Novel Practical Deprotection of N-Boc Compounds Using Fluorinated Alcohols

Choy, Jason; Jaime‐Figueroa, Saul; Jiang, Laurence; Wagner, Paul

doi:10.1080/00397910802238718

Cited by 61 publications

(44 citation statements)

References 11 publications

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“…To expedite the process, we sought to combine a thermal Boc deprotection with the condensation step. Since 2,2,2‐trifluoroethanol (TFE) can afford tert ‐butoxycarbamate (Boc) deprotection at high temperature, we attempted the one‐pot procedure shown in Table , entry 1 . Gratifyingly, the reaction proceeded to completion under these conditions, and, upon cooling to room temperature, the product precipitated to provide analytically pure compound in high yield.…”

Section: Figurementioning

confidence: 99%

“…Since 2,2,2-trifluoroethanol (TFE) can afford tert-butoxycarbamate (Boc) deprotection at high temperature, we attempted the one-pot procedure shown in Table 1, entry 1. [30] Gratifyingly,t he reaction proceeded to completionu nder these conditions, and, upon cooling to room temperature, the product precipitated to providea nalytically pure compound in high yield. Exploring the role of the reagent/solvent in this reaction exemplifies the advantage of using TFE as as olventi nt his reaction.…”

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confidence: 98%

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Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

et al. 2018

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The immunomodulatory drugs (IMiDs) thalidomide, pomalidomide, and lenalidomide have been approved for the treatment of multiple myeloma for many years. Recently, their use as E3 ligase recruiting elements for small-molecule-induced protein degradation has led to a resurgence in interest in IMiD synthesis and functionalization. Traditional IMiD synthesis follows a stepwise route with multiple purification steps. Herein we describe a novel one-pot synthesis without purification that provides rapid access to a multitude of IMiD analogues. Binding studies with the IMiD target protein cereblon (CRBN) reveals a narrow structure-activity relationship with only a few compounds showing sub-micromolar binding affinity in the range of pomalidomide and lenalidomide. However, anti-proliferative activity as well as Aiolos degradation could be identified for two IMiD analogues. This study provides useful insight into the structure-degradation relationships for molecules of this type as well as a rapid and robust method for IMiD synthesis.

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Section: Figurementioning

confidence: 99%

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confidence: 98%

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

et al. 2018

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“…AlCl 3 affected conversion of 3 to 4 , but with significant decomposition. Thermolytic degradation of the N ‐Boc group, in addition to discrete treatment of 3 with trifluoroethanol, were also unsuccessful. Realizing the result in Scheme was commensurate with investigating the preliminary conditions described, a refocused approach to N ‐Boc deprotection of 3 via an addition–elimination strategy.…”

Section: Resultsmentioning

confidence: 99%

Deprotection of N‐tert‐Butoxycarbonyl (Boc) Protected Functionalized Heteroarenes via Addition–Elimination with 3‐Methoxypropylamine

Gulledge

Carrick

2020

Eur J Org Chem

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Continued pursuit of functionalized soft‐N‐donor complexant scaffolds with favorable solubility and kinetics profiles applicable for the separation of the trivalent minor actinides from the lanthanides has attracted significant interest over the last three decades. Recent work from this laboratory resulted in the production of various N‐Boc protected [1,2,4]triazinyl‐pyridin‐2‐yl indole Lewis basic procomplexants which necessitated the removal of the indole N‐Boc protecting group prior to evaluation of complexant efficacy in separations assays. Traditional deprotection strategies involving trifluoroacetic and other protic and Lewis acids proved unsuccessful in removal of the recalcitrant indole‐N‐Boc protecting group necessitating the development of a new strategy for deprotection of this complexant class. A serendipitous result facilitated utilization of 3‐methoxypropylamine as a mild deprotecting agent for various N‐Boc protected heteroarenes via a proposed addition–elimination mechanism. Method development, application to various heteroarenes including indoles, 1,2‐indazoles, 1,2‐pyrazoles, and related derivatives, a ten‐fold scale‐up reaction, and experimental evaluation of a preliminary mechanistic hypothesis are reported herein.

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“…However, upon using azodicarboxylate 2e , the reaction proceeded badly and led to the corresponding product 3ae in only 34 % yield. This low yield could be explained by decomposition in HFIP, which is slightly acidic (p K a = 9.3) Moreover, hydrazide 3ag was obtained from cyclic azodicarboxylate 2f in moderate yield. Unfortunately, azodicarboxylate 2g was not suitable for this reaction.…”

Section: Resultsmentioning

confidence: 99%

Hexafluoro‐2‐propanol Promotes para‐Selective C–H Amination of Free Anilines with Azodicarboxylates

2017

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An effective, mild, and clean method for the C–H amination of free anilines with azodicarboxylates in 1,1,1,3,3,3‐hexafluoro‐2‐propanol (HFIP) without the need for any additional catalysts or reagents was developed. The reaction was found to be highly regioselective and provided a series of p‐aminophenylhydrazine derivatives in excellent yields. Moreover, compatibility with a free amino group makes this protocol an attractive strategy in synthetic chemistry.

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Novel Practical Deprotection of N-Boc Compounds Using Fluorinated Alcohols

Cited by 61 publications

References 11 publications

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

Efficient Synthesis of Immunomodulatory Drug Analogues Enables Exploration of Structure–Degradation Relationships

Deprotection of N‐tert‐Butoxycarbonyl (Boc) Protected Functionalized Heteroarenes via Addition–Elimination with 3‐Methoxypropylamine

Hexafluoro‐2‐propanol Promotes para‐Selective C–H Amination of Free Anilines with Azodicarboxylates

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