Letter pubs.acs.org/acscatalysis
Access to Difluoromethylene-Skipped 1,4-Diynes with gemDifluoropropargyl Bromide Wen-Hao Guo,† Zhi-Ji Luo,† Wenbin Zeng,‡ and Xingang Zhang*,† †
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China ‡ School of Pharmaceutical Sciences, Central South University, Changsha 410013, China S Supporting Information *
ABSTRACT: Difluoromethylene (CF2)-skipped 1,4-diynes are a versatile synthon in organic synthesis, but efficient methods to access such a fluorinated structural motif are very limited. Herein, we report an efficient method for catalytic synthesis of CF2skipped 1,4-diynes through palladium-catalyzed cross-coupling between terminal alkynes and gem-difluoropropargyl bromide. The reaction exhibits high functional group tolerance and broad substrate scope. Applications of the method led to a series of important difluorinated molecules that are of interest in medicinal chemistry. KEYWORDS: alkynes, cross-coupling, 1,4-diynes, gem-difluoropropargyl bromide, palladium
Scheme 1. Strategies for the Synthesis of CF2-Skipped 1,4Diynes
1,4-Diynes are a valuable and versatile synthon in natural product, organometallic complex, and novel molecules synthesis.1 Theoretically, the replacement of the methylene group (CH2) that connects two triple bonds by its difluorinated counterpart (CF2) can stabilize 1,4-diynes due to the tautomeric instability of CH2-bridged diynes, which are prone to generation of allenynes and polymerization.2 Particularly, owing to the unique property of CF2,3 the CF2-skipped 1,4diynes can lead to the discovery of new and interesting molecules in medicinal chemistry and materials science. For instance, the resulting difluorinated natural products from the CF2-skipped 1,4-diynes showed significant hydrolytic stability without loss of the biological activity.4 Furthermore, some of the difluorinated natural products derived from such a structural motif can also serve as probes in the drug discovery and development.5 However, efficient methods to access CF2skipped 1,4-diynes are very limited. To date, only two examples have been reported.6 One is based on the reaction of alkynyl lithiums with gem-difluoropropargyl iodide (Scheme 1a);4,6a the other is through an SN2′ reaction between γ-bromodifluoroallenes and alkynyl lithium (Scheme 1b).6b However, the limited substrate scope, requirement of alkynyl lithiums, and poor important functional group tolerance significantly restrict their wide applications in organic synthesis. To address these issues, a transition-metal-catalyzed cross-coupling between alkynes and readily available gem-difluoropropargyl bromide would be an attractive alternative (Scheme 1c). Although, Sonogashira cross-coupling has been well-established,7 the use of fluoroalkyl halides as coupling partners © XXXX American Chemical Society
through such a process has not been reported thus far. This is because many of the fluoroalkyl halides (Rf−X) are prone to generation of fluoroalkyl radicals via a single-electron transfer (SET) pathway in the presence of low valent transition metals, which can readily react with alkynes to produce the fluoroalkylated alkenes. 8 As a result, the synthesis of fluoroalkylated alkynes require additional steps to prepare prefunctionalized alkynes,6,9 such as alkynyl metal reagents Received: November 12, 2016 Revised: December 16, 2016
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ACS Catalysis (alkynyl−M, M = Li, Cu),6,9a−c alkynyl halides,9d,e or alkynyl hipervalent iodides.9f−h An alternative route is to use oxidative cross-coupling between alkynes and fluoroalkylated nucleophiles,10 but such a strategy is not suitable for the preparation of CF2-skipped 1,4-diynes. As part of a systematic study on transition-metal-catalyzed fluoroalkylations,11 herein, we describe an efficient palladium-catalyzed difluoroalkylation reaction between alkynes and gem-difluoropropargyl bromide. The reaction enables a variety of alkynes to furnish the unsymmetrical CF2-skipped 1,4-diynes under mild reaction conditions with high efficiency and high functional group tolerance. Initially, our studies focus on the copper-catalyzed crosscoupling between phenylacetylene 1a and readily available gemdifluoropropargyl bromide 2.4,6b Although copper-catalyzed propargylation of alkynes is an efficient reaction to access skipped 1,4-diynes,1a no desired product 3a was observed through this reaction; even stoichiometric amount of copper salt was used (for details, see the Supporting Information). The addition of palladium catalyst benefited the reaction, and a 6% yield of CF2-skipped 1,4-diyne 3a was provided when the reaction was carried out with Pd(OAc)2 (5 mol %) and bulky ligand Ad2P(n-Bu)·HI (L1) in the presence of CuI (7.5 mol %) and K2CO3 in dioxane at 80 °C (Table 1, entry 1).
