Reductive addition of the benzenethiyl radical to alkynes by amine-mediated single electron transfer reaction to diphenyl disulfide

Article abstract of DOI:10.1021/ol901084k

Hydrothiolation of alkynes proceeds with diphenyl disulfide and tripropylamine. Amine-mediated single electron transfer to diphenyl disulfide can be proposed for the reaction mechanism. Applications of the method to radical cyclizations of eneyne compound

Full text of DOI:10.1021/ol901084k

ORGANIC
LETTERS
2009
Vol. 11, No. 15
3298-3301
Reductive Addition of the Benzenethiyl
Radical to Alkynes by Amine-Mediated
Single Electron Transfer Reaction to
Diphenyl Disulfide
Tsuyoshi Taniguchi, Tatsuya Fujii, Atsushi Idota, and Hiroyuki Ishibashi*
School of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health
Sciences, Kanazawa UniVersity, Kakuma-machi, Kanazawa 920-1192, Japan
isibasi@p.kanazawa-u.ac.jp
Received May 18, 2009
ABSTRACT
Hydrothiolation of alkynes proceeds with diphenyl disulfide and tripropylamine. Amine-mediated single electron transfer to diphenyl disulfide
can be proposed for the reaction mechanism. Applications of the method to radical cyclizations of eneyne compounds are also presented.
A radical reaction is an efficient tool in synthetic organic
chemistry.1 Bu3SnH has frequently been used for a
hydrogen donor in the presence of a radical initiator such
as AIBN (2,2′-azobisisobutyronitrile). There are, however,
some disadvantages in using Bu3SnH, due to its toxicity
and difficulty in removing tin residue. Therefore, several
substitutes for Bu3SnH have been studied in recent
years.2,3 We have recently reported the synthesis of γ-lac-
tams by a cyclization of trichloroacetamides in heated 1,4-
dimethylpiperazine used as a solvent.4 We considered that
this reaction was a tin-free radical cyclization that proceeded
by a single electron transfer (SET) reaction5,6 of amine to
trichloroacetamides.
In 1964, Wang reported that the sulfur-sulfur bond in
diphenyl disulfide (1) was cleaved by an amine such as N,N-
dimethylaniline to give solidified materials (polymers) by
reaction with acrylonitrile.7 The author proposed that this
reaction proceeded by a single electron transfer mechanism.
However, unfortunately, no synthetic usefulness of this
reaction has so far been demonstrated.
Herein, we report an efficient synthesis of vinyl sulfides
3 by treatment of a mixture of diphenyl disulfide (1) and
alkynes 2 with tripropylamine (Scheme 1, eq 1). Applications
(1) For reviews, see: (a) Renaud, P.; Sibi, M. P. Radical in Organic
Synthesis; Wiley-VCH: Weinheim, 2001. (b) Gansa¨uer, A., Ed. Topics
Current Chemistry; Radicals in Synthesis I and II; Springer: Berlin, 2006;
Vols. 263 and 264.
(4) (a) Ishibashi, H.; Haruki, S.; Uchiyama, M.; Tamura, O.; Matsuo, J.
Tetrahedron Lett. 2006, 47, 6263. (b) Taniguchi, T.; Kawajiri, R.; Ishibashi,
H. ArkiVoc 2008, xiV, 7. (c) Ishibashi, H.; Sasaki, M.; Taniguchi, T.
(2) For reviews, see: (a) Baguley, P. A.; Walton, J. C. Angew. Chem.,
Int. Ed. 1998, 37, 3072. (b) Studer, A.; Amrein, S. Synthesis 2002, 835
.
Tetrahedron 2008, 64, 7771.
(3) For recent examples, see: (a) Schaffner, A.-P.; Darmency, V.;
Renaud, P. Angew. Chem., Int. Ed. 2006, 45, 5847. (b) Medeiros, M. R.;
Schacherer, L. N.; Spiegel, D. A.; Wood, J. L. Org. Lett. 2007, 9, 4427. (c)
Smith, D. M.; Pulling, M. E.; Norton, J. R. J. Am. Chem. Soc. 2007, 129,
770. (d) Gansa¨uer, A.; Fan, C.-A.; Piestert, F. J. Am. Chem. Soc. 2008,
130, 6916. (e) Ueng, S.-H.; Makhlouf Brahmi, M.; Derat, E.; Fensterbank,
L.; Lacoˆte, E.; Malacria, M.; Curran, D. P. J. Am. Chem. Soc. 2008, 130,
10082. (f) Quiclet-Sire, B.; Zard, S. Z. Org. Lett. 2008, 10, 3279. (h)
(5) For a review, see: Rossi, R. A.; Pierini, A. B.; Peory, A. B. Chem.
ReV. 2003, 103, 71
.
(6) For recent examples of a single electron reaction, see: (a) Murphy,
J. A.; Khan, T. A.; Zhou, S.-Z.; Thomason, W. D.; Mahesh, M. Angew.
Chem., Int. Ed. 2005, 45, 1356. (b) McGlacken, G. P.; Khan, T. A. Angew.
Chem., Int. Ed. 2008, 47, 1819
.
(7) (a) Wang, C.-H. Nature 1964, 203, 75. (b) Wang, C.-H.; Linnell,
S. M.; Rosenblum, R.; Wang, N. Experientia 1971, 27, 243. (c) Wang,
C.-H.; Linnell, S. M.; Wang, N. J. Org. Chem. 1971, 36, 525.
Akindele, T.; Yamada, K.; Tomioka, K. Acc. Chem. Res. 2009, 42, 345
.
10.1021/ol901084k CCC: $40.75
Published on Web 07/02/2009
 2009 American Chemical Society

