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Double carbometallation of alkynes: an efficient strategy for the construction of polycycles Yong Luo,a Xiaolin Pan,a Xingxin Yu*b and Jie Wu*ac Cyclization reactions of alkynes, especially the double carbometallation of alkynes, have drawn much interest from organic chemists because of their high efficiency in the construction of polycycles. Utilizing different nucleophiles or catalytic systems, various efficient strategies to access challenging skeletons have been extensively explored in recent years. In this review, achievements in this field are
Received 29th August 2013
presented in three major parts (the syn–syn, anti–anti, and syn–anti addition reactions of diynes or two
DOI: 10.1039/c3cs60313j
alkyne molecules). Cyclization reactions of diynes initiated by nucleophiles, [2+2+n] cycloaddition, or other processes and reactions, involving two identical or different alkynes are described, which provide
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facile and reliable approaches to various p systems, medium-sized rings, and even macrocycles.
Key learning points (1) (2) (3) (4)
Polycycles with molecular complexity and diversity can be generated efficiently via three types of double carbometallation of alkynes. Diverse carbon- or heterocycles can be synthesized by the utilization of different reagents or catalytic systems. Reaction types and their selectivities can be tuned by various parameters. More novel and functionalized polycycles can be constructed. Interesting properties of these synthesized polycycles may lead for further research.
1. Introduction According to the Dictionary of Natural Products, 90% of chemicals are cyclic compounds. Thus, the synthesis of polycycles always draws considerable interest since polycycles exist widely in natural products and pharmaceuticals. Among the various methods for the synthesis of heterocycles and carbocycles, the cyclization of alkynes plays an important role both in academic research and industry because of the high reactivity and ready availability of the starting materials. Recently, several reviews have introduced recent improvements for the synthesis of cyclic compounds involving alkynes.1 However, most of the examples focused on the single addition of the CRC bond and subsequent transformation. The synthesis of polycycles involving multiple CRC bonds is usually ignored. Among the reviews on reactions involving two or more alkynes, only a small aspect (2+2+2 cycloaddition reactions) of the research a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail: [email protected]; Fax: +86 21 6564 1740; Tel: +86 21 6510 2412 b School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. E-mail: [email protected] c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
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in this field was discussed.2 However, the synthesis of polycycles with the utilization of multiple triple bonds is significant, because diversity of products can be easily achieved by controlling the regioselectivity and chemoselectivity of the triple bonds. Also, combination with the addition of alkynes and other transformations can largely increase molecular complexity. In order to provide a clear and simple overview for the construction of complex molecules, only selected examples for the synthesis of polycycles via double carbometallation of the alkynes are presented in this review. The other transformations of alkynes, such as into ketones or allenes, are not discussed. The synthesis of substituted benzene or pyridine involving double triple bonds is also excluded.
2. Addition of triple bonds As we all know, there are two types of addition reactions of triple bonds. Lewis-acids can coordinate and activate the triple bond, followed by nucleophilic attack from the opposite side to afford the anti addition product, whereas syn addition of the triple bond happens in the presence of a transition metal. The combination of these types (syn–syn, anti–anti, and syn–anti types) can result in versatile polycycles, which are difficult to obtain by other means. In recent years, with the application of
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many challenging methodologies, such as C–H bond activation, the strategy of double carbometallation of alkynes has been developed as a powerful tool for the synthesis of complex polycycles. It can largely complement or extend current synthetic methods.
Classical Bergman reactions
Anti–anti addition reactions of two triple bonds, especially the thermally induced cyclization of diynes have been studied for several decades. However, in recent years, various Lewis acids have been employed to mediate such processes. As a result, more mild and easily-handled reaction conditions have been developed with a large increase in reaction diversity. Many types of nucleophiles, for example, carbon-, nitrogen-, and oxygen nucleophiles are incorporated to initiate the reaction processes.
The Bergman cyclization (BC) of enediynes is a typical anti–anti type reaction. Despite the remarkable progress made in recent decades, many new applications of the Bergman cyclization for the construction of interesting complex molecules have also been explored. Basak developed an efficient route to [4]helicenes from diynes, in which Bergman cyclization was the key step (Scheme 1).3 This process was initiated by the Bergman cyclization of diyne 1 to generate the diradical 3 with the formation of two new rings. Because of the shielding of the molecular framework, intramolecular attack was preferred to produce intermediate 4. After hydrogen abstraction, the new diradical 5 was furnished. Finally, the [4]helicene was obtained by abstraction of deuterium and subsequent oxidation. Although a long multi-step synthesis of 1 is required, this reaction has many advantages, for example,
Yong Luo was born in Sichuan (China) in 1984. He obtained his BS (2008) and PhD (2013) from Fudan University under the supervision of Professor Jie Wu. His research mainly focused on developing efficient pathways to synthesize polycycles through palladium-catalyzed tandem reactions. Currently, he works as a postdoctoral fellow in the group of Dr Zhaomin Hou at RIKEN (Japan).
Xiaolin Pan was born in Liaoning (China) in 1989. She received her BS (2011) from the Department of Chemistry at Fudan University. In 2011, she continued her studies as a PhD candidate at Fudan University, under the guidance of Professor Jie Wu. Her current research interests mainly focus on methods development for the synthesis of natural product-like compounds via palladiumcatalyzed tandem reactions.
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3.1
Yong Luo
Dr Xingxin Yu received her PhD in Organic Chemistry from Fudan University in 2012 under the supervision of Prof. Jie Wu (2007–2012). After conducting research as a post-doctoral associate in the Department of Medicinal Chemistry at the University of Minnesota Twin Cities (2012–2013), she joined the School of Pharmacy at the East China University of Science and Technology (ECUST). Her Xingxin Yu research is focusing on designing and developing asymmetric small-molecule based candidates for cancer prevention and treatment and elucidating their corresponding mechanisms of action.
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Xiaolin Pan
Prof. Jie Wu received his BSc in chemistry from Jiangxi Normal University in 1995, and he pursued his PhD studies at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences under the supervision of Prof. Xue-Long Hou (1995–2000). After conducting research as a postdoctoral fellow at Harvard University (2000–2001), he worked as a visiting scientist at the Aaron Diamond AIDS Jie Wu Research Center (2001–2002) and a staff scientist in VivoQuest, Inc. (2002–2004). In 2004, he moved to the Department of Chemistry at Fudan University and held the Professor rank two years later. He got the Thieme Chemistry Journals Award in 2010 and now serves as a member of the Editorial Advisory Board of ACS Combinatorial Science and the Editorial Board of ISRN Organic Chemistry.
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Scheme 1
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Synthesis of [4]helicene with Bergman cyclization.
mild reaction conditions, no extra catalyst, and high efficiency for the construction of three new rings. 3.2
Scheme 2
Gold-mediated 5-exo cyclization of diynes.
Scheme 3
Gold-catalyzed formation of b-phenylnaphthalene.
Scheme 4
Gold-catalyzed 6-endo cyclization of diynes.
Reactions initiated by carbon nucleophiles
Traditional Bergman cyclization which proceeds by a radical mechanism has obvious drawbacks. Because of the nature of the radical, the scope of the substrates is limited. Many groups that can react with the radical cannot be placed in the ortho position of the alkyne. However, non-classical Bergman-type reactions which are initiated by various nucleophiles in the presence of a Lewis acid show a much higher synthetic potential. Dialkynyl compounds can go through direct cyclization in the presence of Lewis acids to form a new carbocycle and the ring size can be controlled by the use of different reaction conditions. Zhang4 reported the gold-mediated 5-exo cyclization of diynes to form the key gold vinylidene intermediate 9. After a 1,5-hydrogen shift and subsequent protodeauration, a tricyclic compound was generated. The experiments showed that the additive N-oxide was critical for this reaction. It acted as a suitable base to facilitate the exchange of the alkyne terminal hydrogen and the gold species. One possible reason for the preference for 5-exo cyclization was that the resulted s coordination between gold and the alkyne increased the nucleophilicity of the b-carbon of the alkyne. Also, the bulky ligand which made the a-carbon more hindered might be helpful for this high regioselectivity (Scheme 2). Although 5-exo cyclization is preferred in the presence of gold catalyst, six-membered rings can also be formed under certain conditions. Hashmi5 found that the gold acetylide 12 could react with benzene to form the gold carbenoid 13. Then, a ring expansion would occur to generate a six-membered ring. After elimination of [AuL] and catalyst transfer, b-phenylnaphthalene would be produced with high yield (Scheme 3). If there were no basic additives in the reaction system, compound 10 could go through 6-endo cyclization to yield a-phenylnaphthalene (Scheme 4). A large number of experiments and mechanism studies revealed that the addition of NEt3 had a great influence on this selectivity. Without NEt3, 6-endo cyclization of 10 would result in the a product directly. However, when NEt3 was added, there was an equilibrium of 10 and gold acetylide 16 in the buffered medium [Et3NH]+[NTf2] . The intermediate 16 which was more
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reactive than 10 could coordinate with the coexisting IPrAuNTf2 (IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, N-heterocyclic carbene) to furnish acetylide 12. Finally, the b product was generated with high selectivity (Scheme 5). In contrast to the gold-catalyzed cyclization of diynes, a pathway involving a diradical in the presence of PtCl2 was proposed by Liu.6
Scheme 5
The effect of NEt3.
