The oxidation of 3-alkylhomophthalimide derivatives by dioxygen in alkaline media and Bischler-Napieralski reactions of cleavage-cyclisation products

The oxidation of 4-alkylhomophthalimide derivatives by dioxygen in the presence of ethanolic sodium hydroxide leads to the rapid formation of α-hydroxy-α-alkylhomophthalimide derivatives and hence, as a result of ring cleavage and lactone formation, to α -amido-α-alkylphthalides that can be converted into analogues of phthalideisoquinoline alkaloids.


Introduction
The chemistry of dioxygen is of considerable current interest in view of its impact on our understanding of a range of chemical and biological reactions. 1The cleavage of ketones by oxygen as a result of the formation of α-hydroperoxyketones has been reported many times, particularly when the ketone forms a stable enol. 2 Even simple ketones have been shown to react with oxygen in a strongly basic medium. 3The autoxidation of ketones can take place without the cleavage of the carbon chain as exemplified by the α-hydroxylation of ()-isorotenone, 4 a number of steroidal 20-ketones, 5 and sesquiterpenoids 6 and triterpenoids, 7 as well as the g-hydroxylation of α,β-unsaturated ketones such as cyperone. 8The direct oxygenation of enolates, generated by anionic oxy-Cope rearrangement reactions, has been reported more recently in connection with the synthesis of polycyclic α-hydroxy ketones, 9 and hydroxylation αto an aryl ketone has also been reported as part of the pinene pathway to taxanes. 10 Other carbonyl compounds such as ISSN 1551-7004 Page 344  ARKAT USA, Inc esters 11 and dialkylmaleic anhydrides 12 have also been shown to give autoxidation products that involve reactions of carbanions.The ease of formation of 3-hydroxy-1,3-dimethyl-5methoxyoxindole during the asymmetric alkylation of 1,3-dimethyl-5-methoxy-oxindole may well be related to the aromatic character of the enolate of the amide function. 13The autoxidation of esters and amides to the related α-hydroxy-derivatives has been studied using titanium enolates 14 and a recent report is concerned with the oxidation of anions derived from a series of b-imidoesters using dibenzoyl peroxide. 15It has been pointed out that the ease of oxidation of ionizable organic compounds depends not only on the degree of conversion to an anion but also on the relative stabilities of the carbanions and the related radicals. 16For example, in a b-dicarbonyl system the enolate ion is more stabilized than the related radical and hence the latter is more difficult to form.It is therefore entirely in accord with expectation that the b-imidoesters could not be oxidised cleanly by dioxygen. 15As far as we are aware there was only one report 17 of reactions of homophthalimide derivatives with dioxygen prior to our preliminary publication, 18 although the dye sensitised photooxygenation of homophthalimides has been reported more recently. 19The earlier study related to reactions of products formed in ring opening reactions of 4-spirocyclopropane derivatives with amines. 17The oxidation reactions were reported to occur spontaneously in the solid state in reactions that clearly depend on the presence of an intramolecular base as shown in Scheme 1.We now record the full details of our observations concerning the autoxidation of some 4-alkylisoquinoline-1,3(2H,4H)-diones and the conversion of two lactone-amides into a phthalide-dihydroisoquinoline and a phthalide-dihydrob-carboline.

Scheme 1
The formation of enolate ions from N-substituted derivatives of homophthalimide is particularly easy and has been used by us previously in order to introduce two alkyl residues at the benzylic carbon. 20In the case of the reaction of N-benzylhomophthalimide with methyl iodide in aqueous ethanolic sodium hydroxide the reaction proceeds rapidly with the formation of the dimethyl derivative.The greater steric requirement of the isopropyl group suggested that the formation of the monoalkylated derivative (1) would be straightforward and this has been confirmed by experiment.A reaction of N-benzylhomophthalimide with isopropyl iodide in aqueous ethanolic sodium hydroxide gave the expected product (1) in 42% yield.On the other hand when we carried out analogous reactions using either ethyl iodode or benzyl bromide we obtained mixtures of the mono-and di-alkylated products which were separated by flash chromatography on silica gel.When a solution of (1) in ethanolic sodium hydroxide was saturated with dioxygen and then heated under reflux the fluorescence was discharged after about three hours and gave a quantitative yield of a product that had incorporated an additional oxygen atom and where the two carbonyl stretching frequencies in the infrared spectrum of the original homophthalimide (nmax 1670 and 1714 cm -1 ) had been replaced by two new absorptions (nmax 1676 and 1773 cm -1 ).An accurate mass measurement on the mass spectrometric molecular ion established the molecular formula and the 1 H and 13 C nuclear magnetic resonance spectra confirmed the structure of the lactone (2) in which a ring contraction from the six-membered to a fivemembered ring had occurred (Scheme 2).It is important to note that the reactions do not proceed in the absence of base, confirming our interpretation of the importance of the b-aminoethylresidues in the reactions exemplified in Scheme 1. 17 Ring contraction reactions from a sixmembered to a five-membered ring have been reported previously, and are exemplified for example by the conversion of N-substituted isoquinolinetriones into ethyl 3-hydroxyisoindolone-3-carboxylates by heating in ethanol in the presence of triethylamine. 21

Scheme 2
The reaction conditions used suggested the intermediacy of a tertiary hydroperoxide but, as with the α-ketohydroperoxide derived from cyclohexanone which is apparently very unstable, 22 we were unable to detect a hydroperoxide by the starch-iodide test.The latter result suggested that the reaction could be catalytic in base and a reaction in the presence of 15 mol% of sodium hydroxide also gave the lactone (2) in high yield.By carrying out the oxidation reaction using a catalytic amount of sodium hydroxide in the presence of an excess of triethyl phosphite 23 and a continuous supply of dioxygen, we were able to stop the isomerisation of the proposed hydroxyhomophthalimide (3).In the latter reaction (Scheme 3) the compound (3) was isolated in 97% yield together with a small amount of recovered starting material (1).

