Visible Light-Induced Oxidative Cross Dehydrogenative Coupling of Glycine Esters with β-Naphthols: Access to 1,3-Benzoxazines

Article abstract of DOI:10.1021/acs.joc.9b01440

A direct aerobic oxidative dehydrogenative coupling reaction of glycine esters with β-naphthols has been achieved via the synergistic combination of photoredox catalysis and Lewis acid catalysis. A wide range of glycine esters and β-naphthols are suitable substrates for this reaction. A variety of 1,3-benzoxazines were obtained in good yields with excellent diastereoselectivities under mild reaction conditions. Moreover, this protocol could be performed on a gram-scale without considerable loss in activity.

Full text of DOI:10.1021/acs.joc.9b01440

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Article
Visible Light-Induced Oxidative Cross Dehydrogenative Coupling
of Glycine Esters with #-Naphthols: Access to 1,3-Benzoxazines
Yuan Zhang, Shilin Li, Yin Zhu, Xiaorong Yang, Huang Zhou, and Ying Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01440 • Publication Date (Web): 13 Apr 2020
Downloaded from pubs.acs.org on April 13, 2020
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Visible Light-Induced Oxidative Cross Dehydrogenative
Coupling of Glycine Esters with β-Naphthols: Access to
1,3-Benzoxazines
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Yuan Zhang , Shilin Li, Yin Zhu, Xiaorong Yang, Huang Zhou, and Ying Li
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou
University, Lanzhou 730000, People’s Republic of China
E-mail: zhangyuan@lzu.edu.cn; liying@lzu.edu.cn.
Abstract:
A direct aerobic oxidative dehydrogenative coupling reaction of glycine esters with β-naphthols
has been achieved via the synergistic combination of photoredox catalysis and Lewis acid
catalysis. A wide range of glycine esters and β-naphthols are suitable substrates for this reaction.
A variety of 1,3-benzoxazines were obtained in good yields and excellent diastereoselectivities
under mild reaction conditions. Moreover, this protocol could be performed on gram-scale,
without considerable loss in activity.
Introduction
The 1,3-benzoxazine skeletons are privileged structural units that exist widely in
pharmaceutically active molecules, which typically exhibit a variety of biological activities, such
1
2
3
as antitumor, antibacterial and anti-HIV activities; some 1,3-naphthoxazine derivatives show
4
potential application prospect for the treatment of Parkinson’s disease. Moreover, these structure
motifs also serve as important synthetic intermediates for the synthesis of bioactive natural
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6
products and thermosetting polymers. Consequently, this privileged structure has attracted great
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interest from synthetic chemists. Despite remarkable advances have been made, searching for
more step-economic and green transformations to construct 1,3-benzoxazines is still in great
demand.
On the other hand, the oxidative cross dehydrogenative coupling (CDC) reaction, which avoids
the tedious prefunctionalization of the starting materials, has emerged as one of the most
straightforward and atom-economical approaches for constructing carbon-carbon and
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carbon-heteroatom bonds. Among these reactions, the oxidation of Csp3–H bonds adjacent to a
nitrogen atom has been regarded as one of the most important and useful strategies for Csp3−H
9
10a
and Maycock10b have led to
functionalization. Pioneering works from the group of Xiao
impressive synthesis of 1,3-benzoxazines via intramolecular oxidative dehydrogenative coupling
of tertiary heterocyclic amines. Inspired by this strategy, several groups, including those of
Jana,10c Maiti,10d Deb and Baruah,10e-10g and others,10h-10k have developed various catalytic systems
for the synthesis of 1,3-benzoxazines via similar intramolecular CDC reactions (Scheme 1, a). In
contrast, however, the synthesis of 1,3- benzoxazines via an intermolecular CDC reaction
employing secondary amines (e.g. glycine derivatives) as substrates is still not easily accessible.11
Glycine derivatives are cheap and abundant starting materials in organic synthesis. Since the
original work of Li,12 the direct oxidative dehydrogenative coupling of glycine derivatives with
various nucleophiles have emerged as an efficient approach for the straightfoward synthesis of
α-amino acid derivatives13 and azo-heterocyclic compounds.14 However, most of these protocols
typically need stoichiometric amounts of sacrificial oxidants to complete the transformation,
thereby leading to toxic waste byproducts and low atom economy; and some of them were carried
out at harsh conditions. In this context, in the past few years, visible light-induced photoredox
15
catalysis has become a promising tool to trigger the CDC reaction, owing to its mild, clean, and
environmentally benign charicteristics.16-18 However, to date, most of the reported photoredox
catalyzed CDC reactions have focused on the α-Csp3–H functionalization of tertiary amines (i.e.,
tetrahydroisoquinolines),16 whereas examples relating to the α-Csp3–H functionalization of
secondary amines, are rather scarce.17
Scheme 1. CDC Process for the Synthesis of 1,3-Benzoxazines
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Our laboratory has a longstanding interest in the visible light-driven CDC reactions for the
sp3-H functionalization of glycine derivatives.18 In our recent study, we reported a visible
C
light-induced oxidative cross-coupling reaction of glycine derivatives with phenols (Scheme 1,
b).18e During the course of this reaction, we detected trace amount of 1,3-benzoxazines. Inspired
by this observation, we hypothesized that whether these arylglycines could trap another equivalent
of imine intermediate, thereby providing a new intermolecular CDC strategy for the synthesis of
1
,3-benzoxazines (Scheme 1, c). Herein, we accordingly report a new photoredox catalytic aerobic
oxidative dehydrogenative coupling/cyclization tandem reaction of glycine esters with β-naphthols
for the efficient synthesis of 1,3-benzoxazines under mild conditions.
Results and Discussion
Our investigation into this new visible-light-induced protocol started with exposure of glycine
4 2
ester 1a and β-naphthol 2a in the presence of Rhodamine 6G (Rh-6G)/FeSO ·7H O in DCE under
the irradiation of a 23 W blue LED strip (Table 1). We found that the addition sequence had an
obvious influence for this reaction: under condition A (the standard condition of our previous work,
18e
as shown in Table 1) , arylglycine 4aa was isolated as the solely product, and only trace
1
1
,3-benzoxazine 3aa could be detected (Table 1, entry 1); Pleasingly, the targeted
,3-benzoxazine3aa could be obtained in 15% yield under condition B (Table 1, entry 2). The
increase of the amount of 1a enhanced the yield of 3aa to 22% (Table 1, entry 3). Notably, 3aa
was isolated as a single diastereomer. The relative configuration of 3aa was established
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unambiguously as trans by single-crystal X-ray diffraction analysis,19 which may be attributed to
the steric effects.
