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An Entry to Vinylcyclopropane through Palladium-catalyzed Intramolecular Cyclopropanation of Alkenes with Unstabilized Allylic tosylhydrazones
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A diastereoselective Pd-catalyzed intramolecular cyclopropanation of alkenes with unstabilized allylic tosylhydrazones were developed. This methodology provides an efficient entry toward synthesis of bicyclo[3.1.0] hexane system with an exo- double bond, and set the basis for future elaboration of more complex polycyclic motifs. Vinylcyclopropanes are useful synthetic intermediates in modern organic synthesis, 1 and are important structural motif in natural products including lindenane-type sesquiterpenoids and the related dimers,2 trans-chrysanthemic acid,3 and ambruticin S.4 Due to their synthetic significance and importance, chemists have developed versatile strategies toward the synthesis of vinylcyclopropanes, which include function group transformation from cyclopropyl compounds (strategy a),5 ring rearrangement (strategy b),6 nucleophilic Michael addition or substitution (strategy c),7 cyclopropanation using diene with diazo compound or through Simmons-Smith reaction (strategy d),8 and cyclopropanation between allylic diazo compound and alkene (strategy e).9 Actually, only strategy a is generally applicable for the synthesis of unstabilized vinylcyclopropanes without electrowithdrawing group (EWG), although requiring multi-step transformation. Several scattered examples following strategy e were also reported for preparing such vinyl cyclopropanes with excess alkene required (Scheme 1). However, cyclopropanation of unstabilized allylic diazo compound with normal alkene is challenging and has never been systematically studied. This scarcity is ascribed to the instability of allylic diazo compounds,9c which is much different from the reactivity of other diazo compounds.10 With this instability in mind, we envisioned that an intramolecular cyclopropanation might work better than an intermolecular version for unstabilized allylic diazo compounds. During total synthesis of bolivianine, we discovered an intramolecular cyclopropanation with compound 1a in the presence of one equivalent of palladium (0) (Scheme 1).11 Considering its potential synthetic application, we were intereted in a catalytic version of this reaction. Herein, we report our efforts on palladium-catalyzed intramolecular cyclopropanation between alkenes and allylic tosylhydrazones, which in-situ generate allylic diazo compound.12 Accordingly, metal-catalyzed intramolecular cyclopropanation This journal is © The Royal Society of Chemistry [year]
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Scheme 1. Examples of cyclopropanation of unfunctionalized allylic diazo compounds
was performed under various conditions in argon atmosphere. In contrast to thermal condition in scheme 1c, no desired product could be detected in the absence of metal catalyst (entry 1, table 1). To compete with the facile destructive decomposition of the starting material, metal catalysts were screened to prompt the desired intramolecular cyclopropanation. Interestingly, silver and copper catalysts showed no effect even in 30 mol% loading (entries 2-3), unlike their impressive high catalytic activity for diazocarbonyl compounds.13,14 To our delight, emplyment of 30 mol% of Ir(cod)Cl afforded the desired product in 37% yield (entry 4). On the basis of its excellent catalytic activity with diazocarbonyl compounds,10 we attempted Rh2(OAc)4 and gladly isolated compound 2a in 63% yield (entry 5). Pd(cod)Cl2 and Pd(MeCN)2Cl2 were also able to produce compound 2a, albeit in lower yields (entries 6-7). Applying Pd2dba3·CHCl3 as the [journal], [year], [vol], 00–00 | 1
ChemComm Accepted Manuscript
Yang Yang,a Jinpeng Li,a Biao Du,a Changchun Yuan,a Bo Liu*a,b and Song Qin*a
ChemComm
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Table 1 Optimization of intramolecular cyclopropanation of 1a
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Table 2. Substrate scope of the intramolecular cyclopropanation
