Expedient synthesis of novel 1,4-benzoxazine and butenolide derivatives

Article abstract of DOI:10.1039/c4ra01736f

A highly efficient and rapid method for the synthesis of 2-hydroxy-1,4-benzoxazine and butenolide derivatives has been developed. The key step in this protocol involves the reduction of benzoxazinone derivatives. Further reaction of 2-hydroxy-1,4-benzoxazine with secondary amines and sodium methoxide affords the corresponding 2-amino-1,4-benzoxazines and butenolide derivatives, respectively, in good yields.

Full text of DOI:10.1039/c4ra01736f

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Expedient synthesis of novel 1,4-benzoxazine and
butenolide derivatives†
Cite this: RSC Adv., 2014, 4, 17969
*
Garima Choudhary, Ram Tilak Naganaboina and Rama Krishna Peddinti
A highly efficient and rapid method for the synthesis of 2-hydroxy-1,4-benzoxazine and butenolide
derivatives has been developed. The key step in this protocol involves the reduction of benzoxazinone
derivatives. Further reaction of 2-hydroxy-1,4-benzoxazine with secondary amines and sodium
methoxide affords the corresponding 2-amino-1,4-benzoxazines and butenolide derivatives,
respectively, in good yields.
Received 27th February 2014
Accepted 17th March 2014
DOI: 10.1039/c4ra01736f
www.rsc.org/advances
of new synthetic technology in heterocyclic compounds,14
herein we report an efficient synthesis of functionalized 1,4-
Introduction
benzoxazine and butenolide derivatives starting from the
commercially available o-aminophenols and dialkyl acetylene-
dicarboxylates (Scheme 1).
Among the various heterocyclic compounds, those containing
benzoxazine and butenolide units have gained considerable
importance due to their occurrences in various natural prod-
ucts.1 Benzoxazine derivatives have been found to demonstrate
a wide range of biological activities like dopamine agonist
activity, and have found applications such as neuroprotective
agents,2 intracellular calcium antagonist,3 and antitumour4 and
antiangiogenic therapeutic agents.5 Some such derivatives are
used as powerful drugs for treating cardiovascular, cancer and
diabetic disorders.6 Benzoxazine derivatives are also used in the
agricultural sector as herbicides.7
The butenolide unit is an important structural moiety found
in many biologically active compounds.8–13 For example,
vitamin C (ascorbic acid) and penicillic acid are the best known
4-hydroxy-2(5H)-furanones having the butenolide unit in their
structures,8 butenolides having substituted o-chlorobenzyl-
amine have been recognized as antibiotic agents against the
multiresistant Staphylococcus aureus and also act as intermedi-
ates in the synthesis of basidalin, which has marked activity
against colon tumors.9 Moreover, the anti-inammatory agent
manoalide holds butenolide moiety in the substructure of the
pyranofuranone.10 In addition, several have been patented as
prodrugs or herbicides and insecticides.11 Ramariolide A, a
spiro oxiranebutenolide isolated from the fruiting bodies of the
coral mushroom Ramaria cystidiophora, exhibits in vitro anti-
microbial activity against Mycobacterium smegmatis and Myco-
bacterium tuberculosis.12 Metabolites possessing the butenolide
sub-unit that are isolated from the tunicate Pseudodistoma
antinboja display antibacterial activity against Gram-positive
strains.13 As a part of our ongoing research on the development
Results and discussion
We have previously reported the synthesis of a series of ben-
zoxazinone derivatives starting from o-aminophenols and dia-
lkyl acetylenedicarboxylates by simple mixing of the reactants
under solvent-free and catalyst-free conditions.14a Because the
hemiacetal linkage is found in some naturally occurring ben-
zoxazine derivatives,15 in further investigation, it occurred to us
that these benzoxazinones would be valuable intermediates for
the synthesis of corresponding 2-hydroxy-benzoxazine deriva-
tives. These 2-hydroxybenzoxazines could be precursors for
Department of Chemistry, Indian Institute of Technology, Roorkee-247667,
Uttarakhand, India. E-mail: rkpedfcy@iitr.ernet.in; ramakpeddinti@gmail.com; Fax:
+91 133 227 3560; Tel: +91 133 228 5438
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
Scheme 1 Proposed route for the synthesis of 2-hydroxy-1,4-ben-
zoxazine, 2-aminobenzoxazine and butenolide derivatives.
spectra of all new compounds. See DOI: 10.1039/c4ra01736f
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Table 1 Reduction of benzoxazinone derivativesa
several target molecules such as 2-aminobenzoxazine deriva-
tives A and butenolide derivatives B (Scheme 1). Thus, we were
interested in synthesizing 2-hydroxybenzoxazine derivatives
from the corresponding benzoxazinone derivatives. As
a
prelude to our objective, the rst step was initiated with the
reduction of benzoxazinone, derived from the mixing of
2-aminophenol with dimethyl acetylenedicarboxylate, using
sodium borohydride in methanol (Scheme 2). In a typical
reaction procedure, 2-aminophenol (2 mmol) was mixed with
dimethyl acetylenedicarboxylate (2 mmol) for 4 min at room
temperature to afford (Z)-3-methoxycarbonylmethylene-3,4-
dihydro-2H-1,4-benzoxazin-2-one in 100% conversion, which
was further stirred with NaBH4 (2.2 mmol) in methanol for 15
min. Initially, the benzoxazinone had signicantly lower solu-
bility in methanol but formed a clear solution with the progress
of the reaction. Aer completion of the reaction, the methanol
was removed completely with the help of a rotary evaporator to
produce a semi-solid state. Upon adding water to the reaction
mixture and scratching with a spatula, a brown solid product
separated out immediately from the reaction mixture. The solid
was ltered, washed with water and dried to furnish methyl (Z)-
2-(2-hydroxy-2H-benzo-1,4-oxazin-3(4H)-ylidene)acetate (1a) as a
brown solid with excellent purity in 93% yield (Table 1, entry 1),
which is pure enough for spectroscopic analysis.
Entry o-Aminophenols
R
Timec (min) Product Yieldd (%)
1
2
Me 4 + 15
Et 5 + 15
1a
1b
93
95
3
4
Me 2 + 10
Et 3 + 10
2a
2b
97
98
5
6
Me 2 + 10
Et 3 + 10
3a
3b
97
96
7
8
Me 2 + 15
Et 3 + 15
4a
4b
93
92
9
10
Me 4 + 10
Et 5 + 10
5a
5b
97
95
11
12
Me 4 + 10
Et 5 + 10
6a
6b
95
96
Similarly other derivatives 2a–6a, 1b–6b were also synthe-
sized by the aforementioned process in excellent to nearly
quantitative yields (92–98%) (Table 1). It is noteworthy to
mention here that this methodology obviates the use of solvents
in purication steps such as column chromatography and
extraction.
a
All reactions were carried out with (2 mmol) each of 2-aminophenol
and dialkyl acetylenedicarboxylates using 2.2 mmol of NaBH4 in
b
methanol. Mixing of reactants with spatula (in a Petri dish or in an
c
RB ask) for 2–5 min. Total time of reaction (mixing + stirring).
d
Yields of isolated pure products.
A number of methods have been developed for the synthesis
of 4-aminofuran-2(5H)-ones. These processes include the use of
Pd–bis(isoxazoline) catalyzed 5-endo-trig-type cyclization b,g-
unsaturated carbonyl compounds,16 etherication and amina-
tion of mucohalic acid17 and [2,3]-Wittig rearrangement of
dienolates.18 TFA mediated synthesis of 3-substituted 4-amino-
furan-2(5H)-ones from 4-hydroxycyclobutenone19 and the
synthesis of 3-unsubstituted 4-aminofuran-2(5H)-ones by amine
addition on acetylenecarboxylates followed by intramolecular
cyclizations20 are also reported. Herein, we disclose a practical
two-step route for the synthesis of novel 4-substituted-5-
methoxyfuran-2(5H)-one derivatives.
Having various 2-hydroxy-1,4-benzoxazines 1a–6a, 1b–6b in
hand, we employed them as reactants for the synthesis of
butenolides 7–12. In the exploration of the reagents for
synthesizing butenolides, we selected benzoxazine 1a as our
model substrate. Several reagents were screened for the reaction
at room temperature and at reux conditions; the results are
summarized in Table 2. The performance of the reaction using
various reagents such as pyridine, DABCO, triethylamine, tri-
phenylphosphine, and acetic anhydride (Table 2, entries 1–10)
was not encouraging. However, when the reaction was carried
out in the presence of 0.5 equiv. of NaOMe in dry methanol at
room temperature, 25% of the desired product 7 was obtained
in 8 h (Table 2, entry 11). At this juncture, an equimolar quantity
of sodium methoxide was used in the reaction, which was found
to improve the yield from 25% to 49% at room temperature
(Table 2, entry 12). Gratifyingly, further enhancement of the
yield was achieved by performing the reaction with 1 equiv. of
NaOMe in dry methanol at reux temperature (Table 2, entry
13). Thus, screening the reagents in various solvents at different
temperatures identied sodium methoxide as a suitable reagent
for the transformation of 2-hydroxybenzoxazine 1a into bute-
nolide 7. Accordingly, the reaction of benzoxazine 1a (1 mmol)
Scheme 2 One-pot synthesis and reduction of benzoxazinone derivatives.
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Table 2 Optimization of reaction conditionsa
Entry
Reagent
Equiv.
