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Mechanistic insights into the gold chemistry of allenes Weibo Yang* and A. Stephen K. Hashmi* Although most mechanistic studies on gold-catalysed reactions focused on alkynes as substrates, some
Received 1st December 2013 DOI: 10.1039/c3cs60441a
knowledge about gold-catalysed conversions of allenic substrates has been obtained. This contribution summarises these insights into the reaction mechanisms of gold-catalysed transformations of allenes which are based on computational studies, labelling studies, the detection of intermediates, chirality
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transfer and diastereoselective product formation.
Key learning points (1) The importance of combining experimental mechanistic evidence like detecting intermediates, isotope labeling studies and chirality transfer and computational chemistry is demonstrated. (2) Fundamental reactivity patterns are provided for cycloaddition and nucleophilic addition reactions. (3) Different types of gold catalysts for the conversions of allenes are discussed. (4) Vinyl gold, gold carbenoid, allyl gold and gem-diaurated intermediates are presented.
1 Introduction The application of gold complexes, soft carbophilic Lewis acids which can activate carbon–carbon multiple bonds towards the attack of a large variety of nucleophiles, has been intensively investigated over the past decade.1–9 In comparison to the extensive methodology development in the field of gold-catalysed transformations, the mechanisms of these transformations remain poorly defined and in most cases represent a significant challenge.10 Therefore the systematic experimental study and the computational analysis of the mechanisms of gold-catalysed reactions are slowly being recognised as important in the development of new goldcatalysed transformations. In the case of experimental studies, the isolation and characterisation of organogold intermediates have become the most efficient tools to understand and support the mechanisms of homogenous gold catalysis. Recently, an outstanding review by Liu and Hammond summarised the advances in the isolation and reactivity of organogold complexes.11 However, these isolable intermediates are very rare and are mainly formed via the addition of nucleophiles to alkynes or alkenes in the presence of the gold catalyst. The aspect of selectivity is problematic in the case of allenes; in addition reactions all chemoselectivity, diastereoselectivity, ¨t Heidelberg, Im Neuenheimer Feld 270, Organisch-Chemisches Institut, Universita 69120 Heidelberg, Germany. E-mail: [email protected]
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enantioselectivity, regioselectivity and positional selectivity can be involved.12 Since allenes possess this unique reactivity and a particular coordination mode to the cationic Au metal center of the catalysts, only a few experimental mechanistic investigations of nucleophilic addition to allenes exist. On the other hand the number of theoretical studies is increasing quite rapidly. In 2011, an intriguing review on the mechanism of gold-catalysed cycloadditions of allenes with a focus on theoretical methods was ´s and co-workers.13 However, to our knowledge, published by Lledo no comprehensive review on the mechanisms of gold-catalysed transformations involving allenes exists. This tutorial review for the first time will summarise and discuss the mechanistic studies on the gold chemistry of allenes not only from an experimental point of view, but also cover computational analysis. Notably, it focuses on gold-catalysed cycloadditions of allenes, gold-catalysed nucleophilic additions to allenes and gold-catalysed [3,3]-sigmatropic rearrangements involving allene intermediates.
2 Mechanistic studies of goldcatalysed cycloadditions of allenes Gold-catalysed cycloadditions of allenes have grown considerably and have become a powerful method for the synthesis of polycyclic products in a highly regio- and stereocontrolled
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Fig. 1
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Four principal coordination modes of (R)-1,3-dimethyl allene to AuBr3 and their relative computational energies.
fashion from relatively simple acyclic organic fragments. Notably, apart from the exploration of new and versatile gold-catalysed cycloadditions of allenes, attempting to gain insight into the mechanism of these transformations is important for organic chemists. It is well established that there exist four different coordination modes of allenes to the Au metal center. Indeed, these different coordination modes can be divided into Z2-coordinated complexes I, s-allylic cations II, zwitterionic carbenes III and Z2-coordinated bent allenes IV (Fig. 1). Furthermore, the coordination mode is an important factor in determining the stereochemical outcome of the transformation. For instance, in axis-to-center transfer the stereochemical information is maintained in species I or IV; however, due to the three carbons and their substitutents being positioned in the same plane, it seems to be lost in II or III. In 2008, Malacria et al. carried out a computational study to gain insight into the nature of these intermediates.14 They investigated the interaction of allenes with gold complexes, specifically (R)-1,3-dimethyl allene in the presence of AuBr3 (AuCl3 and Au+ and some other transition metal complexes were also investigated). Two diastereomeric complexes of type I were local minima, in addition type II and IV complexes. In II and IV the three allene carbons and the metal fragment lie in the same plane. With a relative energy
Weibo Yang
Weibo Yang studied chemistry at Dalian University of Technology, China, and then with a CSC fellowship joined the group of A. S. K. Hashmi in Heidelberg, Germany, in 2010. There he obtained his PhD in 2013 with a remarkable thesis on methodology development in homogeneous gold catalysis. He has now joined the group of J.-Q. Yu at Scripps Institute, California, USA, for his postdoctorate.
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of +3.5 kcal mol1 IV is the least stable form among these local minima. Their results suggest that not only the nature of the allene substituents, but also the properties of the particular gold complex employed have a crucial influence on the coordination modes.
2.1 Mechanistic studies of gold-catalysed intramolecular [4+3] cycloadditions of allenedienes ˜as et al. reported the formation of bicyclo[5.3.0]In 2008, Mascaren decanes by a novel platinum-catalysed intramolecular [4+3] cycloaddition process of allenedienes.15 One year later the same group also described that the same reactions smoothly proceed in the presence of a Au(I) catalyst, generated in situ from [(IPr)AuCl] and AgSbF6, under milder conditions.16 The reaction mechanism is outlined in Scheme 1. Initially, the intermediate A is formed via Z2-coordinated mode I which is a p-activation of the allene 1 by the metal catalyst. Subsequently, a metalbound allylic cation intermediate B is generated, followed by a concerted [4+3] intramolecular cycloaddition with the diene forming the intermediate C. Finally, a 1,2-H shift on the resulting cycloheptenyl metal-carbene produces the expected product 2 and regenerates the catalyst.
A. Stephen K. Hashmi studied chemistry at the LMU Munich, where he obtained his diploma and PhD with Prof. G. Szeimies in the field of nickel- and ironcatalysed cross coupling of strained organic compounds. His postdoctorate with Prof. B. M. Trost at Stanford University covered transition metal catalysed enyne metathesis. After his habilitation on enantiomerically pure organopalladium compounds and A. Stephen K. Hashmi palladium-catalysed conversions of allenes with Prof. J. Mulzer at the FU Berlin, the JWG-University Frankfurt and the University of Vienna, in 1998 he was awarded a Heisenberg fellowship of the DFG for a proposal on gold-catalysed reactions for organic synthesis – still a major focus of the group. The next stations were University of Tasmania 1999, Marburg University 1999–2000, in 2001 he was appointed Professor for Organic Chemistry at Stuttgart University and since 2007 he occupies a chair for Organic Chemistry at Heidelberg University.
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Scheme 3 Trapping the gold carbenoid intermediate by oxygen transfer from diphenylsulfoxide.
Scheme 1
Mechanistic hypothesis for a diene–allene [4+3] cycloaddition.
Moreover, this mechanism was explored by a DFT calculation analysis using dimethylallene 1 as the model substrate together with AuCl, AuCl3, (NHC)Au+ and PtCl2 complexes as catalysts (Scheme 2). The DFT calculation results are consistent with the experimental observation. The different energy barriers evolved from A and the relative stability of the allylic cation intermediate B indicated that the nature of the metal complexes played a significant role during this process. The lowest energy barrier and the most stable intermediate C showed that a fast and
Scheme 2
irreversible [4+3] cycloaddition process occurs within the overall catalytic cycle for all the catalysts. The highest energy barrier was observed in the last step, consisting of a 1,2-H-shift with simultaneous coordination of the newly formed double bond to the metal, which might become the rate-determining step. The highest relative energy barrier (25.6 kcal mol1) can perfectly explain the fact that a PtCl2-catalysed aforementioned [4+3] cycloaddition requires a high temperature (110 1C), whereas a good conversion was obtained for AuCl and AuCl3 catalysts at room temperature with the energy barriers of 14.6 kcal mol1 and 12.3 kcal mol1, respectively. For the cationic (NHC)Au+, generated in situ from [(IPr)AuCl] and AgSbF6, which exhibits the lowest energy barrier of 8.6 kcal mol1, the reaction can be carried out at 0 1C in less than 1 h. Apart from the DFT calculations for the gold-catalysed diene–allene [4+3] cycloaddition, an additional experimental mechanistic proof was presented by the same authors. They attempted to introduce phenyl sulfoxide as an oxidant in order to trap the gold carbenoid intermediate C (Scheme 3). Fortunately, they succeeded in trapping this stable gold carbenoid intermediate C by isolating the corresponding ketone 4 in 25% yield. 2.2 Mechanistic studies of gold-catalysed intramolecular [4+2] cycloadditions of allenedienes During the investigation of the gold-catalysed intramolecular [4+3] cycloaddition of allenedienes, the same group discovered a competing [4+2] cycloaddition reaction when using a specific
Comparison of the DFT energy profiles for different gold catalysts and PtCl2 (relative gas phase electronic energies in kcal mol1).
