14 research outputs found
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A Diels-Alder approach to biaryl synthesis
An expedient approach to the synthesis of a wide range of highly programmable biaryl templates has been accomplished. Utilizing the Diels-Alder [4+2] cycloaddition, a wide range of tri- and tetra-ortho-substituted biaryls have been synthesized in only three to four steps from commercially available materials. We have successfully synthesized entire classes of biaryl compounds that would not be readily accessible from alternative methods. In fact, the successful construction of biaryl compounds possessing four different atoms (N, Cl/Br, O and P for the phosphorus series and N, Cl/Br, O and C for the carbonyl and tertiary alcohol series) at the four ortho positions has not been accomplished by any other method. One intriguing feature of these Diels-Alder processes is their ability to construct sterically challenging functionality under mild conditions. In many cases, the cycloaddition sequence appears to work better on the more substituted systems. Additionally, the strong directing ability of the ortho-nitro moiety, even in the presence of ketones, esters and amides is noteworthy.
The synthesis of the western biaryl portion of the anti-cancer compound TMC-95 provided the groundwork for our current methodology and is described herein. Also, studies were performed to probe the role of the nitro moiety using both experimental data and molecular modeling calculations.
Through a series of phosphorus-containing and carbonyl-containing dienophiles, the scope of the Diels-Alder approach to biaryl synthesis was greatly expanded. The use of ketones, esters, amides and imides led to a wide variety of highly functionalized biaryl compounds. The exploration into propargylic tertiary alcohols as dienophiles in the Diels-Alder reaction proved fruitful as well. A plethora of dienophiles were constructed using a variety of alkyl, aromatic, cyclic and acyclic ketones as electrophiles. Each of the aforementioned compounds underwent smooth cycloaddition and cycloextrusion with a range of mono- and bis-oxygenated dienes to give the highly substituted biaryls in good yields. We have demonstrated the utility of this methodology in designing a highly active catalyst for Suzuki-couplings and Buchwald-Hartwig C-N couplings. Biological application includes preliminary work in the synthesis of axially chiral biaryl amino acids
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Highly Regioselective Nitrile Oxide Dipolar Cycloadditions with ortho-Nitrophenyl Alkynes
The dipolar cylcoadditions of ortho-nitrophenyl alkynes with aryl nitrile oxides has been demonstrated. A range of substituents are tolerated on the alkyne. These reactions proceed with excellent levels of regioselectivity. Subsequent functionalization of the isoxazole scaffold has been demonstrated.This is the author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the Royal Society of Chemistry and can be found at: http://pubs.rsc.org/en/journals/journalissues/ob. Supplementary information is included in the publisher's online version of the article
(E)-3-[4-(1H-Imidazol-1-yl)phenyl]-1-(4-methylphenyl)prop-2-en-1-one
Imidazole-containing chalcones have been shown to be strongly effective against Aspergillusfumigatus, the causative agent for the disease pulmonary aspergillosis. Claisen–Schmidt condensation of 4-(1H-imidazol-1-yl)benzaldehyde with 4′-methylacetophenone using aqueous sodium hydroxide in methanol yielded the novel compound (E)-3-[4-(1H-imidazol-1-yl)phenyl]-1-(4-methylphenyl)prop-2-en-1-one in good yield and purity after recrystallization from hot methanol. With the known antifungal properties of these combined pharmacophores, this novel compound is suitable for anti-aspergillus activity study
(E)-3-[4-(1H-Imidazol-1-yl)phenyl]-1-(3-chloro-4-fluorophenyl)prop-2-en-1-one
Imidazole-containing chalcones have been shown to be effective against Aspergillus fumigatus, the pathogenic agent for pulmonary aspergillosis. Claisen-Schmidt condensation of 4-(1H-imidazol-1-yl)benzaldehyde with 3′-chloro-4′-fluoroacetophenone using aqueous sodium hydroxide in methanol yielded the novel compound (E)-3-[4-(1H-imidazol-1-yl)phenyl]-1-(3-chloro-4-fluorophenyl)prop-2-en-1-one in good purity after purification by silica gel column chromatography. This novel compound is suitable for testing the antifungal properties of the combined pharmacophores against Aspergillus and other pathogenic fungi
(E)-3-(4-Chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one
