Indian Journal of Chemistry Vol. 49B, March 2010, pp. 382-385 Note aisen-schmidt condensation under solventfree conditions K Mogilaiah*, T Kumara Swamy, A Vinay Chandra, N Srivani & K Vidya Department of Chemistry, Kakatiya University, Warangal 506 009, India E-mail: mogilaiah_k@yahoo.co.in Received 16 January 2009; accepted (revised) 26 ctober 2009 aisen-schmidt condensation of 2-(4-acetyl-phenylamino)-3- (4-chlorophenyl)-1,8-naphthyridine 3 with various aromatic aldehydes under solvent-free conditions to prepare α-βunsaturated ketones 4 using solid NaH as catalyst has been described. The reaction proceeds efficiently at room temperature in high yields and in a state of excellent purity. Keywords: aisen-schmidt condensation, 1,8-naphthyridine, α-β-unsaturated ketones, solid NaH, solvent-free conditions. The development of new strategies for the preparation of organic molecules in neat conditions is a challenging area of organic synthesis. For instance, a large number of organic reactions are typically carried out under anhydrous conditions, using volatile organic solvents like benzene, which are the cause of environmental problems and are also potentially carcinogenic. Hence, it is required to develop safe, practical and environment friendly processes. The pioneering work of Toda et al. 1,2 has shown that many exothermic reactions, can be accomplished in high yield by just grinding solids together using mortar and pestle, a technique known as Grindstone Chemistry which is one of the Green Chemistry Techniques. Reactions are initiated by grinding, with the transfer of very small amount of energy through friction 3. In addition to being energy efficient Grindstone Chemistry also results in high reactivity and less waste products., Chalkones, more generally α,βunsaturated ketones are versatile intermediates as they can be readily converted into biologically interesting heterocycles 4-6. Further, the 1,8-naphthyridine ring system is an important pharmacophoric element in medicinal chemistry 7-11. In view of this, and in continuation of our interest on solvent-free organic reactions on 1,8-naphthyridine derivatives 12-14 we report herein the aisen-schmidt condensation under solvent-free conditions. Treatment of 2-amino-3-(4-chlorophenyl)-1,8- naphthyridine with HN 2 gave 1,2-dihydro-3-(4- chlorophenyl)-1,8-naphthyridin-2-one, which on interaction with P 3 yielded the desired synthon, 2- chloro-3-(4-chlorophenyl)-1,8-naphthyridine 1 (ref. 15). The reaction of 1 with 4-aminoacetophenone 2 in the presence of Na 2 C 3 in the solid state afforded 2-(4- acetylphenylamino)-3-(4-chlorophenyl)-1,8-naphthyridine 3 in 96% yield. aisen-schmidt condensation of 3 with various aromatic aldehydes in the presence of solid NaH in