Synthesis of α,α-disubstituted α-amino esters: Nucleophilic addition to iminium salts generated from amino ketene silyl acetals

Article abstract of DOI:10.1021/jo201692x

Alkoxycarbonyl iminium species are prepared easily by the oxidation of tetrasubstituted amino ketene silyl acetals, and subsequent nucleophilic addition of Grignard reagents to the iminium salts gives α,α- disubstituted α-amino ester derivatives in moderate to good yields, in which aryl and ethynyl substituents are readily introduced.

Full text of DOI:10.1021/jo201692x

Article
pubs.acs.org/joc
Synthesis of α,α-Disubstituted α-Amino Esters: Nucleophilic Addition
to Iminium Salts Generated from Amino Ketene Silyl Acetals
Shingo Hata, Hiroshi Koyama, and Makoto Shimizu*
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan
S
* Supporting Information
ABSTRACT: Alkoxycarbonyl iminium species are prepared
easily by the oxidation of tetrasubstituted amino ketene silyl
acetals, and subsequent nucleophilic addition of Grignard
reagents to the iminium salts gives α,α-disubstituted α-amino
ester derivatives in moderate to good yields, in which aryl and
ethynyl substituents are readily introduced.
diethylzinc sometimes induced undesirable hydrogenation and
N-alkylation as well as C-alkylation of α-imino esters.7c
Iminium salts are very reactive and attractive species in
organic synthesis. Regarding the synthesis of natural products
such as alkaloids, iminium ion mediated cyclization is effective.8
Reported examples using iminium species involve addition of
organometallic reagents for the synthesis of β-amino acids,9a,b
β-amino ketones, 1,3-amino alcohols,9c and so on.9d−jPetasis
reported the synthesis of α-monosubstituted α-amino acids by
the nucleophilic addition of boronates to the iminium ions,
which were prepared by the condensation of primary or
secondary amines with ethyl glyoxylate in situ.10 Although the
use of iminium ion is a promising procedure, there is much
room for the general synthesis of α,α-disubstituted α-amino
acids, since only limited examples are available.10b
We have recently reported that an alkoxycarbonyl iminium
species is generated easily from trisubstituted amino ketene silyl
acetal by oxidation, and the subsequent nucleophilic addition of
various nucleophiles readily affords the addition products.11
The applicability of our iminium system would be greatly
enhanced with a more convenient synthesis of α,α-disubstituted
α-amino acids possessing sp- or sp2-hybridized carbons: e.g.,
α,α-diaryl α-amino acids. Therefore, tetrasubstituted amino
ketene silyl acetal was chosen as a suitable precursor to the
iminium salt. This paper describes a convenient synthesis of
α,α-disubstituted α-amino acids, which uses the nucleophilic
addition of Grignard reagents to iminum salts generated from
amino ketene silyl acetals.
INTRODUCTION
■
α,α-Disubstituted α-amino acids have received considerable
attention, because oligopeptides containing them alter the
stabilization and the conformation of the secondary structure of
the protein.1 Although various approaches to the synthesis of
α,α-disubstituted α-amino acids have been reported,2 to the
best of our knowledge, only a few acceptable methods are
known. A practical synthesis of α,α-disubstituted α-amino acids
has been achieved using a phase-transfer catalyst.3 This type of
alkylation of the ester enolate has been successfully applied to
the synthesis of α-substituted amino acids.4 However, there are
some drawbacks associated with the scope of the reaction. In
addition, conventional alkylation approaches are not always
applicable to vinylation, arylation, and alkynylation.
Formation of sp2−sp3 and sp−sp3 bonds at the position α to
carbonyls has recently been resolved by utilizing Pd-catalyzed
coupling reactions.5,6 Although very useful direct α-arylation-
s6a,b of ketone,6c−f ester,6g−i amino ester,6j−l and amide6m have
been reported using palladium catalysts, there still remains a
need for a new arylation method for acyclic α,α-disubstituted α-
amino esters as well as in the intramolecular cases.6l
Consequently, it is of importance to develop methodologies
more compatible with the diverse spectra of functional groups.
Although more straightforward synthetic approaches involve
nucleophilic addition to α-imino esters, they sometimes suffer
from lower electrophilicity of the imino moiety as compared
with that of α-keto esters, and regio- and chemoselectivity
between imino and ester groups is also a critical issue. Except
for some reports, the following methods have been used to
circumvent the problems: introduction of an electron-with-
drawing group at the imino nitrogen moiety, the use of ate
complexes as nucleophiles, activation by Lewis acids, and
generation of the iminium ions.4e For example, iminomalo-
nates, regarded as highly reactive imine derivatives, reacted with
organolithium or Grignard reagents to give addition products in
moderate yields.7a,b In addition, organometallic reagents such as
RESULTS AND DISCUSSION
■
Amino ketene silyl acetals 3a,b and 4 were prepared from 2-
amino esters 1a,b and 2. On treatment of ethyl 2-amino
propanoates 1a,b with LDA (Scheme 1, method A) followed by
Received: August 14, 2011
Published: October 19, 2011
© 2011 American Chemical Society
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Scheme 1. Preparation of Amino Ketene Silyl Acetals 3, 4,
and 10 from 2-Amino Esters
Scheme 2. Isomerization of Iminium Salt 7 into Enamine 8
enamine. The reaction of amino ketene silyl acetal 4 with
isopropylmagnesium chloride or isopropylmagnesium bromide
gave the amino ester 9d without a side reaction involving
isomerization (Table 1, entries 8 and 9). The oxidation
reagents were also examined for the preparation of the iminium
salt from amino ketene silyl acetal 4 followed by alkylation with
ethylmagnesium bromide (entries 10−18). Oxidation with N-
bromosuccinimide (NBS) or N,N-dibromodimethylhydantoin
(DBDMH) followed by ethylation gave the amino ester 9b in
moderate yields (entries 10 and 14). In order to improve the
yield, the addition of a Lewis acid was investigated next. The
presence of BF3·OEt2 was found to be effective to give the
desired adduct 9b in 73% yield (entry 15). The reaction
conditions were further investigated regarding the temperature,
time, and amounts of reagents and additives (Tables 2 and 3).
silylation, the desired products 3a,b were obtained in moderate
yields. In the case of ethyl 2-(dibenzylamino)-2-phenylacetate
(2a), the use of KHMDS as a base gave a better result (method
B).
An initial examination was carried out to find a suitable
oxidation reagent for the preparation of iminium salt from
amino ketene silyl acetals 3a,b and 4 followed by alkylation
with Grignard reagents. Table 1 summarizes the results.
Table 2. Examination into Amounts of Reagents
Table 1. Oxidation and Isopropylation or Ethylation of
Amino Ketene Silyl Acetals 3a,b and 4
amt of DBDMH
(equiv)
amt of EtMgBr
(equiv)
amt of BF3·OEt2
yield
(%)
entry
(equiv)
1
2
3
4
5
6
1.0
1.0
1.0
1.0
1.0
0.5
1.2
1.5
2.0
2.0
2.0
2.0
1.0
1.0
1.0
1.5
2.0
1.0
32
59
73
60
62
53
a
entry substrate oxidn reagent
RMgX
solvent product yield (%)
1
3a
3a
3a
3a
3a
3a
3b
4
NBS
i-PrMgCl DME
i-PrMgCl THF
i-PrMgCl Et2O
5a
5a
5a
0
2
NBS
trace
6
3
NBS
4
NBS
i-PrMgCl EtCN 5a
i-PrMgCl EtCN 5a
i-PrMgCl EtCN 5a
i-PrMgCl EtCN 5b
i-PrMgCl EtCN 9d
i-PrMgBr EtCN 9d
22
0
5
PhI(OAc)2
DBDMH
NBS
6
trace
7
The best result was obtained using 4 (0.10 mmol), EtMgBr
(0.20 mmol) as a nucleophile, DBDMH (0.055 mmol) as an
oxidation reagent, and BF3·OEt2 (0.10 mmol) as an additive in
EtCN at 0 °C for 5 min (Table 3, entry 5).
Further studies were carried out to examine the use of alkyl,
vinyl, and aryl Grignard reagents. Results of the nucleophilic
addition of several Grignard reagents are summarized in Table
4. The reaction of iminium salts derived from amino ketene
silyl acetal 4 with Grignard reagents gave the desired product 9
with primary and secondary alkyl, aryl, and vinyl moieties at the
α-position in moderate to good yields (entries 1−6 and 8−14).
Unfortunately, bulky tert-butyl Grignard reagent did not give
satisfactory results (entry 7).
