Nucleophilic displacements ofN-aryl and heteroaryl groups. Part 3. Pyrylium-mediated synthesis of unsymmetrical diarylamines from anilines

摘要

J. CHEM. SOC. PERKIN TRANS. I 1983 261 1 Nucleophilic Displacements of N-Aryl and Heteroaryl Groups. Part 3.' Pyryl ium -med iated Synthesis of Unsymmet rical Diarylamines from AniI ines Alan R. Katritzky and Andrew J. Cozens Department of Chemistry, University of Florida, Gainesville, Fla. 3261 1,U.S.A., and School of Chemical Sciences, University of East Englia, Norwich, NR4 7JJ 2-Ethoxycarbonyl-4,6-diphenylpyrylium salts (1) reacted with various ring-substituted anilines to give the corresponding pyridinium salts (2) (average yield 90) ; these were hydrolysed to the pyridinium betaines (3) (75) and treated with thionyl chloride followed by an aniline to give the amides (4) (70).Refluxing in toluene with sodium hydride for 12 h transfers intramolecularly the 1 -aryl group of the pyridinium salt (4) to the nitrogen of the amide.Aqueous work-up cleaves (6) and the diarylamine is purified by sublimation (60) (overall yield ca. 30). Diarylamines have been prepared from anilines by copper- catalysed condensation with an aryl halide, the Ullmann reaction,2a typically in pentyl alcohol at 130 "Cin the presence of a base to remove the liberated hydrogen halide. The yields of diarylamines are strongly dependent on the nature of the ring substituents. Activating groups in the aryl halide give rise to good yields (80-90) whilst their absence leads to greatly reduced yields as does low nucleophilicity of the aniline as caused by electron-withdrawing meta-or para-or any ortho-substituents.2b For diarylamines that contain no nitro or carboxy groups, the Goldberg reaction 3*4 can be used; the aniline is first con- verted into an N-acylaniline and then treated with aryl halides in nitrobenzene at 180 "Cand finally hydrolysed.Diarylamines also result by treating an aniline with a phenol5 at 250 "C with antimony trichloride as a catalyst. Nitrobenzene and phenylmagnesium bromide were reported to give diphenylamine (45).6 Certain symmetrical diaryl- amines are formed by pyrolysis of equimolar amounts of the aniline and its hydrochl~ride.~ Another method of preparing diarylamines is the Smiles rearrangement of amide~,~ but this requires a strongly elec- tron-withdrawing group ortho or para to the displaced group. All diarylamines prepared by this method contain at least one nitro substituent.The amide is refluxed in ethanolic sodium ethoxide for 15-20 min, and yields are generally 60-80 depending on the degree of acti~ation.~ The five-step synthesis of diarylamines from anilines via the Chapman rearrangement of imino ethers (Scheme 1) *JOJ~ gives overall yields of ca. 30. The anilines and acid chloride form the amides (75) which are converted by phosphorus pentachloride into imino halides (70).13 Treatment with a substituted phenol forms the imino ethers (700/0),14 which undergo thermolysis (200-300 "C) to the amides and on hydrolysis give diarylamines (85-90). Electron-withdraw-ing groups in the displaced aryl nucleus enhance the rearrange- ment, whereas reduced yields are obtained if electron-donating substituents are present? PCl5 RCOCl -k ArNH2 --+ RCONHAr -RCCI: NAr IAr'OH tOH-Heat ArAr'NH -RCONArAr' -RC(0Ar'):NAr None of the aforementioned methods constitutes