cis-1-Benzyl­pyrrolidine-2,5-dicarbonitrile

Ponugoti, P.R.; Penthala, N.R.; Dwoskin, L.P.; Parkin, S.; Crooks, P.A.

doi:10.1107/S1600536811006258

organic compounds

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ISSN: 2056-9890

Volume 67| Part 4| April 2011| Page o747

doi:10.1107/S1600536811006258

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cis-1-Benzylpyrrolidine-2,5-dicarbonitrile

Purushothama Rao Ponugoti,^a Narsimha Reddy Penthala,^a Linda P. Dwoskin,^a Sean Parkin ^b and Peter A. Crooks ^a ^*

^aDepartment of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA, and ^bDepartment of Chemistry, University of Kentucky, Lexington, KY 40506, USA
^*Correspondence e-mail: pcrooks@uky.edu

(Received 10 January 2011; accepted 18 February 2011; online 2 March 2011)

In the title compound, C₁₃H₁₃N₃, the cyano groups at the 2- and 5-positions are eclipsed with each other. The phenyl ring is disordered over two sets of sites, with refined occupancies of 0.520 (5) and 0.480 (5). The angles between the mean plane of the pyrrolidine ring and the two cyano groups are 71.7 (9) and 75.0 (12)°.

Related literature

For Robinson–Schopf condensations with succinaldehyde, see: McIntosh (1988 ). For lobelane (systematic name 2-[6-(2-hydroxy-2-phenyl-ethyl)-1-methyl-2-piperidyl]-1-phenyl-ethanone) analog activity: Zheng et al. (2005 ).

Experimental

Crystal data

C₁₃H₁₃N₃
M_r = 211.26
Monoclinic, P 2₁ /c
a = 10.9898 (3) Å
b = 9.4494 (2) Å
c = 11.4768 (3) Å
β = 103.0735 (11)°
V = 1160.94 (5) Å³
Z = 4
Mo Kα radiation
μ = 0.08 mm⁻¹
T = 150 K
0.24 × 0.20 × 0.16 mm

Data collection

Nonius KappaCCD diffractometer
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997 ) T_min = 0.982, T_max = 0.988
19299 measured reflections
2662 independent reflections
1574 reflections with I > 2σ(I)
R_int = 0.061

Refinement

R[F² > 2σ(F²)] = 0.051
wR(F²) = 0.154
S = 1.04
2662 reflections
164 parameters
12 restraints
H-atom parameters constrained
Δρ_max = 0.17 e Å⁻³
Δρ_min = −0.18 e Å⁻³

Data collection: COLLECT (Nonius, 1998 ); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 and local procedures.

Supporting information

Crystal structure: contains datablocks global, I. DOI: 10.1107/S1600536811006258/hg2792sup1.cif

Structure factors: contains datablock I. DOI: 10.1107/S1600536811006258/hg2792Isup2.hkl

checkCIF report

Comment top

With the aim of developing lobelane analogs as potent antagonists at dihydrotetrabenazine (DTBZ) binding sites on VMAT2, and as inhibiters of [³H]-DA uptake into vesicles (Zheng et al. 2005), we have undertaken the design, synthesis and structural analysis of a series of 2,5-disubstitued phenethylpyrrolidine analogs via a key intermediate, cis-N-benzylpyrrolidine-2,5-dicarbonitrile. The primary goal of the ananlysis of the title compound is to confirm the stereochemistry of the molecule, and to obtain detailed information on the structural conformation of the molecule. The crystal X-ray studies revealed that the central pyrrolidine ring is not planar, and that the geometry of cyano groups at the C2 and C5 positions are equatorial. The angles between the exact plane defined by N1, C2, C1 and by the mean plane passing closest to the atoms of the pyrrolidinium ring (N1, C2, C3, C4, C5), and between the exact plane defined by N1, C5, C6 to the pyrrolidinium ring (N1, C2, C3, C4, C5) for the molecule are 72.48 (9)° and 75.92 (12)° respectively.

Related literature top

For Robinson–Schopf condensations with succinaldehyde, see: McIntosh (1988). For lobelane analog (systematic name 2-[6-(2-hydroxy-2-phenyl-ethyl)-1-methyl-2-piperidyl]-1-phenyl-ethanone) activity: Zheng et al. (2005).

