Concise synthesis of 3,4-dihydro-1,4-benzoxazines by three-component reactions of acyl chlorides, o-aminophenols and 1,2-dichloroethane

Article abstract of DOI:10.1016/j.tet.2018.05.037

The Cu(OAc)₂-catalyzed three-component reactions of o-aminophenols, acyl chlorides and 1,2-dichloroethane (DCE) have been established for the efficient synthesis of 3,4-dihydro-2H-benzo[b][1,4]oxazines (3,4-dihydro-1,4-benzoxazines). This metho

Full text of DOI:10.1016/j.tet.2018.05.037

Accepted Manuscript
Concise synthesis of 3,4-dihydro-1,4-benzoxazines by three-component reactions of
acyl chorides, o-aminophenols and 1,2-dichloroethane
Yunyun Liu, Xuwen Chen
PII:
S0040-4020(18)30570-2
10.1016/j.tet.2018.05.037
TET 29544
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 21 March 2018
Revised Date: 3 May 2018
Accepted Date: 14 May 2018
Please cite this article as: Liu Y, Chen X, Concise synthesis of 3,4-dihydro-1,4-benzoxazines by three-
component reactions of acyl chorides, o-aminophenols and 1,2-dichloroethane, Tetrahedron (2018), doi:
10.1016/j.tet.2018.05.037.
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Concise synthesis of 3,4-dihydro-1,4-
benzoxazines by three-component reactions
of acyl chorides, o-aminophenols and 1,2-
dichloroethane
Leave this area blank for abstract info.
Yunyun Liu,* Xuwen Chen
College of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P.R. China

1
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Tetrahedron
journal homepage: www.elsevier.com
Concise synthesis of 3,4-dihydro-1,4-benzoxazines by three-component reactions of
acyl chorides, o-aminophenols and 1,2-dichloroethane
Yunyun Liua,* and Xuwen Chena
aCollege of Chemistry and Chemical Engineering, Jiangxi Normal University, Nanchang 330022, P.R. China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The Cu(OAc)2-catalyzed three-component reactions of o-aminophenols, acyl chlorides and 1,2-
dichloroethane (DCE) have been established for the efficient synthesis of 3,4-dihydro-2H-
benzo[b][1,4]oxazines (3,4-dihydro-1,4-benzoxazines). This method features advantages of the
one-pot operation enabling N-acylation, C-Cl bond amidation and etherification, as well as the
structural divergence of the synthesized products.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
Keyword_1 Three-component
Keyword_2 Copper catalysis
Keyword_3 Selective
Keyword_4 3,4-Dihydro-1,4-benzoxazine
Keyword_5 o-Chloroalkoxyl N-acyl aniline
frequently used methods in 3,4-dihydro-1,4-benzoxazine ring
construction are the annulation using o-aminophenol or its
derivatives to incorporate different electrophilic partners such as
vicinal dihaloalkanes,12 imines,13 vinyl selenones,14 α-
haloketones,15 α-haloesters16 and vinyl bromides.17 In most of
these known methods, the problems of multi-step operation, prior
elaboration on the substrates, utility of noble metal catalyst
and/or harsh reaction conditions remain as challenges. Therefore,
it is yet highly demanding to develop more alternative synthetic
methods which are able to overcome one or more of the present
restrictions to afford 3,4-dihydro-1,4-benzoxazines. Herein, we
report a three-component approach to synthesize N-acyl 3,4-
dihydro-1,4-benzoxazines by the copper-catalyzed reactions of o-
aminophenols, acyl chlorides and 1,2-dichloroethane (DCE). To
our best knowledge, the known method for N-acyl 3,4-dihydro-
1,4-benzoxazine synthesis is the N-acylation of prior prepared
NH-3,4-dihydro-1,4-benzoxazines,18 this is the first example
enabling the synthesis of such products via one-step, three-
component operation, which benefits the advantages of the step
economy and rapid generation of expanded product diversity of
multicomponent reactions.19
1. Introduction
3,4-Dihydro-1,4-benzoxazine is
a motif with prevalent
presence in natural products and biologically functional
molecules.1 For instance, levofloxacin (1) is
a clinical
antiinflammatory drug for various symptoms,2 and
obscurinervidine (2) is an important natural aspidosperma
alkaloid found in A. obscurinervium Azambuja and A. neblinae
Monachino. (Fig. 1).3 Potential utilization of 3,4-dihydro-1,4-
benzoxazines in the treatment of heart disease,4 diabetes,5 and
divergent other biological profiles have also been reported.6
Figure 1 Valuable 3,4-Dihydro-1,4-benzoxazine derivatives
Owing to their known and potential merits, 3,4-dihydro-1,4-
benzoxazines have received long lasting research interest as
target molecules in organic synthesis. Thus, a range of synthetic
tactics toward these heterocyclic scaffolds have been developed
over the past decade.7 For example, the [5+1] type of annulation
using 2-halo-1,3-dicarbonyl compounds and imines,8 the
palladium-catalyzed intramolecular etherification,9 the stepwise
reactions of epoxides with o-haloanilines,10 and the reduction of
2H-benzo[b][1,4]oxazines11 are typical methods of the category.
Regardless these important advances, however, the most
2. Results and discussion
To start the investigation, the reaction of o-aminophenol 3a,
benzoyl chloride 4a and DCE (as solvent) 5 was carried out in
the presence of Cu(OAc)2 and Cs2CO3, which provided the 3,4-
dihydro-1,4-benzoxazine 6a with 43% yield (entry 1, Table 1).
