Zhenggen Zha

Selective Iodine‐Catalyzed Intermolecular Oxidative Amination of C(sp3)H Bonds with ortho‐Carbonyl‐Substituted Anilines to Give Quinazolines

Transition-metal-catalyzed intermolecular or intramolecular direct oxidative aminations of C(sp) H bonds, including activated and unactivated C(sp) H bonds, have emerged as important methods for C N bond formations, because they are straightforward and have economic advantages over present procedures by employing prefunctionalized substrates (Scheme 1a). However, these aminations are restricted because of the toxicity of catalysts and their use of expensive transition metals as catalysts. Furthermore, only amides (acetamides or sulfonamides) were employed as coupling partners in most cases. Recently, Chang and Muniz have developed interesting metal-free aminations of benzylic and allylic C H bonds, respectively, with sulfonamides in the presence of stoichiometric amounts of hypervalent iodine(III) reagents. Although a transition metal was not required, large amounts of iodobenzene were generated as by-product, and the substrate scope was limited to sulfonamides (Scheme 1b). Therefore, a new, more efficient, and environmentally friendly catalyst for oxidative C(sp) H amination with anilines is highly desirable. Recently, Ishihara and Wan have developed Bu4NIcatalyzed oxidative functionalization of C(a) H bonds for C O bond formations. Meanwhile, our group has focused on the development of metal-free C(sp) H functionalization for C C or C N bond formation. We hoped to realize iodinecatalyzed intermolecular oxidative aminations of C(sp) H bonds with anilines. To the best of our knowledge, such a protocol has not been reported to date. Herein, we report an iodine-catalyzed intermolecular oxidative amination of a C(sp) H bond adjacent to the nitrogen or oxygen atom of N-alkylamides, ethers, or alcohols with ortho-carbonyl-substituted anilines. A domino process that includes C N or C O bond cleavage, attack of ammonia, condensation, and oxidation subsequently leads to quinazolines in good to excellent yields (Scheme 1c). The additional nitrogen and carbon atom of the quinazolines originate from ammonia and the methyl group adjacent to the nitrogen or oxygen atom of the solvents, respectively. To the best of our knowledge, this is the first example of using a combination of inorganic nitrogen sources and organic solvents for the formation of hetercycles. We began our study with the reaction of one equivalent of 2-aminobenzophenone (1a), two equivalents of NH4HCO3, four equivalents of tert-butyl hydroperoxide (TBHP, 70% in water) as the oxidant, and 20 mol% of N-iodosuccinimide (NIS) as the catalyst. When the reaction mixture was heated in N,N-dimethylacetamide (DMA, 2a) in air at 120 8C for four hours, 4-phenylquinazoline (3a) was obtained in more than 99% yield, determined by GC–MS analysis (Table 1, entry 1). In the absence of NH4HCO3, desired product 3a was not detected, thus indicating that NH4HCO3 is the source of the additional nitrogen atom of the product (Table 1, entry 2). Various ammonia-based reagents could be used as N sources without influencing the reaction yields (Table 1, entries 3–6). To examine the source of the additional carbon atom, various solvents (2b–2 f) were tested in the reaction. Use of solvents 2b, 2d, and 2 f gave desired product 3a, whereas solvents 2c and 2e gave 2-methyl-4-phenylquinazoline (3a’) with low yields, rather than product 3 a (Table 1, entries 7–11). These results implied that the additional carbon atom of 3a presumedly originated from the N,N-dimethyl moiety of DMA. In addition, various iodine reagents were used as the catalyst; while PhI gave 3a in a similar yield, other iodinecontaining catalysts gave 3a in lower yields (Table 1, entries 12–15). Among the various oxidants that were examined, such as di-tert-butylperoxide (DTBP), 2,3-dichloro-5,6[*] Dr. Y.-Z. Yan, Y.-H. Zhang, Dr. C.-T. Feng, Prof. Z.-G. Zha, Prof. Dr. Z.-Y. Wang Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of Soft Matter Chemistry, and Department of Chemistry, University of Science and Technology of China Hefei, 230026 (P. R. China) E-mail: zwang3@ustc.edu.cn

