An efficient and diastereoselective synthesis of trans β-lactams and β-aminocarbonyl compounds

Article abstract of DOI:10.1055/s-2005-861803

Efficient and diastereoselective syntheses of trans β-lactams and anti β-aminocarbonyl compounds from carboximide 1 and imines 2 under the classical Reformatsky reaction conditions are described. An enolate-imine mechanism has been proposed for this react

Full text of DOI:10.1055/s-2005-861803

PAPER
725
An Efficient and Diastereoselective Synthesis of trans b-Lactams and b-Amino-
carbonyl Compounds
D
S
iastereoselec
h
tive Synthes
a
is of trans
b
n
-Lactams an
-
d
b
-
Ami
Z
nocarbonyl Com
h
pounds ong Jian, Cheng Ma, Yan-Guang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
Fax +86(571)87951512; E-mail: orgwyg@zju.edu.cn
Received 13 September 2004; revised 25 November 2004
pensive salicylamide according to the literature proce-
Abstract: Efficient and diastereoselective syntheses of trans b-lac-
tams and anti b-aminocarbonyl compounds from carboximide 1 and
imines 2 under the classical Reformatsky reaction conditions are de-
dure,6 with imine derived from aniline and phenyl
aldehyde afforded 100% trans b-lactam and the auxiliary
scribed. An enolate-imine mechanism has been proposed for this re- 4 could be recycled (Scheme 1). The reaction proceeded
action.
in THF under reflux, and was finished within 10–20 min-
utes. The trans configuration was determined by the H-3/
Key words: b-lactams, imines, Reformatsky reaction, b-aminocar-
bonyl compounds
H-4 coupling constant values (Jtrans = 1.5–2.5 Hz; Jcis
.5–6.0 Hz). This fact demonstrated that the use of the
=
4
auxiliary 4 led to an efficient asymmetric induction. We
then examined other imines and the results are summa-
rized in Table 1.
The discovery of penicillin and cephalosporin focused the
attention of synthetic chemists on cis b-lactams. Interest
turned to trans b-lactams when thienamycin and several As shown in Table 1, imines derived from anilines and ar-
other antibiotics were found to belong to the trans family.1 omatic or aliphatic aldehydes gave good-to-satisfactory
Some trans b-lactams are good cholesterol absorption in- yields (50–82%) (Table 1, entries 1–19). Unfortunately,
2
hibitors. The ketene-imine cycloaddition (Staudinger re- N-benzylimine did not react (Table 1, entry 20). Compar-
1
action) and the ester enolate-imine condensation ison of the H NMR spectra of the crude b-lactams with
7
(
Gilman–Speeter reaction) are two major methods for the existing literature data indicated that only the trans iso-
synthesis of b-lactams. Some earlier studies were directed mers were available. There was no b-amino carbonyl 5
toward the formation of trans b-lactams using the formed as the by-products in these reactions, which is usu-
Staudinger reaction, but special conditions, such as high- ally a big trouble for the reported Reformatsky-type reac-
1
power microwave irradiation were required and usually tions. This may be due to the good leaving ability of the
3
gave low yields. The Gilman–Speeter reaction gave al- auxiliary 4, which facilitates the cyclization of the inter-
most always a mixture of cis and trans b-lactams with the mediate (vide infra). However, b-aminocarbonyl com-
4
1
cis isomer predominating. The synthesis of trans b-lac- pounds 5 were the only products when R was ortho-
5
tams using chiral imines also has been reported. Herein, methoxyphenyl group (Scheme 1). As shown in Table 2,
we would like to disclose a novel method for the stereose- the imines derived from both aromatic (Table 2, entries 1–
lective synthesis of trans b-lactams.
4, 6 and 7) and aliphatic aldehydes (Table 2, entries 5 and
) afforded anti b-aminocarbonyl compounds 5 in good
yields (70–85%).
