tert-Butyl 2-(3-acetyl­amino-2-oxo-1,2-dihydro-1-pyrid­yl)acetate

N David Karis; Wendy A Loughlin; Ian D Jenkins; Peter C Healy

doi:10.1107/S1600536808039810

. 2008 Nov 29;64(Pt 12):o2492–o2493. doi: 10.1107/S1600536808039810

tert-Butyl 2-(3-acetylamino-2-oxo-1,2-dihydro-1-pyridyl)acetate

N David Karis ^a, Wendy A Loughlin ^b, Ian D Jenkins ^a, Peter C Healy ^b,^*

PMCID: PMC2959903 PMID: 21581454

Abstract

The title compound, C₁₃H₁₈N₂O₄, crystallizes as discrete molecules associated as N—H⋯O hydrogen-bonded dimers disposed about a crystallographic inversion centre. The structure is the first solid-state structure for a 3-acetylpyridone without C-4 to C-6 substituents. The amide subsituent at C-3 is coplanar with the pyridone ring, while the tert-butyl ester group is orthogonal to the pyridine ring. The amide and ester carbonyl O atoms are not involved in strong hydrogen bonding with only a number of intramolecular and intermolecular C—H⋯O interactions apparent in the structure.

Related literature

For general background, see: Bernstein et al. (1994 ▶); Dragovich et al. (2002 ▶); Hu et al. (2008 ▶); Karis et al. (2007 ▶); Kim et al. (2008 ▶); Loughlin et al. (2004 ▶); Reiner et al. (1999 ▶); Semple et al. (1998 ▶); Veale et al. (1995 ▶). For the synthesis, see: Sanderson et al. (1997 ▶); Tamura et al. (1996 ▶). For related structures. see: Karis et al. (2006 ▶); Yang & Craven (1998 ▶).

Experimental

Crystal data

C₁₃H₁₈N₂O₄
M _r = 266.29
Monoclinic,
a = 13.9417 (15) Å
b = 5.585 (1) Å
c = 17.861 (2) Å
β = 97.039 (9)°
V = 1380.3 (3) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 295 (2) K
0.40 × 0.30 × 0.20 mm

Data collection

Rigaku AFC-7R diffractometer
Absorption correction: none
2731 measured reflections
2428 independent reflections
1482 reflections with I > 2σ(I)
R _int = 0.046
3 standard reflections every 150 reflections intensity decay: 0.6%

Refinement

R[F ² > 2σ(F ²)] = 0.052
wR(F ²) = 0.162
S = 1.02
2428 reflections
176 parameters
H-atom parameters constrained
Δρ_max = 0.27 e Å⁻³
Δρ_min = −0.27 e Å⁻³

Data collection: MSC/AFC7 Diffractometer Control Software (Molecular Structure Corporation, 1999 ▶); cell refinement: MSC/AFC7 Diffractometer Control Software; data reduction: TEXSAN for Windows (Molecular Structure Corporation, 2001 ▶); program(s) used to solve structure: TEXSAN for Windows; program(s) used to refine structure: TEXSAN for Windows and SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 (Farrugia, 1997 ▶); software used to prepare material for publication: TEXSAN for Windows and PLATON (Spek, 2003 ▶).

Supplementary Material

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536808039810/bt2816sup1.cif

e-64-o2492-sup1.cif^{(21.8KB, cif)}

Structure factors: contains datablocks I. DOI: 10.1107/S1600536808039810/bt2816Isup2.hkl

e-64-o2492-Isup2.hkl^{(116.9KB, 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—H3⋯O2ⁱ	0.86	2.34	3.164 (3)	161
C4—H4⋯O3	0.95	2.23	2.830 (3)	120
C14—H14A⋯O3ⁱⁱ	0.96	2.56	3.465 (4)	157
C15—H15A⋯O11	0.96	2.44	2.980 (4)	115
C16—H16A⋯O11	0.96	2.44	2.978 (5)	115
C32—H32C⋯O2ⁱ	0.96	2.33	3.222 (3)	155

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

Acknowledgments

We acknowledge financial support of this work by Griffith University, Eskitis Institute for Cell and Molecular Therapies, Griffith University, and Natural Product Discovery, Griffith University. We also thank Alan White for professional support in this work.

