Cu-Catalyzed Arylation of Bromo-Difluoro-Acetamides by Aryl Boronic Acids, Aryl Trialkoxysilanes and Dimethyl-Aryl-Sulfonium Salts: New Entries to Aromatic Amides
1
Laboratory of Homogeneous Catalysis and Molecular Design at the Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Łodź, Poland
2
Institute of Bioorganic Chemistry, Polish Academy of Sciences, Noskowskiego 12/14, 61-704 Poznań, Poland
3
Institute of General and Ecological Chemistry, Lodz University of Technology, Zeromskiego 116, 90-924 Lodz, Poland
4
Department of Chemistry, University of Copenhagen, Universitetsparken 5, 2100 Copenhagen, Denmark
5
Dipartimento di Chimica e Biologia “A. Zambelli” Università di Salerno, Via Giovanni Paolo II, 84084 Fisciano (SA), Italy
6
Department of Chemistry, University of Helsinki, A.I. Virtasen aukio 1, 00014 Helsinki, Finland
*
Authors to whom correspondence should be addressed.
Molecules 2021, 26(10), 2957; https://doi.org/10.3390/molecules26102957
Original submission received: 30 April 2021
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Revised: 13 May 2021
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Accepted: 14 May 2021
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Published: 16 May 2021
(This article belongs to the Special Issue Organofluorine Chemistry and Beyond)
Abstract
:We describe a mechanism-guided discovery of a synthetic methodology that enables the preparation of aromatic amides from 2-bromo-2,2-difluoroacetamides utilizing a copper-catalyzed direct arylation. Readily available and structurally simple aryl precursors such as aryl boronic acids, aryl trialkoxysilanes and dimethyl-aryl-sulfonium salts were used as the source for the aryl substituents. The scope of the reactions was tested, and the reactions were insensitive to the electronic nature of the aryl groups, as both electron-rich and electron-deficient aryls were successfully introduced. A wide range of 2-bromo-2,2-difluoroacetamides as either aliphatic or aromatic secondary or tertiary amides were also reactive under the developed conditions. The described synthetic protocols displayed excellent efficiency and were successfully utilized for the expeditious preparation of diverse aromatic amides in good-to-excellent yields. The reactions were scaled up to gram quantities.
1. Introduction
The amide functional group is abundant in peptides and numerous natural products and is also ubiquitous in a vast range of biologically active compounds, marketed drugs, and a broad spectrum of agrochemicals [1,2,3,4,5,6,7]. The presence of the amide motif or its isosteres condition biological activity of many privileged scaffolds [7]. By recent estimates, almost a quarter of all marketed pharmaceuticals possesses an amide bond, making this functional group the most encountered in medicinal chemistry. Amides are prevalent in advanced materials [7,8], and many life science relevant substances; amides also play pivotal roles in supramolecular chemistry [9,10], molecular recognition [9,10,11], and catalysis [12,13]. The amide functional group can be tuned electronically and conformationally to gain desired structural, physical, and biological properties. The chemistry of amide group is vast, and by its virtue amides can be transformed into many other functional groups [14,15,16,17,18,19,20]. Due to the omnipresence and profound importance of the amide functionality, the development of principally new synthetic routes aiming at installation of the amide structural moiety is of current importance in both modern organic and medicinal chemistry. In this context, many new synthetic routes were elaborated [21,22,23,24]. Among those, it is important to mention such game-changing strategy as aminocarbonylations of aryl halides utilizing CO [25,26,27].
One conceptually underexplored strategy to prepare new amides was the installation of the amide structural unit by the attaching an appropriate substituent onto the prefunctionalized CO-N structural motif bearing a tuned leaving group on the amide carbon. Analysis of the literature revealed that this tactic has been realized using C-N synthons bearing Cl [28] and CHal3 (Hal = Cl, Br, I) as a leaving group [29,30,31]. These strategies were predominately used for the construction of aromatic amides with different substituents on the nitrogen atom. Another method was developed that is based upon the transition-metal-catalyzed arylation of N-substituted formamides by different aryl-containing reagents, predominantly aryl halides [32,33,34].
Based on a mechanistic consideration, we considered that 2-bromo-2,2-difluoroacetamides 1 would be particularly attractive for the formation of aryl-amides by activation using transition-metal catalysis. Combining the halogens in this particular fashion on the trihaloacetamide enables us to harness the attractive features of copper catalysis and fluoride-mediated catalysis. We set out to explore 2-bromo-2,2-difluoroacetamides 1 in coupling reactions with aryl boronic acids 2 and (aryl)trialkoxysilanes 3 arylation agents as donors of aryl or heteroaryl substituents (Scheme 1a). We hypothesized (Scheme 1b) that using transition-metal-assisted catalysis, a 2-bromo-2,2-difluoroacetamide unit could undergo an oxidative addition on an appropriately tuned by ligands metal nuclei, forming an organometallic intermediate (structure 6) [35,36,37], followed by a rearrangement possibly via a CF2-carbene complex 7, which undergoes loss of difluorocarben and simultaneous exchange of Br versus F giving rise to an organometallic (intermediate 8) capable of undergoing reaction with aryl boronic acids or aryl trialkoxysilanes to deliver a new intermediate (9), which after the reductive elimination would result in the formation of a new C-C bond to yield the desired aryl amide (5). An alternative mechanistic pathway could be via copper-intermediate 11 (Scheme 1c), as a result of the reaction between a fluorinated transition-metal catalyst and an aryl boronic acid (or aryl trialkoxysilane). This species could react with a carbon-centered radical 10 to form the species 9, which then decomposes into the final amide product 5. The formation of the radical species 10 would be unusual from the mechanistic point of view. A similar mechanism has, however, been suggested on the instance of palladium-catalyzed carboxylate-assisted ethoxycarboxylation of aromatic acids by ethyl bromodifluoroacetate in a very recent study [38,39]. It is worth noting that the concept of F versus B(OR)2 (or Si(OR)3) exchange on the copper nuclei, which we are postulating here, was suggested by Giri and Brawn for the mechanism in their copper-catalyzed Suzuki–Miyaura C-C couplings. These protocols were operational not only for boronic esters, but also for a broad range of trialkoxysilanes [40,41,42]. Based on the assumption of a fluoride-bearing Ar-Cu-F intermediate being active (similar to structure 8), and in a view of the resent literature on copper-supported C-C coupling protocols, we envisioned the use of copper catalysts. We also envisioned the preparation of aromatic amides as a result of the C-C coupling between aryl boronic acids, aryl trialkoxysilanes, or sulphonium salts with 2-bromo-2,2-difluoroacetamides according to the general synthetic scenario depicted in the Scheme 1.
We first considered the use of 2-bromo-2,2-difluoroacetamides as a source of the -CO-NR2 synthon. The only literature example known to date where ethoxycarboxylation of aromatic acids occurs using ethyl bromodifluoroacetate was described recently by Zhao et al. [38]. Similar access was proposed by Shi and co-workers in an alkoxycarbonylation of benzamides utilizing chloroformates [28]. Trifluoroacetyl amides have been used for the construction of aromatic and aliphatic amides via C(O)-CF3 bond cleavage utilizing the reaction with Grignard reagents [43]. The routes proposed by us utilize commercially or readily available reagents aryl donors and are visibly more atom economic and efficient than those using metalorganic reagents, thus enabling the creation larger amide structural diversities.
2. Results and Discussion
We selected three model reactions and performed a set of trial experiments to identify the trends and generalities depicted in Scheme 2 and Table 1, Table 2 and Table 3. After testing numerous reaction parameters, among which are catalysts, ligands, solvents, and bases, we noticed that some of the copper salts in combination with nitrogen-containing ligands (not indicated in the optimization Tables), in particular solvents, facilitate the expected C-C-coupling reaction and thus the formation of the desired aromatic amide. Furthermore, we succeeded in establishing the optimal reaction conditions for synthetic protocols (a) and (b), which were identical and consisted in the use of CuBr2 (0.1 equiv.), KF (2 equiv.), MgCl2 (1 equiv.) with hexafluoropropanol as the solvent, where all reactions were conducted in ACE pressure tubes at 70 °C for 8 h. One crucial aspect appeared to be the addition of calix[4]arene derivatives, which most probably act as ligands for the coper salt. The best efficiency was observed for the corresponding calix[4]arene L1. The magnesium salt, due to the high affinity of Mg2+ towards electron rich fluoride ion (hardness of Mg2+ in terms of the Pearson Hard-Soft acid-base theory), is most probably involved in the activation of one of the C-Hal bonds, like the corresponding C-F bond, by the coordination onto fluorine (where the fluoride ion in turn is a hard base, as per the Pearson Hard-Soft acid-base theory) and formation of the Mg-haloalkane complex [44,45]. The optimized reaction conditions allowed the efficient preparation of the model amide compound 5a in 87% and 90%, respectively (Table 1 and Table 2). This success encouraged further exploration of the scope and limitation of these two new protocols. We set out to test the scope and limitations of these coupling reactions by selecting twenty-two 2-bromo-2,2-difluoroacetamides 1 and reacting those with a range of aryl boronic acids 2 (twenty-three different substrates) and aryl trialkoxysilanes 3 (seventeen substrates). In a result of this study, we successfully prepared thirty-one amide derivativities 5 in good-to-excellent yields.
Focusing first on the reactions utilizing aryl boronic acids and aryl trialkoxysilanes, these synthetic protocols were tolerant to numerous functional groups placed on both coupling partners. In particular, both methodologies allowed the coupling of aryl substrates bearing a vast range of electron-withdrawing and electron-donating substituents placed in ortho-, meta-, and para- positions, respectively; among those are alkyl groups, alkoxy groups, Ph, halogens including fluorine, as well as CF3, CF3O, and CF3S groups. Substrates bearing 1-naphthyl, 1-thiophenyl, and 3-pyridyl moieties also showed excellent efficiency with some discrepancy for the formation of the thionyl derivative 5n (Scheme 3). Interestingly, both protocols were operational for aryl substrates bearing diverse ortho substituents (Me, F, Cl, Br, CF3, CF3O). Of note, highly fluorinated boronic acids and aryl trialkoxysilanes were prone to enter those protocols readily delivering the corresponding amides 5g, 5o, 5q. Regarding the reactivity of 2-bromo-2,2-difluoroacetamide counterparts 1, we did not observe any influence on the reaction efficiency of the substituents placed on the amide nitrogen—both alkyl and aryl groups as well as mixed derivatives exerted excellent tolerability within the developed protocols (Scheme 3). These reactions were not affected by changing a substitution pattern on the 2-bromo-2,2-difluoroacetamides: Species with alkyl as well as aryl substituents on the amide motif were equally effective within both synthetic protocols (Scheme 2). To further demonstrate the synthetic utility of these methodologies, the gram-scale reactions were successfully performed using 10 mmol of the 2-bromo-2,2-difluoroacetamides, which yielded the expected products in high yields.
To the general scope and limitations, it is also important to note: (1) Within both described syntactic protocols we tried numerous other N-substituted and N-unsubstituted derivatives of 2-bromo-2,2-difluoroacetic acid, for instance: 2-bromo-2,2-difluoroethane-thioamides, 2-bromo-2,2-difluoroacetimidamides, 2-bromo-2,2-difluoroacetohydrazonamides; all these substrates were not prone to enter the developed arylation protocols; (2) Aryl pinacol borates as well as aryl trifluoroborates in the form of potassium salts act as arylation agents in the frames of both synthetic protocols (2 and 4 examples respectively, Scheme 3); (3) 2,2-Difluoro-2-iodoacetamides exerted similar activity as the corresponding bromo derivatives (2 examples, Scheme 3).
