N-(2-Fluoro­ethyl)-3β-(4-iodo­phenyl)-8-methyl-8-aza­bi­cyclo­[3.2.1]­octane-2α-carbox­amide: a new cocaine derivative with equatorially attached ligands

In the title compound, C₁₇H₂₂FIN₂O, both the amide and the iodo­phenyl substituents of the tropane ring lie in equatorial positions. The crystal packing is determined by N—H...O and C—H...F intermolecular hydrogen-bonding interactions.

S1. Comment

The dopamine transporter (DAT) is a widely accepted marker for the integrity of the presynaptic dopaminergic system (Innis et al., 1993). A markedly reduced DAT density has been demonstrated in brains from patients with degenerative brain disorders such as Parkinson's and Alzheimer's diseases. When combined with positron emission tomography (PET) or single photon emission tomography (SPECT), radioligands binding specifically to the DAT are potentially useful as non-invasive in vivo imaging tools for studying the various illnesses and evaluating the degrees of success of their treatments (Schenk, 2002; Torres et al., 2003). Therefore, development and evaluation of suitable radioligands is required. Cocaine analogues are known to result in the best effects (Singh, 2000). The structure of the title amide derivative, (I) (Krebs et al., 2003), of the established radioligand β-CIT (Carroll et al., 1991) is described here. \sch

The molecular structure of (I) shows the usual piperidine chair conformation (Fig. 1). The absolute configuration was determined from anomalous dispersion effects by refining the Flack parameter (Flack, 1983). Both the amide and the iodophenyl group are equatorially attached to the central tropane ring, adopting 2α- and 3β-positions, respectively. The relevant torsion angles are C1—C2—C15—N2 86.3 (4)° and C2—C3—C9—C10 60.2 (5)°. The related molecular structures of cocaine (Hrynchuk et al., 1982) and cocaine salts (Shen et al., 1975; Zhu et al., 1999) show corresponding torsion angles for their methoxycarbonyl groups of −61, −46 and −17°. In (I), the phenyl ring and the best plane through the amide group (atoms C15, O1, N2 and C16) are perpendicular, with a dihedral angle of 89.2 (1)°. The N8—C1 and N8—C5 bond lengths of 1.472 (5) and 1.486 (7) Å, respectively, compare well with the values of 1.460 (7) and 1.467 (6) Å from cocaine. The same is valid for C2—C15, with values of 1.518 (5) and 1.509 (6) Å in (I) and in cocaine, respectively, but the C15═O1 bond of 1.229 (5) Å in (I) is longer than the corresponding distance of 1.188 (5) Å in cocaine.

The crystal packing of (I) shows two intermolecular hydrogen bonds (details in Table 2) between molecules related by a twofold screw axis, thus generating a chain in the b direction (Fig. 2).

Table 2. Selected hydrogen bonding geometry (Å, °) (Note that F11 and F12 are the disorder components of the same F atom).

S2. Experimental

Triethylamine (28 mg, 0.28 mmole) was added at 273 K over 10 min to a stirred mixture of the carboxylic acid of β-CIT (98 mg, 0.264 mmole), fluoroethylamine (29 mg, 0.29 mmole) and diethylcyanophosphonate (47 mg, 0.29 mmole) in dimethylformamide (1 ml). The mixture was stirred at 273 K for 30 min and then at room temperature for 1 h. It was then diluted with AcOEt and washed with H₂O, saturated aqueous NaHCO₃ and saturated aqueous NaCl, and dried over K₂CO₃. Column chromatography of the resulting residue (EE:MeOH:Et₃N = 8.5:1:0.5; R_f = 0.62; EE is ?) gave colourless crystals of the amide (99 mg, 90%, m.p. 418 K 145). Recrystallization from CH₂Cl₂/Et₂O (Ratio?) yielded crystals of (I) suitable for X-ray analysis. Spectroscopic analysis: ¹H NMR (250 MHz, CDCl₃, δ, p.p.m.): 1.69–2.31 [m, 6H, 2CH₂ (H6, H7), H4A, H5], 2.41 (s, 3H, CH₃), 3.17–3.42 (m, 4H, H2, H3, H1, H4B), 4.08–4.48 [m, 4H, F(CH₂)₂], 6.18 (d, 1H, NH), 7.04 (d, 2H, C₆H₄), 7.56 (d, 2H, C₆H₄); ¹³C NMR (250 MHz, CDCl₃, δ, p.p.m.): 22.98 (CH₂), 26.38 (CH₂), 36.72 (CH₃), 39.81 (CH₂), 40.75 (CH), 53.77 (CH), 62.37 (CH), 65.36 (CH), 81.37 (CH₂), 84.68 (CH₂), 92.23 (CI), 130.30, 137.98, 143.27 (C₆H₄), 172.30 (C═O).

