Increasing appendage diversity on 3,4-dihydro-3-oxo-2H-1,4-benzoxazines via Aphos-Pd(OAc)2-catalyzed Suzuki-Miyaura cross-coupling of aryl chlorides

Article abstract of DOI:10.1016/j.tet.2013.09.057

A library of 32 members of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines has been synthesized from two substituted 2-aminophenols via microwave-assisted one-pot regioselective annulation of 2-bromoalkanoates and subsequent Suzuki-Miyaura cross-coupling of the chloro-substituted scaffolds. The latter transformation was carried out using our Aphos-Pd(OAc)₂ catalyst and the coupling of the aryl chlorides with arylboronic acids proceeded under mild reaction conditions at 60-80 C in THF-H₂O (10:1) in the presence of K ₃PO₄·3H₂O as the base to furnish the corresponding biaryl products in 80-98% yields.

Full text of DOI:10.1016/j.tet.2013.09.057

Tetrahedron 69 (2013) 10488e10496
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Increasing appendage diversity on 3,4-dihydro-3-oxo-2H-1,4-
benzoxazines via AphosePd(OAc)2-catalyzed SuzukieMiyaura
cross-coupling of aryl chlorides
,
,b, ,
Gongli Yu a, Yu Zheng a c, Jinlong Wu a, Wei-Min Dai a
y
*
a Laboratory of Asymmetric Catalysis and Synthesis, Department of Chemistry, Zhejiang University, Hangzhou 310027, China
b Laboratory of Advanced Catalysis and Synthesis, Department of Chemistry, The Hong Kong University of Science and Technology, Clear Water Bay,
Kowloon, Hong Kong SAR, China
c School of Pharmacy, Liaoning University of Traditional Chinese Medicine, Dalian 116600, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 August 2013
Received in revised form 7 September 2013
Accepted 19 September 2013
Available online 25 September 2013
A library of 32 members of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines has been synthesized from two
substituted 2-aminophenols via microwave-assisted one-pot regioselective annulation of 2-
bromoalkanoates and subsequent SuzukieMiyaura cross-coupling of the chloro-substituted scaffolds.
The latter transformation was carried out using our AphosePd(OAc)2 catalyst and the coupling of the aryl
chlorides with arylboronic acids proceeded under mild reaction conditions at 60e80 ꢀC in THFeH2O
(10:1) in the presence of K3PO4$3H2O as the base to furnish the corresponding biaryl products in 80e98%
yields.
Keywords:
2-Aminophenols
Appendage diversity
Aryl chlorides
Ó 2013 Elsevier Ltd. All rights reserved.
1,4-Benzoxazines
Microwave
SuzukieMiyaura cross-coupling
1. Introduction
equilibrating 1,4-benzenoid diradical species. The latter, upon re-
leasing from the apoprotein, is the reactive species for DNA strand
Benzoxacystol (1, Fig. 1)1 is a thioester of 3,4-dihydro-7-methoxy-
2-methylene-3-oxo-2H-benzo[1,4]oxazine-5-carboxylic acid. It is
a novel secondary metabolite of the strain NTK 935, a marine member
of the Streptomyces griseus 16S rRNA clade isolated from deep-sea
sediment. The latter was collected from the Canary Basin at the
edge of the Saharan debris flow near the Canary Islands. Compound 1
lesions.6 In contrast to the limited examples of the naturally occurring
benzoxazines, numerous bioactive derivatives of synthetic origin
have been reported in the literature.7 Fig. 2 illustrates some chlori-
nated 1,4-benzoxazines. The 6-chlorinated derivatives 3a,b and 5
were reported as potassium channel modulators with vasorelaxant
activity.8 Among them, the 4-(dimethylamino)methyl analogue 3a
possessed preferential relaxant activity for guinea pig trachealis.8c
The o-, m-, and p-chlorobenzyl substituents at the nitrogen atom
(position 4) of 1,4-benzoxazine core were disclosed. Compounds 49a
and 79b are the novel antibacterial agents with inhibitory activity
against bacterial histidine protein kinase. The 4-(p-chlorobenzyl)
derivative 6 was reported as a histidine kinase inhibitor and a po-
tentially useful antimicrobial agent for vancomycin-susceptible and
-resistant enterococci.10 A 1,4-benzoxazine compound appended
with both 4-(p-chlorobenzyl) and 6-[(4-oxo-2-thioxothiazolidin-5-
ylidene)methyl] subunits was discovered as a potent inhibitor of
delivers an inhibitory activity against glycogen synthase kinase 3
(GSK-3 M against the recombinant enzyme) and
; IC50¼1.35ꢁ0.15
a weak antiproliferative activity against mouse fibroblast cells (18%
inhibition at 50 M). GSK-3 is known as a key regulator of various
b
b
m
m
b
signaling pathways and it has emerged as a prominent target for the
treatment of Alzheimer’s disease2 and type 2 diabetes.3 The same 1,4-
benzoxazine scaffold was reported for C-1027 chromophore (2),4 one
of the nine-membered enediyne antitumor antibiotics.5 The 1,4-
benzoxazine subunit of 2 was recognized to be responsible for
binding, in a synergetic manner with other structural motifs, to its
apoprotein, and thus for stabilizing the enediyne core and the
PI3Kinase
derivative
(structure not shown) were reported as PPAR
assay for activation of aP2 gene in pooled human preadipocytes (2.1
and 2.4 M) and in PPAR -Gal4Luciferase cotransfection assay (1.3
g
(structure not shown).11 Moreover, the p-chlorobenzyl
and the corresponding m-chlorobenzyl analogue
agonists in functional
8
g
* Corresponding author. Tel./fax: þ86 571 89953128; e-mail addresses: chdai@
ust.hk, chdai@zju.edu.cn (W.-M. Dai).
y
Tel.: þ852 23587365; fax: þ852 23581594.
m
g
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.09.057

G. Yu et al. / Tetrahedron 69 (2013) 10488e10496
10489
and 1.9
m
M).12 PPAR
g
is a target protein for a growing number of
1,4-benzoxazines and the known analogues 12 (X¼6-Cl),15b re-
spectively, with arylboronic acids20 for increasing appendage di-
versity on the 1,4-benzoxazine core.21
agonists useful in the treatment of type 2 diabetes13 and Parkinson’s
disease.14
MeO
O
O
R
O
MeO
O
9 + ArCHO + R1CH(Br)CO2H + R2NC
MeOH, MW
X
N
H
N
H
O
N
H
O
H
N
Me
10
S
O
O
O
O
O
CO2H
R1
Br
OH
RCH(Br)CO2Et
DBU, NMP , MW
X
1: benzoxacystol
O
O
N
O
Me
OH
O
O
OH
O
OH
Ar
Me
OH
Me
N
Me
X
HN
13
R2
Cl
NH2
9
NH2
aq K2CO3, MW
2: C-1027 chromophore
ArCHO, NaBH(OAc)3
OH
O
N
R1
Fig. 1. Structures of benzoxacystol (1) and C-1027 chromophore (2).
X
O
O
X
X
Ar = o-BrC6H4
NH
Ar
Ar
O
N
O
N
O
HN
H
N
R2
11
14
NH2
Cl
O
O
RCH(Br)CO2Et
K2CO3,DMF−H2O, MW
NH
R1
O
R
O
N
X
Cl
CuI
3a: R = NMe2
3b: R = CO2Et
O
N
R
O
4
DMF, MW
O
Me
N
O
N
O
O
Ar
R2
Me
O
12
15
Cl
N
O
NH3+Cl −
Scheme 1. 3,4-Dihydro-3-oxo-2H-1,4-benzoxazines from 2-aminophenols.
CO2 Et
Cl
2. Results and discussion
5
6
CO2H
The 2-aminophenol 16 was selected as the representative sub-
strate, which was transformed into three N-chlorobenzylated de-
rivatives 18aec upon reductive N-alkylation with chlorobenza-
ldehydes 17aec using NaBH(OAc)3 in ClCH2CH2Cl at room tempera-
ture (Scheme 2). Three 2-bromoalkanoates 19aec were used for the
one-pot annulation with 18aec in the presence of 1.5 equiv of K2CO3
in DMFeH2O (2:1) at 120 ꢀC for 1 h under controlled microwave
heating, furnishing 4-(o-, m-, or p-chlorobenzyl)-3,4-dihydro-3-oxo-
2H-1,4-benzoxazines 20aei in86e93% isolatedyields (Table 1). It was
found that the o-, m-, and p-chlorobenzyl groups in 18aec and the
three alkyl groups in 19aec did not affect the yields of the annulation
reaction.
H
N
O
N
NH2
NH
O
N
O
Me
O
O
Cl
Cl
7
8
Fig. 2. Selected bioactive 3,4-dihydro-3-oxo-2H-1,4-benzoxazines.
In our previous studies we have developed a microwave-assisted
one-pot synthesis of both 3,4-dihydro-3-oxo-2H-1,4-benzoxazines
1015a directly from readily available 2-aminophenols 9 and the 4-
arylmethyl derivatives 1215b from 11 prepared by reductive N-al-
kylation of 9 (Scheme 1).16 Moreover, a microwave-assisted one-pot
Ugi four-component reaction (U-4CR) and intramolecular O-alkyl-
ation sequence has been established for synthesis of 3,4-dihydro-3-
oxo-2H-1,4-benzoxazines 1417a via the intermediate 13. A CuI-
catalyzed intramolecular amidation within 14 (Ar¼o-BrC6H4)
has been achieved to afford the CeN bond-linked atropisomeric
conjugates 1517b possessing both 3,4-dihydro-3-oxo-2H-1,4-benzo-
xazine and 2-oxindole scaffolds. Alternatively, compounds 14 could
be formed from 2-aminophenols 9 by the sequence of U-4CR and
intramolecular Mitsunobu reaction.18 As an extension of our pre-
vious work, we report here on synthesis of 3,4-dihydro-3-oxo-2H-
1,4-benzoxazines 12 (X¼7-Me; ArCH2¼o-, m-, p-chlorobenzyl).
