Stereoselective synthesis of 4-oxo-2,5-dienes and conjugated dienes by Stille cross coupling reactions of vinylstannanes

The palladium-catalyzed cross coupling reactions between trineophylstannylvinyl esters and unsaturated acyl chlorides lead mostly to 4-oxo-2,5-dienes in good yields (60-77%). In some cases homocoupling products are also formed. On the other hand, the Stille reaction of Z-di-and trisubstituted vinyl iodides with trineophylvinylstannanes enables the synthesis of polysubstituted butadienes in moderate to good yields (40-60%).


Introduction
The Stille reaction, i.e., the palladium-catalyzed cross coupling reaction between organic halides and organostannanes, is one of the more important methods used to make carbon-carbon bonds. 1 A significant feature of this reaction is that the organotins can be prepared with a wide range of transferable substituents many of which are unavailable using nucleophilic reagents like Grignard, organolithium, and organozinc reagents.Also, the organotin reagents usually employed are air-and moisture-stable.Although numerous applications of the Stille reaction have been reported in recent years, only few examples of palladium-catalyzed cross-couplings involving acyl chlorides can be found in the literature. 2 4-oxo-2,5-diene structural units are of particular interest due to their possible use as intermediates in the synthesis of natural products.
They are also part of antitumor molecules like melodienone and homoisomelodienone, two cytotoxic agents isolated from the Melodrum fruticosum Lour (Anonaceae from southeast Asia). 3n the other hand, we have been engaged for some time in the synthesis of vinylstannanes with well defined stereochemistry containing organotin moieties with bulky organic ligands specially neophyl groups. 4These trineophyltin derivatives have been obtained with good to excellent yields via free radical and palladium catalyzed hydrostannation of mono-and disubstituted alkynes.It should be noted that the viniltrineophylstannanes are more stable than their trimethyl-and tributyltin analogues which have been reported to decompose or isomerize during the chromatographic purification.4b In this paper, we wish to report some results we have obtained in studies related to the palladium-catalyzed cross coupling reactions between trineophylstannylvinyl esters and unsaturated acyl chlorides as well as to the couplings between some vinyliodides and vinylstannanes carried out in order to determine their possible use in the synthesis of 4-oxo-2,5dienes and of conjugated dienes respectively.

Results and Discussion
The Stille reaction between α,β-unsaturated acyl chlorides and trineophylstannylvinyl esters was carried out according to Scheme 1.The two vinylstannanes used were selected taking into account that they have been obtained in quantitative yields via hydrostannation of the corresponding substituted alkynes.4a,e
As shown in Table 1, we found that whereas the reaction between methyl (Z)-3trineophylstannylpropenoate (1) and (E)-3-phenylpropenoyl chloride (3) mediated by Pd(PPh 3 ) 4 (entry 1) leads to the expected acylation product 5, this reaction does not take place using Pd(PPh 3 ) 2 Cl 2 (entry 2) as catalyst.The homocoupling product 8 (entry 1) results from a common side reaction of the vinylstannane 1 observed in many Stille couplings.1b In Table 1 it is also shown that the vinylstannane 1 does not react with methacroyl chloride (4) when the catalyst is Pd(PPh 3 ) 4 (entry 3) and that when the reaction is carried out in the presence Pd(PPh 3 ) 2 Cl 2 (entry 4) the only product obtained is 8, i.e., the homocoupling product in 60% yield.a VT = Vinyltin compound.b AC = Acyl chloride.c Catalyst/solvent ratio relationships used: VT = 1 eq; AC = 1 eq; Catalyst: 0.01 eq; solvent = 5 ml.d Starting material recovered.
These results seem to indicate that the success of the acylation of vinylstannanes with unsaturated acid chlorides catalyzed by palladium complexes, depends mostly on the structural features of the stannanes.It is to add that the new 4-oxo-2,5-dienes 5-7 were obtained with complete regio-and stereoselectivity.
Taking into account that the starting vinylstannanes had been obtained in quantitative yields, the global yield of this two steps synthesis of 4-oxo-2,5-dienes is around 65%.In the literature, only a six steps synthesis that leads in 27 % global yield to methyl (E,E)-6-phenyl-4-oxo-2,5hexadienoate, i.e., the geometric isomer of (Z,E)-5 has been described.3a Conjugated dienes with a well defined stereochemistry are very interesting structures.Many aliphatic natural products contain two or three conjugated double bonds whose geometry is directly connected with the biologic activity of these compounds.We considered it possible to carry out the synthesis of these conjugated systems starting from vinylstannanes via a two step sequence involving a iodo destannylation followed by a Stille cross couplings, according to Scheme 2.
ARKAT USA, Inc. Type II iodides are difficult to obtain following other synthetic routes because they are prone to isomerization in the reaction media usually employed for their preparation. 5As shown in Scheme 2, iodination in CH 2 Cl 2 at room temperature of vinylstannanes 1, 2, and 10 leads to the iodides 11-13 in almost quantitative yield after being purified by column chromatography on silicagel 60.We then carried out the study on the cross coupling reactions mediated by palladium complexes between iodides 11-13 and type III vinyl stannanes according to Scheme 2. These reactions lead with moderate yields and with complete stereoselectivity to the dienes 16-18, as shown in Table 2.Only vinyl iodides 11 and 12 could be used because iodide 13 decomposed under the reaction conditions, probably due to the temperature needed in order to effect the coupling. 5We found that in order to obtain the desired coupling products in reasonable yields, the best catalyst/solvent system was Pd(PPh 3 ) 4 / ICu / DMF.With the other systems studied, ARKAT USA, Inc.
Taking into account that the starting vinylstannanes had been obtained in quantitative yields, the global yield of this three steps synthesis of the 1,3-dienic systems is of about 45%.
Further studies on the application of the cross couplings reactions mediated by palladium complexes to the stereoselective synthesis of insaturated conjugated systems are in advance.

Conclusions
The results reported in this paper suggest that by an adequate selection of the experimental parameters it is possible to obtain 4-oxo-2,5-dienes and conjugated dienes via palladium cross coupling reactions.These compounds were obtained in good to fair yields and with complete stereoselectivity.According to the catalyst/solvent system employed, some products of homocoupling of the starting vinyl stannanes were also obtained in some cases.

Experimental Section
General Procedures.NMR spectra were obtained in a Bruker ARX 300 instrument.Infrared spectra were recorded with a Nicolet Nexus FT spectrometer.Mass spectra were obtained using a Finnigan MAT Model 8230 at Dortmund University (Germany).Microanalyses were performed at Dortmund University.All the solvents, catalysts, and reagents used were analytical reagent grade.

Stille reactions between vinyl iodides and trineophylstannylvinyl compounds
All the reactions were carried out following the same procedure.One experiment is described in detail to illustrate the method used.

Table 1 .
Products obtained in the palladium catalyzed acylation of vinyltin compounds

Table 2 .
Results obtained in the synthesis of conjugated dienes