
==== Front
Org Lett
Org Lett
ol
orlef7
Organic Letters
1523-7060
1523-7052
American Chemical Society

39219538
10.1021/acs.orglett.4c02415
Letter
Rare Gold-Catalyzed 4-exo-dig Cyclization for Ring Expansion of Propargylic Aziridines toward Stereoselective (Z)-Alkylidene Azetidines, via Diborylalkyl Homopropargyl Amines
https://orcid.org/0000-0002-3493-8211
Salvadó Oriol †
Pérez-Ruíz Jorge ‡
Mesas Alba †
https://orcid.org/0000-0001-8295-4059
Díaz-Requejo M. Mar *‡
https://orcid.org/0000-0002-6899-4641
Pérez Pedro J. *‡
https://orcid.org/0000-0001-9025-1791
Fernández Elena *†
† Faculty of Chemistry, University Rovira i Virgili, 43007 Tarragona, Spain
‡ Laboratorio de Catálisis Homogénea, Unidad Asociada al CSIC, Centro de Investigación en Química Sostenible (CIQSO) and Departamento de Química, Universidad de Huelva, 21007 Huelva, Spain
* E-mail: mariaelena.fernandez@urv.cat.
* E-mail: mmdiaz@dqcm.uhu.es.
* E-mail: perez@dqcm.uhu.es.
02 09 2024
13 09 2024
26 36 75357540
04 07 2024
24 07 2024
29 07 2024
© 2024 The Authors. Published by American Chemical Society
2024
The Authors
https://creativecommons.org/licenses/by/4.0/ Permits the broadest form of re-use including for commercial purposes, provided that author attribution and integrity are maintained (https://creativecommons.org/licenses/by/4.0/).

We report an uncommon 4-exo-dig cyclization of N-tosyl homopropargyl amines, catalyzed by [AuCl(PEt3)]/AgOTf, to prepare stereoselective (Z)-2-alkylidene-1-tosylazetidine compounds. The reaction outcome contrasts with the gold-catalyzed cyclization of N-tosyl homopropargyl amines containing a methyl group at the propargylic position that provides substituted 2,3-dihydropyrroles via a 5-endo-dig mechanism. The access to N-tosyl homopropargyl amines is possible by the regioselective nucleophilic attack of α-diboryl alkylidene lithium salts to propargylic aziridines.

Ministerio de Ciencia e InnovaciÃ³n 10.13039/501100004837 PID2020-113797RB-C21 European Regional Development Fund 10.13039/501100008530 NA Ministerio de Ciencia e InnovaciÃ³n 10.13039/501100004837 RED2022-134074-T Ministerio de Ciencia e InnovaciÃ³n 10.13039/501100004837 PID2022-141693NB-I00 document-id-old-9ol4c02415
document-id-new-14ol4c02415
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Special Issue

Published as part of Organic Lettersvirtual special issue “Gold-Mediated Chemistry”.
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pmcStructural modifications of core scaffolds can be performed via skeletal editing strategies, considering subtle changes on the chemical space, avoiding de novo synthetic sequences.1 Changing the ring size in the core of a molecule can significantly impact its biological activity and, hence, speed up drug discovery objectives.2 With that in mind, reactions that break and rejoin atomic bonds by deleting, adding, or swapping atoms are considered a kind of convenient molecular surgery for molecular design.3 Ring expansion of N-tosylaziridines4 to azetidines is a challenging ring size manipulation and there has been very little examples that faced this problem and succeeded. Biocatalytic one-carbon ring expansion of aziridines, via [1,2]-Stevens rearrangement, is a valuable protocol that allows for the synthesis of azetidines, even with asymmetric induction (Scheme 1a).5 Alternative ring expansion of aziridines to azetidines employed phenacyl bromide derivatives via in situ generated ammonium ylides in a silica gel–water system (Scheme 1b).6 Visible light has also induced ring expansion of N-tosylaziridines with 1-bromo-1-nitroalkanes to afford 2-nitro azetidines with controlled regio- and diastereoselectivity (Scheme 1c).7 All of those attempts ran the fruitful ring expansion of N-tosylaziridines to azetidine synthesis, requiring the intermolecular interaction of aziridines with an external carbon. Here, we describe a new azetidine synthesis from propargyl aziridines, involving a rearrangement promoted by regioselective nucleophilic diborylalkylation ring opening, followed by a stereoselective Au-catalyzed ring-closing step, via a 4-exo-dig mechanism (Scheme 1d).

