Mechanistic studies of a reaction promoted by the [YLi 3{tris(binaphthoxide)}] complex: Are three 1,1′-bi-2-naphthol units in a rare-earth-alkali-metal heterobimetallic complex necessary?

Article abstract of DOI:10.1002/anie.200454202

The power of three: Mechanistic studies based on the kinetic profiles of the catalytic asymmetric 1,4-addition of an amine to chalcone revealed that all three binol ligands of the [YLi₃{tris(binaphthoxide)}] complex 1 are involved in the active

Full text of DOI:10.1002/anie.200454202

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Reaction Mechanisms
generated by dissociation of one binol–Li2 unit, as long as Yb
metal was used.Furthermore, the best results in some
asymmetric reactions were observed with catalysts prepared
from RE/binol/M in a ratio different to 1:3:3.Yb/K/binol =
1:1:3 worked best in a nitro-Mannich-type reaction,[4] and Sc/
Li/binol = 1:1:2 in a Strecker-type reaction.[5] The active
Mechanistic Studies of a Reaction Promoted
by the [YLi3{tris(binaphthoxide)}] Complex:
Are Three 1,1’-Bi-2-naphthol Units in a
Rare-Earth–Alkali-Metal Heterobimetallic
Complex Necessary?**
Noriyuki Yamagiwa, Shigeki Matsunaga, and
Masakatsu Shibasaki*
Since the early 1990s,[1a] we have reported series of
rare-earth–alkali-metal heterobimetallic complexes
that enable various catalytic asymmetric reactions.[1]
These complexes, whose structures were determined
by X-ray crystallographic analysis, mass spectrometry,
and NMR spectroscopy, consist of one rare-earth
metal (RE), three 1,1’-2-bi-naphtholate (binol), and
three alkali metal (M) parts (Figure 1).[1b,c] Subse-
quently, independent studies by Aspinall et al.revealed
Figure 2. Debated structures of active species of rare-earth–alkali-metal heterobimetallic
complexes. a) RE/M/binol=1:3:3; b) RE/M/binol=1:1:2. Nu=nucleophile.
species in these reactions has not yet been determined.
Mechanistic studies to clarify the composition of the active
differences in the aqua and anhydrous heterobimetallic
species of the rare-earth–alkali-metal heterobimetallic com-
plex would facilitate the design and application of bimetallic
multifunctional asymmetric catalysis in future research.
Although recent detailed spectroscopic analysis of the
heterobimetallic complexes by Aspinall et al.[2] and Salvadori
and co-workers[3] revealed various new and interesting
properties, their behavior during catalytic cycles of asymmet-
ric reactions have not been studied extensively.To elucidate
the controversial structure of the active species, investigations
based on actual catalytic asymmetric reactions as well as
spectroscopic analysis of the heterobimetallic complex are
essential.Herein, we report our efforts to determine the
active species on the basis of mechanistic studies of a catalytic
asymmetric reaction, including various kinetics studies and
NMR spectroscopic analysis.Mechanistic studies of the
[YLi3{tris(binaphthoxide)}] complex (Figure 1, Li3[Y(bi-
nol)3], YLB, 1) and asymmetric 1,4-addition reaction of O-
methylhydroxylamine catalyzed by YLB (1) suggested that
the active species of the 1,4-addition reaction requires all
three binol units in YLB, although ligand exchange of the
YLB complex occurs easily under the reaction conditions
(À208C).
