Letter pubs.acs.org/acscatalysis
Copper-Catalyzed Functionalized Tertiary-Alkylative Sonogashira Type Couplings via Copper Acetylide at Room Temperature Yu Yamane, Naoki Miwa, and Takashi Nishikata* Graduate School of Science and Engineering, Yamaguchi University, Ube, Yamaguchi 755-8611, Japan S Supporting Information *
ABSTRACT: There are several reports on Sonogashira couplings, but most of the reported reactions have employed aryl or alkenyl halides as coupling partners. Therefore, Sonogashira coupling is unsuitable for alkyl loadings, especially tertiary alkyl groups. In this research, we found that a copper catalyst is effective for a reaction between a terminal alkyne and an α-bromocarbonyl compound to form a quaternary carbon having alkynyl group at room temperature. Control experiments revealed that a copper acetylide is a key intermediate. KEYWORDS: Sonogashira couplings, copper catalyst, quaternary carbons problematic.5,6 Li’s group recently reported light-mediated tert-alkylative couplings with terminal alkynes and unfunctionalized alkyl iodides, but yields were low.7 An electrophilic alkynylation is one of the best options for obtaining tertalkylated alkynes, but reactive iodonium salts, which are not convenient (compared with terminal alkynes), are required (Scheme 1B).8,9 Alkynyl metal reagents react with αbromocarbonyls, but tertiary-alkyl bromides cannot be employed (Scheme 1C).10,11 In this context, we try to develop a tert-alkylative Sonogashira-type reaction using a terminal alkyne and an α-bromocarbonyl compound that is a functionalized tert-alkyl precursor in the presence of a copper catalyst (Scheme 1D). The resulting compounds in this method can easily transform into various derivatives possessing quaternary carbon centers, where many possible manipulations can be applied to the carbonyl and alkyne functionalities. Recently, we have prepared quaternary carbon centers using an α-bromocarbonyl compound and olefins or heteroatoms in the presence of a copper catalyst via radical reactions.12 During the study, we obtained a Sonogashira-type product from the reaction of an α-bromocarbonyl compound and a terminal alkyne via a radical reaction (Scheme 2). One of the difficulties in establishing this coupling reaction is the competing atomtransfer radical addition (ATRA) onto the triple bond,12d,13,14 which affords alkenyl bromides as a product. However, the result shown in Scheme 2 encouraged us to develop the tertalkylative Sonogashira-type coupling reaction, in which Sonogashira-type coupling occurred as a side reaction. At the first stage, we expected the radical reaction of αbromocarbonyl compound 1 and terminal alkyne 2. The reaction did not occur without the ligand, a base, or Cu salt (Table 1, Run 1); thus, various multidentate nitrogen ligands
A
substituted alkyne is undoubtedly a useful functional group for organic synthesis and is synthesized by classical methods1 or Sonogashira coupling.2 Sonogashira coupling is a facile reaction for coupling between a terminal alkyne and an aryl or 1-alkenyl halide in the presence of Pd and Cu catalysts. Although 40 years have passed since this coupling was discovered in 1975,3 Sonogashira coupling with tert-alkyl halides remains a challenge to be overcome (Scheme 1A).4 This is because oxidative addition of a metal to a Csp3−Br bond to generate an alkyl-metal intermediate with β-hydrogen elimination of the resulting alkyl-metal intermediate is Scheme 1. Alkynyl Group Loadings
Received: August 4, 2017 Revised: August 24, 2017
© XXXX American Chemical Society
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ACS Catalysis Table 2. Substituents Effect of 1a
Scheme 2. Preliminary Results
