Ring rearrangements and reactivity of 3-((4-oxo-4H-chromen-3-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one toward some nucleophiles

Hanan Salah; Eman A. Ahmed; Mohamed M. Hassan

doi:10.1016/j.arabjc.2015.03.008

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Original article

10 (

); 548-555

doi:

10.1016/j.arabjc.2015.03.008

Ring rearrangements and reactivity of 3-((4-oxo-4H-chromen-3-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one toward some nucleophiles

Hanan Salah^{^a}, Eman A. Ahmed^{^a}, Mohamed M. Hassan^{^b,⁎,1}

a Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt

b Chemistry Department, Faculty of Education, Ain Sham University, Cairo 11757, Egypt

⁎Corresponding author. Tel.: +966 508293110. mmhassan@chemist.com (Mohamed M. Hassan) m.mahmoud@mu.edu.sa (Mohamed M. Hassan)

Received: 2014-11-3, Accepted: 2015-3-9, Published: 2015-05-01

Disclaimer:
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.

1 Present address: Basic Science Department, Preparatory Year Deanship, Majmaah University, Majmaah 11952, Saudi Arabia.

Abstract

Condensation of 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) with 3-formylchromone (2) afforded a mixture of 3-(chromenylmethylene)[1,5]benzodiazepinone 3 and 14-chromenylbenzodiazepino[2,3:6,5]pyrano[2,3-b]benzodiazepine 4. Ring rearrangements of compound 3 with different nucleophilic reagents, such as potassium hydroxide and/or ammonium acetate led to rearrangement into pyranobenzodiazepine 5 and pyridobenzodiazepine 6, respectively. Treatment of compound 3 with hydrazine hydrate, hydroxylamine hydrochloride, malononitrile, cyanothioacetamide, 2-cyano-3,3-disufanylacrylonitrile, and/or 2-cyano-3-phenylamino-3-sufanylacrylonitrile, has been carried out at different conditions, leading to versatile heterocyclic substituted benzodiazepines at position 3, viz. pyrazole 8, isoxazole 9, pyridines 10 and 11, 1,3-dithiine 12, and 1,3-thiazine 13 derivatives.

Keywords

[1,5]Benzodiazepin-2(3H)-one

3-Formylchromone

Nucleophilic reagents

Ring rearrangement

Heterocyclization

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1 Introduction

Chromone is a gamma pyrone nucleus which has been reported as very useful synthone. Thus chromones and other related analogues have interesting chemical properties toward reaction with mononucleophiles and binucleophiles in which ring opening-ring closure takes place leading to new heterocyclic derivatives (Sabitha, 1996; Quiroga et al., 2002b; Abass and Hassan, 2003; Abass et al., 2007a,b; Ryabukhin et al., 2004 ). Many reports described the implantation of a 3-chromonylmethylene moiety at different active methylene heterocyclic compounds. Consequently, a reactive annular enone system, γ-pyrone ring, is generated which is capable to react efficiently with different nucleophiles leading to ring-opening/ring-closure (RORC) to afford new substituted heterocyclic systems (Ghosh et al., 1998, 2001; Quiroga et al., 2002a; Khodairy, 2007 ). For this purpose 3-formylchromone has been successfully used to prepare a variety of heterocyclic systems. [1,5]Benzodiazepin-2-ones have attracted attention as an important class of heterocyclic compounds in the field of drugs and pharmaceuticals. Thus, many of [1,5]benzodiazepin-2-ones are widely used as anticonvulsant (Narayana et al., 2006), anti-inflammatory (Roma et al., 1991), antiviral (Kavali and Badami, 2000), anti-HIV-1 (Di Braccio et al., 2001), antimicrobial (Kumar and Joshi, 2007), and antitumor (Kamal et al., 2008) agents. In extension to our research project dealing with synthesis of [1,5]benzodiazepine derivatives (Abdel-Ghany et al., 2001; Khodairy et al., 2003, 2007; Khodairy, 2005, 2011 ), we herein subjected the key starting compound to obtain novel [1,5]benzodiazepin-2(3H)-ones bearing five and/or six membered heterocyclic substituents. Using the above synthetic strategy, we described the preparation of the desired derivatives of [1,5]benzodiazepine, starting from 3-((4-oxo-4H-chromen-3-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (3).

2 Results and discussion

3-((4-Oxo-4H-chromen-3-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (3) was prepared by condensation of equimolar amounts of 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) (Akkurt et al., 2012) and 3-formylchromone (2) (Nohara et al., 1974), in the presence of freshly fused sodium acetate, in 60% yield. Interestingly, 14-chromenylbenzodiazepino[2,3:6,5]pyrano[2,3-b][1,5]benzodiazepine 4 was separated as by-product, in 33% yield (Scheme 1). It was found that yield of both compounds 3 and 4 is dependent on molar ratio of reactants. Notably, starting with excess molar amount of aldehyde 2, double ratio, gave compound 3 in 90% yield, while on using half ratio of aldehyde 2 a 2:1 M ratio led to compound 3 in only 20% yield (Table 1). Obviously, condensation of diazepinone 1 with aldehyde 2, leading to methylene derivative 3, is subsequently underwent nucleophilic addition of another diazepinone molecule. Earlier, similar cyclization type was reported (Haas et al., 1981), in which the adduct intermediate underwent an intramolecular cyclization via in situ elimination of a water molecule, accomplishing formation of a trinuclear ring system.

Reaction of 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) with 3-formylchromone (2).

Table 1 Yields obtained from reaction between diazepinone 1 and aldehyde 2.

