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DOI: 10.1055/s-0030-1260028
Inexpensive Copper/Iron-Cocatalyzed Reactions
Publication History
Publication Date:
06 May 2011 (online)
Abstract
Compared with other transition metals, copper and iron salts are inexpensive and stable to air and moisture. Moreover, iron is considered as an environmentally friendly catalyst. Due to these benign characteristics, both copper and iron catalysis have been extensively investigated. More recently, inexpensive copper/iron-cocatalyzed reactions have presented an attractive prospect for organic synthesis. This review presents recent progress in copper/iron-cocatalyzed arylation, alkynylation, C-H functionalization, and conjugate addition reactions.
1 Introduction
2 Arylation Reactions
2.1 C-N Bond Formation
2.2 C-O Bond Formation
2.3 C-S Bond Formation
2.4 Summary
3 Alkynylation Coupling Reactions
3.1 Sonogashira-Type Reactions
3.2 Glaser-Type Coupling
4 C-H Functionalization
5 Conjugate Addition Reactions
6 Conclusion
Key words
copper - iron - cocatalysis
1 Introduction
Transition-metal catalysis has played an important role in modern organic synthesis due to its high efficiency, applications in various transformations, and broad substrate tolerance. [¹] Compared with other noble metals, copper [²] and iron [²a] [³] are inexpensive, robust, and easy-to-handle for industrial applications. In addition, iron is abundant and considered as an environmentally friendly metal. Very recently, copper/iron-cocatalyzed reactions have attracted considerable attention; the potential applications in arylation, alkynylation, C-H functionalization, and conjugate addition reactions have been demonstrated and the activity of the reactions was shown to be improved by the bimetallic combination catalytic system. This review summarizes recent discoveries in this area. Although some plausible mechanisms have been proposed based on experimental data, the mechanistic relationship of iron/copper in various reactions is still uncertain and complicated.
Yijin Su (left) was born in Guangdong, China, in 1984. He received his Bachelors degree (2007) and Master’s degree (2009) (with Prof. Ning Jiao) at Peking University, Beijing. He is currently a second-year Ph.D. student in Professor Ning Jiao’s group at Peking University. Wei Jia was born in Beijing, China, in 1986. She received her Bachelor’s degree (2008) and Master’s degree (2010) (with Prof. Ning Jiao) at Peking University, Beijing. After graduation, she was recruited as a government employee. Ning Jiao (right) was born in Shandong, China, in 1976. He received his B.Sc. degree at Shandong University (1999), and Ph.D. degree (2004) (with Prof. Shengming Ma) at Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Science (CAS). He spent 2004-2006 as an Alexander von Humboldt postdoctoral fellow with Prof. Manfred T. Reetz at the Max Planck Institute für Kohlenforschung (MPI) (Germany). In 2007, he joined the faculty at Peking University as an Associate Professor, and was promoted to Full Professor in 2010. His current research efforts are focused on: (1) the development of green and efficient synthetic methodologies for the synthesis of heterocycles, bioactive molecules, and potential drugs; (2) radical reactions, and the activation of inert chemical bonds; (3) directed evolution of enzymes and protein hybrid catalysts.
2 Arylation Reactions
2.1 C-N Bond Formation
N-Arylation of various nitrogen nucleophiles has been one of a number of very useful protocols for C-N bond formation. [4]
In 2007, Taillefer and co-workers reported the first example of the iron/copper combination catalytic N-arylation reaction of various nitrogen heterocycles with aryl halides (Scheme [¹] ). [5] The reactions catalyzed by the iron or copper catalyst gave a very low yield or no reaction (0% or 4%) (Table [¹] , entries 1-6). In contrast, the yield of 1-phenyl-1H-pyrazole increased to 91% in the presence of both Fe(acac)3 and CuO as catalysts (Table [¹] , entry 8). It is noted that the presence of the acetylacetonate ligand and its precomplexation with iron are required for the high cocatalytic efficiency (Table [¹] , cf. entries 7 and 9). Moreover, the use of an iron(III) precatalyst appears to be essential for this transformation (Table [¹] , cf. entries 9 and 10). Note that there were no byproducts resulting from biaryl coupling or from the reduction of aryl halides.
