chapter 1 introduction to diversity oriented synthesis...

Chapter 1 Introduction to Diversity Oriented Synthesis

(DOS) Using Metal Catalysis and Multicomponent Reactions

Chapter 1: Introduction to DOS using Metal Catalsysis ....

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INTRODUCTION 1.1. Diversity oriented synthesis (DOS) The screening of compound libraries to identify useful modulators of biological systems is fundamental to the drug discovery process and chemical biology studies.1 Traditionally, the molecules in these libraries have come from nature, and there are many examples in which natural products and their derivatives and analogues are either new drug candidates or tools for chemical biology and medicinal chemistry research. However, some difficulties are associated with using natural products in screening experiments; for instance, their purification, meager amounts available, the identification of biologically active components, and nature “fails” to provide several analogues, which are necessary for structure–activity relationship (SAR) studies. These restrictions make chemical synthesis the only alternative to obtain unambiguously characterized, diverse, multifunctional molecules that are similar to natural products. However, finding compounds with novel biological activity in this vast space is like finding a needle in a haystack. To increase the odds, the molecular diversity among the library members should be as great as possible within the boundaries of biological activity space. Diversity-oriented synthesis (DOS), a terminology initially coined by Schreiber,2 is a technique to identify biologically relevant chemical space.3 There have been several definitions of DOS suggested, but in order to facilitate the present discussion the following definition will be adopted. “Diversity-oriented synthesis involves the deliberate, simultaneous and efficient synthesis of more than one target compound in a diversity-driven approach to answer a complex problem.” Applying the principles of DOS to the lead generation step in the drug discovery process could facilitate the discovery of new molecule entities. Several DOS strategies have been reported, such as the build-couple-pair strategy,4 the click-click-cyclize strategy,5 the fragment-based approach,6 and others.7 In recent years, the branching cascade technique has gained much interest, because of its potential to transform a common type of substrate into diverse and distinct molecular/structural frameworks under the influence of either different reagents or different reaction conditions.8

Assessing diversity: Biological macromolecules interact with each other in a three dimensional environment. Functional diversity is directly related to the three-dimensional chemical information that the surface of a small molecule presents to a macromolecule. Thus, the functional diversity is directly associated with the structural


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diversity of a compound collection. Further the structural diversity is typically divided into three fundamental levels of diversity (Figure 1):9 (a) Appendage diversity (combinatorial chemistry)—variation in structural moieties around a common skeleton; (b) Stereochemical diversity—variation in the orientation of potential macromolecule-interacting elements; (c) Scaffold diversity—presence of many distinct molecular skeletons.

Figure 1. The three fundamental levels of structural diversity: appendage, stereochemical, and scaffold diversity.9

The advent of combinatorial chemistry allows for the synthesis of vast numbers of compounds using split-pool combinatorial techniques10 and improvements in robotics enabled high throughput screening (HTS) of these vast libraries against diverse protein targets.11 The problem with combinatorial chemistry so far is that the compounds produced have a limited structural diversity.12 For example, a collection of over two million compounds was reported in the literature,12 but structurally the compounds all look rather similar. This is because only building block diversity was introduced, the molecular framework is nearly the same. In order to achieve the highest levels of structural diversity: (i) the building blocks, (ii) the stereochemistry, (iii) the functional groups and, most importantly, (iv) the molecular framework must be varied. Diversity oriented synthesis on the other hand can be used for exploring large areas of chemical structure space in search of new bioactive small molecules that might not be achieved by conventional synthetic methods. The synthesis of small molecules focused around a lead structure (the target molecule) is relatively easy: diversifying a scaffold with different building blocks. The efficient synthesis of structurally diverse small molecules has been distinguished from target- oriented synthesis (e.g. natural product synthesis and focused ‘library’ synthesis) and termed diversity-oriented synthesis (Figure 2).13


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Figure 2. Comparison of target-oriented synthesis versus diversity-oriented synthesis (DOS).13

1.2. Multi-component reactions Multicomponent reactions14 (MCRs) are increasingly recognized as valuable tools in the realization of diversity oriented synthesis (DOS).15,16 Since the pioneering work of Passerini and Ugi, MCRs have become popular tools for diversity generation during drug development.17 A multicomponent reaction (MCR) is generally defined as any process in which three or more reactants combine in one pot to form a product that incorporates structural features of each reagent.18 As, MCRs, being one-pot reactions, are practically single-step conversions, they are easier to carry out than multistep synthesis. Thus, the MCRs already come quite close to the idea of an “ideal synthesis” (Figure 3).14d,19

Figure 3. The ideal chemical synthesis.14d,19

Besides generating structural complexity in a single step, MCRs offer the advantage of simplicity and synthetic efficiency over conventional chemical reactions. The most useful MCRs have the additional advantages of selectivity, synthetic convergence, and atom-


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economy.20 MCRs represent the cornerstones of both combinatorial chemistry and diversity-oriented synthesis and thus have played a central role in the development of modern synthetic methodology for pharmaceutical and drug discovery research.21

Despite the spectacular investment in, and organic growth of, combinatorial chemistry as a platform technology within the pharmaceutical industry during the 1980s and 1990s, few new MCRs were discovered or developed by corporate research laboratories. Most combinatorial libraries were assembled using traditional, tried-and-true processes such as the Biginelli (1891), Hantzsch (1882), Mannich (1912), Passerini (1921), Strecker (1850), and Ugi (1959) multicomponent reactions. An overview of some of the common multicomponent reactions (MCRs) is given below (Table 1).

Table 1. Some important MCRs leading to heterocycles.

Name of the reaction

Year of discovery Example

Strecker synthesis22 1850

Hantzsch dihydropyridine synthesis23

1882

Radziszewski imidazole synthesis24 1882

Hantzsch pyrrole synthesis25 1890

Biginelli reaction26 1891

Mannich reaction27 1912

Bucherer-Berges hydantoin synthesis28 1941

O

N N

NHNH

OO

O O

NH3+ + CO2 + HCN HNNH

O

O

TT

T = thymine


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1.2.1. Strecker Reaction The Strecker reaction, discovered in 1850, has been recognized as the first multicomponent reaction and has a central importance to the life sciences. The three-component coupling of an amine, a carbonyl compound (aldehyde or ketone), and hydrogen cyanide to give α-aminonitriles constitutes an important indirect route in the synthesis of α-amino acids,29 this perhaps, represents one of the earliest examples to use the chiral amine, 1-phenylethylamine (1) (Scheme 1). The reaction was carried out in the presence of different arylalkyl methyl ketones (2) and sodium cyanide leading, after isolation by crystallization, to only one diastereomer (3) in excellent yield. A careful study of the crude solution mixture by 1H NMR spectroscopy showed that, in fact, the reaction yielded a ~1:1 mixture of two possible diastereomers. However, preferential crystallization of the product under kinetic control, and reversal of the final addition reaction for the other diastereomer, gives as a result only one diastereomeric product.30

Scheme 1. Diastereoselective Strecker MCR with phenylethylamine.

