Synthesis Of Complex Molecules Research Articles

Chelation-Controlled Additions to Chiral α- and β-Silyloxy, α-Halo, and β-Vinyl Carbonyl Compounds.

The science and art of preventing and managing disease and prolonging life is dependent on advances in medicine, biology, and biochemistry. Many of these advances will involve interactions of small molecules with biological entities. As such, they will rely on the efficient synthesis of active compounds with very high stereochemical purity. Although enantioselective reactions are important in this regard, most stereocenters in complex molecule synthesis are installed in diastereoselective reactions. Perhaps the most well-known diastereoselective C-C bond-forming reaction is the addition of nucleophiles to carbonyl groups with α- or β-stereogenic centers. Diastereoselective additions of organometallic reagents to protected chiral α- and β-hydroxy aldehydes and ketones are described by either Cram chelation or Felkin-Anh models, which are protecting group (PG)-dependent. Small PGs (X = OMOM, OBn, etc.) favor Cram chelation, wherein both the carbonyl group and the O-PG bind to the Lewis acidic metal, providing syn diol motifs. In contrast, silyl PGs, with the OSiR3 moiety being both bulky and weakly coordinating, provide anti diols (Felkin addition). It is well-known that exceptions to this paradigm are scarce. Therefore, the choice of PG is based on the desired stereochemical outcome in the addition step and is often inappropriate for the global protection strategy. Thus, it is critical to develop general methods for chelation-controlled additions of organometallics to chiral silyloxy aldehydes and ketones. Once the challenge of developing chelation-controlled additions to silyloxy carbonyl compounds can be met, the next question is what other pendant functional groups can chelate? Herein we introduce the first general methods for the chelation-controlled addition of organometallics to chiral silyloxy aldehydes and ketones. A wide variety of organozinc reagents have been used in these addition reactions, including dialkylzinc reagents that are commercially available or generated using Knochel's methods. Existing protocols for the generation of (E)-di- and -trisubstituted vinylzinc reagents have been employed, and new methods for the generation of (Z)-di- and -trisubstituted vinylzinc reagents have been developed. The generation of 1,1-heterobimetallic reagents based on boron and zinc has been advanced, and the addition of these reagents to silyloxy aldehydes via chelation-control is included. We will first describe the initial discovery and a model to explain the observed diastereoselectivities. A wide array of chelation-controlled additions to chiral α- and β-silyloxy aldehydes and ketones will then be presented. We next describe other functional groups that undergo chelation-controlled additions. α-Halo aldehyde derivatives are well-known to favor Felkin addition (via the Cornforth-Evans model). We introduce a general method for chelation-controlled additions to α-halo aldimines that provides useful precursors to aziridines. Finally, we provide preliminary evidence that even C═C bonds can play the role of chelating groups in additions to β,γ-unsaturated ketones. The results outlined in this Account redefine the commonly held idea that chiral silyloxy- and halo-substituted carbonyl compounds only give Felkin addition products. The key to achieving chelation control in these reactions is the use of weakly coordinating solvents (dichloromethane and toluene) that do not readily bind to the zinc Lewis acids RZnX.

Cascade One‐Pot Synthesis of Indanone‐Fused Cyclopentanes from the Reaction of Donor‐Acceptor Cyclopropanes and Enynals via a Sequential Hydrolysis/Knoevenagel Condensation/[3+2] Cycloaddition

AbstractA cascade reaction of donor‐acceptor cyclopropanes with enynals to construct indanone‐fused cyclopentanes via a sequential hydrolysis/Knoevenagel condensation/[3+2] cycloaddition is reported. The desired indanone‐fused cyclopentanes were obtained in good yields. This method features mild reaction conditions and broad substrate scope, which render it very appealing to chemists for the synthesis of complex molecules containing an indanone‐fused cyclopentane moiety. Moreover, the products could be further converted into compounds with different functional groups through the well‐known transformations.magnified image

Stereospecific, Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Allylic Pivalates To Deliver Quaternary Stereocenters.