Table 1. Initial Studies a
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3aa Yield (%)b
4aaYield (%)b
Entry
Condition
Condition A
Condition B
Condition B
1
trace
15
85
74
69
2
3c
22
a
Condition A: 1a (0.1 mmol), Rh-6G (2 mol %), FeSO
irradiation under air for 3 h at room temperature, then 2a (0.12 mmol) was added, and stirred for another 3 h;
Condition B: 1a (0.1 mmol), 2a (0.12 mmol), Rh-6G (2 mol %), FeSO ·7H O (20 mol %), DCE (1.0 mL), 23 W
4 2
·7H O (20 mol %), DCE (1.0 mL), 23 W blue LED light
4
2
blue LEDs light irradiation under air for 36 h at room temperature. b Yield of the isolated product, determined
c
based on 1a. 0.25 mmol 1a and 0.1 mmol 2a were used, the yields of 3aa and 4aa were determined based on 2a.
Encouraged by these initial results, we then conducted a series of screening studies for this
protocol (Table 2, for details, see the Supporting Information). We first screened a variety of
photocatalysts and Lewis acids (Table 2, entries 1−9). The results identified
3 2 2 2
Ru(bpy) Cl ·6H O/Cu(OTf) as the optimal catalyst combination, and 3aa was obtained in 72%
yield (Table 2, entry 4). It is worth noting that a variety of organic-dyes, such as Eosin Y, Rose
Bengal and Rh-6G, are also capable photocatalysts for this transformation, though slight lower
yields were provided (Table 2, entries 1−3). We also performed this reaction with Brønsted acid
(
e.g. HCl, TfOH), however, complicated products were obtained. Further evaluation of solvents
revealed that DCE or toluene as the solvent were the best choices (Table 2, entries 10−14). A
slight decrease of the concentration enhanced the formation of 3aa in 76% yield (Table 2, entry
1
1
4). Notably, reducing the photocatalyst stoichiometry to 1 mol % and Cu(OTf)
2
stoichiometry to
0 mol % could be well tolerated, affording a good yield (79%) of the 3aa (Table 2, entry 16). The
byproduct of this reaction is the direct coupling product of 1a with 2a (compound 4aa, 10% yield).
Moreover, control experiments indicated that visible light, photocatalyst, acid, and air are all
essential for this reaction (Table 2, entries 17−20).
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Table 2. Optimization of Reaction Conditionsa
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1
1
1
1
1
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1
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2
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2
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Entry
PC/ Acid
Solvent
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
MeOH
Yield(%)b
58
1
2
3
4
5
6
7
8
9
Rh-6G/Cu(OTf)
2
Rose Bengal/Cu(OTf)
2
64
Eosin Y/Cu(OTf)
2
56
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
Ru(bpy)
3
3
3
3
3
3
3
3
3
3
3
3
3
3
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
·6H
2
2
2
2
2
2
2
2
2
2
2
2
2
2
O/Cu(OTf)
O/FeSO
2
72
4
26
O/CuSO
4
66
O/CuCl
60
O/CuBr
2
65
O/Zn(OTf)
2
21
1
0
O/Cu(OTf)
O/Cu(OTf)
O/Cu(OTf)
O/Cu(OTf)
O/Cu(OTf)
O/Cu(OTf)
O/Cu(OTf)
O/Cu(OTf)
2
2
2
2
2
2
2
2
trace
67
11
3
CH CN
1
1
1
1
1
1
1
1
2
2
toluene
EtOAc
DCE
DCE
DCE
DCE
DCE
DCE
DCE
74
3
63
4c
5c,d
6c,d,e
7f
76
76
79
trace
trace
trace
trace
8
－/Cu(OTf)
2
9
Ru(bpy)
3
3
Cl
Cl
2
2
·6H
2
2
O/－
0g
Ru(bpy)
·6H
O/Cu(OTf)
2
a
Reaction conditions: 1a (0.25 mmol), 2a (0.10 mmol), photocatalyst (2 mol %), Lewis acid (20 mol %), solvent
b
c
(
2.0 mL), 23 W blue LEDs light irradiation under air for 36 h at room temperature. Yield of the isolated product.
d
e
f
3
.0 mL DCE was used. 1.0 mol % of Ru(bpy)
3
Cl
2
·6H
2
O was used. 10 mol % of Cu(OTf)
2
was used. Reaction
g
was carried out in the dark. Reaction was carried out under nitrogen.
With the optimized reaction conditions in hand, we next examined the substrate scope of this
visible-light-induced oxidative cross-coupling reaction. We first evaluated the glycine ester
component. As shown in Table 3, the reaction proceeded smoothly with a range of glycine esters
possessing various electron-donating substituted groups in the para-, ortho- or meta-positions at
the benzene rings, giving the corresponding 1,3-benzoxazines in good yields. In general,
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substrates with electron-rich aryl groups exhibited higher reactivities than those with
electron-deficient aryl groups, probably due to the increase in nucleophilicity of the nitrogen.
However, glycine esters bearing electron-withdrawing groups (i.e., halogen and ester) at the
benzene rings failed to give the corresponding products. This may be attributed to the decrease in
nucleophilicity of the nitrogen. The scope of the ester fragment was also examined. A range of
ester substrates, such as methyl ester, isopropyl ester, t-butyl ester, and benzyl ester, were also
amenable to this reaction, affording the products 3ja–3ma with 78−83% yields. We have also
performed the reaction with other substrates, such as N-alkyl glycine ester and other α-amino
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compounds (e.g. ketones and nitriles), however, no reaction occurred (for details see Figure S1).
Table 3. Scope of the Glycine Ester Componenta,b
a
Reaction conditions: 1 (0.25 mmol), 2a (0.10 mmol), Ru(bpy)
3
Cl
2
∙6H
2
2
O (1 mol %), Cu(OTf) (10 mol %), DCE
b
(
3.0 mL), 23 W blue LED light irradiation under air for 36 h at room temperature. Yield of the isolated product,
1
dr values were determined by H NMR.
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The substrate scope of β-naphthol component was subsequently investigated (Table 4). A
variety of β-naphthols with both electron-donating and electron-withdrawing groups underwent
the desired cross-coupling reaction smoothly, giving the corresponding products 3ab−3aj in good
yields (65−85%). Various functional groups such as ester, carboxyl, cyano and halogen are well
tolerated in this transformation, which provide handles for further transformations. Moreover,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
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3
3
3
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3
4
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0
1
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0
1
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0
1
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Table 4. Scope of the β-Naphthol Componenta,b
a
Reaction conditions: 1a (0.25 mmol), 2 (0.10 mmol), Ru(bpy)
3
Cl
2
∙6H
2
2
O (1 mol %), Cu(OTf) (10 mol %), DCE
b
(
3.0 mL), 23 W blue LED light irradiation under air for 36 h at room temperature. Yield of the isolated product, dr
1
values were determined by H NMR.
besides β-naphthols, other electron-rich arenes, such as α-naphthol and phenols were also used as
substrates, however, only arylglycines were obtained in these cases (4ak−4am). When α-naphthol
was used as the substrate, CDC reaction occurred at the para-position of the hydroxyl group, so
the coupling product 4ak could not participate in the subsequent cyclization. When phenols were
used as the substrates, intramolecular hydrogen bonds would be formed between the hydrogen
atom of hydroxyl group and the nitrogen atom, which may dramatically decrease the
nucleophilicity of the nitrogen, thereby inhibiting the second catalytic process. For β-naphthols,
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this type of intramolecular hydrogen bond could not be formed, because in the coupling product
(
e.g. 4aa), the steric effect between α-H of naphthalene ring and ester group would make hydroxyl
group far away from the nitrogen atom (the computational studies also support this point, Figure
). However, other possible reasons for the lack of reactivity with phenols should not be fully
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excluded.
