J. CHEM. SOC. PERKIN TRANS. 1 1994 An Efficient General Route to Furo-, Pyrido- and Thieno-a 2benzazepines via PdO Catalysed Cross Coupling Reactions and Nitrile Ylide Cyclisations Harry Finch,a Donald H. Reece and John T. Sharp* Department of Chemistry, University of Edinburgh, West Mains Road, EdinburghEH9 UJ,UK a Glaxo Group Research Limited, Park Road, Ware, Hertfordshire SG12 ODP, UK The cyclisation of diene-conjugated nitrile ylides of the general type 1, in which the conjugated system consists of a benzene ring and a five- or a six-membered heterocyclic ring, provides an effective route to fully unsaturated heterocyclod 2 benzazepines. The combination of this cyclisation with a direct route to the nitrile ylide precursors via PdO catalysed cross-coupling gives an efficient general synthetic route to these systems from readily available starting materials.This work is concerned with an investigation into the cyclisation of biaryl-conjugated nitrile ylides of type 1 in which C-kC-Ph H/ 1 one of the aromatic rings (A or B) is a benzene ring and the other is a five- or six-membered heterocycle. It follows recent work on the analogous system 2, containing two benzene rings, whose cyclisation provides a good general route to dibenzc,e-azepines 4.' This electrocyclic mode of aromatic substitu- tion has the advantage over electrophilic or nucleophilic substitution in that it is effective for terminal rings carrying substituents (R in 2) which are either electron donating or R @Rbsol; /E--iECPh electroc1.7 ycl.electrocycl. ~ H 2 3 electron withdrawing. The objectives of the present work g2 were to find out whether the nitrile ylide cyclisation step was also effective in biaryl systems containing electron rich or electron poor heterocyclic rings and, if so, thus to develop a general route to tricyclic azepines with one fused benzene ring and one fused heterocyclic ring. Compounds of this type and their functionalised derivatives are of interest for their possible interaction with benzodiazepine, cholecystokinin (CCK) and gastrin receptors. Results and Discussion The general route to nitrile ylides 7 used in the earlier work involved the base-induced 1,3-dehydrochlorination of imidoyl chlorides 6, which were themselves simply derived by the chlorination of amides 5.The intention here was to use the same method and this therefore required the development of efficient routes to amides of the general types 8 and 9. CI 5 6 flCH2NHCOPh H E CH2NHCOPhTP 8 9 (a) Routes to the Amides 8 and 9 as Precursors to Nitrile Y1ides.-In recent years, several direct routes to biaryls have been developed via the palladium(0) catalysed cross-coupling of aryl halides with various organometallic derivatives. Of these, the route developed by Suzuki using arylboronic acids3, is, perhaps, the most general in respect of its tolerance of a wide range of other functional groups and the ease of preparation of p~the reactants. Scheme 1 shows the application of this chemistry to the synthesis of biaryls 12 (Ar = aryl) and heterobiaryls 12 (Ar = hetaryl) containing the o-benzamidomethyl group required as nitrile ylide precursor.In principle, this substituent could be present in either the halide component 10 or in the boronic acid 13; both alternatives have some potential advantages and both have been utilised as described below. The first approach was via the coupling of N-(2-bromobenzyl)- benzamide 10 with a range of heterocyclic boronic acids 11, Scheme 1 (Route 1). This was attractive in that the amide 10 is CH2N HCOPh CH2NHCOPh ii BUCI Scheme 1 Table 1 Yields and physical data on the amides 12a-i, 16 and 17 Yield () time (h) Cryst. M.p. Molecular C () H () N () mlz (M+ 1 Compound Ar Route 1 Route 2 solvent' ("C) formula Found Calc.Found Calc. Found Calc. Found Calc. 12a Ph 865 91 4 E 95-96 12b 2-Thien yl 78 c31 E 119-120 cl gH 1SNoS 293.0878 293.0874 12c 3-Thienyl 80 c51 E 125-126 cl gH 1SNoS 293.0865 293.0874 12d 3-Fuvl 772 852 Eth/H 80-8 1 c1 BH 1SN02 279.1259' 279.1259 12e CPyridyl 73 c11 E 130-131 c1 gH 16NZ0 288.1260 288.1263 121 3-Pyridyl 74 c51 E 116-118 c1 9H16N20 288.1263 288.1263 12g 2-Pyridyl 81 c31 EA/H 104-106 cl gH1 6N20 288.1255 288.1263 12h 2-Pyrimid yl 83 c21 E/H 124.5-1 26.5 C18H15N30 74.2 74.7 5.0 5.2 14.7 14.5 289.1214 289.1215 12i 5-Pyrimid yl 81 121 EA/H 150-151 1EH 1SN30 289.1212 289.1215 16 see text 73.4 73.7 5.2 5.2 4.5 4.8 293.0877 293,0874 17 see text 73.4 73.7 5.2 5.2 4.7 4.8 293.0865 293.0874 (I H = hexane, E = ethanol, Eth = diethyl ether.Lit.,' 94.5-95.5 OC.'FAB, glycerol. J. CHEM. SOC. PERKIN TRANS. 1 1994 easily prepared from commercially available 2-bromobenzyl- amine. The boronic acids were generally prepared by adapt- ations of known routes via the reaction of the heterocyclic Grignard reagent or lithium derivative with trimethyl or triisopropyl borate. Using the improved experimental condi- tions developed by Gron~witz,~ it was found that the coupling reaction worked well for phenylboronic acid to give compound 12a (Ar = Ph) which had been prepared previously by other routes and with a range of thienyl- and furyl-boronic acids to give the amides 12b,c,d; the substituents are identified and the yields are given in Table 1.This route is, therefore, satisfactory for coupling heterocycles such as thiophene or furan whose boronic acid derivatives are readily available but is not applicable to those such as pyridine where this is not the case. This problem can be avoided in some cases by using other organometallic derivatives of the heterocycle, e.g. the commer- cially available diethyl(3-pyridy1)borane which was used under identical conditions to prepare compound 12f in good yield. However, such substitutes are not always available and a more general solution was found by adopting the alternative approach via the use of compound 13 which has the boronic acid function incorporated in the amide. The development of this route, therefore, required