Communications Redox-Neutral Amination Very Important Paper
Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201703704 German Edition: DOI: 10.1002/ange.201703704
Enantioselective Synthesis of Tetrahydroquinolines by Borrowing Hydrogen Methodology: Cooperative Catalysis by an Achiral Iridacycle and a Chiral Phosphoric Acid Ching Si Lim, Thanh Truong Quach, and Yu Zhao* Abstract: We report herein the highly enantioselective synthesis of 2-substituted tetrahydroquinolines through borrowing hydrogen, a process recognized for its environmentally benign and atom-economical nature. The use of an achiral iridacycle complex in combination with a chiral phosphoric acid as catalysts was the key to the development of this highly efficient and enantioselective transformation.
Nitrogen-containing heterocycles are of great importance
in the pharmaceutical and agrochemical industries. One important class of such heterocycles are 1,2,3,4-tetrahydroquinolines, which have found wide application, for example, as ion-channel antagonists/inhibitors and selective estrogen receptor modulators (SERMs; Scheme 1).[1] Accordingly, various protocols have been developed for their synthesis in the past few decades; great progress has also been made for the asymmetric synthesis of this class of compounds. The enantioselective hydrogenation (Scheme 2 a)[2] and transfer hydrogenation (Scheme 2 b)[3, 4] of the corresponding quinolines with hydrogen gas or Hantzsch esters as the reductant, in particular, have been developed into valuable tools for synthesizing these compounds with high enantiomeric purity. However, the necessity to use either hydrogen gas at high pressure or reductants that generate stoichiometric waste has reduced the overall efficiency of these processes. Alternatively, the dearomative coupling of quinolines or quinolinium salts was also used to deliver dihydroquinolines, which could be further reduced to the desired tetrahydroquinoline derivatives (Scheme 2 c).[5] Nonetheless, these process-
Scheme 2. Different strategies for the synthesis of tetrahydroquinolines.
Scheme 1. Selected bioactive tetrahydroquinoline-based compounds. [*] C. S. Lim, T. T. Quach, Prof. Y. Zhao Department of Chemistry, National University of Singapore 3 Science Drive 3, Singapore 117543 (Singapore) E-mail:
[email protected] Supporting information and the ORCID identification number(s) for the author(s) of this article can be found under: https://doi.org/10.1002/anie.201703704.
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es possess similar drawbacks owing to the use of stoichiometric organometallic reagents and reductants. The development of green, economical, and highly efficient synthetic methods for the asymmetric synthesis of heterocycles is still highly desired. We report herein the first highly enantioselective synthesis of tetrahydroquinolines on the basis of borrowing-hydrogen methodology. In this process, readily available racemic amino alcohols are converted into tetrahydroquinolines in an overall redox-neutral fashion without the need for any stoichiometric reagents
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Communications (Scheme 2 d). The use of an achiral iridacycle complex and a chiral phosphoric acid as catalysts resulted in high reactivity and enantioselectivity.[6] In recent years, the amination of alcohols through borrowing-hydrogen methodology has gained much attention, as it is recognized as a green method for amine synthesis with high atom economy.[7] This methodology involves three reactions proceeding in tandem (oxidation, condensation, and reduction) without the use of an external reductant or oxidant, as the alcohol serves as the H2 donor. Water is produced as the sole by-product of the reaction. Fujita et al. first reported the formation of tetrahydroquinolines through the cyclization of amino alcohols in a nonstereoselective fashion.[8] Our research group was attracted to the possibility of enantioselective borrowing hydrogen for chiral-amine synthesis, and developed the first example of the enantioselective amination of racemic secondary alcohols with panisidine by using a Noyori–Ikariya-type iridium complex together with a chiral phosphoric acid as the catalysts.