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Scheme 4 Mechanistic proposal for the [4+2] process based on an initial [4+3] cycloaddition and a subsequent ring contraction (the proposal is based on experimental and computational studies).
allenediene bearing two substituents at the distal position.17 Notably, with more electron-accepting ligands such as phosphites and phosphoramidites, the corresponding trans-fused bicyclic cycloadducts 5 can be obtained in good yields with high chemo- and stereoselectivity (Scheme 4). The proposed mechanism for the formation of the [4+2] cycloadducts might arise from a 1,2-alkyl migration (ring contraction) in the cycloheptenyl Au–carbene intermediate C, itself arising from a [4+3] concerted cycloaddition of the allenediene. In addition, a hypothetical stepwise mechanism involving a common carbocationic intermediate F could also explain the
Scheme 5
Table 1
aforementioned results about the formation of 2 and 5 (Scheme 5). However, this hypothesis was easily discounted by trapping experiments using methanol (Table 1). Subsequently, they chose 6 as the starting material and added different amounts of MeOH in the presence of G as a catalyst in order to intercept the allyl carbocationic intermediate F. However, when the reaction was carried out in CH2Cl2 together with 3 equiv. MeOH as the trapping agent, it provided only the [4+2] cycloadduct 7 (Table 1, entry 1). In a more polar solvent, such as MeNO2, the reaction provided a mixture of products consisting of 7 and an acyclic compound 8 in a ratio of 8.5 : 1.5 (Table 1, entry 2). Indeed, even when switching to the solvent MeOH, the sole products are 8 and its regioisomer 9 (ratio 8 : 9 = 85 : 15), while no traces of trapping products derived from F could be detected (entry 3). This experimental study provides evidence against the stepwise mechanism and indirectly corroborates the 1,2-alkyl and 1,2-H migration mechanism; still it cannot be excluded that the reaction occurs step-wise but the intramolecular reaction of F is faster than the intermolecular reaction with methanol.
Asymmetric cycloaddition reactions of 10 were carried out in the presence of different phosphoramidite–gold catalysts. As can be seen from Table 2, all the different phosphoramidite–gold catalysts bearing enantiomerically pure ligands G1–G5 could
Hypothesis of an involvement of a carbocationic intermediate F in the [4+2] process (proposal based on experimental evidence).
Experimental evidence allowed to discard the mechanism involving a common carbocationic intermediate F
Entrya
Solvent
MeOH
7 : 8 : 9b
1 2 3
CH2Cl2 MeNO2 MeOH
3 equiv. 3 equiv. Solvent
100 : 0 : 0 85 : 15 : 0 0 : 85 : 15
a Conditions: 1b (1 equiv., 0.15 M), G (10 mol%) and AgSbF6 (10 mol%) for 1–3 h. Conversions 499%. crude mixtures.
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b
Ratios determined by 1H NMR in the
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Table 2
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Comparison of the enantioselectivities of 11 and 12, isolated from the reaction of 10 using different Au catalysts
Entrya
L*AuCl
Temp. (1C)
11 : 12b
11, erc
12, erc
1 2 3 4 5 6 7 8
(S)-Catalyst G1 (S,S)-Catalyst G2 (S,S,S)-Catalyst G3 (R,S,S)-Catalyst G3 (S,S)-Catalyst G4 (S,R,R)-Catalyst G5 (S,S,S)-Catalyst G5 (S,S,S)-Catalyst G5
23 23 23 23 23 23 23 15
6:1 3:1 4.5 : 1 3:1 4:1 4:1 7:1 8:1
51 : 49 52 : 48 60 : 40 52 : 48 61 : 39 57 : 43 76 : 24 87 : 13
50.5 : 49.5 52 : 48 59 : 41 53 : 47 61 : 39 56 : 44 76 : 24 87 : 13
a b
Conditions: 1a (1 equiv.), L*-AuCl (10 mol%) and AgSbF6 (10 mol%) in CH2Cl2 (0.15 M) for 1–3 h unless otherwise noted. Conversions 499%. Determined by 1H NMR in the crude mixtures. c er: the enantiomeric ratio (determined by HPLC).
provide almost the same enantiomeric excess for both the major [4+2] product 11 and the minor [4+3] product 12. Also, the same er values for both [4+3] and [4+2] products could be obtained. These results strongly suggest that [4+3] and [4+2] share a common intermediate in the enantiodetermining step, which evolved to either the six or the seven-membered cycloaddition products.
and a key divergent point during the whole catalytic cycle with a relative energy of 12.1 kcal mol1. On the one hand it can provide the [4+3] cycloaddition product by a 1,2-hydrogen shift. On the other hand it can result in the formation of the [4+2] cycloaddition product through a 1,2-alkyl migration. These two competitive pathways need the energy barriers of 10.3 and 8.7 kcal mol1, respectively. This little difference in energy
Based on the experimental studies of the mechanism, the primary DFT analysis of the mechanism of the disubstituted allenedienes with [(MeO)3PAu]+ as the catalyst was performed and indicated reaction pathways similar to the preceding study, the Au catalysts being involved in the two initial steps. As shown in Scheme 6, coming from intermediate A the formation of the allylic cation in the organogold intermediate B requires an energy barrier of 4.2 kcal mol1. Then intermediate B easily gave rise to a 7-membered ring gold carbenoid species C derived from a [4+3] cycloaddition with a relatively low energy barrier of only 2.5 kcal mol1. It should be noted that the cycloheptene–gold species C is the most stable intermediate
barriers indicated that both products can be formed, although the formation of the [4+2] adduct is slightly favored. Subsequently, the same group also carried out another DFT calculation with unsubstituted allenediene as the model substrate to analyse two competitive pathways for 1,2-alkyl and 1,2-H migration which led to [4+2] and [4+3] cycloaddition products, respectively (Scheme 7). It should be noted that these two different products derived from unsubstituted allenedienes still share the two initial steps. Once the 7-membered ring intermediate H is formed, the relative energy barrier for the 1,2-H shift leading to the [4+3] product is 11.7 kcal mol1. With regard to the 1,2-alkyl migration resulting in the formation of
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Scheme 6
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The DFT profile for the cycloaddition of a model substrate 1 with the [(MeO)3PAu]+ catalyst (relative gas phase electronic energies in kcal mol1).
Scheme 7 The DFT energy profile comparing the pathway of the 1,2-alkyl migration (Ts4) and 1,2-H migration (Ts3) using non-substituted allene (relative gas phase electronic energies in kcal mol1).
[4+2] product, however, the relative energy barrier is 23.8 kcal mol1. The obvious results demonstrated that the 1,2-H shift leading to the formation of the [4+3] product is significantly more favorable in unsubstituted allenedienes system. Moreover, the formation of the [4+2] cycloadduct seems to be strongly dependent on the ability of allene distal substituents to stabilise the positive charge located at the adjacent position of the Au–carbene center during the 1,2-alkyl migration process.
2.3 Mechanistic studies of gold(I)-catalysed [2+2] cycloadditions In 2011, Toste and co-workers investigated the mechanism of gold(I)-catalysed [2+2] cycloadditions (forming 18) and gold(I)catalysed cyclisation/alkoxylation (forming 17) reactions of allenenes 16 by computational analysis (Scheme 8).18
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The DFT calculations indicated that both pathways involved a five-membered metallacyclic intermediate formed from intermediates R 0 and R00 (Scheme 9). Notably, the formation of the five-membered metallacyclic intermediate with trans-arrangement of the substitutents on the ring (T 0 ) shows an energy barrier of 10.4 kcal mol1, which is lower than for the cis-arrangement in S 0 (13.3 kcal mol1). In the case of the cis-intermediate S 0 , only a low energy barrier of 2.5 kcal mol1 is required to form the cyclobutane ring in 18 0 . Experimentally, adding MeOH to the isolated 18 0 in the presence of (PhO)3PAuBF4 did not give the alkoxycyclisation product 17 0 , demonstrating that the formation of 18 0 is irreversible under these reaction conditions. This irreversibility was consistent with the calculated high energy barrier of the reverse reaction (24.5 kcal mol1). With regard to the cis pathway, the absence of deuterium loss in the gold(I)-catalysed formation of 17 0 from 16 0 suggests that the
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alkoxycyclisation product is not formed from the addition of MeOH to the styrene moiety of a 1,4-diene (190 ) but from a cationic intermediate T0 , which is in agreement with the computational studies. Additionally, the results suggested that both the cis- and the trans-pathway are competing, but in the presence of a nucleophile (MeOH), the trans-pathway is preferred. However, in the absence of a viable nucleophile, the cis-pathway is operative.
3 Mechanistic studies of goldcatalysed hydroamination, hydroarylation and hydroalkoxylation of allenes
Scheme 8 Gold(I)-catalysed [2+2] cycloadditions and cyclisation/alkoxylation of allenenes 16 (proposal is based on experimental and computational studies).
The gold-catalysed addition of carbon-, oxygen- and nitrogenbased nucleophiles to allenes, leading to the formation of new C–O, C–N or C–C bonds, has emerged as an efficient strategy for the synthesis of natural products.19 However, the mechanistic studies of these reactions are scarce. Therefore, the investigation of the mechanism is highly desirable. It is well-known that both outer sphere and inner sphere mechanisms have been proposed for gold-catalysed nucleophilic addition reactions to allenes (Scheme 10).20,21 In the outer sphere mechanism the cationic gold(I) complex activates the allenes and induces an anti-addition of the nucleophile. Eventually, protodemetalation of the ‘‘anti’’-vinyl gold intermediate then regenerates the gold(I) catalyst. However, in the inner sphere mechanism both the allene and the nucleophile interact with the gold complex at the same time. Subsequently, a syn-addition of the nucleophile and the gold complex across the allene is observed. Then protodemetalation forms the product. In the case of terminal allenes, the products of both pathways are indistinguishable, but in the case of diastereofacial p-faces of the allene, products with the opposite relative configuration of the double bond and the olefin are obtained. 3.1 Mechanistic studies of the gold-catalysed hydroamination of allenes
Scheme 9 The DFT profile for the potential free energy surface for the cis and trans cyclisation pathways.
