An entry to 4-aryl-azetidinones via alkylation of nucleophilic arenes using four-membered acyliminium cations

Article abstract of DOI:10.1016/j.tet.2009.03.048

The acyliminium cations derived from 4-acyloxy-azetidinones in the presence of Lewis acids can be used to alkylate nucleophilic arenes in both the inter- and intramolecular processes. The former reactions were successfully carried out with p-dimethoxy-ben

Full text of DOI:10.1016/j.tet.2009.03.048

Tetrahedron 65 (2009) 4440–4446
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An entry to 4-aryl-azetidinones via alkylation of nucleophilic
arenes using four-membered acyliminium cations
*
´
Bartosz Zambron, Marek Masnyk, Bart1omiej Furman, 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:
The acyliminium cations derived from 4-acyloxy-azetidinones in the presence of Lewis acids can be used
to alkylate nucleophilic arenes in both the inter- and intramolecular processes. The former reactions
were successfully carried out with p-dimethoxy-benzene in moderate yield, whereas the latter reactions
can be done with a variety of nucleophilic arenes in a good yield.
Received 11 December 2008
Received in revised form 17 February 2009
Accepted 6 March 2009
Available online 27 March 2009
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
Recently, we have shown that the 4-vinyloxy-azetidinone (3)7 is
an attractive substrate for the synthesis of 5-oxacephams since it
Ezetimibe (1) (Fig. 1) is a powerful cholesterol absorption in-
hibitor that reduces the plasma low-density lipoprotein fraction
(LDL-C) level and exhibits a long duration of action.1 The syntheses
of ezetimibe (1) and related compounds reported to-date involve
the ester enolate-imine or ketene-imine azetidin-2-one ring con-
struction methodologies.1,2
allows the N-alkylation of the substrate followed by the oxidation
of its vinyloxy group into the acyloxy substituent and subsequent
Lewis acid promoted intramolecular nucleophilic substitution at
C-4 leading to the ring closure.8 This work has prompted us to in-
vestigate the electrophilic aromatic substitution using N-acylimi-
nium ions generated from
b-lactams in both the inter- and
In 1974 Clauss et al.3 reported that the 4-acetoxy-azetidin-2-one
(2) underwent a nucleophilic displacement of acetoxy group with
variety of nucleophiles. This observation prompted many labora-
tories to use 4-acyloxy-azetidinones as substrates for the synthesis
intramolecular processes. This methodology would provide a new
access to 4-aryl-azetidinones related to ezetimibe (1).
2. Result and discussion
of variety of
b
-lactam antibiotics.4 The nucleophilic substitution
proceeds in both basic and acidic media via an active intermediate,
which constitutes an N-acyliminium cation.
The 4-formyloxy-azetidinone (5) and its N-benzyl derivative (6),
readily available from 4-vinyloxy-azetidinone (3)7 and N-benzyl-4-
vinyloxy-azetidinone (4), were used as alkylating reagents,
whereas anisole (7), dimethoxy-hydroquinone (8), 1,3-dimethoxy-
benzene (9), and 1,3,5-trimethoxy-benzene (10) served as the
nucleophilic arenes (Scheme 1). Electrophilic alkylation was per-
formed in the presence of 1 equiv of Lewis acid such as BF3$OEt2,
SnCl4, TMS-OTf, TiCl4, Yb(OTf)3, InCl3, SnCl2/TMSCl at 0 ꢀC. The
typical ratio of reagent 5 or 6 to arenes 7–10 was equal to about 1:5.
The lower excess of arenes 7–10 appeared to reduce the reaction
N-Acyliminium ions are important intermediates in organic
synthesis, particularly during syntheses of diverse nitrogen-con-
taining natural products.5 Such reactive intermediates can act as
the electron-deficient carbocations toward weak nucleophiles
providing useful methodologies for both the inter- and intra-
molecular carbon–carbon and carbon–heteroatom bond forma-
tion.6 The N-acyliminium species have been generated in acidic
media from lactams bearing a leaving group in the a-position to the
nitrogen atom. Over the last 40 years, the cationic cyclization in-
volving benzenoid, alkene or alkyne nucleophiles and N-acylimi-
nium ions has found a broad application in the synthesis of cyclic
systems.5 The electrophilic aromatic substitution employing the N-
OH
OH
acyliminium ions generated from
reported so far.
b-lactams, however, has not been
OR
NH
F
N
O
O
2: R = Ac
CH =CH
1
F
3: R =
2
2
* Corresponding author. Tel.: þ48 22 6318788; fax: þ48 22 6326681.
E-mail address: chmiel@icho.edu.pl (M. Chmielewski).
Figure 1.
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.048

B. Zambron´ et al. / Tetrahedron 65 (2009) 4440–4446
4441
MeO
OMe
NR1
O
11: R1 = H (39%)
12: R1 = Bn (40%)
OMe
OMe
OMe
R2
R4
O
R2
O
O
O
R3
+
+
R1HN
NR1
H2N
OMe
7: R2, R3, R4 = H
NH
O
8: R2, R4 = H, R3 = OMe
9: R2, R3 = H, R4 = OMe
10: R3 = H, R2, R4 = OMe
O
R2
14: R1, R2 = H (13%)
16: R1 = H, R2 = OMe (36%)
17: R1 = Bn, R2 = OMe (50%)
OMe
MeO
5: R1 = H
13 (10%)
6: R1 = Bn
15 (7%)
OMe
O
OMe
MeO
O
OMe
OMe
+
BnHN
BnHN
MeO
OMe
19 (23%)
MeO
OMe
18 (37%)
Scheme 1.
yield by causing a slow decomposition of azetidinones 5 and 6. A
successful alkylation was observed only with arene 8 where com-
pounds 11 and 12 were formed in about 40% yield. In the case of
arenes 7, 9, and 10 the products of double alkylation 14–18 were
obtained. Reaction of azetidinone 5 with anisole (7) gave two
regioisomeric products 14 and 15 in a ratio of about 2:1, respectively.
In the latter case, the careful examination of the post-reaction
mixtureallowedalsoto isolate the desired monosubstituted product
13 in 10% yield. The possible reaction pathway involves the alkyl-
ation of arene to form a reactive complex 209 in the first step
(Scheme 2). Owing to the stabilization of a partial positive charge at
C-4 of the azetidinone ring by the nucleophilic arene and, further-
O
O
O
MeOH
O
O
OMe
N
O
Ts
NH
NH
Ts
Ts
22
21
23
Scheme 3.
MeO
OTBS
OTBS
more, owing to the coordination of the b-lactam carbonyl group by
OAc
NH
24
a Lewis acid, the heterolytic cleavage of the C(4)–N bond in the
complex 20 is facilitated. Consequently, a second molecule of arene
approaches the C-4 carbon atom causing a nucleophilic substitution
against the nitrogen atom. The reaction proceeds with opening of
the four-membered ring leading to compounds 14–18. The second
alkylation process is probably faster than the first one. In the case of
arene 8 when alkylation at the para position is not possible, the
second alkylation step does not take place and consequently, the
expected products 11 and 12 are formed in about 40% yield. This is
probably also the case of formation of compound 13; the first
alkylation may occur at para or ortho position, but the second one at
para only.
