The role of neighbouring group participation in TTF-mediated 'radical- polar crossover' reactions: Trapping of aliphatic radicals by TTF+.

Article abstract of DOI:10.1039/b000786m

Trapping of secondary alkyl radicals with tetrathiafulvalenium tetrafluoroborate (TTF^+.BF₄^-) leads to S-alkyltetrathiafulvalenium tetrafluoroborate salts; the solvolysis of such salts is critically dependent on the presence of appropriately sited neighbouring groups.

Full text of DOI:10.1039/b000786m

The role of neighbouring group participation in TTF-mediated ‘radical-polar
crossover’ reactions: trapping of aliphatic radicals by TTF+·
Nadeem Bashir and John A. Murphy*
Department of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral Street, Glasgow, UK G1 1XL.
E-mail: John.Murphy@strath.ac.uk
Received (in Cambridge, UK) 26th January 2000, Accepted 18th February 2000
Trapping of secondary alkyl radicals with tetrathiafulvalen-
aromatic ring to assist the departure of the TTF molecule from
11 via a cyclopropane intermediate 12. However, the inability
of the ortho-alkoxy group to trigger the solvolysis of 5 shows
that there are strict demands for solvolysis at a primary carbon.5
However, almost all examples of the radical-polar crossover
reaction have involved substitution at secondary carbon. This
paper provides experimental evidence that neighbouring group
participation is mandatory for solvolysis at secondary carbon
under our usual conditions and reveals the requirements for
substrate structure in order for solvolysis to be observed.
To investigate whether solvolysis could occur at a secondary
carbon in the absence of neighbouring groups, an alkyl radical
free of other functionalities was required to be generated under
radical-polar crossover conditions. This was achieved using
intramolecular radical displacement at sulfur. This reaction has
been investigated by the groups of Kampmeier,6 Beckwith7 and
Schiesser.8 More recently, Crich et al. have used this method to
generate acyl radicals both from iodide9 and diazonium salt10
precursors. Accordingly, the cyclohexyl substrate 14 was
prepared (all amines were prepared by reduction of the
corresponding nitro compounds), diazotised and subjected to
the radical-polar crossover conditions (Scheme 2). This af-
forded benzothiophene 16 (48%), (arising from facile elimina-
tion of methanol from methoxydihydrobenzothiophene 17
together with the salt 18 (32%) as major products. The S-
coupled salt 18 was completely resistant to solvolysis under our
conditions (room temperature, 2% water in acetone, 48 h),
showing that a tetrathiafulvalenium salt linked via a secondary
carbon could not of itself undergo solvolysis under these
conditions.
+
ium tetrafluoroborate (TTF BF42) leads to S-alkylte-
·
trathiafulvalenium tetrafluoroborate salts; the solvolysis of
such salts is critically dependent on the presence of
appropriately sited neighbouring groups.
The radical-polar crossover reaction1 (Scheme 1) features a
unique sequence of radical and polar steps in one pot.
Tetrathiafulvalene (TTF) transfers an electron to an arenedia-
zonium salt, dinitrogen is lost and the resulting radical can then
cyclise before being trapped by the radical-cation of TTF to
afford a sulfonium salt and terminate the radical chemistry. In
the polar crossover step, solvolysis of the sulfonium salt occurs
affording a useful functionalisation at the site of the ultimate
radical. The reaction has recently been used as the key step in a
novel route to (±)-aspidospermidine.2
The substitution (solvolysis) step is of particular interest.
Whereas alcohols 8 and 9 were formed on treatment of
diazonium salts 2 and 3 with tetrathiafulvalene 4 in undried
acetone at room temperature, diazonium salt 1 proceeded only
up to the tetrathiafulvalenium salt stage 5. This strongly
suggested that the solvolysis step involved an SN1 substitution;
solvolysis of the salt 5 would not be possible since it would
require the intermediacy of a primary carbocation, while
sulfonium salts 6 and 7 undergo solvolysis without difficulty.
More recently, attempts to force the substitution of the
sulfonium group of 5 uncovered a range of novel fragmentation
reactions.3
Although 5 is resistant to solvolysis, the conversion4 of the
diallylamino diazonium salt 10 to the alcohol 13 suggested that
matters could be more complex. Here, the powerful electron
donating effect of the ortho-amino group must act through the
Because the outcome of the experiment on the cyclohexyl
radical differed from results found with all previously studied
secondary radicals, there was some concern that the sulfur
substitution reaction conditions might in some way have
prevented the normal radical-polar crossover process from
occurring. To test this, the intramolecular sulfur displacement
reaction was used to generate a radical which had been
previously studied under radical-polar conditions, namely 19,
the intermediate in the reaction of 2. The required substrate, 20,
was prepared, diazotised and subjected to the radical-polar
crossover reaction and afforded both dihydrobenzothiophene 21
Scheme 1
Scheme 2 Reagents: i, NOBF4, CH2Cl2; ii, TTF, acetone, H2O.
DOI: 10.1039/b000786m
Chem. Commun., 2000, 627–628
This journal is © The Royal Society of Chemistry 2000
627