Figure 1. Computational Structures of Compounds 4aa (a) and 4al (b). In compound 4aa, the
distance between hydrogen atom of hydroxyl group and the nitrogen atom is ca 4.48 Å, indicating
that intramolecular hydrogen bond could not be formed.
To evaluate the synthetic utility of this protocol, a gram-scale reaction of 1a and 2a (5 mmol)
was conducted (Scheme 2a). The target product 3aa was obtained in 74% yield. Furthermore,
transformations of products were also conducted. As shown in Scheme 2b, the 1,3-benzoxazine
ring was opened when treatment of 3aa with NaOH, giving arylglycine 6 in 65% yield. We also
4
tried the reduction of the ester groups by using LiAlH as the reductant, however, a complicated
mixture was obtained. Finally, the esterification of 3ae with the bioactive podophyllotoxin 7 was
successfully carried out in the presence of DMAP and DCC, affording the ester 8 in 72% yield
(
Scheme 2c).
Scheme 2. Gram-Scale Reactions of 1a and 2a and Transformations of the Products
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
To provide insights about the reaction mechanisms of this transformations, a series of control
experiments were conducted (Scheme 3). Firstly, when excessive TEMPO was subjected to the
model reaction as a radical scavenger, only trace product could be observed (the TEMPO-trapped
product 9 was identified by high-resolution mass spectrometry, see Figure S2), indicating that this
reaction may include a radical process. Next, upon irradiation of 1a with blue LEDs under the
standard conditions, the imine intermediate 5a was isolated in 86% yield. Thirdly, the obtained 5a
reacted readily with 2a under the standard conditions, giving 3aa in 90% yield. Finally,
arylglycine 4aa was synthesized18e and subjected to the standard reaction conditions, and product
3
aa was obtained in 94% yield; however, in the absence of photocatalyst, only trace 3aa was
observed. These results illustrated that 4aa and 5a should be key intermediates of this reaction.
Scheme 3. Control Experiments for Mechanistic Studies
Scheme 4. Proposed Mechanism
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8
9
0
Based upon the above experimental results and precedent literatures, we proposed a possible
mechanism for this photocatalytic oxidative dehydrogenative coupling reaction, as shown in
Scheme 4. Firstly, the excited state [Ru(bpy)
3
]2+* would accept a single electron from glycine ester
]+ and the radical cation A. The photocatalyst was then regenerated by the
1
a to produce [Ru(bpy)
3
∙
-
oxidation of O
2
; an active species O
2
was formed during this process, which may abstract
-
electron and proton from A to produce the iminium ion B. Next, the in situ generated HOO may
abstract a proton from B to form the imine 5a, which subsequently forms the active electrophile C
2
under the influence of Cu(OTf) . Active intermediate C was then captured by β-naphthol 2a to
form arylglycine 4aa, which further underwent intermolecular amination with intermediate C to
afford intermediate D. Finally, a second oxidation of D and the sequential intramolecular
nucleophilic attack and elimination of the aniline would afford the desired product 3aa. The
aniline byproduct could be detected by Thin-Layer Chromatography (TLC). Furthermore, acid
catalyzed elimination of aniline from D to produce an iminium followed by cyclization is another
alternative possible pathway. However, other possible mechanistic pathways should not be fully
excluded. More details for the mechanism of this transform are currently under investigation.
Conclusion
In conclusion, we have realized a highly efficient aerobic oxidative dehydrogenative coupling
reaction of glycine esters with β-naphthols via the synergistic combination of photoredox catalysis
and Lewis acid catalysis. A range of 1,3-benzoxazine derivatives were obtained in good yields
under mild reaction conditions. The potential synthetic value of this novel protocol was
exemplified by gram-scale reactions. Further investigations toward an asymmetric variant of this
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transform are currently underway in this laboratory.
Experimental Section
General Experimental Procedures
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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5
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5
5
5
6
0
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Unless otherwise noted, all reagents were purchased from commercial sources and used as
received without further purification. Unless otherwise indicated, all experiments were carried out
under air atmosphere. Irradiation of photochemical reactions was carried out using a 23 W blue
LED strip. The silica gel (200-300 meshes) was used for column chromatography and TLC
1
13
inspections were taken on silica gel GF254 plates. Liquid H and C NMR spectra were recorded
on a 400 MHz spectrometer. The chemical shifts δ are given in ppm relative to tetramethylsilane
3
and the coupling constants J are given in Hz. The spectra were recorded with CDCl as solvent at
room temperature. High resolution mass spectra (HRMS) were obtained on a mass spectrometer
by using electrospray ionization (ESI) analyzed by quadrupole time-of-flight (QTof).
N-arylglycine derivatives13a,13b were prepared according to literature procedures.
General Procedure for the Visible Light-Induced Oxidative Cross Dehydrogenative Coupling
of Glycine Derivatives Esters with β-Naphthols.
A solution of N-arylglycine ester 1 (0.25 mmol, 2.5 eq), 2 (0.10 mmol, 1.0 eq),
3 2 2 2
Ru(bpy) Cl ·6H O (1 mol %, 0.001 mmol, 0.75 mg), Cu(OTf) (10 mol %, 0.01 mmol, 3.6 mg) in
dry DCE (3.0 mL) was irradiated with 23 W blue LED strip (400−500 nm) (at approximately 5
cm distance from the light source) under air atmosphere at room temperature for 36 h. After
completion of the reaction as monitored by TLC, the solvent was concentrated in vacuo. The
crude product was purified by flash chromatography on silica gel (petroleum ether/acetone = 8:1)
to afford the products.
Diethyl 2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate (3aa).
1
Pale yellow oil (34.4 mg, 79% yield). H NMR (400 MHz, CDCl
3
) δ 7.79 (dd, J
1
= 8.4 Hz, J
2
=
4
1
4
.5 Hz, 2H), 7.69 (d, J = 8.4 Hz, 1H), 7.51–7.44 (m, 1H), 7.41–7.35 (m, 1H), 7.34 (d, J = 9.0 Hz,
H), 7.27–7.20 (m, 2H), 6.79–6.71 (m, 2H), 6.30 (s, 1H), 5.26 (s, 1H), 4.45–4.27 (m, 2H), 4.24–
13
1
.12 (m, 2H), 3.72 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); C { H}NMR (100
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2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
MHz, CDCl
3
) δ 171.2, 166.1, 157.4, 151.8, 140.1, 131.2, 129.9, 129.5, 128.8, 127.1, 126.3, 124.0,
1
21.6, 119.1, 114.2, 110.4, 83.2, 63.7, 61.8, 61.7, 55.3, 14.1, 13.9; HRMS (ESI) calcd for
+
C
25
H26NO
6
(M+H) 436.1760, found 436.1762.
