Note pubs.acs.org/joc
Cite This: J. Org. Chem. 2017, 82, 11626-11630
Synthesis of Azoxybenzenes by Reductive Dimerization of Nitrosobenzene Yu-Feng Chen, Jing Chen, Li-Jen Lin, and Gary Jing Chuang* Department of Chemistry, Chung Yuan Christian University, 200 Chung Pei Road, Chung Li district, Taoyuan City, Taiwan 32023 S Supporting Information *
ABSTRACT: Herein we report an effective and simple preparation method of substituted azoxybenzenes by reductive dimerization of nitrosobenzenes. This procedure requires no additional catalyst/reagent and can be applied to substrates with a wide range of substitution patterns.
T
Scheme 1. Formation Pathways of Azoxybenzene
he azoxy compound, a member of the 1,3-dipole family, carries an unusual nitrogen−nitrogen−oxygen linkage in its functional group. Azoxybenzenes, 1 (also known as diphenyldiazene oxides, Figure 1), played a crucial role in
Figure 1. Structure of azoxybenzene.
liquid crystal and polymer materials due to their physical and chemical properties.1 Moreover, azoxybenzenes received the interest of medicinal chemists for their retinoidal activities.2 In recent years, azoxybenzenes have furthermore drawn the attention of synthetic chemists for its capability to serve as an o-directing group in C−H functionalizations of arenes.3 The condensation of an aryl nitroso with an aryl hydroxylamine is often involved the syntheses of azoxybenzenes; thus, the reported preparations of azoxybenzenes typically utilized the oxidation of anilines or reduction of nitroarenes to generate both of the aforementioned species in situ for the subsequent condensation (Scheme 1). For example, in 2012 Grützmacher and a co-worker demonstrated a Rh(I)-catalyzed transfer hydrogenation of nitrosobenzene with alcohols to produce aldehydes, which also generated azoxybenzene from the in situ condensation of resulting hydroxylamine with nitrosobenzene.4 And more recently, Song and Han have reported a visible-lightdriven reduction of nitrosobenzene to form azoxybenzene using glucose as the external reductant.5 Consequently, overreduction/oxidation of the starting materials and the competing condensation of aniline with nitrosobenzene often generate diazocompounds as byproducts in similar strategies.6 Hence, an effective method for the preparation of these valuable compounds is still receiving significant interest,7−10 and we herein report a simple and byproduct-free synthesis of azoxybenzenes by a reductive dimerization of nitrosobenzenes without the usage of catalysts. © 2017 American Chemical Society
Previously, we have reported a photoinduced reduction of nitrobezenes to anilines.11 And during our subsequent studies, we unexpectedly found that by heating in iPrOH with a catalytic amount of Pd(OAc)2, 4-nitrosobenzonitrile was converted to the corresponding azoxybenzene as the major product. Although initially we suspected the transfer hydrogenation of nitrosobenzene to hydroxylamine and the following condensation were responsible for the formation of azoxy species in such condition, we shortly discovered that neither iPrOH nor Pd was necessary for the transformation, as the same phenomenon was found to occur from simple heating of 2a in benzene (formula 1). We then started the optimization of
this reductive dimerization of nitrosobenzene to form azoxybenzene. As shown in Table 1, different solvents were Received: July 28, 2017 Published: October 5, 2017 11626
DOI: 10.1021/acs.joc.7b01887 J. Org. Chem. 2017, 82, 11626−11630
Note
The Journal of Organic Chemistry Table 1. Optimization of Reaction Conditions
a
Table 2. Substrate Scope of Reductive Dimerization of Nitrosobenzenes
entry
solvent
isolated yield (%)
1 2 3 4 5 6 7 8 9 10a
benzene toluene 1,2-dichloroethane CH3CN THF dioxane DMSO EtOH isopropanol isopropanol
40 38 35 27 37 27 18 36 49 60
Reaction at 0, 17 M of starting material.
tested in the reaction at 100 °C. o-Methyl nitrosobenzene, 2b, was selected as the starting compound for its lower reactivity as compared to other counterparts. We were surprised to find that although the reaction in iPrOH was shown to be the most efficient, the formation of azoxybenzene 1b proceeded in quite a variety of solvents. Reactions in benzene and dichloroethane resulted similar yields to alcohol solvents. And polar aprotic solvents such as DMSO, acetonitrile, THF, and dioxane would also work, albeit resulting lower isolated yields of the product. Reaction at a higher concentration of 2b at 0.17 M gave a higher yield (entry 10), and further incremental changes in the reaction temperature and concentration showed little effect on the reactivity. With optimum conditions in hand, a selection of substituted nitrosobenzenes was subjected to the reaction conditions, and the result is shown in Table 2. As shown in Table 2, the above-mentioned reductive dimerization of nitrosobenzene to generate azoxybenzene could be applied to various nitrosobenzenes with different substituents. Starting compounds with electron-withdrawing groups such as cyano (1a, 1d, and 1e), nitro (1l, 1m), acetyl (1n, 1o), and ester (1p, 1q) at different positions (ortho, meta,and para) were converted to the corresponding products in 85−95% isolated yields. Scaling up worked fairly well as the gram scale reaction of 2a afforded 93% of 1a. In the cases of halogen substituents (1f−1k), 70−92% yields of the products were found. However, reactions of parent nitrosobenzene 1c and counterparts with electron-donating groups of alkyl (1b, 1r) and methoxy(1s) were found to give lower conversion or required a longer reaction time. And in the case of the pdimethylamino group, only starting material was recovered. From examination of the aforementioned reactions, we found that besides the presence of ortho substituents, the installation of electron-donating groups on nitrosobenzenes seems to show a retardation effect on the reaction. Therefore we tested the reaction of 2t again under acidic conditions to see if transforming the amino group into electron-poor ammonium would increase its reactivity. As shown in formula 2, 2t reacted smoothly with a catalytic amount of p-TSA to generate 1t in 80% yield. These superior reactivities of electron-deficient nitrosobenzenes in the formation of the corresponding azoxybenzenes provided guidance toward the possible mechanism of the reaction. Nitrosobenzenes are known to form dimers in a
a
Reaction at 0.17 M of starting material. bIsolated yield. cReaction with 1 g of 1a. dStarting material recovered.
