Preparation and Reaction Chemistry of Novel Silicon-Substituted 1,3-Dienes

2-Silicon-substituted 1,3-dienes containing non transferrable groups known to promote transmetallation were prepared by Grignard chemistry and enyne metathesis. These dienes participated in one pot metathesis/Diels-Alder reactions in regio- and diastereoselective fashions. Electron-rich alkenes showed the fastest rates in metathesis reactions, and ethylene, a commonly used metathesis promoter slowed enyne metathesis. 2-Pyridyldimethylsilyl and 2-thienyldimethylsilyl substituted Diels-Alder cycloadducts participated in cross-coupling chemistry and the 2-thienyldimethylsilyl substituted cycloadducts underwent cross-coupling under very mild reaction conditions.


Introduction
We have been interested in the preparation and reaction chemistry of metal-substituted dienes for over 20 years.Initially, we prepared a number of transition metal-substituted dienes [1,2] for these studies but, more recently, we have been interested in the investigation of silicon-and boron-substituted dienes [3][4][5][6][7].We have reported the preparation of 2-silicon-substituted 1,3-butadienes by a variety of synthetic routes and demonstrated that they could be used in sequential Diels-Alder/cross-coupling reactions [8][9][10][11][12][13].Here we report the preparation of new 2-silicon-substituted 1,3-dienes containing silicon substituents known to promote transmetallation (hence, the ability to participate in cross-coupling OPEN ACCESS reactions under very mild conditions) and their Diels-Alder/cross-coupling reactions.While the new chemistry disclosed here was not aimed specifically at cis-clerodane synthesis targets, we believe it can also be used to access those biologically-significant core structures [14].

2-Silicon-Substituted Diene Synthesis via Grignard Chemistry
In 2014, we first reported the preparation and isolation of buta-1,3-dien-2-yldimethylsilanol (1) [13], however, this molecule proved to be very unstable towards dimerization, so we began to look for alternative silicon-substituted dienes with higher stability but also containing silicon substituents known to promote transmetallation.In 1999, the Denmark group reported silacyclobutanes as masked silanol equivalents [15] and this was followed by reports from the Itami group [16] that the 2-pyridyldimethylsilyl group and from the Hiyama group that the 2-thienyldimethyl silyl group [17] could similarly function as masked silanol precursors.In 2007, we first reported synthesis of 2-silicon-substituted 1,3-butadienes from chloroprene via zinc catalyzed Grignard reactions with the corresponding halo silanes [9].In the present work, we used that same strategy and successfully prepared the 2-pyridyldimethylsilyl (3) and 2-thienyldimethylsilyl (4)-substituted dienes (Scheme 1).Siletane diene (5) was also prepared by this route but we could not completely separate it from xylene by distillation or chromatography so we could not completely characterize it.Scheme 1.Reactions of the Grignard reagent from chloroprene with silyl chlorides.

2-Silicon-Substituted Diene Synthesis via Enyne Metathesis
In 2010 we published a methodology based on enyne metathesis to prepare 4-aryl-and 4-alkyl-2silyl-1,3-butadienes [11].Pietraszuk and co-workers also recently reported a related cross-metathesis protocol for silyl alkynes [18].In the present work, we also wanted to synthesize more highly-substituted silicon dienes containing nontransferable groups known to promote transmetallation.Thus, to investigate that possibility we first prepared both 2-thienyldimethylsilyl-and 2-pyridinyldimethylsilylethyne (21,22) (Scheme 4).These compounds were prepared as described by Denmark via addition of ethynylmagnesium bromide to the appropriate silyl chloride [19].

