769J. CHEM. SOC. PERKIN TRANS. I 1992 Novel Redox Cyclisation Products Derived from 2-Acylpyrroles and trans-3-Bromo-3,4-di hydro-4-hydroxy-2,2-dimethyl-2H-chromene-6-carbonitrile Derek R. Buckle,"ne Susan C. Connor,a Drake S. Eggleston,b Andrew Faller,8 Ivan L. Pinto,a Simon A. Readshawe and David G. Smitha a SmithKline Beecham Pharmaceuticals, Great Burgh, Yew Tree Bottom Road, Epsom, Surrey, KT18 5x0, UK SmithKline Beecham Pharmaceuticals, Physical and Structural Chemistry Department, PO Box 1539, King of Prussia, Pennsylvania, 19406-0939.USA The reaction of 2-(trifluoroacetyl) pyrrole with trans-3-bromo-3,4-di hydro-4- hydroxy-2,2-dimethyl- 2H-chromene-6-carbonitrile under basic conditions has been shown to afford high yields of (4R", 5aS *,I 1bS*) -5a-hydroxy-6,6-dimethyl-4-trifluoromethyl-5a,l1 b-dihydro-4H,6H-pyrrolol',2':4,5 -oxazino2,3-cchromene-lO-carbonitrile rather than the anticipated amino alcohol.The unequivocal structural assignment of this unusual tetracyclic product by spectroscopic and X-ray crystallographic techniques is described and possible mechanistic explanations for its formation are discussed. Analogous reactions of pyrroles substituted in the 2-position by formyl, acetyl and benzoyl moieties have been shown to behave in an essentially similar manner, suggesting that the reaction is general for 2 -acylpyrroles. Continued interest in the potassium channel activators, typified acylpyrroles. Initial attempts to effect reaction of 2-(trifluoro- by the dihydrochromene cromakalim l,t as novel smooth acety1)pyrrole with 2 in tetrahydrofuran (THF) in the presence muscle relaxants has identified a large number of structural of potassium tert-butoxide failed, presumably because of the variants which retain the beneficial properties of this pharmaco- poor nucleophilicity of the delocalised pyrrole anion.In the logical class of compound. Although several structurally presence of TMEDA (tetramethylethylenediamine),however, a diverse compounds which share the same mechanism of action high yield (71) of a new product was obtained, although this as cromakalim have been identified, considerable attention has was not the expected dihydrochromenol9 or its alkene 10, but been focused on the structure of cromakalim itself.This effort the novel tetracyclic product 11(Scheme 1). has resulted in much detailed knowledge regarding the key structural requirements for biological activity within the cromakalim series,2-6 although new avenues of research are regularly being opened. One particular approach has been the study of the C-4 pharmacophore, which has highlighted the NC orthogonal preference of the amide carbonyl such that it is directed to the same face as that of the C-3 hydroxy group.' In continuation of our own interest in this area we have 2investigated the effects of pyrrole substituents at the C-4 1 cromakalim position and now describe an unusual redox reaction observed during attempts to prepare 2-acylpyrrole derivatives. R ...9NcaEDiscussion The reaction of a~ide,'.~ amines * and amides 273 with truns-3- bromo-3,4-di hydro-4- hydroxy-2,2-dimet hyl-2H-chromene-6- 3 4 R = N~,NR'R~,NA'COR~ carbonitrile 2 and its derived epoxide 3 generally leads to the formation of the expected dihydrochromenols 4, accompanied in the latter case by varying quantities of the corresponding alkenes 5.Similar reactions with the anions derived from NR'COR2 substituted pyrroles do not always proceed normally, however, and under the more forcing conditions required for such anions to react with 2, competitive ring contraction reactions leading to the formation of benzofurans 6 have been rep~rted.~ The formation of such compounds is believed to reflect the relative 5 6 R = CN, NO;! ease of pyran ring cleavage and dehydration of the intermediate dihydrochromenols7.As part of our interest in this class of compound, we were anxious to investigate the effects of acyl substitution within the pyrrole nucleus, particularly at the position adjacent to the heteroatom. Accordingly, we have extended our earlier studies to include the reaction of the bromohydrin 2 with selected 2-7 R = CN, NO2 t Only relative stereochemistry shown. 