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Communication

Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes towards Chiral Allylated Triazoles and Tetrazoles

by
Simon V. Sieger
,
Ilja Lubins
and
Bernhard Breit
*
Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstraße 21, 79104 Freiburg im Breisgau, Germany
*
Author to whom correspondence should be addressed.
Catalysts 2022, 12(10), 1209; https://doi.org/10.3390/catal12101209
Submission received: 13 September 2022 / Revised: 29 September 2022 / Accepted: 7 October 2022 / Published: 11 October 2022
(This article belongs to the Special Issue Theme Issue in Memory to Prof. Jiro Tsuji (1927–2022))
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Abstract

:
A general Rh-catalyzed addition reaction of nitrogen containing heterocycles to internal allenes is reported. Starting from racemic internal allenes a dynamic kinetic resolution (DKR) provides N-allylated triazoles and tetrazoles. Simultaneous control of N1/Nx-position selectivity, enantioselectivity and olefin geometry gives access to important building blocks of target-oriented synthesis. The synthetic utility is demonstrated by a gram-scale reaction and a broad substrate scope tolerating multiple functional groups. Deuterium labeling experiments and experiments with enantioenriched allenes as starting material support a plausible reaction mechanism.

Graphical Abstract

1. Introduction

5-membered nitrogen containing heterocycles are found in a variety of bioactive compounds. Molecules containing triazoles exhibit antifungal [1], anxiolytic [2], antibacterial [3], and anticancerogenic [4] activity. Tetrazoles display antifungal [5], immunosuppressive [6], and antiviral [7] properties. In addition, the isosterism of tetrazoles to carboxylic acids makes them a suitable motif in drug design [8]. In particular, the subclass of α-chiral N-alkylated triazoles and tetrazoles features a broad range of biological activity (Figure 1) [5,9,10,11,12].
Due to the importance of these moieties, different strategies for obtaining them have been developed in the past (Scheme 1). Zhao and coworkers published the transition metal catalyzed allylic substitution with sodium benzotriazolide [13,14]. Despite the excellent enantioselectivities in some cases, the method lacks regioselectivity and requires deprotonation of the triazole in a previous step. Khan recently reported the allylic substitution of cyclic carbonates with tetrazoles [15]. However, allylic substitutions in general are not in accordance with the principle of atom economy by releasing stoichiometric amounts of waste [16]. A series of organocatalyzed aza-Michael additions overcomes this shortcoming and in some cases convinces with high selectivities, but the scope of these transformations is limited [17,18,19,20,21,22]. Furthermore, a three-component reaction of tetrazoles, aldehydes, and acid anhydrides should be mentioned, which uses a Dynamic Kinetic Resolution to synthesize α-chiral tetrazoles as hemiaminals [23,24].
In the last decade, our group developed the transition metal-catalyzed addition of a variety of pronucleophiles to allenes and alkynes [25,26]. C- [27,28,29], N- [30,31,32], O- [33,34,35], and S-pronucleophiles [36,37] can thus be allylated enantioselectively, which creates an atom economic analogon to the Tsuji-Trost allylation [38,39,40,41,42,43,44,45] and allylic oxidations [46,47,48]. Furthermore, the synthetic utility of these reactions has already been demonstrated in several total syntheses [49,50,51]. We recently reported on the rhodium-catalyzed addition of pyrazoles to internal allenes [52]. Due to the importance of triazoles and tetrazoles, we also wanted to extend the Rh-catalysis for these heterocycles. Hence an optimized catalytic protocol for the synthesis of such frameworks is presented using a DKR, a powerful and important method in asymmetric catalysis and synthesis [53,54,55,56,57].

