N-(4-Chloro­pyridin-2-yl)-N-(4-methyl­phenyl­sulfon­yl)acetamide

Stefanie Bühler; Dieter Schollmeyer; Wolfgang Albrecht; Stefan Laufer

doi:10.1107/S1600536810048324

. 2010 Nov 27;66(Pt 12):o3320. doi: 10.1107/S1600536810048324

N-(4-Chloropyridin-2-yl)-N-(4-methylphenylsulfonyl)acetamide

Stefanie Bühler ^a, Dieter Schollmeyer ^b, Wolfgang Albrecht ^c, Stefan Laufer ^a,^*

PMCID: PMC3011710 PMID: 21589597

Abstract

The crystal structure of the title compound, C₁₄H₁₃ClN₂O₃S, features a three-dimensional network stabilized by intermolecular C—H⋯O hydrogen bonds between the molecules. The 4-methylphenylsulfonyl ring forms a dihedral angle of 30.6 (1)° with the 4-chloropyridine ring.

Related literature

For the biological activity of 2-alkylaminopyridinyl or 2-acylaminopyridinyl imidazole derivatives as p38α MAPK inhibitors, see: Laufer et al. (2008 ▶, 2010 ▶); Ziegler et al. (2009 ▶). For general background to protecting groups, see: Kocieński (2005 ▶). For the preparation of the N-protected 4-chloropyridine, see: Berliner & Belecki (2005 ▶); Sciotti et al. (2005 ▶); Shi & Wang (2002 ▶).

Experimental

Crystal data

C₁₄H₁₃ClN₂O₃S
M _r = 324.77
Orthorhombic,
a = 12.578 (2) Å
b = 7.5460 (8) Å
c = 30.194 (3) Å
V = 2865.7 (7) Å³
Z = 8
Cu Kα radiation
μ = 3.83 mm⁻¹
T = 193 K
0.35 × 0.35 × 0.25 mm

Data collection

Enraf–Nonius CAD-4 diffractometer
Absorption correction: ψ scan (CORINC; Dräger & Gattow, 1971 ▶) T _min = 0.872, T _max = 0.997
5291 measured reflections
2713 independent reflections
2412 reflections with I > 2σ(I)
R _int = 0.079
3 standard reflections every 60 min intensity decay: 2%

Refinement

R[F ² > 2σ(F ²)] = 0.049
wR(F ²) = 0.129
S = 1.13
2713 reflections
193 parameters
H-atom parameters constrained
Δρ_max = 0.44 e Å⁻³
Δρ_min = −0.33 e Å⁻³

Data collection: CAD-4 Software (Enraf–Nonius, 1989 ▶); cell refinement: CAD-4 Software; data reduction: CORINC (Dräger & Gattow, 1971 ▶); program(s) used to solve structure: SIR97 (Altomare et al., 1999 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: PLATON (Spek, 2009 ▶); software used to prepare material for publication: PLATON.

Supplementary Material

Crystal structure: contains datablocks I, global. DOI: 10.1107/S1600536810048324/bt5410sup1.cif

e-66-o3320-sup1.cif^{(18.6KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536810048324/bt5410Isup2.hkl

e-66-o3320-Isup2.hkl^{(133.3KB, 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
C3—H3⋯O13ⁱ	0.95	2.46	3.404 (3)	174
C14—H14B⋯O10ⁱⁱ	0.98	2.50	3.170 (4)	126
C18—H18⋯O9ⁱⁱⁱ	0.95	2.46	3.334 (3)	152

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

Acknowledgments

The authors would like to thank the Federal Ministry of Education and Research, Germany, Merckle GmbH, Ulm, Germany and Fonds der Chemischen Industrie, Germany for their generous support of this work.

supplementary crystallographic information

Comment

In recent years, compounds with the 2-aminopyridine moiety exhibited interesting biological activities like the 2-alkylaminopyridinyl or 2-acylaminopyridinyl imidazole derivatives as p38α mitogen-activated protein kinase (p38α MAPK) inhibitors. The N-protected 4-chloropyridine is an important precursor to block the nucleophilic and basic properties of the amino-group in the C2 position of the pyridine ring. The analysis of the crystal structure shows that the aromatic C18—H-group of the 4-chloropyridine ring of one molecule interacts with the oxygen-atom O9 of the sulfonyl group of another molecule related to the first by centre of symmetry with a distance of H18···O9 2.47 Å. Furthermore, the aromatic C3—H group of the 4-methylphenylsulfonyl ring forms an intermolecular C3—H3···O13_a hydrogen bond (2.46 Å) to the oxygen atom O13 of the acetamide moiety of a third molecule. An additional hydrogen bond was observed between the methyl-group C14—H₃ of the acetamide moiety and the oxygen-atom O10 of the sulfonyl group of a further molecule, whereas the O10···H14B distance is 2.50 Å. The dihedral angle between the 4-methylphenylsulfonyl ring and the 4-chloropyridine ring is 30.6 (1)°.

Experimental

Synthesis of chloromethyl methyl ether as a solution of toluene: To a solution of dimethoxymethane (44.3 ml, 0.50 mol, 1 equiv) and Zn(OAc)₂ (9.2 mg, 0.01%) in toluene (133 ml) was added acetyl chloride (35.5 ml, 0.50 mol, 1 equiv). During the next 15 min, the reaction mixture warmed slowly at T = 318 K, and then cooled to ambient temperature over 3 h. The progress was again monitored until NMR analysis indicated complete conversion. The solution of MOMCl in toluene prepared using this stoichiometry is approximately 2.1 M.

Synthesis of N-(4-chloropyridin-2-yl)-4-methylbenzenesulfonamide: 2-Amino- 4-chloropyridine (20.1 g, 156 mmol. 1 equiv) and 4-toluenesulfonyl chloride (32.4 g, 168 mmol, 1.1 equiv) were dissolved in dry pyridine (70 ml) and heated at T = 353 K for 5 h. After cooling to room temperature, water was added and the compound N-(4-chloropyridin-2-yl)-4-methylbenzenesulfonamide dropped down as a beige solid with high analytical quality, which was filtered off and washed with water (30.6 g, 70.8%).

Synthesis of N-(4-chloropyridin-2-yl)-N-tosylacetamide: Under a nitrogen atmosphere, N-(4-chloropyridin-2-yl)-4-methylbenzene-sulfonamide (20.0 g, 71 mmol, 1 equiv) was added to a suspension of NaH (4.2 g, 104 mmol, 1.5 equiv) in anhydrous THF (200 ml) with stirring. The resulting reaction mixture was stirred for 20 min, and then the solution of methoxymethyl chloride in toluene (52.1 ml, 1.5 equiv) was slowly added. The mixture was stirred for 3 h and then an aqueous saturated solution of NH₄Cl was added. After separation, the aqueous layer was extracted with EtOAc, dried over Na₂SO₄and evaporated. After treatment with hexane, the compound N-(4-chloropyridin-2-yl)- N-(methoxymethyl)-4-methylbenzenesulfonamide was obtained as the main product of the reaction (15.8 g, 69.7%) and dropped down as a pale yellow solid, whereas the compound N-(4-chloropyridin-2-yl)-N-tosylacetamide was isolated from the filtrate as the byproduct (15.4%). Suitable crystals of the byproduct N-(4-chloropyridin-2-yl)-N-tosylacetamide for X-ray were obtained by slow evaporation at T = 298 K of a solution mixture of EtOAc/hexane.