Radical addition to substituted furans: Diels-Alder like products versus fragmentation reactions

Article abstract of DOI:10.1055/s-1998-1916

The intramolecular addition of alkenyl radicals to furans has been further investigated. The reaction can lead to Diels-Alder like adducts or products derived from a radical cyclisation / fragmentation / electrocyclisation cascade.

Full text of DOI:10.1055/s-1998-1916

November 1998
SYNLETT
1215
Radical Addition to Substituted Furans: Diels-Alder Like products Versus Fragmentation
Reactions
Aydin Demircan and Philip J. Parsons*
The Chemical Laboratories, CPES Arundel Building, University of Sussex, Falmer, Brighton, East Sussex, BN1 9QJ UK.
Fax +44-(0)1273-677196, E-mail: P.J.Parsons@sussex.ac.uk
Received 1 May 1998
Abstract: The intramolecular addition of alkenyl radicals to furans has
been further investigated. The reaction can lead to Diels-Alder like
adducts or products derived from a radical cyclisation / fragmentation /
electrocyclisation cascade.
Cascade reactions are now well established in the armoury of the
synthetic chemist and in our continued search for the ideal synthesis we
have recently developed methods for the construction of polycyclic
structures using palladium and radical cascade sequences.1 We now
report further on our findings on the addition of alkenyl radicals to
furans, in view of a recent publication by Pattenden et al.2 We
discovered that alkenyl radicals (2) add to furans and that the resulting
intermediate radicals (3) can fragment to give the cyclopentenes (4).3
(Scheme 1)
Reagents : i. n-BuLi, then 4-pentyn-1-al, THF, -78°C (62%). ii. DHP /
pTSA / THF, (82%). iii. n-BuLi, (CH2O)n, THF, -78°C, (90%). iv.
LiAlH4 / NaOMe then I2, THF, (70%). v. PhSSPh, Bu3P, THF, (89%).
Scheme 3
Metallation of (5) with n-butyllithium followed by the addition of 4-
pentynal gave the alcohol (6) in 62% isolated yield. Protection of (6) as
its dihydropyranyl ether followed by metallation with n-butyllithium
and reaction of the resulting anion with paraformaldehyde gave the
substituted propargylic alcohol (7) in 90% yield. Reduction of the
alcohol (7) with lithium aluminium hydride in the presence of sodium
methoxide gave an intermediate which upon quenching with iodine4 and
further reaction with diphenyl disulfide in the presence of tri-n-
butylphosphine gave the key iodofuran (8),5 (89%).
The iodofuran (8) was treated with tri-n-butyltin hydride in boiling
toluene in the presence of a catalytic amount of AIBN, resulting in a one
pot conversion of (8) into the aromatic ketone (9). (Scheme 4).
Scheme 1
If the TBSO group in (3) is replaced with PhS, a further reaction
sequence is possible which will allow construction of fused ring systems
in one synthetic operation. (Scheme 2)
Scheme 2
Reagents : i. Bu3SnH / AIBN / PhMe, Reflux, 21 hr, 51%.
In order to evaluate this exciting possibility we synthesised the radical
precursor (8). (Scheme 3)
Scheme 4
With this interesting result in hand, we investigated the use of a
heteroatom linker, in order to construct heterocyclic rings by
cyclisation/fragmentation sequences. (Scheme 5)

1216
LETTERS
SYNLETT
The Diels-Alder pathway appears to be favoured over fragmentation in
the ether series due possibly to the increased strain encountered in
forming dihydrofuran (10); the intermediate radical (15) is also highly
stabilised being both tertiary and β to two oxygen atoms.
Experimental Procedure
Scheme 5
Preparation of 1-tetrahydropyranyloxy-6-heptanoyl-2,3-dihydroindene
(9). To a refluxing solution of 2-[(1-tetrahydropyranyloxy-4-iodo-6-
thiophenyl)-4-hexenyl]-5-n-pentylfuran (8) (0.3 g, 0.52 mmol) and
AIBN (26 mg, 0.15 mmol) in toluene (43 ml) was added a solution of
tri-n-butyltin hydride (0.35 ml, 1.3 mmol) and AIBN (26 mg, 0.15
mmol) in toluene (19 ml) over a period of 18 hr. with the aid of syringe
pump. The reaction was heated at reflux for additional 3 hr, allowed to
cool and concentrated under reduced pressure. The resultant liquid was
diluted with ethyl acetate (30 ml) and potassium fluoride (1.35 g)
followed by water (1.25 ml) was added and the mixture was stirred for 3
hr. Potassium carbonate was then added to the mixture and the solids
filtered off. The resultant solution was concentrated in vacuo and the
residue chromatographed on silica (gradient elution petroleum ether
(40-60) then 5:1 petroleum ether (40-60) : diethyl ether, Rf: 0.29) to
afford the title compound in (0.083 g, 51%) as a mixture of inseparable
diastereoisomers.
In contrast to the reactions observed in the all carbon series, furyl ethers
were found to undergo Diels-Alder like reactions under radical
conditions. (Scheme 6)
ϑmax(cm-1): 2937, 2871, 1684, 1132.
δH(CDCl3, 300 MHz): 7.78 (d., J 7.29 Hz, 1H); 7.20 (m., 2H); 5.12 (m.,
1H); 4.83 (t., J 6.82 Hz, 1H); 3.94 (m., 2H); 3.42 (m., 2H); 2.88 (t., J
7.35 Hz, 2H); 2.32 (m., 2H); 2.12 (m., 2H); 1.80 & 1.35 (m., 6H); 1.28
& 1.11 (m., 4H); 0.78 (m., 3H) ppm.
δC(CDCl3, 75.5 MHz): 201.9, 151, 145.2, 137.3, 130, 126.8, 126.4,
100.2, 81.9, 64.3, 40.1, 35.9, 33, 31.8, 26.9, 25.6, 24.2, 23.9, 21.2, 15.4
ppm.
Scheme 6
The alkenyl bromides (11) were prepared using Williamson’s ether
synthesis6 and each ether (12) in turn was treated with tris-trimethylsilyl
silane in hot toluene containing a catalytic quantity of AIBN. Analysis
of the reaction products showed that (13) and (14) were formed but that
the dihydrofurans (10) were not present. (Table 1)
MS: 316, 260, 232, 215, 158, 129, 115, 85.
High resolution Mass Spectrum: calc. 316.2038; found 316.2023
Acknowledgements
We thank the University of Nigde for generous financial support for A.
D. and we thank Dr. Neil Edwards for his help with the manuscript.
References and notes:
(1) P. J. Parsons, C. S. Penkett, and A. J. Shell, Chem. Rev., 1996, 97,
195-206.
(2) P. Jones, W. S. Li, G. Pattenden and N. M. Thomson, Tetrahedron
Lett., 1997, 38, 9069.
When the reaction was conducted in the presence of tri-n-butyltin
hydride a multicomponent mixture was formed and only traces of (13)
and (14) were observed.
(3) P. J. Parsons, M. Penverne, I. L. Pinto, Synlett, 1994, 721
(4) E. J. Corey, J. A. Katzenellenbogen, J. Am. Chem. Soc., 1970, 21,
4245.
(5) J. A. Marshall and R. C. Andrews, J. Org. Chem., 1985, 50, 1602.
(6) B. A. Stoochnof, N. L. Benoiton, Tetrahedron Lett., 1973, 21.
Scheme 7