C HAPTER III
Scheme 8. Base mediated multicomponent reactions for the synthesis of highly functionalized [1,6]-naphthyridine derivatives
III.3. Present Work
In an initial endeavor, a trial reaction was executed with 4'-chloroacetophenone 1c (1 mmol) and malononitrile 2 (1 mmol) in methanol as solvent in the presence of NaOH (1.0 equiv.) under reflux conditions. The reaction mixture was refluxed for 7 hours and gradual progress of the reaction was monitored by TLC. After usual work up followed by chromatographic purification, a white solid product was isolated in 31% yield, which was characterized as 5- amino-2,4-bis(4-chlorophenyl)-1,2-dihydro-7-methoxy-2-methyl-1,6-naphthyridine-8-carbo nitrile (4c) instead of expected Knoevenagel product A as shown in mechanism in Scheme 10. The product 4c was characterized by recording IR, 1H NMR, 13C NMR spectra and by elemental analysis. In IR spectrum, it showed characteristic absorptions at 3345, 3399 and 3494 cm-1 due to the NH and -NH2 group and a strong absorption at 2204 cm-1 for -CN group. Similarly, in the 1H NMR spectrum of 4c exhibited two broad singlets at δ 5.28 and 4.23 due to NH and NH2 proton, a singlet at δ 5.44 due to =CH proton at dihydropyridine
Chapter III Synthesis of highly functionalized 1,6-Naphthyridines
71
ring and two singlets at δ 3.88 and 1.74 for OMe and Me group in the naphthyridine skeleton. However the expected characteristic stretching frequency of -CN group in the Knoevenagel product A generally exhibits at 2225 cm-1 and in 1H NMR signals at δ 2.62 and 7.51 as singlets for methyl proton and aromatic protons respectively. From this observation, it was clear that two equivalents of 4'-chloroacetophenone and malononitrile are required for obtaining the product 4c. The OMe group has incorporated in the final product 4c from MeOH, which acts as reactant-cum-solvent. The structure of product 4c was also confirmed by X-ray crystal structure as shown in Figure 2.
Table 1. Optimization of the reaction condition for the synthesis of 1,6-naphthyridine
Entry Base Amount (equiv.) Solvent Time (h) Yieldb(%)
1 NaOH 1.0 MeOH 7 62
2 NaOH 1.5 MeOH 7 71
3 NaOH 2.0 MeOH 7 70
4 KOH 1.5 MeOH 12 60
5 K2CO3 1.5 MeOH 12 52
6 NaHCO3 1.5 MeOH 24 22
7 -- -- MeOH 24 N.R.c
8 Et3N 1.5. MeOH 12 42
9 PPh3 1.5 MeOH 12 54
10 DMA 1.5 MeOH 12 trace
11 NaOH 1.5 THFa 24 N.R.c
12 NaOH 1.5 DMFa 24 29
13 NaOH 1.5 MeCNa 12 21
14 NaOH 1.5 H2Oa 12 N.R.c
aFor entries (11-14), MeOH was used 1 equivalent. bIsolated yields. cNR = no reaction.
TH-1522_10612235
Chapter III Synthesis of highly functionalized 1,6-Naphthyridines
Therefore, various reactions using two equivalents of 4'-chloroacetophenone and malononitrile in methanol (3 mL) have been examined with different amount of NaOH. It was noted that increasing the amount of NaOH from 1.0 equiv. to 1.5 equiv. effectively increased the yield from 62 to 71% (Table 1, entries 1-2), yet there was no improvement of yield when the amount of NaOH was further increased to 2.0 equiv. (Table 1, entry 3). To find out efficiency of other bases as well as reaction medium, the same reaction was screened in presence of 1.5 equiv. of KOH, K2CO3, and NaHCO3 (Table 1, entries 4–6), respectively. It was also observed that no desired product was obtained in absence of base even after 24 h of refluxing (Table 1, entry 7). Finally, the similar reactions were also verified in presence of other organic bases like Et3N, PPh3 or N,N-dimethylaniline (DMA) (Table 1, entries 8-10). To verify the suitability of other solvent, similar reaction was executed using 4'-chloroacetophenone (2 equiv.) 1c, malononitrile 2 (2 equiv.) and methanol 3a (1 equiv.) in THF, DMF, CH3CN or water, respectively, in presence of 1.5 equiv. of NaOH under reflux conditions. Unfortunately, the yield of the product did not improve significantly (Table 1, entries 11-14).
With the optimized conditions, the scope and general applicability of the present methodology was examined by carrying out the synthesis of substituted 1,6-naphthyridines using different acetophenonone derivatives tethered with either electron-withdrawing or electron-donating groups on the ring (Table 2). It was found that acetophenone derivatives with neutral or electron-withdrawing groups or electron-donating functionality produced 1,6-naphthyridine derivatives 4a-f in moderate to good yields. The acetophenones with moderately electron withdrawing substituent (F, Cl, Br) procured reasonably better yield (4b-d) than naphthyridine moiety (4e), bearing strongly electron withdrawing nitro substituent. Acetophenone frameworks with electron donating substituent such as –OMe gave upto 73% yield (4f). Similarly, alkyl methyl ketones such as isobutyl methyl ketone also underwent this reaction smoothly to provide the corresponding 1,6-naphthyridine derivative 4g in 55% yield. Likewise, heteroaryl methyl ketone such 2-acetyl thiophene, also provided the desired product 4h in good yield. Unfortunately, no desired product was obtained when the similar reaction was performed with acetophenone derivative containing methyl group on the aromatic ring under identical reaction conditions 4i. To expand the scope of the above cyclization, a series of reactions were performed with different
Chapter III Synthesis of highly functionalized 1,6-Naphthyridines
73
acetophenones, malononitrile in ethanol and the corresponding substituted 1,6-naphthyridine derivatives 4j-l were obtained in moderate to good yields (Table 2). After obtaining the successful results, we wanted to incorporate other alkoxy group in 1,6-naphthyridine ring using n-propanol, n-butanol, t-butanol and iso-propanol. However, we did not obtain the desired products, which may be due to lower nucleophilicity of these alcohols as compared to methanol and ethanol.
Table 2. Substrate scope of 1,6-naphthyridines using alcoholsa,b
aAll the reactions were performed with acetophenones (2.0 mmol), malononitrile (2.0 mmol) and alcohols (3 mL).bIsolated yields.
TH-1522_10612235
Chapter III Synthesis of highly functionalized 1,6-Naphthyridines
Similar reaction was also carried out with 2-propanone, malononitrile and methanol under optimized reaction conditions, however the expected 1,6-naphthyridine 4m (5-amino- 7-methoxy-2,2,4-trimethyl-1,2-dihydro-1,6-naphthyridine-8-carbonitrile) was isolated in 34% yield, which was confirmed from IR, 1H NMR and Mass spectra of the compound 4m as shown in scheme 9.