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Scheme 8 Scheme 6
Firstly, PtCl2 would coordinate to the substrate and activate the alkynes. Then, 6-endo cyclization would afford the diradical species 19. Its resonance form 20 could undertake C–H bond insertion of the alkane to form a new ring. Subsequent transformations would furnish the desired product 18 (Scheme 6). The intermolecular attack of diynes for the assembly of naphthalene derivatives initiated by carbon nucleophiles has been realized by Liu.7 Pyrrole, ethyl acetoacetonate, and silyl enol ether could be incorporated in this reaction with high regioselectivity. Mechanism studies revealed that this reaction went through a nucleophilic addition–insertion process, which was different from other reactions involving ruthenium–vinylidene or cationic naphthyl species (Scheme 7). Besides other metals, B(C6F5)3, which is strongly electrophilic, can also activate alkynes. Erker8 reported that 1,2-bis(alkynyl)benzene could react with B(C6F5)3 to generate the three cyclic compounds 22, 23, and 24. This reaction was initiated by the addition of B(C6F5)3 to the triple bond to form the intermediate 25. After an intramolecular electrophilic aromatic substitution reaction and subsequent transformation, product 22 was produced. However, if 26 underwent 1,2-C6F5 migration subsequently, it would open a pathway to the formation of 23. This strategy was significant for the synthesis of many interesting polycycles, especially polyfluorene-substituted arenes. However, the poor selectivity in generating complex products indicated that further exploration was needed (Scheme 8).
Scheme 7
The reaction of B(C6F5)3 and a diyne.
PtCl2 catalyzed 6-endo cyclization of diynes.
Ru-catalyzed 6-endo cyclization of diynes.
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If there are several reactive sites in the starting materials, the reaction process is much more complex, and controlling the side reactions is a great challenge. In Liu’s example,9 furan is used as an external nucleophile to react with the diyne 28 in the presence of a gold catalyst. As shown in Scheme 9, a Friedel– Crafts reaction through nucleophilic attack of the furan 5-C on a cationic intermediate would occur first to afford 30. After addition of silver salt, 30 could undergo regioselective 7-endo cyclization and intramolecular attack to form cyclopropyl gold carbenoid 31. Rearrangement of this intermediate followed by intramolecular attack of carbonyl oxygen produced the oxetene 32, which then underwent ring opening to afford the product 33. Although several reaction routes existed in this reaction, phenanthrene derivatives could be obtained with moderate yields after careful optimization of the reaction conditions.
Scheme 9
The reaction of furan and a diyne.
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Scheme 10
3.3
Intramolecular amine initiated reactions.
Reactions initiated by nitrogen nucleophiles
In view of the great bioactive potential of indoles, the synthesis of various modified indole derivatives is always the pursuit of organic chemists. It is well-known that such compounds can be obtained by the direct 5-endo cyclization of 2-alkynylaniline. However, if one more triple bond is introduced in these substrates, more complex products can be obtained. Ohno and co-workers10 developed an efficient strategy for the synthesis of benzo[a]carbazole derivatives through a gold-mediated cascade cyclization of substrate 34. This reaction proceeded with 5-endo cyclization and a subsequent 6-endo process (Scheme 10). 3.4
Reactions initiated by oxygen nucleophiles
In a similar manner to nitrogen initiated reactions, various O-fused polycycles can be generated by oxygen nucleophile initiated reactions. Alabugin11 demonstrated the efficiency of the Sonogashira/ 5-endo/6-endo cascade for the preparation of benzofuran-fused polycycles. Diyne 38 could react with compound 37 under standard Sonogashira reaction conditions to afford benzofuran 39 in moderate yield. However, the addition of gold and silver salts could slightly improve the yield of 39 accompanied with the formation of the desired product 40. In this step, the inefficiency of [Au] was mainly attributed to the basic conditions which inhibited the protodemetalation and the coordination of [Au] with the alkyne. After removal of the base, 39 could undergo 6-endo cyclization in excellent yield to form compound 40 (Scheme 11). However, 6-endo cyclization for carbocycles is not always preferred when other nucleophiles are used. Wang12 found that a 6-endo/5-exo cyclization of 41 led directly to the fused indene 42. In contrast to the cascade processes of the phenol initiated reaction (Scheme 11), the two new rings in 42 were formed concertedly and the intermediate generated by only 6-endo cyclization could not undergo further transformation to afford 42 under various conditions (Scheme 12). Reactions involving intermolecular nucleophilic attack of alcohol on diynes were studied by Liu.7 This strategy also
Scheme 11 Intramolecular phenol initiated reactions.
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Scheme 12
Intramolecular carboxylic acid initiated reactions.
showed high regioselectivity in reactions involving carbon nucleophiles (Scheme 7). The addition of the alcohol always occurred at the more electron-rich alkyne carbon, which suggested that nucleophilic addition happened first, not the formation of a naphthyl cation or radical (Scheme 13). 3.5
Reactions initiated by halopalladation
Besides the above nucleophile initiated reactions, halopalladation can also induce the anti addition of alkynes with the introduction of halides. Wu13 developed a facile route to synthesize indenes 46 via the halopalladation of diynes 45. Typically, transition metal assisted insertion of alkynes proceeds with a syn addition. Thus, intermediate 47 would be generated first in this catalytic cycle. However, anti-type addition could also be achieved by Z,E-isomerization of the intermediate at high temperatures. After subsequent insertion of the other triple bond, the totally anti addition species 49 was yielded. Then reductive elimination followed to afford the desired product 46 and Pd(0), which could be oxidized by CuX2 to regenerate PdX2. If an alcohol such as menthol was added, ligand exchange would occur before reductive elimination to introduce a methoxyl group into the product 46. Furthermore, the introduced halides are highly desirable in synthetic chemistry. These obtained products could be converted
Scheme 13
Intermolecular alcohol initiated reactions.
Scheme 14
Halopalladation of diynes.
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to versatile substituted benzofulvenes by the well-established Suzuki– Miyaura reactions (Scheme 14).
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4. Reactions with syn–syn type addition In contrast to Lewis acid catalyzed anti–anti additions, the syn addition of alkynes usually occurs with catalysis by transition metals. Since numerous transition-metal assisted reactions have been explored in organometallic chemistry, the research in this field is abundant and attractive. Until now, diynes, two identical alkynes or two different alkynes have all been demonstrated to be good substrates for this transformation. 4.1
Syn–syn addition of diynes
4.1.1 [2+2+n] Cyclization of diynes. [2+2+n] Cycloaddition reactions of diynes are the most well-known syn–syn type reactions. In recent decades, various transition-metals have been successfully applied to mediate the cycloaddition of diynes and unsaturated compounds. With a large increase in diversity of selectivities and products, this reaction has become a well-established tool for the construction of hetero- or carbocycles. As shown in Scheme 15, there are two possible pathways which produce intermediate I or II accordingly. Substances possessing a p system, such as an alkene, ketone, CO, or CO2 can firstly coordinate with transition metals. The generated complex species undergoes insertion of the two triple bonds of the diynes one by one to form I. Then, the following ringclosing reaction can give the desired polycycles. However, some cases are believed to go through the production of the metalfused five-membered ring II, which would be produced by transition-metal-mediated annulation of two triple bonds simultaneously. If a 1,1-disubstituted alkene is applied to the cycloaddition reaction, a chiral quaternary carbon atom can be generated.
Scheme 15 Syn–syn additions of diynes.
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Fig. 1
[2+2+2] Cycloaddition of diynes with alkenes.
Shibata14 demonstrated that high enantioselectivity could be achieved for the formation of chiral spirocyclic structure in the presence of [Rh(cod){(S)-xylyl-binap}]BF4 in DCE. Ketone- and ester-substituted alkenes reacted with diynes smoothly. And bicyclic metallacyclopentadiene II was believed to be the reactive intermediate (Fig. 1). Pyridine derivatives can be synthesized by the cycloaddition of diyne with nitrile. Furthermore, Maryanoff15 found that macrocycles could be produced in the presence of CpCo(CO)2 when long-chain diynes were employed. As shown in Fig. 2, meta- and para-pyridines were formed in the reaction, because there were two types of cobalt cycle in the first step. The catalyst CpCo(CO)2 still shows efficiency for the transformation of the CQN bond. 2-Phenylethylisocyanate reacted with a diyne to furnish a mixture of 2-oxopyridinophanes 65 and 66 in 68% yield (Fig. 3). Yamamoto16 reported that Cp*RuCl(cod) was efficient in mediating the reactions of diynes with CRN, CQN, and even CQS and NQS bonds. The reaction of isothiocyanate and carbon disulfide gave rise to the corresponding products 67 and 68 in moderate to good yields. However, when N-thionylaniline was employed in this reaction, pyrrole 70 was obtained instead of the expected product 69, which was likely to undergo SO extrusion after formation (Scheme 16). Nickel-catalyzed cycloaddition of diynes and ketenes have been studied by Louie.17 The results suggested that the CQC bonds in the ketenes participated in the reactions, although there were two possible types of coordination to the metal
Fig. 2
[2+2+2] Cycloaddition of diynes with nitrile.
Fig. 3
[2+2+2] Cycloaddition of diynes with CQN bond.
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Scheme 16
[2+2+2] Cycloaddition of diynes with CQS and NQS bonds.
Fig. 4 [2+2+2] Cycloaddition of diynes and ketenes.
center, CQO or CQC binding. Further research indicated that asymmetric synthesis could be achieved by the use of (R)-BINAP at a higher temperature (Fig. 4, 72). In fact, the CQO bond in CO2 could react with diynes to furnish lactones 56.18 Utilizing Ni(cod)2 as the catalyst and IPr as the ligand, a variety of substituted desired products could be obtained in good to excellent yields. In contrast to most cycloaddition reactions of diynes, it was believed that species I, which was formed by [2+2] carboxylation of one alkynyl unit and subsequent insertion of the other triple bond, was the reactive intermediate (Fig. 5). Cycloaddition of diynes is demonstrated to be efficient in the construction of medium-sized rings 54. Murakami19 reported that ring-opening of the strained ring could expand the intermediate I or II to a nine-membered nickelacycle when cyclobutanones were incorporated in the reaction. The subsequent reductive elimination would give rise to products such as 75. Similarly, the employment of azetidinone or oxetanone could furnish eight-membered heterocycles 76 or 77 in good yield.20 The combination of Ni(cod)2 and IPr was still the best catalytic system (Fig. 6). The seven-membered ring 57 could be synthesized by the cycloaddition of diynes with ethyl cyclopropylideneacetate in
Fig. 5
[2+2+2] Cycloaddition of diynes and CO2.