2. Results and Discussion

Coupling benzotriazole (2) with our screening allene, 1, resulted in 96% yield and perfect enantio-, regio-, and E/Z-selectivity by using [Rh(COD)Cl]2, (R,R)-DIOP, and 50 mol% of PPTS at 60 °C. Phenyltetrazole (4) was coupled at 40 °C and with 20 mol% PPTS with ideal regio- and Z/E-selectivity and good enantiomeric excess (Scheme 2) (For optimization and screening tables, see the Supporting Information).
After identifying optimized reaction conditions, the broad applicability is demonstrated by several scopes. Initially we subjected a variety of triazoles to the screening allene 1 (Figure 2).
The benzotriazol-derived substrates (6–12) showed up to 96% yield and enantioselectivities up to 97% ee. While N1/N2-selectivity was consistently greater than 91:9 for symmetrically substituted triazoles (3, 6–8, 13, 14), asymmetric substrates added the challenge of N1/N3-regioselectivity. 5-substituted benzotriazoles (10–12) provided the corresponding products in an almost statistical N1/N3-distribution. Placing the methyl-group in 4- position (9) and thus closer to the reactive site increased N1/N3-selectivity to 4:1. Notably, there was a decrease of E/Z-selectivity for heterosubstituted benzotriazoles (8, 11, 12), whereas a nearly perfect E-selectivity was present in all other cases. The nitro-substituted benzotriazole (12) even led to an inversed olefine geometry, with the Z-product being preferred.
We subsequently tested several allenes for compatibility in the reaction with benzotriazole 2 (Figure 3). Dialkyl substituted allenes (16–18) yielded perfect regioselectivity and enantiomeric excess of up to 98% ee. Even a sterically more demanding (19) and a macrocyclic allene (20) were tolerated as well. The method has its limitations for sterically very demanding and aryl-substituted allenes (21, 22), as well as for a trisubstituted allene (23). For these substrates, yield and selectivity decreased. Next, we subjected several tetrazoles to the corresponding reaction conditions (Figure 4).
Halogen-substituted phenyltetrazoles were coupled in nearly quantitative yields (25–27). Tetrazoles containing thioethers (31, 32) were the only ones to yield products with reduced N2/N1-regioselectivity (about 3:1); however, maintaining quantitative yield and consistently high Z/E- and enantioselectivity. Eventually, we subjected several allenes to the reaction with 5-phenyl-tetrazole (4) (Figure 5).
Except for one sterically more challenging substrate (38), all products were obtained in perfect Z-selectivity. Only the di-cyclohexyl substituted substrate (38) showed shares of the E-product, indicating the limitation of the catalyst controlling the olefin geometry for sterically more demanding allenes. Some mechanistic control experiments were carried out (Scheme 3).
If the catalysis was performed without PPTS, no reaction occurred, revealing the important role of the additive for the reaction. Furthermore, we prepared deuterated nucleophiles, which we subjected to the respective catalysis conditions. The deuterium atoms were found exclusively at the former central atom of the allene. This is in contrast to earlier results with terminal allenes, where deuterium was found at several positions [58,59,60]. Using enantiomerically enriched allenes in the catalysis, both enantiomers of allene yielded the (S)-product for the triazole and the (R)-product for the tetrazole regardless of the configuration of the allene used (Table 1).
When the achiral dppb ligand was used instead of the chiral DIOP ligand in the reactions with enantiomerically enriched allene, the racemic products were obtained, indicating a racemization step in the catalytic cycle. These findings lead us to propose the following reaction mechanism (Scheme 4).
A RhI-DIOP complex is first formed from [Rh(COD)Cl]2 and (R,R)-DIOP (inner box of Scheme 4). With the help of PPTS, the pronucleophile is then added by oxidative addition to form the Rh-hydride species A. Now, syn-hydrometallation from the sterically less demanding side occurs at the respective allene enantiomers. This occurs in such a way that the hydrogen atom results at the former central atom of the allene. Initially, two diastereomeric Z-configured σ-complexes B and dia-B are formed, which are in equilibrium with their corresponding syn, anti-configured π-complexes C and dia-C. Finally, a σ-π-σ-isomerization and a bond rotation lead to the identical pseudo-meso-π-allyl complex D for both diastereomers. Dynamic kinetic resolution is ensured via this syn, syn-configured π-complex, since the initial hydrometallation products B and dia-B can be converted into each other via D. If a triazole is the pronucleophile in the catalysis, reductive elimination occurs of pseudo-meso-π-allyl complex D, with the chiral ligand ensuring enantioselectivity. In contrast, when a tetrazole is used as a pronucleophile, reductive elimination preferentially occurs from syn-anti-π-complex C. This could explain why the (S)-E product is formed for the triazole and the (R)-Z product for the tetrazole.