Experimental top

The title compound was prepared by stirring a mixture of aqueous citric acid (90 ml, 0.1 M), 2,5- dimethoxytetrahydrofuran (8.3 mmol), benzylamine (4.5 mmol), and potassium cyanide (6.15 mmol) at ambient temperature for 48–72 h as per the literature procedure (McIntosh et al. 1988). The reaction mixture was then treated with excess solid sodium bicarbonate, and the reaction product extracted with dichloromethane (2x200 ml). The dichloromethane extracts were combined and dried over anhydrous sodium sulfate. The dried extract was evaporated, and chromatographed on silica gel using ethylacetate/hexane (1:9) as a eluent. From the obtained cis and trans diastereomers of N-benzylpyrrolidine-2,5-dicarbonitrile, the cis-N-benzylpyrrolidine-2,5-dicarbonitrile isomer was recrystallized from a mixture of diethyl ether and hexane (3:7) to afford a product which was suitable for single-crystal X-ray analysis. The 300-MHz proton spectrum of the cis isomer showed the benzylic protons as a clean singlet whereas in trans compound they appeared as an AB quartet. ¹H NMR (CDCl₃): δ 2.31 (m, 4H), 3.93 (d, j=4.1 Hz, 2H), 4.06 (s, 2H), 7.36 (m, 5H) p.p.m.; ¹³C NMR (DMSO-d₆): δ 28.60, 51.10, 53.40, 116.90, 128.31, 128.70, 128.90, 135.20 p.p.m..

Computing details top

Data collection: COLLECT (Nonius, 1998); cell refinement: SCALEPACK (Otwinowski & Minor, 1997); data reduction: DENZO-SMN (Otwinowski & Minor, 1997); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: XP in SHELXTL (Sheldrick, 2008); software used to prepare material for publication: SHELXL97 (Sheldrick, 2008) and local procedures.

Figures top

Fig. 1. A view of the molecule with the atom numbering scheme. Displacement ellipsoids are drawn at the 50% probability level.

1-Benzylpyrrolidine-2,5-dicarbonitrile top

Crystal data top

C₁₃H₁₃N₃	F(000) = 448
M_r = 211.26	D_x = 1.209 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
Hall symbol: -P 2ybc	Cell parameters from 2818 reflections
a = 10.9898 (3) Å	θ = 1.0–27.5°
b = 9.4494 (2) Å	µ = 0.08 mm⁻¹
c = 11.4768 (3) Å	T = 150 K
β = 103.0735 (11)°	Block, colourless
V = 1160.94 (5) Å³	0.24 × 0.20 × 0.16 mm
Z = 4

Data collection top

Nonius KappaCCD diffractometer	2662 independent reflections
Radiation source: fine-focus sealed tube	1574 reflections with I > 2σ(I)
Graphite monochromator	R_int = 0.061
Detector resolution: 9.1 pixels mm^-1	θ_max = 27.5°, θ_min = 1.9°
ω scans at fixed χ = 55°	h = −14→14
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997)	k = −12→12
T_min = 0.982, T_max = 0.988	l = −14→14
19299 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Secondary atom site location: difference Fourier map
R[F² > 2σ(F²)] = 0.051	Hydrogen site location: inferred from neighbouring sites
wR(F²) = 0.154	H-atom parameters constrained
S = 1.04	w = 1/[σ²(F_o²) + (0.0845P)²] where P = (F_o² + 2F_c²)/3
2662 reflections	(Δ/σ)_max = 0.003
164 parameters	Δρ_max = 0.17 e Å⁻³
12 restraints	Δρ_min = −0.18 e Å⁻³

Crystal data top

C₁₃H₁₃N₃	V = 1160.94 (5) Å³
M_r = 211.26	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 10.9898 (3) Å	µ = 0.08 mm⁻¹
b = 9.4494 (2) Å	T = 150 K
c = 11.4768 (3) Å	0.24 × 0.20 × 0.16 mm
β = 103.0735 (11)°

Data collection top

Nonius KappaCCD diffractometer	2662 independent reflections
Absorption correction: multi-scan (SCALEPACK; Otwinowski & Minor, 1997)	1574 reflections with I > 2σ(I)
T_min = 0.982, T_max = 0.988	R_int = 0.061
19299 measured reflections

Refinement top

R[F² > 2σ(F²)] = 0.051	12 restraints
wR(F²) = 0.154	H-atom parameters constrained
S = 1.04	Δρ_max = 0.17 e Å⁻³
2662 reflections	Δρ_min = −0.18 e Å⁻³
164 parameters

