(±)-Methyl and (±)-ethyl 4-(2,3-di­fluoro­phen­yl)-2,6,6-trimethyl-5-oxo-1,4,5,6,7,8-hexa­hydro­quinoline-3-carboxyl­ate

The title compounds, C₂₀H₂₁F₂NO₃ and C₂₁H₂₃F₂NO₃, respectively, belong to a class of 1,4-dihydro­pyridines whose members sometimes display calcium modulatory properties. The 1,4-dihydro­pyridine rings have the usual shallow boat conformation. In each structure, the 2,3-difluoro­phenyl ring is oriented such that the fluoro substituents are in a synperi­planar orientation with respect to the 1,4-dihydro­pyridine ring plane and the oxocyclo­hexene ring has a slightly distorted envelope conformation. Both structures exhibit the same inter­molecular N-H...O hydrogen-bonding motif, in which the mol­ecules are linked into chains by inter­actions involving the carbonyl O atom of the oxocyclo­hexene ring.

S1. Comment

1,4-Dihydropyridine (1,4-DHP) derivatives have yielded many drugs that act as calcium channel agonists. Nifedipine is the prototype of this group, and both it and its structural analogues are used as antianginal and antihypertensive drugs (Janis & Triggle, 1984). Many active derivatives have been synthesized by making various modifications to the nifedipine structure, which yield compounds with calcium agonist or antagonist properties (Rose, 1989, 1990). It is thought that the activity displayed by these compounds may be influenced by their stereochemistry (Langs & Triggle, 1985). Our interest is in the structure and calcium antagonistic behaviour of condensed derivatives of 1,4-DHP (Şimşek et al., 2003; Kısmetli et al., 2004). The crystal structures of some of these derivatives have already been reported (Linden et al., 1998, 2002, 2004; Şimşek et al., 2000) and the title compounds, (I) and (II), respectively, have been prepared as further potentially active 1,4-DHP derivatives. Their structures were confirmed by IR, ¹H NMR and ¹³C NMR spectra, mass spectrometry and elemental analyses. Details of the antagonistic activities of these and related compounds will be published elsewhere. The determination of the three-dimensional conformations of the title compounds, presented here, is important in order to obtain further insight into the structure–activity relationships of these compounds.

The switch from the methyl ester in compound (I) to the corresponding ethyl ester in compound (II) has no major influence on the conformations of the molecules. The 1,4-DHP rings (Figs. 1 and 2, respectively) have shallow boat conformations. In (I), atoms N1 and C4 are 0.159 (2) and 0.348 (2) Å, respectively, from the plane defined by atoms C2, C3, C4A and C8A. The corresponding displacements in compound (II) are 0.142 (1) and 0.287 (1) Å, respectively. The shallowness of the boat is indicated by the ring-puckering parameters (Cremer & Pople, 1975). For compound (I), Q = 0.2986 (15) Å, θ = 75.4 (3)° and ϕ₂ = 183.5 (3)° for the atom sequence N1—C2—C3—C4—C4A—C8A. For the corresponding atom sequence in compound (II), Q = 0.2507 (13) Å, θ = 76.7 (3)° and ϕ₂ = 182.8 (3)°. For an ideal boat, θ and ϕ₂ are 90° and n × 60°, respectively. The conformations of 4-aryl-1,4-DHP rings have been discussed previously (Goldmann & Stoltefuss, 1991; Linden et al. 1998, 2002; Şimşek et al., 2000) and it is usual for the ring to have a shallow boat conformation, although considerable variation in the shallowness of the boat is evident. The displacement of atom C4 from the base of the boat in (I) and (II) corresponds with the values of around 0.30 Å found most frequently for this atom in 1,4-DHP rings (Şimşek et al., 2000). The deviations shown by atom N1 are generally smaller and spread fairly evenly over the range 0.00–0.19 Å (Linden et al., 2000, 2002). The deviation shown by atom N1 in (I) and (II) falls well within this range. In contrast, the 1,4-DHP ring in N,N-diethyl-2,6,6-trimethyl-4-(3-nitrophenyl)-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxamide was found to be completely planar (Linden et al., 2002).

Another measure of the planarity of 1,4-DHP rings is the sum of the magnitudes of the six intraring torsion angles, P, around the ring (Fossheim et al., 1988). For compounds (I) and (II), P is 101.8 (5) and 85.5 (5)°, respectively, which demonstrates that the boat conformations are somewhat deeper than usual. A mean value of 77 (2)° was found previously for reported 1,4-DHP rings (Linden et al., 2002), although the P values generally vary over a wide range from 4 to 130°. For nifedipine itself, P is 72° (Miyamae et al., 1986).

The plane of the 2,3-difluorophenyl ring in each of the title compounds deviates just slightly from being parallel to the N1···C4 axis. Compound (I) has a N1···C4—C13—C18 torsion angle of 12.19 (16)°, while the corresponding torsion angle, N1···C4—C14—C19, in compound (II) is 14.26 (15)°. These values are quite normal. The corresponding torsion angle in related structures is clustered around 0° and rarely exceeds ±30° (Linden et al., 2002). The fluoro substituents lie above the C4—H bond in a synperiplanar orientation and not over the 1,4-DHP ring, which, because of the substituent in the 2-position of the phenyl ring, would be sterically unfavourable.

The Cambridge Structural Database (CSD; Release 5.26 with August 2005 updates; Allen, 2002) contains only five examples of 4-aryl-1,4-DHP compounds with 2,3-disubstitution in the phenyl ring. Three of these compounds are 4-(2,3-dichlorophenyl)-2,6-dimethyl-3,5-dicarboxy-1,4-DHP derivatives (Fossheim, 1986; Lamm et al., 1989; Caignan & Holt, 2000), while there is one 4-(2-chloro-3-nitrophenyl)- (Rovnyak et al., 1988) and one 4-(2,3-methylenedioxyphenyl)- analogue (Fonseca et al., 1986). In each of these compounds, the 2,3-disubstituted phenyl ring has a synperiplanar orientation, similar to that found in compounds (I) and (II), and the 1,4-DHP ring has a shallow boat conformation. The 1,4-DHP ring in compound (I) actually has the most pronounced boat conformation of all of these compounds.

