2-[1′-(Benz­yloxy)spiro­[indane-1,2′-pyrrolidine]-5′-yl]aceto­nitrile

Rodolfo Moreno-Fuquen; Diana M Soto; Luz M Jaramillo-Gómez; Javier Ellena; Juan C Tenorio

doi:10.1107/S1600536813017674

. 2013 Jul 3;69(Pt 8):o1192–o1193. doi: 10.1107/S1600536813017674

2-[1′-(Benzyloxy)spiro[indane-1,2′-pyrrolidine]-5′-yl]acetonitrile

Rodolfo Moreno-Fuquen ^a,^*, Diana M Soto ^a, Luz M Jaramillo-Gómez ^a, Javier Ellena ^b, Juan C Tenorio ^b

PMCID: PMC3793706 PMID: 24109293

Abstract

In the title compound, C₂₁H₂₂N₂O, the planes of the two six-membered rings make a dihedral angle of 89.51 (7)°. The pyrrolidine ring has a puckering amplitude q ₂ = 0.418 (3) and a pseudo-rotation phase angle ϕ₂ = −166.8 (5), adopting a twist conformation (T). The other five-membered ring has a puckering amplitude q ₂ = 0.247 (2) and a pseudo-rotation phase angle ϕ₂ = −173.7 (5), adopting an envelope conformation with the CH₂ atom adjacent to the C atom common with the pyrrolidine ring as the flap. In the crystal, molecules are linked via C—H⋯N, enclosing R ² ₂(20) rings, forming chains propagating along [100]. The acetonitrile group is disordered over two positions and was refined with a fixed occupancy ratio of 0.56:0.44.

Related literature

For radical cyclization of 1-azaspiro compounds, see: El Bialy et al. (2004 ▶); Dake (2006 ▶). For cephalotaxine synthesis, see: Paudler et al. (1963 ▶); Planas et al. (2004 ▶). For esters with antileukemic activity, see: Benderra et al. (1998 ▶); Kantarjian et al. (2001 ▶); Lévy et al. (2006 ▶). For pyrrolidine properties, see: Chen et al. (2012 ▶); Boyd et al. (1999 ▶). For tandem reactions under radical conditions, see: Jaramillo-Gómez et al. (2006 ▶). For bond-length data, see: Allen et al. (1987 ▶). For hydrogen bonding, see: Nardelli (1995 ▶) and for hydrogen-bond motifs, see: Etter (1990 ▶). For ring torsion angles, see: Cremer & Pople (1975 ▶). graphic file with name e-69-o1192-scheme1.jpg

Experimental

Crystal data

C₂₁H₂₂N₂O
M _r = 318.41
Triclinic,
a = 9.1688 (4) Å
b = 10.0800 (4) Å
c = 11.4141 (6) Å
α = 98.826 (2)°
β = 108.777 (2)°
γ = 110.403 (4)°
V = 893.17 (7) Å³
Z = 2
Mo Kα radiation
μ = 0.07 mm⁻¹
T = 295 K
0.29 × 0.25 × 0.15 mm

Data collection

Nonius KappaCCD diffractometer
6429 measured reflections
3617 independent reflections
2307 reflections with I > 2σ(I)
R _int = 0.063

Refinement

R[F ² > 2σ(F ²)] = 0.059
wR(F ²) = 0.191
S = 1.05
3617 reflections
249 parameters
3 restraints
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.11 e Å⁻³
Δρ_min = −0.13 e Å⁻³

Data collection: COLLECT (Nonius, 2000 ▶); cell refinement: SCALEPACK (Otwinowski & Minor, 1997 ▶); data reduction: DENZO (Otwinowski & Minor, 1997 ▶) and SCALEPACK; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: ORTEP-3 for Windows (Farrugia, 2012 ▶) and Mercury (Macrae et al., 2006 ▶); software used to prepare material for publication: WinGX (Farrugia, 2012 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536813017674/hg5325sup1.cif

e-69-o1192-sup1.cif^{(22.2KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536813017674/hg5325Isup2.hkl

e-69-o1192-Isup2.hkl^{(177.3KB, hkl)}

Click here for additional data file.^{(6.8KB, cml)}

Supplementary material file. DOI: 10.1107/S1600536813017674/hg5325Isup3.cml

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
C21—H21⋯N2B ⁱ	0.93	2.61	3.511 (15)	164
C21—H21⋯N2A ⁱ	0.93	2.48	3.390 (18)	168

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Symmetry codes: (i) Inline graphic .