the synthesis of 2-(benzamido- methy1)phenylboronic acid 13 which, it was hoped, would be capable of coupling directly with a range of heterocyclic bromides 14,which are readily available for most heterocyclic systems.The preparation of the boronic acid 13 involved the formation of the dilithiated derivative 15 and its reaction with a borate ester. The dianion 15 was generated by sequential treatment of 10 with methyllithium to deprotonate selectively the amide and then with butyllithium to effect metal-halogen exchange, a technique used earlier in the preparation of analogous 2-lithiated tosyl hydrazones. A problem encoun- tered in this work was that butyllithium proved unsatisfactory in the second step as its use resulted in the formation of some N-(2-butylbenzyl)benzamide via the reaction of the dianion 15 with the l-bromobutane formed in the metal-halogen exchange.This was avoided by the use of tert-butyllithium and it was thus possible to prepare compound 13 routinely in isolated yields of ca. 85. It proved to be highly effective in coupling with a range of hetaryl bromides 14, Scheme 1 (Route 2) (see Table 1 for identification of Ar) and its use, therefore, provides an easy general route to the required amides of the general type 8. It has also proved to be of much general value in this area of chemistry not only for coupling bromoheterocycles but also for coupling with a range of aryl and alkenyl bromides to give the reactants used in related work.Only two examples of amides of the general type 9 have been investigated, the two thiophene derivatives 16 and 17prepared oia Schemes 2 and 3,respectively. i NH2OH/ /ii Z~-NH~OA~NH~ 16 Scheme 2 The physical and spectroscopic properties of the amides are given in Tables 1 and 2, respectively. All showed the expected IR CHzPhth. CHpPhth. PhB(0H)ZaBr0Pdo Ph ,CHzNHCOPh Ph 17 Scheme 3 absorptions for the amide group and all except the 2-thienyl derivative 12b,had the expected 'H NMR signals for the NH (br) and CH, group (doublet) which were similar to those for the phenyl analogue 12a. The spectrum of the 2-thienyl compound 12b showed an interesting difference in that both of these signals were doubled, e.g.the methylene group gave a pair of doublets at 6 4.68 and 4.71 in the ratio 1 :3.8 at 25 "C. It is thought that this effect is due to a non-bonded electrostatic interaction of the sulfur atom of the thiophene with the amide group, as indicated in 18,which restricts the amide rotation. This explanation is consistent with the fact that the dipole moment of thiophene itself has the negative charge on sulfur and is supported by the observations (i) that the two doublets merge when the temperature of the sample is raised to 59 "C and (ii) that the integral ratio of the doublets is diminished when the dielectric constant of the solvent is increased by the addition of the more polar solvents perdeuterio-acetone or -dimethylformamide. 18 19 (b) Cyclisation of the Nitrile Ylides to give Heterocyclo- d2benzazepines.-In all the cyclisations, except those of 12d and 12g,the procedures followed for the cyclisation, work-up and isolation of the products were as described earlier for the analogous biphenyl systems.' The generation of the nitrile ylides, shown in Scheme 4 for the general case, involved the conversion of the amide into an imidoyl chloride by reaction with either thionyl chloride in ether at reflux temperature or, in cases of difficulty, by reaction with the more powerful reagent chlorodimethylformiminiumchloride at room temp.The latter was generated in situ by the reaction of thionyl chloride with DMF. The former method was preferred where possible as any excess of reagent was more easily removed by evapor- ation under high vacuum. The crude imidoyl chlorides, after evaporation of the reagent and solvent, were not further purified but were dissolved in THF, cooled to 0 "C and treated with an excess of potassium tert-butoxide, Scheme 4, to generate the nitrile ylides.In much of this work the potassium tert-butoxide used was the fresh commercial reagent (Aldrich) but more recently it has been found that better conversions are obtained when the base is purified by sublimation under high vacuum (at ca. 200deg;C) before use. The products were isolated by dry- column flash chromatography. In all cases the cyclisations were successful and gave tricyclic azepine systems, Table 3. The cyclisations are discussed in more detail in (i) and (ii) below.The products were identified by the presence in their 'H NMR spectra (Table 4) of the characteristic 'pair of doublets (Jca. 1 1) 1196 J. CHEM. soc. PERKIN TRANS. 1 1994 due to methylene group. These signals showed the expected 2 variation with temperature due to the inversion of the azepine ring; this is discussed in more detail in (c) below.aHe*aHet~12 iorii iii -CHZ-N =$Ph ,c amp;CPh Hrsquo; 20 21 +Scheme 4 Reagents and conditions: i, SOC1,ether-reflux; ii, Me,N= CHCl C1-(SOC1,-DMF), room temp.; iii, K0Bulsquo;-THF (i) Systems containing thiophene orfuran rings. Four systems containing thiophene rings and one containing a furan ring were examined. The first two were the nitrile ylides 21b and 21c and in these cases azepine formation requires electrocyclic substitution of the electron-rich thiophene ring.In both cases the amide precursors were easily converted into the imidoyl chlorides using thionyl chloride in ether under reflux. Both of these nitrile ylides cyclised as expected to give the azepines 22 and 23, respectively. As expected from earlier work on diazo cycli~ations,~the latter cyclised only at the 2-position of the thiophene ring rather than the 4-position. The other two thiophene systems 25 and 2.8 both had the thiophene ring in the a,p position, i.e. carrying the nitrile ylide group and consequently ring closure required electrocyclisation onto the benzene ring. The conversion of their amide precursors 16 and 17, respectively, into