OMe
NH
O
O
25 (33%)
Figure 2.
Analogous processes have been observed by us for adducts of tosyl
isocyanate to glycals 21, which underwent a rapid opening of the four-
membered
sponding glycosides 22, whereas upon standing they underwent
rearrangement to
-unsaturated amides 23 (Scheme 3).10 In that case
b-lactam ring in the presence of an alcohol to form corre-
a,b
the activation of the C–N bond of the azetidinone ring was achieved by
the electron withdrawing substituent at the nitrogen atom.
It should be noted that the commercially available Kaneka azetidi-
none 24,11 in the presence of Lewis acids, undergoes an analogous re-
action with the nucleophilic arenes as the azetidinones 5 and 6. The
desired alkylationproduct 25 was formed in a modest 33% yield, only in
reaction of azetidinone 24 with arene 8 (Fig. 2). The reaction of azeti-
dinone 24 with other nucleophilic arenes 7, 9, and10 led to the complex
mixtures of products, which were not investigated further.
OMe
OMe
R2
N
R2
R2
- H
19
R2
14 - 18
R1
LA
O
The intramolecular alkylation of nucleophilic arenes by acyl-
iminium cations is more effective since the second alkylation step
is not possible (Scheme 4). Consequently, the chemical reaction
yield is much higher. The substrates 27a–e suitable for the intra-
molecular process were obtained by the N-alkylation of the
20: R1= H, Bn
R2= H, OMe
Scheme 2.

4442
B. Zambron´ et al. / Tetrahedron 65 (2009) 4440–4446
OMe
R1
O
OMe
R2
OMe
R2
Br
R1
R1
O
( )n
O
O
R2
LA
O3
N
N
26a: n=2, R1=R2=H
NH
( )n
( )n
O
O
O
26b: n=2, R1=H, R2=OMe
26c: n=2, R1=OMe, R2=H
26d: n=3, R1=OMe, R2=H
26e: n=4, R1=OMe, R2=H
27a: n=2, R1=R2=H
(52%)
28a: n=2, R1,R2=H
(57%)
27b: n=2, R1=H, R2=OMe (20%)
27c: n=2, R1=OMe, R2=H (42%)
27d: n=3, R1=OMe, R2=H (60%)
27e: n=4, R1=OMe, R2=H (57%)
28b: n=2, R1=H, R2=OMe (63%)
28c: n=2, R1=OMe, R2=H (67%)
28d: n=3, R1=OMe, R2=H (73%)
28e: n=4, R1=OMe, R2=H (64%)
R2
MeO
OMe
MeO
OMe
R1
R3
4a
5
R4
11b
8
LA
9a
4
10a
4
6a
6
9b
5a
5
11a
10b
N
N
N
6
3
3
5
O
9
O
O
7
29: n=2; R1,R2,R4=H; R3=OMe (83%)
30: n=2; R1=OMe; R2,R3,R4=H (17%)
31: n=2; R1,R4=OMe; R2,R3=H (79%)
32: n=3; R1,R4=H; R2,R3=OMe (88%)
33 (97%)
34 (28%)
Scheme 4.
azetidinone 3 with arenes 26a–e using the standard phase-
transfer procedure. Compounds 27a–e were subsequently
subjected to ozonolysis to corresponding formates 28a–e. The
intramolecular electrophilic alkylation was performed in the
presence of 1 equiv of Lewis acid such as BF3$OEt2, SnCl4, TMS-OTf,
TiCl4, Yb(OTf)3, InCl3, SnCl2/TMSCl at 0 ꢀC. The expected products
29–34 were obtained in a good overall yield. The best results (up
to 97%) were noticed for SnCl4. In the case of 28a two regioisomers
29 and 30, in a ratio of about 5:1, were obtained. We did not
observe formation of side products having dimeric structures.
4.2. Synthesis of N-benzyl-4-(vinyloxy)azetidin-2-one (4)
To a vigorously stirred mixture of the benzyl bromide (2.26 g,
13.3 mmol) and TBAB (2.85 g, 8.8 mmol) in 50% NaOH (100 mL)/
toluene (100 mL) was added a solution of 4-vinyloxyazetidin-2-
one (3) (1 g, 8.8 mmol) in toluene (20 mL) dropwise at room
temperature within 15 min. The mixture was then poured into
water (200 mL) and extracted with toluene (100 mL). The ex-
tract was dried over MgSO4 and concentrated. Purification of
the crude product by column chromatography on silica gel using
acetone/hexane mixture as an eluant afforded 4 as a colorless
oil. Yield 88%; Rf (25% acetone/hexane) 0.47; 1H NMR (500 MHz,
3. Conclusion
CDCl3)
d
: 7.37–7.25 (m, 5H), 6.29 (dd, J¼14.2, 6.7 Hz, 1H), 5.14
(dd, J¼3.7, 1.2 Hz, 1H), 4.68 (d, J¼15.2 Hz, 1H), 4.29 (dd, J¼14.2,
2.3 Hz, 1H), 4.14 (dd J¼6.7, 2.3 Hz, 1H), 4.13 (d, J¼15.2 Hz, 1H),
3.15 (dd, J¼14.9, 3.7 Hz, 1H), 2.93 (dd, J¼14.9, 1.2 Hz, 1H); 13C
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 aryl-methyl
ethers as an intramolecular process. On the other hand, the in-
termolecular alkylation has limited applicability, and it can be
performed in the case of p-dimethoxybenzene only.
NMR (125 MHz, CDCl3) d: 165.2, 147.9, 135.2, 128.8, 128.3, 127.9,
91.2, 79.5, 44.9, 44.5; IR (CH2Cl2): 3032, 1770, 1641, 1621, 1394,
1195, 1075, 719 cmꢁ1
; HRMS (ESI) calcd for C12H13NO2Na:
226.0839 [MþNa]þ, found 226.0848.
4. Experimental section
4.1. General
4.3. Synthesis of N-benzyl-4-(formyloxy)azetidin-2-one (6)
A mixture of 4 (1 g, 4.9 mmol) and saturated ethanolic so-
lution of ozonizable dye Sudan red 7B (0.1 mL) in anhydrous
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 (0.5 mL) was added and
the solution was brought to the room temperature and stirred
for 30 min. Evaporation of solvent and purification of crude
product by column chromatography on silica gel using acetone/
hexane mixture as an eluant afforded compound 6 as a colorless
oil. Yield 66%; Rf (25% acetone/hexane) 0.41; 1H NMR (500 MHz,
IR spectra were recorded on FT-IR-1600 Perkin–Elmer spec-
trometer. The 1H NMR and 13C NMR spectra were measured on
a Bruker AM 500 spectrometer. 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 chromatography on silica gel (Merck Kie-
selgel 230–400 mesh). The ozonolysis was carried out using Buchi
Ozone Generator OZI.