Reactants (molar ratios) M_diazepinone/M_aldehyde	Yield (%)
Reactants (molar ratios) M_diazepinone/M_aldehyde	Compound 3	Compound 4
1/2	90	05
1/1	60	33
2/1	20	60

The structure of both compounds 3 and 4 was established on basis of their spectral and analytical data. ¹H NMR spectrum of compound 3 showed two singlet signals at δ 7.03 and 8.59, corresponding to methylene and α-chromone protons, respectively. ¹³C NMR spectrum of which revealed two distinctive chemical shifts at δ 193.10 and 193.50, belongs to carbonyl groups, which their stretching vibrations appeared at ν 1686 and 1645 cm⁻¹. On the other hand, IR spectrum of compound 4 exhibited only one carbonyl absorption band, at ν 1684, characteristic for C⚌O stretching vibration of γ-pyrone. ¹H NMR spectrum of this compound indicated the presence of chemical shift signal at δ 5.19 due to methine proton at position 14, beside as singlet peak at δ 8.61 pointing to α-chromone proton.

Treatment of compound 3 with aqueous potassium hydroxide underwent nucleophilic ring rearrangement, furnishing pyrano[b]benzodiazepine 5, in 90% yield. As depicted in Scheme 2, chromone nucleus is attacked by hydroxide ion at the α-carbon leading to ring-opening. Subsequently, diazepinolate ion underwent an intramolecular aldol addition followed by elimination of a hydroxide ion. This cascade base catalyzed RORC led to a rearrangement to annulated pyrano[b]diazepine system (Hassan et al., 2013). Elemental microanalysis for C, H, and N elements (within ±0.32%) showed no difference in these elements ratios than the starting material, i.e. both may possess the same formula. Ferric chloride color test indicated the presence of a phenolic OH function, it gives deep violet coloration. IR spectrum of compound 5 showed disappearance of both chromone and diazepinone carbonyl stretching bands and instead a stretching vibrational band was observed at ν 1635 cm⁻¹ due to benzoyl C⚌O. ¹H NMR spectrum of the product revealed the presence of two singlet signals at δ 7.74 and 7.79, belong to α- and γ-pyran protons besides a wide range multiplet peaks, at δ 7.09–7.63, due to chemical shift of thirteen aromatic protons. ¹³C NMR spectrum of compound 5 supported the proposed structure.

Rearrangement of compound 3 into pyranobenzodiazepine 5.

Ammonialysis of compound 2 using ammonium acetate, in boiling dimethylformamide, led to another RORC reaction in which pyrido[3,2-b]benzodiazepine derivative 6 was afforded in 66% yield (Scheme 3). Herein ammonium acetate liberated ammonia which nucleophilically attacked the α-carbon of chromone ring causing ring-opening (Ghosh et al., 2001). Subsequently, amine intermediate that obtained underwent an intramolecular nucleophilic addition–elimination (condensation reaction) at position 2 of diazepinone. The product gave a violet color with ferric chloride color reaction, showing the presence of a phenolic OH function. IR spectrum represented a stretching vibration at ν 1655 cm⁻¹ due to benzoyl C⚌O. Mass spectrum exhibited an (M+H) ion peak at m/z 392 (7.6%) beside a base peak at m/z 77 (100%) characteristic for phenylium ion. ¹H NMR spectrum of the product revealed the presence of two singlet signals, at δ 8.05 and 8.25, attributed to α- and γ-pyridine protons besides a wide range multiplet peaks at δ 6.80–7.73 due to chemical shift of thirteen aromatic protons.

Rearrangement of compound 3 into pyridobenzodiazepine 6.

Surprisingly, compound 1 was reacted with hydrazine hydrate and/or hydroxyl amine hydrochloride, in glacial acetic acid, afforded 3-((pyrazolyl and isoxazolyl)methylene)benzodiazepin-2-one derivatives 8 and 9, respectively (Scheme 4). According to the literature reports in similar cases (Abass and Hassan, 2003; Abass et al., 2007a; Shanker et al., 1992 ), pyrazolo[3,4-b]- and/or isoxazolo[4,5-b]benzodiazepines 7, are probable products for such reaction. In acidic medium addition of binucleophiles may regioselectively be oriented to methylenediazepinone exocyclic enone system rather than attack the chromone nucleus. Elemental microanalyses as well as mass spectra cannot differ between the two possible products. However, the ferric chloride color reaction gives violet coloration with both products 8 and 9, indicating the presence of phenolic OH function. IR spectra of compounds 8 and 9 fortified this result where broad bands appeared at ν 3377–3337 and 3204–3207 cm⁻¹, due to H-bonded O—H and N—H functions. Moreover, ¹H NMR spectra of both compounds 8 and 9 revealed the existence of a methylenic proton appears as singlet signal at δ 7.03–7.06 besides a broad singlet peak at δ 13.09–13.13, due to a downfield shifted chemical shift of H-bonded O—H.

Reaction of compound 3 with hydrazine and hydroxylamine.

Reaction of the compound 3 with malononitrile, in the presence of sodium ethoxide, gave 3-(pyridin-5-yl)methylenebenzodiazepin-2(3H)-one 10, in 86% yield (Scheme 5). Formation of the compound 10 is explicable by the nucleophilic attack, of carbanion in situ obtained from malononitrile, at α-carbon of chromone nucleus. Consequent enolized side chain oxygen added at a cyano function leading to an iminopyran intermediate, which in turn underwent Dimroth-type rearrangement into pyridone (Abdelrazek and Elsayed, 2009). IR spectrum of compound 10 showed absorption bands at ν 3450–3209 cm⁻¹ due to H-bonded N—H and tautomeric O—H. In addition, the spectrum represented a sharp medium band at ν 2201 cm⁻¹ due to C≡N function and two strong absorption bands at ν 1665 and 1624, attributed to C⚌O of diazepinone and pyridone. ¹H NMR spectrum of compound 10 revealed the existence of chemical shifts appeared as singlets corresponding to methylenic and γ-proton of pyridone at δ 6.80 and 8.74, respectively. ¹³C NMR spectrum showed the chemical shift corresponding to sp-carbon (C≡N) at δ 200 and the two sp2-carbon due to C⚌O appeared at δ 181.

Reaction of compound 3 with some 1,3-binucleophiles.