1.2.2. Mannich Reaction The classic Mannich reaction, discovered in 1912, is an aminoalkylation of carbonylic compounds involving ammonia (or an amine derivative), a non-enolizable aldehyde (usually formaldehyde), and an enolizable carbonyl compound. From a modern viewpoint, the potential of this reaction is rather modest due to limitations such as undesired by-products, unsatisfactory regio- and stereocontrol, etc. However, the exceptional attractiveness of final products makes the challenge of overcoming these drawbacks worthwhile. The starting chiral compound can be the aldehyde (4) (Scheme 2). The reaction catalyzed by ytterbium triflate in water afforded the expected aminoketone (7) in excellent yield, although with a disappointing diastereomeric ratio.31


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Scheme 2. Diastereoselective Mannich MCR with a chiral aldehyde.

1.2.3. Biginelli Reaction The Biginelli dihydropyrimidine synthesis,32 first described in 1891, consists of the condensation of urea (8), a 1,3-ketoester (9), and an aldehyde (10). The accepted mechanism involves, first, the condensation of urea with the aldehyde to yield an iminium intermediate, which is then trapped by an aldol-type reaction with the enol derived from the ketoester. The first example reported used different aldehydes derived from cyclic and acyclic pentoses, which yielded only one diastereomer after purification.33 However, a further study with pentoses and hexoses34 showed that the diastereoselectivity was far superior in the case of hexose derivatives. The best result was obtained with the galactosyl derivative (10), with one equivalent of CuCl and BF3 and catalytic amounts of acetic acid (Scheme 3).

Scheme 3. Diastereoselective Biginelli MCR.

1.2.4. Petasis Reaction The condensation already reported in 1993 between carbonyl compounds, amines, and aryl or vinyl boronic derivatives is recognized as the Petasis reaction. The reaction can be performed with chiral amines, chiral carbonyl compounds, and chiral boronic acid derivatives. The use of chiral phenylglycinol (12) in combination with (E)-2-


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phenylvinylboronic acid (13) and glyoxylic acid (14) yielded the expected amino acid derivative (15) with excellent diastereoselectivity (Scheme 4). Its further hydrogenolysis gave D-homophenylalanine which demonstrates the utility of this new approach in the synthesis of α-amino acids.35

Scheme 4. Diastereoselective Petasis MCR with chiral amines.

1.2.5. Hantzsch Multicomponent Reaction Another venerable and old MCR is the synthesis of 1,4-dihydropyridines by the reaction of enamines, aldehydes, and 1,3-dicarbonyl compounds, it was first reported in 1882.36 However, to date its enantioselective version is unknown, and in the few examples reported, the diastereoselectivity is far from acceptable. The chiral starting material used can be either the 1,3-dicarbonyl compound, the enamine derivative,37 or even the aldehyde.38 However, in all cases the diastereomeric ratio is lower than 60:40, probably due to the harsh conditions used in the standard procedures (Scheme 5), under which the chiral enamine (16) gave a very low diastereoselectivity.

Scheme 5. Diastereoselective Hantzsch MCR.

1.2.6. The Passerini Reaction The classic reaction between carboxylic acids, oxo compounds and C-isocyanides, described by Passerini in 1921 and later given his name, opens the access to α-acyloxycarboxamides in one step.39 In contrast to the Ugi reaction, the Passerini


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reaction is accelerated in aprotic solvents, indicating a nonionic mechanism.40 A plausible mechanism which agrees with the experimental data is the formation of a loosely hydrogen-bonded adduct (20) from a carbonyl compound (18) and a carboxylic acid (19), followed by the α-addition of the electrophilic carbonyl carbon and the nucleophilic oxygen atom of the carboxylic acid to the isocyanide carbon formation of a cyclic transition state (21) involving all three parent compounds (Scheme 6). The α-adduct (cyclic transition state) (21), which cannot be isolated, rearranges in an intramolecular transacylation to the stable α-acyloxy carboxamide (22).

Scheme 6. Suggested mechanism for the P-3CR.

A comprehensive study of the Passerini reaction has been performed with the α-aminoaldehydes (23) derived from natural amino acids.41,42 The results were very homogeneous, independent of the carboxylic acid or isocyanide reagents used, and the aldehyde side chain was found to have little influence on the diastereoselectivity (Scheme 7). This strategy has been applied to the solid-phase synthesis of different oligopeptides by using a supported isocyanide and a chiral phenylalaninal derivative; the diastereoselectivity was appreciably lower than for the reaction in solution.43

Scheme 7. Diastereoselective Passerini MCR with a chiral aldehyde.


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1.2.7. Ugi Reaction The Ugi MCR, first described in 1959, has been more widely studied and used than any other MCR.44 This extraordinary success is associated with the fact that it introduces a higher degree of diversity than other processes. Moreover, the two possible amide bonds that link the reagents in the final chiral product are especially suitable for the synthesis of peptidomimetics.45A simplified reaction mechanism for U-4CRs with carboxylic acids is shown in Scheme 8. In the first step, the oxo component and the amine condense to the imine (25) which can be understood as a carbonyl analogue. Like most imine reactions, the U-4CR runs better upon activation of the imine (25). For this, the acid component protonates the nitrogen atom of the imine, thus increasing the electrophilicity of the C=N bond. The electrophilic iminium ion (28) and the nucleophilic acid anion add to the isonitrile carbon to form the intermediate 27. This α-adduct can be seen as a hetero analogue of an acid anhydride in which an exo-oxygen atom has been substituted by an NR group. Acid anhydrides are strong acylating agents, as are their heteroanalogues formed here. The closest acylable atom is the nitrogen of the former amine. After an intramolecular acylation and subsequent amide rearrangement the stable Ugi product (28) is obtained. This type of intramolecular acylation was first described in 1910 by Mumm and was subsequently called the Mumm rearrangement.46 All elementary steps of this reaction are in equilibrium, except the last step. The latter, giving a stable product, drives the whole reaction in the right direction. In the course of the U-4CR, one C-C bond and three heteroatom-C bonds are newly formed (Scheme 8).

Scheme 8. Possible mechanism for Ugi-four component reaction.


