Synthesis of 2-amide-3-carboxylate-4-aryl-4H-chromene derivatives

Article abstract of DOI:10.1007/s11164-012-0500-6

Tetrabutyl ammonium bromide (TBAB) catalyzed one-pot synthesis of 4H-chromene via a three-component cyclocondensation of aryl aldehydes, cyanoacetate and dimedone in green media-water. Then, 4H-chromene reacted with acyl chloride in acetonitrile at refluxing with catalytic amount of DMAP to yield the title compounds in good yields. The structures of all title compounds were confirmed by ¹H NMR, MS and elementary analyses. The X-ray crystallography of compound 3n indicated that there were strong intermolecular hydrogen bonds. Springer Science+Business Media B.V. 2012.

Full text of DOI:10.1007/s11164-012-0500-6

Res Chem Intermed (2012) 38:1751–1760
DOI 10.1007/s11164-012-0500-6
Synthesis of 2-amide-3-carboxylate-4-aryl-
4H-chromene derivatives
•
•
•
Zhi-gang Zeng Lan-ying Wang Yang Cao
Yan-ping Luo
Received: 3 January 2012 / Accepted: 20 January 2012 / Published online: 3 February 2012
ꢀ Springer Science+Business Media B.V. 2012
Abstract Tetrabutyl ammonium bromide (TBAB) catalyzed one-pot synthesis of
4H-chromene via a three-component cyclocondensation of aryl aldehydes, cyanoacetate
and dimedone in green media–water. Then, 4H-chromene reacted with acyl chloride in
acetonitrile at refluxing with catalytic amount of DMAP to yield the title compounds in
good yields. The structures of all title compounds were confirmed by 1H NMR, MS and
elementary analyses. The X-ray crystallography of compound 3n indicated that there
were strong intermolecular hydrogen bonds.
Keywords Aromatic aldehydes Á Cyanoacetate Á Dimedone Á One-pot synthesis Á
4H-chromene Á 2-amide-3-carboxylate-4H-chromene
Introduction
Heterocyclic compounds, especially pyran and benzopyran derivatives, have played
an important role in medicines, pesticides, dyes, and other fine chemical industries.
Pyran ring, because of its intrinsic activity, has become a very useful synthon for
other heterocyclic compounds [1]. Benzopyran derivatives exhibit excellent
physiological and pharmacological activity [2], such as anti-hypoplasia [3], anti-
allergic effects [4], treatment of allergic bronchitis [5], and anti-cancer [6].
Furthermore, amides occupy an important place in medicines and pesticides due
to their broad-spectrum, high-efficiency active features, for example, bactericidal
[7], acaricidal [8], pesticidal [9], herbicidal [10], and other biological activities.
In order to find bioactive compounds, we designed and synthesized a series of
Z. Zeng Á L. Wang Á Y. Cao Á Y. Luo (&)
Key Laboratory of Protection and Development Utilization of Tropical Crop Germplasm Resources,
Ministry of Education, College of Environment and Plant Protection, Hainan University, Haikou,
Hainan 570228, People’s Republic of China
e-mail: yanpluo@yahoo.com.cn
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Z. Zeng et al.
2-amide-4H-benzo[b]pyran derivatives by assembling benzopyran and amide using
particular methodology and obtaining the following results.
Results and discussion
The synthesis of 4H-benzo[b]pyran derivatives has been reported previously in the
literature. Aryl aldehydes, alkyl nitriles, and dimedone have been synthesized in
organic solvents (e.g., acetonitrile [1], ethanol [11, 12] and DMF [13]), ionic liquid
[14], microwave [15], and so on. The main drawbacks of these methods stem from the
requirement for organic solvents, drastic reaction conditions, high temperatures, long
reaction times, or the complicated preparation of the catalysts. The methods of solvent-
free grinding in the presence of a catalyst (e.g., triethylbenzylammonium chloride,
TEBA [16]) and utilizing the reactants in a solid or molten state [17] have also been
used for synthesis of these derivatives. Although these reactions were relatively novel,
they had some limitations, such as the two-step reaction, very high temperature or
requirement for a longer period of time. Recently, organic synthesis in water, such as
the Claisen Rearrangement, Aldol Condensation, Diels–Alder Reaction, Michael
Addition, and Knoevenagel Condensation, has been reported [18–23]. Three-
component one-pot reaction in water could be important for bioactive compounds.
