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Pd-catalyzed asymmetric allylic alkylation using furanoside diphosphinite ligands
Inorganica Chimica Acta 358 (2005) 3824–3828 www.elsevier.com/locate/ica
Pd-catalyzed asymmetric allylic alkylation using furanoside diphosphinite ligands Eugeni Guimet, Montserrat Die´guez *, Aurora Ruiz, Carmen Claver Departament de Quı´mica Fı´sica i Inorga`nica, Universitat Rovira i Virgili, C/MarcelÆlı´ Domingo s/n, 43007 Tarragona, Spain Received 31 March 2005; accepted 11 June 2005 Available online 1 August 2005
Abstract We have tested furanoside diphosphinite ligands 7 and 8, derived from inexpensive D-(+)-xylose, in the Pd-catalyzed allylic alkylation of two substrates with different steric properties. Enantiomeric excesses of up to 31% with good activities were obtained in the Pd-catalyzed allylic alkylation of substrate rac-1,3-diphenyl-3-acetoxyprop-1-ene 9 with dimethylmalonate as nucleophile. Our results show that the absolute configuration at carbon C-3 of the carbohydrate backbone controlled the sense of enantioselectivity. Models for asymmetric induction are discussed based on the absolute stereochemistry of the product. 2005 Elsevier B.V. All rights reserved. Keywords: Palladium; Diphosphinite; Furanoside ligands; Allylic alkylation; Asymmetric catalysis
1. Introduction Palladium-catalyzed allylic alkylation is a useful synthetic method for the formation of carbon–carbon bonds [1]. The selection of chiral ligands for highly enantioselective allylic substitution has focused on the use of mixed bidentate donor ligands such as phosphorus– nitrogen, phosphorus–sulfur and sulfur–nitrogen [1,2]. The efficiency of this type of hard–soft heterodonor ligands has been attributed to the different electronic effects of the donor atoms. However, though to a lesser extent, homodonor ligands (such as P–P [1b,3], N–N [4] and S–S [2,5]) have also demonstrated their potential utility in this process, mainly based on the chiral discrimination induced by the C2 or C1 backbones symmetry. The early success of C2-symmetric diphosphine ligands in asymmetric hydrogenations led to their direct application in the asymmetric allylic alkylation reaction, where *
Corresponding author. Fax: +34 977559563. E-mail addresses: [email protected], dieguez@quimica. urv.es (M. Die´guez). 0020-1693/$ - see front matter 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ica.2005.06.004
good-to-excellent results were obtained by choosing the appropriate substrate or palladium catalysts. Unlike diphosphines, diphosphinites have been less well developed as ligands in this type of reaction [6]. In 1995, Seebach and coworkers [6a] first prepared C2-symmetric diphosphinite 1 from TADDOL, tested it in the asymmetric allylic substitution and obtained ee of up to 76% ee (Fig. 1). Subsequently, RajanBabu and coworkers [6b] reported the use of an extensive family of pyranoside diphosphinite ligands 2 that provided low-to-moderate enantioselectivity (ees up to 59%) (Fig. 1). These ligands contained substituents with different electronic and steric properties in the aromatic ring of the phosphorus atom. The results of these authors indicate an unprecedented electronic effect. Electron-withdrawing and electron-rich diphosphinite ligands therefore lead to products with opposite stereochemistry. Sterically bulky substituents have the same effect as electron-rich ones. Moreover, diphenylphosphinite derivative gave 0% ee. In 1999, RajanBabu and coworkers prepared a series of C2symmetric diphosphinites derived from tartaric acid and binaphthol and systematically studied the effect of the
E. Guimet et al. / Inorganica Chimica Acta 358 (2005) 3824–3828
Ph Ph O
OPPh2
O
OPPh2
Ph
O O R2PO
O OPh R2PO
Ph Ph 1
2
2 a b c d e f g h i
Me2N Bn Ph2PO
3825
R
%ee
Ph 3,5-bis-TMS-C6H3 3,5-bis-t-Bu-4-OMe-C6H2 3,5-bis-CF3-C6H3 4-F-C6H4 3,5-bis-F-C6H3 4-CF3-C6H4 Et Cy
0 16 (R ) 25 (R ) 39 (R ) 17 (S ) 41 (S ) 55 (S ) 18 (R ) 59 (R )
OPPh2 Bn NMe2
OPR2
R2PO 3a 3i
4
Fig. 1. Diphosphinite ligands 1–4 previously used in Pd-catalyzed asymmetric allylic alkylation of diethyl malonate to 1,3-diphenylprop-2-enyl acetate.