supplementary crystallographic information

Comment

Increased binding affinity of pyridone based scaffolds as P4—P2 conformational restraints (Dragovich et al., 2002; Reiner et al., 1999; Semple et al., 1998; Veale et al., 1995; Bernstein et al., 1994) in peptidiomimetics (Loughlin et al., 2004, and references therein) is often associated with the substituent functionality at N1 and C3 of the pyridone ring. This has been reflected by enzyme-ligand crystal structures of a C3-amidoaryl pyridone with human rhinovirus (HRV) 3 C protease (3CP) (Dragovich et al., 2002), and a C3-sulfonylamide pyridone with porcine pancreatic elastase (Bernstein et al., 1994). Similiarly, other enzyme-ligand interactions have been observed in the solid state with kinases; a N1-aryl pyridone with Met kinase (Kim et al., 2008) and a N1-aryl C3-aryl pyridone with KDR kinase (Hu et al., 2008). Thus an understanding of the structure of substituted pyridone compounds is important. Elsewhere, the facile synthesis of N1, C3-substituted pyridones is reported (Karis et al., 2007). Herein we report the first solid state structure (II) for a 3-acetylpyridone without C4 to C6 substituents.

The structure of (II) consists of discrete molecular units (Fig. 1) which form N3—H3···O2 hydrogen bonded dimers disposed about a crystallographic centre of symmetry (Figure 2, Table 1). The amide N3—C31—O3—C32 is co-planar with the pyridone ring with the O3···H4 contact distance 2.23 Å. The tert-butyl ester group attached to N1 lies orthogonal to the pyridone ring with the C2—N1—C11—C12 torsion angle -81.1 (2)°. The geometry of the pyridone ring is in accord with related structures (Yang & Craven, 1998; Karis et al., 2006) with the C2—C3 distance 1.440 (3)Å while the other C—C and C—N distance range from 1.333 (4) - 1.402 (4) Å. The N3—C31 distance of 1.362 (3)Å is shorter than the N3—C3 distance of 1.399 (3) Å; indicating a preference for involvement of N3 in conjugation with the amide rather than the pyridone. The carbonyl groups C31—O3 and C21—O11 are not involved in strong hydrogen bonding interactions with only a number of C—H···O interactions apparent in the crystal lattice (Table 2).

Experimental

Tert-Butyl 2-(3'-amino-2'-oxopyridin-1'(2H)-yl)acetate (compound (I)) was prepared by N-alkylation of nitropyridone with sodium hydride and tert-butyl bromoacetate (Sanderson et al., 1997; Tamura et al., 1996), and subsequent hydrogenation over palladium-on-carbon (Tamura et al., 1996).

For the preparation of compound (II), compound (I) (0.78 g, 3.48 mmol) was dissolved in a mixture of dry dichloromethane (10 ml) and triethylamine (0.97 ml, 6.96 mmol) under nitrogen. Acetyl chloride (0.50 ml, 6.96 mmol) was added dropwise at 295 K. The resulting mixture was stirred for 4 h and then concentrated to give a suspension of the product and triethylamine hydrochloride. The suspension was directly transferred to a silica gel column using dichloromethane with 0.5% triethylamine and eluted with an ethyl acetate /dichloromethane gradient (0 to 20% ethyl acetate, with 0.5% triethyl amine. Red crystals of (II) (m.p. 415–418 K) (0.91 g, 98%) were isolated by slow evaporation from an ethyl acetate /dichloromethane solution. Analysis found: C 58.73, H 6.84, N 10.36%; calculated for C₁₃H₁₈N₂O₄: C 58.64, H 6.81, N 10.52%. ν_max(KBr) cm^-1 3318, 2974, 1716, 1646, 1605, 1532, 1512. δ_H (400 MHz, CDCl₃, p.p.m.) 1.49 (9H, s, C(CH₃)₃), 2.19 (3H, s, CH₃), 4.58 (2H, s, H2), 6.27 (1H, dd, J = 7.0, 7.0 Hz, H5'), 6.92 (1H, dd, J = 7.0, 1.6 Hz, H6'), 8.35 (1H, brs, W_h1/2 = 11 Hz, NH), 8.39 (1H, dd, J = 7.2, 1.6 Hz, H4'). δ_C (100 MHz, CDCl₃) 24.7 (CH₃), 28.0 (C(CH₃)₃), 51.6 (C2), 83.1 (C(CH₃)₃), 106.8 (C5'), 122.4 (C4'), 129.3 (C3'), 130.2 (C6'), 157.4 (C2'), 166.2 (C1), 169.0 (CO). MS (ES⁺) 289.2 (MNa⁺, 30%) 273.2 (MLi⁺, 40%).