Furthermore, our AphosePd(OAc)2 catalyst system19 is used for
SuzukieMiyaura cross-coupling reaction of these chlorinated
Me
OH
Cl
Me
OH
NH
OHC
NaBH(OAc)3
+
NH2
ClCH2CH2Cl
rt, 2 h
Cl
16
17a−c
18a: o- (89%)
18b: m- (84%)
18c: p- (85%)
Me
O
N
R
RCH(Br)CO2Et (19a−c)
O
K2CO3 (1.5 eq)
DMF−H2O (2:1)
120 oC, 1 h, MW
(see Table 1)
Cl
20a−i
Scheme 2. Synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines 20aei.

10490
G. Yu et al. / Tetrahedron 69 (2013) 10488e10496
product 27b even after heating at 60 ꢀC for 36 h (entry 3, Table 2).
Therefore, the conditions in entry 2 of Table 2 were used for the
cross-coupling of 25aee with three selected arylboronic acids.
Table 1
Synthesis of 1,4-benzoxazines 20aei from 18aec and 19aec
Compound
18
19: R
Yielda (%)
mpb (ꢀC)
20a
20b
20c
20d
20e
20f
20g
20h
20i
18a: o-Cl
18a: o-Cl
18a: o-Cl
18b: m-Cl
18b: m-Cl
18b: m-Cl
18c: p-Cl
18c: p-Cl
18c: p-Cl
19a: Me
19b: Et
19c: n-Pr
19a: Me
19b: Et
19c: n-Pr
19a: Me
19b: Et
91
87
90
93
86
92
89
89
92
95e96
109e110
62e63
78e79
dc
Table 2
The SuzukieMiyaura cross-coupling of 25b with PhB(OH)2
O
N
Et
O
O
N
Et
O
dc
Pd(OAc)2:Aphos 26a (1:2)
94e95
86e87
91e92
Cl
Ph
PhB(OH)2 (1.5 eq)
K3PO4.3H2O (3 eq)
THF−H2O (10:1)
19c: n-Pr
a
O
O
Isolated yields.
Recrystallized from EtOAcehexane.
25b
27b
b
i-Pr
i-Pr
c
A colorless oil.
N
O
26a: Ar = H
26b: Ar = 3-NO2C6H4 (Aphos-N)
According to our reported work,15b 2-amino-4-chlorophenol
(21) was subjected to the reductive N-alkylation with aldehydes
22aed to give the N-arylmethylated 2-aminophenols 23aed in
82e95% yields (Scheme 3). The latter were then transformed into
Ar
PCy2
Entry
Pd (mol %)
T (ꢀC)
t (h)
Yielda (%)
1
2
3
0.5
0.5
0.1
80
60
60
14.5
21.5
36
91
90
Trace
the
known
6-chloro-3,4-dihydro-3-oxo-2H-1,4-benzoxazines
25aee via the microwave-assisted one-pot annulation with ethyl
bromoacetate (24) and ethyl 2-bromoalkanoates 19b,c in 70e98%
yields, respectively.
a
Isolated yield.
Table 3 lists the structures and yields of the 6-aryl-3,4-dihydro-
3-oxo-2H-1,4-benzoxazines 27e29 synthesized from 25aee. In
general, the remote R and Ar groups from the coupling reaction site
did not affect the yields, allowing incorporation of 2-furyl and 3-
pyridinyl groups into the 1,4-benzoxazine core in the products. In
contrast, 2-methoxyphenylboronic acid showed slightly lower re-
activity, resulting in prolonged reaction times or lower yields.
Therefore, in the synthesis of the products 28cee, 1 mol % palla-
dium was used (entries 8e10, Table 3).
OH
OH
NH
NaBH(OAc)3
Ar CHO
+
Cl
NH2
Cl
THF, rt, 1−2 h
21
22a−d
Ar
23a: Ar = 2-furyl (92%)
23b: Ar = Ph (95%)
23c: Ar = 4-MeOC6H4 (83%)
23d: Ar = 3-Py (82%)
BrCH2CO2Et (24) or
O
N
R
RCH(Br)CO2Et (19b,c)
Table 3
Cl
O
K2CO3 (1.5 eq)
DMF−H2O (2:1)
Synthesis of 6-aryl-substituted 1,4-benzoxazines 27e29a
Ar
180 oC, 30 min, MW
O
N
R
O
O
N
R
O
O
N
R
O
25a−e
(70−98%)
MeO
Me
Ph
Scheme 3. Synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines 25aee.
Ar
Ar
Ar
28a−e
29a−e
27a−e
Entry
Product
R
Ar
t (h)
Yieldb (%)
The SuzukieMiyaura cross-coupling reaction22 is one of the
powerful synthetic tools for carbonecarbon bond formation. We
envisioned that the above chlorinated 3,4-dihydro-3-oxo-2H-1,4-
benzoxazines 20aei and 25aee could be used as the precursors
for further derivatization via the palladium-catalyzed Suzu-
kieMiyaura cross-coupling reaction with arylboronic acids.23 In our
previous work, we demonstrated that the C4-arylated Aphos-N 26b
(Table 2) could catalyze the coupling reactions of unactivated aryl
chlorides with arylboronic acids at room temperature. In the
presence of 1e2 mol % Pd(OAc)2 (Pd/26a¼1:1.5) excellent yields of
the biaryls could be obtained after 24e36 h. In order to speed up
the cross-coupling reaction in the current synthesis of arylated 1,4-
benzoxazines, we decided to use the parent Aphos 26a at mild
heating temperatures.24 Using 6-chloro derivative 25b as the sub-
strate, the coupling reaction with phenylboronic acid was per-
formed in the presence of 0.5 mol % Pd(OAc)2 and 1 mol % Aphos
26a as the catalyst precursors with 3 equiv of K3PO4$3H2O as the
base in THFeH2O (10:1). After heating at 80 ꢀC for 14.5 h, the 6-
phenyl-substituted product 27b was isolated in 91% yield (entry
1, Table 2). The same coupling reaction proceeded at 60 ꢀC for 21.5 h
to afford 27b in 90% yield (entry 2, Table 2). Unfortunately, re-
duction of the palladium loading to 0.1 mol % failed to produce the
1
2
3
4
5
6
7
27a
27b
27c
27d
27e
28a
28b
28c
28d
28e
29a
29b
29c
29d
29e
H
Et
n-Pr
n-Pr
n-Pr
H
2-Furyl
2-Furyl
Ph
4-MeOC6H4
3-Py
2-furyl
2-furyl
Ph
4-MeOC6H4
3-Py
2-Furyl
2-Furyl
Ph
4-MeOC6H4
3-Py
16.5
21.5
19
20
17
18
24
19
17
18
12
12
12.5
14
91
91
95
94
94
95
80
97
91
93
94
93
96
98
99
Et
8c
9c
10c
11
12
13
14
15
n-Pr
n-Pr
n-Pr
H
Et
n-Pr
n-Pr
n-Pr
14
a
Reaction was carried out with 0.5 mol % Pd(OAc)2, 1 mol % Aphos 26a, 1.5 equiv
of Ar2B(OH)2, and 3.0 equiv of K3PO4$3H2O in THFeH2O (10:1) at 60 ꢀC.
b
Isolated yields.
Use 1 mol % Pd(OAc)2 and 2 mol % Aphos 26a.
c
As compared to the 6-chloro-3,4-dihydro-3-oxo-2H-1,4-
benzoxazines 25aee, the o-, m-, and p-chlorobenzyl groups in
20aei demonstrated relatively lower reactivity toward the Suzu-
kieMiyaura cross-coupling reaction. Palladium loadings of 1 and

G. Yu et al. / Tetrahedron 69 (2013) 10488e10496
10491
2 mol % were then applied for the cross-coupling reaction of 20aei
with phenylboronic acid as the representative coupling partner
(Table 4). The biphenyl-2-yl products 30aec and the biphenyl-4-yl
analogue 32c were formed from 20aec and 20i, respectively, with
1 mol % Pd(OAc)2 at 60 ꢀC in 91e94% yields (entries 1e3 and 9, Table
4) while biphenyl-3- and -4-yl products 31aec and 32a,b were
synthesized from 20deh with 2 mol % Pd(OAc)2 at 80 ꢀC in 86e98%
yields (entries 4e8, Table 4). It is expected the SuzukieMiyaura
cross-coupling reaction of 20aei with other arylboronic acids, such
as those used in Table 3 should take place under the modified ca-
talysis conditions.
(now under Biotage AB, Uppsala, Sweden) with temperature mea-
sured by an external IR sensor. The microwave-assisted reaction
time is the hold time at the final temperature. The procedures for
synthesis of the compounds 23aed and 25aee (Scheme 3) and
their characterization data are found in our reported work.15b
4.2. General procedure for reductive N-alkylation of 2-amino-
5-methylphenol 16
A mixture of 2-amino-5-methylphenol (16, 862.0 mg, 7.0 mmol)
and NaBH(OAc)3 (4.45 g, 21.0 mmol) in 1,2-dichloroethane (60 mL)
was stirred at room temperature for 30 min followed by adding 2-,
3-, and 4-chlorobenzaldehyde (17aec, 1.08 g, 7.7 mmol), re-
spectively. The resultant mixture was stirred for another 1.5 h at
room temperature. The reaction was quenched by water and
extracted with EtOAc (50 mLꢂ3). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, and evaporated
under reduced pressure. The residue was purified by flash column
chromatography (silica gel, 5% EtOAcePE) to provide the products
18aec in 84e89% yields (Scheme 2).
