Palladium-Catalyzed Thiomethylation via a Three-Component Cross-Coupling Strategy

Article abstract of DOI:10.1021/acs.orglett.8b02677

In this report, the combination of masked inorganic sulfur and dimethyl carbonate was designed to achieve thiomethylated cross coupling of aryl chlorides. Remarkably, this powerful strategy realized thiomethylation of nucleosides bearing unprotected ribose, chloride-containing pharmaceuticals with late-stage coupling, and herbicides possessing multiple heteroatoms and steric hindrance. Moreover, this protocol is practically amenable to multigram-scale synthesis with a lower catalysis loading and a higher yield.

Full text of DOI:10.1021/acs.orglett.8b02677

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium-Catalyzed Thiomethylation via a Three-Component
Cross-Coupling Strategy
Ming Wang,†,‡ Zongjun Qiao,†,‡ Jiaoyan Zhao,† and Xuefeng Jiang*,†,§
†Shanghai Key Laboratory of Green Chemistry and Chemical Process, School of Chemistry and Molecular Engineering, East China
Normal University, 3663 North Zhongshan Road, Shanghai 200062, People’s Republic of China
§State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, People’s Republic of China
S
* Supporting Information
ABSTRACT: In this report, the combination of masked inorganic
sulfur and dimethyl carbonate was designed to achieve thiomethylated
cross coupling of aryl chlorides. Remarkably, this powerful strategy
realized thiomethylation of nucleosides bearing unprotected ribose,
chloride-containing pharmaceuticals with late-stage coupling, and
herbicides possessing multiple heteroatoms and steric hindrance.
Moreover, this protocol is practically amenable to multigram-scale
synthesis with a lower catalysis loading and a higher yield.
rganosulfur chemistry is gaining more and more
our group,16 we envision that a masked group on inorganic sulfur
Osignificance since carbon−sulfur bonds are continuously will drastically decrease the BDE of Pd−S, which realize the
ubiquitous in biological molecules,1 pharmaceuticals,2 and
CAr−S bond formation in the cross coupling. Meanwhile,
dimethyl carbonate (DMC)17 decreases the electron cloud
density of sulfur with carbonic ester, which will be an ideal
methylating agent with depressed catalysis poison. Herein, we
report an efficient thiomethylation strategy for the construction
of diverse functionalized aryl methyl sulfides via a palladium-
catalyzed three-component cross coupling (Figure 1C).
Modern drug discovery relies on the rapid late-stage
modification approach and preparation of a panel of structurally
related derivatives.18 Therefore, our initial study focused on the
thiomethylation of chlorine-containing pharmaceuticals with
miscellaneous sensitive functional groups. We commenced our
study with Fenofibrate19 1a, potassium thioacetate,20 and DMC,
under the assistance of palladium catalyst and potassium tert-
butyloxide, affording an 84% yield of methylthioarene 2a.
Deutero-dimethyl carbonate was explored, affording deuterium
product 2a′ in a yield of 77%, which undoubtly demonstrated
that DMC served as a green methyl source (see the Supporting
Information (SI)).
agrochemicals.3 Sulfur-containing molecules have been com-
monly and widely applied in antibacterials, antiviral, and
anticancer since the establishment of the U.S. Food and Drug
Administration (FDA) in the early 20th century.4 Aryl methyl
sulfide, sulfoxide, and sulfone motifs are of great significance in
modern pharmaceutical science; these are used in compounds
such as the antipsychotic drug Thioridazine5 (Novartis), the
cardiovascular drug Sulmazole6 (Roche), the basal-cell
carcinoma drug Vismodegib7 (Roche), the proliferative diseases
drug Thiocolchicine,8 the nonsteroidal anti-inflammatory drug
Sulindac9 (Merck), and the nonsteroidal anti-inflammatory drug
Firocoxib10 (as illustrated in Figure 1A). Conventionally, the
application of methylthiol is the most common pathway for the
“MeS” functional group,11 which is introduced through
nucleophilic substitution with only electron-deficient substrates
or the methylation of thiols.12 However, intractable problems13
associated with catalysts poisoning, oxidation compatibility, and
environmental pollution were found from thiols adoption
(Figure 1B). Methanethiol, which is a hazardous and fetid gas,
possessing low coupling reactivity with aryl halide, because of
strong coordination to the transition-metal catalysts, causes
terrible risks during the manufacturing process. Alternative
sodium methyl mercaptide is formed during coupling in aqueous
solution at a maximum concentration of 20%, which impedes the
application of association with water compatibility.14 In the
catalytical cycle of the coupling with aryl halide, the bond energy
of Pd−SMe (bond dissociation energy (BDE) of 92−99 kcal
mol−1) is higher than CAr−SMe bond cleavage (BDE = 82−85
kcal mol−1),15 which challenges the reductive elimination
process. With the concept of masked sulfurating strategies in
Under the optimized conditions, different types of aryl halides
were comprehensively investigated (see Scheme 1). Substrates
bearing Csp2−I, Csp2−Br, and even Csp2−Cl on the phenyl ring
could afford desired product with excellent yields. The method
is compatible with both single-substituted aryl molecules (2b−
2g) and multiple functional group substituted (2h−2k).
