Chemical Science EDGE ARTICLE Skeletal diversity in Pt- and Au-catalyzed Cite this: Chem. Sci., 2020, 11, 4209 annulations of allenedienes: dissecting All publication charges for this article unconventional mechanistic pathways† have been paid for by the Royal Society of Chemistry Ronald Nelson, ‡ab Martı́n Calvelo, ‡a Rebeca Garcı́a-Fandiño, a Agustı́ Lledós, c Gregori Ujaque,c José L. Mascareñas *a and Fernando López *ad We describe the discovery of unprecedented annulation processes of 1,7-allenedienes, promoted by Pt or Au catalysts. These transformations revealed mechanistic pathways that had not been previously observed in reactions involving carbophilic catalysis. In particular, we have found that allenedienes bearing a silyl ether in the carbon tether connecting the diene and the allene divergently afford cyclopropane-embedded Received 3rd February 2020 Accepted 26th March 2020 tricyclic derivatives, 6,6-fused bicarbocyclic products or 5,6-fused bicarbocyclic systems, depending on the type of Au or Pt catalyst used. We have carried out experimental and computational studies that DOI: 10.1039/d0sc00650e shed light on the mechanistic reasons behind this rich and unusual skeletal divergence, and provide new rsc.li/chemical-science lessons on the drastic influence of platinum ancillary ligands on the reaction outcome. 20 ), through a formal [4C + 3C] cycloaddition (Scheme 1a, a), Introduction catalysts featuring bulky p–acceptor ligands such as Au3 afford Throughout the last two decades, carbophilic catalysis has [4C + 2C] adducts (3), provided that terminally disubstituted reshaped the eld of organic synthesis by providing an exten- allenes are used (Scheme 1a, b). Theoretical and experimental sive portfolio of methods that allow transformation of simple data conrmed that the reactions involve a common metal unsaturated precursors into highly valuable cyclic skeletons.1 Our group has contributed to this eld with the development of a variety of Pt- and Au-catalyzed formal cycloadditions involving allenes as key reaction partners.2,3 In particular, in 2009, we and the Toste group, independently demonstrated that gold(I) complexes of type LAuCl/AgX could efficiently promote intramolecular cycloadditions of allenedienes of type 1 in a reagent-controlled, divergent manner (Scheme 1a).4–6 Thus, while gold catalysts bearing s-donating ligands such as IPr (Au1) or JohnPhos (Au2) lead to 5,7-fused bicyclic systems 2 (or a Centro Singular de Investigación en Quı́mica Biolóxica e Materiais Moleculares (CiQUS), Departamento de Quı́mica Orgánica, Universidade de Santiago de Compostela, 15782 Santiago de Compostela, Spain. E-mail: joseluis.mascarenas@ usc.es b Departamento de Quı́mica, Universidad Católica del Norte, Av. Angamos 0610, Antofagasta, Chile c Departament de Quı́mica, Universitat Autònoma de Barcelona, Cerdanyola del Valles, 08193, Catalonia, Spain d Instituto de Quı́mica Orgánica General CSIC, Juan de la Cierva 3, 28006, Madrid, Spain. E-mail: fernando.lopez@csic.es † Electronic supplementary information (ESI) available: Full experimental procedures, optimization of the catalyst, characterization of all new compounds (including NMR spectra), computational details (including Fig. S8–S18), and Cartesian coordinates are provided. CCDC 1964184–1964188. For ESI and crystallographic data in CIF or other electronic format see DOI: Scheme 1 (a) Previous Au(I) and Pt(II)-catalyzed allenediene cycload- 10.1039/d0sc00650e ditions and (b) current divergent annulations. ‡ R. N. and M. C. contributed equally. This journal is © The Royal Society of Chemistry 2020 Chem. Sci., 2020, 11, 4209–4220 | 4209 Chemical Science Edge Article carbene intermediate (A), which evolves from 1,2-hydride or 1,2- alkyl migrations to deliver the observed adducts. The divergence of the process is controlled by stereoelectronic factors of the ancillary ligand, the cationic character of the gold carbene, and the substitution pattern at the carbene adjacent positions.4b,7 Therefore, in several cases, mixtures of cycloheptene (2/20 ) and cyclohexene (3) adducts are obtained. Remarkably, the performance of the Au(I) catalysts contrasts with that of their Pt(II) counterparts which, albeit less active, Fig. 1 X-ray structure of 4a,13 and the sesquiterpenes cubebols and had been previously shown to deliver exclusively cycloheptene a cubebene. products (2/20 ).8,9 Indeed, we have exploited this selectivity in short total synthesis of Englerin A, a sesquiterpene natural product with antitumor properties.10 exhibited an unanticipated 5,3,6-tricyclic skeleton with four The catalyst-dependent [4C + 3C]/[4C + 2C] annulation of consecutive stereocenters (Scheme 2). allenedienes was further conrmed by other groups,5,11 and The structure and relative stereochemistry of both products thus it seemed to be a well-established reactivity paradigm. were determined by NMR, and those of 4a were conrmed by X- However, we have now found new, surprising annulation ray analysis (Fig. 1).13 This type of tryciclo[4.4.0.01,5]decane pathways that revealed unprecedented ligand-dependent skel- skeleton is relevant as it forms the basic core of important etal rearrangements. In particular, we demonstrate herein that natural products like cubebenes, currently used in the fragrance 1,7-allenedienes with a silyl ether pendant in