The Quest for Palladium-Catalysed Alkyl-Nitrogen Bond Formation

Our interest in the development of transition-metal catalysis for the realisation of vicinal diamination reactions of alkenes started about a decade ago. A number of successful transformations in this area have been developed using palladium catalysis. As a challenging aspect of major importance, the palladium-catalysed coupling of alkyl–nitrogen bonds constitutes the second step in diaminations of alkenes. We here discuss the details that led us to consider high-oxidation-state palladium catalysis as a key feature in such C–N bond-forming reactions. This work discusses both our own contributions and the ones from colleagues and combines the discussion of catalytic reactions and stoichiometric control experiments. It demonstrates that reductive alkyl–nitrogen bond formation from palladium(IV) proceeds with a low activation barrier and through a linear transition state of nucleophilic displacement

Diamination of Pi-systems Using Simple Urea Derivatives and Exploring Ecologically Relevant Biological Activities Through Natural Products Synthesis

Diamination of olefins has found broad applications in synthesis of pharmaceuticals and catalysts. Vicinal diamination of olefins has been well developed; however versatile methods that install higher order 1,n -diamine moieties (e.g., n = 3− 5) are not comprehensively explored. We have developed 1,4-diamination of cyclic dienes via diaza-(4+3) cycloadditions of putative diaza-oxyallyl cationic intermediates. This novel intermediate was generated by base-mediated dehydrohalogenation of N-chloro urea reagents. Various aromatic and non-aromatic cylic dienes underwent successfully cycloaddition reaction with diaza-oxyallyl cationic intermediate and provided good to excellent yields. Although it was a first example of selective 1,4-diamination of dienes using N-chloro urea reagents, this methodology suffers from limited substrate scope and poor regioselectivity with mono substituted furans by providing 1:1 ratio of regiosisomers. In order to over come the limitations in our previous method, we have developed an alternative oxidative 1,4-diamination of conjugated dienes using simple urea reagents. The desired putative symmetric diaza-oxyallyl cationic intermediate for the oxidative diaza-(4+3) cycloaddition reaction was generated by direct oxidation of urea reagents with hypervalent iodine reagent. Oxidative 1,4-diamination is exclusively selective for the 1,4-difunctionalization of conjugated dienes due to the required Woodward-Hoffmann orbital symmetry rules. This reaction method is compatible with various substrates including aromatic, acyclic, and cyclic dienes, and provides functionalized unique heterocyclic products. In addition it does not require large excess of diene, which is unusual in (4+3) type of cycloaddition reaction of allyl cations. This reaction also demonstrated its compatibility for oxidative intramolecular 1,4-diamination, and provides polyheterocyclic molecule. Inspired by the reactivity of daiza-oxyallyl cation for 1,4-daimination we have developed an oxidative diaza-(3+2) cycloaddition reaction of simple urea derivatives with substituted indoles. This transformation provides rapid access to highly functionalized imidazolo- indolines that are represented in large number of designed bioactive compounds. This methodology is compatible with wide variety of functional groups and provides unique heterocyclic scaffolds. Plants defend themselves from pathogens like bacteria, viruses and herbivores by using mixture of multiple secondary metabolites as chemical defense. In order to understand one of the long-standing and underexplored questions in chemical ecology, we have developed a scalable access to enantiopure octopamine and aegeline analogues and evaluated the biological assays. These mixtures of products showed synergistic activity in defensive mechanism against generalist herbivore (Spodoptera). One of the natural product (aegeline) analogue exhibited potency against root growth of Arabodopsis Thaliana (a model organism for studying plant cell wall development)

