Formation of trisubstituted buta-1,3-dienes and α,β-unsaturated ketones via the reaction of functionalized vinyl phosphates and vinyl phosphordiamidates with organometallic reagents

We studied the reactions of vinyl phosphates and vinyl phosphordiamidates containing an ester functional group with organometallic reagents. We found that the functionalized vinyl phosphates were smoothly converted into tri- and tetrasubstituted buta-1,3-dienes via the reaction with aryllithium reagents. Moreover, the vinyl phosphordiamidates were converted into α,β-unsaturated ketones using Grignard reagents. Based on the performed experiments, we proposed a reaction mechanism, which was confirmed by means of the isolation of key intermediates.


Introduction
A Kumada-Tamao-Corriu (KTC) reaction is a representative example of the traditional cross-coupling reaction of an electrophilic template with an organometallic reagent, as represented by Grignard reagents. This reaction is frequently used for the formation of a C-C bond. 1 Among the various electrophilic templates that are suitable for use in a KTC reaction, substrates containing an activated C-O bond are considered particularly attractive. The reason behind the popularity of such substrates is their availability, which is associated with their preparation. Recent examples of the cross-coupling reactions of ethers, 2 tosylates, 3 and triates 4 with Grignard reagents all illustrate the KTC reaction potential of compounds with an activated C-O bond. Using this approach, a wide variety of substances can be prepared, including substituted alkenes.
The stereoselective synthesis of di-, tri-, 5 and tetrasubstituted 6 double bonds has been the subject of signicant research attention in recent decades. Vinyl phosphates also play a key role in the synthesis of substituted alkenes. Unsurprisingly, a number of KTC reactions have been described in which the reaction of the vinyl phosphates has been catalyzed by iron, 7 nickel, 8 or palladium 9 catalysts in order to prepare the substituted double bond.
Despite considerable progress having been made in relation to the preparation and application of functionalized Grignard reagents, 10 the preparation of alkenes with functional groups that react with Grignard reagents using the KTC reaction remains difficult (Scheme 1). The vinyl phosphates 1 with a carbonyl group attached to the vinyl unit have been used in the stoichiometric synthesis of organoselenium 11 and organotellurium compounds. 12 A methodology for the stoichiometric Scheme 1 General scheme representing the replacement of the phosphate group of the functionalized vinyl phosphates 1.
cross-coupling reaction of the functionalized vinyl phosphates with dialkylcuprates has also been described. 13 This methodology has been successfully used in the eld of organic synthesis 14 as well as in the total synthesis of naturally occurring compounds. 15 The catalytic reactions of the functionalized vinyl phosphates represented by the general structure 1 include reactions with organoaluminum compounds, 16 iron-catalyzed reactions with methylmagnesium halides, 17 and nickelcatalyzed cross-coupling reactions with trimethylsilylmethylmagnesium chloride. 18 These prior results contrast with a recent report of the KTC reaction of functionalized vinyl tosylates being performed in dry acetonitrile at 45 C. 3b The absence of a general methodology for the KTC reaction of the functionalized vinyl phosphates 1 with Grignard reagents may indicate that this type of vinyl phosphate exhibits low stability in the presence of Grignard reagents. Our review of the literature indicated that a systematic study of the reactivity of the functionalized vinyl phosphates 1 with organometallic reagents has not previously been reported. Thus, based on our earlier studies of the cross-coupling reactions of vinyl phosphates, 19 we decided to investigate the stability of the functionalized vinyl phosphates 2a-2c in the presence of Grignard reagents.