8R=H +QCOCF, A 11 9 OCOCF, 10 Scheme 1 Reagents: i, KOBulsquo;, TMEDA, THF In order to test the generality of this unusual redox reaction, analogous studies were carried out using 2-benzoylpyrrole, 2- formylpyrrole and 2-acetylpyrrole. Thus, the condensation of 2- benzoylpyrrole with the bromohydrin 2 also afforded tetracyclic products, but in this instance the hydroxy compound 13 (17) was accompanied by the corresponding unsaturated derivative 15 (16).Whilst it is likely that the formation of the alkene 15 proceeds under the reaction conditions, it was noticed that with time the alcohol 13 gradually eliminated water to generate 15.A similar transformation of the trifluoromethyl compound 11 with time was not observed. 2-Formylpyrrole also underwent condensation with the bromohydrin 2 to give the unstable tetracyclic alcohol 14 in modest (13) yield. The poor overall yield in this instance probably reflects the instability of 2-formylpyrrole under the reaction conditions, although no attempt has been made to identify the numerous by-products from this reaction.13 R =Ph12 14R=H 15 R =Ph 17 16R=Me J. CHEM. SOC. PERKIN TRANS. 1 1992 In contrast to the above reactions, in which only tetracyclic products were isolated, 2-acetylpyrrole furnished a 1:1 mixture of the alkene 16 (18) and the unrearranged chromene 17 (18) after reaction with the bromohydrin 2. The formation of 17 suggests that intramolecular cyclisation is disfavoured with less electron deficient acyl substituents to the extent that competi- tive dehydration becomes a significant alternative rea~tion.~ It seems likely that the acetyl group provides a convenient proton source for the intermediate alkoxide which is sufficient to initiate elimination to afford the benzopyran 17. Structural Elucidation of Compound 11.-From the IR spectrum it was evident that the product no longer had a carbonyl stretching frequency at ca.1680 cm-rsquo;, although the strong absorbance at 3580 cm-rsquo; suggested that a hydroxy moiety had been retained. Since the elemental and MS data confirmed the anticipated molecular formula C, 8H1 5F3N203, it was clear that a stoichiometric combination of the two substrates had taken place. The lsquo;H NMR spectrum was particularly informative in that no vicinally coupled proton resonances characteristic for protons 3-H and 4-H in compound 9, were evident (Table 1). Furthermore, the NMR spectrum showed the presence of a methine quartet at 6, 5.48 (J6.5 Hz) which indicated the attachment of the trifluoromethyl group to a carbon atom bearing one proton which was not coupled to any other proton.A second methine resonating as a singlet at 6, 5.45 was consistent with that normally observed for 4-H, but lacking the a-hydrogen at C-3. Analysis of the 13C NMR spectroscopic data (Table 1) also showed a number of features inconsistent with the anticipated product 9; in particular, the absence of the low field carbonyl signal and that expected for the hydroxy bearing carbon atom at C-3. Instead the I3C NMR spectrum contained a methine quartet at dC 67.7 (3JcF 33.4 Hz), indicative of the carbon bearing the trifluoromethyl group, as well as a quaternary resonance at dC 92.0, suggesting the presence of a hemiacetal moiety. Analysis of the long-range carbon-proton correlations (usually through 2- or 3- bonds, Table l), as measured in the lsquo;H, 3C COLOC experiment, completed the structure elucidation and suggested the tetracyclic structure 11 (see 12 for numbering system).In particular, the long-range correlations observed between the carbon resonating at 53.2 ppm and the ex-changeable proton at 7.21 ppm, and that 7.48 ppm (11-H), confirmed