Gold meets rhodium: Tandem one-pot synthesis of β-disubstituted ketones via meyer-schuster rearrangement and asymmetric 1,4-addition

Article abstract of DOI:10.1021/ol4011739

An asymmetric one-pot tandem Au/Rh-catalyzed synthesis of highly enantioenriched β-disubstituted ketones starting from racemic propargyl alcohols is disclosed. The compatibility of the two metal complexes (Au/Rh) and their orthogonal ligand systems (NHC/d

Full text of DOI:10.1021/ol4011739

ORGANIC
LETTERS
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Vol. XX, No. XX
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Gold Meets Rhodium: Tandem One-Pot
Synthesis of β‑Disubstituted Ketones
via MeyerꢀSchuster Rearrangement
and Asymmetric 1,4-Addition
Max M. Hansmann,† A. Stephen K. Hashmi,*,‡ and Mark Lautens*,†,‡
Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario
€
M5S 3H6, Canada, and Organisch-Chemisches Institut, Ruprecht-Karls-Universitat
Heidelberg, Im Neuenheimer Feld 270, 69120 Heidelberg, Germany
hashmi@hashmi.de; mlautens@chem.utoronto.ca
Received April 26, 2013
ABSTRACT
An asymmetric one-pot tandem Au/Rh-catalyzed synthesis of highly enantioenriched β-disubstituted ketones starting from racemic propargyl
alcohols is disclosed. The compatibility of the two metal complexes (Au/Rh) and their orthogonal ligand systems (NHC/diene) in this bimetallic
catalytic system is investigated.
Recently, the combination of several transition-metal-
catalyzed transformations in one single reaction vessel
(one-pot) has gained increasing interest as molecular com-
plexity is rapidly generated without the need for isola-
tion or purification of intermediates, therefore enhancing
efficiency and sustainability by reducing costs and waste
production.1 On the other hand, the combination of
several metal complexes in one reaction flask dramatically
increasesthesystem’scomplexityenablingredox-processes
or ligand-exchange reactions between the metal centers
leading toundesired side reactions or catalyst deactivation.
As part of our interest in tandem one-pot transfor-
mations,2 we envisioned combining gold and rhodium
catalysis in a new one-pot transformation. While there
are numerous reports of one-pot transformations in parti-
cular involving palladium catalysis,3 much less is known
about other bimetallic systems utilizing homogeneous gold
catalysts. The one-pot combination of gold and palladium
recently gained increasing attention and is by far the best
studied system,4 while the combination of gold and other
† University of Toronto.
‡
€
Ruprecht-Karls-Universitat Heidelberg.
(1) For early reports on one-pot dual-metal catalysis, see: (a) Arriola,
D. J.; Carnahan, E. M.; Hustad, P. D.; Kuhlman, R. L.; Wenzel, T. T.
Science 2006, 312, 714. (b) Jeong, N.; Seo, S. D.; Shin, J. Y. J. Am. Chem.
Soc. 2000, 122, 10220. (c) Zimmermann, B.; Herwig, J.; Beller, M.
Angew. Chem., Int. Ed. 1999, 38, 2372. For reviews on one-pot reactions,
see: (d) Allen, A. E.; MacMillan, D. W. C. Chem. Sci. 2013, 3, 633.
(e) Patil, N. T.; Shinde, V. S.; Gajula, B. Org. Biomol. Chem. 2012, 10,
211. (f) Albrecht, Ł.; Jiang, H.; Jørgensen, K. A. Angew. Chem., Int. Ed.
2011, 50, 8492. (g) Climent, M. J.; Corma, A.; Iborra, S. Chem. Rev.
2011, 111, 1072. (h) Walji, A. M.; MacMillan, D. W. C. Synlett 2007,
1477. (i) Wasilke, J.-C.; Obrey, S. J.; Baker, R. T.; Bazan, G. C. Chem.
Rev. 2005, 105, 1001.
(3) For a review, see: (a) Lee, J. M.; Na, Y.; Han, H.; Chang, Y.
Chem. Soc. Rev. 2004, 33, 302. (b) van den Beuken, E. K.; Feringa, B. L.
