A Facile Synthesis of 4-Diarylmethyl-1-(2H)phthalazinones from 2,2-Diaryl-1,3-indanediones

Abstract

Refluxing of 2,2-diaryl-1,3-indanediones in hydrazine hydrate for a brief period affords 4-diarylmethyl-1-(2H)phthalazinones in very high yield.

Key words

2,2-diaryl-1,3-indanediones - 4-diarylmethyl-1-(2H)-phthalazinones - arylation - heterocycles - nucleophilic additions

References

• 1 Engelbrecht HJ, and Lenke D. inventors; German (East) patent  19629.  ; Chem. Abstr. 1961, 55, 22346.
• 2 Abd El-Fattah B. Al-Ashmani MI. El-Feky S. Roeder E. Egypt. J. Pharm. Sci.  1987,  28:  383 
• 3 Horn H, Unverferth K, Laban G, and Lohmann D. inventors; German (East) patent  286354.  ; Chem. Abstr. 1991 , 115, 8820.
• 4 inventors; Fujsawa Pharmaceutical Co. Ltd.; Japan patent  62252774.  ; Chem. Abstr. 1988, 109, 6531.
• 5 Marcaccini S. Pepino R. Polo C. Pozo MC. Synthesis  2001,  85 
• 6 Epsztajn J. Malinowski Z. Brzezinki JZ. Karzatka M. Synthesis  2001,  14:  2085 
• 7 Saito Y. Sakamoto T. Kikugawa Y. Synthesis  2001,  2:  221 
• 8 Abdel-Khalik MM. Agamy MS. Elnagdi MH. Synthesis  2001,  12:  1861 
• 9 Patel NR. In Condensed pyridazines Including Cinnolines and Phthalazines   Castle RN. Wiley-Interscience; New York: 1973.  p.383-385  
• 10 Horn H, Unverferth K, Koerner B, Lohmann D, and Laban G. inventors; German (East) Patent  274218.  ; Chem Abstr. 1990, 113, 23938.
• 11 Horn H. Morgenstern E. Unverferth K. Pharmazie  1990,  45:  724 
• 12 Klumpp DA. Fredrick S. Lau S. Jin KK. Bau R. Surya Prakash GA. Olah GA. J. Org. Chem.  1999,  64:  5152 

13

General Procedure for Preparation of 4a-4g, 5a-5c : The appropriate substrate 1a-1g, 3a-3c (1.4 mmol) was added to hydrazine hydrate (10mL, 99%) and the mixture refluxed for about 15 minutes. The cooled reaction mixture was acidified with 6 N HCl to pH 6. The solid product separated was extracted with CHCl₃ and worked up as usual. The residue from the CHCl₃ layer was purified by column chromato-graphy over silica gel and CHCl₃ eluate fractions afforded pure solid products 4a-4g, 5a-5c which were crystallised from CHCl₃ -light-petroleum.

14

2,2′- Diaryl-1,3-indanediones 3a-3c were synthesized following step-a and step-b (Scheme [1] ). Initially the mono-arylated ninhydrin adducts, 2a-2c were synthesised by stirring ninhydrin (1.4 mmol) and the appropriate hydro-carbon Ar-H (4.2 mmol) in a mixture of acetic acid (10 mL) and concd H₂SO₄ (1.0 mL) for about 0.5 h at room temperature. The solid product separated was filtered out and washed thoroughly with acetic acid and then with water. The product was purified by silica-gel column chromato-graphy using acetone as the eluent (yield ˜85%).
For the 2nd arylation of 2a-2c, the appropriate hydrocarbon Ar′-H (4.2 mmol) was added to a solution of monoarylated ninhydrin 2a-2c (1.4 mmol) in a mixture of acetic acid (10 ml) and concd H₂SO₄ (3-4 mL). The mixture was stirred at 25 °C for 6 h and then poured over ice. The product was extracted into CHCl₃ and the organic phase was washed twice with water, twice with brine, further washed with water, dried over Na₂SO₄, and concentrated in vacuo. The resulting solid was further purified by recrystallisation from CHCl₃ (yield ˜70%).

15

Spectral data for 4c: IR (KBr): (cm^-1) 1659 (CO), 3170 (NH); ¹H NMR (δ): 10.8 (1 H, s, NH), 8.46 (1 H, m, H-8), 7.73 (3 H, m, H-5, H-6, H-7), 7.28 (4 H, apparent d, J = 8.6 Hz, H-3′, H-3′′, H-5′, H-5′′), 7.13 (4 H, apparent d, J = 8.6 Hz, H-2′, H-2′′, H-6′, H- 6′′), 5.90 (1 H, s, H-α); ¹³C NMR (δ): 159.9 (C-1), 147.2 (C-4), 139.1 (C-1′, C-1′′), 133.6 (C-6), 133.2 (C-4′, C-4′′), 131.5 (C-7), 130.6 (C-2′, C-2′′, C-6′, C-6′′), 129.7 (C-9 or C-10), 128.9 (C-3′, C-3′′, C- 5′, C-5′′), 128.5 (C-10 or C-9), 127.3 (C-8), 124.8 (C-5), 52.0 (C-α). Anal. Calcd for C₂₁H₁₄Cl₂N₂O: C 66.15; H 3.70; Cl 18.60; N 7.35. Found: C 66.06; H 3.78; Cl 18.52; N 7.29%.
Spectral data for 4f: IR (KBr): (cm^-1) 1667 (CO), 3176 (NH); ¹H NMR (δ): 10.4 (1 H, br, NH), 8.45 (1 H, m, H-8), 7.79 (1 H, m, H-6), 7.71 (2 H, m, J = 8.6 Hz, H-5, H-7), 7.12 (4 H, apparent d, J = 8.7 Hz, H-2′, H-2′′, H-6′, H-6′′), 6.84 (4 H, apparent d, J = 8.7 Hz, H-3′, H-3′′, H-5′, H-5′′), 5.88 (1 H, s, H-α), 3.77 (6 H, s, 2 × OCH₃); ¹³C NMR (δ): 159.9 (C-1), 158.6 (C-4′, C-4′′), 148.6 (C-4), 133.4 (C-6), 133.3 (C-1′, C-1′′), 131.1 (C-7), 130.2 (C-2′, C-2′′, C-6′, C-6′′), 130.1 (C-9 or C-10), 128.5 (C-10 or C-9), 127.1 (C-8), 125.2 (C-5), 114.1 (C-3′, C-3′′, C-5′, C-5′′), 55.2 (2 × OCH₃), 51.7 (C-α). Anal. Calcd for C₂₃H₂₀N₂O₃: C 74.17; H 5.41; N 7.52. Found: C 74.14; H 5.37; N 7.48%.