General Synthesis of Alkenyl Sulfides by Palladium-Catalyzed Thioetherification of Alkenyl Halides and Tosylates

Article abstract of DOI:10.1021/acs.orglett.8b00854

The cross-coupling reaction of alkenyl bromides with thiols catalyzed by palladium complexes derived from inexpensive dppf ligand is reported. These reactions occur under low catalyst loading and in high yields and display wide scope, including the coupling of bulky thiols and trisubstituted bromoolefins, and functional group tolerance. In addition, the thioetherification of less reactive chloroalkenes and, for the first time, alkenyl tosylates was accomplished using a catalyst generated from CyPFtBu alkylbisphosphine ligand.

Full text of DOI:10.1021/acs.orglett.8b00854

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
General Synthesis of Alkenyl Sulfides by Palladium-Catalyzed
Thioetherification of Alkenyl Halides and Tosylates
Noelia Velasco, Cintia Virumbrales, Roberto Sanz, Samuel Suarez-Pantiga,*
́
and Manuel A. Fernandez-Rodríguez*,†
́
́
Area de Química Organ
́
ica, Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Pza. Misael Banuelos s/n, 09001
̃
Burgos, Spain
S
* Supporting Information
ABSTRACT: The cross-coupling reaction of alkenyl bromides with thiols
catalyzed by palladium complexes derived from inexpensive dppf ligand is
reported. These reactions occur under low catalyst loading and in high yields
and display wide scope, including the coupling of bulky thiols and trisubstituted
bromoolefins, and functional group tolerance. In addition, the thioetherification
of less reactive chloroalkenes and, for the first time, alkenyl tosylates was
accomplished using a catalyst generated from CyPFtBu alkylbisphosphine
ligand.
lkenyl sulfides are valuable building blocks widely used as
Aenolate surrogates, Michael acceptors, or intermediates to
4- and 5-membered cyclic compounds.1 They have found
applications in total synthesis2 and material science3 and are
also frequently found in natural products, pharmaceuticals, and
biologically active compounds.4 Consequently, great effort has
been made in the past decade for the development of general
synthetic methodologies to access alkenyl sulfides.5 Among all
established strategies, the addition of thiols to alkynes is the
most straightforward approach. Nevertheless, the regio- and
stereoselectivity of the process is difficult to control in an
efficient way, even under metal-catalyzed conditions,5,6 and the
scope displays restrictions that include the addition of branched
aliphatic thiols5d and the formation of fully substituted alkenyl
sulfides. Alternatively, access to alkenyl sulfides from the
corresponding alkenyl halides is also feasible by halogen−
lithium exchange reactions followed by treatment with
disulfides, although this protocol presents important drawbacks
associated with the low functional group tolerance of
organolithiums.
To overcome these limitations, the metal-catalyzed C−S
cross-coupling reactions of haloalkenes appear as the best
alternative for the preparation of alkenyl thioethers. In this
sense, several copper-catalyzed protocols have been reported.7
However, these processes require high temperatures and/or
high catalyst loadings and are typically restricted to iodoalkenes
or β-bromostyrenes, whose reactions could be attributable to a
noncatalyzed thiolate addition followed by bromide elimina-
tion.7a,8 In contrast to related reactions with aryl halides,5b,c
palladium-catalyzed couplings of haloalkenes9 with thiols have
been poorly explored, and the reported studies are limited to
particular examples10 or to intramolecular reactions to produce
benzo[b]thiophenes.11 These drawbacks have restrained the
use of this methodology for the synthesis of relevant alkenyl
thioethers. Therefore, the development of a general and
scalable cross-coupling procedure for the C−S alkenylation is
highly desirable.