Anhydrous THF was distilled from LiAlH4 and CH2Cl2 was dis-
tilled from CaH2. Compounds 3 and 5 were obtained following
known procedures.7
Bromides 26a–e were obtained from commercially available
corresponding alcohols or acids according to standard pro-
cedures12,13 and their properties were consistent with the pub-
lished values.14
CDCl3)
d
: 7.98 (s, 1H), 7.37–7.28 (m, 5H), 6.01 (d, J¼3.9 Hz, 1H),
4.56 (d, J¼15.2 Hz, 1H), 4.23 (d, J¼15.2 Hz, 1H), 3.30 (dd, J¼15.1,
3.9 Hz, 1H), 3.01 (d, J¼15.1 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d:
164.9, 160.1, 135.4, 128.8, 128.3, 127.9, 75.6, 45.2, 45.0; IR
(CH2Cl2): 3032, 2938, 1771, 1725, 1391, 1352, 1151, 1091, 1010,
709 cmꢁ1
;
HRMS (ESI) calcd for C11H11NO3Na: 228.0631
[MþNa]þ, found 228.0629.

B. Zambron´ et al. / Tetrahedron 65 (2009) 4440–4446
4443
4.4. Alkylation of nucleophilic arenes 7–10 by 4-formyloxy-
azetidin-2-one (5) and 1-benzyl-4-formyloxy-azetidin-2-one
(6). General procedure
4.4.6. 3,3-Bis-(20,40-dimethoxyphenyl)-propionamide (16)
Yield 36%; colorless needles, mp 115–117 ꢀC; Rf (50% acetone/
hexane) 0.38; 1H NMR (500 MHz, CDCl3)
d
: 7.05 (d, J¼8.2 Hz, 2H),
6.44–6.39 (m, 4H), 5.66 (br s, 1H), 5.41 (br s, 1H), 4.95 (t, J¼8.0 Hz,
To a mixture of azetidinone 5 or 6 (0.3 mmol) and arenes 7–10
(1.5 mmol) in anhydrous CH2Cl2 (5 mL) the solution of SnCl4 in
anhydrous CH2Cl2 (1 M, 0.3 mL, 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). Sub-
sequently a saturated water solution of NaHCO3 (1 mL) was added,
and stirring was continued for 10 min. The mixture was then
poured into the water (20 mL) and extracted with CH2Cl2 (20 mL).
The organic 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
11–19.
1H), 3.77 (s, 6H), 376 (s, 6H), 2.93 (d, J¼8.0 Hz, 2H); 13C NMR
(125 MHz, CDCl3) d: 174.6 159.4, 157.9, 128.8, 123.9, 104.1, 98.9, 55.6,
55.3, 36.7, 34.0; IR (CH2Cl2): 3347, 3194, 2957, 2938, 1663, 1610,
1587, 1504, 1208, 1034, 832, 772 cmꢁ1; HRMS (EI) calcd for
C19H23NO5: 345.1576 [M]þ, found 345.1564.
4.4.7. N-Benzyl-3,3-bis-(20,40-dimethoxyphenyl)-propion-
amide (17)
Yield 50%; colorless needles, mp 137–138 ꢀC; Rf (35% acetone/
hexane) 0.20; 1H NMR (500 MHz, CDCl3)
d: 7.21 (m, 1H), 7.21 (d,
J¼2.5 Hz, 2H), 7.09 (d, J¼8.4 Hz, 2H), 6.96–6.92 (m, 2H), 6.41 (dd,
J¼8.4, 2.5 Hz, 2H), 6.38 (d, J¼2.5 Hz, 2H), 5.97 (br s, 1H), 4.97 (t,
J¼8.2 Hz, 1H), 4.32 (d, J¼5.5 Hz, 2H), 3.77 (s, 6H), 3.68 (s, 6H), 2.97
4.4.1. 4-(2,5-Dimethoxyphenyl)-azetidin-2-one (11)
(d, J¼8.2 Hz, 2H); 13C NMR (125 MHz, CDCl3)
d: 171.8, 159.3, 157.8,
Yield 39%; colorless needles, mp 135–136 ꢀC; Rf (35% acetone/
138.3, 128.9, 128.4, 127.5, 127.1, 123.9, 104.1, 98.9, 55.4, 55.3, 43.4,
41.4, 33.9; IR (CH2Cl2): 3290, 2956, 2936, 1645, 1611, 1504, 1208,
1035, 832 cmꢁ1; HRMS (EI) calcd for C26H29NO5: 435.2046 [M]þ,
found 435.2054.
hexane) 0.22; 1H NMR (500 MHz, CDCl3)
d
: 6.91 (d, J¼1.5 Hz, 1H),
6.8 (d, J¼2.3 Hz, 2H), 6.26 (br s,1H), 4.94 (dd, J¼5.4, 2.6 Hz,1H), 3.80
(s, 3H), 3.78 (s, 3H), 3.41 (ddd, J¼14.8, 5.4, 2.6 Hz), 2.84 (dd, J¼14.8,
2.6 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d: 168.3, 153.7, 151.1, 129.4,
113.0, 112.2, 111.3, 55.81, 55.78, 46.1, 45.9; IR (CH2Cl2): 3233, 1739,
1500, 1217 cmꢁ1; HRMS (EI) calcd for C11H13NO3: 207.0895 [M]þ,
found 207.0886.
4.4.8. N-Benzyl-3,3-bis(20,40,60-trimethoxyphenyl)-propan-
amide (18)
Yield 37%; colorless needles, mp 148–149 ꢀC; Rf (50% acetone/
hexane) 0.44; 1H NMR (500 MHz, CDCl3)
d: 7.23–7.20 (m, 3H), 7.06–
4.4.2. N-Benzyl-4-(2,5-dimethoxyphenyl)azetidin-2-one (12)
Yield 40%; colorless oil; Rf (50% acetone/hexane) 0.36; 1H NMR
7.02 (m, 2H), 6.22 (br s, 1H), 6.02 (s, 4H), 5.16 (t, J¼8.3 Hz, 1H), 4.35
(d, J¼5.5 Hz, 2H), 3.75 (s, 6H), 3.63 (s, 12H), 3.18 (d, J¼8.3 Hz, 2H);
(500 MHz, CDCl3)
d: 7.31–7.23 (m, 3H), 7.19–7.16 (m, 2H), 6.80–6.78
13C NMR (125 MHz, CDCl3)
d: 173.5, 161.6, 159.1, 138.7, 128.4, 127.7,
(m, 3H), 4.78 (dd, J¼5.4, 2.5 Hz, 1H), 4.74 (d, J¼15.1 Hz, 1H), 3.92 (d,
127.0, 113.0, 93.0, 55.3, 55.1, 43.4, 40.1, 29.1; IR (CH2Cl2): 3315, 2937,
2835, 1652, 1603, 1591, 1454, 1228, 1203, 1150, 1126 cmꢁ1; HRMS
(EI) calcd for C28H33NO7: 495.2257 [M]þ, found 495.2246.
