A one-pot asymmetric organocatalytic tandem reaction for the synthesis of oxazine derivatives

Article abstract of DOI:10.1039/c0ob00669f

An easy one-pot tandem reaction catalyzed by a chiral secondary amine for the synthesis of optically active oxazine derivatives has been performed and the corresponding substituted benzo[d]pyrido[2,1-b][1,3]oxazine derivatives were afforded in generally high yields (up to 99%) and excellent enantioselectivities (up to >99%).

Full text of DOI:10.1039/c0ob00669f

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PAPER
A one-pot asymmetric organocatalytic tandem reaction for the synthesis of
oxazine derivatives†
Zhichao Jin, Feng Yu, Xiao Wang, Huicai Huang, Xiaoyan Luo, Xinmiao Liang and Jinxing Ye*
Received 4th September 2010, Accepted 7th December 2010
DOI: 10.1039/c0ob00669f
An easy one-pot tandem reaction catalyzed by a chiral secondary amine for the synthesis of
optically active oxazine derivatives has been performed and the corresponding substituted
benzo[d]pyrido[2,1-b][1,3]oxazine derivatives were afforded in generally high yields (up to 99%)
and excellent enantioselectivities (up to >99%).
have resulted in the success of the synthesis of many complicated
Introduction
heterocyclic compounds in a highly enantioselective manner.10 For
Heterocyclic compounds have always been one of the most popular
example, an enantioselective secondary-amine-catalyzed conju-
structures in almost every discipline in chemistry.1 Most of them
have diverse biological or medical activities and are very common
in natural and non-natural compounds.2 The synthesis of them has
drawn the attention of many organic chemists for over a century
and it is still a challenging subject today both in the total synthesis
of natural products and organic synthetic methodologies.3
gate addition for the synthesis of optically active quinolizidine
derivatives has been performed by Franze´n et al.11 recently, and
a similar structure which has been accomplished by Zhao12 and
coworkers also represents an elegant example of this methodology.
Herein, we wish to describe an enantioselective tandem reaction
catalyzed by a simple secondary amine to afford a series of
substituted benzo[d]pyrido[2,1-b][1,3] oxazine derivatives.
Among the large numbers of heterocyclic compounds, fused
heterocycles are a family of the most important ones, which are
considered as “privileged structures” and contribute greatly to
both the pharmaceutical and agrochemical industries.4 There-
fore, great efforts have been made in order to develop efficient
approaches for the preparations of various fused heterocyclic
compounds.5 Of these well established strategies, asymmetric
organocatalytic tandem reaction has been one of the most
attractive methods mainly due to its high stereoselectivities, easy
operation and “environmental friendliness”.6
Substituted oxazine derivatives have emerged as a challenging
synthetic structure recently and have appealed to the interests of
several scientists.7 For example, Liu8 and coworkers reported an ef-
ficient one-pot gold-catalyzed tandem coupling/cyclization reac-
tion for the synthesis of pyrrolo/pyrido[2,1-a][1,3]benzoxazinones
and pyrrolo/pyrido [2,1-a]quinazolinones recently, and Eycken9
et al. previously described a solvent-free procedure for the
synthesis of different pyridopyridazines and quinolines under both
MW and conventional heating conditions. However, to the best
of our knowledge, no reports have presented efficient protocols
for the enantioselective synthesis of this kind of fused benzo-
pyrido-oxazine derivatives. Asymmetric organocatalytic tandem
reactions, especially those catalyzed by proline and its derivatives,
Results and discussion
Initially, the rationally designed aryl amide 1a was applied in the
tandem reaction with cinnamyl aldehyde 2a in order to prepare the
pyrido[1,2-a]quinazoline derivative 3 as shown in Scheme 1 (Route
a). The model reaction was firstly carried out using Jørgensen–
Hayashi catalyst A for the Michael addition under reported
conditions.13 As we expected, the process went smoothly and the
aryl amide 1a vanished within 1 h. Then excess aqueous HBr
solution was added into the reaction mixture to promote the
annulation step of the tandem reaction. To our great surprise,
Engineering Research Centre of Pharmaceutical Process Chemistry, Min-
istry of Education, School of Pharmacy, East China University of Science
and Technology, 130 Meilong Road, Shanghai 200237, China. E-mail: yejx@
ecust.edu.cn
† Electronic supplementary information (ESI) available. CCDC reference
number 793001. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob00669f
Scheme 1 Two possible processes for the tandem reaction of aryl amide
1a and cinnamyl aldehyde 2a.
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Table 1 Optimization of the reaction conditions for the Michael addition
of the tandem reaction
Table 2 Screening of the acid additives for the hydrolyzation/annulation
step of the tandem reaction
Entrya
Acid additive
T/◦Cb
tc
Yield(%)d
d.r.e
1
2
3
4
5
6
7
40% HBr aq
40% HBr aq
37% HCl aq
TFA
diphenyl phosphate
TsOH·H2O
TsOH·H2O
r.t.
-20
r.t.
r.t.
r.t.
r.t.
4
12 h
7 d
12 h
12 h
3 d
3 d
3 d
nd
12
nd
16
79
74
61
63 : 37
65 : 35
64 : 36
75 : 25
70 : 30
80 : 20
71 : 29
Entrya
1
Cat.
Equiv.b
Solvent
Conv. (%)c
ee(%)d
1
2
3
4
5
6
7
8
1a
1b
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
A
A
B
C
A
A
A
A
A
A
A
A
A
A
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.02
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DMF
Full
Fulle
13
38
Full
63
64
Full
79
64
92
96
92
—
f
a Unless otherwise indicated, all reactions were carried out using 1.0
equiv of 1a (0.20 mmol), 1.5 equiv of 2a, 0.5 mL CH2Cl2, and 2.0
equiv of the certain acid additive. b The temperature under which the
hydrolyzation/annulation step of the tandem reaction was carried out.
c The reaction time taken for the hydrolyzation/annulation step. d Isolated
yield. e Determined by 1H NMR on the crude reaction mixture.
72
96
92
92
95
91
90
THF
Toluene
CH3CN
1,4-Dioxane
EtOAc
2-Propanol
CH3Cl
9
10
11
12
13
14
f
—
could be obtained with excellent ee values ranging from 90% to
96%. A slight increase of enantioselectivity was observed when the
reaction was carried out using 5.0 mol% of catalyst A in CH2Cl2.
When the loading of catalyst A was decreased to 2.0 mol%, the
same level of ee value could also be obtained while the reaction
rate was found to be subject to an obvious decrease.
Full
Full
50
94
97
97
CH2Cl2
CH2Cl2
a Unless otherwise indicated, all reactions were carried out using 1.0 equiv
of 1 (0.20 mmol), 1.5 equiv of 2a, 0.5 mL solvent, and 2.0 equiv of HBr
aq. b The amount of catalyst used in each reaction. c Determined by H
1
NMR on the crude reaction mixture before the addition of HBr in water.
d Enantiomeric excess of the major diastereoisomer, which was determined
by chiral HPLC. e 4 days was needed for the Michael addition step of
the tandem reaction. f No annulation product was isolated in 24 h after
aqueous HBr had been added.
