O- Alkylation amides

It is necessary for the intermediate cation or complex to bear considerable car-bocationic character at the carbon center in order for effective hydride transfer to be possible. By carbocationic character it is meant that there must be a substantial deficiency of electron density at carbon or reduction will not occur. For example, the sesquixanthydryl cation l,26 dioxolenium ion 2,27 boron-complexed imines 3, and O-alkylated amide 4,28 are apparently all too stable to receive hydride from organosilicon hydrides and are reportedly not reduced (although the behavior of 1 is in dispute29). This lack of reactivity by very stable cations toward organosilicon hydrides can enhance selectivity in ionic reductions. 

To 5 mL of THF or Et,0 under an inert atmosphere is added with magnetic stirring, 0.003 mol of (E)- or (Z) 2-butenol followed by 0.003 mol of mcthyllithium (1.55 M in Et20) at r.t. After the mixture is stirred for 5min, 0.003 mol of the O-alkylated amide salt, prepared by treatment of the neat amide with a stoichiometric amount of methyl triflatc, is added in 4 mL of THF or CH2C12. The mixture is allowed to stir at r.t. for the specified time, diluted with 20 mL of CH2C12, washed with three 20-mL portions of sat. aq Na,COj and one 20-mL portion of brine, then dried over MgSQ4 and concentrated in vacuo. 

The SM reactions are eompatible with the solid-phase synthesis what is applied in the combinatorial chemistry [95,97]. The arylboronic acids can be immobilized on the polystyrene eontaining diethanolamine-moieties by forming boronate esters XXV. A wide variety of thus bounded arylboronic acids bearing a bromomethyl, carboxylic, amino or aldehyde-group have been converted by N- or O-alkylation, amidation, reductive alkylation and some other reactions, to amines, esters, amides, ureas, etc [96]. The resulting arylboronic acid can be regenerated from the resin by simple... 

Takase M, Miyazawa Y, Tsubokura S (2002) Methods for highly selectively o-alkylating amide compounds with the use of copper salts. US 6462195... 

Another variation of the Madelung synthesis involves use of an O-alkyl or O-silyl imidate as the C2 electrophile. The mechanistic advantage of this modification stems from avoiding competing N-deprotonation, which presumably reduces the electrophilicity of the amide group under the classical conditions. Examples of this approach to date appear to have been limited to reactants with a EW substituent at the o-alkyl group[15,16]. 

Caprolactam is an amide and, therefore, undergoes the reactions of this class of compounds. It can be hydrolyzed, Ai-alkylated, O-alkylated, nitrosated, halogenated, and subjected to many other reactions (3). Caprolactam is readily converted to high molecular weight, linear nylon-6 polymers. Through a complex series of reactions, caprolactam can be converted to the biologically and nutritionally essential amino acid L-lysine (10) (see Amino acids). 

Vinylogous amides, which have an enamine function in conjugation with a carbonyl group, constitute tridentate systems and thus open the possibility of alkylation on carbon, nitrogen, or oxygen. It has been found that the pyrrolidine enamine of acetylacetone gives rise to a carbon mcthylation but an oxygen ethylation product 41). The alkylation of cyclic 1,3-diketone-derived enamines has been studied 41,283). O Alkylation was found in alcohol solvents and predominant C alkylation in nonprotonic solvents. 

Treatment of an amide with BnOC(=NH)CCl3 (TMSOTf, CH2CI2, 85-88% yield) protects the amide by O-alkylation." ... 

The respective amide was prepared from 7-substituted 5-oxo-2,3-dihydro-5//-pyrido[l,2,3-de]-l,4-benzoxazine-6-carboxylic acids via acid chlorides with different benzylamines (00M1P3). 6-Carboxamides were N-benzylated, and a side-chain phenolic hydroxy group was O-alkylated. 7-Aryl-5-oxo-2,3-dihydro-5//-pyrido[l, 2,3-r/e]-1,4-benzoxazine-6-carboxylic acid was obtained from the ethyl ester by alkalic hydrolysis. 

Deprotonation of the amide moieties in dibenzodiazocinediones and trapping with electrophiles always leads to iV-substituted derivatives 2 5,58 no O-alkylation has been described. 

Amides are very weak nucleophiles, far too weak to attack alkyl halides, so they must first be converted to their conjugate bases. By this method, unsubstituted amides can be converted to N-substituted, or N-substituted to N,N-disubstituted, amides. Esters of sulfuric or sulfonic acids can also be substrates. Tertiary substrates give elimination. O-Alkylation is at times a side reaction. Both amides and sulfonamides have been alkylated under phase-transfer conditions. Lactams can be alkylated using similar procedures. Ethyl pyroglutamate (5-carboethoxy 2-pyrrolidinone) and related lactams were converted to N-alkyl derivatives via treatment with NaH (short contact time) followed by addition of the halide. 2-Pyrrolidinone derivatives can be alkylated using a similar procedure. Lactams can be reductively alkylated using aldehydes under catalytic hydrogenation... 

Neutral tertiary and secondary amides react with very reactive alkylating agents, such as triethyloxonium tetrafluoroborate, to give O-alkylation.63 The same reaction occurs, but more slowly, with tosylates and dimethyl sulfate. Neutralization of the resulting salt provides iminoethers. 

Another approach to reduction of an amide group in the presence of other groups that are more easily reduced is to convert the amide to a more reactive species. One such method is conversion of the amide to an O-alkyl derivative with a positive charge on nitrogen.102 This method has proven successful for tertiary and secondary, but not primary, amides. 