Similarly, when compound 3 was subjected to react with cyanothioacetamide, in the presence of sodium ethoxide, chromone ring-opening and a consequent pyridine ring-closure took place. This ring transformation led to 3-(2-thioxopyridin-5-yl)methylene) benzodiazepin-2-one 11, in 78% yield (Scheme 5). The reaction mechanism may proceed via first nucleophilic addition of carbanion of cyanothioacetamide, at the α-carbon of chromone, leading to ring-opening. Thence, nucleophilic addition of NH₂ and elimination of water molecule took place, resulting in pyridinethione ring-closure. The product gave a violet color against ferric chloride color test, indicating the presence of phenolic OH function. Elemental analysis revealed the presence of sulfur in the product. IR spectrum showed bands corresponding to O—H, N—H and C≡N groups at ν 3436, 3344–3280 and 2156 cm⁻¹, respectively. ¹H NMR spectrum showed two singlet signals corresponding to methylenic and γ-proton of pyridone at δ 6.90 and 8.14, respectively. Furthermore, inspection of the ¹H NMR spectrum using deuterium oxide showed that there are three deuterium exchangeable protons appeared as broad singlets at δ 8.55, 10.60, and 13.18. The first two are back to the ring N—H of both pyridinethione and diazepinone while the last one is attributed to the phenolic O—H.

Ketene S,S- and N,S-acetals had attracted an exceptional concern due to their synthetic role in preparation of a versatile heterocyclic compounds (Tominaga et al., 1990; El-Sayed et al., 1997; Elgemeie et al., 1997 ). Hence, multi-component reaction (MCR) including compound 3 and a mixture of carbon disulfide and malononitrile or phenyl isothiocyanate and malononitrile was investigated. The reaction was carried out under phase transfer catalysis conditions (PTC), using potassium carbonate as base catalyst and tetrabutylammonium bromide (TBAB) as PTC-agent. Surprisingly, the reaction in both cases afforded a mixture of pyrano[b]benzodiazepine 5 and 2-(4-benzodiazepinyl-1,3-dithiinylidene)malononitrile 12 or 2-(4-benzodiazepinyl-1,3-thiazinylidene)malononitrile 13, in 30–38% yields (Scheme 5). Formation of compound 5 as the main product, in 45–55% yields, can be attributed to the effect of base catalyst (K₂CO₃) which is mandatory used during this reaction. It is well known that chromone ring can be easily opened under this conditions which is also enough for annulation of pyrano[b]benzodiazepine ring. Elemental analyses of both products 12 and 13 revealed the presence of sulfur element. Also both of them gave violet coloration against ferric chloride color test. IR spectra of these two compounds exhibited vibrational bands at ν 2205 cm⁻¹, characteristic for C≡N function in addition to strong stretching vibration at ν 1660–1669 and 1645–1635 cm⁻¹ due to C⚌O functions of benzoyl and diazepinone moieties, respectively. ¹H NMR spectrum of dithiine derivative 12 demonstrated two chemical shifts due to dithiine ring hydrogens appeared as singlet peaks at δ 3.80 and 6.80 in addition to three deuterium exchangeable protons appeared as broad singlets at δ 8.92, 10.60, and 13.14 due to two N—H of diazepinone and O—H of salicyloyl moiety. Similar evidences were observed in spectra and analysis of compound 13. Furthermore ¹³C NMR of compound 13 revealed the presence of two chemical shifts at δ 190 and 188 due to two sp carbons of C≡N functions and two signals at δ 183 and 180 due two sp² carbons of C⚌O functions. Elemental microanalyses for C, H, and N-elements (within ±0.4%) of both compounds 12 and 13, are satisfactorily in good accordance with the calculated formula.

3 Conclusions

The reaction of chromonylmethylenebenzodiazepinone 3 with some selected nucleophilic reagents gave new interesting five and six-membered heterocyclic derivatives of benzodiazepine. Alkaline treatment of chromonyl derivative 3 causes ring rearrangement, furnishing fused triheterocyclic systems. It was found that chromonyl moiety is good precursor for synthesis of different substituted benzodiazepines. PTC have been proved to be useful in base-catalyzed reaction of chromonyl derivative 3 with ketene S,S- and N,S-acetals, leading to 1,3-diazainylbenzodiazepinones in addition to pyranobenzodiazepine.

4 Materials and methods

4.1

4.1 General

All melting points were determined on a Koffler melting points apparatus and are uncorrected. IR spectra were obtained on a Nicolet 710 FT-IR spectrometer. ¹H NMR spectra, at 400 MHz, and ¹³C NMR spectra, at 100 MHz, were recorded on a Bruker Avance III-400 MHz instrument, using DMSO-d₆ as solvent. The mass spectra were scanned on a Varian Mat CH-7 instrument at 70 eV. Elemental microanalyses were performed on a Perkin–Elmer CHN-2400 elemental analyzer. All compounds were checked for their purity on TLC plates. Starting materials 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) (Akkurt et al., 2012) and 3-formylchromone (2) (Nohara et al., 1974) 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) (Akkurt et al., 2012) and 3-formylchromone (2) (Nohara et al., 1974) were prepared as described in the literature.

4.2

4.2 Reaction between 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) and 3-formylchromone (2)

A mixture of benzodiazepinone 1 (2.36 g, 10 mmol), 3-formylchromone 2 (1.74 g, 10 mmol), and freshly fused sodium acetate (3 g, 36 mmol), in glacial acetic acid (50 mL) was heated under reflux 4 h. The reaction mixture was left to cool to room temperature, and then poured onto crushed-ice. The solid so formed was filtered, washed with cold water, and dried. This crude solid material was boiled in absolute ethanol (50 mL) for 15 min. and filtered off insoluble residue. The filtered solid was washed thoroughly several times with hot ethanol (ca. 50 mL) and crystallized from glacial acetic acid to give compound 3. The collected ethanol filtrate was concentrated to about one-fourth of its volume (ca. 25 mL) and left to stand at room temperature over-night to give crystalline needle-like deposits which were collected by filtration to afford compound 4.