Having established the best reaction conditions for the Michael
addition, the hydrolyzation/annulation step catalyzed by acid
additives was subsequently investigated, mainly based on the total
yield and the diastereomeric ratio of the final product 4a (Table 2).
Experimental data showed that the type of the acid used had a
significant influence on both the d.r. value and the total yield of 4a,
while the temperature under which the hydrolyzation/annulation
step was carried out contributed little to the diastereoselectivity
of the final product. After a series of investigations, the oxazine
derivative 4a could be obtained as two separable diastereoisomers
with a 4 : 1 ratio in 74% yield.
With the optimized conditions for both the Michael addition
and the hydrolyzation/annulation steps at hand, the scope of this
approach was next examined by synthesizing a series of substituted
benzo[d]pyrido[2,1-b][1,3]oxazine derivatives (Table 3). To our
delight, all the main products were obtained with excellent
enantioselectivities in moderate to good yields, regardless of the
properties of the substituents on the cinnamyl aldehydes, albeit
with generally moderate diastereoselectivities for the two separable
diastereoisomers. It could be inferred that the reaction time for the
hydrolyzation/annulation step affected the total yields of the final
products greatly. For example, the product 4a could be afforded
in a yield of 58% after stirring for 1 day after the acid TsOH·H2O
was added, but when the reaction time of the second step was
prolonged to 3 days, the yield of the final product 4a could be
raised to 74%.
the product we got upon isolation by column chromatography
was the oxazine derivative 4a instead of the predicted quinazoline
derivative 3! Obviously, a hydrolyzation process had occurred on
the addition of the aqueous acid solution before the annulation
step took place (Scheme 1, Route b). This unexpected result
prompted us to examine the direct synthesis of 4a from the
carboxylic acid 1b. Results showed that neither the reactivity
nor the enantioselectivity of the reaction could be as good as
that of the reaction in which 1a was applied as the nucleophilic
reagent (Table 1, entries 1 and 2), which was most probably
because of the serious hindrance against the Michael addition
step by the interactions between the carboxylic group in 1b and
the aminocatalyst A.
The reaction conditions for the Michael addition of the tandem
sequence were then firstly optimized using the aryl amide 1a as
the nucleophilic reagent based on both the conversion of 1a and
the ee value of the final product 4a. After screening of a number
of different catalysts and solvents, it was found that the tandem
reaction proceeded very well in a wide scope of solvents with both
high enantioselectivities and reactivities when A was applied as the
catalyst at room temperature. It appeared that the reaction failed
to complete in protonic solvents such as 2-propanol while in non-
protonic solvents, regardless of the polarities of them, the product
Having successfully extended the scope of the tandem reaction
of 1a and a variety of cinnamyl aldehydes 2 in an enantioselective
manner, we next tried to apply this approach further to include
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Table 3 Expanding of the scope of the tandem reaction
of catalyst A at room temperature for the Michael addition. Unfor-
tunately, the diastereomeric ratios failed to increase conspicuously
after a number of attempts at the annulation step of the sequences,
probably due to the flexibility of the methylene group in the aryl
amide.
The absolute configuration of the isolated major diastereoiso-
mer 4k was determined by an X-ray analysis on the single
crystal (Scheme 2),14 which was identical to that produced by our
assumed process summarized in Scheme 3, based on previous work
by Jørgensen et al.,15 Franze´n et al.11 and Rios et al.,16 as well as
other related reports.17
b
c
Entrya
R
t1
t2
Yield(%)d Product ee(%)e d.r.f
1
2
3
4
5
6
7
8
H
3-CH3
1.5 h 1 d (3 d) 58 (74)
6 h
4a
4b
4c
4d
4e
4f
97
97
93
95
95
97
95
93
95
94
94
>99
94
80 : 20
79 : 21
80 : 20
79 : 21
79 : 21
81 : 19
83 : 17
84 : 16
85 : 15
82 : 18
81 : 19
81 : 19
81 : 19
1 d
3 d
57
63
52
48
69
35
84
84
76
85
78
89
2- OCH3 1 d
4-CH3
4- OCH3 2.5 h 1 d
1.5 h 1 d
2-Cl
3-Cl
4-Cl
2-F
1 d
3 di
3 dg,h 3 d
4g
4h
4i
4j
4k
4l
3 h
2 di
2 d
9 h
3 h
1 d
3 d
3d
3 d
3 d
3 d
3 d
9
10
11
12
13
4-F
2-Br
4-Br
4-NO2
4m
Scheme 2 X-ray crystal structure of 4k.
a Unless otherwise indicated, all reactions were carried out using 1.0 equiv
of 1a (0.40 mmol), 1.5 equiv of 2, 0.05 equiv of catalyst A, 1.0 mL CH2Cl2,
and 2.0 equiv of. TsOH·H2O. b The time needed for the first step of Michael
addition, which was determined by TLC evidence of the disappearance of
the nucleophilic reagent. c The time needed for the cyclization step of the
tandem reaction. d Isolated yield of both diastereoisomers. e Enantiomeric
excess of the major diastereoisomer, which was determined by chiral
HPLC. The value within parentheses represents the ee value of the minor
diastereoisomer. f Determined by 1H NMR on the crude reaction mixture.
g Without full conversion of 1a. h 10 mmol% catalyst was used. i 0.5 mL
CH2Cl2 was added.
Table 4 Further expanding of the scope of the tandem reaction
Scheme 3 Assumed process of the tandem reaction.
Entrya
R
Timeb
Yield(%)c Product
ee(%)d
d.r.e
1
2
3
4
5
6
7
8
9
H
1.5 h
1.5 h
1.5 h
1.5 h
3 df,g
1.5 h
1.5 h
1.5 h
1.5 h
86
97
89
98
76
99
99
63
86
4n
4o
4p
4q
4r
4s
4t
94/97
97/97
99/94
92/93
97/97
93/93
95/94
99/94
99/96
67 : 33
52 : 48
61 : 39
62 : 38
56 : 44
59 : 41
60 : 40
67 : 33
57 : 43
Conclusions
3-CH3
4-CH3
4-OCH3
3-Cl
4-Cl
2-F
In conclusion, an easy one-pot tandem reaction catalyzed by
a chiral secondary amine which afforded a series of oxazine
derivatives has been developed. This approach could prepare the
required substituted benzo[d]pyrido[2,1-b][1,3]oxazine derivatives
in generally high yields and excellent enantioselectivities. Further
investigations towards this methodology are currently being
studied well and will be presented in the near future.
4-F
4-Br
4u
4v
a Unless otherwise indicated, all reactions were carried out using 1.0 equiv
of 1c (0.40 mmol), 1.5 equiv of 2, 0.05 equiv of catalyst A, 1.0 mL CH2Cl2,
and 2.0 equiv of. TsOH·H2O. b The time needed for the first step of Michael
addition, which was determined by TLC evidence of the disappearance of
the nucleophilic reagent. c Isolated yield of the product mixture 4 of both
diastereoisomers. d Enantiomeric excess of both diastereoisomers, which
was determined by chiral HPLC. e Determined by 1H NMR on the product
mixture. f Without full conversion of 1c. g 0.7 mL CH2Cl2 was added.
