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Synthesis and structural and conformational study of some esters derived from 8-α-hydroxy-3-phenethyl-3-azabicyclo [3.2.1] octan-8-β-carboxylic acid
Journal of Molecular Structure, 246 (1991) 339-357 Elsevier Science Publishers B.V., Amsterdam
339
Synthesis and structural and conformational study of some esters derived from 8-c~-hydroxy-3-phenethyl-3azabicyclo [ 3.2.1 ] octan-8-fl-carboxylic acid
M. Diez, M.L. Izquierdo, E. Galvez ~ and M.S. Arias Departamento de Quimica Orgdnica, Universidad de Alcald de Henares, Madrid (Spain)
I. Fonseca and J. Sanz-Aparicio Instituto "Rocasolano" UEI Cristalografia, C.S.I.C. Serrano 121, 28006 Madrid (Spain) (Received 19 November 1990)
Abstract
A series of 8-fl-alcoxycarbonyl-8-ot-hydroxy-3-phenethyl-3-azabicyclo[3.2.1]octane derivatives have been synthesized and studied by IR, 1H and 13C NMR spectroscopy, and the crystal structure of ethyl-8-a-hydroxy-3-phenethyl-3-azabicyclo[3.2.1.]octane-8-fl-carboxylate(VI) has been determined by X-ray diffraction. The compounds studied display in deuterochloroform and benzene-de the same preferred chair-envelope conformation flattened at N-8 and puckered at C3 with both the phenethyl and hydroxy groups in the equatorial position with respect to the piperidine ring. These results are in close agreement with those found for compound VI in the crystalline state. By comparing the NMR parameters of these compounds with those of 3-phenethyl-3-azabicyclo[ 3.2.1. ] octan-8-o~-ol (VII) several stereoelectronic effects have been deduced.
INTRODUCTION
Previous papers [ 1,2 ] reported the synthesis, 'H NMR, ~3C NMR, IR studies and X-ray diffraction data for 3-phenethyl-3-azabicyclo [3.2.1. ]octan-8-a (and /Y)-ols. In a research program devoted to the development of new GABAB receptor antagonists, we have synthesized a new series of esters derived from 8c~-hydroxy-3-phenethyl-3-azabicyclo [3.2.1 ]octan-8-fl-carboxylic acid in which the 7-aminobutyric acid (GABA) skeleton is included (Scheme 1 ). In order to establish several structural and electronic relationships, X-ray, ~H and ~3C NMR parameters of the corresponding alcohol (VII) are also included. 1Author to whom correspondence should be addressed.
0022-2860/91/$03.50
© 1991 - - Elsevier Science Publishers B.V.
340 =..---N"(Ch~)2-~
/ N
I(cH2)2-Ph
H~=(IHeq3-N" (CH2)2"Rh
HO
attack
NC
H00(~ II a
ROOC Il l a
Hx IVa R=Me Va R=Et
p o ~ ~N'(cHz~-P~
N/(CH2)2-Ph (z
N/(CH2)2-Ph
N/(CH2)2 "Ph
I
Lattack
H :
NC-,,~_____~...~ OH
H00C . , , ] ~ J - . , . ~
ROOC.~_~'~.~
OH
OH
II b
Ill b
IVb R=Me
Vb R= Et
Scheme 1. H2(4)eq=H2(4)~, H2 (4)ax--H2 (4)p. EXPERIMENTAL Experimental and X-ray structural data for compound VI are collected in Table I [ 3-9 ]. All melting points were taken in open capillary tubes in an Electrothermal IA6304 apparatus, and are uncorrected. The elemental analyses were carried out in a Perkin-Elmer Elemental Analyzer model 240E. The IR spectra were recorded in the solid state (KBr) using a Perkin-Elmer 883 spectrophotometer. The 1H N M R spectrum of ca. 4% w / v CDCla solution of II was recorded at 400 Mz on a Brucker AM 400 spectrometer at a spectral width of 5000 Hz in 16k memory and acquisition time of 1.638 s over 184 transients. The 1H N M R spectra of ca. 4% w / v CDCla, C6D6 or CD3OD solutions of IV, V and V I were recorded at 300 M H z using a Varian U N I T Y - 3 0 0 spectrometer. Spectral parameters included sweep widths of 4000 Hz in 24k memory and acquisition times of 3.0 s over 64 transients. Resolution enhancement using LB = - 0.80, GF = 0.50 and GFS = 0.20 was followed by zero filling into 32k memory prior to Fourier transformations. Conventional irradiation was used for the double resonance experiments. The homonuclear 1H chemical shift correlated 2D diagrams were performed by application of the COSY 45 experiment at 300 M H z on a Varian U N I T Y 300 spectrometer. COSY spectra were run with a 512 × 512data matrix truing 256 increments in the second dimension and 512 data points in the first dimension. Sine bell window functions in both dimensions were used. Each ex-
341 TABLE 1 Experimental data and structure refinement procedures Crystal data Formula Crystal size (mm 3) Symmetry Unit cell determination: Unit cell dimensions Packing: V (~3), Z Dc (g cm-3), M, F(000) /z (cm -1) Experimental data Technique
Scanning range for 0 Number of reflections Measured Observed Range of hkl Absorption Solution and refinement Solution Refinement Number of variables H atoms Final shift/error w-Scheme
ClsH2~N03 0.20 × 0.32 × 0.30 Triclinic, p i Least-squares fit from 35 reflections (8 < 20 < 84 ° ) 14.072(1), 11.038(1), 10.894(1) ~,, 98.13(1), 86.61(1), 92.25(1) ° 16.71.4(2), 4 1.2057, 303.4, 656 6.165
Four circle diffractometer: Philips PW 1100 Bisecting geometry Graphite oriented monochromator: CuKol w/20 scan 2<0<65 ° 5114 3326 (I>3a(I)criterion) 17/-17,13/-13,0/13 No correction applied [3] Direct methods L.S. on Fobswith 1 block 397 Difference Fourier synthesis 0.005 Empirical so as to give no trends in (wA2F) vs. ( F o ) and (sin0/
~> [4] Final R and Rw Computer and programs Scattering factors Anomalous dispersion
0.O59, 0.073 VAX 11/750, Pesos [4] Multan80 [5], Dirdif [6], XRAY76 [7], Parst [8] Int. Tables X-Ray Crystallography [9 ] Int. Tables X-Ray Crystallography [9]
periment involved sixteen scans and two dummy scans with an initial delay of ls.
The 13C N M R spectra were obtained at 20 MHz on a Varian FT-80 A (PFT)
spectrometer using ca. 25% w/v CDC13 and DMSO solutions. Two types of spectra were recorded: proton-noise decoupled spectra (to determine the chemical shifts) and off-resonance decoupled spectra (to help assign the signals), at a spectral width of 5000 Hz, using an acquisition time of 1.638 s, a delay time of 1.640 s and a pulse width of 5/zs.
342
All measurements were carried out at 303 K using TMS as the internal reference.
3-Phenethyl-8-fl-cyan-3-azabicyclo [3.2.1.] octan-8-ol-ol (ID A solution of 3-phenethyl-3-azabicyclo[3.2.1]octan-8-one (3 g, 0.013 tool) [1], potassium cyanide (0.845 g, 0.013 mole) and ammonium chloride (0.955 g, 0.013 mol) in 1,4-dioxane/water (35:10; 30 ml) was magnetically stirred at room temperature for 5 days; then the mixture was poured on water (50 ml) and the aqueous layer extracted with ethyl ether (4)< 50 ml). The organic phase was separated, washed with water, dried over magnesium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column prepacked with hexane. By elution of the column with hexane/ethyl acetate (7: 3 v/v), two products were isolated which were identified as the aminonitrile (III) Rf= 0.36 (this will be reported in a future paper) and the title compound (II) Rf=0.5 in 75% yield, m.p. 110-112°C. IR (KBr) OH, 3399 cm-1; CN, 2236 cm-1; 1H NMR (see Table 2); 18C NMR (see Table 3). TABLE 2 1H chemical shifts ~ of compounds II, I V - V I ~i ( p p m ) I I (CDC13)
H-6(7)n(m) b H-6(7)x(m) b H-1 (5) (brs)
W1/2 (Hz) H-2 ( 4 ) ~ ( d ) H-2(4)p(dd) H-2' ( m ) e H-I' (m) e Ph (m) b OH (brs) CH3 CH2-O
1.76 1.90 2.35 ~ 10 2.62 2.85 d 2.73 2.80 d 7.23 2.40
I V (CD3OD)
1.98 2.21 2.62 ~ 9.5 3.39 3.71 3.10 3.27 f 7.31
V (CDC13)
1.69 1.90 2.25 ~ 10 2.37 2.73 d 2.56 2.73 d 7.24 3.79(s)
VI (CDCIa)
(C6D~)
1.69 1.91 2.25 ~ 10 2.41 2.73 d 2.57 2.73 d 7.23 2.25 g 1.32(t) 4.26(q)
1.73 1.97 2.21 ~ 9.5 2.48 c 2.57 d 2.47 ~ 2.60 d 7.12 1.83 0.95(t) 3.98(q)
aAbbreviations: br, broad; dd, doublet of doublets; m, multiplet; q, quartet; s, singlet; t, triplet. values were deduced by first order analysis of the spectra; error ___0.05 ppm. bMultiplets of low resolution; tabulated chemical shifts correspond to the center of the multiplets, c'dSignals are partially overlapped, e H - l ' a n d H - 2 ' methylene protons of the phenethyl group appear as a four spin A2B2 system. ~Fhis signal is partially concealed by t h e solvent signal. ~Overlapping resonance between OH a n d H-1 (5) signals was observed.
343 TABLE 3 13C chemical shifts ~ (ppm) for compounds II, I V - V I in CDC13 II C1- (5) C2- (4) C6- (7) C8 CI' C2' C---N C=O CH3 CH2 C 1" C2" (6") C3" (5") C4"
45.12 56.29 25.95 77.43 58.09 33.69 120.46
140.57 128.76 128.33 126.01
IV a
V
VI
40.15 55.84 24.21 80.68 57.99 29.81
42.16 56.10 26.18 83.85 58.55 33.53
42.21 56.08 26.27 83.71 58.53 33.57
173.13
172.58 51.72
137.37 129.16 128.97 127.17
140.61 128.58 128.12 125.75
172.20 60.65 14.10 140.71 128.56 128.07 125.69
~DMSO.
Analysis. Calculated for C16H2oN20: C, 74.97; H, 7.86; N, 10.96. Found: C, 74.64; H, 8.16; N, 10.62.
8-a-Hydroxy-3-phenethyl-3-azabicyclo[3.2.1]octan-8-fl-carboxylic acid hydrochloride (IV) Compound II (0.5 g, 1.6 retool) was added portionwise to aqueous HC1 (20 ml, 11 N) externally cooled at 0 ° C, the mixture was magnetically stirred and maintained at 0 ° C during this operation. The mixture was stirred at - 2 ° C for 30 rain and kept at - 5 °C for 24 h. The solution was refluxed for 6 h, allowed to cool at room temperature and the solvent evaporated under reduced pressure. The solid residue was treated with acetone and filtered. The title compound, which was purified by crystallization from ethanol, was obtained in 80% yield, m.p. 222-224°C. IR (KBr) CO, 1724 cm-1; IH N M R (see Table 2); '3C N M R (see Table 3). Analysis. Calculated for C16H21N03 HCI: C, 61.63; H, 7.11; N, 4.49. Found: C, 61.43; H, 7.10; N, 4.25.
Synthesis of the esters V, VI General procedure Anhydrous hydrogen chloride was bubbled into a solution of IV (0.75 g, 24 mmol) in the corresponding alcohol (25 ml) until saturation, with external cooling and magnetic stirring. The mixture was maintained at 0 °C for 48 h,
344 and refluxed (with anhydrous bubbling HC1) for 2 h. The solution was allowed to cool at room temperature and the solvent removed by evaporation under reduced pressure. The residue was dissolved in cooled water (0 oC ), neutralized with potassium carbonate and extracted with methylene chloride (3 × 25 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to give a crude ester as a white solid which was purified by crystallization from hexane.