combination with grinding at room temperature in the absence of solvent afforded 2-(4-cinnamoylphenylamino)-3-(4-chlorophenyl)-1,8-naphthyridines 4 (Chalkones or α,β-unsaturated ketones, Scheme I). The yields of the products are good to excellent and purity is high. The process is simple, efficient, economical and environmentally benign. The transformation is very clean and rapid and devoid of any by-products, and the work-up procedure is simple and convenient. In a typical case, an equimolar mixture of 3, benzaldehyde and solid NaH was ground in a mortar by pestle at room temperature for 5.5 min. Work-up of the reaction-mixture afforded 4a ( = C 6 H 5 ) in 90% yield, m.p. >300ºC. The generality of this facile condensation was established by condensing other aromatic aldehydes with 3 in the presence of solid NaH under solventfree grinding conditions to get the corresponding cinnamoylphenylamino 1,8-naphthyridines 4b-j. The results are summarized in Tables I and II. The structures of the compounds 3 and 4 were established by their elemental analyses and spectral (IR and 1 H NMR) data. The significant advantages of this procedure are operational simplicity, high purity of the products, very good yields, short reaction times and minimum environmental impact. Experimental Section Melting points were determined on a Cintes melting point apparatus and are uncorrected. The purity of the compounds was checked using precoated TLC plates (Merck, 60F-254). IR spectra (KBr, cm -1 )
NTES 383 were recorded on a Perkin-Elmer spectrum BX series FT-IR spectrophotometer and 1 H NMR spectra on a
384 INDIAN J. CHEM., SEC B, MARCH 2010 N N + H 2 N 1 Na 2 C 3 Grinding 2 N N NH 3 -CH solid NaH Grinding N N NH a, C 6 H 5 b, 4-CH 3 C 6 H 4 c, 4-CH 3 C 6 H 4 d, 2-C 6 H 4 e, 4-C 6 H 4 4 f, 4-FC 6 H 4 g, 3-N 2 C 6 H 4 h, 4-N 2 C 6 H 4 i, 4-(CH 3 ) 2 NC 6 H 4 j, 2-HC 6 H 4 Scheme I Table I IR and 1 H NMR spectral data of 2-(4-cinnamoylphenylamino)-3-(4-chlorophenyl)-1,8-naphthyridines 4 Compd 4a 4b 4c 4d IR ν max in cm -1 3410 (NH), 1662 (C=), 1605 (C=N), 985 (HC=CH, trans) 3425 (NH), 1674 (C=), 1608 (C=N), 982 (HC=CH, trans) 3420 (NH), 1674 (C=), 1604 (C=N), 984 (HC=CH, trans) 3428 (NH), 1673 (C=), 1607 (C=N), 985 (HC=CH, trans) 1 H NMR (400 MHz, DMS-d 6 ) (δ ppm) 6.62 (d, 1H, olefinic C α -H), 7.90 (m, 1H, C 6 -H), 8.20 (m, 2H, C 4 -H, C 5 -H), 8.52 (m, 1H, C 7 -H), 7.22-7.82 (m, 14H, olefinic C β -H, 13-H), 12.35 (s, 1H, NH) 2.32 (s, 3H, CH 3 ), 6.64 (d, 1H, olefinic C α -H), 7.94 (m, 1H, C 6 -H), 8.18 (m, 2H, C 4 -H, C 5 -H), 8.54 (m, 1H, C 7 -H), 7.20-7.80 (m, 13H, olefinic C β - H, 12-H), 12.36 (s, 1H, NH) 3.82 (s, 3H, CH 3 ), 6.62 (d, 1H, olefinic C α -H), 7.00 (d, 1H, olefinic C β - H), 7.90 (m, 1H, C 6 -H), 8.15 (m, 2H, C 4 -H, C 5 -H), 8.56 (m, 1H, C 7 -H), 7.23-7.78 (m, 12H -H), 12.35 (s, 1H, NH) 6.62 (d, 1H, olefinic C α -H), 7.95 (m, 1H, C 6 -H), 8.19 (m, 2H, C 4 -H, C 5 -H), 8.53 (m, 1H, C 7 -H), 7.25-7.80 (m, 13H, olefinic C β -H, 12-H), 12.36 (s, 1H, NH) Contd