the tether (e.g. 1a) and food industries.14 Notably, while previous routes to these can divergently afford cyclopropane-embedded tricyclic deri- scaffolds involve numerous steps from chiral pool sources,15 the vates of type 4, 6,6-fused bicarbocyclic products such as 5, or above annulation proposes a straightforward, fully stereo- 5,6-fused bicyclic adducts 3, depending on the Au or Pt catalyst selective entry to their basic cores from readily accessible acyclic employed (Scheme 1b). The drastic reactivity switch when the precursors.16 PtCl2-catalyzed reactions are carried out in the presence of CO, The synthetic relevance of the tricyclic product and, an effect that is absent in previous Pt-catalysed reactions, is specially, the intriguing mechanistic features of the trans- particularly relevant. Curiously, we did not observe the other- formation, prompted us to further study the process. The wise expected [4 + 3] adducts of type 2 (2a/2a0 Scheme 1b). reaction promoted by Au1 can be reproduced in substrate 1b, an More importantly, we describe mechanistic studies that shed allenediene that lacks the methyl group in the diene (Table 1). light on the reasons behind this divergence, and reveal unan- Again, we obtained a mixture of the tricyclic product 4b and the ticipated pathways that had never been observed in carbophilic formal [4C + 2C] adduct 3b, with good selectivity towards the metal catalysis. Thus, our work conrms the importance of former (4b : 3b ¼ 5 : 1). Accordingly, the cyclopropyl adduct 4b generally overlooked homo-hyperconjugative interactions in Pt was isolated in a good 70% yield. catalysis and shows how subtle conformational and stereo- Interestingly, other gold(I) complexes previously reported to electronic factors can critically determine the reaction outcome. promote formal [4C + 3C] cycloadditions of allenedienes, also failed to give the cycloheptenyl adduct 2b. Thus, while the JohnPhos-based catalyst Au20 provided a complex mixture of Results and discussion products (entry 2), gold(I) complexes with Xphos and Ruphos Initial results: discovery of catalyst-dependent multifold paths ligands provided very modest yields of 4b (entries 3 and 4). of allenedienes Noteworthily, the N-heterocyclic carbene gold complex We initiated our studies by analyzing the cycloaddition of alle- IPrMeAuCl/AgNTf2 (Au6) was completely selective towards the nediene 1a, which was designed as a potential precursor of the tricyclic product 4b (96% yield at rt, entry 5). carbocyclic core of guaiane sesquiterpenes.12 Surprisingly, when In consonance with previous reports, the formal [4C + 2C] allenediene 1a was treated with IPrAuCl/AgSbF6 (Au1) in adduct 3b could be obtained in good yields when complexes CH2Cl2, the adduct 2a was not observed. Instead, we obtained bearing p–acceptor ligands, such as Au3 or Au7, are used as a 1 : 2 mixture of the formal [4C + 2C] adduct 3a and the catalysts (entries 6–7).4b,5 On the other hand, gold(III) complexes cyclopropyl derivative 4a (isolated in 57% yield), which such as AuCl3 or AuBr3 provided complex mixtures at rt (entries 8 and 9), whereas the 2-picolinate derivative PicAuCl2 showed some reactivity at high temperature (reuxing toluene), but gave a very modest yield of 4b (17%, aer 8 h, entry 10). Surprisingly, the reaction of 1b with catalytic amounts of PtCl2, in reuxing toluene, also provided the tricyclic product 4b with complete selectivity, but with moderate yield (entry 11). Other catalysts such as [PtCl2(ethene)2]2 or PtCl2/P(C6F5)3 afforded the same product in moderate to good yields, under Scheme 2 Unexpected reaction outcome of 1a using IPrAuCl/AgSbF6 otherwise identical reaction conditions (entries 12–13). (Au1). Amongst these catalysts, PtCl2 turned out to be the most 4210 | Chem. Sci., 2020, 11, 4209–4220 This journal is © The Royal Society of Chemistry 2020 Edge Article Chemical Science Table 1 Exploration of the cycloaddition of 1b; selectivity with different Au and Pt catalystsa Entry [M] T ( C) t (h) 4b : 3b ratiob Yieldc (%) 1 IPrAuCl/AgSbF6 (Au1) rt 2 5:1 70 (4b) 2 JohnPhosAuNTf2 (Au20 ) rt 12 — —d 3 XPhosAuNTf2 (Au4)e 80 12 1.1 : 1 18 (4b) 4 RuPhosAuNTf2 (Au5) 40 12 16 : 1 32 (4b) 5 IPrMeAuCl/AgNTf2 (Au6) rt 2 1:0 96 (4b) 6 (ArO)3PAuCl/AgSbF6 (Au3)f 15 1.5 1:7 66 (3b) 7 (C6F5)3PAuCl/AgNTf2 (Au7)g 15 1 1 : 12 70 (3b) 8 AuCl3 rt 12 — —d 9 AuBr3 rt 12 — —d 10h PicAuCl2 110 8 1:0 17 (4b) 11h PtCl2 110 0.5 1:0 43 (4b) 12h [PtCl2(ethene)2]2g 110 1 1:0 53 (4b) 13h PtCl2/(C6F5)3P (1 : 1) 110 1 1:0 62 (4b) 14h PtCl2 70 2 1:0 81 (4b) 15i PtCl2 50 2 1:0 88 (4b) 16j PtCl2 30 2.5 1:0 99 (4b) 17j PtCl2 (1 mol%) 30 24 1:0 92 (4b) a Carried out with [M] (10 mol%) in CH2Cl2 (0.05 M), unless otherwise noted. See Tables S1–S2 for the structures of Au complexes and further examples. b Ratio determined by 1H-NMR of the crude mixtures. c Isolated yield. d Complex mixture of products. e Carried out in 1,2-DCE. f Ar ¼ 3,5-(tBu)2C6H3. g Carried out with 5 mol% catalyst. h Carried out in toluene. i Carried out in cyclohexane (with 1 ppm of water). j Carried out in 1,4-dioxane. efficient one, providing a 81% yield at 70  C (entry 14). The previously employed to accelerate PtCl2 catalyzed processes – we solvent also played a key role in the rate and efficiency of the observed a new type of adduct, the biscyclohexenyl product 5b