The scope of amino ketene silyl acetals was next examined
using addition reaction with EtMgBr, and the results are shown
in Table 5. The functionalized amino ketene silyl acetals 10
with aryl moieties bearing either electron-withdrawing or
electron-donating groups were employed successfully to give
the corresponding adducts in moderate to good yields.
The results of the nucleophilic addition of various Grignard
reagents with the alkynyl-substituted amino ketene silyl acetal
10f are shown in Table 6. The alkynyl derivative 10f was not a
suitable substrate for the present oxidative generation of
iminium salt followed by nucleophilic addition, and the
products were obtained in poor to moderate yields.
7
8
NBS
53
64
62
4
9
4
NBS
10
11
12
13
14
15
16
17
18
4
NBS
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtMgBr
EtCN 9b
EtCN 9b
EtCN 9b
EtCN 9b
EtCN 9b
EtCN 9b
EtCN 9b
EtCN 9b
EtCN 9b
4
NCS
4
NIS
56
44
63
73
36
0
4
DCDMH
DBDMH
DBDMH
DIDMH
PhI(OAc)2
DDQ
4
b
4
4
4
4
10
a
Reaction conditions: 3a,b and 4 (0.20 mmol), oxidation reagent
(0.20 mmol), RMgX (0.40 mmol), and EtCN (1.0 mL) were used. In
b
the presence of BF3·OEt2 (0.20 mmol).
Although several reaction conditions were investigated
(entries 1−7), satisfactory results were not obtained by the
oxidation of amino ketene silyl acetal 3 (R2 = Me) followed by
reaction with isopropylmagnesium chloride, presumably due to
an undesirable side reaction involving isomerization of the
iminium salt 7 into the enamine 8 (Scheme 2).
Amino ketene silyl acetal 4 (R2 = Ph) seemed to be a more
suitable substrate because of the ease of oxidation at the
benzylic position without a possible isomerization into
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Table 3. Examination into Reaction Temperature and Time
entry
temp and time
yield (%)
1
2
3
4
5
−78 to −50 °C, 1 h
60
71
70
76
78
−78 °C, 5 min, then room temp, 10 min
−78 °C, 5 min, then room temp, 30 min
−78 °C, 5 min, then room temp, 1 h
0 °C, 5 min
nucleophilic addition reaction to the iminium salt gives the
product 16.
Table 4. Nucleophilic Addition of Grignard Reagents Using
4
CONCLUSION
■
We have studied the generation and reactivity of alkoxycarbonyl
iminium salts by the oxidation of amino ketene silyl acetals
followed by nucleophilic addition and have found several
interesting features. We found that the iminium salts from
tetrasubstituted amino ketene silyl acetals, except for the
alkynyl-substituted case, were readily prepared using oxidation
with N,N-dibromodimethylhydantoin and that subsequent
nucleophilic addition with several Grignard reagents proceeded
in moderate to good yields. Since α,α-disubstituted α-amino
acids and oligopeptides containing them have received
considerable attention because of their biological interest, for
a more systematic study of these useful molecules, this
methodology provides us with a straightforward access to
them with alkyl, aryl, and vinyl moieties at the α-position, and
an easy entry into reactive iminium salts is also shown.
entry
RMgX
MeMgBr
product
yield (%)
1
9a
9b
9c
9d
9e
9f
83
78
80
74
2
EtMgBr
3
n-PrMgBr
4
i-PrMgBr
a
5
c-PrMgBr
84
6
c-HexMgBr
t-BuMgCl
66
b
7
9g
9h
9i
18
8
BnMgCl
66
80
65
52
56
88
82
9
(vinyl)MgBr
PhMgBr
10
11
12
13
14
9j
4-MeC6H4MgBr
4-MeOC6H4MgBr
(2-thienyl)MgBr
(ethynyl)MgBr
9k
9l
9m
9n
EXPERIMENTAL SECTION
■
a
b
The reaction was performed for 30 min. The reaction was
General Considerations. 1H NMR and 13C NMR spectra were
recorded on 270, 400, and/or 500 MHz spectrometers using
tetramethylsilane as an internal standard. Infrared spectra were
determined on an FT-IR spectrometer with the substance as a neat
film on a NaCl plate or as a pellet in a mixture with KBr. Mass spectra
were recorded on EI, AccuTOFF, and/or CI spectrometers. All
solvents were dried and distilled according to standard procedures
prior to use. Purification of products was performed by column
chromatography on silica gel (silica gel 60 N (spherical, neutral)) and/
or preparative TLC on silica gel (Kiesel Gel PF254). All reactions were
carried out under an argon atmosphere. KHMDS, n-butyllithium,
methylmagnesium bromide, vinymagnesium bromide, and ethynyl-
magnesium bromide were purchased and used as received. Other
Grignard reagents were prepared by the usual methods using the
appropriate alkyl (aryl) halides and magnesium.
performed at −78 °C for 30 min.
Table 5. Nucleophilic Addition of Grignard Reagents Using
10
Preparation of 2-Amino Esters 1a,b and 2a−2e. Typical
Procedure for 1a,b. Under an argon atmosphere, to a solution of
ethyl 2-bromopropionate (20.9 g, 115 mmol) in EtOH (30.0 mL) was
added diallylamine (15.6 mL, 127 mmol). After the reaction mixture
was refluxed for 19 h, it was concentrated in vacuo, followed by
addition of 1 M aqueous NaOH. The layers were separated, and the
aqueous layer was extracted with CH2Cl2 (70 mL × 3). The combined
extracts were dried over anhydrous Na2SO4 and concentrated in vacuo.
The crude product was purified by column chromatography on silica
gel (n-hexane/AcOEt 10/1) to give ethyl 2-(diallylamino)propanoate
(1a; 65%, 15.0 g).
a
The reaction was performed at −78 °C for 5 min and then at room
temperature for 1 h.
A plausible mechanism is shown in Scheme 3. The oxidation of
amino ketene silyl acetal 13 gives α-bromo ester 14, and the
subsequent elimination of the bromide ion leads to the
formation of iminium salt 15.12 It seems that the presence of
BF3·OEt2 promotes an elimination of the bromide ion or
activates the oxidation process as a Lewis acid. Finally, the
Ethyl 2-(Diallylamino)propanoate (1a). Colorless oil. 1H NMR
(400 MHz, CDCl3): δ 1.28 (t, J = 7.3 Hz, 6H), 3.14 (dd, J = 6.9, 14.6
Hz, 2H), 3.28 (dd, J = 5.5, 14.6 Hz, 2H), 3.58 (q, J = 7.3 Hz, 1H),
4.10−4.22 (m, 2H), 5.10 (dd, J = 1.9, 10.0 Hz, 2H), 5.19 (dd, J = 1.9,
17.4 Hz, 2H), 5.76−7.86 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ
14.3, 14.8, 53.5, 57.3, 60.0, 116.9, 136.5, 173.8. IR (neat): 3081, 2980,
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Table 6. Nucleophilic Addition of Grignard Reagents Using 10f
entry
RMgBr
R in 12
product
yield (%)
a
1
MeMgBr
EtMgBr
Me
Et
12a
12b
12c
12d
28
57
16
34
2
3
4
VinylMgBr
PhMgBr
Vinyl
Ph
a
DBDMH (1.7 equiv) was used.
Step 2: to a solution of ethyl 2-bromo-2-p-tolylacetate (11.8 g, 48.8
mmol) in EtOH (50.0 mL) was added dibenzylamine (10.3 mL, 53.6
mmol). The reaction mixture was refluxed for 22 h. After the reaction,
the whole mixture was concentrated in vacuo followed by the addition
of 1 M aqueous NaOH. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (80 mL × 3). The combined extracts
were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by column
chromatography on silica gel (n-hexane/AcOEt 20/1) to give ethyl 2-
(dibenzylamino)-2-p-tolylacetate (2b; 15%, 2.82 g).
Scheme 3. Plausible Reaction Mechanism
Ethyl 2-(Dibenzylamino)-2-phenylacetate (2a).11b Colorless oil.
1H NMR (500 MHz, CDCl3): δ 1.30 (t, J = 7.3 Hz, 3H), 3.73 (d, J =
14.2 Hz, 2H), 3.75 (d, J = 14.2 Hz, 2H), 4.20−4.34 (m, 2H), 4.60 (s,
1H), 7.19−7.35 (m, 15H). 13C NMR (125.7 MHz, CDCl3): δ 14.4,
54.2, 60.4, 65.8, 127.0, 127.7, 128.2, 128.3, 128.8, 136.8, 139.6, 172.1.
