Design of a Selective Ring-Closing Enyne Metathesis-Reduction for the Generation of Different Synthetic Scaffolds

Article abstract of DOI:10.1021/acs.joc.8b01511

A tandem process of ring-closing enyne metathesis (RCEYM)-reduction using modern ruthenium catalysts and a hydrogen donor is described. This straightforward methodology is useful for C(sp³) generation under mild reaction conditions. Variables s

Full text of DOI:10.1021/acs.joc.8b01511

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DESIGN OF A SELECTIVE RCEYM-REDUCTION FOR THE
GENERATION OF DIFFERENT SYNTHETIC SCAFFOLDS
Denis Nihuel Prada Gori, Caterina Permingeat Squizatto, Patricia Griselda Cornier, and Carina M.L. Delpiccolo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01511 • Publication Date (Web): 24 Sep 2018
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DESIGN OF A SELECTIVE RCEYM-REDUCTION FOR THE GENERATION OF
DIFFERENT SYNTHETIC SCAFFOLDS
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Denis N. Prada Gori, Caterina Permingeat Squizatto, Patricia G. Cornier and Carina M.L.
Delpiccolo*
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Instituto de Química Rosario (CONICET-UNR), Departamento de Química Orgánica,
Facultad de Ciencias Bioquímicas y Farmacéuticas, Universidad Nacional de Rosario,
Rosario, 2000, Argentina.
delpiccolo@iquir-conicet.gov.ar
ABSTRACT: A tandem process of RCEYM-
reduction using modern ruthenium catalysts
and a hydrogen donor is described. This
straightforward methodology is useful for
C(sp3) generation under mild reaction
conditions. Variables such as solvent, catalyst,
hydride source and temperature were adjusted
towards the exclusive formation of different
products.
Nowadays, the availability of selective and environmentally friendly synthetic methods is
essential for fine chemicals and pharmaceutical processes.1 Although, for methodological
simplicity, the tendency to generate molecules with a high percentage of planarity is very
elevated, it is clearly counterintuitive since biological world have a 3D-geometry. The
incorporation of a greater degree of saturation in organic molecules has been recently
proposed for improving clinical outcomes.2 Double bond formation and reduction reactions
are widely used in organic synthesis, being the latter very suitable for the generation of sp3
carbon atoms.
In general, not very safe, high hydrogen pressure experiments are required in the
conventional C-C double bond reductions.3 In recent years, with the development of
modern transition metal catalysts, new options have emerged, much more ecological,
secure and selective. On this line, the transition metal-catalyzed hydrogen transfer
strategy is a practical and safer alternative for this type of chemical transformations.
Furthermore, various elegant reports about sequential catalytic reactions, using a single
catalyst in one tandem process, have been reported.4 Tandem processes are economic,
environmentally friendly and efficient methodologies, mainly because several
transformations occur in one-pot and in a single vessel, without isolating the intermediates,
avoiding unnecessary work-ups and purifications between synthetic steps.5 In addition, the
whole process could involve the formation of synthetically useful multiple bonds and
stereocenters.
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Ruthenium carbenes (Figure 1) are interesting catalysts for a large number of metathetic
or non-metathetic reactions, exhibing remarkable functional group tolerance and good
catalytic power in mild and easy-to-use conditions.6 Among the Ru-catalyzed reactions,
ring-closing enyne metathesis (RCEYM) allows an efficient, easy and rapid access to high
added-value carbo or heterocyclic derivatives from simple substrates.7 Since Ru-catalyzed
non-metathetic reductions have been also reported, the same catalyst could be used to
promote both transformations.
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Figure 1. Commonly used ruthenium carbene catalysts.
Ring-closing metathesis (RCM), ring-opening metathesis polymerization (ROMP) and
cross metathesis (CM), combined with reduction in a one-pot procedure, have been
reported using Grubbs catalysts and different hydride donors (triethylsilane, H2, formic
acid).8 In these systems, ruthenium hydride species are likely involved as hydrogen
transfer source.9 These complexes act as mild reducing agent, allowing a better control of
the hydrogenation selectivity. Thus, a one-pot RCEYM-reduction strategy could be highly
attractive for the synthesis of libraries of synthetic and biologically interesting compounds.
In this work, an efficient and practical tandem RCEYM-reduction process is described,
being an excellent strategy for the synthesis of cyclic and heterocyclic compounds with
different degrees of saturation.
