Very Simple and Highly Modular Synthesis of Ferrocene-Based Chiral

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Very Simple and Highly Modular Synthesis of Ferrocene-Based Chiral Phosphines with a Wide Variety of Substituents at the Phosphorus Atom(s) Huifang Nie, Lin Yao, Bing Li, Shengyong Zhang,* and Weiping Chen* School of Pharmacy, Fourth Military Medical University,169 Changle West Road, Xi’an 710032, People’s Republic of China S Supporting Information *

ABSTRACT: Chiral ferrocene-based phosphines with a wide variety of substituents at the phosphorus atom(s) have been simply and modularly synthesized by ortho lithiation of Ugi’s amine and then reaction with PCl3 and finally treatment with Grignard or organolithium reagents.

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INTRODUCTION The ferrocene moiety has played a significant role as a backbone or a substituent in phosphine ligands due to (i) its specific and unique geometries (adequate rigidity, steric bulkiness and planar chirality), (ii) its electronic (redox) properties (electron rich), and (iii) its easy accessibility and derivatization as well as its stability.1 Since the pioneering work of Kumada and Hayashi in 1974,2 chiral ferrocene-based phosphines have witnessed enormous development and now constitute a class of “privileged” ligands that give outstanding performance in a wide variety of enantioselective reactions.3 Among these systems, 1,2-disubstituted ferrocene compounds are the most studied planar chiral phosphine ligands. Since Ugi’s seminal work on the diastereoselective generation of planar chirality of ferrocenes,4 the synthesis of planar chiral 1,2-disubstituted ferrocene compounds has been an important topic in synthetic chemistry, and diastereoselective ortho lithiation with an appropriate chiral ortho-directing group and subsequent in situ trapping with an electrophilic diaryl (or dialkyl) chlorophosphine has become a standard methodology for the preparation of planar chiral ferrocene-based phosphines (Scheme 1).5−20

Scheme 2. General Highly Stereoselective Synthesis of PStereogenic Ferrocene-Based Phosphines

Figure 1. Trifer and ChenPhos.

and phosphorus-centered chirality and planar chirality, have been successfully developed and applied in the highly enantioselective hydrogenation of some challenging substrates. The ease of varying the nature of the substituents at the phosphorus atoms, allowing the steric and electronic tuning of the ligands, is a very important feature and is often decisive for achieving good catalyst performance. Although the known methodologies for the preparation of chiral ferrocene-based phosphines are highly stereoselective and efficient, the modularity of ferrocene-based phosphines is limited by the availability of diaryl (or dialkyl) chlorophosphines and aryl (or alkyl) dichlorophosphines.24 Herein, we describe a very simple and highly modular synthesis of chiral ferrocene-based phosphines with a wide variety of substituents at the phosphorus atom(s).

Scheme 1. General Synthesis of Ferrocene-Based Phosphines by Diastereoselective Ortho Lithiation Followed by Reaction with R2PCl

Previously, we reported a very simple and highly stereoselective synthesis of ferrocene-based P-stereogenic phosphine ligands using a straightforward strategy: reaction of a dichlorophosphine with a chiral lithiated ferrocene, followed by a second Grignard or organolithium reagent (Scheme 2).21 On the basis of this new methodology, novel diphosphines Trifer22 and ChenPhos23 (Figure 1), which combine carbon© 2014 American Chemical Society

Received: March 31, 2014 Published: April 15, 2014 2109

dx.doi.org/10.1021/om500341v | Organometallics 2014, 33, 2109−2114

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RESULTS AND DISCUSSION Recently, Hey-Hawkins reported the preparation of racemic and enantiomerically pure aminoalkylferrocenyldichlorophosphines25a and their reaction with monolithiated 1,2-dicarbacloso-dodecaborane.25b Inspired by Hey-Hawkins’ elegant work, we first developed the synthesis of PPFA derivatives (RC,SFc)-3 bearing a wide variety of substituents at the phosphorus atom (Scheme 3).

Next, this methodology was applied in the higly stereoselective synthesis of P-stereogenic phosphines (Table 2). Table 2. Highly Stereoselective Synthesis of P-Stereogenic Phosphines

Scheme 3. Very Simple and Highly Modular Synthesis of PPFA Derivatives

a

Table 1. Synthesis of PPFA Derivatives

a

R

M

product

yield (%)a

1 2 3 4 5 6 7 8

C6H5 C6H5 4-Br-C6H4 4-Ph-C6H4 3,5-Me2C6H3 3,5-tBu2C6H3 2-thienyl n-C10H21

MgBr Li Li Li MgBr MgBr Li MgBr

3a 3a 3b 3c 3d 3e 3f 3g

74 75 43 62 73 71 63 66

R

R′

product

yield (%)a

1 2 3 4 5 6

C6H5 3,5-Me2C6H3 C6H5 2-MeOC6H4 C6H5 3,5-tBu2C6H3

3,5-Me2C6H3 C6H5 2-MeOC6H4 C6H5 3,5-tBu2C6H3 C6H5

4a 4b 4c 4d 4e 4f

49 44 40 45 49 45

Isolated yield.

