Highly efficient sequential N,N,C-trialkylation of α-N-acyloxyimino esters

Article abstract of DOI:10.1016/j.tet.2015.04.111

α-N-Acyloxyimino esters serve as highly efficient substrates for the N,N,C-trialkylation reaction that can introduce various patterns of nucleophiles at the imino nitrogen and carbon atoms to synthesize N,N-dialkylated and N,N,C-trialkylated α-amino esters in moderate to high yields.

Full text of DOI:10.1016/j.tet.2015.04.111

Tetrahedron 71 (2015) 5793e5799
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Tetrahedron
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Highly efficient sequential N,N,C-trialkylation of a-N-acyloxyimino
esters
*
Isao Mizota, Tatsuya Maeda, Makoto Shimizu
Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507 Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
a
-N-Acyloxyimino esters serve as highly efficient substrates for the N,N,C-trialkylation reaction that can
introduce various patterns of nucleophiles at the imino nitrogen and carbon atoms to synthesize
N,N-dialkylated and N,N,C-trialkylated -amino esters in moderate to high yields.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 20 February 2015
Received in revised form 28 April 2015
Accepted 29 April 2015
a
Available online 7 May 2015
Keywords:
Nucleophilic addition
a
-Acyloxyimino ester
N-Alkylation
Tandem reaction
Umpolung reaction
1. Introduction
N-alkylation/C-alkylation (Scheme 1(a)).5j However, there are
some problems wherein the N,N-dialkylation is too rapid and
cannot be controlled during N-monoalkylation. Moreover, these
reactions have some limitation of scope of substrates and nucleo-
philes, and overall yields are not always satisfactory. In this study,
we conducted further examinations to solve these problems, and
N,N-Dialkyl-a-amino acids and their a-alkylated derivatives
along with amino alcohols formed from them are the core moieties
in many important pharmaceuticals and catalyst scaffolds in or-
ganic synthesis.1 In addition, they frequently serve as useful in-
termediates in the synthesis of bioactive materials such as
antiarrhythmic agents.2 Thus, the development of efficient
methods that flexibly incorporate substituents in both the nitrogen
report a new type of a-imino ester with an N-acyloxy group (an N-
p-toluoyloxy group) that can introduce two types of nucleophiles
freely on the imino nitrogen to give the N,N-dialkylated amino
esters. A highly efficient N,N,C-trialkylation of N-p-toluoyloxyimino
and carbon atoms at the a-positions of amino acids is important
and represents an attractive objective for synthetic studies. Al-
though this topic has received considerable attention over the past
decades, to the best of our knowledge, only a few methods that
enable the construction of the N,N-dialkyl-
a
-amino acid framework
with high efficiency are available.3 Amination using
a-imino esters
allows electrophilic N-alkylation, an otherwise difficult process
owing to the nucleophilicity of nitrogen.
An umpolung of an
cause of the electronegativity of the imino group.4 Our laboratory
has developed umpolung reactions of -imino esters along with
a-imino ester is a difficult amination be-
a
various tandem CeC bond formation reactions using the metal
enolate produced by N-alkylation.5 We have previously reported
N,N-di- and N,N,C-trialkylations of
a-sulfoximino esters, featuring
both -imino esters and oximes based on tandem amination/
a
* Corresponding author. Tel./fax: þ81 59 231 9413; e-mail address: mshimizu@
Scheme 1. Previous and present works.
chem.mie-u.ac.jp (I. Mizota).
http://dx.doi.org/10.1016/j.tet.2015.04.111
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

5794
I. Mizota et al. / Tetrahedron 71 (2015) 5793e5799
esters with three kinds of nucleophiles was also developed for
construction of trialkylated amino esters in good yields (Scheme
1(b)).
As shown in Scheme 2, we have previously demonstrated that
(Z)-a-sulfoximino ester such as ethyl (Z)-2-phenyl-2-[(tosyloxy)
imino]acetate (Z)-1a is a suitable substrate for the N,N-dialkylation
reaction to afford the diethylated product 3a, while (E)-isomers
such as ethyl (E)-2-[(2,4-dinitrophenyl)sulfonyloxy]imino-2-
phenylacetate (E)-1b can provide the monoethylated product 2a
preferentially but in a low yield.5j Although it is not trivial to stop
the reaction at the N-monoalkylation stage, these results provide
a possible strategy for introducing two different alkyl substituents
at the nitrogen atom.
To find the optimum reaction conditions, we next screened
several parameters for this reaction, and the results are summa-
rized in Table 2. As shown in entries 1e5, 2.2 equiv of Grignard
reagent were suitable for the reaction. Further optimization with
respect to the reaction temperature and the solvent was carried out
for this reaction (entries 6e13). Temperatures greater than ꢀ78 ꢁC
slightly decreased the product yields (entries 6e8). Regarding the
solvent, toluene was found to be the best, and decreased product
yields were observed in other examined solvents (entries 9e13).
When other organometallic reagents such as Et2AlCl, Et2Zn were
used, the desired products were not obtained at all (entries 15 and
16). Under the optimum reaction conditions (2.2 equiv of EtMgBr in
toluene at ꢀ78 ꢁC, entry 3), a further enhancement of the yield was
observed using the N-p-toluoyloxyimino ester, and 78% yield was
achieved (entry 18).
Table 2
Optimization of the reaction conditions
Scheme 2. N-Monoethylation and N,N-diethylation of a-sulfoximino esters.
Entry R (1)
Et-[M] (x equiv) Solvent T (ꢁC)
Yielda (%) (Z/E)
1
2
3
4
5
6
7
8
Bz (1g)
EtMgBr (1.5)
EtMgBr (2.0)
EtMgBr (2.2)
EtMgBr (2.5)
EtMgBr (3.0)
EtMgBr (2.2)
EtMgBr (2.2)
EtMgBr (2.2)
EtMgBr (2.2)
EtMgBr (2.2)
EtMgBr (2.2)
EtMgBr (2.2)
EtMgBr (2.2)
EtMgBr (2.2)
Et2AlCl (2.2)
Et2Zn (2.2)
toluene ꢀ78
toluene ꢀ78
toluene ꢀ78
toluene ꢀ78
toluene ꢀ78
44 (88/12)
64 (86/14)
76 (96/4)
74 (90/10)
61 (90/10)
2. Results and discussion
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
Bz (1g)
In this context, we examined monoethylation of various sulfo-
nates; Table 1 summarizes the results. Although -sulfoximino
a
toluene ꢀ78 to 30 55 (88/12)
esters with various substituents such as 4-ClC6H4SO2, 2,4-
Cl2C6H3SO2, 4-FC6H4SO2 and C6F5SO2 were examined initially, the
desired products were not obtained (entries 1e4). We found that
monoethylated product 2 was obtained in 74% yield when ethyl (Z)-
2-(benzoyloxy)imino-2-phenylacetate (Z)-1g was used (entry 6),
whereas for the isomer (E)-1g, N,N-diethylation proceeded to give
the N,N-diethylated product 3 in 37% yield (entry 5). The substrate
with an acetoxy group at the nitrogen, (Z)-1h also gave the product
in a good yield (entry 7), whereas that with a methoxy group, (Z)-1i
gave no product (entry 8). Substrates having aromatic groups with
electron-withdrawing and electron-donating para-substituents,
heteroaromatic group, and ethoxycarbonyl group (Z)-1j-l and 1m
did not undergo the desired reaction to give the monoethylated
products 2; instead, the diethlyated product 3 was obtained in
53e84% yields (entries 9e12).
toluene
0
66 (93/7)
51 (90/10)
68 (90/10)
74 (91/9)
60 (91/9)
65 (89/11)
69 (94/6)
72 (91/9)
0
toluene 30
CH2Cl2 ꢀ78
9
10
11
12
13
14b
15
16
17
18
EtCN
Et2O
THF
ꢀ78
ꢀ78
ꢀ78
ꢀ78
DME
toluene ꢀ78
toluene ꢀ78
toluene ꢀ78
toluene ꢀ78
toluene ꢀ78
0
4-ClC6H4CO (1n) EtMgBr (2.2)
73 (95/5)
78 (91/9)
p-toluoylc (1o)
EtMgBr (2.2)
a
Yield of the isolated product.