catalyst improved the yield to 73% (entry 8), while Pd2dba3 proved to be superior by affording 81% yield in DMF (entry 9). Using Pd2dba3 with 7 mol% loading discounted the yield (entry 10), but 50 mol% catalyst loading could not improve the yield too much (entry 11). Accordingly, 15 mol% catalyst loading of Pd2dba3 was chosen as the optimal one. Notably, the yield with Pd(dba)2 in 15 mol% loading is comparable with that of Pd2dba3 in 7 mol% loading (entry 10 vs entry 12). However, the existence of a typical ligand, such as triphenylphosphine, was deleterious to the activity of palladium (0) catalyst (entry 13), indicating that the active catalyst species should not be coordinated by ligand. The impact of different bases on the reaction were evaluated as well, and sodium methoxide in methanol was testified to be the best (entries 9, 14-17). Different solvents were examined and DMF proved to be the optimal (entry 9 vs. entries 18-22).15
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
base(1.5 eq) NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaHf NaHMDSf KHMDSf LiHMDSf NaOMe NaOMe NaOMe NaOMe NaOMe
cat. (15 mol%) --AgOTfc Cu(acac)2c Ir(cod)Clc Rh2(OAc)4 Pd(cod)Cl2c Pd(MeCN)2Cl2c Pd2dba3·CHCl3 Pd2dba3 Pd2dba3d Pd2dba3e Pd(dba)2 Pd(PPh3)4 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3
solvent DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMA NMP ether DCM toluene
ent ry
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ratio yiel Article View Online b c
. ditio d DOI: 10.1039/C5CC00235D
1a
1b
na
(%)
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> 20:1
A
63
> 20:1
B
72
6:1
2a
2 2b
3
a
yield (%)b 0 0 0 37 63 55 48 73 81 45 88 42 0 65 49 63 52 36 55 31 50 39
1c
2c
4
Ar=4-MeC6H4, 1d
Ar=4-MeC6H4, 2d
B
71
6:1
5
Ar=4-MeOC6H4, 1e
Ar=4-MeOC6H4, 2e
B
70
6:1
6
Ar=4-ClC6H4, 1f
Ar=4-ClC6H4, 2f
B
72
7:1
7
Ar=4-FC6H4, 1g
Ar=4-FC6H4, 2g
B
75
3:1
A
67
> 20:1
A
74
---
Ad
86e
β/α 1.7: 1
A
59
> 20:1
A
39
> 20:1
8
Enlightened by the catalytic effect of Pd2dba3, we started to examine substrate scope of this methodology (Table 2). Similar to the excellent diastereoselectivity obtained under the optimal condition with compound 1a (entry 1, table 2), compound 1b afforded the corresponding product as a sole diastereomer (entry 2), indicating that the intramolecular cyclopropanation is insensitive to the steric hindrance of the allylic position. The catalytic system could be further extended to comopound 1c (entry 3), while the temperature should be increased to 60 ℃ to maintain the reactivity; and excess dibenzylideneacetone (dba) was used (method B), which probably could prevent or diminish the generation of inactive palladium cluster at higher temperature. Introduction of electro-donating groups (Me-, MeO-) or electrowithdrawing groups (Cl-, F-) on aryl ring did not display any deteriorative effect on the reactivity or diastereoselectivity (entries 4-7). Moreover, compound 1h with dialkyl-substituted alkene was a suitable substrate as well (entry 8). As for the compounds with a aryl linker (1i) or a linear linker (1j), Pd2dba3
1h
2h
1i
2i
9
10 1j
Conditions: (1) 1a, base/MeOH, 5 min at 0 ℃, then 15 min at rt, removing solvent; (2) 15 mol% metal catalyst, DMF, 35 ℃, TLC control until full conversion of 1a. b Isolated yield. c 30 mol%. d 7 mol%. e 50% mol%. f THF was used instead of MeOH.
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Condition A: (1) substrate, NaOMe/MeOH, 5 min at 0 ℃, then 15 min at rt, removing MeOH; (2) 15 mol% Pd2dba3, DMF, 35 ℃, 5h. Condition B: (1) the same as that in condition A; (2) 15 mol% Pd2dba3, additional dba (1 eq.), DMF, 60 ℃, 5h. b Isolated yield of the major diaseteomer. c Major isomer: the sum of other isomers; determined by 1H NMR. d At 60 ℃. e Combined yield of the isomers.
was also manifested to be effective (entries 9 and 10). The 1.7:1 dr of compound 2j may stem from the rotation freedom of compound 1j, lack for conformational constraint. The reaction of compounds 1k and 1l is more sluggish and afforded the corresponding product in relatively lower yield (entries 11-12), because of the background decomposition of the starting material. The stereochemistry of compound 2f was elucidated by X-ray This journal is © The Royal Society of Chemistry [year]