Solvent
Temperature
Time (h)
Product/yieldb (%)
1
2
3
4
5
6
7
8
Pyridine
DABCO
Et3N
Ph3P
(CH3CO)2O
POCl3, P2O5
DMAP
NaH, under N2
1
0.5
1
0.5
5
5
0.5
1
0.5
0.5
0.5
1
MeOH
MeOH
MeOH
THF
Neat
Neat
Toluene
THF
Toluene
DCM
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
Reux
Reux
Reux
Reux
Reux
Reux
Reux
rt
Reux
rt
rt
rt
Reux
rt
12
12
12
12
12
12
12
16
12
16
8
8
4
16
16
6
—
—
—
—
—
—
—
—
9
Pyridiniumtoluene-4-sulphonate
I2
—
—
10
11
12
13
14
15
16
NaOMe
NaOMe
NaOMe
Piperidine
Piperidine
Piperidine
7/25
7/49
7/78
13a/trace
13a/21
13a/71
1
0.5
1.5
1.5
rt
Reux
a
Reactions were performed with 1a (0.5 mmol) using different reagents in the presence of 2 mL of solvent. b Yields of pure and isolated products.
was performed with 1 equiv. of sodium methoxide in dry (1.5 mmol) was added to a solution of 2 (1 mmol) in methanol
methanol at reux temperature for four hours. Aer completion (4 mL), and the resulting mixture was stirred at the reux
of the reaction, the contents were concentrated and subjected to temperature for a period of time as mentioned in Table 4. The
silica gel (pre-treated with triethylamine) column chromatog- reaction contents were then concentrated and the residue was
raphy using ethyl acetate and hexanes as eluents to obtain the subjected to silica gel (pre-treated with triethylamine) chroma-
desired butenolide 7 in 78% yield (Table 3, entry 1).
tography to obtain pure products. As shown in Table 4,
The structure of the products was elucidated on the basis of regardless of the electronic nature of the aromatic substitu-
1
collective information obtained from IR, H and 13C NMR and tion, good to excellent yields (54–86%) were realized in the
HRMS spectral data of pure and isolated products. For example, reactions except in the case of compounds bearing the tert-
the carbonyl stretch at 1744 cmꢀ1 along with an olenic stretch butyl group (Table 4, entries 7 and 8). When the reaction of 4a
at 1644 cmꢀ1 in the IR spectrum of 11 is a characteristic band was performed in methanol with 1.5 equiv. of piperidine, the
for butenolide systems. The olenic proton of the lactone ring reaction times signicantly increased, and product 16a was
resonates at d 5.90 ppm. The proton attached to the methoxy obtained in 56% yield. The reaction of 4b proceeded in a
group resonates at d 5.09 ppm in 1H NMR, and the lactone similar manner to provide 16b in 54% yield. All reactions
carbonyl carbon resonates at d 171.8 ppm in 13C NMR.
proceeded smoothly to provide the desired products 13a–18a,
While optimizing the reaction for the conversion of ben- 13b–18b in good to excellent yields. To expand the scope of
zoxazine derivatives 1a into butenolide 7 (Table 2) using this novel protocol, the reactions of 1a–6a with pyrrolidine
piperidine in methanol, an unexpected formation of product were conducted to give the corresponding products 19–24 in
13a was observed. Spectroscopic analysis conrmed the product good yields. Similarly, treatment of the vinylogous carba-
as aminobenzoxazine derivative 13a. Aer conrming the mates 1a–5a with N,N-dibenzylamine resulted in the forma-
structure, we then turned our attention towards the optimiza- tion of hemiaminals 25–29 (Scheme 3). The reaction of
tion of reaction conditions. It was observed that at room benzoxazinol 1a with morpholine in methanol did not
temperature, the product was not obtained even aer 16 h proceed under reux conditions. Consequently, the reaction
(Table 2, entry 14) with 50 mol% of the piperidine. When the of 1a and morpholine was performed in a sealed tube at
piperidine loading was further increased to 1.5 equivalents the 100 ꢁC, and the required product 30 was obtained in 72%
product was obtained in 21% yield aer 16 h of stirring at rt yield. The other aminobenzoxazines 31–34 were achieved
(Table 2, entry 15). For further improvement, the inuence of using this procedure in acceptable yields. The reaction of
temperature on the reaction was also investigated (Table 2, benzoxazinols 1a–5a with N-benzylpiperazine afforded hem-
entries 14 and 16). To our delight, the yield of the reaction iaminals 35–39 in good yields (Scheme 3). The structures of
improved dramatically to 71% yield of 13a at reux temperature all the products are assigned on the basis of data collected
(Table 2, entry 16). In a typical reaction procedure, piperidine from modern analytical tools.
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Table 3 Synthesis of butenolide derivativesa
Table 4 Scope of substrates with piperidinea
Time (h) Product Yieldb (%)
Entry Substrate
R
Time (h) Product Yieldb (%)
Entry Substrate
R
1
2
1a Me
1b Et
5
6
7
7
78
76
1
2
1a Me
1b Et
5
5
13a
13b
71
74
3
4
2a Me
2b Et
4
6
8
8
84
81
3
4
2a Me
2b Et
4
4
14a
14b
75
76
5
6
3a Me
3b Et
4
6
9
9
82
83
5
6
3a Me
3b Et
4
4
15a
15b
75
77
7
8
4a Me
4b Et 10
8
10
10
61
58
7
8
4a Me
4b Et
8
8
16a
16b
56
54
9
10
5a Me
5b Et
4
6
11
11
89
91
9
10
5a Me
5b Et
4
4
17a
17b
79
81
11
12
6a Me
6b Et
4
4
18a
18b
86
81
11
12
6a Me
6b Et
4
6
12
12
90
87
a
a
All reactions were performed with benzoxazine derivative (0.5 mmol)
4 mL of methanol with piperidine (0.75 mmol) at reux
All reactions were performed with benzoxazine derivative (0.5 mmol)
in 4 mL of methanol with sodium methoxide (0.5 mmol) at reux
temperature. b Yields of pure and isolated products.
in
temperature. b Yields of pure and isolated products.
at 7.26 ppm and 77.0 ppm and those from DMSO-d6 at 2.50 ppm
Conclusions
1
and 39.5 ppm were set as reference peaks in H NMR and 13C
NMR spectra, respectively. The following abbreviations were
used to explain the multiplicities: s ¼ singlet, d ¼ doublet, dd ¼
double doublet, dt ¼ doublet of triplet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet, b ¼ broad. High-resolution mass spectra
In summary, we have demonstrated a novel procedure for the
reduction of benzoxazinone derivatives into 2-hydroxy-1,4-ben-
zoxazines. Our methodology provides an easy access to a series
of butenolide derivatives and 2-amino-1,4-benzoxazine deriva-
tives. In light of the simplicity of the procedure, mild conditions
and considerable generality, these reactions are certainly
noteworthy.
¨
(HRMS) were obtained on a Bruker micrOTOF™-Q II mass
spectrometer (ESI-MS).
2
General procedures
Experimental
Procedure for the synthesis of benzoxazine derivative 1a. In a
1
General methods
typical reaction procedure, 2-aminophenol (2 mmol) was mixed
Unless otherwise noted, chemicals were purchased from Sigma- with dimethyl acetylenedicarboxylate (2 mmol) for 4 minutes at
Aldrich at the highest purity grade available and were used room temperature. Followed by the addition of NaBH4 (2.2
without further purication. IR spectra of the compounds were mmol), the reaction mixture was stirred for 15 minutes in
recorded on a Thermo Nicolet FT-IR Nexus™ and are expressed methanol. Aer completion of the reaction, methanol was
as wave numbers (cmꢀ1). NMR spectra were recorded in CDCl3 removed completely with the help of rotary evaporator which
¨
and DMSO-d6 using TMS as an internal standard on a Bruker gave a semi-solid substance.
1
AMX-500 instrument. Chemical shis of H NMR spectra were
Aer adding water to the reaction mixture and scratching
given in parts per million with respect to TMS, and the coupling with a spatula, a brown solid product separated out immedi-
constant J was measured in Hz. The signals from solvent CDCl3, ately from the reaction mixture. It was ltered, washed with
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Scheme 3 Reactions of 2-hydroxy 1,4-benzoxazine derivatives with secondary amines.
water, and dried to afford (Z)-methyl 2-(2-hydroxy-2H-benzo-1,4- 0.75 mmol) was added to a solution of 1a (0.5 mmol) in meth-
oxazin-3(4H)-ylidene)acetate (1a) in 93% yield. The other anol (4 mL), and the resulting mixture was stirred at the reux
derivatives 2a–6a and 1b–6b were prepared in 92–98% yield temperature for a period of time as mentioned in Table 4 and
following the same procedure.
Scheme 3. Aer concentrating the reaction contents, the crude
Procedure for the synthesis of 2-aminobenzoxazine deriva- reaction mixture was subjected to column chromatography on
tive 13a. In a typical reaction procedure, a secondary amine silica gel (pre-treated with triethylamine) and was puried by
(piperidine/pyrrolidine/dibenzylamine/N-benzyl
piperazine, using ethyl acetate and hexanes (90 : 10 hexanes–EtOAc) as
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eluents to obtain pure product 13a in 71% yield. The other 4.87 (s, 1H), 4.16–4.06 (m, 2H), 3.56 (br s, 1H), 2.28 (s, 3H),
derivatives 14a–18a, 13b–18b, 19–29 and 35–39 were prepared 1.27 (t, J ¼ 7.0 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): d
in 54–86% yield using the same procedure.
