J. CHEM.SOC. PERKIN TRANS. I 1992 Reaction of N-Substituted Cyclic Amines with 2,4-Dichloroquinazoline, 2,4-Dichloropyrimidine, and its 5-Methyl Derivative Kenji Yoshida and Masahiro Taguchi Pharmaceuticals Research Center, Kanebo Ltd., 5-90,Tomobuchi-cho I -Chome, Miyakojima-ku, Osaka 534, Japan The reaction of N-substituted cyclic amines with 2,4-dichloroquinazoline 2 and 2,4-dichloro-5-methyI- pyrimidine 3b afforded 2-ami no-4-c h loroq u inazolines and 2 -amino -4 -c hloro-5-met h yIpyri mid ines, respectively. However, the reaction of these amines with 2,4-dichloropyrimidine 3a afforded not only 2-amino-4-chloropyrimidines but also the isomeric 4-amino-2-chloropyrimidines. The regio-selectivity of these reactions was considered to be determined by the steric nature of the substrates 2,3a and 3b.In our previous paper, we described how the reaction of quinazoline-2,4(1H,3H)-dione with N-substituted cyclic amines in combination with phosphoryl trichloride afforded 4-chloro- 2-(cyclic amin0)quinazolines regioselectivel y. ' Moreover, we reported that 2,4-dichloroquinazoline 2 was considered as an intermediate in the reaction. We have now found that the reaction of compound 2 with N-methylpiperidine Ib in 1,4- dioxane afforded 4-chloro-2-piperidinoquinazoline4a.In order to elucidate the regioselectivity of the reaction, we focused on the reaction of N-substituted cyclic amines (la-f) with 2,4- dichloropyrimidine3a and 2,4-dichloro-5-methylpyrimidine3b. This paper describes the reactions of cyclic amines la-f with substrates 2,3a and 3b.When compound 2 was allowed to react with N-methyl- piperidine lb (1.2 mol equiv.) in 1,4-dioxane at 100 "Cfor 1 h, 4-chloro-2-piperidinoquinazoline4a was isolated in 92 yield. The structure of the product 4a was confirmed by comparison with an authentic sample prepared by the method described in our previous paper.' In order to elucidate the scope and limitation of this type of reaction, the reaction of compound 2 with other cyclic amines was examined. The results are summarized in Table 1. In the case of six- or seven-membered cyclic amines (1be), the reaction proceeded regioselectively, and only quinazoline derivatives (4a or 4b), in which cyclic amines were substituted at the 2-position of quinazoline, were isolated.On the other hand, the reaction of compound 2 with five-membered cyclic amine la afforded 4-chloro-2-N-(4- chlorobuty1)-N-methylaminoJquinazoline 5. These results were in good accord with those of the reaction of quinazoline- 2,4( 1H,3H)-dione with N-substituted cyclic amines in combin- ation with phosphoryl trichloride.' It is well known that the 4-position of the quinazoline 2 is more reactive than the 2-position toward nucleophilic attack by primary or secondary amines.' The above reaction, however, indicates that the 2-position of compound 2 is more reactive than the 4-position for the attack by tertiary amines. In order to elucidate the regioselectivity ofthe above reaction, the reaction of substrates la-f with 2,4-dichloropyrimidine 3a and 2,4- dichloro-5-methylpyrimidine3b was examined.The reaction of the methylpyrimidine 3b with N-methyl-piperidine 1b afforded 4-chloro-5-met hyl-2-piperidinopyrimi- dine 6c in 84 yield. The structure of compound 6c was confirmed by comparison with an authentic sample prepared by chlorination of 5-methyl-2-piperidinopytimidin-4(3H)-0ne.