摘要:

1980 949 On the Chirality of 2-Hydroxy-NN-dial kylthiobenzamides. Demonstr-ation of Three Consecutive Conformational Processes By Ulf Berg and Jan Sandstrom, Division of Organic Chemistry 1, Chemical Center, The University of Lund, P.O. Box 740, S-220 07 Lund 7, Sweden W. Brian Jennings and David Randall, Department of Chemistry, The University of Birmingham, P.O. Box 363, Birmingham B1 5 2TT The geminal anisochronism observed in the lH n.m.r. spectra of some of the title compounds has previously been ascribed to different causes. It has now been unequivocallyshown that the geminal anisochronism is a consequence of the molecular chirality arising from slow rotation of the aryl ring with respect to the thioamide group. The free- energy barrier to this process has been found to lie in the range 11.2-1 3.4 kcal mol- I, increasing with the size of the N-alkyl groups.A lower energy process (AGO = 8.6 kcal mal- l) in 2-hydroxy-NN-di-isobutylthiobenzamidehas been identified as the exchange of the isobutyl groups between two anti-periplanar positions. The third process with the highest barrier in each case (AGt = 13.4-1 5.6 kcal mol- l) is the E-Z exchange of the alkyl groups by rotation around the C(S)-N bond. RECENTLYthere has been considerable discussion in the benzamides have anisochronous geminal methylene literature regarding the conformation of ortho-sub-protons below ca. 0 0C.1929395 Accordingly, it has been stituted thiobenzamides (1) and the origin of the chemical- suggested that the geminal non-equivalence in these shift-non-equivalence of geminal methylene hydrogens in compounds might be due to a locked arrangement of the the N-alkyl groups.1-8 Rotation around the C(S)-N N-alkyl groups [as depicted in (2)3 rather than a locked non-coplanar conformation around the N-aryl bond as in other 2-substituted thiobenzamides.5 Recent n.m.r.studies of related systems have shown locked arrange- ments of NRq groups (on the n.m.r. time-scale).g The present study is directed at differentiating between these two possible origins of the NCH, geminal anisochronism in 2-hydroxythiobenzamides and obtaining a clearerY understanding of the conformation and stereodynamics (2) of these molecules. A series of 2-hydroxythiobenz-a; Y = Me amides (3a-c), which contain an additional prochiral b; Y = Ph isopropyl substituent on the aryl ring, have been pre- C; Y = Pri pared and their dynamic behaviour investigated by n .m .r.spectroscopy. bond in thiobenzamides is normally Slow on the n.m.r. Furthermore, conformational exchange processes in time-scale at around ambient temperature as shown by the observation of two sets of N-alkyl signals. Addi-S tionally, steric interactions between the ortlzo X or H pri&L!-NR2substituents and the proximate N-CH, group or sulphur a; R = Me atom normally force the aryl ring to twist out of the b; R = Et thioamide plane. Provided that rotation of the aryl C; R =-[CH21s-ring through the thioamide plane is slow, the molecule is (3) chiral on thc n.m.r. time-scale and the paired geniinal three "-di (primary alkyl)-2-1lydroxythiobenzainides hydrogens attached to the prochiral methylene carbons (2a-c) have been studied in order to gain information are diastereotopic and potentially anisochronous.This about the possible rotation of the N-alkyl groups. situation pertains in the case of thiobenzamides bearing non-chelating ortho-substituents (e.g. X = OMe or RESULTS AND DISCUSSION Cl).495 Other suggestions regarding the origin of the In common with other 2-hydroxytliiobenz-geminal anisochronism in these compounds have not the ambient-temperature n.m.r. spectra withstood critical e~amination.