Download citation
Download citation
link to html
The title compound, C14H11NO4, consists of a methoxy-substituted coumarin skeleton fused to a 2-methyl-4-pyridone ring. The ring system of the mol­ecule is approximately planar and the methoxy group is roughly coplanar with the ring plane. The 4-pyridone ring exists in a 4-hydroxy tautomeric form and is stabilized by an intramolecular hydrogen bond between the O-H and C=O groups. Comparison of the results with those found for other structures containing the 4-pyridone substructure reveals a substantial effect of the nature of the substituents bonded to the pyridine ring on the keto-enol tautomerism.

Supporting information

cif

Crystallographic Information File (CIF) https://doi.org/10.1107/S0108270101002360/av1068sup1.cif
Contains datablocks default1, 2e

hkl

Structure factor file (CIF format) https://doi.org/10.1107/S0108270101002360/av10682esup2.hkl
Contains datablock 2e

CCDC reference: 164658

Comment top

Compounds incorporating the 2H-pyran-2-one moiety, and especially the coumarin substructure, have attracted much attention because of their widespread occurrence in natural products (Dickinson, 1993) and their broad spectrum of biological activities (Patil et al., 1993), the ability to inhibit HIV protease being one of the most important. Following reports (Thaisrivongs et al., 1996) that 3-substituted 4-hydroxypyranones and 4-hydroxycoumarins display potent and selective HIV protease inhibitory activity, we prepared a series of 1,5-dihydro-2-methyl-4H-1-benzopyrano[4,3-b]pyridine-4,5-diones, (1) (Světlík et al., 2000), as potential non-peptidic antiviral agents. As the pyridone ring in (1) is, in principle, able to exist in tautomeric forms (I) and (II), detailed structural information on these heterocycles is indispensable for an analysis of the structure-activity relationships. \sch

To establish the structure of compounds (1), standard spectral methods were first employed. In the 1H NMR spectra, a relatively low-field resonance of the peri-proton H10 (δH 8.13–8.80 p.p.m.) was observed; the downfield shift, as compared with the value reported for the analogously positioned atom H5 (δH 7.46 p.p.m.) in unsubstituted coumarin (Brueger, 1979), is rather unusual and may be due to an anisotropy of the nearby pyridone ring (Světlík et al., 2000). We were also surprised that only the unsubstituted benzopyranopyridine, (1a), and the 8-diethylamino analogue, (1 b), showed two absorption bands for lactone (ca 1720 cm1) and pyridone (ca 1660 cm1) carbonyls in the IR spectra, whereas the remaining derivatives, (1c)-(1f), revealed only single peaks in the range 1683–1697 cm1. To resolve this ambiguity of the spectral data and, at the same time, to determine the precise molecular structures of the compounds, we selected the title compound (1 e), since it was the only derivative which gave good crystals suitable for a single-crystal X-ray analysis.

An ORTEPII (Johnson, 1976) view of the molecule of (1 e) and the atom-numbering scheme are shown in Fig. 1. The 14-atom ring system of the molecule is essentially planar [r.m.s. deviation 0.013 (2) Å], and atoms O4 and O5 are displaced by -0.035 (3) and 0.028 (3) Å, respectively, on opposite sides of the plane [out-of-plane displacements of atoms O7 and C11 are 0.031 (2) and 0.072 (4) Å, respectively]. The C atom of the methoxy group also lies approximately in the ring plane [torsion angle C8—C7—O7—C12 = 11.1 (4)°].

Bond lengths and angles (Table 1) within the 7-methoxycoumarin moiety are normal and agree with those found previously for a vast number of coumarin derivatives, as revealed by a search of the Cambridge Structural Database (CSD; Allen et al., 1983). The coumarin skeleton appears to be rather insensitive to substitutional effects, except for the C4aC10b double bond, which varies in the broad range 1.30–1.41 Å de pending on the groups attached at C4a and/or C10b. This distance in (1 e) is at the upper limit of the range [1.398 (3) Å], obviously due to the fusion of the N-heterocyclic ring.

