Abstract:Privileged scaffolds: Breaking the symmetry of 1,4‐diyne scaffolds by nucleophilic amine addition onto one of two equivalent alkynoate units affords chain‐functionalized tetrasubstituted pyrroles with five points of functional diversity and two points for complexity generation. The domino reaction manifold entails an aza‐Michael addition, a 5‐endo‐digonal cyclization, and a [3,3]‐sigmatropic rearrangement.
“…The MWassisted reaction of primary amines with TSDs 2 afforded the corresponding pyrroles 11 in good yields (55−85%) (Scheme 6a). 22 As expected, the 5-endo-dig cyclization needed energy (MW heating) to proceed, being the rate-limiting step of the domino process (the cyclization requires alkynoate deconjugation). On the other hand, sodium sulfide, a larger and bivalent nucleophile, generated the corresponding thietane 12 in 70% yield at room temperature.…”
Section: Nucleophile-driven Domino Process (Michael Addition/cyclizat...supporting
confidence: 52%
“…The MW-assisted reaction of primary amines with TSDs 2 afforded the corresponding pyrroles 11 in good yields (55–85%) (Scheme a) . As expected, the 5-endo-dig cyclization needed energy (MW heating) to proceed, being the rate-limiting step of the domino process (the cyclization requires alkynoate deconjugation).…”
During the last years, we have been involved in the development of a diversity-oriented synthetic strategy aimed at transforming simple, linear, and densely functionalized molecular platforms into collections of topologically diverse scaffolds incorporating biologically relevant structural motifs such as N- and O- heterocycles, multifunctionalized aromatic rings, fused macrocycles, etc. The strategy merges the concepts of pluripotency (the property of an array of chemical functionalities to express different chemical outcomes under different chemical environments) and domino chemistry (chemistry based on processes involving two or more bond-forming transformations that take place while the initial reaction conditions are maintained, with the subsequent reaction resulting as a consequence of the functionality installed in the previous one) to transform common multifunctional substrates into complex and diverse molecular frameworks. This design concept constitutes the ethos of the so-called branching cascade strategy, a branch of diversity-oriented synthesis focused on scaffold diversity generation. Two pluripotent molecular platforms have been extensively studied under this merging (branching) paradigm: C4-O-C3 propargyl vinyl ethers (PVEs) and C7 tertiary skipped diynes (TSDs). These are conveniently constructed from simple and commercially available raw materials (alkyl propiolates, ketones, aldehydes, acid chlorides) through multicomponent manifolds (ABB' three-component reaction for PVEs; A2BB' four-component reaction for TSDs) or a simple two-step procedure (for PVEs). Their modular origin facilitates their structural/functional diversification without increasing the number of synthetic steps for their assembly. These two pluripotent molecular platforms accommodate a well-defined and dense array of through-bond/through-space interrelated functionalities on their structures, which defines their primary reactivity principles and establishes the reactivity profile. The PVEs are defined by the presence of an alkyne (alkynoate) function and a conjugated enol moiety and their mutual through-bond/through-space connectivity. This functional array accommodates a number of domino reactions launched either by a Michael addition on the alkynoate moiety (conjugated alkynes) or by a [3,3]-propargyl Claisen rearrangement (conjugated and nonconjugated alkynes). The reactivity profile of the TSDs is defined by the two connected alkynoate moieties (Michael addition) and the bispropargylic ester group ([3,3]-sigmatropic rearrangement). Using these first reactivity principles, each platform selectively delivers one unique and different skeleton (topology) from each domino transformation. Thus, through the use of 11 instrumentally simple and scalable domino reactions, we have transformed these two linear (rod-symmetric) pluripotent molecular platforms into 16 different scaffolds incorporating important structural motifs and multifunctional decorative patterns. The generated scaffolds entail carbocycles, heterocycles, aromatics, β...
