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Arylid-Box: A new family of chiral bis-oxazoline ligands for metal mediated catalytic enantioselective synthesis
Inorganic Chemistry Communications 9 (2006) 823–826 www.elsevier.com/locate/inoche
Arylid-Box: A new family of chiral bis-oxazoline ligands for metal mediated catalytic enantioselective synthesis Elisabete da Palma Carreiro, Serghei Chercheja, Nuno M.M. Moura, Cla´udia S.C. Gertrudes, Anthony J. Burke * Departamento de Quı´mica and Centro de Quı´mica de E´vora,Universidade de E´vora, Rua Roma˜o Romalho 59, 7000 E´vora, Portugal Received 26 April 2006; accepted 29 April 2006 Available online 13 May 2006
Abstract A new family of chiral non-racemic bis-oxazolines containing an arylidene bridging unit (and appropriately termed Arylid-Box) have been prepared from malonate esters in satisfactory yields. These ligands have been screened in the Cu(I) catalysed enantioselective cyclopropanation of styrene and a-methylstyrene with ethyl diazoacetate giving enantioselectivities of up to 89% ee. The tBu substituted ligands (2d, 3d and 4d) gave the best ees. Our experiments seemed to indicate that there was no overall dependency of the reaction stereoselectivity or efficiency on reaction conditions, like, solvent, counter ion or temperature. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Asymmetric catalysis; Enantioselectivity; Bis-oxazoline; Cyclopropanation; DFT study
Over the past 15 years chiral non-racemic C2 symmetric bidentate bis-oxazoline ligands in conjunction with appropriate metals [1] have been shown to be very useful catalysts demonstrating good to excellent enantioselectivities in a number of catalytic asymmetric reactions, like: olefin cyclopropanations [2], aziridinations [2b,3], hydrosilylations [4], transfer hydrogenations [5], lewis acid catalysed cycloadditions [6], aldol reactions [7], carbonyl 1,2 and 1,4 additions [8], additions to imines [9] and Pd asymmetric allylic alkylations [10], etc. A current goal, one which has been taken up by Evans’ group [11], is the investigation of bis-oxazoline ligands which can be electronically or stereochemically tuned to meet the requirements of the reaction and the substrates under study. Indeed, Nishiyama and co-workers [12] have looked at the influence of remote electronic control in asymmetric cyclopropanations with chiral Ru-Pybox catalysts and found that the enantioselectivity could be tuned with appropriate electron-withdraw-
*
Corresponding author. Tel.: +351 266745310; fax: +351 266744971. E-mail address: [email protected] (A.J. Burke).
1387-7003/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.inoche.2006.04.031
ing groups. Evans and co-workers [13] recently investigated the contribution of electronic effects on the reaction enantioselectivity of a series of Cu(II) catalysed Hetero-Diels-Alder reactions by incorporating both electron donating and withdrawing groups in the para position of both phenyl rings of their Box ligand. They found that the ee remained unchanged when a para-hydrogen was replaced by a methoxyl group and dropped very slightly when substituted by a Cl atom. However, given the break in the delocalisation between the aryl ring and the oxazoline nitrogen, this result would be expected. More recently, Lee and Pagenkopf [14] used a series of other derivatives of Evans’ Box ligand which contained electron-donating groups in both the ortho- and meta-positions and gave in some cases better ees and yields for the copper catalysed asymmetric aldol addition of dienolsilane to pyruvate and glyoxylate esters. This was presumably due to stereochemical effects. We recently introduced a new family of C2 symmetric bis-oxazoline ligands 1a–d [15] (Fig. 1, which were called Isbut-Box) bearing an isobutylene bridge between the oxazoline rings which were screened in Cu(I) catalysed
824
E.P. Carreiro et al. / Inorganic Chemistry Communications 9 (2006) 823–826
O
O N R
O
O
N
N
N R
1a,b
second generation family of such ligands containing an arylidene bridge (Arylid-Box) with a variety of para-substituted phenyl rings and our attempts to electronically tune the resulting catalyst. We have applied our previously established method for the synthesis of the IsBut-Box family [15] of ligands to the synthesis of the Arylid-Box ligands 2a–d, 3c, 3d, 4c and 4d (Fig. 2) [16]. Ligands 2a–d, 3c, 3d, 4c and 4d were prepared in satisfactory yields starting from commercially available diethyl benzylidenemalonate 5a (Scheme 1) or p-methoxybenzylidenemalonate 5b (Scheme 2) or p-chlorobenzylidenemalonate 5c (Scheme 2). We decided to evaluate the efficacy and selectivity of this new family of Box ligands for catalytic asymmetric synthesis by screening them in the Cu(I) catalysed asymmetric cyclopropanation of styrene and a-methylstyrene with ethyl diazoacetate (Scheme 3 and Tables 1 and 2). Besides looking at the effect of the oxazoline structure on the reaction efficiency and stereoselectivity, we also looked at the effect of the substrate structure, solvent, temperature, counter ion and quantity of catalyst on these parameters. Both [Cu(CH3CN)4]PF6 and Cu(OTf)2 were used as the precatalysts. The reactions using [Cu(CH3CN)4]PF6 were performed using Andersson’s method [17] whilst those using Cu(OTf)2 according to our previously reported method where the Cu(I) species was generated in situ [15].
