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-10435423-B2
Publication Date
2019-10-08
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 a method for preparing a product compound having a structure represented by a formula in which n is 0 or 1. The method comprises reacting a first compound having a structure represented by a first formula with a second compound having a structure represented by a second formula to prepare the product compound.
The structural scope is controlled through definitions of Cy1 and Cy2, R1, R2, R3, R4, and in additional embodiments R7, including broad selections of aryl, heteroaryl, cycloalkyl, and heterocycloalkyl options. The product compound includes an electron-withdrawing group EWG, with a proviso that the first atom of EWG adjacent to the position denoted α is substituted with oxo.
The disclosure also includes methods for preparing NHP-thiourea-derived phosphonylation products and phospha-Michael-type additions using NHP-thiourea catalysts with Michael acceptors, including α,β-unsaturated aldehydes and α,β-unsaturated ketones. The products include 2-oxido-1,3,2-diazaphospholidin-2-yl substituted propanals, butan-2-ones, cyclohexanones, and nitroalkene-derived phospholidine 2-oxides.
Claims Coverage
The consolidated claim coverage includes independent method claims directed to preparing a product compound by reacting a first compound with a second compound. The core inventive features center on a formula-defined product structure with tightly constrained substituent and ring-system selections, including an electron-withdrawing group with an oxo substitution adjacent to the α position.
Reacting first and second compounds to form a formula-defined product
A method comprising reacting a first compound having a structure represented by a first formula with a second compound having a structure represented by a second formula to prepare a product compound having a structure represented by a formula, where n is 0 or 1.
Defined ring systems for Cy1 and Cy2
Cy1 and Cy2 are independently selected from aryl, 5- or 6-membered heteroaryl, 5- or 6-membered cycloalkyl, and 5- or 6-membered heterocycloalkyl, with substituent choices including halogen, hydroxyl, amine, alkylamino, dialkylamino, C1-C4 alkyl, and C1-C4 alkoxy.
Electron-withdrawing group constraints for R2
R2 is selected from hydrogen, halogen, hydroxyl, amine, alkylamino, dialkylamino, C1-C4 alkyl, C1-C4 alkoxy, and an electron-withdrawing group, and the first atom of EWG adjacent to the position denoted α is substituted with oxo.
Carbonyl and ring-substituted options for R3 and R4
R3 and R4 are selected from hydrogen and functional groups including —C(O)OH, —C(O)OR5, —C(O)R5, and —C(O)NHR6, together with aryl and ring-system options containing O, S, and NR1.
Cycloalkyl or heterocycloalkyl formation from combined R2 and R3
R2 and R3 together with the intervening atoms comprise a 5- or 6-membered cycloalkyl or heterocycloalkyl having 1, 2, or 3 ring-members selected from O, S, and NR1, with defined substituent groups.
Second-compound limitation including R7 selection
In the additional embodiment, R7 is selected from hydrogen, hydroxyl, amine, alkyl amine, dialkylamine, C1-C4 alkyl, and C1-C4 alkoxy, with corresponding structural limitation options where R7 and R4 together with intervening atoms comprise a 5- or 6-membered cycloalkyl or heterocycloalkyl.
Catalyst-present reacting step
The reacting step is described in some coverage as being performed with a catalyst.
The consolidated independent claim coverage centers on preparation of a formula-defined product compound by reacting a first compound with a second compound, while tightly defining allowable substituent patterns through Cy1, Cy2, R1, R2, R3, R4, and R7, including the EWG proviso requiring oxo substitution at the atom adjacent to α.
Stated Advantages
Products are isolated and analytically characterized using yields, IR, 1H NMR, 13C NMR, 31P NMR, and HRMS.
Provides substrate-dependent outcome in phospha-Michael additions, including conversion of selected aldehydes to tetra-substituted phosphonates.
Supports moderate-yield phospha-Michael products for α,β-unsaturated ketones via Brønsted-acid hydrogen-bond activation.
Shows product compatibility with both electron-donating and electron-withdrawing substituents on enones.
Enables formation of tetra-substituted phosphonates in reported yields, including 55% for one aldehyde example and moderate yields for ketone examples.
Documented Applications
Preparation of 2-oxido-1,3,2-diazaphospholidin-2-yl substituted propanals, butan-2-ones, and cyclohexanones.
Preparation of nitroalkene-derived phospholidine 2-oxides.
Substrate scope evaluation for phospha-Michael additions using NHP-thiourea catalysts, including α,β-unsaturated aldehydes and α,β-unsaturated ketones.
Potential biological/pharmaceutical relevance as enzyme inhibitors and utility as synthetic intermediates for further drug-like compounds.
Reference contexts include a matrix metalloprotease (MMP-2) inhibitor, an osteoclastic acid phosphatase (OAP) inhibitor, Fosmidomycin, FR-900098, 3-phosphonopropionate, and a dental adhesive.
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