A New Pathway to 3-Hetaryl-2-oxo-2H-chromenes: On the Proposed Mechanisms for the Reaction of 3-Carbamoyl-2-iminochromenes with Dinucleophiles

Abstract

The present account summarizes the author’s studies to elucidate the mechanisms of the recently reported rearrangements resulting from inter- and/or intramolecular reactions of 2-imino-2H-chromene-3-carboxamides with different dinucleophiles.

Introduction

The coumarin (2H-chromen-2-one) moiety is often found in natural products [1]. In view of the ubiquity of this fragment in a variety of biologically active compounds, the synthesis of various 2H-chromen-2-one analogs is important in gauging their potential as a source of chemotherapeutics [2]. As part of our investigations on the reactivity of 3-carbamoyl-2-imino-2H-chromenes [3], we recently introduced a new method for synthesis of 3-hetaryl-2-oxo-2H-chromenes [4]. This method was based on the rearrangements of 2-imino-2H-chromene-3-carboxamides into 3-hetaryl-2-oxo-2H-chromenes under the action of dinucleophiles. In this account, results of our studies on clarification of the mechanism of the above-mentioned rearrangements are summarized and exemplified by utilizing anthranilic acid, its derivatives, and arylhydrazides as N-nucleophiles. In order to elucidate the mechanisms of the applied rearrangements, a model system approach based on isolation of stable reaction intermediates or their structural analogs was used.

Results and Discussion

Several methods for synthesis of quinazolinylcoumarin derivatives of type 7 have been reported. For example, compounds of type 7 have been prepared by aminolysis of 4-oxo-2-(2-oxo-2H-chromen-3-yl)-4H-3,1-benzoxazines with aqueous ammonia [5], ammonium acetate or formamide [6]. Various

Scheme 1. Proposed mechanism for the transformations of 2-imino-2H-chromenes 1 into 3- (quinazolin-2-yl)-2H-chromen-2-ones 7 by the action of anthranilic acid (2) under non-acidic conditions

Scheme 1. Proposed mechanism for the transformations of 2-imino-2H-chromenes 1 into 3- (quinazolin-2-yl)-2H-chromen-2-ones 7 by the action of anthranilic acid (2) under non-acidic conditions

7-diethylamino-3-(4-oxo-3H-quinazolin-2-yl)-2H-chromen-2-one dyes have been synthesized [7] by the reactions of: (i) ethyl 7-diethylamino-2-oxo-2H-chromene-3-carboxylate with anthranilamides; (ii) cyclization of 4-diethylamino-2-hydroxybenzaldehyde with 2-(cyanomethyl)quinazolin-4(3H)-ones; (iii) 7-amino-2-oxo-2H-chromene-3-carboxamides with isatoic anhydride or of 4-diethylamino-2-hydroxybenzaldehyde with acetanilides and subsequent cyclization of the product formed with urethane and phosphorus pentoxide.

Kametani et al. reported [8] the synthesis of 3-substituted quinazolin-4(3H)-ones starting from a sulfinamide anhydride, prepared from anthranilic acid (2) and thionyl chloride, and primary and secondary amides. Our attempts to synthesize quinazolinylcoumarin 7a by simple heating of 2-oxo- 2H-chromene-3-carboxamide (25 [9], cf. Scheme 9) and anthranilic acid (2) without any additional reagents failed. However, it was found that refluxing of compounds 1a,b and 2 in degassed toluene afforded compounds 7a,b in moderate yields as the sole products (Scheme 1A). In the course of the reaction, a strong liberation of ammonia was detected. In order to fully characterize compounds 7a,b, they were also synthesized by an alternative method via Knoevenagel condensation of 2-(cyanomethyl)quinazolin-4(3H)-one 8 [10] with salicylaldehydes 9a,b in ethanol and using piperidine as a catalyst and subsequent acid hydrolysis of the formed imines 10 (Scheme 1B).

A mechanism was postulated (Scheme 1A) for the formation of 2H-chromen-2-one and quinazolin- 4(3H)-one moieties via a rearrangement of 2-imino-2H-chromene-3-carboxamides 1 by the action of anthranilic acid (2) as N-nucleophile [11] under non-acidic conditions. It may involve several consecutive or concerted steps: (i) intermolecular nucleophilic attack of NH2 on C-2 of the iminolactone ring (1 + 2 ⇆ 3), (ii) iminolactone ring opening (3 ⇆ 4), (iii) thermal E/Z isomerization [12] of intermediate 4 (4 ⇆ 5), iv) cyclization of intermediate 5 to amidine 6; and (v) subsequent formation of 2H-chromen-2-one and pyrimidine fragments (6 → 7).

To prove the proposed mechanism, we directed our studies to isolation of intermediate amidines of type 6. With this objective in view various heterocyclic systems, not prone to spontaneous cyclization, were designed and synthesized. As an example, refluxing of iminocarboxamide 1a and benzohydrazide (11) (Scheme 2A) in butan-1-ol afforded amide-hydrazone 12, which was also synthesized independently (Scheme 2B) from chromenethiocarboxamide 13 [13] through the intermediacy of carboximidothioate 14. Furthermore, amidines 16a,b were synthesized (Scheme 3) in moderate yields employing the same rearrangement conditions.