Results and discussion
We began our study by synthesizing the vinyl phosphate 2a by means of the enolization of ethyl acetoacetate, followed by the reaction of the formed enolate with diethyl chlorophosphate. The prepared phosphate 2a was mixed with phenylmagnesium chloride, and then the reaction mixture was stirred for 2 hours at 23 C. Aer the reaction mixture was quenched with aqueous ammonium chloride, the formation of a complex mixture of products was observed based on analysis of the 1 H nuclear magnetic resonance ( 1 H NMR) spectrum of the mixture. However, we isolated the trisubstituted diene 3a as a pure compound in an isolated yield of 27%. This nding was particularly interesting, as the synthesis of trisubstituted dienes is generally limited. The palladium-catalyzed coupling of tosylhydrazones with aryl halides, 20 the selective arylation of vinylarenes, 21 and diethyl-phosphite-promoted carbonyl olenation 22 are recently reported methods for the synthesis of substituted buta-1,3-dienes. We observed that the isolated yield of the diene 3a strongly depended on the reaction workup, with comparatively higher yields of the alkene 3a being achieved with hydrochloric acid, sulfuric acid, and phosphoric acid ( Table 1, entries 3-5). The isolated yield of the alkene 3a did not affect the increased equivalents of phenylmagnesium chloride or the use of the diphenylphosphate 2b (Table 1, entries 6 and 7). The best isolated yield of the diene 3a was obtained when phenyllithium was used in combination with the phenyl ester 2c (Table 1, entry 9).
Optimized reaction conditions were used to evaluate the scope of the reaction (Scheme 2). The diethyl phosphate 2c reacted with the aryllithium reagents, thereby affording the corresponding dienes 3a-3d in a single step and in good isolated yields. 2-Methoxyphenyllithium, as an example of an ortho-substituted phenyl, gave the product 3e in a high isolated yield. A similar reactivity pattern was observed with regard to the diethyl phosphate with an extended alkyl chain 2d. In this case, the dienes 3f-3i were obtained in similar isolated yields to the dienes 3a-3c. The phosphate 2d was also reacted with 2methoxyphenyllithium and 2-thienyllithium, as an example of a heteroaryl reagent, in order to give the dienes 3j and 3k. The dienes 3f-3k were obtained as an inseparable mixture of the (E)and (Z)-stereoisomers and the double-bond geometry was determined by means of nuclear Overhauser effect (NOE) experiments. The use of an alkyllithium reagent, for example, nbutyllithium, failed to give the expected product. Instead, a complex reaction mixture was formed, as observed via the 1 H NMR spectroscopy of the crude reaction mixture. It is worth noting that all the dienes 3a-3e were stored in a freezer, as signicant decomposition was observed when they were stored at room temperature. However, the tetrasubstituted dienes 3f-3k showed excellent long-term storage stability. We synthesized the vinyl phosphordiamidates 2e-2g so as to test their behavior during the developed one-pot synthesis of the substituted buta-1,3-dienes 3. Surprisingly, the vinyl phosphate 2e reacted smoothly with phenylmagnesium chloride to give the a,b-unsaturated ketone 4a in a high isolated yield (Scheme 3). a,b-Unsaturated ketones are known for their medicinal applications, 23 and they are also valuable building blocks in relation to organic synthesis. 24 Therefore, signicant research efforts have been dedicated to identifying a novel approach to conjugated enones. 25 Nickel-catalyzed 1,2-acyl migration, 26 nucleophilic addition to enones, 27 the crosscoupling reaction between acid uorides and vinyl triates, 28 and carbonyl group olenations 29 are examples of such reactions. The conversion of the vinyl phosphordiamidate 2e into the ketone 4a observed in our study represents a hitherto undescribed reaction of phosphordiamidate en route to becoming a,b-unsaturated ketones. Further investigation in this regard showed that a signicantly lower isolated yield of the ketone 4a was obtained with phenyllithium. Uniformly high yields of the corresponding ketones were obtained with the other para-, meta-, and ortho-substituted phenylmagnesium halides 4b-4f. Almost the same isolated yields of the ketones 4h-4m were obtained for the vinyl phosphordiamidate 2f. Additionally, the 2-thienylmagnesium bromide 4n, benzylmagnesium chloride 4o, and octylmagnesium chloride 4p reacted well with the phosphordiamidate 2f under the tested reaction conditions. The examination of the reactivity of the variously substituted vinyl phosphordiamidates was also extended to a phosphordiamidate with a phenyl substituent rather than an alkyl group, and the alkenes 4q and 4r were obtained in quantitative isolated yields.
Scheme 3 Synthesis of trisubstituted a,b-unsaturated ketones via the reaction of the phosphordiamidates 2e-2g with Grignard reagents. Our attempts to prepare enones with a tetrasubstituted double bond by means of the reaction of the vinyl phosphordiamidate 2h with phenylmagnesium chloride proved to be less effective, with the formation of the ketones 5a and 6 being observed (Table 2, entry 1). Therefore, we tried to optimize the studied reaction in order to obtain only the ketone 5a. However, the use of phenylmagnesium chloride always gave a mixture of the ketones 5a and 6, regardless of the reaction conditions (Table 2, entries 2 and 3). The desired outcome was ultimately achieved through the reaction between phenyllithium and the phosphordiamidate 2h, and the ketone 5a was obtained in an isolated yield of 67% (Table 2, entry 4).
The extension of the studied reaction to the cyclic vinyl phosphordiamidates 2i and 2j was successful in terms of the preparation of substituted cyclopentanones and cycloheptanones. In both cases, the expected ketones 5b, 5c, 5d, and 5e were obtained in very good isolated yields. Similar results were obtained for the acyclic phosphordiamidate 2k. Only the use of 2-thienyllithium proved less effective, and the reaction products 5f and 5i were obtained in low isolated yields (Scheme 4).
As a result of the performed experiments, we were able to propose a mechanism for the observed transformations. We assumed that during the rst step, an organometallic reagent addition to the ester functional group occurred and formed a common intermediate 7. The intermediate 7 with a phosphate group subsequently underwent trans-phosphorylation, with the resultant elimination forming an unsaturated ketone 4a, which was obtained in a low isolated yield of 35% when the crude reaction mixture was quenched at À78 C. The resulting ketone 4a reacted with an organolithium reagent to form the corresponding tertiary alcohol, which was then dehydrated by phosphoric acid to give the diene 3a. This hypothesis was conrmed by the reaction of the ketone 4a with phenyllithium, with the subsequent dehydration giving the diene 3a in a 93% isolated yield. We also veried that ethyl acetoacetate did not provide the ketone 4a or the diene 3a under the studied conditions. In the case of the intermediate 7 with phosphordiamidate moiety, the trans-phosphorylation reaction is sluggish and the intermediate 7 was converted into the tertiary alcohol 8. The formation of this intermediate was conrmed by means of the hydrolysis of the crude reaction mixture with water, and the corresponding alcohol 8 was obtained in a 79% isolated yield. The formation of the ketone 4a was completed by the alcohol 8 dehydration. This was again conrmed by the dehydration of the independently prepared alcohol 8 into the product 4a in a quantitative isolated yield. Alternatively, the dehydration of the alcohol 8 could be performed using phosphoryl chloride in the presence of triethylamine in a similar isolated yield (Scheme 5).