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In 2010, Toste and co-workers reported an intermolecular gold(I)-catalysed hydroamination reaction of allenes with hydrazide nucleophiles and investigated the mechanism of this transformation (Scheme 11).22 They used 31P NMR methods to investigate the nature of gold(I) intermediates. Two samples containing Ph3PAuNTf2 and methyl carbazate (1 : 1 ratio) and Ph3PAuNTf2 and 24 (1 : 10 ratio) in CD3NO2 were prepared. The former sample showed a broadened 31P NMR signal at 29.7 ppm and the 31P NMR signal at 45.2 ppm was observed in the latter sample. These results indicated that the gold–allene complex intermediate was favored at the beginning and is the resting state of the reaction and the gold–amine intermediate is less stable due to the weak nitrogen gold(I) interaction. Moreover, the chirality transfer was further carried out to determine whether the reaction proceeded through chiral or planar gold intermediates. They observed that the best chiral transfer was 56%, and this was achieved in the presence of
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Scheme 10
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Outer sphere and inner sphere mechanisms proposed for nucleophilic addition reactions to allenes.
Scheme 11 The gold(I)-catalysed intermolecular hydroamination reaction of allenes using hydrazide and two gold intermediates was monitored by 31P NMR analysis.
more than 4 equiv. of methyl carbazate. This indicates that the reaction cannot be proceeding exclusively through a planar intermediate. Otherwise, the racemisation can occur through a planar intermediate process (Table 3). Subsequently, they attempted to probe whether the intermolecular hydroamination reaction is reversible or not. The enantioenriched 27 (56% ee) together with 2 equiv. of methyl carbazate were reacted in the presence of 10 mol% Ph3PAuNTf2
Table 3 Chirality transfer for the hydroamination of chiral 26 in the presence of Ph3PAuNTf2 catalyst at various equivalents of methyl carbazate
Equiv. of Nuc
Yield (%)
ee (%)
1.0 2.0 4.0 8.0
81 75 81 79
28 48 56 56
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at 45 1C (Scheme 12). No erosion of enantiopurity was observed; the remaining 27 after 6 h still showed the identical 56% ee, supporting an irreversible protodemetalation. However, a reversible reaction regenerates an enantioenriched allene, the latter then reacts with methyl carbazate providing 27 with good chirality transfer, which could also explain the conservation of the enantiomeric excess. A competitive trapping experiment successfully excluded the reversible protodemetalation mechanism; no 29 could be detected. 3.2 Mechanistic studies of the gold-catalysed hydroarylation of allenes ´ and co-workers developed a highly selective In 2008, Gagne intramolecular gold(I)-catalysed allene hydroarylation reaction, producing vinyltetrahydronaphthalenes in good to excellent yields (Scheme 13).23 They initially proposed the vinyl-gold(I) intermediate 32 to be involved in the mechanism. However, subsequent experimental studies indicated that both 32 and 34 might be catalytic intermediates of the mechanistic cycle. It should be noted that the similar dinuclear species 34 have been postulated on the basis of DFT studies. In order to validate
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Scheme 12 Experimental proof of the irreversibility of the gold(I)-catalysed intermolecular hydroamination.
Scheme 13 The proposed catalytic cycle for the gold(I)-catalysed intramolecular hydroarylation of allenes (proposal is based on experimental evidence).
these intermediates by experimental studies, in situ 31P NMR ´ et al. observed that the 31P NMR analysis was used.24 Gagne spectra of the intermediate 34 showed two peaks in a 1 : 1 ratio at around d = 36 ppm rather than the expected peaks at around d = 44 ppm. Additionally, the 1H NMR spectra of vinyl hydrogen atoms showed large upfield shifts of the syn (d = 6.43 ppm (34) to d = 4.97 ppm (32)) and anti (d = 5.91 ppm (34) to d = 5.62 ppm (32)), suggesting significantly different chemical environments in the two intermediates. The relevance of vinyl gold complexes 32 and 34 was evaluated by stoichiometric experiments. Compound 32 was found to readily react with stoichiometric quantities of HX (X = Cl, NTf2) by protodeauration to yield 33 and the expected gold(I) species (Scheme 14). The compounds 34 and 33 can be obtained by adding 0.5 equivalent of HNTf2 into 32. 34 does not directly protodeaurate, by cleaving off Ph3PAu+; it is in equilibrium with 32, which then is protodeaurated. Additionally, 32 and 1.0 equivalent of PPh3AuNTf2 can be rapidly and cleanly converted into the digold-vinyl intermediate 34.
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3.3 Mechanistic studies of the gold-catalysed hydroalkoxylation of allenes The gold-catalysed intramolecular addition of alcohols to allenes in principle is highly related to the corresponding intramolecular nucleophilic additions of alcohols to alkynes. The first evidence for an in situ reduction of gold(III) catalysts in these reactions was obtained in the context of the AuCl3-catalysed cycloisomerisation of allenyl carbinols.25 These 1,1-disubstituted allenyl carbinols gave the products of an oxidative dimerisation. As this occurred even under exclusion of any other oxidants and in amounts correlating with the applied amount of AuCl3 (Scheme 15), this indicated that gold(III) had to be the oxidant and is reduced in the process. ´ and Widenhoefer reported the mechanistic investigaGagne tion of the gold(I)-catalysed intramolecular hydroalkoxylation of 2,2-diphenyl-4,5-hexadien-1-ol (37) to form 2-vinyltetrahydrofuran 38 (Scheme 16).26 The air-stable as well as thermally stable vinyl gold intermediate 39 (Scheme 17) was obtained by crystallisation from
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Scheme 14
Reactivity of intermediate 32.
Scheme 15 Direct evidence for the in situ reduction of gold(III) by oxidative dimerisation of the vinyl gold intermediate in the catalytic cycle.
Scheme 16
The gold(I)-catalysed intramolecular hydroalkoxylation.
warm hexanes in 87% yield. Subsequent treatment of 39 with (L)AuOTs (1 equiv.) in CD2Cl2 at 0 1C led to the immediate formation of the bis(gold) vinyl intermediate 40 in 98% NMR yield. Notably, the 31P NMR spectrum of 40 displayed a 1 : 1 ratio of resonances at d 61.7 and 60.9, which indicated the presence of chemically inequivalent (L)Au+ fragments. The change of chemical shifts in the 1H NMR shifts of the vinylic protons of 40 [d 4.84 and 3.90] relative to those of 39 [d 5.48 and 4.45] further demonstrated interaction of the vinyl moiety of 40 with both (L)Au+ fragments.
Scheme 17
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Reaction of 37 and a stoichiometric amount of (L)AuOTs in CD2Cl2 at 80 1C resulted in the fast formation of a 1 : 1 mixture of 37 and 40 without generation of a detectable amount of 39 or 38, which established that the C–O bond formation and aggregation are favorable compared to the protodeauration (Scheme 18). Next, a transfer of 39 to 40 was investigated. Treatment of mono(gold(I)) vinyl species 39 with TsOH (1 equiv.) at 25 1C led to the fast formation of tetrahydrofuran 38 in 99 5% yield. However, 1 H NMR analysis of the reaction of 39 with TsOH (1 equiv.) at 80 1C revealed immediate ring opening/aggregation to form a 1 : 1 mixture of 37 and 40 in 490% combined yield. Therefore, these experimental studies supported a mechanism for the gold-catalysed conversion of 37 to 38 involving a rapid and reversible outer sphere C–O bond formation and an off-cycle catalyst mode. 3.4 Mechanistic studies of gold-catalysed additions of carbonyl oxygen atoms to allenes In 2005, Gevorgyan and co-workers reported a gold-catalysed regiodivergent cycloisomerisation of bromoallenyl ketones 13, regiodivergent with regard to the formation of the isomeric bromofurans 14 and 15 (Scheme 19).27 The mechanism of the gold(III)-catalysed conversion of bromoallenyl ketones was proposed through a 1,2-Br migration leading to the product 14. Alternatively, 1,2-H migration was involved in this gold(I)catalysed reaction forming the product 15. Later the mechanistic aspects of this amazing reaction were investigated by Xia and Li, using DFT methods.28
Formation of the vinyl gold intermediate 39 and the gem-diaurated intermediate 40.
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Scheme 18
Relevance of the vinyl gold intermediate and the digold vinyl intermediate.
Scheme 19
Regiodivergent Au(III)- and Au(I)-catalysed cycloisomerisations of bromoallenyl ketones.
The energy profile for the AuCl3-catalysed cycloisomerisations of 13 is depicted in Scheme 20. The result indicates that the cyclic intermediate O is immediately formed after the
Scheme 20 Calculated free energies for the AuCl3-catalysed cycloisomerisations of 13.
