Tricyclic carboxylic acid

In the initial applications of Diels-Alder chemistry to yohimbine alkaloid synthesis, the Kametani (24-27) and Takano (28) groups have both examined reactions between furan derivatives and maleic anhydride. In the initial investigations of Kametani and his coworkers (24) (Scheme 3.10), the Diels-Alder adduct (57) of furan and maleic anhydride underwent bromolactonization to give the tricyclic carboxylic acid 58 (94). This compound has four [C(15), C(16), C(17), and C(18)] of the five contiguous stereocenters of the reserpine E-ring in place. Acid 58 was converted to diazoketone 59 which underwent Wolff rearrangement followed by tryptamine trapping to afford amide 60. Bischler-Napieralski cyclization of this substance afforded the tetracyclic... 

A classical way to achieve regioselectivity in an (a -i- d -reaction is to start with a-carbanions of carboxylic acid derivatives and electrophilic ketones. Most successful are condensations with 1,3-dicarbonyl carbanions, e.g. with malonic acid derivatives, since they can be produced at low pH, where ketones do not enolize. Succinic acid derivatives can also be de-protonated and added to ketones (Stobbe condensation). In the first example given below a Dieckmann condensation on a nitrile follows a Stobbe condensation, and selectivity is dictated by the tricyclic educt neither the nitrile group nor the ketone is enolizable (W.S. Johnson, 1945, 1947). 

The smooth intramolecular nucleophilic displacement of biphenyl carboxylic acids leading to benzocoumarins (See Section II.A.) inspired also investigation of the behavior of similar diphenyl ether, diphenyl sulfide and A-methyldiphenyl amine derivatives 458 under similar conditions. However, all these attempts to achieve cyclization to tricyclic compounds 459 were unsuccessful, probably due to the unfavorable stereochemistry for the formation of the required seven-mem-bered transition states and also to the presence of the deactivating bridge groups X (Eq. 42) [68JCS(C)1030]. 

Dihydro-2//-pyrido[l,2-n]pyrimidin-2-one was used in the synthesis of antiallergic tricyclic triazolobenzazepine derivatives (99MIP3). 8-[2-(4-f-Propyl-2-thienyl)ethenyl]- and 8-[(4-/-propryl-2-thienyl)methoxy]-4-oxo-4//-pyrido[l,2-n]pyrimidine-3-carboxylic acids were patented for the treatment of preventing and/or treating microbial infectious diseases (OlMIPl). 

R = H, R =Br, R" =Et) was prepared by cyclization of aroylacetate 314 (R = H, R =Br, r2 = H, X = F) (OOMIPIO). 9,10-Difluoro-3(5)-methyl-7-oxo-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylic acid and its racemic form were prepared in the reaction of ethyl 2-(2,3,4,5-tetrafluorobenzoyl)-2-ethoxymethyleneacetate and (R)- or (i ,5)-2-aminopropanol and subsequent hydrolysis of the ring closed tricyclic esters (98MI45). Cyclization of ethyl 2-(2,3-difluoro-5-iodobenzoyl)-2-[A-(2-hydroxyethyl)aminomethylene]acetate 315 in the presence of K2CO3 in DMF at 95 °C for 3.5 h yielded 9-iodo-7-oxo-2,3-dihydro-7//-pyrido[l,2,3- /e]-l,4-benzoxazine-6-carboxylate (01MIP2). 

The tricyclic antidepressants (as well as, incidentally the antipsychotic drugs) are characterized by a three carbon chain between the ring system and the basic nitrogen. Incorporation of one of those carbon atoms into an additional fused ring is apparently consistent with activity. Preparation of this compound involves first homologation of the side chain. Thus the carboxylic acid 147 is first converted... 

Imine formation via condensation of aminotriazole 260 with l-methyl-4,5-dioxopyrrolidine-3-carboxylic acid methyl ester 259 leads to formation of the linear tricyclic system 261 under base-mediated conditions (Equation 71) <1997PHA276>. 

A radical tandem cyclization, consisting of two radical carbocyclizations and a heterocoupling reaction, has been achieved by electrolysis of unsaturated carboxylic acids with different coacids. This provides a short synthetic sequence to tricyclic products, for example, triquinanes, starting from carboxylic acids which are accessible in few steps (Scheme 6) [123]. The selectivity for the formation of the tricyclic, bi-cyclic, and monocyclic product depending on the current density could be predicted by applying a mathematical simulation based on the proposed mechanism. 

Methyl-3,3 -bipyridine has been oxidized by permanganate to 3,3 -bi-pyridine-4-carboxylic acid. " 3,3 -Bipyridine carboxylic acids are easily decarboxylated and have been esterified and converted to amides, hydrazides, and acylazides. The Hofmann degradation, of the diamide of 3,3 -bipyridine-2,2 -dicarboxylic acid affords the expected 2,2 -diamino-3,3 -bipyridine, but some of the tricyclic system 108 is formed as well. A 2,2 -bis(acylazide) is converted to a similar tricyclic system with ethanol via the intermediate isocyanate, and several related reactions have been described. The simultaneous dehydration... 

The reaction of M, /-2,f-3,c-4-cyclopcntane-l, 2,3,4-tetracarboxylic acid with sulfur tetrafluoride proceeds with preferential cyclization of the 2,3-carboxylic acid group the bis(trif-luoromethyl)bicyclic mono-ether 18 and the tricyclic di-ethcr 19 are formed in a ratio of ca, 5 1 and 95% total yield.249... 

As an alternative to decarboxylation, dry distillation of the carboxylic acids results in the formation of tricyclic compounds of the type (403) and (404) (B-77MI30500). 

Attempts to prepare an anhydride from 3-carboxymethylquinucli-dine-2-carboxylic acid (40) in the presence of acetic anhydride and sodium acetate led unexpectedly to the tricyclic j8-diketone (59).133 This reacts with compounds containing active hydrogen (water, alcohols, and amines) to yield 2-acetylquinuclidine-3-acetic acid derivatives (60).133... 

Formation of quinuclidine-3-carboxylic acid derivatives (68) from these reactions was conclusive proof of saponification of the ethoxy-carbonyl group at position 2 of the diester (61). A similar reaction takes place with diethyl quinuclidine-2,3-dicarboxylate.100 This is in agreement with the known principle of easier saponification of a- than j8-amino acid esters. Some 3-(j8-acyloxyethyl)-2-diethylaminomethyl-quinuclidines (69, 70)123 on distillation at atmospheric pressure cyclize with loss of ester and formation of a new tricyclic system, quinuclidino[2,3-c]piperidine (72). The same reaction takes place by heating the corresponding amino alcohol (71) with phthalic anhydride in the presence of benzenesulfonic acid.123... 

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