Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
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Palladium-Catalyzed Highly Enantioselective Cycloaddition of Vinyl Cyclopropanes with Imines Xiao-Bing Huang,† Xian-Jing Li,† Tian-Tian Li,† Bo Chen,† Wen-Dao Chu,*,† Long He,*,†,‡ and Quan-Zhong Liu*,† †
Chemical Synthesis and Pollution Control Key Laboratory of Sichuan Province, College of Chemistry and Chemical Engineering, China West Normal University, No. 1, Shida Road, Nanchong 637002, P.R. China ‡ College of Pharmaceutical Sciences, Guizhou University of Chinese Medicine, Guiyang 550025, P.R. China
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S Supporting Information *
ABSTRACT: Palladium-catalyzed asymmetric formal [3 + 2] cycloaddition of vinyl cyclopropanes and aldimines or isatinderived ketimines proceeded smoothly in the presence of chiral phosphoramidite ligands. The corresponding highly functionalized and optically enriched pyrrolidine or spiro[pyrrolidin-3,2′-oxindole] derivatives are obtained in up to 94% yield and with up to 96% ee and 7:1 dr.
P
Scheme 1. Cycloaddition of VCPs and Imines
yrrolidines are important structural units in organic chemistry and are abundant in many natural products and pharmaceutically active compounds.1 In spite of the substantial efforts that have been made toward the stereoselective synthesis of functionalized pyrrolidines, [3 + 2] cycloaddition reactions are one of the most efficient methods for the synthesis of cyclic skeletons due to “atom-economy”.2 Asymmetric catalytic 1,3dipolar cycloaddition between azomethine ylides and activated alkenes has been extensively studied (path A, Figure 1).3
Figure 1. Possible routes for pyrrolidine synthesis through [3 + 2] cycloaddition reactions.
However, few enantioselective [3 + 2] annulations of donor− acceptor (D−A) cyclopropane with imine have been documented (path B, Figure 1).4 In 2010, Johnson and co-workers reported the first dynamic kinetic asymmetric transformation of racemic (D−A) cyclopropanes via chiral Lewis acid (pybox)2MgI2-catalyzed reaction with various (E)-imines for the enantioselective synthesis of 2,5-cis-pyrrolidines (Scheme 1a).5 Although the work represents a significant breakthrough, the reaction is limited to aldehyde-derived imines. In recent years, vinyl cyclopropanes (VCPs) have enjoyed a renaissance as versatile building blocks in organic synthesis.6 VCP derivatives with electron-withdrawing groups are known to act as 1,3-dipole equivalents in the presence of a palladium catalyst. The in situ generated 1,3-dipole equivalents are reactive in the formal [3 + 2] cycloaddition reactions with dipolarophiles such as electron-deficient olefins,7,8 imines,9 aldehydes,10 © XXXX American Chemical Society
isatins,11 and 3-diazooxindoles,12 and VCPs can provide direct routes to different substituted five-membered rings. Although important progress has been achieved toward asymmetric formal [3 + 2] cycloadditions of VCPs with electron-deficient olefins,8 imines have seldom been utilized as reaction partners in catalytic asymmetric formal [3 + 2] cycloadditions.9 In 2018, the Guo,9a Vitale,9b and de Figueiredo9c groups, respectively, attempted Received: January 22, 2019
A
DOI: 10.1021/acs.orglett.9b00274 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