a general preparation of diarylamines containing thermally sensitive but no activating substituents.Our search for a mild method for the conversion of anilines into other functionalities via pyridinium salts has demon- strated l5 that, whereas intermolecular nucleophilic displace- ments of 1-aryl substituents occurs only at high temperature, if at all, if a suitable nucleophilic centre is built into the molecule intramolecular nucleophilic displacement can occur under relatively mild conditions. Such displaced aryl groups need not contain activating ~~b~tifuents.*~'~ We now describe a Ar (2) Ph -Ph vi Phnc+oN+ II Ar N H Ar' /.i i Ph + ArAr'NH PhQc+o I Nt3+ Ar ONAr' (7 1 (6) (For designations of Ar and Ar' in (2), (3), (4), (3,(6), and (8) see Tables 1, 3, 5, and 7) Scheme 1.Preparation of diarylamines by the Chapman rearrange- Scheme. Reugents: i, ArNH2; ii, NaOH-H20; iii, SOClz; iv, ment Ar"H2; v, HBF,; vi, PhMe-NaH; vii, Heat; viii, HzO 2612 J. CHEM. SOC. PERKIN TRANS. I 1983 Table 1. Preparation of l-aryl-2-ethoxycarbonyl-4,6-diphenylpyridiniumsalts Found () (Required )Time Yield r-PCompd. 1-Substituent Anion Solvent (h) () M.p." ("C) C H N (2a) Ph BF4 CHzCIz 2 95 184-186' (2a) Ph CF3SO3 CHzClz 3 90 160-162 61.2 4.1 2.6 (61.2 4.2 2.7)67.3 5.0 2.9 (67.0 4.8 2.9)59.8 4.3 2.5 (59.7 4.4 2.6)(2C) 4-ClGH4 BF4 CHzClz 3 77 185-187 62.2 4.0 2.7 (62.2 4.2 2.8)(2d) 4-MeOC6H4 BF4 CHzClz 3 92 176-177 64.9 4.9 2.8 (65.2 4.8 2.8)(2e) 4-NOzC6H4 BF4 EtOH 8 84 189-190 60.6 4.1 5.4 (60.9 4.1 5.5) Recrystallised from 95 EtOH. Lit.,'* m.p.185-186 "C. Table 2. *HN.m.r." of 1-aryl-2-ethoxycarbonyl-4,6-diphenylpyridiniumsalts Aromatic protons of 1-substituent 0-0-3-CH 5-CH (m) CHzCH3 CHzCHj h(1 H, d, (1 H, d, 4,6-Diphenyl (2 H, q, (3 H, t, Other Compd. 1-Substituent J 2) J 2) (10 H, m) 6 H 6 H J 7) J7) (3 H, s) (2a) Ph 8.30 8.10 7.25-7.65 7.80 3 6.90 2 4.15 1.05 -(2b) 4-MeC6H4 8.35 8.05 7.20-7.60 7.80 2 6.90 2 4.10 0.95 2.22 (2C) 4-ClC6H4 8.45 8.05 7.25-7.60 7.80 2 7.10 2 4.20 1.05 -(2d) 4-MeOC 8.40 8.15 7.15-7.60 7.80 2 6.75 2 4.20 1.10 3.78 (2e) 4-NOzC6H4 8.30 8.15 7.10-7.45 7.75 2 7.05 2 4.30 1.15 -G(CDC13),J in Hz.Table 3. Preparation of 1 -aryl-4,6-diphenylpyridinium-2-carboxylates Found () Required () AYield a r-7 Molecular r-v Compd. 1-Substituent () M.p. ("C) C H N formula C H N (3a) Ph 85 150-151 81.6 4.9 3.8 Cz4Hi,NO2 82.0 4.9 4.0 (3 b) 4-MeC6H4 86 162-1 63 82.2 5.2 3.8 CzSH19NOz 81.8 5.1 3.6 (3C) 4-ClCsH4 73 146-148 71.1 4.5 3.5 CZ~H~~C~NOZ.H~O71.4 4.5 3.5 (3d) 4-MeOC,H4 69 141-142 71.4 4.9 3.1 C2sH1sN03.2HzO 71.6 4.5 3.3 (3e) 4-NO2CsH4 68 155-156' Reactions carried out in water at 25 "C for 24 h. 'Lit.," m.p. 150 "C. Hygroscopic, characterised from spectral data.method of preparing diarylamines from anilines via 1-aryl-ethoxide failed. However pyridinium betaines (3a-d) re-pyridinium salts which have an amide functionality at the 2- fluxed in dichloromethane with thionyl chloride and pyridine position. gave the acid chloride, converted in situ by an added aniline into the 2-(N-arylcarbamoyl)pyridinium salts (4a-i) (ca. Preparation of 1-Aryl-2-ethoxycarbonyl-4,6-diphenylpyrid-70) (Table 5). inium Salts (2) and the Corresponding Betaines (3).-2-Ethoxy-carbonyl-4,6-diphenylpyrylium (1) tetrafluoroborate l6 and Intramolecular Rearrangement of 2-(N-ArylcarbamoyZ)-trifluoromethanesulphonate were prepared as previously pyridinium Salts (4).