Friedel-Crafts formylation

In the case of 1,3-diphenylfuro[3,2-c]pyrazole (58) most electrophilic substitutions, e.g., Vilsmeier formylation, Friedel-Crafts acylation, and monobromination, take place in the furan ring. Excess bromine gives the second bromination in the 4-position of the 1-phenyl group, but nitration gives the l-(4-nitrophenyl) derivative and a second, uncharacterized, product (78YZ204). 

Gattermann-Koch reaction Formylation of an aromatic hydrocarbon to yield the corresponding aldehyde by treatment with CO, HCl and AICI3 at atmospheric pressure CuCl is also required. The reaction resembles a Friedel-Crafts acylation since methanoyl chloride, HCOCl, is probably involved. 

Hydroxy-4-methylthiazole failed to react when submitted to Friedel-Crafts benzoylation conditions (349) on the other hand, it reacted normally in Gattermann and in Reimer-Tiemann formylation reactions, affording the 5-formyl derivative (348). 4-Methylthiazole is insufficiently activated and fails to react under the same conditions. 2,4-Dimethylthiazole undergoes perfluoroalkylation when heated at 200° for 8 hr in a sealed tube with perfluoropropyl iodide and sodium acetate (116) (358). 

Aldehyde Synthesis. Formylation would be expected to take place when formyl chloride or formic anhydride reacts with an aromatic compound ia the presence of aluminum chloride or other Friedel-Crafts catalysts. However, the acid chloride and anhydride of formic acid are both too unstable to be of preparative iaterest. 

Aromatics containing electron releasing groups such as phenols, dim ethyl am in oben 2en e and indole are formylated by 2-ethoxy-l,3-dithiolane in the presence of boron trifluoroetherate, followed by hydrolysis (114). The preformed dithiolanium tetrafluoroborate also undergoes Friedel-Crafts reaction with aromatics such as dim ethyl am in oben 2en e and indole (115), and was used to generate dithiolanium derivatives (formyl precursors) from the enoltrimethylsilyl ether derivatives (116). 

Whereas the above reactions are appHcable to activated aromatics, deactivated aromatics can be formylated by reaction with hexamethylenetetramine in strong acids such as 75% polyphosphoric acid, methanesulfonic acid, or trifluoroacetic acid to give saUcylaldehyde derivatives (117). Formyl fluoride (HCOF) has also been used as formyl a ting agent in the Friedel-Crafts reaction of aromatics (118). Formyl fluoride [1493-02-3] in the presence of BF was found to be an efficient electrophilic formyl a ting agent, giving 53% para-, 43% ortho- and 3.5% meta-tolualdehydes upon formylation of toluene (110). 

Attempts to use acetic-formic anhydride with Friedel-Crafts catalysts resulted only in acetylation. However, using anhydrous HF as a catalyst, a small amount of aldehyde is also formed in accordance with the fact that acetic—formic anhydride gives both acetyl and formyl fluoride with HF. By continuous removal of the low boiling HCOF, the reaction can be shifted to the formation of this compound (118). 

Aromatic and heterocycHc compounds are formylated by reaction with dialkyl- or alkylarylformamides in the presence of phosphoms oxychloride or phosgene (Vilsmeier aldehyde synthesis) (125). The Vilsmeier reaction is a Friedel-Crafts type formylation (126), since the intermediate cation formed by the interaction of phosphoms oxychloride with formamide is a typical electrophilic reagent. Ionic addition compounds of formamide with phosgene or phosphoms oxychloride are also known (127). 

Quaternary Salts. Herbicides paraquat (20) and diquat (59) are the quaternary salts of 4,4 -bipyridine (19) and 2,2 -bipyridine with methyl chloride and 1,2-dibromoethane, respectively. Higher alkylpyridinium salts are used in the textile industry as dye ancillaries and spin bath additives. The higher alkylpyridinium salt, hexadecylpytidinium chloride [123-03-5] (67) (cetylpyridinium chloride) is a topical antiseptic. Amprolium (62), a quaternary salt of a-picohne (2), is a coccidiostat. Bisaryl salts of butylpyridinium bromide (or its lower 1-alkyl homologues) with aluminum chloride have been used as battery electrolytes (84), in aluminum electroplating baths (85), as Friedel-Crafts catalysts (86), and for the formylation of toluene by carbon monoxide (87) (see QuaternaryAA ONiUM compounds). 