this carbon as being C-llb whilst at the same time indicating that a hydroxy group must be present at C-5a. From this assignment it followed that the pyrrole nitrogen was attached to C-llb, and this was further supported by the COLOC correlations between 11b-H and the pyrrole carbons C-3a and C-1 and the NOE from l-H to 11-H, as well as the mutual NOESbetween 11 b-H and l-H.Although these data were consistent with the tetracyclic structure 11, the morpholine geometry and the relative stereo- chemistry of its substituents could not be assigned. Single crystal X-ray analysis (Fig. 1; see Tables 2, 3 and 4 for atomic coordinates and bortd lengths and angles) confirmed the conclusions derived from the NMR spectroscopic data and unambiguously assigned the relative configuration of the three chiral centres. Thus, the morpholine and pyran rings were shown to be cis fused and the 4-trifluoromethyl and 5a-hydroxy groups shown to be orientated trans to each other. Subsequent analysis of the NMR spectroscopic data indicated that the solution state conformation of 11 agreed with that of the solid- state X-ray structure. The syn-1,3-diaxial relationship of 6-CH,,, and proton llb-H was confirmed in solution by their mutual NOE and the syn-1,3-diaxial relationship of the C-5a hydroxy group and proton 4-H, relative to the morpholine ring, was confirmed by the NOE between 4-H and 5a-OH (Table 1).J. CHEM. SOC. PERKIN TRANS. 1 1992 771 Table 1 NMR spectroscopic data for compound 11 Atom 6, 6, a COLOC correlations NOES observed at 122.8 7.40 llb-H' 11 b-H, 1 l-H, 2-H 1 2 108.6 6.28 1 -H 105.6 6.09 1-H 2-H, 4-H 3 3a 1 15.6 -1lb-H,' 3-H, 2-H, 1-H, 4-H 67.7 5.48 3-H, 5a-OH 4 5a 92.1 -6-CH3 ax, 6-CH3 eq, 1 1 b-H 6 81.0 -6-CH3 ax, 6-CH3 eq 7a 154.8 -1 l-H 8 118.0 6.98 133.0 7.63 1 l-H 9 -10 102.3 132.0 7.4811 -1 la 122.9 llb 53.2 5.45 5a-OH, ll-H 6-CH3 ax, 5a-OH, 1 l-H, 1-H 4-CF3 123.4 -4-H 5a-OH -7.21 6-CH3 ax 21.7 1.36 6-CH3 eq 6-CH3 eq, 5a-OH, 1 lb-H 6-CH3 eq 20.6 1.56 6-CH3 ax 6-CH3 ax, 5a-OH 10-CN 118.8 -1 l-H 'Solvent: (CD3),S0, 6, relative to dTMS0;6, relative to dTMS0.COLOC correlations arising from long range coupling between carbon n and the 6.5 Hz.protons tabulated. 'Additional COLOC correlations measured as a CDC13CD3),SO-D,0 solution. ,JCF33.4 Hz;3J~~ 'JcF279.7 Hz. Mechanistic Considerations.-The initial step in the sequence leading to the tetracyclic product 11 is believed to be dehydro- halogenation of 2 to the epoxide 3, and this is consistent with the formation of 11on treatment of 2-(trifluoroacety1)pyrrole with 3 under essentially similar reaction conditions.Attack of the pyrrole anion in the anticipated manner would then proceed at C-4 to generate the alkoxide 18(Scheme2). One possibility (path 18 a) is that the alkoxide 18 is then predisposed for a 1,5-hydride 18 shift from C-3 to the pyrrole acyl group to give 19 which is IWhb appropriately orientated for intramolecular cyclisation to the hemiacetal anion 20. Protonation of 20 on work-up results in the formation of 11. That compound 18 might undergo such a transformation may be rationalised by the strong tendency of the trifluoroacetyl moiety to assume tetrahedral character, as found in the formation of stable hydrates with electron deficient ketones such as hexafluoroacetone. Alternatively, 18 may undergo intramolecular cyclisation to the isomeric hemiacetal anion of 21 (path b) which then leads to the oxonium ion 22.A 1,3-hydride shift to 23 and subsequent hydration would again 19 21 generate compound 11. Although the alkoxide 18 is the most likely intermediate in the formation of 11, an authentic sample of 9, prepared by trifluoroacetylation of 8, unfortunately failed I I to yield identifiable products on treatment under conditions approximating those leading to 11. As found with other 20 22 1.3-H ShinI U 23 Scheme 2 Fig. 1 X-ray molecular structure of compound 11 24 25 iii, N OH t J 'Me 27 26 29 