8
Initially, we found that the Refomatsky-type reaction of
carboximide 1, which could be prepared easily from inex-
R1
R3
O
NH
N
trans
3
+
O
R2
O
O
O
R2
R1
N
4
N
Zn
+
Br
THF, reflux
R3
NHR2
R3
O
O
O
N
1
2
R1
O
anti
5
Scheme 1
SYNTHESIS 2005, No. 5, pp 0725–0730
x
x
.
x
x
.2
0
0
5
Advanced online publication: 09.02.2005
DOI: 10.1055/s-2005-861803; Art ID: F13004SS
Georg Thieme Verlag Stuttgart · New York
©

7
26
S.-Z. Jian et al.
PAPER
Table 1 Diastereoselective Synthesis of b-Lactams
a
b
Entry
R1
R2
R3
b-Lactam
3a
3b
3c
Yield (%)
1
2
3
4
5
6
7
8
9
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
Ph
Ph
75
Ph
4-ClPh
4-MeOPh
76
Ph
80
Ph
3,4-(OCH O)Ph
3d
3e
71
2
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
4-ClPh
4-ClPh
4-ClPh
4-ClPh
Ph
Ph
75
4-ClPh
4-MeOPh
3f
72
3g
3h
3i
82
3,4-(OCH O)Ph
79
2
Ph
66
10
11
12
13
14
15
16
17
18
19
20
4-ClPh
4-MeOPh
3j
50
3k
3l
75
3,4-(OCH O)Ph
70
2
Ph
3m
3n
3o
3p
3q
3r
83
Et
4-MeOPh
Ph
4-ClPh
4-MeOPh
79
Et
80
Et
4-MeOPh
Ph
3,4-(OCH O)Ph
82
2
Me
Et
trans-Styryl
trans-Styryl
iso-Propyl
Ph
75
Ph
81
Me
Me
4-MeOPh
Bn
3s
80
–
No reaction
a
1
Determined by H NMR to be 100% trans.
b
Isolated yield based on imine.
Table 2 Diastereoselective Synthesis of b-Amino Carbonyls
R1
R2
R3
b-Amino carbonyl
Yield (%)
a
Entry
1
2
3
4
5
6
7
Me
Me
Me
Me
Me
Et
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
2-MeOPh
Ph
5a
5b
5c
5d
5e
5f
83
76
85
80
70
82
80
80
4-MeOPh
4-ClPh
4-FPh
iso-Propyl
Ph
Et
4-ClPh
iso-propyl
5g
5h
8
Et
a
Isolated yield based on imine.
Synthesis 2005, No. 5, 725–730 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of trans b-Lactams and b-Aminocarbonyl Compounds
727
Two possible mechanisms are suggested for the formation Synthesis of trans b-Lactams 3 and anti b-Aminocarbonyl Com-
pounds 5; General Procedure
A mixture of carboximide 1 (1.2 mmol), imines 2 (1 mmol) and zinc
dust (2 mmol) in THF (5 mL) was refluxed for 10–20 min, cooled
of trans b-lactams: the ketene-imine mechanism and the
enolate-imine mechanism (Scheme 2). The former hy-
pothesized that ketene 6 formed by treatment of 1 with Zn
could be added to imine to give the trans b-lactam. How-
ever, this mechanism could not explain the production of
and poured into water (5 mL), and then extracted with CH Cl (3 ×
2
2
5
mL). The combined extracts were washed with brine, dried over
anhyd Na SO , and evaporated in vacuo. The residue was purified
2
4
5
. The latter mechanism hypothesized that the chair-like by flash column chromatography on silica gel (eluted with hexane–
8
transition state 8 involving the imine and the (Z)-enolate
EtOAc) to give the products.
gave the intermediate 9, which cyclized to produce the
trans b-lactam. The existence of the (Z)-enolate 7, which
was different from the traditional (E)-enolate, had been
trans-3-Methyl-1,4-diphenylazetidin-2-one10 (3a)
Colorless oil.
–
1
6
IR (KBr): 1745 cm .
proved by the literature. Formation of b-amino carbonyl
compounds 5 could also be well explained by this mecha- 1H NMR (500 MHz, CDCl
): d = 1.48 (d, J = 7.4 Hz, 3 H), 3.13 (dq,
3
1
J = 2.4, 7.4 Hz, 1 H, H-3), 4.58 (d, J = 2.4 Hz, 1 H, H-4), 7.02–7.05
nism. When R was ortho-methoxyphenyl group, the
1
(m, 1 H) 7.22–7.39 (m, 9 H).
strong electronegativity of R reduced the nucleophilicity
of the nitrogen, which hindered the subsequent cycliza- ESI–MS: m/z = 238 [M + 1]+.
tion of 9 and 5 formed. Therefore, the enolate-imine
9
trans-4-(4-Chlorophenyl)-3-methyl-1-phenylazetidin-2-one4a
mechanism was more reasonable. Though the structural
determination was not made, we could deduce from the
mechanism that the stereochemistry of the b-amino carbo-
nyl was anti.
