Synthesis of 4-aryl-azetidinones via intramolecular alkylation of nucleophilic arenes using acyliminium cations

Article abstract of DOI:10.1016/j.tet.2010.09.024

The acyliminium cations derived from 4-vinyloxy- or 4-acyloxy-azetidin-2- ones in the presence of Lewis acids can alkylate nucleophilic arenes bound to the β-lactam nitrogen atom through methyloxy, or methylthio tethers. The reactions smoothly proceed to afford the corresponding 3-oxa- or 3-thia-4,5-benzocephams in a good yield. The sulfur atom can be easily removed by Raney nickel reduction to provide the title compounds.

Full text of DOI:10.1016/j.tet.2010.09.024

Tetrahedron 66 (2010) 8974e8981
Contents lists available at ScienceDirect
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Synthesis of 4-aryl-azetidinones via intramolecular alkylation of nucleophilic
arenes using acyliminium cations
*
ꢀ
Bartosz Zambron, Marek Masnyk, Bart1omiej Furman, Przemys1aw Kalicki, Marek Chmielewski
Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 6 July 2010
Received in revised form 16 August 2010
Accepted 6 September 2010
Available online 17 September 2010
The acyliminium cations derived from 4-vinyloxy- or 4-acyloxy-azetidin-2-ones in the presence of Lewis
acids can alkylate nucleophilic arenes bound to the
b-lactam nitrogen atom through methyloxy, or
methylthio tethers. The reactions smoothly proceed to afford the corresponding 3-oxa- or 3-thia-4,5-
benzocephams in a good yield. The sulfur atom can be easily removed by Raney nickel reduction to
provide the title compounds.
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
b-Lactams
Acyliminium cations
Electrophilic aromatic substitution
1. Introduction
We have shown that acyliminium cations derived from 4-acy-
loxy-azetidinones in the presence of Lewis acids can be used to
We have demonstrated that the 4-vinyloxy-azetidinone (1)
(Chart 1) is an attractive substrate for the synthesis of a variety of
bicyclic b-lactams since it allows the N-alkylation of the substrate
followed by the oxidation of its vinyloxy group into the acyloxy
substituent and subsequent Lewis acid promoted nucleophilic
substitution at the C-4 carbon atom to provide oxa-,1 or carba-
cephams.2,3 It has been shown that the 4-vinyloxy substituent
itself in the presence of a Lewis acid can frequently play a role of
a leaving group to allow nucleophilic displacement in a similar
yield.4
alkylate nucleophilic arenes.3 The intermolecular reaction can be
successfully carried out only with p-dimethoxy-benzene, in
a moderate yield. Reactions with anisol, or di- and tri-methoxy
aryls lead to the opening of the four-membered ring by a second
aryl molecule. In the case of the intramolecular process, however,
the reaction can be done in a moderate to very good yield if the aryl
is bound to the nitrogen atom via a di-, tri-, or tetramethylene
tether (Scheme 1).
The search for a new, efficient synthesis of Ezetimibe (2)
(Chart 1), a powerful cholesterol absorption inhibitor,5,6 and related
4-aryl-azetidinones, prompted us to investigate the acid-catalyzed
alkylation of arenes by 4-acyloxy-azetidin-2-ones.
OMe
MeO
N
O
O
R
MeO
OMe
N
O
LA
O
R
OH
R=H, Bn
OH
40%
O
NH
OMe
F
OMe
N
O
O
O
O
1
LA
F
N
OMe
OMe
Ezetimibe (2)
( )n
O
N
( )n
O
Chart 1.
n=1 (88%)
n=2 (97%)
n=3 (28%)
* Corresponding author. Tel.: þ48 22 631 8788; fax: þ48 22 632 6681; e-mail
Scheme 1.
address: chmiel@icho.edu.pl (M. Chmielewski).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.09.024

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B. Zambron et al. / Tetrahedron 66 (2010) 8974e8981
8975
Anticipating the possibility of exploration of additional trans-
formations, such as hydrolysis or the reduction at the later stages of
synthesis, we decided to substitute an alkyl-only tether with the N-
methyloxy or N-methylthio unit.
prompted us to abandon further efforts of synthesis of 4-aryl-
azetidinones via 3-oxa-cephams 16 and 17.
Formation of 4-aryl-azetidinones via an N-methylthio
linkage looked more promising. Suitable substrates: 3, obtained as
above and 18, obtained by treatment of 1 with ethyl glyoxalate,
were used to alkylate the methoxy-thio-phenols 19 and 20
(Scheme 4).
2. Results and discussion
In contrast to the cyclization of aryloxymethyl compounds, only
the p-methoxy-thiophenyl derivative 21 in the presence of Lewis
acid underwent decomposition providing 4-aryloxy-azetidinone
24. Vinyl ethers 22 and 23 provided expected 3-thia-cephams
25e28 in a good yield, as mixtures of two possible regioisomers
(Scheme 5). Alkylation para to the methoxy group dominated in all
cases.
4-Vinyloxy-azetidinone (1) treated with formaldehyde yielded
the N-hydroxymethyl derivative 3 in an excellent yield.7 Compound
3 was subsequently transformed into N-chloromethyl compound 4,
which was used without purification for alkylation of phenols 5e7
to provide the corresponding aryl ethers 8e10. Ozonolysis of the
double bond in 8e10 yielded formates 11e13, respectively
(Scheme 2).
O
O
O
O
O
5 -7, PTC
1. O3
CH2O
1150C
N
O
R1
R2
N
O
R1
NH
N
R
2. Me2S
O
HO
R1
R2
O
O
O
1
R2
3: R = OH (96%)
4: R = Cl
8: R1, R2 = H
(49 %)
5: R1, R2 = H
11: R1, R2 = H
(70 %)
9: R1 = H; R2=OMe; (46%)
10: R1 = OMe; R2 = H (59 %)
6: R1 = H; R2=OMe
7: R1 = OMe; R2 = H
12: R1 = H; R2=OMe; (79%)
13: R1 = OMe; R2 = H (70 %)
Scheme 2.
Vinyl ethers 8e10 in the presence of Lewis acids did not furnish
the expected 4,5-benzo-3-oxa-cephams providing instead a com-
plicated mixture of products. In the case of 8 and 9, N-substituted
4-aryloxy compounds 14 and 15 were isolated in a very low yield. In
the case of formates 11 and 12, alkylation of the aryl moiety by the
acyliminium cation generated from the azetidinone residue affor-
ded the expected products 16 and 17, respectively, in 20e30% yield
(Scheme 3).
Attempts to open the thiazine ring in 25 by acid hydrolysis, or by
treatment with mercury salts were unsuccessful. Both methods
lead to the opening of the b-lactam ring leaving the methylene
bridge unchanged (29), or to degradation of the substrate. We as-
sume that the initially formed mercapto group may subsequently
attack the
undergoes
b
b
-lactam carbonyl group to form thiololactone, which
-elimination to form thiocumarine derivative 30
(Scheme 6).
Oxidation of the sulfur atom in 25 with m-CPBA gave two
diastereomeric sulfoxides 31 and 32 in a ratio 1:1. Compounds
31 and 32 were separated by chromatography. The relative con-
figuration of stereogenic centers was resolved by X-ray crystallog-
raphy (Fig. 1).9 All attempts to perform a Pummerer rearrangement
on sulfoxide 31 were unsuccessful. As in the case of hydrolysis of 25,
O
O
R
Lewis acid
CH2Cl2
N
O
N
O
O
O
R
R
the liberation of the mercapto group leads to the opening of the b-
8: R = H
9: R = OMe;
lactam ring to provide dihydro-thiocumarine derivative 33, which
was accompanied by deoxygenated compound 25 (Scheme 7).
