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Governing effects in the mechanism of the gold-catalyzed cycloisomerization of allenic hydroxylamine derivatives†‡ Sofia Kiriakidi,a Olalla Nieto Faza,b Antonios Kolocouris*a and Carlos Silva López
*c
The formation of chiral heterocycles via cycloisomerization reactions of allene derivatives has gained relevance due to their associated efficiency and atom-economy. The only drawback that keeps these reactions away from being routine synthetic strategies is the control in the regioselectivity (most often 5-endo vs. 6-endo). In this work, we computationally explore the experimental chemistry reported by Krause using N-hydroxy-α-aminoallenes and hydroxylamine ethers as substrates and provide a rationale for the Received 24th May 2017, Accepted 16th June 2017
different reactivity observed. The drastic effects observed experimentally when changing the nature of the gold catalyst have also been studied mechanistically. These results are expected to help in the design of
DOI: 10.1039/c7ob01275f
improved regioselective protocols for the formation of medium sized chiral heterocycles from allene
rsc.li/obc
substrates.
1 Introduction Electrophilic activation of C–C multiple bonds by gold species deserves a prominent site in the toolbox of organic chemists. Its extensive use in recent years responds to the versatility of this chemistry and the rather unique preference of gold for unsaturation versus other ligands. A wealth of transformations have been reported by specialists in the field which aimed at the synthesis of compounds with large chemical diversity through mild, selective and sustainable synthetic routes.1–7 Among these transformations, cycloisomerization reactions involving allene and alkyne fragments are particularly interesting, from the point of view of atom economy to construct heterocyclic compounds.8–12 However, Krause, Alcaide and Almendros have recently reflected on the fact that reactions involving hydroxy allenylamines are severely underrepresented and underdeveloped, probably due to chemoselectivity
a Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens Panepistimioupolis Zografou, Athens, 15771, Greece. E-mail: [email protected] b Departamento de Química Orgánica, Facultad de Ciencias, Campus Universitario, Ourense, Spain c Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, Campus Lagoas-Marcosende, 36310, Vigo, Spain. E-mail: [email protected]; Tel: +34 986813268 † To the memory of Elena Soriano. ‡ Electronic supplementary information (ESI) available: SCF energies, Cartesian coordinates, the number of imaginary frequencies for all computed structures and a scheme including the mechanism for the activation of N-hydroxyα-aminoallene R1a with Au+. See DOI: 10.1039/C7OB01275F
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issues.13,14 Turning this challenge into an opportunity, both groups have succeeded in developing procedures that allow the switchable synthesis15–17 of two heterocycles from the same substrate by changing the catalyst or the reaction conditions. Alcaide and Almendros accompained their findings with a thorough mechanistic study that assisted in the development. Krause on his side relied on kinetic principles relating nucleophilicity and ring closure preferences to establish a delicate balance that could be shifted in the desired direction. How to control chemoselectivity to obtain the desired products over unwanted isomers is the principal issue in these cyclization reactions and there is a profound benefit in understanding the reaction mechanisms.18 Providing justification for this delicate balance and a detailed account for the driving forces that are affecting it however should help in understanding the underlying chemistry and give an impulse to this small but promising field. The chemistry by Krause involves the first gold-catalyzed synthesis of heterocycles with two heteroatoms from allenic precursors i.e. the gold-catalyzed 5-endo cycloisomerization of N-hydroxy-α-aminoallenes 1 to furnish exclusively N-hydroxy-3pyrrolines 2 (and not the oxazine 3) and hydroxylamine ether analogues 4 to 4,5-dihydroisoxazoles 5 or 3,6-dihydro-1,2-oxazines 6 (Fig. 1). In both cases, the nitrogen atom acts as the nucleophile and attacks the allene in a 5-endo or 6-endo fashion but, in the case of hydroxylamine ether analogues, depending on the catalyst used, a different regioselectivity was observed.15,19 Thus, in the case of allenic hydroxylamine ethers, the regioselectivity can be shifted either towards dihydroisoxazoles by employing cationic gold precatalysts (complex A,
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substrate was achieved to obtain the Boc-protected dihydrooxazine 8 (see Fig. 1). Various hydroxylamine ethers gave similar results. In contrast, the use of cationic gold complexes ([Au(PPh3)]BF4/AgBF4 or A) or AgBF4 led to decomposition of the substrate.13 We hereby aim to provide a detailed mechanistic picture of the pioneering work from Krause. This information may be valuable to provide a new impulse to the switchable gold mediated cycloisomerizations of allene-containing substrates.
Fig. 1 A: Gold-catalyzed cycloisomerization of allenic hydroxylamine 1 to N-hydroxypyrroline 2. B: Gold-catalyzed cycloisomerization of allenic hydroxylamine ether 3 with a preferred product being either dihydro1,2-oxazine 4 or dihydroisoxazole 5 depending on the catalyst applied. C: Gold-catalyzed cycloisomerization of N-Boc-protected allenic hydroxylamine ether 6 resulted in dihydro-1,2-oxazine 7 or decomposition depending on the catalyst applied.
