Jian-Xing Xua,
Fei Yea,
Xing-Feng Baiab,
Yu-Ming Cuia,
Zheng Xua,
Zhan-Jiang Zhenga and
Li-Wen Xu*ab
aKey Laboratory of Organosilicon Chemistry and Material Technology of Ministry of Education, Hangzhou Normal University, Hangzhou 311121, P. R. China. E-mail: liwenxu@hznu.edu.cn; Fax: +86 2886 5135; Tel: +86 2886 5135
bState Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences, Lanzhou 730000, P. R. China. E-mail: licpxulw@yahoo.com
First published on 22nd July 2016
To shield light on the mechanism of palladium-catalyzed allylic substitutions with structurally diverse nucleophiles (up to 99% ee) in the presence of Fei-Phos ligand (chiral trans-1,2-diaminocyclohexane-derived biphosphine, CycloN2P2-Phos) as an effective chiral P-ligand, mechanistic studies were performed for clarification of the role of multifunctional Fei-Phos in this reaction. The cooperative action of nitrogen and phosphorous atoms in the present Pd-catalyzed allylic alkylation is proved to be a diphosphine-based catalyst system but not a nitrogen-controlled or monophosphine-involved transition state.
Recently, we have ever developed a new multifunctional and multidentate ligand bearing multiple stereogenic centers,6 and it is a structurally novel cyclic tertiary diamine-based biphosphine having two nitrogen atoms (CycloN2P2-Phos) derived from chiral trans-1,2-diaminocyclohexane, also called as Fei-Phos in the previous work (Scheme 1).6,7
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Scheme 1 Pd/Fei-Phos catalyzed asymmetric allylic substitution of structurally diverse nucleophiles with allylic acetate. |
It was found that the asymmetric palladium-catalysed alkylation of structurally diverse hard/soft nucleophiles, including allylic etherification of alcohols, silanols, allylic alkylation of activated methylene compounds, indoles, and aromatic amines, resulted in good to excellent yields and excellent enantioselectivities (up to 99% ee). However, the full and detailed mechanism with possible transition state, as well as the role of phosphorous centers and nitrogen atoms of Fei-Phos in this reaction remains unclear. In addition, a true palladium catalyst that heretofore has not been determined in the previous work, thus we also became intrigued by the possibility of generating coordinated palladium complex (Pd/Fei-Phos) with nitrogen atoms or phosphorous centers. Meanwhile, the clarification of related reaction results and catalysis chemistry is an interesting task in this work. Herein, to shield light on the mechanism of the palladium-catalyzed allylic substitutions with structurally diverse nucleophiles (up to 99% ee) in the presence of the multifunctional Fei-Phos ligand (chiral trans-1,2-diaminocyclohexane-derived diphosphine, CycloN2P2-Phos) as an effective chiral P-ligand, the mechanistic studies were performed for the clarification of the role of Fei-Phos in this reaction.
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Scheme 2 Proposed transition-state model in the catalytic asymmetric allylic etherification: diphosphine-involved model of allylic etherification of alcohols with biphosphine ligand (Fei-Phos)? |
Initially, we performed the ESI(+)-MS analysis of the mixture of [Pd(η3-C3H3)Cl]2 and Fei-Phos. Fig. 1 shows that the ESI(+)-MS collected the chiral palladium/Fei-Phos intermediate of m/z 835.3. Therefore the Pd/Fei-Phos complex could be possibly by the detection of these key ions. On the basis of the schematic drawing of three possible Pd/Fei-Phos complexes (Fig. 1, or S1 of ESI†), the relative energy of three possible palladium/Fei-Phos complex (I–III) derived from different coordination model is varied from 0 to 21.9 kcal mol−1.8 As shown in the schematic drawing of Fig. 2, the coordination of Fei-Phos with palladium probably led to the formation of more stable complex I formed by one palladium linked with two phosphorous atoms in comparison to that of other type of palladium/Fei-Phos complex II or III. Therefore, it looks reasonable that the Brønsted basic nitrogen-center on the biphosphine ligand (Fei-Phos) would be a control element for the discrimination of the reactivity of various alcohols and thus lead to different performance of substrate activation (Scheme 2). However, the outcomes of calculated relative energy could not provide direct evidence and information for the supporting of the mechanism of palladium-catalyzed allylic alkylation with alcohols with superior catalytic activity of Fei-Phos ligand in this reaction. Furthermore, it is not so easy because the true palladium/Fei-Phos should be clarified in this work as well as the expanding of palladium/Fei-Phos – catalyzed allylic alkylation with various nucleophiles.
