Primary iodides

Scheme 3b). It is instructive at this point to reiterate that the furan nucleus can be used in synthesis as a progenitor for a 1,4-dicarbonyl. Whereas the action of aqueous acid on a furan is known to provide direct access to a 1,4-dicarbonyl compound, exposure of a furan to an alcohol and an acid catalyst should result in the formation of a 1,4-diketal. Indeed, when a solution of intermediate 15 in benzene is treated with excess ethylene glycol, a catalytic amount of / ara-toluenesulfonic acid, and a trace of hydroquinone at reflux, bisethylene ketal 14 is formed in a yield of 71 %. The azeotropic removal of water provides a driving force for the ketalization reaction, and the presence of a trace of hydroquinone suppresses the formation of polymeric material. Through a Finkelstein reaction,14 the action of sodium iodide on primary bromide 14 results in the formation of primary iodide 23, a substance which is then treated, in crude form, with triphenylphosphine to give crystalline phosphonium iodide 24 in a yield of 93 % from 14.

Yet another approach uses electrolysis conditions with the alkyl chloride, Pe(CO)s and a nickel catalyst, and gives the ketone directly, in one step. In the first stage of methods 1, 2, and 3, primary bromides, iodides, and tosylates and secondary tosylates can be used. The second stage of the first four methods requires more active substrates, such as primary iodides or tosylates or benzylic halides. Method 5 has been applied to primary and secondary substrates. 

Scheme 9). Although cyanohydrin acetonide 64 could conceivably have been used, the silyl ether 75 was chosen. This compound is readily available from (l)-malic acid, and can undergo electrophilic activation under far more mild conditions than compound 64. Alkylation of the 1,3-diol synthon 75 with bromide 76 created the C11-C26 framework of roflamycoin, in 85% yield. A two-step conversion of the terminal siloxy group to the primary iodide (78) proceeded in 80% overall yield. 

Entry 10 illustrates the application of the Mitsunobu reaction to synthesis of a steroidal iodide and demonstrates that inversion occurs. Entry 11 shows the use of the isolated Ph3P-Br2 complex. The reaction in Entry 12 involves the preparation of a primary iodide using the Ph3P-I2-imidazole reagent combination. 

Organomagnesium and organolithium compounds are strongly basic and nucleophilic. Despite their potential to react as nucleophiles in SN2 substitution reactions, this reaction is of limited utility in synthesis. One limitation on alkylation reactions is competition from electron transfer processes, which can lead to radical reactions. Methyl and other primary iodides usually give the best results in alkylation reactions. 

Secondary benzylic bromides, allylic bromides, and a-chloro ethers can undergo analogous reactions using ZnBr2 as the catalyst.1 2 Primary iodides react with silyl... 

The C(9)-C(14) segment VI was prepared by Steps D-l to D-3. The formation of the vinyl iodide in Step D-3 was difficult and proceeded in only 25-30% yield. The C(15)-C(21) segment VII was synthesized from the common intermediate 17 by Steps E-l to E-6. A DDQ oxidation led to formation of a 1,3-dioxane ring in Step E-l. The A-methoxy amide was converted to an aldehyde by LiAlH4 reduction and the chain was extended to include C(14) and C(15) using a boron enolate of an oxazo-lidinone chiral auxiliary. After reductive removal of the chiral auxiliary, the primary alcohol group was converted to a primary iodide. The overall yield for these steps was about 25%. 

The branched cyclodextrins (CDs, 17 a, 17 b) and their analogues with D-galactosyl and a-D-mannosyl residues (17c, 17d) have also been prepared under mild conditions by the approach depicted in Scheme 6 [24,25]. Selective in situ S-deacetylation and activation was obtained by treatment of peracetylated 1-thioglycoses (10a, 8e, 8g) by cysteamine in the presence of diAioerythritol in HMPA [26]. This method was very efficient for ffie synthesis of branched CDs (17a) (80%), (17b) (60%), and (17c) (85%) when the acceptor molecule (15b) bearing primary iodide was used. However, peracetylated 1-thioa-D-mannose (8f) failed as a donor under these conditions, but tetra-O-acetyl-l-thio-a-mannose (8 b) afforded the expected CD (17d) in high yield (83%). 

The high chemoselectivity of organozinc reagents also allowed the use of the functionalized secondary a-acetoxy alkyl bromide 50 which was converted to 34a (equation 19)36, a product previously obtained by the cyclization of a 5-ethylenic primary iodide bearing the acetoxy group at the allylic position (equation 13). 

Primary amines can be prepared from alkyl halides by the use of hexamethylenetetramine814 followed by cleavage of the resulting salt with ethanolic HC1. The method, called the Delepine reaction, is most successful for active halides such as allylic and benzylic halides and a-halo ketones, and for primary iodides. 