To this aim, the coupling of α-bromostyrene 1a with a slight
excess of 1-decanethiol 2a (1.1 equiv) was selected as model
reaction, and the most significant results are summarized in
Table 1. Using Pd2(dba)3 as palladium source, several ligands
were tested. Initial results with 1.0 mol % of catalyst indicated
that ferrocenyl phosphines L2 and L3 were the most efficient
ligands, achieving total conversion to the desired alkenyl sulfide
3a after 14 h (entries 1−3). Reactions in the absence of
palladium or with catalysts derived from biaryl phosphine
ligands, such as Sphos, RuPhos, BrettPhos, or XPhos, led to
<5% conversion to the coupled product accompanied by thiol
oxidation to disulfide.12 Encouraged by the results with
bisphosphine ligands L2 and L3, the catalyst loading was
considerably decreased (entries 4−6). At very low catalyst
amounts (0.01 mol %) CyPFtBu ligand (L3) failed to promote
the reaction to full conversion (entry 5), whereas when dppf
was used as ligand (L2) 3a was obtained in 93% yield, which
corresponds to a remarkable turnover number of 9300 (entry
4). Not surprisingly, a reduced reaction time of less than 2 h
was achieved by just using 0.1 mol % of the latter catalyst
system (entry 6). Reactions employing other palladium sources
such as Pd(OAc)2, Pd[P(o-tol)3]2, or [allylPdCl]2 were not or
less efficient under the same conditions.12 Next, the depend-
ence on the reaction temperature was studied. When the
transformation was performed at 90 °C (entries 7−9), 70 °C
(entry 13), or even at 25 °C (entry 14), full conversion was
achieved just by increasing the catalyst loading up to 2.5 mol %.
Furthermore, the use of 1,2-DME as solvent (entry 9) or bases
different from LiHMDS such as NaOtBu, Cs2CO3, or K3PO4
Received: March 16, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00854
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Table 1. Optimization of Reaction Conditions
Scheme 1. Pd-Catalyzed Coupling of α-Bromostyrene 1a
with Alkyl and Aryl Thiols 2*
a
entry
base
cat. (mol %)
temp (°C)
conv (%)
1
2
3
4
5
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
LiHMDS
NaOtBu
Cs2CO3
Pd2(dba)3/L1 (1.0)
Pd2(dba)3/L2 (1.0)
Pd2(dba)3/L3 (1.0)
Pd2(dba)3/L2 (0.01)
Pd2(dba)3/L3 (0.01)
Pd2(dba)3/L2 (0.1)
Pd2(dba)3/L2 (0.01)
Pd2(dba)3/L2 (0.05)
Pd2(dba)3/L2 (0.05)
Pd2(dba)3/L2 (0.05)
Pd2(dba)3/L2 (0.05)
Pd2(dba)3/L2 (0.05)
Pd2(dba)3/L2 (0.1)
Pd2(dba)3/L2 (2.5)
110
110
110
110
110
110
90
<50
100
100
100 (93)
52
b
6
100 (94)
46
7
8
90
100 (90)
<5
c
9
90
10
11
12
13
14
90
<5
90
<5
K3PO4
90
<5
LiHMDS
LiHMDS
70
100 (94)
100 (93)
25
a
1
Conversion and yield (in parentheses) estimated by H NMR (300
b
Hz) employing CH2Br2 as internal standard. Reaction completed in
less than 2 h. Reaction conducted in DME.
c
*
Isolated yields of reactions performed using 0.4 mmol of 1a.
a
b
Reaction conducted overnight with 0.01 mol % of catalyst. Reaction
performed at 7 mmol scale.
was unproductive under the reported conditions (entries 10−
12).
Having identified the combination Pd2(dba)3/dppf as the
optimal catalytic system for the alkenyl thioetherification under
low catalyst loading, the scope of this reaction was explored by
first varying the thiol counterpart (Scheme 1). Reaction
conditions employing 0.1 mol % of catalyst were selected to
ensure complete conversions in short reaction times (<4 h).
Thus, primary (2a), secondary (2b), and tertiary alkyl thiols
(2c) and even the bulky HSTIPS (2d) were successfully
coupled under these conditions with α-bromostyrene in high to
excellent yields. The efficiency of the formation of alkenyl
thioethers 3b−d derived from branched secondary and tertiary
aliphatic thiols 2b−d is highly remarkable because, as
mentioned in the introduction, their access via the addition
of the branched thiol to an alkyne is challenging. Moreover, this
methodology could be efficiently applied to synthesize alkenyl
sulfides from aryl thiols bearing neutral (3e) and both electron-
donating (3f−i,m) and electron-withdrawing groups (3j−l).