NTES 385 Table I IR and 1 H NMR spectral data of 2-(4-cinnamoylphenylamino)-3-(4-chlorophenyl)-1,8-naphthyridines 4 Contd Compd IR ν max in cm -1 4e 3425 (NH), 1652 (C=), 1605 (C=N), 980 (HC=CH, trans) 4f 3422 (NH), 1673 (C=), 1602 (C=N), 982 (HC=CH, trans) 4g 3415 (NH), 1656 (C=), 1606 (C=N), 982 (HC=CH, trans) 4h 3408 (NH), 1658 (C=), 1605 (C=N), 985 (HC=CH, trans) 4i 3425 (NH), 1651 (C=), 1607 (C=N), 980 (HC=CH, trans) 4j 3500 (NH), 1674 (C=), 1605 (C=N), 986 (HC=CH, trans) 1 H NMR (400 MHz, DMS-d 6 ) (δ ppm) 6.63 (d, 1H, olefinic C α -H), 7.90 (m, 1H, C 6 -H), 8.16 (m, 2H, C 4 -H, C 5 -H), 8.52 (m, 1H, C 7 -H), 7.22-7.78 (m, 13H, olefinic C β -H, 12-H), 12.37 (s, 1H, NH) 6.62 (d, 1H, olefinic C α -H), 7.02 (d, 1H, olefinic C β -H), 7.92 (m, 1H, C 6 -H), 8.18 (m, 2H, C 4 -H, C 5 -H), 8.53 (m, 1H, C 7 -H), 7.05-7.78 (m, 12H, -H), 12.35 (s, 1H, NH) 6.64 (d, 1H, olefinic C α -H), 7.95 (m, 1H, C 6 -H), 8.18 (m, 2H, C 4 -H, C 5 -H), 8.50 (m, 1H, C 7 -H), 7.20-7.80 (m, 13H, olefinic C β -H, 12-H), 12.36 (s, 1H, NH) 6.62 (d, 1H, olefinic C α -H), 7.90 (m, 1H, C 6 -H), 8.20 (m, 2H, C 4 -H, C 5 -H), 8.54 (m, 1H, C 7 -H), 7.22-7.83 (m, 13H, olefinic C β -H, 12-H), 12.37 (s, 1H, NH) 6.74 (d, 1H, olefinic C α -H), 7.93 (m, 1H, C 6 -H), 8.15 (m, 2H, C 4 -H, C 5 -H), 8.56 (m, 1H, C 7 -H), 7.20-7.82 (m, 13H, olefinic C β -H, 12-H), 12.36 (s, 1H, NH) 3.38 (s, 1H, H), 6.65 (d, 1H, olefinic C α -H), 7.95 (m, 1H, C 6 -H), 8.18 (m, 2H, C 4 -H, C 5 - H), 8.55 (m, 1H, C 7 -H), 7.23-7.82 (m, 13H, olefinic C β -H, 12-H), 12.35 (s, 1H, NH) Table II Physical and analytical data of 2-(4-cinnamoylphenylamino)-3-(4-chlorophenyl)-1,8-naphthyridines 4 Compd Reaction m.p. Yield Mol. formula Found (%) (Calcd) time (min) ºC (%) C H N 4a C 6 H 5 5.5 >300 90 C 29 H 20 N 3 75.57 (75.41 4.36 4.33 9.17 9.10) 4b 4-CH 3 C 6 H 4 6.5 310 94 C 30 H 22 N 3 75.76 (75.71 4.67 4.63 8.89 8.83) 4c 4-CH 3 C 6 H 4 7.0 300(d) 92 C 30 H 22 N 3 2 73.40 (73.23 4.52 4.48 8.62 8.55) 4d 2-C 6 H 4 8.0 280 90 C 29 H 19 N 3 2 70.32 (70.16 3.86 3.83 8.53 8.47) 4e 4-C 6 H 4 7.5 >300 96 C 29 H 19 N 3 2 70.31 (70.16 3.88 3.83 8.54 8.47) 4f 4-FC 6 H 4 8.0 290(d) 92 C 29 H 19 N 3 F 72.75 (72.58 4.00 3.96 8.83 8.76) 4g 3-N 2 C 6 H 4 5.5 >300 87 C 29 H 19 N 4 3 68.87 (68.71 3.81 3.75 11.13 11.06) 4h 4-N 2 C 6 H 4 5.0 >300 90 C 29 H 19 N 4 3 68.88 (68.71 3.80 3.75 11.15 11.06) 4i 4-(CH 3 ) 2 NC 6 H 4 6.5 >300 92 C 31 H 25 N 4 73.92 (73.74 5.00 4.96 11.18 11.10) 4j 2-HC 6 H 4 7.0 280 88 C 29 H 20 N 3 2 73.04 (72.88 4.23 4.19 8.86 