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Highly Diastereoselective Palladium-Catalyzed Oxidative Carbocyclization of Enallenes Assisted by a Weakly Coordinating Hydroxyl Group Daniels Posevins, Youai Qiu, and Jan-E. Bäckvall J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b13563 • Publication Date (Web): 09 Feb 2018 Downloaded from http://pubs.acs.org on February 9, 2018
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Journal of the American Chemical Society
Highly Diastereoselective Palladium-Catalyzed Oxidative Carbocyclization of Enallenes Assisted by a Weakly Coordinating Hydroxyl Group Daniels Posevins, Youai Qiu,* and Jan-E. Bäckvall* Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University, SE-106 91 Stockholm, Sweden
Supporting Information ABSTRACT: A highly diastereoselective palladium-catalyzed oxidative carbocyclization-borylation of enallenes assisted by a weakly coordinating hydroxyl group was developed. The reaction afforded functionalized cyclohexenol derivatives, in which the 1,3-relative stereochemistry is controlled (d.r. >50:1). Other weakly coordinating oxygen-containing groups (ketone, alkoxide, acetate) also assisted the carbocyclization towards cyclohexenes. The reaction proceeds via a ligand exchange on Pd of the weakly coordinating group with a distant olefin group. The high diastereoselectivity of the hydroxyl-directed reaction could be rationalized by a face-selective coordination of the distant olefin. It was demonstrated that the primary coordination of the close-by oxygen-containing functionality was necessary for the reaction to occur and removal of this functionality shut down the reaction. Palladium catalyzed C–H bond functionalization utilizing various directing groups has recently emerged as an effective and step-economical approach towards selective formation of carbon-carbon and carbon-heteroatom bonds.1 Compared to the widely developed chelation-assisted C–H activation, in the presence of e.g. pyridyl, amino, or amido groups, the use of weakly coordinating moieties has been challenging, which is mainly due to the less efficient formation of the key cyclopalladation intermediate.2 In particular, the examples that include the use of hydroxyl/carbonyl functionalities as directing groups are still limited, even though these functional groups occur in a wide range of natural products, as well as in many pharmaceutical ingredients. A few elegant examples of new methodologies utilizing hydroxyl/carbonyl groups as assisting groups for promoting the C–H bond cleavage have recently been reported.3,4 For example palladium-catalyzed C(sp2)–H functionalization, that relies on the use of hydroxyl as a directing group was recently reported by Yu.3c,e,f It was demonstrated, that the reaction of A to B proceeds via an arylpalladium(II) intermediate Int-A generated through a C(sp2)–H bond cleavage, which was directed by a weakly coordinating hydroxyl group (Scheme 1a).3c On the basis of these observations and our long-term interest in Pd(II)-catalyzed oxidative carbocyclization5,6 of allenes containing various C-C π-bond moieties,7-10 we were particularly interested in palladium-catalyzed selective carbocyclization of enallene 1 bearing a hydroxyl. An important question to answer is whether a weakly coordinating group, such as a hydroxyl group, would be able to trigger the allene attack on palladium resulting in intermediate Int-B. Previously, it was shown that more strongly coordinating ligands, e.g. an olefin or acetylene,7f,h,9c were required for this activation of the allene. Furthermore, and more importantly, we
Scheme 1. Previous Work and Proposal for this Work
envisioned that diastereoselective intramolecular ligand exchange between the hydroxyl group and the olefin may occur, leading to formation of a stereodefined and valuable borylated carbocyclization product 211,12 with two chiral centers in a 1,3-relationship (Scheme 1b). Control of diastereoselectivity of the process would be of great importance13 and would lead to valuable products. Based on this concept, we initially chose a readily accessible enallene 1a as the standard substrate. When 1a was treated with Pd(OAc)2 (5 mol%), B2pin2 (1.3 equiv), and BQ (p-benzoquinone) (1.1 equiv) in THF at room temperature for 12 h (Scheme 2a) carbocyclization product 2a was obtained in 62% yield as a