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crystallography.15 And the stereochemistry of compounds 2c-2e and 2g was deduced by comparing their NMR spectra with those of compound 2f. The relative stereochemistry of other products was determined by NOESY experiment.15 Palladium-catayzed reactions with diazo compounds have been extensively studied in recent years.16,17 Unlike the widely accepted Pd (II) carbene mechanism in Pd-catalyzed cross coupling between organo-halide and diazo compounds,16 Pd (0) carbene mechanism was proposed and computationally supported for Pd-catalyzed cyclopropanation of alkene by diazomethane.18 Interestingly, it was demonstrated that Pd (0) nanoparticle could be generated from Pd (II) precatalyst by diazomethane and was more active than Pd(0) complexes in cyclopropanation of cyclohexenone.18b In our intramolecular cyclopropanation system without an oxidant, we considered Pd (0) catalyst without a ligand might be the real active catalytic species, based on the follwing facts: (1) Pd (0) exhibited catalytic activity more effectively than Pd (II) (table 1);19 (2) the existence of PPh3 demolished the desired reactivity of both Pd (0) and Pd (II) precatalysts (entry 13, table 1);20 (3) the ratio of Pd(0) to dba is variable to retain the catalytic activity (entry 10 vs entry 12, table 1), but excess dba might be able to stabilize the Pd (0) nanoparticle catalyst at higher temperature to prevent its precipitation (method B, table 2). Based on the above analysis, we can propose a mechanism for the representative transformation from 1a to 2a, as illustrated in Scheme 2.21
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Scheme 2. Proposed mechanism
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In summary, we have developed a novel solution for the diastereoselective synthesis of various bicyclo[3.1.0] hexane system through Pd-catalyzed intramolecular cyclopropanation of alkene with unstabilized allylic diazo compound. Taking the large excess of alkene in the intermolecular cyclopropanation (Scheme 1) into account, the generally satisfactory yields and selectivities in our intramolecular cyclopropanation compensate its 15 mol% catalyst loading. This methodology provided a facile entry toward the synthesis of lindenane-type terpenoids and the related analogs, and actually has been applied to prepare 2a in a tengram scale. Further elaboration of the resultant vinylcyclopropanes is underway in our laboratory.1 We appreciate the financial support from the National Natural Science Foundation of China (21172154, 21290180, 21322205, 21321061, J1103315) and the Ministry of Education of China (20130181110022). We also thank the comprehensive training platform of the Specialized Laboratory in the College of Chemistry at Sichuan University for compound testing. This journal is © The Royal Society of Chemistry [year]
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a Key Laboratory of Green Chemistry & Technology View of Ministry of Article Online Education, College of Chemistry, Sichuan University, Chengdu 610064, DOI: 10.1039/C5CC00235D P. R. China. Tel. & Fax: +86 28 8541 3712; E-mail: [email protected] b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China. † Electronic Supplementary Information (ESI) available: Experimental and computational data of compounds. See DOI: 10.1039/b000000x/ 1 (a) L. Jiao and Z.-X., Yu, J. Org. Chem., 2013, 78, 6842; (b) T. Hudlicky and J. W. Reed, Angew. Chem. Int. Ed., 2010, 49, 4864. (a) Y. J. Xu Chem. Biodiversity, 2013, 10, 1754; (b) X. F. He, S. 2 Yin, Y. C. Ji, Z. S. Su, M. Y. Geng and J. M. Yue, J. Nat. Prod., 2010, 73, 45. D. Arit, M. Jautelat and R. Lantzsch, Angew. Chem. Int. Ed., 3 1981, 20, 703. S. Hanessian, T. Focken, X. Mi, R. Oza, B. Chen, D. Ritson and 4 R. Bequdegnies, J. Org. Chem., 2010, 75, 5601. 5 For selected examples, see: (a) E. B. Hay, H. Zhang and D. P. Curran, J. Am. Chem. Soc., 2015, DOI: 10.1021/ja510608u; (b) V. A. Rassadin, V. V. Sokolov, A. F. Khlebnikov, N. V. Ulin, S. I. Kozhushkov and A. De Meijere, Synthesis, 2012, 44, 372; (c) Y. Liang, X. Jiang and Z.-X. Yu, Chem. Commun., 2011, 47, 6659; (d) W. Tang, X. Wei, N. K. Yee, N. Patel, H. Lee, J. Savoie and C. H. Senanayake, Org. Process Res. Dev., 2011, 15, 1207; (e) H. Zhang and D. P. Curran, J. Am. Chem. Soc., 2011, 133, 10376; (f) B. M. Trost, Y. Nishimura, K. Yamamoto and S. S. McElvain, J. Am. Chem. Soc., 1979, 101, 1328; (g) T. H. Yan and L. A. Paquette, Tetrahedron Lett., 1982, 23, 3227; (h) W. Kirmse, B. G. Bűlow and H. Schepp, Justus Liebigs Ann. Chem., 1966, 691, 41; (i) C. G. Overberger and A. E. Borchert, J. Am. Chem. Soc., 1960, 82, 4896. 6 (a) M.-Y. Chang, Y.-C. Chen and C.-K. Chan, Tetrahedron, 2014, 70, 8908; D. Craig, S. J. Gore, M. I. Lansdell, S. E. Lewis, A. V. W. Mayweg and A. J. P. White, Chem. Commun., 2010, 46, 4991. 7 (a) B.-H. Zhu, R. Zhou, J.-C. Zheng, X.-M. Deng, X.-L. Sun, Q. Shen and Y. Tang, J. Org. Chem., 2010, 75, 3454; (b) H.