Tin-free generation of alkyl radicals from alkyl 4-pentynyl sulfides via homolytic substitution at the sulfur atom

Article abstract of DOI:10.1021/ol800046k

Homolytic substitution at the sulfur atom of β-(phenylsulfanyl)vinyl radicals, obtained by radical reaction of benzenethiol with easily accessible alkyl 4-pentynyl sulfides, is a mild, effective, tin-free route for the generation of all types of alkyl radicals. This protocol can be employed in reductive defunctionalizations as well as cyclizations onto both electron-rich and electron-poor C-C double bonds.

Full text of DOI:10.1021/ol800046k

ORGANIC
LETTERS
2008
Vol. 10, No. 6
1127-1130
Tin-Free Generation of Alkyl Radicals
from Alkyl 4-Pentynyl Sulfides via
Homolytic Substitution at the Sulfur
Atom†
Giorgio Bencivenni, Tommaso Lanza, Rino Leardini, Matteo Minozzi,*
Daniele Nanni,* Piero Spagnolo,* and Giuseppe Zanardi
Dipartimento di Chimica Organica “A. Mangini”, UniVersita` di Bologna,
Viale Risorgimento 4, I-40136 Bologna, Italy
minus@ms.fci.unibo.it; nanni@ms.fci.unibo.it; spagnolo@ms.fci.unibo.it
Received January 9, 2008
ABSTRACT
Homolytic substitution at the sulfur atom of
alkyl 4-pentynyl sulfides, is a mild, effective, tin-free route for the generation of all types of alkyl radicals. This protocol can be employed in
reductive defunctionalizations as well as cyclizations onto both electron-rich and electron-poor C C double bonds.
â-(phenylsulfanyl)vinyl radicals, obtained by radical reaction of benzenethiol with easily accessible
−
In recent papers1a,b we have shown that the radical reaction
of benzenethiol with S-4-pentynylthiol esters provides a
valuable method for the generation of acyl radicals, which
arise from intramolecular homolytic substitution at the sulfur
atom by initial â-sulfanylvinyl radicals. The protocol was
employed both for the synthesis of cyclic compounds, by
cyclization of suitable acyl radicals,1a and as a new synthetic
method for the radical reduction of carboxylic acids to
aromatic and aliphatic aldehydes under stannane/silane-free
conditions.1b By adopting an analogous procedure, N-benzyl-
and N-tosyl-substituted pentynyl carbamothioates were simi-
larly found to release corresponding carbamoyl radicals in
an efficient fashion.2 N-Benzylcarbamoyl radicals gave
pyrrolidinones/indolones through 5-exo cyclization onto
internal alkenyl groups, whereas the N-tosylcarbamoyl
counterparts displayed a peculiar tendency to yield iso-
cyanates by â-elimination of tosyl radical. Recently, our
method has been suitably adopted by Malacria to achieve a
novel, effective generation of P-centered radicals from
S-pentynyl thiophosphonates.3
Herein, we report that our original protocol can be
interestingly extended even to the tin-free generation of
unstabilized alkyl radicals via analogous homolytic substitu-
tion at the sulfur atom of alkyl 4-pentynyl sulfides. The
intramolecular homolytic substitution of alkyl sulfides as a
route to alkyl radicals is actually a long known process that
has found considerable theoretical and synthetic attention.
Recent studies have shown the precious utility of alkyl
sulfides for generation of alkyl radicals, especially when other
common radical precursors such as alkyl halides are in-
adequate. However, in the reported instances, not only were
difficult to access alkyl haloaryl sulfides invariably employed,
but additionally, those radical precursors were often undesir-
ably reacted with toxic or rather expensive stannane/silane
† This paper is dedicated to Prof. Luisa Benati on the occasion of her
retirement.
(1) (a) Benati, L.; Calestani, G.; Leardini, R.; Minozzi, M.; Nanni, D.;
Spagnolo, P.; Strazzari, S. Org. Lett. 2003, 5, 1313. (b) Benati, L.; Leardini,
R.; Minozzi, M.; Nanni, D.; Scialpi, R.; Spagnolo, P.; Zanardi, G. Synlett
2004, 987. For a nice review on homolytic substitution at the sulfur atom
as a tool for organic synthesis, see: (c) Crich, D. HelV. Chim. Acta 2006,
89, 2167. For comprehensive reviews on tin-free methodologies, see: (d)
Baguley, P. A.; Walton, J. C. Angew. Chem., Int. Ed. 1998, 37, 3072. (e)
Studer, A.; Amrein, S. Synthesis 2002, 835.
(2) Benati, L.; Bencivenni, G.; Leardini, R.; Minozzi, M.; Nanni, D.;
Scialpi, R.; Spagnolo, P.; Zanardi, G. J. Org. Chem. 2006, 71, 3192.
(3) Carta, P.; Puljic, N.; Robert, C.; Dhimane, A.-L.; Fensterbank, L.;
Lacoˆte, E.; Malacria, M. Org. Lett. 2007, 9, 1061.
10.1021/ol800046k CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/16/2008