Methyl-8-~-hydroxy-3-phenethyl-3-azabicyclo[3.2.1.]octan-8-fl-carboxylate (v) This compound was obtained in 72% yield, m.p. 82-84°C, IR (KBr) OH, 3436 cm-1; CO, 1733 cm-1; 1H NMR (see Table 2); 13C NMR (see Table 3). Analysis. Calculated for C17H2aNO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.68; H, 8.01; N, 4.74.
Ethyl-8-t~-hydroxy-3-phenethyl-3-azabicyclo[3.2.1]octan-8-fl-carboxylate
(VD
This compound was obtained in 70% yield, m.p. 77-79°C; IR (KBr) OH, 3397 cm -1; CO, 1697, 1735 cm-1; 1H NMR (see Table 2 ); 13C NMR (see Table
3). Analysis. Calculated for ClsH25N03: C, 71.25; H, 8.30; N, 4.62. Found: C, 71.02; H, 8.60; N, 4.88. RESULTS AND DISCUSSION
Description and discussion of the structure of VI The final atomic parameters are given in Tables 4-6 (numbers correspond to those given in figures). Bond lengths and bond and torsion angles for the two independent molecules (A and B) which exist in the asymmetric unit are given in Tables 7 and 8. Figure 1 displays a view of the asymmetric part of VI with the numbering used in the crystallographic study and Fig. 2 shows a projection of the structure along the c axis. The two independent molecules in the asymmetric unit are related by a pseudo symmetric center. The pseudo symmetry is broken by two intermolecular hydrogen bonds. In both molecules the bicyclic system assumes a chair-envelope conformation similar to that found in other compounds [1,2,11,12]. The deviations of C4 and N1 from the main plane through C2, C3, C5 and C8 are respectively 0.868 (3), 0.637 (2) .~ in molecule A and 0.859(3), 0.631(2) A in molecule B (0.90 and 0.58 A for the 3phenethyl-3-azabicyclo [ 3.2.1. ] octan-8-~-ol (VII) [ 2 ] ). The less pronounced puckering at the C atom in compound VI as compared to VII can be explained as due to the syndiaxial steric effect exerted by the ethoxycarbonyl group on H2(4)ax. The less pronounced flattening at the N atom in compound VI can be due to the steric effect exerted by the ethoxycar-
345 TABLE 4 Atomic parameters for non H-atoms; coordinates and thermal parameters given as U~q= (1/3 )'sum[ Uii.ai*.aj*'ai'aj'cos ( ai,aj) ] " lO**4 Atom
x
y
z
U~q
N1A O1A O2A 03A C2A C3A C4A C5A C6A C7A C8A C9A C10A CllA C12A C13A C14A C15A C16A C17A C18A C19A N1B OIB 02B 03B C2B C3B C4B C5B C6B C7B CSB COB C10B CllB C12B C13B C14B C15B C16B C17B C18B C19B
0.2017(2) 0.3435(2) 0.1226(2) 0.1748 (2) 0.2128(2) 0.2952 (2) 0.2698(2) 0.2713(2) 0.3675(2) 0.3831(2) 0.1883(2) 0.1338(2) 0.0283(2) -0.0331(2) -0.0479(2) 0.1037(3) -0.1454(3) -0.1308(2) -0.0750(2) 0.1797(2) 0.0983(3) 0.1197(3) 0.5345(2) 0.3980(2) 0.6119(2) 0.5688(2) 0.5112(2) 0.4331(2) 0.4704(2) 0.4793(2) 0.3811(3) 0.3510(2) 0.5597(2) 0.6007(2) 0.7029(3) 0.7639(2) 0.8071(3) 0.8631(4) 0.8749(4) 0.8320(4) 0.7772(3) 0.5587(2) 0.6411(3) 0.5997(3)
0.0677(2) 0.4151(2) 0.4154(3) 0.4409 (2) 0.1431 (3) 0.2364 (3) 0.3245(3) 0.2355(3) 0.1740(3) 0.1737(3) 0.1418(3) -O.O354(3) -0.0037(3) -0.1199(3) -0.1914(3) -0.2987(3) -0.3345(3) -0.2653(3) -0.1591(3) 0.3949(3) 0.5256(4) 0.5880(4) 0.9083(2) 0.5557(2) 0.5381(2) 0.5647(2) 0.8364(3) 0.7402(3) 0.6507(3) 0.7347(3) 0.7938(3) 0.7978(3) 0.8302(3) 1.0112(3) 0.9807(3) 1.0946(3) 1.1543(4) 1.2611(5) 1.3084(4) 1.2510(4) 1.1454(4) 0.5809(3) 0.4834(4) 0.3763(5)
0.7685(2) 0.8407(2) 0.9001(3) 0.7083 (2) 0.6687(3) 0.6944 (3) 0.8135(3) 0.9096(3) 0.8750(3) 0.7324(3) 0.8902(3) O.7465(3) 0.7465(4) 0.7286(3) 0.8238(3) 0.8080(3) 0.6965(4) 0.6017(3) 0.6175(3) 0.8140(3) 0.7032(4) 0.5921(4) 0.7196(2) 0.6483(2) 0.6025(2) 0.8048(2) 0.8209(3) 0.7835(3) 0.6725(3) 0.5721(3) 0.5873(3) 0.7269(3) 0.6031(3) 0.7503(3) 0.7746(4) 0.8033(4) 0.7089(4) 0.7381(6) 0.8603(7) 0.9528(6) 0.9250(4) 0.6883(3) 0.8339(4) 0.8674(8)
453 (8) 546 (8) 822(11) 587 (8) 453(10) 421 (9) 414 (9) 457(10) 519(11) 488(10) 463(10) 530(11) 641(13) 515(11) 615(12) 655(13) 646(13) 632(13) 577(12) 498(10) 780(16) 800(16) 452 (8) 555 (8) 702(10) 704(10) 492(10) 466(10) 451 (9) 489(10) 595(12) 566(12) 517(11) 505(10) 696(14) 597(13) 810(17) 1015(23) 1032(25) 995(22) 754(15) 496(11) 801(17) 1377(35)
346 TABLE 5 Atomic parameters for non-H atoms; thermal parameters given as: exp [-2.u**2.sum(Uij'ai*'aj*'hi" hi). 10"'4 ] Atom
Un
U22
U33
/-]12
U13
U2s
N1A O1h 02A 03A C2A CaA C4A C5A C6A C7A C8A C9A C10A CllA C12A ClaA C14A C15A C16A C17A C18A C19A N1B O1B O2B OaB C2B CaB C4B C5B C6B C7B C8B C9B C 10 B CIIB C 12 B C13B C14B C15B C16B C17B C18B C19B
465(14) 616(13) 909(19) 592(13) 490(17) 421(15) 424(15) 493(17) 487(16) 430(17) 530(17) 442(17) 468(18) 392(16) 551(19) 631(21) 566(20) 569(20) 526(18) 550(18) 699(24) 851(28) 505(14) 622(13) 644(15) 787(17) 580(18) 511(17) 500(16) 584(18) 656(21) 496(18) 643(19) 463(16) 522(19) 425(17) 703(24) 757(29) 769(30) 1052(36) 809(26) 556(18) 664(23) 640(27)
415(13) 492(12) 839(18) 611(13) 455(16) 451(16) 415(15) 503(17) 599(19) 559(18) 443(16) 438(16) 488(10) 509(18) 740(23) 685(23) 583(20) 625(21) 577(19) 438(16) 776(26) 662(24) 380(13) 460(12) 726(16) 692(16) 478(17) 451(16) 390(15) 470(17) 554(19) 579(19) 469(17) 385(16) 447(18) 477(18) 771(27) 823(32) 639(17) 699(28) 616(23) 378(15) 785(27) 803(32)
475(14) 529(12) 728(17) 588(14) 411(15) 394(15) 396(15) 375(15) 501(17) 492(17) 410(16) 695(21) 950(27) 626(20) 526(19) 631(22) 730(24) 694(23) 643(21) 480(17) 925(29) 944(30) 462(14) 573(13) 688(16) 701(16) 407(16) 429(16) 452(16) 412(16) 605(20) 631(20) 413(16) 655(20) 1103(31) 898(27) 945(31) 1503(51) 1703(59) 1251(42) 872(28) 539(19) 1051(32) 2902(90)
-45(11) -181(10) 325(15) 187(11) -14(13) -2(12) -58(12) -64(13) -19(14) 25(14) -70(13) -47(13) -15(15) -9(13) -27(17) -13(18) -117(16) -69(17) -24(16) -16(14) 315(20) 145(21) -53(11) -189(10) 101(13) 190(13) -11(14) -28(13) -82(13) -92(14) -57(16) 22(15) -143(15) -8(13) 6(15) 27(14) -42(21) -136(25) -158(23) -60(27) 12(20) -65(14) 58(20) -17(24)
-68(11) -129(10) 266(15) -16(10) -91(13) -26(12) -62(12) -63(12) -127(14) -39(13) -29(13) -98(14) -129(17) -50(14) 45(15) 165(17) 71(17) -159(17) -140(15) 34(15) -35(21) -246(23) -48(11) -62(10) -50(13) -16(13) -34(13) -16(13) -32(13) -62(13) -189(16) -35(15) 5(14) -102(14) -196(19) -141(16) -33(22) 39(31) -423(34) -623(33) -325(22) -54(15) -169(21) -267(38)
40(10) 80 (9) 194(14) 141(10) 30(12) 75(12) 42(11) 70(12) 147(14) 118(13) 60(12) 20(14) 14(17) 12(15) 33(16) 127(17) -2(17) 39(17) 105(15) 14(13) 246(22) 196(21) 33(10) 79 (9) -96(13) 297(12) 31(12) 56(12) 44(12) 73(13) 142(15) 109(15) 37(13) 12(13) -14(18) 78(17) 102(2) 384(32) 122(33) -17(28) 111(19) 28(13) 402(23) 937(44)
347 TABLE 6 Atomic parameters for H-atoms; coordinates and thermal parameters given as exp [ - 8. ~'*'2" U" (sin0/Jt)**2.10"'3 ] Atom
x
y
z
U
H1A H21A H22A H3A H5A H61A H62A H71A H72A HSlA HS2A H91A H92A H 101A H102A H12A H13A H14A H15A H16A H181A HlS2A H191A H192A H193A H1B H21B H22B H3B H5B H61B H62B H71B H72B H81B H82B H91B H92B H101B H 102B H12B H13B H14B H15B H16B HlSlB H182B H191B H192B H193B
0.357 (0) 0.234 (0) 0.141(0) 0.306 (0) 0.264(0) 0.360(0) 0.429 (0) 0.395 (0) 0.549(0) 0.116(0) 0.186(0) 0.145(0) 0.151(0) 0.012 (0) 0.014(0) -0.011(0) -0.116(0) -0.186(0) -0.173(0) -0.058 (0) 0.036 (0) 0.094 (0) 0.107(0) 0.067(0) 0.185(0) 0.405 (0) 0.582 (0) 0.483 (0) 0.413(0) 0.492 (0) 0.330(0) 0.339 (0) 0.285 (0) 0.336 (0) 0.639(0) 0.561 (0) 0.567 (0) 0.602 (0) 0.713(0) 0.739 (0) 0.803 (0) 0.899 (0) 0.918(0) 0.863(0) 0.734(0) 0.685 (0) 0.691(0) 0.645 (0) 0.541(0) 0.537(0)