EtMgBr in THF was used.
p-toluoyl¼4-MeC6H4CO.
b
c
Next, tandem N,N-dialkylations with two different nucleophiles
were examined using ethyl and n-propyl Grignard reagents. As
an initial reaction, ethyl (Z)-2-(4-methylbenzoyloxy)imino-2-
phenylacetate (Z)-1o first reacted with 2.2 equiv of EtMgBr in tol-
uene at ꢀ78 ꢁC for 30 min followed by an umpolung reaction with
2.0 equiv of n-PrMgBr at ꢀ78 ꢁC for 30 min. Unfortunately the
monoethylated product 2 was obtained in 75% yield instead of the
desired N-ethyl-N-n-propyl product 4a (Table 3, entry 1). When the
reaction was performed at ꢀ78 to 30 ꢁC, the desired product 4a was
obtained in 33% (entry 2). To improve the yield of 4a, the effects of
additives as reaction promoters were next examined (entries 3e5).
The use of additives such as TMSCl and BF.3OEt2 gave the product 4a
in 69% and 17% yields, respectively (entries 3 and 4). Benzoic acid
was the most effective additive in this reaction (entry 5). In the
presence of 0.75 equiv of benzoic acid, the N,N-dialkylated product
4a was isolated in 79% yield, whereas the use of 1.0 equiv of benzoic
acid gave the product 4a in 63% yield (entries 6 and 7). The role of
benzoic acid is to quench an excess Grignard reagent after the first
electrophilic amination.6 The optimized reaction conditions were
thus found to be using benzoic acid as an additive in toluene as
solvent at ꢀ78 to 30 ꢁC (entry 6).
Table 1
Screening of the N-monoethylation of a-imino ester
Entry
R1
R2
1
Product yielda (%)
2 (Z/E)
3
1
2
3
4
5
6
7
8
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4-ClC6H4SO2
2,4-Cl2C6H3SO2
4-FC6H4SO2
C6F5SO2
Bz
Bz
Ac
Me
Ts
Ts
(E)-1c
(E)-1d
(E)-1e
(E)-1f
(E)-1g
(Z)-1g
(Z)-1h
(Z)-1i
(Z)-1j
(Z)-1k
(E)-1l
1m
0
0
22
0
0
0
0
0
0
37
0
74 (90/10)
69 (91/9)
0
0
0
0
0
0
0
9b
10b
11b
12b
4-ClC6H4
4-MeOC6H4
2-thienyl
CO2Et
84
59
61
53
Ts
Ts
a
The scope of second nucleophiles was next examined under the
optimized reaction conditions (Table 3, entry 6), and the results are
Yield of isolated product.
EtMgBr (2.2 equiv), 30 ꢁC, 15 min.
b

I. Mizota et al. / Tetrahedron 71 (2015) 5793e5799
5795
Table 3
Examination of additives for tandem N,N-dialkylation with different nucleophiles
Entry
Additive (x equiv)
T1 (ꢁC)
y (equiv)
T2 (ꢁC)
Yielda (%)
4a
2a (Z/E)
3a
1
2
3
4
5
6
7
d
d
2.0
2.0
2.0
2.0
2.0
1.75
2.5
ꢀ78
0
33
69
17
78
79
63
75 (91/9)
13
0
0
27
6
0
0
d
d
ꢀ78 to 30
TMSCl (2.0)
BF3$OEt2 (2.0)
PhCO2H (0.5)
PhCO2H (0.75)
PhCO2H (1.0)
ꢀ78
30
30
30
30
30
ꢀ78 to 30
ꢀ78 to 30
ꢀ78 to 30
ꢀ78 to 30
15 (86/14)
0
0
0
0
0
a
Yield of isolated product.
summarized in Scheme 3. Methyl Grignard reagent was not effec-
tive in this reaction. Primary and secondary alkyls such as n-Pr, i-Pr
and Bn group were able to be introduced to the imino nitrogen to
give the products 4a,c,f in good to high yields, while in the case of
an alicyclic substituent, Cy, the yield of the desired product 4d
decreased slightly. A bulky tert-butyl Grignard reagent gave the
product 4e in low yield.7
Scheme 4. Screening of the third nucleophiles for the tandem N,N,C-trialkylation to
p-toluoyloxyimino ester.
a-
the monoalkylated imino ester 2 in situ followed by the rapid second
N-alkylation to give N,N-dialkylaion product (Scheme 5(b)).
Regarding di- and trialkylations with different nucleophiles, the sec-
ond Grignard reagent activates the imino ester 2 to form a five-
membered intermediate E, and the second N-alkylation proceeds to
givea magnesiumenolateFfollowed by the oxidationwithDBDMHto
the iminium salt G. The final step is the reaction of the third Grignard
reagent with the iminium salt G to afford the trialkylated product 5
(Scheme 5c).
Scheme 3. Screening of the second nucleophiles for the tandem N,N-dialkylation to
p-toluoyloxyimino ester.
a-
Finally we also investigated a sequential N,N,C-trialkylation with
three differentnucleophilesunder theoptimizedreactionconditions
(Scheme 4). When a series of nucleophiles such as primary, sec-
ondary, aromatic, and vinyl Grignards were examined, the desired
products 5aef were obtained in moderate to good overall yields.
Notably, this one-pot sequential reaction is an effective method to
synthesize the N,N,C-trialkylated amino acid derivatives, which are
important pharmaceuticals, andbuildingblocks inorganicsynthesis.
A proposed reaction mechanism is shown in Scheme 5. First,
Grignard reagent coordinates with the two carbonyl oxygens of
acyloxyand ester moietyof (Z)-acyloxyimino ester (Z)-1 to activate an
imino ester via an intermediate A. Amination proceeds to give
a monoalkylated imino ester 2 through the formation of an eight-
membered magnesium enolate intermediate B.8 We assume that
thesecondN-alkylationwithGrignardreagentisunlikelyowingtothe
stability of this eight-membered intermediate B (Scheme 5(a)); in the
case of (E)-acyloxyimino ester, the magnesium enolate D isformed via
a five-membered intermediate C after the N-monoalkylation to give
3. Conclusion
In conclusion, a-N-acyloxyimino ester is an excellent substrate
for the sequential amination/umpolung N-alkylation/C-alkylation
reaction, which can introduce various substituents freely on the
imino nitrogen and carbon atoms. This unique method offers a new
type of approach to N,N-dialkylated and N,N,C-trialkylated a-amino
esters and an attractive method for the construction of tertiary and
quaternary N,N-dialkylamino acids and alcohols. These products
are used in bioactive materials such as antiarrhythmic drugs.