Figure 1. Structure of (S,S,S)-Li3[Y(binol)3] (YLB, 1), (S)-binol-H2, and
(S)-binol-Li2.
complexes in the solid-phase structures.[2] They also reported
preliminary results on the solution-phase structure of hetero-
bimetallic complexes.More recently, Salvadori and co-work-
ers reported a detailed spectroscopic analysis of Yb–alkali-
metal heterobimetallic complexes in solution phase, raising
the question as to whether the Yb/M/binol = 1:3:3 structure is
really an active species or just a precatalyst (Figure 2).[3] They
reported that binol in the Yb/K/binol = 1:3:3 heterobimetallic
complex is labile (confirmed by an exchange spectroscopy
experiment) and proposed that the active species could be
We selected an asymmetric 1,4-addition of O-methylhy-
droxylamine (3) catalyzed by 1 as a target for the mechanistic
studies (Scheme 1).[6] Because Aspinall et al.reported
detailed spectroscopic data for both the solid-phase and
solution-phase structures of YLB (1),[2] this reaction was most
[*] N. Yamagiwa, Dr. S. Matsunaga, Prof. Dr. M. Shibasaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
Fax: (+81)3-5684-5206
E-mail: mshibasa@mol.f.u-tokyo.ac.jp
[**] This work was partially supported by a Grant-in-Aid for Specially
Promoted Researchand a Grant-in-Aid for Encouragement for
Young Scientists (B) (for S.M.) from the JSPS and MEXT.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Scheme 1. Catalytic asymmetric 1,4-addition of O-methylhydroxylamine
(3) promoted by YLB (1) and results of initial rate kinetic experiments.
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suitable to investigate the behavior during the reaction
however, differed greatly, depending on the optical purity of
the catalyst.For example, the reaction rate with catalyst with
33% ee was only 1/34 (v33% ee = 2.98 ” 10À4 MhÀ1) of that
observed with optically pure catalyst (v100% ee = 1.01 ”
10À2 MhÀ1).The reaction rate with 0% ee catalyst was 1/199
(v0% ee = 5.07 ” 10À5 MhÀ1) of that with optically pure cata-
lyst.[8]
pathway.[7] We first examined the reaction profile of the
catalytic asymmetric 1,4-addition of amine 3 to chalcone (2a).
Initial rate-kinetics studies revealed that several properties of
the reaction:
1) first-order dependence on the YLB complex 1;
2) first-order dependence on chalcone (2a);
3) zeroth order dependence on amine 3 (Scheme 1);[8]
4) negligible retro-1,4-addition;
5) only slight product inhibition (the reaction rate decreased
by 34% in the presence of as much as 100 equiv of product
4e (relative to 1), and the results suggested that product
inhibition at the initial stage of the reaction was negli-
gible);
Possible catalytic cycles of the reaction to explain the
observed kinetic properties 1)–5) are summarized in Fig-
ures 4A–C.In Figure 4A, the active species is postulated to
be the Y/Li/binol = 1:3:3 complex coordinated by amine3.
Formation of active species A-II from an amine-free YLB
complex I should be fast, and the rate-determining step (rds)
of the reaction is the 1,4-addition to 2a.In Figures 4B and C,
the active species is postulated to be the Y/Li/binol = 1:1:2
complex.Although the latter complex is thermodynamically
unstable,[10] it might exist because of stabilization with
amine 3 and/or chalcone (2a).In Figure 4B, the amine
coordinates to the Y/Li/binol = 1:1:2 complex (B-II).The
rate-determining step of the reaction is the 1,4-addition to 2a.
In Figure 4C, the active species is postulated to be the Y/Li/
binol = 1:1:2 complex coordinated by 2a.Formation of the
active species by replacing one binol-Li2 unit of YLB with
chalcone should be the rate-determining step, and the 1,4-
addition of amine is fast.We evaluated the validity of these
three possible reaction mechanisms with additional mecha-
nistic experiments.
6) retardation of reaction rate upon addition of H2O;
7) strong, positive, nonlinear effects[9] (Figure 3).
