Catalyst-free thiophosphorylation of in situ formed ortho-quinone methides.

A metal-, chloride reagent and base-free thiophosphorylation reaction of in situ formed ortho-quinone methide (o-QM) to synthesize functionalized thiophosphates has been developed. The reaction is an atom-economical process, producing water as the sole byproduct. (EtO)2P(O)SH functions as both a Brønsted acid and nucleophilic thiolate to produce the o-QM intermediate and the thiophosphate product, respectively. The aza o-QMs were also successfully thiophosphorylated in the presence of catalytic TsOH to form sulfonamido thiophosphates.

Selective hydrolysis of phosphorus(V) compounds to form organophosphorus monoacids.

An azide and transition metal-free method for the synthesis of elusive phosphonic, phosphinic, and phosphoric monoacids has been developed. Inert pentavalent P(v)-compounds (phosphonate, phosphinate, and phosphate) are activated by triflate anhydride (Tf2O)/pyridine system to form a highly reactive phosphoryl pyridinium intermediate that undergoes nucleophilic substitution with H2O to selectively deprotect one alkoxy group and form organophosphorus monoacids.

Oxidative Dehydrosulfurative Cross-Coupling of 3,4-Dihydropyrimidine-2-thiones with Alkynes for Access to 2-Alkynylpyrimidines.

A reaction method is described for the one-step synthesis of 2-alkynylpyrimidines from 3,4-dihydropyrimidin-1H-2-thiones (DHPMs) via dehydrosulfurative Sonogashira cross-coupling with concomitant oxidative dehydrogenation using a Pd/Cu catalytic system. Together with the ready availability of DHPMs possessing various substituents at the C4-C6 positions, this transformation offers rapid and general access to diverse 2-alkynylpyrimidine derivatives.

Metal- and chloride reagent-free synthesis of mixed thiophosphates.

A mild, efficient synthetic strategy for the synthesis of mixed thiophosphate compounds from thiophosphates has been developed. A highly reactive thiophosphorylpyridinium salt, generated in situ by treating thiophosphates with Tf2O/pyridine, transiently undergoes a substitution reaction with various arenols to forge potential agrochemicals and pharmaceuticals.

Tf2O-Promoted Activating Strategy of Phosphate Analogues: Synthesis of Mixed Phosphates and Phosphinate.

A metal-, toxic chloride reagent-free activating strategy of various phosphates has been developed. This method enables the facile synthesis of functional phosphates such as alkyl phosphates, aza phosphates, thiophosphate, and mixed diaryl phosphates. A transient phosphorylpyridin-1-ium species in situ generated from phosphates with Tf2O/pyridine readily undergoes a substitution reaction with diverse nucleophiles to form versatile phosphate compounds.

Base-controlled Fe(Pc)-catalyzed aerobic oxidation of thiols for the synthesis of S-S and S-P(O) bonds.

Fe(Pc)-Catalyzed aerobic oxidation of thiols for the synthesis of disulfides has been developed under mild reaction conditions. In addition, an aerobic oxidative cross-dehydrogenative coupling (CDC) reaction of thiols with P(O)-H compounds (H-phosphonates and H-phosphine oxide) for the formation of S-P(O) bonds has been demonstrated under the Fe(Pc) catalysis system with a base additive. Control experiments revealed that the use of a base (DIPA) in this system controls the synthetic pathways in which thiophosphates are formed.

Direct Aryloxylation/Alkyloxylation of Dialkyl Phosphonates for the Synthesis of Mixed Phosphonates.

A strategy for the direct functionalization strategy of inertial dialkyl phosphonates with hydroxy compounds to afford diverse mixed phosphonates with good yields and functional-group tolerance has been developed. Mechanistic investigations involving both NMR studies and DFT studies suggest that an unprecedented highly reactive PV species (phosphoryl pyridin-1-ium salt), a key intermediate for this new synthetic transformation, is generated in situ from dialkyl phosphonate in the presence of Tf2 O/pyridine.

Regio- and Stereoselective Hydrophosphorylation of Ynamides for the Synthesis of ß-Aminovinylphosphine Oxides.

