Novel synthetic approach for N-acyl imines of trichloropyruvate

Article abstract of DOI:10.1055/s-0030-1258317

A convenient synthesis for N-acyl imines of trichloropyruvates [2-(acylimino)-3,3,3-trichloropropanoates] based on consecutive silylation-chlorinative desilylation of readily accessible α-(acylamino)- substituted dichloroacrylates was developed. The use o

Full text of DOI:10.1055/s-0030-1258317

PAPER
65
Novel Synthetic Approach for N-Acyl Imines of Trichloropyruvate
N
-Acyl Imines
e
of
T
richlo
t
ropyruv
r
ate o P. Onys’ko,* Yaroslav Y. Khomutnyk, Tetyana V. Kim, Olena I. Kyselyova, Yuliya V. Rassukana,
Volodymyr S. Brovarets, Anatoly D. Synytsya
Institute of Organic Chemistry, National Academy of Sciences, 5 Murmans’ka St, Kiev 02660, Ukraine
Fax +380(44)5732643; E-mail: onysko@rambler.ru
Received 2 August 2010; revised 1 October 2010
Cl
Cl
COOMe
Cl
Cl
COOMe
O
Me3SiCl, Et3N
Abstract: A convenient synthesis for N-acyl imines of trichloropy-
ruvates [2-(acylimino)-3,3,3-trichloropropanoates] based on con-
secutive silylation–chlorinative desilylation of readily accessible a-
(acylamino)-substituted dichloroacrylates was developed. The use
of the 2-iminopropanoates obtained for the amidoalkylation of S-,
O-, N-, and C-centered nucleophiles to afford amino acids deriva-
tives is disclosed.
O
N
– Et3N⋅HCl
HN
80–86%
Me3Si
Ar
Ar
2a,b
1a,b
Cl
Cl
COOMe
MeOOC
Cl3C
Ar
Key words: N-acyl imines, enamides, iminocarboxylates, trichlo-
romethyl, silylation, chlorination, nucleophilic addition
benzene, Cl2, r.t.
– Me3SiCl
O
N
SiMe3
N
O
Ar
2'a,b
3a,b
N-Acyl imines are valuable highly electrophilic building
blocks for the synthesis of various functionalized nitro-
1a–3a: Ar = Ph
1b–3b: Ar = 4-Tol
gen-containing compounds.1 Activated imines bearing an Scheme 1
alkoxycarbonyl group at the imine carbon atom are espe-
cially promising as their functionalization leads to biorel-
Iminopyruvates 3 were purified by distillation in vacuo.
Their composition and structure were confirmed by ana-
lytical and spectral data. In particular, characteristic are
evant a-amino acids derivatives. Specifically, (acyl-
imino)trifluoropyruvates easily react with various nucleo-
philes to afford biologically important trifluoroalanine de-
rivatives.1c,2 At the same time iminotrichloropyruvates
remain almost unexplored and (aroylimino)trichloropyru-
vates, to the best of our knowledge, are so far unknown.
This is most likely connected with the absence of conve-
nient methods for their synthesis. The approaches de-
scribed in the literature are based on the use of hard-to-
access trichloropyruvates.3
the chemical shifts of C=N and NC=O carbons in the 13
C
NMR spectra (dC = 154 and 176, respectively) and the ap-
pearance of the stretching vibrations of the C=N (1615
cm–1) and C=O bonds (1710, 1755 cm–1) in the IR spectra.
Compounds 3 contain a highly polarized C=N bond, al-
lowing the introduction of various, even weakly, nucleo-
philic functional groups under mild conditions.
Specifically, they easily react with S-, O-, N-, and C-cen-
tered nucleophiles across the C=N bond to afford highly
functionalized trichloroalanine derivatives (Scheme 2).
Reaction with alcohols or 4-chlorothiophenol leads to
stable O,N-acetals 4a,b or S,N-thioacetal 5a. Addition of
thioglycolic acid or its ester gives functionalized alani-
nates 5b–d possessing an additional carboxylic moiety in
the molecule. Cyclic nitrogen nucleophiles are easily ami-
doalkylated with 3 to afford trichloroalaninates bearing
the heterocyclic residue bound through the endo- (6) or
exocyclic nitrogen atom (7, 8).
