Copper(I)-catalyzed uneven decarboxylative Mannich response enabled by acidic activation of two H -azirines

Optimization of response circumstances

The response between α-methyl-α-phenyl cyanoacetic acid (1a) and 2H-azirine 2a was studied for the optimization of response circumstances as proven in Desk 1. The decarboxylative Mannich response proceeded easily within the presence of 5 mol % of CuOAc and 5 mol % of (R)-BINAP at zero oC in tetrahydrofuran (THF), which delivered product 3a in 81% yield with dr and eight% ee for the main diastereoisomer (Desk 1, entry 1). Screening of the commercially obtainable bisphosphine ligands, together with (R)-TOL-BINAP, (R)-SEGPHOS, (R)-DIFLUORPHOS, (R,R)-QUINOXP*, (R,R)-Ph-BPE, (R,RP)-TANIAPHOS, (R)-DTBM-SEGPHOS, and (R)-DIPA-MeO-BIPHEP, recognized (R)-DTBM-SEGPHOS and (R)-DIPA-MeO-BIPHEP as the appropriate ligands (Desk 1, entries 2–9). With (R)-DTBM-SEGPHOS because the ligand, product 3a was generated in 88% yield with dr and 93% ee for the main diastereoisomer (Desk 1, entry eight). Within the case of (R)-DIPA-MeO-BIPHEP, product 3a was obtained in 62% yield with 5.7/1 dr and 91% ee for the main diastereoisomer (Desk 1, entry 9).

Desk 1 Optimization of the response conditionsa

With (R)-DTBM-SEGPHOS because the ligand, the research of copper(I) supply, response solvent, and temperature impact weren’t fruitful (see Supplementary Desk 1-Three for particulars). Fortuitously, reducing the response temperature to −20 oC resulted in improved yield, diastereo-, and enantioselectivities within the case of (R)-DIPA-MeO-BIPHEP (Desk 1, entry 10). By additional reducing the response temperature to −60 oC, product 3a was generated in 98% yield with >20/1 dr and 98% ee (Desk 1, entry 11). Furthermore, the loading of CuOAc-(R)-DIPA-MeO-BIPHEP complicated was efficiently decreased to three mol % by prolonging the response time from 24 h to 36 h (Desk 1, entry 12). It was verified that each CuOAc and ligand ((R)-DIPA-MeO-BIPHEP) had been indispensable, as no product 3a was noticed within the absence of both (Desk 1, entries 13, 14). The catalyst loading was additional decreased to 2 mol % with the success of a gram-scale response as proven in Fig. 2. Remarkably, 1.358 g of aziridine 3a was remoted in 91% yield with >20/1 dr and 97% ee.

Fig. 2Fig. 2

Gram-scale response. Circumstances: 1a (9 mmol, 1.577 g), 2a (6 mmol, zero.703 g), CuOAc (2 mol %), (R)-DIPA-MeO-BIPHEP (2 mol %), and THF (60 mL), −60 oC, 50 h

Substrate scope

The examine of the substrate scope of fragrant 2H-azirines (2) with Three mol % of CuOAc-(R)-DIPA-MeO-BIPHEP complicated was described in Desk 2. Each electron-donating teams and electron-withdrawing teams had been accepted on the para-positon of the phenyl group (3a–3j). Though the diastereoselectivity was average in some instances, each the yield and the enantioselectivity had been excessive to glorious. A number of fragrant 2H-azirines with a substituent on the meta-position served as applicable substrates to afford the aziridines in good to glorious stereoselectivities (3k–3n). Sadly, a substituent was not nicely tolerated on the ortho-position largely as a result of elevated steric hindrance. 2H-Azirine with a 2-naphthyl group was additionally an acceptable substrate as glorious outcomes had been obtained (3o). Furthermore, each Three-thienyl and benzo[b]thiophen-2-yl teams didn’t have a unfavourable impact on the response outcomes (3p and 3q).

Desk 2 Substrate scope of fragrant 2H-azirinesa

Then, complicated molecules containing an fragrant 2H-azirine moiety had been investigated. 2,Four-Dichlorophenoxyacetic acid, a systemic herbicide, was efficiently hooked up to the 2H-azirine group via an ester linker (2r). 2r underwent the copper(I)-catalyzed decarboxylative Mannich response easily to afford product 3r in glorious each yield and stereoselectivity. Through the use of the identical linker, isoxepac acid (a complicated intermediate towards the synthesis of olopatadine, which is offered as a prescription eye drop), probenecid (a drugs that’s primarily utilized in treating gout and hyperuricemia), and gabapentin (a drugs that’s used primarily to deal with seizures and neuropathic ache) had been hooked up with the 2H-azirine moiety to generate 2s, 2t, and 2u. These three 2H-azirines reacted with 1a properly to furnish the aziridines (3s, 3t, and 3u) in uniformly glorious yield, excessive diastereoselectivity, and glorious enantioselectivity. It was famous ketone unit, a tertiary sulfonate amide, and a secondary carbamate didn’t disturb each the reactivity and the stereoselectivity. Furthermore, the 2H-azirine moiety was launched to lithocholic acid (a pure steroid molecule) via the identical linker to generate a posh 2H-azirine (2v), which additionally served as a reliable substrate to furnish product 3v in glorious each yield and diastereoselectivities.