(
3b)
Colorless oil.
–
1
IR (film): 1748 cm .
1
H NMR (500 MHz, CDCl ): d = 1.49 (d, J = 7.4 Hz, 3 H), 3.15 (dq,
3
In conclusion, we have developed an efficient method for
the synthesis of trans b-lactams 3 and anti b-amino carbo-
nyl compounds 5 by the Reformatsky-type reaction of
imines 2 with carboximide 1, which was derived from the
recyclable auxiliary 4. The reaction gave high diastereo-
selectivity and satisfactory to good yields.
J = 2.3, 7.4 Hz, 1 H, H-3), 4.56 (d, J = 2.3 Hz, 1 H, H-4), 7.18–7.40
(
m, 9 H).
ESI–MS: m/z = 272 [M + 1]+.
trans-4-(4-Methoxyphenyl)-3-methyl-1-phenylazetidin-2-one4a
(3c)
Yellow solid; mp 76–77 °C.
–
1
IR (KBr): 1745 cm .
1
All chemicals were obtained from commercial suppliers and used
without further purification. Melting points are uncorrected. Flash
column chromatography was carried out on 300–500 mesh silica
gel. IR spectra were recorded on a Perkin-Elmer 983 FT-IR spec-
H NMR (500 MHz, CDCl ): d = 1.48 (d, J = 7.4 Hz, 3 H), 3.11 (dq,
J = 2.2, 7.4 Hz, 1 H, H-3), 3.73 (s, 3 H), 4.56 (d, J = 2.2 Hz, 1 H, H-
4), 6.76–7.38 (m, 9 H).
ESI–MS: m/z = 268 [M + 1]+.
3
1
trometer. H NMR spectra were recorded on a Bruker Avance DMX
5
3
00 instrument. ESI–MS data were obtained on a Bruker Esquire
000 plus instrument. HRMS data were recorded on a Bruker FT-
trans-3-Methyl-4-[3,4-(methyleneoxy)phenyl]-1-phenylazeti-
ICR-MS Apex III apparatus.
4
a
din-2-one (3d)
Colorless oil.
–
1
IR (film): 1746 cm .
O
O
O
O
R1
R2
N
C
N
1
imine
R HC
C
O
3
Br
R1
R3
6
1
ketene-imine mechanism
Zn
BrZn
O
R2
Br
O
N
Zn
O
O
R1
N
R3
imine
O
O
no
N
R1
5
cyclization
N
O
R3
O
O
ZnBr
N
R2
9
R1
7
8
enolate-imine mechanism
Scheme 2
Synthesis 2005, No. 5, 725–730 © Thieme Stuttgart · New York

7
28
S.-Z. Jian et al.
PAPER
1
H NMR (500 MHz, CDCl ): d = 1.45 (d, J = 7.4 Hz, 3 H), 3.09 (dq,
trans-1-(4-Chlorophenyl)-3-methyl-4-[3,4-(methyleneoxyl)phe-
nyl]azetidin-2-one (3l)
3
4
a
J = 2.3, 7.4 Hz, 1 H, H-3), 4.49 (d, J = 2.3 Hz, 1 H, H-4), 5.95 (m,
2
H), 6.78–7.30 (m, 8 H).
Colorless oil.
ESI–MS: m/z = 281 [M + 1]+.
IR (film): 1745 cm–1.
1
H NMR (500 MHz, CDCl ): d = 1.46 (d, J = 7.4 Hz, 3 H), 3.11 (dq,
trans-1-(4-Methoxyphenyl)-3-methyl-4-phenylazetidin-2-one4b
3
J = 2.3, 7.4 Hz, 1 H, H-3), 4.47 (d, J = 2.3 Hz, 1 H, H-4), 5.96 (m,
2
ESI–MS: m/z = 316 [M + 1]+.
