Synthesis of novel coumarin derivatives based on 6-aminocoumarin ...

Monatsh Chem (2016) 147:735–747 DOI 10.1007/s00706-015-1550-4

ORIGINAL PAPER

Synthesis of novel coumarin derivatives based on 6-aminocoumarin, kinetic inspection of base hydrolysis, and spectrophotometric tracer of intermediate progress Omyma Abd El Aziz Abd Allah1 • Lobna Abdel-Mohsen E. Nassr1

Received: 29 April 2015 / Accepted: 4 August 2015 / Published online: 28 August 2015 Springer-Verlag Wien 2015

Abstract The importance of 6-aminocoumarin, D-glucose, and ethyl cyanoacetate in pharmaceutical field was documented in literatures. Therefore, 6-aminocoumarin was reacted with single and double molarity of D-glucose forming Schiff’s base and bis-compound derivatives. Also, it was reacted with CS2 in phase transfer catalysis condition producing dithiocarbamate, which was used as an intermediate for the preparation of fused and polyfused derivatives. Additionally, it was reacted with dicarbonyl compounds via the condensation reaction to give the polycarbonyl derivatives. 6-Aminocoumarin was reacted with ethyl cyanoacetate via the addition and condensation reaction mechanisms; the effect of the side chains at the stability of some of these coumarins has been recorded. The kinetics of the base hydrolysis of 6-aminocoumarin and some of its derivatives was studied spectrophotometrically in aqueous medium at 298 K under pseudo-firstorder conditions ([OH-] [[ [Compound]). The suggested general rate equation can be given as: rate = {k1 ? k2 [OH-]} [complex]. The reasonable mechanism suggested that the investigated reaction proceeded via the formation of an intermediate and the ring opening of the formed intermediate was the rate determining step. This is the first time in which the kinetics of the formation and decay of the intermediate were followed (at [OH-] B 3.5 9 10-2 mol dm-3).

Electronic supplementary material The online version of this article (doi:10.1007/s00706-015-1550-4) contains supplementary material, which is available to authorized users. & Omyma Abd El Aziz Abd Allah [email protected] 1

Chemistry Department, Faculty of Science, Sohag University, Sohag, Egypt

Graphical Abstract

Keywords 6-Aminocoumarin Diethyl oxalate Triethyl orthoformate Phase transfer catalysis Base hydrolysis Kinetics

Introduction Coumarin and some of its derivatives have important effects on plant biochemistry and physiology, acting as antioxidants, enzyme inhibitors, and precursors of toxic substances. These compounds are involved in the actions of plant growth hormones and growth regulators control of respiration, photosynthesis, as well as defense against infection [1–4]. Coumarins are widely used as additives in food, perfumes, and cosmetics [5], also have super thermal stability and outstanding optical properties, since these compounds are used as laser dyes and nonlinear optical chromophores. Aminocoumarin derivatives, in particularly are known to be a category of important fluorogenic dyes [6, 7] and also show high activity as antiplatelet agents [8]. Coumarins also have a wide spectrum of biological activities [9–11], many of these derivatives have proven to be active as anti-HIV [12], antitumor agents [13], anticoagulant [14], antibacterial [15], antifungal [16],

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O. A. Abd Allah, L. A. E. Nassr

antiinflammatory [17], and antibiotics [18]. In view of these observations and in continuation of our work on coumarin-based heterocycles [19–26], this study was directed to synthesize a new series of coumarins, to understand the kinetics of the base hydrolysis for some of these new synthesized derivatives and to gain more information about the stability of them. The preparation and the new knowledge about these compounds can be helpful in different coumarin applications.

Results and discussion For the biological importance of the glucose compound, we react the starting 6-aminocoumarin (1) [27] with D-glucose in 1:1 and 2:1 molar ratio in refluxing ethanol via the condensation reaction of the aldehyde group in the glucose molecule with amino group in one or two molecules of compound 1 to form Schiff’s base derivative 6-(2,3,4,5,6-pentahydroxyhexylidene)amino-2H-1-benzopyran-2-one (2) and the 6,60 [(2,3,4,5,6-pentahydroxyhexylidene)diimino]bis[2H-1-benzopyran-2-one] (3), respectively. Compound 1 was condensed also with cinnamaldehyde in refluxing acetic acid to form

Scheme 1

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6-[(3-phenyl-2-propen-1-ylidene)amino]-2H-1-benzopyran2-one (4) (Scheme 1). The structures of the products 2–4 were confirmed by spectral analyses. Their IR spectral data showed the absence of NH2 signals and the presence of new signals characteristic to each compound. MS analyses of compounds 2–4 showed the molecular ion peaks at m/z = 323 (M?), 484.80 (M?), and 275.3 (M?), respectively. Compound 3 showed also molecular ion peaks at m/z = 485.80 ([M?1]?) and 486.80 ([M?2]?) for the presence of several heteroatoms (N and O) which accepted hydrogen atom during the analysis. The side chains of the new two Schiff’s bases 2 and 4 have different inductive effects on the benzopyrane ring. From this point, the fundamental characteristics of these compounds have been tested to know what extent these moieties can affect the stability of the benzopyrane ring in the basic medium (Schemes 4, 5). In a one-pot reaction using liquid–solid phase transfer catalysis (PTC) technique [DMF/K2CO3/tetrabutylammonium bromide (TBAB)] and in equimolar ratio compound 1 was reacted with CS2 forming dithiocarbamate derivative M. This intermediate M was reacted with triethyl orthoformate to form the non-cyclized product diethoxymethyl (2-oxo-2H-1-benzopyran-6-yl)carbamodithioate (5), which

Synthesis of novel coumarin derivatives based on…

737

Scheme 2

in turn was cyclized spontaneously by the reaction of the side chain with benzene moiety via the elimination of ethanol molecule to afford 10-ethoxy-3,10-dihydro-2thioxopyrano[2,3-f][1,3]benzothiazin-7(2H)-one (6) in a low yield as the second product (Scheme 2). IR spectra of compounds 5 and 6 showed characteristic bands at 1704, 1713 cm-1 (C=O groups) and at 1162, 1180 cm-1 (C=S groups), respectively. 1H NMR spectrum of compound 5 revealed new signals at d = 3.30–3.17, 1.65–1.42 ppm (2 q, CH2) and at 1.3–1.2, 0.94 ppm (2 t, CH3) due to the presence of two –OCH2CH3 groups and its MS analysis showed peak at m/z = 337 (M? - 2H), whereas the 1H NMR spectrum of compound 6 showed signals at 2.7 ppm (q) for CH2 group and at 1.3 ppm (t) for CH3 group assigned to the presence of -OCH2CH3 group and its MS analysis pointed to the molecular ion peaks at m/z = 293

