Enantioselective Syntheses of 4 H-3,1-Benzoxazines via Catalytic Asymmetric Chlorocyclization of o-Vinylanilides

Article abstract of DOI:10.1021/acs.joc.9b02395

The catalytic asymmetric halocyclization of alkene is a powerful and straightforward strategy for the synthesis of chiral heterocyclic compounds. Herein, an effective approach to chiral benzoxazine derivatives through organocatalyzed chlorocyclization of o-vinylanilides was reported. This method provides facile access to a series of chiral benzoxazines in good to excellent yields (up to 99% yield) and with high-level enantiocontrol (up to 92% ee).

Full text of DOI:10.1021/acs.joc.9b02395

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Article
Enantioselective Syntheses of 4H-3,1-Benzoxazines via
Catalytic Asymmetric Chlorocyclization of o-Vinylanilides
Qinxia Xie, Hai-Jiao Long, Qiong-Yin Zhang, Pei Tang, and Jun Deng
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02395 • Publication Date (Web): 27 Dec 2019
Downloaded from pubs.acs.org on December 29, 2019
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Page 1 of 36
The Journal of Organic Chemistry
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Enantioselective Syntheses of 4H-3,1-Benzoxazines via Catalytic
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Asymmetric Chlorocyclization of o-Vinylanilides
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Qinxia Xie,† Hai-Jiao Long,† Qiong-Yin Zhang,† Pei Tang*, †, ‡ and Jun Deng*, †
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†Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, Innovative Drug
Research Centre, School of Pharmaceutical Sciences, Chongqing University, 55 Daxuecheng South
Road, Shapingba, Chongqing 401331, China
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‡Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan
Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision
Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China
E-mail: peitang@scu.edu.cn; jdeng@tju.edu.cn
R1
N
R1
Cl
O
DCDMH (1.2 equiv)
H
O
R2
VI
(10 mol %)
R2
O
N(o-toly)2
-78 oC, MeOH, 24 h
N
R3
NH
R3
N
up to 99% yield
up to 92% ee
O
VI
ABSTRACT: The catalytic asymmetric halocyclization of alkene is a powerful and straightforward
strategy for the synthesis of chiral heterocyclic compounds. Herein, an effective approach to chiral
benzoxazine derivatives through organocatalyzed chlorocyclization of o-vinylanilides was reported.
This method provides facile access to a series of chiral benzoxazines in good to excellent yields (up to
99% yield) and with high level enantiocontrol (up to 92% ee).
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INTRODUCTION
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2
4H-3,1-benzoxazines are important heterocyclic compounds in medicinal chemistry due to their
wide spectrum of biological activities.1 Although substantial effort has been devoted to the synthesis of
benzoxazine derivatives,2 methods for enantioselective synthesis of 4H-3,1-benzoxazines are rare. To
the best of our knowledge, only a few examples to prepare 4H-3,1-benzoxazine analogues
stereoselectively have been reported.3 Pioneering enantioselective synthesis of 4H-3,1-benzoxazines was
reported by the group of Toste through treating o-vinylanilides with monoalkyl DABCO-derived
(Bis)aminehalonium reagent via chiral anion phase-transfer catalysis (Scheme 1a).3a Afterwards, an
asymmetric synthesis of 4H-3,1-benzoxazines via enantioselective iridium-catalysed intramolecular
allylic amidation has been developed by Feringa’s group (Scheme 1b).3b Very recently, Hu and
coworkers reported an approach to benzoxazines involving rhodium-catalyzed electrophilic trapping of
zwitterionic intermediates by imines (Scheme 1c).3c Despite these progresses, the novel approach to the
enantioselective synthesis of 4H-3,1-benzoxazines allowing various substitution patterns is still highly
desirable.
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The catalytic asymmetric halogenation of alkene is one of the most promising research fields in
recent years,4 especially the intramolecular alkene halofunctionalization reactions have been
successfully applied as powerful and straightforward strategies to construct the chiral cyclic compounds
such as lactones,5 cyclic ethers,6 nitrogen heterocycles,7 and related structures8. However, the
improvement of these reactions scope to understand the reactivity of halonium ions and access valuable
chiral heterocyclic products remain attractive. Consequently, inspired by the success of asymmetric
chlorocyclization reactions for the synthesis of chiral oxazolines, dihydrooxazines and related
compounds,9 we wish to report here our efforts toward the novel synthesis of the chiral 4H-3,1-
benzoxazines via the chlorocyclization of o-vinylanilides.
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Scheme 1. The Approaches to Chiral 4H-3,1-Benzoxazines
1
2
3
Previous works:
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9
Ar
R2
R1
R2
N
N
X
N
N
a)
X
Ar
-
R1
NH
(BF4 )3
X = Br, Cl
O
R3
R3
N
R4
Chiral anion
phase-transfer catalysis
O
R4
up to 94% yield
up to 99% ee
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LG
b)
Ir/chiral phosphoramidite
O
R1
R1
Intramolecular allylic amidation
N
R2
NH
up to 93% yield
up to 97% ee
O
R2
Ar2
Ar2HN
Ar1
c)
N2
Ar1
N
CO2Me
CO2Me
[Rh2(OAc)4/chiral phosphoric acid
O
OMe
NH OMe
Trapping of zwitterionic
intermediate
N
O
up to 80% yield
up to 98% ee
This work:
Asymmetric chlorocyclization
R1
N
R1
Cl
O
DCDMH (1.2 equiv)
VI
H
O
R2
(10 mol %)
-78 oC, MeOH, 24 h
R2
O
N(o-toly)2
NH
N
R3
N
O
R3
VI
RESULTS AND DISCUSSION
At the initial stage of our investigation, the easily synthesized N-(2-(1-
phenylvinyl)phenyl)benzamide 1a was selected as the model substrate for the evaluation of various
o
chiral organocatalysts, and all reactions were carried out in MeOH at -80 C for 6 h using DCDMH as
the chlorenium source (Scheme 2). Firstly, when (DHQD)2PHAL was used as the catalyst, the desired
product 2a can be obtained in good enantioselectivity while the yield is poor. Disappointingly, the
thiourea catalyst II and III also afforded 2a with unacceptable yields (10% and 5%, respectively).
Although above chiral privileged catalysts were not able to deliver the benzoxazine with excellent yield
and enantioselectivity, we are very pleased to finally find that by using the IV as catalyst, the desired
product 2a was obtained in 78% yield and 46% ee. Encouraged by this result, a series of Cinchonidine-
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derived chiral esters V-VII were examined, to our delight, the best yield and enantioselectivity could be
achieved by using catalyst VI (84% yield and 92% ee), this catalyst has been successfully proved as an
efficient catalyst in our previous work for asymmetric synthesis of 1,4-dihydro-2H-3,1-benzoxazin-2-
one.9i Moreover, the structure and absolute configuration of the product 2a were confirmed by X-ray
crystallography.10 Afterwards, the similar catalysts VIII-X derived from Cinchonine, Quinine and
Quinidine were further investigated, however, none of them could provide favorable results.
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After identified the suitable catalyst, the solvents were then screened to determine the optimal
reaction conditions, (Table 1, entries 1 to 6). The screening results of different solvents revealed that
CH2Cl2, toluene, THF and the mixture of MeOH/CF3CH2OH resulted in the remarkable decrease of the
enantioselectivies (Table 1, entries 2 to 6). The alcoholic solvents showed obvious advantage, methanol
provided the best result in terms of the enantioselectivity and the yield. Ethanol was also found to be a
suitable solvent but provided the product in lower enantioselectivity (80% ee, entry 2). Furthermore, the
chlorenium source such as TCCA, NCS and DCDPH (Table 1, entries 7 to 10) showed great negligible
impact on the reaction, led to significant decrease in the enantioselectivities or completely retarded the
reaction. Unfortunately, this catalysis system was proved wholly ineffective in the bromocyclization and
iodocyclization by using DBDMH, NBS, DIDMH and NIS as the halogen source, delivered the
products with very low yields or enantioselectivities (Table 1, entries 11 to 14).
Scheme 2. The Catalyst Evaluation of Asymmetric Chlorocyclization a, b, c
Cl
Ph
DCDMH (1.2 equiv)
Ph
Cat. (10 mol%)
O
-80 oC, MeOH, 6 h
NH
N
Ph
O
Ph
1a
2a
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Et
1
2
3
Et
N N
N
H
N
H
N
N
N
CF3
O
O
H
H
H
4
S
MeO
OMe
5
6
CF3
N
N
N
7
8
II
: 10% yield, -3% ee
I
: 5% yield, -69% ee
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NMe2
N
N
O
NH
NH
O
H
H
S
O
NAr2
MeO
O
NAr2
N
N
: Ar = o-toly, 88% yield, 35% ee
F3C
CF3
VIII
IV
V
VI
VII
: Ar = Ph, 78% yield, 46% ee
: Ar = p-toly, 82% yield, 51% ee
: Ar = o-toly, 84% yield, 92% ee
: Ar = o-isopropylphenyl, 69% yield, 37% ee
II
I: 5% yield, -89% ee
N
N
O
O
H
MeO
H
O
NAr2
O
NAr2
N
: Ar = o-toly, 47% yield, -45% ee
N
IX
X
: Ar = o-toly, 75% yield, -54% ee
31
32
33
a
The reaction was carried out with 1a (0.10 mmol), DCDMH (0.12 mmol) and chiral catalyst (0.01
o
b
mmol) in MeOH (2.0 mL) at -80 C; DCDMH = 1,3-Dichloro-5,5-dimethylhydantoin; yield of
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isolated; c ee was determined by HPLC analysis on a chiral stationary phase.
Table 1. Effects of Solvent and Halogenium Sourcea
X
Ph
X+ source (1.2 equiv)
Ph
VI
(10 mol%)
O
-80 oC
NH
Ph
N
Ph
Solvent, 6 h
O
X = Cl, Br, I
1a
Entry
1
Halogenium Source
DCDMH
Solvent
Yield (%)b
84
Ee (%)c
92
MeOH
EtOH
2
DCDMH
83
80
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3
4d
5
DCDMH
DCDMH
DCDMH
DCDMH
TCCA
CH2Cl2
23
N.D.
41
47
---
15
57
55
79
---
---
11
18
1
1
2
3
4
5
6
7
8
toluene
THF
9
6
MeOH/CF3CH2OH
MeOH
98
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83
8
DCDPH
NCS
MeOH
95
9d
10d
11
12
13
14
MeOH
ND
ND
93
NCP
MeOH
DBDMH
NBS
MeOH
MeOH
8
DIDMH
NIS
MeOH
31
MeOH
2
37
a The reaction was carried out with 1a (0.10 mmol), X+ (0.12 mmol) and chiral catalyst VI (0.01 mmol)
o
b
c
in solvent (2.0 mL) at -80 C. Isolated yield. Determined by HPLC analysis on a chiral stationary
phase. d not detected.
