Letter pubs.acs.org/OrgLett
Fe-Catalyzed Direct Dithioacetalization of Aldehydes with 2‑Chloro1,3-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.
D
conditions and green chemistry. The iron-catalyzed construction 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 methodologies. 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-1,3dithiane 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-
ithianes introduced by Corey and Seebach are widely used as attractive acyl anion equivalents (umpolung) for a 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
advances have occurred in the development of dithioacetalization 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 1,3propanedithiol equivalent.5 Very recently, Jung and Bräse 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 © XXXX American Chemical Society
Received: June 19, 2014
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Table 1. Optimization of the Reaction Conditionsa
Scheme 2. Dithioacetalization of Aryl Aldehydes 1 with 2Chloro-1,3-dithiane 2a
entry
cat. (x mol %)
additives
temp (°C)
time (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14
FeCl3 (5) FeCl3 (15) FeCl3 (30) FeCl2 (5) FeCl2 (15) FeCl2·̀ 4H2O (15) FeCl3·̀ 6H2O (15) FeCl3 (15) FeCl3 (15) FeCl3 (15) FeCl3 (15) FeCl3 (15) FeCl3 (15) none
− − − − − − − − − DTBPd H2O2 TBHP DDQ DTBP
50 50 50 50 50 50 50 25 80 50 50 50 50 50
18 4 3 18 6 48 4 48 4 4 48 48 48 48
43 89 (82)c 88 46 86 80 87 60 85 85 trace trace trace 0
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 = 1,2dichloroethane. bIsolated yields. cReaction was performed on 10 mmol scale. d2.0 equiv of additives.
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 ironcatalyzed 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. b Room temperature. c 80 °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 2,2,6,6tetramethyl-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 1,3dithiane 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 2Chloro-1,3-dithiane 2a
Figure 1. EPR investigation of isobutyraldehyde 4c and 2-chloro-1,3dithiane 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 Isolated yields. c50 °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. 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 mechanism of this process as well as extensions of the scope of reactions are ongoing in our laboratory.
Scheme 3. Mechanism Investigations
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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.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest. C
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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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