(M?), 294 ([M?1]?) in addition to m/z = 295 ([M?2]?) for the presence of the isotope 34S atom. These results confirmed the suggested molecular structure. The cyclization reaction of compound 5 with hydrazine hydrate in refluxing DMF gave 6-[(4,5-dihydro-5-ethoxy-1,3,4-thiadiazol-2-yl)amino]-2H-1-benzopyran-2-one (7). Its IR spectrum revealed the disappearance of C=S group and mass spectrum showed a peak corresponding to the molecular ion at m/z = 291.3 (M?). In the same previous condition and in equimolar ratio, the dithiocarbamate M was reacted with chloroacetonitrile in stirred DMF at 70 C forming two products cyanomethyl (2-oxo-2H-1-benzopyran-6-yl)carbamodithionate (8) in a good yield and bis(cyanomethyl) (2-oxo-2H-1-benzopyran6-yl)imidotetrathiodicarbonate (9) in a low yield. This revealed that the reaction of compound 1 with CS2 and

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Scheme 3

chloroacetonitrile took place in 1:1:1 and 1: 2: 2 molar ratios, respectively (Scheme 2). IR spectrum of compound 8 showed absorption bands at 3440 cm-1 (NH), 2198 cm-1 (CN), and 1714 cm-1 (C=O) and its 1H NMR spectrum displays characteristic signals at 6.48 ppm (D2Oexchangeable) due to the presence of NH group and at 3.16 ppm to the presence of CH2 group. The IR spectrum of compound 9 revealed the absence of NH signal and the presence of two signals at 2199 and 2057 cm-1 due to 2 CN groups and its MS analysis showed peak at m/z = 392 ([M?1]?) (Scheme 2). Compound 1 was used as a starting material for the synthesis of polycarbonyl coumarin derivatives 10–13 via its reaction with diethyl oxalate and diethyl malonate to form the polycarbonyl polyfused derivatives pyrano[2,3f]indole-2,3,6(1H)-trione (10), 2H-pyrano[2,3-g]quinoline2,7,9(6H,8H)-trione (12) as a major products in addition to the N,N0 -bis(2-oxo-2H-1-benzopyran-6-yl)oxalic acid diamide (11) and N,N0 -bis(2-oxo-2H-1-benzopyran-6yl)malonic acid diamide (13), respectively (Scheme 3). 13C NMR spectra for the products 10–13 substantiated the

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results of the IR, 1H NMR, and MS analyses and in agreement with the suggested structures. The reaction of compound 1 with ethyl cyanoacetate in refluxing DMF took place with two different mechanisms pathway. The first one is the nucleophilic attack of amino group in 6-aminocoumarin molecule at the carbonyl group in ethyl cyanoacetate followed by elimination of an ethanol molecule to form N-(2-oxo-2H-1-benzopyran-6-yl)cyanoacetamide (14) in a good yield. The second mechanism can be attributed to the reaction resulted through the nucleophilic addition reaction of the amino group in 6-aminocoumarin at CN group in ethyl cyanoacetate molecule forming ethyl (E)-3-amino-3-[(2-oxo-2H-1benzopyran-6-yl)amino]propenoate (15) in a low yield (Scheme 3). IR spectrum of compound 14 pointed to new signals at 3540 cm-1 for OH group due to the formation of the keto-enol form (CN–CH2–(C=O)– $ CN–CH = (C– OH)–), at 2264 cm-1 for CN group, and at 1710 cm-1 for C=O group. Its MS analysis showed the molecular ion peaks at m/z = 228.2 (M?), 229.2 ([M?1]?), and 230.2 ([M?2]?) for the presence of several heteroatoms (N and


O) which accepted hydrogen atom during the analysis. IR spectrum of compound 15 revealed the new signals at 3328, 3233 cm-1 for NH2, 3075, 2926, 2865 cm-1 for CH groups, and 1699 cm-1 for C=O group. 1H NMR spectrum display characteristic signals at 5.20 ppm for NH2 group (D2O-exchangeable), 1.3–1.1 ppm (q) for CH2 group, and 0.87–0.86 ppm (t) for CH3 group and 13C NMR analysis pointed to signals at d = 160.4, 150.0 (2 C=O), 160.2, 146.0, 119.1, 117.0, 116.3, 110.6 (CH), 135.0, 126.9, 124.8,123.6 (4C s), 67.8 (CH2), 14.8 (CH3) ppm. All these spectral analyses indicate the suggested molecular structures. The comparison between the structures effect of the side chain moiety at the stability of the benzopyrane ring in compounds 14 and 15 were tack place in different concentrations of NaOH solutions (Scheme 5). Finally, 6-aminocoumarin was reacted with 2-thieno-5phenyl-1,3,4-oxadiazole in the basic medium via the nucleophilic attack of NH2 group of compound 1 at the O– C=S group with the opening of the oxadiazole ring followed by another nucleophilic attack of the formed NH group at the –C–O– group with the elimination of water molecule to form N-substituted triazole derivative named 6-(3-mercapto-5-phenyl-4H-1,2,4-triazol-4-yl)-2H-1-benzopyran-2-one (16) (Scheme 3). Its structure was stapled by IR spectrum which showed the disappearance of NH2 bands and the appearance of new band at 1611 cm-1 for C=N group in addition to the original C=O group at 1714 cm-1. Its 13C NMR spectrum showed characteristic signals at 177.9 ppm (C=O) and an additional band at 160.8 ppm (C=S), these spectral analyses confirmed the suggested structure. From literature it is known that coumarin and its derivatives were hydrolyzed in the basic medium via the opening of the pyrane ring forming coumarinic acid [28] derivatives which has assigned on orthoquinonoid structures. In this work the side chain effect at the stability and at the rate of base hydrolysis of benzopyrane ring of compound 1 and some of the new prepared compounds 2, 4, 14, and 15 had been traced through the reaction of these compounds with different concentrations of NaOH solutions. On the addition of NaOH (0.5 B [OH-]/mol dm-3 B 3.5) to the investigated compounds, firstly the metal salts of compounds 2, 4, 14, and 15 were formed very fast depending on the structure of the side chain for each one (Schemes 1, 3). These salts were formed by the reaction of the active methylene groups in compounds 14, 15 with NaOH and by the base hydrolysis of Schiff’s bases in compounds 2 and 4 via the nucleophilic attack of the OHanion at –CH = N– groups (Schemes 1, 3). After that, the formed salt was attacked by another OH- ion in fast step resulted in the formation of an intermediate according to the proposed mechanism (Schemes 4, 5). These results can

739

Scheme 4 H 2N O

O

+ HO

k

H 2N

a

Fast

O OH

O

A

B k

H 2N

k

H 2O +

O

O O

b

Slow

H 2N c

Fast

HO

O

+

O

D

OH

C

Scheme 5 R

R O

O

+ HO

,

ka

+ H 2O O

Very fast

O

B

A

k HO +

, R

b

Fast

, R kc

O O

OH

D

HO

O

Slow

O OH

C

+ k

d

, R O

Fast

O

O

+ H 2O

E

be inferred from the UV–Vis spectra, exemplified by compounds 2 and 14 with main bands at 363, 282, 242 nm and 333, 278, 236 sh nm, respectively, shifted to a new weak band at 360 nm only (Fig. 1) after mixing with NaOH. This band at 360 nm decayed with formation of another new band at 323 nm (Fig. 1) due to the rate determining opening of the pyrane ring as found in previous publications [22–26]. The observed first-order rate constants (kobs) were obtained by a least-squares procedure from the spectral scans (Fig. 1; Table 1). Linear plots of kobs vs. [OH-] are obtained (Fig. 2) in a good correlation with the following equation: kobs ¼ k1 þ k2 ½OH

