Radical-polar crossover reactions with a water-soluble tetrathiafulvalene derivative

Article abstract of DOI:10.1016/S0040-4039(99)02075-4

The water-soluble TTF reagent 7 undergoes the radical-polar crossover reaction in 1:1 acetone:water with a range of arenediazonium tetrafluoroborates and in water with diazonium chlorides. Purification of the reaction products is greatly facilitated by us

Full text of DOI:10.1016/S0040-4039(99)02075-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 421–424
Radical-polar crossover reactions with a water-soluble
tetrathiafulvalene derivative
Balaram Patro,a Martin C. Merrett,a Scott D. Makin,a John A. Murphy a,∗ and
Kevin E. B. Parkes b
aDepartment of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral St, Glasgow G1 1XL, UK
bRoche Discovery Welwyn, 40 Broadwater Road, Welwyn Garden City, Hertfordshire AL7 3AY, UK
Received 5 October 1999; accepted 2 November 1999
Abstract
The water-soluble TTF reagent 7 undergoes the radical-polar crossover reaction in 1:1 acetone:water with a
range of arenediazonium tetrafluoroborates and in water with diazonium chlorides. Purification of the reaction
products is greatly facilitated by using 7 compared with TTF. © 2000 Elsevier Science Ltd. All rights reserved.
The chemistry of free radicals has undergone a massive renaissance over the past thirty years. The real
burst in synthetic applications arose from the use of trialkyltin and triaryltin hydrides as radical-chain
carriers. However, the toxicity of the tin reagents, coupled with the difficulty in separation of their by-
products from the desired reaction products, meant that they were never acceptable to the pharmaceutical
industry. Although improved methods1 of separation and operation have been developed, there is still a
reluctance to use toxic tin reagents. This is unfortunate, since the properties of free radicals — e.g. lack
of solvation (useful in assembling congested quaternary carbons) and predictable kinetics regardless of
the reaction solvent (useful for predicting the relative speed of desired vs side-reactions) — give them a
unique advantage in certain synthetic manoeuvres.
The radical-polar crossover reaction2 shown below affords a means of conducting radical-based
carbon–carbon bond formation avoiding the use of toxic organotin derivatives. Here, tetrathiafulvalene
(TTF, 1) donates an electron to the diazonium group. Loss of dinitrogen affords an aryl radical which
cyclises, and the resulting radical couples with TTF+· to form a sulfonium salt, solvolysis of which
affords either an alcohol 2 or an amide 3. Hence this reaction affords a unique polar termination to the
radical chemistry, allowing novel functionalisation of the site of the ultimate radical. The applicability
of this chemistry to the synthesis of complex molecules is demonstrated in our recent synthesis of (±)-
aspidospermidine.3
The reaction has some key features making it worthy of attention. The tetrathiafulvalene reagent can be
used catalytically. Moreover, since diazonium salts are, in principle, water-soluble, and since the products
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02075-4
tetl 16003

422
of the reaction with water, alcohols, in general are not, use of a water-soluble version of tetrathiafulvalene
should permit isolation of the reaction product simply by extraction. This paper reports our initial results
with a water-soluble derivative of TTF.
At the start, the feasibility of the whole project was in doubt following the extensive and elegant
work4–6 performed over many years by the groups of Shine4,5 and Parker6 who had shown that sulfur
radical-cations derived from thianthrene 4 are readily trapped by water in a complex reaction which
affords thianthrene as well as its sulfoxide. If this process occurred rapidly with TTF+·, it could
completely inhibit the radical-polar crossover reaction. Whereas we had previously been successful
in carrying out such reactions in undried acetone, the concentrations of water involved under those
conditions are very small by comparison with carrying out the reaction in pure water or 1:1 acetone:water.
To carry out these studies, the sulfonate 7 was prepared (Scheme 1). It is important to note that although
alkylthio derivatives of TTF 5 abound in the literature, we could not use such a derivative, since they are
less powerful electron-donors than TTF and alkyl TTFs, and we have shown in unpublished preliminary
studies that alkylthio derivatives cannot trigger the radical-polar crossover reaction. Tetrathiafulvalene 1
was converted into the hydroxymethyl derivative 6 by the literature procedure.7 Reaction of the sodium
salt of this alcohol with 1,3-propanesultone afforded the sulfonate salt 7.
Scheme 1. Reagents and conditions. (a) LDA, PhNMeCHO; (b) NaBH4, EtOH; (c) NaH, 1,3-propane sultone
This was reacted firstly with diazonium tetrafluoroborate salt 8 in water as solvent. The reaction was
initially not very successful, since the tetrafluoroborate salt was sparingly soluble in water. However, we
were pleased to find that a change of reaction medium to 1:1 water:acetone afforded 57% of alcohol
10. At the end of the reaction, simple extraction into organic solvent and evaporation afforded 95%
pure products, which were further purified by column chromatography. The residual water-layer was
evaporated to leave a dark-coloured solid. Extraction with acetone afforded a solution containing no
significant organic compound. The residue consisted of the water-soluble reagent 7 in its radical-cation
form. (The NMR spectrum showed the signals of the side-chain, while the signals of the TTF nucleus are
too broad to observe).

423
A series of aromatic amines was then prepared and converted into the corresponding diazonium
tetrafluoroborates 9, 13, 16, 17 and 18 by reaction with nitrosonium tetrafluoroborate. The diazonium
salts were reacted directly with sulfonate 7 in 1:1 water:acetone to afford the alcohols 11 (37%), 14
(23%), 19 (21%) plus 20 (5%), 21 (35%) and 22 (20%). The quoted yields represent the conversions to
isolated product from the amine precursors.
Diazonium chlorides are much cheaper to prepare than diazonium tetrafluoroborates. They also have
the advantage of being more water-soluble, and so it should be possible both to prepare and react them
with 7 in water. The potential complication is that chloride could now compete as a nucleophile in the
final stage of the radical-polar crossover reaction. Salts 12, 15 and 23 were prepared and reacted in situ
in water with 7 and afforded 11 (32%), 14 (37%) and 22 (20%), respectively. No trace of the proposed
chloride products was detected.
Scheme 2. Reagents and conditions. (a) DEAD, PPh3, THF, rt; (b) NaBH4/Cu(acac)2/EtOH; (c) TBAF, THF, 12 h, rt; (d) (i)
NOBF4, CH2Cl2; (ii) 7, degassed acetone:water 1:1
Finally, the more complex amines 23 and 24 were prepared as shown in Scheme 2.8,9 These compounds
were converted into the corresponding diazonium tetrafluoroborates which successfully underwent rad-
ical cyclisation, radical-polar crossover and intramolecular termination in 1:1 acetone:water, demon-

424
strating that the water-soluble reagents can effect reaction with more complex substrates, providing that
solubility is not a problem.
In conclusion, the radical-polar crossover reaction has been effected for the first time with a water-
soluble derivative of tetrathiafulvalene, allowing very easy isolation of the organic products.
Acknowledgements
We thank the EPSRC for funding and EPSRC Mass Spectrometry Service, Swansea, for high resolu-
tion mass spectra and Roche Discovery Welwyn for a CASE award to S.D.M. We thank Professor Jan
Becher for samples of water-soluble alkylthio-TTF derivatives used in preliminary experiments.
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