DOI: 10.1002/chem.201500371
Communication
& Tandem Reactions
Tandem Gold/Silver-Catalyzed Cycloaddition/Hydroarylation of 7-Aryl-1,6-enynes to Form 6,6-Diarylbicyclo[3.2.0]heptanes Bradley D. Robertson, Rachel E. M. Brooner, and Ross A. Widenhoefer*[a] mediates in noble metal-catalyzed enyne cycloaddition,[3, 4] most notably in the cycloisomerization of 7-aryl-1,6-enynes to bicyclo[3.2.0]hept-6-enes (Scheme 1).[4] However, in contrast to cyclopropyl carbenoid intermediates, nucleophilic trapping of these intermediates to form bicyclo[3.2.0]heptanes remains undocumented.[5, 6] We recently validated intermediates III through the spectroscopic characterization of complex 1, generated in the goldcatalyzed cycloisomerization of enyne 2 to form bicyclo[3.2.0]hept-6-ene 3 (Scheme 2).[7] Identification of 1 as a local mini-
Abstract: Mixtures of [{PCy2(o-biphenyl)}AuCl] and AgSbF6 catalyze the tandem cycloaddition/hydroarylation of 7aryl-1,6-enynes with electron-rich arenes to form 6,6-diarylbicyclo[3.2.0]heptanes in good yield under mild conditions. Experimental observations point to a mechanism involving gold-catalyzed cycloaddition followed by silvercatalyzed hydroarylation of a bicyclo[3.2.0]hept-1(7)-ene intermediate.
Electrophilic noble metal complexes catalyze the cycloaddition of 1,6-enynes to form a range of products including vinylcyclopentenes, alkylidenecyclohexenes, and/or bicyclo[4.1.0]heptenes,[1] presumably via highly delocalized metal cyclopropyl carbenoid intermediates (I and II; Scheme 1).[1, 2] Alternatively,
Scheme 2. Spectroscopic detection of 1 in the gold-catalyzed conversion of 2 to 3.
Scheme 1. Potential pathways and intermediates for enyne cycloaddition catalyzed by electrophilic noble metal complexes.
these cyclopropyl carbenoid intermediates can be trapped with nucleophiles prior to demetallation to further expand the palette of molecular structures accessible via enyne cycloaddition (Scheme 1).[2] In addition to intermediates I and II, metalstabilized bicycloheptyl cations (III) have been invoked as inter[a] B. D. Robertson, R. E. M. Brooner, Prof. R. A. Widenhoefer French Family Science Center, Duke University Durham, NC 27708–0346 (USA) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500371. Chem. Eur. J. 2015, 21, 5714 – 5717
mum on the reaction coordinate suggested that these intermediates might be susceptible to nucleophilic trapping. Guided by this hypothesis, we have developed and herein report the gold/silver-catalyzed tandem cycloaddition/hydroarylation of 7-aryl-1,6-enynes to form 6,6-diarylbicyclo[3.2.0]heptanes.[8] However, in contrast to our expectations, gold was not involved in the hydroarylation event and, rather, our experimental observations point to a mechanism involving gold-catalyzed cycloaddition followed by silver-catalyzed hydroarylation of a bicyclo[3.2.0]hept-1(7)-ene intermediate. We targeted electron-rich arenes as trapping agents for the gold bicycloheptyl cations generated via enyne cycloaddition owing to the precedence for the hydroarylative trapping of cyclopropyl carbenoid intermediates.[1] In apparent support of our hypotheses, treatment of a 1:2 mixture of enyne 2 and 1,3,5-trimethoxybenzene (TMB) with a catalytic 1:1.1 mixture of [{PCy2(o-biphenyl)}AuCl] (4 a; 5 mol %) and AgSbF6 at 25 8C for 3 h formed bicyclo[3.2.0]heptane 5 a in 82 % yield with 25:1 endo/exo selectivity (Table 1, entry 1). However, subsequent experimentation revealed the critical role of silver in the hydroarylation event, which argued against the hydroarylation of a gold-stabilized bicycloheptyl cation. In particular, reaction of 2 with TMB catalyzed by the silver-free gold complex [{PCy2(obiphenyl)}Au(NCMe)] + SbF6¢ (4 b; 5 mol %) at 25 8C for 6 h formed bicyclo[3.2.0]hept-6-ene 3 in 47 % yield without forma-
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Communication or gold/silver-catalyzed hydroarylation of 3 with TMB confirmed that hydroarylation of 3 was too slow to account for the formation of 5 a in the reaction of 2 with TMB and also established AgSbF6 as a stand-alone catalyst for bicycloheptene hydroarylation [Eq. (1)].
