A highly efficient and broadly applicable cationic gold catalyst

Article abstract of DOI:10.1002/anie.201310239

Gold catalysts capable of promoting reactions at low-level loadings under mild conditions are the exception rather than the norm. We examined reactions where the regeneration of cationic gold catalyst (e.g., protodeauration) was the turnover limiting stag

Full text of DOI:10.1002/anie.201310239

Angewandte
Chemie
DOI: 10.1002/anie.201310239
Gold Catalysis
A Highly Efficient and Broadly Applicable Cationic Gold Catalyst**
Deepika Malhotra, Mark S. Mashuta, Gerald B. Hammond,* and Bo Xu*
Abstract: Gold catalysts capable of promoting reactions at
low-level loadings under mild conditions are the exception
rather than the norm. We examined reactions where the
regeneration of cationic gold catalyst (e.g., protodeauration)
was the turnover limiting stage. By manipulating electron
density on the substituents around phosphorus and introducing
steric handles we designed a phosphine ligand that contains
two electron-rich ortho-biphenyl groups and a cyclohexyl
substituent. This ligand formed a gold complex that catalyzed
common types of gold-catalyzed reactions including intra- and
on the three major factors that account for the high loading of
gold catalysts. These factors are: the decay of the gold catalyst
during the reaction, the formation of off-cycle gold species,
and the mismatch of electronic effects within the gold ligand.
We used the intermolecular hydroamination of phenyl
acetylene 1 with aniline as a study model.[7] As seen in
Figure 1, a popular ligand like Ph3P is not a good choice in the
À
intermolecular X H (X = C, N, O) additions to alkynes and
cycloisomerizations, with high turnover numbers at room
temperature or slightly elevated temperatures (ꢀ 508C). Our
new ligand can be prepared in one step from commercially
available starting materials.
G
old catalysis is a landmark addition to the field of organic
synthesis.[1] Goldꢀs synthetic usefulness notwithstanding, the
relatively large catalyst loading needed in many gold-cata-
lyzed applications is impractical in large-scale synthesis or
multistep syntheses because gold is an expensive metal and
the catalyst is difficult to recycle. Catalyst loadings in the ppm
range have been reported for a narrow set of gold-catalyzed
reactions.[2] Notable examples include the [(NHC)AuI]-cata-
lyzed (NHC = N-heterocyclic carbene) alkyne hydration,
reported by Nolan and co-workers;[3] the [(NHC)AuI]-cata-
lyzed intramolecular addition of diol to alkyne, reported by
Hashmi and co-workers;[4] the hydroamination of alkynes
with a hyperhalogenated carba-closo-dodecaborate anionic
ligand, reported by Lavallo and co-workers;[5] and the ester
assisted hydration of alkynes catalyzed by small gold clusters,
reported by Corma and co-workers.[6] In some exceptional
cases, even higher turnovers have been achieved but at the
cost of employing relatively high temperatures (e.g. 1208C).[3]
Our goal is to develop a broadly applicable, readily
prepared cationic gold catalyst that is efficient at ppm loading
levels and reaction temperatures equal or below 508C. The
use of relative low temperatures is important for the synthesis
of complex target molecules, which usually contain sensitive
functional groups. To design such a gold catalyst we focused
Figure 1. Ligand effect in hydroamination of 1.
reaction of 1 because the reaction is relatively slow (20%
conversion after 18 h). The low reaction rate could have been
caused by the electronic effect mismatch in the ligand, as this
reaction needs an electron-rich ligand; furthermore, the
gradual deactivation of the catalyst contributed to the low
rate of the reaction. By replacing one phenyl ring in Ph3P with
an o-biphenyl group (L2 in Figure 1) the reaction rate
increased significantly. Keeping the biphenyl group and
increasing the electron density of ligand by introducing two
electron-rich tBu groups (L3, JohnPhos) produced an even
higher rate and full conversion to product.
