Studies on Intramolecular Diels−Alder Reactions of Furo[3,4-c]pyridines in the Synthesis of Conformationally Restricted Analogues of Nicotine and Anabasine
Abstract:En route to conformationally restricted analogues of nicotine and anabasine, a novel synthetic route to bridged anabasines is described that hinges on a domino intramolecular [4 + 2]-cycloaddition/ring opening-elimination sequence of 3-amino-substituted furo[3,4-c]pyridines. Extension of this route to bridged nicotines, however, proved abortive, even when the dienophile tether is activated by a p-tolylsulfonyl group or when the diene moiety is activated by an electron-releasing methoxy substituent. A detailed … Show more
“…In contrast, heteroanalogues of isobenzofurans have received much less attention, although this situation is rapidly changing in recent years. , The heteroaromatic isobenzofurans reported to date include furo[3,4- b ]furans, thieno[2,3- c ]furans, furo[3,4- d ]oxazoles, furo[3,4- d ]isooxazoles, furo[3,4- d ]thiazoles, furo[3,4- b ]benzofurans, benzo[4,5]thieno[2,3- c ]furans, furo[3,4- b ]indoles, furo[3,4- b ]pyridines, furo[3,4- c ]pyridines, furo[3,4- d ]pyridazines, furo[3,4- d ]quinoxalines, and furo[3,4- c ]cinnolines . During the course of our studies on heteroisobenzofurans, we have recently reported the synthesis of a remarkably stable furo[3,4- c ]pyridine intermediate and established the unique advantages of intramolecular Diels−Alder reactions of furo[3,4- c ]pyridines in the synthesis of conformationally restricted analogues of nicotine and anabasine . The utility of heteroisobenzofurans as potential building blocks for the construction of polycyclic heteroaromatics is critically dependent on their availability as appropriate dienes.…”
Section: Introductionmentioning
confidence: 99%
“…The utility of heteroisobenzofurans as potential building blocks for the construction of polycyclic heteroaromatics is critically dependent on their availability as appropriate dienes. The methods so far reported for the generation of furo[3,4- c ]pyridines include (i) thermal retro-Diels−Alder reactions of 1,4-epoxides, (ii) lithiation and subsequent o -silylation of pyridine-phthalides, and (iii) the Hamaguchi−Ibata reaction of o -aminodiazocarbonyl precursors. , As part of our continuing interest in the chemistry of azaisobenzofurans, we were particularly interested in the generation of thio-substituted furo[3,4- c ]pyridines by a Pummerer-based route and their applications in the synthesis of heterocyclic analogues of 1-arylnaphthalene lignans of biological significance. 1 2 3 …”
The Pummerer reaction of an o-benzoyl-substituted pyridylmethyl sulfoxide generates an alpha-thiocarbocation, the interception of which by a neighboring keto functionality produces an alpha-thio-substituted furo[3,4-c]pyridine as transient intermediate; the latter undergoes a Diels-Alder cycloaddition with an added dienophile. Base-induced ring opening of the cycloadduct followed by aromatization gives an isoquinoline derivative that may be looked upon as a heterocyclic analogue of 1-arylnaphthalene lignans. This procedure occurs readily with electron-poor dienophiles and the entire sequence can be run in one pot. The facility of the sequential Pummerer-Diels-Alder reaction hinges on the experimental conditions, the best results being obtained with heptafluorobutyric anhydride as the triggering agent in toluene containing a catalytic amount of p-toluenesulfonic acid. In the absence of a dienophile it is possible to isolate and characterize a rather unstable furo[3,4-c]pyridine derivative. An intramolecular variant of this protocol is also feasible with use of unactivated alkenyl tethers of variable length; however, the bridged cycloadducts are unisolable in these cases as they undergo spontaneous ring opening and aromatization to yield cycloalka[h]isoquinolines. The usefulness of the sequential Pummerer-Diels-Alder reaction is further demonstrated through the synthesis of a heterolignan with a built-in lactone ring via oxidation of the initial [4+2]-cycloadduct followed by extrusion of phenyl sulfinate and elaboration of the resulting hydoxylated isoquinoline derivative.
