Stereospecific Synthesis of 3,4-Dihydro-2 H-naphtho-1,4-oxazin-2-ones by Unification of Benzoxepine-4-carboxylates with Chiral Amino Acid Ethyl Esters

Article abstract of DOI:10.1021/acs.joc.9b02624

A novel and efficient stereocontrolled method has been developed for the preparation of chiral 3,4-dihydro-2H-naphtho[1,2-b][1,4]oxazin-2-ones by the reaction of benzoxepine-4-carboxylates with chiral amino acid ethyl esters for the first time. The chiral 3,4-dihydro-2H-naphtho-1,4-oxazinones have been achieved in one step by the formation of C-N, C-C, and C-O bonds.

Full text of DOI:10.1021/acs.joc.9b02624

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Article
Stereospecific Synthesis of 3,4-Dihydro-2H-naphtho-1,4-oxazin-2-ones by
Unification of Benzoxepine-4-carboxylates with Chiral Amino Acid Ethyl Esters
Veera Prasad Kasagani, Siva Hariprasad Kurma, and China Raju Bhimapaka
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02624 • Publication Date (Web): 29 Jan 2020
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Page 1 of 13
The Journal of Organic Chemistry
Stereospecific Synthesis of 3,4-Dihydro-2H-naphtho-1,4-oxazin-2-ones by
Unification of Benzoxepine-4-carboxylates with Chiral Amino Acid Ethyl
Esters
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Veera Prasad Kasagani, Siva Hariprasad Kurma and China Raju Bhimapaka*
8
9
Department of Organic Synthesis and Process Chemistry, CSIR-Indian Institute of Chemical Technology,
Hyderabad-500007, India
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60
O
OC2H5
H
N
CO2C2H5
R
O
*
R
* CO2C2H5
NH2
p-TsOH, DCM
O
+
reflux
O
O
ABSTRACT: A novel and efficient stereocontrolled method has been developed for the preparation of chiral 3,4-dihydro-2H-
naphtho[1,2-b][1,4]oxazin-2-ones by the reaction of benzoxepine-4-carboxylates with chiral amino acid ethyl esters for the first
time. The chiral 3,4-dihydro-2H-naphtho-1,4-oxazinones have been achieved in one step by the formation of C-N, C-C and C-O
bonds.
INTRODUCTION
general strategies for the synthesis of enantiopure
Naphthoxazinones and benzoxazinones constitute an im-
dihydronaphthoxazinone framework has become attractive and
portant class of bio-active compounds and useful interme-
challenging.
diates for the preparation of pharmaceuticals.1 These
Cyclo addition
heterocyclic compounds particularly benzoxazinones are
R2
N
R2
N
Benzoylquinidine
Sc(OTf)3
R
R3
O
synthetic building blocks and present in a variety of natural
products.2 Further, these compounds are photo active
molecules which possess fluorescent, photophysical and
photochemical properties.3 Similarly, chiral 3,4-dihydro-1,4-
naphthoxazin-2-ones and 3,4-dihydro-1,4-benzoxazin-2-ones
represent the structural motif of several natural products with
interesting biological properties. Hence, the preparations of
these heterocyclic compounds have attracted much attention to
synthetic organic and medicinal chemists. To the best of our
knowledge only two approaches are available for the
preparation of chiral dihydrobenzoxazinones (Scheme 1). The
enantioselective cycloaddition of ortho-benzoquinone imides
with chiral ketene enolates furnished the chiral
R
*
O
R3
+
Hunig's base
THF, -78 o
R1
O
R1
O
Cl
C
Thomas Lectka et al
Assymetric hydrogenation
H
Assymetric
hydrogenation
R1
O
N
R1
O
N
O
*
R
Ref. 5
R
O
Assymetric synthesis
Cl
H
N
O
i. NH2CH(R)CO2H
KOH, MeOH, rt, 24 h
HO
R
O
*
Cl
O
ii. NaBH4, H2O, rt,
4h
Cl
O
Gorohovsky et al
O
OC2H5
This work
H
N
CO2C2H5
R
O
*
R
* CO2C2H5
NH2
p-TsOH, DCM
+
O
reflux
dihydrobenzoxazinones.4
Asymmetric
reduction
of
O
O
benzoxazinones is the another approach to access the
dihydrobenzoxazinones.5 Interestingly, there is only one
method reported by Gorohovsky et al6 for the preparation of
chiral dihydronaphthoxazinones by the reaction of 2,3-
dichloro-1,4-naphthoquinones with natural amino acids as
chiral source (Scheme 1). Therefore, the development of new
Stereospecific formation (R or S)
(Amino acid dependent)
Scheme 1. Previous approaches for the preparation of chiral
dihydro[1,4]benzoxazinones and naphthoxazinone
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Our research group is interested in the development of better species when compared to its acid. Therefore, the ethyl
1
2
3
4
5
6
7
8
novel methods for the preparation of heterocyclic compounds.7
The research work on benzoxepine-4-carboxylates have
produced novel heterocyclic compounds.8 In continuation of
our work on benzoxepine-4-carboxylates, recently we have
prepared useful oxygenated heterocycles.9 The present work
(S)-2-amino-3-phenylpropanoate 2a was prepared from 2 by
standard esterification protocol.10 Thus obtained ester 2a (1
equiv.) was reacted with 1a (1 equiv.) in the presence of p-
TsOH (30 mol %) with ethanol under reflux conditions
(Scheme 2). This furnished compound 3a with improved yield
(45%, Table 1, entry 2). Other solvents such as MeOH,
toluene, xylene, diethyl ether, DCM, DCE, MeCN and THF
(Table 1, entry 3-10) were also studied to see the effect of
solvents. We observed that DCM and DCE solvents are
superior when compared to other tested solvents and produced
compound 3a in good yields (69%, 58%, Table 1, entry 7-8).
The reaction at room temperature with DCM is inferior when
compared to reflux condition (3a, 36% yield, Table 1, entry
11). A similar result was obtained with both low (20 mol %)
and high (50 mol %) equivalents of p-TsOH (Table 1, entry
12-13) when we tested the reaction of 1a with 2a in DCM
under reflux conditions.
envision to develop
a stereospecific method for the
9
construction of 3,4-dihydro-2H-1,4-naphtho-1,4-oxazin-2-
ones by the reaction of benzoxepine-4-carboxylates with
chiral amino acid ethyl esters.
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RESULTS AND DISCUSSION
In an initial experiment, we have carried out the reaction of
benzoxepine-4-carboxylate (1a, 1 equiv. Prepared as per our
previous
reported
method)
with
(S)-2-amino-3-
phenylpropanoic acid (2, 1 equiv.) in the presence of p-TsOH
(30 mol %) with ethanol under reflux conditions (Scheme 2).
A
pale yellow solid was obtained after column
chromatography (20% yield). The compound was identified as
ethyl (S)-3-benzyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
Table 1. Optimization Study
O
OC2H5
H
N
CO2C2H5
b][1,4]oxazine-5-carboxylate 3a based on spectral data. The
reaction is stereocontrolled and specifically obtained
compound 3a. This work represents the first example for the
stereospecific construction of 3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazin-2-one by the formation of C-N, C-C and C-O
bonds in one-pot starting from benzoxepine-4-carboxylate.
CO2C2H5
NH2
Ph
O
+
O
O
O
1a
3a
2a
____________________________________________________________
Yield[d]
Catalyst (equiv)
Solvent
Entry
Time[h]
____________________________________________________________
01a,b
02b
03b
04b
05b
EtOH
EtOH
MeOH
toluene
xylene
p-TsOH (0.3)
p-TsOH (0.3)
p-TsOH (0.3)
p-TsOH (0.3)
p-TsOH (0.3)
20
45
31
20
38
16
16
18
18
18
06b
07b
08b
09b
10b
11c
12b
13b
14b
15b
16b
17b
18b
19b
20b
21b
22b
p-TsOH (0.3)
p-TsOH (0.3)
p-TsOH (0.3)
ether
DCM
32
24
18
42
69
58
Scheme 2. Preparation of compound 3a
1,2-DCE
(S)-2-Amino-3-
Ethyl (S)-2-amino-
p-TsOH (0.3)
p-TsOH (0.3)
p-TsOH (0.3)
p-TsOH (0.2)
18
18
48
32
47
43
36
62
CO2C2H5
O
MeCN
THF
DCM
DCM
phenylpropanoic
3-phenyl
2
acid
2a
propanoate
p-TsOH
EtOH, reflux
p-TsOH
EtOH, reflux
O
1a
p-TsOH (0.5)
HCl (1.0)
22
15
18
16
07
68
31
37
30
34
DCM
DCM
DCM
DCM
DCM
O
OC2H5
O
OC2H5
AcOH (0.3)
TFA (0.3)
AlCl3 (0.3)
H
N
H
N
Ph
Ph
O
O
O
O
FeCl3 (0.3)
Cu(OAc)2 (0.3)
DCM
DCM
16
16
18
10
10
33
3a
, 45%
3a
, 20%
Trace
Trace
49
CuI (0.3)
Bi(OTf)3 (0.3)
La(OTf)3 (0.3)
DCM
DCM
DCM
46
____________________________________________________________
a(S)-2-Amino-3-phenylpropanoic acid used as reactant, b reflux,
c room temperature, disolated yield.