Thus, Ugi’s amine (R)-1 was lithiated with t-BuLi, followed by reaction with PCl3 at −78 °C, and then reaction with phenyllithium and finally with (3,5-dimethylphenyl)lithium to afford the single diastereomer (RC,SFc,SP)-4a (as judged by 1H NMR and 31P NMR spectroscopy) in 49% yield (Table 2, entry 1). Importantly, (RC,SFc,RP)-4b, a epimer of (RC,SFc,SP)-4a, which has the opposite configuration at the phosphorus atom, can be prepared simply by inversing the addition sequence of phenyllithium and (3,5-dimethylphenyl)lithium (entry 1 vs entry 2). A variety of ferrocene-based P-stereogenic phosphines could similarly be prepared as a single diastereomer in moderate yield (entries 3−6). The absolute configuration of the product (RC,SFc,SP)-4c was determined previously by singlecrystal X-ray diffraction analysis,21a and the absolute configuration of each compound in the series 4 was inferred from the established stereochemistry of (RC,SFc,SP)-4c and the plausible mechanism for the highly stereoselective formation of Pstereogenic phosphines 4 (Scheme 4).21a

This method is very simple (“one-pot” synthesis): using a modified Hey-Hawkins procedure to prepare the dichlorophosphine (RC,SFc)-2, which reacted in situ with an excess Grignad or organolithium reagent to give the desired (RC,SFc)-3 in good yield (Table 1). Thus, lithiation of Ugi’s amine (R)-1 with tert-

entry

entry

Scheme 4. Plausible Mechanism for Highly Stereoselective Formation of P-Stereogenic Phosphines 4

Isolated yield.

Finally, the application of this methodology was exemplified in the synthesis of P-stereogenic diphosphines Trifer22 and ChenPhos.23 The reaction of monochlorophosphine 7 with a simple alkyl and aryl Grignard or organolithium reagent R′M generally gives almost perfect diastereoselectivity, and the absolute configuration of phosphorus-centered chirality is normally predictable (Scheme 4).21 However, the diastereoselectivity was variable (often low) when the R′Li was derived from another ferrocene derivative, as in the synthesis of Trifer (Scheme 5). Thus, Ugi’s amine (R)-1 was lithiated with t-BuLi, followed by reaction with PCl3 at −78 °C, and then reaction with phenyllithium and finally with 1,1′-dilithioferrocene N,N,N’N’-tetramethylethylenediamine (TMEDA) complex to give a mixture of the three diastereomers (RC,RC)-(SFc,SFc)(RP,RP)-5a (31P NMR spectroscopy: δ −31.8 (s)), the

BuLi in in t-butyl methyl ether (TBME) at 0 °C, followed by reaction with PCl3 at −78 °C gave (RC,SFc)-2. The resulting (RC,SFc)-2 was reacted in situ with 3.0 equiv of phenylmagnesium bromide at −78 °C to room temperature to afford the desired PPFA (RC,SFc)-3a in 74% isolated yield (Table 1, entry 1). Replacement of the Grignard reagent with the corresponding lithium reagent gave similar results (entry 1 vs entry 2). As shown in Table 1, all substituted phenyl (entries 3−5), even very bulky 3,5-di-tert-butylphenyl (entry 6), heteroaryl (entry 7), and alkyl (entry 8) derived PPFA derivatives, could be obtained in good yield. The relatively low yield of the 4-bromophenyl derivative (RC,SFc)-3b (entry 3) is possibly caused by the selectivity of monolithiation of 1,4dibromobenzene. 2110

dx.doi.org/10.1021/om500341v | Organometallics 2014, 33, 2109−2114

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Scheme 5. Synthesis of Trifer and ChenPhos

