4. Mechanistic Insight
4.5. Nature of the nucleophile
To further backup the “π-allyl theory”, a study of the nature of the nucleophile appeared to be crucial. As initial working hypothesis, the mechanistic rational proposed by Tunge for the Cp*Ru-catalyzed version of the reaction was envisaged (Scheme 4-14).17 Oxidative addition of the metal complex onto the substrate leads to the release of a ketoacetate moiety which, upon decarboxylation, generates an “unstabilized” enolate. This nucleophilic enolate
18 (a) Bolm, C.; Bienewald, F.; Seger, A. Angew. Chem. Int. Ed. Engl. 1996, 35, 1657-1659. (b) Mikami, K.;
Yamanaka, M. Chem. Rev. 2003, 103, 3369-3400. (c) Kagan, H. B. New Front. Asymmetric Catal. 2007, 207-219.
-80%
-40%
0%
40%
80%
-100% -50% 0% 50% 100%
ee of 2c
ee of L18f
subsequently adds to the π-allyl complex to regenerate the catalytically active ruthenium complex and furnishes the corresponding γ,δ-unsaturated ketone.
Ar O O R
O
Ar [Ru*]
O O R
O
Ar [Ru*]
R O
Ar
CO2 [Ru*]+
Ar R
O 1
2 3
R O
2+
2+
Scheme 4-14: Mechanistic rational for the Cp*Ru-catalyzed Carroll rearrangement proposed by Tunge.19,20 Since the nucleophilic species could not be observed directly either, attempts to intercept the nucleophilic intermediates were made to confirm their nature. When the reaction of 1c was conducted in the presence of 1 equivalent of dimethylmalonate,19 no incorporation of the malonate fragment onto the allyl fragment was observed (GC-MS). Rather surprisingly, this tends to show that the addition of the alleged “unstabilized” enolate onto the allyl fragment is much faster than the deprotonation of the acidic malonic ester. Moreover, in contrast to the observation of Tunge using a Cp*Ru-based catalyst,20 the enolate could not be trapped by a Michael acceptor (typically substituted methylenemalononitriles) in the standard reaction conditions. In view of the lack of interception of the nucleophilic species, it was then debatable whether the reaction proceeded intramolecularly rather than intermolecularly.
To solve this issue, a double crossover experiment was performed using a 1:1 mixture of 1a and 1r (Scheme 4-15). Gas chromatographic and mass spectrometric analysis of the resulting crude reaction mixture showed, after 6 hours, the formation of all possible branched and linear products compatible with intermolecular processes (2a, 3a, 2r, 3r and cross-over 9a, 10a, 9r, 10r). This result indicates that the alkylation reaction proceeds clearly through a state where in-situ generated nucleophilic and electrophilic fragments are separated in solution
19 Burger, E. C.; Tunge, J. A. Org. Lett. 2004, 6, 2603-2605.
20 Wang, C.; Tunge, J. A. Org. Lett. 2005, 7, 2137-2139.
resulting in a cross-over. As postulated by Tunge, bimolecular addition of a ruthenium enolate to a ruthenium allyl remains a possibility.19
O
4b(2 mol%) L18f(2.4 mol%)
THF, 60 °C 6 h
O O
MeO
O O O
O
MeO
O
MeO
O O
2a32 %
13r19 %
13a23 %
2r26 % b:l99 : 1
b:l97 : 3 b:l96 : 4
b:l99 : 1 1a52 %
1r48 %
Scheme 4-15: Double cross-over experiment, linear products 3 and linear cross-over products 13 are omitted for clarity (products distribution and b:l ratios measured by GC-MS ).
To further characterize the nucleophilic species and probe the generality of the reaction, several more elaborate cinnamyl ketoesters were synthesized (1l to 1q). As some of these substrates react quite slowly, 10 mol% of catalyst were used instead of 2 mol% to afford faster kinetics; their reactions are summarized in Table 4-4. Substrates 1l to 1n bearing an α-substituent between the carbonyl moieties reacted with similar kinetics and enantioselectivities to unsubstituted 1c (Table 3-5, entry 3 vs. Table 4-4, entries 1 to 3). The regiochemistry in favor of the branched adducts was however noticeably lower (down to 81:19 at most). Clearly, the bulkier is the nucleophile, the larger the amount of linear product.