process: cyclohexane and 1,4-dioxane proved to be optimal, (59% yield), together with minor amounts of 4b (5b : 4b ratio ¼ respectively delivering 4b in 88% yield (2 h at 50  C, entry 15) 8 : 1, Scheme 3). X-ray analysis of a desilylated derivative (5b0 ) and 99% yield (2.5 h at 30  C, entry 16). Moreover, the reaction conrmed its 6,6-bicyclic structure.13 could be scaled up (gram scale), and the amount of the catalyst This type of bicarbocyclic skeleton is quite common in could also be reduced to 1 mol%, without notably affecting the several sesquiterpenes (Scheme 3, bottom).17 Importantly, yield and/or selectivity (entry 17). carrying out the reaction in cyclohexane (with a 1 ppm content Surprisingly, when the reaction of 1b with PtCl2 was carried of water) at 50  C for 2 h resulted in 5b in 85% yield (5b : 4b ratio out in the presence of CO (balloon) – a strategy that has been ¼ 9 : 1). While using completely dry cyclohexane the reaction was slightly less efficient (79% yield, Scheme 3; also see Table S3†). Scheme 3 PtCl2-catalyzed reaction of 1b under a CO atmosphere. Scheme 4 Catalyst-dependent skeletal diversity from 1a. This journal is © The Royal Society of Chemistry 2020 Chem. Sci., 2020, 11, 4209–4220 | 4211 Chemical Science Edge Article In analogy with the above results, treatment of the precursor 1a with PtCl2, in cyclohexane at 50  C, gave the tricyclic adduct 4a (88% yield), whereas performing this reaction under a CO atmosphere produced the bicarbocyclic adduct 5a in 85% yield (Scheme 4). Alternatively, when using Au7 as the catalyst, the same precursor (1a) provides the expected 5,7-fused bicyclic product 3a (54% yield, formal [4 + 2] cycloadduct).13 Overall, these results conrm an interesting case of multi- fold reactivity, in which the acyclic precursor can be trans- formed in a catalyst-dependent, divergent manner. Moreover, the above-described examples represent the rst demonstration of a drastic change in the outcome of a Pt-catalyzed reaction, when it is carried out in the presence of CO.18 Preliminary exploration of the synthetic potential of the products A preliminary analysis of the synthetic potential of the tricyclic adducts 4 revealed interesting reactivity proles (Scheme 5). Therefore, treatment of 4b with H2 (1 atm) over Pd/C (10 mol%) resulted in the hydrogenation of the double bond with concomitant cyclopropane opening, affording the trans-fused bicyclic product 6b in quantitative yield and with complete diastereoselectivity (Scheme 5, eqn (1), conditions a).19 An alternative hydrogenation using Pd(OH)2/C in MeOH also pro- ceeded with equal selectivity, albeit the TBS group was also removed (eqn (1), conditions b). In contrast, the use of PtO2 Scheme 6 (a) Mechanistic probes (eqn (1)–(3)) and the (b) mechanistic (10 mol%) under H2 pressure (5 bar) led to the exclusive hypothesis. hydrogenation of the double bond, quantitatively affording the tricyclic system 7b, which presents a carbocyclic core analogous to that of cubeb derivatives (eqn (2)). Finally, the OTBS group of identiable product (Scheme 6a, eqn (1) and Tables S4–S6†).13 4b could also be easily converted into its corresponding ketone Given that the mechanistic proposals to explain the formation (8b), paving the way for further variations at this position (eqn of adducts 2 and 3 invoked the presence of carbene interme- (3)). diates (A, Scheme 1), and envisioning that the same type of intermediate could also be behind the novel reactivity, we Experimental mechanistic studies sought to trap the putative carbene species using different oxidants.20 Gratifyingly, aer some experimentation (Table S7†), The above annulation reactions are especially intriguing from we found that treatment of 1b with IPrAuNTf2 (10 mol%) and a mechanistic perspective. In this context, we rst questioned 3,5-dichloropyridine oxide (10 equiv) provided, together with whether the 6,6-bicarbocyclic cycloadducts (such as 5b) could the tricyclic adduct 4b (67% yield), a substantial amount of the be formed by cleavage of the cyclopropyl ring in the adduct 4b. ketone 9b (z30% yield, Scheme 6, eqn (2)). This product was However, treatment of this tricyclic compound with PtCl2/CO, identied aer reduction of the crude residue with NaBH4, under standard conditions, neither generated 5b nor any other which afforded the alcohols 10b and 10b0 (30% overall yield). Although this result is not fully conclusive, as the pyridine oxide Scheme 5 Preliminary exploration of the synthetic potential of adducts 4. Scheme 7 Pt(II)- and Au(I)-catalyzed annulations of 1d. 4212 | Chem. Sci., 2020, 11, 4209–4220 This journal is © The Royal Society of Chemistry 2020 Edge Article Chemical Science elimination of the catalyst, would produce the adducts 3 (migration of C10) and 5 (migration of C7) (Scheme 6b). Other allenediene precursors with OTIPS or OTES groups in the tether also provided the same reactivity prole as 1a or 1b (Table S10†). However, treatment of allenediene 1d, equipped with a gem-diester in the tether, with PtCl2 produced the ex- pected seven-membered cycloadduct 2d in quantitative yield (Scheme 7).8 Moreover, when this reaction was carried out under a CO atmosphere, in cyclohexane, we observed the same product (2d) again. Likewise, we also obtained the adduct 2d by using the gold catalyst Au1. Neither the 6,6-fused