Min-Tao
Chen
,
Xiang-Ying
Tang
and
Min
Shi
*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, University of Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China. E-mail: mshi@mail.sioc.ac.cn; Fax: +86-21-64166128
First published on 20th October 2016
A facile approach for the trifluoromethylthiolation of methylenecyclopropanes (MCPs) has been developed by using AgSCF3/Na2S2O8 as a trifluoromethylthiolation source (SCF3) to give trifluoromethylthiolated 1,2-dihydro-naphthalene derivatives in moderate to good yields, and the reaction has been proven to go through a radical-type pathway. The products can easily be aromatized upon oxidation, offering a new method for the construction of trifluoromethylthiolated naphthalenes.
![]() | ||
Scheme 1 A general review of recent work on trifluoromethylthiolation using AgSCF3 as a trifluoromethylthio radical source. |
On the other hand, methylenecyclopropanes (MCPs) are conveniently available organic building blocks9 with special reactivity, which can easily undergo ring-opening or participate in tandem cyclizations when exposed to cationic or radical species. Thus it would be intriguing to bring methylenecyclopropanes (MCPs) and trifluoromethylthio radical (˙SCF3) together to form some fascinating compounds. Inspired by this idea, a first attempt was made and fortunately it works (Scheme 1, this work). Herein, we wish to report a facile approach for the trifluoromethylthiolation of methylenecyclopropanes along with a mechanistic investigation.
Our exploration was initiated with MCP 1a (0.2 mmol), AgSCF3 (0.3 mmol), K2S2O8 (0.6 mmol), and HMPA (0.1 mmol) in MeCN at 80 °C under an argon atmosphere for 6 h. The isolated yield of 2a was 25%, along with an aromatized product 3a derived from the further oxidation of 2a (see ESI†). The yield was not satisfactory but it strengthened our faith that a further optimization of the reaction conditions was worthwhile.
Entry | Solvent (3 mL) | Oxidant (3 eq.) | Additive (0.5 eq.) | Temp./°C |
2a![]() ![]() |
Yieldc (%) |
---|---|---|---|---|---|---|
a The reaction conditions: 1a (0.2 mmol), AgSCF3 (0.3 mmol), oxidant (0.6 mmol), and additive (0.1 mmol) were dissolved in 3 mL DMSO and the reaction mixture was stirred at 80 °C for 6 h. b Determined by 19F NMR with p-bromobenzotrifluoride as an internal standard and 1a was taken as a standard for yield evaluation. c The total yield of 2a and 3a. d The reaction time was prolonged to 12 h. | ||||||
1 | DMSO | Na2S2O8 | — | 80 | —![]() ![]() |
46 |
2 | CH3CN | Na2S2O8 | — | 80 | —![]() ![]() |
13 |
3 | DMF | Na2S2O8 | — | 80 | 37![]() ![]() |
39 |
4 | Dioxane | Na2S2O8 | — | 80 | 4![]() ![]() |
4 |
5 | DMSO | K2S2O8 | — | 80 | 21![]() ![]() |
43 |
6 | DMSO | (NH4)2S2O8 | — | 80 | —![]() ![]() |
44 |
7 | DMSO | Na2S2O8 | K2CO3 | 80 | 10![]() ![]() |
45 |
8 | DMSO | Na2S2O8 | K3PO4 | 80 | 15![]() ![]() |
40 |
9 | DMSO | Na2S2O8 | Cs2CO3 | 80 | 4![]() ![]() |
40 |
10 | DMSO | Na2S2O8 | AgOAc | 80 | —![]() ![]() |
17 |
11 | DMSO | Na2S2O8 | HMPA | 80 | 47![]() ![]() |
52 |
12 | DMSO | Na2S2O8 |
![]() |
80 | —![]() ![]() |
42 |
13 | DMSO | Na2S2O8 |
![]() |
80 | —![]() ![]() |
48 |
14d | DMSO | Na2S2O8 | HMPA | 60 | 44![]() ![]() |
51 |
15d | DMSO | Na2S2O8 | HMPA | 40 | 31![]() ![]() |
35 |
Now, we were still faced with two problems: the yield was still not satisfactory and the oxidation of 2a to 3a was not under control. Further control experiments demonstrated that substrate 1a was not stable and could be easily oxidized by Na2S2O8 in the reaction system, which might limit the yield of 2a or 3a (see ESI†). To overcome these problems, we decided to change the ratio of 1a and oxidant with regard to AgSCF3 to improve the yield of 2a and the results are shown in Table 2. To our delight, we found that when the employed amounts of substrate 1a and Na2S2O8 (oxidant) were raised to 3.0 equiv. (m/n = 3/3) and AgSCF3 was taken as 1.0 equiv., 2a was obtained in a yield of 56% as a single product (Table 2, entry 3).
