Acyl chlorides adducts

Carboxylic acids can be converted to acyl chlorides and bromides by a combination of triphenylphosphine and a halogen source. Triphenylphosphine and carbon tetrachloride convert acids to the corresponding acyl chloride.100 Similarly, carboxylic acids react with the triphenyl phosphine-bromine adduct to give acyl bromides.101 Triphenviphosphine-iV-hromosuccinimide also generates acyl bromide in situ.102 All these reactions involve acyloxyphosphonium ions and are mechanistically analogous to the alcohol-to-halide conversions that are discussed in Section 3.1.2. 

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

Isoquinoline alkaloids. The regioselective allylation of N-acyl heterocycles (13, 10) can be used for synthesis of isoquinoline alkaloids. Thus simultaneous reaction of the dihydroisoquinoline (1) with a diunsaturated acyl chloride (2) and allyltributyltin affords the 1,2-adduct (3), which undergoes a Diels-Alder cyclization... 

Cleavage of the oxirane C-0 bond produces a zwitterionic intermediate (Fig. 10.22), which that can undergo chloride shift (Pathway a) to 2,2-dich-loroacetyl chloride (10.90) followed by hydrolysis to 2,2-dichloroacetic acid (10.91). Furthermore, the zwitterionic intermediate reacts with H20 or H30+ (Pathway b) by pH-independent or a H30+-dependent hydrolysis, respectively. The pH-independent pathway only is shown in Fig. 10.22, Pathway b, but the mechanism of the H30+-dependent hydrolysis is comparable. Hydration and loss of Cl, thus, leads to glyoxylyl chloride (10.92), a reactive acyl chloride that is detoxified by H20 to glyoxylic acid (10.93), breaks down to formic acid and carbon monoxide, or reacts with lysine residues to form adducts with proteins and cytochrome P450 [157], There is also evidence for reaction with phosphatidylethanolamine in the membrane. 

The use of ethylene adduct lb is particularly important when the species added to activate catalyst la is incompatible with one of the reaction components. Iridium-catalyzed monoallylation of ammonia requires high concentrations of ammonia, but these conditions are not compatible with the additive [Ir(COD)Cl]2 because this complex reacts with ammonia [102]. Thus, a reaction between ammonia and ethyl ciimamyl carbonate catalyzed by ethylene adduct lb produces the monoallylation product in higher yield than the same reaction catalyzed by la and [Ir(COD)Cl]2 (Scheme 27). Ammonia reacts with a range of allylic carbonates in the presence of lb to form branched primary allylic amines in good yield and high enantioselectivity (Scheme 28). Quenching these reactions with acyl chlorides or anhydrides leads to a one-pot synthesis of branched allylic amides that are not yet directly accessible by metal-catalyzed allylation of amides. 

This method is very useful for the construction of 1-substituted 3,4-dihydroisoquinolines, which if necessary can be oxidized to isoquinolines. A P-phenylethylamine (l-amino-2-phenylethane) is the starting material, and this is usually preformed by reacting an aromatic aldehyde with nitromethane in the presence of sodium methoxide, and allowing the adduct to eliminate methanol and give a P-nitrostyrene (l-nitro-2-phenylethene) (Scheme 3.17). This product is then reduced to the p-phenylethylamine, commonly by the action of lithium aluminium hydride. Once prepared, the p-phenylethylamine is reacted with an acyl chloride and a base to give the corresponding amide (R = H) and then this is cyclized to a 3,4-dihydro-isoquinoline by treatment with either phosphorus pentoxide or phosphorus oxychloride (Scheme 3.18). Finally, aromatization is accomplished by heating the 3,4-dihydroisoquinoline over palladium on charcoal. 

Malonyl chloride reacted with boiling acetone to give the bicyclic 2 1 adduct 210 comprising a pyranone and a l,3-dioxan-4-one moiety (Scheme 99). The modest yield was compensated for by the ease of its preparation. Compound 210 bears a chloride which is almost as reactive as an acyl chloride and which can be substituted by various nucleophiles in a Stille coupling in modest yields <1997SL895>. Treatment of malonyl chloride with ketene and acetone at low temperature afforded symmetric bis(l,3-dioxin-4-ones) in 60% yield although a different reaction pathway may be assumed (Scheme 99) <2000TL4959>. 

