J. CHEM. SOC. PERKIN TRANS. I 1989 639 The Chemistry of N-Substituted Benzotriazoles. Part 20.' Mono-N-t-Butylation of Aromatic and Heteroaromatic Amines Alan R. Katritzky" and Jean-Jacques Vanden Eynde Department of Chemistry, University of Florida, Gainesville, Florida 3267 7, U.S.A. Adducts RICH (Bt) N HAr, readily available from aldehydes, primary aromatic or heteroaromatic amines, and benzotriazole are converted by H,O,-SeO, into mixtures of R'CONHAr and HCONR'Ar in proportions which depend rationally on the nature of the R' group. For R' = But, the formamide HCON(But)Ar is formed in satisfactory yields thus enabling the title reaction to be achieved. We have recently applied benzotriazole chemistry to the mono- N-alkylation of aromatic and heteroaromatic primary amines.2 In this procedure, which was shown to possess considerable advantages over others available, an aldehyde R'CHO, the amine ArNH,, and benzotriazole form an adduct, R'CH(Bt)- NHAr [cj (1); Scheme], which is then treated with a Grignard reagent RMgBr to form the alkylated amine R1R2CHNHAr.In this sequence, R' can be hydrogen, so primary or secondary alkyl groups can be introduced: however, the scope of the analogous reaction to form compounds of the type R'NHAr where R' is a tertiary group is very limited.3 We now report a method for the mono-N-t-butylation of aromatic and hetero- aromatic amines which is potentially extendible to the introduction of tertiary alkyl groups in general. Our method is based on the oxidation and subsequent rearrangement of the benzotriazole adducts (1) in which R' is a t-butyl group.A series of adducts (1) (Table 1) were prepared from an aldehyde, an amine, and benzotriazole by one of the standard procedure^,^ and their oxidation studied under various conditions. We observed that these adducts (1) are readily converted by hydrogen peroxide in the presence of selenium di- oxide into mixtures of formamide (4) and amide (5) (Scheme). Aqueous hydrogen peroxide was found to be the best oxidant, despite the fact that under these conditions hydrolysis of (1) occurs to a significant extent. For example, (la) reacted neither with potassium permanganate in the presence of dicyclohexano- 18-crown-6 nor with pyridinium dichromate; with m-chloro- perbenzoic acid,' reaction was very slow and yielded, beside the expected amides, a complex mixture of by-products.The mechanism of the reaction probably involves the known reversible ionic dissociation of (1) into (2) followed by oxidation to an oxaziridine [(3); Scheme]. As in other three- membered ring systems, relief of ring strain provides the driving force for bond cleavage. In the oxaziridine series, N-0 bond cleavage is preferred when there are alkyl group(s) on the carbon atom and an aryl group on the nitrogen atom; the bond fission is accompanied by the 1,2 shift of a group from the carbon atom to the nitrogen atom so that a mixture of two isomeric amides can be obtained." The results of the hydrogen peroxide oxidation experiments are summarized in Table 2 (analytical data in Table 3).The two types of products (4) and (5) are easily distinguished by n.m.r. spectroscopy. Indeed, in the '3C n.m.r. spectra, the carbon atom of the carbonyl function in the formamide (4) appears