[*] D. Malhotra, M. S. Mashuta, Prof. Dr. G. B. Hammond,
Prof. Dr. B. Xu
These experiments underscore the importance of ortho-
substitution and electronic density matching within the
ligand, both of which were discussed in an earlier paper
from our group.[7] In that paper we suggested that: 1) the
proximity of the o-phenyl to the gold center may prevent the
deactivation of gold(I)[7] (see A in Figure 2), and 2) the
turnover limiting stage in the majority of gold-catalyzed
reactions is the regeneration of the cationic gold catalyst from
the gold s-complex intermediate (e.g., vinyl gold complex A,
Figure 2) via protodeauration. An electron-rich ligand capa-
Department of Chemistry, University of Louisville
Louisville, KY 40292 (USA)
E-mail: gb.hammond@louisville.edu
bo.xu@louisville.edu
[**] We are grateful to the NSF for financial support (CHE-1111316) and
the use of CREAM Mass Spectrometry Facility (University of
Louisville), funded by NSF/EPSCoR (EPS-0447479).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310239.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
These are not the final page numbers!

.
Angewandte
Communications
Table 1: Relative rates of hydroamination for various ligands.
Figure 2. Ligand design for gold catalysis.
ble of supplying electronic density to the gold metal center
would facilitate the regeneration of the cationic gold catalyst.
Two significant literature reports should be noted:
Widenhoefer and co-workersꢀ[8] finding that the off-cycle
gold species bis-Au-vinyl species B may reduce turnover, and
Buchwald and co-workersꢀ development of phosphine ligands
with an o-biphenyl dialkylphosphine backbone (e.g., John-
Phos, XPhos), which are widely used in transition metal
catalysis.[9] With the above findings as preamble, we hypothe-
sized that two sterically demanding biaryls on the phosphine
ligand could surround the gold center further and discourage
the formation of B (Figure 2). Thus, we designed ligand L1
(Figure 2) that featured two electron-rich and sterically
demanding ortho-biphenyl groups and one electron-rich
cyclohexyl group. We prepared L1 in a single step from
commercially available starting materials[10] (see Supporting
Information). The crystallographic structure of L1-AuCl
(Figure 2)[11] demonstrated that the two ortho-biphenyl
motifs were able to surround or embed the gold center.
A comparison between our new ligand L1 and other
benchmark ligands is shown in Table 1. We chose the carbene-
based gold catalyst L4 as a yardstick because of its proven
efficiency towards gold catalyzed reactions. L1 was the most
reactive ligand (Table 1). A ligand with three o-biphenyl
motifs (L14) was less effective, probably because of its lower
electronic density. The importance of the ligand electronic
density on the rate of hydroamination became apparent when
we kept the o-biphenyl motif unchanged and modulated the
electron densities of the two remaining groups connected to
phosphorus (L5 to L8). In this subset, electron-richer ligands
produced higher reaction rates. Substituting the o-biphenyl
group with ferrocene decreased the reaction rate significantly
(Table 1, L8 and L9). The merits of L1 were further assessed
in other gold-catalyzed intermolecular and intramolecular
reactions with C, N, or O nucleophiles so as to determine the
reaction conditions needed to achieve the highest possible
turnover for each of the reactions tested.
reported an efficient gold-catalyzed intermolecular hydro-
amination of alkynes using the precatalyst [PPh3AuCH3] in
the presence of H3PW12O40 acting as acidic promoter.[12]
Using an acidic promoter is fitting in hydroamination
because protodeauration is the rate-limiting step.[7] Shi and
co-workers reported an even higher turnover using
a
Ph3PAuOTf/benzotriazole/H3PW12O40 system (Sche-
me 1a).[13] When we used Tanakaꢀs acidic promoter with our
L1-AuCl precatalyst and the alkali salt of the bulky counter-
À [14]
ion CTf3
we found that the catalytic loading could be
reduced to 0.0025% (25 ppm) and the reaction still reached
an impressive TON of 31200. To the best of our knowledge,
no other catalyst system has matched this prowess at such low
temperature (508C). Our catalyst system also worked equally
well in relatively larger scales (10 mmol).