(3e)
H), 6.77–7.24 (m, 7 H).
Colorless oil.
–1
IR (film): 1749 cm .
1
trans-3-Ethyl-1,4-diphenylazetidin-2-one4a (3m)
Colorless oil.
H NMR (500 MHz, CDCl ): d = 1.46 (d, J = 7.4 Hz, 3 H), 3.10 (dq,
3
J = 2.2, 7.4 Hz, 1 H, H-3), 3.80 (s, 3 H), 4.53 (d, J = 2.2 Hz, 1 H, H-
4
), 6.89–7.29 (m, 9 H).
IR (film): 1757 cm–1.
ESI–MS: m/z = 268 [M + 1]+.
1
H NMR (500 MHz, CDCl ): d = 1.09 (t, J = 7.4 Hz, 3 H), 1.85 (m,
3
1
7
H), 1.95 (m, 1 H), 3.06 (m, 1 H, H-3), 4.67 (d, J = 2.2 Hz, 1 H),
trans-4-(4-Chlorophenyl)-1-(4-methoxyphenyl)-3-methylazeti-
.02–7.46 (m, 10 H).
din-2-one4 (3f)
b
ESI–MS: m/z = 274 [M + 23]+.
Colorless oil.
–1
IR (film): 1745 cm .
trans-4-(4-Chlorophenyl)-3-ethyl-1-(4-methoxyphenyl)azeti-
din-2-one (3n)
Colorless oil.
1
4a
H NMR (500 MHz, CDCl ): d = 1.46 (d, J = 7.4 Hz, 3 H), 3.10 (dq,
3
J = 2.2, 7.4 Hz, 1 H, H-3), 3.79 (s, 3 H), 4.49 (d, J = 2.2 Hz, 1 H, H-
4
), 6.87–7.24 (m, 8 H).
IR (film): 1747 cm–1.
ESI–MS: m/z = 302 [M + 1]+.
1
H NMR (500 MHz, CDCl ): d = 1.09 (t, J = 7.5 Hz, 3 H), 1.85 (m,
3
1
2
H), 1.96 (m, 1 H), 3.00 (m, 1 H, H-3), 3.74 (s, 3 H), 4.61 (d, J =
trans-1,4-Bis(4-methoxyphenyl)-3-methylazetidin-2-one4b (3g)
Colorless oil.
.1 Hz, 1 H, H-4), 7.02–7.46 (m, 8 H).
ESI–MS: m/z = 338 [M + 23]+.
–1
IR (film): 1743 cm .
1
trans-3-Ethyl-4-(4-methoxyphenyl)-1-phenylazetidin-2-one4b
(3o)
H NMR (500 MHz, CDCl ): d = 1.46 (d, J = 7.4 Hz, 3 H), 3.08 (dq,
3
J = 2.2, 7.4 Hz, 1 H, H-3), 3.74 (s, 3 H), 3.80 (s, 3 H), 4.49 (d, J =
2
.2 Hz, 1 H, H-4), 6.76–7.27 (m, 8 H).
Colorless oil.
ESI–MS: m/z = 298 [M + 1]+.
IR (film): 1748 cm–1.
1
H NMR (500 MHz, CDCl ): d = 1.09 (t, J = 7.4 Hz, 3 H), 1.85 (m,
3
trans-1-(4-Methoxyphenyl)-3-methyl-4-[3,4-(methyleneox-
1
2
H), 1.95 (m, 1 H), 3.03 (m, 1 H, H-3), 3.79 (s, 3 H), 4.62 (d, J =
4
b
yl)phenyl]azetidin-2-one (3h)
.1 Hz, 1 H, H-4), 6.89 (m, 3 H), 7.01 (m, 1 H), 7.21–7.29 (m, 5 H).
Colorless oil.
ESI–MS: m/z = 282 [M + 1]+.
–1
IR (film): 1746 cm .
