Regio-and stereoselective Diels-Alder reaction of diphenyl 5-methylhexa-1,3,4-trien-3-yl phosphine oxide with N -(4-substituted-phenyl)maleimides and maleic anhydride

Regio-and stereoselective Diels-Alder reaction of diphenyl 5-methylhexa-1,3,4-trien-3-yl phosphine oxide 1 with N -(4-substituted-phenyl)maleimides or maleic anhydride and the formation of a series of the 5-(diphenylphosphinoyl)-4-isopropylidene-2-(4-substituted-phenyl)- 3a,4,7,7a-tetrahydroisoindole-1,3-diones 5a - g and the 5-(diphenylphosphinoyl)-4- isopropylidene-3a,4,7,7a-tetrahydroisobenzofuran-1,3-dione 3 respectively is described.

The synthetic utility of functionalized vinylallenes has been demostrated by Okamura and coworkers, 31,36 in a variety of preparations and interesting reactions, including the preparation of vinylallenes which are useful intermediates in organic synthesis in general 22 and natural polyenes, such as Vitamins A and D, in particular. 31uring our previous works concerning electrophilic cyclization reactions of alkatrienyl phosphine oxides, we were able to show that 1-37 and 3-vinylallenyl 38 phosphine oxides are readily accessible by [2,3]-sigmatropic rearrangement of the corresponding 1-and 3vinylpropargylic phosphinites, formed in the reactions of the corresponding -alkynols with diphenylphosphinous chloride.
Note that when the reaction mixture was stirred in benzene at room temperature, thin-layer chromatography showed that the two reactants still interacted (much more slowly) and the reaction was complete within 48 hours with the formation of the desired cycloadduct 3a.It is necessary to carry out this reaction under argon atmosphere since vinylallenyl phosphine oxides are sensitive to the moisture in air. 37,38The desired product 3a was obtained in 42% yield (see Table 1, entry 1).When the reaction was carried out at reflux, it was complete within 14 hours and the yield was considerably higher (71%, entry 2).Lower yield was obtained in THF at reflux for 24 hours (entry 5) and similar yields were obtained in chlorinated hydrocarbons as solvents (entries 6-8).Polar solvents such as ethanol, acetonitrile, nitromethane and ethyl acetate gave low yields, even with longer reaction times (48 hours) and mainly recovered starting materials and/or polymeric residue (entries 9, 10, 11 and 12, respectively).Fortunately, when toluene was used as solvent at reflux for 13 hours, the yield improved to 78% (entry 13).Reaction in xylene at reflux for 13 hours gave lower yield (63%, entry 14).We therefore, conducted the remaining reactions in toluene at reflux using 1.0 equiv. of the 1-vinylallenyl phosphine oxide 1 and 1.5 equiv. of the dienophiles 2. The cyclic product 3a was fully characterized by means of NMR ( 1 H, 13 C, and 31 P), and IR spectroscopy.
Having determined the optimized condition, we explored the score of the Diels-Alder reaction and some of the results that we obtained are listed in Table 2. Generally, when the reaction was carried out with N-(4-substituted-phenyl)maleimides 2a-g, the corresponding cyclic products 3a-g were obtained with 69-82% yield, irrespective of the electronic nature of the substituents on the benzene ring.Both electron-donating and electron-withdrawing substituents were tolerated and desired products 3a-g were obtained in high yields.
To establish the generality of this methodology, the Diels-Alder reaction of the 1-vinylallenyl phosphine oxide 1 with classical dienophile -maleic anhydride 4 -was examined under the optimized conditions.Interestingly, this protocol can also be successfully applied to that Diels-Alder reaction and the 5-(diphenylphosphinoyl)-4-isopropylidene-3a,4,7,7atetrahydroisobenzofuran-1,3-dione 5 was isolated in 84% yield after heating at reflux for 12 hours (see Scheme 2).Heating at temperatures above these values (for example -in xylene) or reaction time longer than 12 hours decreases the yields due to polymerization of the starting vinylallenic material or decomposition of the cycloadduct 5.Although the exact mechanistic aspects of this transformation have not been rigorously elucidated, the following pathway could be a probable stereochemical route on the basis of experimental results as illustrated in Scheme 3. Structural assignments of the new cyclic compounds 3a-g and 5 are based on the 1 H, 13 C, and 31 P NMR data, IR spectra, as well as elemental analyses.The coupling constants J3a-7a=7.0-7.2Hz and 9.0 Hz in the 1 H NMR spectra of cyclic products 3a-g and 5 respectively, approve the syn-position of the corresponding protons 25,44 .
This study reveals the possibility for synthetic innovations as well as the potential of the Diels-Alder reaction of the vinylallenyl phosphine oxides to selectively construct exocyclic double bond on six-membered rings.Further expansion and applications of this methodology are in progress at our laboratories and will be reported in due course.
Results of an initial investigation of the physiological activity of the compounds prepared were encouraging and the activity of selected compounds is now under investigation.A continuation of these studies towards the synthesis and electrophilic cyclization and cycloaddition reactions of other functionalized vinylallenes is currently in progress in our laboratories.

Scheme 1 .
Scheme 1. Role of the allenes as dienophiles and the vinylallenes as diene components in Diels-Alder reaction.

Table 1 .
Screening of reaction conditions for the Diels-Alder reaction of vinylallenyl phosphine oxide 1 with N-phenylmaleimide 2a

Table 2 .
Synthesis a The reaction was carried out with 1 (1 mmol) and 2 (1.5 mmol) in toluene at reflux.b Isolated yields by chromatographical purification on silica gel.