~ The structure of product 6c was further confirmed by comparison of its NMR spectra with those of 2-chloro-5- methyl-4-piperidinopyrimidine7c, which was prepared by the reaction of dichloride 3b with piperidine. The 'H and 13C CI CI la; R=Me,n =4 2 3a; R=H b; R=Me,n =5 b; R=Me c; R=Me,n =6 d; R = CHpCH=CH2, n = 5 e; R=CHPPh,n =5 f; R=Pr,n =5 CI CI IMe 4a; n =5 b; n =6 6a; R=H, n =5 7a; R=H,n =5 b; R=H,n =6 b; R=H,n =6 c; R=Me,n =5 c; R=Me,n =5 d; R=Me,n =6 7' 8a; R=H 9 b; R=Me NMR assignments of regioisomers 6c and 7c were made based on C-H COSY, COLOC, and LSPD spectra and the data are shown in Tables 2 and 3.In the UV spectra, regioisomers 6c and 7c showed an absorption maximum at 325 and 289 nm, respectively. The results of the reaction of dichloride 3b with other N-substituted cyclic amines are summarized in Table 1. In the case of N-substituted six- or seven-membered cyclic amines, 4-chloro-2-(cyclicamino)-5-methylpyrimidines(6c or 6d) were obtained. However, in the case of N-substituted five-membered cyclic amine la, 4-chloro-2-N-(4-chlorobutyl)-N-methyl- 920 J.CHEM. SOC. PERKIN TRANS. I 1992 Table 1 Reaction of N-substituted cyclic amines (la-f) with 2,4-dichloroquinazoline 2, 2,4-dichloropyrimidines 3a, or 2,4-dichloro-5-methylpyrimidine 3b in 1,Cdioxane Reaction Reaction Isolation Amine Dichloride temp. ("C) time (r/h) Product yield () la 2 100 0.5 lb 2 100 1 lc 2 100 1 Id 2 120 6 le 2 120 12 la 3a 120 1 lb 3a 120 1.5 lc 3a 120 2 Id 3a 120 6 le 3a 120 12 If 3a 120 4 la 3b 100 4 lb 3b 100 4 lc 3b 120 2 Id 3b 120 12 le 3b 120 36 " Recovered. Table 2 'H and 13C NMR chemical shifts (6) of compound 6c in CDCI,, and results of COLOC experiments" 'H 1.54-1.67 2.12 3.73 8.04 I3C (3'-,4'-, 5'-H) (5-Me) (2'-,6'-H) (6-H) 160.6 (C-4) Jb 3J 160.4 (C-2) ,J 158.7 (C-6) 'J 115.3 (C-5) 2J zJ 44.7 (C-2', -6') 'J 25.6 (C-3', -5') 'J 2J 24.6 (C-4') J 15.1 (5-Me) 'J " 'J, ,J and 4Jindicate long-range coupling through two, three and four bonds, respectively.Change of the multiplicity was observed in LSPD experiment irradiated at 6 3.73. Table 3 'H and 13C NMR chemical shifts (6) of compound 7c in CDCI,, and results of COLOC experiments" 'H 1.62-1.74 2.19 3.49 7.88 I3C (3'-, 4'-, 5'-H) (5-Me) (2'-, 6'-H) (6-H) 165.3 (C-4) ,Jb 3J 159.0 (C-6) 'J 157.6 (C-2) ,J 114.9 (C-5) 'J 2J 48.3 (C-2', -6') 'J 25.7 (C-3', -5') 'J 'J 24.3 (C-4') 'J ,J 17.3 (5-Me) 'J 'J 'J, ,Jand 4Jindicate long-range coupling through two, three and four bonds, respectively.Change of the multiplicity was observed in LSPD experiment irradiated at 6 3.49. amino-5-methylpyrimidine 8b was obtained. The UV spectra of products 6c,6d and 8b showed an absorption maximum at -320 nm (Table 4) and suggested that the amino