Desulfurization of thioethers 25 and 27 with Raney nickel gave
much better results (Scheme 8). Removal of sulfur proceeded
readily in ethanol solution in 15 min to provide the expected
compounds 34 and 35, respectively. 4-Aryl-azetidinone 35 was
accompanied by the open chain amide 37. It was shown that pro-
longation of the reaction time lead to formation of open chain
compounds as the sole products. It was exemplified by hydro-
genolysis of 25 to obtain amide 36.
SnCl4
BF3OEt2 14: R = H
SnCl4
14: R = H
(2%)
(4%)
15: R = OMe (9%)
BF3OEt2 15: R = OMe (33%)
R
O
O
Lewis acid
CH2Cl2
N
O
N
O
O
O
R
TMS-OTf, 16: R=OMe (29%)
BF3OEt2, 16: R=OMe (22%)
11: R=H
12: R=OMe
3. Conclusion
TMS-OTf, 17: R=H
(23%)
Scheme 3.
The alkylation of nucleophilic arenes by acyliminium cations,
generated from the 4-acyloxy-azetidinones in the presence of
Lewis acids, proceeds successfully with a variety of aryls linked to
the nitrogen atom by the N-methyloxy, or N-methylthio tethers.
Efforts to achieve the hydrolysis of the N,O-acetal or N,S-thioacetal
centers as well as attempts to carry out the Pummerer rearrange-
ment of sulfoxides were unsuccessful. On the other hand, the de-
sulfurization with Raney nickel readily proceeds to provide
expected 4-aryl-azetidinones.
Attempts to hydrolyze the N,O-acetal fragment in 16 and 17
were unsuccessful. The use of mineral acids in protic solvents led to
opening of the azetidinone ring followed by further decomposition.
Hydrolysis under mild conditions, such as treatment with
ethyl nitroacetate8 left the substrate unchanged. The low yield of
3-oxacepham formation and the failure of the acetal hydrolysis

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B. Zambron et al. / Tetrahedron 66 (2010) 8974e8981
8976
1. SOCl2
2,6-lutidine
O
O
O
R1CHO
1150C
N
OH
N
S
R2
R3
NH
2. 19 and 20, PTC
O
O
O
R1
R1
3: R1=H (96%)
R2
R3
1
HS
18a/18b: R1=CO2Et (46%, 1:1 dr)
21: R1,R2=H; R3=OMe (61%)
22: R1,R3=H; R2=OMe (76%)
23a/23b: R1=CO2Et; R2=OMe; R3=H (79%, 1:07 dr)
19: R2 =H; R3=OMe
20: R2 =OMe; R3=H
Scheme 4.
OMe
MeO
N
S
OMe
Lewis
acid
O
Lewis
acid
N
S
N
S
R2
N
S
+
S
O
CH2Cl2
CH2Cl2
O
O
O
R1
R1
OMe
R1
SnCl4 26: R1=H (22%)
R3
SnCl4 25: R1=H (67%)
BF3OEt2
TMS-OTf
24
SnCl4
BF3OEt2 (32%)
TMS-OTf (31%)
(35%)
21-23
(50%)
(41%)
BF3OEt2
TMS-OTf
(14%)
(13%)
SnCl4 27: R1=CO2Et (45%)
SnCl4 28:R1=CO2Et (22%)
Scheme 5.
4.2. Synthesis of 1-(hydroxymethyl)-4-(vinyloxy)azetidin-2-
one (3)
O
S
NH
CO2Me
OMe
S
1. HgX2/MeOH
2. H2S
HCl
MeOH/H2O
A mixture of 1 (1 g, 8.8 mmol) and paraformaldehyde (530 mg,
17.6 mmol) was stirred at 115 ꢀC until disappearance of the sub-
strate. Purification of the crude product by flash chromatography
on silica gel using acetone/hexane mixture as an eluant afforded 3
as a colorless oil. Yield 1378 mg (96%); Rf (40% acetone/hexane)
N
S
O
55%
X = Cl 6%
MeO
25
MeO
30
29
X = OAc 35%
Scheme 6.
Fig. 1. X-ray structures of racemic sulfoxides 31 and 32 with crystallographic numbering scheme.
4. Experimental section
4.1. General
0.45; 1H NMR (500 MHz, CDCl3)
d
: 6.45 (dd, J¼14.3, 6.7 Hz, 1H), 5.52
(dd, J¼3.9, 1.4 Hz, 1H), 4.92 (br dd, J¼11.6, 4.4 Hz, 1H), 4.54 (br dd,
J¼11.6, 8.9 Hz, 1H), 4.45 (dd, J¼14.3, 2.5 Hz, 1H), 4.25 (dd, J¼6.7,
2.5 Hz, 1H), 3.35e3.29 (m, 1H), 3.20 (dd, J¼15.2, 3.9 Hz, 1H), 2.96
IR spectra were recorded on FT-IR-1600 PerkineElmer spec-
trometer. The 1H NMR and 13C NMR spectra were measured on
a Bruker AM 500 and VariandNMRdvnmrs 600 spectrometers.
The high-resolution mass spectra were measured on AMD 606
mass spectrometer. The thin-layer chromatography (TLC) was done
using the Merck precoated TLC plates (silica gel 60 GF254, 0.25 mm).
The products were purified by the preparative column chroma-
tography on silica gel (Merck Kieselgel 230e400 mesh). The ozo-
nolysis was carried out using Buchi Ozone Generator OZI.
Anhydrous THF was distilled from LiAlH4 and CH2Cl2 was dis-
tilled from CaH2. 4-Vinyloxy-azetidinone (3) was obtained follow-
ing known procedure.1a
(dd, J¼15.2, 1.4 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d: 165.7, 148.2,
91.3, 78.3, 63.6, 45.1; IR (CH2Cl2): 3392, 2949,1764,1643, 1381,1196,
1039, 944, 841 cmꢁ1; HRMS (ESI) calcd for C6H9NO3Na: 166.0475
[MþNa]þ, found 166.0481.
4.3. Synthesis of ethyl 2-hydroxy-2-(2-oxo-4-(vinyloxy)
azetidin-1-yl)acetate (18)
A mixture of 1 (1 g, 8.8 mmol) and w50% ethyl glyoxalate so-
lution in toluene (3.6 g of solution, containing 17.6 mmol of sub-
strate) was heated in a sealed tube at 115 ꢀC until disappearance of
the substrate. The mixture was then diluted with CH2Cl2 (50 mL),

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B. Zambron et al. / Tetrahedron 66 (2010) 8974e8981
8977
OMe
OMe
OMe
H
H
N
mCPBA
CH2Cl2
+
N
S
S
N
S
O
O
O
O
O
25
31 (45%)
32 (47%)
OMe
+
Ac2O
OMe
OMe
no reaction
1000C
H
H
O
N
TMS-O Tf
S
Hunigs base
CH2Cl2
N
S
N
S
O
(CF3CO)2O
Ac2O
O
O
O
tarry
31
1000C
products
33 (25%)
25 (11%)
Scheme 7.
chlorides were dissolved in dry acetonitrile (10 mL) and added to
the vigorously stirred mixture of 4e6 or 19e20 (7.5 mmol), K2CO3
(5 g), and TBAB (1610 mg, 5 mmol) in dry acetonitrile (20 mL) in one
portion at rt. After 5 min K2CO3 excess was filtered off and the
mixture was concentrated. Purification of the crude product by
column chromatography on silica gel using acetone/hexane or ethyl
acetate/hexane mixture as an eluant afforded 8e10, 21, 22, 23a/23b
(1:1 dr) as colorless oils.