Fig. 6
Cycloaddition of diynes and four-membered rings.
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Fig. 7 Cycloaddition of diynes and cyclopropanes.
Fig. 8 Cycloaddition of diynes and CO.
the presence of Ni(cod)2 and phosphine-based ligands. Saito21 proposed that insertion of cyclopropylideneacetate into intermediate II followed by ring-opening of cyclopropane and reductive elimination generated the desired products (Fig. 7). IrCl(CO)(PPh3)2 mediated carbonylation of diynes for synthesizing five-membered rings 53 has been realized by Shibata.22 This strategy still showed high efficiency with CO at a partial pressure of ca. 0.2 atm. Under standard conditions, various bicycles, even tetracycles could be formed in moderate to excellent yields (Fig. 8). 4.1.2 Reactions with diynes initiated by oxidative addition. Aryl halides which are very stable and readily available starting materials are widely used in synthetic chemistry. Since oxidative addition of the aryl halides is typically the initial step, the reaction sequence of the substances can be controlled to yield the desired product with high selectivity. Recent research of Wu and co-workers23 revealed that the intermediates generated by the oxidative addition of aryl halides could also insert into the two triple bonds of diynes 82 sequently. If X = H, C–H activation and subsequent reductive elimination could afford the product 87 in good yield. However, when X = I, Pd(IV) species were formed by a further oxidative addition. After reductive elimination to give 88, the resultant Pd(II) species could oxidize the p-xylene to regenerate the active catalyst Pd(0). Utilizing this strategy, various substituted large p systems were synthesized. Further research of their photophysical properties and electrochemistry indicated that different types of product had diverse quantum yields and HOMO potentials, which was useful for screening for efficient electroluminescence materials (Scheme 17). The construction of strained rings meets many challenges in synthetic chemistry. However, Suffert24 developed an efficient method for the synthesis of four-membered ring-fused polycycles via intramolecular double insertion to triple bonds. As shown in Scheme 17, there are two possible pathways for the transformation of intermediate 91. A 6p electrocyclization led to the intermediate 93, which underwent syn dehydropalladation elimination to generate the product 90. An alternative mechanism was that a Heck addition of palladium species to CQC bond would give rise to 92. Then, a rare but known anti dehydropalladation elimination would furnish the desired product (Scheme 18).
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Scheme 17
Scheme 18
Scheme 19
Intermolecular reactions of diynes and amines.
Scheme 20
Halopalladation initiated reactions with diynes.
Intermolecular reactions of diynes and aryl halides.
Intramolecular reactions of diynes and vinyl bromide.
4.1.3 Reactions with diynes initiated by nucleophilic attack. The introduction of other hetero units is also highly desirable because heterocycles exist widely in bioactive molecules. Lu25 found that amines could react with diynes to afford tetracycles in the presence of PdCl2. Firstly, nucleophilic attack of the amine on the triple bond would afford 96 via aminopalladation. After insertion of the second triple bond, the intermediate 97 would undergo C–N bond formation to produce the product 95 and Pd(0), which was oxidized by DMSO to regenerate the active catalytic species Pd(II). The research of the photophysical properties of compound 95 indicated that the fluorescence was efficiently quenched when either nitrobenzene or 2,4,6-trinitrotoluene was gradually added. Thus, it might be used as an alternative sensory materials for the trace detection of these compounds (Scheme 19). 4.1.4 Reactions with diynes initiated by halopalladation. Halopalladation is widely used in organic chemistry, because it can introduce halides with synthetic potential into molecules. Jiang26 reported that chloropalladation of diyne 98 and subsequent Heck reaction afforded triene 101. This newly formed C–Cl bond could go through the Heck reaction to furnish the product 99 (Scheme 20). 4.2
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of diynes usually needs multiple steps, and the scope of substitutions is limited. Thus, reactions involving intermolecular alkynes are much more attractive. In recent years, various efficient methods with the participation of two molecules of identical or different alkynes have been developed. 4.2.1 Reactions involving two identical alkynes. Addition of two identical alkynes offers a simple and efficient approach for the synthesis of p conjugate systems which have important roles in photochemistry. The starting materials in this strategy are easily prepared, some are even commercially available, and stable. For example, utilizing boronic acid 103 as the starting material, Miura and co-workers27 developed a facile route to synthesize naphthalene derivatives and their analogues (Fig. 9). The proposed mechanism consisted of several steps, including transmetalation of the catalyst [Cp*RhCl2]2 with 103, double insertion of the alkynes, C–H bond activation, and reductive elimination to form a C–C bond (Scheme 21). Similar products could be synthesized by using different initial steps. For example, Takahashi28 reported that the reactions of o-diiodoarenes 104 and alkynes could give rise to naphthalenes via a similar mechanism as shown in Scheme 16.
Syn–syn addition of two alkynes
Although great progress has been made in the research of diynes, these substrates have several drawbacks. The preparation
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Fig. 9
The reactions of boronic acids and alkynes.
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Scheme 22
Homocoupling of haloenynes.
Scheme 23
The reaction of haloenyne and an amine.
Scheme 21 Syn additions of two identical alkynes.
Fig. 10 The active intermediates in the reaction of arenes and alkynes.
Double C–H bond activation of arenes 105 could lead to naphthalenes with a high atom economy. However, in contrast to sequent insertion of the C–Pd bond to two alkynes in other examples, Wu and co-workers29 believed that the concerted [2+2] cycloaddition would occur to firstly form palladacyclopentadiene 109. After reacting with xylene 105, the intermediate 110 would be generated. After that, a subsequent C–H bond activation occurred to afford the desired product (Fig. 10). C–C bond activation is challenging because of its stability. In recent decades, C–C bond activation via decarboxylation of vinyl carboxylic acids has made remarkable progress. Utilizing this strategy for the synthesis of polycycles provides an alternative route for synthetic chemists. Miura and co-workers30 reported that substituted carbazoles could be obtained by the reaction of indole-3carboxylic acids 106 and alkynes via decarboxylation. Firstly, carboxyl oxygen directed C–H bond activation of the C2-position and subsequent insertion of the alkyne would produce the intermediate 111. Then decarboxylation would occur to generate the palladacycle 112. Insertion of another molecule of alkyne and reductive elimination took place to yield the product (Fig. 11). Tilley31 reported the synthesis of pentalene derivatives via a palladium-catalyzed homocoupling of haloenynes. Interestingly, Pd nanoparticles were found under the reaction conditions, which indicated that this reaction was likely to be catalyzed by nanometallic Pd (Scheme 22). Wu and co-workers32 found that the reaction of haloenynes and an amine could lead to hetero polycycles such as 115, not indoles as previously reported. It is well-known that 2-alkynylbenzeneamine
Fig. 11 The active intermediates in the reaction of carboxylic acids and alkynes.
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117 would be produced first in this reaction. In contrast to the mechanism for the formation of indoles, highly regioselective insertion of the triple bond of 117 was followed to generate the intermediate 118. Then the intramolecular insertion of the second triple bond and C–N bond formation would take place to afford compound 115 (Scheme 23). Wu33 demonstrated that nitriles could also react with haloenynes in the presence of Ni to produce nitrogen-containing molecules. After oxidative addition of the iodonaphthalene, insertion of the C–Ni bond to the CRN bond of nitrile would occur to afford 121. Then, a highly regioselective insertion of two CRC bonds would generate the intermediate 122. Followed by insertion of the CQN bond, oxidative addition, and reductive elimination would yield the product 120. This method stands out because of its high functional group-tolerance and high efficiency in the construction of large p systems (Scheme 24). 2-Alkynylphenol can react with CO in a ratio of 2 : 1 to afford the heterocycle 125.34 Furthermore, the one-pot synthesis starting from
Scheme 24
The reaction of haloenyne and nitriles.
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Scheme 25
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The reaction of 2-alkynylphenol with CO. Scheme 27
2-iodophenol and alkyne was achieved with a comparable isolated yield. As shown in Scheme 23, the Sonogashira reaction would occur first to afford 2-alkynylphenol 126. Then, Lewis-acidic Pd(II) activated the triple bond to undergo cyclization to form the benzofuranylpalladium species 127. After incorporation of another alkyne, the following carbonylation and reductive elimination would give rise to the product (Scheme 25). 4.2.2 Reactions involving two different alkynes. Compared with reactions involving double alkynes, transformations of two different alkynes which can introduce more diversity have greater synthetic potential. However, this method remains a great challenge because it is difficult to control the reaction order of two alkynes. Finding optimized reaction conditions to avoid homodimerization is always the pursuit of organic chemists. Ikeda35 successfully realized the cyclotrimerization of an enone and two different alkynes in the presence of a nickel catalyst. With slow addition of aryl alkyne, intermediate 131 formed first. Then insertion of the CQC bond of 129 to the C–Ni bond in 131 afforded the seven-membered nickelacycle 132. The following reductive elimination would lead to compound 133 with the regeneration of Ni(0). In order to obtain a better analysis of its regiochemistry, this product was exposed to air for aromatization to generate compound 130 as the final product. This reaction achieved high selectivity because other types of nickelacyclopentadiene were suppressed by a low concentration of substrate or were too unreactive to undergo further transformation (Scheme 26). Wu and co-workers36 found that alkynes bearing ortho nucleophiles could react with 2-alkynylarylbromide to afford tri- or tetracycles. The high regioselectivity achieved, which was attributed to the directing effect of the nucleophile was crucial to accomplish the catalytic cycle. For example, in the reaction of 113 with 134, methyl malonate directed two syn insertions of
Scheme 26
The reaction of enones and alkynes.
