Hydrogen bonds involving polar CH groups. Part 8. The synthesis andX-ray crystal structure of 2-(2,2-dimethyl-3-piperidinopropyl)-1,3-dithian 1,1,3,3-tetraoxide; a sterically crowded cyclic disulphone

摘要

J. CHEW SOC. PERKIN TRANS. I 1983 Hydrogen Bonds involving Polar CH Groups. Part 8.1 The Synthesis and X-Ray Crystal Structure of 2-(2,2-Dimethyl-3-piperidinopropyl)-1,3-dithian I ,I ,3,3=Tetraoxide;a Sterically Crowded Cyclic Disulphone Richard L. Harlow Central Research and Development Department, Experimental Station, E. I. du Font de Nemours and Company, Wiimington, Delaware 19898,U.S.A. Reaction between 2,2-dimethyl-3-piperidinopropanal (8) and lithio-2-trimethylsilyl-l,3-dithian givesa keten dithioacetal (10), which is reduced to a dithioacetal (11) with trimethylsilane in trifluoroacetic acid, and oxidised to the title compound (2) with potassium permanganate in acetic acid. The advantages of trimethylsilane as a reducing agent are discussed. Crystal structure analysis of the disulphone (2),designed as a model for intramolecular C-H * N interactions, shows it to have an extended conform- ation, the desired cyclic conformation being disfavoured by steric effects. The structure was solved by direct methods, and refined to R 0.039 for 2 232 independent reflections.The crystals are monoclinic, a = 7.107(2),b = 25.373(4), c = 9.929(2) A, j3 = 108.55(2)",space group P2,/c, and Z = 4. As part of a programme designed to determine the optimum structural requirements for intramolecular C-H X a (2) R=Me (3) R=H gous to (9,but having R' = R2= stronger interact ion. (4)R'=R~:H (6) (5) R1 = Mc,R2: HResults and Discussion Synthesis of the Disufphone (2).-Compounds of type (1) Me Me Me Mehave been prepared by reaction between the anion derived X 'C'from the disulphone (6) and appropriately substituted alkyl halides.' However, difunctionalised derivatives (7) of 2,2-'CHC bsol;CHfZ dimethylpropane are sterically hindered towards SN2dis-H placement reactions, and attempts to prepare compound (2) (7) (8)from structures of this type and the disulphone (6) failed.An attractive alternative approach was to condense the aldehyde (8) from a Mannich reaction between piperidine, methanal, and 2-methylpr~panal~ with the disulphone (6), and to reduce the resulting double bond to give (2). However, attempts to carry out the condensation under a wide variety 4e Le of conditions failed, owing again to excessive steric crowding. Seebach and co-workers have prepared keten dithioacetals in high yields by reaction between lithio trimethylsilyl dithio- acetals, such as (9), and carbonyl compounds, including sterically crowded aldehydes and ketones? The approach (9) (10) shown in the Scheme was thus attempted.Reaction between compounds (8) and (9) gave a moderate yield of the expected product (lo), a type of structure which has been reduced effectively by triethylsilane in trifluoro- Meacetic acid (TFAA).SAlthough this reagent reduced compound H bsol;/ Me (10) in moderate yield, the product (11) could not be freed completely from triethylsilanol either by fractional distillation or by