Frontier orbital theory predicts that electrophilic substitution of pyrroles with soft electrophiles will be frontier controlled and occur at the 2-position, whereas electrophilic substitution with hard electrophiles will be charge controlled and occur at the 3-position. These predictions may be illustrated by the substitution behaviour of 1-benzenesulfonylpyr-role. Nitration and Friedel-Crafts acylation of this substrate occurs at the 3-position, whereas the softer electrophiles generated in the Mannich reaction (R2N=CH2), in formylation under Vilsmeier conditions (R2N=CHC1) or in formylation with dichloromethyl methyl ether and aluminum chloride (MeO=CHCl) effect substitution mainly in the 2-position (81TL4899, 81TL4901). Formylation of 2-methoxycarbonyl-l-methylpyrrole with... 

A/ -Methoxycarbonyl-2-pyrroline undergoes Vilsmeier formylation and Friedel-Crafts acylation in the 3-position (82TL1201). In an attempt to prepare a chloropyrroline by chlorination of 2-pyrrolidone, the product (234) was obtained in 62% yield (8UOC4076). At pH 7, two molecules of 2,3-dihydropyrrole add together to give (235), thus exemplifying the dual characteristics of 2,3-dihydropyrroles as imines and enamines. The ability of pyrrolines to react with nucleophiles is central to their biosynthetic role. For example, addition of acetoacetic acid (possibly as its coenzyme A ester) to pyrroline is a key step in the biosynthesis of the alkaloid hygrine (236). 

Although in general azoles do not undergo Friedel-Crafts type alkylation or acylation, several isolated reactions of this general type are known. 3-Phenylsydnone (120) undergoes Friedel-Crafts acetylation and Vilsmeier formylation at the 4-position, and the 5-alkylation of thiazoles by carbonium ions is known. 

Substituted pyrazoles are formylated (Vilsmeier-Haack reaetion) and aeetylated (Friedel-Crafts reaction) at C-4 (B-76MI40402). Both hydroxy and amino substituents in positions 3 and 5 facilitate the reaetion (80ACH(105)127,80CHE1), but the heteroatoms eompete with the C-substitution. For instanee, when the amino derivative (91 R = = Ph, R = H)... 

Isoxazoles are presently known to undergo hydrogen exchange, nitration, sulfonation, halogenation, chloroalkylation, hydroxymethylation, Vilsmeier-Haack formylation, and mercuration. The Friedel-Crafts reaction on the isoxazole nucleus has not yet been reported. 

Friedel-Crafts acylation usually fails (72AHC(14)43), but 3-substituted l-methyl-2,1-benzisothiazole 2,2-dioxides can be acetylated at the 5-position (73JHC249). l-Methyl-2,1-benzisothiazol-3-one can be chlorsulfonated at the 5-position (78JHC529). Vilsmeier-Haack formylation causes cleavage of the isothiazole ring (80JCR(S)197). 

This activation of the ortho position is most strikingly illustrated in the reactivity of 2,5-dimethylthiophene, which competitive experiments have shown to undergo the SnCb-catalyzed Friedel-Crafts reaction more rapidly than thiophene and even 2-methylthiophene. The influence of the reagent on the isomer distribution is evident from the fact that 2-methoxythiophene is formylated and bromi-nated (with A -bromosuccinimide) only in the 5-position. Similarly, although 3-bromo-2-methylthiophene has been detected in the bromi-nation of 2-methylthiophene with bromine, only the 5-isomer (besides some side-chain bromination) is obtained in the bromination of alkylthiophenes with A -bromosuccinimide. ° However, the mechanism of the latter type of bromination is not established. No lines attributable to 2-methyl-3-thiocyanothiophene or 2-methyl-3-chIoro-thiophene could be detected in the NMR spectra of the substitution products (5-isomers) obtained upon thiocyanation with thiocyanogen or chlorination with sulfuryl chloride. 2-Methyl- and 2-ethyl-thiophene give, somewhat unexpectedly, upon alkylation with t-butyl chloride in the presence of Feds, only 5-t-butyl monosubstituted and... 

The most important method for the synthesis of aromatic ketones 3 is the Friedel-Crafts acylation. An aromatic substrate 1 is treated with an acyl chloride 2 in the presence of a Lewis-acid catalyst, to yield an acylated aromatic compound. Closely related reactions are methods for the formylation, as well as an alkylation procedure for aromatic compounds, which is also named after Friedel and Crafts. 

The preparation of a formyl-substituted aromatic derivative 3 from an aromatic substrate 1 by reaction with hydrogen cyanide and gaseous hydrogen chloride in the presence of a catalyst is called the Gattermann synthesis This reaction can be viewed as a special variant of the Friedel-Crafts acylation reaction. 

The applicability of the Gattermann synthesis is limited to electron-rich aromatic substrates, such as phenols and phenolic ethers. The introduction of the formyl group occurs preferentially para to the activating substituent (compare Friedel-Crafts acylation). If the /jara-position is already substituted, then the ort/zo-derivative will be formed. 

