organic compounds\(\def\hfill{\hskip 5em}\def\hfil{\hskip 3em}\def\eqno#1{\hfil {#1}}\)

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ISSN: 2056-9890

6-Chloro-1-(3,5-di­methyl­phenyl­sulfon­yl)-1H-benzimidazol-2(3H)-one

aInstitute of Pharmaceutical and Toxicological Chemistry, "P. Pratesi", University of Milano, via L. Mangiagalli, 25, 20133-Milano, Italy, and bDepartment of Pharmaceutical Chemistry, University of Messina, viale Annunziata, 98168-Messina, Italy
*Correspondence e-mail: fiorella.meneghetti@unimi.it

(Received 28 November 2008; accepted 15 December 2008; online 20 December 2008)

The title compound, C15H13ClN2O3S, is one of a series of N1-benzyl-1,3-dihydro-2H-benzimidazol-2-one derivatives, a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors. The dihedral angle between the two pharmacophoric groups, the dimethyl­benzene ring and the benzimidazolone ring system, is 88 (1)°, giving a butterfly-like conformation to the mol­ecule. The mol­ecular packing is characterized by a bifurcated N—H⋯(O,O) hydrogen bond and short Cl⋯O contacts of 3.122 (2) Å. In addition, ππ stacking of the benzimidazolone rings is also present, with inter­planar separations of 3.95 (1) Å.

Related literature

For the role of the substituents on the benzene nucleus in anti-HIV-1 compounds, see: Barreca et al. (2007[Barreca, L. M., Rao, A., De Luca, L., Iraci, N., Monforte, A. M., Maga, G., De Clercq, E., Pannecouque, C., Balzarini, J. & Chimirri, A. (2007). Bioorg. Med. Chem. Lett. 17, 1956-1960.]). For related literature, see: Barreca et al. (2005[Barreca, L. M., Rao, A., De Luca, L., Zappala, M., Monforte, A. M., Maga, G., Pannecouque, C., De Clercq, E., Balzarini, J., Chimirri, A. & Monforte, P. (2005). J. Med. Chem. 48, 3433-3437.]); Beddoes et al. (1986[Beddoes, R. L., Dalton, L., Joule, J. A., Mills, O. S., Street, J. D. & Watt, C. I. F. (1986). J. Chem. Soc. Perkin Trans. 2, pp. 787-797.]); Liu et al. (2007[Liu, Y., Gribble, G. W. & Jasinski, J. P. (2007). Acta Cryst. E63, o735-o737.]).

[Scheme 1]

Experimental

Crystal data
  • C15H13ClN2O3S

  • Mr = 336.78

  • Monoclinic, P 21 /c

  • a = 12.173 (3) Å

  • b = 14.036 (3) Å

  • c = 8.949 (2) Å

  • β = 95.77 (2)°

  • V = 1521.3 (6) Å3

  • Z = 4

  • Mo Kα radiation

  • μ = 0.40 mm−1

  • T = 293 (2) K

  • 0.5 × 0.4 × 0.3 mm

Data collection
  • Enraf–Nonius CAD-4 diffractometer

  • Absorption correction: none

  • 3964 measured reflections

  • 3634 independent reflections

  • 3214 reflections with I > 2σ(I)

  • Rint = 0.014

  • 3 standard reflections frequency: 120 min intensity decay: 1%

Refinement
  • R[F2 > 2σ(F2)] = 0.057

  • wR(F2) = 0.133

  • S = 1.19

  • 3634 reflections

  • 199 parameters

  • H-atom parameters constrained

  • Δρmax = 0.23 e Å−3

  • Δρmin = −0.27 e Å−3

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A D—H H⋯A DA D—H⋯A
N2—H2⋯O1i 0.86 2.18 2.852 (3) 135
N2—H2⋯O2i 0.86 2.39 3.075 (3) 138
Symmetry code: (i) [x, -y+{\script{1\over 2}}, z+{\script{1\over 2}}].

Data collection: CAD-4 Software (Enraf–Nonius, 1989[Enraf-Nonius (1989). CAD-4 Software. Enraf-Nonius, Delft, The Netherlands.]); cell refinement: CAD-4 Software; data reduction: XCAD4 (Harms & Wocadlo, 1995[Harms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.]); program(s) used to solve structure: SIR92 (Altomare et al., 1994[Altomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A., Burla, M. C., Polidori, G. & Camalli, M. (1994). J. Appl. Cryst. 27, 435.]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008[Sheldrick, G. M. (2008). Acta Cryst. A64, 112-122.]); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997[Farrugia, L. J. (1997). J. Appl. Cryst. 30, 565.]); software used to prepare material for publication: WinGX (Farrugia, 1999[Farrugia, L. J. (1999). J. Appl. Cryst. 32, 837-838.]).