We observed that the above reaction is very slow and
produced compound 3a in low quantity. The unreacted starting
materials were recovered even after prolonged reaction time.
This may be due to the amino acid is not reacted well under
these conditions. We thought the amino acid ethyl ester is
Having optimized the reaction conditions, next, the re-
action of 1a with 2a was tested with various catalysts such as
protic acids (Table 1, entry 14-16), Lewis acids (Table 1, entry
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17-20) and triflates (Table 1, entry 21-22) in DCM under phenylpropanoate 2b under our optimized reaction conditions
1
reflux conditions. All these reactions have produced
compound 3a in moderate yields. No product formation was
observed when the reaction was carried out in absence of
catalyst. The above results revealed that 30 mol % p-TsOH is
sufficient to promote the reaction in DCM under reflux
conditions to produce the compound 3a (69% yield, Table 1,
entry 7). The compound 3a was obtained stereospecifically
and this was confirmed by chiral HPLC analysis (Table 2,
enantiomeric purity = 99.89%, see SI). Then we have carried
out the reaction of 1a with ethyl (R)-2-amino-3-
to obtain 3b (Table 2, enantiomeric purity = 99.95%, see SI).
Further, we also carried out the reaction of 1a with ethyl 2-
amino-3-phenylpropanoate 2c (Table 2) to furnish racemic (±)
naphthoxazinone compound 3c (S = 50.61%; R = 49.39%, see
SI). The HPLC analysis of the chiral compounds 3a-b was
compared with the racemic compound 3c. The present
protocol was found to be stereocontrolled and specifically
formed the chiral compounds.
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Further to explore the present protocol, we have
investigated the reaction with substrates present on
benzoxepine-4-carboxylates. Accordingly, the electron
withdrawing (bromo 1b, chloro 1c) and electron donating
(methoxy 1d, methyl 1e-f) groups present on benzoxepine-4-
carboxylates were prepared as per our earlier reported
method.8a The benzoxepines 1b-f were reacted with ethyl (S)-
2-amino-3-phenylpropanoate 2a and ethyl (R)-2-amino-3-
phenylpropanoate 2b under our optimized conditions. All
these reactions proceeded smoothly and produced the
corresponding chiral naphthoxazinones 3b-m (Table 2). The
electron donating groups produced the compounds with better
yields when compared to electron withdrawing groups. All the
compounds were characterized by spectral data and the
enantiomeric purity of the compounds were analyzed by chiral
HPLC (>97-99%, see SI).
Table 2. Preparation of 3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylates 3a-m
O
OC2H5
H
CO2C2H5
CO2C2H5
*
N
*
p-TsOH
NH2
+
O
R
DCM, reflux
O
O
2a-c
O
R
2a
2b
2c
= Ethyl (S)-2-amino-3-phenylpropanoate
= Ethyl (R)-2-amino-3-phenylpropanoate
= Ethyl 2-amino-3-phenylpropanoate
1a-f
3a-m
O
OC2H5
H
N
O
OC2H5
H
N
O
OC2H5
H
N
Ph
Ph
Ph
O
O
O
O
O
O
3a
24h, 69%,
3b
24h, 68%,
3c
24h, 59%,
ee = >99%
ee = >99%
O
OC2H5
H
N
O
OC2H5
H
N
O
OC2H5
H
N
Ph
Ph
Ph
O
O
O
O
O
O
Br
Br
Cl
3d
18h, 28%,
3e
18h, 27%,
To broaden the scope of the present stereospecific
reaction, the following amino acid ethyl esters 2d-v have been
prepared from their corresponding amino acids (see SI).10
Accordingly, 1a was reacted with 2d-t under our optimized
reaction conditions (Table 3).11 The reactions underwent
smoothly with amino acid ethyl esters such as 2d-l, 2n-p and
2r provided the corresponding chiral naphthoxazinones 3n-v,
3x-z and 3zb with >92-99% enantiomeric purity (Table 3).
Whereas, the amino acid ethyl esters such as 2m, 2q and 2s-t
could not provide the target compounds under these reaction
conditions and the starting materials were recovered. The
reaction of 1a with ethyl (R)-2-amino-2-phenylacetate 2u and
ethyl (S)-2-amino-2-phenylacetate 2v provided the compounds
3ze and 3zf (Table 4). The compound 3ze afforded with low
enantiomeric purity (R isomer = 16.25%, S isomer = 83.75%
see SI) and compound 3zf obtained in racemic (±) mixture (R
isomer = 46.46%, S isomer = 53.54%, see SI). As the α-
ee = >99%
3f
20h, 25%,
ee = >97%
ee = >99%
O
OC2H5
O
OC2H5
O
OC2H5
H
N
H
N
H
N
Ph
Ph
Ph
O
O
O
O
O
O
Cl
H3CO
3g
20h, 24%,
H3CO
3h
28h, 59%,
ee = >99%
3i
28h, 59%,
ee = >99%
ee = >99%
O
OC2H5
H
N
O
OC2H5
H
N
O
OC2H5
H
N
Ph
Ph
Ph
O
O
O
O
O
O
H3C
H3C
CH3
3j
28h, 57%,
3k
28h, 58%,
ee = >99%
ee = >99%
3l
28h, 55%,
ee = >99%
O
OC2H5
H
N
Ph
O
O
CH3
3m
28h, 54%,
ee = >99%
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hydrogen is more acidic in case of 2-amino-2-phenylacetic reaction of benzoxepine-4-carboxylates 1c and 1f with 2v
1
2
3
4
5
6
7
8
acid this type of recemization is possible. 2D NMR spectra
were recorded for the compounds 3zb, 3ze and 3zg and
incorporated in the SI.
under our optimized conditions (Table 4). Interestingly, the
electron donating group present on benzoxepine produced
chiral compound 3zg (enantiomeric purity for R isomer = >
99%, see SI) and electron withdrawing group present on
benzoxepine could not provided the compound 3zh (Table 4,
see SI). This result indicated that the racemization has not
been observed when electron donating group present on
benzoxepine. All the obtained compounds were characterized
by spectroscopy and enantiomeric purity analyzed by chiral
HPLC (see SI).
Table 3. Preparation of 3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylates 3n-zd
9
_______________________________________________________________________________________
10
11
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O
OC2H5
H
N
CO2C2H5
O
R
O
R
CO2C2H5
*
*
p-TsOH
+
DCM, reflux
NH2
O
O
1a
2d-t
3n-zd
_______________________________________________________________________________________
O
OC2H5
O
OC2H5
O
OC2H5
H
N
H
N
H
N
CH3
O
CH3
O
Table 4. Preparation of compounds 3ze-zh
O
O
O
O
O
OC2H5
O
OC2H5
H
N
H
N
3p
24h, 55%,
3o
28h, 31%,
3n
56h, 18%,
ee = >99%
ee = >95%
O
O
O
O
O
OC2H5
O
OC2H5
H
N
O
OC2H5
H
N
CH3
CH3
H
N
3ze
24h, 43%,
ee = >67%
3zf
24h, 42%,
CH3
CH3
O
O
O
O
O
O
O
OC2H5
H
N
O
OC2H5
H
N
3r
28h, 44%,
3q
28h, 44%,
3s
24h, 41%,,
ee = >99%
ee = >99%
ee = >99%
O
O
O
O
OC2H5
H
N
O
OC2H5
H
N
O
OC2H5
H
N
O
O
O
O
SCH3
SCH3
CH3
Cl
3zg
24h, 31%,
ee = >99%
3zh
48h, 0%,
O
O
O
O
O
O
3t
24h, 47%,
3u
3v
20h, 40%,
20h, 44%,,
ee = >99%
ee = >94%
ee = >92%
To further demonstrate the present protocol, chiral 3,4-
dihydro-2H-naphtho[1,2-b][1,4]oxazin-2-ones 3a, 3c and 3f
have been prepared in gram scale by the reaction of
benzoxepine compounds 1a (2.5 g) with 2a, 1a (2.2 g) with
2c, and 1c (1.2 g) with 2a under our optimized conditions and
the results were depicted in Scheme 3.