Scheme 1 Ring Expansion Protocols To Transform Aziridines into Azetidines

The ability to precisely edit a four-membered heterocyclic ring from the corresponding propargylic aziridine not only represents an interesting ring expansion but also allows for the stereoselective formation of (Z)-2-alkylidene-1-tosylazetidine compounds that, to the best of our knowledge, are prepared for the first time in this work.

Our first goal is focused on the regioselective ring opening of propargylic aziridines with organoboron compounds. Whereas SN2 borylative ring opening of aziridines and vinyl aziridines to generate β-aminoboronate compounds are well-known processes,8 the borylative ring opening of propargylic aziridines is illustrated in one single example, providing the corresponding allenyl boronate product, following a preferred SN2′ process.9 Alternatively, the synthesis of γ-aminoboronic esters can be conducted via nucleophilic ring opening of aziridines10 and vinyl aziridines11 with α-borylcarbanions,12 although propargylic aziridines have never been explored toward this synthetic goal.13 To explore the regioselective nucleophilic attack of α-diborylcarbanions on propargylic aziridines, we selected bis(pinacolato)borylmethane 1a to react with lithium diisopropylamide (LDA), in tetrahydrofuran (THF) at 0 °C, followed by the addition of 2-(phenylethynyl)-1-tosylaziridine (2) (Table 1).14

Table 1 Regioselective Ring Opening of 2-(Phenylethynyl)-1-tosylaziridine (2) with α-Diboryl Alkylidene Lithium Saltsa

a Reaction conditions: gem-diborylalkane (0.24 mmol, 1.2 equiv), LDA (0.3 mmol, 1.5 equiv), and THF at 0 °C for 30 min, followed by the addition of 2-(phenylethynyl)-1-tosylaziridine (2) (0.2 mmol) at room temperature for 16 h.

The transformation was quantitative after 16 h at room temperature with the formation of the major regioisomeric product 3a, demonstrating that the diborylalkylation/ring opening took place at the most hindered position of aziridine, by virtue of the electronic properties of the adjacent triple bond (entry 1 in Table 1). The regioisomeric product 4a was also observed by nuclear magnetic resonance (NMR) in a 13% yield. We generalized the regioselective trend for diborylalkylation/ring opening of compound 2, even introducing steric hindrance at the diborylalkane reagent 1, with R = Me (1b), R = iPr (1c), and R = Cy (1d). We proved the formation of products 3b, 3c, and 3d, as major regioisomers, together with the formation of products 4b, 4c, and 4d in <10% (entries 2–4 in Table 1). Interestingly, the most sterically hindered reagent 1e, with R = SiMe3, reacted efficiently to synthesize the regioisomer 3e in 75% isolated yield with 7% of the minor regioisomer 4e (entry 5 in Table 1). This is in line with the stereoselective C–C bond formation when diborylsilylalkyl lithium salts react with vinyl epoxides15 for ring-opening reactions.

Having explored the viability of the regioselective diborylalkylation/ring opening of compound 2, we selected reagents 1a, 1b, and 1e to react with propargylic aziridines modified electronically,14 replacing the phenyl group by p-MeOC6H4 in compound 5 or p-ClC6H4 in compound 8 (Scheme 2).

Scheme 2 Substrate Scope on Nucleophilic Attack of α-Diborylcarbanions on Propargylic Aziridines

Reaction conditions: gem-diborylalkane (0.24 mmol, 1.2 equiv), LDA (0.3 mmol, 1.5 equiv), and THF at 0 °C for 30 min, followed by the addition of 2-(phenylethynyl)-1-tosylaziridine (2) (0.2 mmol) at room temperature for 16 h.

We observed that electron-donating or electron-withdrawing properties on propargylic aziridines 5 and 8, respectively, do not affect the reaction outcome when reacted with compounds 1a and 1b. The use of the more hindered diborylsilylalkyl lithium salts allowed for the isolation of the regioisomers 6e and 9e in 81 and 77% yields, respectively (Scheme 2). When propargylic aziridine 11, with 2-naphthyl substituent, was employed as a substrate for diborylalkylation/ring opening with compounds 1a, 1b, and 1e, we noticed that the major isomer was isolated in moderate yield (41% for compound 12a, 61% for compound 12b, and 61% for compound 12e), presumably as a result of the steric hindrance on the substrate. Interestingly, when the substituent on propargylic aziridine 14 was the cyclohexyl group, products 15a, 15b, and 15e were also formed as the preferred regioisomers (isolated yields of 40, 61, and 77%, respectively), despite the lack of aryl groups conjugated to the triple bond. A similar behavior was observed for the n-hexyl substituent of propargyl aziridine 17 that generated products 18a, 18b, and 18e in 39, 38, and 73%, respectively. Eventually, propargylic aziridine 20, with R′ = CH2–CH2–Ph, also favored the diborylalkylation/ring opening with reagents 1a, 1b, and 1e on the most hindered position, producing products 21a, 21b, and 21e in 51, 64, and 65% isolated yields, respectively (Scheme 2).

