4-Phenyl-1-(prop-2-yn-1-yl)-1H-1,5-benzodiazepin-2(3H)-one

Mohamed Loughzail; José A Fernandes; Abdesselam Baouid; Mohamed Essaber; José A S Cavaleiro; Filipe A Almeida Paz

doi:10.1107/S1600536811027371

. 2011 Jul 23;67(Pt 8):o2075–o2076. doi: 10.1107/S1600536811027371

4-Phenyl-1-(prop-2-yn-1-yl)-1H-1,5-benzodiazepin-2(3H)-one

Mohamed Loughzail ^a, José A Fernandes ^b, Abdesselam Baouid ^a,^*, Mohamed Essaber ^a, José A S Cavaleiro ^c, Filipe A Almeida Paz ^b,^*

PMCID: PMC3213519 PMID: 22091098

Abstract

4-Phenyl-1H-1,5-benzodiazepin-2(3H)-one reacts in the presence of a concentrated aqueous solution of sodium hydroxide and a quaternary ammonium salt (as catalyst) in benzene (phase transfer catalysis) with propargyl bromide, affording the title benzodiazepine derivative, C₁₈H₁₄N₂O. In the molecule, the mean plane of the propargyl substituent is almost perpendicular with that of the amide group [dihedral angle = 87.81 (8)°]. In the crystal, the molecules are linked by C—H⋯O and C—H⋯N interactions.

Related literature

For general background to applications of benzodiazepines, see: Ahmed et al. (1983 ▶); Bird (1996 ▶); Di Braccio et al. (1990 ▶, 2001 ▶); Goetzke et al. (1983 ▶); Kavita et al. (1988 ▶); Sieghart & Schuster (1984 ▶); Wolff (1996 ▶). For examples of benzodiazepines used as medicine, see: Wolff (1996 ▶). For the pharmacological effects of benzodiazepines, see: Meldrum & Chapman (1986 ▶). For examples of synthetic pathways of new benzodiazepines, see: Aatif et al. (2000 ▶); Baouid et al. (2001 ▶); Boudina et al. (2007 ▶); Nardi et al. (1973 ▶). For previous work from our groups on organic crystals, see: Fernandes et al. (2011 ▶); Amarante, Figueiredo et al. (2009); ▶ Amarante, Gonçalves & Almeida Paz (2009); ▶ Paz & Klinowski (2003); ▶ Paz et al. (2002) ▶.

Experimental

Crystal data

C₁₈H₁₄N₂O
M _r = 274.31
Monoclinic,
a = 8.2574 (14) Å
b = 18.961 (3) Å
c = 9.0914 (15) Å
β = 102.962 (4)°
V = 1387.1 (4) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 150 K
0.12 × 0.08 × 0.04 mm

Data collection

Bruker X8 Kappa CCD APEX II diffractometer
Absorption correction: multi-scan (SADABS; Sheldrick, 1997 ▶) T _min = 0.990, T _max = 0.997
11049 measured reflections
5228 independent reflections
3621 reflections with I > 2σ(I)
R _int = 0.034

Refinement

R[F ² > 2σ(F ²)] = 0.052
wR(F ²) = 0.143
S = 1.05
5228 reflections
190 parameters
H-atom parameters constrained
Δρ_max = 0.45 e Å⁻³
Δρ_min = −0.25 e Å⁻³

Data collection: APEX2 (Bruker, 2006 ▶); cell refinement: SAINT-Plus (Bruker, 2005 ▶); data reduction: SAINT-Plus; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: DIAMOND (Brandenburg, 2009 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) global, I. DOI: 10.1107/S1600536811027371/tk2762sup1.cif

e-67-o2075-sup1.cif^{(18.6KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811027371/tk2762Isup2.hkl

e-67-o2075-Isup2.hkl^{(256KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811027371/tk2762Isup3.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C1—H1A⋯O1ⁱ	0.99	2.14	3.1074 (15)	166
C3—H3⋯N2ⁱⁱ	0.95	2.58	3.4269 (18)	149

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Symmetry codes: (i) Inline graphic ; (ii) .