Scheme 1 N-Arylation reaction cocatalyzed by copper and iron
| Entry | X | [Fe] (30 mol%) | [Cu] (10 mol%) | Yieldb (%) | |||||||||||||||
| 1 | Br, I | Fe(acac)3 | - | 0 | |||||||||||||||
| 2 | Br, I | FeCl3 | - | 0 | |||||||||||||||
| 3 | Br, I | - | CuI | 0 | |||||||||||||||
| 4 | Br, I | - | Cu(acac)2 | 0 | |||||||||||||||
| 5 | I | - | Cu | 0 | |||||||||||||||
| 6c | I | - | Cu + Cu(acac)2 | 4 | |||||||||||||||
| 7 | I | Fe(acac)3 | Cu | 100 | |||||||||||||||
| 8 | Br | Fe(acac)3 | CuO | 91 | |||||||||||||||
| 9 | I | FeCl3 | Cu(acac)2 | 30 | |||||||||||||||
| 10 | I | FeCl2 | Cu(acac)2 | 0 | |||||||||||||||
|
| |||||||||||||||||||
|
a Using: pyrazole
(1.5 equiv), iodo- or bromobenzene (PhX, 1 equiv), Cs2CO3 (2
equiv), DMF, 100 ˚C, 15 h. b Yields obtained by GC using 1,3-dimethoxybenzene as internal standard. c CuI/Cu(acac)2 = 1:1. | |||||||||||||||||||
The scope of the reaction is broad for a vast array of functional groups including various electron-withdrawing and -donating substituents on the aryl halides. Nitrogen heterocycles, such as azoles and cyclic amide derivatives, are also tolerated under these conditions. It is noteworthy that an activated aryl chloride reacted at 140 ˚C giving very encouraging results (Scheme [¹] ).
Wakharkar and co-workers [6] synthesized a double-layered hydrotalcite catalyst containing Cu-Fe from their corresponding nitrites, potassium hydroxide, and potassium carbonate. It is noteworthy that the Cu-Fe-hydrotalcite catalyst can be easily removed from the product simply by filtration and reused.
A wide range of primary aliphatic amines, arylamines, and indole were tolerated leading to N-arylation products in good to excellent yields. However, other nitrogen heterocycles such as imidazole, triazole, benzimidazole, and substituted indole derivatives did not work, which indicated the high selectivity of the catalyst towards primary amines. The good yield obtained in the reaction of 1-bromo-4-chlorobenzene implied the high chemoselectivity between bromide and chloride (Scheme [²] ).
Scheme 2 N-Arylation reaction reported by Wakharkar and co-workers
In 2008, Fu and co-workers developed a bimetallic catalyst FeCl3, CuO, and rac-BINOL that could promote the N-arylation of aliphatic amines and arylamines (Scheme [³] ). [7] A wide range of amines, such as primary and secondary aliphatic amines, arylamines, and nitrogen-containing heterocycles were compatible under the reaction conditions. The chemoselectivity was very high in the reactions of 1-chloro-4-iodobenzene and 1-bromo-4-iodobenzene with the retention of chloride or bromide, respectively (Scheme [³] ).
Scheme 3 N,O-Arylation reaction reported by Fu and co-workers
To meet the demands of convenient and rapid transformations, dedicated microwave reactors have been developed for many applications in organic synthesis. In 2010, Liu and co-workers reported a ligand-free iron/copper-cocatalyzed N-arylation reaction of various amines with aryl halides under microwave irradiation (Scheme [4] ). [8] The reaction time could be shortened to 30 minutes with moderate to good yields. As shown in Table [²] , the bimetallic combination of Fe2O3 and Cu(acac)2 gave the highest yield (83%) (Table [²] , entry 1). Using Fe2O3 alone was not able to promote the reaction (Table [²] , entry 2), and this indicated that the copper salt was important for the process; the presence of Cu(acac)2 alone gave the product in 62% yield (Table [²] , entry 3).