It was also shown that 2-imino-2H-chromene-3-carboxamides of type 1 undergo transformation into 2-oxo-2H-chromene-3-carbonitriles 35 in basic aprotic solvents: DMF, DMSO, pyridine, quinoline and N-formylpiperidine (Scheme 4) [14]. In contrast, the corresponding 2-oxo-2H-chromene-3- carboxamides 1 did not undergo dehydration to afford 2-oxo-2H-chromene-3-carbonitriles even after prolonged boiling for 3–4 h in the above-mentioned solvents. The reaction mechanism of this transformation should be analogous to that presented in Scheme 1A. In this case, solvent acts as a nucleophile and opens the iminolactone ring (1 + base) and then is eliminated with the formation of nitrile group (1 → 35, Scheme 4).

In connection with this, a study on isomerization of chromen-2-imines in DMSO-d₆ has to be mentioned. O’Callaghan et al. revealed [15] that when unsubstituted 2-imino-2H-chromene-3-carboxamide (1a) was dissolved in DMSO-d₆, the NMR spectra showed that a mixture of both 2-imino-2H-chromene-3-carboxamide and the isomeric 2-cyano-3-(2-hydroxyphenyl)-prop-2-enamide (Figure 1) was present. Other chromen-2-imines behaved similarly, but the degree of isomerization varied considerably, depending on the nature and position of the substituents.

As shown in Scheme 5 (paths A and B), two distinct pathways leading to different products were envisioned to be involved in the acid-catalyzed rearrangements of 2-imino-2H-chromene-3-carboxamides 1. Thus, depending on reaction conditions, two types of products might be formed: (i) under non-aqueous acidic conditions compounds, comprising 2H-chromen-2-one and quinazoline or benzoxazine moieties 23 (1 → 19 → 23, Scheme 5, path A) or (ii) in aqueous acidic media, where H₂O acts as O-nucleophile, N-substituted 2-oxo-2H-chromene-3-carboxamides 28 (1 → 19 → 28, Scheme 5, path B). In this case, a competing reaction could be a simple hydrolysis (19 → 25), although a full understanding of the factors controlling this competition has not been attained. General intermediates for transformations presented in Scheme 5 are 2-(arylimino)-2H-chromenes of type 19. To verify our assumption of two possible mechanisms of reaction between 2-imino-2H-chromene-3-carboxamides 1 and anthranilates in acidic media, we directed our studies to isolation of intermediate 2-(arylimino)-2H-chromenes 19 and, starting from them, to the synthesis of 3-substituted 2H-chromen-2-ones of type 23 and 28.

A method for synthesis of 2-(arylimino)chromenes 19 was recently introduced in our laboratory and it was shown that a variety of 2-(aryl- or alkylimino)-substituted 2H-chromen-2-ones of type 19 could be prepared [3]. This method is based on aminolysis of cyclic imido esters and is similar to the reaction of simple imidates with amines [16]. This type of reactions should also be similar to the acid hydrolysis of 2-imino-2H-chromenes to 2H-chromen-2-ones which proceeds through the formation of the corresponding benzopyrylium salts [17,18].

The principal feature of the method for synthesis of 2-(arylimino)chromenes 19 is the use of either amine hydrochloride [3,19,20] or benzopyrylium salts of type 17 [3]. Finally, we found a different methodology [4] based on using glacial acetic acid for in situ formation of the corresponding salts, their reaction and subsequent removal of the ammonia released.

As shown in Scheme 6, Scheme 7, Scheme 8, Scheme 9 and Scheme 10, syntheses of the desired 2-(arylimino)chromenes 30, 31, 39 and 41 were finally performed by adding equivalent amounts of the corresponding 2-iminochromene derivatives 1 to a solution of anthranilates 29, 2, 38 or benzohydrazide (11) in glacial acetic acid. After stirring the reaction mixture at room temperature, products were precipitated and subsequently isolated, purified, characterized and used for further transformations.

It was found that in acidic anhydrous media (glacial acetic acid or acetic anhydride), 2-(N-substituted imino)chromenes 30 and 31 reacted intramolecularly (cf. Scheme 5, path A) to produce expected derivatives 7a (Scheme 6) and 32 (Scheme 7A) in good yields.

