On the curious oxidations of 2-furylethanols

Article abstract of DOI:10.1016/j.tetlet.2009.11.119

Rather than giving the corresponding aldehyde or carboxylic acid, Jones oxidation of 5-substituted-2-furylethanols gives rise to high yields of the corresponding dihydro-2-(2-oxoethyl)furan-3(2H)-ones, following Achmatowicz-type oxidative ring opening and subsequent reclosure by a 5-exo Michael addition of the pendant hydroxy group to the enedione function. Other oxidation methods such as a Swern reaction give lower yields of the same products while magnesium perphthalate tends to yield the intermediate enediones, and IBX tends to yield the furyl aldehydes.

Full text of DOI:10.1016/j.tetlet.2009.11.119

Tetrahedron Letters 51 (2010) 720–723
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
On the curious oxidations of 2-furylethanols
a
b
Simon J. Hayes a, David W. Knight a, , Andrew W. T. Smith , Mark J. O’Halloran
*
a School of Chemistry, Cardiff University, Main College, Park Place, Cardiff CF10 3AT, UK
b Technical and Business Development, GlaxoSmithKline, Shewalton Road, Irvine KA11 5AP, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Rather than giving the corresponding aldehyde or carboxylic acid, Jones oxidation of 5-substituted-2-
furylethanols gives rise to high yields of the corresponding dihydro-2-(2-oxoethyl)furan-3(2H)-ones, fol-
lowing Achmatowicz-type oxidative ring opening and subsequent reclosure by a 5-exo Michael addition
of the pendant hydroxy group to the enedione function. Other oxidation methods such as a Swern reac-
tion give lower yields of the same products while magnesium perphthalate tends to yield the intermedi-
ate enediones, and IBX tends to yield the furyl aldehydes.
Received 9 October 2009
Revised 17 November 2009
Accepted 27 November 2009
Available online 1 December 2009
Keywords:
Oxidation
2-Furyl ethanols
Jones
Ó 2009 Elsevier Ltd. All rights reserved.
Furans
Ring opening
The need for ever more efficient, mild and especially environ-
mentally friendly synthetic processes continues to drive the devel-
opment of heteroaromatic syntheses, despite the existence of
many viable routes to these molecules. One of our recent contribu-
tions to this area has been the discovery that silver(I) nitrate ab-
sorbed on silica gel [10% AgNO3–SiO2], more often associated
with a role as a stationary phase for the chromatographic separa-
tion of alkene stereoisomers, is a superbly efficient heterogeneous
catalyst for the conversion of 3-alkyne-1,2-diols 1 into the corre-
sponding furans 2 (Scheme 1), the only by-product being an equiv-
alent of water.1
can induce deep-seated rearrangements, one of the best known
being the Achmatowicz oxidation, which originally used bromine
in methanol to give pyranones,2 while photo-oxygenation usually
leads to 4-hydroxybutenolides.3 Alternatively, exposure of these
R2
OH
cat. 10% AgNO3-SiO2
R1
R2
R3
CH2Cl2, 20 oC
>95%
R1
R3
O
HO
1
2
In one endeavour aimed at extending the utility of this method-
ology, we undertook a study of such cyclisations when applied to
substrates 3 having unprotected hydroxyalkyl substituents in or-
der to examine whether incorporation of these would result in
the occurrence of any competing cyclisation modes. The motiva-
tion for this was to determine whether the need for protecting
groups could be obviated; if such competing cyclisations did in-
deed occur, we hoped that protection methodology would provide
a solution.
Scheme 1.
R2
(CH2)nOH
OH
R2
(CH2)nOH
R1
Ag+
?
R1
O
HO
3
4
We also hoped that, given the successful outcome of such cyc-
lisations, the resulting 2-furylalkanols 4 would act as precursors
to additional derivatives such as the corresponding carboxylic
acids 5 (Scheme 2).
It has been known for many years that oxidations of furylic
alcohols (2-furylmethanols) do not always follow the expected
pathway to the corresponding aldehydes or ketones, but rather
[O]?
R2
(CH2)n-1CO2H
R1
O
5
* Corresponding author.
E-mail address: knightdw@cf.ac.uk (D.W. Knight).