groups were substituted at the 2-position of the pyrimidine ring. On the other hand, the reaction of the piperidine lb with dichloropyrimidine 3a afforded not only 4-chloro-2-piperidino- pyrimidine 6a but also its regioisomer 2-chloro-4-piperidino- pyrimidine 7a in 24 and 76 yield, respectively. The structure of 5 43 4a 92 4b 87 4a, 2" 12,77" 4a, 2" 8,72" 8a, 9 5, 80 6a, 7a 24,76 6b, 7b 34,60 6a, 7a, 3a" 43,31,16" 6a, 7a, 3a" 22,20,49 " 6a,7a, 3a" 40,38, 14" 8b 78 6c 84 4d 83 6c,3b" 19,74" 6c,3b" 4,87" the products 6a and 7a was confirmed by comparison with authentic samples, which were prepared by chlorination of 2-piperidinopyrimidin-4(3H)-one and by the reaction of dichloride 3a with piperidine, respectively.These structures were further confirmed by the UV absorption maximum, at 315 and 290 nm respectively, which were in good accord with those of compounds 6c and 7c, respectively. The reaction of dichloride 3a with other N-substituted six- or seven-membered cyclic amines also afforded not only 2-chloro- 4-(cyclic amino)-5-methylpyrimidine (6a or 6b) but also the regioisomeric 4-chloro-2-(cyclic amino)-5-methylpyrimidine (7a or 7b).In the case of N-methyl five-membered cyclic amine la, 4-chloro-2-N-(4-chlorobutyl)-N-methylaminopyrimidine 8a and 2-chloro-4-N-(4-chlorobutyl)-N-methylaminopyrimi-dine 9 were obtained. The results are summarized in Table 1 and the structure of the products was assigned by their UV and * H NMR spectral data (Tables 4 and 5). It was reported that the reactivity of the 2-position of dichloride 3a relative to the 4-position increases as the solvent polarity and the nucleophilicity of the primary and secondary amines are decreased.6 In the above reaction of compound 3a with tertiary amines, the ratios of 2-amino-4-chloropyrimidines to 4-amino-2-chloropyrimidinesincreased with the increased bulk of the N-substituent and the ring size of the cyclic amines (8a/9,6a/7a and 6b/7b).The 4-position of compound 3a is considered to be more hindered than the 2-position by the presence of a hydrogen atom at the 5-position. Therefore, the increase of these ratios is explained by the steric hindrance between N-substituted cyclic amines and the hydrogen atom at the 5-position of compound 3a. On the other hand, compound 2 has a hydrogen atom at the 5-position (peri-position) and compound 3b has a methyl group at the 5-position. Owing to the presence of these groups, the 4-position of compounds 2 and 3b is considered to be more hindered than that of compound 3a. The steric interaction between these groups and the N-substituted cyclic amines is considered to be a main reason for the regioselective attack by the cyclic amines on the 2-position of substrates 2 and 3b.In conclusion, the regioselectivity of the reaction of compound 2,3a or 3b with the N-substituted cyclic amines are reasonably explained by the steric hindrance between the N-substituted cyclic amines and the substituent at the 5-position of the substrate 2, 3a or 3b. The reaction of compounds 2 and 3b with the N-substituted