Catalytic Selective Oxidative Coupling of Secondary N-Alkylanilines

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Letter Cite This: Org. Lett. XXXX, XXX, XXX−XXX

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Catalytic Selective Oxidative Coupling of Secondary N‑Alkylanilines: An Approach to Azoxyarene Lei Ke,† Guirong Zhu,‡ Hui Qian,‡ Guangya Xiang,† Qin Chen,*,‡ and Zhilong Chen*,† †

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School of Pharmacy, Huazhong University of Science and Technology (HUST), 13 Hangkong Road, Wuhan, Hubei 430030, P.R. China ‡ Research Center for Molecular Recognition and Synthesis, Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P.R. China S Supporting Information *

ABSTRACT: Azoxyarenes are among important scaffolds in organic molecules. Direct oxidative coupling of primary anilines provides a concise fashion to construct them. However, whether these scaffolds can be prepared from secondary N-alkylanilines is not well explored. Here, we present a catalytic selective oxidative coupling of secondary N-alkylaniline to afford azoxyarene with tungsten catalyst under mild conditions. In addition, azoxy can be viewed as a bioisostere of alkene and amide. Several “azoxyarene analogues” of the corresponding bioactive alkenes and amides showed comparable promising anticancer activities.

M

sieves,5s heteropolyoxotungstate,5t phosphotungstate,5u tungstate-based nanoparticle (NP),5v and Zn-NP5w (Figure 1B). On the other hand, whether the secondary N-alkylaniline can also selectively afford azoxyarene remains to be explored. Such a transformation is more challenging, requiring both efficient selective (alkyl)C−(aryl)N bond cleavage and (aryl)N−(aryl)N bond formation. The secondary N-alkylaniline, under oxidative reaction conditions, can afford many useful cross-dehydrogenative coupling (CDC) products6 or tetraaryhydrazines7 as reported (Figure 1Ca,b). On the basis of the CDC reaction mechanism proposed by Li, an imine intermediate would form first which was then trapped by diverse nucleophiles, offering an excellent method to prepare the secondary or tertiary amines.6 In theory, a primary aniline could be generated from hydrolysis of the imine intermediate as well,8 which would then be selectively oxidized into azoxyarene by utilizing the reported procedure.5 However, avoiding the competing formations of tetraaryhydrazines7 or other CDC products6 is still challenging. Additionally, the intrinsic high reactivity of aniline under oxidative conditions can lead to the distribution of products in an uncontrollable manner. Nevertheless, this transformation can potentially offer a complementary approach to azoxyarene and new aspects for the transformations of secondary N-alkylaniline to some extent, leading to our efforts for investigation (Figure 1Cc).

olecules embodying N−N bonds belong to important compounds in organic chemistry, including azo, azoxy, and tetraaryhydrazine. Among them, azoxyarene is of great interest, as it can be found in many bioactive natural products, functional materials, and organic dyes1 (e.g., antifungal compounds and energy materials). Azoxy can also be viewed as a bioisotere for alkene and amide, considering that they have similar bond lengths, conformations, and molecular weights (MW).2 Compared to amide, the E/Z isomerization of azoxy is much more difficult, which could lead to undesired off-target effects.3 Meanwhile, the LogP of azoxy is smaller than that of amide but larger than that of alkene. In addition, azoxy is also metabolically more stable than alkene and amide when treated with P450.4 From this perspective, it would be possible to tune both the potency and ADME (absorption, distribution, metabolism, and excretion) properties of certain lead compounds by simply replacing the alkene or amide motifs with azoxy while maintaining the MW (Figure 1A). Direct oxidative coupling of anilines enables a concise and appealing access to construction of azoxyarenes, in particular considering their abundance in organic synthesis. For example, symmetric azoxyarenes can be conveniently prepared from selective oxidative coupling of primary anilines in the presence of peroxymonosulfate,5a sulfonic acids,5b perfluoroketone,5c,d Oxone in a ball mill,5e or chemoenzyme.5f In addition, several homogeneous transition-metal and heterogeneous catalysts were also reported to facilitate this transformation, including Ru,5g Re,5h,i Mo,5j Ti,5k−n Co,5o Cu,5p,q SeO2,5r molecular © XXXX American Chemical Society

Received: April 5, 2019

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DOI: 10.1021/acs.orglett.9b01200 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Substrate Scope for Homocoupling

Figure 1. Azoxyarene in natural products, material science, and medicinal chemistry.