O
O
O
O
O
I
N
Cl
Br
N
Cl
N
Me
Me
Me
Me
Me
Me
Cl
Cl
O
Ph
Ph
N
N
N
N
Cl
N
Cl
N I
N
Br
O
O
O
O
O
N
N
I
N
N
Br
N
Cl
O
O
O
O
O
O
O
O
Cl
Cl
DCDMH
TCCA
DCDPH
NCS
NCP
DBDMH
NBS
DIDMH
NIS
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Having established the optimized reaction conditions, the scope and limitations of the substrates
1
2
have been investigated. The substrates bearing various substituents on the phenyl ring at the alkene
moiety were firstly explored. Most electron-donating groups including methyl and methoxy and
electron-withdrawing groups such as trifluoromethyl were perfectly compatible with the reaction
conditions, and the corresponding products were obtained in 65-92% yield with 16-92% ee (Scheme 3,
2a to 2h). To our surprise, there is a sharp loss of ee value when o-methyl group substituted (Scheme 3,
entry 2b), which could be possibly ascribed to the enhanced steric hindrance. 2-Naphthyl substituted
substrate provided the corresponding product 2h in moderate yield and good ee. It is noteworthy that
aliphatic substrates also could deliver the products 2i and 2j in excellent yields with slightly low
enantioselectivities. The substrates of various substituted aniline derivatives were further examined
(Scheme 3, 2k to 2p). However, the reaction exhibited poor tolerance to substituents of the aniline no
matter is the electron-donating or electron-withdrawing group, only the 5-fluoro substituted aniline
derived o-vinylanilide could provide the best result, 56% yield and 91% ee were obtained (Scheme 3,
entry 2o). In addition, to demonstrate the potential synthetic utility of this new method, a 1.0 mmol scale
reaction of 1a was carried out and the chiral 4H-3,1-benzoxazine product 2a was isolated in 80% yield
and 91% ee.
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Scheme 3. Scope of Substratesa
R2
Cl
DCDMH (1.2 equiv)
R2
R1
VI
(10 mol%)
O
R1
-80 o
NH
Ph
C, MeOH, 6 h
N
Ph
O
2
1
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1
2
3
4
5
6
7
8
Me
Me
Me
Cl
Cl
Cl
Cl
O
O
O
O
N
Ph
N
Ph
N
Ph
N
Ph
2a:
84%, 92% ee
80%, 91% eeb
2b:
2c:
2d:
65%, 16% ee
77%, 89% ee
92%, 82% ee
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CF3
F3C
OMe
Cl
O
Cl
O
Cl
O
Cl
O
N
Ph
N
Ph
N
Ph
N
Ph
2e:
2f:
2g:
2h:
88%, 87% ee
88%, 87% ee
93%, 90% ee
66%, 84% ee
Cl
O
Cl
Cl
Cl
O
Ph
Ph
Me
O
O
N
Ph
N
Ph
2k:
86%, 60% ee
Me
2l:
N
Ph
N
Ph
2i:
90%, 64% ee
92%, 76% ee
2j
: 96%, 49% ee
Cl
Cl
Ph
Ph
Cl
Cl
Ph
O
Ph
F
O
O
O
N
Ph
N
Ph
N
Ph
F
N
Ph
F
Me
2m:
2n:
2o:
2p:
56%, 70% ee
20%, 75% ee
56%, 91% ee
92%, 80% ee
a
Reaction conditions: 1 (0.10 mmol), DCDMH (0.12 mmol) and chiral catalyst VI (0.01 mmol) in
MeOH (2.0 mL) at -80 oC, isolated yields; b 1.0 mmol scale reaction.
To further explore the scope compatibility of the reaction, a series of amides were then investigated
(Scheme 4). The electronic nature of substituent to the aromatic ring of amide had no obvious impact on
the enantioselectivity. Both electron-donating groups such as methoxy and electron-withdrawing groups
including fluoro, chloro, and bromo even the para-NO2 were perfectly compatible with the reaction
conditions, and the corresponding products were obtained in 62-99% yield with 80-89% ee (Scheme 4,
4a to 4j). Additionally, the positions of the substituent on the phenyl ring didn’t dramatically affect the
chemical yield and stereoselectivity of the reaction. For substrates bearing halogen or methoxy group to
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the aromatic ring moiety on different positions, good yields and high ees were generally obtained
(Scheme 4, entries 4a, 4d to 4i). Gratifyingly, the aliphatic amides were well compatible with the
present conditions, leading to the desired products in good yields and high enantioselectivies (Scheme 4,
entries 4k to 4m), and the structure and absolute configuration of the product 4k were further confirmed
by X-ray crystallography.10 Nonetheless, heteroarylamide also reacted smoothly to give the 4H-3,1-
benzoxazine product with 96% yield and 70% ee (Scheme 4, entry 4n).
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Scheme 4. Scope of Amidesa
1
2
3
4
5
6
7
Cl
R
Ph
DCDMH (1.2 equiv)
VI
Ph
NH
(10 mol%)
O
-80 o
C, MeOH, 6 h
N
O
R
4
3
8
9
Cl
Cl
10
11
12
13
14
15
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60
Ph
Cl
Ph
Ph
O
O
N
O
N
N
Br
F
Cl
4a:
4b:
4c:
88%, 89% ee
99%, 87% ee
62%, 88% ee
Cl
Cl
Cl
Ph
Ph
Ph
O
N
O
F
O
F
N
N
NO2
4d:
4e:
99%, 80% ee
99%, 86% ee
4f:
65%, 87% ee
Cl
Cl
Ph
Ph
Cl
Ph
O
N
O
N
OMe
O
OMe
N
OMe
4i:
90%, 86% ee
4g:
4h:
90%, 85% ee
65%, 83% ee
Cl
Ph
Cl
Ph
O
N
O
N
4k:
89%, 91% ee
Cl
4j:
85%, 86% ee
Cl
Ph
Ph
Cl
Ph
O
N
O
O
N
N
N
4l:
90%, 92% ee
4m:
4n:
96%, 70% ee
99%, 74% ee
a Reaction conditions: 1 (0.10 mmol), DCDMH (0.12 mmol) and catalyst VI (0.01 mmol) in MeOH (2.0
mL) at -80 oC, isolated yields.
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Scheme 5. Proposed Working Model
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2
3
N
4
5
6
7
8
O
N
O
Ar2N
Cl
H
Me
O
9
O
10
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H
N
According to the above results and previous studies,9a, d, h a plausible working model was proposed
in Scheme 5 (the hydantoin ion was omitted). On the one hand, the tertiary amine in the cinchonidine
moiety may activate the chloronium specie to provide a chiral environment; on the other hand, H-bond
formed between the benzamide NH in the substrate and the catalyst possibly mediated by MeOH
increases the nucleophilicity of the amide group, meanwhile, the formed spatial configuration maybe is
another factor for the high level enantiocontrol of the reaction.
CONCLUSIONS
In conclusion, an efficient protocol for the rapid synthesis of chiral 4H-3,1-benzoxazines by
catalytic asymmetric chlorocyclization of o-vinylanilides has been described. Notably, a broad range of
valuable chiral 4H-3,1-benzoxazines were synthesized in good yields with high enantioselectivities by
means of this newly developed method. The biological evaluation of these optically active 4H-3,1-
benzoxazines is currently ongoing in our laboratory.
EXPERIMENTAL SECTION
General Methods. Unless otherwise mentioned, all commercially available reagents were used without
further purification. Chromatographic separations were performed using silica gel 200–300 mesh. The
NMR spectra reagents were recorded in CDCl3 on 400 or 600 MHz instrument with TMS as the internal
standard. Chemical–shift values are given in ppm and referenced to the internal standard, TMS
(tetramethylsilane). The peak patterns are indicated as follows: s, singlet; d, doublet; t, triplet; q,
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quadruplet; m, multiplet; dd, doublet of doublets, and br s, broad singlet. The coupling constants (J) are
reported in Hertz (Hz). Melting points were determined using a micromelting point apparatus without
corrections. High–resolution mass spectra (HRMS) were recorded on a BioTOFQ mass spectrometer
with an ESI source. X-ray crystallography analysis of the single crystal was performed on an Agilent
SuperNova-CCD X-ray diffractometer. Optical rotation was obtained from Rudolph Research
Analytical Autopol VI automatic polarimeter. Enantiomeric excesses were determined by HPLC using
Daicel® Chiralcel OJ–H, OD–H or Daicel® Chiralpak AD–H, IF, IA column using n–hexane/i–PrOH as
a mobile phase and detected by UV at 254 nm. Melting points were measured using a SGWX-4A
microscopy melting point meter and are uncorrected.
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Compounds 1a-1j,2l, 2p, 11 1k–1p,13 3a-3m,2l, 2p, 11 3n12 were prepared according to the literature
methods. 1a,2p 1i,3a 1j,14 1k,2p 1m-1n,2p 3d,2o 3k,15 3l-3m16 are known compounds and their analysis
data were identical with the reported data.
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N–(2–(1–(o–tolyl)vinyl)phenyl)benzamide (1b): 217 mg, 88% yield, white solid, mp: 46 – 48 °C. H
NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.2 Hz, 1H), 8.03 (s, 1H), 7.48 – 7.45 (m, 1H), 7.37 – 7.26 (m,
13
7H), 7.22 – 7.14 (m, 3H), 5.60 (d, J = 27.9 Hz, 2H), 2.07 (s, 3H); C{1H}NMR (100 MHz, CDCl3) δ
165.2, 147.6, 140.4, 136.1, 135.1, 134.8, 132.6, 131.7, 131.5, 130.2, 129.7, 128.8, 128.6, 128.5, 126.9,
126.8, 124.6, 121.7, 121.3, 20.9; IR (KBr, cm-1) 3406, 1678, 1579, 1520, 1446, 1299, 1250, 918, 758,
707, 587.
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N–(2–(1–(m–tolyl)vinyl)phenyl)benzamide (1c): 173 mg, 98% yield, white solid, mp: 72 – 76 °C. H
NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.35 – 7.28 (m, 2H), 7.25 – 7.21 (m,
13
1H), 7.21 – 7.01 (m, 9H), 5.74 (s, 1H), 5.28 (s, 1H), 2.21 (s, 3H); C{1H}NMR (100 MHz, CDCl3) δ
165.0, 146.6, 139.1, 138.9, 135.5, 134.9, 131.8, 131.6, 130.6, 129.6, 129.1, 129.0, 128.5, 127.5, 126.8,
124.3, 124.1, 121.0, 117.8, 21.5; IR (KBr, cm-1) 3405, 1678, 1579, 1520, 1446, 1299, 1250, 918, 758,
707, 587.
