Amides bases, with heterocycles

Chelate-assisted C-H bond trifluoromethylations are rare, and so far, only two reagents have been used successfully in these reactions. The first reagent 19 is an electrophilic source of CF, which reacts under Pd catalysis with substrates bearing directing groups (Scheme 23.27) [92, 93]. The reaction also requires the presence of Cu(OAc)j and trifluoroacetic acid as promoters both amide-based and heterocyclic directing groups can be employed. 

Successful lithiation of aryl halides—carbocyclic or heterocyclic—with alkyUithiums is, however, the exception rather than the rule. The instability of ortholithiated carbocyclic aryl halides towards benzyne formation is always a limiting feature of their use, and aryl bromides and iodides undergo halogen-metal exchange in preference to deprotonation. Lithium amide bases avoid the second of these problems, but work well only with aryl halides benefitting from some additional acidifying feature. Chlorobenzene and bromobenzene can be lithiated with moderate yield and selectivity by LDA or LiTMP at -75 or -100 °C . 

A terminal cyclic urea derivative of valine is present at one terminus in lopinavir (43). Preparation of this heterocyclic moiety begins with conversion of valine (35) to its phenoxycarbonyl derivative by reaction with the corresponding acid chloride. Alkylation of the amide nitrogen with 3-chloropropylamine in the presence of base under very carefully controlled pH results in displacement of the phenoxide group to give the... 

Five-membered ring heterocycles are common in numerous pharmaceuticals. In particular, the imidazole core structure, an element of histidine and its decarboxylation metabolite histamine, is often found [53]. The exceptional properties and wide applicability of the imidazole pharmacophore are due to its hydrogen-bond donor/acceptor capabilities and its high affinity for metals (present in many protein active sites, e.g., Zn, Fe, Mg) [54-58]. In addition, peptide-based protease inhibitors with improved pharmacokinetics and bioavailability have been obtained by replacing an amide bond with an imidazole [59]. 

New information on the three-membered phosphorus(v) heterocycles which are often postulated as reactive intermediates comes from a study of the reactions of phosphonic diamides R P(0)(NHR )2. On treatment with t-butyl hypochlorite these are converted into the mono-N-chloro-amides, which with base lose hydrogen chloride, forming the diazaphosphoridine oxide (53). The structure is supported by spectroscopic data and by the quantitative formation of the hydra-zide (54) on reaction with methanol. New phosphorus(v)-nitrogen-phosphorus(in) systems (55) have been synthesized by transamination reactions between... 

The choice of the IV-protec ting group (Al-Boc) proved to be critical for achieving a high enantiomeric excess of the cyclization reaction. In contrast to KHMDS, lithium amide bases (LHMDS or LiTMP) did not afford detectable quantities of the anticipated heterocycles. The mechanism of asymmetry transfer was proposed to rely on the formation of axially chiral nonracemic enolate (eq 66) with a chiral C-N axis, the racemization barrier for which was found to be 16.0 kcal mol. ... 

Nucleotides bear the same relation to a nucleic acid that amino acids do to a protein they are its monomeric units. The connecting links in proteins are amide groups in nucleic acids they are phosphate ester linkages. Phosphate esters link the 3 -OH of one ribose (or deoxyribose) with the 5 -OH of another. This makes the nucleic acid a long unbranched chain with a backbone of sugar and phosphate units with heterocyclic bases protruding... 

A "heterocyclic" strategy used an oxazolidone ring as a protected carboxyl (an amide) which also served as a chiral auxiliary. Treatment of 6.127 with a boron triflate, for example, gave boron enolate reagent 6.128 in situ, and it reacted with N-Boc leucinal to form 6.129. Boron enolates have been used in many syntheses as an alternative to lithium or sodium enolate in Aldol reactions.S7 Hydrogcnolysis of the methylthio moiety gave a methylene moiety and treatment of the amide auxiliary with base gave 6.95 (24% overall yield). 

The use of carbonyl function is classic approach in heterocyclic synthesis. In case of fluorinated pyrroles this approach was frequently used. Convenient method for synthesis of pyrroles 221 is based on the reaction of fluorinated 5-keto acid esters or amides 220 with ammonia. In case of methyl and ethyl esters amidolysis was... 

To verify that this is purely based on the hydrogen-bond strength of the donors and acceptors, it is important to establish whether the balance between an aromatic N-heterocycle and an amide can be reversed by lowering sufficiently the hydrogen-bond accepting property of the aromatic nitrogen atom. With this in mind, we synthesized a set of ditopic supramolecular reagents that combined an amide moiety with a very weak base, pyrazole. The idea was that if the basicity of the... 

Most ring syntheses of this type are of modern origin. The cobalt or rhodium carbonyl catalyzed hydrocarboxylation of unsaturated alcohols, amines or amides provides access to tetrahydrofuranones, pyrrolidones or succinimides, although appreciable amounts of the corresponding six-membered heterocycle may also be formed (Scheme 55a) (73JOM(47)28l). Hydrocarboxylation of 4-pentyn-2-ol with nickel carbonyl yields 3-methylenetetrahy-drofuranone (Scheme 55b). Carbonylation of Schiff bases yields 2-arylphthalimidines (Scheme 55c). The hydroformylation of o-nitrostyrene, subsequent reduction of the nitro group and cyclization leads to the formation of skatole (Scheme 55d) (81CC82). 

The mononuclear heterocyclic rearrangement (MHR) of isoxazole-3-amidoxime 108 in the presence of a base and hydroxylamine with concomitant removal of the amide moiety affords furazan acetaldoxime 109 (Scheme 56) (91CHE651, 91KGS827). 

Of the several syntheses available for the phenothiazine ring system, perhaps the simplest is the sulfuration reaction. This consists of treating the corresponding diphenylamine with a mixture of sulfur and iodine to afford directly the desired heterocycle. Since the proton on the nitrogen of the resultant molecule is but weakly acidic, strong bases are required to form the corresponding anion in order to carry out subsequent alkylation reactions. In practice such diverse bases as ethylmagnesium bromide, sodium amide, and sodium hydride have all been used. Alkylation with (chloroethyl)diethylamine affords diethazine (1), a compound that exhibits both antihista-minic and antiParkinsonian activity. Substitution of w-(2-chloroethyl)pyrrolidine in this sequence leads to pyrathiazine (2), an antihistamine of moderate potency. 

Thiadiazoles have proven of some utility as aromatic nuclei for medicinal agents. For example, the previous volume detailed the preparation of a series of "azolamide" diuretic agents based on this class of heterocycle. It is thus of note that the 1,2,5-thiadiazole ring provides the nucleus for a clinically useful agent for treatment of hypertension which operates by an entirely different mechanism, p-adrenergic blockade. In its preparation, reaction of the amide-nitrile 211 with sulfur monochloride leads directly to the substituted thiadiazole 212. ... 

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