J¼15.1 Hz,1H), 3.72 (s, 3H), 3.70 (s, 3H), 3.31 (dd, J¼14.6, 5.4 Hz,1H),
2.85 (dd, J¼14.6, 2.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d: 167.9,
153.9, 151.7, 136.0, 128.6, 128.5, 127.5, 127.3, 113.6, 112.7, 111.9, 55.9,
55.7, 48.9, 45.6, 45.3; IR (CH2Cl2): 2953,1751,1501,1218,1045 cmꢁ1
HRMS (EI) calcd for C18H19NO3: 297.1365 [M]þ, found 207.1370.
;
4.4.9. (E)-N-Benzyl-3-(20,40,60-trimethoxyphenyl)-acrylamide (19)
Yield 23%; colorless needles, mp 162–163 ꢀC; Rf (50% acetone/
hexane) 0.56; 1H NMR (500 MHz, CDCl3)
d
: 8.04 (d, J¼15.9 Hz, 1H),
4.4.3. 4-(2-Methoxyphenyl)azetidin-2-one (13)
7.35–7.31 (m, 4H), 7.27 (m, 1H), 6.77 (d, J¼15.9 Hz, 1H), 6.11 (s, 2H),
Yield 10%; colorless needles, mp 146–149 ꢀC; Rf (50% acetone/
5.82 (br s, 1H), 4.57 (d, J¼5.5 Hz, 2H), 3.84 (s, 6H), 3.83 (s, 3H); 13C
hexane) 0.86; 1H NMR (500 MHz, CDCl3)
d: 7.34–7.27 (m, 2H), 7.29
NMR (125 MHz, CDCl3) d: 167.9, 162.2, 161.0, 138.9, 131.9, 128.6,
(dt, J¼7.5, 0.9 Hz,1H), 6.88 (d, J¼8.2 Hz,1H), 6.14 (br s, 1H), 4.96 (dd,
128.0, 127.3, 120.2, 106.1, 90.5, 55.7, 55.3, 43.8; IR (CH2Cl2): 3278,
2938, 1647, 1600, 1580, 1324, 1210, 1203, 1157, 1122, 1033, 812,
700 cmꢁ1; HRMS (EI) calcd for C26H29NO5: 327.1471 [M]þ, found
327.1458.
J¼5.3, 2.6 Hz, 1H), 3.84 (s, 3H), 3.41 (ddd, J¼14.8, 5.4, 2.6 Hz, 1H),
2.87 (ddd, J¼14.8, 2.7, 0.9 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d:
168.3, 157.0, 129.0, 128.2, 125.7, 120.6, 110.3, 96.1, 55.3, 46.0, 45.9; IR
(CH2Cl2): 3193, 1747, 1712, 1494, 1250, 1027, 749 cmꢁ1; HRMS (EI)
calcd for C10H11NO2: 177.0790 [M]þ, found 177.0787.
4.4.10. (10R,3R,4R)-3-(10-tert-Butyldimethylsilyloxy-ethyl)-4-(2,5-
dimethoxyphenyl)-azetidin-2-one (25)
4.4.4. 3,3-Bis-(40-methoxyphenyl)-propionamide (14)
Compound 24 was obtained from 23 according to the general
procedure described above. Yield 33%; colorless needles, mp 148–
Yield 13%; colorless oil; Rf (50% acetone/hexane) 0.55; 1H NMR
(500 MHz, DMSO-d6)
d
: 7.26 (br s, 1H), 7.13 (d, J¼8.7 Hz, 4H), 6.81
151 ꢀC; Rf (25% acetone/hexane) 0.45; 1H NMR (500 MHz, CDCl3)
d:
(d, J¼8.7 Hz, 4H), 6.66 (br s, 1H), 4.35 (t, J¼8.0 Hz, 1H), 3.69 (s, 6H),
6.96 (d, J¼2.3 Hz, 1H), 6.80–6.79 (m, 2H), 5.97 (br s, 1H), 5.05 (d,
J¼2.3 Hz, 1H), 4.31 (m, 1H), 3.81 (s, 3H), 3.77 (s, 3H), 3.10 (m, 1H),
1.27 (d, J¼6.3 Hz, 3H), 0.9 (s, 9H), 0.11 (s, 3H), 0.10 (s, 3H); 13C NMR
2.73 ppm (d, J¼8.0 Hz, 2H); 13C NMR (125 MHz, DMSO-d6)
d: 172.2,
157.4, 136.8, 128.3, 113.6, 54.9, 44.9, 41.4; IR (CH2Cl2): 3346, 3191,
1666, 1509, 1246, 1177, 1027, 825 cmꢁ1; HRMS (EI) calcd for
C17H19NO3: 285.1365 [M]þ, found 285.1360.
(125 MHz, CDCl3) d: 169.2, 153.8, 151.2, 129.4, 113.14, 113.05, 111.4,
66.9, 65.1, 55.8, 55.6, 47.9, 25.8, 22.3, 18.0, ꢁ4.3, ꢁ5.0; IR (CH2Cl2):
3170, 1926, 1752, 1034, 777 cmꢁ1; HRMS (EI) calcd for C19H31NO4Si:
365.2022 [M]þ, found 365.2029.
4.4.5. 3-(20-Methoxyphenyl)-3-(40-methoxyphenyl)-propion-
amide (15)
Yield 7%; colorless needles, mp 97–100 ꢀC; Rf (50% acetone/
4.5. General procedure for synthesis of N-substituted-4-
vinyloxyazetidin-2-ones 27a–e
hexane) 0.51; 1H NMR (500 MHz, CDCl3)
d
: 7.22–7.12 (m, 4H), 6.93–
6.79 (m, 4H), 5.53–5.30 (m, 2H), 4.83 (t, J¼8.0 Hz, 1H), 3.79 (s, 3H),
3.76 (s, 3H), 2.97 (m,1H), 2.90 (m,1H); 13C NMR (125 MHz, CDCl3)
d:
To a vigorously stirred mixture of alkyl–aryl bromides 26a–e
(17.7 mmol) and TBAB (2.85 g, 8.8 mmol) in 50% NaOH (100 mL)/
toluene (100 mL) was added a solution of 4-vinyloxyazetidin-2-one
(3) (1 g, 8.8 mmol) and a second portion of alkyl-aryl bromide
(17.7 mmol) in 20 mL of toluene dropwise at 0 ꢀC within 2 h. The
174.1, 158.1, 156.7, 135.2, 132.2, 128.9, 127.8, 127.7, 120.7, 113.8, 111.0,
55.5, 55.2, 41.6, 39.9; IR (CH2Cl2): 3333, 3192, 1663, 1511, 1246, 1179,
1030, 755 cmꢁ1; HRMS (EI) calcd for C17H19NO3: 285.1365 [M]þ,
found 285.1354.

4444
B. Zambron´ et al. / Tetrahedron 65 (2009) 4440–4446
mixture was then poured into the water (200 mL) and extracted
with toluene (100 mL). The organic extracts were dried over MgSO4
and concentrated. Purification of residue by column chromatography
on silica gel using acetone/hexane mixture as eluant afforded corre-
sponding products as colorless oils.
111.30, 91.12, 80.19, 55.93, 55.83, 44.74, 40.63, 34.81, 28.80, 27.46; IR
(CH2Cl2): 2936, 1766, 1516, 1261, 1028 cmꢁ1; HRMS (ESI) calcd for
C17H23NO4Na: 328.1519 [MþNa]þ, found 328.1514.
