DOI: 10.1002/chem.201404302
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Mechanistic Study of Silver-Mediated Furan Formation by Oxidative Coupling Jnos Daru,[a, b] Zsuzsanna Benda,[a] dm Pti,[c] Zoltn Novk,*[c] and Andrs Stirling*[b]
the catalyst for the ionic steps, which is in accordance with the experimental observations. The two most important aspects of the optimal route are the formation of a silver–acetylide, reacting subsequently with the enolate radical, and the aromatic furan-ring formation in a single step at the latter, ionic segment of the reaction path. Our findings could explain several experimental observations, including the “key-promoter role” of silver, the preference for ionic cyclization, and the reduced reactivity of internal acetylides.
Abstract: Density functional calculations and experiments have been carried out to unravel the mechanism of a silvermediated furan formation by oxidative coupling. Various possible reaction paths were considered and the most favorable channel has been identified on the basis of the calculated solvent-corrected Gibbs free-energy profiles. The mechanism represented by this route consists of a radical and a subsequent ionic route. The silver cation has a double role in the mechanism: it is the oxidant in the radical steps and
1. Introduction Oxidative cross-coupling is a new field in current synthetic chemistry.[1] While it is still in its infancy, recent developments represent significant steps toward more economic processes under milder conditions.[2] Catalyzed by transition metals, this class of reactions provides an efficient way for CC-bond formations by CH functionalization. A large variety of transition metals has been proven to be effective in CC coupling reactions, such as Ni, Fe, Cu, Pd, etc.[2, 3, 5, 4] Silver has also been found to be effective in oxidative coupling processes.[5–9] By employing silver salts as an oxidant, very diverse classes of heterocycles have been synthesized, such as quinolines,[6] benzo[b]phosphole oxides,[7] heteroaromatic imidazo[1,2-a]pyridines,[8] or substituted pyrrols.[9] Very recently, an efficient silver-mediated route leading to various polysubstituted furans from terminal alkynes and b-ketoesters has been described by Lei et al. (Scheme 1).[10]
Scheme 1. Silver-mediated oxidative CH/CH functionalization of 1 and 2.
These heterocycles are particularly important from a synthetic point of view because they play a significant role in numerous pharmaceutical and agrochemical processes. In addition, furans and their derivatives are building blocks of various natural products and they can also be found in living organisms.[11] The new synthetic route for polysubstituted furans is a onestep procedure employing a silver-mediated oxidative CC coupling strategy.[10] In this reaction, terminal alkynes and 1,3dicarbonyl compounds are coupled by simultaneous CH functionalizations, and the coupling was shown to be highly selective with good to excellent yields and a very low tendency for homocoupling. Some mechanistic aspects of this intriguing reaction have been addressed by Lei et al.[10] They suggested that the silver– acetylide may be an intermediate of the reaction and that the excess silver salt is necessary for oxidation. On the other hand, employing styrene instead of the terminal alkyne resulted in no cyclization. This indicates that the cyclization does not proceed along a radical route, as opposed to the well-known transition-metal-induced oxidative radical cyclizations of alkenes with 1,3-dicarbonyl compounds.[12] Motivated by the undeniable significance of this protocol and by our recent interest in oxidative coupling reactions, we decided investigate the mechanistic details of this reaction. To this end, we set out to explore several possible pathways leading to the formation of the furan frame. On the basis of the results, we propose a plausible mechanism featuring a radical
[a] J. Daru, Z. Benda Eçtvçs University, Pzmny Pter stny 1/a 1117 Budapest (Hungary) [b] J. Daru, Dr. A. Stirling Institute of Organic Chemistry Research Centre for Natural Sciences of the Hungarian Academy of Sciences Magyar Tudsok Kçrffltja 2, 1117 Budapest (Hungary) E-mail: [email protected] [c] . Pti, Dr. Z. Novk MTA-ELTE “Lendlet” Catalysis and Organic Synthesis Research Group Institute of Chemistry, Eçtvçs University Pzmny Pter stny, 1/a, 1117 Budapest (Hungary) E-mail: [email protected] Homepage: zng.elte.hu Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404302. Chem. Eur. J. 2014, 20, 1 – 7
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Full Paper and a subsequent ionic-path segment. A few additional experiments were conducted to verify the findings and to provide support for the proposed mechanism.
