from benzaldehyde and thiophenol, and aliphatic thio-
acetal 5i (entry 9).
type compounds we envisaged the preparation of
a
-keto esters
with thio or amino substituents at the
the results of this study.
g
-position. Here, we present
Possible functionalizations of the resulting products were
demonstrated by the conversion of 6a into oxime 7. Following
a method described by Skarzewski,14
a-oxime-g-thio ester 7 was
2. Results and discussion
Taking into account the importance of sulfur-containing com-
pounds in organic synthesis,10 conversions of thioacetals 5 were
first investigated. For the preparation of suitable starting materials
aldehydes were treated with thiols in the presence of CuBr as cat-
alyst following a method described by Adapa.11 A Lewis acid
screening (Table 1) in reactions between ethyl 2-(trimethylsilyloxy)
acrylate (1a) and thioacetal 5a obtained from benzaldehyde and
ethanethiol revealed that scandium(III)triflate was the optimal
catalyst. Use of 10 mol % of this Lewis acid, which is known to act as
Table 2
Substrate scope in reactions between 1a and Thioacetals 5
SR
SR
O
OSiMe3
Sc(OTf)3
OEt
OEt
+
SR
DCM, 0°C
O
O
1a
5
6
Entry
1
Substrate 5
Product 6
SEt
% Yielda
62
catalyst in a variety of organic reactions,12 provided
a-keto-g-thio
O
SEt
OEt
ester 6a in 62% yield (entry 1). An attempt to improve this result by
addition of trifluoroethanol to the reaction mixture remained un-
successful affording 6a in only 19% yield (entry 2).13 To our surprise,
the yield of 6a was also low (20%, entry 3) with copper(II)triflate,
which had been the best metal catalyst in the acetal trans-
formations. Applying 10 mol % of borontrifluoride etherate led to
the same result (entry 4). Zinc triflate proved inactive (entry 5).
Next, the reaction scope was studied. All catalyses were per-
formed with 10 mol % of Sc(OTf)3 in dichloromethane at 0 ꢀC. The
results are summarized in Table 2.
SEt
O
5a
6a
SEt
SEt
O
OEt
2
3
4
49
53
14
SEt
5b
O
6b
Me
Me
MeO
Br
SEt
SEt
O
OEt
SEt
O
5c
6c
MeO
Br
Table 1
Screening of Lewis acids in reactions between 1a and Thioacetal 5aa
SEt
SEt
5d
SEt O
SEt
SEt
SEt
O
OEt
OSiMe3
OEt
Lewis acid
OEt
+
O
O
6d
SEt
O
O
1a
5a
6a
O
O
SEt
SEt
5e
OEt
OEt
% Yieldb
5
6
35
Entry
Lewis acid
Sc(OTf)3
Sc(OTf)3
Cu(OTf)2
BF3$OEt2
Zn(OTf)2
1
2
3
4
5
62
19
20
20
d
6e
SEt
c
SEt
SEt
d
O
a
5f
6f
O2N
O2N
Reaction conditions: the Lewis acid (10 mol %) was dissolved in DCM, and the
resulting solution was cooled to 0 ꢀC before 1a and 5a were added.
b
After column chromatography.
Trifluoroethanol (1.1 equiv) was added.
SEt
SEt O
c
OEt
7
8
SEt
d
O
The reactions between ethyl 2-(trimethylsilyloxy)acrylate (1a)
5g
6g
Me2N
Me2N
and thioacetals 5 to give the corresponding a-keto-g-thio esters 6
SPh O
SPh
SPh
5h
proved to be more challenging than the previously studied analo-
gous transformations starting from 1a and acetals.9 In particular,
the product isolation was difficult due to the formation of several
side products, which could not be identified. The best result was
obtained in the reaction between 1a and 1-[bis(ethylthio)methyl]
benzene (5a). After a careful optimization of the reaction time and
temperature the yield of a-keto-g-thio ester 6a reached 62% (Table
2, entry 1). Using thioacetals with substituted arenes led to lower
yields. For example, p-methyl and p-methoxy-substituted
OEt
OEt
d
d
O
O
6h
SEt
O
SEt
SEt
9
5i
6i
a
After column chromatography.

A. Krebs, C. Bolm / Tetrahedron 67 (2011) 4055e4060
4057
Table 3
Synthesis of
obtained in 74% yield upon treatment of 6a with the HCl salt of
hydroxylamine in the presence of KHSO4 (Scheme 3). Eventually,
compound 7 could provide access to carboxy-substituted iso-
xazoles by intramolecular ring-closure in analogy to the work by
g
-amino-
a
-keto esters 9a
NH-PG
PG
NH
O
OSiMe3
Cu(OTf)2
OEt
OEt
+
OMe
Skarzewski14 or
g-thio-substituted amino acids (by C]N reduction
DCM, 0°C
O
O
1a
followed by NeO cleavage).
11
9
Entry
Substrate
Product
% Yieldb
O
NH-Bz
OMe
11a
Ph
NH
O
1
2
3
72
OEt
Scheme 3. Reaction between a-keto-g-thio ester 6a and hydroxylamine.