cyclic amines offers a new synthetic J. CHEM. SOC. PERKIN TRANS. I 1992 921 Table 4 Physical data for 2-amino-4-chloropyrimidines(6a-d,8a, 8b) and 4-amino-2-chloropyrimidines (7a-c, 9) Found () (Requires) Compound M.p. ("C) Recrystallizationsolvent m/z 1,,, (EtOH)/nm(/dm3 mol-' cm-I) Formula C H N 64' 6b 6c 6d 71 7b 7c 8a 8b 9 oil oil oil oil 8 1-82 oil 6 1-62 oil oil oil hexane hexane 197 (M'), 96 (base) 211 (M+), 70 (basej 21 1 (M +), 204 (base) 225 (M +,base), 164 197 (M + ,base), 218 211 (M'), 232 (base) 283 (M'), 206 (base) 233 (M'), 9 1 (base) 247 (M +), 206 (base) 233 (M+), 9 1 (base) 315 (2300), 251 (22 800) 318 (2400), 251 (22 200) 325 (2500), 250 (25 600) 327 (2000), 251 (20400) 290 (4800), 254 (17 900) 290 (4700), 253 (16 900) 289 (7000), 262 (10 600) 316 (2700), 248 (23 100) 324 (2700), 248 (24 300) 289 (4400), 251 (15 600) C9H 1 2C1N3 C ,H I ,GIN,*O.1 H,O 1OH c1 1 16C1N3 C9H 12C1N3 1 OH 14C1N3 1OH 14C1N3 C9H I 3C12N3 CIOH 1 SC1ZN3 C9H1 ,C12N3 54.5 (54.69 56.3 (56.26 56.45 (56.74 58.4 (58.53 54.8 (54.69 56.7 (56.74 56.7 (56.74 46.3 (46.17 48.3 (48.40 46.35 (46.17 6.2 6.12 6.6 6.70 6.5 6.67 7.1 7.14 6.1 6.12 6.6 6.67 6.5 6.67 5.5 5.60 6.0 6.09 5.6 5.60 21.2 21.26) 19.5 19.68) 19.8 19.85) 18.5 18.62) 21.3 2 1.26) 19.6 19.85) 19.9 19.58) 17.8 17.95) 16.9 16.93) 17.7 17.95) a Ref.4. Ref. 5. Ref. 7. Table 5 H NM R spectral data for 2-amino-4-chloropyrimidines (6a4, Sa, 8b) and 4-amino-2-chloropyrimidines(7a-c,9). Chemical shifts (6)and coupling constant (Hz, in parentheses) Compound 5-H 6- H Others 6a 6.43 (d, J 5.1) 8.12 (d, J 5.1) 1.54-1.74 (6 H, m, CH,CH,), 3.77 (4 H, t, J5.4, NCH,) 6b 6.44(d,J5.1) 8.13(d, J5.1) 1.52-1.84 (8 H, m, CH,CH,), 3.73 (4 H, t, J6.0, NCH,) 6c 8.04 (s) 1.54-1.74 (6 H, m, CH,CH,), 2.13 (3 H, s, 5-Me), 3.73 (4 H, t, J 5.3, NCH,) 6d 8.05 (s) 1.52-1.88 (8 H,m, CH,CH,), 2.14 (3 H, s, 5-Me), 3.70 (4 H, t, J 5.9, NCH,) 7a 6.38 (d, J 6.2) 7.97 (d, J 6.2) 1.57-1.77 (6 H, m, CH,CH,), 3.52-3.72 (4 H, m, NCH,) 7b 6.29 (d, J 6.2) 7.97 (d, J 6.2) 1.48-1.86 (8 H, m, CH,CH,), 3.36-3.86 (4 H, m, NCH,) 7c 7.89 (s) 1.62-1.74 (6 H, m, CH,CH,), 3.43-3.53 (4 H, m, NCH,) 8a 6.47 (d, J 5.1) 8.13 (d, J 5.1) 1.72-1.88 (4 H, m,CH,CH,), 3.13 (3 H, s, NMe), 3.53-3.72 (4 H, m, NCH, and CH,CI) 8b 8.05 (s) 1.68-1.85 (4 H, m, CH,CH2), 2.14 (3 H, s, 5-Me), 3.1 1 (3 H, s, NMe), 3.563.70 (4 H, m, NCH, and CH,CI) 6.30 (d, J 6.1) 8.01 (d, J6.1) 1.68-1.88 (4 H, m, CH,CH,), 3.06 (3 H, s, NMe), 3.50-3.74 (4 H, m, NCH, and CH,CI) method for 4-chloro-2-(cyclic amino)quinazolines and 4-chloro- Preparation of 4-Chloro-2-piperidinopyrimidine6a.-A mix-2-(cyclicamino)-5-methylpyrimidines. ture of 2-piperidinopyrimidin-4(3H)-one,(0.18 g, 1 .O mmol) and phosphoryl trichloride (0.31 g, 2.0 mmol) was heated at 100°C for 1 h.After being cooled to room temperature, the Experimental mixture was dissolved in CHC13 (10 cm3) and poured into ice- M.p.s were measured with a Yamato capillary melting point water. After being neutralized with 2 mol dm-, NaOH, the apparatus, model MP-21, and are uncorrected. 