Azetidin-2,3-dione synthon for stereoselective synthesis of cis- and trans-C-3-alkyl/aryl azetidin-2-ones

Article abstract of DOI:10.1055/s-2005-921746

1,4-Bis-(4-methoxyphenyl)azetidin-2,3-dione has been prepared and used as a synthon for the stereoselective synthesis of C-3-alkyl/aryl azetidin-2-ones. Some of these are well known for their cholesterol absorption inhibitor activity. A regioselective Gri

Full text of DOI:10.1055/s-2005-921746

PAPER
115
Azetidin-2,3-dione Synthon for Stereoselective Synthesis of cis- and trans-C-3-
Alkyl/Aryl Azetidin-2-ones
S
D
tereoselective
S
y
h
nthesis of cis
a
-
and trans-
r
C-3-Alk
m
yl/Aryl Azetidin-2-
e
ones ndra Kumar Tiwari, Vikas K. Gumaste, Abdul Rakeeb A. S. Deshmukh*
Division of Organic Chemistry (Synthesis), National Chemical Laboratory, Pune 411 008, India
Fax +91(20)25893153; fax +91(20)25893355; E-mail: aras.deshmukh@ncl.res.in
Received 28 June 2005; revised 12 July 2005
action of acid chlorides with tertiary amines. The
Abstract: 1,4-Bis-(4-methoxyphenyl)azetidin-2,3-dione has been
prepared and used as a synthon for the stereoselective synthesis of
C-3-alkyl/aryl azetidin-2-ones. Some of these are well known for
cholesterol absorption inhibitory property is normally as-
5
sociated with trans-azetidin-2-ones, however, in some
their cholesterol absorption inhibitor activity. A regioselective cases C-3-alkyl cis-azetidin-2-ones have been shown to
9
Grignard reaction at a keto-group followed by highly stereoselec- be better cholesterol absorption inhibitors. Although sev-
eral syntheses are described in the literature,7
,8,10
there are
tive removal of the hydroxyl group via reductive removal of the
xanthate ester is a key step in this synthesis. Base-induced isomer-
ization of cis-azetidin-2-ones to the thermodynamically stable
trans-isomer was also studied.
very few reports wherein a suitably substituted azetidin-2-
11
one itself has been used as a synthon for the preparation
of desired C-3-substituted b-lactams.
Keywords: azetidin-2,3-diones, azetidin-2-ones, b-lactam, Grig-
nard reaction, tributyltin hydride
As a part of our ongoing research program on the applica-
12
tion of azetidin-2-ones as synthons, we herein report the
synthesis of various 3-alkyl/aryl azetidin-2-ones from
azetidin-2,3-diones, a common starting material. We en-
visaged that a regioselective Grignard reaction at a ketone
would give us 3-alkyl-3-hydroxy-b-lactam. The approach
of the Grignard reagent would be controlled by the C-4
substituent on the ring, giving rise to trans stereochemis-
try in the product. The reductive removal of the hydroxyl
group by ionic hydrogenation using triethylsilane should
provide the desired 3-alkyl b-lactam with inversion of ste-
reochemistry at the C-3 position. Varying the Grignard re-
agent would furnish a variety of 3-alkyl b-lactams
(Scheme 1).
Azetidin-2-ones are an important class of organic com-
pounds having a wide range of biological activities. As
1
–3
well as antibacterial agents, they are also being increas-
ingly used as synthons for the synthesis of a variety of
4
pharmaceutically useful products. The strain energy as-
sociated with the four-membered azetidinone ring is re-
sponsible for the selective bond cleavage, giving a variety
of transformation products. Moreover, there are many
methods available to prepare them in the reasonable quan-
13
tities required for synthetic purpose. Since trans-azetidin-
5
2
-ones 1 and 2 were shown to inhibit cholesterol absorp-
tion (Figure 1) there has been a renewed interest in the The starting azetidin-2,3-dione 7 can be easily obtained
syntheses of C-3-alkyl b-lactams. Large numbers of b- by oxidation of the corresponding 3-hydroxy-b-lactam 6,
lactams have been synthesized to study their structure–ac- which in turn can be obtained from 3-acetoxy-b-lactams.
tivity relationship (SAR) in cholesterol absorption inhibi- Since enantiomerically pure 3-hydroxy-b-lactams are also
6
14
tors. In most of the syntheses the azetidinone ring is available, the corresponding azetidindiones can also be
constructed either by enolate-imine cycloconden- prepared by oxidation of the hydroxyl group. However, to
5
a,b,6a,7
sation
of appropriately substituted esters and imines establish the synthetic protocol we have used racemic b-
or by the Staudinger ketene-imine cycloaddition reac- lactams for our work.
7
i,8
tion. Ketenes are normally generated in situ from the re-
Figure 1
SYNTHESIS 2006, No. 1, pp 0115–0122
0
6
.
0
1
.2
0
0
6
Advanced online publication: 16.12.2005
DOI: 10.1055/s-2005-921746; Art ID: Z12505SS
Georg Thieme Verlag Stuttgart · New York
©

1
16
D. K. Tiwari et al.
PAPER
Scheme 1
Staudinger’s cycloaddition reaction of acetoxyacetyl was prepared by reacting the hydroxy compound 8a with
chloride (3) with imine 4 gave 3-acetoxy-azetidin-2-one carbon disulfide followed by methylation. Reductive re-
5
, which upon careful hydrolysis with saturated sodium moval of the xanthate ester group by tributyltin hydride in
bicarbonate in methanol gave the corresponding 3-hy- the presence of AIBN was successful and the reduced
droxy-b-lactam 6. Oxidation of the hydroxyl group was product 10a was obtained in excellent yield. The H NMR
carried out by a known procedure using phosphorous pen- of the product showed the formation of a mixture of cis-
toxide and dimethyl sulfoxide to give the desired azeti- and trans-isomers (90:10). The major cis-isomer could be
din-2,3-dione 7 (Scheme 2). The Grignard reagent was easily obtained pure by column chromatography. The ste-
prepared from the corresponding alkyl or aryl halide, reochemistry of the major isomer was established from
which was added slowly to a solution of dione 7 in anhy- the coupling constant of the azetidinone ring protons
drous diethyl ether at 0 °C. The mixture was stirred for (J = 5.9 Hz for the cis-isomer and J = 2.3 Hz for the trans-
1
1
5
two hours at room temperature. Usual work up gave the isomer). The S 2 substitution of the xanthate by hydride
N
addition product 8 in good to moderate yields (Table 1). A with inversion of configuration at C-3 results in a cis-b-
single isomer was formed indicating that the addition oc- lactam. This synthetic protocol (Scheme 3) was used for
curred exclusively from the site opposite to the C-4 sub- the synthesis of many C-3 substituted b-lactams 10a–g
stituent on the azetidinone ring.
(Table 2).