Radical 1.2 can most likely react with either a phenylacetylene (2) molecule or with its Ag salt 2.1,[13] resulting in the first CC coupling, as depicted in Scheme 2 together with the corresponding free-energy profiles. Along the route leading to the formation of 3.1, the reaction is exergonic by 11.0 kcal 2. Results and Discussion mol1. Similarly, the second path features 12.1 kcal mol1 reaction free energy for the formation of 3.2 with an Ag atom as An important issue in our study is to define the initial (referbyproduct that is assumed to form elementary bulk silver. This ence) free-energy level. Experimentally, the reactants and oxiassumption is in line with the experimental observation of dant are brought together in the solvent, and the solution is a thin silver mirror on the wall of the reaction vessel during stirred at 80 8C under N2 for 12 h. On the basis of various the reaction. The formation of 3.2 has been assumed in dimer-formation energies, we concluded that in the initial restRef. [10] but not been verified. As shown later, this species reping state of this solution the dominant form of Ag + is solvated resents a crucial stage in the mechanism: it separates the radiAg2CO3. The concentration of other possible Ag compounds is cal and ionic phases of the most favorable reaction channel. significantly lower or negligible (see the Supporting InformaAn important difference between the two mechanisms is tion for details). In the free-energy diagrams, the levels are refthe exergonic pre-equilibrium along the second path, which is erenced to this state. It is worth noting that the initial level of shifted toward the formation of silver–phenylacetylide (2.1). the free-energy profiles strongly depends on the solubility of Despite the low solubility of Ag2CO3 and the similar barriers for Ag2CO3, which is an endergonic process. Albeit its extent is unknown, it shifts all the levels uniformly; therefore, it does not CC couplings for 2 and 2.1 (15.0 and 14.3 kcal mol1, respectively), it is more probable that the reaction proceeds via the have any effect on the selection of the mechanism. We indienergetically favored organometallic species 2.1. This conclucate this free-energy investment on the profiles by an initial sion is supported by the experimental observation[10] that the upward dash line. Accordingly, we will also indicate the freeenergy gain at the final portions of the profiles. The base KOAc reaction also yields product 4 from 2.1. The formation of 2.1 is assumed to be in its dissociated form. The difference bein other coupling reactions of terminal alkynes under similar tween the basicity of CO32 and OAc indicates that the pricircumstances has also been proposed and confirmed.[14–16] mary acceptor for protons dissociating from the organic speTherefore, in the following studies, we first focus on pathways cies is the carbonate anion. featuring 2.1. Then, we also investigate a mechanistic alternaThe initial step is necessarily the formation of enolate 1.1 tive in which the terminal hydrogen atom is retained during the reaction. This pathway is compatible with the coupling refrom ethyl acetoacetate 1 by proton transfer to a carbonate anion formed by the dissociation of Ag2CO3, as shown in actions of internal alkynes, thus, we can also study the effect of substituents on the mechanism. Scheme 2. This is an exergonic process by 5.9 kcal mol1. The We note that other possibilities, such as an attack on the non-terminal alkyne carbon atom, CO couplings, as well as CC or CO couplings by the enolate anion preceding the radical formation, have also been considered and safely excluded by their higher barriers and much less favorable reaction free energies. The energy profiles of these routes are collected and discussed in the Supporting Information. Starting from 3.2, four distinct reaction channels can be envisioned. The reaction routes are shown in Schemes 3–6. First, we note that the formation of 3.2 becomes even more favorable in terms of free energy by precipitation of Ag (56.9 kcal mol1). We devised and followed three possible routes starting Scheme 2. Free-energy profile and mechanism for the CC-coupling part. Values are in kcal mol1. from this situation. In the first route (path A), a silver cation assists the ring closure with the carbonyl oxygen atom (Scheme 3). From an AgOAc molecule the silver ion coordinates to 3.2, forming 3.3 with 16.5 kcal further oxidation of 1.1 by an Ag + ion releases an additional mol1 endergonicity. The Ag + ion polarizes the triple bond 11.8 kcal mol1 free energy and yields the enolate radical 1.2. Experiments with TEMPO ((2,2,6,6-tetramethyl-piperidin-1and, thus, facilitates the nucleophilic attack of the carbonyl yl)oxyl) and BHT (3,5-di-tert-butyl-4-hydroxytoluene) supported group. The calculated free-energy barrier of the cyclization is this picture. Although we could not isolate adducts of the uti23.9 kcal mol1, and the formation of intermediate 4.1 is enderlized scavengers and any radical intermediates, we found that gonic by 17.1 kcal mol1 with respect to 3.3. 4.1 then transthe presence of one equivalent of scavenger completely forms to intermediate 4.2 by deprotonation, which results in stopped the transformation. This clearly shows that the reacthe aromatic-ring formation of the furan ring accompanied by tion goes through a radical intermediate. a large free-energy release (57.3 kcal mol1). &
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Scheme 3. Free-energy profile and mechanism for path A. Values are in kcal mol1.
step is considerably favorable by 19.0 kcal mol1. Along path B, the cyclization of 3.4 is, however, endergonic by 16.5 kcal mol1 and has an activation freeenergy barrier of 29.5 kcal mol1. By contrast, the subsequent protonation of intermediate 4.4 represents a strong driving force (24.2 kcal mol1) to complete the reaction, leading to the formation of product 4.
It is sensible to assume that the reaction ends up at this stage and that the acidic workup of the reaction mixture gives rise to product 4 by protonolysis of the organosilver compound. To probe this scenario, we quenched the reaction mixture with both HCl/H2O and DCl/D2O. However, we did not observe deuterium incorporation into the furan ring.[17] This shows that the Scheme 5. Free-energy profile and mechanism for path C. Values are in kcal mol1. protonolysis should occur before the quenching step. Therefore, The presence of a silver cation can further enhance this we followed the reaction path from the transformation of 4.2 mechanism along pathway C (Scheme 5). Enolate 3.4 can form to product 4. an adduct (3.5) with a Ag + ion that is released from a solvated This transformation involves the formation of adduct 4.3 between 4.2 and an acetic acid molecule. This step requires AgOAc molecule. This step is slightly endergonic (6.4 kcal 17.2 kcal mol1 free energy. The protonolysis of the silver–furmol1). The silver-assisted ring closure of 3.5 yielding 4.2 re1 anyl species proceeds through a 9.9 kcal mol free-energy barquires a much lower activation free energy (15.0 kcal mol1) rier and the overall exergonicity of the exchange is 3.0 kcal compared to the formation of 4.4 in path B. In addition, this mol1. step is exergonic with 11.1 kcal mol1. At this point, path C Further calculations revealed that this mechanism can be rejoins path A and after going through intermediate 4.3 and markably improved, as shown by routes B and C. Schemes 4 passing a barrier of 9.9 kcal mol1 it arrives at product 4. In this and 5 displays these pathways with the corresponding freestep, the silver cation is recovered, similarly to path A. It is energy profiles. worth noting that as the reaction proceeds, the concentration The crucial step along these routes is a proton transfer from of Ag + is decreasing; therefore, the transformation 4.2 Ð 4 is shifted toward the product formation. The favorable reaction adduct 3.2 to a carbonate anion, yielding enolate 3.4. This barrier along route C is due to the fact that the aromaticity of the furan group is built in the cyclization step, which is in contrast to path A in which an additional step is necessary for the formation of the aromatic ring. Path C is calculated to be even more effective than path B because the aromatic-ring formation in 4.2 is accompanied by charge recombination, whereas the furan ring in 4.4 on pathway B carries a negative charge. An interesting option for silver assistance is when the ring closure by CO bond formation takes place in the presence of a Ag radical atom, that is, after the formation of intermediate 3.2 and before Ag precipitation (path D, Scheme 6). The formation of 3.2 without Ag precipitation is accompanied by a smaller reaction energy (12.1 kcal mol1). On the one hand, the difference is attributed to the missing Ag precipitation energy Scheme 4. Free-energy profile and mechanism for path B. Values are in kcal and, on the other hand, to the weak association of 3.2 with mol1. Chem. Eur. J. 2014, 20, 1 – 7
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Full Paper mol1 barrier height. The intermediate anion can subsequently form an energetically slightly favored silver-ion complex 3.7. For the final step, we could identify an oxidative ring closure that results in product 4 and silver. This step is characterized by a relatively small activation free energy of 16.3 kcal mol1. We anticipated that substitution of the terminal hydrogen atom to a methyl or phenyl group would remarkably influence the CC coupling step by changing the electron-density distribution on the attacked carbon atom. In fact, experimental observations[10] support this picture: the methyl derivative gave a low (< 10 %) yield, whereas the phenyl derivative yielded only traces of the corresponding product. Our calculated freeenergy profiles shown in Scheme 8 are in good agreement
Scheme 6. Free-energy profile and mechanism for path D. Values are in kcal mol1. The dash–dot line indicates that intermediates between 4.5 and 4 along the segment have not been identified.
