Iron-Induced regio- and stereoselective addition of sulfenyl chlorides to alkynes by a radical pathway

Article abstract of DOI:10.1002/anie.201408121

The radical addition of the ClS s-bond in sulfenyl chlorides to various C~C triple bonds has been achieved with excellent regio- and stereoselectivity in the presence of a catalytic amount of a common iron salt. The reaction is compatible with a variety of functional groups and can be scaled up to the gram-scale with no loss in yield. As well as terminal alkynes, internal alkynes underwent stereodefined chlorothiolation to provide tetrasubstituted alkynes. Preliminary mechanistic investigations revealed a plausible radical process involving a sulfur-centered radical intermediate via iron-mediated homolysis of the ClS bond. The resulting chlorothiolation adducts can be readily transformed to the structurally complex alkenyl sulfides by cross-coupling reactions. The present reaction can also be applied to the complementary synthesis of the potentially useful bis-sulfoxide ligands for transition-metal-catalyzed reactions.

Full text of DOI:10.1002/anie.201408121

Angewandte
Chemie
DOI: 10.1002/anie.201408121
Iron Catalysis
Iron-Induced Regio- and Stereoselective Addition of Sulfenyl
Chlorides to Alkynes by a Radical Pathway**
Masayuki Iwasaki, Tomoya Fujii, Kiyohiko Nakajima, and Yasushi Nishihara*
À
Abstract: The radical addition of the Cl S s-bond in sulfenyl
corresponding adducts can be converted into complex and
À
chlorides to various C C triple bonds has been achieved with
diverse alkenyl sulfides by the transformation of the chloro
moieties. Therefore, several efficient methods have been
developed to synthesize 2-chloroalkenyl sulfides by chloro-
excellent regio- and stereoselectivity in the presence of
a catalytic amount of a common iron salt. The reaction is
compatible with a variety of functional groups and can be
scaled up to the gram-scale with no loss in yield. As well as
terminal alkynes, internal alkynes underwent stereodefined
chlorothiolation to provide tetrasubstituted alkynes. Prelimi-
nary mechanistic investigations revealed a plausible radical
process involving a sulfur-centered radical intermediate via
À
thiolation of alkynes through S Cl bond cleavage of sulfenyl
chlorides.[6,7] The reaction of terminal alkynes 1 with sulfenyl
chloride 2 proceeds in an anti fashion to give adduct (E)-3 as
the sole product, probably via the thiirenium intermediate
A[6c–e] (Scheme 1A). However, conventional methods could
not provide the other isomers (Z)-3 and (E)/(Z)-4.[8] More-
À
iron-mediated homolysis of the Cl S bond. The resulting
chlorothiolation adducts can be readily transformed to the
structurally complex alkenyl sulfides by cross-coupling reac-
tions. The present reaction can also be applied to the
complementary synthesis of the potentially useful bis-sulfoxide
ligands for transition-metal-catalyzed reactions.
A
ddition of heteroatom–heteroatom bonds to carbon–
carbon triple bonds has been considered to be one of the
most powerful methods to install two heteroatoms efficiently
in one step.[1] Among such reactions, the addition of organo-
sulfur compounds to alkynes has been extensively studied[2]
owing to the utility of the resulting alkenyl sulfides as
bioactive compounds.[3] Although various addition reactions
À
of S E (E = B, Si, P, S, Se, Te, etc.) bonds to alkynes have been
reported,[4,5] chlorothiolation across alkynes represents an
attractive research topic in organic synthesis because the
[*] Dr. M. Iwasaki, T. Fujii, Prof. Dr. Y. Nishihara
Division of Earth, Life, and Molecular Sciences
Graduate School of Natural Science and Technology
Okayama University, 3-1-1 Tsushimanaka, Kita-ku
Okayama 700-8530 (Japan)
E-mail: ynishiha@okayama-u.ac.jp
Prof. Dr. K. Nakajima
Scheme 1. Chlorothiolation of alkynes.
Department of Chemistry, Aichi University of Education
Igaya, Kariya 448-8542 (Japan)
Prof. Dr. Y. Nishihara
ACT-C Japan Science and Technology Agency
4-1-8 Honcho, Kawaguchi, Saitama 332-0012 (Japan)
over, when unsymmetrical internal alkynes were employed
without any catalysts, the reaction gave a mixture of the regio-
and stereoisomers.[6c–e] To overcome such significant draw-
backs, we have investigated the transition-metal-catalyst-
controlled regio- and stereoselective chlorothiolation of
alkynes. Recently, we showed that a palladium catalyst
could totally switch the reaction mode in the chlorothiolation
of terminal alkynes, affording syn adducts (Z)-4 with high
regio- and stereoselectivity (Scheme 1B).[9] Although (E)-3
and (Z)-4 had been prepared, the selective synthesis of (E)-4
isomers has not been well-studied. This is because organo-
sulfur compounds had been believed to be a catalyst poison[10]
for the transition-metal catalysts that can control the selec-
[**] This work was partly supported by a Grant-in-Aid for Scientific
Research (KAKENHI) (No. 26810060) from JSPS and the MEXT
program for promoting the enhancement of research universities.