Scheme 4 N-Arylation reaction reported by Liu and co-workers
A wide range of functional groups were well-tolerated under these reaction conditions. Notably, ortho-substituted aryl iodides, such as 1-iodo-2-methoxybenzene and 1-(trifluoromethyl)-2-iodobenzene, underwent reaction, although in low yields. Because of the spatial steric effect, the results show the reactivity order of substituted aryl halides: para > meta > ortho (Scheme [4] ).
Recently, the scope was expanded to aqueous ammonia by Darcel and Wu. [9] The use of inexpensive iron and copper salts as cocatalysts, and easy-to-handle aqueous ammonia, makes this method attractive (Table [³] ). The reaction cocatalyzed by CuI and Fe(acac)3 or Fe2O3 showed very high efficiencies (90% and 100%; Table [³] , entries 3 and 4). In contrast, in the absence of an iron source, catalytic amounts of CuI afforded a moderate GC yield of aniline (30%; Table [³] , entry 2). Moreover, the use of iron salts alone as the catalyst gave almost no reaction (Table [³] , entries 1 and 5).
Scheme 5 N-Arylation reaction reported by Darcel and Wu
Under these optimized conditions, various anilines can be easily prepared in moderate to good yields (Scheme [5] ). The electronic effects on the reactivity were limited. Interestingly, the ortho-substituted aryl iodide, 2-iodoanisole, was efficiently converted into the desired product in 90% yield. In addition, 1-bromo-4-iodobenzene led selectively to the corresponding bromoaniline in good yield without detection of a diaminobenzene derivative. The good yields obtained in the reactions of 4-iodoaniline implied that there was good chemoselectivity between arylamine and aqueous ammonia.
The scope of this transformation has been expanded to aryl reagents other than aryl halides. A method for the solvent-free copper/iron-cocatalyzed N-arylation of nitrogen-containing heterocycles with trimethoxysilanes has been developed by Li and co-workers (Scheme [6] ). [¹0a] As described in Table [4] , when the reaction was carried out only with 40 mol% Cu or 40 mol% FeCl3, the yields were 61% and 60%, respectively (Table [4] , entries 1 and 2). The yield was enhanced to 81% in the presence of 1 mol% of Cu and 1 mol% of FeCl3 (Table [4] , entry 3), which revealed that both Cu and FeCl3 played a crucial role in the reaction.
Scheme 6 Scope and plausible mechanism of N-arylation reaction reported by Li and co-workers
The system was found to be general for the cross-coupling between various nitrogen-containing heterocycles and trimethoxysilanes. Unfortunately, the other silanes such as allyltrimethoxysilane and trimethyl(phenyl)silane did not proceed by this transformation to give the expected products. Based on the results obtained in their studies and the previously proposed mechanism, [³a] [¹0b] the authors proposed a modified mechanism for this transformation (Scheme [6] ). There are two possible pathways: (1) Trimethoxysilane reacts with tetrabutylammonium fluoride to form a pentavalent silicate intermediate 2, which undergoes transmetalation with intermediate 1, obtained from the coordination of the nitrogen atom with the catalyst [Cu(II) and/or Fe(III)], to generate intermediate 3. Then, reductive elimination of intermediate 3 takes place directly to give the target product 5 and a lower-valent species [Cu(0) and/or Fe(II)]. (2) Alternatively, the corresponding higher-oxidation-state intermediate 4 could be generated by the oxidation or disproportionation of intermediate 3 with the aid of an oxidant, which undergoes more efficient reductive elimination than intermediate 3. Subsequent reductive elimination leads to the expected product.