Table 1. Effect of gold, silver, and Brønsted acid on the cycloaddition/hydroarylation of 2 with 1,3,5-trimethoxybenzene (TMB).
Entry 1[b] 2[c] 3[b] 4[c] 5[d] 6[c] 7[c]
Au source 4a 4b 4a 4b none 4b none
Ag [mol %]
HOTf [mol %]
Time [h][a]
3 [%]
5 [%]
5.5 0 20 20 20 0 0
0 0 0 0 0 5 5
3 6 1.5 1.5 24 6 24
2 47 2 2 2 10 2
82 2 90 87 2 73 2
[a] Reaction progress monitored by TLC (unless otherwise stated). [b] Yield of isolated product. [c] Yield determined by 1H NMR analysis. [d] Reaction progress monitored by GC.
tion of detectable quantities of 5 a (Table 1, entry 2). Further increasing the silver loading to 20 mol % in combination with either 4 a or 4 b (5 mol %) further decreased the reaction time to approximately 1.5 h and increased the yield of 5 a (Table 1, entries 3 and 4). Conversely, AgSbF6 alone led to no detectable cycloaddition (Table 1, entry 5). In the presence of a catalytic 1:4 mixture of 4 a (5 mol %) and AgSbF6 (20 mol %), 1,6-enynes possessing a 7-(2-naphthyl) (6 a) or 7-(3,5-dimethylphenyl) (6 b) group, 4,4-gem-acetoxymethyl (6 c) or acetonide (6 d) groups, a 3-methyl (6 e) or 3phenyl (6 f) group, or 3,3-gem-dimethyl (6 g) groups underwent efficient gold/silver-catalyzed cycloaddition/hydroarylation with TMB to form the corresponding bicycloheptanes 7 a– g in 64–86 % yield with 25:1 endo/exo selectivity (Table 2, entries 1–7). In addition to TMB, a number of mono-, di-, and trisubstituted arenes underwent gold/silver-catalyzed cycloaddition/hydroarylation with 2 to form 6,6-diarylbicycloheptanes 5 b–g in > 80 % yield as mixtures of endo/exo diastereomers ranging from 1:7 in the case of 2,6-di-tert-butylphenol to 25:1 in the case of 3,5-dimethoxytoluene (Table 2, entries 9– 13). A number of additional experiments employing 2 and 1,3,5trimethoxybenzene (TMB) were performed to further clarify the role of silver and the nature of the intermediates involved in the hydroarylation event of catalytic cycloaddition/hydroarylation. For example, periodic analysis of the gold/silver-catalyzed cycloaddition/hydroarylation of 2 with TMB revealed that 3 accumulated slowly throughout the reaction, reaching a maximum relative concentration of approximately 6 % at 90 % conversion,[9] which is inconsistent with the intermediacy of 3 in the conversion of 2 to 5 a. Independent analysis of the silverChem. Eur. J. 2015, 21, 5714 – 5717
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Rather, hydroarylation of the bicyclo[3.2.0]hept-1(7)-ene intermediate 8 was implicated through the gold/silver-catalyzed reaction of 2 with 2,4,6-trideutero-1,3,5-trimethoxybenzene ([D3]TMB; 97 % deuterium incorporation), which formed [D3]5 a with approximately 75 % deuterium incorporation at the C1 bridgehead position without detectable deuteration at C7 (Schemes 3 and 4). Owing to the potential generation of Brønsted acid from gold/silver mixtures[10] and the recent demonstration of gold/ Brønsted acid tandem catalysis,[11, 12] we evaluated the potential role of Brønsted acid in gold/silver-catalyzed enyne cycloaddition/hydroarylation. Indeed, treatment of 2 and TMB with a 1:1 mixture of 4 b and HOTf for 6 h at 25 8C formed 5 a in 73 % yield and 3 in 10 % yield (by 1H NMR analysis; Table 1, entry 6). Periodic analysis of a similar reaction mixture revealed that the relative concentration of 3 increased to approximately 20 % after 56 % conversion and then decreased to approximately 10 % at 95 % conversion, suggesting competitive hydroarylation of both 8 and 3.[9]
Scheme 3. Gold/silver-catalyzed hydroarylation of 2,4,6-trideutero-1,3,5-trimethoxybenzene ([D3]TMB).