Diethyl 2-(4-ethoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate (3ba).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Pale yellow solid (36.9 mg, 82% yield), mp 68–69 ℃. H NMR (400 MHz, CDCl
3
) δ 7.79 (dd, J
1
=
2
8.3 Hz, J = 5.3 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.42–7.30 (m, 2H),
7
4
.22 (d, J = 8.9 Hz, 2H), 6.73 (d, J = 8.9 Hz, 2H), 6.29 (s, 1H), 5.26 (s, 1H), 4.45–4.26 (m, 2H),
13
.25–4.10 (m, 2H), 3.94 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.0 Hz, 6H), 1.12 (t, J = 7.1 Hz, 3H); C
{1
3
H}NMR (100 MHz, CDCl ) δ 171.2, 166.1, 156.8, 151.9, 139.9, 131.3, 129.9, 129.5, 128.8,
1
27.1, 126.3, 124.0, 121.6, 119.2, 114.8, 110.5, 83.2, 63.7, 63.5, 61.8, 61.7, 14.7, 14.1, 13.9;
+
HRMS (ESI) calcd for C26
H28NO
6
(M+H) 450.1917, found 450.1919.
Diethyl
2-(4-isopropoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate
1
(3ca). Pale yellow oil (38.9 mg, 84% yield). H NMR (400 MHz, CDCl
3
) δ 7.80 (dd, J
1
= 8.4 Hz,
J
2
= 5.1 Hz, 2H), 7.70 (d, J = 8.3 Hz, 1H), 7.51–7.46 (m, 1H), 7.41–7.37 (m, 1H), 7.35 (d, J = 9.0
Hz, 1H), 7.27–7.16 (m, 2H), 6.78–6.70 (m, 2H), 6.31 (s, 1H), 5.28 (s, 1H), 4.46–4.37 (m, 2H),
4.35–4.31 (m, 1H), 4.27–4.12 (m, 2H), 1.36 (d, J = 7.2 Hz, 3H), 1.28 (dd, J = 6.0 Hz, J =3.7 Hz,
) δ 171.2, 166.1, 155.7, 151.9,
1
2
1
3
1
6H), 1.13 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz, CDCl
3
139.9, 131.3, 129.9, 129.5, 128.8, 127.0, 126.3, 123.9, 121.6, 119.2, 116.2, 110.5, 83.2, 70.0, 63.7,
+
6
4
1.8, 61.7, 21.9, 21.8, 14.1, 13.8; HRMS (ESI) calcd for C27
64.2077.
H30NO
6
(M+H) 464.2073, found
Diethyl 2-(4-butoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate (3da).
1
Pale yellow oil (38.7 mg, 81% yield). H NMR (400 MHz, CDCl
3
) δ 7.79 (dd, J
1
= 8.4 Hz, J
2
=
5
.0 Hz, 2H), 7.68 (d, J = 8.4 Hz, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.40–7.36 (m, 1H), 7.34 (d, J = 9.0
Hz, 1H), 7.25–7.18 (m, 2H), 6.74 (d, J = 8.9 Hz, 2H), 6.30 (s, 1H), 5.26 (s, 1H), 4.47–4.38 (m,
1
1
H), 4.36– 4.26 (m, 1H), 4.25–4.12 (m, 2H), 3.86 (t, J = 6.5 Hz, 2H), 1.74–1.67 (m, 2H), 1.47–
.40 (m, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H), 0.94 (t, J = 7.4 Hz, 3H); 13C
{1
3
H}NMR (100 MHz, CDCl ) δ 171.2, 166.1, 156.9, 151.8, 139.9, 131.3, 129.9, 129.5, 128.8,
1
1
27.1, 126.3, 124.0, 123.6, 121.6, 119.2, 114.9, 114.8, 110.4, 83.2, 67.8, 63.8, 61.7, 61.6, 31.2,
+
9.1, 14.1, 13.9, 13.8. HRMS (ESI) calcd for C28
H32NO
6
(M+H) 478.2230, found 478.2235.
Diethyl
2-([1,1'-biphenyl]-4-yl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate
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(
3ea). Pale yellow solid (27.9 mg, 58% yield), mp 123–124 ℃. H NMR (400 MHz, CDCl
3
) δ
= 3.9 Hz, 2H), 7.74 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.51–7.47 (m, 3H),
.46 (s, 1H), 7.43–7.36 (m, 6H), 7.35–7.31 (m, 1H), 6.38 (s, 1H), 5.49 (s, 1H), 4.44–4.33 (m, 2H),
7
7
4
1 2
.80 (dd, J = 8.4 Hz, J
13
1
.28–4.19 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz,
) δ 171.1, 166.2, 151.8, 146.3, 140.4, 137.7, 131.2, 130.1, 129.6, 128.8, 128.7, 127.8, 127.2,
27.1, 126.8, 124.1, 123.5, 121.6, 119.1, 110.5, 82.6, 63.8, 61.9, 14.1, 13.8; HRMS (ESI) calcd
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
CDCl
3
1
+
5
for C30H28NO (M+H) 482.1967, found 482.1971.
Diethyl 2-(4-phenoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate (3fa).
1
Pale red oil (33.3 mg, 67% yield). H NMR (400 MHz, CDCl
3
) δ 7.86–7.78 (m, 2H), 7.72 (d, J =
8
7
.4 Hz, 1H), 7.53–7.49 (m, 1H), 7.44–7.38 (m, 1H), 7.36 (d, J = 9.0 Hz, 1H), 7.33–7.29 (m, 4H),
.10–7.06 (m, 1H), 6.98–6.93 (m, 2H), 6.92–6.85 (m, 2H), 6.34 (s, 1H), 5.35 (s, 1H), 4.44–4.33
13
1
(
m, 2H), 4.29–4.18 (m, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H); C { H}NMR (100
MHz, CDCl ) δ 171.1, 165.9, 157.2, 154.6, 151.8, 142.5, 131.2, 130.1, 129.6, 129.5, 128.9, 127.1,
3
125.9, 124.1, 123.1, 121.6, 119.5, 119.1, 118.5, 110.3, 82.9, 63.8, 61.9, 61.8, 14.1, 13.9; HRMS
+
(ESI) calcd for C30
H28NO
6
(M+H) 498.1917, found 498.1923.