Table 4
Synthesis of biphenyl-substituted 1,4-benzoxazines 30e32a
Me
O
N
R
O
Me
O
N
R
O
Me
O
N
R
O
4.2.1. 2-(20-Chlorobenzylamino)-5-methylphenol (18a). Yield 89%;
a yellow solid; mp 78e79 ꢀC (EtOAcehexane); Rf¼0.41 (10%
31a−c
32a−c
30a−c
EtOAcehexane); IR (KBr): 3355, 3078 (br), 1529, 1441, 1250 cmꢃ1
;
Entry
Product
R
Pd (mol %)
T (ꢀC)
Yieldb (%)
1H NMR (400 MHz, CDCl3)
6.65e6.57 (m, 2H), 6.55 (br d, J¼7.6 Hz, 1H), 5.00e4.00 (br s, 2H),
4.39 (s, 2H), 2.22 (s, 3H); 13C NMR (100 MHz, CDCl3)
144.6, 136.8,
d 7.42e7.35 (m, 2H), 7.24e7.18 (m, 2H),
1
2
3
4
5
6
7
8
9
30a
30b
30c
31a
31b
31c
32a
32b
32c
Me
Et
n-Pr
Me
Et
n-Pr
Me
Et
1
1
1
2
2
2
2
2
1
60
60
60
80
80
80
80
80
60
94
91
93
87
92
86
98
97
94
d
133.6, 133.3, 129.4, 129.2, 128.8, 128.3, 126.9, 121.6, 115.5, 114.1, 47.0,
20.6; MS (þEI) m/z 122 (MþꢃC7H5Cl, 100), 247 (Mþ, 40), 249
(Mþþ2, 14). Anal. Calcd for C14H14ClNO: C, 67.88; H, 5.70; N, 5.65.
Found: C, 67.71; H, 5.77; N 5.64%.
n-Pr
4.2.2. 2-(30-Chlorobenzylamino)-5-methylphenol (18b). Yield 84%;
a yellow solid; mp 89e90 ꢀC (EtOAcehexane); Rf¼0.24 (10%
EtOAcehexane); IR (KBr): 3332, 3040 (br), 1524, 1461, 1421, 1245,
aReaction was carried out with 1e2 mol % Pd(OAc)2 (Pd/Aphos 26a¼1:2), 1.5 equiv
of PhB(OH)2, and 3.0 equiv of K3PO4$3H2O in THFeH2O (10:1) at 60e80 ꢀC for 24 h.
b
Isolated yields.
1129 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
7.35 (s, 1H), 7.25e7.20 (m,
3H), 6.64e6.47 (m, 3H), 4.70e4.25 (br s, 2H), 4.27 (s, 2H), 2.19 (s,
3H); 13C NMR (100 MHz, CDCl3)
143.9, 141.8, 134.4, 133.8, 129.8,
3. Conclusion
d
128.4, 127.5, 127.3, 125.5, 121.7, 115.4, 113.3, 48.5, 20.5; MS (þEI) m/z
122 (MþꢃC7H5Cl, 100), 247 (Mþ, 38), 249 (Mþþ2, 13). Anal. Calcd
for C14H14ClNO: C, 67.88; H, 5.70; N, 5.65. Found: C, 67.74; H, 5.76;
N, 5.62%.
We have synthesized o-, m-, and p-chlorobenzyl-substituted
3,4-dihydro-3-oxo-2H-1,4-benzoxazines 20aei according to our
previously established microwave-assisted one-pot annulation
protocol.15b The AphosePd(OAc)2-catalyzed SuzukieMiyaura cross-
coupling reaction of aryl chlorides with arylboronic acids19 has
been demonstrated as the efficient method for increasing ap-
pendage diversity on the 1,4-benzoxazine scaffolds.21,25 The syn-
thesized library of the chlorinated 3,4-dihydro-3-oxo-2H-1,4-
benzoxazines 20aei and 25aee as well as the biaryl analogues
27e32 would be used for various applications.8e14
4.2.3. 2-(40-Chlorobenzylamino)-5-methylphenol (18c). Yield 85%;
a yellow solid; mp 96e97 ꢀC (EtOAcehexane); Rf¼0.33 (10%
EtOAcehexane); IR (KBr): 3313, 3086 (br), 1522, 1472, 1421,
1125 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
7.30 (s, 4H), 6.65e6.51 (m,
3H), 4.80e4.20 (br s, 2H), 4.28 (s, 2H), 2.21 (s, 3H); 13C NMR
(100 MHz, CDCl3)
d
144.0, 138.0, 133.9, 132.9, 128.9 (ꢂ2), 128.7 (ꢂ2),
128.5, 121.7, 115.6, 113.4, 48.4, 20.5; MS (þEI) m/z 122 (MþꢃC7H5Cl,
100), 247 (Mþ, 35), 249 (Mþþ2, 13). Anal. Calcd for C14H14ClNO: C,
67.88; H, 5.70; N, 5.65. Found: C, 67.87; H, 5.66; N, 5.64%.
4. Experimental
4.1. General methods
4.3. General procedure for microwave-assisted one-pot syn-
thesis of 1,4-benzoxazines 20aei
1H and 13C NMR spectra were recorded in CDCl3 (400 or
500 MHz for 1H and 100 for 13C, respectively). IR spectra were taken
on an FT-IR spectrophotometer. Mass spectra (MS) were measured
by the ESI or EI method. Melting points are uncorrected. Silica gel
plates pre-coated on glass were used for thin-layer chromatogra-
phy using UV light, or 7% ethanolic phosphomolybdic acid and
heating as the visualizing methods. Silica gel was used for flash
column chromatography. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials. Petroleum
ether (PE) of 60e90 ꢀC fraction was used in this work. The
microwave-assisted reactions were carried out on an Emrys creator
(single-mode microwave reactor) from Personal Chemistry AB
A 10 mL pressurized process vial was charged with a mixture of 2-
(20-chlorobenzylamino)-5-methylphenol (18a, 247.7 mg, 1.0 mmol),
ethyl 2-bromopropanoate (362.1 mg, 2.0 mmol), and K2CO3
(207.3 mg,1.5 mmol) in water (1 mL) and DMF (2 mL) and was tightly
sealed with a cap containing a silicon septum. The loaded vial was
then placed into the microwave reactor cavity and was heated at
120 ꢀC for 1 h. After cooled to room temperature the reaction mixture
was diluted with water (5 mL) and the resultant mixture was
extracted with EtOAc (10 mLꢂ3). The combined organic layer was
washed with brine, dried over anhydrous Na2SO4, and evaporated

10492
G. Yu et al. / Tetrahedron 69 (2013) 10488e10496
under reduced pressure. The residue was purified by flash column
chromatography over silica gel to furnish the product 20a. The yields
are listed in Table 1.
114.8, 78.2, 44.5, 23.7, 20.6, 9.4; MS (þEI) m/z 315 (Mþ, 100), 317
(Mþþ2, 33). HRMS (þESI) calcd for C18H18ClNNaO2 338.0918
(MþNaþ), found 338.0912.
4.3.1. 4-(20-Chlorobenzyl)-3,4-dihydro-2,7-dimethyl-3-oxo-2H-1,4-
benzoxazine (20a). Yield 91%;
4.3.6. 4-(30-Chlorobenzyl)-3,4-dihydro-7-methyl-3-oxo-2-propyl-
2H-1,4-benzoxazine (20f). Yield 92%; a colorless oil; Rf¼0.64 (10%
EtOAcehexane); IR (film): 2961, 2873, 1682, 1513, 1398, 1292, 1149,
a
white solid; mp 95e96 ꢀC
(EtOAcehexane); Rf¼0.67 (10% EtOAcehexane); IR (KBr): 1685,
1518, 1406, 1314, 1293, 1113, 1038 cmꢃ1; 1H NMR (400 MHz, CDCl3)
1031 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d 7.27e7.19 (m, 3H), 7.11 (d,
d
7.41 (d, J¼8.8 Hz, 1H), 7.23e7.13 (m, 2H), 6.97 (d, J¼7.2 Hz, 1H),
J¼6.0 Hz, 1H), 6.84 (s, 1H), 6.72e6.67 (m, 2H), 5.15 and 5.00 (ABq,
J¼16.0 Hz, 2H), 4.67 (t, J¼6.8 Hz, 1H), 2.25 (s, 3H), 1.92 (dt, J¼7.2,
7.2 Hz, 2H), 1.69e1.54 (m, 2H), 1.00 (t, J¼7.6 Hz, 3H); 13C NMR
6.84 (s, 1H), 6.71 (d, J¼8.0 Hz, 1H), 6.58 (d, J¼8.8 Hz, 1H), 5.23 and
5.17 (ABq, J¼16.8 Hz, 2H), 4.76 (q, J¼6.8 Hz, 1H), 2.26 (s, 3H), 1.64 (d,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
166.9,144.2,134.1,133.2,
(100 MHz, CDCl3) d 166.6, 143.8, 138.5, 134.7, 134.2, 130.0, 127.6,
132.6, 129.6, 128.4, 127.1, 126.7, 126.2, 123.2, 117.8, 115.0, 73.6, 42.8,
20.7, 16.4; MS (þEI) m/z 266 (MþꢃCl, 100), 301 (Mþ, 36), 303
(Mþþ2, 13). Anal. Calcd for C17H16ClNO2: C, 67.66; H, 5.34; N, 4.64.
Found: C, 67.69; H, 5.34; N, 4.64%.
126.6, 126.1, 124.6, 123.0, 118.0, 114.8, 76.9, 44.5, 32.2, 20.7, 18.3,
13.6; MS (þEI) m/z 162 (Mþꢃm-ClC6H4CH2eC3H6, 100), 329 (Mþ,
75), 331 (Mþþ2, 25). HRMS (þESI) calcd for C19H20ClNNaO2
352.1075 (MþNaþ), found 352.1066.