Recognizing the importance of all-carbon, quaternary stereocenters in complex molecule synthesis, a stereospecific, nickel-catalyzed cross-coupling of allylic pivalates with arylboroxines to deliver products equipped with quaternary stereocenters and internal alkenes was developed. The enantioenriched allylic pivalate starting materials are readily prepared, and a variety of functional groups can be incorporated on both the allylic pivalate and the arylboroxine. Additional advantages include the use of a commercially available and air-stable Ni(II) salt and BISBI ligand, mild reaction conditions, and high yields and ee's. The observed stereoinversion of this reaction is consistent with an open transition state in the oxidative addition step.

Silicon-Tethered Strategies for C-H Functionalization Reactions.

Selective and efficient functionalization of ubiquitous C-H bonds is the Holy Grail of organic synthesis. Most advances in this area rely on employment of strongly or weakly coordinating directing groups (DGs) which have proven effective for transition-metal-catalyzed functionalization of C(sp2)-H and C(sp3)-H bonds. Although most directing groups are important functionalities in their own right, in certain cases, the DGs become static entities that possess very little synthetic leverage. Moreover, some of the DGs employed are cumbersome or unpractical to remove, which precludes the use of this approach in synthesis. It is believed, that development of a set of easily installable and removable/modifiable DGs for C-H functionalization would add tremendous value to the growing area of directed functionalization, and hence would promote its use in synthesis and late-stage functionalization of complex molecules. In particular, silicon tethers have long provided leverage in organic synthesis as easily installable and removable/modifiable auxiliaries for a variety of processes, including radical transformations, cycloaddition reactions, and a number of TM-catalyzed methods, including ring-closing metathesis (RCM) and cross-coupling reactions. Employment of Si-tethers is highly attractive for several reasons: (1) they are easy to handle/synthesize and are relatively stable; (2) they utilize cheap and abundant silicon precursors; and (3) Si-tethers are easily installable and removable/modifiable. Hence, development of Si-tethers for C-H functionalization reactions is appealing not only from a practical but also from a synthetic standpoint, since the Si-tether can provide an additional handle for diversification of organic molecules post-C-H functionalization. Over the past few years, we developed a set of Si-tether approaches for C-H functionalization reactions. The developed Si-tethers can be categorized into four types: (Type-1) Si-tethers possessing a reacting group, where the reacting group is delivered to the site of functionalization; (Type-2) Si-tethers possessing a DG, designed for selective C(sp2)-H functionalization of arenes; (Type-3) reactive Si-tethers for C-H silylation of organic molecules; and finally, (Type-4) reactive Si-tethers containing a DG, developed for selective C-H silylation/hydroxylation of challenging C(sp3)-H bonds. In this Account, we outline our advances on the employment of silicon auxiliaries for directed C-H functionalization reactions. The discussion of the strategies for employment of different Si-tethers, functionalization/modification of silicon tethers, and the methodological developments on C-C, C-X, C-O, and C-Si bond forming reactions via silicon tethers will also be presented. While the work described herein presents a substantial advance for the area of C-H functionalization, challenges still remain. The use of noble metals are required for the C-H functionalization methods presented herein. Also, the need for stoichiometric use of high molecular weight silicon auxiliaries is a shortcoming of the presented concept.

Unlocking Reactivity of TrpB: A General Biocatalytic Platform for Synthesis of Tryptophan Analogues.