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N–(2–(1–(p–tolyl)vinyl)phenyl)benzamide (1d): 254 mg, 98% yield, white solid, mp: 91 – 95 °C. H
NMR (400 MHz, CDCl3) δ 8.54 (d, J = 8.2 Hz, 1H), 7.88 (s, 1H), 7.48 – 7.41 (m, 2H), 7.37 – 7.28 (m,
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7H), 7.26 – 7.16 (m, 3H), 5.90 – 5.85 (m, 1H), 5.41 – 5.36 (m, 1H), 2.37 (s, 3H); 13C{1H}NMR (100
MHz, CDCl3) δ 165.0, 146.2, 138.9, 136.1, 135.5, 134.9, 131.8, 131.6, 130.6, 129.8, 128.9, 128.5,
126.8, 124.3, 120.9, 116.9, 21.2; IR (KBr, cm-1) 2924, 1787, 1721, 1680, 1604, 1580, 1522, 1448, 1304,
1251, 1215, 1019, 828, 760, 708.
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N–(2–(1–(3–(trifluoromethyl)phenyl)vinyl)phenyl)benzamide (1e): 257 mg, 70% yield, white solid, mp:
118 – 122 °C. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.61 (s, 1H), 7.49
(d, J = 7.0 Hz, 1H), 7.43 – 7.28 (m, 4H), 7.27 – 7.22 (m, 4H), 7.20 – 7.10 (m, 1H), 5.91 (s, 1H), 5.47 (s,
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1H); C{1H}NMR (100 MHz, CDCl3) δ 165.2, 145.4, 140.2, 135.4, 134.7, 131.9, 131.5 (q, JC-F =32.4
Hz), 131.2, 130.7, 130.4, 129.7, 129.5, 128.8, 126.6, 125.4 (q, JC-F = 3.2Hz), 124.8, 124.0 (q, JC-F
=
271.0 Hz), 123.1 (q, JC-F = 3.5 Hz), 121.8, 119.4; IR (KBr, cm-1) 3666, 3222, 1821, 1636, 1579, 1521,
1488, 1443, 1339, 1304, 1172, 1131, 1073, 913, 812, 772, 755, 710, 644.
N–(2–(1–(4–(trifluoromethyl)phenyl)vinyl)phenyl)benzamide (1f): 419 mg, 87% yield, white solid, mp:
136 – 143 °C. 1H NMR (400 MHz, CDCl3) δ 8.40 (d, J = 8.2 Hz, 1H), 7.67 – 7.56 (m, 3H), 7.52 – 7.41
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(m, 4H), 7.36 – 7.19 (m, 6H), 6.00 (s, 1H), 5.57 (s, 1H); C{1H}NMR (100 MHz, CDCl3) δ 165.3,
145.5, 142.8, 135.3, 134.8, 131.9, 131.3, 131.2, 130.9 (q, JC-F = 33.1 Hz), 130.7, 130.6, 129.5, 128.8,
127.2, 126.7, 126.0 (q, JC-F = 3.5Hz), 124.8, 124.1 (q, JC-F = 272.0 Hz), 121.9, 119.8; IR (KBr, cm-1)
3240, 1647, 1524, 1485, 1326, 1157, 1120, 1068, 850, 749, 714, 690.
N–(2–(1–(3–methoxyphenyl)vinyl)phenyl)benzamide (1g): 247 mg, 75% yield, white solid, mp: 76 – 80
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°C. H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.1 Hz, 1H), 7.82 (s, 1H), 7.48 – 7.30 (m, 7H), 7.27 –
7.14 (m, 2H), 7.11 (d, J = 1.4 Hz, 1H), 7.02 – 6.95 (m, 1H), 6.64 (d, J = 7.5 Hz, 1H), 5.96 – 5.90 (m,
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1H), 5.43 (s, 1H), 3.78 (s, 3H). C{1H}NMR (100 MHz, CDCl3) δ 165.0, 159.9, 146.4, 138.9, 136.4,
135.5, 131.8, 130.7, 129.6, 129.2, 129.1, 128.9, 126.8, 124.4, 121.1, 118.3, 118.1, 117.8, 112.2, 55.5; IR
(KBr, cm-1) 3417, 1678, 1579, 1522, 1489, 1449, 1306, 1247, 1042, 912, 760, 707.
N–(2–(1–(naphthalen–2–yl)vinyl)phenyl)benzamide (1h): 420 mg, 86% yield, white solid, mp: 109 –
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111 °C. H NMR (400 MHz, CDCl3) δ 8.53 (1H, d, J = 8.2 Hz), 7.85 (3H, q, J = 8.3 Hz), 7.80 – 7.75
(2H, m), 7.56 (1H, d, J = 8.5 Hz), 7.52 – 7.45 (3H, m), 7.30 (1H, t, J = 7.4 Hz), 7.26 – 7.22 (1H, m),
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7.12 (2H, d, J = 7.7 Hz), 7.06 (2H, t, J = 7.6 Hz), 6.03 (1H, s), 5.52 (1H, s); C{1H}NMR (150 MHz,
CDCl3) δ 165.2, 146.5, 136.6, 135.7, 134.8, 133.6, 133.4, 131.7, 131.6, 130.7, 129.2, 129.0, 128.5,
127.7, 126.8, 126.7, 126.5, 124.5, 124.4, 121.1, 118.4; IR (KBr, cm-1) 3416, 3058, 1678, 1580, 1521,
1447, 1304, 1252, 900, 823, 755, 708, 584, 476.
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N–(5–methyl–2–(1–phenylvinyl)phenyl)benzamide (1l): 133 mg, 88% yield, white solid, mp: 92 – 94
°C. 1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 7.77 (s, 1H), 7.48 – 7.34 (m, 6H), 7.27 (m, 5H), 7.02 (d,
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J = 7.6 Hz, 1H), 5.88 (s, 1H), 5.42 (s, 1H), 2.45 (s, 3H). C{1H}NMR (100 MHz, CDCl3) δ 165.1,
146.5, 139.3, 139.2, 135.3, 135.0, 131.6, 130.5, 129.1, 129.0, 128.8, 128.6, 126.9, 126.8, 125.2, 121.7,
117.6, 21.7; IR (KBr, cm-1) 3420, 3059, 1679, 1609, 1573, 1529, 1466, 1418, 1296, 1253, 1027, 908,
821, 783, 704, 595.
N–(5–fluoro–2–(1–phenylvinyl)phenyl)benzamide (1o): 350 mg, 99% yield, white solid, mp: 72 – 80
°C. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J = 8.2 Hz, 1H), 8.06 (s, 1H), 7.54 – 7.28 (m, 11H), 6.95 (t, J
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= 8.5 Hz, 1H), 6.21 (s, 1H), 5.50 (s, 1H); C{1H}NMR (100 MHz, CDCl3) δ 165.3, 160.1 (d, JC-F
=
243.4 Hz), 139.2, 138.1, 137.3 (d, JC-F = 4.9 Hz), 134.8, 132.0, 129.8 (d, JC-F = 9.4 Hz), 129.1, 129.0,
128.8, 126.9, 126.3, 119.6, 119.2 (d, JC-F = 19.5 Hz), 116.1 (d, JC-F = 3.0 Hz), 111.2 (d, JC-F = 22.3 Hz);
IR (KBr, cm-1) 3418, 3061, 1684, 1583, 1523, 1492, 1461, 1308, 1251, 1119, 1028, 982, 919, 787, 747,
707, 660, 583, 531.
N–(2–fluoro–6–(1–phenylvinyl)phenyl)benzamide (1p): 190 mg, 98% yield, white solid, mp: 114 – 116
°C. 1H NMR (400 MHz, CDCl3) δ 7.49 – 7.42 (m, 1H), 7.39 (d, J = 7.3 Hz, 2H), 7.29 (q, J = 8.9, 8.1
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Hz, 8H), 7.22 (d, J = 13.7 Hz, 2H), 7.03 (s, 1H), 5.72 (s, 1H), 5.43 (s, 1H). C{1H}NMR (100 MHz,
CDCl3) δ 165.3, 158.04 (d, JC-F = 249.1 Hz), 146.5, 140.5, 140.0, 133.7, 131.8, 128.9, 128.4, 128.3,
128.1 (d, JC-F = 8.5Hz), 127.2, 126.6, 126.1 (d, JC-F = 2.8 Hz), 122.7 (d, JC-F = 13.2 Hz), 117.5, 116.0 (d,
JC-F = 20.6Hz); IR (KBr, cm-1) 3285, 3060, 1660, 1606, 1578, 1514, 1491, 1466, 1294, 1263, 1026, 959,
909, 782, 707.
4–Fluoro–N–(2–(1–phenylvinyl)phenyl)benzamide (3a): 163 mg, 92% yield, white solid, mp: 108 – 112
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°C. H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.2 Hz, 1H), 7.71 (s, 1H), 7.53 – 7.35 (m, 7H), 7.31 –
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7.18 (m, 3H), 6.99 (t, J = 8.5 Hz, 2H), 5.93 (s, 1H), 5.47 (s, 1H); C{1H}NMR (100 MHz, CDCl3) δ
164.8 (d, JC-F = 251.0 Hz), 164.0, 146.4, 139.0, 135.4, 131.7, 131.1 (d, JC-F = 3.0 Hz), 130.8, 129.2,
129.2 (d, JC-F = 3.3 Hz), 129.1, 128.9, 126.9, 124.6, 121.2, 118.1, 115.6 (d, JC-F = 21.9 Hz); IR (KBr, cm-
1) 3225, 1644, 1602, 1530, 1500, 1446, 1315, 1231, 909, 847, 765, 678, 576.
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4–Chloro–N–(2–(1–phenylvinyl)phenyl)benzamide (3b): 171 mg, 95% yield, white solid, mp: 118 – 121
°C. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.39 – 7.24 (m, 7H), 7.15 (dd,
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J = 13.5, 8.0 Hz, 3H), 7.05 (d, J = 8.4 Hz, 2H), 5.81 (s, 1H), 5.34 (s, 1H); C{1H}NMR (100 MHz,
CDCl3) δ 164.0, 146.3, 139.0, 137.9, 135.2, 133.3, 131.8, 130.8, 129.3, 129.2, 129.0, 128.8, 128.2,
126.9, 124.7, 121.1, 118.2; IR (KBr, cm-1) 3224, 1680, 1638, 1593, 1524, 1488, 1447, 1308, 1091, 911,
843, 760, 706.
4–Bromo–N–(2–(1–phenylvinyl)phenyl)benzamide (3c): 167 mg, 86% yield, white solid, mp: 128 – 131
°C. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 7.60 (s, 1H), 7.31 (m, 8H), 7.14 (q, J = 8.1,
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7.5 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 5.81 (s, 1H), 5.35 (s, 1H); C{1H}NMR (100 MHz, CDCl3) δ
164.1, 146.3, 139.0, 135.2, 133.8, 131.8, 130.8, 129.3, 129.2, 129.0, 128.4, 126.9, 126.4, 124.7, 121.1,
118.2; IR (KBr, cm-1) 3419, 1680, 1585, 1522, 1487, 1447, 1307, 1251, 1072, 1010, 910, 841, 757, 706,
582, 517.