An important feature of the antibiotic chloramphenicol (9) is the presence of the dichloroacetamide function. Inclusion of this amide in a simpler molecule, teclozan (15), leads to a compound with antiamebic activity. Whether this is cause and effect or fortuitous is unclear. The synthesis begins with alkylation of the alkoxide derived from ethanolamine (10) with ethyl iodide to give the aminoether (11). Reaction of a,a -dibromo-p-xylene (12) with 2-nitropropane in the presence of base leads to dialdehyde (13). The reaction probably proceeds by O-alkylation on the nitropropyl anion... 

Figure 5.65 provides theoretical evidence that resonance-assisted H-bonding can serve as an effective mechanism for switching a methyl rotor from one preferred conformation to another, or for controlling the stiffness of torsional motions in alkylated amides. In particular, the torsional potentials of proteins (more specifically, the Ramachandran b angle at Ca) should be sensitive to N—H- O and related H-bonding interactions involving the amide backbone. In principle, this electronic... 

Indeed, the choice of a nitrogen compound to be used as carrier in such O-alkyl prodrugs is not restricted to benzamides. Other amides were examined, e.g., phthalimide, succinimide, and saccharin. Thus, the saccharin prodrug of estradiol (11.50, R = 17/J-estradiol) underwent rapid nonenzymatic hydrolysis in rat and human plasma [85]. Administration of the prodrug to rats led to an impressive fivefold increase in the oral bioavailability of estradiol, and it was approximately nine times more potent orally, based on the 50% effective dose. 

O-Protonated cations of eimides in concentrated and anhydrous acids are now well characterized by nmr spectroscopy. O-Protonated cations of N,N-dimethyl amides are most easily observed, even in 72% perchloric acid which has a water activity of about 10 , because for tertiary amides the N-protonated forms is relatively less stabilized by hydration (Liler, 1972a). O-Protonated cations of N-alkyl amides show considerable exchange of NH-protons with the solvent in 72% perchloric acid owing to the intervention of the N-protonated form. For primary amides (acetamide), however, O-protonated cations are not observable in that solvent (Liler, 1972b),... 

As shown in Scheme 4, alkynyl metallates derived from propynoic acid amides can also be used as source of the allenylidene C3 unit, their reactions with the tetrahydrofuran solvates [M(CO)5(THF)] affording the N/O-substimted allenylidene complexes 6 after selective O-alkylation with [R30][BF4] [29]. 

The isomerization of the (Z)-isomer into the ( )-isomer promoted by the iridium complex explains the lack of stereospecificity of the transformation. O-Alkylated oximes and ketoximes do not react and this fact suggests that the presence of both hydrogen and a hydroxyl group is required for the success of the transformation. The authors proposed that the initial displacement of a chloride ion of the iridium complex by the oxime allows the iridium to remove both the oxygen and the hydride from the initial oxime. Swapping places of both substituents produces the amide. 

Alkylations by oxonium salts have added several new weapons to the synthetic chemist s armamentarium. For example, the O-alkylated products from amides [R1C(OR)=NR2R3]+ (R == CH3 or C2H5) may be hydrolyzed under mild conditions to amines and esters,14-34 reduced to the amines RjCH-jNRaRa by sodium borohydride,13 converted to amide acetals RiC(OR)2NR2R3 by alkoxides,4-16 and (for R3 = H) deproton-ated to the imino esters R1C(OR)=NR2.16-18 Amide acetals and imino esters are themselves in turn useful synthetic intermediates. Indeed, oxonium salts transform the rather intractable amide group into a highly reactive and versatile functionality, a fact elegantly exploited in recent work on the synthesis of corrins.34... 

Treatment of 7-chloroamine 363 with potassium /i t/-butoxide in refluxing THE gave rise to a mixture of (Z-tert-butyl)-5,5-dimethyl-5,6-dihydro-4f/-l,3-oxazine 366 and 1-pivaloylazetidine 367 (Scheme 67). The heterocycles 366 and 367 were formed through generation of the Favorskii intermediate 364 by dehydrocyanation, which was followed by opening of the cyclopropylideneamine by /r-rt-butoxide with the subsequent loss of isobutene and a subsequent intramolecular N-alkylation or O-alkylation of the amide anion 365 <1999EJ0239>. 

The earliest report on such lactim ether formation was from Sammes [72JCS(P1)2494], who converted piperazine-2,5-dione to 2,5-diethoxy-3,6-dihydropyrazine (173) with an excess of triethyloxonium fluoroborate. Subsequently, Rajappa and Advani (73T1299) converted proline-based piperazine-2,5-diones into the corresponding monolactim ethers. The starting material was a piperazinedione in which one of the amino acid units was the secondary amino acid proline, and the other a primary amino acid. This naturally led to the regiospecific formation of a monolactim ether (169) (on O-alkylation) from the secondary amide, whereas the tertiary amide remained intact. This was later extended to piperazine-2,5-diones in which the secondary amino acid was sarcosine [74JCS(P 1)2122], leading to the monolactim ethers (170). 

O -Alkylations of azepin-2-ones, and benzazepin-2-ones, are most efficiently brought about by trialkyloxonium tetrafluoroborates (Meerwein s reagents) (B-69MI51600,73JOC1090, 81HCA373). S-Alkylation of the thiones is effected similarly. These oxonium salts have also proved useful for the alkylation of azepinedione precursors of azatropones and azatropolones (72JOC208) (see also Section 5.16.3.1.2). 5//-Dibenz[f>,e]azepine-6,11 -dione with triethyloxonium tetrafluoroborate O-ethylates at the amide carbonyl and not at the ketonic carbonyl as was first proposed (72AJC2421). 

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