Basic substituents

The low order of structural specificity required for classical antihistaminic activity was noted earlier. It has been found possible to substitute an indene nucleus for one of the two aromatic rings that most of these agents possess. The basic side chain may be present as either dimethylaminoethyl or itself cyc-lized to provide an additional fused ring. 

Alkylation of 1-indanone with 2-dimethylaminoethyl chloride affords the substituted ketone (1). Condensation with the lithium reagent obtained from 2-ethylpyridine affords the alcohol (2). Dehydration under acidic conditions gives dimethyl-pyrindene (3).  

Anticoagulant therapy was developed with the adventitious discovery of dicoumarol (8). A fuller discussion of the rationale for the use of such compounds is found in the chapter on Five-Mem-bered Heterocycles Fused to One Benzene Ring. The reader s attention is directed, however, at the fact that dicoumarol is a polycarbonyl compound containing a very acidic hydrogen. A series of similarly acidic 1,3-indandiones have been found to constitute an additional class of anticoagulant agents. 

Condensation of an appropriately substituted phenylacetic acid with phthalic anhydride in the presence of sodium acetate leads to aldol-like reaction of the methylene group on the acid with the carbonyl on the anhydride. Dehydration followed by decarboxylation of the intermediate affords the methylenephthal-ides (12). Treatment of the phthalides with base affords directly the indandiones, probably via an intermediate formally derived from the keto-acid anion (13). The first agent of this class to be introduced was phenindandione (14) this was followed by anisindandione (1S) and chlorindandione (16).  

Replacement of the phenyl group at the 2 position by diphe-nylacetyl affords an anticoagulant with long duration of action and improved therapeutic ratio. Condensation of dimethyl phthal-ate with 1,1-diphenylacetone (17) in the presence of base affords phenindandione (18).  

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Copolymers can be used to introduce a mixture of chemical functionalities into a polymer. Acidic and basic substituents can be introduced, for example, through comonomers like acrylic acid and vinyl pyridine. The resulting copolymers show interesting amphoteric behavior, reversing their charge in solution with changes of pH. 

Incorporation of less than a stoichiometric amount of alkyl sulfonamides of copper phthalocyanines into copper phthalocyanine improves the pigment s properties in rotogravure inks (67). Monomeric and polymeric phthalocyanine derivatives with basic substituents adsorb strongly to the pigment surface and promote the adsorption of binder molecules (68—72). 

As expected from the design of the experiment, the HPLC column packed with CSP 14 containing all 36 members of the library with tt-basic substituents separated 7t-acid substituted amino acid amides. Although encouraging since it suggested the presence of at least one useful selector, this result did not reveal which of the numerous selectors on CSP 14 was the most powerful one. Therefore, a deconvolution process involving the preparation of series of beads with smaller numbers of attached selectors was used. The approach is schematically outlined in Fig. 3-17. 

Lewis basic substituents on boron, themselves capable of ir-bonding with boron, such as MeO and Me2N, drastically slow down the rearrangement rate45 by increasing the activation energy to attain [45]. An ab initio calculation has estimated a A of 9.2 kcal, which falls at the lower limit of experimental values (10-15 kcal/mol).21... 

A group of arylalkylketones containing a basic substituent in the side chain shows CNS activities. Roletamide (190) is a hypnotic agent. It is prepared from 3,4,5-trimethoxybenzaldehyde (187) by addition of sodium acetylide (to give 188), followed by Jones oxidation of ethynylarylketone 189. Michael addition... 

The keto carbonyl group can be hydrogenated fairly readily and many of the characteristics of aldehyde hydrogenations also apply here. Initially, the alcohol is produced, but overhydrogenation may result in hydrogenolysis of the C-O bond to form the alkane (Fig. 2.23). Acidic media facilitate hydrogenolysis whereas basic media or basic substituents inhibit hydrogenolysis. 

Pd(OAc)2 works well with strained double bonds as well as with styrene and its ring-substituted derivatives. Basic substituents cannot be tolerated, however, as the failures with 4-(dimethylamino)styrene, 4-vinylpyridine and 1 -vinylimidazole show. In contrast to Rh2(OAc)4, Pd(OAe)2 causes preferential cyclopropanation of the terminal or less hindered double bond in intermolecular competition experiments. These facts are in agreement with a mechanism in which olefin coordination to the metal is a determining factor but the reluctance or complete failure of Pd(II)-diene complexes to react with diazoesters sheds some doubt on the hypothesis of Pd-olefin-carbene complexes (see Sect. 11). 

Since the regioselectivity of mercuration reactions is often hard to control, recent efforts have focused on the use of Lewis-basic substituents whose role is to direct the approach of the mercuric ion to a specific position. Reaction of the diazo derivative 74 with Hg(OAc)2 leads to mercuration of the naphthalene moiety in the 8-position rather than mercuration of the electron-rich imidazole carbon atoms. 4 Presumably, the diazo-imidazole bidentate moiety coordinates to the mercuric cation, thereby directing substitution at the naphthalene 8-position (Equation (27)). 