The reaction between imines 1a,b and 2 in aqueous acidic media (80% acetic acid) (Scheme 8A) proceeded differently. Refluxing in this solvent for 2 h gave N-(2-carboxyphenyl)-2-oxo-2H-chromene-3-carboxamides 36a,b. A mechanism that accounts for the products is detailed in Scheme 5, path B. To prove that mechanism, a reaction between 1a and 2 (Scheme 8A) was initially performed in acetic acid at room temperature. It took place without iminolactone ring opening and furnished expected intermediate 31, which was converted into compound 36a by further boiling in aqueous acetic acid. For unambiguous structure elucidation, 2-(2-oxo-2H-chromen-3-yl)-4H-3,1-benzoxazin-4-one 32 [21] and N-aryl-2-oxo-2H-chromene-3-carboxamides 36a,b were also prepared independently from 2-(cyanomethyl)-4H-3,1-benzoxazin-4-one 33 [22] or ethyl 2′-carboxymalonanilate 37 [23] and salicylaldehydes 9 as depicted in Scheme 7B and Scheme 8B.

Taking into consideration the results observed for synthesis of N-aryl-2-oxo-2H-chromene-3-carboxamides 36 (Scheme 8A), we examined the possibility of rearrangement of 2-(arylimino)-2H-chromene-3-carboxamide 39 into N-aryl-2-oxo-2H-chromene-3-carboxamide 40 by the action of water as O-nucleophile (Scheme 9). However, compound 40 was not detected presumably due to simple hydrolysis (cf. Scheme 5, path B), which took place to furnish the known 2-oxo-2H-chromene-3-carboxamide 25 [9].

As a further development of the methodology outlined in Scheme 5, path A, a new approach to 2-oxo-3-(5-aryl-1,3,4-oxadiazol-2-yl)-2H-chromenes of type 45 was elaborated [4e].

As exemplified in Scheme 10 (path A), the procedure was based on the rearrangement of 2-(N-aroylhydrazono)-2H-chromene-3-carboxamides 41, which are readily obtained by the reaction of 2-imino-2H-chromene-3-carboxamides 1 with benzohydrazide (1 1 ) in an acidic medium. Oxadiazolylchromene 45a was also synthesized separately from amide-hydrazone 12 (cf. Scheme 2) by refluxing it in AcOH/H₂SO₄ mixture (Scheme 10, pat B). Furthermore, as part of our program on structure-activity relationship studies of different heterocycles as potential tyrosine kinase inhibitors [24], we were especially interested in a short and selective entry into heterocyclic compounds comprising 2-imino- or 2-oxo-2H-chromene and tetrahydrobenzo[b]thiophene moieties. In our synthetic approach to heterocycles of this type [4f,g] we also applied the approach summarized in Scheme 5, path A.

Conclusion

The results obtained in the study of the rearrangements of 2-imino-2H-chromene-3-carboxamides with different N-nucleophiles clearly indicate that the reactions studied follow the mechanisms described in Scheme 1 and Scheme 5. Finally, this work opened a new avenue for the synthesis of a variety of new 3-hetaryl substituted 2-oxo-2H-chromene derivatives.

Experimental

General

Melting points (°C) were measured on a Büchi melting point apparatus and are uncorrected. Thin layer chromatography (TLC) was performed on aluminum sheets precoated with silica gel (Merck, Kieselgel 60 F-254). ¹H-NMR spectra were recorded on Bruker WP-100 SY, Bruker DPX-250, Bruker AMX-400 or Varian WXR-400 spectrometers in DMSO-d₆ or DMSO-d₆–CDCl₃ using TMS as an internal standard (chemical shifts in δ ppm). Mass spectra (MS) were obtained with Finnigan MAT-4615B spectrometer at an ionization potential of 70 eV. Combustion analyses of all compounds synthesized gave satisfactory microanalytical data. Infrared spectra (IR) were recorded in KBr pellets on Nicolet Protege 460 FT-IR or an IBM 486 computer-controlled Specord M-80 spectrometers.

2-Imino-2H-chromene derivatives 1a–c were prepared (1a (R = H; refs. [9,25]); 1b (R = 6-OCH₃; ref. [26]); 1c (R = 6-OH, 7-n-C₆H₁₃; ref. [4b]) by condensing cyanoacetamide with salicylaldehydes 9a–c in ethanol at room temperature using piperidine as a catalyst to form the expected imino compounds 1a–c.

(4-Oxo-3,4-dihydroquinazolin-2-yl)acetonitrile (8) [10], 2-oxo-2H-chromene-3-thiocarboxamide (13) [13], 1-amino-4,6-dimethyl-2(1H)-oxopyridine-3-carbonitrile (15) [27], (4-oxo-4H-3,1-benzoxazin-2-yl)acetonitrile (33) [22], ethyl 2′-carboxymalonanilate 37 [23] and salicylaldehyde 9c [28] were prepared by known literature procedures.

Solvents were purified by conventional methods [29]. Starting materials, anthranilic acid (2), salicylaldehydes (9a,b), benzohydrazide (11), anthranilamide (29) and methyl anthranilate (38) were purchased from Aldrich^®.

