Part A
2-Methyl-3-o-tolyl-4(3H)-quinazolinone (Methaqualone) and various other 2-methyl-3-aryl-4(3H)-quinazolinones were functionalized by active hydrogen condensations at the 2-methyl position. For example, methaqualone was metalated at the lateral 2-methyl group with lithium diisopropylamide at O⁰ in tetrahydrofuran (THF) and the resulting lithio salt was condensed with various electrophiles including alkyl halides and carbonyl compounds.
Results of aldol condensations involving the lateral lithio salt of methaqualone revealed the severe steric requirements imposed upon this nucleophile by the 3-o-tolyl group. For instance, the secondary alcohol resulting from condensation with benzaldehyde underwent facile retroaldol condensation or dehydration. These degradative processes apparently relieve the extreme van der Waals repulsions between the 3-o-tolyl group and the bulky 2-(2-hydroxy-2-phenylethyl) substituent. These steric interactions were further evidenced by the ¹H NMR spectrum of this alcohol which revealed the existence of diastereomeric rotational isomers.
A comparison between aldol condensations involving the less hindered lithio salt of 2,3-dimethyl-4(3H)-quinazolinone and the lithio salt of methaqualone further demonstrated the importance of the steric constraints in the latter anion.
Sodium hydride promoted acylations at the 2-methyl group of methaqualone were achieved in refluxing 1,2-dimethoxyethane (DHE) with ethyl acetate as well as with various nonenolizable esters, such as ethyl trifluoroacetate and substituted benzoate esters. Since these acylations afforded the desired 2-(2-ketoalkyl)-3-o-tolyl-4(3H)- quinazolinones in good yield, and since these products represented a totally new class of 2-substituted-3-aryl-4-(3H)-quinazolinones, various other esters were employed in this synthetic scheme to prepare a representative group of derivatives of this pharmacologically active parent molecule. Likewise, other 2-methyl-3-aryl-4(3H)-quinazolinones were similarly acylated and a preliminary structure-activity correlation with respect to CNS depression and anticonvulsant activity was derived.
Part B
The use of potassium hydride to achieve possible twofold kaliation of acetylacetone and benzoylacetone was investigated. As expected, the hydride readily ionized the methylene proton of these diketones at room temperature in THF to form the expected monoanions. After refluxing the monoanion of acetylacetone in the presence of excess potassium hydride for 4 hours, evidence for formation of the 1,3-dianion was obtained by measurement of hydrogen evolution and trapping experiments using benzyl chloride and benzophenone to form the corresponding terminal derivative of the diketone. Addition of benzophenone to a THF solution of the monopotassio salts of acetylacetone and benzoylacetone at room temperature resulted in rapid evolution of a second equivalent of hydrogen and formation of the tertiary alcohols derived from condensation of benzophenone at the terminal methyl group of the diketone. A detailed study of the mechanism of this reaction was carried out. Several possible mechanisms were discarded. A proposed sequence of steps involving complexation of benzophenone with the diketone monoanions prior to ionization of a terminal methyl proton of the monoanion is presented. / Ph. D.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/87318 |
| Date | January 1976 |
| Creators | Rathman, Terry Lee |
| Contributors | Chemistry, Chemistry |
| Publisher | Virginia Polytechnic Institute and State University |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation, Text |
| Format | vi, 153 leaves, application/pdf, application/pdf |
| Rights | In Copyright, http://rightsstatements.org/vocab/InC/1.0/ |
| Relation | OCLC# 40293961 |
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