Fig. 1), the formation of a mixture of both isomers when using AuCl or preferred formation of the dihydrooxazine by using N-Boc-protected precursors.13 In the work by Krause, upon treatment of 1 with 5 mol% AuCl at room temperature, regioselective 5-endo-cyclization was observed to yield N-hydroxy-3-pyrroline 2. In contrast, the use of the more reactive Lewis acids, i.e., the cationic gold complex A, developed by Echavarren for the cyclization of 1,6enynes and 1,5-enynes, or [AuCl(PPh3)]/AgBF4 resulted in slower reactions and decreased yields because of incomplete conversion. Various substituted N-hydroxy-α-aminoallenes were treated with AuCl in CH2Cl2 and N-hydroxy-3-pyrrolines were obtained with excellent yields and high degree of chirality transfer.13 Krause also explored the reactivity of the allenic substrate in which the heteroatom positions of 1 were exchanged, resulting in allenic hydroxylamine ether 4. Treatment of 4 with AuCl afforded a mixture of 3,6-dihydro-1,2-oxazine 5 (47% yield) and 4,5-dihydroisoxazole 6 (19%) through the nucleophilic attack of the nitrogen in a 6-endo or 5-endo cyclization, respectively. The dihydrooxazine 5 was also formed with complete chirality transfer. A highly regioselective cyclization of 4 to 4,5-dihydroisoxazole 6 was achieved in the presence of cationic Au(I) complexes [Au(PPh3)]BF4 or A (Fig. 1). Particularly, the more reactive gold complex A gave not only the highest yield of 81% but also the best selectivity 6/5 of 96 : 4. Under these optimized conditions, various allenic hydroxylamine ethers were converted into the corresponding dihydroisoxazoles in high yields.13 Interestingly, when N-Boc protected derivatives 7 were used, a completely regioselective 6-endo cycloisomerization of the
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2
Results
2.1
Heterocycloisomerization of N-hydroxy-α-aminoallenes
In our computations, we considered four possible reaction pathways for the conversion of an N-hydroxy-α-aminoallene, such as R1a (Fig. 2): the AuCl catalyzed 5-endo cycloisomerization to yield the N-hydroxypyrroline derivative P1a and the alternative involving a 6-endo cyclization towards dihydrooxazine P2a, and the same two competitive profiles for the more active cationic catalyst Au[P(OMe)3]+ which represents a simpler analogue of the complex A used by Krause (see Fig. 1). The AuCl 5-endo reaction follows a simple one step mechanism in which, upon allene activation by the metal, a nucleophilic attack from the nitrogen directly furnishes the 5-membered
Fig. 2 Reaction profiles considered for the transformation of N-hydroxy-α-aminoallene R1a into N-hydroxypyrroline P1a and dihydrooxazine P2a with a neutral and a cationic gold catalyst.
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ring scaffold of the N-hydroxypyrroline (3a in Fig. 2). The activation barrier for this process is 13 kcal mol−1, a value that supports the formation of the final product under mild conditions and in short reaction times, in a reasonable agreement with the experimental setup (0.5 h at room temperature when employing a 5% catalyst load). Numerous attempts to locate the transition state associated with the 6-endo attack of oxygen were unsuccessful and the optimizations always ended in TS2a3a. We therefore concluded that the activation with AuCl was incompatible with the formation of the six member ring due to an insufficient match between the nucleophile (a hard and relatively electron deficient oxygen atom) and the electrophile (the soft gold-activated allene unit). The use of a more active catalyst like complex A provides a slightly better match in terms of the hard–soft character of the species involved in the C–O bond forming event and both 5-endo and 6-endo pathways could be obtained. The activation barrier for the 5-endo attack increases slightly with the cationic catalyst (13.0 vs. 15.4 kcal mol−1 for TS2a3a and TS4a5a, respectively). Moreover, in terms of the reaction mechanism, the cycloisomerization proceeds in essentially the same way as in the AuCl version. Experimentally, the use of cationic gold is found to reduce the reaction yield and prolong the reaction time. This observation is compatible with the higher activation energy computed. To confirm the effect of using cationic gold in this reaction, we decided to test a limit case scenario in which bare Au+ is used to activate the allene unit. Under these conditions, the hard–soft match between the nucleophile and electrophile should be enhanced compared to [AuP(OMe)3]+. Oxygen is a relatively worse nucleophile than nitrogen in this context, but both are too hard with respect to the activated allene as an electrophile under the Pearson theory. We therefore anticipated that hardening the electrophile should have a strong effect in the reaction profile. Indeed, the barrier for the 5-endo cyclization dropped in ∼9 kcal mol−1, leaving TS2a3a only 6.6 kcal mol−1 above 4a. The potentially competitive 6-endo cyclization with the cationic complex A is similar to the 5-endo alternative involving activation and a direct nucleophilic attack, but in this case being carried out from the oxygen side. The nucleophilic attack is however non-competitive due to a high activation barrier (23.5 kcal mol−1) and a rather unstable cyclic intermediate 6a (20.7 kcal mol−1). In this scenario, the 6-endo pathway is very much a dead-end in terms of producing a reaction product. We nevertheless tested the limit case of activation using bare Au+ as above to verify our hypothesis regarding the nature of the gold activation in these systems. When we computed the activation of the 6-endo cyclization activated by bare gold, we obtained a barrier of only 13.9 kcal mol−1 (a reduction of 10 kcal mol−1 with respect to the phosphite complex) strongly suggesting that the oxygen atom is in a significant mismatch situation to undergo nucleophilic attack onto the allene. The computed profiles illustrated in Fig. 2 therefore rationalize well the experimental observations by Krause:13 (1) activation of an N-hydroxy-α-aminoallene with gold (irrespective of
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Organic & Biomolecular Chemistry
