Direct etherification

In 2004-2005, we reported direct etherification of tautomerizable heterocycles with oxygen nucleophiles via phosphonium coupling to produce biaryl ethers or alkyl aryl ethers. Phenols are moderately strong nucleophiles, therefore the NaOi-Bu-promoted phosphonium coupling condition was found to be better than the Et3N-promoted condition (04AP702,05JOC1957). 

In 2007,Wan and coworkers prepared the diaryl ether via direct etherification of the tautomerizable heterocycle using BOP in the presence of DBU in MeCN (07JOCI0I94). 

In 2010, Kokatla and coworkers screened the reaction conditions for direct etherification of tautomerizable heterocycles using BOP in the presence of CS2CO3 in THE The optimal reaction condition led to the synthesis of many alkyl aryl ethers and diaryl ethers from various pyrimidines and nucleosides under mild conditions in high yields (10OL4478). 

Direct etherification via C—H activation is rarely documented, especially on heterocycles. Shi used an N-(pyridinyl-2-yl)isopropylcarboxamide as directing group for the direct methoxylation of heteroarenes including pyridines, pyridazines, and thiophenes (137 138) (Scheme 69)... 

Direct etherification of retinol (1) to give retinyl methyl ether (571) was successfully carried out using dimethyl sulfate and n-butyllithium (Hanze et aL, 1948), and this method was also used to prepare a water-soluble retinyl glucosyl ether from retinol (1) (Takabayashi et aL, 1970). 

The potential advantages of LPG concern essentially the environmental aspects. LPG s are simple mixtures of 3- and 4-carbon-atom hydrocarbons with few contaminants (very low sulfur content). LPG s contain no noxious additives such as lead and their exhaust emissions have little or no toxicity because aromatics are absent. This type of fuel also benefits often enough from a lower taxation. In spite of that, the use of LPG motor fuel remains static in France, if not on a slightly downward trend. There are several reasons for this situation little interest from automobile manufacturers, reluctance on the part of automobile customers, competition in the refining industry for other uses of and fractions, (alkylation, etherification, direct addition into the gasoline pool). However, in 1993 this subject seems to have received more interest (Hublin et al., 1993). 

An unusual sensitivity of this reaction to structure was reported by Ram and Neumeyer (51). When R = H (1), hydrogenolysis could not be effected either directly or by catalytic hydrogen transfer (13), but etherification to give 2 (R = CH3) permitted slow formation of 3, The mild conditions of hydrogenation were required to avoid racemization at the 6a-position. Hydrogenolysis is usually much more facile than is indicated by this example. 

Intermediate 8, the projected electrophile in a coupling reaction with intermediate 7, could conceivably be derived from iodolactone 16. In the synthetic direction, cleavage of the acetonide protecting group in 16 with concomitant intramolecular etherification could result in the formation of the functionalized tetrahydrofuran ring of... 

Arguably the most challenging aspect for the preparation of 1 was construction of the unsymmetrically substituted sec-sec chiral bis(trifluoromethyl)benzylic ether functionality with careful control of the relative and absolute stereochemistry [21], The original chemistry route to ether intermediate 18 involved an unselective etherification of chiral alcohol 10 with racemic imidate 17 and separation of a nearly 1 1 mixture of diastereomers, as shown in Scheme 7.3. Carbon-oxygen single bond forming reactions leading directly to chiral acyclic sec-sec ethers are particularly rare since known reactions are typically nonstereospecific. While notable exceptions have surfaced [22], each method provides ethers with particular substitution patterns which are not broadly applicable. 

PECH was modified under similar reaction conditions, except that dimethylformamide (DMF) was used as the reaction solvent. In addition, the phase-transfer-catalyzed etherification of the chloromethyl groups of PECH with sodium 4-methoxy -4 -biphenoxide was used to synthesize PECH with direct attachment of the mesogen to the polymer backbone. Similar notations to those used to describe the functionalized PPO are used for functionalized PECH. In this last case, PPO was replaced with PECH. Esterification routes of both PPO and PECH are presented in Scheme I. 

The first reactor is a selective hydrogenation reactor, which product is split into LCN and HCN. The LCN cut is substantially S-free and could be directed to etherification... 

