Catalytic Hydrothiolation: Regio- and Enantioselective Coupling of Thiols and Dienes

Article abstract of DOI:10.1021/jacs.8b06957

We report a Rh-catalyzed hydrothiolation of 1,3-dienes, including petroleum feedstocks. Either secondary or tertiary allylic sulfides can be generated from the selective addition of a thiol to the more substituted double bond of a diene. The catalyst tolerates a wide range of functional groups, and the loading can be as low as 0.1 mol %.

Full text of DOI:10.1021/jacs.8b06957

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
Catalytic Hydrothiolation: Regio- and Enantioselective Coupling of
Thiols and Dienes
Xiao-Hui Yang, Ryan T. Davison, and Vy M. Dong*
Department of Chemistry, University of California−Irvine, Irvine, California 92697, United States
S
* Supporting Information
enantioselective fashion, thus allowing petroleum feedstocks to
be transformed into enantioenriched building blocks.9
ABSTRACT: We report a Rh-catalyzed hydrothiolation
of 1,3-dienes, including petroleum feedstocks. Either
secondary or tertiary allylic sulfides can be generated
from the selective addition of a thiol to the more
substituted double bond of a diene. The catalyst tolerates
a wide range of functional groups, and the loading can be
as low as 0.1 mol %.
Though asymmetric hydroamination of dienes has been
demonstrated,10 thiols are more nucleophilic and acidic than
amines, thus providing distinct challenges and opportunities
for hydrofunctionalization.11,12 In this study, we focus on Rh
complexes I, which we imagined could bind and activate the
diene 1 by η4-coordination (Figure 2). The resulting olefin-
he pursuit of catalysts capable of forging carbon−sulfur
Tlinkages is a valuable goal, as molecules essential to life,
from metabolites to macromolecules, contain sulfur atoms.1 In
addition, approximately 20% of all FDA approved drugs are
organosulfur compounds.2 The direct addition of a thiol to a
double bond represents an attractive and atom-economical3
approach for generating C−S bonds.4 Inspired by this
challenge, we chose to focus on the hydrothiolation of
conjugated dienes, which are readily available and include
commodity chemicals, such as butadiene and isoprene (Figure
1).5 One previous hydrothiolation of 1,3-dienes was reported
by He, where the application of Au catalysts resulted in
racemic mixtures.6 By using Rh-catalysis, Breit pioneered an
enantioselective hydrothiolation of allenes7 and Hull achieved
a regiodivergent addition to allylic amines.8 As a complement
to these strategies, we herein communicate that Rh-catalysts
generate allylic sulfides from 1,3-dienes, in a regio- and
Figure 2. Proposed Rh-catalyzed hydrothiolation of 1,3-dienes.
complex II undergoes oxidative addition to a thiol 2 to yield
III. From III, Rh-hydride insertion can occur via 1,4- or 1,2-
insertion, wherein rhodium adds to the less-hindered position
of the diene. In path a, Rh-hydride insertion provides a Rh-π-
allyl IV after 1,4-insertion. Because reductive elimination tends
to favor branched products,13 we reasoned IV would yield
tertiary allylic sulfides 3.14 In path b, 1,2-insertion provides V
and reductive elimination gives homoallyic sulfides 4.
With this hypothesis in mind, we chose 1,3-cyclohexadiene
(1a) as the model substrate because its symmetric structure
minimizes the number of isomers possible. We studied the
coupling of 1a and thiophenol (2a) using different bidentate
phosphine ligands in the presence of Rh(cod)2SbF6 (Table 1).
With the JosiPhos (L1), DuPhos (L2), and BPE (L3) ligands,
we observed a mixture of the allylic and homoallylic sulfides. In
contrast, the BINAP family afforded excellent regioselectivity
for the allylic sulfide 3aa (>20:1 rr) in high yields and
enantioselectivity (>91% yields, and >85:15 er). With (S)-Tol-
Received: July 2, 2018
Figure 1. Inspiration for hydrothiolation of 1,3-dienes.
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.8b06957
J. Am. Chem. Soc. XXXX, XXX, XXX−XXX