We chose the gold-catalyzed intermolecular addition of
N-hydroxy benzotriazole 4 to an alkyne as our model system
[15]
À
for O H addition. We were able to reduce the catalytic
We revisited the hydroamination reaction because it is
loading to 0.1% (Scheme 1b). This result is a significant
improvement over the original literature report (Scheme 1b),
which needed 5% catalyst loading.
À
a representative example of a C N bond forming reaction
where nitrogen is the nucleophile. Tanaka and co-workers
2
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
À
Scheme 1. Use of L1-AuCl in X H (X=N, O) addition to alkynes.
À
We also tested the intramolecular version of X H
addition to alkyne, which is, in general, more efficient than
the intermolecular version. For example, in the gold-catalyzed
cyclization of homopropargylic diols,[16] we observed that L1-
AuCl needed only 20 ppm to yield 92% of product 7 after
24 h at room temperature (Scheme 1c). This result was
significantly better than the 2% catalyst loading cited in the
literature.[16] L1-AuCl was also efficient in the intramolecular
cyclization of 4-pentynoic acid 8 (Scheme 1d), as demon-
strated by the TON of 9900 achieved at room temperature.
This result was far better than the available literature report
(Scheme 1d).[17]
À
À
Scheme 2. C H additions to alkynes (C C bond formations).
yields could be achieved in this reaction using low catalyst
loadings in the presence of a co-catalyst, Ga(OTf)3.[19] L1-
AuCl also performed efficiently in the synthesis of a-pyrone
(Scheme 2c). We obtained the pyrone product 15 in 95%
yield at 508C using only a catalyst load of 0.05% (500 ppm)
whereas the corresponding reaction cited in the literature[20]
needed a 5% loading.[21] We reduced the catalyst loading to
0.02% (200 ppm) and still managed to obtain a respectable
80% yield (Scheme 2c). To broaden the applicability of our
À
Since C C bond formation is the most important class of
À
À
reactions in synthesis, we studied several gold catalyzed C H
gold catalyst L1-AuCl we chose another example of a C H
additions to alkynes. We evaluated the Conia–ene reaction of
b-ketoester 10 first[18] (Scheme 2a). Again, L1-AuCl worked
very well in this reaction: it needed only 0.004% (40 ppm)
catalyst loading at room temperature to furnish the product in
95% yield. The use of an acidic promoter enhanced the
reactivity, just as it was the case in the hydroamination
reaction described earlier.
addition to an alkyne, namely the hydroarylation of 16[22]
(Scheme 2d). The product, 2H-chromene 17, was obtained in
95% yield at room temperature using a catalyst loading of
0.05% (500 ppm).
Enyne cycloisomerization is a class of reactions where
gold catalysis has proved its efficiency.[23] Using 1,6-enyne 18
as model substrate, we found that our gold catalyst needed
only a loading of 0.02% (200 ppm) to drive the enyne
cycloisomerization to completion, furnishing 19 in almost
L1-AuCl also worked well in the intermolecular version of
the Conia–ene reaction (Scheme 2b); very good to excellent
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
3
These are not the final page numbers!

.
Angewandte
Communications
[5] V. Lavallo, J. H. Wright, F. S. Tham, S. Quinlivan, Angew. Chem.
2013, 125, 3254 – 3258; Angew. Chem. Int. Ed. 2013, 52, 3172 –
3176.
[6] J. Oliver-Meseguer, J. R. Cabrero-Antonino, I. Domꢁnguez, A.
Leyva-Pꢂrez, A. Corma, Science 2012, 338, 1452 – 1455.
[7] W. Wang, G. B. Hammond, B. Xu, J. Am. Chem. Soc. 2012, 134,
5697 – 5705.
[8] T. J. Brown, D. Weber, M. R. Gagnꢂ, R. A. Widenhoefer, J. Am.