around 160 p.p.m. whereas for the amide (5) that signal is shifted downfield to around 175 p.p.m. Furthermore, in the 'H n.m.r. spectra, the chemical shift of the proton(s) of the methylene or methine group adjacent either to the nitrogen atom [around 4.5 p.p.m. for the formamides (4)] or to the carbonyl function [around 2 p.p.m. for the amides (5)] also affords unambiguous proof of the formation of the isomeric derivatives. The inte- R'CHO + R~NH~+ UN3 oN\i +H20 ' N' I I N CH R' /\NHR' (1) r H202/S e02 4 (3) 0 IIR~-C-N H R~ (5) Scheme. grated intensity of these signals was used to determine the ratio (4) :(5) (see Table 2).The relative proportion of (4) and (5) formed depends dramatically on the nature of the R1 group and this dependency can be compared to that observed during the pinacol rearrangement ''with the migration aptitude being the same as the order of increasing bulk. That parallelism is not surprising as the rearrangement of certain 1,2-diols was proved12 to proceed via epoxides, the structures of which are closely related to those of the oxaziridines postulated in the mechanism outlined in the Scheme. In particular, when R' = But the formamides (4) are formed in moderate yield, but practically exclusively.Our method then provides a useful synthetic route to the non-symmetrically disubstituted formamides (4a-k) of which to date, the sole example reported in the literature is (4h). As emphasized in a previous paper in this series, the mono- N-alkylation of aromatic amines with alkyl halides is frequently a tedious process because for most methods N,N-(dialky1)aryl- amines are invariably by-products.' Moreover, with most branched alkyl halides, yields fall dramatically because of competing amine-induced elimination: yields as low as 12% 640 J. CHEM. SOC. PERKIN TRANS. I 1989 Table 1. Preparation and analytical data of the benzotriazole precursors (1) Found (%) (Required) 13Cn.m.r.Yield Crystal P6 N-C-N R' R2 Formula (%) form M.p. ("C) C H N @.P*m.) Pr 2-Pyrid yl'1SH1 7N5 80 66.9Needles 128-1 29 67.3 6.4 26.4 (67.3 6.4 26.2) Pr' 2-P yridyl ClSH1,NS 95 Prisms 168-169" 67.2 6.4 26.3 71.9' (67.4 6.4 26.2) But 2-Pyridyl 1gH1 9NS 85 Prisms 210-211" 68.6 6.9 24.9 74.6 ' (68.3 6.8 24.9) Pr' 3-Pyridyl Cl SH1,NS 80 Needles 146-148 67.4 6.4 26.5 76.5' (67.4 6.4 26.2) Bu' 3-Pyridyl 85 Needles 157-159 68.5 6.9 25.1 dC16H 19NS (68.3 6.8 24.9) Bu' 4-Methyl-2-pyridyl cl 7H2 lNS 90 Prisms 201-203 69.0 6.9 23.7 73.5 ' (69.1 7.2 23.7) Bu' 5-Chloro-2-pyridyl c1SH1&IN, 95 Needles 184-186 61.0 5.7 22.35 d (60.85 5.75 22.2) C17H20N4 95 Needles 160-162 73.1 7.3 20.3 76.2' (72.8 7.2 20.0) But 3-Chlorophen yl 17H1 gClN4 90 Needles 170-172 64.7 6.1 17.8 76.6' (64.9 6.1 17.8) But 3-Nitrophenyl 85 Needles 168-169 62.6 5.9 21.5 76.0' C17H19NS02 (62.8 5.9 21.5) But 4-Nitrophenyl 90 Prisms 172-173 62.8 5.9 21.55C17H19NS02 (62.8 5.9 21.5) 'Ref.4a. Spectrum in CDCl,. 'Spectrum in [ZH6]DMS0. Insoluble. Table 2. Oxidation of the adducts (la-k) HCONR'R' (4) Ratio (4):(5) I R'CONHR' A (5)' -I Starting material & Yield Yield (%) r No R' A R2 \ No Yield (%)isolated determined by n.m.r. No I3C n.m.r. (CDCl,) 6 C=O (p.p.m.) determined by n.m.r. Calc. total yield (%) (la) (lb) (lc) (Id) (le) (If) (Ih) (li) (lj) (lk) (1g) Pr Pr' But Pr' But But But But Bu' Bu' Bu' 2-P yridyl 2-Pyrid yl 2-P yrid yl 3-P yrid yl 3-Pyridyl 4-Methyl-2-pyridyl 5-Chloro-2-pyrid yl Ph 3-Chlorophen yl 3-Nitrophenyl 4-Nitrophenyl 20 20 29 20 34 29 39 24 34 29 34 1 4 10 4 10 10 10 10 10 10 10 171.9 176.0 176.6 b b 176.3 176.9 b b b b 20 5 2 5 t2 2 2 2 2 2 2 40 25 30 25 35 30 40 25 35 30 35 " Not isolated.Not detected. 