Alkylidenephosphoranes in Heterocyclic Synthesis: Reactivity of Benzoxazinones with Resonance-Stabilized Phosphorus Ylides

Abstract

2H-3,1-Benzoxazine-2,4(1H)-dione and its N-methyl analogue react with alkylidenephosphoranes to give substituted quinolines and benzazepines as well as indanone and furan derivatives. Reaction mechanisms to explain the formation of products obtained are outlined.

isatoic anhydrides - heteroring transformations - resonance-stabilized alkylidenephosphoranes - quinoline derivatives

References and Notes

1a El-Hashash MA. Sayed MA. Egypt. J. Chem.  1979,  2:  115 

1b Dash B. Dora EK. Panda CS. J. Indian Chem. Soc.  1980,  57:  835 

1c Fahmy AFM. Aly NF. Bull. Chem. Soc. Jpn.  1976,  49:  1391 

1d Baddar FG. Fahmy AFM. Aly NF. J. Chem. Soc., Perkin Trans. 1  1973,  2448 

2a Witt A. Bergman J. Tetrahedron  2000,  56:  7245 

2b Coppola GM. Tetrahedron Lett.  1998,  39:  8233 

2c de Silva JFM. Gorden SJ. Pinto AC. J. Braz. Chem. Soc.  2001,  12:  273 

2d Kovalenko SM. Bylov IE. Sytnik KM. Chernykh VP. Bilokin YV. Molecules  2000,  5:  1146 

3a Coppola GM. Synthesis  1980,  505 ; and references cited therein

3b Connor DT. von Strantmann M. J. Org. Chem.  1973,  38:  1047 

3c McIntosh JM. Steevensz RS. Can. J. Chem.  1974,  52:  1934 

3d McIntosh JM. Steevensz RS. Can. J. Chem.  1977,  55:  2442 

3e Coppola GM. Hardtmann GE. Pfister OR. J. Org. Chem.  1976,  41:  825 

3f Minami T. Matsumoto M. Suganuma H. Agawa T. J. Org. Chem.  1978,  43:  2149 

4a Kamel AA. Phosphorus, Sulfur Silicon Relat. Elem.  2007,  182:  765 

4b Abdou WM. Fahmy AFM. Kamel AA. Eur. J. Org. Chem.  2002,  1696 

4c Abdou WM. Kamel AA. Khidre MD. Synth. Commun.  2004,  34:  4119 

4d Abdou WM. Kamel AA. Khidre MD. Heteroat. Chem.  2004,  15:  77 

5 Abdou WM. Kamel AA. Synth. Commun.  2007, accepted for publication

6

Typical Procedure for the Reaction of Isatoic Anhydrides 1a,b with Ester Ylides 6a,b (a) In dioxane: A mixture of alkoxycarbonylmethylene (triphenyl)phosphorane 6a (or 6b, 5.2 mmol) and 1a (or 1b, 4.9 mmol) in 40 mL dry dioxane was heated under reflux for 3 d. After removal of the solvent, EtOAc (30 mL) was added. The material that precipitated was collected and crystallized from EtOAc-CH₂Cl₂ to give the known ylide 7a (from the reaction of 6a,b with 1a; ca. 38%), mp >300 °C (from acetone; lit.^3b mp 320 °C), or 7b (from the reaction of 6a,b with 1b; ca. 40%), mp 252-254 °C [from acetone-Et₂O (2:1); lit.^3b mp 252-253 °C, from EtOAc-CH₂Cl₂]. Components present in the filtrate were separated by column chromatography on silica gel.
Compounds 1a and 6a: Elution with n-hexane-EtOAc (3:7 v/v) gave colorless needles of ethyl 2,4-dihydroxyquinoline-3-carboxylate (13a, 156 mg, 14%), mp 206-208 °C (from CHCl₃; lit.⁷ mp. 208 °C, from EtOAc]. The second fraction (n-hexane-EtOAc, 1:9 v/v) gave straw-colored crystals of diethyl 2,5-dihydroxybenzazepine-3,4-dicarboxylate (15a, 282 mg, 18%), mp 215-217 °C (from acetone).
Compounds 1a and 6b: Elution with n-hexane-EtOAc (3:7 v/v) gave yellow crystals of methyl 2,4-dihydroxyquinoline-3-carboxylate (13b, 172 mg, 16%), mp 202-204 °C (from MeOH; lit.⁸ mp 203-204 °C, from Et₂O]. The second fraction (n-hexane-EtOAc, 1:9 v/v) gave straw-colored crystals of dimethyl 2,5-dihydroxybenzazepine-3,4-dicarboxylate (15b, 300 mg, 21%), mp 239-242 °C (from acetone).
Compounds 1b and 6a): Elution with n-hexane-EtOAc (8:2 v/v) gave yellow crystals of ethyl 4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate (13c, 145 mg, 13%), mp 100-103 °C (from cyclohexane; lit.⁹ mp 100-102 °C, from Et₂O]. The second fraction (n-hexane-EtOAc, 7:3 v/v) gave straw-colored crystals of diethyl 2,5-dihydroxy-1-methylbenz-azepine-3,4-dicarboxylate (15c, 270 mg, 18%), mp 113-114 °C (from CH₂Cl₂).
Compounds 1b and 6b: Elution with n-hexane-EtOAc (4:6 v/v) gave yellow crystals of methyl 4-hydroxy-1-methyl-2-oxoquinoline-3-carboxylate (13d, 126 mg, 12%), mp 164-166 °C (from benzene; lit.¹⁰ mp. 166-167 °C, from benzene]. The second fraction (n-hexane-EtOAc, 3:7 v/v) gave straw-colored crystals of diethyl 2,5-dihydroxy-1-methylbenzazepine-3,4-dicarboxylate (15d, 303 mg, 22%), mp 142-144 °C (from benzene). Percentage yields, physical and spectral data of the new products 15a-d are listed in Table [1] .