4.2.1

4.2.1 3-((4-Oxo-4H-chromen-3-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (3)

Yield (2.36 g, 60%), mp 240–242 °C. IR (KBr), ν (cm⁻¹): 3245 (N—H), 1686 (C⚌O_chromone), 1645 (C⚌O_diazepinone), 1606, 1592, 1554. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.03 (s, 1H, H_olefin), 7.14–7.93 (m, 13H, H_arom), 8.59 (s, 1H, α-H_chromone), 10.46 (bs, 1H, N—H disappeared on addition of D₂O). ¹³C NMR (100 MHz, DMSO-d₆) δ: 69.47, 105.32, 111.43, 112.11, 113.51, 117.43, 120.04, 122.66, 124.62, 125.56, 127.22, 129.22, 130.39, 131.30, 134.42, 136.19, 137.33, 139.22, 141.54, 143.32, 144.40, 145.19, 157.16, 193.10, 193.50. Analysis calcd. for C₂₅H₁₆N₂O₃ (392.41); C, 76.52; H, 4.11; N, 7.14%. Found: C, 76.30; H, 4.00; N, 7.20%.

4.2.2

4.2.2 13,15-Diphenyl-14-(4-oxo-4H-[1]chromen-3-yl)-5H,7H,14H-[1,5]benzodiazepino-[2,3:6,5]pyrano[2,3-b][1,5]benzodiazepine (4)

Yield (1.0 g, 33%), mp 271–272 °C. IR (KBr), ν (cm⁻¹): 3266 (N—H), 1684 (C⚌O_chromone), 1608 (C = N), 1580, 1553, 1495. ¹H NMR (400 MHz, DMSO-d₆) δ: 5.19 (s, 1H, 14-H_γ-pyran), 6.80–8.08 (m, 22 H, H_arom), 8.61 (s, 1H, α-H_chromone), 13.75 (b, 2H, N-H_diazepine, disappeared on addition of D₂O). ¹³C NMR (100 MHz, DMSO-d₆) δ: 90.91, 96.76, 99.32, 100.55, 110.45, 111.09, 113.60, 117.06, 119.09, 120.12, 122.38, 123.03, 124.52, 126.71, 127.11, 130.63, 131.54, 132.55, 133.11, 135.22, 137.44, 140.76, 143.43, 144.88, 146.60, 147.80, 150.12, 152.77, 155.41, 158.44, 159.11, 160.22, 163.07, 165.70, 168.22, 170.00, 174.55, 176.74, 176.44, 186.55. Analysis calcd. for C₄₀H₂₆N₄O₃ (610.66); C, 78.67; H, 4.29; N, 9.17%. Found: C, 78.40; H, 4.20; N; 9.20%.

4.3

4.3 3-(2-Hydroxybenzoyl)-5-phenylpyrano[2,3-e][1,5]benzodiazepine (5)

To a solution of compound 3 (1.02 g, 2.6 mmol) in dioxane (25 mL), aqueous potassium hydroxide solution (25 mL, 50 mmol; 2 M) was added. The alkaline solution was warmed at 60 °C and stirred for 15 min. The turbid solution was diluted with excess cold water (100 mL) to get a clear yellow solution. Acidification of the solution using dilute hydrochloric acid (0.5 M) till be red to litmus gave a pale yellow fine particles which was digested for 15 min over a boiling water-bath. Filtration, drying and crystallization of the pale yellow precipitate from DMF furnished compound 5. Yield (0.92 g, 90%), mp > 300 °C. IR (KBr), ν (cm⁻¹): 3447(O—H), 1635 (C⚌O), 1605 (C⚌N), 1590, 1575, 1552, 1509. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.09–7.63 (m, 13H, H_arom), 7.74 (s, 1H, γ-H_pyran), 7.79 (s, 1H +α-H_pyran), 13.09 (b, 1H, H-bonded O—H, disappeared on addition of D₂O). ¹³C NMR (100 MHz, DMSO-d₆) δ: 102.85, 105.08, 109.66, 110.90, 112.33, 118.11, 120.32, 122.98, 124.87, 126.44, 128.55, 129.00, 130.43, 133.09, 137.77, 139.08, 140.33, 143.09, 145.66, 148.33, 150.65, 153.00, 154.09, 157.06, 188.00. Analysis calcd. for C₂₅H₁₆N₂O₃ (392.41): C, 76.52; H, 4.11; N, 7.14%. Found: C; 76.20; H, 3.90; N, 7.00%.

4.4

4.4 3-(2-Hydroxybenzoyl)-5-phenyl-11H-pyrido[2,3-b][1,5]benzodiazepine (6)

A mixture of compound 3 (0.78 g, 2 mmol) and ammonium acetate (0.23 g, 3 mmol), in DMF (10 mL), was heated under reflux for 30 min. The reaction mixture was poured into ice cold water (100 mL) containing HCl (5 mL). The formed precipitate was filtered, dried, and crystallized from dioxane to give pyridobenzodiazepine 6. Yield (0.52 g, 66%), mp 285–286 °C. IR (KBr), ν (cm⁻¹): 3442 (O—H), 3280 (N—H), 3075, 1655 (C⚌O), 1612, 1605, 1585. ¹H NMR (400 MHz, DMSO-d₆) δ: 6.80–7.73 (m, 13H, H_arom), 8.05 (s, 1H, γ-H_pyridine), 8.25 (s, 1H, α-H_pyridine), 9.92 (s, 1H, N—H disappeared on addition of D₂O), 13.20 (s, 1H, O—H, disappeared on addition of D₂O). MS, m/z (I%): 392 (7.60, M+1), 363 (5.20), 290 (4.80), 289 (15.20), 288 (4), 275 (3.2), 274 (10), 167 (25.2), 121 (34.2), 77 (100). Analysis calcd. for C₂₅H₁₇N₃O₂ (391.42): C, 76.71; H, 4.38; N, 10.74%. Found: C, 76.80; H, 4.50; N, 10.50%.

