Synthesis of Multisubstituted Benzimidazolones via Copper-Catalyzed Oxidative Tandem C-H Aminations and Alkyl Deconstructive Carbofunctionalization.

Benzimidazolone constitutes the core structure of numerous pharmaceuticals, agrochemicals, inhibitors, pigments, herbicides, and fine chemicals. Amination of hydrocarbons is an attractive tool for the creation of nitrogen-containing products. However, the multiple steps, harsh conditions, and low atom efficiencies often present in these reactions remain challenging. We present a multicomponent synthesis of functional benzimidazolones from arylamines, dialkylamines, and alcohols, acting via the sequence of copper-catalyzed oxidative tandem C-H aminations and alkyl deconstructive carbofunctionalization. The catalytic transformation forms multiple bonds in one single operation, uses readily available feedstocks and a naturally abundant Cu/O2 catalyst system, has broad substrate scope, avoids pre-installation of aminating agents and directing groups, and provides high chemo- and regioselectivity, resulting in direct functionalization of inert C-H and C-C bonds via single-electron oxidation-induced activation mode. This platform can be expected to provide structurally diverse products with interesting biological, chemical, and physical properties.

Introduction

Conventionally, the construction of functional organic products mainly relies on pre-preparation of active reactants followed by noble metal-catalyzed coupling steps, which can easily result in environmental pollution and low utilization efficiency of resources. In this context, there is a high demand for the development of novel catalytic transformations that, via direct functionalization of ubiquitous but poorly reactive C–H and C–C bonds in readily available feedstocks, generate the desired products in the presence of naturally abundant catalyst systems, as such transformations featuring high step and atom efficiency as well as sustainability would pave the ways to address the existing issues.

Among the various functionalizations of hydrocarbons, C–H amination constitutes a particularly attractive tool for the creation of nitrogen-containing products (Park et al., 2017, Kim and Chang, 2017, Beccalli et al., 2017, Boursalian et al., 2016). To date, a number of approaches have been elegantly explored for this purpose (Breslow and Gellman, 1983, Paudyal et al., 2016, Liang et al., 2018; Wertz et al., 2011, Yin et al., 2010, Kim et al., 2010, Gao et al., 2018, Wang et al., 2017a, Wang et al., 2017b, Tang et al., 2018, Wu et al., 2011, Wu et al., 2017, Wang et al., 2016, Wang et al., 2017a, Wang et al., 2017b, Margrey et al., 2017, Romero et al., 2015, Ouyang et al., 2017, Liu et al., 2017, Yang et al., 2017, Zhang et al., 2017). However, some key issues remain to be addressed in this field, such as the need for the pre-installation of specific aminating agents (e.g., nitrenes, N-atom with a leaving substituent, azoles) and directing groups, the use of waste-generating oxidants/additives, and harsh conditions. As such, the search for new C–H amination strategies involving free amines as the aminating agents in the absence of directing groups still remains a highly demanding goal. In terms of carbofunctionalization, much effort has been directed during the past decade toward the difunctionalization of alkenes (Qin et al., 2016, Shen et al., 2013, Shen et al., 2016, Li et al., 2016) and alkynes (Li et al., 2017, Urgoitia et al., 2017, Rubinstein et al., 2014, Rao et al., 2017). Moreover, carbofunctionalization via the cleavage of unsaturated C–C bonds (Sagadevan et al., 2017, Shen et al., 2013, Shen et al., 2016, Qin et al., 2016) has also been nicely established. In comparison, owing to a surrounding environment composed of four bonding atoms, regioselective alkyl deconstructive carbofunctionalization has at present remained a challenging but highly valuable topic in synthetic chemistry, as this process would offer the potential to develop novel transformations producing functional molecules that are difficult to prepare or inaccessible by conventional approaches (Liu et al., 2018). For instance in this regard, the Zhu group has reported a number of transformations on the cleavage of strained alkyl chains such as cyclobutanols (Ren et al., 2015, Ren et al., 2016, Yu et al., 2016, Zhao et al., 2015). Very recently, Roque et al. have demonstrated interesting examples on deconstructive functionalization of cyclic tertiary amines (Roque et al., 2018a, Roque et al., 2018b). However, to the best of our knowledge, the elaboration of functional molecules, via the strategy combining direct C–H amination with deconstructive carbofunctionalization of unstrained alkyl chain, remains a new subject to be explored.