4. Experimental section
4.1. General aspects
Infrared spectra were determined on a JASCO FT/IR-460 plus
spectrometer. 1H NMR and 13C NMR spectra were recorded with

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I. Mizota et al. / Tetrahedron 71 (2015) 5793e5799
4.2. General procedure for the synthesis of
esters 1aef and 1jem
a-sulfoximino
Compounds (Z)-1a, (E)-1a, (E)-1b and (E)-1d were prepared
according to the reported procedure.5j
In a 50-mL two-necked round-bottomed flask equipped with
a magnetic stirring bar, a rubber septum, and an argon balloon was
placed oxime ester (2.50 mmol) in CH2Cl2 (5.0 mL) at 0 ꢁC, and to it
were added i-PrNEt (3.00 mmol) and sulfonyl chloride (2.80 mmol).
The whole mixture was warmed to room temperature and stirred
for 24 h. The reaction was quenched with H2O (10 mL), and the
mixture was extracted with CH2Cl2 (10 mLꢂ3). The combined ex-
tracts were washed with satd NaCl aq (10 mL) and dried over an-
hydrous Na2SO4, and concentrated in vacuo to give a crude product,
which was purified by silica gel column chromatography (n-hex-
ane/ethyl acetate¼4/1) to give the compound 1.
4.2.1. Ethyl (E)-2-[(4-chlorophenyl)sulfonyloxy]imino-2-
phenylacetate ((E)-1c). Yield 93%; Yellow solid; mp 85e86 ꢁC; 1H
NMR (400 MHz, CDCl3)
7.44e7.56 (m, 7H), 7.94e7.97 (m, 2H); 13C NMR (100 MHz, CDCl3)
13.9, 63.0,126.9,128.4,129.2,129.4,130.6,131.3,133.2,141.3,156.8,
d
1.34 (t, J¼7.1 Hz, 3H), 4.34 (q, J¼7.1 Hz, 2H),
d
161.8; IR (neat) 3098, 2982, 1731, 1387, 1314, 1211, 1189, 1092, 1058,
891, 834, 685 cmꢀ1; HRMS (EI) Calcd for C13H9ClNO3S (M-C3H5O2)þ
293.9992, found 293.9994.
4.2.2. Ethyl (E)-2-[(4-fluorophenyl)sulfonyloxy]imino-2-
phenylacetate ((E)-1e). Yield 95%; Yellow solid; mp 74e75 ꢁC; 1H
NMR (400 MHz, CDCl3)
7.23e7.27 (m, 2H), 7.42e7.50 (m, 5H), 8.03e8.06 (m, 2H); 13C NMR
(100 MHz, CDCl3)
d
1.34 (t, J¼7.1 Hz, 3H), 4.34 (q, J¼7.1 Hz, 2H),
d
13.9, 63.0, 116.5 (d, J¼23.0 Hz), 126.9, 128.4,
129.2, 130.7 (d, J¼2.9 Hz), 131.3, 132.2 (d, J¼9.6 Hz), 156.7, 161.9,
166.3 (d, J¼257.8 Hz); IR (neat) 2985, 1738, 1592, 1494, 1387, 1231,
1194, 1094, 1051, 837, 778, 690 cmꢀ1; HRMS (EI) Calcd for
C
16H14FNO5S (M)þ 351.0577, found 351.0563.
4.2.3. Ethyl (E)-2-[(perfluorophenyl)sulfonyloxy]imino-2-
phenylacetate ((E)-1f). Yield 17%; Yellow oil; 1H NMR (400 MHz,
CDCl3)
d
1.40 (t, J¼7.1 Hz, 3H), 4.39(q, J¼7.1 Hz, 2H), 7.44e7.66(m, 3H),
8.05e8.12(m, 2H);13CNMR(100MHz,CDCl3)
d
14.2,63.4,112.4,118.8,
128.6, 129.1, 129.5, 132.1, 132.7, 133.3, 148.3, 158.7; IR (neat) 2983,
1738, 1657, 1450, 1305, 1256, 1208, 1179, 916, 769, 987 cmꢀ1; HRMS
(EI) Calcd for C10H10NO3 (M-C6F5O2S)þ 192.0661, found 192.0667.
4.2.4. Ethyl (Z)-2-(4-chlorophenyl)-2-[(tosyloxy)imino]acetate ((Z)-
1j). Yield 90%; Yellow solid; mp 59e60 ꢁC; 1H NMR (400 MHz,
Scheme 5. Plausible mechanism.
CDCl3)
7.35e7.38 (m, 4H), 7.47e7.51 (m, 2H), 7.88e7.90 (m, 2H); 13C NMR
(100 MHz, CDCl3) 14.1, 21.7, 63.0, 126.4, 128.6, 128.9, 129.3, 129.8,
d
1.40 (t, J¼7.1 Hz, 3H), 2.44 (s, 3H), 4.47 (q, J¼7.1 Hz, 2H),
d
131.9, 138.6, 145.6, 156.9, 160.6; IR (neat) 2984, 1741, 1593, 1383,
a JEOL ECX-400P, or a JEOL A-500 spectrometer using tetrame-
thylsilane as an internal standard. Mass spectra were recorded
on a JEOL MS-700D spectrometer and a SIMADZU GCeMS-
1223, 1196, 1093, 864, 772, 591 cmꢀ1; HRMS (EI) Calcd for
C
17H16ClNO5S (M)þ 381.0438, found 381.0437.
QP2010 Ultra (CI) spectrometer. Toluene was dried over calcium
4.2.5. Ethyl
(Z)-2-(4-methoxyphenyl)-2-[(tosyloxy)imino]acetate
1.40 (t,
((Z)-1k). Yield 90%; Black oil; 1H NMR (400 MHz, CDCl3)
d
ꢀ
chloride, distilled, and stored over Molecular Sieves
4
A.
Dichloromethane (CH2Cl2) was distilled from calcium hydride
and stored over Molecular Sieves 4 A. Propionitrile (EtCN) was
J¼6.4 Hz, 3H), 2.43 (s, 3H), 3.81 (s, 3H), 4.46 (q, J¼6.4 Hz, 2H),
6.87e6.89 (m, 2H), 7.33e7.49 (m, 4H), 7.88e7.90 (m, 2H); 13C NMR
ꢀ
distilled from phosphorus pentaoxide and then from calcium
hydride and stored over Molecular Sieves 4 A. Diethylether
(100 MHz, CDCl3) d 14.1, 21.6, 55.4, 62.7, 114.4, 120.0, 128.9, 129.1,
ꢀ
129.7, 132.1, 145.3, 157.7, 161.2, 162.8; IR (neat) 2982, 2938, 2843,
(Et2O) and tetrahydrofuran (THF) were distilled from benzo-
phenone ketyl immediately before use. Dimethoxyethane
(DME) was distilled from calcium hydride and then cupper(I)
chloride and stored over sodium. Purification of products was
performed by column chromatography on silica gel (Kanto Silica
Gel 60N) and/or preparative TLC on silica gel (Merck Kiesel Gel
GF254).