We have developed a novel convenient synthesis of
(acylimino)trichloropyruvates
[2-(acylimino)-3,3,3-
trichloropropanoates] based on readily available a-(acyl-
amino)-substituted dichloroacrylates.4 Essentially, the
method involves silylation of amides 1, subsequent mild
chlorination of silyl derivatives 2 (Cl2, benzene, r.t.) fol-
lowed by elimination of chlorotrimethylsilane
1
(Scheme 1). According to H NMR spectroscopy, com-
pounds 2 exist in solution as a mixture of N- and O-sily-
lated isomers 2 and 2¢. In CDCl3 solution the separate
signals of the SiMe3 (d = 0.2 and 0.4) and OMe groups
(d = 3.8 and 3.6) were observed for regioisomers 2 and 2¢
respectively (2/2¢) ~1.5:1. In C6D6 the resonances of these
groups appear as broad signals (d = 0.2–0.4 and 3.1–3.4,
respectively) suggesting dynamic equilibrium. It is note-
worthy that nonsilylated starting amides 1 cannot be chlo-
rinated under similar conditions.5
The reaction of 3a,b with a-methyl-substituted push–pull
enamine 9 proceeds not at the b-position of the enamine,
but at the methyl group to give highly functionalized ami-
nodicarboxylic acids derivatives 10a,b. Note that the
enamine fragment of 9 remains unaltered in the course of
reaction in Scheme 3. The involvement of the methyl
group of push–pull enamines in their reactions with N-
(alkoxycarbonyl)imines of trifluoropyruvate was de-
scribed recently by Kostyuk et al.6 Significant in the proof
of the structure 10 is the presence in their 1H NMR spectra
of the signals of the diastereotopic CH2 group (AB sys-
SYNTHESIS 2011, No. 1, pp 0065–0068
x
x
.
x
x
.2
0
1
0
Advanced online publication: 25.10.2010
DOI: 10.1055/s-0030-1258317; Art ID: P12310SS
© Georg Thieme Verlag Stuttgart · New York

66
P. P. Onys’ko et al.
PAPER
(120 mL) and the mixture was stirred at r.t. for 48 h. The precipitat-
ed Et3N·HCl was filtered off and the filtrate was evaporated in
vacuo to yield O,N-silylated isomers 2 and 2¢, which were charac-
O
Ar
O
Ph
O
Ar
Cl3C
NH
Cl3C
Cl3C
MeOOC
NH
SR
NH
1
MeOOC
OR
terized by H NMR and used without purification. A soln of Cl2
MeOOC
N
(100 mmol) in benzene (30 mL) was added dropwise to ice cooled
soln of 2 and 2¢ in benzene (100 mL). The mixture was stirred over-
night at r.t., evaporated under reduced pressure and distilled in
vacuo.
4a,b
6
5a–d
N
H
N
ROH
RSH
N
Methyl 2-(Benzoylimino)-3,3,3-trichloropropanoate (3a)
Colorless oil; yield: 80%; bp 135–137 °C/0.133 mbar.
IR (neat): 1615 (C=N), 1710 (NHC=O), 1755 cm–1 (OC=O).
Cl3C
N
O
1H NMR (CDCl3): d = 3.83 (s, 3 H, Me), 7.51 (t, 3JHH = 7.4 Hz, 2 H,
O
Ar
Ph), 7.64 (t, 3JHH = 7.4 Hz, 1 H, Ph), 7.89 (d, 3JHH = 7.2 Hz, 2 H, Ph).
OMe
3a,b
13C NMR (CDCl3): d = 53.86 (Me), 92.12 (CCl3), 128.94, 129.13
(o-C, m-C, Ph), 131.14 (ipso-C, Ph), 134.25 (p-C, Ph), 153.89
(C=N), 157.96 (OC=O), 175.95 (NC=O).
X
HN
H2N
O
N
Anal. Calcd for C11H8Cl3NO3: C, 42.82; H, 2.61; Cl, 34.47; N 4.54.
Found: C, 42.53; H, 2.52;Cl, 35.13; N, 4.68.
