Cyclobutene vs 1,3-Diene Formation in the Gold-Catalyzed Reaction of Alkynes with Alkenes: The Complete Mechanistic Picture

The intermolecular gold(I)-catalyzed reaction between arylalkynes and alkenes leads to cyclobutenes by a [2 + 2] cycloaddition, which takes place stepwise, first by formation of cyclopropyl gold(I) carbenes, followed by a ring expansion. However, 1,3-butadienes are also formed in the case of ortho-substituted arylalkynes by a metathesis-type process. The corresponding reaction of alkenes with aryl-1,3-butadiynes, ethynylogous to arylalkynes, leads exclusively to cyclobutenes. A comprehensive mechanism for the gold(I)-catalyzed reaction of alkynes with alkenes is proposed on the basis of density functional theory calculations, which shows that the two pathways leading to cyclobutenes or dienes are very close in energy. The key intermediates are cyclopropyl gold(I) carbenes, which have been independently generated by retro-Buchner reaction from stereodefined 1a,7b-dihydro-1H-cyclopropa[a]naphthalenes.


■ INTRODUCTION
Cycloisomerizations of 1,n-enynes catalyzed by gold(I) and other electrophilic metals proceed by mechanistically complex, multistep transformations that lead to novel architectures 1 and have been applied for the total synthesis of a variety of natural products. 2 The parent intermolecular reaction between terminal alkynes 1 and alkenes 2 gives rise to cyclobutenes 3 as a result of a [2 + 2] intermolecular cycloaddition (Scheme 1). 3 Key for the success of this reaction was the use of cationic gold(I) complex A with a very bulky phosphine. By exchanging the anion of catalyst A from SbF 6 − to softer BAr 4 F− , cyclobutenes 3 were obtained in better yields presumably by decreasing the rate of formation of σ,π-digold(I) alkyne complexes, which were shown to be unproductive dead ends in this transformation. 4 We have extended this [2 + 2] cycloaddition for the synthesis of up to 15-membered ring macrocycles by performing the reaction with 1,n-enynes (n = 10−16), 5 which has been applied for the enantioselective total synthesis of rumphellaone A. 6 Cyclobutenes are highly valuable synthons for the preparation of functionalized cyclobutanes and other compounds. 7,8 Besides photochemical processes, 9 other transition metals different from gold(I) have been used to promote [2 + 2] cycloaddition reactions, which are however rather limited with respect to the range of alkenes that can be used. 10,11 Thus, the rhodium-catalyzed [2 + 2] cycloaddition only proceeds with electron-deficient 12,13 or strained alkenes. 14 Other transitionmetal catalysts also promote the [2 + 2] cycloaddition of strained alkenes with alkynes. 15,16 The reaction of propiolates and other alkynes bearing electron-withdrawing groups with alkenes in the presence of Lewis 17 or Brønsted 18 acids also leads to cyclobutenes. 19 Interestingly, in the presence of gold(I), this type of alkyne reacts with alkenes to form 1,3dienes 5 or lactones 6 (Scheme 1). 20 On the basis of studies on the mechanism of gold(I)catalyzed cyclization of 1,n-enynes 21−24 and other electrophiles, 25,26 we hypothesized that the reaction of alkynes with alkenes could take place by the electrophilic addition of (η 2alkyne)gold(I) complexes 7 to the alkene to form intermediate cyclopropyl gold(I) carbenes 8, which undergo ring expansion to give (η 2 -cyclobutene)gold(I) complexes 9 (Scheme 2). An intermediate (η 2 -cyclobutene)gold(I) complex has been spectroscopically detected at low temperature from a 1, 6enyne. 27 In the case of electron-rich alkynes, the alkene reacts by attack at the internal carbon, 3,4 whereas electron-deficient alkynes react at the terminal carbon, leading to intermediates 10, which can undergo formal 1,3-migration to give 1,3-dienes 5 or experience intramolecular attack by the carboxylic acid (Z = CO 2 H) to afford 6 (Scheme 2). 20 The very different outcomes of the reactions of electron-rich aryl-or cyclopropyl-substituted alkynes and alkynes bearing electron-withdrawing groups are rather striking. Therefore, we decided to examine in detail the reaction of a broader range of terminal alkynes to get a clearer perspective of this fundamental reaction in gold(I) chemistry. Surprisingly, we found that some ortho-substituted arylalkynes react with alkenes to give 1,3dienes in a metathesis-type process. On the other hand, less sterically demanding 1,3-butadiynes lead exclusively to cyclobutenes. Here we report these results along with a detailed theoretical analysis of the mechanism of formation of cyclobutenes or 1,3-dienes. To support the initial involvement of cyclopropyl gold(I) carbenes in these transformations, we also studied the generation of these intermediates by a retro-Buchner reaction. This study leads to a comprehensive picture of the gold(I)-catalyzed reactions of alkynes with alkenes.
1,3-Dienes 11b−h were obtained as single E-stereoisomers, which was determined by NOE experiments. This assignment was confirmed in the case of 11e (Table 1, entry 5) by X-ray diffraction of crystalline derivative 11w, obtained from 11e by Suzuki coupling with p-nitrophenylboronic acid (Scheme 3).