170.5, 148.5, 138.5, 133.1, 126.2, 123.5, 117.8, 116.2, 91.0,
Procedure for the reactions of 2-hydroxy 1,4-benzoxazine 84.9, 59.7, 21.0, 14.6 ppm. HRMS (ES+): m/z calcd for
derivatives 1a–5a with morpholine. To a mixture of methanol (4 [C13H15NO4 + Na]+: 272.0893, found: 272.0876.
mL) and 2-hydroxy 1,4-benzoxazine derivative 1a (0.5 mmol) in a
Methyl (Z)-2-(2-hydroxy-7-methyl-2H-benzo[b][1,4]oꢁxazin-
dry sealed tube, morpholine (2 mmol) was added, and the 3(4H)-ylidene)acetate (3a). Brown solid, mp: 113–114 C. IR
reaction mixture was allowed to heat at 100 ꢁC for 5 h. Aer (KBr): vmax 3324, 3270, 2980, 2917, 2859, 1652, 1621, 1513,
completion of the reaction as shown by the TLC, the crude 1412, 1367, 1287, 1230, 1164 cmꢀ1 1H NMR (500 MHz,
.
reaction mixture was subjected to column chromatography on CDCl3): d 10.09 (br s, 1H), 6.95–6.93 (m, 2H), 6.85 (d, J ¼ 8.0
silica gel (pre-treated with triethylamine) and was eluted with Hz, 1H), 5.71 (s, 1H), 4.91 (s, 1H), 3.70 (s, 3H), 2.33 (s, 3H)
ethyl acetate and hexanes (90 : 10 hexanes–EtOAc) to obtain the ppm. 13C NMR (125 MHz, CDCl3): d 170.3, 156.1, 139.8, 138.2,
desired products 30–34.
133.1, 126.3, 121.6, 117.3, 114.5, 89.9, 83.5, 51.4, 20.8 ppm.
Procedure for the synthesis of butenolide derivative 7. To a HRMS (ES+): m/z calcd for [C12H13NO4 + Na]+: 258.0737,
solution of 1a/1b (0.5 mmol) in 4 mL of dry methanol, sodium found: 258.0731.
methoxide (0.5 mmol) was added and stirred at reux temper-
Ethyl (Z)-2-(2-hydroxy-7-methyl-2H-benzo[b][1,4]oꢁxazin-
ature for 4 h. The reaction was monitored by TLC at regular 3(4H)-ylidene)acetate (3b). Brown solid, mp: 141–142 C. IR
intervals. Upon completion of the reaction, the crude reaction (KBr): vmax 3323, 3270, 2980, 2917, 2859, 1652, 1621, 1513,
mixture was puried by silica gel column chromatography 1412, 1367, 1287, 1230, 1164 cmꢀ1 1H NMR (500 MHz,
.
using ethyl acetate and hexanes (85 : 15 of hexanes–EtOAc) as CDCl3): d 10.02 (br s, 1H), 6.79–6.74 (m, 3H), 5.67 (s, 1H), 4.86
the eluting solvent system to obtain the desired pure product 7 (s, 1H), 4.18–4.13 (m, 2H), 2.28 (s, 3H), 1.28 (t, J ¼ 7.0 Hz, 3H)
in 78% yield. The other derivatives 8–12 were prepared in 58– ppm. 13C NMR (125 MHz, CDCl3): d 170.1, 156.2, 138.9, 139.1,
91% yield using the same procedure.
133.0, 126.3, 121.8, 117.3, 114.5, 90.4, 84.9, 60.2, 20.8, 14.3
ppm. HRMS (ES+): m/z calcd for [C13H15NO4 + Na]+: 272.0893,
found: 272.0898.
3
Spectroscopic data
Methyl (Z)-2-(6-tert-butyl-2-hydroxy-2H-benzo[b][1,4]oxazin-
Methyl (Z)-2-(2-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)-ylidene)- 3(4H)-ylidene)acetate (4a). Brown solid, mp: 135–136 ꢁC. IR
acetate (1a). Brown solid, mp: 174–175 ꢁC. IR (KBr): vmax 3286, (KBr): vmax 3377, 3310, 2957, 2871, 1656, 1613, 1506, 1437, 1370,
1738, 1667, 1597, 1275 cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.03 1294, 1220, 1070, 1003 cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.06
(br s, 1H), 6.98–6.91 (m, 3H), 6.86 (d, J ¼ 7.5 Hz, 1H), 5.70 (s, 1H), (br s, 1H), 6.95 (dd, J ¼ 2.0, 8.5 Hz, 1H), 6.91 (s, 1H), 6.88 (d, J ¼
4.90 (s, 1H), 3.67 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d 170.4, 2.0 Hz, 1H), 5.69 (s, 1H), 4.89 (s, 1H), 3.67 (s, 3H), 1.29 (s, 9H)
149.2, 141.2, 126.4, 122.3, 122.2, 117.3, 115.0, 90.3, 83.4, 50.4 ppm. ppm. 13C NMR (125 MHz, CDCl3): d 170.5, 149.4, 145.5, 138.9,
HRMS (ES+): m/z calcd for [C11H11NO4 + Na]+: 244.0580, found: 125.6, 119.1, 116.6, 112.2, 90.3, 83.0, 50.3, 33.9, 31.1 ppm.
244.0567.
Ethyl (Z)-2-(2-hydroxy-2H-benzo[b][1,4]oxazin-3(4H)yli-dene)- 300.1208.
HRMS (ES+): m/z calcd for [C15H19NO4 + Na]+: 300.1206, found:
ꢁ
acetate (1b). Brown solid, mp: 145–146 C. IR (KBr): vmax 3330,
3269, 2986, 1657, 1621, 1500, 1413, 1364, 1305, 1232, 1166 cmꢀ1
Ethyl (Z)-2-(6-tert-butyl-2-hydroxy-2H-benzo[b][1,4]oxazin-
3(4H)-ylidene)acetate (4b). Brown solid, mp: 121–122 ꢁC. IR
.
1H NMR (500 MHz, CDCl3): d 10.06 (br s, 1H), 6.97 (t, J ¼ 7.0 Hz, (KBr): vmax 3426, 3311, 2973, 1664, 1625, 1507, 1422, 1366, 1287,
2H), 6.93 (d, J ¼ 8.0 Hz, 1H), 6.86 (d, J ¼ 7.0 Hz, 1H), 5.70 (s, 1H), 1225, 1164 cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.10 (br s, 1H),
4.89 (s, 1H), 4.17–4.09 (m, 2H), 3.60 (br s, 1H), 1.27 (t, J ¼ 7.0 Hz, 6.94 (dd, J ¼ 2.5, 8.5 Hz, 1H), 6.90 (s, 1H), 6.88 (d, J ¼ 2.0 Hz,
3H) ppm. 13C NMR (125 MHz, CDCl3): d 170.7, 148.3, 140.7, 126.2, 1H), 5.68 (d, J ¼ 4.5 Hz, 1H), 4.88 (s, 1H), 4.21–4.11 (m, 2H), 3.43
123.2, 122.9, 117.9, 115.5, 90.7, 84.7, 59.7, 14.3 ppm. HRMS (ES+): (br d, J ¼ 7.0 Hz, 1H), 1.28 (s, 12H) ppm. 13C NMR (125 MHz,
m/z calcd for [C12H13NO4 + Na]+: 258.0737, found: 258.0729.
CDCl3): d 171.0, 148.5, 146.4, 138.3, 125.5, 119.9, 117.4, 113.1,
(Z)-2-(2-hydroxy-6-methyl-2H-benzo[b][1,4]oxazin- 91.2, 84.5, 59.5, 34.0, 31.3, 14.6 ppm. HRMS (ES+): m/z calcd for
3(4H)-ylidene)acetate (2a). Brown solid, mp: 158–159 ꢁC. IR [C16H21NO4 + Na]+: 314.1363, found: 314.1343.
Methyl
(KBr): vmax 3336, 3270, 2925, 1659, 1623, 1514, 1408, 1351, 1290
Methyl (Z)-2-(6-chloro-2-hydroxy-2H-benzo[b][1,4]oꢁxazin-
cmꢀ1. 1H NMR (500 MHz, CDCl3): d 9.97 (br s, 1H), 6.86 (d, J ¼ 3(4H)-ylidene)acetate (5a). Brown solid, mp: 175–176 C. IR
8.0 Hz, 1H), 6.72 (d, J ¼ 8.5 Hz, 1H), 6.68 (s, 1H), 5.67 (s, 1H), (KBr): vmax 3321, 3270, 2982, 2912, 1653, 1624, 1515, 1413,
4.88 (s, 1H), 3.67 (s, 3H), 3.49 (br s, 1H), 2.28 (s, 3H) ppm. 13C 1364, 1289, 1234, 1170 cmꢀ1. 1H NMR (500 MHz, DMSO-d6): d
NMR (125 MHz, CDCl3): d 170.7, 149.4, 139.5, 132.2, 126.2, 10.04 (br s, 1H), 6.90–6.86 (m, 3H), 5.71 (s, 1H), 4.94 (s, 1H),
123.0, 117.3, 115.7, 90.6, 83.5, 50.6, 20.7 ppm. HRMS (ES+): m/z 3.71 (s, 3H), 3.40 (br s, 1H) ppm. 13C NMR (125 MHz, DMSO-
calcd for [C12H13NO4 + Na]+: 258.0737, found: 258.0736.
d6): d 169.2, 148.0, 140.1, 128.9, 125.9, 121.4, 119.0, 115.8,
Ethyl (Z)-2-(2-hydroxy-6-methyl-2H-benzo[b][1,4]oꢁxazin- 90.0, 84.7, 50.5 ppm. HRMS (ES+): m/z calcd for [C11H10ClNO4
3(4H)-ylidene)acetate (2b). Brown solid, mp: 148–149 C. IR + Na]+: 278.0191, found: 278.0192.
(KBr): vmax 3328, 3264, 1654, 1621, 1489, 1415, 1353, 1288
Ethyl (Z)-2-(6-chloro-2-hydroxy-2H-benzo[b][1,4]oxazin-
cmꢀ1. 1H NMR (500 MHz, CDCl3): d 9.99 (br s, 1H), 6.85 (d, J ¼ 3(4H)-ylidene)acetate (5b). Brown solid, mp: 144–145 C. IR
ꢁ
8.0 Hz, 1H), 6.72 (d, J ¼ 8.0 Hz, 1H), 6.67 (s, 1H), 5.67 (s, 1H), (KBr): vmax 3329, 3267, 2986, 1657, 1608, 1495, 1414, 1341,
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1303, 1228, 1169 cmꢀ1
.
