The chemistry of benzotriazole. Part 8. A novel two-step procedure for theN-alkylation of amides

摘要

J. CHEM. SOC. PERKIN TRANS. I 1988 The Chemistry of Benzotriazole. Part 8.lsquo; A Novel Two-step Procedure for the N-Alkylation of Amides Alan R. Katritzky * and Malgorzata Drewniak Department of Chemistry, University of Florida, Gainesville, FL 3261 1, USA Benzotriazole, aldehydes RCHO, and amides Rrsquo;CONH, react together with elimination of water to form I :I :1 adducts which are reduced smoothly by NaBH, to give the N-substituted amides Rrsquo;CONHCH,R. Both steps occur in high yields and can be carried out on a large scale, thus comprising a convenient general method for the N-alkylation of amides. The amide moiety is an important constituent of many biologically significant compounds, and the N-alkylation of existing amides to give more substituted analogues has attracted much attention.The N-alkylation of amides has also been used as an intermediate step in the synthesis of secondary and tertiary amines having different alkyl groups.rsquo; The neutral amide group generally reacts with electrophiles under kinetic control at the carbonyl oxygen atom (see e.g. refs. 4 and 5) and indeed amides are protonated at oxygen.6 Amide anions usually react with electrophiles at the nitrogen atom, and indeed treatment of amide anions with alkyl halides has frequently been used for their N-alkylation. However, these methods require the use of a very strong base (often in large excess), such as potassium hydroxide in water,rsquo; ethanol,rsquo; or DMS0,9*rsquo;o sodium hydroxide in toluene,rsquo; rsquo; sodium in toluene,rsquo; and have been said rsquo; lsquo;to produce impure products in indifferent yields under fierce conditions.rsquo; Phase-transfer catalysis has been successful using NaOH-benzene for mono- alkylation of both unsubstituted l4 and monosubstituted amides,I3 but perhaps the most successful N-alkylation of amides with alkyl halides is that reported by Sukatals using KOH on alumina at 60 ldquo;C.Recently Shono and co-workers l6 reported an electro-reductive N-alkylation with alkyl halides which gave good yields; however, the method was only applied to secondary amides. The use of reagents other than alkyl halides to substitute amides is more rare. N-Alkylation of amides in variable yields with alcohols at 180 ldquo;C was carried out by Watanabe et al., using ruthenium complexes as catalysts.rsquo; Treatment of amides with formaldehyde gives hydroxymethyl derivatives, and these can be reduced to N-methylamides with triethylsilane,rsquo; rsquo;but alkylation of amides by other aldehydes has not been reported except for a brief note without experimental detail.rsquo; Methylation of amides has been reported by treatment with MeSCH,CI followed by reduction with Raney nickel,rdquo; but again no experimental detail was given.The Michael reaction of