imidoyl chlorides caused some initial difficulty as the latter, 24 and 27, seemed to be unusually unstable.Reaction with thionyl chloride in ether at reflux, as used for the two previous thiophene-containing systems, gave little of the expected products and much black tar. The problem was solved by the use of the more reactive reagent chloro- dimethylformiminium chloride at a lower temperature. The relatively high instability of compounds 24 and 27 probably has its origins in the electron-rich nature of the thiophene ring. All benzimidoyl chlorides tend to decompose at high temperatures via the extrusion of benzonitrile and in these cases this process would be favoured by the effect of the electron-rich thiophene ring in stabilising the incipient thienylmethyl carbocation which, once formed, could then undergo further reactions such as alkylation.Generation of the nitrile ylides was carried out in the usual way and they cyclised to give compounds 26 and 29 in satisfactory yields. All of these thiophene-containing azepines showed a reluctance to crystallise even more marked than some of their dibenzo analogues and it was generally found to be most efficient to purify them by Kugelrohr distillation. The furan-containing imidoyl chloride 20d could not be isolated. Both methods were used to generate it from its amide precursor 12d and in both cases it cyclised spontaneously to give the furobenzazepine 31 in high yield. It seems likely that this takes place by a Bischler-Napieralski type of electrophilic substitution via 30 as shown.That this takes place for this compound and not for the thiophene analogue reflects the much higher reactivity of furan than thiophene to electrophilic substitution (e.g. 140 x for trifluoroacetylation and 107 x for formylation). (ii) Systems containing pyridine rings. The three isomeric pyridine-containing systems 21e, 21f and 21g have been studied. These contrast with the above in that azepine formation now requires the electrocyclic substitution of electron-deficient heterocyclic rings. In all cases the formation of the imidoyl chlorides required the use of chlorodimethylformiminium chloride. The 4-substituted derivative 21e cyclised to give 5-* Experiment designed and carried out by Dr.D. Reed, Chemistry Dept., University of Edinburgh. 06lsquo;rdquo;rdquo;-3 ,C -CPh H-Bulsquo;o-36 Scheme 5 phenyl-7H-pyrido3,4-d2benzazepine 32 in good yield. The 3-substituted analogue 21f cyclised at both of the lsquo;orthorsquo; positions to give a mixture of the two isomers 5-phenyl-7H- pyrido2,3-d 2 benzazepine 33 and 5-phenyl-7H-pyrido4,3- d2 benzazepine 34.These compounds were formed in a ratio of 1 :1.4 but could not be separated and it is not known which of the two is the major product. On the basis of other work which has shown that the reaction rate is increased by the proximity of electron-withdrawing groups to the cyclisation site it seems likely that the major product is compound 33.One of the main points of interest in looking at this pyridine series was to find out what would happen in the case of the 2-pyridyl compound 21g (Scheme 5) which has one of the two potential cyclisation sites occupied by the pyridine nitrogen atom. Some initial lack of reproducibility in this series of reactions indicated the need to look closely at the reaction of the amide 12g with the chlorinating reagent. lsquo;H NMR studies were therefore carried out in which the reaction of compound 12g with perdeuterio- dimethylformamidinium chloride was carried out in perdeuterio- DMF in an NMR tube and monitored until completion. The results from this reaction were compared with similar reactions of two comparators, the phenyl analogue 12a and the 4-pyridyl analogue 12e.In the reaction of lsquo;phenylrsquo; amide 12a the methylene doublet at 6 4.42 had virtually disappeared after 15 min to be replaced by a more deshielded singlet at 6 4.74 due to the CH, of the imidoyl chloride. The 4-pyridyl analogue 12e showed a similar but slower transformation in which the amide doublet at 6 4.42 was replaced by the imidoyl chloride singlet at 6 4.89; the reaction was essentially complete in 1 h. This slower reaction accords with our general observations on the effects of electron withdrawing groups on imidoyl chloride formation.rsquo; The reaction of the lsquo;2-pyridylrsquo; amide 12g gave a product spectrum, Fig. 1, which was quite different from those of the two comparators. The disappearance of the amide CH, J.CHEM. SOC. PERKIN TRANS. I 1994 --212b C-NECPh -+-amp;Ph N d HH 21b 22 21c 23 H-24 25 26 H,-+ H,C-N ZCPh H, I 27 28 29 12d -Ph I CI HH 2od 30 31 21e 32 I---H4H 21f 33 34 doublet was slower than for the 4-pyridyl analogue and it was imidoyl chloride (Scheme 5). This formulation is supported by replaced largely by a pair of doublets at 6 4.91 and 4.72 (J its 'H NMR spectrum; the methylene group gives the expected 11.1) together with a singlet at S 5.14. The aromatic region pair of doublets (which resonate at positions quite different also showed major changes, unlike the previous cases. The from those in the final product 36 or its hydrochloride). The conversion was virtually complete after 12 h and the spectrum major changes in the aromatic region of the spectrum are remained unchanged after a further 10 h at room temp.The consistent with the quaternisation of the pyridine nitrogen major product is thought to be the 2,4-benzodiazepinium atom. As a basis for comparison the chemical shifts of the salt 35 formed by nucleophilic ring closure in the first-formed pyridine protons for the amide 12g, its hydrochloride salt 37 J. CHEM. soc. PERKIN TRANS. 