Letter pubs.acs.org/OrgLett
Diastereoselective Synthesis of Dibenzo[b,d]azepines by Pd(II)Catalyzed [5 + 2] Annulation of o‑Arylanilines with Dienes Lu Bai,‡ Yan Wang,‡ Yicong Ge, Jingjing Liu, and Xinjun Luan* Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of the Ministry of Education, College of Chemistry & Materials Science, Northwest University, Xi’an 710127, China S Supporting Information *
ABSTRACT: An efficient method for the construction of dibenzo[b,d]azepines containing two distinct stereogenic elements in a highly diastereoselective fashion is described. The key of the [5 + 2] reaction is to form a π-allylpalladium species through sequential C−H activation and regiospecific migratory insertion of the diene. This observation contrasts with the behavior of 1,2-alkenes that generally underwent direct alkenylation via β-hydride elimination.
T
Huang showed a Rh(III)-catalyzed alkenylation/amidation domino reaction to access a variety of dibenzo[b,d]azepinones.7 In this letter, we describe a novel Pd(II)-catalyzed [5 + 2] reaction by employing 1,3-dienes as two-carbon synthons to couple with aminobiaryls, leading to a new class of intriguing dibenzo[b,d]azepines with both axial and central stereogenic elements in a highly diastereoselective manner (Scheme 1a).
he ubiquity of various azaheterocycles continues to make the development of new applicable methods for their preparation an important research topic.1 Dibenzo[b,d]azepines, which usually possess one asymmetric center and one atropisomeric biphenyl axis, represent a unique structural motif for many biologically active natural products and pharmaceuticals (Figure 1).2 Traditional synthetic methods for accessing
Scheme 1. Pd(II)-Catalyzed Annulations of Aminobiaryls with Olefins
Figure 1. Selected examples containing the dibenzo[b,d]azepine core.
these scaffolds were mainly established through intramolecular cyclizations of highly functionalized substrates that often require multistep synthesis.3 Therefore, the pursuit of alternative methods starting from less expensive and more readily available reagents is of foremost interest. In this context, transition-metalcatalyzed C−H functionalization4 has proven to be a powerful tool for rendering shorter synthetic routes to these frameworks through intermolecular annulation of free aminobiaryls with twocarbon synthons.5−7 For instance, Zhang reported an elegant example of Pd(II)-catalyzed free-amine-directed alkenylation/ hydroamination cascade with α-branched styrenes to build up the seven-membered rings bearing a quaternary center.5 Later on, our group disclosed a Pd(II)-catalyzed [5 + 2] oxidative annulation of aminobiaryls with alkynes for the stereoselective synthesis of imine-type dibenzo[b,d]azepines.6 Very recently, © XXXX American Chemical Society
During the course of our exploration for the transition-metalcatalyzed C−H functionalization/dearomatizing spiroannulations of biaryls with unsaturated partners,8 the reaction between N-Ts-2-arylanilines and 1,3-dienes was found to proceed through an alternative [5 + 2] annulation pathway under Pd(II)-catalysis. Remarkably, this reaction represents a very rare example of [5 + 2] annulations with olefins involving a C−H activation step for the one-step assembly of seven-membered heterocycles.9 In sharp contrast to the prior reports5,10,11 on the formal [5 + 1] annulations of aminobiaryls with monosubstituted olefins Received: February 19, 2017
A
DOI: 10.1021/acs.orglett.7b00503 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Survey the Scope of 2-Arylanilinesa
(Scheme 1b), which were realized by cyclizing the C−H alkenylated product A′ to give dihydrophenanthridines10 or phenanthridine,5,11 this new [5 + 2] annulation process occurred with a completely different mechanistic mode through the direct reductive elimination of π-allylpalladium intermediate A to generate dibenzo[b,d]azepines. At the outset, we started the studies by reacting N-tosyl-2aminobiphenyl (1a) with an electron-deficient diene 2a that engaged well in the known C−H functionalization reactions,12 and the representative data are summarized in Table 1. When the Table 1. Optimization of the Reaction Conditionsa
yield (%)b entry
[M]
oxidant
solvent
3a
4a
1 2 3 4 5 6 7 8 9 10 11 12
Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2 Pd(TFA)2
Cu(OAc)2 Cu(TFA)2 CuCO3·Cu(OH)2 AgOAc BQ K2S2O8 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2 Cu(OAc)2
MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN 1,4-dioxane DMSO DMF DMA
46 22 13 20 0 0 68 82 0 0 74 66
10 0 2 15 0 59 11 6 5 38 22 29
a
0.2 mmol of 1a, 0.4 mmol of 2a, 5.0 mol % of [Pd], and 0.4 mmol of oxidant were used. bIsolated yield.
