Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Electrochemically Promoted Fluoroalkylation−Distal Functionalization of Unactivated Alkenes Zhenlei Zou,† Weigang Zhang,† Yang Wang,† Lingyu Kong,† Georgios Karotsis,‡ Yi Wang,*,† and Yi Pan† †
Org. Lett. Downloaded from pubs.acs.org by UNIV OF TEXAS AT DALLAS on 02/28/19. For personal use only.
Jiangsu Key Laboratory of Advanced Organic Materials, State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University, 163 Xianlin Avenue, 210023 Nanjing, China ‡ School of Chemistry, Environmental & Life Sciences, University of The Bahamas, Nassau, 999154, The Bahamas S Supporting Information *
ABSTRACT: Difunctionalization of olefins represents a powerful synthetic tool and yet a challenging task. This work describes an electrochemically enabled fluoroalkylation− migration reaction of unactivated olefins in the absence of a strong oxidant or heavy metal catalyst, affording fluorinated (hetero)aryl ketones in good yields and excellent regioselectivities. The efficient and sustainable electrochemical strategy provides a rapid access to a dual functionalized fluorine-containing heterocyclic manifold.
T
avoids using strong oxidants, and minimizes byproduct formation. So far, several electrochemically enabled strategies have been developed for radical trifluoromethylation− functionalization of olefins (Scheme 1). The most popular
he vicinal difunctionalization of olefins represents an attractive and versatile method for the rapid transformation of a complex scaffold.1 Considerable progress has been made with fluorinated radicals to provide divergent approaches for the difunctionalization of olefins, especially difluoromethylation,2 trifluoromethylation,3 and perfluoroalkylation.4 However, a majority of the studies concentrated on the modification of styrene and other activated alkenes.5 In the matter of distal unsubstituted olefins, the lack of p−π conjugation increases the lability of carbon radicals and frustrates the functionalization of unactivated olefins.6 Recently, dual functionalizations of unactivated alkenes through radical fluoroalkylation with subsequent intramolecular formyl, vinyl, alkynyl, cyano, aryl, and heteroaryl functional group migrations have been reported.7 In particular, the radical trifluoromethylation−distal migration procedure has been documented by Zhu,8 Studer,9 and Yu10 independently. These protocols provide rapid access to fluoroalkylated ketones with a variety of vicinal β-functionalization in a radical cascade fashion. However, a number of those examples required the use of excess oxidants6a,b,7d,8 and/or noble heavy metals.6c−h The development of a sustainable and effective approach to realize such a fluoroalkylation−distal functionalization sequence still represents an unmet challenge and is in urgent demand. Electrochemistry utilizes direct interaction of electrons from the anode and cathode with the nucleus instead of a chemical oxidant or reductant.11 The redox efficiency, innate scalability, and sustainability of such a process prompted the investigation of electrochemical olefin difunctionalization reactions.12 The combination of the electrochemical catalytic cycle with a radical mechanism has currently emerged as a new approach for olefin dual activation that maximizes substrate generality, © XXXX American Chemical Society
Scheme 1. Electrochemically Enabled Alkene Difunctionalization: Radical Trifluoromethylation Strategies
method is through radical addition of styrene followed by anodic oxidation to form carbocation and nucleophilic addition to install the second functionality.13 However, an unstabilized carbocation often leads to intricate side reactions such as hydration and overoxidation. An alternative strategy is using preformed metal−halogen radical species to capture the carbon radical intermediate and anodically coupled electrolysis to generate the CF3-halogen difunctionalized product. The pioneering work on Mn-catalyzed electrochemical fluoroalkyReceived: February 4, 2019
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DOI: 10.1021/acs.orglett.9b00444 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
and 10). Increasing or decreasing the voltage of the cell afforded poor yields (entries 12 and 13). Under the optimized conditions, we investigated the substrate scope of this reaction by using various alkyl and aryl substituted alkenes 1 (Scheme 2). The electrochemically generated trifluoromethyl radical
