Haack Formylation

R = alkyl, aryl acid chloride POCI3, SOCl2,COCl2, (COCI)2, Ph3PBr2, 2.4.6-trichloro-1.3.5-triazine solvent DCM, DMF, POCI3 EDG = OH, O-alkyl, O-aryl, NR2 R = H, alkyl, aryl R = alkyl, aryl X = O, NR, CH2, CR2 Y = O, S, NR, NH R = H, alkyl, aryl 

Formation of the Vilsmeier reagent (an equilibrium mixture of iminium salts)  

Electrophilic aromatic substitution of the electron-rich aromatic substrate followed by hydrolysis  

The total synthesis of the calophylium coumarin (-)-calanolide A was accomplished by D.C. Baker and co-workers. This compound attracted considerable attention because it is a potent inhibitor of HIV-1 reverse transcriptase. In order to introduce a formyl group at C8, a regioselective Vilsmeier reaction was employed on a coumarin lactone substrate. 

In the laboratory of F.E. Ziegler, the cyclization of a chiral aziridinyl radical into an indole nucleus was utilized to prepare the core nucleus of the potent antitumor agent FR-900482. In the early stages of the synthetic effort, the VUsmeier-Haack formylation was chosen to install an aldehyde functionality at the C3 position of a substituted indole substrate. The initial iminium salt was hydrolyzed under very mildly basic conditions to minimize the hydrolysis of the 

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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). 

Vilsmeier-Haack formylation, 4, 222 Indole, dimethyl- C NMR, 4, 172 Indole, 1,2-dimethyl-bis-allylation, 4, 357 Indole, 1,3-dimethyl-nitration, 4, 211 reactions... 

UV spectroscopy, 4, 178, 179 vertical resonance energy, 4, 191 Vilsmeier-Haack formylation, 4, 221, 222 3H-Indoles... 

Vilsmeier-Haack formylation, 6, 26 Isoxazole, 3-anilino-nitration, 6, 22... 

Vilsmeier-Haack formylation, 6, 26 Isoxazole-3-thiol, 5-phenyl-reactions, 6, 57 Isoxazolethiols reactions, 6, 57 Isoxazole-3-thiols synthesis, 6, 57, 88 Isoxazole-5-thiols synthesis, 6, 88... 

Vilsmeier-Haack formylation, 4, 222 Pyrrole, 3-acetyl-oxidation, 4, 289 protodeaeetylation, 4, 208 synthesis, 4, 218... 

Vilsmeier-Haack formylation of 2-(4-methyl-l-piperazinyl)-4//-pyrido-[l,2-n]pyrimidin-4-one with a mixture of POCI3 and DMF at 95°C gave a 3-formyl derivative (93FES1225) while ethyl 4-oxo-6,7,8, 9-tetrahydro-4//-pyrido[l,2-n]pyrimidine-2-acetate at 50 °C yielded a 9-dimethylaminomethylene-3-formyl derivative (01MI4). 3-Formyl-2-hydroxy-8-[2-(4-isopropyl-l,3-thiazol-2-yl)-l-ethenyl]-4//-pyrido[l,2-n]pyri-midin-4-one was obtained from the 3-unsubstituted derivative with oxalyl chloride-DMF reagent in CH2CI2 at room temperature for 3h (OlMIPl). 

Vilsmeyer-Haack formylation of 7-hydroxy-2,3,6,7-tetrahydro-l//,5//-pyrido[3,2,l-y]quinazoline-l,3-dione with POCI3/DMF gave 7-chloro-6-formyl-2,3-dihydro-l//,5// derivative. Boiling a toluene solution of the aforementioned 7-hydroxy derivative in the presence of pTSA yielded dehydrated 2,3-dihydro derivative (01MI28). 