EXPERIMENTAL SECTION

General Remarks. The 1H (400 MHz), 13C (100.6 MHz), and 31P (162 MHz) NMR spectra were recorded on a spectrometer with an internal deuterium lock. Chemical shifts are quoted as parts per million and referenced to CHCl3 (δ H 7.26) and/or CDCl3 (δ C 77.0, central line of triplet). 13C and 31P NMR spectra were recorded with broadband proton decoupling. Coupling constants (J) are quoted in hertz. Melting points were obtained on a Micro melting point instrument that was uncalibrated. Optical rotation analyses were performed on a Model 343 polarimeter. HRMS were recorded on a spectrometer with ES ionization (ESI). All commercially available reagents were used as received. Solvents and reagents were purified and dried by standard methods prior to use. Products were purified by flash column chromatography on silica gel. All reactions involving air- or moisturesensitive species were performed under an inert atmosphere in ovendried glassware. General Procedure for the Preparation of 3 using Grignard Reagent. To a solution of (R)-Ugi’s amine (2.57 g, 10 mmol) in TBME (20 mL) was added 1.3 M t-BuLi solution in n-hexane (8.5 mL, 11.05 mmol) at 0 °C. After addition was complete, the mixture was warmed to room temperature and stirred for 1.5 h at room temperature. The mixture was then cooled to −78 °C and a solution of PCl3 (1 mL, 11.46 mmol) in TBME was added slowly, and the mixture was warmed to room temperature overnight. The mixture was then cooled to −78 °C again, and a suspension of RMgBr (prepared from RBr (C6H5Br, 4.71 g, 30 mmol (a); 3,5-Me2C6H3Br, 5.55 g, 30 mmol (d); 3,5-t-Bu2C6H3Br, 8.07 g, 30 mmol (e)) and magnesium powder (0.75 g, 31.25 mmol) in THF at reflux temperature; prepared from 1-bromodecane (6.63 g, 30 mmol (g)) and magnesium powder (0.75 g, 31.25 mmol) in Et2O at reflux temperature) was added slowly via a cannula. The mixture was stirred overnight from −78 °C to room temperature and quenched by the addition of saturated NH4Cl solution (40 mL). The organic layer was separated and dried over Na2SO4 and the solvent removed under reduced pressure. The residue was purified by chromatography to afford the title compounds 3a,2 3d,2 3e,26 and 3g. Characterization of 3a: orange solid; 3.26 g, 74% yield; mp 141− 143 °C; [α]D25 = −350.9° (c 0.25, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.61−7.57 (m, 2H), 7.37−7.33 (m, 3H), 7.22−7.14 (m, 5H), 4.37 (s, 1H), 4.24 (t, J = 2.3 Hz, 1H), 4.15 (dd, J = 6.7, 2.5 Hz, 1H), 3.94 (s, 5H), 3.86 (s, 1H), 1.77 (s, 6H), 1.26 (d, J = 7.0 Hz, 3H). Characterization of 3d: orange oil; 3.63 g, 73% yield; [α]D25 = −278.9° (c 0.25, CHCl3); 1H NMR (500 MHz, CDCl3) δ 7.24 (d, J = 8.0 Hz, 2H), 6.98 (s, 1H), 6.79 (d, J = 7.8 Hz, 2H), 4.35 (s, 1H), 4.22 (t, J = 2.3 Hz), 4.09 (qd, J = 6.7, 2.7 Hz, 1H), 3.92 (s, 5H), 3.87 (s, 1H), 2.32 (s, 6H), 2.18 (s, 6H), 1.81 (s, 6H), 1.28 (d, J = 6.7 Hz, 3H). Characterization of 3e: yellow foam; 4.72 g, 71% yield; [α]D25 = −246.8° (c 0.25, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.53 (dd, J = 8.2, 1.8 Hz, 2H), 7.39 (s, 1H), 7.22−7.16 (m, 3H), 4.33 (s, 1H), 4.22 (s, 1H), 4.15 (dd, J = 6.7, 2.5 Hz, 1H), 3.92 (s, 5H), 3.85 (s, 1H), 1.68 (s, 6H), 1.31 (s, 18H), 1.27 (d, J = 6.6 Hz, 3H), 1.21 (s, 18H); 31 P NMR (202 MHz, CDCl3) δ −22.79 (s); 13C NMR (126 MHz, CDCl3) δ 149.74 (d, J = 7.5 Hz), 149.15 (d, J = 7.3 Hz), 138.87 (d, J = 3.8 Hz), 137.13 (d, J = 7.2 Hz), 129.52 (d, J = 22.1 Hz), 127.15 (d, J = 20.5 Hz), 122.54, 121.10, 96.24, 78.40 (d, J = 9.2 Hz), 71.61 (d, J = 5.4 Hz), 69.54, 69.15 (d, J = 3.8 Hz), 67.89, 57.18 (d, J = 7.1 Hz), 39.23, 34.81 (d, J = 22.8 Hz), 31.51 (d, J = 7.6 Hz), 10.66; HRMS (ESI) calcd for C42H60FeNP [M + H]+ 666.3891, found 666.3875. Characterization of 3g: orange oil; 3.76 g, 66% yield; [α]D25 = −92.1° (c 0.7, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 4.26 (s, 1H), 4.19 (s, 1H), 4.11 (s, 1H), 4.10−4.15 (m, 1H), 4.05 (s, 5H), 2.08 (s, 6H), 1.66−1.42 (m, 6H), 1.43−1.07 (m, 33H), 0.92−0.83 (m, 6H); 31 P NMR (202 MHz, CDCl3) δ −39.17 (s); 13C NMR (126 MHz, CDCl3) δ 96.49 (d, J = 13.5 Hz), 78.85 (d, J = 11.9 Hz), 69.45, 69.33, 68.78, 67.30, 56.77 (d, J = 5.1 Hz), 39.35, 31.92 (d, J = 2.8 Hz), 31.83, 31.73, 31.42 (d, J = 8.7 Hz), 29.69, 29.63, 29.53, 29.38, 29.34, 28.99 (d, J = 12.3 Hz), 27.37, 27.21, 25.49 (d, J = 8.1 Hz), 25.08, 22.69 (d, J = 3.4 Hz), 14.13, 8.27 (d, J = 8.6 Hz); HRMS (ESI) calcd for C34H60FeNP [M + H]+ 570.3891, found 570.3892.

pseudomeso-(RC,RC)-(SFc,SFc)-(RP,SP)-5a (δ −32.0 (s) and −34.8 (s)), and (RC,RC)-(SFc,SFc)-(SP,SP)-5a (δ −35.2 (s)) in about a 2:1:1 ratio as determined by 31P NMR spectroscopy. Fortunately, we found that the desired (RC,RC)-(SFc,SFc)(SP,SP)-5a is thermodynamically more stable and could be readily prepared from the mixture of three diastereomers by thermal epimerization through pyramidal inversion. When a solution of the mixture in toluene was refluxed, (RC,RC)(SFc,SFc)-(RP,RP)-5a completely disappeared after 40 min and an equilibrium had been reached with a ratio of 6.7:1 for the (RC,RC)-(SFc,SFc)-(SP,SP)-5a/(RC,RC)-(SFc,SFc)-(RP,SP)-5a after 60 min. The desired (RC,RC)-(SFc,SFc)-(SP,SP)-5a was isolated in 41% yield by flash chromatography. Similarly, Cy-Trifer (5b) and ChenPhos (6) were synthesized in 44% and 38% yields, respectively (Scheme 5). The absolute configurations of (RC,RC)-(SFc,SFc)-(SP,SP)-5a22 and (RC,SFc,RP)-623a were determined previously by single-crystal X-ray diffraction analysis. This new methodology is economical and very simple, since it can be completed from readily available starting materials without the purification of intermediates (“one-pot” synthesis). Most importantly, the synthesis is highly modular; the R and R′ groups can be any aryl or alkyl group that tolerates lithiation and a Grignard reaction, allowing the easy tuning of the steric and electronic properties of the ligands. This feature is very important and often decisive for achieving good catalyst performance.