Experimental
General methods
Proton nuclear magnetic resonance (1H NMR) spectra and carbon
nuclear magnetic resonance (13C NMR) spectra were recorded on a
Bruker AV-400 spectrometer (400 MHz and 100 MHz). Chemical
shifts for protons are reported in parts per million downfield from
tetramethylsilane and are referenced to residual protium in the
reaction of the newly designed aryl amide 1c under similar
conditions (Table 4). These reactions proceeded well with high
enantioselectivities in good to excellent yields even with 5.0 mol%
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NMR solvent (CDCl3: d 7.26). Chemical shifts for carbon are
reported in parts per million downfield from tetramethylsilane and
are referenced to the carbon resonances of the solvent (CDCl3: d
77.16). Data are represented as follows: chemical shift, integration,
multiplicity (br = broad, s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), coupling constants in Hertz (Hz).
Mass spectra (ESI) were measured on a Waters Micromass LCT
spectrometer. High performance liquid chromatography (HPLC)
was performed on an Agilent 1100 Series chromatographs using a
Daicel Chiralpak IA and IC column (0.46 cm ¥ 25 cm) as noted.
(br s, 1H), 7.54–7.52 (d, J = 8.0 Hz, 1H), 7.48–7.47 (d, J = 7.2 Hz,
1H), 7.28–7.18 (m, 2H), 5.29 (br s, 1H), 4.55 (s, 2H), 3.69 (s, 3H),
3.55 (s, 2H). 13C-NMR (100 MHz, (CD3)2SO): d (ppm) 168.8,
164.6, 135.7, 135.2, 127.8, 127.4, 125.6, 124.6, 60.3, 52.4, 43.4.
HRMS (EI): exact mass calculated for [M]+ (C11H13NO4) requires
m/z 223.0845, found m/z 223.0846.
(2R,3S,4aS)-Methyl 1,6-dioxo-3-phenyl-1,2,3,4,4a,6-hexahy-
drobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate
(4a). The
product was◦obtained in 58% yield, white solid. Mp 72–74 ◦C;
[a]2D2 = +46.3 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d (ppm) 8.17–8.14 (dd, J = 8.0, 1.2 Hz, 1H), 7.87–7.85 (d, J =
8.4 Hz, 1H), 7.71–7.67 (td, J = 15.6, 1.6 Hz, 1H), 7.46–7.37 (m,
3H), 7.34–7.28 (m, 3H), 5.75–5.74 (d, J = 2.4 Hz, 1H), 4.05–3.98
(td, J = 25.2, 2.8 Hz, 1H), 3.90–3.87 (d, J = 12.4 Hz, 1H), 3.61 (s,
3H), 2.63–2.58 (m, 1H), 2.53–2.45 (m, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 167.9, 165.7, 163.3, 140.7, 139.2, 134.4, 130.4,
129.2, 128.0, 127.0, 126.9, 124.4, 119.8, 84.6, 57.0, 52.5, 37.7,
34.1. HRMS (EI): exact mass calculated for [M]+ (C20H17NO5)
requires m/z 351.1107, found m/z 351.1105. The enantiomeric
excess was determined by HPLC. [IC column, 254 nm, DCM,
1.0 mL min-1]: 9.0 min (major), 16.0 min (minor), ee = 97%.
General procedure for the asymmetric tandem reaction of 1a and 2
To a solution of aryl amide 1a (0.4 mmol) in CH2Cl2 (0.6 mL) was
added the solution of the catalyst A (0.02 mmol) and cinnamyl
aldehyde (0.6 mmol) in CH2Cl2 (0.4 mL) and the reaction mixture
was stirred at room temperature for 1.5 h (determined by TLC
evidence of the disappearance of 1a). Then TsOH·H2O (0.8 mmol)
was added into the mixture in one portion and the solution was
stirred for 1 day. Lastly the reaction mixture was separated by
column chromatography with petrol ether : ethyl acetate = 9 : 1 to
4 : 1 as eluant to give the product of both diastereoisomers as a
white solid with a yield of 53%.
(2R,3S,4aS)-Methyl 1,6-dioxo-3-m-tolyl-1,2,3,4,4a,6-hexahy-
drobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate
(4b). The
General procedure for the asymmetric tandem reaction of 1c and 2
◦
product was◦obtained in 57% yield, white solid. Mp 97–101 C;
[a]2D2 = +70.6 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d (ppm) 8.16–8.14 (dd, J = 8.0, 0.8 Hz, 1H), 7.87–7.85 (d, J =
8.4 Hz, 1H), 7.71–7.66 (td, J = 15.6, 1.2 Hz, 1H), 7.45–7.41 (t, J =
15.2 Hz, 1H), 7.28–7.25 (t, J = 14.0 Hz, 1H), 7.13–7.00 (m, 3H),
5.74–5.73 (d, J = 2.4 Hz, 1H), 4.01–3.94 (td, J = 25.2, 3.2 Hz, 1H),
3.89–3.86 (d, J = 12.4 Hz, 1H), 3.61 (s, 3H), 2.60–2.56 (m, 1H),
2.51–2.44 (m, 1H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3): d
(ppm) 168.0, 165.8, 163.3, 140.7, 139.1, 138.8, 134.4, 130.4, 129.0,
128.7, 127.7, 127.0, 124.4, 123.8, 119.8, 84.7, 56.9, 52.5, 37.6, 34.1,
21.5. HRMS (EI): exact mass calculated for [M]+ (C21H19NO5)
requires m/z 365.1263, found m/z 365.1259. The enantiomeric
excess was determined by HPLC. [IC column, 254 nm, DCM,
1.0 mL min-1]: 8.3 min (major), 14.4 min (minor), ee = 97%.
To a solution of methyl 3-(2-(hydroxymethyl)phenylamino)-3-
oxopropanoate 1c (0.4 mmol) in CH2Cl2 (0.6 mL) was added the
solution of the catalyst A (0.02 mmol) and cinnamyl aldehyde (0.6
mmol) in CH2Cl2 (0.4 mL) and the reaction mixture was stirred at
room temperature for 1.5 h (determined by TLC evidence of the
disappearance of 1c). Then the reaction mixture was cooled down
to -20 ◦C and stirred for about an hour. After that TsOH·H2O
(0.8 mmol) was added into the mixture in one portion and the
solution was stirred at -20 ◦C for 4 days. Lastly the reaction
mixture was separated by column chromatography with petrol
ether : ethyl acetate = 9 : 1 as eluant to give the product mixture of
both diastereoisomers as a white solid with a yield of 86%.
Methyl 3-(2-carbamoylphenylamino)-3-oxopropanoate (1a).
(2R,3S,4aS)-Methyl 3-(2-methoxyphenyl)-1,6-dioxo-1,2,3,4,4a,
6-hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4c).