'A. Mndzhoyan and V. Afrikyan, Izv. Akad. Nauk. Armyan. SSSR, Ser. Khim. Nauk., 1957, 10, 143 (Chem. Abstr., 52,4641b). J. Turner, J. Org. Chem., 1983,48, 3401. H. Rapoport, M. Look, and G. Kelly, J. Am. Chem. SOC.,1952,74,6293. F. El-Zahraa, S. El-Basil, M. El-Sayed, K. M. Ghoneim, and M. Khalifa, Pharmazie, 1979, 34, 12. M. Nojima, F. Shiba, M. Yoshimura, and N. Tokura, Chem. Lett., 1972, 1133. H. Freund, H. Arndt, and R.Rusch, G. P. 1,166,647/1962 (Chem. Abscr., 60, 16438e). P. Verkade, B. Wepster, and P. Witjens, Red. Trav. Chim.Pays-Bas, 1951, 70, 127. have been reported l4 for the mono-N-t-butylation of aniline. N-paper 21 has reported the preparation of a (mono-t-butyl-t-Butylaniline is somewhat more conveniently prepared by the amino)pyridine: the 2-isomer was obtained in poor yield (5%) action of t-butylamine on bromobenzene in the presence of by the irradiation of 2-fluoropyridine in the presence of t-sodium (30%)," by reaction of nitrobenzene with t-butyl- butylamine. 2-(t-Butylamino)pyridine, previously described as magnesium chloride (40%),16by oxidative coupling of lithium a brown oil, was obtained by us as a white crystalline solid. di-t-butylcuprate with aniline (46%),' by vapour-phase As the deformylation of formamides is routine, hydrolysis of alkylation of aniline with 2-methylpropan-2-01 (55%),'* or compounds (4) should yield secondary amines.This assumption by methylation of acetone anil with methyl-lithium (61%).'9 is confirmed by the conversion of three examples, (&), (4g), and However, none of these routes is especially attractive as a (4j) into 2-(t-butylamino)pyridine, 2-(t-butylamino)-5-chloro-general method. Moreover, for heterocyclic amines containing pyridine, and N-t-butyl-3-nitroanilinerespectively. Thus, the one (or more) nitrogen atom@) in the ring, the problem of t-sequence described in this paper represents a novel route to alkylation is intensified because alkylation with an alkyl halide secondary non-symmetrical amines and, more particularly, to usually occurs on the ring nitrogen atom to a greater extent than mono-N-t-butyl (hetero)arylamines, previously accessible only on the exocyclic amino function.20 To our knowledge, only one with difficulty, if at all. J.CHEM. SOC. PERKIN TRANS. I 1989 641 Table 3. Analytical data for the formamides (4a-k) Found (%)(Required)Crystal r I3C n.m.r. (CDCl,) 1 R' R2 Formula Form M.p. ("C) C H N 6 C=O (p.p.m.) Pr 2-Pyridyl C9H1 ZN20 Oil 65.9 7.4 162.0 (65.8 7.4 17.1)Pr' 2-Pyrid y l C9H1 ZN20 Oil 65.75 7.4 162.3 (65.8 7.4 17.1)But 2-Pyridyl CIOH 14N20 Oil 67.4 7.9 162.3, 162.1 (67.4 7.9 15.7)Pr' 3-Pyridyl C9H1ZNZO Oil 65.7 7.4 162.1, 161.4 (65.8 7.4 17.6)But 3-Pyridyl lCtH14NZ0 Prisms 52-53 67.6 8.0 15.8 162.5, 162.2 (67.4 7.9 15.7)But 4-Methyl-2-pyridyl CllHd2O Oil 68.65 8.4 14.95 162.0, 161.8 (68.7 8.4 14.6)But 5-Chloro-Zpyridyl ClOHl3ClN2O Needles' 80-8 1 56.3 6.1 13.6 162.2 (56.5 6.2 13.2)But