single diastereoisomer. Analysis of the crude reaction mixture by NMR showed a d.r. >50:1 for 2. To further demonstrate the necessity of the assisting hydroxyl group in the substrate 1a, we performed a control experiment using substrate 1ab lacking the hydroxyl group in the β-position of the allene moiety (Scheme 2b). When substrate 1ab was subjected to the same reaction conditions as in Scheme 2a the corresponding six-membered ring product 2ab was formed in 50:1 d.r. trans-/cis-).15 To our delight, cyclopropyl-substituted (R1) allene also underwent the carbocyclization-borylation reaction under the optimized reaction conditions to afford the desired product 2e in 70% yield. Cyclopentylidene and cyclohexylidene allenes 1f and 1g were also found to be viable substrates in this transformation and afforded cyclohexene derivatives 2f and 2g in good yields (65% and 66%, respectively) with excellent diastereoselectivity. Further studies of the substrate scope revealed, that substrates bearing phenyl or naphthyl groups on the allene moiety are also tolerated, hence products 2h and 2i were both obtained in 86% yields. Finally, the reaction of enallenes containing tertiary alcohol assisting groups provided the borylated cyclohexene derivatives 2j and 2k in good yields with slightly decreased diastereomeric ratios (20:1 and 10:1, respectively). Substrates with one extra methylene unit between the hydroxyl group and the olefin failed to provide the desired cyclized seven-membered ring product 2l, probably due to the inability to produce the corresponding olefin-chelated vinyl-palladium intermediate (analogous to Int-C in Scheme 1b). Scheme 3. Scope of Hydroxyl-assisted Palladium-catalyzed Oxidative Carbocyclizationa
Entry
Catalyst
Solvent
Yield of 2a (%)b
Recovery of 1a (%)b
1
Pd(OAc)2
THF
62
-
2
Pd(OAc)2
Toluene
25
32
3
Pd(OAc)2
Dioxane
65
-
4
Pd(OAc)2
MeCN
10
65
5
Pd(OAc)2
acetone
72
11
6
Pd(OAc)2
MeOH
59
10
7
Pd(OAc)2
DCM
79
-
8
Pd(OAc)2
PhCl
81
-
9
Pd(OAc)2
DCE
88
-
10
Pd(TFA)2
DCE
42
31
11
Pd(OPiv)2
DCE
68
-
DCE
8
76
12 13c
Pd(OAc)2
DCE
28
25
14
d
Pd(OAc)2
DCE
53
20
15
e
Pd(OAc)2
DCE
72
-
a
The reaction was conducted in the indicated solvent (2 mL) at room temperature using 1a (0.2 mmol), B2pin2 (1.3 equiv), BQ (1.1 equiv) in the presence of Pd catalyst (5 mol%). b Determined by NMR using anisole as the internal standard. c F4-BQ was used
a
The reaction was conducted in DCE (2 mL) at room temperature using 1 (0.2 mmol), B2pin2 (1.3 equiv), BQ (1.1 equiv) in the presence of Pd(OAc)2 (5 mol%). b Complex mixture.
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Journal of the American Chemical Society It is worth noting, that in addition to carbocyclizationborylation (Scheme 3), phenylboronic acid can also be used as a transmetallating agent under similar reaction conditions to afford the carbocyclization-arylation product 3a in 57% yield and excellent diastereoselectivity (eq 1).
To demonstrate the synthetic utility of the newly developed transformation, enallene 1a (1.04 g) was converted to the corresponding cyclohexene derivative 2a (1.47 g, 88%) on gram scale (Scheme 6). Subsequent oxidation of the boronic ester functionality of 2a using NaBO3.H2O afforded the diol product 6 as a single diastereoisomer in 91% yield.18 Scheme 6. Gram Scale Synthesis of 2a and its Further Transformation to 6
To gain further insight into the possible role of the weakly coordinating hydroxyl group in the transformations in Scheme 3, we examined the reactivity of enallenes 1ac, 1ad and 1ae, in which the hydroxyl functionality is replaced by an acetoxy, methoxy or tert-butyldimethylsilyloxy (OTBS) group, respecttively (Scheme 4).16 In all three cases the desired carbocyclization-borylation products were obtained in good yields and reasonable diastereoselectivity (6:1, 5:1 and 4:1 ratio of trans-/cisproducts, respectively).17 The lower diastereoselectivity for 1ac, 1ad and 1ae compared to 1a may be explained by a weaker coordination ability of these oxygen-containing groups to the Pd center compared to the hydroxyl group (cf. Int-1 and Int-2 in Scheme 8; see also Int-2 in Figure 1).
The use of an enantiomerically enriched substrate (S)-1a (96% ee) in the newly developed reaction was also studied. The carbocyclization product (S,S)-2a was obtained in 85% yield with complete enantioretention (96% ee) and with d.r. >50:1 (eq 2).