Entry | m/nb | 2a:3ac | Yieldd (%) |
---|---|---|---|
a The reaction conditions: 1a (m equiv.), AgSCF3 (0.2 mmol), oxidant (n equiv.), and additive (0.1 mmol, 0.5 equiv.) were dissolved in 3.0 mL DMSO and the reaction mixture was stirred at 80 °C for 6 h. b The ratio of 1a/Na2S2O8. c Determined by 19F NMR with p-bromobenzotrifluoride as an internal standard. d The yield of 2a and AgSCF3 was taken as a standard for yield evaluation. | |||
1 | 1![]() ![]() |
36![]() ![]() |
36 |
2 | 2![]() ![]() |
53![]() ![]() |
53 |
3 |
3
![]() ![]() |
56
![]() ![]() |
56 |
4 | 4![]() ![]() |
52![]() ![]() |
52 |
With the optimized conditions in hand, we then examined the substrate scope of this trifluoromethylthiolation of methylenecyclopropanes as summarized in Scheme 2. Substrates 1 with a variety of substituents at the aromatic ring were successfully converted into the desired products in yields ranging from 25% to 65%.
In general, substrates 1b–1f bearing electron-withdrawing substituents gave the desired products in relatively low yields. For example, substrate 1b having a strongly electron-withdrawing nitro group afforded the corresponding product 2b in 25% yield. As for substrates bearing electron-donating groups, the transformations of 1 to 2 are generally favored. For instance, the conversion efficiency of 1j to 2j with three electron-donating methoxy groups was much higher than others. However, in the case of 1i, the desired product 2i was formed in 40% yield, presumably due to its instability in the presence of a large amount of oxidant. It should be also noted that in the cases of 1c and 1e, two trifluoromethylthiolated regioisomers were formed at the same time. The p-toluenesulfonylamino group-containing substrates 1m and 1n can be well tolerated under the reaction conditions, affording the desired products 2m and 2n in good yields. The X-ray crystal structure of 2n has been obtained (Fig. 1) and the CIF data are given in the ESI.† Diphenylmethylenecyclopropane 1p was also compatible in this transformation, but naphthylmethylenecyclopropane only resulted in a complex product mixture under the standard conditions.
Product 2 could undergo dehydrogenation to a great tendency in the presence of oxidants and the formation of the aromatized product 3 provided a new synthetic protocol to prepare trifluoromethylthiolated naphthalene derivatives. Inspired by the result that the aromatized compound was obtained while screening the reaction conditions (Table 1, entry 1), we attempted to use the same oxidant Na2S2O8 to achieve the dehydrogenation. After a brief investigation, using 4.0 equiv. of Na2S2O8 alone and stirring the reaction mixture for 4–6 h at 80 °C could produce the aromatized products 3 in moderate to good yields ranging from 40% to 80% and the results are summarized in Scheme 3.
![]() | ||
Scheme 3 Substrate scope of 2. The reaction conditions: 2 (0.2 mmol), Na2S2O8 (0.8 mmol) in 3.0 mL DMSO. All the yields are isolated yields. |
In order to directly obtain 3a, we just needed to mix 1a (1.0 eq.), AgSCF3 (1.5 eq.), and Na2S2O8 (3 eq.) together in DMSO upon heating at 80 °C for about 6 h, directly giving 3a in 46% yield in a one pot manner (Table 1, entry 1 or Scheme 4).
It was believed that the reaction proceeded via a radical-type pathway on the basis of previously reported literature.4d,i,8 Therefore, control experiments with radical inhibitors TEMPO and BHT were performed as shown in Scheme 5. The formation of the corresponding trifluoromethylthiolated product was significantly suppressed (for more details, see ESI†), rendering a radical process reasonable. However, it is true that AgSCF3 decomposed partially in the presence of a large amount of BHT and even completely decomposed in the presence of a large amount of TEMPO, thus such control experiments can only give mechanistic support to some degree. Moreover, F3CSSCF310 can be detected in the reaction system by 19F NMR spectroscopy resulting from coupling of two SCF3 radicals. Overall, we believe that this reaction goes through a radical process.
Taking all the above information into consideration, a plausible mechanism of this trifluoromethylthiolation has been proposed in Scheme 6. AgSCF3 can release SCF3 radical upon oxidation with Na2S2O8 and the SCF3 radical can be transformed into its dimer F3CSSCF3, which can also be converted into SCF3 radical with the help of Ag+.4d,i Then, the SCF3 radical adds to the double bond of substrate 1 to form a ring-opening radical intermediate A, followed by a cyclization to give intermediate B. The intermediate B is oxidized by SO4˙− to afford product 2, which can be easily dehydrogenated and aromatized by Na2S2O8 to afford product 3.
In summary, we have developed a practical method for the facile trifluoromethylthiolation of methylenecyclopropanes (MCPs) in the presence of AgSCF3/Na2S2O8, and a variety of substrates can tolerate the oxidative conditions to give trifluoromethylthiolated 1,2-dihydronaphthalene derivatives in moderate to good yields. The products can conveniently be further aromatized upon oxidation with Na2S2O8, offering a new synthetic method for the preparation of trifluoromethylthiolated naphthalenes. Efforts are in progress for the application of this new methodology to synthesizing interesting biologically active trifluoromethylthiolated compounds in our laboratory.
Footnote |
† Electronic supplementary information (ESI) available: Experimental procedures, characterization data of new compounds. CCDC 1493132. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6qo00536e |
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