Letter pubs.acs.org/OrgLett
Pd-Catalyzed Regioselective 1,2-Difunctionalization of Vinylarenes with Alkenyl Triflates and Aryl Boronic Acids at Ambient Temperature Zhijie Kuang,† Kai Yang,† and Qiuling Song*,†,‡ †
Institute of Next Generation Matter Transformation and ‡Fujian Provincial Key Laboratory of Biochemical Technology, College of Chemical Engineering at Huaqiao University, 668 Jimei Boulevard, Xiamen, Fujian 361021, P. R. China S Supporting Information *
ABSTRACT: A Pd-catalyzed highly regioselective 1,2-difunctionalization of vinylarenes is disclosed in which multisubstituted olefins are efficiently and conveniently constructed under ambient temperature with good compatibility and a broad substrate scope. Notably, a quarternary carbon center could be readily built up from 1,1-disubstituted styrenes, which are big challenges in the previous methods.
P
by changing the vinyl triflate with aromatic diazonium salt rendering corresponding 1,2-diarylation products (Scheme 1c).13 To our surprise, as the most abundant and simplest aryl olefin−styrene derivatives, no practical and efficient 1,2diarylation methods have been successfully developed from them yet with two different aryl species; therefore, it is highly desirable yet very challenging to develop such methods given that the corresponding products are valuable structural motifs in pharmaceuticals and organic synthesis.14 On the basis of our previous studies,15 the key issue to access 1,2-difunctionalization product of styrene derivatives lies in the feasibility to obtain comparable stable Heck addition Pd intermediate. We envision that 2-vinylnaphthalene should be a good starting olefin due to the extensive π system adjacent to the in situ generated Heck addition Pd intermediate. If our assumption is correct, we then might extend our system to styrene derivatives under the proper conditions. Meanwhile, 1,1-disubstituted ethylenes are normally inert substrates for 1,2difunctionalization, probably due to steric hindrance during the second functionalization to generate a quarternary carbon center. Herein, we report a mild and efficient 1,2-difunctionalization of olefins with aryl boronic acids and vinyl OTf as coupling partners. This transformation features broad substrate scope and good functional group tolerance as well as very mild reaction conditions. Both vinylnaphthalene and styrene derivatives are good candidates for this transformation; remarkably, 1,1-disubstituted olefins are compatible under the transformation, constructing two new C−C bonds along with a newly formed quarternary carbon center (Scheme 1d). At the outset, 2-vinylnaphthalene (1) (1.0 equiv), (4methoxyphenyl)boronic acid (2) (1.2 equiv), and the vinyl triflate (3) (1.2 equiv) were chosen as the primal substrates in the presence of Cs2CO3 (2.0 equiv) and Pd2(dba)3·CHCl3 (5 mol %) in DMF under N2 for 12 h. To our delight, the desired
alladium-catalyzed difunctionalization of olefins, such as aliphatic alkenes, aromatic alkenes, or cyclic norbornenes, has been extensively explored, and it has become an important strategy to access valuable molecules from readily available starting materials via simultaneous construction of two C−X bonds.1−10 Despite great advances, 1,2-difunctionalization of olefins with two other species, so-called three-component reactions is still a big challenge in Pd catalysis. In 2009, Sigman and co-workers11 reported a palladium-catalyzed 1,2-diarylation of styrenes with 2 equiv of arylstannanes in which the aryl moiety is limited to two of the same toxic and difficult to handle arylstannane compounds (Scheme 1a). In order to Scheme 1. Summary of 1,2-Difunctionalization of Olefins
overcome the deficiency, the same group selected monosubstituted 1,3-dienes as substrates two years later and successfully obtained 1,2-difunctionalization of one C−C double bond (not 1,4-difunctionalization) with aromatic boronic acids and vinyl triflates as two coupling partners, while another C−C double bond was untouched (Scheme 1b).12 Three years later, the same group further broadened the application of this strategy © 2017 American Chemical Society
Received: April 6, 2017 Published: May 11, 2017 2702
DOI: 10.1021/acs.orglett.7b01036 Org. Lett. 2017, 19, 2702−2705
Letter
Organic Letters product 4 was obtained in 86% GC yield (Table 1, entry 1). Further base screening suggested that only K2CO3 can improve
Scheme 2. Scope of the Boronic Acids and the Vinyl Triflatesa
Table 1. Optimization of the Reaction Conditionsa
entry
base (2.0 equiv)
solvent (1.5 mL)
yield (%) of 4b
1 2 3 4 5 6 7c 8 9d 10e 11f
Cs2CO3 K2CO3 Na2CO3 K3PO4 KF K2CO3 K2CO3 K2CO3 K2CO3 K2CO3 K2CO3
DMF DMF DMF DMF DMF t-Am-OH THF DMA DMF DMF DMF
86 89 68 70 53 60 trace 60 98 88 >99 (92)
a
Reaction conditions: all reactions were performed on a 0.2 mmol scale with respect to 1. bYields determined by GC by utilizing dodecane as internal standard; number in parentheses represents the separation yield. cWhen THF was changed to H2O, DMSO, 1,4dioxane, or toluene the yield of 4 was still only a trace. dK2CO3 was increased to 2.5 equiv. e2 was increased to 1.5 equiv and the reaction proceeded for 16 h. f2 was increased to 1.5 equiv, K2CO3 was increased to 2.5 equiv, and the reaction proceeded for 16 h.
