Synthesis of a biofuel target through conventional organic chemistry

Article abstract of DOI:10.1016/j.tetlet.2018.02.073

In this work, the biofuel target compound 2-ethyl-5,5-dimethylcyclopenta-1,3-diene (1) and its exo isomers (9a and 9b), were successfully synthesized via two different pathways from the common intermediate 4,4-dimethylcyclopent-2-ene-1-one (2). The first pathway produced the endocyclic product as a pure isomer via a triflate intermediate obtained from ketone 2 in 60% yield, followed by copper-catalyzed coupling with ethyl magnesium bromide in 63% yield. The second pathway employed a Grignard reaction with ketone 2, which generated an alcohol that was immediately subjected to mild acid-catalyzed elimination to yield primarily a mixture of exo isomers 9a and 9b in 46% yield. The preparation method developed by this work allowed for the production of a sufficient quantity of these targets to evaluate their fuel properties, which will be reported in a separate study.

Full text of DOI:10.1016/j.tetlet.2018.02.073

Tetrahedron Letters xxx (2018) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of a biofuel target through conventional organic chemistry
⇑
Jordan P. Page, Joshua W. Robinson, Karl O. Albrecht, Lelia Cosimbescu
Energy and Environment Directorate, Pacific Northwest National Laboratory, 902 Battelle Blvd, Richland, WA 99354, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
In this work, the biofuel target compound 2-ethyl-5,5-dimethylcyclopenta-1,3-diene (1) and its exo iso-
mers (9a and 9b), were successfully synthesized via two different pathways from the common interme-
diate 4,4-dimethylcyclopent-2-ene-1-one (2). The first pathway produced the endocyclic product as a
pure isomer via a triflate intermediate obtained from ketone 2 in 60% yield, followed by copper-catalyzed
coupling with ethyl magnesium bromide in 63% yield. The second pathway employed a Grignard reaction
with ketone 2, which generated an alcohol that was immediately subjected to mild acid-catalyzed elim-
ination to yield primarily a mixture of exo isomers 9a and 9b in 46% yield. The preparation method devel-
oped by this work allowed for the production of a sufficient quantity of these targets to evaluate their fuel
properties, which will be reported in a separate study.
Received 29 January 2018
Revised 16 February 2018
Accepted 24 February 2018
Available online xxxx
Keywords:
Biofuels
Cyclopentadiene
Alkenes
Grignard cross-coupling
Divergent synthesis
Ó 2018 Published by Elsevier Ltd.
Introduction
major effort to find potential fuel candidates or blending compo-
nents. To that end, several fuel properties such as boiling point,
The need for renewable sources of light, combustible hydrocar-
bons with low net-carbon footprints is growing in order to offset
adverse effects such as climate change. The United States Depart-
ment of Energy and similar institutions around the globe are cur-
rently searching for new transportation energy sources, with
biomass-derived energy becoming widely employed to produce
octane numbers, density, were calculated/simulated and this com-
pound was determined to be one of interest. The fuel properties
evaluation is beyond the scope of this work, and will be disclosed
in a future manuscript. This work describes the challenging syn-
thetic pathways for 1, one such target. The route to synthesize 1
3
would go through the known
first been described by Magnus and coworkers (Scheme 1). It
a,b-unsaturated ketone 2 that had
1
4,5
different fuel types from renewable feedstock. The Co-Optimiza-
tion of Fuels and Engines Initiative (Co-Optima) is a major collab-
oration of several national laboratories operated for the
Department of Energy aimed at co-development of highly efficient
engines and fuels. One of the goals of this work is to develop a
method to produce multi-gram quantities of a potentially promis-
ing biomass-derived light hydrocarbon in order to test its fuel
properties. Ultimately, it may be possible that the compound could
be added to current commercial gasoline to allow spark ignition
engines to run more efficiently should it be determined that the
compound has promising fuel properties.
was desired that the synthesis of compound 1 would occur via a
suitable sp cross-coupling partner and subsequent attachment
2
of the ethyl appendage. Furthermore, functionalized cyclopentadi-
enes via cross-coupling are useful intermediate building blocks in
6
natural product synthesis.
Results and discussion
The lack of advanced, reasonably priced commercial precursors
required that a multistep synthesis be devised to prepare the tar-
get. One approach that was initially explored was the synthesis
Several compounds were identified as potential fuel candidates
2
7
by Strobel et al., in volatile hydrocarbons produced by the fungus
of the target from a pathway derived by Paquette et al. to generate
Gliocladium roseum. The quantities produced were quite small, and
were isolated for characterization purposes only. Subsequent
efforts to synthesize the compounds in gram quantities by conven-
tional methods were undertaken so that their fuel properties could
be evaluated. The target compound 2-ethyl-5,5-dimethylcy-
clopenta-1,3-diene 1, had been previously identified as part of a
a key vinyl bromide intermediate that would undergo a final cross-
coupling. However, this pathway involved a total of nine steps and
delivered a 34% overall yield at best, while only producing a vinyl
bromide that was at least one step away from the final compound.
Attempts to reproduce the synthesis did not generate yields that
approached those previously reported, and the intermediates
required extensive purification. Therefore, an alternate pathway
was investigated to make the key intermediate based on two
Organic Synthesis preparations that followed the sequence outlined
⇑
Corresponding author.
E-mail address: lelia.cosimbescu@pnnl.gov (L. Cosimbescu).
https://doi.org/10.1016/j.tetlet.2018.02.073
040-4039/Ó 2018 Published by Elsevier Ltd.
0
Please cite this article in press as: Page J.P., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.02.073

