The synthesis of pyrroles from N-alkenylisoxazol-5 ( 2 H )-ones

Isoxazol-5(2H)-ones undergo Michael addition to propiolate esters under mildly basic conditions to form N-alkenylisoxazolones, with small amounts of the isomeric Cor O-alkylated materials. The former lose carbon dioxide when subjected to flash vacuum pyrolysis or photolysis, and give pyrroles in ca 40% yields. Minor accompanying products arise from capture of the intermediate carbene by solvent, or from hydrogen atom abstraction.


Introduction
In our study of the photochemical or thermal reactions of isoxazol-5(2H)-ones 1 we have uncovered two new routes for the synthesis of pyrroles from these species.The first was an intermolecular reaction, in which the carbenoid intermediate obtained from the photolysis was reacted with an aromatic amine or an enamine (Scheme 1). 2

Scheme 1
Because of the sensitivity of isoxazolones towards base, 10 this procedure would always be of limited application.In the event, we have found that reaction of several isoxazolones, such as 1, with NBS or t-butyl hypochlorite occurs at carbon rather than nitrogen, the assignment being based primarily on the 13 C nmr resonance of C-4 in the product 2 at 49.3 ppm (Scheme 4), confirming the earlier report of De Sarlo 11 with another isoxazolone.In spite of the formation of the 4-bromo or chloro compounds, the products should be good electrophiles, and it appeared possible that addition to alkenes could still give the desired compounds through the intermediate bromonium ion 3, but in the event addition of 2 and styrene gave the C-4 adduct, 4.

Scheme 4
An alternative approach was to react the salt of the isoxazolone with a vinyl triflate, readily prepared from the corresponding ketone.However, we have been unable to observe any such substitution; presumably the isoxazolone is insufficiently nucleophilic. 12 In view of the above failure to obtain the N-alkenylisoxazolones, we have investigated in further detail the procedure we had used previously, 3 the addition of isoxazolones to propiolic esters.The necessity for base catalysis creates difficulties with 3-unsubstituted isoxazolones, as we had noted previously 13 in the reaction of 4phenylisoxazolone with ethyl propiolate: while reaction in the presence of triethylamine at room temperature in benzene gave the N-alkenyl product, in ethanol at 80 o C the N-alkylated isoxazolone rearranged to the malonamide (Scheme 5).

Scheme 5
The reaction of the 4-ethoxycarbonylisoxazolone 5 with ethyl propiolate in benzene in the presence of triethylamine at room temperature gave a solid whose structure was shown to be the salt 6a.Thus, although the product showed the desired vinyl doublets at δ 6.31 and 7.20 ppm, the infrared absorption had dropped from 1760 cm -1 to 1718 cm -1 , consistent with the anionic charge.Addition of dilute HCl to the salt allowed recovery of the isoxazolone 5.When the salt was heated, either under FVP conditions at 540 o C, or simply sublimed at 150 o C, the isoxazolone 5 was recovered, together with the Hofmann elimination product ethyl 3-diethylaminopropenoate 7a (Scheme 6).McCulloch and McInnes 14 have reported that triethylamine reacts with ethyl propiolate to give the betaine 8, isolated only in low yield.This suggested to us that reaction of triethylamine with ethyl propiolate to form the acetylide is rapid, and the isoxazolone 5 functions mainly to allow rearrangement to the zwitterion 9 which is rapidly protonated.Indeed, nmr observation showed that triethylamine and ethyl propiolate react essentially instantly in CDCl 3 at 28 o C, presumably to form the acetylide, but the formation of 6a requires 2-3 h for completion.

