Alkyl hahde synthesis

Strategy Problem 1 The wrong substitution pattern . Making aromatic compounds m-substituted with two o -directing groups is always a problem. What strategies can you suggest An example (TM 412) is the alkyl hahde used in the synthesis of some steroids. 

Nitdles may be prepared by several methods (1). The first nitrile to be prepared was propionitdle, which was obtained in 1834 by distilling barium ethyl sulfate with potassium cyanide. This is a general preparation of nitriles from sulfonate salts and is referred to as the Pelou2e reaction (2). Although not commonly practiced today, dehydration of amides has been widely used to produce nitriles and was the first commercial synthesis of a nitrile. The reaction of alkyl hahdes with sodium cyanide to produce nitriles (eq. 1) also is a general reaction with wide appHcabiUty ... 

Hydroxyl Group. Reactions of the phenohc hydroxyl group iaclude the formation of salts, esters, and ethers. The sodium salt of the hydroxyl group is alkylated readily by an alkyl hahde (WiUiamson ether synthesis). Normally, only alkylation of the hydroxyl is observed. However, phenolate ions are ambident nucleophiles and under certain conditions, ring alkylation can also occur. Proper choice of reaction conditions can produce essentially exclusive substitution. Polar solvents favor formation of the ether nonpolar solvents favor ring substitution. 

Preparation of Memfield resin-bound nitro acetates, which is a suitable bndding block for the development of combinatorial solid phase synthesis, is repotted. The anion of ethyl nitro acetate is generated in DMF by an electrochemical method using Pt cathode, magnesium rod anode, and tetrabutylairunonium bromide as an electrolyte. Alkylaton of this anion with alkyl hahdes gives mono-alkylated products in 80% yield." ... 

Two principle strategies have been employed for the synthesis of siloxide-containing molecular precursors. The first involves a silanolysis, or condensation, reaction of the Si - OH groups with a metal amido, alkyl, hahde, or alkoxide complex. The second method involves salt metathesis reactions of an alkali metal siloxide with a metal hahde. Much of our work has been focused on formation of tris(tert-butoxy)siloxide derivatives of the early transition metals and main group elements. The largely imexplored regions of the periodic table include the lanthanides and later transition metals. 

The direct allylation of radical precursors (e.g., alkyl hahdes, thioacyl derivatives) with allyltributylstannane in the presence of an initiator represents a well-established protocol for carbon-carbon bond formation [29,30]. This methodology provides a convenient means for introducing an allyl group to the anomeric carbon of carbohydrates [31]. hi their recent work on the preparation of building blocks for C-glycoside synthesis, Postema and coworkers... 

This reaction gives good results for a variety of activated and unactivated alkyl hahdes [112] Oxidation of 2-bromoketones with N-phenyltriflaimde was used in a one pot synthesis of pyrazmes by the sequence of reactions shown m equaUon 57 [113] The procedure was successfully applied to the synthesis of deoxyaspergillic acid [ I14 ... 

HASS-BENDER CartJonylSynthesis or ketone synthesis by reaction o( an alkyl haHde with the sodum salt of 2-nitroalkanss. 

The synthesis can be extended to the preparation of ketones in six distinct ways. " These include quenching 180 with a second alkyl halide (R X) rather than acetic acid omitting PPhs with first RX and then adding the second, R X treatment with RX in the presence of CO, followed by treatment with R X treatment with an acyl halide followed by treatment with an alkyl hahde or an epoxide, gives an a,p-unsaturated ketone. The final variations involve reaction of alkyl halides or tosylates with Na2Fe(CO)4 in the presence of ethylene to give alkyl ethyl ketones when 1,4-dihalides are used, five-mem-... 

One-pot malonic ester synthesis. A separate hydrolysis step can be avoided by use of the dilithium salt of ethyl malonate, prepared by reaction of the ester with 2 eq. of lithium isopropylcyclohexylamide (4, 306-309) in THE at -78° HMPT and the alkyl hahde are then added and the reaction mixture is allowed to come to room temperature for 2 hr. Decarboxylation is then effected by overnight reflux. 