such as TPMA (tris(2-pyridylmethyl)amine), PMDETA (N,N,N′N″,N″-pentamethyldiethylenetriamine), and Me6TREN (tris[2-(dimethylamino)ethyl]amine), which are very effective for radical reactions, were used as ligands for copper salts.15 However, selectivities were not changed, and ATRA predominated (Runs 2−4). On the contrary, when a bidentate ligand, 1,10-phen (1,10-phenanthroline), was used instead of multidentate nitrogen ligands, Sonogashira coupling predominated over the ATRA reaction (Run 5). Compared with multidentate nitrogen ligands, bidentate nitrogen ligands are not generally effective for smooth radical reactions.15 Bertrand described that the triple bond is protected in σ,πbis(copper)acetylide generated from the reaction of a terminal alkyne and a Cu salt, which retards addition to the alkyne.16 Perhaps, σ,π-bis(copper)acetylide species, which suppress ATRA, might be generated in our reaction. After further careful optimization including the use of various additives and bases, it was found that the use of two equivalents of Cs2CO3 improved the yield (Run 6). These conditions are very reliable. For example, when we carried out gram scale synthesis of 3a (see SI), 1 g of 3a (81% yield) was obtained. The reason for the best Cu/ligand ratio (1:2) is unclear, but the formation of active Cu complex may require excess ligand. We also tried TMEDA and bpy as a ligand, but those were not effective. Notably, 10 mol % catalyst was needed to obtain good yield of the product, and the decreasing amounts of catalyst were not effective even at high temperature. The reactivities of substituted α-bromoamides 1 were examined under the optimized reaction conditions (Table 2). The scope of substituents on an amide group is very broad. For example, 3 possessing aryl ether (3b), ester (3c), a C-halogen bond (3c, 3d), multiple bonds (3e, 3f), heterocycles including sulfur, oxygen, or nitrogen (3f, 3g, 3h, 3i), nitrile (3l), and other carbon functional groups (3j, 3k) were obtained in yields ranging from 58% to 86%. Although products 3 possessing an aliphatic group substituted amide had a low yields of products
a
Conducted at rt for 24 h in toluene with 10 mol % CuBr, 1,10-Phen (20 mol %), Cs2CO3 (2.0 equiv), 1 (0.50 mmol, 1 equiv), and 2a (1.5 equiv). All yields were isolated. bNaOH was used instead of Cs2CO3.
(3g−3l) under the optimal conditions. Adding NaOH instead of Cs2CO3, or heating, was effective in increasing the yields (3g, 3j, 3l, 3r, 3t). Interestingly, boryl substituted α-bromoamide 1m produced the corresponding alkynylated product 3m without loss of the boron−carbon bond, which is extremely active in a copper catalyst system.17 In this case, a side reaction was not observed, and the starting material was recovered. We also checked the reactivities of substrates 1 possessing various degrees of steric bulkiness at the carbonyl α-position (1n−1t). As a result, various lengths of alkyl chains showed good reactivities under the optimal or modified conditions. Steric bulkiness and functional groups in 1 did not affect the current coupling process, but α-bromoesters and ketones were not
Table 1. Ligand Effectsa
run
ligands
3a (%)
4a (%)
run
ligands
3a (%)
4a (%)
1 2 3
none TPMA PMDETA
0 trace trace
0 60 19
4 5 6b
Me6TREN 1,10-Phen 1,10-Phen
0 79 99(85)
10 0 0
a Conducted at rt for 24 h in toluene with 10 mol % CuBr, ligand (20 mol %), Cs2CO3 (1.5 equiv), 1a (0.50 mmol, 1 equiv), and 2a (1.5 equiv). Yields were determined by 1H NMR analysis. Isolated yield was shown in parentheses. b2 equiv of Cs2CO3 was used.
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ACS Catalysis reactive, which was probably due to the importance of the ligation of copper to the amide group during alkynylation at the carbonyl α-position. Loh and co-workers described the importance of the amide group in copper-catalyzed selective C−C bond formations.18 We next examined the reactivities of substituted alkynes 2b− 2p (Table 3). The reactions of para- or meta-substituted
Scheme 3. Transformations of 3
Table 3. Substituents effect of 2a
the synthesis of a multicycle compound possessing nitrogen atom. Terminal alkyne 7 was obtained via deprotection of 3hh followed by benzylation of 6. The resulting 7 was subjected to cycloaddition to produce 8 in 70% yield (Scheme 3C).20 Mechanistic study is still underway, but we have two possible mechanism in Figure 1. Path I is involving organocopper a
Conducted at rt for 24 h in toluene with 10 mol % CuBr, 1,10-Phen (20 mol %), Cs2CO3 (2.0 equiv), 1a (0.50 mmol, 1 equiv), and 2 (1.5 equiv). All yields were isolated. bCuI was used instead of CuBr. cNo ligand was used.
