Self-terminating radical cyclizations: How are thiyl radicals performing?

Article abstract of DOI:10.1002/ejoc.201000655

The performance of thiyl radicals RS' in "self-terminating radical cyclisations" was explored. Using the medium-sized cyclodecyne (1) as model system, the reaction of PhS' generated by photolysis of (PhS)₂ was used to study the intermolecular S-radical addition and subsequent intramolecular radical translocations. This reaction resulted in the formation of three stereoisomeric sulfides 17a in very good yield, which all possess the bicyclo[4.4.0]decane framework with either cis and trans ring fusion. The isomeric bicyclo[5.3,0]decane framework was not: formed. Product identification was performed using a combination of techniques, e.g. synthesis of authentic samples, X-ray analysis and computational studies of the potential energy surface, which also revealed valuable insight into the mechanism, of this radical cyclisation cascade. The (PhS)₂/PhS' system provides an efficient source for in situ generated thiols, which mediate reduction of the α-thio radical, e.g., 13a→17a. The radical cascade initiated by the addition of BnS', tBuS' or AllylS', respectively, to cycloalkyne 1 was typically terminated also by reduction, even in the absence of an apparent H-donor, and resulted in formation of various bicyclic and monocyclic thioethers. The desired "selftermination", e.g., β-fragmentation of the S-R bond in radical intermediate 12/13 and release of a stabilized radical R', was only observed, as minor reaction, pathway in one particular instance where tBuS' was generated by autoxidation of tBuSH. Computional studies showed that the different stereochemical outcome of the radical cyclizations involving S-radicals, compared to O- or N-centred radicals, could be attributed to the reversibility of the initial intermolecular Sradical addition to the C≡C triple bond in cycloalkyne 1.

Full text of DOI:10.1002/ejoc.201000655

FULL PAPER
DOI: 10.1002/ejoc.201000655
Self-Terminating Radical Cyclizations: How Are Thiyl Radicals Performing?
Kristine J. Tan,[a] Jonathan M. White,[b] and Uta Wille*[a]
Dedicated to Professor Bernd Giese on the occasion of his 70th birthday
Keywords: Radicals / Radical cyclizations / Thiyl radicals / Alkynes / Computational chemistry / Reaction mechanisms
The performance of thiyl radicals RS· in “self-terminating
radical cyclisations” was explored. Using the medium-sized
generated thiols, which mediate reduction of the α-thio radi-
cal, e.g., 13aǞ17a. The radical cascade initiated by the ad-
cyclodecyne (1) as model system, the reaction of PhS· gener- dition of BnS·, tBuS· or AllylS·, respectively, to cycloalkyne 1
ated by photolysis of (PhS)2 was used to study the intermo-
lecular S-radical addition and subsequent intramolecular
radical translocations. This reaction resulted in the formation
of three stereoisomeric sulfides 17a in very good yield, which
all possess the bicyclo[4.4.0]decane framework with either
cis and trans ring fusion. The isomeric bicyclo[5.3.0]decane
framework was not formed. Product identification was per-
formed using a combination of techniques, e.g. synthesis of
authentic samples, X-ray analysis and computational studies
of the potential energy surface, which also revealed valuable
insight into the mechanism of this radical cyclisation cascade.
The (PhS)2/PhS· system provides an efficient source for in situ
was typically terminated also by reduction, even in the ab-
sence of an apparent H-donor, and resulted in formation of
various bicyclic and monocyclic thioethers. The desired “self-
termination”, e.g., β-fragmentation of the S–R bond in radical
intermediate 12/13 and release of a stabilized radical R·, was
only observed as minor reaction pathway in one particular
instance where tBuS· was generated by autoxidation of
tBuSH. Computional studies showed that the different
stereochemical outcome of the radical cyclizations involving
S-radicals, compared to O- or N-centred radicals, could be
attributed to the reversibility of the initial intermolecular S-
radical addition to the CϵC triple bond in cycloalkyne 1.
Introduction
Compared with intermolecular radical additions to
alkenes, radical reactions initiated by addition of C- or het-
eroatom-centred radicals to alkynes have been much less
explored. Self-terminating radical cyclisations are a recent
concept in radical chemistry developed by our group, by
which alkynes can be oxidized to carbonyl compounds un-
der mild conditions in a radical cyclisation cascade initiated
by the addition of O-centered radicals to CϵC triple
bonds.[1] The suggested mechanism of this sequence, which
is based both on experimental and computational stud-
ies,[1,2] is shown in Scheme 1 (with Y = O) for the general-
ized reaction of O-radicals RO· using the medium-sized cy-
cloalkyne 1 as example.
The initial radical addition is strongly exothermic and
leads to the Z-configured vinyl radical 2, which undergoes
[a] ARC Centre of Excellence for Free Radical Chemistry and
Biotechnology, School of Chemistry and BIO21 Molecular
Science and Biotechnology Institute, The University of
Melbourne,
30 Flemington Rd, Parkville, VIC 3010, Australia
Fax: +61-3-93478189
E-mail: uwille@unimelb.edu.au
[b] School of Chemistry and BIO21 Molecular Science and
Biotechnology Institute, The University of Melbourne,
30 Flemington Rd, Parkville, VIC 3010, Australia
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000655.
Scheme 1.
View this journal online at
wileyonlinelibrary.com
4902
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4902–4911

Self-Terminating Radical Cyclizations
a transannularly favourable 1,5- or 1,6-hydrogen atom Eq. (1), by photolysis, Eq. (2), or by autoxidation in the
transfer (HAT), 2Ǟ3/4, followed by cis selective 5-exo and presence of excess oxygen, Eq. (3), and also through photo-
6-exo radical cyclizations, 3/4Ǟ5/6, respectively. The se- chemical cleavage of disulfides, Eq. (4).
quence is terminated through β-fragmentation of the O–R
bond in 5/6 by which the carbonyl group in the ketones cis-
1. Reaction of Cyclodecyne (1) with PhS·
7/8 is formed, with release of R·.