O
Ar
O
Ar
Cl3C
MeOOC
Cl3C
MeOOC
NH
NH
HN
X
Methyl 3,3,3-Trichloro-2-[(4-methylbenzoyl)imino]propanoate
(3b)
White solid; yield: 86%; bp 130–131 °C/0.107 mbar; mp 74–75 °C.
N
N
8a,b
7a,b
O
IR (KBr): 1615 (C=N), 1710 (NHC=O), 1755 cm–1 (OC=O).
4a: R = Me, Ar = 4-Tol
4b: R = Et, Ar = Ph
5a: R = 4-ClC6H4, Ar = 4-Tol
5b: R = CH2COOMe, Ar = Ph
5c: R = CH2COOMe, Ar = 4-Tol
5d: R = CH2COOH, Ar = Ph
7a: X = CH, Ar = 4-Tol
7b: X = N, Ar = 4-Tol
8a: Ar = Ph
1H NMR (CDCl3): d = 2.44 (s, 3 H, MeC), 3.83 (s, 3 H, MeO), 7.30
(d, 3JHH = 8.5 Hz, 2 H, Ar), 7.78 (d, 3JHH = 8.5 Hz, 2 H, Ar).
13C NMR (CDCl3): d = 21.85 (MeC), 53.73 (MeO), 92.21 (CCl3),
128.52 (ipso-C, Ar), 129.23, 129.63 (o-C, m-C, Ar), 145.28 (p-C,
Ar), 153.88 (C=N), 158.11 (OC=O), 175.83 (NC=O).
8b: Ar = 4-Tol
Scheme 2
Anal. Calcd for C12H10Cl3NO3: C, 44.68; H, 3.12; Cl, 32.97; N 4.34.
Found: C, 44.37; H, 2.94; Cl, 32.83; N, 4.15.
O
Ar
N
COOEt
Cl3C
O
COOEt
O
Cl3C
9
NH
Alkoxyalaninates 4a,b; General Procedure
A soln of imine 3 (0.2 mmol) in anhyd MeOH or EtOH (1 mL) was
left at r.t. overnight. The solvent was evaporated to leave analytical-
ly pure adducts 4.
N
benzene, 80 °C
MeOOC
O
Ar
OMe
N
3a,b
10a,b
a: Ar = Ph
b: Ar = 4-Tol
O
Methyl 3,3,3-Trichloro-2-methoxy-N-(4-methylbenzoyl)alani-
nate (4a)
Scheme 3
White solid; yield: 98%; mp 75–78 °C.
IR (KBr): 1685 (NHC=O), 1765 (OC=O), 3375 cm–1 (NH).
tem, dA = 3.43, dB = 4.78, JAB = 15 Hz) and the absence of
1H NMR (CDCl3): d = 2.44 (s, 3 H, MeC), 3.67 (s, 3 H, MeOC-N),
3.92 (s, 3 H, COOMe), 6.92 (s, 1 H, NH), 7.30 (d, 3JHH = 8.3 Hz, 2
H, Ar), 7.73 (d, 3JHH = 8.3 Hz, 2 H, Ar).
a singlet for the methyl group.
In summary, we have developed a simple and efficient
synthesis of (acylimino)trichloropyruvates 3 and demon-
strated their synthetic potentialities for the preparation of
functionalized amino acid derivatives possessing a
trichloroalanine fragment. We are currently investigating
other types of addition and cycloaddition reactions of
imines 3.
Anal. Calcd for C13H14Cl3NO4: C, 44.03; H, 3.98; Cl, 29.99; N,
3.95. Found: C, 44.10; H, 3.97; Cl, 29.87; N, 3.99.
Methyl N-Benzoyl-3,3,3-trichloro-2-ethoxyalaninate (4b)
White solid; yield: 98%; mp 97–99 °C.
IR (KBr): 1685 (NHC=O), 1765 (OC=O), 3382 cm–1 (NH).
