Iron-catalyzed radical oxidative coupling reaction of aryl olefins with 1,3-dithiane

Article abstract of DOI:10.1021/ol500850d

An alternative method to an iron-catalyzed radical oxidative cross-coupling reaction followed by 2-chloro-1,3-dithiane and aryl olefins for the synthesis of β-chloro substituent 1,3-dithiane products is presented. The described method has the advantage of mildness of the reaction conditions and tolerates a variety of functional groups. Preliminary mechanistic studies have confirmed the first example of a coupling of 1,3-dithiane with unactivated alkenes that proceeds via an iron-catalyzed oxidative radical intermediate along the reaction pathway.

Full text of DOI:10.1021/ol500850d

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Radical Oxidative Coupling Reaction of Aryl Olefins
with 1,3-Dithiane
Wenbin Du,† Lixia Tian,† Junshan Lai,† Xing Huo,† Xingang Xie,‡ Xuegong She,‡ and Shouchu Tang*,†
†School of Pharmacy, Lanzhou University, Lanzhou 730000, P. R. China
‡State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: An alternative method to an iron-catalyzed radical
oxidative cross-coupling reaction followed by 2-chloro-1,3-dithiane and
aryl olefins for the synthesis of β-chloro substituent 1,3-dithiane products
is presented. The described method has the advantage of mildness of the
reaction conditions and tolerates a variety of functional groups.
Preliminary mechanistic studies have confirmed the first example of a
coupling of 1,3-dithiane with unactivated alkenes that proceeds via an
iron-catalyzed oxidative radical intermediate along the reaction pathway.
1, 3-Dithianes are widely used as attractive acyl anion
equivalents (umpolung) for construction of carbon−carbon
bonds for over half a century.1 They have also been applied as
building blocks for the preparation of a wide variety of
chemicals and target molecules. For example, 1,3-dithiane
anions can be frequently exploited for the generation of a wide
variety of aldol linkages (linchpin reaction) and for the union of
advanced fragments in numerous natural products synthesis2
(Scheme 1, eq 1). We identified a modular set of 1,3-dithianes
substrate scope of these reactions is limited, and these available
methods suffer from issues of imperfect functional group
tolerance. Further, the application of these reactions is
particularly problematic for the polymerization process,4
owing to our continuing studies in enantioselective carboli-
thiation transformations of styrenes with 1,3-dithiane.5 Thus, it
was necessary to discover a new strategy for direct
functionalization of aryl olefins with 1,3-dithiane.
Radical oxidative coupling reactions have provided increas-
ingly important innovations for the construction of carbon−
carbon and carbon−heteroatom bonds over the past decades.6
In particular, radical oxidative cross-coupling methods by
inexpensive iron catalyst provide a useful approach to C−C
bond construction.7 In 2009, Tu and co-workers reported a
novel iron-catalyzed radical coupling reaction of alcohols with
alkenes.8 Similarly, Lei and co-workers have described a radical
oxidative coupling of phenols and olefins using less expensive
iron catalysts.9 However, seeking novel RH or RXH as
nucleophiles and applying them in alkene difunctionalization
still remains a challenge.10 There are relatively few reports on
the addition of 1,3-dithiane to unactivated olefins,11 possibly
because the radical derived from 1,3-dithiane is relatively
electron-rich, and the coupling reaction of 1,3-dithiane with
alkenes was successful only when electron-deficient alkenes
were employed.11b Herein, we present a method, based on the
iron-catalyzed radical oxidative cross-coupling pathway mani-
folds, that concatenates simple 1,3-dithiane with available
arylalkenes to form a wide range of dithiane derivatives
(Scheme 1, eq 3). In addition, this protocol circumvents issues
of alkene difunctionalization and proceeds efficiently under
friendly iron-catalyzed conditions, allowing for excellent
functional group compatibility.