Derivatives of the amino acid tryptophan (Trp) serve as precursors for the chemical and biological synthesis of complex molecules with a wide range of biological properties. Trp analogues are also valuable as building blocks for medicinal chemistry and as tools for chemical biology. While the enantioselective synthesis of Trp analogues is often lengthy and requires the use of protecting groups, enzymes have the potential to synthesize such products in fewer steps and with the pristine chemo- and stereoselectivity that is a hallmark of biocatalysis. The enzyme TrpB is especially attractive because it can form Trp analogues directly from serine (Ser) and the corresponding indole analogue. However, many potentially useful substrates, including bulky or electron-deficient indoles, are poorly accepted. We have applied directed evolution to TrpB from Pyrococcus furiosus and Thermotoga maritima to generate a suite of catalysts for the synthesis of previously intractable Trp analogues. For the most challenging substrates, such as nitroindoles, the key to improving activity lay in the mutation of a universally conserved and mechanistically important residue, E104. The new catalysts express at high levels (>200 mg/L of Escherichia coli culture) and can be purified by heat treatment; they can operate up to 75 °C (where solubility is enhanced) and can synthesize enantiopure Trp analogues substituted at the 4-, 5-, 6-, and 7-positions, using Ser and readily available indole analogues as starting materials. Spectroscopic analysis shows that many of the activating mutations suppress the decomposition of the active electrophilic intermediate, an amino-acrylate, which aids in unlocking the synthetic potential of TrpB.

Synthesis of 3,3'-Disubstituted Indolenines Utilizing the Lewis Acid Catalyzed Alkylation of 2,3-Disubstituted Indoles with Trichloroacetimidates.

Trichloroacetimidates function as effective electrophiles for the selective C3-alkylation of 2,3-disubstituted indoles to provide 3,3'-disubstituted indolenines. These indolenines are common synthetic intermediates that are often utilized in the synthesis of complex molecules. Effective reaction conditions utilizing Lewis acid catalysts have been determined, and the scope of the reaction with respect to indole and imidate reaction partner has been investigated. This chemistry provides an alternative to base promoted and transition metal catalyzed methods that are more commonly utilized to access similar indolenines.

Catalytic Asymmetric Synthesis of Butenolides and Butyrolactones.

γ-Butenolides, γ-butyrolactones, and derivatives, especially in enantiomerically pure form, constitute the structural core of numerous natural products which display an impressive range of biological activities which are important for the development of novel physiological and therapeutic agents. Furthermore, optically active γ-butenolides and γ-butyrolactones serve also as a prominent class of chiral building blocks for the synthesis of diverse biological active compounds and complex molecules. Taking into account the varying biological activity profiles and wide-ranging structural diversity of the optically active γ-butenolide or γ-butyrolactone structure, the development of asymmetric synthetic strategies for assembling such challenging scaffolds has attracted major attention from synthetic chemists in the past decade. This review offers an overview of the different enantioselective synthesis of γ-butenolides and γ-butyrolactones which employ catalytic amounts of metal complexes or organocatalysts, with emphasis focused on the mechanistic issues that account for the observed stereocontrol of the representative reactions, as well as practical applications and synthetic potentials.

Unified Synthesis of 1,2-Oxy-aminoarenes via a Bio-inspired Phenol-Amine Coupling

Summary 1,2-Aminophenols and their related nitrogen-containing heterocycles are ubiquitous in medicine, agriculture, and materials science. Here, we describe a bio-inspired and unified approach for their synthesis through a direct, catalytic aerobic coupling of phenols and amines. Key to the formation of the aromatic C–N bond is a facile condensation between the amine and an ortho -quinone, which triggers redox isomerization to an ortho -iminophenol before a series of downstream events. We discuss the factors that govern regioselectivity during aerobic ortho -oxygenation of the phenol and condensation of the amine, and we demonstrate synthetic utility by preparing a structurally diverse family of immunosuppressive heterocycles and the indole alkaloid cephalandole A. Our conditions involve a wide range of simple, un-activated substrates, occur at room temperature with an earth-abundant copper-catalyst and a commercially available diamine ligand, and produce water as the only stoichiometric by-product.

Stepwise Synthesis of Metal-Organic Frameworks.

