Synthesis and proton nuclear magnetic resonance spectra of diastereoisomeric ethyl 3-hydroxy-2-methyl-3-(p-substituted phenyl)butyrates

摘要

2548 J.C.S. Perkin ISynthesis and Proton Nuclear Magnetic Resonance Spectra of Diastereo-isomeric Ethyl 3-Hydroxy-2-methyl-3-(p-substituted phenyl) butyratesBy Aldo Balsamo, Pier Luigi Barili, Paolo Crotti, Maria Ferretti, Bruno Macchia,' and Franco Macchia,A series of erythro- and threo-ethyl 3-hydroxy-Z-methyl-3- (p-substituted phenyl) butyrates has been preparedThe l H n.m.r. spectra of these compounds and their use in assigning diastereoisomeric configurations are discussedlstituti di Chimica Farmaceutica e di Chimica Organica dell'Universit8, 561 00 Pisa, ItalyIN connection with a programme for the synthesis ofcompounds of pharmacological interest ,l it was necessaryto prepare a series of ethyl 3-hydroxy-2-methyl-3-($-substituted pheny1)butyrates (111) and (IV).Pureerythru- (111) and threo-diastereoisomers (IV) were alsoneeded2 (Table 1). Mixtures of (111) and (IV) wereobtained from the Reformatsky reaction of aceto-phenones (I) with ethyl cc-bromopropionate (11). Thediastereoisomeric composition of these mixtures changes1 A. Balsamo, P. L. Barili, P. Crotti, B. Macchia, F. Macchia,A. Pecchia, A. Cuttica, and N. Passerini, submitted for publicationin J . Medicin. Chem.A. Balsamo, P. L. Barili, P. Crotti, M. Ferretti, B. Macchia,and F. Macchia, Tetrahedron Letters, 1974, 1005.with the reaction time, owing to a slower equilibrationof (111) and (IV) in the reaction The com-positions of the crude reaction mixtures after 2 h reactionare shown in Table 2; the erythro-p-hydroxyesters (111)predominate in each case, in agreement with the resultsof the analogous reaction of unsubstituted acetophenone(I; R = H).394 The isomers (111) and (IV) wereseparated by preparative g.1.c.and t.1.c. Conformationalanalysis of these esters through their n.m.r. spectra canJ. Canceill, J.-J. Basselier, and J. Jacques, Bull. SOC. chim.Y . Beziat and M. Mousseron-Canet, Bull. SOC. chtm. Fmnce,France, 1967, 1024.1968, 11871974 2549be used to assign the relative configurations to thesecompounds.By calculating the non-bonding gazde interactionsand possible attractive interactions (such as intramolecu-lar hydrogen bonding) between groups in the threectiastereoisomers (IVb and c). Therefore, the popul-ations of these conformers should be favoured * withrespect to those of conformers (IIIb) and (IVa), respec-tively.Of conformers (IIIa) and (IIIc), (IIIa) shouldbe favoured because of the strong Ar-Me interactionH(d) H (dl( C l ( e l ( a )CH3 ( C 1 t C02CH2CH3 (el (a)CH3 t C02CH2CH3TABLE 1erythro-(111) and fhveo-Ethyl 3-hydroxy-2-methyl-3-(fi-substituted phenyl) butyrstesIH N.m.r. spectra (6 values, J in Hz)AP- Found (yo) Required () ICompoiiiid nD20 C H Formula C H CH3(a) CH3(b) CH3(c) H(d) CH2(e) C,H4R(f) Jae(111; R = MeO) 1.5066 68-56 8.0 C,4H.