Scheme 7 O-Arylation reaction reported by Zhang and co-workers
2.2 C-O Bond Formation
It is well known that the Ullmann ether synthesis, in which a new C-O bond is formed, has played a significant role in the preparation of diaryl ethers and related derivatives. [²c] [¹¹] Although fewer publications have been reported for C-O than for the related C-N coupling reactions cocatalyzed by iron/copper, several significant works have been published recently.
A FeCl3/CuO-cocatalyzed O-arylation of phenols was disclosed by Fu and co-workers (Scheme [³] ). [8] The versatile and efficient iron/copper-cocatalyst can be widely used to build the (aryl)C-O(aryl) bonds from aryl iodides and bromides. Interestingly, although aryl bromides were slightly inferior substrates, the addition of two equivalents of potassium iodide to the reaction system improved the yields of the target products.
Another efficient iron/copper-cocatalyzed O-arylation of phenols was reported by Zhang and co-workers in 2010. [¹²] It is worthy of note that the catalytic loading is much lower than the above methods. Under these mild conditions, diaryl ethers were produced from bromoarenes in good to excellent yields (Scheme [7] ). Electron-rich, electron-poor, and hindered phenols underwent coupling with aryl bromides giving the corresponding diaryl ethers in good to excellent yields. The results demonstrate the reactivity order of aryl halides: iodide > bromide >> chloride. Furthermore, both electron-rich and electron-deficient aryl bromides perform well in the coupling reaction.
2.3 C-S Bond Formation
The metal-catalyzed formation of C-S bonds has been one of the most important tools in organosulfur chemistry. [¹³] With the development of copper/iron-cocatalyzed arylation reactions involving C-O and C-N formation, the iron/copper-cocatalyzed S-arylation of thiols with aryl halides was reported by Liu and co-workers (Scheme [8] ). [¹4] Without a copper source, FeCl3, Fe(acac)3, or Fe2O3 could not complete the reaction (Table [5] , entries 1-3). The other experiments in the absence of an iron salt but in the presence of Cu(acac)2 or Cu(OAc)2 afforded moderate yields of phenyl 4-tolyl sulfide (Table [5] , entries 5 and 6). Combined with Fe2O3 as cocatalyst, Cu(OAc)2 exhibited high efficiency giving phenyl 4-tolyl sulfide in 94% yield (Table [5] , entry 4).
Scheme 8 S-Arylation reaction reported by Liu and co-workers
It is outstanding that no undesired disulfide was observed as byproduct in these mild and practical transformations (air and moisture tolerant). A wide range of functional groups were well-tolerated under the reaction conditions.
2.4 Summary
From the above studies, it appears that aryl halides are the most used aryl reagents in copper/iron-cocatalyzed arylation reactions. In most studies, the results illustrated the reactivity order of aryl halides: iodides > bromides >> chlorides. ortho-Substituted aryl halides were deactivated, due to the strong steric effect. Generally, electron-withdrawing aryl halides are more efficient than those with electron-donating groups in these transformations. Both electronic and steric effects of nucleophiles are slighter than that of aryl halides in copper/iron-cocatalyzed arylation reactions. Organometallic compounds should be considered as an efficient alternative to aryl halides in future studies of these transformations.
3 Alkynylation Coupling Reactions
3.1 Sonogashira-Type Reactions
Sonogashira reactions constructing C(sp)-C(sp²) bond are widely used in organic synthesis. [¹5] Recently, several alkynylation coupling reactions catalyzed by inexpensive, readily available, nontoxic copper salts and iron salts have been reported. In 2008, Vogel and co-workers developed an efficient iron/copper-cocatalytic system for the C-C cross-coupling of aromatic iodides with terminal acetylenes (Scheme [9] ). [¹6] It is clear that both iron salt and copper salt play essential roles in this transformation (Table [6] ).
The scope of the reaction is broad with tolerance of functional groups including trifluoromethyl, cyano, nitro, methoxy, and bromo substituents. Unfortunately, aryl bromides and aryl chlorides do not give the desired products (Scheme [9] ).