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The reaction of two different alkynes bearing nucleophiles.
the C–Pd species to the triple bonds, while 5-endo cyclization of 134 is widely reported in previous research. After that, reductive elimination with the formation of a C–C bond furnished the tetracarbocycle 135 (Scheme 27). Other challenging transformations, such as C–H bond activation can also be applied in the reactions of two different alkynes. Minami37 reported the cyclization of alkynyl ethers with simple alkynes to generate chromenes via C–H bond activation. In contrast to typical weak coordination directing ortho C–H bond activation, this process was initiated by the formation of the zwitterionic palladium complex 140. Then, cyclization and a 1,2-H shift induced oxidative addition to give 142. After that, either inter- or intramolecular insertion of the alkyne could result in the formation of product 139. However, the substitutents of the alkynyl ether were limited to a silyl group, since it was thought to stabilize the negative charge to facilitate the formation of 140 (Scheme 28). Strained four-membered rings could also be synthesized by the reactions of two different alkynes. Suffert38 reported that compound 145 could undergo intramolecular insertion of the triple bond and a subsequent Sonogashira reaction to give 147. Under proper reaction conditions, regioselective attack of the terminal alkyne on the triple bond of 147 would occur to afford 148. Subsequently, 8p electrocyclization would take place followed by rearrangement to furnish the strained tetracycle 150 (Scheme 29).
Scheme 28 activation.
The reaction of two different alkynes involving C–H bond
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Scheme 29 rings.
Scheme 30
Scheme 31
Intramolecular [3+2] cyclization of diynes.
Scheme 32
Intramolecular [4+2] cyclization of diynes.
The reaction of two different alkynes for synthesis of strained
The reaction of two different alkynes involving dibromoolefins.
Diederich39 developed an alternative pathway for the construction of pentalene derivatives with the utilization of gemdibromoolefins. The initial step was the coordination of Pd(II) to the triple bond of 129, directing the oxidative addition to the desired C–Br bond. Intramolecular carbopalladation at the triple bond followed to give rise to the fulvene 132. Subsequent intermolecular carbopalladation of another alkyne and zincpromoted cyclization furnished the product 130 (Scheme 30).
5. Reactions with syn–anti type addition 5.1
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[3+2] or [4+2] cyclization reactions
When an alkyne reacts with another triple bond along with its substitutent, a [3+2] or [4+2] cyclization can proceed with syn– anti type additions. Liu40 realized intramolecular [3+2] cyclization of diynes in the presence of a gold catalyst. This process was initiated by nucleophilic attack of the phenyl substituent of 134 at the triple bond activated by gold salt, providing the vinylgold(I) intermediate 136. Protonation of the other triple bond was proposed to take place subsequently, followed by 5-exo cyclization to form the desired product 135 (Scheme 31). Intramolecular [4+2] cyclization of diynes was developed by Danheiser and a new strategy for the synthesis of indoles was
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reported.41 For example, enynamide 137 could go through concerted [4+2] cyclization to generate the strained isoaromatic cyclic allene 138. After that, indoline 139 was generated via a proton or hydrogen atom transfer pathway. With the utilization of different substrates, indolines bearing various substitutents at the C-4 or C-7 position could be synthesised. Furthermore, subsequent oxidation led to the corresponding indoles in good yields (Scheme 32). Intermolecular [4+2] cyclization could also be utilized to synthesize polycycles. Miura42 developed an efficient pathway to construct naphthalenes via cyclodimerization of two alkynes. In the presence of Rh(I), oxidative addition of HX occurred first to generate the active Rh(III) species 143. Insertion of 140 to the Rh–H bond and Z,E-isomerization followed to form 144. Then, C–H activation and selective insertion of 141 to this intermediate furnished the desired product 142 (Scheme 33). Diyne 28 has been demonstrated to be a good substrate for anti–anti type reaction (Scheme 9). However, syn–anti type addition can also take place in the presence of electrophilic regents. Chen43 reported that 28 reacted with NIS forming tetracyclic benzo[a]fluorenols under mild conditions. During the catalytic cycle, the electrophile would activate the triple bond. The following electrophilic attack of another triple bond
Scheme 33
Intermolecular [4+2] cyclization of diynes.
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Fig. 12 Intermediate and product of the reaction of 2-alkynylbenzaldehydes and alkynes.
Scheme 34
Synthesis of a seven-membered ring.
Scheme 37
Synthesis of a five-membered ring.
Reactions of diynes and electrophiles.
would generate the vinylic carbocation 147. Then, intramolecular Friedel–Crafts cyclization gave rise to tetracycles 148. However, this compound was unstable under the reaction conditions. The hydroxy group could be released by the activation of Lewis acid. Subsequent tautomerization would afford a more stable positive ion intermediate 149, in which the cation was stabilized by three aryl groups. Finally, this cation trapped by hydroxy group would furnish the desired product 146 (Scheme 34). 5.2
Scheme 36
Reactions initiated by intramolecular nucleophilic attack
An alkyne bearing a nucleophile can undergo intramolecular nucleophilic attack first to produce an anti addition intermediate. Another alkyne can react with this intermediate through an [n+2] cyclization with syn addition. Yamamoto44 reported that naphthyl ketones could be synthesized by the reaction of 2-alkynylbenzaldehydes with alkynes. Furthermore, either terminal or internal alkynes could be incorporated in this process with high regioselectivity, which was derived from stepwise [4+2] cycloaddition of auric ate complex 151 and alkynes (Scheme 35). The zwitterionic intermediate 152 generated was more stable than its counterpart 154 because of the stabilization of the propyl group. After intramolecular cyclization and bond rearrangement, naphthalenes 153 could be obtained with a ratio of 92 : 8. However, when a electronwithdrawing group was introduced, a totally reverse ratio o1 : 99 was obtained (Fig. 12, 155).
When this reaction proceeded in an intramolecular manner, steric effects would predominate the regioselectivity. Utilizing this strategy, Oh45 succeeded in synthesizing seven-membered rings under mild conditions. Au–carbene species 157 was believed to be the key intermediate during the catalytic cycle, while other types of intermediate were too strained and unstable to be formed (Scheme 36). With the employment of the ketone 159, Zhang46 demonstrated that this strategy was also efficient in the construction of five-membered rings. Firstly, a Rh species acting as a Lewisacid would activate the triple bond to facilitate cyclization to furnish the furanyl-rhodium carbocation 162. Then, oxidative cyclization would occur to generate the furanyl-fused cyclorhodium intermediate 163. The Rh(III) species would catalyzed regioselective insertion of the triple bond, followed by reductive elimination to afford the final product 161 in good yield (Scheme 37).
6. Outlook and conclusion
Scheme 35 Synthesis of naphthyl ketones by the reaction of 2-alkynylbenzaldehydes and alkynes.
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Double carbometallation of alkynes is an efficient route to various polycycles which are not easily obtained by other means. This approach also deepens our understanding of the nature of the chemistry of double carbometallation of alkynes, for example, via the chemoselectivity of two different alkynes. Based on the versatile reaction types, various substituted p systems could be obtained with the advantage of mild reaction conditions, high functional group tolerance, and high efficiency.
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Preliminary research of their utilities may provide new areas of research for photochemistry. It is believed that more and more catalytic systems will be developed for the double addition of alkynes to introduce diversity and molecular complexity, and this strategy will continue to contribute to synthetic chemistry in the future.
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21 K. Maeda and S. Saito, Tetrahedron Lett., 2007, 48, 3173. 22 T. Shibata, K. Yamashita, H. Ishida and K. Takagi, Org. Lett., 2001, 3, 1217. 23 Y.-H. Kung, Y.-S. Cheng, C.-C. Tai, W.-S. Liu, C.-C. Shin, C.-C. Ma, Y.-C. Tsai, T.-C. Wu, M.-Y. Kuo and Y.-T. Wu, Chem.–Eur. J., 2010, 16, 5909. 24 G. Blond, C. Bour, B. Salem and J. Suffert, Org. Lett., 2008, 10, 1075. 25 X. Chen, J. Jin, Y. Wang and P. Lu, Chem.–Eur. J., 2011, 17, 9920. 26 P. Zhou, M. Zheng, H. Jiang, X. Li and C. Qi, J. Org. Chem., 2011, 76, 4759. 27 T. Fukutani, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2009, 11, 5198. 28 W. Huang, X. Zhou, K. Kanno and T. Takahashi, Org. Lett., 2004, 6, 2429. 29 Y.-T. Wu, K.-H. Huang, C.-C. Shin and T.-C. Wu, Chem.–Eur. J., 2008, 14, 6697. 30 M. Yamashita, K. Hirano, T. Satoh and M. Miura, Org. Lett., 2009, 11, 2337. 31 Z. U. Levi and T. D. Tilley, J. Am. Chem. Soc., 2009, 131, 2796. 32 Y. Luo, X. Pan and J. Wu, Org. Lett., 2011, 13, 1150. 33 T.-C. Wu, C.-C. Tai, H.-C. Tiao, M.-Y. Kuo and Y.-T. Wu, Chem.–Eur. J., 2011, 17, 1930. 34 Y. Luo and J. Wu, Org. Lett., 2011, 13, 5858. 35 N. Mori, S. Ikeda and Y. Sato, J. Am. Chem. Soc., 1999, 121, 2722. 36 Y. Luo, X. Pan and J. Wu, Adv. Synth. Catal., 2012, 354, 3071, and references therein. 37 Y. Minami, Y. Shiraishi, K. Yamada and T. Hiyama, J. Am. Chem. Soc., 2012, 134, 6124. 38 M. Charpenay, A. Boudhar, G. Blond and J. Suffert, Angew. Chem., Int. Ed., 2012, 51, 4379. 39 P. Rivera-Fuentes, M. W. Rekowski, W. B. Schweizer, J.-P. Gisselbrecht, C. Boudon and F. Diederich, Org. Lett., 2012, 14, 4066. 40 J.-J. Lian, P.-C. Chen, Y.-P. Lin, H.-C. Ting and R.-S. Liu, J. Am. Chem. Soc., 2006, 128, 11372. 41 J. R. Dunetz and R. L. Danheiser, J. Am. Chem. Soc., 2005, 127, 5776. 42 K. Sakabe, H. Tsurugi, K. Hirano, T. Satoh and M. Miura, Chem.–Eur. J., 2010, 16, 445. 43 Z. Chen, M. Zeng, J. Yuan, Q. Yang and Y. Peng, Org. Lett., 2012, 14, 3588. 44 N. Asao, K. Takahashi, S. Lee, T. Kasahara and Y. Yamamoto, J. Am. Chem. Soc., 2002, 124, 12650. 45 N. Kim, Y. Kim, W. Park, D. Sung, A. K. Gupta and C. H. Oh, Org. Lett., 2005, 7, 5289. 46 H. Gao and J. Zhang, Chem.–Eur. J., 2012, 18, 2777.