Practical and stereoselective electrocatalytic 1,2-diamination of alkenes

1,2-二胺结构广泛存在于天然产物、药物和不对称合成中使用的催化剂中。烯烃双胺化，即在烯烃两端同时引入两个氨基，是合成1,2-二胺最为简便和高效的方法之一。但该方法面临着诸多挑战，是有机合成中有待解决的难题。其难点主要是源于二胺产物对过渡金属催化剂的抑制作用以及难以控制反应非对映选择性和区域选择性。徐海超课题组对电化学促进的烯烃双官能团化反应进行了深入研究，通过进一步脱除磺酰基成功实现了高非对映选择性和区域选择性的烯烃双胺化反应，为1,2-二胺类化合物提供高效、简便的合成方法。该工作通过有机电子转移催化剂与电的结合避免了过渡金属催化剂和氧化剂的使用，且增强了底物和官能团的兼容性。 该项研究实验部分主要由博士生蔡晨燕完成，研究助理束晓敏参与了部分化合物的合成。The 1,2-diamine motif is widely present in natural products, pharmaceutical compounds, and catalysts used in asymmetric synthesis. The simultaneous introduction of two amino groups across an alkene feedstock is an appealing yet challenging approach for the synthesis of 1,2-diamines, primarily due to the inhibitory effect of the diamine products to transition metal catalysts and the difficulty in controlling reaction diastereoselectivity and regioselectivity. Herein we report a scalable electrocatalytic 1,2-diamination reaction that can be used to convert stable, easily available aryl alkenes and sulfamides to 1,2-diamines with excellent diastereoselectivity. Monosubstituted sulfamides react in a regioselective manner to afford 1,2-diamines bearing different substituents on the two amino groups. The combination of an organic redox catalyst and electricity not only obviates the use of any transition metal catalyst and oxidizing reagent, but also ensures broad reaction compatibility with a variety of electronically and sterically diverse substrates.We acknowledge the financial support of this research from MOST (2016YFA0204100), NSFC (No. 21672178), Program for Changjiang Scholars and Innovative Research Team in University and Fundamental Research Funds for the Central Universities. 研究工作得到国家重点研发计划纳米科技重点专项、国家自然科学基金、长江学者和创新团队发展计划、中央高校基本科研业务费专项资金的资助

Development and application of metal-catalyzed diamination reactions, The

2014 Fall.Includes bibliographical references.Nitrogen-rich molecules are of great interest in chemistry and incorporation of nitrogen into molecules is an on-going active field of study. In particular, vicinal diamines are important functional moieties that are found throughout biologically active molecules and natural products as well as highly effective chiral control agents in organic synthesis. There has been much effort directed toward the efficient synthesis of vicinal diamines; however the development of a direct route has proven to be challenging. This dissertation discusses the application of diamination products from existing methods to synthesize biologically active motifs, as well as the development of new metal-catalyzed diamination methods for the synthesis of biologically interesting motifs from readily available starting materials. The β, γ-diamino acid motif is an area of active research because of its prevalence in biologically active molecules and its use in peptide library syntheses. Cyclization of β, γ-diamino acids give the closely related 4-aminopyrrolidinones. These five-membered amino lactams have been reported to potentiate insulin activity when incorporated into hypoglycemic peptide analogues and made the analogues more stable towards physiological degradation. Current methods for the synthesis of these compounds require multi-step procedures and rely heavily on commercially available amino acids as starting materials, thus limiting the structural variability for biological studies. Using a diamination method discovered in our lab, 4-aminopyrrolidinones were efficiently synthesized in 40% overall yield, over five steps from readily available terminal olefins or conjugated dienes, providing a comparable process in the synthesis of these compounds. As part of our ongoing efforts to study the mechanism of metal-catalyzed diaminations using diaziridinone as nitrogen source, it was found that regioselectivity in the diamination of conjugated dienes could be controlled using Cu(I) as catalyst and varying reaction conditions. An alternative nitrogen source, thiadiaziridine 1,1-dioxide, which has shown to display interesting reactivity, was chosen to further investigate the Cu(I)-catalyzed regioselective diamination. Upon varying reaction conditions with Cu(I) catalysts, regioselective diamination occurred for various conjugated dienes and allowed direct access to a range of diverse cyclic sulfamides which have interesting biological potential. With the racemic synthesis of cyclic sulfamides, it was of interest to obtain these compounds asymmetrically, as their biological properties are of value and current methods for their asymmetric synthesis do not allow much variation in substitution patterns. Using Pd2(dba)3 and a chiral phosphoramidite ligand, a variety of chiral cyclic sulfamides were synthesized in moderate to high yields and with ee's greater than 90%, providing direct access to these valuable compounds in one step from readily available conjugated diene substrates. Lastly, N,N-Di-tert-butyl thiadiaziridine 1,1-dioxide has been found to be a versatile reagent for interesting reactivity. Other uses of this reagent include the Pd(II)-catalyzed terminal diamination of conjugated dienes, diamination of allenes, and the Pd-catalyzed oxidation of alcohols to form α, β-unsaturated compounds

Copper-catalysed radical reactions of alkenes, alkynes and cyclopropanes with N–F reagents

The mild generation of nitrogen-centred radicals from N–F reagents has become a convenient synthetic tool. This methodology provides access to the aminative difunctionalisation of alkenes and alkynes and the radical ring-opening of cyclopropanes, among other similar transformations. This review article aims to provide an overview of recent developments of such processes involving radical reactions and N–F reagents using copper-based catalysts.We thank Ministerio de Economía y Competitividad (MINECO) (CTQ2017-82893-C2-1-R) and Universidad de Huelva (PO FEDER 2014-2020 UHU-1254043) for grants

