Oxetane ethers are formed reversibly in the lithium-catalyzed Friedel–Crafts alkylation of phenols with oxetanols: Synthesis of dihydrobenzofurans, diaryloxetanes, and oxetane ethers

Croft, Rosemary A.; Mousseau, James J.; Choi, Chulho; Bull, James A.

doi:10.1016/j.tet.2018.02.069

Cited by 16 publications

(13 citation statements)

References 36 publications

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“…The synthesis of targets 1a and 2a (scheme 1a) was achieved via a catalytic Friedel-Crafts alkylation from a readily accessible alcohol precursor, a method developed in our previously disclosed work. 18 3-Indolyloxetanol 11a was furnished from commercially available oxetanone and 3-iodo-methylindole in the presence of nBuLi. Subjecting oxetanol 11a to a Friedel-Crafts alkylation using o-cresol or phenol and an inexpensive lithium triflimide catalyst under mild conditions led to diaryloxetane 5a in 67% yield, whereas oxetane 6a was obtained in 28%.…”

Section: Figure 2 Selected Molecules For the Proposed Pairwise Analysismentioning

confidence: 99%

“…This partnership expediently developed a new way into 3,3-diaryloxetanes through a lithium-catalyzed Friedel-Crafts manifold, which provided unprecedented access to decorated 3,3-diaryloxetane motifs. 18 Mechanistic understanding enabled the development of other interesting 3,3-disubstituted oxetanes. With these new methods in hand, and cognizant of the lack of understanding of the impact of 3,3-diaryloxetanes on physicochemical properties, we proceeded to a matched molecular pair analysis (MMPA) to probe the effect of replacing a benzophenone with a diaryloxetane on lipophilicity, cell permeability, clearance, solubility, and chemical stability, amongst others.…”

Section: Figure 1 Developments Of Oxetane Bioisosteresmentioning

confidence: 99%

“…This partnership expediently developed a new way into 3,3-diaryloxetanes through a lithium-catalyzed Friedel-Crafts manifold, which provided unprecedented access to decorated 3,3-diaryloxetane motifs. 18 Mechanistic understanding enabled the development of other interesting 3,3-disubstituted oxetanes. 11,19 Furthermore, we have been able to demonstrate that 3,3-diaryloxetanes are robust to a range of chemical transformations, enabling access to a range of compounds with diverse functionality.…”

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confidence: 99%

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Investigating 3,3-Diaryloxetanes as Potential Bioisosteres in Drug Discovery

Maj¹,

Croft²,

Ding³

et al. 2021

Preprint

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<div><div><div><p>Oxetanes have received increasing interest in medicinal chemistry as attractive polar and low molecular weight motifs. The application of oxetanes as replacements for methylene, methyl, gem-dimethyl and carbonyl groups has been demonstrated to often improve chemical properties of target molecules for drug discovery purposes. The investigation of the properties of 3,3-diaryloxetanes, particularly of interest as a benzophenone replacement, remains largely unexplored. With recent synthetic advances in accessing this motif we studied the effects of 3,3-diaryloxetanes on the physicochemical properties of ‘drug-like’ molecules. Here, we describe our efforts in the design and synthesis of a range of drug-like compounds for matched molecular pair analysis to investigate the viability of the 3,3-diaryloxetane motif as a replacement group in drug discovery. We conclude that the properties of the diaryloxetanes and ketones are similar, and generally superior to related alkyl linkers, and that diaryloxetanes provide a potentially useful new design element.</p></div></div></div>

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Section: Figure 2 Selected Molecules For the Proposed Pairwise Analysismentioning

confidence: 99%

Section: Figure 1 Developments Of Oxetane Bioisosteresmentioning

confidence: 99%

“…This partnership expediently developed a new way into 3,3-diaryloxetanes through a lithium-catalyzed Friedel-Crafts manifold, which provided unprecedented access to decorated 3,3-diaryloxetane motifs. 18 Mechanistic understanding enabled the development of other interesting 3,3-disubstituted oxetanes. 11,19 Furthermore, we have been able to demonstrate that 3,3-diaryloxetanes are robust to a range of chemical transformations, enabling access to a range of compounds with diverse functionality.…”

mentioning

confidence: 99%

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Investigating 3,3-Diaryloxetanes as Potential Bioisosteres in Drug Discovery

Maj¹,

Croft²,

Ding³

et al. 2021

Preprint

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“…We have developed methods for the formation of oxetane carbocations using Lewis acid catalysts to dehydrate 3-aryloxetan-3-ols. 17 , 18 Specifically, reaction with 4-substituted phenols gave a Friedel–Crafts reaction at the 2-position of the phenol and was followed by opening of the oxetane ring by the phenolic oxygen under the Lewis acidic conditions to yield dihydrobenzofurans ( Figure 1 D). 17 Similarly, Sun reported the synthesis of indolines using In(OTf) 3 as a Lewis acid catalyst.…”

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Oxetan-3-ols as 1,2-bis-Electrophiles in a Brønsted-Acid-Catalyzed Synthesis of 1,4-Dioxanes

et al. 2022

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Annulations that combine diacceptors with bis-nucleophiles are uncommon. Here, we report the synthesis of 1,4-dioxanes from 3-aryloxetan-3-ols, as 1,2-bis-electrophiles and 1,2-diols. Brønsted acid Tf 2 NH catalyzes both the selective activation of the oxetanol, to form an oxetane carbocation that reacts with the diol, and intramolecular ring opening of the oxetane. High regio- and diastereoselectivity are achieved with unsymmetrical diols. The substituted dioxanes and fused bicyclic products present interesting motifs for drug discovery and can be further functionalized.

