Catalytic Hydrothiolation: Counterion-Controlled Regioselectivity

Article abstract of DOI:10.1021/jacs.8b11395

In this Article, we expand upon the catalytic hydrothiolation of 1,3-dienes to afford either allylic or homoallylic sulfides with high regiocontrol. Mechanistic studies support a pathway in which regioselectivity is dictated by the choice of counterion associated with the Rh center. Non-coordinating counterions, such as SbF₆^-, allow for η⁴-diene coordination to Rh complexes and result in allylic sulfides. In contrast, coordinating counterions, such as Cl^-, favor neutral Rh complexes in which the diene binds η² to afford homoallylic sulfides. We propose mechanisms that rationalize a fractional dependence on thiol for the 1,2-Markovnikov hydrothiolation while accounting for an inverse dependence on thiol in the 3,4-anti-Markovnikov pathway. Through the hydrothiolation of an essential oil (β-farnesene), we achieve the first enantioselective synthesis of (-)-agelasidine A.

Full text of DOI:10.1021/jacs.8b11395

Article
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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Catalytic Hydrothiolation: Counterion-Controlled Regioselectivity
Xiao-Hui Yang,† Ryan T. Davison,† Shao-Zhen Nie,†,‡ Faben A. Cruz,† Tristan M. McGinnis,†
and Vy M. Dong*,†
†Department of Chemistry, University of California, Irvine, California 92697, United States
‡College of Pharmacy, Liaocheng University, Liaocheng, Shandong 252059, China
S
* Supporting Information
ABSTRACT: In this Article, we expand upon the catalytic
hydrothiolation of 1,3-dienes to afford either allylic or homoallylic
sulfides with high regiocontrol. Mechanistic studies support a
pathway in which regioselectivity is dictated by the choice of
counterion associated with the Rh center. Non-coordinating
counterions, such as SbF6 , allow for η4-diene coordination to Rh
−
complexes and result in allylic sulfides. In contrast, coordinating
counterions, such as Cl−, favor neutral Rh complexes in which the diene binds η2 to afford homoallylic sulfides. We propose
mechanisms that rationalize a fractional dependence on thiol for the 1,2-Markovnikov hydrothiolation while accounting for an
inverse dependence on thiol in the 3,4-anti-Markovnikov pathway. Through the hydrothiolation of an essential oil (β-
farnesene), we achieve the first enantioselective synthesis of (−)-agelasidine A.
homoallylic sulfide (Figure 1C). While regiodivergent hydro-
thiolation of dienes has not previously been reported, Hull
demonstrated regiodivergent hydrothiolations of allylic amines
dictated by choice of ligand on Rh.10 Regiodivergent
hydrosilylation of 1,3-dienes has been reported by Ritter,
achieved through the use of an Fe versus Pt catalyst.11 In this
study, we enable access to homoallylic sulfides by simply
changing the counterion that coordinates to Rh from non-
INTRODUCTION
■
Given the value of organosulfur compounds as metabolites and
medicines,1 synthetic chemists strive to develop versatile
methods for accessing these motifs.2 Both allylic and
homoallylic sulfides, as well as their respective derivatives
(e.g., sulfones and thioesters), comprise natural products and
analogs with a wide range of bioactivities (Figure 1A).3 The
hydrothiolation of olefins and dienes represents an atom-
economical strategy4 for constructing C−S bonds.5,6 Despite
its high atom economy, hydrothiolation remains an unex-
ploited strategy for the synthesis of complex targets, and
further development is warranted. Breit demonstrated an
enantioselective hydrothiolation of allenes to generate allylic
sulfides via Rh catalysis (Figure 1B).7a,b Using Au catalysis, the
He group achieved the hydrothiolation of 1,3-dienes to access
allylic sulfides, with excellent 3,4-Markovnikov selectivity,
albeit as racemic mixtures (Figure 1C).7c Our laboratory
recently communicated the first enantioselective 1,2-Markov-
nikov hydrothiolation of 1,3-dienes to generate allylic sulfides
(Figure 1C).8 Although hydrothiolations have been developed
to access allylic sulfides, selective access to the homoallylic
isomer has been elusive.
In the work described in this Article, to expand the power of
diene hydrothiolation, we focused on elucidating the
mechanism for the 1,2-Markovnikov hydrothiolation. In
theory, the addition of a thiol to an unsymmetrical diene
(e.g., 2-phenyl-1,3-diene) can afford up to 11 isomers.9 Yet, the
use of cationic Rh and a bidentate phosphine ligand afforded
secondary and tertiary sulfide motifs with excellent regio-
selectivity and enantioselectivity. By studying the mechanism,
we determined the fundamental steps that govern regiocontrol.
Guided by these insights, we then focused on developing a
complementary hydrothiolation to provide access to the
−
coordinating (SbF6 ) to coordinating (Cl−). The scope and
mechanism of this new hydrothiolation of 1,3-dienes are
presented. Within this Article, we also showcase hydro-
thiolation in the first enantioselective synthesis of (−)-agela-
sidine A, a natural product that bears a chiral tertiary sulfide-
derived motif (Figure 1A).
RESULTS AND DISCUSSION
■
In our previous studies, we observed that different 1,3-diene
substitution patterns require the use of different ligand families
for optimal results (Figure 2).8 By using this empirical guide,
one can identify either the desired product or the commodity
diene of choice to functionalize. For cyclic, 1-substituted, 1,2-
disubstituted, and 2,3-disubstituted dienes, we found that the
BINAP ligand family is best for furnishing enantioenriched
allylic sulfides, whereas 2-substituted dienes require the use of
the Josiphos ligand family. The Garphos ligand scaffold
provides good yields and enantioselectivities for 1,3-butadiene.