The arene groups in (r/ -arcnc)tricarbonylchromium complexes are typically electron poor and display poor reactivity toward electrophiles. In the case of mercuration reactions, this lack of reactivity can be overcome by attachment of Lewis-basic substituents to the arene ring. For example, in the case of 75a-c, the presence of a pyridyl, oxazolyl, or methyl-A,A-dimcthylami no group promotes ortho-mercuration, leading to the formation of the bimetallic complexes 76a-c (Equation (28)). 07... 

Aromatic substrates containing Lewis basic substituents can undergo ort/io-lithiation. Quenching these anions with dinitrogen tetroxide at low temperature is an example of nucleophilic aromatic nitration." Similar examples have been reported with anions generated from Grignard reactions with arylhalides." ... 

What is the difference between the isoelectric pH and the isoionic pH of a protein with many different acidic and basic substituents ... 

Cellulose can also be esterified by aromatic acids. However, derivatives of any importance are only the cellulose cinnamic and salicylic acid esters. A number of nitrogen-containing esters are also known, for example, cellulose dialkyl di ami noacetate, cellulose acetate-N,N-dimethylaminoacetate, and cellulose propionate-3-morpholine butyrate. Because of the presence of basic substituents these derivatives, although water insoluble, can be dissolved in acidic solutions. Such derivatives have found use as surface coatings in photographic films and in tablets for pharmaceutical purposes. 

A systematic study of N-alkylaled DHPs as MDR modulators has shown that the derivatives with an arylalkyl substituent on the nitrogen atom were more active than verapamil in potentiating the anticancer activity of vincristine in in vitro, but not in in vivo. However, the additional introduction of basic substituents in the C-3 ester group led to DHPs with in vivo activity [89] (e.g. 20 (50)). 

The correct identification of the sandwich structure of ferrocene led Fischer to consider the possibility of arenes acting as hexahapto 6VE ligands. By simple arithmetic, a neutral bis(arene) sandwich complex of a zerovalent Group 6 element, e.g. chromium (Figure 6.71), was anticipated, a line of reasoning which led Fischer to develop the synthesis of dibenzenechromium. His approach resulted in the comparatively general Fischer-Hafner synthesis (1955), which is applicable to many metals and arenes (devoid of Lewis-basic substituents, Figure 7.34). 

A similar mechanism might operate in the activation of an azolium salt by a transition metal compound forming the metal carbene complex. However, since a basic substituent on the metal (acetate, alkoxide, hydride) usually reacts with the H -proton, the proton is removed from the reaction as the conjugate acid and reductive elimination does not occur. 

A Lewis-basic substituent in the alkene can also promote addition of a Grignard reagent to a double or triple bond. Allyl, benzyl, and t-butyl Grignard reagents add readily to allylic and homoallylic alcohols and alkynols (equation 49). A magnesium alkoxide, formed initially, apparently assists intramolecularly in the addition. There appear to be multiple mechanistic pathways, with different stereochemistries. OR and NR2 groups also activate addition. 

The Diels-Alder reaction is a key reaction in organic synthesis. Its high versatility in the synthesis of six-membered ring compounds and its potential for the control of up to four stereogenic centers have attracted much attention. Lewis acid catalysis has further enhanced the scope of this reaction. Lewis acids activate the dienophile by coordination to a Lewis basic substituent (usually a carbonyl group) and direct the stereochemistry. Boron Lewis acids are often the catalysts of choice for the Diels-Alder reaction. Early (Ti(IV)) and late (Cu(II)) transition metal complexes in combination with chiral ligands have also been used with much success and the reader is referred to the relevant chapters in this book. 

An interesting modification of the benzyl ester group is the introduction of chromo-phores that allow visual monitoring of the isolation and purification steps. Esters of 4-(dimethylamino)-4 -(hydroxymethyl)azobenzene additionally provide a basic substituent that enables attachment to ion-exchange resins and thus facilitates removal of excess starting materials, e.g. acylating agents, and possible byproducts.P ... 

The trends are easy to understand in qualitative terms. For instance, acidic and basic substituents that are nr-electron donors, such as OH and NHj, become more acidic and less basic in the excited state, respectively. The ability of the substituent to transfer electron density into the arene is greatly increased upon excitation, since it then can occur into one of the bonding orbitals that were doubly occupied in the ground state. (Cf. Section 2.4.2.) The increased positive charge on the substituent functionality increases its acidity and reduces its basicity. 

FIGURE 38.16 Solubility and bioavailability are enhanced by basic substituents on an aromatic ring. 

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