Preparation and reaction chemistry of novel silicon-substituted 1,3-dienes

Article abstract of DOI:10.3390/molecules200916892

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.

Full text of DOI:10.3390/molecules200916892

Molecules 2015, 20, 16892-16907; doi:10.3390/molecules200916892
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Preparation and Reaction Chemistry of Novel
Silicon-Substituted 1,3-Dienes
Partha P. Choudhury and Mark E. Welker *
Department of Chemistry, Wake Forest University, P. O. Box 7486, Winston-Salem, NC 27109, USA;
E-Mail: pchoudhury@gru.edu
* Author to whom correspondence should be addressed; E-Mail: welker@wfu.edu;
Tel.: +1-336-758-5758; Fax: +1-336-758-4656.
Academic Editor: Georgios C. Vougioukalakis
Received: 17 August 2015 / Accepted: 8 September 2015 / Published: 16 September 2015
Abstract: 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.
Keywords: organosilanes; 1,3-dienes; enyne metathesis; Diels-Alder; cross coupling
1. 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 [3–7]. 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 [8–13]. 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

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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. Results and Discussion
2.1. 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.

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2.2. Diels-Alder/Cross-Coupling Reactions
We first monitored the reactivity of dienes 3 and 4 with N-phenylmaleimide under pseudo-first order
reaction conditions at 25 °C in CDCl3 by 1H-NMR, and calculated t1/2’s of 22 min and 29 min, respectively.
These 2 dienes are not quite as reactive as the silatrane diene we reported back in 2007 (t1/2 of 18 min at
0 °C) but they are very similar in reactivity to Danishefsky’s diene [9]. We then took diene 3 and reacted
it with three types of dienophiles (methyl acrylate, N-phenylmaleimide, and N-phenyl citraconimide)
followed by Pd (II) catalyst, tetra-n-butylammonium fluoride (TBAF) and aryl halide in one-pot sequential
Diels-Alder/cross-coupling reactions (Scheme 2). The unsymmetrical dienophiles produced predominantly
para products (6, 9) and yields for the two step process ranged from 62%–74% (avg per step 79%–87%).
The 2-thienyldimethylsilyl diene 4 also reacted with these same dienophiles and cycloadducts (11, 12,
15, 17, 18) were again obtained in good yields, albeit with slightly lower regioselectivities than observed
with diene 3 for the unsymmetrical dienophiles (Scheme 3). However, we were initially not able to
produce cross-coupled cycloadducts from these Diels-Alder products (11, 12, 15, 17, 18) using conditions
which worked for the 2-pyridyldimethylsilyl cycloadducts (mild heating to 50 °C just lead to cycloadduct
decomposition). Cross-coupling reactions performed under even milder conditions (25 °C for 1–3 h) did
produce the desired cross-coupled products (13, 14, 16, 19, 20) in excellent yields (Scheme 3). These
Diels-Alder products (11, 12, 15, 17, 18) are the first silicon-substituted cyclohexenes that we are aware
of that would participate in cross-coupling reactions at 25 °C.
Scheme 2. Diels-Alder/cross-coupling reactions of 2-pyridyldimethylsilyl-1,3-butadiene.

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Scheme 3. Diels-Alder reactions of 2-thienyldimethylsilyl-1,3-butadiene.
2.3. 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-2-
silyl-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

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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.
Scheme 5. Initial attempts at enyne metathesis of 21 and 22.
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 1H-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)

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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 1H-NMR as described above.
Scheme 7. Enyne metathesis of 21.
Table 1. Enyne Metathesis Conditions.
Catalyst Loading
Time (Disappearance of the
Alkyne Peak in 1H-NMR)
R
Temperature
(mol %)
-OCH3
-OCH3
-H
7
3
6
6
RT
3 h
2 h
reflux
reflux
reflux
12 h
30 h
-Cl
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.

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2.4. 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 1H-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.
R
R
O
O
Pd (II) Cat 5 mol%
N
N
Si
O
O
S
I
27
25
a) R = H, 72%
b) R = OMe, 78%
c) R = Cl, 65%
Scheme 9. Cross-coupling of aryl substituted 2-thienyldimethylsilyl-substituted cycloadducts.

