Combining Organometallic Reagents,the Sulfur Dioxide Surrogate DABSO,and Amines: A One‐Pot Preparation of Sulfonamides,Amenable to Array Synthesis

We describe a method for the synthesis of sulfonamides through the combination of an organometallic reagent, a sulfur dioxide equivalent, and an aqueous solution of an amine under oxidative conditions (bleach). This simple reaction protocol avoids the need to employ sulfonyl chloride substrates, thus removing the limitation imposed by the commercial availability of these reagents. The resultant method allows access to new chemical space, and is also tolerant of the polar functional groups needed to impart favorable physiochemical properties required for medicinal chemistry and agrochemistry. The developed chemistry is employed in the synthesis of a targeted 70 compound array, prepared using automated methods. The array achieved a 93 % success rate for compounds prepared. Calculated molecular weights, lipophilicities, and polar surface areas are presented, demonstrating the utility of the method for delivering sulfonamides with drug‐like properties.     

Titanium(IV) isopropoxide mediated solution phase reductive amination on an automated platform: application in the generation of urea and amide libraries

Amine libraries and their derivatives are important targets for high throughput synthesis because of their versatility as medicinal agents and agrochemicals. As a part of our efforts towards automated chemical library synthesis, a titanium(IV) isopropoxide mediated solution phase reductive amination protocol was successfully translated to automation on the Trident(TM) library synthesizer of Argonaut Technologies. An array of 24 secondary amines was prepared in high yield and purity from 4 primary amines and 6 carbonyl compounds. These secondary amines were further utilized in a split synthesis to generate libraries of ureas, amides and sulfonamides in solution phase on the Trident(TM). The automated runs included 192 reactions to synthesize 96 ureas in duplicate and 96 reactions to synthesize 48 amides and 48 sulfonamides. A number of polymer-assisted solution phase protocols were employed for parallel work-up and purification of the products in each step.     

Do Sulfonamides Interact with Aromatic Rings?

Aromatic rings form energetically favorable interactions with many polar groups in chemical and biological systems. Recent molecular studies have shown that sulfonamides can chelate metal ions and form hydrogen bonds, however, it is presently not established whether the polar sulfonamide functionality also interacts with aromatic rings. Here, synthetic, spectroscopic, structural, and quantum chemical analyses on 2,6-diarylbenzenesulfonamides are reported, in which two flanking aromatic rings are positioned close to the central sulfonamide moiety. Fine-tuning the aromatic character by substituents on the flanking rings leads to linear trends in acidity and proton affinity of sulfonamides. This physical-organic chemistry study demonstrates that aromatic rings have a capacity to stabilize sulfonamides via through-space NH–π interactions. These results have implications in rational drug design targeting electron-rich aromatic rings in proteins.     

Fluorous scavenger for parallel preparation of tertiary sulfonamides leading to secondary amines

Alkylation of secondary sulfonamides by alkyl halides or alcohols (Mitsunobu reaction) is an efficient method for secondary amines preparation. However, its application to parallel chemistry is often difficult due to partial reaction. In this Letter, we propose a fluorous technique to bypass this problem. Thus, o-nitrobenzenesulfonamides were prepared and alkylated in parallel (Fukuyama method) with various alkyl halides or alcohols. Depending on the nature of the alkyl halide or alcohol, this step remained incomplete. A reactive fluorous alkyl iodide was then used to trap the unreacted sulfonamide allowing for a rapid and efficient fluorous solid-phase extraction (FSPE). Some examples of the isolated tertiary sulfonamides were converted in parallel to the corresponding secondary amines with good purity.     

Synthesis, structure, and reactivity of a zirconocene-carboryne precursor

Transition metal-benzyne complexes have found many applications in organic synthesis, mechanistic studies, and the synthesis of functional materials. In sharp contrast, the reaction chemistry of transition metal-carboryne complexes is virtually unknown although the theoretical calculations indicated that the formation of carboryne (1,2-C2B10H10) and benzyne is very energetically comparable. This communication reports a novel zirconocene-carboranyl complex Cp2Zr(mu-Cl)(mu-C2B10H10)Li(OEt2)2 (1), an efficient precursor of the zirconocene-carboryne species, prepared from the reaction of Cp2ZrCl2 with 1 equiv of Li2C2B10H10 in Et2O. The reactivity studies indicated that 1 resembles zirconocene-benzyne in reactions with polar unsaturated organic molecules. On the other hand, it shows no reactivity toward alkynes and alkenes, a reactivity pattern which is quite different from that of zirconocene-benzyne. This work also furnishes a novel method for the preparation of functional o-carboranes and their metal complexes which cannot be synthesized by other methods presently known.     