The authors gratefully thank Prof. Dr. Yoshimi Sueishi and Misato
Sue (Okayama University) for the ESR measurements and fruitful
discussions, Megumi Kosaka and Motonari Kobayashi (Department
of Instrumental Analysis, Advanced Science Research Center,
Okayama University) for the measurements of elemental analyses,
and the SC NMR Laboratory of Okayama University for the NMR
measurements.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201408121.
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tivity of the addition reaction. As a result of their potential
utility as synthetic intermediates,[11] a practical synthetic route
to prepare (E)-4 has been required for many years. During the
course of our work, we found that cheap and abundant iron
catalysts could absolutely control the selectivity of the
reaction to yield (E)-4 (Scheme 1C). Notably, unsymmetrical
internal alkyne 5 served as the substrate to furnish tetrasub-
stituted olefin (E)-6 with perfect selectivity. Herein, we report
the first complementary synthesis of 2-chloroalkenyl sulfides
by a radical pathway by simply selecting the appropriate
transition-metal catalyst.
by comparison of the spectroscopic data for the known
sulfone 7, which was prepared by oxidation of (E)-4a. The
precise configuration was unambiguously confirmed by
single-crystal X-ray analysis of 7 (Figure 1).[14]
To investigate the regio- and stereoselectivity of chloro-
thiolation using transition-metal catalysts, we first examined
the reaction of phenylacetylene (1a) with benzenesulfenyl
chloride (2a) in toluene at room temperature (Scheme 2).[12]
In the absence of any catalyst, an anti chlorothiolation adduct
Figure 1. ORTEP Drawing of 7 with thermal ellipsoids set at 30%
probability. Hydrogen atoms on the benzene rings are omitted for
clarity.
Next, we carried out the iron-induced chlorothiolation of
various terminal alkynes 1 with benzenesulfenyl chloride (2a)
to obtain the corresponding adducts (E)-4. Instead of 1a,
various arylethynes 1b–1e which have an electron-donating
methyl group and electron-withdrawing chloro, cyano, or
trifluoromethyl groups reacted with 2a to give the corre-
sponding adducts (E)-4b–4e in good yield (Table 1, entries 1–
Scheme 2. Addition of benzenesulfenyl chloride (2a) to phenylacety-
lene (1a).
Table 1: Iron-induced chlorothiolation of terminal alkynes 1 with sulfenyl
chlorides 2.[a]
(E)-3a was solely formed in 38% yield, as reported previ-
ously.[6] In sharp contrast, in the presence of Pd(tfa)2
(10 mol%; tfa = trifluoroacetate), the reaction provided
(Z)-4a in 84% NMR yield with high regio- and stereo-
selectivity.[9] After extensive surveys of transition-metal
catalysts,[12] we found that iron salts facilitate the novel
anti chlorothiolation to yield (E)-4a preferentially over the
other three regio- and stereoisomers. Indeed, the desired
product (E)-4a was obtained in 36% yield when FeCl3 was
employed as the catalyst. FeCl2 and FeBr2 were shown to be
the optimal catalysts, both of which could catalyze the
Entry
R
R’
Product Yield [%][b]
1
2
3
4
Ph (1a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
Ph (2a)
(E)-4a
(E)-4b
(E)-4c
(E)-4d
(E)-4e
(E)-4 f
(E)-4g
(E)-4h
(E)-4i
(E)-4j
(E)-4k
(E)-4l
(E)-4m
(E)-4n
81
76
81
66
p-MeC6H4 (1b)
p-ClC6H4 (1c)
p-NCC6H4 (1d)
p-F3CC6H4 (1e)
2-Naphthyl (1 f)
1-Naphthyl (1g)
nHex (1h)
Cl(CH2)4 (1i)
TsO(CH2)4 (1j)
PhthN(CH2)4 (1k) Ph (2a)
Me3Si (1l)
PhS (1m)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
5
71
6[c]
7[c]
8
71
À
selective addition of a Cl S bond to give (E)-4a predom-
60[e]
70
inantly. Other iron(II) catalysts, such as Fe(BF4)2·7H2O,
FeSO4·7H2O (melanterite), and Fe(acac)2 (acac = acetyl-
acetonato), were less effective, affording lower yields of
(E)-4a. To our surprise, metallic iron also showed catalytic