The target product was not practically provided in the absence of
either Cu(OAc)2 or Cs2CO3 (entries 2-3, Table 1), suggesting the
crucial importance of both reagents. Utilization of different
copper salts, such as CuSO4, CuCl2, Cu2O and CuI etc led to no

2
Tetrahedron
identification of better catalyst (entries 4-8, Table 1).
Table 2 Scope on the synthesis of N-acyl 3,4-dihydro-1,4-
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benzoxanesa,b
Subsequently, the impact of catalyst loading (entries 9 and 10,
Table 1), base species (entries 11-14, Table 1) were screened, but
no further improvement on the product yield was achieved. The
higher loading of base additive, on the other hand, turned out to
be helpful in enhancing the yield of 6a (entries 15-16, Table 1).
The reactions conducted at varied external temperature confirmed
o
that 110 C external heating was proper for the reaction (entries
17-18, Table 1). It should be noted that prolonging the reaction to
24 h provided 6a with high yield even without employing copper
catalyst, indication the major role of the Cu(OAc)2 was
accelerating the reaction rate (entry 19, Table 1).
Table 1 Optimization of the reaction conditionsa
Entry
1
Catalyst
Cu(OAc)2
Cu(OAc)2
no
CuSO4
CuCl2
Cu2O
CuI
CuCl
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
no
Base
Cs2CO3
no
Yield (%)b
43
0
trace
35
31
0
12
39
25
42
31
15
27
32
79
52
61
50
79
aReaction conditions: 3 (0.2 mmol), 4 (0.24 mmol), 5 (2 mL),
2
Cu(OAc)2 (0.04 mmol), Cs2CO3 (0.6 mmol), reflux with external
3c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Na2CO3
CH3Ona
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
o
b
heating at of 110 C, 12 h. Yield of isolated product based on 3
4
5
6
7
were reported.
In further study, we observed that simply lowering the
reaction temperature switched the reaction selectivity to provide
acyclic amides 7 by using identical substrates. These reactions
involving simple acyl chloride amidation and Williamson
etherification also tolerated well to aryl, vinyl and alkyl
functionalized acyl chlorides (Table 3).
8
9d
10e
11
12
13
14
15f
16g
17h
18i
19f,j
Table 3 Selective synthesis of N-(o-chloroethoxyphenyl)
amidesa,b
aThe reactions conditions: 3a (0.2 mmol), 4a (0.24 mmol), 5a
(2 mL), catalyst (0.04 mmol), base (0.4 mmol), external heating
b
at 110 °C (reflux) for 12 h; nr = no reaction. Yield of isolated
product based on 3. cThe product of type 7 was produced in 70%
d
e
yield (see Table 3). 0.02 mmol Cu(OAc)2 was used. 0.06 mmol
Cu(OAc)2 was used. f3 equiv. Base was used. g4 equiv. Base was
used. hThe external heating temperature was 100 oC. iThe
o
j
external heating temperature was 120 C. The reaction time was
24 h.
To demonstrate the substrate scope, the reactions employing
various acyl halides 4 as well as different o-aminophenols 3 were
carried out in DCE under the optimized conditions. Generally,
the reactions employing all these different substrates gave
corresponding products with good to excellent yields (Table 2).
The tolerance to functional groups with both electron donating
and withdrawing effect in the acyl chloride component was
indicated. More notably, heteroaryl functionalized acyl chlorides
such as thiophenyl and furyl carbonyl chlorides could also
smoothly take part in the reaction (6g, 6h, 6m and 6n, Table 2).
In addition, the alkenyl-based carbonyl chloride underwent the
three-component process to give enamide 6i with moderate yield.
On the other hand, alkyl functionalized carbonyl chlorides such
as acetyl chloride was not applicable in such synthesis by the
present operation. In addition, when the 1,2-dichloroethane was
used to react with 3a and 4a, complex mixture was observed and
the expect product of type 6 was not obtained.
To examine the potential reactivity of the dichloroalkane with
longer alkyl chain, the 1,3-dichloropropane 8 was utilized to react
with benozyl chloride and o-aminophenol under the standard
conditions employed in Table 2, but only the acyclic product 7e
was obtained (Eq 1).
Successively, to probe the possible intermediate of the
reaction, the compound 7a was heated in the presence of only
Cs2CO3, which provided the annulated product 6a with excellent
yield (Eq 2), supporting that the formation of products 6 involved
in the generation of 7 as intermediate. Moreover, the N-acyl o-
aminophenol 9a was found to provide product 6a with much
lower yield in the absence of copper catalyst, suggesting the
Cu(OAc)2 plays crucial role in accelerating the subsequent
transformation after the formation of 9 (Eq 3).

3
In a 25 mL round bottom flask equipped with stirring bar
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and condenser were charged with o-aminophenol 3 (0.2 mmol),
acyl chloride 4 (0.24 mmol), DCE 5 (2 mL), Cu(OAc)2 (0.04
mmol) and Cs2CO3 (0.6 mmol). The resulting mixture was stirred
at 110 oC external heating (80 oC for the synthesis of 7a-d) at air
atmosphere for 12 h. Upon completion, the reaction mixture was
allowed to cool down to rt, and H2O (10 mL) was added to the
vessel. The resulting suspension was extracted with ethyl acetate
(3 × 10 mL). The organic phases were combined and dried over
Na2SO4. After filtration, the solvent was removed from the
solution under reduced pressure. The acquired residue was then
subjected to silica gel column chromatography to provide pure
product by using mixed petroleum ether/ethyl acetate 10:1 (v/v)
as the eluent.