column chromatography. The alternative triphenyl- silane gave only a very low yield of (11). In contrast, the sterically smaller trimethylsilane effected the reduction in good yield in TFAA, and the lower boiling (31-34 "C/26 scheme.J. CHEW SOC. PERKIN TRANS. I 1983 ~~ ~ Table 1. Selected bond lengths (A), valency angles (O), and torsion angles(O), with e.s.d.s in parentheses Ton)trimethylsilanol was readily removed together with the solvent under reduced pressure, leaving the product (1 1) essentially pure. We thus suggest trimethylsilane as a con- venient alternative reagent to its triethyl analogue in reduc- tions of this type. For the final oxidation step we used potas- sium permanganate in acetic acid, this being one of the few reagents available for the oxidation of sulphides to sulphones in the presence of tertiary amines.6 Disulphone (2) was formed in good yield.The lH n.m.r. chemical shift of the disulphone ring methine proton has proved to be the most sensitive probe for intra- molecular C-H X interactions as in structure (1).2 Thus, for compounds (3), (4), and (5) in which interactions were indicated, values respectively of G(CD2Clz) 5.03, 4.62, and 5.53 were observed, as compared with 6 4.23 found in the homologue of (4) having six methylene groups in the side chain.* In the disulphone (2) the methine signal was found at 6 4.83, an ambiguous result, but one which showed clearly that the introduction of a second side-chain methyl group reduced, rather than enhanced, the interaction apparent in compound (5). To establish the molecular conformation adopted by com- pound (2) in the solid state, crystals were examined by X-ray diffraction methods.The structure determination was of additional interest since there have been no reports to date giving crystal structures of monocyclic disulphones, although the conformations of such systems have been inferred from dipole-moment measurements.' Structure of the Disulphone (2).-Selected bond lengths, valency angles, and torsion angles are given in Table 1. An ORTEP drawing (Figure) shows the molecule to have an extended conformation which prohibits an intramolecular H(l) N interaction. Both rings are in chair conform- ations, and the part of the molecule including C(6), C(7), C(13), C(14), and the piperidine ring is almost symmetrical about a plane through C(6), C(7), N, and C(lO), though the ring is rotated about the N-C(7) bond by nearly 2".The other half of the molecule deviates from symmetry about this plane in two senses: first there is a twist of nearly 4" about the C(5)-C(6) bond, apparently to relieve O(2) H(14) and O(4) H(13) interactions (Table 2), and second the di- sulphone ring is itself distorted about an axis through C(l) and C(3). This latter distortion is apparent from a comparison of the torsion angles C(l)-S(l)-C(2)-C(3) with C(l)-S(2)- C(4)-C(3) and 0(2)-S(l)-C(2)-C(3) with 0(4)-S(2)-C(4)- C(3) (Table lc), and from Table 3 in which S(l) and C(4) are seen to lie below, and S(2) and C(3) above, a plane defined by these four atoms.This distortion probably helps to relieve interactions among 0(1), 