ð1Þ

and the overall rate law for the investigated base-catalyzed reaction is

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Fig. 1 I Repeated spectral scan of compound 14 at [OH-] = 3.5 mol dm-3. a Compound 14 before the addition of NaOH; b compound 14 after 53 h from the addition of NaOH; II repeated spectral scan of compound 2 at [OH-] = 0.5 mol dm-3. a Compound

2 before the addition of NaOH; b compound 2 after 47 h from the addition of NaOH. I = 3.5 mol dm-3, time interval = 20 min and 298 K

Table 1 The observed first-order rate constant values (104 kobs/s-1) for the base hydrolysis reaction of the investigated compounds in aqueous medium at different [HO-], I = 3.5 mol dm-3 and 298 K

applied reaction conditions, it was found that k2 values are more significant than k1 values (Table 2). It can be realized from the repeated spectral scans (Fig. 1) that the effect of NaOH on the investigated compounds leads to opening of the pyrane ring as the rate determining stage. According to the previous literatures and from the obtained kinetic data, the suggested mechanism of the base hydrolysis of the studied compound 1 can be represented as shown in Scheme 4 and the suggested mechanism for the studied compounds 2, 4, 14, and 15 can be represented as shown in Scheme 5. On applying the steady-state approximation of the intermediates B and C on the suggested reaction mechanism (Scheme 4) for compound 1, where the total concentration of the compound: [A]T = [A] ? [B] ? [C]. Thus, the rate equation can be expressed as:

[OH-]/mol dm-3

104 kobs/s-1 1

2

4

14

15

0.5

1.51

1.39

0.84

1.34

1.74

1

2.85

2.23

1.46

2.89

2.65

2

5.15

4.16

3.41

4.33

4.26

3

7.36

6.59

–

6.84

–

3.5

9.09

7.77

5.52

8.52

9.40

Rate =

ka kb kc ½OH ½AT ka kb þ kb kc þ ka kc ½OH

ð3Þ

where kobs ¼

Fig. 2 The relationship between [OH-] and kobs values for the base hydrolysis of the investigated compounds in aqueous media at I = 3.5 mol dm-3 and 298 K

d½Compound=dt ¼ ðk1 þ k2 ½OH Þ ½Compound

ð2Þ

where k1 term resulted from the influence rate determining dissociation of the compounds and k2 term is a rate determining attack by OH- at the compounds. Under the

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ka kb kc ½OH ka kb þ kb kc þ ka kc ½OH

ð4Þ

On the other hand, when the steady-state approximation is applied for the concentration of the intermediates B, C, and D on the suggested reaction mechanism (Scheme 5) for compounds 2, 4, 14, and 15 the rate equation can be stated as: Rate =

kb kc kd ½OH ½AT kb kc þ kc kd þ kb kd ½OH

ð5Þ

and kobs ¼

kb kc kd ½OH kb kc þ kc kd þ kb kd ½OH

ð6Þ


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Table 2 The values of (k1 ? k2), (k0 1 and k0 2 ), and (k00 1 þ k00 2 ) (obtained from plot kobs vs. [OH-]) and the values of kb or kc obtained from plot 1/kobs vs. 1/[OH-], for the base hydrolysis of the investigated compounds in aqueous medium at 298 K 1 105 k1/s-1 4

10 k2/mol

-1

3

dm s

-1

104 k0 1 /s-1

2

4

3.01

1.41 0.22

2.45

2.14 1.59

7.90 13.70

103 k0 2 /mol-1dm3 s-1 14.35 35.08 105 k00 1 /s-1 4

-1

3

-1

10 k00 2 /mol dm s 3

10 kb or kc/s

-1

14

15

Notes

2.58

0.59 At 0.5 B [OH-]/mol dm-3 B 3.5

2.26

2.55

7.84 10.42 Formation of the intermediate at 0.5 9 10-2 B [OH-]/mol dm-3 B 3.5 9 10-2 42.13 28.69

1.99

2.47

1.43

2.02 Decay of the intermediate at 0.5 9 10-2 B [OH-]/mol dm-3 B 3.5 9 10-2

5.01

7.42

2.18

2.20

3.53

1.81 3.83

4.01

1.26 According to the steady-state approximation

observed rate constant (k0 obs) were cited in Table 3. As shown in Fig. 5 the relation between the observed rate constant values k0 obs vs. [OH-] is linear and in a good correlation with the following equation: 0 kobs ¼ k10 þ k20 ½OH ð7Þ and the overall rate law for the intermediate formation is d½Compound=dt ¼ k10 þ k20 ½OH ½Compound ð8Þ

Fig. 3 The relationship between 1/[OH-] and 1/kobs values for the base hydrolysis of the investigated compounds in aqueous media at I = 3.5 mol dm-3 and 298 K

where the total concentration of the compound: [A]T = [B] ? [C] ? [D], because [A] is very small and neglectable as it reacts very fast with the base to form the intermediate B. According to the above approximations, the plots of 1/kobs vs. 1/[OH-] at -3 -3 (0.5 B [OH ]/mol dm B 3.5 and I = 3.5 mol dm ) are linear and the values of rate constant of the slow step in the suggested mechanisms (kb for compounds 1 or kc for compounds 2, 4, 14, and 15) can be determined from the intercept of the plots [29, 30] (Fig. 3 and Table 2). On studying the base hydrolysis of the investigated coumarin compounds in low base concentrations (0.5 9 10-2 B [OH-]/mol dm-3 B 3.5 9 10-2), formation and decay of a greenish-blue intermediate were observed in case of compounds 1, 2, 14, and 15. The value of kmax for 6-aminocoumarin (1) intermediate is found to be at 604 nm where for compounds 2, 14, and 15 it was located at 594 nm (Fig. 4). The formation rate of the intermediate differs from compound to another dependent on the used [OH-]. The kinetics of the formation and decay of the intermediate were followed and the values of

The values of k0 1 range from 13.7 9 10-4 s-1 to 7.84 9 10-4 s-1 where the values of k0 2 range from 42.13 9 10-3 mol-1 dm3 s-1 to 14.35 9 10-3 mol-1 dm3 s-1 (Table 2). The formed intermediate decays slowly as shown in Fig. 6 and the values of observed rate constant k00 obs of the intermediate decay were cited in Table 4. From Fig. 5, it is clear that the relation between kobs and [OH-] can be represented according to the following equation: 00 kobs ¼ k100 þ k200 ½OH ð9Þ that k00 2 values are more momentous than k00 1 values (Fig. 7) and the overall rate law for the intermediate decay is: d½Compound=dt ¼ ðk100 þ k200 ½OH Þ ½Compound

