Functionalized phosphonates via Michael addition
Inventors
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Assignees
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University of Nevada, Las VegasThe University of Nevada, Las Vegas is a public research university offering comprehensive undergraduate, graduate, and professional programs. The institution is recognized for research initiatives, interdisciplinary curriculum, community partnerships, and diverse student support. UNLV provides resources spanning financial assistance, technology, career development, outreach, and research, advancing individual achievement and community engagement in a multicultural environment.
The University of Nevada, Las Vegas is a public research university offering comprehensive undergraduate, graduate, and professional programs. The institution is recognized for research initiatives, interdisciplinary curriculum, community partnerships, and diverse student support. UNLV provides resources spanning financial assistance, technology, career development, outreach, and research, advancing individual achievement and community engagement in a multicultural environment.
Publication Number
US-11174278-B2
Publication Date
2021-11-16
Expiration Date
Abstract
Provided herein are functionalized phosphonates and methods for making same via phosphite addition to an atom alpha to an electron withdrawing group. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to catalyst-dependent synthetic methods for preparing structured product compounds and functionalized phosphonate compounds. The disclosed methods comprise reacting a first compound having a defined structural formula with a second compound having a defined structural formula to form the product compound, with ring substituents specified in terms of independently substituted aryl groups and variable substituent groups selected from enumerated classes.
The described chemistry includes phospha-Michael addition of NHP-thiourea and related N-heterocyclic phosphine analogs to nitroolefins, α,β-unsaturated aldehydes, α,β-unsaturated ketones, cyanoolefins, and α-substituted electron-withdrawing-group acceptors to form phosphonate-type products and related phospholidine 2-oxide products. The disclosure reports substituted phosphonate analogs, phospholidinyl phosphonate/phosphonylation products, diazaphospholidine 2-oxide products, pyrrolidine-2,5-dione derivatives, and representative product compounds such as 3a and 2-(2-nitro-1-phenylethyl)-1,3-diphenyl-1,3,2-diazaphospholidine 2-oxide.
The invention further describes scope and reactivity across substituted substrates, including steric and electronic effects on yield and reaction efficiency. A proposed mechanistic rationale is presented involving thiourea Brønsted-acid or hydrogen-bond activation, diazaphosphonium or iminium-type intermediates, proton transfer or tautomerization, and C–P bond formation to give the disclosed products.
Claims Coverage
The consolidated claim coverage includes three independent method claims. Across these claims, the inventive coverage centers on preparing a product compound by reacting a first compound with a second compound, while defining the product by explicit substitution patterns on Cy1/Cy2, Cy1/Cy3, or Cy1/Cyt and by enumerated selections for R1, R2, and R3.
Reacting a first compound with a second compound to form a defined product compound
A method for preparing a product compound having a structure represented by a formula by reacting a first compound having a structure represented by a formula with a second compound having a structure represented by a formula.
Substituted aryl Cy groups with enumerated substituent sets
Each of Cy1 and Cy2, or Cy1 and Cy3, or Cy1 and Ct, is independently aryl substituted with 0, 1, 2, or 3 groups independently selected from halogen, hydroxyl, amine, alkylamino, dialkylamino, C1-C4 alkyl, and C1-C4 alkoxy.
Enumerated R group selections for the product structure
R1 is selected from aryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, and —(C1-C4 alkyl)aryl, and R2 is selected from hydrogen and C1-C4 alkyl. R3 is selected from hydrogen, hydroxyl, amine, alkyl amine, dialkylamine, C1-C4 alkyl, C1-C8 alkenyl, C1-C4 alkoxy, —C(O)OH, —C(O)OR5, —C(O)R5, —C(O)NHR6, aryl, a 5- or 6-membered heteroaryl having 1, 2, or 3 ring-members selected from O, S, and NR1, a 5- or 6-membered cycloalkyl, (C1-C4 alkyl)aryl, and (C1-C4 alkenyl)aryl.
Across the independent claims, the core claim coverage is a react-and-form method for preparing defined phosphine-containing or phosphonate-type product compounds, while controlling the allowable substituent patterns on the Cy groups and the selected R group classes. The consolidated claim scope also includes dependent refinements that narrow substituent choices, restrict the product to specific depicted compound sets, and in some variants specify the presence of a base or amine catalyst.
Stated Advantages
Variable yields and substrate scope are reported for the corresponding phosphonate adducts.
Optimization is described where halogenated solvent CHCl3 and higher concentration improve yield and shorten time.
The disclosure reports reactivity across substrates bearing electron-donating and electron-withdrawing substituents.
The examples and scope sections report optimized outcome values in a tabulated format.
The disclosure reports yields for multiple example adducts across the scope tables and schemes.
The document provides characterization data including yields, melting points, IR, 1H NMR, 13C NMR, 31P NMR, and HRMS (ESI+).
Documented Applications
Synthetic manipulation of a representative adduct into alcohols, vinyl diazaphosphonates, acids, reductive amination products, and β-oximephosphonates.
Preparation of phosphonate-type products, including phospholidinyl phosphonate/phosphonylation products and β-nitrodiazaphosphonate products.
Synthesis of N-heterocyclic phosphine (NHP)-thiourea-derived phospholidine/phospholidinone products by amine-catalyzed phospha-Michael addition.
Synthesis of phospholidine 2-oxide products derived from NHP-thioureas reacted with nitroolefins or nitroalkenes.
Phosphite addition to maleimides employing NHP-thioureas as phosphorus reagents.
Large-scale reaction scheme referenced, followed by subsequent synthesis of compound 4a.
Synthesis of diazaphospholidine 2-oxide products and pyrrolidine-2,5-dione derivatives with varying substituents.
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