As the final accord of this work, we turned our attention to aryl sulphonium salts 4. These are donors of aryl groups and are often considered as equivalents of aryl halides, possessing low reduction potentials [46,47,48]. We assumed that those species might have capacity to enter the title synthetic protocol (Scheme 2c). These compounds did not react well under previously optimized reaction conditions, where the model compound 5a was obtained in 47% yield (Table 3, Entry 1). Thus, we embarked once more on the search for new operational reaction conditions for the model reaction. It is worthwhile to note that in the case of this reaction, we had to increase the amount of copper salt to 0.3 equiv. and add 0.2 equiv. of [Ru(p-cymene)Cl2]2, which was superior to other TM co-catalysts (Table 3). Finally, by employing CuBr2 (0.3 equiv.), [Ru(p-cymene)Cl2]2 (0.2 equiv.), KF (2 equiv.), MgCl2 (1 equiv.) and 0.25 equiv. of calix[5]arene derivative (L2), in hexafluoropropanol, the model amide 5a was prepared in 84% yield. Further study of the scope resulted in the preparation of ten amides in total (Scheme 3c).
To gain the insight to the reaction mechanism, we performed several control experiments: (a) Reactions without addition of calixarenes; (b) reactions without CuBr2 and MgCl2; (c) reactions in the dark and (d) reactions with 2 equiv. and 3 equiv. of TEMPO, which led to the modest decrease of the yield of title model amid compound. All these experiments are depicted in the Table 1, Table 2 and Table 3.
3. Materials and Methods
Commercially available starting materials, reagents, catalysts, anhydrous, and degassed solvents were used without further purification. Flash column chromatography was performed with Merck Silica gel 60 (230–400 mesh). The solvents for column chromatography were distilled before the use. Thin layer chromatography was carried out using Merck TLC Silica gel 60 F254 and visualized by short-wavelength ultraviolet light or by treatment with potassium permanganate (KMnO4) stain. 1H, 13C, and 19F-NMR spectra were recorded on a Bruker 250 and 500 MHz at 20 °C. All 1H-NMR spectra are reported in parts per million (ppm) downfield of TMS and were measured relative to the signals for CHCl3 (7.26 ppm) and DMSO (2.50 ppm). All 13C{1H}-NMR spectra were reported in ppm relative to residual CHCl3 (77.00 ppm) or DMSO (39.70 ppm) and were obtained with 1H decoupling. Coupling constants, J, are reported in Hertz (Hz). Gas chromatographic analyses was performed on Gas Chromatograph Mass Spectrometer GCMS-QP2010 Ultra instrument.
The optimal reaction conditions were identified by microscale high-†hroughput experimentation screening. Parallel synthesis was accomplished in an MBraun glovebox operating with a constant Ar-purge (oxygen and water <5 ppm). Screening reactions were carried out in 10 mL vials using suitable heating blocks. Liquid chemicals were dosed using gas tight micro syringes. Isolation of obtained compounds was achieved by column chromatography on Silica gel.
All used boronic acids 2 and some aryl trialkoxysilanes 3 are commercially available and were purchased from appropriate vendors. 2-Bromo-2,2-difluoroacetamides [49,50,51,52,53,54,55,56,57], 1, 2-iodo-2,2-difluoroacetamides [54], aryl trialkoxysilanes 3 [58,59,60,61,62,63,64], sulfonium salts 4 [65,66,67], and calixarenes L1, L2 [68,69] are known compounds in the literature and were prepared according to the known literature, and the spectral data are identical with the corresponding literature. Copies 1H and 13C-NMR spectra are placed in Supplementary Materials.
General procedure for the synthesis of amides 5 by the reaction of 2-bromo-2,2-difluoroacetamides 1 with aryl boronic acids 2.
Under inert atmosphere (glovebox operating with a constant Ar-purge), to an 18 mL ACE pressure tube equipped with a stir bar, consequently, an appropriate 2-bromo-2,2-difluoroacetamide (1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid (1.3 mmol, 1.3 equiv.), the L1 (0.2 mmol, 0.2 equiv.), and finally CuBr2 (0.1 mmol, 0.1 equiv.) were placed; then the hexafluoropropanol (0.12 mmol/mL) was added and the reaction vessel was properly capped by Teflon stopper. Finally, the reaction vessel was removed from the glovebox and subjected to heating under vigorous stirring for 8 h. The progress of the reaction was controlled by TLC. After completion, the reaction mixture was evaporated until it reached dryness using a rotary evaporator, the content of the flask was generously treated with distilled water, filtered, and finally properly dried in vacuum. The resulting crude was directly subjected to gradient flash chromatography on silica gel using a mixture of hexane/ethyl acetate as eluent to isolate the desired amide derivative.
The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide.
General procedure for the synthesis of amides 5 by the reaction of 2-bromo-2,2-difluoroacetamides 1 with aryl trialkoxysilanes 3.
Under inert atmosphere (glovebox operating with a constant Ar-purge), to an 18 mL ACE pressure tube equipped with a stir bar, an appropriate 2-bromo-2,2-difluoroacetamide (1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane (1.4 mmol, 1.4 equiv.), the L1 (0.2 mmol, 0.2 equiv.), and finally CuBr2 (0.1 mmol, 0.1 equiv.) was consequently placed; then the hexafluoropropanol (0.12 mmol/mL) was added and the reaction vessel was properly capped by Teflon stopper. Finally, the reaction vessel was removed from the glovebox and subjected to heating under vigorous stirring for 8 h. The progress of the reaction was controlled by TLC. After completion, the reaction mixture was evaporated until it reached dryness using a rotary evaporator, the content of the flask was generously treated with distilled water, filtered, and finally properly dried in vacuum. The resulting crude was directly subjected to gradient flash chromatography on silica gel using a mixture of hexane/ethyl acetate as eluent to isolate the desired amide derivative.
The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide.
General procedure for the synthesis of amides 5 by the reaction of 2-bromo-2,2-difluoroacetamides 1 with (aryl)dimethylsulfonium salts 4.
Under inert atmosphere (glovebox operating with a constant Ar-purge), to an 18 mL ACE pressure equipped with a stir bar, an appropriate 2-bromo-2,2-difluoroacetamide (1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt (1.6 mmol, 1.6 equiv.), the L2 (0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (0.2 mmol, 0.2 equiv.), and finally CuBr2 (0.3 mmol, 0.3 equiv.) was consequently placed; then the hexafluoropropanol (0.12 mmol/mL) was added and the reaction vessel was properly capped by Teflon stopper. Finally, the reaction vessel was removed from the glovebox and subjected to heating under vigorous stirring for 11 h. The progress of the reaction was controlled by TLC. After completion, the reaction mixture was evaporated until it reached dryness using rotary evaporator, the content of the flask was generously treated with distilled water, filtered, and finally properly dried in vacuum. The resulting crude was directly subjected to gradient flash chromatography on silica gel using a mixture of hexane/ethyl acetate as eluent to isolate the desired amide derivative. The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide.
N-phenyl-4-(trifluoromethyl)benzamide 5a. The title compound was prepared, starting with 2-bromo-2,2-difluoroacetamide 1a (250 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl boronic acid 2n (247 mg, 1.3 mmol, 1.3 equiv.), L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5a (231 mg, 0.87 mmol, 87%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1a and the amide 5a was prepared in 80% yield (2.12 g, 8 mmol). Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1a (250 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3k (372 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5a (239 mg, 0.90 mmol, 90%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1a and the amide 5a was prepared in 77% yield (2.04 g, 7.7 mmol).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1a (250 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4a (584 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5a (222 mg, 0.84 mmol, 84%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1a and the amide 5a was prepared in 79% yield (2.09 g, 7.9 mmol).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1a (250 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate potassium trifluoro(4-(trifluoromethyl)phenyl)borate (328 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5a (228 mg, 0.86 mmol, 86%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1a and the amide 5a was prepared in 73% yield (1.93 g, 7.3 mmol).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1a (250 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate 4,4,5,5-tetramethyl-2-(4-(trifluoromethyl)phenyl)-1,3,2-dioxaborolane (354 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5a (222 mg, 0.84 mmol, 84%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1a and the amide 5a was prepared in 73% yield (1.93 g, 7.3 mmol).
Alternatively, the title compound was prepared starting with an appropriate 2,2-difluoro-2-iodo-N-phenylacetamide (297 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2n (247 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5a (222 mg, 0.84 mmol, 84%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1a and the amide 5a was prepared in 76% yield (2.01 g, 7.6 mmol).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 3:1 as an eluent to provide the corresponding amide product.
White solid, mp 184–185 °C. 1H-NMR (500 MHz, DMSO-d6): δ 7.12 (t, 1H, 3J = 7.3 Hz, CHAr), 7.37 (t, 2H, 3J = 8.3 Hz, CHAr), 7.80 (d, 2H, 3J = 7.6 Hz, CHAr), 7.89 (d, 2H, 3J = 8.2 Hz, CHAr), 8.16 (d, 2H, 3J = 8.1 Hz, CHAr), 10.5 (s, 1H, NH).
13C{1H}-NMR (126 MHz, DMSO-d6): δ 120.5, 123.9 (q, 1JCF = 273.8 Hz, CF3), 124.0, 125.4 (d, JCF = 3.1 Hz), 128.6, 128.7, 131.4 (q, 2JCF = 30.3 Hz, CCF3), 138.8 (d, JCF = 11.3 Hz), 164.4.
HRMS (TOF MS ES+): Calcd for C14H11NOF3 (M+H) 266.0809. Found 266.0793.
4-(tert-butyl)-N-(naphthalen-1-yl)benzamide 5b. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1e (300 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2a (231 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5b (245 mg, 0.81 mmol, 81%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1e (300 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3a (414 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5b (242 mg, 0.80 mmol, 80%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1e (300 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4h (312 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5b (233 mg, 0.77 mmol, 77%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 3:1 as an eluent to provide the corresponding amide product.
White solid, mp 146–147 °C. 1H-NMR (500 MHz, CDCl3): δ 1.38 (s, 9H, tBu), 7.46–7.51 (m, 5H, CHAr), 7.72 (d, 1H, 3J = 8.4 Hz, CHAr), 7.87–7.90 (m, 3H, CHAr), 7.92 (s, 1H, CHAr), 7.97 (br. s, 1H, CHAr), 8.33 (s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 31.2, 35.0, 120.79, 120.80, 121.2, 125.7, 125.9, 126.3, 127.1, 127.5, 127.51, 128.7, 131.9, 132.5, 134.1.
HRMS (TOF MS ES+): Calcd for C21H22NO (M + H) 304.1707. Found 304.1701.
N-(o-tolyl)-3-(trifluoromethoxy)benzamide 5c. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1d (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2r (268 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5c (245 mg, 0.83 mmol, 83%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1d (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3n (395 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.) CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5c (257 mg, 0.87 mmol, 87%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 5:1 as an eluent to provide the corresponding amide product.
White solid, mp 94–95 °C. 1H-NMR (500 MHz, CDCl3): δ 2.30 (s, 3H, Me), 7.12–7.15 (m, 1H, CHAr), 7.21–7.24 (m, 2H, CHAr), 7.40 (d, 1H, 3J = 8.1 Hz, CHAr), 7.50 (t, 1H, 3J = 7.9 Hz, CHAr), 7.74–7.78 (m, 3H, CHAr), 7.81 (br s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 17.8, 120.1, 120.4 (q, 1JCF = 258.6 Hz), 123.6, 124.1, 125.1, 125.9, 126.8, 130.0, 130.2, 130.6, 135.2, 137.0, 149.5, 164.2.