0(3), H(3), H(5A), and H(5B) (Table 2a).Adjacent axial atoms deviate less than 6" from an antiperiplanar conformation (Table 1 c). An examination of space-filling models suggests that the conformation adopted by the disulphone (2) in the crystal is the most stable, a conformation as in structure (1) being higher in energy owing to a serious steric interaction between one methyl group and a sulphone oxygen atom. This interaction is lacking in the analogous conformation of the monomethyl compound (3,thus permitting a C-H N close approach and accounting for the lower field chemical shift of the di- sulphone ring methine proton. Bond lengths and angles appear to be normal from a comparison with molecules having related structural units.* Smaller incremental shifts were found in analogues having OMe in place of the NR2 group, showing that the electronegativity of X was not the major contributor to the downfield shift of the methine proton. (b)Valency angles O(l)-S(1)-0(2) O(1)-S( 1 )-C( 1) O(1)-S( 1)-C(2) 0(2)-S( 1 )-C( 1) 0(2)-S(I)-C(2) C( 1 )-S( 1)-C(2)0(3)-S(2)-0(4) 0(3)-S(2)-C(l)0(3)-S(2)-C(4) 0(4)-S(2)-C(1) 0(4)-S(2)-C(4) C( 1)-S(2)-C(4) S(1)-C(1)-S(2) S(1)-C( 1)-c(5) S(2)-C(l )-C( 5) S(l)-C(2)-C(3) C(2)-C(3)-C(4) 1.442( 1) 1.430(2) 1.799(2) 1.765(2) 1.436(1)1.433(2) 1.813(2) 1.766(2) 1.539(3)0.95(2) 1.523(3) 1.508(3) 118.2(1) 108.7( 1 ) 108.6( 1) 107.3( 1 ) 109.7(1) 103.3( 1 ) 118.5(1) 106.8(1)109.5(1) 107.0(1) 109.3( 1) 105.0(1) 111.9(1) 1 1 1.2(2) 10942) 112.0(2) 113.6(2) C(5)-C(6) C(6)-C(7)C( 6)-C( 13) C(6)-C(14)N-C( 7) N-C(8)N-C( 12) C@)-C(9)C(9)-C( 10) C( 1 0)-C( 1 1) C( 1 1)-C(12) S(2)-c(4)-c(3) C( l)-C(5)-C(6) 1.536(3) 1.531 (3) 1.529(3) 1.521(3) 1.467(3) 1.460(3) 1.459(3) 1.520(4) 1.494(5) 1.508(5) 1.514(4) 113.8(2) 116.2(2) 105.6(2) 11 1 .q2) 110.7(2) 109.9(2) 109.4(2) 110.1(2) 113.2(2) 112.1(2) 112.8(2) 110.3(2) 110.7(2) 11 1.4(3) 109.2( 3) 11 133) 110.8(2) C(5)-C(6)-C(7)C(5)-C(6)-C(13) C(S)-C(6)-C( 14) C(7)-C(6)-C( 13) C(7)-C(6)-C( 14) C(13)-C(6)-C( 14) N-C( 7)-C( 6) C( 7)-N-C(8) C( 7)-N-C( 1 2) C( 8)-N-C( 1 2) N-C( 8)-C( 9) C(8)-C(9)-C( 10) C(9)-C(lO)-C(11) C( 1 0)-C( 1 1 )-C( 12) N-C( 12)-C( 1 1) (c) Torsion angles S(1 )-C( 1 )-S( 2)-c(4)S(1 )-C( 1 )-C( 5)-C( 6) S( I)-C(2)-C(3)-C(4) S(2)-C( 1)-S( 1)-C(2) S(2)-C(l)-C( 5)-C(6) S(2)-C(4)-C( 3)-c(2) O(1)-S( 1)-C( 1)-H( 1) O(l)-S(l)-C(2)-H(2A) 0(2)-S( l)-C(2)-c(3) 0(3)-S(2)-C( 1)-H( 1) O(3)-S(2)-C(4)-H(4B) 0(4)-S(2)-C(4)-C( 3)N-C( 7)-C( 6)-C( 5) N-C(7)-C(6)-C( 13) N-C(7)-C(6)-C( 14) N-C(8)-C(9)-C( 10) N-C( 12)- C( 1 1 )-C( 10) C(1)-S( 1 )-C(2)-C( 3) C(1 )-S(2)-C(4)-C(3) C( 1 )-C( 5)-C( 6)-C( 7) C(6)-C( 7)-N-C( 8) C( 6)-C( 7)-N-C( 1 2) C(8)-C(9)-C( 10)-C( 1 1) C(9)-C( 1 0)-C( 11 )-C( 12) H(2A)-C(2)-C( 3)-H( 3A) H( 3A)-C( 3)-C(4)-H(4B) -50.7 117.0 68.9 53.9 -118.8 -65.0 -174.3 179.3 -174.7 177.8 174.5 168.0 -179.4 -59.6 61.5 -57.9 57.1 -60.5 53.7 176.4 115.5 -119.3 54.5 -54.2 -176.0 176.4 Thus for two structures having the fragment S02-CHz-S02,B*9 relevant bond parameters are, respectively, C-S 1.79 and 1.798 A, S=O 1.44 and 1.428 A, S-C-S 111.5 and 112.9", 0-S-O 118.2 and 118.9", and C-S-C 104.9 and 