OMe
OMe
OMe
Ra Ni
O
N
R1
EtOH
N
S
O
HN
R1
15 min
O
R1
25 R1=H
34 (97%)
35 (74%)
36 (traces)
37 (14%)
27 R1=CO2Et
OMe
4.4.1. 1-(Phenoxymethyl)-4-(vinyloxy)azetidin-2-one(8). Yield 537 mg
(49%); Rf (30% ethyl acetate/hexane) 0.50; 1H NMR (500 MHz, CDCl3)
OMe
RaNi
O
d
: 7.33e7.28 (m, 2H), 7.04e6.99 (m, 3H), 6.44 (dd, J¼14.3, 6.7 Hz, 1H),
EtOH
24 h
N
S
HN
5.43 (dd, J¼3.9, 1.3 Hz, 1H), 5.38 (d, J¼11.4 Hz, 1H), 4.98 (d, J¼11.4 Hz,
1H), 4.45 (dd, J¼14.3, 2.5 Hz, 1H), 4.24 (dd, J¼6.7, 2.5 Hz, 1H), 3.18 (dd,
J¼15.3, 3.9 Hz, 1H), 2.96 (br d, J¼15.3, 1H); 13C NMR (125 MHz, CDCl3)
Me
36 (73%)
Scheme 8.
O
25
d: 165.2, 156.1, 148.3, 129.8, 122.2, 115.3, 91.3, 78.7, 66.7, 45.2; IR
(CH2Cl2): 3066, 3043, 2948, 1780, 1623, 1496, 1377, 1200, 1013, 757,
693 cmꢁ1; HRMS (EI) calcd for C12H13NO3: 219.0895 [M]þ, found
219.0889.
washed with water (3ꢂ150 mL), dried over MgSO4, and concen-
trated. The residue was purified by flash chromatography on silica
gel using acetone/hexane mixture as an eluant to afford 18a and 18b
in 1:1 ratio as colorless oils. Yield 952 mg (46%). Compound 18a: Rf
4.4.2. 1-((4-Methoxyphenoxy)methyl)-4-(vinyloxy)azetidin-2-one
(9). Yield 573 mg (46%); Rf (35% ethyl acetate/hexane) 0.50; 1H
(40% ethyl acetate/hexane) 0.40; 1H NMR (500 MHz, CDCl3)
d: 6.44
NMR (500 MHz, CDCl3) d: 6.97e6.93 (m, 2H), 6.86e6.82 (m, 2H),
(dd, J¼14.2, 6.7 Hz,1H), 5.48 (dd, J¼3.8,1.4 Hz,1H), 5.23 (d, J¼8.4 Hz,
1H), 4.44 (dd, J¼14.2, 2.4 Hz, 1H), 4.30 (q, J¼7.2 Hz, 2H), 4.28 (dd,
J¼6.7, 2.4 Hz,1H), 3.90 (d, J¼8.4 Hz,1H), 3.22 (dd, J¼15.3, 3.8 Hz,1H),
3.00 (dd, J¼15.3, 1.4 Hz, 1H), 1.35 (t, J¼7.2 Hz, 3H); 13C NMR
6.43 (ddd, J¼14.3, 6.7, 0.3 Hz, 1H), 5.30 (dd, J¼3.9, 1.4 Hz, 1H), 5.30
(d, J¼11.4 Hz, 1H), 4.92 (dd, J¼11.4, 0.6 Hz, 1H), 4.45 (dd, J¼14.3,
2.5 Hz, 1H), 4.24 (dd, J¼6.7, 2.5 Hz, 1H), 3.77 (s, 3H), 3.17 (dd, J¼15.3,
3.9 Hz, 1H), 2.95 (ddd, J¼15.3, 1.4, 0.6 Hz, 1H); 13C NMR (125 MHz,
(125 MHz, CDCl3) d: 168.2, 164.2, 147.9, 92.0, 79.2, 71.8, 63.2, 45.3,
CDCl3) d: 165.2, 155.0, 150.0, 148.3, 116.7, 114.9, 91.3, 78.7, 67.6, 55.6,
14.0; IR (CH2Cl2): 3330, 2985, 2940, 1746, 1668, 1538, 1224, 1106,
1020, 859, 604 cmꢁ1; HRMS (ESI) calcd for C9H13NO5Na: 238.0686
[MþNa]þ, found 238.0696. Compound 18b: Rf (40% acetone/hex-
45.2; IR (CH2Cl2): 3116, 3046, 2953, 1780, 1642, 1624, 1509, 1376,
1197, 1037, 829 cmꢁ1; HRMS (ESI) calcd for C13H15NO4Na: 272.0893
[MþNa]þ, found 272.0889.
ane) 0.35; 1H NMR (500 MHz, CDCl3)
d
: 6.33 (dd, J¼14.1, 6.6 Hz, 1H),
5.51 (dd, J¼4.2, 1.5 Hz, 1H), 5.47 (d, J¼6.2 Hz, 1H), 4.35 (dd, J¼14.1,
2.3 Hz, 1H), 4.30 (q, J¼7.2 Hz, 2H), 4.21 (dd, J¼6.6, 2.3 Hz, 1H), 4.07
(d, J¼6.2 Hz, 1H), 3.21 (dd, J¼15.3, 4.1 Hz, 1H), 2.99 (dd, J¼15.3,
4.4.3. 1-((3-Methoxyphenoxy)methyl)-4-(vinyloxy)azetidin-2-one
(10). Yield 735 mg (59%); Rf (30% ethyl acetate/hexane) 0.55; 1H
NMR (600 MHz, CDCl3)
d
: 7.19 (t, J¼8.4, 1H), 6.62e6.60 (m, 2H), 6.59
1.5 Hz,1H),1.33 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d: 169.4,
(ddd, J¼8.2, 2.2, 0.6 Hz, 1H), 6.44 (dd, J¼14.3, 6.8 Hz, 1H), 5.45 (dd,
J¼4.0,1.1 Hz,1H), 5.37 (d, J¼11.6 Hz,1H), 4.98 (d, J¼11.6 Hz,1H), 4.45
(dd, J¼14.3, 2.5 Hz,1H), 4.25 (dd, J¼6.8, 2.5 Hz,1H), 3.79 (s, 3H), 3.19
(dd, J¼15.3, 4.0 Hz, 1H), 2.97 (br d, J¼15.3 Hz, 1H); 13C NMR
164.8,147.7, 91.6, 77.8, 70.5, 63.4, 45.0, 13.9; IR (CH2Cl2): 3332, 2985,
2940, 1745, 1667, 1538, 1225, 1106, 1019, 859, 604 cmꢁ1; HRMS (ESI)
calcd for C9H13NO5Na: 238.0686 [MþNa]þ, found 238.0693.
(150 MHz, CDCl3) d: 165.2, 161.0, 157.2, 148.3, 130.2, 108.2, 107.2,
101.3, 91.3, 78.7, 66.6, 55.3, 45.2; IR (CH2Cl2): 2944,1781,1605,1494,
1376, 1146, 1042, 1022, 839, 769, 688 cmꢁ1; HRMS (EI) calcd for
C13H15NO4: 249.1001 [M]þ, found 249.0993.
