Manganese-catalyzed regiospecific sp3 C-S bond formation through C-C bond cleavage of cyclobutanols

Article abstract of DOI:10.1039/c6cc01843b

A manganese-catalyzed regioselective sp³ C-S bond formation through C-C bond cleavage of cyclobutanols is described. A variety of primary and secondary alkyl thioethers are efficiently prepared under mild reaction conditions. The mechanistic pathways involving radical-mediated tandem C-C bond cleavage and C-S bond formation are proposed.

Full text of DOI:10.1039/c6cc01843b

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DOI: 10.1039/C6CC01843B
o C-C cleavage
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26 examples
A manganese-catalyzed regioselective sp3 C-S bond formation through C-C bond
cleavage of cyclobutanols is described.

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DOI: 10.1039/C6CC01843B
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Manganese-Catalyzed Regiospecific sp3 C-S Bond Formation
through C-C Bond Cleavage of Cyclobutanols
Received 00th January 20xx,
Accepted 00th January 20xx
Rongguo Ren,a,§ Zhen Wu,a,§ and Chen Zhu*,a,b
DOI: 10.1039/x0xx00000x
www.rsc.org/
A manganese-catalyzed regioselective sp3 C-S bond formation
through C-C bond cleavage of cyclobutanols is described. A variety
of primary and secondary alkyl thioethers are efficiently prepared
under mild reaction conditions. The mechanistic pathways
involving radical-mediated tandem C-C bond cleavage and C-S
bond formation are proposed.
obtained under the silver catalysis.8 Nevertheless,
a
competitively intramolecular ring expansion of cyclobutanols
leading to the formation of α-tetralones was concurrent in the
silver-catalyzed ring opening of cyclobutanols that significantly
limited the applications of this protocol.9 As a result, a
modification of manganese-catalyzed ring-opening azidation of
cyclobutanols was developed, which efficiently suppressed the
intramolecular cyclization and furnished a variety of γ-
azidoketones (Scheme 1B).10 This method was subsequently
applied to the formation of C-C bond, affording a wide array of
γ-cyano and alkynyl substituted ketones (Scheme 1C).11 To
further extend the utility of the method, we herein report a
manganese-catalyzed ring opening of cyclobutanols to
construct sp3 C-S bond. A variety of alkyl thioethers have been
efficiently generated with good regioselectivities (Scheme 1D).
The systematic examination of reaction parameters was
conducted to define the optimum reaction conditions (Table 1).
Under the manganese catalysis, the addition of N, N-bidentate
The C-S bond ubiquitously exists in natural products,
pharmaceutically active compounds, and organic materials.1
Owing to its utmost importance, the formation of C-S bond has
attracted extensive attention.2 Among those preparation
methods, the construction of sp3 C-S bond is relatively less
studied. The most common route to the sp3 C-S bond is the
nucleophilic replacement of alkyl halides by sulfides or
nucleophilic addition of sulfides to unsaturated bonds.
However, the pre-installation of halogen or unsaturated
functionality at the desired position can be difficult in some
cases. Therefore, the development of a straightforward and
efficient approach to build up sp3 C-S bond is still in demand.
The C-C bond constitutes the fundamental of organic
molecules. The elaboration of C-C bonds into targeted
functionality represents one of the most ideal transformations,
but breaking inert C-C bonds is always challenging due to the
high BDEs.3 We are interested in tertiary cycloalkanols since
they are viable to cleave the strained cyclic C-C bond,4 thereby
serving as privileged precursors for the production of distally
substituted ketones.5,6 Recently, we disclosed the first silver-
catalyzed fluorination of cyclopropanols and cyclobutanols to
produce β- and γ-fluoroketones (Scheme 1A).7 Later, a series
of distally chlorinated and brominated ketones were also
Scheme 1. Radical-Mediated Ring-Opening Functionalization of
Cyclobutanols
a.Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry,
Chemical Engineering and Materials Science, Soochow University, 199 Ren-Ai
Road, Suzhou, Jiangsu 215123, China. Email: chzhu@suda.edu.cn
b.Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai
200032, China
§ R. R and Z. W. contributed equally.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Table 1. Reaction Parameters Survey
Journal Name
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DOI: 10.1039/C6CC01843B
Scheme 2. Substrate Scope
entry
1
ligand
--
oxidant
BI-OH
--
solvent
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCE
yield (%)a
30
2
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
Bipy
31
3b
4b
5b
6b
7
BI-OH
IBX
66
37
PIDA
PhIO
BI-OH
BI-OH
BI-OH
BI-OH
BI-OH
BI-OH
73
< 10
82
8
42
9
toluene
dioxane
THF
48
10
11
12
79
46
DMF
80
a Yields of isolated products. b Use of 2.0 equiv of oxidant.
ligand and oxidant were requisite for achieving satisfactory
reaction outcome (entries 1-2). While a set of hypervalent
iodine reagents served as efficient oxidant enabling the redox
cycle of manganese catalyst, the use of BI-OH provided the
best yield (entries 3-6). Raising the quantity of BI-OH from 2 to
3 equiv appreciably improved the chemical yield (entry 7).