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3. Experimental Section
3.1. General Information
The proton nuclear magnetic resonance (1H-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. 13C-NMR spectra were obtained using a Bruker Avance 300 MHz spectrometer operating
at 75.5 MHz. 1H- and 13C-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.
3.2. Silyl Diene Synthesis via Grignard Chemistry
3.2.1. 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

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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
1
3 was obtained as a colorless liquid (3.69 g, 19.5 mmol, 78%). H-NMR (300 MHz, Chloroform-d) δ
8.79 (dt, J = 4.9, 1.4 Hz, 1H), 7.66–7.48 (m, 2H), 7.19 (ddd, J = 7.1, 4.9, 1.8 Hz, 1H), 6.49 (dd, J = 17.7,
10.7 Hz, 1H), 5.92 (d, J = 3.0 Hz, 1H), 5.58 (d, J = 3.0 Hz, 1H), 5.13 (d, J = 17.7 Hz, 1H), 5.02 (d,
J = 10.7 Hz, 1H), 0.44 (s, 6H); 13C-NMR (75 MHz, Chloroform-d) δ 166.5, 150.2, 146.8, 141.0, 133.9,
130.7, 129.7, 122.7, 116.8, −2.9; HRMS calcd for C11H16NSi (M + H)+ 190.1052, found 190.1056.
3.2.2. 2-(Buta-1,3-dien-2-yldimethylsilyl)thiophene 4
A 250 mL two-neck round-bottom flask equipped with magnetic stir bar was flame-dried and cooled
under Ar. Mg (3.00 g, 123 mmol) was added and a reflux condenser and addition funnel were attached.
The set up was kept under a positive pressure of Ar. THF (10 mL), and 1,2-dibromoethane (0.8 mL, 9.28 mmol)
was added the reaction mixture. Activation of Mg was confirmed by the evolution of ethane. ZnCl2
(0.504 g, 3.7 mmol) was dissolved in THF (5 mL) and was added to the reaction mixture. After stirring
for 5 min the color of the solution became milky white. THF (20 mL) was added and it was set to reflux
under Ar. After refluxing for 30 min chloroprene in 50% xylenes (15.1 mL, 78 mmol) was loaded into
the addition funnel. 1,2-Dibromoethane (1.6 mL, 18.6 mmol) and THF (15 mL) were mixed with the
chloroprene and it was slowly added over 30 min, followed by reflux for 45 min. The color of the reaction
mixture turned green and it was cooled to room temperature. In a separate flame-dried one-neck 500 mL
flask a magnetic stir bar was added. A rubber septum was attached. Dimethyldichlorosilane (9.1 mL,
75 mmol) was diluted with THF (50 mL) and were added through the septum. The halo diene Grignard
reagent was cannula transferred to this solution under Ar and was stirred at room temperature for 2 h.
The solution was then cooled to −78 °C and 2-lithiothiophene (75 mL of a 1 M soln in THF/hexanes,
75 mmol) was added drop-wise. After overnight stirring, it was diluted with diethyl ether (100 mL) and
the reaction mixture was washed with 1 M HCl (20 mL), saturated NaHCO3 (20 mL) solution and brine
(20 mL). The organic layer was collected, dried over sodium sulfate, and concentrated using a rotary
evaporator. The pure compound was isolated by vacuum distillation at 50 °C at 4 mm Hg (12.2 g,
63 mmol, 84%). 1H-NMR (300 MHz, Chloroform-d) δ 7.62 (dd, J = 4.6, 0.9 Hz, 1H), 7.31 (dd, J = 3.3,
1.0 Hz, 1H), 7.19 (dd, J = 4.6, 3.3 Hz, 1H), 6.49 (dd, J = 17.7, 10.8 Hz, 1H), 5.87 (d, J = 2.9 Hz, 1H),
5.53 (d, J = 3.0 Hz, 1H), 5.22 (d, J = 17.7 Hz, 1H), 5.06 (d, J = 10.7 Hz, 1H), 0.50 (s, 6H). 13C-NMR
(75 MHz, Chloroform-d) δ 147.3, 140.7, 137.5, 135.1, 130.9, 130.3, 128.1, 116.6, −1.0; LRMS calcd for
C10H15SSi (M + H)+ 195.1, found 195.1.
3.2.3. 1-(Buta-1,3-dien-2-yl)-1-methylsiletane 5
Chloroprene in 50% xylenes (1.0 mL, 5.15 mmol) and 1-chloro-1-methylsiletane (0.53 mL,
4.3 mmol) were used according to the procedure described above to yield a light yellow colored liquid.
1H-NMR of the crude product (1.1 g) indicated formation of the diene (1H-NMR diagnostic peaks)
(300 MHz, Chloroform-d) δ 6.50 (ddt, J = 17.7, 10.5, 0.8 Hz, 1H), 5.82 (dt, J = 3.1, 0.7 Hz, 1H), 5.57
(ddd, J = 3.5, 1.2, 0.6 Hz, 1H), 5.24–5.07 (m, 2H), 1.34–0.86 (m, 6H), 0.42 (s, 3H).