a Ag atom. Along path D, the ring closure has to overcome a significant free-energy barrier of 33.8 kcal mol,1 yielding intermediate 4.5 featuring a moderate endergonic reaction free energy (9.9 kcal mol1). Then, 4.5 transforms to product 4 with a significant release of free energy (93.7 kcal mol1). It is worth noting that the route linking 4.5 with product 4 has not been calculated in details because the initial large kinetic barrier highlights that this mechanism is clearly unfavorable. Scheme 7 displays the free-energy profile of the reaction pathway E departing from 3.1. Along this route, the hydrogen atom of the terminal alkyne remains unaffected; therefore, the effect of substitution on the carbon atom of the terminal alkyne can be efficiently probed. The reactivity of internal phenylalkynes has also been tested experimentally,[10] although these processes cannot be considered double CH functionalizations. The mechanism E proceeds via an exergonic deprotonation step (14.0 kcal mol1) through a moderate 18.2 kcal
Scheme 8. Free-energy profiles for the CC-coupling reaction of terminal and two different internal alkynes. Values are in kcal mol1.
with the experiment. We found that the transformation of the internal alkynes proceeds through a higher barrier than that of 2. In addition, they are also less favorable thermodynamically. We also noticed that the order of the activation energies explains qualitatively the experimental substituent effect. Clearly, a slower formation of the CC-coupled intermediates can increase the probability of side reactions and the recombination of radical 1.2, which can appreciably decrease the efficiency of these routes. A comparison of the free-energy profiles shows that the most likely mechanisms are path C and path E. On the basis of the barrier heights, the other routes do not represent kinetically feasible alternatives. Further inspection shows that the equilibrium between 2 and 2.1 favors route C. Indeed, the freeenergy difference between the two states (9.7 kcal mol1) is equivalent to a six order of magnitude difference in concentration at 80 8C. Although the barriers are similar along routes C and E, the much larger initial concentration of 2.1 results in several orders of magnitude faster rate. The most favorable route C involves a radical and an ionic segment. The first radical route features the oxidation of enolate 1 a by a silver cation and the subsequent radical coupling with the Ag salt of phenylacetylene. In the second ionic part, the CO-bond formation takes place to give the furan ring. In this part of the reaction, silver cations play only a catalytic role. The present mechanism is consistent with the picture derived from experimental observations. The calculations clearly demonstrated the twofold role of silver (catalysts and reactant) postulated by Lei et al.[10] In particular, we have shown that silver–acetylide has important roles in the CC coupling: its formation opens a favorable reaction channel for the coupling and provides the oxidizing partner (Ag + ), which transforms the radical mechanism to an ionic one. The calculations have also shown that the cyclization
Scheme 7. Free-energy profile and mechanism for path E. Values are in kcal mol1.
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mechanisms. On these profiles, we will indicate the structures of the stable minima at the corresponding energy levels. For the TSs, only free-energy values are shown and their coordinates are collected in the Supporting Information. An important technical issue is the free-energy contribution of the formation of solid, precipitated Ag in DMF. On the basis of Hess’s law, we calculated it by taking into account the solvation of a Ag atom and the experimental free energy of the Ag(g)!Ag(s) process. The free energy obtained in this way is 56.9 kcal mol1 (see the Supporting Information for additional details). Although this estimation brings some ambiguity into the calculated profiles, the apparent large energy differences allow to identify reliably the most likely mechanism. All calculations have been performed by using the Gaussian package.[20] In the experiments, we have followed and successfully reproduced the protocol described in Ref. [10]. In the radical trapping experiments, we have employed two frequently used radical scavengers: TEMPO ((2,2,6,6-tetramethyl-piperidin-1yl)oxyl) and BHT (3,5-di-tert-butyl-4-hydroxytoluene). Deuterated experiments were followed by MS measurements. Further experimental details are given in the Supporting Information.
3. Conclusion We have carried out a mechanistic study to elucidate the mechanism of a silver-mediated furan formation by oxidative coupling. Density functional calculations and experiments revealed a multistep pathway featuring radical and ionic segments, separated by intermediate 3.2. An important aspect of the most favorable path is that the cyclization is accompanied by the simultaneous build-up of aromaticity. Our findings support and explain several experimental observations. In particular, the mechanism can account for the twofold role of the silver cation: it is a reactant initializing the radical steps and a catalyst for the cyclization and product-formation steps. We have also shown the crucial role of silver–acetylide in the mechanism: its favorable formation under the reaction conditions drives the reaction into the most favorable channel. The calculations also revealed that reactions employing internal alkynes would proceed with less favorable thermodynamics and with higher barriers, which is in accordance with the experiments.
Acknowledgements Support of the “Lendlet” Research Scholarship of the Hungarian Academy of Sciences (LP2012-48/2012), OTKA Grant K101115, TT-10-1-2011-0245 grant and computational resources provided by NIIF Supercomputer Center are acknowledged.