R
R
1c, d
i
t
a: R = Pr, b: R = Bn, c: R = Ph d: R = Bu
Fig. 1. Isbut-Box ligands
asymmetric olefin cyclopropanation reactions giving moderate ees. In this paper we wish to report our preliminary results on the synthesis and catalytic asymmetric reactions of a
X
O
O N R
X
O
O
N
N
R 2a X = H, R = i Pr 2b X = H, R = Bn
N
R R 2c X = H, R = Ph 2d X = H, R = t Bu 3c X = Cl, R = Ph 3d X = Cl, R = t Bu 4c X = OMe, R = Ph 4d X = OMe, R =t Bu
Fig. 2. Arylid-Box ligands.
EtO
i
OEt O
Cl
O
O
5a
OH
ii
Cl O
R
6a (45% 2 steps)
H N
H N
OH
iii
O
O N
O O R 7a R = iPr (28%) 7b R = Bn (43%)
N
R 2a (74%) R 2b (64%)
Scheme 1. (i) (a) NaOH, EtOH, (b) (COCl)2, DMF, CH2Cl2, 0 °C; (ii) (+)-phenylalaninol or (L)-valinol (2 equiv.), NEt3, CH2Cl2; (iii) CH3SO2Cl (2.5 equiv.), NEt3 (6 equiv.), CH2Cl2.
X
X
MeO
i
OMe O
Cl
O
Cl O
X ii
O
X 5b X=OMe 5c X=Cl iii
6b X=OMe (52% 2 steps) 6c X=Cl (45% 2 steps) O
O N
N
OH
R
H N
OH
H N O
O
R
7c X = H, R = Ph (41%) 7d X = H, R = t Bu (50%) 7e X = Cl, R = Ph (46%) 7f X = Cl, R = t Bu (33%) 7g X = OMe, R =Ph (33%) 7h X = OMe, R = t Bu (40%)
R R 2c X = H, R = Ph (54%) 2d X = H, R = t Bu (67%) 3c X = Cl, R = Ph (51%) 3d X = Cl, R = t Bu (60%) 4c X = OMe, R = Ph (37%) 4d X = OMe, R = t Bu (59%)
Scheme 2. (i) (a) NaOH, EtOH, (b) (COCl)2, DMF, CH2Cl2, 0 °C; (ii) (D)-phenylglycinol (2 equiv.) or (L)-tert-leucinol, NEt3, CH2Cl2; (iii) CH3SO2Cl (2.5 equiv.), NEt3 (6 equiv.), CH2Cl2.
E.P. Carreiro et al. / Inorganic Chemistry Communications 9 (2006) 823–826 R N2
CO2Et
825
R CO2Et
+
Cu(I), L*
R
CO2Et
R = H, Me Scheme 3. Cu(I) catalysed cyclopropantion of styrene and a-methylstyrene.
