Pyridine 1-oxide reaction with acetic anhydride

A powerful oxidizer. Explosive reaction with acetaldehyde, acetic acid + heat, acetic anhydride + heat, benzaldehyde, benzene, benzylthylaniUne, butyraldehyde, 1,3-dimethylhexahydropyrimidone, diethyl ether, ethylacetate, isopropylacetate, methyl dioxane, pelargonic acid, pentyl acetate, phosphoms + heat, propionaldehyde, and other organic materials or solvents. Forms a friction- and heat-sensitive explosive mixture with potassium hexacyanoferrate. Ignites on contact with alcohols, acetic anhydride + tetrahydronaphthalene, acetone, butanol, chromium(II) sulfide, cyclohexanol, dimethyl formamide, ethanol, ethylene glycol, methanol, 2-propanol, pyridine. Violent reaction with acetic anhydride + 3-methylphenol (above 75°C), acetylene, bromine pentafluoride, glycerol, hexamethylphosphoramide, peroxyformic acid, selenium, sodium amide. Incandescent reaction with alkali metals (e.g., sodium, potassium), ammonia, arsenic, butyric acid (above 100°C), chlorine trifluoride, hydrogen sulfide + heat, sodium + heat, and sulfur. Incompatible with N,N-dimethylformamide. 

Treatment of 4-ethoxy-6-methylpyrimidine-l-oxide (602) with acetic anhydride at 25-35 °C in chloroform followed by the addition of diketene at <20°C caused an exothermic reaction from which was isolated 7-acetyl-4-ethoxy-2-methyloxazolo[4,5-c]pyridine (603) (22%) and 7-acetyl-4-ethoxy-3-methylisoxazolo[4,5-c]pyridine (604) (8%) (88CPB168). A plausible mechanism for the formation of the isomers (603) and (604) is shown in Scheme 77. Acetylation with acetic anhydride furnishes an initial intermediate, l,2-diacetoxy-l,2-dihydropyrimidine (605). Electrophilic attack by diketene at C-5 then yields an acetoacetyl intermediate (606). Ring-opening and recyclization of (606) then gives via intermediates (607) and (608) the pyridine (609). Compound (609), which is not... 

Reaction of the N-oxide (44) with acetic anhydride-pyridine provides a direct means for the in situ generation of the highly reactive dehydrosecodine intermediate (45). This species undergoes spontaneous cyclization to give vincadifformine (46 12%) via an intramolecular Michael reaction followed by B/c ring closure (Scheme 8). i((-Vincadifformine (48) is also produced in this reaction via the enamine... 

Nucleophilic substitution by halide, cyanide, carbon nucleophiles, such as enamines, and acetate (by reaction with acetic anhydride), with concomitant loss of the oxide function, occur smoothly in all three systems, though the site of introduction of the nucleophile is not always that predicted by analogy with pyridine chemistry (a to the AT-oxide), as illustrated by two of the examples below. 

Reaction with acetic anhydride/pyridine yielded the monoacetate (CX), confirming the presence of only one secondary hydroxyl group in browniine. Permanganate oxidation of CX produced the lactam CXI which when hydrolyzed yielded oxobrowniine (CXII). Reduction of dehydrooxobrowniine with sodium borohydride gave predominantly... 

Reaction with (V-Oxides. Pyridine 1-oxide reacts with acetic anhydride to produce 2-acetoxypyridine, which can be hydrolyzed to 2-p3Tidone (eq 38). ... 

Alkoxythiazoles are prepared by heterocyclization (274, 462). The Williamson method using catalytic amounts of KI and cupric oxide is also possible (278. 288, 306). 5-Acetoxy-4-alkenylthiazoles are obtained by treatment of 242 with acetyl chloride and triethylamine or with acetic anhydride and pyridine (450). Similarly, the reaction of diphenylketene with 242 affords 5-acyloxy-4-alkenylthiazoles (243) (Scheme 120) (450). The readiness of these o-acetylations suggests that 4-alkylidene thiazoline-5-one might be in equilibrium with 4-alkenyl-5-hydroxythiazoles (450). 

The N-oxide function has proved useful for the activation of the pyridine ring, directed toward both nucleophilic and electrophilic attack (see Amine oxides). However, pyridine N-oxides have not been used widely ia iadustrial practice, because reactions involving them almost iavariably produce at least some isomeric by-products, a dding to the cost of purification of the desired isomer. Frequently, attack takes place first at the O-substituent, with subsequent rearrangement iato the ring. For example, 3-picoline N-oxide [1003-73-2] (40) reacts with acetic anhydride to give a mixture of pyridone products ia equal amounts, 5-methyl-2-pyridone [1003-68-5] and 3-methyl-2-pyridone [1003-56-1] (11). 