In an effort to better understand the catalyst design and its
effects on the hydrofunctionalizations of dienes, we inter-
rogated the hydrothiolation mechanism to elucidate the factors
that affect selectivity.
Received: October 22, 2018
© XXXX American Chemical Society
A
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Figure 1. Inspiration for the regiodivergent hydrothiolation of 1,3-
dienes.
Figure 2. Empirical guide for optimal ligand choice for 1,2-
Markovnikov hydrothiolation. Results previously published.8
Mechanism of 1,2-Markovnikov Hydrothiolation of
1,3-Dienes. On the basis of both literature precedence and
the following mechanistic studies, we propose the 1,2-
Markovnikov hydrothiolation mechanism depicted in Figure
3. Ligand exchange between 1,5-cyclooctadiene (cod) with a
bidentate phosphine ligand, thiol 1, and diene 2 generates
intermediate I. In the turnover-limiting step, oxidative addition
results in formation of an η4-diene-coordinated Rh−H
intermediate II.12 Subsequent 1,4-insertion of the diene into
the Rh−H furnishes Rh-π-allyl intermediate III.13 Intermediate
III undergoes reductive elimination to provide IV, where
product 3 remains coordinated to Rh. Ligand exchange of
product 3 with thiol 1 and diene 2 regenerates the Rh catalyst
I.
For the model system, we chose to study the mechanism
using an achiral ligand, Xantphos, because we previously
observed that it is an effective ligand for the transformation.8
This bidentate ligand bears a coordinating oxygen atom that
can act as a hemilabile ligand.14 Our initial mechanistic studies
used thiophenol (1a) and myrcene (2a) to explore the kinetic
profile of the transformation. We found a first-order depend-
ence on the catalyst and a zeroth-order dependence on diene
2a, which is consistent with a mechanism where the Rh
complex I is saturated with diene 2 or diene 2 coordination
occurs after the turnover-limiting step (Figure 3). We found
that thiophenol (1a) can participate in two reaction pathways:
desired hydrothiolation (path a) or dimerization (path b).15
Thiophenol (1a) dimerization increases proportionally with its
concentration. When adding bis(4-methoxyphenyl) disulfide to
Figure 3. Proposed mechanism of 1,2-Markovnikov hydrothiolation
of 1,3-dienes.
a mixture of thiophenol with myrcene under the standard
conditions, we observed crossover products, which suggests
B
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that thiol dimerization (path b) is reversible (see SI, Figure
S4). In accordance with these competing pathways, we
observed a fractional-order dependence (0.4) on thiophenol
(1a).
We also performed deuterium-labeling experiments to
further probe the mechanism (Figure 4). When we subjected
intermediate IV as the resting state in the catalytic cycle
(Figure 3).
To investigate the turnover-limiting step, we carried out
several kinetic experiments. First, a H/D kinetic isotope effect
(KIE) experiment with thiophenol (1a) and deuterated
thiophenol (d-1a) was performed. The initial rate constants
were determined in parallel, and we observed a primary KIE
(kH/kD = 2.8, Figure 5). Second, a Hammett plot was
Figure 5. KIE from two parallel reactions using initial rates (1,2-
Markovnikov).
constructed, using various para-substituted thiophenols, to
determine if there was a rate dependence on the electronic
character of the thiol 1 partner (Figure 6). A relatively small ρ
Figure 4. Deuterium-labeling studies for the 1,2-Markovnikov
hydrothiolation of 1,3-dienes.
deuterated thiophenol (d-1a) and myrcene (2a) to the
standard conditions, we found that the recovered diene
starting material 2a exhibited no deuterium incorporation
(eq 1 in Figure 4). This lack of scrambling supports our
proposal that Rh−H insertion is an irreversible step in the
catalytic cycle. However, we observed deuterium scrambling in
the allylic sulfide product d-3aa. To examine the origin of this
deuterium incorporation, we subjected a non-deuterated
product 3aa to a mixture of deuterated thiophenol (d-1a),
Rh(cod)2SbF6, and Xantphos (eq 2 in Figure 4). We detected
similar deuterium incorporation only in the terminal olefin
moiety of d-3aa′. Collectively, these results suggest that
deuterium scrambling in product 3aa occurs from a pathway
external to the catalytic cycle. We hypothesize that
intermediate IV can undergo oxidative addition to an
equivalent of thiol to form complex V (Figure 3). Subsequent
reversible Rh−H insertion into the terminal olefin results in
the deuterium scrambling observed in d-3aa.
Figure 6. Hammett plot (log k/kH = mσ+ + b (m = −0.22 0.02; b =
Next, we studied key steps of the hydrothiolation by NMR
spectroscopy. First, we monitored a mixture of thiophenol
(1a), Rh(cod)2SbF6 (10 mol%), and Xantphos (10 mol%) in
0.03 0.01).