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3.3. General Procedure of One-Pot Diels-Alder and Cross-Coupling Reactions of 3
Diene 3 (1 equiv) was added to dienophile (1.1 equiv) and heated in a round-bottom flask with THF
solvent (5–10 mL) for 24 h under Ar. Pd (II) catalyst (5 mol %) was added with aryl halide (1 equiv)
and TBAF (1 equiv). The reaction mixture was heated under Ar for 4 h at 60 °C. The reaction mixture
was filtered through a silica gel pad (EtOAc) and solvent was removed under reduced pressure. The
crude product was purified by column chromatography (dichloromethane mobile phase).
3.3.1. Methyl 2,3,4,5-Tetrahydro-[1,1′-biphenyl]-4-carboxylate 6 and Methyl 2,3,4,5-Tetrahydro-[1,1′-
biphenyl]-3-carboxylate 7
Following the general procedure, diene 3 (0.1 g, 0.53 mmol) and methyl vinyl ketone (0.48 g, 0.69 mmol),
PdCl2(PhCN)2 (0.010 g, 0.026 mmol), iodobenzene (0.108 g, 0.53 mmol), and TBAF (0.53 mL of a
1 M soln in THF, 0.53 mmol) were reacted. The crude product was purified by silica gel flash column
chromatography using pure DCM to yield 6 and 7 (Rf 0.6, 0.073 g, 0.37 mmol, 69%) identical by 1H-NMR
comparison to previously reported material.[25] Ratio of para and meta regio-isomers was determined
by 1H-NMR (3.2:1).
3.3.2. 2,5-Diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione 8
Following the general procedure diene 3 (0.094 g, 0.5 mmol), N-phenylmaleimide (0.094 g, 0.55 mmol),
PdCl2(PhCN)2 (0.010 g, 0.026 mmol), iodobenzene (0.102 g, 0.5 mmol), and TBAF (0.5 mL of a 1 M soln
in THF, 0.5 mmol) were used. The crude product was purified by silica gel flash column chromatography
using DCM to yield 8 (Rf 0.5, 0.112 g, 0.0.37 mmol, 74%), identical by 1H-NMR comparison to previously
reported material [25].
3.3.3. 3a-Methyl-2,6-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione 9 and
3a-Methyl-2,5-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione 10
Following the general procedure diene 3 (0.094 g, 0.5 mmol), 2 methyl-N-phenylmaleimide (0.103 g,
0.55 mmol), PdCl2(PhCN)2 (0.010 g, 0.026 mmol), iodobenzene (0.102 g, 0.5 mmol), and TBAF (0.5 mL
of a 1 M soln in THF, 0.5 mmol) in THF solution were used. The crude product was purified by silica
gel flash column chromatography using DCM to yield 9 and 10 (Rf 0.53, 0.095 g, 0.31 mmol, 62%),
identical by 1H-NMR comparison to previously reported material [25]. Ratio of para:meta product was
found out to be 5:1 by 1H-NMR.
3.4. General Procedure of Diels-Alder Reactions of Diene 4
Diene 4 (1.2 equiv) was added to a 10 mL pressure tube followed by anhydrous THF (4 mL).
Dienophile (1 equiv) was added and degassed for 4 min. The tube was sealed using a crimp cap and the
vial was heated as described below.