O
9a
O
With the vision to prepare analogous g-amino a-keto esters 9,
NH-Boc
OMe
we focused our attention on reactions between 1a and aminals 8
(Scheme 4). However, neither bis(dimethylamino)-substituted
8a15a nor bis(pyrrolidinyl)benzaminal (8b)15b could sufficiently be
activated by Cu(OTf)2 or Sc(OTf)3. No reactions occurred in solvents,
such as dichloromethane or diethyl ether.
O
NH
O
51
OEt
11b
O
9b
O
NH-Bz-p-OMe
X
NR2
O
Lewis acid
NH
O
OSiMe3
OEt
53
98
OMe
OEt
MeO
Ph
OEt
+
X
O
11c
O
O
1a
9c
8a: X = NMe2
8b: X = N
9
O
Lewis acid =
Sc(OTf)3 or Cu(OTf)2
NH-Cbz
OMe
O
NH
O
4
OEt
Scheme 4. Attempted reactions between 1a and aminals 8 leading to
esters 9.
g-amino-a-keto
11d
O
9d
Hypothesizing that aminals were too stable under the applied
reaction conditions protected N,O-acetals 11 were tested as elec-
trophiles next. Benzoyl-protected 11a was selected as model sub-
strate. Its synthesis started from benzaldehyde, aniline, and
benzotriazole and proceeded via intermediate 10 (Scheme 5, top).16
For the preparations of N,O-acetals 11bed bearing other N-pro-
tecting groups a protocol developed by Dujardin was subsequently
used (Scheme 5, bottom).17
a
Reaction conditions: Cu(OTf)2 (0.1 equiv) was dissolved in DCM, and the
resulting solution was cooled to 0 ꢀC before the acetal (1 equiv) and the acrylic ester
(1.5 equiv) were added.
b
After column chromatography.
Finally, possible functionalizations of products 9 were shown by
the reaction of g-amino-a-keto ester 9a with the HCl salt of hy-
droxylamine in the presence of KHSO4, which gave oxime 12 in 97%
yield (Scheme 6).
O
O
HN
Ph
N
N
HN
N
Na
MeOH
PhCHO + PhNH2 + benzotriazole
OMe
11a
10
PG
Scheme 6. Reaction between a-keto-g-thio ester 9a and hydroxylamine.
PG
HN
HN
Na
MeOH
SO2Ph
PhCHO + PG-NH2 + PhSO2Na
OMe
11b-d
12b-d
3. Conclusion
A simple method for the preparation of
b: PG = Boc c: PG = p-MeO-Bz d: PG = Cbz
g-substituted a-keto
Scheme 5. Syntheses of protected N,O-acetals 11.
esters has been developed. Starting from ethyl (trimethylsilyloxy)
acrylic ester (1a) and differently substituted acetals the corre-
sponding products with
g-thio or g-amino groups have been
To our delight, Cu(OTf)2 smoothly catalyzed the reaction be-
tween 1a and N,O-acetal 11a, and in the presence of 10 mol % of this
metal salt product 9a was obtained in 72% yield (Table 3, entry 1). In
obtained in good yields. Either scandium(III)triflate or copper(II)
triflate served as catalysts. No tedious work up was required, and
for product isolation the reaction mixture could be directly sub-
mitted to column chromatography. Subsequent reactions with hy-
contrast, Sc(OTf)3 was inactive. Optimization studies revealed 0 ꢀ
C
to be the reaction temperature of choice, and DCM to be the most
suitable solvent. More strongly coordinating media hampered the
catalysis, and no product was observed. From N,O-acetals 11bed
with Boc, p-methoxybenzoyl, and Cbz groups at the nitrogens the
droxylamine afforded the corresponding a-oximes revealing the
possibility to further functionalize the initial products. In future
studies we plan to utilize the products as key building blocks for
potentially bioactive heterocycles. Attempts to render the reaction
sequence asymmetric are currently being pursued in our
laboratory.
corresponding
g-amino-a-keto esters (9bed) were obtained in
yields of 51%, 53%, and 98%, respectively (Table 3, entries 2e4).

4058
A. Krebs, C. Bolm / Tetrahedron 67 (2011) 4055e4060
4. Experimental section
NMR (100 MHz, CDCl3) d 14.4, 26.4, 52.6, 65.9, 125.8, 126.1, 126.2,
126.3, 127.6, 127.8, 128.6, 132.9, 133.0, 137.6.
4.1. General information
4.2.7. 1-[Bis(ethylthio)methyl]-4-dimethylaminobenzene (5g).18 1H
All solvents were dried before use. Dichloromethane was dis-
tilled over CaH2. Analytical TLC was performed with aluminum
sheets silica gel 60 F254, and the products were visualized by UV
detection or by KMnO4-stain. Flash chromatography was carried
out with silica gel 60 (63e100 mesh) as the stationary phase. NMR
spectra were recorded at 300 or 400 MHz (1H NMR) and 75 or
NMR (400 MHz, CDCl3)
(s, 6H), 4.83 (s, 1H), 6.58e6.62 (m, 2H), 7.22e7.26 (m, 2H); 13C NMR
(100 MHz, CDCl3) 14.5, 26.3, 40.6, 52.0, 112.2, 128.5, 149.9.
d 1.12e1.17 (m, 6H), 2.40e2.56 (m, 4H), 2.88
d
4.2.8. 1-[Phenyl(phenylthio)methyl]benzene
(300 MHz, CDCl3)
(75 MHz, CDCl3)
139.7.