Special details top

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 > 2σ(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 (Å²) top

	x	y	z	U_iso*/U_eq	Occ. (<1)
N1	0.25240 (11)	0.12585 (13)	0.75852 (10)	0.0358 (4)
N2	0.23554 (17)	0.03238 (18)	0.46559 (13)	0.0694 (5)
N3	0.04139 (14)	0.30177 (17)	0.53565 (13)	0.0566 (5)
C1	0.24055 (16)	0.01114 (17)	0.56447 (15)	0.0450 (5)
C2	0.24688 (14)	−0.00845 (16)	0.69427 (12)	0.0359 (4)
H2	0.3214	−0.0673	0.7306	0.043*
C3	0.12832 (15)	−0.07866 (18)	0.71691 (14)	0.0449 (4)
H3A	0.0811	−0.1259	0.6435	0.054*
H3B	0.1499	−0.1499	0.7815	0.054*
C4	0.05140 (16)	0.04144 (19)	0.75352 (14)	0.0480 (5)
H4A	−0.0327	0.0454	0.6996	0.058*
H4B	0.0422	0.0280	0.8366	0.058*
C5	0.12448 (14)	0.17649 (17)	0.74314 (13)	0.0386 (4)
H5	0.1189	0.2424	0.8099	0.046*
C6	0.07641 (14)	0.24816 (17)	0.62628 (14)	0.0408 (4)
C7	0.34472 (15)	0.23004 (18)	0.73940 (15)	0.0454 (4)
H7A	0.3261	0.3209	0.7747	0.054*
H7B	0.3324	0.2451	0.6521	0.054*
C8	0.4794 (12)	0.1971 (13)	0.7882 (9)	0.0289 (16)	0.520 (5)
C9	0.5668 (13)	0.1649 (14)	0.7247 (11)	0.0361 (17)	0.520 (5)
H9	0.5473	0.1805	0.6408	0.043*	0.520 (5)
C10	0.6835 (16)	0.110 (3)	0.7786 (13)	0.0491 (6)	0.520 (5)
H10	0.7346	0.0671	0.7319	0.059*	0.520 (5)
C11	0.7226 (12)	0.1187 (14)	0.8995 (13)	0.049 (2)	0.520 (5)
H11	0.8052	0.0920	0.9382	0.058*	0.520 (5)
C12	0.6406 (5)	0.1667 (6)	0.9648 (5)	0.0595 (12)	0.520 (5)
H12	0.6677	0.1747	1.0492	0.071*	0.520 (5)
C13	0.5194 (6)	0.2035 (6)	0.9100 (5)	0.0512 (12)	0.520 (5)
H13	0.4635	0.2334	0.9573	0.061*	0.520 (5)
C8'	0.4716 (13)	0.1665 (15)	0.8006 (9)	0.0289 (16)	0.480 (5)
C9'	0.5535 (15)	0.1343 (16)	0.7288 (12)	0.0361 (17)	0.480 (5)
H9'	0.5246	0.1279	0.6445	0.043*	0.480 (5)
C10'	0.6791 (18)	0.111 (3)	0.7824 (14)	0.0491 (6)	0.480 (5)
H10'	0.7401	0.1175	0.7357	0.059*	0.480 (5)
C11'	0.7147 (13)	0.0806 (16)	0.9011 (14)	0.049 (2)	0.480 (5)
H11'	0.7986	0.0545	0.9357	0.058*	0.480 (5)
C12'	0.6276 (6)	0.0876 (7)	0.9703 (6)	0.0595 (12)	0.480 (5)
H12'	0.6494	0.0607	1.0522	0.071*	0.480 (5)
C13'	0.5090 (6)	0.1337 (6)	0.9200 (6)	0.0512 (12)	0.480 (5)
H13'	0.4508	0.1433	0.9694	0.061*	0.480 (5)

