Catalytic Asymmetric Synthesis of α-Tetrasubstituted α-Trifluoromethyl

Jul 22, 2019 - 23, but many challenges need to be overcome in order to build the tetrasubstituted ... the trifluoromethyl group may render the Cα pos...
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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Catalytic Asymmetric Synthesis of α‑Tetrasubstituted α‑Trifluoromethyl Homoallylic Amines by Ir-Catalyzed Umpolung Allylation of Imines Yingwei Wang, Li-Fan Deng, Xia Zhang,* and Dawen Niu* Department of Emergency, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and School of Chemical Engineering, Sichuan University, Chengdu, 610041, China Downloaded via NOTTINGHAM TRENT UNIV on August 16, 2019 at 22:20:54 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.

S Supporting Information *

ABSTRACT: A general and mild method to prepare enantioenriched αtrifluoromethyl, α-stereogenic homoallylic amines is established. This reaction, which involves an Ir-catalyzed umpolung allylation of imines and a 2-aza-Cope rearrangement cascade, could yield both tetrasubstituted and trisubstituted stereocenters. This transformation employs readily available starting materials and displays broad substrate scope. The isolation and structural determination of reaction intermediates revealed factors critical for the efficiency and stereoselectivity of this transformation.

C

hiral amines1 are ubiquitous motifs in pharmaceuticals, agrochemicals, materials, and ligands to transition metals. In synthetic chemistry, the attack of a carbon-based nucleophile to imines (1 to 2 to 3, Scheme 1a) represents

advantages notwithstanding, successful implementation of the umpolung functionalization of imines, the asymmetric variants9 in particular, remains uncommon. α-Trifluoromethyl amines10 are important scaffolds in many bioactive molecules (see Scheme 2a for examples). Nucleophilic addition to trifluoromethyl imines (as electrophiles) constitutes a classical approach11 to make chiral α-trifluoromethyl amines. Recently, great advances have also been made in the synthesis of these compounds by umpolung approaches. For example, Deng and co-workers developed an elegant strategy to make enantioenriched α-trifluoromethyl amines by the umpolung addition of trifluoromethyl imines to electrophiles including enals and enones (7 + 8 to 9 via 7′, Scheme 2b).9b−g The Zhang group successfully applied the umpolung strategy to the asymmetric synthesis of α-trifluoromethyl amines from trifluoromethyl imines and Morita−Baylis− Hillman carbonates (7 + 10 to 11 via 7′, Scheme 2b).9h,i Both of the two approaches involved the intermediacy of 1trifluoromethyl-2-azaallyl anion 7′. The interaction between the anionic intermediate 7′ with chiral cations (derived from chiral phase-transfer catalysts or organophosphine catalysts) lays the foundation of stereoinduction in these cases. Both methods were capable of preparing α-tetrasubstituted αtrifluoromethyl amines, a class of compounds that are particularly challenging to access. We reasoned that if 1trifluoromethyl-2-azaallyl anions could be engaged in transition-metal-catalyzed transformations, products beyond the scope of the previous strategies may be accessed. We considered the possibility of the cascade transformation depicted in Scheme 1c being used to prepare α-tetrasub-

Scheme 1. Conventional and Umpolung Approaches to Make Chiral Amines

one of the most often used approaches2 to make chiral amines. The majority of established catalytic asymmetric methods to make chiral amines are based on such a platform. Recently, the umpolung3 functionalization of imines (4 to 6 via 4′ and 5, Scheme 1b), in which imines serve as nucleophiles via the intermediacy of 2-aza-allyl anions,4−8 has attracted significant attention. This unconventional bond-forming mode could avoid the use of sensitive organometallic nucleophiles and allow synthesis of products that are traditionally difficult to prepare. Moreover, the resulting products could be converted to primary amines by mild, hydrolytic conditions. These © XXXX American Chemical Society

Received: July 22, 2019

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DOI: 10.1021/acs.orglett.9b02550 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. α-Trifluoromethyl Amines: Significance and Some Synthetic Methods Based on Umpolung Approaches

tetrasubstituted center by such a process is not well precedented. Despite the above-mentioned challenges, we demonstrate in this work the feasibility of such a transformation to generate tetrasubstituted, α-trifluoromethyl homoallylic amines. This reaction proceeds under mild conditions and displays broad substrate scope. Isolation and structural characterization of key intermediates provide insights into the mechanism of this transformation and the foundation of its high stereoselectivity. We commenced our study by investigating the Ir-catalyzed allylation14 of 2-azaallyl anion 29 (Table 1). While anion 29 Table 1. Condition Optimizationa

