Article pubs.acs.org/Organometallics
Chromium-Catalyzed Regioselective Hydropyridination of Styrenes Yuexuan Li, Gongda Deng, and Xiaoming Zeng* Center for Organic Chemistry, Frontier Institute of Science and Technology, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, P. R. China S Supporting Information *
ABSTRACT: The first chromium-catalyzed regioselective addition of para-C−H bonds of pyridines across styrenes is disclosed. The hydrofunctionalization reaction was promoted by a low-cost chromium(III) chloride combining with a cyclohexyl Grignard reagent and 2,2′-bipyridine, which allows for the highly selective formation of branched products via the cleavage of inert C−H bonds of pyridines.
P
triethylborane as a crucial additive for achieving high regioselectivity.11,12 In the past years, the employment of earth-abundant firstrow transition metals as alternatives to expensive late transitionmetal catalysts attracted immense attention for developing costeffective synthetic protocols.13,14 As one of the earth-abundant sources,15 chromium salts have been widely used in the promotion of ethylene oligomerization16 and classic Nozaki− Hiyama−Kishi reactions,17 but their catalytic ability in the cleavage of inert chemical bonds has rarely been investigated.18−21 Herein, we report a chromium-catalyzed selective addition of pyridines across styrenes via the cleavage of paraC−H bonds (Scheme 1b). This hydrofunctionalization reaction was enabled by a simple, inexpensive chromium(III) chloride combining with a Grignard reagent as reductant, leading to branch-selective pyridine derivatives under mild conditions. At the beginning, the effect of Grignard reagents on the selective addition of pyridine into styrene was studied. Using a mixture of CrCl2, 2,2′-bipyridine, and methyl Grignard reagent, we were pleased to find that the branch-selective adduct 3a was produced via the activation of the para-C−H bond of pyridine (Table 1, entry 2). Replacement with an alternative cyclohexyl Grignard resulted in an increased conversion (entry 3). Interestingly, the employment of chromium(III) chloride slightly improved the reaction, leading to 3a in 40% yield and high branch selectivity (entry 4). Other ligands, including 4,4′di-tert-butyl bipyridine (dtbpy), 1,10-phenanthroline, 1,3dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), phosphines (S-Phos and Dppe), and N-heterocyclic carbene (IPr), cannot improve the transformation (entries 5−10). Common chromium salts such as Cr(acac)3 and Cr(CO)6 led to a low conversion, implying an important anion effect in the catalysis (entries 11 and 12). Further screening revealed that the use of organic base as additive could dramatically increase the reaction rate. A good result was obtained when using 1,8diazabicyclo[5.4.0]undec-7-ene (DBU) (1.5 equiv) (entry
yridines are important structural motifs that exist in a diverse range of pharmaceuticals, natural products, ligands, and materials.1 Thus, the development of straightforward, stepeconomical strategies to achieve pyridine functionalization gained broad interests of chemists.2,3 Among the various methods for the modification of pyridines, the direct addition of C−H bonds across unsaturated C−C bonds provides a practical route to introduce a functional alkyl or alkenyl substituent with 100% atom efficiency but remains a great challenge because of the low reactivity of pyridine and the siteselectivity issue.4 Compared to the remarkable achievements in the transformation of ortho-C−H bonds of pyridines with Rh,5 Ru,6 Ni,7 Zr,8 and Ln catalysts,9 examples of hydropyridination reaction by the direct addition of para-C−H bonds are still rare (Scheme 1a). Nakao, Hiyama, and Ong’s pioneering work disclosed the selective modification of pyridines via the activation of para-C−H bonds with a nickel/Lewis acid catalytic system.10 Cobalt-promoted alkylation of pyridines was recently described by Matsunaga and Kanai by use of Scheme 1. Transition-Metal-Catalyzed Hydropyridination
Received: December 22, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.5b01021 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics Table 1. Optimizing Reaction Conditionsa,b
entry
metal salt
ligand
R
additive
1 2 3 4 5 6 7 8 9 10 11 12 13d 14d 15d 16d,e 17d,e,f 18d,e,f 19d,e,g 20d,e,h 21d,e,g 22d,e 23d,e 24d,e
none CrCl2 CrCl2 CrCl3 CrCl3 CrCl3 CrCl3 CrCl3 CrCl3 CrCl3 Cr(acac)3 Cr(CO)6 CrCl3 CrCl3 CrCl3 CrCl3 CrCl3 CrCl3 CrCl3 CrCl3 CrCl3 Ni(cod)2 FeCl3 CoCl2