amides with electrophilic alkenes rsquo;rsquo; represents a specialized type of N-alkylation. We now report a novel two-step N-monoalkylation of amides of considerable generality using common reagents. Our previous work with benzotriazole has shownrdquo; that this heterocyclic system reacts easily with amines and aldehydes to form N-(aminoalky1)benzotriazoles.We have demonstrated that benzotriazole, an aliphatic or aromatic aldehyde, and an amide also react to form the corresponding 1: 1 :1 adducts in good yields (Scheme 1). In a one-pot reaction, benzotriazole, the aldehyde, and the amide (in equimolar amounts) are refluxed in dry toluene for 2448 h. The reaction probably involves the formation of a r 1 1 RcHoHI (11 Rrsquo;CONH~1 + H,O Nrsquo; R I CHRa; H I b; Prrsquo; AHCRrsquo; c; Pr IId; Pentyl 0 e; Octyl f; Ph g; PM~C~H, Scheme 1. hydroxyalkylbenzotriazoleintermediate (1)which subsequently reacts with the amide (Scheme 1). The water formed as a side- product was removed azeotropically with toluene. This pro- cedure was successful for aliphatic and aromatic aldehydes and amides on 0.1 molar scale; details are given in Tables 1 and 2.The structures of the adducts were established on the basis of their spectral properties. In the rsquo;3C n.m.r. spectra of adducts (2) and (3), the chemical shifts of the carbons of the benzotriazole ring (Table 3) corresponded closely to those previously reported for other 1-substituted benzotria~oles.rsquo;~ Thus C-7 and C-7a appeared at 6 11 1.2-109.6 and 132.3-131.0. The chemical shifts for C-3a and C-4 were slightly shielded and occurred at 6 145.4-144.5 and 119.3-1 18.3, whereas C-5 and C-6 appeared at 6 124.2-122.9 and 127.7-126.2, respectively. The chemical shifts of the carbonyl carbons for compounds (2) and (3) fall in the region 170.8-166.7 p.p.m.(Table 4). In addition, the 13C n.m.r. spectra of the adducts (2) showed four signals corresponding to the aromatic carbons of benz- amide. Compared with the 13C n.m.r. shifts in unsubstituted benzamide, the C-1rsquo; carbon was slightly deshielded (1.6-1.1 p.p.m.); the other carbons were little affected.24 In the adduct (3) the acetamide methyl group resonated at 22.5-21.3 ~.p.rn.~rsquo;As expected, the absorption peak for the characteristic C-a between the heterocyclic ring and amide nitrogen appeared at 6 69.6- 2340 J. CHEM. SOC. PERKIN TRANS. I 1988 Table 1. Preparation of the N-1-(benzotriazol-1-yl)alkylamides (2) and (3) R' of Time Yield Recryst. M.p. Crystal Product R of RCHO R'CONH2 Method" (h) ( solvent ("C) form H Ph 24 78 MeOH 177-179 Needles Pr' Ph 24 52 MeOH 191-193 Prisms Pr Ph 24 59 MeOH 156-159 Prisms Pentyl Ph 48 48 MeOH 110-1 15 Microcr'yst.Octyl Ph 48 74 MeOH 102-105 Plates Ph Ph 24 60 MeOH 1 88- 190 Needles Pr' Me 48 51 Benzene 164-167 Prisms Ph Me 48 45 Benzene 174-177 Needles p-MeCamp; Me 40 42 Benzene 186-189 Needles 'For methods A and B see