Functionalized β-lactams based on (E)-1-(furan-2-yl)-N-[(4-methoxyphenyl)methyl]methanimine and its imine–imine rearrangement initiated by potassium hydride

Article abstract of DOI:10.1134/S1070428016070058

Functionalized β-lactams were synthesized by reaction of (E)-1-(furan-2-yl)-N-[(4-methoxyphenyl)-methyl]methanimine with ketenes generated in situ from chloro- and dichloroacetic acids and 3-(methoxyimino) butanoic acid. (E)-1-(Furan-2-yl)-N-[(4-methoxyphenyl)methyl]methanimine underwent imine–imine rearrangement by the action of potassium hydride to give thermodynamically more stable (E)-N-[(furan-2-yl)-methyl]-1-(4-methoxyphenyl)methanimine.

Full text of DOI:10.1134/S1070428016070058

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2016, Vol. 52, No. 7, pp. 950–955. © Pleiades Publishing, Ltd., 2016.
Original Russian Text © Z.R. Valiullina, N.K. Selezneva, S.L. Khursan, F.A. Gimalova, M.S. Miftakhov, 2016, published in Zhurnal Organicheskoi Khimii,
2
016, Vol. 52, No. 7, pp. 958–963.
Functionalized β-Lactams Based on (E)-1-(Furan-2-yl)-
N-[(4-methoxyphenyl)methyl]methanimine and Its Imine–Imine
Rearrangement Initiated by Potassium Hydride
Z. R. Valiullina, N. K. Selezneva, S. L. Khursan, F. A. Gimalova, and M. S. Miftakhov*
Ufa Institute of Chemistry, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
*
e-mail: bioreg@anrb.ru
Received March 10, 2016
Abstract—Functionalized β-lactams were synthesized by reaction of (E)-1-(furan-2-yl)-N-[(4-methoxyphenyl)-
methyl]methanimine with ketenes generated in situ from chloro- and dichloroacetic acids and 3-(methoxy-
imino)butanoic acid. (E)-1-(Furan-2-yl)-N-[(4-methoxyphenyl)methyl]methanimine underwent imine–imine
rearrangement by the action of potassium hydride to give thermodynamically more stable (E)-N-[(furan-2-yl)-
methyl]-1-(4-methoxyphenyl)methanimine.
DOI: 10.1134/S1070428016070058
During many years β-lactam antibiotics deservedly
generated from chloro- and dichloroacetic acids and
3-(methoxyimino)butanoic acid (2). Ketenes were
generated according to the procedure described in [5]
through the corresponding N-acylimidazoles with the
use of 1,1′-carbonyldiimidazole as activator. Schiff
base 1 was prepared by a conventional method, con-
densation of furfural with 4-methoxybenzylamine in
occupied leading positions in the treatment of infec-
tious diseases [1, 2]. Unique chemotherapeutic prop-
erties of these compounds are determined by the pres-
ence in their molecules of a highly reactive azetidin-2-
one cyclic system. The mechanism of action of
β-lactam antibiotics is explained by their ability to
inhibit biosynthesis of bacterial cell walls via covalent
bonding to penicillin-binding proteins [3]. The main
problem of the clinical use of β-lactam antibiotics is
resistance of bacteria to the drug, which develops with
time [4]. An efficient way to solve the resistance
problem is the design of new structures and synthesis
of modified analogs.
the presence of MgSO (Scheme 1). O-Methyloxime 2
4
(a mixture of isomers at a ratio of ~1 : 1.3) was
synthesized by alkaline hydrolysis of ester 3 which is
readily available by condensation of ethyl acetoacetate
with O-methylhydroxylamine hydrochloride in
pyridine.
The cycloaddition of Schiff base 1 with N-acyl-
imidazole generated from dichloroacetic acid by the
action of 1,1′-carbonyldiimidazole gave 73% of lactam
4 (Scheme 2). Analogous reaction of 1 with N-acyl-
imidazole derived from chloroacetic acid was charac-
With the goal of obtaining sufficient amounts of
initial compounds for the synthesis of modified
β-lactam analogs, in the present work we have studied
[
2+2]-cycloadditions of Schiff base 1 with ketenes
Scheme 1.
