Letter Cite This: Org. Lett. 2019, 21, 5021−5025
pubs.acs.org/OrgLett
Pd-Catalyzed Boroperfluoroalkylation of Alkynes Opens a Route to One-Pot Reductive Carboperfluoroalkylation of Alkynes with Perfluoroalkyl and Aryl Iodides Sylwester Domański, Beata Gatlik, and Wojciech Chaładaj* Institute of Organic Chemistry, Polish Academy of Sciences, Kasprzaka 44/52, 01-224 Warsaw, Poland
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ABSTRACT: A three-component tandem Pd-catalyzed perfluoroalkylative borylation of terminal and internal alkynes is presented. On the basis of this methodology, the first reductive dicarbofunctionalization of alkynes with two electrophiles (perfluoroalkyl and aryl iodides) through a temperature-controlled sequence of iodoperfluoroalkylation−borylation coupling is developed. This regio- and stereoselective process is easily controllable by a temperature program, providing access to fluoroalkyl-substituted vinyl iodides, vinyl boronates, or olefins from the very same complex reaction mixture (four substrates, catalysts, base, and additives).
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outset of our research.14 Furthermore, we envisioned potential for utilization of such borylation for reversing polarity of perfluoroalkyl-substituted vinyl iodide, enabling its reaction with electrophilic partners in one-pot sequential process. All of the above-mentioned reactions are redox neutral and could originate in disconnections formally leading to nucleophilic and electrophilic partners added across a triple C−C bond (Scheme 1a). An alternative approach could be imagined, enabling the installation across the alkyne of two groups originating from formally electrophilic reagents in a reductive process (Scheme 1b). Although such an approach is unprecedented in the context of metal-catalyzed alkyne difunctionalizations, a handful of catalytic reductive dicarbofunctonalizations of alkenes have been reported. In 2017, Nevado disclosed a Ni-catalyzed reductive difunctionalization of alkenes with tertiary alkyl and aryl iodides.15 Scarce examples of similar transformations were later reported by other groups.16 While working on the boroperfluoroalkylation of alkynes, we envisioned the possibility for development of a sequential transformation involving iodoperfluoroalkylation−borylation coupling, establishing formally reductive dicarbofunctionalization of alkynes with fluoroalkyl and aryl halides. Herein, we present a regio- and stereoselective method for boroperfluoroalkylation of both terminal and internal alkynes (with perfluoroalkyl iodide and (Bpin)2) under palladium catalysis and its utilization for one-pot temperature-controlled sequential iodoperfluoroalkylation−borylation coupling. This protocol, employing in situ umpolung of the key intermediate by swap of iodide to boronic ester in the perfluoroalkyl-substituted vinyl moiety represents the first example of reductive dicarbofunctionalization of alkynes with two electrophiles perfluoroalkyl and aryl iodides. This highly controllable process
eactions initiated by the addition to C−C triple bonds offer an attractive opportunity for the direct synthesis of substituted olefins,1 of which tandem or multicomponent transformations are particularly attractive due to the possibility of rapid buildup of molecular complexity.2 Such strategies involving the addition of fluorinated organic groups to alkynes have emerged recently as a powerful tool paving a direct way to highly elaborated olefins3target molecules or valuable building blocks, important due to unique properties of the incorporated fluorinated function.4 Many of the developed protocols, however, employ expensive highly elaborated fluoroalkylating reagents, limiting the access to these structural motifs. In contrast relatively few methods utilizing inexpensive and readily available perfluoroalkyl iodides or related iododifluoroacetic acid derivatives were disclosed. We are focused on employment of such reagents in multicomponent transformations enabling straightforward construction of variously substituted olefins in highly controllable manner. In 1950, Halszedine studied the reaction of acetylene with iodotrifluoromethane under thermal and photochemical conditions.5 Since this pioneering work, many protocols for iodoperfluoroalkylation of alkynes utilizing various radical initiators6 as well as complexes of Pd,7 Fe,8 Co,9 and Ru10 (under photoredox conditions) as catalysts were reported. Over the last four years, based on Pd catalysis, several tandem threeand four-component difunctionalizations of alkynes were developed, providing effective, straightforward access to fluoroalkyl-substituted olefins11,12 and α,β-unsaturated carbonyl systems13 from simple and readily available substrates: alkynes, iodoperfluoroalkanes (or derivatives of iododifluoroacetic acid), nucleophilic coupling partners (e.g., arylboronic acid), and optionally carbon monoxide. We foresaw a possibility of employment of this strategy for the synthesis of fluoroalkylsubstituted vinylboronates via a sequence of iodoperfluoroalkylation and Miyaura borylation, which was unprecedented at the © 2019 American Chemical Society