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In the case of α-amino acid derivatives (29) as acid partners, the dipeptide (30) was obtained with almost no diastereoselectivity, regardless of the aldehyde, the isocyanide, or the side chain of the acid (Scheme 9).47 Similar results were obtained when a solution of ammonia was used instead of the amine,48or when the isocyanide was bound to a solid phase.49 Even the use of polyfunctionalized β-amino acid derivatives did not lead to any diastereoselectivity.50

Scheme 9. Diastereoselective Ugi four-component reaction with a chiral acid.

However, judging from numerous recent reports,51 interest has now intensified within academic laboratories in the development of new MCRs as the basis for complexity-generating strategies for the synthesis of small molecules. The earliest MCRs were almost certainly discovered by chance or serendipity. With the emergence of rational, well defined reaction mechanisms guided by the concepts of structure and bonding in organic chemistry, opportunities arose for rational analysis and design of MCRs. For example, it seems likely (although uncertain) that the discovery of the Ugi four component synthesis of R-amino acid diamides was based on Ugi’s prior knowledge of the Passerini three-component synthesis of O-acylated R-hydroxyamides (vide infra). That link notwithstanding, the rational design (or improvement) of practical and versatile multicomponent reactions, especially those that form medicinal or natural product-like frameworks, remained, until recently, a largely unmined area of chemical research. Figure 4 depicts a general approach to improving known MCRs that takes advantage of a detailed knowledge of reaction mechanisms. A typical four-component reaction of interest in combinatorial synthesis would employ inputs A, B, C, and D, each representing a family of compounds. The overall transformation might be visualized as a linear series of individual bimolecular reactions successively producing the symbolic intermediates A-D and A-D-C on the way to the final MCR product, A-D-C-B.


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A-D-C-BA-D-CA-D

X + Y

Q + R + S

A + B + C + D

Figure 4. Improving known MCRs by retrosynthetic analysis.52

However, the notion that the creative or serendipitous elements involved in inventing or discovering new MCRs might also be guided, somehow, by a rationally designed process seems far less obvious. Nevertheless, Figure 5 depicts a general strategy whereby mechanistic insights into a known MCR might serve as an innovation platform for finding new MCRs using a process nicknamed the single reactant replacement (SRR) approach. This approach begins with a systematic assessment of the mechanistic or functional role of each reactant in a known MCR. Based on the resulting chemical insights, one input (A, in this case) is then replaced with a different input W that mimics the key chemical reactivity or property necessary for condensation to occur with B and C. By embedding additional reactivity or functionality (either explicit or latent) into W, the resulting MCR might be directed to a different outcome, for example, either a new structural framework or ring system. Thus, the chemist‘s mechanistic insight into a known MCR can serve as an innovation platform from which to design or create imaginative SRR substitutions.52

Figure 5. The single reactant replacement approach to finding new MCRs.52


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1.3. Rational Design Strategies for MCRs Although the above examples demonstrate the potential of post-MCR cyclization strategies to increase molecular diversity and complexity, the most straightforward approach to address the issue of limited scaffold diversity is the rational design of novel (multicomponent) reactions. Four strategies for the design of novel multicomponent reactions are represented schematically in Figure 4: a) Single reactant replacement (SRR); b) modular reaction sequences (MRS); c) conditions-based divergence (CBD), and d) combination of multicomponent reactions (MCRs). 1.3.1. Single Reactant Replacement The phrase “single reactant replacement” (SRR) was first coined by Ganem52 and involves the development of new MCRs by systematic assessment of the mechanistic or functional role of each component in a known MCR. It involves the replacement of one reactant (C) with a different reactant (D-X) that displays the same essential reactivity mode required for the multicomponent condensation. By incorporating additional reactivity or functionality, the resulting MCR may be directed to a different product scaffold. Probably one of the first examples of SRR was reported by Ugi, who replaced the carbonyl component used in the Passerini 3CR53 by an imine, which resulted in the well-known Ugi reaction (Scheme 10). Ugi also replaced the carboxylic acid input of the Ugi reaction by different acidic components to afford diverse scaffolds. The mechanism of the Ugi reaction is generally believed to involve protonation of the imine by a weak acid (e.g. a carboxylic acid) followed by nucleophilic addition of the isocyanide to the iminium ion. The resulting nitrilium ion is subsequently attacked by the conjugate base of the weak acid (e.g. a carboxylate), which only needs to be weakly nucleophilic. Thus, the carboxylic acid in the classical Ugi reaction may be replaced by a variety of weak inorganic acids [e.g. HOCN and HSCN could be used to afford (thio)hydantoinimides 33a and 33b, respectively]. These are formed from the corresponding α-adducts by cyclization of the intermediate β-amino iso(thio)


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cyanates. The use of hydrazide (HN3) resulted in the formation of tetrazoles (34) by spontaneous cyclization of the α-adduct. When water or hydrogen selenide is used, the corresponding α-adducts undergo tautomerization to afford amides (35a) and selenoamides (35b), respectively.

Scheme 10. Sequential SRR from the Passerini to the Ugi reaction (SRR1) to Ugi variations (SRR2).

A second strategy for the discovery of novel MCRs involves modular reaction sequences (MRSs, Figure 5). This approach is related to SRR, but involves a versatile reactive intermediate that is generated from substrates by an initial MCR.54 This reactive intermediate is then treated in situ with a range of final differentiating components (D, E, and F) to yield a diverse set of scaffolds. One striking example is the use of 1-azadiene (36) as the intermediate to achieve scaffold diversity (37-49).55 The 1-azadiene (36) is generated in situ from a phosphonate, a nitrile, and an aldehyde by a 3CR involving a Horner–Wadsworth–Emmons (HWE) reaction (Scheme 11).56


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Scheme 11. Modular reaction sequence involving the 1-azadiene 3CR as the initial MCR, to which several fourth components were added.

1.3.2. Divergence through Changing the Reaction Conditions Conditions-based divergence in MCRs generates multiple molecular scaffolds from the same starting materials by merely applying different conditions. For example, the use of specific catalysts, solvents, or additives may direct the course of the reaction along different pathways that produce distinct scaffolds. In 2008, Chebanov et al. reported an excellent example of a condition-based divergence by the multicomponent reaction of 5-aminopyrazole (50), cyclic 1,3-diketones (51), and aromatic aldehydes (Scheme 12).57 5-Aminopyrazole (50) has at least three non-equivalent nucleophilic centers (N1, C4, NH2), but the authors were able to direct the reaction to three distinct scaffolds (52, 56, 58) by changing the reaction conditions.