-Initially, 2-(N-arylcarbamoyl)pyridin-described from benzylideneacetophenone and ethyl pyruvate.ium salts (4) were treated with base at 25 "C in attempts to The pyrylium salts (1) smoothly reacted with a series of ring- form the amido anion (5) as an isolable zwitterion; experi- substituted anilines in dichloromethane to give l8 the cor-ments using bases such as hydride and ethoxide in tetra- responding pyridinium salts (2a-e) (ca. 90) (Table 1). hydrofuran or ethanol indicated, however, that complete Basic hydrolysis of (2a-e) with aqueous sodium hydroxide at conversion into the amido anion did not occur. Amide anions ambient temperature gave l8 the corresponding betaines are frequently difficult to isolate." However reaction in re- (3a-e) (ca. 75) (Table 3). fluxing toluene with sodium hydride forms the amide anion (5) in situ and causes spontaneous rearrangement into the pyri- Preparation of l-Aryl-2-(N-arylcarbanzoyl)-4,6-diphenyl-dine derivative (6).Removal of the solvent and addition of pyridinium Salts (4).-Initial attempts to prepare the pyridin- water results in cleavage of (6) into the sodium salt of 2,4-ium amides (4)by reaction of 2-ethoxycarbonylpyridinium diphenylpicolinic acid (7) and the diarylamine (8). The acid salts (2) with aniline and also in the presence of bases such as (7) was obtained on acidification. The diarylamine (8) was 2613J. CHEM. SOC. PERKIN TRANS. I 1983 Table 4. 'H N.m.r." of 1-aryl-4,6-diphenylpyridinium-2-carboxylates Aromatic protons of 1-substituent3-CH 5-CH (1 H, d, (1 H, d, 4,6-Diphenyl (m) > OtherI Compd.1-Substituent J 2) J 2) (10 H, m) 6 H 6 €3 (3 H, s) (34 Ph 8.15 7.94 7.30-7.42 7.64 3 7.05 2 -(3b) 4-M 8.18 7.90 7.30-7.53 7.66 2 7.05 2 2.26 (3c) 4-ClC6H4 8.08 7.87 7.25-7.45 7.60 2 7.15 2 -(34 4-MeOC6H4 8.12 7.88 7.25-7.50 7.60 2 7.10 2 3.75 (3e) 4-NOzCsH4 8.05 7.90 7.28-7.45 7.65 2 7.05 2 -6(CDC13),J in Hz. Table 5. Preparation of 1-aryl-2-(N-arylcarbamoyl)-4,6-diphenylpyridiniumtetrafluoroborates Found ()(Required )I + Time YieldCompd. N-Ar CONHAr' (min) () M.p." ("C) r C H N 3 Molecular formula 80 68 141 -1 43 67.6 4.9 5.3 C~~H~JBF~N~O*H~O (67.7 4.7 5.3) 135 72 245-247 70.4 4.8 5.3 (70.5 4.8 5.3)75 65 265-267 73.2 5.0 5.2 (73.3 5.0 5.2) 135 70 252-254 63.7 4.5 4.8 (64.0 4.5 4.8)135 63 257-259 68.6 4.7 5.0 (68.8 4.8 5.0) 135 72 248-250 68.5 4.7 -(68.8 4.8 5.0) 135 60 238-240 63.8 4.6 4.8 (64.0 4.5 4.8)75 68 270-272 66.7 4.6 4.9 (66.9 4.7 4.9)135 74 185-1 88 69.8 5.0 -(69.4 5.1 4.4) a Obtained as needles, recrystallised from methanol.obtained by sublimation at 150-180 "C/3.5 mmHg (ca. 60) state. Dipolar Meisenheimer spiro complexes have been (Table 7). observed 2o as intermediates in aryl migrations. Such com- plexes have been postulated for Smiles, Chapman, Stevens, 'H N.m.r. Spectra.-All the compounds were characterised and Newman-Kwarts rearrangements 21 and are likely to be spectroscopically. l-Aryl-2-ethoxycarbonyl-4,6-diphenyl-formed in the presently reported reaction. pyridinium salts (2a-e) and the corresponding betaines (3a-e) show characteristic 'H n.m.r. spectra in complete Synthetic Utility of Present Material.