When propargylic aziridines contain a methyl group at the propargylic position (23, R′ = Ph; 26, R′ = 2-naphthyl), the diborylalkylation/ring opening with reagent 1a occurred without apparent regioselectivity (see products 24a and 25a in Scheme 3). A similar trend has been observed when the more hindered reagents 1b or 1e were employed in the diborylalkylation/ring opening of model substrate 23. The diborylalkylation of the most hindered propargylic aziridine 26 with the most hindered reagent 1e also produced both regioisomers 27e and 28e in similar isolated yields (Scheme 3).

Scheme 3 Nucleophilic Ring Opening of Me-Substituted Propargylic Aziridines with α-Diborylcarbanions

Reaction conditions: gem-diborylalkane (0.24 mmol, 1.2 equiv), LDA (0.3 mmol, 1.5 equiv), and THF (1 mL) at 0 °C for 30 min, followed by the addition of propargyl aziridines (0.2 mmol) at room temperature for 16 h.

Remarkably, it seems that the electronic properties of propargylic carbon favor the formation of the vicinal quaternary centers in products 24a/24b/24e and 27e, despite the sterically hindered position. The formation of the propargylamines 25a/25b/25e and 28e also represents a straightforward access to valuable tetrasubstituted carbon centers with diverse polyfunctionality (Scheme 3).16

Considering the chemical structure of the N-tosyl homopropargyl amines prepared in this work, we planned to conduct the gold-catalyzed cyclization to synthesize heterocyclic compounds.17 We selected the complex [AuCl(PEt3)] (10 mol %), in the presence of AgOTf (10 mol %), as a scavenger of the Cl anion, because it is known that AgOTf does not catalyze this cyclization.18 We explored the gold-catalyzed cyclization on N-tosyl homopropargyl amine 24e, and after 16 h at 90 °C, we isolated the corresponding substituted 2,3-dihydropyrrole 29e, as a single diastereoisomer in 91% isolated yield (Scheme 4, top) suggesting a 5-endo-dig cyclization pathway. The configuration of the quaternary center was unequivocally assigned with the methyl group cis to the N-tosyl moiety, as confirmed by X-ray diffraction studies of compound 29e (Scheme 4). The direct 5-endo-dig cyclization of the N-tosyl homopropargyl amine 24e seems to follow the favored Baldwin’s rules for the synthesis of the heterocyclic dihydropyrrole ring.20

Scheme 4 Au-Catalyzed Cyclization of N-Tosyl Homopropargyl Amines

Reaction conditions: N-tosyl homopropargyl amine (0.1 mmol, 1 equiv), [AuCl(PEt3)] (0.01 mmol, 3.51 mg), AgOTf (0.01 mmol, 2.57 mg), and THF (1 mL) at 90 °C for 16 h.

However, when we conducted the gold-catalyzed cyclization of the analogous N-tosyl homopropargyl amine 3e, the corresponding alkylidene azetidine 30e was formed instead (Scheme 4, bottom). The formation of the four-membered ring alkylidene azetidine 30e can be explained by the unlikely 4-exo-dig cyclization, which, on the basis of the acute angle formed by the interacting atoms, had been considered unfavorable by Baldwin rules.21 Because those rules have been comprehensively revisited, the mechanism for 4-exo-dig cyclization could be justified by a plausible obtuse angle of attack (Scheme 4).22 Scare examples of gold-catalyzed 4-exo-dig cyclization have been described,23 together with other catalytic or radical initiators for 4-exo-dig carbocyclization of alkynes.24 We extended the 5-endo-dig cyclization pathway for N-tosyl homopropargyl amines containing a methyl group at the propargylic position. In consequence, the cyclization of compounds 24b and 27e, provided, in both cases, 2,3-dihydropyrroles 29b and 31e, in moderate to high isolated yields (Scheme 5). In our attempt to demonstrate the feasibility of gold-catalyzed 4-exo-dig cyclization, we explored the gold-catalyzed cyclization of N-tosyl homopropargylamines 3b, 9b, and 12b, generating the corresponding four-membered alkylidene azetidines 30b, 32b, and 33b (Scheme 5). Electron-withdrawing substituents on the aryl group seem to have a beneficial influence on the cyclization, because product 32e could be isolated in 93% yield, proceeding from N-tosyl homopropargyl amine 9e, despite the steric hindrance associated with the SiMe3 group (Scheme 5). For these N-tosyl homopropargyl amines containing alkyl groups, instead of aryl groups, the formation of the corresponding alkylidene azetidines 34e and 35e was also feasible, noting that the unreacted substrate N-tosyl homopropargyl amine was isolated as the corresponding ketone as a consequence of the aqueous workup.