optimizing the reaction conditions showed that the use of triotolyphosphine [P(o-Tol)3, L2] could suppress the defluorination side reactions, although only 35% yield of 3a was obtained along with starting material 2 (45% yield) and side product 4a12 (14% yield) (entry 3). Encouraged by these results, a survey of the reaction parameters was conducted (entries 4−7, for details, see the Supporting Information). It was found that the palladium catalyst, solvent, and the ratio of [Pd]/L2 are critical for the reaction efficiency. A 65% yield of 3a was provided when the reaction was carried out with Pd2(dba)3· CHCl3 (2.5 mol %) and L2 (20 mol %) in toluene (entry 7). However, 4a was still obtained in 29% yield. Considering that the formation of 4a is a three-component reaction and low reaction concentration would decrease the yield of 4a, a diluted reaction was performed, providing 3a in 84% yield upon isolation (entry 8). The absence of either palladium or phosphane ligand led to no product (entries 9 and 10), thus demonstrating the essential role of palladium catalyst in promotion of the reaction. To ascertain the substrate scope of this method, a variety of aromatic terminal alkynes 1 were examined (Table 2). Generally, the electronic nature of substituents on the aromatic ring did not interfere with the reaction efficiency. Substrates 1 bearing either electron-rich or electron-deficient substituents all provided the corresponding CF2-skipped 1,4-diynes 3 in good to high yields. It should be mentioned that the ortho-substituted aromatic alkynes afforded relatively higher yields than other substrates and only small amount of side products 4 were observed (3b, 3d, 3i, 3r, 3u, and 3v). This is probably because the steric hindrance of ortho-substituents suppress the insertion of gem-difluoropropargyl palladium complex (BrPdCF2CCTips) into the carbon−carbon triple bond of alkynes 1, thus decreasing the formation of 4. The current process exhibits high functional group tolerance to a variety of versatile synthetic handles, including base- and nucleophilesensitive moieties such as esters, formyl, nitro, and cyano, and other groups such as fluoride and chloride (3j−3t). Remarkably, a vinyl-containing substrate was also viable in the reaction without observation of Heck-type side products (3u). In light of the importance of the enediyne motif in organic synthesis, such a transformation is highly relevant for the complex fluorinated molecules synthesis. Furthermore, heterocycles, such as thiochromane and thiophene, underwent the reaction smoothly and provided 3x−3z in good yields. To demonstrate the generality of this method further, other terminal alkynes 5 were also investigated (Table 3). Conjugated and silyl-substituted alkynes furnished the corresponding CF2skipped 1,4-diynes 6 with good to high yields (6a, 6c, and 6d). Importantly, the unsymmetrical silyl-substituted 1,4-diynes 6c and 6d provides a good platform for downstream transformation through selective deprotection of silyl groups. The aliphatic terminal alkynes were also amenable to the reaction with [Pd(allyl)Cl]2 as a catalyst and L1 as a ligand (6e−6i). Although moderate yields of 6e−6i were obtained, the current process remains useful for medicinal chemistry. For instance, ethynodiol diacetate can be readily gem-difluoropropargylated through this method (6j), thus demonstrating the potential utility of this protocol in drug discovery and development. However, the aryl substituted gem-difluoropropargyl bromides were not suitable substrates and will be addressed in the future. The importance and utility of this protocol have also been highlighted by the transformation of CF2-skipped 1,4-diynes to a variety of difluoromethylenated molecules. As shown in
Table 1. Representative Results for Optimization of PdCatalyzed Cross-Coupling of 1a with 2a
entry
[Pd]
base (x)
solvent
yield (%)b 3a/ 4a
1c,d 2d 3e 4e 5f 6 7 8g 9g 10g,h
Pd(OAc)2 [Pd(allyl)Cl]2 [Pd(allyl)Cl]2 Pd2(dba)3·CHCl3 Pd2(dba)3·CHCl3 Pd2(dba)3·CHCl3 Pd2(dba)3·CHCl3 Pd2(dba)3·CHCl3 none Pd2(dba)3·CHCl3
K2CO3 (2.0) Cs2CO3 (3.5) Cs2CO3 (3.5) Cs2CO3 (3.5) Cs2CO3 (3.5) Cs2CO3 (3.5) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0)
dioxane CYH CYH CYH CYH CYH toluene toluene toluene toluene
6/0 55/0 35/14 42/23 46/25 57/29 65/29 (84)/12 nr/nr nr/nr
a
Reaction conditions (unless otherwise specified): 1a (1.5 equiv), 2 (0.2 mmol, 1.0 equiv), L2 (20 mol %), solvent (2.0 mL). bDetermined by 19F NMR using fluorobenzene as an internal standard, and the number in parentheses is isolated yield. c7.5 mol % of CuI was used. d5 mol % of L1 was used. e5 mol % of L2 was used. f10 mol % of L2 was used. g8.0 mL of toluene was used. hReaction run in the absence of L2. CYH, cyclohexane.