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Scheme 12. Tuning a 3CR to three different scaffolds by adapting the reaction conditions.

1.3.3. Combination of MCRs The combination of MCRs is a fourth strategy for the rational design of novel MCRs that combine two (or more) different types of MCRs in a one-pot process. The presence of orthogonal reactive groups on the product of the primary MCR, which is either formed during the primary MCR or present in one of the inputs allows the combination with the secondary MCR.58 Varying the successive MCR will make diverse (and complex) scaffolds available, thus making this strategy excellent for application in DOS. The combination of MCRs in one pot was first introduced by Dömling and Ugi who developed a seven-component reaction (7CR) by the one-pot combination of a modified Asinger 4CR59 and the Ugi 4CR. In this 7CR, an α- or β-halo aldehyde, NaSH/NaOH, NH3, another aldehyde, an isocyanide, CO2, and a primary alcohol (solvent) are combined to afford complex thiazolidines (60) efficiently (Scheme 13). However, NaSH/NaOH, NH3, and CO2 are invariable components in this reaction, which significantly limits the appendage diversity and thus the scope of the MCR.


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Scheme 13. Combination of the modified Asinger 4CR and an Ugi-type MCR to afford thiazolidines.

1.4. Towards stereoselective multicomponent reactions (MCRs) One of the main limitations of MCRs as synthetic tools is the typical lack of stereocontrol. For example, a generally applicable catalytic asymmetric Ugi reaction is considered a holy grail in MCR chemistry. In practice, however, the stereoselectivity of many (isocyanide-based) MCRs is notoriously poor. Although there are some examples of catalytic asymmetric Passerini(-type) three-component reactions (P-3CR),60 the enantioselectivities are generally modest and only good in specific cases, with aluminum–salen complexes being the most promising catalysts.61 Zhu and co-workers have recently reported very promising results for their isocyanide-based MCRs for the synthesis of oxazoles.62 The general problem is that many MCRs, including the U-4CR, are essentially uncatalyzed. The discovery of a catalyst for a certain MCR is the important first step in the development of a (catalytic) asymmetric version.63 For example, acid-catalyzed classical MCRs such as the Hantzsch,25 Biginelli,26 Povarov,64 and Mannich27 reactions have greatly benefited from the recent rise of chiral Brønsted acid catalysis (Scheme 14).65 Other recent developments in organocatalysis have led to the development of a number of very elegant asymmetric cascade processes.66

1.5. Transition metal catalysis Heterocyclic compounds are worth our attention for many reasons; chief among them are their biological activities, and many drugs contain heterocyclic moieties. The most common approaches used for the synthesis of these compounds include: (1) C-C bond formation from the corresponding acyclic precursors and (2) C-Y bond formation from the corresponding acyclic precursors, as shown in Scheme 15.


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Scheme 14. a) Organocatalytic asymmetric Biginelli 3CR using chiral phosphoric acid (65). b) Organocatalytic asymmetric Hantzsch 4CR using chiral phosphoric acid (66). c) Organocatalytic asymmetric Povarov 3CR using chiral phosphoric acid (67). d) Organocatalytic asymmetric Mannich 3CR using chiral phosphoric acid (67).

Scheme 15. Two major processes of heterocycle synthesis.67-71


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It can be seen from Scheme 16 that the heterocycle synthesis with transition-metal catalysts is classified on the basis of both starting substrates and reaction patterns. It is noteworthy that all the starting materials possess C-C and/or C-heteroatom unsaturated bond(s) in (a) certain position(s) of their structural framework and those functional groups become a reactive site for making a new C-C and/or C-heteroatom bond (C-Y bond). This is a logical outcome, since the formation of a complex between a transition metal and C-C (or C-Y) unsaturated bond plays an important role in the transition-metal-catalyzed67 reaction and often triggers a key reaction for producing heterocycles. It should be also noted that, in most sections, the very popular and modern reactions in the field of transition-metal-catalyzed chemistry are utilized for the synthesis of heterocycles, for example, ring-closing metathesis (RCM), Pauson-Khand, Heck, Suzuki, Stille, and Tsuji-Trost reactions. Compared to the traditional organic transformations leading to heterocycles, the transition-metal-catalyzed transformation seems to be not straight forward and not easily understandable in many cases. This is presumably due to the fact that sequential processes often are involved in the catalytic transformation, which makes it difficult to understand at a glance the conversion from a starting substrate to a final product. Accordingly, in this review, reaction processes of a complicated transformation are shown when the total conversion from a starting material to a product seems to be not easily understandable. An important feature in the modern heterocycle synthesis68 with transition-metal catalysts is that asymmetric catalytic synthesis is becoming very popular and attracting keen interest of a wide range of organic chemists.69

Transition-metal-catalyzed intramolecular reactions of carbon-carbon unsaturated compounds tethered with N-H, O-H, CdO, and CdN groups have been extensively studied and have become a powerful tool for the synthesis of heterocycles. Alkenes, allenes, methylenecyclopanes, and alkynes have been utilized as a carbon-carbon unsaturated compound, and a wide variety of transition-metal complexes, such as palladium, platinum, gold, copper, titanium, tungsten, and organolanthanides, have been used as a catalyst. In these reactions the heterocyclic compounds are produced via carbon-heteroatom (C-Y) bond formation (see Scheme 16).


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Scheme 16. Classification of heterocycle synthesis, based on starting substrates and reaction patterns.71


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The transition-metal catalyzed intramolecular addition reaction of Y-H to the C-C unsaturated bonds is classified into two major groups, as illustrated in Scheme 17. In the presence of a higher valent transition-metal catalyst, such as PdII, AuIII, and HgII, the reaction having a Y-H group is initiated by the formation of the π-olefin complex through the coordination of the carbon-carbon unsaturated bond to the transition metal.70 Subsequent intramolecular nucleophilic attack of the heteroatom to the electron-deficient unsaturated bond produces the new heterocyclic organometallics. On the other hand, the ruthenium, titanium, and organolanthanide-catalyzed reaction of the amine derivatives starts from the formation of the metal-amido complex, and the following intramolecular aminometalation of the C-C unsaturated bond produces the new heterocyclic organometallics. The organometallic compounds undergo either β-elimination or the reaction with electrophiles to give the corresponding heterocyclic products.71

Scheme 17. Heterocyclization of C-C unsaturated compounds having a heteroatom-hydrogen bond.70,71