Tetrahedron 1998, 54, 12985.
(4) (a) Hashmi, A. S. K.; Ghanbari, M.; Rudolph, M.; Rominger, F.
€
Chem.;Eur. J. 2012, 18, 8113. (b) Hashmi, A. S. K.; Lothschutz, C.;
€
Dopp, R.; Ackermann, M.; de Buck, J.; Rudolph, M.; Scholz, C.;
Rominger, F. Adv. Synth. Catal. 2012, 354, 133. (c) Hirner, J. J.; Roth,
K. E.; Shi, Y.; Blum, S. A. Organometallics 2012, 31, 6843. (d) Pennell,
M. N.; Unthank, M. G.; Turner, P.; Sheppard, T. D. J. Org. Chem. 2011,
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76, 1479. (e) Lauterbach, T.; Livendahl, M.; Rosellon, A.; Espinet, P.;
Echavarren, A. M. Org. Lett. 2010, 12, 3006. (f) Hashmi, A. S K.;
€
€
Lothschutz, C.; Dopp, R.; Rudolph, M.; Ramamurthi, T. D.;
Rominger, F. Angew. Chem., Int. Ed. 2009, 48, 8243. (g) Shi, Y.; Roth,
K. E.; Ramgren, S. D.; Blum, S. A. J. Am. Chem. Soc. 2009, 131, 18022.
(h) Shi, Y.; Peterson, S. M.; Haberaecker, W. W., III; Blum, S. A. J. Am.
Chem. Soc. 2008, 130, 2168.
(2) (a) Zhang, L.; Sonaglia, L.; Stacey, J.; Lautens, M. Org. Lett.
2013, 15, 2128. (b) Tsui, G. C.; Tsoung, J.; Dougan, P.; Lautens, M. Org.
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Chem., Int. Ed. 2011, 50, 9089.
r
10.1021/ol4011739
XXXX American Chemical Society

transition metals is far less explored.5 To the best of
our knowledge there is only one report on a one-pot
Rh/Au dual-catalytic system in which the gold-catalyst is
a simple Au(III) halide precursor without any ligand
system on gold.6
conditions were suitable for a very fast Rh-catalyzed
conjugate addition. These conditions turned out to be
very general and allowed the synthesis of a large library
of racemic β-disubstituted ketones.
In order to study the metalꢀligand interactions of the
first one-pot Au(I)/Rh(I) system, we envisioned to use a
Au(I)-catalyzed MeyerꢀSchuster rearrangement of a pro-
pargyl alcohol 1 leading, with complete atom-economy,7
to the corresponding enone 2 followed by a Rh-catalyzed
boronic acid 1,4-addition to access β-disubstituted ketones
3 in a very rapid fashion from easily accessible starting
materials (Scheme 1).
Scheme 2. Racemic Au/Rh Sequential Tandem Sequence
Scheme 1. One-Pot Au(I)/Rh(I) Dual Catalysis
Control experiments combining the two transition me-
tals from the start of the reaction demonstrated that free
phosphine ligand employed in the first step slows down
the MeyerꢀSchuster rearrangement significantly, presum-
ably caused by the formation of the catalytic inactive
species [NHCAuL]þ (L = BINAP) (see the Supporting
Information).
At this stage, we invisioned using an orthogonal ligand
system on gold and rhodium while at the same time
developing an asymmetric tandem transformation by uti-
lizing a chiral diene ligand. Diene ligands are known to
efficiently bind to Rh(I),11 yet be very poor ligands for
Au(I),12 making them ideal for an orthogonal-ligand
system in this bimetallic tandem tranformation and also
unique in comparison to the well studied tandem-phos-
phine ligandꢀAu/M transformations.
