On the origin of opposite stereoselection in the asymmetric hydrogenation of phenyl- and tert-butyl-substituted enamides [19]

Full text of DOI:10.1021/ja005554g

10486
J. Am. Chem. Soc. 2000, 122, 10486-10487
Scheme 1. Hydrogenation of 1 and 2 with H2
On the Origin of Opposite Stereoselection in the
Asymmetric Hydrogenation of Phenyl- and
tert-Butyl-Substituted Enamides
Ilya D. Gridnev,* Natsuka Higashi, and Tsuneo Imamoto*
Department of Chemistry, Faculty of Science
Chiba UniVersity, Chiba 263-8522, Japan
ReceiVed August 26, 2000
The mechanistic studies of the asymmetric hydrogenation were
actively carried out by many groups during the last three decades.1
However, most of these works used dehydroamino acids as
substrates. We are unaware of any data relevant to the mechanism
of asymmetric hydrogenation of enamides. Usually the explana-
tions of the mechanism of stereoselection in the asymmetric
hydrogenation of dehydroamino acids regard the carboxy group
as an important stereoregulating factor.1,2 In the structure of an
enamide the carboxy group is replaced by aryl or alkyl substituent,
and the steric demand of this substituent may be different in
various substrates. In this respect the striking difference in the
stereochemical outcome of asymmetric hydrogenations of 1-acet-
amido-1-phenylethene (1) and 2-acetamido-3,3-dimethyl-1-butene
(2) reported recently by Burk et al.3 has drawn our attention. Thus,
whereas enamide 1 was hydrogenated in the presence of (S,S)-
Me-DuPHOS-Rh catalyst to give S-hydrogenation product with
>95% ee,4 the hydrogenation of 2 with the same catalyst rendered
corresponding R-product with >99% ee.3 Being interested in the
mechanism of stereoselection in asymmetric hydrogenations
catalyzed by BisP*-Rh catalysts,5 we have chosen to explore the
hydrogenation of 1 and 2 in the presence of (S,S)-bis(tert-
butylmethylphosphino)ethane-Rh complex (3).
Scheme 2. Hydrogenation of 1 and 2 with HD
demonstrated by 1H, 2H, and 13C NMR data. Therefore, the
migratory insertion step in the catalytic cycles of asymmetric
hydrogenation of 1 and 2 is irreversible.
Addition of 2-fold excess of enamide 1 to the deuteriomethanol
solution of solvate complex 6 at -20 °C resulted in immediate
formation of two diastereomers of catalyst-substrate complex 7
in ratio changing from 4:1 at -90 °C to 2:1 at 0 °C. No detectable
amounts of the solvate complex 6 could be detected in equilibrium
with 7 within the temperature interval from -90 to +30 °C,8
and therefore the tightness of the substrate binding is comparable
to that in the catalyst-substrate complex of 6 and methyl (Z)-
R-acetamidocinnamate.5
Similarly to the above cited results of Burk et al., we have
found that in the presence of 3 both 1 and 2 gave quantitative
yields of almost enantiomerically pure amides 4 and 5 (ee in both
cases was 99%), but the sense of stereoselection was opposite:
(R)-4 and (S)-5 were obtained (Scheme 1). To rationalize this
striking difference, we have studied the structure of detectable
intermediates and carried out the isotope-labeling experiments in
both cases.
The catalyst-substrate complex 8 prepared from 6 and enamide
2 was notably less stable compared to 7; significant equilibrium
amounts of 6 were found in the whole temperature interval from
-100 to +30 °C.9 Only one isomer of 8 was observed.
