Letter Cite This: Org. Lett. 2017, 19, 5637-5640
pubs.acs.org/OrgLett
Enantioselective [4 + 1]-Annulation of α,β-Unsaturated Imines with Allylic Carbonates Catalyzed by a Hybrid P‑Chiral Phosphine Oxide− Phosphine Hanyuan Li, Jiesi Luo, Bojuan Li, Xizhen Yi, and Zhengjie He* The State Key Laboratory of Elemento-Organic Chemistry and Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), College of Chemistry, Nankai University, Tianjin 300071, P. R. China S Supporting Information *
ABSTRACT: A highly enantio- and diastereoselective [4 + 1]-annulation reaction between α,β-unsaturated imines and allylic carbonates has been realized under the catalysis of a novel hybrid P-chiral phosphine oxide− phosphine, providing enantioenriched polysubstituted 2-pyrrolines in good to excellent yields and up to 99% ee. Based on Han’s methods, the catalyst featuring a sole P(O)-chirality in the molecule is readily accessible and represents a class of new chiral phosphine organocatalysts. In the plausible catalytic mechanism, an intramolecular Coulombic interaction between the in situ generated phosphonium cation and polar chiral PO moiety may play a positive role. hiral five-membered nitrogen heterocycles, including 2- and 3-pyrrolines and their hydrogenated derivatives, pyrrolidines, are found as the feature substructures in a wide array of natural and artificial bioactive compounds.1,2 The development of efficient synthetic methods for such motifs has thus become an attractive objective.3 In this context, the chiral phosphinecatalyzed asymmetric [3 + 2]- and [4 + 1]-annulations of imines or other nitrogen sources provide a powerful and convergent synthetic strategy.4 Over the past decade, much effort has accordingly been devoted to the asymmetric Lu [3 + 2]annulations5 of electron-deficient allenes or alkynoates with imines, which provide convenient access to chiral pyrrolines,6 and significant advances have been made, particularly from the groups of Jacobsen,6e Lu,6g,i and Kwon.6h In contrast with the popularity of the [3 + 2]-annulation reactions, the asymmetric [4 + 1]-annulation has been much less explored.4,7 In 2015, a chiral spirophosphine-catalyzed [4 + 1]annulation between allenes and sulfonated amines was realized by Fu in good to excellent enantioselectivities (Scheme 1, eq 1).4a Notably, the above-mentioned asymmetric [3 + 2]- and [4 + 1]annulations of allenes or alkynoates unexceptionally deliver enantioenriched 3-pyrrolines.4a,6 As an efficient and straightforward protocol to construct 2-pyrrolines, the [4 + 1]-annulation of α,β-unsaturated imines (1-aza-1,3-dienes) with one-carbon partners such as reactive ylides based on N, S, and P elements has already been developed.8 Highly enantioselective syntheses of 2-pyrrolines9 have also been achieved by employing stoichiometric chiral sulfur ylides8b or by chiral amine catalysis.8e However, the phosphorus ylide-based variant of the reaction has met with little success.7 In 2011, our group first reported a phosphine-catalyzed [4 + 1]-annulation of α,β-unsaturated imines with allylic carbonates, leading to a facile synthesis of 2pyrrolines.8d This reaction presumably proceeds through in situ generated allylic phosphorus ylide intermediate. Recently, a single
C
© 2017 American Chemical Society
Scheme 1. Chiral Phosphine-Catalyzed [4 + 1]-Annulations To Give Enantioenriched Pyrrolines
example of the asymmetric variant was realized in a moderate enantioselectivity under the catalysis of a chiral phosphine by Shi (Scheme 1, eq 2).7 On the basis of our previous work,8d we recently developed a highly enantio- and diastereoselective [4 + 1]-annulation between α,β-unsaturated imines and allylic carbonates with the aid of a new P-chiral phosphine oxidephosphine catalyst (Scheme 1, eq 3). Herein we communicate the relevant results. Over the past two decades, chiral phosphine organocatalysis has gradually become a powerful tool in the asymmetric synthesis arsenal, while a large number of asymmetric reactions, including the Morita−Baylis−Hillman reaction10c,d and various annulation Received: September 7, 2017 Published: October 3, 2017 5637