the catalyst being neutral, AuCl, or cationic, complex A) afforded only the N-hydroxypyrroline and (2) regarding efficiency the reaction is activated more effectively by AuCl than phosphite gold complexes.20 The switchable reactivity for N-hydroxy-α-aminoallenes was intuitivelly suggested by Krause on the grounds of the relative rates for nitrogen and oxygen nuclephilic attacks and 5 and 6-membered ring formation. Oxygen was expected to undergo faster nucleophilic attack than nitrogen, but then a 6 member ring formation usually implies slower kinetics than a 5 member ring formation. This balance, oxygen/6-membered ring and nitrogen/5-membered ring, could drive the reaction to one or the other product. Our results agree with the ring formation dominating this balance. Actually, according to our results, oxygen does not act as a good nucleophile (it produces a very unstable intermediate through a high barrier). The stronger nucleophilicity anticipated by Krause and therefore the subtle kinetic balance between 5 and 6 member ring formation is clearly observed however when activating the allene with bare gold. 2.2
Heterocycloisomerization of allenic hydroxylamine ethers
Interestingly, when swapping O with N in the initial substrate and hence considering the cycloisomerization of hydroxylamine allenyl ethers, the reactivity changes dramatically. The selectivity issues in this case are not due to competition between nucleophiles (since the terminal amine is much more nucleophilic than the oxygen atom, which is compromised in an ether group). They however arise due to nitrogen being able to attack in two fashions, 6-endo and 5-endo onto the distal and cumulenic centers of the allene moiety. In the experiments reported by Krause, both neutral and cationic gold catalysts provided a mixture of 5-endo and 6-endo cycloisomerization products, but with opposite selectivities. AuCl and AuCl3 catalysts furnished the dihydrooxazine as a major product (selectivities higher than 2 : 1) whereas cationic gold catalysts strongly favoured the formation of the 4,5-dihydroisoxazole (observed selectivities of 4 : 96, see Fig. 1). According to our calculations, the reaction mechanisms are again quite straightforward and they essentially involve activation and a subsequent nucleophilic attack. Once the nucleophile has undergone the attack, the heterocycle ring formation is fully achieved and the final product is only a protodeauration step away. This is strictly true for the 6-endo attack to form the dihydrooxazine derivative whereas the 5-endo attack has a slightly longer mechanism requiring a final keto-enolic equilibrium to arrive to the final 4,5-dihydroisoxazole. Our results (summarized in Fig. 3) suggest that AuCl can only catalyze efficiently the formation of the six member ring. The nucleophilic attack on the cumulene carbon involves a transition structure (TS2b3b) requiring almost 20 kcal mol−1, which is non competitive with the alternative pathway. The attack onto the distal allene position requires only 14.3 kcal mol−1 (TS2b7b), which seems compatible with the reaction conditions employed in the experimental work. The use of a more electrophilic gold catalyst has an interesting impact in the reaction profiles. The six member ring formation is
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ethers furnished products only with AuCl. Activation with harder electrophiles like AuCl3 or cationic [Au(PPh3)]BF4 or complex A yielded incomplete conversion or induced decomposition of the substrate. Gratifyingly, the use of AuCl provided high selectivity towards the 6-endo attack and therefore towards the formation of dihydrooxazines. To rationalize these findings, we computed again the energy profiles for the four possible mechanisms operating in this chemistry (Fig. 4). Given the reduced nucleophilicity of the amine, it was not surprising to find that the reaction mechanism did not change in terms of the transformation, but that the associated activation barriers were significantly larger. The protected amine undergoes 6-endo cyclization through a barrier of 22.5 kcal mol−1 (compared with 14.3 kcal mol−1 for the unprotected amine). This also affected the 5-endo cyclization, which raised the barrier of the rate limiting step to almost 27 kcal mol−1. These barriers seem to be in agreement with the exclusive formation of the 6-endo cycloisomerization product at room temperature. The results obtained with complex A however suggest that this activation should also lead to product formation since barriers are not only comparable but also slightly lower than in the AuCl activation mechanism (Fig. 4). With these results we would predict, contrary to the observed decomposition, that
Fig. 3 Reaction profiles considered for the transformation of hydroxylamine allenyl ether R1b into 4,5-dihydroisoxazole P1b and dihydrooxazine P2b with a neutral and a cationic gold catalyst.
essentially unaffected by the change of the catalyst. Actually, the reaction is just slightly disfavored kinetically compared to the AuCl activation (14.3 vs. 15.0 kcal mol−1). In contrast, the reaction barrier for the 5-endo cyclization is reduced by 3 kcal mol−1 (from 19.8 to 16.8 kcal mol−1), bringing this alternative pathway into close competition (Fig. 3). Our calculations must have captured the correct trend in this chemistry, but the overall effect has to be somewhat more acute in the experiment, since not only competition, but reversal of product formation is observed with the cationic catalyst. Probably, the large and rather exotic selection of ligands in the cationic catalysts employed by Krause has a non-innocent effect that obviously our calculations could not reproduce. However, the overall picture and trends obtained from our calculations are in fairly good agreement with the experimental observations. 2.3 Heterocycloisomerization of allenic BOC-protectedhydroxylamine ethers Once confirmed that the gold activation of allenic hydroxylamine ethers furnishes 4,5-dihydro-isoxazoles or dihydrooxazines selectively on choosing the appropriate catalyst, Krause explored hydroxylamines with reduced nucleophilicity. Interestingly, the use of allenic BOC-protected-hydroxylamine
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Fig. 4 Reaction profiles considered for the transformation of acetylated hydroxylamine allenyl ether R1c into 4,5-dihydroisoxazole P1c and dihydrooxazine P2c with a neutral and a cationic gold catalyst.
