Cycloisomerization of bifunctionalized allenes: Synthesis of 3(2h)-furanones in water

Article abstract of DOI:10.1021/jo102416e

A simple protocol for the efficient synthesis of 3(2H)-furanones by cycloisomerization of allenic hydroxyketones is described. This transformation is achieved in water and in the absence of any expensive metal catalysts.

Full text of DOI:10.1021/jo102416e

NOTE
pubs.acs.org/joc
Cycloisomerization of Bifunctionalized Allenes:
Synthesis of 3(2H)-Furanones in Water
Manojkumar Poonoth and Norbert Krause*
Organic Chemistry, Dortmund University of Technology, Otto-Hahn-Strasse 6, D-44227 Dortmund, Germany
S Supporting Information
b
ABSTRACT: A simple protocol for the efficient synthesis of 3(2H)-furanones by
cycloisomerization of allenic hydroxyketones is described. This transformation is
achieved in water and in the absence of any expensive metal catalysts.
he 3(2H)-furanone moiety is a central structural unit in a
T
number of natural products such as bullatenone,1 jatrophone,2
eremantholide,3 geiparvarin,4 pseurotin,5 and the recently reported
metabolite longianone,6 some of which were considered as promis-
ing pharmaceutical candidates (Figure 1). Therefore, many strategies
have been developed for the construction of this five-membered ring
system, among which the acid-catalyzed cyclization-dehydration of
appropriately substituted R0-hydroxy-1,3-diketones2c,4c is the most
general method. Other approaches include the hydrogenolysis and
subsequent acidic hydrolysis of isoxazoles,7 the aldol reaction of
3-silyloxyfuranes,8 the cyclization of 1-halo-2,4-diketones with bases,9
and the Knoevenagel-type condensation of γ-acetoxy-β-ketoesters.10
Recent developments in the synthesis of 3(2H)-furanones involve
the use of transition metal catalysts, for example, in the Au-, Pd-, or
Hg-catalyzed cyclization of hydroxyalkynones,11 the Pt- or Au-
catalyzed cyclization/rearrangement of propargyl alcohols,12 or the
gold-catalyzed cyclization of 2-oxo-3-butynoates.13 In this paper, we
report that allenic hydroxyketones can be cyclized to 3(2H)-
furanone derivatives by using simple aqueous NaOH.
Figure 1. Natural products containing a 3(2H)-furanone subunit.
Scheme 1. Possible Reactions of Allenic Hydroxyketones A
In the past decade, allene chemistry14 has been a rapidly
growing research area in organic synthesis, providing various
reactivity modes to construct complex chemical architectures in a
stereoselective manner. As a part of our studies directed toward
the development of efficient cycloisomerization reactions of
functionalized allenes,15 we became interested in bifunctiona-
lized allenes comprising a carbonyl and hydroxyl group such as A.
This molecule can be considered as a combination of an R-
allenone and a β-allenol and might have different reactivity
profiles under Brønsted or Lewis acid catalysis (Scheme 1).
Besides 5-endo-trig cycloisomerization to furans B16 or 6-endo-
trig cyclization to pyranones D,17 intramolecular oxa-Michael
addition might afford 3(2H)-furanones C.
An attempt to synthesize an allenic hydroxyketone by selective
oxidation of a 3,4-dien-1,2-diol with activated manganese dioxide
resulted in the formation of the corresponding allenic aldehyde
by glycol cleavage.18 In contrast to this, monoprotected allenic
diols 2 (which are readily accessible from propargyl oxiranes 1 by
copper-promoted SN20-substitution19) were smoothly oxidized
to allenones 3 with activated manganese dioxide in dichloro-
methane at 0 °C (Scheme 2). When phenyl-substituted allenone
3a was subjected to TBS deprotection by using TBAF 3H2O at
3
0 °C, 3(2H)-furanone 5a was formed directly after just 20 min
(Scheme 3). In an analogous manner, the benzyl-substituted
allenone 3b afforded heterocycle 5b with 57% yield; in this case,
2.5 h of reaction time was required for a complete conversion.
Received: December 12, 2010
Published: February 03, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo102416e J. Org. Chem. 2011, 76, 1934–1936
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Scheme 2. Synthesis of Allenones 3.
Scheme 4. Deprotection and Basic Cyclization of Allenones
3c-g
Scheme 3. Deprotection and Spontaneous Cyclization of
Allenones 3a/b
Scheme 5. Transformations of/via 3(2H)-Furanones 5
With alkyl-substituted allenones 3c-g, TBS deprotection
gave the bifunctionalized allenes 4 as the exclusive product
within 10 min (Scheme 4). Prolonged reaction times (2.5 h)
afforded a trace amount of the furanone product, whereas stirring
of 3e with TBAF 3H2O for 18 h resulted in polymerization.
3
Surprisingly, the allenic hydroxyketones failed to give any
cycloisomerization product in the presence of various gold or
silver catalysts which were used previously for the cyclization of
allenic ketones16 and alcohols.15,17 Thus, treatment of 4c with