We have shown that this radical cyclization cascade can
be performed with every major class of inorganic and or-
1.1 Optimization of the Reaction Conditions
ganic O-centred radicals, such as, amongst others, nitrate,
Because of the fast enolization of C=S groups in thio-
·
NO3 , or acyloxyl radicals, RЈC(O)O·, respectively.[1] Since ketones, resulting in formation of an activated alkene moi-
the released R· has, so far, not been observed to propagate ety,[6] which could be attacked by radicals in an unwanted
a radical-chain process, in these reactions RO· can be con- secondary reaction, we decided to study first the reaction
sidered as synthon for O atoms in solution. We have re- of PhS· with 1 in order to explore whether the first three
cently found that self-terminating radical cyclizations can steps of the cyclization cascade, e.g. initial radical addition
principally also be performed with N-centred aminium and and the subsequent two transannular radical translocation
amidyl radicals, where termination of the sequence occurs steps (HAT and exo cyclization) are principally possible.[7]
through a pathway involving a redox process.[3]
Because of the poor stability of Ph·, the terminating homo-
In our ongoing quest to extend the concept of self-termi- lytic S–Ph bond cleavage 12a/13aǞ14/15 (Scheme 1) was
nating radical cyclizations to other heteroatom-centred rad- not expected to occur (and no enolization of the thiocarb-
icals, we decided to systematically study the reaction se- onyl moiety), so that insight into the stereoselectivity of
quence shown in Scheme 1 using S-centered thiyl radicals, the radical cyclization could be obtained. The experiments
RS·, which are known to undergo (reversible) addition to π were performed on analytical scale, where PhS· was gener-
systems in alkenes or alkynes.[1d,4] Thus, if the substituent ated through photolysis of diphenyl disulfide (PhS)2 at λ =
R in RS· would form a stabilized radical in the terminating 350 nm according to procedures established for self-termin-
β-fragmentation step, this sequence would represent a mild ating radical cyclizations with photochemically generated
access to thioketones (for example 14/15 in the reaction in- O- and N-centred radicals.[1b,1d,3] Careful exclusion of resid-
volving 1), which could be an interesting and mild alterna- ual oxygen was essential to avoid trapping of the S-radicals
tive to the existing synthetic procedures that require harsh by O2 prior to their addition to the alkyne.[4b,8] The reaction
reaction conditions.[5]
mixtures were directly analyzed by GC–MS and quantita-
In this work, we wish to report the results of our study tive GC, using n-hexadecane as internal standard (for de-
on the performance of S-radicals in self-terminating radical tails see Exp. Sect. and Supporting Information).
cyclizations, namely phenylthiyl (PhS·), benzylthiyl (BnS·),
In this reaction three isomeric compounds were formed
tert-butylthiyl (tBuS·) and allylthiyl radicals (AllylS·), using as main products with approximately equal GC signal in-
the reaction with the well-explored cyclodecyne (1) as tensities. High Resolution Mass Spectrometry (HRMS) of
model system (Scheme 1).[1,3] In addition to experimental the mixture revealed the protonated molecular ion, [M +
studies, extensive computational studies were performed to H+] at m/z = 247.15148 for all three compounds, which is
obtain detailed insight into the potential energy surface of in excellent agreement with the calculated value of m/z =
these radical cyclizations and the reaction mechanism.
247.15150 for C16H22S and suggests formal addition of
PhSH to cycloalkyne 1. Unfortunately, purification of the
products obtained from a reaction performed on prepara-
tive scale only led to separation of two of the three sulfides,
with both fractions being contaminated with the third prod-
uct, which suggests that these compounds must be structur-
ally very similar. Although DEPT-13C NMR analysis of
both fractions clearly revealed that all products possess a
bicyclic carbon-framework,[9] it was not possible to deter-
mine from these mixtures the ring size and stereochemistry
at the bridging carbons in the various compounds. In fact,
product identification turned out to be unexpectedly chal-
lenging and was only possible using a combination of dif-
ferent experimental and computational techniques, which
will be described in section 1.2.
Results and Discussion
In this work, the S-radicals were generated in the pres-
ence of cycloalkyne 1, as shown in Scheme 2, from the re-
spective thiols through reaction with a radical initiator,
Thus, in order to simplify the following discussion, the
products were tentatively assigned as isomers of the bicyclic
sulfides 16a/17a (Scheme 3), which could be formed
through reduction of the α-thio radical intermediates 12a/
13a through a yet unknown H atom donor. Evidence sup-
porting the structures in Scheme 3 will be presented below.
Scheme 2.
Eur. J. Org. Chem. 2010, 4902–4911
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4903

K. J. Tan, J. M. White, U. Wille
FULL PAPER
Table 1 compiles the experimental conditions and combined attempts were made to further consolidate its structure. In
yields of the products 16a/17a, determined by quantitative addition to this, a number of aromatic thiols were also
GC.
formed, such as PhSH and di- and trisulfides of type 20/
21. These products were assigned by GC/MS through their
respective [M+] signals (in the case of PhSH also through
comparison with reference EI-mass spectra[10]), and charac-
teristic fragment ions (see Supporting Information). PhSH,
20 and 21 are formed through light-induced coupling of
(PhS)2, as was verified by an independent experiment,
where a solution of (PhS)2 in benzene was irradiated in the
absence of cycloalkyne 1.[11] The suggested mechanism for
formation of these thiols is outlined in Scheme 4.
Scheme 3.
Table 1. Experimental conditions and results for the reaction of
photochemically generated PhS· with cyclodecyne (1).[a]
Entry [1]
/m
[(PhS)2]
/m
Solvent[b]
Irradiation % Yield[c]
time /h
16a + 17a
1
2
3
4
5
6
7
10[d]
10[d]
10[d]
10[d]
20[d]
10[d]
10
50
50
50
50
50
25
5[d]
Me2CO
MeCN
C6H6
c-C6H12
C6H6
C6H6
C6H6
6.5
6
6
6.5
17.75
17.75
6
70
41
50
48
57
67
34
Scheme 4.
Radical addition of PhS· at (PhS)2 (exemplary shown for
para attack) leads to the intermediate radical adduct 22,
which is re-aromatized through HAT by PhS·. The resulting
trisulfide 23 likely undergoes photochemical cleavage of the
disulfide bond, leading to S-radicals 24 and PhS·. Their
subsequent trapping through addition to PhSH, followed
by re-aromatization yields sulfides 20 and 21. We suggest
that this light-induced formation of thiols PhSH, 20 and 21
provides an in situ source for H atoms, which mediate ef-
ficient reduction of the α-thio radicals 12a/13a to sulfides
16a/17a. We will discuss stereochemical aspects of this pro-
cess in detail below. This unexpected side reaction of PhS·
with (PhS)2 explains, why an excess of (PhS)2 was required
to drive consumption of cycloalkyne 1 to completion.
[a] Irradition at λ = 350 nm. [b] In 5 mL. [c] Combined quantitative
GC yield with respect to alkyne 1, using n-hexadecane as internal
standard (see text). [d] Complete reactant consumption.
Assuming quantitative conversion of the disulfide ac-
cording to (PhS)2 Ǟ2 PhS·, initial experiments were per-
formed using a ten-fold excess of PhS· {e.g., [(PhS)2]/[1] =
5} in order to ensure complete consumption of alkyne 1.