Scheme 1
.
Thiol-Mediated Radical Hydrothiolation of Alkynes
Table 1. Screening of Amines
of the method to radical cyclizations of eneyne compounds
12 are also presented.8
It is well-known that the benzenethiyl radical formed from
thiophenol in the presence of AIBN undergoes an addition
reaction with alkynes to give vinyl sulfides (Scheme 1, eq
2).9 In this reaction, the use of ill-smelling thiophenol and a
hazardous radical initiator such as AIBN was required.
Although many reactions of alkynes with disulfides have
developed, disulfidation products are generally obtained.10
To the best of our knowledge, reductive radical reaction of
alkynes with disulfide to give 1-alkenyl sulfides has not been
explored.11
a Yield of isolated products. b Ratio of E:Z determined by 1H NMR
We initiated our investigation by examining the reaction
of diphenyl disulfide (1) with phenylacetylene (2a) with 40
equiv of boiling 1,4-dimethylpiperazine to give vinyl sulfide
3a in 63% yield as a 4:1 mixture of E- and Z-isomers along
with a small amount (7% yield) of disulfidated compound
4a (Table 1, entry 1). A similar reaction using triethylamine
was found to improve the yield of desired compound 3a in
a short reaction time (Table 1, entry 3). Pyridine, however,
gave no compounds 3a and 4a (Table 1, entry 7). Of the
several amines examined, tripropylamine gave the best
results, affording 3a in 83% yield (E:Z ) 85:15) together
with 4a (4%) (Table 1, entry 4).12
analysis.
At room temperature, however, a long reaction time was
required, and the yield of 3a also decreased (Scheme 2, eq
Scheme 2. Amine-Mediated Radical Hydrothiolation of
Phenylacetylene under Various Reaction Conditions
Reactions of a mixture of 1 and 2a with tripropylamine
were examined in more detail. The use of a reduced amount
of tripropylamine gave products in lower yield.13 When the
reactions were carried out in a temperature range of 80-140
°C, no dramatic change in the yield of 3a was observed.13
(8) For a review on thiol-mediated radical cyclizations, see: Majumdar,
K. C.; Debnath, P. Tetrahedron 2008, 64, 9799.
(9) Benati, L.; Montevecchi, P. C.; Spagnolo, P. J. Chem. Soc., Perkin
Trans. 1 1991, 2103.
(10) For recent examples of disulfination of alkynes, see: (a) Usugi, S.-
i.; Yorimitsu, H.; Shinokubo, H.; Oshima, K. Org. Lett. 2004, 6, 601. (b)
Ananikov, V. P.; Kabeshov, M. A.; Beletskaya, I. P.; Khrustalev, V. N.;
Antipin, M. Y. Organometallics 2005, 24, 1275. Thioselenation of alkynes
using disulfide and photoirradiation has also been reported by Ogawa and
co-workers, see: (c) Ogawa, A.; Obayashi, R.; Ine, H.; Tsuboi, Y.; Sonoda,
N.; Hirao, T. J. Org. Chem. 1998, 63, 881.
(11) For recent examples of hydrothiolation of alkynes, see: (a) Kondoh,
A.; Takami, K.; Yorimitsu, H.; Oshima, K. J. Org. Chem. 2005, 70, 6468.
(b) Wang, Z.-L.; Tang, R.-Y.; Luo, P.-S.; Deng, C.-L.; Zhong, P.; Li, J.-H.
Tetrahedron 2008, 64, 10670. (c) Sato, A.; Yorimitsu, H.; OshimaK. Synlett
2009, 28. (d) Weiss, C. J.; Wobser, S. D.; Marks, T. J. J. Am. Chem. Soc.
2009, 131, 2062. (e) Yang, J.; Sabarre, A.; Fraser, L. R.; Patrick, B. O.;
Love, J. A. J. Org. Chem. 2009, 74, 182.
1). We soon found that the addition of water at room
temperature improved the yield of 3a (Scheme 2, eq 1). This
was presumed to be because water accelerated the hydrogen
atom donation to the vinyl radical intermediate 10 (vide infra)
to give 3a.14 On the other hands, no reaction occurred with
the addition of a substoichiometric amount of TEMPO
(2,2,6,6-tetramethyl-1-piperidinyl 1-oxyl) as a radical scav-
(12) It is well known that the thiyl radical isomerizes the Z-isomer of
the olefinic compound to the corresponding E-isomer. However, (Z)-1-
phenyl-2-(phenylsulfanyl)ethene was not entirely isomerized to the E-isomer
by treatment of diphenyl disulfide (3) with tripropylamine. For a example
of thiol-mediated olefin isomerization, see: Chatgilialoglu, C.; Ferreri, C.
Acc. Chem. Res. 2005, 38, 441.
(14) It was reported that the rate of radical trapping by thiol was
increased in the presence of water. See: Tranche, C.; Martinez, F. N.; Horner,
J. H.; Newcomb, M. Tetrahedron Lett. 1996, 37, 5845.
(13) See Supporting Information.
Org. Lett., Vol. 11, No. 15, 2009
3299