Article
The alternative product, 11e-d 1 ′, resulting from a doublecleavage-type rearrangement (formal cleavage of both the alkyne and the alkene; see below), was not observed.
For a deeper insight into the mechanism of the formation of cyclobutenes 3 and/or 1,3-dienes 11 as well as the influence of the substituents on the substrates in the reaction outcome, we performed density functional theory (DFT) calculations 35 using PMe 3 as the ligand for gold(I). 36 We examined the reaction between phenylacetylene (1a) and α-methylstyrene (2a) to give cyclobutene 3a as well as the reaction of (o-bromophenyl)acetylene (1e) with 2a leading to 1,3-diene 11e as the major product.
Electron-rich alkenes coordinate preferentially with gold(I), 4 leading to (η 2 -alkene)gold(I) complexes that can be isolated and structurally characterized. 37 Accordingly, the reaction begins with the associative ligand exchange of (η 2 -alkene)gold-(I) complex Int1a to generate the slightly less stable (η 2alkyne)gold(I) complex Int2a (Scheme 6). The attack of the alkene to the gold(I) alkyne complex Int2a can take place in an anti or a syn fashion to form intermediates Int4a and Int4b, which are in equilibrium due to C3−C4 bond rotation via ringopened intermediate Int4ab. 38 In both cases, formation of intermediates Int4a,b with the gold(I) carbene at the terminal carbon is kinetically more favored than the formation of regioisomeric Int3a,b by at least 3.8 kcal/mol. Although formation of Int4b requires 0.9 kcal/mol lower energy than Int4a, further evolution of Int4a to other intermediates proceeds through lower energy barriers. 39 The possibility of an oxidative cyclometalation was also considered. 40 However, neither the intermediate with the alkyne and the alkene coordinated simultaneously to gold(I) nor the gold(III) metalacyclopentene was found as a stable species.
Intermediate Int4a is also in equilibrium via C4 migration with the cyclopropyl-type intermediate Int5a, whose ring opening leads directly to (1,3-diene)gold(I) complex Int8a through TS 5−8 a (ΔG ⧧ = 9.9 kcal/mol) (Scheme 7). The alternative C3 migration would lead to a less stable cyclopropyl methyl intermediate to ultimately form a different type of 1,3diene that was not observed experimentally. The opening of the cyclopropane of Int5a via TS 5−6 a (ΔG ⧧ = 10.7 kcal/mol) to form the less stable intermediate Int6a, followed by a highly exothermic 1,2-H shift, would give 1,3-diene−gold(I) complex Int9a. However, formation of either Int8a or Int9a from Int5a requires higher activation energies than the conversion of Int5a to Int4a (ΔG ⧧ = 5.7 kcal/mol). Comparing all the activation energies, the most favored reaction pathway is the ring expansion of Int4a to give (η 2 -cyclobutene)gold(I) complex Int7a (ΔG ⧧ = 8.9 kcal/mol). Conrotatory ring opening of Int7a to form Int10a is unlikely as it would have to overcome a prohibitively high energy barrier of 32.1 kcal/mol. 41 Thus, our calculations predict that cyclobutene 3a would be the product of the reaction, which is consistent with the formation of 3a in a 95% yield from 1a and 2a (Table 1, entry 1). 3,4,42 The reaction of (o-bromophenyl)acetylene (1e) with αmethylstyrene (2a) is more complex as four different approaches of the alkene toward the Int4c−f could be conceived (Scheme 8) depending on the relative orientation

