Abstract
This report describes the development and optimization of the one-pot method for the synthesis of N-protected 1-aminoalkylphosphonium salts based on the three-component coupling of aldehydes and either amides, carbamates, lactams, imides, or urea in the presence of triarylphosphonium salts. The proposed strategy is very efficient and easy to carry out even on a larger scale (20 g) in any typical laboratory. Most reactions occur at temperatures between 50 and 100 °C in a short time (1–2 h) without requiring any catalyst, and simple workup procedures afford good to excellent yields. The exceptions are condensations with imides, which require much higher temperatures (150–170 °C) and longer reaction times (even 30 h). The possibility of carrying out the synthesis under solvent-free conditions (neat reactions) is also demonstrated. It is especially important for less reactive substrates (imides), and reactions required high temperature (or generally harsher conditions). Finally, we prove the developed one-pot methodology can be successfully applied for the synthesis of structurally diverse N-protected 1-aminoalkylphosphonium salts. Mechanistic studies showed the intermediate products of described couplings are 1-hydroxyalkylphosphonium salts, not N-hydroxyalkylamides, -imides, etc., as initially expected.
Highlights
Phosphonium salts comprise a class of organic compounds that has enjoyed unwavering interest from the chemistry community for decades because of their applicability as reagents, catalysts, or solvents (e.g., phosphonium ionic liquids (PILs)) in the synthesis of biologically active compounds.[1−8]
During the search for a new, general method for the preparation of N-protected 1-aminoalkylphosphonium salts, we turned our attention to the three-component condensations used for the synthesis of structurally related α-amido sulfones or N-[1-(benzotriazo-1-yl)alkyl]amides (Scheme 2).[16−18]
This research revealed mechanistic insights regarding the examined transformations, including the unexpected formation of structurally interesting 1-hydroxyalkylphosphonium salts in the intermediate stage following the reaction of aldehydes with triarylphosphonium tetrafluoroborates or bromides
Summary
Phosphonium salts comprise a class of organic compounds that has enjoyed unwavering interest from the chemistry community for decades because of their applicability as reagents (e.g., ylide precursors), catalysts, or solvents (e.g., phosphonium ionic liquids (PILs)) in the synthesis of biologically active compounds.[1−8]Certain structural features of N-protected 1-aminoalkylphosphonium salts make them a very interesting and promising type of phosphonium compounds; their synthetic potential has not yet been fully elucidated. The presence of an acylamino group next to a positively charged phosphonium moiety permits the use of N-protected 1-aminoalkylphosphonium salts as very effective α-amidoalkylating agents (i.e., precursors of N-acylimines or N-acyliminium cations) in the αamidoalkylation reaction. The introduction of electron-withdrawing substituents (e.g., Cl, CF3) into the phosphonium moiety weakens the Cα−P+ bond, thereby facilitating its cleavage and promoting the generation of iminium-type cations, which are the proper α-amidoalkylating agents. This phenomenon highlights the possibility of conducting catalyst-free α-amidoalkylation,[13,14] which is an interesting alternative or complementary approach to those already described in the literature (mostly acid-catalyzed reactions).[15−22]. There are several other interesting methods for the synthesis of N-protected 1aminoalkylphosphonium salts described in the literature.[36−39] in most cases, they are multistep, time- and laborconsuming, and have a narrow scope of application, which in practice is limited to N-acylaminomethylphosphonium salts (see Table S1, Supporting Information).[20]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