Preparation of sulfonamides from N-silylamines

Sulfonamides have been prepared in high yields by the reactions of N-silylamines with sulfonyl chlorides and fluorides. In a competition experiment, the sulfonyl chlorides were found to be far more reactive than sulfonyl fluorides. The chemistry may be used to prepare aliphatic, aromatic, tertiary, secondary, and primary sulfonamides. It may also be done in the absence of solvent and the byproduct trimethylsilyl chloride recovered in good yield. Primary sulfonamides were synthesized from the sulfonyl chloride with aminotriphenyl silane (Ph₃SiNH₂), a conversion demonstrated with the synthesis of the carbonic anhydrase inhibitor, acetazolamide.     

Oxidative spirocyclization of phenolic sulfonamides: scope and applications

A full account of the oxidative dearomatization of para- and ortho-phenolic sulfonamides is provided together with an overview of the chemistry of the products and their elaboration to building blocks for spirocyclic alkaloids. A concise total synthesis of putative lepadiformine complements the discussion.     

Recognition properties of carboxylic acid bioisosteres: anion binding by tetrazoles, aryl sulfonamides, and acyl sulfonamides on a calix[4]arene scaffold

Tetrazoles and acyl sulfonamides are functional groups that are common in medicinal chemistry but virtually unexplored as recognition elements in supramolecular chemistry. We report here on the anion binding properties of these highly acidic N-H functional groups. We have prepared two new calixarene-based tetrazole-containing hosts, as well as new acetyl sulfonamide and benzoyl sulfonamide hosts. We also report on analogous hosts bearing the better-known aryl sulfonamide functional group as a point of comparison. We find that these hosts are competent anion binders and that the recognition of anions by these groups is highly dependent on their conformational preferences. We also report in detail on the preferred molecular shape of each acid bioisostere as determined by calculations and structural database surveys, and discuss how these shapes impact binding in the context of the reported hosts.     

Parallel electrosynthesis of alpha-alkoxycarbamates, alpha-alkoxyamides, and alpha-alkoxysulfonamides using the spatially addressable electrolysis platform (SAEP)

The spatially addressable electrolysis platform (SAEP) has been designed and constructed. It is demonstrated that the advantages of electrochemistry can be readily adapted to combinatorial chemistry and parallel synthesis formats. Parallel electrosynthesis of alpha-alkoxycarbamates, alpha-alkoxyamides, and alpha-alkoxysulfonamides via anodic oxidation of carbamates, amides, and sulfonamides, respectively, highlights the main features of the SAEP.     

A simple and efficient method for sulfonylation of amines, alcohols and phenols with cupric oxide under mild conditions

Cupric Oxide efficiently catalyzed the synthesis of sulfonamides and sulfonic esters. This method has been applied to a variety of substrates including nucleophilic and sterically-hindered amines, alcohols and phenols with excellent yields of sulfonamides and sulfonic esters. The remarkable selectivity under mild and neutral conditions of this commercially available inexpensive catalyst is an attractive feature of this method.     

Lead-oriented synthesis: a new opportunity for synthetic chemistry

The pharmaceutical industry remains solely reliant on synthetic chemistry methodology to prepare compounds for small-molecule drug discovery programmes. The importance of the physicochemical properties of these molecules in determining their success in drug development is now well understood but we present here data suggesting that much synthetic methodology is unintentionally predisposed to producing molecules with poorer drug-like properties. This bias may have ramifications to the early hit- and lead-finding phases of the drug discovery process when larger numbers of compounds from array techniques are prepared. To address this issue we describe for the first time the concept of lead-oriented synthesis and the opportunity for its adoption to increase the range and quality of molecules used to develop new medicines.     

Preparation,Characterization and Optical Property of Chitosan-Phenothiazine Derivative by Microwave Assisted Synthesis

In this article, we have described microwave assisted synthesis of 3-formyl-10H phenothiazine and preparation of chitosan-phenothiazine derivative film with potential for optical properties in biomedical applications, vis-à-vis it is also important to ensure that chemical processes used in converting biopolymer to useful material through green chemistry approach. From optical properties and biomedical application point of views, it is a benign technique. Chitosan-derivative film was prepared from hydrogel by solution casting method. The prepared chitosan-phenothiazine derivative was confirmed by Fourier transform infrared spectroscopy (FTIR). The film was evaluated by XRD, thermal analysis, surface morphology, photoluminescence (PL) spectrscopy and second harmonic generation (SHG) study. Overall, the chitosan-phenothiazine derivative film opens new perspectives to optical material for biomedical applications.     

分子模拟技术研究17种磺胺类药物与抗体亲和力构效关系

应用量子力学AM1方法对17种磺胺类药物(Sulfonamides, SAs)进行分子构型优化, 得到了SAs的最低能量结构, 并计算了SAs分子的重要构型参数(键长、键角和两面角)、电性参数(R基团和重要原子的电量)和物化参数(水合能、Log P值等). 通过比较SAs各个分子理化性质的差异, 讨论了SAs与4株磺胺二甲基嘧啶(Sulfamethazine, SM2)多克隆抗体之间的构效关系, 结果显示水合能和Log P在SM2抗体-抗原(SAs)构效关系中发挥重要作用, 分子的空间结构和电子特性的作用有限.     