1H NMR (500 MHz, CDCl3): d 10.08 3.54 (s, 3H), 1.14 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3): d
(br s, 1H), 6.89–6.87 (m, 3H), 5.70 (d, J ¼ 5.5 Hz, 1H), 4.94 (s, 170.4, 156.1, 147.6, 138.4, 123.7, 120.0, 116.4, 112.4, 99.9, 85.0,
1H), 4.19 (q, J ¼ 7.0 Hz, 2H), 3.24 (d, J ¼ 6.0 Hz, 1H), 1.30 (t, J 61.3, 36.0, 31.2 ppm. HRMS (ES+): m/z calcd for [C15H19NO4 +
¼ 7.5 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): d 169.0, Na]+: 300.1206, found: 300.1208.
147.8, 139.7, 127.5, 126.4, 121.2, 117.6, 114.4, 89.7, 84.5,
4-(5-Chloro-2-hydroxyphenylamino)-5-methoxyfuran-2(5H)-
one (11). Viscous liquid. IR (KBr): 3393, 3289, 2929, 1744, 1644,
58.1, 13.5 ppm. HRMS (ES+): m/z calcd for [C12H12ClNO4
+
Na]+: 292.0347, found: 292.0321.
1590, 1538, 1433, 1312, 1178, 1124 cmꢀ1. H NMR (500 MHz,
1
Methyl (Z)-2-(7-chloro-2-hydroxy-2H-benzo[b][1,4]oxazin- DMSO-d6): d 10.34 (br s, 1H), 8.96 (s, 1H), 7.18 (d, J ¼ 2.0 Hz,
3(4H)-ylidene)acetate (6a). Brown solid, mp: 179–180 ꢁC. IR 1H), 7.02 (dd, J ¼ 2.5, 9.0 Hz, 1H), 6.91 (d, J ¼ 8.5 Hz, 1H), 5.90
(KBr): vmax 3336, 3285, 1658, 1627, 1493, 1423, 1284, 1224, 1017 (s, 1H), 5.09 (s, 1H), 3.45 (s, 3H) ppm. 13C NMR (125 MHz,
cmꢀ1. 1H NMR (500 MHz, CDCl3): d 9.90 (br s, 1H), 7.36 (br d, J ¼ DMSO-d6): d 171.8, 160.2, 147.7, 128.5, 124.7, 122.7, 120.3,
5.0 Hz, 1H), 6.78–6.74 (m, 2H), 6.64 (d, J ¼ 8.5 Hz, 1H), 5.50 (br 116.9, 99.6, 85.1, 55.1 ppm. HRMS (ES+): m/z calcd for
d, J ¼ 4.0 Hz, 1H), 4.73 (s, 1H), 3.54 (s, 3H) ppm. 13C NMR (125 [C11H10ClNO4 + Na]+: 278.0191, found: 278.0192.
MHz, CDCl3): d 169.6, 148.0, 141.3, 126.2, 124.8, 121.9, 116.9,
4-(4-Chloro-2-hydroxyphenylamino)-5-methoxyfuran-2(5H)-
115.3, 90.1, 83.6, 50.0 ppm. HRMS (ES+): m/z calcd for one (12). Viscous liquid. IR (KBr): vmax 3278, 2932, 1711, 1621,
1
[C11H10ClNO4 + Na]+: 278.0191, found: 278.0181.
Ethyl
1576, 1531, 1428, 1361, 1168, 1111 cmꢀ1. H NMR (500 MHz,
(Z)-2-(7-chloro-2-hydroxy-2H-benzo[b][1,4]oxazin- CDCl3): d 10.08 (br s, 1H), 7.05 (s, 1H), 7.99 (d, J ¼ 7.5 Hz, 2H),
3(4H)-ylidene)acetate (6b). Brown solid, mp: 138–139 ꢁC. IR 6.81 (q, J ¼ 8.0, 15.0 Hz, 2H), 5.80 (s, 1H), 5.34 (s, 1H), 3.56 (s,
(KBr): vmax 3271, 2988, 1656, 1622, 1497, 1412, 1291, 1224, 1169, 3H) ppm. 13C NMR (125 MHz, CDCl3): d 170.1, 156.4, 138.5,
1021 cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.08 (br s, 1H), 6.98 130.9, 125.1, 122.6, 118.1, 116.6, 99.2, 85.0, 51.7 ppm. HRMS
(d, J ¼ 2.0 Hz, 1H), 6.95 (dd, J ¼ 2.5, 8.5 Hz, 1H), 6.78 (d, J ¼ 8.5 (ES+): m/z calcd for [C11H10ClNO4 + Na]+: 278.0191, found:
Hz, 1H), 5.70 (s, 1H), 4.91 (s, 1H), 4.19–4.11 (m, 2H), 3.49 (br s, 278.0199.
1H), 1.29 (t, J ¼ 7.0 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): d
Methyl
(Z)-2-(2-(piperidin-1-yl)-2H-benzo[b][1,4]oxazin-
169.6, 148.2, 141.5, 126.4, 125.3, 122.1, 117.4, 115.6, 90.1, 84.0, 3(4H)-ylidene)acetate (13a). Pale yellow viscous liquid. IR
59.0, 13.7 ppm. HRMS (ES+): m/z calcd for [C12H12ClNO4 + Na]+: (KBr): vmax 3289, 1655, 1623, 1504, 1426, 1377, 1295, 1134
292.0347, found: 292.0355.
cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.36 (br s, 1H), 7.15 (t, J
4-(2-Hydroxyphenylamino)-5-methoxyfuran-2(5H)-one (7). ¼ 8.0 Hz, 2H), 7.03 (dt, J ¼ 1.5, 8.0 Hz, 1H), 6.97 (d, J ¼ 8.0 Hz,
Viscous liquid. IR (KBr): vmax 3299, 2936, 1717, 1615, 1580, 1533, 1H), 5.16 (s, 2H), 3.87 (s, 3H), 2.98 (quintet, J ¼ 5.5 Hz, 2H),
1436, 1367, 1157, 1121 cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.18 2.67 (quintet, J ¼ 5.5 Hz, 2H), 1.61–1.54 (m, 4H), 1.51–1.44
(br s, 1H), 7.03 (dt, J ¼ 1.5, 8.0 Hz, 1H), 7.17–7.13 (m, 3H), 6.97 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 170.3, 155.9,
(d, J ¼ 8.0 Hz, 1H), 5.80 (s, 1H), 5.34 (s, 1H), 3.72 (s, 3H) ppm. 140.0, 138.1, 125.7, 124.1, 122.8, 117.0, 114.8, 90.7, 85.2, 51.5,
13C NMR (125 MHz, CDCl3): d 170.3, 155.9, 140.0, 138.1, 125.7, 49.1, 28.1, 24.1 ppm. HRMS (ES+): m/z calcd for [C16H20N2O3
122.8, 117.0, 114.8, 100.2, 84.9, 51.6 ppm. HRMS (ES+): m/z + Na]+: 311.1366, found: 311.1359.
calcd for [C11H11NO4 + Na]+: 244.0580, found: 244.0573.
Ethyl (Z)-2-(2-(piperidin-1-yl)-2H-benzo[b][1,4]oxazin-3(4H)-yli-
4-(2-Hydroxy-5-methylphenylamino)-5-methoxyfuran-2(5H)- dene)acetate (13b). Pale yellow viscous liquid. IR (KBr): vmax
1
one (8). Viscous liquid. IR (KBr): vmax 3345, 3277, 2931, 1653, 3278, 1647, 1594, 1426, 1368, 1279, 1134 cmꢀ1. H NMR (500
1
1605, 1527, 1438, 1323, 1167, 1130 cmꢀ1. H NMR (500 MHz, MHz, CDCl3): d 10.43 (s, 1H), 6.93–6.87 (m, 3H), 6.82–6.80 (m,
CDCl3): d 10.06 (br s, 1H), 7.15 (s, 1H), 6.98 (s, 1H), 6.83 (d, J ¼ 1H), 5.18 (s, 1H), 5.11 (d, J ¼ 0.5 Hz, 1H), 4.25–4.17 (m, 2H),
8.0 Hz, 1H), 6.78 (d, J ¼ 8.0 Hz, 1H), 5.31 (s, 1H), 5.79 (s, 1H), 3.06–3.01 (m, 2H), 2.72–2.68 (m, 2H), 1.63–1.58 (m, 4H), 1.53–
3.53 (s, 3H), 2.26 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d 1.50 (m, 2H), 1.33 (t, J ¼ 7.5 Hz, 3H) ppm. 13C NMR (125 MHz,
170.3, 156.1, 138.2, 135.7, 123.7, 123.4, 117.6, 116.7, 100.2, 84.9, CDCl3): d 171.0, 150.5, 144.4, 126.6, 122.5, 122.0, 116.6, 115.0,
51.4, 20.9 ppm. HRMS (ES+): m/z calcd for [C12H13NO4 + Na]+: 90.8, 83.6, 59.4, 49.1, 26.2, 24.3, 14.5 ppm. HRMS (ES+): m/z
258.0737, found: 258.0738.
calcd for [C17H22N2O3 + Na]+: 325.1523, found: 325.1522.
4-(2-Hydroxy-4-methylphenylamino)-5-methoxyfuran-2(5H)-
Methyl (Z)-2-(6-methyl-2-(piperidin-1-yl)-2H-benzo[b][1,4]-
one (9). Viscous liquid. IR (KBr): vmax 3288, 2927, 1725, 1629, oxazin-3(4H)-ylidene)acetate (14a). Pale yellow viscous liquid. IR
1
1586, 1528, 1432, 1366, 1169, 1117 cmꢀ1. H NMR (500 MHz, (KBr): vmax 3278, 1666, 1622, 1504, 1442, 1381, 1281, 1153 cmꢀ1
.