Acetonitrile was found to be superior to other common
organic solvents (entries 8-12).
With the optimized reaction conditions in hand, the
generality of the protocol was then evaluated. A variety of
alkyl thioethers were readily generated under mild conditions
through the ring opening of cyclobutanols (Scheme 2). Both
electron-rich and deficient aryl substituted cyclobutanols were
tolerated in the reaction. In general, the electron-rich
substrates delivered better yields than electron-poor ones. The
steric hindrance seemed to have little impact on the reaction
outcome, giving comparable yields of products (2e-2g). Halides
were intact in the reaction and the example of 2k was
noteworthy, as the presence of bromide provided a platform
for later product modification through cross-coupling reactions.
In addition to aryl cyclobutanols, alkyl and heteroaryl (e.g.,
furyl and thienyl) cyclobutanols were also apt substrates to
afford the corresponding ketones in synthetically useful yields
(2m-2p). Notably, cyclobutanols with sensitive functional
groups, such as alkynyl and alkenyl, were compatible with the
reaction conditions (2q and 2r), albeit with reasonable lower
yields. Besides primary alkyl thioethers, many secondary alkyl
thioethers (2s-2v) were prepared from the cyclobutanols with
2 | J. Name., 2012, 00, 1-3
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multiple substitutions on the cyclobutyl ring, which were
usually regarded less reactive according to the Thorpe-Ingold
effect.12 Taking bicyclic tertiary alcohol 1u for example, the C-C
cleavage/ C-S formation smoothly proceeded in unique
regioselectivity, giving rise to c-pentyl thioether 2u in the form
of two diastereomers (1.2:1 ratio) in good yield. Likewise,
bicyclic tertiary alcohol 1v was converted into a mixture of
isomeric products 2v with 1:1 ratio in high yield. With electron-
rich or -deficient diaryl disulfides or dialkyl disulfides, the
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reactions also proceeded to give the desired products (2w-2z).
However, the conversion of secondary cyclobutanol resulted in
cyclobutanone through direct oxidation. It was noted that the
reaction with cyclopropanol also led to the corresponding
thioether in modest yield.
-
To gain insights into the possibly mechanistic pathways, a
set of experiments were performed (Scheme 3). Firstly, radical
inhibitor TEMPO or BHT was added to the reaction. In either
case the reaction was significantly suppressed, which
suggested a radical-mediated pathway (Scheme 3A). Afterward,
we examined the ligand effect. Under the oxidative reaction
conditions, the ligand Bipy got the chance to be oxidized to the
Figure 1. Proposed Mechanism
The practicality of the method was illustrated by the gram-
scale preparation of 2a Under the standard reaction
.
corresponding N-oxide 3 13
Replacing Bipy with 3 delivered a
.
conditions, 1 gram of 1a was readily converted to 2a in
80%yield (Scheme 4A). The thioether could be divergently
oxidized by mCPBA to synthetically useful sulfoxide and
sulfone, which could be elaborated to complex molecules
through the Julia olefination or Pummerer rearrangement
(Scheme 4B). For instance, the Pummerer reaction of sulfoxide
similar yield to the reaction without ligand (Scheme 3Ba vs
Table 1, entry 1), which implied that Bipy was the virtual ligand
in the conversion. Using pyridine instead of Bipy in the
reaction did not appreciably improve the reaction outcome,
indicating that the role of Bipy was more likely as ligand than
as base (Scheme 3Bb).
4
led to the
-acetyloxy thioether 6 in good yield (Scheme 4C).
Scheme 3. Mechanistic Studies
Scheme 4. Applications
Based on the experimental observations, a postulated
mechanism is outlined (Figure 1). Initially, the interactions
among MnIII salt, Bipy, and BI-OH lead to MnV species a 14
.
The
with the intermediate
, which simultaneously undergoes single-
electron oxidation of O-H bond to form cyclobutyloxy radical
and MnIV species
. The tautomerization of gives rise to the
ring-opened alkyl radical , which reacts with diaryl disulfide to
coordination of cyclobutanol
generates complex
1
a
In summary, we have described a manganese-catalyzed
regioselective sp3 C-S bond formation through C-C bond
cleavage of cyclobutanols. A variety of primary and secondary
alkyl thioethers are furnished under mild reaction conditions.
The reaction can be readily scaled up to gram quantities. The
radical-mediated C-C cleavage/ C-S formation mechanistic
pathway has been proposed. Other applications for
manganese-catalyzed ring-opening functionalization of
cyclobutanols are ongoing in our laboratory.
b
d
c
d
e
eventually afford the product 2 c is reduced
. The MnIV species
by the in situ formed thiyl radical, regenerating the MnIII
complex.
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8349; (m) Y. Li, Z. Ye, T. M. Bellman, T. Chi and M. Dai, Org.
We are grateful for the financial support from Soochow
University, the National Natural Science Foundation of China
(Grant no. 21402134), the Natural Science Foundation of
Jiangsu Province (Grant no. BK20140306), and the Priority
Academic Program Development of Jiangsu Higher Education
Institutions (PAPD).
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