Aryl halides with carboxylic esters

Suzuki and Stille couplings. For coupling of aryl chlorides with arylboronic acids the catalytic system contains (CyjPjjPdClj, CsF in NMP. co-Arylalkanoic acids are prepared by coupling of aryl halides with carboxylic esters bearing a 9-BBN substituent at the other terminus, and saponification. A biaryl synthesis from two different aryl halides is accomplished with in situ boronate formation which depends on the (dppfjPdClj catalyst. For access to aryl boronates either the coupling of aryl triflates with bis(pinacolato)diboron" or that of aryl iodides with pinacolborane may be employed. 

In addition to halides, leaving groups can be other OR, and so on, even OH. Acid salts, RCOO, are sometimes used as nucleophiles. Good yields of aryl benzoates can be obtained by the treatment of aryl halides with cuprous benzoate in diglyme or xylene at 140-160°C. " Unactivated substrates have been converted to carboxylic esters in low-to-moderate yields under oxidizing condi-... 

The direct coupling of t-butyl thiazole-4-carboxylate at C-2 is successful with a wide range of (hetero) aryl halides, the hindered ester (rather than the methyl ester), together with the use of tri-o-tolylphosphine as ligand, giving optimum selectivity for C-2 vs. C-5 for iodoarenes and heteroarenes. Changing the ligand to JohnPhos allows extension to chloro- and bromo-heterocycles. ... 

The Pd(0)-mediated a-arylation of esters is an efficient and versatile tool for the preparation of a-aryl carboxylic acids and a-aryl amino acids. Using areadily available catalyst system, e.g., Pd2(dba)3 dba and carbene precursor or t-Bu3P, many aryl halides and esters, in the presence of a strong base, react to form a series of ester-protected a-aryl carboxylic acids, e.g., 6a and 7a react to give 8a. A similar protocol facilitates the a-arylation of imine-protected glycinates with aryl halides to form ester-protected a-aryl amino acids. A useful example is the reaction of 6c and 7c to give 8c (eqs 9-11). 

The reaction between acyl halides and alcohols or phenols is the best general method for the preparation of carboxylic esters. It is believed to proceed by a 8 2 mechanism. As with 10-8, the mechanism can be S l or tetrahedral. Pyridine catalyzes the reaction by the nucleophilic catalysis route (see 10-9). The reaction is of wide scope, and many functional groups do not interfere. A base is frequently added to combine with the HX formed. When aqueous alkali is used, this is called the Schotten-Baumann procedure, but pyridine is also frequently used. Both R and R may be primary, secondary, or tertiary alkyl or aryl. Enolic esters can also be prepared by this method, though C-acylation competes in these cases. In difficult cases, especially with hindered acids or tertiary R, the alkoxide can be used instead of the alcohol. Activated alumina has also been used as a catalyst, for tertiary R. Thallium salts of phenols give very high yields of phenolic esters. Phase-transfer catalysis has been used for hindered phenols. Zinc has been used to couple... 

Vinylic and aryl halides can be used to vinylate or arylate carboxylic esters (but not ketones) by the use of NiBr2 as a catalyst. " However, ketones have been vinylated by treating their enol acetates with vinylic bromides in the presence of a Pd... 

Palladium complexes also catalyze the carbonylation of halides. Aryl (see 13-13), vinylic, benzylic, and allylic halides (especially iodides) can be converted to carboxylic esters with CO, an alcohol or alkoxide, and a palladium complex. Similar reactivity was reported with vinyl triflates. Use of an amine instead of the alcohol or alkoxide leads to an amide. Reaction with an amine, AJBN, CO, and a tetraalkyltin catalyst also leads to an amide. Similar reaction with an alcohol, under Xe irradiation, leads to the ester. Benzylic and allylic halides were converted to carboxylic acids electrocatalytically, with CO and a cobalt imine complex. Vinylic halides were similarly converted with CO and nickel cyanide, under phase-transfer conditions. ... 