Supporting information


Comment top

In the course of previous studies on new anti-HIV agents, some of us reported the synthesis and anti-HIV activity of a series of N1-benzyl-1,3-dihydro-2H-benzimidazol-2-ones, a new class of non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) (Barreca et al. 2005). More recently molecular modeling studies led to the discovery of N1-phenylsulfonyl-1,3-dihydro-2H-benzimidazol-2-ones as highly potent NNRTIs active at nanomolar concentration (Barreca et al. 2007). In this paper we report the results of the X-ray structure determination of 6-chloro-1-(3,5-dimethylphenylsulfonyl)-1,3-dihydro-2H-benzimidazol-2-one (I) the most potent derivative of the series, active against wild-type and mutant HIV-1 strains (Barreca et al., 2007). On this respect, its geometrical features defined by X-ray analysis (Fig. 1), could be an useful tool to understand the structure-activity relationship of this class of compounds. The bicyclic part of the molecule consists of an aromatic ring (C2 to C7) and an imidazol-2(3H)-one nucleus approximately planar. This bicyclic fragment makes a dihedral angle of 88 (1)° with the dimethylphenyl ring. Such geometry is in agreement with the best docked conformation previously calculated (Barreca et al., 2007) and match well with the pharmacophoric model proposed for the interactions with the macromolecule. As previously observed in other N-(phenylsulfonyl)indoles (Liu et al., 2007) and N-phenylsulfonamides, (Beddoes et al., 1986) the N atom lone pair eclipses the sulfonyl group; accordingly the corresponding torsion angle O(2)—S(1)—N(1)—C(7) is 48.4 (2)°. In the crystal packing are present two intermolecular hydrogen bonds (Fig. 2) between N2—H2 and O1I at a distance of 2.18 (2) Å, angle 134.2 (2)° and N2—H2 with O2I of 2.39 (2) Å, angle 137.9 (4)°, forming a biforcated linkage with the adjacent molecule at x; 1/2 - y; z + 1/2. The crystal structure is also stabilized by π-π stacking of the benzimidazolone moieties [3.95 (1) Å] and by short intermolecular Cl(1)···O(3)I contacts [3.122 (2) Å].

Related literature top

For the role of the substituents on the benzene nucleus in anti-HIV-1 compounds, see: Barreca et al. (2007). For related literature, see: Barreca et al. (2005); Beddoes et al. (1986); Liu et al. (2007).

Experimental top

The compound I has been synthesized as previously reported (Barreca et al., 2007). Single crystals were obtained at room temperature by slow evaporation of a CHCl3 solution.

Refinement top

All non-H-atoms were refined anisotropically. Hydrogen atoms were introduced at calculated positions, in their described geometries and allowed to ride on the attached carbon atom with fixed isotropic thermal parameters (1.2Ueq and 1.5Ueq of the parent carbon atom for aromatic H-atoms and methyls H-atoms, respectively).

Computing details top

Data collection: CAD-4 Software (Enraf–Nonius, 1989); cell refinement: SHELXL97 (Sheldrick, 2008); data reduction: XCAD4 (Harms & Wocadlo, 1995); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: WinGX (Farrugia, 1999).