ð10Þ

On studying the base hydrolysis of the investigated coumarin compounds in low base concentrations (0.5 9 10-2 B [OH-]/mol dm-3 B 3.5 9 10-2), the change of the reaction mixture color from yellow to greenish-blue in case of compounds 1, 2, 14, and 15 was observed by naked eyes and followed spectrophotometrically (Fig. 4) but not observed in case of compound 4. After that the greenishblue color decayed with time (Fig. 6).The color change suggested formation and decay of an intermediate which cannot be observed in the presence of higher concentrations from the base (0.5 B [OH-]/mol dm-3 B 3.5) because of its fast rate of formation and decay. Good inspection of the proposed mechanism (Schemes 4, 5) leads to suggest that the formed greenish-blue intermediate

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Fig. 4 I Repeated spectral scan of 6-aminocoumarin (1) (formation of an intermediate at 604 nm). a 6-aminocoumarin before the addition of NaOH; II repeated spectral scan of compound 15 (formation of an Table 3 The observed first-order rate constant (103 kobs/s-1) values for the formation of the intermediate during the base hydrolysis reaction of the investigated compounds in aqueous medium at different [HO-], I = 3.5 9 10-2 mol dm-3 and 298 K [OH-]/mol dm-3

103 kobs/s-1 1

2

14

15

0.005

0.84

1.54

0.91

1.2

0.01

0.95

1.76

1.27

1.33

0.02 0.03

1.09 1.20

2.03 2.39

1.67 2.08

1.60 1.86

0.035

1.30

2.64

2.20

2.09

Fig. 5 The relationship between [OH-] and kobs values for the formation of the intermediate during the base hydrolysis of the investigated compounds in aqueous media at I = 3.5 9 10-2 mol dm-3 and 298 K. kmax = 604 and 594 nm for 6-aminocoumarin and other compounds, respectively

can be B intermediate in Scheme 4 or C intermediate in Scheme 5. Because it can be inferred that the fast step of the formation of the mentioned intermediate at higher

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intermediate at 594 nm). [OH-] = 3 9 10-2 mol dm-3, -2 -3 I = 3.5 9 10 mol dm , time interval = 10 min and 298 K

[OH-] is turned to slow step at lower [OH-]. On the other hand, the slow step of the pyrane ring opening which is the rate determining step in case of higher [OH-] turned to extremely slow step and the change in absorbance at its characteristic wavelength 323 nm (Fig. 1) is not significant at lower [OH-] (0.5 9 10-2 B [OH-]/mol dm-3 B 3.5 9 10-2 in the present work). The detection of the formation of some intermediates in the presence of low concentrations from the reactants was observed previously [31] but it is the first time for coumarin derivatives. The order of enhancement the formation of the greenishblue intermediate was found to be as follows: compound 1 \ compound 15 \ compound 2 \ compound 14. This order can be attributed to the effect of the side chain (R) attached in position 6 in the coumarin compounds (Schemes 1, 3). The order of the electron donation ability of the side chain moiety increase as follows: compound 1 [ compound 15 [ compound 2 [ compound 14 [ compound 4, which is coincide with the order of enhancement the formation of the greenish-blue intermediate (Fig. 5; Tables 2, 3). The first step in Scheme 4 and the second step in Scheme 5 represented the nucleophilic attack of OH- at C=O group in the pyrane ring, this step affected by the electron density on the side chain group. As the electron donation ability of the side chain moiety increase the rate of the nucleophilic attack step decrease because of the increase in the electron density on the pyrane ring which retard the attack of OH- on the carbonyl group [24–26]. The greenish-blue color was not observed in compound 4 because of the side chain moiety is a good electron withdrawing group, this decrease the electron density at the pyrane ring and increase the velocity of the nucleophilic attack of OH- at the C=O group, it leads to the disappearance of the greenish-blue color.


743

Fig. 6 Repeated spectral scan of compound 2 at [OH-] = 3.5 9 10-2 mol dm-3, I = 3.5 9 10-2 mol dm-3, time interval = 10 min and 298 K after 30 min from the beginning of the reaction (decay of an intermediate at 594 nm)

Table 4 The observed first-order rate constant (105 kobs/s-1) values for the decay of the intermediate during the base hydrolysis reaction of the investigated compounds in aqueous medium at different [HO-], I = 3.5 9 10-2 mol dm-3 and 298 K [OH-]/mol dm-3

105 kobs/s-1 1

2

14

15

0.005

2.27

2.78

1.52

2.12

0.01

2.46

3.33

1.66

2.26

0.02 0.03

2.99 3.43

3.87 4.63

1.87 2.07

2.47 2.63

0.035

3.79

5.13

2.19

2.82

containing 6-aminocoumarin moiety fused with different organic compounds exemplified by D-glucose molecule have been synthesized and characterized. Additionally, the inductive effect of the side chain moieties at the reactivity of some of these new prepared derivatives has been discussed. Moreover, the kinetics of the base-catalyzed hydrolysis of some of these compounds were studied in wide range of [OH-] to gain more information about their stability. For the first time, the formation and decay of an intermediate in the reaction mechanism were detected for coumarin derivatives in presence of low [OH-]. It is believed that this kinetic study would add something new and useful body of information about these new, interesting and vital compounds to widen their applications.

Experimental

Fig. 7 The relationship between [OH-] and kobs values for the decay of the intermediate during the base hydrolysis of the investigated compounds in aqueous media at I = 3.5 9 10-2 mol dm-3 and 298 K. kmax = 604 nm and 594 nm for 6-aminocoumarin and other compounds, respectively

Conclusion Because of the wide applications of 6-aminocoumarin and its derivatives in addition to their super thermal stability, new series of fused and polyfused heterocyclic compounds

All melting points were determined by Kofler melting point apparatus. IR spectra were recorded from KBr discs on a Shimadzu DR-8001 spectrophotometer. NMR spectra were recorded at 400 MHz on a Varian Gemini NMR spectrometer and also 400 MHz on a Varian Mercury-300 BB at Sohag University in DMSO-d6. The chemical shift is expressed in d value (ppm) using TMS as an internal reference; 1H-1H coupling constants (J values) are given in Hertz. Mass spectra were performed on Micro mass 7070 E1-spectrometer using direct inlet and Shimadzu Qp-2010 Plus mass spectrometer using electronic ionization mode operating at 70 eV. 6-(2,3,4,5,6-Pentahydroxyhexylidene)amino-2H-1benzopyran-2-one (2, C15H17NO7) To a solution of 1.6 g compound 1 [27] (0.01 mol) in 30 cm3 ethanol, 1.8 g glucose (0.01 mol) in 3 cm3 H2O and few drops of piperidine were added. The reaction mixture was refluxed for 3 h and concentrated under reduced pressure. After cooling the mixture, the separated