Scheme 1. Reactions of 1,3-Dithianes for Construction of
Carbon−Carbon Bonds
as being highly desirable for the installation of acyl relevant
moieties. During the past few years, we disclosed a new
carbolithiation protocol for the conversion of carbon−carbon
bonds to 1,3-dithiane derivatives using lithiated 1,3-dithiane
anions as electrophiles with olefinic substrates3 (Scheme 1, eq
2). These alternative routes were important advances in this
field and provided 1,3-dithiane protocols complementary to
known chemistry. Despite significant improvements, the
Received: March 21, 2014
Published: April 21, 2014
© 2014 American Chemical Society
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Letter
We started our initial investigations with the transformation
of 1 into 1,3-dithiane derivative 3a using various radical initiator
sources and catalysts. We hypothesized that a readily accessible
iron catalyst would be useful for this transformation, which it
has shown to be effective in radical cross-coupling reaction of
alkene. As shown in Table 1, FeCl3 was utilized as the catalyst
Table 2. Iron-Catalyzed Cross-Coupling between 1,3-
Dithiane and Alkenes
a
Table 1. Cross-Coupling Reaction between 1,3-Dithiane and
a
Styrene under Varied Conditions
b
c
entry
catalyst
activating agent
solvent
yield (%)
1
FeCl3 (10%)
CuI (15%)
PdCl2 (5%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
None
DDQ
DDQ
DDQ
None
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
NCS
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
trace
0
2
3
trace
0
4
5
75
6
86
0
7
DCE
8
FeCl3 (10%)
FeCl3 (5%)
FeCl3 (15%)
FeCl3 (10%)
FeCl3 (10%)
FeCl3 (10%)
DCE
trace
83
9
DCE
10
11
12
13
DCE
84
toluene
DMF
0
0
THF
trace
a
Reaction conditions: all of the reactions were performed with 1 (30
mg, 0.25 mmol), 2a (23.4 mg, 0.225 mmol), catalyst, and activating
b
agent (0.3 mmol) in 2 mL of solvent for 12 h. The reaction
temperature: rt to 100 °C (entries 1−4); 0 °C (entries 5−14).
c
Isolated yield.
in the presence of 2,3-dichloro-5,6-dicyano-1,4-benzoqinone
(DDQ) and gave little to no desired product in these reactions.
Since 2-H-1,3-dithiane is sparingly stable in an FeCl3 catalyst
system, after some experimentation, we reasoned that use of an
initiator might be beneficial and N-chlorosuccinimide (NCS)
was necessary to facilitate the coupling in a preactivation step.12
To our delight, upon warming to 0 °C, the aggregates 2-chloro-
1,3-dithianes appear to disappear and 1,3-dithiane is efficiently
converted with 2a to furnish the desired product 3a in 75%
yield (Table 1). In contrast, none of the desired product was
generated in these reactions when N-bromosuccinimide (NBS)
was used. One possibility is that 2-bromodithiane in solution is
unstable and unreactive. To test this postulate, we ran the
reaction with NBS with 1,3-dithaine in 1,2-dichloroethane
(DCE) without olefins and obtained oxidative hydrolysis
results. We have now found that the amount of NCS is
essential to the outcome of the reaction, which we propose
occurs by electrophilic activation using FeCl3 as a catalyst
without the need for an added ligand, whereas the use of FeCl3
(5−15 mol %) did not have a positive influence on the
outcome of the reaction. The reaction performed best with use
of a halogenated solvent such as DCE, whereas C−C bond
formations were less efficient in solvents such as toluene, N,N-
dimethylformamide (DMF), and tetrahydrofuran (THF).
With optimized reaction conditions in hand, the scope of
these radical processes with regard to the arylalkenes and 1,3-
dithiane was next examined (Table 2). We focused our
attention on substitutions on the styrene ring. Electron-rich
olefins gave good to excellent yields of cross-coupling products.
a
Reaction conditions: 1,3-dithiane 1 (0.25 mmol), alkene 2 (0.225
mmol), NCS (1.2 equiv), FeCl3 (10 mol %), 2 mL of DCE, −30 °C to
[b]
[c]
rt, 24 h.
Isolated yield. Reaction time: 2 h.
By increasing the reaction temperature to rt, complete
conversion of electron-deficient olefins to the desired products
was achieved. In addition, aryl olefins with sterically hindered
ortho substituents could also be obtained in moderate to good
yields (Table 2, entries 4, 8, 12, 16, and 19). In these cases, the
substrates shown gave clean conversion to the β-chloro
substituted 1,3-dithiane derivatives. Substrates containing free
OH substituents (o-, m-, and p-styrenes) have, to date, failed to
be transformed to dithiane-coupling products (Table 2, entry
22). On a gram scale, the coupling of 1,3-dithiane with 2b
proceeded the desired product 3b in 81% yield. Importantly,
the dithiane moieties can be removed without loss of the Cl
moiety, thereby providing a diverse series of correponding β-
chloro substituted formyl systems. The above procedure proved
to be general for the complementary to current protocols and
allows for the synthesis of β-chloro substituted 1,3-dithiane
derivatives that are not readily accessible via traditional linchpin
and carbolithiation means.