4.4. General procedure for synthesis of N-substituted-4-
vinyloxy-azetidin-2-ones 8e10, 21, 22, 23a, 23b
SOCl2 (890 mg, 7.5 mmol) was added dropwise under argon to
a stirred solution of 3 or 18a/18b (1:1 dr) (5 mmol) and 2,6-lutidine
(1070 mg, 10 mmol) in dry THF (70 mL) at ꢁ20 ꢀC. The mixture was
stirred at ꢁ20 ꢀC until disappearance of the substrate (TLC moni-
toring) and then evaporated. Subsequently the residue was dis-
solved in benzene (25 m), filtrated, and evaporated. The crude
4.4.4. 1-((4-Methoxyphenylthio)methyl)-4-(vinyloxy)azetidin-2-one
(21). Yield 809 mg (61%); Rf (35% ethyl acetate/hexane) 0.45; 1H
NMR (500 MHz, CDCl3) d: 7.42e7.38 (m, 2H), 6.88e6.84 (m, 2H),
6.33 (dd, J¼14.2, 6.7 Hz, 1H), 5.38 (dd, J¼3.9, 1.4 Hz, 1H), 4.86 (d,
J¼14.2 Hz, 1H), 4.42 (dd, J¼14.2, 2.3 Hz, 1H), 4.20e4.15 (m, 2H), 3.80

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(s, 3H), 3.03 (dd, J¼15.0, 3.9 Hz, 1H), 2.84 (dt, J¼15.0, 1.4 Hz, 1H); 13
C
1H), 3.03 (dd, J¼15.6,1.3 Hz,1H); 13C NMR (125 MHz, CDCl3)
d: 164.6,
NMR (150 MHz, CDCl3)
d
: 164.7, 160.0, 148.2,134.5, 123.1, 115.0, 91.4,
160.0,155.0,149.9,117.1,114.8, 74.9, 68.7, 55.5, 45.1; IR (CH2Cl2): 2955,
1784, 1731, 1509, 1376, 1218, 1199, 1145, 1036, 1015, 830 cmꢁ1; HRMS
(EI) calcd for C12H13NO5: 251.0794 [M]þ, found 251.0791.
78.7, 55.3, 45.2, 44.7; IR (CH2Cl2): 2940,1771, 1641, 1622, 1592, 1495,
1382, 1246, 1182, 1079, 1029, 827,685, 523 cmꢁ1; HRMS (ESI) calcd
for C13H15NO3NaS: 288.0665 [MþNa]þ, found 288.0673.
4.5.3. 1-((3-Methoxyphenoxy)methyl)-4-(formyloxy)azetidin-2-one
4.4.5. 1-((3-Methoxyphenylthio)methyl)-4-(vinyloxy)azetidin-2-one
(13). Yield 879 mg (70%); Rf (30% ethyl acetate/hexane) 0.35; 1H NMR
(22). Yield 1007 mg (76%); Rf (30% acetone/hexane) 0.60; 1H NMR
(500 MHz, CDCl3)
d
: 8.09 (s, 1H), 7.19 (t, J¼8.7 Hz, 1H), 6.62e6.56 (m,
(500 MHz, CDCl3)
d
: 7.23 (t, J¼8.2, 1H), 7.01e6.97 (m, 2H), 6.80
3H), 6.21 (dd, J¼4.2,1.2 Hz,1H), 5.26 (d, J¼11.4 Hz,1H), 5.05 (d, J¼11.4,
1H), 3.79 (s, 3H), 3.34 (dd, J¼15.6, 4.2 Hz, 1H), 3.04 (dd, J¼15.6,1.2 Hz,
(ddd, J¼8.2, 2.4, 0.8 Hz, 1H), 6.35 (dd, J¼14.2, 6.6 Hz, 1H), 5.37 (dd,
J¼3.8, 1.2 Hz, 1H), 5.04 (d, J¼14.5 Hz, 1H), 4.41 (dd, J¼14.2, 2.3 Hz,
1H), 4.28 (dd, J¼14.5, 1.2 Hz, 1H), 4.20 (dd, J¼6.6, 2.3 Hz, 1H), 3.81
(s, 3H), 3.05 (dd, J¼15.0, 3.8 Hz, 1H), 2.86 (dt, J¼15.0, 1.2 Hz, 1H);
1H); 13C NMR (125 MHz, CDCl3)
d: 164.7, 161.0, 160.1, 157.2, 130.2,
108.3,107.5,101.6, 75.0, 67.6, 55.3, 45.2; IR (CH2Cl2): 2948,1784,1731,
1604, 1494, 1375, 1147, 1016, 837, 770, 689 cmꢁ1; HRMS (EI) calcd for
C12H13NO5: 251.0794 [M]þ, found 251.0791.
13C NMR (150 MHz, CDCl3)
d: 164.7, 160.0, 148.0, 134.1, 130.0, 122.2,
115.0, 113.4, 91.3, 78.5, 55.3, 44.5, 42.8; IR (CH2Cl2): 2939, 1771,
1590, 1482, 1382, 1250, 1194, 1080, 1038, 859, 846, 688 cmꢁ1
;
4.6. Reactions of N-substituted-azetidin-2-ones 8, 9, 11, 12, 21,
22 and 23a/23b in the presence of Lewis acids
HRMS (ESI) calcd for C13H15NO3NaS: 288.0665 [MþNa]þ, found
288.0658.
To a solution of compounds 8, 9,11,12, 21, 22 or 23a/23b (1:1 dr),
(0.3 mmol) in anhydrous CH2Cl2 (5 mL) Lewis acid (0.3 mmol) was
added dropwise at 0 ꢀC under the argon atmosphere. The mixture
was stirred at 0 ꢀC until disappearance of the substrate (TLC
monitoring). The saturated solution of NaHCO3 (1 mL) was then
added and stirring was continued for 10 min. The mixture was then
poured into water (20 mL) and extracted with CH2Cl2 (20 mL). The
extracts were dried over MgSO4 and concentrated. The residue was
purified by column chromatography on silica gel to afford com-
pounds 14e17, 24e28.
4.4.6. Ethyl 2-(4-methoxyphenylthio)-2-(2-oxo-4-(vinyloxy) azeti-
din-1-yl)acetate (23a, 23b). Yield 1332 mg (79%) (23a/23b¼1:1); Rf
(30% acetone/hexane) 0.55; 1H NMR (600 MHz, CDCl3)
d:
8.71e8.67 (m, 2H), 7.16e7.13 (m, 2H), 7.02 (ddd, J¼7.7, 2.4, 0.7 Hz,
1H), 7.00e6.98 (m, 1H), 6.88 (ddd, J¼8.4, 2.5, 1.1 Hz, 1H), 6.86 (ddd,
J¼8.4, 2.4, 0.7 Hz, 1H), 6.49 (dd, J¼13.9, 6.6 Hz, 1H), 6.42 (dd,
J¼14.3, 6.6 Hz, 1H), 5.83 (s, 1H), 5.77 (dd, J¼4.2, 1.4 Hz, 1H), 5.63 (s,
1H), 5.47 (dd, J¼4.2, 1.7 Hz, 1H); 4.43 (dd, J¼14.3, 2.4 Hz, 1H), 4.41
(dd, J¼13.9, 2.4 Hz, 1H), 4.25e4.21 (m, 6H), 3.81 (s, 3H), 3.80 (s,
3H), 3.21 (dd, J¼15.3, 4.2 Hz, 1H), 2.99 (dd, J¼15.3, 4.2 Hz, 1H), 2.93
(dd, J¼15.3, 1.4 Hz, 1H), 2.92 (dd, J¼15.3, 1.7 Hz, 1H), 1.31e1.28 (m,
4.6.1. 4-Phenoxy-1-(phenoxymethyl)azetidin-2-one (14). Yield 2 mg
(2%) (SnCl4), 3 mg (4%) (TMS-OTf); colorless needles, mp 63e65 ꢀC;
6H); 13C NMR (150 MHz, CDCl3)
d: 166.9, 165.8, 165.1, 164.9, 160.1,
159.9, 148.6, 148.1, 133.0, 132.1, 130.2, 129.9, 125.5, 124.2, 118.2,
117.1, 115.1, 114.7, 91.7, 91.6, 81.9, 79.3, 62.8, 62.5, 59.1, 58.0, 55.40,
55.37, 45.4, 44.5, 14.0, 13.9; IR (CH2Cl2): 3529, 3069, 2982, 2939,
1779, 1742, 1590, 1480, 1364, 1323, 1250, 1195, 1082, 1038, 845,
782, 689 cmꢁ1; HRMS (EI) calcd for C16H19NO5S: 337.0984 [M]þ,
found 337.0984.