O
OC2H5
H
N
O
OC2H5
H
N
OC2H5
H
N
SH
O
O
OH
O
O
OH
O
O
3y
26h, 18%,
3x
26h, 19%,
3w
48h, 0%,
ee = >99%
ee = >99%
O
OC2H5
H
N
OC2H5
H
N
O
OC2H5
H
N
OH
OH
O
O
O
O
O
O
Scheme 3. Gram scale preparation of compounds 3a, 3c &
3z
3zb
32h, 14%,
28h, 33%,
3za
48h, 0%,
3f
ee = >99%
OC2H5
N
ee = >99%
O
OC2H5
H
N
O
OC2H5
O
OC2H5
H
N
O
OC2H5
H
N
N
O
Ph
Ph
Ph
O
O
O
O
O
O
O
O
O
Cl
3zc
3zd
48h, 0%,
48h, 0%,
3f
, 23.59% (0.42 g)
3a
3c
, 57.60% (1.97 g)
, 67.35% (2.62 g)
Since we obtained racemic target compound 3zf from ethyl
(S)-2-amino-2-phenylacetate 2v, then we sought to conduct the
reaction with electron withdrawing and electron donating
group present on benzoxepine-4-carboxyltes in order to check
the racemization. Accordingly, we have carried out the
A plausible reaction pathway for the preparation of 3a was
depicted in Scheme 4. The benzoxepine-4-carboxylate 1a with
ethyl (S)-2-amino-3-phenylpropanoate 2a under acidic
medium forms the Schiff base A. The imine (Schiff base)
upon rearrangement provides enamine intermediate B. The
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capillary tubes on a Stuart melting point apparatus and are
rearrangement of intermediate
B
and subsequent
1
2
3
4
5
6
7
8
1
uncorrected. H NMR and 13C NMR spectra were recorded on
intramolecular cyclization through C-E furnish the compound
3a with the elimination of ethanol.
Avance 400 MHz and 500 MHz spectrometers in CDCl3 using
TMS as internal standard. FT-IR spectra were recorded on a
Thermo Nicollet Nexus 670 spectrometer. Mass spectra were
obtained on Agilent LCMS instrument. HRMS were measured on
Agilent Technologies 6510, Q-TOFLC/MS ESI-Technique.
Optical rotations were recorded on Anton Paar, MCP-200
polarimeter with 1 mL cell. Chiral HPLC analysis was carried out
by Shimadzu SPD-M20A, PDA detector using Chiral column:
CHIRALPAK IC-3, 250 mm. Eluent: n-hexane/isopropyl alcohol
= 85:15; flow rate: 0.6 mL/min; 200-500 nm. The Chiral HPLC
analyses for the amino acid ethyl esters 2e-f and 2p-q have been
analyzed by CHIRALPAK IC-G, 250 mm. Eluent: n-
hexane/isopropyl alcohol = 85:15; flow rate: 0.5 mL/min using
RID detector.
Scheme 4. Plausible Reaction Mechanism
CO2C2H5
CO2C2H5
NH2.HCl
p-TsOH
N
*
R
O
+
*
9
R
-H2O
O
CO2C2H5
O
C2H5O2C
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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35
36
37
38
39
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44
45
46
47
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49
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56
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58
59
60
1a
A
2a
CO2C2H5
NH
CO2C2H5
CO2C2H5
NH
NH
R
*
R
O
O+
HO
H
*
C2H5O2C
*
C2H5O2C
R
B
C2H5O2C
H
D
C
O
OC2H5
H
CO2C2H5
N
*
R
O
-C2H5OH
NH
*
O
R
General procedure for the preparation of ethyl 3-oxo-2,3-
dihydrobenzo[b]oxepine-4-carboxylates 1a-f: The benzoxepine-
4-carboxylates 1a-f have been prepared from ethyl 2-
(chloromethyl)-2-hydroxy-2H-chromene-3-carboxylates by Wittig
homologation as per our previous reported method and the
compounds were compared with our reported compounds.8a,c,9
Typical procedure for the preparation of 3,4-dihydro-2H-
naphtho[1,2-b][1,4]oxazin-2-ones: p-TsOH (0.057 g, 0.3 mmol)
was added to the stirred solution of ethyl (S)-2-amino-3-
phenylpropanoate (2a, 0.229 g, 1.0 mmol) and ethyl 3-oxo-2,3-
dihydrobenzo[b]oxepine-4-carboxylate (1a, 0.232 g, 1.0 mmol)
in DCM at room temperature. The contents were refluxed. After
completion of the reaction (TLC, 24h), the solvent was removed
under reduced pressure. The crude product was purified by
column chromatography using silica gel (60:120, hexane: ethyl
acetate, 98:2) as eluent afforded ethyl (S)-3-benzyl-2-oxo-3,4-
dihydro-2H-naphtho[1,2-b][1,4]oxazine-5-carboxylate 3a as pale
yellow solid in 69% yield. The target compounds 3b-v, 3x-z, 3zb
and 3ze-zg were prepared by the reaction of ethyl 3-oxo-2,3-
dihydrobenzo[b]oxepine-4-carboxylates 1a-f with amino acid
ethyl esters 2b-l, 2n-p, 2r and 2u-v under similar conditions.
OH
C2H5O
3a
E
O
CONCLUSIONS
In conclusion, a facile stereospecific method has been
developed for the preparation of chiral 3,4-dihydro-1,4-
naphthoxazin-2-ones by the reaction of benzoxepine-4-
carboxylates with chiral amino acid ethyl esters for the first
time. The present protocol is efficient and practical one-step
process to construct the chiral naphthoxazinones. The
synthesized compounds can be utilized as lead compounds in
the area of pharmaceuticals, agrochemicals and material
science.
EXPERIMENTAL SECTION
General Information. Salicylaldehydes, ethyl 4-chloro-3-
oxobutanoate and amino acids such as glycine, phenylglycine,
alanine, phenylalanine, valine, serine, tyrosine, methionine,
leucine, isoleucine and cystein were procured from Sigma-
Aldrich. Triphenylphosphine, p-TsOH, thionyl chloride and
solvents were obtained from local suppliers. All the reactions
were carried out under reflux conditions using oil bath. The
reactions were monitored by thin layer chromatography (TLC) on
pre-coated silica gel 60 F254 (mesh) and spots were visualized
under UV light. Merck silica gel (60-120 mesh) was used for
chromatography. Melting points were determined in open glass
Ethyl
(S)-3-benzyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3a). Pale yellow solid (108 mg,
20
º
69% Yield); [α]D = +20.12 (c = 0.33, CHCl3); mp: 168-170 C;
1H NMR (500 MHz, CDCl3): δ 8.34 (s, 1H), 8.06 (dd, J = 8.5, 0.7
Hz, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.58-7.54 (m, 1H), 7.36-7.31
(m, 3H), 7.27 (dd, J = 9.5, 3.4 Hz, 1H), 7.21-7.18 (m, 2H), 7.11
(s, 1H), 4.38-4.25 (m, 3H), 3.35 (dd, J = 13.8, 3.8 Hz, 1H), 3.02
(dd, J = 13.8, 10.0 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H). 13C {1H}
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NMR (126 MHz, CDCl3): δ 166.8, 165.5, 135.9, 134.1, 129.6,
117.7, 115.9, 61.5, 55.4, 37.5, 14.3. FT-IR (KBr): 3336, 2992,
1
2
3
4
5
6
7
8
129.4, 129.1, 128.9, 128.8, 127.3, 126.3, 126.0, 124.2, 119.2,
115.1, 61.3, 55.6, 37.3, 14.3. FT-IR (KBr): 3332, 2990, 1768,
1688, 1466, 1298, 1211, 1154, 1047, 740 cm-1. MS-ESI: m/z 362
[M+H]+; HRMS-ESI: calcd for C22H20NO4 [M+H]+ 362.1392;
found 362.1386. HPLC analysis: enantiomeric purity = 99.89%.