reagents.1c,4 On the contrary, our procedure employs very
easily accessible alkyl 4-pentynyl sulfides and thiophenol,
which is rather inexpensive, definitely much less toxic than
stannanes, and practically inert toward most functional
groups.
The synthesis of the starting sulfides 1 can be smoothly
accomplished in a very straightforward, convenient way by
reacting either 5-chloro-1-pentyne with aliphatic thiols or
4-pentyne-1-thiol with alkyl chlorides, bromides, iodides, or
tosylates (Scheme 1).5
Table 1. Synthesis of Sulfides 1a-i
entry
R
method
yield (%)
a
b
c
d
e
f
nC12H25
PhCH2CH(Me)
1-adamantyl
4-MeO-C6H4-CH2
Ph(CH2)3O(CO)CH2
Ph(CH2)3
a, b
a, b
b
a, b
b
a
a, b
b
95, 98
93, 98
95
95, 95
78
96
90, 85
80
g
h
i
(allyl)2N(CO)CH2
PhCHdCHCH2O(CO)CH2
Ph(CH2)3O(CO)CHdCH(CH2)4
a
52
Scheme 1 a
radical 2, which gives rise to homolytic substitution at the
sulfur atom to afford the desired alkyl radical together with
thiophene derivatives 39 (Scheme 2). Hydrogen transfer from
a X ) Cl, Br, I, OTs.
Scheme 2
5-Chloro-1-pentyne is a cheap, commercially available
compound that is also a suitable starting material for the
synthesis of 4-pentyne-1-thiol. This was indeed obtained in
just two steps by reaction of 5-chloro-1-pentyne with
potassium thiolacetate in acetone, followed by treatment with
sodium methoxide in methanol.6 However, there is no need
to isolate the rather unstable thiol, since the desired alkyl
sulfides can be directly obtained in good to excellent yields
by treating S-(4-pentynyl) thiolacetate with either lithium
hydroxide in methanol or potassium hydroxide in aqueous
DMSO in the presence of the alkylating reagent.7 The former
conditions are appropriate only for primary alkyl groups,
whereas the latter can be used for both primary and secondary
alkyls (both stabilized and unstabilized). Tertiary alkyl
sulfides can be readily obtained from the corresponding thiols
and 5-chloro-1-pentyne. The prepared sulfides are reported
in Table 1 together with their synthetic methods (see Scheme
1) and yields (yields for compounds 1e,g-i are for the whole
multistep syntheses; see Supporting Information).
benzenethiol to the alkyl radical (or intermediates thereof,
see below) yields alkane 4 and a new benzenesulfanyl radical
that sustains the radical chain reaction. Under these optimized
conditions byproducts such as diphenyl disulfide and, above
all, vinyl sulfide 5, arising from competing hydrogen transfer
to vinyl radical 2, were formed in trace amounts only.10
Sulfides 1a-f, when treated under the standard conditions