(5h).18 1H
5.42 (s, 1H), 7.20e7.37 (m, 15H); 13C NMR
d 60.4, 127.8, 127.9, 128.0, 128.4, 128.8, 132.5, 134.5,
NMR
d
100 MHz (13C NMR). Chemical shifts (
million relative to TMS (
¼0 ppm) or the solvent residual peak
(CDCl3:
d
) are given in parts per
d
d
¼7.26 ppm) as internal standard. Coupling constants J are
reported in Hertz and coupling patterns are described as br¼broad,
s¼singlet, d¼doublet, dd¼doublet of doublet, t¼triplet, q¼quartet,
m¼multiplet. IR were recorded on a FT system and wave numbers
4.2.9. 1-Bis(ethylthio)butane (5i).19 1H NMR (400 MHz, CDCl3)
d
0.90 (t, J¼7.3 Hz, 3H), 1.23 (t, J¼7.4 Hz, 6H), 1.48e1.56 (m, 2H),
1.73e1.78 (m, 2H), 2.52e2.70 (m, 4H), 3.77 (t, J¼8.0 Hz, 1H); 13C
are given in cmꢁ1
.
NMR (100 MHz, CDCl3) d 13.7, 14.7, 20.8, 24.2, 38.3, 51.2.
If not otherwise mentioned all reagents were purchased from
commercial suppliers and used without further purification. All
reactions were carried out under argon atmosphere using standard
Schlenck-technique. Ethyl 2-(trimethylsilyloxy)acrylic ester (1a),1
compounds 8a15a and 8b15b as well as 11a16a were synthesized
according to literature procedures. Thioacetals and N,O-acetals
were prepared according to the slightly modified literature pro-
cedures described below.
4.3. General procedure for the synthesis of the
esters 6
a-keto-g-thio
Sc(OTf)3 (0.04 mmol) was dissolved in DCM (2 mL) and cooled to
0
ꢀC. Then, the thioacetal (0.4 mmol) and acrylic ester 1a
(0.6 mmol) were added. The reaction was monitored by TLC and
after consumption of the starting materials the reaction mixture
was submitted to column chromatography. The product was iso-
lated by using pentane/diethyl ether 20:1 as eluent.
4.2. General procedure for the synthesis of thioacetals11
The aldehyde (5 mmol) and the thiol (11 mmol) were dissolved
in acetonitrile (10 mL) and CuBr (0.25 mmol) was added. The re-
action mixture was then stirred overnight at room temperature.
After the addition of 4 N NaOH (10 mL), the mixture was extracted
with DCM and the combined organic layers were washed with
water. After drying over MgSO4 the solvents were evaporated. The
product was purified by column chromatography, using a mixture
of pentane and ether (10:1) as eluent.
4.3.1. Ethyl 4-(ethylthio)-2-oxo-4-phenyl-butanoate (6a). 1H NMR
(300 MHz, CDCl3)
d
1.09 (t, J¼7.4 Hz, 3H), 1.27 (t, J¼7.2 Hz, 3H),
2.24e2.32 (m, 2H), 3.33 (d, J¼7.4 Hz, 2H), 4.21 (q, J¼7.2 Hz, 2H),
4.30e4.37 (m, 1H), 7.14e7.32 (m, 5H); 13C NMR (75 MHz, CDCl3)
d
13.9, 14.2, 25.3, 43.4, 45.7, 62.6, 127.5, 127.7, 128.6, 129.0, 141.2,
160.4,191.1; MS (EI, 70 eV) m/z (%) 266.1 ([M]þ,10), 249.1 (10), 248.0
(60), 205.1 (11), 175.0 (9), 151.1 (53), 135.1 (13), 131.1 (100), 121.1 (9),
105.1 (36), 104.1 (23), 103.1 (26), 91.1 (14), 77.2 (16), 45.3 (12); IR
(capillary) 3451, 2978, 2923, 1729, 1602, 1451, 1264, 1080, 749, 700,
571 cmꢁ1; HRMS (C14H18O332S) calcd: 266.0971, found: 266.0971.
4.2.1. 1-[Bis(ethylthio)methyl]benzene (5a).18 1H NMR (300 MHz,
CDCl3)
d
1.15 (t, J¼7.4 Hz, 6H), 2.39e2.59 (m, 4H), 4.85 (s, 1H),
7.16e7.39 (m, 5H); 13C NMR (75 MHz, CDCl3)
d
14.3, 26.2, 52.4, 127.7,
4.3.2. Ethyl 4-(ethylthio)-4-(4-methylphenyl)-2-oxo-butanoate (6b).
128.5, 140.5.