O
NH2 CH Cl , MgSO
N
2
2
4
+
CHO
O
MeO
MeO
1
MeO
Me
MeO
MeONH ·HCl
2
O
O
N
O
OH–
N
O
pyridine
Me
OEt
OEt
Me
OH
3
2
9
50

FUNCTIONALIZED β-LACTAMS
951
Scheme 2.
Cl
Cl
Cl
Cl
Zn, MeOH
NH Cl
Cl
O
CH Cl , 20°C
1
4
2
2
OH
Im
+
O
O
Cl
Cl
–
ImH, –CO2
O
O
Im
Im
N
N
O
O
PMB
PMB
4
7
PMB
O
Cl
HN
OH
O
O
O
Cl
O
+
N
N
PMB
PMB
5
6
Im = 1H-imidazol-1-yl, PMB = 4-MeOC
6
H
4
CH .
2
terized by considerably lower yield, and it led to the
formation of a mixture of lactams 5 and 6 which were
separated by column chromatography on silica gel
ester 3 in the reaction with 1. No reaction between 1
and 3 was observed in the presence of sodium hydride,
whereas potassium hydride, being a stronger base,
initiated a different reaction. Instead of expected
β-lactam 8, after treatment of the reaction mixture with
aqueous ammonium chloride and chromatographic
(
yield (22 and 12%, respectively). Obviously, cis-
lactam 6 is the product of S 2 substitution of the
N
chlorine atom in position 2 of trans-lactam 5 by
p-methoxybenzylamine. The latter is likely to be
formed as a result of side hydrolysis of the initial imine
or substitution therein by imidazole. Reductive de-
chlorination of 4 smoothly afforded cis-lactam 7.
purification (SiO ), we isolated aldehyde 10 and Schiff
2
base 9 as minor rearrangement product (Scheme 3).
We presumed that aldehyde 10 is formed from Schiff
base 9 during the isolation procedure (treatment with
From acid 2 we obtained trans-lactam 8 in a mod-
erate yield (Scheme 3). We made an attempt to im-
prove the yield of 8 by performing the condensation in
the ester enolate–imine version [6]. Sodium and potas-
sium hydrides were tried to generate carbanion from
aqueous NH Cl and silica gel chromatography). To
4
verify this assumption, the reaction of 1 with potas-
sium hydride in THF was carried out in the absence of
3, and the reaction mixture was then treated with
water. In this case, no hydrolysis of 1 was observed,
Scheme 1.
OMe
Me
N
MeO
N
O
O
Me
OH
O
N
PMB
2
8
CHO
(
(
1) KH, THF
O
+
2) H /H O
N
2
+
MeO
O
MeO
Me
N
N
O
OMe
+
9
, 10%
10, 80%
MeO
OEt
NaH, THF, 20°C
1
3
8
(
1) KH, THF; (2) H O; (3) SiO2
2
1
9
+
10
10%
8
3%
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

9
52
VALIULLINA et al.
NOE
NOE
NOE
generated in situ from chloroacetic acids and 3-(me-
thoxyimino)butanoic acid. The products are promising
as building blocks for the synthesis of more complex
modified analogs.
HHMBC H
H
H
H
HMBC
N
O
OMe
EXPERIMENTAL
Key HMBC correlations and NOEs in (E)-N-[(furan-2-yl)-
methyl]-1-(4-methoxyphenyl)methanimine (9).
The IR spectra were recorded on a Shimadzu IR
Prestige-21 spectrometer from samples prepared as
and imine 9 was isolated in a good yield (83%). The
structure of 9 was confirmed by spectral data (see
figure), as well as by the isolation of aldehyde 10 as
the major product when the reaction mixture was
1
13
films or dispersed in mineral oil. The H and C NMR
spectra were recorded on Bruker AM-300 (300.13 and
7
5.47 MHz, respectively) and Bruker Avance-500
spectrometers (500.13 and 125.77 MHz); the chemical
shifts were measured relative to the residual proton and
treated with aqueous NH Cl.
