Acyl chloride intermediates

Mitotane, or o,p -DDD, is an oral medication used in the treatment of adrenocortical carcinoma. Chemically it is an isomere of DDT. Following its metabolism in the adrenal cortex to a reactive acyl chloride intermediate, mitotane covalently binds to adrenal proteins, specitically inhibiting adrenal cortical hormone production. The drug accumulates in fat tissue. It is eliminated mainly by the kidneys with a half-life of 18-159 days. Common side effects include anorexia, nausea, lethargy, sleepiness and skin problems. 

Metabolism of DDT proceeds at a very slow rate. Liver microsomal P450 and other microsomal enzymes initially dechlorinate DDT to l,l-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) and reduce to 1,1 -dichloro-2,2-bis(p-chlorophenyl)ethane (DDD). The conversion of DDD to bis(p-chlorophenyl)acetic acid (DDA) involves the formation of an acyl chloride intermediate by hydroxylation followed by hydrolysis to yield the final product. 

Three different mechanisms have been proposed [1] for the Fries rearrangement with AICI3 (i) an intramolecular mechanism with a direct acyl shift from the oxygen atom to a carbon atom of the ring (ii) a monomolecular deacylation-acylation mechanism with an acyl chloride intermediate and (iii) an intermolecular mechanism (transacylation). 

In these cases the acyl azides formed have been used to prepare amines via Curtius rearrangement. The acyl chloride or azide intermediates can. however, also be reacted with amines or alcohols to form amides or esters. 

Acyi halides are reactive compounds and react with nucleophiles without a catalyst, but they are activated further by forming the acylpalladium intermediates, which undergo insertion and further transformations. The decarbonyla-tive reaction of acyl chlorides as pseudo-halides to form the aryipalladium is treated in Section 1,1.1.1. The reaction without decarbonylation is treated in this section. 

Acyl halides are intermediates of the carbonylations of alkenes and organic-halides. Decarbonylation of acyl halides as a reversible process of the carbo-nylation is possible with Pd catalyst. The decarbonylation of aliphatic acid chlorides proceeds with Pd(0) catalyst, such as Pd on carbon or PdC, at around 200 °C[109,753]. The product is a mixture of isomeric internal alkenes. For example, when decanoyl chloride is heated with PdCF at 200 C in a distillation flask, rapid evolution of CO and HCl stops after I h, during which time a mixture of nonene isomers was distilled off in a high yield. The decarbonylation of phenylpropionyl chloride (883) affords styrene (53%). In addition, l,5-diphenyl-l-penten-3-one (884) is obtained as a byproduct (10%). formed by the insertion of styrene into the acyl chloride. Formation of the latter supports the formation of acylpalladium species as an intermediate of the decarbonylation. Decarbonylation of the benzoyl chloride 885 can be carried out in good yields at 360 with Pd on carbon as a catalyst, yielding the aryl chloride 886[754]. 

Ketones can be prepared by trapping (transmetallation) the acyl palladium intermediate 402 with organometallic reagents. The allylic chloride 400 is car-bonylated to give the mixed diallylic ketone 403 in the presence of allyltri-butylstannane (401) in moderate yields[256]. Alkenyl- and arylstannanes are also used for ketone synthesis from allylic chlorides[257,258]. Total syntheses of dendrolasin (404)f258] and manoalide[259] have been carried out employing this reaction. Similarly, formation of the ketone 406 takes place with the alkylzinc reagent 405[260],... 

FIGURE 20 2 Hydrolysis of an acyl chloride proceeds by way of a tetrahedral intermediate For mationofthe tetrahedral intermediate is rate determining... 

The sp hybridized carbon of an acyl chloride is less sterically hindered than the sp hybridized carbon of an alkyl chloride making an acyl chloride more open toward nude ophilic attack Also unlike the 8 2 transition state or a carbocation intermediate m an Stvfl reaction the tetrahedral intermediate m nucleophilic acyl substitution has a stable arrangement of bonds and can be formed via a lower energy transition state... 

There are large differences in reactivity among the various carboxylic acid derivatives, such as amides, esters, and acyl chlorides. One important factor is the resonance stabilization provided by the heteroatom. This decreases in the order N > O > Cl. Electron donation reduces the electrophilicity of the carbonyl group, and the corresponding stabilization is lost in the tetrahedral intermediate. 