S3. Refinement

The largest residual electron-density peak lies close to a heavy atom, 0.98 Å from atom I1. The F atom is disordered and was refined with a split model over two positions, with occupancies of 0.638 (9) for F11 and 0.362 (9) for F12. H atoms were placed at calculated positions, riding on their attached C or N atoms, with U_iso(H) = 1.2U_eq(C,N) or 1.5U_eq(CH₃). CH₃ groups were allowed to rotate but not to tip or distort.

Computing details

Data collection: SMART (Bruker, 2002); cell refinement: SAINT (Bruker, 2002); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Bruker, 2002); program(s) used to refine structure: SHELXTL; molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Figures

	Fig. 1. The molecular structure of (I). Only one position is shown for the disordered F atom. Displacement ellipsoids are drawn at the 50% probability level.
	Fig. 2. The crystal packing in (I), viewed along [100], with hydrogen bonds indicated by dashed lines (O atoms are shaded and F atoms cross-hatched). Only one position (F11) of the disordered F atom is shown, and H atoms not involved in hydrogen bonding have been omitted.

N-(2-Fluoroethyl)-3β-(4-iodophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2α- carboxamide

Crystal data

C17H22FIN2O	F(000) = 416
Mr = 416.27	Dx = 1.607 Mg m^−3
Monoclinic, P21	Mo Kα radiation, λ = 0.71073 Å
a = 8.9837 (8) Å	Cell parameters from 3506 reflections
b = 9.5600 (8) Å	θ = 2.3–28.3°
c = 10.1222 (9) Å	µ = 1.87 mm^−1
β = 98.225 (2)°	T = 120 K
V = 860.39 (13) Å^3	Block, colourless
Z = 2	0.40 × 0.20 × 0.12 mm

Data collection

Bruker SMART CCD area-detector diffractometer	4021 independent reflections
Radiation source: sealed tube	3602 reflections with I > 2σ(I)
Graphite monochromator	Rint = 0.031
ϕ and ω scans	θmax = 28.4°, θmin = 2.0°
Absorption correction: multi-scan (SADABS; Bruker, 2002)	h = −11→12
Tmin = 0.574, Tmax = 0.799	k = −12→11
7235 measured reflections	l = −11→13

Refinement

Refinement on F^2	Secondary atom site location: difference Fourier map
Least-squares matrix: full	Hydrogen site location: difference Fourier map
R[F^2 > 2σ(F^2)] = 0.031	H-atom parameters constrained
wR(F^2) = 0.071	w = 1/[σ^2(Fo^2) + (0.0344P)^2] where P = (Fo^2 + 2Fc^2)/3
S = 1.00	(Δ/σ)max = 0.002
4021 reflections	Δρmax = 1.29 e Å^−3
211 parameters	Δρmin = −0.63 e Å^−3
3 restraints	Absolute structure: Flack (1983), with x Friedel pairs
Primary atom site location: structure-invariant direct methods	Absolute structure parameter: −0.02 (2)

Special details

Experimental. ¹H and ¹³C NMR spectra were obtained at 250 MHz using a Bruker DPX-200 spectrometer (Avance 200) in 5% solution at 298 K

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.