Our efforts to remove the hydroxyl group of 8a by ionic Since the cholesterol absorption inhibition activity is
5
hydrogenation using triethylsilane in the presence of mainly associated with trans-b-lactams, base-catalyzed
1
3a
13b
BF ·OEt
or trifluoroacetic acid were unsuccessful, epimerization of cis-b-lactams was studied (Scheme 4). 3-
3
2
even changing the solvent from dichloromethane to Phenyl-b-lactam 10f was refluxed in benzene in the pres-
acetonitrile did not help. Therefore, xanthate ester 9a ence of a catalytic amount of DBU. The reaction was
1
3c
Scheme 2 Reagents and conditions: (a) Et N, CH Cl , 0 °C to r.t., 12 h; (b) NaHCO , Na CO , MeOH–H O, r.t., 7 h; (c) P O , DMSO, r.t.,
3
2
2
3
2
3
2
2
5
24 h
Table 1 3-Alkyl/Aryl-3-hydroxy-1,4-bis(4-methoxyphenyl)azetidin-2-ones 8a–g and Xanthate Esters 9a–g
Compd
R
Yield (%)a
Mp (°C)
Oil
Compd
9a
R
Yield (%)a
Mp (°C)
Oil
8a
8b
8c
8d
8e
8f
Hexyl
68
65
68
72
66
67
57
Hexyl
89
75
96
83
97
92
95
Pentyl
Oil
9b
Pentyl
Oil
Tetradecyl
Decyl
Oil
9c
Tetradecyl
Decyl
Oil
Oil
9d
Oil
Nonyl
Oil
9e
Nonyl
Oil
Phenyl
3-Phenylpropyl
164–166
Oil
9f
Phenyl
3-Phenylpropyl
176–178
Oil
8g
9g
a
Isolated yields.
Synthesis 2006, No. 1, 115–122 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of cis- and trans-C-3-Alkyl/Aryl Azetidin-2-ones
117
Scheme 3 Reagents and conditions: (a) RMgBr, anhyd Et O, 0 °C to r.t., 2 h; (b) NaH, CS , MeI, THF, 0 °C to r.t., 3 h; (c) Bu SnH, AIBN,
2
2
3
toluene, reflux, 3 h
Table 2 3-Alkyl/Aryl-1,4-bis(4-methoxyphenyl)azetidin-2-ones
0a–g
regioselective addition of Grignard reagent to the ketone
was the key step in the synthesis. The removal of the hy-
droxyl group was efficiently achieved via reductive re-
moval of xanthate ester using tributyltin hydride and
AIBN. Base-catalyzed epimerization of cis-b-lactam to
trans-b-lactam was also achieved. Thus the synthesis of
both cis- and trans-3-alkyl/aryl-azetidin-2-ones was
achieved from azetidin-2,3-dione.
1
Compd
R
Ratioa
Yield (%)b Mp (°C)
cis/trans
1
1
1
1
1
1
1
0a
0b
0c
0d
0e
0f
Hexyl
90:10
90:10
88:12
88:12
94:6
93
96
92
90
90
92
95
Oil
Pentyl
Oil
Tetradecyl
Decyl
Oil
1H NMR and 13C NMR spectra were recorded on a Bruker AC 200,
Bruker MSL-300, and Bruker DRX-500 spectrometer and chemical
Oil
1
Nonyl
Oil
shifts are reported in ppm downfield from TMS for H NMR. IR
spectra were recorded on Shimadzu FTIR-8400 using NaCl optics.
MS were recorded on a Finnigan Mat 1020 mass spectrometer at 70
eV using electron spray ionization. Mps were determined on a Ther-
monik Campbell melting point apparatus and were uncorrected. The
microanalyses were performed on a Carlo-Erba, CHNS-O EA 1108
elemental analyzer. Column chromatography was carried out with
silica gel. Petroleum ether used had a bp range 60–80 °C.
Phenyl
95:5
144–146c
96–98c
0g
3-Phenylpropyl
70:30
a
b
c
1
Ratios were determined by H NMR spectroscopy.
Isolated yields.
Mp of pure cis-isomer.
3
-Acetoxy-1,4-bis-(4-methoxyphenyl)azetidin-2-one (5)
1
A soln of acetoxyacetyl chloride (3; 4.83 mL, 45.00 mmol) in anhyd
complete in three hours (TLC) and the H NMR spectrum
of the crude reaction mixture showed the trans-isomer
formed predominantly (88%). The pure trans-compound
CH Cl (10 mL) was added slowly to a mixture of imine 4 (7.23 g,
2
2
3
0.00 mmol) and Et N (14.6 mL, 105 mmol) in anhyd CH Cl (20
3 2 2
mL) at 0 °C. After completion of the addition, the reaction mixture
1
1a was easily obtained by a single crystallization from was allowed to warm to r.t., and stirred for 18 h. The reaction mix-
dichloromethane–petroleum ether. In the case of cis-1,4- ture was then washed with H O (3 × 50 mL), a sat. aq soln of
2
NaHCO (3 × 50 mL), and brine (50 mL). The organic layer was
bis(4-methoxyphenyl)-3-(3-phenylpropyl)azetidin-2-one
10g), no epimerization was observed even after refluxing
3
dried over Na SO and the solvent was removed under reduced
2
4
(
pressure. The crude product was purified by column chromatogra-
phy (EtOAc–petroleum ether, 15:85) to give 3-acetoxy-b-lactam 5
as a crystalline solid.
in benzene or toluene with DBU for 24 hours. However,
epimerization of 10g was achieved by stirring a solution
of same in THF at 0 °C in the presence of a catalytic
Yield: 62.21%; mp 152–154 °C.
1
amount of potassium tert-butoxide for two hours. H
–
1
IR (CHCl ): 1753 cm .
NMR spectroscopy revealed a mixture of trans- and cis-
3
isomers in a 84:16 ratio. Pure trans-isomer 11b was ob- 1H NMR (CDCl
, 200 MHz): d = 1.73 (s, 3 H), 3.75 (s, 3 H), 3.80
s, 3 H), 5.27 (d, J = 5.1 Hz, 1 H), 5.87 (d, J = 5.1 Hz, 1 H), 6.77 (d,
3
(
tained by crystallization from dichloromethane–petro-
leum ether.
J = 9.00 Hz, 2 H), 6.86 (d, J = 9.00 Hz, 2 H), 7.22 (d, J = 9.0 Hz, 2
H), 7.25 (d, J = 9.00 Hz, 2 H).
1
3
C NMR (CDCl , 50.3 MHz): d = 19.8, 55.1, 55.3, 61.0, 76.4,
3
1
13.8, 114.3, 118.7, 123.9, 129.2, 130.2, 156.4, 159.8, 161.3, 169.2.
MS: m/z = 342 (M + 1).
Anal. calcd for C H NO : C, 66.85; H, 5.61; N, 4.10. Found: C,
1
9
19
5
6
6.93; H, 5.75; N, 4.08.