1 1994 Table 2 Spectroscopic data for the amides 12a-i, 16 and 17 Compound Ar Spectroscopic data 12a Ph 12b 2-Thien yl 1242 3-Thienyl 12d 3-Fuvl 12e 4-Pyridyl 12f 3-Pyridyl 1 2-Pyridyl 12h 2-Pyrimidyl 12i 5-Pyrimidyl 16 17 4.62 (d, J 5.6, CH,), 6.23 (br s, NH) and 7.25-7.50 (12 H, m) 1625 (GO)and 3320 (NH) 4.71 (d, J 5.6), 4.68 (d, J 5.9; combined integral 2 H, CH,), 5.36 (br s), 5.79 (br s); combined integral 1 H, NH) and 7.04-7.75 (12 H, m, Ar-H) 1630 (M)and 3320 (NH) 275 (67), 274 (1 00) and 17 1 (25) 4.65 (d, J5.6, CH,), 6.28 (br s, NH) and 7.41-7.82 (12 H, m, Ar-H) 1625 (GO)and 3275 (NH) 293 (55), 188 (25), 172 (loo), 171 (60) and 122 (55) 4.63 (d, J5.5, CH,), 6.53 (dd, J 1.8 and 0.9,4'-H), 6.95 (br s, NH), 7.23-7.49 (9 H, m, Ar-H) and 7.61-7.75 (2 H, m, Ar-H) 1635 (C =0)and 3250 (NH) 279 (M + 1,48), 278 (loo), 157 (92), 129 (50) and 105 (98) 4.54(d, J5.6,CH2),6.80(brs,NH),7.18-7.50(9H,m,Ar-H),7.6217.71(2H,m,Ar-H)and8.56(2H,brs, Ar-H) 1630 (GO) and 3375 (N-H) 287 (16), 183 (20), 167 (loo), 105 (31), 77 (38) and 69 (48) 4.54(d, J5.6,CH2),6.74(brs,NH),7.16-7.71(11 H,m,Ar-H)and8.48-8.53(2H,m,Ar-H) 1630 (C==O)and 3375 (NH) 183 (18), 168 (48), 166 (51), 105 (57), 77 (100) and 69 (24) 4.55 (d, J 6.1, CH,), 7.25-7.89 (1 2 H, m, Ar-H and N-H) and 8.64-8.7 1 (2 H, m, Ar-H) 41.0(quat.) 121.8, 123.8, 126.6, 126.7, 127.9, 128.0, 128.2, 129.4, 130.7, 134S(quat.), 136.6, 137.2(quat.), 139.4 (quat.), 148.5, 158.8, 161.3, 161.6, 161.8, 161.9 and 165.7 (quat.) 289 (69), 183 (20), 167 (100) and 105 (19) 1645 (C==O)and 3320 (NH) 4.71 (d, J 6.3, CH,), 7.24-7.49 (6H,m, Ar-H), 7.62-7.69 (1 H, m, Ar-H), 7.77-7.83 (2 H, m, Ar-H), 8.01-8.09 (1 H, m, Ar-H), 8.26 (br s, NH) and 8.86 (2 H, d, J4.9, Ar-H) 289 (4573, 184 (18), 168 (loo), 131 (17), 119 (23) and 69 (67) 1625 (W)and 3230 (N-H) 4.48 (d, J 5.7, CH,), 6.89 (br s, NH), 7.14-7.5 1 (7 H, m, Ar-H), 7.63-7.70 (2 H, m, Ar-H), 8.66 (2 H, s, 4'-H and 6'-H) and 9.1 1 (s, 2'-H) 288 (573, 168 (loo), 157 (17), 131 (21), 119 (20), 105 (36), 77 (44)and 69 (59) 1635 (W)and 3350 (NH) 4.82(d,J5.4,CH2),6.67(brs,NH),7.06(d,J5.2,4-H),7.25(d,J5.2,5-H),7.28-7.51(8H,m,Ar-H)and 7.68-7.74 (2 H, m, Ar-H) 294 (2179,293 (loo), 172 (20) and 69 (97) 1635 (W)and 3290 (NH) 4.65 (d, J 5.4, CH,), 6.59 (br s, NH), 7.10 (d, J 5.2,4-H), 7.24 (d, J 5.2, 5-H), 7.28-7.49 (8 H, m, Ar-H) and 7.667.72 (2 H, m, Ar-H) 293 (69), 105 (100) and 77 (31) 1645 (W)and 3355 (NH) a J-Values are given in Hz.The 'H NMR spectrum was also run in mixtures of deuteriochloroform and either perdeuterio-acetone or -DMF, the results are discussed in the text.FAB (glycerol). In 'H,DMF. CI' H CH2NHCOPh 37 and the product formulated as 35 have been determined by 2D 'H NMR COSY experiments.* The results are given in Table 5. The first key point is that all the four pyridine protons are still present in the spectrum of 35 and that they are all strongly deshielded in comparison to those in the amide 12g. A similar but weaker effect is seen in the spectrum of the hydrochloride salt 37of the amide 12g,thus supporting the contention that the new compound contains a quaternised nitrogen atom. Nuclear Overhauser experiments (NOE) on compound 35 also support the proposed structure, irradiation at position 1 produced an effect at positions 2 (1-5) and 11 (4) only, and at position 4 produced an effect at positions 3 (2) and 2' (1).The singlet at 6 5.14 in Fig. 1 is attributed to the presence of some of the imidoyl chloride 20g, Scheme 5, present in equilibrium with 35 in the ratio ca. 1: 3. This interpretation is supported by the fact that hydrolysis of the reaction mixture produced only the amide 12g. A preparative-scale reaction of the amide with chloro- dimethylformiminium chloride was carried out under identical conditions and after 12 h the reaction mixture was diluted with THF and treated with potassium tert-butoxide. Work-up gave 5-phenyl-7H-pyrido3,2-d2benzazepine 36 in ca. 70 yield. It seems like that it is formed in the usual way via the nitrile ylide 21g which itself may be formed either directly from the imidoyl chloride 20g or via the deprotonation and ring opening of compound 35, Scheme 5.The cyclisation of 21g thus apparently takes place normally at the free 'ortho' position and the only observable effect of the presence of the pyridine nitrogen atom is in the ring closure/opening equilibration of the imidoyl chloride 20g with compound 35. The reactions of the pyrimidin-2- and 5-yl amides 12h and 12i with thionyl chloride-dimethylformamide appear to be more complicated and will be reported in a later publication. (c) Ring Inversion of the Fused Azepines.-The results of the VT NMR studies on the tricyclic azepines are given in Table 6.The ease of ring inversion is clearly much affected by the size and nature of the fused heterocyclic ring. The replacement of one of the fused benzene rings in the dibenzazepine 4 (R = H) by pyridine, thiophene or furan makes the system progressively more flexible. The trend is consistent with earlier work on fused diazepines in which it was found that replacement of a fused I3 c bsol;o bsol;oP Table 3 Yields and physical data on the heterocyclic-fused benzazepines Cryst. M.p. B.p. Molecular c () euro;3 (I N () mlz (M+)Compound Method" Yield () ("C) ("C) formula Found Calc. Found Calc. Found Calc. Found Calc. 22 (i) 68 185-190 C18H 13NS 275.0775 275.0769 0.3 mmHgPicrate 88 237-238 Cz4Hl6N4oS 57.1 57.1 3.2 3.2 11.2 11.1 23 (2) 65 190-195 c1 8H 1 3NS 275.0771 275.0769 0.4 mmHg Picrate 92 235-236 CZ4Hl6N4OS 56.9 57.1 3.15 3.2 11.1 11.1 26 (ii) 69 H 10amp;108 Cl *H1,NS 78.6 78.5 4.7 4.8 4.9 5.1 275.0773 275.0769 28 (ii) 74 175-1 80 c,8H13NS 276.0847' 276.0847 0.3 mmHg 31 (i)/(ii)d 78 170-1 75 cl BH1 260.1075' 260.1075 0.3 mmHg 32 (ii) 81 not distilled CI9Hl4N2 270.1 155 270.1 157 33-34 (ii) 61 205-2 10 C19H14N2 270.1154 270.1 157 1:1.4 (ii) 0.1 mmHg (ii) 68 EA/H 186.5-187.5 ClP 14N2 270.1 143 270.1 157 a Method of imidoyl chloride formation Scheme 7.H = hexane, EA = ethyl acetate. 'For (M + I), FAB, glycerol. For details see text. 1200 J. CHEM. soc. PERKIN TRANS. 