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

	x	y	z	Uiso*/Ueq	Occ. (<1)
I1	1.08693 (2)	0.24881 (4)	1.17178 (2)	0.03047 (8)
O1	0.5589 (3)	0.0690 (3)	0.5609 (3)	0.0261 (6)
N2	0.5914 (4)	0.2812 (3)	0.4709 (3)	0.0221 (8)
H2B	0.5805	0.3702	0.4777	0.026*
N8	0.1984 (4)	0.3609 (4)	0.6762 (4)	0.0233 (8)
C1	0.2806 (4)	0.2803 (4)	0.5859 (4)	0.0195 (9)
H1A	0.2747	0.3275	0.4993	0.023*
C2	0.4464 (4)	0.2699 (4)	0.6530 (3)	0.0168 (9)
H2A	0.4860	0.3648	0.6691	0.020*
C3	0.4580 (4)	0.1932 (4)	0.7878 (4)	0.0190 (7)
H3A	0.4407	0.0934	0.7697	0.023*
C4	0.3341 (3)	0.2461 (9)	0.8679 (3)	0.0248 (7)
H4A	0.3272	0.1834	0.9420	0.030*
H4B	0.3612	0.3381	0.9040	0.030*
C5	0.1818 (3)	0.2539 (9)	0.7796 (3)	0.0260 (7)
H5A	0.1031	0.2814	0.8323	0.031*
C6	0.1376 (5)	0.1186 (5)	0.7015 (5)	0.0280 (10)
H6A	0.1815	0.0376	0.7499	0.034*
H6B	0.0292	0.1077	0.6855	0.034*
C7	0.2011 (4)	0.1371 (4)	0.5695 (4)	0.0253 (8)
H7A	0.1212	0.1375	0.4941	0.030*
H7B	0.2718	0.0631	0.5572	0.030*
C8	0.0528 (5)	0.4082 (5)	0.6092 (5)	0.0345 (10)
H8A	−0.0099	0.3287	0.5833	0.052*
H8B	0.0667	0.4612	0.5313	0.052*
H8C	0.0057	0.4660	0.6688	0.052*
C9	0.6120 (4)	0.2091 (4)	0.8709 (4)	0.0187 (10)
C10	0.6691 (5)	0.3383 (5)	0.9113 (4)	0.0247 (10)
H10A	0.6150	0.4183	0.8826	0.030*
C11	0.8067 (6)	0.3518 (6)	0.9944 (5)	0.0273 (12)
H11A	0.8454	0.4399	1.0187	0.033*
C12	0.8839 (4)	0.2335 (7)	1.0396 (3)	0.0232 (9)
C13	0.8295 (6)	0.1019 (5)	0.9994 (5)	0.0242 (11)
H13A	0.8824	0.0217	1.0295	0.029*
C14	0.6946 (5)	0.0920 (5)	0.9134 (4)	0.0245 (10)
H14A	0.6593	0.0043	0.8839	0.029*
C15	0.5382 (4)	0.1961 (4)	0.5592 (4)	0.0191 (8)
C16	0.6671 (4)	0.2258 (5)	0.3644 (3)	0.0232 (11)
H16A	0.7174	0.1392	0.3941	0.028*
H16B	0.7431	0.2919	0.3453	0.028*
C17	0.5613 (5)	0.1990 (6)	0.2404 (5)	0.0433 (14)
H17A	0.6187	0.1622	0.1739	0.017 (10)*	0.50
H17B	0.4918	0.1264	0.2592	0.017 (10)*	0.50
H17C	0.6132	0.1398	0.1854	0.017 (10)*	0.50
H17D	0.5460	0.2871	0.1950	0.017 (10)*	0.50
F11	0.4840 (7)	0.3034 (5)	0.1889 (5)	0.0555 (19)	0.639 (10)
F12	0.4368 (8)	0.1468 (10)	0.2443 (8)	0.045 (3)	0.361 (10)

