One-pot assembly of 7-methylene-6,8-dioxabicyclo[3.2.1]octanes, congeners of frontalin, from ketones and acetylene

Article abstract of DOI:10.1002/ejoc.200900853

A facile, consecutive, self-consisting assembly of two molecules of ketones with two molecules of acetylene to afford 7methylene-6,8-dioxabicyclo[3.2.1] octanes, which are unknown congeners of widespread insect pheromones, has been discovered. The reactio

Full text of DOI:10.1002/ejoc.200900853

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200900853
One-Pot Assembly of 7-Methylene-6,8-dioxabicyclo[3.2.1]octanes, Congeners
of Frontalin, from Ketones and Acetylene
Boris A. Trofimov,*[a] Elena Yu. Schmidt,[a] Igor A. Ushakov,[a] Albina I. Mikhaleva,[a]
Nadezhda V. Zorina,[a] Nadezhda I. Protsuk,[a] Elena Yu. Senotrusova,[a]
Elena V. Skital’tseva,[a] Olga N. Kazheva,[b] Grigorii G. Alexandrov,[c] and
Oleg A. Dyachenko[b]
Keywords: Ketones / Alkynes / Oxygen heterocycles / Pheromones / Superbasic systems
A facile, consecutive, self-consisting assembly of two mole-
cules of ketones with two molecules of acetylene to afford 7-
methylene-6,8-dioxabicyclo[3.2.1]octanes, which are un-
known congeners of widespread insect pheromones, has
been discovered. The reaction is realized in a one-pot pro-
cedure in a MOH/DMSO system (M = K, Cs) at 80 °C for 1 h
under acetylene pressure or under atmospheric pressure; the
isolated yields of the bicycles reached 86%. The new reac-
tion conceptually contributes to the synthesis of insect phero-
mones as well as to the chemistry of ketones and acetylene.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Introduction
Results and Discussion
It is well known that ketones react with acetylene in the
presence of bases to furnish acetylenic alcohols (Favorsky
reaction).[1] To our surprise, when conducting the reaction
of aromatic and heteroaromatic ketones 1a–e with acetylene
in MOH/DMSO (M = K, Cs) at 80 °C for 1 h under acetyl-
ene pressure (autoclave, initial acetylene pressure at ambient
temperature 12–14 atm), we isolated, instead of the ex-
pected acetylenic alcohols 2a–e, 7-methylene-6,8-dioxabicy-
clo[3.2.1]octanes 3a–e as the only products in up to 86%
yield (Scheme 1, Table 1).
The 6,8-dioxabicyclo[3.2.1]octane[2] scaffold is an impor-
tant structural organization (assembly) present in a number
of pheromones and natural products such as frontalin, bre-
vicomin, multistriatin, bullerone, and palytoxin.[3] Frontalin
(1,5-dimethyl-6,8-dioxabicyclo[3.2.1]octane) is the aggrega-
tion pheromone of pine beetles of the Dendroctonus fam-
ily.[4] This pheromone has also been isolated from the bark
of several angiosperm trees[5] and from the temporal gland
of the male Asian elephant during sexual activity.[6] These
compounds are now successfully used to control the pro-
gression of pine beetle infestations in forests.[4] Therefore, a
great deal of effort is now being spent to develop concise
and rational approaches to the synthesis of frontalin and
its congeners.[4,7,8] However, most of the proposed strategies
are either multistep[9] or require hardly accessible starting
materials.[3,10] Our serendipitous discovery of the one-pot
assembly of the frontalin scaffold originates a new synthetic
concept in this important area.
Scheme 1. The assembly of 7-methylene-6,8-dioxabicyclo[3.2.1]-
octanes 3a–e from ketones 1a–e and acetylene.
The structures of compounds 3a–e unambiguously fol-
low from the single-crystal X-ray diffraction of compound
3e (Figure 1) as a typical representative of this series. Its
structure is formed by one crystallographically independent
molecule, C18H20O2S2. In the dioxabicyclooctane fragment,
the dihedral angle formed by the O(1)O(2)C(8) and O(1)
C(3)O(2) planes equals 153.0°, the dihedral angle between
the O(1)O(2)C(8) and O(1)C(7)C(8) planes is 157.4°, and
the dihedral angle between the O(1)C(3)O(2) and O(1)C(7)
C(8) planes is 132.8°. The dihedral angle between the planes
of the thiophene heterocycles equals 98.3°. Torsion angles
in the dioxolane heterocycle are O(1)C(7)C(8)O(2) 22.5(1)°,
[a] A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch,
Russian Academy of Sciences
1 Favorsky Str., 664033 Irkutsk, Russia
Fax: +7-3952-419346
E-mail: boris_trofimov@irioch.irk.ru
[b] Institute of Problems of Chemical Physics, Russian Academy of
Sciences
Acad. Semenov av. 1, Chernogolovka, Moscow region 142432,
Russia
[c] N. S. Kurnakov Institute of General and Inorganic Chemistry,
Russian Academy of Sciences
Leninsky prp. 31, Moscow 119991, Russia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200900853.
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Eur. J. Org. Chem. 2009, 5142–5145