-J. Pyun, K. Chaudhary, J. R. Somoza, X. C. Sheng and C. U. Kim, Tetrahedron Lett., 2009, 50, 3833; (c) T. Hayashi, A. Yamamoto, Y. Ito, Tetrahedron Lett., 1988, 29, 669. 8 (a) J. Barluenga, N. Quiñones, M. Tomás-Gamasa and M.-P. Cabal, Eur. J. Org. Chem., 2012, 2312; (b) R. C. Larock and E. K. Yum, Tetrahedron, 1996, 52, 2743; (c) T. Hudlicky, T. M. Kutchan, S. R. Wilson and D. T. Mao, J. Am. Chem. Soc., 1980, 102, 6351; (d) E. J. Corey and R. H. Wollenberg, J. Org. Chem., 1975, 40, 2265; (e) M. B. Jarstfer, B. S. J. Blagg, D. H. Rogers and C. D. Poulter, J. Am. Chem. Soc., 1996, 118, 13089. 9 (a) H. Jiang, X.-L. Sun, C.-Y. Zhu, L.-X. Dai and Y. Tang, Tetrahedron, 2008, 64, 5032; (b) J.-L. Zhang, P. W. H. Chan and C. M. Che, Tetrahedron Lett., 2003, 44, 8733; (c) A. de Meijere, T.-J. Schulz, R. R. Kostikov, F. Graupner, T. Murr and T. Bielfeldt, Synthesis, 1991, 547; (d) J. Barluenga, N. Quiñones, M. TomásGamasa and M.-P. Cabal, Eur. J. Org. Chem., 2012, 2312; (e) L. A. Adams, V. K. Aggarwal, R. V. Bonnert, B. Bressel, R. J. Cox, J. Shepherd, J. de Vicente, M. Walter, W. G. Whittingham and C. L. Winn, J. Org. Chem., 2003, 68, 9433. 10 For recent reviews, see: (a) H. M. L. Davies and J. S. Alford, Chem. Soc. Rev., 2014, 43, 5151; (b) D. Gillingham and N. Fei, Chem. Soc. Rev., 2013, 42, 4918; (c) X. Guo and W. Hu, Acc. Chem. Res., 2013, 46, 2427; (d) Q. Xiao, Y. Zhang and J. Wang, Acc. Chem. Res., 2013, 46, 236; (e) M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem. Rev., 2010, 110, 704; (f) H. M. L. Davies and J. R. Denton, Chem. Soc. Rev., 2009, 38, 3061. 11 (a) B. Du, C. Yuan, T. Yu, L. Yang, Y. Yang, B. Liu and S. Qin, Chem. Eur. J., 2014, 20, 2613; (b) C. Yuan, B. Du, L. Yang and B. Liu, J. Am. Chem. Soc., 2013, 135, 9291. 12 Tosylhydrazones were used as a safer alternative instead of diazo compounds; for a tutorial review, see: Z. Shao and H. Zhang, Chem. Soc. Rev., 2012, 41, 560 and the references cited thereof. 13 (a) L. Zhao, J. Wang, H. Zheng, Y. Li, K. Yang, B. Cheng, X. Jin, X. Yao and H. Zhai, Org. Lett., 2014, 16, 6378; (b) C.-D. Wang and
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R.-S. Liu, Org. Biomol. Chem., 2012, 10, 8948; (c) H.-L. Wang, Z. Li, G.-W. Wang and S.-D. Yang, Chem. Commun., 2011, 47, 11336; (d) J. F. Briones and H. M. L. Davies, Org. Lett., 2011, 13, 3984; (e) J. H. Hansen, H. M. Davies, Chem. Sci., 2011, 2, 457. X. Zhao, Y. Zhang and J. Wang, Chem. Commun., 2012, 48, 10162 and references cited thereof. See Supplementary Information for more details. For tutorial reviews, see: (a) Y. Zhang and J. Wang, Eur. J. Org. Chem., 2011, 1015; (b) J. Barluenga and C. Valdés, Angew. Chem. Int. Ed., 2011, 50, 7486. For recent examples, see: (a) Y. Xia, Y. Xia, Z. Liu, Y. Zhang and J. Wang, J. Org. Chem., 2014, 79, 7711; (b) X.-L. Xie, S.-F. Zhu, J.-X. Guo, Y. Cai and Q.-L. Zhou, Angew. Chem. Int. Ed., 2014, 53, 2978; (c) Y. Zhu, X. Liu, S. Dong, Y. Zhou, W. Li, L. Lin and X. Feng, Angew. Chem. Int. Ed., 2014, 53, 1636; (d) P.-S. Wang, H.-C. Lin, X.-L. Zhou and L.-Z. Gong, Org. Lett., 2014, 16, 3332; (e) M. Kitamura, M. Kisanuki, K. Kanemura and T. Okauchi, Org. Lett., 2014, 16, 1554. For the proposed Pd (0) carbene mechanism, see: (a) C. Martin, F. Molina, E. Alvarez and T. R. Belderrain, Chem. Eur. J., 2011, 17, 14885; (b) O. Illa, C. Rodriguez-Garcia, C. Acosta-Silva, I. Favier, D. Picurelli, A. Oliva, M. Gómez, V. Branchadell and R. M. Ortuño, Organometallics 2007, 26, 3306; (c) B. F. Straub, J. Am. Chem. Soc., 2002, 124, 14195; (d) A. Nakamura, T. Yoshida, M. Cowie, S. Otsuka and J. A. Ibers, J. Am. Chem. Soc., 1977, 99, 2108. Other Pd (II) catalysts, such as Pd(OAc)2, Pd(TFA)2, Pd(PhCN)2Cl2, Pd(PPh3)2Cl2 and Pd(dppf)Cl2 failed to catalyze the reaction. The combination of Pd2dba3 + PPh3 and Pd(dba)2 + PPh3 exhibited no catalytic activity at all in this reaction. For support from computational chemistry, see Supplementary Information for details.
Page 4 of 4
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ChemComm Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: Y. Yang, J. Li, B. Du, C. Yuan, B. Liu and S. Qin, Chem. Commun., 2015, DOI: 10.1039/C5CC00235D.
This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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An Entry to Vinylcyclopropane through Palladium-catalyzed Intramolecular Cyclopropanation of Alkenes with Unstabilized Allylic tosylhydrazones
Published on 03 March 2015. Downloaded by Université Laval on 04/03/2015 05:28:09.
