Acyl chlorides enolization

Acyl chloride Enol form of acyl chloride... 

A number of other methods exist for the a halogenation of carboxylic acids or their derivatives. Acyl halides can be a brominated or chlorinated by use of NBS or NCS and HBr or HCl. The latter is an ionic, not a free-radical halogenation (see 14-2). Direct iodination of carboxylic acids has been achieved with I2—Cu acetate in HOAc. " ° Acyl chlorides can be a iodinated with I2 and a trace of HI. Carboxylic esters can be a halogenated by conversion to their enolate ions with lithium A-isopropylcyclohexylamide in THF and treatment of this solution at -78°C with... 

Disconnection of the 1,3-dlketone obviously comes next but it will be better to add an activating group to control the reaction. One possibility is to acylate specific enol equivalent (56) with acid chloride (57). 

In summary, reactions of nitronates with acid anhydrides or acyl chlorides give the O-acylated products, and reactions with acyl imidazoles, phenyl esters, acyl nitriles, and enol-lactones gives the C-acylated products, (see Eq. 5.13).25 The C/O selectivity of nitronate acylation by RCOX is qualitatively correlated with strength (pKJ of the acid HX conjugated to the leaving group X .25... 

Acylated product 25 can be obtained by reacting the enolate of 24 with acyl chloride. Interestingly, syn- or anti-26 can be obtained upon treating the acylated enolate 25 with Zn(BH4)2 and KBEt3H, respectively (Scheme 3-11 and... 

Reactions of titanocene-methylidene generated from titanacyclobutanes with acyl chlorides 55 [46] or acid anhydrides 56 [47] lead initially to the titanium enolates 57 (Scheme 14.24), which then afford aldols upon treatment with the carbonyl compounds. On the other hand, five-membered cyclic anhydrides are methylenated with dimethyltitanocene (Table 14.5, entry 7) [45]. 

Scheme 14.24. Formation of titanium enolates by the reaction of titanacyclobutanes with acyl chlorides or acid anhyd rides.

An interesting bifunctional system with a combination of In(OTf)3 and benzoyl-quinine 65 was developed in p-lactam formation reaction from ketenes and an imino ester by Lectka [Eq. (13.40)]. High diastrereo- and enantioselectivity as well as high chemical yield were produced with the bifunctional catalysis. In the absence of the Lewis acid, polymerization of the acid chloride and imino ester occurred, and product yield was moderate. It was proposed that quinine activates ketenes (generated from acyl chloride in the presence of proton sponge) as a nucleophile to generate an enolate, while indium activates the imino ester, which favors the desired addition reaction (66) ... 

Another important part of Organic 11 is carbonyl chemistry. We look at the basics of the carbonyls in Chapter 9. It s like a family reunion where 1 (John, one of your authors) grew up in North Carolina — everybody is related. You meet aldehydes, ketones, carboxylic acids, acyl chlorides, esters, cimides, and on and on. It s a quick peek, because later we go back and examine many of these in detail. For example, in Chapter 10 you study aldehydes and ketones, along with some of the amines, while in Chapter 11 we introduce you to other carbonyl compounds, enols and enolates, along with nitroalkanes and nitriles. 

Acylation of ester enolates can also be carried out with more reactive acylating agents such as acid anhydrides and acyl chlorides. These reactions must be done in inert solvents to avoid solvolysis of the acylating agent. The preparation of diethyl benzoylmalonate (entry 1 in Scheme 2.14) is an example employing an acid anhydride. Entries 2-5 illustrate the use of acyl chlorides. Acylations with these more reactive compounds can be complicated by competing O-acylation. /V-Mcthoxy-iV-methylamidcs are also useful for acylation of ester enolates. 

Magnesium enolates play an important role in C-acylation reactions. The magnesium enolate of diethyl malonate, for example, can be prepared by reaction with magnesium metal in ethanol. It is soluble in ether and undergoes C-acylation by acid anhydrides and acyl chlorides (entries 1 and 3 in Scheme 2.14). Monoalkyl esters of malonic acid react with Grignard reagents to give a chelated enolate of the malonate monoanion. 

The HC1 generated in this reaction destroys one equivalent of diazomethane. This can be avoided by including a base, such as triethylamine, to neutralize the acid.74 Cyclic z-diazoketones, which are not available from acyl chlorides, can be prepared by reaction of an enolate equivalent with a sulfonyl azide. This reaction is called diazo transfer 5 Various arenesulfonyl azides76 and methanesulfonyl azide77 are used most frequently. Several types of compounds can act as the carbon nucleophile. These include the anion of the hydroxymethylene derivative of the ketone78 or the dialkylaminomethylene derivative of... 

An unexpected reactivity in the functionalization of 2-acyl-l,3-dithianes has been reported by Mioskowski and co-workers. They found that 2-acyl-l,3-dithianes with no further heteroatom at the acyl side chain react with aldehydes to give 2-acyl-2-hydroxyalkyl-l,3-dithianes, whereas a silyl-protected hydroxy group in the side chain of the 2-acyl-l,3-dithiane led to formation of the aldol product at the opposite site of the carbonyl group. Acyl chlorides always react with 2-acyl-l,3-dithianes to give the enol esters (Scheme 81) <2003TL213>. 

Use of I was explored in a study of the reaction of enolates with acyl chlorides as a route to 1,3-diketones (equation I). 

Picard has reported more direct approaches to acyl silanes and to their silyl enol ethers by reductive silylation of substituted benzoates and of w./i-dihalo-a, /Tunsaturated acyl chlorides, respectively, using a similar reagent mixture of trimethylchlorosilane, magnesium and IIMPA96. 

