Formylating agents

My early work with acyl fluorides also involved formyl fluoride, ITCOF, the only stable acyl halide of formic acid, which was first made in 1933 by Nyesmeyanov, who did not, however, pursue its chemistry. 1 developed its use as a formylating agent and also explored formyla-tion reactions with CO and HF, catalyzed by BF3. 

The anhydride of formic acid has not been isolated, but mixed anhydrides are known, and, with acetic acid, the latter have utifity as formylating agents (22). The only known formyl haUde is the fluoride, which has a boiling poiat of —29° C. 

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) ... 

Dibenzothiophene has recently been synthesized from 2-allylbenzo-[fcjthiophene (24) by treatment with dichloromethyl butyl ether and anhydrous stannic chloride at low temperatures, as shown in Eq. (1) (55%). This sequence has been extended by the use of substituted allyl groups and modified formylating agents to yield dibenzothiophenes substituted in the 1-, 1,3-, and 3-positions. For example, treatment of 2-allylbenzo[6]thiophene with the modified formylating agent EtOCCl2-... 

D Ambrosio, M. GuerriCTO, A. Dd)itus, C. Ribes, O. Pi a, F. (1993) On the novel free porphyrins corallistin B, C, D, and E. Isolation from the demosponge Corallisles sp. of the Coral Sea and reactivity of their nickel(II) complexes toward formylating agents. Helv. Chim. Acta, 76, 1489-96. 

Similarly, poly (p-formyloxy styrene) (IV) can be prepared by formylation of poly(p-hydroxystyrene) using formic acid-acetic anhydride mixture as a formylating agent (Scheme 4). The formylation reaction is best... 

Ferrocene is similar to other highly reactive aromatic systems, in that it is readily formylated by N-methylformanilide in the presence of phosphorus oxychloride (5, 29, 107, 113, 118). Only the mono-substituted product, ferrocene-carboxaldehyde (XVI), is produced even when a large excess of formylating agent is used. 

The limit is reached with 1,3,5-triazine. This reacts very easily even with weak nucleophiles, and ring cleavage nearly always follows. Thus, it behaves as a formylating agent toward amines and other active hydrogen compounds. 

Approach B generate metal-carbon bond Possible routes (i) attack by formylating agent 0=CHX (ii) oxidative addition of 0=CH2... 

After the formation of a 1 1 substrate - Lewis acid adduct, the rearrangement proceeds in two steps, beginning with the cleavage of the ester bond and the release of formyl chloride in situ, which, in turn, acts as a formylating agent, introducing... 

The formylating agent, also known as the Vilsmeyer-Haack Reagent, is formed in situ from DMF and phosphorus oxychlorid ... 

Importantly, a Friedel-Crafts formylation has not yet been successful. Formyl chloride and formic anhydride are not stable reagents. The mixed anhydride H—C(=0)—O—C(=0)CH3 acts as a formylating reagent in reactions with many nucleophiles (cf. Section 6.3.3). However, in reactions with aromatic compounds under Friedel-Crafts conditions, it acts as an acetylating agent rather than as a formylating agent. Last but not least, formic acid and mineral acids proceed to react via the acylium ion H—C=0 to form carbon monoxide and water in an OC-elimination. We ll solve this problem later. 

Formate. .. is quite unreactive under physiological conditions and must be activated to serve as an efficient formylating agent. The fundamental importance of [THF] is to maintain formaldehyde and formate in chemically poised states, not so reactive as to pose toxic threats to the cell but available for essential processes by specific enzymatic action. 

The Vilsmeier formylation has been used for the solid-phase functionalization of five different 2-carboxyindoles 375 (Equation 86) <2001JC0542>. In all experiments the formylating agent was prepared in a separate vessel and resins 375 were added to the mixture after 20 min in 1,2-dichloroethane. The reaction time and the equivalents of formylating agent were kept constant in each attempt (16 h and lOequiv, respectively). The aldehyde functionality has been utilized in the preparation of 0-benzylhydroxyureas. 

In the H4folate system, formate is the formylating agent for A °-formyl-H4folate synthesis this reaction requires ATP (Fig. 5) ... 

Dehydrogenations of piperazines to pyrazines have been described in Section II.6, and the conversion of piperazine over catalysts (e.g., CuO) to give mostly pyrazine (90-94%) has been studied (1718). The oxidation of 1,4-diphenylpiperazine with manganese dioxide in chloroform at 20° to yield A, A -diformyl-A(, -diphenyl-ethylenediamine has been reported (1719). Formylpiperazines have been reported as formylating agents. Thiophene, 1,4-diformylpiperazine, and phosphoryl chloride are reported to give 2-formylthiophene (1720). 

Mixed Claisen condensations are feasible when one partner does not have acidic a-hydrogens, as in EtO-CHO (a formylating agent), PhC02Et, Et02CCO2Et, and (Et0)2C=0 (an ethoxycarbonylating agent). Eormate esters are the most reactive since they are part aldehyde. ... 

From formylation reactions of CH-acidic compounds, which take place if mixtures of carboxylic acid amides and anhydrides are used as formylating agents, it was concluded that the latter compounds form similar adducts to those from amides and acid halides. ... 

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