Direct Amidation of Alcohols with N-Substituted Formamides under Transition-Metal-Free Conditions

and C [9]H oxidative amidation, have alsoproven to be efficient methods for the construction of amidebonds.Although considerable progress has been made towardsmethods facilitating amide formation, efficient and low costsyntheses of N,N-dimethyl-substituted amides under metal-free conditions are still less explored. In general, the tradi-tional syntheses of N,N-dimethyl-substituted amides are lim-ited by the need for prior activation of carboxylic acids(Scheme 1a).

Mild Metal-Free Sequential Dual Oxidative Amination of C(sp3)–H bonds: Efficient Synthesis of Imidazo[1,5-a]pyridines

A metal-free sequential dual oxidative amination of C(sp(3))-H bonds under ambient conditions was the first developed, affording imidazo[1,5-a]pyridines in good to excellent yields. The reaction was involved in two oxidative C-N couplings and one oxidative dehydrogenation process with six hydrogen atoms removed.

Highly enantioselective Henry reactions in water catalyzed by a copper tertiary amine complex and applied in the synthesis of (S)-N-trans-feruloyl octopamine.

Water, known as a safe, harmless, cheap, and environmentally benign solvent, has attracted continuous attention in the field of organic synthesis. In addition to the potential advantages of replacing organic solvents, water shows special properties as the reaction medium. Synthetic aqueous chemistry may help us to understand details of some biological phenomena. g] Development of aqueous asymmetric reactions could avoid tedious procedures of removing water from reactions carried out in organic solvents. Moreover, some special substrates, such as compounds commercially available as aqueous solutions or proton-containing compounds, may react smoothly in aqueous media. Many challenges remain in catalytic asymmetric C C bond formation in water, especially for asymmetric transition-metal catalysis, although considerable progress has been made in this area. Enantioselective Henry reactions have been extensively studied since 1992 due to the importance of C C bond formation. Although several Lewis acid complexes and organocatalysts have exhibited high activities and stereoselectivities for these transformations, successful examples in water are quite limited. Recently, the bifunctional guanidine–thiourea catalyst was reported in a biphasic system of water and toluene in which the corresponding products were obtained in good yields and enantiomeric excess (ee). Enzymatic catalysis has been employed for Henry reactions. These reactions were catalyzed by hydroxynitrile lyase in a biphasic aqueous system and the desired products were obtained with moderate yields and ee values. Despite these impressive contributions, reports on the use of aldehydes as substrates are limited and the enantioselectivities still need to be improved. Therefore, the development of new, more efficient, and environmentally benign catalysts for the aforementioned reaction in water is still desired and challenging. We have been focusing on investigating aqueous organic reactions. The asymmetric reaction in water is one of our main aims. Previously, we have reported an asymmetric Henry reaction catalyzed by copper Schiff base 1. Herein, we developed a highly enantioselective Lewis acid catalyzed nitroaldol reaction with water as the solvent. Excellent yields (99%) and ee values (99 %) were achieved for a wide range of aldehydes. Considering the broad application of proline derivates in aqueous aldol reactions 6] and based on ligand 1, we designed proline derivates 2 a–2 c, which were used in the asymmetric Henry reaction in water (Scheme 1). With ligands 2 a–2 c in hand, the addition of nitromethane 4 to benzaldehyde 3 a in water was chosen as a model reaction. Initially, copper acetate was employed as the Lewis acid to coordinate in situ with ligands 2 a, 2 b, and 2 c and afford the corresponding catalysts. As shown in Table 1, ligand 2 c was prominent in providing nitroalcohol 5 a in 51 % yield and [a] G. Lai, F. Guo, Y. Zheng, Y. Fang, H. Song, K. Xu, Dr. S. Wang, Dr. Z. Zha, Prof. Dr. Z. Wang Hefei National Laboratory for Physical Sciences at Microscale CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry University of Science and Technology of China, Hefei Anhui, 230026 (P.R. China) Fax: (+86) 551-3603185 E-mail : zgzha@ustc.edu.cn zwang3@ustc.edu.cn Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201002915. Scheme 1. Structures of the ligands used in this study. Bn =benzyl.