The preparation of these salts is usually performed by a simple N-alkylation of 1-methylimidazole generating a l-alkyl-3-methylimidazolium cation followed by anion metathesis [27]. The synthesis can also start with imidazole, which is consecutively alkylated with alkyl hahdes (Scheme 3.5-9). The 1,3-dialkylimidazolium cations will be abbreviated throughout this section as [C Cylm], where Im stands for imidazolium and x and y are the number of the carbons of the alkyl chains. 

The Williamson ether synthesis is not a useful reaction with secondary alkyl hahdes. 

Aliphatic phosphonate synthesis from the reaction of alkyl hahdes with phosphites. 

A more efficient and more generahy applicable cobalt-catalysed Mizoroki-Heck-type reaction with aliphatic halides was elegantly developed by Oshima and coworkers. A catalytic system comprising C0CI2 (62), l,6-bis(diphenylphosphino)hexane (dpph 73)) and Mc3 SiCH2MgCl (74) allowed for intermolecular subshtution reactions of alkenes with primary, secondary and tertiary alkyl hahdes (Scheme 10.25) [51, 53]. The protocol was subsequently applied to a cobalt-catalysed synthesis of homocinnamyl alcohols starting from epoxides and styrene (2) [54]. 

Syntheses of amines using the Gabriel synthesis are, as we might expect, restricted to the use of methyl, primary, and secondary alkyl hahdes. The use of tertiary halides leads almost exclusively to eliminations. 

Hydroxyl groups of sugars can be converted to ethers using a base and an alkyl hahde by a version of the Williamson ether synthesis (Section 11.11B). 

Keto esters represent interesting substrates that permit ready and various opportunities for further stmctural manipulation, but until 2002 only limited asymmetric a-alkylation procedures were developed [85]. In 2002, Dehmlow et al. [86] demonstrated the use of cinchonidinium bromide Ic in asymmetric a-alkylation of p-ketoester 24 when the corresponding benzylated product 29 (Scheme 8.11, entry 1) was obtained in excellent yield (97%), satisfying 46% ee. Better results in terms of enantioselectivity (up to 97% ee) were reported by Kim and co-workers [87], who showed the effectiveness of bulky cinchonine-derived catalysts IL in asymmetric a-alkylation of P-ketoesters(Scheme 8.11, entry 2). An asymmetric a-alkylation procedure with broad generahty in terms of the stmcture of P-ketoesters 25 and alkyl hahdes under PTC with C2-symmetric PTC L was developed by Maruoka and co-workers [88] (Scheme 8.11, entry 3). Further optimization led to the development of a reliable route for the asymmetric synthesis of not only a,a-dialkyl-P-hydroxy and p-amino esters, but also functionalized aza-cyclic a-amino esters [89], a-alkylated ketolactones [90], and functionalized a-benzoyloxy-P-ketoesters [91]. Shghtly changed catalyst XXV (Scheme 8.12) was also successfully used for the constmction of enantiomerically enriched various a-alkyl-a-fluoro-P-keto esters... 

Ketone Synthesis. The monoalkylated MT-sulfone undergoes further alkylation by action of alkyl halide and NaH or n-BuLi to give a dialkylated product. Since the dialkylated product can be hydrolyzed easily, MT-sulfone has proven to be very useful for synthesizing ketones (eq 5). Symmetrical ketones are prepared by direct dialkylation with NaH and alkyl hahde in DMF and hydrolysis (eq 6). Cyclic ketones are also synthesized from a,a>-dihaloalkanes. An efficient synthesis of a-hydroxy ketones is also achieved by the addition of the monoalkyl derivative to an aldehyde to give an adduct and subsequent hydrolysis (eq 7). ... 

When simple primary alkyl halides are permitted to react with alkoxide anions, substitution of the alkoxide for the halide occurs or, alternatively, the alkyl group has been substituted for the hydrogen which was on oxygen. Variants of this reaction, the Williamson ether synthesis, have been seen before as a substitution reaction at carbon (of the alkyl hahde) and will be seen again as an addition reaction of alcohols. 

