Improved Schmidt Conversion of Aldehydes to Nitriles Using Azidotrimethylsilane in 1,1,1,3,3,3-Hexafluoro-2-propanol

Motiwala, Hashim F.; Yin, Qin; Aubé, Jeffrey

doi:10.3390/molecules21010045

Cited by 9 publications

(3 citation statements)

References 65 publications

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“…Similar enhancements of efficiency and selectivity was observed for the intermolecular Schmidt reaction of aromatic aldehydes with TMSN 3 , affording nitriles, using a substoichiometric amount of TfOH in HFIP (Scheme ). Compared to a protocol that employed 3.0 equiv of TfOH in ACN, the use of strong hydrogen-bond-donating HFIP as a cosolvent with ACN enabled dramatic reduction in the catalyst loading to 0.40 equiv and simplified purification by eliminating the need for aqueous work up.…”

Section: Rearrangements Isomerizations and Migrationsmentioning

confidence: 77%

HFIP in Organic Synthesis

et al. 2022

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1,1,1,3,3,3-Hexafluoroisopropanol (HFIP) is a polar, strongly hydrogen bond-donating solvent that has found numerous uses in organic synthesis due to its ability to stabilize ionic species, transfer protons, and engage in a range of other intermolecular interactions. The use of this solvent has exponentially increased in the past decade and has become a solvent of choice in some areas, such as C–H functionalization chemistry. In this review, following a brief history of HFIP in organic synthesis and an overview of its physical properties, literature examples of organic reactions using HFIP as a solvent or an additive are presented, emphasizing the effect of solvent of each reaction.

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Section: Rearrangements Isomerizations and Migrationsmentioning

confidence: 77%

HFIP in Organic Synthesis

et al. 2022

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“…Thus, tetrazoles were the major products under conditions in the absence of large excesses of TMSN 3 , rendering this one of the most attractive synthetic pathways for converting ketones to ring-expanded tetrazoles. In separate work, we have disclosed that similar enhancements of efficiency and selectivity are possible for yet another reaction of TMSN 3 with carbonyls, in which aromatic aldehydes are converted cleanly to nitriles accompanied by little or no formamide formation (Scheme b) . Taken together, this body of work demonstrates that practical utility, for example, higher yields and often purer products, as well as changes in reaction pathways and selectivity, results from carrying out Schmidt reactions in HFIP relative to more traditional solvents.…”

Section: Discussionmentioning

confidence: 99%

Remodeling and Enhancing Schmidt Reaction Pathways in Hexafluoroisopropanol

et al. 2016

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The effect of carrying out two variations of the Schmidt reaction with ketone electrophiles in hexafluoroisopropanol (HFIP) solvent has been studied. When TMSN3 is reacted with ketones in the presence of triflic acid (TfOH) promoter, tetrazoles are obtained as the major products. This observation is in contrast to established methods, which usually lead to amides or lactams arising from formal NH insertion as the major products. The full product profiles of several examples of this reaction are also reported and found to include mechanistically interesting products (e.g., double ring expansion). Application of TfOH promoter in HFIP was also found to promote the reaction of a hydroxyalkyl azide with a ketone, which affords lactams following nucleophilic opening of initially formed iminium ether more efficiently than previously reported methods.

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“…The use of aldehydes as starting materials is highly attractive because aldehydes are commercially available and directly afford nitriles without the need to isolate the oxime. Several nitrogen sources for use with aldehydes include the highly toxic sodium azido used in the Schmidt reaction, explosive hydroxylamines and derivatives, and ammonia coupled with transition-metal catalysis or stoichiometric iodine . However, few Brønsted acid catalyzed nitrile syntheses from aldehydes at ambient temperature have been reported .…”

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confidence: 99%