Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Catalytic Asymmetric Umpolung Allylation/2-Aza-Cope Rearrangement for the Construction of α‑Tetrasubstituted α‑Trifluoromethyl Homoallylic Amines Chong Shen,† Ruo-Qing Wang,† Liang Wei,† Zuo-Fei Wang,† Hai-Yan Tao,† and Chun-Jiang Wang*,†,‡
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†
Engineering Research Center of Organosilicon Compounds & Materials, Ministry of Education, College of Chemistry and Molecular Sciences, Wuhan University, Wuhan 430072, China ‡ State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, China S Supporting Information *
ABSTRACT: A general protocol for the preparation of enantioenriched α-tetrasubstituted α-trifluoromethyl homoallylic amines is disclosed. Despite the significant challenge in stereoselectivity control, Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoromethylated fluorenone imines with allylic carbonates was realized with excellent efficiency and remarkable stereoselectivity. These were enabled by the suitable protective imino moiety and an unexpectedly exclusive E-geometrical imine of the allylation intermediate. This methodology is also applicable to facile access to chiral α-trisubstituted αtrifluoromethyl homoallylic amines in similarly high yield and stereoselectivity. he presence of fluorine atom in various pharmaceutically and agrochemically important molecules has had a unique and beneficial impact on their biological activities and stimulates an exponentially increasing demand for developing expedient methodologies to synthesize fluorinated compounds.1,2 Among organofluorine molecules, enantioenriched α-(trifluoromethyl)amines play a significant role in medicinal chemistry, as introducing CF3 at the α-position to nitrogen often dramatically decreases the basicity and imparts enhanced lipophilicity and metabolic stability compared with that of the corresponding α-methyl amines. 1d,3 In thlight of the importance of those fluorinated compounds, various powerful methodologies have been reported recently for the preparation of chiral α-(trifluoromethyl)amines, such as asymmetric trifluoromethylation of imines,4 asymmetric hydrogenation,5 or nucleophilic addition6 to fluorinated imines and organocatalyzed isomerization fluorinated imines.7 Most recently, we disclosed a protocol to enantioselective synthesis of αtrisubstituted α-trifluoromethyl homoallylic amines8 via an Ircatalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoroethylisatin ketimine (Scheme 1a). However, the scope of the nucleophilic partner is restricted to trifluoroethylamine-derived isatin ketimine and therefore cannot be applied to the enantioselective preparation of αtetrasubstituted α-trifluoromethyl homoallylic amines. Although α-tetrasubstituted α-(trifluoromethyl)amines are found in biologically active molecules or pharmaceuticals9 (Figure 1), a catalytic asymmetric synthesis of α-tetrasubstituted α-trifluoromethyl homoallylic amines10 bearing an
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© XXXX American Chemical Society
unsaturated CC double bond for further elaborations remains a challenge and is yet to be developed. In this regard, we surmised that an appropriate imino moiety connected to αsubstituted α-trifluoroethylamine should be capable of activating these substrates via 2-azaallyl carbanion and, therefore, toggling them into cascade asymmetric umpolung allylation/2-aza-Cope rearrangement to deliver enantioenriched α-tetrasubstituted α-trifluoromethyl homoallylic amines (Scheme 1b, top). However, two challenging issues had to be considered in this design (Scheme 1b, bottom): (1) a suitable imino moiety, which can stabilize the adjacent carbanion but would not retard the nucleophilicity of the generated 2-azaallyl anion in the initial allylation step, should be installed at the Nterminus of α-substituted α-trifluoroethylamines, and (2) the intuitive Z−E isomerization of the imino moiety in the branched allylation intermediate, which results in remarkably reduced energy barrier difference between 2-aza-Cope rearrangement transition state TSC ([R(ax)+ CF3(eq)]) and TSD ([R(eq) + CF3(ax)]) (shown in Scheme 1b, ax: axial position; eq: equatorial position), compared with the distinct energy barrier difference between the corresponding rearrangement transition state TSA ([H(ax) + CF3(eq)]) (shown in Scheme 1a) and TSB ([H(eq) + CF3(ax)]) (not shown in Scheme 1a) for isatin ketimine, would inevitably bring deterioration to the efficacy of the chirality transfer. Herein, we documented the development and substrate scope Received: July 21, 2019
A
DOI: 10.1021/acs.orglett.9b02543 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 1. (a) Asymmetric Synthesis of α-Trisubstituted αCF3 Homoallylic Amine (Previous Work); (b) Design and Potential Challenge Associated with Asymmetric Synthesis of α-Tetrasubstituted α-CF3 Homoallylic Amines (This Work)
Table 1. Effect of Reaction Parameters on the Asymmetric Cascade Umpolung Allylation/2-Aza-Cope Rearrangement for Asymmetric Synthesis of α-Tetrasubstituted α-CF3 Homoallylic Aminesa
entry
variation from standard conditions
yieldb (%)
1 2 3 4 5 6 7 8 9 10 11
1a instead of 1d 1b instead of 1d 1c instead of 1d none L2 instead of L1 Et3N instead of DBU TBD instead of DBU Cs2CO3 instead of DBU (CH2Cl)2 instead of PhMe THF instead of PhMe Et2O instead of PhMe
trace trace trace 90 25 99 96 99 96 98 96 98 98 94 98 >99 98 98 95 91 97 92
a
All reactions were carried out with 0.20 mmol of 5, 0.22 mmol of 2, 0.01 mmol of Ir/(S,S,S)-L, and 0.2 mmol of base in 2 mL of PhMe. b Yields refer to the isolated products after chromatographic purification. cThe ee value was determined by HPLC analysis. d15 mol % Ir/(S,S)-L2 was used, and (R)-6d was obtained in 48 h. eX-ray structure of tosylated (S)-6h was obtained. fWithout acidic workup to facilitate HPLC analysis.
