1-Amino-6-chloro-2-(1H-pyrrol-2-yl)­benz­imidazole (RS 1350)

The title compound (RS 1350), C₁₁H₉ClN₄, was recently synthesized by a Smiles rearrangement of 1-[(5-chloro-2-nitro­phenyl)­sulfonyl]-1H-pyrrole-2-carbohydrazide or 1-(5-chloro-2-nitro­phenyl)-1H-pyrrole-2-carbohydrazide in pow­der­ed iron-glacial acetic acid medium. From the crystallographic analysis, it is observed that, in the title compound, the benz­imidazole moiety is planar and forms a dihedral angle of 3.8 (2)° with the pyrrole ring. The near planarity of the two rings indicates an extended conjugation.

Key indicators

• Single-crystal X-ray study
• T = 293 K
• Mean [sigma](C-C) = 0.006 Å
• R factor = 0.042
• wR factor = 0.070
• Data-to-parameter ratio = 8.2

checkCIF results

No syntax errors found

ADDSYM reports no extra symmetry


 Alert Level C:



REFNR_01  Alert C Ratio of reflections to parameters is < 10 for a
          centrosymmetric structure
          sine(theta)/lambda                0.8085
          Proportion of unique data used    0.2557
          Ratio reflections to parameters   8.2345

PLAT_420  Alert C D-H Without Acceptor       N(2)   -   H(1B)             ?


 0 Alert Level A = Potentially serious problem

 0 Alert Level B = Potential problem

 2 Alert Level C = Please check

---

S1. Comment

HIV-1 Reverse transcriptase (RT), the enzyme which catalyses the transcription of viral single-stranded RNA into double-stranded DNA, is the most investigated target in searching for anti-AIDS drugs. In the last decade, many RT inhibitors were synthesized and some were selected as lead compounds for clinical trials (Artico, 1996; Pedersen et al., 1999). Two classes of RT inhibitors were identified (Vandamme et al., 1998). The nucleoside analogues (NRTIs) act as competitive inhibitors or DNA chain terminator. The non-nucleoside analogues (NNRTIs) are allosteric inhibitors of the RT enzyme which bind to an hydrophobic pocket in the enzyme-DNA complex close to the active site (Spence et al., 1995; Vandamme et al., 1998; De Clercq, 1998). Despite their different structures, NNRTIs adopt a common `butterfly-like' active conformation, having two π-electron-donor regions between a lipophilic site (Schaefer et al., 1993). The major problem related to NNRTIs concerns the rapid development of mutations in the RT, with failure of therapy. The synthesis of NNRTIs active on a wide panel of viral resistant mutants useful in anti-AIDS drug combination strategies is a very actual goal. Our engagement in the field of anti-AIDS chemotherapy (Silvestri et al., 1994, 1995, 1997, 1998; Silvestri, Artico et al., 2000; Silvestri, Pifferi et al., 2000; Artico et al., 1994, 1995, 2000; Artico, Silvestri, Massa et al., 1996; Artico, Silvestri, Pagnozzi, Stefancich, Massa & La Colla, 1996; Ettorre et al., 2001) led to the discovery of the pyrrolo[1,2-b][1,2,5]benzothiadiazepin-10(11H)ones (PBTDs), a novel class of NNRTIs endowed with anti-HIV-1 RT activity comparable with that of nevirapine (Artico, Silvestri, Pagnozzi, Stefancich, Massa, Loi et al., 1996). Pursuing our research on novel PBTDs active toward resistant mutants, we planned the synthesis of 7-chloro-11-hydrazinopyrrolo[1,2-b][1,2,5]benzothiadiazepin-10(11H)one 5,5-dioxide, (IV), by iron powder–acetic acid reduction of 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide, (II) (Silvestri, Pifferi et al., 2000). Unexpectedly instead of (IV), the reaction furnished 1-amino-6-chloro-2-(1H-pyrrol-2-yl)benzimidazole, (I), as the sole product. We supposed that (II) underwent Smiles rearrangement to give (I). In fact, 1-[(5-chloro-2-nitrophenyl)sulfonyl]-1H-pyrrole-2-carbohydrazide, (II), possesses the structural features required to achieve Smiles rearrangement, i.e. (i) a strongly electron-withdrawing ortho-nitro group activating the aromatic ring; (ii) the sulfonyl group as a good leaving group; (iii) the nucleofilicity; (iv) the acidity of CONHNH₂ entering group (Truce et al., 1971).