Diethyl
2-(4-(benzyloxy)phenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate
1
(3ga). Pale yellow oil (36.8 mg, 72% yield). H NMR (400 MHz, CDCl
3
) δ 7.79 (dd, J
1
= 8.3 Hz,
J
2
= 5.8 Hz, 2H), 7.68 (d, J = 8.3 Hz, 1H), 7.50–7.45 (m, 1H), 7.40–7.29 (m, 7H), 7.26–7.19 (m,
2
2
1
1
H), 6.85–6.78 (m, 2H), 6.29 (s, 1H), 5.26 (s, 1H), 4.98 (s, 2H), 4.41–4.29 (m, 2H), 4.24–4.11 (m,
13
1
3
H), 1.36 (t, J = 7.1 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz, CDCl ) δ 171.2,
66.1, 156.5, 151.8, 140.3, 136.8, 131.2, 129.9, 129.5, 128.8, 128.5, 127.9, 127.4, 127.1, 126.3,
24.0, 121.6, 119.2, 115.2, 110.4, 83.1, 70.1, 63.7, 61.8, 14.2, 13.9; HRMS (ESI) calcd for
+
C
31
H30NO
6
(M+H) 512.2073, found 512.2079.
Diethyl 2-(2,5-dimethoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate
1
(
3ha). Pale yellow solid (38.6 mg, 83% yield), mp 116–117 ℃. H NMR (400 MHz, CDCl
3
) δ
7
2
.97 (d, J = 8.5 Hz, 1H), 7.83 (dd, J
1
= 8.4 Hz, J
2
= 4.8 Hz, 2H), 7.57–7.49 (m, 1H), 7.46–7.38 (m,
= 8.8 Hz, J = 2.7
H), 7.34 (d, J = 2.1 Hz, 1H), 6.65 (s, 1H), 6.54 (d, J = 2.7 Hz, 1H), 6.31 (dd, J
1
2
Hz, 1H), 5.36 (s, 1H), 4.40–4.31 (m, 3H), 4.19–4.15 (m, 1H), 3.98 (s, 3H), 3.79 (s, 3H), 1.38 (t, J
13
1
=
7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz, CDCl
3
) δ 158.2, 154.9, 151.3,
1
31.5, 129.8, 129.5, 129.1, 128.6, 126.7, 124.5, 123.8, 122.3, 119.2, 110.2, 103.3, 100.2, 83.2,
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1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
6
7
1.6, 61.5, 61.2, 56.0, 55.4, 14.1, 13.8; HRMS (ESI) calcd for C26H28NO (M+H) 466.1866,
found 466.1872.
Diethyl
2-(4-methoxy-2-methylphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-di-
1
carboxylate (3ia). Pale yellow oil (34.6 mg, 77% yield). H NMR (400 MHz, CDCl
3
) δ 7.80 (d, J
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
=
9.3 Hz, 2H), 7.67 (d, J = 8.4 Hz, 1H), 7.48–7.42 (m, 1H), 7.42–7.32 (m, 2H), 7.21 (d, J = 8.8 Hz,
H), 6.75 (d, J = 2.9 Hz, 1H), 6.49 (dd, J = 8.8 Hz, J = 2.9 Hz, 1H), 6.32 (s, 1H), 4.97 (s, 1H),
.37–4.34 (m, 2H), 4.14–4.02 (m, 2H), 3.71 (s, 3H), 2.49 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H), 1.03 (t,
1
4
1
2
13
1
J = 7.1 Hz, 3H); C { H}NMR (100MHz, CDCl
3
) δ 171.3, 165.9, 157.9, 151.6, 138.3, 131.4,
1
1
29.9, 129.5, 128.8, 127.4, 127.0, 123.9, 121.6, 119.3, 116.2, 110.9, 110.1, 83.4, 61.6, 61.5, 55.2,
+
6
8.7, 14.2, 13.7; HRMS (ESI) calcd for C26H28NO (M+H) 450.1917, found 450.1923.
Dimethyl
2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate
1
(3ja). White solid (32.2 mg, 79% yield), mp 115–116 ℃. H NMR (400 MHz, CDCl
3
) δ 7.80 (dd,
J
1
= 8.4 Hz, J
2
= 4.1 Hz, 2H), 7.64 (d, J = 8.3 Hz, 1H), 7.51–7.45 (m, 1H), 7.39 (t, J = 7.1 Hz, 1H),
7.33 (d, J = 8.9 Hz, 1H), 7.21 (d, J = 9.0 Hz, 2H), 6.74 (d, J = 9.0 Hz, 2H), 6.30 (s, 1H), 5.29 (s,
1
3
1
3
1H), 3.89 (s, 3H), 3.72 (s, 6H); C { H}NMR (100 MHz, CDCl ) δ 166.5, 157.4, 151.8, 139.9,
131.2, 130.1, 129.5, 128.9, 127.3, 126.1, 124.1, 121.5, 119.1, 114.3, 110.3, 83.2, 63.6, 55.3, 52.9,
+
52.7; HRMS (ESI) calcd for C23
H22NO
6
(M+H) 408.1447, found 408.1452.
Diisopropyl 2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate
1
(
3ka). Pale yellow solid (38.5 mg, 83% yield), mp 122–123 ℃. H NMR (400 MHz, CDCl
3
) δ
7
1
2
3
1
6
4
.79 (dd, J
3.5Hz, J
H), 5.08–4.95 (m, 1H), 3.72 (s, 3H), 1.34 (dd, J
1
= 8.4 Hz, J
= 8.1 Hz, 2H), 7.27–7.22 (m, 2H), 6.75 (d, J = 9.0 Hz, 2H), 6.22 (s, 1H), 5.23–5.19 (m,
= 6.2 Hz, J = 3.2 Hz, 6H), 1.20 (d, J = 6.3 Hz,
H), 1.01 (d, J = 6.2 Hz, 3H); C { H}NMR (100 MHz, CDCl ) δ 170.8, 165.6, 157.3, 151.9,
2 1
= 5.5 Hz, 2H), 7.66 (d, J = 8.4 Hz, 1H), 7.49–7.43 (m, 1H), 7.36 (dd, J =
2
1
2
1
3
1
3
40.2, 131.3, 129.8 129.4, 128.8, 126.9, 126.5, 123.9, 121.7, 119.2, 114.0, 110.5, 83.1, 69.5, 69.3,
+
3.9, 55.3, 21.7, 21.6, 21.5, 21.2; HRMS (ESI) calcd for C27
64.2069.
H30NO
6
(M+H) 464.2073, found
Di-tert-butyl 2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate
1
(3la). Pale yellow oil (38.3 mg, 78% yield). H NMR (400 MHz, CDCl
3
) δ 7.77 (t, J = 8.7 Hz, 2H),
7
1
.63 (d, J = 8.4 Hz, 1H), 7.48–7.44 (m, 1H), 7.38–7.31 (m, 2H), 7.30–7.26 (m, 2H), 6.14–6.04 (m,
13
1
3
H), 5.09 (s, 1H), 3.73 (s, 3H), 1.56 (s, 9H), 1.30 (s, 9H); C { H}NMR (100 MHz, CDCl ) δ
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70.6, 165.1, 157.1, 152.0, 140.5, 131.4, 129.7, 129.4, 128.7, 126.9, 126.4, 123.8, 121.7, 119.2,
13.9, 110.8, 82.9, 82.4, 82.2, 64.9, 55.4, 27.9, 27.6; HRMS (ESI) calcd for C29
92.2386, found 492.2391.