1772, 1690, 1465, 1330, 1277, 1159, 1048, 810 cm-1. MS-ESI:
m/z 440 [M+H]+; HRMS-ESI: calcd for C22H19BrNO4 [M+H]+
440.0497; found 440.0500. HPLC analysis: enantiomeric purity =
99.76%.
Ethyl
(R)-3-benzyl-8-bromo-2-oxo-3,4-dihydro-2H-
Ethyl
(R--3-benzyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3e). Pale yellow
9
20
b][1,4]oxazine-5-carboxylate (3b). Pale yellow solid (106 mg,
solid (38 mg, 27% Yield); [α]D = -8.60 (c = 0.2, CHCl3); mp:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20
º
68% Yield); [α]D = -19.52 (c = 0.33, CHCl3); mp: 167-169 C;
1H NMR (500 MHz, CDCl3): δ 8.34 (s, 1H), 8.06 (d, J = 8.5 Hz,
1H), 7.79 (d, J = 8.3 Hz, 1H), 7.58-7.54 (m, 1H), 7.37-7.31 (m,
3H), 7.27 (dd, J = 9.5, 3.4 Hz, 1H), 7.20 (d, J = 7.0 Hz, 2H), 7.11
(s, 1H), 4.37-4.26 (m, 3H), 3.35 (dd, J = 13.8, 3.8 Hz, 1H), 3.02
(dd, J = 13.8, 10.1 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H). 13C {1H}
NMR (126 MHz, CDCl3): δ 166.8, 165.2, 135.9, 134.1, 129.6,
129.4, 129.1, 128.9, 128.8, 127.3, 126.3, 126.0, 124.2, 119.2,
115.1, 61.3, 55.6, 37.3, 14.3. FT-IR (KBr): 3331, 2989, 1768,
1688, 1465, 1298, 1210, 1154, 1047, 740 cm-1. MS-ESI: m/z 362
[M+H]+; HRMS-ESI: calcd for C22H19NNaO4 [M+Na]+ 384.1206;
found 384.1229. HPLC analysis: enantiomeric purity = 99.95%.
168-170 ºC; 1H NMR (400 MHz, CDCl3): δ 8.23 (s, 1H), 7.92 (d,
J = 9.7 Hz, 2H), 7.60 (dd, J = 9.0, 1.8 Hz, 1H), 7.32 (t, J = 7.2 Hz,
2H), 7.27 (d, J = 7.4 Hz, 1H), 7.19 (d, J = 6.9 Hz, 2H), 7.16 (s,
1H), 4.38-4.26 (m, 3H), 3.35 (dd, J = 13.8, 3.8 Hz, 1H), 3.02 (dd,
J = 13.7, 9.9 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H). 13C {1H} NMR
(101 MHz, CDCl3): δ 166.5, 165.1, 135.7, 134.1, 132.5, 130.8,
130.1, 129.4, 128.9, 127.6, 127.4, 127.2, 124.3, 121.0, 117.7,
115.9, 61.5, 55.4, 37.5, 14.3. FT-IR (KBr): 3335, 2990, 1772,
1690, 1464, 1330, 1276, 1159, 1048, 810 cm-1. MS-ESI: m/z 440
[M+H]+; HRMS-ESI: calcd for C22H19BrNO4 [M+H]+ 440.0497;
found 440.0479. HPLC analysis: enantiomeric purity = 98.63%.
Ethyl
(S)-3-benzyl-8-chloro-2-oxo-3,4-dihydro-2H-
Ethyl
3-benzyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3f). Pale yellow
20
b][1,4]oxazine-5-carboxylate (3c). Pale yellow solid (93 mg,
59% Yield); mp: 152-154 °C; 1H NMR (400 MHz, CDCl3): δ 8.35
(s, 1H), 8.06 (dd, J = 8.6, 0.8 Hz, 1H), 7.79 (dd, J = 8.0, 4.5 Hz,
1H), 7.60-7.52 (m, 1H), 7.37-7.26 (m, 4H), 7.22-7.17 (m, 2H),
7.11 (s, 1H), 4.38-4.25 (m, 3H), 3.35 (dd, J = 13.7, 3.8 Hz, 1H),
3.02 (dd, J = 13.7, 10.1 Hz, 1H), 1.40-1.35 (m, 3H). 13C {1H}
NMR (101 MHz, CDCl3): δ 166.7, 165.5, 135.8, 134.0, 129.6,
129.3, 129.1, 128.6, 128.8, 127.3, 126.3, 125.7, 124.1, 119.1,
115.1, 61.3, 55.5, 37.2, 14.3. FT-IR (KBr): 3563, 3371, 3328,
1766, 1702, 1641, 1520, 1475, 1382, 1304, 1212 cm-1. MS-ESI:
m/z 362 [M+H]+; HRMS-ESI: calcd for C22H20NO4 [M+H]+
362.1392; found 362.1392. HPLC analysis: enantiomeric purity =
50.61% for (S) and 49.39% for (R).
solid (36 mg, 25% Yield); [α]D = +7.55 (c = 0.05, CHCl3); mp:
º
168-170 C; 1H NMR (500 MHz, CDCl3): δ 8.23 (s, 1H), 7.99 (d,
J = 9.1 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 9.1, 2.0
Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.19
(d, J = 7.0 Hz, 2H), 7.15 (s, 1H), 4.38-4.27 (m, 3H), 3.36 (dd, J =
13.8, 3.8 Hz, 1H), 3.02 (dd, J = 13.8, 9.9 Hz, 1H), 1.37 (t, J = 7.1
Hz, 3H). 13C {1H} NMR (126 MHz, CDCl3): δ 166.5, 165.1,
135.7, 134.1, 130.1, 129.9, 129.8, 129.4, 128.9, 127.7, 127.5,
127.4, 126.7, 124.2, 121.0, 116.1, 61.5, 55.4, 37.5, 14.3. FT-IR
(KBr): 3337, 2925, 1770, 1690, 1465, 1333, 1279, 1153, 1046,
809 cm-1. MS-ESI: m/z 396 [M+H]+; HRMS-ESI: calcd for
C22H19ClNO4 [M+H]+ 396.1003; found 396.0965. HPLC analysis:
enantiomeric purity = 99.99%.
Ethyl
(S)-3-benzyl-8-bromo-2-oxo-3,4-dihydro-2H-
Ethyl
(R)-3-benzyl-8-chloro-2-oxo-3,4-dihydro-2H-
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3d). Pale yellow
solid (40 mg, 28% Yield) ; [α]D20 = +6.91 (c = 0.33, CHCl3); mp:
170-172 ºC; 1H NMR (500 MHz, CDCl3): δ 8.23 (s, 1H), 7.93 (dd,
J = 7.9, 5.3 Hz, 2H), 7.60 (dd, J = 9.0, 1.5 Hz, 1H), 7.32 (t, J =
7.4 Hz, 2H), 7.27 (d, J = 7.6 Hz, 1H), 7.19 (d, J = 7.3 Hz, 2H),
7.16 (s, 1H), 4.38-4.27 (m, 3H), 3.36 (dd, J = 13.8, 3.8 Hz, 1H),
3.02 (dd, J = 13.8, 9.9 Hz, 1H), 1.37 (t, J = 7.1 Hz, 3H). 13C {1H}
NMR (126 MHz, CDCl3): δ 166.5, 165.1, 135.7, 134.1, 132.5,
130.8, 130.1, 129.3, 128.9, 127.6, 127.4, 127.2, 124.3, 121.0,
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3g). Pale yellow
20
solid (33 mg, 24% Yield); [α]D = -7.0 (c = 0.2, CHCl3); mp:
º
167-169 C; 1H NMR (500 MHz, CDCl3): δ 8.23 (s, 1H), 7.99 (d,
J = 9.1 Hz, 1H), 7.76 (d, J = 1.9 Hz, 1H), 7.48 (dd, J = 9.1, 2.0
Hz, 1H), 7.32 (t, J = 7.3 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 7.19
(d, J = 7.0 Hz, 2H), 7.15 (s, 1H), 4.38-4.27 (m, 3H), 3.36 (dd, J =
13.8, 3.8 Hz, 1H), 3.02 (dd, J = 13.8, 9.9 Hz, 1H), 1.37 (t, J = 7.1
Hz, 3H). 13C {1H} NMR (126 MHz, CDCl3): δ 166.5, 165.1,
135.7, 134.1, 130.1, 129.9, 129.8, 129.3, 128.9, 127.7, 127.5,
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The Journal of Organic Chemistry
127.4, 126.7, 124.1, 120.9, 116.0, 61.5, 55.4, 37.5, 14.3. FT-IR
7, 135.9, 134.3, 133.8, 131.8, 129.4, 128.9, 128.8, 128.1, 127.8,
1
2
3
4
5
6
7
8
(KBr): 3336, 2924, 1770, 1690, 1464, 1333, 1279, 1152, 1046,
809 cm-1. MS-ESI: m/z 396 [M+H]+; HRMS-ESI: calcd for
C22H19ClNO4 [M+H]+ 396.1003; found 396.0971. HPLC analysis:
enantiomeric purity = >99%.
