3. Catalytic System Optimization
3.2. Optimization of the Ligand
3.2.1. Use and Synthesis of Pymox Ligands
N,N-ligands5 have received a lot of attention in the context of asymmetric metal-catalyzed reactions and more particularly ligands incorporating heteroaromatic fragments such as pyridines.6 Though pymox ligands were introduced in the late 80s by Brunner, they have only received limited attention in other fields than coordination chemistry and their application to highly enantioselective reactions remains rare. Historically, pymox ligands were prepared by converting 2-cyanopyridine to the corresponding imidate by addition of methanol followed by addition of the corresponding optically active amino alcohol.7 Later Bolm described the direct ZnCl2-condensation of aminoalcohol onto 2-cyanopyridine (Scheme 3-3).8
1)catNaOMe MeOH
Scheme 3-3: Syntheses of pymox ligands and chosen examples.
Ligand L12 was used in the Rh-catalyzed enantioselective hydrosilylation of ketones with diphenylsilane.9 Ligands L13 and L14, bearing additional stereogenic elements on the pyridine moiety, were used in the Rh-catalyzed enantioselective hydrosilylation10 and the Pd-catalyzed asymmetric allylic alkylation of 1,3-diphenylprop-2-enyl pivalate with dimethyl malonate, respectively.11 Ligands L15 and L16, prepared with similar strategies, were active
5 Togni, A.; Venanzi, L. M. Angew. Chem. Int. Ed. Engl. 1994, 33, 497-526.
6 (a) Fache, F.; Schulz, E.; Tommasino, M. L.; Lemaire, M. Chem. Rev. 2000, 100, 2159-2231. (b) Kwong, H.
L.; Yeung, H. L.; Yeung, C. T.; Lee, W. S.; Lee, C. S.; Wong, W. L. Coord. Chem. Rev. 2007, 251, 2188-2222.
7 Brunner, H.; Obermann, U.; Wimmer, P. J. Organomet. Chem. 1986, 316, C1-C3.
8 Bolm, C.; Weickhardt, K.; Zehnder, M.; Ranff, T. Chem. Ber. 1991, 124, 1173-1180.
9 Brunner, H.; Henrichs, C. Tetrahedron-Asymmetry 1995, 6, 653-656.
10 Brunner, H.; Storiko, R.; Nuber, B. Tetrahedron-Asymmetry 1998, 9, 407-422.
11 Nordström, K.; Macedo, E.; Moberg, C. J. Org. Chem. 1997, 62, 1604-1609.
in Pd-catalyzed asymmetric allylic alkylation.12 Ligand L17, with a remote chiral substituent, was obtained from (S)-mandelic acid and was used in the Rh-catalyzed hydrosilylation of 4-methylacetophenone with trichlorosilane.13
3.2.2. Ligand Structure Screening
Several pymox ligands were thus synthesized following the procedure of Bolm8 and were subjected to the standard allylation reaction conditions developed for the pyridine-imine ligands.3 The results are summarized in Table 3-1.14
[CpRu(MeCN)3][PF6] (10 mol%)
the results being the average of at least two runs; b sign of optical rotation of 2a;c ratios of branched (2) to linear (3) products were determined by
1H NMR (400 MHz).
Table 3-1: Ligand screening, oxazoline part.a
Ligand L18a, bearing the same oxazoline than the most selective ligand of Bruneau,15 proved to be already quite efficient in our case: the Carroll rearrangement of substrate 1a yielded the expected product 2a with full conversion and perfect b:l ratio in less than 2 h with a decent ee value of 53 % (entry 2). A gradual increase of the bulk of the substituent α to the N-atom improved the enantiomeric excess up to 72 % with the valinol-derived pymox L18d without any loss of regioselectivity (entries 3-5). Surprisingly, ligand L18e derived from tert-leucinol
12 Bremberg, U.; Rahm, F.; Moberg, C. Tetrahedron-Asymmetry 1998, 9, 3437-3443..
13 Malkov, A. V.; Liddon, A. J. P. S.; Ramirez-Lopez, P.; Bendova, L.; Haigh, D.; Kočovský, P. Angew. Chem.
Int. Ed. 2006, 45, 1432-1435.
14 Conversions are given (but not isolated yields) since it was possible to isolate the mixtures of 2a and 3a in yields above 95 % each time. The yields are thus considered to be virtually quantitative in all cases.
15 In the context of O-allylation of phenols: Mbaye, M. D.; Renaud, J. L.; Demerseman, B.; Bruneau, C. Chem.
Commun. 2004, 1870-1871.
displayed no catalytic activity whatsoever (entry 6). The completely-rigid ligand L18f, derived from (1R,2S)-cis-1-amino-2-indanol, afforded solely the desired branched product 2a with an enantioselectivity of 80 % at full conversion (entry 7). Ligand L18f performed thus as regio- and enantioselectively as the most efficient pyridine-imine ligand L11c but with a much higher catalytic activity (2 h vs.24 h for L18f and L11c respectively).
In order to further optimize the structure of the ligand, variations on the substitution pattern of the pyridine part were undertaken and a few other structures were synthesized using the above mentioned methods.7,8
the results being the average of at least two runs; b sign of optical rotation of 2a; c ratios of branched (2) to linear (3) products were determined by
1H NMR (400 MHz).
Table 3-2: Ligand screening, heteroaromatic part.a
Electron poor pyrimidine and pyrazine derived ligands (L18g and L18h respectively) were thus synthesized in a similar manner to L18f. These two ligands afforded solely the branched product 2a with the same ee value of 78 %. However, for these two electron-poor ligands, the reactions were noticeably slower than for the unsubstituted pyridine ligand L18f (Table 3-2, entries 1 and 2). On the other hand, ligand L18i (entry 3), bearing an electron-donating methyl group para to the N-atom of the pyridine, afforded a faster reaction with excellent regioselectivity but a lower enantioselectivity (73 % ee in 1.5 h for L18i, vs. 80 % ee in 2 h for L18f). Electronic factors on the pyridine side of the ligand seem to play a crucial role on
N
the kinetics of the reaction (electron poor ligands affording slower reactions) but accelerating the reaction seems detrimental to the enantioselectivity of the process.3 In addition, the 5-methyl substituted pyridine ligand L18j (entry 4) allowed reaching full conversion of 1a into 2a but with a strongly detrimental effect on the kinetics of the reaction (76 % ee in 4 h for L18j, vs. 80 % ee in 2 h for L18f). The additional methyl group, in the latter cases, is probably sterically interacting with the π-allyl fragment and overall slowing down the reaction. Replacing the pyridine moiety by a NH- or NBn-benzimidazole (L18k and L18l) proved to have a detrimental effect on both reaction kinetics and enantioselectivities (entries 5 and 6). However the deprotonated benzimidazole-oxazoline ligand L18m afforded a much faster reaction than its NH equivalent (entry 7). This effect is not likely due to the Li cation since the addition of LiPF6 to the reaction of 1a with ligands L18f of L18k did not have any measurable effect on the outcome of the reaction. Ligand L18n (entry 8) did not show any catalytic activity at all; probably due to the always-present disfavored steric interaction between the Cp and the indenyl moieties.
A “naked” pyridine moiety combined with an indanyl-oxazoline on the ligand thus seems to be the best compromise to fulfill the stereoelectronic requirements for the reaction to proceed.
Ligand L18f thus appeared as the most suitable candidate for further reaction optimization.