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solid was filtered off and crystallized from ethanol/water. Yield: 77 %; m.p.: 164 C; 1H NMR (400 MHz, DMSOd6): d = 7.94–7.92 (d, J = 8 Hz, 1H, CHarom), 7.20–7.18 (d, J = 8 Hz, 1H, CHarom), 7.01–6.99 (d, J = 8 Hz, 1H, CHvinylic), 6.91 (s, 1H, CHarom), 6.50–6.49 (d, J = 4 Hz, 1H, =CH), 6.41–6.39 (d, J = 8 Hz, 1H, CHvinylic), 4.93 (s, 4H, 4 OH), 4.38 (s, 1H, OH), 3.48 (m, 1H, CH), 3.38 (m, 1H, CH), 3.28–3.26 (m, J = 7.7 Hz, 1H, CH), 3.18–3.16 (m, J = 8 Hz, 1H, CH), 2.51 (d, J = 4 Hz, 2H, CH2) ppm; 13 C NMR (400 MHz, DMSO-d6): d = 160.8 (C=O), 146.4, 145.0, 144.6, 119.4, 118.8, 116.9, 116.4, 110.1 (coumarin ring), 85.6 (CH=N), 78.2, 77.8, 73.5, 70.6 (4 CH.OH), 61.3 (CH2) ppm; IR (KBr): V = 3413 (br, OH), 1557 (C=N), 1301 (C–O–), 2925 (CH), 1680 (C=O) cm-1; MS: m/ z (%) = 323 (M?, 2.16), 321.10 (2.87), 316 (1.95), 310 (1.95), 309 (2.64), 306.1 (0.01), 305.15 (1.64), 303.15 (1.72), 300.40 (1.01), 293.40 (2.12), 283.4 (1.43), 257.20 (2.33), 200.25 (0.96), 186.05 (1.74), 172.20 (2.25), 150.1 (4.37), 63.95 (100), 62.05 (3.23). 6,60 -[(2,3,4,5,6-Pentahydroxyhexylidene)diimino]bis[2H-1-benzopyran-2-one] (3, C24H24N2O9) To a solution of 3.2 g compound 1 [27] (0.02 mol) in 30 cm3 ethanol, 1.8 g glucose (0.01 mol) in 3 cm3 H2O and few drops of piperidine were added. The reaction mixture was refluxed for 3 h and concentrated under reduced pressure. After cooling the mixture, the separated solid was filtered off and crystallized from ethanol/water. Yield: 82 %; m.p.: 210 C; 1H NMR (400 MHz, DMSOd6): d = 7.94–7.91 (d, J = 10 Hz, H, N–CH–N), 7.20–7.18 (d, J = 7.2 Hz, 2H, CHvinylic), 7.01–6.80 (m, 6H, CHarom), 6.41–6.39 (d, J = 7.6 Hz, 2H, CHvinylic), 6.10 (s, H, OH), 4.91 (s, 3H, 3 OH), 4.38 (s, H, OH), 3.47–3.44 (t, J = 8.6 Hz, 2H, 2 CH), 3.29–3.27 (m, H, CH), 3.25–3.17 (m, H, CH), 3.15–3.10 (d, J = 12 Hz, 2H, CH2) ppm; 13C NMR (400 MHz, DMSO-d6): d = 157.0 (2 C=O), 146.4, 145.0, 144.6, 119.4, 118.8, 116.9, 116.4, 110.1 (16 C coumarin ring), 85.6 (N–CH–N), 78.2, 77.8, 73.5, 70.6 (4 CH.OH), 61.3 (CH2) ppm; IR (KBr): V = 3381 (br, OH), 2929 (CH), 1687 (C=O), 1308 (C– O–) cm-1; MS: m/z (%) = 486.80 ([M?2]?, 0.01), 485.80 ([M?1]?, 20.01), 484.80 (M?, 1.01), 482.80 (0.01), 481.80 (0.02), 4.79 (0.01), 478 (0.01), 477.8 (0.02), 476.8 (0.02), 469.7 (0.01), 468.7 (0.01), 452.75 (0.03), 451.85 (0.02), 377.45 (0.03), 376.45 (0.02), 316.45 (0.02), 315.5 (0.02), 293.35 (0.04), 283.35 (0.09), 257.35 (0.019), 180.25 (0.12), 80.05 (100), 71.15 (1.77), 62.15 (0.71). 6-[(3-Phenyl-2-propen-1-ylidene)amino]-2H-1benzopyran-2-one (4, C18H13NO2) To a solution of 1.6 g compound 1 [27] (0.01 mol) in 20 cm3 acetic acid, 1.3 cm3 cinnamaldehyde (0.01 mol) was added. The mixture was refluxed for 6 h. After cooling the reaction mixture was added to ice-cold water, the