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TUTORIAL REVIEW
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Double carbometallation of alkynes: an efficient strategy for the construction of polycycles Yong Luo,a Xiaolin Pan,a Xingxin Yu*b and Jie Wu*ac Cyclization reactions of alkynes, especially the double carbometallation of alkynes, have drawn much interest from organic chemists because of their high efficiency in the construction of polycycles. Utilizing different nucleophiles or catalytic systems, various efficient strategies to access challenging skeletons have been extensively explored in recent years. In this review, achievements in this field are
Received 29th August 2013
presented in three major parts (the syn–syn, anti–anti, and syn–anti addition reactions of diynes or two
DOI: 10.1039/c3cs60313j
alkyne molecules). Cyclization reactions of diynes initiated by nucleophiles, [2+2+n] cycloaddition, or other processes and reactions, involving two identical or different alkynes are described, which provide
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facile and reliable approaches to various p systems, medium-sized rings, and even macrocycles.
Key learning points (1) (2) (3) (4)
Polycycles with molecular complexity and diversity can be generated efficiently via three types of double carbometallation of alkynes. Diverse carbon- or heterocycles can be synthesized by the utilization of different reagents or catalytic systems. Reaction types and their selectivities can be tuned by various parameters. More novel and functionalized polycycles can be constructed. Interesting properties of these synthesized polycycles may lead for further research.
1. Introduction According to the Dictionary of Natural Products, 90% of chemicals are cyclic compounds. Thus, the synthesis of polycycles always draws considerable interest since polycycles exist widely in natural products and pharmaceuticals. Among the various methods for the synthesis of heterocycles and carbocycles, the cyclization of alkynes plays an important role both in academic research and industry because of the high reactivity and ready availability of the starting materials. Recently, several reviews have introduced recent improvements for the synthesis of cyclic compounds involving alkynes.1 However, most of the examples focused on the single addition of the CRC bond and subsequent transformation. The synthesis of polycycles involving multiple CRC bonds is usually ignored. Among the reviews on reactions involving two or more alkynes, only a small aspect (2+2+2 cycloaddition reactions) of the research a
Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China. E-mail: [email protected]; Fax: +86 21 6564 1740; Tel: +86 21 6510 2412 b School of Pharmacy, East China University of Science and Technology, 130 Meilong Road, Shanghai 200237, China. E-mail: [email protected] c State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
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in this field was discussed.2 However, the synthesis of polycycles with the utilization of multiple triple bonds is significant, because diversity of products can be easily achieved by controlling the regioselectivity and chemoselectivity of the triple bonds. Also, combination with the addition of alkynes and other transformations can largely increase molecular complexity. In order to provide a clear and simple overview for the construction of complex molecules, only selected examples for the synthesis of polycycles via double carbometallation of the alkynes are presented in this review. The other transformations of alkynes, such as into ketones or allenes, are not discussed. The synthesis of substituted benzene or pyridine involving double triple bonds is also excluded.
2. Addition of triple bonds As we all know, there are two types of addition reactions of triple bonds. Lewis-acids can coordinate and activate the triple bond, followed by nucleophilic attack from the opposite side to afford the anti addition product, whereas syn addition of the triple bond happens in the presence of a transition metal. The combination of these types (syn–syn, anti–anti, and syn–anti types) can result in versatile polycycles, which are difficult to obtain by other means. In recent years, with the application of
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many challenging methodologies, such as C–H bond activation, the strategy of double carbometallation of alkynes has been developed as a powerful tool for the synthesis of complex polycycles. It can largely complement or extend current synthetic methods.
Classical Bergman reactions
Anti–anti addition reactions of two triple bonds, especially the thermally induced cyclization of diynes have been studied for several decades. However, in recent years, various Lewis acids have been employed to mediate such processes. As a result, more mild and easily-handled reaction conditions have been developed with a large increase in reaction diversity. Many types of nucleophiles, for example, carbon-, nitrogen-, and oxygen nucleophiles are incorporated to initiate the reaction processes.
The Bergman cyclization (BC) of enediynes is a typical anti–anti type reaction. Despite the remarkable progress made in recent decades, many new applications of the Bergman cyclization for the construction of interesting complex molecules have also been explored. Basak developed an efficient route to [4]helicenes from diynes, in which Bergman cyclization was the key step (Scheme 1).3 This process was initiated by the Bergman cyclization of diyne 1 to generate the diradical 3 with the formation of two new rings. Because of the shielding of the molecular framework, intramolecular attack was preferred to produce intermediate 4. After hydrogen abstraction, the new diradical 5 was furnished. Finally, the [4]helicene was obtained by abstraction of deuterium and subsequent oxidation. Although a long multi-step synthesis of 1 is required, this reaction has many advantages, for example,
Yong Luo was born in Sichuan (China) in 1984. He obtained his BS (2008) and PhD (2013) from Fudan University under the supervision of Professor Jie Wu. His research mainly focused on developing efficient pathways to synthesize polycycles through palladium-catalyzed tandem reactions. Currently, he works as a postdoctoral fellow in the group of Dr Zhaomin Hou at RIKEN (Japan).
Xiaolin Pan was born in Liaoning (China) in 1989. She received her BS (2011) from the Department of Chemistry at Fudan University. In 2011, she continued her studies as a PhD candidate at Fudan University, under the guidance of Professor Jie Wu. Her current research interests mainly focus on methods development for the synthesis of natural product-like compounds via palladiumcatalyzed tandem reactions.
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3.1
Yong Luo
Dr Xingxin Yu received her PhD in Organic Chemistry from Fudan University in 2012 under the supervision of Prof. Jie Wu (2007–2012). After conducting research as a post-doctoral associate in the Department of Medicinal Chemistry at the University of Minnesota Twin Cities (2012–2013), she joined the School of Pharmacy at the East China University of Science and Technology (ECUST). Her Xingxin Yu research is focusing on designing and developing asymmetric small-molecule based candidates for cancer prevention and treatment and elucidating their corresponding mechanisms of action.
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Xiaolin Pan
Prof. Jie Wu received his BSc in chemistry from Jiangxi Normal University in 1995, and he pursued his PhD studies at the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences under the supervision of Prof. Xue-Long Hou (1995–2000). After conducting research as a postdoctoral fellow at Harvard University (2000–2001), he worked as a visiting scientist at the Aaron Diamond AIDS Jie Wu Research Center (2001–2002) and a staff scientist in VivoQuest, Inc. (2002–2004). In 2004, he moved to the Department of Chemistry at Fudan University and held the Professor rank two years later. He got the Thieme Chemistry Journals Award in 2010 and now serves as a member of the Editorial Advisory Board of ACS Combinatorial Science and the Editorial Board of ISRN Organic Chemistry.
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Scheme 1
Tutorial Review
Synthesis of [4]helicene with Bergman cyclization.
mild reaction conditions, no extra catalyst, and high efficiency for the construction of three new rings. 3.2
Scheme 2
Gold-mediated 5-exo cyclization of diynes.
Scheme 3
Gold-catalyzed formation of b-phenylnaphthalene.
Scheme 4
Gold-catalyzed 6-endo cyclization of diynes.