entry

base

ligand

solvent

yield

ee

1 2 3 4 5 6 7 8 9 10 11

LiHMDS tBuOK DBU Barton’s Base DABCO DABCO DABCO DABCO DABCO DABCO DABCO

L1 L1 L1 L1 L1 L2 L3 L4 L3 L3 L3

THF THF THF THF THF THF THF THF CH3CN toluene 1,4-dioxane

trace trace 20% 76% 91% 24% 98% 65% 84% trace 79%

− − −80% −54% −74% 85% 97% −5% 92% − 82%

a

Reaction conditions: 26 (0.05 mmol, 1 equiv), 28 (0.055 mmol 1.1 equiv). The yield was determined by 1H NMR analysis using 1,3,5trimethoxybenzene as the internal standard. Ee’s were determined by HPLC. The absolute configuration of 30 was determined by X-ray crystallographic analysis after being derivatized (see SI).

stituted, α-trifluoromethyl homoallylic amines (12 + 13 to 14). We9j,k and others9q,r,s have shown the feasibility of this cascade to build trisubstituted stereocenters using pronucleophiles 21− 23, but many challenges need to be overcome in order to build the tetrasubstituted stereocenters shown in Scheme 1c. First, the allylation of 15 should occur at the Cα′-site with high regioselectivity. However, the electron-withdrawing ability of the trifluoromethyl group may render the Cα position of 15 more reactive (to give 18 instead of 16), as suggested by the transformations shown in Scheme 1b. Second, the allylation of 15 should occur at a sufficiently rapid rate to prevent the potential β-fluorine elimination12 event (cf. 20). Additionally, in order for the final product to have high enantiopurity, not only the C3 of 16 should be constructed with high stereoselectivity during the allylation step, the imine double bond in 16 should be generated with high E/Z ratio as well (cf. 19 in Scheme 1c). Nevertheless, general methods to control the geometry of double bonds in related transformations are uncommon. Lastly, the 2-aza-Cope rearrangement13 from 16 to 17 should remain thermodynamically favorable and kinetically accessible, although the generation of a congested

could in principle be generated by the deprotonation of the fluorenyl Cα′−H bond of 27, our attempts to make 27 were not successful. We instead chose imine 26, the tautomer of 27 as our model substrate, although we assumed it might be more difficult to deprotonate the Cα-H in 26 than the Cα′−H in 27. Regardless, imine 26 could be readily prepared in excellent yield by the condensation between α-trifluoromethyl amine 24 and imine 25, with the precipitation of NH4Cl from the reaction mixture likely being the driving force. Condition optimization for this model reaction between 26 and 28 started from the screening of bases, with [Ir(COD)Cl]2 and You’s ligand15 L1 used as catalyst precursors. Surprisingly, the mild, trialkylamine base DABCO gave the best results in terms of reaction efficiency and stereoselectivity among various bases investigated (entries 1−5). Although the enantiopurity of product 30 under the conditions in entry 5 is only moderate, B

DOI: 10.1021/acs.orglett.9b02550 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

could participate in this reaction. Functional groups such as nitro (33k) or aryl halide (33j) are tolerated. Cinnamyl carbonates with ortho-substituents could be used (33l). Alkyl substituted allylic carbonates (33p−q) could also be employed, although, in these cases, a higher reaction temperature (reflux in toluene) was needed to accelerate the rearrangement event (see Supporting Information (SI) for details). This method could also be adapted to produce trisubstituted α-trifluoromethyl homoallylic amines9s under slightly modified conditions. As shown in Table 3, various allylic carbonates

such results validated that ketimines such as 26 could be used as pronucleophiles in the Ir-catalyzed allylation reactions and established that the proposed cascade in Scheme 1c is viable and facile. We then screened several other types of phosphoramidite ligands (entries 5−8) and identified L3 that afforded the desired product in almost perfect yield and ee. We have also tried different solvents for this transformation (entries 8−11) and found THF to be the best choice of solvent. Having established the optimal conditions for the asymmetric umpolung allylation of trifluoromethyl imines in the model system, we proceeded to investigate the scope. The results are summarized in Table 2. We first established that this

Table 3. Substrate Scope for the Synthesis of Trisubstituted Homoallylic Amines

Table 2. Substrate Scope for the Synthesis of Tetrasubstituted Homoallylic Aminesa

a Conditions: 34 (0.3 mmol), 32 (0.33 mmol), [Ir(COD)Cl]2 (3 mol %), L5 (6 mol %), Barton’s Base (0.06 mmol), DCM (0.1 M), 35 °C for 24 h. Isolated yields (IY) of the amines were reported; ee’s were determined by HPLC analysis. b6 mol % of [Ir(COD)Cl]2 and 12 mol % of L5 were used. cConditions shown in Table 2 were employed. dThe ketimine product was reduced instead of being hydrolyzed. See SI for experimental details.