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gold(III) complex coordination with the distal double bond of the allene 13. This step is barrierless and a highly exergonic process with a relative free energy of 32.6 kcal mol1 in the gas phase. In the next step the intermediate O through the transition state TS1 to generate the product complex P possesses an energy barrier of 15 kcal mol1. However, a relatively high energy barrier (28.6 kcal mol1) was required for the generation of the product complex Q via TS2. Therefore, the 1,2-Br migration was favored over the 1,2-H migration, which is in good agreement with the experimental observation of nearly exclusive 1,2-Br migration in the presence of AuCl3. The DFT study of the Au(I)-catalysed reaction revealed that both in the [(R3P)Au]+- and in the AuCl-catalysed reactions, the 1,2-Br migration is more favorable with an energy barrier of only 13 kcal mol1. However, a [(R3P)Au]+-catalysed 1,2-H shift can be assisted by the counterion TfO, which is consistent with the experiments. Following initial work on the addition of oxygen nucleophiles to allenes,29 in the case of N-allenylmethyl carboxamides 41 the formation of oxazines 42 was investigated in detail (Scheme 21).30 First of all, there is a high selectivity for an exocyclic double bond, in the case of a protodeauration with D+
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Scheme 21 Regioselective addition of carboxamides to allenes.
a specific deuteration at the endocyclic position of the allylic system in 42-D is observed. In situ 31P NMR spectroscopy, including low temperature NMR, revealed that during the catalytic conversion only the catalyst and one of the three conceivable allyl gold(I) complexes (endocyclic s-allyl U, p-allyl V and exocyclic s-allyl W) are present. Computational chemistry (Scheme 22) indicated that the species lowest in energy is the exocyclic s-allyl complex W, the p-allyl species V is the transition state of the 1,3-metallotropic shift in the system. Overall, this is the evidence for the protodeauration following an SE1 0 reaction with allylic inversion.
4 Mechanistic studies of the goldcatalysed [3,3]-sigmatropic rearrangement of propargylic esters involving allene intermediates Among the various types of homogeneous gold-catalysed reactions which were developed during the last decade, goldcatalysed rearrangement reactions of propargylic ester have attracted much interest in several groups.31–35 This high interest is not only based on the easily accessible starting material,
Scheme 22
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but also because this transformation normally can be realised using a wide variety of gold catalysts [either gold(I) or gold(III)] under mild conditions without inert atmosphere protection. Although it was apparently simple, the mechanistic aspects that determine the outcome of this transformation are still under investigation. Up to now, with increasing experimental evidence and density functional theory (DFT) studies, it has been established that in gold-catalysis propargylic esters can undergo [2,3]or [3,3]-sigmatropic migration leading to form a gold vinyl carbenoid species or a gold allenic intermediate (Scheme 23),36 which can be further trapped by other functional groups to allow the synthesis of many other organic products. In the case of [2,3]-sigmatropic rearrangements, the mechanism involving a gold carbenoid species has been supported by a variety of transformations such as cyclopropanation, insertion into C–H bonds and oxidation.37–39 In this section, we only focus on the mechanism of gold-catalysed [3,3]-sigmatropic rearrangements of propargylic esters involving allene intermediates. In 2008, Cavallo and co-workers firstly postulated that gold-catalysed [3,3]-sigmatropic rearrangements of propargylic esters are reversible processes by DFT studies.40 Subsequently, Toste et al. obtained experimental evidence for the reversibility of the [3,3]-sigmatropic rearrangement by employing a stereochemically defined starting material.41 Experimentally, they observed that the relative stereochemistry at the propargylic position was completely lost after only 2 min, suggesting that the first event is a very fast and reversible rearrangement of the pivaloate group. They also found that a slow cis-to-trans isomerisation of the cyclopropyl moiety took place within 1 h (Scheme 24), leaving the trans-cyclopropyl isomer (as a 1 : 1 mixture of diastereomers of propargyl ester)
Relative energies of the different allyl gold(I) species involved (B3LYP, cc-pVDZ basis, relativistic effective core potential for gold).
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Scheme 23
Two competing mechanistic pathways for gold-catalysed reactions of propargylic esters.
as the predominant isomer. Moreover, this result was supported by computational studies which are similar to those obtained by Cavallo and co-workers. As can be seen, the low activation barrier
Scheme 24
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in the first step was predicted to be 7.5 kcal mol1 and intermediates 50 and 51 appeared to be isoenergetic and more stable than 49 by 4.3 kcal mol1.
Experimental evidence and DFT studies supporting the reversibility of propargylic ester rearrangements.
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5 Conclusions
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Scheme 25 The co-workers.
18
O labeling experiment performed by Toste and
On the basis of a computational study Cavallo and co-workers suggested that the [3,3]-sigmatropic rearrangement may be the result of two consecutive [2,3]-acyloxy migrations. In order to investigate this assumption, an isotopic labeling study was conducted by Toste and co-workers (Scheme 25). They synthesised the 18O-enriched ester and subjected it to the standard conditions. The cyclopentene 18Oproduct was isolated in 76% yield. Mass and IR spectra showed that the 18O label resided exclusively at the carbonyl oxygen position. Otherwise, a double [2,3]-acyloxy migration would place the 18O label at the carbonyl oxygen and vinyl oxygen position. Therefore, this result contradicts Cavallo’s computational study. Chirality transfer is well established as a tool in the mechanistic studies of gold-catalysed [3,3]-sigmatropic rearrangements of propargylic esters involving allene intermediates. In 2006, the group of Gagosz reported that synthesis of acetoxybicyclo[3.1.0]hexenes was easily possible by introducing a methylene tether between a propargylic ester and alkene (Scheme 26).42 They proposed the mechanism involving an allene intermediate formed by a goldcatalysed [3,3]-sigmatropic rearrangement. To validate this hypothesis, an enantioenriched substrate 55 was used and the stereochemical information of the substrate was almost completely transferred to the final product. This positive result strongly supported the existence of the allene intermediate in the gold-catalysed [3,3]-sigmatropic rearrangement.
Scheme 26 The mechanism involving an allene intermediate was supported by Gagosz and co-workers.
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For gold-catalysed conversions of allenes only a limited amount of the mechanistic insights has so far been obtained, although a variety of these gold-catalysed transformations have been successfully developed in last few years. In this tutorial review we have highlighted the mechanistic analysis of gold-catalysed reactions of allenes, starting from systematic experimental studies up to computational analysis. Notably, this assessment demonstrated that DFT calculation occupies an important position in the mechanistic analysis of gold-catalysed cycloadditons of allenes. With regard to gold-catalysed nucleophilic additions to allenes, in situ NMR methods play an important role in the mechanistic investigation. Furthermore, labeling experiments and chirality transfer strategy provide insights into the mechanism of goldcatalysed [3,3]-sigmatropic rearrangements involving allene intermediates. We anticipate that this could provide a guide for future design of new gold-catalysed transformations of allenes.
References 1 A. S. K. Hashmi, Gold Bull., 2003, 36, 3–9. 2 A. S. K. Hashmi and G. J. Hutchings, Angew. Chem., Int. Ed., 2006, 45, 7896–7936. 3 A. S. K. Hashmi, Chem. Rev., 2007, 107, 3180–3211. ¨rstner and P. W. Davies, Angew. Chem., Int. Ed., 2007, 4 A. Fu 46, 3410–3449. 5 D. J. Gorin, B. D. Sherry and F. D. Toste, Chem. Rev., 2008, 108, 3351–3378. ´nez-Nu ´nez and A. M. Echavarren, Chem. Rev., 2008, 6 E. Jime 108, 3326–3350. 7 Z. G. Li, C. Brouwer and C. He, Chem. Rev., 2008, 108, 3239–3265. 8 A. S. K. Hashmi and M. Rudolph, Chem. Soc. Rev., 2008, 37, 1766–1775. 9 A. S. K. Hashmi and M. Rudolph, Chem. Soc. Rev., 2012, 41, 2448–2462. 10 A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49, 5232–5241. 11 L.-P. Liu and G. B. Hammond, Chem. Soc. Rev., 2012, 41, 3129–3139. 12 A. S. K. Hashmi, Angew. Chem., Int. Ed., 2000, 39, 3590–3593. ´pez, J. L. Mascaren ˜ as and 13 S. Montserrat, G. Ujaque, F. Lo ´s, Top. Curr. Chem., 2011, 302, 225–248. A. Lledo `re, A. Hours, L. Fensterbank and 14 V. Gandon, G. Lemie M. Malacria, Angew. Chem., Int. Ed., 2008, 47, 7534–7538. ´pez, M. Guı´as, L. Castedo and J. L. Mascaren ˜as, 15 B. Trillo, F. Lo Angew. Chem., Int. Ed., 2008, 47, 951–954. ´pez, S. Montserrat, G. Ujaque, L. Castedo, 16 B. Trillo, F. Lo ´s and J. L. Mascaren ˜as, Chem. – Eur. J., 2009, 15, A. Lledo 3336–3339. ´pez, S. Montserrat, G. Ujaque, 17 I. Alonso, B. Trillo, F. Lo ´s and J. L. Mascaren ˜ as, J. Am. Chem. L. Castedo, A. Lledo Soc., 2009, 131, 13020–13030. ´lez, D. Benitez, E. Tkatchouk, W. A. Goddard III 18 A. Z. Gonza and F. D. Toste, J. Am. Chem. Soc., 2011, 133, 5500–5507.