HRMS (TOF MS ES+): Calcd for C15H13NO2F3 (M + H) 296.0901. Found 296.0898.
N-(2,4-difluorophenyl)-3-methylbenzamide 5d. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1j (286 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2b (177 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5d (217 mg, 0.88 mmol, 88%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1j (286 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3b (297 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5d (207 mg, 0.84 mmol, 84%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 4:1 as an eluent to provide the corresponding amide product.
White solid, mp 106–107 °C. 1H-NMR (500 MHz, CDCl3): δ 2.41 (s, 3H, Me), 6.85–6.90 (m, 2H, CHAr), 7.35–7.36 (m, 2H, CHAr), 7.63–7.65 (m, 1H, CHAr), 7.68 (s, 1H, CHAr), 8.02 (br s, 1H, NH), 8.29–8.33 (m, 1H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 21.4, 103.4 (d, JCF = 26.5 Hz), 103.6 (d, JCF = 26.5 Hz), 111.2 (dd, JCF = 21.7 Hz, JCF = 3.6 Hz), 122.6 (dd, JCF = 10.5 Hz, JCF = 3.7 Hz), 123.1 (d, JCF = 9.3 Hz), 124.0, 127.8, 128.6, 132.9, 134.1, 138.7, 152.9 (dd, 1JCF = 246.4 Hz, JCF = 11.9 Hz), 158.6 (dd, 1JCF = 246.5 Hz, JCF = 11.4 Hz), 165.7.
HRMS (TOF MS ES+): Calcd for C14H12NOF2 (M + H) 248.0894. Found 248.0898.
3-chloro-N-(3,4-dimethoxyphenyl)benzamide 5e. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1g (310 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2a (203 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5e (242 mg, 0.83 mmol, 83%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1g (310 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3i (326 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5e (239 mg, 0.82 mmol, 82%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 4:1 as an eluent to provide the corresponding amide product.
Light purple, solid mp 127–128 °C. 1H-NMR (500 MHz, CDCl3): δ 3.79 (s, 3H, OMe), 3.83 (s, 3H, OMe), 6.77 (d, 1H, 3J = 8.4 Hz, CHAr), 7.02 (dd, 1H, 3J = 8.7 Hz, 4J = 2.1 Hz, CHAr), 7.32 (t, 1H, 3J = 7.9 Hz, CHAr), 7.36–7.37 (m, 1H, CHAr), 7.44 (dd, 1H, 3J = 8.0 Hz, 4J = 1.0 Hz, CHAr). 7.70 (d, 1H, 3J = 7.0 Hz, CHAr), 7.81 (s, 1H, CHAr), 8.26 (s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 55.7, 55.9, 105.2, 111.1, 112.6, 125.1, 127.3, 129.9, 131.1, 131.6, 134.7, 136.6, 146.1, 148.8, 164.5.
HRMS (TOF MS ES+): Calcd for C15H15NO3Cl (M + H) 292.0738. Found 292.0740.
3-methoxy-N-phenylbenzamide 5f. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1a (250 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2w (198 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5f (207 mg, 0.91 mmol, 91%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1a (250 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3j (378 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5f (200 mg, 0.88 mmol, 88%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1a (250 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4b (410 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5f (204 mg, 0.90 mmol, 90%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 4:1 as an eluent to provide the corresponding amide product.
White solid, mp 116–117 °C. 1H-NMR (500 MHz, CDCl3): δ 3.78 (s, 3H, OMe), 7.02 (dd, 1H, 3J = 8.2 Hz, 4J = 2.5 Hz, CHAr), 7.13 (t, 1H, 3J = 7.5 Hz, CHAr), 7.28–7.40 (m, 5H, CHAr), 7.64 (d, 2H, 3J = 7.9 Hz, CHAr), 8.23 (s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 55.3, 112.3, 117.9, 118.8, 120.3, 124.5, 128.9, 129.6, 136.3, 137.9, 159.8, 165.8.
HRMS (TOF MS ES+): Calcd for C14H14NO2 (M + H) 228.1025. Found 228.1025.
4-fluoro-N-(m-tolyl)-3-(trifluoromethyl)benzamide 5g. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1c (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2p (270 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5g (267 mg, 0.90 mmol, 90%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 5:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 121–122 °C. 1H-NMR (500 MHz, DMSO-d6): δ 2.31 (s, 3H, Me), 6.94 (d, 1H, 3J = 7.4 Hz, CHAr), 7.24 (d, 1H, 3J = 8.2 Hz, CHAr), 7.56 (d, 2H, 3J = 8.3 Hz, CHAr), 7.60 (s, 1H, CHAr), 8.33–8.36 (m, 2H, CHAr), 10.36 (s, 1H, NH),
13C{1H}-NMR (126 MHz, DMSO-d6): δ 21.2, 116.5 (dd, JCF = 33.5 Hz, JCF = 12.1 Hz), 117.5 (d, JCF = 20.8 Hz), 117.7, 121.1, 122.4 (q, 1JCF = 272.3 Hz, CF3), 124.8, 126.9, 128.5, 131.7 (d, JCF = 3.1 Hz), 135.1 (d, JCF = 9.4 Hz), 137.9, 138.7, 160.6 (d, 1JCF = 257.0 Hz), 163.0.
HRMS (TOF MS ES+): Calcd for C15H12NOF4 (M + H) 298.0861. Found 298.0855.
N-(p-tolyl)-2-(trifluoromethoxy)benzamide 5h. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1b (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2q (268 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5h (218 mg, 0.74 mmol, 74%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1b (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3m (395 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5h (221 mg, 0.75 mmol, 75%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 5:1 as an eluent to provide the corresponding amide product.
White solid, mp 108–109 °C. 1H-NMR (500 MHz, CDCl3): δ 2.35 (s, 3H, Me), 7.18 (d, 2H, 3J = 8.0 Hz, CHAr), 7.32 (d, 1H, 3J = 8.0 Hz, CHAr), 7.42 (t, 1H, 3J = 7.5 Hz, CHAr), 7.51–7.55 (m, 3H, CHAr), 8.04 (d, 1H, 3J = 7.7 Hz, CHAr), 8.30 (s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 20.9, 120.3 (q, 1JCF = 261.0 Hz, OCF3), 120.4, 121.2, 127.6, 128.3, 129.6, 131.9, 132.6, 134.6, 135.0, 145.7, 162.1.
HRMS (TOF MS ES+): Calcd for C15H13NO3F3 (M + H) 312.0847. Found 312.0848.
N-(4-methoxyphenyl)-2-(trifluoromethoxy)benzamide 5i. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1f (280 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2q (268 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5i (239 mg, 0.77 mmol, 77%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1f and the amide 5i was prepared in 63% yield (1.96 g, 0.63 mmol).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1f (280 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialckoxysilane 3m (395 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5i (224 mg, 0.72 mmol, 72%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 6:1 as an eluent to provide the corresponding amide product.
Pink solid, mp 117–118 °C. 1H-NMR (500 MHz, CDCl3): δ 3.81 (s, 3H, OMe), 6.88–6.92 (m, 2H, CHAr), 7.32 (d, 1H, 3J = 8.2 Hz, CHAr), 7.42 (dt, 1H, 3J = 7.6 Hz, 4J = 0.7 Hz, CHAr), 7.51–7.54 (m, 3H, CHAr), 8.02 (dd, 1H, 3J = 7.8 Hz, 4J = 1.7 Hz, CHAr), 8.25 (s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 55.5, 114.2, 120.3 (q, 1JCF = 260.4 Hz, OCF3), 121.2, 122.2, 127.6, 128.3, 130.6, 131.8, 132.5, 145.7, 156.8, 162.1.
HRMS (TOF MS ES+): Calcd for C15H13NO2F3 (M + H) 296.0904. Found 296.0898.
N-(m-tolyl)-2-(trifluoromethyl)benzamide 5j. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1c (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2o (247 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5j (239 mg, 0.65 mmol, 65%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1c (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3m (372 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5j (224 mg, 0.67 mmol, 67%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 5:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 120–121 °C. 1H-NMR (500 MHz, CDCl3): δ 2.35 (s, 3H, Me), 6.98 (d, 1H, 3J = 7.57 Hz, CHAr), 7.22 (t, 1H, 3J = 8.1 Hz, CHAr), 7.33 (d, 1H, 3J = 7.6 Hz, CHAr), 7.44 (s, 1H, CHAr), 7.54–7.57 (m, 3H, CHAr), 7.69–7.71 (m, 3H, NH, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 21.4, 117.3, 120.8, 123.7 (q, 1JCF = 276.1 Hz, CF3), 125.7, 126.4 (q, JCF = 5.2 Hz, CF3), 127.1 (q, 2JCF = 31.5 Hz, CCF3), 128.5, 128.9, 130.0, 132.1, 135.7, 137.4, 139.0, 165.7.
HRMS (TOF MS ES+): Calcd for C15H13NOF3 (M + H) 280.0957. Found 280.0949.
N-(4-chlorophenyl)-2-methylbenzamide 5k. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1h (285 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2c (177 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5k (172 mg, 0.70 mmol, 70%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1h (285 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3c (297 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5k (182 mg, 0.74 mmol, 74%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 3:1 as an eluent to provide the corresponding amide product.
White solid, mp 136–138 °C. 1H-NMR (500 MHz, CDCl3): δ 2.41 (s, 3H, Me), 7.17 (t, 1H, 3J = 7.2 Hz, CHAr), 7.20 (d, 1H, 3J = 7.2 Hz, CHAr), 7.25 (d, 2H, 3J = 8.7 Hz, CHAr), 7.31 (dt, 2H, 3J = 7.6 Hz, 4J = 0.8 Hz, CHAr), 7.36 (d, 1H, 3J = 7.2 Hz, CHAr), 7.50 (d, 1H, 3J = 8.4 Hz, CHAr), 7.87 (br s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 19.7, 121.2, 125.8, 126.6, 129.0, 129.4, 130.3, 131.2, 135.9, 136.3, 136.5, 168.2.
HRMS (TOF MS ES+): Calcd for C14H13NOCl (M + H) 246.0690. Found 246.0686.
2-bromo-N-(3,4-dimethoxyphenyl)benzamide 5l. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1g (310 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2m (261 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5l (185 mg, 0.55 mmol, 55%). Flash column chromatography was performed using a mixture of hexane/ethyl acetate 2:1 as an eluent to provide the corresponding amide product.
Purple solid, mp 140–141 °C. 1H-NMR (500 MHz, CDCl3): δ 3.83 (s, 3H, OMe), 3.84 (s, 3H, OMe), 6.79 (d, 1H, 3J = 8.7 Hz, CHAr), 7.00 (dd, 1H, 3J = 8.4 Hz, 4J = 2.6 Hz, CHAr), 7.22–7.26 (m, 1H, CHAr), 7.29–7.32 (m, 1H, CHAr), 7.41 (d, 1H, 4J = 2.3 Hz, CHAr), 7.51 (dd, 1H, 3J = 7.6 Hz, 4J = 1.6 Hz, CHAr), 7.55 (d, 1H, 3J = 8.3 Hz, CHAr), 7.96 (s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 55.8, 56.0, 104.8, 111.2, 112.0, 119.2, 127.5, 129.4, 131.2, 131.4, 133.3, 137.7, 146.0, 148.9, 165.5.