Scheme 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.11.119

S. J. Hayes et al. / Tetrahedron Letters 51 (2010) 720–723
721
R2
OH
OH
cat. 10% AgNO3-SiO2
CH2Cl2, 20 oC, 3 h
Ph
R2
1O2, MeOH
O
Ph
OH
O
R1
OH
O
O
11
HO
OH
97%
O
6
7
R1
10
Scheme 3.
MeOH
sensitive furyl alcohols to acidic conditions and by implication to
acidic oxidising agents such as the Jones reagent results in the for-
mation of a 4-hydroxy-2-cyclopentenone by alcohol protonation,
water loss assisted by the furyl ring oxygen and the re-addition
of water, but at the distal 5-position of the furan, followed by ring
opening and finally aldol cyclisation.4 We were therefore most un-
clear as to what would happen when we attempted to oxidise the
2-furylethanols 4, especially as there appeared to be no references
to any such transformations in the literature. However, a very re-
cent report of the photo-oxidation chemistry of similar substrates5
prompts us to report, in preliminary form, our own studies in this
area.
R2
R2
Me2S
R1
MeO
R1
MeO
OH
OH
O
O
OH
13
OOH
12
R1
R2
HO
O
R2
5-exo-trig
R1
O
O
O O
8
9a
Our initial studies showed that a phenyl-substituted alkyne-
1,2-diol 6 underwent very smooth silver-catalysed cyclisation to
provide a virtually quantitative yield of the 2-furylethanol 7 with-
out any interference from the unprotected primary hydroxy group
(Scheme 3).1,6
Scheme 5.
It was at this point that we became aware of the publication by
Tofi et al.5 in which they describe the formation of very similar
keto-tetrahydrofurans but using a photo-oxidation method to gen-
erate the intermediate enediones [cf. 8] (Scheme 5). This chemistry
involves the Diels–Alder-like addition of photochemically gener-
ated singlet oxygen to the furan nucleus 10 to give an endoperox-
ide 11, which is then opened by nucleophilic attack of the
methanol used as the solvent. The resulting hydroperoxide 12
and presumably its positional isomer are then reduced in situ by
the addition of dimethyl sulfide to give a hemiacetal 13 which is
in equilibrium with the open chain enedione 8, exactly the same
type of species as we proposed as the intermediate in the Jones oxi-
dation method (Scheme 4). A Michael addition then completes the
sequence in the same way.
Comparisons of spectroscopic and analytical data reported from
the foregoing Scheme 5 supported our structural assignments. The
alternative pyranone structure 14 which could be formed by a less-
favoured8 6-endo-trig cyclisation was ruled out mainly on the con-
sideration of this mechanism and on the basis of comparative spec-
troscopic data.
When the 2-furylethanol 7 was exposed to the Jones reagent at
0 °C,7 an oxidation clearly occurred as green chromium(III) salts
became visible. However, quenching with aqueous carbonate fol-
lowed by a simple solvent extraction gave an excellent yield of a
product which clearly no longer contained a furan residue and
equally clearly was not an aldehyde or a carboxylic acid. Further,
to our surprise, its richly detailed 1H NMR spectrum strongly sug-
gested the formation of an aliphatic product as it showed the com-
plete absence of alkenyl protons. Subsequent coupling constant
and COSY analyses identified two separate groups of protons, a
three-proton ABX system and a four-proton AA0BB0 pattern. Fur-
ther, infrared, and especially 13C NMR data, showed the presence
of two ketone groups [dC 215.8 and 196.1], the latter likely to be
due to the presence of a benzoyl group, PhCO. Further, the coupling
constant values strongly indicated that most of the protons were
attached to a cyclic system. That an oxidation had indeed occurred
was confirmed by molecular weight determination: while the ini-
tial furylethanol 7 [C12H12O2] had a molecular weight of 188, the
new product showed m/z = 227 for [M+Na]+, equivalent to a
molecular weight of 204, and therefore contained an additional
oxygen [C12H12O3], a conclusion confirmed by high resolution
measurements.
It therefore appeared that the furan ring had undergone an ini-
tial oxidative ring opening, perhaps related to the Achmatowicz
reaction,2 to give an intermediate enedione 8 (Scheme 4). This
could then undergo ring closure by an intramolecular Michael
addition of the pendant hydroxy group to the enedione acceptor,
to give either a five- or a six-membered cyclic ether. In view of
the Baldwin rule prediction that 5-exo-trig processes are generally
preferred to 6-endo-trig competitors,8 we favoured the keto-tetra-
hydrofuran structure 9 as being that of the unexpected product.9
O
Ph
O
O
14
We then wondered whether the initial example 9 was a special
case that perhaps, for instance, depended on the presence of the
phenyl group. We therefore examined the behaviour of related 5-
alkyl-substituted 2-furylethanols when exposed to Jones reagent,
using exactly the same conditions which were used previously.9
Thus the 5-butyl derivative 15 was converted into the keto-tetra-
hydrofuran 16 in 77% isolated yield.