4.3.2. 4-(20-Chlorobenzyl)-2-ethyl-3,4-dihydro-7-methyl-3-oxo-2H-
1,4-benzoxazine (20b). Yield 87%; a white solid; mp109e110 ꢀC
(EtOAcehexane); Rf¼0.69 (10% EtOAcehexane); IR (KBr): 2965,
2935, 1685, 1516, 1404, 1322, 1296, 1039 cmꢃ1; 1H NMR (400 MHz,
4.3.7. 4-(40-Chlorobenzyl)-3,4-dihydro-2,7-dimethyl-3-oxo-2H-1,4-
benzoxazine (20g). Yield 89%;
a
white solid; mp 94e95 ꢀC
(EtOAcehexane); Rf¼0.57 (10% EtOAcehexane); IR (KBr): 1675,
1512, 1400, 1293, 1156, 1111, 1011 cmꢃ1; 1H NMR (400 MHz, CDCl3)
CDCl3)
d
7.41 (dd, J¼7.6, 1.2 Hz, 1H), 7.22e7.12 (m, 2H), 6.96 (d,
d
7.28 (d, J¼8.4 Hz, 2H), 7.17 (d, J¼8.4 Hz, 2H), 6.82 (s,1H), 6.72e6.67
J¼8.0 Hz, 1H), 6.85 (s, 1H), 6.69 (d, J¼8.4 Hz, 1H), 6.57 (d, J¼8.8 Hz,
1H), 5.26 and 5.14 (ABq, J¼16.8 Hz, 2H), 4.60 (dd, J¼9.2, 5.2 Hz, 1H),
2.26 (s, 3H), 2.20e1.80 (m, 2H), 1.13 (t, J¼7.6 Hz, 3H); 13C NMR
(m, 2H), 5.11 and 5.06 (ABq, J¼16.4 Hz, 2H), 4.72 (q, J¼6.4 Hz, 1H),
2.26 (s, 3H), 1.61 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
166.8, 144.2,134.8,134.1, 133.1, 128.9 (ꢂ2), 128.0 (ꢂ2), 126.2,123.0,
(100 MHz, CDCl3)
d
166.5, 143.8, 134.1, 133.2, 132.6, 129.6, 128.4,
117.9, 114.9, 73.5, 44.5, 20.6, 16.3; MS (þEI) m/z 125 (p-ClC6H4CHþ2 ,
100), 301 (Mþ, 53), 303 (Mþþ2, 18). Anal. Calcd for C17H16ClNO2: C,
67.66; H, 5.34; N, 4.64. Found: C, 67.68; H, 5.35; N, 4.62%.
127.1, 126.6, 126.0, 123.0, 117.9, 114.8, 78.3, 42.7, 23.8, 20.6, 9.5; MS
(þEI) m/z 280 (MþꢃCl, 100), 315 (Mþ, 40), 317 (Mþþ2, 13). Anal.
Calcd for C18H18ClNO2: C, 68.46; H, 5.75; N, 4.44. Found: C, 68.36; H,
5.81; N, 4.42%.
4.3.8. 4-(40-Chlorobenzyl)-2-ethyl-3,4-dihydro-7-methyl-3-oxo-2H-
1,4-benzoxazine (20h). Yield 89%; a white solid; mp 86e87 ꢀC
(EtOAcehexane); Rf¼0.60 (10% EtOAcehexane); IR (KBr): 2968,
4.3.3. 4-(20-Chlorobenzyl)-3,4-dihydro-7-methyl-3-oxo-2-propyl-
2H-1,4-benzoxazine (20c). Yield 90%; a white solid; mp 62e63 ꢀC
(EtOAcehexane); Rf¼0.76 (10% EtOAcehexane); IR (KBr): 2958,
2926, 1680, 1514, 1406, 1323, 1290, 1041 cmꢃ1; 1H NMR (400 MHz,
2932, 1678, 1514, 1406, 1297, 1146, 1086, 1008 cmꢃ1 1H NMR
;
(400 MHz, CDCl3)
d
7.28 (d, J¼8.4 Hz, 2H), 7.16 (d, J¼8.4 Hz, 2H), 6.83
(s, 1H), 6.69e6.65 (m, 2H), 5.15 and 5.01 (ABq, J¼16.4 Hz, 2H), 4.56
CDCl3)
d
7.41 (d, J¼8.0 Hz, 1H), 7.22e7.13 (m, 2H), 6.96 (d, J¼7.2 Hz,
(dd, J¼8.4, 4.4 Hz, 1H), 2.26 (s, 3H), 2.00e1.88 (m, 2H), 1.11 (t,
1H), 6.83 (s, 1H), 6.69 (d, J¼8.4 Hz, 1H), 6.57 (d, J¼8.0 Hz, 1H), 5.26
and 5.13 (ABq, J¼16.8 Hz, 2H), 4.69 (t, J¼6.4 Hz, 1H), 2.26 (s, 3H),
1.94e1.88 (m, 2H), 1.68e1.53 (m, 2H), 1.00 (t, J¼7.6 Hz, 3H); 13C
J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.4, 143.8,134.8,134.1,
133.1, 128.9 (ꢂ2), 127.9 (ꢂ2), 126.0, 122.9, 118.0, 114.8, 78.2, 44.3,
23.7, 20.6, 9.4; MS (þEI) m/z 125 ðp ClC6H4CH2þ; 100Þ; 315 (Mþ,
57), 317 (Mþþ2, 19). Anal. Calcd for C18H18ClNO2: C, 68.46; H, 5.75;
N, 4.44. Found: C, 68.44; H, 5.82; N, 4.43%.
NMR (100 MHz, CDCl3)
d 166.7, 143.7, 134.1, 133.2, 132.5, 129.6,
128.4, 127.1, 126.6, 126.0, 123.0, 118.0, 114.8, 76.9, 42.7, 32.2, 20.6,
18.3, 13.6; MS (þEI) m/z 294 (MþꢃCl, 100), 329 (Mþ, 45), 331
(Mþþ2, 15). Anal. Calcd for C19H20ClNO2: C, 69.19; H, 6.11; N, 4.25.
Found: C, 69.14; H, 6.14; N, 4.22%.
4.3.9. 4-(40-Chlorobenzyl)-3,4-dihydro-7-methyl-3-oxo-2-propyl-
2H-1,4-benzoxazine (20i). Yield 92%; a white solid; mp 91e92 ꢀC
(EtOAcehexane); Rf¼0.62 (10% EtOAcehexane); IR (KBr): 2960, 2929,
4.3.4. 4-(30-Chlorobenzyl)-3,4-dihydro-2,7-dimethyl-3-oxo-2H-1,4-
benzoxazine (20d). Yield 93%;
1677, 1514, 1405, 1258, 1148, 1091, 1011 cmꢃ1 1H NMR (400 MHz,
;
a
white solid; mp 78e79 ꢀC
CDCl3)
d
7.28 (d, J¼8.4 Hz, 2H), 7.16 (d, J¼8.4 Hz, 2H), 6.81 (s, 1H),
(EtOAcehexane); Rf¼0.44 (10% EtOAcehexane); IR (KBr): 1680,
6.71e6.65 (m, 2H), 5.15 and 5.5.00 (ABq, J¼16.0 Hz, 2H), 4.65 (t,
J¼6.8 Hz, 1H), 2.26 (s, 3H), 1.88 (dt, J¼7.2, 7.2 Hz, 2H), 1.66e1.51 (m,
1518, 1403, 1314, 1295, 1159, 1015 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
7.28e7.22 (m, 3H), 7.12 (d, J¼6.8 Hz, 1H), 6.84 (s, 1H), 6.73 (d,
2H), 0.99 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.6, 143.7,
J¼8.8 Hz, 1H), 6.69 (d, J¼8.4 Hz, 1H), 5.14 and 5.06 (ABq, J¼16.0 Hz,
134.8,134.1,133.1,128.9 (ꢂ2),127.9 (ꢂ2),126.1,122.9,118.0,114.8, 76.9,
44.3, 32.2, 20.6, 18.3, 13.6; MS (þEI) m/z 125 ðp ClC6H4CH2þ; 100Þ;
329 (Mþ, 53), 331 (Mþþ2,18). Anal. Calcd forC19H20ClNO2: C, 69.19;H,
6.11; N, 4.25. Found: C, 69.13; H, 6.15; N, 4.19%.
2H), 4.75 (q, J¼6.8 Hz, 1H), 2.28 (s, 3H), 1.63 (d, J¼7.2 Hz, 3H); 13C
NMR (100 MHz, CDCl3)
d 166.9, 144.2, 138.4, 134.7, 134.2, 130.1,
127.6, 126.6, 126.3, 124.6, 123.1, 117.9, 114.9, 73.5, 44.7, 20.7, 16.4; MS
(þEI) m/z 301 (Mþ, 100), 303 (Mþþ2, 33). Anal. Calcd for
C
17H16ClNO2: C, 67.66; H, 5.34; N, 4.64. Found: C, 67.62; H, 5.31; N,
4.4. General procedure for the SuzukieMiyaura cross-
coupling reaction catalyzed by AphosePd(OAc)2
4.60%.
4.3.5. 4-(30-Chlorobenzyl)-2-ethyl-3,4-dihydro-7-methyl-3-oxo-2H-
1,4-benzoxazine (20e). Yield 86%; a colorless oil; Rf¼0.52 (10%
EtOAcehexane); IR (film): 2971, 2935, 1682, 1514, 1398, 1293, 1149,
Preparation of a stock solution of the catalyst precursors. A 10 mL
pressurized process vial was charged with Pd(OAc)2 (2.7 mg,
1.2ꢂ10ꢃ2 mmol), Aphos 26a (9.6 mg, 2.4ꢂ10ꢃ2 mmol). The vial was
sealed with a cap containing a silicon septum and then evacuated
through a needle under vacuum and backfilled with nitrogen (this
sequence was repeated for three times). Degassed THF (4 mL) was
added via a syringe to make a stock solution of the catalyst
precursors.