3
-Hydroxy-1,4-bis(4-methoxyphenyl)azetidin-2-one (6)
To a soln of 3-acetoxy-b-lactam 5 (8.35 g, 24.48 mmol) in MeOH
Scheme 4
(70 mL) was added a sat. aq soln of NaHCO (35 mL) followed by
3
solid Na CO (0.88 g, 8.30 mmol). The reaction mixture was stirred
at r.t. for 7 h. After the reaction was complete (TLC), MeOH was
evaporated under reduced pressure, and the resultant residue was
In conclusion, azetidin-2,3-dione was efficiently used for
the synthesis of 3-alky/aryl azetidin-2-ones, one of which
2
3
1
1b, is used as a cholesterol absorption inhibitor. The
Synthesis 2006, No. 1, 115–122 © Thieme Stuttgart · New York

1
18
D. K. Tiwari et al.
PAPER
extracted with CH Cl (3 × 50 mL). The combined organic layers
Anal. calcd for C H NO : C, 72.04; H, 7.62; N, 3.65. Found: C,
71.98; H, 7.46; N, 3.78.
2
2
23 29
4
were dried over Na SO and the solvent was removed. The crude
2
4
product was purified by column chromatography (EtOAc–petro-
leum ether, 3:7) to give 3-hydroxy-b-lactam 6 as a white solid.
3-Pentyl-3-hydroxy-1,4-bis(4-methoxyphenyl)azetidin-2-one
8b)
Yield: 65%; thick oil.
(
Yield: 86%; mp 146–149 °C.
–
1
IR (CHCl ): 3353, 1708 cm .
3
–1
IR (CHCl ): 3338, 1751, 1716 cm .
3
1
H NMR (DMSO-d , 200 MHz): d = 2.15 (br s, 1 H), 3.76 (s, 3 H),
6
1
H NMR (CDCl , 200 MHz): d = 0.94 (t, J = 7.0 Hz, 3 H), 1.30–
3
3
6
.81 (s, 3 H), 5.05 (d, J = 5.7 Hz, 1 H), 5.13 (d, J = 5.7 Hz, 1 H),
.70 (d, J = 9.0 Hz, 2 H), 6.84 (d, J = 8.9 Hz, 2 H), 7.15 (d, J = 8.9
1
.40 (m, 6 H), 1.92–2.09 (m, 2 H), 3.76 (s, 3 H), 3.81 (s, 3 H), 4.98
(s, 1 H), 6.81 (d, J = 9.1 Hz, 2 H), 6.95 (d, J = 8.9 Hz, 2 H), 7.23 (d,
Hz, 2 H), 7.24 (d, J = 9.0 Hz, 2 H).
J = 8.9 Hz, 2 H), 7.29 (d, J = 9.1 Hz, 2 H).
1
3
C NMR (DMSO-d , 75.48 MHz): d = 55.0, 55.1, 61.7, 76.7,
6
13
C NMR (CDCl , 75.48 MHz): d = 13.9, 22.4, 23.2, 31.9, 35.3,
3
1
13.6, 114.3, 118.2, 126.5, 129.3, 130.7, 155.5, 159.0, 166.4.
5
1
5.2, 55.3, 66.9, 86.0, 114.3, 114.5, 118.8, 125.7, 128.4, 130.7,
56.3, 159.9, 167.9.
MS: m/z = 300 (M + 1).
Anal. calcd for C H NO : C, 68.22; H, 5.73; N, 4.68. Found: C,
17
17
4
MS: m/z = 370 (M + 1).
6
8.32; H, 5.80; N, 4.61.
Anal. calcd for C H NO : C, 71.52; H, 7.36; N, 3.79. Found: C,
2
2
27
4
7
1.89; H, 7.80; N, 3.71.
3
,4-Bis(4-methoxyphenyl)azetidin-2,3-dione (7)
To anhyd P O (0.98 g, 3.50 mmol, calcd for P O ) was added an-
hyd DMSO (15 mL) at r.t. The suspension was stirred for 5 min at
2
5
4
10
3
-Tetradecyl-3-hydroxy-1,4-bis(4-methoxyphenyl)azetidin-2-
one (8c)
Yield: 68%; thick oil.
the same temperature and the corresponding 3-hydroxy-b-lactam 6
(1.5 g, 5.00 mmol) was then added in one portion with vigorous stir-
–
1
ring. The reaction mixture was stirred for 24 h. After the reaction
was complete, the reaction mixture was poured slowly into a cold
IR (CHCl ): 3400, 1737, 1731 cm .
3
1
H NMR (CDCl , 200 MHz): d = 0.89 (t, J = 6.80 Hz, 3 H), 1.08–
3
sat. aq soln of NaHCO (50 mL), and extracted with EtOAc. The or-
3
1
.90 (m, 24 H), 1.98–2.10 (m, 2 H), 3.76 (s, 3 H), 3.81 (s, 3 H), 4.97
ganic layer was washed with brine (3 × 50 mL) and dried over
(s, 1 H), 6.81 (d, J = 9.0 Hz, 2 H), 6.95 (d, J = 8.6 Hz, 2 H), 7.23 (d,
Na SO . The solvent was removed under reduced pressure to afford
2
4
J = 8.6 Hz, 2 H), 7.29 (d, J = 9.0 Hz, 2 H).
the crude product, which was purified by column chromatography
1
3
C NMR (CDCl , 75.48 MHz): d = 14.1, 22.6, 23.5, 29.4, 29.8,
(
EtOAc–petroleum ether, 2:8) to give keto-b-lactam 7 as a yellow
3
3
1
1.8, 35.3, 55.2, 55.3, 66.8, 85.9, 114.2, 114.5, 118.8, 125.6, 128.3,
30.6, 156.1, 159.8, 168.0.
solid.
Yield: 81%; mp 144 °C.
MS: m/z = 496 (M + 1).
Anal. calcd for C H NO : C, 75.11; H, 9.15; N, 2.83. Found: C,
7
–
1
IR (CHCl ): 1832, 1809, 1753 cm .
3
1
31
45
4
H NMR (CDCl , 200 MHz): d = 3.79 (s, 3 H), 3.75 (s, 3 H), 5.52
3
4.95; H, 8.72; N, 2.98.
(
(
1
s, 1 H), 6.90 (d, J = 9.00 Hz, 2 H), 6.30 (d, J = 8.6 Hz, 2 H), 7.25
d, J = 8.6 Hz, 2 H), 7.46 (d, J = 9.0 Hz, 2 H).
3
(8d)
-Decyl-3-hydroxy-1,4-bis(4-methoxyphenyl)azetidin-2-one
3
C NMR (CDCl , 50.32 MHz): d = 55.2, 55.4, 74.4, 114.62, 114.8,
3
1
19.6, 123.5, 127.7, 129.8, 157.8, 160.1, 160.4, 191.1.
Yield: 72%; thick oil.
–
1
MS: m/z = 298 (M + 1).
IR (CHCl ): 3392, 1745 cm .
3
1
Anal. calcd for C H NO : C, 68.68; H, 5.08; N, 4.71. Found: C,
H NMR (CDCl , 200 MHz): d = 0.89 (t, J = 6.0 Hz, 3 H), 1.10–
17
15
4
3
6
8.85; H, 5.13; N, 4.67.