reaction was performed in the presence of Pd(OAc)2 (5 mol %) and Cu(OAc)2 (2.1 equiv) in MeCN at 120 °C for 36 h, the envisioned [5 + 2] annulation product dibenzo[b,d]azepine 3a was obtained in 46% yield, albeit with the concomitant generation of 10% byproduct 4a (entry 1). The examination on other oxidants (entries 2−6) indicated that Cu(OAc)2 was clearly the better choice for the [5 + 2] annulation. For instance, the reaction with K2S2O8 only provided N-Ts-substituted carbazole 4a,13 while the expected alkene migratory insertion for the generation of product 3a did not occur at all (entry 6). To our delight, the reaction performance was greatly improved by using more electrophilic Pd(TFA)2 (entry 8). Further attempts with other solvents that were often used for Pd(II)-catalyzed C− H functionalization reactions led to either poor reactivities or low chemoselectivities (entries 9−12). Remarkably, the potential alkenylated byproduct through β-hydride elimination was completely prevented by using conjugated diene 2. Finally, it is important to mention that no similar [5 + 2] annulation reaction was observed with the aminobiaryls being N-substituted with a carbonyl, alkyl, aryl, or heteroaryl group. With the optimized reaction conditions in hand, we first examined the substrate scope with respect to 2-arylanilines. As shown in Scheme 2, a number of 2-arylanilines 1a−r bearing various substituents on both aromatic rings reacted properly with 2a, providing the desired [5 + 2] products 3a−r in 29−83% yields with excellent diastereoselectivities (>19:1). Gratifyingly, a broad range of synthetically variable functional groups such as
a
Isolated yield. bThe reaction was run at 1.0 mmol scale.
cyano (1d), chloro (1e), ester (1f), and nitro (1i) groups were well tolerated, offering valuable synthetic handles for further derivatization of dibenzo[b,d]azepines. Moreover, the reaction was compatible with several challenging substrates (1h,m,p) that would cause more sever steric clash for assembling the sevenmembered N-heterocycles, giving products 3h, 3m, and 3p in 72%, 66%, and 29% yield, respectively. Remarkably, substrate 1o, containing two possible C−H functionalization sites, proceeded preferentially at the least sterically encumbered position to generate 3o as the sole product. We next investigated the scope of 1,3-dienes for the [5 + 2] oxidative annulation (Scheme 3). In all cases, the reaction occurred regiospecifically toward the terminal double bond, and other possible regioisomers were not detected. Notably, the more electron-deficient 1,3-diene (2b) containing two ester groups could undergo the title [5 + 2] annulation with 1a, affording a diastereomeric mixture (5:1 dr) of 3a′ in 62% yield. As expected, the amide substrate 2c was applicable for the generation of 3b′. More interestingly, (E)-2,4-pentadienoic acid (2d) was found to participate well in this Pd(II)-catalyzed [5 + 2] annulation, providing compound 3c′ in moderate yield (42%). To our knowledge, it is the first time that the carboxylate diene B
DOI: 10.1021/acs.orglett.7b00503 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 3. Survey the Scope of 1,3-Dienesa
(Scheme 4). The KIE result suggested that the palladiummediated C−H cleavage might not be involved in the rateScheme 4. Kinetic Isotope Experiment
determining step for this domino reaction. On the basis of the results of the experiment and precedent literature,5,9−12 a plausible reaction mechanism for the Pd(II)-catalyzed [5 + 2] annulation reaction is presented in Scheme 5. The catalytic cycle Scheme 5. Proposed Mechanism
a
Isolated yield.