1741, 1597, 1516, 1379, 1263, 1226, 1179, 1022, 815, 769, 661 cmꢀ1
HRMS (EI) Calcd for C18H19NO6S (M)þ 377.0933, found 377.0916.
;
4.2.6. Ethyl (E)-2-(thiophen-2-yl)-2-[(tosyloxy)imino]acetate ((E)-
1l). Yield 47%; Yellow solid; 55e56 ꢁC; 1H NMR (400 MHz, CDCl3)
d
1.40 (t, J¼7.1 Hz, 3H), 2.44 (s, 3H), 4.47 (q, J¼7.1 Hz, 2H), 7.04e7.06
(m, 1H), 7.25e7.26 (m, 1H), 7.34e7.36 (m, 2H), 7.48e7.49 (m, 1H),

I. Mizota et al. / Tetrahedron 71 (2015) 5793e5799
5797
7.88e7.91 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
14.1, 21.7, 63.1,
CDCl3)
5H), 7.77e7.80 (m, 2H), 7.96e8.00 (m, 2H); 13C NMR (100 MHz,
CDCl3) 14.3, 62.5, 126.6, 127.6, 128.3, 129.0, 129.0, 131.0, 132.2,
d
1.41 (t, J¼7.1 Hz, 3H), 4.52 (q, J¼7.1 Hz, 2H), 7.45e7.56 (m,
127.8, 129.0, 129.7, 130.6, 131.4, 131.8, 132.3, 145.5, 153.2, 160.0; IR
(neat) 3112, 2984, 1743, 1595, 1426, 1382, 1322, 1221, 1194, 912, 864,
815, 771 cmꢀ1; HRMS (EI) Calcd for C15H15NO5S2 (M)þ 353.0392,
found 353.0407.
d
140.2, 158.2, 162.0, 162.1; IR (neat) 2984, 1745, 1595, 1488, 1248,
1090, 1068, 1008, 909, 845, 749, 687 cmꢀ1; HRMS (EI) Calcd for
C
14H9ClNO2 (M-C3H5O2)þ 258.0322, found 258.0317.
4.2.7. Diethyl 2-[(tosyloxy)imino]malonate (1m). Yield 84%; White
solid; mp 64e65 ꢁC; 1H NMR (400 MHz, CDCl3)
d
1.32 (t, J¼7.1 Hz,
4.3.6. Ethyl (Z)-2-(4-methylbenzoyloxy)imino-2-phenylacetate ((Z)-
3H), 1.36 (t, J¼7.1 Hz, 3H), 2.46 (s, 3H), 4.33 (q, J¼7.1 Hz, 2H), 4.40 (q,
1o). Yield 88%; White solid; mp 72e73 ꢁC; 1H NMR (400 MHz,
J¼7.1 Hz, 2H), 7.36e7.38 (m, 2H), 7.87e7.89 (m. 2H); 13C NMR
CDCl3)
7.26e7.29 (m, 2H), 7.44e7.55 (m, 3H), 7.78e7.81 (m, 2H),
7.93e7.95 (m, 2H); 13C NMR (100 MHz, CDCl3)
14.3, 21.7, 62.4,
d
1.41 (t, J¼7.1 Hz, 3H), 2.43 (s, 3H), 4.52 (q, J¼7.1 Hz, 2H),
(100 MHz, CDCl3)
d 13.8, 13.9, 21.7, 63.3, 63.4, 129.2, 129.9, 131.1,
146.2, 149.7, 157.9, 158.0; IR (neat) 2986, 2941, 1752, 1392, 1324,
1259, 1197, 1182, 1100, 828, 752, 661 cmꢀ1; HRMS (EI) HRMS (EI)
Calcd for C14H17NO7S (M)þ 343.0726, found 343.0733.
d
125.3, 127.6, 128.6, 129.0, 129.3, 129.8, 132.0, 144.6, 157.8, 162.4,
162.9; IR (neat) 2982, 1747, 1611, 1250, 1179, 1065, 1010, 743, 687,
580 cmꢀ1; HRMS (EI) Calcd for C18H17NO4 (M)þ 311.1158, found
311.1162.
4.3. General procedure for the synthesis of a-acyloxyimino
esters 1gei, 1n, 1o
4.4. General procedure for the N-monoalkylation of
esters
a-imino
In a 50-mL two-necked round-bottomed flask equipped with
a magnetic stirring bar, a rubber septum, and an argon balloon was
placedethyl 2-hydroxyimino-2-phenylacetate A(5.00 mmol)in DMF
(5.0 mL) and DMAP (1.00 mmol) at 0 ꢁC, and to it were added i-PrNEt
(10.5 mmol) and benzoyl chloride (10.0 mmol). The whole mixture
was warmed to room temperature and stirred for 21 h. The reaction
was quenched with H2O (10 mL), and the mixture was extracted with
ethyl acetate (10 mLꢂ3). The combined extracts were washed with
satd NaCl aq (10 mL) and dried over anhydrous Na2SO4, and con-
centrated in vacuo to give a crude product, which was purified by
silica gel column chromatography (n-hexane/ethyl acetate¼4/1) and
recrystallization from CH2Cl2 to give the compound 1.
Under an argon atmosphere, a suspension of a-imino esters 1
(0.20 mmol) in toluene (5.0 mL) was stirred at ꢀ78 ꢁC for 5 min, and
to it was added EtMgBr (0.50 mmol, 0.98 N in Et2O) slowly. After the
mixture was stirred for 30 min, it was quenched with satd NH4Cl aq
(5.0 mL), and the whole mixture was extracted with ethyl acetate
(5.0 mLꢂ3). The combined extracts were washed with brine, dried
over anhydrous Na2SO4, and concentrated in vacuo. The crude
product was purified by silica gel on TLC (n-hexane/ethyl acetate/
Et3N¼10/1/1) to give the monoalkylated and/or dialkylated
products.
4.3.1. Ethyl (E)-2-(benzoyloxy)imino-2-phenylacetate ((E)-1g). Yield
4.4.1. Ethyl 2-ethylimino-2-phenylacetate (2a).5j Yield 74%, Z/E¼90:
67%; White solid; mp 88e89 ꢁC; 1H NMR (400 MHz, CDCl3)
d
1.42 (t,
J¼7.3 Hz, 3H), 4.44 (q, J¼7.3 Hz, 2H), 7.38e7.59 (m, 8H), 7.86e7.88
(m, 2H); 13C NMR (100 MHz, CDCl3)
14.0, 63.0, 127.8, 128.3, 128.6,
10; Brown oil; 1H NMR (400 MHz, CDCl3)
d
1.26 (t, J¼7.3 Hz, 0.3H),
1.33 (t, J¼7.3 Hz, 2.7H), 1.39 (t, J¼7.3 Hz, 3H), 3.49 (q, J¼7.3 Hz,
0.2H), 3.58 (q, J¼7.3 Hz, 1.8H), 4.33 (q, J¼7.3 Hz, 0.2H), 4.42 (q,
J¼7.3 Hz, 1.8H), 7.37e7.45 (m, 3H), 7.70e7.73 (m, 2H); 13C NMR
d
128.7, 128.9, 129.8, 130.7, 133.7, 156.9, 162.8, 162.9; IR (neat) 2983,
1766, 1725, 1447, 1314, 1209, 1064, 1000, 930, 854, 704 cmꢀ1; HRMS
(EI) Calcd for C14H10NO2 (M-C3H5O2)þ 224.0712, found 224.0707.