ligand backbone and electronic and steric properties of the phosphinite moieties in this reaction [6c]. The electronic effects with these ligands were similar to those with ligands 2. Diphosphinite 3 (BINAPO), based on diphenylphosphinite-(3a) and cyclohexenylphosphinite-(R)binaphthol (3i), gave the best enantioselectivities (63% (R) and 66% (S), respectively) (Fig. 1). In 2000, Jiang and coworkers reported the last example of diphosphinite ligands applied to this process. Enantioselectivities of up to 86% were obtained in the Pd-catalyzed asymmetric allylic alkylation of diethyl malonate to 1,3-diphenylprop-2-enyl acetate with ligand 4 [6d] (Fig. 1). Following our interest in carbohydrates as an inexpensive and highly modular chiral source for preparing ligands [7], and encouraged by the promising results with the above diphosphinite ligands and the success of furanoside diphosphite ligands [3c,3d,3h] 5 and 6 (Fig. 2) in this reaction, in this paper we report the use of furanoside diphosphinite ligands 7 and 8 in the Pdcatalyzed enantioselective asymmetric allylic alkylation (Fig. 3). These ligands are easily prepared in a few steps from inexpensive D-(+)-xylose [8] and have an opposite
O
O P O
O O
P OO O
O
O CH3 P P O OO
configuration at C-3 of the carbohydrate backbone, whose effect in the catalytic performance can be studied. 2. Results and discussion 2.1. Asymmetric allylic alkylation reactions For initial evaluation of diphosphinite ligands 7 and 8, we chose the Pd-catalyzed allylic substitution of rac1,3-diphenyl-3-acetoxyprop-1-ene 9, which is widely used as a model substrate, with dimethyl malonate (Eq. (1)). The catalysts were generated in situ from p-allyl-palladium chloride dimer [PdCl(g3-C3H5)]2, the corresponding ligand and a catalytic amount of the corresponding base. The nucleophile was generated from dimethyl malonate in the presence of N,O-bis(trimethylsilyl)-acetamide (BSA). OAc Ph 9
[Pd(π-C3H5)Cl]2 / 7 - 8
Ph
Ph 10
ð1Þ
O O
t-Bu
O
O O
t-Bu
=
O
O
5 (90% (S))
CH(COOMe)2
CH2(COOMe)2 / BSA
Ph
O
O
t-Bu
t-Bu
6 (95% (S))
Fig. 2. Pd-catalyzed asymmetric allylic alkylation of diethyl malonate to 1,3-diphenylprop-2-enyl acetate using furanoside diphosphite ligands 5 and 6. Enantioselectivities are shown in parentheses.
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E. Guimet et al. / Inorganica Chimica Acta 358 (2005) 3824–3828
Ph Ph P O
5
P OO
4
Ph Ph
Ph Ph P O
1
O
2 3
O
O O
Ph P O Ph
7
O
8
Fig. 3. Furanoside diphosphinite ligands 7 and 8.
We studied the effect of the solvent, base and ligandto-palladium ratio using the catalyst precursor containing ligand 7 (Table 1). Our results show that both the solvent and the base affected the catalytic performance (entries 1–7). The optimum trade-off between enantioselectivities and activities was obtained when dichloromethane was used as solvent and lithium carbonate was used as base (entry 7). The enantiomeric excess obtained with tetrahydrofurane was comparable to that with dichloromethane, but activity was lower. On the other hand, dimethylformamide yielded high relative conversion, but ees were lower. In summary, good activity (TOF > 200 mol (mol h)1) and low enantioselectivity (up to 31% (R)) were obtained. Varying the ligand-to-palladium ratio showed that an excess of ligand was not needed (entries 1 vs 8). Diphosphinite ligand 8, whose configuration of carbon atom C-3 is opposite to that of ligand 7, produced the same value for enantioselectivity but in the S-product (entry 1 vs 9). These results indicate that the configuration at C-3 controls the sense of enantioselectivity. This behavior is similar to that observed in related diphosphite ligands [3d] and also suggests that the nucleophilic attack takes place trans to the phosphinite moiety attached to C-5. Since diphosphinite 7 led to the R-product as the major enantiomer, the reaction Table 1 Pd-catalyzed allylic alkylation of 1,3-diphenyl-3-acetoxyprop-1-ene 9 using ligands 7 and 8a Entry
Ligand
Solvent
Base
% Conv. (min)b
% eec
1 2 3 4 5 6 7 8d 9
7 7 7 7 7 7 7 7 8
CH2Cl2 DMF THF Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
KOAc KOAc KOAc KOAc K2CO3 NaOAc Li2CO3 KOAc KOAc
100 100 83 25 70 100 100 100 100