1.63 (m, 16 H), 1.88–2.05 (m, 2 H), 3.76 (s, 3 H), 3.81 (s, 3 H), 4.97
(s, 1 H), 6.80 (d, J = 9.0 Hz, 2 H), 6.94 (d, J = 8.7 Hz, 2 H), 7.22 (d,
3
-Hexyl-3-hydroxy-1,4-bis(4-methoxyphenyl)azetidin-2-one
J = 8.7 Hz, 2 H), 7.29 (d, J = 9.0 Hz, 2 H).
(
8a); Typical Procedure
13
C NMR (CDCl , 75.48 MHz): d = 14.0, 22.6, 23.6, 29.2, 29.4,
3
To a soln of dione 7 (0.89 g, 3.00 mmol) in anhyd Et O (10 mL) was
2
2
1
9.5, 29.8, 31.8, 35.4, 55.2, 55.4, 66.9, 86.0, 114.3, 114.6, 118.8,
25.8, 128.4, 130.8, 156.3, 160.0, 167.9.
added a soln of HexMgBr (3.90 mmol) in anhyd Et O (10 mL) at 0
2
°
C. The mixture was stirred for 2 h at r.t. A sat. aq soln of NH Cl
4
MS: m/z = 440 (M + 1).
was then added and the reaction mixture was extracted with EtOAc
3 × 15 mL). The combined organic layers were dried over Na SO
(
2
4
Anal. calcd for C H NO : C, 73.77; H, 8.48; N, 3.19. Found: C,
2
7
37
4
and the solvent was removed under reduced pressure. The residue
was purified by flash column chromatography (EtOAc–petroleum
ether, 15:85) to give 8a as a thick oil.
7
3.95; H, 8.22; N, 3.20.
3
-Hydroxy-1,4-bis(4-methoxyphenyl)-3-nonylazetidin-2-one
(
8e)
Yield: 68%.
Yield: 66%; thick oil.
–
1
IR (CHCl ): 3394, 1745, 1730 cm .
3
–
1
IR (CHCl ): 3394, 1726 cm .
1
3
H NMR (CDCl , 200 MHz): d = 0.95 (t, J = 6.6 Hz, 3 H), 1.30–
3
1
H NMR (CDCl , 200 MHz): d = 0.89 (t, J = 6.0 Hz, 3 H), 1.11–
1
.40 (m, 8 H), 1.85–2.05 (m, 2 H), 3.77 (s, 3 H), 3.82 (s, 3 H), 4.91
3
1
.66 (m, 14 H), 1.90–2.10 (m, 2 H), 2.55 (br s, 1 H), 3.76 (s, 3 H),
.81 (s, 3 H), 4.97 (s, 1 H), 6.81 (d, J = 8.4 Hz, 2 H), 6.94 (d, J = 7.6
(s, 1 H), 6.77 (d, J = 9.0 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2 H), 7.19 (d,
3
J = 8.8 Hz, 2 H), 7.25 (d, J = 9.0 Hz, 2 H).
Hz, 2 H), 7.23 (d, J = 7.6 Hz, 2 H), 7.29 (d, J = 8.5 Hz, 2 H).
1
1
3
C NMR (CDCl , 50.3 MHz): d = 14.0, 22.5, 23.5, 29.4, 31.6, 35.3,
3
3
C NMR (CDCl , 75.48 MHz): d = 14.0, 22.6, 23.5, 29.2, 29.4,
5
1
5.2, 55.3, 66.8, 85.93, 114.2, 114.5, 118.8, 125.6, 128.4, 130.6,
56.2, 159.8, 168.0.
3
2
1
9.8, 31.8, 35.3, 55.2, 55.3, 66.8, 85.8, 114.2, 114.5, 118.8, 125.6,
28.4, 130.6, 156.1, 159.8, 168.0.
MS: m/z = 384 (M + 1).
MS: m/z = 426 (M + 1).
Synthesis 2006, No. 1, 115–122 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of cis- and trans-C-3-Alkyl/Aryl Azetidin-2-ones
119
1
Anal. calcd for C H NO : C, 73.38; H, 8.29; N, 3.29. Found: C,
H NMR (CDCl , 200 MHz): d = 0.95 (t, J = 6.20 Hz, 3 H), 1.30–
26
35
4
3
7
3.56; H, 8.22; N, 3.20.
1.40 (m, 8 H), 1.85–2.05 (m, 2 H), 2.32 (s, 3 H), 3.77 (s, 3 H), 3.81
(
s, 3 H), 5.19 (s, 1 H), 6.77 (d, J = 9.1 Hz, 2 H), 6.85 (d, J = 8.9 Hz,
3
-Hydroxy-1,4-bis(4-methoxyphenyl)-3-phenylazetidin-2-one
2 H), 7.25 (d, J = 8.9 Hz, 2 H), 7.31 (d, J = 9.1 Hz, 2 H).
(
8f)
13
C NMR (CDCl , 50.3 MHz): d = 14.0, 19.2, 22.5, 23.3, 29.2, 31.4,
3
Yield: 67%; white solid; mp 164–166 °C.
3
2.3, 55.1, 55.3, 66.9, 95.3, 113.7, 114.2, 119.0, 130.1, 155.4,
–
1
IR (CHCl ): 3404, 1739 cm .
159.6, 162.6, 210.9.
3
1
H NMR (CDCl , 200 MHz): d = 2.74, (br s, 1 H), 3.77 (s, 3 H), 3.83
MS: m/z = 474 (M + 1).
3
(
2
s, 3 H), 5.17 (s, 1 H), 6.83 (d, J = 8.7 Hz, 2 H), 6.94 (d, J = 8.6 Hz,
Anal. calcd for C H NO S : C, 63.40; H, 6.59; N, 2.96; S, 13.54.
2
5
31
4 2
H), 7.17–7.37 (m, 9 H).
Found: C, 63.55; H, 6.80; N, 3.01, S; 13.45.
1
3
C NMR (CDCl , 75.48 MHz): d = 55.2, 55.3, 70.1, 86.6, 114.2,
3
1
1
14.4, 119.1, 124.9, 125.4, 128.4, 128.7, 128.8, 130.2, 138.8, 156.3,
60.0, 166.5.
Dithiocarbonic Acid O-[3-Pentyl-1,2-bis(4-methoxyphenyl)-4-
oxoazetidin-3-yl]-S-methyl Ester (9b)
Yield: 75%; thick oil.
MS: m/z = 376 (M + 1)
–
1
IR (CHCl ): 1755 cm .
3
Anal. calcd for C H NO : C, 73.58; H, 5.64; N, 3.73. Found: C,
7
23
21
4
1
3.69; H, 5.62; N, 3.85.