activity, producing regio- and stereoselective chlorothiola-
tion. Further examination revealed that the reaction pro-
ceeded smoothly (83% yield) even in the presence of FeCl2
(5 mol%), although the yield of (E)-4a was decreased to 54%
when FeCl2 (1 mol%) was employed.[13] Other ligands, such as
PPh3, DPPE (1,2-bis(diphenylphosphino)ethane), and
TMEDA (N,N,N’,N’-tetramethylethylenediamine), used
with the FeCl2 catalyst gave lower yields of (E)-4a.[12] The
choice of the reaction solvent was found to be crucial; non-
polar solvents (toluene, benzene, and chlorobenzene) can be
utilized, but polar solvents (THF, DMF, and AcOEt) were
ineffective.[12] Notably, the present reaction is scalable, and
1.9 g of (E)-4a was isolated in a comparable yield (77%) to
that obtained when the reaction was performed on a 1.0 mmol
scale (81%). The stereochemistry of (E)-4a was determined
9
59[e]
60[f]
46[e]
47
10[c]
11
12
13
14
15
16
17
18
19
20[d]
Ph (2a)
Ph (2a)
p-MeC6H4 (2b)
p-MeOC6H4 (2c) (E)-4o
p-BrC6H4 (2d)
p-F3CC6H4 (2e)
o-MeC6H4 (2 f)
o-BrC6H4 (2g)
Me (2h)
34[g]
88
81
83
58
96
86
54
(E)-4p
(E)-4q
(E)-4r
(E)-4s
(E)-4t
[a] Conditions: 1 (1.0 mmol), 2 (1.2 mmol), FeCl2 (0.050 mmol), toluene
(24 mL). [b] Yields of isolated product (E)-4, based on 1 after silica gel
column chromatography. [c] The reaction was performed with FeCl2
(10 mol%) for 24 h. [d] The reaction was performed with FeCl2
(10 mol%). [e] Obtained as a mixture of stereoisomers in a 93:7 ratio.
[f] Obtained as a mixture of stereoisomers in a 92:8 ratio. [g] Obtained as
a mixture of stereoisomers in a 74:26 ratio. PhthN=phthalimidyl.
TsO =tosyloxy, CH3C6H4SO3.
2
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Table 2: Iron-induced chlorothiolation of internal alkynes 5 with sulfenyl
chlorides 2.[a]
5). As well as 2-naphthylacetylene (1 f) giving rise to (E)-4 f,
the reaction of the sterically congested 1-naphthylacetylene
(1g) also afforded the desired product (E)-4g in 60% yield
(entries 6 and 7). An aliphatic terminal alkyne such as
1-octyne (1h) reacted with 2a under the same reaction
conditions to furnish the corresponding product (E)-4h in
70% yield (entry 8). No isomerization of (E)-4h with 2a was
detected in the present reaction in the nonpolar solvent
(toluene).[6f,g] Various functional groups were tolerated in the
chlorothiolation of 1 with 2a: chloro, tosyloxy, and phthali-
mide groups participated in the reaction to provide (E)-4i–4k
without any loss of the functional moieties (entries 9–11). It is
of note that both alkynylsilane 1l and alkynyl sulfide 1m
derivatives also underwent chlorothiolation to give 1,1,2-
trifunctionalized ethenes (E)-4l and (E)-4m (entries 12
and 13).
With the optimized conditions in hand, a wide range of
arenesulfenyl chlorides 2 were found to be employable in the
chlorothiolation of 1a (Table 1). The reaction was compatible
with electron-rich (methyl and methoxy) and electron-
deficient (bromo and trifluoromethyl) groups in the para
position of benzenesulfenyl chlorides 2b–2e (entries 14–17).
The substituents in the ortho position did not affect the
product yields and (E)-4r and (E)-4s were obtained in 96%
and 86% yields, respectively (entries 18 and 19).
Entry
R
R’
5
2
Product
Yield [%][b]
1
2
3
4
Ph
Ph
Ph
Ph
Ph
Ph
Ph
CO2Et
Me
Me
5a
5a
5b
5c
5d
5e
5 f
2a
2i
(E)-6a
(E)-6b
(E)-6c
(E)-6d[d]
(E)-6e
(E)-6 f
(E)-6g
(E)-6h
94
88
91
73
97
53
47
30
nBu
iPr
CO2Et
COMe
Cl
2a
2a
2a
2a
2a
2a
5[c]
6
7
8[c]
nBu
5g
[a] Conditions: 1 (1.0 mmol), 2 (1.2 mmol), FeCl2 (0.050 mmol), toluene
(24 mL). [b] Yields of isolated product (E)-6, based on 5 after silica gel
column chromatography. [c] The reaction was performed with FeCl2
(15 mol%) and Cl-SPh (3.6 equiv). [d] (Z)-6d was formed in 24% yield.