Furthermore, ortho substitution on the parent aryl thiol is well-
tolerated, providing access to the desired compounds also in
high yields. Even the reaction with a di-ortho-substituted thiol
occurred in excellent yield without the need of increasing the
catalyst loading (3m). Not surprisingly, considering the
established faster oxidative addition of alkenyl over aryl
halides,13 thioetherification of o-bromobenzenethiol (2l) took
place selectively on the alkenyl position of 1a over the bromide
on 2l. This result enhances the synthetic utility of the
developed methodology, allowing the preparation of alkenyl
sulfides bearing bromine atoms in their structure amenable for
further derivatizations. Finally, the developed catalytic system is
also capable of coupling π-deficient (2n) or π-excessive (2o)
heteroaromatic thiols.
substrates in the presence of just 100 ppm of Pd/ligand
occurred to completion and with comparable or slightly
decreased yields (see compounds 3a,e,f,h,l). A limitation was
found with sterically hindered tertiary alkyl thiols that produced
the corresponding sulfides (3c,d) to lesser extent with 100 ppm
of catalyst, and therefore, the catalyst loading could not be
lowered from 0.1 mol %.
On the other hand, the demonstrated high efficiency of
Pd2(dba)3/dppf as the catalytic system makes this methodology
amenable for scale up. Gratifyingly, reaction of α-bromostyrene
1a with decanethiol or o-bromobenzenethiol on a 7 mmol scale
provided 1.86 g (95% yield) and 1.78 g (87% yield) of the
alkenyl thioethers 3a and 3l, respectively (Scheme 2).
Next, the thioetherification of a collection of diverse
bromoalkenes was accomplished in short reaction times
(typically <4 h) using just 0.25 mol % of the catalyst system
(Scheme 2). Under these conditions, β-bromostyrene, used as a
mixture of geometrical isomers, successfully reacted with a
variety of alkyl and aryl thiols, including challenging sterically
hindered ones, to afford the corresponding alkenyl sulfides
(4a−d) in high to excellent yields. It should be noted that
reactions of β-bromostyrene without catalyst gave mostly rise
to disulfides and less than 5% of the desired alkenyl sulfides,
thus ruling out the addition−elimination mechanism described
in copper-catalyzed related couplings.7a Notably, the functional
group tolerance of the methodology is not restricted to
halogens, alkoxy groups, or free amino groups, as shown in
Scheme 1, and has been extended to more demanding
functionalities. Thus, alkenyl bromides bearing a nitro or a
nitrile coupled with thiophenol to form the corresponding
sulfides (4e−f) in good yields. Moreover, reactions of
substrates having ketone or ester groups, unsuccessful under
the standard conditions, occurred in the presence of CyPFtBu
Although the scope of the thiol coupling was surveyed
employing 0.1 mol % of catalyst, overnight reactions of selected
B
DOI: 10.1021/acs.orglett.8b00854
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
derived from dppf ligand, even at higher loadings (1.0 mol %).
Nevertheless, as demonstrated for related thioetherifications of
aryl chlorides,14 bis-phosphine CyPFtBu was revealed as the
ligand of choice for the coupling of chloroalkenes, enabling the
synthesis of alkenyl sulfides 3a and 3e by simply using 0.5−1.0
mol % of this catalytic system (entries 3 and 4). Reactions of 1-
chlorocyclopentene also occurred with the model thiols under
the same reaction conditions (entries 5 and 6).
Scheme 2. Pd-Catalyzed Coupling of Diverse Alkenyl
Bromides 1 with Representative Thiols 2*
Alkenyl sulfonates are attractive alternatives to halides, as
they are easily synthesized from abundantly available ketones
and increase the range of available substitution patterns. Among
sulfonates, alkenyl tosylates are more convenient counterparts
than the corresponding triflates because of the lower cost of the
sulfonating reagents used for their preparation, as well as their
greater crystallinity and stability to water, which allows their
storage.15 However, this stability makes the oxidative addition
to Pd(0) more challenging, and therefore, alkenyl tosylates are
less reactive in palladium-catalyzed processes.16 Consequently,
couplings of alkenyl tosylates with thiols are unknown.