It shows that the regioselectivity of the reaction is not only controlled by the electronic factors of the π-allyl described in the section 4.3.1. Furthermore, for these particular substrates, the presence of the α-substituent leads to the introduction of a novel stereogenic centre and, as a result, four stereoisomers of compounds 2 and two enantiomeric linear adducts 3 were obtained.
For branched derivative 2l, GC analysis indicated that the diastereoselectivity linked to the presence of the new stereocentre was low (ca. 2:1).21 As a similarly low selectivity was also observed for (cyclic) 2m and 2n (Table 4-4 entries 2 and 3); this is probably not due to a lack of control of the E / Z geometry of a possible enolate intermediate. Interestingly and
21 A similar result (dr 1.9) was observed by Tunge for substrate 1m. See reference 19.
somewhat in contrast with what has just been detailed, the chiral linear products 3l and 3m were obtained with decent enantioselectivities (ee 67 % and 79 % respectively). It shows that the facial approach of the alleged enolate is better controlled when the attack onto the electrophilic fragment occurs at the unsubstituted allylic terminal position rather than α to the aromatic moiety (Scheme 4-9 (c)).22
O Ph
O O
1q O
O O
O O O O
O O
1o 1p
1m
O O O
1n O
O O
1l
Entry Ester Time b Conv. c b:l d drd % ee (b1, b2, l) e Conf. f 1 1l 9 h > 97 % 81:19 68:32 72, nd., g 67 (–) 2 1m 9 h > 97 % 87:13 64:36 nd., g 81, 79 (–) 3 1n 9 h > 97 % 86:14 64:36 77, 77, nd. g (–)
4 1o 9 h > 97 % 83:17 - 57 (–)
5 1p 9 h > 97 % 85:15 - 67 (–)
6 1q 5 h > 97 % 92:8 - 78 (–)
7 1q h 24 h > 97 % 95:5 - 83 (–)
8 1q i 64 h > 97 % 95:5 - 86 (–)
a 4b (2.5 mol%), ligand L18f (3 mol%), THF, 60 °C, c(1) 2 M; the results being the average of at least two runs; b reaction time without 1 h induction time; c determined by 1H NMR (400 MHz); d ratios of branched (2) to linear (3) products and diastereomeric ratios among compounds 2 (dr) were determined at complete conversion by GC-MS; e ee of first and second eluted branched stereoisomers of 2 and of linear 3 respectively; f sign of optical rotation of 2; g not determined due to absence of peak separation; h reaction was performed at 40 °C; i reaction was performed at 25 °C.
Table 4-4: CpRu catalyzed rearrangement of allylic esters 1.a
In addition, when substrate 1m was reacted in the presence of 1 equivalent of ethyl 2-oxocyclopentanecarboxylate, in the standard conditions, GC-MS analysis of the crude reaction mixture revealed the incorporation of ethyl 2-oxocyclopentanecarboxylate onto the cinnamyl fragment as well as a corresponding amount of cyclopentanone (Scheme 4-16).
This tends to show that the bulkier the nucleophile, the slower the nucleophilic addition since
22 (a) Trost, B. M.; VanVranken, D. L. Chem. Rev. 1996, 96, 395-422. (b) Trost, B. M. J. Org. Chem. 2004, 69, 5813-5837. (c) Lu, Z.; Ma, S. M. Angew. Chem. Int. Ed. 2008, 47, 258-297. (d) Mohr, J. T.; Stoltz, B. M. Chem.
Asian J. 2007, 2, 1476-1491.
the enolate could, this time, be partially intercepted by deprotonation of an activated ketoester.
O
O O
EtO
O O
4b(2.5 mol%) L18f (3 mol%) THF, 60°C
O O
EtO2C
O O
CO2Et 1m
2m72 % 3m18 %
8 % 2 %
Scheme 4-16: Incorporation of activated ketoesters into rearranged 1m (ratios determined by GC-MS).