1045 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d 7.27e7.19 (m, 3H), 7.11 (d,
J¼6.0 Hz, 1H), 6.85 (s, 1H), 6.72e6.67 (m, 2H), 5.15 and 5.02 (ABq,
J¼16.4 Hz, 2H), 4.58 (dd, J¼8.4, 4.4 Hz, 1H), 2.26 (s, 3H), 2.03e1.90
(m, 2H), 1.13 (t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.4,
143.8,138.4,134.7,134.1,130.0,127.6,126.6,126.1,124.6,122.9,118.0,

G. Yu et al. / Tetrahedron 69 (2013) 10488e10496
10493
A separate 10 mL pressurized process vial containing a magnetic
stirring bar was charged with the aryl chloride (3.0ꢂ10ꢃ1 mmol,
1 equiv), the arylboronic acid (4.5ꢂ10ꢃ1 mmol, 1.5 equiv), and
K3PO4$H2O (239.7 mg, 9.0ꢂ10ꢃ1 mmol, 3.0 equiv). The vial was
sealed with a cap containing a silicon septum and then evacuated
through a needle under vacuum and backfilled with nitrogen (this
sequence was repeated for three times). The THF stock solution
of the catalyst precursors (1 mL, 3.0ꢂ10ꢃ3 mmol Pd and
J¼6.4 Hz,1H), 3.78 (s, 3H),1.97e1.91 (m, 2H),1.72e1.55 (m, 2H),1.02
(t, J¼7.6 Hz, 3H); 13C NMR (100 MHz, DMSO-d6)
d 166.7,158.8,143.4,
140.4, 135.7, 129.0, 128.8 (ꢂ2), 128.2, 128.0 (ꢂ2), 127.1, 126.7 (ꢂ2),
122.5, 117.5, 114.2 (ꢂ2), 114.1, 76.0, 55.2, 44.5, 32.3, 18.3, 13.6; MS
(þESI) m/z 410 (MþNaþ, 100). Anal. Calcd for C25H25NO2: C, 77.49,
H, 6.50, N, 3.61. Found: C, 77.49, H, 6.52, N, 3.65%.
4.4.5. 3,4-Dihydro-3-oxo-6-phenyl-2-propyl-4-(30-pyridinylmethyl)-
2H-1,4-benzoxazine (27e). Yield 94%; a white solid; mp 82e83 ꢀC
(EtOAcehexane); Rf¼0.22 (50% EtOAcehexane); IR (KBr): 2955,
2926, 1686, 1486, 1427, 1378, 1262, 1024 cmꢃ1; 1H NMR (400 MHz,
6.0ꢂ10ꢃ3 mmol Aphos 26a) and degassed water (100
mL) were
added via a syringe. The resultant mixture was heated at 60 or 80 ꢀC
with vigorous stirring for the indicated times. The reaction mixture
was diluted with EtOAc (5 mL), filtered through a thin pad of Celite
with washing by water and EtOAc. The filtrate was extracted with
EtOAc and the organic layer was dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure. The residue was
purified by flash column chromatography over silica gel to give the
products. For the catalyst loading other than 1 mol % Pd, the
amounts of the THF stock solution and water were adjusted to
maintain a 10:1 ratio for THF and H2O. The reaction times and yields
are found in Tables 3 and 4.
CDCl3)
d
8.63 (d, J¼1.6 Hz, 1H), 8.54 (dd, J¼4.0, 0.8 Hz, 1H), 7.60 (d,
J¼8.0 Hz, 1H), 7.41e7.26 (m, 6H), 7.20 (dd, J¼8.4, 2.4 Hz, 1H), 7.06 (d,
J¼7.6 Hz, 1H), 7.03 (d, J¼2.0 Hz, 1H), 5.29 and 5.14 (ABq, J¼16.4 Hz,
2H), 4.71 (t, J¼7.2 Hz,1H), 1.96e1.89 (m, 2H),1.69e1.54 (m, 2H),1.07
(t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.8, 148.9, 148.3,
143.4, 140.1, 136.1, 134.7, 132.0, 128.9 (ꢂ2), 128.6, 127.3, 126.7 (ꢂ2),
123.8, 123.0, 117.9, 113.6, 77.0, 42.7, 32.2, 18.3, 13.6; MS (þESI) m/z
381 (MþNaþ, 50), 359 (MþHþ, 100). HRMS (þESI) calcd for
C
23H22N2O2Na 381.1573 (MþNaþ), found 381.1576.
4.4.1. 3,4-Dihydro-4-(20-furylmethyl)-3-oxo-6-phenyl-2H-1,4-
benzoxazine (27a). Yield 91%; a white solid; mp 122e124 ꢀC
(EtOAcehexane); Rf¼0.62 (20% EtOAcehexane); IR (KBr): 1686,
4.4.6. 3,4-Dihydro-4-(20-furylmethyl)-6-(20-methoxyphenyl)-3-oxo-
2H-1,4-benzoxazine (28a). Yield 95%; a white solid; mp 116e118 ꢀC
(EtOAcehexane); Rf¼0.47 (20% EtOAcehexane); IR (KBr): 2955,
1494, 1426, 1375, 1283, 1133, 1976, 1041, 1005 cmꢃ1
;
1H NMR
1686, 1482, 1428, 1374, 1266, 1228, 1053, 1024 cmꢃ1 1H NMR
;
(400 MHz, CDCl3)
d
7.54e7.50 (m, 2H), 7.48e7.42 (m, 3H), 7.38e7.33
(400 MHz, CDCl3)
d
7.46 (d, J¼2.0 Hz, 1H), 7.36e7.31 (m, 2H), 7.28
(m, 2H), 7.23 (dd, J¼8.4, 24 Hz, 1H), 7.05 (d, J¼8.0 Hz, 1H), 6.38 (d,
(dd, J¼7.6, 1.6 Hz, 1H), 7.16 (dd, J¼8.4, 2.0 Hz, 1H), 7.04 (br dd, J¼8.0,
J¼3.2 Hz, 1H), 6.34 (dd, J¼3.6, 2.0 Hz, 1H), 5.16 (s, 2H), 4.68 (s, 2H);
8.0 Hz, 2H), 6.99 (d, J¼8.0 Hz, 1H), 6.35e6.32 (m, 2H), 5.11 (s, 2H),
13C NMR (100 MHz, CDCl3)
d
164.3, 149.5, 144.6, 142.3, 140.3, 136.1,
4.68 (s, 2H), 3.80 (s, 3H); 13C NMR (100 MHz, CDCl3)
d 164.34, 156.1,
128.9 (ꢂ3), 127.3, 126.8 (ꢂ2), 122.7, 117.2, 114.2, 110.6, 108.9, 67.7,
38.2; MS (þESI) m/z 328 (MþNaþ, 100). Anal. Calcd for C19H15NO3:
C, 74.74; H, 4.95; N, 4.59. Found: C, 74.75; H, 4.94; N, 4.71%.
149.5, 144.0, 142.0, 133.0, 130.4, 129.4, 128.6, 128.0, 125.0, 120.8,
116.7, 116.4, 111.0, 110.4, 108.6, 67.6, 55.3, 38.2; MS (þESI) m/z 358
(MþNaþ, 100). Anal. Calcd for C20H17NO4: C, 71.63; H, 5.11; N, 4.18.
Found: C, 71.65; H, 5.12; N, 4.18%.
4.4.2. 3,4-Dihydro-2-ethyl-4-(20-furylmethyl)-3-oxo-6-phenyl-2H-
1,4-benzoxazine (27b). Yield 91%; a yellow oil; Rf¼0.59 (20%
EtOAcehexane); IR (film): 2972, 2930, 1683, 1487, 1433, 1273, 1215,
4.4.7. 3,4-Dihydro-2-ethyl-4-(20-furylmethyl)-6-(20-methox-
yphenyl)-3-oxo-2H-1,4-benzoxazine (28b). Yield 80%; a yellow oil;
Rf¼0.49 (20% EtOAcehexane); IR (film): 2972, 2930, 1688, 1488,
1149 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d 7.54e7.50 (m, 2H),
7.46e7.40 (m, 3H), 7.38e7.32 (m, 2H), 7.23 (dd, J¼8.4, 1.6 Hz, 1H),
7.06 (d, J¼8.0 Hz, 1H), 6.34 (s, 2H), 5.18 and 5.12 (ABq, J¼16.4 Hz,
2H), 4.55 (dd, J¼8.4, 4.8 Hz, 1H), 2.01e1.89 (m, 2H), 1.11 (t, J¼7.6 Hz,
1430, 1372, 1249, 1027 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d 7.40 (d,
J¼1.6 Hz, 1H), 7.34 (d, J¼1.6 Hz, 1H), 7.32e7.27 (m, 2H), 7.16 (dd,
J¼8.8, 2.0 Hz, 1H), 7.05e7.01 (m, 2H), 6.98 (d, J¼8.0 Hz, 1H),
6.33e6.29 (m, 2H), 5.13 and 5.07 (ABq, J¼16.4 Hz, 2H), 4.55 (dd,
J¼8.8, 5.2 Hz, 1H), 3.80 (s, 3H), 1.99e1.92 (m, 2H), 1.10 (t, J¼7.2 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d 166.2, 149.8, 143.5, 142.2, 140.5,
135.8, 129.0, 128.8 (ꢂ2), 127.2, 126.8 (ꢂ2), 122.7, 117.5, 113.9, 110.6,
108.6, 78.3, 38.5, 23.7, 9.4; MS (þESI) m/z 356 (MþNaþ, 100), 334
(MþHþ, 32). HRMS (þESI) calcd for C21H19NO3Na 356.1257
(MþNaþ), found 356.1260.
3H); 13C NMR (100 MHz, CDCl3)
d 166.3, 156.3, 149.9, 143.1, 142.0,
132.8, 130.6, 129.7, 128.6, 128.2, 125.1, 120.9, 116.8, 116.4, 111.2, 110.5,
108.3, 78.3, 55.5, 38.6, 23.7, 9.4; MS (þESI) m/z 386 (MþNaþ, 100).
HRMS (þESI) calcd for C22H21NO4Na 386.1363 (MþNaþ), found
386.1351.