Interestingly, a 5 mol % of the combination Pd2(dba)3/
CyPFtBu ligand catalyzed the coupling of α-(p-
toluenesulfonyl)styrene with both decanethiol and thiophenol
in high yields (Scheme 3, 3a,e). The usefulness of this reaction
*
a
Isolated yields of reactions performed at 0.4 mmol scale. Reaction
b
conducted with 1.1 equiv of base. Reaction performed with CyPFtBu
as ligand and Cs2CO3 as base. Reaction conducted with 1.0 mol % of
catalyst system.
c
Scheme 3. Pd-Catalyzed Coupling of Alkenyl tosylates 5 with
Representative Thiols 2*
ligand (1.0 mol %) and the weaker Cs2CO3 base (4g,h).
Regarding the substitution degree of the resultant sulfide, the
method is also competent in the preparation of disubstituted
(acyclic 4i and cyclic 4j) and trisubstituted alkenyl sulfides
(4k−m) using catalyst loadings up to 1.0 mol % and reaction
times between 4 and 24 h. Remarkably, the latter fully
substituted alkenyl thioethers (4k−m) are inherently not
accessible by the thiol addition to alkynes strategy.
Once the generalization of the alkenyl thioetherification
process with a wide range of alkenyl bromides was
demonstrated, we decided to evaluate other haloalkenes as
potential coupling partners with 1-decanethiol (1a) and
thiophenol (1e) (Table 2). Whereas more reactive iodoalkenes
performed similarly to their parent bromoalkenes (entries 1 and
2), less reactive chloroalkenes failed to react with the catalyst
*
a
Isolated yields of reactions performed at 0.4 mmol scale. Cs2CO3
(2.0 equiv) used as base.
was further demonstrated by the efficient couplings of alkenyl
tosylates derived from branched aliphatic, alkyl disubstituted,
cyclic or functionalized ketones (Scheme 3, 4n−r), for which
corresponding bromoalkenes are not easily available.
Table 2. Pd-Catalyzed Coupling of Alkenyl Iodides and
Chlorides with Decanethiol and Thiophenol
In conclusion, a general, selective, and scalable methodology
for the synthesis of alkenyl sulfides through palladium-catalyzed
C−S bond cross-coupling has been developed on the basis of
the use of inexpensive bisphosphine dppf ligand. This synthetic
approach is capable of coupling a wide variety of aliphatic and
(hetero)aromatic thiols to alkenyl bromides with diverse
substitution patterns and functionalities under very low catalyst
loading (generally 0.01−0.25 mol %) in high yields. The scope
of the process is broad and includes the employment of
sterically hindered alkyl and aryl thiols and access to fully
substituted alkene derivatives, overcoming the main synthetic
limitations of the metal-catalyzed direct reaction of thiols with
alkynes. In addition, catalytic species generated from Pd2(dba)3
and CyPFtBu ligand allowed less reactive chloroalkenes and, for
the first time, readily available tosyloxyalkenes to also be active
coupling counterparts for the alkenyl thioetherification with
both alkyl and aryl thiols.
a
Isolated yields of reactions performed at 0.4 mmol scale.
C
DOI: 10.1021/acs.orglett.8b00854
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Two Distinct Optoelectronic Functionalities. Macromolecules 2013, 46,
5998−6012.
ASSOCIATED CONTENT
■
S
* Supporting Information
(4) (a) Lavecchia, A.; Cosconati, S.; Limongelli, V.; Novellino, E.
Modeling of Cdc25B Dual Specifity Protein Phosphatase Inhibitors:
Docking of Ligands and Enzymatic Inhibition Mechanism. Chem-
MedChem 2006, 1, 540−550. (b) Sader, H. S.; Johnson, D. M.; Jones,
R. N. In Vitro Activities of the Novel Cephalosporin LB 11058 against
Multidrug-Resistant Staphylococci and Streptococci. Antimicrob. Agents
Chemother. 2004, 48, 53−62. (c) Johannesson, P.; Lindeberg, G.;
Johansson, A.; Nikiforovich, G. V.; Gogoll, A.; Synnergren, B.; Le
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00854.