~.5*8 -of compounds (2a-c) and (3a-c) showed evidence of 2-Hydroxythiobenzamides (1 ; X = OH) present a dynamic behaviour in that the N-alkyl signals were S interaction has an attractive exchange-broadened. On lowering the temperature to special case as the X component due to intramolecular hydrogen bonding (as around 0 "C the N-alkyl signals separated into two sets.shown by i.r. studies 29396). Intuitively this effect might At lower temperature (-20 to -60 "C) the isopropyl be expected to greatly facilitate torsional oscillation of methyl doublet of (3a-c) collapsed and then reappeared the aryl ring through the thioamide plane. However, as two doublets (Figure 1). The geminal NCH, protons several recent reports indicate that 2-hydroxythio-in (2a-c), (3b), and (3c) were also observed to become J.C.S. Perkin I1 non-equivalent in this temperature range and generally with the corresponding free energies of activation.The showed complex multiplet structures which simplified to C(S)-N rotational barrier in the NN-dimethyl compound AB systems on irradiation of the corresponding vicinal (3a) is close to that in 2-hydroxy-NN-dimethylthiobenz-proton signals (Figure 1). amide (AGZ 15.3 kcal mol-l at 30 oC).s Therefore the 3-Stereodynamics about the C(S)-N Bond.-The higher-isopropyl substituent only exerts a relatively small t t t I I I I I I I I 1 I I I I 1-9 8 7 6 5 4 3 2 1 0 s 1FIGURE 100-MHz 'H N.ni.r. spectra of (3b) in [2HH,]toluene: (a) probe temperature $29 "C; (b) probe temperature -50 "C (theapparent triplet signal centred at 6 1.20 results from overlap of two isopropyl doublets) ; (c) spectrum obtained at -50 "C with con- comitant irradiation of the methyl triplet at 6 0.46; (d) spectrum obtained at -50 "C with decoupling of the methyl triplet at 6 0.99 temperature process which renders the syn and anti N-effect (ca.-0.7 kcal mol-l) on the C(S)-N rotational alkyl groups non-equivalent is clearly restricted rotation barrier. The barrier decreases from the NMe, to the around the C(S)-N bond. Kate constants for this NEt, compound in both series (2) and (3), but in the process, determined in the region of maximum exchange former series it increases again for the NBu', compound. broadening, are given in Tables 1 and 2, together This may be rationalized by differential steric repulsions TABLE 1 Dynamic lH n.m.r.data for site exchange in NN-dialkyl-2-hydroxy-3-isupropylthiobenzalrlitles(3) Exchange Protons AGt/kcal mol-l Compound process studied T/"C h bls-1 (30) -CHS NCH, 25 126 14.6 i0.1FN-/ (3b) d:o NCH,CH, 20 165 14.2 f0.1 NCH,CH, 13 113 14.0 f-0.1 (3,) do NCH, 2 I so 13.4 * 0.1 (30) Arf.CPS CH(CH,) -53 11.5 11.7 0.2 >N-(3b) d:o CWCH,), -36 9.5 12.7 -f 0.2 NCH, -19c 37 d 13.0 * 0.3 0.2CH (CHJ, -24 25.0 12.9 ( 3c ) d: o NCH, -201 18 a 13.3 0.3 Deterniined in [2H,]toluene solution at 100 MHz. Exchange rate obtained by band-shape analysis in the region of maximum exchange broadening (TO). c High-field NCH, group was used in the analysis as this showed the larger geminal anisochronism. Determined by analysing the exchanging band-shape of the AB system resulting from decoupling of the vicinal protons.The precision of these measurements is lowered by possible exchange effects arising from the syn-anti exchange process. Spectra deter- mined at 220 MHz due to small signal separation at 100 MHz. f Low-field NCH, group was used in the analysis as this showed the larger geminal anisochronism. in the ground state and the transition state. Similar effects may be responsible for the further decrease in AGt on going to (3c), though changes in the geometry at nitrogen along the rotational co-ordinate could be reflected in a ring-strain factor.