Under these conditions, after 6–6.5 hours of irradiation in
different solvents, combined yields of 41–70% were ob-
tained (entries 1–4), with the highest yield being found in
acetone (entry 1), whereas the reaction in acetonitrile per-
formed poorest (entry 2). The reaction in benzene was se-
lected to study the influence of irradiation time, reactant
ratio and concentration on the reaction outcome. Using
[PhS·]/[1] = 5, a drastically elongated irradiation led to a
1.2 Identification of the Bicyclic Sulfides 16a/17a
Because isolation of the isomeric sulfides 16a/17a and
slight improvement of the yield (entry 5), but, most import- their identification by spectroscopic methods was not pos-
antly, this experiment also showed that the sulfides 16a/17a sible, their structures were determined using a combination
were photochemically stable under these conditions. Inter- of techniques, such as independent synthesis of authentic
estingly, when the total reactant concentration was halved, samples, chemical modification for X-ray structural analysis
the yield of sulfides 16a/17a rose to 67% (entry 6). This and computational studies.
observation is consistent with earlier findings where related
a) Identification using authentic samples: In principle, the
photo-initiated radical reactions were found to perform bet- bicyclic framework in 16a/17a could be either cis or trans
ter in not too concentrated solutions.[1b] With [PhS·]:[1] = 1 fused. Our synthetic route to the trans sulfides trans-16a/
consumption of 1 was incomplete whereas the disulfide was 17a is outlined in Scheme 5.
fully consumed (entry 7), which can be taken as indication
The self-terminating radical cyclization of cycloalkyne 1
with electrogenerated NO3 was used to access the required
·
for side reactions of PhS· (see below).
In addition to the bicyclic saturated sulfides 16a/17a, the [4.4.0]- and [5.3.0]-bicyclic framework, and the ketones
reaction of PhS· with 1 led also to formation of a very were obtained with a GC ratio of cis-7:cis-8 = 2.3 (see
minor by-product possessing a [M+] at m/z = 244. Although Scheme 1).[1a] This mixture was isomerized to the respective
this could be tentatively assigned as unsaturated bicyclic trans configured bicyclic ketones trans-7/8 through treat-
sulfide of type 18a/19a (Scheme 3), which could result from ment with hydrochloric acid in methanol. Reduction of the
disproportionation of the α-thio radicals 12a/13a, no carbonyl group in trans-7/8 with sodium borohydride oc-
4904
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4902–4911

Self-Terminating Radical Cyclizations
Scheme 6.
HRMS of this mixture, which contained, as expected,
one major product (relative GC peak area = 85%), revealed
the sodiated molecular ion, [M + Na+], at m/z = 301.12344,
which was in good agreement with the calculated value of
m/z = 301.12327 for C16H22O2S.
Scheme 5.
The major compound could be separated by crystalli-
zation and analysed by X-ray diffraction analysis. This re-
vealed a cis-bicyclo[4.4.0]decane framework with the sul-
fone group at C2 in equatorial position and trans to the
proton H1 (cis-28, Scheme 7). H NMR was used to con-
firm that the oxidation shown in Scheme 6 did not change
curred in a non-diastereoselective fashion, and was followed
by bromination of the resulting mixture of four isomeric
alcohols (not shown). The latter reaction proceeded with a
moderate combined yield of 47% and gave only two iso-
meric bromides (suggesting that the other two isomers obvi-
ously underwent decomposition), which were not separated.
Since GC analysis revealed a peak area ratio of 2.2 for these
two bromides, which is similar to the ratio of ketones 7/8 in
the first step of this reaction sequence, it was concluded
that the product mixture contained both the [4.4.0] and the
[5.3.0]-bicyclic framework. In the final step, the mixture of
these two bromides, trans-25/26, was converted into a mix-
ture of the respective thioethers trans-16a/17a by treatment
with thiophenolate, which was confirmed by their respective
GC–MS signals showing an [M+] at m/z = 246. The minor
isomer trans-17a, which possessed the [4.4.0]-bicyclic frame-
work, could be isolated by column chromatography in 11%
yield, but the stereochemistry at C-2 could not be assigned.
In contrast to this, the major isomer possessing the [5.3.0]-
bicyclic framework, trans-16a, could not be obtained in
pure form, but the quality of the sample was satisfactory
for the subsequent analytical experiments.
1
the absolute configuration at C2. Thus, the signal of H2 in
3
cis-28 at δ = 2.94 ppm revealed a coupling constant of J =
12.6 Hz associated with the doublet component, which is
characteristic for axial-axial interactions.[9] In the sulfide
mixture 16a/17a, which was used to synthesize cis-28, the
H2 signal of the major isomer at δ = 3.26 ppm showed a
practically identical coupling constant of 3J = 12.8 Hz asso-
ciated with the doublet component (Scheme 7). It can there-
fore be concluded that cis-17a, which possesses a 1S,2R,6S
configuration at the various stereocentres, was also formed
as product in the reaction of PhS· with 1.
GC co-injection of these two independently synthesized
sulfides trans-16a and trans-17a, respectively, with the sulf-
ide mixture 16a/17a isolated from the reaction of PhS· with
cycloalkyne 1 revealed unequivocally that trans-17a is a
product of this reaction. On the other hand, the isomeric
sulfide trans-16a possessing the trans-configured [5.3.0]-bi-
cyclic framework was not formed.
Unfortunately, synthesis of the respective cis-fused thio-
ethers cis-16a/17a through a reaction sequence similar to
that shown in Scheme 5 (without the cis/trans isomerization
of cis-7/8) was not possible, which illustrates the difficulty
to access complex cis fused bicyclic frameworks using con-
ventional ionic methods, compared to radical cyclizations.
b) Identification using X-ray diffraction analysis: Because
of the limited synthetic availabiltiy of authentic samples,
product identification was also pursued using single-crystal
X-ray diffraction analysis. For this, a mixture of sulfides
16a/17a, which could be enriched in one isomer (relative
Scheme 7.
c) Computational modeling: Because experimental meth-
GC peak area = 75%) by chromatography, was oxidized ods only revealed the structure of two of the sulfides formed
with meta-chloroperoxybenzoic acid (mCPBA) to give the in the reaction of PhS· with 1, of which one showed a so
sulfone mixture 27/28 (Scheme 6).[12]
far unprecedented (with regard to self-terminating radical
Eur. J. Org. Chem. 2010, 4902–4911
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4905

K. J. Tan, J. M. White, U. Wille
FULL PAPER
cyclizations) trans fused bicyclic framework,[13] we used our experimental finding of sulfide cis-17a as a product in
computational methods to calculate the potential energy the reaction of PhS· with cycloalkyne 1, which results from
surface of the reaction of PhS· with cycloalkyne 1, in order reduction of α-thio radical cis-13a.
to obtain insight into the reaction mechanism and, based
Because of the flexibility of the ten-membered ring sys-
on these data, to predict the so far unassigned product. The tem, the various radical intermediates possess a number of
calculations were carried out with the hybrid density func- different low-energy conformations. Indeed, calculations of
tional BHandHLYP[14] in combination with the 6-311G** the potential energy surface leading to the trans configured
or cc-pVTZ basis set, respectively. These methods have been α-thio radical intermediates trans-12a/13a, revealed confor-
shown in our previous work on related systems to give reli- mational isomers of the vinyl radical, e.g. 9a*, and the sec-
able energy data.[3] Energy values are reported in kJmol–1, ondary radicals, e.g. 10a*/11a* (see Supporting Infor-
with zero-point vibrational energy correction (ZPC) in- mation). These conformers could principally arise from
cluded. Further details are given in the Experimental Sec- ring-flips in 9a and/or 10a/11a, respectively. However, com-
tion and Supporting Information.
