Pyridines cyclization

The Skraup reaction and Friedlander synthesis have found application in the preparation of pyrazolo[3,4-fc]pyridines. Cyclization of l-benzyl-5-aminopyrazoles (51 R1 = CH2Ph R2 = H,Me)88,89 under usual Skraup conditions gave the 1-benzyl derivatives (73) in moderate yield. The 1 -H derivative (73, R1 = H, R2 = Ph), however, was isolated only in poor yield.89... 

Thus, when the aldopentose diethyl dithioacetals are treated with 1 mole of p-toluenesulfonyl chloride in pyridine, cyclization to form a 2,5-anhy-dride is observed in each instance except in the arabino series, where a 5-O-p-tolylsulfonyl derivative can be isolated. It may be supposed (23) that the energy of activation for the cyclization reaction, being the difference between the ground-state and the transition-state energies, is smaller in those stereoisomers where conformational factors bring 0-2 into close... 

Protocol 6 involves heating Mannich compound 10 in DMSO, apparently causing elimination of dimethylamine and formation of enone 20 as a reactive intermediate. The corresponding enone has been synthesized in the 9-butyl series,6,22 but comparable yields are obtained in pyridine cyclization reactions involving either the preformed enone or the Mannich HQ salt.7 Prior to addition of 10, ketone 9 is heated with ammonium chloride in DMSO to promote the formation of imine 21. Isomerization of this imine to the enamine tautomer 22, Michael addition of this nucleophile to enone 20, and elimination of water account for the formation of product 11. Like many polycyclic terpyridyl analogues, this product is sparingly soluble in DMSO and is readily isolated by filtration of the reaction mixture. 

In possibly the first synthesis of an imidazothiazine, treatment of (703) with potassium isothiocyanate afforded (704), which upon heating in pyridine cyclized to 6-amino-2-bromo-l,5-dihydroimidazo[4,5-e][1.3]thiazine (705) (34JIC867). 

This group was developed as an oxidatively cleavable group for 5-protection in oligonucleotide synthesis. It is prepared either from the carhonylimidozolide or the 4-nitrophenyl carbonate. Alternatively the alcohol to be protected can be treated with carbonyl diimidazole followed by sulfenyl protected diol. Yields range from 70% to 93%. The MTFOC group is cleaved upon oxidation with I2, which releases the alcohol that in the presence of pyridine cyclizes to form a carbonate with release of the nucleotide. The oxidation step is fast (<1 min), and the cyclization to form the carbonate has a half-life of 51 min. ... 

With the catalysis of strong Lewis acids, such as tin(IV) chloride, dipyrromethenes may aiso be alkylated. A very successful porphyrin synthesis involves 5-bromo-S -bromomethyl and 5 -unsubstituted 5-methyl-dipyrromethenes. In the first alkylation step a tetrapyrrolic intermediate is formed which cyclizes to produce the porphyrin in DMSO in the presence of pyridine. This reaction sequence is useful for the synthesis of completely unsymmetrical porphyrins (K.M. Smith, 1975). 

Probably first obtained by Hantzsch and Arapides (105) by condensation of a,/3-dichlorether with barium thiocyanate, and identified by its pyridine-like odor, thiazole was first prepared in 1889 by G. Popp (104) with a yield of 10% by the reduction in boiling ethanol of thiazol-2-yldiazonium sulfate resulting from the diazotization of 2-aminothiazole. prepared the year before by Traumann (103). The unique cyclization reaction affording directly the thiazole molecule was described in 1914 by Gabriel and Bachstez (106). They applied the method of cyclization, developed by Gabriel (107, 108), to the diethylacetal of 2-formylamino-ethanal and obtained thiazole with a yield of 62% - Thiazole was also formed in the course of a study on the ease of decarboxylation of the three possible monocarboxylic acids derived from it (109). On the other... 

Metliylpyridine can also be prepared by the condensation of acrolein and ammonia. Yields of 40—50% are obtained with pyridine as a by-product. Higher yields have been claimed when both propionaldehyde and acrolein have been used. A recent U.S. patent claims better selectivity if the cyclization is carried out in the presence of 2eohtes (3). 

Only one successful penem synthesis involving a [nitrogen, C-3] ring closure has been described (119). Cyclization of the ketomalonate (79) usiag hydrofluoric acid-pyridine afforded the penams (80) which were converted to the penem (81). Attempts to adapt the versatile diazoketoester-carbapenem cyclization for penem synthesis failed (120). 

No examples exist of this class of cyclization starting from pyridine intermediates. 

The vast majority of this type of cyclization start from pyridines. One obvious route converts o- acylaminopyridine acids, esters or their equivalents to pyridopyrimidines using a one-atom ammonia or amine fragment, e.g. (173) (174). Examples are known mainly... 