Table 1 Catalytic asymmetric cyclopropanation of styrenea Entry
Substrate
Cu(I) source (mol%)
Ligand (mol%)
Solvent
Yieldb (%)
trans:cisb
trans (% ee)c
cis (% ee)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 16 17 18
Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene
Cu(OTf)2 (2) Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 (1) [Cu(CH3CN)4]PF6 (2) Cu(OTf)2 (2) Cu(OTf)2 (2) Cu(OTf)2 (2) Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 (2) [Cu(CH3CN)4]PF6 (2) Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 (1) [Cu(CH3CN)4]PF6 (2) Cu(I)(CH3CN)4PF6 (2) [Cu(CH3CN)4]PF6 (2) [Cu(CH3CN)4]PF6 (2) [Cu(CH3CN)4]PF6 (2) Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 (1) [Cu(CH3CN)4]PF6 (2)
2a (2.2) 2a (2.2) 2a (1.1) 2a (2.2) 2b (2.2) 2b (2.2) 2b (2.2) 2c (2.2) 2c (2.2) 2c (2.2) 2d (2.2) 2d (1.1) 2d (2.2) 3c (2.2) 3d (2.2) 3d (2.2) 3d (2.2) 4c (2.2) 4c (1.1) 4d (2.2)
CH2Cl2 Toluene CH2Cl2 CH2Cl2 CH2Cl2 Toluene CH2Cl2 Toluene CH2Cl2 Toluene Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene Toluened CH2Cl2 CH2Cl2 CH2Cl2
19 86 60 39 48 37 35 25 30 20 18 19 81 35 20 38 36 17 39 46
57:43 57:43 64:36 62:38 61:39 62:38 60:40 65:35 65:35 65:35 55:45 56:44 62:38 65:35 61:39 68:32 65:35 70:30 64:36 62:38
73 74 57 61 54 43 49 47 57 54 58 78 84 61 86 89 87 61 48 83
77 77 51 58 57 43 35 39 45 47 49 69 77 53 78 76 78 69 41 75
a
Ethyl diazoacetate, olefin [10 equiv. using [Cu(CH3CN)4]PF6 and 3.34 equiv. using Cu(OTf)2], Cu catalyst and ligand, r.t. After removal of the chiral complex by column chromatography the yield and the ratio of the cis- and trans-isomers were determined by GC analysis of the styrene – product mixture. c The % ee was determined by chiral GC analysis (on a cyclodex-B capillary column). d Conducted at 40 °C. b
Table 2 Catalytic asymmetric cyclopropanation of a-methylstyrenea Entry
Substrate
Cu(I) source (mol%)
Ligand (mol%)
Solvent
Yieldb (%)
trans:cisb
trans (% ee)c
cis (% ee)c
1 2 3 4 5 6
a-Methylstyrene a-Methylstyrene a-Methylstyrene a-Methylstyrene a-Methylstyrene a-Methylstyrene
Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6
2d (2.2) 2d (2.2) 3c (2.2) 3d (2.2) 4c (2.2) 4d (2.2)
Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
30 32 52 13 23 32
56:44 46:54 53:47 38:62 49:51 51:49
44 86 49 85 41 84
37 77 48 79 42 76
(2) (2) (2) (2) (2)
a
Ethyl diazoacetate, olefin [10 equiv. using [Cu(CH3CN)4]PF6 and 3.34 equiv. using Cu(OTf)2], Cu catalyst and ligand, r.t. After removal of the chiral complex by column chromatography the yield and the ratio of the cis- and trans-isomers were determined by GC analysis of the styrene – product mixture. c The % ee was determined by chiral GC analysis (on a cyclodex-B capillary column). b
We found that the tBu-substituted ligands 2d–4d gave the best ees (Table 1, entries 13, 15 and 16) and (Table 2, entry 4) for both styrene and a-methylstyrene. The type of solvent had very little effect on the ee when such Cu(I) catalysts were used, and there seemed to be no temperature effect on the ee (compare entry 16 with 17, Table
1). Although our studies were not extensive, with respect to the counter ions used (PF6 and OTf ) there was no overall best counter ion, which gave the highest ee’s, de’s or yields right across the board. The diastereoselectivities were moderate in all cases, a maximum of 40% was obtained when styrene was used as substrate (Table 1,
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E.P. Carreiro et al. / Inorganic Chemistry Communications 9 (2006) 823–826
entry 16) and in all cases, apart from two reactions (Table 2, entries 2 and 4), the trans-isomer was the major isomer. The yields were generally moderate, apart from the cyclopropanation of styrene using ligands 2a and 2d (Table 1, entries 2 and 13), which gave yields of 86% and 81%, respectively. There was no temperature effect on the yield, either (compare entry 16 with 17, Table 1). This might be due to stabilisation of the metal-carbene intermediate by the electron-donating arylidene Box ligands, thus making it less susceptible to electrophilic attack. We observed also, that the catalyst loading had a discernable effect on the reaction enantioselectivity, with a catalyst loading of 2 mol% giving superior ees to a loading of 1 mol% (compare entry 3 with 4 and entry 12 with 13, Table 1). In the case of ligand 2d, the diastereoselectivity was slightly better using a catalyst loading of 2 mol%. We have ruled out the possibility that the Arylid-Box ligands suffer cyclopropanation with diazoacetate by conducting appropriate experiments [18]. Although the electron donating and withdrawing groups are at quite a distance from the oxazoline ring nitrogen, we expected at least some correlation between the type of para-substituent and the stereoselectivities and yields, which we did not find. To try and rationalise this result we conducted a DFT quantum chemical study on the Cu(I)-2d complex using GAMESS-US with the 631G* basis-set for C, N, O and H (or for the lightest atoms) [19]. This calculation predicted that the phenyl ring should be twisted out of the plane by 28.6° [20], thus supporting the conjecture that the substituent present in the ortho position of the back-bone benzene ring has little or no effect on such factors as stereoselectivity or reaction efficiency owing to poor electronic communication between the benzene ortho substituent and the oxazoline nitrogens. In summary, we have synthesised an interesting ligand system with unusual structural features and electronic properties with much potential for transition metal mediated catalytic asymmetric synthesis. We are currently evaluating these ligands in other transition metal promoted catalytic asymmetric reactions and immobilising such ligands to appropriate solid supports.