O
Bu
Jones
HO
O
Ph
Bu
OH
O
5-exo-trig
O
5-exo-trig
Jones
O
7
Ph
O
77%
O
O O
15
16
8
9
The more sensitive citronellyl-derived furylethanol 17 similarly
gave the keto-tetrahydrofuran 18 in 64% yield.
Scheme 4.

722
S. J. Hayes et al. / Tetrahedron Letters 51 (2010) 720–723
proved unsuccessful. By contrast, treatment of the alcohols 7, 15
and 17 with magnesium monoperphthalate (MMPP)15 in aqueous
ethanol at ambient temperature for two hours gave a second prod-
uct type, the (Z)-enediones 22a–c (Scheme 7). This is a known
transformation16 but one which gave us a definitive insight into
the mechanism of the present chemistry.
OH
Jones
O
17
5-exo-trig
64%
A second reaction of the products 22 strongly supported their
intermediacy in the foregoing unexpected oxidation chemistry:
exposure to catalytic p-toluenesulfonic acid,5 as shown (Scheme
8), led to smooth formation of the corresponding keto-tetra-
hydrofurans by an acid-induced 5-exo-trig Michael addition.
A final contrast was shown by the use of IBX17 which under typ-
ical conditions delivered excellent yields of the aldehydes 23 from
the two representative 2-furylethanols 7 and 15 (Scheme 9).
Therefore, despite our initial concerns, this chemistry has pro-
ven to be synthetically useful in the sense that, by a careful choice
of oxidising reagent, three different product types can be obtained
from 2-furylethanols. The 3-keto-tetrahydrofurans in particular
may turn out to be especially useful as this is a structural type
which is poorly represented in the current literature. Quite why
the Jones chemistry and other oxidations follow this unexpected
pathway remains unclear but, possibly, the b-hydroxy group in
the 2-furylethanols could form complexes with the chromium-
based or other activated oxidation moieties, thereby strongly
encouraging such reactive species to interact directly with the fur-
an ring, aided by the oxygen atom of the latter, leading to an inter-
mediate enedione [cf. 22]. This induced proximity could render
O
O
O
18
In much the same way as the Jones reagent can directly transform
O-silyl ethers into the corresponding carbonyl compounds by
sequential deprotection and oxidation,10 exposure of the t-butyldi-
methylsilyl ether 19 to the Jones reagent led to a similar yield of the
keto-tetrahydrofuran 9 as that obtained from the parent alcohol.
Jones
9
Ph
OTBS
O
5-exo-trig
76%
19
During attempts to probe the origins of the unexpected keto-
tetrahydrofurans, we treated the initial 5-phenylfurylethanol 7
with acidic acetone, essentially Jones reagent9 without the chro-
mium salts, and were surprised to isolate a reasonable yield of
the Friedel–Crafts product 20 (Scheme 6). When this was exposed
to the ‘normal’ Jones reagent,9 we were able to isolate, but in poor
yield, the keto-tetrahydrofuran 21 as a 1.5:1 mixture of diastereo-
isomers. It seemed remarkable that such a sensitive product had
survived the acidic conditions but, presumably, this is reflected
in both the poor yield and the observation of the formation of a
multitude of other, as yet unidentified products.
such reactions faster than proton loss
a-to the oxygen and alde-
hyde formation, as in a more usual oxidation. Under the acidic
Jones conditions, such an intermediate would surely undergo ra-
pid, acid-catalysed cyclisation to the observed keto-tetrahydrofu-
rans. Efforts to further define and exploit this methodology are
under way.