enger, suggesting that this reaction proceeds by a radical
mechanism (Scheme 2, eq 1). The use of 0.6 equiv of 1 at
140 °C did not result in a significant decrease in yield of 3a
(Scheme 2, eq 2), suggesting that two sulfur atoms of
disulfide might be incorporated into phenylacetylene (2a).
Interestingly, the use of dimethyl disulfide in place of
diphenyl disulfide gave no product (Scheme 2, eq 3).
A plausible mechanism for the reaction is shown in
Scheme 3. The reaction may be initiated by single electron
Table 2. Amine-Mediated Addition of Benzenethiyl Radical to
Various Alkynes
yield (%)a
entry
2
R1
R2
t (h)
3 (E:Z)b
4
1
2
3
4
5
6
7
b
c
d
e
f
4-ClC6H4
4-MeOC6H4
4-NO2C6H4
C6H13
TBDPSOCH2
TsNHCH2
Ph
H
H
H
H
H
H
Me
3
2
24
2.5
18.5
6
2
2
10
10
64 (71:29)
79 (71:29)
trace
2
trace
trace
trace
5
-
-
-
-
-
Scheme 3. Plausible Mechanism
74 (50:50)
63 (67:33)
68 (63:37)
66 (57:43)
88 (57:43)c
52 (n.d.)
g
h
8
i
Ph
Ph
60 (n.d.)c
a Yield of isolated products. b Ratio of E:Z determined by 1H NMR
analysis. c 2 equiv of water was added.
smelling thiophenol, and (2) products can be obtained after
simple removal of tripropylamine by a conventional evapora-
tor followed by usual chromatography.
transfer (SET) reaction of tripropylamine to disulfide 1 to
generate an anion radical 5 and a cation radical 6. The S-S
bond fission of anion radical 5 generates benzenethiyl radical
(7) and thiolate anion 8. An attack of thiyl radical 7 on the
alkyne 2a gives the vinyl radical 10, which then abstracts a
hydrogen atom from benzenethiol (9) to give vinyl sulfide
3a together with the benezenthiyl radical (7). It should be
noted that the formation of benzenethiol (9) might be a result
of the removal of a proton of cation radical 6 (proton removal
of 6 gives radical 11). Therefore, a single electron transfer
reaction between tripropylamine and diphenyl disulfide (3)
to form cation radical 6 is important to give vinyl sulfides
3a. Partial formation of compound 4a might be a result of
an attack of vinyl radical 10 on diphenyl disulfide (1).
The results of the reactions of 1 with other alkynes 2 (1.0
equiv) with tripropylamine are summarized in Table 2.
Arylacetylenes 2b and 2c bearing a halogen and an electron-
donating group on the aromatic ring provided the corre-
sponding vinyl sulfides 3b and 3c in good yields (Table 2,
entries 1 and 2), whereas p-nitrophenylacetylene (2d) gave
only a trace amount of the desired product 3d (Table 2, entry
3). Several aliphatic alkynes 2e-g gave the corresponding
vinyl sulfides 3e-g in good yields (Table 2, entries 4-6).
Furthermore, the internal alkynes 2h,i underwent the desired
reaction to give the corresponding vinyl sulfides 3h,i in good
yields (Table 2, entries 7 and 8).15
Applications of this method to radical cyclization of
eneyne derivatives 12 were examined next. When the
cyclization precursor 12a was treated with 1.1 equiv of
phenyl disulfide in 40 equiv of tripropylamine at 140 °C, a
mixture of 5-exo products 13a and 14a and 6-endo products
15a was obtained in 76% total yield (Table 3, entry 1).
Table 3. Amine-Mediated Radical Cyclization of Eneyne 14a
entry
1 (equiv)
t (h)
yield (%)a
ratiob (13a:14a:15a)
1
1.1
1.1
1.1
2.0
8
10
8
76
84
79
79
46:11:43
28:4:68
50:11:39
56:17:27
1
2c
3d
4d
The advantages of the present reaction are as follows: (1)
all reagents employed herein are inexpensive and have low
toxicity, and the reaction does not require the use of ill-
7
a Yield of isolated products. Ratio determined by H NMR analysis.
b
c 400 equiv of Pr3N was employed. d 2 equiv of water was added.
(15) For examples of addition of thiyl radical to internal alkynes, see:
(a) Ichinose, Y.; Wakamatsu, K.; Nozaki, K.; Birbaum, J.-L.; Oshima, K.;
Utimoto, K. Chem. Lett. 1987, 16, 1647. (b) Montevecchi, P. C.; Navacchia,
M. L.; Spagnolo, P. Eur. J. Org. Chem. 1998, 1219. (c) Montevecchi, P. C.;
Navacchia, M. L.; Spagnolo, P. Tetrahedron 1998, 54, 8207. (d) Ferna´ndez-
Gonza´lez, M.; Alonso, R. J. Org. Chem. 2006, 71, 6767.
Formation of 15a can be explained by a rearrangement of
intermediate A via a ring expansion process of the cyclo-
3300
Org. Lett., Vol. 11, No. 15, 2009