ligand L3 delivered a diastereomeric mixture (2:1), and the minor isomer was 59% ee (entry 3). Introduction of bromine atoms at the 3,3′-position of the binaphthyl framework resulted in better selectivity. An ee of 72% was observed for the major isomer, and the diastereomeric ratio slightly increased to 3:1 (entry 4). Switching the N-substituent from isopropyl to methyl or ethyl yielded 3a with worse selectivity (entries 5 and 6). Significantly, the selectivity is highly dependent on the group at the 3,3′-position of the naphthyl motif. For example, L7 with two phenyl groups at the 3,3′-position afforded 76% ee for the major isomer with diastereomeric ratio 3:1 (entry 7). The ligand L8 substituted with 3,5-trifluoromethyl phenyl exhibited the best selectivities. The enantioselectivity for the major diastereomer was 91% ee with dr = 4:1 (entry 8). When the ligand L8 loading was reduced to 0.1 equiv, the product was obtained in 90% yield and without loss of stereocontrol (entry 9). We further investigated the effects of solvent on the reaction. Among the solvents tested, tetrahydrofuran (THF) was the best choice in terms of yield and selectivity (entries 8−14). When the reaction was carried out at lower temperature, the reaction proceeded much more slowly and required more time to reach completion. For example, at 0 °C, after 4 days, only 53% yield was obtained, although much better selectivities was observed for both isomers (entry 15). With the optimized reaction conditions in hand, the reaction scope was then evaluated, and the results are summarized in Table 2. At first, using dimethyl 2-vinylcyclopropane-1,1-
Pd-catalyzed asymmetric [3 + 2] cycloaddition of VCPs with imines, but without satisfactory results. In 2013, the Matsubara group developed an efficient nickel-catalyzed [3 + 2] cycloaddition of imines and VCPs (Scheme 1b),13 but only one asymmetric example (56% ee) was presented in the reaction. With our continuing efforts to develop the asymmetric cycloadditions of VCPs,8d,e we hopefully develop an enantioselective and diastereoselective cycloaddition of VCPs and imines. Herein, we report a palladium-catalyzed asymmetric formal [3 + 2] cycloaddition of VCPs and imines, including isatin-derived ketimines and aromatic aldimines, to give highly functionalized pyrrolidines (Scheme 1c). We initiated the model reaction using isatin-derived imine 2a and VCP 1a as the substrates, and the representative results are summarized in Table 1. When 1a and 2a were combined with Table 1. Optimization of the Reaction Conditionsa
entry
ligand
time (h)
yieldb (%)
eec (%)
drd
1 2 3 4 5 6 7 8 9e 10f 11g 12h 13i 14j 15k
L1 L2 L3 L4 L5 L6 L7 L8 L8 L8 L8 L8 L8 L8 L8
60 22 39 78 29 10 40 18 18 21 40 45 75 10 130
>99 >99 44 99 45 94 99 71 90 93 80 66 87 96 53
52, 42 40, 53 25, 59 72, 61 58, 16 55, 53 76, 73 91, 77 91, 78 88, 80 90, 84 84, 82 89, 76 93, 79 94, 89
2:1 2:1 2:1 3:1 2:1 3:1 3:1 4:1 4:1 3:1 4:1 3:1 2:1 2:1 4:1
Table 2. Substrate Scope for Isatin-Derived Ketiminesa
a
Unless otherwise stated, all reactions were carried out at room temperature using 0.1 mmol of imine 2a, 0.12 mmol (1.2 equiv) of 1a, 10 mol % of Pa(dba)2, and 20 mol % of ligand in 1 mL of tetrahydrofuran (THF). bIsolated yields. cDetermined by HPLC. d Determined by 1H NMR of the crude product. e10 mol % of Pd(dba)2 and 10 mol % of L8 was employed. f1,4-Dioxane used as the solvent. gDimethoxyethane used as the solvent. hXylene used as the solvent. iDichloromethane as the solvent. jDMF as the solvent. kThe reaction was carried out at 0 °C.
entry
R1
R2
yieldb (%)
eec (%)
drd
1 2 3 4 5 6 7 8 9 10 11 12 13
Bn CH3 Ac MOM Bn Bn Bn Bn Bn Bn Bn Bn Bn
H, 2a H, 2b H, 2c H, 2d 5-Me, 2e 5-OMe, 2f 5-OCF3, 2g 5,7-Me2, 2h 5-F, 2i 5-Cl, 2j 6-OMe, 2k 6-Me, 2l 7-Cl, 2m
3a, 90 3b, 81 3c, 84 3d, 91 3e, 91 3f, 92 3g, 90 3h, 94 3i, 93 3j, 93 3k, 94 3l, 90 3m, 92
92, 78 82, 70 81, 69 85, 78 91, 86 90, 82 90, 83 96, 76 90, 74 96, 73 90, 87 91, 49 90, 80
4:1 4:1 5:1 5:1 5:1 4:1 3:1 3:1 3:1 3:1 3:1 3:1 2:1
a
Unless otherwise stated, all reactions were carried out at room temperature using 0.1 mmol of imine 2, 0.12 mmol (1.2 equiv) of 1a, 10 mol % of Pa(dba)2, and 10 mol % of ligand in 1 mL of tetrahydrofuran (THF) for 18 h. bIsolated yields. cDetermined by HPLC. dDetermined by 1HNMR of crude product.
