Acylation of Carbon Nucleophiles

The reactions that are discussed in this section involve addition of carbon nucleophiles to carbonyl centers having a potential leaving group. The tetrahedral intermediate formed in the addition step reacts by expulsion of the leaving group. The overall 

The reaction pattern can be used for the synthesis of 1,3-dicarbonyl compounds and other systems in which an acyl group is (3 to an anion-stabilizing group. 

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One route to o-nitrobenzyl ketones is by acylation of carbon nucleophiles by o-nitrophenylacetyl chloride. This reaction has been applied to such nucleophiles as diethyl malonatc[l], methyl acetoacetate[2], Meldrum s acid[3] and enamines[4]. The procedure given below for ethyl indole-2-acetate is a good example of this methodology. Acylation of u-nitrobenzyl anions, as illustrated by the reaction with diethyl oxalate in the classic Reissert procedure for preparing indolc-2-carboxylate esters[5], is another route to o-nitrobenzyl ketones. The o-nitrophenyl enamines generated in the first step of the Leimgruber-Batcho synthesis (see Section 2.1) are also potential substrates for C-acylation[6,7], Deformylation and reduction leads to 2-sub-stituted indoles. 

Acylation of carbon nucleophiles can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must... 

In chapter 10 we compared C-C disconnections with related two-group C-X disconnections, mainly at the alcohol oxidation level. In this chapter we deal more fully with carbonyl compounds, chiefly aldehydes and ketones, by two related disconnections. We start by comparing the acylation of heteroatoms by acid derivatives such as esters (a 1,1-diX disconnection 1 that can also be described as a one-group C-X disconnection) with the acylation of carbon nucleophiles and move on to compare the 1,2-diX disconnection 3 with the alkylation of enolates 6. Here we have reversed the polarity. We mention regioselectivity—a theme we shall develop in chapter 14. 

Nucleophilic substitution at an alkyl carbon is said to alkylate the nucleophile. For example, the above reaction between RI and NMe3 is an alkylation of tri-methylamine. Similarly, nucleophilic substitution at an acyl carbon is an acylation of the nucleophile. 

The asymmetric Mannich addition of carbon nucleophiles to imines catalyzed by the cyclohexane-diamine catalysts has developed significantly in the past decade. List and co-workers reported the asymmetric acyl-cyanantion of imines catalyzed by a cyclohexane-diamine catalyst [103], Using a derivative of Jacobsen s chiral urea catalyst, the authors optimized reaction conditions and obtained chiral iV-acyl-aminonitriles in high yield and enantioselectivities (Scheme 51). The scope of the reaction was explored with both aliphatic and aromatic imines, providing good to high selectivities for a variety of substrates. 

The range of carbon nucleophiles that have been successfully employed for 1,4-addition to -a,/i-unsaturated iron-acyl complexes is limited to simple alkyl- and aryllithium species. Grignard reagents and the 1,3-propanedioate anion are reported to fail to react with. E-complexes36. The effect of varying the phosphane ligand has been examined little effect upon... 

Figure 6.50 displays acylations of C nucleophiles with NMe(OMe) derivatives of carbonic instead of carboxylic acids. The discussion of acylation reactions with NMe(OMe) derivatives of carboxylic acids ( Weinreb amides ) in Figures 6.42 and 6.44 revealed that the NMe(OMe) group has two effects first, it increases the reactivity and second, it is responsible for the occurrence of clean acylations. Against this background we will leave you to your own studies of a picture without words, namely Figure 6.50. Convince yourself that the approaches A —4 C, D —> C and E —> C to Weinreb amides outlined in this figure work and find out why alternative ketone syntheses D —> H and E —> H are also possible ...

The Weinreb amides 40 are particularly efficient in acylating reactive carbon nucleophiles.18 An alkyl-lithium adds to form the chelated lithium derivative 41 which decomposes on work-up to give the ketone 42. Compounds 60 and 63 in chapter 5 are examples of Weinreb amides. 

Acetic anhydride and aluminum chloride in carbon disulfide gives a high yield of the para-acylated product with thioanisole,93 and in dichloromethane the same reagents give an almost quantitative yield of 3-acetyl-1-benzenesulfonylindole.94 Acylation of more nucleophilic heterocycles can be achieved using milder catalysts, such as zinc chloride. It has been known for some time that furan can be acylated very efficiently using acetic anhydride and zinc chloride. The Paal-Knorr furan synthesis (1,4-diketone, acetic anhydride and zinc chloride) can sometimes result in acylation as well as cyclization (equation 40).95 Equations (41) and (42) further exemplify the acylation of furan derivatives that have been used in the synthesis of cytotoxic furanonaphthoquinones. 