Ziarani et al. [24]. have reported 2-amine-3-cyano-4H-chromenes, which were
efficiently synthesized by the one-pot reaction of appropriate aromatic aldehydes,
malononitrile and dimedone, in the presence of SiO2–Pr–SO3H as a solid acid catalyst.
Due to the complicated preparation of the solid acid catalyst, it was difficult to apply
this as the industrial process. Moreover, Bandgar et al. [25] have reported catalyst-free
synthesis of those very similar products in one-pot reactions in aqueous media.
The uncatalyzed reactions have been carried out smoothly at reflux in 3.5 h via three-
component reactions of malononitrile, aryl aldehydes, and dimedone. But this method
was not suitable for the three-component cyclocondensation involving ethyl cyano-
acetate. In our research, the reactions needed a very long time, and during the
procedures, clumps were very prone to form. It was difficult to accomplish the three-
component reactions to substitute malononitrile with ethyl cyanoacetate under the
same conditions. The reason may be that methylene in malononitrile was more active
than in ethyl cyanoacetate. Because the electron withdrawing ability of cyano-group
was stronger than the ester-group. Here, we have found an efficient, green, and
convenient procedure to synthesize 2-amine-3-carboxylate-4H-benzo[b]pyran deriva-
tives using phase-transfer catalyst in water. We chose tetrabutyl ammonium bromide
(TBAB) as a catalyst, and aryl aldehydes, ethyl cyanoacetate, and dimedone reacted to
give highly functionalized 4H-benzo[b]pyrans in water at 85 ꢁC in excellent yields
(Table 1). Furthermore, TBAB catalyzed to synthesize 2-amine-3-carboxylate-4H-
chromenes in one-pot in water has not previously been reported (Scheme 1).
In order to synthesize compounds 3, we have studied the reaction conditions to use
compound 1a and benzoyl chloride as a template reaction, and the results were shown
in Table 2. It was obvious that the reaction would be accomplished comfortably in
acetonitrile at refluxing conditions with a catalytic amount of DMAP. In other
conditions, the reaction either did not carry on, or carried on very slowly, and yield
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Synthesis of 2-amide-3-carboxylate-4-aryl-4H-chromene derivatives
Table 1 Physico-chemical properties of the compounds 1
1753
No.
R1
Time (h)
Yieldsa (%)
Mp (ꢁC)
Found
Report
1a
1b
1c
1d
1e
a
C6H5
3.5
5
94
89
96
95
91
160–162
170–172
156–158
128–130
177–179
158–160 [26]
169.4–170.8 [27]
155–157 [28]
128–129 [29]
176–178 [30]
2-NO2C6H4
3,4-(MeO)2C6H3
2-Furyl
3
3
2,4-Cl2C6H3
4
Isolated yields
O
R1
O
CO2C2H5
TBAB, H2O
85°C
R1CHO +
NCCH2CO2C2H5
+
O
NH2
O
1a-e
Scheme 1 The synthesis of compounds 1
was trace. At room temperature, no matter in what kind of solvent, no reaction
carried on. The reason may be a strong impact from electron-withdrawing groups
(e.g., its ortho-ester and benzene ring); the amino group of the pyran ring was not
active enough. When the reaction was refluxing, the yields were different from
nonpolar solvent to polar solvent, and the yields were very low. Under the condition
of catalyst, the yields were higher than with no catalyst. So, it could be speculated
that higher temperature, polar solvent, and catalyst were all useful to accomplish the
title compounds synthesis. Additionally, an acid-binding agent such as triethylamine
should be added, while the reaction system must also be kept dry.
All compounds 3 gave satisfactory elementary analyses and spectroscopic data
(1H NMR and MS) consistent with their assigned structures. For example, in the
1H NMR spectra, compounds 3 revealed a singlet at d 11.88–12.26 ppm, which was
attributed to amide hydrogen protons. The MS spectra revealed that the molecular
ion peaks and fragmentation peaks were in accordance with the synthesized
structures of the title compounds 3, and the molecular ion peaks were observed for
all the title compounds (Scheme 2).
The single-crystal structure of 3n was determined by X-ray crystallography as shown
in Fig. 1. The crystal of 3n revealed an intermolecular hydrogen bond. The distance of
˚
N(1)–H(1)…O(5) was 2.64 A, and the angle of N(1)–H(1)…O(5) was 136.48.
