Oxidation products of 2-acyl-4,5-dihydrofurans

Article abstract of DOI:10.1016/j.tetlet.2006.06.122

2-Benzoyl-4,5-dihydrofuran (5) readily undergoes oxidation in air, during chromatography on silica, or following exposure to oxidising agents (MCPBA, DMDO), to give 2-benzoylbutyrolactone (6) and tricycle 7 as the major products.

Full text of DOI:10.1016/j.tetlet.2006.06.122

Tetrahedron Letters 47 (2006) 6285–6287
Oxidation products of 2-acyl-4,5-dihydrofurans
Jeremy Robertson,a,* Andrew J. Tyrrella and Sarah Skerrattb
aDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory, Mansfield Road, Oxford OX1 3TA, UK
bPfizer Global Research and Development, Ramsgate Road, Sandwich CT13 9NJ, UK
Received 8 June 2006; accepted 22 June 2006
Available online 17 July 2006
Abstract—2-Benzoyl-4,5-dihydrofuran (5) readily undergoes oxidation in air, during chromatography on silica, or following expo-
sure to oxidising agents (MCPBA, DMDO), to give 2-benzoylbutyrolactone (6) and tricycle 7 as the major products.
Ó 2006 Elsevier Ltd. All rights reserved.
As part of a project to develop enantiospecific routes to
pyrrolizidine alkaloids, we had occasion to study the
Stille cross-coupling of 2-(tributylstannyl)dihydrofuran
11 and the aspartate-derived acid chloride 2.2 Under
the standard conditions,3 this reaction proceeded
smoothly to give 2-acyldihydrofuran 3 in admixture
with Bu3SnCl (Scheme 1). We noticed decomposition
and a low mass recovery following attempted chromato-
graphic purification and therefore assayed some of the
well-known procedures for removal of tin residues from
reaction mixtures: (1) partitioning between petrol and
acetonitrile4 gave only a partial separation; (2) stirring
a petrol/ethyl acetate solution with NaOH and filtration
through silica 5 gave no recovery of coupled product; (3)
stirring with aq KF and filtration6 to remove precipi-
tated polymeric Bu3SnF resulted in an inseparable
mixture of products; (4) column chromatography on
KF-impregnated silica7 succeeded in producing tin-free
product but only in trace quantities.
In an attempt to identify reliable conditions for producing
this type of compound in a pure form, free of tin residues,
we focused on the synthesis and purification of a simple
model (5, Scheme 2) rather than waste further acid
O
O
Cl
1% Pd(PPh3)2Cl2,
O
O
O
+
SnBu3
HN
HN
O
O
O
PhH, 80 °C, 3 h
CF3
CF3
CF3
CF3
2
3
1
Scheme 1.
H
H
from 1: PhCOCl
(as Scheme 1)
O
see text
Ph
O
+
O
O
M
O
O
O
from 4:
PhCO.NMe2, THF,
–78 °C, 10 h; 87%
O
O
O
Ph
O
Ph Ph
1, M = SnBu3
4, M = Li
5
6
(
ca.
4
:
3)
7
Scheme 2.
Keywords: Dihydrofuran; Dihydropyran; Oxidation; Rearrangement; Lactones.
*
Corresponding author. Tel.: +44 0 1865 275660; fax: +44 0 1865 285002; e-mail: jeremy.robertson@chem.ox.ac.uk
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.06.122