Scheme 5 Substrate Scope for Au-Catalyzed 4-exo-dig Cyclization and 5-endo-dig Cyclization of N-Tosyl Homopropargyl Amines

Reaction conditions: N-tosyl homopropargyl amine (0.1 mmol, 1 equiv), [AuCl(PEt3)] (0.01 mmol, 3.51 mg), AgOTf (0.01 mmol, 2.57 mg), and THF (1 mL) at 90 °C for 16 h.

Eventually, we explored the functionalization of the pending gem-diborylalkyl group, and toward this end, we prepared the substrate 1-tosyl-2-((4-(trifluoromethyl)phenyl)ethynyl)aziridine that was regioselectively converted into products 36a, 36b, and 36e as favored regioisomers (Scheme 6). When we performed the gold-catalyzed cyclization of products 36a and 36b, the alkylidene azetidines 38a and 38b were exclusively formed and isolated in a moderate yield (Scheme 6). The functionalization was explored via base-mediated protodeborylation, generating product 39 in a high yield, as a mixture of 1:1 diastereoisomers (Scheme 6). The oxidation of the alkylidene azetidine 39 with NaBO3 allowed for the isolation of product 40 with a pending secondary alcohol, in a 1:1 mixture of diastereoisomers (Scheme 6). This is a straightforward access to alkylidene azetidines with a 1-hydroxyethan-1-ide pendant moiety that confers potential antibacterial activity to the heterocyclic four-membered ring, in combination with the structural alkylidene function on the C4 position with a (Z) stereochemistry that proved to have more beneficial biological activity than the (E) stereosiomer.25

Scheme 6 Strategic Synthesis of Alkylidene Azetidines with a 1-Hydroxyethan-1-ide Pendant Moiety

Reaction conditions: gem-diborylalkane (0.24 mmol, 1.2 equiv), LDA (0.3 mmol, 1.5 equiv), and THF (1 mL) at 0 °C for 30 min, followed by the addition of propargyl aziridines (0.2 mmol) at room temperature for 16 h. For cyclization: N-tosyl homopropargyl amine (0.1 mmol, 1 equiv), [AuCl(PEt3)] (0.01 mmol, 3.51 mg), AgOTf (0.01 mmol, 2.57 mg), and THF (1 mL) at 90 °C for 16 h. For protodeborylation: NaOtBu (1.5 equiv) at 60 °C for 5 h. For oxidation: NaBO3·H2O (0.3 mmol, 3 equiv) for 16 h.

We conclude that the ability to precisely edit a four-membered heterocyclic ring from the corresponding propargylic aziridine not only represents an interesting ring expansion but also allows for the stereoselective formation of (Z)-2-alkylidene-1-tosylazetidine compounds, prepared for the first time in this work, that can be functionalized toward alkylidene azetidines with 1-hydroxyethan-1-ide pendant moieties that are synthetic cores with potential antibacterial activity.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.4c02415.Experimental procedures, product characterization, NMR spectra, and X-ray single-crystal diffraction analysis for product 29e (PDF)

Supplementary Material

ol4c02415_si_001.pdf

The authors declare no competing financial interest.

Acknowledgments

The authors thank Ministerio de Economía y Competitividad and Fondo Europeo de Desarrollo Regional (FEDER) through Projects PID2022-141693NB-I00, PID2020-113797RB-C21, and RED2022-134074-T, founded by MCIN/AEI/10.13039/501100011033 and “ERDF—A Way of Making Europe”.
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