bicyclic Fig. 2 Gibbs energy profile (kcal mol1) for the activation of 1b by adduct 5d nor the tricyclic product 4d was detected. These PtCl2(CO) and its subsequent [4C + 3C] cycloaddition in cyclohexane (SMD model). The TBS group is omitted from the 3D representation of results conrm that the structure of the precursor also has I3co for clarity.22 a critical inuence on the reaction outcome. DFT analysis of the new, divergent processes could somehow alter the mechanistic pathway, the formation of The observation that, even in the presence of CO, 1d performs cycloheptenone 9b is a priori compatible with a concerted very differently from 1a and 1b, added further interest to the allenediene [4C(4p) + 3C(2p)] cycloaddition that delivers the mechanistic study, and to uncover the reasons behind the hypothesized carbene species A0 (Scheme 6a, eqn (2)). skeletal divergence. We therefore performed extensive DFT Importantly, allenedienes Z-1b and 1c, respectively bearing computational studies, using allenedienes 1b and 1d, and a cis-conjugated diene or a methyl group at the diene internal different Pt and Au complexes as catalysts.22 position, did not provide any product regardless of the type of Reaction prole for 1b using [PtCl2(CO)] as the catalyst.23 the catalyst used (Scheme 6a, eqn (3), Tables S8–S9†). These The Gibbs energy prole for the reaction of 1b promoted by results are consonant with a concerted cycloaddition to provide PtCl2(CO) is shown in Fig. 2 and 3, together with the most a metal carbene species like A0 (Scheme 6b), which can evolve in relevant stationary points (see also Fig. S8–S9†). Aer initial a divergent way to give the observed products. Indeed, we coordination of the allene moiety to PtCl2(CO) (I1co) and initially envisioned that a putative C(7)–H carbene insertion generation of the Pt-substituted allyl cation I2co, there is could provide the tricyclic adduct of type 4,21 whereas alterna- a concerted exo-like [4C(4p) + 3C(2p)] cycloaddition, with an tive 1,2-alkyl migrations of C10 and C7, with concomitant energy barrier of only 6.6 kcal mol1 (via Ts2-3co). In this Fig. 3 Gibbs energy profile (kcal mol1) of the reaction of 1b with PtCl2(CO) in cyclohexane: the most relevant divergent pathways from I3co (energy of I1co, shown in Fig. 2, is considered as the reference; see Fig. S8–S9† for a complete profile).22 Optimized structures of selected stationary points (TBS omitted for clarity). This journal is © The Royal Society of Chemistry 2020 Chem. Sci., 2020, 11, 4209–4220 | 4213 Chemical Science Edge Article of Wiberg bond indexes (WBIs) of 3.91, a value which is divided into ve different bonds. Thus, this analysis provided WBIs of 0.18 and 0.52 for the critical C2–C7 and C2–Pt bonds, whereas those of C2–C3 and C3–C7 bonds are clearly higher, 0.89 and 1.07, respectively (Fig. S10†).27 Importantly, the evolution of I30 co to I40 co is much more favorable than either the 1,2-hydride migration towards 2b (via Ts30 -2bco), or the 1,2-alkyl (C7) migration via Ts30 -5bco [DDG‡ ¼ 3.8 and 8.4 kcal mol1, respectively; Fig. 3].28 Curiously, DFT calculations indicate that intermediate I40 co could undergo a very easy skeletal rearrangement to the more stable 6,6-bicyclic system I50 co, through an early transition state (Ts40 -50 co, DG ¼ 3.1 kcal mol1), which shows how the C2–C7 bond is being formed with net inversion of conguration at C2 [d(C2–C7) ¼ 1.754 Å] while the Pt complex migrates stereospe- cically from C2 to C3. The three different C–C bonds of the Fig. 4 Key distances and NBO representation of relevant HOMO's of cyclopropyl ring generated in this transition state are mostly, I40 co, Ts40 -50 co and I50 co. The TBS groups are truncated for clarity.22 but not completely formed (see Fig. 4 for C–C bond distances, and Fig. S10† for WBIs and Laplacian electron density maps). Also, remarkably, in this transition state, the Pt, C2, C3 and C7 cycloaddition, the OTBS group prefers to be placed in a pseudo- atoms, together with the p orbital of C7, adopt a W-shape axial disposition, affording the 5,7-bicyclic carbene interme- conformation similar to that found in cyclopropanation reac- diate I3co, which is also thermodynamically favored over the tions of different organometallic species (e.g. Fe, Sn,.), pseudo-equatorial conformer (I3coeq) by 3.0 kcal mol1 wherein hyperconjugative interactions are also critical.29 (Fig. S9†).24 The higher stability of I50 co compared to I40 co (6.8 kcal mol1) From the cycloheptenyl carbene I3co, we could locate a tran- is probably the consequence of the release of ring strain and the sition state for the 1,2-alkyl migration of carbon C7 (seven- strengthening of homohyperconjugative interactions. Indeed, membered ring contraction, Ts3-5bco), which generates the the HOMO1 molecular orbital of I50 co (NBO analysis) shows experimentally observed dicyclohexene product 5b (denoted as clear homo-hyperconjugative stabilization by an orbital that 5b-[Pt]co, Fig. 3, red path, Ea: 20 kcal mol1). However, the 1,2- extends over C3 and C7 (Fig. 4). Accordingly, the C7–C3 distance alkyl (C10) migration leading to the formal [4 + 2] adduct 3b in I50 co (2.297 Å) is signicantly shorter than that of the C7–C1 (denoted as 3b-[Pt]co), and the 1,2-hydrogen (H-3) migration bond (2.528 Å, Fig. 3 and 4). Finally, from I50 co, a stereospecic leading