1H NMR (CDCl3): d = 1.29 (t, 3JHH = 7.2 Hz, 3 H, MeCH2), 3.77 (m,
1 H, OCH2), 3.91 (s, 3 H, OMe), 4.10 (m, 1 H, OCH2), 6.98 (s, 1 H,
IR spectra were obtained with a UR-20 instrument. 1H NMR spectra
were recorded on a Varian VXR-300 spectrometer (operating fre-
quency 299.95 MHz) relative to internal TMS; 13C NMR spectra
were recorded on a Bruker Avance DRX 500 instrument operating
at 125.76 MHz. Melting points are uncorrected. Solvents were dried
before use according to standard methods. All reactions were car-
ried out under an argon atmosphere.
3
3
NH), 7.51 (t, JHH = 7.2 Hz, 2 H, Ph), 7.60 (t, JHH = 7.2 Hz, 1 H,
Ph), 7.83 (d, 3JHH = 7.2 Hz, 2 H, Ph).
Anal. Calcd for C13H14Cl3NO4: C, 44.03; H, 3.98; Cl, 29.99; N,
3.95. Found: C, 44.15; H, 3.95; Cl, 30.45; N, 3.92.
Methyl 3,3,3-Trichloro-2-[(4-chlorophenyl)thio]-N-(4-methyl-
benzoyl)alaninate (5a)
Iminotrichloropropanoates 3a,b; General Procedure
Et3N (41.1 mmol) was added dropwise at r.t. to a stirred soln of
amide 1 (27.4 mmol) and TMSCl (27.4 mmol) in anhyd benzene
4-Chlorothiophenol (50 mg, 0.34 mmol) was added at r.t. to a stirred
soln of imine 3b (110 mg, 0.34 mmol) in anhyd Et2O (2 mL). The
mixture was stirred overnight, the solvent was evaporated in vacuo,
Synthesis 2011, No. 1, 65–68 © Thieme Stuttgart · New York

PAPER
N-Acyl Imines of Trichloropyruvate
67
and the solid residue was washed with hexane; white solid; yield:
85%; mp 139–142 °C (dec).
Anal. Calcd for C14H12Cl3N3O3: C, 44.65; H, 3.21; Cl, 28.24; N,
11.16. Found: C, 44.60; H, 3.20; Cl, 28.21; N, 11.19.
IR (KBr): 1690 (NC=O), 1765 (MeOC=O), 3415 cm–1 (NH).
Methyl 3,3,3-Trichloro-N-(4-methylbenzoyl)-2-(pyridin-2-
ylamino)alaninate (7a)
White solid; yield: 82%; mp 180–182 °C.
IR (KBr): 1690 (NHC=O), 1760 (OC=O), 3370 cm–1 (NH).
1H NMR (CDCl3): d = 2.40 (s, 3 H, MeC), 3.91 (s, 3 H, MeO), 6.48
3
(s, 1 H, NH), 7.20 (d, JHH = 8.9 Hz, 2 H, C6H4Cl), 7.26 (d,
3JHH = 8.9 Hz, 2 H, C6H4Cl), 7.35 (d, 3JHH = 8.2 Hz, 2 H, C6H4Me),
7.60 (d, 3JHH = 8.2 Hz, 2 H, C6H4Me).
1H NMR (CDCl3): d = 2.38 (s, 3 H, MeC), 3.90 (s, 3 H, MeO), 6.74
Anal. Calcd for C18H15Cl4NO3S: C, 46.28; H, 3.24; Cl, 30.35; N,
3.00. Found: C, 46.20; H, 3.26; Cl, 30.43; N, 3.05.
(br, 1 H, Py), 6.90 (br, 1 H, Py), 7.21 (d, 3JHH = 7.7 Hz, 2 H, Ar),
3
7.53 (m, 2 H, Py, NH), 7.65 (d, JHH = 7.7 Hz, 2 H, Ar), 7.97 (d,
3J = 4.6 Hz, 1 H, 6-HPy), 8.30 (br s, 1 H, NHCO).
Compounds 5b–d; General Procedure
Methyl thioglycolate or mercaptoacetic acid (0.4 mmol) were added
to a stirred soln of imine 3 (0.4 mmol) in Et2O (2 mL). After reacting
at r.t. for 2 h, the precipitate formed was filtered and washed with
Et2O.