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separated solid was filtered off and recrystallized from ethanol. Yield: 69 %; m.p.: 140 C; 1H NMR (400 MHz, DMSO-d6): d = 9.6–9.47 (d, J = 12 Hz, 1H, CH), 9.0–8.89 (d, J = 8 Hz, 1H, CH), 8.30–8.07 (m, 1H, CH), 7.58–7.56 (d, J = 8 Hz, 1H, CHvinylic), 6.74-6.72 (d, J = 7.8 Hz, 1H, CHvinylic), 8.40-6.40 (m, 8H, CHarom) ppm; 13C NMR (400 MHz, DMSO-d6): d = 168.9 (C=O), 160.2, 156.2, 155.0, 153.2, 145.0, 144.8, 138.4, 136.3, 134.3, 132.6, 129.3, 123.6, 121.1, 120.5, 117.9, 116.9, 113.4 ppm; IR (KBr): V = 3050 (CH arom), 2929 (CH), 1723 (C=O), 1610 (C=N), 1262 (C–O) cm-1; MS: m/ z (%) = 275.3 (M?, 1.46), 274.3 (0.83), 273.3 (0.44), 270.3 (0.79), 269.3 (0.9), 267.3 (0.88), 266.3 (0.96), 265.3 (0.95), 264.3 (1.31), 258.3 (0.17), 250 (0.97), 233.2 (0.82), 228.2 (0.35), 200 (0.12), 199 (1.29), 150.15 (1.08), 149.15 (7.15), 148.15 (1.4), 147.15 (3.79), 80 (100), 78.1 (64.33), 57.1 (70.03). Synthesis of 5 and 6 To a solution of 1.61 g compound 1 [27] (0.01 mol) in 20 cm3 DMF, 4 g of anhydrous potassium carbonate, catalytic amount of TBAB and 0.76 cm3 CS2 (0.01 mol) were added. The reaction mixture was stirred for 1 h at r.t. The formed intermediate was treated with 1.64 cm3 of triethyl orthoformate (0.01 mol). The mixture was stirred for an additional 4 h at 60 C and filtered off. After cooling the organic layer (DMF), the separated solid was filtered off, dried, and crystalized from DMF to form compound 5. The filtrate was added to 100 cm3 ice-cold water, the resulting solid mass was filtered off, dried, and crystalized from proper solvent to give compound 6. Diethoxymethyl (2-oxo-2H-1-benzopyran-6-yl)carbamodithioate (5, C15H17NO4S2) Crystallized from ethanol. Yield: 52 %; m.p.: 220 C; 1H NMR (400 MHz, DMSO-d6): d = 10 (s, 1H, NH D2O exchangeable), 8.00–8.02 (d, J = 8 Hz, 1H, CHarom), 7.77–7.67 (d, J = 8.2 Hz, 1H, CHarom), 7.42–7.40 (d, J = 7.6 Hz, 1H, CHvinylic), 6.52–6.49 (d, J = 9 Hz, 1H, CHvinylic), 3.31 (s, 1H, CH), 3.30–3.17 (q, J = 10 Hz, 2H, CH2), 1.65-1.49 (q, J = 10 Hz, 2H, CH2), 1.3-1.2 (t, J = 8.8 Hz, 3H, CH3), 0.94 (t, J = 4 Hz, 3H, CH3) ppm; 13 C NMR (400 MHz, DMSO-d6): d = 181.0 (C=O), 160.4 (C=S), 151.1 (C–N–), 144.5, 129.2, 124.0, 116.8 (6 CH), 136.0, 119.0 (C=C), 23.5 (2 CH2), 19.6 (2 CH3) ppm; IR (KBr): V = 3259 (NH), 3061 (CH), 2929 (CH), 1713 (C=O), 1268 (C–O), 1180 (C = S) cm-1; MS: m/ z (%) = 337 (M? - 2H, 0.20), 336.6 (0.5), 335.6 (0.7), 308.2 (0.3), 267.66 (0.1), 264.14 (0.02), 257.74 (0.3), 247.75 (0.4), 246.7 (0.2), 232.8 (0.1), 231.8 (0.9), 216.1 (0.2), 214.85 (0.2), 207.44 (0.4), 203.9 (12.7), 202.9 (79.4), 161 (100), 105.03 (2.3), 103.98 (15.2), 87.9 (1.8), 86.9 (1.3).


10-Ethoxy-3,10-dihydro-2-thioxopyrano[2,3-f] [1,3] benzothiazin-7(2H)-one (6, C13H11NO3S2) Crystallized from DMF. Yield: 48 %; m.p.: 288 C; 1H NMR (400 MHz, DMSO-d6): d = 9.8, 8.1 (s, 1H, NH ? SH), 8.0–7.6 (m, 2H, CHarom), 7.40 (d, J = 8 Hz, 1H, CHvinylic), 6.4 (d, J = 8.2 Hz, 1H, CHvinylic), 2.9 (s, 1H, OCH), 2.7 (q, J = 4 Hz, 2H, CH2), 1.3 (t, J = 8.2 Hz, 3H, CH3) ppm; 13C NMR (400 MHz, DMSO-d6): d = 168.9 (C=O), 162.7, 158, 147.2, 144.6, 119.3, 116.4, 57.0, 55.7, 54.4, 45.4 (10 C), 31.3 (CH2), 10.1 (CH3) ppm; IR (KBr): V = 3441 (NH), 3039 (CH), 2929 (CH), 1704 (C=O), 1276 (C–O), 1162 (C=S) cm-1; MS: m/ z (%) = 295 ([M?2]?, 5.3), 294 ([M?1]?, 7.74), 293 (M?, 6.8), 286 (7.12), 285.4 (2.6), 281.4 (2.3), 278.4 (7.02), 277.4 (6.44), 276.4 (0.67), 270.4 (5.96), 265.4 (0.34), 251.3 (0.10), 228.3 (2.36), 195 (2.12), 194.05 (7.74), 193.2 (8.22), 183.2 (3.56), 181.2 (3.46), 126.2 (5.38), 101.15 (1.35), 63.95 (100). 6-[(4,5-Dihydro-5-ethoxy-1,3,4-thiadiazol-2-yl)amino]2H-1-benzopyran-2-one (7, C13H13N3O3S) To a solution of 0.68 g compound 5 (0.002 mol) in 20 cm3 DMF, 0.13 cm3 hydrazine hydrate (0.002 mol) was added. The reaction mixture was refluxed for 3 h until H2S gas evaluation ceasing. After cooling the reaction mixture the separated solid was filtered off, dried, and crystalized from DMF. Yield: 58 %; m.p.: [258 C; 1H NMR (400 MHz, DMSO-d6): d = 8.95, 8.19 (s, 2H, 2 NH), 8.17–7.34 (m, 3H, CHarom), 7.59–7.57 (d, J = 7.85 Hz, 1H, CHvinylic), 6.52–6.50 (d, J = 7.8 Hz, 1H, CHvinylic), 4.12 (q, J = 8.8 Hz, 2H, CH2), 3.6 (s, 1H, CH), 1.23 (t, J = 7.6 Hz, 3H, CH3) ppm; 13C NMR (400 MHz, DMSO-d6): d = 162.7 (C=O), 160.1, 149.2, 144.2, 142.2, 136.5, 128.5, 122.6, 119.2, 117, 115.2 (10 C), 29.4 (CH2), 14.3 (CH3) ppm; IR (KBr): V = 3421 (NH), 3100 (CH), 2927 (CH), 1714 (C=O), 1183 (C–O), 1112 (C=S) cm-1; MS: m/z (%) = 291.3 (M?, 5.4), 289.3 (0.56), 285.3 (1.82), 284.35 (1.32), 283.3 (0.05), 282.3 (0.96), 281.3 (4.76), 275.3 (0.86), 269.2 (3.44), 261.2 (0.41), 258.5 (1.93), 241.25 (2.03), 228.1 (1.57), 199.15 (7.04), 198.15 (12.31), 194.15 (1.32), 168.15 (2.53), 166.1 (3.5), 128 (10.69), 127 (4.61), 124.2 (7.8), 85.1 (100), 73.05 (6.03), 70.1 (3.65). Synthesis of compounds 8 and 9 To a solution of 1.61 g compound 1 [27] (0.01 mol) in 20 cm3 DMF, 4 g of anhydrous potassium carbonate, catalytic amount of TBAB and 0.76 cm3 CS2 (0.01 mol) were added and the reaction mixture was stirred for an hour at r.t. The formed intermediate was treated with 0.63 cm3 of chloroacetonitrile (0.01 mol). The mixture was stirred for an additional 4 h at 60 C and filtered off. After cooling the