As to the 4-pyridone ring, which is of prime interest here, the ring clearly occurs in the tautomeric form (II), as evidenced by (i) the position of the acidic H atom, which was found in the Δρ map bonded to O4, not to the N atom, (ii) the pattern of bond orders within the pyridone ring, which are all close to 1.5, as estimated from the bond-length-bond-order curves proposed by Burke-Laing & Laing (1976), and (iii) the C4—O4 bond distance [1.348 (2) Å], which falls in the range normally observed for a hydroxy group bonded to an aromatic carbon (Ulický et al., 1987). Thus, the actual structure of the title compound is (2 e), not (1 e). The OH group is oriented so as to form an intramolecular hydrogen bond with the adjacent carbonyl O5 atom; the details of this O4—H···O5 hydrogen bond are: O—H 0.99, H···O 1.75 and O···O 2.634 (3) Å, and O—H···O 147°.

In order to examine the keto-enol tautomerism in the 4-pyridone system in a more general way, we searched the CSD for compounds containing this molecular fragment (in either keto or enol form) and found the following six structures: 3,5-dichloro-2,6-dimethyl-4-pyridinol [clopidol; hereafter (3)], 2-amino-5-cyano-6-methyl-4(1H)-pyridone, (4), 3-hydroxy-2-methyl-4-pyridinone, (5), 2-(2-butenyl)-3,7-dihydro-3-[methoxy(hydroxy)methyl]-3-methyl-5-phenylfuro- [2,3-b]pyridin-4(2H)-one, (6), 2,3,5,6-tetrachloro-4-hydroxypyridine, (7), and ethyl 5-formyl-4-hydroxy-6-phenylpyridine-2-carboxylate, (8). The central pyridone ring in compounds (3)-(6) exists in the keto form, whereas molecules (7) and (8) have the pyridinol structure.

Comparison of the molecular dimensions in compounds (2 e) and (3)-(8) has revealed that while the corresponding bond lengths and angles in the 4-pyridinol fragment vary in narrow ranges, the opposite is true for molecules (3)-(6) incorporating the pyridone structure. The structural variability of the latter compounds originates from various degrees of π-electron delocalization of the lone pair on the N atom through the π system of the ring up to the carbonyl function, implying that both neutral, (Ia), and zwitterionic, (Ib), canonical forms contribute to the (π) electronic structure of the molecules. The extent of polarization of the π-electron cloud, and hence the relative contribution of (Ia):(Ib), can be estimated from the pattern of bond lengths and angles, and in particular from the endocyclic bond angle at the N atom, α, and the length of the formal CO double bond, d, These two parameters gradually change from 123.0 (6)° and 1.253 (7) Å, respectively, in (3), through 122.8 (3)° and 1.255 (4) Å in (4), and 121.8 (2)° and 1.280 (2) Å in (5), to 114.0 (4)° and 1.329 (4) Å in (6), as the contribution of (Ib) increases. It is interesting to note that for (6), in which the percentage of (Ib) approaches 100%, the values of α and d are similar to those found in the 4-hydroxy tautomers, even though the proton remains bonded to the N atom. Although the keto-enol tautomerism and the proportion of (Ia):(Ib) can be easily monitored by a geometry consideration, the factors (i.e. effects of the nature and position of the substituents) that govern these equilibria are somewhat unclear. For the present molecule the hydroxy tautomer, (2 e), is favoured over the keto isomer, (1 e), on thermodynamic grounds, as shown by both molecular mechanics (MM+ force field; ΔEs = 18.2 kcal mol-1; 1 cal = 4.1868 J) and AM1 quantum chemical (ΔΔHf = 12.4 kcal mol-1) calculations using the HYPERCHEM (Hypercube, 1994) suite of programs.