3. Materials and Methods

3.1. Materials

Toluene was freshly distilled over Sodium/Benzophenone and degassed with argon prior to use. Solvents employed for work-up and column chromatography were purchased in technical grade quality and distilled by rotary evaporator before use. [Rh(COD)Cl]2 was purchased from Sigma-Aldrich (St. Louis, MO, USA). (R,R)-DIOP was prepared according to the procedure shown in the Supplementary Materials.

3.2. Methods

A 20 mL screw-cap Schlenk tube was dried under a vacuum, backfilled with argon (Argon 5.0 Sauerstoffwerke Friedrichshafen, Friedrichshafen, Germany), and cooled to room temperature using a standard Schlenk line apparatus. The tube was filled with [Rh(COD)Cl]2 (6.2 mg, 0.013 mmol, 5.0 mol%), (R,R)-DIOP (12.5 mg, 0.025 mmol, 10.0 mol%), PPTS (31.5 mg, 0.125 mmol, 50.0 mol% or 12.6 mg, 0.05 mmol, 20.0 mol%), and triazole (0.500 mmol, 2.0 equiv.) or tetrazole (0.30 mmol, 1.2 equiv.). The tube was put on a vacuum and backfilled with argon again. Freshly distilled toluene (1.25 mL) and allene (0.25 mmol, 1.0 equiv.) were added by syringe under a flow of argon, and then the tube was sealed by a screw cap. The mixture was stirred at 60 °C (for triazoles) or 40 °C (for tetrazoles) for 16 h. The tube was cooled to room temperature, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography using AcOEt and hexanes as eluent on silica gel. In the case of the synthesis of racemic samples dppb was used as the catalyst.

4. Conclusions

To conclude, we developed a highly selective Rh-catalysis to add triazoles and tetrazoles to internal allenes. In only one step, allylated triazoles and tetrazoles were constructed in an enantio-, stereo-, and regioselective fashion. Mechanistic studies with deuterated pronucleophiles and enantioenriched substrates led us to propose a DKR mechanism. Further investigations in terms of compatible pronucleophiles that can be subjected to this catalytic system is the goal of future research in our laboratories.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/catal12101209/s1, screening tables, preparation of ligand and substrates, analytical data, 1H and 13C NMR spectra, determination of absolute configuration, HPLC chromatograms of products and enantioenriched allenes, more detailed materials and methods [61,62,63,64,65,66].

Author Contributions

Conceptualization, B.B.; methodology, S.V.S. and B.B.; investigation, S.V.S. and I.L.; writing—original draft preparation, S.V.S.; writing—review and editing, S.V.S., I.L. and B.B.; supervision, B.B.; funding acquisition, B.B. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the Fonds der Chemischen Industrie. S.V.S. is grateful for a Ph.D. fellowship from the Fonds der Chemischen Industrie.

Data Availability Statement

All experimental data is contained in the article and supplementary material.

Acknowledgments

Jan Klauser, José Candia, and Julia Schmidt (Albert-Ludwigs Universität Freiburg) are acknowledged for their motivated technical assistance. Sincere thanks are given to Manfred Keller for NMR experiments, analysis of isomers and Joshua Emmerich for HPLC separations (Analytical Department of Albert-Ludwigs Universität Freiburg).

Conflicts of Interest

The authors declare no conflict of interest.