4.6. Synthesis of N-alkyl-aryl-4-formyloxy-azetidin-2-nones
28a–e
4.5.1. 1-(30-Methoxyphenethyl)-4-vinyloxy-azetidin-2-one (27a)
Yield 52%; Rf (30% acetone/hexane) 0.53; 1H NMR (500 MHz,
N-Alkyl-aryl-4-formyloxy-azetidin-2-nones 28a–e were pre-
pared from compounds 27a–e according to procedure described
for 6.
CDCl3)
d
: 7.22 (t, J¼7.8 Hz, 1H), 6.81–6.74 (m, 3H), 6.29 (dd, J¼14.3,
6.7 Hz, 1H), 5.07 (dd, J¼3.6, 1.0 Hz, 1H), 4.32 (dd, J¼14.3, 2.2 Hz, 1H),
4.18 (dd, J¼6.7, 2.2 Hz, 1H), 3.80 (s, 3H), 3.57 (ddd, J¼14.2, 8.2,
6.0 Hz, 1H), 3.40 (dt, J¼14.2, 7.8 Hz, 1H), 3.08 (dd, J¼14.8, 3.6 Hz,
1H), 2.95–2.81 (m, 2H), 2.83 (br d, J¼14.8 Hz, 1H); 13C NMR
4.6.1. N-[20-(300-Methoxyphenyl-ethyl)-4-formyloxy-azetidin-
2-one (28a)
(125 MHz, CDCl3)
d
: 165.3, 159.9, 147.9, 139.9, 129.6, 120.9, 114.3,
Yield 57%; colorless oil; Rf (30% acetone/hexane) 0.50; 1H NMR
112.1, 91.2, 80.6, 55.2, 44.8, 41.9, 34.5; IR (CH2Cl2): 2938, 1767, 1621,
(500 MHz, CDCl3)
d
: 8.01 (d, J¼0.6 Hz, 1H), 7.21 (t, J¼7.8 Hz, 1H),
1398, 1262, 1194 cmꢁ1
;
HRMS (ESI) calcd for C14H13NO3Na:
6.80–6.74 (m, 3H), 5.93 (ddd, J¼3.9, 1.2, 0.6 Hz, 1H), 3.80 (s, 3H),
3.60 (ddd, J¼14.2, 8.4, 6.8 Hz,1H), 3.35 (ddd, J¼14.2, 8.3, 6.3 Hz,1H),
3.21 (dd, J¼15.0, 3.9 Hz, 1H), 2.93 (ddd, J¼13.7, 8.4, 6.3 Hz, 1H), 2.92
(br d, J¼15.0, 1H), 2.85 (ddd, J¼13.7, 8.3, 6.8 Hz, 1H); 13C NMR
270.1101 [MþNa]þ, found 270.1091.
4.5.2. 1-(20,50-Dimethoxyphenethyl)-4-vinyloxy-azetidin-2-
one (27b)
(125 MHz, CDCl3) d: 164.9, 160.3, 159.8, 139.6, 129.6, 121.0, 114.3,
Yield 20%; Rf (30% acetone/hexane) 0.49; 1H NMR (500 MHz,
112.2, 76.0, 55.2, 44.6, 42.5, 34.3; IR (CH2Cl2): 2939,1771,1727,1262,
1397, 1154, 1100, 1009 cmꢁ1; HRMS (EI) calcd for C13H15O4N:
249.1001 [M]þ, found: 249.1008.
CDCl3)
d
: 6.79–6.73 (m, 3H), 6.29 (dd, J¼12.4, 6.7 Hz, 1H), 5.09 (dd,
J¼3.7, 1.1 Hz, 1H), 4.33 (dd, J¼14.2, 2.2 Hz, 1H), 4.16 (dd, J¼6.7,
2.2 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.56 (ddd, J¼14.1, 7.8, 6.4 Hz,
1H) 3.37 (dt, J¼14.1, 7.5 Hz, 1H), 3.06 (dd, J¼14.8, 3.7 Hz, 1H), 2.92–
2.80 (m, 2H), 2.82 (dd, J¼14.8, 1.1 Hz, 1H); 13C NMR (125 MHz,
4.6.2. N-[20-(200,500-Dimethoxyphenyl-ethyl)]-4-formyloxy-azetidin-
2-one (28b)
CDCl3):
d
165.3, 153.6, 151.9, 148.1, 127.8, 116.7, 112.2, 111.3, 96.1, 91.1,
Yield 63%; colorless oil; Rf (30% acetone/hexane) 0.46; 1H NMR
80.5, 55.8, 55.7, 44.7, 40.4, 29.6; IR (CH2Cl2): 2935, 1767, 1640, 1502,
1224, 1046 cmꢁ1; HRMS (EI) calcd for C15H19O4N: 277.1314 [M]þ,
found: 277.1321.
(500 MHz, CDCl3)
d
: 7.97 (d, J¼0.7 Hz, 1H), 6.78–6.71 (m, 2H), 6.72
(s, 1H), 5.97 (dt, J¼3.9, 0.7 Hz, 1H), 3.78 (s, 3H), 3.75 (s, 3H), 3.58 (dt,
J¼14.1, 7.4 Hz, 1H), 3.34 (ddd, J¼14.1, 7.2, 6.6 Hz, 1H), 3.19 (dd,
J¼15.0, 3.9 Hz,1H), 2.91–2.86 (m, 3H); 13C NMR (125 MHz, CDCl3)
d:
4.5.3. 1-(30,40-Dimethoxyphenethyl)-4-vinyloxy-azetidin-2-
one (27c)
164.9, 160.2, 153.5, 151.9, 127.6, 116.8, 112.2, 111.3, 76.0, 55.8, 55.7,
44.6, 41.1, 29.5; IR (CH2Cl2): 2939,1773,1728,1503,1225,1158,1089,
1046 cmꢁ1; HRMS (EI) calcd for C14H17O5N: 279.1107 [M]þ, found:
279.1102.
Yield 42%; Rf (25% acetone/hexane) 0.40; 1H NMR (500 MHz,
CDCl3)
d
: 6.81 (d, J¼7.9 Hz, 1H), 6.74 (dd, J¼7.9, 2.0 Hz, 1H), 6.73
(s, 1H), 6.31 (dd, J¼14.2, 6.7 Hz, 1H), 5.06 (dd, J¼3.6, 1.0 Hz, 1H),
3.42 (dd, J¼14.2, 2.2 Hz, 1H), 4.18 (dd, 6.7, 2.2 Hz, 1H), 3.86 (s, 3H),
3.87 (s, 3H), 3.55 (ddd, J¼14.2, 8.4, 6.0 Hz, 1H), 3.38 (dt, J¼14.2,
7.9 Hz, 1H), 3.07 (dd, J¼14.8, 3.6 Hz, 1H), 2.92–2.79 (m, 3H); 13C
4.6.3. N-[20-(300,400-Dimethoxyphenyl-ethyl)]-4-formyloxy-azetidin-
2-one (28c)
Yield 67%; colorless oil; Rf (25% acetone/hexane) 0.36; 1H NMR
NMR (125 MHz, CDCl3)
d: 165.3, 149.1, 147.84, 147.80, 130.8, 120.6,
(500 MHz, CDCl3)
d
: 8.03 (s, 1H), 6.80 (br d, J¼8.8 Hz, 1H), 6.74 (dd,
111.9, 111.4, 91.2, 80.5, 55.92, 55.89, 44.8, 42.1, 34.0; IR (CH2Cl2):
2936, 1767, 1517, 1264, 1028 cmꢁ1; HRMS (EI) calcd for C15H19O4N:
277.1314 [M]þ, found: 277.1308.
