Secondary alkyl iodide

For a monograph, see Reutov, O.A. Beletskaya, I.P. Kurts, A.L. Ambident Anions Plenum NY, 1983. For a review, see Black, T.H. Org. Prep. Proced. Int., 1989, 21, 179. Both cyanates and isocyanates have been isolated in treatment of secondary alkyl iodides with NCO Holm, A. Wentrup, C. Acta Chem. Scand., 1966, 20, 2123. 

The reaction of alkyl halides with metal nitrites is one of the most important methods for the preparation of nitroalkanes. As a metal nitrite, silver nitrite (Victor-Meyer reaction), potassium nitrite, or sodium nitrite (Kornblum reaction) have been frequently used. The products are usually a mixture of nitroalkanes and alkyl nitrites, which are readily separated by distillation (Eq. 2.47). The synthesis of nitro compounds by this process is well documented in the reviews, and some typical cases are listed in Table 2.3.92a Primary and secondary alkyl iodides and bromides as well as sulfonate esters give the corresponding nitro compounds in 50-70% yields on treatment with NaN02 in DMF or DMSO. Some of them are described precisely in vol 4 of Organic Synthesis. For example, 1,4-dinitrobutane is prepared in 41 -46% yield by the reaction of 1,4-diiodobutane with silver nitrite in diethyl ether.92b 1-Nitrooctane is prepared by the reaction with silver nitrite in 75-80% yield. The reaction of silver nitrite with secondary halides gives yields of nitroalkanes of about 15%, whereas with tertiary halides the yields are 0-5%.92c Ethyl a-nitrobutyrate is prepared by the reaction of ethyl a-bromobutyrate in 68-75% yield with sodium nitrite in DMF.92d Sodium nitrite is considerably more soluble in DMSO than in DMF as a consequence, with DMSO, much more concentrated solutions can be employed and this makes shorter reaction times possible.926... 

Charette et al. converted both primary and secondary alkyl iodides to the corresponding alkylzinc iodides, using either ethylzinc iodide or isopropylzinc iodide.34 The reactions, for example, Scheme 30, which were performed in UV-irradiated (X > 280 nm) chloroform solutions, gave conversions as high as 88% in less than 4h. 

Functionalized organozinc halides are best prepared by direct insertion of zinc dust into alkyl iodides. The insertion reaction is usually performed by addition of a concentrated solution (approx. 3 M) of the alkyl iodide in THF to a suspension of zinc dust activated with a few mol% of 1,2-dibromoethane and MeaSiCl [7]. Primary alkyl iodides react at 40 °C under these conditions, whereas secondary alkyl iodides undergo the zinc insertion process even at room temperature, while allylic bromides and benzylic bromides react under still milder conditions (0 °C to 10 °C). The amount of Wurtz homocoupling products is usually limited, but increases with increased electron density in benzylic or allylic moieties [45]. A range of poly-functional organozinc compounds, such as 69-72, can be prepared under these conditions (Scheme 2.23) [41]. 

This reaction can also be applied to the preparation of heterocyclic organocopper reagents such as 77 from readily available secondary alkyl iodides. Ring-closure in this case is catalyzed by Ni(acac)2 rather than by Pd(0), affording new heterocyclic molecules such as 78 (Scheme 2.26) [55]. These cyclization reactions are key steps in the preparation of such natural products as (-)-methylenolactocin 79 [57] and methyl epijasmonate 80 [58] (Scheme 2.27). 

The scope of these reactions is illustrated by the variety of functionalized nitrate esters which can be prepared (Table 3.1). In general, primary and secondary alkyl iodides and bromides... 

Oxidation of iodoalkanes involves removal of an electron from the halogen nonbonding orbital. The radical-cations of primary and secondary alkyl iodides can be identified in aqueous solution by their absorption spectra and have half-lives of microseconds [1]. They are formed during pulse radiolysis of the iodoalkane in aqueous solution in the presence of nitrous oxide. This system generates hydroxyl radicals, which remove an electron from the iodine atom lone pair. Iodoalkane radical-anions complex with the lone-pair on other heteroatoms to form a lollo three-electron bond. In aqueous solution, the radical-cation of iodomethane is involved in an equlibrium indicated by Equation 2.1. 

For secondary alkyl iodides, the two one-electron polarographic waves are more separated. Reduction of 2-iodooctane at the potential of the first wave alfords the dialkylmercury and 7,8-dimethyl-tetradecane by reactions of the sec-octyl radical. At the potential of the second wave only octane and octenes are isolated [37]. 2-Bromooctane shows only one polarographic wave and yields octane and octene on reduction at any potential [37]. Radicals generated by reduction of primary and secondary iodoalkanes will react with other cathode materials including tin, lead and thallium to form metal alkyls [48,49],... 

