Hydrolysis orthoformate

Nature often exploits large pJQ shifts in enzymes to effect chemical catalysis similarly, we hoped to apply the large shifts in the effective basicities of encapsulated guests to reaction chemistry. Initial studies focused on the hydrolysis of orthoformates, a class of molecules responsible for much ofthe formulation ofthe Bronsted theory of acids almost a century ago [98]. While orthoformates are readily hydrolyzed in acidic solution, they are exceedingly stable in neutral or basic solution [99]. However, in the presence of a catalytic amount of 1 in basic solution, small orthoformates are quickly hydrolyzed to the corresponding formate ester [38]. Addition of NEt4 to the reaction inhibited the catalysis but did not affect the hydrolysis rate measured in the absence of 1. With a limited volume in the cavity of 1, substantial size selectivity was observed in the orthoformate hydrolysis. Orthoformates smaller than tripentyl... 

Fig. 2. Synthesis of uma2enil (18). The isonitrosoacetanihde is synthesized from 4-f1iioroani1ine. Cyclization using sulfuric acid is followed by oxidization using peracetic acid to the isatoic anhydride. Reaction of sarcosine in DMF and acetic acid leads to the benzodiazepine-2,5-dione. Deprotonation, phosphorylation, and subsequent reaction with diethyl malonate leads to the diester. After selective hydrolysis and decarboxylation the resulting monoester is nitrosated and catalyticaHy hydrogenated to the aminoester. Introduction of the final carbon atom is accompHshed by reaction of triethyl orthoformate to...

Compounds i, ii, and iii can be prepared by an acid-catalyzed reaction of a diol and the cycloalkanone in the presence of ethyl orthoformate and mesitylenesul-fonic acid. The relative ease of acid-catalyzed hydrolysis [0.53 M H2SO4, H2O, PrOH (65 35), 20°] for compounds i, iii, acetonide, and ii is C5 C7 > ace-... 

A variety of cyclic ortho esters,including cyclic orthoformates, have been developed to protect czs-1,2-diols. Cyclic ortho esters are more readily cleaved by acidic hydrolysis (e.g., by a phosphate buffer, pH 4.5-7.5, or by 0.005-0.05 M HCl) than are acetonides. Careful hydrolysis or reduction can be used to prepare selectively monoprotected diol derivatives. 

Bromobenzaldehyde has been prepared by the oxidation of -bromotoluene with chromyl chloride/ by saponification of the acetal from />-bromophenylmagnesium bromide and orthoformic ester/ by the oxidation of ethyl -bromobenzyl ether with nitric acid/ by the oxidation of /j-bromobenzyl bromide with lead nitrate/ and by the hydrolysis of i-bromobenzal bromide in the presence of calcium carbonate. ... 

Orthoesters are stable to base, although nucleophilic attack may occur under drastic conditions. Orthoformates are split by acids to free diols, whereas controlled acid hydrolysis leads to monoformates. " Higher orthoesters are usually split by mineral or organic acids to give monoesters. 

The orthoformate is formed by the acid-catalyzed reaction of a catechol with triethyl orthoformate (82% yield) and is cleaved by acid-catalyzed hydrolysis (TsOH, MeOH, H2O, rt, 16 h, 80-88% yield.). ... 

This approach has been extended by Tieckelmann, Mulvey, and Gottis to 2-amino-5-cyanonicotinamides (16 and 18), whiob were prepared directly by partial hydrolysis of the corresponding dir itriles. Diethyl carbonate, ethyl orthoacetate, and ethyl orthoformate all underwent reaction to yield the corresponding pyrido[2,3-( ]pyri-midines (17 and 19). 

Orthoformates have been used in the lipase-catalyzed esterification aimed at the kinetic resolution of racemic acids such as flurbiprofen, a nonsteroidal anti-inflammatory drug (Figure 6.18). Orthoformates trap the water as it is formed through hydrolysis, and therefore prevent the reverse reaction, and, at the same time, provide the alcohol for the esteriflcation [65]. 

Dining dehydration of manganese(II) perchlorate [1] or nickel(II) perchlorate [2] with dimethoxypropane, heating above 65°C caused violent explosions, probably involving oxidation by the anion [1] (possibly of the methanol liberated by hydrolysis). Triethyl orthoformate is recommended as a safer dehydrating agent [2] (but methanol would still be liberated). 