The oxocyclohexene ring in each of the title compounds has a slightly distorted C7-envelope conformation, as demonstrated by the ring puckering parameters (Cremer & Pople, 1975). For compound (I), Q = 0.4832 (17) Å, θ = 59.10 (19)° and ϕ₂ = 173.9 (2)° for the atom sequence C4A—C5—C6—C7—C8—C8A. Atom C7 is 0.658 (2) Å from the plane defined by atoms C4A, C5, C6, C8 and C8A. The maximum deviation of these latter five atoms from their mean plane is 0.043 (1) Å for atom C8A. For the corresponding atom sequence in compound (II), Q = 0.4448 (15) Å, θ = 62.18 (18)° and ϕ₂ = 185.2 (2)°, atom C7 is 0.606 (1) Å from the plane defined by the remaining ring atoms, and the maximum deviation of these latter five atoms from their mean plane is 0.051 (1) Å for atom C5. In both structures, atom C7 of the ring flips up on the same side of the oxocyclohexene ring plane as the 2,3-difluorophenyl substituent of the adjacent 1,4-DHP ring. It has been found that atom C7 is always the out-of-plane atom in structures involving the 5-oxoquinoline or 1,8-dioxoacridine moiety and that the side of the oxocyclohexene ring to which C7 deviates is, in the majority, but not all, of these structures, the same as that in (I) and (II) (Linden et al., 2002).

Most of the bond lengths and angles in (I) and (II) have normal values. There are small angular distortions about atoms C2 and C10 (Tables 1 and 3) which result from steric interactions between the methyl substituent at C2 and atom O1O of the ester substituent at C3 [O10···C9 = 2.8248 (19) and 2.8736 (19) Å for (I) and (II), respectively)]. The presence of π-electron conjugation keeps the ester group at C3 almost coplanar [C2═C3—C10═O10 = −10.6 (2) and 4.4 (2)° for (I) and (II), respectively] with the endocyclic double bond and prevents the ester group from rotating into a sterically more amenable orientation. These properties are consistent with those of the related compound, methyl 4-(2-chloro-5-nitrophenyl)-2,7,7-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate (Linden et al., 2004), and the many other 2-methyl-3-carboxy-4-aryl-1,4-DHP compounds archived in the CSD.

In compounds (I) and (II), an intermolecular hydrogen bond between the amine group and the carbonyl O atom of the oxocyclohexene ring of a neighbouring molecule (Tables 2 and 4) links the molecules into extended chains which run parallel to the [100] direction and can be described by a graph-set motif of C(6) (Bernstein et al., 1995). The same C(6) motif has been observed in the crystal structures of several other closely related 1,4-DHP compounds (Linden et al., 1998, 2002, 2004; Şimşek et al., 2000).

S2. Experimental

For the synthesis of the title compounds, equimolar amounts of 2,3-difluorobenzaldehyde, 4,4-dimethylcyclohexanedione and methyl acetoacetate [for (I)] or ethyl acetoacetate [for (II)], together with ammonia (1 ml), were refluxed in methanol for 6 h. The solution was then poured into water, and the precipitate was filtered, dried and recrystallized from ethanol (m.p. 519 and 484 K, respectively).

S3. Refinement

For each structure, the position of the amine H atom was determined from a difference Fourier map and refined freely along with its isotropic displacement parameter. The methyl H atoms were constrained to an ideal geometry with C—H = 0.98 Å and U_iso(H) = 1.5U_eq(C), but were allowed to rotate freely about the C—C bonds. All remaining H atoms were placed in geometrically idealized positions (C—H = 0.95–1.00 Å) and constrained to ride on their parent atoms with U_iso(H) = 1.2U_eq(C). For (I) and (II), four and two low angle reflections, respectively, were omitted from the final cycles of refinement because their observed intensities were much lower than the calculated values as a result of being partially obscured by the beam stop.

Computing details

For both compounds, data collection: COLLECT (Nonius, 2000); cell refinement: DENZO-SMN (Otwinowski & Minor, 1997); data reduction: DENZO-SMN and SCALEPACK (Otwinowski & Minor, 1997); program(s) used to solve structure: SIR92 (Altomare et al., 1994); program(s) used to refine structure: SHELXL97 (Sheldrick, 1997); molecular graphics: ORTEPII (Johnson, 1976); software used to prepare material for publication: SHELXL97 and PLATON (Spek, 2003).

Figures

	Fig. 1. View of the molecule of (I), showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. View of the molecule of (II) showing the atom-labelling scheme. Displacement ellipsoids are drawn at the 50% probability level.

(I) (±)-methyl 4-(2,3-difluorophenyl)-2,6,6-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

Crystal data

C20H21F2NO3	Z = 2
Mr = 361.39	F(000) = 380
Triclinic, P1	Dx = 1.403 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 7.2055 (2) Å	Cell parameters from 4905 reflections
b = 9.6702 (4) Å	θ = 2.0–30.0°
c = 12.9606 (6) Å	µ = 0.11 mm^−1
α = 93.9639 (19)°	T = 160 K
β = 92.624 (2)°	Prism, colourless
γ = 107.904 (2)°	0.27 × 0.22 × 0.20 mm
V = 855.15 (6) Å^3

Data collection

Nonius KappaCCD area-detector diffractometer	3409 reflections with I > 2σ(I)
Radiation source: Nonius FR590 sealed tube generator	Rint = 0.053
Horizontally mounted graphite crystal monochromator	θmax = 30.0°, θmin = 3.0°
Detector resolution: 9 pixels mm^-1	h = 0→10
ϕ and ω scans with κ offsets	k = −13→12
21670 measured reflections	l = −18→18
4980 independent reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.053	Hydrogen site location: geom & difmap
wR(F^2) = 0.137	H atoms treated by a mixture of independent and constrained refinement
S = 1.05	w = 1/[σ^2(Fo^2) + (0.0583P)^2 + 0.1694P] where P = (Fo^2 + 2Fc^2)/3
4976 reflections	(Δ/σ)max = 0.001
243 parameters	Δρmax = 0.32 e Å^−3
0 restraints	Δρmin = −0.27 e Å^−3