Atomic displacement parameters (Ų)

	U^11	U^22	U^33	U^12	U^13	U^23
I1	0.02715 (11)	0.03791 (14)	0.02424 (12)	−0.00150 (19)	−0.00359 (7)	0.00588 (19)
O1	0.0366 (16)	0.0185 (15)	0.0241 (15)	0.0035 (11)	0.0081 (12)	−0.0008 (11)
N2	0.0332 (16)	0.011 (2)	0.0230 (16)	−0.0010 (12)	0.0068 (13)	0.0003 (11)
N8	0.0223 (19)	0.023 (2)	0.024 (2)	0.0050 (14)	0.0007 (15)	−0.0023 (14)
C1	0.0236 (16)	0.021 (3)	0.0132 (15)	0.0002 (14)	−0.0005 (12)	0.0003 (13)
C2	0.0244 (15)	0.009 (3)	0.0163 (15)	0.0021 (14)	−0.0001 (11)	−0.0001 (14)
C3	0.0227 (17)	0.0184 (18)	0.0149 (17)	0.0022 (13)	−0.0007 (14)	0.0009 (14)
C4	0.0281 (15)	0.0320 (19)	0.0140 (14)	−0.007 (3)	0.0022 (11)	−0.005 (3)
C5	0.0250 (15)	0.034 (2)	0.0198 (15)	0.004 (3)	0.0046 (12)	0.004 (3)
C6	0.027 (2)	0.034 (3)	0.023 (2)	−0.006 (2)	0.0041 (18)	0.0024 (19)
C7	0.031 (2)	0.024 (2)	0.019 (2)	−0.0010 (17)	−0.0008 (16)	−0.0021 (16)
C8	0.031 (2)	0.040 (3)	0.032 (3)	0.012 (2)	−0.0003 (19)	0.002 (2)
C9	0.0227 (18)	0.022 (3)	0.0106 (17)	0.0036 (14)	0.0010 (14)	−0.0001 (13)
C10	0.031 (3)	0.021 (3)	0.020 (2)	0.007 (2)	−0.0031 (18)	0.002 (2)
C11	0.038 (3)	0.019 (3)	0.023 (2)	−0.004 (2)	−0.002 (2)	−0.0061 (19)
C12	0.0217 (14)	0.031 (3)	0.0156 (15)	0.005 (2)	0.0002 (11)	0.001 (2)
C13	0.025 (2)	0.021 (3)	0.024 (2)	0.0044 (19)	−0.0019 (17)	0.0037 (19)
C14	0.028 (2)	0.022 (3)	0.023 (2)	0.0009 (19)	0.0026 (16)	−0.0007 (19)
C15	0.0215 (17)	0.0215 (19)	0.0129 (17)	0.0000 (13)	−0.0021 (14)	−0.0040 (13)
C16	0.0265 (16)	0.022 (3)	0.0221 (17)	0.0023 (16)	0.0081 (13)	0.0018 (16)
C17	0.045 (3)	0.065 (4)	0.022 (2)	0.006 (2)	0.010 (2)	−0.011 (2)
F11	0.069 (4)	0.067 (4)	0.027 (3)	0.035 (3)	−0.006 (2)	−0.001 (2)
F12	0.026 (4)	0.067 (7)	0.040 (5)	−0.006 (4)	−0.005 (3)	−0.021 (4)

Geometric parameters (Å, º)