1
H NMR (500 MHz, CDCl ): d = 1.44 (d, J = 7.4 Hz, 3 H), 3.07 (dq,
trans-3-Ethyl-1-phenyl-4-[3,4-(methyleneoxy)phenyl]azetidin-
2-one (3p)
3
4
a
J = 1.8, 7.4 Hz, 1 H, H-3), 3.74 (s, 3 H), 4.45 (d, J = 1.8 Hz, 1 H, H-
4
), 5.94 (m, 2 H), 6.77–7.24 (m, 7 H).
Colorless oil.
ESI–MS: m/z = 312 [M + 1]+.
IR (film): 1743 cm–1.
1
H NMR (500 MHz, CDCl ): d = 1.08 (t, J = 7.4 Hz, 3 H), 1.84 (m,
trans-1-(4-Chlorophenyl)-3-methyl-4-phenylazetidin-2-one4a
3
1
2
7
H), 1.94 (m, 1 H), 3.00 (m, 1 H, H-3), 3.73 (s, 3 H), 4.54 (d, J =
.1 Hz, 1 H, H-4), 5.94 (m, 2 H), 5.94 (m, 2 H), 6.77–6.84 (m, 3 H),
.23 (m, 2 H).
(
3i)
Colorless oil.
–1
IR (film): 1748 cm .
ESI–MS: m/z = 326 [M + 1]+.
1
H NMR (500 MHz, CDCl ): d = 1.49 (d, J = 7.4 Hz, 3 H), 3.15 (dq,
3
J = 2.3, 7.4 Hz, 1 H, H-3), 4.56 (d, J = 2.3 Hz, 1 H, H-4), 7.18–7.40
trans-3-Methyl-1-phenyl-4-(trans-styryl)azetidin-2-one10 (3q)
(
m, 9 H).
Colorless oil.
ESI–MS: m/z = 272 [M + 1]+.
IR (film): 1748 cm–1.
1
H NMR (500 MHz, CDCl ): d = 1.44 (d, J = 7.4 Hz, 3 H), 3.13 (dq,
3
trans-1-(4-Chlorophenyl)-4-(4-methoxyphenyl)-3-methylazeti-
J = 1.7, 7.4 Hz, 1 H, H-3), 4.24 (dd, J = 1.1, 8.1 Hz, 1 H, H-4), 6.28
din-2-one4a (3k)
Colorless oil.
(
1
dd, J = 8.4, 15.9 Hz, 1 H), 6.80 (d, J = 15.9 Hz, 1 H), 7.05–7.45 (m,
0 H).
–1
IR (film): 1746 cm .
+
+
ESI–MS: m/z = 264 [M + 1] , 549 [2 × M + Na] .
1
H NMR (500 MHz, CDCl ): d = 1.46 (d, J = 7.4 Hz, 3 H), 3.10 (dq,
3
J = 2.2, 7.4 Hz, 1 H, H-3), 3.79 (s, 3 H), 4.49 (d, J = 2.2 Hz, 1 H, H-
trans-3-Ethyl-1-phenyl-4-(trans-styryl)azetidin-2-one4a (3r)
4
), 6.87–7.24 (m, 8 H).
Colorless oil.
ESI–MS: m/z = 302 [M + 1]+.
IR (film): 1754 cm–1.
1
H NMR (500 MHz, CDCl ): d = 1.09 (t, J = 7.4 Hz, 3 H), 1.83 (m,
3
1
H), 1.94 (m, 1 H), 3.06 (m, 1 H, H-3), 4.33 (dd, J = 1.9, 8.4 Hz, 1
Synthesis 2005, No. 5, 725–730 © Thieme Stuttgart · New York

PAPER
Diastereoselective Synthesis of trans b-Lactams and b-Aminocarbonyl Compounds
729
H, H-4), 6.30 (dd, J = 8.4, 15.9 Hz, 1 H), 6.78 (d, J = 15.9 Hz, 1 H),
.03–7.50 (m, 10 H).
anti-3-[3-(2-Methoxyanilino)-3-(4-fluorophenyl)-2-methylpro-
pionyl]spiro[2H-1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-one
(5d)
7
+
+
ESI–MS: m/z = 278 [M + 1] , 577 [2 × M + Na] .
White crystal; mp 167–170 °C.