Conclusion
In conclusion, we developed an easy and mild method to synthesize a new series of
2-amide-3-carboxylate-4H-benzo[b]pyrans in good yields. Further investigations on
structural optimization and bioactivities are well under way.
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Z. Zeng et al.
Table 2 Conditions optimization of synthesis of compound 3b
Entry
Solvent
Temp (ꢁC)
Catalyst
Time (h)
Yields
1
Et2O
r.t.
\
96
96
No reaction
No reaction
No reaction
No reaction
Trace
2
Et2O
Reflux
Reflux
r.t.
\
3
Et2O
DMAP
96
4
CH2Cl2
CH2Cl2
CH2Cl2
PhCH3
PhCH3
PhCH3
THF
\
\
5
Reflux
Reflux
r.t.
\
120
120
83
6
DMAP
Trace
7
\
No reaction
5.2%
8
Reflux
Reflux
r.t.
\
[83
83
9
DMAP
9.3%
10
11
12
13
14
15
\
96
No reaction
6.8%
THF
Reflux
Reflux
r.t.
\
96
THF
DMAP
96
11.5%
CH3CN
CH3CN
CH3CN
\
24
No reaction
20.6%
Reflux
Reflux
\
[24
11
DMAP
69.8%
r.t. Room temperature
Scheme 2 The synthesis of compounds 3
Experimental
Melting points were measured on the 96 micromelting-point apparatus (China)
1
and are uncorrected. H NMR spectra were recorded on a Bruker AV 400 NMR
spectrometer in CDCl3 with TMS as the internal reference. MS spectra were
determined using a Finnigan Trace MS 2000 organic mass spectrometry, and signals
were given in m/z. Elementary analyses were performed on a Vario EL III
elementary analysis instrument. All chemical reagents were commercially available
and treated with standard methods before use. Solvents were dried in a routine way
and redistilled.
Preparation of the 2-amine-3-carboxylate-4H-chromenes (1)
To a stirred solution of cyanoacetate (2.2 mmol) in water (10 mL), a catalytic
amount of TBAB, dimedone (5, 5-dimethyl-1, 3-cyclohexanedione, 2.2 mmol) and
benzaldehyde (2 mmol) were added. The reaction mixture was stirred at 85 ꢁC for
3–5 h according to thin layer chromatographic (TLC) analysis, and filtered off by
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Synthesis of 2-amide-3-carboxylate-4-aryl-4H-chromene derivatives
1755
Fig. 1 Crystal structure of compound 3n
suction. For further purification, samples were recrystallized from 95% ethanol to
yield the compounds (1).
General procedure for the synthesis of the title compounds (3)
Compounds 1 (2 mmol), triethylamine (2.4 mmol) and catalytic amount of DMAP
were added to dry acetonitrile (10 mL) in turn. Then, fresh acyl chlorides 2
(2.2 mmol) was slowly dropped into the mixture by strong stirring on an ice bath.
Next, the reaction mixture was refluxed for 10–14 h according to TLC analysis. The
mixture was poured into 100 mL of water, extracted with chloroform (30 mL 9 3),
the organic layer was dried with anhydrous magnesium sulfate, and the solvent was
evaporated to give the crude product, which was purified by chromatography on
silica using petroleum ether/ethyl acetate as the eluent to give the title compounds
3a–t.
Ethyl
2-acetamido-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chro-
mene-3-carboxylate (3a) white solid; yield, 63.1%; mp 198–200 ꢁC; 1H NMR
(400 MHz, CDCl3), d 0.97 (s, 3H, CH3), 1.13 (s, 3H, CH3), 1.19 (t, 3H, CH3,
J = 7.12 Hz), 2.18 (s, 3H, CH3), 2.21 (q, 2H, CH2, J = 16.28 Hz), 2.60 (s, 2H,
CH2), 4.08–4.13 (m, 2H, CH2), 4.85 (s, 1H, CH), 7.07–7.26 (m, 5H, ArH), 11.88 (s,
1H, NH); MS (EI): m/z (%) 382 ([M-1]?, 22), 368 (43), 241 (27), 227 (100), 199
(13), 171 (17), 102 (26), 83 (37). Anal. Calcd for C22H25NO5: C, 68.91; H, 6.57;
N, 3.65. Found: C, 68.93; H, 6.48; N, 3.66.
