Ruthenium hydroxide complexes in the racemization of secondary alcohols

Article abstract of DOI:10.1021/om200956r

Two well-defined 16-electron ruthenium hydroxide complexes were prepared and successfully used in the racemization of aromatic and aliphatic secondary alcohols. The intrinsic basicity of these new complexes permits for the exclusion of KO^tBu in the racemization reaction.

Full text of DOI:10.1021/om200956r

Communication
pubs.acs.org/Organometallics
Ruthenium Hydroxide Complexes in the Racemization of Secondary
Alcohols
Pierrick Nun, George C. Fortman, Alexandra M. Z. Slawin, and Steven P. Nolan*
EaStCHEM, School of Chemistry, University of St. Andrews, St. Andrews, KY16 9ST, U.K.
*
S Supporting Information
ABSTRACT: Two well-defined 16-electron ruthenium hydroxide
complexes were prepared and successfully used in the racemization of
aromatic and aliphatic secondary alcohols. The intrinsic basicity of
t
these new complexes permits for the exclusion of KO Bu in the
racemization reaction.
ontrolled racemization is of essential importance in the
them, complex D was successfully employed in the
1
C
industrial synthesis of optically pure compounds. As an
application, dynamic kinetic resolution (DKR) has proven to be
a powerful process in which an enantiomerically pure
compound is obtained using a racemic mixture, in the presence
of an enzyme reacting with only one enantiomer and a catalyst
racemization of secondary alcohols, providing good catalytic
9,10
racemization in only 30 min at room temperature.
According to the accepted mechanism of the catalytic cycle
involving complexes B−D, an initial reaction between the
t
ruthenium precatalyst and KO Bu results in a metathesis
2
which racemizes the remaining unreacted isomer. This concept
reaction generating the catalytically active ruthenium alkoxide
3
9
has first been applied to the acetylation of alcohols by Williams
species (eq 1). In the case of complexes B and C, Bac
̈
kvall
̈
and then developed by Backvall with the use of a ruthenium-
based catalyst for the racemization of alcohols and Candida
4
Antarctica Lipase B (CAL-B) as an acylating enzyme. Several
3,5
catalysts have been developed for the racemization reaction,
and to date, the most active are Ru-based complexes. The
prototypical example is the dinuclear catalyst A, shown in
Figure 1, which was developed by Shvo.
11
6
proposed this exchange to be assisted by coordinated CO. In
the case of complexes of type C, once generation of the Ru
alkoxide species has occurred, CO dissociation has been
proposed to be a crucial step in the formation of an active 16-
12
electron species.
We recently examined the role of built-in Brønsted−Lowry
basic groups in gold catalysis. In this approach, a catalyst
bearing a hydroxide moiety proved quite active in numerous
13
gold-mediated transformations. We reasoned that such a
14
built-in feature could also prove attractive in ruthenium-
mediated racemization protocols, as it would alleviate the need
for external bases and might also shed further light on the exact
mechanism at play in the racemization of secondary alcohols.
The synthetic strategy led to the isolation of two novel 16-
electron complexes, with the formulation [Cp*Ru(NHC)OH]
(Cp* = pentamethylcyclopentadiene), that could be simply
prepared from the corresponding [Cp*Ru(NHC)Cl], where
NHC = IPr (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)
Figure 1. Ruthenium-based alcohol racemization catalysts.
Upon thermal activation, A dissociates to generate an 18-
electron ruthenium(II) complex and the active 16-electron
ruthenium(0) complex. Avoiding the required dissociation of a
dimeric species, new families of 18-electron complexes were
(
(
1), IMes (1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene)
2). These complexes can be prepared simply by stirring
7
developed by Park in the form of complex B and by Bac
̈
kvall
8
with complex C. These new catalysts proved their efficiency in
alcohol racemization under mild conditions after in situ
activation with sodium or potassium tert-butoxide. In a recent
contribution, we have reported the use of well-defined 16-
electron N-heterocyclic carbene (NHC) and phosphine-
containing complexes enabling this transformation. Among
[
Cp*Ru(NHC)Cl] with dried CsOH overnight or in a one-pot
synthesis involving the precursor [Cp*RuCl] in the presence
4
Received: October 10, 2011
Published: November 15, 2011
©
2011 American Chemical Society
6347
dx.doi.org/10.1021/om200956r | Organometallics 2011, 30, 6347−6350