While the classical MeyerꢀSchuster rearrangement8
requires harsh reaction conditions (strong acids and ele-
vated temperatures), there have been several reports on
much milder conditions employing Au catalysis starting
from propargyl acetates9 or more conveniently directly
from the corresponding propargyl alcohol.10
After initial screening experiments, we found reaction
conditions compatible with a sequential Au/Rh tandem
transformation (Scheme 2). Propargyl alcohol 1a was
transferred into product 3a by employing an NHC ligand
on the gold catalyst (3 mol % IPrAuNTf2) and a bidentate
phosphine ligand (5 mol % rac-BINAP) as a ligand on the
Rh-precursor. [(cod)RhOH]2 (2.5 mol %) was sufficient
to undergo the conjugate addition reaction to give 3a in
a remarkably high yield of 93% in a sequential one-pot
transformation. A solvent mixture of MeOH/H2O af-
forded a fast (ca. 1ꢀ2 h) and mild (room temperature)
Au-catalyzed MeyerꢀSchuster reaction, while the same
A ligand screening of several chiral diene ligands demon-
strated that there is no ligandꢀligand exchange between
the two metal centers and that Hayashi’s diene ligand L7 is
a very effcient ligand in inducing high enantioselectivies
(96% ee) in the 1,4-addition with this fairly challenging
substrate13 to yield 3a in moderate yields (Scheme 3). It is
noteworthy that there are not many dual-metal-catalyzed
tandem transformations involving an asymmetric reaction
step; in particular, there are no asymmetric dual-metal-
catalyzed transformations with one metal being gold.14
(5) (a) Hashmi, A. S. K.; Molinari, L. Organometallics 2011, 30, 3457.
(b) Dai, L. Z.; Shi, M. Chem.;Eur. J. 2010, 16, 2496. (c) Ye, L.; Zhang,
L. Org. Lett. 2009, 11, 3646. (d) Egi, M.; Yamaguchi, Y.; Fujiwara, N.;
Akai, S. Org. Lett. 2008, 10, 1867. (e) Milton, M. D.; Inada, Y.;
Nishibayashi, Y.; Uemura, S. Chem. Commun. 2004, 2712. For reviews
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on bimetallic systems involving gold, see: (f) Perez-Temprano, M. H.;
Casares, J. A.; Espinet, P. Chem.;Eur. J. 2012, 18, 1864. (g) Hirner,
J. J.; Shi, Y.; Blum, S. A. Acc. Chem. Res. 2011, 44, 603.
(6) Aksin-Artok, O.; Krause, N. Adv. Synth. Catal. 2011, 353, 385.
Scheme 3. Ligand Optimization
€
(7) Trost, B. M. Science 1991, 254, 1471.
(8) Meyer, K. H.; Schuster, K. Chem. Ber. 1922, 55, 819.
(9) (a) de Haro, T.; Nevado, C. Chem. Commun. 2011, 47, 248.
(b) Zanoni, G.; D’Alfonso, A.; Porta, A.; Feliciani, L.; Nolan, S. P.;
Vidari, G. Tetrahedron 2010, 66, 7472. (c) Nun, P.; Gaillard, S.; Slawin,
A. M. Z.; Nolan, S. P. Chem. Commun. 2010, 46, 9113. (d) Hopkinson,
M. N.; Giuffredi, G. T.; Gee, A. D.; Gouverneur, V. Synlett 2010, 2737.
(e) Wang, D.; Ye, X.; Shi, X. Org. Lett. 2010, 12, 2088. (f) Marion, N.;
Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750. (g) Marion, N.;
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Carlqvist, P.; Gealageas, R.; de Fremont, P.; Maseras, F.; Nolan, S. P.
Chem.;Eur. J. 2007, 13, 6347.
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(10) (a) Ramon, R. S.; Gaillard, S.; Slawin, A. M. Z.; Porta, A.;
D’Alfonso, A.; Zanoni, G.; Nolan, S. P. Organometallics 2010, 29, 3665.
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(b) Ramon, R. S.; Marion, N.; Nolan, S. P. Tetrahedron 2009, 65, 1767.
(c) Engel, D. A.; Lopez, S. S.; Dudley, G. B. Tetrahedron 2008, 64, 6988.
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B
Org. Lett., Vol. XX, No. XX, XXXX

The lowered yields with ligands L5 and L7 were caused
by the formation of 2c as a side product which is generated
by methanol addition to the corresponding enone 2b.15
The formation of this side product is fast upon addition of
base to the Au-catalysis system. The addition of external
base in the ligand screening experiments (1 equiv Cs2CO3)
was necessary in order to promote the Rh-catalyzed 1,4-
addition when starting with the [RhCl(C2H4)2]2 precursor.