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Z. Zeng et al.
Ethyl
2-benzamido-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-4H-chro-
mene-3-carboxylate (3b). white solid; yield, 69.8%; mp 214–216 ꢁC; 1H NMR
(400 MHz, CDCl3), d 0.98 (s, 3H, CH3), 1.13 (s, 3H, CH3), 1.21 (t, 3H, CH3,
J = 7.12 Hz), 2.22 (q, 2H, CH2, J = 16.28 Hz), 2.64 (s, 2H, CH2), 4.10–4.16 (m,
2H, CH2), 4.83 (s, 1H, CH), 7.13–7.99 (m, 10H, ArH), 11.94 (s, 1H, NH); MS (EI):
m/z (%) 445 ([M]?, 8), 368 (38), 322 (6), 294 (6), 105 (100), 77 (24). Anal. Calcd
for C27H27NO5: C, 72.79; H, 6.11; N, 3.14. Found: C, 72.68; H, 6.09; N, 3.15.
Ethyl 2-(4-bromobenzamido)-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-
4H-chromene-3-carboxylate (3c). white solid; yield, 60.0%; mp 276–278 ꢁC;
1H NMR (400 MHz, CDCl3), d 0.98 (s, 3H, CH3), 1.11 (s, 3H, CH3), 1.22 (t, 3H,
CH3, J = 7.12 Hz), 2.23 (q, 2H, CH2, J = 16.28 Hz), 2.64 (s, 2H, CH2), 4.11–4.15
(m, 2H, CH2), 4.80 (s, 1H, CH), 7.22–8.03 (m, 9H, ArH), 12.16 (s, 1H, NH); MS
(EI): m/z (%) 526 ([M?2]?, 18), 524 ([M])?, 42), 448 (16), 402 (29), 316 (25), 107
(100), 77 (36). Anal. Calcd for C27H26BrNO5: C, 61.84; H, 5.00; N, 2.67. Found:
C, 61.67; H, 5.08; N, 2.68.
Ethyl 2-(4-methoxybenzamido)-7,7-dimethyl-5-oxo-4-phenyl-5,6,7,8-tetrahydro-
1
4H-chromene-3-carboxylate (3d). white solid; yield, 71.3%; mp 245–247 ꢁC; H
NMR (400 MHz, CDCl3), d 0.99 (s, 3H, CH3), 1.15 (s, 3H, CH3), 1.23 (t, 3H, CH3,
J = 7.12 Hz), 2.25 (q, 2H, CH2, J = 16.28 Hz), 2.61 (s, 2H, CH2), 3.92 (s, 3H,
CH3), 4.10–4.17 (m, 2H, CH2), 4.81 (s, 1H, CH), 7.11–7.91 (m, 9H, ArH), 11.98 (s,
1H, NH); MS (EI): m/z (%) 476 ([M?1]?, 15), 399 (43), 353 (17), 325 (13), 131
(22). Anal. Calcd for C28H29NO6: C, 70.72; H, 6.15; N, 2.95. Found: C, 70.74;
H, 6.19; N, 2.77.
Ethyl 2-acetamido-7,7-dimethyl-4-(2-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
1
chromene-3-carboxylate (3e). white solid; yield, 57.4%; mp 170–172 ꢁC; H NMR
(400 MHz, CDCl3), d 0.95 (s, 3H, CH3), 1.06 (s, 3H, CH3), 1.10 (t, 3H, CH3,
J = 7.12 Hz), 2.18 (s, 3H, CH3), 2.20 (q, 2H, CH2, J = 16.28 Hz), 2.62 (s, 2H,
CH2), 4.03–4.16 (m, 2H, CH2), 5.80 (s, 1H, CH), 7.25–7.46 (m, 4H, ArH), 11.99
(s,1H, NH); MS (EI): m/z (%) 428 ([M]?, 25), 385 (76), 370 (42), 341 (100), 295
(58), 230 (36), 128 (19). Anal. Calcd for C22H24N2O7: C, 61.67; H, 5.65; N, 6.54.
Found: C, 61.64; H, 5.59; N, 6.65.
