A-alkylated products

OC-All lation of Carbonyl Compounds and Derivatives. The organoborate iatermediates generated by the reaction of alkylboranes with carbanions derived from a-halocarbonyl compounds and a-halonitriles rearrange to give a-alkylated products. 

Alkylation of pyrazinones and quinoxalinones may be carried out under a variety of conditions and it is usually observed that while O-alkylation may occur under conditions of kinetic control, to yield the corresponding alkoxypyrazines or alkoxyquinoxalines, under thermodynamic control the A-alkylated products are formed. Alkylation using trialkyl-oxonium fluoroborate results in exclusive O-alkylation, and silylation under a variety of conditions (75MI21400) yields specifically the O-silylated products. Alkylation with methyl iodide or dimethyl sulfate invariably leads to A-methylation. 

The generality of this protocol was established with a variety of terminal alkenes and alkynes (Scheme 8) (95JA1888). The initial a-alkylation product always spontaneously lactonizes to 25, whereas the /3-alkylation product 26 was always isolated uncyclized. 

It seems likely that direct alkylation of a tautomeric quinoxalinone invariably gives a mixture of O- and A-alkylated products in which the more soluble... 

An unprecedented ring contraction of the 7-azapteridine system has been observed when fervenulone 109 reacts with r-butyl bromoacetate using potassium carbonate/acetonitrile to yield 110 and the 0-alkylate in a 7 1 ratio. The mechanism proposed for this reaction is shown in Scheme 18. The use of sodium hydride/DMF yields the A-alkylated product 111 <95JOC7063>. 

Electroreduction of the cationic Rh(IlI) complex [Rh(Por)(MeNFl2)2l in CH2CI2 followed by reaction with alkyl halides has been utilized to form a-alkyl products. The reaction scheme proposed for this reaction was one-electron reduction of Rh(lll) to form Rh(Por)-. This can either dimerize or attack the carbon atom of the alkyl halide RCH2X, the latter step involving elimination of either X- or 2t7.2.ix reactions of Co(ll) and Fe(II) porphyrins M(Por) with... 

Carbanion 239 derived from vinyl sulfone 238 was shown to be alkylated regiospecifi-cally at the a-carbon atom The carbanions 240 and 241 derived from <5-ketosulfones were shown to be alkylated at both a- and y-carbons . Alkylation of 240 gave a-alkylated products predominantly, while the a/y ratio varied markedly by change of the alkylating agent in the reaction with 241. For example, methylation with methyl iodide gave the products in the a/y ratio of 72 28, while the a/y ratio was 27 73 in the ethylation with ethyl bromide ... 

Deprotonation of allylic aryl sulfoxides leads to allylic carbanions which react with aldehyde electrophiles at the carbon atom a and also y to sulfur . With benzaldehyde at — 10 °C y-alkylation predominates , whereas with aliphatic aldehydes at — 78 °C in the presence of HMPA a-alkylation predominates . When the a-alkylated products, which themselves are allylic sulfoxides, undergo 2,3-sigmatropic rearrangement, the rearranged compounds (i.e., allylic sulfenate esters) can be trapped with thiophiles to produce overall ( )-l,4-dihydroxyalkenes (equation 24). When a-substituted aldehydes are used as electrophiles, formation of syn-diols 27 occurs in 40-67% yields with diastereoselectivities ranging from 2-28 1 (equation 24) . ... 

Benzannulated 1,3,2-diazaphospholes 5 form readily upon condensation of monosubstituted o-phenylenediamines (R=H, alkyl, Ph) with P(NMe2)3 [13, 14] (Scheme 2). A -Alkylated products can be detected by NMR but evade isolation by... 

Successive treatments of chiral acylsultam 50 with -BuLi or NaHMDS and primary alkyl halides, followed by crystallization, give the pure a,a-alkylation product 52 (Scheme 2-28). Under these conditions, the formation of C-10-alkylated by-product is inevitable. It is worth mentioning, however, that product 52 can readily be separated from the C(a)-epimers by crystallization. In fact,... 

Substituted ureas are alkylated under solidrliquid phase-transfer catalytic conditions to yield the A -alkylated products to the exclusion of N- and Oalkylated derivatives [23]. Surprisingly, A-aryl ureas do not react under similar conditions. 

In contrast with the amides, which yield only A-alkylated products, the corresponding reaction of 5,5-dimethylisoxazolidin-3-one (Scheme 5.8) produces both the /V-and 0-alkylated derivatives [24] (Table 5.15). With the exception of the sec-bromobutane, the overall yields from primary and secondary haloalkanes are comparable, but there is a tendency for the secondary haloalkanes to produce slightly higher yields of the ethers. 