1 1994 Table 4 Spectroscopic data for the fused azepines Compound Spectroscopic data 4 (R=H)' 6, (298 K)' 3.77 (1 H, d, J 10.2), 4.87 (1 H, d, J 10.2) and 7.24-7.87 (13 H, m, Ar-H) 22 8, (298 K) 4.52 (br s, CH,) and 7.03-7.70 (1 1 H, m, Ar-H) (280 K) CH, -3.95 (d J 10.75) and 5.10 (d, J 10.75) mlz 275 (57), 274 (loo), 171 (28), 28 (98) 23 6H (298 K) 4.55 (br s, CH,) and 7.24-7.71 (1 1 H, m, Ar-H) (280 K) CH, -3.97 (d, J 11.2) and 5.13 (d, J 11.2) mlz 275 (51), 274 (100) and 171 (47) 26 6, (298 K) 4.50 (br s, CH,) and 7.1k7.77 (1 1 H, m, ArH) (275 K) CH, -3.93 (d, J 12.1) and 5.07 (d, J 12.1) mlz 276 (2023,275 (90), 274 (loo), 171 (37) and 59 (21) 28 6, (307 K) 4.41 (br s, CH,) and 7.06-7.76 (1 1 H, m, Ar-H) (250 K) CH, -3.70 (d, J 11.3) and 5.12 (d, J 11.3) mlz 276 (loo), 171 (20), 49 (26), 43 (31), 36 (21), 28 (98) 31 6, (298 K) 4.57 (br s, CH,), 6.94 (d, J 1.8,4-H fur) and 7.33-7.65 (10 H, m, Ar-H) (228 K) CH, -3.91 (d, J 11.2) and 5.23 (d, J 11.2) mlz 259 (loo), 128 (15), 105 (12), 77 (13), 44(lo), 36 (26) and 32 (25) 32 6, (307 K)' 3.83 (d, J 10.6, CH,), 4.95 (d, J 10.6, CH,), 7.41-7.63 (8 H, m, Ar-H), 7.80-7.91 (2 H, m, Ar-H), 8.53 (1 H, s, 2-H pyr) and 8.79 (1 H, d, J5.2, 6-H, pyr) (390 K) 4.89 (br s, CH,) mlz 270 (loo), 269 (61), 167 (24), 139 (14) and 120 (9) 33-34 6, (307 K)' 3.80(1 H,d, J11),3.91 (1 H,d, J11),4.93(1 H,d,J11),4.98(1 H,d,J11),7.2amp;8.00(21 H,m,Ar-H),8.18-8.36 (1 H, m, Ar-H) and 8.62-8.76 (2 H, m, Ar-H) (288 K) 4.46 (br s, 2 x CH,) mlz 270 (loo), 269 (64),167 (35) and 32 (21) 36 6, (298 K)' 3.99 (1 H, d, J 11.7), 4.98 (1 H, d, J 11.7), 7.43-7.60 (9 H, m, Ar-H), 7.79 (dd, J 7.9 and 144-H pyrido) and 8.06-8.16 (1 H, m, Ar-H), 8.95 (dd, J 4.5 and 1.8,6-H, pyridyl) (344 K) 4.49 (2 H, br s)6, (360 MHz) (298K)e 3.81 (1 H, d, J 10.6), 4.87 (1 H, d, J 10.6), 7.23-7.46 (7 H, m, Ar-H), 7.71 (1 H, dd, J7.9 and 1.8,4-H, pyr), 7.88 (2 H, br s, Ar-H), 8.02 (1 H, m, Ar-H) and 8.82 (dd, J4.7 and 1.8, 6-H pyr) mlz 270 (82), 269 (loo), 205 (23), 167 (42), 143 (27) and 31 (25) All NMR spectra in CDCl, at 80 MHz unless otherwise indicated.'For preparation and other spectra see ref. 1. 'C2H,DMS0. FAB (glycerol). C2H,DMF. Table 5 Chemical shifts of the pyridyl protons in 12g, 37 and 35 Position (6)35 Compound 1 2 3 4 1 7.56 7.83 7.29 8.64 37 8.02 8.44 7.88 8.85 (+0.46) (+0.61) (+0.59) (+0.21)35 8.67 8.95 8.23 9.18 (+l.ll) (+1.12) (+0.94) (+0.54)9.2 8.8 8.4 8.0 7.6 7.2 6.8 6.4 6.0 '5.6 5.2 4.8 I ppm Table 6 Coalescence temperatures and free energies for ring inversion AG Azepine Solvent TJ' C kJ mol-' 31 CDC1, -22 49.6 29 CDCl 2 54.5 23, picrate CDCl, 2 55.1 22,picrate CDCl, 17 58.3 9.2 8.8 8.4 8.0 7.6 7.2 6.8 6.4 6.0 5.6 5.2 4.8 26 CDCl, 23 59.3 PPm 23 CDCl, 24 59.5 Fig.1 22 CDCl, 28 60.3 36 (CD3)2So 71 69.7 334 (CD3)2S0 112 78.2 32 (CD3)2S0 115 78.6benzene ring with thiophene decreased the activation energy for 4,R = H (CD3)2S0 149 86.1ring inver~ion.~ This was rationalised in terms of the different effects of five- and six-membered rings on angle strain in the puckered and planar states.Other differences are not so easily explained. For example, it was suggested' that the high (d) ConcZusions.-This work has shown that electrocyclic activation energy for inversion of the dibenzazepine system 4 aromatic substitution using nitrile ylides is effective in forming was due largely to the increased steric interaction of the two azepines fused to a variety of heteroaromatic rings. In hydrogen atoms at positions 1 and 11 in the planar transition combination with the use of Pd" cross-coupling reactions as a state. The lower activation energy for 29 than 26 is consistent route to the nitrile ylide precursors, it provides an efficient with this but the situation is reversed for 22 and 23. general synthetic route from easily available starting materials J.CHEM. soc. PERKIN TRANS. 1 1994 to a range of tricyclic azepines with fused benzene and heterocyclic rings. In the case of the furan derivative 12d it has been shown that azepine formation occurs spontaneously uia uncatalysed electrophilic cyclisation of the imidoyl chloride 30. Similar reactions are not observed for the thiophene analogues. These results, in general, illustrate the distinctive features of the electrocyclic substitution process which make ring closure possible on to both electron rich and electron deficient aromatic rings, the latter being particularly important since alternative modes of cyclisation are not easily available. Experimental NMR spectra were run as solutions in deuteriochloroform unless otherwise stated.Chemical shifts are recorded as 6 values and J values are given in Hz. In the I3C spectra, carbon multiplicity was established by single-frequency, off-resonance decoupling or by DEPT. Mass spectra were obtained using electron ionisation at 70 eV unless otherwise stated. Preparative chromatography was carried out by the 'dry-column flash' technique using silica gel (1 5 pm, Fluka Fieselgel GF254) and eluting solvents based on light petroleum (b.p. 4040deg;C) admixed with ether or ethyl acetate. Ether refers to diethyl ether. Evaporation of solvents indicates evaporation under reduced pressure using a rotary evaporator. All drying of solutions was done with anhydrous magnesium sulfate. Solvents, Reagents and Starting Materials.-Tetrahydro furan (THF) was distilled under nitrogen from sodium diphenylketyl immediately before use.1 ,ZDimethoxyethane (DME) and N,N-dimethylformamide (DMF) were distilled from calcium hydride and stored over molecular sieves (4 A), the former was passed through a column of alumina immediately before use in the coupling reactions. 2-Bromobenzylamine hydrochloride and tetrakis(triphenylphosphine)palladium(o) were obtained from Aldrich Chemical Company and used without further purification. The following were prepared by literature routes and had the reported physical and spectroscopic properties: 2-thienyl- boronic acid, lo 3-thienylboronic acid,' ' phenylboronic acid (also obtained from Aldrich Chemical Company),' 3-furyl-boronic acid.' N-(2-Bromobenzyl)benzamide 10.