Ethyl 2-(Dibenzylamino)-2-p-tolylacetate (2b).11b Colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.28 (t, J = 7.3 Hz, 3H), 2.32 (s, 3H),
3.76 (s, 4H), 4.18−4.32 (m, 2H), 4.57 (s, 1H), 7.13−7.34 (m, 15H).
13C NMR (100.5 MHz, CDCl3): δ 14.4, 21.1, 54.2, 60.3, 65.7, 126.9,
128.2, 128.7, 128.8, 129.0, 133.7, 137.4, 139.7, 172.3.
2938, 2819, 1732, 1642, 1449, 1378, 1159, 993, 920 cm−1. MS (EI):
calcd for C11H19NO2 (M − C3H5O2)+ 124.1126, found 124.1127.
Ethyl 2-(Dibenzylamino)propanoate (1b).11b Colorless oil. 1H
NMR (400 MHz, CDCl3): δ 1.33−1.34 (m, 6H), 3.49 (q, J = 7.3 Hz,
1H), 3.65 (d, J = 14.0 Hz, 2H), 3.83 (d, J = 14.0 Hz, 2H), 4.13−4.27
(m, 2H), 7.20−7.39 (m, 10H). 13C NMR (125.7 MHz, CDCl3): δ
14.5, 15.0, 54.4, 56.1, 60.1, 126.9, 128.2, 128.6, 140.0, 173.8.
Typical Procedure for 2a,d,e. Step 1: to a solution of ethyl 2-
phenylacetate (8.21 g, 50 mmol) in CCl4 (50.0 mL) were added
successively N-bromosuccinimide (10.68 g, 60.0 mmol) and benzoyl
peroxide (1.211 g, 5.0 mmol). The reaction mixture was refluxed for
2.5 h. After the whole mixture was stirred for 8 h at ambient
temperature, it was filtered through a Celite pad with CCl4. The whole
mixture was concentrated in vacuo. The crude product was purified by
column chromatography on silica gel (n-hexane/AcOEt 10/1) to give
ethyl 2-bromo-2-phenylacetate (52%, 6.28 g).
Ethyl 2-(Dibenzylamino)-2-(4-methoxyphenyl)acetate (2c).11b
1
Colorless oil. H NMR (500 MHz, CDCl3): δ 1.28 (t, J = 7.3 Hz,
3H), 3.73 (d, J = 14.0 Hz, 2H), 3.76 (s, 3H), 3.77 (d, J = 14.0 Hz,
2H), 4.14−4.36 (m, 2H), 4.54 (s, 1H), 6.85−6.87 (m, 2H), 7.19−7.35
(m, 12H). 13C NMR (125.7 MHz, CDCl3): δ 14.4, 54.1, 55.2, 60.3,
65.2, 113.7, 126.9, 128.2, 128.7, 128.7, 129.9, 139.6, 159.1, 172.3.
Ethyl 2-(4-Chlorophenyl)-2-(dibenzylamino)acetate (2d).11b Col-
1
orless oil. H NMR (400 MHz, CDCl3): δ 1.31 (t, J = 7.3 Hz, 3H),
3.71 (d, J = 13.8 Hz, 2H), 3.76 (d, J = 13.8 Hz, 2H), 4.19−4.35 (m,
2H), 4.54 (s, 1H), 7.21−7.34 (m, 14H). 13C NMR (100.5 MHz,
CDCl3): δ 14.4, 54.2, 60.6, 65.2, 127.1, 128.3, 128.5, 128.8, 130.1,
133.6, 135.4, 139.3, 171.6.
Ethyl 2-(Dibenzylamino)-2-(naphthalen-1-yl)acetate (2e). Color-
less oil. 1H NMR (500 MHz, CDCl3): δ 1.31 (t, J = 7.3 Hz, 3H), 3.82
(d, J = 13.4 Hz, 2H), 3.94 (d, J = 13.4 Hz, 2H), 4.23−4.30 (m, 1H),
4.34−4.40 (m, 1H), 5.26 (s, 1H), 7.16−7.27 (m, 10H), 7.34−7.46 (m,
4H), 7.72−7.79 (m, 3H). 13C NMR (100.5 MHz, CDCl3): δ 14.4,
54.6, 60.4, 63.3, 124.6, 124.8, 125.7, 125.8, 126.4, 127.0, 128.1, 128.4,
128.9, 129.4, 132.1, 132.5, 134.1, 139.5, 172.7. IR (neat):: 3058, 3028,
2980, 2900, 2845, 1734, 1190, 1026, 752, 699 cm−1. HRMS (EI): calcd
for C28H27NO2 (M − C3H7)+ 336.1752, found 336.1760.
Preparation of 2-Amino Ester 2f. Ethyl 2-(dibenzylamino)-4-
phenylbut-3-ynoate (2f) was synthesized according to the literature.13
Under an argon atmosphere, to a solution of CuBr2 (447 mg, 2.0
mmol) and molecular sieves 4 Å (10 g) in toluene (50.0 mL) were
added ethyl glyoxylate (50% in toluene, 4.0 mL, 20 mmol),
phenylacetylene (2.2 mL, 20 mmol), and dibenzylamine (10.3 mL,
53.6 mmol). After the reaction mixture was stirred at room
temperature for 24 h, it was concentrated in vacuo followed by
filtration through a Celite pad with n-hexane. The crude product was
purified by column chromatography on silica gel (n-hexane/AcOEt
20/1) followed by recrystallization from EtOH to give ethyl 2-
(dibenzylamino)-4-phenylbut-3-ynoate (2f; 21%, 1.66 g).
Step 2: to a solution of ethyl 2-bromo-2-phenylacetate (4.03 g, 16.6
mmol) in EtOH (50.0 mL) was added dibenzylamine (3.50 mL, 18.2
mmol). The reaction mixture was refluxed for 19 h. After the reaction,
the whole mixture was concentrated in vacuo, followed by the addition
of 1 M aqueous NaOH. The layers were separated, and the aqueous
layer was extracted with CH2Cl2 (70 mL × 3). The combined extracts
were dried over anhydrous Na2SO4 and concentrated in vacuo. The
crude product was purified by column chromatography on silica gel (n-
hexane/AcOEt 20/1) to give ethyl 2-(dibenzylamino)-2-phenylacetate
(2a; 83%, 4.95 g).
Preparation of 2-Amino Esters 2b,c. Step 1: to a solution of 2-p-
tolylacetic acid (10.0 g, 66.6 mmol) in CCl4 (10.0 mL) was added
thionyl chloride (19.4 mL, 266 mmol). The reaction mixture was
refluxed for 0.5 h. N,N-Dibromodimethylhydantoin (11.4 g, 79.9
mmol), HBr (a few drops), and CCl4 (50 mL) were added to the
reaction mixture. The reaction mixture was heated at 85 °C for 2 h.
After cooling, the whole mixture was concentrated in vacuo followed
by the addition of EtOH (4.7 mL, 79.9 mmol). The reaction mixture
was stirred for a few minutes and concentrated in vacuo. Filtration
through a Celite pad with CCl4 followed by concentration in vacuo
gave the 2-bromo ester. The crude product was purified by column
chromatography on silica gel (n-hexane/AcOEt 20/1) to give ethyl 2-
bromo-2-p-tolylacetate (73%, 11.8 g).
Preparation of Tetrasubstituted Amino Ketene Silyl
Acetal. Scheme 1, Method A, 3a. Under an argon atmosphere,
to a solution of diisopropylamine (3.08 mL, 22 mmol) in THF (40.0
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mL) was added n-butyllithium (1.61 M in n-hexane, 13.7 mL, 22
mmol) at 0 °C. Solutions of ethyl 2-(diallylamino)propanoate (3.946
g, 20 mmol) in THF (20.0 mL) and tert-butyldimethylchlorosilane
(3.316 g, 22 mmol) in THF (20.0 mL) were successively added to a
solution of LDA at −78 °C. The reaction mixture was warmed to
ambient temperature with stirring for 24 h. The whole mixture was
concentrated in vacuo followed by filtration through a Celite pad with
n-hexane. The crude product was purified by column chromatography
on silica gel (n-hexane/AcOEt 20/1) to give the amino ketene silyl
acetal 3a (50%, 3.154 g, E/Z = >99/<1). The stereochemistry of
amino ketene silyl acetal 3a was determined in analogously to the
amino ketene silyl acetal 10c.