Rf (30% ethyl acetate/hexane) 0.50; 1H NMR (500 MHz, CDCl3)
d:
7.35e7.28 (m, 4H), 7.09e7.00 (m, 4H), 6.99e6.94 (m, 2H), 5.74 (dd,
J¼3.8,1.1 Hz,1H), 5.45 (d, J¼11.5 Hz,1H), 4.99 (d, J¼11.5 Hz,1H), 3.31
(dd, J¼15.2, 3.8 Hz, 1H) 3.08 (br d, J¼15.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) d: 165.4, 156.2, 156.0, 129.9, 129.8, 122.7, 122.2,
115.7, 115.3, 78.7, 66.6, 46.0; IR (CH2Cl2): 2923, 1779, 1597, 1493,
1376, 1220, 1012, 753, 691 cmꢁ1
; HRMS (ESI) calcd for
4.5. Synthesis of N-substituted-4-formyloxy-azetidin-2-ones
(11)e(13)
C16H15NO3Na: 292.0944 [MþNa]þ, found 292.0945.
4.6.2. 4-(4-Methoxyphenoxy)-1-((4-methoxyphenoxy)methyl) azeti-
din-2-one (15). Yield 9 mg (9%) (SnCl4), 33 mg (33%) (TMS-OTf);
colorless oil; Rf (35% ethyl acetate/hexane) 0.45; 1H NMR (500 MHz,
A mixture of 8e10 (5 mmol) and saturated ethanolic solution of
ozonizable dye Sudan red 7B (0.1 mL) in freshly distilled CH2Cl2
(50 mL) was cooled to ꢁ78 ꢀC and ozone was bubbled through it
until the deep red color of the reaction mixture turned to pale
yellow. Dimethyl sulfide (1 mL) was then added and the solution
was brought to the rt and stirred for 30 min. Evaporation of solvent
and purification of crude product by column chromatography on
silica gel using ethyl acetate/hexane mixture as an eluant afforded
compound 11e13 as a colorless oils.
CDCl3) d: 6.97e6.93 (m, 2H), 6.92e6.89 (m, 2H), 6.86e6.81 (m, 4H),
5.63 (dd, J¼3.9, 1.3 Hz, 1H), 5.35 (d, J¼11.4 Hz, 1H), 4.92 (dd, J¼11.4,
0.5 Hz, 1H), 3.78 (s, 3H), 3.77 (s, 3H), 3.24 (dd, J¼15.2, 3.9 Hz, 1H),
3.05 (ddd, J¼15.2, 1.3, 0.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d:
165.5, 155.4, 155.0,150.1, 150.0, 117.4,116.8,114.94, 114.86, 79.6, 67.7,
55.68, 55.65, 45.84; IR (CH2Cl2): 2934, 1775, 1507, 1373, 1213, 1034,
826 cmꢁ1; HRMS (ESI) calcd for C18H19NO5Na: 352.1155 [MþNa]þ,
found 352.1169.
4.5.1. 1-(Phenoxymethyl)-4-(formyloxy)azetidin-2-one (11). Yield
774 mg (70%); Rf (30% ethyl acetate/hexane) 0.35; 1H NMR
(500 MHz, CDCl3) d: 8.08 (s, 1H), 7.33e7.28 (m, 2H), 7.04e7.00 (m,
4.6.3. 8-Methoxy-1,9b-dihydroazeto[1,2-c]benzo[e][1,3]oxazin-2
(4H)-one (16). Yield 29% (TMS-OTf), 22% (BF3OEt2); colorless nee-
dles, mp 79e82 ꢀC; Rf (40% acetone/hexane) 0.55; 1H NMR
3H), 6.21 (dd, J¼4.2, 1.2 Hz, 1H), 5.27 (d, J¼11.3 Hz, 1H), 5.07 (d,
J¼11.3, 1H), 3.34 (dd, J¼15.6, 4.2 Hz, 1H), 3.04 (dd, J¼15.6, 1.2 Hz,
(500 MHz, CDCl3)
d
: 6.88 (d, J¼9.3 Hz, 1H), 6.76 (ddt, J¼9.3, 3.1,
1H); 13C NMR (125 MHz, CDCl3)
d
: 164.7, 160.0, 156.0, 129.7, 122.3,
0.9 Hz, 1H), 6.59 (dt, J¼3.1, 0.9 Hz, 1H), 5.21 (dt, J¼3.2, 0.7 Hz, 1H),
4.68 (br d, J¼16.6 Hz, 1H), 4.19e4.15 (m, J¼11.4, 1H), 3.76 (s, 3H),
3.33 (ddd, J¼15.2, 3.2, 2.0 Hz, 1H), 2.99 (br d, J¼15.2 Hz, 1H); 13C
115.6, 75.0, 67.7, 45.2; IR (CH2Cl2): 2948, 1784, 1729, 1597, 1495,
1374, 1221, 1201, 1143, 1012, 757, 693 cmꢁ1; HRMS (EI) calcd for
C11H11NO4: 221.0688 [M]þ, found 221.0691.
NMR (125 MHz, CDCl3) d: 167.6, 154.8, 146.0, 119.2, 118.5, 114.7,
111.5, 75.4, 55.7, 46.1, 39.2; IR (CH2Cl2): 3373, 2935,1771,1496,1388,
1202, 1043, 864 cmꢁ1; HRMS (ESI) calcd for C11H11NO3Na: 228.0631
[MþNa]þ, found 228.0642.
4.5.2. 1-((4-Methoxyphenoxy)methyl)-4-(formyloxy)azetidin-2-one
(12). Yield 992 mg (79%); Rf (35% ethyl acetate/hexane) 0.45; 1H NMR
(500 MHz, CDCl3)
d: 8.08 (d, J¼0.5 Hz, 1H), 6.98e6.94 (m, 2H),
6.86e6.82 (m, 2H), 6.21e6.18 (ddd, J¼4.2, 1.3, 0.5 Hz, 1H), 5.21 (d,
J¼11.2Hz,1H),5.99(d,J¼11.2,1H), 3.77(s, 3H), 3.33(dd,J¼15.6, 4.2 Hz,
4.6.4. 1,9b-Dihydroazeto[1,2-c]benzo[e][1,3]oxazin-2(4H)-one
(17). Yield 12 mg (23%) (TMS-OTf); colorless needles, mp

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B. Zambron et al. / Tetrahedron 66 (2010) 8974e8981
8979
92e93 ꢀC; Rf (30% ethyl acetate/hexane) 0.55; 1H NMR (500 MHz,
CDCl3)
167.5, 167.2, 157.1, 129.3, 128.3, 119.4, 118.9, 107.4, 62.2, 55.5, 48.7,
45.2, 44.9, 14.0; IR (CH2Cl2): 2925, 1770, 1742, 1574, 1460, 1309,
1262, 1046, 775 cmꢁ1; HRMS (EI) calcd for C14H15NO4S: 293.0722
[M]þ, found 293.0708.
d
: 7.22e7.18 (m, 1H), 7.08e7.05 (m, 1H), 7.00 (td, J¼7.6,
1.2 Hz, 1H), 6.95 (dd, J¼8.2, 0.8 Hz, 1H), 5.27 (d, J¼3.2 Hz, 1H), 4.71
(d, J¼16.5 Hz, 1H), 4.21 (br d, J¼16.5 Hz, 1H), 3.36 (ddd, J¼15.0 3.2,
2.1 Hz, 1H), 3.02 (d, J¼15.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d:
128.5, 127.2, 122.4, 118.4, 117.7, 75.3, 46.3, 39.0; IR (KBr): 2955, 2916,
1762, 1490, 1390, 1218, 1045, 766 cmꢁ1; HRMS (EI) calcd for
C10H9NO2: 175.0633 [M]þ, found 175.0640.