As our sustained effort has been directed toward the functionalization of N-heterocycles (Zhao et al., 2019, Xie et al., 2017, Xie et al., 2018, Xie et al., 2019, Chen et al., 2017), we have recently reported a site-specific fluoroalkylation of aniline derivatives with in situ-formed electrophilic radicals (Zhao et al., 2019). This work motivated us to conceive a protocol to aminate the para-site of relatively electron-poor diarylamine 1 with electron-rich dialkylamine 2. As illustrated in Scheme 1, the presence of a suitable catalyst and oxidant is expected to lead to single electron oxidation (SEO) of 2 and generate radical cation 2′, which then interacts with the zwitterionic form A of diarylamine 1 at the sterically less-hindered para-site, and generates the amination product B via further SEO and deprotonations. However, when we tested the reaction of diphenylamine 1a and azepane 2a in i-butanol by using CuCl/O2 as a catalyst system, we observed that, instead of the anticipated aryl para-C–H amination product B, a novel functional benzimidazolone 4aaa was isolated in 22% yield by combining two molecules of 1a, one molecule of 2a, and i-butanol 3a (solvent). In such a reaction, three C–N and three C–O bonds are formed in one single operation. Especially, the aryl C–H aminations take place at positions 2 and 4 of diphenylamine 1a, and the alkyl cleavage in amine 2a occurs selectively between the α- and β-sties, which leads to α-carboamidation and β-carboesterification, respectively.

Scheme 1

Previous Work and the New Observation

It is important to note that benzimidazolone constitutes the core structure of numerous pharmaceuticals, agrochemicals, inhibitors, pigments, herbicides, and fine chemicals (Monforte et al., 2010, Palin et al., 2008, Mastalerz and Oppel, 2012, Mir et al., 2012, Nale and Bhanage, 2015). To date, although there are a number of approaches reported for the synthesis of such compounds, including the cyclization of o-phenylenediamine with phosgene or CO surrogates (Scheme 2, path a), (Monforte et al., 2009, Kuethe et al., 2004, Diao et al., 2009) the cyclization of o-haloanilines involving C–N bond formation (paths b and c) (Zou et al., 2007, An et al., 2016), the oxidative aryl C–H amidation of N-disubstituted ureas (path d) (Beyer et al., 2001, Li et al., 2008, Yu et al., 2015), PhIO-induced Hofmann rearrangement of amides followed by intramolecular nucleophilic attack by an ortho-amino group (path e) (Łukasik and Wróbel, 2016), and the addition of anilines to isocyanates followed by intramolecular oxidative C–H amidation (path f) (Youn and Kim, 2016, Allen and Tidwell, 2013), to the best of our knowledge, the direct construction of benzimidazolones incorporated with additional functionalities from easily available feedstocks is still lacking. On the basis of our new observation, we herein present, for the first time, a multicomponent synthesis of functional benzimidazolones via tandem C–H aminations and alkyl deconstructive carbofunctionalization.

Scheme 2

Existing Main Approaches for the Synthesis of Benzimidazolones

Results and Discussion

Initially, we focused on screening an efficient catalyst system by choosing the coupling of 1a and 2a in i-butanol (3a) as a model reaction. After evaluation of a series of reaction parameters (Table S1, Supplemental Information), an optimal isolated yield for product 4aaa was obtained when the reaction charged with an O2 balloon was performed at 100°C for 12 h with 20 mol % of CuCl2, 2 equiv. of pyridine, and Na2CO3 (standard conditions), in which Na2CO3 was used to neutralize the combined HCl in the cyclic amine salts.