In contrast, starting with [(cod)RhOH]2 did not require
addition of external base, as the rhodium hydroxide is
assumed to be the catalytic active species.16 As Hayashi’s
ligand L7 showed excellent enantioselectivities, we per-
formed some solvent screening experiments on the initial
MeyerꢀSchuster rearrangement in order to avoid the
use of methanol as solvent in the tandem transformation
(see the Supporting Information). Interestingly, the sol-
vent has a large impact on the E/Z-selectivity of 2b, and
only MeOH/H2O gave high E-selectivities. Performing,
for example, the catalysis in dioxane/H2O (5:1) led to a
4:1 mixture of E/Z-isomers, while interestingly, employing
this mixture in the dual-metal catalysis still yielded the final
product in 86% yield and 86% ee, making a matchedꢀ
mismatched combination of the chiral-diene complex
with the two E/Z-isomers likely to rationalize the still high
enantioselectivity.
In addition to arylboronic acids, also (E)-styryl boronic
acid led to the corresponding allyl compound 3h in good
yields with reduced enantioselectivities. A heteroaromatic
boronic acid such as 3-thienylboronic acid was equally
suitable, affording 3i with high enantioselectivities, but a
low conversion for the second step was observed.
Scheme 5. Scope of Propargyl Alcohols
As the next step, several propargyl alcohols with diverse
aromatic substitution were analyzed (Scheme 5). In gen-
eral, electron-rich systems (3a, 3j, 3m,n) led in high yields
(>80%) and inhighenantioselectivities tothe correspond-
ing products. Changing the alkyl group from methyl to
isopropyl (3k) as well as sterically demanding groups (3m)
increased the enantioselectivities. Electron-deficient(3o) as
well as heteroaromatic backbones such as 3p and 3q led to
the products in high yields and enantioselectivities.
A base screening experiment led to the optimized reac-
tion conditions for the asymmetric tandem transforma-
tion. Changing the base to KOH and reducing the amount
to 50 mol % generates, in the presence of boronic acid,
a buffered solution in which methanol addition is slow
relative to the Rh-catalyzed addition and 3a could be
isolated in 97% yield and 93% ee.
With these optimized conditions in hand the scope of
boronic acids was investigated (Scheme 4).
This tandem transformation also works with the readily
available diarylpropargyl alcohols when heated slightly to
50 °C, and then the MeyerꢀSchuster rearrangement is as
fast as with substrates from Scheme 5. Various 3,3-diaryl
ketones, important substructures of many pharmaceuti-
cals containing a diarylmethine stereocenters,17 can be
Scheme 4. Scope with Regard to the Boronic Acid
(11) (a) Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J. P.;
Darses, S. Angew. Chem., Int. Ed. 2008, 47, 7669. (b) Paquin, J. F.;
Defieber, C.; Stephenson, C. R. J.; Carreira, E. M. J. Am. Chem. Soc.
2005, 127, 10850. (c) Fischer, C.; Defieber, C.; Suzuki, T.; Carreira,
E. M. J. Am. Chem. Soc. 2004, 126, 1628. (d) Hayashi, T.; Ueyama, K.;
Tokunaga, N.; Yoshida, K. J. Am. Chem. Soc. 2003, 125, 11508. For a
review on Rh-catalyzed asymmetric 1,4-addition, see: (e) Edwards, H. J.;
Hargrave, J. D.; Penrose, S. D.; Frost, C. G. Chem. Soc. Rev. 2010, 39,
2093. (f) Hayashi, T.; Yamasaki, K. Chem. Rev. 2003, 103, 2829.
(g) Fagnou, K.; Lautens, M. Chem. Rev. 2003, 103, 169.
(12) Cinellu, M. A. In Modern Gold Catalyzed Synthesis, Chapter 7,
GoldꢀAlkene Complexes; Hashmi, A. S. K., Toste, F. D., Eds.; Wiley-VCH:
Weinheim, 2012.
(13) In most reports, Rh-catalyzed 1,4-additions are performed with
cyclic enones while this particular acyclic substrate contains only a small
methyl group as stereodifferentiating group.