Among the transition metal catalysts, gold- 72 and platinum-73 catalyzed electrophilic activations of alkynes represent a recent advent in organic synthesis.74 Recently, in the synthesis of alkenyl arenes and heteroarenes,75 Reetz and Sommer76 found independently that gold complexes catalyze the intermolecular hydroarylation of alkynes. On the other hand, Fürstner et al. reported a similar reaction for the synthesis of phenanthrenes that is catalyzed by PtCl2 and other metal halides.77 Sames and co-workers have developed an intramolecular hydroarylation catalyzed by PtCl4 that proceeds under mild conditions.78


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1.6. Gold catalyzed intramolecular cyclization Gold salts and complexes have emerged in the past few years as the most powerful catalysts for electrophilic activation of alkynes towards a variety of nucleophiles (O-, N-, C-nucleophiles)78-80 under homogeneous conditions. In a simplified form, a nucleophilic attack on the [AuL]+-activated alkyne (68) proceeds via π-complexes to give trans-alkenyl gold complexes (69) as intermediates (Scheme 18). In most cases, the reaction occurs under very mild reaction conditions and with high functional-group tolerance. Only with the gold catalyst, often a cationic gold species, coordinated to the alkyne in a gold–alkyne complex, is the reaction rate enhanced.81

Scheme 18. Synthesis of alkenyl gold complexes.82

1.6.1. Intramolecular hydroamination of C–C triple bonds In recent years, the development of hydroamination reactions, achieved in the presence of certain catalysts,82-84 has received much attention. It is important to understand that alkynes undergo hydroamination reactions more easily than alkenes. Gold complexes have attracted intense interest for the development of environmentally benign alternative routes of hydroamination of unactivated alkenes, alkynes, allenes, and 1,3-dienes.85 Utimoto et al.86 investigated the intramolecular hydroamination reaction of alkynes (70) under mild and neutral conditions, where gold(III) catalysts were superior to palladium(II) catalysts for the 6-exo-dig cyclization. After the initial enamine (71) formation by hydroamination, a subsequent tautomerization led to the thermodynamically more stable imine (72) as a product. They used sodium tetrachloroaurate as the catalyst and needed relatively high catalyst loadings of 5 mole% (Scheme 19).


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Scheme 19. Intramolecular hydroamination reaction of alkynes.

In an interesting approach by Dyker et al.,87 substrates were assembled by an Ugi four-component reaction. The cyclization of 73 with 3 mole% of AuCl3 in acetonitrile at 80 oC delivered both the products of a 6-endo-dig cyclization 74 and of the 5-exo-dig cyclization 76, the latter delivering only the shown diastereomer and obviously forms by aromatization of the initial hydroamination product 75 (Scheme 20).

Scheme 20. 5-exo/6-endo-dig intramolecular hydroamination.

Further, an intramolecular hydroamination of compound 77 to 78 was observed in reactions for the construction of the complex polycyclic communesin ring system by Crawley and Funk (Scheme 21).88

Scheme 21. Intramolecular hydroamination to synthesize polycyclic communesin ring system.


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Further, enamines resulting from the hydroamination of amine89 or aniline,90,91 readily cyclize onto alkynes to form pyrroles or indoles (Scheme 22). Alternatively, the gold-catalyzed cyclization of 2-alkynylaniline (81) can generate indolyl-gold species (83), which then adds to α,β-unsaturated ketone, or through a gold-catalyzed Friedel Crafts-type process to form C-3-functionalized indole (86) (Scheme 23).91

Scheme 22. Hydroamination of amine/aniline, to synthesize pyrroles / indoles.

Scheme 23. Synthesis of C-3 functionalized indole derivative.

The intramolecular imine addition to alkyne 87 forms a gold-containing azomethine ylide 88, which then undergoes a [3+2] cycloaddition with electron-rich vinyl ether leading to carbene intermediate 89 (Scheme 24). The subsequent 1,2-migration eventually affords tricyclic compound 90.92


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Scheme 24. Synthesis of a tricyclic indole derivative via intramolecular hrdroamination.

1.6.2. Intramolecular hydroarylation of C-C triple bonds The hydroarylation of gold-activated alkynes, allenes, and alkenes can be characterized as a Friedel Crafts reaction mechanistically. In these cases, an electron-rich aromatic system is more prone to react as a nucleophile.

The intramolecular hydroarylation reactions of aryl alkynoates (91) proceed smoothly to form coumarins (92) using AuCl3/AgOTf (Scheme 25).93 The intermolecular version of this reaction could be achieved under solvent-free conditions.

Scheme 25. Intramolecular hydroarylation reactions of aryl alkynoates to synthesize coumarins.

The intramolecular hydroarylation of substrate 93 involving an alkyne and an indole moiety was achieved with remarkable regioselectivity. While the gold(I) catalyst (94) favors the 7-exo-dig cyclization, the gold(III) catalyst AuCl3 promotes the 8-endo-dig cyclization (Scheme 26).94 With N-propargyl N-tosylaniline (97) or O-propargyl aryl


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ether (99), the 6-endo-trig cyclization reactions are preferred to give 1,2-dihydroquinoline (98) and chromene (100), respectively (Scheme 27).95

Scheme 26. Regioselctive switch in intramolecular hydroarylation of an alkyne on indole moiety.

Scheme 27. Intramolecular 6-endo-trig cyclization to form 1,2-dihydroquinoline (98) and chromene (100).

In another very interesting example, Shenming Ma and co-workers96,97 have documented an intramolecular hydroarylation of homopropargylic alcohols (101) using AuCl3 catalyst to synthesize carbazole derivatives (102) (Scheme 28).

Scheme 28. Synthesis of carbazole derivatives.


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A different transformation involving the indole nucleus was found by Zhang (Scheme 29).98 Thus, the 1,3-acyl migration of propargylic carboxylates (103) catalyzed by Au(I) was coupled with a subsequent reaction of the resulting allenes (104) with indoles to give tetracyclic compounds (125). Allene (104) was isolated when the reaction was performed with AuCl3 as catalyst.

Scheme 29. Syntehsis of tetracyclic indole compounds (105) via Allene intermediate (104).

The heterocyclic carbene gold complex can catalyze tandem processes of [3,3] rearrangement and intramolecular hydroarylation of allene intermediates to form substituted indenes (Scheme 30).99,100 This remarkably efficient reaction is typically complete within 5 min at rt. With internal alkyne substrate 106, a sequential 1,2-shift rather than a 1,3-shift as supported by a recent computational study,101,102 leads to aryl allene intermediate 1110, which is followed by a gold-promoted hydroarylation to form indene 111. With terminal alkyne substrate 107, after one 1,2-shift, a C-H insertion of intermediate occurs to furnish the indene product 109 (Scheme 30).

