Palladium-Catalyzed Synthesis of 3-Trifluoromethyl-Substituted 1, 3

Letter pubs.acs.org/OrgLett

Palladium-Catalyzed Synthesis of 3‑Trifluoromethyl-Substituted 1,3Butadienes by Means of Directed C−H Bond Functionalization Qun Zhao, Vincent Tognetti, Laurent Joubert, Tatiana Besset, Xavier Pannecoucke, Jean-Philippe Bouillon,* and Thomas Poisson* Normandie Université, INSA Rouen, UNIROUEN, CNRS, COBRA (UMR 6014), 76000 Rouen, France S Supporting Information *

ABSTRACT: A palladium-catalyzed C−H bond functionalization of acrylamides was developed to build up stereoselectively trifluoromethylated 1,3-butadienes. Using a tertiary amide as a directing group, olefins were selectively functionalized with 2bromo-3,3,3-trifluoropropene to access these important fluorinated compounds. The methodology was extended to the construction of pentafluoroethyl-substituted 1,3-dienes. Mechanistic studies supported by density functional theory calculations suggested a redox neutral mechanism for this transformation.

F

Scheme 1. State of the Art and Present Work

luorinated molecules play an important role in the drug discovery process. Indeed, the unique properties of the fluorine atom,1 like its electronegativity and small size, along with the unique features of the C−F bond, give it a pivotal role in medicinal chemistry. As a consequence, a phalanx of marketed drugs bear at least one fluorine atom.2 Hence, the implementation of new transformations, the discovery of original reagents to introduce the fluorine atom or fluorinated groups, and the design of new fluorinated building blocks became an active field of research.3 As part of this blossoming research area, the introduction of the CF3 group received a lot of attention toward accessing important trifluoromethylated molecules.4 1,3-Butadienes are versatile building blocks in organic chemistry.5 This key synthetic unit is widely used to access more complex molecules through cycloaddition reactions,6 Ziegler−Natta polymerization,7 or conjugated addition,8 for instance. Moreover, this motif is widely found in natural products, particularly in retinoids.9 Quite surprisingly, the synthesis of fluorinated 1,3-butadienes and particularly the trifluoromethylated ones is scarcely depicted in the literature. In spite of the obvious advantage that this motif represents in the toolbox of fluorinated building blocks, their access remains underexplored (Scheme 1). Indeed, their synthesis relies on (1) a poorly stereoselective olefination reaction of trifluoromethyl ketones using phosphonium ylides or phosphonate-stabilized carbanions,10 (2) the dehydration of the 2-(trifluoromethyl)-2,3butanediol to synthesize the corresponding β-(trifluoromethyl)butadiene,11 (3) the Negishi cross-coupling reaction with vinyl halides,12 and (4) a unique example of decarboxylative trifluoromethylation of an α,β,γ,δ-unsaturated carboxylic acid.13 Therefore, the need to develop a stereoselective and efficient access to these building blocks appears as a matter of importance. As part of our ongoing research program devoted to the direct introduction of fluorinated building blocks14 and stimulated by recent progress dealing with the transition-metal-catalyzed C−H © 2017 American Chemical Society

bond functionalization of olefins to access 1,3-dienes,15 we report herein a stereoselective access to 3-trifluoromethylated-1,3butadienes. By using a palladium-catalyzed directed C−H bond functionalization of α-substituted acrylamides with 2-bromo3,3,3-trifluoropropene (BTP), an inexpensive and nonozone depleting fluorinated reagent,16 the first catalytic process to selectively synthesize the Z-trifluoromethylated 1,3-dienes was designed. At the outset of the study, we chose the α-phenyl-N,Ndiisopropylacrylamide 1a as a model substrate to find suitable reaction conditions (Table 1). Received: March 10, 2017 Published: April 5, 2017 2106

DOI: 10.1021/acs.orglett.7b00704 Org. Lett. 2017, 19, 2106−2109

Letter

Organic Letters Table 1. Optimization of the Reaction Conditionsa

entry

x

1 2 3 4 5c 6d 7e 8 9 10f 11 12 13 14

15 15 15 15 15 15 15 15 15 10 10 10 10 10

additive AgOTf AgBF4 AgSbF6 AgOTf AgOTf AgOTf AgOTf AgOTf AgOTf In(OTf)3 Bi(OTf)3 Sc(OTf)3 Yb(OTf)3

solvent

yieldb (%)