Ethyl 2-benzamido-7,7-dimethyl-4-(2-nitrophenyl)-5-oxo-5,6,7,8-tetrahydro-4H-
1
chromene-3-carboxylate (3f). white solid; yield, 51.9%; mp174–176 ꢁC; H NMR
(400 MHz, CDCl3), d 0.95 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.09 (t, 3H, CH3,
J = 7.12 Hz), 2.20 (q, 2H, CH2, J = 16.28 Hz), 2.61 (s, 2H, CH2), 4.02–4.18 (m,
2H, CH2), 5.84 (s, 1H, CH), 7.26–8.00 (m, 9H, ArH), 12.17 (s, 1H, NH); MS (EI):
m/z (%) 490 ([M] ?, 2), 473 (4), 369 (3), 225 (5), 105 (100). Anal. Calcd for
C27H26N2O7: C, 66.11; H, 5.34; N, 5.71. Found: C, 66.23; H, 5.14; N, 5.76.
Ethyl
2-(4-bromobenzamido)-7,7-dimethyl-4-(2-nitrophenyl)-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carboxylate (3g). white solid; yield, 55.3%; mp
235–236 ꢁC; 1H NMR (400 MHz, CDCl3), d 0.97 (s, 3H, CH3), 1.08 (s, 3H,
CH3), 1.10 (t, 3H, CH3, J = 7.12 Hz), 2.23 (q, 2H, CH2, J = 16.28 Hz), 2.61 (s,
2H, CH2), 4.02–4.19 (m, 2H, CH2), 5.88 (s, 1H, CH), 7.30–8.11 (m, 8H, ArH),
12.11 (s, 1H, NH); MS (EI): m/z (%) 571 ([M?2]?, 10), 569 ([M]?, 16), 497 (23),
480 (20), 356 (95), 125 (100), 77 (24). Anal. Calcd for C27H25BrN2O7: C, 56.95;
H, 4.43; N, 4.92. Found: C, 56.86; H, 4.46; N, 4.84.
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Synthesis of 2-amide-3-carboxylate-4-aryl-4H-chromene derivatives
1757
Ethyl 2-(4-methoxybenzamido)-7,7-dimethyl-4-(2-nitrophenyl)-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carboxylate (3h). white solid; yield, 60.2%; mp
220–222 ꢁC; 1H NMR (400 MHz, CDCl3), d 0.96 (s, 3H, CH3), 1.07 (s, 3H,
CH3), 1.09 (t, 3H, CH3, J = 7.12 Hz), 2.21 (q, 2H, CH2, J = 16.28 Hz), 2.63 (s,
2H, CH2), 3.97 (s, 3H, CH3), 4.01–4.18 (m, 2H, CH2), 5.82 (s, 1H, CH), 7.27–8.07
(m, 8H, ArH), 12.19 (s, 1H, NH); MS (EI): m/z (%) 520 ([M]?, 18), 447 (57), 370
(23), 202 (32), 106 (100), 77 (21), 51 (10). Anal. Calcd for C28H28N2O8: C, 64.61;
H, 5.42; N, 5.38. Found: C, 64.63; H, 5.37; N, 5.38.
Ethyl 2-acetamido-4-(3,4-dimethoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahy-
dro-4H-chromene-3-carboxylate (3i). white solid; yield, 65.7%; mp162–164 ꢁC;
1H NMR (400 MHz, CDCl3), d 1.00 (s, 3H, CH3), 1.13 (s, 3H, CH3), 1.20 (t, 3H,
CH3, J = 7.12 Hz), 2.15 (s, 3H, CH3), 2.20 (q, 2H, CH2, J = 16.28 Hz), 2.60 (s, 2H,
CH2), 3.91 (s, 3H, OCH3), 3.96 (s, 3H, OCH3), 4.10–4.15 (m, 2H, CH2), 4.85 (s, 1H,
CH), 7.11–8.30 (m, 3H, ArH), 12.20 (s, 1H, NH); MS (EI): m/z (%) 443 ([M]?, 26),
351 (84), 261 (100), 233 (19), 216 (15), 172 (10). Anal. Calcd for C24H29NO7:
C, 65.00; H, 6.59; N, 3.16. Found: C, 64.87; H, 6.63; N, 3.26.