Scheme 3 Reagents: i, NaH; ii, D,O, THF; iii, NaBH,, CeCI,; iv, pTSA, toluene, reflux; v, NBS, H,O, DMSO; vi, KOBu', TMEDA, THF compoundsof this general type,9 however, the neopentylic nature of the hydroxy moiety in 9 is likely to hinder deprotonation, thus allowing alternative decomposition pathways to ensue.In an endeavour to add support to these two possible mechanisms the selectively deuteriated bromohydrin 27 was prepared by the route shown in Scheme 3. Thus, base catalysed deuterium exchange of the ketone 24 afforded 25, having 95 replacement of the hydrogen atoms at C-3 by deuterium, together with some 62 incorporation of label into the gem- dimethyl group. Deuterium incorporation into the alkyl groups of compound 25 is presumed to occur via the reversible retro- Michael reaction shown in Scheme 4 in which the transient formation of the phenoxide 28 is favoured by the stabilising effect of the aromatic nitrile substituent.Reduction of 25 with sodium borohydride and dehydration with toluene-p-sulfonic acid in toluene at reflux resulted in the alkene 26 which underwent facile hydrohalogenation to the bromohydrin 27. Treatment of 27 with 2-(trifluoroacetyl)pyrrole under the conditions described above furnished the tetracyclic compound 29 with 100 retention of deuterium at position 4.This was evident from the total absence of the fluorine-coupled proton signal at 8, 5.48 in the 'H NMR spectrum. The quantitative retention of deuterium in compound 28 argues for the transfer of hydrogen from the pyran C-3 position to the acyl carbonyl group, but it is debatable, however, as to whether it serves to favour one of the suggested mechanisms over the other.It does, nonetheless, provide evidence to differentiate these mechanisms from others in which such a transfer does not occur. 0-1 0 28 Scheme 4 J. CHEM. SOC. PERKIN TRANS. 1 1992 Table 2 Positional parameters and their estimated standard deviations for compound 11 Atom" X Y Z 0.322 6(3) 0.355 6(2) 0.177 3(2) 0.205 3(2) 0.409 6(2) 0.313 7(2) 0.191 8(2) 0.31 1 9(2) 0.311 l(2) 0.194 8(2) 0.082 9(2) -0.358 4(2) -0.034 5(2) -0.136 7(2) -0.122 6(3) -0.06 3(3) 0.095 6(2) 0.419 7(3) 0.309 3(3) 0.329 7(3) 0.254 4(3) 0.141 3(3) 0.169 9(3) 0.241 3(4) 0.299 O(4) 0.097 4(2) -0.259 O(3) -0.040 9(2) -0.090 2(3) 0.159 8(2) 0.029 4(2) 0.054 6(2) -0.180 2(2) -0.324 l(3) 0.144 2(3) 0.034 O( 3) -0.082 4( 3) -0.156 9(3) -0.135 4(3) -0.016 4(3) -0.060 3(3) 0.079 4( 3) 0.058 2(3) 0.127 7(4) 0.262 6(3) -0.035 4(3) 0.518 3(2) 0.734 l(3) 0.664 4(3) 1.037 4(2) 0.759 O(2) 0.795 9(2) 0.612 5(2) 0.778 4(3) 0.979 l(3) 0.820 7(3) 0.757 l(3) 0.838 9(3) 0.783 6(3) 0.865 4(3) 1.003 2(3) 1.057 3(3) 0.975 8(3) 1.045 9( 3) 1.018 6(3) 0.653 5(3) 0.559 6(3) 0.505 2(3) 0.386 5(3) 0.4 18 5( 3) 0.642 l(4) 0.812 8(3) 1.183 7(2) 1.184 7(3) 1.216 8(3) 0.821 5(2) 0.709 9(3) 0.927 O(2) 0.838 6(3) 1.064 O(4) 0.733 7(3) 0.874 O(3) 0.773 6(3) 0.841 O(3) 0.890 l(3) 0.954 5(3) 0.968 8(4) 0.919 6(4) 0.858 5(3) 0.585 3(4) 0.746 4(4) 0.991 9(4) 0.456 95(7) 0.449 08(6) 0.461 52(7) 0.553 88(6) 0.593 8q7) 0.527 25(6) 0.574 26(7) 0.559 7( 1) 0.576 70(9) 0.570 94(9) 0.586 3q8) 0.570 15(8) 0.569 88(8) 0.558 6q9) 0.546 93(9) 0.543 3( 1) 0.557 45(8) 0.557 O( 1) 0.622 4( 1) 0.517 2(1) 0.542 2( 1) 0.595 2( 1) 0.576 5(1) 0.542 8(1) 0.471 4(1) 0.559 7( 1) 0.673 98(9) 0.717 ll(8) 0.651 96(9) 0.772 Ol(6) 0.670 48(7) 0.699 38(6) 0.705 38(8) 0.864 3(1) 0.735 43(9) 0.707 68(9) 0.730 78(9) 0.773 49(9) 0.795 17(9) 0.833 55(9) 0.851 4(1) 0.830 6( 1) 0.79 1 66(9) 0.750 l(1) 0.713 4(1) 0.672 O(1) -0.163 6(3) -0.304 9(3) -0.362 5(4) -0.276 O(4) -0.016 4(4) -0.238 6(3) 0.947 4(5) 0.807 8(5) 0.899 l(7) 0.985 2(6) 1.144 9(4) 1.014 5(4) 0.679 3(1) 0.705 3( 1) 0.678 O( 1) 0.661 l(1) 0.678 7( 1) 0.852 2(1) Atom numbers are designated in Fig. I.Regardless of the mechanism by which the tetracyclic compound 11 is formed, the exclusive formation of the 5a,l lb cis-fused product is consistent with semi-empirical quantum mechanical calculations based on the AMPAC-AM 1 program using the keyword PRECISE.' Such calculations indicated that the cis-fused ring junction was thermodynamically preferred relative to that of trans-fused by approximately 5.4 kcal mol-'.