Synthetic Auxiliary Research Articles

Harnessing benzotriazole as a sustainable ligand in metal-catalyzed coupling reactions.

Coupling reactions play a crucial role in drug development enabling the rapid expansion of structure-activity relationships (SARs) during drug discovery programs to identify a clinical candidate and simplify subsequent drug development processes. In particular, their relevance in clinical medicine and drug discovery has increased significantly in the last two decades. To facilitate these metal-catalyzed coupling reactions, suitably designed ligands are necessary and from the industrial point of view, sustainable and cost-effective ligands are of current need. Benzotriazole, a non-toxic, thermally stable, and inexpensive bidentate ligand, exhibits strong electron donating and electron accepting properties, along with excellent solubility in various organic solvents. It has been extensively explored as a synthetic auxiliary in the past; in recent years, benzotriazole and its derivatives have been used as ligands in metal-catalyzed coupling reactions. The facile construction of carbon-carbon and carbon-heteroatom bonds in the presence of versatile benzotriazole ligands makes it an indispensable ligand for catalytic transformations. The present feature article mainly emphasizes the advances in the utilization of benzotriazole as a ligand in a diverse range of C-C, C-N, C-O, and C-S coupling reactions.

Organoplatinum‐Bridged Cyclotribenzylene Dimers

AbstractCyclotribenzylenes (CTBs) combining carbonitrile (−CN) and alkyne (−C2H) substituents were synthesized as racemic mixtures and resolved by HPLC on chiral stationary phases. Two of these compounds were used to prepare platinum‐bridged CTB dimers, in which PtII is bound to the CTBs via Pt−alkynyl bonds in cis configuration. The organometallic complexes were examined by mass spectrometry and NMR spectroscopy, which indicated that they were obtained as mixtures of diastereoisomers (a meso or syn form and a pair of chiral or anti forms) when racemic CTBs were used. Enantiomerically pure complexes were prepared from resolved CTBs, which allowed us to distinguish the NMR signals of the chiral and meso forms in the diastereoisomeric mixtures. In certain conditions, the platinum complexes played the role of a pincer π‐alkynyl ligand for Cu(I) coming from the copper iodide used as a synthetic auxiliary. The Cu+ cations could be easily removed by treatment with NaCN, affording the mononuclear bis‐cyclotribenzylene complexes. These compounds failed to lead to metallo‐cryptophanes by coordination of two [M(dppp)]2+ complex subunits (M=Pd, Pt; dppp=1,3‐bis(diphenylphosphino)propane), each to two carbonitrile substituents belonging to different CTBs, pointing to the superiority of the one pot self‐assembly processes for the preparation of metallo‐cryptophanes.

Triphosgene and its Application in Organic Synthesis

In this study, we want to have an extensive overview on the application of triphosgene in organic synthesis. We begin with an introductory discussion of the nature of triphosgene, and introduce several procedures for the preparation of triphosgene. It holds an advantage over other similar reagents, such as phosgene and diphosgene, of being a safe and easy to handle solid. On the other hand, it is safer and more convenient to transport and store. Exact amounts may be weighed easily and used to perform desired chemical transformations and reaction requires only one-third equivalent of triphosgene in most cases. We then survey the reactions and transformations that performed using triphosgene. The reactions have been performed using triphosgene are carried out under mild conditions and afford good to excellent yields. The use of triphosgene as a synthetic auxiliary in the preparation of many important classes of organic compounds has been investigated intensively in the last years. Finally, we summarize the advantages of triphosgene in organic synthesis. Keywords: Triphosgene, crystalline solid, organic synthesis, phosgene, economical, mild conditions.

Imidazolium-supported benzotriazole: an efficient and recoverable activating reagent for amide, ester and thioester bond formation in water

An efficient and recyclable imidazolium-supported benzotriazole reagent (Im-CH2-BtH) as a novel synthetic auxiliary has been synthesized and explored for its carboxyl group activating capability for the synthesis of amides, esters and thioesters in water.

A convenient synthesis of new NSAID esters containing amino acid, urea and amide moieties

Abstract A convenient synthetic method for the preparation of novel NSAID twin esters 6a-i containing amino acid residue, urea and amide moieties has been developed. The synthetic pathway applied for the preparation of target compounds and key intermediates 1-benzotriazolecarboxylic acid chloride (1), NSAID benzotriazolides 2a-c and N-(1-benzotriazolecarbonyl)-amino acids 3a-d involved benzotriazole as a synthetic auxiliary. The final preparation step of esters 6a-i included the solvent-free reaction of compounds 2a-c with amino acid derivatives 5a-g, bearing two hydroxyl groups, one at each terminal, beside urea and amide functionalities.