Metal-organic frameworks (MOFs) are a category of porous materials that offer unparalleled control over their surface areas (demonstrated as higher than for any other material), pore characteristics, and functionalization. This allows them to be customized for exceptional performance in a wide variety of applications, most commonly including gas storage and separation, drug delivery, luminescence, or heterogeneous catalysis. In order to optimize biomimicry, controlled separations and storage of small molecules, and detailed testing of structure-property relationships, one major goal of MOF research is "rational design" or "pore engineering", or precise control of the placement of multiple functional groups in pores of chosen sizes and shapes. MOF crystal growth can be controlled through judicious design of stepwise synthetic routes, which can also allow functionalization of MOFs in ways that were previously synthetically inaccessible. Organic chemists have developed a library of powerful techniques over the last century, allowing the total synthesis and detailed customization of complex molecules. Our hypothesis is that total synthesis is also possible for customized porous materials, through the development of similar multistep techniques. This will enable the rational design of MOFs, which is a major goal of many researchers in the field. We have begun developing a library of stepwise synthetic techniques for MOFs, allowing the synthesis of ultrastable MOFs with multiple crystallographically ordered and customizable functional groups at controlled locations within the pores. In order to design MOFs with precise control over pore size and shape, stability, and the placement of multiple different functional groups within the pores at tunable distances from one another, we have concentrated on methods which allow us to circumvent the lack of control inherent to one-pot MOF crystallization. Kinetically tuned dimensional augmentation (KTDA) is an approach using preformed metal clusters as starting materials and monotopic carboxylates as equilibrium shifting agents to make single crystals of ultrastable MOFs. Postsynthetic metathesis and oxidation (PSMO) takes advantage of the fast ligand exchange rate of a metal ion at the low oxidation state as well as the kinetic inertness of the same metal at high oxidation state to make ultrastable and highly crystalline MOFs. Multiple similar strategies have been successful for the metathesis of Fe-based MOFs to Cr3+. Several highly crystalline Ti-MOFs have also been prepared. Kinetically controlled linker installation and cluster metalation methods utilize a stable MOF with inherent coordinatively unsaturated sites as matrix and postsynthetically install linkers or grow clusters on the matrix, so that a robust MOF with precisely placed functionalities is realized. This method has diverse applications especially when specific functional groups or metals having synergistic effects are desired in the proper proximity. Exceptional porosity and stability are required for many potential applications. We have demonstrated several of these, including entrapment of nanoscaled functional moieties such as enzymes. We have developed a series of metal-organic frameworks (PCN-333) with rationally designed ultralarge mesoporous cages as single-molecule traps for enzyme encapsulation. We successfully incorporated metalloporphyrins, well-known biofunctional moieties, into robust MOFs for biomimetic catalytic applications. By rationally tuning the synthetic conditions, we obtained several different porphyrinic Zr-, Fe-, and Ti-MOFs with distinct pore size and concentrated acid or base stability, which offer eligible candidates for different applications. These and other stepwise kinetic tuning and catalyst incorporation methods are small steps toward achieving the grand challenge of detailed control of the placement of matter on an atomic and molecular level.

O-Glycosylation Enabled by Remote Activation

O-Glycosylation is a critically important and recurring step in the synthesis of oligosaccharides and other natural and non-natural products. While many approaches to O-glycosylation have been reported, those strategies involving remote activation are distinguished by the mildness and orthogonality that they often engender. As a result, O-glycosylation using remote activation strategies has been utilized successfully in the synthesis of complex molecules that include oligosaccharides and macrolides. Herein, we discuss a number of contributions that have been made to this area since the 1970s. This includes our own recent contribution involving the visible-light activation of 4-<i>p</i>-methoxyphenyl-3-butenylthioglycosides toward O-glycosylation in the presence of Umemoto’s reagent. 1 Introduction 2 Fraser-Reid’s Development of n-Pentenylglycosides as Glycosyl Donors 3 Hanessian’s Remote Activation of 2-Pyridylthioglycosides 4 Gold-Catalyzed O-Glycosylation (Hotha and Yu) 5 Wan’s ‘Interrupted Pummerer’ Approach to O-Glycosylation 6 O-Glycosylation with 4-<i>p</i>-Methoxyphenyl-3-butenylthioglycosides 7 Conclusions

Palladium-Catalyzed Direct Intermolecular Amination of Unactivated Methylene C(sp3)–H Bonds with Azodiformates via Bidentate-Chelation Assistance

An efficient and convenient method enabling direct amination of unactivated methylene C(sp3)–H bonds to form C–N bonds with azodiformates as amino source is described. This method highlights the emerging strategy of unactivated methylene as versatile functional groups in organic synthesis and provides a strategy to construct functionalized C–N bonds for the synthesis of complex molecules.

