Mildly basic conditions

Itaconic acid (1) is isomeric with citraconic [498-23-7] (2) and mesaconic [498-24-8] (3) acids. Under acidic, neutral, or mildly basic conditions and at moderate temperatures, itaconic acid is stable. At elevated temperatures or under strongly basic conditions, the isomers are interconvertible. 

Etherification. Many of the mono alkylphenols and some of the dialkylphenols are converted into ethoxylates which find commercial apphcation as nonionic surfactants (9). For example, -nonylphenol reacts with ethylene oxide under mild basic conditions. 

Although most of the reactions of preparative importance involving the a-alkyl carbanions are usually carried out under controlled conditions with NHa /NHs being used as the base, a number of reactions using less severe conditions are known, both in the pyrazine and quinoxaline series. In the case of alkylquinoxalines, where an increased number of resonance possibilities exist, mildly basic conditions are usually employed in condensation reactions. 

The reaction is reversible and (52) can be cyclized with aldehydes under neutral or mildly basic conditions. ... 

To circumvent the need for strong acid and allow the dehydration of secondary alcohols, reagents have been developed that are effective under mild, basic conditions. One such reagent, phosphorus oxychloride (POCI3) in the basic amine solvent pyridine, is often able to effect the dehydration of secondary and tertiary alcohols at 0 °C. 

Trichlorosilanc reacts with allyl halides under mildly basic conditions, subsequent treatment with methylmagnesium bromide giving rise to allyl(trimethyl)silanes15-16. 

D. Miscellaneous.—A further study of the reactions of diphenyl-phosphine oxide with tetracyclone has confirmed that the reaction yields the oxide (30) under mild, basic conditions, and that the reaction is thermally reversible. The displacement of halogen from phosphorus by amino-compounds has been used in the synthesis of a number of aminofluoro-phosphine oxides (31), and of A-methyl-AA-bis(dichlorophosphinyl)-amine (32). ... 

Disubstituted tetrazoles are conveniently prepared from acyl hydrazines (98) and diazonium salts.166 The reaction proceeds through the intermediate tetrazenes (99) followed by cyclization to the tetrazole (100) (Scheme 13). The intermediate can be isolated under mildly basic conditions. Symmetrically 1,2-diacylated hydrazines yield 1-substituted tetrazoles through the elimination of one of the acyl groups.166 - 168 Diformyl-hydrazine is a very convenient starting material for 1-substituted tetrazoles.166, Unsymmetrically 1,2-diacylated hydrazine usually results in mixtures.169... 

Alternatively, two phosgene equivalents were studied, methyl chloroformate and p-nitrophenyl chloroformate. When methyl chloroformate was used for the end game, N-carbamate 54 was obtained smoothly but subsequent cyclization to ben-zoxazinone 1 was sluggish. Furthermore, removal of the unreacted intermediate methyl carbamate 54 from Efavirenz was not trivial, thus we did not pursue this method. On the other hand, reaction of 53 and p-nitrophenyl chloroformate initially provided the corresponding p-nitrophenyl carbamate 55 under mild basic conditions (KHC03). Carbamate 55 was smoothly cyclized to 1 upon increasing... 

The soluble polymer support was dissolved in dichloromethane and treated with 3 equivalents of chloroacetyl chloride for 10 min under microwave irradiation. The subsequent nucleophilic substitution utilizing 4 equivalents of various primary amines was carried out in N,N-dimethylformamide as solvent. The resulting PEG-bound amines were reacted with 3 equivalents of aryl or alkyl isothiocyanates in dichloromethane to furnish the polymer-bound urea derivatives after 5 min of micro-wave irradiation (Scheme 7.75). After each step, the intermediates were purified by simple precipitation with diethyl ether and filtration, so as to remove by-products and unreacted substrates. Finally, traceless release of the desired compounds by cyclative cleavage was achieved under mild basic conditions within 5 min of micro-wave irradiation. The 1,3-disubstituted hydantoins were obtained in varying yields but high purity. 

In certain systems the crown thioether ligand itself may undergo some chemical transformation when coordinated to a metal ion. For example, in mildly basic conditions the Rh(III) species [Rh([9]aneS3)2]3+ and [Rh([18]aneS6)]3+... 

Catalytic reduction of bridgehead enol lactone over Pd/C indicates that, indeed, the syn addition from the exo face of the bridgehead double bound establishes the relative configuration of all substituents [264], Equilibration studies performed in EtONa/EtOH also established that the ratio of the epimers corresponds to an equilibrium mixture. Under mild basic conditions (NajCOj/ EtOH), the product isomerization occurs to a very small extent. The product distribution is best understood by rapid conformational relaxation to one of the two low-eneigy half-chair conformations. The stereochemistry is established at the subsequent protonation step. This takes place with a strong preference for axial protonation from the /I face at carbon 2 to produce the most stable chair conformation (Scheme 14.12). 

In contrast with the reactions involving sulphide or hydrogen sulphide anions, aryl alkyl thioethers and unsymmetrical dialkyl thioethers (Table 4.3) are obtained conveniently by the analogous nucleophilic substitution reactions between haloalkanes and aryl or alkylthiols under mildly basic conditions in the presence of a quaternary ammonium salt [9-15] or polymer-supported quaternary ammonium salt [16]. Dimethyl carbonate is a very effective agent in the formation of methyl thioethers (4.1.4.B) [17]. 