Sulfonic esters are most frequently prepared by treatment of the corresponding halides with alcohols in the presence of a base. The method is much used for the conversion of alcohols to tosylates, brosylates, and similar sulfonic esters. Both R and R may be alkyl or aryl. The base is often pyridine, which functions as a nucleophilic catalyst, as in the similar alcoholysis of carboxylic acyl halides (10-21). Primary alcohols react the most rapidly, and it is often possible to sulfonate selectively a primary OH group in a molecule that also contains secondary or tertiary OH groups. The reaction with sulfonamides has been much less frequently used and is limited to N,N-disubstituted sulfonamides that is, R" may not be hydrogen. However, within these limits it is a useful reaction. The nucleophile in this case is actually R 0 . However, R" may be hydrogen (as well as alkyl) if the nucleophile is a phenol, so that the product is RS020Ar. Acidic catalysts are used in this case. Sulfonic acids have been converted directly to sulfonates by treatment with triethyl or trimethyl orthoformate HC(OR)3, without catalyst or solvent and with a trialkyl phosphite P(OR)3. ... 

Coupling of Organometallic Compounds with Aryl Halides, Ethers, and Carboxylic Esters... 

Tertiary benzylic nitriles are useful synthetic intermediates, and have been used for the preparation of amidines, lactones, primary amines, pyridines, aldehydes, carboxylic acids, and esters. The general synthetic pathway to this class of compounds relies on the displacement of an activated benzylic alcohol or benzylic halide with a cyanide source followed by double alkylation under basic conditions. For instance, 2-(2-methoxyphenyl)-2-methylpropionitrile has been prepared by methylation of (2-methoxyphenyl)acetonitrile using sodium amide and iodomethane. In the course of the preparation of a drug candidate, the submitters discovered that the nucleophilic aromatic substitution of aryl fluorides with the anion of a secondary nitrile is an effective method for the preparation of these compounds. The reaction was studied using isobutyronitrile and 2-fluoroanisole. The submitters first showed that KHMDS was the superior base for the process when carried out in either THF or toluene (Table I). For example, they found that the preparation of 2-(2-methoxyphenyl)-2-methylpropionitrile could be accomplished h... 

Vinylic and aryl halides can be used to vinylate or arylate carboxylic esters (but not ketones) by the use of NiBr2 as a catalyst.1463 However, ketones have been vinylated by treating their enol acetates with vinylic bromides in the presence of a Pd compound catalyst.1464 Also as in 0-94, this reaction can be used to close rings.1465 In one example of this, rings have been closed by treating a diion of a dialkyl succinate with a l,cu-dihalide or ditosylate,1466, e.g. ... 

We have previously seen (0-96) that dianions of carboxylic acids can be alkylated in the a position. These ions can also be acylated on treatment with a carboxylic ester1705 to give salts of p-keto acids. As in 0-96, the carboxylic acid can be of the form RCH2COOH or RR"CHCOOH. Since p-keto acids are so easily converted to ketones (2-40), this is also a method for the preparation of ketones R COCHiR and R COCHRR", where R can be primary, secondary, or tertiary alkyl, or aryl. If the ester is ethyl formate, an a-formyl carboxylate salt (R = H) is formed, which on acidification spontaneously de-carboxylates into an aldehyde.1706 This is a method, therefore, for achieving the conversion RCH2COOH — RCH2CHO, and as such is an alternative to the reduction methods discussed in 0-83. When the carboxylic acid is of the form RR CHCOOH. better yields are obtained by acylating with acyl halides rather than esters.1707... 

The at complex from DIB AH and butyllithium is a selective reducing agent.16 It is used tor the 1,2-reduction of acyclic and cyclic enones. Esters and lactones are reduced at room temperature to alcohols, and at -78 C to alcohols and aldehydes. Acid chlorides are rapidly reduced with excess reagent at -78 C to alcohols, but a mixture of alcohols, aldehydes, and acid chlorides results from use of an equimolar amount of reagent at -78 C. Acid anhydrides are reduced at -78 C to alcohols and carboxylic acids. Carboxylic acids and both primary and secondary amides are inert at room temperature, whereas tertiary amides (as in the present case) are reduced between 0 C and room temperature to aldehydes. The at complex rapidly reduces primary alkyl, benzylic, and allylic bromides, while tertiary alkyl and aryl halides are inert. Epoxides are reduced exclusively to the more highly substituted alcohols. Disulfides lead to thiols, but both sulfoxides and sulfones are inert. Moreover, this at complex from DIBAH and butyllithium is able to reduce ketones selectively in the presence of esters. 

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