Chem. Soc. 2012, 134, 9134 – 9137.
[9] a) D. S. Surry, S. L. Buchwald, Angew. Chem. 2008, 120, 6438 –
6461; Angew. Chem. Int. Ed. 2008, 47, 6338 – 6361; b) R. A.
Altman, S. L. Buchwald, Nat. Protoc. 2007, 2, 3115 – 3121;
c) D. S. Surry, S. L. Buchwald, Chem. Sci. 2011, 2, 27 – 50;
d) E. J. Cho, T. D. Senecal, T. Kinzel, Y. Zhang, D. A. Watson,
S. L. Buchwald, Science 2010, 328, 1679 – 1681; e) D. A. Watson,
M. Su, G. Teverovskiy, Y. Zhang, J. Garcꢁa-Fortanet, T. Kinzel,
S. L. Buchwald, Science 2009, 325, 1661 – 1664.
[10] C. S. J. Keller, C. Nolte, P. Mayer, B. F. Straub, Synthesis 2006,
354 – 365.
Scheme 3. Enyne and allenone cycloisomerization.
[11] CCDC 973355 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.
cam.ac.uk/data_request/cif.
[12] E. Mizushima, T. Hayashi, M. Tanaka, Org. Lett. 2003, 5, 3349 –
3352.
[13] H. Duan, S. Sengupta, J. L. Petersen, N. G. Akhmedov, X. Shi, J.
Am. Chem. Soc. 2009, 131, 12100 – 12102.
[14] See Supporting Information.
quantitative yield (Scheme 3a). In contrast, a similar reaction
reported in the literature[23] needed a 2% catalyst loading. We
also investigated the cycloisomerization of allenone 20, first
reported by Hashmi and co-workers[24] and later refined by
Che and co-workers (Scheme 3b).[25] Using 0.01% (100 ppm)
of our catalyst L1-AuCl, we obtained the desired furan 16 in
quantitative yield after 7 h at room temperature; this result
corresponded to a TON of 10000.
[15] M. Kumar, M. Scobie, M. S. Mashuta, G. B. Hammond, B. Xu,
Org. Lett. 2013, 15, 724 – 727.
In summary, we have found a broadly applicable cationic
gold catalyst system that is highly efficient at extremely low
loadings and relatively low temperatures. Our reactions were
conducted in open-air containers using commercial solvents
that needed no prior purification. The catalyst L1-AuCl is
now available from Aldrich under the name BisPhePhos XD
gold(I) chloride (catalog no. L511846).
[16] a) L.-P. Liu, G. B. Hammond, Org. Lett. 2009, 11, 5090 – 5092;
b) S. Antoniotti, E. Genin, V. Michelet, J.-P. GenÞt, J. Am. Chem.
Soc. 2005, 127, 9976 – 9977.
[17] a) E. Tomꢃs-Mendivil, P. Y. Toullec, J. Dꢁez, S. Conejero, V.
Michelet, V. Cadierno, Org. Lett. 2012, 14, 2520 – 2523; b) P. Y.
Toullec, E. Genin, S. Antoniotti, J.-P. GenÞt, V. Michelet, Synlett
2008, 707 – 711.
[18] J. J. Kennedy-Smith, S. T. Staben, F. D. Toste, J. Am. Chem. Soc.
2004, 126, 4526 – 4527.
[19] a) Y. Xi, D. Wang, X. Ye, N. G. Akhmedov, J. L. Petersen, X. Shi,
Org. Lett. 2014, 16, 306 – 309; b) R.-V. Nguyen, X.-Q. Yao, D. S.
Bohle, C.-J. Li, Org. Lett. 2005, 7, 673 – 675; c) Y.-P. Xiao, X.-Y.
Liu, C.-M. Che, Angew. Chem. 2011, 123, 5039 – 5043; Angew.
Chem. Int. Ed. 2011, 50, 4937 – 4941.
Received: November 26, 2013
Revised: February 25, 2014
Published online: && &&, &&&&
Keywords: biaryl · gold catalysis · phosphine ligand
.