127.3, 126.7, 124.3, 119.1, 115.1, 61.3, 55.6, 37.2, 21.4, 14.3. FT-
IR (KBr): 3331, 2973, 2927, 1757, 1689, 1488, 1337, 1292, 1158,
1049, 809 cm-1. MS-ESI: m/z 376 [M+H]+; HRMS-ESI: calcd for
C23H22NO4 [M+H]+ 376.1543; found 376.1554. HPLC analysis:
enantiomeric purity = 99.56%.
Ethyl
(S)-3-benzyl-8-methoxy-2-oxo-3,4-dihydro-2H-
Ethyl
(R)-3-benzyl-8-methyl-2-oxo-3,4-dihydro-2H-
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3h). Pale yellow
solid (99 mg, 59% Yield); [α]D20 = +26.23 (c = 0.33, CHCl3); mp:
9
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3k). Pale yellow
solid (85 mg, 58% Yield); [α]D20 = -18.12 (c = 0.33, CHCl3); mp:
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
º
166-168 C; 1H NMR (400 MHz, CDCl3): δ 8.22 (s, 1H), 7.98 (d,
º
J = 9.3 Hz, 1H), 7.33 (t, J = 7.2 Hz, 2H), 7.29-7.22 (m, 2H), 7.19
(d, J = 6.9 Hz, 2H), 7.08 (d, J = 2.2 Hz, 1H), 6.95 (s, 1H), 4.36-
4.27 (m, 2H), 4.26-4.21 (m, 1H), 3.90 (s, 3H), 3.34 (dd, J = 13.8,
3.7 Hz, 1H), 3.00 (dd, J = 13.7, 10.1 Hz, 1H), 1.36 (t, J = 7.1 Hz,
3H). 13C {1H} NMR (101 MHz, CDCl3): δ 166.8, 165.7, 156.4,
136.0, 134.8, 129.4, 128.9, 128.2, 127.5, 127.3, 127.0, 122.6,
121.7, 120.9, 115.6, 106.5, 61.3, 55.6, 55.4, 37.2, 14.3. FT-IR
(KBr): 3320, 2969, 2935, 1757, 1686, 1517, 1339, 1289, 1160,
1024, 826, 698 cm-1. MS-ESI: m/z 392 [M+H]+; HRMS-ESI:
calcd for C23H22NO5 [M+H]+ 392.1498; found 392.1495. HPLC
analysis: enantiomeric purity = >99%.
183-185 C; 1H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 7.97 (d,
J = 8.7 Hz, 1H), 7.56 (s, 1H), 7.43-7.39 (m, 1H), 7.33 (t, J = 7.2
Hz, 1H), 7.30-7.24 (m, 2H), 7.19 (d, J = 6.9 Hz, 2H), 7.03 (s, 1H),
4.32 (qd, J = 7.1, 3.6 Hz, 2H), 4.25 (dd, J = 10.8, 3.2 Hz, 1H),
3.34 (dd, J = 13.7, 3.7 Hz, 1H), 3.01 (dd, J = 13.7, 10.1 Hz, 1H),
2.47 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (101 MHz,
CDCl3): δ 166.9, 165.7, 135.9, 134.3, 133.8, 131.7, 129.4, 128.9,
128.8, 128.1, 127.8, 127.3, 126.7, 124.3, 119.1, 115.1, 61.3, 55.6,
37.2, 21.4, 14.3. FT-IR (KBr): 3330, 2972, 2927, 1757, 1689,
1488, 1336, 1292, 1158, 1049, 808 cm-1. MS-ESI: m/z 376
[M+H]+; HRMS-ESI: calcd for C23H21NNaO4 [M+Na]+ 398.1363;
found 398.1386. HPLC analysis: enantiomeric purity = 99.59%.
Ethyl
(R)-3-benzyl-8-methoxy-2-oxo-3,4-dihydro-2H-
Ethyl
(S)-3-benzyl-10-methyl-2-oxo-3,4-dihydro-2H-
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3i). Pale yellow
solid (99 mg, 59% Yield); [α]D20 = -24.92 (c = 0.33, CHCl3); mp:
165-167 ºC; 1H NMR (500 MHz, CDCl3): δ 8.24 (s, 1H), 7.99 (d,
J = 9.2 Hz, 1H), 7.33 (t, J = 7.3 Hz, 2H), 7.30-7.23 (m, 2H), 7.19
(d, J = 7.1 Hz, 2H), 7.09 (d, J = 2.4 Hz, 1H), 6.95 (s, 1H), 4.36-
4.28 (m, 2H), 4.24 (ddt, J = 10.0, 3.6, 1.8 Hz, 1H), 3.90 (s, 3H),
3.34 (dd, J = 13.8, 3.8 Hz, 1H), 3.01 (dd, J = 13.8, 10.1 Hz, 1H),
1.36 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (126 MHz, CDCl3): δ
166.8, 165.7, 156.5, 135.9, 134.8, 129.4, 128.9, 128.2, 127.5,
127.3, 127.0, 122.6, 121.7, 120.9, 115.6, 106.5, 61.3, 55.7, 55.4,
37.2, 14.3. FT-IR (KBr): 3319, 2967, 2934, 1757, 1686, 1517,
1338, 1287, 1160, 1024, 824, 698 cm-1. MS-ESI: m/z 392
[M+H]+; HRMS-ESI: calcd for C23H22NO5 [M+H]+ 392.1492;
found 392.1500. HPLC analysis: enantiomeric purity = 99.98%.
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3l). Pale yellow
solid (79 mg, 55% Yield); [α]D20 = +19.02 (c = 0.33, CHCl3); mp:
º
189-191 C; 1H NMR (400 MHz, CDCl3): δ 8.30 (s, 1H), 7.61 (d,
J = 8.1 Hz, 1H), 7.32 (dd, J = 13.2, 5.9 Hz, 3H), 7.27 (d, J = 8.1
Hz, 1H), 7.18 (dd, J = 6.9, 5.0 Hz, 4H), 4.37-4.28 (m, 2H), 4.19
(ddd, J = 9.8, 3.7, 1.5 Hz, 1H), 3.34 (dd, J = 13.8, 3.8 Hz, 1H),
3.02 (dd, J = 13.7, 9.9 Hz, 1H), 2.93 (s, 3H), 1.37 (t, J = 7.1 Hz,
3H). 13C {1H} NMR (101 MHz, CDCl3): δ 166.7, 165.6, 136.2,
135.9, 132.2, 131.9, 130.8, 129.8, 129.4, 128.9, 127.8, 127.7,
127.3, 125.8, 123.8, 114.7, 61.3, 54.9, 36.9, 24.4, 14.3. FT-IR
(KBr): 3333, 2989, 2930, 1759, 1688, 1448, 1325, 1292, 1163,
1047, 785 cm-1. MS-ESI: m/z 376 [M+H]+; HRMS-ESI: calcd for
C23H22NO4 [M+H]+ 376.1549; found 376.1545. HPLC analysis:
enantiomeric purity = 99.30%.
