Fe-catalyzed direct dithioacetalization of aldehydes with 2-chloro-1,3-dithiane

Article abstract of DOI:10.1021/ol502276r

Present methods to synthesize 1,3-dithiane molecules require either harsh reaction conditions or highly specialized reagents. We have developed a catalytic dithioacetalization process that directly gains access to the corresponding 1,3-dithianes using aldehydes and 2-chloro-1,3-dithiane in a highly efficient manner. This methodology is beneficial due to mildness of the reaction conditions, and the dithioacetaliation process results in good to excellent yields by using 15 mol % of an iron catalyst.

Full text of DOI:10.1021/ol502276r

Letter
pubs.acs.org/OrgLett
Fe-Catalyzed Direct Dithioacetalization of Aldehydes with 2‑Chloro-
1,3-dithiane
Junshan Lai,† Wenbin Du,† Lixia Tian,† Changgui Zhao,‡ 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: Present methods to synthesize 1,3-dithiane molecules require
either harsh reaction conditions or highly specialized reagents. We have
developed a catalytic dithioacetalization process that directly gains access to
the corresponding 1,3-dithianes using aldehydes and 2-chloro-1,3-dithiane in
a highly efficient manner. This methodology is beneficial due to mildness of
the reaction conditions, and the dithioacetaliation process results in good to excellent yields by using 15 mol % of an iron catalyst.
ithianes introduced by Corey and Seebach are widely
used as attractive acyl anion equivalents (umpolung) for a
conditions and green chemistry. The iron-catalyzed construc-
tion of carbon−carbon and carbon−heteroatom bonds has
become popular over the past decades.7,8 In 2014, we reported
a novel iron-catalyzed oxidative radical cross-coupling protocol
for the synthesis of dithiane derivatives.9 The example proceeds
via an iron-catalyzed oxidative dithiane radical intermediate
along the reaction pathway.10 On the basis of this result, we
wondered whether it would be possible to achieve an iron
catalytic dithioacetalization in which a dithiane radical
intermediate was directly reacted with aldehydes. Herein, we
present an efficient direct dithioacetalization process using
accessible odorless 2-chloro-1,3-dithiane reagent to form a wide
range of dithiane compounds. The key feature of this method is
introducing a nonvolatile, odorless, solid dithioacetalization
reagent as a 1,3-propanedithiol equivalent for the preparation of
the corresponding dithianes. It is a highly experimentally
straightforward transformation and would potentially address
many of the shortcomings of the aforementioned method-
ologies.
D
range of useful transformations.1 Furthermore, dithiane
compounds are also widely used as building blocks for the
preparation of a wide variety of chemicals and for the union of
advanced fragments in an array of natural product synthesis.2,3
However, traditional methods for the introduction of a dithiane
into a framework usually suffer from issues of harsh reaction
conditions, strong odor of 1,3-propanedithiol, or multiple steps
(Scheme 1, eq 1).4 During the past few years, significant
Scheme 1. Dithioacetalization Methodologies of Aldehydes
With a view toward accomplishing the transformation
envisioned in Scheme 1, eq 2, we undertook an intensive
screening of a variety of iron catalysts and additives, to test our
proposal using 4-methoxybenzaldehyde 1a and 2-chloro-1,3-
dithiane 2 as the dithioacetalization partners (Table 1). Indeed,
the reaction of 1a with 2 was complete in the presence of a
catalytic amount of FeCl3 (15%), affording the desired product
3a in 89% yield. None of the acyl radical cross-coupling product
was detectable.11 Reactions conducted with a related Fe(II)
catalyst resulted in quite similar outcomes (Table 1, entry 5).