2-(2-Oxo-2H-chromen-3-yl)quinazolin-4(3H)-one (7a):

Method A: A mixture of 1a (282 mg, 1.5 mmol) and anthranilic acid 2 (370 mg, 2.7 mmol) in dry and degassed toluene (10 mL) was refluxed for 5-6 h (TLC monitoring) through a column equipped with a Dean-Stark trap containing a thimble filled with 4Å molecular sieves which had been activated at 325 °C for 24 h. In the course of the reaction, ammonia was released. The mixture was cooled and a yellow precipitate was filtered off and recrystallized from DMF/BuOH to afford 205 mg (47%) of 7a: M.p. 275-277 °C (lit. [5] m.p. 243 °C; lit. [6] m.p. 245 °C). ¹H-NMR (400 MHz, DMSO-d₆): δ 7.49 (dddd, 1H, J = 8.3, 7.8, 0.6, 0.4 Hz, ArH); 7.58 (m, 2H, ArH); 7.79 (m, 2H, ArH); 7.90 (m, 1H, ArH); 8.03 (ddd, 1H, J = 7.7, 1.6, 0.4 Hz, ArH); 8.18 (m, 1H, ArH); 8.97 (s, 1H, H-4); 12.07 (br s, 1H, NH). IR (KBr), cm^-1: ν 3254 (NH), 1706 (C=O, lactone), 1690 (C=O, amide), 1606, 1579, 1553, 1465. MS (EI, 70 eV) m/z (rel.%): 290 (M^+·, 83), 262 (17), 145 (8), 119 (100), 92 (19), 76 (5), 53 (10). Anal. Calcd for C₁₇H₁₀N₂O₃ (290.28): C, 70.34; H, 3.47; N, 9.65. Found: C, 70.29; H, 3.61; N, 9.79.

Method B: To a well stirred solution of quinazoline-2-acetonitrile 8 [10] (185 mg, 1 mmol) in propan-2-ol (5 mL) was added the equivalent amount of salicylaldehyde 9a (0.1 mL) and a few drops of piperidine as a catalyst. The reaction mixture was stirred at room temperature for 2 h. The precipitated product was filtered off, washed with propan-2-ol and recrystallized from butan-1-ol to afford 214 mg (74%) of 2-(2-imino-2H-chromen-3-yl)quinazolin-4(3H)-one (10a): M.p. 225-228 °C. ¹H-NMR (100 MHz, DMSO-d₆): δ 7.22-7.28 (m, 2H, ArH); 7.46 (dd, 1H, J = 8.3, 7.8 Hz, ArH); 7.52-7.73 (m, 4H, ArH); 8.14 (d, 1H, J = 7.8 Hz, ArH); 8.96 (s, 1H, H-4); 8.98 (s, 1H, C=NH); 14.04 (br s, 1H, NH). IR (KBr), cm^-1: ν 3435 (NH), 3319 (NH), 3060, 1689 (C=O, amide), 1678 (C=N), 1655, 1599. MS (EI, 70 eV) m/z (rel.%): 289 (M^+·, 76), 272 (100), 171 (10), 146 (30), 119 (62), 92 (19), 77 (6), 63 (9). A solution of the corresponding 10a (189 mg, 0.65 mmol) in 10 mL of a mixture of ethanol/water/~32% hydrochloric acid (30:1:1, v/v/v) was refluxed with vigorous stirring for 1 h. After cooling to room temperature, the precipitated product was filtered off and recrystallized from DMF/BuOH to afford 169 mg (89%) of the title compound 7a.

Method C: A solution of 30 (309 mg, 1.0 mmol) in glacial (99.8%) acetic acid (5 mL) was refluxed for 30 min. The mixture was cooled, the yellow precipitate was filtered off, washed with water and recrystallized from DMF/BuOH to afford 201 mg (70%) of 7a. According to ¹H-NMR and IR spectral data as well as the melting points, the products obtained by Methods A, B and C are identical.

2-(6-Methoxy-2-oxo-2H-chromen-3-yl)quinazolin-4(3H)-one (7b):

Method A: The reaction of 1b (327 mg, 1.5 mmol) was performed using the reaction conditions described for preparation of 7a to give 187 mg (39%) of 7b: ¹H-NMR (100 MHz, DMSO-d₆): δ 3.87 (s, 3H, OCH₃); 7.26-8.06 (m, 6H, ArH); 8.18 (d, 1H, J = 8.0 Hz, ArH); 8.99 (s, 1H, H-4); 12.00 (br s, 1H, NH). IR (KBr), cm^-1: ν 3242 (NH), 3065, 3010, 2971, 1706 (C=O, lactone), 1683 (C=O, amide), 1566, 1491. MS (EI, 70 eV) m/z (rel.%): 320 (M^+·, 100), 292 (23), 277 (28), 249 (6), 221 (8), 146 (13), 119 (95), 90 (21), 76 (17). Anal. Calcd for C₁₈H₁₂N₂O₄ (320.31): C, 67.50; H, 3.77; N, 8.74. Found: C, 67.71; H, 3.81; N, 8.69.