In order to aid our interpretation of the mechanism, a series
of experiments were performed as outlined in Scheme 2.
Initially, we found that no desired product was formed in the
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Organic Letters
Letter
system to give reactive radicals. After 50 min, the signal peaks
slowly became weak. It demonstrated that the new generated
radicals would be consumed by nucleophile 2a during the
coupling reaction process.
Scheme 2. Mechanistic Experiments
According to the above experimental results, a plausible
explanation of mechanism is depicted in Scheme 3. After the
Scheme 3. Proposed Mechanism
presence of an excess of 2,2,6,6-tetramethyl-1-piperidinyloxy
(TEMPO), strongly indicating that the coupling transformation
might proceed via a radical pathway (Scheme 2, a). To our
surprise, when 2,6-di-tert-butyl-4-methylphenol (BHT, 1.2
equiv) was added under the standard conditions, the coupling
reaction still afforded desired product in good yields. These
results might disfavor the 1,3-dithiane radical anion transfer to
phenol radical (Scheme 2, b). To gain a more thorough
understanding of the origin of radical pathway, we carried out
several competition experiments. The Cl substituent product
was obtained when the reaction was performed in the presence
of a large quantity of NaN3 under standard reaction conditions,
suggesting that the coupling might not occur through attack by
the nucleophilic N3 anion13 (Scheme 2, c). However, the yield
of desired product 3 was dropped quickly by trapping with 5
equiv of methanol.14 It is highly likely that methanolysis of the
1,3-dithiane substrate interfered with the success of the
coupling reaction (Scheme 2, d).
generation of 2-chloro-1,3-dithiane A, FeCl3 as a catalyst might
afford radical 1,3-dithiane B15 and [Cl] C species via a SET/
radical pathway for C−Cl bond cleavage, which might promote
the radicals and assist addition with alkenes 2 to produce the
corresponding radical intermediate D. Subsequently, the
generation of radical intermediate could be direct trapped by
radical Cl to give the desired product 3. The alternative
explanation is that 2-chloro-1,3-dithiane can coordinate catalyst
FeCl3 to afford [Fe]IV-intermediate E followed by simultaneous
free-radical addition and a Cl transfer to give the coupling
product. At present, there are still uncertainties concerning the
mechanism that governs this transformation. However, we
favor the explanation that proceeds via an iron-catalyzed radical
oxidative coupling pathway.
In conclusion, we have reported a new and efficient protocol
involving the radical oxidative cross-coupling process, which
holds great promise in the 1,3-dithiane area of diversity-
oriented synthesis. In addition, the application of this new
method to alkene derivatives led us to obtain 1,3-dithiane
derivatives in high yields, making this method suitable for
synthetic purposes in a one-pot procedure. Further inves-
tigations into the mechanism of this reaction as well as
extensions of the substrate scope are ongoing in our laboratory.
Subsequently, electron paramagnetic resonance (EPR)
experiments were performed under optimized conditions. All
EPR signals were detected with a g-factor of 9.447. As shown in
Figure 1A, no EPR signal was observed when the mixture of 1
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 1. (A) EPR spectra from the reaction between (1) FeCl3, 1,
NCS; (2) NCS and 1 or FeCl3; (3) the mixture of FeCl3, 1, and NCS
in DCE at room temperature. (B) EPR spectra acquired during the
cross-coupling reaction time course between 1 and 2a.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tangshch@lzu.edu.cn.
Notes
and NCS was tested. The EPR experiment of the mixture of 1,
FeCl3, and NCS displayed a strong signal peak (orange line),
suggesting that FeCl3 should be assigned to form 1,3-dithiane
radical initially. According to Figure 1B, we monitored the
cross-coupling reaction of 1 and 2a by EPR spectroscopy. After
FeCl3 was added to the mixture of 1, 2a, and NCS, a strong
signal peak was observed clearly (25 min); these EPR results
indicated that catalyst FeCl3 activated the above reaction
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful for the generous financial support by the
National Natural Science Foundation of China (No.
21102064), the Natural Science Foundation of Department
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Letter
of Science & Technology of Gansu Province (No.
1208RJYA030), and Fundamental Research Funds for the
Central Universities (No. lzujbky-2013-73). We thank Dr.
Changgui Zhao (SKLAOC) for helpful discussions, Dr. Ziyun
Yuan (SKLAOC) for NMR analysis, and Dr. Runfeng Han
(SKLAOC) for the MS analysis.
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