Oxidation of Hindered Allylic C-H Bonds with Applications to the Functionalization of Complex Molecules.

We report the palladium-catalyzed oxidation of hindered alkenes to form linear allylic esters. The combination of palladium(II) benzoate, 4,5-diazafluoren-9-one, and benzoquinone catalyzes the mild oxidation of terminal alkenes with tert-butyl benzoyl peroxide as an oxidant in the presence of diverse functional groups. Selective oxidation of terminal alkenes in the presence of trisubstituted and disubstituted alkenes has been achieved, and the ability to conduct the reaction on a gram scale has been demonstrated. The mild conditions and high tolerance for auxiliary functionality make this method suitable for the synthesis and derivatization of complex molecules.

Cyclocarbopalladation as a Key Step in Cascade Reactions: Recent Developments

Cascade reactions are step-economical processes for the synthesis of complex molecules as they allow, in one step, the formation of multiple bonds. Over the last two decades cyclocarbopalladation has emerged as a powerful key step when integrated into these sequences and has allowed unprecedented valuable polycyclic scaffolds to be obtained. This review is focused on recent developments in this field including original cascade sequences, novel activation modes (C–H activation for instance) and unprecedented families of substrates. 1 Introduction 2 Formation of Carbocycles 2.1 4-<i>exo</i> Cyclocarbopalladation 2.2 5-<i>exo</i> Cyclocarbopalladation 2.3 5-<i>endo</i> Cyclocarbopalladation 2.4 Cyclocarbopalladation with Formation of Six-Membered Carbocycles 2.5 Cyclocarbopalladation with Formation of Seven-Membered Carbocycles 3 Formation of Heterocycles 3.1 Formation of Nitrogen Heterocycles 3.2 Formation of Oxygen Heterocycles 3.3 Formation of Sulfur Heterocycles 3.4 Formation of Silicon-Containing Heterocycles 4 Conclusion

Silica-based nanocatalysts in the C[sbnd]C and C-heteroatom bond forming cascade reactions for the synthesis of biologically active heterocyclic scaffolds

The design and development of hybrid materials with application in catalysis science is an interesting researching field, especially in the chemical industry for fine chemicals production. The properties of nanostructured catalysts can be changed by tuning the interaction between the support and the active phases. Silica nanoparticles are very convenient solid supports for the synthesis of organic-inorganic hybrid nanocatalysts, endowing them of the required features to optimize activity and selectivity, stability and recyclability. In this review, we analyze the latest developments and give a perspective concerning the recent applications of silica-based nanocatalysts for the synthesis of heterocyclic scaffolds, biologically active, via cascade reactions.Heterocyclic rings often are the structural cores responsible of the biological activities in natural products and synthetic compounds. These systems are frequently synthesized by multicomponent reactions (MCRs), through cascade reactions. Such versatile catalytic systems have been successfully applied in a great variety of organic transformations for the synthesis of complex molecules and would play a key role in establishing new and more efficient sustainable technologies.