The product was obtained in 63% yield, white solid. Mp 99–101 ◦C;
[a]D22 = +69.7◦ (c = 1.00 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d (ppm) 8.17–8.15 (dd, J = 8.0, 1.2 Hz, 1H), 7.89–7.87 (d, J =
8.0 Hz, 1H), 7.71–7.66 (td, J = 15.6, 1.6 Hz, 1H), 7.45–7.41 (t, J =
15.2 Hz, 1H), 7.31–7.28 (m, 1H), 7.22–7.19 (dd, J = 7.6, 1.2 Hz,
1H), 6.98–6.93 (m, 1H), 5.71–5.70 (d, J = 2.8 Hz, 1H), 4.39–4.35
(d, J = 12.4 Hz, 1H), 4.20–4.12 (td, J = 25.2, 3.2 Hz, 1H), 3.91
(s, 3H), 3.59 (s, 3H), 2.88–2.80 (m, 1H), 2.54–2.50 (m, 1H). 13C
NMR (100 MHz, CDCl3): d (ppm) 168.4, 166.4, 163.6, 157.7,
140.9, 134.3, 130.4, 129.4, 129.1, 126.8, 126.5, 124.3, 121.0, 119.8,
111.3, 85.1, 55.4, 54.4, 52.4, 35.6, 31.6. HRMS (EI): exact mass
calculated for [M]+ (C21H19NO6) requires m/z 381.1212, found m/z
381.1213. The enantiomeric excess was determined by HPLC. [IC
column, 254 nm, DCM, 1.0 mL min-1]: 8.9 min (major), 30.9 min
(minor), ee = 93%.
◦
1
Mp 120–121 C; H-NMR (400 MHz, CDCl3): d (ppm) 11.79
(br s, 1H), 8.42–8.40 (d, J = 8.4 Hz, 1H), 8.28 (br s, 1H), 7.82–7.80
(d, J = 7.2 Hz, 1H), 7.75 (br s, 1H), 7.52–7.48 (t, J = 14.8 Hz,
1H), 7.17–7.13 (t, J = 14.8 Hz, 1H), 3.68 (s, 3H), 3.57 (s, 2H).
13C-NMR (100 MHz, (CD3)2SO): d (ppm) 171.0, 168.3, 164.4,
139.4, 132.5, 129.0, 123.4, 121.0, 52.5, 44.9. HRMS (EI): exact
mass calculated for [M]+ (C11H12N2O4) requires m/z 236.0797,
found m/z 236.0799.
2-◦(3-Methoxy-3-oxopropanamido)benzoic acid (1b). Mp 112–
1
114 C; H-NMR (400 MHz, CDCl3): d (ppm) 11.39 (br s, 1H),
8.75 (br s, 1H), 8.72–8.70 (d, J = 8.4 Hz, 1H), 8.16–8.13 (dd, J =
7.6 Hz, 0.8 Hz, 1H), 7.64–7.60 (td, J = 15.6 Hz, 0.8 Hz, 1H),
7.19–7.16 (t, J = 15.2 Hz, 1H), 3.83 (s, 3H), 3.61 (s, 2H). 13C-NMR
(100 MHz, (CD3)2SO): d (ppm) 171.7, 168.2, 164.6, 140.9, 135.3,
131.7, 123.5, 121.0, 115.2, 52.7, 44.3. HRMS (EI): exact mass
calculated for [M]+ (C11H11NO5) requires m/z 237.0637, found
m/z 237.0633.
(2R,3S,4aS)-Methyl
1,6-dioxo-3-p-tolyl-1,2,3,4,4a,6-hexa-
Methyl
3-(2◦-(hydroxymethyl)phenylamino)-3-oxopropanoate
hydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4d). The
(1c). Mp 75–76 C; 1H-NMR (400 MHz, CDCl3): d (ppm) 9.61
1812 | Org. Biomol. Chem., 2011, 9, 1809–1816
product was obtained in 52% yield, white solid. Mp 174–175 ◦C;
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[a]D22 = +149.4◦ (c = 1.00 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d (ppm) 8.15–8.13 (dd, J = 8.0, 1.2 Hz, 1H), 7.86–7.84 (d, J =
8.4 Hz, 1H), 7.70–7.66 (td, J = 15.6, 1.2 Hz, 1H), 7.44–7.41 (t, J =
15.2 Hz, 1H), 7.18 (s, 4H), 5.73–5.73 (d, J = 2.4 Hz, 1H), 4.00–3.93
(td, J = 25.2, 3.2 Hz, 1H), 3.87–3.84 (d, J = 12.4 Hz, 1H), 3.60
(s, 3H), 2.59–2.54 (m, 1H), 2.51–2.43 (m, 1H), 2.35 (s, 3H). 13C
NMR (100 MHz, CDCl3): d (ppm) 168.0, 165.8, 163.3, 140.7,
137.7, 136.2, 134.4, 130.4, 129.8, 126.9, 126.7, 124.4, 119.8, 84.7,
57.1, 52.5, 37.3, 34.1, 21.1. HRMS (EI): exact mass calculated for
[M]+ (C21H19NO5) requires m/z 365.1263, found m/z 365.1260.
The enantiomeric excess was determined by HPLC. [IC column,
254 nm, DCM, 1.0 mL min-1]: 8.9 min (major), 12.6 min (minor),
ee = 95%.
mass calculated for [M]+ (C20H16NO5Cl) requires m/z 385.0717,
found m/z 385.0721. The enantiomeric excess was determined
by HPLC. [IC column, 254 nm, DCM, 1.0 mL min-1]: 7.7 min
(major), 8.9 min (minor), ee = 95%.
(2R,3S,4aS)-Methyl 3-(4-chlorophenyl)-1,6-dioxo-1,2,3,4,4a,6-
hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4h).
The◦product was ob◦tained in 84% yield, white solid. Mp 188–
190 C; [a]2D2 = +89.5 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 8.11–8.10 (d, J = 6.8 Hz, 1H), 7.82–7.80 (d, J =
8.0 Hz, 1H), 7.68–7.63 (td, J = 15.6, 1.2 Hz, 1H), 7.43–7.39 (t,
J = 15.2 Hz, 1H), 7.35–7.33 (d, J = 8.4 Hz, 2H), 7.24–7.22 (d,
J = 8.4 Hz, 2H), 5.73–5.73 (d, J = 2.0 Hz, 1H), 4.00–3.93 (td,
J = 24.8, 3.2 Hz, 1H), 3.85–3.82 (d, J = 12.4 Hz, 1H), 3.59 (s,
3H), 2.55–2.42 (m, 2H). 13C NMR (100 MHz, CDCl3): d (ppm)
167.8, 165.4, 163.2, 140.6, 137.7, 134.5, 133.8, 130.4, 129.4, 128.4,
127.0, 124.3, 119.7, 84.5, 56.9, 52.6, 37.2, 33.8. HRMS (EI): exact
mass calculated for [M]+ (C20H16NO5Cl) requires m/z 385.0717,
found m/z 385.0719. The enantiomeric excess was determined
by HPLC. [IA column, 254 nm, DCM, 0.7 mL min-1]: 5.9 min
(minor), 7.1 min (major), ee = 93%.
(2R,3S,4aS)-Methyl 3-(4-methoxyphenyl)-1,6-dioxo-1,2,3,4,4a,
6-hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4e).