With the optimal conditions established, we then examined the generality of the synthetic protocol. First, various unsymmetrical diarylamines (1b-1h) in combination with cyclic amines 2a in i-butanol 3a were explored. As shown in Scheme 3, all the reactions proceeded smoothly and furnished the desired products (4aaa-4haa) in good isolated yields. The substituents with different electronic properties on the aryl ring of the diarylamines slightly influenced the product yields. Then, we tested the transformation of secondary cyclic amines with different ring sizes (2b-2e). Similarly all the substrates smoothly coupled with diphenylamine 1a and i-butanol 3a and provided the N-alkyl products with tunable chain lengths (4aba-4aea) in moderate to good yields. Interestingly, the use of 4-methylpiperidyl salt 2e led to the generation of product 4aea, which involves an additional chlorination at the tertiary α-site of the ester group, and the combined HCl in 2e is believed to serve as the chlorine source. Furthermore, the variation of alcohols had no significant influence on the product formation. Thus different types of alcohols, including linear, branched, (hetero)aryl, and heteroatom-containing alcohols, efficiently reacted with 1a and 2a to give the desired products (4aab-4aag) in good yields. Owing to the excellent compatibility of the different coupling partners, the developed chemistry offers a versatile way for the synthesis of benzimidazolones with structural diversity.

Scheme 3

Variation of the Three Coupling Partners

Also see Figures S1–S37.

The successful transformation of secondary cyclic amines (Scheme 3) subsequently encouraged us to apply the synthetic protocol to the open-chain dialkylamines. As shown in Scheme 4, a series of such substrates (2f-2m) in combination with diphenylamine 1a and alcohol 3a were tested. Gratifyingly, both linear and branched dialkylamines 2 underwent efficient alkyl cleavage between the α- and β-carbons, and the α-carboamidation generated the N-alkylated benzimidazolone products 5 (i.e., 5af-5aj), whereas the β-carboesterofication led to the liberation of the ester by-products 5’. It is noteworthy that unsymmetrical N-ethylbutan-1-amine (2k) generated two products (5af and 5ah) with similar yields, whereas the reaction of N-ethylpropan-2-amine (2l) exclusively generated the N-propyl product 5al with a 35% yield (as confirmed by single-crystal X-ray diffraction, CCDC: 1508570, for details, see Figure S88 and Tables S2–S6), and the C–C bond cleaved at the sterically less-hindered ethyl group. It is also of interest that diallylamine 2m generated the product 5am in 62% yield with the retention of the allylic functionality.

Scheme 4

Variation of Open-Chain Dialkylamines

Standard condition deviation: without addition of Na2CO3. Also see Figures S38–S51 and S88 and Tables S2–S6.

Subsequently, we focused on the variation of both diarylamines and open-chain dialkylamines (Scheme 5). Here, substrates 1 with different functionalities on the aryl ring, including –Me, –Et, –t-Bu, –Ph, –F, –Cl, –Br, –CN, –CO2Et, –NO2, and –CF3, were well tolerated and afforded the desired products (5bf–5ff, 5if, 5bg, 5jg, 5kg, 5lg, 5mf–5nf, and 5og) in moderate to excellent yields. The electronic properties of these substituents significantly influenced the product formation. In particular, the electron-rich diarylamines provided much higher yields (5bf, 5bg, 5jg, 5mf, 5og, and 5pf) than those of strong electron-withdrawing diarylamines (5if, 5kg, and 5lg). This phenomenon is explained as the result of electron-rich diarylamines favoring the oxidation process to form active intermediates. In addition to diarylamines, N-alkyl aniline 1p was also favorable for the transformation and produced the desired product 5pf in high yield.

Scheme 5

Variation of Both Dialkyl- and Arylamines

Standard condition deviation: without addition of Na2CO3. Also see Figures S52–S83.