Aziridines can add to carbon—carbon multiple bonds. Elevated temperature and alkali metal catalysis are required in the case of nonpolarized double bonds (193—195). On the other hand, the addition of aziridines onto the conjugated polarized double or triple bonds of a,p-unsaturated nitriles (196—199), ketones (197,200), esters (201—205), amides (197), sulfones (206—209), or quinones (210—212) in a Michael addition-type reaction frequendy proceeds even at room temperature without a catalyst. The adducts obtained from the reaction of aziridines with a,p-unsaturated ketones, eg, 4-aziridinyl-2-butanone [503-12-8] from 3-buten-2-one, can be converted to 1,3-substituted pyrrolidines by subsequent ring opening with acyl chlorides and alkaline cyclization (213). 

However, in the presence of a catalytic amount of tris(dimethylamino)sulfonium difluorotrimethylsilicate ( TASF ), pivaldehyde imine yields the N-unsubstituted adduct, whereas acetone imine leads to the corresponding BSMA amides accompanied with the addition product of THF to DMAD. Formation of amides might be explained by the loss of HC1 from the iminium resulting from condensation of acyl chloride with imine, leading to a vinyl amide which is easily hydrolyzed. No explanation was presented for the formation of the THF adduct.241... 

Condensation of an MSMA isonitrile with an aroylfluoride gives a salt which undergoes loss of trimethylsilyl fluoride to form a nitrile ylid. This transient species reacts with DMAD to form 2-aroyl pyrrole in high yield.162 Substitution of acyl chloride for acyl fluoride in the reaction affords only poor yields of adducts.465... 

Chloramphenicol and secobarbital exhibit properties similar to those of tienilic acid, but they have not been studied in humans (11). Oxidative dechlorination of chloramphenicol with formation of reactive acyl chlorides appears to be an important metabolic pathway for irreversible inhibition of CYP. Chloramphenicol binds to CYP, and subsequent substrate hydroxylation and product release are not impaired. The inhibition of CYP oxidation and the inhibition of endogenous NADPH oxidase activity suggest that some modification of the CYP has taken place, which inhibits its ability to accept electrons from the CYP reductase (11). Secobarbital completely inactivates rat CYP2B1 functionally, with partial loss of the heme chromophore. Isolation of the N-alkylated secobarbital heme adduct and the modified CYP2B1 protein revealed that the metabolite partitioned between heme N-alkylation, CYP2B1 protein modification, and epoxidation. A small fraction of the prosthetic heme modifies the protein and contributes to the CYP2B1 inactivation (12). 

Dechlorination of 4-chloro-6-methylthieno[2,3-d]pyrimidine 164 with zinc in ethanol and acetic acid at 80°C gave compound 165. The latter was subjected to the Reissert reaction using two equivalents each of tributyltin cyanide and acyl chloride in dichloromethane at room temperature. With benzoyl chloride the mono-Reissert adduct 166 was obtained, whereas with acetyl chloride the di-Reissert product 167 (86JHC545). 

Reaction of 1 with 2,4,6-tri-t-butylbenzoyl chloride formed a 2,3-diphosphabuta-l,3-diene as well as a phosphaethyne (equation 5)20. An amino-substituted phosphaethyne was prepared starting from 1 and isopropyl isocyanate by an addition-elimination-silatropy reaction (equation 6)21. Addition of 1 to kinetically stabilized phosphaketene (see Section HI) gave a 1 1 adduct22 or a 1 2 adduct23 the former was converted to 1,3-diphospha-buta-1,3-dienes by treatment with acyl chlorides (equation 7)22. Both adducts could be converted to the same 1,2,4-triphosphabuta-l,3-diene23,24. 

The route described by Hoffmann-La Roche scientists in 1995 was designed to make use of the drug substance 5-DFCR (10) to prepare capecitabine in a few steps without multiple protection/deprotection transformations.19 In this process, 5 -deoxy-5-fluorocytodine (10)24 27 was added to three equivalents of -pentyl chloroformate and pyridine in methylene chloride while maintaining an internal temperature below -5 °C, ultimately providing the tris-acylated cytodine adduct 26 in a 92% isolated yield. Removal of the two ester functional groups by selective hydrolysis with aqueous sodium hydroxide in methanol at -10 °C for a short time followed by adjustment to pH5 with concentrated HCI provided the crude carbamate 1 in quantitative yield. Purification of... 