to cycloheptene 2b (denoted as 2b-[Pt]co) were found to 1,2-migration of the hydrogen at C3 to the carbocation center involve signicantly lower energy barriers (Fig. 3, blue and (C7), with concomitant elimination of PtCl2(CO), delivers the orange paths). experimentally observed product 5b, which is complexed to the Importantly, more detailed DFT scrutiny revealed an unan- Pt center (denoted as 5b-[Pt]co). ticipated but energetically more viable alternative, which is Overall, the above-calculated route towards 5b from I30 co is initiated by a conformational change in Pt–carbene species I3co highly exergonic and proceeds through transition states that to generate I30 co, a conformer in which ve out of the seven exhibit the lowest energy barriers of all the different calculated carbons of the cycloheptene (C3, C7–C10) are almost coplanar proles (DG‡ varying from 3.1 to 6.0 kcal mol1; Fig. 3). (Fig. 3). This species is 1.2 kcal mol1 less stable than I3co, but Therefore, these data are fully consistent with the experimental accessible through an activation barrier of only 6.5 kcal mol1 observation of adduct 5b as the major product in the reactions (see Fig. 3 and S8†). Therefore, this easy conformational promoted by PtCl2 under a CO atmosphere.30 evolution warrants eventual Curtin–Hammet conditions. Reaction prole for 1b using PtCl2(ethene) as the catalyst. From I30 co we located an unexpected, very favorable migra- We next analyzed the energy prole with a Pt catalyst that tion of the hydrogen at C7 to the Pt–carbene center (C2) to give affords the cyclopropyl-containing tricyclic product 4. In the carbocationic intermediate I40 co (Fig. 3, magenta path). This particular, we focused on PtCl2(ethene)2 since it provides the is an interesting species which can be viewed as a non-classical same selectivity as PtCl2 (see Table 1, entry 12), but its four carbocation stabilized by homohyperconjugation (also called coordinating sites at the square planar Pt centre are well the g-effect),25 namely donation of electron density from the dened, providing an accurate model for computational back lobe of the Pt–C2 orbital to the empty p orbital of C7. The studies.31 HOMO1 molecular orbital of I40 co, obtained by NBO analysis, The overall prole for this Pt catalyst is similar to that clearly shows that it is the hyperconjugation, rather than previously found for PtCl2(CO), but with some key differences a hypothetical allyl-cation conjugation (with the C8–C9 double (Fig. 5 and S12†). As in the previous case, we found that the bond), what accounts for the relative stability of I40 co (Fig. 4).26 conformational change from I3et to I30 et is instrumental in The atoms in molecules (AIM) topological analysis of I40 co revealing the most favorable energy alternatives (for a complete further conrms this bonding pattern, providing for C2 a sum prole including less favored pathways from I3et, see Fig. S12†). 4214 | Chem. Sci., 2020, 11, 4209–4220 This journal is © The Royal Society of Chemistry 2020 Edge Article Chemical Science Fig. 5 Gibbs energy profile (kcal mol1) for the reaction of 1b catalyzed by PtCl2(ethene) in cyclohexane; energy of I1et (Fig. S12,† complete profile) is considered as the reference.22 Optimized structures of selected stationary points (TBS omitted for clarity). For I30 et, the lowest energy barrier of the processes involves not fully clear, but they are likely related to the particularly a 1,3-hydrogen migration from C7 to the carbene center (C2), to strong s-donor properties of the CO ligand. Some insights could deliver the carbocationic species I40 et (DG‡ ¼ 8.2 kcal mol1), be obtained from the NBO analysis, which indicates that the also stabilized by homohyperconjugation. carbon attached to the Pt center (C2), has a higher negative Importantly, the presence of ethene at the platinum center, charge in I40 co than in I40 et.33 This might favor stronger homo- instead of CO, determines a different evolution of this inter- hyperconjugation interactions in the former, hampering the mediate (vs. I40 co). Indeed, it undergoes a very easy trans- decoordination of the Pt–CO complex while favoring the rear- formation (via Ts40 -4bet, DG‡ ¼ 1.5 kcal mol1) into the rangement and migration of the metal from C2 to C3. Moreover, cyclopropyl-containing product 4b, with the Pt complex the Pt atom has a more cationic character in Pt–ethene [PtCl2(ethene)] completely de-coordinated from cyclopropane. complexes than in their analogous Pt–CO counterparts, which is Overall, the transformation from I30 co into the cyclopropane 4 in consonance with its tendency to be released (Scheme 8). constitutes a stepwise C(sp3)–H insertion on a Pt-carbene with Overall, the energy barriers of the pathway leading to cyclo- concomitant cyclopropanation. This is a very uncommon propyl tricycle 4b from I1et are compatible with the thermal pathway that, to the best of our knowledge, is unprecedented for requirements of the reaction. The calculations suggest that the Pt–carbene species.32 initial [4C + 3C] cycloaddition that delivers the carbene I3et is Therefore, the carbocationic species I40 evolves differently the step with the highest energy barrier (DG‡ ¼ 8.9 kcal mol1). depending on whether the platinum contains a CO ligand or Aer conformational evolution to I30 et, a 8.2 kcal mol1 energy not. The