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“…Catalytic functionalization of π-activated alcohols provides an attractive synthetic approach, as it avoids preactivation and generates only water as a byproduct. , We recently reported the synthesis of 3,3-diaryloxetanes and 3,3-diarylazetidines by a catalytic Friedel–Crafts alkylation with tertiary benzylic oxetan-3-ols and azetidin-3-ols. Relatively few examples of thioetherification of functionalized activated alcohols can be found in the literature, often requiring higher loadings of expensive metal catalyst or harsher conditions .…”

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Synthesis of 3-Aryl-3-Sulfanyl Azetidines by Iron-Catalyzed Thiol Alkylation with N-Cbz Azetidinols

et al. 2019

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New small ring derivatives can provide valuable motifs in new chemical space for drug design. 3-Aryl-3-sulfanyl azetidines are synthesized directly from azetidine-3-ols in excellent yield by a mild Fe-catalyzed thiol alkylation. A broad range of thiols and azetidinols bearing electron donating aromatics are successful, proceeding via an azetidine carbocation. The N-Cbz group is a requirement for good reactivity, and enables the NH-azetidine to be revealed. Further reactions of the azetidine sulfides demonstrate their potential for incorporation in drug discovery programs. New chemical motifs with appropriate physicochemical properties offer valuable opportunities in drug design. 1,2 As a result, there has been significant recent attention on the synthesis of new modules that may be readily incorporated in medicinal chemistry, as fragments, building blocks or isosteres. 3 Small heterocyclic rings are attractive in this context due to low molecular weight and defined exit vectors. 4,5 Small rings readily access new chemical and IP space, particularly when combined with medicinally relevant substituents, which is partly due to their limited synthetic accessibility preventing their investigation. Sulfur functional groups are prevalent in pharmaceuticals and agrochemicals, 6 with thioethers being important in their own right and as intermediates to access sulfoxide, sulfone and sulfoximine moieties. There are examples of azetidine thioethers in biologically active compounds in the literature with the majority 3-monosubstituted, including compounds having RBP4-lowering activity and antibacterial activity (Figure 1A). 7,8 3,3-Disubstituted azetidine sulfides, without additional C2 or C4 1 2a 5 a Isolated yields quoted. Alternative 3-aryl-azetidin-3-ol substrates (3-8) were prepared by the addition of Grignard reagents to commercially available N-Cbz azetidine-3-one (Scheme 2). 16 Preinstalled benzyl-and TIPS-protected phenols were tolerated under the reaction conditions producing 9 and 10 in excellent yield. Increasing the steric demands of the azetidinol with ortho-substituted aromatics gave azetidine 11 in 92% yield. Benzodioxole and trimethoxybenzene azetidinols reacted similarly well giving products 12 to 14 in good yield using benzylic, aryl or alkyl thiols respectively as nucleophiles. Importantly, indole containing sulfanylazetidine 15 was formed in 97% yield. As such, a range of 3-sulfanyl azetidines can be readily prepared with appealing functionalities of interest to medicinal chemists, varying both the thiol and preinstalled aryl group. 3-Phenylazetidin-3-ol returned starting material, even increasing the temperature to 80 °C, indicating the need for electron-rich aromatics to stabilize the postulated azetidine carbocation intermediate. The reaction could be extended to the 5 and 6-membered N-heterocycles giving piperidine 16 and pyrrolidine 17 in 95% and 93% yield respectively using benzylmercaptan. 6 Scheme 2. Scope of azetidinols. a a Isolated yields quoted. The derivatization of various 3-sulfanyl azetidi...

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Oxetane ethers are formed reversibly in the lithium-catalyzed Friedel–Crafts alkylation of phenols with oxetanols: Synthesis of dihydrobenzofurans, diaryloxetanes, and oxetane ethers

Cited by 16 publications

References 36 publications

Investigating 3,3-Diaryloxetanes as Potential Bioisosteres in Drug Discovery

Investigating 3,3-Diaryloxetanes as Potential Bioisosteres in Drug Discovery

Oxetan-3-ols as 1,2-bis-Electrophiles in a Brønsted-Acid-Catalyzed Synthesis of 1,4-Dioxanes

Synthesis of 3-Aryl-3-Sulfanyl Azetidines by Iron-Catalyzed Thiol Alkylation with N-Cbz Azetidinols

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