described above and after column chromatography, afforded
practically quantitative yields of the corresponding alkanes
4a-f (Scheme 3). As one can see, the reaction outcome is
The optmized reaction conditions for generation of alkyl
radicals from sulfides 1 entail syringe pump addition (2-4
h) of a degassed toluene (13 mL) solution of PhSH (1.1
equiv) and ACCN8 (0.25 equiv) to a boiling toluene (13 mL)
solution of 1 (1 mmol) kept under a nitrogen atmosphere,
followed by additional 1 h of reflux.
(9) Mixtures of E- and Z-isomers. Under certain conditions and with
some substrates an isomeric form of 3 was also isolated; studies are
underway to determine its structure.
The reaction mechanism involves addition of benzene-
sulfanyl radical to the triple bond of sulfide 1 to give vinyl
(10) Very satisfactory results can be obtained also at 80 °C with AIBN
as a radical initiatior, but only with stabilized radicals (e.g. 1e). With other
unstabilized R groups significant amounts of vinyl sulfides 5 were always
obtained. Other solvents such as alcohols, acetonitrile, THF, or fluoroben-
zene gave much poorer results. Unsatisfactory outcomes were also achieved
with other thiols that, on a theoretical basis, would possess less powerful
hydrogen-donor properties. Indeed, treatment of sulfide 1a with tert-
dodecanethiol and methyl thioglycolate (HSCH2COOMe) yielded, respec-
tively, only unreacted starting material and a mixture of starting material
and vinyl sulfide 5a (Ph ) CH2CO2Me). The efficiency of the SHi
mechanism at the sulfur atom is substantiated by the fact that unstabilized
alkyl radicals can even be obtained by direct, one-pot treatment of the
corresponding 4-pentynyl sulfides with benzenethiol, i.e., without syringe
pump addition of the latter, although under these conditions significant
amounts of vinyl sulfides 5 were also obtained.
(4) Ooi, T.; Furuya, M.; Sakai, D.; Maruoka, K. AdV. Synth. Catal. 2001,
343, 166.
(5) The whole synthetic array of possibilities was fully examined with
sulfide 1f (see Supporting Information).
(6) This is an improved procedure with respect to that previously reported
(ref 1a), which started from 4-pentyn-1-ol. See also: Minozzi, M.; Nanni,
D.; Spagnolo, P. 4-Pentyne-1-thiol. In The Encyclopedia of Reagents for
Organic Synthesis (eEROS); Wiley: Chichester, 2008; Build 13, in press.
(7) For general methods for conversion of thiolesters into thiols, see:
Zheng, T.-C.; Burkart, M.; Richardson, D. E. Tetrahedron Lett. 1999, 40,
603 and references therein.
(8) Azobis(cyclohexanecarbonitrile).
1128
Org. Lett., Vol. 10, No. 6, 2008