-This synthesis of accord with previously described l8 members of these com- diarylamines from anilines has synthetic potential as well as pound classes.The 3-CH and 5-CH signals appear as doublets mechanistic interest. The overall yields are comparable to (J2 Hz) in the region of 6 8.1 and 8.3 respectively; the ethyl those obtained from the Chapman rearrangement from ester groups of (2a-e) are seen near 6 4.1 and 1.0 and are anilines, however activation is not needed and the process absent from the betaines (3a-e) (Tables 2 and 4). does not require the use of high temperatures. The pyridinium substituted amides (4a-i) show 3-CH and 5-CH doublet resonances at 6 9.0 and 8.7 (J 2 Hz) shifted downfield possibly due to the anisotropic effects of the aryl- Experimental amido group.'H N.m.r. spectra were recorded with a Varian EM 360L The pyridinium 1-aryl group shows the two protons closest spectrometer using Me4 as a standard. 1.r. spectra were to the electronegative atom shifted downfield at 6 8.3, the obtained using NaCl plates on a Perkin-Elmer 283B spectro- remaining protons are observed at ca. 6 7.2. The aryl group photometer as solutions in CHBr3. Melting points were record- of the amide function is seen at 6 7.20-7.60, NH as a broad ed on a Kofler hot-stage apparatus and are uncorrected. singlet at ca. 6 2.5. The following were prepared by using literature methods: 2-ethoxycarbonyl-4,6-diphenylpyrylium tetrafluoroborate Mechanism.-Our results show that nucleophilic substitu- (m.p.153-155 "C; lit.,16 m.p. 154 "C) and trifluoromethane- tion of an unactivated aryl nucleus occurs if the system is sulphonate (m.p. 182 "C; lit.,17 m.p. 182-183 "C). designed so that the nucleophile is held in close proximity to the carbon which bears the leaving group. In this system aryl General Method for the Preparation of 1 -Aryl-2-ethoxy- displacement occurs via a five-membered transition state; carbonyl-4,6-d@henylpyridinium Tetrafluoroborates and Tri-previous results 1*15 in which aryl displacement occurs, using fluoromethanesulphonates (2).-The arylamine (3.3 mmol) a different system, involved a six-membered cyclic transition was added at 25 "C to a suspension of 2-ethoxycarbonyl-4,6- 2614 J. CHEM.SOC. PERKIN TRANS. I 1983 Table 6.'H N.m.r." of 1-aryl-2-(N-arylcarbamoyl)-4,6-diphenylpyridiniumtetrafluoroborates 3-CH 5-CH -r (1 H, d, (1 H, d, 4,6-Diphenyl-HN-Ar J 2) J 2) (10 H, m) 9.08 8.75 7.35-7.85 8.72 8.55 7.42-7.98 9.05 8.73 7.30-7.83 9.13 8.83 7.3 3-8 .OO 9.00 8.72 7.32-7.80 9.03 8.76 7.30-7.93 8.95 8.65 7.20-7.80 9.02 8.75 7.30-7.9 1 9.07 8.77 7.50-7.97 ArH 7 -(m) NH CH3 Compd. 6 H 6 H (1 H, s) (3 H, s) 8.30 2 7.20 3 7.20-7.50 2.44 -8.00 2 7.28 3 7.28-7.60 2.45 2.44 8.30 2 7.20 2 7.20-7.55 2.50 2.20,2.26 8.43 2 7.26 2 7.16-7.66 2.56 2.27 8.32 2 7.20 2 7.20-7.55 2.46 2.25 3.66 8.33 2 7.23 2 7.15-7.60 2.43 2.13 3.66 8.23 2 7.10 2 7.10-7.50 2.33 2.10 -8.34 2 7.1 5 2 7.15-7.60 2.42 -3.63, 3.65 8.36 2 7.20 2 7.20-7.46 2.43 2.13 Table 7.Preparation of diarylamines Subln. pressure Lit. M.p. Compd. Ar Ar' Temp. ("C) (mmHg) Time (h) Yield () M.p. ("C) ("C) (8a) Ph Ph 150 3 2 65 52-53 53 a (8b) 4-MeC6H4 4-MeC6H4 180 3 2 65 73-75 78-79 (8c) 4-MeC6H4 4-PhC6H4 180 5 4 62 97-98 -(8d) 4-MeGH4 4-MeOGa 150 5 3 55 51-53 55 4-MeC6H4 4-ClC 180 5 2 58 81-83 85 (8f) Ph 4-MeCsH4 150 5 2 63 84-86 89 'I. Goldberg, Ber., 1907, 40, 4541. D. G. Daniels, F. T. Naylor, and B. C. Saunders, J. Chem. Soc., Perkin Trans. I, 1951, 3433. m/z259.1361 (M+. Calc. for CI9Hl7N: m,259.1362).A. R. Sen and A. K. Sen Gupta, J. Indian Chem. Soc., 1957, 34, 413. F. Ullmann, Liebigs Ann. Chem., 1907, 355, 312. Table 8. 