According to all the reaction results acquired in the
experiments, the reaction mechanism in providing products 6 and
7 is proposed as Scheme 1. The original transformation is the
base promoted N-acylation of o-aminophenol 3 providing amide
9.20 Presumbly, the Cu(II) catalyst may incorporate the hydroxyl
4.2.1. (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-
yl)(phenyl)methanone (6a)
in
9 to generate intermediate 10, which facilitates the
nucleophilic etherification by reacting with the dichloromethane
to form acyclic products 7. The role of the copper(II) catalyst in
enhancing the reaction rate forming 7 is partially supported by
the results in Table 1 (entry 19) and the reaction in Eq 3. As
outlined in Eq 2, higher temperature as well as the promotion of
Cs2CO3 then enable the intramolecular N-alkylation of the amino
group to give products 6.
Light yellow solid; mp 106-108 oC; 1H NMR (400 MHz,
CDCl3): δ 7.50 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 2 H), 7.42 (t, J = 7.2
Hz, 1 H), 7.35 (t, J = 7.2 Hz, 2 H), 6.97 (td, J1 = 7.6 Hz, J2 = 1.2
Hz, 2 H), 6.90 (dd, J1 = 8.2 Hz, J2 = 1.4 Hz, 1 H), 6.65 (t, J = 7.4
Hz, 1 H), 4.34 (t, J = 4.4 Hz, 2 H), 3.98 (t, J = 4.4 Hz, 2 H); 13C
NMR (100 MHz, CDCl3): 168.9, 146.2, 135.3, 130.7, 128.52,
128.47, 126.1, 125.6, 124.5, 119.9, 117.3, 66.4, 42.6; IR (KBr,
cm-1): 3062, 2952, 1642, 1498, 1370, 1268, 1228, 1048, 920;
ESI-HRMS Calcd for C15H14NO2 [M + H]+ 240.1019, found
240.1010.
4.2.2. (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-
yl)(p-tolyl)methanone (6b)
o
1
Yellow solid; mp 77-79 C; H NMR (400 MHz, CDCl3): δ
7.41 (d, J = 8.0 Hz, 2 H), 7.16 (d, J = 8.0 Hz, 2 H), 6.96 (t, J =
7.2 Hz, 2 H), 6.90 (t, J = 4.0 Hz, 1 H), 6.66 (t, J = 7.6 Hz, 1 H),
4.35 (t, J = 4.6 Hz, 2 H), 3.99 (t, J = 4.8 Hz, 2 H), 2.37 (s, 3 H);
13C NMR (100 MHz, CDCl3): 169.0, 146.1, 141.1, 132.3, 129.1,
128.7, 126.3, 125.5, 124.5, 119.9, 117.2, 66.5, 42.7, 21.5; IR
(KBr, cm-1): 3069, 3035, 2970, 1645, 1500, 1369, 1269, 1238,
1048, 924; ESI-HRMS Calcd for C16H16NO2 [M + H]+ 254.1176,
found 254.1175.
Scheme 1. The proposed reaction mechanism
3. Conclusions
In conclusion, we have establihsed a practical new three-
component approach for the synthesis of N-acyl 3,4-dihydro-1,4-
benzoxazines by using o-aminophenol, acyl chloride and DCE.
The reactions enable access to structurally divergent products
with simple catalytic condition and operation. Simple
modification on the reaction temperature enables the switchable
synthesis of N-(o-chloroethoxyphenyl) amides. The present
method is useful for the synthesis of these target products
because of the authentically facile process involved therein.
4.2.3. (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-
yl)(4-fluorophenyl)methanone (6c)
Light yellow solid; mp 112-114 oC; 1H NMR (400 MHz,
CDCl3): δ 7.55-7.51 (m, 2 H), 7.05 (td, J1 = 7.7 Hz, J2 = 1.8 Hz, 2
H), 6.99 (td, J1 = 7.7 Hz, J2 = 1.2 Hz, 1 H), 6.91 (dd, J1= 8.4 Hz,
J2 = 1.6 Hz, 1 H), 6.82 (s, 1 H), 6.66 (t, J = 7.6 Hz, 1 H), 4.39 (t,
J = 4.6 Hz, 2 H), 4.02 (t, J = 4.6 Hz, 2 H); 13C NMR (100 MHz,
CDCl3): 167.7, 164.1 (d, J = 250 Hz), 146.2, 131.2, 131.1 (d, J =
9 Hz), 126.1, 125.8, 124.4, 120.0, 117.4, 115.6 (d, J = 21 Hz),
66.5, 42.3; 19F NMR (375 MHz, CDCl3): δ -107.8 (s); IR (KBr,
cm-1): 3081, 2965, 1709, 1511, 1089, 892; ESI-HRMS Calcd for
C15H13FNO2 [M + H]+ 258.0925, found 258.0923.