The◦product was ob◦tained in 48% yield, white solid. Mp 194–
196 C; [a]2D2 = +89.2 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 8.15–8.13 (dd, J = 7.6, 0.8 Hz, 1H), 7.85–7.83 (d,
J = 8.0 Hz, 1H), 7.70–7.65 (td, J = 15.6, 1.2 Hz, 1H), 7.44–7.40 (t,
J = 15.2 Hz, 1H), 7.22–7.20 (m, 2H), 6.91–6.89 (m, 2H), 5.73–5.72
(d, J = 2.4 Hz, 1H), 3.98–3.91 (td, J = 25.2, 3.2 Hz, 1H), 3.83–
3.80 (m, 4H), 3.60 (s, 3H), 2.58–2.53 (m, 1H), 2.49–2.41 (m, 1H).
13C NMR (100 MHz, CDCl3): d (ppm) 168.0, 165.8, 163.3, 159.1,
140.7, 134.4, 131.2, 130.4, 128.0, 126.9, 124.4, 119.8, 114.5, 84.7,
57.3, 52.3, 52.5, 36.9, 34.2. HRMS (EI): exact mass calculated for
[M]+ (C21H19NO6) requires m/z 381.1212, found m/z 381.1213.
The enantiomeric excess was determined by HPLC. [IC column,
254 nm, DCM, 1.0 mL min-1]: 15.4 min (major), 25.1 min (minor),
ee = 95%.
(2R,3S,4aS)-Methyl 3-(2-fluorophenyl)-1,6-dioxo-1,2,3,4,4a,6-
hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate
(4i).
The◦product was ob◦tained in 84% yield, white solid. Mp 180–
182 C; [a]2D2 = +70.9 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 8.12–8.10 (d, J = 7.6 Hz, 1H), 7.84–7.82 (d,
J = 8.4 Hz, 1H), 7.68–7.64 (td, J = 15.6, 1.2 Hz, 1H), 7.42–7.38
(t, J = 15.2 Hz, 1H), 7.32–7.26 (m, 2H), 7.15–7.06 (m, 2H),
5.73–5.72 (d, J = 2.4 Hz, 1H), 4.18–4.03 (m, 2H), 3.57 (s, 3H),
2.75–2.68 (td, J = 26.8, 4.0 Hz, 1H), 2.57–2.53 (m, 1H). 13C NMR
(100 MHz, CDCl3): d (ppm) 167.9, 165.5, 163.3, 140.7, 134.4,
130.3, 129.8, 129.6, 127.0, 125.7, 124.8, 124.4, 119.8, 116.5, 116.3,
84.7, 55.1, 52.5, 34.2, 32.1. HRMS (EI): exact mass calculated for
[M]+ (C20H16NO5F) requires m/z 369.1013, found m/z 369.1010.
The enantiomeric excess was determined by HPLC. [IC column,
254 nm, DCM, 1.0 mL min-1]: 7.8 min (major), 14.9 min (minor),
ee = 95%.
(2R,3S,4aS)-Methyl 3-(2-chlorophenyl)-1,6-dioxo-1,2,3,4,4a,
6-hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4f).
The◦product was obt◦ained in 69% yield, white solid. Mp 186–
188 C; [a]2D2 = +115.2 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 8.13–8.11 (d, J = 7.6 Hz, 1H), 7.85–7.83 (d, J =
8.0 Hz, 1H), 7.68–7.64 (t, J = 16.0 Hz, 1H), 7.46–7.39 (m, 2H),
7.32–7.23 (m, 3H), 5.72–5.71 (d, J = 2.8 Hz, 1H), 4.55–4.48 (td,
J = 25.6, 2.4 Hz, 1H), 4.15–4.12 (d, J = 12.4 Hz, 1H), 3.60 (s,
3H), 2.62–2.59 (m, 1H), 2.48–2.38 (m, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 167.7, 165.6, 163.2, 140.6, 136.3, 134.4, 133.9,
130.6, 130.4, 129.1, 127.6, 127.0, 124.3, 119.8, 84.6, 55.0, 52.6,
34.7, 33.0, 26.9. HRMS (EI): exact mass calculated for [M]+
(C20H16NO5Cl) requires m/z 385.0717, found m/z 385.0709.
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, DCM, 0.7 mL min-1]: 5.6 min (minor), 6.6 min (major),
ee = 97%.
(2R,3S,4aS)-Methyl 3-(4-fluorophenyl)-1,6-dioxo-1,2,3,4,4a,6-
hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate
(4j).
The product was obtained in 76% yield, colorless oil. [a]D22
=
+72.5◦ (c = 1.00 in CH2Cl2); H NMR (400 MHz, CDCl3): d
(ppm) 8.13–8.11 (dd, J = 8.0, 1.2 Hz, 1H), 7.84–7.82 (d, J =
8.0 Hz, 1H), 7.69–7.64 (td, J = 15.6, 1.2 Hz, 1H), 7.44–7.40 (t, J =
15.2 Hz, 1H), 7.29–7.25 (m, 2H), 7.09–7.04 (m, 2H), 5.74–5.73 (d,
J = 2.4 Hz, 1H), 4.02–3.95 (td, J = 24.8, 3.2 Hz, 1H), 3.84–3.81 (d,
J = 12.4 Hz, 1H), 3.59 (s, 3H), 2.57–2.53 (m, 1H), 2.51–2.43 (m,
1H). 13C NMR (100 MHz, CDCl3): d (ppm) 167.9, 165.5, 163.5,
163.2, 161.0, 140.6, 135.0, 134.4, 130.4, 128.6, 128.6, 127.0, 124.3,
119.7, 116.2, 116.0, 84.5, 57.1, 52.6, 37.0, 34.0. HRMS (EI): exact
mass calculated for [M]+ (C20H16NO5F) requires m/z 369.1013,
found m/z 369.1014. The enantiomeric excess was determined
by HPLC. [IC column, 254 nm, DCM, 1.0 mL min-1]: 7.7 min
(major), 9.7 min (minor), ee = 94%.
1
(2R,3S,4aS)-Methyl 3-(3-chlorophenyl)-1,6-dioxo-1,2,3,4,4a,6-
hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4g).
The◦product was ob◦tained in 35% yield, white solid. Mp 190–
192 C; [a]2D2 = +81.2 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 8.16–8.14 (d, J = 7.6 Hz, 1H), 7.86–7.84 (d,
J = 8.4 Hz, 1H), 7.71–7.67 (t, J = 15.6 Hz, 1H), 7.46–7.42 (t, J =
15.2 Hz, 1H), 7.35–7.28 (m, 3H), 7.22–7.18 (m, 1H), 5.75–5.74 (d,
J = 2.4 Hz, 1H), 4.03–3.96 (td, J = 25.6, 2.8 Hz, 1H), 3.86–3.83
(d, J = 12.4 Hz, 1H), 3.63 (s, 3H), 2.60–2.57 (m, 1H), 2.51–2.44
(m, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 167.7, 165.3,
163.1, 141.2, 140.6, 135.0, 134.5, 130.5, 128.3, 127.1, 127.1, 125.3,
124.4, 119.7, 84.4, 56.8, 52.7, 37.4, 33.8. HRMS (EI): exact
(2R,3S,4aS)-Methyl 3-(2-bromophenyl)-1,6-dioxo-1,2,3,4,4a,6-
hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4k).