4
Among the described reactions, the isomerization
of 1 to 9 is of undoubted interest. Presumably, the
driving force of this isomerization is the formation of
intermediate benzyl anion stabilized by delocalization,
which is smoothly converted to thermodynamically
more favorable isomer 9. The relative thermodynamic
stabilities of 1 and 9 were estimated by DFT quantum
chemical calculations with the solvent effect included
in terms of the polarizable continuum model (PCM).
The most stable conformations of both isomers were
determined, and their thermodynamic potentials were
calculated. The standard Gibbs free energies of 1 and
carbon signals of the solvent (CDCl , δ 7.27,
3
δ 77.00 ppm; acetone-d , δ 2.07, δ 28.83 ppm).
C
6
C
The mass spectra (atmospheric pressure chemical
ionization) were obtained on a Shimadzu LCMS-
2
4
010EV instrument (positive ion detection, pin voltage
.5 kV); samples were introduced as solutions in
methylene chloride–acetonitrile at a flow rate of
0
9
2
2
.1 mL/min using a syringe; eluent acetonitrile–water,
5:5; capillary temperature 250°C, capillary voltage
5 V; heater temperature 200°C, vaporizer temperature
30°C; nebulizer gas nitrogen, flow rate 1.5 L/min.
9
(THF) were –708.498484 and –708.500254 Ha,
The elemental compositions were determined using
respectively; thus, isomer 9 is more thermodynam-
ically stable than 1 by 4.6 kJ/mol. This difference in
the Gibbs energies corresponds to equilibrium popula-
tions of 9 and 1 at a ratio of 0.87:0.13.
a Euro EA-3000 CHNS-analyzer.
Quantum chemical calculations were performed
with the aid of GAUSSIAN‑09 software package [9].
The molecular structures were optimized, and thermo-
dynamic potentials were calculated, at the
TPSSTPSS/6‑311+G(d,p) level of theory [10, 11] with
a correction for solvation in terms of IEF-PCM (SMD)
[12]. The progress of reactions was monitored by TLC
on Sorbfil plates; spots were detected by treatment
with a 10% solution of 4-methoxybenzaldehyde in
ethanol acidified with sulfuric acid or with an alkaline
solution of potassium permanganate.
Although the results of calculations indicate distinct
preference of structure 9 and irreversibility of the
isomerization 1 → 9, the KH-promoted 1,2-migration
of the C=N double bond in 1 may formally be regarded
as a specific example of tautomerism. As noted in [7],
cis/trans isomerization of enamino ketones involves
tautomeric imine. Analogous transformation was
reported for Schiff bases derived from acetophenone
and benzylamines (ketimines A), which came to
equilibrium with N-benzylideneamines B in the pres-
ence of chiral alcoholates [8] (Scheme 4).
(
E)-1-(Furan-2-yl)-N-[(4-methoxyphenyl)-
methyl]methanimine (1). A solution of 1.50 g
(
10.93 mmol) of 4-methoxybenzylamine in 2 mL of
In summary, in this work we have synthesized new
methylene chloride was added to a suspension of
1.05 g (10.93 mmol) of furfural and 2.62 g
β-lactams by reactions of Schiff base 1 with ketenes
Scheme 4.
