Merging C–H Bond Functionalization with Amide Alcoholysis: En

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Research Article pubs.acs.org/acscatalysis

Merging C−H Bond Functionalization with Amide Alcoholysis: En Route to 2‑Aminopyridines Dinesh Kumar, Sandeep R. Vemula, and Gregory R. Cook* Department of Chemistry and Biochemistry, North Dakota State University, Fargo, North Dakota 58108-6050, United States S Supporting Information *

ABSTRACT: A new route for the synthesis of 2-aminopyridines has been developed that merges C−H functionalization with amide alcoholysis. The key component of this method is the ability of a quinazolinone to template the chemo- and regioselective construction of a latent pyridine ring via site-selective olefinic C−H bond functionalization under Ru(II) catalysis. Thus, highly substituted 2-aminopyridines were prepared in good yield. Mechanistic studies provide insight into the mechanism of the key oxidative C−H activation/annulation process. KEYWORDS: 2-aminopyridine, ruthenium catalysis, site-selective C−H activation, amide alcoholysis, quinazolinone

T

C−H activation has demonstrated that transition-metal catalysts are effective for annulation through chelation-assisted functionalization of C−H/X−H (X = O/N) bonds.14 While great advances in C−H functionalization/annulation have been made in recent years, the ability to selectively functionalize specific sp2 C−H bonds15 in the presence of competing C−H bonds remains a challenge and is key to the success of this tandem process. To evaluate the tandem C−H bond functionalization/amide alcoholysis to access 2-aminopyridines such as 3a, the oxidative alkyne annulation of the diphenylacetylene 1 with tautomerizable quinazolinone 2a was investigated as a model reaction. The reaction was carried out with Ru catalysts in DMF at 120 °C for 24 h in the presence of AgOAc and trifloroethanol (TFE) (Table 1). Mixed results were obtained, with yields ranging from 0% to 27% (entries 1−6, Table 1). Other transition-metal catalysts (Pd, Rh, Ni, Fe, Ir, Co, Mo, and Au) were completely ineffective (see the Supporting Information). A survey of solvents showed that the transformation was sensitive to the reaction media. While only traces of 3a formation was observed in DMSO (entry 7, Table 1), other tested solvents (PhMe, THF, MeCN, DME, DMC, MeNO2) were found compatible for this reaction, with the yields ranging from 14 to 21% (entries 8−13, Table 1). 1,4-Dioxane was

he 2-aminopyridyl motif is an important structural component of pharmaceuticals, agrochemicals, natural products, and organic materials.1 As a result, the design and development of general robust methods for the preparation of substituted 2-aminopyridines is highly significant. Classical methods for 2-alkyl-/2-arylaminopyridines rely on the nucleophilic addition and/or aromatic substitution reaction of pyridine derivatives, including 2-halopyridines,2 2-alkoxypyridines,3 pyridinium,4 pyridone,5 pyridine N-oxides,6 and transition-metal (Pd, Cu, Ni)-catalyzed aminations7−11 (Scheme 1). These methods often require multiple synthetic steps for the required pyridine precursors and high temperature and overall offer limited functionalized 2-aminopyridines. A general preparation of 2-aminopyridines via the direct construction of the pyridine ring has not been reported. The cooperative merging of synthetic tools in tandem to achieve more efficient syntheses of high-value products is a valuable strategy.12 We envisioned that quinazolinone heterocycles could serve as a template for C−H bond functionalization, affording annulated products as a latent pyridine. Upon in situ amide alcoholysis, the fused quinazolinone would open to reveal highly substituted 2-aminopyridines (Scheme 2) In recent years, transition-metal-catalyzed C−H bond functionalizations13 have evolved rapidly due to their potential to generate a diverse range of products efficiently while avoiding the need to prepare preactivated substrates. This results in fewer steps and a reduction of waste, rendering their synthesis more step and atom economical. Pioneering work in © 2016 American Chemical Society

Received: March 12, 2016 Revised: April 19, 2016 Published: April 22, 2016 3531

DOI: 10.1021/acscatal.6b00728 ACS Catal. 2016, 6, 3531−3536

Research Article

ACS Catalysis Scheme 1. Reported and Present Synthetic Strategy for the 2-Arylaminopyridines and Reported Ru-Catalyzed Similar Template-Based Annulation

Table 1. Tandem Ru-Catalyzed C−H Functionalization/ Amide Alcoholysis of 2a to 3aa

entry

catalyst

solvent

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

RuCl3·xH2O [Ru(COD)Cl2]n Ru(Me-allyl)2(cod) Ru3(CO)12 RuH2(CO)(PPh3)3 [Ru(p-cymene)Cl2]2 [Ru(p-cymene)Cl2]2 [Ru(p-cymene)Cl2]2 [Ru(p-cymene)Cl2]2 [Ru(p-cymene)Cl2]2 [Ru(p-cymene)Cl2]2 [Ru(p-cymene)Cl2]2 [Ru(p-cymene) Cl2]2 [Ru(p-cymene)Cl2]2 [Ru(p-cymene)Cl2]2 [Ru(p-cymene)Cl2]2

