Alkylations and hydroxymethylations of pyrazines via green minisci-type reactions

Article abstract of DOI:10.1021/ol500776j

A new general methodology utilizing Minisci-type chemistry has been developed that cleanly and efficiently prepares alkyl- and (hydroxymethyl) pyrazines. The new methods eliminate toxic catalysts and halogenated solvents, providing a greatly improved route to these natural products which are prevalent in many natural systems as bacterial volatiles, plant volatiles, and insect pheromones.

Full text of DOI:10.1021/ol500776j

Letter
pubs.acs.org/OrgLett
Alkylations and Hydroxymethylations of Pyrazines via Green Minisci-
Type Reactions
Bjorn Bohman,†,‡,§ Benjamin Berntsson,† Ruby C. M. Dixon,† Craig D. Stewart,† and Russell A. Barrow*,†
†Research School of Chemistry and ‡Research School of Biology, The Australian National University, Canberra, ACT 0200, Australia
§School of Chemistry and Biochemistry, The University of Western Australia, Crawley, WA 6009, Australia
S
* Supporting Information
ABSTRACT: A new general methodology utilizing Minisci-type chemistry has
been developed that cleanly and efficiently prepares alkyl- and
(hydroxymethyl)pyrazines. The new methods eliminate toxic catalysts and
halogenated solvents, providing a greatly improved route to these natural
products which are prevalent in many natural systems as bacterial volatiles,
plant volatiles, and insect pheromones.
yrazine natural products are well-known for their
further analyses of the mass spectra suggested which
Pinvolvement in chemical communication in several bio- substituents were present. The fragmentation-based hypothesis
logical systems, most commonly in insects.1−12 Furthermore,
was further supported by microderivatization experiments.
However, without the benefit of techniques such as NMR and
IR, the substitution pattern around the ring and exact
distribution of the atoms were unclear. In practice, this resulted
in the need to prepare a series of (hydroxymethyl)-
diethylmethylpyrazines and (hydroxymethylethyl)dimethyl-
pyrazines to allow unambiguous identification of the natural
products.
many pyrazine-derived compounds are used in the food
industry as flavoring agents, and these compounds are formed
naturally from amino acids in Maillard reactions as food is
heated.13−19 Pyrazines have also been found in bacterial
odors,20−22 and recently an increasing number of more
complex derivatives have been discovered as products from
microorganism reactions.23−31
Existing methods for synthesis of substituted pyrazines
normally involve Negishi or Kumada chemistry, where
palladium, zinc, magnesium, and nickel reagents and/or
catalysts are required and chlorinated solvents are used.39−42
These reactions are reliable for the preparation of most
compounds; however, apart from the toxicity of reagents and
solvents employed and/or the demanding reaction conditions,
the strategy generally involves multiple steps generating the
products in low overall yields. There are also cases where these
methods are not applicable, for example where the required
chloropyrazine intermediate is difficult to prepare.43 Other
methods involve condensation of amino acids or their
derivatives, which are labor-intensive and low-yielding reac-
tions44 and alkylations under harsh reaction conditions.45
Of interest to us were examples in the literature where
Minisci-type chemistry had been used for C−H functionaliza-
tion of heteroaromatic bases. These reactions proceed via a
postulated radical addition process under aqueous acidic
conditions, without the need for toxic catalysts.46−50 By
utilizing Minisci alkylations and hydroxymethylations, all six
products 7−9 and 20−22 could be readily prepared in two to
four steps from the commercially available dimethylpyrazines
1−3 without the use of toxic reagents or catalysts (Scheme 1).
The three (hydroxymethyl)ethyldimethylpyrazines 7−9 were
prepared in two steps in 15−27% total yields (29−48% based
We have recently identified several alkylated and hydrox-
ymethylated pyrazines as semiochemicals involved in the
pollination of sexually deceptive orchids and as wasp sexual
pheromones.32,33 Sexually deceptive orchids employ mimicry of
the sex pheromones of female insects to lure sexually excited
males as pollinators.34,35 One of the most sophisticated of all
sexually deceptive systems is that of the Western Australian