H34NO
6
(M+H)+
Dibenzyl
2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-dicarboxylate
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
(3ma). Pale yellow oil (44.8 mg, 80% yield). H NMR (400 MHz, CDCl
3
) δ 7.80 (dd, J
= 4.5 Hz, 2H), 7.63–7.56 (m, 1H), 7.39–7.36 (m, 4H), 7.36–7.26 (m, 7H), 7.21–7.15 (m, 4H),
.67 (d, J = 9.0 Hz, 2H), 6.33 (s, 1H), 5.44–5.25 (m, 3H), 5.22 (d, J = 12.1 Hz, 1H), 5.11 (d, J =
1
= 6.9 Hz,
J
2
6
1
1
1
13
1
2.1 Hz, 1H), 3.72 (s, 3H); C { H}NMR (100 MHz, CDCl
3
) δ 170.9, 165.9, 157.3, 151.8, 139.9,
35.3, 134.8, 131.1, 130.0, 129.4, 128.8, 128.6, 128.5, 128.4, 128.3, 128.2, 128.0, 127.1, 126.1,
24.0, 121.5, 119.1, 114.2, 110.1, 83.1, 67.3, 67.2, 63.8, 55.2; HRMS (ESI) calcd for C35H30NO
6
+
(
M+H) 560.2073, found 560.2069.
Diethyl
9-bromo-2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-di-
1
carboxylate (3ab). Pale red oil (39.6 mg, 77% yield). H NMR (400 MHz, CDCl
3
) δ 7.92 (s, 1H),
7.73 (d, J = 9.0 Hz, 1H), 7.65 (d, J = 8.7 Hz, 1H), 7.49–7.41 (m, 1H), 7.33 (d, J = 9.0 Hz, 1H),
7.22 (d, J = 9.0 Hz, 2H), 6.76 (d, J = 4.0 Hz, 1H), 6.74 (d, J = 4.1 Hz, 1H), 6.35 (s, 1H), 5.19 (s,
1H), 4.47–4.42 (m, 1H), 4.33–4.28 (m, 1H), 4.26 – 4.11 (m, 2H), 3.72 (s, 3H), 1.40 (t, J = 7.1 Hz,
1
3
1
3
3H), 1.12 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz, CDCl ) δ 171.1, 166.0, 157.5, 152.6,
139.8, 132.5, 130.3, 129.8, 129.4, 127.9, 127.4, 126.3, 124.4, 121.6, 119.6, 116.6, 114.3, 109.7,
+
8
3.2, 63.2, 62.0, 61.9, 55.4, 14.1, 13.9; HRMS (ESI) calcd for C25
H
25BrNO
6
(M+H) 514.0865,
found 514.0871, 516.0851 (isotopic mass).
Diethyl
8-bromo-2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-
1
dicarboxylate (3ac). Pale yellow solid (37.6 mg, 73% yield), mp 140–141 ℃. H NMR (400 MHz,
CDCl
3
) δ 7.93 (d, J = 1.8 Hz, 1H), 7.68 (d, J = 9.0 Hz, 1H), 7.58–7.51(m, 2H), 7.34 (d, J = 9.0 Hz,
1
4
H), 7.25–7.18 (m, 2H), 6.78–6.72 (m, 2H), 6.28 (s, 1H), 5.22 (s, 1H), 4.37–4.32 (m, 2H), 4.20–
13
1
.16 (m, 2H), 3.72 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); C { H}NMR (100
) δ 170.9, 165.9, 157.5, 152.1, 139.9, 130.7, 130.2, 129.8, 129.0, 126.3, 123.5, 120.3,
17.7, 116.6, 114.2, 110.7, 83.2, 63.5, 61.9, 61.8, 55.3, 14.1, 13.8; HRMS (ESI) calcd for
MHz, CDCl
3
1
+
C
25
H
25BrNO
6
(M+H) 514.0865, found 514.0870, 516.0850 (isotopic mass).
Diethyl
8-cyano-2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-
1
dicarboxylate (3ad). White solid (37.8 mg, 82% yield), mp 135–136 ℃. H NMR (400 MHz,
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2
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2
2
2
2
2
2
2
3
3
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3
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3
3
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3
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CDCl
3
) δ 8.15 (d, J = 1.4 Hz, 1H), 7.83 (d, J = 9.1 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.60 (dd, J
1
=
8.8 Hz, J
2
= 1.7 Hz, 1H), 7.44 (d, J = 9.0 Hz, 1H), 7.24–7.17 (m, 2H), 6.79–6.72 (m, 2H), 6.30
(
s, 1H), 5.23 (s, 1H), 4.44–4.30 (m, 2H), 4.25–4.11 (m, 2H), 3.72 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H),
13
1
1
1
6
1
3
.11 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz, CDCl ) δ 170.7, 165.5, 157.6, 154.3, 139.6,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
34.5, 133.1, 130.4, 128.5, 127.8, 126.2, 122.9, 121.2, 119.0, 114.3, 110.8, 107.4, 83.4, 63.4, 62.1,
+
2.0, 55.3, 14.1, 13.8; HRMS (ESI) calcd for C26
H
25
N O
2 6
(M+H) 461.1713, found 461.1718.
,3-Bis(ethoxycarbonyl)-2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-8-carb
1
-
oxylic acid (3ae). Pale yellow solid (35.0 mg, 73% yield), mp 152–153 ℃. H NMR (400 MHz,
Acetone-d6) δ 8.61 (d, J = 1.6 Hz, 1H), 8.10–8.06 (m, 2H), 7.85 (d, J = 9.1 Hz, 1H), 7.37 (d, J =
9
4
.0 Hz, 1H), 7.23–7.20 (m, 2H), 6.82–6.79 (m, 2H), 6.24 (s, 1H), 5.41 (s, 1H), 4.35–4.30 (m, 2H),
13
1
.15–4.12 (m, 2H), 3.71 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H); C { H}NMR
(
100 MHz, CDCl
3
) δ 171.8, 170.9, 165.8, 157.5, 154.1, 139.8, 134.3, 132.7, 131.5, 128.6, 126.8,
1
26.3, 124.7, 122.1, 120.3, 114.3, 110.7, 83.3, 63.6, 62.0, 61.9, 55.4, 14.2, 13.9; HRMS (ESI)
+
calcd for C26
H26NO
8
(M+H) 480.1658, found 480.1663.