* Experimental M.p.s were determined using a Biichi apparatus and are recorded uncorrected.IR spectra were measured as liquid films for oils or as solutions (CHC13) for solids, using a Perkin-Elmer * 1 cal = 4.184J. J. C'HEM. SOC. PERKIN TRANS. 1 1992 773 Table 3 Bond distances (A) for compound 11 Atom Ih Atom2 Distance Atom 1 Atom 2 Distance Atom 1 Atom 2 Distance 1.318(4) 1.397(4) C( 18') 1.144(5) 1.324(4) 1.435(4) C(3') 1.526(4) 1.3635) 1.378(4) (39') 1.527(5) 1.447( 3) I .392(4) C(10') 1.526(5) I .354(3) I .498(5) (34') I .522(4) 1.394(3) I .486(5) C(4A') 1.519(4) 1.422(3) 1.374(4) C(5') 1.390(4) 1.430(4) 1.344(4) C(8A') 1.394(4) 1.453(3) 1.4 I2( 5) C(6') 1.384(4) 1.374(4) 1.320(5) C(7') I .392(5) 1.374(4) 1.334(5) C(18') I .438(5) 1.138(4) 1.33l(5) C(8') 1.368(5) 1.545(4) I .448(4) C(8A') 1.386(4) I .523(4) 1.365(4) C(12') 1.502(5) 1.514(4) 1.389(4) C(17') 1.509(5) 1.528(4) 1.431(4) C(16') 1.372(5) 1.519(3) 1.4 19(4) C(15') 1.365(7) 1.392(4) I .443(4) C(16') 1.400(7) 1.397(4) 1.366(5) 1.397(4) 1.396(4) Numbers in parentheses are estimated standard deviations in the least significant digits.Atom numbers are designated in Fig.I. Table 4 Bond angles ( ) for compound 11 Atom 1" Atom2 Atom3 Angle Atom 1 Atom2 Atom3 Angle Atom 1 Atom 2 Atom 3 Angle I 18.3(2) 12 1.5( 3) C( 12') 123.8(3) 1 I3.3(2) 1 17.9(2) C(14') 126.4(3) 123.8(2) 1 19.2( 3) C(14') 109.7(3) 1 26.9( 2) I20.3( 3) (33') I 09. I (2) 108.9(2) 123.4(2) C(9') 108.2(3) 109.3(2) 1 I5.3(2) C(10') 105.8(2) 104.2(2) 121.2(2) C(9') 1 12.0( 3) 108.6(2) 1 12.6( 3) C(10') 11 1.5(3) 11 1.7(2) 105.7(3) C( 10') 1 1O.O( 3) 1 1 1 S(2) 112.9(3) (23') 109.7(2) 1 1 1.3(2) 119.8(3) C(2') I08.3(2) 112.1(2) 107.6(3) 1 13.8(2) 11 1.4(2) 132.3(3) C(2') 106.8(2) 106.8( 2) 108.3(3) C(47 107.6(2) 106.5(2) 108.2(3) C(4') 110.5(2) 109.0( 2) 107.1(3) C(37 108.I (2) 1 1 1.O( 2) 108.2(3) C(4A') 1 12.6(3) 107.8(2) I05.9(3) C(4A') 109.0(2) 114.2(2) 1 12.2( 3) (35') 12 I .3(3) 110.5(2) 104.8(3) C(8A') 120.8( 3) 121 S(2) 1 13.7(3) C(8A') I 17.9(3) 120.0(2) 1 I 1.4(3) (36') 120.7(3) 1 18.3( 2) 175.9(3) C(7') 120.3(3) 1 20.4( 2) 1 18.3(2) C(18') 117.5(3) 120.6(2) 115.6(2) C(18') 121.9(3) 119.5(3) 1 12.3(3) F(2') 106.1(3) 120.2(3) 118.9(3) F(3') 108.1(3) 122.7(3) 108.0(3) C( 11') I 12.6(3) 116.0(3) 132.6( 4) F(3') 106.8(3) 121.2(3) 105.6(4) C(l1') 112.4(3) 113.1(3) 109.8(4) C(1I') 110.5(3) 105.3(3) I06.8( 4) C(6') 175.3(3) ~ ~ ~ ~ ~ ~ ~ ~~~~~ ~~ ~~~~~~ Numbers in parentheses are estimated standard deviations in the least significant digits.Atom numbers are designated in Fig. I. 197spectrometer. 'H and I3CNMR spectra were acquired on a Varian EM 360, EM 390, JEOL GX 270 or Bruker AM 400 spectrometer using CDC1,-TMS solutions unless otherwise noted.J Values are given in Hz. All 2D NMR experiments were conducted on a Bruker AM 400 spectrometer using standard Bruker software. The 2D 'H, 13CCOSY NMR spectrum I' was acquired with 'H decoupling in both dimensions and was tuned for lJCH= 140 Hz with 64 scans for each of 128 x 4K FIDs. The 2D 'H, * 3CCOLOC experiment was tuned for "JCH= 8.5 Hz and acquired with 120 scans for each of 256 x 4K FIDs. The sweep widths for all the 2D NMR experiments were optimised prior to acquisition. The NOE difference experiments were conducted using a modification of the method of Hall and Saunders l4 as described previously.' Mass spectral data were obtained from a JEOL SX102 instrument.All organic extracts were dried over MgS04 and samples were chromatographed on silica gel except where stated. (4R*,5aS*,1 1bS*)-5a-Hq~dro.~~-6,6-di~z~~tiz~~~-4-rriJI-4'1-5a,11b-dihydro-4H,6H-pyrrolo1',2':4,5o.razino2,3-c- chromene- 10-carbonitrile 11.