21 17 23 13 23 24 31 23 23
(30) (5) (30) (30) (30) (30) (30) (30) (30)
(R) (R) (R) (R) (R) (R) (R) (R) (S)
probably proceeded through the endo-diastereoisomer A rather than through the exo-diastereoisomer B (Fig. 4(a)). Examination of the models suggests that the steric repulsion in the intermediate A between a phenyl moiety on the phosphorus atom and a phenyl group of the p-allyl moiety seems to be smaller than in B. Therefore, the greater contribution of the intermediate A could be established in the equilibrium. However, with ligand 8, which has an opposite configuration at C-3, there is a preference for the nucleophilic attack on the exo-diastereoisomer B 0 , as the predominant formation of the S-product suggests (Fig. 4(b)). This is due to the lack of steric interaction between the phenyl ring on the phosphorus atom and the phenyl group of the substrate in intermediate B 0 . Moreover, the lower enantioselectivity with diphosphinite ligands 7 and 8 than with their related diphosphite ligand 5 (Fig. 2) may be due to a decrease in the ratio of the two diastereoisomeric intermediates A to B [3d]. This can be attributed to the greater steric hindrance provided by the bulky phosphite moities. Further modifications to ligands 7 and 8 can therefore be aimed at introducing bulkier phosphinite moieties. If we compare ligands 7 and 8 with diphosphinite ligands 1, 2a, 3a and 4 (Fig. 1) reported in the literature [6], which have the same substituent in the phosphinite moiety, we find that the furanoside backbone is more effective in transferring the chirality (enantiomeric excesses up to 31%) than the pyranoside backbone (ligand 2a, null enantiomeric excess) at the same conditions. However, enantiomeric excesses are lower than those obtained with diphosphinites 1 [6a], 3a [6c] and 4 [6d] (Fig. 1). Note that ligands 7 and 8 showed much higher activities than the diphosphinite ligands 1–4 reported in the literature [6]. We then applied these diphosphinite ligands 7 and 8 in the Pd-catalyzed allylic alkylation of rac-3-acetoxycyclohexene 11 (Eq. (2)), which is usually used as a model cyclic substrate. It is usually more difficult to control enantioselectivity in cyclic substrates, mainly because of the presence of less sterically syn substituents, which are thought to play a crucial role in the enantioselection observed with acyclic substrates in the corresponding Pd-allyl intermediate [1]. OAc
CH2(COOMe)2 / BSA
CH(COOMe)2
ð2Þ
[Pd(π-C3H5)Cl]2 / 7 - 8 11
12
a
0.5 mol% [Pd(p-C3H5)Cl]2, 1.1 mol% ligand, room temperature; 3 equiv of CH2(COOMe)2 and N,O-bis(trimethylsilyl)acetamide (BSA), a pinch of the corresponding base, room temperature. b Measured by 1H NMR. Reaction time in minutes shown in parentheses. c Determined by HPLC (Chiralcel OD). Absolute configuration drawn in parentheses. d L/Pd = 2.
We investigated the effect of the solvent and the ligandto-palladium ratio using the potassium acetate as a base (Table 2). In general, the allylic alkylation of substrate 11 followed the same trend as for substrate 9 but the enantiomeric excesses were lower.
E. Guimet et al. / Inorganica Chimica Acta 358 (2005) 3824–3828
O
P Ph
O +
O
O
O
O
P
P
Pd
O
O +
O P
Ph
Ph Nu-
A
Ph
B
CH(CO2Me)2
CH(CO2Me)2
(R)
O
Pd
Ph
Nu-
3827
(S)
Ph
Ph
Ph
a
O O
O O P
O
O +
Pd
O O
O
P
Ph
P Ph
O +
Pd
P
Ph Nu-
A'
Ph
B'
CH(CO2Me)2
CH(CO2Me)2
(R)
Ph Nu-
(S) Ph
Ph
Ph
b Fig. 4. Proposed diastereoisomer intermediates for the Pd-catalyzed asymmetric allylic alkylation of dimethyl malonate to rac-1,3-diphenyl-3acetoxyprop-1-ene 9 with diphosphinite ligands 7 and 8.
Table 2 Pd-catalyzed allylic alkylation of 3-acetoxycyclohexene 11 with ligands 7 and 8a Entry
Ligand
Solvent
% Conv. (min)b
% eec
1 2 3 4 5d 6
7 7 7 7 7 8
CH2Cl2 DMF THF Toluene CH2Cl2 CH2Cl2
100 100 89 67 73 89
4 6 6 6 7 8
(30) (15) (30) (30) (30) (30)
(S) (S) (S) (S) (S) (R)
a
0.5 mol% [Pd(p-C3H5)Cl]2, 1.1 mol% ligand, room temperature; 3 equiv of CH2(COOMe)2 and N,O-bis(trimethylsilyl)acetamide (BSA), a pinch of potassium acetate, room temperature. b Conversion percentage determined by GC. Reaction time in minutes shown in brackets. c Enantiomeric excesses determined by GC (F/S-b-Cyclodex). Absolute configuration drawn in parentheses. d L/Pd = 2.