putations showed also that such ring-flips are associated
We first explored the initial radical addition, transannu- with high activation barriers of some 80 kJmol–1 for
lar HAT and exo cyclization step (according to Scheme 1, 9aǞ9a* and ca. 91 and 98 kJmol–1 for 10aǞ10a* and
with Y = S and R = Ph). The calculated activation barriers 11aǞ11a*, respectively, which are caused by strain in the
(E‡) and reaction energies (∆E) are compiled in Table 2.
medium-sized ring. Thus, these slow ring-inversions cannot
compete with the reverse fragmentation or transannular
HAT in vinyl radical 9a, or the respective exo cyclisations
10aǞcis-12a and 11aǞcis-13a (entries 3 and 5). We there-
fore believe that the experimentally observed formation of
a trans-fused ring system is due to the reversibility of the
PhS· addition to the CϵC triple bond in 1, which could
lead directly to 9a* (entry 6).
Table 2. Calculated activation barriers E‡ and reaction energies ∆E
for the reaction of PhS· with cycloalkyne 1 (BHandHLYP/6-
311G**).[a]
Entry Reaction
E‡
∆E
I. Formation of cis-fused bicyclic framework
1
2
3
4
5
Addition: [PhS· + 1][b] Ǟ9a
1,5-HAT: 9aǞ10a
5-exo: 10aǞcis-12a
1,6-HAT: 9aǞ11a
6-exo: 11aǞcis-13a
50.7
41.6
22.6
27.6
20.6
16.8
The computed E‡ and ∆E data for the reaction steps
leading to trans-12a/13a (see Table 2) show that the transan-
nular radical translocation in 9a* is associated with a
slightly (1,5-HAT), or significantly (1,6-HAT) higher acti-
vation barrier, respectively, compared to the analog pro-
cesses in the conformational isomer 9a. Interestingly, the
5-exo cyclization 10a*Ǟtrans-12a requires a considerable
activation energy of 78 kJmol–1 (entry 8). Thus, although
this pathway is exothermic (∆E = –95.1 kJmol–1), it is ki-
netically unfavourable. This is experimentally supported by
the fact that the trans configured [5.3.0]-bicyclic framework,
e.g. trans-16a, was not formed in the reaction of PhS· with
cycloalkyne 1. On the other hand, the 6-exo cyclization
leading to trans-13a is associated with a low activation bar-
–52.3
–74.1
–41.3
–118.7
II. Formation of trans-fused bicyclic framework[c]
6
7
8
9
Addition: [PhS· + 1][b] Ǟ9a*
1,5-HAT: 9a*Ǟ10a*
5-exo: 10a*Ǟtrans-12a
1,6-HAT: 9a*Ǟ11a*
6-exo: 11a*Ǟtrans-13a
50.7
46.6
78.0
46.1
29.0
19.6
–44.5
–95.1
–32.1
–128.9
10
[a] Energies in kJmol–1, including ZPC. [b] Via association complex
of PhS· and 1. [c] Cyclization cascade proceeds through conforma-
tional isomers of radical intermediates 9a–11a, e.g. 9a*, 10a* and
11a* (see text).
Addition of PhS· to 1 proceeds via an association com- rier of 29 kJmol–1 and is exothermic (entry 11). Thus, ac-
plex of both reactants and leads to the Z configured vinyl cording to the computational data, of the possible trans bi-
radical 9a in a reversible and endothermic reaction (entry cyclic frameworks, only formation of the [4.4.0]-bicyclic sys-
1). Because of transannular ring strain formation of an E tem is both kinetically and thermodynamically favourable.
configured vinyl radical is energetically unfavourable (not This is in excellent agreement with the experimental finding
shown). The reverse fragmentation of 9a is associated with of sulfide trans-17a as reaction product.
E‡ = 33.9 kJmol–1 and ∆E = –16.8 kJmol–1. However, this
It is worth to note that the kinetic preference for forma-
fragmentation is competing with the 1,5- or 1,6-HAT pro- tion of the bicyclo[4.4.0]-framework in the reaction of S-
cesses, respectively, which both are strongly exothermic and radicals with cycloalkyne 1 differs from self-terminating
associated with moderate to low activation barriers (entries radical cyclizations initiated by addition of O- or N-centred
2 and 4). The subsequent 5-exo or 6-exo cyclisations, radicals to 1. Both experimental and computational studies
respectively, proceed in a cis selective fashion and are both have clearly shown that the latter are much less regioselec-
fast and highly exothermic (entries 3 and 5), which could tive and always lead to formation of both isomeric bicyclic
be explained with mesomeric and hyperconjugation stabili- frameworks. This clearly indicates that the nature of the
zation effects[15] of the unpaired electron by the adjacent radical initiating the radical cyclization cascade has a strong
sulfur atom in cis-12a/13a. According to the computational influence on the reaction pathway.[1–3]
predictions, the pathway leading to the α-thio radical cis-
In order to assign the structure of the third sulfide
13a possessing the [4.4.0]-framework is both kinetically and formed in the reaction of PhS· with cycloalkyne 1, we next
thermodynamically significantly more preferable, than for- performed calculations to explore the stereoselectivity of
mation of the [5.3.0] framework in cis-12a. This supports the reduction of the α-thio radical intermediates cis-12a/
4906
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4902–4911

Self-Terminating Radical Cyclizations
13aǞcis-16a/17a using PhSH as model H donor. Re- than reduction from the Re face. Interestingly, the opposite
duction of the isomeric trans-12a/13a was not explored, is the case for the reduction of the isomeric cis-13a, where
since (i) the computations predicted, in agreement with ex- attack from the Re face requires an activation energy, which
perimental findings, that formation of trans-12a is kinet- is ca. 5 kJmol–1 higher than the Si face attack.
ically not favourable, and (ii) the sulfide trans-17a, resulting
When these results are now combined with the data
from reduction of trans-13a, was already identified as reac- shown in Table 2, where radical intermediate cis-12a is ther-
tion product (albeit with a non-defined stereochemistry at modynamically less stable by more than 44 kJmol–1 com-
C2).
pared to cis-13a (entry 3 vs. 5), formation of sulfide cis-17a
The α-thio radical intermediates cis-12a/13a exhibit a ne- possessing the [4.4.0]-bicyclic framework through Si-face
arly planar geometry at the carbon atom bearing the un- reduction of cis-13a should be the kinetically and thermo-
paired electron, and reduction could principally occur from dynamically most favourable pathway. This is in excellent
both faces. This would lead to the diastereomeric [5.3.0]- agreement with the experimental finding of this compound
bicyclic sulfides cis-16a (after Si attack) and cis-16aЈ (after as reaction product. In addition to this, the agreement be-
Re attack) and/or the [4.4.0]-bicyclic sulfides cis-17a (after tween experiment and computational prediction that trans-
Si attack) and cis-17aЈ (after Re attack), respectively 17a should is formed, but not its [5.3.0]-bicyclic isomer
(Scheme 8). The calculated activation barriers (E‡) and re- trans-16a, justifies our conclusion that the computational
action energies (∆E) are given in Table 3.
data are reliable and can be used to predict the nature of
the third product. Based on this, we conclude that the cis
configured sulfide cis-17aЈ possessing a [4.4.0] framework
and an axial SPh substituent at C2, which results from re-
duction of cis-13a from the Re face, must also be formed in
the reaction of PhS· with cycloalkyne 1. All identified bicy-
clic sulfides in this reaction are shown in Scheme 9.