103.2".Likewise, the parameters for the piperidine ring closely match those for an N-alkyl analogue,'' though in other examples J. CHEM. soc. PERKIN TRANS. I 1983 Figure. ORTEP drawing of the disulphone (2) showing the atom numbering system used -H contacts Table 3. Least-squares mean plane equation, and distances (A)from the plane for atoms in the disulphone ring" Atom X Y z W)* 1.1392 3.5768 6.4706 4.9674 3.8842 4.7515 C(2)*C(4)* C(1) (33) 2.3272 4.3803 2.0839 3.4939 7.7264 6.491 1 4.9483 7.7025 3.5262 4.3602 3.7228 4.5057 Distance -0.026(1) 0.026(1) 0.031(3)-0.031(3) 0.783(2)-0.709(3) (a)Intramolecular 3.0A 0(1) --H(3A) 2.67(2) O(3) -H(3A) 2.88(2) 0(1) --H(5A) 2.71(2) O(3) H(5B) 2.60(2) O(2) H(14A) 2.88(2) O(2) H(14C) 2.97(3) O(4) H(13B) 2.84(2) (b)Intermolecular 2.6 A 0(1) H(l) 2.54(2) 0(1) H(2A) 2.54(2) O(2) H(4B) 2.59(2) O(3) H(2A) 2.42(2) O(3) * -H(4B) 2.45(2) O(3) * H(9B) 2.57(3) a The equation is of the form (0.1370)~+ (-0.3481)~+ (-0.9274)~+ (-5.6720) = 0.x, y, and z are orthogonalised co-ordinates inamp; The atoms used in the plane calculation are indicated with an asterisk. under reduced pressure, and the residue used directly in the next stage, crude yield 1.32 g (73); M+' 273; G(CDC13) 4.11 (1 H, t, J5 Hz, dithian CH), 3.0-2.7 (4 H, m, CH2S), 2.44 (4 H, in) and 2.05 (2 H, s) (CH2N), 2.0 (2 H, m,dithian CH2), 1.58 (2 H, d, J 5 Hz, side-chain CH2), 1.41 (6 H, m, piperidine CH2), and 0.92 (6 H, s, CH3). Oxidation to disulphone (2). A solution of the dithian (11) (1.0 g, 0.0037 mol) in glacial AcOH (30 ml) was treated with powdered KMn04 (0.29 g, 0.0018 mol). The mixture was stirred at 25 "C for 36 h, rendered colourless with SO2gas, adjusted to pH 10 with solid Na2C03, and extracted continu- ously with Et20 overnight.The residue from evaporation of the Et20 was dissolved in 2wHC1 (50 ml), the solution was extracted with CHC13 (3 x 25 ml), and the aqueous phase was treated with excess of solid Na2C03. The solution was again extracted with CHC13 (3 x 25 ml), and the extracts were dried (MgS04) and evaporated. Recrystallisation of the residue (CHC13-CC14) gave the disulphone (2) (0.75 g, 60) as plates, m.p. 205 "C (Found: C, 50.1; H, 8.2; N, 4.3. c14H27' NOamp; requires C, 49.8; H, 8.1; N, 4.15); M+' 337; vmX. 2 805 (CH2N), 1 330, and 1 142 cm-' (SOz); 6('H) (CD2C12) 4.86 l H, t, J 3.9 Hz, H(l), 3.47-3.11 4 H, m, H(2) and H(4), 2.49-2.36 6 H, m, H(3), H(8), and H(12), 2.18 2 H, s, H(7), 2.14 12 H, d, .I3.9 Hz, H(5), 1.45 6 H, m, H(9), H(lo), and H( 1l), and 0.94 6 H, s, H(13) and H( 14); S(I3C) (CD2C12) 78.11 C(l), 70.20 C(7), 57.67 C(8) and C(12), 51.27 C(2) and C(4), 35.38 C(6), 30.13 C(S), 27.10 C(13) and C(14), 25.99 C(9) and C(ll), 24.53 C(lO), and 17.78 p.p.m.C(3)1. Crystal Data for the Disulphone (2).