Neil K. Garg

Angewandte Chemie International EditionVolume 56, Issue 14 p. 3748-3748 Author ProfileFree Access Neil K. Garg First published: 31 January 2017 https://doi.org/10.1002/anie.201700568Citations: 1AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Graphical Abstract „I can never resist jelly beans. I would have liked to have discovered the wheel. ...“ This and more about Neil K. Garg can be found on page 3748. Neil K. Garg The author presented on this page has recently published his 10th article in Angewandte Chemie in 10 years: “Nickel-Catalyzed Esterification of Aliphatic Amides”: L. Hie, E. L. Baker, S. M. Anthony, J.-N. Desrosiers, C. Senanayake, N. K. Garg, Angew. Chem. Int. Ed. 2016, 55, 15129; Angew. Chem. 2016, 128, 15353. Date of birth: December 18, 1978 Position: Professor, Department of Chemistry and Biochemistry, University of California, Los Angeles E-mail: neilgarg@chem.ucla.edu Homepage: http://garg.chem.ucla.edu/ ORCID: 0000-0002-7793-2629 Education: 2000 BS, New York University 2005 PhD supervised by Professor Brian M. Stoltz, California Institute of Technology 2005–2007 Postdoctoral studies with Professor Larry E. Overman, University of California, Irvine Awards: 2015 Arthur C. Cope Scholar Award; 2016 Mitsui Chemicals Catalysis Science Award of Encouragement; 2016 Merck Award, Royal Society of Chemistry; 2016 Guggenheim Fellowship; 2016 Thieme–IUPAC Prize; 2016 Tetrahedron Young Investigator Award; 2017 Elias J. Corey Award for Outstanding Original Contribution in Organic Synthesis, American Chemical Society Research: Methodology, catalysis, total synthesis Hobbies: Hiking, editing videos, watching basketball I can never resist jelly beans. I would have liked to have discovered the wheel. The most exciting thing about my research is my co-workers and their ideas. Guaranteed to make me laugh is the movie Forgetting Sarah Marshall. The most enjoyable chemistry adventure in my career was chasing the dragmacidin alkaloids in cahoots with Richmond Sarpong and Daniel Caspi, as a graduate student in the Stoltz Lab. My top three films of all time are Zoolander, Cinema Paradiso, and Star Wars. The downside of my job is that it is fun and perhaps too addictive. My favorite quote is “I feel like I am taking crazy pills” (Mugatu from Zoolander). I like refereeing because it is a great way to engage in the newest science and be an advocate for my field. The biggest problem that scientists face is being overly critical of each other. What I look for first in a publication is something unexpected. My favorite piece of research is the Woodward/Eschenmoser synthesis of vitamin B12. If I won the lottery, I would invest the cash. When I'm frustrated, I try to have a good laugh. My 5 top papers: References 1“The First Total Synthesis of Dragmacidin D”: N. K. Garg, R. Sarpong, B. M. Stoltz, J. Am. Chem. Soc. 2002, 124, 13179. (Led to my current interests in complex-molecule synthesis and cross-coupling methods.) 2“Total Synthesis of (−)-Sarain A”: N. K. Garg, S. Hiebert, L. E. Overman, Angew. Chem. Int. Ed. 2006, 45, 2912; Angew. Chem. 2006, 118, 2978. (My contributions as a postdoc to the total synthesis of sarain A, which had been an ongoing pursuit in the Overman laboratory). 3“Cross-Coupling Reactions of Aryl Pivalates with Boronic Acids”: K. W. Quasdorf, X. Tian, N. K. Garg, J. Am. Chem. Soc. 2008, 130, 14422. (This was the first paper from my independent career. Demonstrated that phenol-derived esters can undergo cross-coupling reactions by using nickel catalysis.) 4“Total Synthesis of (−)-N-Methylwelwitindolinone C Isothiocyanate”: A. D. Huters, K. W. Quasdorf, N. K. Garg, J. Am. Chem. Soc. 2011, 133, 15797. (The first total synthesis of a long-standing target.) 5“Conversion of amides to esters by the nickel-catalysed activation of amide C−N bonds”: L. Hie, N. F. F. Nathel, T. K. Shah, E. L. Baker, X. Hong, Y.-F. Yang, P. Liu, K. N. Houk, N. K. Garg, Nature 2015, 524, 79 (An exciting “post-tenure” direction for my laboratory, involving the activation of amide C−N bonds). Citing Literature Volume56, Issue14March 27, 2017Pages 3748-3748 ReferencesRelatedInformation

Back Cover: Bicatalytic Multistep Reactions En Route to the One‐Pot Total Synthesis of Complex Molecules: Easy Access to Chromene and 1,2‐Dihydroquinoline Derivatives from Simple Substrates (ChemCatChem 1/2017)

Back Cover: Bicatalytic Multistep Reactions En Route to the One‐Pot Total Synthesis of Complex Molecules: Easy Access to Chromene and 1,2‐Dihydroquinoline Derivatives from Simple Substrates (ChemCatChem 1/2017)

Metal-free Cross-Dehydrogenative Coupling of HN-azoles with α-C(sp3)-H Amides via C-H Activation and Its Mechanistic and Application Studies.