[20] T. Luo, M. Dai, S.-L. Zheng, S. L. Schreiber, Org. Lett. 2011, 13,
2834 – 2836.
[21] The use of AgOTf is less effective in our catalytic system.
[22] N. Mꢂzailles, L. Ricard, F. Gagosz, Org. Lett. 2005, 7, 4133 – 4136.
[23] a) C. Bartolomꢂ, Z. Ramiro, P. Pꢂrez-Galꢃn, C. Bour, M.
Raducan, A. M. Echavarren, P. Espinet, Inorg. Chem. 2008, 47,
11391 – 11397; b) C. Bartolomꢂ, Z. Ramiro, D. Garcꢁa-Cua-
drado, P. Pꢂrez-Galꢃn, M. Raducan, C. Bour, A. M. Echavarren,
P. Espinet, Organometallics 2010, 29, 951 – 956; c) C. Nieto-
Oberhuber, M. P. MuÇoz, E. BuÇuel, C. Nevado, D. J. Cꢃrdenas,
A. M. Echavarren, Angew. Chem. 2004, 116, 2456 – 2460; Angew.
Chem. Int. Ed. 2004, 43, 2402 – 2406.
[24] a) A. S. K. Hashmi, L. Schwarz, J.-H. Choi, T. M. Frost, Angew.
Chem. 2000, 112, 2382 – 2385; Angew. Chem. Int. Ed. 2000, 39,
2285 – 2288; b) C.-Y. Zhou, P. W. H. Chan, C.-M. Che, Org. Lett.
2006, 8, 325 – 328.
[25] C.-Y. Zhou, P. W. H. Chan, C.-M. Che, Org. Lett. 2006, 8, 325 –
328.
[1] a) A. S. K. Hashmi, Chem. Rev. 2007, 107, 3180 – 3211; b) M.
Rudolph, A. S. K. Hashmi, Chem. Soc. Rev. 2012, 41, 2448 –
2462; c) D. J. Gorin, B. D. Sherry, F. D. Toste, Chem. Rev. 2008,
108, 3351 – 3378; d) Z. Li, C. Brouwer, C. He, Chem. Rev. 2008,
108, 3239 – 3265; e) P. Garcia, M. Malacria, C. Aubert, V.
Gandon, L. Fensterbank, ChemCatChem 2010, 2, 493 – 497;
f) A. Arcadi, Chem. Rev. 2008, 108, 3266 – 3325.
[2] a) J. H. Teles, S. Brode, M. Chabanas, Angew. Chem. 1998, 110,
1475 – 1478; Angew. Chem. Int. Ed. 1998, 37, 1415 – 1418; b) E.
Mizushima, K. Sato, T. Hayashi, M. Tanaka, Angew. Chem. 2002,
114, 4745 – 4747; Angew. Chem. Int. Ed. 2002, 41, 4563 – 4565.
[3] N. Marion, R. S. Ramon, S. P. Nolan, J. Am. Chem. Soc. 2009,
131, 448 – 449.
[4] M. C. Blanco Jaimes, C. R. N. Bçhling, J. M. Serrano-Becerra,
A. S. K. Hashmi, Angew. Chem. 2013, 125, 8121 – 8124; Angew.
Chem. Int. Ed. 2013, 52, 7963 – 7966.
4
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Gold Catalysis
D. Malhotra, M. S. Mashuta,
G. B. Hammond,* B. Xu*
&&&& — &&&&
A Highly Efficient and Broadly Applicable
Cationic Gold Catalyst
Less is better: A broadly applicable
cationic gold catalyst was developed that
works at extremely low loading and
relatively low temperature. The new gold
catalyst containing a bis(biphenyl) phos-
phane ligand was tested in many
common types of gold-catalyzed reac-
tions including intra- and intermolecular
À
X H (X=C, N, O) additions to alkynes
(see example) and cycloisomerizations of
enyne and allenone.
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!