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the 6-endo attack should also be the most favourable pathway and that dihydrooxazine P2c should be the major product in the cycloisomerization mediated by complex A. In an attempt to understand the deleterious effect of the protected amine when using a cationic catalyst, we focused on the tert-butoxycarbamoyl group. Once recollected that most of the subtle effects observed in this chemistry can be related to the match or mismatch in terms of the HSAB theory, we considered the following hypothesis. The mode of activation of AuCl is probably unchanged upon amine protection because soft gold finds the amide non competitive with respect to the unsaturation, however, the harder cationic gold complex may find that the carbamoyl group is a competitive ligand. If this is the case, complexation of the cationic gold with the carbamoyl group not only would eliminate the activation of the allene moiety, but would also block the nucleophile. Both effects could make the cycloisomerization impossible. Calculation of the relative stability of both modes of complexation for AuCl indicated that the allene complex is 2 kcal mol−1 more stable than the gold bound to the carbamoyl group. The AuCl activation of the allene is therefore not compromised by the protection of the amine. When the cationic complex is considered, however, our calculations predict that the carbamoyl complex is more stable than the allene complex by 7.6 kcal mol−1 (Fig. 5). This is a significant energy difference for exchanging isomeric structures at room temperature. Moreover, since the carbamoyl complex is more stable, the barriers for the cationic gold mediated cycloisomerization have to be corrected considering this complex. Even in the most favourable scenario, assuming that carbamoyl and allene complexes exchange through a low energy barrier (hence applying
Organic & Biomolecular Chemistry Table 1 Summary of the activation energies for all the mechanisms explored in this work (ΔG++ in kcal mol−1)
Product
ΔG++
R1a to N-hydroxypyrroline P1a or P2a N/distal C AuCl N/distal C [Au]+ O/distal C AuCl O/distal C [Au]+
P1a P1a P2a P2a
13.0 15.4 — 23.5
R1b to 4,5-dihydroisoxazole P1b or P2b N/cumulene C AuCl N/cumulene C [Au]+ N/distal C AuCl N/distal C [Au]+
P1b P1b P2b P2b
19.8 16.8 14.3 15.0
R1c to 4,5-dihydroisoxazole P1c or P2c N/cumulene C AuCl N/cumulene C [Au]+ N/distal C AuCl N/distal C [Au]+
P1c P1c P2c P2c
26.9 30.5 22.5 25.1
Attacking atom/target site
Curtin–Hammett), the barriers for the cycloisomerization raise to 25.1 and 30.5 kcal mol−1 for the 6-endo and 5-endo attacks, respectively, thus making both reactions inoperative at room temperature. Additionally, the carbamoyl activation may open the door for gold mediated chemistry on the protecting group, which could explain the decomposition reported by Krause and coworkers. Table 1 provides a summary of all the computed activation energies for the four explored reaction pathways including updated barriers in the case of the carbamoyl group establishing more stable complexes with gold.
3
Fig. 5 Complexation modes for 4c (through the allene, top, and the carbamoyl moiety, bottom). The most stable of several conformers considered are shown. A conformation featuring a chelate combining both modes of complexation resulted in loss of the allene–gold bond and only the carbamoyl group remained as a ligand.
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Catalyst
Conclusions
The gold-catalyzed cycloisomerization of functionalized allenes involving oxygen and nitrogen atoms is a valuable method for the synthesis of N- and O-containing heterocycles. In this context, the Krause conversion of N-hydroxyα-aminoallenes and hydroxylamine ethers, where nitrogen and oxygen nucleophic centers are interchanged, is a pioneering example of this chemistry. Thus, although a few following studies on similar reactions and computational investigation are now available,14 the prototype Krause reaction opened questions that have never been addressed. The control in the nucleophilicity (N or O)/member formation (5 and 6 member respectively) and the regioselectivity (most often 5-endo vs. 6-endo) was investigated with respect to the substrate structure (N-hydroxy-α-aminoallenes and allenic hydroxylamine ethers and N-Boc protected derivatives) and the different catalytic properties of the Au(I) catalyst when it is subjected to drastic changes in its structure (i.e. neutral as in AuCl to cationic in [AuP(OMe)3]+ or bare Au+ as an extreme model of activation). We showed that N/5 member ring formation governs kinetically the N-hydroxypyrroline product formation and that using an electron depleted catalyst worsened the results due to a hard/soft nucleophile/electrophile mismatch. In the case of allenic hydroxylamine ethers both 6 member (dihydrooxazine)
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and 5 member rings (dihydroisoxazole) were predicted when using both AuCl and [AuP(OMe)3]+ although with the first catalyst favoring the 6 member ring. Our calculations predicted correctly that the presence of a cationic gold catalyst reduced more effectively the 5 member ring formation reaction barrier although they were unable to accurately reproduce the relative magnitudes for the 5 and 6 member ring formation. Finally, in the case of the N-Boc allenic hydroxylamine ethers, our calculations predicted correctly the oxazine formation with AuCl and the deleterious effect of the N-Boc group with more active Au(I) catalysts. We suggested that this has happened due to the carbamoyl carbonyl complexation which stabilized the allenic hydroxylamine ether substrate giving rise to higher reaction barriers incompatible with the reaction conditions and consistent with the observed decomposition via secondary paths.
4 Computational methods Throughout this work, the Kohn–Sham formulation of density functional theory was employed.21,22 The four-rung metahybrid density functional M06-2X 23 has been used with the extended double-ζ quality Def2-SVPP basis set for all the static calculations. This combination of density functional and basis set has been found to provide good performance in homogeneous gold catalysis.24,25 All geometry optimizations have been carried out using tight convergence criteria and a pruned grid for numerical integration with 99 radial shells and 590 angular points per shell. In some challenging cases, this grid was enlarged to 175 radial shells and 974 points per shell for first row atoms and 250 shells and 974 points per shell for heavier elements. These challenging optimizations are usually associated with very soft vibrational modes (usually internal rotations). Analysis of the normal modes obtained via diagonalization of the Hessian matrix was used to confirm the topological nature of each stationary point. The wavefunction stability for each optimized structure has also been checked.26 Solvation effects have been taken into account variationally throughout the optimization procedures via the polarizable continuum model (PCM) using parameters for dichloromethane and taking advantage of the smooth switching function developed by York and Karplus.27,28 Concerning the structures involved in these simulations, we simplified the cationic gold complex employed in the experimental work (complex A) using Au[P(OMe)3]+ instead of ((1,3tBu)-Ph-O)3-P-Au+ in order to find a balance between accuracy and computational efficiency. All the calculations performed in this work have been carried out with the Gaussian 09 program.29
Acknowledgements The authors thank the Centro de Supercomputación de Galicia (CESGA) for time on HPC infrastructure. Ministerio de Economía y Competitividad (MINECO, PCTQ2016-75023-C2-2-
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P) is also acknowledged for financial support. A. K. thanks to Chiesi Hellas for supporting the visit of S. K. from A. K. lab to C. S. L. lab through a collaborative PhD work.