Acknowledgments

RMF and LMJG are grateful to the Universidad del Valle, Colombia, for partial financial support.

supplementary crystallographic information

Comment

The title compound, 1'-(benzyloxy)-5'-cyanomethyl-2,3-dihydrospiro [inden-1,2'-pyrrolidine], (trans-IIIa), belongs to the family of spirocyclic compounds. It is worthwhile to stand out the natural occurring and synthetic cyclic alkaloids which contain a nitrogen atom adjacent to the spiro carbon. Of special interest are the structures exhibiting the 1-azaspiro[4.4]nonane (I) system (El Bialy et al., 2004) which represents the central core of the cephalotaxine, a natural occurring product isolated from evergreen plum yews of the genus Cephalotaxus (Paudler et al., 1963; Planas et al., 2004), whose ester derivatives as homoharringtonine exhibited a pronounced antileukemic activity (Benderra et al., 1998; Kantarjian et al., 2001; Lévy et al., 2006). Pyrrolidine is a heterocyclic amine used as building block or base in pharmaceutical and fine chemical manufacturing (Boyd et al., 1999; Chen et al., 2012). Therefore, considerable attention has been focused toward the synthesis of molecules with the embedded 1-azaspiro [4.4]nonane (I) system in their structures, using mainly ionic strategy and only scarce examples via radical cyclisation to form out them (El Bialy et al., 2004; Dake, 2006).

Continuing with our current interest in applying tandem reactions under radical conditions, with the participation of aryl and neutral alkyl oxyaminyl radicals (Jaramillo-Gómez et al. 2006), we are reporting here, the synthesis of the azaspirocyclic 1'-(benzyloxy)-5'-cyanomethyl-2,3-dihydrospiro [inden-1,2'-pyrrolidine] (III), as a mixture of the diastereomers cis and trans, being able to crystallize in the pure form, the isomer trans IIIa. The interesting azaspiro [4.4] nonano (I) framework embedded in (III) was obtained in one single synthetic step, from the oxime ether 6-(benzyloxy-imino)-8-(2-iodophenyl)oct-2-enenitrile (II), through a sequential process of two closures 5-exo under standard radical conditions, (scheme 2). The molecular structure of (trans IIIa) is shown in Fig. 1.

The title compound crystallizes in the monoclinic space group P2₁/c. The two phenyl rings are oriented to each other with a dihedral angle of 89.51 (7)°. Analysis of torsion angles, and least-square plane calculation, indicate that pyrrolidine ring shows a puckering amplitude q₂= 0.418 (3) and pseudo-rotation phase angle φ₂= -166.8 (5) adopting a twist conformation T with the N atom above the mean plane of the ring. In the same way the other five member ring shows a puckering amplitude q₂= 0.247 (2) and pseudo-rotation phase angle φ₂= -173.7 (5) adopting an envelope conformation E with the atom C9 below the mean plane of the ring (Cremer & Pople, 1975). The N-O bond length is close to the mean value [1.463 (12) Å] reported in the literature (Allen et al., 1987) and the torsion angle formed by the atoms [N1-O1-C15-C16] which links the pyrrolidine and phenyl rings is 179.41 (13)°. The crystal packing reveals that the molecules are linked through a network of weak C—H···N and C—H···O intermolecular interactions (see Table 1, Nardelli, 1995). The C21 atom in the molecule at (x,y,z) donates a proton to N2a y N2b atoms in the molecule at (-x+2,-y+2,-z+1), forming as a result of these interactions R²₂(20) rings (Etter, 1990). These rings are in turn linked by a weak C-H···O interaction. Indeed, the C23 atom in the molecule at (x,y,z) donates a proton to O1 atom of the molecule at (-x+1,-y+2,-z+1) forming layers parallel to (001) as shown in Fig. 2.

Experimental

The reagents and solvents for the synthesis were obtained from the Aldrich Chemical Co., and were used without additional purification. A solution of 6-(benzyloxyimino)-8-(2-iodophenyl)oct-2-enenitrile (II) (129 mg, 0.29 mmol), 2,2'-azobisisobutyronitrile (AIBN, 14 mg, 0.09 mmol) and tributyltin hydride (n-Bu₃SnH, 0.09 ml, 0.35 mmol) in cyclohexane (Cy, 13 mL) was degassed for 1 h by bubbling dry argon, and subsequently stirred at 353 K for 7 h. After cooling to room temperature the solvent was removed under reduced pressure and the crude product treated with a mixture of 20% KF aqueous solution (2 mL) and ethyl acetate (2 mL), stirring overnight. The organic layer was separated, dried with anhydrous Na₂SO₄ and filtered over silica gel. The purification was carried out by flash column chromatography with 60-95% benzene/hexane (gradient 5%) to afford a mixture of two diastereomers IIIa and IIIb (59 mg, 65%) as yellow oil. By addition of hexane to this oil, white crystals suitable for X-ray diffraction, fell down [20 mg, 21%, m.p. 372 (1) K] of the diastereomeric spirocycle trans-IIIa suitable for X-ray analysis. Elemental Analysis: Calculated: C 79.20, H 6.98, N 8.80; Found: C 79.25, H 6.73, N 8.85.