Experimental details, characterization data, and NMR
spectra for all new compounds (PDF)
̀ ́
Greves, M.; Nyberg, F.; Karlen, A.; Hallberg, A. Vinyl Sulfide Cyclized
AUTHOR INFORMATION
■
Analogues of Angiotensin II with High Affinity and Full Agonist
Activity at the AT1 Receptor. J. Med. Chem. 2002, 45, 1767−1777.
(d) Dvorak, C. A.; Schmitz, W. D.; Poon, D. J.; Pryde, D. C.; Lawson,
J. P.; Amos, R. A.; Meyers, A. I. The Synthesis of Streptogramin
Antibiotics: (−)-Griseoviridin and Its C-8 Epimer. Angew. Chem., Int.
Ed. 2000, 39, 1664−1666.
Corresponding Authors
*E-mail: mangel.fernandezr@uah.es.
*E-mail: svsuarez@ubu.es.
ORCID
(5) Revisions: (a) Pan, X.-Q.; Zou, J.-P.; Yi, W.-B.; Zhang, W. Recent
Advances in Sulfur- and Phosphorous-Centered Radical Reactions for
the Formation of S−C and P−C Bonds. Tetrahedron 2015, 71, 7481−
7529. (b) Lee, C.-F.; Liu, Y.-C.; Badsara, S. S. Transition-Metal-
Catalyzed C−S Bond Coupling Reaction. Chem. - Asian J. 2014, 9,
706−722. (c) Beletskaya, I. P.; Ananikov, V. P. Transition-Metal-
Catalyzed C−S, C−Se, and C−Te Bond Formation via Cross-
Coupling and Atom-Economic Addition Reactions. Chem. Rev. 2011,
111, 1596−1636. (d) Zyk, N. V.; Beloglazkina, E. K.; Belova, M. A.;
Dubinina, N. S. Methods for the Synthesis of Vinyl Sulfides. Russ.
Chem. Rev. 2003, 72, 769−786.
Roberto Sanz: 0000-0003-2830-0892
Samuel Suarez-Pantiga: 0000-0002-4249-7807
́
Manuel A. Fernandez-Rodríguez: 0000-0002-0120-5599
́
Present Address
†
́
́
(M.A.F.-R.) Departamento de Quimica Organ
́
ica y Quimica
de Henares,
Inorgan
Madrid, Spain.
́
ica, Universidad de Alcala, 28805, Alcala
́
́
Notes
The authors declare no competing financial interest.
(6) Revisions: (a) Dondoni, A.; Marra, A. Metal-Catalyzed and
Metal-Free Alkyne Hydrothiolation: Synthetic Aspects and Applica-
tion Trends. Eur. J. Org. Chem. 2014, 2014, 3955−3969.
ACKNOWLEDGMENTS
■
́
(b) Castarlenas, R.; Di Giuseppe, A.; Perez-Torrente, J. J.; Oro, L.
We are grateful to the Junta de Castilla y Leon
́
and FEDER
A. The Emergence of Transition-Metal-Mediated Hydrothiolation of
Unsaturated Carbon−Carbon Bonds: A Mechanistic Outlook. Angew.
Chem., Int. Ed. 2013, 52, 211−222. Selected references: (c) Strydom,
́
(BU076U16) and Ministerio de Economia y Competitividad
(MINECO) and FEDER (CTQ2016-75023-C2-1-P) for
financial support. N.V. and S.S.-P. thank the Junta de Castilla
́
I.; Guisado-Barrios, G.; Fernandez, I.; Liles, D. C.; Peris, E.;
́
y Leon and FEDER for predoctoral and postdoctoral contracts,
respectively. C.V. thanks Universidad de Burgos for a
predoctoral contract.
Bezuidenhout, D. I. A Hemilabile and Cooperative N-Donor-
Functionalized 1,2,3-Triazol-5-Ylidene Ligand for Alkyne Hydro-
thiolation Reactions. Chem. - Eur. J. 2017, 23, 1393−1401.
(d) Degtyareva, E. S.; Burykina, J. V.; Fakhrutdinov, A. N.; Gordeev,
E. G.; Khrustalev, V. N.; Ananikov, V. P. Pd-NHC Catalytic System for
the Efficient Atom-Economic Synthesis of Vinyl Sulfides from
Tertiary, Secondary, or Primary Thiols. ACS Catal. 2015, 5, 7208−
REFERENCES
■
(1) (a) Li, Q.; Dong, T.; Liu, X.; Lei, X. A Bioorthogonal Ligation
Enabled by Click Cycloaddition of o-Quinolinone Quinone Methide
and Vinyl Thioether. J. Am. Chem. Soc. 2013, 135, 4996−4999.