N,N-Diallyl-1-(tert-butyldimethylsilyloxy)-1-ethoxyprop-1-en-2-
amine (3a). E/Z = >99/<1. Colorless oil. 1H NMR (500 MHz,
CDCl3): δ 0.03 (s, 6H), 0.84 (s, 9H), 1.15 (t, J = 6.7 Hz, 3H), 1.41 (s,
3H), 3.16 (d, J = 6.7 Hz, 4H), 3.80 (q, J = 6.7 Hz, 2H), 4.91 (dd, J =
1.9, 8.6 Hz, 2H), 5.02 (dd, J = 1.9, 17.0 Hz, 2H), 5.71−7.59 (m, 2H).
13C NMR (125.7 MHz, CDCl3): δ −4.4, 10.8, 15.2, 18.0, 25.7, 56.3,
7.17−7.44 (m, 12H). 13C NMR (100.5 MHz, CDCl3): δ −5.3, 14.7,
17.8, 21.2, 25.5, 55.9, 65.0, 113.8, 126.5, 127.9, 128.1, 129.2, 130.2,
135.2, 135.4, 140.0, 148.9. IR (neat): 3061, 3027, 2930, 2858, 1641,
1456, 1254, 1203, 1155, 1047, 839, 698 cm−1. MS (CI): calcd for
C31H41NO2Si (M+) 487.29, found 487.30.
N,N-Dibenzyl-2-(tert-butyldimethylsilyloxy)-2-ethoxy-1-(4-
1
methoxyphenyl)ethenamine (10c). E/Z = 95/5. Colorless oil. H
NMR (400 MHz, CDCl3): δ −0.38 (s, 6H), 0.72 (s, 9H), 1.06 (t, J =
7.3 Hz, 3H), 3.41 (q, J = 7.3 Hz, 2H), 3.80 (s, 3H), 3.92 (s, 4H),
6.80−6.83 (m, 2H), 7.18−7.23 (m, 2H), 7.27−7.35 (m, 8H), 7.43−
7.45 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ −5.3, 14.7, 17.8,
25.5, 55.2, 55.9, 65.1, 112.8, 113.5, 126.5, 127.9, 129.2, 130.8, 131.4,
140.0, 148.5, 157.7. IR (neat): 3062, 3029, 2930, 2857, 1644, 1508,
1244, 1202, 1151, 1040, 840, 699 cm−1. HRMS (EI): calcd for
C31H41NO3Si (M+) 503.2856, found 503.2857.
N,N-Dibenzyl-2-(tert-butyldimethylsilyloxy)-2-ethoxy-1-(4-chloro-
1
phenyl)-2-ethoxyethenamine (10d). E/Z = 88/12. Colorless oil. H
NMR (400 MHz, CDCl3): δ −0.37 (s, 6H), 0.73 (s, 9H), 1.08 (t, J =
7.3 Hz, 3H), 3.45 (q, J = 7.3 Hz, 2H), 3.92 (s, 4H), 7.16−7.33 (m,
12H), 7.44−7.47 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ −5.2,
14.7, 17.8, 25.5, 56.1, 65.0, 112.8, 126.7, 127.5, 127.9, 129.1, 129.2,
130.9, 131.4, 137.3, 139.7, 149.7. IR (neat): 3062, 3029, 2931, 2858,
1636, 1489, 1254, 1207, 1156, 1045, 839, 699 cm−1. MS (CI): calcd
for C30H38ClNO2Si (M+) 507.24, found 507.25.
N,N-Dibenzyl-2-(tert-butyldimethylsilyloxy)-2-ethoxy-1-(naph-
thalen-1-yl)ethenamine (10e). E/Z = >99/<1. Colorless oil. 1H
NMR (400 MHz, CDCl3): δ −0.64 (s, 3H), −0.27 (s, 3H), 0.30 (s,
9H), 1.27 (t, J = 7.3 Hz, 3H), 3.66−3.74 (m, 1H), 3.80−3.86 (m, 1H),
3.99 (s, 4H), 7.17−7.49 (m, 12H), 7.69−7.87 (m, 3H). 13C NMR
(100.5 MHz, CDCl3): δ −5.8, −4.8, 15.0, 17.4, 24.9, 56.3, 65.5, 111.9,
124.8, 124.8, 124.9, 126.6, 127.0, 127.3, 127.8, 127.9, 128.6, 129.2,
132.7, 133.7, 135.6, 140.2, 149.0. IR (neat): 3060, 3031, 2930, 2857,
1652, 1455, 1254, 1216, 1154, 1031, 908, 839, 781, 737, 700 cm−1. MS
(CI): calcd for C34H41NO2Si (M+) 523.29, found 523.30.
N,N-Dibenzyl-1-ethoxy-1-(tert-butyldimethylsiloxy)-4-phenylbut-
1-en-3-yn-2-amine (10f). E/Z = >99/<1. Colorless oil. 1H NMR
(400 MHz, CDCl3): δ −0.08 (s, 6H), 0.90 (s, 9H), 1.19 (t, J = 7.3 Hz,
3H), 3.79 (q, J = 7.3 Hz, 2H), 3.83 (s, 4H), 7.17−7.35 (m, 9H), 7.43−
7.47 (m, 3H). 13C NMR (100.5 MHz, CDCl3): δ −4.7, 15.1, 18.1,
25.5, 58.8, 65.2, 85.4, 95.0, 97.9, 124.8, 126.6, 127.0, 127.9, 128.2,
129.3, 130.8, 139.7, 158.8. IR (neat): 3061, 3029, 2931, 2858, 2188,
1720, 1633, 1595, 1495, 1453, 1252, 1167, 1106, 1028, 840, 755, 699
cm−1. MS (CI): calcd for C32H39NO2Si (M+) 497.28, found 497.30.
Preparation of α,α-Disubstituted Amino Acid Ethyl Esters
5a,b: Typical Procedure (Table 1, Entry 4). Under an argon
atmosphere, to N-bromosuccinimide (35.6 mg, 0.20 mmol) were
successively added a solution of amino ketene silyl acetal 3a (62.3 mg,
0.20 mmol) in EtCN (1.0 mL) and 0.93 M i-PrMgCl in THF (0.43
mL, 0.40 mmol) at −78 °C. The reaction mixture was warmed to
ambient temperature with stirring for 7 h. It was quenched with
saturated aqueous NaHCO3 (10 mL). The layers were separated, and
the aqueous layer was extracted with ethyl acetate (30 mL × 3). The
combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product
was purified by preparative TLC on silica gel (developed twice with n-
hexane/AcOEt 20/1) to give ethyl 2-(diallylamino)-2,3-dimethylbuta-
noate (5a; 22%, 11.1 mg).
65.2, 107.7, 115.7, 137.1, 150.8. IR (neat): 3076, 2932, 2859, 1734,
1686, 1468, 1362, 1201, 1127, 836, 782 cm−1. MS (FI): calcd for
C17H33NO2Si (M+) 311.23, found 311.23.
Scheme 1, Method A, 3b. Under an argon atmosphere, to a
solution of diisopropylamine (3.08 mL, 22 mmol) in THF (40.0 mL)
was added n-butyllithium (1.61 M in n-hexane, 13.7 mL, 22 mmol) at
0 °C. A solution of ethyl 2-(dibenzylamino)propanoate (5.95 g, 20
mmol) in THF (20.0 mL) and a solution of tert-butyldimethyl-
chlorosilane (3.32 g, 22 mmol) in THF (20.0 mL) were successively
added to the preceding solution of LDA at −78 °C. The reaction
mixture was warmed to ambient temperature with stirring for 25 h.
After the reaction, the whole mixture was concentrated in vacuo,
followed by filtration through a Celite pad with n-hexane. The crude
product was purified by column chromatography on silica gel (n-
hexane/AcOEt 20/1) to give tetrasubstituted amino ketene silyl acetal
3b (59%, 4.89 g, E/Z = >99/<1). The stereochemistry of amino
ketene silyl acetal 3b was determined analogously to the amino ketene
silyl acetal 10c.
N,N-Dibenzyl-1-(tert-butyldimethylsilyloxy)-1-ethoxyprop-1-en-
1
2-amine (3b). E/Z = >99/<1. Colorless oil. H NMR (500 MHz,
CDCl3): δ −0.00 (s, 6H), 0.97 (s, 9H), 1.36 (t, J = 6.7 Hz, 3H), 1.62
(s, 3H), 3.79 (q, J = 6.8 Hz, 2H), 3.96 (s, 4H), 7.28−7.42 (m, 6H),
7.47−7.52 (m, 4H). 13C NMR (125.7 MHz, CDCl3): δ −4.8, 12.1,
15.1, 17.6, 25.6, 57.1, 64.8, 108.5, 126.5, 127.9, 128.7, 140.4, 150.3. IR
(neat): 3062, 3029, 2932, 2858, 1733, 1681, 1495, 1453, 1361, 1254,
1191, 1145, 838, 698 cm−1. MS (CI): calcd for C25H37NO2Si (M+)
411.26, found 411.30.