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Fig. 2 What's the true role of nitrogen and phosphorous atoms on Fei-Phos in the palladium catalysis? Potential energy for coordination of Fei-Phos with palladium center calculated at B3LYP/6-31G(d,p) level of theory.8 |
To understand the role of phosphorous atoms in the Pd/Fei-Phos catalysis and the true structure of the palladium catalyst with ligand Fei-Phos, we fortunately obtained the complex Pd/Fei-Phos through the coordination of Fei-Phos ligand with [Pd(η3-C3H3)Cl]2 in dichloromethane and toluene at room temperature for several days. Unexpectedly and interestingly, the crystal structure of the palladium/Fei-Phos complex was shown in Fig. 3. As seen from Fig. 3, the Fei-Phos ligand coordinated to palladium atom with phosphorous atom and benzyl ring via a conformationally restricted eight-membered palladium-containing heterometal ring. To the best of our knowledge, it is the first example of a new class of isolable and enantiomerically pure eight-membered-palladium complex. The only one related example of X-ray crystallographic studies on π–allylpalladium complexes coordinated with a chiral phosphine–olefin ligand was reported by Hayashi in 2005.9 It is a bicyclo[2.2.1]heptane-derived five-membered palladium-containing heterometal ring system combined with eight-membered ring. These characteristics of bonding structure showed in Fig. 3 might attribute to rigid diphenylpiperazine backbone of the ligand and the large chelate ring formed by the dephosphorous Fei-Phos ligand. Therefore, this structure character of Pd/Fei-Phos complex directly interprets its high enantioselectivity and activity in the palladium-catalyzed asymmetric allylic etherification of alcohols because of its capable of formation of conformationally restricted eight-membered P–Pd–C bond-involving heterometal ring.
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Fig. 3 ORTEP illustration of the palladium/Fei-Phos complex (CCDC 1446415). All hydrogen atoms are omitted for clarity. Selected bond lengths [Å] and angles [°]: Pd(1)–C(1) 2.009(8), Pd(1)–P(1) 2.234(2), P(1)–C(29) 1.797(9), P(1)–C(23) 1.822(9), P(1)–C(22) 1.835(7), C(17)–C(22) 1.371(10), C(16)–C(17) 1.522(10), C(7)–C(16) 1.503(10), C(6)–C(7) 1.511(9), C(1)–C(6) 1.392(10); C(1)–Pd(1)–P(1) 86.3(2), C(29)–P(1)–C(23) 105.6(4), C(29)–P(1)–C(22) 107.1(4), C(23)–P(1)–C(22) 98.4(4), C(17)–C(22)–P(1) 121.8(6), C(22)–C(17)–C(16) 123.3(6), C(7)–C(16)–C(17) 106.5(6), C(16)–C(7)–C(6) 113.7(6), C(1)–C(6)–C(7) 123.2(6), C(6)–C(1)–Pd(1) 128.0(6). |
Inspired by this finding that the carbon–phosphorous bond cleavage occurs in the formation of novel palladium complex in the presence of Fei-Phos, we then investigated the effect of the phenylboronic acid on the synthesis of palladium/Fei-Phos complex. As expected, the addition of phenylboronic acid or iodobenzene led to the formation of triphenylphosphine (PPh3) in the presence of base (Scheme 3),10 which gave indirect evidence to support the structure of palladium/Fei-Phos complex in Fig. 3.