* The entropy of activation for a simple bond-rotational process should normally be very small unless either the ground or transition states are highly hindered, or solute-solvent interactions are strong.Hence AGI should mainly reflect the enthalpy changes in the system. Some early dynamic n.m.r. studies of simple amides afforded large AS: values for C-N bond rotation, but these were probably artefacts of the analysis.lO~ll It is now evident that the errors in AS1 determined by dynamic n.m.r. can be very large unless the system is 2-h ydrox y-4-methoxy-NN-dimeth ylt hiobenzamide and 1-h ydrox y -NN-dimet h yl-2-thionaphthamide respect-ively.6 The C(S)-N torsional barriers in 2-hydroxythio- benzamides are appreciably lower than those in 2-methoxy-, 4-hydroxy-, or unsubstituted thiobenz-amides. Possible reasons for this effect have been I1 /OH C-N \ CH~H~Y Mey discussed elsewhere,6 but intramolecular hydrogen bonding to the sulphur atom is probably responsible for the relative lowering of the C(S)-N torsional barrier.Origin of the Gcminal Anisochronism.-The geminal non-equivalence of the isopropyl methyl groups and the NCH, protons observed in the spectra of the diethyl compound (3b)recorded below -40 “C could be rational- ised in terms of a locked arrangement of the diethyl- amino-moiety [as depicted in (4)],with a rapidly rotating SC H E M E favourable,and even then the errors are appreciable.11*12 or planar aryl-C(S) moiety.5 Conformation (4) is Compound (3a) was selected for detailed investigation since the separation of the N-methyl signals at -36 “C was very large (66.5 Hz at 100 MHz) relative to the line- width (1.5Hz), and there was only one exchange process involving these signals.Band-shape analysis was under- taken at 13 temperatures over the range -9 to +51 “C. A linear regression of ln(k/T) on 1/Tgave AH1 14.6 & 0.4 kcal mol-l and AS: 0.1 5 3 cal K-l mol-1 (correlation coefficient 0.998). A previous investigation of ovtho-hydroxythiobenz-amides has also indicated that AS1 for C(S)-N bond rotation is close to zero, viz. 1.O and -2.4 cal 1C-l mol-l in chiral due to the ah-periplanar arrangemcnt of the methyl groups (Y = Me), and hence the paired geminal substituents on the prochiral aryl-CH or NCH, carbons would be diastereotopic.l3 However, the data for coin- pounds (3a) and (3c) rule out this explanation of the geminal non-equivalence.Thus, the dirnethylamino-analogue (3a) will exhibit rapid rotation around the N-CH3 bonds at all accessible temperatures and the * The nitrogen atom could become more pyramidal (due to reduced conjugation) as the NR, moiety rotates out of the C=S plane. This could lead to a reduction in the strain energy of the piperidino-ring in the transition state for C(S)-N torsion. piperidino-analogue (3c) cannot achieve the anti-conformation depicted in (4) for geometric reasons, yet both of these compounds as well as (2a-c) exhibit geminal anisochronism in the same temperature range as the diethylamino-derivative (3b). Clearly the origin of the geminal non-equivalence in these and other 2- hydroxythiobenzamides is the same as for other thio- benzamides,* namely the molecular chirality (on the n.m.r.time-scale) brought about by a frozen non-coplanar C-aryl ring conformation (5). The AGJ values determined from the geminal Me,CH and geminal NCH, signal coalescence (Table 1) are the same within the experimental error and refer to the rate of degenerate enantiomerization involving rotation around the aryl-C(S) bond through the thioamido-plane. The aryl-C(S) torsional barrier in (3a) is 1.0 kcal molt1 lower than in (3b) or (3c). The coplanar transition state for this process is more hindered than the twisted -4Pc 4.5 4.0 3.5 3.0 J.C.S. Perkin II process as a cause for the temperature dependence of the lH n.m.r. spectra of compounds (2a) and (2b).Byincreasing the size of the group Y in (2) one could, however, expect to be able to observe both