Pd(dba)2 (10 mol %) and phosphoramidite ligand L1 (10 mol %) in THF at room temperature, the desired [3 + 2]cycloadduct was observed in almost quantitative yield with 2:1 dr and 52% ee (entry 1, Table 1). Encouraged by the results, we investigated the effects of other phosphoramidites on the selectivity. The ligand L2 which bears bulky substituents at the N atom afforded decreased enantioselectivities with almost unchanged diastereoselectivity (entry 2, Table 1). We then turned our attention toward the H8-BINOL-derived chiral phosphoramidites L3−L8 which are expected to exhibit high performance because of the relatively bigger dihedral angle. The
dicarboxylate (1a) as the model substrate, we examined various isatin-derived ketimines 2 bearing different N-protecting groups (Table 2, entries 1−4). The benzyl group is the best in terms of selectivity compared with methyl, acetyl, and methoxymethyl, providing 92% ee for the major isomer with 4:1 dr. The substitution pattern of the isatin nucleus has no apparent effect on the reaction. A series of ketimines 2e−m bearing electronneutral, -deficient, or -rich aromatic substituents were smoothly reacted with VCP 1a to give the corresponding pyrrolidines 3e− B
DOI: 10.1021/acs.orglett.9b00274 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters m in 90−94% yields with 2/1−5/1 diastereoselectivities and 90−96% ee values (Table 2, entries 5−13). It should be mentioned the purity of the imines has a great impact on the reaction. In our investigation, all of imines were recrystallized from a mixture of hexane and ethyl acetate. We found that trace amounts of impurities retarded the reaction. We surmised that the tert-butyloxycarbonyl (Boc) amine from the decomposition of imines may react with the amphiphilic palladium complex and, thus, inhibit the catalytic performance of palladium catalyst. We also investigated the cycloaddition of aldimines. In this case, the chiral phosphoramidite L9 gave the best selectivities under identical conditions (Table 3).14 As summarized in Table
Scheme 2. Scale-up Experiment and Post-Functionalization Reactions
Table 3. Substrate Scope for Aldiminesa
entry
Ar
yieldb (%)
eec (%)
drd
1 2 3 4 5 6 7 8 9 10 11 12 13 14
Ph, 4a, 3-BrC6H4, 4b 3-ClPh, 4c 3-MePh, 4d 4-FPh, 4e 4-CF3Ph, 4f 4-MePh, 4g 2-ClPh, 4h 3-Py, 4i 3-OMePh, 4j 4-BrPh, 4k 2-furyl, 4l 3-thiophene-yl, 4m 2-thiophene-yl, 4n
5a, 75 5b, 70 5c, 72 5d, 55 5e, 65 5f, 80 5g, 51 5h, 48 5i, 70 5j, 70 5k, 68 5l, 65 5m, 64 5n, 77
92, 77 82, 78 83, 79 82, 65 89, 78 93, 88 92, 77 85, 82 84, 60 90, 50 74, 50 84, 49 82, 42 82, 35
5:1 3:1 3:1 4:1 4:1 4:1 4:1 2:1 5:1 5:1 5:1 4:1 4:1 7:1
adduct 3i can be readily removed by treatment of trifluoroacetic acid in dichloromethane to yield compound 3′i in 91% yield. During the transformation, the erosion of enantioselectivity was not observed. The absolute configurations of 3′i and 5k were determined by X-ray diffractions of single crystals by recrystallization from ethyl acetate/hexane (Figure 2). The configurations of other products are deduced by analogy.
a
Unless otherwise stated, all reactions were carried out at room temperature using 0.1 mmol of imine 2a, 0.12 mmol (1.2 equiv) of 1a, 10 mol % of Pa(dba)2, and 10 mol % of ligand in 1 mL of tetrahydrofuran (THF) for 36 h. bIsolated yields. cDetermined by HPLC. dDetermined by 1HNMR of crude product.