HRMS (TOF MS ES+): Calcd for C15H15NO3Br (M + H) 266.0809. Found 266.0793.
N-(4-fluorophenyl)nicotinamide 5m. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1i (268 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2t (160 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5m (173 mg, 0.80 mmol, 80%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1i (268 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3o (277 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5m (166 mg, 0.77 mmol, 77%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 1:1 as an eluent to provide the corresponding amide product.
White solid, mp 130–131 °C. 1H-NMR (500 MHz, CDCl3): δ 7.02 (t, 2H, 3J = 8.7 Hz, CHAr), 7.34–7.37 (m, 1H, CHAr), 7.55–7.58 (m, 2H, CHAr), 8.15 (d, 1H, 3J = 8.3 Hz, CHAr), 8.66 (dd, 1H, 3J = 4.7 Hz, 4J = 1.4 Hz, CHAr), 8.80 (s, 1H, NH), 9.03 (s, 1H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 115.7 (d, JCF = 22.2 Hz), 122.5 (d, JCF = 7.0 Hz), 123.7, 130.6, 133.5, 135.6, 147.9, 152.2, 159.7 (d, 1JCF = 244.1 Hz), 164.1.
HRMS (TOF MS ES+): Calcd for C15H12NOF3Na (M + Na) 302.0769. Found 302.0769.
N-(m-tolyl)thiophene-2-carboxamide 5n. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1c (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2u (166 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5n (154 mg, 0.71 mmol, 71%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1c (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3p (286 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5n (169 mg, 0.78 mmol, 78%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1c (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4c (470 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5n (174 mg, 0.80 mmol, 80%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 6:1 as an eluent to provide the corresponding amide product.
Brownish solid, mp 160–161 °C. 1H-NMR (500 MHz, CDCl3): δ 2.32 (s, 3H, Me), 6.94 (t, 1H, 3J = 7.8 Hz, CHAr), 7.01–7.08 (m, 1H, Thiophene), 7.21 (t, 1H, 3J = 7.8 Hz, CHAr), 7.39 (d, 1H, 3J = 8.1 Hz, CHAr), 7.47 (s, 1H, CHAr), 7.51 (d, 1H, 3J = 4.8 Hz, Thiophene), 7.64 (d, 1H, 3J = 3.6 Hz, Thiophene).
13C{1H}-NMR (126 MHz, CDCl3): δ 21.4, 117.4, 121.0, 125.4, 127.8, 128.4, 128.8, 130.7, 137.5, 138.9, 139.4, 160.1.
HRMS (TOF MS ES+): Calcd for C12H12NOS (M + H) 240.1394. Found 218.0640.
3,4-difluoro-N-isopropylbenzamide 5o. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1k (216 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2g (205 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5o (238 mg, 0.90 mmol, 90%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1k (216 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3g (386 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5o (233 mg, 0.88 mmol, 88%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 8:1 as an eluent to provide the corresponding amide product.
White solid, mp 105–106 °C. 1H-NMR (500 MHz, CDCl3): δ 1.14 (d, 6H, 3J = 6.2 Hz, Me), 4.08 (m, 1H, CH), 7.49–7.54 (m, 1H, CHAr), 7.73–7374 (m, 1H, CHAr), 7.87–7.91 (m, 1H, CHAr), 8.32 (d, 1H, 3J = 6.8 Hz, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 22.2, 41.3, 116.6 (d, JCF = 18.3 Hz), 117.3 (d, JCF = 17.5 Hz), 124.7 (m), 132.2 (m), 149.1 (dd, 1JCF = 247.3 Hz, 1JCF = 12.3 Hz), 151.2 (dd, 1JCF = 250.2 Hz, 1JCF = 12.3 Hz), 163.0.
HRMS (TOF MS ES+): Calcd for C13H19NOCl (M + H) 240.1157. Found 240.1155.
4-chloro-N,N-diisopropylbenzamide 5p. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1l (258 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2j (203 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5p (263 mg, 0.91 mmol, 91%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1l (258 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3h (326 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5p (266 mg, 0.92 mmol, 92%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 8:1 as an eluent to provide the corresponding amide product.
White solid, mp 129–130 °C. 1H-NMR (500 MHz, CDCl3): δ 1.15 (s, 6H, Me), 1.48 (s, 6H, Me), 3.58 (m, 2H, 2xCH), 7.24 (dt, 2H, 3J = 8.5 Hz, 4J = 2.0 Hz, CHAr), 7.34 (dt, 2H, 3J = 8.3 Hz, 4J = 1.7 Hz, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 20.7, 127.1, 128.7, 134.6, 137.2, 169.9.
HRMS (TOF MS ES+): Calcd for C13H19NOCl (M + H) 240.1157. Found 240.1155.
2,3,4-trifluoro-N,N-diisopropylbenzamide 5q. Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1l (258 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2h (229 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5q (215 mg, 0.83 mmol, 83%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 11:1 as an eluent to provide the corresponding amide product.
White solid, mp 48–50 °C. 1H-NMR (500 MHz, CDCl3): δ 1.10 (m, 6H, 2xMe), 1.50 (s, 3H, Me), 1.52 (s, 3H, Me), 3.50–3.53 (m, 1H, NCH), 3.65–3.68 53 (m, 1H, NCH), 6.97–7.00 (m, 2H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 20.5 (m), 46.2, 51.3, 112.9 (dd, JCF = 18.0 Hz, JCF = 3.3 Hz), 121.3 (m), 124.3 (dd, JCF = 16.4 Hz, JCF = 2.2 Hz), 139.7 (dt, 1JCF = 253.7 Hz, JCF = 15.2 Hz), 147.2 (ddd, 1JCF = 249.8 Hz, JCF = 10.9 Hz, JCF = 3.1 Hz), 151.2 (ddd, 1JCF = 251.3 Hz, JCF = 9.8 Hz, JCF = 2.4 Hz), 163.5.
HRMS (TOF MS ES+): Calcd for C13H17NOF3 (M + H) 260.1262. Found 260.1262.
N-cyclohexyl-2-fluorobenzamide 5r. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1p (258 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2i (203 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5r (188 mg, 0.85 mmol, 85%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1p (258 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate potassium trifluoro(2-fluorophenyl)borate (263 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5r (192 mg, 0.87 mmol, 87%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 10:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 45–46 °C. 1H-NMR (500 MHz, CDCl3): δ 1.19–1.29 (m, 3H, Cy), 1.36–1.46 (m, 2H, Cy), 1.58–1.62 (m, 1H, Cy), 1.69–1.73 (m, 2H, Cy), 1.98–2.01 (m, 2H, Cy), 3.98–4.00 (m, 1H, Cy), 6.61 (s, 1H, NH), 7.04–7.08 (m, 1H, CHAr), 7.19–7.22 (m, 1H, CHAr), 7.38–7.42 (m, 1H, CHAr), 8.03 (dd, 1H, 3J = 7.9 Hz, 4J = 1.8 Hz, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 24.7, 25.5, 32.9, 48.5, 115.8 (d, JCF = 23.6 Hz), 121.5 (d, JCF = 11.0 Hz), 124.6 (d, JCF = 2.7 Hz), 131.9, 133.0 (d, JCF = 9.0 Hz), 160.4 (d, 1JCF = 246.0 Hz, CF), 162.1 (d, JCF = 2.4 Hz).
HRMS (TOF MS ES+): Calcd for C13H17NOF (M + H) 222.1294. Found 222.1294.
N-cyclohexyl-N-methyl-[1,1′-biphenyl]-4-carboxamide 5s. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1o (270 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2e (257 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5s (255 mg, 0.87 mmol, 87%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1o (270 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3e (442 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5s (243 mg, 0.83 mmol, 83%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 8:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 105 - 106 °C. 1H-NMR (500 MHz, CDCl3): δ 1.07–1.09 (m, 2H, Cy), 1.47–1.56 (m, 4H, Cy), 1.72–1.82 (m, 4H, Cy), 2.83, 3.00 (s, 3H, Me cis/trans), 3.54, 4.51 (s, 1H, Cy cis/trans), 7.33–7.36 (m, 1H, CHAr), 7.42–7.45 (m, 4H, CHAr), 7.60–7.61 (m, 4H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 25.0, 25.3, 25.4, 27.4, 29.4, 29.5, 30.7, 31.9, 52.7, 58.1, 126.5 126.7, 126.9, 127.1, 127.2, 127.5, 128.7, 135.8, 140.1, 141.8, 171.4.
HRMS (TOF MS ES+): Calcd for C20H24NO (M + H) 294.1856. Found 294.1858.
N-benzyl-3-methoxybenzamide 5t. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1u (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2w (198 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5t (217 mg, 0.90 mmol, 90%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1u (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3j (378 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5t (210 mg, 0.87 mmol, 87%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1u (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4b (410 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.17 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5t (202 mg, 0.84 mmol, 84%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1u (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate potassium trifluoro(3-methoxyphenyl)borate (278 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5t (193 mg, 0.80 mmol, 80%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1u (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate 2-(3-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (304 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5t (200 mg, 0.83 mmol, 83%).
Alternatively, the title compound was prepared starting with an appropriate N-benzyl-2,2-difluoro-2-iodoacetamide (311 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2w (198 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5t (210 mg, 0.87 mmol, 87%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 7:1 as an eluent to provide the corresponding amide product.
White solid, mp 77–78 °C. 1H-NMR (500 MHz, CDCl3): δ 2.36 (s, 3H, Me), 4.60 (d, 2H, 3J = 5.6 Hz, CH2), 6.78 (br s, 1H, NH), 7.26–7.33 (m, 7H, CHAr), 7.57 (d, 1H, 3J = 7.2 Hz, CHAr), 7.63 (s, 1H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 21.2, 43.9, 123.9, 127.4, 127.7, 127.8, 128.3, 128.6, 132.1, 134.2, 138.3, 167.6.
HRMS (TOF MS ES+): Calcd for C15H16NO (M + H) 226.1234. Found 226.1232.
N-cyclohexyl-N-phenyl-4-(trifluoromethyl)benzamide 5u. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1n (332 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2n (247 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5u (312 mg, 0.90 mmol, 90%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1n (332 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3k (372 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5u (312 mg, 0.90 mmol, 90%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1n (332 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4a (584 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5u (281 mg, 0.81 mmol, 81%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 8:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 195–196 °C. 1H-NMR (500 MHz, CDCl3): δ 0.97 (tq, 1H, 3J = 13.4 Hz, 4J = 2.9 Hz, Cy), 1.22 (dq, 2H, 3J = 12.9 Hz, 4J = 2.9 Hz, Cy), 1.45 (d, 2H, 3J = 12.4 Hz, Cy), 1.61 (d, 1H, 3J = 13.3 Hz, Cy), 1.78 (d, 2H, 3J = 13.3 Hz, Cy), 1.96 (d, 2H, 3J = 11.1 Hz, Cy), 4.72 (s, 1H, Cy), 7.00 (d, 2H, 3J = 6.9 Hz, CHAr), 7.19–7.20 (m, 3H, CHAr), 7.31 (d, 2H, 3J = 7.3 Hz, CHAr), 7.36 (d, 2H, 3J = 6.9 Hz, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 25.3, 25.8, 31.5, 55.3, 123.7 (q, 1JCF = 271.2 Hz, CF3), 124.6, 127.8, 128.3, 128.6, 130.4 (q, 2JCF = 28.0 Hz, CCF3), 130.6, 139.2, 140.8, 169.1.