Special details

Experimental. Solvent used: EtOH Cooling Device: Oxford Cryosystems Cryostream 700 Crystal mount: glued on a glass fibre Mosaicity (°.): 0.573 (2) Frames collected: 406 Seconds exposure per frame: 10 Degrees rotation per frame: 2.0 Crystal-Detector distance (mm): 35.0

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 (Ų)

	x	y	z	Uiso*/Ueq
F1	0.55963 (12)	0.41606 (10)	0.29982 (7)	0.0313 (2)
F2	0.55884 (13)	0.30670 (10)	0.48190 (7)	0.0348 (2)
O5	0.60328 (14)	0.73105 (11)	0.24549 (8)	0.0258 (2)
O10	−0.09097 (16)	0.21379 (12)	0.02186 (9)	0.0356 (3)
O11	0.22881 (14)	0.27902 (11)	0.06998 (8)	0.0273 (3)
N1	−0.07918 (17)	0.60996 (13)	0.19709 (10)	0.0228 (3)
H1	−0.187 (3)	0.641 (2)	0.2032 (14)	0.043 (5)*
C2	−0.0968 (2)	0.47989 (15)	0.13909 (11)	0.0208 (3)
C3	0.05715 (19)	0.42745 (15)	0.13928 (11)	0.0201 (3)
C4	0.24052 (19)	0.50149 (15)	0.21054 (11)	0.0193 (3)
H4	0.3569	0.4945	0.1739	0.023*
C4a	0.2606 (2)	0.66214 (15)	0.23426 (11)	0.0197 (3)
C5	0.4540 (2)	0.76767 (15)	0.25426 (11)	0.0195 (3)
C6	0.4723 (2)	0.92792 (15)	0.28174 (12)	0.0229 (3)
C7	0.2881 (2)	0.93810 (17)	0.33260 (13)	0.0271 (3)
H71	0.2822	0.8962	0.4004	0.033*
H72	0.2964	1.0420	0.3454	0.033*
C8	0.1023 (2)	0.85787 (16)	0.26556 (13)	0.0274 (3)
H81	−0.0131	0.8554	0.3050	0.033*
H82	0.0957	0.9104	0.2033	0.033*
C8a	0.0982 (2)	0.70525 (15)	0.23318 (11)	0.0214 (3)
C9	−0.2905 (2)	0.41411 (17)	0.07901 (12)	0.0259 (3)
H91	−0.2700	0.3808	0.0086	0.039*
H92	−0.3585	0.4875	0.0758	0.039*
H93	−0.3698	0.3311	0.1134	0.039*
C10	0.0510 (2)	0.29734 (15)	0.07182 (11)	0.0222 (3)
C12	0.2413 (2)	0.16022 (17)	0.00046 (13)	0.0309 (4)
H121	0.1659	0.0675	0.0254	0.046*
H122	0.3784	0.1638	−0.0024	0.046*
H123	0.1881	0.1684	−0.0690	0.046*
C13	0.2361 (2)	0.42794 (15)	0.31152 (11)	0.0198 (3)
C14	0.3958 (2)	0.39328 (15)	0.35196 (11)	0.0220 (3)
C15	0.3952 (2)	0.33561 (16)	0.44632 (12)	0.0248 (3)
C16	0.2364 (2)	0.30959 (17)	0.50472 (12)	0.0285 (4)
H16	0.2385	0.2720	0.5704	0.034*
C17	0.0721 (2)	0.33991 (18)	0.46493 (13)	0.0297 (4)
H17	−0.0412	0.3208	0.5031	0.036*
C18	0.0724 (2)	0.39750 (17)	0.37044 (12)	0.0259 (3)
H18	−0.0417	0.4171	0.3446	0.031*
C19	0.6511 (2)	1.00115 (18)	0.35628 (14)	0.0357 (4)
H191	0.7688	0.9937	0.3244	0.054*
H192	0.6372	0.9526	0.4207	0.054*
H193	0.6623	1.1042	0.3717	0.054*
C20	0.4957 (3)	1.00363 (18)	0.18072 (14)	0.0343 (4)
H201	0.4846	1.1017	0.1937	0.051*
H202	0.3932	0.9468	0.1284	0.051*
H203	0.6242	1.0107	0.1556	0.051*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.0243 (5)	0.0426 (6)	0.0328 (5)	0.0172 (4)	0.0055 (4)	0.0086 (4)
F2	0.0344 (5)	0.0418 (6)	0.0352 (6)	0.0222 (4)	−0.0048 (4)	0.0070 (4)
O5	0.0191 (5)	0.0238 (5)	0.0351 (6)	0.0085 (4)	0.0008 (4)	0.0002 (5)
O10	0.0258 (6)	0.0310 (6)	0.0452 (7)	0.0067 (5)	−0.0083 (5)	−0.0119 (5)
O11	0.0223 (5)	0.0258 (6)	0.0330 (6)	0.0089 (4)	−0.0011 (4)	−0.0081 (5)
N1	0.0166 (6)	0.0238 (6)	0.0293 (7)	0.0085 (5)	0.0017 (5)	0.0006 (5)
C2	0.0190 (7)	0.0225 (7)	0.0203 (7)	0.0047 (6)	0.0030 (5)	0.0047 (6)
C3	0.0195 (7)	0.0205 (7)	0.0194 (7)	0.0051 (6)	0.0014 (5)	0.0018 (6)
C4	0.0169 (7)	0.0204 (7)	0.0208 (7)	0.0064 (5)	0.0005 (5)	0.0000 (6)
C4a	0.0188 (7)	0.0201 (7)	0.0208 (7)	0.0074 (6)	0.0009 (5)	0.0012 (6)
C5	0.0197 (7)	0.0210 (7)	0.0183 (7)	0.0076 (6)	−0.0005 (5)	0.0017 (6)
C6	0.0216 (7)	0.0204 (7)	0.0270 (8)	0.0074 (6)	0.0007 (6)	0.0000 (6)
C7	0.0276 (8)	0.0225 (8)	0.0318 (9)	0.0093 (6)	0.0029 (6)	−0.0019 (6)
C8	0.0216 (7)	0.0233 (8)	0.0398 (9)	0.0110 (6)	0.0033 (6)	0.0001 (7)
C8a	0.0195 (7)	0.0219 (7)	0.0224 (7)	0.0057 (6)	0.0024 (6)	0.0024 (6)
C9	0.0188 (7)	0.0288 (8)	0.0292 (8)	0.0061 (6)	0.0004 (6)	0.0030 (7)
C10	0.0203 (7)	0.0219 (7)	0.0238 (8)	0.0057 (6)	−0.0004 (6)	0.0028 (6)
C12	0.0311 (8)	0.0271 (8)	0.0350 (9)	0.0132 (7)	−0.0033 (7)	−0.0092 (7)
C13	0.0209 (7)	0.0168 (7)	0.0207 (7)	0.0053 (5)	−0.0009 (5)	−0.0013 (5)
C14	0.0204 (7)	0.0202 (7)	0.0255 (8)	0.0070 (6)	0.0015 (6)	−0.0005 (6)
C15	0.0264 (8)	0.0221 (7)	0.0283 (8)	0.0124 (6)	−0.0053 (6)	0.0004 (6)
C16	0.0351 (9)	0.0291 (8)	0.0224 (8)	0.0110 (7)	0.0015 (6)	0.0055 (6)
C17	0.0281 (8)	0.0322 (9)	0.0293 (9)	0.0087 (7)	0.0060 (7)	0.0059 (7)
C18	0.0221 (7)	0.0283 (8)	0.0282 (8)	0.0091 (6)	0.0002 (6)	0.0035 (6)
C19	0.0300 (9)	0.0276 (9)	0.0469 (11)	0.0101 (7)	−0.0089 (7)	−0.0117 (8)
C20	0.0410 (9)	0.0262 (8)	0.0391 (10)	0.0132 (7)	0.0102 (8)	0.0087 (7)