In an effort to obtain some mechanistic insights into the reaction route, we conducted several control experiments as illustrated in Scheme 6, Equations 1–4 (also see Figures S84–S87). Interruption of the model reaction conducted under standard conditions after 1 h led to the generation of a small concentration of the homo-coupling product 1aa, which arose from the para-C–H amination of diphenylamine 1a. Thus we employed 1aa to react with amine 2a and alcohol 3a under standard conditions, and benzimidazolone 4aaa was generated in high yield (Equation 1). This result indicates that 1aa is a key reaction intermediate. Then the addition of excess 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) to the model reaction completely suppressed the formation of product (Equation 2), indicating that the reaction involves radical intermediates. Furthermore, the reaction of N-phenyl-2-(piperidin-1-yl)aniline 1q with 1a and 3a produced benzimidazolone 6qa in a 78% yield (Equation 3), where diphenylamine 1a was not incorporated in the terminal product. However, the para-site-blocked diarylamine (1o) was unable to couple with amine 2a to yield product 5rf (Equation 4). These results indicate that the first aryl para-C–H amination of 1a occurs before the second aryl ortho-C–H amination with 2a and product 4aaa derives from tandem dual aryl C–H aminations followed by alkyl deconstructive intramolecular α-carboamidation and intermolecular β-carboesterification.

Scheme 6

Control Experiments

Also see Figures S84–S87.

Based on the above findings, the possible reaction pathway is depicted in Figure 1. Owing to the lower oxidation potential, preferential SEO of dialkylamine 2 (from 2 to 2′) followed by single-electron transfer from arylamine 1 to the resulting radical cation 2′ would form more stable diarylamino radical cation 1’. Then, 1′ interacts with another molecule of diarylamine 1 and generates the first aryl para-C–H amination product 1-1 via further SEO and deprotonations. Similarly, the aryl radical cation arising from 1-1 interacts with the sterically less hindered dialkylamine 2 at the less congested ortho-site and gives rise to the 2,4-diamino intermediate 4-1. Then, the oxidation of relatively electron-rich alkylamino motif of 4-1 followed by intramolecular nucleophilic addition gives the cyclization adduct 4-3. Noteworthy, the preferential transformation from dimer 1-1 to 4-1 and 4-3 suppresses the formation of trimeric adducts of diarylamine 1. Furthermore, the second round oxidation of the alkylamino unit generates iminium ion 4-4 and diamino alkene 4-5, successively. The O2-mediated oxidation of electron-rich C–C double bond in 4-5 would lead to selective C–C bond cleavage (from 4-5 to 4-6) (Ando et al., 1975) and intramolecular α-carboamidation in conjunction with the formation of an aldehyde functionality at the β-site. Finally, the oxidative carboesterification of the aldehyde with alcohol 3 would produce product 4. For the reaction applying open-chain dialkylamine 2, the C(α)–C(β) cleavage leads to liberation of the ester by-product.

Figure 1

Plausible Reaction Pathway

Limitations of Study

Anilines and specific cyclic amines such as tetrahydroquinolines and indolines were not applicable in the present reactions and no benzimidazolones products were generated.

Conclusion

In summary, we have demonstrated, for the first time, a multicomponent synthesis of functional benzimidazolones via tandem C–H aminations and deconstructive carbofunctionalization of unstrained alkyl chain. The catalytic transformation proceeds with the striking features of the formation of three C–N and three C–O bonds in one single operation, the use of readily available feedstocks and a naturally abundant Cu/O2 catalyst system, broad substrate scope, no need for pre-installation of specific aminating agents and directing groups, and high chemo- and regioselectivities, which offers an important basis in direct functionalization of inert C–H and C–C bonds via SEO-induced activation mode. The significant utility of benzimidazolones in combination with this novel platform that can be expected to provide structurally diverse products possessing original biological, chemical, and physical properties will incite extensive interest in the scientific community.

Methods

All methods can be found in the accompanying Transparent Methods supplemental file.