3–Fluoro–N–(2–(1–phenylvinyl)phenyl)benzamide (3e): 408 mg, 64% yield, white solid, mp: 105 – 107
°C. 1H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 8.2 Hz, 1H), 7.70 (s, 1H), 7.50 – 7.30 (m, 7H), 7.24 (dq,
J = 14.7, 7.7 Hz, 2H), 7.12 (t, J = 7.7 Hz, 1H), 6.97 (d, J = 7.9 Hz, 2H), 5.90 (s, 1H), 5.44 (s, 1H).
13C{1H}NMR (100 MHz, CDCl3) δ 163.8 (d, JC-F = 2.1Hz), 162.8 (d, JC-F = 246.8 Hz), 146.4, 139.0,
137.2 (d, JC-F = 6.5 Hz), 135.2, 131.9, 130.8, 130.3 (d, JC-F = 7.8 Hz), 129.3, 129.2, 129.1, 126.9, 124.7,
122.3 (d, JC-F = 2.8 Hz), 121.3, 118.7 (d, JC-F = 21.2 Hz), 118.1, 114.2 (d, JC-F = 22.9 Hz); IR (KBr, cm-1)
3418, 1680, 1584, 1523, 1489, 1447, 1306, 1265, 1194, 755, 708.
4–Nitro–N–(2–(1–phenylvinyl)phenyl)benzamide (3f): 177 mg, 83% yield, white solid, mp: 149 – 158
°C. 1H NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.2 Hz, 1H), 8.07 (d, J = 8.6 Hz, 2H), 7.67 (s, 1H), 7.44
– 7.30 (m, 7H), 7.27 (d, J = 8.8 Hz, 2H), 7.21 (t, J = 7.5 Hz, 1H), 5.86 (s, 1H), 5.40 (s, 1H);
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13C{1H}NMR (100 MHz, CDCl3) δ 162.9, 149.6, 146.1, 140.4, 138.9, 134.8, 132.0, 130.9, 129.4, 129.3,
129.1, 127.9, 126.9, 125.3, 123.8, 121.3, 118.5; IR (KBr, cm-1) 1681, 1603, 1525, 1448, 1347, 1304,
1253, 851, 764, 712, 580.
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2–Methoxy–N–(2–(1–phenylvinyl)phenyl)benzamide (3g): 247 mg, 75% yield, white soild, mp: 89 – 93
°C. 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.18 (d, J = 6.7 Hz, 1H), 7.35
(dd, J = 17.3, 7.2 Hz, 4H), 7.22 (dq, J = 13.8, 6.8 Hz, 3H), 7.12 (dt, J = 14.6, 6.7 Hz, 2H), 7.01 (t, J =
7.5 Hz, 1H), 6.81 (d, J = 8.3 Hz, 1H), 6.00 (s, 1H), 5.34 (s, 1H), 3.51 (s, 3H). 13C{1H}NMR (100 MHz,
CDCl3) δ 163.4, 157.2, 146.0, 139.0, 136.5, 133.1, 132.5, 132.3, 130.0, 128.6, 128.3, 126.4, 123.9,
121.8, 121.3, 116.3, 111.3, 55.5; IR (KBr, cm-1) 3337, 1667, 1583, 1532, 1449, 1309, 1236, 1021, 757,
711.
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3–Methoxy–N–(2–(1–phenylvinyl)phenyl)benzamide (3h): 169 mg, 79% yield, white solid, mp: 117 –
120 °C. 1H NMR (400 MHz, CDCl3) δ 8.49 (d, J = 8.2 Hz, 1H), 7.81 (s, 1H), 7.49 – 7.30 (m, 7H), 7.19
(dt, J = 12.7, 7.8 Hz, 2H), 7.11 (s, 1H), 6.98 (d, J = 8.1 Hz, 1H), 6.63 (d, J = 7.5 Hz, 1H), 5.93 (s, 1H),
5.43 (s, 1H), 3.78 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 165.0, 159.9, 146.3, 138.9, 136.4, 135.5,
131.8, 130.7, 129.6, 129.2, 129.1, 128.9, 124.4, 121.1, 118.3, 118.1, 117.8, 112.2, 55.5; IR (KBr, cm-1)
1678, 1581, 1520, 1489, 1446, 1305, 1270, 1041, 911, 757, 709, 595.
4–Mthoxy–N–(2–(prop–1–en–2–yl)phenyl)benzamide (3i): 230 mg, 71% yield, white soild, mp: 110 –
113 °C. 1H NMR (400 MHz, CDCl3) δ 8.47 (d, J = 8.2 Hz, 1H), 7.72 (s, 1H), 7.38 (tt, J = 18.9, 7.7 Hz,
7H), 7.21 (dd, J = 18.4, 8.0 Hz, 3H), 6.78 (d, J = 8.4 Hz, 2H), 5.90 (s, 1H), 5.42 (s, 1H), 3.80 (s, 3H).
13C{1H}NMR (100 MHz, CDCl3) δ 164.6, 162.3, 146.5, 139.1, 135.7, 131.5, 130.7, 129.2, 129.1, 128.9,
128.7, 127.2, 126.9, 124.1, 121.0, 117.9, 113.8, 55.5; IR (KBr, cm-1) 3422, 1674, 1606, 1579, 1505,
1446, 1305, 1249, 1176, 1112, 1029, 909, 842, 762, 704, 576.
N–(2–(1–phenylvinyl)phenyl)–1–naphthamide (3j): 319 mg, 91% yield, white solid, mp: 86 – 89 °C. 1H
NMR (600 MHz, CDCl3) δ 8.62 (d, J = 7.4 Hz, 1H), 8.30 (d, J = 7.9 Hz, 1H), 7.85 (dd, J = 18.4, 8.0
Hz, 2H), 7.64 (s, 1H), 7.55 – 7.45 (m, 3H), 7.36 (d, J = 7.5 Hz, 1H), 7.34 (s, 5H), 7.27 (d, J = 8.6 Hz,
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2H), 6.82 (d, J = 6.9 Hz, 1H), 5.84 (s, 1H), 5.40 (s, 1H); C{1H}NMR (150 MHz, CDCl3) δ 167.1,
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146.2, 139.1, 135.7, 134.3, 133.8, 132.0, 131.0, 130.7, 130.2, 129.1, 129.0, 128.7, 128.3, 127.3, 126.8,
126.5, 125.5, 124.7, 124.6, 121.3, 117.7; IR (KBr, cm-1) 1676, 1515, 1446, 1302, 1136, 906, 779, 707,
592, 503.
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N–(2–(1–phenylvinyl)phenyl)isonicotinamide (3n): 414 mg, 69% yield, yellow solid, mp: 125 – 128 °C.
1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 4.7 Hz, 2H), 8.40 (d, J = 8.1 Hz, 1H), 7.76 (s, 1H), 7.45 (t, J
= 7.7 Hz, 1H), 7.38 (s, 6H), 7.29 – 7.21 (m, 1H), 7.05 (d, J = 5.0 Hz, 2H), 5.91 (s, 1H), 5.44 (s, 1H).
13C{1H}NMR (100 MHz, CDCl3) δ 163.0, 150.6, 146.1, 141.9, 138.9, 134.7, 132.0, 130.9, 129.3, 129.1,
126.8, 125.2, 121.4, 120.5, 118.5, 118.4, 118.3; IR (KBr, cm-1) 3224, 1648, 1602, 1528, 1489, 1313,
905, 760, 682.
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General Procedure for the Synthesis of 4H-3,1-benzoxazine.
To a solution of substrate (0.1 mmol, 1.0 equiv), VI (5.9 mg, 0.01 mmol, 0.1 equiv) in MeOH (4
o
mL) at -80 C was added DCDMH (23.6 mg, 0.12 mmol, 1.2 equiv). The resulting mixture was stirred
o
at -80 C and monitored by TLC. Upon completion, the reaction was quenched by saturated aqueous
o
solution of Na2S2O4 at –80 C, then warmed to room temperature. The aqueous phase was extracted
with CH2Cl2, the combined organic phases were dried over anhydrous Na2SO4, filtered, and evaporated
in vacuo. The residue was purified by flash column chromatography (PE/EA = 10:1) to afford the
product.
(S)–4–(Chloromethyl)–2,4–diphenyl–4H–benzo[d][1,3]oxazine (2a): 28.1 mg, 84% yield, yellow solid,
mp: 90 – 93 °C; [α]D20 = 53.1 (c 0.10, CDCl3, 92% ee); 1H NMR (600 MHz, CDCl3) δ 8.31 (d, J = 7.5
Hz, 2H), 7.55 (t, J = 7.2 Hz, 1H), 7.49 (dd, J = 18.6, 7.6 Hz, 4H), 7.42 (d, J = 6.9 Hz, 2H), 7.37 (tt, J =
14.2, 6.0 Hz, 3H), 7.28 (d, J = 5.0 Hz, 1H), 7.14 (d, J = 7.5 Hz, 1H), 4.34 – 4.25 (m, 2H). 13C{1H}NMR
(150 MHz, CDCl3) δ 156.2, 140.1, 139.7, 132.3, 131.8, 129.8, 128.8, 128.7, 128.5, 128.3, 126.7, 126.6,
125.8, 125.7, 125.1, 83.0, 48.6; IR (KBr, cm-1) 2959, 2924, 2853, 1626, 1597, 1573, 1480, 1450, 1320,
1261, 1220, 1084,1026, 772, 731, 634; HRMS (M + H)+ calcd for C21H17ClNO 334.0993, found
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334.0993; HPLC conditions: Daicel Chiralpak AD–H, i–PrOH/hexane = 0.5/99.5, 0.3 mL/min, 254 nm,
t1 = 36.3 min (major), t2 = 40.5 min (minor).
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(S)–4–(Chloromethyl)–2–phenyl–4–(o–tolyl)–4H–benzo[d][1,3]oxazine (2b): 22.5 mg, 65% yield,
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yellow solid, mp: 176–183 °C; [α]D = 13.7 (c 0.10, CHCl3, 16% ee); H NMR (600 MHz, CDCl3) δ
8.25 (d, J = 7.7 Hz, 2H), 7.68 – 7.61 (m, 1H), 7.51 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.41 –
7.29 (m, 4H), 7.25 – 7.18 (m, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.59 (d, J = 7.6 Hz, 1H), 4.30 – 4.18 (m,
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2H), 2.06 (s, 3H). C{1H}NMR (150 MHz, CDCl3) δ 155.9, 139.3, 137.0, 133.4, 132.2, 131.8, 129.9,
13
129.2, 128.5, 128.4, 127.3, 126.9, 125.9, 125.4, 125.1, 83.0, 49.0, 21.7; IR (KBr, cm-1) 2961, 2925,
2855, 1624, 1594, 1573, 1493, 1478, 1456, 1379,1322, 1300, 1261, 1176, 1084, 1070, 1026, 864, 799,
766, 724, 694, 633; HRMS (M + H)+ calcd for C22H19ClNO 348.1150, found 348.1142; HPLC
conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 5/95, 0.5 mL/min, 254 nm, t1 = 9.7 min (major),
t2 = 11.4 min (minor).