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x A diastereoselective Pd-catalyzed intramolecular cyclopropanation of alkenes with unstabilized allylic tosylhydrazones were developed. This methodology provides an efficient entry toward synthesis of bicyclo[3.1.0] hexane system with an exo- double bond, and set the basis for future elaboration of more complex polycyclic motifs. Vinylcyclopropanes are useful synthetic intermediates in modern organic synthesis, 1 and are important structural motif in natural products including lindenane-type sesquiterpenoids and the related dimers,2 trans-chrysanthemic acid,3 and ambruticin S.4 Due to their synthetic significance and importance, chemists have developed versatile strategies toward the synthesis of vinylcyclopropanes, which include function group transformation from cyclopropyl compounds (strategy a),5 ring rearrangement (strategy b),6 nucleophilic Michael addition or substitution (strategy c),7 cyclopropanation using diene with diazo compound or through Simmons-Smith reaction (strategy d),8 and cyclopropanation between allylic diazo compound and alkene (strategy e).9 Actually, only strategy a is generally applicable for the synthesis of unstabilized vinylcyclopropanes without electrowithdrawing group (EWG), although requiring multi-step transformation. Several scattered examples following strategy e were also reported for preparing such vinyl cyclopropanes with excess alkene required (Scheme 1). However, cyclopropanation of unstabilized allylic diazo compound with normal alkene is challenging and has never been systematically studied. This scarcity is ascribed to the instability of allylic diazo compounds,9c which is much different from the reactivity of other diazo compounds.10 With this instability in mind, we envisioned that an intramolecular cyclopropanation might work better than an intermolecular version for unstabilized allylic diazo compounds. During total synthesis of bolivianine, we discovered an intramolecular cyclopropanation with compound 1a in the presence of one equivalent of palladium (0) (Scheme 1).11 Considering its potential synthetic application, we were intereted in a catalytic version of this reaction. Herein, we report our efforts on palladium-catalyzed intramolecular cyclopropanation between alkenes and allylic tosylhydrazones, which in-situ generate allylic diazo compound.12 Accordingly, metal-catalyzed intramolecular cyclopropanation This journal is © The Royal Society of Chemistry [year]
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Scheme 1. Examples of cyclopropanation of unfunctionalized allylic diazo compounds
was performed under various conditions in argon atmosphere. In contrast to thermal condition in scheme 1c, no desired product could be detected in the absence of metal catalyst (entry 1, table 1). To compete with the facile destructive decomposition of the starting material, metal catalysts were screened to prompt the desired intramolecular cyclopropanation. Interestingly, silver and copper catalysts showed no effect even in 30 mol% loading (entries 2-3), unlike their impressive high catalytic activity for diazocarbonyl compounds.13,14 To our delight, emplyment of 30 mol% of Ir(cod)Cl afforded the desired product in 37% yield (entry 4). On the basis of its excellent catalytic activity with diazocarbonyl compounds,10 we attempted Rh2(OAc)4 and gladly isolated compound 2a in 63% yield (entry 5). Pd(cod)Cl2 and Pd(MeCN)2Cl2 were also able to produce compound 2a, albeit in lower yields (entries 6-7). Applying Pd2dba3·CHCl3 as the [journal], [year], [vol], 00–00 | 1
ChemComm Accepted Manuscript
Yang Yang,a Jinpeng Li,a Biao Du,a Changchun Yuan,a Bo Liu*a,b and Song Qin*a
ChemComm
10
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Table 1 Optimization of intramolecular cyclopropanation of 1a
Published on 03 March 2015. Downloaded by Université Laval on 04/03/2015 05:28:09.
