651316-65-3

Upstream product

• 1436389-35-3 (4-{3-[(tert-butoxycarbonyl)(methyl)amino]-1-phenylpropoxy}phenyl)(difluoro)acetic acid 
• 402-43-7 p-trifluoromethylphenyl bromide 
• 244059-08-3 tert-butyl N-(3-hydroxy-3-phenylpropyl)-N-methylcarbamate 
• 24424-99-5 di-tert-butyl dicarbonate 
• 54910-89-3 FLUOXETINE 
• 329-14-6 1-(methylsulfanyl)-4-(trifluoromethyl)benzene 
• 402-45-9 4-hydroxybenzotrifluoride 
• 42142-52-9 3-methylamino-1-phenylpropan-1-ol 
• 1456616-19-5 tert-butyl (3-(4-bromophenoxy)-3-phenylpropyl)(methyl)carbamate 
• 75-46-7 trifluoromethan 
• 18776-12-0 3-chloro-1-phenyl-propan-1-ol 
• 106-41-2 4-bromo-phenol 
• 1436389-46-6 ethyl (4-{3-[(tert-butoxycarbonyl)(methyl)amino]-1-phenylpropoxy}phenyl)(difluoro)acetate 
• 5053-63-4 3-amino-1-phenylpropan-1-ol 

Downstream Products

• 54910-89-3 FLUOXETINE 
• 1436389-37-5 N-methyl-3-phenyl-3-[4-(trifluoromethyl)phenoxy]propan-1-amine trifluoroacetic acid 

Relevant academic research and scientific papers

Discriminating non-ylidic carbon-sulfur bond cleavages of sulfonium ylides for alkylation and arylation reactions

A sulfonium ylide participated alkylation and arylation under transition-metal free conditions is described. The disparate reaction pattern allowed the separate activation of non-ylidic S-alkyl and S-aryl bond. Under acidic conditions, sulfonium ylides serve as alkyl cation precursors which facilitate the alkylations. While under alkaline conditions, cleavage of non-ylidic S-aryl bond produces O-arylated compounds efficiently. The robustness of the protocols were established by the excellent compatibility of wide variety of substrates including carbohydrates.

Tuning the activity of known drugs via the introduction of halogen atoms, a case study of SERT ligands – Fluoxetine and fluvoxamine

The selective serotonin reuptake inhibitors (SSRIs), acting at the serotonin transporter (SERT), are one of the most widely prescribed antidepressant medications. All five approved SSRIs possess either fluorine or chlorine atoms, and there is a limited number of reports describing their analogs with heavier halogens, i.e., bromine and iodine. To elucidate the role of halogen atoms in the binding of SSRIs to SERT, we designed a series of 22 fluoxetine and fluvoxamine analogs substituted with fluorine, chlorine, bromine, and iodine atoms, differently arranged on the phenyl ring. The obtained biological activity data, supported by a thorough in silico binding mode analysis, allowed the identification of two partners for halogen bond interactions: the backbone carbonyl oxygen atoms of E493 and T497. Additionally, compounds with heavier halogen atoms were found to bind with the SERT via a distinctly different binding mode, a result not presented elsewhere. The subsequent analysis of the prepared XSAR sets showed that E493 and T497 participated in the largest number of formed halogen bonds. The XSAR library analysis led to the synthesis of two of the most active compounds (3,4-diCl-fluoxetine 42, SERT Ki = 5 nM and 3,4-diCl-fluvoxamine 46, SERT Ki = 9 nM, fluoxetine SERT Ki = 31 nM, fluvoxamine SERT Ki = 458 nM). We present an example of the successful use of a rational methodology to analyze binding and design more active compounds by halogen atom introduction. ‘XSAR library analysis’, a new tool in medicinal chemistry, was instrumental in identifying optimal halogen atom substitution.

C(sp3)?H Cyanation Promoted by Visible-Light Photoredox/Phosphate Hybrid Catalysis

Inspired by the reaction mechanism of photo-induced DNA cleavage in nature, a C(sp3)?H cyanation reaction promoted by visible-light photoredox/phosphate hybrid catalysis was developed. Phosphate radicals, generated by one-electron photooxidation of phosphate salt, functioned as a hydrogen-atom-transfer catalyst to produce nucleophilic carbon radicals from C(sp3)?H bonds with a high bond-dissociation energy. The resulting carbon radicals were trapped by a cyano radical source (TsCN) to produce the C?H cyanation products. Due to the high functional-group tolerance and versatility of the cyano group, the reaction will be useful for realizing streamlined building block syntheses and late-stage functionalization of drug-like molecules.