(S)–4–(Chloromethyl)–2–phenyl–4–(m–tolyl)–4H–benzo[d][1,3]oxazine (2c): 26.0 mg, 77% yield,
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yellow oil; [α]D = 48.8 (c 0.11, CHCl3, 89% ee); H NMR (400 MHz, CDCl3) δ 8.34 – 8.23 (m, 2H),
7.50 (dt, J = 14.5, 7.0 Hz, 3H), 7.44 – 7.36 (m, 2H), 7.31 – 7.20 (m, 4H), 7.12 (dd, J = 20.2, 5.7 Hz,
2H), 4.34 – 4.19 (m, 2H), 2.32 (s, 3H); C{1H}NMR (100 MHz, CDCl3) δ 156.3, 140.0, 139.6, 138.4,
13
132.3, 131.8, 129.7, 129.6, 128.5, 128.4, 128.3, 127.3, 126.7, 125.7, 125.2, 123.6, 83.1, 48.6, 21.8; IR
(KBr, cm-1) 2956, 2925, 2854, 1627, 1597, 1574, 1492, 1480, 1456, 1319, 1261, 1243, 1085, 1070, 765,
738, 695; HRMS (M + H)+ calcd for C22H19ClNO 348.1150, found 348.1139; HPLC conditions: Daicel
Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 14.0 min (major), t2 = 15.7 min
(minor).
(S)–4–(Chloromethyl)–2–phenyl–4–(p–tolyl)–4H–benzo[d][1,3]oxazine (2d): 32.0 mg, 92% yield,
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yellow oil; [α]D = 34.0 (c 0.10, CHCl3, 82% ee); H NMR (600 MHz, CDCl3) δ 8.26 (d, J = 7.6 Hz,
2H), 7.55 – 7.49 (m, 1H), 7.47 (t, J = 7.4 Hz, 2H), 7.39 (d, J = 5.8 Hz, 2H), 7.32 (d, J = 8.0 Hz, 2H),
7.24 (t, J = 7.0 Hz, 1H), 7.16 (d, J = 7.9 Hz, 2H), 7.10 (d, J = 7.5 Hz, 1H), 4.30 – 4.20 (m, 2H), 2.32 (s,
3H); C{1H}NMR (150 MHz, CDCl3) δ 156.4, 139.7, 138.7, 137.2, 132.3, 131.8, 129.7, 129.4, 128.5,
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128.4, 126.7, 126.5, 125.8, 125.7, 125.1, 83.1, 48.6, 21.2; IR (KBr, cm-1) 2957, 2954, 2854, 1626, 1597,
1573, 1511, 1492, 1480, 1455, 1320, 1260, 1244, 1176, 1085, 1070, 1026, 1000, 934, 816, 765, 742,
721; HRMS (M + H)+ calcd for C22H19ClNO 348.1150, found 348.1134; HPLC conditions: Daicel
Chiralcel OD–H, i–PrOH/hexane = 5/95, 0.5 mL/min, 254 nm, t1 = 11.1 min (major), t2 = 13.4 min
(minor).
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(S)–4–(Chloromethyl)–2–phenyl–4–(3–(trifluoromethyl)phenyl)–4H–benzo[d][1,3]oxazine (2e): 35.0
mg, 88% yield, colorless oil; [α]D20 = 81.0 (c 0.10, CHCl3, 87% ee); 1H NMR (400 MHz, CDCl3) δ 8.31
– 8.21 (m, 2H), 7.74 (s, 1H), 7.64 (dd, J = 21.2, 7.8 Hz, 2H), 7.58 – 7.45 (m, 4H), 7.42 (d, J = 4.0 Hz,
13
2H), 7.27 – 7.21 (m, 1H), 7.03 (d, J = 7.6 Hz, 1H), 4.25 (s, 2H); C{1H}NMR (100 MHz, CDCl3) δ
155.9, 141.0, 139.5, 132.0, 131.9, 131.1 (q, JC-F = 32.2 Hz), 130.2, 129.2, 128.6, 128.4 , 127.0, 126.0,
125.7 (q, JC-F = 3.3 Hz), 125.1, 124.9, 123.9 (q, JC-F = 271.0Hz), 123.6 (q, JC-F = 3.9 Hz), 82.5, 48.0; IR
(KBr, cm-1) 2959, 2928, 2856, 1727, 1627, 1597, 1574, 1493, 1480, 1450, 1330, 1288,1260, 1242,
1166, 1129, 1079, 1027, 907, 843, 804, 765, 745, 721; HRMS (M + H)+ calcd for C22H16ClF3NO
402.0867, found 402.0848; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 5/95, 0.5
mL/min, 254 nm, t1 = 11.1 min (major), t2 = 13.0 min (minor).
(S)–4–(Chloromethyl)–2–phenyl–4–(4–(trifluoromethyl)phenyl)–4H–benzo[d][1,3]oxazine (2f): 35.0
mg, 88% yield, colorless oil; [α]D20 = 65.4 (c 0.09, CHCl3, 87% ee); 1H NMR (400 MHz, CDCl3) δ 8.30
– 8.23 (m, 2H), 7.62 (q, J = 8.5 Hz, 4H), 7.55 (t, J = 7.3 Hz, 1H), 7.49 (t, J = 7.5 Hz, 2H), 7.41 (d, J =
13
4.0 Hz, 2H), 7.26 – 7.21 (m, 1H), 7.06 (d, J = 7.7 Hz, 1H), 4.25 (s, 2H); C{1H}NMR (100 MHz,
CDCl3) δ 155.9, 143.8, 139.5, 132.1, 131.9, 130.9 (q, JC-F = 32.4 Hz), 130.2, 128.6, 128.3, 127.2, 127.0,
126.0, 125.7 (q, JC-F = 3.7 Hz), 125.1, 124.8, 124.1 (q, JC-F = 271.0 Hz), 82.6, 48.1; IR (KBr, cm-1) 28,
2849, 1627, 1597, 1574, 1479, 1457, 1410, 1327, 1261, 1170, 1089, 1071, 1019, 801, 766, 749, 725,
695; HRMS (M + H)+ calcd for C22H16ClF3NO 402.0867, found 402.0850; HPLC conditions: Daicel
Chiralcel OD–H, i–PrOH/hexane = 5/95, 0.5 mL/min, 254 nm, t1 = 11.0 min (major), t2 = 15.1 min
(minor).
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(S)–4–(Chloromethyl)–4–(3–methoxyphenyl)–2–phenyl–4H–benzo[d][1,3]oxazine (2g): 30.0 mg, 86%
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yield, colorless oil; [α]D = 47.0 (c 0.09, CHCl3, 90% ee); H NMR (400 MHz, CDCl3) δ 8.28 (d, J =
7.2 Hz, 2H), 7.50 (dq, J = 14.6, 7.0 Hz, 3H), 7.39 (d, J = 4.7 Hz, 2H), 7.28 (d, J = 8.2 Hz, 1H), 7.26 –
7.21 (m, 1H), 7.14 (d, J = 7.3 Hz, 1H), 7.04 – 6.95 (m, 2H), 6.85 (dd, J = 8.3, 2.5 Hz, 1H), 4.25 (s, 2H),
3.71 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 159.8, 156.2, 141.7, 139.7, 132.3, 131.8, 129.8, 129.7,
128.5, 128.3, 126.7, 125.8, 125.6, 125.0, 118.8, 113.9, 112.9, 83.0, 55.3, 48.6; IR (KBr, cm-1) 2956,
2925, 2854, 1672, 1626, 1598, 1575, 1523, 1482.1457, 1377, 1319, 1291, 1261, 1085, 1041; 766, 739,
694; HRMS (M + H)+ calcd for C22H19ClNO2 364.1099, found 364.1087; HPLC conditions: Daicel
Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 23.7min (major), t2 = 26.1 min
(minor).
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(S)–4–(Chloromethyl)–4–(naphthalen–2–yl)–2–phenyl–4H–benzo[d][1,3]oxazine (2h): 25.3 mg, 66%
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yield, colorless oil; [α]D =108.8 (c 0.10, CHCl3, 84% ee); H NMR (400 MHz, CDCl3) δ 8.31 (d, J =
6.9 Hz, 2H), 7.90 – 7.75 (m, 4H), 7.65 – 7.60 (m, 1H), 7.58 – 7.45 (m, 5H), 7.42 (d, J = 6.0 Hz, 2H),
7.27 – 7.22 (m, 1H), 4.45 – 4.30 (m, 2H). C{1H}NMR (100 MHz, CDCl3) δ 156.2, 139.8, 137.4,
13
133.2, 132.8, 132.3, 131.8, 129.9, 128.7, 128.6, 128.5, 128.4, 127.7, 127.0, 126.7, 126.2, 125.9, 125.8,
125.3, 124.2, 83.2, 48.5; IR (KBr, cm-1) 2956, 2925, 2854, 1626, 1597,1573, 1479, 1456, 1377, 1318,
1290, 1262, 1242, 1084, 1070, 1027, 931, 900, 856, 817, 765, 694, 477; HRMS (M + H)+ calcd for
C25H19ClNO 384.1150, found 384.1134; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane =
1/99, 0.5 mL/min, 254 nm, t1 = 27.4 min (major), t2 = 30.8 min (minor).
(S)–4–(Chloromethyl)–4–methyl–2–phenyl–4H–benzo[d][1,3]oxazine (2i): 24.1 mg, 90% yield, yellow
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solid, mp: 56–59 °C; [α]D = 8.1 (c 0.11, CHCl3, 64% ee); H NMR (400 MHz, CDCl3) δ 8.21 (d, J =
7.1 Hz, 2H), 7.48 (dt, J = 14.6, 7.0 Hz, 3H), 7.41 – 7.32 (m, 2H), 7.28 – 7.21 (m, 1H), 7.18 (d, J = 7.8
Hz, 1H), 3.76 (dd, J = 87.5, 11.9 Hz, 2H), 1.91 (s, 3H); C{1H}NMR (100 MHz, CDCl3) δ 156.4,
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139.3, 132.4, 131.7, 129.7, 128.4, 128.3, 127.0, 126.9, 125.6, 123.4, 79.0, 50.7, 24.0; IR (KBr, cm-1)
2954, 2925, 2854, 1626, 1600, 1574, 1482, 1451, 1378, 1322, 1266, 1250, 1212, 1173, 1096, 1071,
1028, 942, 882, 864, 847, 163, 723, 695, 608, 527, 499; HRMS (M + H)+ calcd for C16H15ClNO
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272.0837, found 272.0833; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5
mL/min, 254 nm, t1 = 13.1 min (major), t2 = 15.5 min (minor).