4.7. Synthesis of methyl 2-(7-methoxy-3,4-dihydro-2H-benzo
[e][1,3]thiazin-4-yl)acetate (29)
A solution of 25 (66 mg, 0.3 mmol) in 5 mL of 1 N methanolic
hydrochloric acid (prepared by dilution of 1 mL of 38% aqueous
hydrochloric acid to 12 mL with absolute methanol) was stirred at
rt for 24 h. The mixture was then poured into water (40 mL) and
extracted with CH2Cl2 (20 mL). The extracts were dried over
MgSO4 and concentrated. The residue was purified by column
chromatography on silica gel using acetone/hexane mixture as an
eluant to afford compounds 29. Yield 42 mg (55%); colorless
needles, mp 78e81 ꢀC; Rf (30% acetone/hexane) 0.55; 1H NMR
4.6.5. 4-(4-Methoxyphenylthio)-1-((4-methoxyphenylthio) methyl)
azetidin-2-one (24). Yield 38 mg (35%) (SnCl4), 35 mg (32%)
(BF3OEt2), 34 mg (31%) (TMS-OTf); colorless needles, mp 47e49 ꢀC;
Rf (35% ethyl acetate/hexane) 0.40; 1H NMR (500 MHz, CDCl3)
d:
7.39e7.36 (m, 2H), 7.35e7.32 (m, 2H), 6.87e6.82 (m, 4H), 4.88 (d,
J¼14.1 Hz, 1H), 4.85 (dd, J¼5.1, 2.4 Hz, 1H), 4.22 (dd, J¼14.1, 0.8 Hz,
1H), 3.81 (s, 3H), 3.79 (s, 3H), 3.11 (dd, J¼15.1, 5.1 Hz, 1H), 2.70 (ddd,
J¼15.1, 2.4, 0.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d: 164.8, 160.6,
159.9, 137.0, 134.5, 123.3, 119.6, 114.94, 114.89, 57.8, 55.33, 55.29,
45.1, 43.9; IR (CH2Cl2): 2938, 1762, 1591, 1494, 1373, 1287, 1246,
1173, 1029, 828 cmꢁ1; HRMS (ESI) calcd for C18H19NO3NaS2:
384.0699 [MþNa]þ, found 384.0687.
(500 MHz, CDCl3)
d
: 6.99 (d, J¼8.5 Hz, 1H), 6.64 (d, J¼2.6 Hz, 1H),
6.60 (dd, J¼8.5, 2.6 Hz, 1H), 4.51 (d, J¼12.4 Hz, 1H), 4.45 (dd, J¼9.1,
5.3 Hz, 1H), 4.34 (d, J¼12.4 Hz, 1H), 3.75 (s, 3H), 3.71 (s, 3H),
2.88e2.77 (m, 2H), 2.25 (br s, 1H); 13C NMR (125 MHz, CDCl3)
d:
171.7, 158.3, 133.8, 127.9, 125.0, 112.5, 111.5, 55.3, 52.5, 51.8, 45.0,
40.2; IR (CH2Cl2): 3331, 2950, 1735, 1600, 1493, 1437, 1232, 1058,
1035, 755 cmꢁ1; HRMS (EI) calcd for C12H15NO3S: 253.0773 [M]þ,
found 253.0777.
4.6.6. 7-Methoxy-1,9b-dihydroazeto[1,2-c]benzo[e][1,3]thiazin-2
(4H)-one (25). Yield 44 mg (67%) (SnCl4), 33 mg (50%) (BF3OEt2),
27 mg (41%) (TMS-OTf); colorless needles, mp 96e97 ꢀC; Rf (30%
acetone/hexane) 0.45; 1H NMR (500 MHz, CDCl3)
d: 7.05 (d,
J¼8.4 Hz, 1H), 6.76e6.71 (m, 2H), 4.83 (d, J¼12.4 Hz, 1H), 4.69 (dd,
J¼5.2, 2.2 Hz, 1H), 4.28 (dd, J¼12.4, 0.7 Hz, 1H), 3.78 (s, 3H), 3.50
(ddd, J¼15.1, 5.2, 0.7 Hz, 1H), 2.80 (dd, J¼15.1, 2.2 Hz, 1H); 13C NMR
4.8. Synthesis of 7-methoxy-2H-thiochromen-2-one (30)
4.8.1. Method A. A solution of 25 (66 mg, 0.3 mmol) and HgCl2
(163 mg, 0.6 mmol) in absolute methanol (5 mL) was stirred at
reflux for 24 h. Subsequently the mixture was cooled to 0 ꢀC and
H2S was bubbled through it for 20 min. HgS was then filtered off,
washed twice with absolute methanol (20 mL), and the solvent was
removed under reduced pressure. The crude product was purified
by flash chromatography on silica gel using acetone/hexane mix-
ture as an eluant to give 30. Yield 4 mg (7%); colorless needles, mp
98e100 ꢀC; Rf (30% acetone/hexane) 0.80; 1H NMR (500 MHz,
(125 MHz, CDCl3) d: 168.2, 158.6, 132.0, 128.4, 124.1, 113.2, 112.9,
55.4, 47.8, 44.3, 39.1; IR (CH2Cl2): 2937, 1761, 1602, 1494, 1237, 1058,
871, 811, 701 cmꢁ1; HRMS (ESI) calcd for C11H11NO2NaS: 244.0403
[MþNa]þ, found 244.0396.
4.6.7. 9-Methoxy-1,9b-dihydroazeto[1,2-c]benzo[e][1,3]thiazin-2
(4H)-one (26). Yield 15 mg (22%) (SnCl4), 9 mg (14%) (BF3OEt2),
8 mg (12%) (TMS-OTf); colorless needles, mp 162e164 ꢀC; Rf (30%
acetone/hexane) 0.45; 1H NMR (500 MHz, CDCl3)
d
: 7.14 (td,
CDCl3)
d
: 7.64 (d, J¼10.6 Hz, 1H), 7.53e7.70 (m, 1H), 6.96e6.94 (m,
J¼8.1, 0.5 Hz, 1H), 6.77 (dd, J¼8.1, 0.8 Hz, 1H), 6.65 (dd, J¼8.1,
0.7 Hz, 1H), 4.86 (d, J¼12.6 Hz, 1H), 4.70 (dd, J¼5.2, 2.4 Hz, 1H),
4.31 (dd, J¼12.6, 0.5 Hz, 1H), 3.83 (s, 3H), 3.53 (dd, J¼15.4, 5.2 Hz,
2H), 6.41 (d, J¼10.6 Hz, 1H), 3.89 (s, 3H); 13C NMR (125 MHz, CDCl3)
d
: 185.2, 160.9, 143.7, 140.2, 133.0, 121.2, 119.7, 114.7, 109.1, 55.7; IR
(CH2Cl2): 2921, 2851, 1639, 1604, 1535, 1342, 1219, 1025, 839 cmꢁ1
HRMS (EI) calcd for C10H8O2S: 192.0245 [M]þ, found 192.0250.
