Process Intensification for the Synthesis of 6-Allyl-6-azabicyclo[3.1.0]hex-3-en-2-ol from 1-Allylpyridinium Salt Using a Continuous UV-Light Photoflow Approach

Abstract

A new home-made UV photochemical reactor (95 cm of irradiation zone) consisting of a 12 parallel quartz tubes flow reactor, PQT6 (95 cm under irradiation and an internal diameter of 0.6 cm) was assembled to perform photochemical transformations in continuous-flow. PQT6 was evaluated for the photoreaction of 1-allylpyridinium bromide (1a) to 6-allyl-6-azabicyclo[3.1.0]hex-3-en-2-ol (2a), in a continuous process. This technology provides reduced reaction times, continuous production of 2a, and a productivity of 129 mg h−1, corresponding to 1.94 g of isolated 2a after 15 h of irradiation.

Palladium-catalyzed allylic substitution between C-based nucleophiles and 6-azabicyclo[3.1.0]-hex-3-en-2-oxy derivatives: A new selectivity paradigm

“…Scheme 3. Process intensification for the synthesis of a-hydroxycyclopenten-aziridines using continuous UV-light photoflow home-made reactors [29,31]. appropriate pK a window to allow the allylic substitution to take place (Scheme 5).…”

“…Subsequently, several groups, including those of Mariano [6e8], Burger [9e12], Ganem [13] and Penkett [14e16] revisited and extended the scope of this chemistry, achieving synthetically important targets such as (þ)-mannostatin A [17], (þ)-castanospermine [18], (À)-swainsonine [19], the aminocyclopentitol cores of allosamidine [20], trehazolin [21] and 3-amino-3-deoxy sugars [22e28]. More recently, we contributed to this topic, by accomplishing the generation and the subsequent ring opening of the resulting a-oxycyclopenten-aziridines in water at physiological pH using heteroatom-based nucleophiles, including the peptide hormone salmon calcitonin (sCT) [29], and by performing the photoelectrocyclization/nucleophilic interception sequence using different home-made continuous UV-light photoflow reactors [30,31]. Our process allowed the production of a-hydroxycyclopenten-aziridines in gram scale, e.g.…”

(1R,4S,5S)-5-((3-Hydroxypropyl)amino)-4-((1-methyl-1H-tetrazol-5-yl)thio)cyclopent-2-en-1-ol

“…[14,15] The implementation of flow enabled the synthesis of bicyclic vinyl aziridines with larger productivity when compared to reported batch methods [16] and also the achievement of a gram scale production [15] (Scheme 2A). [14,15], improvements over batch methodology [16,17]; previous work on (B) palladium-catalyzed allylic substitutions on bicyclic vinyl aziridines using carbon-based nucleophiles [18] and (C) nucleophilic ring-opening reactions of bicyclic vinyl aziridines with thiol and nitrogen nucleophiles [17]; (D) this work: nucleophilic ringopening reaction of bicyclic vinyl aziridine ring (2c) by 1-methyl-1H-tetrazole-5-thiol to produce 3c. Mannostatin A is a natural product, first isolated from a soil microorganism Streptoverticillus, and is among the most potent inhibitors of class II α-mannosidase.…”

“…Our group studied the photochemical reactions of pyridinium salts to bicyclic vinyl aziridines under continuous-flow [14,15]. The implementation of flow enabled the synthesis of bicyclic vinyl aziridines with larger productivity when compared to reported batch methods [16] and also the achievement of a gram scale production [15] (Scheme 2A). desired aminocyclopentitol.…”

“…[14,15] The implementation of flow enabled the synthesis of bicyclic vinyl aziridines with larger productivity when compared to reported batch methods [16] and also the achievement of a gram scale production [15] (Scheme 2A). [14,15], improvements over batch methodology [16,17]; previous work on (B) palladium-catalyzed allylic substitutions on bicyclic vinyl aziridines using carbon-based nucleophiles [18] and (C) nucleophilic ring-opening reactions of bicyclic vinyl aziridines with thiol and nitrogen nucleophiles [17]; (D) this work: nucleophilic ringopening reaction of bicyclic vinyl aziridine ring (2c) by 1-methyl-1H-tetrazole-5-thiol to produce 3c. [14,15], improvements over batch methodology [16,17]; previous work on (B) palladium-catalyzed allylic substitutions on bicyclic vinyl aziridines using carbon-based nucleophiles [18] and (C) nucleophilic ring-opening reactions of bicyclic vinyl aziridines with thiol and nitrogen nucleophiles [17]; (D) this work: nucleophilic ring-opening reaction of bicyclic vinyl aziridine ring (2c) by 1-methyl-1H-tetrazole-5-thiol to produce 3c.…”