0.455 (0) 0.082 (0) 0.193 (0) 0.283 (0) 0.291(0) 0.079(0) 0.231 (0) 0.073 (0) 0.772(0) 0.193(0) 0.084(0) -0.099(0) -0.095(0) 0.055 (0) 0.054(0) -0.170(0) -0.350(0) -0.426(0) -0.291 (0) -0.094(0) 0.460 (0) 0.600 (0) 0.509 (0) 0.641 (0) 0.633 (0) 0.526 (0) 0.797 (0) 0.898 (0) 0.697(0) 0.680 (0) 0.735(0) 0.887 (0) 0.739 (0) 0.897 (0) 0.792(0) 0.884(0) 1.064 (0) 1.065 (0) 0.921(0) 0.916 (0) 1.098(0) 1.319 (0) 1.395 (0) 1.298(0) 1.104(0) 0.524 (0) 0.464(0) 0.321 (0) 0.319(0) 0.373(0)
0.768 (0) 0.581 (0) 0.658(0) 0.602 (0) 1.013(0) 0.913(0) 0.932 (0) 0.684 (0) 0.291(0) 0.904(0) 0.967(0) 0.828(0) 0.654(0) 0.846 (0) 0.661(0) 0.922(0) 0.891(0) 0.680(0) 0.520(0) 0.533 (0) 0.678 (0) 0.799 (0) 0.520(0) 0.573 (0) 0.598(0) 0.566 (0) 0.858(0) 0.901 (0) 0.874(0) 0.480 (0) 0.520(0) 0.552 (0) 0.745 (0) 0.773 (0) 0.616(0) 0.520(0) 0.931 (0) 0.666 (0) 0.860(0) 0.684 (0) 0.600(0) 0.659 (0) 0.899 (0) 1.060(0) 1.017{0) 0.898(0) 0.762(0) 0.896 (0) 0.303(0) 0.916(0)
45 (0) 40 (0) 40(0) 34 (0) 37(0) 44(0) 44 (0) 41 (0) 41(0) 41(0) 41 (0) 47{0) 47(0) 54 (0) 54(0) 54(0) 58(0) 55(0) 55(0) 49 (0) 65 (0) 65 (0) 68(0) 68(0) 68(0) 46 (0) 43 (0) 43 (0) 40(0) 42 (0) 55 (0) 55 (0) 49 (0) 49 (0) 45 (0) 45 (0) 44 (0) 44 (0) 58(0) 58 (0) 77(0) 90 (0) 84(0) 84(0) 68(0) 74 (0) 74(0) 99 (0) 99(0) 99(0)
348 TABLE 7 Bond distances (.~) Bond
Distance (A)
Bond
Distance (A)
NIA-C2A NIA-C8A
1.459 (4) 1.462 (4)
N IB-C2B NIB-C8B
1.463 (4) 1.463 (4)
N 1A-C9A O1A-H1A O1A-C4A 02A-C17A 03A-C 17A 03A-C18A C2A-C3A C3A-C4A C3A-C7A C4A-C5A C4A-C17A C5A-C6A C5A-C8A C6A-C7A C9A-C10A C10A-CllA C11A-C12A CllA-C16A C12A-C13A C13A-C14A C14A-C15A C15A-C16A ClSA-C19A
1.460(4) 0.961 (2) 1.426(3) 1.201(4) 1.329(4) 1.461(5) 1.532(4) 1.540(4) 1.546(4) 1.536(4) 1.512 (4) 1.543(4) 1.535(4) 1.555(5) 1.539(5) 1.514(5) 1.391 (5) 1.384(5) 1.391 (5) 1.380(5) 1.371(6) 1.381(5) 1.485 (7)
N1B-C9B O1B-H1B O1B-C4B 02B-C17B 03B-C 17B 03B-C18B C2B-C3B C3B-C4B C3B-C7B C4B-C5B C4B-C17B C5B-C6B C5B-C8B C6B-CTB C9B-C10B C10B-CllB C11B-C12B CllB-C16B C12B-C13B C13B-C14B C14B-C15B C15B-C16B C18B-C19B
1.455 (4) 0.915 (2) 1.442(4) 1.214(4) 1.322(4) 1.460(5) 1.530(4) 1.530(4) 1.541(5) 1.528(4) 1.519(5) 1.541(5) 1.533(4) 1.550(5) 1.536(5) 1.501(5) 1.396(6) 1.384(6) 1.401 (7) 1.377(10) 1.364(9) 1.382(6) 1.383(7)
bonyl rest on the N-phenethyl group. The asymmetric parameters [ 13 ] are in the six-membered ring: ¢2 = - 0 . 7 1 ( 1 . 2 7 ) , 02=168.6(2) and QT=0.666(3) (molecule A) and ~2 = - 176.8 (1.4), 02 = 11.8 (2) and QT=0.661 (3) (molecule B). The five-membered ring has an envelope conformation with the C4 atom - 0.761 (3) A (molecule A) and 0.751 (3) A (molecule B ) from the plane of the C3, C5, C6 and C7 atoms; ring puckering coordinates are ¢ 2 = 3 6 . 6 ( 4 ) , 02=0.511(3) (molecule A) and ¢ 2 = - 1 4 3 . 6 ( 4 ) , 02=0.506(3) (molecule B). The oxygen atom joined to the C4 atom and the radical attached to N1 atom are in the equatorial position while the ethoxy-carbonyl group occupies an axial position with respect to the piperidine ring. The phenethyl and the ethoxycarbonyl groups are oriented perpendicularly. The angles defined by the COO plane and the phenyl ring are 89.8 (1) ° (molecule A ) and 94.4 (2) ° (molecule B ). The ethyl chain presents disorder as is reflected by the high values of the thermal parameters of C18 and C19 atoms; due to this disorder, the C18-C19
349 TABLE 8 Bond angles and torsion angles Angle
Value (deg)
Torsion angle
Value (deg)
C8A-N 1A-C9A C2A-N1A-C9A C2A-NIA-CSA HIA-OIA-C4A C 17A-O3A-C 18A NIA-C2A-C3A C2A-C3A-C7A C2A-C3A-C4A C4A-C3A-C7A 01A-C4A-C3A C3A-C4A-C 17A C3A-C4A-C5A 01A-C4A-C17A O1A-C4A-C5A CSA-C4A-C17A C4A-C5A-CSA C4A-C5A-C6A C6A-C5A-C8A CSA-C6A-C7A C3A-C7A-C6A NIA-C8A-CSA NIA-C9A-C10A C9A-C10A-C11A C10A-C11A-C16A C10A-C11A-C12A C12A-C11A-C16A C11A-C12A-C13A C12A-C13A-C14A C13A-C14A-C15A C14A-C15A-C16A C 11A-C16A-C15A O3A-C17A-C4A O2A-C17A-C4A O2A-C 17A-O3A O3A-C18A-C19A C8B-NIB-C9B C2B-NIB-C9B C2B-NIB-CSB H1B-OIB-C4B C 7B-O3B-C 18B N1B-C2B-C3B C2B-C3B-C7B C2B-C3B-C4B C4B-C3B-CTB OIB-C4B-C3B
114.3 (2) 114.6 (2) 111.9 (2) 108.0 (2) 116.5 (2) 109.4 (2) 110.7 (2) 109.2 (2) 101.7 (2) 111.6 (2) 116.4 (2) 99.6 (2) 105.5(2) 107.5 (2) 116.2 (2) 109.3 (2) 101.8 (2) 110.9 (3) 104.8 (2) 105.0 (2) 109.5 (2) 116.5(3) 110.0 (3) 121.5 (3) 120.5 (3) 118.0 (3) 120.9 (3) 119.6 (3) 120.0 (3) 120.2 (3) 121.2 (3) 110.9 (3) 125.8 (3) 123.2 (3) 107.4 (3) 114.3 (2) 114.4 (2) 111.7 (2) 106.3(2) 120.0 (3) 109.9 (2) 110.8 (3) 109.3 (3) 101.3 (2) 107.2 (2)
NIA-C2A-C3A-C4A C2A-C3A-C4A-C5A C3A-C4A-C5A-CSA C4A-C5A-CSA-NIA C2A-NIA-CSA-C5A C8A-NIA-C2A-C3A C3A-C4A-C5A-C6A C4A-C5A-C6A-CTA C5A-C6A-C7A-C3A C4A-C3A-C7A-C6A C 7A- C6A-C4A-C5A C2A-NIA-C9A-C 10A 01A-C4A-C17A-O2A H22A-C2A-C3A-H3A H21A-C2A-C3A-H3A H3A-C3A-C7A-H71A H5A-C5A-CSA-H81A H5A-C5A-C8A-H82A H5A-C5A-C6A-H61A H5A-C5A-C6A-H62A H62A-C6A-C7A-H71A H61A-C6A-C7A-H71A H92A-C9A-C10A-H101A H91A-CgA-C10A-H101A H92A-C9A-C10A-H102A H91A-C9A-C10A-H102A N1B-C2B-C3B-C4B C2B-C3B-C4B-C5B C3B-C4B-C5B-CSB C4B-C5B-C8B-NIB C2B-NIB-C8B-CSB C8B-NIB-C2B-C3B C3B-C4B-CSB-C6B C4B-CSB-C6B-C7B CSB-C6B-C7B-C3B C4B-C3B-CTB-C6B CTB-C6B-C4B-C5B C2B-N1B-C9B-C10B 01B-C4B-C17B-O2B H22B-C2B-C3B-H3B H21B-C2B-C3B-H3B H3B-C3B-C7B-H71B H3B-C3B-C7B-H72B H5B-C5B-CSB-H81B H5B-C5B-CSB-H82B
- 64.4 (3) 68.0 (3) - 67.8 (3) 64.2 (3) - 55.5 (3) 55.7 (3) 49.5 (3) - 30.9 (3) 0.6 (3) 29.8 (3) - 49.0 (3) - 68.5 (4) -96.0(4) - 65.0 (3) 55.4 (3) - 84.4 (3) 59.6 (3) - 53.6 (3) 84.6 (3) - 29.0 (4) 116.6 (3) -6.9(4) 117.8 (3) 62.7 (3) - 60.9 (4) - 176.9 (3) 63.2 (3) -68.0(3) 68.2 (3) - 64.2 (3) 55.0 (3) - 54.5 (3) - 49.3 (3) 30.4 (3) - 0.3 (3) - 29.8(3) 49.0 (3) 66.8 (4) 85.5(4) - 55.3 (3) 60.1 (3) - 34.9 (4) 83.1 (3) - 65.9 (4) 55.9 (3)
350 TABLE 8 (Continued) Angle
Value (deg)
Torsion angle
Value (deg)
C3B-C4B-C17B C3B-C4B-C5B O1B-C4B-C17B O1B-C4B-C5B C5B-C4B-C17B C4B-C5B-C8B C4B-C5B-C6B C6B-C5B-CSB C5B-C6B -C7B C3B-C7B-C6B N1B-CSB-C5B N1B-C9B-C10B C9B-C10B-C11B C10B-CllB-C16B C10B-CllB-C12B C12B-CllB-C16B CllB-C12B-C13B C12B-C13B-C14B C13B-C14B-C15B C 14B-C 15B-C 16B CllB-C16B-C15B 03B-C17B-C4B O2B-C17B-C4B 02B-C17B-O3B 03B-C18B-C19B
117.7(3) 100.4 (2) 103.7 (2) 112.2 (2) 115.8(3) 108.7 (2) 101.5 (2) 111.5 (3) 104.8 (3) 105.3(3) 109.8 (2) 116.9 (3) 111.4 (3) 120.7 (3) 121.4(4) 118.0 (4) 120.3 (5) 120.1(5) 119.9{5) 120.5 (5) 121.3 (4) 112.9{3) 123.8{3) 123.2(3) 110.9 (4)
H5B-C5B-C6B-H61B H5B-C5B-C6B-H62B H62B-C6B-C7B-H71B H61B-C6B-C7B-H71B H62B-C6B-C7B-H72B H61B-C6B-C7B-H72B
25.2(4) --88.8(3) 128.1(3) 2.6(4) 6.5(4) --119.0(3)
bond distance values are shorter than normal (1.485(7) A in molecule A and 1.383 (7) A in molecule B). The molecules are linked by two crystallographically independent hydrogen bonds between adjacent molecules (Fig. 2); their geometry is given in Table 9.
Infrared spectra The IR spectrum of YI in the solid state showed a broad asymmetric band at 3397 cm -1 (with a shoulder at 3374 cm-1), which is assigned to the OH . . . . . O stretching vibrations. In the carbonyl region, two strong bands are observed at 1735 and 1697 cm-1 which are attributed to the vCO free and hydrogen-bonded carbonyl groups respectively. These results are in accord with X-ray data.