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Scheme 3 The direct detection of triphenylphosphine by GC-MS: the C–P bond cleavage of Fei-Phos and new C–P bond-forming in the presence of palladium catalyst. |
Furthermore, the addition of a catalytic amount of phenylboronic acid also led to improved yield of 2a (90% yield), and the enantioselectivity remained excellent (96% ee) in comparison to that of phenylboronic acid-free reaction conditions (Scheme 4). Notably, we observed that the use of the novel palladium complex in Fig. 3 as catalyst also resulted in the same level of enantioselectivity in this reaction. We also examined the reaction of phenylboronic acid with ligand L1, the analogues of Fei-Phos, in the presence of palladium and base. Under identical conditions, the carbon–phosphorous bond cleavage did not occur, suggesting that the structure of palladium/Fei-Phos is significantly influenced by the multistereogenic diphenylpiperazine and diphenylphosphine backbone. For example, no dicyclohexyl(phenyl)phosphine was detected in the reaction of ligand L1 and phenylboronic acid in the presence of [Pd(η3-C3H3)Cl]2 (Scheme 5). Overall, this study led to the conclusion that the palladium-catalyzed allylic etherification reaction might be promoted by the novel eight-membered palladium/Fei-Phos complex (Fig. 3), which is possibly different from that of the preliminary hypothesis in Scheme 2 and Fig. 2. However, the reaction mechanism of such Fei-Phos – involved palladium-catalyzed allylic substitution reaction is quite complicated than that of our speculation because the eight-membered-Pd/Fei-Phos complex provided in this work are still insufficient for supporting the true palladium catalyst in these allylic alkylation reactions. Alternative pathway with cooperative activation is not completely ruled out because of the use of multifunctional Fei-Phos ligand bearing structural specifically backbone in this reaction.
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Scheme 5 The possible reaction of ligand L1 and phenylboronic acid in the presence of palladium and base: no desired dicyclohexyl(phenyl)phosphine. |
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Scheme 6 Comparison of activity of various alkyl alcohols in the Pd/Fei-Phos – catalyzed asymmetric allylic alkylation reaction under the optimized reaction conditions. |
It is well-known that pKa is arguably one of the most important physical constants for alcohols, which provided useful information in this reaction in term of the reactivity of these alcohols. Traditionally, for palladium-catalyzed allylic alkylation reactions, “soft” and “hard” nucleophiles have been identified by their pKa. In generally, hard nucleophiles (pKa > 25) is less acidic than soft nucleophiles (pKa < 25).11 Of course, for most pronucleophiles, such functional compounds with a resonance-stabilizing group could increase the polarizability of the molecular orbitals and would lower the pKa value, in which it is difficult to discriminate classic hard/soft reactivity trends.12 Thus, the interpretation of the unexpected results in this allylic etherification reaction should take into account the acidities of alcohols that should match for structure of palladium/Fei-Phos complex. On the basis of the experimental results and the systematic data of pKa for the various alcohols evaluated in this reaction,13 we can concluded that our Pd/Fei-Phos catalyst system exhibited extraordinarily selectivity for methanol and benzyl alcohols that the pKa (in H2O) would be in a certain range of about 12.5 to 15.5 (or pKa = 23.5 to 27.9 in DMSO), owing to high yield and promising enantioselectivity of catalytic asymmetric allylic alkylation reactions with methanol, trifluoroethanol, and benzyl alcohols or its analogues. Thus the equilibrium acidities (pKa) provided a fundamental data base for assessment of the reactivity of structurally diverse alcohols brought from the electronic and steric effects,13b which inspired us to deduce the importance of nitrogen atoms in the Pd/Fei-Phos – catalyzed asymmetric allylic alkylation with 1,3-diphenyl-2-propenyl acetate because of possibly matchable interaction between nitrogen-centered Brønsted base and Brønsted acidic alcohol.
