2-Butyl-11-phenyl-5,10-dihydro-1H-benzo[e]imidazo[1,5-a][1,4]diazepine-1,3(2H)-dione

Gary S Nichol; Steven Gunawan; Justin Dietrich; Christopher Hulme

doi:10.1107/S1600536810005477

. 2010 Feb 13;66(Pt 3):o625. doi: 10.1107/S1600536810005477

2-Butyl-11-phenyl-5,10-dihydro-1H-benzo[e]imidazo[1,5-a][1,4]diazepine-1,3(2H)-dione

Gary S Nichol ^a,^*, Steven Gunawan ^b, Justin Dietrich ^b, Christopher Hulme ^b

PMCID: PMC2983587 PMID: 21580382

Abstract

The title compound, C₂₁H₂₁N₃O₂, was obtained following a five-step synthetic procedure yielding weakly diffracting rod and needle-shaped crystals which crystallized concomitantly. Structural analysis of a rod-shaped crystal showed that the central seven-membered heterocyclic ring adopts a conformation that is perhaps best described as a distorted boat, with the H-bearing (CH₂ and NH) atoms lying well out of the least-squares mean plane fitted through the other five atoms in the ring (r.m.s. deviation 0.075 Å). In the crystal, the compound packs as a twisted chain, which propagates along the b axis by means of an R ¹ ₂(6) motif formed by one of the carbonyl O atoms acting as a bifurcated acceptor in an N—H⋯O and C—H⋯O interaction. No diffraction was observed from the needle-shaped crystals.

Related literature

For background to the synthetic procedure, see: Hulme & Gore (2003 ▶); Hulme et al. (2000 ▶). For graph-set analysis of hydrogen-bond networks, see: Bernstein et al. (1995 ▶).

Experimental

Crystal data

C₂₁H₂₁N₃O₂
M _r = 347.41
Monoclinic,
a = 12.192 (4) Å
b = 7.638 (2) Å
c = 18.514 (6) Å
β = 95.494 (5)°
V = 1716.1 (9) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 100 K
0.29 × 0.14 × 0.08 mm

Data collection

Bruker Kappa APEXII DUO CCD diffractometer
Absorption correction: numerical (SADABS; Sheldrick, 1996 ▶) T _min = 0.975, T _max = 0.993
14047 measured reflections
2724 independent reflections
1908 reflections with I > 2σ(I)
R _int = 0.067
θ_max = 24.1°

Refinement

R[F ² > 2σ(F ²)] = 0.065
wR(F ²) = 0.181
S = 1.03
2724 reflections
239 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.71 e Å⁻³
Δρ_min = −0.29 e Å⁻³

Data collection: APEX2 (Bruker, 2007 ▶); cell refinement: SAINT (Bruker, 2007 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXTL; molecular graphics: ORTEP-3 for Windows (Farrugia, 1997 ▶) and Mercury (Macrae et al., 2008 ▶); software used to prepare material for publication: SHELXTL and local programs.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810005477/bh2272sup1.cif

e-66-0o625-sup1.cif^{(20.6KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810005477/bh2272Isup2.hkl

e-66-0o625-Isup2.hkl^{(133.8KB, hkl)}

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
N3—H3N⋯O1ⁱ	0.86 (4)	2.10 (4)	2.944 (3)	165 (3)
C8—H8⋯O1ⁱ	0.95	2.57	3.326 (4)	136

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Symmetry code: (i) Inline graphic .

Acknowledgments

The diffractometer was purchased with funding from NSF grant No. CHE-0741837.

supplementary crystallographic information

Comment

We recently investigated a three step solution phase protocol for the synthesis of arrays of tricyclic fused hydantoin-benzodiazepines as part of broader research on multi-component reactions (Figure 1). Interestingly, the major product of this unique synthetic route was the tautomer 5 derived from the originally desired product 4, the structure being confirmed by X-ray crystallography. The methodology employs ortho-N-Boc benzylamines 1 and phenylglyoxaldehydes 2 in the rarely used five component Ugi reaction with CO₂ to assemble desired diversity in product 3 (Hulme et al., 2000). Acid treatment unmasks an internal amino nucleophile and promotes rapid formation of the diazepine ring of generic structure 4. Subsequent base treatment employs the amidic NH of the Ugi scaffold as a second internal nucleophile promoting hydantoin formation and an unexpected 1,3-H shift to give 5. As such the methodology represents an example of a post-condensation Ugi modification (Hulme & Gore, 2003) that employs two internal nucleophiles in distinct operations, generating a novel scaffold of high complexity in three succinct functional operations.

Two types of crystals were formed: very fine yellow needles together with a few slightly larger rod-shaped pale yellow crystals. The needles did not give any measurable diffraction and the rod crystals showed weak diffraction with 60 second exposure times; a resolution cutoff of 0.87Å was applied to the dataset. The identity of the needle crystals was not established. The molecular structure of 5 is shown in Figure 2. Molecular dimensions are unexceptional. The amine hydrogen atom was located in a difference Fourier map and its presence is confirmed by participation in hydrogen bonding discussed below. The central 7-membered heterocyclic ring adopts a conformation that is perhaps best described as a distorted boat with the H-bearing (C3 and N3) atoms lying well out of a least squares mean plane fitted through the other five atoms in the ring [r.m.s. deviation 0.075 Å; C3 deviates by 0.679 (5) Å and N3 deviates by 0.301 (4) Å]. The compound packs as a twisted chain which propagates along the b axis by means of an R¹₂(6) motif (Bernstein et al., 1995) formed by one of the carbonyl oxygen atoms acting as bifurcated acceptor in an N–H···O and C–H···O interaction (Figure 3).

Experimental

Ugi reaction (For R₁, R₂=H, R₃= n-butyl)

CO₂ gas was bubbled through a stirring solution of MeOH for 25 minutes to generate methyl carbonic acid. In a separate 25 ml flask, phenyl glyoxal 2 (226 mg, 1.687 mmol) was added to BOC-2-aminobenyzlamine 1 (250 mg, 1.125 mmol). Methyl carbonic acid (10 ml) and N-butyl isonitrile (0.237 ml, 2.252 mmol) were then added to the latter flask. The reaction was stirred at room temperature under an atmosphere of CO₂ for 16 h. The solvent was evaporated in vacuo and the crude product purified with a Biotage Isolera4^TMsystem (hexane/EtOAc 10-30%) to afford the Ugi product 3 (218 mg, 0.438 mmol, 39%) as a yellow oil.

De-BOC and Cyclization

3 (0.180 g, 0.362 mmol) was treated with a 5 ml 10% TFA solution in 1,2-dichloroethane which was irradiated in a Biotage InitiatorTM at 80°C for 20 min. The resulting orange solution was washed with 1M NaHCO₃ (4 × 2.5 ml) and the organic layer dried (Na₂SO₄), filtered and evaporated in vacuo. MeOH (1.5 ml), THF (0.75 ml), H₂O (0.5 ml) were added to the crude product 4 (0.102 g, 0.269 mmol) followed by a 1 g/1 ml solution of KOH in H₂O (0.03 ml). The solution was irradiated at 100°C for 20 min and resultant orange solution partitioned between EtOAc (5 ml) and 1M NaHCO₃ (5 ml). The organic layer was dried (Na₂SO₄), filtered and evaporated in vacuo. Final crude product was purified with a Biotage Isolera4^TM (hexane/EtOAc 30%) to afford the final product 5 (0.074 g, 0.214 mmol, 80%) as a yellow solid. FT-ICR calculated for C₂₁H₂₂N₃O₂ [M+H]⁺: 348.1707, found: 348.1707.