Scheme 6. Ligand Substitution and Formation of Key
Intermediates Int4 a a Free energies in kcal/mol. L = PMe 3 . b Calculations using 2methylpropene instead of α-methylstyrene. c Depicted configuration of C3 for Int3a. Opposite configuration of C3 for Int3b.

Journal of the American Chemical Society
Article of the phenyl groups of the substrates (anti or syn) and the position of the ortho-substituent in the alkyne with respect to the olefin carbons (ortho-substituent closer to either the terminal or internal alkene carbon). Thus, four distinct reaction pathways were computed for this system (c−f, Scheme 8). As in the case of the reaction of phenylacetylene (1a) with alkene 2a, formation of the cyclopropyl gold(I) carbene at the internal alkyne carbon (Int4c−f, ΔG ⧧ = 16.7−17.5 kcal/mol) is more favorable than at the terminal alkyne carbon (Int3c−f, ΔG ⧧ = 18.8−20.1 kcal/mol). 39 Comparison of the activation energies of the transformations of Int4c−f into Int5c−f or Int7c−f suggests that the o-bromo substituent hampers the rearrangement of the near alkene carbon and favors the rearrangement of the further alkene carbon. In fact, cyclopropyl gold(I) carbenes Int4d and Int4f bearing the bromo atom closer to C3 prefer to form intermediates Int5d and Int5f via rearrangement of C4, which then lead to 1,3-diene−gold(I) complexes Int8d and Int8f, respectively. In contrast, cyclopropyl gold(I) carbene Int4e bearing the o-bromo substituent closer to C4 prefers to undergo ring expansion through C3 to give the (η 2cyclobutene)gold(I) complex Int7e. Analyzing all the energy barriers (including bond rotations), the most favored pathway is that to 1,3-diene−gold(I) complex Int8d. This is in agreement with the experimental result, as 1,3-diene 11e is obtained in a 45% yield and only traces of cyclobutene 3e are detected (Table 1, entry 5). Nevertheless, the difference in the activation energies of the rearrangements of cyclopropyl gold(I) carbenes Int4 are not large, so subtle changes in the substitution pattern of the substrates modify the steric interactions and, consequently, the reaction outcome. Then, reasonably, different ratios of cyclobutene and 1,3-diene products were experimentally obtained depending on the differently substituted substrates.
For the sake of completeness, the mechanism of the gold(I)catalyzed reaction between 1-phenyl-1,3-butadiyne (12a) and alkenes was also studied computationally (Scheme 9). Gold(I) complex Int2h, in which gold(I) is coordinated to the terminal alkyne, is 2.8 kcal/mol more stable than the complex Int2g with gold(I) coordinated to the internal alkyne. The preferential binding of gold(I) to the less substituted multiple bond has been experimentally observed in the case of allenes. 43 (Alkyne)gold(I) complex Int2g shows an almost symmetrical η 2 -coordination with a significant bending back of the phenyl group, which is consistent with reported structures of related (alkyne)gold(I) complexes. 44 In contrast, in complex Int2h, the terminal alkyne binds very unsymmetrically with gold(I), resulting in longer bonds with the substituted carbon atom, as also observed in terminal (alkene)gold(I) complexes. 37,45 The free energy of activation for the attack of the alkene on the terminal alkyne is 3.4 kcal/mol lower than the barrier corresponding to the attack at the internal alkyne (Scheme 9). Consequently, on both thermodynamic and kinetic grounds, the alkene selectively attacks complex Int2h at the terminal alkyne as a π-nucleophile, forming distorted cyclopropyl gold(I) carbene Int4h. The ring expansion of Int4h through C3 (ΔG ⧧ = 7.0 kcal/mol) gives the (η 2 -cyclobutene)gold(I) complex Int7h. 39 The alternative ring expansion of cyclopropyl gold(I) carbene Int4h through the terminal alkene carbon C4 generates a distorted (cyclobutene)gold(I) complex Int12h through a low barrier of 5.2 kcal/mol. Interestingly, an intermediate similar to Int12h was not found in the reaction of phenylacetylene derivatives 1a and 1e with alkene 2a discussed above. Intermediate Int12h undergoes formal