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organic layer (DMF), the separated solid was filtered off dried and crystalized from ethanol, the insoluble solid mass form compound 8 after cooling the filtrate, the resulting solid mass was filtered off and dried to give compound 9. Cyanomethyl (2-oxo-2H-1-benzopyran-6-yl)carbamodithionate (8, C12H8N2O2S2) Crystallized from ethanol. Yield: 67 %; m.p.: 230 C; 1H NMR (400 MHz, DMSO-d6): d = 8.0–7.84 (m, 3H, CHarom), 7.6–7.53 (d, J = 6 Hz, 1H, CHvinylic), 6.58–6.57 (d, J = 4 Hz, 1H, CHvinylic), 6.48 (s, H, NH D2Oexchangeable), 3.16 (s, 2H, CH2) ppm; 13C NMR (400 MHz, DMSO-d6): d = 204 (C=O), 160.5, 144.7, 120, 117.4, 97.9, 88.2, 83.7, 58.1, 28.5 (10 C), 116.9 (CN), 19.6 (CH2) ppm; IR (KBr): V = 3440 (NH), 3080, 2938 (CH), 2198 (CN), 1714 (C=O), 1255 (C–O), 1123 (C=S) cm-1. Bis(cyanomethyl) (2-oxo-2H-1-benzopyran-6-yl)imidotetrathiodicarbonate (9, C15H9N3O2S4) Crystallized from DMF. Yield: 30 %; m.p.: 241 C; 1H NMR (400 MHz, DMSO-d6): d = 8.0-7.84 (m, 3H, CHarom), 7.68-7.6 (d, J = 10 Hz, 1H, CHvinylic), 6.576.48 (d, J = 12 Hz, 1H, CHvinylic), 3.00 (s, 4H, 2 CH2) ppm; 13C NMR (400 MHz, DMSO-d6): d = 163 (C=O), 160.5, 144.7, 133.2, 129.9, 129.4, 127.7, 119.2, 117, 110.7, 58.17 (10 C), 116.3 (2 CN), 23.5, 19.6 (2 CH2) ppm; IR (KBr): V = 3080, 2933 (CH), 2199, 2057 (CN), 1715 (C=O), 1257 (C-O), 1187, 1113 (C=S) cm-1; MS: m/z (%) = 392.6 ([M?1]?, 0.9), 384 (2.4), 371.9 (2.7), 367 (6.40), 357.2 (3.0), 350.12 (21.5), 310.3 (14.5), 285.9 (3.9), 217 (3.6), 161.3 (100), 104 (28.8), 63.85 (30.9). Synthesis of compounds 10 and 11 Compound 1 [27] (0.01 mol, 1.61 g) was dissolved in 1.46 cm3 diethyl oxalate (0.01 mol). The reaction mixture was refluxed, a solid precipitate was formed after 3 h and filtered off on hot. The separated solid was crystallized from ethanol, the insoluble precipitate filtered off to give compound 10, after cooling the filtrate the separated solid was filtered off to form compound 11. Pyrano[2,3-f]indole-2,3,6(1H)-trione (10, C11H5NO4) Yield: 71 %; m.p.: [300 C; 1H NMR (400 MHz, DMSOd6): d = 11(s, 1H, NH D2O-exchangeable), 8.2 (s, 1H, CHarom), 8.07 (s, 1H, CHarom), 7.44-7.42 (d, J = 7.2 Hz, 1H, CHvinylic), 6.51–6.49 (d, J = 7.4 Hz, 1H, CHvinylic) ppm; 13C NMR (400 MHz, DMSO-d6): d = 160.3 (C=O), 159.0 (C=O), 150.7 (C=O), 137.0, 134.4, 125.2 (4 C), 144.6, 119.9, 119.1, 117.1 (4 CH) ppm; IR (KBr): V = 3303 (NH), 3075 (CH), 1719, 1690 (C=O), 1259 (C–O) cm-1.

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746

N,N’-Bis(2-oxo-2H-1-benzopyran-6-yl)oxalic acid diamide (11, C20H12N2O6) Yield: 58 %; m.p.: 156 C; 1H NMR (400 MHz, DMSOd6): d = 8.93, 6.37 (s, 2H, 2NH D2O-exchangeable), 8.05–6.48 (m, 6H, CHarom), 7.57–7.54 (d, J = 8 Hz, 1H, CHvinylic), 6.76 (d, J = 8 Hz, 1H, CHvinylic) ppm; 13 C NMR (400 MHz, DMSO-d6): d = 160.9, 160.5 (4 C=O), 153.0, 149.1, 145.9 (6 C), 160.2, 144.7, 136.4, 123.6, 119.5, 119.2, 117.0, 116.9, 116.3, 110.7 (10 CH) ppm; IR (KBr): V = 3280 (NH), 3070 (CH), 1719, 1690 (2 C=O), 1185 (C-O) cm-1; MS: m/z (%) = 377 ([M?1]?, 8.8), 376 (M?, 7.4), 219 (4.4), 217 (17.6), 203 (5.9), 188 (10.3), 176 (5.9), 175 (2.9), 162 (5.9), 133 (61.8), 114 (7.4), 106 (17.6), 89 (20.6), 78 (100), 73 (38.2). Synthesis of compounds 12 and 13 Compound 1 [27] (0.01 mol, 1.61 g) was dissolved in 1.13 cm3 diethyl malonate (0.01 mol). The reaction mixture was refluxed for 4 h, through the reflux a solid precipitate was formed after 3 h. The separated solid was filtered off on hot, crystallized from ethanol, the precipitate give compound 12, after cooling the filtrate the separated solid form compound 13. 2H-Pyrano[2,3-g]quinoline-2,7,9(6H,8H)-trione (12, C12H7NO4) Crystallized from ethanol. Yield: 68 %; m.p.: [300 C; 1H NMR (400 MHz, DMSO-d6): d = 10.15 (s, 1H, NH D2Oexchangeable), 8.07–7.62 (s, 2H, CHarom), 7.35-7.32 (d, J = 8 Hz, 1H, CHvinylic), 6.47 (d, J = 8.1 Hz, 1H, CHvinylic), 2.06 (s, 2H, CH2) ppm; 13C NMR (400 MHz, DMSO-d6): d = 170.0, 162.0, 154.0 (3 C=O), 149.0, 144.8, 136.0, 123.5 (4 C), 144.8, 119.1, 117.9, 117.0 (4 CH), 24.3 (CH2) ppm; IR (KBr): V = 3293 (NH), 3070, 2927 (CH), 1715, 1630 (C=O), 1618 (C=N), 1184(C–O) cm-1. N,N’-Bis(2-oxo-2H-1-benzopyran-6-yl)malonic acid diamide (13, C21H14N2O6) Crystallized from ethanol. Yield: 40 %; m.p.: 180 C; 1H NMR (400 MHz, DMSO-d6): d = 10.15 (s, 1H, CH), 8.037.33 (m, 6H, CHarom), 7.63 (d, J = 8 Hz, 2H, 2CHvinylic), 6.46 (d, J = 8 Hz, 2H, 2CHvinylic), 6.8, 6.9 (s, 2H, 2 NH), 7.8 (s, 1H, OH) ppm; 13C NMR (400 MHz, DMSO-d6): d = 168.9 (2 C=O), 160.4 (2 C=O), 144.0, 136.1 (6 C), 149.6, 123.5, 117.8, 116.9, 116.8 (10 CH), 24.3 (CH2) ppm; IR (KBr): V = 3436 (OH), 3293 (NH), 3077, 2930 (CH), 1715 (C=O), 1618 (C=N), 1258 (C–O) cm-1; MS: m/z (%) = 392.9 ([M?2]?, 0.3), 373.7 (1), 372.58 (0.5), 370.9 (1.1), 369.94 (0.2), 367.8 (0.5), 357.77 (0.7), 356.6 (1.8), 355.9 (1.5), 351.14 (62.6), 349.14 (100), 340 (1.1), 310.93 (19), 261.4 (0.5), 210.11 (4.9), 205.2 (3.4), 131.7 (2.6), 122.5 (0.3), 73.14 (0.7), 60.13 (1.1).