[9, 10] In this system, both enantiomers of the racemic alcohol substrate are converted into the enantiomerically enriched chiral amine product, as the first oxidation step proceeds in a nonstereoselective fashion, whereas the last reduction step proceeds stereoselectively. Owing to the importance of chiral tetrahydroquinolines, we set out to explore the possibility of the enantioselective cyclization of racemic amino alcohols through borrowing hydrogen. Initial screening of the cyclization of readily available amino alcohol 1 a was carried out with the chiral phosphoric acid 4 a together with transition-metal complexes 3 a–c, which are catalysts for hydrogenation and transfer-hydrogenation reactions (Table 1).[11] The desired product could be obtained in moderate yield by the use of complex (S,S)-3 a or (R,R)-3 a with 4 a, but poor enantioselectivity was observed (Table 1, entries 1 and 2).[9a] The analogous Rh complexes 3 b exhibited poorer reactivity with no improvement in enantioselectivity (entries 3 and 4), whereas the isoelectronic Ru analogues 3 c gave only a trace amount of the desired product (entries 5 and 6). Other transition-metal complexes, such as [IrIII(mCl)ClCp*]2 and the Shvo catalyst, used in combination with 4 a, resulted in moderate to good yields but a total lack of stereoselectivity (entries 7 and 8). In an effort to improve the enantioselectivity of the synthesis of 2 a, a range of iridiumbased complexes were explored. To our delight, use of the achiral iridacycle complex 3 d (reported by Ikariya and coworkers for the transfer hydrogenation of ketones)[12] with 4 a led to the formation of 2 a in 80 % yield with a much improved enantiomeric ratio of 81:19 (entry 9). To our knowledge, the use of such an iridacycle complex in borrowing-hydrogen methodology has not been reported previously. In this case, the chirality of the phosphoric acid alone led to an enantioselective reaction. After this promising result, further optimization of the reaction parameters was carried out. Although the reaction with 3 a and 4 a at a lower temperature of 80 8C led to no product formation, the amination reaction proceeded to full conversion at 80 8C when iridacycle 3 d and 4 a were used as the catalysts, and 2 a was produced in an excellent yield (96 %) with e.r. 82:18 (Table 1, entry 10). The improved yield in this Angew. Chem. Int. Ed. 2017, 56, 7176 –7180
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case was primarily due to suppression of the oxidation of the tetrahydroquinoline product to the undesired quinoline side product at this lower reaction temperature. The formation of quinoline side product increased with time after the completion of the reaction. At this point, much effort was spent on probing the effect of varying the iridacycle catalyst. Electronic variation of the iridium complex (catalysts 3 e and 3 f) led to diminished efficiency and selectivity (entries 11 and 12), and the introduction of chirality on the iridacycle backbone led to no improvement either (entries 13–16). Various solvents were screened, and the use of the green solvent dimethyl carbonate (DMC)[13] resulted in an excellent yield of 94 % and improvement of the enantioselectivity to e.r. 92:8 (entry 17). A reaction temperature of 80 8C and the use of DMC as the solvent were then adopted for further optimization. To further improve the selectivity of the reaction, we also prepared and screened more chiral phosphoric acids. With the spirocyclic phosphoric acid catalyst 4 g, the desired product was obtained in good yield but with moderate enantioselectivity (Table 1, entry 18). Less sterically hindered phosphoric acids, such as 4 b, showed no enantiodiscrimination (entry 19), thus further indicating the importance of sterically bulky groups on the phosphoric acid for good enantioselectivity. Phosphoric acids 4 c and 4 d, which are optimal catalysts for transfer hydrogenation with Hantzsch esters, did not improve the enantioselectivity of the reaction (entries 20 and 21).
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Table 1: Optimization of the enantioselective cyclization of 1 a.
Entry
Catalyst
4
Solvent
T [88C]
Yield [%][a]
e.r.[b]
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24[c] 25[d] 26
(S,S)-3 a (R,R)-3 a (S,S)-3 b (R,R)-3 b (S,S)-3 c (R,R)-3 c Shvo catalyst [{IrCp*Cl2}2] 3d 3d 3e 3f 3g ent-3 g 3h ent-3 h 3d 3d 3d 3d 3d 3d 3d 3d 3d 3d
4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4a 4g 4b 4c 4d 4e 4f 4f 4f –
tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH tAmOH DMC DMC DMC DMC DMC DMC DMC DMC DMC DMC
110 110 110 110 110 110 110 110 110 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80 80
47 44 33 26