(14) For a review on asymmetric tandem transformations, see:
Clavier, H.; Pellissier, H. Adv. Synth. Catal. 2012, 354, 3347.
(15) The addition of methanol has been observed in the case of
Au-catalyzed MeyerꢀSchuster rearrangements when non-substituted
highly reactive enones were formed; see: Pennell, M. N.; Turner, P. G.;
Sheppard, T. D. Chem.;Eur. J. 2012, 18, 4748and ref 10b.
(16) Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am.
Chem. Soc. 2002, 124, 5052.
The addition of electron-rich (3a,b), electron-poor
(3cꢀe), base-sensitive (3f), sterically hindered ortho-
substituted (3g) boronic acids was possible in excellent
yields with very high enantioselectivities (93ꢀ96% ee).
(17) Chen, G.; Xing, J.; Cao, P.; Liao, J. Tetrahedron 2012, 68, 5908.
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 6. Au/Rh-Tandem Synthesis of β-Diaryl Ketones
Figure 1. Solid-state molecular structures of (S)-3n and (S)-3u.
Scheme 7. Rh-Catalyzed Arylation in the Presence of Gold
by acting as a transmetalation cocatalyst20 is currently
under investigation.
synthesized in one step in excellent yields and enantio-
selectivities (Scheme 6).
The absolute configuration of the final products was
assigned by the X-ray crystal structure analysis of (S)-3n
and (S)-3u (Figure 1) and by synthesis of (S)-1,3-diphe-
nylbutan-1-one and comparison with the literature data
(see the Supporting Information).
Attempts to add all components from the start did
not result in full conversion. Instead, [Rh(cod)Cl]2 and
[Rh(cod)OH]2 turned out to be inhibitors for the Meyerꢀ
Schuster reaction (see the Supporting Information), which
can be rationalized through the formation of the inactive
IPrAuX species.18 Changing the counterion on rhodium
to a weakly coordinating ion such as Rh(cod)2OTf
resulted in the formation of the Rh-catalyzed arylation
product 4, which is generated in the absence of gold
(Scheme 7).19
While the ligand systems on both metals are orthogonal,
the counterions on the two metals seem crucial in tuning
the desired reactivity. It is likely that under the reaction
conditions the gold catalyst abstracts the counterion on
rhodium, generating a highly active cationic Rhꢀdiene
catalyst explaining the mild reaction conditions. If the
IPrAuCl generated can also further accelerate the reaction
In conclusion, this novel and general Au/Rh tandem
transformation provides β-disubstituted ketones as valu-
able compounds for synthesis in high yields and enantio-
selectivities from easily accessible racemic propargyl
alcohols by mimicking the concept of dynamic kinetic
resolution. This is achieved by transformation into
achiral intermediates by the gold catalyst and a subse-
quent enantioselective conversion by the chiral rhodium
catalyst. This process is only possible as the ligand
systems (NHC vs diene) are orthogonal in their binding
affinities toward the two metals.
Acknowledgment. M.M.H. is grateful to the Fonds
der chem. Industrie for a Chemiefonds scholarship and
the Studienstiftung des dt. Volkes. We thank Merck and
NSERC for an Industrial Research Chair, the University
of Toronto for financial support, and Dr. Alan Lough
(X-ray analysis, University of Toronto).
Supporting Information Available. Experimental pro-
cedures, X-ray data (CIF), and full characterization for
all compounds. This material is available free of charge
via the Internet at http://pubs.acs.org.
(18) IPrAuOH is a poor catalyst in the MeyerꢀSchuster rearrange-
ꢀ
ꢀ
ment, see: Gomez-Suarez, A.; Oonishi, Y.; Meiries, S.; Nolan, S. P.
(20) Shi, Y.; Blum, S. A. Organometallics 2011, 30, 1776.
Organometallics 2013, 32, 1106 and ref 10a.
(19) Panteleev, J.; Huang, R. Y.; Lui, E. K. J.; Lautens, M. Org. Lett.
2011, 13, 5314.
The authors declare no competing financial interest.
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Org. Lett., Vol. XX, No. XX, XXXX