A catalyst with 33% ee afforded products with 95% ee,
which was comparable with that obtained in the presence of
an optically pure catalyst (96% ee).The reaction rate,
First, we evaluated the mechanism in Figure 4B.The
results of initial rate kinetic studies 1–3 listed above suggested
that the formation of active species B-II by releasing one
binol-Li2 unit should be favorable (KB1[3]/[B-II] = [binol-Li2]/
[I] @ 1) if the mechanism shown in Figure 4B is correct.[11]
Thus, the active species would be observed by spectroscopic
analysis on the basis of kinetic experiments.NMR spectros-
copic analysis of the YLB complex under various conditions
(a) (S,S,S)-1, b) (S,S,S)-1 + (S)-binol-Li2 (1 equiv), c) (S,S,S)-
1 + (S)-binol-Li2 (3 equiv), d) (S)-binol-Li2, e) (S,S,S)-1 + 3
(10 equiv), and f) (S,S,S)-1 + 3 (10 equiv) + binol-Li2
(1 equiv) were examined (in b–f, equiv with respect to 1;
NMR spectra are available in the Supporting Information).In
b, c, and f, binol-Li2 was observed independently from peaks
derived from YLB.Binol-Li , however, was not observed in
2
e).These observations do not support the proposed mecha-
nism in Figure 4B, thus the mechanism in Figure 4B is
unlikely.There was no difference in the reaction rate when
using 1 mol% of YLB with or without additional binol-Li2 (1–
3 mol%) (Figure 5).[8] The enantioselectivities observed for
the product 4a were 96% ee (1 alone), 96% ee (1 + 1 mol%
binol-Li2), 96% ee (1 + 2 mol% binol-Li2), 96% ee (1 +
3 mol% binol-Li2), and 17% ee (3 mol% binol-Li2).The
results in Figure 5 also suggested that the mechanism in
Figure 4B is incorrect.
In the case of the mechanism shown in Figure 4C, the
formation of active species C-II by releasing one binol-Li2
unit should be slow, based on the observed initial rate kinetic
properties 1–3 (see list above).[11] Thus, NMR spectroscopic
analysis of the active species would be difficult to obtain,
because the existence of the active species would be minor
and the majority would be in the resting state (Y/Li/binol =
Figure 3. Positive nonlinear effects in catalytic asymmetric 1,4-addition
of 3 to 2a promoted by YLB1.
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Figure 5. Initial rate kinetics using 1 mol% of (S,S,S)-1 withadditional
(S)-binol-Li2. (0–3 mol%).
Figure 6. Substituents effects of chalcone 2 on initial rate.
2 would accelerate the reaction, because electron-rich chal-
cone would accelerate the exchange with binol-Li2.The
tendency shown in Figure 6, however, suggests that the rate-
determining step is the 1,4-addition step and not the
formation of active species II-C.
Figure 4. Possible catalytic cycles of catalytic asymmetric 1,4-addition
withYLB ( 1). A) withY/Li/binol =1:3:3; B) and C) withY/Li/
binol=1:1.2.
The mechanism shown in Figure 4A is therefore the most
probable of the three.[11] The mechanism shown in Figure 4A
fits all the observed kinetic profiles 1–6 (see list above) and
additional mechanistic studies (NMR spectroscopic analysis,
1
1:3:3).On the other hand, the 1,4-addition step is fast in this
mechanism.This mechanism was ruled out, however, when
substituent effects on the reaction rate were examined
(Figure 6).[8] If the mechanism in Figure 4C were correct,
then introduction of an electron-donating group on chalcone
Figure 5, and Figure 6). 13C and H NMR spectra of 1 alone
and 1 with amine did show small differences, suggesting that
amine3 coordinates to the Y complex without breaking the Y/
Li/binol = 1:3:3 framework.[12] Inhibition of the reaction with
H2O (kinetic data 6) is explained by the reversible coordina-
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tion of H2O to YLB.H 2O would compete with chalcone.
with 33% ee.[14] The ee value of the product was same with
ligands with over 33% ee, whereas the reaction rate increased
drastically by increasing the ee value of the ligands from 33 to
> 99% ee, because the amount of (S,S,S)-1 increased accord-
ingly (Figure 3).
NMR spectroscopic analysis supported the reversible coordi-
nation of H2O to 1.[13] Thus, the properties of 1 are quite
different to those of the Yb heterobimetallic complexes
reported by Salvadori and co-workers.[3] The mechanism
shown in Figure 4A involving a seventh axial ligand would be
reasonable in the case of 1.