The identity of 2 associated with the FeCl3·6H2O did not have
a positive influence on the outcome of the reaction (Table 1,
entry 7). Whereas reactions employing other addictives
provided unsatisfactory yields of the desired product, no
desired dithiane product was observed in the presence of
H2O2,12 tert-butyl hydroperoxide (TBHP),13 and 2,3-dichloro-
advances have occurred in the development of dithioacetaliza-
tion methodologies.5,6 Of particular interest has been the
acquisition of the ability to utilize solid supported reagents, as
well as the odorless dithiolan-ylidene derivatives as a 1,3-
propanedithiol equivalent.5 Very recently, Jung and Brase
̈
disclosed an effective dithioacetalization using resin-bound
supported, odorless dithiane ylidene salts.6 Despite this
progress, several challenges still exist in the field of advanced
dithioacetalization. By far, the development of a catalytic,
economically reasonable, and general protocol remains elusive.
Iron-catalyzed methods for bonds formations can offer a
complementary approach to the environmentally benign
Received: June 19, 2014
© XXXX American Chemical Society
A
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Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Dithioacetalization of Aryl Aldehydes 1 with 2-
Chloro-1,3-dithiane 2
a
b
entry
cat. (x mol %)
additives temp (°C) time (h) yield (%)
1
FeCl3 (5)
−
−
−
−
−
−
−
−
50
50
50
50
50
50
50
25
80
50
50
50
50
50
18
4
43
c
2
FeCl3 (15)
FeCl3 (30)
FeCl2 (5)
89 (82)
88
3
3
4
18
6
46
5
FeCl2 (15)
FeCl ·4H O (15)
86
6
48
4
80
̀
2
2
7
FeCl ·6H O (15)
87
̀
3
2
8
FeCl3 (15)
FeCl3 (15)
FeCl3 (15)
FeCl3 (15)
FeCl3 (15)
FeCl3 (15)
none
48
4
60
9
−
DTBP
85
d
10
11
12
13
14
4
85
H2O2
48
48
48
48
trace
trace
trace
0
TBHP
DDQ
DTBP
a
Reaction conditions: Fe source (x mol %), 1a (0.25 mmol), and 2
(1.2 equiv) in DCE (2 mL) at the indicated temperature. DCE = 1,2-
b
c
dichloroethane. Isolated yields. Reaction was performed on 10 mmol
scale. 2.0 equiv of additives.
d
5,6-dicyano-1,4-benzoquinone (DDQ)14 (Table 1, entries 11−
13). These studies show that the combination of simple iron
sources is essential to the outcome of the dithioacetalization
reaction.15 Moreover, use of 5%, rather than 15%, FeCl3 led to
a lower yield of the desired product.
With these results in hand, we sought to examine the scope
and generality of the method. As shown in Scheme 2, the iron-
catalyzed processes for aryl aldehydes with a variety of
substituted dithianes have broad scope. In general, 15 mol %
of FeCl3 is sufficient to obtain a high yield after 4−24 h at 50
°C in 1,2-dichloroethane (DCE). As can be seen in Scheme 2,
the presence of strongly electron-donating substituents at the
ortho or para position has no deleterious effects (Scheme 2, 3a,
3j, 3m−3o). In the case of 3c, the reaction has been carried out
with FeCl3 at rt and resuts in a 91% yield. Furthermore,
deactivated aryl aldehydes could be dithioacetalized (3e, 3f,
3r−3t). Electron-withdrawing groups such as nitro (3h, 3u)
and nitrile (3g) groups were well tolerated. As expected, the
reaction time of electron-poor aldehydes was somewhat longer
than that for electron-rich substrates (12−24 h versus 4−12 h).
Free functional groups such as a free phenol (3i, 3p, 3q) and an
indole (3v) were found to readily undergo dithioacetalization
and are well-tolerated. Thus, dithianes containing hindered,
electron-rich and electron-poor, and heterocyclic substituents
were synthesized in good to excellent yields with this method.
We next explored the use of other aldehydes in this process.
We found that this reaction is applicable to several alkyl- and
α,β-unsaturated aldehydes. As shown in Table 2, both the
propionaldehyde 4a and butyraldehyde 4b afforded the desired
dithiane products in 58% and 54% yields, respectively (Table 2,
entries 1, 2). Even hindered substrates with an i-Pr or a t-Bu
group also furnished the respective products (5c and 5d).