There are alternatives to the addition-elimination mechanism for nucleophilic substitution of acyl chlorides. Certain acyl chlorides are known to react with alcohols by a dissociative mechanism in which acylium ions are intermediates. This mechanism is observed with aroyl halides having electron-releasing substituents. Other acyl halides show reactivity indicative of mixed or borderline mechanisms. The existence of the SnI-like dissociative mechanism reflects the relative stability of acylium ions. 

The characteristic reaction of acyl chlorides, acid anhydrides, esters, and amides is nucleophilic acyl substitution. Addition of a nucleophilic reagent Nu—H to the carbonyl group leads to a tetrahedral intermediate that dissociates to give the product of substitution ... 

The Rosenmund reduction is usually applied for the conversion of a carboxylic acid into the corresponding aldehyde via the acyl chloride. Alternatively a carboxylic acid may be reduced with lithium aluminum hydride to the alcohol, which in turn may then be oxidized to the aldehyde. Both routes require the preparation of an intermediate product and each route may have its advantages over the other, depending on substrate structure. 

Hydrazides (RCONHNH2) are highly useful starting materials and intermediates in the synthesis of heterocyclic molecules.2 They can be synthesized by hydrazinolysis of amides, esters and thioesters.3 The reaction of hydrazine with acyl chlorides or anhydrides is also well known,4 but it is complicated by the formation of 1,2-diacylhydrazines, and often requires the use of anhydrous hydrazine which presents a high thermal hazard. Diacylation products predominate when hydrazine reacts with low molecular weight aliphatic acyl chlorides, which makes the reaction impractical for preparatory purposes.5... 

There are some problems associated with the use of functional derivatives of carboxylic acids. Long-chain acid anhydrides are not commercially available, and one half of the acylation reagent is not utilized. Acyl chlorides require the use of tertiary base catalysts, whose double role has been explained before. Some of the intermediate acyl ammonium compounds formed are, however, insoluble in the solvent system. Examples include RCO - N+EtsCL in LiCl/DMAc, where RCO refers to the propionyl, hexanoyl, and stearoyl moiety, respectively. Hexanoyl- and stearoyl-pyridinium chlorides are also insoluble in the same solvent system [185]. 

Previous syntheses An example of this point can be recognized by examination of one known synthesis of thienobenzazepines (Scheme 6.1). This synthetic route involves a key palladinm-catalyzed cross-conpling of stannyl intermediate 3, prepared by method of Gronowitz et al., with 2-nitrobenzyl bromide. Acetal deprotection and reductive cyclization afforded the desired thienobenzazepine tricycle 4. In support of structure activity relationship studies, this intermediate was conveniently acylated with varions acyl chlorides to yield several biologically active componnds of structure type 5. While this synthetic approach does access intermediate 4 in relatively few synthetic transformations for stractnre activity relationship studies, this route is seemingly nnattractive for preparative scale requiring stoichiometric amounts of potentially toxic metals that are generally difficult to remove and present costly purification problems at the end of the synthesis. 

This reagent combination also converts carboxylic acids to acyl chlorides (see Section 3.4.1). The mechanistic basis for the special effectiveness of benzotriazole has not yet been determined, but it seems likely that nucleophilic catalysis is involved. Sulfinyl ester intermediates may be involved, because Z-2-butene-l,4-diol gives a cyclic sulfite ester with one equivalent of reagent but the dichloride with two equivalents. 

The intermediate adduct can be substituted at the a-position by a variety of electrophiles, including acyl chlorides, epoxides, aldehydes, and ketones.79... 

A somewhat different scheme is used to gain entry to the alternate symmetrical 1,3,4-thiadiazole ring system. Reaction of thiosemicarbazide with isovaleric acid affords the ring system (217) in one step. The reaction may be rationalized by positing acylation to intermediate 216 as the first step. Sulfonylation of the amino group of 217 with p-methoxybenzenesulfonyl chloride affords the oral... 

Bergman and co-worker reported the two-step cyclocondensation beginning with aminoamide 131 and acyl chlorides 132 to fotm diamide intermediates 133, which cyclized upon treatment with sodium hydroxide to give quinazolin-4-ones 134 <00T7245>. 

Less nucleophilic amines are readily incorporated into these cascades if PdCy precatalysts and acyl chlorides are employed. Typical examples are shown in Fig. 8. In these cases, the intermediate amide can be isolated. 

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