X
X
R*OK
Me
N
Me
N
Ph
Ph
A
B
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

FUNCTIONALIZED β-LACTAMS
953
1
(
21.86 mmol) of MgSO in 15 mL of methylene
of 1.6 :1 ( H NMR), yellow oily material, R 0.37
4
f
–
1
chloride. The mixture was stirred for 7 h at room tem-
perature and filtered, and the filtrate was concentrated
under reduced pressure to obtain a yellow oily residue
which was used in further syntheses without additional
(petroleum ether–EtOAc, 4:1). IR spectrum, ν, cm :
1
1738, 1637, 1410, 1096, 891. H NMR spectrum
(acetone-d , 500 MHz), δ, ppm: major isomer: 1.22 t
6
(3H, CH , J = 7.1 Hz), 1.84 s (3H, CH ), 3.18 s (2H,
3
3
1
purification (purity ~95% according to the H NMR
CH ), 3.77 s (3H, OMe), 4.12 q (2H, OCH , J =
2
2
data). R 0.22 (petroleum ether–EtOAc, 4:1). IR spec-
7.1 Hz); minor isomer: 1.19 t (3H, CH , J = 7.1 Hz),
f
3
–
1
trum, ν, cm : 1645, 1610, 1511, 1247, 1175, 1034,
1.88 s (3H, CH ), 3.31 s (2H, CH ), 3.73 s (3H, OMe),
3
2
1
13
8
22, 751. H NMR spectrum (acetone-d , 500 MHz), δ,
4.10 q (2H, OCH , J = 7.1 Hz). C NMR spectrum
6
2
ppm: 3.76 s (3H, OMe), 4.67 s (2H, CH ), 6.55 q (1H,
(acetone-d , 125 MHz), δ , ppm: major isomer: 13.49
2
6
C
3
-H, J = 1.7 Hz), 6.87–6.88 m (1H, 4-H), 6.89 d (2H,
(Me), 19.54 (Me), 40.54 (CH ), 60.34 (OCH ), 60.58
2
2
H
, J = 8.7 Hz), 7.25 d (2H, H , J = 8.7 Hz),
(OMe), 151.20 (C=N), 169.20 (C=O); minor isomer:
13.47 (Me), 19.54 (Me), 34.31 (CH ), 60.27 (OCH ),
arom
arom
7
.67 d (1H, 5′-H, J = 0.9 Hz), 8.25 s (1H, CH=N).
C NMR spectrum (acetone-d , 125 MHz), δ , ppm:
2
2
1
3
60.47 (OMe), 150.02 (C=N), 168.20 (C=O). Found, %:
6
C
3
4
5
1
1
4.57 (OMe), 64.17 (CH ), 111.65 (C ), 113.13 (C ),
C 52.75; H 8.17; N 8.87. C H NO . Calculated, %:
2
7
13
3
13.65 (CH ), 129.18 (CH ), 131.62 (C ),
C 52.82; H 8.23; N 8.80.
arom
arom
arom
5
2
44.72 (C ), 149.89 (CH=N), 152.35 (C ), 158.77
Lactams 4‒6 (general procedure). 1,1′-Carbonyl-
diimidazole (CDI), 1.10 mmol, was added to a solution
of 1.0 mmol of the corresponding acid in 5 mL of
methylene chloride. The mixture was stirred for 1 h,
(
C
). Found, %: C 72.41; H 6.15; N 6.61.
arom
C H NO . Calculated, %: C 72.54; H 6.09; N 6.51.
1
3
13
2
3
-(Methoxyimino)butanoic acid (2). Potassium
hydroxide, 0.07 g (1.25 mmol), was added to a solu-
0
.93 mmol of Schiff base 1 was added, and the mixture
tion of 0.10 g (0.63 mmol) of ester 3 in 4 mL of THF–
was stirred for 2 h at room temperature (until the initial
compounds disappeared according to the TLC data).
The mixture was filtered through a finely ground
zeolite, the filtrate was evaporated, and the residue was
purified by column chromatography on silica gel using
petroleum ether–ethyl acetate (5:1) as eluent.
H O (3:1), and the mixture was stirred for 4 h (TLC).