6286
J. Robertson et al. / Tetrahedron Letters 47 (2006) 6285–6287
chloride 2. The choice of benzoyl as the acyl substituent
was based on the expectation that this would impart
non-volatility to the sample. Interestingly, benzoyl-
dihydrofuran 5, prepared analogously to compound 3,
was found to be converted, either during chromatogra-
phy, or on stirring with silica in ethyl acetate for 7 h, into
two major products, 6 and 7 (83% combined yield), in
addition to a very minor component that has so far not
been isolated and identified. Whilst butyrolactone 68
was readily identified following routine spectroscopic
analysis (e.g., mmax/cmꢀ1 1769s, 1682s), the identity of
the tricyclic bisacetal 7 was less obvious; fortunately,
the compound crystallised out of ethyl acetate and the
structure was solved by X-ray crystallography (Fig. 1).9
separate study,11 we had prepared 2-formyl-4,5-
dihydrofuran12 without complication. Therefore, in
order to confirm that this reactivity was not an artefact
induced by residual reagents from the cross-coupling
reaction, substrate 5 was prepared directly from 2-lithio-
dihydrofuran according to Meyers’ method.13 Once
more, the product was initially obtained reasonably
cleanly but was found to evolve into the two major
products 6 and 7 as before.
Clearly, these results reflect an inherent propensity for
2-benzoyldihydrofuran (5) to undergo aerial oxidation.
The same behaviour could be induced deliberately by
exposing dihydrofuran 5 to either MCPBA (CH2Cl2,
0 ! 20 °C, 1 h) or DMDO (acetone, 0 ! 20 °C, 1 h).
On this basis, it is reasonable to propose that the enol
ether double bond is epoxidised14 (!8, Scheme 3), that
the epoxide then has a tendency to ring-open (!9 or a
protonated analogue) to place a partial positive charge
remote from the acyl group, and that benzoyl group
migration15 completes the formation of butyrolactone
6 in a formal dyotropic rearrangement16 (i.e., 8!6). In
this scenario, tricycle 7 would arise by the trapping of
polarised intermediate 9 by the starting dihydrofuran (5).
A survey of the literature revealed no suggestions of a
particular instability of 2-acyldihydrofurans10 and, in a
2-Acetyldihydrofuran17 also proved to be unstable
towards chromatography on silica, and 2-acetylbutyro-
lactone was observed in the product mixture; however,
this compound showed a reduced tendency towards
air-oxidation and chromatography using deactivated
silica (triethylamine) was sufficient to obtain pure prod-
uct. 2-Benzoyl-4,5-dihydro-6H-pyran (10)13 showed no
tendency to undergo such oxidation and rearrangement;
treatment of the latter with DMDO resulted in diol 11
after chromatography (Scheme 4).
In summary, 2-benzoyldihydrofuran (5) exhibits a previ-
ously unrecognised proclivity towards oxidation to give
δ+
O
δ–
O
[1,2]
O
O
6
O
O
Ph
Ph
8
9
5
H
Bz
+
O
H
7
–
O
Bz
O
Scheme 3.
OH
DMDO, acetone,
O
OH
O
O
O
0 → 20 °C, 18 h
72%
Ph
Ph
11
Figure 1. (Upper): ORTEP view of tricycle 7; (lower): rotated view
highlighting the step-like ring system (phenyl groups omitted for
clarity).9
10
Scheme 4.