Scheme 4. Proposed mechanism for the conversion of 2 and TMB to 5 a via gold/silver tandem catalysis.
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Communication Furthermore, the greater efficacy of AgSbF6 as a hydroarylation catalyst, even with only Entry Enyne Arene Product (yield [%])[a] endo/exo[b] 0.1 mol % excess relative to 4 a (Table 1, entry 2), as compared to HOTf (5 mol %) appears incongruent with hidden Brønsted acid catalysis in the former 1 6 a (Ar = 2-naphthyl) 7 a (84 %) 25:1 case.[13] We therefore propose 7 b (84 %) 25:1 2 6 b (Ar = 3,5-C6H5Me2) a mechanism for the cycloaddition/hydroarylation of 2 with TMB involving gold-catalyzed cycloaddition of 2 followed by 3 6 c [X = C(CH2OAc)2] 7 c (80 %) 25:1 silver-catalyzed hydroarylation of 7 d (64 %) 25:1 4 8, presumably via a silver-stabilized bicycloheptyl cation (Scheme 4). In this context, it is worth noting that although there is a growing body of work 5 6 e (R1 = Me, R2 = H) 7 e (79 %; 2:1)[c] 25:1 that documents the ability of 1 2 [c] 7 f (86 %; 3:1) 25:1 6 6 f (R = Ph, R = H) silver salts to affect the out1 2 7 g (77 %) 25:1 7 6 g (R = R = Me) comes of gold(I)-catalyzed transformations,[14, 15] in only one case have gold and silver been 2 shown to function orthogonally 8 R = Me 5 b (85 %) 1:1.8 in two discrete steps of 9 R=H 5 c (83 %) 1:2.5 a tandem catalytic process in which the silver salt functions as a simple Lewis acid for carbonyl activation.[16, 17] 2 In summary, we have devel10 R = Me 5 d (85 %) 1:1.3 oped an effective tandem gold/ 11 R=H 5 e (72 %) 1:3.6 silver-catalyzed protocol for the cycloaddition/hydroarylation of 12 1:7 7-aryl-1,6-enynes to form 6,6-dia2 rylbicyclo[3.2.0]heptanes.[8] Our 5 f (86 %) experimental observations regarding the gold/silver-catalyzed 13 25:1 cycloaddition/hydroarylation of 2 with TMB point to a mecha2 5 g (88 %) nism involving sequential gold[a] Yield of product isolated in > 95 % purity. [b] endo/exo ratio determined by 1H NMR analysis of the crude recatalyzed conversion of 2 to 8 action mixture. [c] Mixture of C2 diastereomers. followed by silver-catalyzed hydroarylation of 8. These transformations represent the first examples involving efficient trapping of the bicyclo[3.2.0]heptAlthough the experiments described in the preceding para1(7)-ene intermediate generated via enyne cycloaddition to graph established the viability of Brønsted acid-catalyzed pathgenerate functionalized bicyclo[3.2.0]heptanes. ways for bicycloheptene hydroarylation, the relevance of these pathways to the gold/silver-catalyzed cycloaddition/hydroarylation of 2 is not clear. We previously established the participaAcknowledgements tion of Brønsted acid in the gold-catalyzed cycloisomerization of 2 to 3, specifically the isomerization of 8 to 3.[12] However, We acknowledge the NSF (CHE-1213957) for support of this resilver was not the apparent source of Brønsted acid in these search. transformations and rather, silver inhibited the conversion of 1 to 3. Similarly, attempts to generate Brønsted acid in the Keywords: aromatic substitution · cycloaddition · enynes · gold/silver-catalyzed reaction of 2 with TMB through addition gold · silver of catalytic amounts of water led to inhibition of the reaction. Table 2. Cycloaddition/hydroarylation of 7-aryl-1,6-enynes catalyzed by a mixture of 4 a (5 mol %) and AgSbF6 (20 mol %) in CH2Cl2 at 25 8C for 1.5 h [Z = C(CO2Me)2].