-A mixture of 2-bromo- benzylamine hydrochloride (3.92 g, 17.6 mmol), anhydrous sodium carbonate (4.01 g, 37.8 mmol) and benzoyl chloride (2.64 g, 18.8 mmol) in dichloromethane (60 cm3)was stirred at room temperature for 1 h and then boiled under reflux for 30 min. After it had cooled, the reaction mixture was diluted with water (30 cm3) and dichloromethane (40cm3). The organic phase was then separated, dried and evaporated and the residue recrystallised from ethanol to give the product (4.78 g, 93) as white crystals, m.p. 133-134 "C (Found: C, 58.0; H, 4.3; N, 4.9. C,,H,,BrNO requires C, 58.0; H, 4.2; N, 4.8); 6,(80 MHz) 4.68 (d, J 6.0, CH,), 6.81 (br s, NH) and 6.98-7.82 (9 H, m, Ar-H); m/z (FAB), glycerol) 290 (M + 1, 98), 274 (54) and 257 (100); v,,,(Nujol)/cm-' 3300 (N-H) and 1640 (GO).2-(Benzylamidomethyl)phenylboronicAcid 13.-To a solution of the benzamide 10 (2 g, 7 mmol) in THF (50 cm3) under nitrogen at -78 "C were added dropwise firstly methyllithium (1.5 mol dm-3 solution in diethyl ether; 7.0 cm3) and then, after stirring for 1 h, tert-butyllithium (1.7 mol dm-3 solution in pentane; 12.2 cm'). After 1 h at -78 "C triisopropyl borate (9.2 cm3, 0.04 mol) was added to the mixture which was then allowed to warm to room temperature. The solution was acidified with hydrochloric acid (2 mol dmP3) and then stirred for 10 min. Separation, drying and evaporation of the organic layer and crystallisation of the resulting residue from dimethyl sulfoxide (DMSOFwater gave the title compound (1 SO g, 84), m.p.170-173 "C (Found: C, 66.0; H, 5.6; N, 5.4. C14H14BN03 requires C, 65.9; H, 5.5; N, 5.5); dH(360 MHz; C2H6DMS0) 4.63 (d, J6.1, CH,), 7.20-7.66 (7 H, m, Ar-H), 7.92 (d, J7.4, 2'-H), 8.32 (2 H, s, OH) and 9.00 (br s, NH); NOE: irradiation of B(OH), affected only 6-H (5) and CH, (3), and of CH, affected only 3-H (4), B(OH), (4) and NH (10); dB(36O MHz; C2H,DMSO) 31.44 (s, B-OH); m/z 238 (1 l), 212 (lo), 167(20), 149(100), 117(19), 105(97),91(63),85(20),74(72),58 (83), 48 (38), 42 (67) and 30 (36); v,,(Nujol)/cm-' 3350 (OH), 3260 (N-H) and 1610 (M). Preparation of the Amides 12 (Scheme 1: Routes 1 and 2).- The general method is exemplified below for the preparation of N-(2-phenylbenzyl)benzamide 12a.Compounds 12a-d were prepared via Route 1 and 12a, d, e, g-i uia Route 2. Compound 12f was prepared by a reaction similar to that in Route 1 but using diethylpyridylborane ' under the same reaction condi- tions as below. In all cases the reactions were monitored by HPLC, using conditions similar to those given for 12a below. The yields, reaction times and physical properties are given in Table 1 and the spectroscopic characteristics in Table 2. N-(2-Phenylbenzyl)benzamide12a.-The benzamide 10 (3 g, 10.3 mmol) and tetrakis(triphenylphosphine)palladium(o) (0.36 g, 0.3 mmol) were added to DME (50 cm3) with stirring under dry nitrogen. After 20 min a solution of sodium carbonate (anhydrous, 1.09 g, 10.3 mmol) in water (15 cm3) and phenyl- boronic acid (1.51 g, 12.4 mmol) were added to the mixture which was then boiled under reflux.Monitoring by HPLC (5 pm silica ODs, 20 water in methanol) indicated complete consumption of starting material after 5 h. The DME was evaporated and the mixture was extracted with ethyl acetate. Drying and evaporation of the extract gave a brown solid. (In cases where the crude product was very dark, the most effective way to remove the colour was to pre-adsorb the mixture6 onto alumina before dry -column flash chromatography on silica.) Dry-column flash chromatography (silica, ethyl acetate-hexane, 1 :9) gave the title compound 12a as a white crystalline solid (2.54 g, 86). 2-(Benzamidomethyl)-3-phenylthiophene16 via Scheme 2.- 3-Phenylthiophene-2-carbaldehydeoxime. 3-Phenylthiophene, m.p.88-89 "C (lit.," 89.5-90.5 "C), was prepared (91) by the method of Suzuki and converted into 3-phenylthiophene-2- carbaldehyde (76), m.p. 35-36 "C (lit.,4 36-36.5 "C) by the Gronowitz method. The latter (4.5 g, 24 mmol), on reaction at room temp. with a solution of hydroxylamine hydrochloride (1.81 g, 26 mmol) and sodium acetate (2.21 g, 26 mmol) in water (20 cm3) gave the corresponding oxime (2.98 g, 61), m.p. 115-116 "C (from ethanol) (Found: C, 64.9; H, 4.3; N, 6.9; M+, 203.0408. C,,H,NOS requires C, 65.0; H, 4.5; N, 6.9; M, 203.0405); 6,(80 MHz) 7.11 (d, J 5.2, 4-H), 7.33 (dd, J 5.2 and 0.7, 5-H), 7.40 (5 H, m, phenyl), 8.30 (d, J 0.7, CH) and 8.45 (br s, OH); m/z 203 (65), 202 (96), 186 (100) and 115 (37); vmax(Nujol)3180 cm-' (OH).2-(Aminomethyl)-3-phenylthiophene.The above oxime (3.30 g, 16.2 mmol), zinc dust (8.49 g, 0.13 mol), ammonium acetate (1.00 g, 13 mmol), aqueous ammonia (d 0.88; 97 cm3) and ethanol (50 cm3) were boiled under reflux for 18 h. The mixture was then evaporated and the residue stirred with aqueous potassium hydroxide (33 w/v; 100 cm3). Ether (30 cm) was added to the mixture which was then filtered through a pad of Celite. The organic layer was then separated, dried and evaporated to leave 2-(aminomethyl)-3-phenylthiopheneas a brown oil (2.89 g, 94). This product was used without further purification (Found: M+, 189.0609. C1 ,H,,NS requires M, 189.0612);6,(200 MHz) 1.62 (br s, NH,), 4.10 (s, CH,), 7.06 (d, J 5.2,4-H), 7.23 (d, J 5.2, 5-H) and 7.24-7.47 (5 H, m, Ar-H); m/z 189 (loo), 188 (78), 173 (27), 171 (32) and 112 (24); v,,,(film)/cm-' 3375 (NH).The thiophene 16.The crude amine obtained above (2.8 g, 14.8 mmol) was benzoylated by the method described above for compound 10.Dry-column flash chromatography (silica, ethyl acetate-petroleum, 1:3) gave the product as white crystals (3.63 g, 88), m.p. 117-1 18 "C (from ethanokyclohexane). Its physical and spectroscopic properties are given in Tables 1 and 2. 3-(Benzamidomethyl)-2-phenylthiophene17 (Scheme 3).