Scheme 3
It is clear that a number of alternative routes are available to the initial radical (B), for example the involvement of the hydroxyl radical in removing an electron from the anion would also regenerate hydroxide ion.Similarly the radical (B) would be generated by interaction of the starting material (A) with the oxy-radical (C).A mechanistic sequence that accounts for the observed results is shown in Scheme 4.

Scheme 4
We found that the ethyl analogue (4) of the compound (1) is converted more slowly than the compound (1) and gave, after 9h, a similar lactone (6) in 25% yield together with a second product that was formed in 36% yield in a reaction using a catalytic quantity of sodium hydroxide.The products were separated by flash chromatography and the second product was shown to be the expected intermediate hydroxyhomophthalimide (5).The hydroxyhomophthalimide (5) was converted into the phthalide derivative (6) in a quantitative yield when it was heated under reflux in ethanolic sodium hydroxide solution.The benzyl derivative (7) was shown to react even more slowly than the ethyl derivative (4) and gave the hydroxy compound (8) in 33% yield together with the lactone (9) in 11% yield and unchanged starting material (56%) when the reaction was allowed to proceed for 17h using a catalytic ISSN 1551-7004 Page 347  ARKAT USA, Inc quantity of sodium hydroxide.A substituent is clearly required on the benzylic carbon in a homophthalimide for the autoxidation to proceed; we found that N-benzylhomophthalimide does not undergo the autoxidation reaction under the conditions reported herein.

ISSN 1551-7004
Page 348  ARKAT USA, Inc In conclusion, we have developed a mild protocol that allows the direct oxygenation of tertiary benzylic imide centres that not only produces compounds of potential biological interest, but also produces phthalides by ring cleavage and recyclisation that can be used as precursors to analogues of phthalideisoquinoline alkaloids.

Experimental Section
General Procedures.Commercially available solvents and reagents were used throughout without further purification, except for those detailed below which were purified as described.Chromatographic procedures -Analytical thin layer chromatography was carried out using glass-backed plates coated in Merck Kieselgel 60 PF254.Plates were visualised by UV light (at 254 and/or 360 nm) or by exposure to an appropriate staining agent.Flash chromatography was carried out using Merck silica gel 60.Pressure was applied at the head of the column with hand bellows.Samples were applied as a concentrated solution in an appropriate solvent.Spectroscopic techniques -Infared spectra were recorded in the range 4000-600 cm -1 using a Nicolet FT-205 spectrometer with internal calibration.Spectra were recorded as thin films or as Nujol mulls. 1 H and 13 C NMR spectra were recorded using Bruker AC-250 and Bruker DPX-400 instruments. 1 H NMR spectra are referenced against residual undeuterated solvent, in the case of deuteriochlorofom this is 7.260 ppm.Signals are described as singlets (s), doublets (d), double doublet (dd), quartets (q), multiplet (m) etc. High and low resolution mass spectra were recorded on a Kratos MS80 instrument.
Other data and instrumentation -Melting points were measured on a Electrothermal digital melting point apparatus or using a Kofler hot stage apparatus and are uncorrected.Bulb to bulb distillations were performed on a Büchi GKR-51 Kugelrohr; boiling points refer to air bath temperatures and are uncorrected.All of the following experimental reactions were carried out under an atmosphere of nitrogen except where it was obviously unnecessary.The modulus of coupling constants (J ) are quoted in Hertz.

General method for 1,2,3,4-tetrahydro-1,3-isoquinolinediones formation
The amine (1 equivalent) was added to homophthalic anhydride and stirred at 70 o C. The reaction mixture was then heated to the stated temperature for a given length of time.After allowing the mixture to cool to room temperature, the product was purified either by recrystallisation or by flash chromatography on silica gel.The following 1,3-isoquinolinediones were prepared:

Reactions of 1,2,3,4-tetrahydro-1,3-isoquinolinediones with alkyl-or arylalkyl halides (1 equivalent) and aqueous alcoholic sodium hydroxide (1 equivalent). General method
A magnetically stirred solution of the particular 1,3-isoquinolinedione, sodium hydroxide (1 equivalent) and the appropriate alkylating agent (1 equivalent, unless otherwise stated) in aqueous ethanolic solution [1:1] (ca.150 mL) was heated under reflux for a given length of time.Subsequently, the reaction mixture was allowed to cool to room temperature then DCM (150 mL) and water (150 mL) were added to the reaction mixture followed by vigorous shaking.The organic layer was then collected and the aqueous layer was further extracted with DCM (100 mL).The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by flash chromatography on silica gel and/or recrystallisation.

Bischler-Napieralski cyclisation of isobenzofuran carboxamides. General method
A magnetically stirred solution of the particular isobenzofuran carboxamide and phosphoryl chloride (5-10 equivalents) in a given volume of dry acetonitrile was heated under reflux for a given length of time.Subsequently, the reaction mixture was allowed to cool to room temperature.The reaction mixture was then quenched carefully with dilute aqueous ammonia solution.Then DCM (100 mL) and water (100 mL) were added to the reaction mixture followed by vigorous shaking.The organic layer was then collected and the aqueous layer was further extracted with DCM (100 mL).The combined organic extracts were dried over magnesium sulfate, concentrated in vacuo and the residue was purified by flash chromatography on silica gel and/or recrystallisation.
Light petroleum refers to the fraction boiling between 40 o C and 60 o C. Light petroleum and ethyl ISSN 1551-7004 Page 349  ARKAT USA, Inc acetate were distilled from anhydrous calcium chloride through a 36 cm Vigreux column before use.Dichloromethane was distilled from phosphorus pentoxide.