(b) In EtOAc with benzoic acid: The same reaction between ester ylides 6a,b (7.5 mmol) and 1a,b (4.9 mmol) was repeated in EtOAc containing benzoic acid (0.3 g), heating under reflux for 2 d. After the usual workup, yellow crystals of 13a (313 mg, 28% yield) and 15a (720 mg, 46%, from 6a and 1a), 13b (279 mg, 28% yield) and 15b (728 mg, 51%, from 6b and 1a), 13c (334 mg, 30% yield) and 15c (662 mg, 44%, from 6a and 1b), and 13d (263 mg, 25% yield) and 15d (662 mg, 48%, from 6b and 1b) were obtained. All products were identified by mixed mp as well as comparison of IR and mass spectral data with those of the materials previously obtained. Compounds 7a,b were not isolated from this reaction.

7 Grundon MF. McCrokinale NJ. J. Chem. Soc.  1955,  4284 

8 Koller G. Ber. Dtsch. Chem. Ges.  1927,  60:  1108 

9 Coppola GM. Hardtmann GE. J. Heterocycl. Chem.  1979,  16:  1605 

10 Zikou G. Athanasellis G. Detsi A. Zografos A. Mitsos C. Igglessi-Markopoulou O. Bull. Chem. Soc. Jpn.  2004,  77:  1505 

11

Typical Procedure for the Reaction of Isatoic Anhydrides 1a,b with Keto Ylides 16a,b A solution of acetylmethylene(triphenyl)phosphorane (4.9 mmol) and 1a (or 1b, 5.2 mmol) in 40 mL EtOAc containing benzoic acid was refluxed for 2 d. After usual workup, the products 18a and 21a or 18b and 21b were obtained (see Table [1] ).
Compounds 18c or 18d were likewise obtained upon reacting 1a (or 1b) with an equimolar amount of benzoylmethylene(triphenyl)phosphorane under the same conditions as mentioned above and workup (data for 18c and 18d are listed in Table [1] ).

12

Typical Procedure for the Reaction of Isatoic Anhydrides 1a,b with Phosphonium Salt 22 Diphenylmethylene(triphenyl)phosphonium bromide (22, 5.2 mmol) was added dropwise to a solution of abs. EtOH (50 mL) containing Na metal (0.4 g). The reaction mixture was stirred at r.t. for 1 h followed by addition of 1a (or 1b, 4.9 mmol), and then heated under reflux for 15 h. The product mixture was concentrated and diluted with a small amount of distilled H₂O, followed by solvent extraction (EtOAc), drying, and evaporation. The resulting residue was purified by chromatography on silica gel, gradient eluting using CHCl₃-EtOAc to yield compounds 24a and 25a, or 24b and 25b, respectively. Compound 25a was obtained as pale yellow needles (130 mg, 16%), mp 36-38 °C (from pentane); mp and mixed mp, as well as IR and mass spectral data were comparable to those of an available sample. Compound 24a was obtained as colorless plates (643 mg, 46%), mp 212-214 °C (from EtOH; lit.¹³ mp 212-214 °C, from acetone). Compound 25b was obtained as pale yellow liquid (105 mg, 13%), with IR and mass spectral data comparable to those of an available sample. Compound 24b was obtained as colorless plates (716 mg, 53%), mp 176-177 °C (from EtOH).¹⁴

13 Sheehan JC. Frankenfeld JW. J. Am. Chem. Soc.  1961,  83:  4792 

14 Bruni P. Conti C. Tosi G. J. Mol. Struct.  1997,  408/409:  477