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(S)-4-Butyl-4-(chloromethyl)-2-phenyl-4H-benzo[d][1,3]oxazine (2j): 30 mg, 96% yield, colorless oil;
[α]D20 = 10.5 (c 0.20, CHCl3, 49% ee); 1H NMR (400 MHz, CDCl3) δ 8.20 (d, J = 7.1 Hz, 2H), 7.49 (m,
3H), 7.36 (d, J = 4.3 Hz, 2H), 7.24 (m, 1H), 7.11 (d, J = 7.6 Hz, 1H), 3.88 (d, J = 11.8 Hz, 1H), 3.75 (d,
J = 11.8 Hz, 1H), 2.28 (m, 1H), 2.07 (m, 1H), 1.50 – 1.26 (m, 4H), 0.87 (t, J = 7.0 Hz, 3H);
13C{1H}NMR (100 MHz, CDCl3) δ 156.3, 139.9, 132.6, 131.6, 129.4, 128.4, 128.2, 126.7, 125.8, 125.0,
123.7, 82.1, 51.2, 37.0, 25.8, 22.9, 14.0. IR (KBr, cm-1) 2959, 2926, 2858, 1628, 1600, 1574, 1485,
1455, 1321, 1261, 1088, 1024, 800, 764, 721; HRMS (M + H)+ calcd for 314.1306, found 314.1303;
HPLC conditions: Daicel Chiralcel OJ–H, i–PrOH/hexane = 10/90, 1.0 mL/min, 254 nm, t1 = 5.3 min
(major), t2 = 6.5 min (minor).
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(S)–4–(Chloromethyl)–6–methyl–2,4–diphenyl–4H–benzo[d][1,3]oxazine (2k): 30.0 mg, 86% yield,
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yellow solid, mp: 95–104 °C; [α]D = 34.7 (c 0.12, CHCl3, 60% ee); H NMR (400 MHz, CDCl3) δ
8.58 (d, J = 7.2 Hz, 2H), 7.80 (dt, J = 17.4, 6.4 Hz, 5H), 7.65 (dt, J = 23.6, 7.3 Hz, 4H), 7.50 (d, J = 7.9
13
Hz, 1H), 7.20 (s, 1H), 4.64 – 4.48 (m, 2H), 2.67 (s, 3H); C{1H}NMR (100 MHz, CDCl3) δ 155.5,
140.2, 137.3, 136.6, 132.4, 131.6, 130.4, 128.7, 128.6, 128.4, 128.2, 126.6, 125.6, 125.5, 82.9, 48.6,
21.6; IR (KBr, cm-1) 2960, 2924, 2854, 1628, 1602, 1577, 1493, 1449, 1318, 1260, 1248, 1176, 1086,
1070, 1026, 826, 798, 778, 757, 732, 694, 642, 566, 547, 508; HRMS (M + H)+ calcd for C22H19ClNO
348.1150, found 348.1144; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5
mL/min, 254 nm, t1 = 16.4 min (major), t2 = 20.3 min (minor).
(S)–4–(Chloromethyl)–7–methyl–2,4–diphenyl–4H–benzo[d][1,3]oxazine (2l): 19.6 mg, 56% yield,
colorless oil; [α]D20 =61.1 (c 0.11, CHCl3, 76% ee); 1H NMR (400 MHz, CDCl3) δ 8.31 – 8.24 (m, 2H),
7.57 – 7.40 (m, 5H), 7.40 – 7.28 (m, 3H), 7.24 (s, 1H), 7.10 – 6.97 (m, 2H), 4.31 – 4.19 (m, 2H), 2.39
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(s, 3H); C{1H}NMR (100 MHz, CDCl3) δ 156.2, 140.4, 139.8, 139.5, 132.4, 131.7, 128.7, 128.6,
128.5, 128.3, 127.4, 126.5, 126.3, 124.9, 122.8, 83.0, 48.7, 21.3; IR (KBr, cm-1) 2956, 2924, 2854,
1630, 1606, 1571, 1493, 1450, 1317, 1301, 1270, 1175, 1087, 1070, 1026, 1001, 884, 811, 778, 757,
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732, 695, 631, 597, 582, 549; HRMS (M + H)+ calcd for C22H19ClNO 348.1150, found 348.1142; HPLC
conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 15.8 min (major),
t2 = 17.6 min (minor).
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(S)–4–(Chloromethyl)–8–methyl–2,4–diphenyl–4H–benzo[d][1,3]oxazine (2m): 32.3 mg, 92% yield,
colorless oil; [α]D20 = 66.3 (c 0.10, CHCl3, 80% ee); 1H NMR (400 MHz, CDCl3) δ 8.35 – 8.23 (m, 2H),
7.57 – 7.39 (m, 5H), 7.33 (q, J = 8.4, 7.4 Hz, 3H), 7.26 – 7.20 (m, 1H), 7.13 (t, J = 7.6 Hz, 1H), 6.95 (d,
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J = 7.6 Hz, 1H), 4.30 – 4.19 (m, 2H), 2.55 (s, 3H); C{1H}NMR (100 MHz, CDCl3) δ 155.1, 140.3,
137.9, 134.4, 132.7, 131.6, 131.1, 128.7, 128.6, 128.4, 126.6, 126.0, 125.6, 122.7, 83.0, 48.5, 17.3; IR
(KBr, cm-1) 2956, 2924, 2853, 1626, 1589, 1576, 1493, 1462, 1450, 1377, 1317, 1302, 1255, 1228,
1176, 1094, 1070, 1026, 1000, 847, 803, 761, 732, 715, 694, 666, 646, 624, 563, 551; HRMS (M + H)+
calcd for C22H19ClNO 348.1150, found 348.1144; HPLC conditions: Daicel Chiralcel OJ–H, i–
PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 32.4 min (major), t2 = 40.1 min (minor).
(S)–4–(Chloromethyl)–6–fluoro–2,4–diphenyl–4H-benzo[d][1,3]oxazine (2n): 7.1mg, 20% yield,
colorless oil; [α]D20 = 64.9 (c 0.12, CHCl3, 75% ee); 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 7.4 Hz,
2H), 7.57 – 7.41 (m, 5H), 7.41 – 7.29 (m, 4H), 7.09 (td, J = 8.5, 2.6 Hz, 1H), 6.83 (dd, J = 8.6, 2.6 Hz,
13
1H), 4.23 (q, J = 12.6 Hz, 2H); C{1H}NMR (100 MHz, CDCl3) δ 161.08 (d, JC-F = 245.0 Hz), 155.6,
139.5, 136.1 (d, JC-F = 2.7Hz), 132.0, 131.9, 129.0, 128.9, 128.5, 128.2, 127.4 (d, JC-F = 8.1 Hz), 127.2
(d, JC-F = 7.4 Hz), 126.4, 116.6 (d, JC-F = 22.1 Hz), 112.5 (d, JC-F = 75.5 Hz), 82.8, 48.3; IR (KBr, cm-1)
2960, 2926, 2854, 1728, 1627, 1578, 1485, 1450, 1432, 1318, 1288, 1251, 1208, 1178, 1157, 1085,
1071, 1026, 956, 911, 864, 825, 800, 779, 755, 733, 694, 643, 569, 552, 512; HRMS (M + H)+ calcd for
C21H16ClFNO 352.0899, found 352.0886; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane =
5/95, 0.5 mL/min, 254 nm, t1 = 12.6 min (major), t2 = 13.5 min (minor).
(S)–4–(Chloromethyl)–7–fluoro–2,4–diphenyl–4H–benzo[d][1,3]oxazine (2o): 20.1 mg, 56% yield,
colorless oil; [α]D20 = 63.4 (c 0.10, CHCl3, 91% ee); 1H NMR (400 MHz, CDCl3) δ 8.31 (d, J = 7.3 Hz,
2H), 7.58 – 7.40 (m, 5H), 7.35 (q, J = 5.8 Hz, 3H), 7.23 – 7.10 (m, 2H), 6.92 (d, J = 7.1 Hz, 1H), 4.33 –
4.20 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ 156.7, 156.4 (d, JC-F = 252.4 Hz), 154.7 (d, JC-F = 26.6
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Hz), 144.2, 139.8, 132.1, 131.9, 129.0, 128.5 (d, JC-F = 2.7 Hz), 128.8, 127.8, 126.8 (d, JC-F = 3.9 Hz),
126.4, 120.6 (d, JC-F = 3.7 Hz), 116.6 (d, JC-F = 19.7 Hz), 83.0, 48.6; IR (KBr, cm-1) 2957, 2923, 2852,
1627, 1605, 1575, 1494, 1475, 1450, 1320, 1303, 1261, 1247, 1178, 1090, 1070, 1026, 1000, 896, 790,
777, 763, 748, 734, 713, 694, 668, 649, 630; HRMS (M + H)+ calcd for C21H16ClFNO 352.0899, found
352.0897; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 =
21.9 min (major), t2 = 26.5 min (minor).
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(S)–4–(Chloromethyl)–8–fluoro–2,4–diphenyl–4H–benzo[d][1,3]oxazine (2p): 13.7 mg, 38% yield,
colorless oil; [α]D20 = –92 (c 0.17, CHCl3, 70% ee); 1H NMR (400 MHz, CDCl3) δ 8.23 (d, J = 7.2 Hz,
2H), 7.57 – 7.37 (m, 5H), 7.37 (d, J = 8.1 Hz, 3H), 7.37 – 7.23 (m, 4H), 7.22 (d, J = 7.8 Hz, 1H), 7.07 –
6.97 (m, 1H), 4.55 (d, J = 12.2 Hz, 1H), 4.35 (d, J = 13.8 Hz, 1H); 13C{1H}NMR (100 MHz, CDCl3) δ
158.2 (d, JC-F = 246.4 Hz), 156.5, 142.1 (d, JC-F = 2.9 Hz), 140.4, 132.0, 131.9, 130.6 (d, JC-F = 10.1 Hz),
129.2, 128.9, 128.5, 128.2, 125.8, 122.1 (d, JC-F = 2.4 Hz), 114.2 (d, JC-F = 23.5 Hz), 112.4 (d, JC-F = 12.8
Hz), 82.8, 77.5, 50.6; IR (KBr, cm-1) 2957, 2925, 2855, 1745, 1610, 1577, 1461, 1377, 1261, 1095,
1020, 866, 799, 694; HRMS (M + H)+ calcd for C21H16ClFNO 352.0899, found 352.0895; HPLC
conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 12.3 min (major),
t2 = 14.7 min (minor).