(b) Shaikh, A. k.; Cobb, A. J. A.; Varvounis, G. Mild and Rapid
Method for the Generation of ortho-(Naphtho)quinone Methide
Intermediates. Org. Lett. 2012, 14, 584−587. (c) Zhu, Y.; Xie, M.;
Dong, S.; Zhao, X.; Lin, L.; Liu, X.; Feng, X. Asymmetric
Cycloaddition of β,γ-Unsaturated α-Ketoesters with Electron-Rich
Alkenes Catalyzed by a Chiral Er(OTf)3/N,N′-Dioxide Complex:
Highly Enantioselective Synthesis of 3,4-Dihydro-2H-pyrans. Chem. -
Eur. J. 2011, 17, 8202−8208. (d) Sabarre, A.; Love, J. Synthesis of 1,1-
Disubstituted Olefins via Catalytic Alkyne Hydrothiolation/Kumada
Cross-Coupling. Org. Lett. 2008, 10, 3941−3944. (e) Farhat, S.;
Marek, I. From Vinyl Sulfides, Sulfoxides, and Sulfones to Vinyl
Transition Metal Complexes. Angew. Chem., Int. Ed. 2002, 41, 1410−
1413.
́
7213. (e) Di Giuseppe, A.; Castarlenas, R.; Perez-Torrente, J. J.;
Crucianelli, M.; Polo, V.; Sancho, R.; Lahoz, F. J.; Oro, L. A. Ligand-
Controlled Regioselectivity in the Hydrothiolation of Alkynes by
Rhodium N-Heterocyclic Carbene Catalysts. J. Am. Chem. Soc. 2012,
134, 8171−8183. (f) Weiss, C. J.; Marks, T. J. Organozirconium
Complexes as Catalysts for Markovnikov-Selective Intermolecular
Hydrothiolation of Terminal Alkynes: Scope and Mechanism. J. Am.
Chem. Soc. 2010, 132, 10533−10546. (g) Cao, F.; Fraser, L. R.; Love,
J. A. Rhodium-Catalyzed Alkyne Hydrothiolation with Aromatic and
Aliphatic Thiols. J. Am. Chem. Soc. 2005, 127, 17614−17615.
(7) (a) Kao, H.-L.; Lee, C.-F. Efficient Copper-Catalyzed S-
Vinylation of Thiols with Vinyl Halides. Org. Lett. 2011, 13, 5204−
5207. (b) Kabir, M. S.; Lorenz, M.; Van Linn, M. L.; Namjoshi, O. A.;
Ara, S.; Cook, J. M. A Very Active Cu-Catalytic System for the
Synthesis of Aryl, Heteroaryl, and Vinyl Sulfides. J. Org. Chem. 2010,
75, 3626−3643.
(2) (a) Pearson, W. H.; Lee, I. Y.; Mi, Y.; Stoy, P. Total Synthesis of
the Kopsia lapidilecta Alkaloid ( )-Lapidilectine B. J. Org. Chem.
2004, 69, 9109−9122. (b) Mizuno, H.; Domon, K.; Masuya, K.;
Tanino, K.; Kuwajima, I. Total Synthesis of (−)-Coriolin. J. Org. Chem.
1999, 64, 2648−2656. (c) Bratz, M.; Bullock, W. H.; Overman, L. E.;
Takemoto, T. Total Synthesis of (+)-Laurencin. Use of Acetal-Vinyl
Sulfide Cyclizations for Forming Highly Functionalized Eight-
Membered Cyclic Ethers. J. Am. Chem. Soc. 1995, 117, 5958−5966.
(3) (a) Kausar, A.; Zulfiqar, S.; Sarwar, M. I. Recent Developments in
Sulfur-Containing Polymers. Polym. Rev. 2014, 54, 185−267.