a
Reaction conditions: all reactions were performed under the standard conditions. Isolated yields are reported. b1.5 mmol of compound 1 under standard conditions for 20 h.
yield and regional selectivity16 (entry 2). Then the effect of solvent was explored, and surprisingly, only DMF, DMA, or tAm-OH was enable the transformation smoothly; others, such as H2O, toluene, or DMSO, just led to a significant decrease in the yields as well as in regioselectivity (entries 6−8). When the amount of K2CO3 was increased to 2.5 equiv or (4methoxyphenyl)boronic acid (2) was increased to 2.0 equiv, the yield of product 4 was increased dramatically (entries 9 and 10). After extensive optimizations, we finally determined the optimal conditions for the reaction (entry 11): 1.0 equiv of olefin 1, 1.5 equiv of (4-methoxyphenyl)boronic acid (2), and 1.0 equiv of vinyl triflate 3 reacted with K2CO3 (2.5 equiv) in the presence of Pd2dba3CHCl3 (5 mol %) in DMF under N2 atmosphere at ambient temperature for 16 h. With the optimal conditions in hand, the scope of boronic acids and vinyl triflates was first investigated with 2-vinylnaphthalene (1), and the results are depicted in Scheme 2. Gratifyingly, both the electron-donating groups (OMe, tBu, or Me) and the electron-withdrawing groups (acyl, F, and Cl) on the aromatic rings of boronic acids were tolerable under the standard conditions and the corresponding desired products were obtained in good to excellent yields (4−6, 10, 11, 16 and 7−9). Steric hindrance had little effect on the transformation since the ortho-substituent on the aromatic ring of boronic acids still led to the desired product in good yield (10). (4Vinylphenyl)boronic acid was predicted to be incompatible under the standard conditions due to the coupling reaction between the vinyl group on (4-vinylphenyl)boronic acid and vinyl triflate; interestingly, the desired product 12 was still obtained in 33% yield. Naphthylboronic acid was also a good
substrate, rendering the desired product in moderate yield (13). Serendipitously, thiophene-3-yl boronic acid was a good candidate in the reaction, leading to product 14 in 51% yield, and it should to be pointed out that the same boronic acid did not work in the previous reports.9,10,12,13 Furthermore, the scope of vinyl triflates was explored under the standard conditions (15−20). The vinyl triflates ranging from medium to large rings (five- to eight-membered rings) were all good candidates and smoothly converted into the target products in excellent yields (15−18). The tBu substituent on the alignment of the ring did not affect the efficiency of the transformation (19). The vinyl triflate with a strong electron-withdrawing group (ester group) on was also tolerable in this transformation, rendering α,β-unsaturated compound 20 in 64% yield. Notably, the compound 20 could be further manipulated to increase its diversification. Under the optimal conditions, we subsequently investigated the scope of vinylarenes (Scheme 3). Not surprisingly, a variety of vinylnaphthalenes bearing both electron-donating or electron-withdrawing substituents underwent the reactions successfully to afford the corresponding 1,2-difunctionalization products 21−25 in good yields and excellent regioselectivities. Even the 1-vinylnaphthalene could lead to the product 23 in 71% yield. However, styrene derivatives are poor candidates under the optimal conditions, and the target molecule was only obtained in 28% GC yield. Gratifyingly, when the optimal conditions were finely tuned (see the SI for detailed information on optimization of reaction conditions for the styrene), the styrene derivatives were smoothly transformed into the corresponding desired products in decent yields (26− 2703
DOI: 10.1021/acs.orglett.7b01036 Org. Lett. 2017, 19, 2702−2705
Letter
Organic Letters Scheme 3. Scope of the Olefinsa