2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy dtbpy 1,10-phen DMPU S-Phos Dppe IPr·HCl IPr·HCl IPr·HCl 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy 2,2′-bpy
Me Me Cy Cy Cy Cy Cy Cy Cy Cy Cy Cy Cy Cy Cy Cy Cy Cy n BuLi Zn DIBA-H Cy Cy Cy
Et3N (1.0) DBU (1.0) DBU (1.0) DBU (1.5) DBU DBU DBU DBU DBU DBU
(1.5) (1.5) (1.5) (1.5) (1.5) (1.5)
3a (%) nd 9 36 40 32 36 33 30 20 22 15 50:1 >50:1 >30:1 >99:1 >50:1 >50:1
>50:1 >50:1 >30:1 >30:1 >30:1 >30:1
a
Conditions: 1a (0.5 mmol), 2a (0.65 mmol), Cr salt (0.05 mmol), RMgBr (0.5 mmol, 1.0 M in THF), ligand (0.05 mmol), additive (X equiv), 60 °C, 20 h. b1H NMR yield using dibromomethane as internal standard. cThe regioisomeric ratio was estimated by 1H NMR analysis of crude products. d2,2′-Bipyridine (0.1 mmol) was employed. e80 °C. f48 h, isolated yield gnBuLi or DIBA-H (0.25 mmol) was employed. hZn (1 mmol) was employed.
17).22 It was worth mentioning that the hydrofunctionalization was carried out with high site selectivity, typically producing para- and branch-selective alkylated compounds. Notably, forming a small amount of bicyclohexane as byproduct was observed in these cases. The corresponding ortho- and metaalkylated products of pyridine, as well as the alkylation product of 2,2′-bipyridine, were not detected. On the other hand, the addition of pyridine to styrene did not take place by use of n BuLi, zinc powder, or DIBA-H as reductive reagent (entries 19−21). Other first-row transition-metal salts including Ni(cod)2, FeCl3, and CoCl2 cannot improve the conversion under the present conditions (entries 22−24). Inspired by the results, the substrate scope was next examined. As shown in Table 2, with a mixed CrCl3, 2,2′bipyridine, cyclohexylmagnesium bromide, and DBU, the hydropyridination reaction using 4-methyl and tert-butylsubstituted styrenes occurred effectively, leading to branched compounds 3b and 3c in good yields (entries 2 and 3). The incorporation of substituents of methyl and ethyl into the orthoposition of pyridine has no obvious influence on the transformation (entries 4−9). Strikingly, the hydrofunctionalization reaction with 3-methylpyridine took place smoothly, suggesting that the steric hindrance around the para-C−H bond does not hamper the efficiency of the conversion (entries 10−12). Similarly, introducing the electron-donating methoxy
group into the meta-position of pyridine allowed for forming the branched adducts 3m−3p in moderate to good yields (entries 13−16). Note that 2-phenylpyridine is suitable for the hydrofunctionalization reaction with absolute cleavage of the para-C−H bond of pyridine (entry 17). Moreover, the reactions of 5,6,7,8-tetrahydroquinoline and 2,3-cyclopentenopyridine with styrene provide easy access to the branched products 3r and 3s (entries 18 and 19). However, the addition of other N-heterocycles such as quinoline, pyrazine, and pyrimidine across styrene does not take place in our case. Further study shows that the hydrofunctionalization of unactivated aliphatic alkene cannot form the desired adduct. To gain insight into the mechanism, the deuterium experiment was carried out by the treatment of 1a-d5 (>99% D) with styrene (Scheme 2a). It was found that almost no deuterium was lost at the electrophilic ortho-position of pyridine. It may imply that a nucleophilic addition/rearomatization process can be excluded.11 Similar to the result of Nakao/Hiyama’s reaction, only a trace amount of hydrogen was detected at the meta-position of pyridine.10a We then performed the intermolecular kinetic isotope effect (KIE) experiment (Scheme 2b). A slightly lower value of 1.2 was obtained, suggesting that the cleavage of the C−H bond of pyridine may not be the turnover-limiting step. In the absence of pyridine, forming ethylbenzene in 20% yield was observed B
DOI: 10.1021/acs.organomet.5b01021 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics Table 2. Cr-Catalyzed Hydropyridination of Styrenesa,b
Scheme 2. H/D Scrambling Experiments
In summary, we have disclosed a new chromium-catalyzed regioselective hydropyridination of styrenes by the cleavage of para-C−H bonds of pyridines. It is the first time to demonstrate that chromium possesses practical ability in the activation of inert C−H bonds by dispensing with a Grignard partner. This reaction provides a cost-effective strategy for the direct functionalization of synthetically appealing pyridines. Further mechanistic studies on the synthesis and characterization of active intermediates and exploring a plausible reaction pathway are ongoing.