reversible equilibrium, as shown in formula 3.12 And electronwithdrawing groups on the nitrosobenzene tend to favor the
formation of dimers.13 This is in accordance to our observation on the reaction if we assume the dimer is responsible for the subsequent reduction to produce azoxybenzene. Hence in Scheme 2, we propose the mechanism of reductive dimerization of nitrosobenzene to form azoxybenzene. First, nucleophilic attack of iPrOH, which served as solvent, to one of the cationic nitrogens on the dimer occurs to form intermediate A. This explains the origin of the better reactivity of electron poor nitrosobenzene, since electron-withdrawing groups not only promote dimer formation but also increase the electrophilicity of the dimer. Subsequent abstraction of the α-proton on iPrOH 11627
DOI: 10.1021/acs.joc.7b01887 J. Org. Chem. 2017, 82, 11626−11630
Note
The Journal of Organic Chemistry
Table 3. Syntheses of Dissymmetrical Azoxybenzenesa
Scheme 2. Proposed Mechanisms of Reductive Dimerization of 2 To Form 1 in iPrOH
substituent R1 = COMe, R2 = CN R1 = COMe, R2 = Br
breaks down the intermediate to form B and protonated acetone. And then the protonation of B leads to the elimination of water to form 1. Since the reactions also proceed in solvents which are not considered as hydrogen donors (Table 1), we have also proposed an alternative mechanism. Since the solvents tested in Table 1 were not anhydrous, water could serve as a proton donor and protonate the dimer of nitrosobenzene. Then nucleophilic attack detached the previously formed hydroxyl group on the substrate to generate 1 with H2O2 as the side product. Since many of the nitrosobenzenes used in our methodology were prepared by the oxidation of corresponding anilines,14 we tried to further increase the practicality by a one-pot procedure to generate azoxybenzenes directly from aniline. To our delight, by treatment of oxone in water/iPrOH and then subsequent heating, substituted anilines 3 were converted to the corresponding azoxybenzenes (as shown in Scheme 3). In addition, this procedure could also be applied to gram-scale reaction (1q, 61%).
a
1(R1R2)/ yield (%)
1(R2R1)/ yield (%)
1(R1R1)/ yield (%)
1(R2R2)/ yield (%)
1na (21%)
1an (3%)
1n (13%)
1a (37%)
1nf (10%)
1fn (12%)
1n (69%)
1f (0%)
In both reactions, small amounts of starting materials were recovered.
Figure 2. ORTEP diagram of 1fn.
to a one-pot process to generate azoxybenzenes from the corresponding anilines (Scheme 3), which would be convenient for synthetic chemists interested in the utilizations of this unique 1−3-dipole moiety. Application of this method to the synthesis of dissymmetrical azoxybenzenes is underway.
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EXPERIMENTAL SECTION
General Procedure for the Reductive Dimerization of Nitrosobenzenes, 2 To Form Azoxybenzenes 1. A solution of 2 in of iPrOH (0.17 M) in a Teflon-lined screw cap vial was heated to 100 °C. After full consumption of 2 (checked by TLC), the reaction vial was then cooled to rt. Solvent was then evaporated by rotavap, and 1 was isolated using column chromatography of the crude mixture of the reaction. 1,2-Bis(4-cyanophenyl)diazene oxide 1a (10 mg, 95%; and for 1 g of starting material, 875 mg, 93%, yellowish solid, mp = 195.7−198.1 °C): Rf = 0.13 (EtOAc/n-hexane = 1:8); 1H NMR (300 MHz, CDCl3, 24 °C, δ): 8.46 (d, J = 9.0 Hz, 2H), 8.23 (d, J = 8.9 Hz, 2H), 7.87 (d, J = 9 Hz, 2H), 7.80 (d, J = 8.9 Hz, 2H). 13C NMR (100 MHz, CDCl3, 24 °C, δ):150.2 (C), 146.3 (C), 133.0 (CH × 2), 132.8 (CH × 2), 126.0 (CH × 2), 123.3 (CH × 2), 118.2 (C), 117.3 (C), 116.1 (C), 113.5 (C). HRMS (EI-TOF): m/z calculated for C14H8N4O [M]+, 248.0698; found, 248.0696. 1,2-Di-o-tolyldiazene oxide 1b (12 mg, 60%, yellowish solid, mp = 57.8−58.5 °C): Rf = 0.25 (EtOAc/n-hexane = 1:30); 1H NMR (400 MHz, CDCl3, 24 °C, δ): 8.03 (d, J = 5.9 Hz, 1H), 7.68−7.67 (m, 1H), 7.41−7.24 (m, 6H), 2.52 (s, 3H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3, 24 °C, δ): 149.3 (C), 142.7 (C), 134.0 (C), 131.7 (CH), 131.1 (C), 130.7 (CH), 129.9 (CH), 128.5 (CH), 126.5 (CH), 126.0 (CH), 123.5 (CH), 121.4 (CH), 18.3 (CH), 18.3 (CH). HRMS (EI-TOF): m/z calculated for C14H14N2O [M]+, 226.1106; found, 226.1111. 1,2-Diphenyldiazene oxide 1c (14 mg, 92%, yellowish solid, mp