Ph Cl 1Hl ,NO Oil 162.7, 161.9 Bu' 3-Chlorophenyl C, ,HI4CINO Needles 89-90 62.3 6.7 6.6 162.7, 162.2 (62.4 6.7 6.6)But 3-Nitrophenyl C11H14N203 Needles 133-134 59.5 6.4 12.7 162.3, 162.2 (59.45 6.35 12.6)But 4-Nitrophenyl C11H14N203 Needles 116-1 17 59.4 6.4 12.6 162.1 (59.45 6.35 12.6) * C.Yoder, J. Sandberg, and W. Moore, J. Am. Chem. Soc., 1974,96,2260. From ether. From light petroleum (b.p. 38-56 "C). From ethanol. Experimental ml x 3). The organic layers were collected, dried (MgSO,), M.p.s were determined on a hot-stage microscope and are concentrated, and the residue was purified by column uncorrected.'H n.m.r. spectra were recorded on a Varian EM- chromatography on silica gel with benzene-ether (4: 1) as eluant. 360L (60MHz) or on a Varian XL-200 (200 MHz) and I3C (a) 2-(t-Butylarnino)pyridine,previously described as a brown n.m.r. spectra were recorded on a Varian XL-200 (50 MHz) oil,,' was isolated as a white solid (0.68 g, 90%) and spectrometer; tetramethylsilane was used as internal reference. recrystallized from light petroleum (b.p. 38-56 "C), m.p. 52- Elemental analyses were carried out under the supervision of 53 "C (Found: C, 71.65; H, 9.4; N, 18.5. C,H,,N, requires C, Dr. R. W. King, University of Florida (solids), or by the Atlantic 72.0; H, 9.4; N, 18.65%); S,(60 MHz; CDC1,) 1.4 (9 H, s, Me), 4.8 Microlab, Inc., Atlanta, Georgia (liquids).(1 H, br s, NH), 6.5 (2 H, m, 3-H and 5-H), 7.2 (1 H, m, 4-H), and 8.2 (1 H, m, 6-H); 6,(50 MHz, CDCl,) 29.4 (CH,), 50.5 (CMe,),Benzotriazole Adducts (1): General Procedure.-The appro-108.5 (3-C), 112.1 (5-C), 136.6 (4-C), 147.9 (6-C), and 158.3 (2-C). priate aldehyde (10 mmol), the appropriate amine (10 mmol), (b) 5-Chloro-2-(t-butylarnino)pyridinewas isolated as an oil and benzotriazole (1.19 g, 10 mmol) were heated in ethanol (10 (0.83 g, 90%) (Found: C, 58.6; H, 7.1. C,H,,ClN, requires C, ml) under reflux for 4 h. The solvent was evaporated under 58.5; H,7.1%); 6,(60 MHz; CDCl,) 1.3 (9 H, s, Me), 4.4 (1 H, br reduced pressure and the residue was triturated with ether to s,NH),6.2(1 H,d, 3-H), 7.1 (1 H,dd,4-H),and 7.9(1 H,d,6-H); afford the crude product (1).Analytical samples of (1) were 6,(50 MHz; CDCl,) 29.1 (CH,), 50.7 (CMe,), 109.5 (3-C), 118.9 obtained by recrystallization from ethanol. Yields and physical (5-C),136.3 (4-C), 146.0 (6-C), and 156.5 (2-C). properties are given in Table 1. (c) 3-Nitro-N-t-butylanilinewas isolated as an oil (0.78 g, 80%) (Found: C, 62.0 H, 7.3. C,,H,,N,O, requires C, 61.8; H, Oxidation with Hydrogen Peroxide: General Procedure.-The 7.3); 6,(60 MHz; CDCl,) 1.4 (9 H, s, Me), 3.9 (1 H, br s, NH),benzotriazole adduct (1) (10 mmol), aqueous 30% hydrogen and 6.8-7.5 (4 H, m, Ar); 6,(50 MHz; CDCl,) 29.6 (CH,), 51.4 peroxide (1.2 ml, 10 mmol), and a catalytic amount of selenium (CMe,), 109.1 (2-C), 11 1.7 (4-C), 121.4 (6-C), 129.4 (5-C), 147.7 dioxide were heated in methanol (10 ml) under reflux for 6 h.(1-C or 3-C), and 149.1 (3-C or 1-C). The methanol was removed under reduced pressure and the residue extracted with chloroform (25 ml x 3). An aliquot of the organic solution was dried (MgS0,) and concentrated to afford the crude reaction products which were analysed by Acknowledgements r1.m.r. spectroscopy. The remaining chloroform solution was One of us (V. E.