1
DCE-d4 by H NMR analysis. A resonance at −13.5 ppm was
1
observed in less than 10 min at room temperature in the H
value (−0.22
0.02) is observed with more electron-rich
NMR spectrum, which is consistent with previously reported
values for Rh−H complexes.16 This observation suggests that a
Rh−H is rapidly generated from the catalyst precursor
Rh(cod)2SbF6 in the presence of Xantphos and thiophenol
(1a). While observation of a Rh−hydride does not necessitate
its involvement in catalysis, we found that this hydride species
is consumed when treated with an equivalent of diene
(myrcene, 2a). In this stoichiometric experiment, we observed
formation of a new Rh complex with non-equivalent phosphine
resonances in the 31P NMR spectrum at −40 °C [a pair of
doublet of doublet signals (δ = 26.6 ppm, JRh−P = 174 Hz, JP−P
= 8 Hz; δ = 16.0 ppm, JRh−P = 115 Hz, JP−P = 8 Hz)]. When we
subjected the product 3aa to a mixture of Rh(cod)2SbF6 and
Xantphos in DCE-d4, we observed the same species by 31P
NMR spectroscopy. Based on these results, we label Rh
thiophenols undergoing hydrothiolation slightly faster. We
hypothesize that the thiol initially coordinates to Rh to provide
a transient species (see I, Figure 3), which then undergoes
insertion of the Rh into the S−H bond to form the Rh−H
species (see II). Electron-rich thiols can accelerate this process
by stabilizing positive charge build up on the Rh-center during
the transition state for oxidative addition.
Based on these mechanistic studies, we reason that the
elementary steps from intermediate II to IV account for the
observed regioselectivity (Figure 3). Hydrometalation occurs
with the bulky Rh center preferentially adding to the less
sterically encumbered terminal position (C4). This net 1,4-
insertion ultimately yields the Rh-π-allyl intermediate III.
Reductive elimination of III at the more-substituted position
to form the branched product is preferred, which is consistent
C
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with other Rh-catalyzed alkyne, allene, and diene hydro-
functionalizations.17
When intermediate II bears a chiral thiolate ligand, the
configuration appears to have little/no influence on the
stereochemical outcome. Our initial report included an
example of a chiral cysteine-derived thiol undergoing hydro-
thiolation to selectively give one diastereomer, depending on
which enantiomer of the bisphosphine ligand was used (Figure
7, entry A).8 To elaborate on this observation, we investigated
Figure 8. Enantioselective synthesis of (−)-agelasidine A. Reagents
and conditions: (a) Rh(cod)2SbF6 (5 mol%), Josiphos (5 mol%, R =
Cy, Figure 2), DCE, 30 °C, 15 h. (b) (NH4)6Mo7O24·4H2O (10 mol
%), H2O2, MeOH, rt, 4 h. (c) NaH, EtOH, NH2C(NH)NH2·HCl,
1,4-dioxane, rt, 12 h.
sulfides to the corresponding sulfones.20 We observed high
reactivity (77% yield) when using catalytic (NH4)6Mo7O24·
4H2O and H2O2 to oxidize sulfide 3ec to sulfone 5.20i
Following Ichikawa’s report, we found that enantioenriched
sulfone 5 could be transformed to (−)-agelasidine A (4, 67%
yield) in the presence of excess guanidine.18c Collectively, our
approach requires only three steps from commercially available
β-farnesene (2c) to afford enantioenriched (−)-4 in 40%
overall yield. We anticipate that this methodology will be
applicable to other natural products and synthetic targets
bearing C−S bonds.21
Figure 7. Catalyst-controlled diastereoselective 1,2-Markovnikov
hydrothiolation.
Development of 3,4-anti-Markovnikov Hydrothiola-
tion of 1,3-Dienes. Based on the 1,2-Markovnikov
mechanism depicted in Figure 3, we reasoned that it would
be possible to access other hydrothiolation regioisomers by
tuning the ligands22 and/or counterions on Rh. Previous
reports have demonstrated that coordination modes of 1,3-
dienes to a metal center can switch the observed regio-
selectivity of transition-metal-catalyzed hydrofunctionaliza-
tions. For example, Ritter and co-workers found that η4-
diene coordination provides 1,4-addition products,11a whereas
η2-diene coordination gives 3,4-anti-Markovnikov hydrosilyla-
tion products.11b We envisioned using this concept to design a
regiodivergent hydrothiolation of 1,3-dienes by switching from
η4- to η2-diene binding. As shown in Figure 9, cationic Rh
chiral secondary thiols, where the chiral information is closer
to the Rh-center. Hydrothiolation occurs with high reactivity
(3cb and 3db, 83−92% yield, entries B and C), regioselectivity
(>20:1 rr), and diastereoselectivity (>20:1 dr) when using
chiral secondary thiols (1c and 1d). These results demonstrate
complete catalyst control when forging the C−S bond. Thus,
chiral secondary thiols can be transformed to sulfides in a
diastereodivergent fashion. With a better understanding of the
1,2-Markovnikov hydrothiolation mechanism, we set out to
apply this asymmetric hydrothiolation methodology to the
total synthesis of a natural product.
Total Synthesis of (−)-Agelasidine A. (−)-Agelasidine A
(4), an antifungal and antimicrobial agent isolated from marine
sponges of the genus Agelas,3b has previously been synthesized
as a racemate from farnesol. Ichikawa reported two different
methods for the installation of the key tertiary sulfide moiety of
( )-agelasidine A; a [2,3]-sigmatropic rearrangement or
hetero-Claisen rearrangement has been used to construct the
C−S bond and access ( )-4 in three and eight steps,
respectively.18
We focused on intercepting an enantioenriched variant of
sulfone 5, which was previously elaborated to ( )-4 in
Ichikawa’s synthesis (Figure 8). To achieve this goal, we
focused on coupling β-farnesene (2c), which is a renewable
feedstock found in many essential oils,19 and 2-mercaptoethyl
acetate (1e). Referencing our hydrothiolation guide (Figure 2),
the Josiphos ligand scaffold is the most promising choice for
achieving high reactivity and selectivity because 2c is a 2-
substituted 1,3-diene. In line with this guide, we found that β-
farnesene (2c) can be coupled with 1e to give the tertiary
sulfide 3ec in 78% yield with high enantioselectivity (>99:1 er)
when using a Josiphos ligand (R = Cy, Figure 2). Various
methods have been developed to chemoselectively oxidize
Figure 9. Proposed counterion-controlled regiodivergent hydro-
thiolations.
precatalysts prefer η4-diene binding due to the presence of two
open coordination sites. In contrast, a neutral Rh species would
prefer η2-diene binding due to the availability of only one
coordination site. Subsequent 1,2-insertion would lead to an
intermediate B in which Rh adds to the less sterically hindered
terminal position. Reductive elimination of this Rh-alkyl
species B would yield homoallylic sulfides 6.