1,2-DIAMINATION OF ALKENES VIA REDUCTION OF 1,2,3-TRIAZOLINIUM IONS

1,2-Diamine substructures are prevalent functional motifs in natural products, pharmaceutical compounds, and ligands. The interesting functionalities of 1,2-diamines have inspired many synthetic chemists to design various methodologies for preparing these structures from simple precursors such as alkenes. In this work, we described two different but related methods using simple and easily accessible reagents for 1,2-diamination of alkenes. In the first method, an alkene undergoes 1,3-dipolar cycloaddition with an organic azide to form a 1,2,3-triazoline. Subsequent N-alkylation of the generated 1,2,3-triazoline gives the 1,2,3-triazolinium ion, which is then hydrogenated over Raney Ni with a balloon of H2 to produce 1,2-diamine. Traditionally, it has been believed that a 1,2,3-triazoline is an unstable species in the presence of heat or light and will readily extrude N2 to form an imine or an aziridine. However, most of the 1,2,3-triazolines prepared in this work were stable to the extrusion of N2 at the temperature required for their formation. In the second method, an alkene undergoes 1,3-dipolar cycloaddition with a 1,3-diaza-2-azoniaallene (azidium ion, our neologism) to afford a 1,2,3-triazolinium ion directly. The 1,2,3-triazolinium ions are reduced to the corresponding 1,2-diamines using the same conditions described above. As was expected, cyclic alkenes provide cis 1,2-diamines, and acyclic trans alkenes provide threo 1,2-diamines due to syn cycloaddition of the alkene to the azidium ion and preservation of the stereochemistry of the 1,2,3-triazolinium ion during the hydrogenation. Surprisingly, the reduction of acyclic cis alkenes proceeded with complete or partial inversion of relative stereochemistry instead of the complete formation of the expected erythro isomer. We hypothesized that this isomerization occurs during the hydrogenation step by Raney Ni. More surprisingly, the reduction of the 1,2,3-triazolinium derived from 5-hexen-2-one produced the diamine product with an additional C–C bond. The X-ray crystallographic analysis and 1D/2D NMR spectra confirmed the structure and the relative stereochemistry of the synthesized 1,2,3-triazolinium ions and 1,2-diamines. Additionally, we had planned to apply the developed 1,2-diamination methodology toward the total synthesis of loline alkaloids. Lolines are a group of nitrogen-containing natural products produced in cool-season grasses and have shown insecticidal and antifeedant properties. In our designed retrosynthesis, disconnection between C(3) and N(4) in loline tricyclic ring, will lead us to the bicyclic intermediate consist of tetrahydrofuran and pyrrolidine ring. We hypothesized that this intermediate can be produced by hydrogenolysis of the corresponding 1,2,3-triazolinium ion synthesized from 2-deoxy-D-ribose (the ether linkage provider). In my attempt toward this total synthesis, the corresponding 1,2,3-triazoline was synthesized as a first key intermediate in seven steps from 2-deoxy-D-ribose. The N-alkylation of the 1,2,3-triazoline, reduction of the produced 1,2,3-triazolinium ion, and completion of the final stages of this total synthesis are still under investigation

SYNTHETIC STUDIES TOWARDS THE SYNTHESIS OF ANATOXIN-A(S)

Three routes toward the total synthesis of the neurotoxin anatoxin-a(s) have been explored. They focus on the assembly of the backbone utilizing both Pd(0)- and Pd(II)-mediated processes. Our current route leads to a late-stage precursor of anatoxin-a(s), hydroxy guanidine 134, in 18 steps and in 8.0% overall yield utilizing an amidoalkylation step in the key cyclization

触媒的結合活性化による新規分子変換反応の開発

Tohoku University金鉄男課

Palladium(II)-Catalysed Oxidation of Alkenes

This review provides a summary of recent developments in the palladium(II)-catalysed oxidation of alkenes, focusing largely on reactions which lead to the formation of new carbon–oxygen or carbon–nitrogen bonds. Three classes of reaction are covered: i) oxidations proceeding via allylic C–H bond cleavage and formation of a π-allyl complex; ii) Wacker-type oxidations proceeding via nucleopalladation followed by β-hydride elimination; and iii) 1,2-difunctionalisation of alkenes proceeding via nucleopalladation followed by functionalisation of the resulting σ-alkylpalladium(II) intermediate. The mechanisms are discussed alongside the scope and limitations of each reaction