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Catalysts 12 01209 g001 550
Figure 1. Bioactive compounds possessing an α-chiral triazole or tetrazole scaffold [5,9,10,11].
Figure 1. Bioactive compounds possessing an α-chiral triazole or tetrazole scaffold [5,9,10,11].
Catalysts 12 01209 g001
Catalysts 12 01209 sch001 550
Scheme 1. Selected methods for the synthesis of α-chiral triazoles and tetrazoles [13,14,15,16,17,18,19,20,21,22,23,24].
Scheme 1. Selected methods for the synthesis of α-chiral triazoles and tetrazoles [13,14,15,16,17,18,19,20,21,22,23,24].
Catalysts 12 01209 sch001
Catalysts 12 01209 sch002 550
Scheme 2. Optimized reaction conditions of the Rh-catalyzed hydroamination of racemic 1,3-disubstituted allenes. Scale: 0.25 mmol; 1.25 mL of toluene (0.2 m). Yields reported for isolated products. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. COD = cyclooctadien, PPTS = pyridinium p-toluenesulfonate. Gram-scale catalysis (4.03 mmol allene): benzotriazole: 96% yield, N1/N2 96:4, E/Z > 95:5, 95% ee; phenyltetrazole: 84% yield, Z/E > 95:5, 85% ee. For determination of absolute configuration, see the Supporting Information.
Scheme 2. Optimized reaction conditions of the Rh-catalyzed hydroamination of racemic 1,3-disubstituted allenes. Scale: 0.25 mmol; 1.25 mL of toluene (0.2 m). Yields reported for isolated products. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. COD = cyclooctadien, PPTS = pyridinium p-toluenesulfonate. Gram-scale catalysis (4.03 mmol allene): benzotriazole: 96% yield, N1/N2 96:4, E/Z > 95:5, 95% ee; phenyltetrazole: 84% yield, Z/E > 95:5, 85% ee. For determination of absolute configuration, see the Supporting Information.
Catalysts 12 01209 sch002
Catalysts 12 01209 g002 550
Figure 2. Scope of the addition of Triazoles to rac-1,7-diphenyl-hepta-3,4-diene (1). Reactions were performed at 0.25 mmol scale. Cumulative yield for all isolated isomers. E/Z-selectivities determined by 1H-NMR. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. Unless specified, ee-values refer to main-stereoisomer of the main-regioisomer. Shown regioisomer is designated as an N1-product.
Figure 2. Scope of the addition of Triazoles to rac-1,7-diphenyl-hepta-3,4-diene (1). Reactions were performed at 0.25 mmol scale. Cumulative yield for all isolated isomers. E/Z-selectivities determined by 1H-NMR. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. Unless specified, ee-values refer to main-stereoisomer of the main-regioisomer. Shown regioisomer is designated as an N1-product.
Catalysts 12 01209 g002
Catalysts 12 01209 g003 550
Figure 3. Scope of the addition of Benzotriazole (2) to different racemic allenes. Reactions were performed at 0.25 mmol scale. Cumulative yield for all isolated isomers. E/Z-selectivities determined by 1H-NMR. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. Unless specified, ee-values refer to main-stereoisomer of the main-regioisomer. [a] Reaction was heated for 72 h.
Figure 3. Scope of the addition of Benzotriazole (2) to different racemic allenes. Reactions were performed at 0.25 mmol scale. Cumulative yield for all isolated isomers. E/Z-selectivities determined by 1H-NMR. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. Unless specified, ee-values refer to main-stereoisomer of the main-regioisomer. [a] Reaction was heated for 72 h.
Catalysts 12 01209 g003
Catalysts 12 01209 g004 550
Figure 4. Scope of the addition of Tetrazoles to rac-1,7-diphenyl-hepta-3,4-diene. (1) Reactions were performed at 0.25 mmol scale. Cumulative yield for all isolated isomers. Z/E-selectivities were determined by 1H-NMR. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. Unless specified, ee-values refer to main-stereoisomer of the main-regioisomer. Unless specified full N2-selectivity was obtained. [a] Reaction was performed at 60 °C.