4. Experimental Section Methods The calculations have been performed by employing the M06 exchange–correlation functional.[18] For geometry optimizations and frequency calculations, we have employed the 6-31 + G* basis set for the main-group atoms, whereas for Ag we have used the LanL2DZ basis set completed with a set of polarization and diffuse functions taken from the corresponding augcc-pVDZ-PP basis set. For the optimized structures, the final solvent-corrected energies have been calculated by using the 6-311 + + G(3df,3dp) basis set for the main-group atoms, while the basis of Ag has been taken from the LANL2TZ(f) set augmented with an additional set of polarization and diffuse functions from the aug-cc-pVTZ-PP basis (see the Supporting Information for the details). The optimized intermediates and transition states (TSs) have been tested by frequency calculations. Additional IRC and normal optimization calculations have also been carried out to verify that a calculated TS indeed connects the two corresponding minima. Note that in case of protonolyses, fast pre-equilibria between CH3COOH/CO32 and HCO3/ CH3COO acid–base forms are not discussed but the corresponding free energies are always taken into account. The solvent effects have been taken into account by using the SMD implicit continuum solvation model.[19] The solvent is N,N-dimethylformamide. The Gibbs free-energy contributions to the electronic energy contribution have been calculated by employing the harmonic oscillator, rigid rotor, ideal gas approximation at 80 8C and 1 mol dm3 concentration, and including the solvation free-energy changes. See the Supporting Information for additional details. By using these data, we have constructed the free-energy profiles of the various possible Chem. Eur. J. 2014, 20, 1 – 7
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Keywords: CH activation · density functional calculations · furans · radical reactions · silver [1] a) A. N. Campbell, S. S. Stahl, Acc. Chem. Res. 2012, 45, 851 – 863; b) Y. Wu, J. Wang, F. Mao, F. Y. Kwong, Chem. Asian J. 2014, 9, 26 – 47; c) C. Chen, K. M. Engle, D. H. Wang, J. Q. Yu, Angew. Chem. Int. Ed. 2009, 48, 5094 – 5115; Angew. Chem. 2009, 121, 5196 – 5217; d) C. Liu, L. Jin, A. Lei, Synlett 2010, 17, 2527 – 2536. [2] a) C. Liu, H. Zhang, W. Shi, A. Lei, Chem. Rev. 2011, 111, 1780 – 1824; b) J. Wencel-Delord, T. Drçge, F. Liu, F. Glorius, Chem. Soc. Rev. 2011, 40, 4740 – 4761; c) T. S. Mei, L. Kou, S. Ma, K. M. Engle, J. Q. Yu, Synthesis 2012, 44, 1778 – 1791. [3] C. J. Li, Acc. Chem. Res. 2009, 42, 335 – 344. [4] W. Shi, C. Liu, A. Lei, Chem. Soc. Rev. 2011, 40, 2761 – 2776. [5] M. M. Daz-Requejo, P. J. P rez, Chem. Rev. 2008, 108, 3379 – 3394. [6] X. Zhang, B. Liu, X. Shu, Y. Gao, H. Lv, J. Zhu, J. Org. Chem. 2012, 77, 501 – 510. [7] Y. R. Chen, W. L. Duan, J. Am. Chem. Soc. 2013, 135, 16754 – 16757. [8] C. He, J. Hai, H. Xu, Y. Mo, H. Liu, J. Han, A. Lei, Chem. Commun. 2012, 48, 11073 – 11075. [9] M. Zhao, F. Wang, X. Li, Org. Lett. 2012, 14, 1412 – 1415. [10] C. He, S. Guo, J. Ke, H. Xu, H. Chen, A. Lei, J. Am. Chem. Soc. 2012, 134, 5766 – 5769. [11] a) Heterocycles in Natural Product Synthesis (Eds.: K. C. Majumdar, S. K. Chattopadhyay), Wiley-VCH, Weinheim, 2011; b) H. N. C. Wong, P. Yu, C. Yick, Pure Appl. Chem. 1999, 71, 1041 – 1044; c) W. B. Stillman, A. B. Scott, U. S. Patent 1947, 241, 664; d) M. A. McKervey, M. P. Doyle, Modern Catalytic Methods for Organic Synthesis with Diazo Compounds, Wiley, New York, 1998; e) H. M. L. Davies, J. R. Manning, Nature 2008, 451, 417 – 424; f) B. Liu, S. F. Zhu, W. Zhang, C. Chen, Q. L. Zhou, J. Am. Chem. Soc. 2007, 129, 5834 – 5835; g) E. C. Lee, G. C. Fu, J. Am. Chem. Soc. 2007, 129, 12066 – 12067; h) C. Chen, S. F. Zhu, B. Liu, L. X. Wang,
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[12] [13]
[14] [15] [16] [17]
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Q. L. Zhou, J. Am. Chem. Soc. 2007, 129, 12616 – 12617; i) F. M. Dean, in Advances in Heterocyclic Chemistry, Vol. 30 (Ed.: A. R. Katritzky), Academic Press, New York, 1982, pp. 167 – 238; j) F. M. Dean, M. V. Sargent, in Comprehensive Heterocyclic Chemistry, Vol. 4, Part 3 (Eds.: C. W. Bird, G. W. H. Cheeseman), Pergamon Press, New York, 1984, pp. 531 – 598; k) B. H. Lipshutz, Chem. Rev. 1986, 86, 795 – 819. J. Iqbal, B. Bhatia, N. K. Nayyar, Chem. Rev. 1994, 94, 519 – 564. The reaction between 1.2 and 2.1 can be considered as a radical–nucleophile interaction. This interaction is common for radical oxidative couplings; for details, see: a) Q. Liu, R. Jackstell, M. Beller, Angew. Chem. Int. Ed. 2013, 52, 13871 – 13873; Angew. Chem. 2013, 125, 14115 – 14117; b) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan, A. Lei, Angew. Chem. Int. Ed. 2014, 53, 502 – 506. J. Liu, Z. Fang, Q. Zhang, Q. Liu, X. Bi, Angew. Chem. Int. Ed. 2013, 52, 6953 – 6957; Angew. Chem. 2013, 125, 7091 – 7095. M. Gao, C. He, H. Chen, R. Bai, B. Cheng, A. Lei, Angew. Chem. Int. Ed. 2013, 52, 6958 – 6961; Angew. Chem. 2013, 125, 7096 – 7099. J. Ke, H. Chuan, H. Liu, M. Lia, A. Lei, Chem. Commun. 2013, 49, 7549 – 7551. Deuterium incorporation could not be observed for reactions starting from either 2 or 2.1. This also underlines the role of 2.1 in the mechanism.
