Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Arylation/Intramolecular Conjugate Addition of 1,6-Enynes Enabled by Manganese(I)-Catalyzed C−H Bond Activation Yun-Xuan Tan,†,¶ Xing-Yu Liu,†,‡,¶ Yi-Shuang Zhao,† Ping Tian,*,†,§ and Guo-Qiang Lin*,†,‡,§ †
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CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China ‡ School of Physical Science and Technology, ShanghaiTech University, 100 Haike Road, Shanghai 201210, China § Innovation Research Institute of Traditional Chinese Medicine (IRI), Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai 201203, China S Supporting Information *
ABSTRACT: An arylation/intramolecular conjugate addition of cyclohexadienone-containing 1,6-enynes has been established through initiation by manganese(I)-catalyzed C−H bond activation. This tandem reaction involved unusual E/Zisomerized alkenyl-Mn intermediates and proceeded smoothly with high chemoselectivities and perfect atom economy. The cyclization products could be further transformed to various structures. Mechanistic studies suggested that cleavage of the C−H bond was involved in the turnover-limiting step, and a manganese carbene anion intermediate was proposed to explain such an E/Z isomerization process.
Scheme 1. Strategic Design
During the past two decades, transition-metal-catalyzed C−H bond activation reactions have made remarkable progress and become a reliable, attractive, and atom-economical tool in organic synthesis.1 While most C−H bond functionalizations were achieved by using precious transition metals, the application of Earth-abundant first-row transition metals has increasingly received much attention.2 In particular, manganese catalysts are extremely impressive, because of their low toxicity, low cost, and potentially unique reactivities.3 Recently, significant advances have been realized in the field of manganese-catalyzed C−H bond activation reactions on arenes with a variety of coupling partners having CC, CC, C N, CO, and CN bonds.4−8 As shown in Scheme 1a, the insertion of alkynes to arylmanganese species, generated from manganese-catalyzed C−H bond activation of arenes, yields the key alkenyl-Mn(I) intermediates (DG = directing group). Three types of their post-conversions have been disclosed: H-transfer or direct protonation of the alkenyl-Mn intermediates could result in the C−H alkenylation products (Scheme 1a, Type A);5a,6l,8a When the directing group was imine, the alkenyl-Mn complexes could undergo a dehydrogenative [4 + 2] annulation process to afford diverse isoquinolines (Scheme 1a, Type B);5c Moreover, β-elimination of the alkenyl-Mn intermediates was developed by Ackermann and Glorius, providing a direct C−H bond alkynylation and allenylation of arenes (Scheme 1a, Type C).6f,7b,c To the best of our knowledge, no examples demonstrated that the alkenyl-Mn intermediate generated by C−H bond activation might undergo a subsequent tandem conjugate addition.9 As part of our continuous efforts on transition-metalcatalyzed tandem reactions,10 we speculated that an intra© XXXX American Chemical Society
molecular enone would be a suitable choice to trap the in-situformed alkenyl-Mn intermediate (Scheme 1b). However, two potential challenges must be addressed. One is the chemoselectivity that requires the aryl-manganese species to react Received: October 15, 2018
A
DOI: 10.1021/acs.orglett.8b03288 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Scheme 2. Scope of 1,6-Enynes and 2-Arylpyridinesa
with alkyne, rather than enone to form the key alkenyl-Mn intermediate T. The other is the competitive protonation reaction, which means intermediate T should avoid the alternative protonation process so that the subsequent conjugate addition to enone could occur.11 Herein, we report an arylation/intramolecular conjugate addition of cyclohexadienone-containing 1,6-enynes initiated by manganesecatalyzed C−H bond activation. We commenced our studies using 2-phenylpyridine (1a) and 1,6-enyne 2a as model substrates and selected results are summarized in Table 1. In the presence of MnBr(CO)5 (10 Table 1. Selected Optimization Studiesa
entry
1a:2a
solvent
temperature (°C)
E/Zb
yieldc (%)
1 2 3 4 5 6 7 8 9 10 11d 12 13f
1.2 1.2 1.2 1.2 1.2 1.2 1.5 2.0 2.0 2.0 2.0 2.0 2.0
DCE Et2O 1,4-dioxane DMF EtOH DCM DCM DCM DCM DCM DCM DCM/TFEe DCM/TFEe
80 80 80 80 80 80 80 80 100 60 80 80 80
85/15 − 85/15 60/40 67/33 85/15 84/16 85/15 85/15 85/15 − 85/15 85/15
30 5 15 25 25 44 54 69 57 22