Electron-donating substituents were proven to be entirely
compatible in various positions when sodium thiosulfate is
employed as the sulfur source, instead of potassium thioacetate
Received: August 21, 2018
© XXXX American Chemical Society
A
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Letter
(2aa−2ah). Note that a sugar-containing structure was perfectly
tolerated, affording the desired thiomethylation product 2ag.
Notably, thiomethylation of heteroaromatics led to the
formation of desired products in good to excellent yields
under the standard conditions. A variety of heteroaromatic
chlorides, such as pyridine 2l, quinoline 2m, pyridazine 2n,
purine 2o, and 1H-pyrrolo[2,3-d]pyrimidine 2p were com-
petent coupling partners. 7H-pyrrolo[2,3-d]pyrimidine with
free amino group 2q was well-tolerated in this transformation.
Methoxyl groups at the 6-position and 7-position on quinazoline
were tolerated and afforded 2r in an 85% yield. In particular, 6-
chloropurine substituted by pyran on N1 position, afforded
desired product 2s successfully. Dihalides with two active
reaction sites are also excellent candidates, both aromatic
product (2t) and aromatic heterocyclic products (isoquinoline
2u, pyrimidine 2v, pyrazine 2w, thieno[3,2-d]pyrimidine 2x, and
1,3,5-triazine 2y) were generated via dithiomethylation
reactions.
The application on 1,3,5-triazine demonstrates the potential
utility of this methodology for the synthesis of pesticide
scaffolds. A nucleoside,21 consisting of a nucleobase and a five-
carbon sugar, is a significant building block for DNA and RNA,
which crucially expresses genetic information.22 Because of the
great compatibility and applicability, we commenced our
thiomethylation with the unprotected nucleoside (see Scheme
2). When 2-chloro-adenosin without any protection on ribose
and amino group was subjected to the standard conditions,
thiomethylation product 3a could be successfully afforded in a
77% yield, which was further confirmed via single-crystal study
(see the SI). Thus, it is possible that the thiomethylated method
Figure 1. Siginificant methylsulfides.
a
Scheme 1. Thiomethylation of Various Aryl Halides
a
Condition A: X = Cl, 1 (0.2 mmol), KSAc (0.6 mmol), DMC (1.0 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), t-BuOK (0.6 mmol), and
DMSO (2.0 mL) at 120 °C. Condition B: X = Br, 1 (0.1 mmol), Na2S2O3·5H2O (0.2 mmol), DMC (0.5 mmol), Pd(acac)2 (10 mol %), PtBu3·
HBF4 (20 mol %), t-BuOK (0.2 mmol), TBAB (0.3 mmol), and DMSO (1.0 mL) at 120 °C.
b
B
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Chloro-N2-isopropyl-N4-methyl-1,3,5-triazine-2,4-diamine,
which was readily prepared from cyanuric chloride, was
thiomethylated to furnish Desmetryn 5d in a yield of 86%.