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[18] a) Y. Zhao, D. G. Truhlar, Theor. Chem. Acc. 2008, 120, 215 – 241; b) Y. Zhao, D. G. Truhlar, Acc. Chem. Res. 2008, 41, 157 – 167. [19] A. V. Marenich, C. J. Cramer, D. G. Truhlar, J. Phys. Chem. A J. Phys. Chem. B. 2009, 113, 6378 – 6396. [20] Gaussian 09, Revision C.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A. Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada, M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N. Kudin, V. N. Staroverov, R. Kobayashi, J. Normand, K. Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O. Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, . Farkas, J. B. Foresman, J. V. Ortiz, J. Cioslowski, D. J. Fox, Gaussian, Inc. Wallingford CT, 2010.
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FULL PAPER & Mechanistic Studies J. Daru, Z. Benda, . Pti, Z. Novk,* A. Stirling* && – &&
Radical or ionic mechanism? Both. The detailed mechanism of a silver-mediated furan formation by oxidative CH/CH activation has been revealed by DFT calculations and additional experiments. The reaction path starts with a radical
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CC coupling process. Then, an aromatic cyclization occurs featuring an ionic mechanism, which completes the furan formation. Silver plays crucial roles in the reaction: it is an oxidant and a catalyst simultaneously.
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Mechanistic Study of Silver-Mediated Furan Formation by Oxidative Coupling
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& Mechanistic Studies
Mechanistic Study of Silver-Mediated Furan Formation by Oxidative Coupling Jnos Daru,[a, b] Zsuzsanna Benda,[a] dm Pti,[c] Zoltn Novk,*[c] and Andrs Stirling*[b]
the catalyst for the ionic steps, which is in accordance with the experimental observations. The two most important aspects of the optimal route are the formation of a silver–acetylide, reacting subsequently with the enolate radical, and the aromatic furan-ring formation in a single step at the latter, ionic segment of the reaction path. Our findings could explain several experimental observations, including the “key-promoter role” of silver, the preference for ionic cyclization, and the reduced reactivity of internal acetylides.
Abstract: Density functional calculations and experiments have been carried out to unravel the mechanism of a silvermediated furan formation by oxidative coupling. Various possible reaction paths were considered and the most favorable channel has been identified on the basis of the calculated solvent-corrected Gibbs free-energy profiles. The mechanism represented by this route consists of a radical and a subsequent ionic route. The silver cation has a double role in the mechanism: it is the oxidant in the radical steps and
1. Introduction Oxidative cross-coupling is a new field in current synthetic chemistry.[1] While it is still in its infancy, recent developments represent significant steps toward more economic processes under milder conditions.[2] Catalyzed by transition metals, this class of reactions provides an efficient way for CC-bond formations by CH functionalization. A large variety of transition metals has been proven to be effective in CC coupling reactions, such as Ni, Fe, Cu, Pd, etc.[2, 3, 5, 4] Silver has also been found to be effective in oxidative coupling processes.[5–9] By employing silver salts as an oxidant, very diverse classes of heterocycles have been synthesized, such as quinolines,[6] benzo[b]phosphole oxides,[7] heteroaromatic imidazo[1,2-a]pyridines,[8] or substituted pyrrols.[9] Very recently, an efficient silver-mediated route leading to various polysubstituted furans from terminal alkynes and b-ketoesters has been described by Lei et al. (Scheme 1).[10]
Scheme 1. Silver-mediated oxidative CH/CH functionalization of 1 and 2.
These heterocycles are particularly important from a synthetic point of view because they play a significant role in numerous pharmaceutical and agrochemical processes. In addition, furans and their derivatives are building blocks of various natural products and they can also be found in living organisms.[11] The new synthetic route for polysubstituted furans is a onestep procedure employing a silver-mediated oxidative CC coupling strategy.[10] In this reaction, terminal alkynes and 1,3dicarbonyl compounds are coupled by simultaneous CH functionalizations, and the coupling was shown to be highly selective with good to excellent yields and a very low tendency for homocoupling. Some mechanistic aspects of this intriguing reaction have been addressed by Lei et al.[10] They suggested that the silver– acetylide may be an intermediate of the reaction and that the excess silver salt is necessary for oxidation. On the other hand, employing styrene instead of the terminal alkyne resulted in no cyclization. This indicates that the cyclization does not proceed along a radical route, as opposed to the well-known transition-metal-induced oxidative radical cyclizations of alkenes with 1,3-dicarbonyl compounds.[12] Motivated by the undeniable significance of this protocol and by our recent interest in oxidative coupling reactions, we decided investigate the mechanistic details of this reaction. To this end, we set out to explore several possible pathways leading to the formation of the furan frame. On the basis of the results, we propose a plausible mechanism featuring a radical
[a] J. Daru, Z. Benda Eçtvçs University, Pzmny Pter stny 1/a 1117 Budapest (Hungary) [b] J. Daru, Dr. A. Stirling Institute of Organic Chemistry Research Centre for Natural Sciences of the Hungarian Academy of Sciences Magyar Tudsok Kçrffltja 2, 1117 Budapest (Hungary) E-mail: [email protected] [c] . Pti, Dr. Z. Novk MTA-ELTE “Lendlet” Catalysis and Organic Synthesis Research Group Institute of Chemistry, Eçtvçs University Pzmny Pter stny, 1/a, 1117 Budapest (Hungary) E-mail: [email protected] Homepage: zng.elte.hu Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201404302. Chem. Eur. J. 2014, 20, 1 – 7
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Full Paper and a subsequent ionic-path segment. A few additional experiments were conducted to verify the findings and to provide support for the proposed mechanism.
