Under Vilsmeier conditions

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... 

Perumal investigated a novel variation that involved the combination of a Vilsmeier reaction with a Paal-Knorr condensation. Reaction of 3-benzoylpropionic acid (87) under Vilsmeier conditions furnished chloroformylfuran 88 in 75% yield, while reaction of acetonylacetone (89) provided formylfuran 90 in 60% yield." ... 

Heterocyclization under Vilsmeier conditions and its possibilities in drug research 95E439. 

With respect to aromatic substrates, the Vilsmeier formylation reaction works well with electron-rich derivatives like phenols, aromatic amines and aromatic heterocycles like furans, pyrroles and indoles. However various alkenes are also formylated under Vilsmeier conditions. For example the substituted hexatriene 6 is converted to the terminal hexatrienyl aldehyde 7 in 70% yield ... 

Treatment of tricarbonylh4-1-(ethoxycarbonyl)-l//-azepine]iron(0) (30) with acetic anhydride and tetrafluoroboric acid at 0 C (Method A) yields the 3-acetyl derivative 31.226 The acetyl derivative is also formed, but in lower yield, by the action of acetic anhydride and tin(IV) chloride (Method B) on complex 30. The 3-propanoyl derivative (20% mp 95-96 C) can be prepared similarly, whereas formylation to give aldehyde 32 is successful under Vilsmeier conditions. 

Nitration with concentrated nitric acid in acetic anhydride and glacial acetic acid affords a mixture of 2- and 3-nitrothiophenes (in the ratio 6 1) (Scheme 6.33). However, bromination with bromine in diethyl ether and 48% hydrobromic acid, starting at -25 °C and allowing the reaction temperature to rise to -5 °C, gives 2-bromothiophene. If the experiment is initiated at -10 °C and the temperature is then allowed to rise to + 10 °C, 2,5-dibromothiophene is formed. 2,3,5-Tribromination occurs in 48% hydrobromic acid, starting the experiment at room temperature and allowing the temperature to rise to 75 °C. Acetylation with acetyl chloride in the presence of the Lewis acid tin(IV) chloride gives 2-acetylthiophene, and efficient 2-formylation takes place under Vilsmeier conditions (see Section 6.1.2). 

Kislyi et al. facilitated the formation of [l,2,3]triazolo[4,5-r lpyrimidin-7-ones from 5-amino-l,2,3-triazole-4-carbox-amides under Vilsmeier conditions (Scheme 47) or using triethyl orthoacetate and acetic anhydride (Scheme 48) <2003RCB1770>. These methods could be used to isolate the respective 5-formamidine 69 and 5-imidoate 70 reaction intermediates, if lower temperatures and shorter reaction times were employed. 

Duocarmycin derivative 99 does not undergo formylation under Vilsmeier conditions at the expected position in the A-ring, but instead is formylated at the amine group of the C-ring although no yields are reported for this transformation <2000BMC1195>. 

Direct electrophilic substitution of benz- and dibenz-azepines remains relatively unexplored. Most substituted benzazepines have been prepared from benzene precursors bearing the desired substituents (74AHC(17)45). The bulk of the reported electrophilic substitutions have been carried out on 5//-dibenz[6,/]azepine (74CRV101), MO calculations on which predict that substitution should occur at the 2- and 4-positions, i.e. para and ortho to the azepine ring nitrogen. These predictions are borne out by Friedel-Crafts alkylation and acylation studies, although it is apparent that a second alkyl group enters at the 8- rather than at the 4-position. Formylation under Vilsmeier conditions yields the 2-aldehyde. As noted earlier (Section 5.16.3.4), however, the 10,11-dihydro system exhibits different behavior and acylates at the benzylic 10,11-positions. Nitration with mixed acids of the... 

Substitution products can be obtained from some 1,4-dithiins. Thus, 2,5-diphenyldithiin is formylated under Vilsmeier conditions, and mono- or di-nitrated and brominated in the heterocyclic ring. 1,4-Benzodithiin shows similar properties (see Scheme 51). 