DOI: 10.1021/acs.orglett.7b02800 Org. Lett. 2017, 19, 5637−5640
Letter
Organic Letters reactions,10e,f have been continuously achieved under the catalysis of chiral phosphines.10 Among the reported chiral phosphine catalysts,10a,b the overwhelming majority are those bearing at least one chirality unit such as a chiral carbon center in the molecular skeleton; only a few chiral phosphine catalysts possess Pstereogenic center(s).6h,11 To the best of our knowledge, until now there has only been one report in which the chiral phosphine (R,R)-DIPAMP, solely bearing P-stereogenic centers, was successfully applied by Loh in a highly enantioselective [3 + 2]annulation of 3-butynoates and electron-poor alkenes (Scheme 2).11b The P-chiral phosphines have been very unexplored in
into its corresponding tosylate I-3 in high yield. I-3 then underwent a highly diastereoselective cyclization with phenylphosphonyl dichloride, followed by selective P−N bond cleavage with Grignard reagent ArMgBr, to yield intermediate I-5. Treatment of I-5 with in situ generated lithium amide from a primary amine and n-butyllithium readily delivered the chiral phosphinamide I-6 and intermediate I-3, which was recovered and reused in the next synthesis. Deprotonation of I-6 with sodium hydride in DMF followed by condensation with o(diphenylphosphino)benzyl chloride smoothly afforded the catalysts P (Scheme 3). The experimental details about the synthesis of the catalysts P are available in the Supporting Information (SI). The prepared P by this procedure has S absolute configuration, which is also confirmed by the X-ray structure of P4. With the catalysts P in hand, we commenced a brief survey about their catalytic activity in the phosphine-catalyzed [4 + 1]annulation reaction between α,β-unsaturated imines 1 and allylic carbonates 2 (Table 1). On the basis of our previous work,8d we
Scheme 2. Enantioselective [3 + 2]-Annulation Catalyzed by PChiral Phosphine
Table 1. Brief Survey on the Asymmetric [4 + 1]-Annulation of Imines 1 and Allylic Carbonates 2a
asymmetric organocatalysis, presumably due to the vulnerability to oxidation and configurational instability of three-coordinate Pchiral centers,12 although P-chiral phosphines have been extensively applied as chiral ligands in transition-metal catalysis.13 Conversely, four-coordinate P-chiral compounds such as P-chiral phosphine oxides are generally considered to be oxidatively and configurationally stable. Also, compared to the C-chiral center, the tetrahedral P(O)-chiral center possesses a unique and strongly polar P−O bond. With these facts in mind, we recently designed a series of P-chiral phosphine oxide−phosphines P in search of new chiral phosphine catalysts (Figure 1). Although
Figure 1. P-Chiral Phosphine Oxide−Phosphines.
some P-chiral phosphine oxide−phosphines have been successfully utilized as hemilabile ligands in asymmetric metal catalysis,14 this type of compound has never been examined before as an organocatalyst in asymmetric reactions. Following the convenient and highly efficient synthetic methods for P-chiral phosphine oxides and phosphinamides developed by Han et al.,15,16 the catalysts P were smoothly prepared by using commercially available (R)-2-(1-aminoethyl)phenol (Scheme 3). First, the enantiopure phenol was derived
entry
1
2
cat. P
solvent
3, yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14
1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1c 1a 1a
2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2a 2b 2c
P1 P2 P3 P4 P5 P6 P7 P5 P5 P5 P5 P5 P5 P5
CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 THF toluene CH3CN CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
3a, 74 3a, 84 3a, 81 3a, 72 3a, 79 3a, 93 3a, 53 3a, 64 3a, 57 3a, 38 3b, 69 3c, 74 3ab, 62 3ac, 87
6 7 13 −12 99 56 −27 23 32 12 21 6 84 28
a
Typical conditions: under a N2 atmosphere, to a mixture of 1 (0.1 mmol) and 2 (0.15 mmol) in a solvent (1.0 mL) was added the catalyst P (0.015 mmol). The mixture was then stirred at rt for 48 h. b Isolated yields. cIn all cases, the dr ratios of 3 were >20:1 as determined by 1H NMR assay of the isolated products, and the ee values were determined by chiral HPLC.