reasons behind this ligand-dependent dichotomy are barrier connects this carbene species with I40 et, and eventually with the tricyclic product 4b. Key steps in the gold(I)-catalyzed process. The energy prole for the allenediene 1b, using [(C6F5)3P–Au]+ as a model catalyst, is shown in Fig. 6 (related to Table 1, entry 7). Interestingly, the Scheme 8 Divergent paths observed with CO and ethene ligands Fig. 6 Key steps of the Gibbs energy profile of the reaction of 1b from species I40 . Key distances and NBO charges.22 catalyzed by [(F5C6)3P–Au]+, in CH2Cl2.22 This journal is © The Royal Society of Chemistry 2020 Chem. Sci., 2020, 11, 4209–4220 | 4215 Chemical Science Edge Article Fig. 7 Gibbs energy profile for the reaction of 1d catalyzed by PtCl2(CO) in cyclohexane; energy of I1m (Fig. S15†) is considered as the reference. The gem-diesters [X ¼ C(CO2Me)2] are omitted for clarity. See Fig. S15 and S16† for the entire energy profile.22 ring contraction of the gold-carbene intermediate I3Au7 to give Fig. 7). Therefore, in consonance with the experimental results the the experimentally observed cyclohexenyl adduct 3b, is more most favored pathway is that leading to the [4C + 3C] adduct 2d. easily achieved than in the case of the Pt catalysts [(DG‡ ¼ Comparing the energy proles of 1d and 1b it can be seen 4.3 kcal mol1 vs. 12.5 kcal mol1 for PtCl2(CO) and 15.6 for that the barrier associated with the formation of cycloheptene PtCl2(ethene)]. The corresponding transition state, Ts3-3bAu7, 2d (via Ts30 -2dm) is 2.2 kcal mol1 lower than that required for even sits energetically below that corresponding to the confor- obtaining the analog [4C + 3C] adduct 2b from 1b (via Ts30 -2bco, mational change towards I30 Au7 (Ts3-30 Au7). The ease of the ring Fig. 8). Moreover, the highest energy barrier in the pathway contraction seems to be related to the carbocationic nature of towards products of type 5 and 4, requiring rst the migration of the C2-carbene center, which favors the orbital interactions the hydrogen at C7 into the metal carbene center (C2), is with C10. Therefore, our calculations are in qualitative agree- considerably higher in the case of the substrate 1d than with 1b ment with the experimentally observed selectivity towards the [4 [DDG‡ ¼ 3.4 kcal mol1, Fig. 8].37 Therefore, for substrate 1b, + 2] adduct 3b using gold complexes bearing p–acceptor ligands with the OTBS pendant in the connecting tether, there is (e.g. Au7 or Au3).34 destabilization of transition state Ts30 -2b0 co and stabilization of Inuence of the connecting tether: reaction prole for 1d in Ts30 -40 co, and both effects synergistically contribute to the the presence of PtCl2(CO). Overall, the above calculations have switch of selectivity compared to allenedienes such as 1d. provided a quite comprehensive mechanistic overview of the reactivity of allenedienes such as 1a and 1b. But, why does the analogous precursor 1d, lacking the OTBS group, behave in such a different way? To shed light on this dichotomy we per- formed a computational analysis on the evolution of 1d, using PtCl2(CO) as the catalyst (Fig. 7, S15 and S16†). The formation of carbene I3m through a concerted [4C(4p) + 3C(2p)] cycloaddition proceeds with an energy barrier similar to that observed in previous cases, albeit now there are no signif- icant conformational preferences within the ensuing ve membered ring (DDG‡ ¼ 0.3 kcal mol1, Fig. S15†).35 Platinum carbene intermediate, I3m, can also easily evolve to its conformer I30 m, which is almost isoenergetic (Fig. S15†). Remarkably, in contrast to what was observed for 1b, the most energetically favored evolution of I30 m is the 1,2-hydrogen migration leading to the cycloheptene adduct 2d (Ts30 –2dm, DG‡ ¼ 7.6 kcal mol1, Fig. 7).36 The alternative pathway observed for substrate 1b, involving the 1,3-hydrogen migration and gener- ation of carbocationic species I40 m is almost 2 kcal mol1 more costly (Fig. 7). A stepwise pathway leading to the decalin 5d from I40 m could not be located, whereas the direct migration of C7, through Ts30 - Fig. 8 Comparison of energy barriers in pathways to cycloheptene 2 5d0 m presents the highest energetic barrier (>16 kcal mol1, and adducts 4/5, from 1b and 1d; energies of I30 co and I30 m are used as the reference. 4216 | Chem. Sci., 2020, 11, 4209–4220 This journal is © The Royal Society of Chemistry 2020 Edge Article Chemical Science Fig. 9 Comparison of H7–C2 distances in I30 co and I30 m (a), and major steric repulsions within I30 co (b); space filling models using Van del Waals radii are used in specific atoms to highlight the steric interactions. But, what are the physical reasons behind these differences? quite close to the [PtCl] moiety (Fig. 10a). Moreover, the positive The stabilization of the transition state Ts30 -40 co, corresponding charge generated at the ensuing sp2 carbon, C3, is further to the migration of the hydrogen atom at C7 to the carbene intensied by inductive effects generated by the oxygen atom at center, can be qualitatively understood by analyzing the its b position (see Fig. 10 for atomic charges). In this regard, conformations of their immediate precursor I30 co. In particular, NBO analysis of this transition state did not show any hyper- the distance between the hydrogen atom that migrates from C7 conjugative