Ethyl
(S)-3-benzyl-8-methyl-2-oxo-3,4-dihydro-2H-
Ethyl
(R)-3-benzyl-10-methyl-2-oxo-3,4-dihydro-2H-
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3j). Pale yellow
solid (87 mg, 57% Yield); [α]D20 = +18.32 (c = 0.33, CHCl3); mp:
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3m). Pale yellow
solid (76 mg, 54% Yield); [α]D20 = -18.92 (c = 0.33, CHCl3); mp:
º
186-188 C; 1H NMR (500 MHz, CDCl3): δ 8.25 (s, 1H), 7.96 (d,
º
J = 8.7 Hz, 1H), 7.55 (s, 1H), 7.40 (d, J = 8.7 Hz, 1H), 7.33 (t, J =
7.3 Hz, 2H), 7.29 -7.24 (m, 1H), 7.19 (d, J = 7.3 Hz, 2H), 7.02 (s,
1H), 4.35-4.27 (m, 2H), 4.27-4.22 (m, 1H), 3.34 (dd, J = 13.8, 3.7
Hz, 1H), 3.00 (dd, J = 13.7, 10.2 Hz, 1H), 2.47 (s, 3H), 1.36 (t, J
= 7.1 Hz, 3H). 13C {1H} NMR (126 MHz, CDCl3): δ 166.9, 165.
187-189 C; 1H NMR (500 MHz, CDCl3): δ 8.30 (s, 1H), 7.61 (d,
J = 8.1 Hz, 1H), 7.32 (dd, J = 13.9, 6.4 Hz, 3H), 7.27 (d, J = 8.6
Hz, 1H), 7.22-7.16 (m, 4H), 4.37-4.28 (m, 2H), 4.19 (ddd, J = 9.9,
3.9, 1.6 Hz, 1H), 3.34 (dd, J = 13.8, 3.9 Hz, 1H), 3.03 (dd, J =
13.8, 9.9 Hz, 1H), 2.93 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H). 13C {1H}
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NMR (126 MHz, CDCl3): δ 166.7, 165.6, 136.2, 135.9, 132.2,
Ethyl (S)-3-isopropyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3q). Pale yellow solid (60 mg,
1
2
3
4
5
6
7
8
131.9, 130.8, 129.7, 129.4, 128.9, 127.8, 127.7, 127.3, 125.8,
123.8, 114.7, 61.3, 54.9, 36.9, 24.4, 14.3. FT-IR (KBr): 3332,
2987, 2929, 1759, 1688, 1448, 1324, 1291, 1163, 1047, 784 cm-1.
MS-ESI: m/z 376 [M+H]+; HRMS-ESI: calcd for C23H21NNaO4
[M+Na]+ 398.1363; found 398.1389. HPLC analysis:
enantiomeric purity = 99.83%.
20
º
44% Yield); [α]D = +65.16 (c = 0.33, CHCl3); mp: 72-74 C; 1H
NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H),
7.77 (d, J = 8.2 Hz, 1H), 7.57-7.51 (m, 1H), 7.45 (s, 1H), 7.32 (t,
J = 7.5 Hz, 1H), 4.45 (tt, J = 7.2, 3.6 Hz, 2H), 3.94 (dd, J = 6.1,
1.8 Hz, 1H), 2.28 (m, 1H), 1.47 (t, J = 7.1 Hz, 3H), 1.12 (d, J =
6.9 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H). 13C {1H} NMR (101 MHz,
CDCl3): δ 167.5, 165.0, 133.5, 130.2, 129.3, 129.1, 128.6, 125.9,
123.8, 119.1, 114.3, 61.4, 59.9, 30.3, 19.0, 17.8, 14.3. FT-IR
(KBr): 3327, 2963, 2928, 1764, 1692, 1475, 1342, 1296, 1156,
1046, 783 cm-1. MS-ESI: m/z 314 [M+H]+; HRMS-ESI: calcd for
C18H20NO4 [M+H]+ 314.1392; found 314.1391. HPLC analysis:
enantiomeric purity = >99%.
9
Ethyl 2-oxo-3,4-dihydro-2H-naphtho[1,2-b][1,4]oxazine-5-
carboxylate (3n). Pale yellow solid (21 mg, 18% Yield); mp:
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19
20
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º
127-129 C; 1H NMR (500 MHz, CDCl3): δ 8.37 (s, 1H), 8.06 (d,
J = 8.5 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.57 (t, J = 7.7 Hz, 1H),
7.35 (t, J = 7.5 Hz, 1H), 7.21 (s, 1H), 4.44 (q, J = 7.1 Hz, 2H),
4.17 (d, J = 1.5 Hz, 2H), 1.47 (t, J = 7.1 Hz, 3H). 13C {1H} NMR
(126 MHz, CDCl3): δ 167.4, 163.9, 134.2, 130.9, 129.5, 129.1,
128.8, 126.3, 126.3, 124.2, 119.1, 114.7, 61.4, 44.5, 14.3. FT-IR
(KBr): 3364, 2924, 2854, 1777, 1695, 1461, 1376, 1300, 1042,
786 cm-1. MS-ESI: m/z 272 [M+H]+. HRMS-ESI: calcd for
C15H14NO4 [M+H]+ 272.0923; found 272.0920.
Ethyl (R)-3-isopropyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3r). Pale yellow solid (60 mg,
20
º
44% Yield); [α]D = -60.66 (c = 0.33, CHCl3); mp: 70-72 C; 1H
NMR (500 MHz, CDCl3): δ 8.35 (s, 1H), 8.04 (d, J = 8.5 Hz, 1H),
7.77 (d, J = 8.2 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.45 (s, 1H),
7.31 (t, J = 7.5 Hz, 1H), 4.45 (dd, J = 13.2, 6.7 Hz, 2H), 3.94 (d, J
= 5.0 Hz, 1H), 2.28 (m, 1H), 1.47 (t, J = 7.1 Hz, 3H), 1.12 (d, J =
6.8 Hz, 3H), 1.03 (d, J = 6.7 Hz, 3H). 13C {1H} NMR (126 MHz,
CDCl3): δ 167.5, 165.0, 133.5, 130.2, 129.3, 129.1, 128.6, 125.9,
123.8, 119.1, 114.4, 61.4, 59.9, 30.3, 19.0, 17.8, 14.4. FT-IR
(KBr): 3326, 2962, 2928, 1764, 1692, 1474, 1342, 1295, 1156,
1045, 783 cm-1. MS-ESI: m/z 314 [M+H]+; HRMS-ESI: calcd for
C18H20NO4 [M+H]+ 314.1387; found 314.1376. HPLC analysis:
enantiomeric purity = 99.88%.
Ethyl
(S)-3-methyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3o). Pale yellow solid (38 mg,
20
º
31% Yield); [α]D = +9.01 (c = 0.2, CHCl3); mp: 102-104 C; 1H
NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 8.09-8.03 (m, 1H), 7.80
(d, J = 8.3 Hz, 1H), 7.56 (m, 1H), 7.38-7.32 (m, 1H), 7.17 (s,
1H), 4.44 (q, J = 7.1 Hz, 2H), 4.09 (m, 1H), 1.63 (d, J = 6.7 Hz,
3H), 1.47 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (101 MHz, CDCl3):
δ 167.4, 166.5, 134.4, 130.8, 129.4, 129.1, 128.6, 126.3, 126.2,
124.2, 119.2, 114.7, 61.4, 49.8, 17.3, 14.3. FT-IR (KBr): 3330,
2980, 2925, 1772, 1692, 1466, 1377, 1298, 1212, 1042, 784 cm-1.
MS-ESI: m/z 286 [M+H]+; HRMS-ESI: calcd for C16H16NO4
[M+H]+ 286.1074; found 286.1090. HPLC analysis: enantiomeric
purity = 97.84%.
Ethyl
(S)-3-isobutyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3s). Pale yellow solid (58 mg,
20
41% Yield); [α]D = +4.76 (c = 0.4181, CHCl3); mp: 76-78 °C;
1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 8.08-8.02 (m, 1H),
7.82-7.76 (m, 1H), 7.58-7.52 (m, 1H), 7.33 (dd, J = 9.2, 5.1, 1.7
Hz, 2H), 4.48-4.40 (m, 2H), 4.11 (dd, J = 8.8, 4.9, 1.6 Hz, 1H),
1.91-1.73 (m, 3H), 1.49-1.45 (m, 3H), 1.00 (dd, J = 6.2, 5.3 Hz,
6H). 13C {1H} NMR (101 MHz, CDCl3): δ 167.4, 166.2, 133.9,
130.2, 129.3, 129.1, 128.6, 126.2, 126.0, 124.0, 119.1, 114.7,
61.4, 52.2, 39.6, 24.3, 23.1, 21.3, 14.3. FT-IR (KBr): 3324, 3053,
2978, 2928, 1728, 1652, 1490, 1316, 1232, 1101, 1047 cm-1. MS-
ESI: m/z 328 [M+H]+; HRMS-ESI: calcd for C19H22NO4 [M+H]+
328.1549; found 328.1557. HPLC analysis: enantiomeric purity =
>99%.