CDCl3): d 10.05 (br s, 1H), 7.09–7.03 (m, 1H), 6.94 (br s, 1H), 6.74 1H NMR (500 MHz, CDCl3): d 10.31 (br s, 1H), 6.77 (d, J ¼ 8.0 Hz,
(d, J ¼ 8.0 Hz, 2H), 5.78 (s, 1H), 5.23 (s, 1H), 3.54 (s, 3H), 2.26 (s, 1H), 6.66 (dd, J ¼ 1.0, 7.5 Hz, 1H), 6.01 (d, J ¼ 1.5 Hz, 1H), 5.11
3H) ppm. 13C NMR (125 MHz, CDCl3): d 173.5, 159.7, 146.7, (s, 1H), 5.08 (s, 1H), 3.72 (s, 3H), 3.00 (quintet, J ¼ 5.5 Hz, 2H),
135.6, 121.4, 119.4, 116.6, 100.1, 85.7, 55.1, 20.9 ppm. HRMS 2.67 (quintet, J ¼ 5.5 Hz, 2H), 2.54 (s, 3H), 1.60–1.53 (m, 4H),
(ES+): m/z calcd for [C12H13NO4 + Na]+: 258.0737, found: 1.50–1.43 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 170.4,
258.0741.
156.0, 138.2, 135.7, 123.7, 123.5, 117.6, 116.7, 115.1, 90.4, 85.6,
4-(5-tert-Butyl-2-hydroxyphenylamino)-5-methoxyfuran-2(5H)- 51.4, 48.0, 29.6, 24.2, 20.9 ppm. HRMS (ES+): m/z calcd for
one (10). Viscous liquid. IR (KBr): vmax 3295, 2953, 1716, 1621, [C17H22N2O3 + Na]+: 325.1523, found: 325.1519.
1578, 1532, 1441, 1372, 1168, 1122 cmꢀ1
.
1H NMR (500 MHz,
Ethyl (Z)-2-(6-methyl-2-(piperidin-1-yl)-2H-benzo[b][1,4]-oxa-
CDCl3): d 10.11 (br s, 1H), 7.09 (d, J ¼ 8.5 Hz, 1H), 7.05 (dd, J ¼ zin-3(4H)-ylidene)acetate (14b). Pale yellow viscous liquid. IR
2.0, 9.0 Hz, 2H), 6.97 (d, J ¼ 2.0 Hz, 1H), 5.77 (s, 1H), 5.27 (s, 1H), (KBr): vmax 3308, 1661, 1618, 1507, 1439, 1379, 1285, 1147 cmꢀ1
.
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1H NMR (500 MHz, CDCl3): d 10.31 (br s, 1H), 6.77 (d, J ¼ 8.0 Hz, (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 170.9, 149.7, 142.9,
1H), 6.66 (d, J ¼ 8.0 Hz, 1H), 6.61 (s, 1H), 5.11 (s, 1H), 5.08 (s, 127.5, 126.6, 122.0, 117.5, 114.8, 90.9, 84.5, 50.7, 49.0, 29.7, 24.2
1H), 4.22–4.11 (m, 2H), 3.00 (quintet, J ¼ 5.5 Hz, 2H), 2.67 ppm. HRMS (ES+): m/z calcd for [C16H19ClN2O3 + Na]+:
(quintet, J ¼ 5.5 Hz, 2H), 2.25 (s, 3H), 1.61–1.53 (m, 4H), 1.52– 345.0976, found: 345.0988.
1.42 (m, 2H), 1.31 (t, J ¼ 6.5 Hz, 3H) ppm. 13C NMR (125 MHz,
Ethyl (Z)-2-(6-chloro-2-(piperidin-1-yl)-2H-benzo[b][1,4]-oxa-
CDCl3): d 169.9, 156.1, 138.1, 138.0, 135.7, 124.0, 123.4, 116.6, zin-3(4H)-ylidene)acetate (17b). Pale yellow viscous liquid. IR
115.0, 90.9, 82.9, 60.3, 49.0, 25.7, 20.9, 14.3 ppm. HRMS (ES+): (KBr): vmax 3243, 1655, 1621, 1507, 1379, 1311, 1222, 1140 cmꢀ1
m/z calcd for [C18H24N2O3 + Na]+: 339.1679, found: 339.1667. 1H NMR (500 MHz, CDCl3): d 10.39 (br s, 1H), 6.80–6.78 (m, 3H),
.
Methyl (Z)-2-(7-methyl-2-(piperidin-1-yl)-2H-benzo[b][1,4]- 5.11 (s, 2H), 4.22–4.12 (m, 2H), 2.99 (quintet, J ¼ 5.5 Hz, 2H),
oxazin-3(4H)-ylidene)acetate (15a). Pale yellow viscous liquid. IR 2.67 (quintet, J ¼ 5.5 Hz, 2H), 1.62–1.54 (m, 4H), 1.51–1.43 (m,
1
(KBr): vmax 3268, 1648, 1524, 1430, 1374, 1271, 1134 cmꢀ1. H 2H), 1.29 (t, J ¼ 7.0 Hz, 3H) ppm. 13C NMR (125 MHz, CDCl3): d
NMR (500 MHz, CDCl3): d 10.34 (br s, 1H), 6.72 (s, 1H), 6.68–6.67 169.7, 155.4, 138.5, 130.8, 125.2, 122.5, 118.1, 114.7, 92.7, 84.4,
(m, 2H), 5.13 (s, 1H), 5.06 (d, J ¼ 0.5 Hz, 1H), 3.71 (s, 3H), 3.02– 60.6, 49.1, 26.7, 23.2, 14.2 ppm. HRMS (ES+): m/z calcd for
2.97 (m, 2H), 2.68–2.64 (m, 2H), 2.25 (s, 3H), 1.60–1.54 (m, 4H), [C17H21ClN2O3 + Na]+: 359.1133, found: 359.1123.
1.51–1.47 (m, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 171.2,
Methyl
(Z)-2-(7-chloro-2-(piperidin-1-yl)-2H-benzo[b][1,4]-
150.6, 144.1, 132.4, 124.0, 122.3, 117.0, 114.6, 90.7, 82.4, 50.5, oxazin-3(4H)-ylidene)acetate (18a). Pale yellow viscous liquid. IR
49.0, 26.1, 24.2, 20.8 ppm. HRMS (ES+): m/z calcd for (KBr): vmax 3321, 1657, 1619, 1511, 1433, 1373, 1289, 1131 cmꢀ1
.
[C17H22N2O3 + Na]+: 325.1523, found: 325.1533.
1H NMR (500 MHz, CDCl3): d 10.42 (br s, 1H), 7.17 (d, J ¼ 2.0 Hz,
Ethyl (Z)-2-(7-methyl-2-(piperidin-1-yl)-2H-benzo[b][1,4]-oxa- 1H), 7.12 (dd, J ¼ 2.5, 8.5 Hz, 1H), 6.90 (d, J ¼ 9.0 Hz, 1H), 5.12
zin-3(4H)-ylidene)acetate (15b). Pale yellow viscous liquid. IR (s, 1H), 5.08 (s, 1H), 3.82 (s, 3H), 3.00 (quintet, J ¼ 5.0 Hz, 2H),
1
(KBr): vmax 3278, 1660, 1515, 1453, 1382, 1274, 1147 cmꢀ1. H 2.67 (quintet, J ¼ 5.5 Hz, 2H), 1.53–1.42 (m, 4H), 1.41–1.34 (m,
NMR (500 MHz, CDCl3): d 10.36 (br s, 1H), 6.72 (s, 1H), 6.67 (s, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 170.7, 149.6, 144.9,
2H), 5.13 (s, 1H), 5.05 (s, 1H), 4.22–4.12 (m, 2H), 3.00 (quintet, J 126.8, 125.2, 121.7, 116.9, 115.4, 91.1, 86.3, 50.7, 49.4, 29.6, 25.2
¼ 5.5 Hz, 2H), 2.67 (quintet, J ¼ 5.5 Hz, 2H), 2.26 (s, 3H), 1.60– ppm. HRMS (ES+): m/z calcd for [C16H19ClN2O3 + Na]+:
1.55 (m, 4H), 1.50–1.45 (m, 2H), 1.31 (t, J ¼ 7.0 Hz, 3H). 13C NMR 345.0976, found: 345.0977.
(125 MHz, CDCl3): d 170.9, 150.5, 144.2, 132.3, 124.1, 122.3,
Ethyl (Z)-2-(7-chloro-2-(piperidin-1-yl)-2H-benzo[b][1,4]oxa-
117.0, 114.7, 90.8, 82.9, 59.2, 49.0, 25.9, 20.8, 14.5 ppm. HRMS zin-3(4H)-ylidene)acetate (18b). Pale yellow viscous liquid. IR
(ES+): m/z calcd for [C18H24N2O3 + Na]+: 339.1679, found: (KBr): vmax 3266, 1659, 1604, 1486, 1436, 1328, 1266, 1148 cmꢀ1
339.1665.
1H NMR (500 MHz, CDCl3): d 10.42 (br s, 1H), 6.85–6.83 (m, 2H),
.