Ahlbrecht and coworkers showed that the stereoselective alkylation of Af-cinnamyl (5 )-2-methoxymethylpyrrolidine (STdR), followed by hydrolysis, affords enantiomerically enriched 3-substituted phenylpropionaldehydes, as shown in Scheme 45. This method is analogous to the asymmetric alkylation of S AMP/RAMP hydrazones, as the anions are isoelectronic. The mechanisms of asymmetric induction for the two systems are probably similar. For the lithio cinnamyl amine, methylation can be optimized up to 97.5% ds. Most of the procedures in this paper include potassium tert-butoxide, so the cation in these examples may be potassium. Under these conditions, methyl, primary and secondary alkyl iodides typically afford the products with selectivities in the 90-93% ds range. 

Under these conditions, a broad range of polyfunctional alkyl iodides are converted to the corresponding organozinc halides in high yields . In the case of primary alkyl iodides, the insertion occurs at 40-50 °C whereas secondary alkyl iodides already react at 25-30°C. Secondary alkyl bromides also react under these conditions , but primary alkyl bromides are usually inert with this type of activation and much better results are obtained by using Rieke zinc L Thus, the reduction of zinc chloride with finely cut lithium and naphthalene produces within 1.5 h highly reactive zinc (Rieke zinc). 

All of the alkyl electrophiles shown in Schemes 73-78 are primary alkyl derivatives. On the other hand, cross-coupling of primary alkylzincs with secondary alkyl iodides and bromides was shown to be feasible with 4% Ni(COD)2, 8% s-Bu-Pybox (3) and DMA(N,N-Dimethylacetamide)88k (Scheme 79). More recently, a modification of this procedure through the use of -Pr-Pybox and 7 1 DMI/THF, where DMI is 1,3-dimethyl-2-imidazolidinone, in place of v-Bu-Pybox (3) and DMA has been shown to permit enantioselective alkylation of racemic secondary a-bromoamides with organozincs210 (Scheme 79). 

Secondary alkyl iodides were even more reactive and underwent a smooth Pd-catalyzed carbozincation which proceeded with moderate cis diastereoselectivity (cis/trans = 70/30 to 81/19)39,40. Interestingly, 54 could be effectively cyclized to the organozinc species 55, a result which seemed to rule out the involvement of an open-chain organozinc species... 

Secondary alkyl iodides bearing an additional substituent at the allylic position underwent highly diastereoselective Pd-catalyzed carbozincations, as illustrated for 56 which led after allylation with ethyl 2-bromomethylacrylate to the trisubstituted cyclopentane 57 (C1-C2 trans/cis > 99/1, C2-C3 cis/trans = 95/5) (equation 23)39,40. 

Both cyanates and isocyanates have been isolated in treatment of secondary alkyl iodides with NCO Holm Wentrup Acta Chem. Scand. 1966, 20, 2123. 

The design of an efficient chain reaction to facilitate the reduction of secondary alkyl iodides adjacent to electron-withdrawing groups has been accomphshed by reaction... 

Another example of transient formation of a palladacycle is the Pd-mediated ortho-alkylation and ipso-vinylation of aryl iodides depicted in Scheme 8.23. In this multicomponent reaction the ability of norbomene to undergo reversible arylation and palladacycle formation is exploited. This reaction also illustrates that aryl halides undergo oxidative addition to Pd faster than do alkyl halides, and that aryl-alkyl bond-formation by reductive elimination also proceeds faster than alkyl-alkyl bond-formation. The large excess of alkyl iodide used in these reactions prevents the formation of biaryls. Benzocyclobutenes can also be formed in this reaction, in particular when the alkyl group on the aryl iodide is sterically demanding or when a secondary alkyl iodide is used [161]. 

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>. 

Tertiary iodides and bromides usually are reduced with Bu3SnH or (Me3Si)3SiH via a radical chain reaction, as discussed in Section 1.10. Primary and secondary alkyl iodides, bromides, and xanthates can be reduced with the same reagents under the same conditions via the same radical mechanism. 

Negishi-type cross-coupling reactions of primary and secondary alkyl iodides 1 and alkylzinc bromides 2 proceeded with 10 mol% of Ni(py)4Cl2/(sBu)-PyBOX 5a (entry 6) [48]. Based on calculations, an alkylNi(I)(PyBOX) complex is formed by initial SET reduction, which carries much of the spin density in the ligand, similar to Vicic s catalysts 9. Based on this result a Ni(I)-Ni(II)-Ni(III) catalytic cycle was proposed to operate. 

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