Scheme 9.
2. Reaction of Cyclodecyne (1) with BnS·, tBuS· and AllylS·
Scheme 8.
In the previous section, we have shown that S-radical
addition to the CϵC triple bond and the subsequent trans-
Table 3. Calculated activation barriers E‡ and reaction energies ∆E annular HAT and cyclisation steps do readily occur. We
for the reduction of cis-12a/13a by PhSH (BHandHLYP/6-
next explored, whether the entire self-terminating radical
311G**).[a]
cyclisation cascade can be performed with S-radicals pos-
Entry
Reaction[b]
E‡
∆E
sessing a substituent R, which could be released as R·
through homolytic β-fragmentation of the S–R bond in the
α-thio radical intermediates 12/13 (Scheme 1).
1
2
3
4
Si attack: cis-12aǞcis-16a
Re attack: cis-12aǞcis-16aЈ
Si attack: cis-13aǞcis-17a
Re attack: cis-13aǞcis-17aЈ
37.2
31.1
21.8
26.6
–50.4
–38.1
–60.9
–57.9
2.1 Computational Studies on the β-Scission of the S–R
Bond
[a] Energies in kJmol–1, including ZPC. [b] Via association com-
plexes of cis-12a/13a and PhSH, and cis-16a(Ј)/17a(Ј) and PhS·.
In order to gain theoretical insight into the energetics of
the β-fragmentation step in dependence on the nature of R,
computations of the potential energy surface were per-
formed using α-thio radicals 29a–d as simplified model sys-
tems (Scheme 10). The calculated activation barriers (E‡)
and reaction energies (∆E) are given in Table 4.
In general, the proposed HAT is energetically highly
feasible. As expected, products possessing the SPh substitu-
ent in equatorial position, which are formed through re-
duction from the Si face, are thermodynamically more
favourable, although the energy difference is very small for
the diastereomeric sulfides cis-17a/17aЈ. Reduction of the α-
thio radicals cis-12a is associated with a slightly higher E‡
by 5 (Re-face attack) to 15 (Si-face attack) kJmol–1, com-
pared to cis-13a. This could be explained by an increase in
strain in the seven-membered ring of the former associated
with the transition from an sp2 hybridized radical centre to
the sp3 carbon in the closed-shell product. Si-face reduction
of cis-12a requires a 6.1 kJmol–1 higher activation energy Scheme 10.
Eur. J. Org. Chem. 2010, 4902–4911
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4907

K. J. Tan, J. M. White, U. Wille
FULL PAPER
Table 4. Calculated activation barriers E‡ and reaction energies ∆E alkyl ring, which could be taken as indication for formation
for the β-fragmentation in 29a–d (BHandHLYP/cc-pVTZ).[a]
of the ten-membered thioenol ether 31b, in analogy to the
reaction of 1 with tBuS·, which will be described in section
2.3.
Entry
Reaction[b]
E‡
∆E
1
2
3
4
29aǞ30 + Me·
29bǞ30 + Bn·
29cǞ30 + tBu·
29dǞ30 + Allyl·
100.0
54.8
56.0
53.6
84.5
21.3
46.0
11.5
Although we did not further pursue identification of the
reaction products, it appears that under the experimental
conditions the radical cyclisation cascade was terminated
by reduction of various radical intermediates, with BnSH
being the likely source of H. Whereas formation of the bicy-
clic sulfides 16b/17b results from reduction of the α-thio
radical intermediates 12b/13b, the cyclodecene derivative
31b could be formed through trapping of the initially
formed vinyl radical 9b and/or the secondary radicals 10b/
11b (see Scheme 1). It should be noted that in this reaction
also trace amounts of a product with [M+] at m/z = 258
were formed, which can be taken as indication for an unsat-
urated bicyclic sulfide 18b/19b that could result from dis-
proportionation of radical intermediates 12b/13b.
[a] Energies in kJmol–1, including ZPC. [b] Via association complex
of 30 and R·.
According to the computations, β-fragmentation in 29a–
d is endothermic in all cases. As expected, release of the
unstabilized Me· (entry 1) is both kinetically and thermody-
namically highly unlikely, compared to release of Bn·, tBu·
and Allyl·, respectively. For the latter three, the computed
E‡ values are very similar and around 55 kJmol–1, but the
reaction energies vary. Quite obviously, resonance stabiliza-
tion in the released R· renders β-fragmentation thermody-
namically more favourable than inductive stabilization (en-
tries 2 and 4 vs. 3). With regards to self-terminating radical
cyclizations, we envisaged that, although as an isolated step
the homolytic S–R bond cleavage is endothermic, the high
overall exothermicity associated with formation of the α-
thio radical intermediates 12/13 through the radical cycliza-
tion cascade (see Table 2), should outweigh the energy re-
quired for the final radical fragmentation, when R· = Bn·,
tBu· or Allyl·, respectively.
2.3 Reaction of Cyclodecyne with tBuS·
tBuS· was generated in the presence of 1 by photolysis of
neat tBuSH at λ = 254 nm, Equation (2).[17] Under these
conditions, however, only formation of the unsaturated sul-
fide 31c in 36% isolated yield (Scheme 12) occurred, which
was confirmed by standard characterization techniques.
Thioketones 14/15 were not found.
2.2 Reaction of Cyclodecyne with BnS·
BnS· was generated, in analogy to literature pro-
cedures,[16] from BnSH in refluxing fluorobenzene in the
presence of excess cycloalkyne 1 using 2,2-azobisisobutyro-
nitrile (AIBN) as initiator (Scheme 11).
Scheme 12.
Since vinyl sulfide 31c obviously results from rapid re-
ductive trapping of the respective vinyl radical 9c and/or
the secondary radicals 10c/11c by excess tBuSH, the reac-
tions were also performed in either acetonitrile or cyclohex-
ane as solvent, respectively, with [tBuSH]:[1] = 10. Under
these conditions, however, trapping of radical intermediates
Scheme 11.