Our attempts to use alkyl-substituted sulfenyl chlorides
for the present iron-promoted chlorothiolation of alkynes
1 were unsuccessful because such sulfenyl chlorides were too
unstable to isolate and readily decomposed to generate
disulfides. We thus examined the one-pot reaction involving
the preparation of sulfenyl chloride and the subsequent
chlorothiolation of a terminal alkyne (entry 20). Dimethyl
disulfide was treated with sulfuryl chloride in situ to form
methanesulfenyl chloride (2h).[15] Phenylacetylene (1a) and
a catalytic amount of FeCl2 were subsequently added to the
reaction mixture, and the desired adduct (E)-4t was obtained
in 54% yield with high regio- and stereoselectivity.
Scheme 3. Proposed chlorothiolation reaction mechanism by a radical
pathway.
To our delight, iron-induced chlorothiolation of unsym-
metrical internal alkynes 5 also proceeded with excellent
regio- and stereoselectivity, whereas the reaction gave
of terminal alkyne 1 with sulfenyl chloride 2, as shown in
Scheme 3. As the first step toward the generation of the
radical species (initiation step), iron-mediated homolysis of
À
a
mixture of isomers without FeCl2 (Table 2). When
the S Cl bond of 2 may take place to give the corresponding
1-phenyl-1-propyne (5a) was employed, the selective reaction
with 2a and p-chlorobenzenesulfenyl chloride (2i) proceeded
exclusively to afford (E)-6a and (E)-6b as the single products
in 94% and 88% yields, respectively (entries 1 and 2).[16]
Additionally, other 1-alkyl-2-arylethynes, such as 1-phenyl-
1-hexyne (5b) and 1-phenyl-3-methyl-1-butyne (5c), pro-
vided (E)-6c and (E)-6d with the chlorine atom located at the
sulfenyl radical B.[19] Then, sulfur-centered radical B adds to
the less sterically hindered terminal carbon of 1 to form the
alkenyl radical C. This step may control the excellent
regioselectivity of the reaction. Finally, the radical
SH2 substitution of C with 2 affords the product (E)-4 and
regenerates the sulfenyl radical B to complete the radical
chain.[20] The high E-selectivity of the reaction can be
rationalized as follows. The alkenyl radical D may be as
abundant as C at equilibrium.[21] However, sulfenyl chloride 2
may approach the intermediary alkenyl radical C more
readily than D to avoid a steric repulsion from the sulfenyl
group.[22]
benzylic
position
(entries 3
and 4).
Furthermore,
phenylpropiolate 5d, ynone 5e, and alkynyl chloride 5 f also
underwent regio- and stereoselective chlorothiolation to give
the desired adducts (E)-6e–6g in moderate to high yields
(entries 5–7). It should be noted that ethyl 2-heptynolate (5g)
can also be used as the substrate, furnishing (E)-6h sub-
stituted with a chlorine in the a-position of an ester group
(entry 8).[17]
The present chlorothiolation was found to proceed
through a radical process by ESR analysis.[12,18] We thus
propose a radical mechanism for the present chlorothiolation
With respect to the regioselectivity in the chlorothiolation
of internal alkynes 5, the stability of the generated alkenyl
radical C has to be considered, as well as a steric congestion of
the substituents on alkynes 5.[23] As the benzylic radical is
highly stabilized by its delocalization into the benzene ring,[24]
(E)-6a–6g were obtained with perfect regioselectivity. The
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Communications
formation of (E)-6h can be explained by the stability order of
the alkenyl radical intermediates with the substituents
(CO2Et >alkyl). On the other hand, its stereoselectivity can
be explained by a mechanism that involves the addition of an
SRꢀ radical to develop a singly occupied sp2-hybridized
orbital on the side opposite to the SR’ group, which is
salt with 13 afforded the benchtop-stable palladium complex
14,[31] which could be a potent catalyst precursor similar to
Whiteꢀs catalyst.[32,33]
In summary, we have developed the first radical addition
of sulfenyl chlorides to alkynes by employing an iron catalyst,
which afforded (E)-2-chloroalkenyl sulfides with excellent
regio- and stereoselectivity. The present method provides
a synthesis for chlorothiolation adducts that could not be
prepared by earlier procedures. Several mechanistic studies
revealed that the reaction involves radical intermediates. The
synthetic utility of the present chlorothiolation was also
demonstrated by cross-coupling reactions (arylation,
alkynylation, and alkylation) of the adducts. The scalable
catalytic reaction proceeded with high functional group
compatibility under mild conditions, which should contribute
to the practical syntheses of bioactive complex alkenyl
sulfides.