meric excesses of up to 31% with good activities were obtained in the Pd-catalyzed allylic alkylation of substrate rac-1,3-diphenyl-3-acetoxyprop-1-ene 9 using dimethylmalonate as nucleophile, lithium carbonate as base and dichloromethane as solvent. In this process, we also found that the absolute configuration of the carbon C-3 of the ligand controlled the configuration of the allylic alkylation product. Examination of the models for the Pd-allyl intermediate suggests that for ligand 7 there is a preference for the nucleophilic attack on the endo-diastereoisomer, while for ligand 8, which has an opposite configuration at C-3, the reaction proceeds through the exo-diastereoisomer. Further research of more selective catalysts is now in progress to exploit the fact that these carbohydrate ligands can be modified so easily. 4. Experimental
3. Conclusions 4.1. General comments We have tested the readily available diphosphinite ligands 7 and 8 in the Pd-catalyzed allylic alkylation of two substrates with different steric properties. Enantio-
All syntheses were performed using standard Schlenk techniques under argon atmosphere. Solvents were
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E. Guimet et al. / Inorganica Chimica Acta 358 (2005) 3824–3828
purified by standard procedures. Compounds 7 and 8 were prepared by previously described methods [8]. Racemics 1,3-diphenyl-3-acetoxyprop-1-ene 9 [9] and 3-acetoxycyclohexene 11 [10] were prepared as previously reported. All other reagents were used as commercially available. 1H spectra were recorded on a Varian Gemini 400 MHz spectrometer. Chemical shifts are relative to SiMe4 (1H) as internal standard. 4.1.1. Typical procedure of allylic alkylation of rac-1,3-diphenyl-3-acetoxyprop-1-ene (9) A degassed solution of [PdCl(g3-C3H5)]2 (1.8 mg, 0.005 mmol) and the diphosphinite ligand (0.011 mmol) in dichloromethane (0.5 mL) was stirred for 30 min. Subsequently, a solution of rac-9 (126 mg, 0.5 mmol) in dichloromethane (1.5 mL), dimethyl malonate (171 lL, 1.5 mmol), N,O-bis(trimethylsilyl)-acetamide (370 lL, 1.5 mmol) and a pinch of corresponding base was added. The reaction mixture was stirred at room temperature. After 5 min, the reaction mixture was diluted with Et2O (5 mL) and a saturated NH4Cl (aq) (25 mL) was added. The mixture was extracted with Et2O (3 · 10 mL) and the extract dried over MgSO4. The solvent was removed and conversion was measured by 1H NMR. To determine the ee by HPLC (Chiralcel OD, 0.5% 2-propanol/hexane, flow 0.5 mL/min), a sample was filtered over basic alumina using dichloromethane as the eluent. 4.1.2. Typical procedure of allylic alkylation of rac-3-acetoxycyclohexene (11) A degassed solution of [PdCl(g3-C3H5)]2 (1.8 mg, 0.005 mmol) and the diphosphinite ligand (0.011 mmol) in dichloromethane (0.5 mL) was stirred for 30 min. A solution of rac-11 (70 mg, 0.5 mmol) in dichloromethane (1.5 mL), dimethyl malonate (171 lL, 1.5 mmol), N,Obis(trimethylsilyl)-acetamide (370 lL, 1.5 mmol) and a pinch of KOAc was then added. The reaction mixture was stirred at room temperature. After 30 min, the reaction mixture was diluted with Et2O (5 mL) and a saturated NH4Cl (aq) (25 mL) was added. The mixture was extracted with Et2O (3 · 10 mL) and the extract dried over MgSO4. Conversion and enantiomeric excess was determined by GC using a FS-Cyclodex b-I/P (25 m column, internal diameter 0.2 mm and film thickness 0.33 mm).
Acknowledgment We thank the Spanish Ministerio de Educacio´n, Cultura y Deporte for their financial support (BQU20010656).
References [1] For recent reviews, see: (a) J. Tsuji, Palladium Reagents and Catalysis, Innovations in Organic Synthesis, Wiley, New York, 1995; (b) B.M. Trost, D.L. van Vranken, Chem. Rev. 96 (1996) 395; (c) M. Johannsen, K.A. Jorgensen, Chem. Rev. 98 (1998) 1689; (d) A. Pfaltz, M. Lautens, in: E.N. Jacobsen, A. Pfaltz, H. Yamamoto (Eds.), Comprehensive Asymmetric Catalysis, vol. 2, Springer, Berlin, 1999 (Chapter 24); (e) B.M. Trost, M.L. Crawley, Chem. Rev. 103 (2003) 2921. [2] A.M. Masdeu-Bulto´, M. Die´guez, E. Martin, M. Go´mez, Coord. Chem. Rev. 242 (2003) 159, and references therein. [3] See for example: (a) B.M. Trost, Acc. Chem. Res. 29 (1996) 355; (b) Y.Y. Yan, T.V. RajanBabu, Org. Lett. 2 (2000) 199; (c) M. Die´guez, S. Jansat, M. Go´mez, A. Ruiz, G. Muller, C. Claver, Chem. Commun. (2001) 1132; (d) O. Pa`mies, G.P.F. van Strijdonck, M. Die´guez, S. Deerenberg, G. Net, A. Ruiz, C. Claver, P.C.J. Kamer, P.W.N.M. van Leeuwen, J. Org. Chem. 66 (2001) 8867; (e) J.H. Xie, H.F. Duan, B.M. Fan, X. Cheng, L.X. Wang, Q.L. Zhou, Adv. Synth. Catal. 