(S)–4–(Chloromethyl)–2–(4–fluorophenyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4a): 29.0mg, 88%
yield, colorless oil; [α]D20 =45.8 (c 0.10, CHCl3, 89% ee); 1H NMR (400 MHz, CDCl3) δ 8.35 – 8.21 (m,
2H), 7.50 – 7.29 (m, 7H), 7.24 (dd, J = 10.6, 4.9 Hz, 1H), 7.19 – 7.06 (m, 3H), 4.32 – 4.20 (m, 2H);
13C{1H}NMR (100 MHz, CDCl3) δ 165.2 (d, JC-F = 250.8 Hz), 155.3, 140.0, 139.6, 130.6 (d, JC-F = 8.8
Hz), 129.8, 128.9, 128.7, 128.5 (d, JC-F = 2.7 Hz), 126.7, 126.6, 125.7, 125.6, 125.1, 115.6 (d, JC-F = 21.8
Hz), 83.2, 48.5; IR (KBr, cm-1) 2958, 2925, 2854,1679, 1658, 1627, 1598, 1577, 1554, 1508, 1478,
1461, 1378, 1316, 1292, 1261, 1236, 1153, 1083, 1015, 846, 807, 766, 734, 696, 677; HRMS (M + H)+
calcd for C21H16ClFNO 352.0899, found 352.0890; HPLC conditions: Daicel Chiralcel OD–H, i–
PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 20.4 min (major), t2 = 23.8 min (minor).
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(S)–4–(Chloromethyl)–2–(4–chlorophenyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4b): 34.3 mg, 99%
yield, white solid, mp: 42–48 °C; [α]D20 =92.2 (c 0.09, CHCl3, 87% ee); 1H NMR (400 MHz, CDCl3) δ
8.20 (d, J = 8.2 Hz, 2H), 7.39 (ddt, J = 20.3, 14.4, 7.6 Hz, 9H), 7.26 – 7.21 (m, 1H), 7.10 (d, J = 7.6 Hz,
1H), 4.31 – 4.19 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ 155.3, 140.0, 139.5, 138.0, 130.8, 129.9,
129.7, 128.9, 128.8, 128.8, 128.7, 126.9, 126.6, 125.8, 125.6, 125.2, 83.2, 48.5; IR (KBr, cm-1) 2955,
2925, 2854, 1625, 1596, 1568, 1488, 1456, 1402, 1378, 1317, 1260, 1241, 1171, 1092, 1032, 1014, 839,
802, 766, 733, 696, 676, 669; HRMS (M + H)+ calcd for C21H16Cl2NO 368.0604, found 368.0593;
HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 18.3 min
(major), t2 = 21.1 min (minor).
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(S)–2–(4–Bromophenyl)–4–(chloromethyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4c): 20.5 mg, 62%
yield, yellow solid, mp: 85–91 °C; [α]D20 =75.9 (c 0.11, CHCl3, 88% ee); 1H NMR (400 MHz, CDCl3) δ
8.13 (d, J = 8.1 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.38 (dt, J = 19.0, 7.3 Hz, 7H), 7.23 (d, J = 2.8 Hz,
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1H), 7.10 (d, J = 7.6 Hz, 1H), 4.31 – 4.19 (m, 2H); C{1H}NMR (100 MHz, CDCl3) δ 155.4, 140.0,
139.5, 131.8, 131.3, 129.9, 129.8, 128.9, 128.7, 126.9, 126.6, 126.5, 125.8, 125.6, 125.2, 83.2, 48.5; IR
(KBr, cm-1) 2957, 2925, 2854, 1624, 1591, 1565, 1524, 1485, 1457, 1397, 1378, 1318, 1261, 1173,
1084, 1011, 835, 801, 766, 732, 696, 670, 634, 590; HRMS (M + H)+ calcd for C21H16BrClFNO
412.0098, found 412.0079; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5
mL/min, 254 nm, t1 = 19.8 min (major), t2 = 23.8 min (minor).
(S)–4–(Chloromethyl)–2–(2–fluorophenyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4d): 35.0 mg, 99%
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yield, colorless oil; [α]D = 30.8 (c 0.27, CHCl3, 80% ee); H NMR (400 MHz, CDCl3) δ 8.16 – 8.06
(m, 1H), 7.46 (dd, J = 12.9, 7.4 Hz, 3H), 7.42 – 7.32 (m, 5H), 7.31 – 7.21 (m, 2H), 7.18 (dd, J = 12.4,
3.8 Hz, 1H), 7.13 (d, J = 7.3 Hz, 1H), 4.34 – 4.23 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ 161.6 (d,
JC-F = 257.1 Hz), 154.4 (d, JC-F = 4.4 Hz), 133.1 (d, JC-F = 8.8 Hz), 140.2, 139.5, 131.5, 129.8, 128.8 (d,
JC-F = 26.8 Hz), 128.6, 127.1, 126.8, 126.0, 125.2, 125.0, 124.1 (d, JC-F = 3.6 Hz), 120.8 (d, JC-F
=
9.0Hz), 117.1 (d, JC-F = 22.3 Hz) 83.6, 48.8; IR (KBr, cm-1) 2960, 2925, 2855, 1626, 1597, 1574, 1490,
1454, 1325, 1273, 1259, 1223, 1158, 1114, 1074, 1032, 1001, 950, 860, 809, 763, 733, 697, 635, 584,
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566, 548, 517, 497; HRMS (M + H)+ calcd for C21H16ClFNO 352.0899, found 352.0893; HPLC
conditions: Daicel Chiralpak AD–H, i–PrOH/hexane = 1/99, 0.3 mL/min, 254 nm, t1 = 38.8 min
(major), t2 = 42.0 min (minor).
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(S)–4–(Chloromethyl)–2–(3–fluorophenyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4e): 35.0 mg, 99%
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yield, colorless oil; [α]D = 67.7 (c 0.12, CHCl3, 86% ee); H NMR (400 MHz, CDCl3) δ 8.06 (d, J =
7.7 Hz, 1H), 7.95 (d, J = 9.7 Hz, 1H), 7.53 – 7.29 (m, 8H), 7.29 – 7.16 (m, 2H), 7.11 (d, J = 7.5 Hz,
1H), 4.33 – 4.15 (m, 2H); 13C{1H}NMR (100 MHz, CDCl3) δ 162.8 (d, JC-F = 244.7 Hz), 155.0, 140.0,
139.4, 134.6 (d, JC-F = 7.9 Hz), 130.0 (d, JC-F = 8.0 Hz), 129.9, 128.9, 128.7, 127.0, 126.5, 125.9, 125.6,
125.1, 124.0 (d, JC-F = 2.6 Hz), 118.7 (d, JC-F = 21.3 Hz), 115.2 (d, JC-F = 23.4 Hz), 83.3, 48.6; IR (KBr,
cm-1) 2960, 2926, 2853, 1627, 1586, 1485, 1447, 1322, 1269, 1243, 1193, 1154, 1083, 1069, 1034,
1001, 9445, 929, 874, 818, 796, 767, 733, 722, 697, 673, 635, 6002, 581, 549, 520, 494; HRMS (M +
H)+ calcd for C21H16ClFNO 352.0899, found 352.0896; HPLC conditions: Daicel Chiralcel OD–H, i–
PrOH/hexane = 5/95, 0.5 mL/min, 254 nm, t1 = 12.1 min (major), t2 = 13.8 min (minor).
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(S)–4–(Chloromethyl)–2–(4–nitrophenyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4f): 21.4 mg, 65%
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yield, yellow solid, mp: 133–137 °C; [α]D =79.6 (c 0.10, CHCl3, 87% ee); H NMR (400 MHz,
CDCl3) δ 8.42 (d, J = 8.6 Hz, 2H), 8.30 (d, J = 8.6 Hz, 2H), 7.46 – 7.33 (m, 7H), 7.33 – 7.28 (m, 1H),
7.26 (s, 1H), 7.12 (d, J = 7.6 Hz, 1H), 4.27 (q, J = 12.7 Hz, 2H); C{1H}NMR (100 MHz, CDCl3) δ
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154.1, 149.8, 139.8, 139.1, 138.2, 130.0, 129.1, 128.8, 127.8, 126.5, 126.3, 125.5, 125.3, 123.7, 83.7,
48.6; IR (KBr, cm-1) 2956, 2925, 2854, 1627, 1595, 1522, 1482, 1457, 1409, 1347, 1318, 1261, 1243,
1085, 1014, 858, 845, 801, 771, 761, 733, 702, 635, 594; HRMS (M + H)+ calcd for C21H16ClN2O3
379.0844, found 379.0829; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 10/90, 1.0
mL/min, 254 nm, t1 = 11.8 min (major), t2 = 24.3 min (minor).
(S)–4–(Chloromethyl)–2–(2–methoxyphenyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4g): 21.5 mg, 65%
yield, white solid, mp: 101–104 °C; [α]D20 =42.1 (c 0.09, CHCl3, 83% ee); 1H NMR (400 MHz, CDCl3)
δ 7.82 (d, J = 7.2 Hz, 1H), 7.58 – 7.30 (m, 8H), 7.24 (dd, J = 13.4, 5.5 Hz, 2H), 7.10 – 6.91 (m, 3H),
4.28 (s, 2H), 3.88 (s, 3H); 13C{1H}NMR (100 MHz, CDCl3) δ 158.7, 157.0, 140.3, 139.4, 132.4, 131.3,
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129.7, 128.8, 128.5, 127.1, 126.8, 125.8, 125.3, 124.9, 122.4, 120.6, 112.1, 83.6, 56.1, 48.8; IR (KBr,
cm-1) 2957, 2924, 2853, 1630, 1599, 1576, 1492, 1461, 1435, 1322, 1280, 1257, 1171, 1164, 1122,
1075, 1046, 1025, 1001, 794, 758, 733, 697, 634; HRMS (M + H)+ calcd for C22H19ClNO2 364.1099,
found 364.1087; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 2/98, 0.5 mL/min, 254
nm, t1 = 32.0 min (major), t2 = 36.2 min (minor).
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(S)–4–(Chloromethyl)–2–(3–methoxyphenyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4h): 29.7 mg, 90%
yield, colorless oil; [α]D20 =84.2 (c 0.09, CHCl3, 85% ee); 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J = 7.7
Hz, 1H), 7.83 (s, 1H), 7.45 (d, J = 7.0 Hz, 2H), 7.43 – 7.30 (m, 6H), 7.28 – 7.22 (m, 1H), 7.16 – 7.05
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(m, 2H), 4.27 (q, J = 12.0 Hz, 2H), 3.89 (s, 3H); C{1H}NMR (100 MHz, CDCl3) δ 159.7, 156.0,
140.0, 139.6, 133.7, 129.7, 129.5, 128.8, 128.7, 126.7, 126.5, 125.8, 125.7, 125.1, 120.8, 118.2, 113.0,
83.0, 55.5, 48.5; IR (KBr, cm-1) 2959,2925, 2854, 1625, 1599, 1575, 1485, 1453, 1432, 1378, 1326,
1286, 1262, 1222, 1181, 1093, 1040, 870, 800, 768, 723, 697, 683, 669; HRMS (M + H)+ calcd for
C22H19ClFNO2 364.1099, found 364.1087; HPLC conditions: Daicel Chiralcel OD–H, i–PrOH/hexane =
10/90, 1.0 mL/min, 254 nm, t1 = 6.7 min (minor), t2 = 8.8 min (major).