Interestingly, the absence of copper species with [Pd(allyl)Cl]2 as a catalyst and Cs2CO3 as a base could improve the yield of 3a to 55% (entry 2). However, the gem-difluoropropargyl bromide was totally consumed under these reaction conditions, and except for 3a, no other fluorine signal was observed by 19F NMR, thus implying that certain of fluorinated species generated during the reaction process were instable and prone to decomposition via a defluorination pathway. Further 897
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Table 2. Palladium-Catalyzed Cross-Coupling of Aromatic Terminal Alkynes 1 with gem-Difluoropropargyl Bromide 2a
a
Reaction conditions (unless otherwise specified): 1 (1.5 equiv), 2 (0.3 mmol, 1.0 equiv), toluene (9.0 mL), 24 h. bReaction run at 100 °C.
(Scheme 2d).14,16 Because heterocycles are a vital structural motif found in numerous pharmaceuticals, the current transformation provides a facile route for applications in medicinal chemistry. To get some mechanistic insights into the current process, a series of experiments were conducted. Previously, we found that a SET pathway that proceeded via a difluoroalkyl radical was involved in the oxidative step between Pd(0)Ln and difluoroalkyl bromides (R2CF2Br, R2 = PO(OEt)2, CO2Et, (Het)Ar).11a,17 To probe whether a gem-difluoropropargyl radical existed in the current process, we performed several radical inhibition experiments. It was found that no decreased yields of 3a were observed when a radical scavenger (TEMPO), radical inhibitors (hydroquinone or BHT), or an electrontransfer inhibitor (1,4-dinitrobenzene) was added to the
Scheme 2a, hydrogenation of 3k with Lindlar catalyst led to a new useful building block enyne with high efficiency.13 Considering that CF2-skipped 1,4-dienes have been used as probes in life science,5 compound 8 was efficiently prepared from 6g in 3 steps, thus demonstrating the utility of this technique in medicinal chemistry (Scheme 2b). Compounds 3 or 6 can also serve as versatile building blocks to construct difluorinated heteroarenes. For instance, the difluorinated isoxazole 9 can be readily prepared through [3 + 2] cyclization,14 which subsequently underwent ring-opening via N−O bond cleavage15 afforded another useful fluorinated structure β-enaminoketone 10 in high yield (Scheme 2c). Most remarkably, the unsymmetrical, CF2-skipped diheteroarenes 12 could also be efficiently constructed through selective deprotection of silyl group from 6c, followed by cyclization 898
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ACS Catalysis Table 3. Palladium Catalysis of Other Terminal Alkynes 5 with gem-Difluoropropargyl Bromide 2a
a
Reaction conditions (unless otherwise specified): 5 (1.5 equiv), 2 (0.3 mmol, 1.0 equiv), toluene (9.0 mL), 24 h. b[Pd(allyl)Cl]2 (2.5 mol %), L1 (5 mol %), Cs2CO3 (3.5 equiv), toluene (4.0 mL), 36 h.