HRMS (TOF MS ES+): Calcd for C20H21NOF3 (M + H) 348.1581. Found 348.1575.
N-((1s,3s)-adamantan-1-yl)-4-(trifluoromethyl)benzamide 5v. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1q (308 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2n (247 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5v (281 mg, 0.87 mmol, 87%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1q (308 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3k (372 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5v (291 mg, 0.90 mmol, 90%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1q (308 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate potassium trifluoro(4-(trifluoromethyl)phenyl)borate (328 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5v (271 mg, 0.84 mmol, 84%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 12:1 as an eluent to provide the corresponding amide product.
White solid, mp 158–159 °C. 1H-NMR (500 MHz, CDCl3): δ 1.70 (s, 6H, Adam), 2.11 (s, 9H, Adam), 5.91 (s, 1H, NH), 7.61 (d, 2H, 3J = 8.6 Hz, CHAr), 7.78 (d, 2H, 3J = 7.9 Hz, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 29.4, 36.2, 41.5, 52.6, 123.7 (q, 1JCF = 273.6 Hz, CF3), 125.4 (m), 127.2, 132.6 (q, 2JCF = 31.1 Hz, CCF3), 139.3.
HRMS (TOF MS ES+): Calcd for C18H21NOF3 (M + H) 324.1583. Found 324.1575.
3-chloro-N-cyclopropylbenzamide 5w. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1r (214 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2k (203 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5w (127 mg, 0.65 mmol, 65%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1r (214 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3i (326 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5w (125 mg, 0.64 mmol, 64%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1r (214 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4d (516 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5w (113 mg, 0.58 mmol, 58%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 7:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 142—143 °C. 1H-NMR (500 MHz, CDCl3): δ 0.83–0.86 (m, 2H, CH2), 1.06–1.09 (m, 2H, CH2), 1.48- 1.53 (m, 1H, CH), 7.04 (d, 1H, 3J = 7.9 Hz, CHAr), 7.20 (t, 1H, 3J = 8.7 Hz, CHAr), 7.32 (d, 1H, 3J = 7.9 Hz, CHAr), 7.63 (br. s, 1H, CHAr), 7.74 (s, 1H, NH).
13C{1H}-NMR (126 MHz, CDCl3): δ 8.2, 15.7, 17.7, 19.9, 124.0, 129.9, 134.6, 139.2, 172.3.
HRMS (TOF MS ES+): Calcd for C10H11NOCl (M + H) 196.0532. Found 196.0529.
[1,1′-biphenyl]-4-yl(pyrrolidin-1-yl)methanone 5x. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1s (228 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2e (257 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5x (326 mg, 0.91 mmol, 91%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1s (228 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3e (442 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5x (223 mg, 0.89 mmol, 89%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1s (228 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4e (582 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5x (206 mg, 0.82 mmol, 82%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 8:1 as an eluent to provide the corresponding amide product.
White solid, mp 139–140 °C. 1H-NMR (500 MHz, CDCl3): δ 1.86 (m, 4H, Pyrr), 3.39 (s, 2H, Pyrr), 3.58 (s, 2H, Pyrr), 7.34 (t, 1H, 3J = 7.7 Hz, CHAr), 7.43 (t, 2H, 3J = 7.7 Hz, CHAr), 7.57 – 7.59 (m, 6H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 24.3, 26.3, 46.1, 49.5, 126.7, 127.0, 127.6, 128.7, 135.8, 140.1, 142.4, 169.3.
HRMS (TOF MS ES+): Calcd for C17H18NO (M + H) 252.1391. Found 252.1388.
N-phenethyl-1-naphthamide 5y. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1t (278 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2d (224 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5y (228 mg, 0.83 mmol, 83%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1t and the amide 5y was prepared in 78% yield (2.15 g, 7.8 mmol).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1t (278 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3d (347 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5y (212 mg, 0.77 mmol, 77%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1t and the amide 5y was prepared in 70% yield (1.93 g, 7 mmol).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 5:1 as an eluent to provide the corresponding amide product.
White solid, mp 117–118 °C. 1H-NMR (500 MHz, CDCl3): δ 3.00 (t, 2H, 3J = 6.1 Hz, CH2), 3.80 (q, 2H, 3J = 7.2 Hz, CH2), 6.13 (s, 1H, NH), 7.27–7.28 (m, 3H, CHAr), 7.33–7.37 (m, 2H, CHAr), 7.40–7.43 (m, 1H, CHAr), 7.48–7.54 (m, 3H, CHAr), 7.86–7.88 (m, 1H, CHAr), 7.89 (d, 1H, 3J = 8.0 Hz, CHAr), 8.20–8.22 (m, 1H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 35.6, 41.0, 124.6, 124.85, 125.3, 126.3, 126.5, 127.0, 128.2, 128.7, 128.8, 130.0, 130.4, 133.6, 134.5, 138.7.
HRMS (TOF MS ES+): Calcd for C19H18NO (M + H) 276.1396. Found 276.1388.
N-benzyl-3-chlorobenzamide 5z. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1u (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2k (203 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5z (209 mg, 0.85 mmol, 85%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1u (264 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3i (372 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5z (194 mg, 0.79 mmol, 79%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 2:1 as an eluent to provide the corresponding amide product.
Yellowish solid, mp 93–94 °C. 1H-NMR (500 MHz, CDCl3): δ 4.57 (d, 2H, 3J = 5.5 Hz, CH2), 6.77 (s, 1H, NH), 7.27–7.35 (m, 6H, CHAr), 7.44 (dd, 1H, 3J = 8.0 Hz, 4J = 1.0 Hz, CHAr), 7.64 (d, 1H, 3J = 8.0 Hz, CHAr), 7.77 (d, 1H, 4J = 1.8 Hz, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 44.1, 125.1, 127.3, 127.6, 127.8, 128.7, 129.8, 131.5, 134.7, 136.1, 137.8, 166.1.
HRMS (TOF MS ES+): Calcd for C14H13NOCl (M + H) 246.0686. Found 246.0686.
N-(4-fluorobenzyl)-2-methylbenzamide 5aa. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1v (282 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2l (203 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5aa (189 mg, 0.72 mmol, 72%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1v (282 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4f (516 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5aa (158 mg, 0.60 mmol, 60%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1v (282 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate potassium (2-chlorophenyl)trifluoroborate (283 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5aa (181 mg, 0.69 mmol, 69%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 4:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 119–120 °C. 1H-NMR (500 MHz, CDCl3): δ 2.36 (s, 3H, Me), 4.46 (d, 2H, 3J = 5.7 Hz, CH2), 6.40 (s, 1H, NH), 6.97 (t, 2H, 3J = 8.7 Hz, CHAr), 7.11–7.17 (m, 2H, CHAr), 7.23–7.28 (m, 4H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 19.7, 42.9, 115.4 (d, JCF = 22.0 Hz), 125.6, 126.6, 129.3 (d, JCF = 8.9 Hz), 129.9, 130.9, 134.1 (d, JCF = 2.3 Hz), 136.0 (d, JCF = 2.7 Hz), 126.1 (d, 1JCF = 243.3 Hz), 169.9.
HRMS (TOF MS ES+): Calcd for C15H15NOF (M + H) 244.1143. Found 244.1138.
N,N-dibenzyl-4-fluorobenzamide 5ab. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (354 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2f (174 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ab (290 mg, 0.91 mmol, 91%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1m and the amide 5ab was prepared in 83% yield (2.65 g, 8.3 mmol).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (354 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3f (361 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ab (287 mg, 0.90 mmol, 90%). The gram scale synthesis was performed on 10 mmol of the starting 2-bromo-2,2-difluoroacetamide 1m and the amide 5ab was prepared in 78% yield (2.45 g, 7.8 mmol).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (354 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), aryl sulphonium salt 4g (490 mg, 1.6 mmol, 1.6 equiv.), the L2 (202 mg, 0.25 mmol, 0.25 equiv.), [Ru(p-cymene)Cl2]2 (122 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (67 mg, 0.3 mmol, 0.3 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ab (281 mg, 0.88 mmol, 88%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (354 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate 2-(4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (289 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ab (284 mg, 0.89 mmol, 89%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 3:1 as an eluent to provide the corresponding amide product.
White solid, mp 86–87 °C. 1H-NMR (500 MHz, CDCl3): δ 4.20 (s, 2H, CH2), 4.71 (s, 2H, CH2), 7.07 (t, 2H, 3J = 7.6 Hz, CHAr), 7.15 (br. s, 2H, CHAr), 7.30–7.33 (m, 4H, CHAr), 7.36–7.39 (m, 4H, CHAr), 8.50–7.53 (m, 2H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 47.2, 51.6, 115.6 (d, JCF = 22.2 Hz), 126.8 (m), 127.7 (m), 128.4 (m), 128.7 (m), 128.9, 129.0, 132.0 (m), 136.5 (d, JCF = 67.9 Hz), 163.3 (d, 1JCF = 247.5 Hz), 171.3.
HRMS (TOF MS ES+): Calcd for C21H19NOF (M + H) 320.1455. Found 320.1451.
N,N-dibenzyl-4-((trifluoromethyl)thio)benzamide 5ac. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (354 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2s (289 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ac (337 mg, 0.84 mmol, 84%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 3:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 68–70 °C. 1H-NMR (500 MHz, CDCl3): δ 4.39 (s, 2H, CH2), 4.74 (s, 2H, CH2), 7.13 (d, 2H, 3J = 6.9 Hz, CHAr), 7.30–7.34 (m, 4H, CHAr), 7.37–7.40 (m, 4H, CHAr), 7.54 (d, 2H, 3J = 8.1 Hz, CHAr), 7.67 (d, 2H, 3J = 8.1 Hz, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 47.1, 51.5, 127.1 (q, 1JCF = 258.2 Hz, SCF3), 126.9, 127.7, 128.2, 128.4, 128.8, 129.0, 135.9, 136.2, 136.5, 138.6, 170.8.
HRMS (TOF MS ES+): Calcd for C22H19NOF3S (M + H) 402.1141. Found 402.1139.
N,N-dibenzyl-2-(trifluoromethyl)benzamide 5ad. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (354 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate aryl boronic acid 2o (247 mg, 1.3 mmol, 1.3 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ac (247 mg, 0.67 mmol, 67%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (354 mg, 1.0 mmol, 1.0 equiv.), KF (116 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (95 mg, 1.0 mmol, 1.0 equiv.), appropriate trialkoxysilane 3l (372 mg, 1.4 mmol, 1.4 equiv.), the L1 (130 mg, 0.2 mmol, 0.2 equiv.), CuBr2 (22.3 mg, 0.1 mmol, 0.1 equiv.), and hexafluoropropanol (0.12 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ab (229 mg, 0.62 mmol, 62%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 4:1 as an eluent to provide the corresponding amide product.
Colorless solid, mp 135–136 °C. 1H-NMR (500 MHz, CDCl3): δ 4.11 (t, 2H, 3J = 15.3 Hz, CH2), 4.25 (d, 1H, 3J = 15.8 Hz, CH2), 5.33 (d, 1H, 3J = 14.8 Hz, CH2), 7.11 (m, 2H, 3J = 7.1 Hz, CHAr), 7.29–7.37 (m, 8H, CHAr), 7.47–7.51 (m, 2H, CHAr), 7.56 (t, 1H, 3J = 7.1 Hz, CHAr), 7.71 (d, 1H, 3J = 7.8 Hz, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 46.4, 51.1, 123.7 (q, 1JCF = 274.8 Hz, CF3), 126.6 (m), 127.3, 127.4, 127.7, 127.8, 128.5, 128.8, 129.1, 129.1, 132.1, 135.0, 135.5, 136.1, 169.2.