A Highly anti‐Selective Asymmetric Henry Reaction Catalyzed by a Chiral Copper Complex: Applications to the Syntheses of (+)‐Spisulosine and a Pyrroloisoquinoline Derivative

A highly anti-selective asymmetric Henry reaction has been developed, affording synthetically versatile β-nitroalcohols in a predominately anti-selective manner (mostly above 15:1) and excellent ee values (mostly above 95%). Moreover, the anti-selective Henry reaction was carried out in the presence of water for the first time with up to 99% ee. The catalytic mechanism was proposed based on the detection of the intermediates by extractive electrospray ionization mass spectrometry (EESI-MS). Furthermore, the anti adducts have been successfully transformed into the biochemically important (+)-spisulosine and a pyrroloisoquinoline derivative.

A novel approach for the one-pot preparation of α-ketoamides by anodic oxidation

The direct oxidative synthesis of α-ketoamides via anodic oxidation was developed by using dioxygen as a reactant under mild conditions. This methodology has a broad substrate scope (aromatic amines, aliphatic amines and ammonium acetate) and opens up an interesting and attractive avenue for the synthesis of α-ketoamide derivatives.

Catalyst-free thiolation of indoles with sulfonyl hydrazides for the synthesis of 3-sulfenylindoles in water

A catalyst-free thiolation of indoles with sulfonyl hydrazides was efficiently developed in water under mild conditions without any ligand or additive. The reaction provided a variety of 3-sulfenylindoles with good to excellent yields and the only by-products were nitrogen and water.

Highly active and selective synthesis of imines from alcohols and amines or nitroarenes catalyzed by Pd/DNA in water with dehydrogenation

A direct imination was developed from alcohols and amines under catalysis of Pd/DNA by dehydrogenation without additional oxidant, affording the corresponding imines in moderate to good yields with excellent chemoselectivity. By virtue of the liberated molecular hydrogen, the nitroarenes could also be deoxidized in situ into amines and a one-pot tandem synthesis of imines was achieved from nitroarenes. This heterogeneous catalyst can be recovered and reused at least five times by taking advantage of its water-soluble reversibility. All these conformations were performed smoothly in water under mild conditions, and an atom economical and environmentally benign synthesis was embodied in this imination.

Catalyst-free sulfonylation of activated alkenes for highly efficient synthesis of mono-substituted ethyl sulfones in water

A catalyst-free sulfonylation reaction of activated alkenes with sulfonyl hydrazides was efficiently developed under mild and environmentally benign conditions, in water without any ligand or additive. The reaction gave a range of structurally diverse mono-substituted ethyl sulfones with excellent yields, in which the by-product was nitrogen.

Electrochemical synthesis of the aryl α-ketoesters from acetophenones mediated by KI.

