Before I came here I was confused about this subject. Having listened to your lecture I am still confused. But on a higher level…
Enrico Fermi (1901-1954)
6.1. Conclusion
The objective of this work was to further develop the chemistry of ruthenium-catalyzed Carroll rearrangement reactions previously reported by Tunge1 and by our group.2 As shown in the introductory chapter 2, the field of allylic substitution reactions is extremely varied, but ruthenium catalyzed reactions remain little studied.
In the third chapter, we have shown that readily-accessible pyridine mono-oxazolines were ligands very well suited for the CpRu-catalyzed Carroll rearrangement reactions. Ligand L18f appeared especially appropriate for this transformation since excellent regioselectivities (up to > 99:1) good enantioselectivities (up to ca. 80 %) and improved reactivities (up to 20 times faster than the first-generation pyridine imine ligands) could be obtained.
The aim of the fourth chapter was to better understand the transformation and especially its mechanism. Many reactions were performed in an attempt to characterize the different steps of the mechanism. It was unfortunately not possible to directly prove the nature of the different intermediates but mechanistic evidence were gathered and analyzed, sufficient to afford a plausible mechanistic rational. The reaction seems to proceed following a pathway very similar to what is described for palladium catalyzed allylic alkylation reactions.
As a follow-up to this mechanistic rational, a co-catalytic strategy based on magnesium salts was developed and successfully applied to the Carroll rearrangement. Enhanced reactivities were achieved allowing the reaction to be performed at lower temperature (room temperature) and with consequently better enantioselectivity.
The fifth chapter describes the application of the catalytic combinations to intermolecular allylic substitution reactions. They appeared well suited, when used in conjunction with a lithium salt, for “base free” alkylation reactions. Good regioselectivities (generally around 9:1
1 (a) Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 2603-2605. (b) Burger, E. C.; Tunge, J. A. Chem. Commun.
2005, 2835-2837.
2 (a) Constant, S.; Tortoioli, S.; Muller, J.; Lacour, J. Angew. Chem. Int. Ed. 2007, 46, 2082-2085. (b) Constant,
in favour of the branched regioisomer) were obtained for a wide variety of classical activated prenucleophiles. The problem of low diastereoselectivity (generally around 1:1) of the branched product still remains largely unsolved.
The same asymmetric protocol could also be applied to the decarboxylative “rearrangement”
of cinnamyl carbamates and carbonates. The reactions of N-based substrates are problematic since neither chemoselectivity (double alkylation reactions) nor regioselectivity could be controlled satisfyingly. The cinnamyl aryl carbonates were much better substrates and good regio and enantioselectivities were obtained.
Overall the straightforward combination of air-stable [CpRu(η6-napht)][PF6] with simple-to-make ligand L18f allowed the reactions to be performed under easy experimental conditions.
Ligand L18f appeared to be very interesting due to the simplicity in its synthesis but more interestingly due to the fact that both enantiomers of the starting indenyl aminoalcohol are commercially available for a moderate price ((+)- or (–)-aminoindanol 5g ~ 200 CHF).3
6.2. Outlook
As shown in the different parts of this manuscript, the catalytic combinations described herein still suffers from a few limitations mainly in terms of reactivity and enantioselectivity. Due to simplicity of the catalytic system there still remain a lot of room for structural improvements.
Firstly, except for the unsuccessful attempts to use Cp*Ru complexes, no structural variations have been made to the roof of the half sandwich precatalytic complex. Firstly, as a more electron rich roof seems to be beneficial for the reactivity and selectivity (especially in the endo / exo isomerism of the π-allyl complex) of allylation reactions as reported by Pregosin4 and by Trost,5 it seems appropriate to substitute the Cp moiety with some electron donating groups (Scheme 6-1 (a)). The Cp* appeared too bulky for a combination with L18f, as such di- or tri-substituted Cp’ moieties could be appropriate (C2 symmetrical Cp’ should be privileged to avoid planar chirality of subsequent complex).
Another strategy could be to substitute the Cp ring with a group able to activate the ketoester moiety in a similar way to the co-catalytic approach. For example structures similar to
3 Senanayake, C. H. Aldrichim. Acta 1998, 31, 3-15.
4 Hermatschweiler, R.; Fernandez, I.; Pregosin, P. S.; Breher, F. Organometallics 2006, 25, 1440-1447.
Shvo’s6 catalyst, bearing a hydroxy group on the Cp Scheme 6-1 (b), could serve as a useful structural scaffold in this context. Many different variations have been published and successfully applied in the context of chemoenzymatic dynamic kinetic resolutions of amines and alcohols.7
Scheme 6-1: Possible structural variations on the roof of the ruthenium half sandwich complex.
The other straightforward modifications concern the N,N-ligand. Indeed, since the chirality at the metal centre was only poorly controlled by ligand L18f in many CpRu(N,N’)X complexes, it would be interesting to enhance the steric hindrance between the Cp ring and the ortho-substituent of the indenyl moiety (Scheme 6-2). Two feasible strategies emerge: (a) introduce a more bulky R group and (b) vary the distance between the Cp and the R group by making a bigger middle ring (n = 1, 2 or 3).