Geometric parameters (Å, º)

F1—C14	1.3540 (16)	C8—C8a	1.497 (2)
F2—C15	1.3607 (16)	C8—H81	0.9900
O5—C5	1.2388 (16)	C8—H82	0.9900
O10—C10	1.2155 (17)	C9—H91	0.9800
O11—C10	1.3474 (16)	C9—H92	0.9800
O11—C12	1.4379 (18)	C9—H93	0.9800
N1—C8a	1.3651 (18)	C12—H121	0.9800
N1—C2	1.3878 (18)	C12—H122	0.9800
N1—H1	0.915 (19)	C12—H123	0.9800
C2—C3	1.3537 (19)	C13—C14	1.3842 (19)
C2—C9	1.499 (2)	C13—C18	1.401 (2)
C3—C10	1.470 (2)	C14—C15	1.378 (2)
C3—C4	1.5253 (19)	C15—C16	1.369 (2)
C4—C4a	1.5234 (19)	C16—C17	1.390 (2)
C4—C13	1.5292 (19)	C16—H16	0.9500
C4—H4	1.0000	C17—C18	1.380 (2)
C4a—C8a	1.3570 (19)	C17—H17	0.9500
C4a—C5	1.452 (2)	C18—H18	0.9500
C5—C6	1.5296 (19)	C19—H191	0.9800
C6—C19	1.525 (2)	C19—H192	0.9800
C6—C20	1.535 (2)	C19—H193	0.9800
C6—C7	1.535 (2)	C20—H201	0.9800
C7—C8	1.520 (2)	C20—H202	0.9800
C7—H71	0.9900	C20—H203	0.9800
C7—H72	0.9900
C10—O11—C12	115.61 (11)	C2—C9—H92	109.5
C8a—N1—C2	122.11 (12)	H91—C9—H92	109.5
C8a—N1—H1	117.6 (12)	C2—C9—H93	109.5
C2—N1—H1	119.6 (12)	H91—C9—H93	109.5
N1—C2—C3	119.21 (13)	H92—C9—H93	109.5
N1—C2—C9	113.94 (12)	O10—C10—O11	121.76 (13)
C3—C2—C9	126.83 (13)	O10—C10—C3	126.97 (13)
C2—C3—C10	120.94 (13)	O11—C10—C3	111.28 (12)
C2—C3—C4	120.62 (12)	O11—C12—H121	109.5
C10—C3—C4	118.44 (11)	O11—C12—H122	109.5
C3—C4—C4a	109.74 (11)	H121—C12—H122	109.5
C4a—C4—C13	109.92 (11)	O11—C12—H123	109.5
C3—C4—C13	111.54 (11)	H121—C12—H123	109.5
C4a—C4—H4	108.5	H122—C12—H123	109.5
C3—C4—H4	108.5	C14—C13—C18	116.31 (13)
C13—C4—H4	108.5	C14—C13—C4	122.08 (12)
C8a—C4a—C5	120.92 (13)	C18—C13—C4	121.57 (12)
C4—C4a—C8a	119.69 (12)	F1—C14—C15	117.50 (12)
C5—C4a—C4	119.36 (11)	F1—C14—C13	120.73 (13)
O5—C5—C4a	121.20 (12)	C15—C14—C13	121.77 (13)
O5—C5—C6	119.80 (12)	F2—C15—C16	119.98 (13)
C4a—C5—C6	118.94 (12)	F2—C15—C14	118.42 (13)
C19—C6—C5	110.60 (12)	C16—C15—C14	121.59 (13)
C19—C6—C20	109.23 (13)	C15—C16—C17	117.95 (14)
C5—C6—C20	107.55 (12)	C15—C16—H16	121.0
C19—C6—C7	109.27 (13)	C17—C16—H16	121.0
C5—C6—C7	109.55 (12)	C18—C17—C16	120.50 (14)
C20—C6—C7	110.63 (12)	C18—C17—H17	119.8
C8—C7—C6	112.17 (13)	C16—C17—H17	119.8
C8—C7—H71	109.2	C17—C18—C13	121.85 (13)
C6—C7—H71	109.2	C17—C18—H18	119.1
C8—C7—H72	109.2	C13—C18—H18	119.1
C6—C7—H72	109.2	C6—C19—H191	109.5
H71—C7—H72	107.9	C6—C19—H192	109.5
C8a—C8—C7	110.47 (12)	H191—C19—H192	109.5
C8a—C8—H81	109.6	C6—C19—H193	109.5
C7—C8—H81	109.6	H191—C19—H193	109.5
C8a—C8—H82	109.6	H192—C19—H193	109.5
C7—C8—H82	109.6	C6—C20—H201	109.5
H81—C8—H82	108.1	C6—C20—H202	109.5
C4a—C8a—N1	120.38 (13)	H201—C20—H202	109.5
C4a—C8a—C8	123.26 (13)	C6—C20—H203	109.5