-Belgium) is indebted to the N.A.T.O. washed successively with 1~ hydrochloric acid (15 ml), IM Scientific Committee for a research grant. sodium hydroxide (1 5 ml), and water (1 5 ml). The organic layer was dried (MgSO,), concentrated, and the residue purified by column chromatography on silica gel with benzenexther (4: 1) as eluant.Yields and physical properties of the formamides (4) References are given in Tables 2 and 3. 1 For Part 19, see A. R. Katritzky and C. V. Hughes, Chem. Scripta, in the press. Hydrolysis of the Formamides (4c), (4g), and (43: General 2 (a) A. R. Katritzky, S. Rachwal, and B. Rachwal, J. Chem. SOC., Perkin Trans. 1, 1987,805;(6) See also A. R. Katritzky, S. Rachwal,Procedure.-The formamide (5 mmol) was heated in IM sodium and J. Wu, unpublished work. hydroxide (2 ml) and ethanol (8 ml) under reflux for 6 h. After 3 A. R. Katritzky, N. Najzarek, and Z. Dega-Szafran, submitted for cooling, the solution was extracted with chloroform (25 publication in Synthesis. 4 (a) A.R. Katritzky, S. Rachwal, and B. Rachwal, J. Chem. SOC., Perkin Trans. 1, 1987, 799; (b) See also A. R. Katritzky, B. Pilarski, and L. Urogdi, unpublished work. 5 S.-I. Murahashi and T. Shiota, Tetrahedron Lett., 1987, 28, 2383. 6 D. J. Sam and H. F. Simmons, J. Am. Chem. SOC.,1972,94,4024. 7 E. J. Corey and G. Schmidt, Tetrahedron Lett., 1979, 399. 8 L. F. Fieser and M. Fieser, in ‘Reagents for Organic Synthesis,’ Wiley, New-York, 1967, vol. I, p. 135. 9 (a) A. R. Katritzky, K. Yannakopoulou, W. Kuzmierkiewicz, J. M. Aurrecoechea, G. J. Palenik, A. E. Koziol, M. Szczesniak, and R. Skarjune, J. Chem. Soc.,Perkin Trans. 1,1987,2673;(b)P. Barzynski, unpublished work. 10 (a) H.Krimm, Chem. Ber., 1958, 91, 1057; (b) J. S. Splitter and M. Calvin, J. Org. Chem., 1965, 30, 3427. 11 M. Stiles and R. P. Mayer, J. Am. Chem. SOC.,1959,81, 1497. 12 (a) K. Matsumoto, Tetrahedron, 1968, 24, 6851; (b) Y. Pocker and B. P. Ronald, J. Org. Chem., 1970, 35, 3362; (c) J. Am. Chem. Soc., 1970,92, 3385. 13 W. W. Lewis,Jr., U.S.P.2,541,655/1951(Chern. Abstr., 1952,46,3565). J. CHEM. SOC. PERKIN TRANS. I 1989 14 E. G. Rozantsev and F. M. Egidis, Izu. Akad. Nauk. SSSR, Ser. Khim., 1967, 932 (Chem. Abstr., 1967, 67, 90473s). 15 L. David, A. Gazel, and A. Kergomard, Bull. SOC.Chin?. Fr., 1978,587. 16 V. I. Savin, Zh. Org. Khim., 1978, 14, 2090. 17 H. Yamamoto and K. Maruoka, J. Org. Chem., 1980,45, 2739. 18 N. S. Lobanova and M. A. Popov, Zh. Prikl. Khim. (Leningrad), 1970, 43, 938 (Chem. Abstr., 1970, 73, 250328). 19 R. S. Neale, R. G. Schepers, and M. R. Walsh, J.Org. Chem., 1964,29, 3390. 20 (a)R. B. Petigara and H. L. Yale, J.Heterocycl. Chem., 1974,11,331; (b)H. L. Yale and R. B. Petigara, G. P., 2,352,918/1974 (Chem. Abstr., 1974, 81, 1356513); (c) H. L. Yale and J. A. Bristol, U.S.P. 3,933,836/1976 (Chem. Abstr., 1976, 84, 135484r); (d) E. I. Fedorov and B. I. Mikhantev, Tr. Probl. Lab. Khim. Vysokomol. Soedin., Voronezh.Gos. Unilj., 1966,48(Chem. Abstr., 1968,69,18986k); (e)P. Beak, J.-K. Lee, and B. G. McKinnie, J. Org. Chem., 1978,43, 1367. 21 G. Andrew and K. Stefan, J. Chem. SOC.,Perkin Trans. I, 1980,2531. Received 15th July 1988; Paper 8/02849D
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