As mentioned above, another purpose of this structure determination was to provide a clue for resolving the inconsistency of the spectral data on compounds (1) [or (2)]. Although the calculated 13C NMR chemical shift values (ACD CNMR Predictor; Advanced Chemistry Development, 1996) for the critical C4 atoms, i.e. CO and C—OH, are clearly different for the two tautomers (ca 186 versus. 164 p.p.m.), the literature data of some simple pyridines appear not to be useful for resolving the problem. Thus, δC(CO) for N-methyl-4-pyridone is 176.60, δC(C—OH) for 4-hydroxypyridine 175.70, and δC(C-OMe) for 4-methoxypyridine 164.90 p.p.m. (Voegeli & Philipsborn, 1973). All our products consistently showed the corresponding C4 signal at about 165–168 p.p.m. (Světlík et al., 2000), demonstrating that it is somewhat difficult to distinguish between the two isomers on the basis of the 13C NMR data, even though the observed values fit better those calculated for the hydroxy structure, (2). Nevertheless, in the light of the 4-hydroxypyridine structure determined here, the low-field shift of atom H10 mentioned above can be rationalized in terms of a deshielding anisotropic effect induced by the lone pair lying in-plane on the adjacent sp2 nitrogen. On the other hand, the observed single absorption band near 1690 cm-1 can be assigned to a stretching vibration of the coumarin carbonyl, the frequency of which is lowered due to the intramolecular hydrogen bonding with the neighbouring hydroxy function.

As the only hydrogen-bond donor of the molecule is involved in intramolecular hydrogen bonding, the crystal packing is governed by van der Waals forces.

Related literature top

For related literature, see: Advanced (1996); Allen et al. (1983); Brueger (1979); Burke-Laing & Laing (1976); Dickinson (1993); Hypercube (1994); Johnson (1976); Patil et al. (1993); Světlík et al. (2000); Thaisrivongs et al. (1996); Ulický et al. (1987); Voegeli & von Philipsborn (1973).

Experimental top

The synthesis of the title product, (2 e), was described previously by Světl\'k et al. (2000). In short, to a solution of 4-hydroxy-6-methyl-2H-pyran-2-one (0.60 g, 4.75 mmol) and 2-hydroxy-3-methoxybenzaldehyde (0.72 g, 4.75 mmol) in acetic acid (15 ml) was added ammonium acetate (0.70 g, 9.0 mmol), and the mixture was refluxed for 15 h. After cooling, the crystallized product was collected by concentration of the mixture and finally crystallized from acetonitrile to afford colourless crystals of (2 e) (0.42 g, 32% yield, m.p. 480–481 K).

Refinement top

H atoms were located from a difference Fourier map but were refined as riding atoms, with Uiso set to 1.2 (1.5 for the methyl H atoms) times Ueq of the parent atom.

Computing details top

Data collection: XSCANS (Siemens, 1991); cell refinement: XSCANS; data reduction: XSCANS; program(s) used to solve structure: SHELXS97 (Sheldrick, 1990); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97.