lation/halogenation of terminal alkenes was achieved by the Lin group.14 In their case, a preformed Mn−X adduct is required for electrochemical dual functionalization. We speculated that a synthetically more convenient protocol might be realized via a radical addition procedure with concomitant functional group migration to alkenes. Through a selection of suitable fluoroalkylating reagents in combination with remotely functionalized unactivated alkenes, radical cascades of 5-exo cyclizations with subsequent ring opening lead to highly stabilized oxygen-adjacent radical intermediates and minimize the single-electron oxidation. This electrochemically enabled dual functionalization process can be precisely initiated and ceased by fine-tuning of the cell voltage to avoid overoxidation of the olefins and regulate subsequent chemical steps. Surprisingly, despite the potential utility of such a transformation, very few examples of electrochemical distal migration have previously been described.15 Inspired by recent developments in the area of remote functionalization,16 we herein reported an electrochemical radical fluoroalkylation−distal functionalization reaction of unactivated olefins with a portfolio of fluorinating sources. This reaction could be conducted at room temperature without an oxidative reagent or metal catalyst. Furthermore, this powerful and green strategy exhibited a wide substrate scope, broad functionality tolerance, and excellent regioselectivity. Our experiments began with a brief survey of benzothiazolesubstituted tertiary alcohol and Langlois’ reagent3j,8,13a,14c,d,17 (CF3SO2Na) in different electrolytes and solvents under constant voltage. This study revealed that n-Bu4NBF4 in DCM/H2O was able to promote the desired migration sequence using an undivided cell at 3.0 V (Table 1, entry 11). Other ammonium halide electrolytes and LiClO 4 delivered poor conversions (entries 1−5). MeCN and DCE were not suitable solvents for this reaction (entries 8 and 9). The use of carbon felt electrodes resulted in higher efficiency compared to that of carbon or platinum electrodes (entries 6
Scheme 2. Electrochemical Distal Heteroaryl Distal Migrationa
Table 1. Optimization of the Reaction Conditionsa
entry
electrolyte
electrode
solventb
1 2 3 4 5 6 7c 8 9 10 11 12 13
n-Bu4NCl n-Bu4NBr n-Bu4NF n-Bu4NI LiClO4 n-Bu4NBF4 n-Bu4NBF4 n-Bu4NBF4 n-Bu4NBF4 n-Bu4NBF4 n-Bu4NBF4 n-Bu4NBF4 n-Bu4NBF4
C+/C− C+/C− C+/C− C+/C− C+/C− C+/C− C+/C− C+/C− C+/C− Pt+/Pt− C felt C felt C felt
DCM/H2O DCM/H2O DCM/H2O DCM/H2O DCM/H2O DCM/H2O DCM/H2O MeCN DCE DCM/H2O DCM/H2O DCM/H2O DCM/H2O
voltage
yield
3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.5 2.5
30% 10% 6% 0% 14% 47% 32% 20% 16% 30% 90% 64% 52%
V V V V V V V V V V V V V
a
Alkene 1 (0.2 mmol), NaSO2CF3 (0.4 mmol), n-Bu4NBF4 (0.5 mmol), water (0.6 mL), and DCM (5.4 mL) with C felt anode and cathode were charged at 3.0 V cell voltage under argon at room temperature for 12 h. bIsolated yield for 1 g scale reaction over 24 h.
reacted with 1 and induced the migration of the benzothiazole to provide 3. Alcohols bearing substituted aryl functionalities (R1), such as methyl, methoxy, and halogen on the benzene ring, resulted in the corresponding benzothiazole-migrated products in good yields (3a−3n). Reactions of alkyl- and cyclic alkyl-substituted alcohols also proceeded smoothly to furnish the desired ketones (3o−3t). A sterically more hindered substrate could also be tolerated to furnish the multisubstituted product in moderate yield (3u). Thiophene and furan functionalities could be tolerated under the reaction conditions (3v−3w). Next, we examined the scope of this electrochemical trifluoromethylation−arylation reaction. Intriguingly, substi-
a
Alkene 1 (0.2 mmol), NaSO2CF3 (0.4 mmol), electrolyte (0.5 mmol), and solvent (6 mL) with carbon felt anode and cathode were charged at 3.0 V cell voltage under argon at room temperature for 12 h. b10:1 DCM/H2O or pure solvent was used. c20:1 DCM/H2O was used. B
DOI: 10.1021/acs.orglett.9b00444 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters tuted benzothiazole and thiazole could migrate to the alkene to realize the difunctionalized ketones (3x−3aa). Considerably lower yields were obtained with pyridine-, imidazole-, and benzoimidazole-bearing alcohols (3bb−3dd). We then sought to demonstrate the generality of this approach with other fluoroalkylating sources (Scheme 3). The
Scheme 4. Further Elaboration with Alkene and Alkyne Migrationsa
Scheme 3. Substrate Scope of Heteroarenea,b
a
Alkene 1 (0.2 mmol), NaSO2CF3 (0.4 mmol), n-Bu4NBF4 (0.5 mmol), water (0.6 mL), and DCM (5.4 mL) with carbon felt anode and cathode were charged at 3.0 V cell voltage under argon at room temperature for 12 h.