H NMR (CDCl , 200 MHz): d = 0.91 (t, J = 6.6 Hz, 3 H), 1.31–
3
1
.40 (m, 6 H), 1.72–1.75 (m, 2 H), 2.30 (s, 3 H), 3.76 (s, 3 H), 3.80
3
-Hydroxy-1,4-bis(4-methoxyphenyl)-3-(3-phenylpropyl)azeti-
(s, 3 H), 5.17 (s, 1 H), 6.79 (d, J = 9.0 Hz, 2 H), 6.84 (d, J = 8.8 Hz,
2 H), 7.26 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 9.0 Hz, 2 H).
din-2-one (8g)
To a soln of dione 7 (0.594 g, 2.00 mmol) in anhyd THF (10 mL)
was added 3-phenylpropyl magnesium bromide (3.00 mmol) in an-
hyd THF (5 mL) at 0 °C. The reaction mixture was stirred for 6 h at
13
C NMR (CDCl , 75.5 MHz): d = 13.9, 19.1, 22.2, 23.1, 31.7, 32.0,
3
5
1
5.1, 55.4, 67.0, 95.5, 113.8, 114.4, 119.0, 125.7, 128.8, 130.1,
56.5, 159.8, 162.6, 210.6.
r.t. A sat. aq soln of NH Cl (10 mL) was added and the majority of
4
MS: m/z = 460 (M + 1).
THF was removed under reduced pressure. The aqueous layer was
then extracted with EtOAc (3 × 15 mL), the combined extracts were
Anal. calcd for C H NO S : C, 62.78; H, 6.36; N, 3.04; S, 13.95.
Found: C, 62.89; H, 6.50; N, 3.10; S, 14.05.
2
4
29
4 2
dried over anhyd Na SO , and the solvent was removed under re-
2
4
duced pressure. The crude product was purified by flash column
chromatography (EtOAc–petroleum ether, 15:85) to give 8g as a
thick oil.
Dithiocarbonic Acid O-[3-Tetradecyl-1,2-bis(4-methoxyphen-
yl)-4-oxoazetidin-3-yl]-S-methyl Ester (9c)
Yield: 96%; thick oil.
Yield: 57%; thick oil.
–
1
–
1
IR (CHCl ): 1755 cm .
IR (CHCl ): 3384, 1747, 1731 cm .
3
3
1
1
H NMR (CDCl , 200 MHz): d = 0.89 (t, J = 6.7 Hz, 3 H), 1.05–
3
H NMR (CDCl , 200 MHz): d = 1.27 (t, J = 7.1 Hz, 2 H), 2.00–
3
1
.57 (m, 24 H), 1.63–1.72 (m, 2 H), 2.28 (s, 3 H), 3.74 (s, 3 H), 3.78
2
4
7
.10 (m, 2 H), 2.77, (t, J = 6.5 Hz, 2 H), 3.80 (s, 3 H), 3.85 (s, 3 H),
.98 (s, 1 H), 6.81 (d, J = 9.1 Hz, 2 H), 6.94 (d, J = 8.6 Hz, 2 H),
.17–7.37 (m, 9 H).
(
s, 3 H), 5.15 (s, 1 H), 6.78 (d, J = 8.9 Hz, 2 H), 6.82 (d, J = 8.9 Hz,
2
H), 7.24 (d, J = 8.9 Hz, 2 H), 7.28 (d, J = 8.9 Hz, 2 H).
1
3
1
3
C NMR (CDCl , 75.5 MHz): d = 13.9, 14.0, 22.6, 23.4, 29.4, 29.3,
C NMR (CDCl , 75.5 MHz): d = 25.2, 34.9, 35.8, 55.1, 55.3, 66.9,
3
3
2
1
9.5, 31.8, 32.2, 55.1, 55.3, 66.8, 85.9, 113.6, 114.2, 118.9, 125.6,
28.2, 130.1, 156.3, 159.6, 168.6, 210.0
8
1
5.7, 114.3, 114.4, 118.8, 125.6, 125.7, 125.8, 128.3, 128.4, 130.6,
41.8, 156.3, 159.8, 167.9.
MS: m/z = 586 (M + 1).
Anal. calcd for C H NO S : C, 67.66; H, 8.09; N, 2.39; S, 10.94.
Found: C, 67.95; H, 8.25; N, 2.65; S, 10.85.
MS: m/z = 418 (M + 1).
Anal. calcd for C H NO : C, 74.80; H, 6.52; N, 3.55. Found: C,
33 47
4 2
26
27
4
7
5.02; H, 6.32; N, 3.75.
Dithiocarbonic Acid O-[3-Decyl-1,2-bis(4-methoxyphenyl)-4-
oxoazetidin-3-yl]-S-methyl Ester (9d)
Yield: 83%; thick oil.
Dithiocarbonic Acid O-[3-Hexyl-1,2-bis(4-methoxyphenyl)-4-
oxoazetidin-3-yl]-S-methyl Ester (9a); Typical Procedure
To a cooled suspension of NaH (60%; 0.024 g, 1.04 mmol) in anhyd
THF (5 mL) was added hydroxy-b-lactam 8a (0.10 g, 0.26 mmol)
slowly. After the addition was complete the reaction mixture was
stirred at r.t. for 30 min. The soln was cooled to 0 °C and a soln of
–1
IR (CHCl ): 1755 cm .
3
1
H NMR (CDCl , 200 MHz): d = 0.92 (t, J = 6.5 Hz, 3 H), 1.05–
3
1
.65 (m, 16 H), 1.92–2.05 (m, 2 H), 2.32 (s, 3 H), 3.77 (s, 3 H), 3.82
CS (0.047 mL, 0.78 mmol) in THF (5 mL) was added. The reaction
2
(
2
s, 3 H), 5.19, (s, 1 H), 6.81 (d, J = 9.0 Hz, 2 H), 6.85 (d, J = 8.7 Hz,
H), 7.30 (d, J = 8.7 Hz, 2 H), 7.28 (d, J = 9.0 Hz, 2 H).
mixture was stirred for 1.5 h at 0 °C, MeI (0.097 mL, 1.56 mmol)
was then added at the same temperature, and the reaction mixture
was stirred at r.t. for 3 h. After the reaction was complete (TLC), a
13C NMR (CDCl
, 75.5 MHz): d = 14.0, 19.2, 22.6, 23.4, 29.2, 29.4,
3
sat. aq soln of NH Cl (10 mL) was added, and THF was removed
31.8, 32.3, 55.1, 55.3, 66.8, 85.3, 113.7, 114.2, 118.8, 118.9, 125.6,
128.2, 130.1, 159.6, 162.6, 210.9.
4
under reduced pressure. The residue was dissolved in CH Cl (25
2
2
mL) and the organic layer was washed with H O (10 mL), brine (10
2
MS: m/z = 530 (M + 1).
mL), and dried over Na SO . The solvent was removed under re-
2
4
Anal. calcd for C H NO S : C, 65.75; H, 7.42; N, 2.64; S, 12.10.
duced pressure to afford the crude product 9a, which was then puri-
fied by flash column chromatography (EtOAc–petroleum ether,
29 39
4 2
Found: C, 66.63; H, 7.22; N, 2.79; S, 12.35.
1
:9).
Dithiocarbonic Acid O-[1,2-Bis(4-methoxyphenyl)-3-nonyl-4-
oxoazetidin-3-yl]-S-methyl Ester (9e)
Yield: 97%; thick oil.