-2-Bromo-3-(bromomethyl)thiophene.A mixture of N-bromosuc- cinimide (19.58 g, 0.11 mol) and benzoyl peroxide (0.4 g, 1.65 mmol) was added portionwise to a refluxing solution of 2- bromo-3-methylthiophene (20 g, 0.1 1 mol) ' and benzoyl peroxide (0.4 g, 1.65 mmol) in dry carbon tetrachloride.The solution was boiled under reflux for a further 3 h, cooled and the succinimide filtered off. The filtrate was evaporated and the residue fractionated to yield 2-bromo-3-(bromomethyl)thio-phene (22.74 g, SIX), b.p. 78-82 "C/1 mmHg (lit., 88-90 "C/4 mmHg); SH(60 MHz) 4.47 (s, CH,), 7.00 (d, J 6, 4-H) and 7.25 (d, J 6, 5-H). 2-Bromo-3-(phthalimidomethyl)thiophene.A solution of 2- bromo-3-(bromomethyl)thiophene(8 g, 0.03 mol) and potas- sium phthalimide (12.97 g, 0.07 mol) in DMF (50 cm') was stirred at room temperature for 90 rnin and then warmed to 45 "C for 90 min.The mixture was evaporated under high vacuum and dichloromethane (30 cm3) was added to the residue. The mixture was washed with aqueous sodium hydroxide (2 mol drn-'; 2 x 20 cm') and water (2 x 10 cm'), dried, and evaporated and the residue recrystallised from ethanol to give 2-bromo-3-(phthalimidomethyl)thiophene (7.58 g, 7979, m.p. 97-99deg;C (Found: C, 48.4; H, 2.4; N, 4.2; M+ + H (FAB, glycerol), 321.9537. C,,H,BrNO,S requires C, 48.6; H, 2.5; N, 4.4; M + H, 321.9537); 6H(200 MHz) 4.80 (~,CH,),6.96(d,J5.7,4-H),7.17(d,J5.7,5-H),7.66-7.74(2H, m, Ar-H) and 7.78-7.88 (2 H, m, Ar-H); m/z(FAB, glycerol) 322 (M + 1, 96), 321 (loo), 274 (47), 257 (50) and 160 (26); vmax(Nujol)/cm-l 17 10 (M). 3-Aminomethyl-2-bromothiophene.A solution of 2-bromo-3- (phthalimidomethy1)thiophene (3.5 g, 1 1 mmol) and hydrazine hydrate (100 solution; 3.4 cm') in methanol (40 cm') was stirred for 1 h at room temp.and then at reflux for 10 min. The insoluble phthaloylhydrazide was filtered off and the filtrate evaporated. Ether (20 cm') and water (20 cm3) were added to the residue after which the organic layer was separated and extracted with aqueous hydrochloric acid (2 mol dm-3; 2 x 10 cm3). The acidic extract was basified with aqueous sodium hydroxide (2 mol dm-'; 2 x 25 cm3) and extracted with dichloromethane (2 x 20 cm'). Separation, drying and evapor- ation of the organic layer gave a brown oil which was distilled (Kugelrohr) to give 3-aminomethyl-2-bromothiopheneas a brown oil (1.15 g, 55); b.p.94-97 "C/0.03 mmHg (Found: M+, 190.9388. CSH,BrNS requires M, 190.9404; dH(200 MHz) 1.74 (br s, NH), 3.72 (s, CH,) and 6.94 (2 H, m, Ar-H); m/z 191 (78), 190 (77), 112 (49), 84 (52) and 69 (100); vmax(Nujol)/cm-' 3 140 (NH). The thiophene 17.3-Aminomethyl-2-phenylthiophene(0.84 g, 4.4 mmol) was benzoylated by the method described above for compound 10.Dry-column flash chromatography (silica, ether- petroleum, 1 :4) gave the product as white crystals (0.79 g, 61), m.p. 11 1-1 12 "C (from ethanol-hexane). Its physical and spectroscopic properties are given in Tables 1 and 2. Preparation of the Imidoyl Chlorides from Amides 12b,e, f, 16 and 17and their Base-promoted Cyclisation to give Heterocyclic- J.CHEM. SOC. PERKIN TRANS. 1 1994 fused Benzazepinex-The amides were converted into imidoyl chlorides by either of the two general methods shown in Scheme 4 and illustrated below for compounds 12band 16.The method used in each case is indicated in Table 3. The imidoyl chlorides were then cyclised by the general method given below to give the fused azepines 22, 23, 26, 29, 32, 33 and 34.The yields and physical characteristics of the products are given in Table 3. Conversion of N-2-(2-thienyl)benzyl)benzamide 12b into N-2-(2-thienyl)benzylbenzimidoylchloride 20band cyclisation to give 4-phenyl-6H-thieno3,2-d2)benzazepine22.N-2-(2-Thi-eny1)benzyl)benzamide (0.50g, 1.7 mmol), dry ether (30 cm') and thionyl chloride (10 cm3, 0.14 mol) were heated overnight at reflux, under a dry nitrogen atmosphere.The solvent was evaporated and the residue kept under high vacuum for 3 h. Dry THF (25 cm') was added to the residue and the mixture cooled to 0 "C. Solid potassium tert-butoxide (0.38 g, 3.4 mmol) was then added to it in one portion with rapid stirring under dry nitrogen. The mixture was stirred for 30 rnin at 0 "C, allowed to warm to room temp. and stirred for a further 30 min. The solution was treated with aqueous ammonium chloride (25 w/v) and stirred for 10 rnin and then diluted with di-chloromethane (20 an3).The organic layer was separated and the aqueous layer extracted with dichloromethane (2 x 10 cm'). The combined organic layer and extracts were dried and evaporated to provide an oil.Dry-column-flash chromato- graphy of this (silica, ethyl acetate-petroleum, 1:9) followed by Kugelrohr distillation gave compound 22 as an oil (0.32 g, 6879, b.p. 185-190 "C/0.3 mmHg. Picrate salt of compound 22.Picric acid (1.17 g, 5.1 mmol) was washed with ethanol (3 x 3 cm'), dried on filter paper and dissolved in acetone (4 cm'). To this was added compound 22 (0.25 g, 0.9 mmol) in acetone (2 cm').After 30 rnin stirring at room temp., the product was filtered off to give yellow needles (0.40 g, 88), m.p. 237-238 "C. Conversion of compound 16 into N-(3-phenyl-2-thienylmeth-y1)benzimidoyl chloride 24 and cyclisation to give 6-phenyl- 4H-thieno2,3-d2benzazepine26. Thionyl chloride (0.46 CM', 6.3 mmol) was added dropwise to a solution of 2-benz- amidomethyl-3-phenylthiophene(1-50 g, 5.1 mmol) in dry DMF (6.14 g, 0.08 mol) at room temp. and the mixture was then stirred for 30 min.The solvent was removed under high vacuum at 30-35 "C for 3 h. THF (60 cm') was added to the residue and the mixture cooled to 0 "C under nitrogen. Solid potassium tert-butoxide (3.24 g, 0.03 mol) was added in one portion to the mixture which was stirred for 30 rnin at 0 "C, and then 30 rnin at room temp. The solution was treated with aqueous ammonium chloride (25 w/v), stirred for 10 rnin and then diluted with dichloromethane (30 cm'). The organic layer was separated and the aqueous layer extracted with dichloromethane (2 x 10 cm'). The combined organic layer and extracts were dried and evaporated.Dry flash chromatography of the residual oil (silica, ether-petroleum, 1:9) followed by crystallisation gave fawn crystals of compound 26 (0.97 g, 69), m.p. 106-108 "C (from hexane). Cyclisation of N-2-(3-Furyl)benzylbenzamide12d to give 4-Phenyl-6H-fur02,3 -d) 2)benzazepine 31.