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19 N. Krause and C. Winter, Chem. Rev., 2011, 111, 1994–2009. 20 N. Nishina and Y. Yamamoto, Angew. Chem., Int. Ed., 2006, 45, 3314–3317. 21 R. A. Widenhoefer and Q. Han, Eur. J. Org. Chem., 2006, 4555–4563. 22 Z. J. Wang, D. Benitez, E. Tkatchouk, W. A. Goddard III and F. D. Toste, J. Am. Chem. Soc., 2010, 132, 13064–13071. ´, J. Org. Chem., 2008, 73, 23 M. A. Tarselli and M. R. Gagne 2439–2441. ´, Angew. Chem., Int. 24 D. Weber, M. A. Tarselli and M. R. Gagne Ed., 2009, 48, 5733–5736. 25 A. S. K. Hashmi, M. C. Blanco, D. Fischer and J. W. Bats, Eur. J. Org. Chem., 2006, 1387–1389. ´ and R. A. Widenhoefer, 26 T. J. Brown, D. Weber, M. R. Gagne J. Am. Chem. Soc., 2012, 134, 9134–9137. 27 A. W. Sromek, M. Rubina and V. Gevorgyan, J. Am. Chem. Soc., 2005, 127, 10500–10501. 28 Y. Xia, A. S. Dudnik, V. Gevorgyan and Y. Li, J. Am. Chem. Soc., 2008, 130, 6940–6941. 29 A. S. K. Hashmi, L. Schwarz, J.-H. Choi and T. M. Frost, Angew. Chem., Int. Ed., 2000, 39, 2285–2288. 30 A. S. K. Hashmi, A. M. Schuster, S. Litters, F. Rominger and M. Pernpointner, Chem. – Eur. J., 2011, 17, 5661–5667.
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31 F. D. Toste, in Modern Gold Catalyzed Synthesis, ed. A. S. K. Hashmi and F. D. Toste, Wiley-VCH, Weinheim, 2012, ch. 4, pp. 75–134 and references therein. 32 S. Z. Wang, G. Z. Zhang and L. Zhang, Synlett, 2010, 692–706. 33 A. S. K. Hashmi, W. Yang, Y. Yu, M. M. Hansmann, M. Rudolph and F. Rominger, Angew. Chem., Int. Ed., 2013, 52, 1329–1332. 34 Y. Yu, W. Yang, F. Rominger and A. S. K. Hashmi, Angew. Chem., Int. Ed., 2013, 52, 7586–7589. ¨sterer and A. S. K. Hashmi, Angew. 35 Y. Yu, W. Yang, D. Pfla Chem., Int. Ed., 2014, 53, 1144–1147. 36 N. Marion and S. P. Nolan, Angew. Chem., Int. Ed., 2007, 46, 2750–2752. 37 C. Fehr and J. Galindo, Angew. Chem., Int. Ed., 2006, 45, 2901–2904. ¨rstner and P. Hannen, Chem. – Eur. J., 2006, 12, 3006–3019. 38 A. Fu 39 C. Fehr, B. Winter and I. Magpantay, Chem. – Eur. J., 2009, 15, 9773–9784. 40 A. Correa, N. Marion, L. Fensterbank, M. Malacria, S. P. Nolan and L. Cavallo, Angew. Chem., Int. Ed., 2008, 47, 718–721. ´n, J. L. Krinsky and F. D. Toste, J. Am. Chem. Soc., 41 P. Mauleo 2009, 131, 4513–4520. 42 A. Buzas and F. Gagosz, J. Am. Chem. Soc., 2006, 128, 12614–12615.
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Mechanistic insights into the gold chemistry of allenes Weibo Yang* and A. Stephen K. Hashmi* Although most mechanistic studies on gold-catalysed reactions focused on alkynes as substrates, some
Received 1st December 2013 DOI: 10.1039/c3cs60441a
knowledge about gold-catalysed conversions of allenic substrates has been obtained. This contribution summarises these insights into the reaction mechanisms of gold-catalysed transformations of allenes which are based on computational studies, labelling studies, the detection of intermediates, chirality
www.rsc.org/csr
transfer and diastereoselective product formation.
Key learning points (1) The importance of combining experimental mechanistic evidence like detecting intermediates, isotope labeling studies and chirality transfer and computational chemistry is demonstrated. (2) Fundamental reactivity patterns are provided for cycloaddition and nucleophilic addition reactions. (3) Different types of gold catalysts for the conversions of allenes are discussed. (4) Vinyl gold, gold carbenoid, allyl gold and gem-diaurated intermediates are presented.
1 Introduction The application of gold complexes, soft carbophilic Lewis acids which can activate carbon–carbon multiple bonds towards the attack of a large variety of nucleophiles, has been intensively investigated over the past decade.1–9 In comparison to the extensive methodology development in the field of gold-catalysed transformations, the mechanisms of these transformations remain poorly defined and in most cases represent a significant challenge.10 Therefore the systematic experimental study and the computational analysis of the mechanisms of gold-catalysed reactions are slowly being recognised as important in the development of new goldcatalysed transformations. In the case of experimental studies, the isolation and characterisation of organogold intermediates have become the most efficient tools to understand and support the mechanisms of homogenous gold catalysis. Recently, an outstanding review by Liu and Hammond summarised the advances in the isolation and reactivity of organogold complexes.11 However, these isolable intermediates are very rare and are mainly formed via the addition of nucleophiles to alkynes or alkenes in the presence of the gold catalyst. The aspect of selectivity is problematic in the case of allenes; in addition reactions all chemoselectivity, diastereoselectivity, ¨t Heidelberg, Im Neuenheimer Feld 270, Organisch-Chemisches Institut, Universita 69120 Heidelberg, Germany. E-mail: [email protected]
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enantioselectivity, regioselectivity and positional selectivity can be involved.12 Since allenes possess this unique reactivity and a particular coordination mode to the cationic Au metal center of the catalysts, only a few experimental mechanistic investigations of nucleophilic addition to allenes exist. On the other hand the number of theoretical studies is increasing quite rapidly. In 2011, an intriguing review on the mechanism of gold-catalysed cycloadditions of allenes with a focus on theoretical methods was ´s and co-workers.13 However, to our knowledge, published by Lledo no comprehensive review on the mechanisms of gold-catalysed transformations involving allenes exists. This tutorial review for the first time will summarise and discuss the mechanistic studies on the gold chemistry of allenes not only from an experimental point of view, but also cover computational analysis. Notably, it focuses on gold-catalysed cycloadditions of allenes, gold-catalysed nucleophilic additions to allenes and gold-catalysed [3,3]-sigmatropic rearrangements involving allene intermediates.
2 Mechanistic studies of goldcatalysed cycloadditions of allenes Gold-catalysed cycloadditions of allenes have grown considerably and have become a powerful method for the synthesis of polycyclic products in a highly regio- and stereocontrolled
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Fig. 1
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Four principal coordination modes of (R)-1,3-dimethyl allene to AuBr3 and their relative computational energies.
fashion from relatively simple acyclic organic fragments. Notably, apart from the exploration of new and versatile gold-catalysed cycloadditions of allenes, attempting to gain insight into the mechanism of these transformations is important for organic chemists. It is well established that there exist four different coordination modes of allenes to the Au metal center. Indeed, these different coordination modes can be divided into Z2-coordinated complexes I, s-allylic cations II, zwitterionic carbenes III and Z2-coordinated bent allenes IV (Fig. 1). Furthermore, the coordination mode is an important factor in determining the stereochemical outcome of the transformation. For instance, in axis-to-center transfer the stereochemical information is maintained in species I or IV; however, due to the three carbons and their substitutents being positioned in the same plane, it seems to be lost in II or III. In 2008, Malacria et al. carried out a computational study to gain insight into the nature of these intermediates.14 They investigated the interaction of allenes with gold complexes, specifically (R)-1,3-dimethyl allene in the presence of AuBr3 (AuCl3 and Au+ and some other transition metal complexes were also investigated). Two diastereomeric complexes of type I were local minima, in addition type II and IV complexes. In II and IV the three allene carbons and the metal fragment lie in the same plane. With a relative energy
Weibo Yang
Weibo Yang studied chemistry at Dalian University of Technology, China, and then with a CSC fellowship joined the group of A. S. K. Hashmi in Heidelberg, Germany, in 2010. There he obtained his PhD in 2013 with a remarkable thesis on methodology development in homogeneous gold catalysis. He has now joined the group of J.-Q. Yu at Scripps Institute, California, USA, for his postdoctorate.
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of +3.5 kcal mol1 IV is the least stable form among these local minima. Their results suggest that not only the nature of the allene substituents, but also the properties of the particular gold complex employed have a crucial influence on the coordination modes.
2.1 Mechanistic studies of gold-catalysed intramolecular [4+3] cycloadditions of allenedienes ˜as et al. reported the formation of bicyclo[5.3.0]In 2008, Mascaren decanes by a novel platinum-catalysed intramolecular [4+3] cycloaddition process of allenedienes.15 One year later the same group also described that the same reactions smoothly proceed in the presence of a Au(I) catalyst, generated in situ from [(IPr)AuCl] and AgSbF6, under milder conditions.16 The reaction mechanism is outlined in Scheme 1. Initially, the intermediate A is formed via Z2-coordinated mode I which is a p-activation of the allene 1 by the metal catalyst. Subsequently, a metalbound allylic cation intermediate B is generated, followed by a concerted [4+3] intramolecular cycloaddition with the diene forming the intermediate C. Finally, a 1,2-H shift on the resulting cycloheptenyl metal-carbene produces the expected product 2 and regenerates the catalyst.