N1—C8a—C8	116.30 (12)	H201—C20—H203	109.5
C2—C9—H91	109.5	H202—C20—H203	109.5
C8a—N1—C2—C3	16.7 (2)	C5—C4a—C8a—C8	−8.3 (2)
C8a—N1—C2—C9	−161.59 (13)	C4—C4a—C8a—C8	173.82 (13)
N1—C2—C3—C10	−174.48 (12)	C2—N1—C8a—C4a	−15.2 (2)
C9—C2—C3—C10	3.6 (2)	C2—N1—C8a—C8	162.02 (13)
N1—C2—C3—C4	6.1 (2)	C7—C8—C8a—C4a	−19.8 (2)
C9—C2—C3—C4	−175.77 (13)	C7—C8—C8a—N1	163.05 (13)
C2—C3—C4—C4a	−26.57 (17)	C12—O11—C10—O10	3.7 (2)
C10—C3—C4—C4a	154.03 (12)	C12—O11—C10—C3	−175.85 (12)
C2—C3—C4—C13	95.50 (15)	C2—C3—C10—O10	−10.6 (2)
C10—C3—C4—C13	−83.90 (15)	C4—C3—C10—O10	168.80 (14)
C3—C4—C4a—C8a	28.03 (18)	C2—C3—C10—O11	168.94 (13)
C13—C4—C4a—C8a	−95.00 (15)	C4—C3—C10—O11	−11.67 (18)
C3—C4—C4a—C5	−149.88 (12)	C4a—C4—C13—C14	−104.31 (15)
C13—C4—C4a—C5	87.09 (15)	C3—C4—C13—C14	133.73 (13)
C8a—C4a—C5—O5	−172.93 (13)	C4a—C4—C13—C18	72.98 (16)
C4—C4a—C5—O5	5.0 (2)	C3—C4—C13—C18	−48.98 (17)
C8a—C4a—C5—C6	4.2 (2)	C18—C13—C14—F1	178.76 (13)
C4—C4a—C5—C6	−177.88 (12)	C4—C13—C14—F1	−3.8 (2)
O5—C5—C6—C19	−35.44 (19)	C18—C13—C14—C15	−1.7 (2)
C4a—C5—C6—C19	147.35 (14)	C4—C13—C14—C15	175.76 (13)
O5—C5—C6—C20	83.75 (16)	F1—C14—C15—F2	0.7 (2)
C4a—C5—C6—C20	−93.45 (15)	C13—C14—C15—F2	−178.85 (12)
O5—C5—C6—C7	−155.95 (13)	F1—C14—C15—C16	179.66 (13)
C4a—C5—C6—C7	26.84 (18)	C13—C14—C15—C16	0.1 (2)
C19—C6—C7—C8	−176.00 (13)	F2—C15—C16—C17	−179.59 (13)
C5—C6—C7—C8	−54.69 (16)	C14—C15—C16—C17	1.5 (2)
C20—C6—C7—C8	63.71 (16)	C15—C16—C17—C18	−1.4 (2)
C6—C7—C8—C8a	51.46 (17)	C16—C17—C18—C13	−0.2 (2)
C5—C4a—C8a—N1	168.68 (13)	C14—C13—C18—C17	1.7 (2)
C4—C4a—C8a—N1	−9.2 (2)	C4—C13—C18—C17	−175.70 (14)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O5^i	0.915 (19)	2.04 (2)	2.9456 (15)	168.0 (17)

Symmetry code: (i) x−1, y, z.

(II) (±)-ethyl 4-(2,3-difluorophenyl)-2,6,6-trimethyl-5-oxo- 1,4,5,6,7,8-hexahydroquinoline-3-carboxylate

Crystal data

C21H23F2NO3	Z = 2
Mr = 375.41	F(000) = 396
Triclinic, P1	Dx = 1.358 Mg m^−3
Hall symbol: -P 1	Mo Kα radiation, λ = 0.71073 Å
a = 7.0677 (2) Å	Cell parameters from 5288 reflections
b = 11.2167 (4) Å	θ = 2.0–30.0°
c = 12.1844 (4) Å	µ = 0.10 mm^−1
α = 83.6482 (15)°	T = 160 K
β = 86.333 (2)°	Plate, colourless
γ = 73.2481 (18)°	0.22 × 0.17 × 0.05 mm
V = 918.74 (5) Å^3

Data collection

Nonius KappaCCD area-detector diffractometer	3911 reflections with I > 2σ(I)
Radiation source: Nonius FR590 sealed tube generator	Rint = 0.055
Horizontally mounted graphite crystal monochromator	θmax = 30.1°, θmin = 3.1°
Detector resolution: 9 pixels mm^-1	h = 0→9
ϕ and ω scans with κ offsets	k = −14→15
25434 measured reflections	l = −16→17
5368 independent reflections