DMF DMF DMF DMF DMF DMF DMF DMA NMP DMI DMI DMI DMI DMI

45 30 30 NR 47 41 NR 66 60 76 (62)g 40 17 NR NR

Scheme 2. Substrate Scopea

a

Conditions: 1a (0.2 mmol), BTP (1 mmol), additive (0.3 mmol), solvent (2 mL), 120 °C, 16 h. bYields were determined by 19F NMR using α,α,α-trifluoroacetophenone as an internal standard. c2 equiv of PivOH was added. d2 equiv of TFA was added. e2 equiv of CsOPiv was added. f2 equiv of AgOTf was used. gIsolated yield. NR: no reaction.

Using Pd(acac)2 as a catalyst17 in the presence of AgOTf as an additive in DMF at 120 °C, we were delighted to observe the desired product 2a in 45% NMR yield as a single Z stereoisomer without traces of homocoupling product (Table 1, entry 1).18 This result demonstrated the effectiveness of the N,Ndiisopropyl group as a directing group.19 Then a survey of Ag salts revealed that AgOTf was the best additive for this reaction, and its presence was crucial to convert 1a into 2a since in its absence no reaction occurred (entries 2−4). Interestingly, the addition of acids, such as PivOH or TFA, did not affect the reaction outcome (entries 5 and 6), while the addition of a base (CsOPiv) suppressed the reaction (entry 7). The solvent of the reaction was found to be an important parameter, and among the polar aprotic solvents tested (entries 1, 8−10), DMI (1,3dimethyl-2-imidazolidinone) was the best one. The desired product 2a was isolated in 62% yield using a decreased amount of Pd(acac)2 in the presence of 2 equiv of AgOTf. (entry 10). Finally, to gain more insight into the role displayed by AgOTf, several other additives and particularly Lewis acids were tested (entries 11−14). Interestingly, In(OTf)3 and Bi(OTf)3 were prompted to promote the reaction (entries 11 and 12), albeit in lower yields than AgOTf. These results precluded the use of AgOTf as an oxidant in the course of the reaction. Having set up the optimized reaction conditions, we turned our attention to the extension of the substrate scope of the reaction (Scheme 2). First, acrylamides bearing halogenated arenes at the α-position were tested. Pleasingly, fluorine, chlorine, and even bromine substituents were well tolerated, giving the corresponding 1,3-dienes (2b−f) in good yields as a single diastereoisomer. α-Methoxy-substituted aryl acrylamides 1g and 1h were also used as substrates, and the targeted dienes 2g and 2h were isolated in moderate to good yields. We found that α-naphthyl- and even α-thienyl-substituted acrylamides were suitable substrates to access the trifluoromethylated butadienes 2i and 2j.

a

Conditions: 1 (0.2 mmol), BTP (1 mmol), AgOTf (0.4 mmol), DMI (2 mL), 120 °C, 2 h, isolated yields provided. bYields determined by 19 F NMR using α,α,α-trifluoroacetophenone as an internal standard. c Reaction was performed on a 4 mmol scale. dReaction was carried out under an air atmosphere.

Note that simple acrylamide 1k, as well as β-substituted ones (1l and 1m), furnished the corresponding trifluoromethylated 1,3-dienes, albeit in lower yields. Interestingly, these substrates furnished the opposite stereoisomer with regard to the α-arylsubstituted acrylamides. We assume that this reverse stereoselectivity could arise from an in situ palladium-catalyzed isomerization of the products.20 Finally, in order to demonstrate the synthetic utility of our process, the reaction was carried out on a 4 mmol scale using 1a as a starting material. The 1,3butadiene 2a was isolated in a 55% yield. Pleasingly, this transformation was not sensitive to an air atmosphere since a similar yield was obtained. We then extended the methodology toward the introduction of the pentafluoroethyl analogue of the BTP (Scheme 3). By using similar reaction conditions, the reaction of 2-bromo3,3,4,4,4-pentafluorobutene 3 with α-aryl-acrylamides was performed. Acrylamides 1a,c,f,h,i were tested to give the corresponding pentafluoroethylated dienes 4a−e in somewhat lower yields compared with the reaction carried out with BTP. Note that the stereochemistry of the diene 4e was unambiguously assigned through X-ray crystallographic analysis.21 Even though the reaction yields remained moderate, this process represents the unique access to this class of perfluorinated 1,3-dienes to date. 2107