processes depicted in the Scheme. For this purpose we prepared the NN-di-isobutyl analogue (2c) and studied its 100-MHz and 270-MHz lH n.m.r. spectra in dichlorofluoro- methane solution. At ambient temperature] all isobutyl resonances were strongly broadened, but at +16 "C two sharp doublets (6 H each, J = 6.8 Hz) appeared at 6 0.72 and 1.05, and two nonatuplets (1 H each, J = 6.8 Hz) at 6 1.95 and 2.53. The NCH, resonance appeared as a broad (Av,,, = 22 Hz) singlet at 6 3.50. At lower temper- atures the Me resonances broadened again and appeared at -42 "C as a doublet of doublets and a triplet respect- ively (Figure 2), and the NCH, resonance appeared as three multiplets that could be analysed as the over-~~ ~ 2-5 2.0 1.5 1.0 6 2FIGURE 100-MHz lH N.m.r.spectrum of (2c)in CHC1,F at -42 "C ground state due to unfavourable interaction between the 6-hydrogen and the E N-alkyl group. In a preliminary comm~nication,~ two of us proposed that 2-hydroxy-NN-diethylthiobenzamide (2a) and its NN-dibenzyl analogue (2b) are involved in a four-site exchange process (see Scheme). The chemical shift non-equivalence observed in the N-CH, proton resonance was suggested to be due to either of two situations: (i) The processes A, +B, and A, =a=B, (aryl-C=S rotation) are slow and A,dA, and B,@B, (N-alkyl rotation) are fast on the n.m.r. time-scale.(ii) The reverse situation applies, i.e. the N-alkyl rotations are slow and the aryl-C rotations are fast (or the aryl-C=S moiety is planar). The molecule would be chiral in both cases, and geminal nuclei in prochiral groups would be diastereo- topic. In a previous report the second alternative was preferred. However, although the anti-periplanar arrangement of primary alkyl groups attached to the nitrogen atom has later been demonstrated for several amides and thioamides19 alternative (ii) is untenable in the light of the results described for compounds (3). The very low barriers observed or calculated for the enantiomerization process in NN-dibenzyl- and NN- diethyl-amides and -thioamides also exclude this lapping AB parts of two ABX spectra.The methine proton resonances remained unchanged in this temper- ature interval. From about -60 "C a new broadening was observed, which affected first the NCH, resonances but gradually all signals. No resolved spectrum was observed down to -130 "C at 100 MHz, though the appearance of new signals in the NCH, region was evident. Inspection of the 270-MHz spectrum at -108 "C (Figure 3), however, clearly showed that the two AB systems observed at -42 "C had split into two sets in the intensity ratio ca. 3: 1. The assignment of the signals is based on the assump- tion that the doublet of doublets appearing at lowest field in the spectrum at -42 "C (denoted Z,, 6 4.58) is due to a proton that resides most of the time in the proximity of the strongly deshielding thiocarbonyl group, i.e.in the 2 (syn) methylene group. It was readily demonstrated by double-resonance experiments that the doublet of doublets at 8 3.23 (Z,)] the nonatuplet at 6 2.53, and the apparent triplet at 8 1.05 also have their origin in the 2 isobutyl group. The chemical shift of the 2, resonance varies linearly with the temperature] and at -108 "C its extrapolated position is 6 4.32. At this temperature this resonance has split into a broad major signal at 6 4.79 and a minor one at ca. 6 3.0, corresponding to a population ratio of 3 : 1. Similarly, 2, gives rise to a minor resonance at ca. 6 4.8 and a major one at 6 2.98. This corresponds to a rather precise exchange of environment of the two 2 methylene protons from rotamer A, to rotamer A, (or from B, to B, in the enantiomeric pair).The E resonance with 6 3.78 at -42 "C (El)is split at -108 "C into a major resonance at 6 