Scheme 4. Carbocyclization Directed by Hydroxyl Derivatives
Based on these encouraging results in the carbocyclization-borylation reaction of enallenes assisted by the weakly coordinating hydroxyl group, we next turned our attention to exploring the possible use of a carbonyl functionality in place of the hydroxyl moiety in this interesting transformation. To our delight, a carbonyl group was also found to function as an assisting group for formation of the intermediate corresponding to Int-C in Scheme 1. Ketone group-bearing enallenes 4 were found to be suitable substrates in palladium-catalyzed carbocyclization (Scheme 5) and afforded the corresponding cylohexenone derivatives (5a-e) in moderate to good yields. Interestingly, a substrate with a relatively more hindered carbonyl group, bearing two methyl groups in the R2-positions afforded the desired borylated cyclohexenone derivative 5f in 70% yield.
To gain further insight into the mechanism of the developed hydroxyl-directed reaction, the deuterium kinetic isotope effects were studied (Scheme 7).19 An intermolecular competition experiment was conducted using a 1:1 mixture of 1a and 1a-d6 at room temperature for 4 h (Scheme 7a). The product ratio 2a/2a-d5 measured at 12.1% conversion was 5:1, and the total yield of 2a/2a-d5 was 12%. From this ratio, the competitive KIE value was determined to be kH/kD = 5.5. Furthermore, parallel kinetic experiments afforded a KIE (kH/kD from initial rate) value of 3.1 (Scheme 7b and 7c). These results indicate that the initial allenic C–H bond cleavage is partially rate-limiting. The large competitive isotope effect in the C–H bond cleavage (kH/kD = 5.5) requires that this step is the first irreversible step. Scheme 7. Kinetic Isotope Effect Studies
Scheme 5. Scope of Carbonyl-assisted Palladium-catalyzed Oxidative Carbocyclizationa
a
The reaction was conducted in DCE (2 mL) at room temperature using 4 (0.2 mmol), B2pin2 (1.3 equiv), BQ (1.1 equiv) in the presence of Pd(OAc)2 (5 mol%).
Based on the experiments in Scheme 2 and the kinetic isotope effect studies in Scheme 7, a plausible mechanism for the hydroxyl group-assisted palladium-catalyzed oxidative carbocyclization of enallenes via ligand exchange is given in Scheme 8. The reaction of palladium with enallene 1 would form chelate complex Int-1, which triggers C–H bond cleavage to give vinylpalladium intermediate Int-2. Then, the vinylpalladium intermediate Int-3
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would be generated from Int-2 via ligand exchange (from hydroxyl group to olefin) in which one face of the olefin is preferentially coordinated to palladium. Intermediate Int-3, now one diastereomer of the two possible diastereomeric complexes would undergo an olefin insertion to give cyclic intermediate Int-4 with excellent diastereoselectivity.15 Subsequent transmetallation of Int-4 with B2pin2 would produce intermediate Int-5, which on reductive elimination gives the target cyclohexene derivative 2. Scheme 8. Proposed mechanism R
Pd(0)
Corresponding Author *
[email protected] *
[email protected] HQ
ACKNOWLEDGMENT
1
Bpin R
R
AUTHOR INFORMATION
The authors declare no competing financial interest.
OH
PdX2
2
Experimental procedures and compound characterization data, including the 1H/13C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.
Notes
R
XBQ +
OH
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OH Pd X
OH
X Int-1
Pd Bpin
OH
Int-5
REFERENCES
allenic attack
H
H PdII
B2pin2
R
R
OH Int-3
R
Pd X
OH
Pd X Int-4
OH
stereoselective olefin R insertion
Int-2
Pd X Int-3
Coordination of the hydroxyl group to Pd(II) in Int-2 followed by a ligand exchange would lead to an axial hydroxyl group in Int-3 (Figure 1). The high diastereoselectivity can be explained by a face selective coordination of the olefin moiety to the Pd(II) center in Int-3.20 The lower diastereoselectivity for the OMe, OAc and OTBDS derivatives (Scheme 4) is consistent with this mechanism. The fact that alcohol (S)-1a gives product (S,S)-2a with enantioretention (eq 2) shows that there is no deterioration of the chiral C-O carbon by reversible beta-H elimination/re-addition. Figure 1. Origin of diastereoselectivity
In conclusion, we have described herein a palladium-catalyzed oxidative carbocyclization of enallenes affording functionalized cyclohexenol derivatives via diastereoselective ligand exchange on Pd(II) from a weakly coordinating hydroxyl group to a remote olefin group. The reaction results in a highly diastereoselective formation of a cyclohexenol product. It was demonstrated that the product can be obtained on gram scale and further transformed into useful derivatives. It was found that other weakly coordinating oxygen-containing groups such as ketone, alkoxide, and acetate also assist the carbocyclization towards the cyclohexene products. Further studies on the scope and synthetic applications of the newly developed transformation are currently carried out in our laboratory.