4.4.3. 4-Benzyl-3,4-dihydro-3-oxo-6-phenyl-2-propyl-2H-1,4-
benzoxazine (27c). Yield 95%; a white solid; mp 99e101 ꢀC
(EtOAcehexane); Rf¼0.68 (20% EtOAcehexane); IR (KBr): 2958,
2928, 1691, 1486, 1430, 1375, 1268 cmꢃ1; 1H NMR (400 MHz, CDCl3)
4.4.8. 4-Benzyl-3,4-dihydro-6-(20-methoxyphenyl)-3-oxo-2-propyl-
2H-1,4-benzoxazine (28c). Yield 97%; a white solid; mp 72e74 ꢀC
(EtOAcehexane); Rf¼0.63 (20% EtOAcehexane); IR (KBr): 2955,
2926, 1678, 1482, 1428, 1257, 1033 cmꢃ1; 1H NMR (400 MHz, CDCl3)
d
7.32e7.175 (m, 10H), 7.11 (dd, J¼8.4, 2.0 Hz, 1H), 7.01 (d, J¼2.0 Hz,
1H), 6.97 (d, J¼8.0 Hz, 1H), 5.22 and 5.03 (ABq, J¼16.4 Hz, 2H), 4.65
(t, J¼6.8 Hz, 1H), 1.90e1.84 (m, 2H), 1.63e1.48 (m, 2H), 0.94 (t,
d
7.37e7.25 (m, 6H), 7.20e7.13 (m, 3H), 7.05 (d, J¼8.0 Hz, 1H), 6.99
J¼7.6 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
166.7,143.4,140.4,136.2,
(ddd, J¼7.6, 7.6, 1.2 Hz, 1H), 6.92 (dd, J¼8.0, 0.8 Hz, 1H), 5.28 and
5.06 (ABq, J¼16.0 Hz, 2H), 4.74 (dd, J¼8.0, 5.6 Hz, 1H), 3.62 (s, 3H),
2.01e1.95 (m, 2H),1.75e1.55 (m, 2H),1.03 (t, J¼7.6 Hz, 3H); 13C NMR
135.8, 129.1, 128.9 (ꢂ2), 128.8 (ꢂ2), 127.5, 127.1, 126.7 (ꢂ2), 126.6
(ꢂ2), 122.6, 117.6, 114.2, 77.0, 45.1, 32.3, 18.3, 13.6; MS (þESI) m/z
380 (MþNaþ, 100). Anal. Calcd for C24H23NO2: C, 80.64; H, 6.49; N,
3.92. Found: C, 80.64; H, 6.46; N, 3.96%.
(100 MHz, CDCl3)
d 166.8, 156.1, 142.9, 136.3, 132.6, 130.4, 129.4,
128.7 (ꢂ2), 128.5, 128.2, 127.2, 126.5 (ꢂ2), 124.9, 120.8, 116.9, 116.8,
111.0, 77.0, 55.2, 45.1, 32.3, 18.3, 13.6; MS (þESI) m/z 410 (MþNaþ,
100). Anal. Calcd for C25H25NO3: C, 77.49; H, 6.50; N, 3.61. Found: C,
77.50; H, 6.56; N, 3.99%.
4.4.4. 3,4-Dihydro-4-(40-methoxybenzyl)-3-oxo-6-phenyl-2-propyl-
2H-1,4-benzoxazine (27d). Yield 94%; a white solid; mp 121e122 ꢀC
(EtOAcehexane); Rf¼0.60 (20% EtOAcehexane); IR (KBr): 2960,
2930, 1686, 1490, 1436, 1249, 1037 cmꢃ1; 1H NMR (400 MHz, CDCl3)
4.4.9. 3,4-Dihydro-4-(40-methoxybenzyl)-6-(20-methoxyphenyl)-3-
oxo-2-propyl-2H-1,4-benzoxazine (28d). Yield 91%; a white solid;
mp 119e120 ꢀC (EtOAcehexane); Rf¼0.51 (20% EtOAcehexane); IR
(KBr): 2957, 2936, 1684, 1490, 1435, 1246, 1173, 1027 cmꢃ1; 1H NMR
d
7.43e7.38 (m, 4H), 7.35e7.30 (m, 1H), 7.25e7.22 (m, 2H), 7.19 (dd,
J¼8.4, 2.0 Hz, 1H), 7.14 (d, J¼1.6 Hz, 1H), 7.05 (d, J¼8.4 Hz, 1H),
6.90e6.86 (m, 2H), 5.24 and 5.05 (ABq, J¼15.6 Hz, 2H), 4.72 (t,

10494
G. Yu et al. / Tetrahedron 69 (2013) 10488e10496
(400 MHz, CDCl3)
d
7.29 (ddd, J¼8.0, 8.0, 1.6 Hz, 1H), 7.22e7.18 (m,
IR (KBr): 2960, 2932, 1679, 1511, 1373, 1249, 1176, 1033 cmꢃ1
;
1H
4H), 7.12 (dd, J¼8.0, 1.6 Hz, 1H), 7.02 (d, J¼8.8 Hz, 1H), 6.99 (dd,
J¼7.6 Hz, 1H), 6.93 (d, J¼7.6 Hz, 1H), 6.86 (d, J¼9.2 Hz, 2H), 5.18 and
4.98 (ABq, J¼16.0 Hz, 2H), 4.69 (dd, J¼7.6, 6.0 Hz, 1H), 3.78 (s, 3H),
3.67 (s, 3H), 1.97e1.90 (m, 2H), 1.71e1.50 (m, 2H), 1.00 (t, J¼7.2 Hz,
NMR (400 MHz, CDCl3)
d
7.27e7.10 (m, 6H), 7.04 (d, J¼8.0 Hz, 1H),
6.93 (dd, J¼8.4, 2.0 Hz, 1H), 6.88e6.85 (m, 3H), 5.18 and 5.05 (ABq,
J¼16.0 Hz, 2H), 4.74 (t, J¼6.8 Hz, 1H), 3.79 (s, 3H), 2.08 (s, 3H),
2.01e1.95 (m, 2H), 1.71e1.58 (m, 2H), 1.05 (t, J¼7.6 Hz, 3H); 13C NMR
3H); 13C NMR (100 MHz, CDCl3)
d
166.7, 158.7, 156.1, 142.9, 132.6,
(100 MHz, CDCl3) d 166.7, 158.8, 142.9, 140.9, 136.1, 135.3, 130.3,
130.5,129.5,128.5,128.4,128.2,128.0 (ꢂ2), 124.9, 120.8,116.9,116.8,
114.1 (ꢂ2), 111.0, 77.0, 55.3, 55.2, 44.5, 32.3, 18.3, 13.6; MS (þESI) m/
z 440 (MþNaþ, 73), 418 (MþHþ, 100). Anal. Calcd for C26H27NO4: C,
74.80; H, 6.52; N, 3.35. Found: C, 74.98; H, 6.54; N, 3.59%.
129.6, 128.1, 128.0, 127.7 (ꢂ2), 127.2, 125.7, 124.6, 116.9, 116.4, 114.2
(ꢂ2), 76.9, 55.2, 44.3, 32.3, 20.1, 18.3, 13.6; MS (þESI) m/z 424
(MþNaþ, 22); 402 (MþHþ, 100). Anal. Calcd for C26H27NO3: C, 77.78;
H, 6.78; N, 3.49. Found: C, 77.75; H, 6.76; N, 3.76%.
4.4.10. 3,4-Dihydro-6-(20-methoxyphenyl)-3-oxo-2-propyl-4-(30-
pyridinylmethyl)-2H-1,4-benzoxazine (28e). Yield 93%; a yellow oil;
Rf¼0.20 (50% EtOAcehexane); IR (film): 2961, 2934, 1679, 1486,
1429, 1373, 1263, 1246, 1123, 1027 cmꢃ1; 1H NMR (400 MHz, CDCl3)
4.4.15. 3,4-Dihydro-3-oxo-2-propyl-4-(30-pyridinylmethyl)-6-(20-
tolyl)-2H-1,4-benzoxazine (29e). Yield 99%; a yellow oil; Rf¼0.38
(50% EtOAcehexane); IR (film): 2961, 2932, 1683, 1484, 1436,
1376, 1263, 1026 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d 8.55 (s, 1H),
d
8.62 (d, J¼1.6 Hz, 1H), 8.52 (d, J¼3.6 Hz, 1H), 7.60 (d, J¼7.6 Hz, 1H),
8.51 (d, J¼4.4 Hz, 1H), 7.55 (d, J¼8.4 Hz, 1H), 7.30e7.15 (m, 4H),
7.09 (d, J¼6.4 Hz, 1H), 7.05 (d, J¼8.0 Hz, 1H), 6.93 (dd, J¼7.6,
1.6 Hz, 1H), 6.77 (d, J¼1.6 Hz, 1H), 5.23 and 5.10 (ABq, J¼16.4 Hz,
2H), 4.73 (t, J¼6.8 Hz, 1H), 2.04 (s, 3H), 1.96 (td, J¼7.6, 6.8 Hz, 2H),
1.73e1.54 (m, 2H), 1.02 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
7.30e7.23 (m, 2H), 7.19 (dd, J¼7.6, 1.6 Hz, 1H), 7.15 (d, J¼1.6 Hz, 1H),
7.13 (dd, J¼8.4, 1.6 Hz, 1H), 7.04 (d, J¼8.4 Hz, 1H), 6.98 (dd, J¼7.6,
7.6 Hz, 1H), 6.92 (d, J¼8.8 Hz, 1H), 5.24 and 5.06 (ABq, J¼16.0 Hz,
2H), 4.71 (dd, J¼7.6, 6.0 Hz, 1H), 3.65 (s, 3H), 1.97e1.90 (m, 2H),
1.73e1.52 (m, 2H), 1.00 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
CDCl3)
d 166.7, 148.8, 148.1, 142.8, 140.5, 136.2, 135.1, 134.3, 131.6,
d
166.7, 155.9, 148.7, 148.4, 142.7, 134.5, 132.7, 132.0, 130.2, 129.0,
130.3, 129.4, 127.6, 127.3, 125.7, 124.9, 123.6, 117.1, 115.8, 76.8, 42.4,
128.6, 127.5, 125.0, 123.5, 120.7, 117.1, 116.2, 110.9, 76.7, 55.1, 42.4,
32.1, 18.1, 13.5; MS (þESI) m/z 389 (MþHþ, 100). HRMS (þESI) calcd
for C24H24N2O3Na 411.1679 (MþNaþ), found 411.1663.