Journal of the American Chemical Society
Article insertion of the terminal alkene carbon C4 into the alkyne carbons to form a more stable cyclopropyl-like intermediate, Int5h. Although intermediates Int4h, Int12h, and Int5h are in equilibrium through low barrier transformations, ring opening of Int5h to form (1,3-diene−gold(I) complex) Int8h is more energetically costly than the expansion of Int4h to (η 2cyclobutene)gold(I) complex Int7h (10.0 vs 7.0 kcal/mol), which is fully consistent with the experimental results.
Further Experimental Support for the Involvement of Cyclopropyl Gold(I) Carbenes. We have discovered a method to generate gold(I) carbenes by the retro-Buchner reaction of 7-substituted 1,3,5-cycloheptatrienes with electrophilic gold(I) catalysts, in a process in which a molecule of benzene is also formed in a formal decarbenation reaction. 46,47 The retro-Buchner reaction proceeds by stepwise cleavage of the norcaradienes, which are in tautomeric equilibrium with the cycloheptatriene. 46 Other related decarbenations have been observed in the presence of gold(I). 48,49 When 7-cyclopropylcycloheptatriene 14 was heated in the presence of catalyst A, (Z,Z)-1,4-diphenyl-1,3-diene [(Z,Z)-15] was formed selectively (Scheme 10). 46 This transformation presumably proceeds via cyclopropyl gold(I) carbene 16a, which undergoes a formal 1,3-shift of a CHPh fragment. Interestingly, 16a would correspond to the intermediate generated in the gold(I)-catalyzed reaction between acetylene and trans-stilbene. The ring expansion of 16a to form cyclobutene 17, which would have given diene (E,E)-15 by conrotatory opening, 50 was not observed. 46 This result predicts that a cis-isomer of 7-cyclopropylcycloheptatriene 14 would give rise to the diene (E,Z)-15. Unfortunately, this isomer could not be prepared by the same method used for the synthesis of 14.
Since the generation of intermediates such as 16a by a totally different process could be relevant to the better understanding of the mechanism of the gold(I)-catalyzed reaction of alkynes with alkenes, we recurred to our initial system for the generation of gold(I) carbenes by decarbenation of 1a,7bdihydro-1H-cyclopropa[a]naphthalenes (Scheme 11). 48 The required starting 1,6-enynes 18a,b were prepared as a ca. 1:1 mixture of epimers at the benzylic position by olefination of the corresponding cyclopropyl carbaldehydes. 51, 52 The gold(I)catalyzed cycloisomerization of 18a,b takes place under mild conditions using catalyst A to furnish enol ethers 19a,b in 48% and 61% yields, respectively, whose relative configurations were determined by X-ray diffraction. When enol ether 19a was heated with catalyst A in 1,2-dichloroethane at 60°C, the decarbenation reaction provided 1-methoxy-3-phenylnaphtha-