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CONCLUSION

In summary, a very simple and highly modular synthesis of chiral ferrocene-based phosphines with a wide variety of substituents at the phosphorus atom(s) has been developed by reaction of the lithiated Ugi amine with PCl3, followed by treatment with Grignard or organolithium reagents. This new methodology offers highly modular construction of ligands and hence generates many possibilities for modifying the structure of these ferrocene-based phosphines. 2111

dx.doi.org/10.1021/om500341v | Organometallics 2014, 33, 2109−2114

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mmol) in TBME (40 mL) at −40 °C) was added slowly via a cannula. The mixture was warmed to room temperature and stirred for 1.5 h. The mixture was then cooled to −78 °C again, and a suspension of R′Li (prepared from (3,5-Me2C6H3Br, 2.22 g, 12 mmol (a); C6H5Br, 1.88 g, 12 mmol (b); 2-MeOC6H4Br, 2.24 g, 12 mmol (c); C6H5Br, 1.88 g, 12 mmol (d); 3,5-t-Bu2C6H3Br, 3.23 g, 12 mmol (e); C6H5Br, 1.88 g, 12 mmol (f)) and 1.6 M n-BuLi solution in pentane (8.4 mL, 13.44 mmol) in TBME (40 mL) at −40 °C) was added slowly via a cannula. The mixture was stirred overnight from −78 °C to room temperature and quenched by the addition of saturated NH4Cl solution (40 mL). The organic layer was separated and dried over Na2SO4 and the solvent removed under reduced pressure. The residue was purified by chromatography to afford the title compounds 4a−f. Characterization of 4a: yellow solid; 2.3 g, 49% yield; mp 177.3− 178.6 °C; [α]D25 = −317.6° (c 0.25, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.62 (s, 2H), 7.35 (s, 3H), 6.79 (s, 3H), 4.36 (s, 1H), 4.23 (s, 1H), 4.12 (d, J = 2.8 Hz, 1H), 3.92 (s, 5H), 3.84 (s, 1H), 2.18 (s, 6H), 1.81 (s, 6H), 1.28 (d, J = 4.5 Hz, 3H); 31P NMR (202 MHz, CDCl3) δ −22.58 (s); 13C NMR (126 MHz, CDCl3) δ 140.45 (d, J = 6.7 Hz), 139.17 (d, J = 9.1 Hz), 136.39 (d, J = 7.0 Hz), 135.27 (d, J = 21.3 Hz), 130.09 (d, J = 18.6 Hz), 128.82, 128.59, 127.80 (d, J = 7.5 Hz), 97.07 (d, J = 24.3 Hz), 71.75 (d, J = 5.2 Hz), 70.15, 69.57, 69.15, 68.16, 57.04 (d, J = 6.5 Hz), 39.21, 21.28, 9.78; HRMS (ESI) calcd for C28H32FeNP [M + H]+ 470.1700, found 470.1695. Characterization of 4b: orange needle crystal; 2.07 g, 44% yield; mp 127.8−128.5 °C; [α]D25 = −337.6° (c 0.25, CH2Cl2); 1H NMR (400 Hz, CDCl3) δ 7.23−7.13 (m, 7H), 6.98 (s, 1H), 4.35 (s, 1H), 4.23 (s, 1H), 4.14 (d, J = 4.8 Hz, 1H), 3.94 (s, 5H), 3.88 (s, 1H), 2.31 (s, 6H), 1.76 (s, 6H), 1.26 (d, J = 6.5 Hz, 3H); 31P NMR (162 Hz, CDCl3) δ −23.02 (s); 13C NMR (101 Hz, CDCl3) δ 140.78 (d, J = 4.7 Hz), 138.33 (d, J = 6.2 Hz), 137.11 (d, J = 7.9 Hz), 132.87 (d, J = 21.4 Hz), 132.36 (d, J = 18.8 Hz), 131.59 (d, J = 8.4 Hz), 130.88 (d, J = 5.5 Hz), 130.41, 128.47 (d, J = 9.9 Hz), 127.84 (d, J = 11.2 Hz), 127.26 (d, J = 6.1 Hz), 127.01, 97.02, 71.82 (d, J = 4.4 Hz), 70.19, 69.62, 69.21, 68.13 (d, J = 4.3 Hz), 57.14, 39.03, 21.35, 9.50; HRMS (ESI) calcd for C28H32FeNP [M + H]+ 470.1700, found 470.1693. Characterization of 4c: 21a orange solid; 1.90 g, 40% yield; mp 127.5−128.4 °C; [α]D25 = −237.2° (c 0.25, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.37−7.30 (m, 1H), 7.23−7.09 (m, 6H), 6.95 (dd, J = 8.1, 4.7 Hz, 1H), 6.87 (t, J = 7.2 Hz, 1H), 4.37 (s, 1H), 4.25 (s, 1H), 4.11 (dd, J = 6.7, 2.7 Hz, 1H), 3.97 (s, 5H), 3.96 (s, 1H), 3.93 (s, 3H), 1.79 (s, 6H), 1.28 (d, J = 6.7 Hz, 3H). 31P NMR (202 MHz, CDCl3) δ −40.53 (s); 13C NMR (126 MHz, CDCl3) δ 161.88 (d, J = 16.8 Hz), 141.45 (d, J = 8.3 Hz), 137.58 (d, J = 3.6 Hz), 132.47 (d, J = 19.4 Hz), 130.46, 127.04 (d, J = 6.4 Hz), 126.68, 126.46 (d, J = 13.3 Hz), 120.47, 110.16, 96.98 (d, J = 3.4 Hz), 76.16 (d, J = 11.0 Hz), 71.89 (d, J = 4.7 Hz), 69.55, 69.37 (d, J = 3.8 Hz), 68.16, 56.83 (d, J = 7.3 Hz), 55.38, 39.33, 10.18. Characterization of 4d: yellow foam; 2.12 g, 45% yield; [α]D25 = −106° (c 0.25, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.35−7.27 (m, 1H), 7.19−7.09 (m, 2H), 6.99−6.80 (m, 4H), 6.76 (t, = J 7.4 Hz, 1H), 6.68 (dd, J = 8.0, 4.6 Hz, 1H), 4.39 (s, 1H), 4.26 (s, 1H), 4.10 (dd, J = 6.7, 3.2 Hz, 1H), 3.97 (s, 5H), 3.90 (s, 1H), 3.58 (s, 3H), 1.84 (s, 6H), 1.32 (d, J = 6.7 Hz, 3H); 31P NMR (202 MHz, CDCl3) δ −53.36 (s); 13C NMR (101 Hz, CDCl3) δ 161.79 (d, J = 18.9 Hz), 159.74 (d, J = 16.0 Hz), 136.42, 134.09, 130.14, 129.89 (d, J = 10.7 Hz), 128.43, 126.07 (d, J = 10.0 Hz), 120.20, 119.55, 109.81 (d, J = 3.0 Hz), 109.56, 97.34 (d, J = 25.2 Hz), 75.42 (d, J = 10.7 Hz), 72.19 (d, J = 4.9 Hz), 69.54, 68.33, 65.86, 56.71 (d, J = 8.8 Hz), 56.10 (dd, J = 122.3, 17.5 Hz), 39.75, 11.26; HRMS (ESI) calcd for C27H30FeNOP [M + H]+ 472.1493, found 472.1478. Characterization of 4e: yellow foam; 2.71 g, 49% yield; [α]D25 = −286.0° (c 0.25, CH2Cl2); 1H NMR (400 Hz, CDCl3) δ 7.70−7.55 (m, 2H), 7.40−7.30 (m, 3H), 7.21 (s, 1H), 7.13 (dd, J = 8.7, 1.2 Hz, 2H), 4.33 (s, 1H), 4.22 (s, 1H), 4.12 (dd, J = 6.7, 2.2 Hz, 1H), 3.94 (s, 5H), 3.84 (s, 1H), 1.67 (s, 6H), 1.24 (d, J = 6.8 Hz, 3H), 1.21 (s, 18H); 31P NMR (162 Hz, CDCl3) δ −22.54 (s); 13C NMR (101 Hz, CDCl3) δ 149.25 (d, J = 7.2 Hz), 139.13 (d, J = 9.5 Hz), 138.69 (d, J = 4.7 Hz), 134.90 (d, J = 21.0 Hz), 128.35, 127.72 (d, J = 7.3 Hz), 127.10 (d, J = 20.3 Hz), 121.11, 96.60, 77.92 (d, J = 9.0 Hz), 71.70 (d,