Acknowledgements We thank the Fundac¸a˜o para a Cieˆncia e a Tecnologia and the Programma Opercional para Cieˆncia Tecnologia e Inovac¸a˜o (POCTI) for generous financial support in the form of a research grant (POCTI/QUI/38797/2001), including grants to (SC and EPC), which was partly funded by the European Community fund FEDER. Mrs. Ana Isabel Rodrigues from the Instituto Nacional de Engenharia, Tecnologia e Inovac¸a˜o and the personnel of the NMR service at C.A.C.T.I (University of Vigo, Spain) are acknowledged for NMR spectra.
References [1] (a) For reviews on chiral bis-oxazolines in asymmetric catalytic synthesis, see: A.K. Ghosh, P. Mathivanan, J. Cappiello, Tetrahedron: Asymm. 9 (1998) 1; (b) F. Fache, E. Schulz, M.L. Tommasino, M. Lemaire, Chem. Rev. 100 (2000) 2159; (c) A. McManus, P.J. Guiry, Chem. Rev. 104 (2004) 4151. [2] (a) Representative examples include: R.E. Lowenthal, A.Masamune. Abiko, Tetrahedron Lett. 31 (1990) 6005; (b) D.A. Evans, K.A. Woerpel, M.M. Hinman, M.M. Faul, J. Am. Chem. Soc. 113 (1991) 726. [3] (a) Representative examples include: D.A. Evans, M.M. Faul, M.T. Bilodeau, B.A. Anderson, D.M. Barnes, J. Am. Chem. Soc. 115 (1993) 5328–5329; (b) F. Fache, E. Schulz, M.L. Tommasino, M. Lemaire, Chem. Rev. 100 (2000) 2159. [4] (a) Representative examples include: S.-g. Lee, C.W. Lim, C.E. Song, I.O. Kim, C.-H.J. Jun, Tetrahedron: Asymm. 8 (1997) 2927; (b) H. Nishiyama, H. Sakaguchi, T. Nakamura, M. Horihata, M. Kondo, K. Itoh, Organometallics 8 (1989) 846. [5] (a) Representative examples include: Y. Jiang, Q. Jiang, X. Zhang, J. Am. Chem. Soc. 20 (1998) 3817; (b) N. Debono, M. Besson, C. Pinel, L. Djakovitch, Tetrahedron Lett. 45 (2004) 2235. [6] (a) Representative examples include: D.A. Evans, J.S. Johnson, C.S. Burgey, K.R. Campos, Tetrahedron Lett. 40 (1999) 2879, and references cited therein; (b) S-g. Lee, C.W. Lim, C.E. Song, I.O. Kim, C.-H.J. Jun, Tetrahedron: Asymm. 8 (1997) 2927. [7] (a) Representative examples include: D.A. Evans, J.A. Murry, M.C. Kozlowski, J. Am. Chem. Soc. 118 (1996) 5814; (b) D.A. Evans, M.C. Kozlowski, J.A. Murry, C.S. Burgey, K.R. Campos, B.T. Connell, R.J. Staples, J. Am. Chem. Soc. 121 (1999) 669. [8] (a) Representative examples include: Y. Takemoto, S. Kuraoka, N. Hamaue, K. Aoe, H. Hiramatsu, C. Iwata, Tetrahedron 52 (1996) 14177; (b) D.A. Evans, T. Rovis, M.C. Kozlowski, C.W. Downey, J.S. Tedrow, J. Am. Chem. Soc. 122 (2000) 9134; (c) X. Li, L.-F. Cun, L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang, Tetrahedron: Asymm. 14 (2003) 3819. [9] (a) Representative examples include: S.E. Denmark, N. Nakajima, O.J.-C. Nicaise, J. Am. Chem. Soc. 116 (1994) 8797; (b) J.N. Rosa, A.G. Santos, C.A.M. Afonso, J. Mol. Catal. A: Chem. 214 (2004) 161–165. [10] (a) Representative examples include: D. Mu¨ller, G.C. Umbricht, B. Weber, A. Pfaltz, Helv. Chim. Acta 74 (1991) 232; (b) M. Go´mez, S. Jansat, G. Muller, M.A. Maestro, J. Mahı´a, Organometallics 21 (2002) 1077–1087. [11] J.S. Johnson, D.A. Evans, Acc. Chem. Res. 33 (2000) 325. [12] S.-B. Park, K. Murata, H. Matsumoto, H. Nishiyama, Tetrahedron: Asymm. 