The most common reaction of this type is the cyclization of various derivatives of hydrazine and substituted hydrazines with pyridine o-dicarboxylic acids and related compounds. Reactions in which the acid derivative reacts directly with the hydrazine are dealt with as [4 + 2] reactions in Section 2.15.10.6.1. 

Early experiments with pyridine-2,3-dicarboxylic mono- and bis-phenylhydrazides were unsuccessful (32JIC145), but later these were cyclized in acetic acid (66CPBIOIO) to give only the 7-phenylpyrido[2,3-[Pg.242]

Reactions involving quinoline hydrazide derivatives have been noted in the pyridazino-[4,3-c]- (64MI21500), -[4,5-f ]- (31M(58)238) and -[4,5-c]-quinoline (71CB3341) series, whilst the double cyclization of (358) to the pyridazino[4,5-f ]quinoline (359) (80CPB3457) and related cyclizations in the same series (80H(14)267) are of a basically similar type. A lone cyclization of this type from cinnoline intermediates involves the o-acetonylcarboxamide type formation of the pyridine ring to give the pyrido[3,4-c]cinnoline (360) (76JCS(Pl)592). 

The vast majority of syntheses of pyrido[2,3-t/]- and pyrido[3,4-t/]-pyridazines fall into this category, resulting from the cyclization of various o-substituted pyridine derivatives (2,3- or 3,4-, respectively) with hydrazine or its congeners. 

As foretold in the introduction, ring formation via attack on a double bond in the endo-trig mode is not well exemplified. The palladium(II) catalyzed oxidative cyclization of o-aminostyrenes to indoles has been described (78JA5800). The treatment of o-methyl-selenocinnamates with bromine in pyridine gives excellent yields of benzoselenophene-2-carboxylates (Scheme 10a) (77BSF157). The base promoted conversion of dienoic thioamides to 2-aminothiophenes is another synthetically useful example of this type (Scheme 10b) (73RTC1331). 

Cyclization onto a heterocyclic ring also readily occurs, as when the 2-substituted pyridine (566) was treated with triethyl phosphite. In this case the pyrrolopyrazole (567) was obtained (79JOC622),... 

The sulfonate ester of o-hydroxyacetophenone oximes, when treated with pyridine, are similarly converted into a benzoxazole, but cyclize to a 1,2-benzisoxazole when treated with aqueous KOH <73JCS(P1)2220, 71T711). 

Other interactions of /3-lactams with electrophiles include the oxidative decarboxylation of the azetidin-2-one-4-carboxylic acid (85) on treatment with LTA and pyridine (81M867), and the reaction of the azetidin-2-one-4-sulfinic acid (86) with positive halogen reagents. This affords a mixture of cis- and trans-4-halogeno-/3-lactams (87), the latter undergoing cyclization to give the bicyclic /3-lactam (88) (8UOC3568). 

Thieno[3,2-c]pyridine, 4-hydrazino-cyclization, 4, 1014 Thieno[3,2-c]pyridine, 3-hydroxy-... 

Krogsgaard-Larsen and co-workers have protected the P-keto functionality as a ketal as a modification to the traditional conditions so attack of hydroxylamine is directed towards the ester. They prepared hydroxamic acid 10 from ester 9 then cyclized with sulfuric acid to isoxazole 11, in route to 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP), a selective GABAa receptor agonist studied clinically for insomnia. 

Kelly applied this chemistry to the synthesis of cyclosexipyridine 66. This is an example of an intramolecular variation to this method. Masked enal 65 was prepared and treated with the standard reagents. The acidic medium liberated the aldehyde from its acetal protection. This in situ formation of the reactive species, similar to the above example, then undergoes cyclization to the expected pyridine derivative 66. 

A green chemistry variation makes use of solventless conditions to minimize the waste stream from reactions of this type. To a mortar are added aldehyde 67, ketone 68 and solid sodium hydroxide. The mixture is ground and within 5 minutes aldol product 69 is produced. Addition of the second ketone and further grinding affords the 1,5-diketone 70, which can be isolated and cyclized to pyridine 71 with ammonium acetate. The authors report that this method can substantially reduce the solid waste (by over 29 times) and is about 600% more cost effective than previously published procedures. 

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

Pyridine and dimethyl acetylenedicarboxylate in methanol yield - a mixture of (33) and (34). It is tempting to assume that a zwitterion (30) is first formed and that this then adds a proton followed by a methoxide ion (Michael addition) under the influence of both the positive charge on the ring and the assisting ester group. The resulting structure (31) could then add another molecule of the ester and cyclize, as indicated, to (32). Subsequent aromatization accompanied by loss of one, or the other, substituent at position 3 would lead to the two products, (33) and (34), actually isolated. 

Three general approaches to the synthesis of pjTido[2,3-d]pyrimi-dines from pyrimidines are available, all of which utilize an appropriately substituted 4-aminopyrimidine. The pyridine ring may be formed by the addition of three (route i), or two (route ii) carbon atoms, or by the intramolecular cyclization of a propionyl derivative (route in). 

---