propane intermediate B.16 This assumption is supported by
the fact that a similar reaction in 400 equiv of tripropylamine
gave predominantly 6-endo product 15a (Table 3, entry 2).
It is well-known that the yield of the rearrangement product
increases when the concentration of the substrate is low.17
Addition of 2.0 equiv of water caused an increase in the
ratio of 5-exo products 13a and 14a (Table 3, entries 3 and
4).
Table 4. Amine-Mediated Radical Cyclization of Various
Eneynes
Table 4 shows the results of radical cyclization of several
eneyne compounds 12 by heating with 2.0 equiv of phenyl
disulfide (1) and 40 equiv of tripropylamine at 140 °C in
the presence of 2.0 equiv of water. The radical precursors
12b and 12c bearing mono- or dimethylated alkene provided
cyclization products 13b and 13c in good yields (Table 4,
entries 1 and 2). Compound 12d underwent radical cycliza-
tion in a 6-endo-trig manner to give cyclohexane derivative
15d along with a small amount of 5-exo products 13d (Table
4, entry 3). The radical precursors 12e, 12f, and 12g gave
the corresponding heterocyclic five-membered products 13e,
13f, and 13g, respectively, in good yields (Table 4, entries
4-6). Compound 12h gave a mixture of 13h and 14h in
61% yield (Table 4, entry 7).
In conclusion, we have developed a method for the
formation of benzenethiyl radical 7 from diphenyl disulfide
(1) with tripropylamine via a single electron transfer (SET)
reaction. Inexpensive and environmentally friendly reagents
were employed, and the experimental procedure is very
simple and safe. Further studies directed toward the elucida-
tion of the reaction mechanism and the application of amine-
mediated radical formation to the various disulfides, het-
eroatoms, and radical precursors are currently underway in
our laboratory.
Acknowledgment. This research was supported by a
Grant-in-Aid for Scientific Research from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan.
Supporting Information Available: Expermental detail
and spectroscopic data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL901084K
a Yield of isolated products. b Ratios determined by 1H NMR analysis.
(16) Broka, C. A.; Reichert, D. E. C. Tetrahedron Lett. 1987, 28, 1503.
(17) Beckwith, A. L. J.; O’Shea, D. M. Tetrahedron 1986, 27, 4525.
Org. Lett., Vol. 11, No. 15, 2009
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