3.87 and a minor one at 6 3.20. The remaining E resonance (E,) is the one that is least affected by the lowered temperature, and the two components at -108 "C have very similar chemical shifts. The process causing broadening of all signals in the spectrum at ambient temperature must be the rotation The notion of an exchange between two anti-periplanar arrangements of the isobutyl groups is strongly supported by the splitting pattern observed for the 2, and 2, resonances. The two 2 proton environments will be quite similar in the A and B rotamers with a strongly deshielded site closer to the C=S bond and a more distant site that is even more shielded than those of the E protons, as found in other NN-di-(primary alky1)amides and -thioamidesg In the A, A, (B, HB,) ex-change one 2 proton goes from a high-field to a low-field site, and the other 2 proton experiences the reverse change, in agreement with the observations.The shieldings of the E protons must have considerable contributions from the magnetic field caused by the aromatic ring current, but since the precise geometries of TABLE2 Dynamic lH n.m.r. data for site exchanges in NN-di(primary alky1)-2-hydroxythiobenzamides(2) u Exchange process Protons studied T/OC k1s-l AGt/kcal mol-1 NCHSCH, 24.0 68 14.9 f0.1 d:o NCH,Ph 33.8 133 15.0 f0.1 d:o N CH,C H(CH,) a 38.4 73 15.6 f0.1 -50.2 51 11.2 f0.2 d:o NCH,Ph -10.0 126 12.8 f0.2 d:o NCH,CH(CH,), -18.1 17 13.4 f0.2 -& NCH,CH(CH,), -84.0 450 8.6 f0.2 R;N-R 5 In dichlorofluoromethane solution.b The Z,resonance. around the -C(S)-NR, bond, its free-energy barrier being in good agreement with those for the same process in other 2-h ydrox y-NN-dialky1thiobenzamides (Tables 1 and 2, ref. 6). The second process causes signal broadening and splitting between +16 and -42 "C of the resonances of the prochiral NCH, and CMe, groups while leaving the methine proton resonances undisturbed. This could, as discussed above, be due to the N-alkyl or Ar-C(S) rotation becoming slow on the n.m.r. time-scale, both processes causing enantionierization of the chiral molecule, but the height of the free-energy barrier (13.4 kcal mol-l) clearly shows that the latter process must be responsible.The third process, affecting the spectrum below -60 "C, is the exchange between the two anti-periplanar arrangements of the isobutyl groups. The population difference probably reflects a slightly larger steric strain in the A,-B, enantiomer pair. The free-energy barrier found for this process, 8.6 & 0.2 kcal mol-l, is in good agreement with barriers for the analo- gous process in other NN-di-isobutylthioamides, 7.5-8.2 kcal rn01-l.~ the two conformers are unknown, no assignment has been attempted. As mentioned above, the chemical shifts of the NCH, protons show some temperature dependence, most striking for the Z, resonance (4.10 x lop3p.p.m.K-'). Much more spectacular effects, however, were observed for the analogous (2a) and (2b). The most interesting behaviour was shown by the dibenzyl compound (2b). As is shown in Figure 4, the AvAIc-T plots for the E and 2 NCH, groups have sigmoid shapes, and change sign between -28 and -90 "C. Attempts have been made to simulate these shapes by assuming a strongly temper- ature-dependent A, *A, equilibrium,(B, -B,) and exchange between a large positive AvAB in A, and an equally large negative AvAUin A,. A sigmoid shape was found in the region around T = AH/AS, but at higher or lower temperatures AvAH went asymptotically towards constant values. In order to have a consider-able deviation from a straight line, it was also necessary to have a rather large positive or negative AS, which may not be realistic.However, one may explain the observed shape as the superposition of two such sigmoid curves, caused