a
Conditions: 1 (0.5 mmol), 2 (0.65 mmol), CrCl3 (0.05 mmol), 2,2′bpy (0.1 mmol), CyMgBr (0.5 mmol, 1.0 M in THF), DBU (0.75 mmol), 80 °C, 48 h. bIsolated yield. cIPr·HCl (0.1 mmol) was employed without DBU.
■
EXPERIMENTAL SECTION
■
ASSOCIATED CONTENT
General Procedure for Chromium-Catalyzed Hydropyridination of Styrenes. In a dried Schlenk flask were placed CrCl3 (8 mg, 0.05 mmol), 2,2′-bipyridine (16 mg, 0.1 mmol), pyridine (40 μL, 0.5 mmol), and DBU (112 μL, 0.75 mmol). Then, a solution of cyclohexylmagnesium bromide in THF (0.5 mmol, 0.5 mL) was added dropwise at 0 °C. After stirring for 30 min, styrene (75 μL, 0.65 mmol) was added, and the reaction mixture was stirred at 80 °C for 48 h. Subsequently, the mixture was cooled to room temperature and quenched with a solution of NH4Cl. The crude product was extracted with ethyl acetate and dried with anhydrous Na2SO4. After removing the volatiles under vacuum, the residue was purified by flash silica gel column chromatography (eluent: petroleum/EtOAc/Et3N = 25/5/1) to give the adduct compound.
(eq 1). Notably, by treating pyridine with a benzyl Grignard reagent under the standard conditions, only a trace amount of the related coupling product 6 was obtained (eq 2). These indicate that a pathway by forming a Grignard reagent with styrene, followed by coupling with pyridine, may not be involved in the transformation.12
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.organomet.5b01021. C
DOI: 10.1021/acs.organomet.5b01021 Organometallics XXXX, XXX, XXX−XXX
Article
Organometallics
■
Chem. Res. 2008, 41, 1500−1511. (g) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061−6067. (15) McDonough, W. F. Science 2011, 331, 1397−1398. (16) For selected recent examples of Cr-promoted ethylene oligomerization, see: (a) Ai, P.; Danopoulos, A. A.; Braunstein, P. Organometallics 2015, 34, 4109−4116. (b) Kulangara, S. V.; Haveman, D.; Vidjayacoumar, B.; Korobkov, I.; Gambarotta, S.; Duchateau, R. Organometallics 2015, 34, 1203−1210. (c) Zhang, J.; Qiu, P.; Liu, Z.; Liu, B.; Batrice, R. J.; Botoshansky, M.; Eisen, M. S. ACS Catal. 2015, 5, 3562−3574. (17) For selected examples of Cr-promoted Nozaki−Hiyama−Kishi reactions, see: (a) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc. 1977, 99, 3179−3181. (b) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Tetrahedron Lett. 1983, 24, 5281−5284. (c) Fürstner, A.; Shi, N. J. Am. Chem. Soc. 1996, 118, 2533−2534. (18) For selected reviews on chromium catalysis, see: (a) Fürstner, A. Chem. Rev. 1999, 99, 991−1045. (b) Hargaden, G. C.; Guiry, P. J. Adv. Synth. Catal. 2007, 349, 2407−2424. (c) Zeng, X.; Cong, X. Org. Chem. Front. 2015, 2, 69−72. (19) Murakami, K.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2007, 9, 1569−1571. (20) (a) Steib, A. K.; Kuzmina, O. M.; Fernandez, S.; Flubacher, D.; Knochel, P. J. Am. Chem. Soc. 2013, 135, 15346−15349. (b) Kuzmina, O. M.; Knochel, P. Org. Lett. 2014, 16, 5208−5211. (c) Steib, A. K.; Kuzmina, O. M.; Fernandez, S.; Malhotra, S.; Knochel, P. Chem. - Eur. J. 2015, 21, 1961−1965. (21) Cong, X.; Tang, H.; Zeng, X. J. Am. Chem. Soc. 2015, 137, 14367−14372. (22) The use of DBU as Lewis base additive in assisting the hydroarylation of styrene was described by Yoshikai’s group. The role of DBU can be addressed in the acceleration of reductive elimination or prevention of catalyst deactivation. See: Xu, W.; Yoshikai, N. Angew. Chem., Int. Ed. 2014, 53, 14166−14170.