The synthesis of the corresponding naphthyridone scaffold was carried out according to the methods reported by Chu et al. [12] and Sanchez et al. [13]. Namely, the hydrolysis of ethyl 2,6-dichloro-5-fluoronicotinate (3) [14] followed by reaction with thionyl chloride results in the formation of 2,6-dichloro-5-fluoronicotinyl chloride (4). Treatment of this compound with monoethyl malonate in THF under n-butyllithium followed by acidification and decarboxylation gives rise to ethyl 2,6-dichloro-5-fluoronicotinylacetate (5). Reaction of compound 5 with ethyl orthoformate in acetic acid followed by cyclopropylamine results in the formation of 3-cyclopropylamino-2-(2,6-dichloro-5-fluoronicotinyl)acrylate (6), the cyclization reaction of which under NaH/THF gives rise to the required ethyl l-cyclopropyl-6-fluoro-7-chloro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (7), as shown in Scheme 3. 

The synthesis of compound 27 was initiated with the treatment of ke-toester 29, reported by Yoshida et al. [25], with ethyl orthoformate in acetic acid, followed by reaction with (l.R,2S)-2-fluoro-1-cyclopropylamine p-toluenesulfonic acid salt in the presence of triethylamine to yield an enam-inoketoester intermediate, cyclization of which under NaH in dioxane yields the 5-nitroquinolone derivative (30). Reduction of the nitro group of compound 30 followed by acid hydrolysis provides compound 27 via the amino-quinolone derivative (31), according to Scheme 7. 

A total synthesis of (35, 4/ )-(+)-eldanolide (246), a sex attractant pheromone, has been reported (243). Compound 246 was synthesized by two different routes, both involving the butenolide 245 as the key precursor. The higher-yielding sequence is described here. Treatment of the tosylate acetal 242 with methanolic sodium methoxide led, as previously described by Hoffman and Ladner (244), to the epoxide 243. Addition of lithium diiso-butenylcuprate to 243 afforded 244, which after successive hydrolysis of the isopropylidene group, treatment with triethyl orthoformate, and pyrolysis,... 

Triethyl orthoformate is often used in reactions with enolates and carbanions to form diethyl acetals that on treatment with dilute acid give the corresponding formyl derivatives. However, when indole is heated at 160 C with triethyl orthoformate the locus of reaction is at N-1 rather than at C-3, and 1-(diethoxymethyl)indole is formed (Scheme 7.6). The A -substituent is easily removed by acidic hydrolysis to reform indole. 

As discussed in this chapter, the fundamental host-guest chemistry of 1 has been elaborated to include both stoichiometric and catalytic reactions. The constrained interior and chirality of 1 allows for both size- and stereo-selectivity [31-35]. Additionally, 1 itself has been used as a catalyst for the sigmatropic rearrangement of enammonium cations [36,37] and the hydrolysis of acid-labile orthoformates and acetals [38,39]. Our approach to using 1 to mediate chemical reactivity has been twofold First, the chiral environment of 1 is explored as a source of asymmetry for encapsulated achiral catalysts. Second, the assembly itself is used to catalyze reactions that either require preorganization of the substrate or contain high energy intermediates or transition states that can be stabilized in 1. 

Having established that 1 catalyzes the hydrolysis of orthoformates in basic solution, the reaction mechanism was probed. Mechanistic studies were performed using triethyl orthoformate (70) as the substrate at pH 11.0 and 50 °C. First-order substrate consumption was observed under stoichiometric conditions. Working under saturation conditions (pseudo-0 order in substrate), kinetic studies revealed that the reaction is also first order in [H+] and in [1]. When combined, these mechanistic studies establish that the rate law for this catalytic hydrolysis of ortho-formates by host 1 obeys the overall termolecular rate law rate = k[H+][Substrate][l], which reduces to rate = k [H ][l] at saturation. 

Scheme 7.7 Mechanism for hydrolysis of orthoformates by 1. The formate ester product is further hydrolyzed by base to formate anion and the corresponding alcohol.

Figure 7.7 Eadie-Hofstee plot for the hydrolysis of triethyl orthoformate in 1, pH 11,100 mM K2CO3,50 C, using NPr4 as a competitive inhibitor.

Pluth, M.D., Bergman, R.G. and Raymond, KN. (2007) Acid catalysis in basic solution A supramolecular host promotes orthoformate hydrolysis. Science, 316, 85-88. 

The hydrated chloride, bromide and iodide (Table 9) are soluble in ethanol, butanol and other organic solvents, but in many systems traces of water cause oxidation, hydrolysis or failure to complex with weak donor ligands. Water can be avoided by dissolving the metal in THF, ethanol or diethyl ether through which hydrogen chloride is bubbled.24,74 75 It is also possible to dissolve or suspend in organic solvents the anhydrous acetate or the halides CrX2 (Table 9), and dehydration of the hydrated halides with 2,3-dimethoxypropane in ethanol, followed by vacuum removal of the liquid, produces mixed alcoholates suitable for use in water-free conditions.76 Triethyl orthoformate may be used similarly. 

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