1,3-Diethyl 8-methyl 2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3,8-
1
tricarboxylate (3af). Pale yellow solid (36.5 mg, 74% yield), mp 158–159 ℃. H NMR (400 MHz,
Acetone-d6) δ 8.58 (d, J = 1.4 Hz, 1H), 8.11–8.03 (m, 2H), 7.85 (d, J = 9.0 Hz, 1H), 7.38 (d, J =
9.0 Hz, 1H), 7.21 (d, J = 9.0 Hz, 2H), 6.82–6.79 (m, 2H), 6.24 (s, 1H), 5.41 (s, 1H), 4.37–4.28 (m,
2
3
1
1
H), 4.16–4.10 (m, 2H), 3.92 (s, 3H), 3.71 (s, 3H), 1.32 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz,
1
3
1
3
H); C { H}NMR (100 MHz, CDCl ) δ 170.9, 166.9, 165.7, 157.5, 153.8, 139.8, 133.7, 131.6,
31.3, 128.6, 126.6, 126.2, 125.5, 121.9, 120.1, 114.2, 110.6, 83.3, 63.5, 61.9, 61.8, 55.3, 52.1,
+
4.1, 13.8; HRMS (ESI) calcd for C27
H28NO
8
(M+H) 494.1815, found 494.1819.
Diethyl
9-hydroxyl-2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-di-
1
carboxylate (3ag). Pale yellow solid (35.7 mg, 79% yield), mp 141–142 ℃. H NMR (400 MHz,
CDCl
3
) δ 7.66 (dd, J
.02 (d, J = 2.2 Hz, 1H), 6.95 (dd, J
.12 (s, 1H), 4.42–4.32 (m, 1H), 4.32–4.24 (m, 1H), 4.24–4.12 (m, 2H), 3.70 (s, 3H), 1.32 (t, J =
1
= 8.8 Hz, J
2
= 6.7 Hz, 2H), 7.24–7.18 (m, 2H), 7.14 (d, J = 9.0 Hz, 1H),
7
5
7
1
6
1
= 8.8 Hz, J = 2.3 Hz, 1H), 6.75–6.67 (m, 2H), 6.26 (s, 1H),
2
13
1
3
.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz, CDCl ) δ 171.4, 166.3, 157.4,
54.9, 152.4, 140.1, 132.7, 130.7, 129.7, 126.3, 124.6, 116.5, 115.5, 114.2, 109.0, 104.6, 83.2,
+
3.9, 61.9, 61.8, 55.3, 14.0, 13.9; HRMS (ESI) calcd for C25
H26NO
7
(M+H) 452.1709, found
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52.1713.
Diethyl
9-methoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-di-
1
carboxylate (3ah). Pale yellow oil (37.5 mg, 81% yield). H NMR (400 MHz, Acetone-d6) δ 7.79
(
t, J = 8.8 Hz, 2H), 7.21–7.18 (m, 2H), 7.11–7.05 (m, 3H), 6.80 (d, J = 9.0 Hz, 2H), 6.24 (s, 1H),
.28 (s, 1H), 4.35–4.30 (m, 2H), 4.14–4.09 (m, 2H), 3.88 (s, 3H), 3.71 (s, 3H), 1.33 (t, J = 7.1 Hz,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
5
3
1
8
1
3
1
3
H), 1.08 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz, CDCl ) δ 171.3, 166.2, 158.8, 157.5,
52.5, 140.1, 132.5, 130.3, 129.6, 129.4, 126.5, 124.7, 116.6, 116.5, 116.1, 114.2, 109.5, 101.1,
+
3.2, 63.8, 61.8, 55.4, 55.2, 14.2, 13.9; HRMS (ESI) calcd for C26
H28NO
7
(M+H) 466.1866,
found 466.1872.
Diethyl
9-ethoxy-2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-
1
dicarboxylate(3ai). White solid (40.8 mg, 85% yield), mp 111–112 ℃. H NMR (400 MHz,
CDCl
.02 (dd, J
5.15 (s, 1H), 4.39–4.29 (m, 2H), 4.25–4.14 (m, 2H), 4.13–4.01 (m, 2H), 3.73 (s, 3H), 1.46 (t, J =
3
) δ 7.69 (dd, J
1
= 8.9 Hz, J
2
= 4.7 Hz, 2H), 7.23 (d, J = 8.9 Hz, 2H), 7.18 (d, J = 8.9 Hz, 1H),
7
1
= 8.9 Hz, J
2
= 2.2 Hz, 1H), 6.97 (d, J = 2.0 Hz, 1H), 6.79–6.67 (m, 2H), 6.30 (s, 1H),
1
3
1
3
7.0 Hz, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.12 (t, J = 7.1 Hz, 3H); C { H}NMR (100 MHz, CDCl ) δ
171.3, 166.2, 158.1, 157.4, 152.4, 140.1, 132.5, 130.3, 129.6, 126.5, 124.6, 116.5, 116.4, 114.2,
109.4, 101.7, 83.2, 63.9, 63.4, 61.8, 61.7, 55.4, 14.8, 14.2, 13.9; HRMS (ESI) calcd for
+
C
27
H30NO
7
(M+H) 480.2022, found 480.2026.
Diethyl 8-(hydroxymethyl)-2-(4-methoxyphenyl)-2,3-dihydro-1H-naphtho[1,2-e][1,3]oxazine-1,3-
1
dicarboxylate (3aj). Pale yellow oil (30.3 mg, 65% yield). H NMR (400 MHz, CDCl
3
) δ 7.79–
= 1.7 Hz, 1H), 7.33 (d, J = 9.0 Hz,
H), 7.25–7.19 (m, 2H), 6.76–6.71 (m, 2H), 6.28 (s, 1H), 5.24 (s, 1H), 4.81 (s, 2H), 4.40–4.28 (m,
7
1
2
1 2
.74 (m, 2H), 7.68 (d, J = 8.7 Hz, 1H), 7.48 (dd, J = 8.7 Hz, J
1
3
H), 4.22–4.13 (m, 2H), 3.72 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H), 1.11 (t, J = 7.1 Hz, 3H); C
{1
H}NMR (100 MHz, CDCl ) δ 171.2, 166.1, 157.4, 151.9, 140.0, 136.5, 130.7, 129.9, 129.4,
3
1
26.5, 126.4, 126.3, 122.1, 119.5, 114.2, 110.5, 83.2, 65.1, 63.7, 61.9, 61.8, 55.3, 14.1, 13.9;
+
HRMS (ESI) calcd for C26
H28NO
7
(M+H) 466.1866, found 466.1872.
Ethyl 2-(4-hydroxynaphthalen-1-yl)-2-((4-methoxyphenyl)amino)acetate(4ak). 18e Pale red oil
1
(23.9 mg, 68% yield). H NMR (400 MHz, CDCl
3
) δ 8.31–8.23 (m, 1H), 7.83–7.77 (m, 1H), 7.49
(
m, 2H), 7.43 (d, J = 8.5 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 6.79 (m, 2H), 6.75 (m, 2H), 5.08 (s,
13
1
1
H), 4.33–4.25 (m, 1H), 4.21–4.13 (m, 1H), 3.72 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); C { H}NMR
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2
2
2
2
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5
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6
(
100 MHz, CDCl
3
) δ 171.2, 154.6, 153.0, 138.8, 134.1, 127.2, 126.8, 126.6, 125.4, 125.2, 122.4,
1
19.4, 117.8, 114.7, 113.2, 63.4, 62.4, 55.5, 13.9. The obtained spectra match those previously
reported.