Chem. Eur. J. 2015, 21, 5714 – 5717
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Communication [1] For recent reviews on gold(I)-catalyzed enyne cycloaddition see: a) C. Obradors, A. M. Echavarren, Acc. Chem. Res. 2014, 47, 902 – 912; b) A. Fìrstner, Acc. Chem. Res. 2014, 47, 925 – 938; c) P. Y. Toullec, V. Michelet, Top. Curr. Chem. 2011, 302, 31 – 80; d) A. M. Echavarren, E. Jim¦nezNfflÇez, Top. Catal. 2010, 53, 924 – 930; e) A. Fìrstner, Chem. Soc. Rev. 2009, 38, 3208 – 3221; f) E. Jim¦nez-NfflÇez, A. M. Echavarren, Chem. Rev. 2008, 108, 3326 – 3350; g) V. Michelet, P. Y. Toullec, J. P. GenÞt, Angew. Chem. Int. Ed. 2008, 47, 4268 – 4315; Angew. Chem. 2008, 120, 4338 – 4386. [2] A. Fìrstner, H. Szillat, B. Gabor, R. Mynott, J. Am. Chem. Soc. 1998, 120, 8305 – 8314. [3] a) F. Marion, J. Coulomb, C. Courillon, L. Fensterbank, M. Malacria, Org. Lett. 2004, 6, 1509 – 1511; b) S. Couty, C. Meyer, J. Cossy, Angew. Chem. Int. Ed. 2006, 45, 6726 – 6730; Angew. Chem. 2006, 118, 6878 – 6882; c) S. I. Lee, S. M. Kim, M. R. Choi, S. Y. Kim, Y. K. Chung, W.-S. Han, S. O. Kang, J. Org. Chem. 2006, 71, 9366 – 9372. [4] a) A. Escribano-Cuesta, P. P¦rez-Galn, E. Herrero-Gûmez, M. Sekine, A. A. C. Braga, F. Maseras, A. M. Echavarren, Org. Biomol. Chem. 2012, 10, 6105 – 6111; b) K. Ota, S. I. Lee, J. M. Tang, M. Takachi, H. Nakai, T. Morimoto, H. Sakurai, K. Kataoka, N. Chatani, J. Am. Chem. Soc. 2009, 131, 15203 – 15211; c) C. Nieto-Oberhuber, P. P¦rez-Galn, E. Herrero-Gûmez, T. Lauterbach, C. Rodrguez, S. Lûpez, C. Bour, A. Rosellûn, D. J. Crdenas, A. M. Echavarren, J. Am. Chem. Soc. 2008, 130, 269 – 279; d) T. Matsuda, S. Kadowaki, T. Goya, M. Murakami, Synlett 2006, 575 – 578; e) C. Nieto-Oberhuber, S. Lûpez, A. M. Echavarren, J. Am. Chem. Soc. 2005, 127, 6178 – 6179; f) A. Fìrstner, P. W. Davies, T. Gress, J. Am. Chem. Soc. 2005, 127, 8244 – 8245; g) Y. T. Lee, Y. K. Kang, Y. K. Chung, J. Org. Chem. 2009, 74, 7922 – 7934. [5] Two related processes involving trapping of gold-stabilized g-cyclobutylallyl cations have been demonstrated in the cycloaddition of alkylidene cyclopropanes: a) S. G. Sethofer, S. T. Staben, O. Y. Hung, F. D. Toste, Org. Lett. 2008, 10, 4315 – 4318; b) H. C. Zheng, R. J. Felix, M. R. Gagn¦, Org. Lett. 2014, 16, 2272 – 2275. [6] Oxidative trapping of bicyclo[3.2.0]hept-1(7)-enes with cyclobutyl ring opening has been reported: a) J. Blum, H. Beer-Kraft, Y. Badrieh, J. Org. Chem. 1995, 60, 5567 – 5569; b) D. V. Patil, H.-S. Park, J. Koo, J. W. Han, S. Shin, Chem. Commun. 2014, 50, 12722 – 12725. [7] R. E. M. Brooner, T. J. Brown, R. A. Widenhoefer, Angew. Chem. Int. Ed. 2013, 52, 6259 – 6261; Angew. Chem. 2013, 125, 6379 – 6381. [8] For a review of biologically active bicyclo[3.2.0]heptanes see: M. Miesch, Curr. Org. Synth. 2006, 3, 327 – 340. [9] See the Supporting Information.