Scheme 5. Mechanistic Studies and Elaborationsa a
Alkene 1 (0.2 mmol), NaSO2CF2H (0.6 mmol), n-Bu4NBF4 (0.5 mmol) in MeCN (5.4 mL) and water (0.6 mL) with carbon felt anode and cathode were charged at 2.5 V cell voltage under argon at room temperature for 12 h. bNaSO2C6F13 (0.4 mmol) in acetonitrile (5.4 mL) and water (0.6 mL) was charged at 3.0 V cell voltage.
CF2H-analogue of Langlois’ reagent NaSO2CF2H, which was readily prepared according the elegant method reported by Hu,18 has been subjected to the electrochemical conditions. Such CF2H radical addition to unsaturated substrate has rarely been achieved under electrochemical conditions.19 Limited examples have been demonstrated on the addition of unactivated alkenes.2c−e,20 Gratifyingly, by using 3 equiv of NaSO2CF2H, the corresponding CF2H-bearing ketones 4a−4e were afforded in moderate yields at 2.5 V cell voltage in MeCN/H2O. When NaSO2C6F13 was applied to the cell reaction, the perfluoroalkyl-functionalized ketone 4f was also obtained in 65% yield at 3.0 V cell voltage. Furthermore, we studied the potential of this electrochemical migration reaction by using the alkyne and alkene-bearing substrates under the standard conditions (Scheme 4). The alkynyl migrating reaction proceeded smoothly and the desired ketone 7a−7c was obtained. 1,5-Vinyl migration also proceeded to realize the corresponding trifluoromethylated ketones (8a−8c). To gain insight into this electrochemical migration reaction, a series of mechanistic studies were conducted. In the radicaltrapping experiment, by adding 3 equiv of TEMPO to the standard conditions, this reaction was inhibited (Scheme 5a). Using diphenylethylene 9 as a trapping reagent, the CF3adduct 10 was detected by GC-MS (Scheme 5b). Thus, radical intermediates are possibly involved in this electrochemical system. The utility of an aryl migrated product was demonstrated (Scheme 5c). Under simple reducing/oxidating conditions, 3y was converted to the corresponding aldehyde 12 in 68% yield. Next, we studied the redox potentials of three fluoroalkylating reagents by cyclic voltammetry (CV) experiments in MeCN (10−4 M) with n-Bu4NBF4 (0.2 M) at a scan rate of 0.2 V·s−1 (Figure 1). The oxidation peak of NaSO2CF2H was observed at the very low point of 0.590 V,
a (a) Control reactions with TEMPO. The yield of 3y and 10 were determined by 19F NMR with PhCF3 as internal standard, 1y (95%) was recovered. (b) Radical-capturing reactions using diphenylethylene. The [M + H]+ peak for 10 was found at 248.1 by GCMS. (c) Further elaborations of 3y.
Figure 1. Cyclic voltammetry studies. Cyclic voltammetry of 2 (10−4 M in MeCN) with n-Bu4NBF4 (0.2 M) using glassy carbon working electrode, Pt wire counter electrode, SCE reference electrode, scan rate = 0.2 V·s−1. C
DOI: 10.1021/acs.orglett.9b00444 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters while NaSO 2CF 3 and NaSO 2 C6 F13 displayed adjacent oxidizing peaks at 0.814 and 0.742 V, respectively. This observation indicated that NaSO2CF2H was much more easily oxidized on the anode than trifluoromethyl and perfluoroalkyl reagents, which quickly decomposed on electrodes. This could explain the unusual high activity of the CF2H radical and yet low conversion in the electrochemical olefin functionalization. Overall, the relative reactivity of these fluoroalkanesulfinates in oxidative radical fluoroalkylation decreases in the following order: CF3SO2Na > C6F13SO2Na > CF2HSO2Na. This reactivity sequence is consistent with their innate nucleophilicity, but different from the relative reactivities of their fluoroalkyl radicals.18 Based on the previous reports10 and the above experimental evidence, a possible mechanism for the electrochemical radical fluoroalkylation−distal migration reaction is illustrated in Scheme 6. Initially, the CF3 radical is generated from 2a via
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Yang Wang: 0000-0002-0222-2083 Yi Wang: 0000-0002-8700-7621 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the financial support from the National Natural Science Foundation of China (Nos. 21472082, 21402088, and 21772085) and the Fundamental Research Funds for the Central Universities (No. 020514380148).
Scheme 6. Proposed Mechanism for the Electrochemical Migration Reaction
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REFERENCES
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Experimental procedures, compound characterization data, and NMR spectra (PDF)
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b00444. D
DOI: 10.1021/acs.orglett.9b00444 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.9b00444 Org. Lett. XXXX, XXX, XXX−XXX
Letter
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DOI: 10.1021/acs.orglett.9b00444 Org. Lett. XXXX, XXX, XXX−XXX