We failed to detect a monohydride intermediate in the case of
enamide 1; hydrogenation of 7 at -100 °C gave directly the
product 4.10 On the other hand, hydrogenation of the equilibrium
mixture of 2, 6, and 8 for 5 min at -100 °C followed by
immediate placement of the sample in the probe of NMR
spectrometer precooled to -100 °C led to the obsevation of a
monohydride intermediate 10 (Scheme 3). A second diastereomer
When 1 and 2 were hydrogenated with deuterium hydride in
the presence of 3, the distribution of deuterium between the R-
and â-positions of the hydrogenation product was in both cases
unequal and opposite (Scheme 2). The ratio of the products 4d1
and 4d2, with deuterium in R- and â-positions respectively,
obtained in hydrogenation of 1 with HD was 1.30 ((0.05):1. On
the other hand, hydrogenation of 2 with HD gave the products
5d1 and 5d2 in the ratio 1:1.20 ((0.05). Thus, the isotope
partitioning in asymmetric hydrogenations with HD evidently
correlated with the difference in stereochemical outcome of the
hydrogenations.
1
of 10 was observed in H- and 31P NMR (the ratio of diastere-
omers is 100:7).11 Monohydride 10 is stable below -85 °C; at
higher temperatures it decomposes rapidly affording 6 and the
hydrogenation product 5. The optical yields and the sense of
stereoselection of the hydrogenation products obtained in the
NMR experiments were always the same as in the catalytic
hydrogenations of either 1 or 2.
To check the reversibility of the migratory insertion step,6,7
we carried out catalytic hydrogenations of 1 and 2 with D2. In
both cases the complete absence of deuterium scrambling was
(1) (a) Brown, J. M. Hydrogenation of Functionalized Carbon-Carbon
Double Bonds; Jacobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer:
Berlin, 1999; Vol. 1, pp 119-182 and references therin. (b) Noyori, R.
Asymmetric Catalysis in Organic Synthesis; John Wiley & Sons: New York,
1994. (c) Ojima, I. Catalytic Asymmetric Synthesis; VCH: Weinheim, 1993.
(2) Knowles, W. S. Acc. Chem. Res. 1983, 16, 106-112.
(3) Burk, M. J.; Casy, G.; Johnson, N. B. J. Org. Chem. 1998, 63, 6084-
6085.
(8) The NMR data suggest that the major isomer of 7 contains re-
coordinated 1, both intra- and intermolecular pathways of interconversion of
7a and 7b were detected by 2D EXSY spectra; the former pathway is notably
faster than the latter.
(9) The ratio 8:6 changes from 5:1 at -100 °C to 1:1 at 0 °C.; the chemical
shift of the R-C in the 13C NMR spectrum is only high-field shifted by 10
ppm, compared to the same signal of free 2 that suggests only weak binding.
(10) In these conditions 4 equilibrates with a catalyst-product complex (see
ref 5).
(11) The minor diasteromer of 10 also gives (S)-5, since the ee is higher
than the diastereomeric ratio of 10.
(4) Burk, M. J.; Wang, Y. M.; Lee, J. R. J. Am. Chem. Soc. 1996, 118, 8,
5142-5143.
(5) Gridnev, I. D.; Higashi, N.; Asakura, K.; Imamoto, T. J. Am. Chem.
Soc. 2000, 122, 7183-7194.
(6) Brown, J. M.; Parker, D. Organometallics 1982, 1, 950-956.
(7) Brauch, T. W.; Landis, C. R. Inorg. Chim. Acta 1998, 270, 285-297.
10.1021/ja005554g CCC: $19.00 © 2000 American Chemical Society
Published on Web 10/06/2000

Communications to the Editor
J. Am. Chem. Soc., Vol. 122, No. 42, 2000 10487
Scheme 3. Formation of Monohydride Intermediate 10
Figure 1. Mechanism of stereoselection in the catalytic hydrogenation
of 2.
Scheme 4. Proposed Mechanism of the Reactions of 1 and 2
with Major Isomer of Solvate Dihydride 9d1
1
In the hydride region of the H NMR spectrum 10 gives a
multiplet at -21.2 ppm. It correlates with two doublets at 53.2
and 86.7 ppm in the 31P NMR spectrum (2JPP is less than 5 Hz).