Scheme 4. Preparation of silyl alkynes.
We initially investigated metathesis of these two alkynes with styrene using Hoveyda Grubbs 2nd generation catalyst and the 5:1 alkene:alkyne ratio we had used originally in 2010 [11].Under these conditions, the 2-pyridyldimethylsilyl alkyne produced no observable diene and the 2-thienyldimethylsilyl alkyne produced a diene, but it was very difficult to separate it from the stilbene (alkene metathesis) byproduct.We increased the amount of ruthenium complex used all the way up to a stoichiometric amount with alkyne 22 and saw no diene, so we suspect the pyridine group prevents the desired metathesis (Scheme 5).We also attempted to prepare a number of other silyl alkynes with the procedure used to prepare 21 and 22 (R1 = R2 = Me, R3 = Cl; R1 = R2 = iPr, R3 = H; R1 = R2 = -CH2CH2CH2-, R3 = Me) but in these other cases those alkynes decomposed upon attempted purification.Since the alkyne decomposition appeared to occur when the extraction solutions were concentrated, we also attempted using these additional alkynes in cross-metathesis without purification, but this also proved unsuccessful.Olefin metathesis competes with enyne cross-metathesis and we found it impossible to completely separate 23 by chromatography or distillation from the large amounts of byproduct stilbene being produced when excess styrene was used.To suppress olefin metathesis we attempted limiting alkene concentrations similar to the work that Clark and Diver had reported in 2011 [20].We are able to drive the reaction to completion (as judged by 1 H-NMR disappearance of the alkyne proton in 21) with styrene with 6 mol % Hoveyda Grubbs 2nd generation catalyst loading at an alkene:alkyne ratio of 1.2:1 (Scheme 6).Grubbs 1st and 2nd generation catalysts, Hoveyda Grubbs 1st generation and the Zhan 1B catalyst were also screened at 6% loadings and none proved superior to Hoveyda Grubbs second generation catalyst for this cross metathesis.Scheme 6. Optimized enyne metathesis.
While we were able to minimize stilbene production in the preparation of 23, we were not able to isolate 23 analytically pure by distillation or chromatography.In our previous work with benzyl(ethynyl) dimethylsilane we had performed sequential metathesis/Diels-Alder chemistry without isolating dienes so we did not view this as an insurmountable synthetic problem [11,12].
We next moved to an investigation of cross-metathesis using styrenes that contained both electron donating and withdrawing groups.The metathesis chemistry of the 2-thienyldimethylsilylethyne (21) proved very different from the trends observed by Diver's group [21] and very different from what we had observed previously with dimethylbenzylsilylethyne [11].The reaction of 21 with p-vinylanisole was complete with 3 mol % catalyst within 2 h under reflux conditions, whereas p-chlorostyrene needed 6 mol % catalyst and was refluxed for 30 h (Scheme 7, Table 1).As mentioned above, Diver's group had studied the effect of alkene electronics with Grubbs second generation catalyst and their work revealed moderate electron withdrawing groups on the phenyl ring facilitated enyne metathesis (p-methoxystyrene was approximately two orders of magnitude slower than p-bromostyrene), and that these reactions went via an arylidene first mechanism [21].Our results here showed the opposite trend, i.e., the moderately electron-withdrawing chlorostyrene was least reactive, but these reactions were performed using Hoveyda Grubbs second generation catalyst rather than the Grubbs second generation catalyst Diver used.Completion of these reactions was judged by disappearance of the alkyne proton of 21 by 1 H-NMR as described above.Ethylene has been reported by researchers [22,23] as a promoter of metathesis until recently Gregg, Keister, and Diver reported on the inhibitory effect of excess ethylene in enyne metathesis [24].These reactions which were inhibited by ethylene proceed via a mechanism where there is a ruthenacyclobutane catalyst resting state and this ruthenacyclobutane is formed via reaction of ruthenium methylidene with ethylene.When we attempted the enyne metathesis reactions reported here in the presence of one atmosphere of ethylene, we also noted metathesis inhibition.Whereas p-methoxystyrene had reacted completely with the silyl alkyne (21) in 3 h at room temperature in the absence of ethylene, we noted only ~50% conversion under ethylene; similarly, styrene after 12 h of reflux under ethylene showed only about 30% conversion.