Method B: The synthesis of 10b was performed starting from 8 (185 mg, 1 mmol) and 9b (0.15 mL) using the reaction conditions described for preparation of 10a to give 227 mg (71%) of 10b: ¹H-NMR (100 MHz, DMSO-d₆): δ 3.79 (s, 3H, OCH₃); 7.17 (s, 1H, ArH); 7.41-7.93 (m, 5H, ArH); 8.12 (d, 1H, J = 7.7 Hz, ArH); 8.85 (s, 1H, H-4); C=NH and NH exchanged deuterium with the solvent. MS (EI, 70 eV) m/z (rel.%): 319 (M^+·, 42), 302 (100), 276 (8), 259 (6), 222 (7), 160 (8), 146 (8), 119 (14). Subsequent acid hydrolysis of 10b (160 mg, 0.5 mmol) employing the reaction conditions described for hydrolysis of 10a afforded 130 mg (81%) of 7b. According to ¹H-NMR, IR spectral data, and the melting points, the compounds obtained by Methods A and B are identical.

N²-Benzoyl-2-oxo-2H-chromene-3-carbohydrazonamide (12):

Method A: A mixture of 1a (188 mg, 1 mmol) and benzohydrazide (11) (136 mg, 1 mmol) in butan-1- ol (5 mL) was refluxed for 15–30 min (TLC monitoring) while ammonia was released. Then the mixture was cooled, the precipitate was filtered off and washed with hot ethanol to afford 267 mg (87%) of 12: M.p. 187-189 °C. ¹H-NMR (100 MHz, DMSO-d₆): δ 6.87 (br s, 2H, NH₂); 7.40-7.90 (m, 9H, ArH); 8.57 (s, 1H, H-4); 10.09 (br s, 1H, CONH). IR (KBr), cm^-1: ν 3418, 3181 (NH), 1704 (C=O, lactone), 1682 (C=O, amide), 1658 (C=N). Anal. Calcd for C₁₇H₁₃N₃O₃ (307.30): C, 66.44; H, 4.26; N, 13.67. Found: C, 66.09; H, 4.51; N, 13.89.

Method B: To a cold (0 °C) solution of 2-oxo-2H-chromene-3-carbothioamide 13 [13] (2.05 g, 10 mmol) in DMF (25 mL) dry acetone (15 mL) followed by iodomethane (2 mL, 32 mmol) were added. The mixture was kept for 24 h at a dark place. The hydroiodide precipitated was filtered off and washed with ether. Hydroiodide (10 mmol) was suspended in 1,4-dioxane (50 mL) and triethylamine (1.5 mL, 10 mmol) was added. After stirring for 1 h at room temperature, the solvent was removed under reduced pressure and the residue was extracted with CHCl₃ (2 x 10 mL). The extract was washed with ice water, dried over Na₂SO₄ and the solvent was removed in vacuo to afford 899 mg (41%) of S-methyl 2-oxo-2H-chromene-3-carboximidothioate (14) [30]: ¹H-NMR (250 MHz, DMSO-d₆): δ 2.47 (s, 3H, SCH₃); 7.11-7.83 (m, 4H, ArH); 8.33 (s, 1H, H-4); 9.89 (s, 1H, NH). IR (KBr), cm: ν 3247 (NH), 1729 (C=O, lactone), 1612 (C=N), 1593. The crude 14 was used without any purification in the following stage. The imidothioester 14 (440 mg, 2 mmol) and benzohydrazide (11) (275 mg, 2 mmol) were dissolved in DMF/EtOH (3/1 mixture, 10 mL). The mixture was heated for 4 h at 80 °C until evolving methanethiol was detected. The solvents were removed under reduced pressure and the residue was washed with hot ethanol to afford 178 mg (29%) of 12. According to ¹H-NMR, IR spectral data as well as the melting points, the compounds obtained by Methods A and B are identical.

N-(3-Cyano-4,6-dimethyl-2(1H)-oxopyridin-1-yl)-2-oxo-2H-chromenes (16):

Amidines 16a,b were prepared from carbamoyliminochromenes 1a,b and 1-aminopyridone 15 [27] using the reaction conditions described in Method A for the synthesis of 12.

1-[1-amino-1-(2-oxo-2H-chromen-3-yl)methylideneamino]-4,6-dimethyl-2(1H)-oxopyridine-3-carbonitrile (16a):

Yield: 31%. M.p. 291-293 °C (dec.). ¹H-NMR (400 MHz, DMSO-d₆–CDCl₃): δ 2.29 (s, 3H, CH₃); 2.36 (s, 3H, CH₃); 6.38 (s, 1H, CH-pyridone); 7.46 (br s, 2H, NH₂); 7.48 (ddd, 1H, J = 7.7, 7.6, 1.0 Hz, H-6); 7.55 (dd, 1H, J = 8.4, 1.0 Hz, H-8); 7.78 (ddd, 1H, J = 8.4, 7.6, 1.4 Hz, H-7); 8.00 (dd, J = 7.7, 1.4 Hz, H-5); 8.74 (s, 1H, H-4). Anal. Calcd for C₁₈H₁₄N₄O₃ (334.33): C, 64.66; H, 4.22; N, 16.76. Found: C, 64.97; H, 4.34; N, 17.02.