351
I.~C19 H2 C15 I;3.6
moI.B
HI
O3(
H2 "~ ~
~
mol.A
Fig. 1. Pluto view of the molecules [ 10 ].
NMR spectra Spectral analysis Assignments of proton and carbon resonances have been made on the basis of the literature data for ~- and fl-epimers of 3-phenethyl-3-azabicyclo [3.2.1. ] octan-8-ol and related systems [ 1,2,11,12 ]. V and VI have been studied in more detail; their 300 MHz 1H NMR spectra, double resonance (DR) experiments and homonuclear 2D COSY-45 [14,15 ] of VI were used to provide the required information. 13C NMR chemical shifts of compounds II, I V - V I are listed in Table 3. Substituent steric and electronic effects on 1~C chemical shifts [ 16,17 ], signal multiplicity obtained from off-resonance decoupled spectra and our previously reported values for related bicyclic systems [1,2,11,12] were taken into consideration.
1H NMR spectra Overlapping resonance between different signals was observed for all the compounds in the solvents employed to record their 1H NMR spectra (see Table 2). The signals due to H - l ( 5 ) , H-6(7)n and H-6(7)x appear well differentiated. In order to clarify the assignment of the signals and to deduce the proton magnetic parameters, homonuclear 2D COSY spectra [14,15 ] in CDC13 and C6D6 for VI and double resonance (DR) experiments in CDC13 for V and VI
352
[5
C
Fig. 2. Projection of the structure along the c axis.
TABLE 9 Interatomic distances (/~) and angles (deg) in the hydrogen bonds a
b
c
OtAOrB-
HIA ..... HIB .....
O1B (x,y,z) 02B (-x+l,
-y+l,
-z+l)
ab
bc
ac
abc
0.96 0.91
1.88 t.89
2.83 2.79
168.27 166.06
353
were performed. The contour plots of the 300 MHz proton COSY spectra are shown in Figs. 3 and 4 (the aromatic proton region is omitted). The cross-connectivity patterns were analyzed taking into account that the non-resolvable wide singlet at 2.25 ppm in CDCI3 (2.21 ppm in C6D6) can be unambiguously assigned to bridgehead H-1 (5) protons. By considering the correlations, the following can be established: (i) the multiplet centered at ca. 2.49 ppm in CDC13 (2.48 ppm in C6Ds) due to four protons correlates with H1 (5) and the signal at ca. 2.73 ppm (ca. 2.58 ppm in C6D8), and must correspond to methylene protons adjacent to the phenyl group of the N-substituent and H-2 (4)a, owing to the very weak cross-peak with H-1 (5) that is in agreement with a small value for 33"2(4) ~-H1 (5) [ 1,2 ]; (ii) the multiplet centered at ca. 2.73 ppm (ca. 2.58 ppm in C6D6), also due to four protons, with a stronger correlation with H- 1 (5), must correspond to H-2 (4) ~ and methylene protons, adjacent to the nitrogen atom, of the phenethyl moiety; (iii) the signal at 1.69 and 1.91 ppm (1.73 and 1.97 ppm in CsD6) should be tentatively assigned to
e
1.5,
_).O
_),5
3.0
3.5
4.0
- I
0
4.5
5.0
. . . .
, 4 5
. . . .
tt , 4.0
. . . .
, 3.5
. . . .
,
. . . .
3.0
, 2.5
. . . .
,
-
2,0
F'I (ppm)
Fig. 3. Contour plot of the 300 MHz proton COSY spectrum of VI in CDC13.
-
-
, 1.5
. . . .
, 1.0
.
.
354
1.0
I~
O 4.0
3.5
3.0
2.5 F1 (ppm)
2.0
1.5
1.0
Fig. 4. Contour plot of the 300 MHz proton COSYspectrum of VI in C6D6. H-6 (7), and H-6 (7)x respectively owing to their shape and the weak correlation between the high-field multiplet and H-1 (5). To verify the assignments of H-6 (7), and H-6 (7)~ chemical shifts, double resonance (DR) experiments were performed for Y and VI (in CDC13 at 300 MHz). On saturating the H-1 (5) signal the high-field multiplet at ca. 1.69 ppm remained practically unchanged, whereas the signal at ca. 1.90 p p m becomes simpler. As in the case of ~- and fl-epimers of 3-phenethyl-3-azabicyclo[3.2.1]octan-8-ol [1,2] a limit value of 0.5 Hz has been admited for 3JH6 (7),-H1 (5) and the high-field signal may therefore be attributed to H-6 (7) ~ in agreement with the correlations observed in the 2D COSY spectra. The H-2(4)~ and H-2(4)p signals were also assigned on the basis of the values of the respective couplings with H-1 (5) protons [ 1,2 ]. The vicinal coupling constant 3JH2 (4)~-H1 (5) presents a low value and could not be established. Bearing in mind the above considerations, the analysis of the spectra
355 TABLE 10 Coupling constants a deduced from the analysis of the 1HMR spectra of compounds II, I V - V I
J (Hz)
II (CDCI3)
H2(4)~-H2(4)p H2(4)y-H1 (5) HI'-H2' CH3-CH2
-11.9 3.7 7.6
IV (CD3OD)
-13.5 3.1 b
V (CDC13)
-11.3 3.8 7.6
VI (CDCI3)
(CsD~)
-11.3 __b 7.6 7.2
-11.4 3.7 7.8 7.1
aError _ 0.2 Hz; 3JH2 (4)~-H 1 (5) could not be established; only a slight broadening of the H2 (4) signal has been observed. Wrhese coupling constants could not be established due to the low resolution and/or overlapping of the corresponding signals.
leads to the establishment of the protonic parameters given in Tables 2 and 10.
Conformational study The 1H and 13C parameters of compounds V and VI are in good agreement with previously reported values for related bicyclic systems in which the cyclopentane and piperidine rings have a flattened C8 envelope and distorted chair conformation puckered at C8 and flattened at N3 respectively. In the 1H NMR (in CDCla and C6D 6 solution) spectra of compounds V and VI, W1/2values for the H1 (5) signal (10, 9.5 Hz) correspond to a piperidine ring in flattened chair conformation [ 1,2,11,12 ]. In benzene -d6 solution 3JI-I2 (4) ~-H 1 ( 5 ) is greater than aJH2 (4) ~-H 1 ( 5 ), and consequently, the dihedral angle H 2 ( 4 ) z - C - C - H I ( 5 ) is smaller than H2 (4)~-C-C-H1 (5) according to the Karplus relationship [ 18 ]. This is also more consistent with a flattened chair conformation than with a boat for the piperidine ring [ 1,2 ]. For compounds V and VI (in CDCI3 and C6D6 solution), the H2(4)p signal appears at a lower field than the H2 (4)~ signal (A0"I-I2(4)pH2 (4), ~ 0.3 ppm in CDC13 and ~ 0.1 ppm in C6D6). This fact is attributed to the field effect exerted by the carbonyl group on H2 (4)p. This fact has been reported by us in several aza and diazabicyclo spirohydantoins [ 19-21] in which the C4=O group occupies the same position with respect to the corresponding axial protons, as the position of the carbonyl group with respect to H2 (4)~ in V and VI. In consequence, it can be supposed that for compounds V and VI in CDC13 and C6D6 solutions the alkoxycarbonyl group adopts a preferred conformation, in which the CO0 plane is perpendicular with respect to the C1, C2, C4 and C5 plane.
356 As would be expected, The oCH6(7)n, 5H6(7)x and 5C1(5), 5C6(7) values for compounds V and VI are similar to the 5-values found for analogous protons and carbon atoms in compound V I I [2]. The ASC2 (4) (V,VI) - C2 (4) ( V I I ) ~ - 2.3 ppm is attributed to the ~-effect exerted by the carbonyl group on H2 (4)p in compounds V and VI. The ASC8 (V,VI) - C8 ( V I I ) ~ 3 ppm is attributed to the electron-attracting effect exerted by the ethoxycarbonyl group on C8 in compounds V and VI. The chemical shift of C1 of the phenethyl group (in V and VI, see Table 3) is in agreement with an equatorial disposition of the N-substituent [ 1,2,11,12 ]. Hence, good agreement of the preferred conformation of C8D6 solution and the solid state for VI has been observed. The cyclopentane and piperidine rings adopt an envelope conformation flattened at C8 and a distorted chair conformation puckered at C8 and flattened at N3, respectively, with the N-substituent in the equatorial position with respect to the piperidine ring. The unique difference is the conformation of the ethoxycarbonyl group which in solid state seems to be governed by the intermolecular hydrogen bonds. ACKNOWLEDGEMENT We t h a n k the ComisiSn Interministerial de Ciencia y Energ/a (Grant FAR88-0440) for support for this research.
REFERENCES 1 M.S.Arias, E. G~lvez,I. Ardid,J. Bellanato,J.V. Garch-Ramos, F. Florencioand S. GarchBlanco, J. Mol. Struct., 161 (1987) 151 and referencescited therein. 2 E. G~lvez,M.S. Arias, I. Ardid,F. Florencio,J. Sanz, J. BeUanatoand J.V. Garch-Ramos, J. Mol. Struct., 196 (1989) 307. 3 N. Walker and P. Stuart, Acta Crystallogr.,Sect. A, 39 (1983) 158-166. 4 M. Martfnez-Ripolland F.H. Cano, PESOS: a computer program for the automatic treatment of weightingschemes, Instituto Rocasolano,C.S.I.C., Madrid, Spain, 1975. 5 P. Main, S.J. Fiske, S.E. Hull, L. Lessinger,G. Germain,J.P. Declercq and M.M. Woolfson, MULTAN: a system of computer programs for the automatic solution of crystal structures from X-ray diffractiondata, Universitiesof York, England and Louvain,Belgium,1980. 6 P.T. Beurkens, W.P. Bosman, H.M. Doesburs, R.O. Gould, T.H.E. Van der Hark, P.A.J. Prick, J.H. Noordik, G. Beurkens and Parthasarathi, DIRDIF Manual 81, Crystallography Laboratory,Toernooiveld,The Netherlands, 1981. 7 J.M. Stewart, F.A. Kundell,J.C. Baldwin.The X-RAY 70 System ComputerScienceCenter, Universityof Maryland, CollegePark, Maryland, 1974. 8 M. Nardelli, Comput. Chem., 7 (1983) 95-98. 9 International Tables for X-Ray Crystallography,Vol. 4, Kynoch Press, Birmingham, 1974. 10 W.D.S.Motherwell and W. Clegg, PLUTO: a program for plotting crystal and molecular structures, CambridgeUniversity,U.K., 1978. 11 E. G~lvez, I. Ardid, L. Fuentes. F. Florencioand S. Garc~a-Blanco,J. Mol. Struct., 142 (1986) 411.
357 12 M.L. Izquierdo, M.S. Arias, E. Gdlvez, B. Rico, I. Ardid, J. Sanz, I. Fonseca, A. Orjales and A. Innerarity, J. Pharm. Sci., in press. 13 D. Cremer and J.A. Pople, J. Am. Chem. Soc., 97 (1975) 1354. 14 A. Bax and R. Freeman, J. Magn. Reson., 44 (1981) 542. 15 A.E. Derome, Modern NMR Tecniques for Chemistry Research, Pergamon Press, Oxford, 1987. 16 F.W. Wehrli and A.P. Marchand, Interpretation of 13C NMR Spectra, 2nd Edn., Wiley, Chichester, 1988. 17 E. Breitmeier and W. Voelter, 13C NMR Spectroscopy: Methods and Application in Organic Chemistry, 2nd end., Verlag Chemie, Weinheim, 1978. 18 C.A.G.Haasnoot, F.A.A.M. de Leeuw and C. Altona, Tetrahedron, 36 (1980) 2783. 19 G.G.Trigo, E. G~lvez and C. Avendafio, J. Heterocycl. Chem., 15 (1978) 907. 20 G.G.Trigo, E. G~lvez, M. Espada and C. Bernal, J. Heterocycl. Chem., 16 (1979) 977. 21 E. G~lvez, M. Martfnez, J. Gonz~lez, G.G. Trigo, P. Smith-Verdier, F. Florencio and S. Garcfa-Blanco, J. Pharm. Sci., 72 (1983) 881.