2
The mixture was acidified to pH 6 with 5% aqueous
HCl, THF was evaporated, and the aqueous phase was
extracted with methylene chloride, The combined
extracts were dried over MgSO and evaporated under
4
reduced pressure. Yield 0.06 g (73%). IR spectrum, ν,
–
1
3,3-Dichloro-4-(furan-2-yl)-1-[(4-methoxy-
cm : 3200–3600, 1717, 1641, 1409, 1178, 1058, 896,
1
phenyl)methyl]azetidin-2-one (4) was obtained from
7
37, 622. H NMR spectrum (CDCl , 500 MHz), δ,
3
0
0
.08 mL of dichloroacetic acid, 0.18 g of CDI, and
ppm: major isomer: 1.92 s (3H, CH ), 3.26 s (2H,
3
.2 g of 1. Yield 0.22 g (73%), R 0.4 (petroleum
f
CH ), 3.86 s (3H, OMe), 11.05 br.s (1H, COOH);
2
–1
ether–EtOAc, 4:1). IR spectrum, ν, cm : 1791, 1652,
minor isomer: 1.98 s (3H, CH ), 3.36 s (2H, CH ),
3
2
1
1
3
1
514, 1249. H NMR spectrum (CDCl , 500 MHz), δ,
3
.83 s (3H, OMe), 11.05 br.s (1H, COOH). C NMR
3
ppm (J, Hz): 3.75 s (3H, OMe), 3.90 d and 4.80 d (1H
spectrum (CDCl , 125 MHz), δ , ppm: major isomer:
3
C
each, CH , J = 14.9 Hz), 4.85 s (1H, 4-H), 6.40 s (2H,
2
1
0.47 (Me), 40.80 (CH ), 61.53 (OMe), 151.23 (C=N),
2
2
3
′-H, 4′-H), 6.80 d (2H, H , J = 8.5 Hz), 7.10 d (2H,
75.08 (C=O); minor isomer: 14.54 (Me), 34.98
arom
1
3
H
, J = 8.5 Hz), 7.50 s (1H, 5′-H). C NMR spec-
(
CH ), 61.41 (OMe), 149.98 (C=N), 174.51 (C=O).
arom
2
trum (CDCl , 125 MHz), δ , ppm: 44.42 (CH ), 55.30
3
C
2
Ethyl 3-(methoxyimino)butanoate (3). A solution
4
3
3′
(
OMe), 66.90 (C ), 84.36 (C ), 111.01 and 112.30 (C ,
of 0.50 mL (3.84 mmol) of ethyl acetoacetate in 1 mL
of anhydrous pyridine was added dropwise under
argon to a solution of 0.38 g (4.60 mmol) of
4
′
5
′
C ); 114.44, 125.31, 129.77 (C ); 145.80 (C ),
arom
2
1
59.64 (C
), 160.96 (C ). Mass spectrum, m/z
arom
+
+
(
I , %): 326 (50) [M] , 121 (100) [CH C H OMe] .
rel
2
6
4
O-methylhydroxylamine hydrochloride (NH OMe·
2
HCl) in 5 mL of anhydrous pyridine. The mixture was
(3R*,4R*)-3-Chloro-4-(furan-2-yl)-1-[(4-me-
stirred for 3 h (TLC) and diluted with diethyl ether
thoxyphenyl)methyl]azetidin-2-one (5) was obtained
(
(
30 mL), the organic layer was washed with water
3×5 mL) and brine, dried over Na SO , and concen-
from 0.1 g of chloroacetic acid. Yield 0.065 g (25%),
R 0.5 (petroleum ether–EtOAc, 4:1). IR spectrum, ν,
2
4
f
–
1
trated under reduced pressure, and the residue was
purified by flash chromatography on silica gel using
petroleum ether–ethyl acetate (9:1) as eluent. Yield
cm : 3380, 2956, 2926, 1768, 1668, 1612, 1514, 1250,
1
1034, 821, 749. H NMR spectrum (CDCl , 500 MHz),
3
δ, ppm: 3.80 s (3H, OMe), 3.84 d (1H, CH , J =
2
0
.58 g (95%), a mixture of Z and E isomers at a ratio
15.1 Hz), 4.41 d (1H, 4-H, J = 1.7 Hz), 4.68 d (1H,
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

9
54
VALIULLINA et al.