-C14H27N04S2, M = 337.50, monoclinic, space group P21/c (No. 14), 2 = 4. At 173 K: a = 7.107(2), 6 = 25.373(4), c = 9.929(2) A, p = 108.55(2)", U = 1697 A', D, = 1.321 g ~rn-~.Mo-K, radiation, h = 0.710 69 A, p(Mo-amp;) = 3.14 cm-'. A crystal with approximate dimensions 0.45 x 0.05 x 0.50 mm was mounted on a Syntex P3 diffractometer equipped with a low-temperature apparatus which cooled the crystal to 173 K.The unit-cell dimensions at this temperature were refined from the setting angles of 44 computer-centred reflections in the range 22" 28 26". the C(9)-C(10) and C(l0)-C(11) distances are greater than those for C(8)-C(9) and C(l 1)-C(12).11*12 The nitrogen atom makes no close intermolecular approaches to hydrogen atoms in other molecules, probably for steric reasons. However, it is noteworthy that the sulphonyl oxygen atoms make several such close approaches, most being to the more polar axial hydrogens H(l), H(2A), and H(4B). Those less than 2.6 A are given in Table 26; it is possible that interactions of this type are responsible for the observed high m.p. of many cyclic disulphones e.g., 308 "C for compound (6).Experimenta1 1.r. spectra were recorded in Nujol on a Perkin-Elmer 577 spectrophotometer, using polystyrene in calibration, 'H and 13C n.m.r. spectra on a JEOL FX 90Q instrument in CDC13, using SiMe4 as internal reference, and mass spectra on a Hitachi RMS-4spectrometer.2,2-Dimethyl-3-piperidinopropanal (8): 2-trimethylsilyl-1 ,3-dithian,4 and trimethylsilane l3 were prepared by pub- lished procedures. Preparation of the Disulphone (2).-2-Methyl-3-piperidino-propan-2-ylketen trimethylene dithioacetal (10). 2-Trimethyl- silyl-1,3-dithian (3.84 g, 0.020 mol) was dissolved in dry tetrahydrofuran (THF) (40ml) at -78 "C, and BunLi (12.8 ml;15 solution in pentane) was added. After 1 h at -50 "C, the solution was treated dropwise with the amino-aldehyde (8) (3.74 g, 0.022 mol), the temperature was raised slowly to -20 "C, and the mixture was stirred at this temperature for 2 h and overnight at 25 "C.Water (10 ml) was added, the mixture was evaporated under reduced pressure, the residue was extracted with CHCl, (50 ml), and the extract dried (MgS03 and evaporated to give the dithioacetal(l0) (2.05 g, 38), b.p. 124 "C/0.2 TOIT; M+' 271; G(CDCl3) 5.99 (1 H, s, '0,3.0-2.7 (4 H, m, CH2S), 2.42 (4 H, m), and 2.30 (2 H, s) (CH2N), 2.08 (2 H, m, dithian CH2), 1.42 (6 H, m, piperidine CH3, and 1.1 6 (6 H, s, CH3).2-(2,2-DimethyZ-3-piperidinopropyl)-1,3-dithian(1 1). Keten dithioacetal (10) (1.8 g, 0.0066 mol) was dissolved in CH2C12 (20 ml), TFAA (2.5 ml) was added, the solution was cooled to 0 "C, and Me3SiH (1.5 ml; precooled to O "C) was added in one portion. The mixture was stirred at 25 "C in a sealed flaskfor 48 h, the solvent and by-product Me3SiOH evaporated Table 4.Final positional parameters (x lo'; for S, x 105) for the non-hydrogen atoms of disulphone (2), with e.s.d.s in parentheses X Y Z 34369(9) 72762(9) 3495(2) 1541(3) 7305(2) 8227(3) 1089(3) 469q3) 4939(4) 7043(4) 8222(4) 3657(4) 278 l(4) 1976(4) 2187(5) 1359(6) -794(6) -1W5) -1006(4)4375(4) 1088(4) 25502(3) 19577(3) 2606( 1) 2544(1) 1968(1) 1527( 1) 190(1)1950(1) 3045( 1) 3036(1) 2558(1) 1467(1) 1068( 1) 615( 1) -304(1) -720(1) -817(1) -301(2) 106(1)862(1) 13 14( 1) 41263(6) 50477(6) 5584( 2) 3048(2) 65W2)4588(2)2815(2) 3955(2) 3 746(3) 4787(3)4632(3) 43 3 8(3) 3 138(3) 3816(3) 3198(3) 2062(3) 183 l(2) 1507(4) 2645(3) 2540(3) 1958(3) Intensity