The◦product was ob◦tained in 85% yield, white solid. Mp 190–
192 C; [a]2D2 = +82.6 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 8.12–8.10 (dd, J = 8.0, 0.8 Hz, 1H), 7.84–7.82 (d,
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J = 8.0 Hz, 1H), 7.70–7.60 (m, 2H), 7.43–7.11 (m, 4H), 5.70-5.70
(d, J = 2.4 Hz, 1H), 4.56–4.49 (td, J = 25.2, 2.4 Hz, 1H), 4.12–4.09
(d, J = 12.8 Hz, 1H), 3.60 (s, 3H), 2.63–2.59 (m, 1H), 2.41–2.32
(m, 1H). 13C NMR (100 MHz, CDCl3): d (ppm) 167.7, 165.6,
163.2, 140.6, 138.0, 134.4, 134.0, 130.4, 129.3, 128.2, 127.2, 126.9,
124.4, 124.3, 119.8, 84.6, 55.2, 52.6, 36.9, 33.4. HRMS (EI): exact
mass calculated for [M]+ (C20H16NO5Br) requires m/z 429.0212,
found m/z 429.0213. The enantiomeric excess was determined
by HPLC. [IA column, 254 nm, DCM, 0.7 mL min-1]: 5.6 min
(minor), 6.8 min (major), ee = 94%.
13.9 min (major), 18.3 min (minor), ee = 94%; 15.9 min (major),
51.4 min (minor), ee = 97%.
(2R,3S)-Methyl 1-oxo-3-m-tolyl-1,2,3,4,4a,6-hexahydrobenzo-
[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4o). The product was
obtained as a mixture◦of both diastereoisomers in 97% yield,
colorless oil. [a]2D2 = -5.4 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 8.16–7.81 (m, 1H), 7.28–7.04 (m, 7H), 5.21–
4.93 (m, 3H), 3.94–3.42 (m, 5H), 2.58–2.10 (m, 5H). 13C NMR
(100 MHz, CDCl3): d (ppm) 169.9, 169.0, 166.1, 165.5, 140.5,
139.9, 138.6, 138.5, 137.2, 135.3, 128.9, 128.8, 128.5, 128.3, 127.8,
127.7, 127.2, 126.8, 126.4, 126.1, 125.7, 125.3, 125.2, 124.5, 124.4,
123.9, 123.8, 123.7, 84.0, 82.8, 67.8, 67.2, 58.4, 57.5, 52.4, 52.2,
38.2, 37.5, 35.3, 35.2. HRMS (EI): exact mass calculated for
[M]+ (C21H21NO4) requires m/z 351.1471, found m/z 351.1468.
[IC column, 254 nm, DCM, 1.0 mL min-1]: 11.6 min (major),
25.0 min (minor), ee = 97%; 14.6 min (major), 48.3 min (minor),
ee = 97%.
(2R,3S,4aS)-Methyl 3-(4-bromophenyl)-1,6-dioxo-1,2,3,4,4a,6-
hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate
(4l).
The◦product was ob◦tained in 78% yield, white solid. Mp 120–
122 C; [a]2D2 = +95.7 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz,
CDCl3): d (ppm) 8.12–8.10 (d, J = 6.8 Hz, 1H), 7.83–7.81 (d,
J = 8.0 Hz, 1H), 7.68–7.64 (td, J = 15.6, 1.2 Hz, 1H), 7.51–7.49
(t, J = 8.4 Hz, 2H), 7.43–7.39 (t, J = 15.2 Hz, 1H), 7.19–7.16 (d,
J = 8.4 Hz, 2H), 5.73–5.72 (d, J = 2.4 Hz, 1H), 4.00–3.93 (td,
J = 24.8, 3.2 Hz, 1H), 3.85–3.82 (d, J = 12.4 Hz, 1H), 3.59 (s,
3H), 2.55–2.52 (m, 1H), 2.50–2.42 (m, 1H). 13C NMR (100 MHz,
CDCl3): d (ppm) 167.8, 165.4, 163.2, 140.6, 138.2, 134.5, 132.3,
130.4, 128.7, 127.1, 124.3, 121.9, 119.7, 84.5, 56.8, 52.6, 37.2,
33.8. HRMS (EI): exact mass calculated for [M]+ (C20H16NO5Br)
requires m/z 429.0212, found m/z 429.0214. The enantiomeric
excess was determined by HPLC. [IC column, 254 nm, DCM,
0.6 mL min-1]: 13.4 min (major), 15.2 min (minor), ee >99%.
(2R,3S)-Methyl 1-oxo-3-p-tolyl-1,2,3,4,4a,6-hexahydrobenzo-
[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4p). The product
was obtained as a mixture of both diastereoisomers in 89% yield,
white solid. Mp 124–126 ◦C; [a]D22 = +9.1◦ (c = 1.00 in CH2Cl2); 1H
NMR (400 MHz, CDCl3): d (ppm) 8.16–7.81 (m, 1H), 7.28–7.03
(m, 7H), 5.20–4.93 (m, 3H), 3.93–3.42 (m, 5H), 2.57–2.06 (m,
5H). 13C NMR (100 MHz, CDCl3): d (ppm) 169.9, 169.0, 166.1,
165.5, 137.5, 137.3, 137.2, 137.1, 137.0, 135.3, 129.7, 129.6, 127.2,
126.8, 126.8, 126.4, 126.1, 125.7, 125.3, 125.2, 124.5, 124.4, 123.7,
84.0, 82.8, 67.8, 67.2, 58.5, 57.6, 52.4, 52.2, 37.9, 37.2, 35.4, 35.2,
21.1. HRMS (EI): exact mass calculated for [M]+ (C21H21NO4)
requires m/z 351.1471, found m/z 351.1469. The enantiomeric
excess was determined by HPLC. [IC column, 254 nm, DCM,
1.0 mL min-1]: 11.3 min (minor), 12.9 min (major), ee = 99%;
16.1 min (major), 31.6 min (minor), ee = 94%.
(2R,3S,4aS)-Methyl 3-(4-nitrophenyl)-1,6-dioxo-1,2,3,4,4a,6-
hexahydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4m).
The product was obtained in 89% yield, yellow solid. Mp 84–
◦
◦
1
86 C; [a]2D2 = +59.3 (c = 1.00 in CH2Cl2); H NMR (400 MHz,
CDCl3): d (ppm) 8.23–8.21 (d, J = 8.4 Hz, 2H), 8.11–8.09 (d,
J = 6.8 Hz, 1H), 7.82–7.80 (d, J = 8.0 Hz, 1H), 7.68–7.64 (td,
J = 15.6, 1.2 Hz, 1H), 7.52–7.49 (d, J = 8.4 Hz, 2H), 7.44–7.40
(t, J = 15.0 Hz, 1H), 5.77 (m, 1H), 4.16–4.07 (m, 1H), 3.95–3.92
(d, J = 12.4 Hz, 1H), 3.58 (s, 3H), 2.58–2.56 (m, 2H). 13C NMR
(100 MHz, CDCl3): d (ppm) 167.5, 164.9, 163.0, 147.6, 146.5,
140.5, 134.6, 130.4, 128.2, 127.2, 124.4, 124.4, 119.7, 84.3, 56.4,
52.7, 37.6, 33.4. HRMS (EI): exact mass calculated for [M]+
(C20H16N2O7) requires m/z 396.0958, found m/z 396.0961. The
enantiomeric excess was determined by HPLC. [IA column,
254 nm, n-hexane/DCM = 1/1, 1.0 mL min-1]: 19.8 min (minor),
31.3 min (major), ee = 94%.
