An improved synthesis of N-aryl and N-heteroaryl substituted piperidones

Schön, Uwe; Messinger, Josef; Buckendahl, M.; Prabhu, M.; Konda, A.

doi:10.1016/j.tetlet.2007.02.053

Cited by 16 publications

(7 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, piperidinol 163 36 was first sourced in three steps, by Buchwald amination of 1-bromo-4-fluorobenzene with 1,4-dioxa-8-azaspiro[4.5]decane, 38 ketal hydrolysis, and reduction (NaBH4). Reaction of epoxides 162 39 and 171 39 with 163 (NaH, DMF, 70 °C) and TBS protection of the liberated hydroxyls provided the desired ethers 165 and 173 in good yield (47-68% overall).…”

Section: Introductionmentioning

confidence: 99%

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

et al. 2017

View full text Add to dashboard Cite

Usage GuidelinesPlease refer to usage guidelines at http://researchonline.lshtm.ac.uk/policies.html or alternatively contact researchonline@lshtm.ac.uk.Available under license: http://creativecommons.org/licenses/by-nc-nd/2.5/ 7-Substituted 2-nitro-5,6-dihydroimidazo [2,1-b] [1,3] that was present in 6-nitroimidazooxazole 5. This was equivalent to a one carbon expansion of the oxazole ring between C-2 and C-3 ( Figure 2). The rationale for this design concept stemmed from initial evidence 21 that delamanid (5) was highly stable towards metabolism, as well as from a report 22 that 7-methyl derivatives of 6 retained excellent antitubercular potency, suggesting that such an approach merited investigation.Serendipitously, we soon discovered 23 that this novel "7-substituted oxazine" class not only showed considerable promise for TB (as later confirmed by others 24,25 ), it also displayed potent antileishmanial activity, comparable to the 6-nitroimidazooxazoles in early screening assays. Therefore, following the success with 4, this new series was similarly repositioned for VL as part of an extensive backup program, run in collaboration with DNDi. In this paper, we first highlight some critical VL hit to lead assessments on the original subset of compounds that had been prepared for TB. We then detail the findings of our lead optimisation study directed at developing backups to 4 having an improved physicochemical/pharmacological profile and better safety, which culminated in the selection of a new preclinical candidate for VL. Finally, in light of these encouraging results and the excellent activities of this novel 7-substituted 2-nitroimidazooxazine class against both TB and Chagas disease, we point to related analogues that might be worthy of further assessment for the latter applications. 5 CHEMISTRYIn order to rapidly access some initial examples, the racemic 7-H and 7-methyl alcohol intermediates, 13 and 20, were first sought (Scheme 1A). These could be obtained in very good overall yield (62-79%) via similar 5 step reaction sequences, starting with base catalysed alkylation of 2-bromo-4-nitroimidazole (8) For more efficient synthesis of 7-H biaryl analogues having a proximal 3-pyridine ring, an epoxide-opening strategy (Scheme 3A) was preferred over the Mitsunobu route described above. Epoxide 67 was obtained in 72% optimised yield from 2-chloro-4-nitroimidazole (40), via alkene 66; in this case, the slow epoxidation step was best achieved under non-buffered conditions at higher concentration (with initial cooling). Ring opening of 67 with 6-bromopyridin-3-ol (68) (K2CO3, MEK, 81-82 °C) gave mainly alcohol 69 (51% using 2 equiv for 35 h, or 57% from 4 equiv and 14 h), together with small amounts of the oxazine 70 (6-12%). Ring closure of purified 69 (NaH, DMF, 0-20 °C) then gave additional 70 in excellent 7 yield (91%). Comparable results were obtained for scale-up of 39 from 67 (62%), as well as for reaction of epoxide 42 with pyridinol 68 and ring closure, leading to oxazine 89 (Scheme 3D). As expected, br...

show abstract

Section: Introductionmentioning

confidence: 99%

7-Substituted 2-Nitro-5,6-dihydroimidazo[2,1-b][1,3]oxazines: Novel Antitubercular Agents Lead to a New Preclinical Candidate for Visceral Leishmaniasis

et al. 2017

View full text Add to dashboard Cite

show abstract

“…Pd 2 (dba) 3 ) 10 at an elevated temperature. 11 Copper-catalyzed methods also have been developed for halide to amine substitutions in heteroaromatic systems. 12 …”

Section: Introductionmentioning

confidence: 99%

A mild, catalyst-free synthesis of 2-aminopyridines

2008

View full text Add to dashboard Cite

show abstract

“…A second series of fused 1,2,3-triazole analogues was prepared based on the previously described multicomponent method, starting from N-phenyl-4-piperidone material 17 which in turn was synthesized according to Buchwald-Hartwig Pd-catalyzed amination of different aryl bromides, presented in Scheme 2. 21 We initially examined the scope of this reaction with respect to primary amines. As we would expect based on the aforementioned results, we managed to synthesize an adequate number of examples in good to excellent yields (18a-d).…”

mentioning

confidence: 99%