-Potassium tert-butoxide (1.232 g, 11 mmol) was added in one portion to a stirred solution of trans-3-bromo-4-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromene-6-carbonitrile2 (1.4 g, 5.0 mmol) in THF (10 cm3). After 5 min 2-trifluoroacetylpyrrolel6 (0.897 g, 5.4 mmol) followed by tetramethylethylenediamine (TMEDA) (10 cm3) was added and the solution was heated under reflux for 18 h. The reaction mixture was cooled, poured into ice-cold dilute hydrochloric acid, extracted with ethyl acetate and the combined organic layers were washed with water and brine.The dried organic phase was concentrated and the residue was chromatographed (2 MeOH-CHCl,) to give the title compound as an off-white foam (1.3 g, 71), m.p. 165-166 "C (EtOAc), v,,,/cm-' 3580br, 2230s, 161 5s, 1560s, 1480s and 114; amp;(CD,2SO) 1.36 (3 H, S, CH,), 1.56 (3 H, S,CHj), 5.45 (1 H, s, llb-H), 5.48 (1 H, q, J6,4-H), 6.09 (1 H, m, 3-H), 6.28 (1 H,m,2-H),6.98(lH,d,J8.5,8-H),7.21(lH,m,OH),7.40(1H, m, 1-H), 7.48 (1 H, br s, ll-H) and 7.63 (1 H, dd, J8.5,2,9-H); Gc(CD32SO) 20.6 (CH,), 21.7 (CH,), 53.2 (CH), 67.7 (4, J 33, CH), 81.0 (q), 92.0 (q), 102.3 (q), 105.6 (CH), 108.6 (CH), 115.6 (q), 118.0 (CH), 118.8 (q), 122.8 (CH), 122.9 (q), 123.4 (9, J 282, CF,), 132.0 (CH), 133.0 (CH) and 154.8 (9) (Found: C, 59.5; H, 4.0; N, 7.5; M+, 364.1028.Cl8Hl5F3N2O3 requires C, 59.3; H, 4.15; N, 7.7; M, 364.1035). (5aS*, 1 1 bS*)-5a-Hydroxy-6,6-dimethyl-5a,1 1 b-dihydro- 4H,6H-pyrrolo 1 ',2':4,5oxazino2,3-~chromene-1 O-carbo- nitrilel4. Reaction of 2-formylpyrrole with the bromohydrin 2 in a similar manner to that described above afforded the title compound, 13, m.p. 145-147 "C (MeOH-Et20), v,,,/cm-' 3500br, 2220s, 1608m and 158Om; 6H(CDC13-CD32SO) 1.41 (3 H, S, CH,), 1.58 (3 H, S, CH,), 4.61 (1 H, d, J 14,4-H), 5.02 (1 J. CHEM. SOC. PERKIN TRANS. 1 1992 ud, J 8.5, 2, 9-H) and 7.8 (1 H, d, J 2, 11-H); G,(CDCl,) 18.0 (CH,), 24.0 (CH,), 25.2 (CH,), 71.8 (CH), 79.0 (q), 103.6 (CH), 104.9 (q), 109.4 (q), 109.7 (CH), 117.0 (CH), 118.3 (CH), 119.0 (q), 119.7 (q), 124.9 (CH), 128.6 (q), 131.6 (CH), 144.6 (9) and 154.5 (9) (Found: c,73.9; H, 5.3; N, 9.55.C18H16N202 requires C, 73.95; H, 5.5; N, 9.6) followed by 4-(2-acetylpyrroZ-l-y1)-2,2-dimethyl-2H-chromene-6-carbonitrile17 18, m.p. 97-98 "C, v,,,/cm-' 3000m, 2240s, 1670s, 1660s, 16 15m, 1490s, 14 15s and 1290s; 6, 1.56 (3 H, S, 2-CH3), 1.61 (3 H, S, 2-CH3), 2.43 (3 H, S, COCH3), 5.65 (1 H, s, 3-H), 6.35 (1 H, m, 3'-H), 6.59 (1 H, d, J2, 5-H), 6.84 (1 H, m, 4'-H), 6.88 (1 H, d, J8, 8-H), 7.11 (1 H, m, 5'-H) and 7.4 (1 H, dd, J 8, 2, 7-H) (Found: C, 73.7; H, 5.4; N, 9.6; M+ 292.1212. Cl8HI6N2O2 requires C, 73.95; H, 5.5; N, 9.6; M, 292.12 12).trans-3-Hydroxy-2,2-dimethyl-4-(2-trijluoroacetylpyrrol-1-yZ)-3,4-dihydro-2H-chromene-6-carbonitrile9.-A mixture of trans-3-hydroxy-2,2-dimethyl-4-(pyrrol-1 -yl)-3,4-dihydro-2H- chromene-6-carbonitrile 8l8(0.268 g, 1 mmol) and trifluoro- acetic anhydride (141 mm3, 1 mmol) in chloroform (3 cm3) was heated under reflux for 1.5 h. The solvent was evaporated and the residue chromatographed. Elution with 0-1 MeOH- CHCI, gave the title compound (0.312 g, 85), m.p. 146-148 "C (EtOAc-hexane), v,,,/cm-' 3605m, 2960br, 2980m, 2220m, 1680s, 1620m, 1550m, 148Os, 1160s, 1145s and 910s; ~5~1.33 (3 H, S, CH3), 1.59 (3 H, S,CH,), 3.03 (1 H, d, J 5, OH), 3.94 (1 H, dd, J 8,5,3-H), 5.03 (1 H,d, J8,4-H), 6.65 (1 H, m, 3'-H), 6.78 (1 H, m, 4'-H), 6.98 (1 H, d, J 9,8-H), 7.06 (1 H, m, 5'-H), 7.52 (1 H, dd, J 9, 2, 7-H) and 7.64 (1 H, br s, 5-H) (Found: C, 59.3; H, 4.0; N, 7.5; MH+ 365.1088.Cl8Hl5F3N2O3 requires C, 59.35; H, 4.15; N, 7.7; MH 365.11 13). H,d,J14,4-H),5.12(1H,m,1lb-H),5.90(1H,m,3-H),6.29(1 H,m,2-H),6.32(1 H,s,OH),6.90(1 H,d, J8,8-H),6.96(1 H,m, trans-3- HI-3- Bromo-4-hydroxy-2,2-dimethyl-3,4-dihydro-l-H),7.43(1H,dd,J8.5,2,9-H)and7.52(1H,dd,J2,1,1l-H); 2H-chromene-6-carbonitrile 27.