J. Robertson et al. / Tetrahedron Letters 47 (2006) 6285–6287
6287
609602. Copies of the data can be obtained, free of
charge, on application to CCDC, 12 Union Road,
Cambridge CB2 1EZ [fax: +44 (0)1223 336033 or e-mail:
deposit@ccdc.cam.ac.uk].
rearranged and dimeric products (6 and 7, respectively).
Although we have not yet studied other 2-aroyl-
dihydrofurans we expect that a similar reactivity pattern
will be observed. This reactivity does not extend to the
dihydropyran analogue 10 nor to the simple 2-alka-
noyldihydrofurans, such as 2-formyl- and 2-acetyl-
dihydrofuran, which show merely the expected
instability towards acidic conditions.
10. Simple dihydrofurans bearing 2-aroyl substituents are
relatively poorly represented in the literature; Satoh, T.;
Itaya, T.; Okuro, K.; Miura, M.; Nomura, M. J. Org.
Chem. 1995, 60, 7267–7271, see also Ref. 13.
11. Withey, J. M. Part II Thesis, University of Oxford, 2000.
12. Paquette, L. A.; Schulze, M. M.; Bolin, D. G. J. Org.
Chem. 1994, 59, 2043–2051.
13. Shimano, M.; Meyers, A. I. Tetrahedron Lett. 1994, 35,
7727–7730.
14. The reaction may proceed by initial SET to give O2 and
Acknowledgements
Åꢀ
We thank the EPSRC and Pfizer Global Research and
Development for a studentship (for A.J.T.), and Dr.
A. R. Cowley for assistance with the X-ray analysis of
tricycle 7.
12; coupling and dioxetane formation may ensue with this
intermediate (13) potentially acting as an oxidising agent
for more of the enol ether (5). In this scenario, the HOMO
energy will be important and this is expected to be
responsive to the nature of the ketone substituent (aryl or
alkyl).
References and notes
O O
.
–
1. This compound was prepared by stannylation of
dihydrofuryllithium. (a) Boeckman, R. K., Jr.; Bruza, K.
J. Tetrahedron 1981, 37, 3997–4006; (b) Soderquist, J. A.;
Hsu, G. J.-H. Organometallics 1982, 1, 830–833.
2. (a) Burger, K.; Rudolph, M. Chem. Zeitung 1990, 114,
249–251; (b) Burger, K.; Gold, M.; Neuhauser, H.;
Rudolph, M. Chem. Zeitung 1991, 115, 77–82.
O2
O
O
O
O
Ph
Ph
12
O
O
5
O
O
3. (a) Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1978, 100,
2 ×
O
O
´
3636–3638; (b) Blanchot, V.; Fetizon, M.; Hanna, I.
O
Ph
Synthesis 1990, 755–756; cf. (c) Golubev, A. S.; Sewald,
N.; Burger, K. Tetrahedron 1996, 52, 14757–14776.
4. Berge, J. M.; Roberts, S. M. Synthesis 1979, 471–472.
5. Renaud, P.; Lacoˆte, E.; Quaranta, L. Tetrahedron Lett.
1998, 39, 2123–2126.
6. Leibner, J. E.; Jacobus, J. J. Org. Chem. 1979, 44, 449–
450, see also Ref. 3a.
7. Harrowven, D. C.; Guy, I. L. Chem. Commun. 2004, 1968–
1969.
Ph
13
8
Alkene oxidation by dioxetanes: (a) Adam, W.; Andler, S.;
Heil, M. Angew. Chem., Int. Ed. Engl. 1991, 30, 1365–
1366; (b) Adam, W.; Blancafort, L. J. Org. Chem. 1996,
61, 8432–8438; For a recent report of unexpected epox-
idation by molecular oxygen, and a presentation of the
mechanism in terms of a diradical pathway, see Eade, S. J.;
Adlington, R. M.; Cowley, A. R.; Walter, M. W.;
Baldwin, J. E. Org. Lett. 2005, 7, 3705–3707.
8. See, for example, Jedlinski, Z.; Kowalczuk, M.; Kurcok,
P.; Grzegorzek, M.; Ermel, J. J. Org. Chem. 1987, 52,
4601–4602.
9. Crystal data for 7: C22H20O5, M = 364.40, colourless
15. For early precedent for this type of process, under Lewis
acidic conditions, see, for example, (a) Allen, C. F. H.;
Gates, J. W., Jr. J. Am. Chem. Soc. 1943, 65, 1230–1235;
(b) House, H. O. J. Am. Chem. Soc. 1954, 76, 1235–1237.
16. Reetz, M. T. Angew. Chem., Int. Ed. Engl. 1972, 11, 129–
130, and 130–131.
fragment, monoclinic, a = 10.6044(2), b = 11.9077(2),
3
˚
˚
c = 14.7870 (3) A, V = 1807.82(6) A , T = 150 K, space
group P21/n, Z = 4, l(Mo Ka) = 0.095 mmꢀ1, 19,769
reflections measured, 4330 unique (Rint = 0.043), final
wR = 0.0377. Crystallographic data for this structure have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication number CCDC
17. Prepared using Meyers’ method [Ref. 13] with N,N-
dimethylacetamide (59% yield).