catalytic system shows good tolerance toward various aryl and heteroaryl allylic carbonates, affording the corresponding αtrifluoromethyl homoallylic amines in high yields with excellent enantioselectivities (entries 2, 3, and 5−16). To be noted, better enantioselectivity was achieved in the current catalytic system compared with that obtained in our previous work employing N-2,2,2-trifluoroethyl isatin ketimine.8 Lower reactivity and asymmetric induction were observed for omethyl cinnamyl carbonate under the optimal reaction conditions with ligand (S,S,S)-L1. However, different from C
DOI: 10.1021/acs.orglett.9b02543 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Proposed Mechanism for the Rationale of Regio-/Stereochemical Results and Control Experiments
the case of the formation of α-tetrasubstituted α-trifluoromethyl homoallylic amines, switching the chiral ligand to (S,S)-L2 could enhance the enantioselectivity significantly, and the desired product was isolated in moderate yield with excellent enantioselectivity (96% ee) (entry 4). Alkyl allylic carbonate also worked well in this reaction, delivering the corresponding product 6r in acceptable yield with high enantioselectivity (entry 17). On the basis of the literature results,11,17 a proposed catalytic cycle incorporating umpolung Ir-catalyzed asymmetric allylation followed by 2-aza-Cope rearrangement is depicted in Scheme 2. The steric congestion around the newly formed carbon−carbon bond and release of electronic strain via rehybridization of CF3-containing carbon from sp2 to sp3 force the branched allylation intermediate 7 to undergo further 2aza-Cope rearrangement, delivering the linear α-tetrasubstituted α-trifluoromethyl homoallylic amine (S,E)-3a. When the reaction of 1d and 2a was performed at room temperature, the cascade reaction became more sluggish. When the reaction was interupted around 8 h, the branched intermediate (S,ECN)-7 could be readily obtained in 40% yield with 98% ee. Therefore, the first allylation is initiated by the nucleophilic attack of in situ generated 2-azaallyl carbanion of 1d via the Cα′ position to electrophilic Ir-α-allyl species C. Considering that the geometry of trifluoroalkyl ketimines was reported as an exclusive (Z)-configuration due to the hyperconjugative interaction of a lone electron pair of nitrogen into the σ* orbital of the carbon−carbon bond between the imine and CF3 group,18 the most prominent feature of the crystal of allylation intermediate 7 is the E-geometry of the CN bond. Meanwhile, the crystal structure also revealed that there is an absence of π−π conjugate system between the perpendicular phenyl group and the imine moiety. The unique E-geometrical propensity of the CN bond in this case could be rationalized by the disfavored A1,3 interaction between the CF3 group and fluorenyl moiety in the corresponding (Z)-ketimine 7 (not shown in Scheme 2), which dictates that the phenyl group in (S,ECN)-7 occupy the less sterically congested perpendicular position without additional π−π conjugated stabilization. The
full rearrangement of (S,ECN)-7 into (R,ECC)-3a could be finished around 3 days at room temperature but complete within 6 h upon heating at 50 °C, delivering the linear αtrifluoromethyl homoallylic amine in good yield without erosion of the enantioselectivity, which is consistent with the proposed cascade allylation/rearrangement reaction pathway. Based on the confirmed E-geometry of the CN bond in the branched allylation intermediate and the E-geometry of the CC bond in the rearranged final product, the stereochemical outcome of the 2-aza-Cope rearrangement could be rationalized as the result of stereospecific chirality transfer through the formation of a highly ordered and favored Zimmerman− Traxler transition state19 (TSC), in which the CF3 group and the perpendicular phenyl group reside in equatorial and axial positions, respectively. In conclusion, we developed a general protocol for the catalytic asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoromethylated fluorenone imines with allylic carbonates. The cascade allylation/rearrangement of a wide range of trifluoromethylated fluorenone imines has been realized with excellent efficiency and remarkable stereoselectivity, enabled by the suitable protective imino moiety and an unexpectedly exclusive E-geometrical imine of the allylation intermediate. Both α-tetra- and α- trisubstituted αtrifluoromethyl homoallylic amines can be generated in good yields with excellent enantioselectivity.
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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.9b02543. Experimental procedures and compound characterization data (PDF) Accession Codes
CCDC 1918183−1918186 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 D
DOI: 10.1021/acs.orglett.9b02543 Org. Lett. XXXX, XXX, XXX−XXX
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Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Chun-Jiang Wang: 0000-0003-3629-6889 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the NSFC (21525207, 21772147) and the China Postdoctoral Science Foundation funded project (BX20190253). We thank Prof. Shu-Li You at SIOC for generously providing (S,S)-L2. The Program of Introducing Talents of Discipline to Universities of China (111 Program) is also appreciated.
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DEDICATION This work is dedicated to Prof. Qing-Yun Chen on the occasion of his 90th birthday. REFERENCES
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Organic Letters
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DOI: 10.1021/acs.orglett.9b02543 Org. Lett. XXXX, XXX, XXX−XXX