alkynes 2b−2e gave the product 3u−3x in moderate to good yields in the presence of CuBr or CuI as a catalyst. Basically, CuBr was the best catalyst, but CuI was also effective. The reaction of ortho-substituted alkynes 2f and 2g or electron-poor alkyne 2h resulted in low yields, which indicated that steric and electronic effects affects the generation of the product. Other alkynes including alkynes possessing halogen (2k, 2l), heterocycles (2i, 2j), or a C−C double bond (2m) can be applicable to this reaction, though long reaction time was required to obtain satisfactory yields. Although alkyl substituted alkyne (2n) was moderate yield in the presence or absence of the ligand, trimethylsilylacetylene 2o gave the product (3hh) in 79% yield. Alcohol substituted alkyne (2p) also reacted with 1a but OH group also coupled with 1a to give the complex product distribution. Overall, the reactivities were good under optimal or modified conditions. The rationale behind the attention given to the synthesis of α-alkynylamides 3 has been based, in part, on its potential to streamline routes toward challenging synthetic targets, including both quaternary carbons and nitrogen atoms (Scheme 3). For example, 3a can be transformed into pyrrolidone derivatives 5 via intramolecular Au-catalyzed amidation (Scheme 3A).19 When the reduction of 3a with LiAlH4 was carried out, trans-alkenylated amine (3a-Red) was obtained in good yield (Scheme 3B). 3hh is a good platform for
Figure 1. Proposed mechanism.
species: The reaction of CuX and alkyne 2 in the presence of a base could give copper acetylide A. It is well-known that A is easily generated from the reaction of CuI and alkyne in the presence of various bases.21The resulting A could react with 1 to generate 3; this probably occurs via a transient intermediate (B or C). We also suspected the generation of reactive aziridinone (α-lactam) from the reaction of 1 and a base. However, we have not detected such an intermediate.22 Furthermore, we checked the formation of Cu-amide complex from the reaction of 1a and stoichiometric amounts of Cu salt, but such a complex was not formed. Another possible mechanism is Path II involving ATRA process: The reaction starts with the generation of tertiary-alkyl radical species D from the reaction between CuI and 1. After the generation of D, ATRA intermediate E is obtained. Finally, 3 could be generated from the base-promoted E2 elimination.7a This catalytic cycle is partly reasonable but may not be the true 6874
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ACS Catalysis ORCID
mechanism because of two reasons; (1) Intermediate E was not obtained or detected under the best conditions using 1,10Phen. (2) When we used multidentate ligands shown in Table 1, intermediate E was obtained as the mixture of E and Z isomers (almost 1:1), and no E2 elimination product was detected. If intermediate E undergoes E2 elimination, the product 3 could be generated. We further investigated the possibility of Path I in Figure 1, and some control experiments were carried out (Scheme 4). A
Takashi Nishikata: 0000-0002-2659-4826 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We warmly thank the program to disseminate tenure tracking system, MEXT, Japan, Grant-in-Aid for Challenging Exploratory Research Grant No:16K13995, Yamaguchi university and the UBE foundation.
Scheme 4. Control Experiments
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did not react with 1a in the absence of 1,10-Phen as a ligand. However, A reacted with 1a to produce 3a (27%), and 1a (60%) was recovered in the presence of 1,10-phen (1 equiv) (Scheme 4, I). When the amount of ligand was increased (2 equiv), 48% of 3a and recovered 1a (50%) were obtained. In the presence of Cs2CO3 with 1,10-phen (2 equiv), 3a was quantitatively generated. We also used A as a catalyst in the reaction of 1a and 2a under the optimized conditions. As a result, 3a was obtained in 98% yield (Scheme 4, II). This result suggests that A is the key intermediate in this reaction. We also added TEMPO or BHT to these reaction mixtures, but the yields were not changed. This result implied that free-radical species may not be generated during the reaction. We do not have any proof of proposed intermediates (copper-stabilized alkyl radicals (B) and oxidative adduct of CuIII (C)), but the existence of B or C cannot be excluded. This type of transient intermediate has been proposed in copper-catalyzed reactions.23 Such a species could undergo rapid reductive elimination to form the carbon−carbon bond. In summary, we have developed Cu-catalyzed Sonogashiratype coupling of α-bromoamide to construct quaternary carbons via Path I, in which alkynylated copper is a key intermediate (Figure 1). This methodology is useful for synthesizing various congested alkynylated nitrogen compounds. Further investigations, including the asymmetric version of this reaction, will be reported by our group.
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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.7b02615. Experimental details and chemical compound information (PDF)
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REFERENCES
AUTHOR INFORMATION
Corresponding Author
*E-mail:
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