Ethyl 2-(6-hydroxybenzo[d][1,3]dioxol-5-yl)-2-((4-methoxyphenyl)amino)acetate(4al).18e White
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
solid (20.0 mg, 58% yield), mp 116–117 ℃. H NMR (400 MHz, CDCl
3
) δ 9.12 (s, 1H), 6.80–
6
4
1
.72 (m, 4H), 6.70 (s, 1H), 6.42 (s, 1H), 5.92 (s, 2H), 4.85 (s, 1H), 4.72 (s, 1H), 4.34–4.24 (m, 1H),
.23–4.13 (m, 1H), 3.74 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C { H}NMR (100 MHz, CDCl
1
) δ
3
71.2, 154.4, 151.9, 148.3, 141.0, 138.8, 117.6, 114.7, 112.3, 108.2, 101.1, 99.5, 62.4, 55.5, 14.0.
The obtained spectra match those previously reported.
Ethyl 2-(2,6-dihydroxyphenyl)-2-((4-methoxyphenyl)amino)acetate(4am).18e White solid (14.3 mg,
1
4
4
4
5% yield), mp 68–69 ℃. H NMR (400 MHz, CDCl
3
) δ 7.05 (d, J = 8.3 Hz, 1H), 6.78–6.73 (m,
H), 6.39 (dd, J = 8.3, 2.5 Hz, 1H), 6.35 (d, J = 2.4 Hz, 1H), 4.94 (s, 1H), 4.30–4.24 (m, 1H),
.22–4.15 (m, 1H), 3.73 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H); 13C { H}NMR (100 MHz, CDCl
1
) δ
3
171.7, 157.5, 157.2, 154.4, 138.9, 130.2, 117.8, 114.7, 113.3, 107.7, 104.3, 62.3, 62.1, 55.5, 14.0.
The obtained spectra match those previously reported.
Procedure for the Synthesis of Arylglycine 6.
3aa (65 mg, 0.15 mmol) was dissolved in anhydrous ethanol (1.0 mL), then NaOH (42 mg, 1.05
mmol) was added to the solution. The mixture was heated to 70 ℃ and stirred at this temperature
for 1 h. The mixture was poured into 3 M HCl and filtered out the salt. The solvent was removed
by vacuo. The residue was suspended in CH
2
Cl
2
2 2
, then filtered (washed with CH Cl ), arylglycine
1
6
was obtained as a pale yellow solid (21.2 mg, 65%), mp 134−136 °C. H NMR (400 MHz,
3
CD OD) δ 7.80 (t, J = 9.0 Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 7.29–7.21
(
m, 3H), 7.18 (d, J = 8.9 Hz, 1H), 6.74 (d, J = 9.0 Hz, 2H), 6.25 (s, 1H), 3.63 (s, 3H); 13C
{1
3
H}NMR (101 MHz, CD OD) δ 171.0, 161.6, 133.6, 129.93, 129.88, 128.7, 127.4, 126.0, 125.2,
1
3
24.3, 122.0, 117.9, 116.3, 115.5, 108.9, 61.9, 55.9. HRMS (ESI) calcd for C19
24.1230, found 324.1226.
H17NO
6
(M+H)+
Procedure for the Esterification of 3ae with Podophyllotoxin 7.
2 2
Podophyllotoxin 7 (62 mg, 0.15 mmol) was dissolved in anhydrous CH Cl (2 mL), then 3ae (47.9
mg, 0.1 mmol), DCC (61.8 mg, 0.3 mmol), and DMAP (1.2 mg, 10 mol%) were added
respectively, the solution was stirred at room temperature. After the reaction was completed as
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monitored by TLC, 3 M HCl was added. The mixture was extracted with CH
organic layer was combined, washed with water and brine respectively, dried over anhydrous
Na SO , and concentrated in vacuo. The crude product was purified by column chromatography
2 2
Cl (5 mL × 3). The
2
4
(
petroleum ether/ethyl acetate = 1:1) to give ester 8 as a white solid (54.7 mg, 72%), mp 150–
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52 °C. H NMR (CDCl
3
, 400 MHz) δ 8.52 (s, 1H), 8.01 (ddd, J = 8.9, 3.4, 1.8 Hz, 1H), 7.86 (d, J
=
8.9 Hz, 1H), 7.73 (dd, J = 8.8, 6.7 Hz, 1H), 7.41 (d, J = 9.0 Hz, 1H), 7.21 (dd, J = 9.0, 0.9 Hz,
H), 6.89 (s, 1H), 6.74 (d, J = 8.9 Hz, 2H), 6.59 (s, 1H), 6.46 (d, J = 1.0 Hz, 2H), 6.29 (d, J = 6.4
Hz, 1H), 6.16 (d, J = 6.7 Hz, 1H), 6.03–5.95 (m, 2H), 5.25 (s, 1H), 4.66 (d, J = 3.1 Hz, 1H), 4.50–
2
4
1
1
1
8
.43 (m, 1H), 4.39–4.28 (m, 3H), 4.23–4.11 (m, 2H), 3.79 (s, 9H), 3.71 (s, 3H), 3.06–2.96 (m, 2H),
13
1
3
.34 (td, J = 7.1, 4.9 Hz, 3H), 1.10 (t, J = 7.1 Hz, 3H); C { H}NMR (101 MHz, CDCl ) δ 173.7,
70.8, 166.7, 165.6, 157.5, 154.2, 152.6, 148.2, 147.7, 139.7, 137.0, 134.8, 134.1, 132.4, 132.0,
31.3, 128.5, 128.3, 126.3, 126.2, 124.5, 122.3, 120.5, 114.2, 110.7, 109.7, 108.0, 107.1, 101.6,
3.3, 74.2, 71.5, 63.5, 62.0, 61.9, 60.7, 56.1, 55.3, 45.6, 43.7, 38.8, 14.2, 13.8; HRMS (ESI) calcd
+
for C48
H
45NO15 (M+H) 876.2867, found 876.2861.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge via the Internet at http://pubs.acs.org.
Optimization of Reaction Conditions; X-Ray Single Crystal Diffraction Data for 3aa; Copies of
1
13
H and C NMR spectra of synthetic compounds.
AUTHOR INFORMATION
Corresponding Author
*
*
E-mail: zhangyuan@lzu.edu.cn
E-mail: liying@lzu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We gratefully acknowledge the National Natural Science Foundation of China (Nos. 21572092
and 21772079) and Natural Science Foundation of Gansu Province (18JR4RA003) for financial
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support. We thank professor Qiang Liu (Lanzhou University) for helpful discussion. We also
thank Mr. Shutao Wang (Lanzhou University) for computational studies.
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19) CCDC 1888972 (3aa) contains the supplementary crystallographic data for this paper. These data can be
obtained
free
of
charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif
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