The chemical shift of the low-field signal in the 31P NMR is
considerably different from those of the known monohydride
intermediates,5,12,13 and is consistent with the presence of a weakly
bound solvent molecule in the trans-site. This fact suggests that
the amide carbonyl is not chelated in 10. In accord with this
conclusion, the carbonyl signal in the 13C NMR spectrum of 10
is not split and is only slightly low-field shifted with respect to
the carbonyl signals of 2 and 5 (δ ) 176; compare with δ ) 185
of the chelated carbonyl in 8, which is split in double doublet).
The signal of the carbon bound to acetamido group in 10 resonates
as a broadened singlet at δ ) 61.7. This signal becomes a doublet
in the gated-decoupled spectrum, indicating that it belongs to a
methyne carbon.14
On the basis of presented evidence we conclude that 10 has
the structure shown in Scheme 3. This conclusion corresponds
to the results of HD hydrogenation. We have shown recently that
upon hydrogenation of solvate complex 6 with HD, the isotopomer
9d1 with apical disposition of deuterium forms predominantly with
the factor 1.3 ((0.1): 1.5 Therefore, if the consequence of substrate
coordination and migratory insertion is faster than the intercon-
version of isotopomers,15 the partitioning of deuterium in the
products indicates the fashion of the substrate coordination during
the migratory insertion step. Predominance of the R-deuterated
product corresponds to coordination of type A and transfer of
the equatorial hydride to the CH2-group of enamide yielding
monohydride intermediate C with Rh bound to Ctert (Scheme 4).
The coordination of type B provokes transfer of equatorial hydride
to Ctert, yielding monohydride intrmediate D, that results in
predominance of â-deuterated product (Scheme 4).16
mechanism of stereoselection in the case of 1 is apparently the
same, and the main stereoregulating factor is minimization of the
repulsion between the chelate ring made by the substrate and the
alkyl groups of the catalyst in the transition state of the migratory
insertion step.5
Apparently, much more pronounced steric demand of enamide
2 makes the formation of a similar chelate cycle extremely
unfavorable, and it chooses an alternative mode of coordination
with the dihydride, in which its t-Bu group is much further
distanced from the alkyl groups of the catalyst. Figure 1 shows
that the minimization of the repulsion between the t-Bu group
from the enamide and the alykyl group from the catalyst results
in formation of (S)-5.
The mode of the binding of the substrate in 7, the sense of
stereoselection, as well as the sense and the order of deuterium
distribution in hydrogenation with HD observed for the phenyl-
substituted enamide 1 are exactly the same as those determined
previously for methyl (Z)-R-acetamidocinnamate.5 Therefore, the
In conclusion, our isotope labeling and NMR data suggest that
the striking difference in the stereochemical outcome of the
asymmetric hydrogenations of 1 and 2 can be explained by the
different mode of the coordination of the substrate at the migratory
insertion step of the catalytic cycle.
(12) Brown, J. M.; Chaloner, P. A. J. Chem. Soc., Chem. Commun. 1980,
344-346.
(13) Chan, A. S. C.; Halpern, J. J. Am. Chem. Soc. 1980, 102, 838-840.
(14) We failed to find in the 13C NMR spectrum the multiplet of the CH2
group due to its low intensity, possible overlap with other signals, and gradual
decomposition of 10 even at -90 °C, preventing correlation experiments. In
the 1H NMR spectrum the relatively sharp multiplet at δ ) 2.95 was assigned
to the signal of the CH2 group bound to rhodium since it is coupled to trans-
phosphorus according to selective decoupling experiments.
(15) There are reasons to suppose this since the reaction is very fast even
at -100 °C.
Acknowledgment. This work was supported by the Research for the
Future program, the Japan Society for the Promotion of Science.
Supporting Information Available: Experimental details and full
characterization data for all new compounds; NMR charts of 4, 5, 4d,
5d, 7, 8, 10. This material is available free of charge via the Internet at
http://pubs.acs.org.
(16) Experimental data give no indication as to whether the substrate is
chelated in the intermediate B.
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