A. Stephen K. Hashmi studied chemistry at the LMU Munich, where he obtained his diploma and PhD with Prof. G. Szeimies in the field of nickel- and ironcatalysed cross coupling of strained organic compounds. His postdoctorate with Prof. B. M. Trost at Stanford University covered transition metal catalysed enyne metathesis. After his habilitation on enantiomerically pure organopalladium compounds and A. Stephen K. Hashmi palladium-catalysed conversions of allenes with Prof. J. Mulzer at the FU Berlin, the JWG-University Frankfurt and the University of Vienna, in 1998 he was awarded a Heisenberg fellowship of the DFG for a proposal on gold-catalysed reactions for organic synthesis – still a major focus of the group. The next stations were University of Tasmania 1999, Marburg University 1999–2000, in 2001 he was appointed Professor for Organic Chemistry at Stuttgart University and since 2007 he occupies a chair for Organic Chemistry at Heidelberg University.
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Scheme 3 Trapping the gold carbenoid intermediate by oxygen transfer from diphenylsulfoxide.
Scheme 1
Mechanistic hypothesis for a diene–allene [4+3] cycloaddition.
Moreover, this mechanism was explored by a DFT calculation analysis using dimethylallene 1 as the model substrate together with AuCl, AuCl3, (NHC)Au+ and PtCl2 complexes as catalysts (Scheme 2). The DFT calculation results are consistent with the experimental observation. The different energy barriers evolved from A and the relative stability of the allylic cation intermediate B indicated that the nature of the metal complexes played a significant role during this process. The lowest energy barrier and the most stable intermediate C showed that a fast and
Scheme 2
irreversible [4+3] cycloaddition process occurs within the overall catalytic cycle for all the catalysts. The highest energy barrier was observed in the last step, consisting of a 1,2-H-shift with simultaneous coordination of the newly formed double bond to the metal, which might become the rate-determining step. The highest relative energy barrier (25.6 kcal mol1) can perfectly explain the fact that a PtCl2-catalysed aforementioned [4+3] cycloaddition requires a high temperature (110 1C), whereas a good conversion was obtained for AuCl and AuCl3 catalysts at room temperature with the energy barriers of 14.6 kcal mol1 and 12.3 kcal mol1, respectively. For the cationic (NHC)Au+, generated in situ from [(IPr)AuCl] and AgSbF6, which exhibits the lowest energy barrier of 8.6 kcal mol1, the reaction can be carried out at 0 1C in less than 1 h. Apart from the DFT calculations for the gold-catalysed diene–allene [4+3] cycloaddition, an additional experimental mechanistic proof was presented by the same authors. They attempted to introduce phenyl sulfoxide as an oxidant in order to trap the gold carbenoid intermediate C (Scheme 3). Fortunately, they succeeded in trapping this stable gold carbenoid intermediate C by isolating the corresponding ketone 4 in 25% yield. 2.2 Mechanistic studies of gold-catalysed intramolecular [4+2] cycloadditions of allenedienes During the investigation of the gold-catalysed intramolecular [4+3] cycloaddition of allenedienes, the same group discovered a competing [4+2] cycloaddition reaction when using a specific
Comparison of the DFT energy profiles for different gold catalysts and PtCl2 (relative gas phase electronic energies in kcal mol1).
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Scheme 4 Mechanistic proposal for the [4+2] process based on an initial [4+3] cycloaddition and a subsequent ring contraction (the proposal is based on experimental and computational studies).
allenediene bearing two substituents at the distal position.17 Notably, with more electron-accepting ligands such as phosphites and phosphoramidites, the corresponding trans-fused bicyclic cycloadducts 5 can be obtained in good yields with high chemo- and stereoselectivity (Scheme 4). The proposed mechanism for the formation of the [4+2] cycloadducts might arise from a 1,2-alkyl migration (ring contraction) in the cycloheptenyl Au–carbene intermediate C, itself arising from a [4+3] concerted cycloaddition of the allenediene. In addition, a hypothetical stepwise mechanism involving a common carbocationic intermediate F could also explain the
Scheme 5
Table 1
aforementioned results about the formation of 2 and 5 (Scheme 5). However, this hypothesis was easily discounted by trapping experiments using methanol (Table 1). Subsequently, they chose 6 as the starting material and added different amounts of MeOH in the presence of G as a catalyst in order to intercept the allyl carbocationic intermediate F. However, when the reaction was carried out in CH2Cl2 together with 3 equiv. MeOH as the trapping agent, it provided only the [4+2] cycloadduct 7 (Table 1, entry 1). In a more polar solvent, such as MeNO2, the reaction provided a mixture of products consisting of 7 and an acyclic compound 8 in a ratio of 8.5 : 1.5 (Table 1, entry 2). Indeed, even when switching to the solvent MeOH, the sole products are 8 and its regioisomer 9 (ratio 8 : 9 = 85 : 15), while no traces of trapping products derived from F could be detected (entry 3). This experimental study provides evidence against the stepwise mechanism and indirectly corroborates the 1,2-alkyl and 1,2-H migration mechanism; still it cannot be excluded that the reaction occurs step-wise but the intramolecular reaction of F is faster than the intermolecular reaction with methanol.
Asymmetric cycloaddition reactions of 10 were carried out in the presence of different phosphoramidite–gold catalysts. As can be seen from Table 2, all the different phosphoramidite–gold catalysts bearing enantiomerically pure ligands G1–G5 could
Hypothesis of an involvement of a carbocationic intermediate F in the [4+2] process (proposal based on experimental evidence).
Experimental evidence allowed to discard the mechanism involving a common carbocationic intermediate F
Entrya
Solvent
MeOH
7 : 8 : 9b
1 2 3
CH2Cl2 MeNO2 MeOH
3 equiv. 3 equiv. Solvent
100 : 0 : 0 85 : 15 : 0 0 : 85 : 15
a Conditions: 1b (1 equiv., 0.15 M), G (10 mol%) and AgSbF6 (10 mol%) for 1–3 h. Conversions 499%. crude mixtures.
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b
Ratios determined by 1H NMR in the
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Table 2
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Comparison of the enantioselectivities of 11 and 12, isolated from the reaction of 10 using different Au catalysts
Entrya
L*AuCl
Temp. (1C)
11 : 12b
11, erc
12, erc
1 2 3 4 5 6 7 8
(S)-Catalyst G1 (S,S)-Catalyst G2 (S,S,S)-Catalyst G3 (R,S,S)-Catalyst G3 (S,S)-Catalyst G4 (S,R,R)-Catalyst G5 (S,S,S)-Catalyst G5 (S,S,S)-Catalyst G5
23 23 23 23 23 23 23 15
6:1 3:1 4.5 : 1 3:1 4:1 4:1 7:1 8:1
51 : 49 52 : 48 60 : 40 52 : 48 61 : 39 57 : 43 76 : 24 87 : 13
50.5 : 49.5 52 : 48 59 : 41 53 : 47 61 : 39 56 : 44 76 : 24 87 : 13
a b
Conditions: 1a (1 equiv.), L*-AuCl (10 mol%) and AgSbF6 (10 mol%) in CH2Cl2 (0.15 M) for 1–3 h unless otherwise noted. Conversions 499%. Determined by 1H NMR in the crude mixtures. c er: the enantiomeric ratio (determined by HPLC).
provide almost the same enantiomeric excess for both the major [4+2] product 11 and the minor [4+3] product 12. Also, the same er values for both [4+3] and [4+2] products could be obtained. These results strongly suggest that [4+3] and [4+2] share a common intermediate in the enantiodetermining step, which evolved to either the six or the seven-membered cycloaddition products.
and a key divergent point during the whole catalytic cycle with a relative energy of 12.1 kcal mol1. On the one hand it can provide the [4+3] cycloaddition product by a 1,2-hydrogen shift. On the other hand it can result in the formation of the [4+2] cycloaddition product through a 1,2-alkyl migration. These two competitive pathways need the energy barriers of 10.3 and 8.7 kcal mol1, respectively. This little difference in energy
Based on the experimental studies of the mechanism, the primary DFT analysis of the mechanism of the disubstituted allenedienes with [(MeO)3PAu]+ as the catalyst was performed and indicated reaction pathways similar to the preceding study, the Au catalysts being involved in the two initial steps. As shown in Scheme 6, coming from intermediate A the formation of the allylic cation in the organogold intermediate B requires an energy barrier of 4.2 kcal mol1. Then intermediate B easily gave rise to a 7-membered ring gold carbenoid species C derived from a [4+3] cycloaddition with a relatively low energy barrier of only 2.5 kcal mol1. It should be noted that the cycloheptene–gold species C is the most stable intermediate
barriers indicated that both products can be formed, although the formation of the [4+2] adduct is slightly favored. Subsequently, the same group also carried out another DFT calculation with unsubstituted allenediene as the model substrate to analyse two competitive pathways for 1,2-alkyl and 1,2-H migration which led to [4+2] and [4+3] cycloaddition products, respectively (Scheme 7). It should be noted that these two different products derived from unsubstituted allenedienes still share the two initial steps. Once the 7-membered ring intermediate H is formed, the relative energy barrier for the 1,2-H shift leading to the [4+3] product is 11.7 kcal mol1. With regard to the 1,2-alkyl migration resulting in the formation of
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Scheme 6
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The DFT profile for the cycloaddition of a model substrate 1 with the [(MeO)3PAu]+ catalyst (relative gas phase electronic energies in kcal mol1).
Scheme 7 The DFT energy profile comparing the pathway of the 1,2-alkyl migration (Ts4) and 1,2-H migration (Ts3) using non-substituted allene (relative gas phase electronic energies in kcal mol1).
[4+2] product, however, the relative energy barrier is 23.8 kcal mol1. The obvious results demonstrated that the 1,2-H shift leading to the formation of the [4+3] product is significantly more favorable in unsubstituted allenedienes system. Moreover, the formation of the [4+2] cycloadduct seems to be strongly dependent on the ability of allene distal substituents to stabilise the positive charge located at the adjacent position of the Au–carbene center during the 1,2-alkyl migration process.