Other reactions with their counterparts in the pyridine series are also well known. Thus, 2,3-dimethylpyrazine 1,4-dioxide reacts with acetic anhydride to yield 2,3-bis(acetoxy-methyl)pyrazine (S3) in good yield (72KGS1275). Pyrazine 1-oxide also reacts directly with acetic anhydride to yield 2(ljH)-pyrazinone by way of the intermediate acetate (Scheme 22). The corresponding reaction in the quinoxaline series is not so well defined and at least three products result (Scheme 23) (67YZ942). 

Protection of an alcohol function by esterification sometimes offers advantages over use of acetal or ether groups. Generally, ester groups are stable under acidic conditions. Esters are especially useful in protection during oxidations. Acetates and benzoates are the most commonly used ester derivatives. They can be conveniently prepared by reaction of unhindered alcohols with acetic anhydride or benzoyl chloride, respectively, in the presence of pyridine or other tertiary amines. 4-Dimethylaminopyridine (DMAP) is often used as a catalyst. The use of A-acylimidazolides (see Section 3.4.1) allows the... 

Nitration of pyridines in other than nitric or sulfuric acids is of little interest here because either no reaction or N-nitration takes place (see Section 2.05.2.10). However, pyridine 1-oxide is considerably more reactive and treatment with benzoyl nitrate ultimately leads to the 3-nitro derivative (Scheme 25) (60CPB28). Annelation of a benzene ring bestows greater reactivity on the 3-position in quinoline, compared with pyridine, and reaction with nitric acid in acetic anhydride furnishes the 3-nitro derivative (ca. 6%) (Scheme 26). This isomer has also been obtained, again at low yield (6-10%), by treatment of quinoline with tetranitratotitanium(IV) in carbon tetrachloride (74JCS(P1)1751>. Nitration of benzo analogues of pyridine occurs much more readily in the benzene ring, and Chapter 2.06 should be consulted for these reactions. 

N-Oxides are normally resistant to hydroxide attack. However, acetic anhydride converts the N-oxide group into iV-acetoxy cations, and such compounds can be attacked by acetate anions. Thus, the reaction of acetic anhydride with pyridine /V-oxide gives 2-pyridone (Scheme 17). This is a very... 

Knoevenagel reaction. Hydrogenation of the double bond, desilylation and oxidation of the released primary alcohol group to the aldehydic function with PCC in dichloromethane in the presence of molecular sieves, gives the branched chain L-riho-hepturonic acid derivative 31. Treatment with acetic anhydride and pyridine results in cyclization, and acetylation of the resulting alcohol affords the acetate 32 in 69% yield. 

The permanganate oxidation of axial and equatorial vinyl orthoesters 140 and 141 was carried out in a buffered solution (pH =10) mixed with acetonitrile. The reaction mixture was then esterified with acetic anhydride and pyridine. Both vinyl orthoesters gave an identical result >95% of acetoxy ester J46 and <5% of bicyclic lactone 147. 

Omeprazole is obtained [15] by the reaction of acetyl ethyl propionate 1 with ammonia to give ethyl -3-amino-2,3-dimethyl acrylate 2. Compound 2 was converted to to 2,4-dihydroxy-3,5,6-trimethyl pyridine 3 by treatment with methyl diethylmalonate. Treatment of compound 3 with phosphorous oxychloride produced 2,4-dichloro-3,5/6-trimethyl pyridine 4. 4-Chloro-3/5,6-trimethyl pyridine 5 was obtained by treatment of compound 4 with hydrogen. On treatment of compound 5 with hydrogen peroxide and acetic acid, 4-chloro-3,5,6-trimethyl-pyridine-N-oxide 6 was produced. Treatment of compound 6 with acetic anhydride gave 4-chloro-2-hydroxymethyl-3,5-dimethyl pyridine 7 which was converted to 2-hydroxymethyl-3,5-dimethyl-4-methoxypyridine 8 by treatment with sodium methoxide. Compound 8 was treated with thionyl chloride to produce 2-chloromethyl-3,5-dimethyl-4-methoxypyridinc 9. Compound 9 interacts with 5-methoxy-2-mercaptobenzimidazole to give 5-methoxy 2-[((4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)thio]-lH-bcnzimidazole 10 which is oxidized to omeprazole 11. 

In a remarkably simple synthesis95 of the corticosteroid side chain (Scheme 10) the oxime (208) was refluxed with acetic anhydride in pyridine to form the enamide (209) which with lead tetra-acetate in benzene under strictly anhydrous conditions gave the acetylimino-compound (210) (90%). Isomerization of (210) with acetic acid-trichloroacetic acid formed the enamide (211) (100%) further lead tetra-acetate oxidation gave the acetylimine (212) (84%). Compound (212) was quantitatively hydrolysed with aqueous acetic acid to the a-acetoxy-ketone (213) and thus led to a rapid synthesis of cortisone. These reactions are essentially one pot syntheses. 

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