General Procedure for the Preparation of 3 using Organolithium Reagent. To a solution of (R)-Ugi’s amine (2.57 g, 10 mmol) in TBME (20 mL) was added 1.3 M t-BuLi solution in nhexane (8.5 mL, 11.05 mmol) at 0 °C. After addition was complete, the mixture was warmed to room temperature and stirred for 1.5 h at room temperature. The mixture was then cooled to −78 °C and a solution of PCl3 (1 mL, 11.46 mmol) in TBME was added slowly, and the mixture was warmed to room temperature overnight. The mixture was then cooled to −78 °C again, and a suspension of RLi (prepared from RBr(C6H5Br, 3.59 g, 23 mmol (a); 1,4-Br2C6H4 5.43 g, 23 mmol (b); 4-PhC6H4Br, 5.36 g, 23 mmol (c)) and 1.6 M n-BuLi solution in pentane (15.8 mL, 25.28 mmol) in TBME (40 mL) at −40 °C; prepared from thiophene (1.93 g, 23 mmol) and 1.6 M n-BuLi solution in pentane (15.8 mL, 25.28 mmol (f)) in TBME (40 mL) at −40 °C) was added slowly via a cannula. The mixture was stirred overnight from −78 °C to room temperature and quenched by the addition of saturated NH4Cl solution (40 mL). The organic layer was separated and dried over Na2SO4 and the solvent removed under reduced pressure. The residue was purified by chromatography to afford the title compounds 3a−c,f. Characterization of 3b: yellow foam; 2.58 g, 43% yield; [α]D25 = −302.8° (c 0.25, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.49 (d, J = 7.9 Hz, 2H), 7.44−7.36 (m, 2H), 7.31 (d, J = 7.4 Hz, 2H), 7.04−6.98 (m, 2H), 4.39 (s, 1H), 4.26 (s, 1H), 4.13 (d, J = 4.6 Hz, 1H), 3.95 (s, 5H), 3.77 (s, 1H), 1.75 (s, 6H), 1.22 (d, J = 2.9 Hz, 3H); 31P NMR (202 MHz, CDCl3) δ −24.36 (s); 13C NMR (126 MHz, CDCl3) δ 139.84 (d, J = 9.0 Hz), 137.68 (d, J = 11.8 Hz), 136.53 (d, J = 22.0 Hz), 133.73 (d, J = 19.3 Hz), 133.03, 131.96, 131.14 (d, J = 7.5 Hz), 130.48 (d, J = 6.7 Hz), 123.46, 121.72, 97.16, 75.67 (d, J = 7.9 Hz), 71.39 (d, J = 5.6 Hz), 69.68, 69.59, 68.42, 57.21 (d, J = 5.2 Hz), 38.74, 8.30 (d, J = 10.9 Hz); HRMS (ESI) calcd for C26H26BrFeNP [M + H]+ 599.9577, found 599.9562. Characterization of 3c: yellow solid; 3.68 g, 62% yield; mp 95.6− 97.0 °C; [α]D25 = −387.6° (c 0.25, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.70 (t, J = 7.6 Hz, 2H), 7.62 (t, J = 7.8 Hz, 4H), 7.57 (d, J = 7.5 Hz, 2H), 7.49−7.26 (m, 10H), 4.39 (s, 1H), 4.27 (s, 1H), 4.19 (dd, J = 6.6, 1.9 Hz, 1H), 3.98 (s, 5H), 3.94 (s, 1H), 1.81 (s, 6H), 1.28 (d, J = 6.4 Hz, 3H);31P NMR (202 MHz, CDCl3) δ −24.35 (s); 13C NMR (126 MHz, CDCl3) δ 141.33, 140.92, 140.62, 139.97 (d, J = 7.3 Hz), 139.67, 137.84 (d, J = 9.8 Hz), 135.67, 135.50, 132.78 (d, J = 18.7 Hz), 128.75 (d, J = 12.9 Hz), 127.47, 127.10 (d, J = 8.4 Hz), 126.91, 126.52 (d, J = 7.7 Hz), 125.94 (d, J = 6.8 Hz), 97.15 (d, J = 4.1 Hz), 71.75 (d, J = 5.5 Hz), 70.32, 69.68, 69.32 (d, J = 3.9 Hz), 68.25, 57.16 (d, J = 6.5 Hz), 39.02, 9.20; HRMS (ESI) calcd for C38H36FeNP [M + H]+ 594.2013, found 594.2009. Characterization of 3f: orange solid; 2.85 g, 63% yield; mp 118.6− 119.8 °C; [α]D25 = −424° (c 0.25, CH2Cl2); 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 4.8 Hz, 1H), 7.52−7.47 (m, 1H), 7.34 (d, J = 4.8 Hz, 1H), 7.15−7.05 (m, 2H), 6.96−6.90 (m, 1H), 4.37 (s, 1H), 4.32 (s, 1H), 4.27 (s, 1H), 4.16 (dd, J = 6.7, 2.1 Hz, 1H), 3.95 (s, 5H), 1.80 (s, 6H), 1.24 (d, J = 6.7 Hz, 3H); 31P NMR (202 MHz, CDCl3) δ −52.08 (s); 13C NMR (126 MHz, CDCl3) δ 142.79 (d, J = 20.3 Hz), 140.42 (d, J = 25.4 Hz), 135.38 (d, J = 31.1 Hz), 132.67 (d, J = 22.7 Hz), 131.12, 129.08, 127.16 (d, J = 9.0 Hz), 126.98 (d, J = 7.3 Hz), 96.54 (d, J = 25.2 Hz), 71.96 (d, J = 7.1 Hz), 70.42, 69.76, 69.09 (d, J = 4.7 Hz), 68.24, 57.19 (d, J = 6.5 Hz), 38.83, 9.48; HRMS (ESI) calcd for C22H24FeNPS2 [M + H]+ 454.0515, found 454.0510. General Procedure for the Preparation of P-Stereogenic 4. To a solution of (R)-Ugi’s amine (2.57 g, 10 mmol) in TBME (20 mL) was added 1.3 M t-BuLi solution in n-hexane (8.5 mL, 11.05 mmol) at 0 °C. After addition was complete, the mixture was warmed to room temperature and stirred for 1.5 h at room temperature. The mixture was then cooled to −78 °C and a solution of PCl3 (1 mL, 11.46 mmol) in TBME was added slowly, and the mixture was warmed to room temperature and then stirred for 1.5 h. The mixture was then cooled to −78 °C again, and a suspension of RLi (prepared from (C6H5Br, 1.75 g, 11.1 mmol (a); 3,5-Me2C6H3Br, 2.05 g, 11.1 mmol (b); C6H5Br, 1.75 g, 11.1 mmol (c); 2-MeOC6H4Br, 2.08 g, 11.1 mmol (d); C6H5Br, 1.75 g, 11.1 mmol (e); 3,5-t-Bu2C6H3Br, 3.0 g, 11.1 mmol (f)) and 1.6 M n-BuLi solution in pentane (7.6 mL, 12.16 2112