J¼8.8, 2.0 Hz, 1H), 6.73 (s, 1H), 5.93 (br d, J¼4.0, 1H), 3.88 (s, 3H),
3.85 (s, 3H), 3.59 (ddd, J¼14.2, 8.4, 6.8 Hz, 1H), 3.33 (ddd, J¼14.2,
8.4, 6.2 Hz, 1H), 3.20 (dd, J¼15.0, 4.0 Hz, 1H), 2.93 (br d, J¼15.0 Hz,
1H), 2.91 (ddd, J¼13.8, 8.4, 6.2 Hz,1H), 2.82 (ddd, J¼13.8, 8.4, 6.8 Hz,
4.5.4. N-[30-(300,400-Dimethoxyphenyl)-propyl]-4-vinyloxy-azetidin-
2-one (27d)
1H); 13C NMR (125 MHz, CDCl3)
d: 165.0, 160.4, 149.1, 147.8, 130.5,
120.7, 111.9, 111.4, 76.0, 55.90, 55.87, 44.6, 42.7, 33.8; IR (CH2Cl2):
2937, 1771, 1725, 1517, 1264, 1158, 1143, 1027 cmꢁ1; HRMS (ESI)
calcd for C14H17NO5Na: 302.1012 [MþNa]þ, found 302.1013.
Yield 60%; Rf (35% acetone/hexane) 0.55; 1H NMR (500 MHz,
CDCl3)
d
: 6.80 (br d, J¼7.9 Hz,1H), 6.73 (s,1H), 6.72 (br d, J¼7.9, 2 Hz,
1H) 6.38 (dd, J¼14.3, 6.7 Hz, 1H), 5.21 (dd, J¼3.6, 1.0 Hz, 1H), 4.34
(dd, J¼14.3, 2.2 Hz,1H), 4.20 (dd, J¼6.7, 2.2 Hz,1H), 3.88 (s, 3H), 3.85
(s, 3H), 3.25 (t, J¼7.1 Hz, 2H), 3.11 (dd, J¼14.8, 3.6 Hz, 1H), 2.87 (br d,
J¼14.8 Hz, 1H), 2.66–2.55 (m, 2H), 1.97–1.83 (m, 2H); 13C NMR
4.6.4. N-[30-(300,400-Dimethoxyphenyl-propyl)]-4-formyloxy-
azetidin-2-one (28d)
Yield 73%; colorless oil; Rf (35% acetone/hexane) 0.51; 1H NMR
(125 MHz, CDCl3)
d
: 165.5, 148.9, 147.7, 147.4, 133.7, 120.2, 111.9,
(500 MHz, CDCl3)
d
: 8.09 (s, 1H), 6.79 (d, J¼7.8 Hz, 1H), 6.73 (s, 1H),
111.4, 91.4, 80.3, 55.9, 55.8, 44.8, 40.5, 32.8, 29.8; IR (CH2Cl2): 2937,
1766, 1516, 1261, 1028 cmꢁ1; HRMS (EI) calcd for C16H21O4N:
291.1471 [M]þ, found: 291.1479.
6.72 (dd, J¼7.8, 2 Hz, 1H), 6.03 (d, J¼3.9 Hz, 1H), 3.88 (s, 3H), 3.85 (s,
3H), 3.34 (dt, J¼14.2, 7.4 Hz, 1H), 3.22 (dd, J¼15.0, 3.9 Hz, 1H), 3.13
(dt, J¼14.2, 6.8 Hz,1H), 2.93 (d, J¼15.0 Hz,1H), 2.59 (t, J¼7.5 Hz, 2H),
1.97–1.84 (m, 2H); 13C NMR (125 MHz, CDCl3)
d: 165.0, 160.3, 148.9,
4.5.5. N-[40-(300,400-Dimethoxyphenyl)butyl]-4-vinyloxy-azetidin-2-
one (27e)
147.4, 133.5, 120.1, 111.8, 111.4, 76.0, 55.9, 55.8, 44.7, 40.8, 32.7, 29.5;
IR (CH2Cl2): 2937, 1770, 1726, 1516, 1261, 1156, 1027 cmꢁ1; HRMS
(ESI) calcd for C15H19NO5Na: 316.1155 [MþNa]þ, found 316.1154.
Yield 57%; Rf (35% acetone/hexane) 0.49; 1H NMR (500 MHz,
CDCl3)
d
: 6.79 (d, J¼7.8 Hz, 1H), 6.71 (dd, J¼7.8, 2.0 Hz, 1H), 6.70 (s,
1H), 6.36 (dd, J¼14.3, 6.7 Hz, 1H), 5.22 (dd, J¼3.6, 1.0 Hz, 1H), 4.33
(dd, J¼14.3, 2.2 Hz,1H), 4.20 (dd, J¼6.7, 2.2 Hz,1H), 3.87 (s, 3H), 3.85
(s, 3H), 3.30–3.18 (m, 2H), 3.11 (dd, J¼14.8, 3.6 Hz, 1H), 2.86 (br d,
J¼14.8 Hz, 1H), 2.62–2.54 (m, 2H), 1.68–1.56 (m, 4H); 13C NMR
4.6.5. N-[40-(300,400-Dimethoxyphenyl-butyl)]-4-formyloxy-azetidin-
2-one (28e)
Yield 64%; colorless oil; Rf (35% acetone/hexane) 0.52; 1H NMR
(500 MHz, CDCl3)
6.72–6.68 (m, 2H), 6.05 (ddd, J¼3.9,1.1, 0.6 Hz,1H), 3.87 (s, 3H), 3.85
d
: 8.07 (d, J¼0.6 Hz, 1H), 6.79 (d, J¼8.7 Hz, 1H),
(125 MHz, CDCl3) d: 165.4, 148.88, 147.25, 134.58, 120.19, 111.81,

B. Zambron´ et al. / Tetrahedron 65 (2009) 4440–4446
4445
(s, 3H), 3.31 (m, 1H), 3.26 (dd, J¼15.0, 3.9 Hz, 1H), 3.14 (m, 1H), 2.94
(d, J¼15.0 Hz, 1H), 2.61–2.54 (m, 2H), 1.67–1.55 (m, 4H); 13C NMR
148.2, 127.5, 126.1, 112.1, 108.7, 56.0, 55.9, 47.3, 45.0, 37.7, 27.7; IR
(CH2Cl2): 2936, 1750, 1515, 1253, 1130 cmꢁ1; HRMS (EI) calcd for
C13H15NO3: 233.1052 [M]þ, found 233.1059.