4.5

4.5 General procedure for preparation of 3-(diazolylmethylene)benzodiazepinones 8 and 9

A mixture of compound 3 (0.78 g, 2 mmol) and hydrazine hydrate (0.1 mL, 2 mmol) or hydroxylamine hydrochloride (0.14 g, 2 mmol) was heated under reflux, in glacial acetic acid (20 mL), for 3 h. Then the reaction mixture was left to cool and the precipitate so formed was filtered, dried, washed with water and crystallized from ethanol.

4.5.1

4.5.1 3-((5-(2-Hydroxyphenyl)-1H-pyrazol-4-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (8)

Yield (0.65 g, 80%), m.p. > 300 °C. IR (KBr), ν (cm⁻¹): 3377, 3207 (O—H, N—H), 1668 (C⚌O), 1608, 1582. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.03 (s, 1H, H_olefin), 7.20–7.86 (m, 12H, H_arom), 8.54 (s, 1H, 3-H_pyrazole), 10.32–10.47 (bs, 2H, N—H, disappeared on addition of D₂O), 13.13 (b, 1H, H-bonded O—H, disappeared on addition of D₂O). MS, m/z (I%): 406 (M⁺; not detected), 404 (M-2, 15.30), 401 (15.10), 300 (70.54), 301 (45.02), 302 (25.89), 303 (15.47), 285 (23.99), 274 (34.95), 261 (24.28), 243 (16.59), 233 (33.51), 218 (27.05), 205 (14.37), 171 (56.57), 156 (19.05), 145 (15.01), 131 (25.08), 119 (30.49), 105 (100), 102 (24.79), 92 (30.82), 77 (24.53). Analysis calcd. for C₂₅H₁₈N₄O₂ (406.44): C, 73.88; H, 4.46; N, 13.78%. Found: C, 73.60; H, 4.20; N, 13.50%.

4.5.2

4.5.2 3-((5-(2-Hydroxyphenyl)isoxazol-4-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (9)

Yield (0.64 g, 79%), m.p. > 300 °C. IR (KBr), ν (cm⁻¹): 3337, 3240 (O—H, N—H), 1659 (C⚌O), 1604, 1590, 1565. ¹H NMR (400 MHz, DMSO-d₆) δ: 7.06 (s, 1H, H_olfen), 7.18–8.20 (m, 12H, H_arom), 8.70 (s, 1H, 3-H_isoxazole), 9.99 (s, 1H, N—H, disappeared on addition of D₂O), 13.09 (b, 1H, O—H, disappeared on addition of D₂O). MS, m/z (I%): 407 (M^+.; 1.7), 318 (11.6), 263 (11.3), 170 (16.1), 105 (100). Analysis calcd. for C₂₅H₁₇N₃O₃ (407.42): C, 73.70; H, 4.21; N, 10.31%. Found: C, 73.50; H; 4.10; N, 10.20%.

4.6

4.6 Procedure for preparation of 3-(pyridylmethylene)- benzodiazepinones 10 and 11

A mixture of compound 3 (0.78 g, 2 mmol,) and malononitrile (0.132 g, 2 mmol) or cyanothioacetamide (0.2 g, 2 mmol), in ethanol (25 mL) was treated with sodium ethoxide (sodium metal (0.23 g) was dissolved in absolute ethanol (5 mL); 10 mmol). Then the reaction mixture was heated, at water-bath, under reflux for 1 h. The mixture was left to cool to room temperature and then poured into ice-cold dilute hydrochloric acid solution (100 mL, 3%). The resulting solid product was filtered, washed with water and crystallized from ethanol.

4.6.1

4.6.1 3-((3-Cyano-6-(2-hydroxyphenyl)-2-oxo-1,2-dihydropyridin-5-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (10)

Yield (0.79 g, 86%), mp 279–281 °C. IR (KBr), ν (cm⁻¹): 3450 (O—H), 3340 (N—H), 3209 (N—H), 2201 (C≡N), 1665 (C⚌O), 1624 (C⚌O), 1605, 1590, 1545. ¹H NMR (400 MHz, DMSO-d₆) δ: 6.80 (s, 1H, H_olefin), 7.06–7.92 (m, 13H, H_arom), 8.55 (m, 1H, 9-H_{benzodiazepine}), 8.74 (s, 1H, γ-H_pyridone), 9.49 (bs, 1H, N—H_pyridone, disappeared on addition of D₂O), 9.87 (bs, 1, H, N—H_diazepinone, disappeared on addition of D₂O), 13.60 (b, 1H, O—H, disappeared on addition of D₂O). ¹³C NMR (100 MHz, DMSO-d₆) δ: 99.32, 110.00, 112.09, 114.81, 117.90, 118.35, 123.12, 124.65, 126.54, 128.44, 130.54, 131.76, 136.88, 138.09, 139.54, 140.55, 140.99, 142.65, 143.89, 144.77, 145.09, 146.88, 149.65, 152.77, 155.84, 158.00, 181.15, 200.09. Analysis calcd. for C₂₈H₁₈N₄O₃ (458.47): C; 73.35; H, 3.96; N, 12.22%. Found: C, 73.54; H, 3.66; N, 12.43%.