-Using thion yl chloride-DMF. A mixture of compound 12d (100 mg, 0.36 mmol), dry DMF (2 cm') and thionyl chloride (60 mg, 0.54 mmol) was stirred overnight at room temp., after which the solvent was removed under high vacuum at 30-35 "C for 3 h. Dichloromethane (10 cm') and water (10 cm3) were added to the mixture and the organic layer was separated; the aqueous layer was then extracted with dichloromethane (2 x 5 cm'). The combined organic layer and extracts were dried and evaporated and the residue was distilled (Kugelrohr) to give compound 31 as an oil (73 mg, 78), b.p.170-175 "C/0.3 mmHg. J. CHEM. soc. PERKIN TRANS. 1 1994 Using thionyl chloride-ether. This conversion was also carried out in 83 yield by heating under reflux overnight a mixture of compound 12d (50 mg, 0.18 mmol) dry ether (5 cm3) and thionyl chloride (1.71 g, 14.4 mmol). Reaction of N-2-(2-Pyridyl)benzylbenzamide 12g with Chlorodimethylformiminium Chloride and Cyclisation to give 5-Phenyl-7H-pyrido3,2-d2benzazepine.-The first part of this reaction was carried out under similar conditions and with the same relative concentrations of reagents as in the NMR study below. A solution of chlorodimethylformiminium chloride in DMF was prepared in a flask equipped with a Suba-seal by adding thionyl chloride (0.908 g, 7.63 mmol) to dry DMF (9.719 g, ca.10 cm3). After this solution had been kept at room temp. for 20 min a portion (3.70 an3,2.69 mmol) was added by syringe to compound 12g (0.516 g, 1.79 mmol) in a flask equipped with a Suba-seal. The amide dissolved rapidly to give a clear yellow solution. After 12 h at room temp. the solution was diluted with dry THF (20 cm3), cooled to 0deg;C and potassium tert-butoxide (freshly sublimed) (0.91 g, 8.07 mmol) was added in one batch with vigorous magnetic stirring. A dark and persistent colour developed immediately. The solution was kept at 0 "C for 15 min and then at room temp.overnight. Work-up (see above) gave, after dry-column flash chromatography (silica, ethyl acetate-hexane, 1 :4), compound 36 (0.33 g, 68), m.p. 186.5-187.5 "C (from hexane-ethyl acetate). NMR Studies of the Reactions of the Amides 12a, 12e and 12g with Chlorodimethylformiminium Chloride.-The spectra obtained in these experiments are discussed in the Results and Discussion section and, for 12g, shown in Fig. 1. N-(2-PhenyZbenzyl)benzamide12a. Thionyl chloride (36 mg, 0.3 mmol) was added by syringe to C2H7DMF (0.25 cm3) contained in a glass vial fitted with a Suba-seal closure. After 5 min, the solution syringed into a solution of compound 12a (50 mg, 0.2 mmol) in 'H,DMF (0.40 cm3)contained in an NMR tube equipped with a septum cap. The resultant mixture was examined by 'H NMR over 12 h.The first spectrum was obtained after 15 min, the last after 12 h. N-2-(4-Pyridyl)benzylbenzamide1. A similar experiment was carried out using compound 12e (50 mg, 0.2 mmol) in 'H,DMF (0.40 cm3) and thionyl chloride (36 mg, 0.3 mmol) in 'H,DMF (0.25 cm3). The resultant mixture was examined by 'H NMR over 16 h. N-2-(2-Pyridyl)benzylbenzamide12g. (a) A similar experi- ment was carried out using compound 12g (50 mg, 0.2 mmol) in 'H,DMF (0.40 cm3) and thionyl chloride (36 mg, 0.3 mmol) in 'H,DMF (0.25 cm3). The resultant mixture was examined by 'H NMR over 22 h. (b) A COSYPHDQ.AU experiment was also run on the sample after 22 h using the following parameters: (360 MHz) S12 = 1024, SI1 = 512; SW2 = 1098.901, SWl = SW2/2 = 549.451; recycle delay (DI) = 3 s, DO = 3 ms, D3 = 3 ms; incremented delay (IN) = 455 ms; PI = 90" pulse, 8 ms; no.of FIDs (NE) = 256; no. of scans (NS) = 48. An NOE experiment was carried out. Irradiation of the doublet at 6 4.73 was carried out in an attempt to observe a saturation transfer effect on the doublet at 6 4.91, however, this experiment resulted only in an NOE of 14. This sample was alsowarmed but no coalescence of the doublets was observed up to 80 "Cwhen the compound degraded. (c) After a similar experiment monitored by NMR, the reaction mixture was treated with aqueous sodium carbonate and gave a product which by 'H NMR contained only the amide 12g. For comparison purposes 2D 'H NMR spectra were also run on the amide 12g and its hydrochloride salt 37.The chemical shifts of the pyridyl protons are shown in Table 5.Acknowledgements We thank the SERC and Glaxo Group Research for a CASE Studentship (D. H. R.). References 1 K. E. Cullenand J. T. Sharp, J. Chem. SOC., Perkin Trans. 1,1993,2961. 2 K. E.Cul1enandJ.T. Sharp, J.Chem. SOC., Chem. Commun., 1991,658. 3 N. Miyaura, T. Yanagi and A. Suzuki, Synth. Commun.,198 1,11,5 13. 4 S. Gronowitz, V. Bobosik and K. Lawitz, Chem. Scr., 1984,23,120. 5 J. T. Sharp and C. E. D. Skinner, Tetrahedron Lett., 1986,27,869. 6 J. T. Sharp, I. Gosney and A. G. Rowley, in Practical Organic Chemistry, a Student Handbook of Techniques,Chapman and Hall, London, 1989. 7 T. K. Miller and J. T. Sharp, J. Chem. SOC., Perkin Trans. 1,1984,223. 8 Various authors in Comprehensive Heterocyclic Chemistry, eds. A. R. Katrisky and C. W. Rees, Pergamon Press, 1978, London. 9 D. P. Munro and J. T. Sharp, J. Chem. SOC., Perkin Trans. 1, 1980, 1718. 10 J. R. Johnson, M. G. Van Campen and 0.Gummitt, J. Am. Chem. SOC.,1938,60, 1 1 1. 11 S. Gronowitz and N. Gjm, Acta Chem. Scand, 1967,21,2823. 12 F. R. Bean and J. R. Johnson, J.Am. Chem. SOC., 1932,54,4415. 13 B. P. Roques, D. Fluorentin and M. Callanquin, J. Heterocycl. Chem., 1975,12,195. 14 M. Terashima, H. Kakimi, M. Isikikura and K. Kamata, Chem. Pharm. Bull., 1983,31,4573. 15 J. A. Blanchette and E. V. Brown, J.Am. Chem. SOC., 1951,79,2779. Paper 3/07 1491 Received 3rd December 1993 Accepted 10th January 1994
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