(b) Nakabayashi, K.; Abiko, Y.; Mori, H. RAFT Polymerization of
S-Vinyl Sulfide Derivatives and Synthesis of Block Copolymers Having
(8) For Cu-catalyzed intramolecular coupling of bromoolefins, see:
Newman, S. G.; Aureggi, V.; Bryan, C. S.; Lautens, M. Intramolecular
Cross-Coupling of gem-Dibromoolefins: A Mild Approach to 2-Bromo
Benzofused Heterocycles. Chem. Commun. 2009, 5236−5238.
(9) For a review on a related amination reaction, see: Barluenga, J.;
Valdes
heterocyclic synthesis. Chem. Commun. 2005, 4891−4901.
(10) (a) Guilarte, V.; Fernandez-Rodríguez, M. A.; García-García, P.;
́
, C. Palladium catalyzed alkenyl amination: from enamines to
́
Hernando, E.; Sanz, R. A Practical, One-Pot Synthesis of Highly
Substituted Thiophenes and Benzo[b]thiophenes from Bromoenynes
D
DOI: 10.1021/acs.orglett.8b00854
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Letter
and o-Alkynylbromobenzenes. Org. Lett. 2011, 13, 5100−5103.
(b) Moreau, X.; Campagne, J. M.; Meyer, G.; Jutand, A. Palladium-
Catalyzed C−S Bond Formation: Rate and Mechanism of the
Coupling of Aryl or Vinyl Halides with a Thiol Derived from a
Cysteine. Eur. J. Org. Chem. 2005, 2005, 3749−3760.
(11) (a) Zeng, F.; Alper, H. Palladium-Catalyzed Domino C−S
Coupling/Carbonylation Reactions: An Efficient Synthesis of 2-
Carbonylbenzo[b]thiophene Derivatives. Org. Lett. 2011, 13, 2868−
2871. (b) Bryan, C. S.; Braunger, J. A.; Lautens, M. Efficient Synthesis
of Benzothiophenes by an Unusual Palladium-Catalyzed Vinylic C−S
Coupling. Angew. Chem., Int. Ed. 2009, 48, 7064−7068.
(12) See the Supporting Information for details.
(13) For an additional competition experiment that further
demonstrates the greater reactivity of alkenyl bromides over aryl
bromides with thiols under the developed catalytic conditions, see the
SI.
(14) (a) Fernandez-Rodríguez, M. A.; Shen, Q.; Hartwig, J. F. Highly
́
Efficient and Functional-Group-Tolerant Catalysts for the Palladium-
Catalyzed Coupling of Aryl Chlorides with Thiols. Chem. - Eur. J.
́
2006, 12, 7782−7796. (b) Fernandez-Rodríguez, M. A.; Shen, Q.;
Hartwig, J. F. A General and Long-Lived Catalyst for the Palladium-
Catalyzed Coupling of Aryl Halides with Thiols. J. Am. Chem. Soc.
2006, 128, 2180−2181.
(15) Chassaing, S.; Specklin, S.; Weibel, J.-M.; Pale, P. Vinyl and Aryl
Sulfonates: Preparations and Applications in Total Synthesis. Curr.
Org. Synth. 2012, 9, 806−827.
(16) For selected examples of Pd-catalyzed coupling reactions of
alkenyl tosylates, see: (a) Li, B. X.; Le, D. N.; Mack, K. A.; McClory,
A.; Lim, N.-K.; Cravillion, T.; Savage, S.; Han, C.; Collum, D. B.;
Zhang, H.; Gosselin, F. Highly Stereoselective Synthesis of
Tetrasubstituted Acyclic All-Carbon Olefins via Enol Tosylation and
Suzuki−Miyaura Coupling. J. Am. Chem. Soc. 2017, 139, 10777−
10783. (b) Fujino, T.; Hinoue, T.; Usuki, Y.; Satoh, T. Synthesis of
Difluorinated Enynes through Sonogashira-Type Coupling. Org. Lett.
2016, 18, 5688−5691. (c) Limmert, M. E.; Roy, A. H.; Hartwig, J. F.
Kumada Coupling of Aryl and Vinyl Tosylates under Mild Conditions.
J. Org. Chem. 2005, 70, 9364−9370.
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DOI: 10.1021/acs.orglett.8b00854
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