;
1H), 2.74 (dd, J¼15.4, 2.4 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d:
168.0, 157.4, 131.8, 128.1, 120.5, 119.7, 107.0, 55.4, 45.0, 44.9, 38.3;
IR (CH2Cl2): 2937, 1761, 1572, 1459, 1259, 1046, 776 cmꢁ1; HRMS
(ESI) calcd for C11H11NO2NaS: 244.0403 [MþNa]þ, found
244.0394.
4.8.2. Method B. A solution of 25 (66 mg, 0.3 mmol) and Hg(OAc)2
(190 mg, 0.6 mmol) in absolute methanol (5 mL) was stirred at rt
for 4 h. Afterward the mixture was cooled to 0 ꢀC and H2S was
bubbled through it for 20 min. HgS was then filtered off, washed
twice with absolute methanol (20 mL), and the solvent was re-
moved under reduced pressure. The crude product was purified by
flash chromatography on silica gel using acetone/hexane mixture
as an eluant to give 30 (20 mg, 35% yield).
4.6.8. Ethyl 7-methoxy-2-oxo-1,2,4,9b-tetrahydroazeto[1,2-c]benzo
[e][1,3]thiazine-4-carboxylate (27). Yield 40 mg (45%) (SnCl4); col-
orless wax; Rf (35% ethyl acetate/hexane) 0.50; 1H NMR (500 MHz,
CDCl3)
d
: 7.08 (d, J¼8.6 Hz, 1H), 6.75 (dd, J¼8.6, 2.6 Hz, 1H), 6.65 (d,
J¼2.6 Hz,1H), 5.59 (s,1H), 5.00 (dd, J¼5.3, 2.3 Hz,1H), 4.26e4.18 (m,
2H), 3.77 (s, 3H), 3.58 (dd, J¼15.1, 5.3 Hz, 1H), 2.74 (dd, J¼15.4,
4.9. Synthesis of sulfoxides (31), (32)
2.3 Hz, 1H), 1.27 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d:
167.3, 166.9, 158.6, 129.5, 128.2, 122.9, 113.3, 111.8, 62.3, 55.4, 49.2,
47.3, 45.6, 14.0; IR (CH2Cl2): 2924, 1770, 1741, 1604, 1497, 1311, 1261,
1240, 1026, 841, 813 cmꢁ1; HRMS (EI) calcd for C14H15NO4S:
293.0722 [M]þ, found 293.0720.
To a solution of 25 (1106 mg, 5 mmol) in freshly distilled CH2Cl2
(50 mL) a m-CPBA (860 mg, 5 mmol) was added in small portions at
0 ꢀC. The mixture was warmed to rt and stirred until disappearance
of the substrate (TLC monitoring). The saturated solution of Na2SO3
(5 mL) was then added, and stirring was continued for 10 min. The
mixture was then poured into the water (150 mL) and extracted
once with CH2Cl2 (25 mL). The extracts were dried (MgSO4) and
concentrated. The residue was purified by flash chromatography on
silica gel to afford compounds 31 and 32.
4.6.9. Ethyl 9-methoxy-2-oxo-1,2,4,9b-tetrahydroazeto[1,2-c]benzo
[e][1,3]thiazine-4-carboxylate (28). Yield 19 mg (22%) (SnCl4); col-
orless wax; Rf (35% ethyl acetate/hexane) 0.55; 1H NMR (500 MHz,
CDCl3)
d
: 7.15 (td, J¼8.1, 0.4 Hz, 1H), 6.71 (dd, J¼8.1, 0.6 Hz, 1H), 6.67
(d, J¼8.1 Hz, 1H), 5.59 (s, 1H), 5.00 (dd, J¼5.3, 2.5 Hz, 1H), 4.26e4.14
(m, 2H), 3.84 (s, 3H), 3.58 (dd, J¼15.5, 5.3 Hz, 1H), 2.80 (dd, J¼15.5,
4.9.1. (5S
*
, 9bS )-7-Methoxy-1,9b-dihydro-2H-azeto[1,2-c][1,3] ben-
*
2.5 Hz, 1H), 1.26 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d:
zothiazin-2-one-5-oxide (31). Yield 533 mg (45%); colorless

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B. Zambron et al. / Tetrahedron 66 (2010) 8974e8981
8980
needles, mp 177e178 ꢀC; Rf (50% acetone/hexane) 0.40; 1H NMR
(500 MHz, CDCl3)
hexane) 0.40; 1H NMR (500 MHz, CDCl3)
d: 7.24e7.20 (m, 2H),
d
: 7.45 (d, J¼2.7 Hz, 1H), 7.20 (d, J¼8.6 Hz, 1H),
6.94e6.90 (m, 2H), 4.43 (dd, J¼5.1, 2.1 Hz, 1H), 3.82 (s, 3H), 3.45
7.05 (dd, J¼8.6, 2.7 Hz, 1H), 5.39 (d, J¼12.0 Hz, 1H), 4.83 (dd, J¼5.5,
2.8 Hz, 1H), 3.91 (d, J¼12.0 Hz, 1H), 3.88 (s, 3H), 3.58 (dd, J¼15.4,
5.5 Hz, 1H), 2.87 (dd, J¼15.4, 2.8 Hz, 1H); 13C NMR (125 MHz, CDCl3)
(ddd, J¼14.6, 5.1, 0.6 Hz, 1H), 2.80 (ddd, J¼14.6, 2.1, 0.9 Hz, 1H),
2.72 (s, 3H); 13C NMR (125 MHz, CDCl3)
d: 167.6, 159.8, 129.9, 127.5,
114.4, 55.3, 55.2, 47.3, 26.9; IR (CH2Cl2): 2959, 1731, 1384, 1031,
832 cmꢁ1; HRMS (EI) calcd for C11H13NO2: 191.0950 [M]þ, found
191.0946.
d: 166.7, 160.2, 142.4, 128.3, 124.9, 118.5, 110.5, 56.6, 55.8, 48.9, 46.8;
IR (CH2Cl2): 3492, 2935, 1757, 1604, 1496, 1351, 1236, 1064, 1040,
816, 531 cmꢁ1; HRMS (EI) calcd for C11H11NO3S: 237.0460 [M]þ,
found 237.0466.