–
1
trans-4-Isopropyl-3-methyl-1-(4-methoxyphenyl)azetidin-2-
IR (KBr): 3383, 1714, 1675 cm .
one4 (3s)
b
1
H NMR (500 MHz, CDCl ): d = 1.07 (d, J = 6.8 Hz, 3 H), 1.40–
.30 (m, 10 H), 3.58 (qd, J = 6.8 Hz, J = 9.9 Hz, 1 H), 3.84 (s, 3 H),
4.58 (d, J = 9.9 Hz, 1 H), 6.40–8.04 (m, 12 H).
3
Colorless oil.
2
–1
IR (film): 1749 cm .
1
13
H NMR (500 MHz, CDCl ): d = 1.05 (m, 6 H), 1.48 (d, J = 7.4 Hz,
C NMR (125 MHz, CDCl ): d = 16.81, 22.56, 22.63, 24.54, 32.83,
3
3
3
H), 2.45 (m, 1 H, H-3), 3.12 (dq, J = 2.2, 1.4 Hz, 1 H), 3.74 (s, 3
33.10, 51.02, 55.95, 61.28, 95.87, 110.04, 111.15, 115.42, 115.59,
116.55, 117.45, 117.68, 121.38, 122.53, 128.59, 129.19, 129.26,
136.23, 137.02, 147.06, 155.66, 161.32, 163.26, 164.07, 183.01.
H), 4.61 (m, 1 H), 6.71–7.22 (m, 4 H).
ESI–MS: m/z = 234 [M + 1]+.
+
+
HRMS (ESI): m/z [M + H] calcd for C H FN O : 503.2341;
3
0
32
2
4
anti-3-[3-(2-Methoxyanilino)-2-methyl-3-phenylpropio-
nyl]spiro[2H-1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-one (5a)
White crystal; mp 176–178 °C.
found: 503.2338.
anti-3-[3-(2-Methoxyanilino)-2,4-dimethylpentanoyl]spiro[2H-
1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-one (5e)
Colorless oil.
IR (film): 3424, 2932, 1718, 1683 cm–1.
–
1
IR (KBr): 3380, 1718, 1678 cm .
1
H NMR (125 MHz, CDCl ): d = 1.08 (d, J = 7.9 Hz, 3 H), 1.40–
3
2
4
.30 (m, 10 H), 3.61 (qd, J = 7.9 Hz, J = 9.9 Hz, 1 H), 3.83 (s, 3 H),
.60 (d, J = 9.9 Hz, 1 H), 6.47–8.05 (m, 13 H).
1
H NMR (500 MHz, CDCl ): d = 0.89 (t, J = 6.7 Hz, 6 H), 1.33 (d,
3
1
3
J = 6.7 Hz, 3 H), 1.50–2.15 (m, 11 H), 3.43 (qd, J = 6.8 Hz, J = 8.9
Hz, 1 H), 3.64 (dd, J = 3.5 Hz, J = 8.9 Hz, 1 H), 3.80 (s, 3 H), 4.70
C NMR (500 MHz, CDCl ): d = 16.79, 22.56, 22.65, 24.55, 32.79,
3
3
1
1
3.10, 51.08, 55.96, 61.97, 95.88, 110.02, 111.18, 116.34, 117.43,
17.74, 121.42, 122.48, 127.57, 127.77, 128.60, 136.15, 137.22,
41.82, 147.03, 155.68, 164.02, 183.26.
(
br s, 1 H), 6.54–7.99 (m, 8 H).
1
3
C NMR (125 MHz, CDCl ): d = 16.43, 16.57, 21.05 22.51 24.44,
3
ESI–MS: m/z = 485 [M + 1]+.
30.84, 32.91, 33.34, 47.99, 55.90, 62.12, 95.90, 110.05, 110.68,
1
15.62, 117.36, 121.52, 122.36, 128.51, 135.88, 139.56, 146.34,
+
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 485.2435;
found: 485.2438.
3
0
33
2
4
155.51, 163.62, 183.99.
HRMS (ESI): m/z [M + H]+ calcd for C H N O : 451.2591;
+
2
7
35
2
4
found: 451.2588.
anti-3-[3-(2-Methoxyanilino)-3-(4-methoxyphenyl)-2-methyl-
propionyl]spiro[2H-1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-
one (5b)
anti-3-[2-{(2-methoxyanilino)(phenyl)methyl}-butanoyl]-
spiro[2H-1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-one (5f)
Yellow crystal; mp 157–160 °C.