Cu(II)-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids to primary aryl sulfonamides

A novel protocol for CuO-catalyzed decarboxylation/elimination of N-arylsulfonyl amino acids was developed. It is the first example of using an accessible amino acid as an ammonia synthetic equivalent for the synthesis of primary aryl sulfonamides via oxidative decarboxylation/elimination reactions. The present protocol shows excellent functional group tolerance and provides an efficient method for the synthesis of primary aryl sulfonamides in excellent yields.     

Fukuyama-Mitsunobu alkylation in amine synthesis on solid phase revisited: N-alkylation with secondary alcohols and synthesis of curtatoxins

The Fukuyama-Mitsunobu amination strategy has emerged as an efficient means of N-alkylation of peptides and sulfonamides, as well as a method for synthesis of polyamines on solid phase. Here, an array of reagent combinations for solid-phase alkylation with secondary alcohols was examined in various solvents. The classical reagents DEAD-PPh₃ as well as DEAD-PEt₃ proved applicable for a single alkylation step. Sharply dropping yields in successive alkylation steps were identified as the most serious limitation of the use of Fukuyama-Mitsunobu reaction in SPS of polyamines using primary and in particular secondary alcohols.     

Preparation of Meldrum's acid-functionalized polyimides exhibiting organo-soluble,reactive, self-crosslinkable,and colorless features

Functional polyimides (PIs) having some desired properties, for example, organo-solubility, chemical reactivity, crosslinkable feature, and high transparency in visible region, are attractive for specific applications. This work reports an effort to integrate the above-mentioned properties in one polyimide through introduction of Meldrum's acid (MA) moieties to polyimide chains with using a MA-containing diamine (MADA) as a monomer. The polyimide prepared with MADA and 4,4′-(hexafluoroisopropylidene) diphthalic anhydride (6FDA) (PI[MADA-6FDA]) has a number-averaged molecular weight of 56,800 g mol⁻¹, shows good solubility in tetrahydrofuran and aprotic high polar solvents, and exhibits post-reactivity/crosslinkability through MA-mediated ketene chemistry. Crosslinked PI(MADA-6FDA) film shows a glass transition temperature of 289°C, a dielectric constant of about 2.78, and high flexibility bearing a near-180° bending. The MA-mediated ketene chemistry contributes to in situ building up covalent linkages between PI chains and silica nanoparticles (SNPs) in preparation of PI/SNPs nanocomposite films (NCF). Formation of the PI/SNPs NCFs enhances the thermal and mechanical properties, reduces the dielectric constants, and increases the transparency. The properties of the MA-functionalized PI are attractive for further studies on their applications.     

Natural products as scaffolds for chemical diversification: solution-phase parallel synthesis of a series of naringin analogues

The flavanone glycoside naringin hydrate is widely abundant in various citrus plants. As an ongoing effort toward the exploitation of natural products as scaffolds for chemical diversification at readily accessible positions, we have prepared a series of analogues of naringin in which the 6-hydroxyl group of the beta-d-glucopyranosyl subunit was converted to sulfonamides, amides, urethanes, and secondary and tertiary amines via the corresponding 6-amino derivative using a solution-phase parallel array protocol.     

PEG化的聚合物载体树脂研究进展

组合化学已成为发现和优化新药、亲和配体和催化过程中的重要组成部分.高分子载体树脂在组合化学中起着关键的作用,各种类型的聚合物树脂在有机合成中已被广泛开发为载体、反应物和催化剂.与传统的Merrifield树脂相比较,聚乙二醇(PEG)化的聚合物树脂具有与极性溶剂更好的相容性、更高的溶剂吸收和溶胀性能.本文主要综述与PEG相关联的聚合物树脂在有机合成载体领域中的最新成果.     

PEG-related polymer resins as synthetic supports

Combinatorial chemistry has become a significant part of the discovery and optimization process for novel drugs, affinity ligands, and catalysts. The polymeric supports play a key role in combinatory chemistry. Therefore, various kinds of functional polymer resins have been exploited as supports, reagents, and catalysts in organic synthesis. In comparison to the conventional Merrifield resins, the poly(ethylene glycol) (PEG)-related polymer resins have advantages including good compatibilities with polar solvents, good solvent absorbency and swelling properties. This review focuses primarily on the more recent work in the field of developing PEG-related polymer resins as supports for organic synthesis.     

General,Straightforward, and Atom-Economical Synthesis of Vinyl Triflimides

Vinyl triflimides were only accessible recently and their chemistry is yet to be discovered. Herein, we describe a general, straightforward and atom-economical synthesis of these materials from alkynes and triflimide. A vast array of terminal and internal alkynes with broad spectrum of functionalities could be employed to generate various di- and trisubstituted vinyl triflimides regiospecifically with high to specific stereoselectivity. Moreover, the protocol could be conducted on gram scale using terminal and internal alkynes. Preliminarily attempts to probe the unprecedented reactivity of vinyl triflimides revealed part of its chemical properties.