Experimental section.Table 2. Elemental analyses of the adducts (2) and (3) -R of R' of I Required () A Molecular 7 Found () 7 Product RCHO R'CONH, C H N formula C H N H Ph 66.7 4.8 22.2 C14H1 zN40 66.9 4.8 22.2 Pr' Ph 69.4 6.2 19.0 cl 7H 1EN40 69.5 6.4 18.9 Pr Ph 69.4 6.2 19.0 1 7H 1EN40 69.4 6.4 18.9 Pentyl Octyl Ph Ph Ph Ph 70.8 72.5 73.1 6.9 7.7 4.9 17.4 15.4 17.1 1gH2 zN40 C22Hz*N,O C20H16N40 70.3 72.2 72.9 7.0 7.9 4.7 17.2 15.2 16.9 Pr' Me 62.0 6.9 24.1 cl lH1 6N40 61.8 7.1 24.5 Ph Me 67.6 5.3 21.0 C15H14N40 67.5 5.3 21.0 p-MeC6H4 Me 68.5 5.8 20.0 cl 6H16N40 68.0 5.8 19.6 Table 3.13C N.m.r. chemical shifts (6) of the benzotriazole carbons in p.p.m. The other aliphatic protons of the acyclic substitutent R compounds (2) and (3)" appeared upfield as complex multiplets. The exception was observed for the methyl groups in compounds (2b)and (3b). The C-3a c-4 c-5 C-6 c-7 C-7a chemical shifts of those two non-equivalent methyl groups in 145.4 118.9 123.8 127.2 11 1.2 132.2 the isopropyl substituent differed by about 0.5 p.p.m. and 145.0 119.0 123.7 127.1 11 1.0 132.0 appeared as sharp doublets with a coupling constant of 6 and 145.2 119.1 123.9 127.1 11 1.1 132.0 7 Hz, respectively.145.3 119.2 124.2 127.7 110.5 132.0 145.4 119.3 124.2 127.7 110.5 132.8 145.3 119.2 123.9 127.3 111.0 132.0 Reduction of Adducts to N-Alkylamides-The adducts 145.0 119.2 124.1 127.6 110.2 133.2 described above are readily reduced by sodium borohydride in 145.3 119.1 123.9 127.2 110.8 131.8 absolute ethanol to the N-alkylated amides (with elimination of 144.5 118.3 122.9 126.2 109.6 131.1 benzotriazole) in excellent yields (Scheme 2). The N-alkylamides 'All spectra were run on Varian XL 200 (50 MHz, FT mode) and in (CD,),SO except those for compounds (2d), (2e), (3b), and (3g)were run in CDCI,.H NaBH4 -+ 51.7. In the 13Cn.m.r. spectra (Table 5a), the aliphatic carbons EtOH of the R substituents of the adducts (2) displayed a similar I pattern as for the aliphatic amines published el~ewhere,~~ CHR whereas the aromatic carbons of phenyl substitutents in 1 NHCR'compounds (20, 30, and (3g) gave rise to the signals in the region 137.4-125.4 (Table 5b). The quaternary carbons could II0 be easily assigned; in addition to C-4', however, the assignments Rof the chemical shifts for C-2' and C-3' are interchangeable. a; HIn the 'H n.m.r. spectra of compounds (2) and (3)(Table 6), b; Pr'the most deshielded aromatic proton has been assigned to C-4 c; Prof the benz~triazole.~~The other aromatic protons of d; Pentylbenzotriazole and phenyl substitutents appeared as a complex e; Octylmultiplet between 8.15 and 7.13 p.p.m.The NH protons f; Ph resonated at 6 10.25-9.79 as a doublet with a coupling constant Scheme 2. in the range 8-9 Hz. The methine proton was significantly deshielded to 6 7.04-6.26 due to the effect exerted by the were identified by comparison of m.p.s with literature values benzotriazole ring and appeared as a well resolved signal with a (Table 7), and by their spectral data. coupling constant in the range 68 Hz. Protons attached to The 13Cn.m.r. spectra of the N-alkylated amides (4) and (5) C-p gave rise to the obscure multiplet in the region 3.49-2.45 (Tables 4 and 5) resembled, in many respects, those of the parent J. CHEM. SOC. PERKIN TRANS.I 1988 2341 Table 4. 