Alkyl chloroformates, intermediates

The replacement of both -OH groups with chlorine produces Ccirbonyl dichloride, also known as phosgene, a useful reactant. For example, phosgene reacts with two moles of alcohol to form a dialkyl carbonate. The reaction of phosgene with one mole of alcohol produces an alkyl chloroformate, which is a useful intermediate in organic syntheses. The reaction of phosgene with four moles of ammonia yields urea and two moles of ammonium chloride, NH Cl. Figure 12-40 shows the structures of some of these compounds. 

Other reagents that have been used to effect the dehydration of ureas to carbodiimides are alkyl chloroformates (for thioureas) [46], phosgene [47], phosphorus oxychloride [48], and phosphorus pentachloride [38, 49]. Di-chlorocarbodiimides have been shown to be intermediates when COCl2 or PC15 reacts with ureas (Eq. 13). If R1 and R3 are H, then the intermediate... 

Dihydro allyl adducts like (254) are obtained by reaction of thiazoles with allyltributyl tin in the presence of alkyl chloroformates acting as activators of the thiazole ring (Scheme 28) (94JOC1319). This reaction most likely takes place via the intermediate azolium salt. Under these conditions even organolithium compounds can add to thiazoles (84TL3633). Similarly, direct ethynylation of thiazole and benzothiazole can be achieved by reaction with bis(tributylstannyl)acetylene (Scheme 29) (94SL557). 

The same substrate (86) gave 2-tm-butoxycarbonyloxy-3,6-diisopropylpyrazine (89), indirectly via the unisolated chloroformyloxy, intermediate (88) [NaH, dioxane, 20°C, until H2f ceased then C12C0C(=0)C1 J, 0 —> 20°C, 12 h then Bu OH/pyridine j, 0 — 20°C, 15 h 53%. This method may be used when the required alkyl chloroformate is not readily available].1375,1380... 

In contrast alkyl chloroformates have been widely utilized and numerous examples have been described especially in the early literature. Intermediate urethanes are usually obtained as in the conversion of (267) with benzylchloroformate in aqueous sodium hydrogen carbonate into the 8-oxopurine (268) directly (Scheme 85) (6lJOC496l,62Ml4090l). 

Both 1-methylpyrrole and 1-methylindole can be easily lithiated and the resulting intermediates have been used extensively in synthesis. The range of electrophiles which can be used with lithiated pyrroles and indoles is quite broad. Aldehydes and ketones give carbinols. A,A-Disubstituted formamides give aldehydes. Carbon dioxide and alkyl chloroformates have been used to make carboxylic acid derivatives. Alkyl halides, sulfates and sulfonates can be used to introduce alkyl groups. Interestingly, even t-butyl bromide has been used successfully for alkylation (see entry 3, Table 7). Some examples are given in Table 7. 

The intermediate (a) can also be arrived at directly from the unprotected linear peptide by applying the mixed anhydride method. After addition of one equivalent of acid, e.g. trifluoroacetic acid, the amino group will be protonated and the (still deprotonated) carboxyl anion will react with alkyl chloroformate to form (a), X = CO—O—Aik. Very conveniently, carbodiimides can be reacted with linear peptides unprotected at both ends to form cyclic peptides in satisfactory yields [26]. Since the carbodiimide method, particularly in the presence of V-hydroxybenzotriazole, is causing little racemization (see p. 93) this system is preferred in most laboratories. 

The most successful realization of the mixed anhydride concept is, however, the generation of reactive intermediates with the help of alkyl chlorocarbonates (also called alkyl chloroformates) ... 

An established method for the activation of carboxylic groups, particularly those of N-protected amino acids or peptides, is to form mixed anhydrides with alkyl chloroformates or dialkyl dicarbonates such as B0C2O. Acyl carbonates can also be essential intermediates in the reactions of anhydrides with carbonates. 

The low spin aryliron complexes Fe(Por)Ar behave differently than their alkyl counterparts toward oxygen. In chloroform the products of the reaction of Fe(Por)Ar with O2 are the iron(IV) alkyl Fe(Por)Ar] and Fe(Por)Cl, while in toluene the aryloxide complexes Fe(Por)OAr are formed with no direct evidence for the formation of arylperoxo intermediates."" The high spin iron(lll) alkynyl complexes which have more ionic character in the Fe—C bond do not react with oxygen, and the order of reactivity of organoiron(lll) complexes toward O2 is given by Fe(Por)(alkyl) > Fe(Por)(aryl) > Fe(Por)(C=CR). ... 

Alkanes are formed when the radical intermediate abstracts hydrogen from solvent faster than it is oxidized to the carbocation. This reductive step is promoted by good hydrogen donor solvents. It is also more prevalent for primary alkyl radicals because of the higher activation energy associated with formation of primary carbocations. The most favorable conditions for alkane formation involve photochemical decomposition of the carboxylic acid in chloroform, which is a relatively good hydrogen donor. 

Administration of chloroform to laboratory animals resulted in the depletion of renal GSH, indicating that GSH reacts with reactive intermediates, thus reducing the kidney damage otherwise caused by the reaction of these intermediates with tissue MMBs (Hook and Smith 1985 Smith and Hook 1983, 1984 Smith et al. 1984). Similarly, chloroform treatment resulted in the depletion of hepatic GSH and alkylation of MMBs (Docks and Krishna 1976). Other studies demonstrated that sulfhydryl compounds such as L-cysteine (Bailie et al. 1984) and reduced GSH (Kluwe and Hook 1981) may provide protection against nephrotoxicity induced by chloroform. The sulfhydryl compound N-acetylcysteine is an effective antidote for poisoning by acetaminophen, which, like chloroform, depletes GSH and produces toxicity by reactive intermediates. 

The key intermediates 692 required for the thermal cyclization were prepared from the readily available indole-2,3-diones 693. The condensation of 693 with 3-methyl-4-phenylbut-3-en-2-one (694) afforded the 3-hydroxy derivatives 695. The dehydration of 695, followed by selective reduction of the 3,1 -double bond of compounds 696, provided the 3-alkyl derivative 697. Finally, the compounds 697 were transformed to the 3-(l,3-butadienyl)indoles 692 by reaction with an excess of ethyl chloroformate (Scheme 5.62). 

A modification of the Pomeranz-Fritsch synthesis <1983JCXI3344> is used in the preparation of thieno[2,3- l-pyridine and its 2-substituted derivatives. An aryl aldehyde undergoes condensation with aminoacetaldehyde dimethyl acetal giving a Schiff base which cyclizes to form an imine product. The imine is treated with ethyl chloroformate followed by triethyl phosphate to form an intermediate carbonate-phosphonate, which then cyclizes to the thienopyr-idine product (Scheme 22) <2004S1935>. Very low product yields (2-17%) are obtained for alkyl- and phenyl-substituted thieno[2,3- ]pyridines however, the unsubstituted product and 2-halogenated derivatives give moderate yields (28-44%). 

Quenching this reaction with deuteriomethanol gave 2-methylcycloheptanone having deuterium at the 2-position (199 E = D) in 75% yield with 95% deuterium incorporation. Aldehydes and benzoyl chloride gave the desired products in 60-70% yields. Alkylation of the enolate intermediate (198) was successfully carried out with alkyl halides in the presence of HMPA in good yields. The reaction with ethyl chloroformate and chlorotri-ethylsilane gave enol carbonate (200) and sUyl enol ether (201) in 74 and 75% yield, respectively. 

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