Reactions initiated by carbon nucleophiles
Traditional Bergman cyclization which proceeds by a radical mechanism has obvious drawbacks. Because of the nature of the radical, the scope of the substrates is limited. Many groups that can react with the radical cannot be placed in the ortho position of the alkyne. However, non-classical Bergman-type reactions which are initiated by various nucleophiles in the presence of a Lewis acid show a much higher synthetic potential. Dialkynyl compounds can go through direct cyclization in the presence of Lewis acids to form a new carbocycle and the ring size can be controlled by the use of different reaction conditions. Zhang4 reported the gold-mediated 5-exo cyclization of diynes to form the key gold vinylidene intermediate 9. After a 1,5-hydrogen shift and subsequent protodeauration, a tricyclic compound was generated. The experiments showed that the additive N-oxide was critical for this reaction. It acted as a suitable base to facilitate the exchange of the alkyne terminal hydrogen and the gold species. One possible reason for the preference for 5-exo cyclization was that the resulted s coordination between gold and the alkyne increased the nucleophilicity of the b-carbon of the alkyne. Also, the bulky ligand which made the a-carbon more hindered might be helpful for this high regioselectivity (Scheme 2). Although 5-exo cyclization is preferred in the presence of gold catalyst, six-membered rings can also be formed under certain conditions. Hashmi5 found that the gold acetylide 12 could react with benzene to form the gold carbenoid 13. Then, a ring expansion would occur to generate a six-membered ring. After elimination of [AuL] and catalyst transfer, b-phenylnaphthalene would be produced with high yield (Scheme 3). If there were no basic additives in the reaction system, compound 10 could go through 6-endo cyclization to yield a-phenylnaphthalene (Scheme 4). A large number of experiments and mechanism studies revealed that the addition of NEt3 had a great influence on this selectivity. Without NEt3, 6-endo cyclization of 10 would result in the a product directly. However, when NEt3 was added, there was an equilibrium of 10 and gold acetylide 16 in the buffered medium [Et3NH]+[NTf2] . The intermediate 16 which was more
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reactive than 10 could coordinate with the coexisting IPrAuNTf2 (IPr: 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene, N-heterocyclic carbene) to furnish acetylide 12. Finally, the b product was generated with high selectivity (Scheme 5). In contrast to the gold-catalyzed cyclization of diynes, a pathway involving a diradical in the presence of PtCl2 was proposed by Liu.6
Scheme 5
The effect of NEt3.
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Scheme 8 Scheme 6
Firstly, PtCl2 would coordinate to the substrate and activate the alkynes. Then, 6-endo cyclization would afford the diradical species 19. Its resonance form 20 could undertake C–H bond insertion of the alkane to form a new ring. Subsequent transformations would furnish the desired product 18 (Scheme 6). The intermolecular attack of diynes for the assembly of naphthalene derivatives initiated by carbon nucleophiles has been realized by Liu.7 Pyrrole, ethyl acetoacetonate, and silyl enol ether could be incorporated in this reaction with high regioselectivity. Mechanism studies revealed that this reaction went through a nucleophilic addition–insertion process, which was different from other reactions involving ruthenium–vinylidene or cationic naphthyl species (Scheme 7). Besides other metals, B(C6F5)3, which is strongly electrophilic, can also activate alkynes. Erker8 reported that 1,2-bis(alkynyl)benzene could react with B(C6F5)3 to generate the three cyclic compounds 22, 23, and 24. This reaction was initiated by the addition of B(C6F5)3 to the triple bond to form the intermediate 25. After an intramolecular electrophilic aromatic substitution reaction and subsequent transformation, product 22 was produced. However, if 26 underwent 1,2-C6F5 migration subsequently, it would open a pathway to the formation of 23. This strategy was significant for the synthesis of many interesting polycycles, especially polyfluorene-substituted arenes. However, the poor selectivity in generating complex products indicated that further exploration was needed (Scheme 8).
Scheme 7
The reaction of B(C6F5)3 and a diyne.
PtCl2 catalyzed 6-endo cyclization of diynes.
Ru-catalyzed 6-endo cyclization of diynes.
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If there are several reactive sites in the starting materials, the reaction process is much more complex, and controlling the side reactions is a great challenge. In Liu’s example,9 furan is used as an external nucleophile to react with the diyne 28 in the presence of a gold catalyst. As shown in Scheme 9, a Friedel– Crafts reaction through nucleophilic attack of the furan 5-C on a cationic intermediate would occur first to afford 30. After addition of silver salt, 30 could undergo regioselective 7-endo cyclization and intramolecular attack to form cyclopropyl gold carbenoid 31. Rearrangement of this intermediate followed by intramolecular attack of carbonyl oxygen produced the oxetene 32, which then underwent ring opening to afford the product 33. Although several reaction routes existed in this reaction, phenanthrene derivatives could be obtained with moderate yields after careful optimization of the reaction conditions.
Scheme 9
The reaction of furan and a diyne.
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Scheme 10
3.3
Intramolecular amine initiated reactions.
Reactions initiated by nitrogen nucleophiles
In view of the great bioactive potential of indoles, the synthesis of various modified indole derivatives is always the pursuit of organic chemists. It is well-known that such compounds can be obtained by the direct 5-endo cyclization of 2-alkynylaniline. However, if one more triple bond is introduced in these substrates, more complex products can be obtained. Ohno and co-workers10 developed an efficient strategy for the synthesis of benzo[a]carbazole derivatives through a gold-mediated cascade cyclization of substrate 34. This reaction proceeded with 5-endo cyclization and a subsequent 6-endo process (Scheme 10). 3.4
Reactions initiated by oxygen nucleophiles
In a similar manner to nitrogen initiated reactions, various O-fused polycycles can be generated by oxygen nucleophile initiated reactions. Alabugin11 demonstrated the efficiency of the Sonogashira/ 5-endo/6-endo cascade for the preparation of benzofuran-fused polycycles. Diyne 38 could react with compound 37 under standard Sonogashira reaction conditions to afford benzofuran 39 in moderate yield. However, the addition of gold and silver salts could slightly improve the yield of 39 accompanied with the formation of the desired product 40. In this step, the inefficiency of [Au] was mainly attributed to the basic conditions which inhibited the protodemetalation and the coordination of [Au] with the alkyne. After removal of the base, 39 could undergo 6-endo cyclization in excellent yield to form compound 40 (Scheme 11). However, 6-endo cyclization for carbocycles is not always preferred when other nucleophiles are used. Wang12 found that a 6-endo/5-exo cyclization of 41 led directly to the fused indene 42. In contrast to the cascade processes of the phenol initiated reaction (Scheme 11), the two new rings in 42 were formed concertedly and the intermediate generated by only 6-endo cyclization could not undergo further transformation to afford 42 under various conditions (Scheme 12). Reactions involving intermolecular nucleophilic attack of alcohol on diynes were studied by Liu.7 This strategy also
Scheme 11 Intramolecular phenol initiated reactions.
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Scheme 12
Intramolecular carboxylic acid initiated reactions.
showed high regioselectivity in reactions involving carbon nucleophiles (Scheme 7). The addition of the alcohol always occurred at the more electron-rich alkyne carbon, which suggested that nucleophilic addition happened first, not the formation of a naphthyl cation or radical (Scheme 13). 3.5
Reactions initiated by halopalladation
Besides the above nucleophile initiated reactions, halopalladation can also induce the anti addition of alkynes with the introduction of halides. Wu13 developed a facile route to synthesize indenes 46 via the halopalladation of diynes 45. Typically, transition metal assisted insertion of alkynes proceeds with a syn addition. Thus, intermediate 47 would be generated first in this catalytic cycle. However, anti-type addition could also be achieved by Z,E-isomerization of the intermediate at high temperatures. After subsequent insertion of the other triple bond, the totally anti addition species 49 was yielded. Then reductive elimination followed to afford the desired product 46 and Pd(0), which could be oxidized by CuX2 to regenerate PdX2. If an alcohol such as menthol was added, ligand exchange would occur before reductive elimination to introduce a methoxyl group into the product 46. Furthermore, the introduced halides are highly desirable in synthetic chemistry. These obtained products could be converted
Scheme 13
Intermolecular alcohol initiated reactions.
Scheme 14
Halopalladation of diynes.
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to versatile substituted benzofulvenes by the well-established Suzuki– Miyaura reactions (Scheme 14).
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4. Reactions with syn–syn type addition In contrast to Lewis acid catalyzed anti–anti additions, the syn addition of alkynes usually occurs with catalysis by transition metals. Since numerous transition-metal assisted reactions have been explored in organometallic chemistry, the research in this field is abundant and attractive. Until now, diynes, two identical alkynes or two different alkynes have all been demonstrated to be good substrates for this transformation. 4.1
Syn–syn addition of diynes
4.1.1 [2+2+n] Cyclization of diynes. [2+2+n] Cycloaddition reactions of diynes are the most well-known syn–syn type reactions. In recent decades, various transition-metals have been successfully applied to mediate the cycloaddition of diynes and unsaturated compounds. With a large increase in diversity of selectivities and products, this reaction has become a well-established tool for the construction of hetero- or carbocycles. As shown in Scheme 15, there are two possible pathways which produce intermediate I or II accordingly. Substances possessing a p system, such as an alkene, ketone, CO, or CO2 can firstly coordinate with transition metals. The generated complex species undergoes insertion of the two triple bonds of the diynes one by one to form I. Then, the following ringclosing reaction can give the desired polycycles. However, some cases are believed to go through the production of the metalfused five-membered ring II, which would be produced by transition-metal-mediated annulation of two triple bonds simultaneously. If a 1,1-disubstituted alkene is applied to the cycloaddition reaction, a chiral quaternary carbon atom can be generated.
Scheme 15 Syn–syn additions of diynes.
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Fig. 1
[2+2+2] Cycloaddition of diynes with alkenes.