Refinement

Refinement on F^2	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.052	Hydrogen site location: geom & difmap
wR(F^2) = 0.143	H atoms treated by a mixture of independent and constrained refinement
S = 1.04	w = 1/[σ^2(Fo^2) + (0.0643P)^2 + 0.1979P] where P = (Fo^2 + 2Fc^2)/3
5366 reflections	(Δ/σ)max = 0.001
252 parameters	Δρmax = 0.31 e Å^−3
0 restraints	Δρmin = −0.23 e Å^−3

Special details

Experimental. Solvent used: EtOH Cooling Device: Oxford Cryosystems Cryostream 700 Crystal mount: glued on a glass fibre Mosaicity (°.): 0.465 (2) Frames collected: 441 Seconds exposure per frame: 80 Degrees rotation per frame: 2.0 Crystal-Detector distance (mm): 35.0

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 (Ų)

	x	y	z	Uiso*/Ueq
F1	0.59458 (13)	0.74050 (9)	0.26922 (9)	0.0500 (3)
F2	0.68396 (19)	0.54270 (11)	0.15493 (12)	0.0746 (4)
O5	0.54219 (14)	1.01966 (10)	0.21033 (9)	0.0376 (3)
O10	1.09813 (17)	0.73249 (11)	0.59527 (9)	0.0425 (3)
O11	0.85140 (14)	0.70866 (9)	0.50152 (8)	0.0320 (2)
N1	1.18550 (16)	0.97819 (11)	0.31155 (10)	0.0285 (3)
H1	1.303 (3)	0.9988 (17)	0.2959 (15)	0.048 (5)*
C2	1.17182 (18)	0.89818 (12)	0.40453 (11)	0.0253 (3)
C3	1.02122 (17)	0.84446 (11)	0.41586 (10)	0.0233 (3)
C4	0.87715 (17)	0.86372 (11)	0.32331 (10)	0.0227 (3)
H4	0.7416	0.8748	0.3577	0.027*
C4a	0.87535 (17)	0.98137 (11)	0.24768 (10)	0.0229 (3)
C5	0.69726 (18)	1.04836 (12)	0.19006 (11)	0.0251 (3)
C6	0.69726 (19)	1.16080 (12)	0.10602 (11)	0.0260 (3)
C7	0.90844 (19)	1.16331 (13)	0.07057 (11)	0.0284 (3)
H71	0.9644	1.0983	0.0193	0.034*
H72	0.9034	1.2455	0.0298	0.034*
C8	1.0446 (2)	1.14116 (13)	0.16683 (12)	0.0299 (3)
H81	1.1823	1.1297	0.1383	0.036*
H82	1.0071	1.2154	0.2092	0.036*
C8a	1.03296 (18)	1.02829 (12)	0.24159 (11)	0.0248 (3)
C9	1.33175 (19)	0.88392 (14)	0.48450 (12)	0.0316 (3)
H91	1.2990	0.8421	0.5550	0.047*
H92	1.3428	0.9667	0.4962	0.047*
H93	1.4578	0.8337	0.4544	0.047*
C10	0.99982 (19)	0.75944 (12)	0.51373 (11)	0.0270 (3)
C12	0.8200 (2)	0.61824 (16)	0.59061 (13)	0.0400 (4)
H121	0.7680	0.6606	0.6579	0.048*
H122	0.9464	0.5542	0.6080	0.048*
C13	0.6750 (2)	0.55821 (16)	0.55373 (15)	0.0460 (4)
H131	0.7270	0.5177	0.4865	0.069*
H132	0.5495	0.6221	0.5384	0.069*
H133	0.6534	0.4955	0.6121	0.069*
C14	0.92645 (19)	0.74954 (12)	0.25832 (10)	0.0261 (3)
C15	0.7836 (2)	0.69489 (13)	0.23440 (13)	0.0351 (3)
C16	0.8315 (3)	0.59033 (15)	0.17584 (14)	0.0461 (4)
C17	1.0211 (3)	0.53591 (14)	0.14110 (13)	0.0463 (4)
H17	1.0522	0.4635	0.1021	0.056*
C18	1.1666 (3)	0.58836 (14)	0.16395 (13)	0.0404 (4)
H18	1.2995	0.5520	0.1403	0.049*
C19	1.1203 (2)	0.69377 (13)	0.22123 (11)	0.0314 (3)
H19	1.2223	0.7290	0.2357	0.038*
C20	0.5862 (2)	1.15390 (15)	0.00419 (12)	0.0377 (3)
H201	0.5860	1.2256	−0.0497	0.057*
H202	0.4497	1.1556	0.0261	0.057*
H203	0.6517	1.0761	−0.0290	0.057*
C21	0.5874 (2)	1.27843 (14)	0.16208 (14)	0.0395 (4)
H211	0.6587	1.2830	0.2272	0.059*
H212	0.4535	1.2747	0.1848	0.059*
H213	0.5799	1.3527	0.1101	0.059*