-2,2-Dimethyl-4-0~0-3,4-di-Sc(CCD312SO) 20.6 (CH,), 21.8 (CH,), 53.3 (CH), 58.3 (CH,), 81.2 (q), 90.9 (q), 101.7 (CH), 102.3 (q), 107.7 (CH), 118.0 (CH), 118.9 (q), 120.7 (CH), 122.7 (q), 123.6 (q), 132.2 (CH), 134.4 (CH) and 155.1 (9) (Found: C, 69.2; H, 5.7; N, 9.65.C1 7H1 6N203 requires C, 68.9; H, 5.45; N, 9.45). (4S*,5aS*, 1 1 bS*)-5a-Hydroxy-6,6-dimethyl-4-phenyl-5a,11b-dihydro-4H,6H-pyrrolo 1 ',2':4,5oxazino 2,3-cchromene- 10- carbonitrile 13. Reaction of 2-benzoylpyrrole' with the bromohydrin 2 under similar conditions to the above gave, after chromatography (30-100 EtOAc-hexane) 6,6-dimethyl-4-phenyl-5a, 1 1 b-dihydro-4H,6H-pyrrolo1',2':4,6oxazine2,3-c-chromene- 10-carbonitrile 15 16, m.p. 108-1 10"C, v,,,/cm-' 2220m, 1660m, 1480s and 1130s; 6,1.33 (3 H, s, CH,), 1.51 (3 H, s,CH3),5.79(1H,m,3-H),6.07(1H,s,4-H),6.34(1 H,m,2-H), hydro-2H-chromene-6-carbonitrile24 (1.7 g, 8.5 mmol, pre- pared by the condensation of 3-acetyl-4-hydroxybenzonitrile with acetone,) was added to a stirred suspension of sodium hydride (0.33 g, 8.25 mmol of a 60 dispersion in mineral oil) in THF (20 cm3) followed by the cautious addition of deuterium oxide (10 cm3).The resulting solution was stirred for 18 h at ambient temperature and then extracted with ethyl acetate. The extracts were dried and concentrated and the residue was chromatographed to give the labelled ketone 25 (1.09 g, 72). 'H NMR spectroscopic analysis confirmed the incorporation of deuterium at C-3 and indicated 62 incorporation into the gem- dimethyl group also. To a stirred solution of the labelled ketone 25 (0.80 g, 4 mmol) in THF-MeOH (7.3 cm3) at 4 "C was added cerium(u1) chloride septahydrate (0.3 g, 0.8 mmol) and sodium 6.96(1H,d,J8,8-H),7.15(1H,m,l-H),7.41(5H,s,Ph),7.44(1borohydride (0.15 g, 4 mmol) and after 1 h the reaction mixture H, dd, J 8, 2, 9-H) and 7.86 (1 H, d, J 2, ll-H) (Found: M+, 354.1 367. C23H1 8N2O2 requires M, 354.1368) followed by 2-benzoylpyrrole and the title compound 17, m.p.118-120 "C, v,,,/cm-' 3560br, 2220m, 1740m, 1605m, 1485s and 1265s; SH 1.49(3 H, s, CH,), 1.55 (3 H, s, CH,), 3.25 (1 H, br s, OH), 5.16 (1 H, s, llb-H), 5.78 (1 H, m, 3-H), 5.99 (1 H, s,4-H), 6.29 (1 H, m, 2-H), 6.9-6.96 (4 H, m, Ar), 7.17-7.21 (3 H, m, Ar) and 7.50-7.51 (2 H, m, Ar) Found: (MH -H20)+, 355.1433. C23H20N20, requires (MH -H20)+, 355.14471. 4,6,6- Trimethyl-Sa, 1 1 b-dihydro-4H,6H-pyrrolo 1 ',2':4,50~- azino2,3-cchromene- 10-carbonitrile 16.-Reaction of 2-acetyl- pyrrole with the bromohydrin 2 under similar conditions to the above gave, after chromatography (10-30 EtOAc-hexane followed by 1 MeOH-CHCl,), the title compound l8, m.p.326-5-227"C,y,,,/cm-' 3000m, 2240s, 1665s, 161Om, 158Omand *5OOS; 'H 1-47(3 H, S, 6-CH,), 1-58(3 H, S, 6-CH3), 2.72 (3 H, d, J 6-59 4-CH3), 5-07 (1 H, 9, J 6.5,4-H), 6.08 (1 H, m, 3-H), 6.33 (1 H,m,2-H),6.96(1H,d,J8.5,8-H),7.07(1H,m, l-H),7.42(1 H, was quenched with hydrochloric acid (2 mol dm-'). Extraction of this mixture with ethyl acetate followed by evaporation of the dried extracts then afforded 0.8 g (100) of the corresponding alcohol, which was converted into the benzopyran 26 (0.645 g, 88) by dehydration in toluene (40 cm3) in the presence of toluene-p-sulfonic acid (0.15 g, 0.8 mmol) at reflux.Treatment of a stirred solution of the benzopyran 26 (0.645 g, 3.5 mmol) in aqueous dimethyl sulfoxide (10 cm3) with N-bromosuccinimide (0.75 g, 4.2 mmol) at room temperature for 6 h then afforded the title compound as a solid (100) after the usual work-up. X-Ray Crystal Analysis of Compound 11.