ASSOCIATED CONTENT Supporting Information
Financial support from the European Research Council (ERC AdG 247014), The Swedish Research Council (2016-03897), the Berzelii Center EXSELENT, and the Knut and Alice Wallenberg Foundation is gratefully acknowledged.
(1) Selected recent reviews of Pd-catalyzed C–H functionalization: (a) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc. Chem. Res. 2001, 34, 633. (b) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173. (c) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (d) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem. Int. Ed. 2009, 48, 5094. (e) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. 2009, 42, 1074. (f) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (g) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (h) Ackermann, L. Chem. Rev. 2011, 111, 1315. (i) Rouquet, G.; Chatani, N. Angew. Chem. Int. Ed. 2013, 52, 11726. (2) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, 45, 788. (3) For selected examples involving hydroxyl-assisted palladium-catalyzed C–H activation, see: (a) Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem. Soc. 2001, 123, 10407. (b) Terao, Y.; Wakui, H.; Nomoto, M.; Satoh, T.; Miura, M.; Nomura, M. J. Org. Chem. 2003, 68, 5236. (c) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916. (d) Huang, C.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406. (e) Lu, Y.; Leow, Wang, D. X.; Engle, K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967. (f) Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 12203. (g) Huang, C.; Ghavtadze, N.; Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 17630. (4) For selected examples involving ester or ketone-assisted palladium-catalyzed C–H activation, see: (a) Gandeepan, P.; Parthasarathy, K.; Cheng, C.-H. J. Am. Chem. Soc. 2010, 132, 8569. (b) Xiao, B.; Gong, T.; Xu, J.; Liu, Z.; Liu, L. J. Am. Chem. Soc. 2011, 133, 1466. (c) Shan, X.; Yang, X.; Ma, L.; Rao, Y. Angew. Chem. Int. Ed. 2012, 51, 13070. (d) Gandeepan, P.; Hung, C.-H.; Cheng, C.-H. Chem. Commun. 2012, 48, 9379. (e) Li, H.; Zhu, R.-Y.; Shi, W.-J.; He, K.-H.; Shi, Z.-J. Org. Lett. 2012, 14, 4850. (f) Li, G.; Wan, L.; Zhang, G.; Leow, D.; Spangler, J.; Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 4391. (5) For selected reviews involving palladium-catalyzed oxidative carbocyclization, see: (a) Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007, 107, 5318. (b) Dénès, F.; Pérez-Luna, A.; Chemla, F. Chem. Rev. 2010, 110, 2366. (c) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Deng, Y.; Persson, A. K. Å.; Bäckvall, J.-E. Chem. Eur. J. 2012, 18, 11498. (6) For selected examples involving palladium-catalyzed oxidative carbocyclizations, see: (a) Wu, T.; Xu, X.; Liu, G. Angew. Chem. Int. Ed. 2011, 50, 12578. (b) Xu, X.; Wu, T.; Wang,
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Journal of the American Chemical Society H.; Guo, Y.; Liu, G. J. Am. Chem. Soc. 2012, 134, 878. (c) Zhu, R.; Buchwald, S. L. Angew. Chem. Int. Ed. 2012, 51, 1926. (d) Jaegli, S.; Dufour, J.; Wei, H.; Piou, T.; Duan, X.; Vors, J.; Neuville, L.; Zhu, J. Org. Lett. 2010, 12, 4498. (e) Wei, Y.; Deb, I.; Yoshikai, N. J. Am. Chem. Soc. 2012, 134, 9098. (7) For selected examples involving palladium-catalyzed oxidative carbocyclizations of enallenes, see: (a) Persson, A. K. Å.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2010, 49, 4624. (b) Persson, A. K. Å.; Jiang, T.; Johnson, M.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2011, 50, 6155. (c) Jiang, T.; Bartholomeyzik, T.; Mazuela, J.; Willersinn, J.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2015, 54, 6024. (d) Qiu, Y.; Yang, B.; Zhu, C.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2016, 55, 6520. (e) Qiu, Y.; Yang, B.; Zhu, C.; Bäckvall, J.-E. J. Am. Chem. Soc. 2016, 138, 13846. (f) Qiu, Y.; Yang, B.; Zhu, C.; Bäckvall, J.-E. Chem. Sci. 2017, 8, 616. (g) Qiu, Y.; Yang, B.; Jiang, T.; Zhu, C.