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3.4.1. 1-(4-(Dimethyl(thiophen-2-yl)silyl)cyclohex-3-en-1-yl)ethan-1-one 11 and
1-(3-(Dimethyl(thiophen-2-yl)silyl)cyclohex-3-en-1-yl)ethan-1-one 12
Diene 4 (1.11 g, 5.72 mmol) and methyl vinyl ketone (0.4 mL, 4.76 mmol) were reacted for 12 h at
66 °C. The solvent was then removed by rotary evaporation and the crude product dried under vacuum.
The crude product was purified by silica gel flash column chromatography using DCM as mobile phase
(Rf 0.6). Compounds 11 and 12 were obtained as a colorless liquid (1.08 g, 4.09 mmol, 88% yield). Ratio
of para:meta isomer was 3:1 (determined by 1H-NMR). Diagnostic 1H-NMR peaks of the major isomer
11: 1H-NMR (300 MHz, Chloroform-d) δ 7.59 (dd, J = 4.6, 0.8 Hz, 1H), 7.26–7.22 (m, 1H), 7.18 (dd,
J = 4.6, 3.3 Hz, 1H), 6.11 (m, 1H), 2.63–2.53 (m, 1H), 2.30–2.17 (m, 3H), 2.14 (s, 3H), 2.12–1.92 (m,
2H), 1.66–1.37 (m, 1H), 0.374 (s, 3H), 0.37 (s, 3 H); Diagnostic 13C-NMR peaks for the major isomer
11 (75 MHz, CDCl3) δ 211.4, 137.8, 136.3, 135.9, 134.7, 130.7, 128.0, 47.0, 28.3, 27.9, 26.4, 24.9, −2.4,
−2.5; HRMS calcd for C14H21OSSi (M + H)+ 265.1082, found 265.1075.
3.4.2. 5-(Dimethyl(thiophen-2-yl)silyl)-2-phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione 15
Diene 4 (0.116 g, 0.6 mmol) and N-phenylmaleimide (0.086 g, 0.5 mmol) were reacted using the general
procedure. The crude product was purified using silica gel (DCM mobile phase) (Rf 0.37). A light yellow
colored solid was obtained (0.151 g, 0.41 mmol, 82%). 1H-NMR (300 MHz, Chloroform-d) δ 7.60 (dd,
J = 4.6, 0.9 Hz, 1H), 7.49–7.31 (m, 3H), 7.25 (dd, J = 3.2, 1.0 Hz, 1H), 7.20–7.08 (m, 3H), 6.38 (ddd,
J = 6.2, 3.5, 2.5 Hz, 1H), 3.25–3.22 (m, 2H), 2.91–2.70 (m, 2H), 2.40–2.22 (m, 2H), 0.38 (s, 6H).
13C-NMR (75 MHz, CDCl3) δ 179.0, 178.6, 140.2, 138.6, 136.3, 135.0, 132.0, 131.0, 129.0, 128.4,
128.2, 126.3, 39.3, 39.2, 26.3, 25.0, −2.6, −2.7; HRMS calcd for C14H21OSSi (M + Na)+ 390.0960,
found 390.0957.
3.4.3. 6-(Dimethyl(thiophen-2-yl)silyl)-3a-methyl-2-phenyl-3a,4,7,7a-tetrahydro-1H-isoindole-
1,3(2H)-dione 17 and 5-(Dimethyl(thiophen-2-yl)silyl)-3a-methyl-2-phenyl-3a,4,7,7a-tetrahydro-1H-
isoindole-1,3(2H)-dione 18
Diene 4 (0.116 g, 0.6 mmol) and 2 methyl-N-phenylmaleimide (0.094 g, 0.5 mmol) were reacted
using the general procedure. The crude product was purified using column chromatography (silica gel,
DCM, Rf 0.56). Compounds 17 and 18 were obtained as a light yellow solid (0.152 g, 0.4 mmol, 80%)
1
1
as 2:1 mixture of isomers. Diagnostic H-NMR peaks of the major isomer 17: H-NMR (300 MHz,
Chloroform-d) δ 7.53 (dd, J = 4.6, 0.9 Hz, 1H), 7.39–7.27 (m, 3H), 7.24 (m, 1H), 7.19–6.96 (m, 3H),
6.30 (dt, J = 6.4, 3.1 Hz, 1H), 2.90–2.59 (m, 3H), 2.23 (m, 1H), 1.91 (m, 1H), 1.36 (s, 3H), 0.3 (s, 6H);
Diagnostic 13C-NMR peaks of the major isomer 17. 13C-NMR (75 MHz, Chloroform-d) δ 181.9, 177.8,
140.5, 139.2, 138.5, 135.0, 132.1, 131.0, 129.0, 128.4, 128.2, 126.3, 47.2, 44.3, 33.8, 26.8, 24.7, −2.5,
−2.6; HRMS calcd for C21H23NNaO2SSi (M + Na)+ 404.1116, found 404.1112.
3.5. 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