D
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To begin our study, we chose isoprene (2d), a petroleum
feedstock, and thiophenol (1a) as model substrates (Figure
10). Since 6ad is achiral, we focused on identifying an achiral
Table 1. 3,4-Anti-Markovnikov Hydrothiolation of 1,3-
Dienes
a
Figure 10. Rh precatalyst leads to a switch in regioselectivity.
Reaction conditions: 1a (0.1 mmol), 2d (0.5 mmol), [Rh] (5 mol%),
ligand (5 mol%), DCE (0.2 mL), 15 h. Isolated yield. Regioselectivity
ratio (rr) is the ratio of 3ad to 6ad, which is determined by 1H NMR
b
analysis of reaction mixture. Using dppe as ligand, 3 h.
ligand for the 3,4-anti-Markovnikov hydrothiolation. In the
early stages of 1,2-Markovnikov hydrothiolation development,
we found that Xantphos is a viable choice for the ligand.
Indeed, with a combination of Rh(cod)2SbF6 and Xantphos,
the expected tertiary allylic sulfide 3ad could be synthesized in
83% yield and >20:1 rr (entry 1). In stark contrast, when using
the neutral [Rh(cod)Cl]2 as a catalyst precursor, the
homoallylic sulfide 6ad was obtained in 74% yield and 1:>20
rr (entry 2). These results suggest that regioselectivity is
controlled by the counterion on Rh (SbF6− vs Cl−), which is in
line with our proposal (η4- vs η2-diene coordination).23
Switching the counterion to I− or MeO− lowers the reactivity
(18% and 49% yield, respectively, entries 3 and 4) while
maintaining high regioselectivity (1:>20 rr). With further
tuning, we found that [Rh(C2H4)2Cl]2 and bidentate
phosphine ligand dppe furnish 6ad in 94% yield with 1:>20
rr in 3 h (entry 5). Furthermore, with this catalyst, we can
lower the loading to 0.1 mol% and synthesize 6ad on gram
scale (1.3 g) in 74% yield with 1:>20 rr.
With these optimal conditions, we examined the coupling of
15 different thiols with isoprene (2d) to generate the
corresponding homoallylic sulfides (Table 1A). High reactivity
(6bd−6sd, 54−95% yield) and regioselectivity (>20:1 rr) are
obtained with both aromatic and aliphatic thiol partners. This
method is also compatible with heteroarene (6nd, 6od), imide
(6sd), amide (6bd), and ester (6bd) functionalities.
Next, we investigated the scope of the 1,3-diene partner in
the 3,4-anti-Markovnikov hydrothiolation using thiophenol
(1a) as a model thiol partner (Table 1B). Both aromatic and
aliphatic 2-substituted 1,3-dienes are converted to the sulfide
products (6aa−6aj) in high yields (60−95%). The electronics
of the 2-aryl ring on the 1,3-diene has a noticeable effect on the
regioselectivity of the transformation. Electron-rich 1,3-dienes
(6af, 6ag, >20:1 rr) yield higher regioselectivity than electron-
poor 1,3-dienes (6ah, 6ai, 13:1 and 8:1 rr, respectively). 3,4-
Anti-Markovnikov hydrothiolation of butadiene (2k) provides
the corresponding homoallylic sulfide (6ak) in 28% yield. A
2,3-disubstituted diene 2l also transforms well to the
homoallylic sulfide 6al (73% yield). Moreover, myrcene (2a)
could be converted to the corresponding homoallylic thiol 8
via a formal addition of H2S, which consisted of 3,4-anti-
Markovnikov hydrothiolation followed by deprotection (Table
1C).24
a
Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), [Rh(C2H4)2Cl]2
(2.5 mol%), dppe (5 mol%), DCE (0.4 mL), 3 h. Isolated yield.
Regioselectivity ratio (rr) is the ratio of 6 to 7, which is determined by
b
1H NMR analysis of reaction mixture. Using [Rh(cod)Cl]2 (2.5 mol
%), Xantphos (5 mol%), and 3,5-dimethylbenzoic acid (50 mol%), 12
h.
Mechanism of 3,4-anti-Markovnikov hydrothiolation
of 1,3-dienes. Based on kinetic studies and NMR experi-
ments, we propose the mechanism shown in Figure 11A for the
3,4-anti-Markovnikov hydrothiolation of 1,3-dienes. Oxidative
addition of thiol 1 with Rh provides intermediate II′. Two
equivalents of thiol 1 can then associate to furnish the resting
state III′. A similar off-cycle resting state with an Ir(III)−H
complex bearing a six-membered ring formed from two
hydrogen bonds to ethanol has been reported.25 Intermediate
III′ displays a hydride resonance at −15.8 ppm with
symmetrical phosphines [doublet (δ = 52.2 ppm, JRh−P = 94
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synthesized in a regiodivergent manner with the choice of the
Rh precatalyst. Mechanistic investigations shed light on the
origin of the high regioselectivity observed for both hydro-
thiolations. Future efforts will focus on the development of a
unified mechanistic approach for accessing different regio-
isomers of 1,3-diene hydrofunctionalizations.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b11395.