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Governing effects in the mechanism of the gold-catalyzed cycloisomerization of allenic hydroxylamine derivatives†‡ Sofia Kiriakidi,a Olalla Nieto Faza,b Antonios Kolocouris*a and Carlos Silva López
*c
The formation of chiral heterocycles via cycloisomerization reactions of allene derivatives has gained relevance due to their associated efficiency and atom-economy. The only drawback that keeps these reactions away from being routine synthetic strategies is the control in the regioselectivity (most often 5-endo vs. 6-endo). In this work, we computationally explore the experimental chemistry reported by Krause using N-hydroxy-α-aminoallenes and hydroxylamine ethers as substrates and provide a rationale for the Received 24th May 2017, Accepted 16th June 2017
different reactivity observed. The drastic effects observed experimentally when changing the nature of the gold catalyst have also been studied mechanistically. These results are expected to help in the design of
DOI: 10.1039/c7ob01275f
improved regioselective protocols for the formation of medium sized chiral heterocycles from allene
rsc.li/obc
substrates.
1 Introduction Electrophilic activation of C–C multiple bonds by gold species deserves a prominent site in the toolbox of organic chemists. Its extensive use in recent years responds to the versatility of this chemistry and the rather unique preference of gold for unsaturation versus other ligands. A wealth of transformations have been reported by specialists in the field which aimed at the synthesis of compounds with large chemical diversity through mild, selective and sustainable synthetic routes.1–7 Among these transformations, cycloisomerization reactions involving allene and alkyne fragments are particularly interesting, from the point of view of atom economy to construct heterocyclic compounds.8–12 However, Krause, Alcaide and Almendros have recently reflected on the fact that reactions involving hydroxy allenylamines are severely underrepresented and underdeveloped, probably due to chemoselectivity
a Department of Medicinal Chemistry, Faculty of Pharmacy, National and Kapodistrian University of Athens Panepistimioupolis Zografou, Athens, 15771, Greece. E-mail: [email protected] b Departamento de Química Orgánica, Facultad de Ciencias, Campus Universitario, Ourense, Spain c Departamento de Química Orgánica, Facultad de Química, Universidad de Vigo, Campus Lagoas-Marcosende, 36310, Vigo, Spain. E-mail: [email protected]; Tel: +34 986813268 † To the memory of Elena Soriano. ‡ Electronic supplementary information (ESI) available: SCF energies, Cartesian coordinates, the number of imaginary frequencies for all computed structures and a scheme including the mechanism for the activation of N-hydroxyα-aminoallene R1a with Au+. See DOI: 10.1039/C7OB01275F
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issues.13,14 Turning this challenge into an opportunity, both groups have succeeded in developing procedures that allow the switchable synthesis15–17 of two heterocycles from the same substrate by changing the catalyst or the reaction conditions. Alcaide and Almendros accompained their findings with a thorough mechanistic study that assisted in the development. Krause on his side relied on kinetic principles relating nucleophilicity and ring closure preferences to establish a delicate balance that could be shifted in the desired direction. How to control chemoselectivity to obtain the desired products over unwanted isomers is the principal issue in these cyclization reactions and there is a profound benefit in understanding the reaction mechanisms.18 Providing justification for this delicate balance and a detailed account for the driving forces that are affecting it however should help in understanding the underlying chemistry and give an impulse to this small but promising field. The chemistry by Krause involves the first gold-catalyzed synthesis of heterocycles with two heteroatoms from allenic precursors i.e. the gold-catalyzed 5-endo cycloisomerization of N-hydroxy-α-aminoallenes 1 to furnish exclusively N-hydroxy-3pyrrolines 2 (and not the oxazine 3) and hydroxylamine ether analogues 4 to 4,5-dihydroisoxazoles 5 or 3,6-dihydro-1,2-oxazines 6 (Fig. 1). In both cases, the nitrogen atom acts as the nucleophile and attacks the allene in a 5-endo or 6-endo fashion but, in the case of hydroxylamine ether analogues, depending on the catalyst used, a different regioselectivity was observed.15,19 Thus, in the case of allenic hydroxylamine ethers, the regioselectivity can be shifted either towards dihydroisoxazoles by employing cationic gold precatalysts (complex A,
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substrate was achieved to obtain the Boc-protected dihydrooxazine 8 (see Fig. 1). Various hydroxylamine ethers gave similar results. In contrast, the use of cationic gold complexes ([Au(PPh3)]BF4/AgBF4 or A) or AgBF4 led to decomposition of the substrate.13 We hereby aim to provide a detailed mechanistic picture of the pioneering work from Krause. This information may be valuable to provide a new impulse to the switchable gold mediated cycloisomerizations of allene-containing substrates.
Fig. 1 A: Gold-catalyzed cycloisomerization of allenic hydroxylamine 1 to N-hydroxypyrroline 2. B: Gold-catalyzed cycloisomerization of allenic hydroxylamine ether 3 with a preferred product being either dihydro1,2-oxazine 4 or dihydroisoxazole 5 depending on the catalyst applied. C: Gold-catalyzed cycloisomerization of N-Boc-protected allenic hydroxylamine ether 6 resulted in dihydro-1,2-oxazine 7 or decomposition depending on the catalyst applied.