Shibata14 demonstrated that high enantioselectivity could be achieved for the formation of chiral spirocyclic structure in the presence of [Rh(cod){(S)-xylyl-binap}]BF4 in DCE. Ketone- and ester-substituted alkenes reacted with diynes smoothly. And bicyclic metallacyclopentadiene II was believed to be the reactive intermediate (Fig. 1). Pyridine derivatives can be synthesized by the cycloaddition of diyne with nitrile. Furthermore, Maryanoff15 found that macrocycles could be produced in the presence of CpCo(CO)2 when long-chain diynes were employed. As shown in Fig. 2, meta- and para-pyridines were formed in the reaction, because there were two types of cobalt cycle in the first step. The catalyst CpCo(CO)2 still shows efficiency for the transformation of the CQN bond. 2-Phenylethylisocyanate reacted with a diyne to furnish a mixture of 2-oxopyridinophanes 65 and 66 in 68% yield (Fig. 3). Yamamoto16 reported that Cp*RuCl(cod) was efficient in mediating the reactions of diynes with CRN, CQN, and even CQS and NQS bonds. The reaction of isothiocyanate and carbon disulfide gave rise to the corresponding products 67 and 68 in moderate to good yields. However, when N-thionylaniline was employed in this reaction, pyrrole 70 was obtained instead of the expected product 69, which was likely to undergo SO extrusion after formation (Scheme 16). Nickel-catalyzed cycloaddition of diynes and ketenes have been studied by Louie.17 The results suggested that the CQC bonds in the ketenes participated in the reactions, although there were two possible types of coordination to the metal
Fig. 2
[2+2+2] Cycloaddition of diynes with nitrile.
Fig. 3
[2+2+2] Cycloaddition of diynes with CQN bond.
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Scheme 16
[2+2+2] Cycloaddition of diynes with CQS and NQS bonds.
Fig. 4 [2+2+2] Cycloaddition of diynes and ketenes.
center, CQO or CQC binding. Further research indicated that asymmetric synthesis could be achieved by the use of (R)-BINAP at a higher temperature (Fig. 4, 72). In fact, the CQO bond in CO2 could react with diynes to furnish lactones 56.18 Utilizing Ni(cod)2 as the catalyst and IPr as the ligand, a variety of substituted desired products could be obtained in good to excellent yields. In contrast to most cycloaddition reactions of diynes, it was believed that species I, which was formed by [2+2] carboxylation of one alkynyl unit and subsequent insertion of the other triple bond, was the reactive intermediate (Fig. 5). Cycloaddition of diynes is demonstrated to be efficient in the construction of medium-sized rings 54. Murakami19 reported that ring-opening of the strained ring could expand the intermediate I or II to a nine-membered nickelacycle when cyclobutanones were incorporated in the reaction. The subsequent reductive elimination would give rise to products such as 75. Similarly, the employment of azetidinone or oxetanone could furnish eight-membered heterocycles 76 or 77 in good yield.20 The combination of Ni(cod)2 and IPr was still the best catalytic system (Fig. 6). The seven-membered ring 57 could be synthesized by the cycloaddition of diynes with ethyl cyclopropylideneacetate in
Fig. 5
[2+2+2] Cycloaddition of diynes and CO2.
Fig. 6
Cycloaddition of diynes and four-membered rings.
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Fig. 7 Cycloaddition of diynes and cyclopropanes.
Fig. 8 Cycloaddition of diynes and CO.
the presence of Ni(cod)2 and phosphine-based ligands. Saito21 proposed that insertion of cyclopropylideneacetate into intermediate II followed by ring-opening of cyclopropane and reductive elimination generated the desired products (Fig. 7). IrCl(CO)(PPh3)2 mediated carbonylation of diynes for synthesizing five-membered rings 53 has been realized by Shibata.22 This strategy still showed high efficiency with CO at a partial pressure of ca. 0.2 atm. Under standard conditions, various bicycles, even tetracycles could be formed in moderate to excellent yields (Fig. 8). 4.1.2 Reactions with diynes initiated by oxidative addition. Aryl halides which are very stable and readily available starting materials are widely used in synthetic chemistry. Since oxidative addition of the aryl halides is typically the initial step, the reaction sequence of the substances can be controlled to yield the desired product with high selectivity. Recent research of Wu and co-workers23 revealed that the intermediates generated by the oxidative addition of aryl halides could also insert into the two triple bonds of diynes 82 sequently. If X = H, C–H activation and subsequent reductive elimination could afford the product 87 in good yield. However, when X = I, Pd(IV) species were formed by a further oxidative addition. After reductive elimination to give 88, the resultant Pd(II) species could oxidize the p-xylene to regenerate the active catalyst Pd(0). Utilizing this strategy, various substituted large p systems were synthesized. Further research of their photophysical properties and electrochemistry indicated that different types of product had diverse quantum yields and HOMO potentials, which was useful for screening for efficient electroluminescence materials (Scheme 17). The construction of strained rings meets many challenges in synthetic chemistry. However, Suffert24 developed an efficient method for the synthesis of four-membered ring-fused polycycles via intramolecular double insertion to triple bonds. As shown in Scheme 17, there are two possible pathways for the transformation of intermediate 91. A 6p electrocyclization led to the intermediate 93, which underwent syn dehydropalladation elimination to generate the product 90. An alternative mechanism was that a Heck addition of palladium species to CQC bond would give rise to 92. Then, a rare but known anti dehydropalladation elimination would furnish the desired product (Scheme 18).
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Scheme 17
Scheme 18
Scheme 19
Intermolecular reactions of diynes and amines.
Scheme 20
Halopalladation initiated reactions with diynes.
Intermolecular reactions of diynes and aryl halides.
Intramolecular reactions of diynes and vinyl bromide.
4.1.3 Reactions with diynes initiated by nucleophilic attack. The introduction of other hetero units is also highly desirable because heterocycles exist widely in bioactive molecules. Lu25 found that amines could react with diynes to afford tetracycles in the presence of PdCl2. Firstly, nucleophilic attack of the amine on the triple bond would afford 96 via aminopalladation. After insertion of the second triple bond, the intermediate 97 would undergo C–N bond formation to produce the product 95 and Pd(0), which was oxidized by DMSO to regenerate the active catalytic species Pd(II). The research of the photophysical properties of compound 95 indicated that the fluorescence was efficiently quenched when either nitrobenzene or 2,4,6-trinitrotoluene was gradually added. Thus, it might be used as an alternative sensory materials for the trace detection of these compounds (Scheme 19). 4.1.4 Reactions with diynes initiated by halopalladation. Halopalladation is widely used in organic chemistry, because it can introduce halides with synthetic potential into molecules. Jiang26 reported that chloropalladation of diyne 98 and subsequent Heck reaction afforded triene 101. This newly formed C–Cl bond could go through the Heck reaction to furnish the product 99 (Scheme 20). 4.2
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of diynes usually needs multiple steps, and the scope of substitutions is limited. Thus, reactions involving intermolecular alkynes are much more attractive. In recent years, various efficient methods with the participation of two molecules of identical or different alkynes have been developed. 4.2.1 Reactions involving two identical alkynes. Addition of two identical alkynes offers a simple and efficient approach for the synthesis of p conjugate systems which have important roles in photochemistry. The starting materials in this strategy are easily prepared, some are even commercially available, and stable. For example, utilizing boronic acid 103 as the starting material, Miura and co-workers27 developed a facile route to synthesize naphthalene derivatives and their analogues (Fig. 9). The proposed mechanism consisted of several steps, including transmetalation of the catalyst [Cp*RhCl2]2 with 103, double insertion of the alkynes, C–H bond activation, and reductive elimination to form a C–C bond (Scheme 21). Similar products could be synthesized by using different initial steps. For example, Takahashi28 reported that the reactions of o-diiodoarenes 104 and alkynes could give rise to naphthalenes via a similar mechanism as shown in Scheme 16.
Syn–syn addition of two alkynes
Although great progress has been made in the research of diynes, these substrates have several drawbacks. The preparation
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Fig. 9
The reactions of boronic acids and alkynes.
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Scheme 22
Homocoupling of haloenynes.
Scheme 23
The reaction of haloenyne and an amine.
Scheme 21 Syn additions of two identical alkynes.
Fig. 10 The active intermediates in the reaction of arenes and alkynes.
Double C–H bond activation of arenes 105 could lead to naphthalenes with a high atom economy. However, in contrast to sequent insertion of the C–Pd bond to two alkynes in other examples, Wu and co-workers29 believed that the concerted [2+2] cycloaddition would occur to firstly form palladacyclopentadiene 109. After reacting with xylene 105, the intermediate 110 would be generated. After that, a subsequent C–H bond activation occurred to afford the desired product (Fig. 10). C–C bond activation is challenging because of its stability. In recent decades, C–C bond activation via decarboxylation of vinyl carboxylic acids has made remarkable progress. Utilizing this strategy for the synthesis of polycycles provides an alternative route for synthetic chemists. Miura and co-workers30 reported that substituted carbazoles could be obtained by the reaction of indole-3carboxylic acids 106 and alkynes via decarboxylation. Firstly, carboxyl oxygen directed C–H bond activation of the C2-position and subsequent insertion of the alkyne would produce the intermediate 111. Then decarboxylation would occur to generate the palladacycle 112. Insertion of another molecule of alkyne and reductive elimination took place to yield the product (Fig. 11). Tilley31 reported the synthesis of pentalene derivatives via a palladium-catalyzed homocoupling of haloenynes. Interestingly, Pd nanoparticles were found under the reaction conditions, which indicated that this reaction was likely to be catalyzed by nanometallic Pd (Scheme 22). Wu and co-workers32 found that the reaction of haloenynes and an amine could lead to hetero polycycles such as 115, not indoles as previously reported. It is well-known that 2-alkynylbenzeneamine
Fig. 11 The active intermediates in the reaction of carboxylic acids and alkynes.
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117 would be produced first in this reaction. In contrast to the mechanism for the formation of indoles, highly regioselective insertion of the triple bond of 117 was followed to generate the intermediate 118. Then the intramolecular insertion of the second triple bond and C–N bond formation would take place to afford compound 115 (Scheme 23). Wu33 demonstrated that nitriles could also react with haloenynes in the presence of Ni to produce nitrogen-containing molecules. After oxidative addition of the iodonaphthalene, insertion of the C–Ni bond to the CRN bond of nitrile would occur to afford 121. Then, a highly regioselective insertion of two CRC bonds would generate the intermediate 122. Followed by insertion of the CQN bond, oxidative addition, and reductive elimination would yield the product 120. This method stands out because of its high functional group-tolerance and high efficiency in the construction of large p systems (Scheme 24). 2-Alkynylphenol can react with CO in a ratio of 2 : 1 to afford the heterocycle 125.34 Furthermore, the one-pot synthesis starting from
Scheme 24
The reaction of haloenyne and nitriles.