1-[1-amino-1-(6-methoxy-2-oxo-2H-chromen-3-yl)methylideneamino]-4,6-dimethyl-2(1H)-oxopyridine-3-carbonitrile (16b):

Yield: 27%. M.p. 312-314 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 2.28 (s, 3H, CH₃); 2.37 (s, 3H, CH₃); 3.85 (s, 3H, OCH₃); 6.21 (s, 1H, CH-pyridone); 7.27 (dd, 1H, J = 9.1, 2.9 Hz, H-7); 7.34 (d, 1H, J = 2.9 Hz, H-5); 7.36 (d, 1H, J = 9.1 Hz, H-8); 7.46 (br s, 2H, NH₂); 8.89 (s, 1H, H-4). Anal. Calcd for C₁₉H₁₆N₄O₄ (364.35): C, 62.63; H, 4.43; N, 15.38. Found: C, 62.49; H, 4.58; N, 15.09.

2-(Phenylimino)-2H-chromene-3-carboxamides 30, 31 and 39:

General procedure

To a stirred solution of anthranilates 29, 2 or 38 (10 mmol) in glacial acetic acid (15 mL) was added an equivalent amount of the corresponding 2-imino-2H-chromene derivatives 1a,b. The reaction mixture was stirred at room temperature overnight. The precipitated products were filtered off, washed with water, propan-2-ol (3 x 5 mL), and dried in air.

2-[(2-Carbamoylphenyl)imino]-2H-chromene-3-carboxamide (30):

Yield: 82%. M.p. 244-246 °C. ¹H-NMR (250 MHz, DMSO-d₆): δ 7.07-7.28 (m, 5H, CONH₂ +ArH); 7.40-7.64 (m, 3H, ArH); 7.75-7.78 (m, 2H, CONH₂+ArH); 7.83 (br s, 1H, CONH₂); 8.41 (s, 1H, H-4); 9.02 (br s, 1H, CONH₂). IR (KBr), cm^-1: ν 3392 (NH), 3168 (NH), 1640 (C=O+C=N), 1588. Anal. Calcd for C₁₇H₁₃N₃O₃ (307.30): C, 66.44; H, 4.26; N, 13.67. Found: C, 66.21; H, 4.39; N, 13.89.

2-[(2-Carboxyphenyl)imino]-2H-chromene-3-carboxamide (31):

Yield: 62%. M.p. 191-192 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 6.98 (d, 1H, J = 8.1 Hz, ArH); 7.10- 7.22 (m, 3H, ArH); 7.41-7.48 (m, 2H, ArH); 7.62 (br s, 1H, CONH₂); 7.64 (dd, 1H, J = 8.2, 0.6 Hz, ArH); 7.90 (dd, 1H, J = 8.5, 0.6 Hz, ArH); 8.42 (s, 1H, H-4); 9.21 (s, 1H, CONH₂). IR (KBr), cm^-1: ν 3300 (NH2+OH), 3160 (NH), 1700 (C=O, acid), 1670 (C=O, amide). MS (EI, 70 eV) m/z (rel.%): 308 (M^+·, 46), 291 (55), 264 (37), 248 (86), 220 (100), 189 (43), 173 (36), 145 (54), 119 (42), 89 (34), 65 (28), 44 (36). Anal. Calcd for C₁₇H₁₂N₂O₄ (308.30): C, 66.23; H, 3.92; N, 9.09. Found: C, 66.19; H, 4.01; N, 9.14.

2-{[(2-Methoxycarbonyl)phenyl]imino}-2H-chromene-3-carboxamide (39):

Yield: 68%. M.p. 214-217 °C. ¹H-NMR (250 MHz, DMSO-d₆): δ 3.71 (s, 3H, OCH₃); 6.98 (d, 1H, J = 8.0 Hz, ArH); 7.17-7.26 (m, 3H, ArH); 7.45-7.52 (m, 2H, ArH); 7.73 (d, 1H, J = 8.2 Hz, ArH); 7.76 (br s, 1H, CONH₂); 7.88 (d, 1H, J = 8.3 Hz, ArH); 8.52 (s, 1H, H-4); 9.17 (br s, 1H, CON H₂). IR (KBr), cm^-1: ν 3424 (NH), 3272 (NH), 1716 (C=O, ester), 1688 (C=O, amide), 1608. Anal. Calcd for C₁₈H₁₄N₂O₄ (322.31): C, 67.07; H, 4.38; N, 8.69. Found: C, 66.79; H, 3.99; N, 8.43.