AuCl3, AuCl, Ph3PAuCl, IPrAuCl, HAuCl4 3H2O, AgNO3, or
3
AgOTf resulted in reisolation of the starting material. However,
treating allene 4c with a stoichiometric amount of K2CO3 in
methanol at room temperature furnished 3(2H)-furanone 5c
with moderate yield (41%). Use of other bases (NaHMDS in
THF, KOtBu in tBuOH, DBU or DABCO in dichloromethane),
as well as treatment with nBu3P or Ph3P in dichloromethane gave
no satisfactory results. A trace of the furanone product 5c was
formed when 4c was stirred with 25 mol % of p-TsOH in methanol
for 16 h. These results seem to indicate that the furanone is formed
only when a protic solvent is used. Accordingly, treatment of 4c
with aqueous NaOH for 1 h induced a clean conversion of the
starting material to the 3(2H)-furanone 5c, which was isolated with
61% yield (Scheme 4). Likewise, allenones 4d-g afforded the
corresponding furanones 5 with 57-73% yield under these con-
ditions. Mechanistically, the transformation may proceed via a
5-endo-dig (oxa-Michael) pathway, followed by base-catalyzed
isomerization of the exocyclic double bond.
The synthetic utility of the 3(2H)-furanones 5 formed by this
method was demonstrated by the smooth dialkylation of 5a to
product 6, as well as by the formation of siloxyfuran 7 from
furanone 5b (Scheme 5). Moreover, the heterocycles participate
in aldol reactions. Thus, adduct 8a20 was obtained with 51% yield
from 5a and anisaldehyde with NaOH in water/ethanol. These
conditions are similar to those used for the formation of the
furanones; accordingly, it is possible to conduct the cyclization/
aldol addition in one pot, as demonstrated by the efficient
formation of product 8d20 from allenic hydroxyketone 4d and
anisaldehyde. This procedure may be particularly useful for the
combinatorial synthesis of compound libraries.
In summary, we present a novel method for the synthesis of
3(2H)-furanones by cycloisomerization of allenic hydroxyke-
tones with aqueous NaOH. With respect to operational conven-
ience, it is important to note that this cyclization protocol does
not require any heating or cooling, or any expensive or toxic
metal catalysts. In addition to their importance as the core
structure of a variety of natural products, the 3(2H)-furanones
can be subjected to various synthetic manipulations. We antici-
pate that further investigation of bifunctionalized allenes will lead
to novel pathways to other interesting heterocyclic systems.
’ EXPERIMENTAL SECTION
Representative Procedure. Allenic hydroxyketone 4c (31 mg,
0.18 mmol) was added to a solution of NaOH (12 mg, (0.28 mmol)
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The Journal of Organic Chemistry
NOTE
in 1.5 mL water, and the mixture was stirred at room temperature until
the TLC control showed complete consumption of the starting material
(1 h). The reaction mixture was then extracted with 3 ꢀ 4 mL of diethyl
ether. The combined organic phases were dried with Na2SO4 and the
solvent was removed in the rotary evaporator (pressure not lower than
250 mbar) to furnish 19 mg (0.11 mmol, 61%) of 5c as a faint yellow
liquid.
4-Methyl-5-(3-methylbutan-2-yl)furan-3(2H)-one (5c): IR
(neat) 2967, 2929, 2873, 1688, 1618, 1462, 1403, 1170, 1054, 909, 735,
650 cm-1; 1H NMR (400 MHz, CDCl3) δ 4.42 (s, 2 H), 2.58-2.51 (m,
1 H), 1.87 (m, 1 H), 1.66 (s, 3 H), 1.19 (d, J = 7.0 Hz, 3 H), 0.99 (d, J =
6.7 Hz, 3 H), 0.88 (d, J = 6.7 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ
204.0, 193.0, 111.3, 73.8, 41.0, 31.9, 21.1, 20.6, 15.1, 5.8; HRMS (ESI)
calcd for C10H16O2 (Mþ) 168.1150, found 168.1138.
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’ ASSOCIATED CONTENT
S
Supporting Information. Experimental procedures, spec-
b
(15) (a) Krause, N.; Belting, V.; Deutsch, C.; Erdsack, J.; Fan, H.-T.;
Gockel, B.; Hoffmann-R€oder, A.; Morita, N.; Volz, F. Pure Appl. Chem.
tral data, and copies of NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
€
2008, 80, 1063. (b) Krause, N.; Aksin-Artok, O.; Breker, V.; Deutsch, C.;
Gockel, B.; Poonoth, M.; Sawama, Y.; Sawama, Y.; Sun, T.; Winter, C.
Pure Appl. Chem. 2010, 82, 1529.
’ AUTHOR INFORMATION
(16) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost, T. M. Angew.
Chem., Int. Ed. 2000, 39, 2285.
(17) Gockel, B.; Krause, N. Org. Lett. 2006, 8, 4485.
(18) Outram, H. S.; Raw, S. A.; Taylor, R. J. K. Tetrahedron Lett.
2002, 43, 6185.
Corresponding Author
*E-mail: norbert.krause@tu-dortmund.de.
’ ACKNOWLEDGMENT
(19) (a) Alexakis, A. Pure Appl. Chem. 1992, 64, 387. (b) Krause, N.;
Hoffmann-R€oder, A. Tetrahedron 2004, 60, 11671.
(20) Aldol adducts 8a/d were obtained as a single isomer, but the
configuration could not be determined spectroscopically.
Financial assistance from Dortmund University of Technol-
ogy is gratefully acknowledged.
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