Ethyl chloroformate, hydrolysis

The ethoxycarbonyl group was developed for the protection of phosphonates. The derivative is prepared by reaction of tris(trimethylsilyl) phosphite with ethyl chloroformate and can be cleaved by hydrolysis of the ester followed by silyla-tion with bistrimethylsilylacetamide. ... 

In this series, too, replacement of the N-methyl by a group such as cyclopropylmethyl leads to a compound with reduced abuse potential by virtue of mixed agonist-antagonist action. To accomplish this, reduction of 24 followed by reaction with tertiary butylmagnesium chloride gives the tertiary carbinol 27. The N-methyl group is then removed by the classic von Braun procedure. Thus, reaction with cyanogen bromide leads to the N-cyano derivative (28) hydrolysis affords the secondary amine 29. (One of the more efficient demethylation procedures, such as reaction with ethyl chloroformate would presumably be used today.) Acylation with cyclopropylcarbonyl chloride then leads to the amide 30. Reduction with lithium aluminum hydride (31) followed by demethylation of the phenolic ether affords buprenorphine (32).9... 

O-acetylophiocarpine (381) with ethyl chloroformate afforded the C-8—N cleaved urethane 382 in quantitative yield. Sequential treatment of 382 with silver nitrate, PCC, sodium hydroxide, and p-toluenesulfonic acid in ethanol furnished acetal 384, which was reduced with lithium aluminum hydride followed by hydrolysis to afford the hemiacetal 385. Oxidation of 385 with PCC provided (+ )-a-hydrastine (369). Similar treatment of O-acetylepi-ophiocarpine (386) afforded ( )-/J-hydrastine (368) however, in this case, C—N bond cleavage of 386 with ethyl chloroformate proceeded without regioselectivity. 

Ring D inversion seems to be a crucial step in biogenetic transformations of protoberberines to related alkaloids such as rhoeadine, retroprotoberberine, spirobenzylisoquinoline, and indenobenzazepine alkaloids. 8,14-Cyclober-bin-13-ol 478 derived from berberine (15) was successively treated with ethyl chloroformate, silver nitrate, and pyridinium dichromate (PDC) in dimethyl-formamide to give the keto oxazolidinone 479 (Scheme 98). Heating of 479 with 10% aqueous sodium hydroxide in ethanol effected hydrolysis, retro-aldol reaction, cyclization, and dehydration to provide successfully the... 

Ethyl 3-oxoalkanoates when not commercially available can be prepared by the acylation of tert-butyl ethyl malonate with an appropriate acid chloride by way of the magnesium enolate derivative. Hydrolysis and decarboxylation in acid solution yields the desired 3-oxo esters [59]. 3-Keto esters can also be prepared in excellent yields either from 2-alkanone by condensation with ethyl chloroformate by means of lithium diisopropylamide (LDA) [60] or from ethyl hydrogen malonate and alkanoyl chloride usingbutyllithium [61]. Alternatively P-keto esters have also been prepared by the alcoholysis of 5-acylated Mel-drum s acid (2,2-dimethyl-l,3-dioxane-4,6-dione). The latter are prepared in almost quantitative yield by the condensation of Meldrum s acid either with an appropriate fatty acid in the presence of DCCI and DMAP [62] or with an acid chloride in the presence of pyridine [62] (Scheme 7). 

Finally, a third way of synthesis is from imipramine (7.1.1), which nndergoes demethylation by snccessive reaction with ethyl chloroformate, giving 5-[3-(Af-carbethoxy-iV-methyl)aniino-propyl]-10,ll-dihydro-5H-dibenz[b,f azepine (7.1.15), the alkaline hydrolysis of which leads to desipramine (7.1.13) [23,24],... 

In the second scheme, the specified reaction of amitriptyline (7.1.4) with ethyl chloroformate leads to the substitution of a methyl group on the amino group with an ethoxycar-bonyl group. Hydrolysis of the formed product leads to nortriptyline (7.1.17) [26]. 

Pyrrole-2-carboxylic acid esters have been prepared from ethyl chloroformate and pyrrolylmagnesium bromide1 2 or pyrrolyllithium,3 by hydrolysis and decarboxylation of dimethyl pyrrole-1,2-dicarboxylate followed by re-esterification of the 2-acid4 and by oxidation of pyrrole-2-carboxaldehyde followed by esterification with diazomethane.4... 

Bohme and Schiirhoff131 have measured the rate of hydrolysis of ethyl chloroformate and found it to be quite slow (kx = 2.0x 10"4sec-1 in water at 25°C). Hall118, investigating the hydrolysis of ethyl chloroformate and dimethyl carbamyl chloride, found the rate sequence for neutral hydrolysis to be... 

The primary products of the hydrolysis of ethyl chloroformate are hydrogen chloride, ethanol and carbon dioxide, the latter two compounds formed from the rapid decomposition of an intermediate monoethyl carbonate, viz. 