We decided to confirm unambiguously the structure of (I) by the crystallographic analysis here reported. The benzimidazole moiety is planar, with Cl1 and N2 deviating from it by -0.030 (2) and 0.038 (3) Å, respectively. The angle between the planar benzimidazole moiety and the pyrrole ring is 3.8 (2)°. No unusual feactures were found in the geometry of the rings. The near planarity of the benzimidazole and the pyrrol rings indicate extended conjugation. The NH₂ group adopts a pyramidal configuration.

S2. Experimental

The title compound was synthesized according to Silvestri, Pifferi et al. (2000).

S3. Refinement

The crystal diffracted quite weakly at room temperature which reduced the number of reflections with significant intensities. The position of the H atoms were calculated geometrically at a distance of 0.96 Å from the corrosponding C or N atom, and a riding model was used during their refinement.

Computing details

Data collection: R3m/V (Siemens, 1989); cell refinement: R3m/V; data reduction: XDISK (Siemens, 1989); program(s) used to solve structure: SIR97 (Altomare et al., 1999); program(s) used to refine structure: CAOS (Camalli & Spagna, 1994); molecular graphics: CAOS; software used to prepare material for publication: CAOS.

Figures

Fig. 1. The molecular structure of (I). Displacement ellipsoids are shown at the 50% probability level.

(I)

Crystal data

C11H9ClN4	Dx = 1.460 Mg m^−3
Mr = 232.67	Mo Kα radiation, λ = 0.71069 Å
Orthorhombic, Pbca	Cell parameters from 32 reflections
a = 10.065 (2) Å	θ = 2.9–16.0°
b = 23.178 (4) Å	µ = 0.34 mm^−1
c = 9.077 (3) Å	T = 293 K
V = 2117.5 (9) Å^3	Prism, brown
Z = 8	0.3 × 0.2 × 0.15 mm
F(000) = 960

Data collection

Siemens P3 automatic four circle diffractometer	Rint = 0.063
Radiation source: X-ray tube	θmax = 35.1°, θmin = 1.8°
Graphite monochromator	h = 0→16
θ/2θ scans	k = 0→37
5213 measured reflections	l = 0→14
4669 independent reflections	3 standard reflections every 97 reflections
1194 reflections with F > 3σ(F)	intensity decay: none

Refinement

Refinement on F	145 parameters
Least-squares matrix: Full	H-atom parameters constrained
R[F^2 > 2σ(F^2)] = 0.042	w = 1/(0.2 + F + 0.0792F^2)
wR(F^2) = 0.070	(Δ/σ)max = 0.001
S = 0.97	Δρmax = 0.26 e Å^−3
1194 reflections	Δρmin = −0.24 e Å^−3

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Ų)

	x	y	z	Uiso*/Ueq
Cl1	0.8484 (1)	0.2755 (1)	0.2733 (2)	0.0703 (5)
N1	0.6985 (3)	0.0643 (1)	0.1606 (3)	0.036 (1)
N2	0.7708 (3)	0.0462 (2)	0.0358 (3)	0.045 (1)
N3	0.5533 (3)	0.0591 (1)	0.3468 (4)	0.041 (1)
N4	0.6142 (4)	−0.0547 (2)	0.0682 (4)	0.048 (1)
C1	0.6053 (4)	0.0316 (2)	0.2325 (4)	0.036 (1)
C2	0.7060 (4)	0.1169 (2)	0.2311 (4)	0.036 (1)
C3	0.6153 (4)	0.1128 (2)	0.3482 (4)	0.039 (1)
C4	0.7788 (4)	0.1668 (2)	0.2034 (4)	0.044 (1)
C5	0.7592 (4)	0.2115 (2)	0.3006 (5)	0.047 (1)
C6	0.6718 (4)	0.2087 (2)	0.4191 (5)	0.048 (1)
C7	0.5993 (4)	0.1592 (2)	0.4451 (4)	0.044 (1)
C8	0.5653 (4)	−0.0262 (2)	0.1893 (4)	0.039 (1)
C9	0.4711 (4)	−0.0606 (2)	0.2537 (5)	0.046 (1)
C10	0.4638 (5)	−0.1115 (2)	0.1688 (5)	0.053 (1)
C11	0.5529 (5)	−0.1064 (2)	0.0557 (5)	0.055 (2)
H1a	0.8641	0.0477	0.0574	0.046*
H1b	0.7514	0.0716	−0.0449	0.046*
H4n	0.6815	−0.0402	0.0030	0.048*
H4c	0.8387	0.1699	0.1216	0.044*
H6	0.6620	0.2414	0.4831	0.048*
H7	0.5394	0.1566	0.5271	0.045*
H9	0.4200	−0.0517	0.3401	0.047*
H10	0.4067	−0.1438	0.1875	0.052*
H11	0.5681	−0.1346	−0.0199	0.057*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
Cl1	0.0788 (9)	0.0509 (6)	0.0812 (9)	−0.0224 (6)	−0.0011 (7)	−0.0001 (6)
N1	0.032 (1)	0.041 (2)	0.036 (2)	0.004 (1)	0.004 (1)	−0.001 (1)
N2	0.041 (2)	0.057 (2)	0.036 (2)	0.001 (2)	0.009 (1)	−0.002 (2)
N3	0.038 (2)	0.042 (2)	0.041 (2)	0.000 (1)	0.004 (2)	−0.000 (1)
N4	0.047 (2)	0.051 (2)	0.047 (2)	0.004 (2)	0.005 (2)	−0.005 (2)
C1	0.032 (2)	0.038 (2)	0.036 (2)	0.000 (1)	−0.003 (2)	0.003 (2)
C2	0.034 (2)	0.040 (2)	0.034 (2)	0.003 (1)	−0.000 (2)	0.003 (2)
C3	0.035 (2)	0.042 (2)	0.038 (2)	0.002 (2)	0.001 (2)	0.001 (2)
C4	0.037 (2)	0.050 (2)	0.043 (2)	−0.002 (2)	−0.001 (2)	0.005 (2)
C5	0.045 (2)	0.041 (2)	0.056 (2)	−0.008 (2)	−0.011 (2)	0.002 (2)
C6	0.054 (3)	0.042 (2)	0.049 (2)	−0.001 (2)	−0.008 (2)	−0.004 (2)
C7	0.042 (2)	0.051 (2)	0.040 (2)	0.005 (2)	−0.002 (2)	−0.006 (2)
C8	0.041 (2)	0.037 (2)	0.039 (2)	0.004 (1)	−0.004 (2)	−0.001 (2)
C9	0.048 (2)	0.041 (2)	0.049 (2)	−0.003 (2)	−0.000 (2)	0.003 (2)
C10	0.058 (3)	0.038 (2)	0.062 (3)	−0.003 (2)	−0.013 (2)	0.005 (2)
C11	0.064 (3)	0.044 (2)	0.058 (3)	0.006 (2)	−0.005 (2)	−0.007 (2)

