Tributyltin hydride-mediated radical cyclisation of aldehydes and unsaturated ketones: The synthesis of hydroxy tetrahydrofurans, chromanols and related compounds

Article abstract of DOI:10.1016/S0040-4039(00)01586-0

The tributyltin hydride-mediated cyclisation of unsaturated ethers bearing an aldehyde or α,β-unsaturated ketone group is reported. Cyclisation proceeds via addition of the tributyltin radical to the carbonyl double bond and the resultant O-stannyl ketyl can add intramolecularly to electron-rich double bonds to form hydroxy tetrahydrofurans, chromanols or related compounds. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01586-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8941–8945
Tributyltin hydride-mediated radical cyclisation of aldehydes
and unsaturated ketones: the synthesis of hydroxy
tetrahydrofurans, chromanols and related compounds
David Bebbington,a,† Jon Bentley,a Paul A. Nilssonb and Andrew F. Parsonsb,*
aVernalis Research Ltd, Oakdene Court, 613 Reading Road, Winnersh, Wokingham RG41 5UA, UK
bDepartment of Chemistry, University of York, Heslington, York YO10 5DD, UK
Received 31 July 2000; revised 4 September 2000; accepted 14 September 2000
Abstract
The tributyltin hydride-mediated cyclisation of unsaturated ethers bearing an aldehyde or a,b-unsatu-
rated ketone group is reported. Cyclisation proceeds via addition of the tributyltin radical to the carbonyl
double bond and the resultant O-stannyl ketyl can add intramolecularly to electron-rich double bonds to
form hydroxy tetrahydrofurans, chromanols or related compounds. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: cyclisation; oxygen heterocycles; radicals and radical reactions; tin and compounds.
Radical cyclisation of unsaturated organohalides, or related compounds, using tributyltin
hydride has attracted considerable synthetic interest in recent years.1 A wide variety of five- and
six-membered rings, in particular, can be prepared under mild reaction conditions using this
method of cyclisation. However, one important drawback to these types of reactions is the loss
of two functional groups (e.g. CꢀX and CꢁC) on cyclisation of the halide precursor to the cyclic
product. In contrast, Enholm and co-workers have shown that O-stannyl ketyls, prepared from
reaction of tributyltin hydride with aldehydes, can undergo cyclisation to produce cyclopentanes
bearing a versatile hydroxyl group.2 Allylic O-stannyl ketyls were also shown to undergo related
cyclisations leading to cyclopentanes possessing a ketone group.3 In these reactions an activating
or electron-withdrawing group on the alkene double bond was found to be essential for
cyclisation. More recently, we have extended this method of cyclisation to the formation of
substituted pyrrolidines and piperidines.4 Both O-stannyl ketyls and allylic O-stannyl ketyls
were shown to undergo cyclisation, onto electron-rich or -poor alkenes, to produce five- or
* Corresponding author. Tel: +44-1904-432608; fax: +44-1904-432516; e-mail: afp2@york.ac.uk
† Present address: Vertex Pharmaceuticals (Europe) Ltd, 88 Milton Park, Abingdon, Oxfordshire OX14 4RY, UK.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01586-0

8942
six-membered nitrogen heterocycles. Having established that these types of (nucleophilic) radical
can undergo cyclisation on to electron-rich alkenes, we now report the application of this
method to the formation of saturated oxygen heterocycles for the first time.5
Initial work concentrated on the formation and cyclisation of aldehydes 1a–b (Scheme 1).
These were prepared by mono-alkylation of ethylene glycol using allylic bromides (in 61–82%
yield), followed by Swern oxidation of the resulting primary alcohols (in 67–73% yield). The
cyclisation of 1a–b was then investigated by reaction with tributyltin hydride. Thus, slow
addition of tributyltin hydride (1.1 equiv.) and AIBN (0.3 equiv.) over 1 h, to a solution of 1a–b
(1 equiv.) in boiling benzene produced the desired hydroxy tetrahydrofurans 3a–b in 59–64%
yield.6 The cyclic products were isolated as a 1:1 mixture of diastereomers (as indicated by the
NMR spectra), which were inseparable by column chromatography. These reactions are
expected to proceed via 5-exo-trig cyclisation of the intermediate O-stannyl ketyls 2a–b followed
by hydrogen-atom transfer from tributyltin hydride and hydrolysis of the tributyltin alkoxide on
aqueous workup. It is of interest to note that no alicyclic alcohols, derived from the reaction of
2a–b with tributyltin hydride, were isolated from these reactions. This method could also be
extended to the formation of tetrahydropyrans. Hence, reaction of aldehyde 1c with tributyltin
hydride (added over 1 h) produced the desired 6-ring product 3c in 44% yield. The lower yield
of 3c compared to 3a is presumably due to the slower rate of 6-exo-trig radical cyclisation and
the possibility of a competing 1,5-hydrogen atom transfer. Indeed, the reaction of 1c also
resulted in the isolation of cinnamyl alcohol (in 40% yield), which may have been formed via an
initial 1,5-hydrogen atom transfer.
Scheme 1.
The cyclisation of aromatic aldehydes was then investigated and reaction of benzaldehyde 4a,
under the same conditions as for 1a–c, produced chromanol 5a, as a 5.5:1 mixture of (separable)
trans-:cis-isomers,7 in an excellent 78% yield (Scheme 2). A similar diastereomer ratio was
observed when the tributyltin hydride was added to 4a over 5 h. This contrasts with the much
Scheme 2.