8.79) (d): decompose Varian Gemini 400 MHz spectrometer (chemical shifts in δ ppm) using TMS as internal standard. The 4-aminoacetophenone 2 was purchased from Aldrich Chemical Company. Synthesis of 2-(4-acetylphenylamino)-3(4-chlorophenyl)-1,8-naphthyridine 3. A mixture of 2-chloro- 3-(4-chlorophenyl)-1,8-naphthyridine 1 (0.01 mole), 4-aminoacetophenone 2 (0.01 mole) and Na 2 C 3 (0.01 mole) was ground by pestle and mortar at room temperature for 5.0 min. n completion of reaction, as monitored by TLC, the reaction-mixture was treated with chilled water. The separated solid was filtered, washed with water and recrystallized from methanol to give 3, yield 96%, m.p. 276 C; Anal. Calcd for C 22 H 16 N 3 : C, 70.84; H, 4.32; N, 11.30. Found: C, 70.98; H, 4.37; N, 11.38%. IR (KBr): 3420(NH), 1672(C=), 1592 cm -1 (C=N); 1 H NMR(DMS-d 6 ): δ 2.05 (s, 3H, CH 3 ), 7.92 (m, 1H, C 6 -H), 8.18 (m, 2H, C 4 -H, C 5 -H), 8.52 (m, 1H, C 7 -H), 7.23-7.80 (m, 8H, -H), 12.35 (s, 1H, NH). Synthesis of 2-(4-cinnamoylphenylamino)-3-(4-chlorophenyl)-1,8-naphthyridines 4. A mixture of 3 (0.01 mole), aromatic aldehyde (0.01 mole) and solid NaH (0.01 mole) was ground by pestle and mortar at room temperature for the period indicated in Table II. After completion of the reaction as indicated by TLC, the reaction-mixture was digested
386 INDIAN J. CHEM., SEC B, MARCH 2010 with cold water. The solid that precipitated was filtered, washed with water and recrystallized from methanol to afford 4 (Table II). Acknowledgement The authors are thankful to the Director, IICT, Hyderabad for providing 1 H NMR spectral data. References 1 Toda F, Synlett (Account), 1993, 303. 2 Tanaka K & Toda F, Chem Rev, 100, 2000, 1025. 3 Bose A K, Pednekar S, Ganguly S N, Chakraborthy G & Manhas S M, Tetrahedron Lett, 45, 2004, 8351. 4 Straub T S, Tetrahedron Lett, 36, 1995, 663. 5 Indira J, Prakash K P & Sarojini B K, J Crystal Growth, 242, 2002, 209. 6 Huang D F, Wang X J, Hu Y L, Zhang Y M & Tang J, Synth Commun, 32, 2002, 971. 7 Balin G B & Tan W L, Aust J Chem, 37, 1984, 1065. 8 Kuroda T, Suzuki F, Tamura T, hmori K & Hosie H, J Med Chem, 35, 1992, 1130. 9 Roma G, Braccio M D, Grossi G, Mattioli F & Ghai M, Eur J Med Chem, 35, 2000, 1021. 10 Badawneth M, Ferrarini P L, Calderone U, Manera G, Martinotti E, Mari C, Saccomanni G & Testai L, J Med Chem, 36, 2001, 925. 11 Tomito K, Tsuzuki Y, Shibamori K, Tashima M, Kajikawa F, Sato Y, Kashimoto S, Chibak & Hino K, J Med Chem, 45, 2002, 5564. 12 Mogilaiah K, Babu H R & Reddy N V, Synth Commun, 32, 2002, 2377. 13 Mogilaiah K, Chowdary D S, Reddy P R & Reddy N V, Synth Commun, 33, 2003, 127. 14 Mogilaiah K & Reddy G R, xidation Commun, 27, 2004, 668. 15 Mogilaiah K, Chowdary D S & Reddy P R, Synth Commun, 32, 2002, 857.