(2R,3S)-Methyl 3-(4-methoxyphenyl)-1-oxo-1,2,3,4,4a,6-hexa-
hydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4q). The
product was obtained as a mixture of both diastereoisomers in
98% yield, yellow solid. Mp 75–77 ◦C; [a]D22 = +11.4◦ (c = 1.00 in
CH2Cl2); 1H NMR (400 MHz, CDCl3): d (ppm) 8.14–7.78 (m, 1H),
7.28–7.13 (m, 4H), 7.05–7.02 (m, 1H), 6.89–6.86 (m, 2H), 5.19–
4.92 (m, 3H), 3.90–3.39 (m, 8H), 2.55–2.05 (m, 2H). 13C NMR
(100 MHz, CDCl3): d (ppm) 169.9, 169.1, 166.0, 165.5, 159.0,
158.8, 137.2, 135.3, 132.6, 132.0, 128.0, 127.9, 127.2, 126.8, 126.4,
126.1, 125.6, 125.3, 125.2, 124.5, 124.4, 123.7, 114.3, 114.3, 84.0,
82.8, 67.8, 67.2, 58.7, 57.9, 55.2, 52.4, 52.2, 37.6, 36.8, 35.5, 35.2.
HRMS (EI): exact mass calculated for [M]+ (C21H21NO5) requires
m/z 367.1420, found m/z 367.1423. The enantiomeric excess was
determined by HPLC. [IC column, 254 nm, DCM, 1.0 mL min-1]:
15.0 min (major), 24.2 min (minor), ee = 92%; 17.0 min (major),
39.9 min (minor), ee = 93%.
(2R,3S)-Methyl 1-oxo-3-phenyl-1,2,3,4,4a,6-hexahydrobenzo-
[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4n). The product
was obtained as a mixture of◦ both diastereoisomers in 86%
yield, colorless oil. [a]2D2 = +11.0 (c = 1.00 in CH2Cl2); 1H NMR
(400 MHz, CDCl3): d (ppm) 8.16–7.80 (m, 1H), 7.36–7.34 (m,
2H), 7.32–7.24 (m, 4H), 7.21–7.15 (m, 1H), 7.07–7.03 (m, 1H),
5.21–4.93 (m, 3H), 3.97–3.42 (m, 5H), 2.59–2.39 (m, 2H). 13C
NMR (100 MHz, CDCl3): d (ppm) 169.8, 169.0, 166.0, 165.5,
140.5, 139.9, 137.1, 135.3, 129.0, 129.0, 127.7, 127.6, 127.2, 127.0,
126.9, 126.8, 126.4, 126.1, 125.7, 125.3, 125.2, 124.5, 124.4, 123.7,
84.0, 82.8, 67.8, 67.2, 58.4, 57.5, 52.4, 52.2, 38.4, 37.6, 35.2, 35.1.
HRMS (EI): exact mass calculated for [M]+ (C20H19NO4) requires
m/z 337.1314, found m/z 337.1313. The enantiomeric excess was
determined by HPLC. [IC column, 254 nm, DCM, 1.0 mL min-1]:
(2R,3S)-Methyl
3-(3-chlorophenyl)-1-oxo-1,2,3,4,4a,6-hexa-
hydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4r). The
product was obtained as a mixture of both diastereoisomers in
◦
76% yield, yellow solid. Mp 78–80 C; [a]2D2 = +4.5◦ (c = 1.00
in CH2Cl2); 1H NMR (400 MHz, CDCl3): d (ppm) 8.13–7.78
(m, 1H), 7.43–7.04 (m, 7H), 5.30–4.94 (m, 3H), 3.95–3.44 (m,
5H), 2.59–2.06 (m, 2H). 13C NMR (100 MHz, CDCl3): d (ppm)
169.6, 168.7, 165.6, 165.0, 142.5, 142.0, 137.0, 135.1, 134.8,
134.7, 130.3, 130.3, 130.2, 128.0, 127.8, 127.3, 127.1, 126.9, 126.5,
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126.1, 125.8, 125.3, 125.2, 125.1, 124.5, 124.4, 123.7, 83.8, 82.6,
67.8, 67.2, 58.1, 57.3, 52.6, 52.4, 38.0, 37.3, 35.0, 34.9. HRMS
(EI): exact mass calculated for [M]+ (C20H18NO4Cl) requires m/z
371.0924, found m/z 371.0921. The enantiomeric excess was
determined by HPLC. [IA column, 254 nm, n-hexane/DCM =
2/1, 1.0 mL min-1]: 12.9 min (minor), 28.3 min (major), ee = 97%;
15.0 min (minor), 17.7 min (major), ee = 97%.
(2R,3S)-Methyl 3-(4-bromophenyl)-1-oxo-1,2,3,4,4a,6-hexahy-
drobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate
(4v). The
product was◦obtained in 86% yield, white solid. Mp 146–148 ◦C;
[a]2D2 = +15.9 (c = 1.00 in CH2Cl2); 1H NMR (400 MHz, CDCl3):
d (ppm) 8.12–7.77 (m, 1H), 7.48–7.46 (m, 2H), 7.27–7.23 (m,
1H), 7.20–7.11 (m, 3H), 7.06–7.02 (m, 1H), 5.20–4.92 (m, 3H),
3.92–3.42 (m, 5H), 2.55–2.06 (m, 2H). 13C NMR (100 MHz,
CDCl3): d (ppm) 169.6, 168.8, 165.6, 165.1, 139.5, 139.0, 137.0,
135.2, 132.1, 132.1, 128.8, 128.7, 127.1, 126.8, 126.4, 126.1, 125.8,
125.3, 124.5, 124.4, 123.7, 121.6, 121.4, 83.8, 82.6, 67.8, 67.2, 58.1,
57.3, 52.5, 52.4, 37.8, 37.1, 35.0, 34.9. HRMS (EI): exact mass
calculated for [M]+ (C20H18NO4Br) requires m/z 415.0419, found
m/z 415.0416. The enantiomeric excess was determined by HPLC.
[IA column, 254 nm, n-hexane/DCM = 3/1, 1.0 mL min-1]:
27.4 min (minor), 102.3 min (major), ee = 99%; 30.4 min (minor),
54.5 min (major), ee = 96%.
(2R,3S)-Methyl 3-(4-chlorophenyl)-1-oxo-1,2,3,4,4a,6-hexahy-
drobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate
(4s). The
product was obtained as a mixture of both diastereoisomers in
◦
99% yield, white solid. Mp 129–132 C; [a]2D2 = +4.3◦ (c = 1.00
in CH2Cl2); 1H NMR (400 MHz, CDCl3): d (ppm) 8.12–7.77
(m, 1H), 7.33–7.30 (m, 2H), 7.26–7.14 (m, 4H), 7.06–7.02 (m,
1H), 5.20–4.92 (m, 3H), 3.93–3.41 (m, 5H), 2.55–2.06 (m, 2H).
