4-(Piperidin-1-yl)-4H-benzo[b]tetra­zolo[1,5-d][1,4]diazepin-5(6H)-one

Gary S Nichol; Zhigang Xu; Christine E Kaiser; Christopher Hulme

doi:10.1107/S1600536810049950

. 2010 Dec 4;67(Pt 1):o23–o24. doi: 10.1107/S1600536810049950

4-(Piperidin-1-yl)-4H-benzo[b]tetrazolo[1,5-d][1,4]diazepin-5(6H)-one

Gary S Nichol ^a,^*, Zhigang Xu ^b, Christine E Kaiser ^b, Christopher Hulme ^b

PMCID: PMC3050344 PMID: 21522729

Abstract

There are two crystallographically unique molecules present in the asymmetric unit of the title compound, C₁₄H₁₆N₆O; in both molecules, the seven-membered diazepinone ring adopts a boat-like conformation and the chair conformation piperidine ring is an axial substituent on the diazepinone ring. In the crystal, each molecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between molecule A and symmetry equivalents forms two ring motifs, the first formed by inversion-related N—H⋯O interactions and the second formed by C—H⋯O and C—H⋯N interactions. The combination of both ring motifs results in the formation of an infinite double tape, which propagates in the a-axis direction. Hydrogen bonding between molecule B and symmetry equivalents forms one ring motif by inversion-related N—H⋯O interactions and a second ring motif by C—H⋯O interactions, which propagate as a single tape parallel with the c axis.

Related literature

The structure of the title compound was determined as part of a larger study on development of synthetic methods for high-throughput medicinal chemistry. For background to the use of multi-component reactions in high-throughput medicinal chemistry, see: Gunawan et al. (2010 ▶); Hulme & Dietrich (2009 ▶); Hulme & Gore (2003 ▶). For the Ugi reaction, see: Ugi & Steinbrückner (1961 ▶). For graph-set notation for hydrogen bonding, see: Bernstein et al. (1995 ▶) and puckering parameters, see: Cremer & Pople (1975 ▶).

Experimental

Crystal data

C₁₄H₁₆N₆O
M _r = 284.33
Triclinic,
a = 8.8210 (7) Å
b = 13.1802 (10) Å
c = 13.4476 (11) Å
α = 105.549 (2)°
β = 99.490 (2)°
γ = 106.623 (2)°
V = 1392.99 (19) Å³
Z = 4
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 100 K
0.39 × 0.28 × 0.09 mm

Data collection

Bruker Kappa APEXII DUO CCD diffractometer
Absorption correction: numerical (SADABS; Sheldrick, 1996 ▶) T _min = 0.965, T _max = 0.992
51078 measured reflections
12177 independent reflections
9733 reflections with I > 2σ(I)
R _int = 0.029

Refinement

R[F ² > 2σ(F ²)] = 0.043
wR(F ²) = 0.123
S = 1.05
12177 reflections
507 parameters
All H-atom parameters refined
Δρ_max = 0.59 e Å⁻³
Δρ_min = −0.23 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/S1600536810049950/kj2167sup1.cif

e-67-00o23-sup1.cif^{(37.7KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810049950/kj2167Isup2.hkl

e-67-00o23-Isup2.hkl^{(595.3KB, 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
N1—H1N⋯O1ⁱ	0.850 (14)	2.069 (14)	2.9089 (9)	169.4 (13)
N51—H51N⋯O51ⁱⁱ	0.886 (16)	1.929 (16)	2.8116 (10)	173.6 (14)
C6—H6⋯N2ⁱⁱⁱ	0.936 (15)	2.531 (15)	3.4638 (11)	174.8 (12)
C7—H7⋯O1ⁱⁱⁱ	0.947 (15)	2.406 (15)	3.3394 (10)	168.4 (13)
C55—H55⋯N54^iv	0.974 (13)	2.548 (13)	3.2293 (11)	127.0 (10)

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

Acknowledgments

The diffractometer was purchased with funding from NSF grant CHE-0741837.

supplementary crystallographic information

Comment

At present there is a huge need for unique small molecules in the lead development stages of drug discovery. In this process, speed is paramount, and the development of high speed parallel synthesis in concert with isocyanide based multi-component reactions (MCRs) has enabled a revolution in high-throughput medicinal chemistry (Gunawan et al., (2010); Hulme & Dietrich (2009); Hulme & Gore (2003)). Following this theme, a novel two step solution phase protocol for the synthesis of an array of tricyclic fused tetrazole-benzodiazepines was recently investigated (Figure 1). The methodology employs ortho-N-Boc benzylisonitriles 1 and ethyl glyoxylate 2 in the 4-component TMS-N₃ modified Ugi reaction (Ugi & Steinbrückner, 1961) to assemble the desired product 3. Subsequent treatment with trifluoroacetic acid unmasks an internal amino nucleophile and promotes cyclization to form the diazepine ring of the generic structure 4. Here we report the crystal structure of 4.

The asymmetric unit of 4 is shown in Figure 2. There are two crystallographically unique molecules in the asymmetric unit; the molecule composed of atoms O1 to C14 will henceforth be referred to as "molecule A" and the molecule composed of atoms O51 to C64 referred to as "molecule B". Where appropriate, discussion will be limited to molecule A with results for molecule B presented in square brackets. Molecular dimensions are unexceptional.

The molecule adopts a U-shaped conformation in which the 7-membered diazepinone ring has adopted a boat-like conformation (total Q parameter 0.8021 (8)Å [0.8177 (9) Å]; Cremer & Pople (1975)) and the chair conformation piperidinyl ring is an axial substituent on the diazepinone ring. Both molecules have a very similar overall shape as shown by an overlay, fitting N1, N5, C4 > C9 with N51, N55, C54 > C59 (these representing the largest planar moiety in the structure, Figure 3).

In the crystal each molecule forms hydrogen bonds with its respective symmetry equivalents. Hydrogen bonding between molecule A and symmetry equivalents forms two ring motifs (Bernstein et al., 1995), an R²₂(8) motif formed by inversion-related N—H···O interactions and an R²₂(9) motif formed by C—H···O and C—H···N interactions. The combination of both ring motifs results in the formation of an infinite double tape which propagates in the a axis direction (Figure 4). Hydrogen bonding between molecule B and symmetry equivalents forms one ring motif composed of an R²₂(8) motif formed by inversion-related N—H···O interactions and an R²₂(10) motif formed by C—H···O interactions (Figure 5). This propagates as a single tape parallel with the c axis.

Experimental

A solution of piperidine (0.017 g, 0.20 mmol) and ethyl glyoxylate (0.04 ml, 50% in toluene, 0.20 mmol) in methanol (0.5 ml) were stirred at room temperature. After 5 minutes, ortho-N-Boc-phenylisonitrile (0.0436 g, 0.20 mmol) and trimethylsilylazide (0.023 g, 0.20 mmol) was added dropwise to the above solution and stirred at room temperature for 23 h. The solvent was evaporated in vacuo and the product was purified using column chromatography (5–30% Hexane/Ethyl Acetate) to afford the desired Ugi product (0.056 g, 0.20 mmol, 65%) as colorless oil. The purified Ugi product was treated with 10% trifluoroacetic acid in dichloroethane (4 ml) and irradiated in a Biotage Initiator™ for 10 minutes at 120°C. The organic layer was washed with 1M NaHCO₃ (3 × 5 ml) and dried (MgSO₄). The solvent was evaporated in vacuo and purified by column chromatography (0–50% Hexane/Ethyl Acetate) to afford the desired product (0.030 g, 0.116 mmol, 92%) as a white solid.