Typical Procedure: Scheme 1, Method B, 4. Under an argon
atmosphere, to a solution of KHMDS (0.50 M in toluene 35.4 mL,
17.7 mmol) were added solutions of tert-butyldimethylchlorosilane
(2.67 g, 17.7 mmol) in THF (20.0 mL) and 2-(dibenzylamino)-2-
phenylacetate (5.31 g, 14.7 mmol) in THF (20.0 mL) successively at
−78 °C. The reaction mixture was warmed to ambient temperature
with stirring for 18 h. The whole mixture was concentrated in vacuo
followed by filtration through a Celite pad with n-hexane. The crude
product was purified by column chromatography on silica gel (n-
hexane/triethylamine 10/1) to give the amino ketene silyl acetal 4
(48%, 1.67 g, E/Z = 90/10). The stereochemistry of amino ketene silyl
acetal 4 was determined analogously to amino ketene silyl acetal 10c.
N,N-Dibenzyl-2-(tert-butyldimethylsilyloxy)-2-ethoxy-1-phenyle-
Ethyl 2-(Diallylamino)-2,3-dimethylbutanoate (5a). Colorless oil.
1H NMR (500 MHz, CDCl3): δ 0.82 (d, J = 6.7 Hz, 3H), 0.90 (d, J =
1
thenamine (4). E/Z = 85/15 to 90/10. Colorless oil. H NMR (400
6.7 Hz, 3H), 1.16 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H), 2.37 (sept, J = 6.7
Hz, 1H), 3.18 (dd, J = 6.5, 15.5 Hz, 2H), 3.39 (dd, J = 5.0, 15.5 Hz,
2H), 4.14 (q, J = 7.1 Hz, 2H), 5.00 (dd, J = 1.5, 10.1 Hz, 2H), 5.11
(dd, J = 1.5, 17.1 Hz, 2H), 5.76−5.84 (m, 2H). 13C NMR (125.7
MHz, CDCl3): δ 14.4, 15.4, 16.0, 18.5, 31.0, 51.9, 59.9, 68.4, 115.3,
138.0, 174.9. IR (neat): 2974, 1721, 1236, 1094, 915 cm−1. HRMS
(EI): calcd for C11H18NO2 (M − C3H7)+ 196.1338, found 196.1343.
Ethyl 2-(Dibenzylamino)-2,3-dimethylbutanoate (5b). Colorless
oil. 1H NMR (400 MHz, CDCl3): δ 0.89 (d, J = 6.6 Hz, 3H), 1.03 (d, J
= 6.6 Hz, 3H), 1.14 (s, 3H), 1.32 (t, J = 7.3 Hz, 3H), 2.58 (sept, J = 6.6
Hz, 1H), 3.71 (d, J = 14.9 Hz, 2H), 3.96 (d, J = 14.9 Hz, 2H), 4.19
MHz, CDCl3): δ −0.38 (s, 6H), 0.71 (s, 9H), 1.06 (t, J = 6.8 Hz, 3H),
3.44 (q, J = 6.8 Hz, 2H), 3.94 (s, 4H), 7.17−7.35 (m, 13H), 7.50−7.54
(m, 2H). 13C NMR (100.5 MHz, CDCl3): δ −5.3, 14.7, 17.8, 25.5,
55.1, 65.0, 114.0, 125.7, 126.6, 127.3, 127.9, 129.2, 130.4, 138.5, 139.9,
149.2. IR (neat): 3060, 3028, 2930, 2858, 1641, 1484, 1453, 1254,
1204, 1045, 838, 697 cm−1. MS (CI): calcd for C30H39NO2Si (M+)
473.28, found 473.30.
N,N-Dibenzyl-2-(tert-butyldimethylsilyloxy)-2-ethoxy-1-p-tolyle-
1
thenamine (10b). E/Z = 92/8. Colorless oil. H NMR (400 MHz,
CDCl3): δ −0.38 (s, 6H), 0.72 (s, 9H), 1.05 (t, J = 7.3 Hz, 3H), 2.32
(s, 3H), 3.41 (q, J = 7.3 Hz, 2H), 3.92 (s, 4H), 7.06−7.09 (m, 2H),
9674
dx.doi.org/10.1021/jo201692x|J. Org. Chem. 2011, 76, 9670−9677

The Journal of Organic Chemistry
Article
(dq, J = 7.3, 10.9 Hz, 1H), 4.20 (dq, J = 7.3, 10.9 Hz, 1H), 7.05−7.17
(m, 6H), 7.20−7.26 (m, 4H). 13C NMR (100.5 MHz, CDCl3): δ 14.6,
16.2, 16.4, 18.9, 30.9, 54.4, 60.0, 70.1, 126.2, 127.7, 128.5, 141.3, 173.7.
2852, 1722, 1492, 1451, 1214, 1029, 746, 698 cm−1. HRMS (EI): calcd
for C24H24N (M − C3H5O2)+ 326.1903, found 326.1906.
Ethyl 2-Cyclohexyl-2-(dibenzylamino)-2-phenylacetate (9f).
White solid. Mp: 103−104 °C. 1H NMR (400 MHz, CDCl3): δ
0.29−0.39 (m, 1H), 0.51−0.61 (m, 1H), 0.75−0.84 (m, 2H), 1.27−
1.31 (4H, including triplet at 1.30 ppm (J = 7.1 Hz, 3H)), 1.42−1.48
(m, 2H), 1.56−1.60 (m, 1H), 1.74−1.78 (m, 1H), 1.87−1.91 (m, 1H),
2.40−2.48 (m, 1H), 3.71−3.90 (m, 4H), 4.12−4.29 (m, 2H), 7.07−
7.36 (m, 15H). 13C NMR (100.5 MHz, CDCl3): δ 14.5, 26.2, 26.6,
26.9, 27.7, 31.1, 60.1, 78.5, 126.4, 126.6, 126.9, 127.8, 129.2, 129.3,
138.2, 139.9, 171.1. IR (neat): 3088, 3028, 2929, 2853, 1719, 1495,
1451, 1215, 1026, 745, 698 cm−1. HRMS (EI): calcd for C27H30N (M
− C3H5O2)+ 368.2373, found 368.2384.
IR (neat): 2974, 1717, 1495, 1456, 1233, 1127, 1026, 744, 697 cm−1
.
HRMS (EI): calcd for C19H22NO2 (M − C3H7)+ 296.1651, found
296.1654.
Preparation of α,α-Disubstituted Amino Acid Ethyl Esters
9a−n and 11a−f: Typical Procedure (Table 4, Entry 2). Under
an argon atmosphere, to N,N-dibromodimethylhydantoin (57.2 mg,
0.20 mmol) were successively added a solution of amino ketene silyl
acetal 4 (94.7 mg, 0.20 mmol) in EtCN (1.0 mL), BF3·OEt2 (0.025
mL, 0.20 mmol), and 0.76 M EtMgBr in Et2O (0.52 mL, 0.40 mmol)
at 0 °C. After the mixture was stirred for 5 min at 0 °C and then for 1
h at room temperature, it was quenched with saturated aqueous
NaHCO3 (10 mL). The layers were separated, and the aqueous layer
was extracted with ethyl acetate (30 mL × 3). The combined organic
extracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified by preparative
TLC on silica gel (developed twice with n-hexane/AcOEt 10/1) to
give ethyl 2-(dibenzylamino)-2-phenylbutanoate (9b; 82%, 64.2 mg).
Ethyl 2-(Dibenzylamino)-2-phenylpropanoate (9a). Colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.25 (t, J = 7.3 Hz, 3H), 1.67 (s, 3H),
3.82 (s, 4H), 4.10 (dq, J = 7.3, 11.0 Hz, 1H), 4.20 (dq, J = 7.3, 11.0
Hz, 1H), 7.04−7.15 (m, 6H), 7.18−7.28 (m, 5H), 7.32−7.36 (m, 2H),
7.61−7.64 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ 14.2, 24.2,
55.7, 60.8, 72.2, 126.3, 127.3, 127.4, 127.7, 128.2, 128.6, 140.1, 143.5,
174.2. IR (neat): 2984, 1724, 1493, 1451, 1237, 1137, 1027, 743, 696
cm−1. HRMS (EI): calcd for C22H22N (M − C3H5O2)+ 300.1752,
found 300.1750.