Radical 1.2 can most likely react with either a phenylacetylene (2) molecule or with its Ag salt 2.1,[13] resulting in the first CC coupling, as depicted in Scheme 2 together with the corresponding free-energy profiles. Along the route leading to the formation of 3.1, the reaction is exergonic by 11.0 kcal 2. Results and Discussion mol1. Similarly, the second path features 12.1 kcal mol1 reaction free energy for the formation of 3.2 with an Ag atom as An important issue in our study is to define the initial (referbyproduct that is assumed to form elementary bulk silver. This ence) free-energy level. Experimentally, the reactants and oxiassumption is in line with the experimental observation of dant are brought together in the solvent, and the solution is a thin silver mirror on the wall of the reaction vessel during stirred at 80 8C under N2 for 12 h. On the basis of various the reaction. The formation of 3.2 has been assumed in dimer-formation energies, we concluded that in the initial restRef. [10] but not been verified. As shown later, this species reping state of this solution the dominant form of Ag + is solvated resents a crucial stage in the mechanism: it separates the radiAg2CO3. The concentration of other possible Ag compounds is cal and ionic phases of the most favorable reaction channel. significantly lower or negligible (see the Supporting InformaAn important difference between the two mechanisms is tion for details). In the free-energy diagrams, the levels are refthe exergonic pre-equilibrium along the second path, which is erenced to this state. It is worth noting that the initial level of shifted toward the formation of silver–phenylacetylide (2.1). the free-energy profiles strongly depends on the solubility of Despite the low solubility of Ag2CO3 and the similar barriers for Ag2CO3, which is an endergonic process. Albeit its extent is unknown, it shifts all the levels uniformly; therefore, it does not CC couplings for 2 and 2.1 (15.0 and 14.3 kcal mol1, respectively), it is more probable that the reaction proceeds via the have any effect on the selection of the mechanism. We indienergetically favored organometallic species 2.1. This conclucate this free-energy investment on the profiles by an initial sion is supported by the experimental observation[10] that the upward dash line. Accordingly, we will also indicate the freeenergy gain at the final portions of the profiles. The base KOAc reaction also yields product 4 from 2.1. The formation of 2.1 is assumed to be in its dissociated form. The difference bein other coupling reactions of terminal alkynes under similar tween the basicity of CO32 and OAc indicates that the pricircumstances has also been proposed and confirmed.[14–16] mary acceptor for protons dissociating from the organic speTherefore, in the following studies, we first focus on pathways cies is the carbonate anion. featuring 2.1. Then, we also investigate a mechanistic alternaThe initial step is necessarily the formation of enolate 1.1 tive in which the terminal hydrogen atom is retained during the reaction. This pathway is compatible with the coupling refrom ethyl acetoacetate 1 by proton transfer to a carbonate anion formed by the dissociation of Ag2CO3, as shown in actions of internal alkynes, thus, we can also study the effect of substituents on the mechanism. Scheme 2. This is an exergonic process by 5.9 kcal mol1. The We note that other possibilities, such as an attack on the non-terminal alkyne carbon atom, CO couplings, as well as CC or CO couplings by the enolate anion preceding the radical formation, have also been considered and safely excluded by their higher barriers and much less favorable reaction free energies. The energy profiles of these routes are collected and discussed in the Supporting Information. Starting from 3.2, four distinct reaction channels can be envisioned. The reaction routes are shown in Schemes 3–6. First, we note that the formation of 3.2 becomes even more favorable in terms of free energy by precipitation of Ag (56.9 kcal mol1). We devised and followed three possible routes starting Scheme 2. Free-energy profile and mechanism for the CC-coupling part. Values are in kcal mol1. from this situation. In the first route (path A), a silver cation assists the ring closure with the carbonyl oxygen atom (Scheme 3). From an AgOAc molecule the silver ion coordinates to 3.2, forming 3.3 with 16.5 kcal further oxidation of 1.1 by an Ag + ion releases an additional mol1 endergonicity. The Ag + ion polarizes the triple bond 11.8 kcal mol1 free energy and yields the enolate radical 1.2. Experiments with TEMPO ((2,2,6,6-tetramethyl-piperidin-1and, thus, facilitates the nucleophilic attack of the carbonyl yl)oxyl) and BHT (3,5-di-tert-butyl-4-hydroxytoluene) supported group. The calculated free-energy barrier of the cyclization is this picture. Although we could not isolate adducts of the uti23.9 kcal mol1, and the formation of intermediate 4.1 is enderlized scavengers and any radical intermediates, we found that gonic by 17.1 kcal mol1 with respect to 3.3. 4.1 then transthe presence of one equivalent of scavenger completely forms to intermediate 4.2 by deprotonation, which results in stopped the transformation. This clearly shows that the reacthe aromatic-ring formation of the furan ring accompanied by tion goes through a radical intermediate. a large free-energy release (57.3 kcal mol1). &
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Scheme 3. Free-energy profile and mechanism for path A. Values are in kcal mol1.
step is considerably favorable by 19.0 kcal mol1. Along path B, the cyclization of 3.4 is, however, endergonic by 16.5 kcal mol1 and has an activation freeenergy barrier of 29.5 kcal mol1. By contrast, the subsequent protonation of intermediate 4.4 represents a strong driving force (24.2 kcal mol1) to complete the reaction, leading to the formation of product 4.