1H NMR (400 MHz, CDCl3)
d
1.09 (t, J¼7.4 Hz, 3H), 1.26 (t, J¼7.1 Hz,
3H), 2.25 (s, 3H), 2.26e2.28 (m, 2H), 3.31 (d, J¼7.4 Hz, 2H), 4.21 (q,
J¼7.1 Hz, 2H), 4.28e4.33 (m, 1H), 7.03e7.05 (m, 2H), 7.16e7.19 (m,
4.2.2. 1-[Bis(ethylthio)methyl]-4-methylbenzene (5b).19 1H NMR
(300 MHz, CDCl3)
d
1.15e1.17 (m, 6H), 2.26 (s, 3H), 2.38e2.59 (m,
2H); 13C NMR (100 MHz, CDCl3)
d 14.1, 14.4, 25.4, 43.2, 45.9,
4H), 4.83 (s, 1H), 7.06 (d, J¼8.4 Hz, 2H), 7.26 (d, J¼7.9 Hz, 2H); 13C
62.6, 127.5, 129.1, 129.2, 129.8, 137.1, 138.1, 161.0, 191.3; MS (EI,
70 eV) m/z (%) 280.1 ([M]þ, 7), 262.1 (33), 219.1 (16),165.1 (21),146.1
(12), 145.1 (100), 119.1 (18), 118.1 (12), 117.1 (21), 115.1 (14), 91.2
(12); IR (capillary) 3415, 2979, 2921, 1905, 1729, 1598, 1448, 1262,
1080, 818, 518 cmꢁ1; HRMS (C15H20O332S) calcd: 280.1128, found:
280.1130.
NMR (75 MHz, CDCl3)
137.5.
d 14.2, 21.1, 26.2, 52.2, 127.6, 129.2, 137.4,
4.2.3. 1-[Bis(ethylthio)methyl]-4-methoxybenzene (5c).18 1H NMR
(400 MHz, CDCl3)
1.20 (t, J¼7.8 Hz, 6H), 2.45e2.56 (m, 4H), 3.79
(s, 3H), 4.89 (s, 1H), 6.82e6.85 (m, 2H), 7.34e7.37 (m, 2H); 13C NMR
(100 MHz, CDCl3) 14.4, 26.3, 51.9, 55.4, 128.9, 132.4, 158.9.
d
d
4.3.3. Ethyl 4-(ethylthio)-4-(4-methoxyphenyl)-2-oxo-butanoate(6c).
1H NMR (400 MHz, CDCl3)
d 1.14e1.17 (m, 3H), 1.32e1.36 (m, 3H),
4.2.4. 1-[Bis(ethylthio)methyl]-4-bromobenzene (5d).18 1H NMR
(400 MHz, CDCl3)
1.15 (t, J¼7.4 Hz, 6H), 2.39e2.57 (m, 4H), 4.80 (s,
1H), 7.25e7.28 (m, 2H), 7.37e7.40 (m, 2H); 13C NMR (100 MHz,
CDCl3) 14.4, 26.4, 51.8, 121.5, 129.4, 131.6, 139.6.
2.31e2.35 (m, 2H), 3.36e3.39 (m, 2H), 3.79 (s, 3H), 4.25e4.31 (m,
d
2H), 4.35e4.40 (m, 1H), 6.83e6.86 (m, 2H), 7.27e7.29 (m, 2H); 13C
NMR (100 MHz, CDCl3) d 14.1, 14.4, 25.4, 42.9, 46.0, 55.3, 62.7, 113.9,
d
128.8, 131.0, 133.0, 148.3, 160.4, 191.3; MS (EI, 70 eV) m/z (%) 296.1
([M]þ, 17), 235.1 (49),181.1 (11),162.2 (13),161.1 (100), 134.1 (16); IR
(capillary) 3447, 2921, 1729, 1592, 1512, 1253, 1077, 1032, 836,
545 cmꢁ1; HRMS (ESI, MeOH) calcd (C15H20O4SNa): 319.0974,
found: 319.0972.
4.2.5. 1-[Bis(ethylthio)methyl]-4-nitrobenzene
(400 MHz, CDCl3)
(5e).18 1H
1.20 (t, J¼7.4 Hz, 6H), 2.48e2.56 (m, 4H), 4.94 (s,
1H), 7.59e7.62 (m, 2H), 8.16e8.19 (m, 2H); 13C NMR (100 MHz,
CDCl3) 14.3, 26.4, 51.8, 123.8, 128.6, 147.2, 148.1.
NMR
d
d
4.3.4. Ethyl 4-(4-bromophenyl)-4-(ethylthio)-2-oxo-butanoate (6d).
4.2.6. 2-[Bis(ethylthio)methyl]naphthalene
(400 MHz, CDCl3)
(5f).18 1H
1.21 (t, J¼7.4 Hz, 6H), 2.49e2.65 (m, 4H), 5.09
(s, 1H), 7.44e7.50 (m, 2H), 7.62e7.64 (m, 1H), 7.80e7.84 (m, 4H); 13C
NMR
1H NMR (300 MHz, CDCl3)
d
1.09 (t, J¼7.4 Hz, 3H), 1.27 (t, J¼6.9 Hz,
3H), 2.28 (q, J¼7.4 Hz, 2H), 3.29 (d, J¼7.4 Hz, 2H), 4.15e4.37 (m, 3H),
7.17e7.49 (m, 4H); 13C NMR (75 MHz, CDCl3)
13.9, 14.2, 25.3, 42.8,
d
d

A. Krebs, C. Bolm / Tetrahedron 67 (2011) 4055e4060
4059
45.6, 62.7, 121.2, 129.5, 130.2, 131.7, 132.4, 140.4, 160.4, 190.0; MS (EI,
70 eV) m/z (%) 346.0 ([MþH]þ, 3), 328.0 (21), 326.0 (21), 285.0 (8),
283.0 (9), 231.0 (15), 229.0 (16), 211.0 (88), 210.1 (12), 209.0 (100),
184.0 (14), 183.0 (19), 182.0 (12), 132.2 (14), 130.1 (11), 104.2 (20),
103.2 (31), 102.2 (75), 101.2 (12), 89.2 (20), 77.3 (20), 76.3 (15), 75.2
(14), 51.4 (11); IR (capillary) 3452, 2977, 2922, 1731, 1606, 1484,
1H), 6.48 (d, J¼9.2 Hz, 1H), 6.91e7.83 (m, 10H); 13C NMR (CDCl3,
75 MHz)
d 55.4, 56.2, 81.8, 113.9, 125.9, 128.5, 128.6, 128.9, 139.5,
162.0; MS (EI, 70 eV) m/z (%) 256.1 ([MꢁCH3]þ, 3), 135.1 (100), 121.2
(20), 107.1 (11), 105.2 (10), 104.1 (10), 92.2 (21), 78.3 (65), 64.3 (12),
51.4 (13); IR (KBr) 3270, 2943, 1633, 1497, 1252, 1184, 1073, 1029,
845, 741, 683 cmꢁ1
; HRMS (ESI, MeOH) (C16H17O3N) calcd
1262, 1073, 1012, 826 cmꢁ1
;
HRMS (ESI, MeOH) calcd
([MþK]þ): 310.0840, found: 310.0842.