Scheme 6
Since the reaction of 5 and ethyl propiolate did not occur under neutral or acidic conditions, we examined the reaction in the presence of more hindered bases.Isoxazolone 5 was recovered unchanged after exposure to ethyl propiolate at 25 o C in the presence of diisopropylethylamine, but the formation of ethyl 3diisopropylaminopropenoate 7b suggested the formation of the betaine analogous to 6a had occurred, followed by rapid Hofmann elimination.In the presence of pyridine reaction was slow, and at 80 o C for 3 h the formation of a 1:2 mixture of the desired Nalkenyl product 10 and the 4-alkenyl product 11 was only 50% complete: the remainder was the pyridine salt of 5.The major, C-alkylated product was a mixture of (Z) and (E) isomers, with the (Z) diastereomer predominating.Reaction at room temperature did not proceed with either 1 or 5, yielding only the respective pyridine salt of the isoxazolone.
Reaction of 3-substituted isoxazolones 12a-12e with propiolate esters was less complicated, but traces of O-alkylated material were formed in most cases, but were readily separable by chromatography, which allowed the recovery of unreacted isoxazolone.Yields of N-and Oalkylated material, after chromatography, are shown in Table 1; yields of crude product were usually of the order of 75%.The isoxazolones 13 were photolysed through pyrex in acetone, or subjected to FVP, yielding the desired pyrrole 15 as the major product, sometimes accompanied by the isomeric pyrrole 16, presumably formed by prior isomerisation of the carbene intermediate (Scheme 7). 3 Isolated yields, after chromatography, are shown in Table 2.The pyrroles 15 and 16 were readily distinguishable by nmr spectroscopy, and were generally accompanied by more minor products that were informative of the reaction pathways that are open to this system.Inspection of Table 2 shows that the rearranged pyrroles 16 are formed predominantly with the isoxazolones 13c and 13d, suggesting that electron rich groups promote the carbene rearrangement by stabilising the intermediate 1H-azirine (Scheme 8).

Scheme 8
The products from the FVP of the 2-naphthylisoxazolone 13d were investigated in more detail, but are typical in that isolated products total ca 70-75%.Photolysis of 13d gave a mixture of five products, as assessed by gc/ms.The pyrroles 15d and 16d were isolated by chromatography, and the structures established by comparison of their spectral data.A third product was characterised as 2-acetylnaphthalene 17 (10%), and another as an acetone addition compound, whose structure remains uncertain (19%).The minor component (1%) was the 4-(2naphthyl)oxazole 18.This compound is derived from the nitronoketene isomer of the isoxazolone, in an analogous process to that described previously. 3Three of the other compounds are derived from the imidoylcarbene, the 2-acetylnaphthalene arising from the triplet state by hydrogen atom abstraction from the acetone solvent, followed by hydrolysis during chromatographic purification (Scheme 9).The acetone adduct obtained from 13d is not of the same type as isolated from other compounds.For instance, photolysis of 19 gave the expected pyrrole 20 in only 15% yield, but this was accompanied by 70% of the acetone adduct 21.The sp 3 bound methyl groups in 21 were non equivale nt in the 1 H and 13 C nmr spectra, but the acetone adduct obtained from 13d is an adduct of the isoxazolone and acetone, having lost neither CO 2 nor CO, and with magnetically equivalent C-Me groups.
Finally, the FVP products from 13g included the pyrrole 15g in 19% isolated yield; the major product was isomeric with it , but appears to have a pyridone structure, and will be the subject of a separate investigation.We conclude that the above synthesis of pyrroles is limited by the lack of a general procedure to form the intermediate N-alkenyl isoxazolones.The conjugation of an ester with the double bond in these compounds clearly reduces the nucleophilicity of the double bond to the extent that what are usually minor reaction pathways of the imidoyl carbene now become significant.
(ii) Sublimation of 6a at 150 o C/0.03 mm gave an oil, the major component of which was identified as ethyl (E)-3-diethylaminopropenoate 7a.
The first fraction contained 4-methoxyacetophenone as a pale yellow oil (0.016 g, 30%), the identity of which was confirmed by direct comparison with an authentic sample.

ISSN 1424-6376
Page 99 © ARKAT USA, Inc Ethanol (8 mL) was added until homogeneity was achieved, and heating was then continued for 30 min.The mixture was then chilled and the product was collected and washed with cold ethanol, giving pale pink needles of the title compound (0.33 g, 76% , 69 (16), 55 (6).