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Scheme 25
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The reaction of 2-alkynylphenol with CO. Scheme 27
2-iodophenol and alkyne was achieved with a comparable isolated yield. As shown in Scheme 23, the Sonogashira reaction would occur first to afford 2-alkynylphenol 126. Then, Lewis-acidic Pd(II) activated the triple bond to undergo cyclization to form the benzofuranylpalladium species 127. After incorporation of another alkyne, the following carbonylation and reductive elimination would give rise to the product (Scheme 25). 4.2.2 Reactions involving two different alkynes. Compared with reactions involving double alkynes, transformations of two different alkynes which can introduce more diversity have greater synthetic potential. However, this method remains a great challenge because it is difficult to control the reaction order of two alkynes. Finding optimized reaction conditions to avoid homodimerization is always the pursuit of organic chemists. Ikeda35 successfully realized the cyclotrimerization of an enone and two different alkynes in the presence of a nickel catalyst. With slow addition of aryl alkyne, intermediate 131 formed first. Then insertion of the CQC bond of 129 to the C–Ni bond in 131 afforded the seven-membered nickelacycle 132. The following reductive elimination would lead to compound 133 with the regeneration of Ni(0). In order to obtain a better analysis of its regiochemistry, this product was exposed to air for aromatization to generate compound 130 as the final product. This reaction achieved high selectivity because other types of nickelacyclopentadiene were suppressed by a low concentration of substrate or were too unreactive to undergo further transformation (Scheme 26). Wu and co-workers36 found that alkynes bearing ortho nucleophiles could react with 2-alkynylarylbromide to afford tri- or tetracycles. The high regioselectivity achieved, which was attributed to the directing effect of the nucleophile was crucial to accomplish the catalytic cycle. For example, in the reaction of 113 with 134, methyl malonate directed two syn insertions of
Scheme 26
The reaction of enones and alkynes.
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The reaction of two different alkynes bearing nucleophiles.
the C–Pd species to the triple bonds, while 5-endo cyclization of 134 is widely reported in previous research. After that, reductive elimination with the formation of a C–C bond furnished the tetracarbocycle 135 (Scheme 27). Other challenging transformations, such as C–H bond activation can also be applied in the reactions of two different alkynes. Minami37 reported the cyclization of alkynyl ethers with simple alkynes to generate chromenes via C–H bond activation. In contrast to typical weak coordination directing ortho C–H bond activation, this process was initiated by the formation of the zwitterionic palladium complex 140. Then, cyclization and a 1,2-H shift induced oxidative addition to give 142. After that, either inter- or intramolecular insertion of the alkyne could result in the formation of product 139. However, the substitutents of the alkynyl ether were limited to a silyl group, since it was thought to stabilize the negative charge to facilitate the formation of 140 (Scheme 28). Strained four-membered rings could also be synthesized by the reactions of two different alkynes. Suffert38 reported that compound 145 could undergo intramolecular insertion of the triple bond and a subsequent Sonogashira reaction to give 147. Under proper reaction conditions, regioselective attack of the terminal alkyne on the triple bond of 147 would occur to afford 148. Subsequently, 8p electrocyclization would take place followed by rearrangement to furnish the strained tetracycle 150 (Scheme 29).
Scheme 28 activation.
The reaction of two different alkynes involving C–H bond
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Scheme 29 rings.
Scheme 30
Scheme 31
Intramolecular [3+2] cyclization of diynes.
Scheme 32
Intramolecular [4+2] cyclization of diynes.
The reaction of two different alkynes for synthesis of strained
The reaction of two different alkynes involving dibromoolefins.
Diederich39 developed an alternative pathway for the construction of pentalene derivatives with the utilization of gemdibromoolefins. The initial step was the coordination of Pd(II) to the triple bond of 129, directing the oxidative addition to the desired C–Br bond. Intramolecular carbopalladation at the triple bond followed to give rise to the fulvene 132. Subsequent intermolecular carbopalladation of another alkyne and zincpromoted cyclization furnished the product 130 (Scheme 30).
5. Reactions with syn–anti type addition 5.1
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[3+2] or [4+2] cyclization reactions
When an alkyne reacts with another triple bond along with its substitutent, a [3+2] or [4+2] cyclization can proceed with syn– anti type additions. Liu40 realized intramolecular [3+2] cyclization of diynes in the presence of a gold catalyst. This process was initiated by nucleophilic attack of the phenyl substituent of 134 at the triple bond activated by gold salt, providing the vinylgold(I) intermediate 136. Protonation of the other triple bond was proposed to take place subsequently, followed by 5-exo cyclization to form the desired product 135 (Scheme 31). Intramolecular [4+2] cyclization of diynes was developed by Danheiser and a new strategy for the synthesis of indoles was
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reported.41 For example, enynamide 137 could go through concerted [4+2] cyclization to generate the strained isoaromatic cyclic allene 138. After that, indoline 139 was generated via a proton or hydrogen atom transfer pathway. With the utilization of different substrates, indolines bearing various substitutents at the C-4 or C-7 position could be synthesised. Furthermore, subsequent oxidation led to the corresponding indoles in good yields (Scheme 32). Intermolecular [4+2] cyclization could also be utilized to synthesize polycycles. Miura42 developed an efficient pathway to construct naphthalenes via cyclodimerization of two alkynes. In the presence of Rh(I), oxidative addition of HX occurred first to generate the active Rh(III) species 143. Insertion of 140 to the Rh–H bond and Z,E-isomerization followed to form 144. Then, C–H activation and selective insertion of 141 to this intermediate furnished the desired product 142 (Scheme 33). Diyne 28 has been demonstrated to be a good substrate for anti–anti type reaction (Scheme 9). However, syn–anti type addition can also take place in the presence of electrophilic regents. Chen43 reported that 28 reacted with NIS forming tetracyclic benzo[a]fluorenols under mild conditions. During the catalytic cycle, the electrophile would activate the triple bond. The following electrophilic attack of another triple bond
Scheme 33
Intermolecular [4+2] cyclization of diynes.
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Fig. 12 Intermediate and product of the reaction of 2-alkynylbenzaldehydes and alkynes.
Scheme 34
Synthesis of a seven-membered ring.
Scheme 37
Synthesis of a five-membered ring.
Reactions of diynes and electrophiles.
would generate the vinylic carbocation 147. Then, intramolecular Friedel–Crafts cyclization gave rise to tetracycles 148. However, this compound was unstable under the reaction conditions. The hydroxy group could be released by the activation of Lewis acid. Subsequent tautomerization would afford a more stable positive ion intermediate 149, in which the cation was stabilized by three aryl groups. Finally, this cation trapped by hydroxy group would furnish the desired product 146 (Scheme 34). 5.2
Scheme 36
Reactions initiated by intramolecular nucleophilic attack
An alkyne bearing a nucleophile can undergo intramolecular nucleophilic attack first to produce an anti addition intermediate. Another alkyne can react with this intermediate through an [n+2] cyclization with syn addition. Yamamoto44 reported that naphthyl ketones could be synthesized by the reaction of 2-alkynylbenzaldehydes with alkynes. Furthermore, either terminal or internal alkynes could be incorporated in this process with high regioselectivity, which was derived from stepwise [4+2] cycloaddition of auric ate complex 151 and alkynes (Scheme 35). The zwitterionic intermediate 152 generated was more stable than its counterpart 154 because of the stabilization of the propyl group. After intramolecular cyclization and bond rearrangement, naphthalenes 153 could be obtained with a ratio of 92 : 8. However, when a electronwithdrawing group was introduced, a totally reverse ratio o1 : 99 was obtained (Fig. 12, 155).
When this reaction proceeded in an intramolecular manner, steric effects would predominate the regioselectivity. Utilizing this strategy, Oh45 succeeded in synthesizing seven-membered rings under mild conditions. Au–carbene species 157 was believed to be the key intermediate during the catalytic cycle, while other types of intermediate were too strained and unstable to be formed (Scheme 36). With the employment of the ketone 159, Zhang46 demonstrated that this strategy was also efficient in the construction of five-membered rings. Firstly, a Rh species acting as a Lewisacid would activate the triple bond to facilitate cyclization to furnish the furanyl-rhodium carbocation 162. Then, oxidative cyclization would occur to generate the furanyl-fused cyclorhodium intermediate 163. The Rh(III) species would catalyzed regioselective insertion of the triple bond, followed by reductive elimination to afford the final product 161 in good yield (Scheme 37).
6. Outlook and conclusion
Scheme 35 Synthesis of naphthyl ketones by the reaction of 2-alkynylbenzaldehydes and alkynes.
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Double carbometallation of alkynes is an efficient route to various polycycles which are not easily obtained by other means. This approach also deepens our understanding of the nature of the chemistry of double carbometallation of alkynes, for example, via the chemoselectivity of two different alkynes. Based on the versatile reaction types, various substituted p systems could be obtained with the advantage of mild reaction conditions, high functional group tolerance, and high efficiency.
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Preliminary research of their utilities may provide new areas of research for photochemistry. It is believed that more and more catalytic systems will be developed for the double addition of alkynes to introduce diversity and molecular complexity, and this strategy will continue to contribute to synthetic chemistry in the future.
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846 | Chem. Soc. Rev., 2014, 43, 834--846
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