346 (2004) 625; (f) X. Chen, R. Guo, Y. Li, G. Chen, C.H. Yeung, A.S.C. Chan, Tetrahedron: Asymmetry 15 (2004) 213; (g) M. Die´guez, O. Pa`mies, C. Claver, J. Org. Chem. 70 (2005) 3363; (h) M. Die´guez, O. Pa`mies, C. Claver, Adv. Synth. Catal., in press. [4] See for example: (a) A. Pfaltz, Acc. Chem. Res. 26 (1993) 339; (b) U. Leutenegger, G. Umbricht, C. Fahrni, P. van Matt, A. Pfaltz, Tetrahedron 48 (1992) 2143; (c) P.G. Andersson, A. Harden, D. Tan˜er, P.O. Norrby, Chem. Eur. J. 1 (1995) 12; (d) M.A. Perica`s, C. Puigjaner, A. Riera, A. Vidal-Ferran, M. Go´mez, F. Jime´nez, G. Muller, M. Rocamora, Chem. Eur. J. 8 (2002) 4164. [5] (a) S. Jansat, M. Go´mez, G. Muller, M. Die´guez, A. Aghmiz, C. Claver, A.M. Masdeu-Bulto´, L. Flores-Santos, E. Martı´n, M.A. Maestro, J. Mahı´a, Tetrahedron: Asymmetry 12 (2001) 1469; (b) N. Khiar, C.S. Arau´jo, E. Alvarez, I. Ferna´ndez, Tetrahedron Lett. 44 (2003) 3401. [6] (a) D. Seebach, E. Devaquet, A. Ernst, M. Hayakawa, F.N.M. Ku¨hnle, W.B. Schweizer, B. Weber, Helv. Chim. Acta 78 (1995) 1636; (b) N. Nomura, Y.C. Mermet-Bouvier, T.V. RajanBabu, Synlett (1996) 745; (c) D.S. Clyne, Y.C. Mermet-Bouvier, N. Nomura, T.V. Rajan Babu, J. Org. Chem. 64 (1999) 7601; (d) A. Zhang, Y. Feng, B. Jiang, Tetrahedron: Aymmetry 11 (2000) 3123. [7] (a) M. Die´guez, O. Pa`mies, C. Claver, Chem. Rev. 104 (2004) 3189; (b) M. Die´guez, O. Pa`mies, A. Ruiz, Y. Diaz, S. Castillo´n, C. Claver, Coord. Chem. Rev. 248 (2004) 2165; (c) O. Pa`mies, M. Die´guez, A. Ruiz, C. Claver, Chem. Today (2004) 12. [8] E. Guimet, M. Die´guez, A. Ruiz, C. Claver, Tetrahedron: Asymmetry 15 (2004) 2247. [9] P.R. Auburn, P.B. Mackenzie, B. Bosnich, J. Am. Chem. Soc. 107 (1985) 2033. [10] C. Jia, P. Mu¨ller, H. Mimoun, J. Mol. Catal. A: Chem. 101 (1995) 127.
Pd-catalyzed asymmetric allylic alkylation using furanoside diphosphinite ligands Eugeni Guimet, Montserrat Die´guez *, Aurora Ruiz, Carmen Claver Departament de Quı´mica Fı´sica i Inorga`nica, Universitat Rovira i Virgili, C/MarcelÆlı´ Domingo s/n, 43007 Tarragona, Spain Received 31 March 2005; accepted 11 June 2005 Available online 1 August 2005
Abstract We have tested furanoside diphosphinite ligands 7 and 8, derived from inexpensive D-(+)-xylose, in the Pd-catalyzed allylic alkylation of two substrates with different steric properties. Enantiomeric excesses of up to 31% with good activities were obtained in the Pd-catalyzed allylic alkylation of substrate rac-1,3-diphenyl-3-acetoxyprop-1-ene 9 with dimethylmalonate as nucleophile. Our results show that the absolute configuration at carbon C-3 of the carbohydrate backbone controlled the sense of enantioselectivity. Models for asymmetric induction are discussed based on the absolute stereochemistry of the product. 2005 Elsevier B.V. All rights reserved. Keywords: Palladium; Diphosphinite; Furanoside ligands; Allylic alkylation; Asymmetric catalysis
1. Introduction Palladium-catalyzed allylic alkylation is a useful synthetic method for the formation of carbon–carbon bonds [1]. The selection of chiral ligands for highly enantioselective allylic substitution has focused on the use of mixed bidentate donor ligands such as phosphorus– nitrogen, phosphorus–sulfur and sulfur–nitrogen [1,2]. The efficiency of this type of hard–soft heterodonor ligands has been attributed to the different electronic effects of the donor atoms. However, though to a lesser extent, homodonor ligands (such as P–P [1b,3], N–N [4] and S–S [2,5]) have also demonstrated their potential utility in this process, mainly based on the chiral discrimination induced by the C2 or C1 backbones symmetry. The early success of C2-symmetric diphosphine ligands in asymmetric hydrogenations led to their direct application in the asymmetric allylic alkylation reaction, where *
Corresponding author. Fax: +34 977559563. E-mail addresses: [email protected], dieguez@quimica. urv.es (M. Die´guez). 0020-1693/$ - see front matter 2005 Elsevier B.V. All rights reserved. doi:10.1016/j.ica.2005.06.004