RX — RSH.1 The reagent converts primary iodides or benzyl bromides directly into thiols. Primary chlorides or bromides undergo the same reaction in acetonitrile in the presence of (C2H5)4NI (equation I). 

The primary iodide is never formed in such reactions. Preparation 123.—iso-Propyl Iodide [2-Iodopropan]. 

More reactive anions such as the 2-lithio-l,3-dithiane derivatives, phenyllithium and r-butyllithium do not require a special solvent and proceed in high yield in THF. While HMPA is known to suppress the migratory insertion to CO in anionic complexes,127 it does not deter the CO insertion in these cases no example of direct alkylation is reported. The only electrophile which adds without CO insertion is the proton, as discussed above. Good alkylating agents (primary iodides and triflates, ally bromide, benzyl... 

Asymmetric alkylation andaldol condensations.2 The enolate (2) of 1 reacts with primary iodides to give essentially a single product (3), in which the alkyl group is syn to the cyclopentadieny ring. Aldol condensation with acetone leads to only one observable product (4). Only two isomeric products are obtained on aldol condensation with prochiral aldehydes and ketones as expected for a rranx-enolate, the i/ww-aldol predominates or is the exclusive product (5) as in the case of pivaldehyde. 

A limitation of the aforementioned methods is that they are unsuitable for the use of primary alkyl iodides. Under Et3B/02 initiation conditions, the desired radical is intended to be generated by iodine atom transfer to ethyl radicals, which is not favorable in the case of primary iodides. Thus ethyl radical addition competes with the desired radical when using triethylborane initiation along with primary iodides. In addition, generating radicals by hydrogen atom transfer from ethers or acetals has limited applicability. Because of the expanded synthetic potential of primary alkyl iodides as... 

A range of iodides were next examined in reactions with and without InCl3, starting with a comparison of secondary and primary iodides (Table 6). When secondary iodides were subjected to coupling with y-hydrazonoester 35a the yields were excellent (entries 1 and 5), while primary iodides gave the desired adducts in moderate yields (33-66%, entries 6-10). All of these reactions occurred with excellent diastereoselectivities, and it was worth noting that both silyl ether and alcohol functionality were compatible with the coupling. 

Addition of RI to a,fi-enones.2 This couple and sonication effect addition of RI to enones. Highest yields are obtained with /-Pr0H/H20 (4 1) or PrOH/ H20 (65-25 35-75) as solvent for primary iodides. C2H50H/H20 (65 35) is the... 

An alternative to the use of the 2-thienyl group as a nontransferable ligand in h.o. cyanocuprates is the anion of DMSO (1) efficient alkylation of primary iodides at -78 °C... 

Hexenyl radicals were used as radical clocks for the indirect measurement of the rate of reduction of radicals to anions using SmI2-HMPA. For example, reduction of primary iodide 4 using SmI2-HMPA resulted in the isolation of coupled product 9 in 20% yield and cyclised-coupled product 7 in 80% yield. As the rate of cyclisation of the intermediate primary hexenyl radical 6 was known, a rate constant of k= 106 M 1 s 1 could be estimated for the reduction... 

Nakata utilised the Sml2-mediated Barbier-type cyclisation of a primary iodide with an ester as part of a convergent synthesis of trans-fused 6,6,6,6-tetracyclic ethers, which are typically found in marine polycyclic ethers.62 Treatment of iodide 50 with excess Sml2 in the presence of 1 mol% of Nil2 led to the smooth formation of intermediate hemiacetal 51, which was dehydrated to give dihy-dropyran 52 that was then further elaborated to give tetracycle 53 (Scheme 7.23).62... 

The mechanism of these transformations seems to be substrate-dependent and only the cycloisomerization of aryl and primary iodides was thought to proceed as shown in Scheme 31. The stereoselectivity of the isomerization of 110 to 111 is better accommodated with the intermediacy of l-methyl-5-hexenyl radical59. Later, it was proposed that the isomerization of 6 to 109 also proceeds via a radical-mediated atom transfer process initiated by homolytic fragmentation of an ate-complex intermediate 112 (Scheme 32)60. 

Komblum et al. had asserted that it was necessary to convert primary iodides to tosylates for the oxidation to proceed. However, Johnson and Pelter have claimed that primary iodides can be oxidized directly. They observed that ketonic substrates failed, undergoing aldol condensation under the reaction conditions, but that hydroxy-containing halides reacted normally. For substrates insoluble in DMSO such as 1-bromododecane, they found that DME worked well as a cosolvent. The most interesting example... 

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