13C N.m.r. chemical shifts (6) for the substituent R' in compounds (2)-(7)"" Product C--O NHCH2R' C-1' c-2' c-3' c-4' NHCH,R (24 166.9 132.8 127.4 128.2 131.7 51.7 (2b) 166.9 133.1 127.6 128.1 131.6 69.6 (24 166.7 133.1 127.6 128.2 131.7 63.8 (24 167.4 133.1 127.4 128.3 131.9 62.7 (2e) 167.3 133.1 127.4 128.4 132.0 62.7 (29 166.9 132.9 127.8 128.4 131.7 66.0 (3b) 170.8 22.5 67.8 65.1(39 169.8 22.2 64.0(3g) 169.3 21.3 (44 168.4 134.3 126.8 128.2 131.0 26.6 (4b) 167.7 134.8 126.8 128.4 131.1 47.3 167.6 134.7 126.8 128.3 131.1 39.7 (44 167.5 134.5 126.8 128.0 130.8 39.9 (4) 167.5 134.7 126.8 128.3 131.1 40.0 (49 167.5 134.2 126.9 128.4 131.4 43.9 (59 170.3 22.5 43.1 (64 55.6 139.7 127.8 128.0 126.6 35.6 (6b) 57.2 140.4 127.7 128.0 126.5 53.7 (6c) 53.7 140.3 127.9 128.2 126.7 48.9(a) 53.9 140.3 127.9 128.0 126.6 49.3 (6e) 54.0 140.4 127.9 128.2 126.7 49.4 (60 53.0 140.2 127.9 128.2 126.7 53.0 (79 d 43.3 14.9 53.6 All spectra were run on Varian XL 200 (50 MHz, FT mode).Spectra of compounds (h),(20, and (39 were run in (CD,),SO. Spectra of compounds (2d--e), (3b), (3g), (4), and (5) were run in CDCI,. See C-1'. Table Sa. I3C N.m.r. of the selected substituents R in compounds (2)-(6)(Iqb b Pr' c; Pr d Pentyl f A r A I f A bsol; Product CH Me Me c-1 c-2 Me c-1 c-2 c-3 c-4 Me (2) 31.0 32.4 19.2 18.9 18.4 18.5 34.8 18.4 13.2 33.9 31.0 25.0 22.2 13.5 (4)(3) 28.1 20.1 20.1 31.5 20.0 13.7 31.2 29.3 26.4 22.3 13.7 (6) 28.1 20.4 20.4 32.0 20.3 13.9 31.6 29.9 26.8 22.4 13.8 e; Octyl Product C-1 (2-2 c-3 c-4 c-5 C-6 c-7 Me (2) (4) (6) 34.0 31.7 31.8 25.4 26.9 27.3 29.1 29.4 29.5 29.0 29.2 29.5 28.8 29.1 29.2 31.6 29.5 30.0 22.5 22.5 22.6 14.0 14.0 14.0 a All spectra were run on Varian XL 200 (50 MHz, FT mode).* All spectra were run in CDCl, except those for compounds (2a-c) which were run in (CD,),SO. Table 5b. I3C N.m.r. of the aromatic substituents R in compounds (2)-(7) Product C-1 c-2 c-3 c-4 Others LiAIH4 H (29 136.2 128.6 128.0 126.8 ____) + THF(3g) 136.3 132.2 127.2 126.5 19.8 (Me) (39 132.2 128.1 125.4 137.4 I RCH, NHCH, R'(50 138.2 128.4 127.7 127.4 CHR (69 140.2 127.9 128.2 126.7 I(79 140.1 128.0 128.2 126.7 NHCR' II"All spectra were run on Varian XL 200 (50 MHz, FT mode).bAll 0spectra were run in CDCl, except those for compounds (20 and (30 which were run in (CD,),SO. R a; H b Pr' c; Pradducts: no significant changes were observed in the chemical d; Pentylshifts of c--O or the carbons of the substitutents R and R'. The e; Octylprincipal differences were in the chemical shifts of the character- C Ph istic C-a which, in the absence of the benzotriazole residue, has been shifted upfield into the 6 47.3-26.6 region (Table 4). The Scheme 3. 