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2017, 56, 3221. For the first demonstration that an olefin or acetylene is required as an assisting group for triggering allene attack on palladium see: (h) Zhu, C.; Yang, B.; Jiang, T.; Bäckvall, J. E. Angew. Chem. Int Ed. 2015, 54, 9066-9069. (8) For selected examples involving palladium-catalyzed oxidative carbocyclizations of allenynes, see: (a) Deng, Y.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2013, 52, 3217. (b) Bartholomeyzik, T.; Pendrill, R.; Lihammar, R.; Jiang, T.; Widmalm, G.; Bäckvall, J.-E. J. Am. Chem. Soc. 2018, 140, 298. (9) For selected examples involving palladium-catalyzed oxidative carbocyclizations of bisallenes, see: (a) Volla, M. R.; Bäckvall, J.-E. ACS Catal., 2016, 6, 6398. (b) Naidu, V. R.; Posevins, D.; Volla, M. R.; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2017, 56, 1590. (c) Zhu, C.; Yang, B.; Qiu, Y; Bäckvall, J.-E. Angew. Chem. Int. Ed. 2016, 55, 14405 (10) For recent reviews of transition-metal-catalyzed π-bond-assisted C–H bond activation, see: (a) Gandeepan, P.; Cheng, C.-H. Chem. Asian J. 2015, 10, 824. (b) Minami, Y.; Hiyama, T. Acc. Chem. Res. 2016, 49, 67. (11) For selected reviews involving the organoboronates, see: (a) Tsuji, J. Palladium Reagents and Catalysts, John Wiley & Sons, Chichester, England, 2004, pp 289–310. (b) Matteson, D. S. Chem. Rev. 1989, 89, 1535. (c) Matteson, D. S. Acc. Chem. Res. 1988, 21, 294. (d) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555. (12) (a) Brown, H. C.; Liotta, R.; Kramer, G. W. J. Am. Chem. Soc. 1979, 101, 2966. (b) Kister, J.; DeBaillie, A. C.; Lira, R.; Roush, W. R. J. Am. Chem. Soc. 2009, 131, 14174. (c) Jung, B.; Hoveyda, A. H. J. Am. Chem. Soc. 2012, 134, 1490. (d) Semba, K.; Fujihara, T.; Terao, J.; Tsuji, Y. Angew. Chem. Int. Ed. 2013, 52, 12400. (e) Semba, K.; Bessho, N.; Fujihara, T.; Terao, J.; Tsuji, Y. Angew. Chem. Int. Ed. 2014, 53, 9007. (13) (a) Blaisdell, T. P.; Morken, J. P. J. Am. Chem. Soc. 2015, 137, 8712. (b) Park, J.-W.; Chen, Z.; Dong, V. M. J. Am. Chem. Soc. 2016, 138, 3310. (c) Mekareeya, A.; Walker, P. R.; Couse-Rios, A.; Campbell, C. D.; Steven, A.; Paton, R. S.; Anderson, E. A. J. Am. Chem. Soc. 2017, 139, 10104. (14) When the reaction time was increased to 24 h, 2ab was obtained in less than 5% yield (for details, see the Supporting Information). (15) For details on the determination of the relative stereochemistry, see the Supporting Information. (16) (a) Xiao, B.; Fu, Y.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem. Soc. 2010, 132, 468. (b) Iglesias, Á.; Álvarez, R.; de Lera, Á. R.; Muñiz, K. Angew. Chem. Int. Ed. 2012, 51, 2225. (c) Li, G.; Leow, D.; Wan, L.; Yu, J.-Q. Angew. Chem. Int. Ed. 2013, 52, 1245. (17) Methanol was also used as solvent for 1ac, 1ad and 4a and led to a decrease of diastereoselectivity (for details, see the Supporting Information). (18) Jia, T.; Cao, P.; Wang, B.; Lou, Y.; Yin, X.; Wang, M.; Liao, J. J. Am. Chem. Soc. 2015, 137, 13760.
(19) For details of kinetic isotope effect study, see the Supporting Information. (20) We cannot rule out that intermediate Int-3 undergoes a ring flip before cyclization occurs as suggested by one reviewer, and in such a ring flipped intermediate Int-3’ the OH group is equatorial and the alkene pseudo-axial. (For details, see the Supporting Information) This will not change anything concerning the relative stereochemistry since the alkene coordination is not broken. The key to the diastereoselectivity is still that palladium after being bound to the OH group binds selectively to one face of the olefin. Such pseudo-axial positioning of alkenes in diastereoselective alkene insertions into alkenylpalladium complexes has been proposed in other systems.13c
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Graphic Abstract
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