Table 2. Substrate scope of the intramolecular cyclopropanation
catalyst improved the yield to 73% (entry 8), while Pd2dba3 proved to be superior by affording 81% yield in DMF (entry 9). Using Pd2dba3 with 7 mol% loading discounted the yield (entry 10), but 50 mol% catalyst loading could not improve the yield too much (entry 11). Accordingly, 15 mol% catalyst loading of Pd2dba3 was chosen as the optimal one. Notably, the yield with Pd(dba)2 in 15 mol% loading is comparable with that of Pd2dba3 in 7 mol% loading (entry 10 vs entry 12). However, the existence of a typical ligand, such as triphenylphosphine, was deleterious to the activity of palladium (0) catalyst (entry 13), indicating that the active catalyst species should not be coordinated by ligand. The impact of different bases on the reaction were evaluated as well, and sodium methoxide in methanol was testified to be the best (entries 9, 14-17). Different solvents were examined and DMF proved to be the optimal (entry 9 vs. entries 18-22).15
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22
base(1.5 eq) NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaOMe NaHf NaHMDSf KHMDSf LiHMDSf NaOMe NaOMe NaOMe NaOMe NaOMe
cat. (15 mol%) --AgOTfc Cu(acac)2c Ir(cod)Clc Rh2(OAc)4 Pd(cod)Cl2c Pd(MeCN)2Cl2c Pd2dba3·CHCl3 Pd2dba3 Pd2dba3d Pd2dba3e Pd(dba)2 Pd(PPh3)4 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3 Pd2dba3
solvent DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMF DMA NMP ether DCM toluene
ent ry
25
30
35
con
ratio yiel Article View Online b c
. ditio d DOI: 10.1039/C5CC00235D
1a
1b
na
(%)
A
81
> 20:1
A
63
> 20:1
B
72
6:1
2a
2 2b
3
a
yield (%)b 0 0 0 37 63 55 48 73 81 45 88 42 0 65 49 63 52 36 55 31 50 39
1c
2c
4
Ar=4-MeC6H4, 1d
Ar=4-MeC6H4, 2d
B
71
6:1
5
Ar=4-MeOC6H4, 1e
Ar=4-MeOC6H4, 2e
B
70
6:1
6
Ar=4-ClC6H4, 1f
Ar=4-ClC6H4, 2f
B
72
7:1
7
Ar=4-FC6H4, 1g
Ar=4-FC6H4, 2g
B
75
3:1
A
67
> 20:1
A
74
---
Ad
86e
β/α 1.7: 1
A
59
> 20:1
A
39
> 20:1
8
Enlightened by the catalytic effect of Pd2dba3, we started to examine substrate scope of this methodology (Table 2). Similar to the excellent diastereoselectivity obtained under the optimal condition with compound 1a (entry 1, table 2), compound 1b afforded the corresponding product as a sole diastereomer (entry 2), indicating that the intramolecular cyclopropanation is insensitive to the steric hindrance of the allylic position. The catalytic system could be further extended to comopound 1c (entry 3), while the temperature should be increased to 60 ℃ to maintain the reactivity; and excess dibenzylideneacetone (dba) was used (method B), which probably could prevent or diminish the generation of inactive palladium cluster at higher temperature. Introduction of electro-donating groups (Me-, MeO-) or electrowithdrawing groups (Cl-, F-) on aryl ring did not display any deteriorative effect on the reactivity or diastereoselectivity (entries 4-7). Moreover, compound 1h with dialkyl-substituted alkene was a suitable substrate as well (entry 8). As for the compounds with a aryl linker (1i) or a linear linker (1j), Pd2dba3
1h
2h
1i
2i
9
10 1j
Conditions: (1) 1a, base/MeOH, 5 min at 0 ℃, then 15 min at rt, removing solvent; (2) 15 mol% metal catalyst, DMF, 35 ℃, TLC control until full conversion of 1a. b Isolated yield. c 30 mol%. d 7 mol%. e 50% mol%. f THF was used instead of MeOH.
2 | Journal Name, [year], [vol], 00–00
product
1
a
20
substrate
2j
11 1k
2k
12 1l 40
45
50
2l
a
Condition A: (1) substrate, NaOMe/MeOH, 5 min at 0 ℃, then 15 min at rt, removing MeOH; (2) 15 mol% Pd2dba3, DMF, 35 ℃, 5h. Condition B: (1) the same as that in condition A; (2) 15 mol% Pd2dba3, additional dba (1 eq.), DMF, 60 ℃, 5h. b Isolated yield of the major diaseteomer. c Major isomer: the sum of other isomers; determined by 1H NMR. d At 60 ℃. e Combined yield of the isomers.
was also manifested to be effective (entries 9 and 10). The 1.7:1 dr of compound 2j may stem from the rotation freedom of compound 1j, lack for conformational constraint. The reaction of compounds 1k and 1l is more sluggish and afforded the corresponding product in relatively lower yield (entries 11-12), because of the background decomposition of the starting material. The stereochemistry of compound 2f was elucidated by X-ray This journal is © The Royal Society of Chemistry [year]