For the development of the proposed synthetic strategy, our first experiments were
performed treating the acyclic oxygenated enyne 1 with different Grubbs catalysts, using
Cl3CH as a solvent.10 As shown in Table 1, Entry 1, heating the enyne 1 at reflux for 15 h,
in presence of Grubbs 1st Generation catalyst (Ru1, Figure 1), triethylsilane (TESH) and
chloroform, yields only the metathesis product 2. However, under the same conditions but
using Ru2 (Grubbs 2nd Generation catalyst) or Ru3 (Hoveyda-Grubbs 2nd Generation
catalyst), a mixture of the partial 3 and totally reduced 4 tetrahydrofuran derivatives were
obtained (Entries 2 and 3). With these results in hand, the selective formation of 3 and 4
was studied in depth. Accordingly, we assumed that the Ru2 catalyst would have the
adequate reactivity to provide the semi-reduced structure 3 exclusively. In order to
accelerate the reaction times, microwave conditions were evaluated, giving mostly the
metathesis product 2, using 2 equiv of silane (Entry 4), and a mixture of 3 and 4 in a 1: 1
ratio, when TESH equivalents were increased to 3 (Entry 5). When other donor proton
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sources were employed in the reaction, such as pyrrolidine,11 selectivity did not increase
and reproducibility became a challenge (data not shown). The main problem of these
reactions was the lack of reproducibility. Some encouraging results could not be
reproduced, and small modifications in the variables led to unexpected and even illogical
results. Reviewing the literature, low hydrogenation activity in Ru-catalyzed reductions
have been reported using chlorinated solvents,12 which was attributed to the presence of
chlorinated ruthenium species. Based on that, different solvents were evaluated, including
protic solvents such as methanol. Under the conditions of entry 6, only metathesis product
was achieved employing toluene or acetonitrile (Entries 7 and 8).
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Table 1. Initial study of the RCEYM-reduction conditions
Productb (yield)
Equiv of
Et3SiH
Catalyst
Conditionsa
Solvent
Entry
2
1
-
3
-
4
-
1
2
3
4
5
6
7
8
9
Ru1
Ru2
Ru3
Ru2
Ru2
Ru2
Ru2
Ru2
Ru2
2
2
2
2
3
3
3
3
3
reflux, 15 h
reflux, 15 h
Cl3CH
Cl3CH
3
1
1
1
-
1
2
-
reflux, 15 h
Cl3CH
-
100 oC, 20 min, MW
100 oC, 20 min, MW
80 oC, 20 min, MW
80 oC, 20 min, MW
80 oC, 20 min, MW
80 oC, 20 min, MW
Cl3CH
5
-
Cl3CH
1
-
Cl3CH
1
1
1
1
Toluene
Acetonitrile
MeOH
-
-
-
-
1.3
-
1
10
11
Ru2
Ru2
3
3
90 oC, 20 min, MW
MeOH
MeOH
-
-
-
-
(62%)
1
(85%)
90 oC, 20 min, MWc
12
13
14
15
Ru2
Ru2
Ru3
Ru3
3
3
CuI, 90 oC, 20 min, MWc
reflux, 15 h
MeOH
MeOH
MeOH
MeOH
2.4
1d
-
1
-
-
-
20
20
90 oC, 20 min, MW
90 oC, 25 min, MW
-
1 (88%)
1 (100%)
-
-
a
A mixture of substrate 1, 10 mol% Ru catalyst and Et3SiH was stirred in the solvent and the described
conditions in the corresponding entries, unless otherwise stated. b Rates and yields were determined by H
NMR. Yields in brackets were calculated by internal standard. c A mixture of 1, 10 mol % of Ru2 in MeOH was
stirred in MW at 90 °C during 10 min, then 3 equiv of Et3SiH were added and the reaction was stirred 10 more
minutes under the same conditions. d Products of decomposition materials were detected.
1
A promising result was obtained using methanol as solvent since compound 3 was the
major product (Entry 9). The semi-reduced structure 3 was obtained exclusively at 90 °C
(Entry 10), while a greater increase in reaction performance was accomplished when the
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process was carried out in two stages, adding Et3SiH after 10 minutes of MW treatment
(Entry 11), condition that we have called Method A. Under these conditions, compound 3
was obtained in 85% yield by internal standard and 72% yield after column
chromatography. The selectivity observed is opposite to the RCM-reduction sequence
published by Grubbs and coll. in 2001, in which the less-substituted alkene was
hydrogenated.8c Considering that steric environment around both double-bounds in diene
2 is similar, probably stereoelectronic properties could govern the reduction process. No
better results were obtained by adding copper iodide (Entry 12), although it has been
reported that the use of this additive improves the performance of the metathesis reaction,
due to catalyst stabilizing effects.13 Analogous conditions of entry 11 but employing reflux
of methanol were unsuccessful, giving the metathesis product 2 and some decomposition
(Entry 13).