2342 J. CHEM. SOC. PERKIN TRANS. I 1988 Table 6. 'H N.m.r. chemical shifts of compounds (2) and (3)"~~ Benzotriazole and R' CHNH NH Substituent R A, 7-H H 4-H (1 H) Other Ar H H M' M (m) HM Me(3 H) M Product (1 H) d(Hz) (d) (m) (2a) 8.09 (9) d 7.96-7.13 8 6.26 2 d' f (2b) 8.19 (7) 8.05h 7.78-7.40 7 6.60 1 d' 9.79 d' 3.49-3.01 1 CH 1.27 3 d Me 0.67 d' (2c) 8.17 (7) 8.07h 7.99-7.37 7 6.98 1 9' 9.80 d' 2.48-2.45 2 CH, 1.50-1.21 2 m CH, 0.95 th (2d) 8.17 (7) i 8.14-7.41 8 6.92 1 d' 9.80 d' 2.51-2.48 2 CHZ 1.60-1.02 6 m (CH,), 0.83-4.60 m (2e) 8.19 (9) i 7.97-7.27 9 6.96 1 qf i 2.70-2.36 2 CH2 1.40-1.90 12 m (CH2)6 0.9CkO.80 m (20 8.25 (7) i 8.08-7.36 14 i 10.25 dg d (3b) 8.07 (8) 8.87' 7.54-7.37 2 6.44 1 tj 8.58 dk 2.91-2.73 1 CH 1.23 3 dh Me 0.77 dh (30 8.04-7.33 (10 H, m) 2.04 (3 H, s, Me) I 9.8 dk i (3s) 8.00 (8) 7.93k 7.48-7.31 6 7.04 1 dg 9.66 dk 7.17 4 qg (4 x CH) 2.31 s 2.04 (3 H, s, Me) " All spectra were run on Varian XL 200 (200 MHz, FT mode).All spectra were run in (CD,),SO except those for compounds (2d), (2e), (3b), and (3g) which were run in CDCI,. 'Multiplicity: m = multiplet, q = quartet, t = triplet, d = doublet, s = singlet. Signals appeared with other aromatics. 'J = 6 Hz. NH appeared as a broad signal. J = 8 Hz. J = 7 Hz. NH signal appeared together with aromatic protons, non- distinguishable. j J = 10 Hz. J = 9 Hz. J = 9 Hz. Table 7. Preparation of the N-monoalkylated amides (4) and (5) RCH,NHCOR' Product R R' Yield () Recryst. solvent M.p. ("C) Lit. m.p. ("C) (4a) H Ph 96 Light petroleum 75-77 78 26 (4b) Pr' Ph 96 Benzene 55-57 55-58 " (44 Pr Ph 96 EtOH 69-7 1 68-70 28 (44 Pentyl Ph 97 MeOH 55-58 56.5-57 29 Octyl Ph 99 EtOH 48-50 49 30 (4f) Ph Ph 94 MeOH 104-105 105-106 31 (50 Ph Me 98 Benzene 58-40 61 32 Table 8.'H N.m.r. chemical shifts of the N-alkylated amides (4) and (5)"-R' RCH,NH R I 7 -f A bsol; 2-H 3-, 4-H NH H Mb H HM HM Product (2 H, m) (m) H (1 H) (m) (4a) 7.82-7.77 (4b) 7.80-7.76 (4c) 7.81-7.61 (4)7.85-7.80 (4e) 7.81-7.76 (4f) 7.81-7.79' (50 7.27-7.16 (m) 7.43-7.30 7.47-7.35 7.45-7.32 7.45-7.27 7.45-7.28 7.6G7.24 4 3 4 6 6 3 3 c 2.93 6.63' 3.26 e 3.41-3.31 7.01 ' 4.55 c 4.284.25 6.83" 3.45-3.35 6.78' 3.45-3.35 3 2 2 2 2 4 2 dd tf m m m dh m 2.G1.79 1 1.61-1.31 4 1.59-1.53 2 1.61-1.55 2 1.86 3 CH (CH,), CH, CH, C Me 0.95 0.91 1.26-1.25 1.54-1.25 6 df 3 tf 6 m 12 m 2 x Me Me (CHZ), 0.85-0.82 (CH,), 0.90-4.84 3 3 m m Me Me All spectra were run on Varian XL 200 (200 MHz, FT mode), in CDCI,.Multiplicity: m = multiplet, t = triplet, d = doublet, s = singlet. 'See aromatics. J = 5 Hz. 'NH signal was very broad. J = 7 Hz. '4 H. J = 6 Hz. Table 9. Preparation of the N-monoalkylated amines (6) and (7) Reduction of Adducts to Secondary Amines.