Substrates 1l, 1o and 1p, designed to probe the existence of enolate intermediates and their regioisomeric stability, reacted smoothly under the reaction conditions (Table 4-3 entries 1,4 and 5). In the particular case of 1o, as there is no α-hydrogen atom in between the two carbonyl groups, the selective formation of 2o indicates that the decarboxylation of the resulting ketoacetate occurs necessarily prior to the attack onto the π-allyl complex. In addition, the fact that the new C-C bonds in 2l to 2p and 3l to 3p (Scheme 4-17) result solely from the attack of the carbon previously bearing the carboxylate moiety is compatible with the formation of enolates in which the regiochemistry is preserved throughout the catalytic cycle.17,19
O O
+
1o
2o87 % 3o13 % O
O O
O O
+
Not observed THF, 60°C
2p0 % 3p0 % 4b(2.5 mol%)
L18f (3 mol%)
Scheme 4-17: Conservation of the enolate regiochemistry for 1o (ratios determined by GC-MS).
Finally the benzoyl-substituted substrate 1q reacted smoothly with faster kinetics but the same selectivity than 1c in the same conditions (Table 4-3 entries 6 to 8).23 The faster reaction for this substrate allowed the temperature to be lowered to 25 °C and 2q could be obtained with
23 For Ir-catalyzed regio- and enantioselective rearrangement of this type of benzoyl-derived substrates see: He, H.; Zheng, X. J.; Yi, U.; Dai, L. X.; You, S. L. Org. Lett. 2007, 9, 4339-4341.
86 % ee and a b:l ratio of 95:5 within 64 h. This result confirms that better ee values can be obtained if reactions are performed at lower temperature and are in good accordance with the energy-selectivity principle (calculated free Gibbs energy). Similar results on substituted cinnamyl benzoylacetates were obtained by Dr. F. Buron using the same catalytic combination and reaction conditions.
To further study the incorporation phenomenon described in Scheme 4-16, several rearrangement reactions were run using substrates differing only from the ketoester moiety (R, R’ = H or Me) in the presence of activated 1,3-dicarbonyl compounds (Table 4-5). Since the pKa of an unactivated ketone lies around 26 (DMSO), it should be able to deprotonate ethyl malonate (pKa = 16.4 in DMSO) or ethyl acetoacetate (pKa = 14.2 in DMSO) and as such, the incorporation of substantial amounts of the dicarbonyl-fragment into the final allylic substitution product is expected. In the case of substrate 1a (R = R’ = H), no incorporation of the malonate in the product was observed (entry 1). When ethyl acetoacetate was used, 7 % of incorporation product was observed by GC-MS (entry 3) but, no incorporation of the cyclohexanone carboxylate moiety could be seen (entry 2). This is surprising since the pKas of the two latter dicarbonyl products is very similar.
O substitution cross-over products (15/16) were determined by GC-MS.
Table 4-5: Incorporation of activated 1,3-dicarbonyl compounds into Carroll rearrangement products.a
The same situation occurred in the case of 1l (R = Me, R’ = H; entries 4 to 6): only the ethyl acetoacetate fragment was slightly incorporated in the final product (6 %, entry 6). In the case of 1o (R = R’ = Me; entries 7 to 9), the decarboxylation is necessarily occurring prior to the nucleophilic addition onto the allylic fragment. As such, in this case, it is possible to conclude that the nucleophilic species is a decarboxylated fragment. Again, no incorporation of a malonate fragment was observed (entry 7), but some incorporation (10 %) of the cyclohexanone carboxylate moiety was detected by GC-MS. In addition, this time, the product containing the acetoacetate moiety was majorly obtained (60 %). These results do not fit at all with the scale of pKas for the different species showing that the enolates, if formed, are definitely not unstabilized but most probably coordinated to a metal species. In addition, both the bulk of the “enolate” and the prenucleophile play a crucial role on the trapping reactions. This is probably due to differences in the kinetics of the nucleophilic addition and the deprotonation of the activated prenucleophiles: the bulkier the “enolate” the slower the nucleophilic addition and as such a bigger proportion of deprotonation.
Overall it has not been possible to directly observe any of the intermediate nucleophilic species and intercepting them has proven difficult. However, strong evidence in favour of a transient regiochemically stable enolate has been found.