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

: 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 N 1 / N x -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.


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).

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 1 H-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 N 1 -product.

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 1 H-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 N 2 -selectivity was obtained.
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). 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.
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 Rh I -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-σisomerization 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 πcomplex, 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.

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.

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.

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, 1 H and 13 C NMR spectra, determination of absolute configuration, HPLC chromatograms of products and enantioenriched allenes, more detailed materials and methods [61][62][63][64][65][66]. 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.