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Organometallics

Article

then cooled to −78 °C again, and a suspension of 1-bromo-1′lithioferrocene (prepared from 1,1′-dibromoferrocene (3.76 g, 11 mmol) and 1.6 M n-BuLi solution in pentane (7.6 mL, 12.16 mmol) in THF (20 mL) at −20 °C) was added slowly via a cannula. The mixture was stirred overnight from −78 °C to room temperature. To the mixture was added a 1.3 M t-BuLi solution in n-hexane (8.5 mL, 11.05 mmol) at −60 °C, and then the mixture was stirred for 1.5 h. A solution of Cy2PCl (2.7 mL, 12.2 mmol) in 5 mL of dry TBME was added to the above mixture at −60 °C. This mixture was stirred overnight from −60 °C to room temperature and quenched by the addition of saturated NH4Cl solution (20 mL). The organic layer was separated and dried over Na2SO4 and the solvent removed under reduced pressure. The residue was heated at 150 °C for 2 h and then purified by chromatography to afford the title compound 6.23 Characterization of 6: yellow solid; 2.83 g, 38% yield; mp 126.8− 128.3 °C; [α]D25 = −275° (c 1, CH2Cl2); 1H NMR (400 MHz, C6D6) δ 7.68 (t, J = 7.2 Hz, 2H), 7.15−7.05 (m, 3H), 4.64 (s, 1H), 4.38 (s, 2H), 4.31−4.23 (m, 2H), 4.15 (s, 2H), 4.09 (s, 1H), 4.04 (s, 5H), 3.99 (s, 2H), 3.94 (s, 1H), 3.91 (s, 1H), 2.21−2.11 (m, 1H), 2.05−1.95 (m, 3H), 1.95−1.70 (m, 6H), 1.66 (s, 6H), 1.53−1.09 (m, 12H), 1.04 (d, J = 6.7 Hz, 3H); 31P NMR (162 Hz, C6D6) δ −8.37 (s), −36.48 (s).

J = 5.5 Hz), 69.58, 69.08 (d, J = 3.9 Hz), 67.90, 57.09 (d, J = 6.4 Hz), 39.14, 34.72, 31.43, 10.00; HRMS (ESI) calcd for C34H44FeNP [M + H]+: 554.2639, found 554.2641. Characterization of 4f: yellow foam; 2.49 g, 45% yield; [α]D25 = −254.2° (c 0.308, CH2Cl2); 1H NMR (400 Hz, CDCl3) δ 7.47 (dd, J = 8.4, 1.6 Hz, 2H), 7.40 (s, 1H), 7.27−7.19 (m, 2H), 7.19−7.09 (m, 3H), 4.36 (s, 1H), 4.24 (t, J = 2.2 Hz, 1H), 4.21−4.10 (m, 1H), 3.89 (s, 5H), 3.86 (s, 1H), 1.80 (s, 6H), 1.30 (s, 18H), 1.28 (d, J = 6.9 Hz, 3H); 31P NMR (162 Hz, CDCl3) δ −22.48 (s); 13C NMR (101 Hz, CDCl3) δ 149.87 (d, J = 7.6 Hz), 149.25 (d, J = 7.2 Hz), 141.25 (d, J = 6.8 Hz), 137.23 (d, J = 6.7 Hz), 134.90 (d, J = 21.0 Hz), 132.23 (d, J = 18.3 Hz), 129.81 (d, J = 22.5 Hz), 128.36 (s), 127.72 (d, J = 7.3 Hz), 127.14 (t, J = 6.3 Hz), 126.85, 122.66, 96.92 (d, J = 23.6 Hz), 71.62 (d, J = 5.5 Hz), 70.13, 69.54, 69.21 (d, J = 4.2 Hz), 68.18, 57.05 (d, J = 7.4 Hz), 39.19, 34.88, 31.50, 10.03; HRMS (ESI) calcd for C34H44FeNP [M + H]+: 554.2639, found 554.2634. General Procedure for the Preparation of Trifer-Type Diphosphines 5. To a solution of (R)-Ugi’s amine (2.57 g, 10 mmol) in TBME (20 mL) was added a 1.3 M t-BuLi solution in nhexane (8.5 mL, 11.05 mmol) at 0 °C. After addition was complete, the mixture was warmed to room temperature and stirred for 1.5 h at room temperature. The mixture was then cooled to −78 °C, a solution of PCl3 (1 mL, 11.46 mmol) in TBME was added slowly, and the mixture was warmed to room temperature and stirred