Catalytic Asymmetric Synthesis of Î±-Trifluoromethyl Homoallylic

Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

pubs.acs.org/OrgLett

Catalytic Asymmetric Synthesis of α‑Trifluoromethyl Homoallylic Amines via Umpolung Allylation/2-Aza-Cope Rearrangement: Stereoselectivity and Mechanistic Insight Li-Min Shi,†,§ Xi-Shang Sun,†,§ Chong Shen,† Zuo-Fei Wang,† Hai-Yan Tao,† and Chun-Jiang Wang*,†,‡ †

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

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S Supporting Information *

ABSTRACT: An unprecedented Ir-catalyzed asymmetric cascade umpolung allylation/2-aza-Cope rearrangement of trifluoroethylisatin ketimines has been realized. The current method provides a facile access to biologically important αtrifluoromethyl-containing homoallylic amines in high yields with excellent enantioselectivity. Notably, umpolung reactivity of trifluoroethylisatin ketimine was discovered for the first time. Mechanism studies revealed the key intermediates in the initial umpolung allylation and the stereospecific chirality transfer in the subsequent 2-aza-Cope rearrangement. fluorinated imines, asymmetric trifluoromethylation of imines,7 and organocatalyzed isomerization or umpolung nucleophilic addition of fluorinated imines.8 However, much less attention has been paid to the asymmetric construction of αtrifluoromethyl homoallylic amines,9 although the unsaturated double bond can be readily functionalized to various CF3containing building blocks or N-heterocycles. The established method for preparing optically active α-trifluoromethyl homoallylic amines was chiral-auxiliary-induced diastereoselective allylation of trifluoromethylated imine.10 Therefore, the development of efficient and catalytic protocols for their enantioselective preparation with readily available starting material is in high demand. Recently, N-2,2,2-trifluoroethylisatin ketimine derived from 2,2,2-trifluoroethylamine hydrochloride (CF3CH2NH3Cl) emerged as a cost-efficient CF3-containing reagent for the asymmetric construction of α-trifluoromethyl amines,11 in which the carbon adjacent to electron-withdrawing CF3 served as the nucleophilic site (Scheme 1a). Previously, we disclosed that the metalated azomethine ylide was a viable nucleophile in asymmetric Michael addition reaction.12 Most recently, we and others uncovered the successful application of such ylides in asymmetric allylation reactions for the construction of α,αdisubstituted α-amino acids via synergistic bimetallic catalysis.13 Considering the potential N,O-bidentate coordination of trifluoroethylisatin ketimine to copper cation to form a similar N-metalated azomethine ylide, we originally devised an asymmetric synthesis of the branched α-trifluoromethyl

T

he chemistry of organofluorine compounds plays a significant role in the fields of drug discovery and material science.1 The introduction of fluorine atoms, in particular, the CF3 group, into a molecular structure of potentially biological active compounds is a well-established strategy in the research of medicinal chemistry to realize the fine-tuning of physicochemical properties.2 Among various CF3-containing compounds, chiral α-(trifluoromethyl)amine is of primary significance as a proven pharmacophore element in the design of medicinal agents,3 including odanacatib, 3′-trifluoromethyl taxoid, and so on4 (Figure 1). The presence of a CF3 group at the α-position to nitrogen greatly decreases the basicity and therefore modifies their biological properties.3b Previous synthesis of the enantioenriched α-(trifluoromethyl)amine focuses on the asymmetric hydrogenation5 or nucleophilic addition6 to

Figure 1. Selected drugs containing α-(trifluoromethyl)amine pharmacophore. © XXXX American Chemical Society

Received: May 17, 2019

A

DOI: 10.1021/acs.orglett.9b01738 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Initial Test and Reaction Optimizationa