(125 MHz, CDCl3) d: 165.0, 160.3, 148.9, 147.3, 134.5, 120.2, 111.8,
111.3, 75.9, 55.9, 55.8, 44.7, 41.1, 34.8, 28.7, 27.4; IR (CH2Cl2): 2937,
1770, 7127, 1516, 1261, 1237, 1156, 1144, 1028, 1011 cmꢁ1; HRMS (EI)
calcd for C16H21O5N: 307.1420 [M]þ, found: 307.1414.
4.7.5. 8,9-Dimethoxy-1,5,6,10b-tetrahydroazeto[1,2-
a]benzo[c]azepin-2(4H)-one (33)
Yield 33% (BF3$OEt2), 97% (SnCl4), 97% (TMS-OTf); colorless
4.7. General procedure for intramolecular alkylation in N-
needles, mp 129–131 ꢀC; Rf (40% acetone/hexane) 0.36; 1H NMR
alkyl-aryl-4-formyloxy-azetidin-2-ones 29–34
(500 MHz, CDCl3)
d
: 6.66 (s, 1H), 6.57 (s, 1H), 4.78 (dd, J¼5.1, 2.3 Hz,
1H), 4.04 (dt, J¼13.4, 4.8 Hz,1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.39 (ddd,
To a solution of compounds 28a–e (0.3 mmol) in anhydrous
CH2Cl2 (5 mL) a Lewis acid (0.3 mmol) was added dropwise at 0 ꢀC
under the argon atmosphere. The mixture was stirred at 0 ꢀC until
disappearance of the substrate (TLC monitoring). The saturated
solution of NaHCO3 (1 mL) was then added, and stirring was con-
tinued for 10 min. The mixture was then poured into the water
(20 mL) and extracted with CH2Cl2 (20 mL). The extracts were dried
over MgSO4 and concentrated. The residue was purified by column
chromatography on silica gel to afford compounds 29–33.
J¼14.3, 5.1, 1.6 Hz, 1H), 3.17–3.10 (m, 2H), 2.92 (m, 1H), 2.84 (m, 1H),
1.93 (m, 1H), 1.74 (m, 1H); 13C NMR (125 MHz, CDCl3)
d: 166.1, 147.7,
147.0, 133.7, 130.7, 113.9, 110.7, 56.2, 56.0, 53.8, 43.4, 43.1, 34.6, 26.4;
IR (CH2Cl2): 2937, 1746, 1519, 1347, 1212, 1115 cmꢁ1; HRMS (ESI)
calcd for C14H17NO3Na: 270.1092 [MþNa]þ, found 270.1101.
4.7.6. 2,3-Dimethoxy-7,8,11,11a-tetrahydro-5H-azeto[1,2-
a]benzo[c]azocin-10(6H)-one (34)
Yield 28% (SnCl4), 19% (TMS-OTf); colorless needles, mp 143–
144 ꢀC; Rf (35% acetone/hexane) 0.49; 1H NMR (500 MHz, CDCl3)
d:
4.7.1. 7-Methoxy-4,5-dihydro-1H-azeto[2,1-a]isoquinolin-2(9bH)-
one (29)
6.66 (s, 1H), 6.62 (s, 1H), 4.72 (dd, J¼5.1, 2.4 Hz, 1H), 3.88 (s, 3H),
3.87 (s, 3H), 3.84 (m, 1H), 3.29 (ddd, J¼14.5, 5.1, 1.5 Hz, 1H), 3.16–
3.08 (m, 2H), 2.92 (dd, J¼14.5, 2.4 Hz, 1H), 2.65 (dt, J¼14.0, 5.6 Hz,
1H), 1.88 (m, 1H), 1.71 (m, 1H), 1.60 (m, 1H), 1.42 (m, 1H); 13C NMR
Yield 65% (BF3$OEt2), 83% (SnCl4), 52% (TMS-OTf); colorless
needles, mp 100–103 ꢀC; Rf (30% acetone/hexane) 0.47; 1H NMR
(500 MHz, CDCl3)
d
: 7.07 (d, J¼8.5 Hz, 1H), 6.82 (dd, J¼8.5, 2.7 Hz,
(125 MHz, CDCl3) d: 166.7,148.6,147.0,131.0,129.1,114.4,110.7, 56.0,
1H), 6.69 (d, J¼2.7 Hz, 1H), 4.51 (dd, J¼5.0, 2.1 Hz, 1H), 3.90 (ddd,
J¼12.9, 6.5, 4.7 Hz, 1H), 3.80 (s, 3H), 3.44 (ddd, J¼14.7, 5.0, 1.0 Hz,
1H), 3.13 (dddd, J¼12.9, 8.7, 5.3, 1.0 Hz, 1H), 3.04 (m, 1H), 2.77 (dd,
55.9, 55.2, 44.3, 41.6, 30.4, 29.4, 22.0; IR (CH2Cl2): 2926, 1742, 1517,
1347, 1256, 1228, 1117 cmꢁ1; HRMS (EI) calcd for C15H19NO3:
261.1365 [M]þ, found 261.1358.
J¼14.7, 2.1 Hz, 1H), 2.73 (m, 1H); 13C NMR (125 MHz, CDCl3)
d:
169.6,158.6,135.5,128.1,127.1,114.1,113.1, 55.3, 47.1, 44.8, 37.8, 28.5;
IR (CH2Cl2): 2938, 1755, 1611, 1503, 1355, 1245, 1036 cmꢁ1; HRMS
(EI) calcd for C12H13NO2: 203.0946 [M]þ, found 203.0950.
Acknowledgements
This work was supported by the Ministry of Education and
Science, grant PBZ-KBN-126/T09/08/2004.
4.7.2. 9-Methoxy-4,5-dihydro-1H-azeto[2,1-a]isoquinolin-2(9bH)-
one (30)
References and notes
Yield 10% (BF3$OEt2), 17% (SnCl4), 15% (TMS-OTf); colorless
needles, mp 56–57 ꢀC; Rf (30% acetone/hexane) 0.44; 1H NMR
1. Rosenblum, S. B.; Huynh, T.; Afonso, A.; Davis, H. R., Jr.; Yumibe, N.; Clader, J. W.;
Burnett, D. A. J. Med. Chem. 1998, 41, 973.
(500 MHz, CDCl3)
d
: 7.19 (t, J¼7.9 Hz, 1H), 6.77–6.72 (m, 2H), 4.53
2. (a) Brown, M.; Burnett, D. A.; Caplen, M. A.; Chen, L. Y.; Clader, J. W.; Domalski,
M.; Dugar, S.; Pushpavanam, P.; Sher, R.; Vaccaro, W.; Viziano, M.; Zhao, H.
Tetrahedron Lett. 1995, 36, 2555; (b) Thiruvengadam, T. K.; Sudhakar, A. R.; Wu,
G. Process Chemistry in the Pharmaceutical Industry; Dekker: New York, NY,
1999; pp 221–242; (c) Wu, G.; Wong, Y. S.; Chen, X.; Ding, Z. J. Org. Chem. 1999,
64, 3714.