To explain the observed nonlinear effects of the present
1,4-addition reaction (Figure 3), we further analyzed YLB
complex spectroscopically.Aspinall et al.reported that the
(S,S,R)-YLB-type complex is thermodynamically more stable
In summary, various kinetics studies and NMR spectro-
scopic analysis revealed that the active species in the
asymmetric 1,4-addition reaction with YLB as a catalyst is
Y/Li/binol = 1:3:3 coordinated with amine 3, although the
binol unit in YLB is labile under the reaction conditions.Our
conclusion is different from that proposed by Salvadori and
co-workers,[3] probably because the active species differs,
depending on the combination of rare earth metal, alkali
metal, and nucleophile used.The results reported herein do
not necessarily extend to the active species in other reactions.
In particular, the active species when using more-acidic
nucleophiles such as nitroalkanes and phosphonates, which
may or may not be replaced with binol, is the future target of
investigation.Further studies based on kinetic studies of other
asymmetric reactions are essential to clarify the active species.
This project is currently in progress.
À
than the (S,S,S)-YLB complex owing to the C H–p hydrogen
bond.Because they synthesized the ( S,S,R)-YLB-type com-
plex (together with the (S,R,R)-complex) from racemic-binol,
it was uncertain as to whether or not ligand exchange occurs
under the 1,4-addition reaction conditions.To observe the
lability of binol in 1 under the reaction conditions, we
analyzed a YLB solution prepared from (S,S,S)-1 (2 equiv)
and (R,R,R)-1 (1 equiv) by NMR spectroscopy.The mixed
solution revealed only the (S,S,R)-YLB-type complex (> 30:1
ratio when taking the resolution of NMR analysis in consid-
eration: no (S,S,S)-YLB was detected).The spectrum was
identical to that reported by Aspinall et al.[2] The results
clearly indicated that the ligand exchange between (S,S,S)-1
and (R,R,R)-1 occurred smoothly to form a thermodynami-
cally more stable (S,S,R)-YLB-type complex exclusively.On
the other hand, the reaction rate when using (S,S,S)-1
(6.66 mol%) and (R,R,R)-1 (3.33 mol%) mixed at À788C
was as slow as that performed with 10 mol% of the preformed
Received: March 6, 2004 [Z54202]
Keywords: asymmetric catalysis · heterobimetallic complexes ·
.
kinetics · nonlinear effects · rare-earthmetals · yttrium
[1] a) H.Sasai, T.Suzuki, S.Arai, T.Arai, M.Shibasaki,
J. Am.
(S,S,R)-YLB-type complex (Scheme 2).Product
4a was
Chem. Soc. 1992, 114, 4418; b) H.Sasai, T.Suzuki, N.Itoh, K.
Tanaka, T.Date, K.Okamura, M.Shibasaki, J. Am. Chem. Soc.
1993, 115, 10372; for reviews, see: c) M.Shibasaki, H.Sasai, T.
Arai, Angew. Chem. 1997, 109, 1290; Angew. Chem. Int. Ed.
Engl. 1997, 36, 1236; d) M.Shibasaki, N.Yoshikawa, Chem. Rev.
2002, 102, 2187.
obtained in only 10% yield after 24 h (92% ee).The reaction
rate was much slower than that observed with (S,S,S)-1.The
results indicated that ligand exchange occurs smoothly at least
under the 1,4-addition reaction conditions at À208C.On the
basis of these results, the nonlinear effects and the observed
reaction rate tendency in Figure 3 are explained as follows:
The (S,S,R)-YLB-type complex is thermodynamically more
stable than (S,S,S)-YLB.On the other hand, equilibrium
between the (S,S,R)-YLB-type complex and (S,S,S)-YLB
would occur under the reaction conditions.The ( S,S,R)-YLB-
type complex is not active for the 1,4-addition reaction and
only trace (S,S,S)-YLB formed in equilibrium and promoted
the reaction, when the reaction was performed with ligands
[2] a) HC. .Aspinall, JL.M. .Dwyer, N.Greeves, A.Steiner,
Organometallics 1999, 18, 1366; b) H.C.Aspinall, J.F.Bickley,
J.L.M. Dwyer, N. Greeves, R.V. Kelley, A. Steiner,
Organo-
metallics 2000, 19, 5416; Review: c) H.C.Aspinall, Chem. Rev.