One-Pot Assembly of 7-Methylene-6,8-dioxabicyclo[3.2.1]octanes
Table 1. 7-Methylene-6,8-dioxa-bicyclo[3.2.1]octanes 3a–e synthe-
sized according to Scheme 1.
Figure 1. X-ray structure of 3e.
low-field shift of the Hb proton is due to the cis-oxygen
atom that is typical for vinyl ethers.[11] The aliphatic CH2
protons (2- and 4-positions) are represented by multiplets,
owing to the spin–spin coupling with the CH proton in the
3-position. For all compounds 3a–e, nonequivalency of the
aromatic and heteroaromatic protons was observed. The
2D NMR experiments (COSY, NOESY, HSQC, HMBC) in
the 1H and 13C NMR spectra allowed all the resonance
signals to be assigned.
Figure 2. Characteristic NOESY and HMBC correlations of com-
pounds 3a–e.
The NMR spectroscopic data evidence that exclusively
1
one diastereomer is formed in all the cases. Only in the H
and 13C NMR spectra of 3e were weak signals correspond-
[a] The products were isolated and purified by column chromatog-
raphy (basic Al2O3; hexane/diethyl ether, 3:1). [b] Conversion of
ketones 1 according to H NMR spectroscopy.
ing to other isomers in a total amount of ca. 10% detected.
1
In the H and 13C NMR spectra of other bicycles, no sig-
1
nals of minor isomers were discernible.
The reaction was carried out both in KOH/DMSO and
C(7)C(8)O(2)C(3) 2.1(1)°, C(8)O(2)C(3)O(1) 27.0(1)°, O(2) CsOH/DMSO, with nearly equal efficacy, and the ketone/
C(3)O(1)C(7) 41.7(1)°, and C(3)O(1)C(7)C(8) 38.8(1)°.
MOH molar ratio was 1:1. According to the 1H NMR spec-
The H and 13C NMR spectra are in agreement with the tra, the crude material contained only bicycles 3a–e and
structure of compounds 3a–e. In the 1H NMR spectra, unreacted ketones, though in most cases conversion of the
characteristic signals are the two doublets (2J = 2.2–2.4 Hz) latter was complete (Table 1). The reaction can be also real-
of the methylene groups (Ha and Hb, 3.5–4.5 ppm). The sig- ized under atmospheric pressure (flow reactor), but here
nals of the Ha and Hb protons were distinguished by using higher temperatures and longer reaction times are required.
2D NOESY experiments (Figure 2). The chemical shift dif- For example, the conversion of ketone 1a to bicycle 3a
ference of these protons ranged from 0.7 to 1.0 ppm. The (100 °C, 5 h) was 50% (1H NMR spectroscopy).
1
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B. A. Trofimov et al.
SHORT COMMUNICATION
Scheme 2. A tentative sequence for the assembly of 7-methylene-6,8-dioxabicyclo[3.2.1]octanes 3 from ketones and acetylene.
An aliphatic ketone (acetone) was also tested in this as-
Scheme 2 is in keeping with our experimental data that
sembly (KOH/DMSO, 80 °C, 1 h, autoclave, acetylene pres- aliphatic ketones undergo the above assembly nonselec-
sure 14 atm). In the crude material obtained, the expected tively. This might be due to the lower CH acidity of ali-
1,3,5-trimethyl-7-methylene-6,8-dioxabicyclo[3.2.1]octane phatic ketones (less favorable formation of type A carban-
1
was detected (ca. 10%, H NMR spectroscopy) among the ion) and the lower electrophilicity of intermediate α,β-ethyl-
self-condensation products of acetone that complicated the enic ketone C as well as their higher propensity to undergo
separation of the components. Obviously, to improve the self-condensation.
preparative value of the reaction discovered for aliphatic
As seen from Table 1, the new reaction allows diverse
ketones, a special systematic optimization of both the reac- aromatic, heteroaromatic, and condensed aromatic substit-