Anal. Calcd for C17H16Cl3N3O3: C, 49.00; H, 3.87; Cl, 25.52; N,
10.08. Found: C, 49.13; H, 3.82; Cl, 25.60; N, 10.02.
Methyl 3,3,3-Trichloro-N-(4-methylbenzoyl)-2-(pyrazin-2-
ylamino)alaninate (7b)
Methyl N-Benzoyl-3,3,3-trichloro-2-{[(methoxycarbonyl)meth-
yl]thio}alaninate (5b)
White needles; yield: 81%; mp 157 °C.
1H NMR (CDCl3): d = 3.55 (d, 2JHH = 17.1 Hz, 1 H, CH2S), 3.76 (s,
3 H, MeO), 3.91 (s, 3 H, MeO), 4.06 (d, 2JHH = 17.1 Hz, 1 H, CH2S),
7.49 (t, 3JHH = 7.5 Hz, 2 H, Ph), 7.57 (t, 3JHH = 7.5 Hz, 1 H, Ph), 7.93
(d, 3JHH = 7.6 Hz, 2 H, Ph), 8.49 (s, 1 H, NH).
White solid; yield: 75%; mp 195–197 °C.
IR (KBr): 1695 (NHC=O), 1765 (OC=O), 3360, 3415 cm–1 (NH).
1H NMR (CDCl3): d = 2.39 (s, 3 H, MeC), 3.90 (s, 3 H, MeO), 7.23
(m, 3 H, Ar, NH), 7.63 (d, 3JHH = 7.7 Hz, 2 H, Ar), 7.97 (br, 1 H, 5-
HHt), 8.03 (s, 1 H, 3-HHt), 8.06 (br, 1 H, 6-HHt), 8.56 (s, 1 H, NHCO).
Anal. Calcd for C16H15Cl3N4O3: C, 46.01; H, 3.62; Cl, 25.46; N,
13.41. Found: C, 45.95; H, 3.58; Cl, 25.60; N, 13.35.
Anal. Calcd for C14H14Cl3NO5S: C, 40.55; H, 3.40; Cl, 25.65; N,
3.38; S, 7.73. Found: C, 40.77; H, 3.27; Cl, 25.46; N, 3.38; S, 7.73.
Methyl N-Benzoyl-3,3,3-trichloro-2-(morpholin-4-yl)alaninate
(8a)
Methyl 3,3,3-Trichloro-2-{[(methoxycarbonyl)methyl]thio}-N-
(4-methylbenzoyl)alaninate (5c)
White solid; yield: 87%; mp 144–145 °C.
IR (KBr): 1700 (NHC=O), 1775 (OC=O), 3385 cm–1 (NH).
1H NMR (CDCl3): d = 2.42 (s, 3 H, MeC), 3.76 (s, 3 H, OMe), 3.90
(s, 3 H, OMe), 3.54 (d, 2JHH = 17 Hz, 1 H, CH2S), 4.06 (d, 2JHH = 17
Hz, 1 H, CH2S), 7.28 (d, 3JHH = 5.9 Hz, 2 H, Ar), 7.82 (d, 3JHH = 5.9
Hz, 2 H, Ar), 8.43 (s, 1 H, NH).
White solid; yield: 78%; mp 118–119 °C.
IR (KBr): 1695 (NHC=O), 1755 (OC=O), 3382 cm–1 (NH).
1H NMR (CDCl3): d = 3.24 (m, 2 H, morph), 3.66–3.73 (m, 4 H,
morph), 3.84 (s, 3 H, OMe), 4.00 (m, 2 H, morph), 7.51 (t,
3JHH = 7.5 Hz, 2 H, Ph), 7.64 (t, JHH = 7.5 Hz, 1 H, Ph), 7.88 (d,
3
3JHH = 7.5 Hz, 2 H, Ph), 10.06 (br s, 1 H, NH).
Anal. Calcd for C15H17Cl3N2O4: C, 45.53; H, 4.33; Cl, 26.88; N,
7.08. Found: C, 45.50; H, 4.31; Cl, 26.85; N, 7.06.
Anal. Calcd for C15H16Cl3NO5S: C, 42.02; H, 3.76; Cl, 24.81; N,
3.27. Found: C, 41.89; H, 3.81; Cl, 24.73; N, 3.30.
Methyl 3,3,3-Trichloro-N-(4-methylbenzoyl)-2-(morpholin-4-
yl)alaninate (8b)
White solid; yield: 80%; mp 123–125 °C.