'H and 13C organic layer was separated, washed with water, dried over NMR spectra were recorded on a Brucker AM-300 spectro- MgSO,, and evaporated under reduced pressure. Upon PLC meter for solutions in CDCl,, and tetramethylsilane was used hexane-AcOEt (5:1) the residue gave compound 6a (0.17 g, as internal reference.Mass spectra were determined with an 86) as an oil. Hitachi M-80B spectrometer. Analytical and preparative TLC (PLC) were performed on silica gel 60 F,,, precoated plates Preparation of 4-Chloro-5-me thy i-2-piper idin opyr imidine (No. 571 7 and No. 571 5, respectively; Merck). .--A mixture of 5-methyl-2-piperidinopyrimidin-4(3H)-one (0.19 g, 1.0 mmol) and phosphoryl trichloride (0.31 g, 2.0 Reaction of Compounds 2, 3a and 3b with Several N-mmol) was heated at 100 "C for 30 min. After being cooled to Substituted Cyclic Amines.-The results are summarized in room temperature, the mixture was dissolved in CHCl, (10 Table 1. As a typical example, the reaction of dichloride 2 with cm3) and poured into ice-water. After being neutralized with amine lb is described below.A mixture of compound 2 (0.40 g, 2 mol dm-3 NaOH, the organic layer was separated, washed 2.0 mmol) and amine 1b (0.24 g, 2.4 mmol) in 174-dioxane (5.0 with water, dried over MgSO,, and evaporated under reduced cm3) was heated at 100 "C for 1 h. After being cooled to room pressure. Upon PLC (hexane-AcOEt (5 :l) the residue gave temperature, the mixture was concentrated under reduced compound 6c(0.20 g, 93) as an oil. pressure. Upon PLC with hexane-AcOEt (511)as develop- ing solvent, foowed by recrystallization from MeCN, the Preparation of 2-Chloro-5-methyl-4-piperidinopyrimidine 73-7c.-A solution of piperidine (0.34 g, 4.4 mmol) in 1,4-dioxane TeildUe gave compound 4a (046 g, 92) as crystals, m-~.15T. (3.0 cm3) was added dropwise to an ice-cooled solution of 2,4- dichloro-5-methylpyrimidine3b (0.33 g, 2.0 mmol) in 1,4-dioxane (3.0 cm3). The mixture was stirred at room temperature for 2 h and then evaporated under reduced pressure. Upon PLC hexane-AcOEt (3:1) the residue gave compound 7c (0.35 g, 83) as crystals. Acknowledgements We thank Dr. Goro Tsukamoto for his continued interest and encouragement. References 1 K. Yoshida, T. Tanaka and H. Ohtaka, J. Chem SOC.,Perkin Trans. I, 1991,1279. J. CHEM. SOC. PERKIN TRANS. 1 1992 2 W. L. F. Armarego, in The Chemistry of Heterocyclic Compounds, Fused Pyrimidines, Part I, Quinazolines, Wiley, New York, 1967, p. 228. 3 J. Reiter and L. Toldy, Acfa Chim. Acad. Sci. Hung., 1974,82,99. 4 B. Roth and L. A. Schloemer, J. Org. Chem., 1963,28,2659. 5 C.A. H. Rasmussen, H. C. van der Plas, P. Grotenhuis and A. Koudijs, J. Heterocycl. Chem., 1978, 15, 1121. 6 0. A. Zagulyaeva, N. V. Bukhatkina and V. P. Mamaev, Zh. Org. Khim., 1978,14,409. 7 I. I. Kuz’menko, USSR Pat., 551 329, 1977 (Chem. Abstr., 1977, 87, 39530); I. I. Kuz’menko and Yu. V. Bardik, Fiz. Akt. Veshchestua, 1988,20, 1 (Chem. Abstr., 1989, 110, 18178). Paper 1/048 12K Receiued 17th September 1991 Accepted 10th December 1991
展开▼