Ethyl 2-(Dibenzylamino)-3,3-dimethyl-2-phenylbutanoate (9g).
Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.20 (s, 9H), 1.28 (t, J =
7.3 Hz, 3H), 4.01−4.10 (3H, including doublet at 4.04 ppm (J = 15.1
Hz, 2H) and quartet of doublets at 4.06 ppm (J = 7.3, 10.5 Hz, 1H)),
4.17−4.26 (3H, including doublet at 4.19 ppm (J = 15.1 Hz, 2H) and
quartet of doublets at 4.22 ppm (J = 7.3, 10.5 Hz, 1H)), 6.99−7.08
(m, 10H), 7.19−7.26 (m, 3H), 7.77−7.81 (m, 2H). 13C NMR (100.5
MHz, CDCl3): δ 14.1, 30.3, 40.2, 57.3, 60.0, 81.2, 126.0, 127.0, 127.2,
127.5, 128.9, 129.2, 140.4, 141.6, 173.9. IR (neat): 2974, 1720, 1455,
1204, 1031, 748, 700 cm−1. HRMS (EI): calcd for C25H28N (M −
C3H5O2)+ 342.2216, found 342.2206.
Ethyl 2-(Dibenzylamino)-2,3-diphenylpropanoate (9h). Colorless
oil. 1H NMR (400 MHz, CDCl3): δ 1.38 (t, J = 6.9 Hz, 3H), 2.66 (d, J
= 13.3 Hz, 1H), 3.68 (d, J = 13.3 Hz, 1H), 3.83 (d, J = 15.1 Hz, 2H),
4.01 (d, J = 15.1 Hz, 2H), 4.30 (qd, J = 6.9, 10.6 Hz, 1H), 4.37 (qd, J =
6.9, 10.6 Hz, 1H), 6.53−6.55 (m, 2H), 6.91−7.02 (m, 3H), 7.11−7.44
(m, 15H). 13C NMR (100.5 MHz, CDCl3): δ 14.6, 46.3, 55.3, 60.5,
77.1, 125.9, 126.6, 127.1, 127.1, 127.3, 128.0, 128.6, 128.8, 130.9,
137.0, 140.7, 140.8, 170.0. IR (neat): 3086, 3028, 2979, 2845, 1718,
1493, 1452, 1214, 1028, 744, 699 cm−1. HRMS (EI): calcd for
C28H26N (M − C3H5O2)+ 376.2060, found 376.2066.
Ethyl 2-(Dibenzylamino)-2-phenylbutanoate (9b). White solid.
1
Mp: 55−56 °C. H NMR (400 MHz, CDCl3): δ 0.57 (t, J = 7.3 Hz,
3H), 1.31 (t, J = 7.3 Hz, 3H), 1.79 (dq, J = 7.3, 13.7 Hz, 1H), 2.24 (dq,
J = 7.3, 13.7 Hz, 1H), 3.81 (d, J = 15.1 Hz, 2H), 3.90 (d, J = 15.1 Hz,
2H), 4.19 (dq, J = 7.3, 10.5 Hz, 1H), 4.25 (dq, J = 7.3, 10.5 Hz, 1H),
7.08−7.36 (m, 13H), 7.55−7.59 (m, 2H). 13C NMR (100.5 MHz,
CDCl3): δ 9.7, 14.4, 32.6, 55.0, 60.3, 75.9, 126.4, 127.0, 127.1, 127.8,
127.9, 128.0, 128.2, 128.3, 128.6, 128.8, 140.7, 141.3, 172.0. IR (neat):
3086, 3061, 3027, 2978, 2937, 1721, 1602, 1584, 1494, 1454, 1446,
Ethyl 2-(Dibenzylamino)-2-phenylbut-3-enoate (9i). Colorless
1
oil. H NMR (400 MHz, CDCl3): δ 1.25 (t, J = 7.4 Hz, 3H), 3.85
(d, J = 14.7 Hz, 2H), 3.91 (d, J = 14.7 Hz, 2H), 4.14 (dq, J = 7.4, 10.5
Hz, 1H), 4.23 (dq, J = 7.4, 10.5 Hz, 1H), 5.33 (dd, J = 0.9, 11.0 Hz,
1H), 5.39 (dd, J = 0.9, 17.4 Hz, 1H), 6.35 (dd, J = 11.0, 17.4 Hz, 1H),
6.99−7.37 (m, 13H), 7.60−7.63 (m, 2H). 13C NMR (100.5 MHz,
CDCl3): δ 14.2, 56.2, 61.0, 77.2, 117.2, 126.2, 127.5, 128.0, 128.2,
128.6, 128.7, 138.5, 140.3, 140.5, 172.3. IR (neat): 3028, 1728, 1650,
1493, 1452, 1224, 1150, 1029, 928, 743, 695 cm−1. HRMS (EI): calcd
for C23H22N (M − C3H5O2)+ 312.1747, found 312.1741.
1377, 1366, 1222, 1145, 1099, 1077, 1027, 911, 764, 730, 699 cm−1
.
HRMS (EI): calcd for C23H24N (M − C3H5O2)+ 314.1909, found
314.1908.
Ethyl 2-(Dibenzylamino)-2-phenylpentanoate (9c). Colorless oil.
1H NMR (400 MHz, CDCl3): δ 0.62 (t, J = 7.3 Hz, 3H), 0.73−0.86
(m, 1H), 1.03−1.17 (m, 1H), 1.30 (t, J = 7.3 Hz, 3H), 1.76−1.85 (m,
1H), 2.09−2.17 (m, 1H), 3.82 (d, J = 15.1 Hz, 2H), 3.88 (d, J = 15.1
Hz, 2H), 4.16 (qd, J = 7.3, 10.5 Hz, 1H), 4.22 (qd, J = 7.3, 10.5 Hz,
1H), 7.09−7.35 (m, 13H), 7.53−7.56 (m, 2H). 13C NMR (100.5
MHz, CDCl3): δ 14.3, 14.4, 18.5, 41.8, 54.9, 60.4, 75.1, 126.4, 127.0,
127.7, 127.8, 127.8, 128.7, 140.5, 141.6, 172.4. IR (neat): 3086, 3027,
2963, 2871, 1721, 1494, 1454, 1217, 1028, 744, 699 cm−1. HRMS
(EI): calcd for C24H26N (M − C3H5O2)+ 328.2060, found 328.2075.
Ethyl 2-(Dibenzylamino)-3-methyl-2-phenylbutanoate (9d).
Ethyl 2-(Dibenzylamino)-2,2-diphenylacetate (9j). Colorless oil.
1H NMR (400 MHz, CDCl3): δ 1.13 (t, J = 7.3 Hz, 3H), 3.66 (s, 4H),
4.18 (q, J = 7.3 Hz, 2H), 6.89−6.97 (m, 6H), 7.11−7.14 (m, 4H),
7.24−7.37 (m, 6H), 7.68−7.71 (m, 4H). 13C NMR (100.5 MHz,
CDCl3): δ 13.9, 58.1, 61.1, 80.7, 126.0, 127.2, 127.2, 127.6, 128.9,
129.4, 139.6, 139.7, 172.1. IR (neat): 3060, 3029, 1728, 1601, 1495,
1449, 1383, 1224, 1100, 1029, 968, 923, 854, 743, 696 cm−1. HRMS
(EI): calcd for C27H24N (M − C3H5O2)+ 362.1903, found 362.1911.
Ethyl 2-(Dibenzylamino)-2-phenyl-2-p-tolylacetate (9k). Color-
less oil. 1H NMR (400 MHz, CDCl3): δ 1.13 (t, J = 6.8 Hz, 3H), 2.34
(s, 3H), 3.65 (s, 4H), 4.17 (q, J = 6.8 Hz, 2H), 6.88−6.95 (m, 6H),
7.11−7.17 (m, 6H), 7.24−7.36 (m, 3H), 7.55−7.58 (m, 2H), 7.69−
7.71 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ 14.0, 21.0, 58.2, 61.1,
80.4, 125.9, 127.1, 127.2, 127.6, 128.4, 129.0, 129.3, 129.4, 136.7,
136.8, 139.7, 139.9, 172.3. IR (neat): 3087, 3027, 2978, 2844, 1733,
1494, 1455, 1221, 1190, 1029, 741, 695 cm−1. HRMS (EI): calcd for
C28H26N (M − C3H5O2)+ 376.2060, found 376.2066.