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
F1	0.0364 (5)	0.0465 (6)	0.0750 (7)	−0.0210 (4)	−0.0114 (5)	−0.0090 (5)
F2	0.0854 (8)	0.0519 (7)	0.1039 (10)	−0.0365 (6)	−0.0372 (7)	−0.0172 (6)
O5	0.0239 (5)	0.0422 (6)	0.0465 (6)	−0.0149 (4)	−0.0064 (4)	0.0138 (5)
O10	0.0532 (7)	0.0483 (6)	0.0313 (6)	−0.0232 (5)	−0.0158 (5)	0.0058 (5)
O11	0.0307 (5)	0.0383 (6)	0.0289 (5)	−0.0162 (4)	−0.0038 (4)	0.0075 (4)
N1	0.0213 (5)	0.0313 (6)	0.0351 (6)	−0.0118 (4)	−0.0019 (4)	−0.0006 (5)
C2	0.0213 (6)	0.0248 (6)	0.0293 (7)	−0.0045 (5)	−0.0005 (5)	−0.0061 (5)
C3	0.0211 (6)	0.0233 (6)	0.0253 (6)	−0.0053 (5)	−0.0010 (5)	−0.0038 (5)
C4	0.0209 (6)	0.0232 (6)	0.0254 (6)	−0.0083 (5)	−0.0017 (5)	−0.0018 (5)
C4a	0.0226 (6)	0.0208 (6)	0.0258 (6)	−0.0076 (5)	0.0011 (5)	−0.0023 (5)
C5	0.0232 (6)	0.0246 (6)	0.0281 (7)	−0.0080 (5)	−0.0006 (5)	−0.0026 (5)
C6	0.0261 (6)	0.0235 (6)	0.0287 (7)	−0.0082 (5)	−0.0023 (5)	0.0008 (5)
C7	0.0296 (6)	0.0269 (6)	0.0298 (7)	−0.0114 (5)	0.0011 (5)	0.0009 (5)
C8	0.0266 (6)	0.0284 (7)	0.0373 (8)	−0.0134 (5)	−0.0005 (5)	0.0011 (6)
C8a	0.0220 (6)	0.0239 (6)	0.0286 (6)	−0.0071 (5)	0.0003 (5)	−0.0029 (5)
C9	0.0251 (6)	0.0350 (7)	0.0362 (8)	−0.0087 (5)	−0.0061 (5)	−0.0058 (6)
C10	0.0269 (6)	0.0276 (6)	0.0264 (7)	−0.0067 (5)	−0.0018 (5)	−0.0040 (5)
C12	0.0437 (8)	0.0454 (9)	0.0322 (8)	−0.0203 (7)	−0.0010 (6)	0.0107 (7)
C13	0.0437 (9)	0.0397 (9)	0.0551 (10)	−0.0179 (7)	−0.0058 (7)	0.0126 (7)
C14	0.0343 (7)	0.0220 (6)	0.0228 (6)	−0.0099 (5)	−0.0057 (5)	0.0027 (5)
C15	0.0372 (8)	0.0305 (7)	0.0401 (8)	−0.0125 (6)	−0.0106 (6)	−0.0009 (6)
C16	0.0676 (11)	0.0325 (8)	0.0470 (9)	−0.0245 (8)	−0.0247 (8)	−0.0002 (7)
C17	0.0788 (12)	0.0257 (7)	0.0329 (8)	−0.0091 (8)	−0.0140 (8)	−0.0048 (6)
C18	0.0574 (10)	0.0290 (7)	0.0296 (7)	−0.0045 (7)	0.0008 (7)	−0.0023 (6)
C19	0.0402 (8)	0.0266 (7)	0.0265 (7)	−0.0087 (6)	0.0000 (6)	−0.0006 (5)
C20	0.0384 (8)	0.0443 (9)	0.0340 (8)	−0.0194 (7)	−0.0088 (6)	0.0061 (6)
C21	0.0367 (8)	0.0273 (7)	0.0519 (9)	−0.0054 (6)	0.0039 (7)	−0.0057 (6)

Geometric parameters (Å, º)