(125 MHz, CDCl3)
d 14.3, 15.8, 49.5, 61.3, 127.1, 128.5, 130.8, 134.4,
159.8, 165.6; IR (neat) 2978, 2935, 2871, 1734, 1633, 1299, 1206,
1095, 1037, 1017, 691 cmꢀ1; MS (CI) Calcd for C12H15NO2 (MþH)þ
206, found 206.
4.3.2. Ethyl
(Z)-2-(benzoyloxy)imino-2-phenylacetate
((Z)-
1.41 (t,
1g). Yield 83%; Yellow oil; 1H NMR (400 MHz, CDCl3)
d
J¼7.1 Hz, 3H), 4.53 (q, J¼7.1 Hz, 2H), 7.44e7.63 (m, 6H), 7.79e7.81
4.4.2. Ethyl 2-(diethylamino)-2-phenylacetate (3a).5j Yield 37%;
(m, 2H), 8.04e8.06 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
14.2, 62.4,
brown oil; 1H NMR (400 MHz, CDCl3)
d
1.00 (t, J¼7.1 Hz, 6H), 1.23 (t,
127.5, 128.1, 128.4, 128.6, 128.9, 129.7, 132.1, 133.7, 158.0, 162.2,
162.8; IR (neat) 2982, 1742, 1450, 1243, 1060, 1012, 774, 706, 616,
605, 586 cmꢀ1; HRMS (EI) Calcd for C14H10NO2 (M-C3H5O2)þ
224.0712, found 224.0707.
J¼7.1 Hz, 3H), 2.56e2.69 (m, 4H), 4.15 (dq, J¼7.1, 10.5 Hz, 1H), 4.21
(dq, J¼7.1,10.5 Hz,1H), 4.47 (s,1H), 7.26e7.34 (m, 3H), 7.43e7.45 (m,
2H); 13C NMR (100 MHz, CDCl3)
d 11.8, 14.1, 43.6, 60.5, 69.3, 127.8,
128.2, 128.4, 128.7, 137.2, 172.4; IR (neat) 1738, 1454, 1369, 1196,
1155, 1061, 1026, 732, 698 cmꢀ1; HRMS (EI) Calcd for C14H21NO2
(M)þ 235.1572, found 235.1565.
4.3.3. Ethyl (Z)-2-acetoxyimino-2-phenylacetate ((Z)-1h). Yield
86%; Yellow oil; 1H NMR (400 MHz, CDCl3)
d
1.41 (t, J¼7.1 Hz, 3H),
2.22 (s, 3H), 4.49 (q, J¼7.1 Hz, 2H), 7.41e7.53 (m, 3H), 7.70e7.72 (m,
2H); 13C NMR (100 MHz, CDCl3)
14.1, 19.3, 62.3, 127.3, 128.4, 128.9,
4.4.3. Ethyl 2-(4-chlorophenyl)-2-(diethylamino)acetate (3b). Yield
d
84%; Yellow oil; 1H NMR (400 MHz, CDCl3)
d
0.99 (dd, J¼7.1, 7.1 Hz,
132.0, 157.1, 162.1, 167.3; IR (neat) 2985, 2939, 1782, 1741, 1447, 1372,
1334, 1227, 1023, 934, 694 cmꢀ1; HRMS (EI) Calcd for C10H10NO3
(M-C2H3O)þ 192.0661, found 192.0667.
6H), 1.23 (dd, J¼7.1, 7.1 Hz, 3H), 2.55e2.67 (m, 4H), 4.15 (dq, J¼7.1,
11.0 Hz, 1H), 4.21 (dq, J¼7.1, 11.0 Hz, 1H), 4.43 (s, 1H), 7.29e7.40 (m,
4H); 13C NMR (100 MHz, CDCl3)
d 11.9, 14.2, 43.6, 60.7, 68.6, 128.5,
130.0, 133.6, 136.0, 171.9; IR (neat) 2973, 2871, 1737, 1490, 1198,
1156, 1091, 1017, 835, 631 cmꢀ1; HRMS (EI) Calcd for C14H20ClNO2
(M)þ 269.1183, found 269.1170.
4.3.4. Ethyl (Z)-2-methoxyimino-2-phenylacetate ((Z)-1i). Yield
67%; Yellow oil; 1H NMR (400 MHz, CDCl3)
d
1.38 (t, J¼6.9 Hz, 3H),
4.02 (s, 3H), 4.42 (q, J¼6.9 Hz, 2H), 7.36e7.42 (m, 3H), 7.56e7.59 (m,
2H); 13C NMR (100 MHz, CDCl3)
14.2, 61.8, 62.9, 126.2, 128.7, 130.2,
d
4.4.4. Ethyl 2-diethylamino-2-(4-methoxyphenyl)acetate (3c). Yield
130.3, 150.6, 163.6; IR (neat) 2982, 2940, 1738, 1447, 1370, 1331,
59%; Yellow oil; 1H NMR (400 MHz, CDCl3)
6H), 1.23 (dd, J¼7.1, 7.1 Hz, 3H), 2.55e2.68 (m, 4H), 3.80 (s, 3H),
4.13 (dq, J¼7.1, 10.8 Hz, 1H), 4.20 (dq, J¼7.1, 10.8 Hz, 1H), 4.39
(s, 1H), 6.85e6.87 (m, 2H), 7.35e7.37 (m, 2H); 13C NMR (100 MHz,
d
0.99 (dd, J¼7.1, 7.1 Hz,
1222, 1060, 1035, 893, 772, 687 cmꢀ1; HRMS (EI) Calcd for
C
11H13NO3 (M)þ 207.0895, found 207.0892.
4.3.5. Ethyl (Z)-2-(4-chlorobenzoyloxy)imino-2-phenylacetate ((Z)-
CDCl3)
d 11.7, 14.2, 43.4, 55.2, 60.5, 68.9, 113.7, 129.2, 129.9, 159.2,
1n). Yield 86%; White solid; mp 70e71 ꢁC; 1H NMR (400 MHz,
172.6; IR (neat) 2971, 2837, 1736, 1510, 1250, 1176, 1155, 1033, 836,

5798
I. Mizota et al. / Tetrahedron 71 (2015) 5793e5799
793 cmꢀ1; HRMS (EI) Calcd for C15H23NO3 (M)þ 265.1678, found
265.1682.
2982, 2930, 2854, 1739, 1450, 1150, 1028, 742, 696 cmꢀ1; HRMS (EI)
Calcd for C18H27NO2 (M)þ 289.2042, found 289.2041.