5
′
2′
CH , J = 15.1 Hz), 4.87 d (1H, 3-H, J = 1.7 Hz), 6.32 d
129.88 (Carom), 143.66 (C ), 151.0 (C ), 160.0 (Carom),
2
2
(
2H, 3′-H, J = 3.3 Hz), 6.38 m (1H, 4′-H), 6.84 d (2H,
176.5 (C ). Mass spectrum, m/z (Irel, %): 292 (56) [M +
+
+
H
, J = 8.5 Hz), 7.07 d (2H, H , J = 8.5 Hz),
H] , 115 (100) [CH
2
C
6
H
4
OMe] , 106 (41), 74 (42).
arom
arom
1
3
7
.42 d (1H, 5′-H, J = 1.2 Hz). C NMR spectrum
(
3R*,4R*)-4-(Furan-2-yl)-1-[(4-methoxyphenyl)-
(
CDCl , 125 MHz), δ , ppm: 44.62 (CH ), 55.25
3
C
2
methyl]-3-[(1E)-N-methoxyethanimidoyl]azetidin-2-
one (8). Acid 2, 0.60 g (0.46 mmol), was dissolved
in 10 mL of anhydrous methylene chloride, 0.09 g
(0.40 mmol) of imine 1 and 0.08 g (0.49 mmol) of CDI
were added with stirring, and the mixture was refluxed
for 6 h (TLC). The mixture was filtered through
a finely ground zeolite, the filtrate was evaporated, and
the residue was purified by flash chromatography on
silica gel using petroleum ether–ethyl acetate (4:1) as
eluent. Yield 0.03 g (22%), brown oily material,
3
4
(
OMe), 58.09 (C ), 60.22 (C ), 110.74 and 110.98
3
′
4′
(
C , C ), 114.19 (C ), 123.1 (C ), 129.72 (C ),
arom
arom
arom
5
′
2′
2
1
43.5 (C ), 152.5 (C ), 159.2 (C ), 166.5 (C ).
arom
+
Mass spectrum, m/z (I , %): 292 (100) [M + H] , 121
rel
(
54), 74 (14).
(
3R*,4S*)-4-(Furan-2-yl)-1-[(4-methoxyphenyl)-
methyl]-3-{[(4-methoxyphenyl)methyl]amino}-
azetidin-2-one (6) was obtained in a mixture with 5
and was isolated in the pure state by column chroma-
R 0.45 (petroleum ether–EtOAc, 4:1). According to
tography. Yield 12%, R 0.4 (petroleum ether–EtOAc,
f
f
1
–1
the H NMR data, the product was a mixture of lactam
4
:1). IR spectrum, ν cm : 3322, 2955, 2925, 1749,
8
and two minor isomers at a ratio of 5:1:1. IR spec-
1
668, 1612, 1514, 1249, 1176, 1032, 820, 751.
–1
1
trum, ν, cm : 1766, 1756, 1612, 1248, 1176, 1044,
H NMR spectrum (CDCl , 500 MHz), δ, ppm: 3.60 s
3
1
7
1
48. H NMR spectrum (CDCl , 500 MHz), δ, ppm:
(
3H, OMe), 3.69 d and 4.72 d (1H each, CH , J =
3
2
.88 s (CH ), 3.83 s (OCH ), 3.87 s (OCH ), 4.15 d
1
3
4.9 Hz), 4.80 d (1H, 4-H, J = 4.8 Hz), 5.00 d (1H,
-H, J = 4.8 Hz), 6.38 d (2H, 3′-H, J = 3.4 Hz), 6.42 m
3
3
3
(
1H, 3-H, J = 2.3 Hz), 4.60 d (1H, 4-H, J = 2.3 Hz),
4
3
8
5
1
.70 d (2H, CH , J = 14.9 Hz), 6.30 d (1H, 3′-H, J =
(
1H, 4′-H), 6.83 d (2H, H , J = 8.6 Hz), 7.08 d (2H,
2
arom
.2 Hz), 6.35 m (1H, 4′-H), 6.87 d (2H, H , J =
H
, J = 8.6 Hz), 7.47 d (1H, 5′-H, J = 1.3 Hz).