good-to-excellent results were obtained by choosing the appropriate substrate or palladium catalysts. Unlike diphosphines, diphosphinites have been less well developed as ligands in this type of reaction [6]. In 1995, Seebach and coworkers [6a] first prepared C2-symmetric diphosphinite 1 from TADDOL, tested it in the asymmetric allylic substitution and obtained ee of up to 76% ee (Fig. 1). Subsequently, RajanBabu and coworkers [6b] reported the use of an extensive family of pyranoside diphosphinite ligands 2 that provided low-to-moderate enantioselectivity (ees up to 59%) (Fig. 1). These ligands contained substituents with different electronic and steric properties in the aromatic ring of the phosphorus atom. The results of these authors indicate an unprecedented electronic effect. Electron-withdrawing and electron-rich diphosphinite ligands therefore lead to products with opposite stereochemistry. Sterically bulky substituents have the same effect as electron-rich ones. Moreover, diphenylphosphinite derivative gave 0% ee. In 1999, RajanBabu and coworkers prepared a series of C2symmetric diphosphinites derived from tartaric acid and binaphthol and systematically studied the effect of the
E. Guimet et al. / Inorganica Chimica Acta 358 (2005) 3824–3828
Ph Ph O
OPPh2
O
OPPh2
Ph
O O R2PO
O OPh R2PO
Ph Ph 1
2
2 a b c d e f g h i
Me2N Bn Ph2PO
3825
R
%ee
Ph 3,5-bis-TMS-C6H3 3,5-bis-t-Bu-4-OMe-C6H2 3,5-bis-CF3-C6H3 4-F-C6H4 3,5-bis-F-C6H3 4-CF3-C6H4 Et Cy
0 16 (R ) 25 (R ) 39 (R ) 17 (S ) 41 (S ) 55 (S ) 18 (R ) 59 (R )
OPPh2 Bn NMe2
OPR2
R2PO 3a 3i
4
Fig. 1. Diphosphinite ligands 1–4 previously used in Pd-catalyzed asymmetric allylic alkylation of diethyl malonate to 1,3-diphenylprop-2-enyl acetate.
ligand backbone and electronic and steric properties of the phosphinite moieties in this reaction [6c]. The electronic effects with these ligands were similar to those with ligands 2. Diphosphinite 3 (BINAPO), based on diphenylphosphinite-(3a) and cyclohexenylphosphinite-(R)binaphthol (3i), gave the best enantioselectivities (63% (R) and 66% (S), respectively) (Fig. 1). In 2000, Jiang and coworkers reported the last example of diphosphinite ligands applied to this process. Enantioselectivities of up to 86% were obtained in the Pd-catalyzed asymmetric allylic alkylation of diethyl malonate to 1,3-diphenylprop-2-enyl acetate with ligand 4 [6d] (Fig. 1). Following our interest in carbohydrates as an inexpensive and highly modular chiral source for preparing ligands [7], and encouraged by the promising results with the above diphosphinite ligands and the success of furanoside diphosphite ligands [3c,3d,3h] 5 and 6 (Fig. 2) in this reaction, in this paper we report the use of furanoside diphosphinite ligands 7 and 8 in the Pdcatalyzed enantioselective asymmetric allylic alkylation (Fig. 3). These ligands are easily prepared in a few steps from inexpensive D-(+)-xylose [8] and have an opposite
O
O P O
O O
P OO O
O
O CH3 P P O OO
configuration at C-3 of the carbohydrate backbone, whose effect in the catalytic performance can be studied. 2. Results and discussion 2.1. Asymmetric allylic alkylation reactions For initial evaluation of diphosphinite ligands 7 and 8, we chose the Pd-catalyzed allylic substitution of rac1,3-diphenyl-3-acetoxyprop-1-ene 9, which is widely used as a model substrate, with dimethyl malonate (Eq. (1)). The catalysts were generated in situ from p-allyl-palladium chloride dimer [PdCl(g3-C3H5)]2, the corresponding ligand and a catalytic amount of the corresponding base. The nucleophile was generated from dimethyl malonate in the presence of N,O-bis(trimethylsilyl)-acetamide (BSA). OAc Ph 9
[Pd(π-C3H5)Cl]2 / 7 - 8
Ph
Ph 10
ð1Þ
O O
t-Bu
O
O O
t-Bu
=
O
O
5 (90% (S))
CH(COOMe)2
CH2(COOMe)2 / BSA
Ph
O
O
t-Bu
t-Bu
6 (95% (S))
Fig. 2. Pd-catalyzed asymmetric allylic alkylation of diethyl malonate to 1,3-diphenylprop-2-enyl acetate using furanoside diphosphite ligands 5 and 6. Enantioselectivities are shown in parentheses.
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E. Guimet et al. / Inorganica Chimica Acta 358 (2005) 3824–3828
Ph Ph P O
5
P OO
4
Ph Ph
Ph Ph P O
1
O
2 3
O
O O
Ph P O Ph
7
O
8
Fig. 3. Furanoside diphosphinite ligands 7 and 8.