2-(2-Oxo-2H-chromen-3-yl)-4H-3,1-benzoxazin-4-one (32):

Method A: A solution of 2-[(2-carboxyphenyl)imino]-2H-chromene-3-carboxamide (31) (310 mg, 1 mmol) in acetic anhydride (3 mL) was refluxed for 30 min. After completed reaction, the mixture was cooled and the precipitate formed was filtered off, washed with water, cold propan-2-ol (2 x 5 mL) and recrystallized from benzene to give 224 mg (77%) of 32: M.p. 203-204 °C (lit. [5] m.p. 197 °C; lit. [21b] m.p. 195 °C). ¹H-NMR (100 MHz, DMSO-d₆): δ 7.38-7.43 (m, 2H, ArH); 7.65-7.74 (m, 3H, ArH); 7.92-7.96 (m, 2H, ArH); 8.20 (d, 1H, J = 7.9 Hz, ArH); 8.86 (s, 1H, H-4). IR (KBr), cm^-1: ν 3063, 1749 (C=O), 1599. Anal. Calcd for C₁₇H₉NO₄ (291.26): C, 70.10; H, 3.11; N, 4.81. Found: C, 69.89; H, 3.34; N, 5.11.

Method B: 2-(2-Imino-2H-chromen-3-yl)-4H-3,1-benzoxazin-4-one (34) was synthesized from (4-oxo-4H-3,1-benzoxazin-2-yl)-2-acetonitrile (33) [23] (190 mg, 1 mmol) and 2-hydroxybenzaldehyde (9a) (0.1 mL) using the reaction conditions described in Method B for the synthesis of 10a to give 177 mg (61%) of iminochromene 34. The compound 34 was used without any purification in the following reaction. Acid hydrolysis of 34 (130 mg, 0.45 mmol) employing the reaction conditions described for conversion of 10a into 7a afforded 77 mg (59%) of 32. ¹H-NMR, IR spectral data, and melting points confirm identity of the compounds obtained by Methods A and B.

N-aryl-2-oxo-2H-chromene-3-carboxamides 36a,b:

General procedures

Method A: A mixture of 1a or 1b (1.5 mmol) and anthranilic acid 2 (275 mg, 2 mmol) in aqueous (80%) acetic acid (10 mL) was refluxed for 2 h. After the reaction finished, the mixture was cooled and the precipitate was filtered off, washed with water and cold propan-2-ol (2 x 5 mL). The products obtained were recrystallized from an appropriate solvent.

Method B: To a well stirred solution of ethyl 2′-carboxymalonanilate (37) [23] (4 mmol) in ethanol (10 mL) was added an equivalent amount of salicylaldehydes 9a or 9b and a few drops of piperidine as a catalyst. The reaction mixture was stirred at room temperature for ca. 1 day and then poured into water. The products precipitated were filtered off and recrystallized from an appropriate solvent.

N-(2-Carboxyphenyl)-2-oxo-2H-chromene-3-carboxamide (36a):

Yields: 82% (Method A) and 67% (Method B) (recrystallized from AcOH). M.p. 275-276 °C (lit. [5,21b] m.p. 279 °C). ¹H-NMR (400 MHz, DMSO-d₆): δ 7.15 (dd 1H, J = 8.0, 8.0 Hz, ArH); 7.39 (m, 2H, ArH); 7.56 (dd, 1H, J = 8.0, 8.0 Hz, ArH); 7.73 (dd, 1H, J = 7.9, 7.9 Hz, ArH); 7.94 (d, 1H, J = 8.2 Hz, ArH); 8.05 (d, 1H, J = 8.2 Hz, ArH); 8.65 (d, 1H, J = 8.3 Hz, ArH); 8.85 (s, 1H, H-4); 13.52 (br s, 1H, NH). IR (KBr), cm^-1: ν 3266 (NH), 3032 (CH), 1731 (C=O), 1696 (C=O), 1673 (C=O), 1608 (C=C). Anal. Calcd for C₁₇H₁₁NO₅ (309.28): C, 66.02; H, 3.58; N, 4.53. Found: C, 66.32; H, 3.78; N, 4.72.

N-(2-Carboxyphenyl)-6-methoxy-2-oxo-2H-chromene-3-carboxamide (36b):

Yields: 69% (Method A) and 59% (Method B) (recrystallized from butan-1-ol). M.p. 124-125 °C. ¹H-NMR (400 MHz, DMSO-d₆): δ 3.95 (s, 3H, OCH₃); 7.14-7.32 (m, 4H, ArH); 7.42 (d, 1H, J = 8.2 Hz, ArH); 8.01 (d, 1H, J = 8.0 Hz, ArH); 8.60 (d, 1H, J = 8.0 Hz, ArH); 8.89 (s, 1H, H-4); 13.20 (s, 1H, NH). IR (KBr), cm^-1: ν 3287 (NH), 2952 (CH), 1726 (C=O), 1694 (C=O), 1675 (C=O), 1614 (C=C). Anal. Calcd for C₁₈H₁₃NO₆ (339.31): C, 63.72; H, 3.86; N, 4.13. Found: C, 64.00; H, 4.03; N, 3.91.