Tandem Methathesis/Diels-Alder Reactions and Subsequent Cross-Coupling
Once we optimized reaction conditions, we carried out one-pot methatheses and Diels-Alder reactions (Scheme 8).All three dienes reacted in highly regio-, and diastereo-selective fashions.We did not observe any meta Diels-Alder adduct and, in the case of 25a and 26a, the observed syn:anti ratio was 27:1.The syn and anti diastereomers (25a and 26a) were separated and analyzed using NOESY data (Supplementary Material) to establish their stereochemical assignments.When we analyzed crude reaction mixtures of tandem metathesis and Diels-Alder products by 1 H-NMR spectroscopy we did not observe any exo adduct formation for p-chlorostyerene and p-vinylanisole.Upon purification on silica, we exclusively obtained the endo adducts (25b and 25c).All of these silicon-substituted cycloadducts (25a-c) also then participated in cross-coupling reactions with iodobenzene at room temperature to produce cycloadducts (27) (Scheme 9).While the new chemistry disclosed here was not aimed specifically at cis-clerodane targets, we believe it can also be used to access those biologically-significant core structures [14].Scheme 8. One-pot enyne metathesis/Diels-Alder reactions.

General Information
The proton nuclear magnetic resonance ( 1 H-NMR) spectra were obtained using a Bruker Avance 300 MHz spectrometer operating at 300.1 MHz or a Bruker Avance 500 MHz spectrometer operating at 500.1 MHz. 13 C-NMR spectra were obtained using a Bruker Avance 300 MHz spectrometer operating at 75.5 MHz. 1 H-and 13 C-NMR spectra were referenced to the residual proton or carbon signals of the respective deuterated solvents.All elemental analyses were performed by Atlantic Microlabs Inc., Norcross, GA, USA.High-resolution mass spectrometry was performed at the UNC Mass Spectrometry Facility, Chapel Hill, NC, USA or the Northwestern University Mass Spectrometry facility.
All reactions were carried out under an atmosphere of nitrogen.Tetrahydrofuran (THF) was degassed with argon and then passed through two 4 × 36 inch columns of anhydrous neutral A-2 alumina (8 × 14 mesh; activated under a flow of Ar at 350 °C for 3 h) to remove water.Deuterated solvents were purchased from Cambridge Isotope Laboratories (Tewksbury, MA, USA) and dried over molecular sieves.Sodium sulfate, sodium hydroxide, magnesium small turnings, and 1,2-dibromoethane were purchased from Sigma-Aldrich Chemical Company (St. Louis, MO, USA) and used as received.2-Chloro-1,3-butadiene, 50% in xylene (chloroprene) was purchased from Pfaltz & Bauer, Inc. (Waterbury, CT, USA) and used as received.

2-(Buta-1,3-dien-2-yldimethylsilyl)pyridine 3
A 100 mL flame-dried two-neck round-bottom flask was equipped with a magnetic stir bar, addition funnel, and reflux condenser under Ar.Mg turnings (1.00 g, 41.66 mmol) were added, followed by anhydrous THF (5 mL), followed by 1,2-dibromoethane (266 µL, 3.1 mmol).Activation of Mg was confirmed by the evolution of ethane gas.Anhydrous ZnCl2 (0.168 g, 1.23 mmol) was dissolved in THF (3 mL) and was added to the reaction mixture.After stirring for 5 min the color of the solution became milky white.Anhydrous THF (20 mL) was added and it was set to reflux under Ar.After refluxing for 30 min chloroprene in 50% xylenes (5.04 mL, 26 mmol) was loaded into the addition funnel.1,2-Dibromoethane (0.533 mL, 6.2 mmol) and THF (5 mL) were mixed with the chloroprene and it was slowly added over 30 min.Upon completion of the addition, the solution was refluxed for 45 min.The color of the reaction mixture turned green and it was cooled to room temperature.The reaction mixture was cannula transferred to a round bottom flask containing dimethyldichlorosilane (3.00 mL, 25 mmol) and diethyl ether (50 mL) and stirred for 2 h under Ar.In a separate flame-dried one-neck 250 mL flask containing a magnetic stir bar, 2-bromopyridine (2.5 mL, 26 mmol) was added.Anhydrous diethyl ether (15 mL) was added and the flask was sealed with a septum.The entire mixture was kept under positive pressure of Ar and cooled to −78 °C.At the same temperature, n-butyllithium (17 mL of a 1.6 M solution in hexanes, 27.3 mmol) was added and was stirred for 30 min.The color changed to orange.To this reaction mixture buta-1,3-dien-2-ylchlorodimethylsilane was cannula transferred at −78 °C.The solution was allowed to reach room temperature and stirred for 12 h.The resultant mixture was diluted with diethyl ether (100 mL), washed with sat NaHCO3 solution (20 mL) and 1 M HCl (20 mL).The organic layer was collected and dried over Na2SO4, concentrated by rotary evaporation and subsequently purified by column chromatography (neutral alumina stationary phase, 50:1 pentane: ethylacetate, Rf 0.5).Diene 3 was obtained as a colorless liquid (3.69 g, 19.5 mmol, 78%).