Another important issue of this reaction is the variable stereochemical outcome obtained depending upon the solvent used, the temperature, and the sequence of addition of the reactants. These aspects have been carefully studied experimentally by Xu et al. [71-73] in a brilliant series of papers. In particular, since one method for the generation of ketenes consists of the reaction between acyl chlorides (12) and bases (usually tertiary bases such as triethylamine), the direct reaction between compounds (12) with imines (66) was investigated at the B3LYP/6-31G level of theory [52], Under these conditions, it was calculated that formation trans-fi-lactams (70) from enolates (69) is preferred, in agreement with the experimental results [74—76] and with the careful analysis of Xu et al. [72] (Scheme 16). 

Acyliron complexes have found many applications in organic synthesis [40]. Usually they are prepared by acylation of [CpFe(CO)2] with acyl chlorides or mixed anhydrides (Scheme 1.13). This procedure affords alkyl, aryl and a,P-unsaturated acyliron complexes. Alternatively, acyliron complexes can be obtained by treatment of [Fe(C5Me5)(CO)4]+ with organolithium reagents, a,P-Unsaturated acyliron complexes can be obtained by reaction of the same reagent with 2-alkyn-l-ols. Deprotonation of acyliron complexes with butyllithium generates the corresponding enolates, which can be functionalized by reaction with various electrophiles [40]. 

So what is new here We can save time, materials and effort if we combine two reactions in one operation. These tandem processes, as they are called, avoid the isolation of potentially difficult intermediates and may avoid the need for control over reactions in chapter 19 we discussed the need for control in the acylation of enolates. Workers at Merck1 combined the difficult acylation of enolates 7 by acid chlorides with the capture of the intermediates 9 by hydrazine to give stable pyrroles 10. This is a summary of their method ... 

Azetines 575, synthesized by the reaction of IV-acyl thiazolidinethione enolates with enolizable aldoxime ethers, have been successfully converted into the corresponding iV-acyl-substituted /3-aminocarbonyl compounds 576 by simple exposure to benzoyl chloride <2003JA3690>. The reactions presumably involved an acyliminium salt 577, which hydrolyzed to yield 576 (Scheme 74). 

The mechanism of this three-component coupling reaction is probably analogous to the aforementioned insertion of acyl chlorides (above). One can imagine assembling an intermediate acylpalladium species either by oxidative addition to an acyl chloride or, in this case, by oxidative addition to the aromatic iodide followed by migratory insertion into carbon monoxide. Once formed, the acylpalladium intermediate can insert into the SCB to furnish a 7-(chlorosilyl)propyl ketone, which cyclizes in the presence of the amine to afford cyclic enol ethers. 

Chlorovinylaldehydes (22) and /3-chlorovinylketones (23) may be regarded as the acyl chlorides derived from the enol forms of 3-ketoalde-hydes and 1,3-diketones. 

Because of the contribution of structures such as the one on the right to the resonance hybrid, the a-carbon of an enamine is nucleophilic. However, an enamine is a much weaker nucleophile than an enolate anion. For it to react in the SN2 reaction, the alkyl halide electrophile must be very reactive (see Table 8.1). An enamine can also be used as a nucleophile in substitution reactions with acyl chlorides. The reactive electrophiles commonly used in reactions with enamines are ... 

Silyl enolates react with acyl cation equivalents to give the C- and/or O-acylated products (Equation (90)).333 Fluoride-catalyzed reaction using acyl fluorides is valuable for O-acylation of silyl enolates derived from aldehydes and ketones.334 CuCl also promotes the 0-acylation with acyl chlorides.335 The CuCl-promoted reaction of ester silyl enolates results in exclusive (7-acylation. Combined use of BiCfl and Znl2 (or Nal) effects catalytic (7-acylation of ketone silyl enolates with acyl chlorides. 

In the enolate, the oxygen atom has more of the negative charge, but the carbon atom has more of the HOMO. One important consequence is that we can expect reactions dominated by charges and electrostatic interactions to occur on oxygen and reactions dominated by orbital interactions to occur on carbon. Thus acyl chlorides tend to react at oxygen to give enol esters, while alkyl halides tend to react at carbon. 

The carbonyl group is accepting electrons both in the enolization step and in the nucleophilic attack. The same compounds that are the most electrophilic are also the most easily enolizable. This makes acyl chlorides very enolizable. To avoid q... 

The formation of the acyl chloride with SOCl2 and the conversion of the a-bromoacyl chloride into the bromoester with MeOH are simple nucleophilic substitutions at the carbonyl group, just like the synthesis of esters from acyl chlorides in Chapter 12. The intermediate stage, the bromination of the very easily enolized acyl chloride, is a typical enol bromination. 

We established in Chapter 12 a hierarchy for the electrophilic reactivity of acid derivatives that should by now be very familiar to you—acyl chlorides at the top to amides at the bottom. But what about the reactivity of these same derivatives towards enolization at the a position, that is, the CH2 group between R and the carbonyl group in the various structures You might by now be able to work this out. The principle is based on the mechanisms for the two processes, mechanism of nucleophilic attack mechanism of enolate formation... 

We have spent some considerable time and effort in understanding the aldol reaction simply because it is one of the most important reactions in organic chemistry. In the next chapter you will see how these ideas can be extended with almost no addition of principles to the acylation of enolates—the reaction of enols, enolates, and specific enol equivalents with acid chlorides and esters. We hope that you will see that the ideas introduced in this chapter find immediate application in the next. 

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