■
S
Experimental procedures and spectral data for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*dongv@uci.edu
■
ORCID
Vy M. Dong: 0000-0002-8099-1048
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding was provided by UC Irvine, the National Institutes of
Health (R35GM127071), and the National Science Founda-
tion (CHE-1465263). S.-Z.N. thanks Liaocheng University for
a scholarship. F.A.C. is grateful for an NSF Graduate Research
Fellowship. We thank Dr. Peter Dornan (Amgen) and Jan
Riedel for helpful discussions.
REFERENCES
■
(1) For reviews, see: (a) Ilardi, E. A.; Vitaku, E.; Njardarson, J. T.
Data-Mining for Sulfur and Fluorine: An Evaluation of Pharmaceut-
icals To Reveal Opportunities for Drug Design and Discovery. J. Med.
Chem. 2014, 57, 2832−2842. (b) Feng, M.; Tang, B.; Liang, S. H.;
Jiang, X. Sulfur Containing Scaffolds in Drugs: Synthesis and
Application in Medicinal Chemistry. Curr. Top. Med. Chem. 2016,
16, 1200−1216. (c) Scott, K. A.; Njardarson, J. T. Analysis of US
FDA-Approved Drugs Containing Sulfur Atoms. Top. Curr. Chem.
2018, 376, 5.
Figure 11. Mechanistic studies of 3,4-anti-Markovnikov hydro-
thiolation of 1,3-dienes.
Hz)]. Moreover, a negative half-order dependence on thiol 1
supports the proposed side pathway.
In contrast to the η4-diene binding exhibited in II (Figure
3), we propose that the less substituted olefin coordinates to
intermediate II′ to form η2-diene coordinated Rh complex IV′.
This diene binding mode is due to the presence of one
coordination site and could be the foundation for the switch in
regioselectivity. Insertion of the 1,3-diene into the Rh−H bond
then provides the less sterically encumbered intermediate V′.
The observed primary KIE (kH/kD = 1.9, Figure 11B) supports
that either oxidative addition to the S−H bond or diene
insertion into the Rh−H is turnover-limiting. Given the first-
order rate dependence on diene 2e and catalyst (Figure 11A),
as well as the results of deuterium incorporation into the allylic
position of d-6ae (Figure 11C), we postulate diene insertion is
the turnover-limiting step. Rh-π-allyl V′ then undergoes
reductive elimination to yield intermediate VI′, which can
perform a ligand exchange of product 6 with thiol 1 to
regenerate Rh catalyst I′.
(2) For reviews on C−S bond formation, see: (a) Kondo, T.;
Mitsudo, T.-A. Metal-Catalyzed Carbon−Sulfur Bond Formation.
Chem. Rev. 2000, 100, 3205−3220. (b) Arisawa, M.; Yamaguchi, M.
Transition-metal-catalyzed synthesis of organosulfur compounds. Pure
Appl. Chem. 2008, 80, 993−1003. (c) Chauhan, P.; Mahajan, S.;
Enders, D. Organocatalytic Carbon−Sulfur Bond-Forming Reactions.
Chem. Rev. 2014, 114, 8807−8864. (d) Shen, C.; Zhang, P.; Sun, Q.;
Bai, S.; Hor, T. S. A.; Liu, X. Recent advances in C−S bond formation
via C−H bond functionalization and decarboxylation. Chem. Soc. Rev.
2015, 44, 291−314. (e) Yu, J.-S.; Huang, H.-M.; Ding, P.-G.; Hu, X.-
S.; Zhou, F.; Zhou, J. Catalytic Enantioselective Construction of
Sulfur-Containing Tetrasubstituted Carbon Stereocenters. ACS Catal.
2016, 6, 5319−5344. (f) Qian, Z.; Jiang, X. Recent developments in
sulfur−carbon bond formation reaction involving thiosulfates. Org.
Biomol. Chem. 2017, 15, 1942−1946. For a review on enzymatic C−S
bond formation, see: (g) Dunbar, K. L.; Scharf, D. H.; Litomska, A.;
Hertweck, C. Enzymatic Carbon−Sulfur Bond Formation in Natural
Product Biosynthesis. Chem. Rev. 2017, 117, 5521−5577.
CONCLUSION
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̈
̈
(3) (a) Bernstrom, K.; Hammarstrom, S. A novel leukotriene formed
by transpeptidation of leukotriene. Biochem. Biophys. Res. Commun.
1982, 109, 800−804. (b) Nakamura, H.; Wu, H.; Kobayashi, J.;
Ohizumi, Y.; Hirata, Y.; Higashijima, T; Miyazawa, T. Agelasidine-A,
a novel sesquiterpene possessing antispasmodic activity from the
okinawa sea sponge Agelassp. Tetrahedron Lett. 1983, 24, 4105−4108.