3, the reaction with aldimine substrates bearing various substituents on the aromatic ring all proceeded smoothly to afford the corresponding pyrrolidine products 4a−g and 4j,k in moderate to good yields with good to excellent enantioselectivities as well as good diastereoselectivities (Table 3, entries 1−7, 10, and 11). It is noteworthy that the reaction with 2-chlorosubstituted aldimine 4h only gave the cycloaddition product 5h in 48% yield with 2:1 dr (entry 8). We speculated that the steric hindrance has an impact on the reaction. Aldimines with heteroaryl substituents also performed well in the reaction (entries 9 and 12−14). The synthetic potential of this strategy could be also established by performing a scale-up experiment and postfunctionalization reactions (Scheme 2). When starting from 2j (2.0 mmol), the gram-scale preparation of 3j could be performed without a major impact on either reaction yield or enantioselectivity. Furthermore, spiro[pyrrolidin-3,2′-oxindole] 3e can be readily hydrogenated to the compound 6 using Pd/C as the catalyst (92% yield). After hydroboration with 9-BBN and oxidation with hydrogen peroxide under basic conditions, the adduct 3e can also be transformed to the corresponding primary alcohol 7 in 87% yield. The tert-butyloxycarbonyl group in
Figure 2. Determination of absolute configuration.
In summary, we have developed an enantioselective and diastereoselective [3 + 2] cycloaddition of VCPs and aldimines or isatin-derived ketimines. The functionally and optically enriched pyrrolidines were obtained in up to 94% yield and with up to 96% ee and 7:1 dr. Further investigations on the related Pd-catalyzed enantioselective cycloaddition of vinyl cyclopropanes are current underway in our laboratory.
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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.9b00274. 1 H and 13NMR spectra for all compounds, HPLC spectral for chiral compounds (PDF) C
DOI: 10.1021/acs.orglett.9b00274 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Accession Codes
Catal. 2016, 6, 6408. (i) Halskov, K. S.; Naesborg, L.; Tur, F.; Jørgensen, K. A. Org. Lett. 2016, 18, 2220. (j) Laugeois, M.; Ponra, S.; Ratovelomanana-Vidal, V.; Michelet, V.; Vitale, M. R. Chem. Commun. 2016, 52, 5332. (9) (a) Wang, Q.; Wang, C.; Shi, W.; Xiao, Y.; Guo, H. Org. Biomol. Chem. 2018, 16, 4881. (b) Ling, J.; Laugeois, M.; RatovelomananaVidal, V.; Vitale, M. R. Synlett 2018, 29, 2288. (c) Spielmann, K.; Tosi, E.; Lebrun, A.; Niel, G.; van der Lee, A.; de Figueiredo, R. M.; Campagne, J.-M. Tetrahedron 2018, 74, 6497. (10) (a) Parsons, A. T.; Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10, 2541. (b) Parsons, A. T.; Johnson, J. S. J. Am. Chem. Soc. 2009, 131, 3122. (11) Mei, L.-y.; Wei, Y.; Xu, Q.; Shi, M. Organometallics 2013, 32, 3544. (12) (a) Mei, L.-Y.; Tang, X.-Y.; Shi, M. Chem. - Eur. J. 2014, 20, 13136. (b) Cao, B.; Mei, L.-Y.; Li, X.-G.; Shi, M. RSC Adv. 2015, 5, 92545. (13) Tombe, R.; Kurahashi, T.; Matsubara, S. Org. Lett. 2013, 15, 1791. (14) For screening of the reaction conditions, see the Supporting Information.
CCDC 1816558 and 1816653 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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AUTHOR INFORMATION
Corresponding Authors
*E-mail:
[email protected]. *E-mail:
[email protected]. *E-mail:
[email protected]. ORCID
Wen-Dao Chu: 0000-0003-0058-2461 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by the National Natural Science Foundation of China (NSFC 21572183, 21772158, 21801208). REFERENCES
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DOI: 10.1021/acs.orglett.9b00274 Org. Lett. XXXX, XXX, XXX−XXX