HRMS (TOF MS ES+): Calcd for C22H19NOF3 (M + H) 370.1422. Found 370.1419.
N1,N1,N3,N3-tetrabenzylisophthalamide 5ae. The title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (885 mg, 2.5 mmol, 2.5 equiv.), KF (232 mg, 2.0 mmol, 2.0 equiv.), MgCl2 (190 mg, 2.0 mmol, 2.0 equiv.), appropriate aryl boronic acid 2v (166 mg, 1.0 mmol, 1.0 equiv.), the L1 (260 mg, 0.4 mmol, 0.4 equiv.), CuBr2 (44.6 mg, 0.2 mmol, 0.2 equiv.), and hexafluoropropanol (0.08 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ae (445 mg, 0.85 mmol, 85%).
Alternatively, the title compound was prepared starting with an appropriate 2-bromo-2,2-difluoroacetamide 1m (885 mg, 2.5 mmol, 2.5 equiv.), KF (232 mg, 4.0 mmol, 4.0 equiv.), MgCl2 (190 mg, 2.0 mmol, 2.0 equiv.), appropriate trialkoxysilane 3q (318 mg, 1.0 mmol, 1.0 equiv.), the L1 (260 mg, 0.4 mmol, 0.4 equiv.), CuBr2 (44.6 mg, 0.2 mmol, 0.2 equiv.), and hexafluoropropanol (0.08 mmol/mL). The purification of the dry crude performed by column chromatography on silica gel provides the amide 5ae (419 mg, 0.80 mmol, 80%).
Flash column chromatography was performed using a mixture of hexane/ethyl acetate 1:2 as an eluent to provide the corresponding amide product.
White solid, mp 172–173 °C. 1H-NMR (500 MHz, CDCl3): δ 4.39 (s, 4H, 2xCH2), 4.71 (s, 4H, 2xCH2), 7.12 (d, 4H, 3J = 6.8 Hz, CHAr), 7.28–7.37 (m, 16H, CHAr), 7.53 (s, 4H, CHAr).
13C{1H}-NMR (126 MHz, CDCl3): δ 46.9, 51.4, 126.8, 126.9, 127.6, 127.7, 128.4, 128.7, 128.9, 136.0, 136.6, 137.4, 171.3.
HRMS (TOF MS ES+): Calcd for C36H33N2O2 (M + H) 525.2540. Found 525.2539.
4. Conclusions
Summing up, basing on the mechanism assumption, we described three new mechanism-guided copper-catalyzed protocols for the direct arylation of 2-bromo-2,2-difluoroacetamides using aryl boronic acids, aryl trialloxysilanes, and aryl sulphonium salts as the aryl donors. The deployment of the scope of the reactions showcased the unique tolerance of the developed methodologies towards vast range of structural patterns and substituents on all coupling parts. These methods offer rapid entry to structurally diverse aromatic amides from simple and commercially availed precursors. Noteworthily, all methodologies were prone for scale-up to gram quantities.
Supplementary Materials
Scheme S1: List of 2-bromo-2,2-difluoroacetamides 1 used for preparation of amides 5; Scheme S2: List of aryl boronic acids 2 used for preparation of amides 5; Scheme S3: List of (aryl)trialkoxysilanes 3 used for preparation of amides 5; Scheme S4: List of (aryl)dimethylsulfonium salts 4 used for preparation of amides 5; Copies 1H and 13C-NMR spectra.
Author Contributions
Conceptualization, V.O.I. and S.M.; methodology, S.M.; validation, S.M., M.J. and S.L.; investigation, S.M., M.J., S.L., V.O.I. and S.M.; writing—original draft preparation, V.O.I., S.M. and M.P.; writing—review and editing, V.O.I., S.M. and M.P.; visualization, V.O.I., S.M. and M.P.; supervision, V.O.I.; project administration, V.O.I., S.M. and M.P.; funding acquisition, V.O.I., S.M. and M.P. All authors have read and agreed to the published version of the manuscript.
Funding
This research was supported by a grant from National Science Centre (NSC) Poland within the framework of European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant agreement No. 665778 (POLONEZ 2 grant, Nr. 2016/21/P/ST5/00630) obtained by Satenik Mkrtchyan. This research project was also supported by a grant from National Science Centre (NSC) Poland, the SONATA 10 (Nr. 2015/19/D/ST5/02774) obtained by Viktor Iaroshenko. Viktor Iaroshenko also acknowledges the funding for his Visiting Professorship from the University of Salerno. Michael Pittelkow appreciates the support from the Danish Council for Independent Research (DFF 4181-00206 and 9040-00265) and from the University of Copenhagen.
Institutional Review Board Statement
Not applicable.
Informed Consent Statement
Not applicable.
Data Availability Statement
Data is contained within the article or Supplementary Materials.
Acknowledgments
Open access funding provided by University of Helsinki.
Conflicts of Interest
The authors declare no conflict of interest.
Sample Availability
Samples of all compounds are available from the authors.
References
- Harrington, A.; Tal-Gan, Y. The Importance of Amide Protons in Peptide Drug Development. Available online: https://www.future-science.com/doi/abs/10.4155/fmc-2019-0238?journalCode=fmc (accessed on 8 November 2019).
- Allen, C.L.; Williams, J.M. Metal-Catalysed Approaches to Amide Bond Formation. Chem. Soc. Rev. 2011, 40, 3405–3415. [Google Scholar] [CrossRef]
- de Figueiredo, R.M.; Suppo, J.S.; Campagne, J.M. Nonclassical Routes for Amide Bond Formation. Chem. Rev. 2016, 116, 12029–12122. [Google Scholar] [CrossRef]
- Valeur, E.; Bradley, M. Amide Bond Formation: Beyond the Myth of Coupling Reagents. Chem. Soc. Rev. 2009, 38, 606–631. [Google Scholar] [CrossRef] [PubMed]
- Pattabiraman, V.R.; Bode, J.W. Rethinking Amide Bond Synthesis. Nature 2011, 480, 471–479. [Google Scholar] [CrossRef]
- Ojeda-Porras, A.; Gamba-Sanchez, D. Recent Developments in Amide Synthesis Using Nonactivated Starting Materials. J. Org. Chem. 2016, 81, 11548–11555. [Google Scholar] [CrossRef] [PubMed]
- Greenberg, A.; Breneman, C.M.; Liebman, J.F. The Amide Linkage: Structural Significance. In Chemistry, Biochemistry, and Materials Science; Wiley: Hoboken, NJ, USA, 2000. [Google Scholar]
- Yun, S.H.; Ingole, P.G.; Choi, W.K.; Kim, J.H.; Lee, H.K. Synthesis of cross-linked amides and esters as thin film composite membrane materials yields permeable and selective material for water vapor/gas separation. J. Mater. Chem. A 2015, 3, 7888–7899. [Google Scholar] [CrossRef]
- Atwood, J.L. Comprehensive Supramolecular Chemistry II; Elsevier Ltd.: Amsterdam, The Netherlands, 2017; 4568p. [Google Scholar]
- Neri, P.; Sessler, J.L.; Wang, M.-X. Calixarenes and Beyond; Springer: Berlin/Heidelberg, Germany, 2016. [Google Scholar]
- Urbach, A.R.; Ramalingam, V. Molecular Recognition of Amino Acids, Peptides, and Proteins by Cucurbit[n]uril Receptors. Isr. J. Chem. 2011, 51, 664–678. [Google Scholar] [CrossRef][Green Version]
- Zozulia, O.; Dolan, M.A.; Korendovych, I.V. Catalytic peptide assemblies. Chem. Soc. Rev. 2018, 47, 3621–3639. [Google Scholar] [CrossRef] [PubMed]
- Metrano, A.J.; Miller, S.J. Peptide-Based Catalysts Reach the Outer Sphere through Remote Desymmetrization and Atroposelectivity. Acc. Chem. Res. 2019, 52, 199–215. [Google Scholar] [CrossRef]
- Zabicky, J.; Patai, S. (Eds.) The Chemistry of the Amides, Part 1; Wiley: Hoboken, NJ, USA, 2010; ISBN 978-0-470-77123-5. [Google Scholar]
- Chen, D.-H.; Sun, W.-T.; Zhu, C.-J.; Lu, G.-S.; Wu, D.-P.; Wang, A.-E.; Huang, P.-Q. Enantioselective Reductive Cyanation and Phosphonylation of Secondary Amides by Iridium and Chiral Thiourea Sequential Catalysis. Angew. Chem. Int. Ed. 2021, 60, 8827–8831. [Google Scholar] [CrossRef]
- Tona, V.; Maryasin, B.; de la Torre, A.; Sprachmann, J.; González, L.; Maulide, N. Direct Regioselective Synthesis of Tetrazolium Salts by Activation of Secondary Amides under Mild Conditions. Org. Lett. 2017, 19, 2662–2665. [Google Scholar] [CrossRef] [PubMed]
- Ou, W.; Huang, P.-Q. Amides as surrogates of aldehydes for C-C bond formation: Amide-based direct Knoevenagel-type condensation reaction and related reactions. Sci. China Chem. 2020, 63, 11–15. [Google Scholar] [CrossRef]
- Takahashi, Y.; Sato, T.; Chida, N. Iridium-catalyzed Reductive Nucleophilic Addition to Tertiary Amides. Chem. Lett. 2019, 48, 1138–1141. [Google Scholar] [CrossRef]
- Chen, H.; Huang, Y.-H.; Ye, J.-L.; Huang, P.-Q. Double Addition of Alkynyllithium Reagents to Amides/Lactams: A Direct and Flexible Synthesis of 3-Amino-1,4-diynes Bearing an Aza-Quaternary Carbon Center. J. Org. Chem. 2019, 84, 9270–9281. [Google Scholar] [CrossRef] [PubMed]
- Yoritate, M.; Takahashi, Y.; Tajima, H.; Ogihara, C.; Yokoyama, T.; Soda, Y.; Oishi, T.; Sato, T.; Chida, N. Unified Total Synthesis of Stemoamide-Type Alkaloids by Chemoselective Assembly of Five-Membered Building Blocks. J. Am. Chem. Soc. 2017, 139, 18386–18391. [Google Scholar] [CrossRef] [PubMed]
- Dunetz, J.R.; Magano, J.; Weisenburger, G.A. Large-Scale Applications of Amide Coupling Reagents for the Synthesis of Pharmaceuticals. Org. Process Res. Dev. 2016, 20, 140–177. [Google Scholar] [CrossRef]
- Montalbetti, C.A.G.N.; Falque, V. Amide Bond Formation and Peptide Coupling. Tetrahedron 2005, 61, 10827–10852. [Google Scholar] [CrossRef]
- Sabatini, M.T.; Boulton, L.T.; Sneddon, H.F.; Sheppard, T.D. A green chemistry perspective on catalytic amide bond formation. Nat. Catal. 2019, 2, 10–17. [Google Scholar] [CrossRef]
- Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L.J. The Reaction of Thio Acids with Azides: A New Mechanism and New Synthetic Applications. J. Am. Chem. Soc. 2003, 125, 7754–7755. [Google Scholar] [CrossRef]
- Barnard, C.F.J. Palladium-Catalyzed Carbonylation—A Reaction Come of Age. Organometallics 2008, 27, 5402–5422. [Google Scholar] [CrossRef]
- Friis, S.D.; Lindhardt, A.T.; Skrydstrup, T. The Development and Application of Two-Chamber Reactors and Carbon Monoxide Precursors for Safe Carbonylation Reactions. Acc. Chem. Res. 2016, 49, 594–605. [Google Scholar] [CrossRef][Green Version]
- Molander, G.A.; Wolfe, J.P.; Larhed, M. (Eds.) Science of Synthesis: Cross-Coupling and Heck-Type Reactions; Thieme: Stuttgart, Germany, 2013. [Google Scholar]