hammer orchids Drakaea (Orchidaceae), which mimic both the
chemistry of the sexual pheromone and morphology of the
flightless female thynnine wasps.36 Drakaea exploit a diversity
of wasp genera,37 thus providing the opportunity to explore a
range of pheromone systems.
In addition to the compounds involved in the attraction of
sexually deceived Zaspilothynnus and Catocheilus wasps
(Thynnidae) to Drakaea livida,32,33 we have further investigated
seven more species of Drakaea. In all of these systems, tri- or
tetrasubstituted pyrazinylmethanols were identified and con-
firmed to be biologically active. In D. glyptodon, pollinated by Z.
trilobatus, we have very recently identified the wasp sexual
pheromone blend and orchid semiochemicals, confirming a
novel hydroxymethylpyrazine to be a key component of both.38
Owing to the small quantity of sample available in the natural
extracts (∼1−10 ng/flower and wasp),33 further identification
of the physiologically active compounds relied solely on GC−
MS analysis. Utilizing the softer ionization technique available
through chemical ionization (CI−MS) allowed confident
assignment of the quasimolecular ions. Careful analysis of
lower m/z fragments clearly indicated a pyrazine skeleton, and
Received: March 14, 2014
Published: May 13, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Scheme 1. Synthetic Route to New (Hydroxymethyl)trialkylpyrazines
on recovered starting materials) from the corresponding
dimethylpyrazines 1−3. Ethylation was achieved by an Fe-
catalyzed Minisci reaction with propanal in water at rt. By
adjusting the pyrazine/aldehyde ratio, temperature, and
reaction time, the selectivity for the monoethylated product
over the diethylated was over 80%. Compounds 4−6 were
hydroxymethylated, utilizing modified Minisci conditions, to
give the (hydroxymethyl)ethyldimethylpyrazines 7−9 in 38−
59% yields.
branched chain aldehydes such as n-pentanal and isopentanal
(unpublished data). In summary, we have developed a clean
and reliable approach to prepare substituted pyrazines that
avoids the use of toxic metals and chlorinated solvents. With
the prevalence of pyrazines as flavoring agents in foods,51
bacterial volatiles,30,52 and their growing recognition as insect
semiochemicals2,3,9,32,33,53−55 we believe our methods con-
stitute a significant improvement to the current methods used
to prepare these increasingly important compounds.
In order to obtain the (hydroxymethyl)diethylmethyl-
pyrazines 20−22, a similar strategy was applied. The same
starting material was used, but the reaction conditions for the
Minisci alkylation were modified to optimize the yields of
diethylated products. By using an 8-fold excess of propanal the
reaction proceeded to complete alkylation affording the
tetrasubstituted pyrazines. The diethyldimethylpyrazines 10−
12 were N-oxidized to the intermediates 13−16, which were
hydroxymethylated using a Boekelheide rearrangement39 via
the intermediate acetate esters 17−19, which were saponified
to yield the desired products 20−22 in 26−43% total yields
over four steps.
ASSOCIATED CONTENT
* Supporting Information
Experimental details, mass spectra, and H and 13C NMR
spectra of final products. This material is available free of charge
via the Internet at http://pubs.acs.org.
■
S
1
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: rab@anu.edu.au.
Notes
The optimization of the Minisci alkylations was simply to
show that these reactions are general. For our purpose of
preparing the target compounds, we used conditions for a less
specific ethylation of 1−3, yielding mixtures of 4−6 and 10−
12, which were easily separated by column chromatography
(see the Supporting Information), streamlining the preparation.
On a side note, when the hydroxymethylation was attempted
directly on dimethylpyrazines 1−3, the desired products were
obtained in decreased yields with N-oxidation occurring,
indicating the preference of a trialkylated substrate for
hydroxymethylation to take place in this system. We have
successfully alkylated dimethylpyrazines using longer and
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The study was undertaken with the support of an ARC linkage
project to R.B. (LP0989338). B.B. conducted part of this work
while a visiting fellow at UWA.
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