Scheme 1. (a) Trifluoroethylisatin Ketimine as an α-CF3Containing Nucleophile (Previous Work); (b) Original Design; (c) Unexpected Asymmetric Umpolung Allylation/2Aza-Cope Rearrangement (This Work)

homoallylic amine derivatives via the strategy of dual Cu/Ircatalyzed allylation (Scheme 1b). However, to our surprise, an unexpected linear selective trifluoromethyl homoallylic amine14 was observed with exclusive regioselectivity, as revealed by NMR and X-ray analysis (Scheme 1c, vide infra). Mechanistic investigation reveals that this is a tandem process consisting of a Ir-catalyzed umpolung allylation15,16 followed by a spontaneous stereospecific 2-aza-Cope rearrangement,17 in which an unprecedented umpolung reactivity of trifluoroethylisatin ketimine, that is, the electrophilic carbon of such imine serving as the nucleophilic site (distinct from the previous work11), was discovered for the first time. Initially, we began our investigation on the model reaction of trifluoroethylisatin ketamine (1a) and cinnamyl methyl carbonate (3a) under our previously reported conditions for the dual Cu/Ir-catalyzed allylation reaction with Cs2CO3 as the base and dichloromethane as the solvent.13a The reaction finished smoothly, but surprisingly delivered trifluoromethyl homoallylic amine (Z,S,E)-5aa (Z: imine geometry; S: stereogenic center; E: CC geometry) with exclusive linear selectivity (92% yield, 80% ee; Table 1, entry 1). No branched isomers were observed. Since (Z,S,E)-5aa contains an acidic H atom at the αposition adjacent to CF 3 and the imine group, the enantioselectivity could be deteriorated slowly through the epimerization under the basic conditions. Then the reaction was carried out without Cs2CO3, and full conversion was observed with the enhanced enantioselectivity (94% ee). Further optimization revealed that the single Ir complex could realize this transformation with maintained reactivity and enantioselectivity (Table 1, entries 3−6). The inessential Cu(I) complex in this reaction means that trifluoroethylisatin ketamine (1a) only acted as a nucleophilic carbanion precursor instead of forming an N-metalated azomethine ylide. Several privileged phosphoramidite ligands18 were also examined in this reaction, and Feringa’s ligand19 (S,S,S)-L2 exhibited the best asymmetric induction (Table 1, entries 6−9). Upon further examination of the effect of the leaving group of π-allyl precursors and solvents,

entry

Cu(I)/L1

L for Ir(I)

base

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9

+ + − − − − − − −

L2 L2 L2 L2 L2 L2 L3 L4 L5

Cs2CO3

92 95 93 87 92 99 86 84 trace

80 94 80 35 76 95 88 35

Cs2CO3 DBU Et3N

a All reactions were carried out with 0.20 mmol of 1a and 0.22 mmol of 3a in 2 mL of CH2Cl2. bYields refer to the isolated products after chromatographic purification. cThe ee value was determined by HPLC analysis.

no better results could be obtained (see the Supporting Information for details). With the optimized reaction conditions identified, the scope of allylic carbonates was explored.20 As shown in Table 2, a number of para- and meta-substituted cinnamyl methyl carbonates bearing electron-neutral (3a), electron-deficient (3d−f and 3i), or electron-rich (3b, 3c, 3g, and 3h) groups on the phenyl ring performed well to afford the corresponding products in high yields (90−99%) with excellent enantioselectivity (92−95% ee) (Table 2). With the challenging o-methyl carbonate (3j), the corresponding product was obtained in good yield albeit with 15% ee. The enantioselectivity could be significantly improved to 75% ee using You’s ligand (S,S)-L3.18c In addition, excellent yields and enantioselectivities were also achieved for 3,4- (3k) and 3,5-disubstituted (3l and 3m) cinnamyl carbonates. Allylic carbonates with a fused aromatic ring (3n) or various heteroaryl groups, including pyridine (3o and 3r), furan (3p), and thiophene (3q) moieties, are also well tolerated in this transformation. When methyl crotyl carbonate 3s was employed, (Z,S,E)-5as and (Z,R,Z)-5as were formed in 94% yield as inseparable isomers in 2:1 ratio, but the enantioselectivity of either isomer was still kept at a high level (Scheme 2, see the SI for details on the Z- and E-geometry determination of the CC bond). To demonstrate the synthetic utility of this methodology, a gram-scale reaction was carried out under the optimized reaction conditions, affording (S,E)-5aa in 90% yield with 95% ee (Scheme 3). Acidic hydrolysis of (S,E)-5aa afforded αB


Letter

Organic Letters Table 2. Substrate Scope of Allylic Carbonatesa

entry

R

5

yieldb (%)

eec (%)