- Liao, G.; Chen, H.M.; Shi, B.F. Synthesis of Phthalic Acid Derivatives via Pd-catalyzed Alkoxycarbonylation of Aromatic C–H Bonds with Alkyl Chloroformates. Chem. Commun. 2018, 54, 10859–10862. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Diaba, F.; Montiel, J.A.; Serban, G.; Bonjoch, J. Synthesis of Normorphans through an Efficient Intramolecular Carbamoylation of Ketones. Org. Lett. 2015, 17, 3860–3863. [Google Scholar] [CrossRef][Green Version]
- Adachi, M.; Miyasaka, T.; Hashimoto, H.; Nishikawa, T. One-Step Transformation of Trichloroacetamide into Isonitrile. Org. Lett. 2017, 19, 380–383. [Google Scholar] [CrossRef]
- Chen, J.; Guo, Y.P.; Sun, M.H.; Fan, G.T.; Zhou, L. Bromoform reaction of tertiary amines with N,N-dibromosulfonamides or NBS/sulfonamides. Chem. Commun. 2014, 50, 12367–12370. [Google Scholar] [CrossRef] [PubMed]
- Ko, S.; Han, H.; Chang, S. Ru-Catalyzed Hydroamidation of Alkenes and Cooperative Aminocarboxylation Procedure with Chelating Formamide. Org. Lett. 2003, 2687–2690. [Google Scholar] [CrossRef] [PubMed]
- Jo, Y.; Ju, J.; Choe, J.; Song, K.H.; Lee, S. The Scope and Limitation of Nickel-Catalyzed Aminocarbonylation of Aryl Bromides from Formamide Derivatives. J. Org. Chem. 2009, 74, 6358–6361. [Google Scholar] [CrossRef]
- Iranpoor, N.; Panahi, F.; Roozbin, F.; Erfan, S.; Rahimi, S. Palladium-Catalyzed Aminocarbonylation of Aryl Halides with 2,4,6-Trichloro-1,3,5-triazine/Formamide Mixed Reagent. Eur. J. Org. Chem. 2016, 9, 1781–1787. [Google Scholar] [CrossRef]
- Xiang, H.; Zhao, Q.; Tang, Z.; Xiao, J.; Xia, P.; Wang, C.; Yang, C.; Chen, X.; Yang, H. Visible-Light-Driven, Radical-Triggered Tandem Cyclization of o-Hydroxyaryl Enaminones: Facile Access to 3-CF2/CF3-Containing Chromones. Org. Lett. 2017, 19, 146–149. [Google Scholar] [CrossRef] [PubMed]
- An, L.; Xiao, Y.L.; Zhang, S.; Zhang, X.G. Bulky Diamine Ligand Promotes Cross-Coupling of Difluoroalkyl Bromides by Iron Catalysis. Angew. Chem. Int. Ed. 2018, 57, 6921–6925. [Google Scholar] [CrossRef]
- Arlow, S.I.; Hartwig, J.F. Synthesis, Characterization, and Reactivity of Palladium Fluoroenolate Complexes. J. Am. Chem. Soc. 2017, 139, 16088–16091. [Google Scholar] [CrossRef] [PubMed]
- Tao, N.; Wang, J.; Yuan, C.; Zeng, R.; Zhao, Y.-S. Palladium-Catalyzed Carboxylate-Assisted Ethoxycarboxylation of Aromatic Acids to Synthesize Monoethyl Phthalate Derivatives with Ethyl Bromodi fluoroacetate. Org. Lett. 2019, 21, 8607–8610. [Google Scholar] [CrossRef] [PubMed]
- Ma, X.; Song, Q. Recent progress on selective deconstructive modes of halodifluoromethyl and trifluoromethyl-containing reagents. Chem. Soc. Rev. 2020, 49, 9197–9219. [Google Scholar] [CrossRef] [PubMed]
- Santosh, K.; Thapa, G.S.; Vangala, A.S.; Giri, R. Copper-Catalyzed Hiyama Coupling of (Hetero)aryltriethoxysilanes with (Hetero)aryl Iodides. Org. Lett. 2013, 15, 5378–5381. [Google Scholar]
- Gurung, S.K.; Thapa, S.; Kafle, A.; Dickie, D.A.; Giri, R. Copper-Catalyzed Suzuki—Miyaura Coupling of Arylboronate Esters: Transmetalation with (PN)CuF and Identification of Intermediates. Org. Lett. 2014, 16, 1264–1267. [Google Scholar] [CrossRef] [PubMed]
- Gurung, S.K.; Thapa, S.; Shrestha, B.; Giri, R. Copper-catalysed cross-couplings of arylboronate esters with aryl and heteroaryl iodides and bromides. Org. Chem. Front. 2015, 2, 649–653. [Google Scholar] [CrossRef]
- Zhu, L.; Le, L.; Yan, M.; Au, C.-T.; Qiu, R.; Kambe, N. Carbon–Carbon Bond Formation of Trifluoroacetyl Amides with Grignard Reagents via C(O)–CF3 Bond Cleavage. J. Org. Chem. 2019, 84, 5635–5644. [Google Scholar] [CrossRef]
- Pahl, J.; Brand, S.; Elsen, H.; Harder, S. Highly Lewis acidic cationic alkaline earth metal complexes. Chem. Commun. 2018, 54, 8685–8688. [Google Scholar] [CrossRef]
- Harder, S.; Friedrich, A.; Pahl, J.; Eyselein, J.; Langer, J.; Hommes, N.V.E.; Görling, A. Magnesium-Halobenzene Bonding: Mapping the Halogen Sigma-Hole with a Lewis-Acidic Complex. Chem. Sci. 2021, 12, 2410–2418. [Google Scholar]
- Majek, M.; von Wangelin, A.J. Mechanistic Perspectives on Organic Photoredox Catalysis for Aromatic Substitutions. Acc. Chem. Res. 2016, 49, 2316–2327. [Google Scholar] [CrossRef]
- Romero, N.A.; Nicewicz, D.A. Photoredox Catalysis for Building C–C Bonds from C(sp2)–H Bonds. Chem. Rev. 2016, 116, 10075–10166. [Google Scholar] [CrossRef] [PubMed]
- Prier, C.K.; Rankic, D.A.; MacMillan, D.W.C. Visible Light Photoredox Catalysis with Transition Metal Complexes: Applications in Organic Synthesis. Chem. Rev. 2013, 113, 5322–5363. [Google Scholar] [CrossRef][Green Version]
- Lv, Y.; Pu, W.; Wang, Q.; Chen, Q.; Niu, J.; Zhang, Q. Copper-Catalyzed Aminodifluoroalkylation of Alkenes with α-Bromodifluoroacetamides: Synthesis of 3,3-Difluoropyrrolidin-2-ones. Adv. Synth. Catal. 2017, 359, 3114–3119. [Google Scholar] [CrossRef]
- Lv, Y.; Pu, W.; Chen, Q.; Wang, Q.; Niu, J.; Zhang, Q. Cu-Catalyzed Aminodifluoroalkylation of Alkynes and α-Bromodifluoroacetamides. J. Org. Chem. 2017, 82, 8282–8289. [Google Scholar] [CrossRef] [PubMed]
- Zhang, M.; Li, W.; Duan, Y.; Xu, P.; Zhang, S.; Zhu, C. Cascade Photoredox/Iodide Catalysis: Access to Difluoro-γ-lactams via Aminodifluoroalkylation of Alkenes. Org. Lett. 2016, 18, 3266–3269. [Google Scholar] [CrossRef] [PubMed]
- Ye, Z.; Gettys, K.E.; Shen, X.; Dai, M. Copper-Catalyzed Cyclopropanol Ring Opening Csp3–Csp3 Cross-Couplings with (Fluoro)Alkyl Halides. Org. Lett. 2015, 17, 6074–6077. [Google Scholar] [CrossRef] [PubMed][Green Version]
- Wei, X.-J.; Wang, L.; Du, S.-F.; Wub, L.-Z.; Liu, Q. Visible-light photoredox intramolecular difluoroacetamidation: Facile synthesis of 3,3-difluoro-2-oxindoles from bromodifluoroacetamides. Org. Biomol. Chem. 2016, 14, 2195–2199. [Google Scholar] [CrossRef]
- Lermontov, S.A.; Polivanova, A.G.; Shkavrov, S.B. Interaction of α,α-difluoroazides with trivalent phosphorus compounds and triphenylantimony. Russ. J. Gen. Chem. 2010, 80, 1646–1651. [Google Scholar] [CrossRef]
- Deng, S.; Chen, H.; Ma, X.; Zhou, Y.; Yang, K.; Lan, Y.; Song, Q. S8-Catalyzed triple cleavage of bromodifluoro compounds for the assembly of N-containing heterocycles. Chem. Sci. 2019, 10, 6828–6833. [Google Scholar] [CrossRef][Green Version]
- Chen, C.; Zeng, R.; Zhang, J.; Zhao, Y. Ruthenium-Catalyzed Difluoroalkylation of 8-Aminoquinoline Amides at the C5-Position. Eur. J. Org. Chem. 2017, 10, 6947–6950. [Google Scholar] [CrossRef]
- Ye, Z.-P.; Xia, P.-J.; Liu, F.; Hu, Y.-Z.; Song, D.; Xiao, J.-A.; Huang, P.; Xiang, H.-Y.; Chen, X.-Q.; Yang, H. Visible-Light-Induced, Catalyst-Free Radical Cross-Coupling Cyclization of N-Allylbromodifluoroacetamides with Disulfides or Diselenides. J. Org. Chem. 2020, 85, 5670–5682. [Google Scholar] [CrossRef] [PubMed]
- Lu, M.-Z.; Ding, X.; Shao, C.; Hu, Z.; Luo, H.; Zhi, S.; Hu, H.; Kan, Y.; Loh, T.-P. Direct Hiyama Cross-Coupling of (Hetero)arylsilanes with C(sp2)–H Bonds Enabled by Cobalt Catalysis. Org. Lett. 2020, 22, 2663–2668. [Google Scholar] [CrossRef]
- Wang, Z.; Chang, S. Copper-Mediated Transformation of Organosilanes to Nitriles with DMF and Ammonium Iodide. Org. Lett. 2013, 15, 1990–1993. [Google Scholar] [CrossRef] [PubMed]
- Luo, H.; Xie, Q.; Sun, K.; Deng, J.; Xu, L.; Wang, K.; Luo, X. Rh(iii)-catalyzed C-7 arylation of indolines with arylsilanes via C–H activation. RSC Adv. 2019, 9, 18191–18195. [Google Scholar] [CrossRef][Green Version]
- Varenikov, A.; Gandelman, M. Synthesis of chiral α-trifluoromethyl alcohols and ethers via enantioselective Hiyama cross-couplings of bisfunctionalized electrophiles. Nat. Commun. 2018, 9, 3566. [Google Scholar] [CrossRef][Green Version]
- Lu, M.-Z.; Luo, H.; Hu, Z.; Shao, C.; Kan, Y.; Loh, T.-P. Directed Palladium(II)-Catalyzed Intermolecular Anti-Markovnikov Hydroarylation of Unactivated Alkenes with (Hetero)arylsilanes. Org. Lett. 2020, 22, 9022–9028. [Google Scholar] [CrossRef]
- Nguyen, T.V.Q.; Yoo, W.-J.; Kobayashi, S. Copper-Catalyzed Carboxylation of Aryl- and Alkenyltrialkoxysilanes. Asian J. Org. Chem. 2018, 7, 116–118. [Google Scholar] [CrossRef]
- von der Lehr, M.; Ellinghaus, R.; Smarsly, B.M. Hierarchically porous monolithic silica with varying porosity using bis(trimethoxysilyl)arenes as precursors. New J. Chem. 2016, 40, 4455–4463. [Google Scholar] [CrossRef][Green Version]
- Huang, C.; Feng, J.; Ma, R.; Fang, S.; Lu, T.; Tang, W.; Du, D.; Gao, J. Redox-Neutral Borylation of Aryl Sulfonium Salts via C–S Activation Enabled by Light. Org. Lett. 2019, 21, 9688–9692. [Google Scholar] [CrossRef]
- Yanagi, T.; Somerville, R.J.; Nogi, K.; Martin, R.; Yorimitsu, H. Ni-Catalyzed Carboxylation of C(sp2)–S Bonds with CO2: Evidence for the Multifaceted Role of Zn. ACS Catal. 2020, 10, 2117–2123. [Google Scholar] [CrossRef]
- Uno, D.; Minami, H.; Otsuka, S.; Nogi, K.; Yorimitsu, H. Palladium-Catalyzed Mizoroki–Heck-Type Alkenylation of Monoaryldialkylsulfoniums. Chem. Asian J. 2018, 13, 2397–2400. [Google Scholar]
- Sutariya, P.G.; Soni, H.; Gandhi, S.A.; Pandya, A. Luminescent behavior of pyrene-allied calix[4]arene for the highly pH-selective recognition and determination of Zn2+, Hg2+ and I− via the CHEF-PET mechanism: Computational experiment and paper-based device. New J. Chem. 2019, 43, 9855–9864. [Google Scholar] [CrossRef]
- Mendoza-Espinosa, D.; Martinez-Ortega, A.B.; Quiroz-Guzman, M.; Golen, J.A.; Rheingold, L.A.; Hanna, T.A. Synthesis, structures and full characterization of p-tert-butylcalix[5]arene mono-, di-, tri- and pentaanionic ligand precursors. J. Organomet. Chem. 2009, 694, 1509–1523. [Google Scholar] [CrossRef]
Scheme 1.