32.2, 20.1, 18.2, 13.5; MS (þESI) m/z 373 (MþHþ, 100). HRMS
(þESI) calcd for
C
24H24N2O2Na 395.1730 (MþNaþ), found
395.1720.
4.4.11. 3,4-Dihydro-4-(20-furylmethyl)-3-oxo-6-(20-tolyl)-2H-1,4-
4.4.16. 4-(Biphenyl-20-ylmethyl)-3,4-dihydro-2,7-dimethyl-3-oxo-
benzoxazine (29a). Yield 94%;
EtOAcehexane); IR (film): 2954, 2926, 1694, 1486, 1439, 1373, 1277,
1229, 1146, 1058 cmꢃ1; 1H NMR (400 MHz, CDCl3)
a
yellow oil; Rf¼0.52 (20%
2H-1,4-benzoxazine (30a). Yield 94%;
a
white solid; mp:
118e119 ꢀC (EtOAcehexane); Rf¼0.64 (10% EtOAcehexane); IR
d
7.34 (dd, J¼1.6,
(KBr): 1684, 1512, 1402, 1292, 1151, 1065, 1005 cmꢃ1 1H NMR
;
(400 MHz, CDCl3) d 7.52e7.40 (m, 5H), 7.35e7.26 (m, 3H), 7.15 (d,
1.6 Hz, 1H), 7.30e7.19 (m, 5H), 7.04 (d, J¼8.0 Hz, 1H), 6.97 (dd, J¼8.4,
2.0 Hz, 1H), 6.33 (d, J¼1.6 Hz, 2H), 5.11 (s, 2H), 4.70 (s, 2H), 2.25 (s,
J¼6.8 Hz, 1H), 6.80 (s, 1H), 6.62 (d, J¼8.0 Hz, 1H), 6.38 (d, J¼8.4 Hz,
3H); 13C NMR (100 MHz, CDCl3)
d 164.3, 149.4, 144.0, 142.1, 140.9,
1H), 5.12 and 5.06 (ABq, J¼16.4 Hz, 2H), 4.73 (q, J¼6.4 Hz, 1H), 2.24
136.6,135.4,130.4,129.7,128.1,127.4,125.9,124.8, 116.6,116.4,110.6,
108.7, 67.6, 38.2, 20.4; MS (þESI) m/z 342 (MþNaþ, 100). HRMS
(þESI) calcd for C20H17NO3Na 342.1101 (MþNaþ), found 342.1088.
(s, 3H), 1.62 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.9,
144.2, 141.0, 140.4, 133.8, 133.2, 130.1, 129.1 (ꢂ2), 128.5 (ꢂ2), 127.9,
127.5, 127.1, 126.1, 125.7, 122.9, 117.7, 115.2, 73.5, 43.3, 20.6, 16.4; MS
(þEI) m/z 167 ð2-PhC6H2CH2þ; 100Þ; 343 (Mþ, 69). Anal. Calcd for
4.4.12. 3,4-Dihydro-2-ethyl-4-(20-furylmethyl)-3-oxo-6-(20-tolyl)-
2H-1,4-benzoxazine (29b). Yield 93%; a yellow oil; Rf¼0.59 (20%
EtOAcehexane); IR (film): 2964, 2935, 1693, 1482, 1428, 1366, 1257,
C23H21NO2: C, 80.44; H, 6.16; N, 4.08. Found: C, 80.38; H, 6.14; N,
4.05%.
1145, 1033 cmꢃ1; 1H NMR (500 MHz, CDCl3)
d
7.32 (s, 1H), 7.27e7.17
4.4.17. 4-(Biphenyl-20-ylmethyl)-2-ethyl-3,4-dihydro-7-methyl-3-
oxo-2H-1,4-benzoxazine (30b). Yield 91%; a white solid; mp:
94e95 ꢀC (EtOAcehexane); Rf¼0.57 (10% EtOAcehexane); IR
(m, 4H), 7.14 (s, 1H), 7.04 (d, J¼7.5 Hz, 1H), 6.95 (d, J¼8.0 Hz, 1H),
6.30 (d, J¼1.5 Hz, 1H), 6.28 (d, J¼2.5 Hz, 1H), 5.09 (s, 2H), 4.56 (dd,
J¼8.0, 4.5 Hz, 1H), 2.24 (s, 3H), 2.01e1.92 (m, 2H), 1.12 (t, J¼7.5 Hz,
(KBr): 2956, 1686, 1512, 1406, 1329, 1263, 1146, 1047 cmꢃ1 1H
;
3H); 13C NMR (100 MHz, CDCl3)
d
166.2, 149.6, 143.0, 142.0, 141.0,
NMR (400 MHz, CDCl3) d 7.52e7.40 (m, 5H), 7.35e7.26 (m, 3H),
136.2, 135.3, 130.4, 129.7, 128.2, 127.3, 125.8, 124.7, 116.8, 116.0,
110.5, 108.3, 78.2, 38.4, 23.7, 20.4, 9.4; MS (þESI) m/z 370 (MþNaþ,
100). HRMS (þESI) calcd for C22H21NO3Na 370.1414 (MþNaþ),
found 370.1404.
7.14 (d, J¼7.2 Hz, 1H), 6.81 (s, 1H), 6.61 (d, J¼8.0 Hz, 1H), 6.36 (d,
J¼8.4 Hz, 1H), 5.13 and 5.05 (ABq, J¼16.4 Hz, 2H), 4.58 (dd, J¼8.4,
4.8 Hz, 1H), 2.24 (s, 3H), 2.02e1.93 (m, 2H), 1.14 (t, J¼7.6 Hz, 3H);
13C NMR (100 MHz, CDCl3)
d 166.5, 143.8, 141.0, 140.4, 133.8,
133.2, 130.1, 129.1 (ꢂ2), 128.5 (ꢂ2), 127.9, 127.5, 127.1, 126.0,
125.6, 122.8, 117.7, 115.1, 78.3, 43.1, 23.8, 20.6, 9.5; MS (þEI) m/z
167 ð2-PhC6H2CH2þ; 100Þ; 357 (Mþ, 82). Anal. Calcd for
4.4.13. 4-Benzyl-3,4-dihydro-3-oxo-2-propyl-6-(20-tolyl)-2H-1,4-
benzoxazine (29c). Yield 96%;
a
white solid; mp 81e82 ꢀC
(EtOAcehexane); Rf¼0.74 (20% EtOAcehexane); IR (KBr): 2955,
C24H23NO2: C, 80.64; H, 6.49; N, 3.92. Found: C, 80.68; H, 6.41; N,
2926, 1682, 1436, 1378, 1270, 1120 cmꢃ1; 1H NMR (400 MHz, CDCl3)
3.99%.
d
7.37e7.20 (m, 8H), 7.18e7.04 (m, 2H), 6.98e6.93 (m, 1H),
6.90e6.82 (m, 1H), 5.27 and 5.13 (ABq, J¼16.4 Hz, 2H), 4.82e4.75
4.4.18. 4-(Biphenyl-20-ylmethyl)-3,4-dihydro-7-methyl-3-oxo-2-
propyl-2H-1,4-benzoxazine (30c). Yield 91%; a white solid; mp:
113e114 ꢀC (EtOAcehexane); Rf¼0.71 (10% EtOAcehexane); IR
(m, 1H), 2.05e2.01 (m, 5H), 1.78e1.62 (m, 2H), 1.05e1.05 (m, 3H);
13C NMR (100 MHz, CDCl3)
d 166.7, 142.8, 140.8, 136.1, 135.9, 135.2,
130.3, 129.6, 128.8 (ꢂ2), 128.1, 127.3, 127.2, 126.3 (ꢂ2), 125.7, 124.6,
116.9, 116.4, 76.9, 44.8, 32.3, 20.0, 18.3, 13.6; MS (þESI) m/z 394
(MþNaþ, 20), 372 (MþHþ,100). Anal. Calcd for C25H25NO2: C, 80.83;
H, 6.78; N, 3.77. Found: C, 80.84; H, 6.78; N, 3.81%.
(KBr): 2967, 1686, 1512, 1405, 1293, 1146, 1071 cmꢃ1 1H NMR
;
(400 MHz, CDCl3)
d 7.51e7.39 (m, 5H), 7.35e7.25 (m, 3H), 7.13 (d,
J¼7.2 Hz, 1H), 6.79 (s, 1H), 6.61 (d, J¼8.0 Hz, 1H), 6.35 (d, J¼8.0 Hz,
1H), 5.12 and 5.03 (ABq, J¼16.4 Hz, 2H), 4.66 (t, J¼6.8 Hz, 1H), 2.24
(s, 3H), 1.90 (dt, J¼7.2 Hz, 2H), 1.75e1.50 (m, 2H), 1.01 (t, J¼7.2 Hz,
4.4.14. 3,4-Dihydro-4-(40-methoxybenzyl)-3-oxo-2-propyl-6-(20-
tolyl)-2H-1,4-benzoxazine (29d). Yield 98%; a white crystalline
solid; mp 68e70 ꢀC (EtOAcehexane); Rf¼0.64 (20% EtOAcehexane);
3H); 13C NMR (100 MHz, CDCl3)
d 166.7, 143.7, 141.0, 140.4, 133.8,
133.2, 130.1, 129.1 (ꢂ2), 128.5 (ꢂ2), 127.9, 127.5, 127.1, 126.0, 125.6,
122.8, 117.8, 115.1, 76.9, 43.1, 32.2, 20.6, 18.3, 13.6; MS (þEI) m/z 167

G. Yu et al. / Tetrahedron 69 (2013) 10488e10496
10495
ð2-PhC6H2CH2þ; 100Þ; 371 (Mþ, 98). Anal. Calcd for C25H25NO2: C,
140.3, 135.4, 134.0, 128.7 (ꢂ2), 127.5 (ꢂ2), 127.3, 127.0 (ꢂ2), 126.9
(ꢂ2), 126.4, 122.9, 117.9, 115.1, 78.4, 44.8, 23.8, 20.7, 9.5; MS (þEI) m/
80.83; H, 6.78; N, 3.77. Found: C, 80.81; H, 6.74; N, 3.75%.
z
167 ð4-PhC6H2CH2þ; 100Þ; 357 (Mþ, 32). Anal. Calcd for
4.4.19. 4-(Biphenyl-30-ylmethyl)-3,4-dihydro-2,7-dimethyl-3-oxo-
2H-1,4-benzoxazine (31a). Yield 87%; a colorless oil; Rf¼0.43 (10%
EtOAcehexane); IR (KBr): 3033, 2938, 1682, 1513, 1398, 1292, 1157,
C24H23NO2: C, 80.64; H, 6.49; N, 3.92. Found: C, 80.78; H, 6.48; N,
4.00%.