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The implementation of MeOH as solvent, in addition to provide high reproducibility,
allowed the selective formation of the mono-reduced cyclic product 3. Then, the role of
MeOH as hydride donor was considered. There are several published articles describing
the use of primary or secondary alcohols as “hydrogen donors”.14 Therefore, when the
reaction was carried out in absence of Et3SiH, diene 2 was the only product, proving that
the silane is essential for the reaction outcome. Regarding the effectiveness of methanol in
this kind of processes, formation of complexes like Ru4 or Ru5 in methanolic solvents
were described in previous papers (Figure 2).15 Species like Ru5 have been described by
Mol as an efficient hydrogenation catalyst at high temperatures, being very effective in
tandem metathesis-hydrogenation pathways.
On the other hand, employing the more reactive Hoveyda-Grubbs catalyst (Ru3) and more
equivalents of Et3SiH, only saturated product 4 was obtained (Entries 14 and 15). By
applying 20 equiv of Et3SiH in presence of 10 mol% of Ru3 in MeOH at 90 °C during 25
minutes, under MW heating, the saturated tetrahydrofuran derivative 4 was achieved in
quantitative yield (Entry 15), condition that we have called Method B.
Figure 2. Complexes proposed by Mol for Ru1 in MeOH15
Scope and reactivity
In order to further determine the influence of the starting material substitution in the
reactivity, we have applied the optimized conditions for the formation of 1, entry 11
(Method A) and entry 15 (Method B), on a set of substrates. The relative quantities of
different products obtained were dependent on the enyne substitution.
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To analyze the influence of the main chain nature on the reactivity, the malonic ester
derivative 5 (Scheme 1) and the nitrogen derivative 8 (Scheme 2), were evaluated. The
decrease in reduction reactivity could be explained by the presence of electron-attracting
groups within the chain.16 Nevertheless, the selectivity of the most-substituted double bond
reduction was maintained, giving the mono-reduced cyclic derivatives 7 and 10.
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Scheme 1. Reactivity of enyne 5 under the RCEYM-reduction conditions
Scheme 2. Reactivity of enyne 8 under the RCEYM-reduction conditions
When the conditions of the Method A were employed on enynes with terminal alkenes
(substrates 12a-d), only polymerization and decomposition products were recovered
(Scheme 3), showing a prevalence of intermolecular metathetic events. No better results
were observed applying copper iodide under the conditions previously tested. Additionally,
we carried out the RCEYM and reduction in a stepwise manner using CuI for the
metathesis step. RCEYM of 12a was performed at temperatures below 60 °C, yielding the
expected product 13 (Scheme 4). No reaction was observed after further treatment of this
crude with the catalytic system and TESH at 60 °C, giving polymerization at 75 °C or
higher temperatures. According to these results, polymerization could be mainly due to the
temperature, which is necessary to achieve an effective reduction.
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Scheme 3. Reactivity of enynes with terminal alkenes
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Scheme 4. RCEYM and reduction of 12a using CuI
Finally, enynes with vicinal-disubstituted and trisubstituted alkenes were evaluated. Under
the metathesis-reduction conditions of Method A, the crotyl derivative 14 was transformed
into the diene 15 and the cycloalkene 16 in equal amounts (Scheme 5). Several
unidentified products were also detected in the crude material (spectroscopy and
spectrometry data are in agreement with the presence of the compound 17 in the mixture).
Furthermore, using Method A conditions on the enyne 19, yielded only metathesis product
20, which has two equivalent trisubstituted double bonds (Scheme 6). This structural
similarity leads to a loss of selectivity, obtaining a mixture of mono-reduced products 22
and 23, when the reaction was carried at 145 °C. The saturated cyclic compounds 18 and
21 (Scheme 5 and 6) were obtained by applying the conditions of the Method B on
substrates 14 and 19. Using this methodology, 18 and 21 were synthesized in 40% and
62% yield respectively, after purification by column chromatography.
Scheme 5. Reactivity of enynes with vicinal-disubstituted alkenes
Scheme 6. Reactivity of enynes with vicinal- trisubstituted alkenes
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CONCLUSIONS
In summary, a new microwave-based tandem RCEYM-reduction is reported. Depending
on the substitution of the substrate, this methodology selectivity affords different cyclic and
heterocyclic compounds with a variable degree of saturation. It could be applied to
different enynes except to those with terminal alkenes, in which the cross metathesis and
polymerization are the prevalent processes. Although formation of an exclusive product
was not always achieved, the reduction selectivity was maintained, regardless the
substitution of the double bonds present in the metathesis intermediate, being the most
substituted double bond preferentially reduced. The use of methanol as a solvent was also
studied, providing a reproducible and efficient procedure, due to its ability to form very
effective complexes for metathesis-hydrogenation reactions, like Ru5. On the other hand,
this methodology allows a selective preparation of synthetically useful compounds with a
decrease in waste production and energy consumption. An asymmetric version of this
methodology is currently in progress.