(C14H17O3BrSNa): 366.9970, found: 366.9976.
4.4.3. Benzyl N-[methoxy(phenyl)methyl]carbamate (11d). 1H NMR
4.3.5. Ethyl 4-(ethylthio)-4-(naphthalene-2-yl)-2-oxo-butanoate (6f).
(300 MHz, CDCl3) d 3.46 (s, 3H), 5.16 (s, 2H), 5.35 (br m, 1H), 5.89 (d,
1H NMR (400 MHz, CDCl3)
d
1.14 (t, J¼7.4 Hz, 3H), 1.28 (t, J¼7.1 Hz,
J¼9.9 Hz, 1H), 7.29e7.42 (m, 10H); 13C NMR (75 MHz, CDCl3)
d 55.7,
3H), 2.27e2.37 (m, 2H), 3.45e3.48 (m, 2H), 4.21e4.27 (m, 2H), 4.56
67.1, 84.0, 125.8, 128.1, 128.3, 128.5, 128.6, 136.1, 139.1, 155.9; MS
(ESI, MeOH) m/z (%) 294.3 ([MþNa]þ); IR (KBr) 3292, 1693, 1533,
1246, 1083, 971, 690 cmꢁ1; HRMS (ESI, MeOH) (C16H17O3N) calcd
([MþNa]þ): 294.1101, found: 294.1104.
(t, J¼7.4 Hz, 1H), 7.42e7.55 (m, 3H), 7.72e7.81 (m, 4H); 13C NMR
(100 MHz, CDCl3)
d 14.0, 14.4, 25.4, 43.7, 45.6, 62.7, 124.9, 125.5,
125.8,126.1,127.1,128.2,132.5,137.8,160.0,190.6; MS (EI, 70 eV) m/z
(%) 316.1 ([M]þ, 21), 298.1 (20), 255.1 (11), 237.1 (32), 201.1 (17),
182.1 (15), 181.1 (100), 155.1 (24), 154.1 (30), 153.1 (32), 152.1 (27);
4.5. General procedure for the synthesis of
esters 9
g-amino-a-keto
IR (film) 2977, 1725, 1596, 1233,1079, 1018, 928, 817, 748, 698 cmꢁ1
;
HRMS (C18H20O332S) calcd: 316.1128, found: 316.1129.
Cu(OTf)2 (0.04 mmol) was dissolved in DCM (2 mL) and cooled
to 0 ꢀC. The N,O-acetal (0.4 mmol) and acrylate 1a (0.6 mmol) were
added, and the reaction monitored by TLC. After complete con-
sumption of the acrylic ester the reaction mixture was submitted to
column chromatography. The product was isolated using a mixture
of pentane and ethyl acetate (8:2) as eluent.
4.3.6. 4-Ethylthio-4-phenyl-2-hydroxyimino-butyrate (7).