1109, 1012 cmꢃ1
;
1H NMR (400 MHz, CDCl3)
d
7.60e7.57 (m, 2H),
4.4.24. 4-(Biphenyl-40-ylmethyl)-3,4-dihydro-7-methyl-3-oxo-2-
propyl-2H-1,4-benzoxazine (32c). Yield 94%; a white solid; mp
92e93 ꢀC (EtOAcehexane); Rf¼0.50 (10% EtOAcehexane); IR (KBr):
7.52e7.35 (m, 6H), 7.25 (d, J¼7.6 Hz, 1H), 6.86 (d, J¼2.0 Hz, 1H), 6.83
(d, J¼8.0 Hz, 1H), 6.74 (dd, J¼8.4, 1.2 Hz, 1H), 5.24 and 5.19 (ABq,
J¼16.4 Hz, 2H), 4.79 (q, J¼6.8 Hz, 1H), 2.29 (s, 3H), 1.68 (d, J¼7.2 Hz,
2952, 1675, 1512, 1401, 1284, 1149, 1068 cmꢃ1 1H NMR (400 MHz,
;
3H); 13C NMR (100 MHz, CDCl3)
d
166.9, 144.2, 141.8, 140.8, 136.9,
CDCl3)
d
7.60e7.55 (m, 4H), 7.44 (dd, J¼7.6, 7.6 Hz, 2H), 7.38e7.32
134.0, 129.3, 128.8 (ꢂ2), 127.4, 127.2 (ꢂ2), 126.5, 126.3, 125.4, 125.3,
123.1, 117.9, 115.2, 73.6, 45.3, 20.7, 16.5; MS (þEI) m/z 167
ð3-PhC6H2CH2þ; 100Þ; 343 (Mþ, 90); HRMS (þESI) calcd for
(m, 3H), 6.86 (s, 1H), 6.81 (d, J¼8.0 Hz, 1H), 6.74 (d, J¼8.0 Hz, 1H),
5.28 and 5.10 (ABq, J¼16.0 Hz, 2H), 4.72 (t, J¼6.0 Hz, 1H), 2.29 (s,
3H), 1.96 (dt, J¼6.0, 6.0, 2H), 1.73e1.58 (m, 2H), 1.04 (t, J¼7.2 Hz,
C
23H21NNaO2 366.1465 (MþNaþ), found 366.1457.
3H); 13C NMR (100 MHz, CDCl3)
d 166.6, 143.8, 140.6, 140.3, 135.4,
134.0, 128.7 (ꢂ2), 127.5 (ꢂ2), 127.3, 127.0 (ꢂ2), 126.9, 126.3, 122.9,
118.0, 115.1, 77.0, 44.8, 32.3, 20.7, 18.4, 13.7; MS (þEI) m/z 167
ð4-PhC6H2CH2þ; 100Þ; 371 (Mþ, 30); Anal. Calcd for C25H25NO2: C,
80.83; H, 6.78; N, 3.77. Found: C, 80.83; H, 6.86; N, 3.77%.
4.4.20. 4-(Biphenyl-30-ylmethyl)-2-ethyl-3,4-dihydro-7-methyl-3-
oxo-2H-1,4-benzoxazine (31b). Yield 92%; a colorless oil; Rf¼0.50
(10% EtOAcehexane); IR (KBr): 2970, 2933, 1682, 1513, 1399, 1294,
1148, 1044 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d 7.59e7.56 (m, 2H),
7.52e7.35 (m, 6H), 7.24 (d, J¼8.0 Hz, 1H), 6.87 (d, J¼1.2 Hz, 1H), 6.80
(d, J¼8.4 Hz, 1H), 6.72 (dd, J¼8.0, 1.6 Hz, 1H), 5.32 and 5.11 (ABq,
J¼16.0 Hz, 2H), 4.64 (dd, J¼8.8, 5.2 Hz, 1H), 2.28 (s, 3H), 2.06e1.98
Acknowledgements
The Laboratory of Asymmetric Catalysis and Synthesis is
established under the Cheung Kong Scholars Program of The Min-
istry of Education of China.
(m, 2H), 1.17 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 166.4,
143.7, 141.7, 140.7, 136.8, 133.9, 129.2, 128.7 (ꢂ2), 127.3, 127.0 (ꢂ2),
126.2, 126.1, 125.2, 125.2, 122.9, 117.8, 115.0, 78.3, 45.0, 23.7, 20.6,
9.5; MS (þEI) m/z 167 ð3-PhC6H2CH2þ; 100Þ; 357 (Mþ, 93); HRMS
(þESI) calcd for C24H23NNaO2 380.1621 (MþNaþ), found 380.1615.
Supplementary data
1H and 13C NMR spectra for compounds 18aec, 20aei, 27aee,
28aee, 29aee, 30aec, 31aec, and 32aec are available. Supple-
mentary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2013.09.057.
4.4.21. 4-(Biphenyl-30-ylmethyl)-3,4-dihydro-7-methyl-3-oxo-2-
propyl-2H-1,4-benzoxazine (31c). Yield 86%; a colorless oil; Rf¼0.63
(10% EtOAcehexane); IR (KBr): 2961, 1682, 1513, 1398, 1292, 1148,
1030 cmꢃ1 1H NMR (400 MHz, CDCl3)
; d 7.58e7.55 (m, 2H),
7.51e7.34 (m, 6H), 7.23 (d, J¼7.6 Hz, 1H), 6.85 (d, J¼1.2 Hz, 1H), 6.79
(d, J¼8.0 Hz, 1H), 6.71 (dd, J¼8.4, 1.2 Hz, 1H), 5.34 and 5.08 (ABq,
J¼16.0 Hz, 2H), 4.72 (t, J¼6.8 Hz, 1H), 2.28 (s, 3H), 1.95 (dt, J¼7.2,
7.2 Hz, 2H), 1.70e1.58 (m, 2H), 1.03 (t, J¼7.2 Hz, 3H); 13C NMR
References and notes
1. For the structure of benzoxacystol, see Nachtigall, J.; Schneider, K.; Bruntner, C.;
Bull, A. T.; Goodfellow, M.; Zinecher, H.; Imhoff, J. F.; Nicholson, G.; Irran, E.;
(100 MHz, CDCl3)
d 166.6, 143.7, 141.8, 140.8, 136.9, 134.0, 129.3,
€
Sussmuth, R. D.; Firdler, H.-P. J. Antibiot. 2011, 64, 453e457.
128.8 (ꢂ2), 127.4, 127.1 (ꢂ2), 126.3, 126.2, 125.3, 125.2, 123.0, 118.0,
115.1, 77.0, 45.1, 32.4, 20.7, 18.4, 13.7; MS (þEI) m/z 167
ð3-PhC6H2CH2þ; 100Þ; 371 (Mþ, 75). HRMS (þESI) calcd for
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25H25NNaO2 394.1778 (MþNaþ), found 394.1789.
4.4.22. 4-(Biphenyl-40-ylmethyl)-3,4-dihydro-2,7-dimethyl-3-oxo-
2H-1,4-benzoxazine (32a). Yield 98%; a white solid; mp 131e132 ꢀC
(EtOAcehexane); Rf¼0.39 (10% EtOAcehexane); IR (KBr): 1673,
1513, 1402, 1295, 1161, 1110 cmꢃ1 1H NMR (400 MHz, CDCl3)
;
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d
7.58e7.55 (m, 4H), 7.44 (dd, J¼7.6, 7.6 Hz, 2H), 7.34 (t, J¼7.6 Hz,
1H), 7.33 (d, J¼7.6 Hz, 2H), 6.85 (s, 1H), 6.81 (d, J¼8.0 Hz, 1H), 6.74
(d, J¼8.0 Hz, 1H), 5.21 and 5.15 (ABq, J¼16.0 Hz, 2H), 4.77 (q,
J¼6.8 Hz, 1H), 2.28 (s, 3H), 1.66 (d, J¼6.8 Hz, 3H); 13C NMR
(100 MHz, CDCl3)
d 166.9, 144.3, 140.6, 140.3, 135.3, 134.0, 128.7
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ꢀ
ꢀ
(ꢂ2), 127.5 (ꢂ2), 127.3, 127.0 (ꢂ2), 127.0 (ꢂ2), 126.5, 123.1, 117.8,
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115.2,
73.6,
44.9,
20.7, 16.4;
MS (þEI)
m/z
167
ð4-PhC6H2CH2þ; 100Þ; 343 (Mþ, 33). Anal. Calcd for C23H21NO2: C,
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4.4.23. 4-(Biphenyl-40-ylmethyl)-2-ethyl-3,4-dihydro-7-methyl-3-
oxo-2H-1,4-benzoxazine (32b). Yield 97%;
a white solid; mp
99e100 ꢀC (EtOAcehexane); Rf¼0.44 (10% EtOAcehexane); IR
(KBr): 2973, 2936, 1677, 1513, 1403, 1294, 1149, 1047, 1023 cmꢃ1; 1H
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d
7.58e7.54 (m, 4H), 7.43 (dd, J¼7.6, 7.6 Hz,
ꢀ
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(dd, J¼8.8, 4.8 Hz, 1H), 2.28 (s, 3H), 2.07e1.93 (m, 2H), 1.16 (t,
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