(S)–4–(Chloromethyl)–2–(4–methoxyphenyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4i): 29.7 mg, 90%
yield, colorless oil; [α]D20 =84.2 (c 0.09, CHCl3, 86% ee); 1H NMR (400 MHz, CDCl3) δ 8.24 (d, J = 8.9
Hz, 2H), 7.45 (d, J = 6.8 Hz, 2H), 7.42 – 7.27 (m, 5H), 7.22 (ddd, J = 8.5, 5.5, 3.2 Hz, 1H), 7.10 (d, J =
7.6 Hz, 1H), 6.98 (d, J = 8.9 Hz, 2H), 4.25 (q, J = 12.0 Hz, 2H), 3.87 (s, 3H); 13C{1H}NMR (100 MHz,
CDCl3) δ 162.6, 156.1, 140.1, 140.0, 130.2, 129.7, 128.7, 128.6, 126.6, 126.2, 125.6, 125.4, 125.0,
124.7, 113.8, 82.8, 55.5, 48.4. IR (KBr, cm-1) 2956, 2925, 2854, 1622, 1608, 1595, 1571, 1511, 1479,
1461, 1421, 1378, 1323, 1257, 1169, 1084, 1030, 840, 794, 767, 732, 697, 636, 574, 544; HRMS (M +
H)+ calcd for C22H19ClNO2 364.1099, found 364.1089; HPLC conditions: Daicel Chiralcel OD–H, i–
PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 33.4 min (major), t2 = 43.9 min (minor).
(S)–4–(Chloromethyl)–2–(naphthalen–1–yl)–4–phenyl–4H–benzo[d][1,3]oxazine (4j): 27.0 mg, 71%
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yield, colorless oil; [α]D =33.1 (c 0.11, CHCl3, 86% ee); H NMR (400 MHz, CDCl3) δ 9.12 (d, J =
8.6 Hz, 1H), 8.25 (d, J = 7.2 Hz, 1H), 8.00 (d, J = 8.2 Hz, 1H), 7.92 (d, J = 8.1 Hz, 1H), 7.54 (m, 7H),
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7.38 (q, J = 6.8 Hz, 3H), 7.31 (t, J = 7.6 Hz, 1H), 7.16 (d, J = 7.6 Hz, 1H), 4.34 (s, 2H).; 13C{1H}NMR
(100 MHz, CDCl3) δ 157.1, 140.3, 139.6, 134.1, 132.0, 131.2, 129.8, 129.7, 129.1, 128.9, 128.7, 128.6,
127.3, 127.1, 126.8, 126.5, 126.2, 126.0, 125.2, 125.1, 125.0, 83.5, 48.8; IR (KBr, cm-1) 2956, 2925,
2855, 1629, 1589, 1575, 1509, 1456, 1378, 1307, 1261, 1239, 1189, 1116, 1078, 1009, 805, 777, 731,
696, 634, 583, 560; HRMS (M + H)+ calcd for C25H19ClNO 384.1150, found 384.1138; HPLC
conditions: Daicel Chiralpak IF, i–PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 18.0 min (major), t2 =
19.3 min (minor).
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(S)–4–(Chloromethyl)–2–methyl–4–phenyl–4H–benzo[d][1,3]oxazine (4k): 24.1 mg, 89% yield, white
solid, mp: 135–138 °C; [α]D20 = –128.4 (c 0.11, CHCl3, 90% ee); 1H NMR (600 MHz, CDCl3) δ 7.34 (q,
J = 7.5 Hz, 6H), 7.25 – 7.19 (m, 2H), 7.09 (d, J = 7.5 Hz, 1H), 4.14 (s, 2H), 2.24 (s, 3H); 13C{1H}NMR
(150 MHz, CDCl3) δ 159.8, 140.5, 139.1, 129.7, 128.9, 128.7, 126.4, 126.3, 125.1, 124.8, 124.5, 82.8,
48.9, 21.9; IR (KBr, cm-1) 2957, 2925, 2855, 1739, 1647, 1604, 1581, 1481, 1459, 1376, 1259, 1223,
1182, 1164, 1024, 965, 801, 766, 732, 697, 637, 570, 516; HRMS (M + H)+ calcd for C16H15ClNO
272.0837, found 272.0831; HPLC conditions: Daicel Chiralpak IA, i–PrOH/hexane = 10/90, 1.0
mL/min, 254 nm, t1 = 6.0 min (minor), t2 = 8.9 min (major).
(S)–4–(Chloromethyl)–2–isopropyl–4–phenyl–4H–benzo[d][1,3]oxazine (4l): 27.0 mg, 90% yield,
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colorless oil; [α]D = –43.3 (c 0.08, CHCl3, -92% ee); H NMR (600 MHz, CDCl3) δ 7.40 – 7.29 (m,
6H), 7.25 (d, J = 7.3 Hz, 1H), 7.17 (t, J = 7.5 Hz, 1H), 6.97 (d, J = 7.7 Hz, 1H), 4.18 (d, J = 12.5 Hz,
1H), 4.13 (d, J = 12.5 Hz, 1H), 2.73 (p, J = 5.5 Hz, 1H), 1.29 (d, J = 2.4 Hz, 3H), 1.28 (d, J = 2.3 Hz,
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3H); C{1H}NMR (150 MHz, CDCl3) δ 165.7, 140.5, 139.2, 129.6, 128.7, 128.6, 126.7, 126.3, 125.2,
124.8, 82.3, 48.8, 34.6, 19.7, 19.6; IR (KBr, cm-1) 2957, 2925, 2855, 1642, 1601, 1581, 1458, 1378,
1261, 1198, 1148, 1069, 1005, 803, 768, 733, 697, 634, 571; HRMS (M + H)+ calcd for C18H19ClNO
300.1150, found 300.1141; HPLC conditions: Daicel Chiralpak IA, i–PrOH/hexane = 1/99, 0.5 mL/min,
254 nm, t1 = 12.3 min (minor), t2 = 15.4 min (major).
(S)–2–(tert–Butyl)–4–(chloromethyl)–4–phenyl–4H–benzo[d][1,3]oxazine (4m): 37.0 mg, 99% yield,
white solid, mp: 69–73 oC; [α]D20 = 9.3 (c 0.11, CHCl3, 74% ee); 1H NMR (600 MHz, CDCl3) δ 7.38 (d,
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J = 4.2 Hz, 4H), 7.34 (q, J = 4.1 Hz, 1H), 7.31 (t, J = 7.9 Hz, 1H), 7.25 (s, 1H), 7.14 (t, J = 7.5 Hz, 1H),
6.92 (d, J = 7.7 Hz, 1H), 4.17 (d, J = 12.5 Hz, 1H), 4.10 (d, J = 12.5 Hz, 1H), 1.31 (s, 9H);
13C{1H}NMR (150 MHz, CDCl3) δ 167.1, 140.6, 139.4, 129.6, 128.7, 128.5, 126.9, 126.3, 125.5, 125.2,
124.7, 82.2, 48.7, 37.7, 27.8; IR (KBr, cm-1) 2959, 2928, 2868, 1688, 1634, 1600, 1580, 1482, 1456,
1433, 1393, 1364, 1305, 1267, 1219, 1170, 1143, 1117, 1057, 1031, 1003, 971, 942, 806, 769, 756, 735,
721, 697, 636, 596, 572, 540; HRMS (M + H)+ calcd for C19H21ClNO 314.1306, found 314.1301; HPLC
conditions: Daicel Chiralcel OD–H, i–PrOH/hexane = 1/99, 0.5 mL/min, 254 nm, t1 = 9.9 min (major),
t2 = 11.3 min (minor).
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(S)–4–(Chloromethyl)–4–phenyl–2–(pyridin–4–yl)–4H–benzo[d][1,3]oxazine (4n): 32.1 mg, 96% yield,
colorless oil; [α]D20 = 52.2 (c 0.26, CHCl3, 70% ee); 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 2H), 8.12 –
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7.98 (m, 2H), 7.47 – 7.22 (m, 8H), 7.13 (d, J = 7.4 Hz, 1H), 4.26 (q, J = 12.6 Hz, 2H); C{1H}NMR
(100 MHz, CDCl3) δ 154.2, 150.4, 139.9, 139.8, 139.0, 130.0, 129.1, 128.8, 127.7, 126.4, 126.3, 125.6,
125.2, 121.7, 83.5, 48.7; IR (KBr, cm-1) 2956, 2925, 2855, 1629, 1598, 1554, 1479, 1457, 1409, 1378,
1328, 1313, 1264, 1223, 1158, 1094, 1063, 1033, 999, 834, 767, 731, 696, 683, 634, 579, 544; HRMS
(M + H)+ calcd for C20H16ClN2O 335.0946, found 335.0940; HPLC conditions: Daicel Chiralpak IF, i–
PrOH/hexane = 5/95, 0.5 mL/min, 254 nm, t1 = 28.6 min (major), t2 = 30.6 min (minor).
The Procedure for 1 mmol Scale Preparation of 2a.
To a solution of 1a (0.299 g, 1.0 mmol, 1 equiv), VI (59.4 mg, 0.10 mmol, 10 mol%) in MeOH (20
mL) at –80 oC was added DCDMH (236 mg, 1.2 mmol, 1.2 equiv). The resulting mixture was stirred at
o
–80 C and monitored by TLC. Upon completion, the reaction was quenched by saturated aqueous
o
solution Na2S2O4 at –80 C then warmed to room temperature. The aqueous phase was extracted with
CH2Cl2, the combined organic phases were dried over anhydrous Na2SO4, filtered, and evaporated in
vacuo. The residue was purified by flash column chromatography (PE/EA = 10:1) to afford the product
2a as yellow solid (267 mg, 80% yield, 91% ee).
 ASSOCIATED CONTENT
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The Journal of Organic Chemistry
Supporting Information
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The Supporting Information is available free of charge on the ACS Publications website.
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Copies of NMR spectra and HPLC analysis (PDF)
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X-ray crystallographic structure of 2a (CIF)
X-ray crystallographic structure of 4k (CIF)
 AUTHOR INFORMATION
Corresponding Author
* E-mail: peitang@scu.edu.cn
* E-mail: jdeng@cqu.edu.cn
Notes
The authors declare no competing financial interest.
 ACKNOWLEDGMENTS
This work is founded by National Natural Science Foundation of China (21871034, 21702023,
21572154) and Chongqing University (0903005203454). We also thank Dr. Zhi-Xiong Ma of UW-
Madison for helpful discussions and Mr. Xiangnan Gong of Chongqing University for providing X-ray
analysis.
 REFERENCES
(1) (a) Krantz, A.; Spencer, R. W.; Tam, T. F.; Liak, T. J.; Copp, L. J.; Thomas, E. M.; Rafferty, S. P.
Design and synthesis of 4H-3,1-benzoxazin-4-ones as potent alternate substrate inhibitors of human
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