DMF DMF DMF DMF DMF DMF DMSO PhMe THF DCE MeCN DMC MeNO2 dioxane dioxane dioxane

17

[Ru(p-cymene)Cl2]2

dioxane @ 100 °C

additive none none none none none none none none none none none none none none Cu(OAc)2 Cu(OAc)2 + TFA Cu(OAc)2 + TFA

yield (%)b−d 0e 16 0e 0e 0e 27 tracese 20 19 21 18 14 15 36 48f 63f,g 63f,g

a

Reactions were conducted using 0.12 mmol of 1a. bIsolated yield of 3a. cNo amide alcoholysis of 2a was observed. dNo N-2,2,2trifluoroethylation of 2a or 3a was observed. eStarting 2a was recovered intact. fOne equivalent of Cu(OAc)2 was used. gOne equivalent of TFA was used.

Scheme 3. Optimized Ru(II)-Catalyzed Reaction Scheme 2. Tandem C−H Bond Functionalization/Amide Alcoholysis en Route to 2-Aminopyridines

Cu(OAc)2·xH2O, and TFA are all essential for the optimal reaction conditions. To gain insight into the oxidative C−H functionalization/ annulation step, a control experiment was carried out in the

found to be the most efficient solvent, thus providing the highest yield 36% (entry 14, Table 1). Using [Ru(pcymene)Cl2]2 as catalyst and dioxane as solvent, the addition of Cu(OAc)2 as oxidant improved the yield to 48% (entry 9) and the further addition of trifloroacetic acid (TFA) as additive afforded 63% yield (see the Supporting Information) A full optimization study (see the Supporting Information) revealed that the use of 5 mol % of [Ru(p-cymene)Cl2]2 with AgOAc/Cu(OAc)2 and TFA in dioxane/TFE (1/0.4) at 100 °C was optimal (Scheme 3). The use of other alcohols (MeOH, EtOH, iPrOH) proved to be inferior. A series of control experiments was performed. In the absence of any one of the reaction components, either reduced yields or no conversion was observed (Table 2). These results show that the Ru catalyst ([Ru(p-cymene)Cl2]2), AgOAc,

Table 2. Control Experimentsa entry

Ru catalyst (5 mol %)

AgOAc (20 mol %)

Cu(OAc)2· xH2O (1 equiv)

TFA (1 equiv)

yield (%)b

1 2 3 5 9 6

+ + + + − −

+ + + − − +

+ + − − − +

+ − − − − +

63 46 11 traces 0 0

a 1 (32 mg, 0.18 mmol, 1.5 equiv) was treated with 2a (35 mg, 0.12 mmol) under different reaction conditions in 1,4-dioxane/TFE (1 mL, 1/0.4) at 100 °C for 24 h. bIsolated yield of 3a.

3532

DOI: 10.1021/acscatal.6b00728 ACS Catal. 2016, 6, 3531−3536

Research Article

ACS Catalysis absence of TFE (Scheme 4). Gratifyingly, the reaction produced a single product, pyrido[2,1-b]quinazolin-11-one 4a,

Scheme 6. Substrate Scope (R = CH2CF3)

Scheme 4. Control Experiment without TFE

in 76% yield. This was surprising, given that 2b can undergo tautomerization (2b1, 2b, and 2b2) and four different sp2 C−H bonds would be accessible for insertion by the Ru complexes if they were coordinated by heteroatoms in any of the tautomers (Scheme 5). At least six different products could result (4a− Scheme 5. Potential Annulation Pathways

Scheme 7. Deuterium Incorporation and KIE Studies

4a5). In an effort to probe tautomer composition, various reaction conditions that significantly alter the tautomeric equilibria16 were examined. However, no significant difference in the chemo- and regioselectivity was observed. The scope of the tandem annulation/alcoholysis protocol was investigated (Scheme 6).17 A series of 2-styryl quinazolin4(3H)-ones reacted well with 1 to form 2-aminopyridines in good yields. A wide range of functional groups (−OMe, −NMe2, −NO2, −CN, −CF3, −Cl, −F) was tolerated, validating the robustness of this protocol. Further, vinyl quinazolinones bearing heteroaromatic groups (furyl 3m and indolyl18 3n) were formed smoothly. Representative internal alkynes were tested and found compatible with the reaction conditions (bisthiophene 3o, −OMe 3p, −Br 3q, and dialkyl 3r). In contrast, terminal alkynes were unreactive. Fully substituted 2-amino-3,4,5,6-functionalized pyridines could be synthesized using a correspondingly substituted quinazolinone template (3k). In order to gain mechanistic insight, deuterium incorporation studies were undertaken (Scheme 7). When the quinazolinone 2c was subjected to the reaction conditions without the alkyne but with D2O present, deuterium was found largely at the observed site of reactivity Hd (70%) with a trace of incorporation at Hc (