2002, 102, 1807.
[3] L.D.Bari, M.Lelli, G.Pintacuda, G.Pescitelli, F.Marchetti, P.
Salvadori, J. Am. Chem. Soc. 2003, 125, 5549.
[4] K.Yamada, S.J.Harwood, H.Grꢀger, M.Shibasaki,
Angew.
Chem. 1999, 111, 3713; Angew. Chem. Int. Ed. 1999, 38, 3504.
[5] M.Chavarot, J.J.Byrne, P.Y.Chavant, Y.Vallꢁe,
Tetrahedron:
Asymmetry 2001, 12, 1147.
[6] N.Yamagiwa, S.Matsunaga, M.Shibasaki,
J. Am. Chem. Soc.
2003, 125, 16178.
[7] YLB (1) is also most suitable to investigate the effects of H2O on
reactivity and selectivity of heterobimetallic asymmetric catal-
ysis.Anhydrous YLB was essential for the asymmetric 1,4-
addition of amine, whereas aqua YLB was essential for the
catalytic asymmetric cyanoethoxycarbonylation reaction.Com-
parison of these two reactions to clarify the role of H2O will be
reported as a full article.For the use of aqua YLB in the
cyanoethoxycarbonylation reaction, see: a) J.Tian, N.Yama-
giwa, S.Matsunaga, M.Shibasaki,
Angew. Chem. 2002, 114,
3788; Angew. Chem. Int. Ed. 2002, 41, 3636; b) J.Tian, N.
Yamagiwa, S.Matsunaga, M.Shibasaki, Org. Lett. 2003, 5, 3021.
[8] For detailed data of kinetic profiles 1–6, nonlinear effects 7, and
the reaction profiles in Figures 5 6, see Supporting Information.
[9] For reviews, see: a) C.Girard, H.B.Kagan, Angew. Chem. 1998,
110, 3088; Angew. Chem. Int. Ed. 1998, 37, 2922; b) H.B.Kagan,
Scheme 2. 1,4-Addition reaction: a) with( S,S,S)-YLB
(6.66 mol%) + (R,R,R)-YLB (3.33 mol%); b) withpreformed ( S,S,R)-
YLB (10 mol%).
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Adv. Synth. Catal. 2001, 343, 227; for a review discussing kinetic
aspects of nonlinear effects, see: c) D.G. Blackmond, Acc.
Chem. Res. 2000, 33, 402.
[10] NMR spectroscopic analysis suggested that YLB (1) (1:3:3
complex) forms predominantly even when the Y–Li complex
was mixed in a 1:2:2 ratio in THF.Coordination of THF would
not be sufficient to stabilize the coordinatively unsaturated Y/Li/
binol = 1:1:2 species.When the Y–Li complex was mixed in a
1:1:2 ratio (Y/Li/binol), a complicated NMR spectrum was
observed.We speculate that 1 would form, but that other species
derived from remaining Y(HMDS)3 and binol-H2 would also
form, thus resulting in the complicated NMR spectrum.
[11] For a more detailed discussion evaluating mechanisms A-C in
Figure 4, see Supporting Information.
[12] 13C and 1H NMR spectra of YLB and YLB with amine3 are
shown in the Supporting Information.The difference in chemical
shifts is also summarized.
[13] 1H NMR spectra of anhydrous and aqua YLB and experiments
to show the reversibility between aqua and anhydrous YLB are
summarized in the Supporting Information.
[14] The possibility that the (S,S,R)-YLB-type complex is much less
reactive (1/34 of (S,S,S)-YLB), but as enantioselective as (S,S,S)-
YLB (95% ee) cannot be excluded.Further mechanistic studies
are necessary.
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