Allyl iodide, alkylation with

Few other reactions of series of substituted pyridines have been investigated extensively. Dondoni, Modena, and Todesco have measured the rate of N-oxidation of a limited series of pyridines and found a good correlation with normal u-values with a p-value of — 2.23. The A-alkylation of pyridines with alkyl iodides in nitrobenzene has been studied by Brown and Cahn and by Clarke and Rothwell. Unfortunately, the only data available are for the parent compound and for alkyl derivatives, and, since the a-values for the various alkyl groups in a given position are substantially constant, this leaves a correlation of only three independent points. However, the rates of A-alkylation of the j8- and y-alkyl derivatives are so nearly equal that it appears as if no correlation existed. Clarke and Rothwell have also studied the alkylation with allyl bromide in nitromethane at various temperatures, and in this case a more extensive series is available. The authors state that no overall Hammett correlation is obtained however, the j8-substituted derivatives fall on one straight line and the y-derivatives on another one with a different slope. The data are shown in Fig. 2. The line for the j8-compounds, p = — 2.53 0.31, r = 0.95, is seen not to be very good the line for the y-derivatives, p = — 1.42 0.06, r = 0.99, is much more satisfactory. It does not seem likely that the discrepancy is due to the intervention of resonance effects, since in this case one would expect the correlation for the y-derivatives to be poorer than that for the j8-analogs. More extensive studies with a wider variety of substituents would seem very desirable. 

The synthesis of key intermediate 6 begins with the asymmetric synthesis of the lactol subunit, intermediate 8 (see Scheme 3). Alkylation of the sodium enolate derived from carboximide 21 with allyl iodide furnishes intermediate 26 as a crystalline solid in 82 % yield and in >99 % diastereomeric purity after recrystallization. Guided by transition state allylic strain conformational control elements5d (see Scheme 4), the action of sodium bis(trimethylsilyl)amide on 21 affords chelated (Z)-enolate 25. Chelation of the type illustrated in 25 prevents rotation about the nitrogen-carbon bond and renders... 

Both sides of acetone have been alkylated with different alkyl groups, in one operation, by treatment of the Al,lV-dimethylhydrazone of acetone with n-BuLi, followed by a primary alkyl, benzylic, or allylic bromide or iodide then another mole of n-BuLi, a second halide, and finally hydrolysis of the hydrazone. ... 

For enolates with additional functional groups, chelation may influence stereoselectivity. Chelation-controlled alkylation has been examined in the context of the synthesis of a polyol lactone (-)-discodermolide. The lithium enolate 4 reacts with the allylic iodide 5 in a hexane THF solvent mixture to give a 6 1 ratio favoring the desired stereoisomer. Use of the sodium enolate gives the opposite stereoselectivity, presumably because of the loss of chelation.61 The solvent seems to be quite important in promoting chelation control. 

A more traveled route to the absolute configuration represented by cyclohexa-1,4-diene 8 involves Birch reduction-alkylation of benzoxazepinone 9.2.5 heterocycle is best prepared by the base-induced cyclization of the amide obtained from 2-fiuorobenzoyl chloride and (5)-pyrrolidine-2-metha-nol. o The molecular shape of enolate 10 is such that the hydrogen at the stereogenic center provides some shielding of the a-face of the enolate double bond. Thus, alkylation occurs primarily at the 3-face of 10 to give 11 as the major diastereomer. The diastereoselectivity for alkylation with methyl iodide is only 85 15, but with more sterically demanding alkyl halides such as ethyl iodide, allyl bromide, 4-bromobut-1-ene etc., diastereoselectivities are greater than 98 2. 

Two consecutive enolate alkylations were utilized to generate the quaternary carbon atom (Scheme 38). Alcohol 238 was transformed into the protected hydroxy enone 244. Regioselective deprotonation at the a-position of the ketone 244 led to a cross-conjugated enolate that was alkylated with the allylic iodide 245. The vinyl silyl moiety in 245 represents a masked keto group [127]. The choice of the TBS protecting group for the hydroxyl group at of 244 was crucial in order to prevent the deprotonation at the y-posi-... 

The allylic alkylation products represent useful synthons, as exemplified by the reaction sequence outlined in Scheme 10.4. For example, reductive ozonolysis of the allylic alkylation product 15 afforded the y-lactone 16 as a single diastereoisomer. Sequential alkylation with methyl iodide, and reductive alkylation using lithium naphthalenide with allyl iodide furnished the ternary-quaternary substituted y-lactones 17a/17b in 72% overall yield, as a 10 1 mixture of diastereomers favoring 17a [18]. This method provides a versatile approach to the construction of a variety of a-quaternary-/9-ternary stereogenic centers. 

Similarly the enantiomerically pure bicyclic A -propionyl lactam 9 can be enolized and reacted with allyl iodide to give a 56% yield of the alkylation product 10 (d.r. 98 2), which when hydrolysed furnishes (7 )-2-methyl-4-pentenoic acid (11)5. 

Surprisingly, tin vapor fails to react on condensation with alkyl chlorides or bromides. It will react with some alkyl iodides thus, with methyl iodide, a high yield of polymeric MeSnl is obtained together with very small yields of volatile methyliodostannanes. Allyl chloride gives Sn(C3Hs)3Cl in moderate yield. The reaction with HC1 and acetylene is more complex, the intermediate may be H—Sn—Cl ... 

Alkylation at N( 5) of the cyclic intermediates 38 was accomplished using concentrated solutions of alkyl halides in DMF at 50°C. Addition of a base proved not only unnecessary but even counterproductive in terms of the purity of the resulting Al(5)-substituted benzodiazepi nones 39. Alkyl halides producing good results in this reaction include more than 40 benzyl bromides, allyl bromide, various esters of bromoacetic acid, as well as methyl and ethyl iodide. Other alkyl iodides, along with benzyl chlorides and a-bromo acetophenones, however, did not give satisfactory results. 

With benzyl, allyl, and primary alkyl halides the yields are 72-90% they are low with isopropyl iodide (34%) with tert-butyl bromide no reaction occurred. This behavior is consistent with results already reported. Alkylation of anions often give poor results with secondary alkyl halides and no alkylation with tertiary alkyl halides. 

Kotarska et a/.106-282 attributed the 3-substituted structures to the products obtained from the pyrido[l,2-a]pyrimidine (63 R = H) by alkylation with either 1-chloromethylnaphthalene or allyl bromide, or with benzyl chloride in ethanolic potassium hydroxide in the presence of potassium iodide. The melting point of the 3-benzyl compound agreed with the earlier literature datum but that of the 3-allyl compound differed by more than 20 C.100,112... 

Tetrazolyl)-4//-pyrido[l,2-a]pyrimidin-4-ones 441 were alkylated with alkyl iodides, alkyl bromides, triethyl phosphate, cyclopentyl bromide, allyl bromide, propargyl bromide, benzyl chlorides, ethyl bromoace-tate, and methyl chloroformate in dimethylformamide in the presence of potassium carbonate at 80-90°C to give a mixture of 3-(l-substituted 5-tetrazolyl)- and 3-(2-substituted 5-tetrazolyl)-4//-pyrido[l,2-u]pyrimidin-... 

---