A novel tin-free procedure for alkyl radical reactions

Article abstract of DOI:10.1002/anie.200454245

Desulfuration as a source of alkyl radicals: The addition of alkylsulfanyl radicals to isocyanides gives the corresponding alkyl radicals. This methodology can replace the usual tin-mediated radical procedures and allows for the generation of tertiary, secondary, and even nonstabilized primary radicals that can be used efficiently in reductive defunctionalizations and intermolecular additions to electron-rich olefins (see scheme).

Full text of DOI:10.1002/anie.200454245

Communications
for the synthesis of pharmaceuticals. It is therefore no surprise
that alternative ways of carrying out radical reactions are
under intensive investigation, in a search for both efficient
purification protocols (special workup procedures, modified
and polymer-bound tin reagents, etc.) and, above all, tin
substitutes.[2,3]
The great upsurge of alternative processes to tin-based
methodologies that has marked the last decade prompted us
to verify whether isocyanide-based radical chemistry, which
we have been studying for several years, could be also useful
for performing free-radical chain reactions under reductive
tin-free conditions.[4] Indeed, isocyanides are very efficient
radical traps and, by addition of sulfanyl radicals, they are a
valuable source of a-thioimidoyl radicals 1 (Scheme 1).[5]
Radical Reactions
A Novel Tin-Free Procedure for Alkyl Radical
Reactions**
Luisa Benati, Rino Leardini, Matteo Minozzi,*
Daniele Nanni,* Rosanna Scialpi, Piero Spagnolo,
Samantha Strazzari, and Giuseppe Zanardi
Scheme 1. Fragmentation paths of thioimidoyl radicals. InC=initiator.
Although N,S-dialkyl-substituted thioimidoyl radicals can in
À
À
Radical reactions have definitely become a very powerful tool
for synthetic organic chemists. Very useful defunctionaliza-
principle fragment by b-scission of either the C N or the C S
bond, giving thiocyanates and isothiocyanates, respectively,
we have demonstrated that usually only fragmentation of the
latter occurs.[6] This behavior is substantially independent of
the relative stability of the released radicals and even primary,
nonstabilized alkyl radicals can be smoothly generated at
relatively low temperatures from various N-substituted thio-
imidoyls (Scheme 1).
À
À
tions, formation of C C (or even C heteroatom) bonds, and
an assortment of intra- or intermolecular cascade processes
can be conducted, also with high stereoselectivity, under
extremely mild conditions, and many sensitive functional
groups are tolerated without any tedious protecting/depro-
tecting procedures.[1] This success owes much to tin reagents,
and over the last four decades radical chemistry in synthesis
has been literally monopolized by chain methods based on a
variety of organotin derivatives. So pervasive is the presence
of tin reagents in efficient radical syntheses that this
dominance has been referred to as the “tyranny of tin”.[2]
Unfortunately, tin-based chemistry is associated with two
critical drawbacks, that is, the toxicity of organotin com-
pounds and the problems very often encountered in product
purification. The quantitative removal of organotin residues
from the reaction products is usually a difficult task, and this
disadvantage, along with the high toxicity of those residues,
can severely limit the application of tin reagents, for example
As far as the precursors of thioimidoyl radicals are
concerned, isocyanides are easily accessible, stable deriva-
tives,[7] and some of them are also commercially available, for
example, tert-butyl isocyanide. Thiols as well are very handy
compounds that can be readily synthesized from haloalkanes,
alcohols, or their derivatives in manifold ways.[8] Recently,
treatment of halides, epoxides, or alcohols with polymer-
supported hydrosulfide under very mild conditions gave the
products in high yields and excellent chemoselectivity after a
very easy workup.[9] This novel methodology seems to have
made thiols much more easily accessible than ever.
À
In light of both the fast C S b-scission of thioimidoyl
radicals and the ready access to their precursors, we reasoned
that thioimidoyl fragmentations could provide a clean,
convenient entry to alkyl radicals from thiols. In this paper
we show that this procedure can be an efficient substitute for
other radical methods, mainly in defunctionalization reac-
tions and intermolecular addition to olefins.