4. Experimental section
4.1. General experimental information
4.2.4. (4-Chlorophenyl)(2,3-dihydro-4H-benzo[b]
All chemicals were obtained from commercial sources and
used directly without further purification. Solvents used in the
experiment have been treated following standard procedure
[1,4]oxazin-4-yl)methanone (6d)
o
1
Yellow solid; mp 97-99 C; H NMR (400 MHz, CDCl3): δ
7.45 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 7.00 (td, J1 =
7.7 Hz, J2 = 1.4 Hz, 1 H), 6.92-6.83 (m, 2 H), 6.66 (t, J = 7.4 Hz,
1 H), 4.39 (t, J = 4.6 Hz, 2 H), 4.01 (t, J = 4.6 Hz, 2 H); 13C NMR
(100 MHz, CDCl3): 167.6, 146.2, 136.9, 133.6, 130.2, 128.7,
125.9, 124.4, 120.0, 117.4, 66.5, 42.3; IR (KBr, cm-1): 3071,
2926, 1645, 1494, 1378, 1269, 1232, 1044, 917, 745; ESI-HRMS
Calcd for C15H13ClNO2 [M + H]+ 274.0629, found 274.0627.
1
before use. The H and 13C NMR were recorded in 400 MHz
1
apparatus in CDCl3. The frequency used for measuring H NMR
was 400 MHz, and 100 MHz for 13C NMR, respectively.
Chemical shifts were recorded in ppm by employing TMS as
internal standard. HRMS data were obtained under ESI model,
and the melting points were tested with an X-4A apparatus
without temperature correction.
4.2. General procedure for the synthesis of 3,4-dihydro-1,4-
benzoxazines 6 and products 7
4.2.5. (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-
yl)(m-tolyl)methanone (6e)
o
1
Yellow solid; mp 70-72 C; H NMR (400 MHz, CDCl3): δ
7.35 (s, 1 H), 7.24 (s, 3 H), 7.04-6.96 (m, 2 H), 6.90 (dd, J1 = 8.2

4
Tetrahedron
4.2.11. (4-Chlorophenyl)(6-methyl-2,3-dihydro-4H-
Hz, J2 = 1.4 Hz, 1H), 6.68 (t, J = 7.4 Hz, 1 H), 4.35 (t, J = 4.6
ACCEPTED MANUSCRIPT
Hz, 2 H), 3.98 (t, J = 4.6 Hz, 2 H), 2.35 (s, 3 H); 13C NMR (100
MHz, CDCl3): 169.2, 146.1, 138.5, 135.3, 131.4, 129.0, 128.2,
126.1, 125.6, 125.5, 124.4, 119.9, 117.2, 66.4, 42.8, 21.4; IR
(KBr, cm-1): 3075, 2961, 1661, 1391, 1254, 1062, 895; ESI-
HRMS Calcd for C16H16NO2 [M + H]+ 254.1176, found
254.1179.
benzo[b][1,4]oxazin-4-yl)methanone (6k)
o
1
White solid; mp 75-77 C; H NMR (400 MHz, CDCl3): δ
7.45 (d, J = 8.4 Hz, 2 H), 7.34 (d, J = 8.4 Hz, 2 H), 6.79 (s, 2 H),
6.74 (s, 1 H), 4.32 (t, J = 4.4 Hz, 2 H), 3.95 (t, J = 4.2 Hz, 2 H),
2.07 (s, 3 H); 13C NMR (100 MHz, CDCl3): 167.7, 144.0, 136.8,
133.7, 130.1, 129.4, 128.7, 126.6, 125.4, 124.6, 117.0, 66.3, 42.8,
20.6; IR (KBr, cm-1): 3062, 1632, 1501, 1278, 1053, 760; ESI-
HRMS Calcd for C15H13ClNO2 [M + H]+ 288.0786, found
288.0786.
4.2.6. (3-Chlorophenyl)(2,3-dihydro-4H-
benzo[b][1,4]oxazin-4-yl)methanone (6f)
o
1
Yield 90%; White solid; mp 78-80 C; H NMR (400 MHz,
CDCl3): δ 7.53 (t, J = 1.6 Hz, 1 H), 7.43-7.40 (m, 1 H), 7.35-7.27
(m, 2 H), 7.03 (td, J1 = 7.7 Hz, J2 = 1.4 Hz, 1 H), 6.92 (dd, J1 =
8.4 Hz, J2 = 1.2 Hz, 1 H), 6.69 (t, J = 7.0 Hz, 1 H), 4.38 (t, J =
4.6 Hz, 2 H), 4.00 (t, J = 4.6 Hz, 2 H); 13C NMR (100 MHz,
CDCl3): 167.3, 146.2, 137.0, 134.6, 130.8, 129.7, 128.7, 126.6,
126.0, 125.6, 124.4, 117.4, 66.4, 42.8; IR (KBr, cm-1): 3052,
2911, 1621, 1361, 1246, 1084, 765; ESI-HRMS Calcd for
C15H13ClNO2 [M + H]+ 274.0629, found 274.0624.
4.2.12. (3-Chlorophenyl)(6-methyl-2,3-dihydro-4H-
benzo[b][1,4]oxazin-4-yl)methanone (6l)
1
Yellow liquid; H NMR (400 MHz, CDCl3): δ 7.52 (s, 1 H),
7.43-7.40 (m, 1 H), 7.35-7.27 (m, 2 H), 6.80 (s, 2 H), 4.32 (t, J =
4.6 Hz, 2 H), 3.94 (t, J = 4.6 Hz, 2 H), 2.09 (s, 3 H); 13C NMR
(100 MHz, CDCl3): 167.3, 144.1, 137.1, 134.6, 130.7, 129.7,
129.4, 128.6, 126.8, 126.5, 125.1, 124.5, 117.0, 66.2, 43.1, 20.6;
IR (KBr, cm-1): 3071, 1643, 1532, 1263, 768; ESI-HRMS Calcd
for C16H15ClNO2 [M + H]+ 288.0786, found 288.0795.