#4 66.65 8.0 1.00 1.45 1.32 3-00 4.00 7.34 7.12(111; R = Me) 1.4981 70.95 8.5 C14Hzo03 71.15 8.55 0.98 1.43 1.30 2-97 3.92 7-15 7.08(111; R = H) 1.4977 C13H1803 0.95 1.44 1.31 2-97 3.91 7-32 7.110*90d 1 ~ 3 0 ~ 1.23 2.85" 3.780.90 C 1-33 e 1.27 e 2.89 e 3-80 e(111; R = 1;) 1.4840 64.95 7.2 C,,H,,FO, 65.0 7.15 0.99 1-43 1.31 2-97 3.93 7.17 7.14(111; R = C1) 1.5114 G1.05 6-7 Cl3HI7C10, 60.8 6.65 0.99 1.41 1.30 2.92 3.92 7.35 7.10(111; R = Br) 1.5267 51.8 5.7 C,,H,,BrO, 51.85 5-7 1.00 1.41 1.31 2.96 3.93 7.35 7-10(IV; R = MeO) a 66.8 8-05 Cl4HZ,O, 66.65 8.0 1.30 1.57 0.98 2.84 4.31 7.26 7.16(IV; R = Me) 1.4992 71.3 8.55 C14H2,,03 71.15 8.55 1.30 1-56 0.96 2.81 4.22 7.22 7.10(IV; R = H) 1.4984 C13H1803 1.20 1.56 0.95 2.81 4.22 7.37 7.101.22 1.42'l 0*85d 2.80d 4*10a1.28 1.46 0.89 2.72" 4*15O(IV; R = F) b 65-05 6.9 C13H,,F0, 65.0 7.15 1.29 1.55 0.95 2.80 4-22 7.21 7.11(IV; R = CI) c 60.95 6.5 CI3H1,CIO3 60.8 6-65 1-29 1-54 0.95 2-80 4.23 7.37 7.11(IV; R = Br) 1.5261 52.0 5.7 C,,H,,BrO, 51.85 5-7 1.29 1.55 0.95 2.80 4.24 7.37 7.08a M.p.31-31.5" (from light petroleum). M.p. 56-57" (from light petroleum). M.p. 55-56" (from light petroleum).CS2 s ~ l u t i o n . ~ For CC14 s ~ l u t i o n . ~-7J c d7.107.127.137-057.147.137-107.127-127.157.127.10d Forstaggered rotamers of (111) and (IV),6 we can predictwhich conformation will be preferred for each isomer;these conformations would be expected to lead to signifi-cant differences in the n.1n.r. spectra of the two diastereo-isomers. On the basis of the value of their conformation-a1 free energy differences,6.7 the groups attached to theTABLE 2Composition () YieldR (111) (IV) B.P. ("C) mmHgl ()Me0 74 26 145-150 4.5 60Me 73 27 138-142 4 64H * 71 29 108-1 11 0*8 70F 68 32 155-160 6 86c1 69 31 15G-155 6 85Br 64 36 15G-156 3*5 92* Lit.(J. Canceill, J. Gabard, and J. Jacques, Bull. SOC.chim. Fiauce, 1966, 2653). b.p. 109-110 "C at 3 inmHg; yield87.asymmetric carbon atoms in (111) and (IV) can bearranged; More-over, hydrogen bonding between OH and C0,Et groupsis possible 3 9 4 in two of the three rotamers of both theerythro-p-hydroxyesters (IIIa and c) and of the threo-E. Id. Eliel, ' Stereochemistry of Carbon Compounds,'McGraw-Hill, New York, 1962, p. 137, et seq.aryl > Me > C0,Et > OH > H.present in (IIIc). This unfavourable interaction ispresent in both conformers (IVb) and (IVc), but con-former (IVb) should be preferred, since the Me-Aleinteraction present in (IVc) is missing.The n.ni.r.spectra of (111) and (IV) should reflect therelative populations of rotamers present at equilibriumand, therefore, should be in agreement with a time-averaged predominance of conformations (IIIa) and(IVb), respectively.Table 1 summarizes the n.m.r. parameters of the F-hydroxyesters (111) and (IV). From an examination ofthese data, it is evident that the spectra agree with theconfonnational hypothesis. The signals of CH,(a),CH3(b), and CH,(e) are at higher fields for the erythro-than for the threo-compounds. On the other hand,the signals of H(d) and CH,(c) of the erythro-esters areat a lower field than the same protons of the threo-series. The centre of the phenyl resonance is at practic-ally the same field or does not alter appreciably in theE.L. Eliel, N. L. Allinger, S. J. Angyal, and G. A. Morrison,' Conformational Analysis,' Interscience, New York, 1965, p. 44,et seq.J. A. Hirsch, Topics Stereochem., 1967, 1, 199.8 C. A. Kingsbury, J. Org. Chem., 1970, 35, 13192550 J.C.S. Perkin Itwo series; evidently, the diamagnetic anisotropy of thephenyl group, as well as the deshielding effect of thecarbonyl group, are the main causes of the shifts ob-served. By examining molecular models of the expectedmost stable conformers (IIIa) and (IVb), we can observethat CH,(e) and CH,(a) in the erythro-diastereoisomers,Ar ArAr ArCO2 Et( I I I C )HOCH,( llpa 1Ar Arand CH,(c) in the