Fig. 1), the formation of a mixture of both isomers when using AuCl or preferred formation of the dihydrooxazine by using N-Boc-protected precursors.13 In the work by Krause, upon treatment of 1 with 5 mol% AuCl at room temperature, regioselective 5-endo-cyclization was observed to yield N-hydroxy-3-pyrroline 2. In contrast, the use of the more reactive Lewis acids, i.e., the cationic gold complex A, developed by Echavarren for the cyclization of 1,6enynes and 1,5-enynes, or [AuCl(PPh3)]/AgBF4 resulted in slower reactions and decreased yields because of incomplete conversion. Various substituted N-hydroxy-α-aminoallenes were treated with AuCl in CH2Cl2 and N-hydroxy-3-pyrrolines were obtained with excellent yields and high degree of chirality transfer.13 Krause also explored the reactivity of the allenic substrate in which the heteroatom positions of 1 were exchanged, resulting in allenic hydroxylamine ether 4. Treatment of 4 with AuCl afforded a mixture of 3,6-dihydro-1,2-oxazine 5 (47% yield) and 4,5-dihydroisoxazole 6 (19%) through the nucleophilic attack of the nitrogen in a 6-endo or 5-endo cyclization, respectively. The dihydrooxazine 5 was also formed with complete chirality transfer. A highly regioselective cyclization of 4 to 4,5-dihydroisoxazole 6 was achieved in the presence of cationic Au(I) complexes [Au(PPh3)]BF4 or A (Fig. 1). Particularly, the more reactive gold complex A gave not only the highest yield of 81% but also the best selectivity 6/5 of 96 : 4. Under these optimized conditions, various allenic hydroxylamine ethers were converted into the corresponding dihydroisoxazoles in high yields.13 Interestingly, when N-Boc protected derivatives 7 were used, a completely regioselective 6-endo cycloisomerization of the
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2
Results
2.1
Heterocycloisomerization of N-hydroxy-α-aminoallenes
In our computations, we considered four possible reaction pathways for the conversion of an N-hydroxy-α-aminoallene, such as R1a (Fig. 2): the AuCl catalyzed 5-endo cycloisomerization to yield the N-hydroxypyrroline derivative P1a and the alternative involving a 6-endo cyclization towards dihydrooxazine P2a, and the same two competitive profiles for the more active cationic catalyst Au[P(OMe)3]+ which represents a simpler analogue of the complex A used by Krause (see Fig. 1). The AuCl 5-endo reaction follows a simple one step mechanism in which, upon allene activation by the metal, a nucleophilic attack from the nitrogen directly furnishes the 5-membered
Fig. 2 Reaction profiles considered for the transformation of N-hydroxy-α-aminoallene R1a into N-hydroxypyrroline P1a and dihydrooxazine P2a with a neutral and a cationic gold catalyst.
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ring scaffold of the N-hydroxypyrroline (3a in Fig. 2). The activation barrier for this process is 13 kcal mol−1, a value that supports the formation of the final product under mild conditions and in short reaction times, in a reasonable agreement with the experimental setup (0.5 h at room temperature when employing a 5% catalyst load). Numerous attempts to locate the transition state associated with the 6-endo attack of oxygen were unsuccessful and the optimizations always ended in TS2a3a. We therefore concluded that the activation with AuCl was incompatible with the formation of the six member ring due to an insufficient match between the nucleophile (a hard and relatively electron deficient oxygen atom) and the electrophile (the soft gold-activated allene unit). The use of a more active catalyst like complex A provides a slightly better match in terms of the hard–soft character of the species involved in the C–O bond forming event and both 5-endo and 6-endo pathways could be obtained. The activation barrier for the 5-endo attack increases slightly with the cationic catalyst (13.0 vs. 15.4 kcal mol−1 for TS2a3a and TS4a5a, respectively). Moreover, in terms of the reaction mechanism, the cycloisomerization proceeds in essentially the same way as in the AuCl version. Experimentally, the use of cationic gold is found to reduce the reaction yield and prolong the reaction time. This observation is compatible with the higher activation energy computed. To confirm the effect of using cationic gold in this reaction, we decided to test a limit case scenario in which bare Au+ is used to activate the allene unit. Under these conditions, the hard–soft match between the nucleophile and electrophile should be enhanced compared to [AuP(OMe)3]+. Oxygen is a relatively worse nucleophile than nitrogen in this context, but both are too hard with respect to the activated allene as an electrophile under the Pearson theory. We therefore anticipated that hardening the electrophile should have a strong effect in the reaction profile. Indeed, the barrier for the 5-endo cyclization dropped in ∼9 kcal mol−1, leaving TS2a3a only 6.6 kcal mol−1 above 4a. The potentially competitive 6-endo cyclization with the cationic complex A is similar to the 5-endo alternative involving activation and a direct nucleophilic attack, but in this case being carried out from the oxygen side. The nucleophilic attack is however non-competitive due to a high activation barrier (23.5 kcal mol−1) and a rather unstable cyclic intermediate 6a (20.7 kcal mol−1). In this scenario, the 6-endo pathway is very much a dead-end in terms of producing a reaction product. We nevertheless tested the limit case of activation using bare Au+ as above to verify our hypothesis regarding the nature of the gold activation in these systems. When we computed the activation of the 6-endo cyclization activated by bare gold, we obtained a barrier of only 13.9 kcal mol−1 (a reduction of 10 kcal mol−1 with respect to the phosphite complex) strongly suggesting that the oxygen atom is in a significant mismatch situation to undergo nucleophilic attack onto the allene. The computed profiles illustrated in Fig. 2 therefore rationalize well the experimental observations by Krause:13 (1) activation of an N-hydroxy-α-aminoallene with gold (irrespective of