Scheme 9 Alkynylation coupling reaction reported by Vogel and co-workers
The authors supposed that a possible role of the iron salt was to activate the oxidative addition of CuI, or Cu acetylide intermediate, onto aryl iodide by coordination to the iodo moiety of ArI. Alternatively, the activation could involve a SET (single electron transfer) from ArI to the iron(III) salt giving FeX3 - and the corresponding radical cation ArI+ that undergoes a faster oxidative addition than neutral ArI. The formation of the Ar-Cu(I)-acetylide intermediates might be preceded by the formation of Cu acetylides, or by addition of ArCuI to the terminal acetylenes, followed by base-induced HI elimination.
A similar approach to ligand-free iron/copper-cocatalyzed Sonogashira coupling was achieved by Mao and co-workers (Scheme [¹0] ). [¹7] The reaction of 4-iodoanisole with phenylacetylene in N,N-dimethylformamide catalyzed by only CuI produced the corresponding product, 1-(4-methoxyphenyl)-2-phenylacetylene in 42% yield, and the homocoupling product of alkyne was observed. CuI in combination with Fe(acac)3 led to obvious improvement to give the product in 68% yield without the generation of the homocoupling products of the alkynes, indicating that the iron catalyst could suppress the formation of the homocoupling byproduct. Moreover, this Fe/Cu catalytic system has been applied to the coupling reactions of iodobenzene with phenol and thiophenol leading to products with C-O or C-S bonds, respectively; under the optimized condition, the desired diphenyl ether and diphenyl sulfide were obtained in 92% and 97% yields, respectively. However, both of these reactions gave low efficiencies without the use of an iron catalyst. The scope of this transformation was found to be broad. Notably, aryl bromides coupled with phenylacetylene smoothly producing the corresponding products in moderate yields. The terminal aliphatic alkynes were also tolerated in this transformation (Scheme [¹0] ).
Scheme 10 Iron/copper-cocatalyzed coupling reactions reported by Mao and co-workers
Liu and co-workers reported a similar efficient iron/copper-cocatalyzed alkynylation of aryl iodides with various terminal alkynes (Scheme [¹¹] ). [¹8] As displayed in Table [7] , the reaction did not occur in the absence of a copper salt (Table [7] , entries 1 and 3), indicating that the nature of the copper source had a pronounced impact on this process. It is noteworthy that the reaction was very clean, without the formation of undesirable alkyne homocoupling products, which were usually generated in the presence of copper(I) catalysts.
Scheme 11 Alkynylation coupling reaction reported by Liu and co-workers
3.2 Glaser-Type Coupling
The Glaser coupling reaction is a synthetic approach for conjugated diynes and polyynes (linear or cyclic) from terminal alkynes in presence of copper salts. [¹9]
An efficient, environmentally friendly and economical method for homocoupling of terminal alkynes, using Fe(acac)3 and trace quantity of Cu(acac)2 as the cocatalyst and with air used as the oxidant, has been developed by Chen and co-workers (Scheme [¹²] ). [²0]
Scheme 12 Homocoupling reaction of terminal alkynes reported by Chen and co-workers
Both of aromatic and aliphatic acetylenes are efficient substrates for this transformation. Moreover, heterocyclic acetylenes execute the reaction efficiently to give moderate to good yields of homocoupling products. It should be noted that in this transformation, unprotected amino groups are tolerated. Generally, the Glaser coupling is not well-suited for the preparation of unsymmetrical diynes in the presence of a copper salt alone. [¹9] When an excess of another alkyne (5.0 equiv) was used, the cross-coupling product was obtained using this iron/copper-cocatalysis system in moderate to good yield (Scheme [¹³] ).