2-Oxo-2H-chromene-3-carboxamide (25):

A solution of 39 (482 mg, 1.5 mmol) in aqueous (80%) acetic acid (10 mL) was refluxed for 2 h. After the reaction was complete, the mixture was cooled and the precipitate was filtered off, washed with water and cold propan-2-ol (5 mL). The product obtained was recrystallized from ethanol to give 228 mg (81%) of 25: M.p. 279-280 °C (lit. [9] m.p. 280-282 °C). ¹H-NMR (400 MHz, DMSO-d₆): δ 7.47 (ddd, 1H, J = 7.7, 7.7, 1.0 Hz, H-6); 7.53 (dd, 1H, J = 8.4, 1.0 Hz, H-8); 7.79 (ddd, 1H, J = 8.4, 7.7, 1.6 Hz, H-7); 7.96 (br s, 1H, CONH₂); 8.00 (dd, J = 7.7, 1.6 Hz, H-5); 8.12 (br s, 1H, CONH₂); 8.90 (s, 1H, H-4). Anal. Calcd for C₁₀H₇NO₃ (189.17): C, 63.49; H, 3.73; N, 7.40. Found: C, 63.54; H, 3.71; N, 7.51.

2-oxo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromene (45a):

Method A: To a stirred solution of 2-imino-2H-chromene 1a (1.88 g, 10 mmol) in glacial acetic acid (25 mL) was added an equivalent amount of benzohydrazide (11) (1.36 g, 10 mmol) and 2 drops of H₂SO₄. The reaction mixture was warmed to 40 °C and stirred at room temperature for ca. 3 h. The precipitated product was filtered off, washed with ethyl acetate (3 x 5 mL) and recrystallized from propan-2-ol to yield 2.82 g (92%) of 2-(N-benzoylhydrazono)-2H-chromene 41a: M.p. 226-227 °C. ¹H-NMR (100 MHz, DMSO-d₆): δ 7.22-7.90 (m, 9H, ArH); 7.98 (s, 1H, CONH₂); 8.23 (s, 1H, H-4); 9.16 (s, 1H, CONH₂); 11.25 (s, 1H, CONH). IR (KBr), cm^-1: ν 3305, 3238, 3110 (NH), 1698, 1678 (C=O), 1650 (C=N). A solution of benzoylhydrazonochromene 41a (1.54 g, 5 mmol) in dry and degassed nitrobenzene (10 mL) was refluxed for 10–40 min. During the course of reaction, release of ammonia was observed. After reaction was completed (monitoring by TLC), the mixture was cooled and a precipitate was filtered off and recrystallized from benzene to give 1.13 g (78%) of 1,3,4-oxadiazolylchromene 45a with m.p. 216-218 °C (lit [31] m.p. 224 °C). ¹H-NMR (100 MHz, DMSO-d₆): δ 7.45-8.13 (m, 9H, ArH); 9.02 (s, 1H, H-4). IR (KBr), cm^-1: ν 1744 (C=O). MS (EI, 70 eV) m/z (rel.%): 290 (M^+·, 26), 262 (5), 206 914), 189 (12), 173 (32), 105 (100). Anal. Calcd for C₁₇H₁₀N₂O₃ (290.27): C, 70.34; H, 3.47; N, 9.65. Found: C, 70.27; H, 3.62; N, 9.73.

Method B: Benzoylcarbohydrazonamide 12 (cf. Scheme 2) (154 mg, 0.5 mmol) was refluxed in a mixture AcOH/H₂SO₄ (2 mL) for 15–30 min. After the reaction finished, the mixture was cooled and neutralized with aqueous ammonia. The precipitate formed was filtered off, washed with water and cold propan-2-ol (2 x 1 mL). The product obtained was recrystallized from an appropriate solvent to afford 112 mg (78%) of 1,3,4-oxadiazolylchromene 45a. ¹H-NMR, IR spectral data, and melting points corroborate identity of the compounds obtained by Methods A and B.

6-n-Hexyl-7-hydroxy-2-oxo-3-(5-phenyl-1,3,4-oxadiazol-2-yl)-2H-chromene (45b):

1,3,4-Oxadiazolylchromene 45b was prepared from carbamoyliminochromene 1c [4b] and benzohydrazide (11) using the reaction conditions described in Method A for the synthesis of 45a. Yield: 68%. M.p. 241-242 °C. ¹H-NMR (100 MHz, DMSO-d₆): δ °0.86 (t, 3H, J = 7.0 Hz, CH₂(CH₂)₄CH₃); 1.30 (m, 8H, CH₂(CH₂)₄CH₃); 1.56 (m, 2H, CH₂(CH₂)₄CH₃); 6.82 (s, 1H, H-8); 7.64 (m, 4H, ArH); 8.09 (m, 2H, ArH); 8.85 (s, 1H, H-4); 11.09 (br s, 1H, OH). IR (KBr), cm^-1: ν 3088 (OH), 2851 (CH_alkyl), 1744 (C=O), 1618 (C=C), 1570. Anal. Calcd for C₂₃H₂₂N₂O₄ (390.43): C, 70.75; H, 5.68; N, 7.17. Found: C, 70.81; H, 5.80; N, 7.22.