It is sensible to assume that the reaction ends up at this stage and that the acidic workup of the reaction mixture gives rise to product 4 by protonolysis of the organosilver compound. To probe this scenario, we quenched the reaction mixture with both HCl/H2O and DCl/D2O. However, we did not observe deuterium incorporation into the furan ring.[17] This shows that the Scheme 5. Free-energy profile and mechanism for path C. Values are in kcal mol1. protonolysis should occur before the quenching step. Therefore, The presence of a silver cation can further enhance this we followed the reaction path from the transformation of 4.2 mechanism along pathway C (Scheme 5). Enolate 3.4 can form to product 4. an adduct (3.5) with a Ag + ion that is released from a solvated This transformation involves the formation of adduct 4.3 between 4.2 and an acetic acid molecule. This step requires AgOAc molecule. This step is slightly endergonic (6.4 kcal 17.2 kcal mol1 free energy. The protonolysis of the silver–furmol1). The silver-assisted ring closure of 3.5 yielding 4.2 re1 anyl species proceeds through a 9.9 kcal mol free-energy barquires a much lower activation free energy (15.0 kcal mol1) rier and the overall exergonicity of the exchange is 3.0 kcal compared to the formation of 4.4 in path B. In addition, this mol1. step is exergonic with 11.1 kcal mol1. At this point, path C Further calculations revealed that this mechanism can be rejoins path A and after going through intermediate 4.3 and markably improved, as shown by routes B and C. Schemes 4 passing a barrier of 9.9 kcal mol1 it arrives at product 4. In this and 5 displays these pathways with the corresponding freestep, the silver cation is recovered, similarly to path A. It is energy profiles. worth noting that as the reaction proceeds, the concentration The crucial step along these routes is a proton transfer from of Ag + is decreasing; therefore, the transformation 4.2 Ð 4 is shifted toward the product formation. The favorable reaction adduct 3.2 to a carbonate anion, yielding enolate 3.4. This barrier along route C is due to the fact that the aromaticity of the furan group is built in the cyclization step, which is in contrast to path A in which an additional step is necessary for the formation of the aromatic ring. Path C is calculated to be even more effective than path B because the aromatic-ring formation in 4.2 is accompanied by charge recombination, whereas the furan ring in 4.4 on pathway B carries a negative charge. An interesting option for silver assistance is when the ring closure by CO bond formation takes place in the presence of a Ag radical atom, that is, after the formation of intermediate 3.2 and before Ag precipitation (path D, Scheme 6). The formation of 3.2 without Ag precipitation is accompanied by a smaller reaction energy (12.1 kcal mol1). On the one hand, the difference is attributed to the missing Ag precipitation energy Scheme 4. Free-energy profile and mechanism for path B. Values are in kcal and, on the other hand, to the weak association of 3.2 with mol1. Chem. Eur. J. 2014, 20, 1 – 7
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Full Paper mol1 barrier height. The intermediate anion can subsequently form an energetically slightly favored silver-ion complex 3.7. For the final step, we could identify an oxidative ring closure that results in product 4 and silver. This step is characterized by a relatively small activation free energy of 16.3 kcal mol1. We anticipated that substitution of the terminal hydrogen atom to a methyl or phenyl group would remarkably influence the CC coupling step by changing the electron-density distribution on the attacked carbon atom. In fact, experimental observations[10] support this picture: the methyl derivative gave a low (< 10 %) yield, whereas the phenyl derivative yielded only traces of the corresponding product. Our calculated freeenergy profiles shown in Scheme 8 are in good agreement
Scheme 6. Free-energy profile and mechanism for path D. Values are in kcal mol1. The dash–dot line indicates that intermediates between 4.5 and 4 along the segment have not been identified.
a Ag atom. Along path D, the ring closure has to overcome a significant free-energy barrier of 33.8 kcal mol,1 yielding intermediate 4.5 featuring a moderate endergonic reaction free energy (9.9 kcal mol1). Then, 4.5 transforms to product 4 with a significant release of free energy (93.7 kcal mol1). It is worth noting that the route linking 4.5 with product 4 has not been calculated in details because the initial large kinetic barrier highlights that this mechanism is clearly unfavorable. Scheme 7 displays the free-energy profile of the reaction pathway E departing from 3.1. Along this route, the hydrogen atom of the terminal alkyne remains unaffected; therefore, the effect of substitution on the carbon atom of the terminal alkyne can be efficiently probed. The reactivity of internal phenylalkynes has also been tested experimentally,[10] although these processes cannot be considered double CH functionalizations. The mechanism E proceeds via an exergonic deprotonation step (14.0 kcal mol1) through a moderate 18.2 kcal
Scheme 8. Free-energy profiles for the CC-coupling reaction of terminal and two different internal alkynes. Values are in kcal mol1.
with the experiment. We found that the transformation of the internal alkynes proceeds through a higher barrier than that of 2. In addition, they are also less favorable thermodynamically. We also noticed that the order of the activation energies explains qualitatively the experimental substituent effect. Clearly, a slower formation of the CC-coupled intermediates can increase the probability of side reactions and the recombination of radical 1.2, which can appreciably decrease the efficiency of these routes. A comparison of the free-energy profiles shows that the most likely mechanisms are path C and path E. On the basis of the barrier heights, the other routes do not represent kinetically feasible alternatives. Further inspection shows that the equilibrium between 2 and 2.1 favors route C. Indeed, the freeenergy difference between the two states (9.7 kcal mol1) is equivalent to a six order of magnitude difference in concentration at 80 8C. Although the barriers are similar along routes C and E, the much larger initial concentration of 2.1 results in several orders of magnitude faster rate. The most favorable route C involves a radical and an ionic segment. The first radical route features the oxidation of enolate 1 a by a silver cation and the subsequent radical coupling with the Ag salt of phenylacetylene. In the second ionic part, the CO-bond formation takes place to give the furan ring. In this part of the reaction, silver cations play only a catalytic role. The present mechanism is consistent with the picture derived from experimental observations. The calculations clearly demonstrated the twofold role of silver (catalysts and reactant) postulated by Lei et al.[10] In particular, we have shown that silver–acetylide has important roles in the CC coupling: its formation opens a favorable reaction channel for the coupling and provides the oxidizing partner (Ag + ), which transforms the radical mechanism to an ionic one. The calculations have also shown that the cyclization
Scheme 7. Free-energy profile and mechanism for path E. Values are in kcal mol1.