A metal-free hydrophosphorylation of ynamides with diaryl phosphine oxides has been developed. A highly E-selective and ß-regioselective hydrophosphorylation protocol has been established as a general method for the synthesis of diversely hydrophosphinylated products employing an in situ generated electrophilic phosphorus species. Deuterium incorporation experiments suggest that the amino phosphirenium intermediate undergoes a concerted ring-opening hydrolysis upon treatment with H2O to exclusively furnish ß-aminovinylphosphine oxides.

Regioselective Synthesis of α- and γ-Amino Quinolinyl Phosphonamides Using N-Heterocyclic Phosphines (NHPs).

A regioselective phosphonylation of quinolines for the synthesis of α-amino quinolinyl phosphonamides and γ-amino quinolinyl phosphonamides has been developed under mild reaction conditions. An NHP-thiourea enables selective synthesis of α-amino quinolinyl phosphonamides by a Reissert-type reaction, and an NHP-tosylamide affords γ-amino quinolinyl phosphonamides via a 1,4-conjugate addition reaction. The corresponding amino quinolinyl phosphonate adducts were obtained in moderate to excellent yields (up to 99% yield) and regioselectivities (up to 99:1) with good functional group tolerance.

Organocatalytic Phosphonylation of in Situ Formed o-Quinone Methides.

A new class of Brønsted acid catalysts based on N-heterocyclic phosphorodiamidic acids (NHPAs) has been developed. The NHPA catalyst promotes phospha-Michael addition reaction of trialkylphosphites to in situ generated ortho-quinone methides (o-QMs) for the construction of diaryl phosphonates in moderate to excellent yields with 1.5 mol % catalyst. Diastereoselective synthesis of P-chiral phosphinate esters is achieved with the use of dialkyl phenylphosphonites.

Mitsunobu Reaction Using Basic Amines as Pronucleophiles.

A novel protocol for extending the scope of the Mitsunobu reaction to include amine nucleophiles to form C-N bonds through the utilization of N-heterocyclic phosphine-butane (NHP-butane) has been developed. Both aliphatic alcohols and benzyl alcohols are suitable substrates for C-N bond construction. Various acidic nucleophiles such as benzoic acids, phenols, thiophenol, and secondary sulfonamide also provide the desired products of esters, ethers, thioether, and tertiary sulfonamide with 43-93% yields. Importantly, C-N bond-containing pharmaceuticals, Piribedil and Cinnarizine, have been synthesized in one step from the commercial amines under this Mitsunobu reaction system.

Synthesis of Diaryl Diazaphosphonates via 1,6-Hydrophosphonylation of p-Quinone Methides with N-Heterocyclic Phosphine-Thioureas.

A mild, efficient method for the synthesis of diaryl diazaphosphonates via 1,6-hydrophosphonylation/aromatization of p-quinone methides (p-QMs) with N-heterocyclic phosphine-thioureas has been developed. This transformation proceeds without any additive or catalyst under mild reaction conditions and tolerates a wide range of p-QMs. This methodology provides a straightforward access to diaryl phosphonate derivatives in good to excellent yields (up to 99%).

Oxidation-Reduction Condensation of Diazaphosphites for Carbon-Heteroatom Bond Formation Based on Mitsunobu Mechanism.

An efficient oxidation-reduction condensation reaction of diazaphosphites with various nonacidic pronucleophiles in the presence of DIAD as a weak oxidant has been developed for carbon-heteroatom bond formation. This mild process affords structurally diverse tertiary amines, secondary amines, esters, ethers, and thioethers in moderate to excellent yields. The selective synthesis of secondary amines from primary amines has been achieved. Importantly, a practical application to the synthesis of antiparkinsonian agent piribedil has been demonstrated.

A Reagent-Controlled Phospha-Michael Addition Reaction of Nitroalkenes with Bifunctional N-Heterocyclic Phosphine (NHP)-Thioureas.

Bifunctional N-heterocyclic phosphine (NHP)-thioureas have been successfully applied for phospha-Michael addition reaction of nitroalkenes to afford diversely substituted ß-nitrodiazaphosphonates. This transformation takes place at room temperature under catalyst-free conditions and exhibits broad functional group tolerance. The key to success in catalyst, additive-free reaction conditions is the suitable hydrogen-bond activation of the nitro group by a Brønsted acid (thiourea), which artfully combined with the highly nucleophilic NHP motif for a synergetic effect. Importantly, this transformation enables a two-step synthesis of pharmaceutically, biologically significant ß-amino phosphonic acids.