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[10] a) J. R. Cabrero-Antonino, A. Leyva-P¦rez, A. Corma, Chem. Eur. J. 2013, 19, 8627 – 8633; b) R. E. M. Brooner, R. A. Widenhoefer, Chem. Eur. J. 2011, 17, 6170 – 6178; c) O. Kanno, W. Kuriyama, Z. J. Wang, F. D. Toste, Angew. Chem. Int. Ed. 2011, 50, 9919 – 9922; Angew. Chem. 2011, 123, 10093 – 10096; d) T. T. Dang, F. Boeck, L. Hintermann, J. Org. Chem. 2011, 76, 9353 – 9361; e) J. G. Taylor, L. A. Adrio, K. K. Hii, Dalton Trans. 2010, 39, 1171 – 1175; f) C. H. Cheon, O. Kanno, F. D. Toste, J. Am. Chem. Soc. 2011, 133, 12875 – 12879. [11] a) X. Wu, M.-L. Li, P.-s. Wang, J. Org. Chem. 2014, 79, 419 – 425; b) D. Qian, J. Zhang, Chem. Eur. J. 2013, 19, 6984 – 6988; c) Z.-Y. Han, H. Xiao, X.-H. Chen, L.-Z. Gong, J. Am. Chem. Soc. 2009, 131, 9182 – 9183; d) Y. Horino, Y. Takahashi, Y. Nakashima, H. Abe, RSC Adv. 2014, 4, 6215 – 6218; e) H. Wu, Y.-P. He, L.-Z. Gong, Adv. Synth. Catal. 2012, 354, 975 – 980. [12] R. E. M. Brooner, B. D. Robertson, R. A. Widenhoefer, Organometallics 2014, 33, 6466 – 6473. [13] This outcome would require generation of stronger acid from gold/ silver mixtures as compared to gold/HOTf mixtures, but acid strength in both cases should be levelled by the presence of Brønsted bases. [14] a) M. A. Tarselli, A. R. Chianese, S. J. Lee, M. R. Gagn¦, Angew. Chem. Int. Ed. 2007, 46, 6670 – 6673; Angew. Chem. 2007, 119, 6790 – 6793; b) H. Li, R. A. Widenhoefer, Org. Lett. 2009, 11, 2671 – 2674; c) D. W. Wang, R. Cai, S. Sharma, J. Jirak, S. K. Thummanapelli, N. G. Akhmedov, H. Zhang, X. B. Liu, J. L. Petersen, X. D. Shi, J. Am. Chem. Soc. 2012, 134, 9012 – 9019; d) Y. J. Su, Y. W. Zhang, N. G. Akhmedov, J. L. Petersen, X. D. Shi, Org. Lett. 2014, 16, 2478 – 2481; e) A. Homs, I. Escofet, A. M. Echavarren, Org. Lett. 2013, 15, 5782 – 5785; f) F. Schrçder, C. Tugny, E. Salanouve, H. Clavier, L. Giordano, D. Moraleda, Y. Gimbert, V. MouriÀs-Mansuy, J. P. Goddard, L. Fensterbank, Organometallics 2014, 33, 4051 – 4056. [15] a) D. Weber, M. R. Gagn¦, Org. Lett. 2009, 11, 4962 – 4965; b) Y. Y. Zhu, C. S. Day, L. Zhang, K. J. Hauser, A. C. Jones, Chem. Eur. J. 2013, 19, 12264 – 12271; c) S. G. Weber, F. Rominger, B. F. Straub, Eur. J. Inorg. Chem. 2012, 2863 – 2867. [16] Y. P. Xiao, X. Y. Liu, C. M. Che, Beilstein J. Org. Chem. 2011, 7, 1100 – 1107. [17] For additional examples of tandem gold/Lewis acid-catalyzed transformations, see: a) X. Wang, S. Dong, Z. Yao, L. Feng, P. Daka, H. Wang, Z. Xu, Org. Lett. 2014, 16, 22 – 25; b) Y. Xi, D. Wang, X. Ye, N. G. Akhmedov, J. L. Petersen, X. Shi, Org. Lett. 2014, 16, 306 – 309; c) X. Wang, Z. Yao, S. Dong, F. Wei, H. Wang, Z. Xu, Org. Lett. 2013, 15, 2234 – 2237. Received: January 28, 2015 Published online on March 4, 2015
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Communication
& Tandem Reactions
Tandem Gold/Silver-Catalyzed Cycloaddition/Hydroarylation of 7-Aryl-1,6-enynes to Form 6,6-Diarylbicyclo[3.2.0]heptanes Bradley D. Robertson, Rachel E. M. Brooner, and Ross A. Widenhoefer*[a] mediates in noble metal-catalyzed enyne cycloaddition,[3, 4] most notably in the cycloisomerization of 7-aryl-1,6-enynes to bicyclo[3.2.0]hept-6-enes (Scheme 1).[4] However, in contrast to cyclopropyl carbenoid intermediates, nucleophilic trapping of these intermediates to form bicyclo[3.2.0]heptanes remains undocumented.[5, 6] We recently validated intermediates III through the spectroscopic characterization of complex 1, generated in the goldcatalyzed cycloisomerization of enyne 2 to form bicyclo[3.2.0]hept-6-ene 3 (Scheme 2).[7] Identification of 1 as a local mini-