Trial experiments were initially performed with alkane-
thiols and various isocyanides to test the efficiency of the
simple desulfuration reaction. The tests were carried out by
adding a 0.1m solution of the thiol in benzene (10 mL) over
one hour to a solution of isocyanide (1.1 equiv) in benzene
(10 mL) heated at reflux and with azobisisobutyronitrile
(AIBN, 0.1 equiv) as an initiator. Under these conditions the
alkyl radical generated by fragmentation of the intermediate
thioimidoyl radical is smoothly reduced by the starting thiol
[*] Prof. L. Benati, Prof. R. Leardini, Dr. M. Minozzi, Prof. D. Nanni,
Dr. R. Scialpi, Prof. P. Spagnolo, Dr. S. Strazzari, Prof. G. Zanardi
Dipartimento di Chimica Organica “A. Mangini”
Università di Bologna
Viale Risorgimento 4, 40136 Bologna (Italy)
Fax: (+39)051-209-3654
E-mail: minus@ms.fci.unibo.it
nanni@ms.fci.unibo.it
[**] The authors gratefully acknowledge financial support from MIUR,
Rome (2002–2003 Funds for “Radical Processes in Chemistry and
Biology: Fundamental Aspects and Applications in Environment
and Material Science”), and the University of Bologna (2001–2003
Funds for Selected Research Topics).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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DOI: 10.1002/anie.200454245
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Chemie
giving the corresponding alkane in nearly quantitative yield
(Scheme 2). The reactions can be also conducted in toluene
solution at 808C and even at room temperature, when AIBN
is replaced with triethylborane.[10] The reaction outcome was
Scheme 2. Defunctionalization of thiols with isocyanides.
Scheme 3. Defunctionalization of thiol-sugars (Barton–McCombie-type
reaction).
influenced neither by the thiol alkyl chain—tertiary, secon-
dary, and even nonstabilized primary thiols were all desulf-
urated quantitatively—nor by the nature of the isocyanide—
both aromatic and aliphatic isocyanides were used without
any lowering of the reaction efficiency.
product even at room temperature. The ease of workup (see
above) allows for isolation of the final sugar in very high
purity without any other purification procedure (for proof of
the purity of the crude product, see the 1H NMR spectrum of
3 in the Supporting Information). It is worth noting that, in
the case of 4, the corresponding anomeric radical is easily
produced and reduced without the 1,2-shift of the acetoxy
group that is usually observed in tin-based defunctionaliza-
tion procedures.[18]
The latter point has two important consequences as far as
accessibility of starting materials and workup are concerned.
First, the experiments can be carried out with commercially
available tert-butyl isocyanide without any need to synthesize
suitable congeners. Second, the low boiling points of both the
starting isocyanide and its by-product tert-butyl isothiocya-
nate (918C and 1408C at 760 torr, respectively) allow for an
extremely straightforward workup procedure: concentration
of the final reaction mixture under reduced pressure results in
concomitant elimination of solvent, by-product, and excess
starting isocyanide, and the final desulfurated product can be
recovered quantitatively in very high purity simply after
rotary evaporation.[11] In light of all of these features, we think
that this method can therefore be regarded as a very mild,
efficient defunctionalization of thiols and, consequently, their
precursors, that is, halides and alcohols.
The subsequent, logical step was to extend this procedure
to Barton–McCombie-type reactions. Deoxygenation reac-
tions are of huge importance in organic synthesis, and the
Barton–McCombie reaction developed in the 1970s is a major
milestone in the application of radical reactions in syn-
thesis.[12] Although a few catalytic or tin-free deoxygenations
have already been reported,[13] the Barton–McCombie realm
is still strongly dominated by tin reagents. Taking into account
that thiols, like xanthates, thiocarbonyl imidazolides, and
dithiocarbonates, can be synthesized directly from alco-
hols,[9c,d,14,15] we reasoned that our isocyanide-mediated rad-
ical desulfuration of thiols could be a valid alternative to
traditional Barton–McCombie procedures.