To our surprise, GC/MS analysis of the reaction mixture by HAT could also not be avoided, but was at least delayed
revealed no formation of the expected thioketones 14/15. to the stage of the thermodynamically most stable radical
Instead, apart from traces of (BnS)2, which was identified intermediates, e.g. the α-thio radicals 12c/13c. Three iso-
by co-injection with an authentic sample and results from meric products were formed in 20–24% GC yield, which
dimerisation of BnS·, six products with [M+] at m/z = 260 were tentatively assigned as sulfides 16c/17c based on their
(corresponding to a molecular formula C17H24S) were respective molecular ions [M+] at m/z = 226 (corresponding
found in 35% combined GC yield. Since five of these to C14H26S), and their EI-MS fragmentation pattern, which
showed EI-MS fragmentation pattern analog to that of the showed strong analogies with the fragmentation pattern of
bicyclic sulfides 16a/17a formed in the reaction of PhS· with sulfides 16b/17a,b formed in the reaction of PhS· or BnS·,
1, it is suggested that these compounds could be stereoiso- respectively, with 1. Formation of thioketones 14/15 did not
meric bicyclic sulfides 16b/17b. The EI-MS fragmentation occur. The comparably low yield of 16c/17c may be due to
spectrum of the remaining isomer suggests a more stable partial loss of the volatile tBuSH as a result of the nitrogen
connection between the benzylthio moiety and the cyclo- gas stream, which was required to ensure absence of O2.
4908
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4902–4911

Self-Terminating Radical Cyclizations
We also explored the reaction of 1 with tBuS· generated bined GC yields of around 10%, in addition to small
by slow autoxidation of tBuSH (Scheme 3).[18] Using amounts of one unsaturated bicyclic alkene (all assignments
[tBuSH]:[1] = 4 under an atmosphere of O2 in O2-saturated are based on the EI-MS fragmentation pattern and com-
solvent, GC–MS analysis after a reaction time of 5 days parison with the products of the other reactions in this
revealed, besides formation of small amounts of (tBuS)2 study).
(identified by co-injection with an authentic sample), sul-
Thus, although no obvious hydrogen donor (e.g., a thiol)
fides 16c/17c as major products and trace amounts of the was present in these reactions, it appeared that, still, re-
ketones cis-7/8, which were identified by co-injection with duction of the intermediate α-thio radical 12d/13d occurred
an authentic sample (Scheme 13).
at a faster rate than homolytic S–Allyl bond fragmentation.
Although we have not further explored the nature of the
reducing agent in this reaction, it may be suggested that the
allylic hydrogen atoms in the precursor for AllylS· could be
abstracted by 12d/13d. In addition to this, to a minor extent
disproportionation according to 12d/13dǞ16d/17d + 18d/
19d could also occur.
Scheme 13.
Conclusions
In addition to this, small amounts of a new compound
were formed, which showed the protonated molecular ion
[M + H+] at m/z = 169.10460 in the ESI-HRMS, which
corresponds to C10H16S (calcd. 169.10455).[19] Also, a frag-
mentation pattern similar to that of the bicyclic ketones cis-
7/8 was observed in the EI-mass spectrum of this com-
pound, which suggests a similar molecular structure. We
therefore believe that this compound is the desired thio-
ketone 14/15 (and/or its tautomeric thioenol). Unfortu-
nately, we were not able to isolate and characterize this
product. Also, all attempts to synthesise an authentic sam-
ple through an independent pathway were unsuccessful.[20]
In this work, we have explored whether self-terminating
radical cyclizations can be performed with S-radicals RS·.
Using photo-generated PhS· as a model system for S-radi-
cals, for which the terminating homolytic S–Ph bond frag-
mentation in the intermediate α-thio radicals 12a/13a
should not be possible, we were able to show that thiyl radi-
cals readily undergo addition to the CϵC triple bond in
cycloalkyne 1, followed by transannular HAT and exo cycli-
zation. Although the initial radical addition is reversible
and endothermic, computational studies revealed that the
subsequent radical translocation steps are very fast and
exothermic, thus forcing the reaction to proceed. This radi-
cal cyclization resulted in exclusive formation of stereoiso-
meric α-thio radicals 13a possessing a [4.4.0]-bicyclic frame-
work, which were reductively trapped to give three stereo-
isomeric sulfides cis/trans-17a. The latter were identified
using a combination of experimental and computational
methods. Interestingly, reduction of the radical intermedi-
ates 13a appeared to be a highly efficient process, although
the reaction was performed in the absence of an apparent
H atom donor. It turned out that the (PhS)2/PhS· system
provides an efficient source for in situ generated thiols,
which mediate reduction of 13a.
Our studies on the reactions of cycloalkyne 1 with thiyl
radicals BnS·, tBuS· and AllylS·, which were all possessing
stablized radical leaving groups R·, e.g. Bn·, tBu· and Allyl·,
respectively, have shown that a terminating homolytic frag-
mentation of the S–R bond in the α-thio radicals 12b–d/
13b–d can obviously not compete with direct reduction of
the latter through intermolecular HAT. Even when the reac-
tions were performed in the absence of a specific H donor,
the “tug of war” in 12b–d/13b–d between the slightly (R =
Bn, Allyl) or considerably (R = tBu) endothermic unimolec-
ular S–R bond fragmentation on the one hand and the bi-
molecular HAT to give 16b–d/17b–d on the other hand was
always decided in favour of the latter. In the reaction of
cycloalkyne 1 with tBuS· performed by irradiation in neat
tBuSH, reductive trapping occurred already at the stage of
the vinyl radical 9c and/or the secondary radicals 10c/11c,
2.4 Reaction of Cyclodecyne with AllylS·
In order to avoid the unwanted reduction of the α-thio
radical intermediates 12/13, the reaction of AllylS· with ex-
cess cycloalkyne 1 was explored using direct photolysis of
(AllylS)2 or photolysis of (AllylS)2 in the presence of cata-
lytic amounts (5%) of (PhS)2 and phenyl allyl sulfide,
respectively,[20] to generate AllylS·. However, independent of
the radical source, it turned out that neither variation of
reaction time (3.5–18.5 h), solvent (benzene, acetonitrile, cy-
clohexane), batch or syringe addition of the S-radical pre-
cursor(s), and reactant ratios did have a significant influ-
ence on the outcome, and formation of desired thioketones
14/15 was never observed (Scheme 14). Instead, GC–MS
analysis of the reaction mixture indicates formation of three
isomeric bicyclic sulfides 16d/17d in very moderate com-
Scheme 14.