Organometallics
Communication
15
of the free NHC and CsOH. Scheme 1 represents the two
synthetic pathways employed.
Scheme 1. Synthesis of Complexes 1 and 2
In both cases, crystals were grown from saturated pentane
solutions and single-crystal X-ray diffraction studies were
performed to unambiguously confirm the molecular structures
16
of 1 and 2 (Figure 2).
Figure 3. (S)-1-Phenylethanol racemization with 1 and 2.
Selected bond lengths and angles for 1 and 2 can be
compared with data from the corresponding [Cp*Ru(NHC)-
justified by the higher stability of these well-defined complexes,
and then the observed enantiomeric excess decreased rapidly to
ca. 20% and a few more hours were required to observe a
complete racemization in 9 h with 1 and 13 h with 2. As the
catalytic performance of 1 proved superior to that of 2, further
catalytic work was conducted with 1.
1
7,18
Cl] congeners.
In both cases, substituting Cl by OH does
not lead to significant modification in bond lengths and angles
between the NHC, Cp*, and the metal center. We can notice a
reduced bond length between the ruthenium center and the
hydroxide group in comparison to the analogous Ru−Cl bond
(
Ru−OH (Å): 1, 2.001; 2, 2.027).
In a previous study, the mechanism of racemization with 16-
electron complexes of type D was investigated, leading to the
To test the catalytic efficacy of these two new complexes, 1
10
and 2 were launched in the racemization reaction of (S)-1-
phenylethanol and showed a low reactivity at room temperature
with only traces of (R)-1-phenylethanol after 1 h. This
observation could be explained by a higher stability of
formation of a Ru−H intermediate. To support the formation
of a similar intermediate with the new Ru−OH complexes, a
1
stoichiometric H NMR experiment was conducted with 1 and
phenylethanol and showed a signal at −9.6 ppm, supporting the
formation of a ruthenium hydride species.
[
[
Cp*Ru(NHC)OH] as compared to the in situ generated
Cp*Ru(NHC)(OtBu)], which reacted immediately with the
A short reaction scope was examined and a number of
secondary alcohols were reacted overnight at 50 °C with 5 mol
% of catalyst 1. (S)-1-Phenylethanol (entry 1; Table 1) was
fully racemized under these conditions, as were (S)-2-
naphtylethanol and (R)-p-chlorophenylethanol. With these
three examples excellent isolated yields were obtained after
simple purification (entries 2 and 3; Table 1). Unsurprisingly,
an aliphatic alcohol, (S)-3-octanol, was also efficiently race-
mized and characterized after its conversion into the
corresponding benzyl ester (entry 4; Table 1). With catalyst
D, subtrates S-7 and S-8 proved to be less reactive toward
alcohol at room temperature. It has previously been determined
that the NHC’s in 1 or 2 are not the optimum ancillary ligands.
ICy (ICy = 1,3-dicyclohexylimidazol-2-ylidene) has proven
superior to IPr and IMes but the congener hydroxide has
9
proven difficult to isolate to date. Nevertheless, having stable
hydroxides in hand, we decided to profile the racemization of
(
S)-1-phenylethanol with 1 and 2 under slightly harsher
conditions (50 °C), and the results are presented in Figure 3.
With both catalysts, the racemization kinetics appeared very
slow in the first 1 h, characterizing an initiating period and
Figure 2. Molecular structures of 1 and 2. H atoms have been omitted for clarity. Ru−OH (Å): 1, 2.001; 2, 2.027.
6
348
dx.doi.org/10.1021/om200956r | Organometallics 2011, 30, 6347−6350