Yield: 89%; colorless oil.
–
1
IR (CHCl ): 1758 cm .
3
–
1
IR (CHCl ): 1755 cm .
3
Synthesis 2006, No. 1, 115–122 © Thieme Stuttgart · New York

1
20
D. K. Tiwari et al.
PAPER
1
H NMR (CDCl , 200 MHz): d = 0.91 (t, J = 5.8 Hz, 3 H), 1.14–
Anal. calcd for C H NO : C, 75.17; H, 7.95; N, 3.81. Found: C,
75.29; H, 7.87; N, 3.75.
3
23 29
3
1
.50 (m, 14 H), 1.66–1.82 (m, 2 H), 2.31 (s, 3 H), 3.77 (s, 3 H), 3.81
(
s, 3 H), 5.18 (s, 1 H), 6.81 (d, J = 8.4 Hz, 2 H), 6.84 (d, J = 7.6 Hz,
2
H), 7.23 (d, J = 7.6 Hz, 2 H), 7.29 (d, J = 8.4 Hz, 2 H).
3-Pentyl-1,4-bis(4-methoxyphenyl)azetidin-2-one (10b)
1
3
Yield: 96%; thick oil.
C NMR (CDCl , 75.5 MHz): d = 14.0, 19.1, 22.5, 23.3, 29.2, 29.4,
3
–
1
2
1
9.6, 31.7, 32.2, 55.1, 55.3, 66.8, 95.2, 113.6, 114.2, 118.9, 125.6,
28.4, 130.5, 156.3, 159.6, 162.6, 210.8.
IR (CHCl ): 1735 cm .
3
1
H NMR (CDCl , 200 MHz): d = 0.94 (t, J = 7.05 Hz, 3 H), 1.12–
3
MS: m/z = 516 (M + 1).
1.27 (m, 6 H), 1.31–1.39 (m, 2 H), 3.50 (m, 1 H), 3.75 (s, 3 H), 3.81
(
s, 3 H), 5.11 (d, J = 5.7 Hz, 1 H), 6.79 (d, J = 8.9 Hz, 2 H), 6.90 (d,
Anal. calcd for C H NO S : C, 65.21; H, 7.23; N, 2.72; S, 12.43.
Found: C, 65.23; H, 7.36; N, 2.81; S, 11.87.
2
8
37
4 2
J = 8.6 Hz, 2 H), 7.19 (d, J = 8.6 Hz, 2 H), 7.25 (d, J = 8.9 Hz, 2 H).
1
3
C NMR (CDCl , 75.48 MHz): d = 13.8, 22.1, 25.2, 26.8, 31.48,
3
Dithiocarbonic Acid O-[1,2-Bis(4-methoxyphenyl)-4-oxo-3-
phenylazetidin-3-yl]-S-methyl Ester (9f)
Yield: 92%; mp 176–178 °C.
54.6, 55.2, 55.3, 57.9, 113.9, 114.1, 118.3, 126.8, 128.8, 131.2,
155.6, 159.3, 167.9.
MS: m/z = 354 (M + 1).
–
1
IR (CHCl ): 1755 cm .
3
Anal. calcd for C H NO : C, 74.76; H, 7.70; N, 3.96. Found: C,
74.64; H, 7.50; N, 3.81.
2
2
27
3
1
H NMR (CDCl , 200 MHz): d = 2.25 (s, 3 H), 3.75 (s, 3 H), 3.81
3
(
s, 3 H), 5.74 (s, 1 H), 6.80 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 8.6 Hz,
2
H), 7.27–7.62 (m, 9 H).
3-Tetradecyl-1,4-bis(4-methoxyphenyl)azetidin-2-one (10c)
1
3
Yield: 92%; thick oil.
C NMR (CDCl , 75.48 MHz): d = 19.2, 55.2, 55.3, 66.7, 94.5,
3
–
1
1
1
13.8, 114.3, 119.1, 124.9, 126.1, 128.5, 128.7, 129.9, 130.3, 134.3,
56.5, 159.9, 161.2, 209.7.
IR (CHCl ): 1745 cm .
3
1
H NMR (CDCl , 200 MHz): d = 0.90 (t, J = 6.6 Hz, 3 H), 1.10–
3
MS: m/z = 466 (M + 1).
1.49 (m, 24 H), 1.58–1.72 (m, 2 H), 3.50 (m, 1 H), 3.76 (s, 3 H), 3.81
(
s, 3 H), 5.11 (d, J = 5.9 Hz, 1 H), 6.80 (d, J = 8.8 Hz, 2 H), 6.90 (d,
Anal. calcd for C H NO S : C, 64.50; H, 4.98; N, 3.01, S, 13.77.
Found: C, 64.69; H, 4.82; N, 3.05; S, 13.65.
25
23
4 2
J = 8.8 Hz, 2 H), 7.20 (d, J = 8.8 Hz, 2 H), 7.25 (d, J = 8.8 Hz, 2 H).
1
3
C NMR (CDCl , 75.48 MHz): d = 14.0, 22.6, 25.2, 27.1, 29.3,
3
Dithiocarbonic Acid O-[1,2-Bis(4-methoxyphenyl)-3-(3-phenyl-
propyl)-4-oxoazetidin-3-yl]-S-methyl Ester (9g)
Yield: 95%; thick oil.
29.5, 31.8, 54.6, 55.1, 55.3, 57.9, 113.9, 114.1, 118.3, 126.8, 128.3,
131.2, 155.6, 159.3, 167.7.
MS: m/z = 480 (M + 1).
–
1
IR (CHCl ): 1755 cm .
3
Anal. calcd for C H NO : C, 77.62; H, 9.46; N, 2.92. Found: C,
3
1
45
3
1
H NMR (CDCl , 200 MHz): d = 1.66–1.79 (m, 2 H), 1.95–2.05 (m,
77.60; H, 9.32; N, 2.95.
3
1
3
6
H), 2.18 (s, 3 H), 2.60 (t, J = 7.8 Hz, 2 H), 2.86–3.02 (m, 1 H),
.63 (s, 3 H), 3.67 (s, 3 H), 5.02 (s, 1 H), 6.67 (d, J = 9.0 Hz, 2 H),
.71 (d, J = 8.8 Hz, 2 H), 7.08–7.27 (m, 9 H).
3-Decyl-1,4-bis(4-methoxyphenyl)azetidin-2-one (10d)
Yield: 90%; thick oil.
1
3
–1
C NMR (CDCl , 75.48 MHz): d = 19.2, 24.9, 31.9, 35.5, 55.1,
IR (CHCl ): 1745 cm .
3
3
5
1
5.3, 66.8, 95.0, 113.6, 114.2, 118.9, 125.4, 125.8, 128.3, 128.4,
30.5, 141.3, 156.3, 159.6, 162.4, 210.8.
1
H NMR (CDCl , 200 MHz): d = 0.93 (t, J = 6.7 Hz, 3 H), 1.16–
.39 (m, 16 H), 1.52–1.71 (m, 2 H), 3.49–3.59 (m, 1 H), 3.80 (s, 3
3
1
MS: m/z = 508 (M + 1).