“…In contrast, heteroanalogues of isobenzofurans have received much less attention, although this situation is rapidly changing in recent years. , The heteroaromatic isobenzofurans reported to date include furo[3,4- b ]furans, thieno[2,3- c ]furans, furo[3,4- d ]oxazoles, furo[3,4- d ]isooxazoles, furo[3,4- d ]thiazoles, furo[3,4- b ]benzofurans, benzo[4,5]thieno[2,3- c ]furans, furo[3,4- b ]indoles, furo[3,4- b ]pyridines, furo[3,4- c ]pyridines, furo[3,4- d ]pyridazines, furo[3,4- d ]quinoxalines, and furo[3,4- c ]cinnolines . During the course of our studies on heteroisobenzofurans, we have recently reported the synthesis of a remarkably stable furo[3,4- c ]pyridine intermediate and established the unique advantages of intramolecular Diels−Alder reactions of furo[3,4- c ]pyridines in the synthesis of conformationally restricted analogues of nicotine and anabasine . The utility of heteroisobenzofurans as potential building blocks for the construction of polycyclic heteroaromatics is critically dependent on their availability as appropriate dienes.…”
Section: Introductionmentioning
confidence: 99%
“…The utility of heteroisobenzofurans as potential building blocks for the construction of polycyclic heteroaromatics is critically dependent on their availability as appropriate dienes. The methods so far reported for the generation of furo[3,4- c ]pyridines include (i) thermal retro-Diels−Alder reactions of 1,4-epoxides, (ii) lithiation and subsequent o -silylation of pyridine-phthalides, and (iii) the Hamaguchi−Ibata reaction of o -aminodiazocarbonyl precursors. , As part of our continuing interest in the chemistry of azaisobenzofurans, we were particularly interested in the generation of thio-substituted furo[3,4- c ]pyridines by a Pummerer-based route and their applications in the synthesis of heterocyclic analogues of 1-arylnaphthalene lignans of biological significance. 1 2 3 …”
The Pummerer reaction of an o-benzoyl-substituted pyridylmethyl sulfoxide generates an alpha-thiocarbocation, the interception of which by a neighboring keto functionality produces an alpha-thio-substituted furo[3,4-c]pyridine as transient intermediate; the latter undergoes a Diels-Alder cycloaddition with an added dienophile. Base-induced ring opening of the cycloadduct followed by aromatization gives an isoquinoline derivative that may be looked upon as a heterocyclic analogue of 1-arylnaphthalene lignans. This procedure occurs readily with electron-poor dienophiles and the entire sequence can be run in one pot. The facility of the sequential Pummerer-Diels-Alder reaction hinges on the experimental conditions, the best results being obtained with heptafluorobutyric anhydride as the triggering agent in toluene containing a catalytic amount of p-toluenesulfonic acid. In the absence of a dienophile it is possible to isolate and characterize a rather unstable furo[3,4-c]pyridine derivative. An intramolecular variant of this protocol is also feasible with use of unactivated alkenyl tethers of variable length; however, the bridged cycloadducts are unisolable in these cases as they undergo spontaneous ring opening and aromatization to yield cycloalka[h]isoquinolines. The usefulness of the sequential Pummerer-Diels-Alder reaction is further demonstrated through the synthesis of a heterolignan with a built-in lactone ring via oxidation of the initial [4+2]-cycloadduct followed by extrusion of phenyl sulfinate and elaboration of the resulting hydoxylated isoquinoline derivative.
“…Heterocyclic o-quinodimethanes and their stable analogs have been utilized in this regard [32][33][34][35][36]. On the other hand, the use of heteroaromatic isobenzofurans [37][38][39] as dienes is emerging as a powerful alternative to the above method. Furo [3,4-c]pyridine intermediate is one of the interesting member of the heteroaromatic isobenzofurans and important building block for the synthesis of isoquinoline derivatives such as heterocyclic analogues of 1-arylnaphthalene lignans [32].…”
Section: Introductionmentioning
confidence: 99%
“…Furo [3,4-c]pyridine intermediate is one of the interesting member of the heteroaromatic isobenzofurans and important building block for the synthesis of isoquinoline derivatives such as heterocyclic analogues of 1-arylnaphthalene lignans [32]. The generation of this intermediate include (i) thermal retro Diels-Alder reaction of 1,4-epoxides [40], (ii) lithiation and subsequent o-silylation of pyridine-phthalides [41], (iii) the Hamaguchi-Ibata reaction of oaminodiazocarbonyl precursors [33,39], and (iv) sequential Pummerer-Diels-Alder route [32]. Multicomponent coupling reactions offer an incredible level of diversity for the production of diverse structural entities from a few simple components.…”
“…Unfortunately, this approach turned out to be inefficient in the case of constrained nicotines (cf. 4 , n = 1). , In this article we describe an alternative synthesis of both conformationally restricted ana-logues of nicotine and anabasine and their pharmacological activity for the α4β2 and α3β4 subtypes of the nicotinic receptor.…”
A series of novel nicotine and anabasine related conformationally restricted compounds including those with pi-bonds in the connecting tether were synthesized following the hitherto unprecedented phenylsulfanyl group assisted generation of pyridine o-quinodimethane intermediates and their trapping by an intramolecular Diels-Alder reaction. Pharmacological characterization of some of these analogues at activating alpha3beta4 nAChRs was investigated, and constrained anabasine analogues 35 and 43 as well as constrained nicotine analogue 42 were found to exhibit moderately potent nicotinic agonist activity. Of special note is the fact that the pyrrolidinic nitrogen in these compounds is bound to a carbomethoxy group and, therefore, is not free to be protonated unlike all the known analogues of nicotine and anabasine, specifically designed as nAChRs agonists/antagonists. The structure-activity relationship studies indicate that when pi-cation interaction is absent, the position of chlorine atom in the pyridine ring and steric bulk at the connecting tether between the pyridine and pyrrolidine ring of the constrained nicotinic ligands are important descriptors for their binding affinity at alpha4beta2 and alpha3beta4 nAChRs as well as the subtype selectivity issue. These findings are likely to improve our understanding of the structural requirements for selectivity, which, at present, is probably the most important goal in the field of nicotinic ligands.
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