Detailed optimization data, experimental procedures, and characterization data of all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. Notes
The authors declare no competing financial interest.
■
ACKNOWLEDGMENTS Support for this work by the National Natural Science Foundation of China [Nos. 21202128, 21572175] and XJTU is gratefully acknowledged.
■
REFERENCES
(1) (a) Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell Publishing: Oxford, U.K., 2000; pp 63−120. (b) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem. Rev. 2012, 112, 2642−2713. (c) Engle, K. M.; Yu, J.-Q. J. Org. Chem. 2013, 78, 8927−8955. (d) Yamaguchi, J.; Muto, K.; Itami, K. Eur. J. Org. Chem. 2013, 2013, 19−30. (e) Hill, M. D. Chem. - Eur. J. 2010, 16, 12052−12062. (2) For selected examples of arylation of pyridines, see: (a) Tobisu, M.; Hyodo, I.; Chatani, N. J. Am. Chem. Soc. 2009, 131, 12070−12071. (b) Berman, A. M.; Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130, 14926−14927. (c) Ye, M.; Gao, G.-L.; Edmunds, A. J. F.; Worthington, P. A.; Morris, J. A.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19090−19093. (d) Godula, K.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2005, 127, 3648−3649. (e) Chen, Q.; du Jourdin, X. M.; Knochel, P. J. Am. Chem. Soc. 2013, 135, 4958−4961. (3) For selected examples of olefination of pyridines, see: (a) Ye, M.; Gao, G.; Yu, J. J. Am. Chem. Soc. 2011, 133, 6964−6967. (b) Cong, X.; Tang, H.; Wu, C.; Zeng, X. Organometallics 2013, 32, 6565−6575. (4) For a review on the C−H bond functionalization of pyridines, see: Nakao, Y. Synthesis 2011, 2011, 3209−3219. (5) For selected examples, see: (a) Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 5332−5333. (b) Yotphan, S.; Bergman, R. G.; Ellman, J. A. Org. Lett. 2010, 12, 2978−2981. (6) Murakami, M.; Hori, S. J. Am. Chem. Soc. 2003, 125, 4720−4721. (7) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130, 2448−2449. (8) Jordan, R. F.; Taylor, D. F. J. Am. Chem. Soc. 1989, 111, 778−779. (9) (a) Guan, B.-T.; Hou, Z. J. Am. Chem. Soc. 2011, 133, 18086− 18089. (b) Song, G.; O, W. W. N.; Hou, Z. J. Am. Chem. Soc. 2014, 136, 12209−12212. (c) Nagae, H.; Shibata, Y.; Tsurugi, H.; Mashima, K. J. Am. Chem. Soc. 2015, 137, 640−643. (10) (a) Nakao, Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am. Chem. Soc. 2010, 132, 13666−13668. (b) Tsai, C.; Shih, W.; Fang, C.; Li, C.; Ong, T.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887− 11889. (c) Lee, W.-C.; Chen, C.-H.; Liu, C.-Y.; Yu, M.-S.; Lin, Y.-H.; Ong, T.-G. Chem. Commun. 2015, 51, 17104−17107. (11) Andou, T.; Saga, Y.; Komai, H.; Matsunaga, S.; Kanai, M. Angew. Chem., Int. Ed. 2013, 52, 3213−3216. (12) The direct alkylation of pyridine with Grignard reagent has been reported by Urabe and co-workers. See: Mizumori, T.; Hata, T.; Urabe, H. Chem.Eur. J. 2015, 21, 422−426. (13) (a) de Meijere, A., Diederich, F., Eds. Metal-Catalyzed CrossCoupling Reactions, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2004; Vol. 2. (b) Nakamura, E.; Sato, K. Nat. Mater. 2011, 10, 158−161. (c) Bolm, C. Nat. Chem. 2009, 1, 420. (14) For selected recent reviews on first-row transition-metalcatalyzed transformations, see: (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417−1492. (b) Gao, K.; Yoshikai, N. Acc. Chem. Res. 2014, 47, 1208−1219. (c) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011, 111, 1293−1314. (d) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217−6254. (e) Jia, F.; Li, Z. Org. Chem. Front. 2014, 1, 194−214. (f) Sherry, B. D.; Fürstner, A. Acc. D
DOI: 10.1021/acs.organomet.5b01021 Organometallics XXXX, XXX, XXX−XXX