4.11.4. Ethyl
(35). Yield 144 mg (74%); colorless needles, mp 46e48 ꢀC; Rf (30%
acetone/hexane) 0.30; 1H NMR (500 MHz, CDCl3)
: 7.27e7.22 (m,
2-(2-(4-methoxyphenyl)-4-oxoazetidin-1-yl)acetate
4.9.2. (5R
*
, 9bS
*
)-7-Methoxy-1,9b-dihydro-2H-azeto[1,2-c][1,3] ben-
d
zothiazin-2-one-5-oxide (32). Yield 557 mg (47%); colorless needles,
2H), 6.93e6.81 (m, 2H), 4.82 (dd, J¼5.3, 2.2 Hz, 1H), 4.30 (d,
J¼18.0 Hz, 1H), 4.22e4.10 (m, 2H), 3.81 (s, 3H), 3.45 (dd, J¼14.8,
5.3 Hz, 1H), 3.41 (d, J¼18.0 Hz, 1H), 2.89 (dd, J¼14.8, 2.2 Hz, 1H),
mp 191e193 ꢀC; Rf (50% acetone/hexane) 0.30; 1H NMR (500 MHz,
CDCl3)
d
: 7.30 (d, J¼8.6 Hz, 1H), 7.21 (d, J¼2.7 Hz, 1H), 7.15 (dd, J¼8.6,
2.7 Hz, 1H), 5.20 (d, J¼13.6 Hz, 1H), 4.86 (dd, J¼5.4, 3.0 Hz, 1H), 4.11
(d, J¼13.6 Hz, 1H), 3.86 (s, 3H), 3.69 (dd, J¼15.2, 5.4 Hz, 1H), 3.33 (dd,
1.25 (t, J¼7.2 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d: 168.2, 167.7,
159.9, 129.3, 127.8, 114.4, 61.4, 55.3, 54.4, 47.4, 41.5, 14.1; IR
(CH2Cl2): 2981, 2960, 2937, 1764,1743, 1515, 1249, 1204, 1177, 1029,
838 cmꢁ1; HRMS (EI) calcd for C14H17NO4: 263.1158 [M]þ, found
263.1152.
J¼15.2, 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d: 169.6, 159.1, 137.9,
129.6, 124.6, 120.2, 116.0, 58.7, 55.8, 48.3, 48.0; IR (CH2Cl2): 3484,
2986, 1759, 1605, 1497, 1351, 1241, 1016, 853, 668 cmꢁ1; HRMS (EI)
calcd for C11H11NO3S: 237.0460 [M]þ, found 237.0453.
4.11.5. 3-(4-Methoxyphenyl)-N-methylpropanamide
42 mg (73%); colorless wax; Rf (30% acetone/hexane) 0.35; 1H NMR
(500 MHz, CDCl3) : 7.13e7.09 (m, 2H), 6.84e6.80 (m, 2H), 5.37 (br s,
(36). Yield
4.10. Synthesis of N-(7-methoxy-2-oxothiochroman-4-yl)
formamide (33)
d
1H), 3.78 (s, 3H), 2.91 (t, J¼7.7 Hz, 2H), 2.77 (d, J¼3.5 Hz, 3H), 2.44 (t,
To a solution of 31 (71 mg, 0.3 mmol) and Hunigs base (39 mg,
0.3 mmol) in anhydrous CH2Cl2 (5 mL) a TMS-OTf (66 mg, 0.3 mmol)
was added dropwise at 0 ꢀC under the argon atmosphere. The
mixture was stirred at 0 ꢀC until disappearance of the substrate (TLC
monitoring). The reaction was then quenched with saturated solu-
tion of NaHCO3 (1 mL), poured into water (20 mL) and extracted with
CH2Cl2 (10 mL). The extracts were dried over MgSO4 and concen-
trated. The residue was purified by column chromatography on silica
gel to afford 33 (18 mg, 25% yield) and 25 (7 mg, 11% yield).
J¼7.7 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d: 172.8, 158.1, 132.9, 129.3,
114.0, 55.3, 38.7, 31.0, 26.3; IR (CH2Cl2): 3297, 2955, 2925, 2853, 1639,
1569,1456, 1038, 815, 695, 527 cmꢁ1; HRMS (EI) calcd for C11H15NO2:
193.1103 [M]þ, found 193.1100.
4.11.6. Ethyl 2-(3-(4-methoxyphenyl) propanamido)acetate (37).
Yield 11 mg (14%); colorless needles, mp 48e51 ꢀC; Rf (30% ace-
tone/hexane) 0.40; 1H NMR (500 MHz, CDCl3)
d: 7.14e7.10 (m, 2H),
6.84e6.81 (m, 2H), 5.89 (br s, 1H), 4.21 (q, J¼7.1 Hz, 2H), 4.01 (d,
J¼5.0 Hz, 2H), 3.30 (s, 3H), 2.92 (t, J¼7.8 Hz, 2H), 2.52 (t, J¼7.8 Hz,
4.10.1. N-(7-Methoxy-2-oxothiochroman-4-yl)formamide
2H), 1.28 (t, J¼7.1 Hz, 3H); 13C NMR (125 MHz, CDCl3)
d: 172.2,
(33). Yield 18 mg (25%); colorless needles, mp 150e152 ꢀC; Rf (40%
170.0, 158.1, 132.7, 129.2, 114.0, 61.5, 55.2, 41.4, 38.3, 30.6, 14.1; IR
(CH2Cl2): 3312, 2933, 1749, 1656, 1513, 1247, 1200, 1034, 826, 764,
750 cmꢁ1; HRMS (EI) calcd for C14H19NO4: 265.1314 [M]þ, found
265.1309.
acetone/hexane) 0.35; 1H NMR (500 MHz, CDCl3)
d: 8.2 (s, 1H), 7.34
(d, J¼8.2 Hz, 1H), 6.81e6.76 (m, 2H), 6.06 (br s, 1H), 5.50e5.45 (m,
1H), 3.81 (s, 3H), 3.22 (dd, J¼16.0, 4.9 Hz, 1H), 2.92 (dd, J¼16.0,
3.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d: 195.8, 160.4, 160.0, 132.2,
130.4, 123.9, 113.2, 112.7, 55.6, 47.4, 45.3; IR (CH2Cl2): 3264, 3009,
2966, 1684, 1602, 1496, 1237, 1058, 1033, 819 cmꢁ1; HRMS (EI) calcd
for C11H11NO3S: 237.0460 [M]þ, found 237.0465.
Acknowledgements
This work was supported by the Ministry of Education and
Science, grant PBZ-KBN-N N204 124137.
4.11. Reduction of (25) and (27) with Raney nickel
Supplementary data
4.11.1. Method A. To the vigorously stirred suspension of excess of
Raney nickel (500 mg) in absolute EtOH (25 mL) a 25 or 27
(0.3 mmol) was added in one portion at rt. After 30 min the reaction
mixture was filtered through Celite washing thoroughly with EtOH
(50 mL). The organic layer was dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel using acetone/hexane mixture as an
eluant to give 34, 35, and 37.
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.09.024
References and notes
_
_
1. (a) Ka1uza, Z.; Park, H.-S. Synlett 1996, 895; (b) Ka1uza, Z. Tetrahedron Lett.
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1998, 39, 8349; (c) Ka1uza, Z.; qysek, R. Tetrahedron: Asymmetry 1997, 8,
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Z.; Krajewski, P.; Chmielewski, M. Tetrahedron 2000, 56, 5553; (f) Borsuk, K.;
_
4.11.2. Method B. To the vigorously stirred suspension of excess of
Raney nickel (500 mg) in absolute EtOH (25 mL) a 25 (66 mg,
0.3 mmol) was added in one portion at rt. After 24 h the reaction
mixture was filtered through Celite washing thoroughly with EtOH
(50 mL). The organic layer was dried (MgSO4) and concentrated
under reduced pressure. The crude product was purified by flash
chromatography on silica gel using acetone/hexane mixture as an
eluant to give 36 as colorless wax.
_
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Kazimierski, A.; Solecka, J.; Urbanczyk-Lipkowska, Z.; Chmielewski, M. Car-
_
bohydr. Res. 2002, 337, 2005; (g) Ka1uza, Z.; Kazimierski, A.; Lewandowski,
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(h) Borsuk, K.; Suwinska, K.; Chmielewski, M. Tetrahedron: Asymmetry 2001,
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4.11.3. 4-(4-Methoxyphenyl)-1-methylazetidin-2-one
(34). Yield
4440.
55 mg (96%); colorless needles, mp 65e67 ꢀC; Rf (30% acetone/
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_

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