A Highly Efficient and Broadly Applicable Cationic Gold Catalyst
Gold Catalysis DOI:10.1002/anie.201310239 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 intermolecular XàH(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]Gold s 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)Au I]-cata-lyzed(NHC=N-heterocyclic carbene)alkyne hydration, reported by Nolan and co-workers;[3]the[(NHC)Au I]-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 below508C.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 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 acetylene1with aniline as a study model.[7]As seen in Figure1,a popular ligand like Ph3P is not a good choice in the reaction of1because the reaction is relatively slow(20% conversion after18h).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(L2in Figure1)the reaction rate increased significantly.Keeping the biphenyl group and increasing the electron density of ligand by introducing two electron-rich t Bu groups(L3,JohnPhos)produced an even higher rate and full conversion to product.
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 Figure2),and2)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, Figure2)via protodeauration.An electron-rich ligand
capa-Figure1.Ligand effect in hydroamination of1.
[*]D.Malhotra,M.S.Mashuta,Prof.Dr.G.B.Hammond, Prof.Dr.B.Xu
Department of Chemistry,University of Louisville
Louisville,KY40292(USA)
E-mail:gb.hammond@https://www.wendangku.net/doc/f713526409.html,
bo.xu@https://www.wendangku.net/doc/f713526409.html,
[**]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 https://www.wendangku.net/doc/f713526409.html,/10.1002/anie.201310239.
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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-workers [8]finding that the off-cycle gold species bis-Au-vinyl species B may reduce turnover,and Buchwald and co-workers 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 L1in 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 L1and other benchmark ligands is shown in Table 1.We chose the carbene-based gold catalyst L4as a yardstick because of its proven efficiency towards gold catalyzed reactions.L1was 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 (L5to 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,L8and L9).The merits of L1were 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.
We revisited the hydroamination reaction because it is a representative example of a C àN bond forming reaction where nitrogen is the nucleophile.Tanaka and co-workers
reported an efficient gold-catalyzed intermolecular hydro-amination of alkynes using the precatalyst [PPh 3AuCH 3]in the presence of H 3PW 12O 40acting 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 Ph 3PAuOTf/benzotriazole/H 3PW 12O 40system (Sche-me 1a).[13]When we used Tanaka s acidic promoter with our L1-AuCl precatalyst and the alkali salt of the bulky counter-ion CTf 3à[14]we found that the catalytic loading could be reduced to 0.0025%(25ppm)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 (10mmol).
We chose the gold-catalyzed intermolecular addition of N-hydroxy benzotriazole 4to an alkyne as our model system for O àH addition.[15]We were able to reduce the catalytic loading to 0.1%(Scheme 1b).This result is a significant improvement over the original literature report (Scheme 1b),which needed 5%catalyst
loading.
Figure 2.Ligand design for gold catalysis.
Table 1:Relative rates of hydroamination for various
ligands.
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We also tested the intramolecular version of X àH 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 20ppm to yield 92%of product 7after 24h 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 9900achieved at room temperature.This result was far better than the available literature report (Scheme 1d).[17]
Since C àC bond formation is the most important class of reactions in synthesis,we studied several gold catalyzed C àH additions to alkynes.We evaluated the Conia–ene reaction of b -ketoester 10first [18](Scheme 2a).Again,L1-AuCl worked very well in this reaction:it needed only 0.004%(40ppm)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.
L1-AuCl also worked well in the intermolecular version of the Conia–ene reaction (Scheme 2b);very good to excellent
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 15in 95%yield at 508C using only a catalyst load of 0.05%(500ppm)whereas the corresponding reaction cited in the literature [20]needed a 5%loading.[21]We reduced the catalyst loading to 0.02%(200ppm)and still managed to obtain a respectable 80%yield (Scheme 2c).To broaden the applicability of our gold catalyst L1-AuCl we chose another example of a C àH 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%(500ppm).
Enyne cycloisomerization is a class of reactions where gold catalysis has proved its efficiency.[23]Using 1,6-enyne 18as model substrate,we found that our gold catalyst needed only a loading of 0.02%(200ppm)to drive the enyne cycloisomerization to completion,furnishing 19in
almost
Scheme https://www.wendangku.net/doc/f713526409.html,e of L1-AuCl in X àH (X =N,O)addition to
alkynes.
Scheme 2.C àH additions to alkynes (C àC bond formations).
https://www.wendangku.net/doc/f713526409.html,
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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%(100ppm)of our catalyst L1-AuCl,we obtained the desired furan 16in quantitative yield after 7h at room temperature;this result corresponded to a TON of 10000.
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).
Received:November 26,2013Revised:February 25,2014
Published online:March 20,2014
.
Keywords:biaryl ·gold catalysis ·phosphine ligand
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Scheme 3.Enyne and allenone cycloisomerization.
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