Angewandte
Chemie
substrates were readily processed, providing ketones 5b and
substrate 2a, the Gibbs free energy barrier for this process
5c in excellent e.r. (96:4 and 97:3, respectively) following C
was computed to be approximately 14 kcalmolꢀ1. Two hydro-
gen bonds are formed between catalyst and substrate (with
ꢀ
H oxygenation. Importantly, in the case of the methoxy-
substituted substrate, secondary oxidation under Swern con-
ditions resulted in an identical e.r. (97:3) to that recorded for
=
=
C O–NH distances of 1.76 ꢀ for C Ocatalyst–HNsubstrate and
=
1.92 ꢀ for NHcatalyst–O Csubstrate). The hydrogen abstraction is
ꢀ
ꢀ
ꢀ
the initial enantiotopos-selective C H oxygenation process.
associated with bond distances of O H = 1.16 ꢀ and H C =
1.37 ꢀ (O-H-C angle: 1678). The suggested transition state is
in line with the absolute configuration determined for
products 5. Similar computational results were obtained for
calculations performed with substrate 2c (see SI). It is evident
that substituents at the indane aromatic ring do not sterically
interfere with the catalyst, which is in line with the high e.r.
observed for products 5b and 5c. Further inspection reveals
that the C5 position of the spirocyclic oxindole is in close
proximity to one of the polyfluorinated meso aryl groups of
the catalyst. As a result, we believe that as the steric bulk of
the C5 substituent (substrates 2g–i) increases there is
a significant interaction with this aryl group, thereby leading
to a destabilization of the transition state and lowering of the
e.r. The extent to which the repulsion is detrimental correlates
roughly with the size of the substituent (see above). The C6
position is evidently spatially located away from this group
and thus avoids such interactions. Indeed, substrates 2d–f
reacted with enantioselectivities comparable to substrate 2a.
Subsequently, we assessed the influence of substituents at the
C5 and C6 positions of the oxindole ring system (oxindole
numbering, see Figure 3). Substitution at the C6 position by
Br, Cl, and CN (5d, 5e, and 5 f, respectively) gratifyingly also
led to high enantiomeric ratios (91:9 to 95:5), which increased
slightly in the order CN<Cl<Br. The e.r. following the second
oxidation step was found to decrease more significantly as the
electron-withdrawing capacity of the substituent increased
(CN>Cl>Br). The use of substrates that were differentially
substituted at the C5 position led to considerable differences
in enantioselectivity. Whilst CN substitution again resulted in
high e.r. (90:10), the introduction of Cl and CF3 gave lower
selectivity (80:20 and 72:28).
The absolute configuration for the major enantiomer 5b
(from the reaction of substrate 2b) was assessed by compar-
ison of measured and calculated chiroptical data (see SI). It
was shown that the mode of catalyst action relies on substrate
association by two hydrogen bonds.[22,23] If instead of substrate
2a its N-methylated derivative was employed there was no
oxidation reaction to be observed. Remarkably, the N-
methylated derivative of catalyst 4 was incompetent in
performing the oxidation of substrate 2a, with no reaction
observed and starting material 2a re-isolated (see SI).
Mechanistically, it seems safe to assume that compound 4
is a precatalyst, which is oxidized by 2,6-dichloropyridine N-
oxide to a ruthenium oxo complex.[9] With this in mind, we
attempted to rationalize the experimental results using DFT
calculations. Although several attempts to locate the tran-
ꢀ
After the C H abstraction step, a fast rebound process
leads to the transfer of the hydroxy group to the substrate.
Although this process could be observed computationally, its
barrier seems to be very low, and the consequent transition
state could therefore not be located. A rough computational
estimation of the primary kinetic isotope effect (KIE)
ꢀ
associated with the C H abstraction (neglecting tunneling
effects) yielded a value of 6.4 (see SI). To validate this
approximation, an intermolecular competition experiment
(one-pot, 1:1 mixture) was conducted between spirocyclic
oxindole 2a and its deuterated analogue d4-2a (Figure 5). A
primary KIE of 6.1 was obtained, which was in excellent
ꢀ
sition state for a concerted C H oxygenation yielded no
ꢀ
result, we could identify the transition state for a C H
abstraction postulating a RuV intermediate[28] (Figure 4). With
Figure 4. Favored transition state for the reaction 2a!5a as calcu-
lated by DFT methods (M06L functional with SDD basis set and
pseudopotential for ruthenium,[24] 6-31G(d) for all other atoms).[25] All
calculations (see SI) were performed on the untruncated doublet
complexes, employing Gaussian09[26] with D3 dispersion correction by
Grimme.[27]
Figure 5. Measurement of the primary kinetic isotope effect (KIE):
a) Intermolecular competition experiment between 2a and d4-2a.
(b) Determination of the KIE value from the line of best fit. (c) Reac-
~
*
tion profile for compounds 2a ( ) and 5a ( ) and the calculated
&
amount of intermediary formed alcohol 6a ( ).
Angew. Chem. Int. Ed. 2014, 53, 1 – 6
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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