We also examined a number of alternative oxidation proce-
dures in a continued effort to obtain ‘simple’ alcohol oxidation
products from the model substrate 7. Omitting the acidic compo-
nent in a Jones oxidation mixture resulted in the formation of a
ca. 1:1 mixture of the precursor 7 and the keto-tetrahydrofuran
9. Pyridinium dichromate (PDC) in dimethylformamide (DMF) at
ambient temperature11 led to the very slow formation of the
keto-tetrahydrofuran 9, but formation of little else. Even the rather
mild Swern oxidation method12 delivered a similarly low yield of
the keto-tetrahydrofuran 9, while tetrapropyl perrhuthenate
(TPAP)13 and various methods using potassium permanganate14
MMPP
R
R
OH
O
O
O
OH
7, 15, 17
22a
22b
R = Ph [88%]
R = Bu [95%]
22c R = citronellyl [64%]
Scheme 7.
O
R
R
OH
p-TSA
O
O O
OH
toluene, 50 oC
O
O
9 R = Ph [90%]
22
Ph
OH
Ph
OH
O
O
c.H2SO4
47%
16 R = Bu [87%]
18 R = citronellyl [79%]
7
20
Scheme 8.
Jones
27%
OH
O
Ph
IBX
R
O
OH
R
O
O
O
DMSO, 20 oC
2 h
O
7, 15
23a R = Ph [79%]
23b R = Bu [72%]
21
Scheme 6.
Scheme 9.

S. J. Hayes et al. / Tetrahedron Letters 51 (2010) 720–723
723
Chem. Commun. 1976, 736–737; Baldwin, J. E. J. Chem. Soc., Chem. Commun.
1976, 738–739.
Acknowledgements
9. A typical procedure is as follows: Dihydro-2-(2-phenyl-2-oxoethyl)furyl-3(2H)-one
(9): Jones reagent (3 ml, 6.38 mmol)7 was added dropwise to a stirred, ice-cold
solution of 5-phenylfuran-2-ethanol 7 (1.00 g, 5.32 mmol) in acetone (10 ml).
After 0.5 h at this temperature, the mixture was made basic by the addition of
saturated aqueous K2CO3 and the organic products were extracted into EtOAc
(3 ꢀ 20 ml). The combined organic extracts were washed with H2O (50 ml) and
brine (50 ml), then dried (MgSO4), filtered and evaporated. Crystallisation of
the residue from aqueous MeOH gave the keto-tetrahydrofuran 9 (0.812 g, 81%)
as pale orange prisms, mp 48–50 °C. C12H12O3 requires C, 70.6; H, 5.9. Found: C,
We are grateful to Professor Donald Craig (Imperial College) for
a very enlightening discussion and to GSK and the EPSRC for finan-
cial support.
References and notes
1. Hayes, S. J.; Knight, D. W.; Menzies, M. D.; O’Halloran, M.; Tan, W.-F.
Tetrahedron Lett. 2007, 48, 7709–7712.
70.9; H, 6.0; Rf 0.56 (30:70 EtOAc/petrol);
m
max/cmꢁ1 (CH2Cl2) 1756, 1686,
1597, 1449, 1370, 1268, 1219, 1150, 1092, 736, 689; dH (400 MHz, CDCl3) 7.86
(2H, app. d, J 7.2 Hz, 2 ꢀ Ph), 7.51 (1H, app. t, J 7.2 Hz, Ph-H), 7.42–7.38 (2H, m,
2 ꢀ Ph-H), 4.34 (1H, app. dt, J 9.2 and 4.2 Hz, 5-Ha), 4.13–4.05 (2H, m, 2-H and
5-Hb), 3.55 (1H, dd, J 18.0 and 3.4 Hz, 10-Ha), 3.31 (1H, dd, J 18.0 and 5.5 Hz, 10-
Hb), 2.82 (1H, dt, J 18.0 and 9.0 Hz, 4-Ha), 2.51 (1H, ddd, J 18.0, 7.5 and 4.2 Hz, 4-
Hb); dC (125 MHz, CDCl3) 215.8 (3-CO), 196.1 (PhCO), 136.2 (PhC), 133.6
(PhCH), 128.7 (2 ꢀ PhCH), 128.2 (2 ꢀ PhCH), 75.5 (2-CH), 65.3 (5-CH2), 40.6 (10-
CH2), 36.6 (4-CH2); m/z (ES) 227 [M+Na]+.
2. Achmatowicz, O., Jr.; Bukowska, P.; Szachner, B.; Zwierzchowska, Z.; Zamojski,
A. Tetrahedron 1971, 27, 1973–1996; Maier, M. In Organic Synthesis Highlights II;
Waldermann, H., Ed.; VCH: Weinheim, 1995; pp 231–242; Singh, V.; Krishna, U.