At last, to provide indirect evidence for the mechanism of the palladium-catalyzed allylic etherification, we carried out the comparable investigation on the catalytic activity and stereocontrol of the analogues of Fei-Phos ligand, which further support the privileged role of phosphorous and nitrogen atoms on the Fei-Phos ligand. Chiral ligands L1 were then used in the palladium-catalyzed allylic etherification of benzyl alcohol with 1,3-diphenyl-2-propenyl acetate (1). In sharp contrast to the results for Fei-Phos-promoted allylic etherification with excellent enantioselectivity, the ligand L1 gave poor enantioselectivities (only 2% ee).7 The low enantioselectivity of L1 might be aroused from the strong coordination of electron-rich biphosphine and palladium center. Significantly, this observation is consistent with the evidence that Fei-Phos – derived palladium–monophosphine complex is better than biphosphine on the backbone of trans-1,2-diaminocyclohexane (for example, L1). These results also allowed us to conclude that the utility of present palladium/Fei-Phos was one of a privileged palladium complex in this reaction.
It should be noted that, on the basis of Kagan's nonlinear stereochemical effect,14 we hypothesized that the enantioselective induction arose from the formation of possible Pd/Fei-Phos complex with one Fei-Phos ligand. According to the previous report,14 the nonlinear effect would be an important diagnostic tool in mechanistic studies of stereochemistry and asymmetric reactions. And our results of this nonlinear study with catalyst enantiopurity (eecat) on product enantiomeric excess (eeprod), graphically depicted in Fig. 4, demonstrated the linear curve without nonlinear effect might be attributed to the single-metal center with one Fei-Phos. Fortunately, it is easily to distinguish the similar mechanistic process between asymmetric allylic alkylation of alcohols and activated methylene compounds.
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Fig. 4 Relationship between enantioselectivity of the reaction product (eeprod) and enantiomeric excess of the chiral catalyst (eecat). |
The generally accepted mechanism for palladium-catalyzed allylic alkylation could be abbreviated as two key steps,15 the initially oxidative addition of low valent palladium species (Pd(0)L2) to allylic acetate (electrophile) and nucleophilic attack on the corresponding allylic Pd(II) cation, to resulted into the regeneration of Pd(0) complex when simultaneously liberated the product. Thus based on our scenario for the catalytic asymmetric allylic etherification of alcohols with 1,3-diphenyl-2-propenyl acetate (1), the results of palladium-catalyzed allylic alkylation and the related reaction information obtained in this work, we proposed a major and simplified mechanistic procedure and corresponding transition-state model (II) in Scheme 7. In fact, more profitable evidence with NMR analysis (Fig. 5 and S4 in ESI†) also showed that this chiral Pd/Fei-Phos complex (II) – catalyzed allylic alkylation reaction was not completely relied on the pathway of the Pd(II)/Pd(III) catalysis because of the conformationally restricted eight-membered palladium-based catalyst system (Fig. 3).16 As shown in Fig. 5, the 31P-NMR analysis of the Pd/Fei-Phos catalyst system and its mixture with two substrates respectively supported the formation of diphosphine-based Pd complex as major component in this reaction. And the Pd/Fei-Phos complex was enough stable in allylic alkylation of indole with allylic acetate. On the basis of experimental data and spectroscopic analysis, therefore we suggested that diphosphine-based palladium/Fei-Phos complex was possibly acted as more reasonable catalyst system (intermediate II in Scheme 7). In addition, the experimental results as well as the preliminary findings in the mechanistic study revealed that the distinctive activation showed in Scheme 7 is reasonable because of the multifunctional structure of Fei-Phos ligand in the palladium catalysis, which also provide a good example that the mechanistic study based on X-ray analysis but without other evidences was not completely true.
Footnote |
† Electronic supplementary information (ESI) available. CCDC 1446415. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra15665g |
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