We studied the effect of the solvent, base and ligandto-palladium ratio using the catalyst precursor containing ligand 7 (Table 1). Our results show that both the solvent and the base affected the catalytic performance (entries 1–7). The optimum trade-off between enantioselectivities and activities was obtained when dichloromethane was used as solvent and lithium carbonate was used as base (entry 7). The enantiomeric excess obtained with tetrahydrofurane was comparable to that with dichloromethane, but activity was lower. On the other hand, dimethylformamide yielded high relative conversion, but ees were lower. In summary, good activity (TOF > 200 mol (mol h)1) and low enantioselectivity (up to 31% (R)) were obtained. Varying the ligand-to-palladium ratio showed that an excess of ligand was not needed (entries 1 vs 8). Diphosphinite ligand 8, whose configuration of carbon atom C-3 is opposite to that of ligand 7, produced the same value for enantioselectivity but in the S-product (entry 1 vs 9). These results indicate that the configuration at C-3 controls the sense of enantioselectivity. This behavior is similar to that observed in related diphosphite ligands [3d] and also suggests that the nucleophilic attack takes place trans to the phosphinite moiety attached to C-5. Since diphosphinite 7 led to the R-product as the major enantiomer, the reaction Table 1 Pd-catalyzed allylic alkylation of 1,3-diphenyl-3-acetoxyprop-1-ene 9 using ligands 7 and 8a Entry
Ligand
Solvent
Base
% Conv. (min)b
% eec
1 2 3 4 5 6 7 8d 9
7 7 7 7 7 7 7 7 8
CH2Cl2 DMF THF Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
KOAc KOAc KOAc KOAc K2CO3 NaOAc Li2CO3 KOAc KOAc
100 100 83 25 70 100 100 100 100
21 17 23 13 23 24 31 23 23
(30) (5) (30) (30) (30) (30) (30) (30) (30)
(R) (R) (R) (R) (R) (R) (R) (R) (S)
probably proceeded through the endo-diastereoisomer A rather than through the exo-diastereoisomer B (Fig. 4(a)). Examination of the models suggests that the steric repulsion in the intermediate A between a phenyl moiety on the phosphorus atom and a phenyl group of the p-allyl moiety seems to be smaller than in B. Therefore, the greater contribution of the intermediate A could be established in the equilibrium. However, with ligand 8, which has an opposite configuration at C-3, there is a preference for the nucleophilic attack on the exo-diastereoisomer B 0 , as the predominant formation of the S-product suggests (Fig. 4(b)). This is due to the lack of steric interaction between the phenyl ring on the phosphorus atom and the phenyl group of the substrate in intermediate B 0 . Moreover, the lower enantioselectivity with diphosphinite ligands 7 and 8 than with their related diphosphite ligand 5 (Fig. 2) may be due to a decrease in the ratio of the two diastereoisomeric intermediates A to B [3d]. This can be attributed to the greater steric hindrance provided by the bulky phosphite moities. Further modifications to ligands 7 and 8 can therefore be aimed at introducing bulkier phosphinite moieties. If we compare ligands 7 and 8 with diphosphinite ligands 1, 2a, 3a and 4 (Fig. 1) reported in the literature [6], which have the same substituent in the phosphinite moiety, we find that the furanoside backbone is more effective in transferring the chirality (enantiomeric excesses up to 31%) than the pyranoside backbone (ligand 2a, null enantiomeric excess) at the same conditions. However, enantiomeric excesses are lower than those obtained with diphosphinites 1 [6a], 3a [6c] and 4 [6d] (Fig. 1). Note that ligands 7 and 8 showed much higher activities than the diphosphinite ligands 1–4 reported in the literature [6]. We then applied these diphosphinite ligands 7 and 8 in the Pd-catalyzed allylic alkylation of rac-3-acetoxycyclohexene 11 (Eq. (2)), which is usually used as a model cyclic substrate. It is usually more difficult to control enantioselectivity in cyclic substrates, mainly because of the presence of less sterically syn substituents, which are thought to play a crucial role in the enantioselection observed with acyclic substrates in the corresponding Pd-allyl intermediate [1]. OAc
CH2(COOMe)2 / BSA
CH(COOMe)2
ð2Þ
[Pd(π-C3H5)Cl]2 / 7 - 8 11
12
a
0.5 mol% [Pd(p-C3H5)Cl]2, 1.1 mol% ligand, room temperature; 3 equiv of CH2(COOMe)2 and N,O-bis(trimethylsilyl)acetamide (BSA), a pinch of the corresponding base, room temperature. b Measured by 1H NMR. Reaction time in minutes shown in parentheses. c Determined by HPLC (Chiralcel OD). Absolute configuration drawn in parentheses. d L/Pd = 2.
We investigated the effect of the solvent and the ligandto-palladium ratio using the potassium acetate as a base (Table 2). In general, the allylic alkylation of substrate 11 followed the same trend as for substrate 9 but the enantiomeric excesses were lower.
E. Guimet et al. / Inorganica Chimica Acta 358 (2005) 3824–3828
O
P Ph
O +
O
O
O
O
P
P
Pd
O
O +
O P
Ph
Ph Nu-
A
Ph
B
CH(CO2Me)2
CH(CO2Me)2
(R)
O
Pd
Ph
Nu-
3827
(S)
Ph
Ph
Ph
a
O O
O O P
O
O +
Pd
O O
O
P
Ph
P Ph
O +
Pd
P
Ph Nu-
A'
Ph
B'
CH(CO2Me)2
CH(CO2Me)2
(R)
Ph Nu-
(S) Ph
Ph
Ph
b Fig. 4. Proposed diastereoisomer intermediates for the Pd-catalyzed asymmetric allylic alkylation of dimethyl malonate to rac-1,3-diphenyl-3acetoxyprop-1-ene 9 with diphosphinite ligands 7 and 8.