3. Clauss, K.; Grimm, D.; Prossel, G. Liebigs Ann. Chem. 1974, 539.
4. The Organic Chemistry of b-Lactams; Georg, G. I., Ed.; VCH: Weinheim, 1993.
5. Maryanoff, B. E.; Zhang, H. C.; Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem.
Rev. 2004, 104, 1431.
6. (a) Royer, J.; Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311; (b) Wanner, M. J.;
van der Haas, R. N. S.; de Cuba, K. R.; van Maarseveen, J. H.; Hiemstra, H. Angew.
Chem., Int. Ed. 2007, 46, 7485; (c) Raheem, I. T.; Thiara, P. S.; Peterson, E. A.;
Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129, 13404; (d) Raheem, I. T.; Thiara, P. S.;
Jacobsen, E. N. Org. Lett. 2008, 10, 1577.
(br d, J¼5.0 Hz, 1H), 4.03 (m, 1H), 3.83 (s, 3H), 3.47 (dd, J¼15.1,
5.0 Hz, 1H), 3.10–2.96 (m, 2H), 2.75–2.66 (m, 2H); 13C NMR
(125 MHz, CDCl3) d: 169.9, 156.8, 135.1, 128.0, 124.1, 121.6, 107.8,
55.3, 44.91, 44.90, 37.2, 28.0; IR (CH2Cl2): 2935, 1755, 1583, 1471,
1260, 1084 cmꢁ1; HRMS (EI) calcd for C12H13NO2: 203.0946 [M]þ,
found 203.0940.
4.7.3. 6,9-Dimethoxy-4,5-dihydro-1H-azeto[2,1-a]isoquinolin-
2(9bH)-one (31)
Yield 14% (BF3$OEt2), 79% (SnCl4), 41% (TMS-OTf); colorless
needles, mp 127–128 ꢀC; Rf (30% acetone/hexane) 0.47; 1H NMR
_
_
(500 MHz, CDCl3)
d
: 6.72 (d, J¼8.9 Hz, 1H), 6.67 (d, J¼8.9 Hz, 1H),
7. (a) Ka1uza, Z.; Park, H. S. Synlett 1996, 895; (b) Ka1uza, Z. Tetrahedron Lett.
_
1998, 39, 8349; (c) Ka1uza, Z.; qysek, R. Tetrahedron: Asymmetry 1997, 8,
4.50 (dd, J¼5.1, 2.3 Hz,1H), 4.06 (ddd, J¼13.5, 7.4,1.4 Hz,1H), 3.79 (s,
3H), 3.78 (s, 3H), 3.47 (ddd, J¼15.1, 5.1, 1.0 Hz, 1H), 2.96–2.84 (m,
2H), 2.74 (m, 1H), 2.69 (dd, J¼15.1, 2.3 Hz, 1H); 13C NMR (125 MHz,
_
2553; (d) Ka1uza, Z. Tetrahedron Lett. 1999, 40, 1025; (e) Furman, B.; Thu¨ rmer,
_
R.; Ka1uza, Z.; qysek, R.; Voelter, W.; Chmielewski, M. Angew. Chem., Int. Ed.
1999, 38, 1121.
_
8. (a) Furman, B.; Ka1uza, Z.; Krajewski, P.; Chmielewski, M. Tetrahedron 2000, 56,
5553; (b) Borsuk, K.; Suwin´ ska, K.; Chmielewski, M. Tetrahedron: Asymmetry
2001, 12, 979; (c) Borsuk, K.; Kazimierski, A.; Solecka, J.; Urban´ czyk-Lipkowska,
Z.; Chmielewski, M. Carbohydr. Res. 2002, 337, 2005; (d) Ka1uza, Z.; Kazimierski,
A.; Lewandowski, K.; Suwin´ ska, K.; Szcze˛sna, B.; Chmielewski, M. Tetrahedron
2003, 59, 5893; (e) qysek, R.; Borsuk, K.; Furman, B.; Ka1uza, Z.; Kazimierski, A.;
Chmielewski, M. Curr. Med. Chem. 2004, 11, 1813; (f) Kazimierski, A.; Ka1uza, Z.;
Chmielewski, M. ARKIVOC 2004, iii, 213; (g) Kozio1, A.; Frelek, J.; Woz´nica, M.;
Furman, B.; Chmielewski, M. Eur. J. Org. Chem. 2009, 338.
9. Matsuo, J.; Sasaki, S.; Tanaka, H.; Ishibashi, H. J. Am. Chem. Soc. 2008, 130, 11600.
CDCl3) d: 169.4, 151.2, 150.8, 125.3, 124.2, 108.7, 107.2, 55.8, 55.5,
45.1, 44.6, 36.6, 21.7; IR (CH2Cl2): 2943, 1754, 1482, 1258,
1086 cmꢁ1; HRMS (EI) calcd for C13H15NO3: 233.1052 [M]þ, found
233.1045.
_
_
_
4.7.4. 7,8-Dimethoxy-4,5-dihydro-1H-azeto[2,1-a]isoquinolin-
2(9bH)-one (32)
Yield 79% (BF3$OEt2), 88% (SnCl4), 70% (TMS-OTf); colorless oil;
_
_
´
10. (a) Chmielewski, M.; Ka1uza, Z.; Be1zecki, C.; Sa1anski, P.; Jurczak, J. Tetrahedron
Rf (30% acetone/hexane) 0.33; 1H NMR (500 MHz, C6D6)
d: 6.27 (s,
_
_
Lett. 1984, 25, 4797; (b) Chmielewski, M.; Ka1uza, Z.; Be1zecki, C.; Sa1an´ ski, P.;
Jurczak, J.; Adamowicz, H. Tetrahedron 1985, 41, 2441; (c) Mostowicz, D.; Be1-
zecki, C.; Chmielewski, M. J. Carbohydr. Chem. 1988, 7, 805; (d) Mostowicz, D.;
1H), 6.25 (s, 1H), 3.99 (dd, J¼5.2, 2.2 Hz, 1H), 3.80 (ddd, J¼13.0, 6.2,
3.5 Hz, 1H), 3.41 (s, 3H), 3.39 (s, 3H), 3.01 (ddd, J¼14.6, 5.2, 1.0 Hz,
1H), 2.69 (m, 1H), 2.60 (m, 1H), 2.43 (dd, J¼14.6, 2.2 Hz, 1H), 2.07
_
Zegrocka, O.; Chmielewski, M. Carbohydr. Res. 1991, 212, 283.
11. (a) Ohashi, T.; Kazunori, K.; Soda, I.; Miyama, A.; Watanabe, K. E.P.A. 167154/
167155, 8.1.1986; E.P.A. 247378, 2.12.1987; (b) Hungerbuhler, E.; E.P.A. 259268,
(dt, J¼15.4, 3.5 Hz, 1H); 13C NMR (125 MHz, CDCl3)
d: 169.5, 148.3,

4446
B. Zambron´ et al. / Tetrahedron 65 (2009) 4440–4446
9.3.1988; (c) Hungerbuhler, E.; Biollaz, M.; Ernst, I.; Kalvoda, J.; Lang, M.;
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