a-Keto-
g-thio ester 6a was dissolved in ethanol and hydroxylamine hy-
drochloride (1 equiv) and KHSO4 (0.2 equiv) were added. The
reaction mixture was stirred overnight and then, the solvent was
evaporated before the residue was submitted to column chroma-
tography. The product was isolated by using a mixture of pentane
and diethyl ether (8:2) as eluent. 1H NMR (300 MHz, CDCl3)
d
1.07
4.5.1. Ethyl 4-benzamido-2-oxo-4-phenylbutanoate (9a). 1H NMR
(t, J¼7.4 Hz, 3H), 1.19 (t, J¼7.2 Hz, 3H), 2.27 (q, J¼7.4 Hz, 2H),
(400 MHz, CDCl3)
d
1.22 (t, J¼7.1 Hz, 3H), 3.29 (dd, J¼10.9, 5.5 Hz,
3.04e3.24 (m, 2H), 4.12 (q, J¼7.2 Hz, 2H), 4.24e4.32 (m, 1H),
1H), 3.48 (dd, J¼9.9, 6.6 Hz, 1H), 4.18 (q, J¼7.1 Hz, 2H), 5.54 (m, 1H),
7.12e7.30 (m, 5H), 9.65 (br s, 1H); 13C NMR (75 MHz, CDCl3)
d 14.1,
6.78 (d, J¼7.4 Hz, 1H), 7.27e7.72 (m, 10H); 13C NMR (100 MHz,
14.3, 25.2, 31.5, 45.5, 61.8, 127.4, 127.6, 127.7, 128.4, 141.5, 150.3,
163.1; MS (EI, 70 eV) m/z (%) 281.2 ([M]þ, 1), 266.3 (5), 265.2 (16),
264.2 (100), 152.2 (9), 151.2 (96), 130.1 (30), 129.2 (14), 128.1 (35),
123.2 (14), 121.1 (15), 115.1 (15), 107.1 (17), 104.2 (16), 103.2 (39),
102.2 (10), 91.2 (15), 79.2 (19), 78.2 (13), 77.2 (31), 45.4 (20); IR
(CHCl3) 3278, 2921, 1723, 1447, 1300, 1189, 1022, 861, 757, 700,
522 cmꢁ1; HRMS (C14H19O3N32S) calcd: 281.1080, found: 281.1087.
CDCl3) d 14.1, 44.9, 50.3, 62.8, 126.5, 126.9, 127.9, 128.6, 128.9, 131.7,
133.8, 140.0, 160.4, 166.8, 191.9; MS (EI, 70 eV) m/z (%) 326.3
([MþH]þ, 1), 252.3 (19), 220.3 (41), 210.2 (21.8), 146.2 (13), 131.2
(25), 105.2 (100), 104.3 (13), 77.3 (43), 51.4 (13); IR (KBr) 3335, 1723,
1632, 1526, 1281, 1044, 696 cmꢁ1; HRMS (ESI, MeOH) (C19H19O4N)
calcd ([MþH]þ): 326.1367, found: 326.1383.
4.5.2. Ethyl
noate (9b). 1H NMR (300 MHz, CDCl3)
(s, 9H), 3.35e3.37 (m, 2H), 4.28 (q, J¼7.2 Hz, 2H), 5.14e5.92 (m, 2H),
7.21e7.37 (m, 5H); 13C NMR (75 MHz, CDCl3)
13.9, 28.3, 45.9, 51.2,
4-[(tert-butoxycarbonyl)amino]-2-oxo-4-phenylbuta-
4.3.7. N-(Methoxy(phenyl)methyl)benzamide (11a).16a 1H NMR
d
1.35 (t, J¼7.2 Hz, 3H), 1.41
(400 MHz, CDCl3)
d
3.54 (s, 3H), 6.37 (d, J¼9.3 Hz, 1H), 6.64 (d,
J¼9.1 Hz, 1H), 7.32e7.54 (m, 8H), 7.79e7.82 (m, 2H); 13C NMR
d
(100 MHz, CDCl3)
139.3, 167.2.
d
56.3, 81.8, 125.9, 127.1, 128.5, 128.6, 131.9, 133.7,
126.3, 127.8, 128.6, 128.8, 140.7, 155.0, 160.4, 191.6; MS (EI, 70 eV) m/
z (%) 321.1 ([M]þ, 3), 320.2 (11), 266.1 (11), 264.1 (16), 248.2 (12),
221.2 (32), 220.2 (8), 206.2 (34), 205.1 (20), 193.1 (13), 192.1 (68); IR
4.4. General procedure for the synthesis of N,O-acetals 11bed
(film) 3389, 2979, 1724, 1499, 1367, 1251, 1169, 1069, 701, 603 cmꢁ1
;
HRMS (ESI, MeOH) (C17H23O5N) calcd ([MþNa]þ): 344.1468, found:
Benzaldehyde (20 mmol), the amine (10 mmol), the sodium salt
of benzenesulfinic acid (25 mmol), and formic acid (20 mmol) were
dissolved in a mixture of water (20 mL) and methanol (10 mL). After
stirring overnight the reaction mixture was cooled to 0 ꢀC. The
resulting participate was filtered off and then dissolved in DCM.
After drying of the organic phase over MgSO4 the solvent was
evaporated. Then, the product was added to sodium methanolate
prepared from sodium (3 equiv) and methanol (3 equiv per 1 equiv
Na). After stirring overnight water was added. The resulting par-
ticipate was filtered off, dissolved in DCM, and the organic phase
was dried over MgSO4. The solvent was evaporated to yield the
clean product.
344.1468.
4.5.3. Ethyl 4-(4-methoxybenzoylamido)-2-oxo-4-phenylbutanoate
(9c). 1H NMR (300 MHz, CDCl3)
d
1.32 (t, J¼7.0 Hz, 3H), 3.41 (dd,
J¼11.1, 5.4 Hz, 1H), 3.57 (dd, J¼9.6, 6.9 Hz, 1H), 3.81 (s, 3H), 4.27 (q,
J¼7.0 Hz, 2H), 5.64 (dd, J¼7.2, 5.9 Hz, 1H), 6.85e6.89 (m, 2H), 6.98
(d, J¼7.9 Hz, 1H), 7.26e7.40 (m, 5H), 7.69e7.73 (m, 2H); 13C NMR
(75 MHz, CDCl3)
d 13.9, 44.9, 50.1, 55.3, 62.7, 113.7, 126.2, 127.9,
128.9, 140.4, 160.5, 162.3, 166.4, 192.0; MS (EI, 70 eV) m/z (%) 355.2
([M]þ, 1), 220.1 (12), 136.1 (8), 135.1 (100), 131.1 (10), 107.1 (7), 104.2
(7), 92.1 (8), 77.2 (13); IR (film) 3445, 3278, 2937, 1725, 1620, 1543,
1504, 1367, 1252, 1035, 847, 698 cmꢁ1; HRMS (C20H21O5N) calcd:
355.1414, found: 355.1414.