The acetoacetic ester synthesis is a useful technique that converts an alkyl hahde into a methyl ketone with the introduction of three new carbon atoms. 

Sulfonate esters are especially useful substrates in nucleophilic substitution reactions used in synthesis. They have a high level of reactivity, and, unlike alkyl hahdes, they can be prepared from alcohols by reactions that do not directly involve bonds to the carbon atom undergoing substitution. The latter aspect is particularly important in cases in which the stereochemical and structural integrity of the reactant must be maintained. Sulfonate esters are usually prepared by reaction of an alcohol with a sulfonyl halide in the presence of pyridine ... 

The most generally useful method of preparing ethers is by the Williamson ether synthesis, in which an alkoxide ion reacts with a primary alkyl hahde or tosylate in an Sn2 reaction. As we saw earlier in Section 13.2, the alkoxide ion is normally prepared hy reaction of an alcohol with a strong base such as sodium hydride, NaH. 

Because all the alkyl hahde formed from 1-pentene is the desired product, hut only half the alkyl halide formed from 2-pentene is the desired product, 1-pentene is the hest alkene to use for the synthesis. 

The phosphonium ylide needed for a particular synthesis is obtained by an 8 2 reaction between triphenylphosphine and an alkyl hahde with the appropriate number of carbons. A proton on the carbon adjacent to the positively charged phosphorus atom is sufficiently acidic (p Tg = 35) to be removed by a strong base such as butyllithium (Section 12.2). 

When synthesizing an alkene using a Wittig reaction, the first thing you must do is decide which part of the alkene should come from the carbonyl compound and which part should come from the ylide. If both sets of carbonyl compound and yhde are available, the better choice is the set that requires the less sterically hindered alkyl haUde for the synthesis of the ylide via an Sn2 reaction. (Recall that the more stericaUy hindered the alkyl hahde, the less reactive it is in an Sn2 reaction see Section 9.1.)... 

For the synthesis of 3-ethyl-3-hexene, for example, it is better to use a three-carbon alkyl hahde for the ylide and the five-carbon carbonyl compound than the five-carbon alkyl hahde for the ylide and the three-carbon carbonyl con touni because it is easier to form an yhde fi om a primary alkyl halide (1-bromopropane) than from a secondary alkyl hahde (3-bromopentane). 

Synthesis of Unsymmetrical Selenides. Bis(tiimethylsilyl) selenide reacts with equimolar amounts of n-hutyUithium to generate MesSiSeLi, alkylation of which then provides trimethylsi-lyl alkyl selenides. Similar treatment of Me3SiSeR with BuLi / R X successfully leads to unsymmetrical selenides in good yields (eq 5). Use of acid chlorides in place of alkyl hahdes results in the formation of selenoesters. 

Williamson ether synthesis (Section 18.2) A method for synthesizing ethers by Sn2 reaction of an alkyl hahde with an alk-oxide ion. 

The dehydrohalogenation of an alkyl hahde is a good laboratory method for the synthesis of alkenes because alkyl hahdes are readily available from reactions of several other starting materials. Considered by itself, this reaction has a very unfavorable eqmhbrium constant. However, if we use a strong base such as alkoxide anion to extract a proton on the carbon adjacent to the bromine, the reaction becomes highly favorable. 

Consider the following synthesis of the alkyl hahde shown below. 

Use of substituted alkyl hahdes (e.g., Br(CH2) COOR, I(CH2) C1) permits the preparation of linear and cyclic neutral, acidic and basic isotopically labeled a-amino acids of high enantiomeric purity, as demonstrated by the synthesis of e.p. (S)-[2,7- C2]-pipecolic acid, (5)-[2,6- C2]prohne and (5)-[l,2- C2]lysine in excellent yields. Alkylation of (2R)-[1,2- C2]190 with l-chloro-4-iodobutane followed by hydrolytic cleavage of the diphenyhnethylene group gave 2-amino-6-chlorohexanoyl sultam 201, which upon... 

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