4.6.2

4.6.2 3-((3-Cyano-6-(2-hydroxyphenyl)-2-thioxo-1,2-dihydropyridin-5-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (11)

Yield (0.74 g, 78%), mp 280–282 °C. IR (KBr), ν (cm⁻¹): 3436 (O—H), 3344, 3280 (N—H), 2156 (C≡N), 1665 (C⚌O), 1155 (N—C⚌S). ¹H NMR (400 MHz, DMSO-d₆) δ: 6.90 (s, 1H, H_olefin), 7.02–7.79 (m, 13H, H_arom), 8.14 (s, 1H, γ-H_pyridine), 8.55 (s, 1H, N—H_{pyrdinethione}, disappeared on addition of D₂O), 10.60 (bs, 1H, N—H_diazepinone, disappeared on addition of D₂O), 13.18 (b, 1H, O—H, disappeared on addition of D₂O). Analysis calcd. for C₂₈H₁₈N₄O₂S (474.53): C, 70.87; H, 3.82; N, 11.81%. Found: C, 70.50; H, 3.60; N, 11.70%.

4.7

4.7 Procedure for preparation of benzodiazepinyldithiin 12 and benzodiazepinylthiazine 13

A mixture of anhydrous potassium carbonate (3 g, 20 mmol), TBAB (0.32 g, 1 mmol), carbon disulfide (0.25 mL, 3 mmol), or phenyl isothiocyanate (0.4 mL, 3 mmol) and malononitrile (0.2 g, 3 mmol), in dry dioxane (30 mL), was stirred, with gradual warming at 30–60 °C, for 4 h. Afterward, compound 3 (1.18 g, 3 mmol) was added to the previous reaction mixture and stirred, at 80 °C, till the completion of the reaction (TLC) for ca. 3 h. The reaction mixture was filtered off. The filtrate was evaporated in vacuum and the solid residue was washed with water and crystallized from ethanol to give compounds 12 or 13, respectively. The filtered potassium carbonate was washed with dioxane (25 mL), collected, and dissolved in cold water (50 mL). On acidification of the carbonate solution using hydrochloric acid (15 mL, 2 N), pyranobenzodiazepine 5 was precipitated as pale yellow deposits. The product was collected by filtration and crystallized from ethanol.

4.7.1

4.7.1 2-(5-(2-Hydroxybenzoyl)-4-(2-oxo-4-phenyl-2,5-dihydro-1H-[1,5]benzodiazepin-3-yl)-4H-1,3-dithiin-2-ylidene)malononitrile (12)

Yield (0.48 g, 30%), mp 200–202 °C. IR (KBr), ν (cm⁻¹): 3447 (O—H), 3275, 3174 (N—H), 2204 (C≡N), 1660 (C⚌O), 1635 (C⚌O), 1608, 1595, 1540. ¹H NMR (400 MHz, DMSO-d₆) δ: 3.80 (s, 1H, 4-H_dithiin), 6.80 (s, 1H, 6-H_dithiin), 6.94–8.14 (m, 13H, H_arom), 8.92 (s, 1H, N5—H_diazepinone, disappeared on addition of D₂O), 10.60 (bs, 1H, N1—H_diazepinone, disappeared on addition of D₂O), 13.14 (b, 1H, O–H, disappeared on addition of D₂O). Analysis calcd. for C₂₉H₁₈N₄O₃S₂ (534.61): C, 65.15; H, 3.39; N, 10.48%. Found: C; 64.90; H, 3.10; N, 10.20%.

4.7.2

4.7.2 2-(5-(2-Hydroxybenzoyl)-4-(2-oxo-4-phenyl-2,5-dihydro-1H-[1,5]benzodiazepin-3-yl)-3-phenyl-3,4-dihydro-2H-1,3-thiazin-2-ylidene)malononitrile (13)

Yield (0.68 g, 38%), mp 213–215 °C. IR (KBr), ν (cm⁻¹): 3400 (O—H), 2205 (C≡N), 1669 (C⚌O), 1645 (C⚌O), 1608, 1580. ¹H NMR (400 MHz, DMSO-d₆) δ: 3.70 (s, 1H, 4-H_dithiazin), 7.00 (s, 1H, 6-H_dithiazin), 7.14–7.90 (m, 18H, H_arom), 8.92 (s, 1H, N5—H_diazepinone, disappeared on addition of D₂O), 10.56 (bs, 1H, N1—H_diazepinone, disappeared on addition of D₂O), 13.90 (b, 1H, O—H, disappeared on addition of D₂O). ¹³C NMR (100 MHz, DMSO-d₆) δ: 58.50, 60.55, 103.71, 105.90, 109.77, 111.88, 113.55, 114.77, 115.99, 117.54, 119.37, 120.43, 122.90, 123.64, 125.88, 127.78, 130.00, 131.70, 133.73, 135.55, 137.66, 139.12, 140.00, 143.99, 145.56, 147.08, 148.86, 150.06, 155.66, 161.13, 166.00, 180.23, 183.54, 188.22, 190.22. Analysis calcd. for C₃₅H₂₃N₅O₃S (593.65): C, 70.81; H, 3.91; N, 11.80%. Found: C, 70.60; H, 3.60; N, 11.50%.

Acknowledgements

M.M. Hassan, one of the authors, is grateful to Basic Science Research Center for financial assistance under major research Project (award No. 4-1435) at Scientific Research Deanship, Majmaah University.

References

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Khodairy A., El-Sayed A.M., Salah H., Abdel-Ghany H., . Part 6: synthesis of spiro 1,5-benzodiazepine attached with different heterocyclic moieties. Synth. Commun.. 2007;37:3245-3258.
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Quiroga J., Mejia D., Insuasty B., Abonia R., Nogueras M., Sánchez A., Cobo J., Low J.N., . Synthesis of 6-(2-hydroxybenzoyl)pyrazolo[1,5-a]pyrimidines by reaction of 5-amino-H-pyrazoles and 3–formylchromone. J. Heterocycl. Chem.. 2002;39:51-54.
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Introduction

Results and discussion

Conclusions

Materials and methods

General
Reaction between 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) and 3-formylchromone (2)
3-(2-Hydroxybenzoyl)-5-phenylpyrano[2,3-e][1,5]benzodiazepine (5)
3-(2-Hydroxybenzoyl)-5-phenyl-11H-pyrido[2,3-b][1,5]benzodiazepine (6)
General procedure for preparation of 3-(diazolylmethylene)benzodiazepinones 8 and 9
Procedure for preparation of 3-(pyridylmethylene)- benzodiazepinones 10 and 11
Procedure for preparation of benzodiazepinyldithiin 12 and benzodiazepinylthiazine 13