Molecules 2015, 20
16903
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).
3.5.1. 1-(2,3,4,5-Tetrahydro-[1,1′-biphenyl]-4-yl)ethan-1-one (13) and 1-(2,3,4,5-Tetrahydro-[1,1′-
biphenyl]-3-yl)ethan-1-one (14)
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 1H-NMR comparison to previously reported material [25].
3.5.2. 2,5-Diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (16)
Cycloadduct 15 (0.090 g, 0.25 mmol), iodobenzene (0.060 g, 0.294 mmol), Pd(OAc)2 (0.003 g,
0.013 mmol), and TBAF (0.49 mL of a 1 M soln in THF, 0.49 mmol) were reacted for 3 h following the
general procedure. Compound 16 was isolated as a colorless solid (0.066 g, 0.22 mmol, 87%), identical
by 1H-NMR comparison to previously reported material [25].
3.5.3. 3a-Methyl-2,6-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (19) and
3a-Methyl-2,5-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (20)
Mixture of cycloadducts 17 and 18 (0.115 g, 0.3 mmol), iodobenzene (0.073 g, 0.36 mmol), Pd(OAc)2
(0.004 g, 0.018 mmol), and TBAF (0.6 mL of a 1 M soln in THF, 0.6 mmol) were reacted for 3 h following
the general procedure. Compounds 19 and 20 were isolated as a colorless solid (0.084 g, 0.26 mmol,
88%), identical by 1H-NMR comparison to previously reported material [25].
3.6. Silyl Alkyne Preparation
Ethynyldimethyl(thiophen-2-yl)silane (21) was prepared following a published literature procedure [19].
Ethynyldimethyl(pyridin-2-yl)silane (22)
To a 250 mL flame dried flask dimethyldichlorosilane (2.6 mL, 21 mmol) was added followed by
anhydrous diethyl ether (15 mL). Ethynylmagnesiumbromide (44 mL of a 0.5 M soln in THF, 22 mmol)
was added and stirred at RT for 2 h. In a separate 50 mL round-bottom flask 2-bromopyridine (0.348 g,
22 mmol) was added followed by THF (5 mL). n-BuLi (14.5 mL of a 1.6 M soln in hexanes, 23.1 mmol)
was added to the reaction mixture at −78 °C and was stirred under Ar for 10 min. The 2-lithiopyridine soln
was added to the previous flask and was stirred at RT for 10 h. The resultant reaction mixture was washed
with sat NaHCO3 (30 mL) soln. The organic layer was collected, dried over Na2SO4 and concentrated by
rotary evaporation. The crude reaction mixture was distilled at 45 °C at 4 mm of Hg. Compound 22 was
isolated with 90% purity (2.43 g, 15.12 mmol). Diagnostic 1H-NMR peaks (300 MHz, Chloroform-d) δ
8.54 (d, J = 4.9 Hz, 1H), 7.52 (m, 2H), 7.39 (t, J = 8.4 Hz, 1H), 2.32 (s, 1H), 0.26 (s, 6H).