Figures top
[Figure 1] Fig. 1. : The molecular structure of the title compound, showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 40% probability level.
[Figure 2] Fig. 2. : Packing diagram of the title compound, showing the intermolecular interactions as dotted lines.
6-Chloro-1-(3,5-dimethylphenylsulfonyl)-1H-benzimidazol-2(3H)-one top
Crystal data top
C15H13ClN2O3SF(000) = 696
Mr = 336.78Dx = 1.470 Mg m3
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybcCell parameters from 25 reflections
a = 12.173 (3) Åθ = 9–10°
b = 14.036 (3) ŵ = 0.40 mm1
c = 8.949 (2) ÅT = 293 K
β = 95.77 (2)°Prism, colourless
V = 1521.3 (6) Å30.5 × 0.4 × 0.3 mm
Z = 4
Data collection top
Enraf–Nonius CAD-4
diffractometer
Rint = 0.014
Radiation source: fine-focus sealed tubeθmax = 28.0°, θmin = 3.3°
Graphite monochromatorh = 1615
Non–profiled ω/2θ scansk = 018
3964 measured reflectionsl = 011
3634 independent reflections3 standard reflections every 120 min
3214 reflections with I > 2σ(I) intensity decay: 1%
Refinement top
Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.057Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.133H-atom parameters constrained
S = 1.19 w = 1/[σ2(Fo2) + (0.0188P)2 + 1.7615P]
where P = (Fo2 + 2Fc2)/3
3634 reflections(Δ/σ)max = 0.003
199 parametersΔρmax = 0.23 e Å3
0 restraintsΔρmin = 0.27 e Å3
Crystal data top
C15H13ClN2O3SV = 1521.3 (6) Å3
Mr = 336.78Z = 4
Monoclinic, P21/cMo Kα radiation
a = 12.173 (3) ŵ = 0.40 mm1
b = 14.036 (3) ÅT = 293 K
c = 8.949 (2) Å0.5 × 0.4 × 0.3 mm
β = 95.77 (2)°
Data collection top
Enraf–Nonius CAD-4
diffractometer
Rint = 0.014
3964 measured reflections3 standard reflections every 120 min
3634 independent reflections intensity decay: 1%
3214 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0570 restraints
wR(F2) = 0.133H-atom parameters constrained
S = 1.19Δρmax = 0.23 e Å3
3634 reflectionsΔρmin = 0.27 e Å3
199 parameters
Special details top

Geometry. All e.s.d.'s (except the e.s.d. in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell e.s.d.'s are taken into account individually in the estimation of e.s.d.'s in distances, angles and torsion angles; correlations between e.s.d.'s in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell e.s.d.'s is used for estimating e.s.d.'s involving l.s. planes.

Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
S10.78957 (6)0.45343 (4)0.18441 (6)0.04124 (17)
Cl10.89540 (9)0.73749 (6)0.67132 (11)0.0776 (3)
O30.81132 (18)0.55252 (13)0.1756 (2)0.0524 (5)
O10.80048 (19)0.25911 (13)0.3298 (2)0.0545 (5)
N20.85398 (19)0.32965 (15)0.5597 (2)0.0426 (5)
H20.86020.28020.61660.051*
N10.83211 (18)0.42285 (14)0.3607 (2)0.0371 (4)
O20.83888 (19)0.38810 (15)0.0896 (2)0.0567 (5)
C20.8705 (2)0.42257 (18)0.6105 (3)0.0387 (5)
C80.6470 (2)0.4341 (2)0.1704 (3)0.0508 (6)
C70.85543 (19)0.48366 (17)0.4866 (2)0.0351 (5)
C10.8269 (2)0.32671 (17)0.4093 (3)0.0417 (5)
C40.9024 (2)0.5555 (2)0.7717 (3)0.0519 (7)
H40.91770.58170.86700.062*
C60.8637 (2)0.58080 (18)0.5011 (3)0.0425 (5)
H60.85470.62150.41880.051*
C30.8955 (2)0.4574 (2)0.7537 (3)0.0464 (6)
H30.90740.41660.83560.056*
C50.8864 (2)0.61419 (19)0.6469 (3)0.0491 (6)
C130.6006 (3)0.3614 (3)0.0822 (4)0.0734 (10)
H130.64520.32040.03340.088*
C90.5842 (3)0.4951 (3)0.2471 (4)0.0671 (9)
H90.61740.54370.30600.081*
C110.4255 (4)0.4091 (4)0.1443 (5)0.0941 (15)
H110.34950.39980.13620.113*
C100.4705 (3)0.4829 (4)0.2352 (5)0.0858 (12)
C120.4884 (4)0.3499 (3)0.0666 (6)0.0954 (15)
C150.4332 (5)0.2721 (4)0.0324 (8)0.152 (2)
H15A0.39280.23050.02740.229*
H15B0.48840.23620.07720.229*
H15C0.38350.30050.10990.229*
C140.4004 (4)0.5506 (5)0.3165 (7)0.1339 (17)
H14A0.44640.58430.39240.201*
H14B0.34540.51520.36260.201*
H14C0.36500.59530.24620.201*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
S10.0549 (4)0.0401 (3)0.0290 (3)0.0002 (3)0.0055 (2)0.0037 (2)
Cl10.1068 (7)0.0451 (4)0.0801 (6)0.0057 (4)0.0058 (5)0.0229 (4)
O30.0702 (13)0.0436 (10)0.0431 (10)0.0050 (9)0.0043 (9)0.0112 (8)
O10.0876 (15)0.0359 (9)0.0394 (10)0.0034 (9)0.0039 (9)0.0019 (8)
N20.0592 (13)0.0362 (10)0.0325 (10)0.0004 (9)0.0044 (9)0.0061 (8)
N10.0522 (12)0.0326 (9)0.0266 (9)0.0025 (8)0.0046 (8)0.0029 (7)
O20.0803 (14)0.0593 (12)0.0319 (9)0.0065 (11)0.0119 (9)0.0046 (8)
C20.0415 (12)0.0424 (13)0.0326 (11)0.0008 (10)0.0060 (9)0.0002 (9)
C80.0551 (16)0.0537 (16)0.0421 (14)0.0006 (13)0.0025 (12)0.0088 (12)
C70.0357 (11)0.0383 (12)0.0316 (11)0.0015 (9)0.0055 (8)0.0022 (9)
C10.0570 (15)0.0357 (12)0.0327 (11)0.0021 (11)0.0068 (10)0.0021 (9)
C40.0551 (16)0.0606 (17)0.0398 (13)0.0041 (13)0.0039 (11)0.0130 (12)
C60.0491 (14)0.0375 (12)0.0410 (13)0.0005 (11)0.0051 (10)0.0003 (10)
C30.0521 (15)0.0540 (15)0.0332 (12)0.0012 (12)0.0040 (10)0.0017 (11)
C50.0524 (15)0.0400 (13)0.0557 (16)0.0051 (11)0.0096 (12)0.0138 (12)
C130.076 (2)0.0580 (19)0.080 (2)0.0021 (17)0.0227 (19)0.0045 (17)
C90.0559 (18)0.089 (3)0.0559 (18)0.0019 (17)0.0029 (14)0.0021 (17)
C110.060 (2)0.121 (4)0.096 (3)0.021 (2)0.016 (2)0.039 (3)
C100.063 (2)0.123 (4)0.072 (2)0.008 (2)0.0080 (19)0.015 (2)
C120.081 (3)0.079 (3)0.117 (4)0.011 (2)0.033 (3)0.016 (3)
C150.138 (5)0.115 (4)0.1860.035 (4)0.075 (4)0.004 (4)
C140.080 (3)0.1850.140 (5)0.021 (4)0.027 (3)0.019 (5)
Geometric parameters (Å, º) top
S1—O31.419 (2)C6—C51.388 (4)
S1—O21.423 (2)C6—H60.9300
S1—N11.6667 (19)C3—H30.9300
S1—C81.749 (3)C13—C121.368 (6)
Cl1—C51.746 (3)C13—H130.9300
O1—C11.210 (3)C9—C101.388 (5)
N2—C11.354 (3)C9—H90.9300
N2—C21.389 (3)C11—C121.367 (7)
N2—H20.8600C11—C101.395 (7)
N1—C71.419 (3)C11—H110.9300
N1—C11.421 (3)C10—C141.512 (7)
C2—C31.376 (3)C12—C151.520 (7)
C2—C71.399 (3)C15—H15A0.9600
C8—C131.375 (4)C15—H15B0.9600
C8—C91.376 (5)C15—H15C0.9600
C7—C61.372 (3)C14—H14A0.9600
C4—C51.385 (4)C14—H14B0.9600
C4—C31.389 (4)C14—H14C0.9600
C4—H40.9300
O3—S1—O2120.41 (13)C4—C3—H3121.1
O3—S1—N1105.25 (11)C4—C5—C6123.8 (3)
O2—S1—N1106.81 (11)C4—C5—Cl1119.1 (2)
O3—S1—C8109.74 (14)C6—C5—Cl1117.1 (2)
O2—S1—C8109.40 (14)C12—C13—C8119.6 (4)
N1—S1—C8103.86 (12)C12—C13—H13120.2
C1—N2—C2111.5 (2)C8—C13—H13120.2
C1—N2—H2124.2C8—C9—C10119.0 (4)
C2—N2—H2124.2C8—C9—H9120.5
C7—N1—C1109.87 (18)C10—C9—H9120.5
C7—N1—S1127.94 (16)C12—C11—C10122.8 (4)
C1—N1—S1120.99 (16)C12—C11—H11118.6
C3—C2—N2130.5 (2)C10—C11—H11118.6
C3—C2—C7121.3 (2)C9—C10—C11117.8 (4)
N2—C2—C7108.2 (2)C9—C10—C14119.5 (5)
C13—C8—C9122.0 (3)C11—C10—C14122.7 (4)
C13—C8—S1120.2 (3)C11—C12—C13118.7 (4)
C9—C8—S1117.7 (2)C11—C12—C15119.7 (5)
C6—C7—C2122.1 (2)C13—C12—C15121.5 (5)
C6—C7—N1132.8 (2)C12—C15—H15A109.5
C2—C7—N1105.1 (2)C12—C15—H15B109.5
O1—C1—N2129.2 (2)H15A—C15—H15B109.5
O1—C1—N1125.6 (2)C12—C15—H15C109.5
N2—C1—N1105.1 (2)H15A—C15—H15C109.5
C5—C4—C3119.6 (2)H15B—C15—H15C109.5
C5—C4—H4120.2C10—C14—H14A109.5
C3—C4—H4120.2C10—C14—H14B109.5
C7—C6—C5115.5 (2)H14A—C14—H14B109.5
C7—C6—H6122.3C10—C14—H14C109.5
C5—C6—H6122.3H14A—C14—H14C109.5
C2—C3—C4117.7 (2)H14B—C14—H14C109.5
C2—C3—H3121.1
Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2···O1i0.862.182.852 (3)135 (1)
N2—H2···O2i0.862.393.075 (3)138 (1)
Symmetry code: (i) x, y+1/2, z+1/2.