Scheme 30. Tandem [3,3] rearrangement and intramolecular hydroarylation to synthesize substituted indenes.


27

1.6.3. Intramolecular hydroalkoxylation of C-C triple bonds Hashmi et al. reported the gold-catalyzed formation of furans 113 by intramolecular addition of alcohols to alkynes103 and more recently Liu et al. applied this reaction to the synthesis of dihydrofurans 114 (Scheme 31).104 Carbonyl compounds and epoxides also act as nucleophiles in the addition to alkynes to give furans.105,106

Scheme 31. Synthesis of substituted furans.

A related transformation was reported by the group of Floreancig for the synthesis of tetrahydropyran 116 (Scheme 32).107 This transformation involves an elimination of a leaving group at the β-position, followed by a conjugate addition.

Scheme 32. Synthesis of tetrahydropyran.

The group of Barluenga reported the formation of enol ethers 118, which are protonated in situ to form oxonium intermediates 119 that undergo a Prins reaction to afford eight membered ring carbocycles 120 (Scheme 33).108

Scheme 33. Synthesis of eight membered ring carbocycles.


28

The intramolecular addition of a hydroxyl group to a carbon-carbon triple bond has found many synthetic applications. ω-Acetylenic alcohols 121 have been regio- and stereoselectively converted to the corresponding R-alkylidene oxygenated heterocycles 122 in the presence of catalytic amounts of AuCl and K2CO3 (Scheme 34).109

R2

HOR1

n

OR1

R2n

AuCl 10%K2CO3 10%MeCN, rt60-90%

O

tBuPh2SiO

O

BnO

O

BnO

O

MOMO O

BrPh

80% 70% 84% 76%

121 122

Scheme 34. Regioslective intramolecular hydroxylation of ω-Acetylenic alcohols.

The Au-catalyzed cyclization of acetylenic alcohols is a general process because terminal, as well as nonterminal alkynes, functionalized or not, could be cyclized. Nevertheless, the role of a propargylic substituent appeared to be a key factor. The observed regio- and stereoselectivity suggest an activation of the acetylenic moiety through Au(I)-coordination (123 in Scheme 35), which would induce a nucleophilic addition of the alcohol group in an anti-auration process.

Scheme 35. Proposed mechanism for intramolecular hydroxylation of ω-Acetylenic alcohols.


29

The cyclization would lead to a protonated alkoxyorganogold intermediate 124. Potassium carbonate probably deprotonated this intermediate leading to a neutral organogold species 125. Hydrolysis of the carbon-gold bond would then liberate the R-alkylidene heterocycle 122 and regenerate the gold catalyst. The fact that only catalytic amount of potassium carbonate is necessary suggests that the deprotonation as well as the carbon-gold bond hydrolysis are linked in the later step. 1.7. Platinum catalyzed intramolecular cyclizations Platinum complexes are well known for their ability to coordinate to an alkyne moiety and have the potential to initiate the subsequent transformations.110 This Pt–alkyne coordination feature would regioselectively direct an intramolecular ring cyclization with ortho-substituted nucleophilic functionalities, such as nitriles, amides, acids, esters, and hydroxyl groups. There are intriguing mechanistic aspects of these processes in which subtle variations of the reaction conditions and/or substrate structures can lead to completely different products. In particular, intramolecular platinum-catalyzed hydroarylations, hydroamination and cycloadditions offer new ways for the efficient construction of biologically interesting carbo- and heterocycles. 1.7.1. Intramolecular hydroamination of C–C triple bonds Li and co-workers describe the first application of platinum(II)-catalyzed regioselective intramolecular 6-endo-dig cyclization of ortho-alkynylbenzonitriles that lead to isoquinoline and isoquinolone rings using hydrido(dimethylphosphinous acid-κP)[hydrogen bis(dimethylphosphinito-κP)]platinum(II) under simple and mild neutral reaction conditions (Scheme 36).111

Scheme 36. Synthesis of 1-alkoxyisoquinolines (127) and isoquinolones (128) from ortho-alkynylbenzonitriles (126).


30

In an another report, the reaction of ortho-alkylphenylureas 129 in the presence of platinum catalysts proceeds via migration of the carbamoyl group, affording the corresponding indole-3-carbamides 131 in moderate to high yields (Scheme 37).112 Moreover, it was found that the platinum-catalyzed cyclization of ortho-alkynylanilines 130 having an ester group attached to the nitrogen atom produced the corresponding indole-3-carboxylates 132 in good yields. The present reaction proceeds through the addition of a carbon–nitrogen bond to a carbon–carbon triple bond, the so-called carboamination.113

Scheme 37. Intramolecular hydroamination of ortho-alkylphenylureas to afford indole-3-carbamides.

A plausible mechanism of the present reaction is illustrated in Scheme 38. The Lewis acidic platinum catalyst coordinates to the alkynyl moiety of substrate 129 or 130. Intramolecular nucleophilic attack of the nitrogen atom on the triple bond yields cyclized intermediate 134.114 Migration of the carbamoyl or alkoxycarbonyl group followed by elimination of the platinum catalyst, the so called carbodemetalation, gives the desired product.

Scheme 38. Possible mechanism for the synthesis of indole-3-carbamides.


31

In the platinum catalyzed intramolecular reactions of the phenyl substituted alkynyl amide 136, the four isomers 137, 138, 139 and 140 might be produced by nucleophilic addition of the nitrogen or oxygen atom of the amide via 6-exo or 7-endo cyclization after activation of the alkyne by the metal catalyst. When the phenyl substituted alkynyl amide 136 was treated with PtCl2 in dichloroethane at 70 °C, 7-endo cyclized product 137 is obtained as a single isomer exclusively (Scheme 39).115

NNH2

OBn

pNs

PhI, Pd(PPh3)4CuI, Et3NTHF, 84% N

NH2

OBn

pNs

Ph

N NH

Ph

OpNs

BnN

NH

Ph

OBn

pNsN O

Ph

NHpNs

BnN

O

Ph

NHBn

pNs

99%, 7-endo 6-exo 7-endo 6-exo

PtCl2, DCE, 70 oC

135 136

137 138 139 140 Scheme 39. Intramolecular reactions of the phenyl substituted alkynyl amide.

Scheme 40 shows that related reactions can be achieved with suitable aniline derivatives 141, thus opening a novel entry into substituted indoles 142 and 143 by intramolecular (hydro)carboamination.116 A proposed mechanism is shown in Scheme 41.

Scheme 40. Intramolecular aminoacylation of alkynes to synthesize substituted indoles.