Based on studies showing that the close proximity between the porphyrin and the Cm is essential for the observation of an electron transfer process, Fukuzumi and co-workers have prepared the porphyrin-C6o diad 41, in which the C6o-pyrrolidinyl moiety is directly connected to the meso position of the porphyrin macrocycle (Scheme 12) <03JPC(A)8834>. The strategy adopted for the synthesis of the starting porphyrin involved the 2+2 condensation of a maso-unsubstituted dipyrrylmethane with 3,5-di-tert-butylphenyl-substituted dipyrrylmethane and 3,5-di-tert-butylbenzaldehyde, to give 39, in 11.5% yield. Subsequent Ni(II) metallation, followed by Vilsmeier-Haack formylation and demetallation, gave rise to 40 which was used as the 1,3-dipole precursor this dipole in the presence of N-methylglycine and C6o, yielded the expected diad 41. 

When there is an electron-releasing substituent in the 4-position, the electrophile attacks the 1-position. This has been used as a convenient way of preparing 1-substituted dibenzofurans by removal of an amino group at the 4-position. Bromination, chlorination, and diazo coupling of 4-dibenzofuranol occur at the 1-position. Bromination and Vilsmeier-Haack formylation of 4-methoxydibenzofuran provide the 1-substituted derivatives. Nitration and bromination of 4-acetylaminodibenzofuran take a similar course. ... 

Transformation of both the ester and nitrile derivatives 726 or 727 into pyrano[2,3-t7 pyridazines 728 or 729, respectively, by treatment with dilute HCl at room temperature involved nucleophilic displacement of the morpholine group by the hydroxyl group with an acidic hydrolysis followed by intramolecular iminolactonization and then hydrolysis of the formed imino group to a carbonyl group. Compounds 726 and 727 were prepared by Vilsmeier-Haack formylation of 2-methyl-5-morpholino-3(2/7)-pyridazinone 724 followed by condensation of the resulting product 725 with either ethyl a-cyanoacetate or malononitrile in EtOH (Scheme 34) <1994H(37)171>. 

Benzodipyrrole 1 is selectively formylated at the 3- and 6-positions by a Vilsmeier-Haack reaction to produce 3,6-diformylbenzodipyrrole which is reduced by lithium aluminium hydride to give 3,6-dimethylbenzodipyrrole. This can also undergo subsequent Vilsmeier-Haack formylation to afford the 2,5-dialdehyde (Scheme 2) <2005AGE4053>. 

Vielsmeier-Haack formylation of 2-nitro-6,7,8,9-tetrahydro-l 1 //-pyrido-[2,l-b]quinazolin-l 1-one (120, R = 2-N02) (84JHC219) and 1,2,3,4,6,7,8,9-octahydro-ll//-pyrido[2,l-6]quinazolin-l 1-one and its 8- and 9-methyl derivatives (87JHC1045) with a mixture of phosphoryl chloride and dimethyl-formamide at 15-20°C gave 6-formyl-2-nitro-5,7,8,9-tetrahydro- (122) and 6-formyl-l,2,3,4,5,7,8,9-octahydro-ll//-pyrido[2,l-b]quinazolin-ll-ones. 

The Vilsmeier-Haack formylation procedure (Scheme 24) provides the most effective synthesis of formylpyrroles and indoles. Reaction of the heterocycles with the immonium cation (72), derived from DMF or (V-methylformanilide with an acid chloride, such as phosphorus oxychloride, thionyl chloride, phosgene, oxalyl chloride, benzoyl chloride or bromotriphenylphosphonium bromide, yields the intermediate heteroarylimmonium salt (73). Under suitable reaction conditions, this salt may be isolated from the reaction involving phosphorus oxychloride as an impure chlorophosphate (78TH30500) or precipitated from the reaction system as the thermally unstable perchlorate by the addition of sodium... 

Vilsmeier-Haack formylation of carbazoles yields the 3-formyl derivatives (81CKD338). 

CAi90) 123047). The isolation of 2-chloro-5-formylpyrrole from the Vilsmeier-Haack formylation of 2-bromopyrrole (75JOC3161) can be rationalized in terms of an addition-elimination reaction of the intermediate azafulvenium cation (Scheme 82). Displacement... 

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