Experimental details

Crystal data
Chemical formulaC15H13ClN2O3S
Mr336.78
Crystal system, space groupMonoclinic, P21/c
Temperature (K)293
a, b, c (Å)12.173 (3), 14.036 (3), 8.949 (2)
β (°) 95.77 (2)
V3)1521.3 (6)
Z4
Radiation typeMo Kα
µ (mm1)0.40
Crystal size (mm)0.5 × 0.4 × 0.3
Data collection
DiffractometerEnraf–Nonius CAD-4
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
3964, 3634, 3214
Rint0.014
(sin θ/λ)max1)0.661
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.057, 0.133, 1.19
No. of reflections3634
No. of parameters199
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.23, 0.27

Computer programs: CAD-4 Software (Enraf–Nonius, 1989), SHELXL97 (Sheldrick, 2008), XCAD4 (Harms & Wocadlo, 1995), SIR92 (Altomare et al., 1994), ORTEP-3 for Windows (Farrugia, 1997), WinGX (Farrugia, 1999).

Hydrogen-bond geometry (Å, º) top
D—H···AD—HH···AD···AD—H···A
N2—H2···O1i0.862.182.852 (3)134.8 (9)
N2—H2···O2i0.862.393.075 (3)137.5 (9)
Symmetry code: (i) x, y+1/2, z+1/2.
 

References

First citationAltomare, A., Cascarano, G., Giacovazzo, C., Guagliardi, A., Burla, M. C., Polidori, G. & Camalli, M. (1994). J. Appl. Cryst. 27, 435.  CrossRef Web of Science IUCr Journals Google Scholar
First citationBarreca, L. M., Rao, A., De Luca, L., Iraci, N., Monforte, A. M., Maga, G., De Clercq, E., Pannecouque, C., Balzarini, J. & Chimirri, A. (2007). Bioorg. Med. Chem. Lett. 17, 1956–1960.  Web of Science CrossRef PubMed CAS Google Scholar
First citationBarreca, L. M., Rao, A., De Luca, L., Zappala, M., Monforte, A. M., Maga, G., Pannecouque, C., De Clercq, E., Balzarini, J., Chimirri, A. & Monforte, P. (2005). J. Med. Chem. 48, 3433–3437.  Web of Science CrossRef PubMed CAS Google Scholar
First citationBeddoes, R. L., Dalton, L., Joule, J. A., Mills, O. S., Street, J. D. & Watt, C. I. F. (1986). J. Chem. Soc. Perkin Trans. 2, pp. 787–797.  CSD CrossRef Google Scholar
First citationEnraf–Nonius (1989). CAD-4 Software. Enraf–Nonius, Delft, The Netherlands.  Google Scholar
First citationFarrugia, L. J. (1997). J. Appl. Cryst. 30, 565.  CrossRef IUCr Journals Google Scholar
First citationFarrugia, L. J. (1999). J. Appl. Cryst. 32, 837–838.  CrossRef CAS IUCr Journals Google Scholar
First citationHarms, K. & Wocadlo, S. (1995). XCAD4. University of Marburg, Germany.  Google Scholar
First citationLiu, Y., Gribble, G. W. & Jasinski, J. P. (2007). Acta Cryst. E63, o735–o737.  Web of Science CSD CrossRef IUCr Journals Google Scholar
First citationSheldrick, G. M. (2008). Acta Cryst. A64, 112–122.  Web of Science CrossRef CAS IUCr Journals Google Scholar

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