interaction, between C3 and the oxygen lone pairs, to C2 is signicantly shorter in I30 co than in I30 m [Fig. 9a, d(H7– which could stabilize this positive charge of C3.38 In contrast, in C2) ¼ 2.455 Å in I30 co and 2.639 Å in I30 m]. These differences are the analog transition state from 1d (Ts30 -2dm, Fig. 10b), there likely associated with a steric clash in I30 co, between one of the are no such destabilizing interactions, while the positive charge methyl groups of the TBS moiety and the chloride atom at the generated at C3 is stabilized by hyperconjugation with its platinum center. This steric congestion forces the Pt center to adjacent C4–H bond (NBO analysis, Fig. 10b). move far from the methyl, eventually resulting in a higher Thus, all these stereoelectronic factors synergistically proximity of the H7 to the empty p-orbital of the carbene at C2 contribute to determination of the fate of the cycloheptene (Fig. 9b). As a result, the orbital contact for the 1,3-hydride carbene intermediates. migration towards I40 co is facilitated, favoring the overall Importantly, while these results arise from the analysis of process towards 5 and 4. specic substrates, the mechanistic ndings are relevant to Moreover, the destabilization of the transition state leading other reactions that occur through similar types of to cycloheptene 2b (Ts30 -2bco) can be understood by considering intermediates. stereoelectronic factors imposed by the OTBS group. During the required 1,2 H migration (from C3 to C2), the TBS group gets Conclusions To conclude, the presence of a bulky silyl ether substituent in the connecting tether of allenedienes of type 1, allowed the exploration of novel, intramolecular annulations promoted by carbophilic catalysts. Remarkably, the different pathways can be nely tuned by choosing appropriate ligands at the metal center, which helped to obtain a variety of carbocyclic skeletons in a divergent and highly stereoselective manner. The unexpected rearrangements revealed a number of previously unidentied, mechanistic features that are related to the whole eld of synthetic and organometallic chemistry. The effect of a CO ligand in the evolution of platinum inter- mediates formed aer the initial [4C + 3C] cycloaddition step is specically signicant. The presence of the CO ligand hampers the release of the platinum complex from key intermediates, and favors rearrangement processes involving non-classical cationic intermediates which are stabilized by homo-hyperconjugation. These types of interactions, almost ignored in Pt catalysis, should be taken into account when Comparison of steric repulsions (a) and the most relevant Fig. 10 designing other skeletal rearrangements. Finally, we also HOMO orbitals (b) of Ts30 -2bco and Ts30 -2dm (NBO analysis). demonstrate how the obtained annulation products can be This journal is © The Royal Society of Chemistry 2020 Chem. Sci., 2020, 11, 4209–4220 | 4217 Chemical Science Edge Article selectively manipulated, paving the way for the synthetic I. Alonso, H. Faustino, F. López and J. L. Mascareñas, applications of this methodology. Angew. Chem., Int. Ed., 2011, 50, 11496–11500. 5 P. Mauleón, R. M. Zeldin, A. Z. González and F. D. Toste, J. Conflicts of interest Am. Chem. Soc., 2009, 131, 6348–6349. 6 For an interesting gold-catalyzed cycloaddition of alkyne-1,3- There are no conicts to declare. dienes, see: A. Fürstner and C. C. Stimson, Angew. Chem., Int. Ed., 2007, 46, 8845–8849. Acknowledgements 7 (a) D. Benitez, E. Tkatchouk, A. Z. Gonzalez, W. A. Goddard and F. Dean Toste, Org. Lett., 2009, 11, 4798–4801; (b) This work received nancial support from the Spanish MINECO S. Montserrat, I. Alonso, F. López, J. L. Mascareñas, (SAF2016-76689-R, CTQ2016-77047-P, CTQ2017-84767-P, A. Lledós and G. Ujaque, Dalton Trans., 2011, 40, 110095– CTQ2017-87889-P, RYC-2016-20335 and RTI2018-098795-A- 111105; (c) A. H. Christian, Z. L. Niemeyer, M. S. Sigman I00), the Xunta de Galicia (ED431C 2017/19, 2015-CP082, Cen- and F. D. Toste, ACS Catal., 2017, 7, 3973–3978; For studies tro Singular de Investigación de Galicia accreditation 2019– describing particular characteristics of gold-carbenes, see: 2022, ED431G 2019/03 and predoctoral fellowship ED481A- (d) L. Nunes dos Santos Comprido, J. E. M. N. Klein, 2017/068 to M. C.), the ERDF, ERC (Adv. Grant No. 340055), G. Knizia, J. Kästner and A. S. K. Hashmi, Angew. Chem., the Orfeo-Cinqa network (CTQ2016-81797-REDC) and CONICYT Int. Ed., 2015, 54, 10336–10340; (e) L. Nunes dos (grant to RN: PFCHA/72130218). Facilities provided by the Santos Comprido, J. E. M. N. Klein, G. Knizia, J. Kästner Galician Supercomputing Centre (CESGA) are acknowledged. and A. S. K. 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Chem., 2011, 25, 815– a transition state in which the OTBS group is relocated in 819. a pseudo-axial disposition (Fig. S9†). 