-Crystal data. C18H15F3N203,M = 364.10. Monoclinic, a = 20.948(8),b = J. CHEM. SOC. PERKIN TRANS. I 1992 ated Cu-Ka radiation; 5899 reflections measured (2" d 28 d 128",0 d h d 12,O d k 11, -37 d Zd 37),5573unique, Ri,,= 0.035, giving 4351 with 13 341). There were 478 variables including an extinction coefficient which refined to 1.4(7) x 1W6. Structure analysisand rejinement. The structure of compound 11 was solved by direct methods using the SHELXS program series.' Atomic positions were initially refined with isotropic temperature factors and subsequently with anisotropic dis- placement parameters.The function minimised was Cw(lFoI -Weights, MY,were assigned to the data as w = l/a2(1,) + 0.009 Fo21.Positions for hydroxy hydrogen atoms were located from Fourier maps and were allowed to refine. Positions for all other hydrogen atoms were calculated and held fixed. Isotropic temperature factors for hydrogen were held fixed at values calculated as 1.3 (BJ of the attached atom. The large displacement parameters for atoms C( 14'), C( 15') and C(16') suggested the possibility of disorder, however attempts to refine a 2-site occupancy model for these atoms were unsuccessful. The full-matrix least squares refinement converged (max.A/a = 0.20) to values of the conventional crystallographic residuals R = 0.0595, R, = 0.0820. A final difference Fourier map was featureless with maximum density of kO.249 e A-3. Values of the neutral-atom scattering factors were taken from the International Tables for X-ray Crystallography. Atomic co- ordinates are found in Table 2 and principal bond distances and angles are found in Tables 3 and 4 respectively.* Thermal parameters and hydrogen atom coordinates have been deposited at the CCDC.i Acknowledgements We would like to thank Professor P. J. Parsons and Dr. W. B. Motherwell for their helpful discussions and Mr B. Clark for carrying out the quantum mechanical calculations. * Atom numbers as designated in Fig.1. t For full details of the CCDC deposition scheme see 'Instructions for Authors,' J. Chem. Soc., Perkin Trans. I, 1992, issue 1. References 1 For recent reviews see: G. E. Edwards and A. H. Weston, Trends in Pharmacological Sci., 1990, 11, 417; D. W. Robertson and M. I. Steinberg, J. Med. Chem., 1990,33, 1529. 2 V. A. Ashwood, R. E. Buckingham, F. Cassidy, J. M. Evans, E. A. Faruk, T. C. Hamilton, D. J. Nash, G. Stemp and K. Willcocks, J. Med. Chem., 1986,29,2194. 3 D. R. Buckle, J. R. S. Arch, A. E. Fenwick, C. S. V. Houge-Frydrych, I. L. Pinto, D. G. Smith, S. G. Taylor and J. M. Tedder, J.Med Chem., 1990,33,3028. 4 See J. R. S. Arch, D. R. Buckle, C. Carey, H. Parr-Dobrzanski, A.Faller, K. A, Foster, C. S. V. Houge-Frydrych, I. L. Pinto, D. G. Smith and S. G. Taylor, J. Med. Chem., 1991, 34, 2588, and refs. cited therein. 5 D. R. Buckle, C. S. V. Houge-Frydrych, I. L. Pinto, D. G. Smith and J. M. Tedder, J. Chem. Soc., Perkin Trans. 1, 1991,63. 6 D. R. Buckle, D. S. Eggleston, C. S. V. Houge-Frydrych, I. L. Pinto, S. A. Readshaw, D. G. Smith and R. A. B. Webster, J. Chem. SOC., Perkin Trans. 1, 1991,2763. 7 F. Cassidy, J. M. Evans, D. M. Smith, G. Stemp, C. Edge and D. J. Williams, J. Chem. Soc., Chem. Commun., 1989, 377. 8 J. M. Evans, C. S. Fake, T. C. Hamilton, R. H. Poyser and G. A. Showell, J. Med. Chem., 1984,27, 1127. 9 D. R. Buckle, A. Faller, I. L. Pinto and D. G. Smith, Tetrahedron Lett., 1992,33, 1109. 10 W. J. Middleton and R. V. Linsey, Jr., J. Am. Chem. Soc., 1964,86, 4948. 11 M. J. S. Dewar, E. G. Zoebisch, E. F. Healy and J. J. Stewart, J. Am. Chem. SOC.,1985, 107, 3902. AMPAC, QCPE program No. 506. 12 A. Derome, Modern NMR Techniques for Chemislry Research, Pergamon Press, Oxford, 1987. 13 H. Kessler, C. Griesinger and J. Lautz, Angew. Chem., Int. Ed. Engl., 1984,23,444. 14 J. K. M. Saunders and J. D. Mersch, Prog. Nucl. Magn. Reson. Spectrosc., 1982, 15,353. 15 J. R. Everett and J. W. Tyler, J. Chem. Soc., Perkin Trans. 2, 1987, 1659. 16 W. Cooper, J. Org. Chem., 1958,23,1382. 17 V. Cardelli, M. Cardellini and F. Morlacchi, Liebigs Ann. Chem., 1961,51,595. 18 PCT Int. App. WO 85,01290; C.A. 104, P19512f. 19 G. M. Sheldrick, SHELXS, Crystallographic Computing 3, ed. G. M. Sheldrick, C. Kruger and R. Goddard, Oxford University Press, 1985. Paper 1 /06036H Received 28th November 1991 Accepted 14th January 1992
展开▼