6 (1995) 2487. [13] D.A. Evans, J.S. Johnson, E.J. Olhava, J. Am. Chem. Soc. 122 (2000) 1635. [14] J.C.-D. Lee, B.L. Pagenkopf, Org. Lett. 6 (2004) 4097. [15] E.P. Carreiro, S. Chercheja, A.J. Burke, J.P. Prates Ramalho, A.I. Rodrigues, J. Mol. Catal. A: Chem. 236 (2005) 38–45. [16] All ligands gave satisfactory spectroscopic and elemental analysis or equivalent. [17] A.V. Bedekar, E.B. Koroleva, P.G. Andersson, J. Org. Chem. 62 (1997) 2518. [18] A.J. Burke, E.P. Carreiro, unpublished results. [19] M.W. Schmidt, K.K. Baldridge, J.A. Boatz, S.T. Elbert, M.S. Gordon, J.H. Jensen, S. Koseki, N. Matsunaga, K.A. Nguyen, S.J. Su, T.L. Windus, M. Dupuis, J.A. Montgomery, J. Comput. Chem. 14 (1993) 1347. [20] A.J. Burke, J.P. Prates Ramalho, unpublished results.
Arylid-Box: A new family of chiral bis-oxazoline ligands for metal mediated catalytic enantioselective synthesis Elisabete da Palma Carreiro, Serghei Chercheja, Nuno M.M. Moura, Cla´udia S.C. Gertrudes, Anthony J. Burke * Departamento de Quı´mica and Centro de Quı´mica de E´vora,Universidade de E´vora, Rua Roma˜o Romalho 59, 7000 E´vora, Portugal Received 26 April 2006; accepted 29 April 2006 Available online 13 May 2006
Abstract A new family of chiral non-racemic bis-oxazolines containing an arylidene bridging unit (and appropriately termed Arylid-Box) have been prepared from malonate esters in satisfactory yields. These ligands have been screened in the Cu(I) catalysed enantioselective cyclopropanation of styrene and a-methylstyrene with ethyl diazoacetate giving enantioselectivities of up to 89% ee. The tBu substituted ligands (2d, 3d and 4d) gave the best ees. Our experiments seemed to indicate that there was no overall dependency of the reaction stereoselectivity or efficiency on reaction conditions, like, solvent, counter ion or temperature. Ó 2006 Elsevier B.V. All rights reserved. Keywords: Asymmetric catalysis; Enantioselectivity; Bis-oxazoline; Cyclopropanation; DFT study
Over the past 15 years chiral non-racemic C2 symmetric bidentate bis-oxazoline ligands in conjunction with appropriate metals [1] have been shown to be very useful catalysts demonstrating good to excellent enantioselectivities in a number of catalytic asymmetric reactions, like: olefin cyclopropanations [2], aziridinations [2b,3], hydrosilylations [4], transfer hydrogenations [5], lewis acid catalysed cycloadditions [6], aldol reactions [7], carbonyl 1,2 and 1,4 additions [8], additions to imines [9] and Pd asymmetric allylic alkylations [10], etc. A current goal, one which has been taken up by Evans’ group [11], is the investigation of bis-oxazoline ligands which can be electronically or stereochemically tuned to meet the requirements of the reaction and the substrates under study. Indeed, Nishiyama and co-workers [12] have looked at the influence of remote electronic control in asymmetric cyclopropanations with chiral Ru-Pybox catalysts and found that the enantioselectivity could be tuned with appropriate electron-withdraw-
*
Corresponding author. Tel.: +351 266745310; fax: +351 266744971. E-mail address: [email protected] (A.J. Burke).