Figure 4. Scope of the addition of Tetrazoles to rac-1,7-diphenyl-hepta-3,4-diene. (1) Reactions were performed at 0.25 mmol scale. Cumulative yield for all isolated isomers. Z/E-selectivities were determined by 1H-NMR. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. Unless specified, ee-values refer to main-stereoisomer of the main-regioisomer. Unless specified full N2-selectivity was obtained. [a] Reaction was performed at 60 °C.
Catalysts 12 01209 g004
Catalysts 12 01209 g005 550
Figure 5. Scope of the addition of 5-phenyl-2H-tetrazole to different racemic allenes. Reactions were performed at 0.25 mmol scale. Cumulative yield for all isolated isomers. E/Z-selectivities determined by 1H-NMR. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. Unless specified, ee-values refer to main-stereoisomer of the main-regioisomer. Unless specified full N2-selectivity was obtained.
Figure 5. Scope of the addition of 5-phenyl-2H-tetrazole to different racemic allenes. Reactions were performed at 0.25 mmol scale. Cumulative yield for all isolated isomers. E/Z-selectivities determined by 1H-NMR. Enantioselectivities were determined by HPLC analysis using a chiral stationary phase. Unless specified, ee-values refer to main-stereoisomer of the main-regioisomer. Unless specified full N2-selectivity was obtained.
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Catalysts 12 01209 sch003 550
Scheme 3. Control experiments: Without PPTS, only the allene could be reisolated. After reactions with deuterated pronucleophiles, the deuterium was observed exclusively at the former central atom of the allene.
Scheme 3. Control experiments: Without PPTS, only the allene could be reisolated. After reactions with deuterated pronucleophiles, the deuterium was observed exclusively at the former central atom of the allene.
Catalysts 12 01209 sch003
Catalysts 12 01209 sch004 550
Scheme 4. Proposed reaction mechanism of Rh-catalyzed hydroamination of internal allenes with triazoles and tetrazoles. R.E. = Reductive elimination.
Scheme 4. Proposed reaction mechanism of Rh-catalyzed hydroamination of internal allenes with triazoles and tetrazoles. R.E. = Reductive elimination.
Catalysts 12 01209 sch004
Table
Table 1. Control experiments with enantioenriched allene.
Table 1. Control experiments with enantioenriched allene.
#AlleneLigandProduct
Catalysts 12 01209 i001
1(S)-1 99% ee(R,R)-DIOP(S)-3, 91%, N1/N2 95:5, E/Z 95:5, 94% ee
2(R)-1 90% ee(R,R)-DIOP(S)-3, 89%, N1/N2 94:6, E/Z 95:5, 96% ee
3(S)-1 99% eedppbrac-3, 87%, N1/N2 88:12, E/Z 95:5
Catalysts 12 01209 i002
#AlleneLigandProduct
4(S)-1 99% ee(R,R)-DIOP(R)-5, 95%, N2/N1 >95:5, Z/E >95:5, 84% ee
5(R)-1 90% ee(R,R)-DIOP(R)-5, 93%, N2/N1 >95:5, Z/E >95:5, 81% ee
6(S)-1 99% eedppbrac-5, 95%, N2/N1 >95:5, Z/E >95:5
Control experiments with enantiomerically enriched allenes led to the products with the same absolute configuration for (R,R)-DIOP or to the racemic products for the achiral dppb ligand.
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Sieger, S.V.; Lubins, I.; Breit, B. Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes towards Chiral Allylated Triazoles and Tetrazoles. Catalysts 2022, 12, 1209. https://doi.org/10.3390/catal12101209

AMA Style

Sieger SV, Lubins I, Breit B. Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes towards Chiral Allylated Triazoles and Tetrazoles. Catalysts. 2022; 12(10):1209. https://doi.org/10.3390/catal12101209

Chicago/Turabian Style

Sieger, Simon V., Ilja Lubins, and Bernhard Breit. 2022. "Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes towards Chiral Allylated Triazoles and Tetrazoles" Catalysts 12, no. 10: 1209. https://doi.org/10.3390/catal12101209

APA Style

Sieger, S. V., Lubins, I., & Breit, B. (2022). Rhodium-Catalyzed Dynamic Kinetic Resolution of Racemic Internal Allenes towards Chiral Allylated Triazoles and Tetrazoles. Catalysts, 12(10), 1209. https://doi.org/10.3390/catal12101209

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