Journal of the American Chemical Society
Communication
regioselectivity (18:1−>20:1 rr) are observed with both
aliphatic and aromatic thiol partners. Tertiary thiols (such as
tert-butylthiol and triphenylmethanethiol) are unreactive thus
far, presumably due to steric hindrance. This method is
compatible with heteroarene (3ao,16 3as), hydroxyl (3aq),
carboxyl (3ar), amino (3ad, 3ae), and ester groups (3aj).
Next, we investigated hydrothiolation of unsymmetric 1,3-
dienes (Table 3A). For 1-substituted (1b) and 1,2-
Table 1. Ligand Effects on Asymmetric Hydrothiolation of
1a
a
a
Table 3. Hydrothiolation of Various 1,3-Dienes
a
Reaction conditions: 1a (0.2 mmol), 2a (0.1 mmol), Rh(cod)2SbF6
(1 mol %), ligand (1 mol %), DCE (0.2 mL), 3 h. Isolated yield.
Regioselectivity ratio (rr) is the ratio of 3aa to 4aa, which is
determined by 1H NMR analysis of reaction mixture. Enantiose-
lectivity determined by chiral SFC.
BINAP ligand (L5), we lowered the catalyst loading to 0.1 mol
% and isolated (S)-sulfide 3aa15 on gram scale (1.2 g, 95%
yield, 99:1 er).
Table 2 showcases the scope of this method with 18
different thiols and 1a, using catalyst Rh(L5). High reactivity
(3ab−3as, 49−99%), enantioselectivity (96:4−>99:1 er), and
a
Table 2. Hydrothiolation of 1a with Various Thiols
a
Reaction conditions: 1 (0.4 mmol), 2 (0.2 mmol), Rh(cod)2SbF6 (1
mol %), L (1 mol %), DCE (0.4 mL), 30 °C, 5 h. Isolated yields.
Ligand used in parentheses. Regioselectivity ratio (rr) is the ratio of 3
1
to 5, which is determined by H NMR analysis of reaction mixture.
b
Enantioselectivity determined by chiral SFC. Using Rh(cod)2SbF6 (5
c
mol %), L (5 mol %), 15 h. 13:1 rr
disubstituted (1c) dienes, we found that a bulkier BINAP
ligand (L6) afforded the best results (85% yield, 83:17 er and
78% yield, 71:29 er; respectively). In contrast, the 2-
substituted-1,3-dienes reacted poorly in the presence of
BINAP ligands. In this case, the JosiPhos ligands provided a
breakthrough. With L7, myrcene (1d) can be coupled with an
aromatic thiol (3da, 68% yield, 96:4 er, >20:1 rr) or an
aliphatic thiol (3dp, 71% yield, 90:10 er, >20:1 rr). 2-Aryl-1,3-
a
Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), Rh(cod)2SbF6
(1 mol %), L5 (1 mol %), DCE (0.4 mL), 30 °C, 5 h. Isolated yields.
Regioselectivity ratio (rr) is the ratio of 3 to 4, which is determined by
1H NMR analysis of reaction mixture. Enantioselectivity determined
b
by chiral SFC. 18:1 rr.
B
DOI: 10.1021/jacs.8b06957
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Journal of the American Chemical Society
Communication
dienes undergo hydrothiolation as well (3ea−3ga, 73−80%,
93:7−98:2 er); the presence of an electron-withdrawing group
(3ea) on the phenyl ring imparts higher regioselectivity (>20:1
rr) compared to electron-donating substituents (3ga, 7:1 rr).
Isoprene and butadiene are petroleum feedstocks, produced
on a million metric ton scale every year and used as monomers
to make plastics.17 Hydrothiolation of isoprene (1h) with
thiophenol or cyclohexanethiol gives the corresponding tertiary
sulfide (3ha, 3ht) in >89% yield and >13:1 rr (Table 3B). A
commercial diene, 2,3-dimethyl-1,3-butadiene (1i), transforms
into the tertiary sulfide 3ia (93% yield, >20:1 rr). The
construction of chiral products from butadiene remains a
challenge that has inspired hydrohydroxyalkyation,5c cyclo-
additions18 and difunctionalizations.19 To meet this challenge,
we simply switched the ligand to DTBM-GarPhos (L8). With
Rh(L8), high reactivity (81−95%) and regioselectivity (>20:1
rr) are achieved using both aliphatic and aromatic thiols. The
products derived from aromatic thiols (3ja, 3jc, 3jg, 3ju) are
obtained in higher enantioselectivities (95:5−98:2 er) than
those from aliphatic thiols (3jv, 3jw, 3js, 90:10−94:6 er).
Aside from enantioselective examples, we examined the
addition of a L-cysteine ester 2x to 1,3-cyclohexadiene (Figure
3). Either diastereomeric product, 3ax or 3ax′, can be
generated with high diastereoselectivity (>20:1 dr), depending
on the enantiomer of ligand L5 employed.
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 provided by UC Irvine, the National Institutes of
Health (R35GM127071) and the National Science Founda-
tion (CHE-1465263). We thank Alexander Lu for help with
initial studies and the Jarvo Lab for help with chiral SFC
analysis.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.8b06957.
■
S
Experimental procedures and spectral data for all new
compounds (PDF)
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DOI: 10.1021/jacs.8b06957
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DOI: 10.1021/jacs.8b06957
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