339
Synthesis and structural and conformational study of some esters derived from 8-c~-hydroxy-3-phenethyl-3azabicyclo [ 3.2.1 ] octan-8-fl-carboxylic acid
M. Diez, M.L. Izquierdo, E. Galvez ~ and M.S. Arias Departamento de Quimica Orgdnica, Universidad de Alcald de Henares, Madrid (Spain)
I. Fonseca and J. Sanz-Aparicio Instituto "Rocasolano" UEI Cristalografia, C.S.I.C. Serrano 121, 28006 Madrid (Spain) (Received 19 November 1990)
Abstract
A series of 8-fl-alcoxycarbonyl-8-ot-hydroxy-3-phenethyl-3-azabicyclo[3.2.1]octane derivatives have been synthesized and studied by IR, 1H and 13C NMR spectroscopy, and the crystal structure of ethyl-8-a-hydroxy-3-phenethyl-3-azabicyclo[3.2.1.]octane-8-fl-carboxylate(VI) has been determined by X-ray diffraction. The compounds studied display in deuterochloroform and benzene-de the same preferred chair-envelope conformation flattened at N-8 and puckered at C3 with both the phenethyl and hydroxy groups in the equatorial position with respect to the piperidine ring. These results are in close agreement with those found for compound VI in the crystalline state. By comparing the NMR parameters of these compounds with those of 3-phenethyl-3-azabicyclo[ 3.2.1. ] octan-8-o~-ol (VII) several stereoelectronic effects have been deduced.
INTRODUCTION
Previous papers [ 1,2 ] reported the synthesis, 'H NMR, ~3C NMR, IR studies and X-ray diffraction data for 3-phenethyl-3-azabicyclo [3.2.1. ]octan-8-a (and /Y)-ols. In a research program devoted to the development of new GABAB receptor antagonists, we have synthesized a new series of esters derived from 8c~-hydroxy-3-phenethyl-3-azabicyclo [3.2.1 ]octan-8-fl-carboxylic acid in which the 7-aminobutyric acid (GABA) skeleton is included (Scheme 1 ). In order to establish several structural and electronic relationships, X-ray, ~H and ~3C NMR parameters of the corresponding alcohol (VII) are also included. 1Author to whom correspondence should be addressed.
0022-2860/91/$03.50
© 1991 - - Elsevier Science Publishers B.V.
340 =..---N"(Ch~)2-~
/ N
I(cH2)2-Ph
H~=(IHeq3-N" (CH2)2"Rh
HO
attack
NC
H00(~ II a
ROOC Il l a
Hx IVa R=Me Va R=Et
p o ~ ~N'(cHz~-P~
N/(CH2)2-Ph (z
N/(CH2)2-Ph
N/(CH2)2 "Ph
I
Lattack
H :
NC-,,~_____~...~ OH
H00C . , , ] ~ J - . , . ~
ROOC.~_~'~.~
OH
OH
II b
Ill b
IVb R=Me
Vb R= Et
Scheme 1. H2(4)eq=H2(4)~, H2 (4)ax--H2 (4)p. EXPERIMENTAL Experimental and X-ray structural data for compound VI are collected in Table I [ 3-9 ]. All melting points were taken in open capillary tubes in an Electrothermal IA6304 apparatus, and are uncorrected. The elemental analyses were carried out in a Perkin-Elmer Elemental Analyzer model 240E. The IR spectra were recorded in the solid state (KBr) using a Perkin-Elmer 883 spectrophotometer. The 1H N M R spectrum of ca. 4% w / v CDCla solution of II was recorded at 400 Mz on a Brucker AM 400 spectrometer at a spectral width of 5000 Hz in 16k memory and acquisition time of 1.638 s over 184 transients. The 1H N M R spectra of ca. 4% w / v CDCla, C6D6 or CD3OD solutions of IV, V and V I were recorded at 300 M H z using a Varian U N I T Y - 3 0 0 spectrometer. Spectral parameters included sweep widths of 4000 Hz in 24k memory and acquisition times of 3.0 s over 64 transients. Resolution enhancement using LB = - 0.80, GF = 0.50 and GFS = 0.20 was followed by zero filling into 32k memory prior to Fourier transformations. Conventional irradiation was used for the double resonance experiments. The homonuclear 1H chemical shift correlated 2D diagrams were performed by application of the COSY 45 experiment at 300 M H z on a Varian U N I T Y 300 spectrometer. COSY spectra were run with a 512 × 512data matrix truing 256 increments in the second dimension and 512 data points in the first dimension. Sine bell window functions in both dimensions were used. Each ex-
341 TABLE 1 Experimental data and structure refinement procedures Crystal data Formula Crystal size (mm 3) Symmetry Unit cell determination: Unit cell dimensions Packing: V (~3), Z Dc (g cm-3), M, F(000) /z (cm -1) Experimental data Technique
Scanning range for 0 Number of reflections Measured Observed Range of hkl Absorption Solution and refinement Solution Refinement Number of variables H atoms Final shift/error w-Scheme
ClsH2~N03 0.20 × 0.32 × 0.30 Triclinic, p i Least-squares fit from 35 reflections (8 < 20 < 84 ° ) 14.072(1), 11.038(1), 10.894(1) ~,, 98.13(1), 86.61(1), 92.25(1) ° 16.71.4(2), 4 1.2057, 303.4, 656 6.165
Four circle diffractometer: Philips PW 1100 Bisecting geometry Graphite oriented monochromator: CuKol w/20 scan 2<0<65 ° 5114 3326 (I>3a(I)criterion) 17/-17,13/-13,0/13 No correction applied [3] Direct methods L.S. on Fobswith 1 block 397 Difference Fourier synthesis 0.005 Empirical so as to give no trends in (wA2F) vs. ( F o ) and (sin0/
~> [4] Final R and Rw Computer and programs Scattering factors Anomalous dispersion
0.O59, 0.073 VAX 11/750, Pesos [4] Multan80 [5], Dirdif [6], XRAY76 [7], Parst [8] Int. Tables X-Ray Crystallography [9 ] Int. Tables X-Ray Crystallography [9]
periment involved sixteen scans and two dummy scans with an initial delay of ls.
The 13C N M R spectra were obtained at 20 MHz on a Varian FT-80 A (PFT)
spectrometer using ca. 25% w/v CDC13 and DMSO solutions. Two types of spectra were recorded: proton-noise decoupled spectra (to determine the chemical shifts) and off-resonance decoupled spectra (to help assign the signals), at a spectral width of 5000 Hz, using an acquisition time of 1.638 s, a delay time of 1.640 s and a pulse width of 5/zs.
342
All measurements were carried out at 303 K using TMS as the internal reference.
3-Phenethyl-8-fl-cyan-3-azabicyclo [3.2.1.] octan-8-ol-ol (ID A solution of 3-phenethyl-3-azabicyclo[3.2.1]octan-8-one (3 g, 0.013 tool) [1], potassium cyanide (0.845 g, 0.013 mole) and ammonium chloride (0.955 g, 0.013 mol) in 1,4-dioxane/water (35:10; 30 ml) was magnetically stirred at room temperature for 5 days; then the mixture was poured on water (50 ml) and the aqueous layer extracted with ethyl ether (4)< 50 ml). The organic phase was separated, washed with water, dried over magnesium sulfate and the solvent evaporated. The residue was chromatographed on a silica gel column prepacked with hexane. By elution of the column with hexane/ethyl acetate (7: 3 v/v), two products were isolated which were identified as the aminonitrile (III) Rf= 0.36 (this will be reported in a future paper) and the title compound (II) Rf=0.5 in 75% yield, m.p. 110-112°C. IR (KBr) OH, 3399 cm-1; CN, 2236 cm-1; 1H NMR (see Table 2); 18C NMR (see Table 3). TABLE 2 1H chemical shifts ~ of compounds II, I V - V I ~i ( p p m ) I I (CDC13)
H-6(7)n(m) b H-6(7)x(m) b H-1 (5) (brs)
W1/2 (Hz) H-2 ( 4 ) ~ ( d ) H-2(4)p(dd) H-2' ( m ) e H-I' (m) e Ph (m) b OH (brs) CH3 CH2-O
1.76 1.90 2.35 ~ 10 2.62 2.85 d 2.73 2.80 d 7.23 2.40
I V (CD3OD)
1.98 2.21 2.62 ~ 9.5 3.39 3.71 3.10 3.27 f 7.31
V (CDC13)
1.69 1.90 2.25 ~ 10 2.37 2.73 d 2.56 2.73 d 7.24 3.79(s)
VI (CDCIa)
(C6D~)
1.69 1.91 2.25 ~ 10 2.41 2.73 d 2.57 2.73 d 7.23 2.25 g 1.32(t) 4.26(q)
1.73 1.97 2.21 ~ 9.5 2.48 c 2.57 d 2.47 ~ 2.60 d 7.12 1.83 0.95(t) 3.98(q)
aAbbreviations: br, broad; dd, doublet of doublets; m, multiplet; q, quartet; s, singlet; t, triplet. values were deduced by first order analysis of the spectra; error ___0.05 ppm. bMultiplets of low resolution; tabulated chemical shifts correspond to the center of the multiplets, c'dSignals are partially overlapped, e H - l ' a n d H - 2 ' methylene protons of the phenethyl group appear as a four spin A2B2 system. ~Fhis signal is partially concealed by t h e solvent signal. ~Overlapping resonance between OH a n d H-1 (5) signals was observed.
343 TABLE 3 13C chemical shifts ~ (ppm) for compounds II, I V - V I in CDC13 II C1- (5) C2- (4) C6- (7) C8 CI' C2' C---N C=O CH3 CH2 C 1" C2" (6") C3" (5") C4"
45.12 56.29 25.95 77.43 58.09 33.69 120.46
140.57 128.76 128.33 126.01
IV a
V
VI
40.15 55.84 24.21 80.68 57.99 29.81
42.16 56.10 26.18 83.85 58.55 33.53
42.21 56.08 26.27 83.71 58.53 33.57
173.13
172.58 51.72
137.37 129.16 128.97 127.17
140.61 128.58 128.12 125.75
172.20 60.65 14.10 140.71 128.56 128.07 125.69
~DMSO.
Analysis. Calculated for C16H2oN20: C, 74.97; H, 7.86; N, 10.96. Found: C, 74.64; H, 8.16; N, 10.62.
8-a-Hydroxy-3-phenethyl-3-azabicyclo[3.2.1]octan-8-fl-carboxylic acid hydrochloride (IV) Compound II (0.5 g, 1.6 retool) was added portionwise to aqueous HC1 (20 ml, 11 N) externally cooled at 0 ° C, the mixture was magnetically stirred and maintained at 0 ° C during this operation. The mixture was stirred at - 2 ° C for 30 rain and kept at - 5 °C for 24 h. The solution was refluxed for 6 h, allowed to cool at room temperature and the solvent evaporated under reduced pressure. The solid residue was treated with acetone and filtered. The title compound, which was purified by crystallization from ethanol, was obtained in 80% yield, m.p. 222-224°C. IR (KBr) CO, 1724 cm-1; IH N M R (see Table 2); '3C N M R (see Table 3). Analysis. Calculated for C16H21N03 HCI: C, 61.63; H, 7.11; N, 4.49. Found: C, 61.43; H, 7.10; N, 4.25.
Synthesis of the esters V, VI General procedure Anhydrous hydrogen chloride was bubbled into a solution of IV (0.75 g, 24 mmol) in the corresponding alcohol (25 ml) until saturation, with external cooling and magnetic stirring. The mixture was maintained at 0 °C for 48 h,
344 and refluxed (with anhydrous bubbling HC1) for 2 h. The solution was allowed to cool at room temperature and the solvent removed by evaporation under reduced pressure. The residue was dissolved in cooled water (0 oC ), neutralized with potassium carbonate and extracted with methylene chloride (3 × 25 ml). The organic layer was dried over anhydrous magnesium sulfate and the solvent evaporated under reduced pressure to give a crude ester as a white solid which was purified by crystallization from hexane.