data for 2 841 independent reflections (4" 28 50deg;, graphite monochromatised Mo-K, radiation) were col-lected by the a-scan technique. Scans of 0.8" were used with scan rates in the range 4.0-10.0" min-'.Backgrounds were measured at both ends of the scan, with a displaced 1" from the K, peak. Intensities were corrected for Lorentz and polarisation effects and also for absorption, the amount of variance in transmission factors being 0.91-1 .OO. Solution and refinement. These were carried out on a PDP-11 computer using local modifications of the programmes supplied by the Enraf-Nonius Corp.l4The atomic scattering factors were taken from ref.15. The structure was solved in a straightforward fashion by direct methods (MULTAN). The positions of the hydrogen atoms were calculated. Full matrix least-squares refinement of all positional and thermal parameters (anisotropic for C, * For details of the Supplementary Publications scheme, see Instructions to Authors (1983) in J. Chem. SOC.,Perkin Trans. I, 1983,Issue 1, J. CHEM. SOC. PERKIN TRANS. I 1983 N, 0,and S; isotropic for H)using 2232 reflections with FO220(F2) converged at R =ZllFol-lFcll/ZIFol=0.039 and R, =Ew(lFol -~Fc~)2/~w~FozJ*=0.039. The largest peak in the final difference-Fourier map had a magnitude less than 0.27 e A-3. Final positional parameters are given in Table 4, and final observed and calculated structure factors, and thermal parameters are available as a Supplementary Publication (SUP No.23554,21 pages).* Acknowledgement We thank the University of Hong Kong for providing a research grant (for C. L.). References 1 Part 7, K. S. Luk, M.P. Sammes, and R. L. Harlow, J. Chem. SOC.,Perkin Trans. 2, 1980, 1166. 2 Chuen Li and M. P. Sammes, J. Chem. SOC., Perkin Trans. I, following paper. 3 C. Mannich, B. Lesser, and F. Silten, Ber., 1932, 65, 378. 4 D. Seebach, B.-Th. Grobel, A. K. Beck, M.Braun, and K.-H. Geiss, Angew. Chem., Int. Ed. Engl., 1972, 11, 443. 5 F. A. Carey and J. R. Neergaard, J. Org. Chem., 1971,36,2731. 6 A. R. Surrey, W. G. Webb, and R. M.Gesler, J. Am. Chem. SOC.,1958,80,3469; M. P. Sammes and R. L. Harlow, J. Chem. SOC., Perkin Trans. 2, 1976, 1130. 7 C. Pigenet, G. Geminet, and H. Lumbroso, C.R. Hebd. Seances, Acud. Sci. Set. C, 1971,272, 2023. 8 J. Berthou, G. Geminet, and A. Laurent, Acta Crysfallogr., 1972, B28,2480. 9 J. S. Grossert, M.M.Bharadwaj, R. F. Langler, T. S. Cameron, and R. E. Cordes, Can. J. Chem., 1978,56, 1183. 10 A. Ducruix and C. Pascard-Billy, Acta Crystallogr., 1974, B30, 1677. 11 N. Camerman and A. Camerman, J. Am. Chem. SOC.,1972, 94,8553. 12 P. G.Jones and 0.Kennard, Acta Crystallogr., 1977, B33,3444. 13 S. Tannenbaum, S. Kaye, and G. F. Lewenz, J. Am. Chem. SOC.,1953, 75, 3753. 14 B. A. Frenz in 'Computing in Crystallography,' eds. H. Schenk, R. Olthof-Hazekamp, H. van Koningsveld, and G. C. Bassi, Delft University Press,Delft, 1978, pp. 64-71. 15 D. T. Cromer and J. T. Waber, in 'International Tables for X-Ray Crystallography,' eds. J. A. Ibers and W.C. Hamilton, Kynoch Press, Birmingham, 1974, vol. IV,p. 99. Received 1st November 1982;Paper 211833