Formylation of 2-methoxycarbonyl-l-methylpyrrole with dichloromethyl methyl ether and aluminum chloride occurs in the 4-position, while under Vilsmeier conditions the main product is the 5-formyl derivative (78JOC4849). 

Oxidation gives stable radicals (442) which form cycloadducts with dipolarophiles (e.g. 443) (85TL4801). Radicals formed from 3-imidazoline 1-oxides or l-hydroxy-3-imidazolines can be formylated on nitrogen under Vilsmeier conditions and exocyclically brominated or chlorinated by NBS or NCS on a 4-methyl group. 

Interestingly, o-cyanomethoxybenzonitrile (26) gives a Thorpe-Ziegler type of cyclization under Vilsmeier conditions (DMF/POCl3), that is without the addition of a base. Further cyclization of the assumed 3-amino-2-cyanobenzofuran 27 with the Vilsmeier reagent afforded benzofuro-[3,2-d]pyrimidine (28) in poor yield, (91JHC263) (Scheme 7). 

Furo[3,2-fa]benzothiophenes (37) were synthesized in an analogous way (91JHC269) by smooth cyclization of the cyanomethyl ether 36 in the presence of K2C03/DMF. The starting 2-cyano-3-hydroxybenzothiophene 35 was obtained from methyl 2-thiohydroxybenzoate and chloroacetonitrile. Under Vilsmeier conditions (POCl3/DMF), the 2-cyano-3-cyanomethoxy-... 

Formylation of dibenzylketone under Vilsmeier conditions occurs at both methylene groups the tricarbonyl compound closes to give a pyranone which is unsubstituted at the 2- and 6-positions (73ZC175). 

Hydroxyacetophenone reacts with DMF under Vilsmeier conditions to yield chromone-3-carbaldehyde (72LA(765)8). The reaction appears to be generally applicable, various substituents being acceptable in the aromatic ring (74T3553). Furthermore, acetylhydroxy-naphthalenes yield the corresponding benzochromones, and the pyranochromone (452) is formed from the appropriately substituted coumarin. 

In contrast to these two dithiins, the 2,5-diphenyl derivative (47) is much more stable to electrophilic reagents and undergoes various substitution reactions in the dithiin ring. Thus (47) can be smoothly monoformylated under Vilsmeier conditions and mono- and di-nitrated or -brominated. Sequential nitration and bromination gives the tetrasubstituted derivative (48) (B-61MI22601). 

Tlie apparent ease with which certain of the sulfur-containing compounds undergo electrophilic substitution reactions has been considered significant in discussions of the aromaticity of these ring systems e.g. (66HC(21-2)1146). However, whilst this type of reactivity is normally associated with aromatic character it is important to note that the open-chain di(phenylthio)ethylene (52) is also smoothly formylated at the double bond under Vilsmeier conditions to give (53) (B-61MI22601). 

Cyclic enamines and imines, 6, 147 Cyclic hydroxamic acids, 10, 199 Cyclic peroxides. 8, 165 Cyclizations under Vilsmeier Conditions, 31, 207... 

It was reported in 1977 that reaction of 3-phenyl-5-isoxazolone with excess of POCI3 in DMF under Vilsmeier conditions gave the isoxazoline 1. Treatment of 1 with MeOH/NaOMe and with 10% NaOH solution was claimed to give the aldehyde 2 and the azirine 3 respectively. 

Ring closure of (17) under Vilsmeier conditions led to pyridine compound (18) (Scheme 12) <95JHC(32)505>. 

Ring closure under Vilsmeier conditions leads to the pyridine structure (Equation 90) <1995JHC505>. 

Aminothienopyrimidines 81 were reacted under Vilsmeier conditions to give the corresponding 4-dimethylaminomethyleneamino derivatives... 

Cyclazinium salts 48 were obtained under Vilsmeier conditions from 5-methylene-4-azaazulenes 28 on a route shown in Scheme 4 (83CB1174). 

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