Table 2 Pd-catalyzed allylic alkylation of 3-acetoxycyclohexene 11 with ligands 7 and 8a Entry
Ligand
Solvent
% Conv. (min)b
% eec
1 2 3 4 5d 6
7 7 7 7 7 8
CH2Cl2 DMF THF Toluene CH2Cl2 CH2Cl2
100 100 89 67 73 89
4 6 6 6 7 8
(30) (15) (30) (30) (30) (30)
(S) (S) (S) (S) (S) (R)
a
0.5 mol% [Pd(p-C3H5)Cl]2, 1.1 mol% ligand, room temperature; 3 equiv of CH2(COOMe)2 and N,O-bis(trimethylsilyl)acetamide (BSA), a pinch of potassium acetate, room temperature. b Conversion percentage determined by GC. Reaction time in minutes shown in brackets. c Enantiomeric excesses determined by GC (F/S-b-Cyclodex). Absolute configuration drawn in parentheses. d L/Pd = 2.
meric excesses of up to 31% with good activities were obtained in the Pd-catalyzed allylic alkylation of substrate rac-1,3-diphenyl-3-acetoxyprop-1-ene 9 using dimethylmalonate as nucleophile, lithium carbonate as base and dichloromethane as solvent. In this process, we also found that the absolute configuration of the carbon C-3 of the ligand controlled the configuration of the allylic alkylation product. Examination of the models for the Pd-allyl intermediate suggests that for ligand 7 there is a preference for the nucleophilic attack on the endo-diastereoisomer, while for ligand 8, which has an opposite configuration at C-3, the reaction proceeds through the exo-diastereoisomer. Further research of more selective catalysts is now in progress to exploit the fact that these carbohydrate ligands can be modified so easily. 4. Experimental
3. Conclusions 4.1. General comments We have tested the readily available diphosphinite ligands 7 and 8 in the Pd-catalyzed allylic alkylation of two substrates with different steric properties. Enantio-
All syntheses were performed using standard Schlenk techniques under argon atmosphere. Solvents were
3828
E. Guimet et al. / Inorganica Chimica Acta 358 (2005) 3824–3828
purified by standard procedures. Compounds 7 and 8 were prepared by previously described methods [8]. Racemics 1,3-diphenyl-3-acetoxyprop-1-ene 9 [9] and 3-acetoxycyclohexene 11 [10] were prepared as previously reported. All other reagents were used as commercially available. 1H spectra were recorded on a Varian Gemini 400 MHz spectrometer. Chemical shifts are relative to SiMe4 (1H) as internal standard. 4.1.1. Typical procedure of allylic alkylation of rac-1,3-diphenyl-3-acetoxyprop-1-ene (9) A degassed solution of [PdCl(g3-C3H5)]2 (1.8 mg, 0.005 mmol) and the diphosphinite ligand (0.011 mmol) in dichloromethane (0.5 mL) was stirred for 30 min. Subsequently, a solution of rac-9 (126 mg, 0.5 mmol) in dichloromethane (1.5 mL), dimethyl malonate (171 lL, 1.5 mmol), N,O-bis(trimethylsilyl)-acetamide (370 lL, 1.5 mmol) and a pinch of corresponding base was added. The reaction mixture was stirred at room temperature. After 5 min, the reaction mixture was diluted with Et2O (5 mL) and a saturated NH4Cl (aq) (25 mL) was added. The mixture was extracted with Et2O (3 · 10 mL) and the extract dried over MgSO4. The solvent was removed and conversion was measured by 1H NMR. To determine the ee by HPLC (Chiralcel OD, 0.5% 2-propanol/hexane, flow 0.5 mL/min), a sample was filtered over basic alumina using dichloromethane as the eluent. 4.1.2. Typical procedure of allylic alkylation of rac-3-acetoxycyclohexene (11) A degassed solution of [PdCl(g3-C3H5)]2 (1.8 mg, 0.005 mmol) and the diphosphinite ligand (0.011 mmol) in dichloromethane (0.5 mL) was stirred for 30 min. A solution of rac-11 (70 mg, 0.5 mmol) in dichloromethane (1.5 mL), dimethyl malonate (171 lL, 1.5 mmol), N,Obis(trimethylsilyl)-acetamide (370 lL, 1.5 mmol) and a pinch of KOAc was then added. The reaction mixture was stirred at room temperature. After 30 min, the reaction mixture was diluted with Et2O (5 mL) and a saturated NH4Cl (aq) (25 mL) was added. The mixture was extracted with Et2O (3 · 10 mL) and the extract dried over MgSO4. Conversion and enantiomeric excess was determined by GC using a FS-Cyclodex b-I/P (25 m column, internal diameter 0.2 mm and film thickness 0.33 mm).
Acknowledgment We thank the Spanish Ministerio de Educacio´n, Cultura y Deporte for their financial support (BQU20010656).
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