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[1] Abass M., Abdel-Megid M., Hassan M., . Substituted quinolinones, part 12: heterocyclization reactions of 3-(3-chromonyl)acryloylquinolinone with some bifunctional nucleophiles. Synth. Commun.. 2007;37:329-352.
[Google Scholar]

[2] Abass M., Hassan A., . Chemistry of substituted quinolinones VII. Utility in syntheses and reactions of 3-[4-chromen-3-ylmethylene)pyrazolin-3-yl]-quinolin-2(1H)-ones with some bidentate nucleophiles. Chem. Pap.. 2003;57:266-276.
[Google Scholar]

[3] Abass M., Othman E.S., Hassan A., . Substituted quinolinones, part 11: efficient synthesis of different 3-(4-arylidene and hetarylidene-5-oxopyrazolin-3-yl)quinolin-2-ones. Synth. Commun.. 2007;37:609-623.
[Google Scholar]

[4] Abdel-Ghany H., El-Sayed A.M., Khodairy A., Salah H., . Synthesis of new 3-substituted and spiro 1,5-benzodiazepin-2-one under phase transfer catalysis conditions. Synth. Commun.. 2001;31:2523-2535.
[Google Scholar]

[5] Abdelrazek F.M., Elsayed A.N., . About the reaction of β-dimethylamino-α, β-enones with active methylene nitriles. J. Heterocycl. Chem.. 2009;46:949-953.
[Google Scholar]

[6] Akkurt M., Kennedy A.R., Younes S.H.H., Mohamed S.K., Abdelhamid A.A., . 4-Phenyl-1H-1,5-benzodiazepin-2(3H)-one. Acta Crys. E. 2012;68:o3356.
[Google Scholar]

[7] Di Braccio M., Grossi G.C., Roma G., Vargiu L., Mura M., Marongiu M.E., . 1,5-Benzodiazepines. Part XII. Synthesis and biological evaluation of tricyclic and tetracyclic 1,5-benzodiazepines derivatives as nevirapine analogues. Eur. J. Med. Chem.. 2001;36:935-949.
[Google Scholar]

[8] Elgemeie G.H., Elghandour A.H., Elzanate A.M., Ahmed S.A., . Synthesis of some novel α-cyanoketene S, S-acetals and their use in heterocyclic synthesis. J. Chem. Soc. Perkin Trans.. 1997;1:3285-3289.
[Google Scholar]

[9] El-Sayed A.M., El-Saghier A.M.M., Mohamed M.A.A., El-Shafei A.K., . Utility of α-oxoketene dithioacetal in organic synthesis: synthesis of some new spiro(pyran-4,2′-benzothiazole) derivatives. Gazz. Chim. Ital.. 1997;127:605-608.
[Google Scholar]

[10] Ghosh C.K., Bhattachachrya S., Ghoshal N., Achari B., . Benzopyrans. Part 38. Reactions of 4-oxo-4H-1-benzopyran-3-carbaldehyde, 3-carbonitrile and 3-carboxylate with chloroacetone and a note on the stereochemistry of benzo[b]cyclopropa[e]pyrans. J. Chem. Res. M. 1998;859–863(S):178-179.
[Google Scholar]

[11] Ghosh C.K., Ray A., Patra A., . Benzopyrans. Part 42. Reactions of 4-oxo-4H-1-benzopyran-3-carbaldehyde with active methylene compounds in the presence of ammonia. J. Heterocycl. Chem.. 2001;38:1459-1463.
[Google Scholar]

[12] Haas G., Stanton J.L., von Sprecher A., Wenk P., . The synthesis of pyridine derivatives from 3-formylchromone. J. Heterocycl. Chem.. 1981;18:607-612.
[Google Scholar]

[13] Hassan M.M., Othman E.S., Abass M., . Substituted quinolinones. 18. 3-Acetyl-4-methylthioquinolin-2(1H)-one as useful synthon intermediate for synthesis of some new quinolinones. Res. Chem. Intermed.. 2013;39:1209-1226.
[Google Scholar]

[14] Kamal A., Shankaraiah N., Prabhakar S., Reddy C.R., Markandeya N., Laxma K., Devaiah X., . Solid-phase synthesis of new pyrrolobenzodiazepine-chalconeconjugates: DNA-binding affinity and anticancer activity. Bioorg. Med. Chem. Lett.. 2008;18:2434-2439.
[Google Scholar]

[15] Kavali J.R., Badami B.V., . 1,5-Benzodiazepine derivatives of 3-arylsydnones: Synthesis and antimicrobial activity of 3-aryl-4-[2′-aryl-2′,4′,6′,7′-tetrahydro-(1′H)-1′,5′-benzodiazepine-4′-yl]sydnones. Farmaco. 2000;55:406-409.
[Google Scholar]

[16] Khodairy A., . Synthesis of new fused 1,5-benzodiazepines part 3. Phosphorus Sulfur Silicon. 2005;180:1893-1907.
[Google Scholar]

[17] Khodairy A., . Synthetic studies on the synthesis of some new fused heterocyclic compounds derived from 3,5-pyrazolidinedione. J. Chin. Chem. Soc.. 2007;54:93-102.
[Google Scholar]

[18] Khodairy A., . Synthesis of pyrazolo[3,4-b]- and pyrido[2,3-b]-1,5-benzodiazepin-2(3H)-ones. Synth. Commun.. 2011;41:612-621.
[Google Scholar]

[19] Khodairy A., Abdel-Ghany H., El-Sayed A.M., Salah H., . Synthesis of new fused and spiro 1,5-benzodiazepines. J. Chin. Chem. Soc.. 2003;50:1195-1198.
[Google Scholar]

