Tri–<i>tert</i>‐Butanolamine as an Organic Promoter in Nucleophilic Fluorination

Shinde, Sandip S.; Khonde, Nilesh S.; Kumar, Pradeep

doi:10.1002/slct.201601735

Cited by 20 publications

(40 citation statements)

References 37 publications

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“…From the discussions above we proposed that using F − or OMs − as the counter‐anion render the S N Ar fluorination process to be strongly favorable over the side reactions. Further enhancement of rates of fluorination may still be possible by employing Lewis base promoters such as crown ethers, which proved to be phenomenally efficient agents for promoting S N 2 fluorination [ 5,7,28–31 ] : The electronegative O atoms in a crown ether would strongly interact with the counter‐cation Cs + to suppress its retarding Coulombic influence on the nucleophile F − , thereby “freeing” the latter for better reactivity. On the other hand, the amino group may not much be affected by the crown ether; thus, selective acceleration of fluorination would be achieved.…”

Section: Resultsmentioning

confidence: 99%

Effects of protecting group and counter‐anion on fluorination, bromination, and intramolecular cyclization of phenethylamine diaryliodonium salts: Quantum chemical analysis

Choi

2020

J of Physical Organic Chem

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We analyze the effects of protecting group(s) and counter‐anion on the relative efficiency of fluorination, bromination and intramolecular cyclization of phenethylamine diaryliodonium salts (1) for nucleophilic fluorination using CsF as a model system for the synthesis of radiopharmaceuticals such as 18F‐dopa and 18F‐dopamine. We demonstrate by quantum chemical analysis that protection of –NH2 by –Boc groups strongly influences the relative yields of nucleophilic fluorination versus side reactions (bromination and intramolecular cyclization) through intricate interactions with iodonium, counter‐anion (Br−, F−, or OMs−) to iodonium, and counter‐cation Cs+ to the nucleophile F−. Protection of the amino by one or two –Boc group(s) render fluorination to be strongly favored over bromination/cyclization. Possibility of direct attack by counter‐anion is assessed. We propose that mesylate (–OMs−) would be much better counter‐anion than Br− because of its much weaker nucleophilicity. F− is also preferred as a counter‐anion, because using it would exclusively give fluorinated product. We also estimate the capability of crown ether (18‐crown‐6) as a Lewis base promoter for enhancing the rates of fluorination.

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Section: Resultsmentioning

confidence: 99%

Effects of protecting group and counter‐anion on fluorination, bromination, and intramolecular cyclization of phenethylamine diaryliodonium salts: Quantum chemical analysis

Choi

2020

J of Physical Organic Chem

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“…The intricate interplay (Coulombic forces) of the counter-cation, the nucleophile, IL cation and anion helps to form a pre-reaction complex and transition state that is optimal for S N 2 fluorination, prohibiting the formation of by-products (Figure 1). The role of IL anion in this mechanism corresponds to that of electronegative O atoms in oligoethylene glycols [36] or in bulky alcohols [37][38][39] (t-butanol and amyl alcohol) that were proved to act as catalyst/promoter in nucleophilic fluorination, but were probably better because of the explicit negative charge of IL anions. Magnier and coworkers [40] carried out a somewhat different approach to using ILs for nucleophilic fluorination.…”

Section: S N 2 Fluorination In Ionic Liquidsmentioning

confidence: 97%

Harnessing Ionic Interactions and Hydrogen Bonding for Nucleophilic Fluorination

Choi

Park

et al. 2020

Molecules

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We review recent works for nucleophilic fluorination of organic compounds in which the Coulombic interactions between ionic species and/or hydrogen bonding affect the outcome of the reaction. SN2 fluorination of aliphatic compounds promoted by ionic liquids is first discussed, focusing on the mechanistic features for reaction using alkali metal fluorides. The influence of the interplay of ionic liquid cation, anion, nucleophile and counter-cation is treated in detail. The role of ionic liquid as bifunctional (both electrophilic and nucleophilic) activator is envisaged. We also review the SNAr fluorination of diaryliodonium salts from the same perspective. Nucleophilic fluorination of guanidine-containing of diaryliodonium salts, which are capable of forming hydrogen bonds with the nucleophile, is exemplified as an excellent case where ionic interactions and hydrogen bonding significantly affect the efficiency of reaction. The origin of experimental observation for the strong dependence of fluorination yields on the positions of -Boc protection is understood in terms of the location of the nucleophile with respect to the reaction center, being either close to far from it. Recent advances in the synthesis of [18F]F-dopa are also cited in relation to SNAr fluorination of diaryliodonium salts. Discussions are made with a focus on tailor-making promoters and solvent engineering based on ionic interactions and hydrogen bonding.

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“…[36] They chose the fluorination of 30 as model reaction; when 18-crown-6 was utilized as promoter in MeCN, a low yield 46 % of the desired fluorinated product 31, along with 8 % alkene 32, were observed. However, when the specially designed tert -butanol amines were subjected to the reaction, both the yield and selectivity towards 31 increased dramatically.…”

Section: Hydrogen Bonding Controlled Nucleophilic Fluorination By Alkmentioning

confidence: 99%

“…Shinde and co‐workers disclosed that the alkylamine bearing t BuOH moiety could also function as promoter for a highly selective fluorination using CsF as nucleophilic source (Scheme ) . They chose the fluorination of 30 as model reaction; when 18‐crown‐6 was utilized as promoter in MeCN, a low yield 46 % of the desired fluorinated product 31 , along with 8 % alkene 32 , were observed.…”

Section: Hydrogen Bonding Controlled Nucleophilic Fluorination By Alkmentioning

confidence: 99%

Hydrogen Bonding: Regulator for Nucleophilic Fluorination

Liang

Hammond

2017

Chemistry A European J

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The recent advances in nucleophilic fluorination, regulated through hydrogen bonding interactions are summarized. Two main categories of fluorine nucleophiles are discussed. Alkali-metal fluorides are widely used in various fluorination transformations because they are inexpensive and safe nucleophilic fluorine sources. But the non-controllable nucleophilicity and strong basicity of some of them cause undesired side reactions, which led to the introduction of hydrogen bonding to fine tune their nucleophilicity and basicity. In contrast, an HF-based fluorine nucleophile, HF/DMPU, is in some aspects superior to the conventional HF/pyridine (Olah's reagent) or HF/Et N because of the higher hydrogen bond basicity of DMPU. It has been used in several nucleophilic fluorinations such as fluorination of alkynes, fluoro-Prins reaction and fluorination of aziridines.

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Tri–tert‐Butanolamine as an Organic Promoter in Nucleophilic Fluorination

Cited by 20 publications

References 37 publications

Effects of protecting group and counter‐anion on fluorination, bromination, and intramolecular cyclization of phenethylamine diaryliodonium salts: Quantum chemical analysis

Effects of protecting group and counter‐anion on fluorination, bromination, and intramolecular cyclization of phenethylamine diaryliodonium salts: Quantum chemical analysis

Harnessing Ionic Interactions and Hydrogen Bonding for Nucleophilic Fluorination

Hydrogen Bonding: Regulator for Nucleophilic Fluorination

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