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the catalyst being neutral, AuCl, or cationic, complex A) afforded only the N-hydroxypyrroline and (2) regarding efficiency the reaction is activated more effectively by AuCl than phosphite gold complexes.20 The switchable reactivity for N-hydroxy-α-aminoallenes was intuitivelly suggested by Krause on the grounds of the relative rates for nitrogen and oxygen nuclephilic attacks and 5 and 6-membered ring formation. Oxygen was expected to undergo faster nucleophilic attack than nitrogen, but then a 6 member ring formation usually implies slower kinetics than a 5 member ring formation. This balance, oxygen/6-membered ring and nitrogen/5-membered ring, could drive the reaction to one or the other product. Our results agree with the ring formation dominating this balance. Actually, according to our results, oxygen does not act as a good nucleophile (it produces a very unstable intermediate through a high barrier). The stronger nucleophilicity anticipated by Krause and therefore the subtle kinetic balance between 5 and 6 member ring formation is clearly observed however when activating the allene with bare gold. 2.2
Heterocycloisomerization of allenic hydroxylamine ethers
Interestingly, when swapping O with N in the initial substrate and hence considering the cycloisomerization of hydroxylamine allenyl ethers, the reactivity changes dramatically. The selectivity issues in this case are not due to competition between nucleophiles (since the terminal amine is much more nucleophilic than the oxygen atom, which is compromised in an ether group). They however arise due to nitrogen being able to attack in two fashions, 6-endo and 5-endo onto the distal and cumulenic centers of the allene moiety. In the experiments reported by Krause, both neutral and cationic gold catalysts provided a mixture of 5-endo and 6-endo cycloisomerization products, but with opposite selectivities. AuCl and AuCl3 catalysts furnished the dihydrooxazine as a major product (selectivities higher than 2 : 1) whereas cationic gold catalysts strongly favoured the formation of the 4,5-dihydroisoxazole (observed selectivities of 4 : 96, see Fig. 1). According to our calculations, the reaction mechanisms are again quite straightforward and they essentially involve activation and a subsequent nucleophilic attack. Once the nucleophile has undergone the attack, the heterocycle ring formation is fully achieved and the final product is only a protodeauration step away. This is strictly true for the 6-endo attack to form the dihydrooxazine derivative whereas the 5-endo attack has a slightly longer mechanism requiring a final keto-enolic equilibrium to arrive to the final 4,5-dihydroisoxazole. Our results (summarized in Fig. 3) suggest that AuCl can only catalyze efficiently the formation of the six member ring. The nucleophilic attack on the cumulene carbon involves a transition structure (TS2b3b) requiring almost 20 kcal mol−1, which is non competitive with the alternative pathway. The attack onto the distal allene position requires only 14.3 kcal mol−1 (TS2b7b), which seems compatible with the reaction conditions employed in the experimental work. The use of a more electrophilic gold catalyst has an interesting impact in the reaction profiles. The six member ring formation is
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ethers furnished products only with AuCl. Activation with harder electrophiles like AuCl3 or cationic [Au(PPh3)]BF4 or complex A yielded incomplete conversion or induced decomposition of the substrate. Gratifyingly, the use of AuCl provided high selectivity towards the 6-endo attack and therefore towards the formation of dihydrooxazines. To rationalize these findings, we computed again the energy profiles for the four possible mechanisms operating in this chemistry (Fig. 4). Given the reduced nucleophilicity of the amine, it was not surprising to find that the reaction mechanism did not change in terms of the transformation, but that the associated activation barriers were significantly larger. The protected amine undergoes 6-endo cyclization through a barrier of 22.5 kcal mol−1 (compared with 14.3 kcal mol−1 for the unprotected amine). This also affected the 5-endo cyclization, which raised the barrier of the rate limiting step to almost 27 kcal mol−1. These barriers seem to be in agreement with the exclusive formation of the 6-endo cycloisomerization product at room temperature. The results obtained with complex A however suggest that this activation should also lead to product formation since barriers are not only comparable but also slightly lower than in the AuCl activation mechanism (Fig. 4). With these results we would predict, contrary to the observed decomposition, that
Fig. 3 Reaction profiles considered for the transformation of hydroxylamine allenyl ether R1b into 4,5-dihydroisoxazole P1b and dihydrooxazine P2b with a neutral and a cationic gold catalyst.
essentially unaffected by the change of the catalyst. Actually, the reaction is just slightly disfavored kinetically compared to the AuCl activation (14.3 vs. 15.0 kcal mol−1). In contrast, the reaction barrier for the 5-endo cyclization is reduced by 3 kcal mol−1 (from 19.8 to 16.8 kcal mol−1), bringing this alternative pathway into close competition (Fig. 3). Our calculations must have captured the correct trend in this chemistry, but the overall effect has to be somewhat more acute in the experiment, since not only competition, but reversal of product formation is observed with the cationic catalyst. Probably, the large and rather exotic selection of ligands in the cationic catalysts employed by Krause has a non-innocent effect that obviously our calculations could not reproduce. However, the overall picture and trends obtained from our calculations are in fairly good agreement with the experimental observations. 2.3 Heterocycloisomerization of allenic BOC-protectedhydroxylamine ethers Once confirmed that the gold activation of allenic hydroxylamine ethers furnishes 4,5-dihydro-isoxazoles or dihydrooxazines selectively on choosing the appropriate catalyst, Krause explored hydroxylamines with reduced nucleophilicity. Interestingly, the use of allenic BOC-protected-hydroxylamine
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Fig. 4 Reaction profiles considered for the transformation of acetylated hydroxylamine allenyl ether R1c into 4,5-dihydroisoxazole P1c and dihydrooxazine P2c with a neutral and a cationic gold catalyst.