Abstract: Mixtures of [{PCy2(o-biphenyl)}AuCl] and AgSbF6 catalyze the tandem cycloaddition/hydroarylation of 7aryl-1,6-enynes with electron-rich arenes to form 6,6-diarylbicyclo[3.2.0]heptanes in good yield under mild conditions. Experimental observations point to a mechanism involving gold-catalyzed cycloaddition followed by silvercatalyzed hydroarylation of a bicyclo[3.2.0]hept-1(7)-ene intermediate.
Electrophilic noble metal complexes catalyze the cycloaddition of 1,6-enynes to form a range of products including vinylcyclopentenes, alkylidenecyclohexenes, and/or bicyclo[4.1.0]heptenes,[1] presumably via highly delocalized metal cyclopropyl carbenoid intermediates (I and II; Scheme 1).[1, 2] Alternatively,
Scheme 2. Spectroscopic detection of 1 in the gold-catalyzed conversion of 2 to 3.
Scheme 1. Potential pathways and intermediates for enyne cycloaddition catalyzed by electrophilic noble metal complexes.
these cyclopropyl carbenoid intermediates can be trapped with nucleophiles prior to demetallation to further expand the palette of molecular structures accessible via enyne cycloaddition (Scheme 1).[2] In addition to intermediates I and II, metalstabilized bicycloheptyl cations (III) have been invoked as inter[a] B. D. Robertson, R. E. M. Brooner, Prof. R. A. Widenhoefer French Family Science Center, Duke University Durham, NC 27708–0346 (USA) E-mail: [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201500371. Chem. Eur. J. 2015, 21, 5714 – 5717
mum on the reaction coordinate suggested that these intermediates might be susceptible to nucleophilic trapping. Guided by this hypothesis, we have developed and herein report the gold/silver-catalyzed tandem cycloaddition/hydroarylation of 7-aryl-1,6-enynes to form 6,6-diarylbicyclo[3.2.0]heptanes.[8] However, in contrast to our expectations, gold was not involved in the hydroarylation event and, rather, our experimental observations point to a mechanism involving gold-catalyzed cycloaddition followed by silver-catalyzed hydroarylation of a bicyclo[3.2.0]hept-1(7)-ene intermediate. We targeted electron-rich arenes as trapping agents for the gold bicycloheptyl cations generated via enyne cycloaddition owing to the precedence for the hydroarylative trapping of cyclopropyl carbenoid intermediates.[1] In apparent support of our hypotheses, treatment of a 1:2 mixture of enyne 2 and 1,3,5-trimethoxybenzene (TMB) with a catalytic 1:1.1 mixture of [{PCy2(o-biphenyl)}AuCl] (4 a; 5 mol %) and AgSbF6 at 25 8C for 3 h formed bicyclo[3.2.0]heptane 5 a in 82 % yield with 25:1 endo/exo selectivity (Table 1, entry 1). However, subsequent experimentation revealed the critical role of silver in the hydroarylation event, which argued against the hydroarylation of a gold-stabilized bicycloheptyl cation. In particular, reaction of 2 with TMB catalyzed by the silver-free gold complex [{PCy2(obiphenyl)}Au(NCMe)] + SbF6¢ (4 b; 5 mol %) at 25 8C for 6 h formed bicyclo[3.2.0]hept-6-ene 3 in 47 % yield without forma-
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Communication or gold/silver-catalyzed hydroarylation of 3 with TMB confirmed that hydroarylation of 3 was too slow to account for the formation of 5 a in the reaction of 2 with TMB and also established AgSbF6 as a stand-alone catalyst for bicycloheptene hydroarylation [Eq. (1)].