a Conditions: 31 (0.3 mmol), 32 (0.33 mmol), [Ir(COD)Cl]2 (3 mol %), L3 (6 mol %), DABCO (0.3 mmol), THF (0.1 M), 50 °C for 24 h. Ee’s and de’s were determined by HPLC analysis. bThe reaction was performed at 1 mmol scale with ent-L3 used as ligand. cThe 2-azaCope rearrangement event for these substrates was conducted in refluxing toluene. dProducts were isolated without being hydrolyzed. See SI for experimental details.

reaction could be performed at 1 mmol scale (33a). Next, we showed a broad array of imine nucleophiles could participate in this reaction. For example, those containing aromatic rings with different electronic properties (33b−c) proved to be competent reaction partners. Substitution at the para- (33b− c), meta- (33d), or ortho-positions (33e) was all accommodated. Aryl halides reacted smoothly under the reaction conditions (33b, 33d−e), providing opportunities for further derivatization. Trifluoromethyl imines with various heteroaryl groups, including pyridine (33f−g), thiazole (33h), and furan (33i), were tolerated as well. With respect to electrophiles, allylic carbonates containing heterocycles (product 33m−o)

could participate in this reaction. The substituent at the allylic position could be an aryl group with different electronic (35a− d) and steric properties (35g). Importantly, various heteroaryl substituents, including indole (35l), pyridine (35m), furan (35n), and thiophene (35o), can be accommodated, demonstrating the generality of this transformation. This substituent could also be aliphatic (35p) in nature. Moreover, functional groups including halogen atoms (35e−f) were accommodated. The absolute configurations of products in Tables 2−3 were assigned by analogy to that of 30 and 35a, which were determined by X-ray crystallographic analysis C

DOI: 10.1021/acs.orglett.9b02550 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters (CCDC 1921001 and 1921007, respectively) after being cyclized (Figure S1 in SI). Strategies to prepare α-tetrasubstituted α-chiral amines are valuable. We were curious about the origin of the excellent stereoselectivity of our method to produce these tetrasubstituted centers. We reasoned that isolation of the reaction intermediates prior to the 2-aza-Cope rearrangement event could provide important insights. When alkyl substituted allylic carbonates such as 36 were used as electrophiles in our reactions, the reaction could be stopped at the allylation step, to give 37 as an intermediate (Scheme 3). We isolated and