Ametryn 5e, which is widely used in corn, citrus, and sugar cane
protection, was prepared from commercially available Atrazine
in a yield of 86% via a one-step process. Prometryn 5f,25 which is
a methylthio-S-triazine herbicide (registered as Caparol by
Novartis Crop) that is used as protection to control annual
broadleaf and grass weeds, could be efficiently synthesized in a
yield of 91%. Terbutryn 5g, Irgarol 5h, Dimethametryn 5i, and
Methoprotryne 5j were all afforded in excellent yields, which
served as different types of protections for agriculture. Notably,
higher isolated yield (93%) was achieved in the multigram-scale
process for the synthesis of the Simetryn with a lower catalysis
loading (2.5 mol %).
Scheme 2. Thiomethylation on Nucleosides
The current protocol also provided a synthetic shortcut for
the marketed drug Vismodegib,26 which is the first Hedgehog
signaling pathway targeting agent, which gained FDA approval
in Jan. 30, 2012. As shown in Scheme 4, Vismodegib 6c could be
will provide a straightforward approach to modify DNA and
RNA with sulfur. Subsequently, a variety of nucleosides were
thiomethylated through this highly compatible protocol.
Guanosin 3b and purine riboside 3c proceeded smoothly to
afford the corresponding thiomethylation product on the 6-
position of purine ring. Furthermore, methylamine-, ethyl-
amine-, benzylamine-, and even cyclopropylamine- substituted
adenosin were thiomethylated to afford 3d, 3e, 3f, and 3g,
respectively.
Scheme 4. Methylsulfide-Containing Pharmaceutical
Synthesis
Simazine 4a,23 which has a triazine-type structure, could be
directly transformed to Simetryn 5a in an 84% yield, which is
another significant efficient and selective herbicide for paddy
species (see Scheme 3).24 Besides the thiomethyl group,
Scheme 3. Thiomethylation for Pesticides
efficiently produced through highly selective thiomethylation of
6a with multiple functional groups, with free amido linkage,
followed by oxidation. 6a can be smoothly furnished with
different alkyl sources for the corresponding alkyl thioethers
6ba−6bc, which displays potential for drug modification. In
addition, a nonsteroidal anti-inflammatory drug Firocoxib (6f),
which is the first COX-2 inhibitor approved by FDA for horses,
was synthesized from aryl bromide 6d through the current
thiomethylation strategy, followed by oxidation (see Scheme 4).
The application of this thiomethylation strategy for late-stage
diversification was demonstrated on Fenofibrate (marketed as
Tricor by Abbott Laboratories), which serves as a cholesterol
and triglycerides reducer in blood. The thiomethylated
Fenofibrate 2a can be afforded through this strategy in a yield
of 84%, which is the key structure for diversified derivation. The
organosulfur-based Fenofibrate with different oxidative states,
providing methysulfinyl 7a, methysulfonyl 7b, imination
product 7c, N-cyano sulfilimines 7d, and N-(trifluoromethyl)-
sulfonyl sulfilimines 7e, substantially assist the library establish-
ment of organosulfur derivatives for drug discovery (see Scheme
5a).27 Furthermore, late-stage modification of an estrone
thioethylated product 5b could be afforded in a 76% yield
when DMC was replaced by diethyl carbonate (DEC).
Furthermore, sterically hindered dipropyl carbonate (DPC)
could also be applied for thiopropylation, producing 5c
unhinderedly. These results indicated that this catalytic system
could provide different types of thioalkyl functional groups by
varying carbonates. Furthermore, diverse synthetic applications
of pesticide were undertaken using a thiomethylated process. 6-
C
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Letter
derivative 8a can also be efficiently achieved via the present
strategy, providing the thiomethylation product 8b.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xfjiang@chem.ecnu.edu.cn.
ORCID
Scheme 5. Late-Stage Diversification
Ming Wang: 0000-0003-0388-4473
Xuefeng Jiang: 0000-0002-1849-6572
Author Contributions
‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge financial support from the NSFC (Nos.
21722202, 21672069, 21472050; Nos. 21871089 and 21502054
for M.W.), The National Key Research and Development
Program of China (No. 2017YFD0200500), S&TCSM of
Shanghai (Grant No. 18JC1415600), Professor of Special
Appointment (Eastern Scholar) at Shanghai Institutions of
Higher Learning, and the National Program for Support of Top-
Notch Young Professionals.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.8b02677.
Experimental procedures, and full spectroscopic data for
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