While the Friedel-Crafts acylation is a general method for the preparation of aryl ketones, and of wide scope, there is no equivalently versatile reaction for the preparation of aryl aldehydes. There are various formylation procedures known, each of limited scope. In addition to the reactions outlined above, there is the Vdsmeier reaction, the Reimer-Tiemann reaction, and the Rieche formylation reaction The latter is the reaction of aromatic compounds with 1,1-dichloromethyl ether as formylating agent in the presence of a Lewis acid catalyst. This procedure has recently gained much importance. 

In an initial step the reactive formylating agent is formed from N,N-dimethylformamide (DMF) 2 and phosphorus oxychloride. Other N,N-disubstituted formamides have also found application for example A -methyl-A -phenylformamide is often used. The formylating agent is likely to be a chloromethyl iminium salt 4—also called the Vilsmeier complex (however its actual structure is not rigorously known)—that acts as the electrophile in an electrophilic substitution reaction with the aromatic substrate 1 (see also Friedel-Crafts acylation reaction) ... 

Of great importance for porphyrin chemistry is the introduction of carbon substituents by Vilsmeier formylation100 or Friedel-Crafts acylation.100 The introduced substituents allow further carbon-chain elongations and other transformations so that interesting porphyrin derivatives can be synthesized. The Vilsmeier formylation of copper octaethylporphyrin (5) takes place at themethine position. The copper can then be easily removed by treatment with acid.105... 

Both Friedel-Crafts acetylation and Vilsmeier formylation of the 2,3-dihydrooxazole 5 occur at C-5, indicating that the A-acyliminium ion is more stable than the oxonium ion17. This is corroborated by ab initio calculations, which show that 3-formyl-2,5-dihydro-3-oxazolium 7 is ca. 46 kJ mol 1 more stable than 3-formyl-2,4-dihydro-l-oxazolium 817. 

Formaldehyde-to-phenol ratios, 404 V-Formyl amines, 158 Fourier transform infrared (FTIR) spectrometry, 116, 300, 387, 407-408 Fradet, Alain, 17 Free-radical copolymerization, 59 Friedel-Crafts acrylation polymerization, 332-334... 

Besides 11-15-11-17, several other formylation methods are known. In one of these, dichloromethyl methyl ether formylates aromatic rings with Friedel-Crafts catalysts.The Compound ArCHClOMe is probably an intermediate. Orthoformates have also been used. In another method, aromatic rings are formylated with... 

Carbon monoxide, hydrogen cyanide, and nitriles also react with aromatic compounds in the presence of strong acids or Friedel-Crafts catalysts to introduce formyl or acyl substituents. The active electrophiles are believed to be dications resulting from diprotonation of CO, HCN, or the nitrile.64 The general outlines of the mechanisms of these reactions are given below. 

Fluorenecarboxylic acid, 33, 37 Formaldehyde, 30, 51 33, 72 a-Formylethyl methyl ketone, 32, 34 Formyl isobutyl ketone, 32, 34 Friedel-Crafts reaction, 30, 1 31, 88 32, 10... 

Friedel-Crafts acylation reactions of aromatics are promoted by Tilv complexes.104 In some cases, a catalytic amount of the titanium compound works well (Scheme 28). In addition to acyl halides or acid anhydrides, aldehydes, ketones, and acetals can serve as electrophile equivalents for this reaction.105 The formylation of aromatic substrates in the presence of TiCl4 is known as the Rieche-Gross formylation metalated aromatics or olefins are also formylated under these conditions.106... 

Other electrophilic substitution reactions on aromatic and heteroaromatic systems are summarized in Scheme 6.143. Friedel-Crafts alkylation of N,N-dimethyl-aniline with squaric acid dichloride was accomplished by heating the two components in dichloromethane at 120 °C in the absence of a Lewis acid catalyst to provide a 23% yield of the 2-aryl-l-chlorocydobut-l-ene-3,4-dione product (Scheme 6.143 a) [281]. Hydrolysis of the monochloride provided a 2-aryl-l-hydroxycyclobut-l-ene-3,4-dione, an inhibitor of protein tyrosine phosphatases [281], Formylation of 4-chloro-3-nitrophenol with hexamethylenetetramine and trifluoroacetic acid (TFA) at 115 °C for 5 h furnished the corresponding benzaldehyde in 43% yield, which was further manipulated into a benzofuran derivative (Scheme 6.143b) [282]. 4-Chloro-5-bromo-pyrazolopyrimidine is an important intermediate in the synthesis of pyrazolopyrimi-dine derivatives showing activity against multiple kinase subfamilies (see also Scheme 6.20) and can be rapidly prepared from 4-chloropyrazolopyrimidine and N-bromosuccinimide (NBS) by microwave irradiation in acetonitrile (Scheme... 

---