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crystallography.15 And the stereochemistry of compounds 2c-2e and 2g was deduced by comparing their NMR spectra with those of compound 2f. The relative stereochemistry of other products was determined by NOESY experiment.15 Palladium-catayzed reactions with diazo compounds have been extensively studied in recent years.16,17 Unlike the widely accepted Pd (II) carbene mechanism in Pd-catalyzed cross coupling between organo-halide and diazo compounds,16 Pd (0) carbene mechanism was proposed and computationally supported for Pd-catalyzed cyclopropanation of alkene by diazomethane.18 Interestingly, it was demonstrated that Pd (0) nanoparticle could be generated from Pd (II) precatalyst by diazomethane and was more active than Pd(0) complexes in cyclopropanation of cyclohexenone.18b In our intramolecular cyclopropanation system without an oxidant, we considered Pd (0) catalyst without a ligand might be the real active catalytic species, based on the follwing facts: (1) Pd (0) exhibited catalytic activity more effectively than Pd (II) (table 1);19 (2) the existence of PPh3 demolished the desired reactivity of both Pd (0) and Pd (II) precatalysts (entry 13, table 1);20 (3) the ratio of Pd(0) to dba is variable to retain the catalytic activity (entry 10 vs entry 12, table 1), but excess dba might be able to stabilize the Pd (0) nanoparticle catalyst at higher temperature to prevent its precipitation (method B, table 2). Based on the above analysis, we can propose a mechanism for the representative transformation from 1a to 2a, as illustrated in Scheme 2.21
Notes and references 50
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Scheme 2. Proposed mechanism
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In summary, we have developed a novel solution for the diastereoselective synthesis of various bicyclo[3.1.0] hexane system through Pd-catalyzed intramolecular cyclopropanation of alkene with unstabilized allylic diazo compound. Taking the large excess of alkene in the intermolecular cyclopropanation (Scheme 1) into account, the generally satisfactory yields and selectivities in our intramolecular cyclopropanation compensate its 15 mol% catalyst loading. This methodology provided a facile entry toward the synthesis of lindenane-type terpenoids and the related analogs, and actually has been applied to prepare 2a in a tengram scale. Further elaboration of the resultant vinylcyclopropanes is underway in our laboratory.1 We appreciate the financial support from the National Natural Science Foundation of China (21172154, 21290180, 21322205, 21321061, J1103315) and the Ministry of Education of China (20130181110022). We also thank the comprehensive training platform of the Specialized Laboratory in the College of Chemistry at Sichuan University for compound testing. This journal is © The Royal Society of Chemistry [year]
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a Key Laboratory of Green Chemistry & Technology View of Ministry of Article Online Education, College of Chemistry, Sichuan University, Chengdu 610064, DOI: 10.1039/C5CC00235D P. R. China. Tel. & Fax: +86 28 8541 3712; E-mail: [email protected] b State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, P. R. China. † Electronic Supplementary Information (ESI) available: Experimental and computational data of compounds. See DOI: 10.1039/b000000x/ 1 (a) L. Jiao and Z.-X., Yu, J. Org. Chem., 2013, 78, 6842; (b) T. Hudlicky and J. W. Reed, Angew. Chem. Int. Ed., 2010, 49, 4864. (a) Y. J. Xu Chem. Biodiversity, 2013, 10, 1754; (b) X. F. He, S. 2 Yin, Y. C. Ji, Z. S. Su, M. Y. Geng and J. M. Yue, J. Nat. Prod., 2010, 73, 45. D. Arit, M. Jautelat and R. Lantzsch, Angew. Chem. Int. Ed., 3 1981, 20, 703. S. Hanessian, T. Focken, X. Mi, R. Oza, B. Chen, D. Ritson and 4 R. Bequdegnies, J. Org. Chem., 2010, 75, 5601. 5 For selected examples, see: (a) E. B. Hay, H. Zhang and D. P. Curran, J. Am. Chem. Soc., 2015, DOI: 10.1021/ja510608u; (b) V. A. Rassadin, V. V. Sokolov, A. F. Khlebnikov, N. V. Ulin, S. I. Kozhushkov and A. De Meijere, Synthesis, 2012, 44, 372; (c) Y. Liang, X. Jiang and Z.-X. Yu, Chem. Commun., 2011, 47, 6659; (d) W. Tang, X. Wei, N. K. Yee, N. Patel, H. Lee, J. Savoie and C. H. Senanayake, Org. Process Res. Dev., 2011, 15, 1207; (e) H. Zhang and D. P. Curran, J. Am. Chem. Soc., 2011, 133, 10376; (f) B. M. Trost, Y. Nishimura, K. Yamamoto and S. S. McElvain, J. Am. Chem. Soc., 1979, 101, 1328; (g) T. H. Yan and L. A. Paquette, Tetrahedron Lett., 1982, 23, 3227; (h) W. Kirmse, B. G. Bűlow and H. Schepp, Justus Liebigs Ann. Chem., 1966, 691, 41; (i) C. G. Overberger and A. E. Borchert, J. Am. Chem. Soc., 1960, 82, 4896. 