White crystal; mp 185–187 °C.
–
1
IR (KBr): 3385, 1715, 1679 cm .
–
1
IR (KBr): 3380, 1718, 1678 cm .
1
H NMR (500 MHz, CDCl ): d = 1.08 (d, J = 6.8 Hz, 3 H), 1.40–
3
1
H NMR (500 MHz, CDCl ): d = 0.87 (t, J = 7.5 Hz, 3 H), 1.49–2.43
m, 12 H), 3.76 (m, 1 H), 3.82 (s, 3 H), 4.64 (t, J = 8.5 Hz, 1 H), 6.04
d, J = 7.6 Hz, 1 H), 6.40–8.04 (m, 13 H).
3
2
3
.30 (m, 10 H), 3.52 (qd, J = 6.8 Hz, J = 9.9 Hz, 1 H), 3.73 (s, 3 H),
.82 (s, 3 H), 4.54 (d, J = 9.9 Hz, 1 H), 5.80 (br s, 1 H), 6.42–8.04
(
(
(
m, 12 H).
13C NMR (125 MHz, CDCl
): d = 11.71, 22.62, 22.69, 24.36, 24.54,
2.71, 33.24, 56.05, 56.58, 59.93, 96.16, 110.11, 110.79, 116.09,
17.36, 117.81, 121.46, 122.42, 127.40, 127.71, 128.54, 128.66,
36.09, 137.51, 141.95, 147.05, 155.52, 164.21, 181.83.
1
3
3
C NMR (125 MHz, CDCl ): d = 16.78, 22.56, 22.63, 24.48, 33.01,
3
3
1
1
3
1
1
3.15, 51.08, 55.96, 55.90, 61.97, 95.86, 110.02, 111.18, 116.34,
17.43, 117.74, 121.42, 122.48, 127.57, 127.77, 128.60, 136.15,
37.22, 141.82, 147.03, 155.68, 164.02, 183.26.
HRMS (ESI): m/z [M + H]+ calcd for C31 +: 499.2591;
found: 499.2595.
H N O
35 2 4
ESI–MS: m/z = 515 [M + 1]+.
+
+
HRMS (ESI): m/z [M + H] calcd for C H N O : 515.2540;
3
1
35
2
5
found: 515.2538.
anti-3-[2-{(2-Methoxyanilino)(4-chlorophenyl)methyl}bu-
tanoyl]spiro[2H-1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-one
anti-3-[3-(2-Methoxyanilino)-3-(4-chlorophenyl)-2-methylpro-
pionyl]spiro[2H-1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-one
(
5g)
Colorless oil.
(
5c)
–
1
IR (KBr): 3376, 2934, 1716, 1681 cm .
1H NMR (500 MHz, CDCl
): d = 0.87 (t, J = 7.4 Hz, 3 H), 1.49–2.43
m, 12 H), 3.75 (m, 1 H), 3.82 (s, 3 H), 4.62 (t, J = 8.1 Hz, 1 H), 6.04
(d, J = 7.3 Hz, 1 H), 6.40–8.04 (m, 12 H).
White crystal; mp 174–176 °C.
–
1
3
IR (KBr): 3388, 1718, 1678 cm .
(
1
H NMR (500 MHz, CDCl ): d = 1.08 (d, J = 6.9 Hz, 3 H), 1.40–
3
2
4
.30 (m, 10 H), 3.54 (qd, J = 6.9 Hz, J = 9.9 Hz, 1 H), 3.83 (s, 3 H),
.57 (d, J = 9.9 Hz, 1 H), 5.90 (br s, 1 H), 6.35–8.04 (m, 12 H).
1
3
C NMR (125 MHz, CDCl ): d = 11.75, 22.63, 22.69, 24.39, 24.55,
3
3
2.82, 33.28, 56.03, 56.33, 59.38, 96.16, 110.13, 110.78, 116.45,
1
3
C NMR (125 MHz, CDCl ): d = 16.79, 22.56, 22.61, 24.53, 32.84,
3
117.41, 117.67, 121.41, 122.49, 128.63, 128.76, 129.13, 133.05,
36.26, 137.21, 140.63, 147.11, 155.51, 164.31, 181.39.