4.2.7. (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-
yl)(furan-2-yl)methanone (6g)
4.2.13. Furan-2-yl(6-methyl-2,3-dihydro-4H-
o
Yellow solid; mp 113-115 C; 1H NMR (400 MHz, CDCl3): δ
benzo[b][1,4]oxazin-4-yl)methanone (6m)
1
7.46 (d, J = 0.8 Hz, 1 H), 7.18 (d, J = 7.6 Hz, 1 H), 7.03 (td, J1 =
7.7 Hz, J2 = 1.4 Hz, 1 H), 6.98 (d, J = 3.2 Hz, 1 H), 6.92 (dd, J1 =
8.0 Hz, J2 = 1.2 Hz, 1 H), 6.79 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1 H),
6.48 (dd, J1 = 3.2 Hz, J2 = 1.6 Hz, 1 H), 4.36 (t, J = 4.6 Hz, 2 H),
4.08 (t, J = 4.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3): 158.2,
147.3, 146.3, 144.6, 125.8, 125.7, 123.5, 120.1, 117.5, 117.3,
111.6, 66.3, 42.5; IR (KBr, cm-1): 3129, 2968, 1637, 1503, 1370,
1314, 1269, 1235, 1055, 948; ESI-HRMS Calcd for C13H12NO3
[M + H]+ 230.0812, found 230.0808.
Yellow liquid; H NMR (400 MHz, CDCl3): δ 7.48 (s, 1 H),
7.03 (s, 1 H), 6.99 (d, J = 3.6 Hz, 1 H), 6.85-6.80 (m, 2 H), 6.50-
6.49 (m, 1 H), 4.32 (t, J = 4.6 Hz, 2 H), 4.06 (t, J = 4.8 Hz, 2 H),
2.18 (s, 3 H); 13C NMR (100 MHz, CDCl3): 158.3, 147.5, 144.5,
144.1, 129.5, 126.6, 125.1, 123.7, 117.5, 116.9, 111.6, 66.2, 42.9,
20.7; IR (KBr, cm-1): 3121, 2932, 1609, 1286, 1045, 879; ESI-
HRMS Calcd for C14H14NO3 [M + H]+ 244.0968, found
244.0955.
4.2.14. (6-Methyl-2,3-dihydro-4H-benzo[b][1,4]
4.2.8. (2,3-Dihydro-4H-benzo[b][1,4]oxazin-4-
oxazin-4-yl)(thiophen-2-yl)methanone (6n)
Light yellow solid; mp 92-94 oC; 1H NMR (400 MHz,
CDCl3): δ 7.49 (d, J = 4.8 Hz, 1 H), 7.30 (d, J = 3.6 Hz, 1 H),
7.05 (s, 1 H), 6.99 (t, J = 4.2 Hz, 1 H), 6.85-6.79 (m, 2 H), 4.31
(t, J = 4.6 Hz, 2 H), 4.05 (t, J = 4.6 Hz, 2 H), 2.14 (s, 3 H); 13C
NMR (100 MHz, CDCl3): 162.3, 144.3, 137.6, 131.3, 130.5,
129.3, 127.0, 126.8, 125.4, 124.7, 117.0, 66.3, 43.5, 20.7; IR
(KBr, cm-1): 3142, 2960, 1609, 1261, 1032, 867; ESI-HRMS
Calcd for C14H14NO2S [M + H]+ 260.0740, found 260.0739.
yl)(thiophen-2-yl)methanone (6h)
1
Light yellow liquid; H NMR (400 MHz, DMSO-d6): δ 7.85
(dd, J1 = 5.0 Hz, J2 = 1.0 Hz, 1 H), 7.48 (dd, J1 = 3.6 Hz, J2 = 0.8
Hz, 1 H), 7.40 (d, J = 8.0 Hz, 1 H), 7.14 (dd, J1 = 4.8 Hz, J2 = 3.6
Hz, 1 H), 7.03 (td, J1 = 7.8 Hz, J2 = 1.6 Hz, 1 H), 6.93 (dd, J1 =
8.2 Hz, J2 = 1.4 Hz, 1 H), 6.80 (td, J1 = 7.6 Hz, J2 = 1.6 Hz, 1 H),
4.30 (t, J = 4.6 Hz, 2 H), 4.05 (t, J = 4.6 Hz, 2 H); 13C NMR (100
MHz, DMSO-d6): 162.5, 146.6, 137.9, 131.8, 127.9, 126.1,
125.8, 124.4, 120.2, 117.5, 66.3, 44.6; IR (KBr, cm-1): 3126,
2976, 1689, 1358, 1247, 1045, 926, 716; ESI-HRMS Calcd for
C13H12NO2S [M + H]+ 246.0583, found 246.0591.