Methyl (Z)-2-(6-tert-butyl-2-(piperidin-1-yl)-2H-benzo[b]-[1,4]- 6.71–6.68 (m, 1H), 5.19 (s, 1H), 5.11 (s, 1H), 4.25–4.13 (m, 2H),
oxazꢁin-3(4H)-ylidene)acetate (16a). Pale yellow solid, mp: 100– 2.99 (quintet, J ¼ 5.0 Hz, 2H), 2.67 (quintet, J ¼ 5.0 Hz, 2H),
101 C. IR (KBr): vmax 3261, 1661, 1619, 1503, 1435, 1381, 1265, 1.53–1.41 (m, 6H), 1.34 (t, J ¼ 7.5 Hz, 3H) ppm. 13C NMR (125
1
1139 cmꢀ1. H NMR (500 MHz, CDCl3): d 10.39 (br s, 1H), 6.88 MHz, CDCl3): d 170.7, 149.6, 145.0, 126.7, 125.2, 121.7, 116.9,
(dd, J ¼ 2.0, 8.5 Hz, 1H), 6.83–6.81 (m, 2H), 5.15 (s, 1H), 5.11 (s, 115.4, 91.0, 84.3, 59.4, 49.0, 26.1, 24.2, 14.4 ppm. HRMS (ES+):
1H), 3.73 (s, 3H), 3.01 (quintet, J ¼ 5.0 Hz, 2H), 2.68 (quintet, J ¼ m/z calcd for [C17H21ClN2O3 + Na]+: 359.1133, found: 359.1143.
5.0 Hz, 2H), 1.61–1.56 (m, 4H), 1.51–1.45 (m, 2H), 1.27 (s, 9H)
Methyl (Z)-2-(2-(pyrrolidin-1-yl)-2H-benzo[b][1,4]oxazin-
ppm. 13C NMR (125 MHz, CDCl3): d 171.3, 151.0, 145.2, 142.0, 3(4H)-ylidene)acetate (19). Thick brown liquid. IR (KBr): vmax
125.8, 119.3, 115.9, 112.2, 90.8, 82.7, 50.6, 49.1, 34.2, 31.3, 26.0, 3300, 1667, 1622, 1501, 1429, 1269, 1145 cmꢀ1. H NMR (500
1
24.3 ppm. HRMS (ES+): m/z calcd for [C20H28N2O3 + Na]+: MHz, CDCl3): d 10.26 (br s, 1H), 6.90–6.85 (m, 3H), 6.81–6.78 (m,
367.1992, found: 367.1986.
1H), 5.29 (s, 1H), 5.04 (s, 1H), 3.05–3.00 (m, 2H), 2.90–2.85 (m,
Ethyl (Z)-2-(6-tert-butyl-2-(piperidin-1-yl)-2H-benzo[b][1,4]- 2H), 3.72 (s, 3H), 1.81–1.75 (m, 4H) ppm. 13C NMR (125 MHz,
oxazin-3(4H)-ylidene)acetate (16b). Pale yellow viscous liquid. CDCl3): d 171.1, 150.4, 144.1, 126.8, 122.5, 122.1, 116.7, 115.1,
IR (KBr): vmax 3253, 1652, 1616, 1503, 1385, 1310, 1217, 1138 87.5, 83.9, 50.7, 40.8, 24.5 ppm. HRMS (ES+): m/z calcd for
1
cmꢀ1. H NMR (500 MHz, CDCl3): d 10.43 (br s, 1H), 6.89–6.87 [C15H18N2O3 + Na]+: 297.1209, found: 297.1214.
(m, 1H), 6.81–6.80 (m, 2H), 5.14 (s, 1H), 5.09 (s, 1H), 4.25–4.12
Methyl (Z)-2-(6-methyl-2-(pyrrolidin-1-yl)-2H-benzo[b][1,4]-
(m, 2H), 3.01 (quintet, J ¼ 5.5 Hz, 2H), 2.68 (quintet, J ¼ 5.5 Hz, oxazin-3(4H)-ylidene)acetate (20). Thick brown liquid. IR (KBr):
1
2H), 1.61–1.53 (m, 4H), 1.52–1.44 (m, 2H), 1.32 (t, J ¼ 7.0 Hz, vmax 3278, 1667, 1623, 1502, 1434, 1275, 1164 cmꢀ1. H NMR
3H), 1.27 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3): d 170.1, (500 MHz, CDCl3): d 10.20 (br s, 1H), 6.77 (d, J ¼ 8.0 Hz, 1H),
156.2, 149.3, 138.3, 123.6, 119.9, 116.4, 111.7, 90.7, 84.8, 60.3, 6.69–6.61 (m, 2H), 5.23 (s, 1H), 5.01 (s, 1H), 3.72 (s, 3H), 3.04–
50.0, 34.6, 31.3, 26.8, 25.2, 14.3 ppm. HRMS (ES+): m/z calcd for 2.98 (m, 2H), 2.87–2.84 (m, 2H), 2.26 (s, 3H), 1.81–1.74 (m, 4H)
[C21H30N2O3 + Na]+: 381.2149, found: 381.2132.
ppm. 13C NMR (125 MHz, CDCl3): d 170.0, 149.5, 140.9, 130.6,
Methyl
(Z)-2-(6-chloro-2-(piperidin-1-yl)-2H-benzo[b][1,4]- 125.5, 121.9, 115.3, 114.6, 86.5, 82.7, 49.6, 46.9, 23.4, 19.8 ppm.
oxazin-3(4H)-ylidene)acetate (17a). Pale yellow solid, mp: 76– HRMS (ES+): m/z calcd for [C16H20N2O3 + Na]+: 311.1366, found:
ꢁ
78 C. IR (KBr): vmax 3245, 1663, 1608, 1498, 1442, 1333, 1267, 311.1356.
1158 cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.36 (br s, 1H), 6.82–
Methyl (Z)-2-(7-methyl-2-(pyrrolidin-1-yl)-2H-benzo[b][1,4]-
6.77 (m, 3H), 5.13 (s, 2H), 3.73 (s, 3H), 2.98 (quintet, J ¼ 5.5 Hz, oxazin-3(4H)-ylidene)acetate (21). Thick brown liquid. IR (KBr):
1
2H), 2.67 (quintet, J ¼ 5.0 Hz, 2H), 1.59–1.55 (m, 4H), 1.51–1.46 vmax 3287, 1663, 1614, 1516, 1430, 1387, 1271, 1145 cmꢀ1. H
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NMR (500 MHz, CDCl3): d 10.23 (br s, 1H), 6.72 (s, 1H), 6.69–6.68
(m, 2H), 5.26 (s, 1H), 4.99 (s, 1H), 3.71 (s, 3H), 3.03–2.98 (m, 2H),
2.88–2.83 (m, 2H), 2.26 (s, 3H), 1.80–1.74 (m, 4H) ppm. 13C NMR
(125 MHz, CDCl3): d 171.0, 150.3, 143.8, 132.3, 124.2, 122.4,
117.1, 114.6, 87.4, 83.1, 50.5, 47.7, 24.4, 20.7 ppm. HRMS (ES+):
m/z calcd for [C16H20N2O3 + Na]+: 311.1366, found: 311.1369.
Methyl (Z)-2-(6-tert-butyl-2-(pyrrolidin-1-yl)-2H-benzo[b]-[1,4]-
oxazin-3(4H)-ylidene)acetate (22). Thick brown liquid. IR (KBr):
Methyl (Z)-2-(2-(dibenzylamino)-7-methyl-2H-benzo[b][1,4]-
oxazin-3(4H)-ylidene)acetate (27). Yellow solid, mp: 78–79 ꢁC. IR
1
(KBr): vmax 3261, 1665, 1619, 1517, 1452, 1383, 1277 cmꢀ1. H
NMR (500 MHz, CDCl3): d 10.52 (br s, 1H), 7.50 (d, J ¼ 7.5 Hz,
4H), 7.41 (t, J ¼ 7.5 Hz, 4H), 7.33 (t, J ¼ 7.5 Hz, 2H), 6.89 (s, 1H),
6.77–6.73 (m, 2H), 5.40 (s, 1H), 5.33 (s, 1H), 4.17 (d, J ¼ 14.0 Hz,
2H), 3.95 (d, J ¼ 14.0 Hz, 2H), 3.79 (s, 3H), 2.36 (s, 3H) ppm. 13
C
NMR (125 MHz, CDCl3): d 171.0, 151.3, 143.7, 138.2, 132.5,
128.5, 128.4, 127.2, 123.8, 122.6, 117.1, 114.7, 85.6, 82.3, 52.7,
50.5, 20.8 ppm.
vmax 3451, 1664, 1620, 1513, 1458, 1383, 1255, 1174 cmꢀ1 1H
.
NMR (500 MHz, CDCl3): d 10.29 (br s, 1H), 6.88 (dd, J ¼ 2.5, 8.5
Hz, 1H), 6.82 (d, J ¼ 2.0 Hz, 1H), 6.81 (d, J ¼ 8.5 Hz, 1H), 6.80 (s,
1H), 5.28 (s, 1H), 5.03 (d, J ¼ 1.0 Hz, 1H), 3.72 (s, 3H), 3.05–3.00
(m, 2H), 2.90–2.85 (m, 2H), 1.81–1.76 (m, 4H), 1.27 (s, 9H) ppm.
13C NMR (125 MHz, CDCl3): d 171.2, 150.7, 145.3, 141.8, 126.0,
119.4, 116.0, 112.4, 87.5, 83.4, 50.6, 47.8, 34.2, 31.4, 24.5 ppm.
HRMS (ES+): m/z calcd for [C19H26N2O3 + Na]+: 353.1836, found:
353.1839.