Methyl-8-~-hydroxy-3-phenethyl-3-azabicyclo[3.2.1.]octan-8-fl-carboxylate (v) This compound was obtained in 72% yield, m.p. 82-84°C, IR (KBr) OH, 3436 cm-1; CO, 1733 cm-1; 1H NMR (see Table 2); 13C NMR (see Table 3). Analysis. Calculated for C17H2aNO3: C, 70.56; H, 8.01; N, 4.84. Found: C, 70.68; H, 8.01; N, 4.74.
Ethyl-8-t~-hydroxy-3-phenethyl-3-azabicyclo[3.2.1]octan-8-fl-carboxylate
(VD
This compound was obtained in 70% yield, m.p. 77-79°C; IR (KBr) OH, 3397 cm -1; CO, 1697, 1735 cm-1; 1H NMR (see Table 2 ); 13C NMR (see Table
3). Analysis. Calculated for ClsH25N03: C, 71.25; H, 8.30; N, 4.62. Found: C, 71.02; H, 8.60; N, 4.88. RESULTS AND DISCUSSION
Description and discussion of the structure of VI The final atomic parameters are given in Tables 4-6 (numbers correspond to those given in figures). Bond lengths and bond and torsion angles for the two independent molecules (A and B) which exist in the asymmetric unit are given in Tables 7 and 8. Figure 1 displays a view of the asymmetric part of VI with the numbering used in the crystallographic study and Fig. 2 shows a projection of the structure along the c axis. The two independent molecules in the asymmetric unit are related by a pseudo symmetric center. The pseudo symmetry is broken by two intermolecular hydrogen bonds. In both molecules the bicyclic system assumes a chair-envelope conformation similar to that found in other compounds [1,2,11,12]. The deviations of C4 and N1 from the main plane through C2, C3, C5 and C8 are respectively 0.868 (3), 0.637 (2) .~ in molecule A and 0.859(3), 0.631(2) A in molecule B (0.90 and 0.58 A for the 3phenethyl-3-azabicyclo [ 3.2.1. ] octan-8-~-ol (VII) [ 2 ] ). The less pronounced puckering at the C atom in compound VI as compared to VII can be explained as due to the syndiaxial steric effect exerted by the ethoxycarbonyl group on H2(4)ax. The less pronounced flattening at the N atom in compound VI can be due to the steric effect exerted by the ethoxycar-
345 TABLE 4 Atomic parameters for non H-atoms; coordinates and thermal parameters given as U~q= (1/3 )'sum[ Uii.ai*.aj*'ai'aj'cos ( ai,aj) ] " lO**4 Atom
x
y
z
U~q
N1A O1A O2A 03A C2A C3A C4A C5A C6A C7A C8A C9A C10A CllA C12A C13A C14A C15A C16A C17A C18A C19A N1B OIB 02B 03B C2B C3B C4B C5B C6B C7B CSB COB C10B CllB C12B C13B C14B C15B C16B C17B C18B C19B
0.2017(2) 0.3435(2) 0.1226(2) 0.1748 (2) 0.2128(2) 0.2952 (2) 0.2698(2) 0.2713(2) 0.3675(2) 0.3831(2) 0.1883(2) 0.1338(2) 0.0283(2) -0.0331(2) -0.0479(2) 0.1037(3) -0.1454(3) -0.1308(2) -0.0750(2) 0.1797(2) 0.0983(3) 0.1197(3) 0.5345(2) 0.3980(2) 0.6119(2) 0.5688(2) 0.5112(2) 0.4331(2) 0.4704(2) 0.4793(2) 0.3811(3) 0.3510(2) 0.5597(2) 0.6007(2) 0.7029(3) 0.7639(2) 0.8071(3) 0.8631(4) 0.8749(4) 0.8320(4) 0.7772(3) 0.5587(2) 0.6411(3) 0.5997(3)
0.0677(2) 0.4151(2) 0.4154(3) 0.4409 (2) 0.1431 (3) 0.2364 (3) 0.3245(3) 0.2355(3) 0.1740(3) 0.1737(3) 0.1418(3) -O.O354(3) -0.0037(3) -0.1199(3) -0.1914(3) -0.2987(3) -0.3345(3) -0.2653(3) -0.1591(3) 0.3949(3) 0.5256(4) 0.5880(4) 0.9083(2) 0.5557(2) 0.5381(2) 0.5647(2) 0.8364(3) 0.7402(3) 0.6507(3) 0.7347(3) 0.7938(3) 0.7978(3) 0.8302(3) 1.0112(3) 0.9807(3) 1.0946(3) 1.1543(4) 1.2611(5) 1.3084(4) 1.2510(4) 1.1454(4) 0.5809(3) 0.4834(4) 0.3763(5)
0.7685(2) 0.8407(2) 0.9001(3) 0.7083 (2) 0.6687(3) 0.6944 (3) 0.8135(3) 0.9096(3) 0.8750(3) 0.7324(3) 0.8902(3) O.7465(3) 0.7465(4) 0.7286(3) 0.8238(3) 0.8080(3) 0.6965(4) 0.6017(3) 0.6175(3) 0.8140(3) 0.7032(4) 0.5921(4) 0.7196(2) 0.6483(2) 0.6025(2) 0.8048(2) 0.8209(3) 0.7835(3) 0.6725(3) 0.5721(3) 0.5873(3) 0.7269(3) 0.6031(3) 0.7503(3) 0.7746(4) 0.8033(4) 0.7089(4) 0.7381(6) 0.8603(7) 0.9528(6) 0.9250(4) 0.6883(3) 0.8339(4) 0.8674(8)
453 (8) 546 (8) 822(11) 587 (8) 453(10) 421 (9) 414 (9) 457(10) 519(11) 488(10) 463(10) 530(11) 641(13) 515(11) 615(12) 655(13) 646(13) 632(13) 577(12) 498(10) 780(16) 800(16) 452 (8) 555 (8) 702(10) 704(10) 492(10) 466(10) 451 (9) 489(10) 595(12) 566(12) 517(11) 505(10) 696(14) 597(13) 810(17) 1015(23) 1032(25) 995(22) 754(15) 496(11) 801(17) 1377(35)
346 TABLE 5 Atomic parameters for non-H atoms; thermal parameters given as: exp [-2.u**2.sum(Uij'ai*'aj*'hi" hi). 10"'4 ] Atom
Un
U22
U33
/-]12
U13
U2s
N1A O1h 02A 03A C2A CaA C4A C5A C6A C7A C8A C9A C10A CllA C12A ClaA C14A C15A C16A C17A C18A C19A N1B O1B O2B OaB C2B CaB C4B C5B C6B C7B C8B C9B C 10 B CIIB C 12 B C13B C14B C15B C16B C17B C18B C19B
465(14) 616(13) 909(19) 592(13) 490(17) 421(15) 424(15) 493(17) 487(16) 430(17) 530(17) 442(17) 468(18) 392(16) 551(19) 631(21) 566(20) 569(20) 526(18) 550(18) 699(24) 851(28) 505(14) 622(13) 644(15) 787(17) 580(18) 511(17) 500(16) 584(18) 656(21) 496(18) 643(19) 463(16) 522(19) 425(17) 703(24) 757(29) 769(30) 1052(36) 809(26) 556(18) 664(23) 640(27)
415(13) 492(12) 839(18) 611(13) 455(16) 451(16) 415(15) 503(17) 599(19) 559(18) 443(16) 438(16) 488(10) 509(18) 740(23) 685(23) 583(20) 625(21) 577(19) 438(16) 776(26) 662(24) 380(13) 460(12) 726(16) 692(16) 478(17) 451(16) 390(15) 470(17) 554(19) 579(19) 469(17) 385(16) 447(18) 477(18) 771(27) 823(32) 639(17) 699(28) 616(23) 378(15) 785(27) 803(32)
475(14) 529(12) 728(17) 588(14) 411(15) 394(15) 396(15) 375(15) 501(17) 492(17) 410(16) 695(21) 950(27) 626(20) 526(19) 631(22) 730(24) 694(23) 643(21) 480(17) 925(29) 944(30) 462(14) 573(13) 688(16) 701(16) 407(16) 429(16) 452(16) 412(16) 605(20) 631(20) 413(16) 655(20) 1103(31) 898(27) 945(31) 1503(51) 1703(59) 1251(42) 872(28) 539(19) 1051(32) 2902(90)
-45(11) -181(10) 325(15) 187(11) -14(13) -2(12) -58(12) -64(13) -19(14) 25(14) -70(13) -47(13) -15(15) -9(13) -27(17) -13(18) -117(16) -69(17) -24(16) -16(14) 315(20) 145(21) -53(11) -189(10) 101(13) 190(13) -11(14) -28(13) -82(13) -92(14) -57(16) 22(15) -143(15) -8(13) 6(15) 27(14) -42(21) -136(25) -158(23) -60(27) 12(20) -65(14) 58(20) -17(24)
-68(11) -129(10) 266(15) -16(10) -91(13) -26(12) -62(12) -63(12) -127(14) -39(13) -29(13) -98(14) -129(17) -50(14) 45(15) 165(17) 71(17) -159(17) -140(15) 34(15) -35(21) -246(23) -48(11) -62(10) -50(13) -16(13) -34(13) -16(13) -32(13) -62(13) -189(16) -35(15) 5(14) -102(14) -196(19) -141(16) -33(22) 39(31) -423(34) -623(33) -325(22) -54(15) -169(21) -267(38)
40(10) 80 (9) 194(14) 141(10) 30(12) 75(12) 42(11) 70(12) 147(14) 118(13) 60(12) 20(14) 14(17) 12(15) 33(16) 127(17) -2(17) 39(17) 105(15) 14(13) 246(22) 196(21) 33(10) 79 (9) -96(13) 297(12) 31(12) 56(12) 44(12) 73(13) 142(15) 109(15) 37(13) 12(13) -14(18) 78(17) 102(2) 384(32) 122(33) -17(28) 111(19) 28(13) 402(23) 937(44)
347 TABLE 6 Atomic parameters for H-atoms; coordinates and thermal parameters given as exp [ - 8. ~'*'2" U" (sin0/Jt)**2.10"'3 ] Atom
x
y
z
U
H1A H21A H22A H3A H5A H61A H62A H71A H72A HSlA HS2A H91A H92A H 101A H102A H12A H13A H14A H15A H16A H181A HlS2A H191A H192A H193A H1B H21B H22B H3B H5B H61B H62B H71B H72B H81B H82B H91B H92B H101B H 102B H12B H13B H14B H15B H16B HlSlB H182B H191B H192B H193B
0.357 (0) 0.234 (0) 0.141(0) 0.306 (0) 0.264(0) 0.360(0) 0.429 (0) 0.395 (0) 0.549(0) 0.116(0) 0.186(0) 0.145(0) 0.151(0) 0.012 (0) 0.014(0) -0.011(0) -0.116(0) -0.186(0) -0.173(0) -0.058 (0) 0.036 (0) 0.094 (0) 0.107(0) 0.067(0) 0.185(0) 0.405 (0) 0.582 (0) 0.483 (0) 0.413(0) 0.492 (0) 0.330(0) 0.339 (0) 0.285 (0) 0.336 (0) 0.639(0) 0.561 (0) 0.567 (0) 0.602 (0) 0.713(0) 0.739 (0) 0.803 (0) 0.899 (0) 0.918(0) 0.863(0) 0.734(0) 0.685 (0) 0.691(0) 0.645 (0) 0.541(0) 0.537(0)