EXPERIMENTAL SECTION
General Procedures
Chemical reagents were purchased from commercial sources and were used without
further purification unless otherwise noted. Solvents were analytical grade or were purified
by standard procedures prior to use. Nuclear magnetic resonance spectra were obtained
on a Bruker Avance 300 apparatus using CDCl3 as solvent and with tetramethylsilane
(TMS) as internal standard. Chemical shifts (δ) for NMR spectra were reported in units of
parts per million (ppm) downfield from TMS (0.0) and relative to the signal of chloroform-d
(7.26, singlet). NMR yields were determined using the internal NMR standard 1,3,5-
trimethylbenzene (3H, 6.80 ppm, 9H, 2.27 ppm). Gas Chromatography-Mass Spectra (GC-
MS) were recorded on a Shimadzu QP2010 Plus apparatus at an ionization voltage of 70
eV equipped with a SPBTM-1 capillary column (internal diameter 0.25 mm, length 30 m).
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High Resolution Mass Spectra (HRMS) were obtained with a Bruker MicroTOF-Q II
instrument (Bruker Daltonics, Billerica, MA). Detection of ions was performed in
electrospray ionization, positive ion mode. Analytical thin layer chromatography (TLC) was
performed using F254 precoated silica gel plates. Flash column chromatography was
performed using Merck silica gel 60 (230-400 mesh). Elution was carried out with hexane-
ethyl acetate gradient, under positive pressure. Microwave-assisted reactions were
performed using a CEM Discover microwave reactor. In all experiments, the temperature
and the reaction time was setted, then the reactor automatically adjust the power
(maximum of 200 W) in order to maintain a constant temperature. Reactions were
performed in 5 mL sealed vessels. The specified reaction time corresponds to the total
irradiation time. Compounds 1,17, 18, 19 5,20 8,21, 22, 23 12a,20 12b,20 12c,24 12d,25,22 1420, 26 and
1920 were analogously prepared according to reported literature.
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General Procedures for Ring Closing Enyne Metathesis and Reduction. Method A. In
a microwave flask equipped with a magnetic stirrer, the enyne (1 equiv) and Ru2 (0.1
equiv), were dissolved in anhydrous methanol and then, the vessel was placed in the
microwave reactor. The reaction mixture was irradiated under constant microwave for 10
minutes temperature controlled at 90 °C. After this time, triethylsilane (3 equiv) was added
to the flask and the vessel was place again in the microwave reactor. Then the sample was
irradiated at 90 °C for 10 minutes. The solvent was evaporated under reduced pressure on
a rotary evaporator. The yield was determined by NMR using an internal standard. Method
B. In a microwave flask equipped with a magnetic stirrer, the enyne (1 equiv) and Ru3 (0.1
equiv) were dissolved in anhydrous methanol and triethylsilane (20 equiv) was added. The
reaction mixture was irradiated under constant microwave for 25 minutes at 90 °C. The
solvent was evaporated under reduced pressure on a rotary evaporator. The yield was
determined by NMR using an internal standard.
RCEM – Reduction of (E)-3-(prop-3-ynyloxy)-1-phenylpropene (1). Following Method
A, 1 (0.025 g, 0.145 mmol, 1 equiv) and Ru2 (0.012 g, 0.014 mmol, 0.1 equiv) were
dissolved in anhydrous methanol (2.0 mL) and triethylsilane (0.070 mL, 0.436 mmol, 3
equiv) was added. (E)-3-Styryltetrahydrofuran (3) was the only product obtained in 85%
yield (NMR). Purification by silica gel column chromatography using EtOAc/Hexane (1:9)
as the eluent, affords 3 (0.018 g, 72%) as a colorless oil. Following Method B, 1 (0.025 g,
0.145 mmol, 1 equiv) and Ru3 (0.009 g, 0.014 mmol, 0.1 equiv) were dissolved in
anhydrous methanol (2.0 mL) and triethylsilane (0.463 mL, 2.907 mmol, 20 equiv) was
added. 3-Phenethyl tetrahydrofuran (4) was the only product obtained in 88% yield (NMR).
Purification by silica gel column chromatography using EtOAc/Hexane (1:9) as the eluent,
affords 4 (0.008 g, 32%) as a colorless oil.
(E)-3-Styryltetrahydrofuran (3) 1H NMR (300 MHz, CDCl3) δ 7.41 – 7.12 (m, 6H), 6.46 (d, J
= 15.8 Hz, 1H), 6.14 (dd, J = 15.8, 8.4 Hz, 1H), 4.05 – 3.91 (m, 2H), 3.84 (dt, J = 7.8, 7.3
Hz, 1H), 3.54 (dd, J = 8.3, 7.6 Hz, 1H), 3.02 (h, J = 7.8 Hz, 1H), 2.17 (dtd, J = 12.2, 7.5,
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4.7 Hz, 1H), 1.81 (dq, J = 12.3, 8.0 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 137.2, 130.7,
130.5, 128.6, 127.3, 126.1, 73.0, 68.3, 43.2, 33.3. HRMS (ESI) m/z: [(M+K)]+ calcd for
C12H14KO+ 213.0676, found 213.0892.