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Synthesis of compounds 14 and 15 To a solution of 1.61 g compound 1 [27] (0.01 mol) in 20 cm3 DMF, 10.7 cm3 ethyl cyanoacetate (0.01 mol) was added. The reaction mixture was refluxed for 6 h, after cooling the separated solid was filtered off, dried, and crystalized from benzene. The resulting solid was filtered off to give compound 14, the filtrate was cooled and the separated solid mass was filtered off to form compound 15. N-(2-Oxo-2H-1-benzopyran-6-yl)cyanoacetamide (14, C12H8N2O3) Crystallized from benzene. Yield: 74 %; m.p.: 150 C; 1H NMR (400 MHz, DMSO-d6): d = 10.4 (s, 1H, NH D2O exchangeable), 8.10–6.80 (m, 3H, CHarom), 8.3 (s, 1H, =CH), 7.4–7.37 (d, J = 10.4 Hz, 1H, CHvinylic), 6.51–6.48 (d, J = 9 Hz, 1H, CHvinylic), 5.20 (s, H, OH D2O-exchangeable) ppm; 13C NMR (400 MHz, DMSOd6): d = 163 (C=O), 160.9, 160.1, 146, 145.7, 144.7, 128.7, 123.7, 119.2, 117, 110.7 (10 C), 116.3 (CN) ppm; IR (KBr): V = 3540 (OH), 3298 (NH), 3086, 2955 (CH), 2264 (CN), 1710 (C=O), 1610 (C=N), 1295 (C–O) cm-1; MS: m/z (%) = 230.2 ([M?2]?, 0.02), 229.2 ([M?1]?, 0.1), 228.2 (M?, 0.37), 225.2 (0.11), 221.2 (0.04), 219.2 (0.02), 210.2 (0.04), 200.2 (0.09), 190.15 (2.7), 189.15 (22.19), 162.15 (11.29), 161.15 (100), 134.1 (8.75), 133.1 (91.39), 105 (18.32), 104.1(62.9), 78.1(34), 52.9 (13.88). Ethyl (E)-3-amino-3-[(2-oxo-2H-1-benzopyran-6-yl)amino]propenoate (15, C14H14N2O4) Crystallized from benzene. Yield: 48 %; m.p.: 158 C; 1H NMR (400 MHz, DMSO-d6): d = 10.4 (s, 1H, NH D2Oexchangeable), 8.3 (s, H, CH), 7.90–6.80 (m, 3H, CHarom), 7.13-7.10 (d, J = 8.8 Hz, 1H, CHvinylic), 6.38–6.36 (d, J = 7.6 Hz, 1H, CHvinylic), 5.20 (s, 2H, NH2 D2Oexchangeable), 1.4–1.10 (q, J = 9 Hz, 2H, CH2), 0.87–0.86 (t, J = 4 Hz, 3H, CH3) ppm; 13C NMR (400 MHz, DMSO-d6): d = 160.4, 150.0 (2 C=O), 160.2, 146.0, 119.1, 117.0, 116.3, 110.6 (6 CH), 135.0, 126.9,124.8, 123.6 (4 C), 67.8 (CH2), 14.8 (CH3) ppm; IR (KBr): V = 3406 (NH), 3328, 3233 (NH2), 3075, 2926, 2865 (CH), 1699 (C=O), 1288 (C–O) cm-1. 6-(3-Mercapto-5-phenyl-4H-1,2,4-triazol-4-yl)-2H-1benzopyran-2-one (16, C17H11N3O2S) To a solution of 1.61 g compound 1 [27] (0.01 mol) in 20 cm3 DMF, 1.78 g 5-phenyl-1,3,4-oxadiazole-2-thione (0.01 mol) was added. The reaction mixture was refluxed for 4 h. After cooling the reaction mixture was added to 100 cm3 ice-cold water, the resulting solid mass was filtered off, dried, and crystalized from ethanol/H2O. Yield: 69 %; m.p.: 220 C; 1H NMR (400 MHz, DMSO-d6): d = 11 (s, 1H, NH D2O-exchangeable), 8.1-7.85, 7.3 (m, 8H, CHarom), 7.57–7.55 (d, J = 7.6 Hz, 1H, CHvinylic),


6.51–6.49 (d, J = 7.9 Hz, 1H, CHvinylic) ppm; 13C NMR (400 MHz, DMSO-d6): d = 177.9 (C=O), 160.8 (C=S), 144.6, 132.6, 131.4, 129.8, 126.4, 121.8, 119.4, 117.4, 115.4 (10 CH), 158.0, 149.0, 135.6, 122.9, 116.7 (5 C) ppm; IR (KBr): V = 3140 (NH), 3090 (CH), 1714 (C=O), 1617 (C=N), 1293 (C–O), 1178 (C=S) cm-1; MS: m/z (%) = 323 ([M?2]?, 20.6), 322 ([M?1]?, 14.7), 305 (100), 146 (44), 145 (73.5), 144 (17.6), 109 (20.6), 78 (26.5), 68 (14.7), 55 (17.6). Kinetic measurements The kinetics of base-catalyzed hydrolysis of the compounds 1, 2, 4, 14, and 15 was investigated by following the dependence of absorbance on time with Perkin Elmer Lambda 35 spectrophotometer in aqueous medium at 298 K. The required volumes of the isothermal reacting stock solutions were syringed out and mixed in 10 mm cells in thermostated cell jacket compartment (the temperature was fitted at 25 ± 0.1 C). Pseudo first-order conditions were applied by mixing multifold greater concentration of NaOH than that of the studied compound. The reaction was monitored at two ranges of NaOH concentrations: (0.5 B [OH-]/mol dm-3 B 3.5 and I = 3.5 mol dm-3) and (0.5 9 10-2 B [OH-]/mol dm-3 B 3.5 9 10-2 and I = 3.5 9 10-2 mol dm-3). The observed first-order rate constants (kobs) were calculated using least-squares procedures of time-dependence of absorbance plots. It was confirmed that there is no interference from other reagents at the selected wavelength absorption maxima for the investigated compounds.

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