I1—C12	2.107 (3)	C7—H7A	0.9700
C15—O1	1.229 (5)	C7—H7B	0.9700
N2—C15	1.346 (5)	C8—H8A	0.9600
N2—C16	1.454 (5)	C8—H8B	0.9600
N2—H2B	0.8600	C8—H8C	0.9600
N8—C8	1.457 (5)	C9—C10	1.377 (6)
N8—C1	1.472 (5)	C9—C14	1.377 (6)
N8—C5	1.486 (7)	C10—C11	1.399 (7)
C1—C7	1.542 (5)	C10—H10A	0.9300
C1—C2	1.549 (5)	C11—C12	1.371 (8)
C1—H1A	0.9800	C11—H11A	0.9300
C2—C15	1.518 (5)	C12—C13	1.390 (8)
C2—C3	1.539 (5)	C13—C14	1.390 (7)
C2—H2A	0.9800	C13—H13A	0.9300
C3—C9	1.520 (5)	C14—H14A	0.9300
C3—C4	1.552 (5)	C16—C17	1.484 (6)
C3—H3A	0.9800	C16—H16A	0.9700
C4—C5	1.525 (4)	C16—H16B	0.9700
C4—H4A	0.9700	C17—F11	1.284 (6)
C4—H4B	0.9700	C17—F12	1.230 (9)
C5—C6	1.538 (9)	C17—H17A	0.9700
C5—H5A	0.9800	C17—H17B	0.9700
C6—C7	1.536 (6)	C17—H17C	0.9599
C6—H6A	0.9700	C17—H17D	0.9600
C6—H6B	0.9700
C15—N2—C16	121.3 (3)	C1—C7—H7B	111.1
C15—N2—H2B	119.3	H7A—C7—H7B	109.0
C16—N2—H2B	119.3	N8—C8—H8A	109.5
C8—N8—C1	111.7 (3)	N8—C8—H8B	109.5
C8—N8—C5	111.6 (3)	H8A—C8—H8B	109.5
C1—N8—C5	100.8 (4)	N8—C8—H8C	109.5
N8—C1—C7	105.4 (3)	H8A—C8—H8C	109.5
N8—C1—C2	107.3 (3)	H8B—C8—H8C	109.5
C7—C1—C2	113.0 (3)	C10—C9—C14	118.4 (4)
N8—C1—H1A	110.3	C10—C9—C3	121.7 (3)
C7—C1—H1A	110.3	C14—C9—C3	119.9 (3)
C2—C1—H1A	110.3	C9—C10—C11	121.4 (5)
C15—C2—C3	111.1 (3)	C9—C10—H10A	119.3
C15—C2—C1	109.3 (3)	C11—C10—H10A	119.3
C3—C2—C1	111.0 (3)	C12—C11—C10	119.0 (5)
C15—C2—H2A	108.5	C12—C11—H11A	120.5
C3—C2—H2A	108.5	C10—C11—H11A	120.5
C1—C2—H2A	108.5	C11—C12—C13	120.7 (4)
C9—C3—C2	112.6 (3)	C11—C12—I1	120.3 (4)
C9—C3—C4	110.0 (3)	C13—C12—I1	119.0 (4)
C2—C3—C4	110.2 (3)	C12—C13—C14	118.9 (4)
C9—C3—H3A	108.0	C12—C13—H13A	120.5
C2—C3—H3A	108.0	C14—C13—H13A	120.5
C4—C3—H3A	108.0	C9—C14—C13	121.5 (4)
C5—C4—C3	111.1 (3)	C9—C14—H14A	119.2
C5—C4—H4A	109.4	C13—C14—H14A	119.2
C3—C4—H4A	109.4	O1—C15—N2	122.6 (3)
C5—C4—H4B	109.4	O1—C15—C2	123.1 (3)
C3—C4—H4B	109.4	N2—C15—C2	114.3 (3)
H4A—C4—H4B	108.0	N2—C16—C17	112.3 (3)