Ethyl 2-benzamido-4-(3,4-dimethoxyphenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetra-
hydro-4H-chromene-3-carboxylate (3j). white solid; yield, 61.4%; mp
188–189 ꢁC; 1H NMR (400 MHz, CDCl3), d 1.01 (s, 3H, CH3), 1.13 (s, 3H,
CH3), 1.24 (t, 3H, CH3, J = 7.12 Hz), 2.25 (q, 2H, CH2, J = 16.28 Hz), 2.63 (s,
2H, CH2), 3.83 (s, 3H, OCH3), 3.87 (s, 3H, OCH3), 4.13–4.16 (m, 2H, CH2), 4.78 (s,
1H, CH), 7.16–8.12 (m, 8H, ArH), 12.23 (s, 1H, NH); MS (EI): m/z (%) 505 ([M]?,
18), 459 (5), 400 (13), 368 (23), 354 (15), 105 (100), 77 (24). Anal. Calcd for
C29H31NO7: C, 68.90; H, 6.18; N, 2.77. Found: C, 68.95; H, 6.19; N, 2.88.
Ethyl
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (3k). white solid; yield, 59.5%; mp
2-(4-bromobenzamido)-4-(3,4-dimethoxyphenyl)-7,7-dimethyl-5-oxo-
1
260–262 ꢁC; H NMR (400 MHz, CDCl3), d 1.01 (s, 3H, CH3), 1.14 (s, 3H, CH3),
1.21 (t, 3H, CH3, J = 7.12 Hz), 2.20 (q, 2H, CH2, J = 16.28 Hz), 2.62 (s, 2H,
CH2), 3.91 (s, 3H, OCH3), 3.95 (s, 3H, OCH3), 4.12–4.14 (m, 2H, CH2), 4.89 (s, 1H,
CH), 7.16–8.12 (m, 7H, ArH), 12.25 (s, 1H, NH); MS (EI): m/z (%) 586 ([M?2]?,
35), 584 ([M]?, 22), 512 (27), 354 (100), 292 (42), 262 (20), 166 (32). Anal. Calcd
for C29H30BrNO7: C, 59.60; H, 5.17; N, 2.40. Found: C, 59.71; H, 5.09; N, 2.34.
Ethyl 4-(3,4-dimethoxyphenyl)-2-(4-methoxybenzamido)-7,7-dimethyl-5-oxo-
5,6,7,8-tetrahydro-4H-chromene-3-carboxylate (3l). white solid; yield, 75.3%; mp
1
244–246 ꢁC; H NMR (400 MHz, CDCl3), d 1.02 (s, 3H, CH3), 1.14 (s, 3H, CH3),
1.21 (t, 3H, CH3, J = 7.12 Hz), 2.20 (q, 2H, CH2, J = 16.28 Hz), 2.62 (s, 2H,
CH2), 3.89 (s, 3H, CH3), 3.92 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 4.11–4.13 (m, 2H,
CH2), 4.91 (s, 1H, CH), 7.16–8.19 (m, 7H, ArH), 12.26(s, 1H, NH); MS (EI): m/
z (%) 535 ([M]?, 43), 462 (23), 353 (99), 291 (100), 261 (31), 177 (25), 77 (36).
Anal. Calcd for C30H33NO8: C, 67.28; H, 6.21; N, 2.62. Found: C, 67.35; H, 6.26;
N, 2.74.
Ethyl 2-acetamido-4-(furan-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chro-
mene-3-carboxylate (3m). white solid; yield, 71.6%; mp 145–146 ꢁC; 1H NMR
(400 MHz, CDCl3), d 1.09 (s, 3H, CH3), 1.15 (s, 3H, CH3), 1.27 (t, 3H, CH3,
J = 7.12 Hz), 2.29 (s, 3H, CH3), 2.71 (s, 2H, CH2), 4.18–4.23 (m, 2H, CH2), 5.05
(s, 1H, CH), 6.15–7.63 (m, 3H, ArH), 11.89 (s, 1H, NH); MS (EI): m/z (%) 375
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Z. Zeng et al.
([M?2]?, 15), 329 (33), 270 (45), 228 (32), 182 (35), 103 (100), 77 (22). Anal. Calcd
for C20H23NO6: C, 64.33; H, 6.21; N, 3.75. Found: C, 64.45; H, 6.03; N, 3.86.