Ethyl
(R)-3-methyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3p). Pale yellow solid (68 mg,
55% Yield); [α]D20 = -8.81 (c = 0.3818, CHCl3); mp: 124-126 °C;
1H NMR (400 MHz, CDCl3): δ 8.36 (s, 1H), 8.06 (dd, J = 8.6, 0.9
Hz, 1H), 7.83-7.75 (m, 1H), 7.61-7.51 (m, 1H), 7.35 (m, 1H),
7.19 (s, 1H), 4.48-4.40 (m, 2H), 4.13-4.06 (m, 1H), 1.63 (d, J =
6.7 Hz, 3H), 1.50-1.44 (m, 3H). 13C {1H} NMR (101 MHz,
CDCl3): δ 167.4, 166.5, 134.3, 130.8, 129.3, 129.1, 128.5, 126.3,
126.1, 124.1, 119.2, 114.7, 61.4, 49.7, 17.2, 14.2. FT-IR (KBr):
3363, 3023, 1174, 1696, 1471, 1381, 1304, 1215 cm-1. MS-ESI:
m/z 286 [M+H]+; HRMS-ESI: calcd for C16H16NO4 [M+H]+
286.1079; found 286.1094. HPLC analysis: enantiomeric purity =
99.63%.
Ethyl (R)-3-isobutyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3t). Pale yellow solid (66 mg,
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47% Yield); [α]D20 = -2.24 (c = 0.6454, CHCl3); mp: 90-92 °C; 1H
7.34 (t, J = 7.5 Hz, 1H), 7.12 (s, 1H), 7.05 (d, J = 8.4 Hz, 2H),
1
2
3
4
5
6
7
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NMR (400 MHz, CDCl3): δ 8.28 (d, J = 6.9 Hz, 1H), 7.98 (dd, J =
8.5, 0.7 Hz, 1H), 7.71 (t, J = 6.3 Hz, 1H), 7.52-7.45 (m, 1H),
7.30-7.23 (m, 2H), 4.40-4.33 (m, 2H), 4.06-4.00 (m, 1H), 1.84-
1.67 (m, 3H), 1.42-1.38 (m, 3H), 0.92 (dd, J = 6.2, 5.2 Hz, 6H).
13C {1H} NMR (101 MHz, CDCl3): δ 166.4, 165.2, 133.0, 129.2,
128.3, 128.1, 127.6, 125.2, 125.0, 123.0, 118.1, 113.7, 60.4, 51.2,
38.6, 23.4, 22.1, 20.3, 13.3. FT-IR (KBr): 3355, 2964, 1776,
1697, 1640, 1525, 1476, 1382, 1306, 1210 cm-1. MS-ESI: m/z 328
[M+H]+; HRMS-ESI: calcd for C19H22NO4 [M+H]+ 328.1531;
found 328.1549. HPLC analysis: enantiomeric purity = >99%.
6.79 (d, J = 8.4 Hz, 2H), 4.34 (qd, J = 7.1, 3.6 Hz, 2H), 4.26-4.19
(m, 1H), 3.27 (dd, J = 13.9, 3.8 Hz, 1H), 2.95 (dd, J = 13.9, 10.0
Hz, 1H), 1.39 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (75 MHz,
CDCl3): δ 166.9, 165.7, 155.0, 134.0, 130.6, 129.7, 129.4, 129.13,
128. 9, 127.8, 126.3, 126.0, 124.2, 119.2, 115.8, 114.9, 61.4, 55.6,
36.5, 14.3. FT-IR (KBr): 3446, 3332, 2985, 1765, 1687, 1511,
1471, 1332, 1298, 1210, 1158, 1046, 783 cm-1. MS-ESI: m/z 378
[M+H]+; HRMS-ESI: calcd for C22H20NO5 [M+H]+ 378.1341;
found 378.1346. HPLC analysis: enantiomeric purity = 99.79%.
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Ethyl
(R)-3-(4-hydroxybenzyl)-2-oxo-3,4-dihydro-2H-
Ethyl
(S)-3-(2-(methylthio)ethyl)-2-oxo-3,4-dihydro-2H-
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3y). Pale yellow
20
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3u). Pale yellow
solid (31 mg, 18% Yield); [α]D = -1.67 (c = 0.3, CHCl3); mp:
20
º
solid (60 mg, 40% Yield); [α]D = +9.18 (c = 0.4636, CHCl3);
160-162 C; 1H NMR (400 MHz, CDCl3): δ 8.35 (s, 1H), 8.05 (d,
1
mp: 111-113 °C; H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H),
J = 8.5 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H),
7.34 (t, J = 7.5 Hz, 1H), 7.13 (s, 1H), 7.06 (d, J = 8.2 Hz, 2H),
6.79 (d, J = 8.2 Hz, 2H), 4.40-4.30 (m, 2H), 4.23 (d, J = 7.4 Hz,
1H), 3.27 (dd, J = 13.9, 3.6 Hz, 1H), 2.96 (dd, J = 13.8, 10.0 Hz,
1H), 1.39 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (101 MHz, CDCl3):
δ 166.9, 165.7, 154.9, 134.0, 130.6, 129.7, 129.4, 129.13, 128.9,
127.9, 126.3, 126.0, 124.2, 119.2, 115.8, 115.0, 61.4, 55.6, 36.5,
14.3. FT-IR (KBr): 3445, 3330, 2986, 1766, 1687, 1510, 1471,
1330, 1298, 1211, 1155, 1044, 820 cm-1. MS-ESI: m/z 378
[M+H]+; HRMS-ESI: calcd for C22H19NNaO5 [M+Na]+ 400.1155;
found 400.1149. HPLC analysis: enantiomeric purity = 99.79%.
8.05 (dd, J = 8.6, 0.9 Hz, 1H), 7.84-7.75 (m, 1H), 7.56 (m, 1H),
7.40-7.32 (m, 2H), 4.49-4.40 (m, 2H), 4.29 (m, 1H), 2.80-2.65 (m,
2H), 2.35-2.23 (m, 1H), 2.20-2.15 (m, 4H), 1.50-1.44 (m, 3H). 13
C
{1H} NMR (101 MHz, CDCl3): δ 167.3, 165.7, 133.9, 129.9,
129.4, 129.1, 128.7, 126.3, 126.0, 124.1, 119.1, 114.7, 61.9, 61.4,
52.7, 30.2, 29.7, 15.4, 14.3. FT-IR (KBr): 3601, 3358, 3012,
2555, 1777, 1699, 1641, 1526, 1480, 1382, 1301, 1215 cm-1. MS-
ESI: m/z 346 [M+H]+; HRMS-ESI: calcd for C18H20NO4S
[M+H]+ 346.1113; found 346.1104. HPLC analysis: enantiomeric
purity = 96.11%.
Ethyl
(R)-3-(2-(methylthio)ethyl)-2-oxo-3,4-dihydro-2H-
Ethyl
(S)-3-(hydroxymethyl)-2-oxo-3,4-dihydro-2H-
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3v). Pale yellow
solid (56 mg, 44% Yield); [α]D20 = -9.70 (c = 0.2909, CHCl3); mp:
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3z). Pale yellow
20
solid (19 mg, 14% Yield); [α]D = +3.86 (c = 0.23, CHCl3); mp:
1
102-104 °C; H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 8.05
152-154 ºC: 1H NMR (400 MHz, CDCl3): δ 8.37 (s, 1H), 8.04 (d,
J = 8.5 Hz, 1H), 7.79 (d, J = 8.3 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H),
7.47 (s, 1H), 7.35 (t, J = 7.4 Hz, 1H), 4.44 (q, J = 7.1 Hz, 2H),
4.20 (dd, J = 13.0, 8.4 Hz, 2H), 4.08 (d, J = 5.7 Hz, 1H), 2.38 (s,
1H), 1.46 (t, J = 7.1 Hz, 3H). 13C {1H} NMR (101 MHz, CDCl3):
δ 167.4, 165.1, 133.8, 130.2, 129.5, 129.2, 128.9, 126.3, 126.1,
124.2, 119.1, 114.7, 62.6, 61.5, 55.3, 14.3. FT-IR (KBr): 3335,
2981, 1769, 1693, 1471, 1377, 1300, 1176, 1041, 786 cm-1. MS-
ESI: m/z 324 [M+Na]+; HRMS-ESI: calcd for C16H15NNaO5
[M+Na]+ 324.0827; found 324.0842. HPLC analysis:
enantiomeric purity = >99%.