tion conditions and the isolation procedures are needed. uents, as well as the enol ether moiety, to be introduced
This will be a target of our further investigations.
into the frontalin skeleton, which essentially enriches the
As to the preliminary rationalization for the assembly frontalin family with hitherto unknown representatives.
(Scheme 2), we assume that first ketone carbanion A adds
to acetylene and adduct B prototropically isomerizes to α,β-
ethylenic ketone C, which is further attacked by the same Conclusions
ketone carbanion A to give 1,5-diketone D. The latter un-
A new reaction representing a one-pot assembly of two
dergoes the Favorsky reaction with a second molecule of
molecules of aromatic and heteroaromatic ketones (acylar-
enes and -hetarenes) or acylated condensed aromatics with
acetylene to afford acetylenic alcohol E, which then partici-
pates in a domino sequence: formation of hemiacetal F and
two molecules of acetylene to deliver densely substituted 7-
intramolecular nucleophilic addition of its hydroxy group
methylene-6,8-dioxabicyclo[3.2.1]octanes, unknown conge-
at the acetylenic moiety to finalize the assembly.
ners of insect pheromones of the frontalin series, was dis-
The suggested reaction sequence is supported by the fact
covered. The reaction is highly regio- and stereoselective
that acetylene is very sensitive towards nucleophilic at-
and proceeds smoothly in simple MOH/DMSO (M = K,
tack[12] and readily adds diverse nucleophiles in the pres-
Cs) systems at 80 °C for 1 h under elevated or atmospheric
ence of bases,[12,13] particularly superbases[1b,14] without ac-
tivation by the transition metals.
Alternatively, intermediate C could be formed by aldol
condensation of ketone 1 with acetaldehyde, which in turn
pressure; the isolated yields of the assemblies reached 86%.
Aliphatic ketones are potentially also valid for this as-
sembly.
Fundamentally, the reaction essentially extends the fron-
may originate from acetylene hydration (nucleophilic ad-
tiers of the synthetic applications of simple organic com-
dition of water to the triple bond). The transformation of
pounds such as ketones and acetylene. Practically, the reac-
intermediate diketone D into acetylenic alcohol E (addition
tion gives exceptionally facile access to new diversely substi-
of deprotonated acetylene to carbonyl group) is in accord-
tuted derivatives of important insect pheromones, which
ance with the easy deprotonation of acetylene in the KOH/
can be prospective building blocks for organic synthesis and
DMSO system. According to the experimental data (e.g.,
precursors of advanced materials.
see ref.[15]), the pKa value for acetylenes in DMSO is on the
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental data and spectroscopic data.
level of 28–29, whereas the basicity function (H_) of the
KOH/DMSO system is higher than 30 (e.g., see ref.[16]).
Therefore, ionization of acetylenes in such systems exceeds
90%.
CCDC-736221 (for 3e) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
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Eur. J. Org. Chem. 2009, 5142–5145

One-Pot Assembly of 7-Methylene-6,8-dioxabicyclo[3.2.1]octanes
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Received: July 28, 2009
Published Online: September 15, 2009
Eur. J. Org. Chem. 2009, 5142–5145
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www.eurjoc.org
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