2
J.P. Page et al. / Tetrahedron Letters xxx (2018) xxx–xxx
product; however, the reaction proceeded in relatively low yields
(
50% at 0.1 mol scale, and 30% at 2 mol scale).
From ketone 2 intermediate, several coupling strategies were
pursued to generate the target compound. Attempts to make the
vinyl bromide via transforming ketones with P(O)Ph Br as
described by Prati and coworkers proved ineffective with this sub-
3
2
9
1
0
strate. Following Sai cˇ i c´ et al. to convert 2 into a trimethylsilyl
1
1
enol ether, the subsequent Kumada coupling with either Ni
PPh Cl or Ni(acac) were both unsuccessful. However, upon
switching the silyl enol ether to a triflate (7), and employing a
Scheme 1. Approach to the desired 2-ethyl-5,5-dimethylcyclopenta-1,3-diene (1),
an identified biofuel target.
(
3
)
2
2
2
CuI catalyst that was inspired by Bäckvall’s work, the desired endo-
1
2
cyclic isomer was successfully generated (Scheme 3).
8
in Scheme 2. The first Org. Synth. preparation by Salomon and
A second strategy, amenable to scale-up and cost-efficient, uti-
lized a Grignard reaction with ketone 2, followed by acid-catalyzed
dehydration to generate the target compound (Scheme 4). How-
ever, it was discovered upon spectroscopic comparison with the
cross-coupling product 1 that the elimination pathway actually
produced the exo isomers 9a and 9b with a selectivity greater than
90% over the endo isomer 1, which was also present as a minor
product. In an effort to increase the selectivity of the endo isomer
of the elimination reaction, the temperature was varied from -70 to
40 °C. Changing the temperature did not change the product pro-
file, but lowering the temperature below À20 °C caused precipita-
tion of the starting material and low reactivity. These findings led
to the conclusion that the reaction was in fact under kinetic control
and not thermodynamic. By serendipity, the two pathways were
divergent and highly selective for each isomer. The elimination
pathway provided a mixture of the cis-trans and cis-cis isomers in
2:1 ratio, based upon the comparison of the distinctive peaks in
8
a
Ghosh was scaled to three moles of isobutrylaldehyde (3) and
two moles of allyl alcohol (4) to make enal 5 in excellent yields
after distillation. The second Org. Synth. preparation by Hudlicky
8
b
and co-workers carried 5–2 via the keto-aldehyde 6 in two
steps, which consisted of a copper/palladium-catalyzed Wacker
oxidation followed by an intramolecular aldol condensation. This
approach proved more successful than the efforts to reproduce
the original Paquette approach,7 while simultaneously reducing
the number of steps and avoiding the use of DIBAL-H on large
batches. This sequence was reliably scalable well beyond checked
values, did not employ any significantly toxic or pyrophoric
reagents, and provided 120 mL of the key
compound 2) in 55% overall yield after distillation.
One caveat however, was the presence of residual cymene used
as a solvent in the first step (the production of ,d-enal 5) which
unfortunately carried through to the last step, despite efforts to
remove it by conventional methods. After the reaction pathway
was completed, the reaction was attempted under different condi-
tions, to circumvent the use of cymene. The reaction was per-
formed in N-methyl-2-pyrrolidone using magnesium sulfate as
the dehydrating agent in lieu of a Dean-Stark trap to simplify
purification. Indeed, this approach led to the easy isolation of pure
a,b-unsaturated ketone
(
a
1
the H NMR around 5 ppm, which were the two exocyclic alkene
protons for the two respective isomers. Although the original tar-
get was the endo isomer, both endo and exo are equally valuable
as fuel candidates, as they likely have similar properties due to
possessing the same number of carbons, hydrogens, and double
bonds.
Scheme 2. Synthesis to 4,4-dimethylpent-2-en-1-one.
Scheme 3. Generation of triflate 7 and subsequent cross-coupling with a cuprate to 1.
Scheme 4. Grignard-elimination sequence to produce exo isomers 9a and 9b.
Please cite this article in press as: Page J.P., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.02.073