Molecules 2015, 20
16904
3.7. 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.
(3aR,4S,7aS)-6-(Dimethyl(thiophen-2-yl)silyl)-2,4-diphenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole (25a).
Ethynyldimethyl(thiophen-2-yl)silane (21) (0.28 g, 1.68 mmol), styrene (233 µL, 2 mmol), and catalyst
(0.063 g, 0.1 mmol) were refluxed for 12 h under Ar. N-phenylmaleimide (0.262 g, 1.5 mmol) was added
and refluxed for 40 h. After washing with cold methanol, the crude product was chromatographed on silica
gel using 8:1 benzene and ethyl acetate (Rf 0.5). Compound 25 was obtained as a white solid (0.456 g,
1.03 mmol, 69%) along with a mixture of 25 and 26 (0.052 g) which was rechromatographed as
1
described below. H-NMR (300 MHz, Chloroform-d) δ 7.63 (d, J = 4.6 Hz, 1H), 7.44–7.28 (m, 8H),
7.24–7.13 (m, 2H), 6.82 (m, 2H), 6.67 (dd, J = 4.8, 2.2 Hz, 1H), 3.85 (t, J = 5.9 Hz, 1H), 3.47 (dd,
J = 9.1, 6.7 Hz, 1H), 3.37 (td, J = 8.7, 2.6 Hz, 1H), 3.07 (dd, J = 16.5, 2.6 Hz, 1H), 2.51 (ddt, J = 16.4,
8.4, 2.1 Hz, 1H), 0.47 (s, 6H). 13C-NMR (75 MHz, CDCl3) δ 178.1, 176.1, 140.4, 139.6, 138.6, 136.2,
135.2, 131.7, 131.2, 129.1, 128.8, 128.8, 128.4, 128.3, 127.2, 126.2, 45.2, 42.2, 39.0, 25.6, −2.4, −2.6;
HRMS calcd for C26H26NO2SSi (M + H)+ 444.1454, found 444.1449.
(3aS,4S,7aR)-6-(Dimethyl(thiophen-2-yl)silyl)-2,4-diphenyl-2,3,3a,4,7,7a-hexahydro-1H-isoindole (26a).
After isolating 25 as described above, the remaining column fractions (0.052 g) were chromatographed using
4:1 pentane ethyl acetate to yield additional 25 (0.034 g, 0.08 mmol, 5%) (Rf 0.5) followed by compound
1
26 (Rf 0.42) isolated as white solid (0.018 g, 0.04 mmol, 3%). H-NMR (500 MHz, Chloroform-d) δ
7.63 (d, J = 4.8, 1H), 7.45 (t, J = 7.6 Hz, 2H), 7.40–7.34 (m, 3H), 7.33–7.27 (m, 4H), 7.22–7.18 (m, 3H),
6.55–6.50 (m, 1H), 4.12 (m, 1H), 3.44 (dd, J = 9.3, 3.6 Hz, 1H), 3.19 (ddd, J = 9.3, 7.6, 4.8 Hz, 1H),
2.64–2.47 (m, 2H), 0.45 (s, 6H). 13C-NMR (126 MHz, CDCl3) δ 178.5, 178.1, 141.2, 141.0, 139.8, 136.2,
135.1, 131.9, 131.2, 129.0, 128.8, 128.5, 128.35, 127.6, 126.8, 126.3, 46.6, 41.3, 39.0, 26.2, −2.6, −2.7;
HRMS calcd for C26H26NO2SSi (M + H)+ 444.1454, found 444.1449.
(3aR,4S,7aS)-6-(Dimethyl(thiophen-2-yl)silyl)-4-(4-methoxyphenyl)-2-phenyl-2,3,3a,4,7,7a-hexahydro-
1H-isoindole (25b). Ethynyldimethyl(thiophen-2-yl)silane (21) (0.28 g, 1.68 mmol), p-vinyl-anisole
(263 µL, 2 mmol), and catalyst (0.063 g, 0.1 mmol) were refluxed under Ar for 3 h. N-phenylmaleimide
(0.262 g, 1.5 mmol) was added and refluxed for 40 h. The crude product was chromatographed on silica
gel using 8:1 benzene:ethyl acetate (Rf 0.48). Compound 25b was isolated as a light yellow solid (0.506 g,
1.07 mmol, 71%). 1H-NMR (300 MHz, Chloroform-d) δ 7.64 (dd, J = 4.6, 0.9 Hz, 1H), 7.39–7.28 (m,
4H), 7.21 (dd, J = 4.6, 3.3 Hz, 1H), 7.18–7.11 (m, 2H), 6.84 (m, 4H), 6.63 (dd, J = 4.9, 2.1 Hz, 1H),
3.86–3.79 (m, 1H), 3.78 (s, 3H), 3.50–3.25 (m, 2H), 3.06 (dd, J = 16.5, 2.6 Hz, 1H), 2.52 (ddt, J = 16.5,
8.2, 1.8 Hz, 1H), 0.47 (s, 6H). 13C-NMR (126 MHz, CDCl3) δ 178.3, 176.3, 158.8, 140.8, 139.2, 135.2,
131.7, 131.2, 130.4, 130.1, 128.9, 128.3, 127.4, 126.3, 113.8, 55.2, 45.3, 41.5, 39.0, 25.5, −2.4, −2.5;
HRMS calcd for C27H28NO3SSi (M + H)+ 474.1559, found 474.1557.