Organometallics
Communication
a
Table 1. Scope of the Racemization Reaction
ACKNOWLEDGMENTS
■
The ERC (Advanced Investigator Award to S.P.N.) is gratefully
acknowledged for support of this work. S.P.N. is a Royal
Society Wolfson Research Merit Award holder.
REFERENCES
■
(
1) Ebbers, E. J.; Ariaans, G. J. A.; Houbiers, J. P. M; Bruggink, A.;
Zwanenburg, B. Tetrahedron 1997, 53, 9417.
(2) For selected reviews on DKR: (a) Ahn, Y.; Ko, S.-B.; Kim, M.-J.;
Park, J. Coord. Chem. Rev. 2008, 252, 647. (b) Conley, B. L.;
Pennington-Boggio, M. K.; Boz, E.; Williams, T. J. Chem. Rev. 2010,
1
10, 2294. (c) Lee, J. H.; Han, K.; Kim, M.-J.; Park, J. Eur. J. Org.
Chem. 2010, 999. (d) Martin-Matute, B.; Backvall, J.-E. Curr. Opin.
Chem. Biol. 2007, 11, 226. (e) Turner, N. J. Curr. Opin. Chem. Biol.
010, 14, 115. (f) Huerta, F. F.; Minidis, A. B. E.; Backvall, J.-E. Chem.
Soc. Rev. 2001, 30, 321. (g) Pamies, O.; Backvall, J.-E. Chem. Rev. 2003,
03, 3247. (h) Pellissier, H. Tetrahedron 2008, 64, 1563.
3) Dinh, P. M.; Howarth, J. A.; Hudnott, A. R.; Williams, J. M. J.;
Harris, W. Tetrahedron Lett. 1996, 37, 7623.
4) (a) Larsson, A. L. E.; Persson, B. A.; Bac
Int. Ed. 1997, 36, 1211. (b) Persson, B. A.; Larsson, A. L. E.; Le Ray,
M.; Backvall, J.-E. J. Am. Chem. Soc. 1999, 121, 1645.
5) For studies on racemization reactions: (a) Berkessel, A.;
Sebastian-Ibarz, M. L.; Mueller, T. N. Angew. Chem., Int. Ed. 2006, 45,
567. (b) Jerphagnon, T.; Gayet, A. J. A.; Berthiol, F.; Ritleng, V.;
̈
2
̈
̈
1
(
(
̈
kvall, J.-E. Angew. Chem.,
̈
(
6
Mrsic, N.; Meetsma, A.; Pfeffer, M.; Minnaard, A. J.; Feringa, B. L.; de
Vries, J. G. Chem. Eur. J. 2009, 15, 12780. (c) Marr, A. C.; Pollock, C.
L.; Saunders, G. C. Organometallics 2007, 26, 3283. (d) Schnell, B.;
Faber, K.; Kroutil, W. Adv. Synth. Catal. 2003, 345, 653. (e) Wuyts, S.;
Wahlen, J.; Jacobs, P. A.; De Vos, D. E. Green Chem. 2007, 9, 1104.
(f) J. Blacker, A.; Stirling, M. J.; Page, M. I. Org. Process Res. Dev. 2007,
11, 642. (g) Corberan, R.; Peris, E. Organometallics 2008, 27, 1954.
(h) Stirling, M.; Blacker, J.; Page, M. I. Tetrahedron Lett. 2007, 48,
a
Typical reaction conditions: 1 mmol of alcohol, 0.05 mmol of 1, 2
b
mL of toluene, overnight stirring at 50 °C. Determined by HPLC
analysis with Chiralcel OD-H. Isolated yield after purification by
column chromatography. Determined after conversion into the
corresponding benzyl ester. Yield not measured.
c
d
e
1
247.
6) (a) Shvo, Y.; Czarkie, D.; Rahamim, Y.; Chodosh, D. F. J. Am.
(
racemization. Under our conditions, only small amounts of the
new enantiomer could be detected, with only 5 and 11%
racemization respectively detected (entries 5 and 6; Table 1).
In both cases, the steric hindrance and the electron-poor nature
of the substrates appear to be significant barriers for an efficient
reaction with the ruthenium hydroxide.
Chem. Soc. 1986, 108, 7400. (b) Karvembu, R.; Prabhakaran, R.;