À
followed by a rapid chlorine transfer thanks to a weak Cl S
bond.[22,25] As another possible pathway, the reaction could
proceed via cationic intermediates,[26] but no Lewis acid
except FeCl2 promoted selective chlorothiolation.[12]
To demonstrate the synthetic utility of the chlorothiola-
tion adducts obtained by the present method, we undertook
a series of reactions using the representative product (E)-4a
(Scheme 4). Mono-oxidation of (E)-4a with equimolar
Received: August 9, 2014
Revised: September 25, 2014
Published online: && &&, &&&&
Keywords: alkynes · chlorothiolation · iron · radical reactions ·
.
synthetic methods
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Scheme 4. Transformations of (E)-4a. a) mCPBA (1 equiv), CH2Cl2,
408C, 4 h. b) p-MeC6H4B(OH)2 (2 equiv), Pd(OAc)2 (5 mol%), XPhos
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3 h. d) MeMgBr (2 equiv), Pd(dba)2 (5 mol%), PtBu3 (10 mol%), THF,
508C, 4 h. XPhos=2-dicyclohexylphosphino-2’,4’,6’-triisopropyl-
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À
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À
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À
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À
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À
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Scheme 5. Synthesis of bis-sulfoxide ligand 13 and palladium complex
14.
4
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[8] E/Z isomerization of (E)-3 to (Z)-3 was reported in the presence
of an excess amount of sulfenyl chloride 2, see: Refs. [6f]
and [6g].
[9] M. Iwasaki, T, Fujii, A. Yamamoto, K. Nakajima, Y. Nishihara,
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[17] See the Supporting Information for the structural determination
of (E)-6h.
[18] The addition of TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl)
to the reaction of 1a with 2a totally suppressed the formation of
product (E)-4a, instead giving (E)-3a in 10% yield. Garvinoxyl
also suppressed the reaction, dramatically decreasing the yield of
(E)-4a to 20%. See the Supporting Information for details.
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[20] The reaction of 1a with 2a with a stoichiometric amount of
FeBr2 gave (E)-4a in 22% yield, whereas the
bromothiolated product (E)-8 was not detected
at all, which clearly indicates that the chlorine
atom in the product is derived from sulfenyl
chloride. This is also supported by the fact that
a catalytic reaction with FeBr2 did not provide
(E)-8 (Table S1, entry 5).
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[12] See the Supporting Information for details.
[13] As iron-induced chlorothiolation may involve a radical process,
a free-radical-mediated reaction was conducted. In fact, the
reaction with ZnEt2 in air gave (E)-4a in 17% yield although
neither BEt3 in air nor AIBN (azobisisobutyronitrile) systems
facilitated a radical addition. Besides, the reaction under photo-
irradiation with a high-pressure mercury quartz lamp (400 W)
gave a complex mixture of products.
[14] CCDC-1018081 (7) and 1018083 (13) contain the supplementary
crystallographic 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.
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[16] The configurations of (E)-6a and (E)-6b were in agreement with
previous reports, see: a) N. Taniguchi, Tetrahedron 2009, 65,
2782 – 2790; b) See Ref. [6d].
[33] With the prepared palladium/bis-sulfoxide catalyst 14 in hand,
À
allylic C H amidation of 1-decene with methyl N-tosylcarba-
mate was performed, but the yield was not satisfactory (10%),
though regio- and stereoselectivity of the amidation product was
excellent. See the Supporting Information for details.
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

.
Angewandte
Communications
Communications
Iron Catalysis
Radical action: Regio- and stereoselective
chlorothiolation of alkynes is achieved
with an inexpensive and abundant iron
catalyst. The reaction simultaneously
installs chloro and sulfenyl moieties on
terminal and internal alkynes, providing
synthetically useful tri- and tetrasubsti-
tuted alkenes with excellent selectivity by
a radical pathway. The utility of the
reaction is shown by transformations of
the adducts using cross-couplingreac-
tions.
M. Iwasaki, T. Fujii, K. Nakajima,
Y. Nishihara*
&&&& — &&&&
Iron-Induced Regio- and Stereoselective
Addition of Sulfenyl Chlorides to Alkynes
by a Radical Pathway
6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
These are not the final page numbers!