DOI: 10.1021/acs.orglett.7b00704 Org. Lett. 2017, 19, 2106−2109

Letter

Organic Letters

Scheme 5. Proposed Mechanism and DFT Calculationsa

Scheme 3. Extension to the Introduction of the 3,3,4,4,4Pentafluorobuten-2-yl Motifa

a

Conditions: 1 (0.2 mmol), 3 (1 mmol), AgOTf (0.4 mmol), DMI (2 mL), 140 °C, 2 h, isolated yields provided. bYields determined by 19F NMR using α,α,α-trifluoroacetophenone as an internal standard.

To gain insight into this transformation, we conducted mechanistic studies (Scheme 4). We first studied the kinetic Scheme 4. Mechanistic Studies

a

Standard Gibbs energy profile (kcal·mol−1).

Lewis acids in the course of the optimization study (Table 1). Note that according to these calculations and the observed KIE, the carbopalladation step can be considered as the ratedetermining step of this transformation. Another plausible reaction pathway relied on the oxidative addition of the organopalladium species A onto the C−Br bond of the BTP. However, DFT calculations revealed that the formation of the Pd(IV) intermediate D is unlikely.21 Indeed, the intermediate D, resulting from an endothermic oxidative addition, is much higher in energy than the species C resulting from the carbopalladation reaction (ca. 25.5 kcal·mol−1 with respect to C). Therefore, according to DFT calculations, a Pd(II)/Pd(IV) mechanism can be ruled out in favor of a redoxneutral Pd(II)/Pd(II) pathway. In summary, we developed a straightforward and stereoselective access to trifluoromethylated 1,3-dienes by using a palladium-catalyzed C−H bond functionalization of acrylamides using BTP as an inexpensive coupling partner. The reaction proceeded well and was applied to a broad range of substrates. In addition, the reaction was extended to the introduction of the 3,3,4,4,4-pentafluorobuten-2-yl motif. A plausible mechanism involving a redox neutral process was suggested as supported by mechanistic experiments and DFT calculations.

isotopic effect (KIE). An initial set of experiments showed that no H/D scrambling occurred when 1a was reacted in DMF-d7 under the standard reaction conditions without BTP.21 A similar result was obtained with [D]-1a when it was reacted in DMF.21 Then parallel reactions revealed a KIE = 1.1. This result suggested that the C−H bond activation is not the ratedetermining step of the transformation. Finally, we attempted to extend the reaction to 2-bromopropene as a coupling partner. Interestingly, under the standard reaction conditions, no trace of product was detected in the reaction media. This result clearly points out the strong influence of the fluorinated group on the olefin, the so-called “fluorine effect”.22 Thus, we proposed the following mechanism for this transformation, supported by DFT calculations at the M06-L/ 6-311+G(d)-SDD level of theory (Scheme 5).21 First, we assumed the formation of the palladacycle intermediate A, where the metal is coordinated to the oxygen atom of the carbonyl group, as supported by calculations. Then, A coordinated to BTP to form intermediate B. Subsequently, B underwent a carbopalladation reaction leading to the organopalladium intermediate C according to an exothermic process and an activation energy (ca. 25 kcal·mol−1) consistent with the experimental data. Finally, the final product 2 was released according to a bromide elimination step favored by the Ag salt.23 The role of the Ag salt was supported by the efficiency of other

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00704. 2108

DOI: 10.1021/acs.orglett.7b00704 Org. Lett. 2017, 19, 2106−2109

Letter

Organic Letters

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Procedures; characterization data; 1H, 13C, and 19F NMR spectra; characterization data for the X-ray crystal structure of 4e; computational details, views, and Cartesian coordinates of optimized complexes; discussion about DFT results (PDF) X-ray data for compound 4e (CIF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Thomas Poisson: 0000-0002-0503-9620 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by INSA Rouen, Rouen University, CNRS, EFRD, Labex SynOrg (ANR-11-LABX0029), and the Région Normandie (Crunch Network). Q.Z. thanks the China Scholarship Council (CSC) for a doctoral fellowship.

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DOI: 10.1021/acs.orglett.7b00704 Org. Lett. 2017, 19, 2106−2109