Received: May 7, 2019 Published: June 24, 2019 5021
DOI: 10.1021/acs.orglett.9b01618 Org. Lett. 2019, 21, 5021−5025
Letter
Organic Letters
inferior results. Decrease in temperature caused ineffective borylation, while increase led to the formation of a complex mixture of byproducts. Similarly, dilution of the reaction mixture led to incomplete borylation of the vinyl iodide 1, which is effectively formed even in more dilute medium. With satisfactory conditions for the model reaction in hand, we proceeded to explore the scope of the transformation (Table 2). All of the reactions provided the expected perfluoroalkylsubstituted vinylboronates in good to very good yields and excellent regio- and stereoselectivity. Phenylacetylenes substituted with both electron-donating and -withdrawing functions delivered products (2, 3, 5−10, 12−14) in 55−86% yields. Ortho-substituted arylethynes were also tolerated, although increased steric hindrance had a detrimental effect on the efficiency of the reaction. Vinylboronates 4 and 11 were isolated in 45 and 10% yield, respectively. Acetylenes bearing thiophene or olefin moieties, as well as variously functionalized alkyl groups, underwent the boroperfluoroalkylation smoothly in good (50%) to excellent (92%) yields. To our delight, internal alkynes also proved to be competent reaction partners delivering trisubstituted vinylboronates (21−23, 25, and 26) in satisfactory efficiency (68−75%). Noticeably, many functionalities, including aryl bromides (11, 12) and tosylates (7), boronic esters (14), ketones (18), nitriles (20), and alcohols (19), among others, were well tolerated. Finally, the change of model iodoperfluorobutane to other fluoroalkyl iodides, including iododifluoroacetate, did not significantly affect the efficiency, enabling the isolation of compounds 24−26 in 75− 86% yields. Considering the synthetic potential of vinylboronates as reaction partners in cross-coupling chemistry, we envisioned the possibility of sequential boroperfluoroalkylation of alkynes and Suzuki coupling of the resulting vinyboronate under a one-pot regime. Addition of an aryl iodide to the model reaction mixture did not disturb the formation of vinylboronate, which, however, did not undergo coupling, even after longer reaction time. Unfortunately, an increase of the temperature to 120 °C had a detrimental effect on the reaction outcome, producing a complex mixture of byproducts. However, performing the reaction at 70 °C for 4 h, which gave effective formation of the vinylboronate, and then heating the reaction mixture to 120 °C delivered cleanly the expected coupling product. To the best of our knowledge, there is no previous example of reductive dicarbofunctionalization of alkynes with two formally electrophilic partners (here perfluoroalkyl and aryl iodides). The utility of the procedure was demonstrated on a series of aryl iodides which effectively entered the reaction with p-methoxyphenylacetylene, iodoperfluorobutane, and (Bpin)2 (Table 3). Both electron-rich (29, 30) and deficient iodoarenes (34-36) were compatible with reaction conditions, delivering the expected perfluoroalkyl-substituted alkenes in good yields (42−74%). Steric hindrance was also well tolerated, which was demonstrated by the efficient coupling of 1-iodonaphthalene (28) and an o-substituted iodoarene (30). Substrates containing various functional groups, including halogens (32-33), cyano (34), nitro (36), ester (37), as well as unprotected formyl (35) or hydroxy (37) functions, proved to be competent reaction partners. The mechanistic picture of the developed methodologies, proposed on the basis of careful analysis of the reaction outcome, several control experiments,17 as well as available literature data,7,11−13 is depicted in Scheme 2. It comprises two independent catalytic cycles operating simultaneously for
Scheme 1. Strategies for Direct Perfluoroalkylative Difunctionalization of Alkynes
Table 1. Optimization of the Reaction Conditions
entry 1 2 3 4 5 6 7 8 9 10 12 13
difference from optimized conditions
yield of 1 (%)
yield of 2 (%)
no BINAP Pd G3 no XPhos Pd G3 Cs2CO3 (not additionally dried) no H2O H2O (5 equiv) H2O (10 equiv) 2 M aqueous solution of Cs2CO3 50 °C 90 °C 0.125 M 0.25 M
0 0 33 56 85 15 36 81 69 25 54 38
88 62 6 38 4 63 27