H), 3.86 (s, 3 H), 5.16 (d, J = 5.6 Hz, 1 H), 6.84 (d, J = 9.0 Hz, 2 H),
.94 (d, J = 8.8 Hz, 2 H), 7.24 (d, J = 8.8 Hz, 2 H), 7.29 (d, J = 9.0
Hz, 2 H).
6
Anal. Calcd for C H NO S : C, 66.25; H, 5.76; N, 2.76; S, 12.63.
28
29
4 2
Found: C, 66.42; H, 5.62; N, 2.85; S, 12.80.
1
3
C NMR (CDCl , 75.48 MHz): d = 14.0, 17.4, 22.5, 23.3, 27.1,
3
3
-Hexyl-1,4-bis(4-methoxyphenyl)azetidin-2-one (10a); Typical
29.0, 29.2, 29.3, 31.8, 54.6, 55.1, 55.2, 57.8, 113.8, 114.1, 118.1,
126.8, 128.3, 131.2, 155.6, 159.3, 167.7.
Procedure
A soln of Bu SnH (0.12 mL, 0.45 mmol) and AIBN (5 mg) in anhyd
toluene (10 mL) was added dropwise to a refluxing soln of xanthate
3
MS: m/z = 424 (M + 1).
Anal. calcd for C H NO : C, 76.56; H, 8.80; N, 3.30. Found: C,
(0.15 g, 0.3 mmol) in anhyd toluene (20 mL) under an argon atmo-
27 37
3
7
6.60; H, 8.32; N, 2.98
sphere. The reaction mixture was then refluxed for 3 h. The solvent
was removed under reduced pressure and the residue was purified
by flash column chromatography (EtOAc–petroleum ether, 1:9) to
afford 10a as a thick oil.
1
,4-Bis(4-methoxyphenyl)-3-nonyl Azetidin-2-one (10e)
Yield: 90%; thick oil.
–
1
IR (CHCl ): 1745 cm .
Yield: 93%; thick oil.
3
1
–
1
H NMR (CDCl , 200 MHz): d = 0.89 (t, J = 6.6 Hz, 3 H), 1.12–
3
IR (CHCl ): 1741 cm .
3
1
.28 (m, 18 H), 3.47–3.54 (m, 1 H), 3.76 (s, 3 H), 3.82 (s, 3 H), 5.12
1
H NMR (CDCl , 200 MHz): d = 0.83 (t, J = 6.5 Hz, 3 H), 1.10–
3
(
d, J = 5.8 Hz, 1 H), 6.80 (d, J = 8.8 Hz, 2 H), 6.90 (d, J = 8.8 Hz, 2
1
.19 (m, 8 H), 1.25–1.35 (m, 2 H), 3.40 (m, 1 H), 3.74 (s, 3 H), 3.81
H), 7.19 (d, J = 8.7 Hz, 2 H), 7.26 (d, J = 8.7 Hz, 2 H).
(
(
s, 3 H), 5.10 (d, J = 5.60 Hz, 1 H), 6.67 (d, J = 8.9 Hz, 2 H), 6.75
d, J = 8.7 Hz, 2 H), 7.10 (d, J = 8.7 Hz, 2 H), 7.25 (d, J = 8.9 Hz, 2
1
3
C NMR (CDCl , 75.48 MHz): d = 14.0, 22.6, 25.2, 27.1, 29.2,
3
2
1
9.4, 31.8, 54.7, 55.1, 55.3, 57.9, 113.9, 114.1, 118.3, 118.2, 126.9,
28.3, 131.3, 155.7, 159.4, 167.8.
H).
1
3
C NMR (CDCl , 50.3 MHz): d = 13.9, 22.3, 25.2, 27.0, 28.9, 31.3,
3
MS: m/z = 410 (M + 1).
5
1
4.7, 55.2, 55.3, 57.96, 113.9, 114.1, 118.3, 126.9, 128.3, 131.3,
55.7, 159.4, 167.7.
Anal. calcd for C H NO : C, 76.25; H, 8.61; N, 3.42. Found: C,
2
6
35
3
7
6.52; H, 8.32; N, 3.55.
MS: m/z = 368 (M + 1).
Synthesis 2006, No. 1, 115–122 © Thieme Stuttgart · New York

PAPER
Stereoselective Synthesis of cis- and trans-C-3-Alkyl/Aryl Azetidin-2-ones
121
1
,4-Bis(4-methoxyphenyl)-3-phenyl Azetidin-2-one (10f)
tion from (CH Cl –petroleum ether) gave pure trans-azetidin-2-one
11b as white crystals.
2
2
Yield: 92%; mp 144–146 °C.
–
1
IR (CHCl ): 1739 cm .
Yield: 70%; mp 96–98 °C.
3
1
–1
H NMR (CDCl , 200 MHz): d = 3.68 (s, 3 H), 3.77 (s, 3 H), 4.97
IR (CHCl ): 1741 cm .
3
3
(
d, J = 5.9 Hz, 1 H), 5.39 (d, J = 5.8 Hz, 1 H), 6.65 (d, J = 8.7 Hz, 2
1
H NMR (CDCl , 200 MHz): d = 1.83–2.16 (m, 4 H), 2.68 (t,
J = 7.0, 2 H), 3.07–3.15 (m, 1 H), 3.77 (s, 3 H), 3.83 (s, 3 H), 4.60
(d, J = 2.3 Hz, 1 H), 6.81 (d, J = 9.0 Hz, 2 H), 6.88 (d, J = 9.0 Hz, 2
H), 7.17–7.31 (m, 9 H).
3
H), 6.82 (d, J = 9.0 Hz, 2 H), 6.94–7.38 (m, 9 H).
1
3
C NMR (CDCl , 75.48 MHz): d = 55.1, 55.4, 60.1, 90.3, 113.7,
3
1
1
14.4, 118.5, 126.5, 127.0, 128.0, 128.4, 128.8, 131.4, 132.5, 156.1,
59.2, 165.1.
13
C NMR (CDCl , 75.48 MHz): d = 28.3, 28.9, 35.6, 55.2, 55.3,
60.4, 60.8, 114.2, 114.4, 118.8, 125.8, 127.1, 128.2, 128.3, 129.9,
3
MS: m/z = 360 (M + 1).
1
31.2, 141.6, 155.8, 159.5, 167.2.
Anal. calcd for C H NO : C, 76.86; H, 5.89; N, 3.90. Found: C,
23
21
3
7
6.69; H, 5.82; N, 3.95.
MS: m/z = 402 (M + 1).
Anal. calcd for C H NO : C, 77.78; H, 6.78; N, 3.49. Found: C,
2
6
27
3
1
,4-Bis(4-methoxyphenyl)-3-(3-phenylpropyl)azetidin-2-one
7
7.57; H, 6.62; N, 3.65.
(
10g)
Yield: 95%; mp 90–93 °C.
–
1
Acknowledgment
IR (CHCl ): 1741 cm .