Methyl (Z)-2-(6-tert-butyl-2-(dibenzylamino)-2H-benzo[b]-
[1,4]oxazin-3(4H)-ylidene)acetate (28). Yellow solid, mp: 98–
ꢁ
99 C. IR (KBr): vmax 3272, 1665, 1618, 1521, 1492, 1383, 1259
cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.49 (br s, 1H), 7.44 (d, J ¼
7.5 Hz, 4H), 7.36 (t, J ¼ 7.5 Hz, 4H), 7.28 (t, J ¼ 7.0 Hz, 2H), 6.97–
6.92 (m, 2H), 6.84 (d, J ¼ 1.5 Hz, 1H), 5.37 (s, 1H), 5.26 (s, 1H),
4.11 (d, J ¼ 14.0 Hz, 2H), 3.90 (d, J ¼ 14.0 Hz, 2H), 3.75 (s, 3H),
1.30 (s, 9H) ppm. 13C NMR (125 MHz, CDCl3): d 171.2, 151.7,
145.5, 141.6, 138.3, 128.6, 128.5, 127.3, 125.7, 119.5, 116.0,
112.3, 85.7, 82.5, 52.8, 50.7, 34.3, 31.4 ppm.
Methyl (Z)-2-(6-chloro-2-(pyrrolidin-1-yl)-2H-benzo[b][1,4]-
oxazin-3(4H)-ylidene)acetate (23). Thick brown liquid. IR (KBr):
1
vmax 3280, 1669, 1629, 1498, 1435, 1379, 1265, 1158 cmꢀ1. H
NMR (500 MHz, CDCl3): d 10.24 (br s, 1H), 6.80–6.79 (m, 2H),
6.78–6.77 (m, 1H), 5.25 (s, 1H), 5.06 (s, 1H), 3.01–2.97 (m, 2H),
2.87–2.83 (m, 2H), 3.71 (s, 3H), 1.80–1.74 (m, 4H) ppm. 13C NMR
(125 MHz, CDCl3): d 170.8, 149.5, 142.7, 127.8, 126.6, 122.0,
117.6, 114.8, 87.7, 85.1, 50.7, 47.8, 24.4 ppm. HRMS (ES+): m/z
calcd for [C15H17ClN2O3 + Na]+: 331.0820, found: 331.0816.
Methyl (Z)-2-(7-chloro-2-(pyrrolidin-1-yl)-2H-benzo[b][1,4]-
oxazin-3(4H)-ylidene)acetate (24). Thick brown liquid. IR (KBr):
Methyl (Z)-2-(6-chloro-2-(dibenzylamino)-2H-benzo[b][1,4]-
oxazin-3(4H)-ylidene)acetate (29). Pale yellow solid, mp: 108–
ꢁ
109 C. IR (KBr): vmax 3257, 1662, 1617, 1518, 1454, 1363, 1232
1
cmꢀ1. H NMR (500 MHz, CDCl3): d 10.46 (br s, 1H), 7.42–7.41
(m, 4H), 7.37 (t, J ¼ 7.5 Hz, 4H), 7.29 (t, J ¼ 7.5 Hz, 4H), 6.92–6.90
(m, 1H), 6.87 (dd, J ¼ 2.0, 8.5 Hz, 1H), 6.79 (d, J ¼ 2.0 Hz, 1H),
5.39 (s, 1H), 5.27 (s, 1H), 4.10 (d, J ¼ 13.5 Hz, 2H), 3.87 (d, J ¼
14.0 Hz, 2H), 3.75 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d
170.8, 150.4, 142.5, 138.0, 128.5, 128.5, 127.3, 126.9, 122.1,
117.5, 114.8, 85.9, 84.2, 52.8, 50.8 ppm.
1
vmax 3282, 1668, 1623, 1508, 1437, 1382, 1278, 1164 cmꢀ1. H
NMR (500 MHz, CDCl3): d 10.20 (br s, 1H), 6.82 (d, J ¼ 2.0 Hz,
1H), 6.77 (dd, J ¼ 2.0, 8.0 Hz, 1H), 6.63 (d, J ¼ 8.5 Hz, 1H), 5.22
(s, 1H), 4.97 (s, 1H), 3.64 (s, 3H), 2.96–2.91 (m, 2H), 2.81–2.77
(m, 2H), 1.74–1.61 (m, 4H) ppm. 13C NMR (125 MHz, CDCl3): d
170.0, 148.6, 143.7, 125.9, 124.6, 120.9, 116.1, 114.5, 86.8, 83.6,
49.8, 46.8, 23.5 ppm. HRMS (ES+): m/z calcd for [C15H17ClN2O3 +
Na]+: 331.0820, found: 331.0829.
Methyl (Z)-2-(2-(dibenzylamino)-2H-benzo[b][1,4]oxazin-
3(4H)-ylidene)acetate (25). Pale yellow solid, mp: 72–73 ꢁC. IR
(KBr): vmax 3271, 1659, 1612, 1514, 1456, 1374, 1247 cmꢀ1. 1H
NMR (500 MHz, CDCl3): d 10.51 (br s, 1H), 7.46 (d, J ¼ 7.5 Hz,
4H), 7.38 (t, J ¼ 7.5 Hz, 4H), 7.31 (t, J ¼ 7.0 Hz, 2H), 7.05–7.02
(m, 1H), 6.97–6.91 (m, 2H), 6.85–6.81 (m, 1H), 5.39 (s, 1H),
5.32 (s, 1H), 4.14 (d, J ¼ 14.0 Hz, 2H), 3.92 (d, J ¼ 14.0 Hz, 2H),
3.77 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d 171.0, 151.4,
144.0, 138.3, 128.6, 128.5, 127.3, 126.4, 122.6, 122.2, 116.6,
115.0, 85.7, 83.0, 52.9, 50.7 ppm.
Methyl (Z)-2-(2-morpholino-2H-benzo[b][1,4]oxazin-3(4H)-yli-
dene)acetate (30). Yellow solid, mp: 78–79 ꢁC. IR (KBr): vmax
1
3261, 1671, 1630, 1518, 1462, 1362, 1271 cmꢀ1. H NMR (500
MHz, CDCl3): d 10.35 (br s, 1H), 6.92–6.87 (m, 3H), 6.81–6.79 (m,
1H), 5.12 (s, 1H), 5.08 (s, 1H), 3.73 (s, 3H), 3.70 (t, J ¼ 5.0 Hz,
4H), 3.04 (td, J ¼ 4.5, 11.5 Hz, 2H), 2.74 (td, J ¼ 4.5, 11.0 Hz, 2H)
ppm. 13C NMR (125 MHz, CDCl3): d 171.0, 149.3, 143.8, 126.4,
122.7, 122.3, 116.7, 115.1, 89.6, 83.7, 67.0, 50.8, 48.1 ppm.
Methyl (Z)-2-(6-methyl-2-morpholino-2H-benzo[b][1,4]oxa-
ꢁ
zin-3(4H)-ylidene)acetate (31). Yellow solid, mp: 72–73 C. IR
1
(KBr): vmax 3265, 1674, 1632, 1512, 1434, 1378, 1246 cmꢀ1. H
NMR (500 MHz, CDCl3): d 10.28 (br s, 1H), 6.78 (d, J ¼ 8.0 Hz,
1H), 6.67 (d, J ¼ 8.0 Hz, 1H), 6.61 (s, 1H), 5.05 (s, 1H), 5.04 (s,
1H), 3.71 (s, 3H), 3.69 (t, J ¼ 4.5 Hz, 4H), 3.02 (td, J ¼ 4.0, 10.5
Hz, 2H), 2.72 (td, J ¼ 4.5, 10.0 Hz, 2H), 2.25 (s, 3H) ppm. 13C
NMR (125 MHz, CDCl3): d 170.9, 149.4, 141.5, 131.9, 126.0,
123.1, 116.3, 115.6, 89.6, 83.6, 67.0, 50.7, 48.0, 20.7 ppm.
Methyl (Z)-2-(7-methyl-2-morpholino-2H-benzo[b][1,4]oxa-
Methyl (Z)-2-(2-(dibenzylamino)-6-methyl-2H-benzo[b][1,4]-
ꢁ
oxazin-3(4H)-ylidene)acetate (26). Orange solid, mp: 80–81 C.
IR (KBr): vmax 3269, 1663, 1624, 1525, 1491, 1377, 1279 cmꢀ1. 1H
NMR (500 MHz, CDCl3): d 10.41 (br s, 1H), 7.44 (d, J ¼ 7.0 Hz,
4H), 7.37 (t, J ¼ 7.5 Hz, 4H), 7.30–7.27 (m, 2H), 6.90 (t, J ¼ 8.0 Hz,
1H), 6.74 (dd, J ¼ 1.0, 8.0 Hz, 1H), 6.63 (d, J ¼ 1.5 Hz, 1H), 5.40
(s, 1H), 5.25 (s, 1H), 4.11 (d, J ¼ 14.0 Hz, 2H), 3.89 (d, J ¼ 14.0 Hz,
2H), 3.75 (s, 3H), 2.29 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d
171.0, 151.5, 141.8, 138.3, 131.8, 128.6, 128.5, 127.2, 126.1,
123.1, 116.3, 115.5, 85.7, 82.8, 52.8, 50.7, 20.8 ppm.
ꢁ
zin-3(4H)-ylidene)acetate (32). Yellow solid, mp: 95–96 C. IR
1
(KBr): vmax 3261, 1671, 1630, 1507, 1443, 1367, 1271 cmꢀ1. H
NMR (500 MHz, CDCl3): d 10.30 (br s, 1H), 6.70 (s, 1H), 6.65 (s,
2H), 5.04 (s, 1H), 5.00 (s, 1H), 3.68 (s, 3H), 3.65 (t, J ¼ 4.5 Hz,
4H), 2.99 (td, J ¼ 4.5, 11.5 Hz, 2H), 2.68 (td, J ¼ 4.5, 9.5 Hz, 2H),
2.23 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d 170.7, 149.1,
143.4, 132.4, 123.7, 122.5, 116.9, 114.6, 89.4, 82.9, 66.7, 50.4,
47.8, 20.6 ppm.
