Lewis‐acid Promoted Chemoselective Condensation of 2‐Aminobenzimidazoles or 3‐Aminoindazoles with 3‐Ethoxycyclobutanones to Construct Fused Nitrogen heterocycles
Abstract:A Lewis-acid promoted chemoselective condensation of 2-aminobenzimidazoles or 3-aminoindazoles with 3-ethoxycyclobutanones is presented. Diverse fused heterocycles benzo[4,5]-imidazo[1,2-a]pyrimidine and pyrimido[1,2-b]-indazole derivatives were obtained in moderate to high yields under mild conditions, the reaction mechanism of which was in sharp contrast to previous [3 + 3] annulation reaction of 3-ethoxycyclobutanones.
“…In addition, it was noted that the developed approach can be easily scaled without decrease of the yield of the target products (Scheme 20). 63 The above approach to the construction of the pyrimidobenzimidazole structure using cyclic ketones is not the only example of the use of this kind of carbonyl compounds. Thus, a group of Chinese researchers used squaraic acid chloride (67) in the synthesis of a series of alkyl 2-chloropyrimido[1,2-a]benzimidazole-3-carboxylates 68a-g (Scheme 21).…”
Section: Scheme 18mentioning
confidence: 99%
“…In addition, it was noted that the developed approach can be easily scaled without decrease of the yield of the target products (Scheme 20 ). 63 Scheme 20 …”
Section: The Reaction Of Aminobenzimidazoles With Bifunctional Synthetic Equivalentsmentioning
Nitrogen-containing heterocyclic compounds are the basis of many natural and synthetic biologically active substances. 1 More than two-thirds of the known drugs used in clinical practice contain heterocyclic and, above all, nitrogen-containing fragments within their structure. Over the past decades, the chemistry of aza-heterocycles has received considerable attention due to the wide spectrum of their biological activity and numerous therapeutic applications in medicine.Of nitrogenous heterocycles, azoloazines containing fragments similar to the natural heterocycles purines and pyrimidines are currently of great practical importance. Thus, non-natural nucleosides abacavir, famciclovir, remdesivir are known, which are the products of structural modifications of all the components of the nucleotide exhibiting excellent indicators of antiviral action (Fig. 1). [2][3][4] In addition to the generally accepted nucleoside forms, the azoloazines themselves are relevant in the search for means of combating diseases on a global scale. Nitroazolo- [5,1-c][1,2,4]triazines and nitroazolo [1,5-a]pyrimidines, a new family of antiviral compounds has been found. 5 The
“…In addition, it was noted that the developed approach can be easily scaled without decrease of the yield of the target products (Scheme 20). 63 The above approach to the construction of the pyrimidobenzimidazole structure using cyclic ketones is not the only example of the use of this kind of carbonyl compounds. Thus, a group of Chinese researchers used squaraic acid chloride (67) in the synthesis of a series of alkyl 2-chloropyrimido[1,2-a]benzimidazole-3-carboxylates 68a-g (Scheme 21).…”
Section: Scheme 18mentioning
confidence: 99%
“…In addition, it was noted that the developed approach can be easily scaled without decrease of the yield of the target products (Scheme 20 ). 63 Scheme 20 …”
Section: The Reaction Of Aminobenzimidazoles With Bifunctional Synthetic Equivalentsmentioning
Nitrogen-containing heterocyclic compounds are the basis of many natural and synthetic biologically active substances. 1 More than two-thirds of the known drugs used in clinical practice contain heterocyclic and, above all, nitrogen-containing fragments within their structure. Over the past decades, the chemistry of aza-heterocycles has received considerable attention due to the wide spectrum of their biological activity and numerous therapeutic applications in medicine.Of nitrogenous heterocycles, azoloazines containing fragments similar to the natural heterocycles purines and pyrimidines are currently of great practical importance. Thus, non-natural nucleosides abacavir, famciclovir, remdesivir are known, which are the products of structural modifications of all the components of the nucleotide exhibiting excellent indicators of antiviral action (Fig. 1). [2][3][4] In addition to the generally accepted nucleoside forms, the azoloazines themselves are relevant in the search for means of combating diseases on a global scale. Nitroazolo- [5,1-c][1,2,4]triazines and nitroazolo [1,5-a]pyrimidines, a new family of antiviral compounds has been found. 5 The
“…[9] Alternatively, Song et al demonstrated a chemoselective condensation of 3-aminoindazoles with 3-ethoxycyclobutanones promoted by a Lewis acid (Scheme 1a). [10] Gao reported an NH 4 I-promoted multi-component oxidation of 3aminoindazoles, aromatic aldehydes and triethylamine (Scheme 1b). [11] However, these strategies only gave 4substituted pyrimido [1,2-b]indazoles.…”
2-Mono-or 2,3-disubstituted pyrimido[1,2-b]indazoles are synthesized by a (3 + 2 + 1) threecomponent cyclization of 3-aminoindazoles, ketones, and N,N-dimethylaminoethanol as a methine source. The reaction demonstrates good tolerance of both aromatic and aliphatic ketones, as well as various substitution patterns in air. A plausible mechanism is discussed.
“…[9 -11] The synthesis of fused pyrimidines is very interesting for the fusion of biodynamic heterosystems. [12,13] This has proved very useful in developing new molecular structures for drug candidates with different pharmacological activities. Pyrimidine-fused scaffolds are an area of heterocyclic chemistry research that is rapidly expanding.…”
In this study, an efficient one-pot procedure for preparing a new series of pyrazolo [3,4-b]pyridine-fused pyrimidines was described. The target hybrids were developed through a three-component reaction of 3-amino-1H-pyrazolo [3,4-b]pyridine, benzaldehydes, and acetophenones (molar ratio 1 : 1 : 1). The best conditions for the previous reaction were 2.5 equivalents of barium hydroxide in DMF at 150 °C for 6 h. New bis(pyrimidines) were synthesized in high yields using a similar one-pot reaction protocol with some modifications. Thus, two equivalents of each of the appropriate acetophenones and 3-aminopyrazolopyridine were reacted with one equivalent of the appropriate bis(aldehydes). The reaction was carried out at 150 °C for 8 h using 4.5 equivalents of barium hydroxide in DMF. Repeating the previous reaction with the appropriate bis(acetyl) derivatives and benzaldehydes resulted in good yields of the target bis(pyrimidines). The in vitro cytotoxic activity of new pyrimidines against the MCF-7, HEPG2, and Caco2 cell lines was evaluated using the reference doxorubicin (IC 50 values of 4.34 -6.97 μM). Hybrid 6h had the best activity against Caco2 and MCF-7 cell lines, IC 50 values of 12.62 and 14.50 μM, respectively. The IC 50 values for hybrids 6c, 6e, and 6f against MCF-7 and Caco2 cell lines were 23.99 -41.69 and 33.14 -43.33 μM, respectively. Furthermore, hybrid 6e displayed IC 50 value of 20.06 μM HEPG2 cell lines, while the hybrids 6c, 6f and 6h exhibited IC 50 values ranging between 26.29 -50.51 μM. Furthermore, hybrid 6e had an IC 50 value of 20.06 μM for the HEPG2 cell lines, whereas hybrids 6c, 6f, and 6h had IC 50 values ranging from 26.29 to 50.51 μM.
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