4.2.15. Furan-2-yl(7-methyl-2,3-dihydro-4H-
benzo[b][1,4]oxazin-4-yl)methanone (6o)
1
Yield 77%; Yellow liquid; H NMR (400 MHz, CDCl3): δ
4.2.9. (E)-1-(2,3-dihydro-4H-benzo[b][1,4]oxazin-
7.46 (s, 1 H), 7.05 (s, 1 H), 6.96 (d, J = 3.2 Hz, 1 H), 6.73 (s, 1
H), 6.60 (d, J = 8.4 Hz, 1 H), 6.47 (t, J = 1.6 Hz, 1 H), 4.33 (t, J =
4.6 Hz, 2 H), 4.05 (t, J = 4.6 Hz, 2 H), 2.27 (s, 3 H); 13C NMR
(100 MHz, CDCl3): 158.1, 147.4, 146.0, 144.5, 135.9, 123.3,
123.0, 121.0, 117.5, 117.4, 111.6, 66.3, 42.6, 21.0; IR (KBr, cm-
1): 3109, 2949, 1621, 1366, 1266, 1062, 868; ESI-HRMS Calcd
for C14H14NO3 [M + H]+ 244.0968, found 244.0965.
4-yl)-3-phenyl prop-2-en-1-one (6i)
o
1
Yellow solid; mp 73-75 C; H NMR (400 MHz, CDCl3): δ
7.78 (d, J = 55.2 Hz, 1 H), 7.50-7.48 (m, 2 H), 7.38-7.35 (m, 3
H), 7.18 (d, J = 7.6 Hz, 1 H), 7.11 (td, J1 = 7.8 Hz, J2 = 1.6 Hz, 1
H), 7.05 (d, J = 15.2 Hz, 1 H), 6.97-6.88 (m, 2 H), 4.36 (t, J = 4.8
Hz, 2 H), 4.07 (t, J = 4.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3):
164.6, 147.0, 143.2, 135.1, 129.9, 128.9, 128.0, 126.3, 126.0,
124.3, 120.1, 119.0, 117.5, 67.0, 40.2; IR (KBr, cm-1): 3073,
1650, 1498, 1363, 972, 728; ESI-HRMS Calcd for C17H16NO2 [M
+ H]+ 266.1176, found 266.1179.
4.2.16. (7-Methyl-2,3-dihydro-4H-benzo[b]
[1,4]oxazin-4-yl)(thiop hen-2-yl)methanone (6p)
o
1
Yield 68%; Yellow solid; mp 72-74 C; H NMR (400 MHz,
CDCl3): δ 7.47 (d, J = 5.2 Hz, 1 H), 7.28 (d, J = 4.0 Hz, 1 H),
7.04 (d, J = 8.0 Hz, 1 H), 6.99-6.97 (m, 1 H), 6.74 (s, 1 H), 6.55
(d, J = 8.4 Hz, 1 H), 4.34 (t, J = 4.6 Hz, 2 H), 4.05 (t, J = 4.8 Hz,
2 H), 2.26 (s, 3 H); 13C NMR (100 MHz, CDCl3): 162.0, 146.2,
137.5, 136.2, 131.4, 130.4, 127.0, 124.3, 123.3, 120.9, 117.5,
66.6, 43.0, 21.0; IR (KBr, cm-1): 3112, 2906, 1675, 1468, 1239,
868; ESI-HRMS Calcd for C14H14NO2S [M + H]+ 260.0740,
found 260.0736.
4.2.10. (6-Methyl-2,3-dihydro-4H-
benzo[b][1,4]oxazin-4-yl)(p-tolyl)methanone (6j)
o
1
White solid; mp 113-115 C; H NMR (400 MHz, CDCl3): δ
7.41 (d, J = 8.0 Hz, 2 H), 7.17 (d, J = 8.0 Hz, 2 H), 6.89 (s, 1 H),
6.78 (s, 2 H), 4.29 (t, J = 4.6 Hz, 2 H), 3.95 (t, J = 4.6 Hz, 2 H),
2.37 (s, 3 H), 2.08 (s, 3 H); 13C NMR (100 MHz, CDCl3): 169.1,
143.9, 141.0, 132.4, 129.3, 129.0, 128.6, 126.2, 125.7, 124.6,
116.8, 66.3, 43.3, 21.5, 20.7; IR (KBr, cm-1): 3072, 3028, 1642,
1358, 1236, 932; ESI-HRMS Calcd for C17H18NO2 [M + H]+
268.1332, found, 268.1337.
4.2.17. N-(2-(2-Chloroethoxy)phenyl)benzamide
(7a)

5
o
1
White solid; mp 105-107 C; H NMR (400 MHz, CDCl3): δ
References and notes
ACCEPTED MANUSCRIPT
8.76 (s, 1 H), 8.58 (t, J = 4.8 Hz, 1 H), 7.94 (d, J = 6.8 Hz, 2 H),
7.57-7.48 (m, 3 H), 7.08-7.05 (m, 2 H), 6.93-6.90 (m, 1 H), 4.35
(t, J = 5.2 Hz, 2 H), 3.89 (t, J = 5.2 Hz, 2 H); 13C NMR (100
MHz, CDCl3): 165.2, 146.6, 135.0, 131.8, 128.8, 127.1, 123.8,
122.4, 120.2, 112.0, 68.9, 42.6; IR (KBr, cm-1): 3418, 3062,
2927, 1652, 1532, 1453, 1340, 1251, 1041, 906, 752; ESI-HRMS
Calcd for C15H14ClNO2Na [M + Na]+ 298.0605, found 298.0592.