3D-QSAR and Molecular Docking Studies on Benzotriazoles as Antiproliferative Agents and Histone Deacetylase Inhibitors

Benzotriazole is an important synthetic auxiliary for potential clinical applications. A series of benzotriazoles as potential antiproliferative agents by inhibiting histone deacetylase (HDAC) were recently reported. Three-dimensional quantitative structure-activity relationship (3D-QSAR), including comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA), were performed to elucidate the 3D structural features required for the antiproliferative activity. The results of both ligand-based CoMFA model (<TEX>$q^2=0.647$</TEX>, <TEX>$r^2=0.968$</TEX>, <TEX>${r^2}_{pred}=0.687$</TEX>) and CoMSIA model (<TEX>$q^2=0.685$</TEX>, <TEX>$r^2=0.928$</TEX>, <TEX>${r^2}_{pred}=0.555$</TEX>) demonstrated the highly statistical significance and good predictive ability. The results generated from CoMFA and CoMSIA provided important information about the structural characteristics influence inhibitory potency. In addition, docking analysis was applied to clarify the binding modes between the ligands and the receptor HDAC. The information obtained from this study could provide some instructions for the further development of potent antiproliferative agents and HDAC inhibitors.

ChemInform Abstract: Benzotriazole as a Synthetic Auxiliary

AbstractReview: 60 refs.

Novel NSAID 1-acyl-4-cycloalkyl/arylsemicarbazides and 1-acyl-5-benzyloxy/hydroxy carbamoylcarbazides as potential anticancer agents and antioxidants

The novel 1-acyl-4-cycloalkyl/arylsemicarbazides (5a–y) and 1-acyl-5-benzyloxy/hydroxycarbamoylcarbazides (8a–f) derived from the nonsteroidal anti-inflammatory drugs ibuprofen, fenoprofen and reduced ketoprofen were prepared, fully chemically characterized and evaluated for their cytostatic, antiviral and antioxidant activities. Compounds 5 and 8 consist of a region rich in electronegative atoms (five to nine nitrogen and oxygen atoms) framed by aryl or cycloalkyl residues on one or both terminal ends. The synthetic pathways applied for the preparation of the title compounds involved a benzotriazole as a synthetic auxiliary in several steps. Three of the tested compounds, namely 4-benzhydryl-1-[2-(3-phenoxyphenyl)propanoyl]semicarbazide (5l), 4-benzhydryl-1-[2-(3-benzylphenyl)propanoyl]semicarbazide (5s), and 4-benzhydryl-1-[2-(4-isobutylphenyl)propanoyl]semicarbazide (5f) showed pronounced antiproliferative activity in vitro against six cancer cell lines (IC50=3–23μM). The same compounds highly inhibited soybean lipoxygenase (IC50=60 and 51.5μM) and lipid peroxidation as well (99, 88 and 74%, respectively). 4-Benzyloxy-1-[2-(4-isobutylphenyl)propanoyl]semicarbazide (5t) and 5-benzyloxycarbamoyl-1-[2-(3-benzylphenyl)propanoyl]carbazide (8c) exerted complete lipid peroxidation inhibition. Semicarbazides 5w–y and carbazides 8d–f bearing a hydroxamic acid/hydroxyurea moiety showed a modest antiradical activity in DPPH test, while the best radical scavenger was 1-(1-benzotriazolecarbonyl)-4-benzyloxysemicarbazide (7). None of the compounds were inhibitory to a broad panel of DNA and RNA viruses in the cell culture at subtoxic concentrations.

Novel 1-acyl-4-substituted semicarbazide derivatives of primaquine − synthesis, cytostatic, antiviral and antioxidative studies

A series of novel 1,4-substituted semicarbazides 5a–g with a primaquine moiety bridged by a carbonyl group at position 1 and a cycloalkyl, aryl, benzyloxy or hydroxy substituent at position 4 were prepared and biologically evaluated. The synthetic pathways applied for preparation of the title compounds involved benzotriazole as synthetic auxiliary. Primaquine semicarbazides 5a–g and their synthetic precursors benzotriazolecarbonyl semicarbazides 4 were evaluated for cytostatic, antiviral and antioxidative activities. All compounds of the series 5 showed high selectivity towards MCF-7 cells (breast carcinoma) with IC50 values in the low micromolar range and the most active was benzyl derivative 5c (IC50 1 ± 0.2 µM). The benzhydryl derivative 5e showed significant cytostatic activities towards all the tested cell lines (IC50 4–18 µM). The same compound was the strongest lipoxygenase inhibitor as well (51%). The highest antioxidant activity was demonstrated for the hydroxy derivative 5g and benzotriazolecarbonyl semicarbazides 4b,c (61.2–68.5%). No antiviral activity was observed against a wide variety of DNA and RNA viruses.