1
White solid. Mp: 72−73 °C. H NMR (400 MHz, CDCl3): δ 0.68
(d, J = 6.4 Hz, 3H), 0.73 (d, J = 6.4 Hz, 3H), 1.27 (t, J = 7.3 Hz, 3H),
2.93 (sept, J = 6.4 Hz, 1H), 3.83 (d, J = 14.7 Hz, 2H), 3.90 (d, J = 14.7
Hz, 2H), 4.07−4.21 (m, 2H), 7.07−7.31 (m, 11H), 7.50−7.52 (m,
2H). 13C NMR (100.5 MHz, CDCl3): δ 14.6, 16.9, 20.2, 31.2, 60.1,
78.3, 126.4, 126.7, 126.9, 127.7, 129.2, 129.4, 137.2, 139.7, 171.4. IR
(neat): 3028, 2977, 2931, 2869, 1720, 1602, 1493, 1452, 1384, 1364,
1212, 1140, 1094, 1067, 1030, 942, 911, 739, 699 cm−1. HRMS (EI):
calcd for C24H26N (M − C3H5O2)+ 328.2060, found 328.2054.
Ethyl 2-Cyclopropyl-2-(dibenzylamino)-2-phenylacetate (9e).
Ethyl 2-(Dibenzylamino)-2-(4-methoxyphenyl)-2-phenylacetate
1
(9l). Colorless oil. H NMR (400 MHz, CDCl3): δ 1.13 (t, J = 6.9
1
Colorless oil. H NMR (400 MHz, CDCl3): δ −0.02−0.04 (m, 2H),
Hz, 3H), 3.64 (s, 4H), 3.81 (s, 3H), 4.16 (q, J = 6.9 Hz, 2H), 6.86−
6.96 (m, 8H), 7.11−7.12 (m, 4H), 7.25−7.37 (m, 3H), 7.60−7.68 (m,
4H). 13C NMR (100.5 MHz, CDCl3): δ 14.0, 55,2, 58.1, 61.1, 80.2,
113.0, 125.9, 127.1, 127.2, 127.6, 129.0, 129.4, 130.7, 131.8, 139.7,
139.7, 158.6, 172.4. IR (neat): 3087, 3028, 2977, 2841, 1730, 1600,
1495, 1454, 1260, 1220, 1056, 1026, 753, 697 cm−1. HRMS (EI): calcd
for C28H26NO (M − C3H5O2)+ 392.2009, found 392.2010.
0.26−0.30 (m, 1H), 0.35−0.43 (m, 1H), 1.31 (t, J = 7.3 Hz, 3H),
1.49−1.57 (m, 1H), 3.97 (d, J = 15.1 Hz, 2H), 4.02 (d, J = 15.1 Hz,
2H), 4.22 (qd, J = 7.3, 11.0 Hz, 1H), 4.27 (qd, J = 7.3, 11.0 Hz, 1H),
7.03−7.32 (m, 13H), 7.56−7.57 (m, 2H). 13C NMR (100.5 MHz,
CDCl3): δ 2.4, 5.3, 14.4, 19.5, 55.8, 60.5, 76.0, 126.2, 127.3, 127.4,
127.7, 128.5, 128.8, 140.4, 141.2, 172.0. IR (neat): 3084, 3026, 2979,
9675
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Ethyl 2-(Dibenzylamino)-2-phenyl-2-(thiophen-3-yl)acetate
1131, 1071, 1028, 970, 757, 698 cm−1. HRMS (EI): calcd for C25H24N
(M − C3H5O2)+ 338.1903, found 338.1898.
1
(9m). Colorless oil. H NMR (400 MHz, CDCl3): δ 1.15 (t, J = 6.9
Hz, 3H), 3.80 (d, J = 14.6 Hz, 2H), 3.85 (d, J = 14.6 Hz, 2H), 4.01
(qd, J = 6.9, 11.0 Hz, 1H), 4.16 (qd, J = 6.9, 11.0 Hz, 1H), 6.95−7.05
(m, 7H), 7.16−7.31 (m, 9H), 7.67−7.70 (m, 2H). 13C NMR (100.5
MHz, CDCl3): δ 13.9, 57.0, 61.4, 77.7, 125.7, 125.8, 126.2, 127.4,
127.6, 127.9, 128.4, 128.5, 129.0, 139.5, 141.0, 143.9, 171.9. IR (neat):
Preparation of α,α-Disubstituted Amino Acid Ethyl Esters
12a−d: Typical Procedure (Table 6, Entry 2). Under an argon
atmosphere, to N,N-dibromodimethylhydantoin (63.0 mg, 0.22 mmol)
were successively added a solution of amino ketene silyl acetal 10f
(107.8 mg, 0.22 mmol) in EtCN (1.0 mL), BF3·OEt2 (0.028 mL, 0.22
mmol), and RMgBr (0.44 mmol) at −78 °C. The reaction mixture was
warmed to ambient temperature with stirring for 1 h. It was quenched
with saturated aqueous NaHCO3 (10 mL). The layers were separated,
and the aqueous layer was extracted with ethyl acetate (30 mL × 3).
The combined organic extracts were washed with brine, dried over
anhydrous Na2SO4, and concentrated in vacuo. The crude product was
purified by preparative TLC on silica gel (developed with n-hexane/
AcOEt 15/1) to give adduct 12.
3083, 3027, 2979, 2843, 1728, 1492, 1451, 1221, 1026, 749, 698 cm−1
.
HRMS (EI): calcd for C25H22NS (M − C3H5O2)+ 368.1468, found
368.1481.
Ethyl 2-(Dibenzylamino)-2-phenylbut-3-ynoate (9n). Colorless
1
oil. H NMR (500 MHz, CDCl3): δ 1.04 (t, J = 7.3 Hz, 3H), 2.90
(s, 1H), 3.68 (s, 4H), 3.76 (qd, J = 7.3, 14.0 Hz, 1H), 3.94 (qd, J = 7.3,
14.0 Hz, 1H), 7.01−7.09 (m, 6H), 7.16−7.31 (m, 7H), 7.99−8.02 (m,
2H). 13C NMR (125.8 MHz, CDCl3): δ 13.6, 56.8, 62.1, 74.2, 77.4,
78.5, 126.4, 127.5, 128.0, 128.3, 128.6, 129.1, 137.7, 139.2, 169.8. IR
(neat): 3284, 3086, 3028, 2980, 2845, 1740, 1494, 1453, 1227, 1029,
745, 696 cm−1. HRMS (EI): calcd for C26H25NO2 (M)+ 383.1885,
found 383.1885.
Ethyl 2-(Dibenzylamino)-2-p-tolylbutanoate (11b). Colorless oil.
1H NMR (400 MHz, CDCl3): δ 0.58 (t, J = 6.9 Hz, 3H), 1.30 (t, J =
7.3 Hz, 3H), 1.78 (dq, J = 6.9, 14.2 Hz, 1H), 2.22 (dq, J = 6.9, 14.2 Hz,
1H), 2.32 (s, 3H), 3.80 (d, J = 15.1 Hz, 2H), 3.90 (d, J = 15.1 Hz, 2H),
4.17 (dq, J = 7.3, 11.0 Hz, 1H), 4.24 (dq, J = 7.3, 11.0 Hz, 1H), 7.08−
7.26 (m, 12H), 7.42−7.45 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ
9.8, 14.5, 21.0, 32.5, 55.0, 60.3, 75.6, 126.4, 127.8, 127.9, 128.5, 128.6,
136.6, 138.2, 140.7, 172.0. IR (neat): 3085, 3027, 2978, 2854, 1721,
1494, 1453, 1222, 1097, 1026, 747, 698 cm−1. HRMS (EI): calcd for
C24H26N (M − C3H5O2)+ 328.2060, found 328.2056.
Ethyl 2-(Dibenzylamino)-2-methyl-4-phenylbut-3-ynoate (12a).
Colorless oil. 1H NMR (400 MHz, CDCl3): δ 1.31 (t, J = 7.1 Hz, 3H),
1.60 (s, 3H), 3.81 (d, J = 14.9 Hz, 2H), 3.94 (d, J = 14.9 Hz, 2H),
4.12−4.21 (m, 2H), 7.10−7.23 (m, 6H), 7.31−7.35 (m, 3H), 7.36−
7.40 (m, 4H), 7.45−7.48 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ
14.1, 26.9, 55.9, 61.7, 65.8, 85.8, 87.6, 122.9, 126.6, 127.9, 128.2, 128.2,
128.6, 131.9, 140.6, 172.1. IR (neat): 3063, 3025, 2984, 2937, 1739,
1599, 1493, 1455, 1373, 1234, 1118, 1027, 951, 859, 756, 697 cm−1
.