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7
8
1
3-Phenethyl tetrahydrofuran (4) H NMR (300 MHz, CDCl3) δ 7.35 – 7.24 (m, 1H), 7.24 –
7.13 (m, 4H), 3.91 (dd, J = 8.1, 7.4 Hz, 1H), 3.85 (dt, J = 8.1, 4.7 Hz, 1H), 3.74 (dt, J = 7.8,
7.2 Hz, 1H), 3.37 (dd, J = 8.2, 7.2 Hz, 1H), 2.63 (dt, J = 7.9, 3.5 Hz, 2H), 2.20 (p, J = 7.5
Hz, 1H), 2.11 – 2.00 (m, 1H), 1.72 (q, J = 7.8, 7.4 Hz, 2H), 1.57 – 1.50 (m, 1H). 13C NMR
(75 MHz, CDCl3) δ 142.1, 128.4, 128.3, 125.9, 73.3, 68.0, 38.9, 35.2, 34.9, 32.5. HRMS
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(ESI) m/z: [(2M+Na)]+ calcd for: C24H32NaO2 375.2287, found 375.2294.
+
RCEM – Reduction of Dimethyl (E)-cinnamylpropargylmalonate (5). Following Method
A, 5 (0.025 g, 0.087 mmol, 1 equiv) and Ru2 (0.007 g, 0.009 mmol, 0.1 equiv) were
dissolved in anhydrous methanol (2.0 mL) and triethylsilane (0.042 mL, 0.262 mmol, 3
equiv) was added. Dimethyl (E)-3-styrylcyclopent-3-ene-1,1-dicarboxylate (6) was the only
product obtained in 52% yield (NMR). Following Method B, 5 (0.025 g, 0.087 mmol, 1
equiv) and Ru3 (0.005 g, 0.009 mmol, 0.1 equiv) were dissolved in anhydrous methanol
(2.0 mL) and triethylsilane (0.278 mL, 1.748 mmol, 20 equiv) was added. 6 was the only
product obtained in 41% yield (NMR). Following Method A, but setting the reactor at 145
°C, 5 (0.025 g, 0.087 mmol, 1 equiv) and Ru2 (0.005 g, 0.009 mmol, 0.1 equiv) were
dissolved in anhydrous methanol (2.0 mL) and triethylsilane (0.278 mL, 1.748 mmol, 20
equiv) was added. A mixture of 6 and Dimethyl (E)-3-styrylcyclopentane-1,1-dicarboxylate
(7) was obtained in a 1:3 ratio in 13% and 46% yield (NMR), respectively.
NMR spectral data of 627 and 728 was identical to those reported in the literature.
RCEM – Reduction of N-Cinnamyl-4-methyl-N-(prop-2-yn-1-yl)benzenesulfonamide
(8). Following Method A, 8 (0.025 g, 0.077 mmol, 1 equiv) and Ru2 (0.007 g, 0.008 mmol,
0.1 equiv) were dissolved in anhydrous methanol (2.0 mL) and triethylsilane (0.037 mL,
0.231 mmol, 3 equiv) was added. A mixture of (E)-3-Styryl-1-tosyl-2,5-dihydro-1H-pyrrole
(9) and (E)-3-Styryl-1-tosylpyrrolidine (10) was obtained in a 2:1 ratio in 29% and 15%
yield (NMR), respectively. Following Method B, 8 (0.025 g, 0.077 mmol, 1 equiv) and Ru3
(0.005 g, 0.008 mmol, 0.1 equiv) were dissolved in anhydrous methanol (2.0 mL) and
triethylsilane (0.245 mL, 1.538 mmol, 20 equiv) was added. A mixture of 10 and 3-
Phenethyl-1-tosylpyrrolidine (11) was obtained in a 1:2 ratio in 22% and 43% yield (NMR),
respectively.
NMR spectral data of 929 was identical to those reported in the literature.