2.3 Mechanistic studies of gold(I)-catalysed [2+2] cycloadditions In 2011, Toste and co-workers investigated the mechanism of gold(I)-catalysed [2+2] cycloadditions (forming 18) and gold(I)catalysed cyclisation/alkoxylation (forming 17) reactions of allenenes 16 by computational analysis (Scheme 8).18
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The DFT calculations indicated that both pathways involved a five-membered metallacyclic intermediate formed from intermediates R 0 and R00 (Scheme 9). Notably, the formation of the five-membered metallacyclic intermediate with trans-arrangement of the substitutents on the ring (T 0 ) shows an energy barrier of 10.4 kcal mol1, which is lower than for the cis-arrangement in S 0 (13.3 kcal mol1). In the case of the cis-intermediate S 0 , only a low energy barrier of 2.5 kcal mol1 is required to form the cyclobutane ring in 18 0 . Experimentally, adding MeOH to the isolated 18 0 in the presence of (PhO)3PAuBF4 did not give the alkoxycyclisation product 17 0 , demonstrating that the formation of 18 0 is irreversible under these reaction conditions. This irreversibility was consistent with the calculated high energy barrier of the reverse reaction (24.5 kcal mol1). With regard to the cis pathway, the absence of deuterium loss in the gold(I)-catalysed formation of 17 0 from 16 0 suggests that the
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alkoxycyclisation product is not formed from the addition of MeOH to the styrene moiety of a 1,4-diene (190 ) but from a cationic intermediate T0 , which is in agreement with the computational studies. Additionally, the results suggested that both the cis- and the trans-pathway are competing, but in the presence of a nucleophile (MeOH), the trans-pathway is preferred. However, in the absence of a viable nucleophile, the cis-pathway is operative.
3 Mechanistic studies of goldcatalysed hydroamination, hydroarylation and hydroalkoxylation of allenes
Scheme 8 Gold(I)-catalysed [2+2] cycloadditions and cyclisation/alkoxylation of allenenes 16 (proposal is based on experimental and computational studies).
The gold-catalysed addition of carbon-, oxygen- and nitrogenbased nucleophiles to allenes, leading to the formation of new C–O, C–N or C–C bonds, has emerged as an efficient strategy for the synthesis of natural products.19 However, the mechanistic studies of these reactions are scarce. Therefore, the investigation of the mechanism is highly desirable. It is well-known that both outer sphere and inner sphere mechanisms have been proposed for gold-catalysed nucleophilic addition reactions to allenes (Scheme 10).20,21 In the outer sphere mechanism the cationic gold(I) complex activates the allenes and induces an anti-addition of the nucleophile. Eventually, protodemetalation of the ‘‘anti’’-vinyl gold intermediate then regenerates the gold(I) catalyst. However, in the inner sphere mechanism both the allene and the nucleophile interact with the gold complex at the same time. Subsequently, a syn-addition of the nucleophile and the gold complex across the allene is observed. Then protodemetalation forms the product. In the case of terminal allenes, the products of both pathways are indistinguishable, but in the case of diastereofacial p-faces of the allene, products with the opposite relative configuration of the double bond and the olefin are obtained. 3.1 Mechanistic studies of the gold-catalysed hydroamination of allenes
Scheme 9 The DFT profile for the potential free energy surface for the cis and trans cyclisation pathways.
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In 2010, Toste and co-workers reported an intermolecular gold(I)-catalysed hydroamination reaction of allenes with hydrazide nucleophiles and investigated the mechanism of this transformation (Scheme 11).22 They used 31P NMR methods to investigate the nature of gold(I) intermediates. Two samples containing Ph3PAuNTf2 and methyl carbazate (1 : 1 ratio) and Ph3PAuNTf2 and 24 (1 : 10 ratio) in CD3NO2 were prepared. The former sample showed a broadened 31P NMR signal at 29.7 ppm and the 31P NMR signal at 45.2 ppm was observed in the latter sample. These results indicated that the gold–allene complex intermediate was favored at the beginning and is the resting state of the reaction and the gold–amine intermediate is less stable due to the weak nitrogen gold(I) interaction. Moreover, the chirality transfer was further carried out to determine whether the reaction proceeded through chiral or planar gold intermediates. They observed that the best chiral transfer was 56%, and this was achieved in the presence of
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Scheme 10
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Outer sphere and inner sphere mechanisms proposed for nucleophilic addition reactions to allenes.
Scheme 11 The gold(I)-catalysed intermolecular hydroamination reaction of allenes using hydrazide and two gold intermediates was monitored by 31P NMR analysis.
more than 4 equiv. of methyl carbazate. This indicates that the reaction cannot be proceeding exclusively through a planar intermediate. Otherwise, the racemisation can occur through a planar intermediate process (Table 3). Subsequently, they attempted to probe whether the intermolecular hydroamination reaction is reversible or not. The enantioenriched 27 (56% ee) together with 2 equiv. of methyl carbazate were reacted in the presence of 10 mol% Ph3PAuNTf2
Table 3 Chirality transfer for the hydroamination of chiral 26 in the presence of Ph3PAuNTf2 catalyst at various equivalents of methyl carbazate
Equiv. of Nuc
Yield (%)
ee (%)
1.0 2.0 4.0 8.0
81 75 81 79
28 48 56 56
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at 45 1C (Scheme 12). No erosion of enantiopurity was observed; the remaining 27 after 6 h still showed the identical 56% ee, supporting an irreversible protodemetalation. However, a reversible reaction regenerates an enantioenriched allene, the latter then reacts with methyl carbazate providing 27 with good chirality transfer, which could also explain the conservation of the enantiomeric excess. A competitive trapping experiment successfully excluded the reversible protodemetalation mechanism; no 29 could be detected. 3.2 Mechanistic studies of the gold-catalysed hydroarylation of allenes ´ and co-workers developed a highly selective In 2008, Gagne intramolecular gold(I)-catalysed allene hydroarylation reaction, producing vinyltetrahydronaphthalenes in good to excellent yields (Scheme 13).23 They initially proposed the vinyl-gold(I) intermediate 32 to be involved in the mechanism. However, subsequent experimental studies indicated that both 32 and 34 might be catalytic intermediates of the mechanistic cycle. It should be noted that the similar dinuclear species 34 have been postulated on the basis of DFT studies. In order to validate
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Scheme 12 Experimental proof of the irreversibility of the gold(I)-catalysed intermolecular hydroamination.
Scheme 13 The proposed catalytic cycle for the gold(I)-catalysed intramolecular hydroarylation of allenes (proposal is based on experimental evidence).
these intermediates by experimental studies, in situ 31P NMR ´ et al. observed that the 31P NMR analysis was used.24 Gagne spectra of the intermediate 34 showed two peaks in a 1 : 1 ratio at around d = 36 ppm rather than the expected peaks at around d = 44 ppm. Additionally, the 1H NMR spectra of vinyl hydrogen atoms showed large upfield shifts of the syn (d = 6.43 ppm (34) to d = 4.97 ppm (32)) and anti (d = 5.91 ppm (34) to d = 5.62 ppm (32)), suggesting significantly different chemical environments in the two intermediates. The relevance of vinyl gold complexes 32 and 34 was evaluated by stoichiometric experiments. Compound 32 was found to readily react with stoichiometric quantities of HX (X = Cl, NTf2) by protodeauration to yield 33 and the expected gold(I) species (Scheme 14). The compounds 34 and 33 can be obtained by adding 0.5 equivalent of HNTf2 into 32. 34 does not directly protodeaurate, by cleaving off Ph3PAu+; it is in equilibrium with 32, which then is protodeaurated. Additionally, 32 and 1.0 equivalent of PPh3AuNTf2 can be rapidly and cleanly converted into the digold-vinyl intermediate 34.
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3.3 Mechanistic studies of the gold-catalysed hydroalkoxylation of allenes The gold-catalysed intramolecular addition of alcohols to allenes in principle is highly related to the corresponding intramolecular nucleophilic additions of alcohols to alkynes. The first evidence for an in situ reduction of gold(III) catalysts in these reactions was obtained in the context of the AuCl3-catalysed cycloisomerisation of allenyl carbinols.25 These 1,1-disubstituted allenyl carbinols gave the products of an oxidative dimerisation. As this occurred even under exclusion of any other oxidants and in amounts correlating with the applied amount of AuCl3 (Scheme 15), this indicated that gold(III) had to be the oxidant and is reduced in the process. ´ and Widenhoefer reported the mechanistic investigaGagne tion of the gold(I)-catalysed intramolecular hydroalkoxylation of 2,2-diphenyl-4,5-hexadien-1-ol (37) to form 2-vinyltetrahydrofuran 38 (Scheme 16).26 The air-stable as well as thermally stable vinyl gold intermediate 39 (Scheme 17) was obtained by crystallisation from
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Scheme 14
Reactivity of intermediate 32.
Scheme 15 Direct evidence for the in situ reduction of gold(III) by oxidative dimerisation of the vinyl gold intermediate in the catalytic cycle.