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mechanisms. On these profiles, we will indicate the structures of the stable minima at the corresponding energy levels. For the TSs, only free-energy values are shown and their coordinates are collected in the Supporting Information. An important technical issue is the free-energy contribution of the formation of solid, precipitated Ag in DMF. On the basis of Hess’s law, we calculated it by taking into account the solvation of a Ag atom and the experimental free energy of the Ag(g)!Ag(s) process. The free energy obtained in this way is 56.9 kcal mol1 (see the Supporting Information for additional details). Although this estimation brings some ambiguity into the calculated profiles, the apparent large energy differences allow to identify reliably the most likely mechanism. All calculations have been performed by using the Gaussian package.[20] In the experiments, we have followed and successfully reproduced the protocol described in Ref. [10]. In the radical trapping experiments, we have employed two frequently used radical scavengers: TEMPO ((2,2,6,6-tetramethyl-piperidin-1yl)oxyl) and BHT (3,5-di-tert-butyl-4-hydroxytoluene). Deuterated experiments were followed by MS measurements. Further experimental details are given in the Supporting Information.
3. Conclusion We have carried out a mechanistic study to elucidate the mechanism of a silver-mediated furan formation by oxidative coupling. Density functional calculations and experiments revealed a multistep pathway featuring radical and ionic segments, separated by intermediate 3.2. An important aspect of the most favorable path is that the cyclization is accompanied by the simultaneous build-up of aromaticity. Our findings support and explain several experimental observations. In particular, the mechanism can account for the twofold role of the silver cation: it is a reactant initializing the radical steps and a catalyst for the cyclization and product-formation steps. We have also shown the crucial role of silver–acetylide in the mechanism: its favorable formation under the reaction conditions drives the reaction into the most favorable channel. The calculations also revealed that reactions employing internal alkynes would proceed with less favorable thermodynamics and with higher barriers, which is in accordance with the experiments.
Acknowledgements Support of the “Lendlet” Research Scholarship of the Hungarian Academy of Sciences (LP2012-48/2012), OTKA Grant K101115, TT-10-1-2011-0245 grant and computational resources provided by NIIF Supercomputer Center are acknowledged.
4. Experimental Section Methods The calculations have been performed by employing the M06 exchange–correlation functional.[18] For geometry optimizations and frequency calculations, we have employed the 6-31 + G* basis set for the main-group atoms, whereas for Ag we have used the LanL2DZ basis set completed with a set of polarization and diffuse functions taken from the corresponding augcc-pVDZ-PP basis set. For the optimized structures, the final solvent-corrected energies have been calculated by using the 6-311 + + G(3df,3dp) basis set for the main-group atoms, while the basis of Ag has been taken from the LANL2TZ(f) set augmented with an additional set of polarization and diffuse functions from the aug-cc-pVTZ-PP basis (see the Supporting Information for the details). The optimized intermediates and transition states (TSs) have been tested by frequency calculations. Additional IRC and normal optimization calculations have also been carried out to verify that a calculated TS indeed connects the two corresponding minima. Note that in case of protonolyses, fast pre-equilibria between CH3COOH/CO32 and HCO3/ CH3COO acid–base forms are not discussed but the corresponding free energies are always taken into account. The solvent effects have been taken into account by using the SMD implicit continuum solvation model.[19] The solvent is N,N-dimethylformamide. The Gibbs free-energy contributions to the electronic energy contribution have been calculated by employing the harmonic oscillator, rigid rotor, ideal gas approximation at 80 8C and 1 mol dm3 concentration, and including the solvation free-energy changes. See the Supporting Information for additional details. By using these data, we have constructed the free-energy profiles of the various possible Chem. Eur. J. 2014, 20, 1 – 7
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Q. L. Zhou, J. Am. Chem. Soc. 2007, 129, 12616 – 12617; i) F. M. Dean, in Advances in Heterocyclic Chemistry, Vol. 30 (Ed.: A. R. Katritzky), Academic Press, New York, 1982, pp. 167 – 238; j) F. M. Dean, M. V. Sargent, in Comprehensive Heterocyclic Chemistry, Vol. 4, Part 3 (Eds.: C. W. Bird, G. W. H. Cheeseman), Pergamon Press, New York, 1984, pp. 531 – 598; k) B. H. Lipshutz, Chem. Rev. 1986, 86, 795 – 819. J. Iqbal, B. Bhatia, N. K. Nayyar, Chem. Rev. 1994, 94, 519 – 564. The reaction between 1.2 and 2.1 can be considered as a radical–nucleophile interaction. This interaction is common for radical oxidative couplings; for details, see: a) Q. Liu, R. Jackstell, M. Beller, Angew. Chem. Int. Ed. 2013, 52, 13871 – 13873; Angew. Chem. 2013, 125, 14115 – 14117; b) J. Liu, Q. Liu, H. Yi, C. Qin, R. Bai, X. Qi, Y. Lan, A. Lei, Angew. Chem. Int. Ed. 2014, 53, 502 – 506. J. Liu, Z. Fang, Q. Zhang, Q. Liu, X. Bi, Angew. Chem. Int. Ed. 2013, 52, 6953 – 6957; Angew. Chem. 2013, 125, 7091 – 7095. M. Gao, C. He, H. Chen, R. Bai, B. Cheng, A. Lei, Angew. Chem. Int. Ed. 2013, 52, 6958 – 6961; Angew. Chem. 2013, 125, 7096 – 7099. J. Ke, H. Chuan, H. Liu, M. Lia, A. Lei, Chem. Commun. 2013, 49, 7549 – 7551. Deuterium incorporation could not be observed for reactions starting from either 2 or 2.1. This also underlines the role of 2.1 in the mechanism.
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FULL PAPER & Mechanistic Studies J. Daru, Z. Benda, . Pti, Z. Novk,* A. Stirling* && – &&
Radical or ionic mechanism? Both. The detailed mechanism of a silver-mediated furan formation by oxidative CH/CH activation has been revealed by DFT calculations and additional experiments. The reaction path starts with a radical
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CC coupling process. Then, an aromatic cyclization occurs featuring an ionic mechanism, which completes the furan formation. Silver plays crucial roles in the reaction: it is an oxidant and a catalyst simultaneously.
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