0.455 (0) 0.082 (0) 0.193 (0) 0.283 (0) 0.291(0) 0.079(0) 0.231 (0) 0.073 (0) 0.772(0) 0.193(0) 0.084(0) -0.099(0) -0.095(0) 0.055 (0) 0.054(0) -0.170(0) -0.350(0) -0.426(0) -0.291 (0) -0.094(0) 0.460 (0) 0.600 (0) 0.509 (0) 0.641 (0) 0.633 (0) 0.526 (0) 0.797 (0) 0.898 (0) 0.697(0) 0.680 (0) 0.735(0) 0.887 (0) 0.739 (0) 0.897 (0) 0.792(0) 0.884(0) 1.064 (0) 1.065 (0) 0.921(0) 0.916 (0) 1.098(0) 1.319 (0) 1.395 (0) 1.298(0) 1.104(0) 0.524 (0) 0.464(0) 0.321 (0) 0.319(0) 0.373(0)
0.768 (0) 0.581 (0) 0.658(0) 0.602 (0) 1.013(0) 0.913(0) 0.932 (0) 0.684 (0) 0.291(0) 0.904(0) 0.967(0) 0.828(0) 0.654(0) 0.846 (0) 0.661(0) 0.922(0) 0.891(0) 0.680(0) 0.520(0) 0.533 (0) 0.678 (0) 0.799 (0) 0.520(0) 0.573 (0) 0.598(0) 0.566 (0) 0.858(0) 0.901 (0) 0.874(0) 0.480 (0) 0.520(0) 0.552 (0) 0.745 (0) 0.773 (0) 0.616(0) 0.520(0) 0.931 (0) 0.666 (0) 0.860(0) 0.684 (0) 0.600(0) 0.659 (0) 0.899 (0) 1.060(0) 1.017{0) 0.898(0) 0.762(0) 0.896 (0) 0.303(0) 0.916(0)
45 (0) 40 (0) 40(0) 34 (0) 37(0) 44(0) 44 (0) 41 (0) 41(0) 41(0) 41 (0) 47{0) 47(0) 54 (0) 54(0) 54(0) 58(0) 55(0) 55(0) 49 (0) 65 (0) 65 (0) 68(0) 68(0) 68(0) 46 (0) 43 (0) 43 (0) 40(0) 42 (0) 55 (0) 55 (0) 49 (0) 49 (0) 45 (0) 45 (0) 44 (0) 44 (0) 58(0) 58 (0) 77(0) 90 (0) 84(0) 84(0) 68(0) 74 (0) 74(0) 99 (0) 99(0) 99(0)
348 TABLE 7 Bond distances (.~) Bond
Distance (A)
Bond
Distance (A)
NIA-C2A NIA-C8A
1.459 (4) 1.462 (4)
N IB-C2B NIB-C8B
1.463 (4) 1.463 (4)
N 1A-C9A O1A-H1A O1A-C4A 02A-C17A 03A-C 17A 03A-C18A C2A-C3A C3A-C4A C3A-C7A C4A-C5A C4A-C17A C5A-C6A C5A-C8A C6A-C7A C9A-C10A C10A-CllA C11A-C12A CllA-C16A C12A-C13A C13A-C14A C14A-C15A C15A-C16A ClSA-C19A
1.460(4) 0.961 (2) 1.426(3) 1.201(4) 1.329(4) 1.461(5) 1.532(4) 1.540(4) 1.546(4) 1.536(4) 1.512 (4) 1.543(4) 1.535(4) 1.555(5) 1.539(5) 1.514(5) 1.391 (5) 1.384(5) 1.391 (5) 1.380(5) 1.371(6) 1.381(5) 1.485 (7)
N1B-C9B O1B-H1B O1B-C4B 02B-C17B 03B-C 17B 03B-C18B C2B-C3B C3B-C4B C3B-C7B C4B-C5B C4B-C17B C5B-C6B C5B-C8B C6B-CTB C9B-C10B C10B-CllB C11B-C12B CllB-C16B C12B-C13B C13B-C14B C14B-C15B C15B-C16B C18B-C19B
1.455 (4) 0.915 (2) 1.442(4) 1.214(4) 1.322(4) 1.460(5) 1.530(4) 1.530(4) 1.541(5) 1.528(4) 1.519(5) 1.541(5) 1.533(4) 1.550(5) 1.536(5) 1.501(5) 1.396(6) 1.384(6) 1.401 (7) 1.377(10) 1.364(9) 1.382(6) 1.383(7)
bonyl rest on the N-phenethyl group. The asymmetric parameters [ 13 ] are in the six-membered ring: ¢2 = - 0 . 7 1 ( 1 . 2 7 ) , 02=168.6(2) and QT=0.666(3) (molecule A) and ~2 = - 176.8 (1.4), 02 = 11.8 (2) and QT=0.661 (3) (molecule B). The five-membered ring has an envelope conformation with the C4 atom - 0.761 (3) A (molecule A) and 0.751 (3) A (molecule B ) from the plane of the C3, C5, C6 and C7 atoms; ring puckering coordinates are ¢ 2 = 3 6 . 6 ( 4 ) , 02=0.511(3) (molecule A) and ¢ 2 = - 1 4 3 . 6 ( 4 ) , 02=0.506(3) (molecule B). The oxygen atom joined to the C4 atom and the radical attached to N1 atom are in the equatorial position while the ethoxy-carbonyl group occupies an axial position with respect to the piperidine ring. The phenethyl and the ethoxycarbonyl groups are oriented perpendicularly. The angles defined by the COO plane and the phenyl ring are 89.8 (1) ° (molecule A ) and 94.4 (2) ° (molecule B ). The ethyl chain presents disorder as is reflected by the high values of the thermal parameters of C18 and C19 atoms; due to this disorder, the C18-C19
349 TABLE 8 Bond angles and torsion angles Angle
Value (deg)
Torsion angle
Value (deg)
C8A-N 1A-C9A C2A-N1A-C9A C2A-NIA-CSA HIA-OIA-C4A C 17A-O3A-C 18A NIA-C2A-C3A C2A-C3A-C7A C2A-C3A-C4A C4A-C3A-C7A 01A-C4A-C3A C3A-C4A-C 17A C3A-C4A-C5A 01A-C4A-C17A O1A-C4A-C5A CSA-C4A-C17A C4A-C5A-CSA C4A-C5A-C6A C6A-C5A-C8A CSA-C6A-C7A C3A-C7A-C6A NIA-C8A-CSA NIA-C9A-C10A C9A-C10A-C11A C10A-C11A-C16A C10A-C11A-C12A C12A-C11A-C16A C11A-C12A-C13A C12A-C13A-C14A C13A-C14A-C15A C14A-C15A-C16A C 11A-C16A-C15A O3A-C17A-C4A O2A-C17A-C4A O2A-C 17A-O3A O3A-C18A-C19A C8B-NIB-C9B C2B-NIB-C9B C2B-NIB-CSB H1B-OIB-C4B C 7B-O3B-C 18B N1B-C2B-C3B C2B-C3B-C7B C2B-C3B-C4B C4B-C3B-CTB OIB-C4B-C3B
114.3 (2) 114.6 (2) 111.9 (2) 108.0 (2) 116.5 (2) 109.4 (2) 110.7 (2) 109.2 (2) 101.7 (2) 111.6 (2) 116.4 (2) 99.6 (2) 105.5(2) 107.5 (2) 116.2 (2) 109.3 (2) 101.8 (2) 110.9 (3) 104.8 (2) 105.0 (2) 109.5 (2) 116.5(3) 110.0 (3) 121.5 (3) 120.5 (3) 118.0 (3) 120.9 (3) 119.6 (3) 120.0 (3) 120.2 (3) 121.2 (3) 110.9 (3) 125.8 (3) 123.2 (3) 107.4 (3) 114.3 (2) 114.4 (2) 111.7 (2) 106.3(2) 120.0 (3) 109.9 (2) 110.8 (3) 109.3 (3) 101.3 (2) 107.2 (2)
NIA-C2A-C3A-C4A C2A-C3A-C4A-C5A C3A-C4A-C5A-CSA C4A-C5A-CSA-NIA C2A-NIA-CSA-C5A C8A-NIA-C2A-C3A C3A-C4A-C5A-C6A C4A-C5A-C6A-CTA C5A-C6A-C7A-C3A C4A-C3A-C7A-C6A C 7A- C6A-C4A-C5A C2A-NIA-C9A-C 10A 01A-C4A-C17A-O2A H22A-C2A-C3A-H3A H21A-C2A-C3A-H3A H3A-C3A-C7A-H71A H5A-C5A-CSA-H81A H5A-C5A-C8A-H82A H5A-C5A-C6A-H61A H5A-C5A-C6A-H62A H62A-C6A-C7A-H71A H61A-C6A-C7A-H71A H92A-C9A-C10A-H101A H91A-CgA-C10A-H101A H92A-C9A-C10A-H102A H91A-C9A-C10A-H102A N1B-C2B-C3B-C4B C2B-C3B-C4B-C5B C3B-C4B-C5B-CSB C4B-C5B-C8B-NIB C2B-NIB-C8B-CSB C8B-NIB-C2B-C3B C3B-C4B-CSB-C6B C4B-CSB-C6B-C7B CSB-C6B-C7B-C3B C4B-C3B-CTB-C6B CTB-C6B-C4B-C5B C2B-N1B-C9B-C10B 01B-C4B-C17B-O2B H22B-C2B-C3B-H3B H21B-C2B-C3B-H3B H3B-C3B-C7B-H71B H3B-C3B-C7B-H72B H5B-C5B-CSB-H81B H5B-C5B-CSB-H82B
- 64.4 (3) 68.0 (3) - 67.8 (3) 64.2 (3) - 55.5 (3) 55.7 (3) 49.5 (3) - 30.9 (3) 0.6 (3) 29.8 (3) - 49.0 (3) - 68.5 (4) -96.0(4) - 65.0 (3) 55.4 (3) - 84.4 (3) 59.6 (3) - 53.6 (3) 84.6 (3) - 29.0 (4) 116.6 (3) -6.9(4) 117.8 (3) 62.7 (3) - 60.9 (4) - 176.9 (3) 63.2 (3) -68.0(3) 68.2 (3) - 64.2 (3) 55.0 (3) - 54.5 (3) - 49.3 (3) 30.4 (3) - 0.3 (3) - 29.8(3) 49.0 (3) 66.8 (4) 85.5(4) - 55.3 (3) 60.1 (3) - 34.9 (4) 83.1 (3) - 65.9 (4) 55.9 (3)
350 TABLE 8 (Continued) Angle
Value (deg)
Torsion angle
Value (deg)
C3B-C4B-C17B C3B-C4B-C5B O1B-C4B-C17B O1B-C4B-C5B C5B-C4B-C17B C4B-C5B-C8B C4B-C5B-C6B C6B-C5B-CSB C5B-C6B -C7B C3B-C7B-C6B N1B-CSB-C5B N1B-C9B-C10B C9B-C10B-C11B C10B-CllB-C16B C10B-CllB-C12B C12B-CllB-C16B CllB-C12B-C13B C12B-C13B-C14B C13B-C14B-C15B C 14B-C 15B-C 16B CllB-C16B-C15B 03B-C17B-C4B O2B-C17B-C4B 02B-C17B-O3B 03B-C18B-C19B
117.7(3) 100.4 (2) 103.7 (2) 112.2 (2) 115.8(3) 108.7 (2) 101.5 (2) 111.5 (3) 104.8 (3) 105.3(3) 109.8 (2) 116.9 (3) 111.4 (3) 120.7 (3) 121.4(4) 118.0 (4) 120.3 (5) 120.1(5) 119.9{5) 120.5 (5) 121.3 (4) 112.9{3) 123.8{3) 123.2(3) 110.9 (4)
H5B-C5B-C6B-H61B H5B-C5B-C6B-H62B H62B-C6B-C7B-H71B H61B-C6B-C7B-H71B H62B-C6B-C7B-H72B H61B-C6B-C7B-H72B
25.2(4) --88.8(3) 128.1(3) 2.6(4) 6.5(4) --119.0(3)
bond distance values are shorter than normal (1.485(7) A in molecule A and 1.383 (7) A in molecule B). The molecules are linked by two crystallographically independent hydrogen bonds between adjacent molecules (Fig. 2); their geometry is given in Table 9.
Infrared spectra The IR spectrum of YI in the solid state showed a broad asymmetric band at 3397 cm -1 (with a shoulder at 3374 cm-1), which is assigned to the OH . . . . . O stretching vibrations. In the carbonyl region, two strong bands are observed at 1735 and 1697 cm-1 which are attributed to the vCO free and hydrogen-bonded carbonyl groups respectively. These results are in accord with X-ray data.
351
I.~C19 H2 C15 I;3.6
moI.B
HI
O3(
H2 "~ ~
~
mol.A
Fig. 1. Pluto view of the molecules [ 10 ].
