Lactams, alkylation with alkyl halides

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... 

Optically active, a-branched lactams 30 have been built by means of Meyers chiral auxiliaries [ 10]. The key step included the diastereoselective a-alkylations of the initially formed co-i -sulfonamido oxazolines 26. The R or S configuration in the product 27 was obtained reacting the appropriately configured intermediate aza enolates with alkyl halides, high diastereoselectivities have been reported. Several attempts to achieve a complete ring closure to the lactams 30 (via 29) by an acidic cleavage of the oxazolines 27 failed. Varying mixtures of... 

N-Substituted amides and lactams can be rapidly N-alkylated under solid-liquid PTC conditions by use of microwave irradiation. The reactions were performed simply by mixing an amide with 50% excess of an alkyl halide and a catalytic amount of TBAB. These mixtures were absorbed on a mixture of potassium carbonate and potassium hydroxide [41] and then irradiated in an open vessel in a domestic micro-wave oven for 55-150 s (Eq. 28). 

Meyers lactams are widely used in synthesis of substituted synthons of interest and their functionalization is carried out under strong base conditions giving C-alkyl derivatives. Alkylation of bicyclic lactam 182 with electrophiles (alkyl, allyl, benzyl halides, chlorophosphonate), and a strong base (j-BuLi, LiHMDS, or KHMDS HMDS = hexamethyldisilazide) in THF at — 78 °C gave an endo-exo mixture of products where the major one is the rro/o-compound 183 in good yields. The ratios were determined by H NMR spectroscopy and are usually up to... 

Since the trapping of the lactam enolate with electrophiles should not be limited to nitroolefins, extension to conjugate additions to alkenylsulfones, the ring opening of N-tosylaziridines, alkylation with functionalized halides, and silylation with chlorotrimethylsilane were explored. 

The bicyclic lactam acetal (40) was formed when pyrido[2,l-b][l,3]-oxazinium perchlorate (38) was treated with sodium methylate [70JCS(CC)900]. Treatment of 38 with sodium alcoholate and then with an alkyl halide gave quaternary salts 35, presumably as a mixtures of two stereoisomers (79TL809). 

Alkyl halides react with the nitrogen atom of all but the lactam and thiolactam forms of 1,3-oxazines and -thiazines. In the case of thioimides, e.g. (31), it is necessary that the NH group is deprotonated by base treatment prior to alkylation of the resultant anion (Scheme 7) (B-78MI22701). 

The alkylation of y-acetoxy or y,y-difluoro-o ,/3-unsaturated-5-lactams (2) with Me3CuLi2.LiI.3LiBr and an alkyl halide2 gave mainly the 3,6-cis isomer (3) when the alkyl halide was small (Mel), but mainly the 3,6-trans isomer (4) when a bulky (g) alkyl halide was used. Calculations at the B3LYP/6-31G(d) level of theory suggested the mechanism in Scheme 1 where the intermediate is stabilized by an interaction... 

Lactams and some non-cyclic, secondary amides (RCONHR) can be alkylated with high regioselectivity either at nitrogen (Section 6.6) or at oxygen. N-Alkylations are generally conducted under basic reaction conditions whereas O-alkylations are often performed with trialkyloxonium salts, dialkyl sulfates, or alkyl halides/silver salts without addition of bases. Protonated imino ethers are formed these are usually not isolated but are converted into the free imino ethers with aqueous base during the work-up. Scheme 1.8 shows examples of the selective alkylation of lactams and of the formation of 2-pyrrolidinones or 2-iminotetrahydrofurans by cycli-zation of 4-bromobutyramides. 

Lactams may be alkylated at the a-position by reaction with a strong base, such as LDA or hexamethyldisilazide, followed by treatment with an alkyl halide. Baldwin and coworkers have used this methodology in their synthesis of unnatural amino acids from protected pyroglutamates (equation 81)563. The same reaction has been used for alkylating 5- to 9-membered lactams564. It is noteworthy that a-alkylated 7- to 9-membered lactams are... 

Copper(I) salts have been found to be particularly good catalysts for radical addition of alkyl halides to alkenes689. These catalysts have been used in the reaction of carbon tetrachloride with ester-containing alkenes, the products being key intermediates in the synthesis of -lactams (equation 108). 