19 The structure of 6b could be determined by X-ray analysis of 25 (a) I. V. Alabugin, G. dos Passos Gomes and M. A. Abdo, a derivative. See the ESI† for details. Wiley Interdiscip. Rev.: Comput. Mol. Sci., 2019, 9, e1389; 20 Although the oxidative trapping of monosubstituted Pt- and (b) Z. Alamiddine and S. Humbel, Front. Chem., 2014, 1, Au-carbenes is known, that of disubstituted carbenes is 1–9. almost unprecedented, due to their lower reactivity; see 26 (a) NBO calculations did not provide any HOMO or HOMO-n reference 4a and: S. Montserrat, H. Faustino, A. Lledòs, molecular orbital featuring an allyl cation bonding J. L. Mascareñas, F. López and G. Ujaque, Chem. – Eur. J., interaction between C7, C8 and C9; (b) The orbital 2013, 19, 15248–15260. HOMO1 is considered instead of the HOMO since the 21 Very few, isolated examples of C–H insertions with latter exclusively involves the [PtCl2] moiety. The energy concomitant cyclopropanation have been reported with difference between them is 0.34 eV. Pt or Au-carbene species. For Au, see: (a) Y. Horino, 27 Related non-classical Pt-stabilized carbocationic T. Yamamoto, K. Ueda, S. Kuroda and F. D. Toste, J. Am. intermediates were only proposed by Gagné in the context Chem. Soc., 2009, 131, 2809–2811; (b) G. Lemière, of cycloisomerization of 1,6-dienes, see: F. Bell, J. Holland, V. Gandon, K. Cariou, A. Hours, T. Fukuyama, J. C. Green and M. R. Gagné, Organometallics, 2009, 28, A. L. Dhimane, L. Fensterbank and M. Malacria, J. Am. 2038–2045. Chem. Soc., 2009, 131, 2993–3006; (c) A. Escribano- 28 From intermediate I30 co, we could not locate a 1,2-alkyl (C10) Cuesta, V. López-Carrillo, D. Janssen and migration leading to the formal [4 + 2] adduct 3b, likely due A. M. Echavarren, Chem. – Eur. J., 2009, 15, 5646–5650. to an unfavorable conformation. For Pt, see: (d) H. Funami, H. Kusama and N. Iwasawa, 29 (a) M. Brookhart and Y. Liu, J. Am. Chem. Soc., 1991, 113, Angew. Chem., Int. Ed., 2007, 46, 909–911; (e) C. H. Oh, 939–944; (b) C. P. Casey and N. A. Strotman, J. Am. Chem. J. H. Lee, S. M. Lee, H. J. Yi and C. S. Hong, Chem. – Eur. Soc., 2004, 126, 1699–1704; (c) J. B. Lambert, L. A. Salvador J., 2009, 15, 71–74. and J. H. So, Organometallics, 1993, 12, 697–703. 22 (a) DFT calculations have been carried out with Gaussian 09. 30 We also located an analogous route towards 5b from the The geometries of all species were optimized using the initial conformer I3co, through related species I4co and I5co B3LYP hybrid functional together with the 6-31G(d) basis (Fig. S8B†). Nonetheless, this route is signicantly less set for C, H, O, P, Si and Cl and the LANL2DZ basis set for favored than that from I30 co. Pt and Au. Single-point calculations of the optimized 31 Additionally, we theoretically analyzed the reaction of 1b systems were carried out using hybrid functional M06 with the catalyst resulting from PtCl2/P(C6F5)3 (Table 1, together with the 6-3111++g(d,p) basis set for C, H, O, P, Si entry 13). The energy prole (Fig. S13†) is not signicantly and Cl, and the Stuttgart-Dresden (SDD) ECP for Pt and different from that found for PtCl2(ethene). Au, either in cyclohexane (for Pt catalysis) or 32 For an isolated case with a Pt-vinylidene, see: (a) Z. F. Li, dichloromethane (for gold catalysis) as solvents (using the Y. Fan, N. J. Deyonker, X. Zhang, C. Y. Su, H. Xu, X. Xu SMD model). See the ESI† for further details and and C. Zhao, J. Org. Chem., 2012, 77, 6076–6083; In references; (b) For clarity reasons, we depicted the general, stepwise C(sp3)–H insertions on metal carbenes enantiomeric series. are rare. A handful of feasible cases involving Rh and Au 23 According to previous reports, we considered PtCl2(CO) carbenes have been proposed when stable carbocations are as the active catalyst generated from PtCl2/CO; see ref. generated from the initial hydride migration, see: (b) 18b and (a) H. Alper, Y. J. Huang, D. B. Dellamico, J. Hansen, J. Autschbach and H. M. L. Davies, J. Org. F. Calderazzo, N. Pasqualetti and C. A. Veracini, Chem., 2009, 74, 6555–6563; (c) S. Bhunia and R.-S. Liu, J. Organometallics, 1991, 10, 1665–1671; (b) Am. Chem. Soc., 2008, 130, 16488–16489; (d) Y. Wang, D. B. Dell'Amico, R. Bini, F. Calderazzo, L. Carbonaro, Z. Zheng and L. Zhang, J. Am. Chem. Soc., 2015, 137, 5316– L. Labella and A. Vitullo, Organometallics, 2005, 24, 5319. 4427–4431; (c) D. B. Dell'Amico, R. Bini, F. Calderazzo, 33 This trend is observed in all stationary points throughout the L. Carbonaro, L. Labella and A. Vitullo, Organometallics, energy proles with PtCl2(CO) and PtCl2(ethene). 2006, 25, 4913–4916; Moreover, according to the 34 For a related preliminary analysis with a [IPrAu]+ model literature, the reduction of Pt(II) to Pt(0) under these catalyst related to Au1, also consonant with the conditions seems very unlikely, see: (d) D. A. Evans, experimental results, see Fig. S14.† M. F. Hallam, D. M. P. Mingos and R. W. M. Wardle, J. 35 Both conformations of the ensuing ve-membered ring were analyzed and the energy difference between them was This journal is © The Royal Society of Chemistry 2020 Chem. Sci., 2020, 11, 4209–4220 | 4219 Chemical Science Edge Article negligible (see Fig. S15†). Nonetheless, the most favored one, 37 Similar trends are also observed when analyzing the analogous to the previously denoted as pseudo-equatorial, homologous pathways from the conformers I3m and I3co has been considered for Fig. 7 (see the full prole in (Fig. S17†). Fig. S16†). 38 J. S. Kudavalli and R. A. More O'Ferrall, Beilstein J. Org. 36 Moreover, the next favoured process is the homologous 1,2- Chem., 2010, 6, 1035–1042. H migration from the conformer I3m (via Ts3-2dm, DG‡ ¼ 8.1 kcal$mol1, Fig. S16†). 4220 | Chem. Sci., 2020, 11, 4209–4220 This journal is © The Royal Society of Chemistry 2020