The reaction was examined on thiol-sugars 2 and 4
(Scheme 3). Under the usual conditions, at 808C, both
compounds gave nearly quantitative yields of the correspond-
ing desulfurated sugars 3 and 5.[16] At room temperature, the
reactions required longer times and greater amounts of
initiator (BEt3, 5 equiv) to reach completion—probably due
to the presence of the oxygen atoms on the substrates—but
afforded again very good yields of 3 and 5. The result with
substrate 2 is particularly noteworthy, since Barton–McCom-
bie reactions are known to proceed quite ineffectively when
primary radicals are involved.[12c,17] Our reaction proceeds
instead very smoothly and without any significant side
In tin-based radical chemistry, the defunctionalization
reactions are very often combined with intra- or intermolec-
À
ular C C bond-forming processes, in which the initial alkyl
radical is trapped, for instance, by an alkene prior to hydrogen
abstraction: this is undoubtedly one of the major break-
throughs of radical reactions in organic synthesis. Our
isocyanide-based method does not seem suitable for Giese-
type reductive additions of nucleophilic alkyl radicals to
activated olefins. Indeed, hydrogen transfer from the thiol to
the alkyl radical is much faster than its addition to the olefin,
and the yields of adduct products are always very low, even in
the presence of a large excess of alkene and very low
concentrations of thiol. On the contrary, due to polar effects
in the hydrogen-abstraction reaction,[19] electrophilic alkyl
radicals are not easily trapped by the thiol, and they can be
smoothly generated in the presence of nucleophilic olefins to
give the corresponding adducts in good to almost quantitative
yields. Scheme 4 and Table 1 show the results obtained at
808C with our standard method with four alkenes (6A–D,
10 equiv) and three different thiols (7a–c, 1 equiv). Evapo-
ration of the final reaction mixtures removes simultaneously
solvent, excess isocyanide, by-product isothiocyanate, and
excess olefin giving the pure adducts 8. Chromatography is
sometimes needed to further purify compounds 8 and remove
trace amounts of side products.[20]
Scheme 4. Intermolecular addition of electrophilic alkyl radicals to ole-
fins.
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Table 1: Yields of the adducts 8 obtained by the reaction of alkenes 6A–D
with thiols 7a–c and tert-butyl isocyanide in benzene or toluene at 808C.
Entry
Alkene
Thiol
Adduct
Yield [%][a]
1
2
3
4
5
6
7
8
6A
6A
6A
6B
6B
6B
6C
6C
6C
6D
6D
6D
7a
7b
7c
7a
7b
7c
7a
7b
7c
7a
7b
7c
8Aa
8Ab
8Ac
8Ba
8Bb
8Bc[b]
8Ca
8Cb
8Cc
8Da
8Db
8Dc
66 (75)
82 (91)
75 (85)
67 (74)
75 (81)
79 (85)
– (95)[c]
– (83)[c]
– (92)[c]
55 (64)
81 (92)
– (70)[c]
Scheme 6. Radical cyclization of thiol 14 with 4-chlorophenyl isocya-
nide at 1108C.
À
In summary, we have shown that C S b-scission of
thioimidoyl radicals is a very effective route for the gen-
eration of alkyl radicals that can be employed in reductive
defunctionalizations and intermolecular additions to elec-
tron-rich olefins. Owing to the accessibility of the starting
materials, the efficient production of any kind of alkyl radical
even at relatively low temperatures, and extreme ease of
workup and product purification, this procedure can be an
appealing substitute for many stannane/silane-mediated rad-
ical reactions. Studies are underway to find alternative ways
of generation of thioimidoyl radicals not involving the thiol/
isocyanide pair, with the aim of extending the method to other
reactions that could suffer from the presence of a too efficient
hydrogen-transfer reagent.
9
10
11
12
[a] Yields are for pure products isolated by column chromatography;
yields in parentheses were determined by 1H NMR analysis of the crude
mixtures. [b] This compound is an important intermediate for the
synthesis of crop protection agents; see Supporting Information,
ref. [20]. [c] Partial or total decomposition of product was observed by
column chromatography.
The mechanism of the efficient radical chain reaction
involved in this transformation is presented in Scheme 5.
Sulfanyl radical 9, smoothly generated from thiol 7 by AIBN
initiation, adds to isocyanide 10 to give the alkyl radical 12 by
fast b-fragmentation of the thioimidoyl radical 11. The
Received: March 12, 2004 [Z54245]
Keywords: fragmentations · isocyanides · radical reactions ·
.
synthetic methods · thiols
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Scheme 5. Radical chain reaction of alkenes 6, thiols 7, and tert-butyl
isocyanide.
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new chain-propagating species 9.
A preliminary experiment also showed that even intra-
À
molecular C C bond formation can occur, although under
slightly different conditions. Treatment of thiol 14 with 4-
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cyclization product 15 in 80% yield after column chromatog-
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[17] Sugar 5 has been obtained by Barton–McCombie-type proce-
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[20] A common side product is the adduct of the thiol onto the
alkene; however, this was produced in no more than trace
amounts. Reduction of thioimidoyl radical to yield a thioimidate
was observed only at very low temperatures, for example, below
À408C (see: C. M. Camaggi, R. Leardini, D. Nanni, G. Zanardi,
Tetrahedron 1998, 54, 5587 – 5598).
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