Scheme 6-2: Possible structural variations on the N,N-pymox ligand.
[CpRu(MeCN)3][PF6] (10 mol%) results being the average of at least two runs; b ratios of branched (2) to linear (3) products were determined at complete conversion by 1H NMR (400 MHz).
Table 6-1: Ligand screening.a
6 Shvo, Y.; Czarkie, D.; Rahamim, Y.; Chodosh, D. F. J. Am. Chem. Soc. 1986, 108, 7400-7402.
7 (a) Paetzold, J.; Bäckvall, J. E. J. Am. Chem. Soc. 2005, 127, 17620-17621. (b) Prabhakaran, R. Synlett 2004, 2048-2049. (c) Samec, J. S. M.; Ell, A. H.; Aberg, J. B.; Privalov, T.; Eriksson, L.; Bäckvall, J. E. J. Am. Chem.
Finally, early screening reactions were performed to determine the optimal geometry of the ligand (Table 6-1). It appeared that 1,10-phenantroline (phen) was performing quite faster than 2,2’-bypyridine (bpy); probably because of the better planarity of the phenantroline. The use of anionic ligands like PHENPHAT, a hexacoordinated phosphate anion bearing a phenantroline, seemed to be very beneficial to the kinetics of the reaction. Several structural modifications of the N,N-ligand thus seem promising (Scheme 6-3): (a) oxazines from homologation of natural amino acids or different phenol derived amines,8 (b) flatening the ligand as for example in a bridged imidazole structure or (c) using a pymox ligand bearing and anionic moiety like a hexacoordinated phosphate for instance.
(a) (b)
N N
N N O n
N R
O O
O
O O
O P
N
Cl Cl
Cl Cl
Cl Cl
Cl Cl
O N
(c) R
Scheme 6-3: Possible structural variations on the N,N-ligand.
In addition, Kitamura has shown that pyridine or quinoline carboxylates represent a family of ligands (Scheme 6-4 (a)), which, in conjunction with a CpRu source, provide very active catalysts for the deallylation of allylic ethers to provide the corresponding free alcohols.9 Recently Bruneau showed that this class of ligands were, in conjunction with a Cp*Ru source, providing efficient catalysts for classical allylic substitution reactions.10 As such oxazoline-carboxylates as in case (b) or oxazoline-alkoxides as in case (c) (Scheme 6-4) seem to have a strong potential since they combine similar structural features to the pymox ligands with inherent anionic properties. Work is currently being carried out in the laboratory to assess the scope of such ligands in the context of Carroll rearrangement and more classical allylic substitution. In addition, since the carboxylic acid can also be used, it seems possible to apply this family of chiral ligands to allylic substitution under acidic conditions as described by Pregosin.11
8 Bernardinelli, G.; Fernandez, D.; Gosmini, R.; Meier, P.; Ripa, A.; Schupfer, P.; Treptow, B.; Kündig, E. P.
Chirality 2000, 12, 529-539.
9 (a) Saburi, H.; Tanaka, S.; Kitamura, M. Angew. Chem. Int. Ed. 2005, 44, 1730-1732. (b) Tanaka, S.; Saburi, H.; Ishibashi, Y.; Kitamura, M. Org. Lett. 2004, 6, 1873-1875. (c) Tanaka, S.; Saburi, H.; Kitamura, M. Adv.
Synth. Cat. 2006, 348, 375-378.
10 Zhang, H. J.; Demersernan, B.; Toupet, L.; Xi, Z. F.; Bruneau, C. Adv. Synth. Cat. 2008, 350, 1601-1609.
11 Zaitsev, A. B.; Gruber, S.; Pluss, P. A.; Pregosin, P. S.; Veiros, L. F.; Worle, M. J. Am. Chem. Soc. 2008, 130,
(a) (b) N
O O N O
O R O
(c) O
R N O
R'R' or
Scheme 6-4: Possible structural scaffold for new N,O-ligand.
During his postdoctoral stay, Dr. Simone Tortoioli developed an enantioselective decarboxylative rearrangement of activated cinnamyl esters thus proving that the strategy used in the Carroll rearrangement can be widened to other transferable groups (Scheme 6-2).
A careful study of these reactivities should allow determining the scope of Ru-catalyzed enantioselective decarboxylative allylations of nucleophiles, but the preliminary results are promising as far as activated esters are concerned.
[CpRu(MeCN)3][PF6] (10 mol%) L*(10 mol%)
THF, 60 °C
O O
X X
X
N N L*
OMe
Entry Ligand Time Conv. ee 1 Ts b,c 24 h 53 % 25 % d 2 CN c 17 h > 97 % 60 % e 3 NO2 4 h > 97 % 72 % e
a Fresh 4a (10 mol%), ligand L* (10 mol%), THF, 60 °C, c(1a) 0.5 M; the results being the average of at least two runs; b 10 mol% of DBU were used as co-catalyst;c bis-allylated product was also obtained in a 1:1 ratio; d Chiralpak IA (Hexane / iPrOH 90/10, 0.5 mL.min-1, 23 °C; e Chiralpak IB (Hexane / iPrOH 95/5, 0.5 mL.min-1, 23 °C.
Table 6-2: Transferable groups.a