Journal of the American Chemical Society
Article lene (20) and (Z,Z)- 15. 53 Similarly, substrate 19b reacted at 60°C for 1 h with catalyst A to give naphthalene 20 together with a 1:2 mixture of (E,Z)-and (E,E)-15. 54 The retro-Buchner (decarbenation) reaction of 19a should lead to the same cyclopropyl gold(I) carbene 16a (=Int4i) generated from trans-14, whose opening by C3 migration via Int5i leads to Int8i and ultimately to (Z,Z)-15 46 52 In full agreement with the experiments, DFT calculations show that the alternative expansion of cyclopropyl gold(I) carbenes Int4i,j to cyclobutenes Int7i,j is a higher energy process. 39 Although both reaction pathways from 19a,b could in principle be connected by the trans-to cis-isomerization of Int4i to Int4j via open carbocation Int4ij (Scheme 12), in contrast to that found in the equilibrium between Int4a and Int4b (Scheme 6), here the corresponding barriers are much higher in energy than those leading to C3 migration. 56 Finally, it is interesting to compare these results with known examples of formation of cyclobutenes via cyclopropyl carbenes. Thus, the photolysis of cis-and trans-21 has been shown to give cis-and trans-22 cyclobutenes, respectively, as a result of a stereospecific ring expansion (Scheme 13a). 57 In these reactions, methyl propiolate and cis-or trans-2-butene were also obtained as a result of a competitive fragmentation. Likewise, in the presence of AgOTf, cis-and trans-23 undergo stereospecific ring expansion to cyclobutenes cis-and trans-24, respectively (Scheme 13b). 58,59 The thermal decomposition of the potassium salt of tosyl hydrazone 25 also led to a product of ring expansion (26), together with acenaphthylene (27), the product of fragmentation (Scheme 13c). 60 Ring expansion to cyclobutenes and fragmentation to form alkenes and alkynes have also been observed in reactions of simple cyclopropyl carbenes. 57

■ CONCLUSIONS
Electron-rich alkynes have been shown to react with alkenes in the presence of gold(I) catalysts by [2 + 2] cycloaddition to give rise to cyclobutenes, whereas, in contrast, electrondeficient alkynes lead to 1,3-dienes in a metathesis-type process. Now we have found that 1,3-dienes can also be obtained in the reaction of alkenes with electron-rich alkynes bearing ortho-substituted aryls.
The two reaction channels leading to cyclobutenes or 1,3dienes are close in energy. According to all our calculations, the first intermediates in the gold(I)-catalyzed intermolecular reaction of alkynes with alkenes are cyclopropyl gold(I) carbenes, which despite all the experimental efforts 27,61 are still elusive species. To substantiate their involvement in these transformations, we have generated these intermediates by a totally different method based on the gold(I)-promoted retro-Buchner reaction, which also leads to the formation 1,3-dienes

Journal of the American Chemical Society
Article by a metathesis-type mechanism. The formation of 1,3-dienes involves a two-or three-step mechanism in which the carbon− carbon double bond of the alkene is cleaved, similar to that proposed in the gold(I)-catalyzed intramolecular skeletal rearrangements of 1,6-enynes. Products of conrotatory opening of cyclobutenes are not observed in the gold(I)-catalyzed reaction of alkynes with alkenes, which is consistent with the high activation energy required for this process.
The common mechanistic scenario for gold(I)-catalyzed reactions of alkynes with alkenes involves the initial formation of cyclopropyl gold(I) carbene intermediates, followed by fast ring expansion or rearrangement. Formation of 1,3-dienes can take place from both electron-rich and electron-deficient alkynes, although cyclobutenes have only been obtained in gold(I)-catalyzed reactions involving electron-rich alkynes. There is another important difference between the reactions of electron-rich and electron-deficient alkynes since in the former case the alkene reacts with the internal carbon of the alkyne, whereas in the second case the alkene attacks the terminal carbon, leading to regioisomeric cyclopropyl gold(I) carbenes.

* S Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b03005.
All procedures and characterization data for new compounds (PDF) Full details of the theoretical calculations (PDF) X-ray crystallographic data for 3v (CIF) X-ray crystallographic data for 11w (CIF) X-ray crystallographic data for 19a (CIF) X-ray crystallographic data for 19b (CIF) X-ray crystallographic data for 19c (CIF)