IR (KBr): 1695 (NC=O), 1750 (OC=O), 3390 cm–1 (NH).
Methyl 2-[(Carboxymethyl)thio]-3,3,3-trichloro-N-(4-methyl-
benzoyl)alaninate (5d)
White solid; yield: 90%; mp 97–98 °C.
1H NMR (CDCl3): d = 2.43 (s, 3 H, MeC), 3.24 (m, 2 H, morph),
3.65–3.75 (m, 4 H, morph), 3.83 (s, 3 H, OMe), 4.00 (m, 2 H,
morph), 7.29 (d, 3JHH = 7.9 Hz, 2 H, Ar), 7.78 (d, 3JHH = 7.9 Hz, 2
H, Ar), 9.56 (br s, 1 H, NH).
IR (KBr): 1695 (NHC=O), 1770 (OC=O), 3380 cm–1 (NH).
1H NMR (CDCl3): d = 2.40 (s, 3 H, MeC), 3.90 (s, 3 H, OMe), 3.54
(d, 2JHH = 16.9 Hz, 1 H, CH2S), 4.05 (d, 2JHH = 16.9 Hz, 1 H, CH2S),
3
3
7.24 (d, JHH = 7.9 Hz, 2 H, Ar), 7.74 (d, JHH = 7.9 Hz, 2 H, Ar),
Anal. Calcd for C16H19Cl3N2O4: C, 46.91; H, 4.67; Cl, 25.96; N,
6.84. Found: C, 46.86; H, 4.70; Cl, 26.01; N, 6.84.
8.11 (s, 1 H, NH), 8.18 (br s, 1 H, COOH).
Anal. Calcd for C14H14Cl3NO5S: C, 40.55; H, 3.40; Cl, 25.65; N,
3.38. Found: C, 40.10; H, 3.29; Cl, 25.39; N, 3.30.
Compounds 10a,b; General Procedure
Enamine 9 (0.3 mmol) was added to a stirred soln of the imine 3 (0.3
mmol) in benzene (5 mL). After reacting at 80 °C for 6 h, the solvent
was evaporated in vacuo and the solid was washed with hexane.
Compounds 6–8; General Procedure
The respective amine (0.3 mmol) was added at r.t. to a stirred soln
of imine 3 (0.3 mmol) in anhyd Et2O (2 mL). The mixture was
stirred overnight, the solvent was evaporated in vacuo, and the solid
residue was washed with hexane.
1-Ethyl 6-Methyl 5-(Benzoylamino)-3-(morpholin-4-yl)-5-
(trichloromethyl)hex-2-enedioate (10a)
White solid; yield: 83%; mp 195–196 °C.
IR (KBr): 1690 (NHC=O), 1765 (OC=O), 3250 cm–1 (NH).
Methyl N-Benzoyl-3,3,3-trichloro-2-(imidazol-1-yl)alaninate
(6)
1H NMR (CDCl3): d = 1.19 (t, 3JHH = 7.2 Hz, 3 H, MeCH2), 3.13–
3.27 (m, 4 H, morph), 3.43 (d, 2JAB = 15 Hz, 1 H, =CCHAHB), 3.66–
3.78 (m, 4 H, morph), 3.81 (s, 3 H, OCH3), 4.05 (q, 3JHH = 7.2 Hz,
2 H, CH2Me), 4.78 (d, 2JAB = 15 Hz, 1 H, =CCHAHB), 4.99 (s, 1 H,
=CH), 7.44 (t, 3JHH = 7.5 Hz, 2 H, Ph), 7.50 (t, 3JHH = 7.5 Hz, 1 H,
Ph), 7.90 (d, 3JHH = 7.5 Hz, 2 H, Ph), 9.60 (s, 1 H, NH).
White solid; yield: 80%; mp 145–147 °C.
IR (KBr): 1670 (NHC=O), 1755 (OC=O), 3385 cm–1 (NH).