Figures top
[Figure 1] Fig. 1. A view of the molecule of (2 e) showing the atom-labelling scheme. Displacement ellipsoids are shown at the 35% probability level and H atoms are drawn as small spheres of arbitrary radii.
4-hydroxy-7-methoxy-2-methyl-5H-1-benzopyrano[4,3-b]pyridin-5-one top
Crystal data top
C14H11NO4Dx = 1.452 Mg m3
Dm = 1.45 (1) Mg m3
Dm measured by flotation in bromoform/c-hexane
Mr = 257.24Melting point: 480 K
Monoclinic, P21/cMo Kα radiation, λ = 0.71073 Å
a = 7.333 (3) ÅCell parameters from 25 reflections
b = 9.389 (4) Åθ = 7–21°
c = 17.161 (7) ŵ = 0.11 mm1
β = 95.05 (4)°T = 293 K
V = 1176.9 (8) Å3Plate, colourless
Z = 40.35 × 0.30 × 0.10 mm
F(000) = 536
Data collection top
Siemens P4
diffractometer
Rint = 0.045
Radiation source: fine-focus sealed tubeθmax = 27.5°, θmin = 2.4°
Graphite monochromatorh = 91
ω/2θ scansk = 112
3692 measured reflectionsl = 2222
2698 independent reflections3 standard reflections every 97 reflections
1543 reflections with I > 2σ(I) intensity decay: 2%
Refinement top
Refinement on F20 restraints
Least-squares matrix: fullH-atom parameters constrained
R[F2 > 2σ(F2)] = 0.054 w = 1/[σ2(Fo2) + (0.1035P)2 + 0.1985P]
where P = (Fo2 + 2Fc2)/3
wR(F2) = 0.150(Δ/σ)max = 0.001
S = 1.02Δρmax = 0.25 e Å3
2698 reflectionsΔρmin = 0.32 e Å3
172 parameters
Crystal data top
C14H11NO4V = 1176.9 (8) Å3
Mr = 257.24Z = 4
Monoclinic, P21/cMo Kα radiation
a = 7.333 (3) ŵ = 0.11 mm1
b = 9.389 (4) ÅT = 293 K
c = 17.161 (7) Å0.35 × 0.30 × 0.10 mm
β = 95.05 (4)°
Data collection top
Siemens P4
diffractometer
Rint = 0.045
3692 measured reflections3 standard reflections every 97 reflections
2698 independent reflections intensity decay: 2%
1543 reflections with I > 2σ(I)
Refinement top
R[F2 > 2σ(F2)] = 0.0540 restraints
wR(F2) = 0.150H-atom parameters constrained
S = 1.02Δρmax = 0.25 e Å3
2698 reflectionsΔρmin = 0.32 e Å3
172 parameters
Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å2) top
xyzUiso*/Ueq
N10.8137 (3)0.0282 (2)0.10363 (10)0.0390 (5)
C20.8672 (3)0.0677 (3)0.15599 (13)0.0426 (6)
C30.8833 (3)0.2119 (3)0.14082 (14)0.0460 (6)
C40.8497 (3)0.2642 (2)0.06828 (14)0.0423 (6)
O40.8688 (3)0.40450 (18)0.05292 (11)0.0609 (6)
C4a0.7956 (3)0.1664 (2)0.01198 (12)0.0358 (5)
C50.7589 (3)0.2162 (2)0.06476 (13)0.0413 (6)
O50.7743 (3)0.33918 (18)0.08727 (11)0.0618 (6)
O60.7034 (2)0.11987 (17)0.11734 (9)0.0439 (5)
C6a0.6821 (3)0.0229 (2)0.09770 (13)0.0362 (5)
C70.6264 (3)0.1114 (3)0.15770 (13)0.0414 (6)
O70.6004 (3)0.0459 (2)0.22669 (9)0.0536 (5)
C80.6026 (4)0.2551 (3)0.14168 (15)0.0483 (6)
C90.6362 (4)0.3100 (3)0.06881 (16)0.0488 (6)
C100.6929 (3)0.2227 (2)0.01079 (14)0.0425 (6)
C10a0.7169 (3)0.0762 (2)0.02503 (12)0.0347 (5)
C10b0.7776 (3)0.0230 (2)0.03319 (12)0.0334 (5)
C110.9114 (4)0.0071 (3)0.23303 (14)0.0565 (7)
C120.5763 (5)0.1362 (4)0.29246 (17)0.0751 (10)
HO40.85310.41490.00330.073*
H30.91560.28090.18060.055*
H80.56270.31460.18040.058*
H90.61700.41150.06170.058*
H100.72070.26070.03870.051*
H11A0.95870.08120.26720.086*
H11B1.01840.05400.22920.086*
H11C0.80320.00870.26310.086*
H12A0.44850.20380.27890.112*
H12B0.55790.07630.33560.112*
H12C0.68320.20080.30310.112*
Atomic displacement parameters (Å2) top
U11U22U33U12U13U23
N10.0399 (11)0.0431 (11)0.0349 (10)0.0021 (9)0.0078 (8)0.0028 (8)