1. (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (b)
Bourlot, A.-S.; Sanchez, I.; Dureng, G.; Guillaumet, G.;
Massingham, R.; Monteil, A.; Winslow, E.; Pujol, M. D.; Mérour,
J.-Y. J. Med. Chem. 1998, 41, 3142. (c) Katselou, M. G.; Matralis,
A. N.; Kourounakis, A. P. Eur. J. Med. Chem. 2017, 138, 748. (d)
Macías, F. A.; Marín, D.; Oliveros-Bastidas, A.; Molinillo, J. M.
G. Nat. Prod. Rep. 2009, 26, 478.
2. (a) Bucaneve, G.; Micozzi, A.; Menichetti, F.; Martino, P.;
Dionisi, M. S.; Martinelli, G.; Allione, B.; D’Antonio, D.; Buelli,
M.; Nosari, A. M. N. Eng. J. Med. 2005, 353, 977. (b) Fish, D. N.;
Chow, A. T. Clin. Pharmacokinet. 1997, 32, 101. (c) Davis, R.;
Bryson, H. M. Drugs 1994, 47, 677.
3. (a) Brennan, J. P.; Saxton, J. E. Tetrahedron Lett. 1985, 26, 1769.
(b) Kahrl, J.; Gebreyesus, T.; Djerassi, C. Tetrahedron Lett. 1971,
12, 2527. (c) Brown, K. S.; Djerassi, C. J. Am. Chem. Soc. 1964,
86, 2451.
4. Tsutsui, H.; Hori, M.; Watanabe, I.; Harada, K.; Maruo, J.; Morita,
T.; Ohtaka, H.; Yamamoto, T. EP Patent Appl. 719766, 1996.
5. Madhavan, G. R.; Iqbal, J.; Bhuniya, D.; Chakrabarti, R.; Das, S.
K. WO Patent Appl. 03033481, 2003.
6. Achari, B.; Mandal, S. B.; Dutta, P. K.; Chowdhury, C. Synlett
2004, 2449.
7. For reviews, see: (a) Ilas, J.; Stefanic, A. P.; Sollner, D. M.;
Kikelj, D. M. Tetrahedron 2005, 61, 7325. (b) Smist, M.;
Kwiecien, H. Curr. Org. Synth. 2014, 11, 676
8. Zhang, Y.-R.; Xie, J.-W.; Huang, X.-J.; Zhu, W.-D. Org. Biomol.
Chem. 2012, 10, 6554.
9. Kuwabe, S-I.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 12202.
10. (a) Albanese, D.; Landini, D.; Lupi, V.; Penso, M. Adv. Synth.
Catal. 2002, 344, 299. (b) Albanese, D.; Donghi, A.; Landini, D.;
Lupi, V.; Penso, M. Green Chem. 2003, 5, 367.
11. Ciske, F. L.; Barbachyn, M. R.; Genin, M. J.; Grega, K. C.; Lee,
C. S.; Dolak, L. A.; Seest, E. P.; Watt, W.; Adams, W. J.; Friis, J.
M.; Ford, C. W.; Zurenko, G. E. Bioorg. Med. Chem. Lett. 2003,
13, 4235.
12. (a) Kuroita, T.; Ikebe, T.; Murakami, S.; Takehara, S.; Kawakita,
T. Bioorg. Med. Chem. Lett. 1995, 5, 1245. (b) Mayer, S.; Arrault,
A.; Guillaumet, G.; Mérour, J. Y. J. Heterocycl. Chem. 2001, 38,
221. (c) Coudert, G.; Guillaumet, G.; Loubinoux, B. Synthesis,
1979, 541.
13. Xu, D.; Chiaroni, A.; Fleury, M.-B.; Largeron, M. J. Org. Chem.
2006, 71, 6374.
14. Bagnoli, L.; Casini, S.; Marini, F.; Santi, C.; Testaferri, L.
Tetrahedron Lett. 2013, 69, 481.
4.2.18. N-(2-(2-Chloroethoxy)phenyl)-2-(3-
methoxyphenyl)acetamide (7b)
o
1
White solid; mp 102-104 C; H NMR (400 MHz, CDCl3): δ
8.37 (t, J = 4.8 Hz, 1 H), 7.89 (s, 1 H), 7.31 (t, J = 8.2 Hz, 1 H),
6.97-6.92 (m, 3 H), 6.87 (d, J = 6.4 Hz, 2 H), 6.75 (t, J = 4.4 Hz,
1 H), 4.08 (t, J = 5.6 Hz 2 H), 3.80 (s, 3 H), 3.72 (s, 2 H), 3.57 (t,
J = 5.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3): 168.8, 160.2,
146.5, 136.0, 130.3, 128.1, 123.8, 122.0, 119.8, 115.3, 113.1,
111.6, 68.8, 55.3, 45.4, 41.9; IR (KBr, cm-1): 3310, 2968, 2829,
1669, 1546, 1348, 1250, 1149, 1051, 973, 751; ESI-HRMS Calcd
for C17H18ClNO3 [M + Na]+ 342.0867, found 342.0857.