General Procedure for Cross-Coupling Diels-Alder Adducts to Produce Phenyl-Substituted
Cyclohexenes (13,14,16,19,20) In a 5 mL round bottom flask 1 equivalent of Diels-Alder adduct, 1.2 equivalents of iodobenzene, Pd(OAc)2 catalyst (5 mol %), and THF (3 mL) were added.A rubber septum was attached and the solution was degassed for 5 min.Two equivalents of TBAF were added and stirred at RT for 1-3 h.The completion of the reaction was monitored with thin layer chromatography.Upon completion of the reaction it was extracted with sat NaHCO3 soln (15 mL) and of ethyl acetate (2 × 10 mL).The organic layers were dried over Na2SO4 and concentrated under vacuum.The crude product was purified using silica gel (DCM mobile phase).The mixture of cycloadducts 11 and 12 (0.050 g, 0.189 mmol), iodobenzene (0.046 g, 0.226 mmol), Pd(OAc)2 (0.002 g, 0.009 mmol), and TBAF (0.45 mL of a 1 M soln in THF, 0.45 mmol) were reacted for an hour following the general procedure.Compounds (13 and 14) were isolated as a colorless viscous liquid (0.034 g, 0.17 mmol, 91%), identical by 1 H-NMR comparison to previously reported material [25].

General Procedure for Tandem Ene-Yne Cross-Metathesis and Diels-Alder Reactions
In a 5 mL flame-dried round-bottom flask, alkene (1.2 equiv), alkyne (1 equiv), and DCM (3 mL) were added and thoroughly degassed with Ar.Hoveyda-Grubbs 2nd generation catalyst (6 mol %) was added.The reaction mixture was stirred under Ar as described below.N-phenylmaleimide (0.9 equiv) was added and heated for 36 h.The reaction mixture was diluted with ice cold methanol and the methanol extract was filtered through a silica plug to remove catalyst and precipitated stilbene byproduct.The methanol was removed under vacuum and the crude product was purified by flash column chromatography.

General Procedure for Cross-Coupling of 25a-c
In a 5 mL round-bottom flask, 1 equivalent of Diels-Alder adduct, 1.2 equivalent of iodobenzene, Pd(OAc)2 catalyst (5 mol %), and THF (3 mL) were added.A rubber septum was attached and it was degassed for 5 min.Two equivalents of TBAF were added and stirred for at RT for 15 min.The septum was removed and a reflux condenser was attached.The reaction mixture was refluxed for 4 h.Upon completion of the reaction it was washed with sat NaHCO3 soln (15 mL) and extracted with ethyl acetate (10 mL).The organic layers were dried over Na2SO4 and concentrated via rotary evaporator.The crude product was purified using silica gel with a pentane/ethyl acetate mobile phase.Cycloadduct 25a (0.1 g, 0.23 mmol), iodobenzene (0.057 g, 0.28 mmol), Pd(OAc)2 (0.003 g, 0.013 mmol), and TBAF (0.46 mL of a 1 M soln in THF, 0.46 mmol) were reacted following the general procedure.Compound 27a was isolated as white colored solid (0.063 g, 0.17 mmol, 72%), identical by 1 H-NMR comparison to previously reported material [11].