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(E)-3-Styryl-1-tosylpyrrolidine (10) H NMR (300 MHz, CDCl3) δ 7.73 (d, J = 8.2 Hz, 2H),
7.33 (d, J = 7.7 Hz, 2H), 7.29 – 7.15 (m, 5H), 6.33 (d, J = 15.8 Hz, 1H), 5.88 (dd, J = 15.9,
7.8 Hz, 1H), 3.53 (dd, J = 9.9, 7.2 Hz, 1H), 3.45 – 3.38 (m, 1H), 3.36 – 3.25 (m, 1H), 3.03
(dd, J = 9.9, 7.8 Hz, 1H), 2.84 (q, J = 9.3, 8.4 Hz, 1H), 2.42 (d, J = 3.2 Hz, 3H), 2.01 (m,
2H). 13C NMR (75 MHz, CDCl3) δ 143.4, 136.7, 133.9, 131.0, 129.7, 128.5, 128.2, 127.6,
126.1, 52.9, 47.5, 42.0, 32.0, 21.5. HRMS (ESI) m/z: [(M+H)]+ calcd for: C19H22NO2S+
328.1366, found 328.1345.
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3-Phenethyl-1-tosylpyrrolidine (11) H NMR (300 MHz, CDCl3) δ 7.70 (d, J = 8.2 Hz, 2H),
7.31 (d, J = 8.2 Hz, 2H), 7.29 – 7.16 (m, 3H), 7.09 (d, J = 7.2 Hz, 2H), 3.45 (dd, J = 9.6,
7.1 Hz, 1H), 3.34 (ddd, J = 9.7, 8.2, 3.6 Hz, 1H), 3.18 (ddd, J = 9.6, 8.5, 6.9 Hz, 1H), 2.83
(dd, J = 9.8, 7.7 Hz, 1H), 2.54 (t, J = 8.0 Hz, 2H), 2.43 (s, 3H), 2.10 – 1.86 (m, 2H), 1.56
(dt, J = 9.4, 6.7 Hz, 2H), 1.42 (dq, J = 12.1, 8.4 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ
143.3, 141.5, 133.9, 129.6, 128.4, 128.2, 127.5, 126.0, 53.1, 47.5, 38.2, 34.8, 34.4, 31.4,
21.5. HRMS (ESI) m/z: [(M+H)]+ calcd for: C19H24NO2S+ 330.1522, found 330.1496.
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RCEM – Reduction of Dimethyl (E)-2-(but-2-enyl)-2-(prop-2-ynyl)malonate and
Dimethyl (Z)-2-(but-2-enyl)-2-(prop-2-ynyl)malonate (14). Following Method A, 14
(0.025 g, 0.111 mmol, 1 equiv) and Ru2 (0.009 g, 0.011 mmol, 0.1 equiv) were dissolved in
anhydrous methanol (2.0 mL) and triethylsilane (0.053 mL, 0.335 mmol, 3 equiv) was
added. A mixture of (E)-Dimethyl 3-(prop-1-en-1-yl)cyclopent-3-ene-1,1-dicarboxylate (15)
and Dimethyl 3-propylcyclopent-3-ene-1,1-dicarboxylate (16) was obtained in a 1:1 ratio in
18% and 18% yield (NMR), respectively. Following Method B, 14 (0.025 g, 0.111 mmol, 1
equiv) and Ru3 (0.007 g, 0.011 mmol, 0.1 equiv) were dissolved in anhydrous methanol
(2.0 mL) and triethylsilane (0.355 mL, 2.232 mmol, 20 equiv) was added. Dimethyl 3-
propylcyclopentane-1,1-dicarboxylate (18) was the only product obtained in 73% yield
(NMR). Purification by silica gel column chromatography using EtOAc/Hexane (1:99) as
the eluent, affords the product 18 (0.010 g, 39%) as a colorless oil.
NMR spectral data of 1530 was identical to those reported in the literature.
Dimethyl 3-propylcyclopent-3-ene-1,1-dicarboxylate (16) 1H NMR (300 MHz, Chloroform-d)
δ 5.19 (s, 1H), 3.72 (s, 6H), 2.97 (d, J = 2.7 Hz, 2H), 2.90 (s, 2H), 2.00 (d, J = 7.0 Hz, 2H),
1.45 (h, J = 7.3 Hz, 2H), 0.87 (t, J = 7.3 Hz, 3H). HRMS (ESI) m/z: [(M+Na)]+ calcd for:
+
C12H18NaO4 249.1097, found 249.1093.
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Dimethyl 3-propylcyclopentane-1,1-dicarboxylate (18) H NMR (300 MHz, CDCl3) δ 3.71
(d, J = 1.2 Hz, 6H), 2.45 (dd, J = 12.8, 7.1 Hz, 1H), 2.30 (tt, J = 8.9, 4.4 Hz, 1H), 2.20 –
2.07 (m, 1H), 2.03 – 1.77 (m, 2H), 1.69 (dd, J = 13.2, 9.9 Hz, 1H), 1.37 – 1.16 (m, 4H),
1.00 – 0.78 (m, 4H). 13C NMR (75 MHz, CDCl3) δ 173.3, 60.0, 52.6, 40.9, 39.5, 37.5, 33.9,
+
32.1, 21.6, 14.2. HRMS (ESI) m/z: [(M+Na)]+ calcd for: C12H20NaO4 251.1254, found
251.1245.