C20.0389 (12)0.0552 (14)0.0346 (11)0.0015 (11)0.0080 (9)0.0007 (10)
C30.0474 (14)0.0499 (14)0.0423 (13)0.0047 (11)0.0134 (11)0.0094 (10)
C40.0432 (13)0.0365 (12)0.0483 (13)0.0016 (10)0.0097 (10)0.0049 (10)
O40.0872 (15)0.0371 (10)0.0618 (12)0.0078 (9)0.0255 (11)0.0041 (8)
C4a0.0387 (12)0.0352 (11)0.0343 (10)0.0037 (9)0.0076 (9)0.0024 (9)
C50.0506 (14)0.0353 (12)0.0394 (12)0.0029 (10)0.0119 (10)0.0012 (9)
O50.0978 (16)0.0371 (10)0.0542 (11)0.0059 (10)0.0278 (11)0.0089 (8)
O60.0625 (11)0.0360 (8)0.0356 (8)0.0014 (8)0.0167 (8)0.0006 (6)
C6a0.0390 (12)0.0328 (11)0.0379 (11)0.0038 (9)0.0086 (9)0.0021 (9)
C70.0413 (13)0.0465 (13)0.0378 (11)0.0061 (10)0.0114 (10)0.0086 (10)
O70.0705 (12)0.0568 (11)0.0361 (9)0.0061 (9)0.0191 (8)0.0079 (8)
C80.0485 (14)0.0472 (14)0.0501 (14)0.0007 (11)0.0104 (11)0.0154 (11)
C90.0502 (15)0.0355 (12)0.0615 (16)0.0018 (11)0.0101 (12)0.0051 (11)
C100.0468 (14)0.0364 (12)0.0447 (12)0.0013 (10)0.0064 (10)0.0013 (10)
C10a0.0347 (11)0.0353 (11)0.0344 (11)0.0030 (9)0.0050 (9)0.0016 (9)
C10b0.0317 (11)0.0359 (11)0.0330 (11)0.0037 (9)0.0051 (8)0.0002 (8)
C110.0560 (16)0.079 (2)0.0363 (12)0.0015 (14)0.0120 (11)0.0047 (12)
C120.108 (3)0.074 (2)0.0482 (15)0.0243 (19)0.0347 (17)0.0258 (14)
Geometric parameters (Å, º) top
N1—C10b1.349 (3)O7—C121.435 (3)
N1—C21.354 (3)C8—C91.395 (4)
C2—C31.382 (4)C9—C101.382 (3)
C2—C111.501 (3)C10—C10a1.405 (3)
C3—C41.380 (3)C10a—C10b1.463 (3)
C4—O41.348 (3)C3—H30.985
C4—C4a1.415 (3)O4—HO40.987
C4a—C10b1.398 (3)C8—H80.934
C4a—C51.445 (3)C9—H90.969
C5—O51.220 (3)C10—H100.960
C5—O61.365 (3)C11—H11A0.992
O6—C6a1.387 (3)C11—H11B0.970
C6a—C10a1.388 (3)C11—H11C0.920
C6a—C71.411 (3)C12—H12A1.138
C7—O71.363 (3)C12—H12B0.948
C7—C81.385 (4)C12—H12C0.995
C10b—N1—C2116.7 (2)O6—C6a—C7115.18 (19)
N1—C2—C3123.5 (2)C10a—C6a—C7122.0 (2)
N1—C2—C11115.5 (2)O7—C7—C8126.0 (2)
C3—C2—C11121.1 (2)O7—C7—C6a116.0 (2)
C4—C3—C2119.9 (2)C8—C7—C6a118.0 (2)
O4—C4—C3120.0 (2)C7—O7—C12116.9 (2)
O4—C4—C4a122.1 (2)C7—C8—C9120.6 (2)
C3—C4—C4a117.9 (2)C10—C9—C8121.0 (2)
C10b—C4a—C4118.2 (2)C9—C10—C10a119.8 (2)
C10b—C4a—C5121.88 (19)C6a—C10a—C10118.6 (2)
C4—C4a—C5119.9 (2)C6a—C10a—C10b118.3 (2)
O5—C5—O6116.3 (2)C10—C10a—C10b123.0 (2)
O5—C5—C4a125.1 (2)N1—C10b—C4a123.70 (19)
O6—C5—C4a118.6 (2)N1—C10b—C10a118.75 (19)
C5—O6—C6a120.87 (17)C4a—C10b—C10a117.55 (19)
O6—C6a—C10a122.77 (19)
C10b—N1—C2—C30.8 (3)C8—C7—O7—C1211.1 (4)
C10b—N1—C2—C11178.4 (2)C6a—C7—O7—C12169.1 (2)
N1—C2—C3—C42.1 (4)O7—C7—C8—C9179.1 (2)
C11—C2—C3—C4177.1 (2)C6a—C7—C8—C91.2 (4)
C2—C3—C4—O4178.7 (2)C7—C8—C9—C100.4 (4)
C2—C3—C4—C4a1.3 (4)C8—C9—C10—C10a0.1 (4)
O4—C4—C4a—C10b179.4 (2)O6—C6a—C10a—C10179.5 (2)
C3—C4—C4a—C10b0.6 (3)C7—C6a—C10a—C101.0 (3)
O4—C4—C4a—C50.0 (4)O6—C6a—C10a—C10b0.3 (3)
C3—C4—C4a—C5180.0 (2)C7—C6a—C10a—C10b178.8 (2)
C10b—C4a—C5—O5179.0 (2)C9—C10—C10a—C6a0.2 (4)
C4—C4a—C5—O51.7 (4)C9—C10—C10a—C10b179.6 (2)
C10b—C4a—C5—O60.7 (4)C2—N1—C10b—C4a1.2 (3)
C4—C4a—C5—O6178.7 (2)C2—N1—C10b—C10a179.2 (2)
O5—C5—O6—C6a179.8 (2)C4—C4a—C10b—N11.9 (3)
C4a—C5—O6—C6a0.1 (3)C5—C4a—C10b—N1178.7 (2)
C5—O6—C6a—C10a0.6 (3)C4—C4a—C10b—C10a178.4 (2)
C5—O6—C6a—C7179.2 (2)C5—C4a—C10b—C10a0.9 (3)
O6—C6a—C7—O70.2 (3)C6a—C10a—C10b—N1179.24 (19)
C10a—C6a—C7—O7178.7 (2)C10—C10a—C10b—N10.5 (3)
O6—C6a—C7—C8179.9 (2)C6a—C10a—C10b—C4a0.4 (3)
C10a—C6a—C7—C81.5 (4)C10—C10a—C10b—C4a179.8 (2)