devised a model reaction between the chalcone-derived imine 1a bearing a protecting group p-nitrobenzenesulfonyl (Ns) and allylic carbonate 2a (R = Et) under the predetermined conditions. Initial results from N-methyl-substituted chiral phosphines P1− P3 bearing various aryl (Ar) groups showed very disappointing enantioselectivities, although the chemical yields of 3a were good in the model reaction (Table 1, entries 1−3). A series of different N-substituted chiral phosphines P4−P7 with a fixed aryl group (Ar = o-anisyl) at the P(O) center (Figure 1) were further surveyed in the model reaction (Table 1, entries 4−7). Relatively bulkier benzyl-substituted phosphine P4 afforded a low but opposite ee value (Table 1, entry 4); to our delight, N-phenylsubstituted chiral phosphine P5 delivered product 3a in 79% yield
Scheme 3. Synthesis of P-Chiral Phosphines P
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DOI: 10.1021/acs.orglett.7b02800 Org. Lett. 2017, 19, 5637−5640
Letter
Organic Letters and 99% enantioselectivity (Table 1, entry 5); p-anisylsubstituted catalyst P6 gave an improved yield (93%) but substantially lowered ee value (56%) (Table 1, entry 6); again, bulky mesityl-substituted catalyst P7 only afforded a low and opposite enantioselectivity (Table 1, entry 7). With the P5 chosen as the preferred catalyst, other parameters of the model reaction were also examined (Table 1, entries 8−14). The influence of solvents on both yield and enantioselectivity was first tested. Common solvents THF and toluene only gave product 3a in moderate yields and low ee values (Table 1, entries 8 and 9), and polar acetonitrile brought about even worse results (Table 1, entry 10). Solvent CH2Cl2 remained the best. Different imines 1b and 1c bearing substituents tosyl and benzenesulfonyl were also examined in the reactions with allylic carbonate 2a, giving their corresponding annulation products 3b and 3c in moderate yields and poor enantioselectivities (Table 1, entries 11 and 12). Finally, allylic carbonates 2 with various ester groups were also surveyed in the reactions with imine 1a (Table 1, entries 13 and 14). Carbonate 2b bearing a small methyl ester (R = Me) readily afforded its corresponding product 3ab in moderate yield and good ee value (84%) (Table 1, entry 13); conversely, carbonate 2c with a bulky ester group (R = t-Bu) gave its product 3ac in good yield (87%) but low enantioselectivity (Table 1, entry 14). It should be mentioned that, in all cases, the [4 + 1]annulation products 3 were obtained in high diastereoselectivities (dr >20:1) as determined by 1H NMR assay. With respect to enantioselectivity, the reaction conditions for entry 5 were thus identified as optimal. Under the optimal reaction conditions, the substrate scope of the asymmetric [4 + 1]-annulation of α,β-unsaturated imines 1 and allylic carbonate 2a was further investigated (Table 2). An array of aryl-substituted imines 1, bearing either electron-
withdrawing groups such as halo, NO2, CF3, and CN or electron-donating groups like Me and MeO, were all effective for the annulation reaction, uneventfully furnishing their corresponding 2-pyrrolines 3 in good yields and generally high levels of enantioselectivity (Table 2, entries 1−17). Except for imines 1j and 1o that only afforded their products 3j and 3o in moderate enantioselectivities (Table 2, entries 8 and 13), other aryl-substituted imines 1 all readily gave their products 3 in good to excellent enantioselectivities (Table 2, entries 1−17). It should be pointed out that heteroaryl-substituted imine 1l worked well, giving product 3l in excellent yield and ee (Table 2, entry 10). Also, all of the annulation products 3 were obtained in high diastereoselectivities with dr >20:1 (Table 2, footnote c). Thus, this P-chiral phosphine-catalyzed [4 + 1]-annulation reaction of α,β-unsaturated imines 1 and allylic carbonates 2 provides a highly enantio- and diastereoselective method for synthesis of polysubstituted 2-pyrrolines 3. To further explore the potential utilities of the asymmetric [4 + 1]-annulation reaction in organic synthesis, the gram-scale synthesis and base-catalyzed hydrolysis of pyrroline 3a were carried out (Scheme 4). Under the standard conditions and with
Table 2. Enantioselective Synthesis of 2-Pyrrolines 3a