Method D The azole (10 mmol), powdered KOH or K2C03 (10-20 mmol) and TBA-Br (0.16 g, 0.5 mmol) are mixed under ultrasound for 15 min. The haloalkane (10-20 mmol) is added and the mixture is stirred until TLC analysis indicates completion of the reaction. The mixture is extracted with CH2C12 (2 x 25 ml) and the extracts are evaporated to yield the A-alkylated product, which is purified by chromatography. 

The iridium catalytic system can also be applied to the a-alkylation of active methylene compounds. The alkylation of cyanoacetates 93 with primary alcohols 94 was achieved by using [lrCl(coe)2]2 and PPhs to afford saturated a-alkylated products 95 (Equation 10.20) [42]. Here, the alkylation reaction was efficiently accomplished, without the need for any base. 

TetralkylteUnriiims, prepared in situ by the reaction of tellurium tetrachloride with 4 equiv of alkyllithiums, react with arylacetylenes to afford dialkyl tellurides A, alkylation products B, an alkene C and minor amounts of a vinyl telluride D. ... 

Monoalkylation of a-isocyano esters by using tert-butyl isocyano acetate (R = fBu) has been reported by Schollkopf [28, 33]. Besides successful examples using primary halides, 2-iodopropane has been reported to produce the a-alkylated product (1) as well by this method (KOfBu in THF). In the years 1987-1991, Ito reported several methods for the monoalkylation of isocyano esters, including the Michael reaction under TBAF catalysis as described earlier [31], Claisen rearrangements [34], and asymmetric Pd-catalyzed allylation [35]. Finally, Zhu recently reported the first example of the introduction of an aromatic substituent by means of a nucleophilic aromatic substitution (Cs0H-H20, MeCN, 0°C) in the synthesis of methyl ot-isocyano p-nitrophenylacetate [36]. 

Selective O-alkylation of hydroxylamines and their derivatives can be done through deprotonation of the OH group. O-Alkylation (equation 14) of iV-substituted hydrox-amic acid ° (e.g. 21) followed by hydrolysis of the resultant O-alkylation product 22 is the most commonly used approach. Since alkylation of Af-unsubstimted hydrox-amic acid results in a mixture of O- and A-alkylation products, the corresponding O-alkylhydroxylamines are better prepared through alkylation of Af-hydroxysuccinimide or Af-hydroxyphthalimide followed by hydrolysis. 

The first successful preparation of lithium ethyl acetate was using the base lithium hexam-ethyldisilazanide12,14 at — 78 CC in tetrahydrofuran. The much greater stability of the lithium salt as compared to the previously prepared13 sodium ethyl acetate was noted and used in the reaction with carbonyl compounds12. The attack of alkyl halides as electrophiles on the lithium salts of esters, prepared by the action of lithium cyclohexylisopropylamide on the esters at low temperatures in tetrahydrofuran, furnished the a-alkylated products in yields of 50 -90%16,17. 

Ethyl a-lithiocyclopropanecarboxylate (1) could not be alkylated only the self-addition product 2 was isolated60,61. The dilithiated cyclopropane carboxylic acid 4, however, reacted with low conversion to give the a-alkylated products 562. 

When treated with lithium diisopropylamide, the unsubstituted simple bicyclic y-lactam, hexa-hydro-3//-pyrrolizin-3-one (1), furnishes the corresponding enolate which reacts with (halo-methyl)benzenes to give the a-alkylation products with rather poor diastereoselectivity10. The major product 2 has cis configuration. Equilibration of the product with base gives a 72 28 mixture in favor of the frans-diastereomer10. 

In the same manner as for l-(2-alkylbenzoyl)-2-(methoxymethyl)pyrrolidines 8 (vide supra), Birch reduction-alkylation of pyrrolobenzoxazepinones, e.g., 1. gives mainly the a-alkylation products (see Table 6)26,2R u. The chemical yields and diastereoselectivities are usually excellent, except for alkylation with iodomethane when the diastereoselectivity is moderate26. The facial selectivity is opposite to that observed upon direct Birch reduction-alkylation of the ortho-methoxy derivatives, i.e., 2-alkoxymethyl-l-(2-methoxybenzoyl)pyrrolidines (vide supra). 

