Reaction of acetophenone and benzylphenylketone oximes with phenylacetylene : a route to di-and triphenylpyrroles

The reaction of oximes of aromatic ketones with phenylacetylene in the presence of superbase systems (MOH-DMSO, where M = Li, Na, K) has been extensively studied for the first time. The effects of alkaline metal cation, the ketoximes structure and the reaction conditions (temperature, duration) on the products composition have been evaluated. Acetophenone oxime reacts with phenylacetylene (МОН-DMSO, where M = Li, Na, K, 140 С, 6 h) to afford 2,5diphenyl-1H-pyrrole in 14-18% isolated yield. The reaction of benzylphenylketoxime with phenylacetylene (LiОН-DМSО, 120 С, 12 h) delivers 2,3,4-, 2,3,5-triphenyl-1H-pyrroles (in 17% total yield) and 2,3,4-triphenyl-1-[(Z)-2-phenylethenyl]-1H-pyrrole (7% yield).


Introduction
A number of natural and synthetic pyrroles bearing aryl substituents possess high biological activity. 1,2Currently, certain of the di-and triarylpyrroles are extensively employed as pharmaceuticals.For example, the cholesterol reduction drug lipitor (atorvastatin), one of the most commonly used in the United States, contains a 2,3-diphenylpyrrole motif.2а,3 A series of 2,3,4-triphenylpyrrole derivatives exert high hypoglycemic action and can be recommended for diabetes treatment.2а Although arylpyrroles are applied for the synthesis of fluorescent azaindacene dyes of BODIPY family 4 as well as optoelectronic materials, 5 it is their pharmacological appeal that seems to be the chief reason for a steady interest in the development of synthetic procedures for these compounds, reported, in particular, in reviews. 1,2i-and triphenylpyrroles are normally prepared by condensation of 1,4-diketones with ammonia or ammonium acetate, [6][7][8][9] as well as by the reaction of 1,3-diketones 10,11 with different nitrogen-containing compounds (ammonium acetate, aromatic imines, oximes) followed by cyclization of the intermediates formed.Despite the satisfactory yields of the target products, the syntheses reported feature either hard availability of the starting materials 12 or multi-step procedures. 10he reaction of ketoximes with acetylene (the Trofimov reaction) in the superbase systems МОН-DMSO, where М = Li, Na, K, makes it possible to prepare a wide series of substituted pyrroles in one preparative step. 1,13While this reaction is mostly studied with unsubstituted acetylene the applicability of phenylacetylene, an available substituted acetylene, still remains poorly understood. 14Meanwhile, the reaction of oximes of aromatic ketones with phenylacetylene could open a short-cut to pyrroles with several aromatic substituents.
In this work, using the examples of oximes of acetophenone 1 and benzylphenylketone 2 with phenylacetylene 3, we have undertaken a more thorough study of the reaction to gain a clearer understanding of the effect of the alkaline metal cation in the catalyzing systems as well as the influence of the ketoxime structure and reaction conditions on the ratio and yields of the reaction products.Apart from extension of the basic knowledge about the scope and limitations of the pyrrole synthesis from ketoximes and acetylenes it was hoped to elaborate one-step preparative protocols for the synthesis of as yet hardly accessible di-and triphenylpyrroles.

Results and Discussion
The experiments have shown that at 140 о С (6 h) in the MOH-DMSO ketoxime 1 gave with phenylacetylene the expected 2,5-diphenyl-1H-pyrrole (4) in 14-18% isolated yield along with starting acetophenone 5 (yield up to 35-55%) and tar (mostly unidentified products of the basecatalyzed phenylacetylene condensation), 15,16 the conversion of ketoxime 1 ranging from 69 to 80% (depending on the alkaline metal cation nature) (Scheme 1).The highest conversion of 1 (80%) was observed in the case of NaOH whereas those for LiOH and KOH were 77 and 69%, respectively.At the same time the yield of the target pyrrole 4 was not practically affected by the MOH nature, being somewhat higher for KOH (18%).Meanwhile, with LiOH the isolation of pyrrole 4 was found to be easier owing to a lesser amount of persistent side products formed.Therefore, it is LiOH that can be recommended for use in a preparative protocol for synthesis of pyrrole 4 (yield 17%).
The peculiarity of this reaction as compared with those using unsubstituted acetylene is the prevailing of deoximation (formation of ketone 5) over the heterocyclization to pyrrole 4. In fact, it means that the recovered starting ketone 5 can be returned (recycled) to the same reaction again (via ketoxime 1 which can be quantitatively prepared from the ketone and hydroxylamine).Consequently, the yield of pyrrole 4 when calculated on the initial ketone 5 consumed, is about two times higher that isolated one (even not accounting for the incomplete conversion of oxime 1).
Thus, having in mind availability of the starting materials and the straightforward one-pot synthetic procedure, the reaction of acetophenone oxime with phenylacetylene may be considered as acceptable for the preparation of 2,5-diphenyl-1H-pyrrole (4) despite the modest yield.

Scheme 2
The pyrrole 8 is a product of further regio-and stereoselective vinylation of pyrrole 6 with phenylacetylene.Noteworthy that other isomeric pyrrole 7 is not vinylated under these conditions, obviously due to the steric hindrance imposed by phenyl substituents in the position 5 of the pyrrole ring.Since the vinylpyrrole 8 can be easily separated from the mixture of pyrroles 6 and 7 (see experimental), there is an opportunity to isolate pure pyrrole 7 by using excess phenylacetylene and carrying out the reaction up to completed vinylation of pyrrole 6.Another interesting feature of this reaction is that the expected deoximation product, phenylbenzylketone was detected in the reaction mixture in negligible quantities (2%) only.At a lower temperature (120 о С) and dropwise feeding of phenylacetylene, the content of the vinylated pyrrole 8 in the reaction mixture decreased to 9%, and those of 2,3,4-triphenyl-( 6) and 2,3,5-triphenylpyrroles (7) correspondingly dropped (31 and 13%).In this case, the crude product contained 44% of starting oxime 2 (Table 1).
The 1 Н NMR monitoring of the reaction of benzylphenylketoxime (2) with phenylacetylene (LiOH-DMSO, 120 о С) indicates that the pyrrole 6 is formed first, i.e. at a higher rate than the pyrrole 7 (Table 1).From the data of Table 1, it may be assumed that the selective preparation of pyrrole 6 is achievable.Indeed, when the reaction was stopped at ∼20% conversion of oxime 2, the ratio of pyrroles 6 and 7 was 4:1.

Scheme 3
Such a mechanism was experimentally proved in a number of previous works 4,13f,17 where the similar intermediate O-vinyloximes were isolated and separately rearranged to the corresponding pyrroles.
In summary, the reaction of oximes of aromatic ketones with phenylacetylene in MOH-DMSO systems paves a new path to one-pot preparation of di-and triarylpyrroles -promising precursors of pharmaceutically important compounds and optoelectronic materials.

Experimental Section
General Procedures.IR spectra were recorded from КBr pellets on a Bruker IFS-25 instrument.NMR spectra were run on a Bruker DPX 400 spectrometer [400.13 ( 1 H) MHz, 100.6 MHz ( 13 С)]; СDCl 3 as solvent, HMDS as internal standard.Detailed 13 C NMR peak assignments were obtained by careful analysis of HSQC and HMBC 2D NMR spectra.GCMS spectrum was run on a MSD5975C (Agilent), microanalyses were obtained in the A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch of the Russian Academy of Sciences, Russia on an EA FLASH 1112 Series (CHN Analyzer) instrument.