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the 6-endo attack should also be the most favourable pathway and that dihydrooxazine P2c should be the major product in the cycloisomerization mediated by complex A. In an attempt to understand the deleterious effect of the protected amine when using a cationic catalyst, we focused on the tert-butoxycarbamoyl group. Once recollected that most of the subtle effects observed in this chemistry can be related to the match or mismatch in terms of the HSAB theory, we considered the following hypothesis. The mode of activation of AuCl is probably unchanged upon amine protection because soft gold finds the amide non competitive with respect to the unsaturation, however, the harder cationic gold complex may find that the carbamoyl group is a competitive ligand. If this is the case, complexation of the cationic gold with the carbamoyl group not only would eliminate the activation of the allene moiety, but would also block the nucleophile. Both effects could make the cycloisomerization impossible. Calculation of the relative stability of both modes of complexation for AuCl indicated that the allene complex is 2 kcal mol−1 more stable than the gold bound to the carbamoyl group. The AuCl activation of the allene is therefore not compromised by the protection of the amine. When the cationic complex is considered, however, our calculations predict that the carbamoyl complex is more stable than the allene complex by 7.6 kcal mol−1 (Fig. 5). This is a significant energy difference for exchanging isomeric structures at room temperature. Moreover, since the carbamoyl complex is more stable, the barriers for the cationic gold mediated cycloisomerization have to be corrected considering this complex. Even in the most favourable scenario, assuming that carbamoyl and allene complexes exchange through a low energy barrier (hence applying
Organic & Biomolecular Chemistry Table 1 Summary of the activation energies for all the mechanisms explored in this work (ΔG++ in kcal mol−1)
Product
ΔG++
R1a to N-hydroxypyrroline P1a or P2a N/distal C AuCl N/distal C [Au]+ O/distal C AuCl O/distal C [Au]+
P1a P1a P2a P2a
13.0 15.4 — 23.5
R1b to 4,5-dihydroisoxazole P1b or P2b N/cumulene C AuCl N/cumulene C [Au]+ N/distal C AuCl N/distal C [Au]+
P1b P1b P2b P2b
19.8 16.8 14.3 15.0
R1c to 4,5-dihydroisoxazole P1c or P2c N/cumulene C AuCl N/cumulene C [Au]+ N/distal C AuCl N/distal C [Au]+
P1c P1c P2c P2c
26.9 30.5 22.5 25.1
Attacking atom/target site
Curtin–Hammett), the barriers for the cycloisomerization raise to 25.1 and 30.5 kcal mol−1 for the 6-endo and 5-endo attacks, respectively, thus making both reactions inoperative at room temperature. Additionally, the carbamoyl activation may open the door for gold mediated chemistry on the protecting group, which could explain the decomposition reported by Krause and coworkers. Table 1 provides a summary of all the computed activation energies for the four explored reaction pathways including updated barriers in the case of the carbamoyl group establishing more stable complexes with gold.
3
Fig. 5 Complexation modes for 4c (through the allene, top, and the carbamoyl moiety, bottom). The most stable of several conformers considered are shown. A conformation featuring a chelate combining both modes of complexation resulted in loss of the allene–gold bond and only the carbamoyl group remained as a ligand.
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Catalyst
Conclusions
The gold-catalyzed cycloisomerization of functionalized allenes involving oxygen and nitrogen atoms is a valuable method for the synthesis of N- and O-containing heterocycles. In this context, the Krause conversion of N-hydroxyα-aminoallenes and hydroxylamine ethers, where nitrogen and oxygen nucleophic centers are interchanged, is a pioneering example of this chemistry. Thus, although a few following studies on similar reactions and computational investigation are now available,14 the prototype Krause reaction opened questions that have never been addressed. The control in the nucleophilicity (N or O)/member formation (5 and 6 member respectively) and the regioselectivity (most often 5-endo vs. 6-endo) was investigated with respect to the substrate structure (N-hydroxy-α-aminoallenes and allenic hydroxylamine ethers and N-Boc protected derivatives) and the different catalytic properties of the Au(I) catalyst when it is subjected to drastic changes in its structure (i.e. neutral as in AuCl to cationic in [AuP(OMe)3]+ or bare Au+ as an extreme model of activation). We showed that N/5 member ring formation governs kinetically the N-hydroxypyrroline product formation and that using an electron depleted catalyst worsened the results due to a hard/soft nucleophile/electrophile mismatch. In the case of allenic hydroxylamine ethers both 6 member (dihydrooxazine)
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and 5 member rings (dihydroisoxazole) were predicted when using both AuCl and [AuP(OMe)3]+ although with the first catalyst favoring the 6 member ring. Our calculations predicted correctly that the presence of a cationic gold catalyst reduced more effectively the 5 member ring formation reaction barrier although they were unable to accurately reproduce the relative magnitudes for the 5 and 6 member ring formation. Finally, in the case of the N-Boc allenic hydroxylamine ethers, our calculations predicted correctly the oxazine formation with AuCl and the deleterious effect of the N-Boc group with more active Au(I) catalysts. We suggested that this has happened due to the carbamoyl carbonyl complexation which stabilized the allenic hydroxylamine ether substrate giving rise to higher reaction barriers incompatible with the reaction conditions and consistent with the observed decomposition via secondary paths.
4 Computational methods Throughout this work, the Kohn–Sham formulation of density functional theory was employed.21,22 The four-rung metahybrid density functional M06-2X 23 has been used with the extended double-ζ quality Def2-SVPP basis set for all the static calculations. This combination of density functional and basis set has been found to provide good performance in homogeneous gold catalysis.24,25 All geometry optimizations have been carried out using tight convergence criteria and a pruned grid for numerical integration with 99 radial shells and 590 angular points per shell. In some challenging cases, this grid was enlarged to 175 radial shells and 974 points per shell for first row atoms and 250 shells and 974 points per shell for heavier elements. These challenging optimizations are usually associated with very soft vibrational modes (usually internal rotations). Analysis of the normal modes obtained via diagonalization of the Hessian matrix was used to confirm the topological nature of each stationary point. The wavefunction stability for each optimized structure has also been checked.26 Solvation effects have been taken into account variationally throughout the optimization procedures via the polarizable continuum model (PCM) using parameters for dichloromethane and taking advantage of the smooth switching function developed by York and Karplus.27,28 Concerning the structures involved in these simulations, we simplified the cationic gold complex employed in the experimental work (complex A) using Au[P(OMe)3]+ instead of ((1,3tBu)-Ph-O)3-P-Au+ in order to find a balance between accuracy and computational efficiency. All the calculations performed in this work have been carried out with the Gaussian 09 program.29
Acknowledgements The authors thank the Centro de Supercomputación de Galicia (CESGA) for time on HPC infrastructure. Ministerio de Economía y Competitividad (MINECO, PCTQ2016-75023-C2-2-
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P) is also acknowledged for financial support. A. K. thanks to Chiesi Hellas for supporting the visit of S. K. from A. K. lab to C. S. L. lab through a collaborative PhD work.
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