RCEM – Reduction of Dimethyl 2-propargyl-2-prenylmalonate (19). Following Method
A, 19 (0.025 g, 0.105 mmol, 1 equiv) and Ru2 (0.009 g, 0.010 mmol, 0.1 equiv) were
dissolved in anhydrous methanol (2.0 mL) and triethylsilane (0.050 mL, 0.315 mmol, 3
equiv) was added. Dimethyl 3-(2-methylprop-1-enyl)cyclopent-3-ene-1,1-dicarboxylate (20)
was the only product obtained in 71% yield (NMR). Following method B, 19 (0.025 g,
0.105 mmol, 1 equiv) and Ru3 (0.007 g, 0.010 mmol, 0.1 equiv) were dissolved in
anhydrous methanol (2.0 mL) and triethylsilane (0.335 mL, 2.100 mmol, 20 equiv) was
added. Dimethyl 3-isobutylcyclopentane-1,1-dicarboxylate (21) was the only product
obtained in 100% yield (NMR). Purification by silica gel column chromatography using
EtOAc/Hexane (1:99) as the eluent, affords the product 21 (0.016 g, 62%) as a colorless
oil. Following method A, but setting the reactor at 145 °C, 19 (0.025 g, 0.105 mmol, 1
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equiv) and Ru2 (0.009 g, 0.010 mmol, 0.1 equiv) were dissolved in anhydrous methanol
(2.0 mL) and triethylsilane (0.050 mL, 0.315 mmol, 3 equiv) was added. A mixture of 20,
Dimethyl 3-isobutylcyclopent-3-ene-1,1-dicarboxylate (22) and Dimethyl 3-(2-methylprop-
1-enyl)cyclopentane-1,1-dicarboxylate (23) was obtained in a 1:3:4.5 ratio in 8%, 20% and
31% yield (NMR), respectively. Purification by silica gel column chromatography using
EtOAc/Hexane (1:99) as the eluent, affords a mixture of 22 and 23 (0.011 g, 45%) as a
colorless oil.
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NMR spectral data of 2031 was identical to those reported in the literature.
1
Dimethyl 3-isobutylcyclopentane-1,1-dicarboxylate (21) H NMR (300 MHz, CDCl3) δ 3.70
(d, J = 2.2 Hz, 6H), 2.45 (dd, J = 13.1, 6.9 Hz, 1H), 2.30 (ddd, J = 13.6, 8.5, 3.6 Hz, 1H),
2.12 (ddd, J = 13.6, 9.5, 7.5 Hz, 1H), 2.01 (tt, J = 9.9, 7.1 Hz, 1H), 1.91 – 1.79 (m, 1H),
1.65 (dd, J = 13.3, 10.3 Hz, 1H), 1.55 (q, J = 6.9 Hz, 1H), 1.30 – 1.14 (m, 3H), 0.86 (dd, J
13
= 6.6, 1.6 Hz, 6H). C NMR (75 MHz, CDCl3) δ 173.3, 59.9, 52.6, 44.6, 41.1, 37.6, 33.9,
+
32.3, 26.9, 22.8. HRMS (ESI) m/z: [(M+Na)]+ calcd for: C13H22NaO4 265.1410, found
265.1401.
1
Dimethyl 3-(2-methylprop-1-enyl)cyclopentane-1,1-dicarboxylate (22) H NMR (300 MHz,
CDCl3) δ 4.99 (dt, J = 8.8, 1.5 Hz, 1H), 3.70 (s, 6H), 2.77 (ddd, J = 26.2, 10.0, 7.2 Hz, 1H),
2.44 (dd, J = 13.2, 7.2 Hz, 1H), 2.32 (ddt, J = 13.6, 8.7, 8.5 Hz, 1H), 2.23 – 2.08 (m, 1H),
1.88 – 1.80 (m, 1H), 1.80 – 1.68 (m, 1H), 1.66 (d, J = 1.4 Hz, 3H), 1.60 (d, J = 1.4 Hz, 3H),
1.36 (dd, J = 12.5, 8.6 Hz, 1H). 13C NMR (75 MHz, CDCl3) δ 173.2 (2), 132.1, 127.7, 59.9,
52.6 (2), 41.4, 38.7, 34.0, 33.1, 25.6, 18.0. HRMS (ESI) m/z: [(M+Na)]+ calcd for:
+
C13H20NaO4 263.1254, found 263.1254.