Scheme 3 Reagents: i, NOBF4, CH2Cl2; ii, TTF, acetone, H2O.
(52%) and the alcohol 8 (58%), showing that the radical 19
generated under these conditions was behaving exactly as it had
in the reaction of 2.
The contrast between cyclohexyl TTF salt 18 and salt 6
indicated that a solvolysis of a secondary TTF salt could not
occur without some assistance from neighbouring groups. The
nature and extent of the assistance were now probed directly.
First, to investigate whether some special effect resulted from
the dihydrobenzofuran ring system, amine 22 was prepared and
diazotised to afford a diazonium salt analogue of 2 (Scheme 3).
This duly cyclised to form dihydrobenzothiophene 21 (52%)
and the alcohol 23 (53%). No TTF salts were detected after the
solvolysis.
Next, amine 24, lacking the electron-donating oxygen atom,
was prepared and diazotised affording 25. Surprisingly, the
compound also afforded an alcohol product, i.e. 26 (24%),
indicating that the oxygen atom is not essential for solvolysis.
In contrast, when the diazonium salt derived from 27 was
subjected to the radical-polar crossover reaction, 21 was
produced (45%) as well as the sulfur-coupled TTF salt 28
(21%). Intriguingly, this sulfur-coupled salt was stable to
solvolysis. We deduce that there is a sharp demarcation between
substrates that undergo solvolysis in acetone and those that do
not. Salt 25 features an ortho-dialkylarene and so should be
more electron-rich than the monosubstituted arene in 28; hence
it should more effectively promote neighbouring group partic-
ipation.
Scheme 4 Reagents: i, NOBF4, CH2Cl2; ii, TTF, acetone, H2O.
conditions which are totally aliphatic. Although we do not
advocate the intramolecular sulfur displacement reaction as a
synthetic route to aliphatic radicals, it allows us to determine the
properties of such systems. The development of more powerful
radical-polar crossover catalysts than TTF should lead to such
products starting from e.g. alkyl and aryl halides, thus extending
the scope of the reaction.
(ii) A TTF salt linked to a secondary carbon will undergo
solvolysis with a little assistance from the arene—the arene
needs to bear at least two alkyl functions to be sufficiently
electron-rich to trigger the solvolysis in acetone under our
conditions. This contrasts with the situation for primary carbon,
where more powerful assistance is required. (The requirement
for neighbouring group participation at a secondary carbon has
important implications for stereochemical control.)
(iii) Groups other than arenes can participate in the
solvolysis. This extends the scope of the radical-polar crossover
reaction.
The observation of neighbouring group assistance suggests
an answer to one of the key questions on the mechanism of these
reactions. Until now, solvolysis of TTF salts such as 29
(Scheme 4) was thought to involve intermediates such as the
open secondary cation 30. This cation should easily undergo
rearrangement and/or fragmentation (e.g. to products 33 and
34), but this was not observed. With neighbouring group
participation, the delocalised cation 31 can be proposed as the
true intermediate, and this involvement by the aryl ring can
decelerate rearrangements by stabilising the cation and altering
the orbital alignment from that required for rearrangement. (The
delocalised cation could also control the stereochemistry of
attack by the nucleophile water.)
The question now arose about whether groups other than an
aromatic ring could assist the solvolysis step. An immediate
answer was obtained from diazotisation of the silyl ether 35 and
subjection of the product diazonium salt to reaction with TTF
(Scheme 4). This afforded the perhydrobenzofuran 37 (23%
from amine 35) indicating that a side-chain oxygen can
participate. Dihydrobenzothiophene 21 (56% from amine 35)
was also isolated from this reaction.
Notes and references
1 J. A. Murphy, C. Lampard and N. Lewis, J. Chem. Soc., Chem.
Commun., 1993, 295.
2 O. Callaghan, C. Lampard, A. R. Kennedy and J. A. Murphy, J. Chem.
Soc., Perkin Trans 1, 1999, 995.
3 O. Callaghan, X. Franck and J. A. Murphy, Chem. Commun., 1997,
1923.
4 C. Lampard, J. A. Murphy, F. Rasheed, N. Lewis, M. B. Hursthouse and
D. E. Hibbs, Tetrahedron Lett., 1994, 35, 8675.
5 For a review of the extensive area of solvolysis of b-arylakyl substrates,
see: J. C. Lancelot, D. J. Cram and P. von R. Schleyer, Carbonium Ions,
ed. G. A. Olah and P. v. R. Schleyer, Wiley-Interscience, 1972, vol. 3,
pp. 1347–1483.
6 J. A. Kampmeier and T. R. Evans, J. Am. Chem. Soc., 1966, 88,
4096.
7 A. L. J. Beckwith and S. A. M. Duggan, J. Chem. Soc., Perkin Trans. 2,
1994, 1509.
8 B. A. Smart and C. H. Schiesser, J. Chem. Soc., Perkin Trans 2, 1994,
2269; C. H. Schiesser, M. L. Styles and L. M. Wild, J. Chem. Soc.,
Perkin Trans. 2, 1996, 2257.
9 D. Crich and Q. Yao, J. Org. Chem., 1996, 61, 3566.
10 D. Crich and X. L. Hao, J. Org. Chem., 1997, 62, 5982.
Summarising the findings: (i) for the first time, radicals have
been produced under TTF-induced radical-polar crossover
Communication b000786m
628
Chem. Commun., 2000, 627–628