8943
lower yield of 44% for 3c. The introduction of a benzene ring, which is expected to lead to the
formation of a more stable O-stannyl ketyl, clearly has a pronounced effect on the efficiency of
the 6-exo-trig cyclisation. The substitution of the alkene also influences the cyclisation; when the
corresponding O-allyl derivative 4b was reacted under the same conditions the main product
was benzyl alcohol 6b, which was derived from simple reduction. Even when the tributyltin
hydride was added over 5 h (rather than 1 h), benzyl alcohol 6b was formed in 62% yield while
chromanol 5b was only isolated in 24% yield. Chromanol 5b was isolated as an inseparable 5:1
mixture of diastereomers, the major isomer of which was tentatively assigned (from the NMR
spectra) as the trans-isomer. Cyclisation of aromatic ketones, as well as aldehydes, is also
possible as illustrated by the reaction of acetophenone 4c. This underwent cyclisation to afford
chromanol 5c, as an inseparable (4.2:1) mixture of diastereoisomers, in an excellent 82% yield.
The stereochemistry of the major diastereomer was assigned as trans- on the basis of NOE
experiments.
The cyclisation of allylic O-stannyl ketyls was also investigated by treating a,b-unsaturated
ketones 7a–d, which were prepared from the corresponding aldehydes, and Ph3PꢁCHCOMe (in
59–76% overall yield for the alcohol oxidation and Wittig reaction steps), with tributyltin
hydride (Table 1). These 5-exo-trig cyclisations proceeded smoothly to give the expected
disubstituted tetrahydrofurans 8a–d in 50–82% yield. The trans-diastereomer of 8a–d was the
major product isolated from each of these reactions and the predominant formation of the
thermodynamically more stable isomer could be explained by a reversible radical cyclisation
mechanism.9
Table 1
Cyclisation of unsaturated ketones 7a–d to tetrahydrofurans 8a–d
8
R
R1
Yield (%)
D.ra
cis-:trans-
a
b
c
H
H
H
Me
H
50
80
63
82
1:3.1
1:3.7
1:9.0
1:1.8
Me
Me
Ph
d
a Assigned on the basis of the 13C NMR spectra.8
This method of cyclisation could also be applied to the synthesis of butyrolactone 10 (Scheme
3). Hence, reaction of unsaturated ketone 9 with tributyltin hydride resulted in the formation of
10 in 56% yield as a 3:1 mixture of (inseparable) trans-:cis-isomers, respectively.10 In contrast,
reaction of the related aldehyde 11 (under the same conditions) did not lead to any butyrolac-
tone formation. Cyclisations of similar unsaturated esters are known to be relatively slow (due
to conformer effects)11 and so the intermediacy of a more stable allylic O-stannyl ketyl
(compared to the O-stannyl ketyl) is crucial, presumably because this allows time for cyclisation
on to the unsaturated ester double bond. An allylic O-stannyl ketyl can also undergo 6-exo-trig

8944
cyclisation to form a substituted tetrahydropyran (Scheme 4). Hence, reaction of the unsatu-
rated ketone 12 with tributyltin hydride afforded tetrahydropyran 13 in 48% yield (as a 2:1
mixture of diastereomers).
Scheme 3.
Scheme 4.
This work has demonstrated that aldehydes or a,b-unsaturated ketones can undergo cyclisa-
tion to form substituted tetrahydrofurans, or related compounds, on reaction with tributyltin
hydride. The intermediate O-stannyl ketyls, which are nucleophilic, have been shown to cyclise
on to a variety of electron-rich double bonds to give a range of oxygen heterocycles. In addition,
the importance of using intermediate allylic or benzylic O-stannyl ketyls in slow (6-exo-trig or
unsaturated ester) radical cyclisation reactions is reported for the first time. Further studies
directed towards the application of this methodology in natural product synthesis are underway.
Acknowledgements
We thank Vernalis Research Ltd and the EPSRC for funding.
References
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8945
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