Conclusion
In conclusion, we studied the reactivity of both vinyl phosphates and vinyl phosphordiamidates. We found that vinyl phosphates can be converted into tri-and tetrasubstituted buta-1,3-dienes via the reaction with aryllithium reagents in dry THF at À78 C to 23 C. The tetrasubstituted dienes were isolated as a mixture of the (E)-and (Z)-stereoisomers. In the case of the vinyl phosphordiamidates, the reaction with Grignard reagents under the same reaction conditions resulted in the formation of unsaturated ketones, which were isolated in yields ranging from 24% to 97%. Based on the experimental results, we were able to propose a mechanism explaining the origins of both products. spectrometer at 298 K. Chemical shis of 31P NMR spectra are referenced to the signal of 85% H 3 PO 4 that was assigned the chemical shi of 0. Mass spectra were measured on ZAB-SEQ (VG Analytical). The dry and degassed THF was prepared by PureSolv MD7. Silica gel (Merck, Silica Gel 60, 40-63 mm or Merck Silica Gel 60, 63-200 mm) was used for column chromatography. A phosphate 2a was prepared according to a published procedure. 30 n-BuLi (2.5 M solution in hexane), and other compounds were purchased from Sigma-Aldrich, FLuorochem and Acros Organics. Concentration of BuLi was determined by titration using menthol and 1,10-phenanthroline before use.
General procedure for the synthesis of starting phosphates 2a-2d (GP1). 1,3-Dicarbonyl compound was added to a suspension of sodium hydride (1.25 equiv.) in dry THF (5 mL/1 mmol) cooled to 0 C. The resultant mixture was stirred for 30 min at 23 C followed by addition of dialkyl chlorophosphate (1.25 equiv.). Then the reaction mixture was stirred for 2 h at 23 C. The crude reaction mixture was quenched with saturated aqueous solution of ammonium chloride (1 mL/1 mmol), the organic layer was separated and the water layer was extracted with ether (3 Â 3 mL/1 mmol). Combined organic layers were dried over MgSO 4 , the solvents were removed under reduce pressure and column chromatography (Silica gel) gave the product.

Conflicts of interest
There are no conicts to declare.