Note Cite This: J. Org. Chem. 2017, 82, 11304-11309
pubs.acs.org/joc
Synthesis of Indolizines via Palladium Catalyzed Annulation of Propargyl Carbonates and 2‑(Pyridin-2-yl)acetonitrile Derivatives Ting Wu,†,‡ Min Chen,†,‡ and Yuzhu Yang*,†,‡ †
State Key Laboratory of Functions and Applications of Medicinal Plants, Guizhou Medical University, 3491 Baijin Road, Guiyang 550014, P. R. China ‡ The Key Laboratory of Chemistry for Natural Products of Guizhou Province, Chinese Academy of Sciences, 3491 Baijin Road, Guiyang 550014, P. R. China S Supporting Information *
ABSTRACT: A Pd-catalyzed regioselective annulation reaction of propargyl carbonates and 2-(pyridine-2-yl) acetonitrile derivatives has been accomplished, which provides a straightforward and efficient access to polysubstituted indolizines. The choice of the phosphine ligand is crucial to the high regio-selectivity of the reaction.
I
Pd(PPh3)4, the yield of the desired product was dropped (entries 2−3). Both monodentate and bidentate phosphine ligands were examined in this reaction, indicating that tris(4methoxyphenyl)phosphine delivered the product in slightly decreased yield, while other phosphine ligands could not give better results than DPE-Phos (entries 4−7). In spite of DMSO, DMF and DMAc could also be used as solvent for this reaction, albeit affording the product in lower yields (entries 8−9). Decreasing the temperature to 120 °C could not help increase the yield, and when the reaction was performed at 100 °C the yield dropped to 34% (entries 10−11). Changing the base to Na2CO3 or Cs2CO3 led to decreased yields (entries 12−13). Two equivalent of K2CO3 as base in the reaction is necessary for achieving the best yield after the investigation of the amount of K2CO3 in this reaction (entries 14−16). The effect of concentration of the reaction and the ratio of the reactants were also examined and the results indicated that the best case is the ratio of 1a and 2a equals to 2 with the concentration is 0.1 M (entries 17−20). Finally, when half amount of the palladium catalyst and phosphine ligand was subjected in this reaction, the yield was lowered to 56% (entry 21). During the optimization study, the formation of isomer 4a can be observed, but the yield was very low. With the optimal reaction conditions in hand, we studied the substrate scope with different substituted propargyl carbonates and 2-alkylazaarenes, and the results are summarized in Scheme 1. Generally the reactions produced the corresponding indolizines in good yields. The reaction conditions are compatible with aromatic propargyl carbonates bearing both electron-withdrawing groups (−F, −CF3, −Cl, and −OAc) and electron-donating groups (−OMe and −Me), furnishing the desired products in moderate to good yields. We also found the regio-isomer products 4a, 4b, and 4c during the reaction but
ndolizine derivatives are an important class of nitrogen-fused heterocycles, which are ubiquitous in many natural products and bioactive compounds.1 Functionalized indolizines have found wide applications in pharmaceuticals with several biological activities, such as antitubercular,2 anti-inflammatory,3 antifungal,4 anticancer,5 antioxidant,6 and usage as molecular probes.7 Therefore, the development of efficient methods for the construction of indolizine has been received continuous attention in the field of synthetic chemistry and chemical biology. The majority of the methods for indolizine synthesis include 1,3-dipolar cycloaddition of pyridinium N-methylides with electron-deficient alkynes or alkenes8 and transition-metalcatalyzed intramolecular cycloisomerizations of pyridines with specific C2 functionalization.9−12 Recent examples for the synthesis of indolizines included an I2-mediated oxidative tandem cyclization via C−N/C−C bond formation,13 a copper catalyzed radical mediated process via oxidative coupling of alkenes,14 and an amine-NHC relay catalysis system with Michael addition-[3+2] fusion of simple azaarenes and α,βunsaturated aldehydes.15 However, these methods often suffer from limitations, such as substrate availability and involvement of multistage synthesis. Thus, general and convenient methods for the synthesis of indolizines from simple and readily available precursors are still of great value. Herein we report our results of a new synthetic method for the preparation of multisubstituted indolizines via Pd-catalyzed annulations of propargyl carbonates and 2-(pyridin-2-yl)acetonitrile derivatives. We performed the reaction of 2-(pyridin-2-yl)acetonitrile 1a and propargyl carbonate 2a as model substrates for optimization. It was found that the combination of Pd2(dba)3/DPE-Phos in the presence of K2CO3 afforded the highest 61% yield after stirring in DMSO at 140 °C for 16 h, with 15% of isomer 4a (Table 1, entry 1). The structure of compound 3a was determined by NMR and HRMS and was fully confirmed by X-ray diffraction (see ORTEP diagram in SI). When the catalyst system was replaced by PdCl2(PPh3)2 or © 2017 American Chemical Society
Received: September 9, 2017 Published: October 2, 2017 11304
DOI: 10.1021/acs.joc.7b02278 J. Org. Chem. 2017, 82, 11304−11309
Note
The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditionsa
entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21
deviation from the standard conditions no change PdCl2(PPh3)2 instead of Pd2(dba)3/L1 PdCl2(PPh3)2, 20% PPh3 instead of Pd2(dba),/L1 L2 instead of L1 L3 instead of L1 L4 instead of L1 L5 instead of L1 DMF instead of DMSO DMA instead of DMSO 120 °C instead of 140 °C 100 °C instead of 140 °C Na2CO3 instead of K2CO3 Cs2CO3 instead of K2CO3 without K2CO3 1 equiv K2CO3 3 equiv K2CO3 0.05 M instead of 0.1M 0.2 M instead of 0.1 M ratio of la/2a = 1:1 ratio of la/2a = 1:2 2.5% Pd2(dba)3/5% L1 instead of 5% Pd2(dba)3/ 10% L1
Scheme 1. Substrate Scope with Substituted 2-(Pyridin-2yl)acetonitrile Derivatives and Propargyl Carbonatesa
yield of 3a (4a)b 61(15) 46(