Ethyl
2-benzamido-4-(furan-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-
chromene-3-carboxylate (3n). white solid; yield, 67.3%; mp 161–163 ꢁC; 1H
NMR (400 MHz, CDCl3), d 1.07 (s, 3H, CH3), 1.14 (s, 3H, CH3), 1.29 (t, 3H, CH3,
J = 7.12 Hz), 2.31 (s, 2H, CH2), 2.63 (s, 2H, CH2), 4.19–4.25 (m, 2H, CH2), 5.04
(s, 1H, CH), 6.12–7.99 (m, 8H, ArH), 11.91 (s, 1H, NH); MS (EI): m/z (%) 435
([M]?, 3), 389 (8), 362 (8), 330 (16), 284 (6), 105 (100), 77 (25). Anal. Calcd for
C25H25NO6: C, 68.95; H, 5.79; N, 3.22. Found: C, 68.98; H, 5.78; N, 3.10.
Ethyl 2-(4-bromobenzamido)-4-(furan-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahy-
dro-4H-chromene-3-carboxylate (3o). white solid; yield, 60.5%; mp 230–231 ꢁC;
1H NMR (400 MHz, CDCl3), d 1.08 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.28 (t, 3H,
CH3, J = 7.12 Hz), 2.24 (s, 2H, CH2), 2.62 (s, 2H, CH2), 4.21–4.25 (m, 2H, CH2),
5.08 (s, 1H, CH), 6.11–8.03 (m, 7H, ArH), 11.95 (s, 1H, NH); MS (EI): m/z (%) 516
([M?2]?, 5), 514 ([M]?, 16), 469 (12), 429 (25), 397 (22), 249 (100), 77 (21). Anal.
Calcd for C25H24BrNO6: C, 58.38; H, 4.70; N, 2.72. Found: C, 58.25; H, 4.73;
N, 2.75.
Ethyl 4-(furan-2-yl)-2-(4-methoxybenzamido)-7,7-dimethyl-5-oxo-5,6,7,8-tetra-
hydro-4H-chromene-3-carboxylate (3p). white solid; yield, 73.0%; mp 202–204 ꢁC;
1H NMR (400 MHz, CDCl3), d 1.11 (s, 3H, CH3), 1.16 (s, 3H, CH3), 1.30 (t, 3H,
CH3, J = 7.12 Hz), 2.35 (s, 2H, CH2), 2.65 (s, 2H, CH2), 4.20–4.24 (m, 2H, CH2),
5.11 (s, 1H, CH), 6.14–8.12 (m, 7H, ArH), 12.02 (s, 1H, NH); MS (EI): m/z (%) 466
([M?1]?, 16), 420 (25), 318 (19), 286 (100), 240 (36), 77 (24). Anal. Calcd for
C26H27NO7: C, 67.09; H, 5.85; N, 3.01. Found: C, 67.13; H, 5.88; N, 2.92.
Ethyl 2-acetamido-4-(2,4-dichlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahy-
dro-4H-chromene-3-carboxylate (3q). white solid; yield, 59.5%; mp 150–151 ꢁC;
1H NMR (400 MHz, CDCl3), d 1.01 (s, 3H, CH3), 1.13 (s, 3H, CH3), 1.21 (t, 3H,
CH3, J = 7.12 Hz), 2.15 (s, 3H, CH3), 2.21 (q, 2H, CH2, J = 16.28 Hz), 2.55
(s, 2H, CH2), 4.08–4.15 (m, 2H, CH2), 4.81 (s, 1H, CH), 7.11–7.85 (m, 3H, ArH),
12.02 (s, 1H, NH); MS (EI): m/z (%) 453 ([M?1]?, 6), 283 (23), 237 (30), 207 (22),
101 (100), 77 (20). Anal. Calcd for C22H23Cl2NO5: C, 58.42; H, 5.13; N, 3.10.
Found: C, 58.35; H, 5.15; N, 3.15.
Ethyl 2-benzamido-4-(2,4-dichlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahy-
dro-4H-chromene-3-carboxylate (3r). white solid; yield,57.1%; mp 231–233 ꢁC;
1H NMR (400 MHz, CDCl3), d 1.01 (s, 3H, CH3), 1.13 (s, 3H, CH3), 1.20 (t, 3H,
CH3, J = 7.12 Hz), 2.21 (q, 2H, CH2, J = 16.28 Hz), 2.63 (s, 2H, CH2), 4.08–4.16
(m, 2H, CH2), 4.83 (s, 1H, CH), 7.14–7.99 (m, 8H, ArH), 12.05 (s, 1H, NH); MS
(EI): m/z (%) 514 ([M]?, 4), 432 (5), 368 (24), 105 (100), 77 (23). Anal. Calcd for
C27H25Cl2NO5: C, 63.04; H, 4.90; N, 2.72. Found: C, 63.17; H, 4.91; N, 2.74.