1
Dimethyl 3-isobutylcyclopent-3-ene-1,1-dicarboxylate (23) H NMR (300 MHz, CDCl3) δ
5.19 (s, 1H), 3.72 (s, 6H), 2.97 (q, J = 2.0 Hz, 2H), 2.88 (s, 2H), 1.91 (d, J = 7.6 Hz, 2H),
1.78 – 1.71 (m, 1H), 0.85 (d, J = 6.6 Hz, 6H). 13C NMR (75 MHz, CDCl3) δ 172.8 (2),
141.1, 121.5, 59.2, 52.7 (2), 43.0, 40.6, 40.1, 26.4, 22.5 (2). HRMS (ESI) m/z: [(M+Na)]+
+
calcd for: C13H20NaO4 263.1254, found 263.1254.
RCEM – Reduction of Dimethyl allylpropargylmalonate (12a). Following Method A, 12a
(0.025 g, 0.119 mmol, 1 equiv) and Ru2 (0.010 g, 0.012 mmol, 0.1 equiv) were dissolved
in anhydrous methanol (2.0 mL) and triethylsilane (0.057 mL, 0.357 mmol, 3 equiv) was
added. GC and NMR evidenced the presence of different polymerization products.
RCEM – Reduction of Dimethyl methallylpropargylmalonate (12b). Following Method
A, 12b (0.025 g, 0.111 mmol, 1 equiv) and Ru2 (0.009 g, 0.011 mmol, 0.1 equiv) were
dissolved in anhydrous methanol (2.0 mL) and triethylsilane (0.053 mL, 0.335 mmol, 3
equiv) was added. GC and NMR evidenced the presence of different polymerization
products.
RCEM – Reduction of (3-Allyloxy-prop-1-ynyl)-benzene (12c). Following Method A, 12c
(0.025 g, 0.145 mmol, 1 equiv) and Ru2 (0.012 g, 0.014 mmol, 0.1 equiv) were dissolved
in anhydrous methanol (2.0 mL) and triethylsilane (0.070 mL, 0.436 mmol, 3 equiv) was
added. GC and NMR evidenced the presence of different polymerization products.
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RCEM – Reduction of N-(2-Propenyl)-N-(2-propynyl)-4-methylbenzenesulfonamide
(12d). Following Method A, 12d (0.025 g, 0.100 mmol, 1 equiv) and Ru2 (0.009 g, 0.010
mmol, 0.1 equiv) were dissolved in anhydrous methanol (2.0 mL) and triethylsilane (0.048
mL, 0.301 mmol, 3 equiv) was added. GC and NMR evidenced the presence of different
polymerization products.
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI xxxxxxx
Copies of 1H NMR and 13C NMR spectra for compounds 2, 3, 4, 5, 6, 7, 9, 10, 11, 15, 16,
18, 20, 21 and 23.
ACKNOWLEDGEMENTS
Support from CONICET, ANPCyT, Fundación Prats, AUGM, and Universidad Nacional de
Rosario is gratefully acknowledged. D.N.P.G thanks CONICET for fellowship. Special
thanks to Dr. Ernesto Mata for his enriching discussions and a careful proofreading of the
manuscript.
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metathesis and hydrogenation towards cyclic dinucleotides. Chem. Commun. 2002, 18,
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between hydrogenation and metathesis chemistry. Organometallics, 2001, 20 (26), 5495
–
5497.
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reactions: the copper iodide effect. J. Org. Chem. 2011, 76 (11), 4697 4702.
–
(14) (a) Cho, C. S.; Kim, B. T.; Kim, T-J.; Shim, S. C. An Unusual Type of Ruthenium-
Catalyzed Transfer Hydrogenation of Ketones with Alcohols Accompanied by C− C
Coupling. J Org Chem. 2001, 66, 9020
T-J.; Shim, S. C. Ruthenium-catalyzed one-pot β-alkylation of secondary alcohols with
primary alcohols. Organometallics, 2003, 22 (17), 3608 3610.
–9022. (b) Cho, C. S.; Kim, B. T.; Kim, H-S.; Kim,
–
(15) (a) Dinger, M. B.; Mol, J. C. Degradation of the Second‐Generation Grubbs
Metathesis Catalyst with Primary Alcohols and Oxygen−Isomerization and Hydrogenation
Activities of Monocarbonyl Complexes. Eur. J. Inorg. Chem. 2003, 15, 2827–2833. (b)
Dinger, M. B.; Mol, J. C. Degradation of the first-generation Grubbs metathesis catalyst
with primary alcohols, water, and oxygen. Formation and catalytic activity of ruthenium (II)
monocarbonyl species. Organometallics 2003, 22 (5), 1089-1095. (c) Fogg, D. E. Inside
the black box—Perspectives on transformations in catalysis. Can. J. Chem, 2008, 86 (10),
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