Scheme 13 Cross-coupling reaction of two different terminal alkynes reported by Chen and co-workers
Moreover, this iron/copper-catalytic system under nitrogen rather than air has been applied in the coupling reactions of iodobenzene with phenylacetylene leading largely to a Sonogashira-type reaction product with traces of the homocoupling product. The researchers found that ‘O 2 influenced the reaction strongly and the iron catalyst could suppress the homocoupling byproduct in the Sonogashira-type reaction under N 2 and also could enhance the homocoupling product in the homocoupling reaction of terminal alkynes under air.’ [²0]
4 C-H Functionalization
Compared with traditional methods, C-H functionalization presents an advantage of convenience and atom economy, which has been significantly developed in recent years. [²¹] Very recently, Zhang, Zhu and co-workers developed a direct intramolecular C-H amination reaction of 2-(arylamino)pyridines cocatalyzed by copper(II) and iron(III) leading to pyrido[1,2-a]benzimidazole derivatives. [²²] It is a novel direct C-H functionalization that use copper/iron-cocatalysis system instead of more expensive metal catalysts. The authors found that the palladium catalyst which has been widely used in C-H functionalization, was not needed in this transformation (Table [8] ). Although Cu(OAc)2 could catalyze this transformation (Table [8] , entry 3), the yield was efficiently improved by the addition of an iron salt as the cocatalyst (Table [8] , entry 4). Control experiments showed that iron salts themselves did not promote the reaction.
A copper(III)-catalyzed electrophilic aromatic substitution (SEAr) process is proposed to be involved in this transformation. Due to the much lower yield provided by the competition reaction using excess amounts of Cu(OAc)2 in the absence of Fe(NO3)3, the unique role of iron(III) is believed to lie in its ability to enable formation of the more electrophilic copper(III) species, which facilitates the subsequent SEAr process. On the basis of the results of the mechanistic studies, the authors proposed the mechanism described in Scheme [¹4] . A copper(II) adduct 6 is initially formed. In the absence of iron(III), electrophilic aromatic substitution of the intermediate 6 generates a copper(II) intermediate 8 (via 7). Reversible protonation of 8 occurs before it is oxidized to a reactive copper(III) intermediate 9. Subsequent reductive elimination produces the desired product and the copper(I), which can be reoxidized to copper(II) by oxygen to complete the catalytic cycle. In the presence of iron(III), a more electrophilic copper(III) intermediate 10 is generated by the oxidation of the copper(II) adduct 6. Intermediate 10 undergoes the following electrophilic substitution process more readily. Intermediate 9 is subsequently formed through the elimination of the aromatic proton via a six-membered transition state 11. The primary H/D kinetic isotope effect indicates that this step is rate limiting. Reductive elimination then occurs quickly before reversible protonation occurs (Scheme [¹4] ).
Scheme 14 Scope and the proposed mechanism of the iron/copper-cocatalyzed intramolecular C-H amination
In 2011, Dyadchenko and co-workers developed an efficient system for the C-C cross-coupling of ferrocenyl and alkynyl moieties in presence of copper and iron salts (Scheme [¹5] ). [²³] Due to the fact that it is inexpensive and simple, this one-step synthetic reaction is more convenient than other published multistep methods for the preparation of 1-ferrocenyl-substituted acetylenes. It is noteworthy that the target products are not detected in the presence of copper or iron salts alone.
Scheme 15 Reaction of ferrocene with alk-1-ynes
5 Conjugate Addition Reactions
In 2005, Shirakawa, Hayashi and co-workers reported an iron/copper-cocatalyzed arylmagnesiation of alkynes (Scheme [¹6] ). [²4] It showed that the hydroarylation products were obtained in high yield and stereoselectivity by cooperatively using Fe(acac)3 and CuBr catalysts (Table [9] ), which appears to be the first example of iron/copper-cocatalytic arylmagnesiation of alkynes. Based on the further transformations through one-pot reactions with electrophiles such as deuterium oxide, benzaldehyde, and benzyl bromide, arylmagnesiation products are proved to be formed in this catalytic system. For the mechanistic study, the reactions with a stoichiometric amount of Fe(acac)3 or CuBr were examined, respectively. The results indicate that the copper does not participate in the arylmetalation of the alkyne step forming an alkenylmetal species. It is most likely that the main role of the copper catalyst is to promote metal exchange between the alkenyliron and the aryl Grignard reagent.