4.4.5. Ethyl 2-diethylamino-2-(thiophen-2-yl)acetate (3d). Yield
4.5.4. Ethyl 2-(N-tert-butyl-N-ethylamino)-2-phenylacetate
61%; Yellow oil; 1H NMR (400 MHz, CDCl3)
d
1.05 (dd, J¼7.1, 7.1 Hz,
(4e).5j Yield 12%; Yellow oil; 1H NMR (500 MHz, CDCl3)
d 0.49 (t,
6H), 1.29 (dd, J¼7.1, 7.1 Hz, 3H), 2.62e2.71 (m, 4H), 4.22 (dq, J¼7.1,
J¼7.0 Hz, 3H), 1.20 (s, 9H), 1.28 (t, J¼7.0 Hz, 3H), 2.75e2.82 (m, 1H),
10.9 Hz, 1H), 4.27 (dq, J¼7.1, 10.9 Hz, 1H), 4.76 (s, 1H), 6.94e7.01 (m,
3.09e3.17 (m, 1H), 4.15e4.26 (m, 2H), 4.91 (s, 1H), 7.23e7.36 (m,
2H), 7.26e7.28 (m, 1H); 13C NMR (100 MHz, CDCl3)
d
12.6, 14.3, 44.1,
5H); 13C NMR (125 MHz, CDCl3)
d 0.016, 14.2, 19.2, 28.8, 38.4, 55.7,
60.9, 63.9,125.7,126.3,126.4,141.0,171.2; IR (neat) 2972,1738,1465,
60.1, 63.2,127.1,128.0,128.8,139.6,175.3; IR (neat) 2974, 2928,1738,
1372, 1238, 1179, 1025, 808, 698, 569 cmꢀ1; HRMS (EI) Calcd for
1369, 1212, 1163, 1120, 1029, 756, 700 cmꢀ1; HRMS (EI) Calcd for
C
12H19NO2S (M)þ 241.1137, found 241.1142.
C
13H20N (M-C3H5O2)þ 190.1590, found 190.1582.
4.4.6. Diethyl 2-(diethylamino)malonate (3e). Yield 53%; Colorless
oil; 1H NMR (400 MHz, CDCl3)
1.09 (t, J¼7.1 Hz, 6H), 1.29
(t, J¼7.1 Hz, 6H), 2.75 (q, J¼7.1 Hz, 4H), 4.24 (q, J¼7.1 Hz, 4H), 4.27
(s, 1H); 13C NMR (100 MHz, CDCl3)
13.6, 14.1, 45.8, 61.1, 67.2, 168.4;
IR (neat) 2976, 2936, 2872, 1734, 1467, 1372, 1302, 1210, 1154, 1093,
1031, 865 cmꢀ1; HRMS (EI) Calcd for C11H21NO4 (M)þ 231.1471,
found 231.1478.
4.5.5. Ethyl 2-(N-benzyl-N-ethylamino)-2-phenylacetate
(4f).5j Yield 64%; Yellow oil; 1H NMR (400 MHz, CDCl3)
1.01 (t,
d
d
J¼7.3 Hz, 3H), 1.28 (t, J¼7.3 Hz, 3H), 2.61e2.67 (m, 2H), 3.69 (d,
J¼14.2 Hz, 1H), 3.77 (d, J¼14.2 Hz, 1H), 4.21 (dq, J¼7.3, 11.0 Hz, 1H),
4.26 (dq, J¼7.3, 11.0 Hz, 1H), 4.62 (s, 1H), 7.21e7.36 (m, 8H),
d
7.41e7.43 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 12.4,14.3, 44.2, 54.2,
60.4, 67.5,126.7,127.7,128.1,128.3,128.5,128.6,137.2,140.1,172.3; IR
(neat) 2971, 2933, 2850,1734, 1452, 1370,1167,1026, 731, 696 cmꢀ1
HRMS (EI) Calcd for C19H23NO2 (M)þ 297.1729, found 297.1739.
;
4.5. General procedure for the tandem N,N-dialkylation to
a
-p-toluoyloxyimino esters
4.6. General procedure for the tandem N,N,C-trialkylation to
Under an argon atmosphere, a suspension of ethyl (Z)-2-(4-
a-p-toluoyloxyimino esters
methylbenzoyloxy)imino-2-phenylacetate (Z)-1o (0.20 mmol) in
toluene (5.0 mL) was stirred at ꢀ78 ꢁC for 5 min, and to it was
added EtMgBr (0.44 mmol, 1.02 N in Et2O) slowly. After the mixture
was stirred for 30 min, benzoic acid (0.15 mmol) in toluene (1.0 mL)
was added to the reaction mixture at ꢀ78 ꢁC for 10 min and then
warmed up to 30 ꢁC, and stirred for 5 min. Then RMgBr (0.35 mmol)
was added to the mixture and stirred for 30 min. The reaction was
quenched with satd NaHCO3 aq (5.0 mL), and the whole mixture
was extracted with ethyl acetate (5.0 mLꢂ3). The combined ex-
tracts were washed with brine, dried over anhydrous Na2SO4, and
concentrated in vacuo. The crude product was purified on silica gel
TLC (n-hexane/ethyl acetate/Et3N¼10/1/1) to give the compound 4.
Under an argon atmosphere, a suspension of ethyl (Z)-2-(4-
methylbenzoyloxy)imino-2-phenylacetate (Z)-1o (0.20 mmol) in
toluene (5.0 mL) was stirred at ꢀ78 ꢁC for 5 min, and to it was added
EtMgBr (0.44 mmol, 1.09 N in Et2O) slowly. After the mixture was
stirred for 30 min, benzoic acid (0.15 mmol) in toluene (1.0 mL) was
added tothe reaction mixture at ꢀ78 ꢁC for 10 min and thenwarmed
up to 30 ꢁC, and stirred for 5 min. Then n-PrMgCl (0.35 mmol, 0.93 N
in Et2O) was added to the mixture and stirred for 30 min. Then
DBDMH (0.12 mmol) in CH2Cl2 (2.0 mL) was added and the mixture
was stirred for 15 min followed by the addition of RMgBr
(0.40 mmol) with stirring for 15 min. The reaction was quenched
with satd NaHCO3 aq (5.0 mL), and the whole mixture was extracted
with ethyl acetate (5.0 mLꢂ3). The combined extracts were washed
with brine, dried over anhydrous Na2SO4, and concentrated in
vacuo. The crude product was purified on silica gel TLC (n-hexane/
ethyl acetate/Et3N¼10/1/1) to give the trialkylayed compound 5.
4.5.1. Ethyl 2-(N-ethyl-N-propylamino)-2-phenylacetate
(4a).5j Yield 79%, Yellow oil; 1H NMR (400 MHz, CDCl3):
d 0.81 (t,
J¼7.3 Hz, 3H), 0.98 (t, J¼7.3 Hz, 3H), 1.24 (t, J¼7.3 Hz, 3H), 1.35e1.52
(m, 2H), 2.44e2.55 (m, 2H), 2.63 (q, J¼7.3 Hz, 2H), 4.13e4.25 (m,
2H), 4.51 (s, 1H), 7.25e7.34 (m, 3H), 7.40e7.42 (m, 2H); 13C NMR
(125 MHz, CDCl3):
d
11.7, 12.3, 14.2, 20.4, 44.3, 52.0, 60.4, 69.1, 127.7,
4.6.1. Ethyl 2-ethyl(propyl)amino-2-phenylpropanoate (5a). Yield
128.2, 128.7, 137.4, 172.4; IR (neat): 1737, 1453, 1372, 1154, 1067,
1029, 728, 696 cmꢀ1; HRMS (EI) Calcd for C12H18N (M-C3H5O2)þ
176.1434, found 176.1434.