4.4.1. tert-Butyl N-[methoxy(phenyl)methyl]carbamate (11b).17 1H
NMR (400 MHz, CDCl3)
d
1.39 (s, 9H), 3.39 (s, 3H), 5.06 (br d, J¼8.5 Hz,
4.5.4. Ethyl 4-{[(benzyloxy)carbonyl]amino}-2-oxo-4-phenylbutan-
1H), 5.76 (d, J¼9.4 Hz, 1H), 7.19e7.36 (m, 5H); 13C NMR (100 MHz,
oate (9d). 1H NMR (CDCl3, 400 MHz)
d
1.31 (t, J¼7.1 Hz, 3H),
CDCl3)
d
28.4, 55.7, 83.4, 125.8, 128.4, 128.5, 128.9, 129.7, 139.4.
3.32e3.42 (m, 2H), 4.25 (q, J¼7.1 Hz, 2H), 5.05 (d, J¼4.4 Hz, 2H), 5.24
(br m, 1H), 5.54 (br d, J¼8.0 Hz, 1H), 7.28e7.33 (m, 10H); 13C NMR
4.4.2. 4-Methoxy N-[methoxy(phenyl)methyl]benzamide (11c). 1H
NMR (CDCl3, 300 MHz)
3.54 (s, 3H), 3.85 (s, 3H), 6.63 (d, J¼9.4 Hz,
(CDCl3, 100 MHz) d 14.1, 45.5, 51.5, 62.8, 67.0, 126.3, 127.8, 128.1,
d
128.5, 128.8, 136.2, 140.4, 155.5, 160.3, 191.4; MS (EI, 70 eV) m/z (%)

4060
A. Krebs, C. Bolm / Tetrahedron 67 (2011) 4055e4060
282.1 ([MꢁCO2Et]þ, 4), 146.1 (10), 104.1 (10), 91.2 (100), 65.2 (6); IR
(KBr) 3338, 1720, 1683, 1531, 1265, 1046, 735, 697 cmꢁ1; HRMS (ESI,
MeOH) (C20H22O5N) calcd: 356.1492, found: 356.1492.
4. (a) Ruland, Y.; Zedde, C.; Baltas, M.; Gorrichon, L. Tetrahedron Lett. 1999, 40,
7323e7327; (b) Sugisaki, C. H.; Ruland, Y.; Le Clezio, I.; Baltas, M. Synlett 2001,
1905e1908; (c) Sugisaki, C. H.; Ruland, Y.; Baltas, M. Eur. J. Org. Chem. 2003,
672e688; (d) Ruland, Y.; Noereuil, P.; Baltas, M. Tetrahedron 2005, 61,
8895e8903; (e) Filali, H.; Ballereau, S.; Chahdi, F. O.; Baltas, M. Synthesis 2009,
251e256; (f) Filali, H.; Danel, M.; Ballereau, S.; Baltas, M. Carbohydr. Res. 2010,
345, 2421e2426.
4.5.5. Ethyl 4-benzamido-2-hydroxyimino-4-phenylbutanoate (12).
g-Amino-a-keto ester 9a (0.2 mmol) was dissolved in ethanol
5. Bach, T.; Selig, P. Synthesis 2008, 2177e2182.
6. (a) Sugimura, H.; Shigekawa, Y.; Uematsu, M. Synlett 1991, 153e1
Watanabe, M.; Kobayashi, H.; Yoneda, Y. Chem. Lett. 1995, 163.
7. Sugimura, H.; Yoshida, K. Bull. Chem. Soc. Jpn. 1992, 65, 3209e3211.
54; (b)
(2 mL). Hydroxylamine hydrochloride (0.2 mmol) and KHSO4
(0.005 mmol) were added, and the reaction mixture was then
stirred overnight. After washing with water (5 mL) the mixture was
extracted with diethyl ether (3ꢂ5 mL). The combined organic
phases were dried over MgSO4, and the solvent evaporated to yield
8. (a) Sugimura, H.; Miura, M.; Yamada, N. Tetrahedron: Asymmetry 1997, 24,
4089e4099; (b) Audrain, H.; Thorauge, J.; Hazell, R. G.; Jørgensen, K. A. J. Org.
Chem. 2000, 65, 4487e4497; (c) Evans, D. A.; Johnson, J. S.; Olhave, E. J. J. Am.