Geometric parameters (Å, º)

Cl1—C5	1.751 (4)	C3—C7	1.399 (6)
N1—N2	1.411 (4)	C4—C5	1.376 (6)
N1—C1	1.372 (5)	C4—H4c	0.96
N1—C2	1.380 (5)	C5—C6	1.391 (6)
N2—H1a	0.96	C6—C7	1.380 (6)
N2—H1b	0.96	C6—H6	0.96
N3—C1	1.326 (5)	C7—H7	0.96
N3—C3	1.391 (5)	C8—C9	1.370 (6)
N4—C8	1.374 (5)	C9—C10	1.411 (6)
N4—C11	1.354 (6)	C9—H9	0.96
N4—H4n	0.96	C10—C11	1.367 (7)
C1—C8	1.452 (5)	C10—H10	0.96
C2—C3	1.405 (5)	C11—H11	0.96
C2—C4	1.390 (5)
N2—N1—C1	124.8 (3)	Cl1—C5—C6	118.2 (3)
C2—N1—C1	107.8 (3)	C4—C5—C6	123.5 (4)
C2—N1—N2	127.4 (3)	C4—C5—Cl1	118.3 (3)
H1a—N2—H1b	109.5	H6—C6—C5	119.7
N1—N2—H1b	109.0	C7—C6—C5	120.3 (4)
N1—N2—H1a	109.3	C7—C6—H6	119.9
C1—N3—C3	105.1 (3)	H7—C7—C3	120.7
H4n—N4—C11	125.4	C6—C7—C3	118.1 (4)
C8—N4—C11	109.2 (4)	C6—C7—H7	121.1
C8—N4—H4n	125.3	C1—C8—N4	124.1 (3)
N1—C1—C8	124.8 (3)	C9—C8—N4	108.1 (3)
N3—C1—C8	123.1 (3)	C9—C8—C1	127.8 (4)
N3—C1—N1	112.1 (3)	C10—C9—H9	126.7
N1—C2—C3	104.7 (3)	C8—C9—H9	126.5
C4—C2—C3	122.4 (3)	C8—C9—C10	106.8 (4)
C4—C2—N1	132.8 (3)	H10—C10—C9	126.0
C2—C3—N3	110.2 (3)	C11—C10—C9	107.8 (4)
C7—C3—N3	129.9 (3)	C11—C10—H10	126.3
C7—C3—C2	119.8 (4)	C10—C11—N4	108.2 (4)
H4c—C4—C2	122.3	H11—C11—N4	126.1
C5—C4—C2	115.8 (4)	H11—C11—C10	125.7
C5—C4—H4c	121.9