1H NMR (CDCl3): d = 3.93 (s, 3 H, OMe), 7.04 (s, 1 H, NH), 7.4–
3
7.7 (m, 4 H, Ph, Ht), 7.66 (t, JHH = 7.5 Hz, 1 H, Ph), 7.88 (d,
3JHH = 6.5 Hz, 2 H, Ph), 8.16 (s, 1 H, 2-HHt).
Synthesis 2011, No. 1, 65–68 © Thieme Stuttgart · New York

68
P. P. Onys’ko et al.
PAPER
Anal. Calcd for C21H25Cl3N2O6: C, 49.67; H, 4.96; Cl, 20.94; N,
5.52. Found: C, 49.60; H, 4.97; Cl, 21.00; N, 5.50.
1992, 61, 1457; Russ. Chem. Rev. (Engl. Transl.) 1992, 61,
798. (d) Levkovskaya, G. G.; Drozdova, T. I.; Rozentsveig,
I. B.; Mirskova, A. N. Usp. Khim. 1999, 68, 638; Russ.
Chem. Rev. (Engl. Transl.) 1999, 68, 581.
1-Ethyl 6-Methyl 5-[(4-Methylbenzoyl)amino]-3-(morpholin-4-
yl)-5-(trichloromethyl)hex-2-enedioate (10b)
White solid; yield: 81%; mp 198–200 °C (dec.).
IR (KBr): 1685 (NHC=O), 1760 cm–1 (OC=O).
(2) (a) Scarpos, H.; Vorob’eva, D. V.; Osipov, S. N.; Odinets, I.
L.; Breuer, E.; Roschenthaler, G.-V. Org. Biomol. Chem.
2006, 4, 3669. (b) Sewald, N.; Riede, J.; Bissinger, P.;
Burger, K. J. Chem. Soc., Perkin Trans. 1 1992, 267.
(3) (a) Matthies, D.; Malassa, I. Synthesis 1985, 77.
(b) Versleijen, J. P.; Sanders-Hoveas, M. S.; Vanhommerig,
S. A.; Vekemans, J. A.; Meijer, E. M. Tetrahedron 1993, 49,
7793.
(4) (a) Drach, B. S.; Brovarets, V. S.; Smolii, O. S. In Syntheses
of Nitrogen-Containing Heterocyclic Compounds on the
Basis of Amidoalkylating Agents; Naukova Dumka: Kiev,
1992, 176 pages (in Russian). (b) Prokopenko, V. M.; Pilyo,
S. G.; Gakh, A. A.; Brovarets, V. S.; Drach, B. S. J. Org.
Pharm. Chem. 2009, 7, 20.
1H NMR (CDCl3): d = 1.19 (t, 3JHH = 7.2 Hz, 3 H, MeCH2), 2.39 (s,
3 H, MeAr), 3.15–3.26 (m, 4 H, morph), 3.43 (d, 2JAB = 15 Hz, 1 H,
=CCHAHB), 3.66–3.78 (m, 4 H, morph), 3.80 (s, 3 H, OCH3), 4.08
3
2
(q, JHH = 7.2 Hz, 2 H, CH2Me), 4.78 (d, JAB = 15 Hz, 1 H,
3
=CCHAHB), 4.99 (s, 1 H, =CH), 7.21 (d, JHH = 8.1 Hz, 2 H, Ar),
7.81 (d, 3JHH = 8.1 Hz, 2 H, Ar), 9.52 (s, 1 H, NH).
Anal. Calcd for C22H27Cl3N2O6: C, 50.64; H, 5.22; Cl, 20.38; N,
5.37. Found: C, 50.61; H, 5.25; Cl, 20.30; N, 5.35.
References
(5) Compare: Kolotilo, N. V.; Sinitsa, A. A.; Onys’ko, P. P.
Russ. Chem. Bull. 1998, 47, 2044.
(6) Sibgatulin, D. A.; Volochnyuk, D. M.; Rusanov, E. B.;
(1) (a) Weinreb, S. M.; Scola, P. M. Chem. Rev. 1989, 89, 1525.
(b) Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205.
Kostyuk, A. N. Synthesis 2006, 1625.
(c) Osipov, S. N.; Kolomiets, A. F.; Fokin, A. V. Usp. Khim.
Synthesis 2011, No. 1, 65–68 © Thieme Stuttgart · New York