Notably, this process can also be applied to glyoxylic acid 4e
and provided the desired dithiane 5e in good yield. By
increasing the reaction temperature, dithioacetalization of
a
Reaction conditions: performed with 15 mol % FeCl3 and 1.2 equiv
of 2-chloro-1,3-dithiane in DCE (2 mL) at 50 °C for 4−24 h; isolated
yields. Room temperature. 80 °C.
b
c
crotonaldehyde 4f would generate the β-chloro-substituted
dithianes (entry 6).
Subsequently, a series of experiments were performed as
outlined in Scheme 3 to aid our interpretation of the
mechanism. Initially, we found that no dithioacetalization
product was formed in the presence of an excess of 2,2,6,6-
tetramethyl-1-piperidinyloxy (TEMPO), indicating that the
transformation proceed via a radical pathway (eq 3). Next, we
wondered whether an arylketone could serve as a precursor to
the radical oxidative system, while the use of ketones 6a and 6b
did not lead to formation of the desired product under the
optimized reaction conditions, and 2 was recovered completely
using 6b as the substrate (eq 4). Furthermore, the use of 1,3-
dithiane 8 in the presence of 0.15−1.2 equiv of FeCl3 did not
lead to formation of the desired product and 8 was not
consumed even after 8 h at 50 °C (eq 5), indicating that the
dithiane radical generated from 2 might be essential to this
process. In addition, we carried out electron paramagnetic
resonance (EPR) experiments of 4c with 2 to understand the
B
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Table 2. Dithioacetalization of Alkyl Aldehydes 4 with 2-
a
Chloro-1,3-dithiane 2
Figure 1. EPR investigation of isobutyraldehyde 4c and 2-chloro-1,3-
dithiane 2.
Scheme 4. Proposed Mechanism
a
Reaction conditions: aldehydes 4 (0.25 mmol), 2-chloro-1,3-dithiane
2 (1.2 equiv), FeCl3 (15 mol %) in DCE (2 mL) at rt for 4−16 h.
b
c
Isolated yields. 50 °C.
Meanwhile, iron catalyst as Lewis acid would coordinate
aldehydes to produce the corresponding intermediate B.
Subsequently, transformation by electron transfor would take
place to form C and D species that can result in the formation
of corresponging dithianes and regenerate [Fe] catalyst for the
catalytic cycle.
Scheme 3. Mechanism Investigations
In conclusion, we have developed a mild, versatile, and
convenient dithioacetalization reaction of aldehydes using
simple iron sources. This general method affords a reasonably
broad substrate scope and good functional group compatibility,
allowing for the introduction of dithiane units into highly
functionalized organic molecules. During our studies, we expect
this method to be applicable to the preparation of substituted
dithiane compounds and complex molecule syntheses in
academic laboratories. Further studies into the exact mecha-
nism of this process as well as extensions of the scope of
reactions are ongoing in our laboratory.
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures and compound characterization data.
This material is available free of charge via the Internet at
http://pubs.acs.org.
radical pathway and the effect of the iron catalyst.16 As shown
in Figure 1, the EPR experiments of 2 and the iron catalyst and
the reaction mixture of 2, 4c, and FeCl3 displayed obviously
signal peaks (black and red lines); no EPR signal was observed
without FeCl3.
Consistent with these results and on the basis of previous
findings in our group,9 a pausible explanation of mechanism is
depicted in Scheme 4. We postulated that [Fe] as a catalyst
might insert C−Cl bond of 2 and afford key intermeiate A via a
single-electron transfer (SET)/oxidative radical pathway.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: tangshch@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
C
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Letter
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ACKNOWLEDGMENTS
■
We are grateful for the financial support by the National
Natural Science Foundation of China (No. 21102064), the
Natural Science Foundation of Department of Science &
Technology of Gansu Province (No. 1208RJYA030), and
Fundamental Research Funds for the Central Universities (No.
lzujbky-2013-73). We thank Dr. Yingpeng Su (Northwest
Normal University) for helpful discussions and Dr. Runfeng
Han (SKLAOC) for the MS analysis.
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