Hydrothiolation of 1,3-dienes provides an efficient and
straightforward way to construct primary, secondary, and
tertiary C−S centers. A concise total synthesis of (−)-agela-
sidine A (4) exemplifies the facile use of this methodology in a
synthetic setting. Allylic and homoallylic sulfides can be
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(c) Sumiyoshi, H.; Wargovich, M. J. Chemoprevention of 1,2-
Dimethylhydrazine-induced Colon Cancer in Mice by Naturally
Occurring Organosulfur Compounds. Cancer Res. 1990, 50, 5084−
5087. (d) Arora, A.; Siddiqui, I. A.; Shukla, Y. Modulation of p53 in
7,12-dimethylbenz[a]anthracene−induced skin tumors by diallyl
sulfide in Swiss albino mice. Mol. Cancer Ther. 2004, 3, 1459−
1466. (e) Arunkumar, A.; Vijayababu, M. R.; Venkataraman, P.;
Senthilkumar, K.; Arunakaran, J. Chemoprevention of Rat Prostate
Carcinogenesis by Diallyl Disulfide, an Organosulfur Compound of
Garlic. Biol. Pharm. Bull. 2006, 29, 375−379. (f) Taori, K.; Paul, V. J.;
Luesch, H. Structure and Activity of Largazole, a Potent
Antiproliferative Agent from the Floridian Marine Cyanobacterium
Symploca sp. J. Am. Chem. Soc. 2008, 130, 1806−1807.
Dienes with a Pd−PHOX Catalyst. J. Am. Chem. Soc. 2017, 139,
7180−7183. (j) Adamson, N. J.; Wilbur, K. C. E.; Malcolmson, S. J.
Enantioselective Intermolecular Pd-Catalyzed Hydroalkylation of
Acyclic 1,3-Dienes with Activated Pronucleophiles. J. Am. Chem.
Soc. 2018, 140, 2761−2764. (k) Schmidt, V. A.; Kennedy, C. R.;
Bezdek, M. J.; Chirik, P. J. Selective [1,4]-Hydrovinylation of 1,3-
Dienes with Unactivated Olefins Enabled by Iron Diimine Catalysts. J.
Am. Chem. Soc. 2018, 140, 3443−3453. (l) Cheng, L.; Li, M.-M.;
Xiao, L.-J.; Xie, J.-H.; Zhou, Q.-L. Nickel(0)-Catalyzed Hydro-
alkylation of 1,3-Dienes with Simple Ketones. J. Am. Chem. Soc. 2018,
140, 11627−11630.
(7) (a) Pritzius, A. B.; Breit, B. Asymmetric Rhodium-Catalyzed
Addition of Thiols to Allenes: Synthesis of Branched Allylic
Thioethers and Sulfones. Angew. Chem., Int. Ed. 2015, 54, 3121−
3125. (b) Pritzius, A. B.; Breit, B. Z-Selective Hydrothiolation of
Racemic 1,3-Disubstituted Allenes: An Atom-Economic Rhodium-
Catalyzed Dynamic Kinetic Resolution. Angew. Chem., Int. Ed. 2015,
54, 15818−15822. (c) Brouwer, C.; Rahaman, R.; He, C. Gold(I)-
Mediated Hydrothiolation of Conjugated Olefins. Synlett 2007, 2007,
1785−1789.
(4) Trost, B. M. The atom economy–a search for synthetic
efficiency. Science 1991, 254, 1471−1477.
(5) For select hydrothiolations of alkenes, see: (a) Cabrero-
Antonino, J. R.; Leyva-Perez, A.; Corma, A. Iron-Catalysed
Markovnikov Hydrothiolation of Styrenes. Adv. Synth. Catal. 2012,
354, 678−687. (b) Tamai, T.; Ogawa, A. Regioselective Hydro-
thiolation of Alkenes Bearing Heteroatoms with Thiols Catalyzed by
Palladium Diacetate. J. Org. Chem. 2014, 79, 5028−5035. (c) Tamai,
T.; Fujiwara, K.; Higashimae, S.; Nomoto, A.; Ogawa, A. Gold-
Catalyzed Anti-Markovnikov Selective Hydrothiolation of Unactivated
Alkenes. Org. Lett. 2016, 18, 2114−2117. (d) Yi, H.; Song, C.; Li, Y.;
Pao, C.-W.; Lee, J.-F.; Lei, A. Single-Electron Transfer between CuX2
and Thiols Determined by Extended X-Ray Absorption Fine Structure
Analysis: Application in Markovnikov-Type Hydrothiolation of
Styrenes. Chem. - Eur. J. 2016, 22, 18331−18334. (e) Mosaferi, E.;
Ripsman, D.; Stephan, D. W. The air-stable carbocation salt
[(MeOC6H4)CPh2][BF4] in Lewis acid catalyzed hydrothiolation of
alkenes. Chem. Commun. 2016, 52, 8291−8293. (f) Teders, M.;
(8) Yang, X.-H.; Davison, R. T.; Dong, V. M. Catalytic Hydro-
thiolation: Regio- and Enantioselective Coupling of Thiols and
Dienes. J. Am. Chem. Soc. 2018, 140, 10443−10446.
(9) See Supporting Information for details.
(10) Kennemur, J. L.; Kortman, G. D.; Hull, K. L. Rhodium-
Catalyzed Regiodivergent Hydrothiolation of Allyl Amines and
Imines. J. Am. Chem. Soc. 2016, 138, 11914−11919.
(11) (a) Wu, J. Y.; Stanzl, B. N.; Ritter, T. A Strategy for the
Synthesis of Well-Defined Iron Catalysts and Application to
Regioselective Diene Hydrosilylation. J. Am. Chem. Soc. 2010, 132,
̈
13214−13216. (b) Parker, S. E.; Borgel, J.; Ritter, T. 1,2-Selective
̈
́
́
Henkel, C.; Anhauser, L.; Strieth-Kalthoff, F.; Gomez-Suarez , A.;
Kleinmans, R.; Kahnt , A.; Rentmeister , A.; Guldi , D.; Glorius, F. The
energy-transfer-enabled biocompatible disulfide−ene reaction. Nat.