The coordination of the alkyne moiety to PtCl2 gives the σ-complex 144. The intramolecular nucleophilic attack of the ortho-nitrogen atom to the electron-deficient alkyne leads to the zwitterionic intermediate 145. An intramolecular [1,3]-migration of


32

acyl moiety then yields the intermediate 146, which produces substituted indole 142 and PtCl2. The substrates, bearing an acidic proton at the R2-position of amide, gave the corresponding 3-deacylated indoles as byproducts; presumably the deacylation takes place through protonolysis of the C-Pt bond of 146, although it is highly speculative (Scheme 41).117

Scheme 41. Proposed mechanism for intramolecular aminoacylation of alkynes.

1.7.2. Intramolecular hydrarylation of C–C triple bonds Recently Beller and co-workers have reported a mechanistically interesting platinum-catalyzed intramolecular cyclization of alkynes on the pyrrole and the indole core.118 According to the work of Echavarren et al., the best catalyst for the formation of azepinone derivatives by an endo-dig process should be an gold(III) complex, and the expected product should have been the pyrrolo[2,3-c]azepin- 8-one (149). Surprisingly, an intramolecular hydroarylation reaction gave 1,5-dimethyl-8-p-tolyl-5,6-dihydropyrrolo[3,2-c]azepin-4-one (150) as the major product (Scheme 42).119

Cyclic enamine derivatives (enesulfonamides and enamides) tethered to an 1-arylalkynyl fragment undergo a platinum(II)-catalyzed tandem alkyne addition/Friedel-Crafts ring closure to form nitrogen-containing polycyclic structures. Regioselectivity


33

in the initial addition of the enesulfonamide or enamide nucleophile to the platinum(II)-alkyne complex is important. Electron-rich arenes and heterocycles led to the formation of products resulting from an initial 6-endo cyclization (Scheme 43).120

NO

N [PdCl2(PPh3)2], CuITHF/TEA, 60 oC, 20h

4-iodotolueneN

ON

or H2PtCl65 mole% AuCl3

NN

ON

O

N

147 148

149 150 Scheme 42. Intramolecular cyclization of alkyne on pyrrole core.

Scheme 43. Intramolecular platinum(II)-catalyzed tandem alkyne addition/Friedel-Crafts ring closure.

As indicated in the text above, the two products were observed in the reaction with platinum(II) chloride. These compounds arose from differing regiochemical modes of the addition of the enesulfonamide to the alkyne (Scheme 44). Formation of an intermediary platinum-alkyne π-complex 154 activates the alkyne for addition by the nucleophilic enesulfonamide. The addition of the nucleophile to the alkyne complex could occur in a 5-exo fashion to form intermediate 155. Alternatively, the addition could take place through a 6-endo manifold to produce intermediate 156. Each of these


34

intermediates could then undergo a Friedel-Crafts (Pictet-Spengler)-type ring closure and proto-demetalation to generate the observed products, respectively.121

Scheme 44. Formation of regioisomeric products.

Recently, Fürstner et al. have reported the intramolecular formation of phenantharenes and polycyclic heteroarenes catalyzed by a soft Lewis acid, PtCl2.122 They found that the regioselectivity of this reaction was dependent on the catalyst system and on the precursor structure (Scheme 45).123

Scheme 45. Regioselctive intramolecular formation of phenantharenes and polycyclic heteroarenes.

An efficient synthetic method of functionalized naphthalenes having hydrogen, alkyl, alkenyl, aryl, or heteroaryl groups on the 4-position and ethoxycarbonyl group on the 2-


35

position was developed by Lee et al.124 through selective Pt-catalyzed 6-endo intramolecular hydroarylation of ethyl (E)-2-ethynyl/alkynyl cinnamates 160 (Scheme 46).

Scheme 46. 6-endo Intramolecular hydroarylation of ethyl (E)-2-ethynyl/alkynyl cinnamates.

A possible pathway for above intramolecular Pt-catalyzed hydroarylation is shown in Scheme 47. Because aryl enynes cannot be isomerized to an allene, the mechanism of the present reaction is different from that of hydroarylation via isomerization of enynes to allenes. Thus, the reaction would be initiated by activation of the alkynyl group by the Pt-catalyst and followed by 6-endo cyclization to afford zwitterionic intermediate arylplatinum 163. Aromatization to arylplatinum 164 and subsequent protonation would provide naphthalene (Scheme 47).

Scheme 47. Plausible reaction mechanism for intramolecular hydroarylation of ethyl (E)-2-ethynyl/alkynyl cinnamates.

In contrast to the Heck reaction, a hydroarylation approach not only eliminates the requirement for a halogen (or triflate) substituent but also allows for multiple


36

mechanistic possibilities, which in turn may lead to different regioisomeric products. Herein, it was reported that PtCl4 has proven to be a hydroarylation catalyst with an efficiency and substrate scope superior to Heck-type125 of reactions (Scheme 48). This catalyst demonstrated consistent performance with arene-yne substrates of diverse structural features, including propargyl ethers, propargylamines, and alkynoate esters, providing good to excellent yields of the 6-endo products (chromenes, dihydroquinolines, and coumarins).126

Scheme 48. Intramolecular 6-endo-dig cyclization.

Consequently, the same group has documented a concise total synthesis of (±)-deguelin (169), a natural product with a longest linear sequence of six steps in 68% yield employing platinum catalyzed 6-endo hydroarylation of an alkynone intermediate 167 as a key step (Scheme 49).127

Scheme 49. Total synthesis of (±)-deguelin.


37

1.8. Indium catalyzed intramolecular cyclization Designing efficient and selective catalyst systems has always been the primary focus in performing organic reactions.128 In this regard, development of multi-functional catalysts129 that can promote alternative reaction pathways depending on the nature of the substrate is an interesting and intriguing area of research that remains to be explored fully. Indium(III) has emerged as a Lewis acid imparting high regio- and chemoselectivity in various chemical transformations.130

During the last century, organometallic reagents prepared from main group metals, such as organolithium, organomagnesium, and organozinc compounds, have played a central role in the advancement of synthetic organic chemistry. However, the sensitivity of these reactive organometallic species to moisture and air rendered the preparation and handling of these reagents difficult. In addition, the poor compatibility of these organometallic compounds toward important functionalities such as carbonyl and hydroxyl groups also limited their widespread application in organic synthesis. In this regard, organoindium agent, backed by several decades of development, has emerged as an attractive alternative to the aforementioned reactive organometallic species.131

Recently, Nakamura et al.132 demonstrated that in addition with InBr3 as a catalyst the intramolecular hydroarylation of 2-alkynyl-6-methoxy-N-sulfonylanilines (170) proceeds by an unprecedented 1,7-migration of the sulfonyl group to produce the 6-sulfonylindoles (171) as the major product in good to high yields (Scheme 50).