was successfully used as a two-carbon coupling partner for the transition-metal-catalyzed annulation reactions, although the related Heck-process has been known.14 Moreover, the ester group of 2a could be replaced with a variety of aromatic groups being substituted with both electron-donating group (2f) and electron-withdrawing groups (2g,h), giving products 3d′−g′ in excellent yields (82−91%). It is notable that the reactions with 1,3-dienes (2i,j) bearing a 2-thienyl or a 2-furyl group were able to proceed smoothly to deliver 3h′−i′. In addition, alkylsubstituted diene 2k was found to be tolerable as well, providing 3j′ in 89% yield. However, the limitation of this [5 + 2] oxidative annulation protocol became apparent when 1,3-dienes 2l−m were tested. To elucidate the structure of dibenzo[b,d]azepines 3, we performed X-ray crystallographic studies on 3b, 3f, and 3b′,15 and it revealed that all the three compounds existed as the thermodynamically more stable diastereomer with respect to the tertiary carbon center and atropisomeric biaryl axis (Figure 2). To obtain some mechanistic information, we carried out an intermolecular competition experiment between [D1]-1a and -2a, and the value of the kinetic isotope effect (KIE) was 1.0
is initiated with complexation of Pd(II) species with substrate 1a and followed by the electrophilic palladation of C−H bond to generate a six-membered palladium species I. Subsequently, coordination and migratory insertion of the 1,3-diene 2 with I forms an eight-membered palladacycle III, which is further stabilized with the second C−C double bond from 2. Finally, C− N reductive elimination takes place to deliver the desired product 3 and concomitantly regenerates Pd(II) species with Cu(II) oxidant to furnish the catalytic cycle. Additionally, it should be noted that direct reductive elimination of I to form byproduct 4a could be efficiently inhibited by careful control of reaction conditions. More importantly, the use of conjugated diene 3 dramatically prevented the potential reaction pathway to give undesired 5 through the β-hydride elimination of intermediate III. In summary, we have developed a novel palladium(II)catalyzed [5 + 2] oxidative annulation of o-arylanilines with 1,3dienes, providing a highly efficient route to access a new family of dibenzo[b,d]azepines in good yields with excellent diastereoselectivities. Compared to the oxidative Heck processes,5,10,11 this [5 + 2] annulation reaction suppressed the β-hydride elimination with the assistance of an additional C−C double bond in the 1,3dienes and eventually prevented the formation of undesired Heck-type alkenylated byproducts. Remarkably, the method may have potential applications in the synthesis of related natural products and pharmaceuticals.
Figure 2. X-ray structures of 3b, 3f, and 3b′ (from left to right). Thermal ellipsoids shown at 30% probability. C
DOI: 10.1021/acs.orglett.7b00503 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
■
Yang, X.; Liu, J.; Nan, J.; Bai, L.; Wang, Y.; Luan, X. J. Org. Chem. 2015, 80, 3349. (9) To our knowledge, there was only one example within this category, see: Casanova, N.; Del Rio, K. P.; García-Fandiño, R.; Mascareñas, J. L.; Gulías, M. ACS Catal. 2016, 6, 3349. (10) (a) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.; Nomura, M. J. Org. Chem. 1998, 63, 5211. (b) Kim, B. S.; Lee, S. Y.; Youn, S. W. Chem. Asian J. 2011, 6, 1952. (11) Liu, Y.-Y.; Song, R.-J.; Wu, C.-Y.; Gong, L.; Hu, M.; Wang, Z.; Xie, Y.; Li, J. Adv. Synth. Catal. 2012, 354, 347. (12) (a) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagné, M. R.; LloydJones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066. (b) Zhao, D.; Lied, F.; Glorius, F. Chem. Sci. 2014, 5, 2869. (13) (a) Tsang, W. C. P.; Munday, R. H.; Brasche, G.; Zheng, N.; Buchwald, S. L. J. Org. Chem. 2008, 73, 7603. (b) Youn, S. W.; Bihn, J. H.; Kim, B. S. Org. Lett. 2011, 13, 3738. (14) Patel, B. A.; Dickerson, J. E.; Heck, R. F. J. Org. Chem. 1978, 43, 5018. (15) The crystal data of 3b, 3f, and 3b′ have been deposited in CCDC with numbers of 1529191, 1529193, and 1528196.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00503. Experimental procedures and spectral data for all new compounds (PDF) Crystallographic data for 3b (CIF), 3f (CIF), and 3b′(CIF)
■
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Xinjun Luan: 0000-0002-5692-0936 Author Contributions ‡
These authors contributed equally.
Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS This work was supported by the NSFC (21672169), the “1000 Youth Talents Plan”, and the Education Department of Shaanxi Province (12JS113). We thank Ms. Haihua Wang at Northwest University for X-ray crystallographic assistance.
■
REFERENCES
(1) (a) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of Heterocycles: Structures, Reactions, Synthesis, and Applications, 3rd ed; Wiley-VCH: Weinheim, Germany, 2012. (b) Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (c) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642. (2) (a) Pegoraro, S.; Lang, M.; Dreker, T.; Kraus, J.; Hamm, S.; Meere, C.; Feurle, J.; Tasler, S.; Prütting, S.; Kuras, Z.; Visan, V.; Grissmer, S. Bioorg. Med. Chem. Lett. 2009, 19, 2299. (b) Phutdhawong, W.; Eksinitkun, G.; Ruensumran, W.; Taechowisan, T.; Phutdhawong, W. S. Arch. Pharmacal Res. 2012, 35, 769. (c) Zhang, B.; Bao, M.; Zeng, C.; Zhong, X.; Ni, L.; Zeng, Y.; Cai, X. Org. Lett. 2014, 16, 6400. (d) Nair, J. S.; Sheikh, T.; Ho, A. L.; Schwartz, G. K. Anticancer Res. 2013, 33, 1307. (3) (a) Hoffmann-Emery, F.; Jakob-Roetne, R.; Flohr, A.; Bliss, F.; Reents, R. Tetrahedron Lett. 2009, 50, 6380. (b) Tabata, H.; Suzuki, H.; Akiba, K.; Takahashi, H.; Natsugari, H. J. Org. Chem. 2010, 75, 5984. (c) Pan, X.; Wilcox, C. S. J. Org. Chem. 2010, 75, 6445. (d) Bhakuni, B. S.; Kumar, A.; Balkrishna, S. J.; Sheikh, J. A.; Konar, S.; Kumar, S. Org. Lett. 2012, 14, 2838. (e) Liwosz, T. W.; Chemler, S. R. Chem. - Eur. J. 2013, 19, 12771. (f) Saget, T.; Cramer, N. Angew. Chem., Int. Ed. 2013, 52, 7865. (4) For selected reviews, see: (a) Fagnou, K. Top. Curr. Chem. 2009, 292, 35. (b) Wencel-Delord, J.; Dröge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (c) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (d) Engle, K. M.; Mei, T.; Wasa, M.; Yu, J. Acc. Chem. Res. 2012, 45, 788. (e) Colby, D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012, 45, 814. (f) Arockiam, P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879. (g) Ackermann, L. A. Acc. Chem. Res. 2014, 47, 281. (h) Song, G.; Li, X. Acc. Chem. Res. 2015, 48, 1007. (i) Yang, L.; Huang, H. Chem. Rev. 2015, 115, 3468. (j) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A. Chem. Rev. 2015, 115, 12138. (5) Liang, Z.; Ju, L.; Xie, Y.; Huang, L.; Zhang, Y. Chem. - Eur. J. 2012, 18, 15816. (6) Zuo, Z.; Liu, J.; Nan, J.; Fan, L.; Sun, W.; Wang, Y.; Luan, X. Angew. Chem., Int. Ed. 2015, 54, 15385. (7) Bai, P.; Huang, X.; Xu, G.; Huang, Z. Org. Lett. 2016, 18, 3058. (8) (a) Nan, J.; Zuo, Z.; Luo, L.; Bai, L.; Zheng, H.; Yuan, Y.; Liu, J.; Luan, X.; Wang, Y. J. Am. Chem. Soc. 2013, 135, 17306. (b) Zuo, Z.; D
DOI: 10.1021/acs.orglett.7b00503 Org. Lett. XXXX, XXX, XXX−XXX