HRMS (EI): calcd for C24H22N (M − C3H5O2)+ 324.1747, found
324.1754.
Ethyl 2-(Dibenzylamino)-2-(2-phenylethynyl)but-3-enoate
1
(12c). Colorless oil. H NMR (400 MHz, CDCl3): δ 1.21 (t, J =
7.1 Hz, 3H), 3.71 (d, J = 14.6 Hz, 2H), 3.83 (dq, J = 7.1, 10.8 Hz, 1H),
3.87 (d, J = 14.6 Hz, 2H), 3.98 (dq, J = 7.1, 10.8 Hz, 1H), 5.28 (dd, J =
1.1, 9.8 Hz, 1H), 5.86 (dd, J = 1.1, 17.2 Hz, 1H), 6.05 (dd, J = 9.8,
17.2 Hz, 1H), 7.09−7.20 (m, 6H), 7.31−7.38 (m, 7H), 7.56−7.59 (m,
2H). 13C NMR (100.5 MHz, CDCl3): δ 13.9, 55.9, 61.9, 73.2, 83.5,
89.5, 119.0, 122.8, 126.6, 127.7, 128.3, 128.4, 129.1, 132.0, 137.7,
139.6, 169.9. IR (neat): 3062, 3027, 2932, 2843, 1739, 1598, 1491,
Ethyl 2-(Dibenzylamino)-2-(4-methoxypheny)butanoate (11c).
Colorless oil. 1H NMR (400 MHz, CDCl3): δ 0.57 (t, J = 7.3 Hz, 3H),
1.31 (t, J = 7.3 Hz, 3H), 1.75 (dq, J = 7.3, 14.6 Hz, 1H), 2.23 (dq, J =
7.3, 14.6 Hz, 1H), 3.78 (d, J = 15.1 Hz, 2H), 3.79 (s, 3H), 3.90 (d, J =
15.1 Hz, 2H), 4.18 (dq, J = 7.3, 14.1 Hz, 1H), 4.24 (dq, J = 7.3, 14.1
Hz, 1H), 6.85−6.89 (m, 2H), 7.08−7.24 (m, 10H), 7.46−7.51 (m,
2H). 13C NMR (100.5 MHz, CDCl3): δ 9.8, 14.5, 32.6, 54.9, 55.2,
60.3, 75.3, 113.1, 126.4, 127.8, 128.6, 129.1, 133.3, 140.8, 158.4, 172.2.
IR (neat): 3062, 3028, 2979, 2838, 1719, 1612, 1494, 1297, 1250,
1030, 910, 832, 734, 697 cm−1. HRMS (EI): calcd for C24H26NO (M
− C3H5O2)+ 344.2014, found 344.2007.
1454, 1443, 1225, 1124, 1070, 1029, 990, 935, 757, 744, 696 cm−1
.
HRMS (EI): calcd for C25H22N (M − C3H5O2)+ 336.1747, found
336.1756.
Ethyl 2-(Dibenzylamino)-2,4-diphenylbut-3-ynoate (12d). Color-
less oil. 1H NMR (400 MHz, CDCl3): δ 1.08 (t, J = 7.1 Hz, 3H), 3.77
(s, 4H), 3.83 (dq, J = 7.1, 10.7 Hz, 1H), 3.98 (dq, J = 7.1, 10.7 Hz,
1H), 7.01−7.11 (m, 6H), 7.22−7.34 (m, 7H), 7.37−7.40 (m, 3H),
7.59−7.62 (m, 2H), 8.04−8.07 (m, 2H). 13C NMR (100.5 MHz,
CDCl3): δ 13.7, 56.5, 62.0, 74.4, 84.7, 89.4, 122.9, 126.4, 127.5, 128.1,
128.3, 128.4, 128.5, 129.2, 132.1, 138.4, 139.3, 170.2. IR (neat): 3061,
3028, 1740, 1598, 1490, 1449, 1369, 1220, 1116, 1068, 1048, 1029,
981, 794, 756, 695 cm−1. HRMS (EI): calcd for C29H24N (M −
C3H5O2)+ 386.1903, found 386.1903.
Ethyl 2-(4-Chlorophenyl)-2-(dibenzylamino)butanoate (11d).
1
Colorless oil. H NMR (400 MHz, CDCl3): δ 0.54 (t, J = 6.9 Hz,
3H), 1.32 (t, J = 7.3 Hz, 3H), 1.70 (dq, J = 6.9, 13.7 Hz, 1H), 2.24 (dq,
J = 6.9, 13.7 Hz, 1H), 3.79 (d, J = 15.1 Hz, 2H), 3.86 (d, J = 15.1 Hz,
2H), 4.20 (dq, J = 7.3, 14.2 Hz, 1H), 4.26 (dq, J = 7.3, 14.2 Hz, 1H),
7.10−7.25 (m, 10H), 7.30−7.33 (m, 2H), 7.55−7.59 (m, 2H). 13C
NMR (100.5 MHz, CDCl3): δ 9.7, 14.5, 32.5, 54.9, 60.5, 75.4, 126.6,
127.9, 128.0, 128.6, 129.5, 132.8, 140.0, 140.4, 171.4. IR (neat): 3085,
3028, 2979, 2853, 1721, 1492, 1454, 1224, 1098, 1014, 830, 746, 698
cm−1. HRMS (EI): calcd for C23H23ClN (M − C3H5O2)+ 348.1514,
found 348.1503.
Ethyl 2-(Dibenzylamino)-2-(naphthalen-1-yl)butanoate (11e).
White solid; mp 113−114 °C; 1H NMR (400 MHz, CDCl3): δ 0.36 (t,
J = 7.3 Hz, 3H), 1.37 (t, J = 6.7 Hz, 3H), 2.38 (q, J = 7.3 Hz, 2H), 3.92
(d, J = 14.7 Hz, 2H), 4.00 (d, J = 14.7 Hz, 2H), 4.33−4.41 (m, 2H),
7.07−7.13 (m, 11H), 7.37−7.52 (m, 4H), 7.76−7.86 (m, 2H). 13C
NMR (100.5 MHz, CDCl3): δ 10.5, 14.5, 30.4, 56.6, 60.4, 77.2, 73.3,
124.4, 125.1, 125.4, 126.4, 126.8, 127.4, 127.8, 128.8, 129.0, 129.2,
131.7, 134.7, 135.9, 140.8, 172.8. IR (neat): 3061, 3026, 2977, 2864,
1720, 1601, 1495, 1454, 1377, 1218, 1107, 1028, 967, 779, 748, 698
cm−1. HRMS (EI): calcd for C27H26N (M − C3H5O2)+ 364.2060,
found 364.2043.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H NMR and 13C NMR spectra of 1a,b, 2a−e, 3, 4, 10b−f, 9a−
n, 11b−f, and 12a−d and NOESY spectra of 10c. This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Fax: (+81)59-231-9413. E-mail: mshimizu@chem.mie-u.ac.jp.
■
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid for Scientific
Research (B) and on Innovative Areas “Organic Synthesis
Based on Reaction Integration. Development of New Methods
and Creation of New Substances” from the JSPS and MEXT.
Ethyl 2-(Dibenzylamino)-2-ethyl-4-phenylbut-3-ynoate (11f).
1
Colorless oil. H NMR (400 MHz, CDCl3): δ 0.99 (t, J = 7.3 Hz,
3H), 1.31 (t, J = 7.1 Hz, 3H), 1.88 (dq, J = 7.3, 13.9 Hz, 1H), 1.98 (dq,
J = 7.3, 13.9 Hz, 1H), 3.80 (d, J = 14.9 Hz, 2H), 3.97 (d, J = 14.9 Hz,
2H), 4.15 (m, 2H), 7.09−7.22 (m, 6H), 7.30−7.35 (m, 7H), 7.46−
7.49 (m, 2H). 13C NMR (100.5 MHz, CDCl3): δ 9.5, 14.2, 32.1, 55.9,
61.4, 71.5, 86.7, 86.8, 123.0, 126.5, 127.8, 128.2, 128.2, 128.6, 131.9,
140.5, 171.2. IR (neat): 3028, 1734, 1600, 1491, 1455, 1299, 1227,
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