Acknowledgments

We are grateful to the Fundação para a Ciência e a Tecnologia (FCT, Portugal) for their general financial support, for the post-doctoral research grant No. SFRH/BPD/63736/2009 (to JAF) and for specific funding toward the purchase of the single-crystal diffractometer.

supplementary crystallographic information

Comment

Benzodiazepine derivatives are an important class of heterocyclic compounds in the field of drugs, pharmaceuticals and synthetic organic chemistry (Bird, 1996; Wolff, 1996), as they show antiviral (Di Braccio et al., 2001), analgesic (Di Braccio et al., 1990), and antipsychotic (Kavita et al., 1988) activities. These compounds are used worldwide as anticonvulsant agents (Sieghart & Schuster, 1984) or as sedative or hypnotics (Goetzke et al., 1983; Ahmed et al., 1983). Examples of well known diazepines are Alprazolam, Diazepam and Flunitrazepam (Wolff, 1996). Their pharmacological effects come from the activation of the benzodiazepine receptor which interacts with the GABA recognition site (Meldrum & Chapman, 1986). Research in this area is highly active being directed towards the synthesis of compounds with enhanced pharmacological activity. Following the research efforts from some of us concerning novel synthetic pathways of new benzodiazepines (Aatif et al., 2000; Baouid et al., 2001; Boudina et al., 2007), and our interest on the structural features of organic crystals (Fernandes et al., 2011; Amarante, Figueiredo et al., 2009; Amarante, Gonçalves & Almeida Paz , 2009; Paz & Klinowski, 2003; Paz et al., 2002), here we wish to report the synthesis via phase transfer catalysis and the crystallographic studies of the title compound (I).

The asymmetric unit is composed of a whole molecular moiety of I (Fig. 1). All atoms are distributed over four medium planes (see Table 1 for details), which converge in the diazepine ring. The plane of the substituent aromatic ring is extended to the imine group from the diazepine moiety (plane A) and subtends an angle of 71.78 (4)° with the amide plane (C). The plane of the benzo ring (B) subtends, on the other hand, two almost similar angles with the previously described planes [41.76 (4)° with plane A and 40.75 (4)° with plane C]. The plane of the propargyl substituent (D) is almost perpendicular with that of the amide group [87.81 (8)°].

The crystal packing (Fig. 2) features weak supramolecular interactions (see Table 2 for details), namely the C—H and CH₂ groups of the propargyl moiety interact with N2 from the imine and O1 from the amide of neighbouring molecules, respectively.

Experimental

Melting points were taken in an open capillary tube on a Buchi 510 apparatus and are uncorrected. The FT—IR spectrum was obtained from KBr pellets using a Bruker Tensor 27 spectrophotometer. NMR Spectra were recorded with the following instruments: ¹H, Bruker AC-300; ¹³C, Bruker AC-75. TMS was used as an internal reference. Mass spectra were recorded using a Jeol JMS DX 300 instrument. Column chromatography was carried out using E-Merck silica gel 60F₂₅₄. All reagents were purchased from commercial sources and were used without further purification.

The precursor, 4-phenyl-2,3-dihydro-1H-1,5-benzodiazepin-2-one (II), was prepared following literature procedures (Nardi et al., 1973) by refluxing o-phenylenediamine and ethyl benzoylacetate for 2 h in xylene.

A mixture of 1 g (4.6 mmol) of II, 0.43 g (2.3 mmol) of benzyltriethylammonium chloride (TBA-Cl) and 3 ml of a 50% sodium hydroxide aqueous solution in benzene (25 ml) was stirred at ambient temperature. After 15 min, propargyl bromide was added slowly. After 6 h of stirring at 298 K, the reaction mixture was diluted with water (30 ml). The organic layer was extracted with benzene (3 × 10 ml), dried over anhydrous sodium sulfate and evaporated under vacuum. The title compound was isolated by column chromatography on silica gel using hexane/ethyl acetate as eluent. The solid product was recrystallized in dichloromethane to give yellow crystals of I. Yield: 96%. Melting point: 438–440 K.

FT–IR (KBr): 3259(m), 3060(w), 2984(m), 1659(vs), 1602(s), 1586(w), 1570(m), 1496(w), 1479(s), 1452(s), 1431(m), 1379(s), 1362(w), 1321(w), 1307(m), 1293(w), 1279(m), 1262(m), 1211(m), 1162(w), 1014(m), 958(m), 774(s), 688(m), 662(w), 639(w), 598(m), 484(w), 426(w) cm^-1. ¹H NMR (300 MHz, CDCl₃): 7.25-8.14 (9H, Ar-H), 4.19 and 4.27 (AB system, d, J= 17.7 Hz, 2H, N-CH₂-C), 3.04 and 4.76 (AB system, d, J=12 Hz, 2H, CH₂-CO-N), 2.32 (t, J= 2.25 Hz, 1H, HC≡C) ppm.¹³C NMR (75 MHz, CDCl₃): 165 (1C, CO), 160.0 (1C, Ph-C=N), 140.9, 136.9, 133.3, 130.5, 128.1, 127.1, 126.7, 125.7, 125.1, 120.9 (12C, Ar-C), 78.5 (1C, HC≡ C), 71.9 (1C, HC≡C), 39.1 (1C, CH₂-CO-N), 36.9 (1C, N-CH₂-C) ppm. MS (EI, m/z): 275 [M+H]⁺.