of this reaction, delivering the target molecule 33 in moderate yield (50%). However, 2-methoxy-6-(prop-1-en-2-yl)naphthalene could not proceed well under the standard conditions, until heating to 50 °C, and eventually, the desired product 34 was obtained in 45% yield. Of note, when the substituents R on the aromatic ring of styrene derivatives were cyclopropyl (35) or Et (36), the reactions also proceeded, but with considerable isomers and other unknown byproducts, leading to the difficult separation, which might stem from the steric hindrance. Reactions that scaled up to 1.5 or 2.0 mmol were also performed under the standard conditions; to our delight, the corresponding products were obtained in good yield without significant loss of efficiency (18, 21, 27, and 31). In order to gain insight into the mechanism of the transformation, deuterium-labeled experiments were carried out with β,β-dis-deuterated 2-vinylnaphthalene, and 48% of the desired product 4-D2 was obtained with two deuterium atoms intact on the β-position (Scheme 4). In the experiment, the two Scheme 4. Deuterium-Labeled Experiment
deuterium atoms on the β-position did not accept any migrations before or after the reaction. This suggests that the construction of the target product did not go through the process of Pd−D reinsertion over the C−C double bonds stemming from β-H elimination. The plausible mechanism profile is shown in Scheme 5. The vinyl triflate is inserted by Pd0Ln, resulting in the palladium(II) a
Scheme 5. Mechanism Profile
30). Heterocyclic systems, such as 5-vinylbenzo[b]thiophene and 2-vinylthiophene, were both tolerated under the corresponding conditions, and the desired products were obtained in 81% and 84% yield, respectively (25 and 30). It is noteworthy that α-Me-substituted 2-vinylnaphthalene was also a good substrate for this transformation and afforded the desired product 31 along with a newly formed quartenary carbon center in 78% yield. This transformation has rarely been reported in the previous relevant literature.12,13,15 Therefore, we further examined the universality of the discovery (31−34). When the 2-(prop-1-en-2-yl)naphthalene was employed under the standard conditions, the reactions proceeded smoothly, regardless of the electron-donating group (Me) or electronwithdrawing group (CF3) on the aromatic rings of boronic acids (31 and 32). Moreover, the heterocyclic system, 2-(prop1-en-2-yl)benzo[b]thiophene, did not mar the smooth running
complex A at first. Then, migratory insertion of alkenes 1 to A generates the palladium(II) intermediate B, which is tautomerized into π-allyl Pd-intermediate C. Subsequent crosscoupling of the intermediate B or C with an aryl boronic acid generated the final 1,2-difunctionalization product E via transmetalation and reductive elimination. Some applications are accomplished in Scheme 6. The scaleup experiment was carried out further on 8 mmol under the standard conditions; notably, the catalyst loading could be dramatically reduced to 2 mol %, and the desired product 4 was
Reaction conditions: all reactions were performed under the standard conditions except as noted. Isolated yields are shown. b1.5 mmol of vinylarene under the standard conditions for 20 h. cWhen the substrates were styrenes, the reactions were as follows: 0.2 mmol of styrene derivative, 1.5 equiv of boronic acid and 1.0 equiv of vinyl triflate (3) in the presence of Cs2CO3 (2.5 equiv) and Pd2dba3CHCl3 (5 mol %) in DMF under N2 atmosphere at 0 °C for a further 24 h. d2 mmol of 4-nitrostyrene under the standard conditions for 24 h. e1.5 mmol of 2-(prop-1-en-2-yl)naphthalene under the standard conditions for 24 h. fThe reaction temperature was 50 °C.
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DOI: 10.1021/acs.orglett.7b01036 Org. Lett. 2017, 19, 2702−2705
Letter
Organic Letters
Program, the Program of Innovative Research Team of Huaqiao University (Z14X0047), and the Graduate Innovation Fund (for Z.K.) of Huaqiao University is gratefully acknowledged. We also thank the Instrumental Analysis Center of Huaqiao University for instrumental support.