Experimental details

Crystal data
Chemical formulaC14H11NO4
Mr257.24
Crystal system, space groupMonoclinic, P21/c
Temperature (K)293
a, b, c (Å)7.333 (3), 9.389 (4), 17.161 (7)
β (°) 95.05 (4)
V3)1176.9 (8)
Z4
Radiation typeMo Kα
µ (mm1)0.11
Crystal size (mm)0.35 × 0.30 × 0.10
Data collection
DiffractometerSiemens P4
diffractometer
Absorption correction
No. of measured, independent and
observed [I > 2σ(I)] reflections
3692, 2698, 1543
Rint0.045
(sin θ/λ)max1)0.650
Refinement
R[F2 > 2σ(F2)], wR(F2), S 0.054, 0.150, 1.02
No. of reflections2698
No. of parameters172
H-atom treatmentH-atom parameters constrained
Δρmax, Δρmin (e Å3)0.25, 0.32

Computer programs: XSCANS (Siemens, 1991), XSCANS, SHELXS97 (Sheldrick, 1990), SHELXL97 (Sheldrick, 1997), ORTEPII (Johnson, 1976), SHELXL97.

Selected geometric parameters (Å, º) top
N1—C10b1.349 (3)C4a—C51.445 (3)
N1—C21.354 (3)C5—O51.220 (3)
C2—C31.382 (4)C5—O61.365 (3)
C3—C41.380 (3)O6—C6a1.387 (3)
C4—O41.348 (3)C6a—C10a1.388 (3)
C4—C4a1.415 (3)C10a—C10b1.463 (3)
C4a—C10b1.398 (3)
C10b—N1—C2116.7 (2)C10b—C4a—C4118.2 (2)
N1—C2—C3123.5 (2)O6—C5—C4a118.6 (2)
C4—C3—C2119.9 (2)C5—O6—C6a120.87 (17)
C3—C4—C4a117.9 (2)N1—C10b—C4a123.70 (19)
C8—C7—O7—C1211.1 (4)
 

Follow Acta Cryst. C
Sign up for e-alerts
Follow Acta Cryst. on Twitter
Follow us on facebook
Sign up for RSS feeds