Eur. J. Org. Chem. 2010, 4902–4911
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4909

K. J. Tan, J. M. White, U. Wille
FULL PAPER
311G** and BHandHLYP/cc-pVTZ levels of theory, using restric-
ted and unrestricted methods for closed- and open-shell systems,
respectively. The optimized structures were verified by vibrational
frequency analysis at the same levels of theory, and all identified
transition states showed only one imaginary frequency. Vibrational
frequencies also provided zero-point vibrational energy corrections
(ZPC), which were applied to all energies. For each of the opti-
mized geometries, the spin expectation value, ‹s2›, was very close to
0.75 after spin annihilation (‹s2›A) for doublet radicals (except for
the transition state for the reaction 29bǞ30, where ‹s2›A = 0.762).
respectively, to give the cyclodecene derivative 31c, whereas
16c/17c were not formed. Thus, it appears that thiols are
excellent compounds for studying the kinetics of the trans-
annular radical translocation steps in self-terminating radi-
cal cyclizations, and we will explore this in detail in our
future work.
Based on these findings, we have to conclude that self-
terminating radical cyclizations in the “original” sense can-
not be performed with S-radicals. However, the sequence
consisting of intermolecular S-radical addition to alkynes, The archive entries of the Gaussian output files for all optimized
ground and transition state structures are available in the Support-
ing Information
followed by transannular radical translocation and termina-
tion through reduction is energetically highly favourable
and offers exciting opportunities for the synthesis of com-
plex bicyclic frameworks possessing a thioether moiety in a
regioselective fashion in only few steps. Of the various S-
radicals studied in this work, the reaction of cycloalkyne 1
with BnS·, tBuS· and AllylS·, respectively, was considerably
slower, and the cyclization cascade apparently less efficient,
than with PhS·.
Our experimental and computational studies revealed
some remarkable differences between reactions of S-centred
radicals compared to O- and N-centred radicals, respec-
tively. Thus, in contrast to self-terminating radical cycliza-
tions involving O- and N-centred radicals, where only prod-
ucts with cis-fused bicyclic frameworks were obtained,[1–3]
the reactions involving S-centred radicals leads also to
trans-configured bicyclic products, which is highly unusual
for intramolecular radical cyclizations resulting in forma-
tion six-membered ring systems.[21] According to our calcu-
lations, this is caused by the reversibility of the initial S-
radical addition to the CϵC triple bond in cycloalkyne 1.
This leads to different conformational isomers of vinyl radi-
cal 9, which can either undergo a cis or a trans selective
radical translocation/cyclization, respectively.
Another remarkable difference is the apparent regioselec-
tivity of the transannular radical translocation steps follow-
ing initial addition of the S-radical to the CϵC triple bond
in cycloalkyne 1. Whereas the reactions involving O- and
N-centred radicals always give a mixture of products pos-
sessing either a [4.4.0]- or [5.3.0]-bicyclic framework (due to
similar rates of the 1,5- and 1,6-HAT),[1–3] in the reactions
with S-centred radicals (or at least in the case of PhS·,
where unequivocal identification of the major products was
possible), the transannular radical cascade leads exclusively
to the [4.4.0]-bicyclic framework. Although we have cur-
rently no clear explanation for the unexpected preference of
the 1,6-HAT compared to the alternative 1,5-HAT in the
radical cyclizations initiated by S-radicals, it may be sug-
gested that these different regioselectivites are caused by
differences in the electron density at the C=C double bond
in the respective vinyl radicals. Computational studies are
currently underway in our group to explore this hypothesis
further.
Experimental Methods: (PhS)2, BnSH, tBuSH and (AllylS)2 were
commercially available and directly used. Cyclodecyne (1) was syn-
thesized according to ref.[1a] The flame ionization detector of the
GC was calibrated for quantitative analysis against n-hexadecane
as an internal standard using an authentic sample of the sulfide
mixture cis/trans-17a. The obtained peak area correction factor,
fGC, for these compounds was compared with correction values,
fECN, obtained for the same compounds using the incremental ECN
method,[23] to give the correlation factor fc, where fc = fGC/fECN
.
Using the fc value, the peak area correction factors for the sulfide
mixtures obtained in the individual experiments, fGC(calc), were then
determined according to fGC(calc) = fc ϫ fECNx, where fECNx is the
fECN for each of the corresponding sulfides x. Details on all reac-
tions performed in this study, including analytical and spectro-
scopic data, are given in the Supporting Information
General Procedure for Photochemical Generation of Thiyl Radicals:
The solution level of a solution of alkyne 1 and radical precursor
(in benzene, acetone, acetonitrile or cyclohexane) in a pyrex (or
quartz for irradiation at λ = 254 nm) test-tube was marked. A fur-
ther 1–2 mL of solvent was added, and the solution was thoroughly
degassed by sonicating under a constant stream of nitrogen for at
least 15 min, where the solution level returned to the marked level.
The solutions were irradiated λ = 254, 300 or 350 nm in a Rayonet
photoreactor, under an argon atmosphere for the required reaction
time at room temperature. After the reaction, the solvent level was
restored, a known amount of standard solution (n-hexadecane in
ethyl acetate) was added to the reaction solution, and the reaction
mixture was analysed by GC.
Supporting Information (see also the footnote on the first page of
this article): Experimental conditions and spectroscopic data for all
reactions, Gaussian archive entries for all ground and transition
states.
CCDC-779074 (for cis-28) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
Acknowledgments
This work was supported by the Australian Research Council un-
der the Centre of Excellence Scheme the High Performance Com-
puting Resource (“Kirkland”) at the University of Melbourne and
the National Computational Infrastructure facility. K. J. T. is grate-
ful for the receipt of a Science Faculty Scholarship and an Albert
Shimmins Postgraduate Writing-Up Award. We thank Dr. D. Scan-
lon and J. Karas for technical support.
Experimental Section
Computational Methods: Geometry optimizations were performed
[1] a) U. Wille, C. Plath, Liebigs Ann./Recueil 1997, 111–119; b)
C. Jargstorff, U. Wille, Eur. J. Org. Chem. 2003, 3173–3178; c)
with the Gaussian 03 software package[22] at the BHandHLYP/6-
4910
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 4902–4911

Self-Terminating Radical Cyclizations
U. Wille, Org. Lett. 2000, 2, 3485–3488; d) U. Wille, J. Am.
Chem. Soc. 2002, 124, 14–15; e) T. Dreessen, C. Jargstorff, L.
Lietzau, C. Plath, A. Stademann, U. Wille, Molecules 2004, 9,
480–497; f) D. Sigmund, C. H. Schiesser, U. Wille, Synthesis
2005, 1437–1444; g) A. Stademann, U. Wille, Aust. J. Chem.
2004, 57, 1055–1066; h) U. Wille, L. Lietzau, Tetrahedron 1999,
55, 10119–10134.
[12] a) P. Mueller, G. Bernardinelli, H. C. Godoy-Nguyen Thi, Helv.
Chim. Acta 1989, 72, 1627–1638; b) N. S. Simpkins, Sulphones
in Organic Synthesis, Pergamon Press, Oxford, New York, Se-
oul, Tokyo 1993.
[13] It was shown in an undependent experiment that 16a/17a did
not undergo cis/trans isomerization of the bicyclic ring system
under the conditions of the radical reactions.
[14] A. D. Becke, J. Chem. Phys. 1993, 98, 5648–5652.