Reaction of Z-a./j-unsaturated iron-acyl complexes with bases under conditions similar to those above results in exclusive 1,4-addition, rather than deprotonation, to form the extended enolate species. However, it has been demonstrated that in the presence of the highly donating solvent hexamethylphosphoramide, y-deprotonation of the -complex 6 occurs. Subsequent reaction with electrophiles provides a-alkylated products such as 736 this procedure, demonstrated only in this case, in principle allows access to the a-alkylatcd products from both Z- and it-isomers of a,/j-unsaturated iron-acyl complexes. The hexamethylphosphoramide presumably coordinates to the base and thus prevents precoordination of the base to the acyl carbonyl oxygen, which has been suggested to direct the regioselective 1,4-addition of nucleophiles to -complexes as shown (see Section 1.1.1.3.4.1.2.). These results are also consistent with preference for the cisoid conformations depicted. 

Related, achiral cc,/ -unsaturated molybdenum-( 2-acyl) complexes, such as 8, have been shown to undergo nucleophilic 1,4-conjugatc addition upon treatment with sodium borohy-dride or methyllithium to generate enolate species, such as 9 (produced by addition of hydride). Subsequent alkylation by iodomethane provides the a-alkylated product 1088. Extension of this tandem Michael addition-alkylation sequence to nonracemic molybdenum species has not yet been reported. 

When 6-(2-bromoethyl)bicyclo[4.3.0]non-1(9)-en-8-one was treated with potassium /m-butoxide in tert-butyl alcohol, a mixture of the a -alkylation product, tricyclo[7.2.0.016]undec-6-en-8-one (6) and the a-alkylation product, tricyclo[5.2.2.0J6]undec-5-en-8-one (7) was afforded in a ratio of 95 5.7... 

Intramolecular cyclization of 6-(mesyloxymethyl)bicyclo[4.4.0]dcc-l-cn-3-one using lithium diiso-propylamide produced almost exclusively the y-alkylation product tricyclo[5.3.1.01,6]undec-5-en-4-one (17), together with a trace amount of the 2-alkylation product tricyclo[5.3.1 016]undec-5-en-8-one (18).17 Surprisingly, the a-alkylation product 18 was the major product when the cyclization was carried out using potassium tert-butoxide.17 The preference for y-alkylation over a-alkylation can be rationalized by the Hammond postulate which favors y-alkylation due to the less reactant-like transition state when lithium diisopropylamide is used. Alternatively, when potassium /ert-butoxide and 18-crown-6 in hexamethylphosphoric triamide is used, the reactivity of the enolate anion is significantly enhanced. As a result, the transition state becomes reactant-like so that a-alkylation is the predominant process.17... 

As described previously [63], P-ketoester 111 [Fig. (31)] was subjected to Baker s yeast reduction to afford the optically active P-hydroxyester 112 (60-80% yield). Dianion alkylation of 112 with (E)-3-methyl-4-(0-tert-butyldimehtylsilyl)-2-butene afforded the desired a-alkyl product 113 in 58-70% isolated yield. 

The size of silyl groups influences the carbon-carbon bond formation between sily-lalkenes and ketones. Treatment of allylsilanes 12 or vinylsilanes 14 with ketones in the presence of MnC>2 and acetic acid at elevated temperature gives a-alkylation products 13 and 15, respectively (equations 9 and 10)18. The steric effect resulting from the silyl groups plays an essential role on the exclusive C—C bond formation at the terminal sp2 carbon of silylalkenes 12 and 14. The yield of the alkylation is inverse to the size of silyl groups and follows the order listed in entry 7 of Table 1. 

A new iodine-catalysed, remarkably simple Michael reaction of indoles with enones, e.g. PhCH=CHCOR, has been developed.183 The Sml3-catalysed reaction of indoles with electron-deficient alkenes (e.g. enones) afforded the corresponding Michael adducts in high yields. As in the previous case, the substitution on the indole nucleus occurred exclusively at the 3-position and A-alkylation products have not been observed.184... 

The alkylation of 2-pyridone was effected under mild conditions by use of cesium fluoride. Benzyl and allyl chlorides furnished the A-alkylated product selectively, while secondary alkyl iodides gave O-alkylation selectively <95SL845>. 

The a-C-H hydroxyalkylation of THF (1) with aldehydes provides a-alkylated products in comparable yields under triethylborane-air (method A) or triethylbor-ane-TBHP (method B) conditions (Table 1). The ease of operation and the relatively mild conditions are the merits of the former, whereas a short reaction time makes the latter highly efficient. Table 1 shows the general applicability of the two methods to various aldehydes. The yield and threo selectivity of products 3 4 are generally high for all aromatic aldehydes except ortho-substituted benzaldehyde (entry 4) and moderate to low for aliphatic substrates (entries 5 and 6). 

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