a-Ketoesters play an essential role in biological processes. They serve as the backbones in some natural products, such as the 3-deoxy-2-ulosonic acids and their derivatives. In addition, a-ketoesters are also used as key intermediates for the synthesis of highly valued substrates. Over the past several decades, chemists have paid great attention to the synthesis of a-ketoesters. Classical methods include oxidation of a-hydroxy esters with various kinds of oxidant, oxidation of methyl 2-phenylacetate, Friedel– Crafts acylation, hydrolysis and esterification of acyl cyanides, hydrolysis of 2-aryl-2-nitroacetates, and other methods. However, these protocols usually require stoichiometric amounts of metal oxidants, and thus a large amount of waste is formed in the reaction. It has been known that electrochemistry is a green method for fine chemical synthesis. Recently the synthesis of esters from aldehydes and the corresponding alcohols was realized by virtue of an anode oxidation in the presence of N-heterocyclic carbine (NHC)/1,8-diazabicyclo ACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU). In our laboratory, we have been attempting to prepare a-ketoesters from aryl ketones and the corresponding alcohols by an anode oxidation. We conceive that this oxidation of methyl ketones in the presence of potassium iodide could avoid the waste pollution under electrochemical conditions. Previously, the reaction of methyl ketones with iodine was a typical haloform reaction, affording carboxylic acids or esters with a loss of one carbon atom. It is a challenge to functionalize the methelene of methyl ketones without losing the methyl carbon atom. Herein, we describe a novel method to synthesize a-ketoesters via an anode oxidation from acetophenones under mild conditions inhibiting the occurrence of the haloform reaction without any chemical waste. Initially the reaction was carried out in an undivided cell, while MeOH was employed as the solvent, acetophenone as the model substrate, and amine as the additive under an oxygen atmosphere. It was found that the acetophenone can be oxidized into 2-oxo-2-phenylacetaldehyde (see Table S1 in the Supporting Information). Then we screened various amines and tert-butylamine was found to be the most effective additive to afford the desired product with a yield of 64 % (see Table S1 in the Supporting Information). To our knowledge, the 2-oxo-2-phenylacetaldehyde could be an intermediate and further transformed into a hemiacetal in the presence of alcohol. Then this hemiacetal can be converted into the a-ketoester under electrochemical oxidation. To enhance the anode oxidation, we increased the electric current from 20 to 40 mA. As expected, the a-ketoester was obtained in 30 % yield (Table 1, entry 1), which encouraged us to further optimize the reaction conditions. Under the electric current of 40 mA, the reaction base amine was examined again. After examination of various amines, 2,2,6,6-tetramethylpiperidine (TMP) was the best choice for this reaction (see Table S2 in the Supporting Information). From the result of Table S2, it was found that only the amines with a large steric hindrance could catalyze the reaction well. Perhaps the amines without steric hindrance could be converted into a-ketoamides. Subsequently, we attempted to improve the hemiacetal yield by the addition of some additive. At first, we assumed that this additive could catalyze the formation of hemiacetal. This meant that the additive should be an acidic compound. At the same time, this additive could not protonize the amine in the reaction mixture. Therefore ammonium acetate, nitroalkanes, and phenols were examined in the reaction. To our delight, when two equivalents of nitromethane were added to the reaction, a significant increase in yield was observed (Table 1, entry 3). When more than two equivalents of nitromethane was added, the yield decreased a little. Inspired by this result, other nitro compounds were examined and it was found that the p-nitrophenol was the best additive for this transformation, giving the a-ketoester with a high yield of 81 % (entry 10). The dosage of p-nitrophenol in this reaction was also very important. When the amount of p-nitrophenol was increased from 0.5 to 1.0 equivalents, the reaction yield was decreased to 78 % although the reaction time was prolonged to 3 h (entry 11). When the p-nitrophenol was de[a] Z. Zhang, Z. Zha, Prof. Dr. Z. Wang Hefei National Laboratory for Physical Sciences at Microscale CAS Key Laboratory of Soft Matter Chemistry and Department of Chemistry, Univ Sci & Technol China Hefei, Anhui, 230026 (P.R. China) Fax: (+86) 551-3603185 E-mail : zgzha@ustc.edu.cn zwang3@ustc.edu.cn [b] Prof. Dr. J. Su Hefei National Laboratory for Physical Sciences at Microscale and Department of Modern Physics, Univ Sci & Technol China Hefei, Anhui, 230026 (P.R. China) [] These two authors have the equal contribution to this manuscript. Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201302307.