Chem. Soc. 2000, 122, 1635e1649; (d) Jensen, K. B.; Thorauge, J.; Hazell, R. G.;
Jørgensen, K. A. Angew. Chem. 2001, 113, 164e167; Angew. Chem., Int. Ed. 2001,
the product. 1H NMR (400 MHz, CDCl3)
d
1.29 (t, J¼7.1 Hz, 3H), 3.18
(d, J¼8.24 Hz, 2H), 4.28 (q, J¼7.1 Hz, 2H), 5.54 (m,1H), 7.32e7.48 (m,
ꢀ
40, 160e163; (e) Herrera, R. P.; Monge, D.; Martín-Zamora, E.; Fernandez, R.;
9H), 7.78e7.80 (m, 2H), 10.57 (br s); 13C NMR (100 MHz, CDCl3)
Lassaletta, J. M. Org. Lett. 2007, 9, 3303e3306; (f) Yao, W.; Wu, Y.; Wang, G.;
Zhang, Y.; Ma, C. Angew. Chem. 2009, 121, 9893e9896; Angew. Chem., Int. Ed.
2009, 48, 9713e9716.
d
14.2, 32.0, 52.1, 62.4, 125.9, 127.0, 127.5, 128.5, 128.7, 131.6, 133.7,
141.7, 150.0, 164.6, 166.8; MS (ESI, MeOH) m/z (%) 341.1 ([MþH]þ);
9. Krebs, A.; Bolm, C. Synlett 2011, 671e673.
10. Organosulfur Chemistry in Asymmetric Synthesis; Toru, T., Bolm, C., Eds.; Wiley-
IR (KBr) 3320, 1721, 1640, 1530, 1426, 1318, 1196, 1014, 697 cmꢁ1
;
VCH: Weinheim, Germany, 2008.
HRMS (ESI, MeOH) (C19H20N2O4) calcd: 341.1482, found: 341.1495.
11. Varala, R.; Nuvula, S.; Adapa, S. R. Bull. Korean Chem. Soc. 2006, 27, 1079e1082.
12. (a) Kobayashi, S.; Hachiya, I.; Ishitani, H.; Araki, M. Synlett 1993, 472e474; (b)
Kawada, A.; Mitamura, S.; Kobayashi, S. Synlett 1994, 545e546; (c) Kang, Y.-B.;
Tang, Y.; Su, X.-L. Org. Biomol. Chem. 2006, 4, 299e301; (d) Evans, D. A.;
Sweeney, Z. K.; Rovis, T.; Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095e12096
For reviews see: (e) Kobayashi, S. Eur. J. Org. Chem. 1999, 15e27; (f) Kobayashi, S.
In Lewis Acids in Organic Synthesis; Yamamoto, H., Ed.; Wiley-VCH: Weinheim,
Germany, 2000.
Acknowledgements
We thank the Fonds der Chemischen Industrie for support.
Supplementary data
13. In several cases the addition of fluorinated alcohols was found to accelerate the
catalytic turnover in Mukaiyama-type reactions. For examples, see: (a) Kita-
jima, H.; Katsuki, T. Synlett 1997, 568e570; (b) Evans, D. A.; Johnson, S. D. S. Org.
Lett. 1999, 1, 595e598; (c) Evans, D. A.; Willis, M. C.; Johnson, S. D. S. Org. Lett.
1999, 1, 865e868; (d) Evans, D. A.; Rovis, T.; Kozlowski, M. C.; Tedrow, J. S. J. Am.
Copies of 1H and 13C NMR spectra of all unknown compounds.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2011.04.013.
ꢀ
Chem. Soc. 1999, 121, 1994e1996; (e) Langner, M.; Remy, P.; Bolm, C. Chem.dEur.
J. 2005, 11, 6254e6265.
14. Zielinska-Blajet, M.; Kowalczyk, R.; Skarzewski, J. Tetrahedron 2005, 61,
References and notes
5235e5240.
15. (a) Betschart, C.; Schmidt, B.; Seebach, D. Helv. Chim. Acta 1988, 71,
1999e2021; (b) Hatano, B.; Nagahashi, K.; Kijima, T. J. Org. Chem. 2008, 73,
9188e9191.
16. (a) Gizecki, P.; Dhal, R.; Poulard, C.; Gosselin, P.; Dujardin, G. J. Org. Chem. 2003,
68, 4338e4344; (b) Aggarwal, V. K.; Vasse, J.-L. Org. Lett. 2003, 5, 3987e3990.
17. Gizecki, P.; Youcef, R. A.; Poulard, C.; Dhal, R.; Dujardin, G. Tetrahedron Lett.
2004, 45, 9589e9592.
1. Barton, D. H. R.; Chern, C.-Y.; Jaszebrenyi, J. C. Tetrahedron 1995, 51, 1867e1886.
2. (a) Penelle, J.; Verraver, S. Makromol. Chem., Rapid Commun. 1993, 14, 563e568;
(b) Penelle, J.; Verraver, S.; Raucq, P.; Marchand-Brynaert, J. Macromol. Chem.
Phys. 1995, 196, 857e867.
3. (a) Dujardin, G.; Maudet, M.; Brown, E. Tetrahedron Lett. 1994, 35, 8619e8622;
(b) Takeda, K.; Imaoka, I.; Yoshii, E. Tetrahedron 1994, 50, 10839e10848; (c)
Creary, X.; Inocencio, P. A.; Underiner, T. L.; Kostromin, R. J. Org. Chem. 1985, 50,
1932e1938.
18. Wu, Y.-C.; Zhu, J. J. Org. Chem. 2008, 73, 9522e9524.
19. De, S. K. Synthesis 2004, 2837e2840.