Phospha-Michael addition reaction of maleimides employing N-heterocyclic phosphine-thiourea as a phosphonylation reagent: synthesis of 1-aryl-2,5-dioxopyrrolidine-3-yl-phosphonate derivatives.

N-Heterocyclic phosphine (NHP)-thiourea as a novel phosphonylation reagent has been successfully applied for the phospha-Michael reaction of maleimides under catalyst and additive free reaction conditions. This methodology enables desymmetrization of a variety of maleimide derivatives to provide 1-aryl-2,5-dioxopyrrolidine-3-yl-phosphonates in up to 92% yield. Synthetic manipulation of this Michael adduct afforded an ethylphosphonate and a phosphino lactam. Furthermore, a scale-up experiment for its practical usage as a versatile precursor in organic synthesis was readily demonstrated.

Amine-Catalyzed Phospha-Michael Reaction of α,ß-Unsaturated Aldehydes and Ketones with Multifunctional N-Heterocyclic Phosphine-Thioureas as Phosphonylation Reagent.

An efficient amine-catalyzed phospha-Michael addition reaction of α,ß-unsaturated aldehydes/ketones with N-heterocyclic phosphines for the synthesis of γ-ketodiazaphosphonates has been developed. With freedom from nucleophile additives, this mild process affords a range of structurally diverse γ-ketodiazaphosphonates in moderate to excellent yields. Importantly, various α,ß-unsaturated ketones were also tolerated in this process and gave moderate yields.

1,3,2-Diazaphospholidine (N-Heterocyclic Phosphine)-Mediated Carbon-Phosphorus Bond-Forming, One-Pot Tandem Reaction: A Route to α-Amino Phosphonates.

A novel 1,3,2-diazaphospholidine (N-heterocyclic phosphine)-thiourea-mediated phospha-Mannich/intramolecular nucleophilic substitution reaction has been developed for the construction of an N-C-P bond unit. This transformation enabled a rapid access to cyclic tertiary α-amino phosphonates in one-pot procedure under additive-free mild reaction conditions. This study revealed the critical role of thiourea moiety of the N-heterocyclic phosphine-thiourea in the sequential intramolecular nucleophilic substitution reaction of the phosphonylation.

Construction of Stereogenic α,α-Disubstituted Cycloalkanones via 1° Amine Thiourea Dual Catalysis: Experimental Scope and Computational Analyses.

The mechanistic exploration and an expanded experimental discussion of the organocatalyzed, asymmetric Pfau-d'Angelo reaction by exploiting a bifunctional 1° amine thiourea catalyst system is disclosed. Notable breadth in substrate scope has been demonstrated on both the cyclic ketone moiety and the α,ß-unsaturated electrophile. Exploration into the matched and mismatched selectivity of this process with a ketone containing pre-existing stereocenters has been demonstrated. Computational analyses of the reaction mechanism are reported. In concert with kinetic isotope effect (KIE) experiments, these computational results provide a detailed understanding of the likely mechanism, including the aspects of the organocatalyst scaffold that are critical for stereoselectivity.

Utility of Bifunctional N-Heterocyclic Phosphine (NHP)-Thioureas for Metal-Free Carbon-Phosphorus Bond Construction toward Regio- and Stereoselective Formation of Vinylphosphonates.

An efficient and practical protocol for completely regioselective and highly stereoselective synthesis of vinyldiazaphosphonates from N-heterocyclic phosphine (NHP) and allenes via phospha-Michael/intramolecular nucleophilic substitution reaction has been developed. This transformation enabled the synthesis of valuable densely functionalized vinyldiazaphosphonates with a ß-, γ-unsaturated ester moiety under mild reaction conditions. Synthetic utility of vinyldiazaphosphonates was demonstrated by a series of synthetic manipulations.

Primary amine, thiourea-based dual catalysis motif for synthesis of stereogenic, all-carbon quaternary center-containing cycloalkanones.

The enantioselective synthesis of α,α-disubstituted cycloalkanones has been developed using a primary amine, thiourea-based dual catalysis pathway. A range of electrophiles and ring sizes are tolerated under the reaction conditions. A possible catalytic cycle is presented to explain the reactivity.