13C NMR (100 MHz, CDCl3): d (ppm) 169.6, 168.8, 165.7,
165.1, 139.0, 138.5, 137.0, 135.2, 133.5, 133.3, 129.2, 129.1,
128.4, 128.4, 127.1, 126.8, 126.4, 126.1, 125.8, 125.3, 124.5,
124.4, 123.7, 83.8, 82.6, 67.8, 67.2, 58.2, 57.4, 52.5, 52.3, 37.8,
37.0, 35.1, 34.9. HRMS (EI): exact mass calculated for [M]+
(C20H18NO4Cl) requires m/z 371.0924, found m/z 371.0916.
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, n-hexane/DCM = 2/1, 1.0 mL min-1]: 13.5 min (minor),
41.1 min (major), ee = 93%; 14.1 min (minor), 24.1 min (major),
ee = 93%.
(2R,3S,4aR)-Methyl 1,6-dioxo-3-phenyl-1,2,3,4,4a,6-hexahy-
drobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4a1). White
◦
1
solid. Mp 181–183 C; H-NMR (400 MHz, CDCl3): d (ppm)
8.15–8.13 (dd, J = 8.0, 1.2 Hz, 1H), 8.07–8.05 (d, J = 8.4 Hz, 1H),
7.70–7.67 (td, J = 15.6, 1.2 Hz, 1H), 7.42–7.38 (m, 3H), 7.35–7.32
(m, 1H), 7.27–7.26 (m, 2H), 5.89–5.85 (dd, J = 8.4, 6.8 Hz,
1H), 3.82–3.79 (d, J = 12.0 Hz, 1H), 3.65 (s, 3H), 3.59–3.52 (td,
J = 26.0, 2.8 Hz, 1H), 2.79–2.73 (m, 1H), 2.53–2.44 (m, 1H).
13C-NMR (100 MHz, CDCl3): d (ppm) 169.0, 165.3, 162.2, 139.8,
138.8, 134.8, 130.3, 129.2, 128.1, 126.9, 126.5, 123.0, 118.5, 84.4,
57.8, 52.7, 38.1, 34.2. HRMS (EI): exact mass calculated for
[M]+ (C20H17NO5) requires m/z 351.1107, found m/z 351.1106.
The enantiomeric excess was determined by HPLC. [IC column,
254 nm, DCM, 1.0 mL min-1]: 12.6 min (major), 18.1 min (minor),
ee = 98%.
(2R,3S)-Methyl 3-(2-fluorophenyl)-1-oxo-1,2,3,4,4a,6-hexahy-
drobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate
(4t). The
product was obtained as a mixture of both diastereoisomers in
◦
99% yield, yellow solid. Mp 106–111 C; [a]2D2 = -3.4◦ (c = 1.00
in CH2Cl2); 1H NMR (400 MHz, CDCl3): d (ppm) 8.13–7.79 (m,
1H), 7.28–7.04 (m, 7H), 5.21–4.91 (m, 3H), 4.19–3.40 (m, 5H),
2.58–2.16 (m, 2H). 13C NMR (100 MHz, CDCl3): d (ppm) 169.6,
168.9, 165.8, 165.3, 137.1, 135.3, 129.3, 129.3, 129.2, 129.0, 129.0,
128.4, 128.3, 127.2, 127.1, 127.0, 126.8, 126.7, 126.6, 126.4, 126.1,
125.7, 125.3, 125.3, 124.7, 124.7, 124.6, 124.6, 124.5, 124.4, 123.7,
116.3, 116.1, 116.1, 116.0, 83.9, 82.8, 67.8, 67.2, 56.4, 55.6, 52.5,
52.3, 34.2, 33.5, 33.2, 32.9. HRMS (EI): exact mass calculated for
[M]+ (C20H18NO4F) requires m/z 355.1220, found m/z 355.1219.
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, n-hexane/DCM = 1/1, 1.0 mL min-1]: 6.3 min (minor),
9.5 min (major), ee = 95%; 7.3 min (minor), 8.0 min (major), ee =
94%.
(3R,4S,6S)-Methyl 1-(2-carbamoylphenyl)-6-hydroxy-2-oxo-4-
phenyl piperidine-3-carboxylate (4a2). The intermediate product
was isolated as a mixture of two diastereomers by column
chromatography after full conversion of 1a using ethyl acetate and
then 1,4-dioxane as the eluent. White solid. Mp 198–199 ◦C; 1H-
NMR (400 MHz, (CD3)2SO): d (ppm) 8.15–6.89 (m, 9H), 6.46–
5.18 (m, 1H), 3.95–3.81 (m, 1H), 3.57–3.24 (m, 4H), 2.58–2.37
(m, 1H), 2.03–1.37 (m, 1H). 13C-NMR (100 MHz, (CD3)2SO): d
(ppm) 174.9, 174.4, 174.0, 173.9, 170.9, 170.6, 146.9, 144.2, 143.7,
140.8, 139.7, 136.9, 136.0, 135.4, 134.2, 134.0, 133.6, 133.2, 132.9,
132.8, 132.5, 132.4, 132.3, 132.1, 87.0, 86.0, 62.5, 61.8, 56.9, 42.9,
42.2, 41.8, 41.7, 35.7. HRMS (EI): exact mass calculated for [M]+
(C20H20N2O5) requires m/z 368.1372, found m/z 368.1378.
(2R,3S)-Methyl
3-(4-fluorophenyl)-1-oxo-1,2,3,4,4a,6-hexa-
hydrobenzo[d]pyrido[2,1-b][1,3]oxazine-2-carboxylate (4u). The
product was obtained as a mixture of both diastereoisomers in
63% yield, yellow solid. Mp 144–149 ◦C; [a]D22 = +16.2◦ (c = 1.00
in CH2Cl2); 1H NMR (400 MHz, CDCl3): d (ppm) 8.13–7.78
(m, 1H), 7.28–7.02 (m, 7H), 5.30–4.94 (m, 3H), 3.95–3.45 (m,
5H), 2.58–2.08 (m, 2H). 13C NMR (100 MHz, CDCl3): d (ppm)
169.7, 168.9, 165.8, 165.2, 163.3, 160.8, 137.1, 136.3, 136.2, 128.6,
128.5, 127.1, 126.8, 126.4, 125.8, 125.3, 124.5, 124.4, 123.7, 116.0,
115.9, 115.8, 115.7, 83.8, 82.7, 67.8, 67.2, 58.5, 57.7, 52.5, 52.3,
37.7, 36.9, 35.3, 35.1. HRMS (EI): exact mass calculated for
[M]+ (C20H18NO4F) requires m/z 355.1220, found m/z 355.1215.
The enantiomeric excess was determined by HPLC. [IA column,
254 nm, n-hexane/DCM = 3/1, 1.0 mL min-1]: 23.1 min (minor),
78.5 min (major), ee = 99%; 25.8 min (minor), 50.2 min (major),
ee = 94%.
Acknowledgements
We acknowledge National Natural Science Foundation of China
(20902018), the Fundamental Research Funds for the Central
Universities, Shanghai Pujiang Program (08PJ1403300) and In-
novation Program of Shanghai Municipal Education Commission
(11ZZ56) for financial support.
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1816 | Org. Biomol. Chem., 2011, 9, 1809–1816
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The Royal Society of Chemistry 2011
©