Benzotriazole as a Synthetic Auxiliary

Benzotriazole is a very useful synthetic auxiliary with versatile applications in organic chemis¬try. We have used benzotriazole in the synthesis of various heterocyclic compounds (benzoxazine, quinazoline, triazinetrione, hydantoin, oxadiazine and diazepane derivatives), amino acid derivatives, car¬bamates, ureas, semicarbazides, carbazides, sulfonylureas, sulfonylcarbazides, hydantoic acids, non-steroidal antiinflammatory drug (NSAID) and primaquine derivatives, polymer-drug and thiomer-drug conjugates. The results have been published in more than 30 papers and here we give an overview of all syntheses.

ChemInform Abstract: A Novel and Facile Reaction to N6-Alkylated Adenosine via Benzotriazole as a Synthetic Auxiliary.

The reaction of benzotriazole with aliphatic, aromatic or heteroaromatic aldehyde and adenosine leads to a benzotriazole adduct which is reduced with sodium borohydride to the corresponding N6-alkylated adenosine derivatives. This procedure is also utilized in a new route to N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA) which is considered an important adenosine agonist at A3 adenosine receptors.

1H-Benzotriazoles

1H-Benzotriazole (BtH) is a non-volatile, white crystalline powder that melts at 98.5 ˚C. It is insoluble in water, but soluble in aqueous sodium carbonate, and in ethanol. It is intrinsically unreactive, stable under many conditions, cheap, and ready available. Because of its chemical properties, it can be used as a valuable synthetic auxiliary, allowing an enormous variety of reactions. [¹] A benzotriazole group activates the carbon atom to which it is attached in various ways: by acting as a leaving group; by enabling deprotonation; or by acting as an electron donor. An attached benzotriazole group is also an ambient anion-directing group and it can act as a radical or carbanion precursor. [¹]

Benzotriazole: An Ideal Synthetic Auxiliary.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Benzotriazole: an ideal synthetic auxiliary.

Benzotriazole is a synthetic auxiliary that offers many advantages. It is inexpensive, odorless, and stable. A benzotriazole group is easily introduced, activates molecules towards numerous transformations, and can be removed easily at the end of the reaction sequence. This Concept provides some recent examples of the synthetic application of benzotriazole methodology and is intended to draw attention to the versatile applications of benzotriazole in organic chemistry.

Synthesis and Reactions of Benzotriazolyl‐Substituted Spiro[cyclohexane‐1,2′‐2′H‐imidazo[4,5‐b]pyridine

AbstractFor Abstract see ChemInform Abstract in Full Text.

Synthesis and Reactions of Benzotriazolyl-Substituted Spiro[Cyclohexane-1,2′-2′H-Imidazo[4,5-b]Pyridine

The introduction of N and S-nucleophiles into the 2H-4-azabenzimidazole system using the 1H-benzotriazole ring as a synthetic auxiliary, and also the syntheses of novel pentacyclic ring systems by application of the Graebe-Ullmann method, are described.

1H-Benzotriazole as Synthetic Auxiliary in a Facile Route to N6-(Arylmethyl)-2′-deoxyadenosines: DNA Intercalators Inserted into Three-Way Junctions

The 2′-deoxy-N6-(naphthalen-1-ylmethyl)- (5a) and N6-(pyren-1-ylmethyl)adenosine (5b) were synthesized in two steps from 2′-deoxyadenosine and the adequate arenecarbaldehyde with 1H-benzotriazole as a synthetic auxiliary (Scheme). When the N6-(arylmethyl)-2′-deoxyadenosines were inserted into the junction region of a DNA three-way junction, its thermal stability increased.

A novel and facile reaction toN6-alkylated adenosineviabenzotriazole as a synthetic auxiliary

The reaction of benzotriazole with aliphatic, aromatic or heteroaromatic aldehyde and adenosine leads to a benzotriazole adduct which is reduced with sodium borohydride to the corresponding N6-alkylated adenosine derivatives. This procedure is also utilized in a new route to N6-(3-iodobenzyl)adenosine-5′-N-methyluronamide (IB-MECA) which is considered an important adenosine agonist at A3 adenosine receptors.

ChemInform Abstract: A Novel Route to N6‐Alkylated 2′‐Deoxyadenosine Using Benzotriazole as a Synthetic Auxiliary.

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A Novel Route to N6-Alkylated 2'-Deoxyadenosine Using Benzotriazole as a Synthetic Auxiliary.

A Novel Route to N6-Alkylated 2'-Deoxyadenosine Using Benzotriazole as a Synthetic Auxiliary.