6 (a) M.-Y. Chang, Y.-C. Chen and C.-K. Chan, Tetrahedron, 2014, 70, 8908; D. Craig, S. J. Gore, M. I. Lansdell, S. E. Lewis, A. V. W. Mayweg and A. J. P. White, Chem. Commun., 2010, 46, 4991. 7 (a) B.-H. Zhu, R. Zhou, J.-C. Zheng, X.-M. Deng, X.-L. Sun, Q. Shen and Y. Tang, J. Org. Chem., 2010, 75, 3454; (b) H.-J. Pyun, K. Chaudhary, J. R. Somoza, X. C. Sheng and C. U. Kim, Tetrahedron Lett., 2009, 50, 3833; (c) T. Hayashi, A. Yamamoto, Y. Ito, Tetrahedron Lett., 1988, 29, 669. 8 (a) J. Barluenga, N. Quiñones, M. Tomás-Gamasa and M.-P. Cabal, Eur. J. Org. Chem., 2012, 2312; (b) R. C. Larock and E. K. Yum, Tetrahedron, 1996, 52, 2743; (c) T. Hudlicky, T. M. Kutchan, S. R. Wilson and D. T. Mao, J. Am. Chem. Soc., 1980, 102, 6351; (d) E. J. Corey and R. H. Wollenberg, J. Org. Chem., 1975, 40, 2265; (e) M. B. Jarstfer, B. S. J. Blagg, D. H. Rogers and C. D. Poulter, J. Am. Chem. Soc., 1996, 118, 13089. 9 (a) H. Jiang, X.-L. Sun, C.-Y. Zhu, L.-X. Dai and Y. Tang, Tetrahedron, 2008, 64, 5032; (b) J.-L. Zhang, P. W. H. Chan and C. M. Che, Tetrahedron Lett., 2003, 44, 8733; (c) A. de Meijere, T.-J. Schulz, R. R. Kostikov, F. Graupner, T. Murr and T. Bielfeldt, Synthesis, 1991, 547; (d) J. Barluenga, N. Quiñones, M. TomásGamasa and M.-P. Cabal, Eur. J. Org. Chem., 2012, 2312; (e) L. A. Adams, V. K. Aggarwal, R. V. Bonnert, B. Bressel, R. J. Cox, J. Shepherd, J. de Vicente, M. Walter, W. G. Whittingham and C. L. Winn, J. Org. Chem., 2003, 68, 9433. 10 For recent reviews, see: (a) H. M. L. Davies and J. S. Alford, Chem. Soc. Rev., 2014, 43, 5151; (b) D. Gillingham and N. Fei, Chem. Soc. Rev., 2013, 42, 4918; (c) X. Guo and W. Hu, Acc. Chem. Res., 2013, 46, 2427; (d) Q. Xiao, Y. Zhang and J. Wang, Acc. Chem. Res., 2013, 46, 236; (e) M. P. Doyle, R. Duffy, M. Ratnikov and L. Zhou, Chem. Rev., 2010, 110, 704; (f) H. M. L. Davies and J. R. Denton, Chem. Soc. Rev., 2009, 38, 3061. 11 (a) B. Du, C. Yuan, T. Yu, L. Yang, Y. Yang, B. Liu and S. Qin, Chem. Eur. J., 2014, 20, 2613; (b) C. Yuan, B. Du, L. Yang and B. Liu, J. Am. Chem. Soc., 2013, 135, 9291. 12 Tosylhydrazones were used as a safer alternative instead of diazo compounds; for a tutorial review, see: Z. Shao and H. Zhang, Chem. Soc. Rev., 2012, 41, 560 and the references cited thereof. 13 (a) L. Zhao, J. Wang, H. Zheng, Y. Li, K. Yang, B. Cheng, X. Jin, X. Yao and H. Zhai, Org. Lett., 2014, 16, 6378; (b) C.-D. Wang and
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R.-S. Liu, Org. Biomol. Chem., 2012, 10, 8948; (c) H.-L. Wang, Z. Li, G.-W. Wang and S.-D. Yang, Chem. Commun., 2011, 47, 11336; (d) J. F. Briones and H. M. L. Davies, Org. Lett., 2011, 13, 3984; (e) J. H. Hansen, H. M. Davies, Chem. Sci., 2011, 2, 457. X. Zhao, Y. Zhang and J. Wang, Chem. Commun., 2012, 48, 10162 and references cited thereof. See Supplementary Information for more details. For tutorial reviews, see: (a) Y. Zhang and J. Wang, Eur. J. Org. Chem., 2011, 1015; (b) J. Barluenga and C. Valdés, Angew. Chem. Int. Ed., 2011, 50, 7486. For recent examples, see: (a) Y. Xia, Y. Xia, Z. Liu, Y. Zhang and J. Wang, J. Org. Chem., 2014, 79, 7711; (b) X.-L. Xie, S.-F. Zhu, J.-X. Guo, Y. Cai and Q.-L. Zhou, Angew. Chem. Int. Ed., 2014, 53, 2978; (c) Y. Zhu, X. Liu, S. Dong, Y. Zhou, W. Li, L. Lin and X. Feng, Angew. Chem. Int. Ed., 2014, 53, 1636; (d) P.-S. Wang, H.-C. Lin, X.-L. Zhou and L.-Z. Gong, Org. Lett., 2014, 16, 3332; (e) M. Kitamura, M. Kisanuki, K. Kanemura and T. Okauchi, Org. Lett., 2014, 16, 1554. For the proposed Pd (0) carbene mechanism, see: (a) C. Martin, F. Molina, E. Alvarez and T. R. Belderrain, Chem. Eur. J., 2011, 17, 14885; (b) O. Illa, C. Rodriguez-Garcia, C. Acosta-Silva, I. Favier, D. Picurelli, A. Oliva, M. Gómez, V. Branchadell and R. M. Ortuño, Organometallics 2007, 26, 3306; (c) B. F. Straub, J. Am. Chem. Soc., 2002, 124, 14195; (d) A. Nakamura, T. Yoshida, M. Cowie, S. Otsuka and J. A. Ibers, J. Am. Chem. Soc., 1977, 99, 2108. Other Pd (II) catalysts, such as Pd(OAc)2, Pd(TFA)2, Pd(PhCN)2Cl2, Pd(PPh3)2Cl2 and Pd(dppf)Cl2 failed to catalyze the reaction. The combination of Pd2dba3 + PPh3 and Pd(dba)2 + PPh3 exhibited no catalytic activity at all in this reaction. For support from computational chemistry, see Supplementary Information for details.
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