arom
arom
1
3
.5 Hz), 7.13 d (2H, H , J = 8.5 Hz), 7.41 d (1H,
C NMR spectrum (CDCl , 125 MHz), δ , ppm: 44.78
arom
3
C
1
3
3
4
′-H, J = 1.1 Hz). C NMR spectrum (CDCl ,
and 45.56 (CH ), 55.24 (OMe), 55.27 (C ), 75.19 (C ),
3
2
3
′
4′
25 MHz), δ , ppm: 12.51 (CH ), 44.18 (CH ), 50.02
C
3
2
1
10.80 and 111.65 (C , C ); 114.17, 116.4, 129.19,
5′
3
4
(
C ), 55.13 (OMe), 60.89 (OMe), 61.54 (C ), 109.37
1
29.53 (C
); 145.0 (C ). Mass spectrum, m/z
+
arom
3′ 4′
(
C ), 110.42 (C ), 113.93 (CH ), 127.15 (C ),
arom
arom
(
(
I , %): 393 (32) [M + H] , 369 (17), 258 (15), 121
rel
5
′
2′
1
29.52 (CH ), 143.17 (C ), 150.64 (C ), 158.98
arom
100), 74 (67).
(
[
C
). Mass spectrum: m/z 329 (I 100%)
arom
M + H] .
rel
(
3R*,4S*)-3-Chloro-4-(furan-2-yl)-1-[(4-methoxy-
phenyl)methyl]azetidin-2-one (7). Dichlorolactam 4,
.07 g (0.21 mmol), was dissolved in 5 mL of
+
(
E)-N-[(Furan-2-yl)methyl]-1-(4-methoxy-
phenyl)methanimine (9). A solution of 0.25 g
1.16 mmol) of imine 1 in 2 mL of anhydrous THF
was added at 0°C under argon to a mixture of 0.23 g
0
methanol, 3.5 mg (0.07 mmol) of ammonium chloride
and 0.14 g (1.08 mmol) of a Zn–Cu couple were
added, and the mixture was refluxed for 5 h. The
precipitate was filtered off and washed with methylene
chloride, the filtrate was evaporated, and the residue
was purified by column chromatography on silica gel
using petroleum ether–ethyl acetate (5:1) as eluent.
(
(
1.74 mmol) of a 30% suspension of potassium
hydride in mineral oil and 8 mL of anhydrous THF.
The mixture was stirred for 1 h at room temperature
(
TLC), cooled to 0°C, and treated with 5 mL of THF–
H O (2:1). Tetrahydrofuran was evaporated, the aque-
2
Yield 0.02 g (31%), R 0.3 (petroleum ether–EtOAc,
f
–
1
ous layer was extracted with diethyl ether (2×15 mL),
the combined extracts were washed with water (3×
5 mL) and brine, dried over Na SO , filtered, and con-
4
:1). IR spectrum, ν, cm : 2958, 2934, 1767, 1760,
1
648, 1612, 1514, 1398, 1249, 1177, 1032, 823, 747.
1
2
4
H NMR spectrum (CDCl , 500 MHz), δ, ppm: 3.80 s
3
centrated, and the residue was purified by flash chro-
matography on silica gel using petroleum ether–ethyl
acetate (9:1) as eluent to isolate a mixture of com-
pounds 9 and 10.
(
3H, OMe), 3.90 d and 4.72 d (1H each, CH , J =
2
1
3
4.9 Hz), 4.80 d (1H, 4-H, J = 4.8 Hz), 5.00 d (1H,
-H, J = 4.8 Hz), 6.38 d (2H, 3′-H, J = 3.4 Hz), 6.42 m
(
1H, 4′-H), 6.83 d (2H, H , J = 8.6 Hz), 7.08 d (2H,
arom
H
, J = 8.6 Hz), 7.47 d (1H, 5′-H, J = 1.3 Hz).
Schiff base 9. Yield 0.20 g (83%), yellow oily
arom
1
3
C NMR spectrum (CDCl , 125 MHz), δ , ppm: 44.64
material, R 0.31 (petroleum ether–EtOAc, 4:1). IR
f
3
C
3
4
–1
(
CH ), 54.45 (OMe), 55.26 (C ), 60.65 (C ), 110.64
spectrum, ν, cm : 1645, 1606, 1512, 1249, 1167,
2
3
′
4′
1
and 111.09 (C , C ), 114.23 (C ), 126.10 (C ),
1031, 833, 735. H NMR spectrum (acetone-d ,
arom
arom
6
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016

FUNCTIONALIZED β-LACTAMS
955
5
00 MHz), δ, ppm: 3.77 s (3H, OMe), 4.70 s (2H,
4. Worthington, B.J. and Melander, C., J. Org. Chem.,
2
013, vol. 78, p. 4207.