4.2.19. N-(2-(2-Chloroethoxy)phenyl)acrylamide
(7c)
o
1
White solid; mp 87-89 C; H NMR (400 MHz, CDCl3): δ
8.49 (s, 1 H), 8.06 (s, 1 H), 7.06-7.03 (m, 2 H), 6,91-6.89 (m, 1
H), 6.41 (dd, J1 = 16.8 Hz, J2 = 1.2 Hz, 1 H), 6.28 (dd, J1 = 17.2
Hz, J2 = 10.0 Hz, 1 H), 5.76 (dd, J1 = 10.4 Hz, J2 = 1.2 Hz, 1 H),
4.31 (t, J = 5.2 Hz, 2 H), 3.86 (t, J = 5.4 Hz, 2 H); 13C NMR (100
MHz, CDCl3): 163.4, 146.5, 131.7, 128.7, 127.3, 123.9, 122.5,
120.4, 112.6, 69.3, 42.5; IR (KBr, cm-1): 3378, 3054, 2954, 1654,
1445, 1253, 996, 772; ESI-HRMS Calcd for C11H12ClNO2 [M +
Na]+ 248.0449, found 248.0442.
4.2.20. N-(2-(2-Chloroethoxy)phenyl)acetamide
(7d)
o
1
Yellow solid; mp 93-95 C; H NMR (400 MHz, CDCl3): δ
8.37 (t, J = 4.6 Hz, 1 H), 7.91 (s, 1 H), 7.03-7.00 (m, 2 H), 6.89
(t, J = 4.8 Hz, 1 H), 4.30 (t, J = 5.2 Hz, 2 H), 3.85 (t, J = 5.2 Hz,
2 H), 2.20 (s, 3 H); 13C NMR (100 MHz, CDCl3): 168.3, 146.2,
128.9, 123.6, 122.5, 120.2, 112.7, 69.4, 42.5, 24.9; IR (KBr, cm-
1): 3352, 2977, 2735, 1657, 1469, 1146, 863, 751; ESI-HRMS
Calcd for C10H12ClNO2Na [M + Na]+ 236.0449, found 236.0448.
15. Huang, X.; Zhang, Y.-R.; Li, X.-S.; Xu, D.-C.; Xie, J.-W.
Tetrahedron Lett. 2013, 54, 5857.
16. (a) Dai, W.-M.; Wang, X.; Ma, C. Tetrahedron 2005, 61, 6879.
(b) Feng, G.; Wu, J.; Dai, W.-M. Tetrahedron 2006, 62, 4635. (c)
Yu, G.; Zheng, Y.; Wu, J.; Dai, W.-M. Tetrahedron 2013, 69,
10488. (d) Xing, X.; Wu, J.; Feng, G.; Dai, W.-M. Tetrahedron
2006, 62, 6774.
17. Touzeau, F.; Arrault, A.; Guillaumet, G.; Scalbert, E.; Pfeiffer, B.;
Rettori, M. C.; Renard, P.; Merour, J. Y. J. Med. Chem. 2003, 46,
1962.
18. Iakovou, K.; Kazanis, M.; Vavayannis, A.; Bruni, G.; Romeo, M.
R.; Massarelli, P.; Teramoto, S.; Fujiki, H.; Mori, T. Eur. J. Med.
Chem. 1999, 34, 903.
19. For selected recent reviews on MCRs, see: (a) Wan, J.-P.; Gan, L.;
Liu, Y. Org. Biomol. Chem. 2017, 15, 9031. (b) Rotstein, B. H.;
Zaresky, S.; Rai, V.; Yudin, A. K. Chem. Rev. 2014, 114, 8323.
(d) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16,
2958. (e) Gu, Y. Green Chem. 2012, 14, 2091. (e) Dai, W.-M.; Li,
H. Tetrahedron 2007, 63, 12866.
4.2.21. N-(2-(3-Chloropropoxy)phenyl)benzamide
(7e)
1
Yield 79%; Yellow liquid; H NMR (400 MHz, CDCl3): δ
8.53 (dd, J1 = 7.6 Hz, J2 = 1.6 Hz, 2 H), 7.87 (d, J = 7.2 Hz, 2 H),
7.57-7.48 (m, 3 H), 7.10-7.01 (m, 2 H), 6.94 (dd, J1 = 7.6 Hz, J2
= 1.2 Hz, 1 H), 4.25 (t, J = 6.0 Hz, 2 H), 3.73 (t, J = 6.0 Hz, 2 H),
2.35-2.29 (m, 2 H); 13C NMR (100 MHz, CDCl3): 165.2, 147.2,
135.3, 131.8, 128.9, 128.0, 127.0, 124.0, 121.6, 120.1, 111.2,
65.5, 41.4, 32.0; IR (KBr, cm-1): 3420, 3071, 2906, 1658, 1430,
1276, 1060, 914, 749; ESI-HRMS Calcd for C16H16ClNO2 [M +
Na]+ 312.0762, found 312.0748.
Acknowledgments
This work is financially supported by the National Natural
Science Foundation of China (no. 21562024).
20. Dai, W.-M.; Cheung, Y. K.; Tang, K. W.; Choi, P. Y.; Chung, S.
L. Tetrahedron 1995, 51, 12263.
Supplementary Material
Supplementary data associated with this article can be found
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in the online version, at https: . These data include the 1H and 13
NMR spectra of all products.
C

ACCEPTED MANUSCRIPT
Highlights
1. The first example on the synthesis of N-acyl 2,3-dihydrobenzoxazines is reported.
2. Switchable synthesis of functional amides by simply varying reaction temperature.
3. No transition metal, oxidant, strong acid or based throughout the whole synthesis.