Ethyl 2-(4-bromobenzamido)-4-(2,4-dichlorophenyl)-7,7-dimethyl-5-oxo-5,6,7,8-
tetrahydro-4H-chromene-3-carboxylate (3s). white solid; yield, 55.5%; mp
234–236 ꢁC; 1H NMR (400 MHz, CDCl3), d 1.02 (s, 3H, CH3), 1.18 (s, 3H,
CH3), 1.22 (t, 3H, CH3, J = 7.12 Hz), 2.21 (q, 2H, CH2, J = 16.28 Hz), 2.60
(s, 2H, CH2), 4.10–4.16 (m, 2H, CH2), 4.83 (s, 1H, CH), 7.20–8.16 (m, 7H, ArH),
12.08 (s, H, NH); MS (EI): m/z (%) 595 ([M?2]?, 10), 593 ([M]?, 8), 513 (15), 467
123

Synthesis of 2-amide-3-carboxylate-4-aryl-4H-chromene derivatives
1759
(21), 334 (12), 185 (100), 77 (22). Anal. Calcd for C27H24BrCl2NO5: C, 54.66;
H, 4.08; N, 2.36. Found: C, 54.70; H, 4.11; N, 2.41.
Ethyl 4-(2,4-dichlorophenyl)-2-(4-methoxybenzamido)-7,7-dimethyl-5-oxo-5,6,7,
8-tetrahydro-4H-chromene-3-carboxylate (3t). white solid; yield, 64.6%; mp
1
207–209 ꢁC; H NMR (400 MHz, CDCl3), d 1.02 (s, 3H, CH3), 1.19 (s, 3H, CH3),
1.23 (t, 3H, CH3, J = 7.12 Hz), 2.21 (q, 2H, CH2, J = 16.28 Hz), 2.61 (s, 2H, CH2),
3.95 (s, 3H, CH3), 4.10–4.17 (m, 2H, CH2), 4.83 (s, 1H, CH), 7.21–8.15 (m, 7H,
ArH), 12.03 (s, H, NH); MS (EI): m/z (%) 545 ([M?1]?, 7), 463 (13), 361 (29), 212
(18), 140 (100), 77 (24). Anal. Calcd for C28H27Cl2NO6: C, 61.77; H, 5.00; N, 2.57.
Found: C, 61.71; H, 5.02; N, 2.60.
X-ray analysis of compound 3n
The single crystal 3n was obtained by evaporating the solvent. An Orthorhombic
crystal with dimensions of 0.16 9 0.12 9 0.10 mm was mounted on a Bruker
SMART APEX CCD single crystal X-ray diffraction at 100(2)K with graphite-
˚
monochromated MoKa radiation (k = 0.71073 A). The crystal data for 3n:
˚
C25H25NO6; Triclinic, space group P-1, a = 14.838 A, b = 14.838(2) A,
˚
3
3
˚
˚
c = 19.744(3) A, V = 4347.2(9) A , Z = 8, Dc = 1.331 mg/m . A total of
31,275 reflections were measured in the range of 2.06ꢁB h B 27.00ꢁ, of which
4,739 reflections (Rint = 0.1203) were independent and 3,650 were observed with
I[2r (I). The structure was solved by direct methods and refined on F2 by full-
matrix least-squares procedure with Bruker SHELXTL-97 package [31]. All other
calculations were performed with Bruker SAINT System and Bruker SMART
programs [32]. Full-matrix least-squares refinement based on F2 using the weight of
1/[r2(Fo2) ? (0.0602P)2 ? 0.0000P] where P = (Fo2?2Fc2)/3 gave final values of
R = 0.0428, xR = 0.1076, and GOF(F) = 1.036 for 293 variables and 4,739
contributing reflections. Maximum shift/error 0.001, max/min residual electron
-3
˚
density = 0.374/-0.281 e A
.
Acknowledgments We are grateful to financial support from the National NSFC (No.21162007),
Project for Department of Education, Hainan Province (No.Hj2009-19) and Hainan University
Postdoctoral Research Foundation.
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