59%; Yellow oil; 1H NMR (400 MHz, CDCl3)
d
0.79 (dd, J¼7.1, 7.1 Hz,
3H), 1.02 (t, J¼7.1 Hz, 3H), 1.27 (dd, J¼7.1, 7.1 Hz, 3H), 1.41e1.60 (m,
5H, including singlet at 1.60 ppm, 3H), 2.37e2.44 (m,1H), 2.50e2.66
(m, 3H), 4.15e4.27 (m, 2H), 7.20e7.31 (m, 3H), 7.45e7.47 (m, 2H);
4.5.2. Ethyl 2-(N-ethyl-N-isopropylamino)-2-phenylacetate
13C NMR (100 MHz, CDCl3)
d 11.7, 14.3, 16.4, 24.2, 24.3, 46.5, 54.2,
(4c).5j Yield 72%, Yellow oil; 1H NMR (400 MHz, CDCl3)
d
0.90 (t,
60.5, 72.0,126.9,127.9,144.5,174.7; IR (neat) 2965, 2872,1725,1447,
J¼7.3 Hz, 3H), 1.04 (d, J¼6.9 Hz, 3H), 1.05 (d, J¼6.9 Hz, 3H), 1.25 (t,
J¼7.3 Hz, 3H), 2.67 (dq, J¼7.3, 14.2 Hz, 1H), 2.73 (dq, J¼7.3, 14.2 Hz,
1H), 3.12 (sept, J¼6.9 Hz, 1H), 4.16 (dq, J¼7.3, 10.6 Hz, 1H), 4.21 (dq,
J¼7.3, 10.6 Hz, 1H), 4.62 (s, 1H), 7.24e7.33 (m, 3H), 7.37e7.42 (m,
1373,1229,1176,1098,1070, 699 cmꢀ1; HRMS (EI) Calcd for C13H20
(M-C3H5O2)þ 190.1596, found 190.1581.
N
4.6.2. Ethyl 2-cyclohexyl-2-ethyl(propyl)amino-2-phenylacetate
(5b). Yield 31%; Yellow oil; 1H NMR (400 MHz, CDCl3)
0.27e0.36
2H); 13C NMR (100 MHz, CDCl3)
d
14.1, 15.9, 19.0, 20.5, 40.4, 49.2,
d
60.4, 66.0, 127.5, 128.1, 128.5, 138.6, 173.8; IR (neat) 3062, 2969,
2872, 1739, 1453, 1385, 1157, 1030, 726, 696 cmꢀ1; HRMS (EI) Calcd
for C12H18N (M-C3H5O2)þ 176.1434, found 176.1434.
(m, 1H), 0.42e0.52 (m, 1H), 0.74e0.94 (m, 4H, including dd at
0.82 ppm, J¼7.3, 7.3 Hz, 3H),1.05 (dd, J¼7.3, 7.3 Hz, 3H),1.17e1.36 (m,
6H, including dd at 1.30 ppm, J¼7.3, 7.3 Hz, 3H), 1.50e1.68 (m, 6H),
1.94e1.97 (m, 1H), 2.23e2.30 (m, 1H), 2.36e2.44 (m, 1H), 2.59e2.60
(m, 2H), 4.20e4.28 (m, 2H), 7.21e7.34 (m, 5H); 13C NMR (100 MHz,
4.5.3. Ethyl 2-(N-cyclohexyl-N-ethylamino)-2-phenylacetate
(4d).5j Yield 39%; Yellow oil; 1H NMR (500 MHz, CDCl3)
d
0.86 (t,
CDCl3) d 12.0, 14.6, 15.3, 23.4, 26.6, 26.8, 27.0, 27.2, 30.9, 42.3, 59.9,
J¼7.3 Hz, 3H),1.05e1.22 (m, 4H),1.26 (t, J¼7.3 Hz, 3H), 1.34e1.42 (m,
1H), 1.57e1.60 (m, 1H), 1.68e1.77 (m, 3H), 1.92e1.93 (m, 1H),
2.63e2.83 (m, 3H), 4.17 (qd, J¼7.3, 11.0 Hz, 1H), 4.22 (qd, J¼7.3,
77.9,126.3,126.5,129.5,138.9,171.4; IR (neat) 2931, 2852,1719,1492,
1446, 1377, 1207, 1170, 1026, 711 cmꢀ1; HRMS (EI) Calcd for C18H28
(M-C3H5O2)þ 258.2222, found 258.2232.
N
11.0 Hz, 1H), 4.69 (s, 1H), 7.24e7.32 (m, 3H), 7.37e7.39 (m, 2H); 13
C
NMR (125 MHz, CDCl3)
58.7, 60.3, 65.7, 127.4, 128.1, 128.5, 138.8, 174.0; IR (neat) 3061, 3029,
d
14.2, 15.9, 26.2, 26.3, 26.4, 29.9, 31.7, 40.9,
4.6.3. Ethyl 2-ethyl(propyl)amino-2,3-diphenylpropanoate
(5c). Yield 64%; Yellow oil; 1H NMR (400 MHz, CDCl3)
0.86
d

I. Mizota et al. / Tetrahedron 71 (2015) 5793e5799
5799
(t, J¼7.1 Hz, 3H), 1.12 (t, J¼7.1 Hz, 3H), 1.32 (t, J¼7.1 Hz, 3H),
References and notes
1.56e1.66 (m, 2H), 2.46e2.54 (m, 1H), 2.63e2.84 (m, 4H), 3.75 (d,
J¼7.1 Hz, 1H), 4.28 (q, J¼7.1 Hz, 2H), 6.61e6.62 (m, 2H), 6.94e7.12
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M. C.; Seegl, P. K. S.; Slaughter, D. E.; Vyas, K. J. Med. Chem. 1997, 40, 3865e3868;
(c) Ellingboe, J. W.; Spinelli, W.; Winkley, M. W.; Nguyen, T. T.; Parsons, R. W.;
Moubarak, I. F.; Kitzen, J. M.; Engen, D. V.; Bagli, J. F. J. Med. Chem. 1992, 35,
705e716.
(m, 8H); 13C NMR (100 MHz, CDCl3)
d 11.8,14.6,16.4, 24.7, 45.6, 46.3,
53.7, 60.2, 76.3, 125.8, 126.6, 127.0, 127.1, 128.5, 131.0, 137.2, 141.2,
171.1; IR (neat) 3030, 2966, 2872, 1720, 1495, 1451, 1256, 1182, 1029,
700, 618 cmꢀ1; HRMS (EI) Calcd for C22H29NO2 (M)þ 339.2198,
found 339.2196.
4.6.4. Ethyl 2-ethyl(propyl)amino-2,2-diphenylacetate (5d). Yield
57%; Yellow oil; 1H NMR (400 MHz, CDCl3)
1.13 (t, J¼7.1 Hz, 3H), 1.24 (t, J¼7.1 Hz, 3H), 1.60e1.69 (m, 2H),
2.39e2.43 (m, 2H), 2.55 (q, J¼7.1 Hz, 2H), 4.27 (q, J¼7.1 Hz, 2H),
7.13e7.25 (m, 6H), 7.46e7.48 (m, 4H); 13C NMR (100 MHz, CDCl3)
d
0.78 (t, J¼7.1 Hz, 3H),
d
11.9, 14.3, 16.4, 24.4, 47.9, 55.8, 60.7, 80.5, 126.5, 127.5, 128.5, 142.2,
171.8; IR (neat) 3060, 2966, 2933, 2871, 1726, 1598, 1492, 1177, 1026,
916, 742, 705 cmꢀ1; HRMS (EI) Calcd for C21H27NO2 (M)þ 325.2042,
found 325.2053.