NMR spectra Spectral analysis Assignments of proton and carbon resonances have been made on the basis of the literature data for ~- and fl-epimers of 3-phenethyl-3-azabicyclo [3.2.1. ] octan-8-ol and related systems [ 1,2,11,12 ]. V and VI have been studied in more detail; their 300 MHz 1H NMR spectra, double resonance (DR) experiments and homonuclear 2D COSY-45 [14,15 ] of VI were used to provide the required information. 13C NMR chemical shifts of compounds II, I V - V I are listed in Table 3. Substituent steric and electronic effects on 1~C chemical shifts [ 16,17 ], signal multiplicity obtained from off-resonance decoupled spectra and our previously reported values for related bicyclic systems [1,2,11,12] were taken into consideration.
1H NMR spectra Overlapping resonance between different signals was observed for all the compounds in the solvents employed to record their 1H NMR spectra (see Table 2). The signals due to H - l ( 5 ) , H-6(7)n and H-6(7)x appear well differentiated. In order to clarify the assignment of the signals and to deduce the proton magnetic parameters, homonuclear 2D COSY spectra [14,15 ] in CDC13 and C6D6 for VI and double resonance (DR) experiments in CDC13 for V and VI
352
[5
C
Fig. 2. Projection of the structure along the c axis.
TABLE 9 Interatomic distances (/~) and angles (deg) in the hydrogen bonds a
b
c
OtAOrB-
HIA ..... HIB .....
O1B (x,y,z) 02B (-x+l,
-y+l,
-z+l)
ab
bc
ac
abc
0.96 0.91
1.88 t.89
2.83 2.79
168.27 166.06
353
were performed. The contour plots of the 300 MHz proton COSY spectra are shown in Figs. 3 and 4 (the aromatic proton region is omitted). The cross-connectivity patterns were analyzed taking into account that the non-resolvable wide singlet at 2.25 ppm in CDCI3 (2.21 ppm in C6D6) can be unambiguously assigned to bridgehead H-1 (5) protons. By considering the correlations, the following can be established: (i) the multiplet centered at ca. 2.49 ppm in CDC13 (2.48 ppm in C6Ds) due to four protons correlates with H1 (5) and the signal at ca. 2.73 ppm (ca. 2.58 ppm in C6D8), and must correspond to methylene protons adjacent to the phenyl group of the N-substituent and H-2 (4)a, owing to the very weak cross-peak with H-1 (5) that is in agreement with a small value for 33"2(4) ~-H1 (5) [ 1,2 ]; (ii) the multiplet centered at ca. 2.73 ppm (ca. 2.58 ppm in C6D6), also due to four protons, with a stronger correlation with H- 1 (5), must correspond to H-2 (4) ~ and methylene protons, adjacent to the nitrogen atom, of the phenethyl moiety; (iii) the signal at 1.69 and 1.91 ppm (1.73 and 1.97 ppm in CsD6) should be tentatively assigned to
e
1.5,
_).O
_),5
3.0
3.5
4.0
- I
0
4.5
5.0
. . . .
, 4 5
. . . .
tt , 4.0
. . . .
, 3.5
. . . .
,
. . . .
3.0
, 2.5
. . . .
,
-
2,0
F'I (ppm)
Fig. 3. Contour plot of the 300 MHz proton COSY spectrum of VI in CDC13.
-
-
, 1.5
. . . .
, 1.0
.
.
354
1.0
I~
O 4.0
3.5
3.0
2.5 F1 (ppm)
2.0
1.5
1.0
Fig. 4. Contour plot of the 300 MHz proton COSYspectrum of VI in C6D6. H-6 (7), and H-6 (7)x respectively owing to their shape and the weak correlation between the high-field multiplet and H-1 (5). To verify the assignments of H-6 (7), and H-6 (7)~ chemical shifts, double resonance (DR) experiments were performed for Y and VI (in CDC13 at 300 MHz). On saturating the H-1 (5) signal the high-field multiplet at ca. 1.69 ppm remained practically unchanged, whereas the signal at ca. 1.90 p p m becomes simpler. As in the case of ~- and fl-epimers of 3-phenethyl-3-azabicyclo[3.2.1]octan-8-ol [1,2] a limit value of 0.5 Hz has been admited for 3JH6 (7),-H1 (5) and the high-field signal may therefore be attributed to H-6 (7) ~ in agreement with the correlations observed in the 2D COSY spectra. The H-2(4)~ and H-2(4)p signals were also assigned on the basis of the values of the respective couplings with H-1 (5) protons [ 1,2 ]. The vicinal coupling constant 3JH2 (4)~-H1 (5) presents a low value and could not be established. Bearing in mind the above considerations, the analysis of the spectra
355 TABLE 10 Coupling constants a deduced from the analysis of the 1HMR spectra of compounds II, I V - V I
J (Hz)
II (CDCI3)
H2(4)~-H2(4)p H2(4)y-H1 (5) HI'-H2' CH3-CH2
-11.9 3.7 7.6
IV (CD3OD)
-13.5 3.1 b
V (CDC13)
-11.3 3.8 7.6
VI (CDCI3)
(CsD~)
-11.3 __b 7.6 7.2
-11.4 3.7 7.8 7.1
aError _ 0.2 Hz; 3JH2 (4)~-H 1 (5) could not be established; only a slight broadening of the H2 (4) signal has been observed. Wrhese coupling constants could not be established due to the low resolution and/or overlapping of the corresponding signals.
leads to the establishment of the protonic parameters given in Tables 2 and 10.
Conformational study The 1H and 13C parameters of compounds V and VI are in good agreement with previously reported values for related bicyclic systems in which the cyclopentane and piperidine rings have a flattened C8 envelope and distorted chair conformation puckered at C8 and flattened at N3 respectively. In the 1H NMR (in CDCla and C6D 6 solution) spectra of compounds V and VI, W1/2values for the H1 (5) signal (10, 9.5 Hz) correspond to a piperidine ring in flattened chair conformation [ 1,2,11,12 ]. In benzene -d6 solution 3JI-I2 (4) ~-H 1 ( 5 ) is greater than aJH2 (4) ~-H 1 ( 5 ), and consequently, the dihedral angle H 2 ( 4 ) z - C - C - H I ( 5 ) is smaller than H2 (4)~-C-C-H1 (5) according to the Karplus relationship [ 18 ]. This is also more consistent with a flattened chair conformation than with a boat for the piperidine ring [ 1,2 ]. For compounds V and VI (in CDCI3 and C6D6 solution), the H2(4)p signal appears at a lower field than the H2 (4)~ signal (A0"I-I2(4)pH2 (4), ~ 0.3 ppm in CDC13 and ~ 0.1 ppm in C6D6). This fact is attributed to the field effect exerted by the carbonyl group on H2 (4)p. This fact has been reported by us in several aza and diazabicyclo spirohydantoins [ 19-21] in which the C4=O group occupies the same position with respect to the corresponding axial protons, as the position of the carbonyl group with respect to H2 (4)~ in V and VI. In consequence, it can be supposed that for compounds V and VI in CDC13 and C6D6 solutions the alkoxycarbonyl group adopts a preferred conformation, in which the CO0 plane is perpendicular with respect to the C1, C2, C4 and C5 plane.
356 As would be expected, The oCH6(7)n, 5H6(7)x and 5C1(5), 5C6(7) values for compounds V and VI are similar to the 5-values found for analogous protons and carbon atoms in compound V I I [2]. The ASC2 (4) (V,VI) - C2 (4) ( V I I ) ~ - 2.3 ppm is attributed to the ~-effect exerted by the carbonyl group on H2 (4)p in compounds V and VI. The ASC8 (V,VI) - C8 ( V I I ) ~ 3 ppm is attributed to the electron-attracting effect exerted by the ethoxycarbonyl group on C8 in compounds V and VI. The chemical shift of C1 of the phenethyl group (in V and VI, see Table 3) is in agreement with an equatorial disposition of the N-substituent [ 1,2,11,12 ]. Hence, good agreement of the preferred conformation of C8D6 solution and the solid state for VI has been observed. The cyclopentane and piperidine rings adopt an envelope conformation flattened at C8 and a distorted chair conformation puckered at C8 and flattened at N3, respectively, with the N-substituent in the equatorial position with respect to the piperidine ring. The unique difference is the conformation of the ethoxycarbonyl group which in solid state seems to be governed by the intermolecular hydrogen bonds. ACKNOWLEDGEMENT We t h a n k the ComisiSn Interministerial de Ciencia y Energ/a (Grant FAR88-0440) for support for this research.
REFERENCES 1 M.S.Arias, E. G~lvez,I. Ardid,J. Bellanato,J.V. Garch-Ramos, F. Florencioand S. GarchBlanco, J. Mol. Struct., 161 (1987) 151 and referencescited therein. 2 E. G~lvez,M.S. Arias, I. Ardid,F. Florencio,J. Sanz, J. BeUanatoand J.V. Garch-Ramos, J. Mol. Struct., 196 (1989) 307. 3 N. Walker and P. Stuart, Acta Crystallogr.,Sect. A, 39 (1983) 158-166. 4 M. Martfnez-Ripolland F.H. Cano, PESOS: a computer program for the automatic treatment of weightingschemes, Instituto Rocasolano,C.S.I.C., Madrid, Spain, 1975. 5 P. Main, S.J. Fiske, S.E. Hull, L. Lessinger,G. Germain,J.P. Declercq and M.M. Woolfson, MULTAN: a system of computer programs for the automatic solution of crystal structures from X-ray diffractiondata, Universitiesof York, England and Louvain,Belgium,1980. 6 P.T. Beurkens, W.P. Bosman, H.M. Doesburs, R.O. Gould, T.H.E. Van der Hark, P.A.J. Prick, J.H. Noordik, G. Beurkens and Parthasarathi, DIRDIF Manual 81, Crystallography Laboratory,Toernooiveld,The Netherlands, 1981. 7 J.M. Stewart, F.A. Kundell,J.C. Baldwin.The X-RAY 70 System ComputerScienceCenter, Universityof Maryland, CollegePark, Maryland, 1974. 8 M. Nardelli, Comput. Chem., 7 (1983) 95-98. 9 International Tables for X-Ray Crystallography,Vol. 4, Kynoch Press, Birmingham, 1974. 10 W.D.S.Motherwell and W. Clegg, PLUTO: a program for plotting crystal and molecular structures, CambridgeUniversity,U.K., 1978. 11 E. G~lvez, I. Ardid, L. Fuentes. F. Florencioand S. Garc~a-Blanco,J. Mol. Struct., 142 (1986) 411.
357 12 M.L. Izquierdo, M.S. Arias, E. Gdlvez, B. Rico, I. Ardid, J. Sanz, I. Fonseca, A. Orjales and A. Innerarity, J. Pharm. Sci., in press. 13 D. Cremer and J.A. Pople, J. Am. Chem. Soc., 97 (1975) 1354. 14 A. Bax and R. Freeman, J. Magn. Reson., 44 (1981) 542. 15 A.E. Derome, Modern NMR Tecniques for Chemistry Research, Pergamon Press, Oxford, 1987. 16 F.W. Wehrli and A.P. Marchand, Interpretation of 13C NMR Spectra, 2nd Edn., Wiley, Chichester, 1988. 17 E. Breitmeier and W. Voelter, 13C NMR Spectroscopy: Methods and Application in Organic Chemistry, 2nd end., Verlag Chemie, Weinheim, 1978. 18 C.A.G.Haasnoot, F.A.A.M. de Leeuw and C. Altona, Tetrahedron, 36 (1980) 2783. 19 G.G.Trigo, E. G~lvez and C. Avendafio, J. Heterocycl. Chem., 15 (1978) 907. 20 G.G.Trigo, E. G~lvez, M. Espada and C. Bernal, J. Heterocycl. Chem., 16 (1979) 977. 21 E. G~lvez, M. Martfnez, J. Gonz~lez, G.G. Trigo, P. Smith-Verdier, F. Florencio and S. Garcfa-Blanco, J. Pharm. Sci., 72 (1983) 881.