Therefore, N-ethylaniline 3a-1 was selected as a model substrate in reaction condition optimization. First, Cu and Fe catalysts were utilized in this reaction, but disappointing results were obtained. Next, tungstate catalysts caught our attention. In the presence of certain tungsten-based catalysts, secondary amines and tetrahydroquinolines could transfer into nitrones9a,b,10 and cyclic hydroxamic acids,9c,d respectively, as reported by Murahashi, while primary aniline can selectively yield either azodioxy or azoxy as reported by Stowell9f and Ghosh.5v Accordingly, tungstate catalysts could satisfy our hypothesis, but azodioxy products might also dominate the reaction. Luckily, after additional efforts in condition optimization, we were able to obtain azoxyarene 6aa in good yield with ammonium paratungstate (APT, 2.5 mol %) and H2O2 (30% aq, 5.0 equiv) at room temperature (rt) in EtOH (Scheme 1 and Tables ST1 and ST2).

a

All of the reactions were carried out at approximately 1.0 or 2.0 mmol scale unless noted (see the Supporting Information), 8−24 h, isolated yield. b50 mmol scale reaction; 3.8 g of 6aa was obtained. c The reaction was heated to 70 °C. dThe reaction was heated to 50 °C.

desired product in moderate yield with longer reaction time (3a-6). Surprisingly, the alkenyl motif did not significantly influence the efficiency, since it could consume H2O2 in forming oxirane (3a-7 and 3a-15).11 Of note, even if two anilines were linked by one N-alkyl substituent the reaction still worked smoothly (3a-8). As for the aryl scope, overall, many functional groups can be tolerated as well, including halogen (6dd, 6ee, 6kk−6mm), ester (6ff, 6nn), ether (6bb, 6rr), and piperidine (6tt). Arenes bearing electron-deficient substituents showed decreased reaction rate and efficiency. For example, the conversion dropped dramatically with substrate 3f. After reinvestigating the reaction, we were able to obtain 6ff in moderate yield at 70 °C. The steric hindrance on arene evidently influenced the reaction efficiency; for instance, arenes bearing 2-methyl or 2-ethyl only afford moderate yields of azoxy products (6gg−6ii). It is worth pointing out that heteroarene, like pyridine (6oo), carbazole (6ss), and indole (6uu), could also be tolerated in our reaction. Interestingly, a kinetic resolution phenomenon was observed with substrate 3a-18 (prepared from and menthone as a mixture of 1:1 dr). Under standard conditions, the (1R,2S,5R)3a-18-2 was consumed in 10 h, while the (1S,2S,5R)-3a-18-1 was recycled in excellent yield, illustrating that potential

Scheme 1. Optimized Reaction Conditions for Oxdiative Coupling of Secondary N-Alkylaniline To Afford Azoxyarene

Within the optimized conditions in hand, the aniline substrate scope was probed first as shown in Scheme 2. Generally, N-alkyl substituents (primary or secondary) of aniline 3a were well tolerated although with variation of steric and electronic properties, including lots of functional groups, such as electron-rich aryl groups (3a-12, 3a-16), ester (3a-13), and hydroxyl group (3a-14) and protected amide (3a-17). A lower yield was observed with bulky alkyl substituents (3a-3 vs 3a-4). Aniline-bearing cyclopentanyl motif also gave the B

DOI: 10.1021/acs.orglett.9b01200 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters catalytic asymmetric kinetic resolution of racemic N-alkylanilines by chiral tungstate catalyst could be possible (Scheme 3).