3. Ciganek, E. Org. React. 2008, 72, 1e336, and references therein.
4. For N-alkylation to a-imino esters: (a) Fiaud, J.-C.; Kagan, H. B. Tetrahedron Lett.
1971, 12, 1019e1022; (b) Yamamoto, Y.; Ito, W. Tetrahedron 1988, 44, 5415e5423;
(c) Uneyama, K.; Yan, F.; Hirama, S.; Katagiri, T. Tetrahedron Lett. 1996, 37,
2045e2048; (d) Yoo, S. E.; Gong, Y. D. Heterocycles 1997, 45, 1251e1255; (e)
Bertrand, M. P.; Feray, L.; Nouguier, R.; Perfetti, P. Synlett 1999, 1148e1150; (f)
Mae, M.; Amii, H.; Uneyama, K. Tetrahedron Lett. 2000, 41, 7893e7896; (g) Chiev,
K. P.; Roland, S.; Mangeney, P. Tetrahedron: Asymmetry 2002, 13, 2205e2209; (h)
Dickstein, J. S.; Fennie, M. W.; Norman, A. L.; Paulose, B. J.; Kozlowski, M. C. J. Am.
Chem. Soc. 2008, 130, 15794e15795; (i) Dickstein, J. S.; Kozlowski, M. C. Chem.
Soc. Rev. 2008, 37, 1166e1173; (j) Curto, J. M.; Dickstein, J. S.; Berritt, S.; Ko-
zlowski, M. C. Org. Lett. 2014, 16, 1948e1951.
4.6.5. Ethyl 2-ethyl(propyl)amino-2-phenyl-2-(thiophen-2-yl)acetate
(5e). Yield 43%; Yellow oil; 1H NMR (400 MHz, CDCl3)
d 0.76 (t,
J¼7.3 Hz, 3H), 1.08 (dd, J¼7.3, 7.3 Hz, 3H), 1.28 (t, J¼7.3 Hz, 3H),
1.50e1.60 (m, 2H), 2.47e2.51 (m, 2H), 2.63 (q, J¼7.3 Hz, 2H), 4.30 (q,
J¼7.3 Hz, 2H), 6.89e6.91 (m, 1H), 7.10e7.11 (m, 1H), 7.19e7.29 (m,
4H), 7.48e7.50 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 11.9, 14.2, 16.3,
24.3, 48.1, 55.8, 61.1, 78.1, 125.1,125.8,127.2,127.2,127.7,128.1,142.4,
146.4, 171.9; IR (neat) 2965, 2871, 1730, 1447, 1212, 1166, 1025, 802,
749, 699 cmꢀ1; HRMS (EI) Calcd for C19H25NO2S (M)þ 331.1606,
found 331.1615.
5. For N-alkylation to a-imino esters in our laboratory: (a) Shimizu, M.; Niwa, Y.
Tetrahedron Lett. 2001, 42, 2829e2832; (b) Niwa, Y.; Takayama, K.; Shimizu, M.
Tetrahedron Lett. 2001, 42, 5473e5476; (c) Niwa, Y.; Takayama, K.; Shimizu, M.
Bull. Chem. Soc. Jpn. 2002, 75, 1819e1825; (d) Niwa, Y.; Shimizu, M. J. Am. Chem.
Soc. 2003, 125, 3720e3721; (e) Shimizu, M.; Itou, H.; Miura, M. J. Am. Chem. Soc.
2005, 127, 3296e3297; (f) Shimizu, M. Pure Appl. Chem. 2006, 78, 1867e1876; (g)
Shimizu, M.; Hachiya, I.; Mizota, I. Chem. Commun. 2009, 874e889; (h) Mizota, I.;
Tanaka, K.; Shimizu, M. Tetrahedron Lett. 2012, 53, 1847e1850; (i) Nishi, T.;
Mizota, I.; Shimizu, M. Pure Appl. Chem. 2012, 84, 2609e2617; (j) Hata, S.; Maeda,
T.; Shimizu, M. Bull. Chem. Soc. Jpn. 2012, 85, 1203e1205; (k) Shimizu, M.; Takao,
Y.; Katsurayama, H.; Mizota, I. Asian J. Org. Chem. 2013, 2, 130e134; (l) Shimizu,
M.; Kurita, D.; Mizota, I. Asian J. Org. Chem. 2013, 2, 208e211; (m) Sano, T.;
Mizota, I.; Shimizu, M. Chem. Lett. 2013, 42, 995e997; (n) Mizota, I.; Matsuda, Y.;
Kamimura, S.; Tanaka, H.; Shimizu, M. Org. Lett. 2013, 15, 4206e4209; (o) Tanaka,
H.; Mizota, I.; Shimizu, M. Org. Lett. 2014, 16, 2276e2279; (p) Shimizu, M.;
Tateishi, M.; Mizota, I. Chem. Lett. 2014, 43, 1752e1754.
4.6.6. Ethyl 2-ethyl(propyl)amino-2-phenylbut-3-enoate (5f). Yield
54%; Yellow oil; 1H NMR (400 MHz, CDCl3)
d
0.78 (dd, J¼7.3, 7.3 Hz,
3H), 1.05 (dd, J¼7.3, 7.3 Hz, 3H), 1.28 (t, J¼7.3 Hz, 3H), 1.52 (ddq,
J¼7.3, 7.3, 7.3 Hz, 2H), 2.41e2.69 (m, 4H), 4.26 (q, J¼7.3 Hz, 2H),
5.21e5.27 (m, 2H), 6.24 (dd, J¼10.8, 17.5 Hz, 1H), 7.20e7.31 (m, 3H),
7.43e7.45 (m, 2H); 13C NMR (100 MHz, CDCl3)
d 11.7, 14.3, 16.6, 24.6,
47.4, 55.1, 60.6, 77.6, 115.5, 127.1, 127.7, 128.4, 139.5, 141.2, 172.7; IR
(neat) 2964, 2933, 2872, 1728, 1447, 1222, 1130, 1032, 926, 760,
701 cmꢀ1; HRMS (EI) Calcd for C17H25NO2 (M)þ 275.1885, found
275.1890.
6. Although we have not fully examined the effects of the added benzoic acid on a-
sulfoximino esters, the second alkylation was too rapid with (Z)-a-sulfoximino
derivatives regardless of the addition of benzoic acid.
7. The order of addition is very important as shown in the following examples. Less
bulky nucleophiles should be added first.
Acknowledgements
This work was supported by Grants-in-Aid for Scientific Re-
search (B) and on Innovative Areas ‘Organic Synthesis Based on
Reaction Integration, Development of New Methods and Creation
of New Substances’ from JSPS and MEXT, and a grant from the
Hattori Hokokai Foundation.
Supplementary data
8. We assume that one of the important factors to stop the addition reaction at the
mono-N-alkylation stage is the formation of the eight-membered intermediate
B for the (Z)-acyloxyimino ester as proposed in Scheme 5. Isomerization of the
imine geometry of the mono-N-alkylation product may be also involved.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2015.04.111.