Photoredox-Mediated Direct Cross-Dehydrogenative Coupling of Heteroarenes and Amines

A photoredox-mediated direct cross-dehydrogenative coupling reaction to accomplish α-aminoalkylation of N-heteroarenes is reported. This mild reaction has a broad substrate scope, offers the first general method for synthesis of aminoalkylated N-heteroarenes without the need for substrate prefunctionalization, and is scalable to the gram level. Furthermore, the reaction was found to be applicable to other hydrogen donors besides amines (i.e., ethers, an aldehyde, a formamide, p-xylene, and alkanes), thus enabling the preparation of N-heteroarenes bearing various types of substituents.

TCDA: Practical Synthesis and Application in the Trifluoromethylation of Arenes and Heteroarenes

A practical synthesis of the reagent trimethylsilyl chlorodifluoroacetate (TCDA) is reported on 50 g scale. The trifluoromethylation with TCDA was optimized, and the reaction shows very broad scope with respect to electron-deficient, -neutral, -rich aryl/heteroaryl iodides, as well as excellent functional group tolerability, such as ester, amide, aldehyde, hydroxyl, and carboxylic acid. The reagent was also applied to the late-stage trifluoromethylation of three medicinally relevant compounds. Additionally, the building block trifluoromethylpyridine and one drug related molecule Boc-Fluoxetin were synthesized in 10 g scale by this method, demonstrating its practical applications in process chemistry.

Switching on elusive organometallic mechanisms with photoredox catalysis

Transition-metal-catalysed cross-coupling reactions have become one of the most used carbon-carbon and carbon-heteroatom bond-forming reactions in chemical synthesis. Recently, nickel catalysis has been shown to participate in a wide variety of C-C bond-forming reactions, most notably Negishi, Suzuki-Miyaura, Stille, Kumada and Hiyama couplings. Despite the tremendous advances in C-C fragment couplings, the ability to forge C-O bonds in a general fashion via nickel catalysis has been largely unsuccessful. The challenge for nickel-mediated alcohol couplings has been the mechanistic requirement for the critical C-O bond-forming step (formally known as the reductive elimination step) to occur via a Ni(iii) alkoxide intermediate. Here we demonstrate that visible-light-excited photoredox catalysts can modulate the preferred oxidation states of nickel alkoxides in an operative catalytic cycle, thereby providing transient access to Ni(iii) species that readily participate in reductive elimination. Using this synergistic merger of photoredox and nickel catalysis, we have developed a highly efficient and general carbon-oxygen coupling reaction using abundant alcohols and aryl bromides. More notably, we have developed a general strategy to 'switch on' important yet elusive organometallic mechanisms via oxidation state modulations using only weak light and single-electron-transfer catalysts.

CuCF3: A [18F]trifluoromethylating agent for arylboronic acids and aryl iodides

Positron emission tomography has emerged as the leading method for medical imaging with fluorine-18 as the most widely used radioactive isotope. Here we report a semi-automated method for the preparation of valuable [ 18F]trifluoromethylcopper, as well as its use for the radiosynthesis of [18F]trifluoromethylarenes and heteroarenes. Mild conditions of [18F]trifluoromethylation make this method particularly useful for the radiosynthesis of pharmacologically relevant [18F] trifluoromethylarenes and heteroarenes. 18F Radiochemistry: A semi-automated method for the fast preparation of radiolabelled (trifluoromethyl)copper is reported (see scheme), thus making [ 18F]CuCF3 almost as accessible as [18F]fluoride itself for the preparation of radiolabelled trifluoromethylated probes. It can be used for the preparation of radiolabelled trifluoromethylarenes from arylboronic acids and aryliodides. This methodology is clean, efficient and consistent with the specific requirements of radiochemistry.

Catalytic decarboxylative fluorination for the synthesis of Tri- and difluoromethyl arenes

Treatment of readily available α,α-difluoro- and α-fluoroarylacetic acids with Selectfluor under Ag(I) catalysis led to decarboxylative fluorination. This operationally simple reaction gave access to tri- and difluoromethylarenes applying a late-stage fluorination strategy. Translation to [18F]labeling is demonstrated using [ 18F]Selectfluor bis(triflate), a reagent affording [ 18F]tri- and [18F]difluoromethylarenes not within reach with [18F]F2.