1387-7003/$ - see front matter Ó 2006 Elsevier B.V. All rights reserved. doi:10.1016/j.inoche.2006.04.031
ing groups. Evans and co-workers [13] recently investigated the contribution of electronic effects on the reaction enantioselectivity of a series of Cu(II) catalysed Hetero-Diels-Alder reactions by incorporating both electron donating and withdrawing groups in the para position of both phenyl rings of their Box ligand. They found that the ee remained unchanged when a para-hydrogen was replaced by a methoxyl group and dropped very slightly when substituted by a Cl atom. However, given the break in the delocalisation between the aryl ring and the oxazoline nitrogen, this result would be expected. More recently, Lee and Pagenkopf [14] used a series of other derivatives of Evans’ Box ligand which contained electron-donating groups in both the ortho- and meta-positions and gave in some cases better ees and yields for the copper catalysed asymmetric aldol addition of dienolsilane to pyruvate and glyoxylate esters. This was presumably due to stereochemical effects. We recently introduced a new family of C2 symmetric bis-oxazoline ligands 1a–d [15] (Fig. 1, which were called Isbut-Box) bearing an isobutylene bridge between the oxazoline rings which were screened in Cu(I) catalysed
824
E.P. Carreiro et al. / Inorganic Chemistry Communications 9 (2006) 823–826
O
O N R
O
O
N
N
N R
1a,b
second generation family of such ligands containing an arylidene bridge (Arylid-Box) with a variety of para-substituted phenyl rings and our attempts to electronically tune the resulting catalyst. We have applied our previously established method for the synthesis of the IsBut-Box family [15] of ligands to the synthesis of the Arylid-Box ligands 2a–d, 3c, 3d, 4c and 4d (Fig. 2) [16]. Ligands 2a–d, 3c, 3d, 4c and 4d were prepared in satisfactory yields starting from commercially available diethyl benzylidenemalonate 5a (Scheme 1) or p-methoxybenzylidenemalonate 5b (Scheme 2) or p-chlorobenzylidenemalonate 5c (Scheme 2). We decided to evaluate the efficacy and selectivity of this new family of Box ligands for catalytic asymmetric synthesis by screening them in the Cu(I) catalysed asymmetric cyclopropanation of styrene and a-methylstyrene with ethyl diazoacetate (Scheme 3 and Tables 1 and 2). Besides looking at the effect of the oxazoline structure on the reaction efficiency and stereoselectivity, we also looked at the effect of the substrate structure, solvent, temperature, counter ion and quantity of catalyst on these parameters. Both [Cu(CH3CN)4]PF6 and Cu(OTf)2 were used as the precatalysts. The reactions using [Cu(CH3CN)4]PF6 were performed using Andersson’s method [17] whilst those using Cu(OTf)2 according to our previously reported method where the Cu(I) species was generated in situ [15].
R
R
1c, d
i
t
a: R = Pr, b: R = Bn, c: R = Ph d: R = Bu
Fig. 1. Isbut-Box ligands
asymmetric olefin cyclopropanation reactions giving moderate ees. In this paper we wish to report our preliminary results on the synthesis and catalytic asymmetric reactions of a
X
O
O N R
X
O
O
N
N
R 2a X = H, R = i Pr 2b X = H, R = Bn
N
R R 2c X = H, R = Ph 2d X = H, R = t Bu 3c X = Cl, R = Ph 3d X = Cl, R = t Bu 4c X = OMe, R = Ph 4d X = OMe, R =t Bu
Fig. 2. Arylid-Box ligands.