Scheme 16 Arylmagnesiation of alkynes followed by hydrolysis reported by Hayashi and co-workers (the values in parentheses show the ratio of a regioisomer to E- and Z-products)
The scope of the reaction is broad with tolerance of functional groups including various electron-withdrawing and -donating substituents on the arylmagnesium bromide. Both aliphatic and aromatic internal alkynes react well under these conditions. Furthermore, regioselectivities over 95% are observed in the reaction of unsymmetrical aryl- and silylacetylenes (Scheme [¹6] ).
Scheme 17 A possible catalytic cycle of arylmagnesiation of alkynes proposed by Hayashi and co-workers
Based on the experimental results mentioned above, the authors proposed a catalytic cycle for this transformation (Scheme [¹7] ). Alkenyliron 12 is initially generated by the addition of aryliron to alkyne. Then, the alkenyl group on iron transfers to copper by transmetalation with diarylcuprate 13 leading to alkenyl(aryl)cuprate 14 and aryliron. Subsequently, alkenylmagnesium bromide 15 is formed as the arylmagnesiation product by transmetalation between alkenylcuprate 14 and the aryl Grignard reagent to complete the catalytic cycle.
In 2009, our group developed a copper/iron-cocatalyzed, efficient, highly regioselective and stereoselective, one-pot, tandem conjugate addition-cyclization-hydrolysis-decarboxylation reaction of readily available alkynes with Meldrum’s acid derived alkylidenes, leading to (Z)-γ-alkylidene butyrolactones (Scheme [¹8] ). [²5]
Scheme 18 One-pot tandem conjugate addition-cyclization-hydrolysis-decarboxylation reaction
As shown in Table [¹0] , FeCl3 was the most efficient cocatalyst (Table [¹0] , entry 2). This system was found to be general for the transformation between various arylacetylenes and Meldrum’s acid derived alkylidenes and exhibits good functional group tolerance. We considered two pathways for the tandem reaction (Scheme [¹9] ). It is clear that the first conjugate addition step is catalyzed by copper(I). [²6] Although the collaboration of copper and iron was not clear yet, the compatibility of copper and iron is high.
Scheme 19 Possible pathways for the tandem reaction
We believe that both of them act as Lewis acids to promote the cyclization. In the sense of the hard-soft acid-base (HSAB) concept, iron(III), which is a harder Lewis acid than copper(I), prefers to interact with the oxygen atom of the intermediate 17 or 18. Simultaneously, copper(I) binds and activates the π-system of the alkyne rending it susceptible to be attacked by the O-nucleophile. In path a, intermediate 17 would be produced through hydrolysis and decarboxylation reactions, then the intramolecular hydroacyloxylation would proceed to give intermediate 20. In path b, iron, as a Lewis acid, promoted enolization of compound 16, which leads to intermediate 18 that would undergo intramolecular cyclization giving intermediate 19, followed by concurrent rearrangement and liberation of acetone and CO2 to form intermediate 20. A subsequent step from intermediate 20 affords the final product 21 and regenerates metal catalysts. The high Z stereoselectivity can be explained reasonably based on the anti intramolecular addition of the intermediate 17 and 18 to the metal-activated alkyne.
Scheme 20 Deuterated experiments
To further understand this transformation, we carried out some preliminary mechanistic studies. Deuterated product [D]-21 was isolated in 61% yield when deuterium oxide was used instead of water (Scheme [²0] ). However, the hydrogen-deuterium exchange was not observed at the 5-position when compound 21 was treated with deuterium oxide under the reaction conditions (Scheme [²0] ). Based on these results, although both path a and path b are reasonable, we consider that the reaction prefers to occur through path b.