Rhodium catalysts have also been used with increasing frequency for the allylic etherification of aliphatic alcohols. The chiral 7r-allylrhodium complexes generated from asymmetric ring-opening (ARO) reactions have been shown to react with both aromatic and aliphatic alcohols (Equation (46)).185-188 Mechanistic studies have shown that the reaction proceeds by an oxidative addition of Rh(i) into the oxabicyclic alkene system with retention of configuration, as directed by coordination of the oxygen atom, and subsequent SN2 addition of the oxygen nucleophile. 

Although the Ir-catalyzed aUyhc substitution was developed only recently, several applications in the areas of medicinal and natural products chemistry have aheady been reported. In many syntheses the allylic substitution has been combined with a RCM reaction [71]. Examples not directed at natural products targets have aheady been described in Sections 9.4 and 9.5. It has also been mentioned that this strategy had previously been used in conjunction with aUyhc substitutions catalyzed by other transition metals (Figure 9.5). This was pioneered by P. A. Evans and colleagues, who used Rh-catalyzed allylic amination (compound A in Figure 9.5) [72] and etherification (compound B) [73], while Trost and coworkers demonstrated the power of this concept for Pd-catalyzed aUyhc alkylations (compound C) [74] and Alexakis et al. for Cu-catalyzed (compound D) aUyhc alkylations [75]. 

When the R group in the Baylis-Hillman products is not H, a problem might arise in the allylic ring-closing etherification (direct vs allylic attack of the phenolate), leading to mixtures of regio-isomers. Therefore, in an initial study we used parent acid 88 to avoid these problems (Scheme 15). 

Both intermediates 43a and 43b were converted to the final molecule duloxetine (3), as described in Scheme 14.11. Therefore, route A involved direct transformation of the (5)-chloroalcohol 43a into the corresponding iodide, followed by amination and etherification. In contrast, route B consisted of Mitsunobu inversion of (R)-chloroalcohol 43b... 

Methanol homologation - The strong acid hydride HRu(00)3X3, present in the catalytic ruthenium iodide solutions for the methanol homologation, is able to directly protonate the substrate and produce the methyl and successively the acetyl intermediates for the homologation to ethanol (eq. 2). It also catalyzes etherification to dimethyl ether (eq. 3). 

SN2-type Reactions Other leaving groups are also prone to undergo direct Sn reactions in the presence of Fe salts. Zhan and Liu described the direct Fe-catalyzed etherification of propargylic acetates by O-nucleophiles to give rise to a variety of functionalized propargylic ethers (Scheme 7.10) [14]. 

Because of the high stability of the ether function, etherification of unprotected sucrose leads to a kinetic distribution of products directly reflecting the relative reactivity of the hydroxyl groups. This reaction is therefore the best probe for reactivity studies at least for discussing the relative rates of the first substitution. The following substitutions are more difficult to compare, since supplemental factors (electronic and steric) arising from the first substitution interfere with the natural reactivity order of unprotected sucrose. 

The raw ethylsilicate formed is continually fed through an overflow pipe into one of distillation tanks 8. Usually there are several tanks while some are used for distillation, others are filled with etherification products. After the tanks are filled, the temperature is raised to 78-80 °C and during approximately 3 hours the alcohol vapours condensed in cooler 9 are directed through phase separator 10 back into the tank i.e. the tank operates in the self-serving mode. This makes the etherification more complete. After that the temperature is gradually (at the speed of 5-10 grad/h) raised to 140 °C. The excess pressure in distillation tanks should not exceed 0.02 MPa. 

Fig. 26. Production diagram of tetraphenoxysilane and 1,3-bis(triphenoxysiloxy)benzene 1,2- batch boxes 3 - etherificator 4, 11 - backflow condensers 5, 8, 9 - collectors 6 -distillation tank 7 - direct condenser 10 -re-etherificator 12 - receptacle 13 - nutsch filter.

The residue from tank 6, tetraphenoxysilane, flows at 60 °C into collector 9 or directly into apparatus 10 for re-etherification this apparatus is also filled with a calculated amount of resorcinol. The reaction occurs at 220-300 °C. First, apparatus 10 is heated for 2 hours to 220 °C then, at the speed of 20 degrees an hour the temperature is increased to 300 °C. The reactive mixture is kept at this temperature for 2 hours. The vapours of liberated phenol are directed into condenser 11, which is heated with hot water (70-80 °C), and collected in receptacle 12. 

The etherification stage entails only the substitution of chlorine atoms which are situated directly at the silicon atom, forming methyl(chloromethyl)diethoxysilane (the chlorine in the chloromethyl radical is not affected) ... 

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