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0297 (7)	0.0376 (8)	0.0368 (7)	0.0013 (6)	0.0008 (5)	−0.0039 (6)
N2	0.0964 (14)	0.0703 (12)	0.0454 (9)	0.0083 (10)	0.0246 (9)	−0.0027 (8)
N3	0.0476 (9)	0.0639 (11)	0.0530 (9)	0.0107 (8)	0.0002 (7)	0.0081 (8)
C1	0.0508 (11)	0.0431 (10)	0.0412 (10)	0.0029 (8)	0.0104 (8)	−0.0039 (8)
C2	0.0351 (9)	0.0358 (9)	0.0346 (8)	0.0006 (7)	0.0033 (6)	−0.0013 (7)
C3	0.0418 (10)	0.0463 (10)	0.0455 (9)	−0.0057 (8)	0.0076 (7)	−0.0018 (8)
C4	0.0394 (10)	0.0592 (11)	0.0465 (9)	0.0003 (9)	0.0119 (8)	0.0037 (8)
C5	0.0332 (9)	0.0471 (10)	0.0337 (8)	0.0036 (7)	0.0039 (7)	−0.0040 (7)
C6	0.0315 (9)	0.0423 (10)	0.0456 (10)	0.0040 (7)	0.0026 (7)	−0.0053 (8)
C7	0.0397 (10)	0.0376 (9)	0.0545 (10)	−0.0036 (8)	0.0015 (7)	−0.0029 (8)
C8	0.0324 (16)	0.017 (5)	0.0372 (19)	−0.010 (2)	0.0068 (14)	0.0011 (19)
C9	0.038 (3)	0.030 (5)	0.0419 (12)	−0.017 (3)	0.0130 (12)	0.006 (2)
C10	0.0422 (14)	0.0482 (12)	0.0622 (13)	−0.0031 (10)	0.0231 (10)	−0.0089 (10)
C11	0.0317 (16)	0.044 (7)	0.0655 (13)	−0.003 (3)	0.0006 (11)	−0.009 (3)
C12	0.0422 (17)	0.090 (4)	0.0402 (12)	0.004 (3)	−0.0032 (11)	0.001 (3)
C13	0.0392 (15)	0.077 (4)	0.0370 (14)	0.003 (3)	0.0065 (10)	−0.011 (3)
C8'	0.0324 (16)	0.017 (5)	0.0372 (19)	−0.010 (2)	0.0068 (14)	0.0011 (19)
C9'	0.038 (3)	0.030 (5)	0.0419 (12)	−0.017 (3)	0.0130 (12)	0.006 (2)
C10'	0.0422 (14)	0.0482 (12)	0.0622 (13)	−0.0031 (10)	0.0231 (10)	−0.0089 (10)
C11'	0.0317 (16)	0.044 (7)	0.0655 (13)	−0.003 (3)	0.0006 (11)	−0.009 (3)
C12'	0.0422 (17)	0.090 (4)	0.0402 (12)	0.004 (3)	−0.0032 (11)	0.001 (3)
C13'	0.0392 (15)	0.077 (4)	0.0370 (14)	0.003 (3)	0.0065 (10)	−0.011 (3)

Geometric parameters (Å, º) top

N1—C5	1.457 (2)	C8—C13	1.369 (9)
N1—C2	1.4620 (19)	C9—C10	1.392 (10)
N1—C7	1.465 (2)	C9—H9	0.9500
N2—C1	1.1414 (19)	C10—C11	1.359 (10)
N3—C6	1.1427 (17)	C10—H10	0.9500
C1—C2	1.487 (2)	C11—C12	1.373 (9)
C2—C3	1.536 (2)	C11—H11	0.9500
C2—H2	1.0000	C12—C13	1.383 (7)
C3—C4	1.530 (2)	C12—H12	0.9500
C3—H3A	0.9900	C13—H13	0.9500
C3—H3B	0.9900	C8'—C13'	1.374 (9)
C4—C5	1.527 (2)	C8'—C9'	1.385 (10)
C4—H4A	0.9900	C9'—C10'	1.395 (11)
C4—H4B	0.9900	C9'—H9'	0.9500
C5—C6	1.489 (2)	C10'—C11'	1.361 (11)
C5—H5	1.0000	C10'—H10'	0.9500
C7—C8	1.493 (13)	C11'—C12'	1.377 (10)
C7—C8'	1.534 (14)	C11'—H11'	0.9500
C7—H7A	0.9900	C12'—C13'	1.372 (7)
C7—H7B	0.9900	C12'—H12'	0.9500
C8—C9	1.365 (9)	C13'—H13'	0.9500