A metal-free one step coupling reaction between various N-azole rings and diverse α-C(sp3)-H containing amides has been developed under oxidative reaction conditions. Commercially available tetrabutyl ammonium iodide (TBAI) in the presence of terbutylhydroperoxide (TBHP), under neat reaction condition, efficiently catalyzed the coupling. Various azole types, such as 1H-benzotriazoles, 1H-1,2,3-triazoles, 1H-1,2,4-triazoles, 1H-tetrazoles, 1H-pyrazoles, and 1H-benzimidazoles, and α-C(sp3)-H containing amides, such as N,N-dimethylacetamide, N,N-dimethylbenzamide, N-methylacetamide, N,N-diethylacetamide, N-methylpyrrolidine, and pyrrolidine-2-one, were successfully employed for the coupling. A series of designed and controlled experiments were also performed in order to study the involvement of the different intermediates. Based on the evidence, a plausible mechanism is also proposed. These novel, simple, rapid, attractive, and straightforward transformations open the way of the construction of novel highly functionalized N-azoles via direct covalent N-H bond transformations onto N-C bonds. This approach allows to the synthesis of complex molecules requiring number of steps using classical synthetic ways. In addition, the range of α-C(sp3)-H containing amide substrates is virtually unlimited highlighting the potential value of this simple system for the construction of complex heterocyclic molecules, such as fused azoles derivatives.

Ipso-Cyclization: an emerging tool for multifunctional spirocyclohexadienones.

ipso-Annulation represents an attractive approach to synthesize a variety of spirocyclic compounds having a quaternary carbon center. Furthermore, these compounds also serve as a handy synthon for the construction of various complex molecules. This review presents various useful approaches for the intramolecular ipso-cyclization to afford a wide range of spirocyclohexadienones. In addition, the utility of spirocyclic compounds towards the synthesis of complex molecules is also included.

Synthesis of Ferrocene Tertiary Amine Cyclopalladium Compounds and Its Application in Suzuki and Sonogashira Reactions

Ynones, also known as α, β-acetylenic ketones, have been widespread used in modern synthetic organic chemistry. They exist in biologically active compounds, and are used as vital building blocks in complex molecule synthesis. Consequently, a number of me...

Palladium(0)-Catalyzed Benzylic C(sp3)-H Functionalization for the Concise Synthesis of Heterocycles and Its Applications.

C-H functionalization reactions involve the activation of otherwise unreactive C-H bonds, and represent atom economical methods for the direct transformation of simple substrates to complex molecules. While transition metal-catalyzed C(sp2)-H functionalization reactions are regularly used in synthesis, C(sp3)-H functionalization is rarely applied to the synthesis of complex natural products because of the difficulties associated with controlling selectivity. With this in mind, we focused on the development of new palladium (Pd)(0)-catalyzed C(sp3)-H functionalization reactions for the synthesis of complex molecules, resulting in several new methods capable of solving these problems. We initially developed a concise synthetic method for the facile construction of oxindoles and spirooxindoles via a Pd-catalyzed benzylic C(sp3)-H functionalization reaction. This method was subsequently extended to the synthesis of various heterocycles, including 2-arylindoles, benzocarbazole, indolocarbazole, indoloquinazolinone, and indoloquinazolinedione, as well as the total synthesis of several pyrrolophenanthridine alkaloids without the need for any protecting groups. This method was also successfully applied to the synthesis of the right-hand fragment of benzohopane from tetrahydro-2H-fluorene, which was constructed by a Pd-catalyzed benzylic C(sp3)-H functionalization. In this review, we provide a detailed discussion of our most recent investigations pertaining to Pd(0)-catalyzed benzylic C(sp3)-H functionalization.