Chem. 2018, 10, 981−988. (g) Kristensen, S. K.; Laursen, S. L. R.;
Taarning, E.; Skrydstrup, T. Ex Situ Formation of Methanethiol:
Application in the Gold(I)-Promoted Anti-Markovnikov Hydro-
thiolation of Olefins. Angew. Chem., Int. Ed. 2018, 57, 13887−
Hydrosilylation of Conjugated Dienes. J. Am. Chem. Soc. 2014, 136,
4857−4860.
(12) For examples of oxidative addition of thiols with Rh catalysts,
see: (a) Ogawa, A.; Ikeda, T.; Kimura, K.; Hirao, T. Highly Regio-
and Stereocontrolled Synthesis of Vinyl Sulfides via Transition-Metal-
Catalyzed Hydrothiolation of Alkynes with Thiols. J. Am. Chem. Soc.
1999, 121, 5108−5114. (b) Shoai, S.; Bichler, P.; Kang, B.; Buckley,
H.; Love, J. A. Catalytic Alkyne Hydrothiolation with Alkanethiols
using Wilkinson’s Catalyst. Organometallics 2007, 26, 5778−5781.
(c) Han, L.; Li, Y.; Liu, T. Theoretical investigation of the impact of
ligands on the regiodivergent Rh-catalyzed hydrothiolation of allyl
amines. Dalton Trans. 2018, 47, 150−158 and ref 10. .
́
13891. For a review, see: (h) Castarlenas, R.; Di Giuseppe, A.; Perez-
Torrente, J. J.; Oro, L. A. The Emergence of Transition-Metal-
Mediated Hydrothiolation of Unsaturated Carbon−Carbon Bonds: A
Mechanistic Outlook. Angew. Chem., Int. Ed. 2013, 52, 211−222.
(6) For select hydrofunctionalizations of 1,3-dienes, see: (a) Zbieg, J.
R.; Yamaguchi, E.; McInturff, E. L.; Krische, M. J. Enantioselective C-
H Crotylation of Primary Alcohols via Hydrohydroxyalkylation of
Butadiene. Science 2012, 336, 324−327. (b) Chen, Q.-A.; Kim, D. K.;
Dong, V. M. Regioselective Hydroacylation of 1,3-Dienes by Cobalt
Catalysis. J. Am. Chem. Soc. 2014, 136, 3772−3775. (c) Saini, V.;
O’Dair, M.; Sigman, M. S. Synthesis of Highly Functionalized Tri- and
Tetrasubstituted Alkenes via Pd-Catalyzed 1,2-Hydrovinylation of
Terminal 1,3-Dienes. J. Am. Chem. Soc. 2015, 137, 608−611.
(d) Marcum, J. S.; Roberts, C. C.; Manan, R. S.; Cervarich, T. N.;
Meek, S. J. Chiral Pincer Carbodicarbene Ligands for Enantioselective
Rhodium-Catalyzed Hydroarylation of Terminal and Internal 1,3-
Dienes with Indoles. J. Am. Chem. Soc. 2017, 139, 15580−15583.
(e) Jing, S. M.; Balasanthiran, V.; Pagar, V.; Gallucci, J. C.; RajanBabu,
T. V. Catalytic Enantioselective Hetero-dimerization of Acrylates and
1,3-Dienes. J. Am. Chem. Soc. 2017, 139, 18034−18043. (f) Yang, X.-
H.; Lu, A.; Dong, V. M. Intermolecular Hydroamination of 1,3-Dienes
To Generate Homoallylic Amines. J. Am. Chem. Soc. 2017, 139,
14049−14052. (g) Gui, Y.-Y.; Hu, N.; Chen, X.-W.; Liao, L.-L.; Ju, T.;
Ye, J.- H.; Zhang, Z.; Li, J.; Yu, D.-G. Highly Regio- and
Enantioselective Copper-Catalyzed Reductive Hydroxymethylation
of Styrenes and 1,3-Dienes with CO2. J. Am. Chem. Soc. 2017, 139,
17011−17014. (h) Thullen, S. M.; Rovis, T. A Mild Hydro-
aminoalkylation of Conjugated Dienes Using a Unified Cobalt and
Photoredox Catalytic System. J. Am. Chem. Soc. 2017, 139, 15504−
15508. (i) Adamson, N. J.; Hull, E.; Malcolmson, S. J. Enantio-
selective Intermolecular Addition of Aliphatic Amines to Acyclic
(13) For the same sterically preferred 1,4-insertion into an Ir−H,
see: Nguyen, K. D.; Herkommer, D.; Krische, M. J. Enantioselective
Formation of All-Carbon Quaternary Centers via C−H Functional-
ization of Methanol: Iridium-Catalyzed Diene Hydrohydroxymethy-
lation. J. Am. Chem. Soc. 2016, 138, 14210−14213.
(14) Xantphos is a hemilabile ligand that can coordinate through the
oxygen atom: Ren, P.; Pike, S. D.; Pernik, I.; Weller, A. S.; Willis, M.
C. Rh−POP Pincer Xantphos Complexes for C−S and C−H
Activation. Implications for Carbothiolation Catalysis. Organometallics
2015, 34, 711−723.
(15) For the formation of a disulfide under iron-catalyzed alkene
hydrothiolation, see ref 5a.
(16) For Rh−H resonances, see: 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 Hydro-
thiolation of Alkynes by Rhodium N-Heterocyclic Carbene Catalysts.