EtO
i
OEt O
Cl
O
O
5a
OH
ii
Cl O
R
6a (45% 2 steps)
H N
H N
OH
iii
O
O N
O O R 7a R = iPr (28%) 7b R = Bn (43%)
N
R 2a (74%) R 2b (64%)
Scheme 1. (i) (a) NaOH, EtOH, (b) (COCl)2, DMF, CH2Cl2, 0 °C; (ii) (+)-phenylalaninol or (L)-valinol (2 equiv.), NEt3, CH2Cl2; (iii) CH3SO2Cl (2.5 equiv.), NEt3 (6 equiv.), CH2Cl2.
X
X
MeO
i
OMe O
Cl
O
Cl O
X ii
O
X 5b X=OMe 5c X=Cl iii
6b X=OMe (52% 2 steps) 6c X=Cl (45% 2 steps) O
O N
N
OH
R
H N
OH
H N O
O
R
7c X = H, R = Ph (41%) 7d X = H, R = t Bu (50%) 7e X = Cl, R = Ph (46%) 7f X = Cl, R = t Bu (33%) 7g X = OMe, R =Ph (33%) 7h X = OMe, R = t Bu (40%)
R R 2c X = H, R = Ph (54%) 2d X = H, R = t Bu (67%) 3c X = Cl, R = Ph (51%) 3d X = Cl, R = t Bu (60%) 4c X = OMe, R = Ph (37%) 4d X = OMe, R = t Bu (59%)
Scheme 2. (i) (a) NaOH, EtOH, (b) (COCl)2, DMF, CH2Cl2, 0 °C; (ii) (D)-phenylglycinol (2 equiv.) or (L)-tert-leucinol, NEt3, CH2Cl2; (iii) CH3SO2Cl (2.5 equiv.), NEt3 (6 equiv.), CH2Cl2.
E.P. Carreiro et al. / Inorganic Chemistry Communications 9 (2006) 823–826 R N2
CO2Et
825
R CO2Et
+
Cu(I), L*
R
CO2Et
R = H, Me Scheme 3. Cu(I) catalysed cyclopropantion of styrene and a-methylstyrene.
Table 1 Catalytic asymmetric cyclopropanation of styrenea Entry
Substrate
Cu(I) source (mol%)
Ligand (mol%)
Solvent
Yieldb (%)
trans:cisb
trans (% ee)c
cis (% ee)c
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 16 17 18
Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene Styrene
Cu(OTf)2 (2) Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 (1) [Cu(CH3CN)4]PF6 (2) Cu(OTf)2 (2) Cu(OTf)2 (2) Cu(OTf)2 (2) Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 (2) [Cu(CH3CN)4]PF6 (2) Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 (1) [Cu(CH3CN)4]PF6 (2) Cu(I)(CH3CN)4PF6 (2) [Cu(CH3CN)4]PF6 (2) [Cu(CH3CN)4]PF6 (2) [Cu(CH3CN)4]PF6 (2) Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 (1) [Cu(CH3CN)4]PF6 (2)
2a (2.2) 2a (2.2) 2a (1.1) 2a (2.2) 2b (2.2) 2b (2.2) 2b (2.2) 2c (2.2) 2c (2.2) 2c (2.2) 2d (2.2) 2d (1.1) 2d (2.2) 3c (2.2) 3d (2.2) 3d (2.2) 3d (2.2) 4c (2.2) 4c (1.1) 4d (2.2)
CH2Cl2 Toluene CH2Cl2 CH2Cl2 CH2Cl2 Toluene CH2Cl2 Toluene CH2Cl2 Toluene Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 Toluene Toluened CH2Cl2 CH2Cl2 CH2Cl2
19 86 60 39 48 37 35 25 30 20 18 19 81 35 20 38 36 17 39 46
57:43 57:43 64:36 62:38 61:39 62:38 60:40 65:35 65:35 65:35 55:45 56:44 62:38 65:35 61:39 68:32 65:35 70:30 64:36 62:38
73 74 57 61 54 43 49 47 57 54 58 78 84 61 86 89 87 61 48 83
77 77 51 58 57 43 35 39 45 47 49 69 77 53 78 76 78 69 41 75
a
Ethyl diazoacetate, olefin [10 equiv. using [Cu(CH3CN)4]PF6 and 3.34 equiv. using Cu(OTf)2], Cu catalyst and ligand, r.t. After removal of the chiral complex by column chromatography the yield and the ratio of the cis- and trans-isomers were determined by GC analysis of the styrene – product mixture. c The % ee was determined by chiral GC analysis (on a cyclodex-B capillary column). d Conducted at 40 °C. b
Table 2 Catalytic asymmetric cyclopropanation of a-methylstyrenea Entry
Substrate
Cu(I) source (mol%)
Ligand (mol%)
Solvent
Yieldb (%)
trans:cisb
trans (% ee)c
cis (% ee)c
1 2 3 4 5 6
a-Methylstyrene a-Methylstyrene a-Methylstyrene a-Methylstyrene a-Methylstyrene a-Methylstyrene
Cu(OTf)2 (2) [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6 [Cu(CH3CN)4]PF6
2d (2.2) 2d (2.2) 3c (2.2) 3d (2.2) 4c (2.2) 4d (2.2)
Toluene CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
30 32 52 13 23 32
56:44 46:54 53:47 38:62 49:51 51:49
44 86 49 85 41 84
37 77 48 79 42 76
(2) (2) (2) (2) (2)
a
Ethyl diazoacetate, olefin [10 equiv. using [Cu(CH3CN)4]PF6 and 3.34 equiv. using Cu(OTf)2], Cu catalyst and ligand, r.t. After removal of the chiral complex by column chromatography the yield and the ratio of the cis- and trans-isomers were determined by GC analysis of the styrene – product mixture. c The % ee was determined by chiral GC analysis (on a cyclodex-B capillary column). b