3
1
1
3.10, 50.78, 55.94, 61.35, 95.85, 110.05, 111.16, 116.68, 117.45,
17.64, 121.36, 122.53, 128.58, 128.82, 129.12, 136.24, 136.90,
40.48, 147.08, 155.65, 164.06, 182.85.
1
+
+
HRMS (ESI): m/z [M + H] calcd for C H ClN O : 533.2202;
3
1
34
2
4
found: 533.2199.
+
+
HRMS (ESI): m/z [M + H] calcd for C H ClN O : 519.2045;
3
0
32
2
4
found: 519.2037.
Synthesis 2005, No. 5, 725–730 © Thieme Stuttgart · New York

7
30
S.-Z. Jian et al.
PAPER
anti-3-[3-(2-Methoxyanilino)-2-ethyl-4-methylpentanoyl]-
spiro[2H-1,3-benzoxazine-2,1¢-cyclohexan]-4(3H)-one (5h)
Colorless oil.
References
(
1) Bose, A. K.; Banik, B. K.; Manhas, M. S. Tetrahedron Lett.
995, 36, 213.
2) Clader, J. W. J. Med. Chem. 2004, 47, 1.
1
–
1
IR (film): 3424, 2932, 1718, 1683 cm .
(
1
H NMR (500 MHz, CDCl ): d = 0.96 (m, 9 H), 1.47–2.32 (m, 13
(3) (a) Alcaide, B.; Vicente-Rodriguez, A. Tetrahedron Lett.
1998, 39, 6589. (b) Alcaide, B.; Vicente-Rodriguez, A.
Tetrahedron Lett. 1999, 40, 2005.
3
H), 3.60 (m 2 H), 3.07 (s, 3 H), 4.70 (d, J = 9.6 Hz, 1 H), 6.54–7.99
(
m, 8 H).
1
3
(4) (a) Hart, D. J.; Ha, D. C. Chem. Rev. 1989, 89, 1447.
C NMR (125 MHz, CDCl ): d = 11.83, 18.03, 21.33, 22.66, 22.67
3
(
2
b) Chen, L.; Zhao, G.; Ding, Y. Tetrahedron Lett. 2003, 44,
611.
2
1
1
4.08, 24.46, 31.76, 32.97, 33.09, 53.02, 55.98, 59.65, 96.06,
10.12, 115.19, 117.38, 118.03, 121.53, 122.46, 128.64, 135.92,
39.90, 146.44, 155.41, 163.73, 182.53.
(
5) Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.; Spunta,
G. Tetrahedron 1996, 5, 1685.
(6) Kondo, K.; Seki, M.; Kuroda, T.; Yamanaka, T.; Iwasaki, T.
+
+
HRMS (ESI): m/z [M + H] calcd for C H FN O : 465.2748;
found: 465.2745.
2
8
37
2
4
J. Org. Chem. 1997, 62, 2877.
(7) Kagan, H. B.; Basselier, J. J.; Luche, J. L. Tetrahedron Lett.
1
964, 16, 941.
Acknowledgment
(
8) (a) Cainelli, G.; Panunzio, M.; Bandini, E.; Martelli, G.;
Spunta, G. Tetrahedron 1996, 5, 1685. (b) Fukuzawa, S. I.;
Matsuzawa, H.; Yoshimitsu, S. I. J. Org. Chem. 2000, 65,
We thank the National Natural Science Foundation of China (No.
9972037) as well as the Teaching and Research Award Program
2
1
702.
9) Adrian, J. C. Jr.; Barkin, J. L.; Hassib, L. Tetrahedron Lett.
999, 40, 2457.
for Outstanding Young Teachers in Higher Education Institutions
of MOE, P. R. C.
(
1
(
10) Townes, J. A.; Evans, M. A.; Queffelec, J.; Taylor, S. J.;
Morken, J. P. Org. Lett. 2002, 4, 2537.
Synthesis 2005, No. 5, 725–730 © Thieme Stuttgart · New York