pleased to find that it works very well, both with electrophilic
and nucleophilic radicals.13 Indeed, the carbon radicals
derived from sulfides 1g-h gave smooth ring closure onto
their electron-rich C-C double bonds to afford lactam 6 and
lacton 7, respectively, in good yields. Even more interest-
ingly, the alkyl radical derived from 1i gave rise to a very
clean cyclization onto the electron-poor acrylate moiety to
give cyclopentane 8 in 70% yield (Scheme 3).
Scheme 3
The latter is a noteworthy result at least for two reasons.
First, the alkyl radical arising from 1i is nucleophilic in nature
and should therefore be trapped very quickly by the thiol:
however, under our conditions, this reaction is notably slower
than cyclization and no traces of the product of premature
reduction of the alkyl radical (4i) were observed. Second,
this kind of alkyl radical is not accessible by desulfurization
of the corresponding thiol, since the latter immediately
cyclizes onto the C-C double bond upon every attempt of
synthesis: this means that this kind of cyclization is not
available by our previous tin-free procedure,12 and the present
methodology therefore represents a suitable complement of
that.
Attempts of intermolecular addition of alkyl radicals to
olefins were also carried out. Sulfide 1e was indeed reacted
with n-butyl vinyl ether (1-10 equiv) under the standard
conditions. Although the resulting mixtures were always
contaminated by some byproducts formed in variable amounts,
the reaction proved again to be synthetically useful, since in
the presence of 5 equiv of alkene it afforded the addition
product 9 in 40% yield (Scheme 4).
not influenced at all by the nature of the leaving R-group.
Primary, unstabilized alkyl radicals (1a,f) are released with
the same efficiency as more substituted or stabilized radicals
(such as benzyl 1d), which, on the other hand, are capable
of abstracting hydrogen from the thiol at a sufficient rate as
to maintain the chain reaction. Furthermore, both electrophilic
(1e) and nucleophilic (1a-d,f)11 radicals can be generated
and reduced with comparable efficiencies.
Since benzenethiol is totally inert to those functional
groups that are potentially sensitive to the stannane/silane
reagents commonly used in radical reactions and taking into
account that sulfides 1 can be synthesized from both the
corresponding halides (or tosylates) and thiols (see Scheme
1), this procedure can be regarded as a very mild, efficient
defunctionalization method of halogen-, hydroxyl-, and thiol-
containing molecules. Radical dehalogenations and deoxy-
genations (Barton-McCombie reaction) are common tech-
niques in organic synthesis; this is however a realm still
strongly dominated by tin reagents and mild, effective tin-
free procedures to perform these transformations should
always be welcome.1d,e Furthermore, to date only very few
examples of radical desulfuration of thiols have been
reported.12
Scheme 4
In conclusion, we have shown that homolytic substitution
at the sulfur atom of vinyl radicals 2, obtained by benzene-
sulfanyl radical addition to alkyl 4-pentynyl sulfides 1, is a
very effective tool for the generation of all types of alkyl
radicals. Owing to the accessibility of the starting materials,
the low cost and toxicity properties of benzenethiol, and its
compatibility with most functional groups, this procedure
can be an appealing substitute for many stannane/silane-
mediated radical reactions and a valid complement to our
previous tin-free methodology for generation of analogous
radicals. Studies are underway to extend this procedure to
other synthetically interesting targets.
Of course, one of the major breakthroughs of radical
reactions in organic synthesis is the possibility to carry out
C-C bond-forming processes by trapping alkyl radicals prior
to hydrogen abstraction, for instance by cyclization or
intermolecular addition to olefins. Therefore, we tested our
methodology in 5-exo radical cyclizations and we were
(11) Attempts were also made to generate R-oxy (ROCH2-type) radicals
(R ) Ar, nC8H17). The corresponding pentynyl sulfides can be easily
synthesised but cannot be purified, due to their instability under all types
of workup. Some reactions carried out on the crude sulfides yielded the
expected reduction products accompanied by unreacted starting material
and other unidentified side products.
Acknowledgment. We acknowledge financial support
from MIUR (2006-2007 Funds for “Extending the Applica-
tion of Organic Free Radicals to New Synthetic Methods”).
(12) (a) Benati, L.; Leardini, R.; Minozzi, M.; Nanni, D.; Scialpi, R.;
Spagnolo, P.; Strazzari, S.; Zanardi, G. Angew. Chem., Int. Ed. 2004, 43,
3598. (b) Wan, Q.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2007, 46,
9248, and references therein.
(13) Cyclizations were carried out by adding the toluene solution of
benzenethiol and ACCN in 4 h instead of the 2 h required for defunction-
alizations.
Org. Lett., Vol. 10, No. 6, 2008
1129

We also gratefully thank Prof. David Crich (Wayne State
University, Detroit, MI) for helpful suggestions.
and their radical reactions and spectral data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
Supporting Information Available: Experimental pro-
cedures for the synthesis of alkyl 4-pentynyl sulfides 1a-i
OL800046K
1130
Org. Lett., Vol. 10, No. 6, 2008