Table 1. Effect of gold, silver, and Brønsted acid on the cycloaddition/hydroarylation of 2 with 1,3,5-trimethoxybenzene (TMB).
Entry 1[b] 2[c] 3[b] 4[c] 5[d] 6[c] 7[c]
Au source 4a 4b 4a 4b none 4b none
Ag [mol %]
HOTf [mol %]
Time [h][a]
3 [%]
5 [%]
5.5 0 20 20 20 0 0
0 0 0 0 0 5 5
3 6 1.5 1.5 24 6 24
2 47 2 2 2 10 2
82 2 90 87 2 73 2
[a] Reaction progress monitored by TLC (unless otherwise stated). [b] Yield of isolated product. [c] Yield determined by 1H NMR analysis. [d] Reaction progress monitored by GC.
tion of detectable quantities of 5 a (Table 1, entry 2). Further increasing the silver loading to 20 mol % in combination with either 4 a or 4 b (5 mol %) further decreased the reaction time to approximately 1.5 h and increased the yield of 5 a (Table 1, entries 3 and 4). Conversely, AgSbF6 alone led to no detectable cycloaddition (Table 1, entry 5). In the presence of a catalytic 1:4 mixture of 4 a (5 mol %) and AgSbF6 (20 mol %), 1,6-enynes possessing a 7-(2-naphthyl) (6 a) or 7-(3,5-dimethylphenyl) (6 b) group, 4,4-gem-acetoxymethyl (6 c) or acetonide (6 d) groups, a 3-methyl (6 e) or 3phenyl (6 f) group, or 3,3-gem-dimethyl (6 g) groups underwent efficient gold/silver-catalyzed cycloaddition/hydroarylation with TMB to form the corresponding bicycloheptanes 7 a– g in 64–86 % yield with 25:1 endo/exo selectivity (Table 2, entries 1–7). In addition to TMB, a number of mono-, di-, and trisubstituted arenes underwent gold/silver-catalyzed cycloaddition/hydroarylation with 2 to form 6,6-diarylbicycloheptanes 5 b–g in > 80 % yield as mixtures of endo/exo diastereomers ranging from 1:7 in the case of 2,6-di-tert-butylphenol to 25:1 in the case of 3,5-dimethoxytoluene (Table 2, entries 9– 13). A number of additional experiments employing 2 and 1,3,5trimethoxybenzene (TMB) were performed to further clarify the role of silver and the nature of the intermediates involved in the hydroarylation event of catalytic cycloaddition/hydroarylation. For example, periodic analysis of the gold/silver-catalyzed cycloaddition/hydroarylation of 2 with TMB revealed that 3 accumulated slowly throughout the reaction, reaching a maximum relative concentration of approximately 6 % at 90 % conversion,[9] which is inconsistent with the intermediacy of 3 in the conversion of 2 to 5 a. Independent analysis of the silverChem. Eur. J. 2015, 21, 5714 – 5717
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Rather, hydroarylation of the bicyclo[3.2.0]hept-1(7)-ene intermediate 8 was implicated through the gold/silver-catalyzed reaction of 2 with 2,4,6-trideutero-1,3,5-trimethoxybenzene ([D3]TMB; 97 % deuterium incorporation), which formed [D3]5 a with approximately 75 % deuterium incorporation at the C1 bridgehead position without detectable deuteration at C7 (Schemes 3 and 4). Owing to the potential generation of Brønsted acid from gold/silver mixtures[10] and the recent demonstration of gold/ Brønsted acid tandem catalysis,[11, 12] we evaluated the potential role of Brønsted acid in gold/silver-catalyzed enyne cycloaddition/hydroarylation. Indeed, treatment of 2 and TMB with a 1:1 mixture of 4 b and HOTf for 6 h at 25 8C formed 5 a in 73 % yield and 3 in 10 % yield (by 1H NMR analysis; Table 1, entry 6). Periodic analysis of a similar reaction mixture revealed that the relative concentration of 3 increased to approximately 20 % after 56 % conversion and then decreased to approximately 10 % at 95 % conversion, suggesting competitive hydroarylation of both 8 and 3.[9]
Scheme 3. Gold/silver-catalyzed hydroarylation of 2,4,6-trideutero-1,3,5-trimethoxybenzene ([D3]TMB).