3
1
H NMR (CDCl , 200 MHz): d = 1.18–1.66 (m, 4 H), 2.35–2.49 (m,
The authors thank the Department of Science and Technology
(DST) New Delhi for financial support.
3
2
H), 3.46–3.57 (m, 1 H), 3.75 (s, 3 H), 3.83 (s, 3 H), 5.11, (d,
J = 5.7 Hz, 1 H), 6.78 (d, J = 8.9 Hz, 2 H), 6.90 (d, J = 8.9 Hz, 2 H),
7
.00–7.27 (m, 9 H).
References
1
3
C NMR (CDCl , 75.48 MHz): d = 24.9, 28.8, 35.6, 54.5, 55.2,
3
5
1
5.3, 57.9, 114.0, 114.1, 118.3, 125.6, 126.6, 127.1, 128.2, 128.3,
31.2, 141.7, 155.7, 159.4, 167.4.
(1) For reviews on b-lactam antibiotics, see: (a) Dürkheimer,
W.; Blumbach, J.; Lattrell, R.; Scheunemann, K. H. Angew.
Chem., Int. Ed. Engl. 1985, 24, 180. (b) Chemistry and
Biology of b-Lactam Antibiotics, Vol. 1-3; Morin, R. B.;
Gorman, M., Eds.; Academic: New York, 1982.
MS: m/z = 402 (M + 1).
Anal. calcd for C H NO : C, 77.78; H, 6.78; N, 3.49. Found: C,
7
26
27
3
7.57; H, 6.62; N, 3.65.
(
c) Coulton, S.; Hunt, E. In Recent Progress in the Chemical
Synthesis of Antibiotics and Related Microbial Products,
Vol. 2; Lukacs, G., Ed.; Springer-Verlag: Berlin, 1993, 621.
trans-1,4-Bis(4-methoxyphenyl)-3-phenylazetidin-2-one (11a)
To a soln of 10f (0.025 g, 0.06 mmol) in anhyd benzene (7 mL), a
catalytic amount of DBU (5 mg, 0.03 mmol) was added and the
mixture was refluxed for 3 h. Benzene was removed under reduced
pressure and the residue was diluted with CH Cl (15 mL) and
(
d) Southgate, R. Contemp. Org. Synth. 1994, 1, 417.
(
2) The Chemistry of b-Lactams; Page, M. I., Ed.; Chapman and
Hall: London, 1992.
2
2
(3) For comprehensive general reviews, see: (a) Koppel, G. A.
In Small Ring Heterocycles, Vol. 42; Hasner, A., Ed.; Wiley:
New York, 1983, 219. (b) Backes, J. In Houben–Weyl,
Methoden der organischen Chemie, Vol. E16B; Klamann,
D., Ed.; Thieme: Stuttgart, 1991, 31. (c) de Kimpe, N. In
Comprehensive Heterocyclic Chemistry II, Vol. 1B;
Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.; Padwa, A.,
Eds.; Pergamon: Oxford, 1996, 507.
4) (a) Ojima, I. In The Chemistry of b-Lactams; Georg, G. I.,
Ed.; VCH: New York, 1993, 197. (b) Palomo, C.; Aizpurua,
J.; Ganboa, I. In Enantioselective Synthesis of b-Amino
Acids; Juaristi, E., Ed.; Wiley-VCH: New York, 1997, 279;
and references cited therein. (c) For a review on this subject,
see: Ojima, I.; Delaloge, F. Chem. Soc. Rev. 1997, 26, 377.
washed with HCl (1 N; 10 mL). The aqueous layer was extracted
with CH Cl (10 mL), the combined organic layers were dried over
2
2
Na SO , and concentrated under reduced pressure to give a mixture
2
4
of cis/trans-azetidin-2-ones (0.021 g, 12:88). Crystallization
(
CH Cl –petroleum ether) gave pure trans-azetidin-2-one 11a as a
2
2
white crystalline solid.
Yield: 78%; mp 159–161 °C.
(
–
1
IR (CHCl ): 1739 cm .
3
1
H NMR (CDCl , 200 MHz): d = 3.67 (s, 3 H), 3.73 (s, 3 H), 4.16
3
(
d, J = 2.4 Hz, 1 H), 5.79 (d, J = 2.4 Hz, 1 H), 6.73 (d, J = 9.0 Hz, 2
H), 6.85 (d, J = 9.0 Hz, 2 H), 6.94–7.38 (m, 9 H).
1
3
C NMR (CDCl , 75.48 MHz): d = 55.1, 55.4, 60.1, 60.3, 113.7,
3
(
2
d) Alcaide, B.; Almendros, P. Chem. Soc. Rev. 2001, 30,
26. (e) Alcaide, B.; Almendros, P. Synlett 2002, 381.
1
1
14.4, 118.5, 126.5, 127.0, 128.09, 128.4, 128.8, 131.4, 132.5,
56.1, 159.2, 165.1.
(
5) (a) Burnett, D. A.; Caplen, M. A.; Davis, H. R. Jr.; Burrier,
R. E.; Clader, J. W. J. Med. Chem. 1994, 37, 1733.
(b) Burnett, D. A. Tetrahedron Lett. 1994, 35, 7339.
(c) Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R.
Jr.; Yumibe, N.; Clader, J. W.; Burnett, D. A. J. Med. Chem.
1998, 41, 973.
(6) (a) Clader, J. W.; Burnett, D. A.; Caplen, M. A.; Domalski,
M. S.; Dugar, S.; Vaccaro, W.; Sher, R.; Browne, M. E.;
Zhao, H.; Burrier, R. E.; Salisbury, B.; Davis, H. R. Jr. J.
Med. Chem. 1996, 39, 3684. (b) Dugar, S.; Kirkup, M. P.;
Clader, J. W.; Lin, S. I.; Rizvi, R.; Snow, M. E.; Davis, H.
R.; McCombie, S. W. Bioorg. Med. Chem. Lett. 1995, 5,
2947.
MS: m/z = 360 (M + 1).
Anal. calcd for C H NO : C, 76.86; H, 5.89; N, 3.80. Found: C,
23
21
3
7
6.69; H, 5.82; N, 3.95.
trans-1,4-Bis(4-methoxyphenyl)-3-(3-phenylpropyl)azetidin-2-
one (11b)
A cis/trans-mixture of 10g (0.08 g, 0.20 mmol) was dissolved in an-
hyd THF (3 mL). t-BuOK (4 mg) was added and the mixture was
stirred at 0 °C for 2 h. The reaction mixture was partitioned between
HCl (1 N; 3 mL) and Et O (7 mL). The aqueous layer was extracted
2
with Et O (2 × 20 mL). The combined organic layers were dried
2
over Na SO and concentrated under reduced pressure to give a
2
4
mixture of cis/trans-azetidin-2-ones (0.078 g, 16:84). Crystalliza-
Synthesis 2006, No. 1, 115–122 © Thieme Stuttgart · New York

1
22
D. K. Tiwari et al.
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Synthesis 2006, No. 1, 115–122 © Thieme Stuttgart · New York