C5—N1—C2	107.16 (12)	H7A—C7—H7B	107.2
C5—N1—C7	116.28 (12)	C9—C8—C13	117.0 (10)
C2—N1—C7	117.31 (12)	C9—C8—C7	127.1 (9)
N2—C1—C2	177.02 (17)	C13—C8—C7	115.8 (9)
N1—C2—C1	112.60 (13)	C8—C9—C10	122.3 (10)
N1—C2—C3	103.28 (12)	C8—C9—H9	118.9
C1—C2—C3	111.96 (12)	C10—C9—H9	118.9
N1—C2—H2	109.6	C11—C10—C9	118.5 (12)
C1—C2—H2	109.6	C11—C10—H10	120.7
C3—C2—H2	109.6	C9—C10—H10	120.7
C4—C3—C2	105.59 (13)	C10—C11—C12	118.8 (10)
C4—C3—H3A	110.6	C10—C11—H11	120.6
C2—C3—H3A	110.6	C12—C11—H11	120.6
C4—C3—H3B	110.6	C11—C12—C13	121.3 (7)
C2—C3—H3B	110.6	C11—C12—H12	119.4
H3A—C3—H3B	108.8	C13—C12—H12	119.4
C5—C4—C3	105.40 (13)	C8—C13—C12	120.4 (7)
C5—C4—H4A	110.7	C8—C13—H13	119.8
C3—C4—H4A	110.7	C12—C13—H13	119.8
C5—C4—H4B	110.7	C13'—C8'—C9'	117.1 (10)
C3—C4—H4B	110.7	C13'—C8'—C7	125.5 (10)
H4A—C4—H4B	108.8	C9'—C8'—C7	117.3 (9)
N1—C5—C6	113.23 (12)	C8'—C9'—C10'	118.9 (11)
N1—C5—C4	103.07 (13)	C8'—C9'—H9'	120.5
C6—C5—C4	111.40 (13)	C10'—C9'—H9'	120.5
N1—C5—H5	109.7	C11'—C10'—C9'	120.4 (13)
C6—C5—H5	109.7	C11'—C10'—H10'	119.8
C4—C5—H5	109.7	C9'—C10'—H10'	119.8
N3—C6—C5	178.57 (17)	C10'—C11'—C12'	119.2 (12)
N1—C7—C8	117.7 (4)	C10'—C11'—H11'	120.4
N1—C7—C8'	104.9 (5)	C12'—C11'—H11'	120.4
N1—C7—H7A	107.9	C13'—C12'—C11'	119.4 (8)
C8—C7—H7A	107.9	C13'—C12'—H12'	120.3
C8'—C7—H7A	113.7	C11'—C12'—H12'	120.3
N1—C7—H7B	107.9	C12'—C13'—C8'	122.2 (8)
C8—C7—H7B	107.9	C12'—C13'—H13'	118.9
C8'—C7—H7B	114.9	C8'—C13'—H13'	118.9

Experimental details

Crystal data
Chemical formula	C₁₃H₁₃N₃
M_r	211.26
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	150
a, b, c (Å)	10.9898 (3), 9.4494 (2), 11.4768 (3)
β (°)	103.0735 (11)
V (Å³)	1160.94 (5)
Z	4
Radiation type	Mo Kα
µ (mm⁻¹)	0.08
Crystal size (mm)	0.24 × 0.20 × 0.16

Data collection
Diffractometer	Nonius KappaCCD diffractometer
Absorption correction	Multi-scan (SCALEPACK; Otwinowski & Minor, 1997)
T_min, T_max	0.982, 0.988
No. of measured, independent and observed [I > 2σ(I)] reflections	19299, 2662, 1574
R_int	0.061
(sin θ/λ)_max (Å⁻¹)	0.649

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.051, 0.154, 1.04
No. of reflections	2662
No. of parameters	164
No. of restraints	12
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.17, −0.18

Computer programs: COLLECT (Nonius, 1998), SCALEPACK (Otwinowski & Minor, 1997), DENZO-SMN (Otwinowski & Minor, 1997), SHELXS97 (Sheldrick, 2008), XP in SHELXTL (Sheldrick, 2008), SHELXL97 (Sheldrick, 2008) and local procedures.

Acknowledgements

This research was supported by NIH grant RO1 DA13519.

References

McIntosh, J. M. (1988). J. Org. Chem. 53, 447–448. CrossRef CAS Google Scholar
Nonius (1998). COLLECT. Nonius BV, Delft, The Netherlands. Google Scholar
Otwinowski, Z. & Minor, W. (1997). Methods in Enzymology, Vol. 276, Macromolecular Crystallography, Part A, edited by C. W. Carter Jr & R. M. Sweet, pp. 307–326. New York: Academic Press. Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Zheng, G., Dwoskin, L. P., Deaciue, A. G., Norrholm, S. D. & Crooks, P. A. (2005). J. Med. Chem. 48, 5551–5560. Web of Science CrossRef PubMed CAS Google Scholar