for 1.5 h. The mixture was then cooled to −78 °C again, and a suspension of RM (prepared from C6H5Br, 1.75 g, 11.1 mmol (a) and 1.6 M n-BuLi solution in pentane (7.6 mL, 12.16 mmol) in TBME (40 mL) at −40 °C; CyMgBr 1.0 M in THF (11 mL, 11 mmol) (b)) was added slowly via a cannula. The mixture was warmed to room temperature and stirred for 1.5 h. The mixture was then cooled to −78 °C again, and a suspension of 1,1′-dilithioferrocene (prepared from ferrocene (0.93 g, 5.0 mmol), TMEDA (1.4 g, 12 mmol), and 1.6 M n-BuLi solution in pentane (7.0 mL, 11.2 mmol) in TBME (20 mL) at reflux temperature) was added slowly via a cannula. The mixture was stirred overnight from −78 °C to room temperature and quenched by the addition of saturated NH4Cl solution (20 mL). The organic layer was separated and dried over Na2SO4 and the solvent removed under reduced pressure. The residue was refluxed in toluene or xylene for 2− 5 h and then purified by chromatography to afford the title compounds 5a22 and 5b.27 Characterization of 5a: orange solid; 1.87 g, 41% yield; mp 189− 191.2 °C; [α]D25 = −424° (c 0.25, toluene); 1H NMR (400 Hz, CDCl3) δ 7.50−7.34 (m, 4H), 7.23−7.13 (m, 6H), 4.61 (s, 2H), 4.29 (s, 2H), 4.19 (s, 2H), 4.14−4.04 (m, 4H), 4.01 (s, 10H), 3.87 (s, 2H), 3.82 (s, 2H), 3.42 (d, J = 0.8 Hz, 2H), 1.49 (s, 12H), 1.13 (d, J = 6.6 Hz, 6H); 31P NMR (162 Hz, CDCl3) δ −36.0 (s). Characterization of 5b: yellow solid; 2.08 g, 45% yield; mp 182.5− 183.5 °C; [α]D25 = −302.9° (c 0.25, CH2Cl2); 1H NMR (400 Hz, CDCl3) δ 4.67 (s, 2H), 4.50 (d, J = 9.0 Hz, 4H), 4.31 (s, 2H), 4.24 (s, 2H), 4.10−3.99 (m, 4H), 3.93 (s, 10H), 3.69 (s, 2H), 2.42−2.27 (m, 2H), 2.13 (s, 12H), 2.03−1.92 (m, 2H), 1.86−1.57 (m, 11H), 1.27 (d, J = 6.6 Hz, 7H), 1.16−0.75 (m, 6H); 31P NMR (162 Hz, CDCl3) δ −26.25 (s); 13C NMR (101 Hz, CDCl3) δ 96.35 (d, J = 22.9 Hz), 79.61 (d, J = 8.1 Hz), 78.92 (d, J = 16.1 Hz), 76.46 (d, J = 33.2 Hz), 72.00 (d, J = 5.5 Hz), 71.76 (d, J = 4.9 Hz), 70.97 (d, J = 7.5 Hz), 69.52, 68.86 (d, J = 3.5 Hz), 67.00, 65.84, 56.56 (d, J = 7.1 Hz), 39.45, 37.80 (d, J = 7.3 Hz), 32.56 (d, J = 28.8 Hz), 31.16, 28.77 (d, J = 17.8 Hz), 28.25 (d, J = 4.1 Hz), 26.53, 15.28, 7.78. Procedure for the Preparation of ChenPhos (6). To a solution of (R)-Ugi’s amine (2.57 g, 10 mmol) in TBME (20 mL) was added 1.3 M t-BuLi solution in n-hexane (8.5 mL, 11.05 mmol) at 0 °C. After addition was complete, the mixture was warmed to room temperature and stirred for 1.5 h at room temperature. The mixture was then cooled to −78 °C, a solution of PCl3 (1 mL, 11.46 mmol) in TBME was added slowly, and the mixture was warmed to room temperature and stirred for 1.5 h. The mixture was then cooled to −78 °C again, and a suspension of PhLi (prepared from C6H5Br (1.75 g, 11.1 mmol) and 1.6 M n-BuLi solution in pentane (7.6 mL, 12.16 mmol) in TBME (40 mL) at −40 °C) was added slowly via a cannula. The mixture was warmed to room temperature and stirred for 1.5 h. The mixture was