Scheme 6. Scale-up Reaction and Synthetic Utilities
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obtained in 70% for a longer reaction time (40 h). The reductive experiment was conducted with compound 4 as starting material under ((BOH)2)2 at room temperature giving the target product 37 (reduction of C−C double bond to C−C single bond) in 85% yield.17 The oxidative experiment was furtherly performed with 4 under the classic conditions with 3chlorobenzoperoxoic acid (mCPBA) as oxidant, and the corresponding epoxide 38 was obtained in 94% yield.18 In summary, a Pd-catalyzed regioselective 1,2-difunctionalization of vinylarenes with alkenyl triflates and aryl boronic acids was developed to conveniently and efficiently construct multisubstituted olefins under ambient temperature with good compatibility of a wide variety of substrates. Notably, a quarternary carbon center could be easily built from small steric 1,1-disubstituent styrenes, which is rarely reported in similar methods. This reaction has guiding significance for the enantioselective construction of multisubstituted olefins for the simultaneous construction of two new C−C bonds.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01036. Experimental procedure, characterization data, and 1H, 13 C NMR spectra (PDF)
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REFERENCES
(1) (a) Obora, Y.; Tsuji, Y.; Kawamura, T. J. Am. Chem. Soc. 1995, 117, 9814. (b) Bäckvall, J. E.; Nystroem, J. E.; Nordberg, R. E. J. Am. Chem. Soc. 1985, 107, 3676. (c) Miró, J.; del Pozo, C.; Toste, F. D.; Fustero, S. Angew. Chem., Int. Ed. 2016, 55, 9045. (d) Domański, S.; Chaładaj, W. ACS Catal. 2016, 6, 3452. (e) Lin, Y.; Kong, W.; Song, Q. Org. Lett. 2016, 18, 3702. (f) McCammant, M. S.; Shigeta, T.; Sigman, M. S. Org. Lett. 2016, 18, 1792. (2) (a) Yamamoto, E.; Hilton, M. J.; Orlandi, M.; Saini, V.; Toste, F. D.; Sigman, M. S. J. Am. Chem. Soc. 2016, 138, 15877. (b) Yang, K.; Song, Q. J. Org. Chem. 2016, 81, 1000. (3) (a) Wei, F.; Wei, L.; Zhou, L.; Tung, C.-H.; Ma, Y.; Xu, Z. Asian J. Org. Chem. 2016, 5, 971. (b) Vachhani, D. D.; Butani, H. H.; Sharma, N.; Bhoya, U. C.; Shah, A. K.; Van der Eycken, E. V. Chem. Commun. 2015, 51, 14862−14865. (c) Liu, X.; Li, B.; Gu, Z. J. Org. Chem. 2015, 80, 7547−7554. (d) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc. 2010, 132, 2856. (4) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179−7181. (5) Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc. 2009, 131, 3846− 3847. (6) Pinto, A.; Jia, Y.; Neuville, L.; Zhu, J. Chem. - Eur. J. 2007, 13, 961−967. (7) Kalyani, D.; Satterfield, A. D.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 8419. (8) McCammant, M. S.; Sigman, M. S. Chem. Sci. 2015, 6, 1355. (9) Saini, V.; Liao, L.; Wang, Q.; Jana, R.; Sigman, M. S. Org. Lett. 2013, 15, 5008. (10) Saini, V.; Sigman, M. S. J. Am. Chem. Soc. 2012, 134, 11372. (11) Urkalan, K. B.; Sigman, M. S. Angew. Chem., Int. Ed. 2009, 48, 3146. (12) Liao, L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 5784. (13) Stokes, B. J.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S. Org. Lett. 2014, 16, 4666. (14) (a) Fujita, S.; Abe, M.; Shibuya, M.; Yamamoto, Y. Org. Lett. 2015, 17, 3822. (b) Wang, Y.-F.; Zhu, X.; Chiba, S. J. Am. Chem. Soc. 2012, 134, 3679. (c) Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536. (d) Wiley, R. A.; Pearson, D. A.; Schmidt, V.; Wesche, S. B.; Roxon, J. J. J. Med. Chem. 1983, 26, 1077. (15) Yang, K.; Song, Q. Org. Lett. 2016, 18, 5460. (16) In the process of screening, we found some isomers, based on ref 3b and the possible reaction mechanism, which we gave the probable structures shown in the Supporting Information. (17) Cummings, S. P.; Le, T.-N.; Fernandez, G. E.; Quiambao, L. G.; Stokes, B. J. J. Am. Chem. Soc. 2016, 138, 6107. (18) Collins, S. G.; O’Sullivan, O. C. M.; Kelleher, P. G.; Maguire, A. R. Org. Biomol. Chem. 2013, 11, 1706.
AUTHOR INFORMATION
Corresponding Author
*Fax: 86-592-6162990. E-mail:
[email protected]. ORCID
Qiuling Song: 0000-0002-9836-8860 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from the Recruitment Program of Global Experts (1000 Talents Plan), the Natural Science Foundation of Fujian Province (2016J01064), the Fujian Hundred Talents 2705
DOI: 10.1021/acs.orglett.7b01036 Org. Lett. 2017, 19, 2702−2705
