Preparatively Useful SN2 Reactions Alkylations

P-nucleophiles (— precursors for Wittig or Horner-Wadsworth-Emmons reaction) 

At the same time the phosphorus, which was originally present in the oxidation state +3, is oxidized to P(V). This type of chemistry was extensively developed by Mukaiyama. 

Side Note 2.5. Deoxygenation of Primary Alcohols under Tin-free Conditions 

Edwards, One or More CC Bond(s) Formed by Substitution Substitution of Halogen, in Comprehensive Organic Functional Group Transformations (A. R. Katritzky, O. Meth-Cohn, C. W. Rees, Eds.), Vol. 1, 105, Elsevier Science, Oxford, U. K., 1995. 

Scales of Nucleophilicity and Electrophilicity A System for Ordering Polar Organic and Organometallic Reactions, Angew. Chem. Int. Ed. Engl. 1994, 33, 938-958. 

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Thiols can be prepared by SN2 reactions of sodium hydrosulfide with unhindered alkyl halides. The thiol product is still nucleophilic, so a large excess of hydrosulfide is used to prevent the product from undergoing a second alkylation to give a sulfide (R—S—R). 

Step [3] B is prepared from acetylene and two 1 alkyl halides (C and D) by using Sn2 reactions with acetylide anions. 

Organocuprates can react with all alkyl halides except tertiary alkyl halides. Because they can react with vinylic halides and aryl halides (an aryl hahde has a hydrogen attached to a benzene ring), they can be used to prepare compounds that cannot be prepared by Sn2 reactions with Grignard reagents or organolithium compounds. (Remember that vinylic and aryl halides cannot undergo nucleophilic attack Section 9.5). 

A wide array of substances can be prepared using nucleophilic substitution reactions. In fact, we ve already seen examples in previous chapters. The reaction of an acetylide anion with an alkyl halide (Section 8.8), for instance, is an Sn2 reaction in which the acetylide nucleophile replaces halide. 

A better method for preparing primary amines is to use the azide synthesis, in which azjde ion, N3, is used for SN2 reaction with a primary or secondary alkyl halide to give an alkyl azide, RN3. Because alkyl azides are not nucleophilic, overalkylation can t occur. Subsequent reduction of the alkyl azide, either by catalytic hydrogenation over a palladium catalyst or by reaction with LiAlK4. then leads to the desired primary amine. Although the method works well, low-molecular-weight alkyl azides are explosive and must be handled carefully. 

The prominent role of alkyl halides in formation of carbon-carbon bonds by nucleophilic substitution was evident in Chapter 1. The most common precursors for alkyl halides are the corresponding alcohols, and a variety of procedures have been developed for this transformation. The choice of an appropriate reagent is usually dictated by the sensitivity of the alcohol and any other functional groups present in the molecule. Unsubstituted primary alcohols can be converted to bromides with hot concentrated hydrobromic acid.4 Alkyl chlorides can be prepared by reaction of primary alcohols with hydrochloric acid-zinc chloride.5 These reactions proceed by an SN2 mechanism, and elimination and rearrangements are not a problem for primary alcohols. Reactions with tertiary alcohols proceed by an SN1 mechanism so these reactions are preparatively useful only when the carbocation intermediate is unlikely to give rise to rearranged product.6 Because of the harsh conditions, these procedures are only applicable to very acid-stable molecules. 

Thiols are prepared from alkyl halides and sodium hydrosulphide (Na+SH ) by Sn2 reaction. A large excess of Na+SH is used with unhindered alkyl halide to prevent dialkylation (R—S—R). 

The E2 elimination can be an excellent synthetic method for the preparation of alkene when 3° alkyl halide and a strong base, e.g. alcoholic KOH, is used. This method is not suitable for Sn2 reaction. 

Thiols can be prepared by the action of alkyl halides with an excess of KOH and hydrogen sulphide. It is an SN2 reaction and involves the generation of a hydrogen sulphide anion (HS ) as nucleophile. In this reaction, there is the possibility of the product being ionised and reacting with a second molecule of alkyl halide to produce a thioether (RSR) as a by-product. An excess of hydrogen sulphide is normally used to avoid this problem. 

A final method sometimes employed to prepare alkyl halides uses an SN2 reaction with one halogen as the leaving group and a different halide ion as the nucleophile, as shown in the following general equation ... 

Decide which synthesis to use. The acetoacetic ester synthesis is used to prepare methyl ketones, and the malonic ester synthesis is used to prepare carboxylic acids. Both syntheses provide a method to add alkyl groups to the a-carbon. Therefore, next identify the group or groups that must be added to the a-carbon. Remember that the a-carbon is the nucleophile, so the groups to be attached must be the electrophile in the Sn2 reaction they must have a leaving group bonded to the carbon to which the new bond is to be formed. 

Deprotonation of indoles 128 followed by alkylation with 2-methyloxirane led to the secondary alcohols 129 that were used as starting compounds in the preparation of substituted 2-(l//-indol-l-yl)-l-methylethylamines 130, novel agonists of 5HT2C receptors. Sn2 reaction of the corresponding mesylates with sodium azide and reduction of the azides with either hydrogen or LiAlH4 produced amines 130 in excellent yields (Scheme 28) <1997JME2762>. 

The reaction of Pd complexes (such as Pd(PhsP)4) with organic halides and related compounds has been used to prepare a number of stable Pd alkyl and vinyl compounds. This reaction with alkyl halides has the characteristics of an Sn2 reaction. Primary halides react faster than secondary halides. Also, when a chiral halide is used, such as (X)-(-F)-benzyl-o -D chloride, the benzyl palladium product is formed with inversion of configuration at the benzylic carbon (equation 8). With vinylic halides, retention of configuration at the double bond is observed... 

Since in terms of leaving group ability in SN2 reactions I > Br > Cl, a-iodoalkyl alkyl carbonates are the reagents of choice for the chemical modification of either carboxylic acid or phenolic functions. However, these a-iodo carbonates exhibit severe instability (Ref. 78) and are generally prepared in-situ or just before use (Ref. 79,80, 81). 

Yields are ollen poor in this reaction unless an excess of the nucleophile a used, because the product thiol can undergo further Sn2 reaction with al halide to give a symmetrical sulfide as a by-product. For this reason, I thiourea, (NH2)-3C=S, is often used as the nucleophile in the preparation of a thiol from an alkyl halide. The reaction occurs by displacement of the halide ion to yield an intermediate alkylisothiourea salt, which is hydrolyzed by subsequent reaction with aqueous base. ... 

The Gabriel synthesis of amines uses potassium phthalimide (prepared from the reaction of phthalimide with potassium hydroxide). The structure and preparation of potassium phthalimide is shown in Figure 13-13. The extensive conjugation (resonance) makes the ion very stable. An example of the Gabriel synthesis is in Figure 13-14. (The N2H4 reactant is hydrazine.) The Gabriel synthesis employs an SN2 mechanism, so it works best on primary alkyl halides and less well on secondary alkyl halides. It doesn t work on tertiary alkyl halides or aryl halides. 

Primary amines also can be prepared in good yields if azide ion ( N3) is used as the nucleophile in an Sn2 reaction. The product of the reaction is an alkyl azide, which can be reduced to a primary amine. (See Chapter 10, Problem 9.)... 

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