CH ), 6.25 d (1H, 3-H, J = 3.0 Hz), 6.37 d.d (1H, 4-H,
2
J = 2.0, J 3.0 Hz), 6.95 d (2H, H , J = 8.8 Hz),
5. Nahmany, M. and Melman, A., J. Org. Chem., 2006,
arom
7
8
.48 d (1H, 5-H, J = 2.0 Hz), 7.73 d (2H, H , J =
vol. 71, p. 5804.
arom
1
3
.8 Hz), 8.34 s (1H, CH=N). C NMR spectrum
6. Berks, A.H., Tetrahedron, 1996, vol. 52, p. 331.
(
acetone-d , 125 MHz), δ , ppm: 55.64 (OMe),
7. Dabrowski, J. and Terpinski, J., Tetrahedron Lett., 1965,
6
C
3
4
5
7.57 (CH ), 107.69 (C ), 111.09 (C ), 114.69
vol. 6, p. 1363.
2
5
(
CH ), 130.06 (C ), 130.42 (CH ), 142.75 (C ),
8. Willems, J.G.H., de Vries, J.G., Nolte, R.J., and
Zwanenberg, B., Tetrahedron Lett., 1995, vol. 36,
p. 3917.
arom
arom
arom
2
1
54.11 (C ), 162.50 (CH=N), 162.67 (C ). Mass
arom
+
spectrum: m/z 216 (I 100%) [M + H] .
rel
9
. Frisch, M.J., Trucks, G.W., Schlegel, H.B., Scu-
seria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G.,
Barone, V., Mennucci, B., Petersson, G.A., Naka-
tsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmay-
lov, A.F., Bloino, J., Zheng, G., Sonnenberg, J.L.,
Hada, M., Ehara, M., Toyota, K., Fukuda, R., Hase-
gawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O.,
Nakai, H., Vreven, T., Montgomery, J.A., Jr.,
Peralta, J.E., Ogliaro, F., Bearpark, M., Heyd, J.J.,
Brothers, E., Kudin, K.N., Staroverov, V.N., Koba-
yashi, R., Normand, J., Raghavachari, K., Rendell, A.,
Burant, J.C., Iyengar, S.S., Tomasi, J., Cossi, M.,
Rega, N., Millam, J.M., Klene, M., Knox, J.E.,
Cross, J.B., Bakken, V., Adamo, C., Jaramillo, J.,
Gomperts, R., Stratmann, R.E., Yazyev, O., Austin, A.J.,
Cammi, R., Pomelli, C., Ochterski, J.W., Martin, R.L.,
Morokuma, K., Zakrzewski, V.G., Voth, G.A., Sal-
vador, P., Dannenberg, J.J., Dapprich, S., Daniels, A.D.,
Farkas, Ö., Foresman, J.B., Ortiz, J.V., Cioslowski, J.,
and Fox, D.J. Gaussian 09, Revision C.1, Wallingford
CT: Gaussian, 2009.
4
-Methoxybenzaldehyde (10). Yield 0.016 g
(
10%), colorless oil, R 0.32 (petroleum ether–EtOAc,
f
–
1
4
1
:1). IR spectrum, ν, cm : 1697, 1683, 1600, 1577,
1
511, 1260, 1161, 1025, 834, 607. H NMR spectrum
(
acetone-d , 500 MHz), δ, ppm: 3.91 s (3H, OMe),
6
7
8
.10 d (2H, H , J = 8.7 Hz), 7.85 d (2H, H , J =
arom
arom
13
.7 Hz), 9.90 s (1H, CHO). C NMR spectrum
(
(
(
acetone-d , 500 MHz), δ , ppm: 55.22 (OMe), 114.36
6
C
CH ), 130.30 (C ), 131.65 (CH ), 164.65
arom
arom
arom
C
), 190.34 (CHO).
arom
This study was performed under financial support
by the Russian Science Foundation (project no. 15-
3-00039).
1
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1
2
3
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RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 52 No. 7 2016