Hudson et a/.151,152 have concluded that the bimolecular solvolysis of ethyl chloroformate involves heterolysis of the carbon-chlorine bond and not heterolysis of the carbon-oxygen bond. Their data shows that the hydrolysis of ethyl chloroformate is a second-order reaction in water/acetone mixtures, methyl chloroformate reacting about 2.2 times as fast in 65% water/acetone at 50°C. Hydroxide ion accelerates the reaction (3.1 x 107 in 18% water/ acetone and 3.4 x 108 in 85% water/acetone) and catalysis by hydroxide ion was observed with pure water as solvent by Hall118. There is some disagreement about the value for the hydrolysis rate coefficient for ethyl chloroformate in water and in other solvents (Table 21). To date, the data of Queen153 (for pure water), Kivinen92 (for ethanol) and Liemiu101 (for methanol) must be considered the most accurate. 

REPORTED FIRST-ORDER RATE COEFFICIENTS FOR THE HYDROLYSIS OF ETHYL CHLOROFORMATE AT 25°C... 

The cyclohexene 121, which was readily accessible from the Diels-Alder reaction of methyl hexa-3,5-dienoate and 3,4-methylenedioxy-(3-nitrostyrene (108), served as the starting point for another formal total synthesis of ( )-lycorine (1) (Scheme 11) (113). In the event dissolving metal reduction of 121 with zinc followed by reduction of the intermediate cyclic hydroxamic acid with lithium diethoxyaluminum hydride provided the secondary amine 122. Transformation of 122 to the tetracyclic lactam 123 was achieved by sequential treatment with ethyl chloroformate and Bischler-Napieralski cyclization of the resulting carbamate with phosphorus oxychloride. Since attempts to effect cleanly the direct allylic oxidation of 123 to provide an intermediate suitable for subsequent elaboration to ( )-lycorine (1) were unsuccessful, a stepwise protocol was devised. Namely, addition of phenylselenyl bromide to 123 in acetic acid followed by hydrolysis of the intermediate acetates gave a mixture of two hydroxy se-lenides. Oxidative elimination of phenylselenous acid from the minor product afforded the allylic alcohol 124, whereas the major hydroxy selenide was resistant to oxidation and elimination. When 124 was treated with a small amount of acetic anhydride and sulfuric acid in acetic acid, the main product was the rearranged acetate 67, which had been previously converted to ( )-lycorine (108). 

In addition to the preparation of a- and /3-hydrastine described above from the betaine (64), another conversion of a tetrahydroberberine into hydrastine has been reported. Acetylophiocarpine, on treatment with ethyl chloroformate, gives the acetoxy-derivative of (88), which can be hydrolysed to the hydroxymethyl compound and then oxidized to the aldehyde by pyridinium perchlorate. Hydrolysis of the acetoxyl group afforded the hemi-acetal (93 R = H), conversion of which into the mixed acetal (93 R = Et) protected the aldehyde system during reduction of N—C02Et to NMe by lithium aluminium hydride. Hydrolysis of the acetal, followed by oxidation, then gave a-hydrastine, and a similar sequence of reactions starting from O-acetyl-13-epi-ophiocarpine afforded / -hydrastine.119 Methods of synthesis of alkaloids of this group have been reviewed.120... 

Lithium aluminium hydride reduction of 235 followed by mesylation afforded 236. The latter was oxidized with osmium tetroxide and sodium metaperiodate to yield the cyclobutanone 237. Treatment of 237 with acid afforded in 48% yield the ketoacid (238), which was esterified with diazomethane to 239. The latter was converted to the ketal 240 by treatment with ethylene glycol and /7-toluenesulfonic acid. Compound 240 was reduced with lithium aluminium hydride to the alcohol 241. This alcohol had been synthesized previously by Nagata and co-workers (164) by an entirely different route. The azide 242 was prepared in 80% yield by mesylation of 241 and treatment of the product with sodium azide. Lithium aluminium hydride reduction of 242 gave the primary amine, which was converted to the urethane 243 by treatment with ethyl chloroformate. The ketal group of 243 was removed by acidic hydrolysis and the resulting ketone was nitro-sated with N204 and sodium acetate. Decomposition of the nitrosourethane with sodium ethoxide in refluxing ethanol afforded the ketone 244 in 65% yield. The latter had been also synthesized previously by Japanese chemists (165). The ketone 244 was converted to the ketal 246 and the latter to 247... 

From a preparative point of view, the acylation of ketones via enamines is of particular interest. In comparison with pyrrolidine and piperidine enamines, the less reactive morpholine enamines give better yields, as found by Hiinig et al.2iZ j8-Diketones are the products of acylation with an acyl halide followed by acid hydrolysis, whereas with ethyl chloroformate, /J-ketoesters are obtained.212 Hiinig and his collaborators242-247 have used the acylation of 1-morpholino-l-cyclopentene and 1-morpholino-l-cyclohexene to lengthen the chains of acids by five and six carbon atoms, respectively. The reaction may... 

And finally, acylating agents can also be used as electrophiles to react with enamines. Following the hydrolysis of the enaminoketones (i.e., compounds with the substructure R2N-C=C-C(=0)-R ) or enaminoesters (i.e., compounds with the substructure R2N-C=C-C(=0)-0R ) the acylation products of the corresponding ketones are obtained. Figure 12.21 gives the mechanistic details of the acylation with an acid chloride, and Figure 12.22 shows the acylation with ethyl chloroformate. The first acylation yields /1-diketones, the second furnishes a /1-ketoester. 

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