1 2 3 4 5 6 7 8 9 10d 11 12 13 14 15 16 17 18

Ph p-MeC6H4 p-MeOC6H4 p-FC6H4 p-ClC6H4 p-BrC6H4 m-MeC6H4 m-MeOC6H4 m-ClC6H4 o-MeC6H4 benzo[d][1,3]dioxol-5-yl 3,4-Cl2C6H3 3,5-Me2C6H3 2-naphthyl 4-MeO-3-pyridinyl 2-thienyl 2-furyl 3-pyridinyl

5aa 5ab 5ac 5ad 5ae 5af 5ag 5ah 5ai 5aj 5ak 5al 5am 5an 5ao 5ap 5aq 5ar

99 90 92 99 93 93 99 94 97 82 91 83 98 87 92 84 94 99

95 93 94 93 94 94 94 92 93 −75 90 90 95 99 90 94 88 90

diastereoselectivity and maintained enantioselectivity (Scheme 3). Considering the preferentially branched regioselectivity observed in Ir/L2-catalyzed allylation,15 we proposed that the overall reaction might undergo an enantioselective umpolung allylation to form the branched allylation intermediates followed by a spontaneous 2-aza-Cope rearrangement, delivering the observed linear α-trifluoromethyl homoallylic amine derivatives (Scheme 4). Coordination of allylic carbonate to iridacycle B Scheme 4. Proposed Mechanism for Cascade Umpolung Allylation/2-Aza-Cope Rearrangement

followed by oxidative addition−decarboxylation gives Ir-π-allyl species C along with anion MeO−, and the latter serves as the base for the deprotonation of ketimine. The steric congestion caused by the adjacent oxindole ring and phenyl group in the branched allylation intermediates is the key driving force to promote the rearrangement. Since the carbon adjacent to CF3 always served as the nucleophilic site in all previous work11 related to trifluoroethylisatin ketimine, we next focused our study on the mechanism of this reaction. The model reaction of 1a and 3a was continuously monitored by 19F NMR analysis in the hope of finding the branched allyl intermediates. However, no such species were detectable. We inferred that the intermediate might be too shortlived to be observed within the NMR time scale. To verify this speculation, control experiments were performed with the bulky ketimine, which probably decelerates the corresponding rearrangement rate and therefore facilitates monitoring the potential intermediates with 19F NMR analysis. The readily available isatin ketamine 6 [19F: δ −76.60(d)], containing a methyl group at the α-position of CF3 group, was examined. The reaction did become sluggish, and almost 1 week was needed to reach full conversion, affording the product (S,E)-7a [19F: δ −78.95(s)] in 93% yield with 91% ee (Figure 2 and Scheme 5a). Monitoring the reaction mixture by 19F NMR (with CF3C6H5 as internal standard) revealed that two intermediates were initially formed as Int A [δ −74.28(s), major isomer] and Int B [δ −74.26(s), minor isomer] (Figure 2 and Scheme 5a), which is consistent with the intermediates produced by the random attack of either the Re- or Si-face of the nucleophilic aza-allyl anion to the Re-face of the electrophilic π-allyliridium species C.22 As compound 6 is consumed, the intensity of the signal of Int A and Int B gradually increases. The signal of product 7a appears around 2 h, and its intensity increases gradually at the expense of the two intermediates. The minor Int B undergoes 2aza-Cope rearrangement more readily than the major Int A (Figure 2). This rate difference of rearrangement is likely caused

a

All reactions were carried out with 0.20 mmol 1a and 0.22 mmol 3 in 2 mL of CH2Cl2. bYields refer to the isolated products after chromatographic purification. cThe ee value was determined by HPLC analysis. d(S,S)-L3 was used, and (R,E)-5aj was obtained.

Scheme 2. Experimental Results with Methyl Crotyl Carbonate 3s

Scheme 3. Gram-Scale and Synthetic Elaboration

trifluoromethyl homoallylic amine 10 in good yield with no erosion of enantioselectivity. I2-promoted cyclization of 10 affords the biologically important trifluoromethylpyrrolidine21 11 containing three stereocenters in 92% yield with exclusive C