Various substitutions of hydrogen at positions 3 and 4 in -lactams can be performed with electrophilic reagents. The 3-position is activated by the carbonyl group. Alkylation at the 3-position is readily executed via the enolate with alkyl halides, aldehydes, ketones, carbon dioxide, etc. A carboxyl group at C(4) as in 79 does not interfere, the dilithium salt being alkylated at C(3) with excellent stereocontrol, giving the /ra j-disubstituted lactams 80. Hydrolysis leads to -alkyl aspartic acids 81. 

The direct alkylation methods include the reaction of lactams with diazomethane14 and the alkylation of metal salts of lactams with alkyl halides.15 These two methods are not often used nowadays, because the alkylation can more conveniently be carried out with dialkyl sulfates or triethyloxonium fluoroborate. 

Chiral quaternary carbon centers. Meyers et al. have reported an enantioselective synthesis of chiral ot,(t-disubstituted- y-keto acids (6) via the lactam 3 prepared from l-valinol (1) and the y-keto acid 2. Alkylation of 3 with primary alkyl halides gives mainly the endo-isomer (4). /dkylation of 4 also proceeds with endo-selectivity to give 5 with a... 

These compounds can be alkylated twice at the 6-position in a stereocontrolled fashion (eq 2). Treatment of the unsubstimted bicyclic lactam with Lithium Diisopropylamide and reaction of the enolate anion with an alkyl halide affords the monosubstimted product The epimeric mixture is treated again with LDA and a second alkyl halide to give the dialkylated bicyclic lactam. The... 

The limitations of this approach can be seen in the reaction of a saturated solution of ammonia in 90% ethanol with ethyl bromide in a 16 1 molar ratio, under which conditions the yield of primary amine was 34.2% (at a 1 1 ratio the yield was 11.3%). Alkyl amines can be one type of substrate that does give reasonable yields of primary amine (provided a large excess of NH3 is used) are a-halo acids, which are converted to amino acids. A-Chloromethyl lactams also react with amines to give good yields to the A-aminomethyl lactam. Primary amines can be prepared from alkyl halides by 10-43, followed by reduction of the azide (19-32), or by the Gabriel synthesis (10-41). 

The most important method for the preparation of aryl ketones is known as Friedel-Crafts acylation. The reaction is of wide scope. Reagents other than acyl halides can be used," including carboxylic acids," anhydrides, and ketenes. Oxalyl chloride has been used to give diaryl 1,2-diketones." Carboxylic esters usually give alkylation as the predominant product (see 11-11)." A-Carbamoyl p-lactams reacted with naphthalene in the presence of trifluoromethanesulfonic acid to give the keto-amide." ... 

CV studies indicate that Ph3SnY, where Y = Cl, OTf, OCHO, SnPh3, do not serve as a source of the triphenyltin radical because in these instances the radical is generated at potentials where it is either oxidized or reduced [19]. Reaction of the triphenyltin radical with an alkyl halide or a disulfide produces a carbon- or a sulfur-centered radical, respectively. Use of the latter transformation in conjunction with a subsequent intramolecular cyclization onto an alkene is nicely illustrated by the conversion of /6-lactam 62 to the cephalosporin analog 63. 

Oxindole exists as the carbonyl-tautomer, the hydroxy 1-tautomer ( 2-hydroxyindole ) being undetectable. There is nothing remarkable about the reactions of oxindole for the most part it is a typical 5-membered lactam, except that deprotonation at the p-carbon (pA a 18) occurs more readily than with simple amides, because the resulting anion is stabilised by an aromatic indole resonance contributor. Such anions will react with electrophiles like alkyl halides and aldehydes at the p-carbon, the last with dehydration and the production of aldol condensation products. Oxindoles can be oxidised to isatins (20.13.3) via easy 3,3-dibromination, then hydrolysis. Bromination of oxindole with A -bromosuccinimide gives... 

The tributyltin hydride-mediated carbon-carbon bond formation via radical addition and cyclization of alkyl halides with alkenes has often been a choice for construction of various organic molecules [1], However, the requirement for high-temperature initiators or photo initiation and the difficulties associated with purification of the products from tributyltin halides tend to limit the widespread use of these methods, despite the efforts to make the methods easier [Ic, 2], Recently, nickel-mediated radical additions and cyclizations have been introduced as promising alternatives to the tributyltin hydride methods. These are the nickel powder-acetic acid method for cyclization of haloamides to y-lactams, y -lactams and in-dolones, the borohydride exchange resin-nickel boride method for radical addition, nickel-catalyzed electroreductive cyclization and nickel-catalyzed Kharasch addition of polyhalo compounds. 

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