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Methyl (Z)-2-(6-tert-butyl-2-morpholino-2H-benzo[b][1,4]-
Methyl (Z)-2-(2-(4-benzylpiperazin-1-yl)-6-chloro-2H-benzo[b]-
oxazꢁin-3(4H)-ylidene)acetate (33). Pale yellow solid, mp: 114– [1,4]oxazin-3(4H)-ylidene)acetate (39). Orange solid, mp: 84–
115 C. IR (KBr): vmax 3249, 1668, 1615, 1518, 1436, 1371, 1250 85 ꢁC. IR (KBr): vmax 3248, 1668, 1615, 1518, 1438, 1374, 1249
cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.41 (br s, 1H), 6.93 (dd, J ¼ cmꢀ1. 1H NMR (500 MHz, CDCl3): d 10.37 (br s, 1H), 7.34 (d, J ¼
2.0, 8.5 Hz, 1H), 6.86 (s, 1H), 6.84 (s, 1H), 5.13 (s, 1H), 5.10 (s, 4.5 Hz, 4H), 7.31–7.26 (m, 1H), 6.84–6.82 (m, 2H), 6.80 (s, 1H),
1H), 3.75 (s, 3H), 3.73 (t, J ¼ 4.5 Hz, 4H), 3.07 (td, J ¼ 4.5, 10.0 5.16 (s, 1H), 5.12 (s, 1H), 3.75 (s, 3H), 3.54 (s, 2H), 3.10–3.07 (m,
Hz, 2H), 2.77 (td, J ¼ 5.0, 10.0 Hz, 2H), 1.29 (s, 9H) ppm. 13C 2H), 2.78 (td, J ¼ 4.5, 10.5 Hz, 2H), 2.56–2.45 (br s, 4H) ppm. 13
C
NMR (125 MHz, CDCl3): d 171.1, 149.7, 145.6, 141.4, 125.6, NMR (125 MHz, CDCl3): d 170.8, 148.9, 142.6, 129.2, 128.2, 127.3,
119.6, 116.0, 112.3, 89.6, 83.2, 66.9, 50.7, 48.1, 34.3, 31.4 ppm. 127.1, 126.7, 122.1, 117.6, 114.8, 89.6, 84.8, 62.9, 53.0, 50.8 ppm.
Methyl (Z)-2-(6-chloro-2-morpholino-2H-benzo[b][1,4]oxa-
zin-3(4H)-ylidene)acetate (34). Yellow solid, mp: 100–101 ꢁC. IR
(KBr): vmax 3243, 1668, 1630, 1520, 1465, 1389, 1265 cmꢀ1. H
NMR (500 MHz, CDCl3): d 10.32 (br s, 1H), 6.80 (s, 2H), 6.78 (d, J
¼ 0.5 Hz, 1H), 5.09 (s, 1H), 5.06 (s, 1H), 3.71 (s, 3H), 3.68 (t, J ¼
5.0 Hz, 4H), 2.99 (td, J ¼ 4.5, 11.5 Hz, 2H), 2.71 (td, J ¼ 5.0, 10.0
Hz, 2H) ppm. 13C NMR (125 MHz, CDCl3): d 170.6, 148.3, 142.3,
127.3, 126.9, 122.1, 117.6, 114.8, 89.6, 85.0, 66.8, 50.8, 48.0 ppm.
Methyl (Z)-2-(2-(4-benzylpiperazin-1-yl)-2H-benzo[b][1,4]oꢁxa-
zin-3(4H)-ylidene)acetate (35). Pale yellow solid, mp: 80–81 C.
IR (KBr): vmax 3264, 1674, 1624, 1506, 1450, 1376, 1268 cmꢀ1. 1H
NMR (500 MHz, CDCl3): d 10.43 (br s, 1H), 7.37–7.35 (m, 4H),
7.31–7.27 (m, 1H), 6.94–6.90 (m, 3H), 6.84–6.81 (m, 1H), 5.19 (s,
1H), 5.13 (s, 1H), 3.77 (s, 3H), 3.55 (s, 2H), 3.15–3.10 (m, 2H),
2.80 (td, J ¼ 4.5, 10.0 Hz, 2H), 2.60–2.41 (br s, 4H) ppm. 13C NMR
(125 MHz, CDCl3): d 170.9, 149.6, 143.9, 137.8, 129.0, 128.0,
126.9, 126.2, 122.5, 121.9, 116.5, 114.8, 89.4, 83.3, 62.8, 53.0,
50.5 ppm.
1
Acknowledgements
We gratefully acknowledge nancial support from the Council
of Scientic and Industrial Research, New Delhi and Depart-
ment of Science and Technology for providing HRMS facility in
DST-FIST program. Garima and RTN thank CSIR for research
fellowships.
Notes and references
1 (a) W. Wang, H. Kim, S.-J. Nam, B. Jo Rho and H. Kang, J. Nat.
Prod., 2012, 75, 2049–2054; (b) R. C. Cambi, J. Nat. Prod.,
1988, 51, 1014–1016; (c) Y. M. Syah, E. L. Ghisalberti,
B. W. Skelton and A. H. White, J. Nat. Prod., 1997, 60, 49–
51; (d) T. Ishikawa, K. Nishigaya, H. Uchikoshi and
I.-S. Chen, J. Nat. Prod., 1998, 61, 534–537; (e) Y.-W. Guo,
M. Gavagnin, E. Mollo, E. Trivellone and G. Cimino, J. Nat.
Prod., 1999, 62, 1194–1196; (f) J. Hofman and
Methyl (Z)-2-(2-(4-benzylpiperazin-1-yl)-6-methyl-2H-benzo-
[b][1,4]oxazin-3(4H)-ylidene)acetate (36). Orange thick liquid.
IR (KBr): vmax 3274, 1657, 1621, 1513, 1434, 1382, 1254 cmꢀ1. 1H
NMR (500 MHz, CDCl3): d 10.33 (br s, 1H), 7.34 (d, J ¼ 4.0 Hz,
4H), 7.31–7.27 (m, 1H), 6.80 (d, J ¼ 8.0 Hz, 1H), 6.70 (d, J ¼ 8.5
Hz, 1H), 6.63 (s, 1H), 5.14 (s, 1H), 5.08 (s, 1H), 3.75 (s, 3H), 3.53
(s, 2H), 3.13–3.07 (m, 2H), 2.78 (td, J ¼ 4.5, 10.0 Hz, 2H), 2.60–
2.49 (s, 4H), 2.83 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): d
171.0, 149.9, 141.8, 138.0, 131.6, 129.1, 128.1, 127.0, 126.0,
123.0, 116.3, 115.5, 89.5, 83.3, 62.9, 53.1, 50.6, 20.7 ppm.
Methyl (Z)-2-(2-(4-benzylpiperazin-1-yl)-7-methyl-2H-benzo-
[b][1,4]oxazin-3(4H)-ylidene)acetate (37). Thick brown liquid. IR
´
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1695–1705.
1
(KBr): vmax 3264, 1656, 1614, 1513, 1462, 1371, 1264 cmꢀ1. H
NMR (500 MHz, CDCl3): d 10.32 (br s, 1H), 7.33–7.31 (m, 4H),
7.26–7.27 (m, 1H), 6.71 (s, 1H), 6.80 (s, 2H), 5.15 (s, 1H), 5.02 (s,
1H), 3.72 (s, 3H), 3.53 (s, 2H), 3.11–3.06 (m, 2H), 2.80–2.75 (m,
2H), 2.55–2.44 (br s, 4H), 2.26 (s, 3H) ppm. 13C NMR (125 MHz,
CDCl3): d 171.1, 149.8, 143.8, 132.6, 129.2, 128.2, 127.0, 123.8,
122.5, 117.1, 114.7, 89.5, 82.8, 62.9, 53.0, 50.6, 20.8 ppm.
6 (a) W. Yang, Y. Wang, Z. Ma, R. Golla, T. Stouch, R. Seethala,
Methyl
(Z)-2-(2-(4-benzylpiperazin-1-yl)-6-tert-butyl-2H-
¨
¨
S. Johnson, R. Zhou, T. Gungor, J. H. M. Feyenb and
J. K. Dickson, Jr, Bioorg. Med. Chem. Lett., 2004, 14, 2327–
2330; (b) P. J. Rybczynski, R. E. Zeck, J. Dudash, Jr,
D. W. Combs, T. P. Burris, M. Yang, M. C. Osborne,
X. Chen and K. T. Demarest, J. Med. Chem., 2004, 47, 196–
209; (c) H. Su, L. Su, Q. He, J. Zhao, B. Zhao, S. Zhang and
J. Miao, Front. Biol., 2010, 5, 180–186.
benzo[b][1,4]oxazin-3(4H)-ylidene)acetate (38). Thick brown
liquid. IR (KBr): vmax 3226, 1665, 1615, 1509, 1450, 1365, 1256
1
cmꢀ1. H NMR (500 MHz, CDCl3): d 10.38 (br s, 1H), 7.32–7.31
(m, 5H), 6.89 (dd, J ¼ 2.0, 8.0 Hz, 1H), 6.82–6.79 (m, 2H), 5.16 (s,
1H), 5.07 (s, 1H), 3.73 (s, 3H), 3.51 (s, 2H), 3.11–3.04 (m, 2H),
2.81–2.74 (m, 2H), 2.53–2.44 (m, 4H), 1.26 (s, 9H) ppm. 13C NMR
(125 MHz, CDCl3): d 171.2, 150.2, 145.4, 141.7, 129.2, 128.2,
127.0, 125.6, 119.5, 116.0, 112.3, 89.6, 83.0, 63.0, 53.2, 50.7, 34.3,
31.4 ppm.
7 M.-Z. Huang, F.-X. Luo, H.-B. Mo, Y.-G. Ren, X.-G. Wang,
X.-M. Ou, M.-X. Lei, A.-P. Liu, L. Huang and M.-C. Xu,
J. Agric. Food Chem., 2009, 57, 9585–9592.
17978 | RSC Adv., 2014, 4, 17969–17979
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