Letter

Organic Letters

by the conformational difference of the corresponding chairlike transition state (Zimmerman−Traxler model)23 TSA and TSB, in both of which the CF3 group resides in the equatorial position (Scheme 5a). The latter is more energy favored because the bulky substituent (Ph) in the oxindole ring resides in an equatorial position. The reaction was interrupted around 12 h, and (S)-7a was separated in 27% yield with 91% ee and Int A/Int B were obtained in 55% yield as the mixed isomers in a 3:1 ratio. The enantiomeric excesses of both intermediates were determined to be 99% ee after being hydrolyzed to the primary amines 8a/8b (Scheme 5b). When the reaction was interrupted when the signal of minor Int B vanished (∼48 h), (S)-7a was separated in 42% yield with 91% ee, and Int A was obtained as a single isomer in 49% yield with 98% ee (Scheme 5c). The absolute configurations of 8a and 8b were unambiguously determined as (2R,3S) and (2S,3S), respectively, based on the Xray diffraction analysis of the corresponding tosylated 8a/8b (inseparable mixture) and tosylated 8a (Scheme 5d). It worth noting that both of the obtained 8a/8b and 8a could be

Figure 2. 19F NMR studies of the reaction intermediates.

Scheme 5. Mechanism Investigation with 19F NMR, Control Experiments, and X-ray Analysis

D


Letter

Organic Letters Author Contributions

efficiently transferred to (Z,S,E)-5aa in high yields without loss of enantioselectivities with simple treatment with trifluoroacetaldehyde ethyl hemiacetal 9 under catalyst-free conditions, which is consistent with the above proposed 2-aza-Cope rearrangement. The absolute configuration of the chiral center in both 5aa and 7a is stereospecifically controlled by the Sconfiguration of the tertiary stereogenic center in the branched allylation intermediates, which is generated in the initial Ircatalyzed asymmetric allylation. The stereochemical outcome of the 2-aza-Cope rearrangement could be rationalized as the results of the stereospecific chirality transfer originated from the formation of a highly ordered six-membered chairlike transition states. The thermodynamically stable Z-geometry of imine moiety in 5aa and 7a is preferentially formed along with the stereospecific rearrangement of Int B via TSB (Scheme 5a, bottom) or Int A via TSA followed by rapid E- to Z-geometrical isomerization (Scheme 5a, top). The Z-geometrical propensity of isatin ketimine 5aa and 7b (as shown in Scheme 5d) is consistent with that of (Z)-1f reported previously.11a In the case of isatin ketimine 6, the observed chirality loss [99% ee of (Int A and Int B) to 91% ee of the rearranged 7a] is ascribed to the reduced energy barrier difference between TS ([Meax + CF3eq]) (TSA and TSB shown in Scheme 5a) and TS′ [Meeq + CF3ax] (not shown) compared with the remarkable energy barrier difference between the corresponding TS ([Hax + CF3eq]) (TSC and TSD shown in Scheme 5b) and TS′ [Heq + CF3ax] (not shown) for isatin ketimine 1a. In conclusion, we have developed an unprecedented Ircatalyzed cascade asymmetric umpolung allylation/2-aza-Cope rearrangement of trifluoroethylisatin ketimines. This method provides a facile access to optically active α-trifluoromethyl homoallylic amines with a broad substrate scope in high yields and excellent enantioselectivities. The mechanism studies revealed the key intermediates in the initial umpolung allylation and the stereospecific chirality transfer in subsequent 2-azaCope rearrangement. Further explorations to expand the reaction scope and the synthetic application are currently underway.

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§

L.-M.S. and X.-S.S contributed equally.

Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was supported by the NSFC (21525207, 21772147). We thank Prof. Shu-Li You at SIOC for generously providing L3 and Prof. Heng-Jiang Cong at Wuhan University for solving the crystal structures.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01738. Experimental procedures and characterization data for all reactions and products, including 1H and 13C NMR spectra, HPLC spectra, and crystal data (PDF) Accession Codes

CCDC 1899071−1899074 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], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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REFERENCES

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Chun-Jiang Wang: 0000-0003-3629-6889 E


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Organic Letters

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Letter

Organic Letters Methoxylactams: Enantioselective Syntheses of Pyrrolidines and Piperidines. Chem. - Eur. J. 2013, 19, 16746. (23) Zimmerman, H. E.; Traxler, M. D. The Stereochemistry of the Ivanov and Reformatsky Reactions. J. Am. Chem. Soc. 1957, 79, 1920.

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Catalytic Asymmetric Synthesis of Î±-Trifluoromethyl Homoallylic

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