“…The MWassisted reaction of primary amines with TSDs 2 afforded the corresponding pyrroles 11 in good yields (55−85%) (Scheme 6a). 22 As expected, the 5-endo-dig cyclization needed energy (MW heating) to proceed, being the rate-limiting step of the domino process (the cyclization requires alkynoate deconjugation). On the other hand, sodium sulfide, a larger and bivalent nucleophile, generated the corresponding thietane 12 in 70% yield at room temperature.…”
Section: Nucleophile-driven Domino Process (Michael Addition/cyclizat...supporting
confidence: 52%
“…The MW-assisted reaction of primary amines with TSDs 2 afforded the corresponding pyrroles 11 in good yields (55–85%) (Scheme a) . As expected, the 5-endo-dig cyclization needed energy (MW heating) to proceed, being the rate-limiting step of the domino process (the cyclization requires alkynoate deconjugation).…”
During the last years, we have been involved in the development of a diversity-oriented synthetic strategy aimed at transforming simple, linear, and densely functionalized molecular platforms into collections of topologically diverse scaffolds incorporating biologically relevant structural motifs such as N- and O- heterocycles, multifunctionalized aromatic rings, fused macrocycles, etc. The strategy merges the concepts of pluripotency (the property of an array of chemical functionalities to express different chemical outcomes under different chemical environments) and domino chemistry (chemistry based on processes involving two or more bond-forming transformations that take place while the initial reaction conditions are maintained, with the subsequent reaction resulting as a consequence of the functionality installed in the previous one) to transform common multifunctional substrates into complex and diverse molecular frameworks. This design concept constitutes the ethos of the so-called branching cascade strategy, a branch of diversity-oriented synthesis focused on scaffold diversity generation. Two pluripotent molecular platforms have been extensively studied under this merging (branching) paradigm: C4-O-C3 propargyl vinyl ethers (PVEs) and C7 tertiary skipped diynes (TSDs). These are conveniently constructed from simple and commercially available raw materials (alkyl propiolates, ketones, aldehydes, acid chlorides) through multicomponent manifolds (ABB' three-component reaction for PVEs; A2BB' four-component reaction for TSDs) or a simple two-step procedure (for PVEs). Their modular origin facilitates their structural/functional diversification without increasing the number of synthetic steps for their assembly. These two pluripotent molecular platforms accommodate a well-defined and dense array of through-bond/through-space interrelated functionalities on their structures, which defines their primary reactivity principles and establishes the reactivity profile. The PVEs are defined by the presence of an alkyne (alkynoate) function and a conjugated enol moiety and their mutual through-bond/through-space connectivity. This functional array accommodates a number of domino reactions launched either by a Michael addition on the alkynoate moiety (conjugated alkynes) or by a [3,3]-propargyl Claisen rearrangement (conjugated and nonconjugated alkynes). The reactivity profile of the TSDs is defined by the two connected alkynoate moieties (Michael addition) and the bispropargylic ester group ([3,3]-sigmatropic rearrangement). Using these first reactivity principles, each platform selectively delivers one unique and different skeleton (topology) from each domino transformation. Thus, through the use of 11 instrumentally simple and scalable domino reactions, we have transformed these two linear (rod-symmetric) pluripotent molecular platforms into 16 different scaffolds incorporating important structural motifs and multifunctional decorative patterns. The generated scaffolds entail carbocycles, heterocycles, aromatics, β...
“…Skipped diynes are also recognized as versatile synthons for the construction of various hetero- and carbocyclic systems. For example, activated skipped diynes bearing an 3-oxo/3-methylidene group or tetrasubstituted carbon at their 3-position have been used to prepare pyrrole, pyridine, furan, benzene, pyrone, and 1,1′-bitriphenylene derivatives . Furthermore, Czekelius and co-workers reported the development of a gold-catalyzed reaction for the synthesis of carbocycles from skipped diynes bearing a nucleophilic moiety at their tetrasubstituted 3-position by the desymmetrization of two alkynes.…”
A gold-catalyzed cascade reaction of skipped diynes (1,4-diynes) and pyrroles has been developed. This reaction proceeds by the consecutive regioselective hydroarylation of two alkynes with a pyrrole, followed by a 7-endo-dig cyclization to give 1,6-dihydrocyclohepta[b]pyrroles in good yields. The direct synthesis of cyclohepta[b]indoles using indole nucleophiles has also been reported.
“…The structural identity, which is shown in Figure 1, of the studied compounds was determined spectroscopically ( 1 H NMR, 13 C NMR, IR spectroscopy and mass spectrometry). The details of this study, as well as information on the synthesis procedure of the compounds, can be found elsewhere (Tejedor et al , 2009). Figure 1.Structural fragments of 5EA (a) and 5CA (b) compounds.…”
The crystal structure of two chain functionalized pyrroles, methyl 1-benzyl-5-(1-(4-chlorobenzoyloxy)-2-methoxy-2-oxoethyl)-4-(4-chlorophenyl)-1H-pyrrole-2-carboxylate and methyl 1-benzyl-4-(biphenyl-4-yl)-5-(1-(4-biphenylcarbonyloxy)-2-methoxy-2-oxoethyl)-1H-pyrrole-2-carboxylate, which are both important active candidates as antitumoral agents, have been obtained ab initio from synchrotron X-ray powder diffraction data. Both compounds crystallize in the monoclinic system (space group P21/c), with a = 20.2544(3) Å, b = 6.80442(9) Å, c = 21.1981(3) Å, β = 111.6388(9)° and a = 29.7747(6) Å, b = 6.27495(14) Å, c = 18.8525(3) Å, β = 107.053(2)°, respectively. These structures were determined using a direct space approach, by means of Monte Carlo technique, followed by Rietveld refinement.
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