threo-compounds, are located in theshielding region of the phenyl group.In the threo-diastereoisomers, CH,(b) is situated in the deshieldingregion of the carbonyl group.gIt might seem that the chemical shift of H(d) shouldnot change on passing from one diastereoisomer toanother, because its position relative to the aryl group isthe same in both the preferred rotamers (IIIa) and (IVb) ;however, the shift towards higher fields observed onpassing from the erythro to the threo-series may beattributed to a different rotameric position of the phenylgroup in the two conformers (IIIa) and (IVb), owing toits different relative position with respect to the ethoxy-carbonyl group. The values of the shifts due to thediamagnetic anisotropy of the phenyl group are notaffected by the substituent on the phenyl group; thisshows that the different electronic density on the phenylgroup, depending on the different substituent, does notsignificantly influence the shielding effect of the aromaticgroup.Assignment of the signals was based on the agreementof the measured chemical shifts with those expected, andon the basis of the multiplicity and the integration of thesignals.EXPERIMENTALN.m.r. spectra were determined for ca.10 solutions inCDCl, with a JEOL C-60 HL spectrometer using tetra-methylsilane as internal standard. Chemical shifts andcoupling constants were measured directly from the spectradetermined a t a sweep width of 540 Hz. G.1.c. analyseswere run on a Carlo Erba Fractovap GV apparatus with aflame ionization detector using a dual column system withglass columns (2.5 mm x 2 m) packed with 1 neopentyl-glycol succinate on 80-100 mesh silanized Chromosorb TV;the order of retention times was (111) < (IV).Reformatsky Reaction of Acetophenones (I) with Ethyl a-Bronzopropionate (II).-A portion (8 ml) of a solution of theacetophenone (I) (0.09 mol) and (11) (18.1 g, 0.1 mol) inanhydrous benzene (25 ml) was added to zinc powder(7.20 g, 0.1 mol) and the flask was warmed gently untilthe reaction started.Stirring was then started and theremainder of the solution was added a t such a rate that agentle reflux was maintained. The addition was completein 10 min. The mixture was then refluxed for 2 h, cooled a tOo, and hydrolysed by addition of ice-cold 20 sulphuricacid (35 ml). The organic layer was washed with 10sodium carbonate (20 ml) and with water (40 ml), filtered,and evaporated to dryness. The crude residue was exam-ined by g.1.c. (Table 2) and distilled to give the mixture of(111) and (IV).Sefiaration of (111) and (IV).-Portions of distilled mix-tures of (111) and (IV) were subjected to preparative g.1.c.when R = F, C1, or Br, and to preparative t.1.c. whenR = MeO, Me, or H.Preparative g.1.c. was carried out on a Perkin-Elmermodel F-21 gas chromatograph, using a stainless steelcolumn (8 mm x 2 m) packed with 5 Carbowax 20M on60-80 mesh silanized Chromosorb G.Preparative t.1.c. was carried out on silica gel plates(Merck F254), with light petroleum-ether (90 : 10) as eluant;elution was repeated 4 times and the esters were located withU.V. light (245 nm) ; threo-diastereoisomers were extractedfrom the faster-moving band.This work was supported in part by a grant from theConsiglio Nazionale delle Ricerche.4/ 1 173 Received, 17th June, 197419 G. J. Karabatsos, G. C. Sonnichsen, H. Nsi, and D. JFenoglio, J . Amer. Chern. SOC., 1967, 89, 6067