We found that the tBu-substituted ligands 2d–4d gave the best ees (Table 1, entries 13, 15 and 16) and (Table 2, entry 4) for both styrene and a-methylstyrene. The type of solvent had very little effect on the ee when such Cu(I) catalysts were used, and there seemed to be no temperature effect on the ee (compare entry 16 with 17, Table
1). Although our studies were not extensive, with respect to the counter ions used (PF6 and OTf ) there was no overall best counter ion, which gave the highest ee’s, de’s or yields right across the board. The diastereoselectivities were moderate in all cases, a maximum of 40% was obtained when styrene was used as substrate (Table 1,
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entry 16) and in all cases, apart from two reactions (Table 2, entries 2 and 4), the trans-isomer was the major isomer. The yields were generally moderate, apart from the cyclopropanation of styrene using ligands 2a and 2d (Table 1, entries 2 and 13), which gave yields of 86% and 81%, respectively. There was no temperature effect on the yield, either (compare entry 16 with 17, Table 1). This might be due to stabilisation of the metal-carbene intermediate by the electron-donating arylidene Box ligands, thus making it less susceptible to electrophilic attack. We observed also, that the catalyst loading had a discernable effect on the reaction enantioselectivity, with a catalyst loading of 2 mol% giving superior ees to a loading of 1 mol% (compare entry 3 with 4 and entry 12 with 13, Table 1). In the case of ligand 2d, the diastereoselectivity was slightly better using a catalyst loading of 2 mol%. We have ruled out the possibility that the Arylid-Box ligands suffer cyclopropanation with diazoacetate by conducting appropriate experiments [18]. Although the electron donating and withdrawing groups are at quite a distance from the oxazoline ring nitrogen, we expected at least some correlation between the type of para-substituent and the stereoselectivities and yields, which we did not find. To try and rationalise this result we conducted a DFT quantum chemical study on the Cu(I)-2d complex using GAMESS-US with the 631G* basis-set for C, N, O and H (or for the lightest atoms) [19]. This calculation predicted that the phenyl ring should be twisted out of the plane by 28.6° [20], thus supporting the conjecture that the substituent present in the ortho position of the back-bone benzene ring has little or no effect on such factors as stereoselectivity or reaction efficiency owing to poor electronic communication between the benzene ortho substituent and the oxazoline nitrogens. In summary, we have synthesised an interesting ligand system with unusual structural features and electronic properties with much potential for transition metal mediated catalytic asymmetric synthesis. We are currently evaluating these ligands in other transition metal promoted catalytic asymmetric reactions and immobilising such ligands to appropriate solid supports.
Acknowledgements We thank the Fundac¸a˜o para a Cieˆncia e a Tecnologia and the Programma Opercional para Cieˆncia Tecnologia e Inovac¸a˜o (POCTI) for generous financial support in the form of a research grant (POCTI/QUI/38797/2001), including grants to (SC and EPC), which was partly funded by the European Community fund FEDER. Mrs. Ana Isabel Rodrigues from the Instituto Nacional de Engenharia, Tecnologia e Inovac¸a˜o and the personnel of the NMR service at C.A.C.T.I (University of Vigo, Spain) are acknowledged for NMR spectra.
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