by two processes with different AH :AS ratios, but at present we have no proposal as to which these processes could be. 1.r. spectra of (2a-c) and (3a-c) recorded at high II I I 1 I 1 5.0 4.5 4.0 3.5 3.0 2.5 2.0 6 3FIGURE 270-MHz *H N.m.r. spectra of (2c) in CHC1,F at -35 "C and -108 "C. The lines with asterisks mark the averaged signal positions extrapolated to -108 "C dilution indicate the presence of a strong intramolecular hydrogen bond, the 0-H stretching vibration showing as a broad absorption centred at 3220-3295 cm-1 (Table 3).Other 2-hydroxythiobenzamides exhibit similar intramolecular hydrogen-bonding to the sulphur TABLE3 1.r. OH-stretching frequencies (in CCI, solution) Compound Concentration/hI VOIIIcm-' (2a) 0.05 3 260 0.005 3 280 (z'b) 0.05 3 295 0.005 3 295 (24 0.05 3 250 0.005 3 270 (34 0.03 3 210 0.003 3 220 (3b) 0.03 3 280 0.003 3 290 (3c) 0.03 3 230 0.003 3 220 ;tt~rn.~*~,~Therefore, although the n.m.r. data show that the aryl ring and the thioamide moiety are non-coplanar, the twist angle cannot be as large as 90"since the OH S internuclear distance would be too large for strong hydrogen-bonding. An intermediate aryl-C(S) twist J.C.S. Perkin I1 angle of 40-60" would reduce the OH S distance sufficiently for hydrogen-bonding and also be consistent with the fairly high barrier to rotation through the coplanar conformation.Conclusion.-In conclusion,the geminal anisochronism observed in the n.1n.r. spectra of 2-hydroxy-NN-dialkylthiobenzamides containing prochiral substituents has the same origins as the geminal anisochronism in other ortho-substituted benzamides and thiobenzamides, viz. the molecular chirality due to a frozen non-coplanar conformation around the aryl-C(X) b~nd.~J~J~The precise magnitude of the chemical-shift difference between the geminal groups in any given compound is, of course, determined by a subtle interplay of other conformational factors which cannot readily be quanti- fied.13 However, the data for the hindered di-isobutyl derivative indicate that it is also possible for geminal non-equivalence to arise from slow rotation about the N-alkyl bonds at low temperatures.The latter effect is, -20 -Y-30 -LO 1 1 1 1 I I 1 I -30 -LO -50 -60 -70 -80 -90 1/.C RGuw 4 The internal chemical shifts in the E and Z nicthylene groups in (21)) (in CIIC1,F) as a function of the temperature of course, not dependent on the presence of an ortho-substituted C-aryl Although other possible origins of geminal anisochronisin in thiobenzamides and benzamides might be envisaged in isolated cases, 'Occam's Razor 'ought to he applied. EXPERIMENTAL Materials.-"-Diet Ityl-2-hydvoxythiobenzalnids (2a).-1 n a modified Willgerodt-Kindler reaction,I6 2-hydroxy-benzaldehyde (5.0 g), sulphur (2.0 g), and diethylamine (7.0 g) were heated at 100 "C for 4 h.The mixture was treated with ice-water while still hot, and extracted with chloroform. The product was recrystallized from ligroin- benzene (2 :I) to afford pale yellow crystals (6.0 g, 70%), m.p. 84-85 "C (Found: C, 62.9; H, 7.1; N, 6.6; S, 15.3. 980 C,,H,,NOS requires C, 63.1; H, 7.2; N, 6.7; S, 15.3%); 6 (CDCl, at 25 "C) 1.29 (6 H, t, 2 Me), 3.85 (4 H, very broad, 2 NCH,), 6.8-7.3 (4 H, multiplet, aromatic ring), and 7.4 (1 H, broad s, OH). NN-Dibenzyl-2-hydroxythiobenzamide (2b) .-2-Hydroxy- benzaldehyde (6.0 g), sulphur (3 g), and dibenzylamine (20 g) were heated at 130 "C for 4 h.The mixture was poured into ice-water and extracted with diethyl ether. The resulting thick oil was subjected to chromatography on alumina (diethyl ether). The major fraction was recrystallized from ethanol to give pale yellow crystals of the thioamide (2.7g, 17y0), m.p. 84-86 "C (Found: C, 75.1; H, 5.8; N, 4.0; S, 10.0. C,,H,,NOS requires C, 75.6; H, 5.7; N, 4.2; S, 9.6%); 6 (CS, at 25 "C) 5.02 (4 H, broad d, 2 NCH,), 6.55-7.20 (4 H, multiplet, aromatic ring), 7.20 (10 H, s, aromatic), and 7.78 (1 H, s, OH). 