Scheme 50. Intramolecular hydroarylation of 2-alkynyl-6-methoxy-N-sulfonylanilines.

The Lewis-acidic transition metal coordinates to the triple bond of 2-alkynyl-6-methoxy-N-sulfonylanilines (170) to form the π-complex. Nucleophilic attack of the nitrogen atom to the alkynyl moiety then leads to the cyclized intermediate 174. The indium catalyzed reaction of substrates, unprecedented consecutive 1,7-sulfonyl and


38

1,5-proton shifts take place.133 Elimination of InBr3 from the resulting intermediate 176 then gives the 6-sulfonylindoles (171). An interaction between the benzene ring on the sulfonyl group and the indium catalyst might play a crucial role in selectively producing 6-sulfonylindoles, since the InBr3-catalyzed reaction of N-mesylaniline gives a complex mixture of unidentified products (Scheme 51).

Scheme 51. Proposed mechanism for the catalytic formation of 6-sulfonylindoles.

Later on by the same group, it was discovered that indium(III) tris (trifluoromethane-sulfonate), In(OTf)3, is an extremely efficient catalyst for the intermolecular addition of a β-ketoester to an inactivated alkyne.134 Theoretical calculations suggested that this addition reaction involves a defined double-activation mechanism where the indium metal electrophilically activates the alkyne to which the ene part of the indium enolate adds nucleophilically (Figure 5).135 Further it was considered that this mechanism for the In(OTf)3-catalyzed reaction as applied to medium- sized-ring synthesis (Figure 6) would overcome the entropic and enthalpic problems associated with the formation of medium-sized rings: a higher entropy barrier than for the formation of three- to six-membered rings and an unfavorable enthalpy barrier because of transannular interactions in the formation of rings containing more than seven members.


39

Figure 5. Schematic illustration of the calculated transition state for intermolecular In(OTf)3-catalyzed addition of a 1,3-dicarbonyl compound to acetylene.134

Figure 6. Schematic presentation of double activation by indium metal.134,135

The same group reported an indium metal-mediated Conia-ene reactions, using ω-alkynyl-β-ketoesters. It was found that the In(NTf2)3 is the catalyst of choice for seven membered-ring cyclization reactions (Scheme 52). First it was focused on bicyclo[5.3.0]decanes in view of the ubiquity of such rings among sesquiterpenes. However, the cyclization of ω-alkynyl-β-ketoesters 177, which was used as a diastereomeric mixture, afforded the cis-fused cyclization product 178 as a single diastereomer in very good yield.136

Scheme 52. Indium metal-catalyzed Conia-ene reaction, using ω-alkynyl-β-ketoesters (177).

In another interesting report by Sakai et al. the indium-catalyzed intramolecular cyclization of the alkynylaniline having the substituted/ unsubstituted amino group was documented. This reaction occurs predominately to produce the corresponding


40

multifunctionalized indole derivatives. Use of such 2-ethynylaniline (179) having an alkyl or aryl group on the terminal alkyne selectively produced a variety of polyfunctionalized indole derivatives (180) in moderate to excellent yields via indium-catalyzed intramolecular cyclization of the corresponding alkynylaniline (Scheme 53).137

Scheme 53. Indium-catalyzed intramolecular cyclization of the alkynylanilines.

Further, allylsilane was subjected to the reaction with a stoichiometric amount of In(OTf)3 and was found quite effective in the intramolecular allylation of allylsilane 181 to methylenecyclopentane 182 (Scheme 54). A catalytic amount of In(OTf)3 promoted the intramolecular cyclization efficiently.138

Scheme 54. Intramolecular allylation of allylsilane to methylenecyclopentane.

In the intramolecular reaction manifold, a number of potential reaction pathways may be considered. For example, it may be reasoned that exposure of tethered haloenynes (X = O, NR, CR1R2) to indium metal would give the corresponding allylindium species 183 which could exist in equilibrium with the endo isomer 184. Furthermore, such intermediates could be expected to react by (i) a process of carboindation of the alkyne triple bond by either a Markovnikov (pathway A) or anti-Markovnikov (pathway B) route to give the corresponding exo 1,4-dienes or endo 1,3-dienes, respectively139 or (ii) proteodebromination of the organometallic (for example, on workup) to give either the crotyl or allylic species (Scheme 55).


41

Scheme 55. Possible pathways for the reaction between indium and haloallylalkynes.139

Further it was reported that a broad range of terminal haloallylalkynes (185) undergo smooth cyclisation at room temperature in the presence of indium metal via pathway A to give exo-1,4 carbocyclic and heterocyclic dienes (186) cleanly (Scheme 56).140

Scheme 56. Indium-mediated cyclisation of tethered terminal haloallylalkynes.

Kim and co-workers have envisioned that the intramolecular hydroarylation of o-propargylbiaryls (187) provides an expedient access for the regioselctive synthesis of phenanthrenes, 188 (Scheme 57).141 In this reaction, both possible competing cyclization modes of o-propargylbiaryls (187), 6-exo-dig and 7-endo-dig, are favored by Baldwin’s rules142 although the selectivity between these two cyclization modes is influenced by many factors including the stereoelectronic properties and the enthalpy of the transition state.143 A new interesting system has also been generated for the metathesis-type coupling of alkynes with aldehydes (190). The combined use of indium Lewis acids and butanol (BuOH) was found to be effective in this intramolecular coupling (Scheme 58).144

A new multicatalytic system (enamine-type catalysis), composed of an indium salt and an amine was documented, which allows the general and efficient carbocyclization of a broad range of α-disubstituted formyl alkynes 192 to the corresponding functionalized cyclopentanes 193 bearing a quaternary stereogenic center (Scheme 59).145 The condensation of the amine organocatalyst on the aldehyde moiety of the substrate 192 allows the formation of a transient enamine, whereas InCl3 is accountable for the η2 activation of the alkyne group.


42

Scheme 57. Intramolecular hydroarylation of o-propargylbiaryls.

Scheme 58. Cyclization of alkynals.

Scheme 59. Carbocyclization of α-disubstituted formyl alkynes synthesize substituted cyclopentanes.

Heterocyclic compounds have great relevance in many fields of chemistry, and it was shown that transition metal catalysis and multicomponent reactions are an excellent, multipurpose approach to their synthesis. Besides the development of new reactions or improved conditions for the classic ones, future developments in this field will probably involve the application of multicomponent-based strategies to target-oriented synthesis.


43

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