Seyferth and co-workers reported the nucleophilic acylation of carbon electrophiles such as aldehydes [13a],ketones [13a,b],esters[13a,b],lactones [13c], and trialkylchlorosilanes [13d] with acyl- and aroyllithiums generated in situ from the RLi/CO system at very low temperatures (-110 °C to -135 °C). They have also applied this system to the acylation of disulfides, as shown in Eq.8 [14]. 

The alkylation of carbon nucleophiles by SN2-type processes is an important transformation in the synthesis of organic compounds. The generation and alkylation of such nucleophiles are described in this chapter. Alkylation and acylation of nucleophilic carbon species by other mechanisms are discussed in Chapter 2. 

Additions of carbon nucleophiles to carbonyl compounds constitute a complementary strategy to the preceding one. Acylations of organometallie reagents with amino-acid derivatives had previously been reported as a method of amino-ketone synthesis. However, it was found that the stereochemistry of tertiary carbinol centres... 

The reaction of carbon nucleophiles with ketones or aldehydes proceeds by acyl addition, as described in Chapter 18. The reaction of carbon nucleophiles with acid derivatives proceeds by acyl substitution, as described in Chapter 20. Carbon nucleophiles included cyanide, alkyne anions, Grignard reagents, organolithium reagents, and organocuprates. Alkyne anions are formed by an acid-base reaction with terminal alkynes (RC=C-H RCsCr). In this latter transformation, it is clear that formation of the alkyne anion relies on the fact that a terminal alkyne is a weak carbon acid. Other carbon acids specifically involve the proton on an a-carbon in aldehydes, ketones, or esters. With a siiitable base, these carbonyl compounds generate a new type of carbon nucleophile called an enolate anion. 

In this section, we examine nucleophilic acyl addition reactions of aldehydes and ketones with the following types of carbon nucleophiles. 

The growing number of chiral amines found in molecules of pharmacological interest is mirrored by an increasing need for efficient methods to achieve their synthesis [87, 162]. Significant developments involving the use of a variety of chiral catalysts for enantioselective additions of carbon nucleophiles to C=N bonds have been reported in recent years [20, 21, 23, 35). An important case study was reported by a group at Merck, who developed an enantioselective addition of lithium acetylides to the cyclic N-acyl imine 244 in the presence of a stoichiometric amount of quinine (246) as a chiral additive (Scheme 11.34) [163]. Careful optimization of the reaction conditions and the imine N-substituent allowed for the development of an addition process that gives adduct 247 in 97 % ee. This key intermediate was subsequently deprotected to provide a kilo-scale asymmetric synthesis of the HIV reverse transcriptase inhibitor 249. 

Nucleophilic acyl substitution (Sections 20 4 20 6 and 20 12) Acylation of am monia and amines by an acyl chloride acid anhydride or ester is an excep tionally effective method for the for mation of carbon-nitrogen bonds... 

The reaction of tnfluoromethyl-substituted A -acyl umnes toward nucleophiles in many aspects parallels that of the parent polyfluoro ketones Heteronucleophiles and carbon nucleophiles, such as enarmnes [37, 38], enol ethers [38, 39, 40], hydrogen cyanide [34], tnmethylsilylcarbomlnle [2,47], alkynes [42], electron-nch heterocycles [43], 1,3-dicarbonyl compounds [44], organolithium compounds [45, 46, 47, 48], and Gngnard compounds [49,50], readily undergo hydroxyalkylation with hexafluoroace-tone and amidoalkylation with acyl imines denved from hexafluoroacetone... 

The reaction of tnfluoropymvates or their acyl imines with carbon nucleophiles offers a convenient route to a-tnfluornmethyl substituted a-hydroxy or a-ammn acids Reduction of the keto or immo function yields 3,3,3-tnfluorolac-tates or 3,3,3-tnfluoroaIanine esters [32]. 

When a Br nsted base functions catalytically by sharing an electron pair with a proton, it is acting as a general base catalyst, but when it shares the electron with an atom other than the proton it is (by definition) acting as a nucleophile. This other atom (electrophilic site) is usually carbon, but in organic chemistry it might also be, for example, phosphorus or silicon, whereas in inorganic chemistry it could be the central metal ion in a coordination complex. Here we consider nucleophilic reactions at unsaturated carbon, primarily at carbonyl carbon. Nucleophilic reactions of carboxylic acid derivatives have been well studied. These acyl transfer reactions can be represented by... 

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