[20] Khodairy A., El-Sayed A.M., Salah H., Abdel-Ghany H., . Part 6: synthesis of spiro 1,5-benzodiazepine attached with different heterocyclic moieties. Synth. Commun.. 2007;37:3245-3258.
[Google Scholar]

[21] Kumar R., Joshi Y.C., . Synthesis spectral studies and biological activity of 3H-1,5-benzodiazepine derivatives. Arkivoc 2007:142-149.
[Google Scholar]

[22] Narayana B., Vijaya Raj K.K., Ashalatha B.V., Suchetha Kumari N., . Synthesis of some new substituted triazolo[4,3-a][1,4]benzodiazepine derivatives as potent anticonvulsants. Eur. J. Med. Chem.. 2006;41:417-422.
[Google Scholar]

[23] Nohara A., Umetani T., Sanno Y., . Studies on antianaphylactic agents-I: a facile synthesis of 4-oxo-4H-1-benzopyran-3-carboxaldehydes by Vilsmeier reagents. Tetrahedron. 1974;30:3553-3561.
[Google Scholar]

[24] Quiroga J., Mejia D., Insuasty B., Abonia R., Nogueras M., Sánchez A., Cobo J., Low J.N., . Synthesis of 6-(2-hydroxybenzoyl)pyrazolo[1,5-a]pyrimidines by reaction of 5-amino-H-pyrazoles and 3–formylchromone. J. Heterocycl. Chem.. 2002;39:51-54.
[Google Scholar]

[25] Quiroga J., Rengifo A., Insuasty B., Abonia R., Nogueras M., Sánchez A., . A novel product from the reaction of 6-aminopyrimidines and 3-formylchromone. Tetrahedron Lett.. 2002;43:9061-9063.
[Google Scholar]

[26] Roma G., Grossi G.C., Di Braccio M., Ghia M., Mattioli F., . 1,5-Benzodiazepines. IX. A new route to substituted 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepin-5-amines with analgesic and/or anti-inflammatory activity. Eur. J. Med. Chem.. 1991;26:489-496.
[Google Scholar]

[27] Ryabukhin S.V., Plaskon A.S., Volochnyuk D.M., Tolmachev A.A., . 3-Formylchromones in Guareschi synthesis of 5-(2-hydroxybenzoyl)-2-pyridones. Synlett. 2004;13:2287-2290.
[Google Scholar]

[28] Sabitha G., . 3-Formylchromone as a versatile synthon in heterocyclic chemistry. Aldrichim. Acta. 1996;29:15-25.
[Google Scholar]

[29] Shanker M.S.S., Reddy R.B., Chandra Mouli G.V.P., Reddy Y.D., . A novel synthesis of pyrazolyl chromone derivatives. Asian J. Chem.. 1992;4:166-170.
[Google Scholar]

[30] Tominaga Y., Matsuoka Y., Oniyama Y., Uchimura Y., Komiya H., Hirayama M., Kohra S., Hosomi A., . Polarized ethylenes. IV. Synthesis of polarized ethylenes using thioamides and methyl dithiocarboxylates and their application to synthesis of pyrazoles, pyrimidines, pyrazolo[3,4-d]pyrimidines, and 5-aza[2.2.3]cyclazines. J. Heterocycl. Chem.. 1990;27:647-660.
[Google Scholar]

Ring rearrangements and reactivity of 3-((4-oxo-4H-chromen-3-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one toward some nucleophiles

Abstract

Keywords

[1,5]Benzodiazepin-2(3H)-one

3-Formylchromone

Nucleophilic reagents

Ring rearrangement

Heterocyclization

1 Introduction

2 Results and discussion

3 Conclusions

4 Materials and methods

4.1 General

4.2 Reaction between 4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (1) and 3-formylchromone (2)

4.2.1 3-((4-Oxo-4H-chromen-3-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (3)

4.2.2 13,15-Diphenyl-14-(4-oxo-4H-[1]chromen-3-yl)-5H,7H,14H-[1,5]benzodiazepino-[2,3:6,5]pyrano[2,3-b][1,5]benzodiazepine (4)

4.3 3-(2-Hydroxybenzoyl)-5-phenylpyrano[2,3-e][1,5]benzodiazepine (5)

4.4 3-(2-Hydroxybenzoyl)-5-phenyl-11H-pyrido[2,3-b][1,5]benzodiazepine (6)

4.5 General procedure for preparation of 3-(diazolylmethylene)benzodiazepinones 8 and 9

4.5.1 3-((5-(2-Hydroxyphenyl)-1H-pyrazol-4-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (8)

4.5.2 3-((5-(2-Hydroxyphenyl)isoxazol-4-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (9)

4.6 Procedure for preparation of 3-(pyridylmethylene)- benzodiazepinones 10 and 11

4.6.1 3-((3-Cyano-6-(2-hydroxyphenyl)-2-oxo-1,2-dihydropyridin-5-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (10)

4.6.2 3-((3-Cyano-6-(2-hydroxyphenyl)-2-thioxo-1,2-dihydropyridin-5-yl)methylene)-4-phenyl-1H-[1,5]benzodiazepin-2(3H)-one (11)

4.7 Procedure for preparation of benzodiazepinyldithiin 12 and benzodiazepinylthiazine 13

4.7.1 2-(5-(2-Hydroxybenzoyl)-4-(2-oxo-4-phenyl-2,5-dihydro-1H-[1,5]benzodiazepin-3-yl)-4H-1,3-dithiin-2-ylidene)malononitrile (12)

4.7.2 2-(5-(2-Hydroxybenzoyl)-4-(2-oxo-4-phenyl-2,5-dihydro-1H-[1,5]benzodiazepin-3-yl)-3-phenyl-3,4-dihydro-2H-1,3-thiazin-2-ylidene)malononitrile (13)

Acknowledgements

References

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