Scheme 16
The gold(I)-catalysed intramolecular hydroalkoxylation.
warm hexanes in 87% yield. Subsequent treatment of 39 with (L)AuOTs (1 equiv.) in CD2Cl2 at 0 1C led to the immediate formation of the bis(gold) vinyl intermediate 40 in 98% NMR yield. Notably, the 31P NMR spectrum of 40 displayed a 1 : 1 ratio of resonances at d 61.7 and 60.9, which indicated the presence of chemically inequivalent (L)Au+ fragments. The change of chemical shifts in the 1H NMR shifts of the vinylic protons of 40 [d 4.84 and 3.90] relative to those of 39 [d 5.48 and 4.45] further demonstrated interaction of the vinyl moiety of 40 with both (L)Au+ fragments.
Scheme 17
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Reaction of 37 and a stoichiometric amount of (L)AuOTs in CD2Cl2 at 80 1C resulted in the fast formation of a 1 : 1 mixture of 37 and 40 without generation of a detectable amount of 39 or 38, which established that the C–O bond formation and aggregation are favorable compared to the protodeauration (Scheme 18). Next, a transfer of 39 to 40 was investigated. Treatment of mono(gold(I)) vinyl species 39 with TsOH (1 equiv.) at 25 1C led to the fast formation of tetrahydrofuran 38 in 99 5% yield. However, 1 H NMR analysis of the reaction of 39 with TsOH (1 equiv.) at 80 1C revealed immediate ring opening/aggregation to form a 1 : 1 mixture of 37 and 40 in 490% combined yield. Therefore, these experimental studies supported a mechanism for the gold-catalysed conversion of 37 to 38 involving a rapid and reversible outer sphere C–O bond formation and an off-cycle catalyst mode. 3.4 Mechanistic studies of gold-catalysed additions of carbonyl oxygen atoms to allenes In 2005, Gevorgyan and co-workers reported a gold-catalysed regiodivergent cycloisomerisation of bromoallenyl ketones 13, regiodivergent with regard to the formation of the isomeric bromofurans 14 and 15 (Scheme 19).27 The mechanism of the gold(III)-catalysed conversion of bromoallenyl ketones was proposed through a 1,2-Br migration leading to the product 14. Alternatively, 1,2-H migration was involved in this gold(I)catalysed reaction forming the product 15. Later the mechanistic aspects of this amazing reaction were investigated by Xia and Li, using DFT methods.28
Formation of the vinyl gold intermediate 39 and the gem-diaurated intermediate 40.
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Scheme 18
Relevance of the vinyl gold intermediate and the digold vinyl intermediate.
Scheme 19
Regiodivergent Au(III)- and Au(I)-catalysed cycloisomerisations of bromoallenyl ketones.
The energy profile for the AuCl3-catalysed cycloisomerisations of 13 is depicted in Scheme 20. The result indicates that the cyclic intermediate O is immediately formed after the
Scheme 20 Calculated free energies for the AuCl3-catalysed cycloisomerisations of 13.
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gold(III) complex coordination with the distal double bond of the allene 13. This step is barrierless and a highly exergonic process with a relative free energy of 32.6 kcal mol1 in the gas phase. In the next step the intermediate O through the transition state TS1 to generate the product complex P possesses an energy barrier of 15 kcal mol1. However, a relatively high energy barrier (28.6 kcal mol1) was required for the generation of the product complex Q via TS2. Therefore, the 1,2-Br migration was favored over the 1,2-H migration, which is in good agreement with the experimental observation of nearly exclusive 1,2-Br migration in the presence of AuCl3. The DFT study of the Au(I)-catalysed reaction revealed that both in the [(R3P)Au]+- and in the AuCl-catalysed reactions, the 1,2-Br migration is more favorable with an energy barrier of only 13 kcal mol1. However, a [(R3P)Au]+-catalysed 1,2-H shift can be assisted by the counterion TfO, which is consistent with the experiments. Following initial work on the addition of oxygen nucleophiles to allenes,29 in the case of N-allenylmethyl carboxamides 41 the formation of oxazines 42 was investigated in detail (Scheme 21).30 First of all, there is a high selectivity for an exocyclic double bond, in the case of a protodeauration with D+
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Scheme 21 Regioselective addition of carboxamides to allenes.
a specific deuteration at the endocyclic position of the allylic system in 42-D is observed. In situ 31P NMR spectroscopy, including low temperature NMR, revealed that during the catalytic conversion only the catalyst and one of the three conceivable allyl gold(I) complexes (endocyclic s-allyl U, p-allyl V and exocyclic s-allyl W) are present. Computational chemistry (Scheme 22) indicated that the species lowest in energy is the exocyclic s-allyl complex W, the p-allyl species V is the transition state of the 1,3-metallotropic shift in the system. Overall, this is the evidence for the protodeauration following an SE1 0 reaction with allylic inversion.
4 Mechanistic studies of the goldcatalysed [3,3]-sigmatropic rearrangement of propargylic esters involving allene intermediates Among the various types of homogeneous gold-catalysed reactions which were developed during the last decade, goldcatalysed rearrangement reactions of propargylic ester have attracted much interest in several groups.31–35 This high interest is not only based on the easily accessible starting material,
Scheme 22
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but also because this transformation normally can be realised using a wide variety of gold catalysts [either gold(I) or gold(III)] under mild conditions without inert atmosphere protection. Although it was apparently simple, the mechanistic aspects that determine the outcome of this transformation are still under investigation. Up to now, with increasing experimental evidence and density functional theory (DFT) studies, it has been established that in gold-catalysis propargylic esters can undergo [2,3]or [3,3]-sigmatropic migration leading to form a gold vinyl carbenoid species or a gold allenic intermediate (Scheme 23),36 which can be further trapped by other functional groups to allow the synthesis of many other organic products. In the case of [2,3]-sigmatropic rearrangements, the mechanism involving a gold carbenoid species has been supported by a variety of transformations such as cyclopropanation, insertion into C–H bonds and oxidation.37–39 In this section, we only focus on the mechanism of gold-catalysed [3,3]-sigmatropic rearrangements of propargylic esters involving allene intermediates. In 2008, Cavallo and co-workers firstly postulated that gold-catalysed [3,3]-sigmatropic rearrangements of propargylic esters are reversible processes by DFT studies.40 Subsequently, Toste et al. obtained experimental evidence for the reversibility of the [3,3]-sigmatropic rearrangement by employing a stereochemically defined starting material.41 Experimentally, they observed that the relative stereochemistry at the propargylic position was completely lost after only 2 min, suggesting that the first event is a very fast and reversible rearrangement of the pivaloate group. They also found that a slow cis-to-trans isomerisation of the cyclopropyl moiety took place within 1 h (Scheme 24), leaving the trans-cyclopropyl isomer (as a 1 : 1 mixture of diastereomers of propargyl ester)
Relative energies of the different allyl gold(I) species involved (B3LYP, cc-pVDZ basis, relativistic effective core potential for gold).
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Scheme 23
Two competing mechanistic pathways for gold-catalysed reactions of propargylic esters.
as the predominant isomer. Moreover, this result was supported by computational studies which are similar to those obtained by Cavallo and co-workers. As can be seen, the low activation barrier
Scheme 24
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in the first step was predicted to be 7.5 kcal mol1 and intermediates 50 and 51 appeared to be isoenergetic and more stable than 49 by 4.3 kcal mol1.
Experimental evidence and DFT studies supporting the reversibility of propargylic ester rearrangements.
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5 Conclusions
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Scheme 25 The co-workers.
18
O labeling experiment performed by Toste and
On the basis of a computational study Cavallo and co-workers suggested that the [3,3]-sigmatropic rearrangement may be the result of two consecutive [2,3]-acyloxy migrations. In order to investigate this assumption, an isotopic labeling study was conducted by Toste and co-workers (Scheme 25). They synthesised the 18O-enriched ester and subjected it to the standard conditions. The cyclopentene 18Oproduct was isolated in 76% yield. Mass and IR spectra showed that the 18O label resided exclusively at the carbonyl oxygen position. Otherwise, a double [2,3]-acyloxy migration would place the 18O label at the carbonyl oxygen and vinyl oxygen position. Therefore, this result contradicts Cavallo’s computational study. Chirality transfer is well established as a tool in the mechanistic studies of gold-catalysed [3,3]-sigmatropic rearrangements of propargylic esters involving allene intermediates. In 2006, the group of Gagosz reported that synthesis of acetoxybicyclo[3.1.0]hexenes was easily possible by introducing a methylene tether between a propargylic ester and alkene (Scheme 26).42 They proposed the mechanism involving an allene intermediate formed by a goldcatalysed [3,3]-sigmatropic rearrangement. To validate this hypothesis, an enantioenriched substrate 55 was used and the stereochemical information of the substrate was almost completely transferred to the final product. This positive result strongly supported the existence of the allene intermediate in the gold-catalysed [3,3]-sigmatropic rearrangement.
Scheme 26 The mechanism involving an allene intermediate was supported by Gagosz and co-workers.
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For gold-catalysed conversions of allenes only a limited amount of the mechanistic insights has so far been obtained, although a variety of these gold-catalysed transformations have been successfully developed in last few years. In this tutorial review we have highlighted the mechanistic analysis of gold-catalysed reactions of allenes, starting from systematic experimental studies up to computational analysis. Notably, this assessment demonstrated that DFT calculation occupies an important position in the mechanistic analysis of gold-catalysed cycloadditons of allenes. With regard to gold-catalysed nucleophilic additions to allenes, in situ NMR methods play an important role in the mechanistic investigation. Furthermore, labeling experiments and chirality transfer strategy provide insights into the mechanism of goldcatalysed [3,3]-sigmatropic rearrangements involving allene intermediates. We anticipate that this could provide a guide for future design of new gold-catalysed transformations of allenes.
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