[15] J. Fossey, D. Lefort, J. Sorba, Free Radicals in Organic Chemis-
try, John Wiley & Sons, Masson, Chichester, New York, Bris-
bane, Toronto, Singapore, Paris, Milan, Barcelona, 1995.
[16] D. Melandri, P. C. Montevecchi, M. L. Navacchia, Tetrahedron
1999, 55, 12227–12236.
[17] A. R. Knight, in: The Chemistry of the Thiol Group (Ed.: S.
Patai), John Wiley & Sons, London, New York, Sydney, To-
ronto, 1974, pp. 455–479.
[18] a) G. Capozzi, G. Modena, in: The Chemistry of the Thiol
Group (Ed.: S. Patai), John Wiley & Sons, London, New York,
Sydney, Toronto, 1974, pp. 785–839; b) J. Yoshida, S. Nakatani,
S. Isoe, J. Org. Chem. 1993, 58, 4855–4865.
[19] The ESI-HRMS data clearly show that the new compound can
not possess the molecular formula C10H16O2, which has a
calcd. [M + H+] at m/z = 169.12231.
[2] U. Wille, manuscript in preparation.
[3] U. Wille, G. Heuger, C. Jargstorff, J. Org. Chem. 2008, 73,
1413–1421.
[4] a) M. P. Bertrand, C. Ferreri, in: Radicals in Organic Synthesis,
vol. 2 (Eds.: P. Renaud, M. P. Sibi), Wiley-VCH, Weinheim,
New York, Chichester, Brisbane, Singapore, Toronto, 2001, pp.
485–504; b) C. Chatgilialoglu, M. P. Bertrand, C. Ferreri, in:
S-Centered Radicals (Ed.: Z. B. Alfassi), John Wiley & Sons,
Chichester, New York, Weinheim, Brisbane, Singapore, To-
ronto, 1999, pp. 311–354; c) O. Ito, Res. Chem. Intermed. 1995,
21, 69–93.
[5] a) J. Nakayama, K. Takahashi, Y. Sugihara, A. Ishii, Tetrahe-
dron Lett. 2001, 42, 4017–4019; b) J. Nakayama, K. Takahashi,
Y. Ono, M. Morita, Y. Sugihara, A. Ishii, Heteroat. Chem.
2002, 13, 424–430; c) F. Toda, Y. Tokunaga, Chem. Lett. 1987,
1299–1300.
[6] a) W. M. McGregor, D. C. Sherrington, Chem. Soc. Rev. 1993,
22, 199–204; b) E. Schaumann, Top. Curr. Chem. 2007, 274, 1–
34.
[20] K. J. Tan, PhD Thesis, The University of Melbourne, 2009.
[21] D. P. Curran, N. A. Porter, B. Giese, Stereochemistry of Radical
Reactions, VCH, Weinheim, New York, Basel, Cambridge, To-
kyo, 1996.
[7] Radical cascades initiated by intermolecular addition of PhS·
to (predominantly terminal) alkynes have been reported, see
for example: a) G. E. Keck, T. T. Wagner, J. Org. Chem. 1996,
61, 8366–8367; b) P. C. Montevecchi, M. L. Navacchia, Recent
Res. Devel. Org. Bioorg. Chem. 1997, 1, 1–13; c) P. C. Monte-
vecchi, M. L. Navacchia, P. Spagnolo, Tetrahedron Lett. 1997,
38, 7913–7916; d) F. Dénès, F. Beaufils, P. Renaud, Org. Lett.
2007, 9, 4375–4378; e) M. Lachia, F. Dénès, F. Beaufils, P. Re-
naud, Org. Lett. 2005, 7, 4103–4106; f) F. Beaufils, F. Dénès,
P. Renaud, Org. Lett. 2004, 6, 2563–2566; g) G. K. Friestad, T.
Jiang, G. M. Fioroni, Tetrahedron: Asymmetry 2003, 14, 2853–
2856; h) C. A. Broka, D. E. C. Reichert, Tetrahedron Lett.
1987, 28, 1503–1506.
[22] M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria,
M. A. Robb, J. R. Cheeseman, J. A. Montgomery Jr., T.
Vreven, K. N. Kudin, J. C. Burant, J. M. Millam, S. S. Iyengar,
J. Tomasi, V. Barone, B. Mennucci, M. Cossi, G. Scalmani, N.
Rega, G. A. Petersson, H. Nakatsuji, M. Hada, M. Ehara, K.
Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y.
Honda, O. Kitao, H. Nakai, M. Klene, X. Li, J. E. Knox, H. P.
Hratchian, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R.
Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R.
Cammi, C. Pomelli, J. W. Ochterski, P. Y. Ayala, K. Morok-
uma, G. A. Voth, P. Salvador, J. J. Dannenberg, V. G. Zakrzew-
ski, S. Dapprich, A. D. Daniels, M. C. Strain, O. Farkas, D. K.
Malick, A. D. Rabuck, K. Raghavachari, J. B. Foresman, J. V.
Ortiz, Q. Cui, A. G. Baboul, S. Clifford, J. Cioslowski, B. B.
Stefanov, G. Liu, A. Liashenko, P. Piskorz, I. Komaromi, R. L.
Martin, D. J. Fox, T. Keith, M. A. Al-Laham, C. Y. Peng, A.
Nanayakkara, M. Challacombe, P. M. W. Gill, B. Johnson, W.
Chen, M. W. Wong, C. Gonzalez, J. A. Pople, Gaussian 03, rev.
D.01 and E.01, Gaussian, Inc., Wallingford CT, 2004.
[8] K. J. Tan, U. Wille, Chem. Commun. 2008, 6239–6241.
[9] R. M. Silverstein, G. C. Bassler, T. C. Morrill, Spectrometric
Identification of Organic Compounds, 5th ed., John Wiley &
Sons, Inc., New York, Chichester, Brisbane, Toronto, Singa-
pore, 1991.
[10] NIST Chemistry WebBook, NIST Standard Reference Database
Number 69, National Institute of Standards and Technology,
Gaithersburg MD, 20899, http://webbook.nist.gov (Eds.: P. J. [23] a) J. C. Sternberg, W. S. Gallaway, D. T. L. Jones, Gas Chro-
Linstrom, W. G. Mallard) (retrieved 2006–2009).
[11] a) J. L. Wardell, in: The Chemistry of the Thiol Group (Ed.: S.
Patai), John Wiley & Sons, London, New York, Sydney, To-
ronto, 1974, pp. 163–269; b) Y. Schaafsma, A. F. Bickel, E. C.
Kooijman, Tetrahedron 1960, 10, 76–80.
matog., Intern. Symp. 1961 1962, 3, 231–267; b) A. D. Jorgen-
sen, K. C. Picel, V. C. Stamoudis, Anal. Chem. 1990, 62, 683–
689.
Received: May 8, 2010
Published Online: July 16, 2010
Eur. J. Org. Chem. 2010, 4902–4911
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4911