Scheme 4. Proposed mechanism for the conversion of 2 and TMB to 5 a via gold/silver tandem catalysis.
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Communication Furthermore, the greater efficacy of AgSbF6 as a hydroarylation catalyst, even with only Entry Enyne Arene Product (yield [%])[a] endo/exo[b] 0.1 mol % excess relative to 4 a (Table 1, entry 2), as compared to HOTf (5 mol %) appears incongruent with hidden Brønsted acid catalysis in the former 1 6 a (Ar = 2-naphthyl) 7 a (84 %) 25:1 case.[13] We therefore propose 7 b (84 %) 25:1 2 6 b (Ar = 3,5-C6H5Me2) a mechanism for the cycloaddition/hydroarylation of 2 with TMB involving gold-catalyzed cycloaddition of 2 followed by 3 6 c [X = C(CH2OAc)2] 7 c (80 %) 25:1 silver-catalyzed hydroarylation of 7 d (64 %) 25:1 4 8, presumably via a silver-stabilized bicycloheptyl cation (Scheme 4). In this context, it is worth noting that although there is a growing body of work 5 6 e (R1 = Me, R2 = H) 7 e (79 %; 2:1)[c] 25:1 that documents the ability of 1 2 [c] 7 f (86 %; 3:1) 25:1 6 6 f (R = Ph, R = H) silver salts to affect the out1 2 7 g (77 %) 25:1 7 6 g (R = R = Me) comes of gold(I)-catalyzed transformations,[14, 15] in only one case have gold and silver been 2 shown to function orthogonally 8 R = Me 5 b (85 %) 1:1.8 in two discrete steps of 9 R=H 5 c (83 %) 1:2.5 a tandem catalytic process in which the silver salt functions as a simple Lewis acid for carbonyl activation.[16, 17] 2 In summary, we have devel10 R = Me 5 d (85 %) 1:1.3 oped an effective tandem gold/ 11 R=H 5 e (72 %) 1:3.6 silver-catalyzed protocol for the cycloaddition/hydroarylation of 12 1:7 7-aryl-1,6-enynes to form 6,6-dia2 rylbicyclo[3.2.0]heptanes.[8] Our 5 f (86 %) experimental observations regarding the gold/silver-catalyzed 13 25:1 cycloaddition/hydroarylation of 2 with TMB point to a mecha2 5 g (88 %) nism involving sequential gold[a] Yield of product isolated in > 95 % purity. [b] endo/exo ratio determined by 1H NMR analysis of the crude recatalyzed conversion of 2 to 8 action mixture. [c] Mixture of C2 diastereomers. followed by silver-catalyzed hydroarylation of 8. These transformations represent the first examples involving efficient trapping of the bicyclo[3.2.0]heptAlthough the experiments described in the preceding para1(7)-ene intermediate generated via enyne cycloaddition to graph established the viability of Brønsted acid-catalyzed pathgenerate functionalized bicyclo[3.2.0]heptanes. ways for bicycloheptene hydroarylation, the relevance of these pathways to the gold/silver-catalyzed cycloaddition/hydroarylation of 2 is not clear. We previously established the participaAcknowledgements tion of Brønsted acid in the gold-catalyzed cycloisomerization of 2 to 3, specifically the isomerization of 8 to 3.[12] However, We acknowledge the NSF (CHE-1213957) for support of this resilver was not the apparent source of Brønsted acid in these search. transformations and rather, silver inhibited the conversion of 1 to 3. Similarly, attempts to generate Brønsted acid in the Keywords: aromatic substitution · cycloaddition · enynes · gold/silver-catalyzed reaction of 2 with TMB through addition gold · silver of catalytic amounts of water led to inhibition of the reaction. Table 2. Cycloaddition/hydroarylation of 7-aryl-1,6-enynes catalyzed by a mixture of 4 a (5 mol %) and AgSbF6 (20 mol %) in CH2Cl2 at 25 8C for 1.5 h [Z = C(CO2Me)2].
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