-Some of theRCH,NHCH,R' adducts were also reduced by LiAIH, (Scheme 3) to give the G.c.-m.s. expected secondary amines (6)and (7) (Table 9). The identity of AYield bsol; these secondary amines were confirmed by their 'H n.m.r. Product R R' () Calculated Obtained spectra. (6a) R Ph 76 121.089 l(4) 121.088 2(6) In the 'H n.m.r. spectra of the amine (6),the characteristic (6b) Pr' Ph 75 163.136 O(9) 163.136 7(6) methylene protons attached to the aromatic ring appeared as a (k) Pr Ph 58 163.136 O(9) 163.136 l(5) singlet at 6 3.75-3.69, whereas the doublet at 6 2.61-2.40 (6d) Pentyl Ph 66 192.1673(4) 191.1668(2) p.p.m.corresponds to the protons attached to C-a for the (6e) Octyl Ph 64 233.214 3(4) 233.2154(1) (60 Ph Ph 65 197.120 4(4) 198.1 19 3(5) amines (6b-e) (Table 10). The I3C n.m.r. spectra of the N-(70 Me Me 83 135.1047(9) 135.1045(9) alkylated amines (6) and (7) (Tables 4 and 5) showed some similarities to those of the corresponding adducts. The reduced carbonyl carbon appeared as methylene carbon at 6 57.2-53.0 and C-a resonated at 6 53.8-35.6 p.p.m. (Table 4). 'H n.m.r. data of the amides (4) and (5) are shown in Table 8. Table 11 records some of the most characteristic i.r.bands The absorption peaks for the protons attached to C-a are now for compounds (2)-(7). All exhibit the expected absorptions in shifted upfield to 6 4.55-2.96. the regions 3 310-3 265 and 1 600-1 525 cm-', respectively, J. CHEM. SOC. PERKIN TRANS. I 1988 2343 Table 10. 'H N.m.r. chemical shifts of the N-alkylated amines (6) and (7)"' R LR1,2-,3-,4-H NH R'CH, NHCH, I Product (5 H, m) (1 H, s) (2 H, s) (2 H, t, J 7 Hz) (m) H H m (W 7.2 1.89 3.69 2.40 (6b) 7.28-7.26 f 3.73 2.40 1.84-1.64 1 CH 0.88 6 de 2Me (6c) 7.31-7.23 f 3.78 2.61 1.83-1.24 4 (CH,), 0.90 3 ts Me (6d) 7.30-7.20 h 3.75 2.60 1.56-1.28 9 (CH,),, NH 0.91-0.84 3 m Me (amp;) 7.31-7.23 h 3.76 2.60 1.60-1.02 15 (CH,),, NH 0.98-4.78 3 m Me (60 7.30-7.20' 1.67 3.75' (R = R') (70 8.32-8.19 2.47 4.66 3.62-3.51k 2.07-1.99 3 Me " All spectra were run on XL 200 (200 MHz, FT mode).All spectra were run in CDCI,. Reference was Me,Si. Singlet. 3 H, s. NH signal was broad. g J = 7 Hz. hNH signal was in aliphatic region. 10 H. j 4 H. Multiplet. Table 11. 1.r. characteristic bands for compounds (2)--(7)"*b 283B spectrophotometer. 'H N.m.r. spectra were obtained on Varian XL200 (200 MHz, FT mode) spectrometer, with Me,Si NH G-0 NH as an internal standard. I3C N.m.r. spectra were obtained on a stretching stretching bending Varian XL200 (50 MHz) spectrometer. 3 300m 1 650s 1 560m 3 300m 1665m 1575w General Procedure for the Preparation of Adducts (2) and 3 300w 1670m 1 525m (3).