Scheme 2. Transformations of CF2-Skipped 1,4-Diynes
indicate that the possibility of a free gem-difluoropropargyl radical involved in the catalytic cycle is less likely. To study the
reaction of 1a with 2 under standard reaction conditions (for details, see the Supporting Information). Thus, these findings 899
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ACS Catalysis Scheme 3. Mechanistic Studies
Scheme 4. Proposed Reaction Mechanism
competitive reaction through insertion of BrPd-CF2CCTIPS bond into the carbon−carbon triple bond can also be occurred to generate palladium complex C. Subsequently, C reacts with terminal alkynes to deliver intermediate D, which affords the side products 4 upon reductive elimination (Path II).18 In this cycle, the steric substituents on the terminal alkynes 1 or 5 can significantly decrease the formation of C, which may be the possible reason for ortho-substituted aromatic terminal alkynes providing relatively higher yields of CF2-skipped 1,4-diynes than other substrates. In conclusion, we have developed a first example of catalytic synthesis of CF2-skipped 1,4-diynes through palladiumcatalyzed cross-coupling between terminal alkynes and gemdifluoropropargyl bromide. The reaction allows a variety of terminal alkynes with high efficiency and functional group tolerance. Most of these target molecules were previously unknown19 and should become versatile building blocks in organic synthesis and medicinal chemistry. Mechanistic studies reveal that a gem-difluoropropargyl radical involved in the reaction is less likely, which is in sharp contrast to other
reaction mechanism further, the reaction of 2 with Pd(PPh3)4 was conducted and provided gem-difluoropropargyl palladium complex [TIPSCCCF2Pd(PPh3)2Br] (A1) with high yield (90%) (Scheme 3a). Treatment of A1 with triethyl(ethynyl)silane 5d could produce the CF2-skipped-1,4-diyne 6d with good yield (Scheme 3b). A1 could also be used as a catalyst to furnish the product 6d (Scheme 3c). Thus, these results demonstrate that the gem-difluoropropargyl palladium complex A is the key intermediate in the catalytic cycle, and the addition of gem-difluoropropargyl radical to the terminal alkynes, followed by recombination of Pd(I)Ln with the newly formed alkenyl radical E (Path III) illustrated in Scheme 4 is less likely. On the basis of these results and previous reports,7 a plausible reaction mechanism is proposed (Scheme 4). The reaction is initiated by the oxidative addition of gemdifluoropropargyl bromide to Pd(0)Ln. Subsequently, the resulting gem-difluoropropargyl palladium complex A reacts with terminal alkynes to generate key intermediate B, which undergoes reductive elimination to produce the final product and regenerates Pd(0)Ln simultaneously (Path I). Meanwhile, a 900
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Y.; Wu, Y.; Wu, Y. Adv. Synth. Catal. 2016, 358, 1699−1704. (h) Ivanova, M. V.; Bayle, A.; Besset, T.; Poisson, T.; Pannecoucke, X. Angew. Chem., Int. Ed. 2015, 54, 13406−13410. (10) Zhu, S.-Q.; Xu, X.-H.; Qing, F.-L. Org. Chem. Front. 2015, 2, 1022−1025. (11) (a) Feng, Z.; Min, Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X. Angew. Chem., Int. Ed. 2014, 53, 1669−1673. (b) Xiao, Y.-L.; Guo, W.H.; He, G.-Z.; Pan, Q.; Zhang, X. Angew. Chem., Int. Ed. 2014, 53, 9909−9913. (c) Min, Q.-Q.; Yin, Z.; Feng, Z.; Guo, W.-H.; Zhang, X. J. Am. Chem. Soc. 2014, 136, 1230−1233. (12) Compound 4a is not stable, and its structure is assigned by the characterization of compound 4o, see Supporting Information. (13) For the related synthesis of skipped 1,4-ene-ynes, see: Okusu, S.; Okazaki, H.; Tokunaga, E.; Soloshonok, V. A.; Shibata, N. Angew. Chem., Int. Ed. 2016, 55, 6744−6748. (14) Jawalekar, A. M.; Reubsaet, E.; Rutjes, F. P. J. T.; van Delft, F. L. Chem. Commun. 2011, 47, 3198−3200. (15) Koyama, Y.; Matsumura, T.; Yui, T.; Ishitani, O.; Takata, T. Org. Lett. 2013, 15, 4686−4689. (16) (a) Liu, J.; Fang, Z.; Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem., Int. Ed. 2013, 52, 6953−6957. (b) Gao, M.; He, C.; Chen, H.; Bai, R.; Cheng, B.; Lei, A. Angew. Chem., Int. Ed. 2013, 52, 6958−6961. (17) (a) Feng, Z.; Min, Q.-Q.; Zhao, H.-Y.; Gu, J.-W.; Zhang, X. Angew. Chem., Int. Ed. 2015, 54, 1270−1274. (b) Feng, Z.; Min, Q.-Q.; Zhang, X. Synthesis 2015, 47, 2912−2923. (18) Roberts, G. M.; Lu, W.; Woo, L. K. RSC Adv. 2015, 5, 18960− 18971. (19) The CF2-skipped 1,4-diynes are stable under open air for several months and can be purified by silica gel chromatography.
difluoroalkyl bromides, thus opening a new view to understand fluoroalkyl halides based fluoroalkylation reactions. Further studies to develop derivative reactions and their applications are under way in our laboratory and will be reported in due course.
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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/acscatal.6b03216. Detailed experimental procedures, and characterization data for new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xingang Zhang: 0000-0002-4406-6533 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was financially supported by the National Basic Research Program of China (973 Program) (No. 2015CB931900), the Strategic Priority Research Program of the Chinese Academy of Sciences (No. XDB20000000), the National Natural Science Foundation of China (No. 21425208, 21672238, 21332010, and 21421002), and SIOC.
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