F1—C15	1.3446 (18)	C8—H81	0.9900
F2—C16	1.3505 (18)	C8—H82	0.9900
O5—C5	1.2316 (15)	C9—H91	0.9800
O10—C10	1.2092 (16)	C9—H92	0.9800
O11—C10	1.3528 (16)	C9—H93	0.9800
O11—C12	1.4531 (17)	C12—C13	1.493 (2)
N1—C8a	1.3664 (17)	C12—H121	0.9900
N1—C2	1.3819 (17)	C12—H122	0.9900
N1—H1	0.925 (19)	C13—H131	0.9800
C2—C3	1.3592 (17)	C13—H132	0.9800
C2—C9	1.5016 (18)	C13—H133	0.9800
C3—C10	1.4706 (18)	C14—C15	1.3834 (19)
C3—C4	1.5236 (17)	C14—C19	1.4005 (19)
C4—C4a	1.5210 (17)	C15—C16	1.387 (2)
C4—C14	1.5234 (18)	C16—C17	1.363 (3)
C4—H4	1.0000	C17—C18	1.379 (2)
C4a—C8a	1.3572 (17)	C17—H17	0.9500
C4a—C5	1.4467 (18)	C18—C19	1.387 (2)
C5—C6	1.5341 (17)	C18—H18	0.9500
C6—C20	1.5305 (19)	C19—H19	0.9500
C6—C21	1.533 (2)	C20—H201	0.9800
C6—C7	1.5344 (18)	C20—H202	0.9800
C7—C8	1.5182 (19)	C20—H203	0.9800
C7—H71	0.9900	C21—H211	0.9800
C7—H72	0.9900	C21—H212	0.9800
C8—C8a	1.4949 (18)	C21—H213	0.9800
C10—O11—C12	116.25 (11)	H91—C9—H93	109.5
C8a—N1—C2	122.71 (11)	H92—C9—H93	109.5
C8a—N1—H1	118.5 (11)	O10—C10—O11	121.63 (12)
C2—N1—H1	118.8 (11)	O10—C10—C3	127.76 (12)
N1—C2—C3	119.50 (12)	O11—C10—C3	110.59 (11)
N1—C2—C9	112.95 (11)	O11—C12—C13	107.98 (12)
C3—C2—C9	127.53 (12)	O11—C12—H121	110.1
C2—C3—C10	121.43 (12)	C13—C12—H121	110.1
C2—C3—C4	120.62 (11)	O11—C12—H122	110.1
C10—C3—C4	117.82 (11)	C13—C12—H122	110.1
C4a—C4—C14	111.06 (10)	H121—C12—H122	108.4
C3—C4—C4a	110.81 (10)	C12—C13—H131	109.5
C14—C4—C3	110.86 (10)	C12—C13—H132	109.5
C4a—C4—H4	108.0	H131—C13—H132	109.5
C14—C4—H4	108.0	C12—C13—H133	109.5
C3—C4—H4	108.0	H131—C13—H133	109.5
C8a—C4a—C5	120.46 (11)	H132—C13—H133	109.5
C4—C4a—C8a	120.26 (11)	C15—C14—C19	116.80 (13)
C5—C4a—C4	119.05 (10)	C15—C14—C4	121.94 (12)
O5—C5—C4a	121.04 (11)	C19—C14—C4	121.26 (11)
O5—C5—C6	118.95 (11)	F1—C15—C14	120.75 (13)
C4a—C5—C6	119.96 (11)	F1—C15—C16	118.11 (13)
C20—C6—C21	109.44 (12)	C14—C15—C16	121.13 (15)
C20—C6—C5	109.26 (11)	F2—C16—C17	120.59 (15)
C21—C6—C5	106.78 (11)	F2—C16—C15	117.76 (17)
C20—C6—C7	109.26 (11)	C17—C16—C15	121.64 (15)
C21—C6—C7	110.65 (11)	C16—C17—C18	118.46 (14)
C5—C6—C7	111.41 (10)	C16—C17—H17	120.8
C8—C7—C6	113.37 (11)	C18—C17—H17	120.8
C8—C7—H71	108.9	C17—C18—C19	120.49 (16)
C6—C7—H71	108.9	C17—C18—H18	119.8
C8—C7—H72	108.9	C19—C18—H18	119.8
C6—C7—H72	108.9	C18—C19—C14	121.49 (14)
H71—C7—H72	107.7	C18—C19—H19	119.3
C8a—C8—C7	111.16 (11)	C14—C19—H19	119.3
C8a—C8—H81	109.4	C6—C20—H201	109.5
C7—C8—H81	109.4	C6—C20—H202	109.5
C8a—C8—H82	109.4	H201—C20—H202	109.5
C7—C8—H82	109.4	C6—C20—H203	109.5
H81—C8—H82	108.0	H201—C20—H203	109.5
C4a—C8a—N1	120.28 (12)	H202—C20—H203	109.5
C4a—C8a—C8	123.35 (11)	C6—C21—H211	109.5
N1—C8a—C8	116.19 (11)	C6—C21—H212	109.5
C2—C9—H91	109.5	H211—C21—H212	109.5
C2—C9—H92	109.5	C6—C21—H213	109.5
H91—C9—H92	109.5	H211—C21—H213	109.5
C2—C9—H93	109.5	H212—C21—H213	109.5
C8a—N1—C2—C3	14.89 (19)	C4—C4a—C8a—C8	178.14 (11)
C8a—N1—C2—C9	−163.86 (12)	C2—N1—C8a—C4a	−13.8 (2)
N1—C2—C3—C10	−179.55 (11)	C2—N1—C8a—C8	161.54 (12)
C9—C2—C3—C10	−1.0 (2)	C7—C8—C8a—C4a	−22.91 (18)
N1—C2—C3—C4	4.71 (18)	C7—C8—C8a—N1	161.89 (12)
C9—C2—C3—C4	−176.74 (12)	C12—O11—C10—O10	−1.29 (19)
C2—C3—C4—C4a	−22.06 (16)	C12—O11—C10—C3	177.37 (12)
C10—C3—C4—C4a	162.05 (11)	C2—C3—C10—O10	4.4 (2)
C2—C3—C4—C14	101.74 (13)	C4—C3—C10—O10	−179.70 (13)
C10—C3—C4—C14	−74.16 (14)	C2—C3—C10—O11	−174.11 (11)
C14—C4—C4a—C8a	−100.53 (14)	C4—C3—C10—O11	1.74 (16)
C3—C4—C4a—C8a	23.14 (16)	C10—O11—C12—C13	−170.78 (12)
C14—C4—C4a—C5	84.85 (14)	C4a—C4—C14—C15	−104.94 (14)
C3—C4—C4a—C5	−151.48 (11)	C3—C4—C14—C15	131.41 (13)
C8a—C4a—C5—O5	−166.69 (13)	C4a—C4—C14—C19	75.99 (14)
C4—C4a—C5—O5	7.92 (19)	C3—C4—C14—C19	−47.66 (15)
C8a—C4a—C5—C6	10.50 (19)	C19—C14—C15—F1	178.36 (12)
C4—C4a—C5—C6	−174.89 (11)	C4—C14—C15—F1	−0.7 (2)
O5—C5—C6—C20	−45.38 (17)	C19—C14—C15—C16	−0.4 (2)
C4a—C5—C6—C20	137.37 (13)	C4—C14—C15—C16	−179.50 (13)
O5—C5—C6—C21	72.89 (16)	F1—C15—C16—F2	1.7 (2)
C4a—C5—C6—C21	−104.36 (14)	C14—C15—C16—F2	−179.54 (14)
O5—C5—C6—C7	−166.19 (12)	F1—C15—C16—C17	−177.66 (14)
C4a—C5—C6—C7	16.55 (17)	C14—C15—C16—C17	1.1 (2)
C20—C6—C7—C8	−167.20 (11)	F2—C16—C17—C18	179.68 (14)
C21—C6—C7—C8	72.24 (14)	C15—C16—C17—C18	−1.0 (2)
C5—C6—C7—C8	−46.38 (15)	C16—C17—C18—C19	0.2 (2)
C6—C7—C8—C8a	49.59 (15)	C17—C18—C19—C14	0.5 (2)
C5—C4a—C8a—N1	167.69 (12)	C15—C14—C19—C18	−0.4 (2)
C4—C4a—C8a—N1	−6.86 (19)	C4—C14—C19—C18	178.71 (12)
C5—C4a—C8a—C8	−7.3 (2)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O5^i	0.925 (19)	1.990 (19)	2.8712 (14)	158.8 (16)

Symmetry code: (i) x+1, y, z.