2-Hydrox-y-NN-Di-isobutylthiobe~zzamide (2c) .-2-Hydr- oxybenzaldehyde (14 g), sulphur (8 g), and di-isobutylamine (20.8 g) were refluxed for 3 h. The mixture was poured into ice-water and extracted with diethyl ether.The resulting brown oil was distilled in vacuo (b.p. 120-124 "C at 0.02 mmHg) to afford a yellow oil which solidified with time. The product was recrystallized from ligroin affording yellow crystals of this thioamide (9.4 g, 31%) (Found: C, 67.6; H, 8.5; N, 5.3; S, 12.4. C,,H,,NOS requires: C, 67.9; H, 8.7; N, 5.3; S, 12.1%); 6 (CDC1, at 25 "C) 0.9 (12 H, 2 broad doublets, 4 Me), 2.1 (2 H, very broad, 2 CH), 3.8 (4 H, very broad, 2 NCH,), 6.8-7.4 (4 H, multiplet, aromatic ring), and 8.2 (1 H, broad s, OH). 2-Hydroxy-3-isopropylbenzaldehyde, b.p. 88-94" at 6 mmHg, was prepared in 12% yield by the Duff l7 reaction between 2-isopropylphenol and hexamethylenetetramine and purified by steam distillation followed by distillation in vacuo.18 2-Hydroxy-3-isopropyl-NN-dimethylthiobenzarnide (3a).-Dimethylamine was bubbled into a mixture of 2-hydroxy-3-isopropylbenzaldehyde(4.22 g) and powdered sulphur (1.23 g) at 120 "C for 5 11. The resulting oil was extracted with chloroform and distilled in vacuo to afford the thioamide (3.2 g, 56%), b.p. 114-116 "C at 0.05 mmHg as a pale yellow oil which solidified in the receiver, m.p. 80-81 "C from ethanol (Found: C, 64.5; H, 7.5; N, 6.3; S, 14.5. C,,H,,NOS requires C, 64.5; H, 7.7; N, 6.3; S, 14.6%); 6 (CDCl, at 35 "C) 1.32 (6 H, d, CMe,), 3.45 (6 H, broad s, NMe,), 3.35 (1 H, septuplet, CH), 6.9 (2 H, broad d, aromatic ring), 7.25 (1 H, d of d, H-5 of aromatic ring), and ca. 8.2 (1 H, very broad, OH). NN-Diethyl-2-hydroxy-3-isopropylthiobenzamide (3b).-2-Hydroxy-3-isopropylbenzaldehyde(5.3 g), sulphur ( 1.5 g), and diethylamine (3.5 g) were heated at 120 "C for 8 h.Chloroform extraction followed by distillation afforded the thiobenzamide (3.8 g, 470/,), b.p. 118-122 "C at 0.07 mmHg which solidified with time to a zmzxy solid (Found: C, 66.7; H, 8.1; N, 5.3; S, 12.5. C,411,,NOS requires C, 66.9; H, 8.4; N, 5.6; S, 12.8%); 6 (CCl, at 35 "C) 1.25 (6 H, d, CMe,), 1.3 (6 H, broadened triplet, 2 Me), 3.42 (1 H, sep- tuplet, CH), 3.88 (4 H, very broad, BNCH,), 6.84 (2 H, doublets, aromatic ring), 7.23 (1 H, doublet of doublets, aromatic H-5), and 7.55 (1 H, broad singlet, OH). N-(2-Hydroxy-3-isopropylthiobenzoyl)piperidine (3c).-2-Hydroxy-3-isopropylbenzaldehyde (3.5 g), sulphur (1.2 g), and piperidine (3.3 g) were refluxed in pyridine (10 cm3) for 3 h, and then added to dilute hydrochloric acid.The concentrated carbon tetrachloride extract was subjected to column chromatography on silica gel 60-120 mesh (B.D.H.) with light petroleum-chloroform (2.75 : 1) eluant. The major fraction was further separated by short high- pressure column chromatography using Kieselgel G (Merck) packing and chloroform as the eluant to afford pale yellow crystals of thioamide (1.0 g, 19.5y0), m.p. 121-123 "C from acetone (Found: C, 68.6; H, 7.7; N, 5.0; S, 12.2. C,,H,,NOS requires C, 68.4; H, 8.04; N, 5.32; S, 12.17%); 6 (CCl, at 35 "C) 1.25 (6 H, d, CMe,), 1.75 [6 H, broad singlet, (CH,),], 3.44 (1 H, septuplet, CH), 4.05 [4 H, broad singlet, N(CH,),], 6.69 (2 H, doublets, aromatic ring), 7.13 (I H, doublet of doublets, aromatic H-5), and 8.03 (1 H, singlet, OH).Dynamic N.M.R. Studies.-Variable-temperature IH n.m.r. investigations of compounds (3) were performed at 100 MHz on ca. 0.5~-solutions in [2H8]toluene using a Varian Associates XL-100 spectrometer operating in the C.W. mode. Probe-temperature measurement and band-shape analyses were performed as described previously. 