In a short known reaction sequence, enal 250 was obtained from commercially available material 184). With methylamine and magnesium sulfate imine 251 was formed and combined with acyl chloride 252 185) (>4 steps). The use of low temperatures for this acylation led exclusively to the less substituted dienamide 253. The desired basic skeleton of dendrobine 254 was obtained by cyclizing 253 at 180°C in an acceptable 50% yield, Adduct 254 was accompanied by small amounts of the exo-adduct. Epoxidation led exclusively to exo-epoxide 255, which by means of trimethylsilyltriflate was converted into the allylic silyl ether. Acid treatment liberated the hydroxy group and subsequent oxidation of alcohol 256 led to enone 163, an intermediate of Inubushi s dendrobine synthesis and thus concluded this formal synthesis. The intermediate 163 was obtained from commercially not available materials in seven steps in 22.5% overall yield. To reach ( )-dendrobine according to Inubushi et al. would afford six additional steps, reducing the overall yield to 0.4% without including the preparation of the starting materials from commercially available compounds. 

In 1996 the Kurth group described the first sold-phase Reissert reaction (Scheme 5) [42, 43]. Activation of a carboxylic acid functionalized resin to the corresponding acyl chloride, followed by treatment with isoquinoline and TMS-CN (14) afforded the resin-linked Reissert adduct 16. This intermediate was subsequently alkylated at the a-position by treatment with LDA and alkyl iodides 17. Some of these adducts were further manipulated, and finally the substituted isoquinolines 20 were conveniently released using a traceless cleavage with KOH/THF. 

The enantiopure 1-oxa-1,3-diene 278 is prepared by acylation of benzyl vinyl ether with oxalyl chloride. This generates acyl chloride 276, which acylates the lithium salt of 2-oxazolidinone 277. In the presence of Me2AlCl, diene 278 adds to (Z)-l-acetoxy-2-ethoxyethene giving mostly adduct 279, whereas, when using Me3SiOTf as promoter of the hetero Diels-Alder addition, diastereomer 280 is the major adduct (Scheme 13.79). Adducts 279 and 280 have been converted into ethyl P-d-mannopyranoside and ethyl-P-L-mannopyranoside, respectively [149]. 

Due to the attractivity of this method several groups have developed onium salt supported versions of classical reactions. For example, starting from hydroxyl derived imidazolium salts, formation of supported acrylates with acryloyl chloride followed by reaction with diene in refluxing toluene afforded Diels Alder adduct in good yields (>65%). After saponification, products are isolated without further purification [127], Alternatively, starting from carboxylic acid derived imidazolium salts, acyl chloride formation with thionyl chloride in acetonitrile, followed by reaction with 4-aminophenol led to supported N-arylamide. Williamson alkylation using NaOH as a base and subsequent cleavage from the onium salt support under acidic condition (HCI/I I2()/ AcOH) allowed for isolation of various alkoxy substituted anilines with >98% purity... 

Oxoindolizines are obtained by reaction of ethyl pyrrolidinylideneacetate with several acyclic a, -unsaturated carbonyl compounds by cydization of the formed Michael adducts(equation 73). When this reaction was modified by changing the ring size of the enaminoester, the substitution pattern of the enone structure and by varying the conditions, different products were isolated . N-acylation could be accomplished by reaction of acyl chlorides in the presence of pyridine. Bicyclic lactams are yielded by Michael addition of acrylic esters and NaH (equation 74),... 

Acylation with phosgene occurs under very mild conditions to give enamino-acyl chlorides which undergo solvolysis to esters or amides (Scheme 93). Cyanogen chloride reacts with enamines to give cyanoenamines and a-cyanoketones on hydrolysis. Cyanogen bromide and iodide react differently a 1 1 adduct is formed which, on hydrolysis, leads to 2-haloketone (Scheme 94). 

Arndtsen and co-workers developed an isocyanide-mediated three-component synthesis ofthe polysubstituted pyrroles 97, wherein an acyclic imine was activated in situ by acylation [54]. Thus, reaction of an imine, an acyl chloride, an alkyne, and an isocyanide in the presence of PrNEt2 afforded 97 in good to excellent yields (Scheme 5.29). A complex reaction sequence involving formation ofthe N-acyliminium by [4 + 1] followed by [3 + 2] cycloadditions and a retro-cycloaddition was proposed to account the formation of 97. The isocyanide participated actively in this reaction sequence however, it was not incorporated in the final adduct since it was lost as isocyanate by a retro-D-A reaction. The aliphatic imine was shown to be an appropriate substrate, at least in one case, leading to the corresponding pyrrole (R2 = isopropyl) in 72% yield. Azenes participated in this reaction in a similar manner. Thus, the isoquinoline 94 was converted to the benzo-fused pyrrole 98 in 50% yield. 

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