the catalyst P5 used in an even lowered loading (10 mol %), imine 1a (1.0 g) and allylic carbonate 2a (1.5 equiv) were reacted for an elongated time (72 h), readily affording pyrroline 3a in 72% isolated yield and 99% ee (Scheme 4, eq 1). By the lithium hydroxide-promoted hydrolysis in a medium of THF/H2O (v/v = 1:1) at rt and subsequent acidification with aqueous HCl (1.0 M), product 3a could be smoothly transformed into its corresponding optically pure acid 4 in high yield (Scheme 4, eq 2). The structures of catalysts P and products 3 and 4 were identified by 1H, 13C NMR, and HRMS-ESI measurements. X-ray crystallographic analyses for representative compounds P4, 3n, and 3o further confirmed their structural assignments. To rationalize the formation of the annulation product 3, a plausible mechanism is exemplified in Scheme 5. According to closely related reports,7,8d the catalytic sequence is believed to
entry
1
R1
R2
3, yieldb (%)
eec (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
1a 1d 1e 1f 1g 1h 1i 1j 1k 1l 1m 1n 1o 1p 1q 1r 1s
Ph p-CH3C6H4 p-FC6H4 p-ClC6H4 p-BrC6H4 p-OCH3C6H4 m-NO2C6H4 p-CF3C6H4 p-CNC6H4 2-furyl Ph p-FC6H4 p-ClC6H4 m-ClC6H4 m-BrC6H4 p-BrC6H4 p-FC6H4
Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph p-ClC6H4 p-BrC6H4 p-BrC6H4 p-FC6H4 p-FC6H4 p-FC6H4 p-CF3C6H4
3a, 79 3d, 92 3e, 75 3f, 86 3g, 81 3h, 95 3i, 76 3j, 80 3k, 69 3l, 93 3m, 88 3n, 95 3o, 78 3p, 72 3q, 85 3r, 82 3s, 89
99 98 91 98 99 98 85 73 90 99 99 99 64 81 91 95 99
Scheme 4. Gram-Scale Synthesis and Hydrolysis of 3a
Scheme 5. Plausible Formation of Product 3
a
Typical conditions: under a N2 atmosphere, to a mixture of 1 (0.1 mmol) and 2a (0.15 mmol) in CH2Cl2 (1.0 mL) was added the catalyst P5 (0.015 mmol). The mixture was then stirred at rt for 48 h. b Isolated yields. cIn all cases, the dr ratios of 3 were >20:1 as determined by 1H NMR assay of the isolated products, and the ee values were determined by chiral HPLC. 5639
DOI: 10.1021/acs.orglett.7b02800 Org. Lett. 2017, 19, 5637−5640
Organic Letters
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start off with formation of the allylic phosphorus ylide A from allylic carbonate like 2a and the catalyst P5. Ylide A then undergoes the sterically favored γ-carbanion addition to an α,βunsaturated imine like 1a leading to intermediate B, which interconverts with intermediate C. Finally, intermediate C engages in an intramolecular Michael addition followed by elimination of the phosphine to furnish the annulation product 3a and regenerate the catalyst (Scheme 5). By this mechanism, stereoselective conjugate addition of ylide A to α,β-unsaturated imine 1a is critical to enantioselective formation of the annulation product 3a. Based on the stereochemical outcomes of this annulation, we suspect that ylide A forms a cyclic structure through intramolecular Coulombic interaction between the phosphonium unit and polar chiral PO moiety,17 and the cyclic ylide A engages in stereoselective addition to imine 1a in two modes as shown in Scheme 5. In mode I, imine 1a approaches the cyclic ylide A from the side of the phenyl group of P-chiral unit; in mode II, imine 1a gets close to ylide A from the side of oanisyl group. Since o-anisyl group imposes much more steric hindrance than phenyl group does, the mode I is thus favored. By mode I, ylide A tends to attack α,β-unsaturated imine 1a from the Si face, leading to the major enantiomer of product 3a. In summary, we have successfully realized a chiral phosphinecatalyzed asymmetric [4 + 1]-annulation reaction between α,βunsaturated imines and allylic carbonates, providing highly enantio- and diastereoselective synthesis of polysubstituted 2pyrrolines in good to excellent yields and up to 99% ee. Also, a class of novel P-chiral phosphine oxide−phosphine organocatalysts featuring a sole P(O) chirality in the molecule has been developed for the first time. In the asymmetric catalysis of this kind of chiral phosphines, an intramolecular Coulombic interaction between the in situ generated phosphonium cation and polar chiral PO moiety presumably plays a positive role. Since the in situ formation of phosphonium species from nucleophile phosphine is a common step in the phosphine catalysis, this kind of chiral phosphines may be applicable to other phosphine-catalyzed asymmetric reactions.
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REFERENCES
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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.7b02800. Experimental details, characterization data, NMR spectra for new compounds (PDF) Crystallographic data for P4 (CIF) Crystallographic data for 3n (CIF) Crystallographic data for 3o (CIF)
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Letter
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Zhengjie He: 0000-0002-7891-0245 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the National Natural Science Foundation of China (Grant Nos. 21472096 and J1103306) is gratefully acknowledged. 5640
DOI: 10.1021/acs.orglett.7b02800 Org. Lett. 2017, 19, 5637−5640