(dd, J = 8.6, 0.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H), 7.56 (dd, J =
8.4, 6.8, 1.2 Hz, 1H), 7.37 (d, J = 1.1 Hz, 1H), 7.36-7.32 (m, 1H),
4.48-4.41 (m, 2H), 4.29 (dd, J = 7.4, 5.0, 1.4 Hz, 1H), 2.80-2.65
(m, 2H), 2.34-2.23 (m, 1H), 2.20-2.10 (m, 4H), 1.50-1.44 (m,
3H). 13C {1H} NMR (101 MHz, CDCl3): δ 167.4, 165.7, 133.9,
129.9, 129.4, 129.1, 128.7, 126.3, 126.0, 124.1, 119.1, 114.7,
61.4, 52.7, 30.2, 29.8, 15.4, 14.3. FT-IR (KBr): 3684, 3022, 2405,
1773, 1695, 1215 cm-1. MS-ESI: m/z 346 [M+H]+; HRMS-ESI:
calcd for C18H20NO4S [M+H]+ 346.1113; found 346.1102. HPLC
analysis: enantiomeric purity = 97.28%.
Ethyl
(S)-3-(4-hydroxybenzyl)-2-oxo-3,4-dihydro-2H-
Ethyl (S)-3-sec-butyl-2-oxo-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3zb). Pale yellow liquid (47 mg,
naphtho[1,2-b][1,4]oxazine-5-carboxylate (3x). Pale yellow
20
20
1
solid (33 mg, 19% Yield); [α]D = +2.0 (c = 0.3, CHCl3); mp:
33% Yield); [α]D = +2.63 (c = 0.5727, CHCl3); H NMR (400
MHz, CDCl3): δ 8.26 (s, 1H), 7.95 (d, J = 8.5 Hz, 1H), 7.69 (d, J
= 8.3 Hz, 1H), 7.49-7.43 (m, 1H), 7.34 (s, 1H), 7.22 (dd, J = 6.3,
º
158-160 C; 1H NMR (300 MHz, CDCl3): δ 8.34 (s, 1H), 8.05 (d,
J = 8.5 Hz, 1H), 7.78 (d, J = 8.2 Hz, 1H), 7.56 (t, J = 7.7 Hz, 1H),
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4.6, 0.7 Hz, 1H), 4.40-4.33 (m, 2H), 3.95 (dd, J = 6.0, 1.9 Hz,
127.5, 126.2, 123.0, 61.8, 60.3, 24.6, 14.5. FT-IR (KBr): 3697,
1
2
3
4
5
6
7
8
1H), 1.99-1.90 (m, 1H), 1.62-1.45 (m, 2H), 1.41-1.37 (m, 3H),
1.07-0.97 (m, 3H), 0.82 (t, J = 7.4 Hz, 3H). 13C {1H} NMR (101
MHz, CDCl3): δ 166.4, 163.9, 132.3, 129.2, 128.2, 128.1, 127.6,
124.9, 124.8, 122.7, 117.9, 113.2, 60.3, 58.0, 35.8, 23.6, 13.3,
10.2. FT-IR (KBr): 3735, 3594, 3374, 2972, 1778, 1698, 1526,
1476, 1383, 1339, 1302, 1207 cm-1. MS-ESI: m/z 328 [M+H]+;
HRMS-ESI: calcd for C19H22NO4 [M+H]+ 328.1549; found
328.1553. HPLC analysis: enantiomeric purity = >99%.
3021, 2407, 1763, 1524, 1312, 1215, 1026 cm-1. MS-ESI: m/z 362
[M+H]+; HRMS-ESI: calcd for C22H20NO4 [M+H]+ 362.1392;
found 362.1400. HPLC analysis: enantiomeric purity = >99%.
ASSOCIATED CONTENT
Supporting Information
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The copies of H, 13C NMR spectras, structures of the amino
acid ethyl esters 2a-v, HPLC chromatograms and HRMS
spectra were provided in SI. This material is available free of
charge via the internet at http://pubs.acs.org.
Ethyl
(S)-2-oxo-3-phenyl-3,4-dihydro-2H-naphtho[1,2-
b][1,4]oxazine-5-carboxylate (3ze). Pale yellow solid (64 mg,
20
43% Yield); [α]D = -24.26 (c = 0.1909, CHCl3); mp: 138-140
°C; 1H NMR (500 MHz, CDCl3): δ 8.40 (s, 1H), 8.06 (dd, J = 8.5,
0.7 Hz, 1H), 7.79 (t, J = 8.6 Hz, 1H), 7.72 (s, 1H), 7.56 (dd, J =
8.3, 6.8, 1.1 Hz, 1H), 7.47-7.40 (m, 2H), 7.39-7.30 (m, 4H), 5.30
(d, J = 1.5 Hz, 1H), 4.48-4.41 (m, 2H), 1.49-1.44 (m, 3H). 13C
{1H} NMR (126 MHz, CDCl3): δ 167.4, 164.2, 136.2, 133.8,
130.0, 129.4, 129.1, 128.9, 128.8, 127.0, 126.3, 126.1, 124.2,
119.2, 114.5, 61.4, 58.2, 14.3. FT-IR (KBr): 3307, 3022, 1779,
1698, 1636, 1525, 1383, 1300, 1214, 1049 cm-1. MS-ESI: m/z 348
[M+H]+; HRMS-ESI: calcd for C21H18NO4 [M+H]+ 348.1236;
found 348.1240. HPLC analysis: enantiomeric purity = 83.75%.
Ethyl-2-oxo-3-phenyl-3,4-dihydro-2H-naphtho[1,2-
AUTHOR INFORMATION
Corresponding Author
*E-mail: chinaraju@iict.res.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
K.V.P thanks UGC-New Delhi for the fellowship. The authors are
thankful to Mr. T. Ramesh Babu, Fluoro-Agrochemicals division
for chiral HPLC analysis and Mr. K. Sai Teja, JRF (P), OSPC
division for helping in experimental work. B. China Raju
acknowledges Science & Engineering Research Board (SERB),
Department of Science and Technology (DST), New Delhi for the
financial support (EEQ/2017/000314, GAP-0743). IICT
Communication No. IICT/Pubs./2018/359.
b][1,4]oxazine-5-carboxylate (3zf). Pale yellow solid (62 mg,
42% Yield); mp: 142-144 °C; 1H NMR (400 MHz, CDCl3): δ 8.40
(s, 1H), 8.06 (dd, J = 8.6, 0.8 Hz, 1H), 7.80 (d, J = 8.3 Hz, 1H),
7.72 (s, 1H), 7.60-7.53 (m, 1H), 7.46-7.41 (m, 2H), 7.39-7.31 (m,
4H), 5.30 (d, J = 1.7 Hz, 1H), 4.49-4.40 (m, 2H), 1.50-1.44 (m,
3H). 13C {1H} NMR (101 MHz, CDCl3): δ 167.5, 164.3, 136.3,
133.8, 130.1, 129.5, 129.2, 129.0, 128.9, 128.8, 127.1, 126.3,
126.2, 124.2, 119.3, 114.6, 61.5, 58.3, 14.3. FT-IR (KBr): 3364,
3075, 2928, 2341, 1774, 1706, 1387, 1216, 1153 cm-1. MS-ESI:
m/z 348 [M+H]+; HRMS-ESI: calcd for C21H18NO4 [M+H]+
348.1236; found 348.1240. HPLC analysis: enantiomeric purity of
R isomer = 46.46%, S isomer = 53.54%.
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(11) We thank a reviewer’s suggestion to elaborate the scope of
the manuscript.
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Insert Table of Contents artwork here
O
OC2H5
H
N
CO2C2H5
R
O
*
R
* CO2C2H5
NH2
p-TsOH, DCM
O
+
reflux
O
O
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