As (R)-DTBM-SEGPHOS led to higher management of the diastereoselectivity than (R)-DIPA-MeO-BIPHEP (6/1 dr vs. Four/1 dr) within the response of aliphatic 2H-azirine 4a, (R)-DTBM-SEGPHOS was employed for the examine of aliphatic 2H-azirines (Desk Three). Though the diastereoselectivity was not passable within the instances of 5a and 5b, each the yields and the enantioselectivity had been glorious. The identical scenario was additionally noticed within the response of α,β-unsaturated 2H-azirine 4c. The aryl group in α,α-disubstituted cyanoacetic acid (1) was efficiently prolonged to para-methyl-phenyl (1b), para-chloro-phenyl (1c), and 2-thienyl teams (1d) with excessive to glorious stereoselectivities (5d, 5e, and 5f). It was famous that cyanoacetic acid 1c with a para-chloro-phenyl led to average yield. Furthermore, the alkyl group in 1 was efficiently modified from methyl (1a) to ethyl and allyl teams (1e and 1f). Sadly, the yields had been average and the diastereoselectivity decreased considerably, presumably as a result of extenuated distinction of the steric hindrance between phenyl and ethyl or allyl teams (5g and 5h). Moreover, the 2H-azirine moiety was tethered with indometacin (a nonsteroidal anti-inflammatory drug), dehydroepiandrosterone (an endogenous steroid hormone), and a protected glucose to provide three complicated aliphatic 2H-azirines (4i, 4j, and 4k). Their decarboxylative Mannich reactions with 1a proceeded easily to provide the aziridines (5i, 5j, and 5k) in excessive yields with excessive to glorious stereoselectivities.

Desk Three Substrate scope of aliphatic 2H-azirinesa

Demonstration of the technique

The current decarboxylative Mannich response exhibited a powerful benefit over the classical proton-transfer model. As proven in Fig. Three, the proton-transfer Mannich response of 1a’ and 2a proceeded in <5% yield within the presence of 5 mol % of CuOAc-(R)-DIPA-MeO-BIPHEP complicated (Fig. 3b), whereas the decarboxylative model occurred in 98% yield (Fig. 3a). Furthermore, the retro-Mannich response of 3a within the presence of 5 mol % of CuOtBu and 5 mol % of (R)-DIPA-MeO-BIPHEP at −60 oC didn't proceed in any respect, indicating that the very low yield of the proton-transfer Mannich response between 1a’ and 2a was not attributed to the retro-Mannich response of 3a beneath fundamental circumstances. The identical diastereo- and enantioselectivities had been noticed each within the decarboxylative model and within the proton-transfer model, indicating that the identical copper(I) intermediate was generated. It's cheap that the proton-transfer model led to very low yield as 2H-azirine 2a is a poor electrophile as described in literature25,28. As 2H-azirine 2a is an imine base, additionally it is cheap that the protonation of 2a by 1a would possibly happen easily to provide an iminium cation, which is a extremely electrophilic species. Furthermore, it was noticed that the copper(I)-catalyzed decarboxylation protonation of 1a proceeded very slowly within the absence of 2a at −60 oC, which indicated the interplay between 1a and 2a (the activation of 2a by 1a via a hydrogen-bonding impact cannot be excluded fully at current). The distinction of the electrophiles within the Mannich response resulted in numerous yields. The identical tendency was additionally noticed within the Mannich response of aliphatic 2H-azirine 4a with (R)-DTBM-SEGPHOS because the ligand (Fig. 3c, d). It's apparent that the current acidic response circumstances are superior to the classical fundamental proton-transfer response circumstances within the building of contiguous tetrasubstituted and quaternary stereocenters.

Fig. ThreeFig. 3

Demonstration of the technique―one substrate activation by the opposite. a Decarboxylative Mannich response of fragrant 2H-azirine. b Proton-transfer Mannich response of fragrant 2H-azirine. c Decarboxylative Mannich response of aliphatic 2H-azirine. d Proton-transfer Mannich response of aliphatic 2H-azirine


Transformations of 3a had been proven in Fig. Four. After safety of 3a with an acid chloride, the rearrangement of the aziridine moiety in 3a to an oxazoline group produced 6 in 63% yield with maintained enantioselectivity25.The discount of cyano group by DIBAL-H afforded carbamate 7 in 60% yield after safety of the free amine with Boc2O. Furthermore, the acidic opening of the aziridine group in 3a with HCl proceeded easily to furnish amine eight in 80% yield. Clearly, the first alkyl chloride moiety in eight permits additional construction elaboration. Eventually, absolutely the configurations of the stereocenters in eight had been decided by the X-ray evaluation of its single crystals as depicted in Fig. Four, which led to the willpower of the precise stereochemistry of 3a. Then, absolutely the configurations in Three and 5 had been assigned tentatively by analogy (see Supplementary Fig. 40 and Supplementary Desk Four for particulars).

Fig. FourFig. 4

Transformations of the product 3a. Boc, tert-butoxycarbonyl; DIBAL-H, diisobutylaluminium hydride

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