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S Supporting Information *

Figures giving 1H NMR and 31P NMR spectra for all compounds and 13C NMR and HRMS spectra for new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail for W.C.: [email protected]. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Natural Science Foundation of China (21272271) for financial support. REFERENCES

(1) Hayashi, T. In Ferrocenes; Togni, A., Hayashi, T., Ed.; WileyVCH: Weinheim, Germany, 1995; pp 105−142. (2) (a) Hayashi, T.; Yamamoto, K.; Kumada, M. Tetrahedron Lett. 1974, 15, 4405−4408. (b) Hayashi, T.; Mise, T.; Fukushima, M.; Kagotani, M.; Nagashima, N.; Hamada, Y.; Matsumoto, A.; Kawakami, S.; Konishi, M.; Yamamoto, K.; Kumada, M. Bull. Chem. Soc. Jpn. 1980, 53, 1138−1151. (3) For selected reviews on ferrocene-based chiral ligands, see: (a) Gómez Arrayás, R. G.; Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 7674. (b) Blaser, H.-U.; Chen, W.; Camponovo, F.; Togni, A. In Ferrocenes: Ligands, Materials and Biomolecules; Stepnicka, P., Ed.; Wiley-VCH: Weinheim, Germany, 2008; pp 205−236. (c) Chen, W.; Blaser, H.-U. In Phosphorus Ligands in Asymmetric Catalysis; Börner, A., Ed.; Wiley: Hoboken, NJ, 2008; pp 359−392. (d) Dai, L.; Hou, X., Ed., Chiral Ferrocenes in Asymmetric Catalysis. Wiley-VCH: Weinheim, Germany, 2010. (4) (a) Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc. 1970, 92, 5389−5393. (b) Battelle, L. F.; Bau, R.; Gokel, G. W.; Oyakawa, R. T.; Ugi, I. Angew. Chem., Int. Ed. 1972, 11, 138−140. (c) Battelle, L. F.; Bau, R.; Gokel, G. W.; Oyakawa, R. T.; Ugi, I. K. J. Am. Chem. Soc. 1973, 95, 482−486. (5) For a recent review on selective syntheses of planar-chiral ferrocenes, see: Schaarschmidt, D.; Lang, H. Organometallics 2013, 32, 5668−5704. (6) (a) Rebière, F.; Riant, O.; Richard, L.; Kagan, H. B. Angew. Chem., Int. Ed. 1993, 32, 568−570. (b) Riant, O.; Argouarch, G.; Guillaneux, D.; Samuel, O.; Kagan, H. B. J. Org. Chem. 1998, 63, 3511−3514. 2113

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Organometallics

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dx.doi.org/10.1021/om500341v | Organometallics 2014, 33, 2109−2114