Natarajan, K. Coord. Chem. Rev. 2005, 249, 911.
(7) (a) Choi, J. H.; Choi, Y. K.; Kim, Y. H.; Park, E. S.; Kim, E. J.;
Kim, M.-J.; Park, J. J. Org. Chem. 2004, 69, 1972. (b) Choi, J. H.; Kim,
Y. H.; Nam, S. H.; Shin, S. T.; Kim, M.-J.; Park, J. Angew. Chem., Int.
Ed. 2002, 41, 2373.
(
8) (a) Csjernyik, G.; Bogar, K.; Bac
̈
kvall, J.-E. Tetrahedron Lett.
In conclusion, we have synthesized and fully characterized,
for the first time, two well-defined ruthenium hydroxide
2
004, 45, 6799. (b) Martin-Matute, B.; Edin, M.; Bogar, K.; Bac
̈
kvall,
J.-E. Angew. Chem., Int. Ed. 2004, 43, 6535.
complexes from the readily available [Cp*RuCl] or from the
(9) Bosson, J.; Nolan, S. P. J. Org. Chem. 2010, 75, 2039.
4
corresponding [Cp*Ru(NHC)Cl]. These complexes proved to
be active in the racemization of several aliphatic and aromatic
alcohols. Although their catalytic activity was found wanting in
comparison to the previously reported [Cp*Ru(NHC)Cl]/
(10) Bosson, J.; Poater, A.; Cavallo, L.; Nolan, S. P. J. Am. Chem. Soc.
010, 132, 13146.
11) (a) Aberg, J. B.; Nyhlen, J.; Martin-Matute, B.; Privalov, T.;
Backvall, J.-E. J. Am. Chem. Soc. 2009, 131, 9500. (b) Martin-Matute,
B.; Aberg, J. B.; Edin, M.; Backvall, J.-E. Chem. Eur. J. 2007, 13, 6063.
12) Warner, M. C.; Verho, O.; Backvall, J.-E. J. Am. Chem. Soc. 2011,
33, 2820. (b) Nyhle’n, J.; Backvall, J.-E Chem. Eur. J. 2009, 15, 5220.
(13) (a) Gaillard, S.; Bosson, J.; Ramon, R. S.; Nun, P.; Slawin, A. M.
2
(
̈
̈
t
9,10
KO Bu catalytic systems, the ability to perform racemization
under base-free conditions may prove useful in future
circumstances.
(
̈
1
̈
Z.; Nolan, S. P. Chem. Eur. J. 2010, 16, 13729. (b) Gaillard, S.; Slawin,
A. M. Z.; Nolan, S. P. Chem. Commun. 2010, 46, 2742.
ASSOCIATED CONTENT
■
(14) For examples of other metal hydroxides and alkoxides see:
*
S
Supporting Information
Fulton, J. R.; Holland, A. W.; Fox, D. J.; Bergman, R. G. Acc. Chem.
Res. 2002, 35, 44−56.
Text, tables, figures, and CIF files giving synthesis, character-
ization, and crystallographic data of 1 and 2 as well as the
typical racemization procedure and NMR data. This material is
available free of charge via the Internet at http://pubs.acs.org.
(15) Unfortunately, up to now, we have been unable to isolate the
[
Cp*Ru(ICy)OH] complex, which should prove even more active
than 1 or 2.
16) CCDC-833140 (1) and CCDC-833139 (2) contain the
(
supplementary crystallographic data for this contribution. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
AUTHOR INFORMATION
■
Corresponding Author
(17) Jafarpour, L.; Stevens, E. D.; Nolan, S. P. J. Organomet. Chem.
*
E-mail: snolan@st-andrews.ac.uk.
2000, 606, 49.
6
349
dx.doi.org/10.1021/om200956r | Organometallics 2011, 30, 6347−6350

Organometallics
Communication
(
18) Huang, J.; Schanz, H.-J.; Stevens, E. D.; Nolan, S. P.
Organometallics 1999, 18, 2370.
6
350
dx.doi.org/10.1021/om200956r | Organometallics 2011, 30, 6347−6350