J. Am. Chem. Soc. 2012, 134, 8171−8183. See also refs 10 and 12a.
(17) For reviews, see: (a) Koschker, P.; Breit, B. Branching Out:
Rhodium-Catalyzed Allylation with Alkynes and Allenes. Acc. Chem.
Res. 2016, 49, 1524−1536. (b) Haydl, A. M.; Breit, B.; Liang, T.;
Krische, M. J. Alkynes as Electrophilic or Nucleophilic Allylmetal
Precursors in Transition-Metal Catalysis. Angew. Chem., Int. Ed. 2017,
56, 11312−11325. For select papers, see: (c) Chen, Q.-A.; Chen, Z.;
Dong, V. M. Rhodium-Catalyzed Enantioselective Hydroamination of
Alkynes with Indolines. J. Am. Chem. Soc. 2015, 137, 8392−8395.
(d) Yang, X.-H.; Dong, V. M. Rhodium-Catalyzed Hydrofunctional-
G
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Journal of the American Chemical Society
Article
ization: Enantioselective Coupling of Indolines and 1,3-Dienes. J. Am.
Chem. Soc. 2017, 139, 1774−1777.
(18) (a) Ichikawa, Y. First synthesis of agelasidine A. Tetrahedron
Lett. 1988, 29, 4957−4958. (b) Ichikawa, Y.; Kashiwagi, T.; Urano, N.
A biomimetic synthesis of agelasidine A. J. Chem. Soc., Chem.
Commun. 1989, 987−988. (c) Ichikawa, Y.; Kashiwagi, T.; Urano, N.
Biomimetic synthesis of agelasidine A. J. Chem. Soc., Perkin Trans. 1
1992, 1, 1497−1500.
(19) Simionatto, E.; Porto, C.; Stuker, C. Z.; Dalcol, I. I.; da Silva, U.
̈
F. Chemical composition and antimicrobial activity of the essential oil
from Aeolanthus suaveolens Mart. ex Spreng. Quim. Nova 2007, 30,
1923−1925.
(20) (a) Priebe, W.; Grynkiewicz, G. A facile and selective oxidation
of sulfides to sulfones. Tetrahedron Lett. 1991, 32, 7353−7356. (b) Su,
W. An efficient method for the oxidation of sulfides to sulfones.
Tetrahedron Lett. 1994, 35, 4955−4958. (c) Beckerbauer, R.; Smart,
B. E.; Bareket, Y; Rozen, S. Oxidation of Electron-Deficient Sulfides
to Sulfones Using HOF·CH3CN. J. Org. Chem. 1995, 60, 6186−6187.
(d) Barton, D. H. R.; Li, W.; Smith, J. A. Binuclear manganese
complexes as catalysts in the selective and efficient oxidation of
sulfides to sulfones. Tetrahedron Lett. 1998, 39, 7055−7058. (e) Choi,
S.; Yang, J. D.; Ji, M.; Choi, H.; Kee, M.; Ahn, K. H.; Byeon, S. H.;
Baik, W.; Koo, S. Selective Oxidation of Allylic Sulfides by Hydrogen
Peroxide with the Trirutile-type Solid Oxide Catalyst LiNbMoO6. J.
Org. Chem. 2001, 66, 8192−8198. (f) Xu, L.; Cheng, J.; Trudell, M. L.
Chromium(VI) Oxide Catalyzed Oxidation of Sulfides to Sulfones
with Periodic Acid. J. Org. Chem. 2003, 68, 5388−5391. (g) Shaabani,
A.; Teimouri, F.; Lee, D. G. Ion Exchange Catalysis in Oxidation of
Organic Compounds with KMnO4. Synth. Commun. 2003, 33, 1057−
1065. (h) Baciocchi, E.; Gerini, M. F.; Lapi, A. Synthesis of Sulfoxides
by the Hydrogen Peroxide Induced Oxidation of Sulfides Catalyzed
by Iron Tetrakis(pentafluorophenyl)porphyrin: Scope and Chemo-
selectivity. J. Org. Chem. 2004, 69, 3586−3589. (i) Jeyakumar, K.;
Chakravarthy, D. R.; Chand, D. K. Simple and efficient method for
the oxidation of sulfides to sulfones using hydrogen peroxide and a
Mo(VI) based catalyst. Catal. Commun. 2009, 10, 1948−1951.
(21) Stout, E. P.; Yu, L. C.; Molinski, T. F. Antifungal Diterpene
Alkaloids from the Caribbean Sponge Agelas citrina: Unified
Configurational Assignments of Agelasidines and Agelasines. Eur. J.
Org. Chem. 2012, 2012, 5131−5135.
(22) For a regiodivergent hydrothiolation controlled by ligand
choice, see refs 10 and 16.
(23) For coordinating ability of anions to transition metals, see:
Díaz-Torres, R.; Alvarez, S. Coordinating ability of anions and
solvents towards transition metals and lanthanides. Dalton Trans.
2011, 40, 10742−10750.
(24) Jin, L.; Wang, J.; Dong, G. Palladium-Catalyzed γ-C(sp3)−H
Arylation of Thiols by a Detachable Protecting/Directing Group.
Angew. Chem., Int. Ed. 2018, 57, 12352−12355.
(25) Wang, Y.; Huang, Z.; Leng, X.; Zhu, H.; Liu, G.; Huang, Z.
Transfer Hydrogenation of Alkenes Using Ethanol Catalyzed by a
NCP Pincer Iridium Complex: Scope and Mechanism. J. Am. Chem.
Soc. 2018, 140, 4417−4429.
H
DOI: 10.1021/jacs.8b11395
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