The copper/iron-cocatalyzed, highly selective decarboxylation-cyclization reaction of Meldrum’s acid derivatives leading to poly-substituted (Z)-γ-alkylidene butyrolactones in aqueous solvent was also developed (Scheme [²¹] ). [²5]
Scheme 21 Iron/copper-cocatalyzed, tandem decarboxylation-cyclization reaction
6 Conclusion
In this review, we have summarized recent developments in copper/iron-cocatalyzed reactions. Owing to the benign characters of copper and iron, such as their being inexpensive, readily available, environmentally friendly, and stable to air and moisture, the bimetallic combination catalytic system of copper/iron should find more extensive application in organic synthesis in future. Due to the versatile catalytic properties of copper and iron, new types of domino process could be developed to minimize waste in organic synthesis.
Acknowledgment
Financial support from Peking University, National Science Foundation of China (No. 20702002 and 20872003), National Basic Research Program of China (973 Program 2009CB825300), and Program for ‘NCET’ are greatly appreciated
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Yijin Su (left) was born in Guangdong, China, in 1984. He received his Bachelors degree (2007) and Master’s degree (2009) (with Prof. Ning Jiao) at Peking University, Beijing. He is currently a second-year Ph.D. student in Professor Ning Jiao’s group at Peking University. Wei Jia was born in Beijing, China, in 1986. She received her Bachelor’s degree (2008) and Master’s degree (2010) (with Prof. Ning Jiao) at Peking University, Beijing. After graduation, she was recruited as a government employee. Ning Jiao (right) was born in Shandong, China, in 1976. He received his B.Sc. degree at Shandong University (1999), and Ph.D. degree (2004) (with Prof. Shengming Ma) at Shanghai Institute of Organic Chemistry (SIOC), Chinese Academy of Science (CAS). He spent 2004-2006 as an Alexander von Humboldt postdoctoral fellow with Prof. Manfred T. Reetz at the Max Planck Institute für Kohlenforschung (MPI) (Germany). In 2007, he joined the faculty at Peking University as an Associate Professor, and was promoted to Full Professor in 2010. His current research efforts are focused on: (1) the development of green and efficient synthetic methodologies for the synthesis of heterocycles, bioactive molecules, and potential drugs; (2) radical reactions, and the activation of inert chemical bonds; (3) directed evolution of enzymes and protein hybrid catalysts.
Scheme 1 N-Arylation reaction cocatalyzed by copper and iron
Scheme 2 N-Arylation reaction reported by Wakharkar and co-workers
Scheme 3 N,O-Arylation reaction reported by Fu and co-workers
Scheme 4 N-Arylation reaction reported by Liu and co-workers
Scheme 5 N-Arylation reaction reported by Darcel and Wu
Scheme 6 Scope and plausible mechanism of N-arylation reaction reported by Li and co-workers
Scheme 7 O-Arylation reaction reported by Zhang and co-workers
Scheme 8 S-Arylation reaction reported by Liu and co-workers
Scheme 9 Alkynylation coupling reaction reported by Vogel and co-workers
Scheme 10 Iron/copper-cocatalyzed coupling reactions reported by Mao and co-workers
Scheme 11 Alkynylation coupling reaction reported by Liu and co-workers
Scheme 12 Homocoupling reaction of terminal alkynes reported by Chen and co-workers
Scheme 13 Cross-coupling reaction of two different terminal alkynes reported by Chen and co-workers
Scheme 14 Scope and the proposed mechanism of the iron/copper-cocatalyzed intramolecular C-H amination
Scheme 15 Reaction of ferrocene with alk-1-ynes
Scheme 16 Arylmagnesiation of alkynes followed by hydrolysis reported by Hayashi and co-workers (the values in parentheses show the ratio of a regioisomer to E- and Z-products)
Scheme 17 A possible catalytic cycle of arylmagnesiation of alkynes proposed by Hayashi and co-workers
Scheme 18 One-pot tandem conjugate addition-cyclization-hydrolysis-decarboxylation reaction
Scheme 19 Possible pathways for the tandem reaction
Scheme 20 Deuterated experiments
Scheme 21 Iron/copper-cocatalyzed, tandem decarboxylation-cyclization reaction