ORCID

Scheme 3. Isolation and Structural Determination of 37

(1) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments and Applications; Wiley-VCH: Weinheim, Germany, 2010. (2) For reviews, see: (a) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Synthesis and Applications of tert-Butanesulfinamide. Chem. Rev. 2010, 110, 3600−3740. (b) Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Catalytic Enantioselective Formation of C−C Bonds by Addition to Imines and Hydrazones: A Ten-Year Update. Chem. Rev. ́ 2011, 111, 2626−2704. (c) Yus, M.; Gonzalez-Goḿ ez, J. C.; Foubelo, F. Diastereoselective Allylation of Carbonyl Compounds and Imines: Application to the Synthesis of Natural Products. Chem. Rev. 2013, 113, 5595−5698. (d) Kumagai, N.; Shibasaki, M. Recent Advances in Catalytic Asymmetric C−C Bond-Forming Reactions to Ketimines Promoted by Metal-Based Catalysts. Bull. Chem. Soc. Jpn. 2015, 88, 503−517. Enzymatic processes are important alternatives. For example, see: (e) Patel, R. N. Biocatalysis in the Pharmaceutical and Biotechnology Industries; CRC Press LLC: Boca Raton, FL, 2007. (3) (a) Seebach, D. Methods of Reactivity Umpolung. Angew. Chem., Int. Ed. Engl. 1979, 18, 239−258. (b) Romanov-Michailidis, F.; Rovis, T. Natural polarity inverted. Nature 2015, 523, 417−418. (c) Waser, M.; Novacek, J. An Organocatalytic Biomimetic Strategy Paves the Way for the Asymmetric Umpolung of Imines. Angew. Chem., Int. Ed. 2015, 54, 14228−14231. (4) (a) Cram, D. J.; Guthrie, R. D. Electrophilic Substitution at Saturated Carbon. XXVII. Carbanions as Intermediates in the BaseCatalyzed Methylene-Azomethine Rearrangement. J. Am. Chem. Soc. 1966, 88, 5760−5765. (b) Kauffmann, T.; Köppelmann, E.; Berg, H. Ionization and Rearrangement of Diphenylphenoxymethylmagnesium Chloride. Angew. Chem., Int. Ed. Engl. 1970, 9, 163−163. (c) Tang, S.; Zhang, X.; Sun, J.; Niu, D.; Chruma, J. J. 2-Azaallyl Anions, 2-Azaallyl Cations, 2-Azaallyl Radicals, and Azomethine Ylides. Chem. Rev. 2018, 118, 10393−10457. (5) (a) Liu, M.; Li, J.; Xiao, X.; Xie, Y.; Shi, Y. An efficient synthesis of optically active trifluoromethylaldimines via asymmetric biomimetic transamination. Chem. Commun. 2013, 49, 1404−1406. (b) Wu, Y.; Deng, L. Asymmetric Synthesis of Trifluoromethylated Amines via Catalytic Enantioselective Isomerization of Imines. J. Am. Chem. Soc. 2012, 134, 14334−14337. (c) Zhou, X.; Wu, Y.; Deng, L. Cinchonium Betaines as Efficient Catalysts for Asymmetric Proton Transfer Catalysis: The Development of a Practical Enantioselective Isomerization of Trifluoromethyl Imines. J. Am. Chem. Soc. 2016, 138, 12297−12302. (6) (a) Tang, S.; Park, J. Y.; Yeagley, A. A.; Sabat, M.; Chruma, J. J. Decarboxylative Generation of 2-Azaallyl Anions: 2-Iminoalcohols via a Decarboxylative Erlenmeyer Reaction. Org. Lett. 2015, 17, 2042− 2045. (b) Liu, X.; Gao, A.; Ding, L.; Xu, J.; Zhao, B. Aminative Umpolung Synthesis of Aryl Vicinal Diamines from Aromatic Aldehydes. Org. Lett. 2014, 16, 2118−2121. (c) Matsumoto, M.; Harada, M.; Yamashita, Y.; Kobayashi, S. Catalytic imine−imine cross-coupling reactions. Chem. Commun. 2014, 50, 13041−13044. (d) Chen, Y.-J.; Seki, K.; Yamashita, Y.; Kobayashi, S. Catalytic Carbon−Carbon Bond-Forming Reactions of Aminoalkane Derivatives with Imines. J. Am. Chem. Soc. 2010, 132, 3244−3245. (e) Daniel, P. E.; Weber, A. E.; Malcolmson, S. J. Umpolung Synthesis of 1,3-Amino Alcohols: Stereoselective Addition of 2Azaallyl Anions to Epoxides. Org. Lett. 2017, 19, 3490−3453. (f) Li, K. N.; Weber, A. E.; Tseng, L.; Malcolmson, S. J. Diastereoselective

Dawen Niu: 0000-0002-5114-4413 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS Funding from National Natural Science Foundation (Nos. 21772125, 21602145, and 81803359), and start-up funding from Sichuan University is acknowledged.

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characterized the structure of 37 by X-ray crystallography (CCDC 1920983). Several structural features of intermediate 37 are noteworthy. First, the phenyl ring of 37 is laying on top of its fluorenyl ring, indicating the presence of π−π interaction. This favorable interaction could be an important reason for the high E-selectivity of this event. Moreover, the phenyl ring in 37 was forced out of conjugation with the imine double bond, which likely destabilized 37 and rendered the following 2-azaCope rearrangement more thermodynamically favorable and kinetically accessible. In conclusion, we have established a general, stereoselective method to prepare α-trifluoromethyl homoallylic amines. This reaction comprises an iridium-catalyzed, umpolung allylic alkylation of imines and a subsequent 2-aza-Cope rearrangement event. This transformation tolerates a wide range of variations in both the ketimines and the allylic carbonates partners, yielding trisubstituted or tetrasubstituted α-trifluoromethyl homoallylic amines in excellent yields and enantioselectivities. Isolation and structural identification of reaction intermediates revealed some key factors for the high efficiency and selectivity of this process.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b02550. Experimental procedures and spectral data (PDF) Accession Codes

CCDC 1920983, 1921001, 1921007, and 1921012 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/ data_request/cif, or by emailing [email protected]. uk, or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected] (X.Z.). *E-mail: [email protected] (D.N.) D

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DOI: 10.1021/acs.orglett.9b02550 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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Letter

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DOI: 10.1021/acs.orglett.9b02550 Org. Lett. XXXX, XXX, XXX−XXX