J.P. Page et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Conclusion
For the two reaction pathways, the synthetic steps required to
produce the target cyclopentadiene were significantly reduced
when compared to making the vinyl bromide.6 When the Grig-
nard-elimination pathway is considered, in four steps, the overall
yield was 43% of the two exo isomers, while the isomerically pure
endo product was produced in five steps, with an overall yield of
A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at https://doi.org/10.1016/j.tetlet.2018.02.073.
These data include MOL files and InChiKeys of the most important
compounds described in this article.
References
2
1%. The reaction conditions were not optimized to improve yields.
1
.
.
Demirbas A. Progress and recent trends in biofuels. Prog Energy Combust Sci.
007;33:1.
Strobel GA, Knighton B, Kluck K, et al. The production of myco-diesel
hydrocarbons and their derivatives by the endophytic fungus Gliocladium
roseum (NRRL 50072). Microbiology. 2008;154:3319.
These modified pathways show promise for production of
cyclopentadienes at scale, targeting a mixture of exo diastereomers
or the pure endo isomer. Perhaps the most important contribution
from this synthetic effort was the demonstration of a synthetic
route to the cyclic 5,5-dimethyl-1,3-cyclopentadiene-2-triflic
ester. There are no examples in the literature of this class of com-
pounds, yet five-membered rings are a common structural motif in
many organic targets. The expansion of stable 1,3-cyclopentadiene
derivatives for cross-coupling and further manipulation would be
of great benefit to synthetic chemists. This approach has demon-
strated their preparation with relative ease and at a practical scale.
One could envision a sequence of reactions starting from the tri-
flate to rapidly add structural complexity through standard
cross-coupling partners and cycloaddition strategies.
2
2
3.
Butcher MG, Meyer PA, Hallen RT, et al. Fungal metabolites as precursors to
renewable transportation fuels. Fuel. 2018;215:123–141.
4. Cooke F, Schwindeman J, Magnus P. Silicon in Synthesis. C2–C3 Annulation
Using Vinyltrimethylsilane as an Ethylene Equivalent for Bicyclo[n.3.0]enone
Synthesis. Tetrahedron Lett. 1995;1979:20.
5.
Magnus PD, Nobbs MS. A convenient synthesis of 4, 4-dimethylcyclopentenone.
Synth Commun. 1980;10:273–278.
6. Yang J, Long YO, Paquette LA. Concise total synthesis of the bioactive
mesotricyclic diterpenioids jatrophatrione and citlalirione. J Am Chem Soc.
2003;125:1567.
7
8
9
.
.
.
Paquette LA, Nakatani S, Zydowsky TM, Edmondson SD, Sun L-Q, Skerlj R.
Studies directed toward the synthesis of the unusual antileukemic diterpene
jatrophatrione. 1.
A solution to the problem of chirality merger during
elaboration of the entire carbotricyclic framework. J Org Chem. 1999;64:3244.
(a) Salomon RG, Ghosh S. Copper(I)-Catalyzed Photocycloaddition: 3,3-
dimethyl-cis-bicyclo-[3.2.0]-heptan-2-one. Org Synth. 1984;62:125;
Acknowledgements
(
b) Pauley D, Anderson F, Hudlicky T. 4,4-Dimethyl-2-Cyclopenten-1-one. Org
Synth. 1989;67:121.
This research was conducted as part of the Co-Optimization of
Fuels & Engines (Co-Optima) project sponsored by the U.S. Depart-
ment of Energy (DOE) Office of Energy Efficiency and Renewable
Energy (EERE), Bioenergy Technologies and Vehicle Technologies
Offices. Co-Optima is a collaborative project of multiple national
laboratories initiated to simultaneously accelerate the introduction
of affordable, scalable, and sustainable biofuels and high-efficiency,
low-emission vehicle engines. Pacific Northwest National Labora-
tory (PNNL) is operated by Battelle Memorial Institute for the
DOE under Contract No. DE-AC05-76RL01830. The authors kindly
acknowledge contributions from Phillip Koech (PNNL) in the form
of insightful technical discussions, and Jon Egbert (PNNL) and Anil
Shukla (PNNL) for help in providing mass spectral data.
Spaggiari A, Vaccari D, Davoli P, Torre G, Prati F. A Mild Synthesis of Vinyl
Halides and gem-Dihalides Using Triphenyl Phosphite–Halogen-Based
Reagents. J Org Chem. 2007;72:2216.
1
1
0. Lali c´ G, Galoni c´ D, Matovi c´ R, Sai cˇ i c´ RN. A model study of epothilone synthesis:
an alternative synthetic approach to the C1–C7 fragment. J Serb Chem Soc.
2002;67:221.
1. Hayashi T, Katsuro Y, Kumada M. Nickel-catalyzed cross-coupling of silyl enol
ethers with grignard reagents. Regio- and stereocontrolled synthesis of olefins.
Tetrahedron Lett. 1980;21:3915.
12. Karlström ASE, Rönn M, Thorarensen A, Bäckvall J-E. A versatile route to 2-
substituted cyclic 1,3-dienes via a Copper(I)-catalyzed cross-coupling reaction
of dienyl triflates with grignard reagents. J Org Chem. 1998;63:2517.
Please cite this article in press as: Page J.P., et al. Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.02.073