--Method A.N-Hydroxymethylbenzotriazole (14.9 g, 0.1 3 290w 1 665m 1 530m mol), the amide (0.1 mol), and dry toluene (40 ml) were refluxed 3 300m 1 660s 1 580w in a Dean-Stark apparatus for the appropriate length of time 3 280w 1650m 1525m and the water collected was removed azeotropically. The 3 265s 1675s 1535m toluene was removed at 6O0C/3O mmHg. The residue was3 280m 1645s 1 520m treated with diethyl ether (200 ml) and the resulting solid 3 280w 1 690s 1515w 3 300s 164om 1 540m recrystallized from the appropriate solvent to give compound 3 290m 1 640s 1 54om (2) or (3) (see Table 1). 3 300s 1 640s 1535m Method B. Benzotriazole (11.9 g, 0.1 mol), the aldehyde (0.1 3 310m 1640m 1535m mol), and the amide (0.1 mol) were refluxed for 24-48 h in dry 3 310s 1 640s 1 540s toluene (40 ml) in a Dean-Stark apparatus.Water (ca. 1.5 ml) 3 310w 164ow 1 570m was formed and removed azeotropically. Toluene was then 3 290m 1635m 1 540m removed at 60 "C/30 mmHg and the residue was treated with 3 310w 16OOW diethyl ether (200 ml) and the resulting solid was recrystallized 3 300w 16oOW 3 300w 16oOw from the appropriate solvent to give compound (2) or (3) (see 3 300w 16oOw Table 1). 3 300w 1600w 3 310w 16oOW General Procedure for Preparation of N-Alkylated Amides (4) 3 290w 16oOW and (5).-Compound (2) or (3) (3 mmol) was dissolved in " All spectra were run on a Perkin-Elmer 285B spectrophotometer. absolute ethanol (30 ml). Solid sodium borohydride (0.33 g, 9 'Solids were run as mulls in Nujol, the oils (amines) were run as mmol) was added in one portion to the stirred solution.The films. Intensity: s = strong, m = medium, w = weak. clear solution was refluxed for 3 h and the solvent was evaporated at 30 "C. The residue was diluted with water (30 ml) and extracted with chloroform (3 x 30 ml). The organic layer corresponding to the N-H stretching and bending vibrations. was washed with 2M NaOH (30 ml), water (30 ml), and dried Compounds (2)-(5) also showed the characteristic medium to with MgSO, (10 g). The solvent was evaporated at 20 "C, to strong absorption for the amide carbonyl group at 1 670-1 635 afford the amides which were pure by t.l.c., 'H n.m.r., and m.p.s cm-' . (Table 7). General Procedure for Preparation of N-Alkjdated Amines (6)Conclusion and (7).-Compound (2) or (3) (3 mmol) was dissolved in dry The easy formation of acyl- and aroyl-aminobenzotriazole THF (30 ml).Solid lithium aluminium hydride (0.30 g, excess) derivatives thus allows the exclusive N-monoalkylation of was slowly added in three portions to the stirred solution. The aliphatic and aromatic amides by reduction of these adducts resulted suspension was heated for 30 min. Ice (1 g) was added using sodium borohydride in absolute ethanol. Additionally, N-to decompose the unchanged lithium aluminium hydride. The alkylated amines were prepared from the adducts with an excess solvent was evaporated at 30 "C.The residue was treated with of lithium aluminium hydride in THF. The sequences each 2~ NaOH (30 ml) and extracted with chloroform (3 x 30 ml).proceed with good overall yields for both aliphatic and The organic layer was washed with 2~ NaOH (30 ml) and aromatic aldehydes. water (30 ml) and dried with MgSO, (10 g). The solvent was This new method thus allows the N-monoalkylation of evaporated at 20deg;C to afford benzylamines pure by t.l.c., 'H amides in a two-step procedure, applicable on a large scale, and n.m.r., and g.c.