2o The coalescing isopropyl methyl doublets and sets of N-alkyl signals were approximately first-order and were analysed using the classical multi-site programme INMR. Multiplet compo- nents were treated as separate sites with the appropriate relative intensities.The second-order geminal NCH, AB system in (3b) and (3c) was recorded with decoupling of the vicinal protons and the band-shape at coalescence was directly analysed using the programme SPECAB.,I At the AB coalescence temperature the NCH, signals are probably slightly affected by the C(S)-N rotational process and by the decoupling, hence these data are less precise (see Table 1).Compounds (2) were studied in ca. 0.4~-solutions in dichlorofluoromethane. The samples were thoroughly degassed by freeze-thawing under high vacuum before being sealed off. The spectra were recorded with a JEOL model MH-100 and a BRUKER model HX-270 n.m.r. spectrometer with standard variable-temperature probes and temperature controllers. The temperatures were recorded as described previously.22 The rate constants were evaluated by visual comparison between experimental spectra and spectra calculated by superposition of the appropriate number of simple two-site exchange ~pectra.2~ The rate constants to rotation about the N-Bu' bonds were evaluated by fitting only the 2, resonance, simulated by superposition of four two-site spectra above the coalescence temperature.U. B. and J. S. are grateful to the Natural Science Research Council, and IJ. B. also to the Royal Physio- graphic Society of hind, for financial support and to Dr. Kjeld Schaumburg at the Oersted Institute in Copenhagen for aid with the recording of the 270-MHZ spectra. W. B. J. is grateful to the S.K.C. for an allocation of time on the 220- MHz n.m.r.spectrometer at P.C.M.U. Harwell, and D. I<. thanks the S.R.C. for a maintenance grant. [9/823 Received, 25th May, 10701 REFERENCES 1 A. 0. Fulea and P. J. Krueger, Tetrahedron Letters, 1975, 3135. 0 P. J. Krueger, A. 0. Fulea, C. Fulea, and F. Cornea, Spec-troscopy Letters, 1975, 8, 141; A. 0. Fulea and P. J. Krueger, ibid., 1975, 8, 375. 3 A. 0. Fulea and P. J. Kruegcr, Canad. J. Chon., 1977, 55, 227. 4 W, B. Jennings and M. S. Tolley, Tetrahedron Letters, 1976, 695. 5 U. Berg and J. Sandstrom, Tetrahedron Letters, 1976, 3197. U. Berg, Acta Chem. Scand. B, 1976, 30, 695. R. R. Fraser and K. Taymaz, Tetrahedron Letters, 1976, 4573. * W. B. Jennings and D. Randall, Chem. Phys. Letters, 1978, 65, 480.9 U. Berg, M. Grimaud, and J. Sandstrom, Nouveau J. Chim., 1979, 3, 175. lo G. Binsch, Topics Stereochem., 1968, 3, 97. l1 A. Allerhand, H.S. Gutowsky, J. Jonas, and R. A. Meinzer, J. Amev. Chem. SOC.,1966, 88, 3185. 12 R. R. Shoup, E. D. Becker, and M. L. McNeel, J. Phys.Chem., 1972, 76, 71. l3 W.B. Jennings, Chem. Rev., 1975, 75, 307. T. Siddall 111 and R. H. Garner, Canad. J, Chem., 1966, 44, 2387. 15 A. H.Lewin and M. Frucht, Tetrahedron Letters, 1970, 1079. J.C.S. Perkin 11 l6 K.A.Jensen and C. Pedersen, Acta Ckem. Scand., 1961, 15, 1087. l7 J. C. Duff, J. Chem. SOL, 1941, 547; used in the form described by C. F. H. Allen and G. W. Leubner, Org. Synthesis,Coll. Vol. IV, 1963, 866. l8 M. Crawford and J. W. Rasburn, J. Chem. SOC.,1956, 2155. l8 B. J. Hunt and W. Rigby, Chem. and Ind., 1967, 1868. 2o J. Burdon, J. C. Hotchkiss, and W. B. Jennings, J.C.S. Perkin 11,1976, 105%. 21 J. Jonas, A. Allerhand, and H. S. Gutowsky, J. Chem. Phys., 1965, 42, 3396. 22 A. Liddn, C. Roussel, T. Liljefors, M. Chanon, R. E. Carter, J. Metzger, and J. Sandstrom, J. Amer. Chem. Soc., 1976, 98, 2853. Z3 H. M. McConnell, J. Chem. Phys., 1958, 28, 430.

ISSN:1472-779X    

DOI:10.1039/P29800000949

出版商:RSC    

年代:1980

数据来源: RSC