Molecules 2015, 20
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(3aR,4S,7aS)-4-(4-Chlorophenyl)-6-(dimethyl(thiophen-2-yl)silyl)-2-phenyl-3a,4,7,7a-tetrahydro-1H-
isoindole-1,3(2H)-dione (25c). Ethynyldimethyl(thiophen-2-yl)silane (21) (0.07 g, 0.42 mmol),
p-chloro-styrene (60 µL, 0.5 mmol), and catalyst (0.016 g, 0.025 mmol) were refluxed under Ar for
30 h. N-phenylmaleimide (0.066 g, 0.38 mmol) was added and refluxed for 40 h. The crude product was
chromatographed on silica gel using 8:1 benzene:ethyl acetate (Rf 0.52) and isolated as a white solid
(0.112 g, 0.23 mmol, 61%). 1H-NMR (300 MHz, Chloroform-d) δ 7.64 (dd, J = 4.6, 0.9 Hz, 1H), 7.31
(m, 7H), 7.24–7.18 (m, 2H), 6.82 (m, 2H), 6.67 (dd, J = 4.7, 2.1 Hz, 1H), 3.86 (t, J = 5.7 Hz, 1H), 3.48 (dd,
J = 9.1, 6.7 Hz, 1H), 3.38 (td, J = 8.8, 2.6 Hz, 1H), 3.08 (dd, J = 16.5, 2.6 Hz, 1H), 2.52 (dd, J = 16.5, 8.5
13
Hz, 1H), 0.48 (s, 6H). C-NMR (75 MHz, CDCl3) δ 178.2, 176.1, 140.4, 139.5, 138.5, 136.2, 135.2,
131.6, 131.2, 129.1, 128.9, 128.4, 128.37, 128.34, 127.2, 126.0, 45.2, 42.2, 39.0, 25.6, −2.4, −2.6; HRMS
calcd for C26H24ClNNaO2SSi (M + Na)+ 500.0883, found 500.0901.
3.8. 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.
3.8.1. (3aR,4R,7aS)-2,4,6-Triphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-dione (27a)
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
1H-NMR comparison to previously reported material [11].
3.8.2. (3aR,4R,7aS)-4-(4-Methoxyphenyl)-2,6-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-
dione (27b)
Cycloadduct 25b (0.095 g, 0.2 mmol), iodobenzene (0.049 g, 0.24 mmol), Pd(OAc)2 (0.002 g,
0.01 mmol), and TBAF (0.40 mL of a 1 M soln in THF, 0.4 mmol) were reacted following the general
procedure. Compound 27b was isolated as a white solid (0.064 g, 0.16 mmol, 78%), identical by 1H-NMR
comparison to previously reported material [11].
3.8.3. (3aR,4R,7aS)-4-(4-Chlorophenyl)-2,6-diphenyl-3a,4,7,7a-tetrahydro-1H-isoindole-1,3(2H)-
dione (27c)
Cycloadduct 25c (0.106 g, 0.22 mmol), iodobenzene (0.054 g, 0.26 mmol), Pd(OAc)2 (0.003 g,
0.013 mmol), and TBAF (0.44 mL of a 1 M soln in THF, 0.44 mmol) were reacted following the general
procedure. Compound 27c was isolated as a white solid (0.057 g, 0.14 mmol, 65%), identical by
1H-NMR comparison to previously reported material [11].

Molecules 2015, 20
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4. Conclusions
2-Silicon-substituted 1,3-dienes containing nontransferrable groups known to promote transmetallation
were prepared by Grignard chemistry and enyne metathesis. Dienes produced participated in Diels-Alder
reactions in highly regio- and diastereoselective fashions. Electron-rich alkenes showed the fastest rates
in enyne metathesis reactions, and ethylene, a commonly used 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
at room temperature, the first such cycloadducts prepared in our laboratories to do so.
Supplementary Materials
Supplementary materials can be accessed at: http://www.mdpi.com/1420-3049/20/09/16892/s1.
Acknowledgments
We thank the National Science Foundation for their support of this work (CHE-0749759) and
instrumentation used to characterize the compounds reported here. The UNC and Northwestern University
Centers for Mass Spectrometry performed high resolution mass spectral analyses.
Author Contributions
Partha P. Choudhury performed the experimental work described here and Partha P. Choudhury and
Mark E. Welker co-authored the manuscript.
Conflicts of Interest
The authors declare no conflict of interest.
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Sample Availability: Samples of the compounds are not available from the authors.
© 2015 by the authors; licensee MDPI, Basel, Switzerland. This article is an open access article
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