The Ramberg-Backland rearrangement of a-halosulphones to alkenes (Scheme 6.8), for which the choice of base and solvent for optimum yield by classical methods is not trivial, is extremely conveniently conducted under phase-transfer catalytic conditions [66]. The reaction is particularly facile for benzylsulphones and generally gives high yields in relatively short reaction times for a range of systems. In the absence of the catalyst no reaction occurs under the mildly basic conditions. 

Phosphonates and related compounds, which can subsequently be used in the Wittig-Homer reaction (see Section 6.5), are readily alkylated in good yield (Table 6.8) [67-71], Mono-alkylation is observed with mildly basic conditions at 45°C [67] and dialkylation under stronger basic conditions at 60°C [70], Reaction of a,to-dihaloalkanes with phosphonocarboxylates leads to cycloalkylphosphonates [72], The methylenebisphosphonate reacts in a similar manner. 

C-Alkylation of 2-oxazolin-5-ones under catalysed mildly basic conditions provides a convenient route to a-branched a-amino acids (50-80%) [126]. Similarly, A-alkyloxindoles are mono- and di-alkylated at the 3-position [127], For other examples of the alkylation of heteroaryl systems, see Chapter 5. 

Highly acidic triply-activated methylene groups are readily alkylated under mildly basic conditions, e.g. dicyanoacetic esters are converted into the quaternary ammonium salts, which give the 2,2-dicyanopropionic esters upon reaction with iodomethane [129]. 

Cyclohexenones preferentially produce the bicyclic compound (7) (Scheme 6.27, n = 3), whereas the reaction between cyclopentenone and f-butyl 2-chloro-2-phenylethanoate produces (7) and (8) (n = 2) in a ca. 2 1 ratio [49]. In a similar reaction, 3-acylcoumarins react with phenacyl bromide under mildly basic conditions to produce 4,5-benzo-3-oxa-2-oxobicyclo[4.1.0]heptanes [50]. 

Partial hydration of nitriles to form amides is accomplished under mildly basic conditions, when catalysed by the addition of manganese pentacarbonyl bromide and benzyltriethylammonium chloride [30]. Yields are considerably reduced in the absence of the ammonium salt. 

Example 37 the 4-cyano-2-butenyl protecting group has been described by Ravikumar et al. in the synthesis of oligodeoxy ribonucleosides by the phosphoroamidite approach [70]. This group is resistant to acids conditions and its removal proceeds under mild basic conditions by aqueous ammonia. 

Greaney and coworkers have introduced the conjugate addition of thiols to Michael acceptors as an effective adaptive DCL strategy [46,47]. The reaction is well suited for biological DCL synthesis, taking place in water with no requirement for external reagents. As with disulfide bond formation, the reaction is subject to simple and effective pH control. Under mildly basic conditions, the thiolate anion adds rapidly to Michael acceptors under equilibrium conditions. Acidification effectively switches the reaction... 

Under mildly basic conditions the manganese(II) species [MnLH3][MnCl4] [where LH3 = N,N N"-tris[(2S)-2-hydroxypropyl]-1,4,7-triazacyclononane (LH3)] partially deprotonates and on aerial... 

O-Isopropylidene-D-erythrose ( ) (15), obtained either by acetonation of D-erythrose ( ) or by periodate oxidation of 3,4-0-isopropylidene-fi-arabinose (1, ]J), reacted with ethoxycarbonylmethy-lenetriphenylphosphorane in refluxing benzene (18) to give the E-alkene ( ) as the major product (56%) together with the Z -alkene ( ) (21%), As expected (1 -M) the alkenes (14) and (f5) readily cyclized to tetrahydrofurans (16) under very mild basic conditions. Initially the 6 anomer of (16) was favored C86% from (lA) and 100% from ( )] at equilibrium the a anomer preponderated (82%) (19). 

One more useful synthetic application of primary Michael adducts onto 2-chloro-2-cyclopropylideneacetates 1 is the recently reported new approach to oc-tahydrospirocyclopropanepyrazinopyrazines 182. In the first step, the adducts of primary amines onto 1-Me (or 1-fBu) were coupled with AT-Boc- or N-Vmoc-protected glycine derivatives and the resulting products 178, after deprotection, cyclized under mildly basic conditions to give the spirocyclopropanehexahydro-pyrazinones 179,180 and hexahydrodiazepinediones 181 (Scheme 53) [89]. 

An alternative strategy preventing fnrther oxidation of hydroxylamines is based on concomitant O-protection of the hydroxyamino gronp. Reaction of primary amines with benzoyl peroxide affords O-benzoyl hydroxylamines of type 139 (equation 92) that can be deprotected under mildly basic conditions. The oxidation is compatible with a number of functionalities and does not interfere with other functionalities snch as an isolated double bond in the molecule of amine. This reaction is versatile and a number of hydroxylamines has been prepared in this way, although yields are only moderate in most cases . Oxidation of secondary amines with benzoyl peroxide is also possible and usually proceeds in better yields. 

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