-m.s. (Table 9). using readily accessible reagents. Experimental References 1 Part 7, A. R. Katritzky, K. Yannakopoulou, W. Kuzmierkiewicz,M.p.s were determined on a Kofler hot-stage microscope, and J. M. Aurrecoechea, G. J. Palenik, A. E. Koziol, M. Szczesniak, and are uncorrected. 1.r. spectra were recorded on a Perkin-Elmer R. Skarjune J.Chem. Soc., Perkin Trans. I, 1987, 2673. 2 E. R. H. Walker, Chem. SOC.Rev., 1976, 5, 23. 3 B. C. Challis, J. N. Iley, and H. S. Rzepa, J. Chem. SOC., Perkin Trans. 2, 1983, 1037. 4 M. Julia and H. Mestdagh, Tetrahedron, 1983, 39, 433. 5 H. Nishiyama, H. Nagase, and K. Ohno, Tetrahedron Lett., 197 rsquo;,48,4671. 6 A. R. Katritzky and R. A. Y. Jones, Chem. Ind. (London), 1961 722. 7 P. Hepp, Ber., 1877, 10, 327. 8 A. Pictet, Ber., 1887, 20, 3422. 9 G. L. Isele and A. Luttringhaus, Synthesis, 1971, 266. 10 R. A. W. Johnstone and M. E. Rose, Tetrahedron, 1979,35, 2 69. 11 W. S. Jones. J. Ora. Chem.. 1949. 14. 1099. 12 J. D. Park, R. D. Eiglert, and J. S.rsquo;Meek,J. Am. Chem. SOC., 1952,74, 1010. 13 A. Koziara, S. Zawadzki, and A.Zwierzak, Synthesis, 1979, 527. 14 T. Gajda and A. Zwierzak, Synthesis, 1981, 1005. 15 K. Sukata, Bull. Chem. SOC. Jpn., 1985, 58, 838. 16 T. Shono, S. Kashimura, and H. Nogusa, Chem. Lett., 1986, 425. 17 Y. Watanabe, T. Ohta, and Y. Tsuji, Bull. Chem. SOC. Jpn., 1983,56, 2647. 18 J. Auerbach, McFord Zamore, and S. M. Weinreb, J. Org. Chem., 1976, 41, 725. 19 H. E. Johnson and D. G. Crosby, J. Org. Chem., 1962, 27, 2205. 20 L. Bernardi, R. de Castiglione, and U. J. Scarponi, J. Chem. SOC., Chem. Commun., 1975, 320. J. CHEM. SOC. PERKIN TRANS. I 1988 21 J. W. Batty, P. D. Howes, and C. J. M. Stirling, J. Chem. SOC., Perkin Trans. I, 1976, 1543. 22 A. R. Katritzky, S. Rachwal, and B. Rachwal, J. Chem. SOC., Perkin Trans. I, 1987, 799. 23 L. Avila, J. Elguero, S. Julia, and J. M. del Mazo, Heterocycles, 1983, 20, 1787. 24 E. Breitmaier and W. Voelter, lsquo;I3C NMR Spectroscopy,rsquo; 2nd edn., Verlag Chemie, Weinheim, New York, 1978. 25 C. J. Pouchert, lsquo;The Aldrich Library of NMR Spectra,rsquo; 2nd edn., Aldrich Chemical Co., Milwaukee, Wisconsin, 1983, vol. 2, p. 343D. 26 F. L. Dunlap, J. Am. Chem. SOC., 1902, 24, 758. 27 Beil., 9, 203. 28 J. von Braun and J. Weismantel, Ber., 1922, 55, 3165. 29 B. Prajsner and C. Troszkiewicz, Rocz. Chem., 1962, 36, 853. 30 J. von Braun and W. Sobecki, Berl., 1911,44, 1464. 31 lsquo;Dictionary of Organic Compounds,rsquo; 5th edn., Chapman and Hall, New York, 1982, vol. 1, p. 604. 32 lsquo;CRC Handbook of Chemistry and Physics,rsquo; 1984-85, R. C. Weast, CRC Press Inc., p. C-66. Received 28th August 1987; Paper 711579