(a) Synthetic scenario, (b,c) Proposed reaction mechanisms.
Scheme 2.
Model reactions for reaction conditions optimization: (a) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with (4-(trifluoromethyl)phenyl)boronic acid, (b) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with trimethoxy(4-(trifluoromethyl)phenyl)silane, (c) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with dimethyl(4-(trifluoromethyl)phenyl)sulfonium triflate.
Scheme 2.
Model reactions for reaction conditions optimization: (a) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with (4-(trifluoromethyl)phenyl)boronic acid, (b) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with trimethoxy(4-(trifluoromethyl)phenyl)silane, (c) Reaction of 2-bromo-2,2-difluoro-N-phenylacetamide with dimethyl(4-(trifluoromethyl)phenyl)sulfonium triflate.
Scheme 3.
(a) Reactions of 2-bromo-2,2-difluoro-acetamides with aryl boronic acid, (b) Reactions of 2-bromo-2,2-difluoro-acetamides with aryl trialkoxysilanes, (c) Reactions of 2-bromo-2,2-difluoro-acetamides with dimethyl-aryl-sulfonium triflates. Product scope of amides using developed synthetic protocols.
Scheme 3.
(a) Reactions of 2-bromo-2,2-difluoro-acetamides with aryl boronic acid, (b) Reactions of 2-bromo-2,2-difluoro-acetamides with aryl trialkoxysilanes, (c) Reactions of 2-bromo-2,2-difluoro-acetamides with dimethyl-aryl-sulfonium triflates. Product scope of amides using developed synthetic protocols.
Table 1.
Optimization of the reaction conditions for synthetic protocol (a).
| Reaction (a) b | |||
|---|---|---|---|
| Entry | Reagent (Equiv)/Catalyst/Ligand/Additive | Solvent/Temperature/Time | Yield (%) 5a a |
| 1 | boronic acid (1.5)/CuI (0.1)/KF (2.0) | DMF/100 °C/12 h | 0 |
| 2 | boronic acid (1.5)/CuBr2 (0.1)/KF (2.0) | DMF/100 °C/12 h | Trace |
| 3 | boronic acid (1.5)/CuI (0.1)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 12 |
| 4 | boronic acid (1.5)/CuI (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 38 |
| 5 | boronic acid (1.5)/CuF2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 49 |
| 6 | boronic acid (1.5)/CuCl2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 67 |
| 7 | boronic acid (1.5)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 88 |
| 8 | boronic acid (1.3)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/8 h | 87 |
| 9 | boronic acid (1.3)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | DMF/70 °C/8 h | 11 |
| 10 | boronic acid (1.3)/CuBr2 (0.1)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/8 h | 18 |
| 11 | boronic acid (1.3)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/8 h | 0 |
| 12 | boronic acid (1.3)/CuBr2 (0.1)/L1 (0.2)/KF (2.0) | (CF3)2CHOH/70 °C/8 h | 27 |
| 13 | boronic acid (1.3)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0)/TEMPO (2.0) | CF3)2CHOH/70 °C/8 h | 75 |
| 14 | boronic acid (1.3)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0)/TEMPO (3.0) | (CF3)2CHOH/70 °C/8 h | 60 |
| 15 | boronic acid (1.3)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0)—in dark | (CF3)2CHOH/70 °C/8 h | 84 |
a Isolated yield. b All reactions were conducted in inert atmosphere.
Table 2.
Optimization of the reaction conditions for synthetic protocol (b).
| Reaction (b) b | |||
|---|---|---|---|
| Entry | Reagent (Equiv)/Catalyst/Ligand/Additive | Solvent/Temperature/Time | Yield (%) 5a a |
| 1 | aryl trialkoxysilane (1.4)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/8 h | 90 |
| 2 | aryl trialkoxysilane (1.4)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | DMF/70 °C/8 h | 22 |
| 3 | aryl trialkoxysilane (1.4)/CuBr2 (0.1)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/8 h | 21 |
| 4 | aryl trialkoxysilane (1.4)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/8 h | 0 |
| 5 | aryl trialkoxysilane (1.4)/CuBr2 (0.1)/L1 (0.2)/KF (2.0) | (CF3)2CHOH/70 °C/8 h | 25 |
| 6 | aryl trialkoxysilane (1.4)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0)/TEMPO (2.0) | (CF3)2CHOH/70 °C/8 h | 72 |
| 7 | aryl trialkoxysilane (1.4)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0)/TEMPO (3.0) | (CF3)2CHOH/70 °C/8 h | 58 |
| 8 | aryl trialkoxysilane (1.4)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0)—in dark | (CF3)2CHOH/70 °C/8 h | 91 |
a Isolated yield. b All reactions were conducted at room temperature in inert atmosphere.
Table 3.
Optimization of the reaction conditions for synthetic protocol (c).
| Reaction (c) b | |||
|---|---|---|---|
| Entry | Reagent (Equiv)/Catalyst/Ligand/Additive | Solvent/Temperature/Time | Yield (%) 5a a |
| 1 | sulphonium salt (1.4)/CuBr2 (0.1)/L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 47 |
| 2 | sulphonium salt (2)/CuCl2 (0.1), /L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | Trace |
| 3 | sulphonium salt (2)/CuI (0.1), /L1 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | Trace |
| 4 | sulphonium salt (1.6)/CuBr2 (0.3), Pd(OAc)2 (0.2)/L1 (0.25)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 17 |
| 5 | sulphonium salt (1.6)/CuBr2 (0.3)/L2 (0.25)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 29 |
| 6 | sulphonium salt (1.6)/CuBr2 (0.3), PdCl2 (0.2)/L2 (0.25)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 48 |
| 7 | sulphonium salt (1.6)/CuBr2 (0.3), Pd(OAc)2 (0.2)/L2 (0.25)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/12 h | 53 |
| 8 | sulphonium salt (1.6)/CuBr2 (0.3), [Ru(p-cymene)Cl2]2 (0.2)/L2 (0.25)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/11 h | 84 |
| 9 | sulphonium salt (1.6)/CuBr2 (0.3), [Ru(p-cymene)Cl2]2 (0.2)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/11 h | 27 |
| 10 | sulphonium salt (1.6)/[Ru(p-cymene)Cl2]2 (0.2)/L2 (0.25)/KF (2.0), MgCl2 (1.0) | (CF3)2CHOH/70 °C/11 h | 0 |
| 11 | sulphonium salt (1.6)/CuBr2 (0.3), [Ru(p-cymene)Cl2]2 (0.2)/L2 (0.25)/KF (2.0) | (CF3)2CHOH/70 °C/11 h | 18 |
| 12 | sulphonium salt (1.6)/CuBr2 (0.3), [Ru(p-cymene)Cl2]2 (0.2)/L2 (0.25)/KF (2.0), MgCl2 (1.0)/TEMPO (2.0) | (CF3)2CHOH/70 °C/11 h | 69 |
| 13 | sulphonium salt (1.6)/CuBr2 (0.3), [Ru(p-cymene)Cl2]2 (0.2)/L2 (0.25)/KF (2.0), MgCl2 (1.0)/TEMPO (3.0) | (CF3)2CHOH/70 °C/11 h | 55 |
| 14 | sulphonium salt (1.6)/CuBr2 (0.3), [Ru(p-cymene)Cl2]2 (0.2)/L2 (0.25)/KF (2.0), MgCl2 (1.0)—in dark | (CF3)2CHOH/70 °C/11 h | 86 |
a Isolated yield. b All reactions were conducted at room temperature in inert atmosphere.
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Mkrtchyan, S.; Jakubczyk, M.; Lanka, S.; Pittelkow, M.; Iaroshenko, V.O. Cu-Catalyzed Arylation of Bromo-Difluoro-Acetamides by Aryl Boronic Acids, Aryl Trialkoxysilanes and Dimethyl-Aryl-Sulfonium Salts: New Entries to Aromatic Amides. Molecules 2021, 26, 2957. https://doi.org/10.3390/molecules26102957
AMA Style
Mkrtchyan S, Jakubczyk M, Lanka S, Pittelkow M, Iaroshenko VO. Cu-Catalyzed Arylation of Bromo-Difluoro-Acetamides by Aryl Boronic Acids, Aryl Trialkoxysilanes and Dimethyl-Aryl-Sulfonium Salts: New Entries to Aromatic Amides. Molecules. 2021; 26(10):2957. https://doi.org/10.3390/molecules26102957
Chicago/Turabian StyleMkrtchyan, Satenik, Michał Jakubczyk, Suneel Lanka, Michael Pittelkow, and Viktor O. Iaroshenko. 2021. "Cu-Catalyzed Arylation of Bromo-Difluoro-Acetamides by Aryl Boronic Acids, Aryl Trialkoxysilanes and Dimethyl-Aryl-Sulfonium Salts: New Entries to Aromatic Amides" Molecules 26, no. 10: 2957. https://doi.org/10.3390/molecules26102957
