Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
One-Pot Regiospecific Synthesis of Indolizines: A Solvent-Free, Metal-Free, Three-Component Reaction of 2‑(Pyridin-2-yl)acetates, Ynals, and Alcohols or Thiols Daji Yang,† Yue Yu,† Yuanheng Wu,† Huiyi Feng,† Xuechen Li,*,‡ and Hua Cao*,† †
School of Chemistry and Chemical Engineering and Guangdong Cosmetics Engineering & Technology Research Center, Guangdong Pharmaceutical University, Zhongshan 528458, China ‡ Department of Chemistry, State Key Lab of Synthetic Chemistry, The University of Hong Kong, Pokfulam, Hong Kong SAR, China S Supporting Information *
ABSTRACT: A novel approach for the synthesis of indolizines from 2-(pyridin-2-yl)acetates, ynals, and alcohols or thiols has been developed. This MCR (multicomponent reaction) that proceeds under the solvent- and metal-free conditions has provided a straightforward path to construct indolizines. Furthermore, this reaction demonstrates other attractive features such as widely available starting materials, mild conditions, good functional group tolerance, and high efficiency.
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Scheme 1. Natural Products and Synthetic Pharmaceuticals Containing Indolizines
s one of the major classes of heterocyclic compounds, indolizines are a prevalent structural motif found in a number of natural products and synthetic pharmaceuticals. Recent studies have revealed that the natural products1 containing indolizine skeletons such as swainsonine, castanospermine, camptothecin, lamellarin, and so on, and synthetic drugs2 like topotecan show powerful physiological functions, including anticancer, antiviral, antifungal, antihypertensive, etc. Some indolizines also exhibit anti-inflammatory and antioxidant activities and phosphatase inhibition.3 In addition to their pharmacological effects, indolizine derivatives can be used as fluorescent materials and dyestuffs as well.4,5 Over the past years, tremendous efforts have been made toward the synthesis of indolizine derivatives. The main synthetic routes include trans-annulations of pyridotriazoles with alkynes,6 crosscoupling/cyclization of pyridine derivatives and alkenes,7 activation of C−H bonds,8 1,3-dipolar cyclizations,9 and so on.10 Until now, the synthesis of heterocyclic compounds has basically been catalyzed by transition metals or carried out in toxic solvents whose uses have been limited from its noncompliance with the requirements of green chemstry.11,12 Therefore, the more straightforward, regioselective, costeffective, and environmentally friendly routes to construct indolizines are highly needed. Here, we report a novel three-component, metal- and solvent-free transformation to construct functionalized indolizines (Scheme 1), from which we can readily prepare 3-(O/S)substituted indolizines. Initially, ethyl 2-(pyridin-2-yl)acetate 1a, 3-phenylpropiolaldehyde 2a, and alcohol 3a were chosen as the model substrates. The optimization of the reaction conditions is summarized in Table 1. It appeared that the blank reaction without any catalyst did not proceed (entry 1), while the reaction with copper and palladium catalysts such as Cu(OAc)2 and Pd(OAc)2 generated © XXXX American Chemical Society
a trace of the indolizine product (entries 2 and 3). To our surprise, when acetic acid was used as the catalyst for this reaction, the desired product 4a was obtained in 40% yield, and Received: March 15, 2018
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DOI: 10.1021/acs.orglett.8b00835 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Table 1. Optimization of Reaction Conditionsa
entry
cat.
temp (°C)
time (h)
1 2 3 4 5 6 7c 8 9 10 11 12 13 14 15 16 17 18 19 20 21d
Cu(OAc)2 Pd(OAc)2 AcOH AcOH AcOH ZnCl2 FeCl3 AlCl3 TsOH TFA PivOH DABCO DBU NaHCO3 PivOH PivOH PivOH PivOH PivOH PivOH
rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt rt 60 80 100 rt
4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 2 1 2 2 2 2
additivesb
4A 5A 5A 5A 5A 5A 5A 5A 5A 5A 5A 5A 5A 5A 5A 5A 5A
MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS MS
Scheme 2. Substrate Scope of Alcoholsa
yieldc (%) nd