Natural products known as chalcones show promise as chemotherapeutic agents for the neglected tropical disease known as leishmaniasis. Our objective is to synthesize new targets of opportunity that may lead to better treatments of this debilitating disease. Claisen-Schmidt condensation of 4-chlorobenzaldehyde with 2′-fluoro-4′-methoxyacetophenone using aqueous sodium hydroxide in ethanol yielded the novel compound (E)-3-(4-chlorophenyl)-1-(2-fluoro-4-methoxyphenyl)-2-propen-1-one. The product was obtained in good yield and purity after recrystallization from ethyl acetate/hexane. With the known antiparasitic properties of halogenated chalcones, this novel compound is suitable for antileishmanial activity study
Diels–Alder approach to biaryls (DAB): Importance of the ortho-nitro moiety in the [4 + 2] cycloaddition
Synthesis and Computational Analysis of Densely Functionalized Triazoles Using <i>o</i>-Nitrophenylalkynes
Dipolar cylcoadditions with azides using a series of <i>o</i>-nitrophenylethynes and disubstituted alkynes were studied
experimentally
and computationally. Density functional theory computations reveal
the steric and electronic parameters that control the regioselectivity
of these cycloadditions. Several new substrates were predicted that
would either give enhanced regiocontrol or invert the regiochemical
preference. Experimentally, the alkynes were screened in the [3 +
2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally,
the acetylenes containing halogen substitution directly on the alkyne
provided the highest levels of regioselectivity. These haloalkynes
were also shown to tolerate variation of the azide moiety with continued
good levels of regioselectivity in most cases. Diverse functional
groups can be incorporated through the cycloaddition process and their
subsequent orthogonal modification was demonstrated
Synthesis and Computational Analysis of Densely Functionalized Triazoles Using <i>o</i>-Nitrophenylalkynes
Dipolar cylcoadditions with azides using a series of <i>o</i>-nitrophenylethynes and disubstituted alkynes were studied
experimentally
and computationally. Density functional theory computations reveal
the steric and electronic parameters that control the regioselectivity
of these cycloadditions. Several new substrates were predicted that
would either give enhanced regiocontrol or invert the regiochemical
preference. Experimentally, the alkynes were screened in the [3 +
2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally,
the acetylenes containing halogen substitution directly on the alkyne
provided the highest levels of regioselectivity. These haloalkynes
were also shown to tolerate variation of the azide moiety with continued
good levels of regioselectivity in most cases. Diverse functional
groups can be incorporated through the cycloaddition process and their
subsequent orthogonal modification was demonstrated
Synthesis and Computational Analysis of Densely Functionalized Triazoles Using <i>o</i>-Nitrophenylalkynes
Dipolar cylcoadditions with azides using a series of <i>o</i>-nitrophenylethynes and disubstituted alkynes were studied
experimentally
and computationally. Density functional theory computations reveal
the steric and electronic parameters that control the regioselectivity
of these cycloadditions. Several new substrates were predicted that
would either give enhanced regiocontrol or invert the regiochemical
preference. Experimentally, the alkynes were screened in the [3 +
2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally,
the acetylenes containing halogen substitution directly on the alkyne
provided the highest levels of regioselectivity. These haloalkynes
were also shown to tolerate variation of the azide moiety with continued
good levels of regioselectivity in most cases. Diverse functional
groups can be incorporated through the cycloaddition process and their
subsequent orthogonal modification was demonstrated
Synthesis and Computational Analysis of Densely Functionalized Triazoles Using <i>o</i>-Nitrophenylalkynes
Dipolar cylcoadditions with azides using a series of <i>o</i>-nitrophenylethynes and disubstituted alkynes were studied
experimentally
and computationally. Density functional theory computations reveal
the steric and electronic parameters that control the regioselectivity
of these cycloadditions. Several new substrates were predicted that
would either give enhanced regiocontrol or invert the regiochemical
preference. Experimentally, the alkynes were screened in the [3 +
2] cycloaddition with benzyl azide. Of the 11 alkynes screened experimentally,
the acetylenes containing halogen substitution directly on the alkyne
provided the highest levels of regioselectivity. These haloalkynes
were also shown to tolerate variation of the azide moiety with continued
good levels of regioselectivity in most cases. Diverse functional
groups can be incorporated through the cycloaddition process and their
subsequent orthogonal modification was demonstrated