'H N.m.r. spectra of diarylamines Aromatic protons 4-CHJGH4 ~-CHJOC~H~ NH (m) 6) (3 H, s) (1 H, s) 6.80-7.30 (10 H) 5.65 6.85-7.30 (8 H) 2.25 (6 H) 5.50 7.00-7.65 (13 H) 2.20 (3 H) 5.65 6.55-7.20 (8 H) 2.20 (3 H) 3.75 5.50 6.95-7.90 (8 H) 2.20 (3 H) 5.50 6.55-7.30 (9 H) 2.25 (3 H) 5.50 diphenylpyrylium salt (3 mmol) in CH2C1, (25 ml). The red white solid was filtered off and washed with water (500 ml) solution was stirred for the appropriate time (Table 1) at and Et20 (50 ml) to give the pyridinium-2-carboxylate (Table 25 "C. Concentration at 50 "C/25 mmHg and trituration of 3).the residue with Et20 gave the pyridinium salts which were recrystallised from 95 ethanol (Table 1).General Method for the Preparation of 1-Aryl-2-(N-aryl-carbamoyl)-4,6-diphenylpyridinium Tetrafluoroborates (4).-General Method for the Preparation of l-Aryl-4,6-diphenyl-Thionyl chloride (18 mmol) and pyridine (4 mmol) were added (6 mmol)pyridinium-2-carboxylates(3).-The 1-aryl-2-ethoxycarbonyl-to the l-aryl-4,6-diphenylpyridinium-2-carboxylate 4,6-diphenylpyridinium salt (10 mmol) was stirred at 25 "C in CH2C12(15 ml). The mixture was refluxed for 15 min and 25 ml, 12.5 mmol) for 24 h. The the arylamine (18 mmol) added; refluxing was then contin- under aqueous NaOH (0.5~; J. CHEM. SOC. PERKIN TRANS. I 1983 ued for the appropriate time (Table 5). The solvent was re- moved at 50 "C/25 mmHg, and the residue washed succes- sively with water (50 ml) and Et,O (50 ml).The resulting brown gum was dissolved in methanol (15 ml) and tetrafluoro- boric acid (10 mmol) was added to form, after cooling, the 2-(N-arylcarbamoy1)pyridinium tetrafluoroborate, which was recrystallised from methanol (Table 5). General Method for the Preparation of Diarylaniines (5). -The l-aryl-2-(N-arylcarbamoyl)-4,6-diphenylpyridinium tetrafluoroborate (3 mmol) was dissolved in toluene (30 ml), sodium hydride (99, 6 mmol) was added and the mixture refluxed for 12 h. The solvent was removed at 60 OC/lO mmHg and the resulting solid washed with water (40 ml) and filtered. Sublimation gave the diarylamine as needles (Table 7). 2,4-Diphenylpicolinic acid was obtained by acidification of the residue (m.p.150 "C,lit.,22 m.p. 150 "C). Acknowledgements We thank the S.E.R.C. and 3M Minnesota Research Ltd. for financial assistance and Dr. R. C. Patel for her interest. References 1 Part 2, preceding paper. 2 (a) F. Ullman, Chem. Ber., 1903, 36, 2382; (b) R. M. Acheson (ed.), ' Heterocyclic Compounds ;Acridines,' Wiley Interscience, p. 160. 3 T. L. Davis and A. A. Ashdown, J. Am. Chem. SOC., 1924, 46, 1051. 2615 4 P. E. Weston and H. Adkins, J. Am. Chem. SOC.,1928, 50, 859. 5 E. Miiller, ' Methoden der Organischen Chemie,' Georg Thieme, Verlag, Stuttgart, 1957, XI/l, 117. 6 H. Gilman and R. McCracken, J. Am. Chem. SOC., 1929, 51, 821. 7 W. Truce, E.Krieder, and W. Brand, Org. React., 1971, 18, 99. 8 J. W. Schulenburg and S. Archer, Org. React., 1965, 14, 1-51. 9 I. A. Solovbeva and A. G. Guseva, Zh. Org. Khim., 1968, 4, 1973. 10 E. Jones and F. G. Mann, J. Chem. SOC.,1956, 786. 11 M. Lippner and M. Tomlinson, J. Chem. SOC., 1956, 4667. 12 A. E. Arbuzov and V. E. Shishkin, J. Gen. Chem. USSR,1964, 34, 3628. 13 R. 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