N8—C5—C4	105.9 (4)	N2—C16—H16A	109.1
N8—C5—C6	105.1 (3)	C17—C16—H16A	109.1
C4—C5—C6	113.8 (6)	N2—C16—H16B	109.1
N8—C5—H5A	110.6	C17—C16—H16B	109.1
C4—C5—H5A	110.6	H16A—C16—H16B	107.9
C6—C5—H5A	110.6	F11—C17—C16	116.9 (4)
C7—C6—C5	104.5 (4)	F12—C17—C16	121.2 (6)
C7—C6—H6A	110.9	F11—C17—H17A	108.1
C5—C6—H6A	110.9	C16—C17—H17A	108.1
C7—C6—H6B	110.9	F11—C17—H17B	108.1
C5—C6—H6B	110.9	C16—C17—H17B	108.1
H6A—C6—H6B	108.9	H17A—C17—H17B	107.3
C6—C7—C1	103.4 (3)	C16—C17—H17C	106.7
C6—C7—H7A	111.1	C16—C17—H17D	106.5
C1—C7—H7A	111.1	H17C—C17—H17D	106.7
C6—C7—H7B	111.1
C8—N8—C1—C7	−74.3 (4)	C2—C1—C7—C6	88.3 (4)
C5—N8—C1—C7	44.4 (4)	C2—C3—C9—C10	60.2 (5)
C8—N8—C1—C2	165.0 (3)	C4—C3—C9—C10	−63.1 (6)
C5—N8—C1—C2	−76.3 (3)	C2—C3—C9—C14	−123.1 (4)
N8—C1—C2—C15	−176.2 (3)	C4—C3—C9—C14	113.6 (5)
C7—C1—C2—C15	68.1 (4)	C14—C9—C10—C11	−0.6 (7)
N8—C1—C2—C3	61.0 (4)	C3—C9—C10—C11	176.1 (4)
C7—C1—C2—C3	−54.7 (4)	C9—C10—C11—C12	−1.9 (8)
C15—C2—C3—C9	71.2 (4)	C10—C11—C12—C13	2.5 (6)
C1—C2—C3—C9	−167.0 (3)	C10—C11—C12—I1	−177.3 (3)
C15—C2—C3—C4	−165.7 (4)	C11—C12—C13—C14	−0.6 (6)
C1—C2—C3—C4	−43.9 (5)	I1—C12—C13—C14	179.2 (3)
C9—C3—C4—C5	170.7 (5)	C10—C9—C14—C13	2.6 (7)
C2—C3—C4—C5	46.0 (7)	C3—C9—C14—C13	−174.1 (4)
C8—N8—C5—C4	−163.6 (5)	C12—C13—C14—C9	−2.0 (7)
C1—N8—C5—C4	77.7 (5)	C16—N2—C15—O1	5.0 (6)
C8—N8—C5—C6	75.6 (5)	C16—N2—C15—C2	−173.0 (3)
C1—N8—C5—C6	−43.1 (4)	C3—C2—C15—O1	31.1 (5)
C3—C4—C5—N8	−64.0 (7)	C1—C2—C15—O1	−91.7 (4)
C3—C4—C5—C6	51.0 (6)	C3—C2—C15—N2	−150.9 (3)
N8—C5—C6—C7	25.5 (4)	C1—C2—C15—N2	86.3 (4)
C4—C5—C6—C7	−90.0 (4)	C15—N2—C16—C17	91.0 (5)
C5—C6—C7—C1	1.6 (4)	N2—C16—C17—F11	58.0 (6)
N8—C1—C7—C6	−28.6 (4)	N2—C16—C17—F12	−41.1 (8)

Hydrogen-bond geometry (Å, º)

D—H···A	D—H	H···A	D···A	D—H···A
N2—H2B···O1^i	0.86	2.28	3.061 (4)	151
C14—H14A···F11^ii	0.93	2.37	3.284 (7)	167
C10—H10A···F12^i	0.93	2.54	3.41 (1)	156

Symmetry codes: (i) −x+1, y+1/2, −z+1; (ii) −x+1, y−1/2, −z+1.