M.; Vikrant; Trivedi, G. K. Tetrahedron 2008, 64, 3405–3428. and references
therein; For an alternative reagent [PhI(OAc)2], see: De Mico, A.; Margarita, R.;
Piancatelli, G. Tetrahedron Lett. 1995, 36, 3553–3556; But see: De Mico, A.;
Margarita, R.; Partanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62,
6974–6977. for examples of hypervalent iodine reagents which do not cause
any such rearrangements.
3. Graziano, M. L.; Iesce, M. R.; Scarpati, R. J. Chem. Soc., Perkin Trans. 1 1982,
2007–2112; Gollnick, K.; Griesbeck, A. Tetrahedron 1985, 41, 2057–2068; Lee,
G. C. M.; Syage, E. T.; Harcourt, D. A.; Holmes, J. M.; Garst, M. E. J. Org. Chem.
1991, 56, 7007–7014.
10. For a review, see: Muzart, J. Synthesis 1993, 11–27; For a recent example, see:
Zhang, S.; Xu, L.; Trudell, M. L. Synthesis 2005, 1757–1760.
11. Corey, E. J.; Schmidt, G. Tetrahedron Lett. 1979, 20, 399–402.
12. Mancuso, A. J.; Huang, S.-J.; Swern, D. J. Org. Chem. 1978, 43, 2480–2482.
13. Griffith, W. P.; Ley, S. V. Aldrichim. Acta 1990, 23, 13–19; Ley, S. V.; Norman, J.;
Griffith, W. P.; Marsden, S. P. Synthesis 1994, 639–666.
14. Jefford, C. W.; Wang, Y. J. Chem. Soc., Chem. Commun. 1988, 634–635; Menger, F.
M.; Lee, C. J. Org. Chem. 1979, 44, 3446–3448.
15. Brougham, P.; Cooper, M. S.; Cummerson, D. A.; Heaney, H.; Thompson, N.
Synthesis 1987, 1015–1017.
4. Piancatelli, G.; Scettri, A.; Barbadoro, S. Tetrahedron Lett. 1976, 3555–3557;
Piancatelli, G.; Scettri, A. Tetrahedron Lett. 1977, 1131–1134; D’Auria, M.;
D’Onofrio, F.; Piancatelli, G.; Scettri, A. Gazz. Chim. Ital. 1986, 116, 173–175; For
the use of zinc chloride in place of a Brønsted acid, see: Csaky, A. G.; Mba, M.;
Plumet, J. Synlett 2003, 2092–2094.
16. Dominguez, C.; Csáky, A. G.; Plumet, J. Tetrahedron Lett. 1990, 31, 7669–7670.
17. Frigerio, M.; Santagostino, M.; Sputore, S.; Palmisano, G. J. Org. Chem. 1995, 60,
7272–7276; Frigerio, M.; Santagostino, M.; Sputore, S. J. Org. Chem. 1999, 64,
4537–4538; Frigerio, M.; Santagostino, M. Tetrahedron Lett. 1994, 35, 8019–
8022; De Munari, S.; Frigerio, M.; Santagostino, M. J. Org. Chem. 1996, 61, 9272–
9279; For recent reviews, see: Tohma, H.; Kita, Y. Adv. Synth. Catal. 2004, 346,
111–124; Wirth, T. Angew. Chem., Int. Ed. 2001, 40, 2812–2814; Wirth, T.
Angew. Chem., Int. Ed. 2005, 44, 3656–3665.
5. Tofi, M.; Koltsida, K.; Vassilikogiannakis, G. Org. Lett. 2009, 11, 313–316.
6. Hayes, S. J.; Knight, D. W. unpublished observations.
7. Bowden, K.; Heilbron, I. M.; Jones, E. R. H.; Weedon, B. C. L. J. Chem. Soc. 1946,
39–43; Bowers, A.; Halsall, T. G.; Jones, E. R. H.; Lemin, A. J. J. Chem. Soc. 1953,
2548–2551;
Chem.Rochester
[Information
Pages]
[Online]
http://
chem.chem.rochester.edu/~nvd/jonesreagent.html.
8. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–735; Baldwin, J. E.;
Cutting, J.; Dupont, W.; Kruse, L.; Silberman, L.; Thomas, R. C. J. Chem. Soc.,