Scheme 5. Mechanism Studies

Scheme 3. Kinetic Resolution

The cross-coupling also worked smoothly in our reaction. Good chemoselectivities and moderate yield were achieved by subtly tuning the reaction conditions (Table ST3). Generally, the regioselectivities of products from coupling of two anilines bearing different electronic properties were a little bit higher compared to those bearing similar electronic properties, such as 6cj and 6dj. Interestingly, introducing ortho-substituents on arene (3′) can greatly improve the regioselectivity without obvious erosion of yield (6jv, 6jw, 6jx, 6gj, 6hi, 6ij, 6in), serving as another choice for dissymmetric azoxyarene synthesis in high regioselectivity.12 The structure of product 6ij was determined unambiguously by X-ray analysis, and the other products’ structures were assumed by comparison with it (Scheme 4).

insights, aniline 1a, N-hydroxyaniline 10a, nitrone 9a, and Nalkylhydroxyaniline 11a-1 were subjected to the reaction under the same conditions. To our surprise, all of them afforded the azoxyarene 6aa selectively in moderate to excellent yield, indicating that they all could be reaction intermediates (Scheme 5, eqs 4−7). Furthermore, given the difference between their yields, in particular those between Nhydroxyaniline 10a and 1a, it could be hypothesized that 10a was in a later stage than 1a during the reaction pathway. In contrast, both tertiary N-alkylaniline 3a-19 and N-tertiary alkyl aniline 3a′ failed to afford any desired product 6aa, revealing that both N−H and Cα−H were important to the success for this transformation (Scheme 5, eqs 8 and 9). Additionally, according to the kinetic isotope (KIE) study, the (alkyl)C− (aryl)N bond cleavage was not the rate-determining step (RDS). N-Radical species were supposed to be involved in this reaction based on radical-clock experiments (Schemes S10 and S11). On the basis of the results obtained from control experiments, the reaction mechanism was proposed as follows. Compound 3 was first oxidized into N-hydroxylamine 11 in a hydroxyl-transfer procedure9a−d followed by dehydration to afford imine 12. Compound 12 was hydrolyzed into aniline 1, which was later oxidized into N-hydroxylamine 10 (Scheme 6, A, path A). N-Hydroxylamine 11 could be oxidized into compound 13 and nitrone 9 by dehydration in succession as well. Meanwhile, nitrone 9 also could be hydrolyzed into Nhydroxylamine 10.9d Finally, this compound 10 was oxidized into nitrosoarene 14,9h which reacted with N-hydroxyaniline 10 to afford azoxyarene product5 (Scheme 6, A, path B). Since APT (polynuclear) and sodium tungstate (mononuclear) showed almost the same catalytic behavior in this reaction, we wanted to use mononuclear tungsten as a model to explain the hydroxyl-transfer mechanism. In the beginning, the tungstate formed a peroxide intermediate C-II and then peroxocomplex C-III by addition of 1 equiv of H2O2. After addition of another equivalent of H2O2, C-III was transformed into intermediate C-IV13a,b bearing two peroxo moieties, which

Scheme 4. Substrate Scope for Cross-Coupling*

*

All of the reactions were carried out in the presence of 2.5 mol % of APT and H2O2 (30% aq, 5.0 equiv), isolated yield, rr = regioselectivity ratio. a3/3′ = 2:1. b3/3′ = 1:2. c3/3′ = 1:3. dThe yields of two isomers and rr values were determined by 1H NMR of the isolated mixtures.

To explore the reaction mechanism, several control experiments were conducted. As previously hypothesized, the cleavage of the (alkyl)C−(aryl)N bond might be derived from hydrolysis of an imine intermediate, releasing the primary aniline and aldehyde. Thus, substrate 3a,b was utilized to prove this hypothesis. Indeed, aldehyde 2i was isolated in moderate yield from substrate 3a-16 (Scheme 5, eq 3). To gain more C

DOI: 10.1021/acs.orglett.9b01200 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 6. Proposed Reaction Mechanism

Scheme 7. Reactions for Mixture of Starting Materials

was opened by aniline 3 to form intermediate C-V through an external electrophilic oxygen-transfer mechanism.13c Next, intermediate C-V became C-VI by intramolecular proton transfer. Finally compound 11 and intermediate C-III were removed from intermediate C-VI by elimination. It is worth noting that intermediate C-II could also work as a key intermediate for hydroxyl transfer (C-VII) as proposed by Murahashi.9a Intermediate 13 was supposed to be produced from intermediate 11 by another round of catalytic hydroxyltransfer cycle (Scheme 6, B). According to our previous mechanism study, even when the starting material was a mixture with different N-alkyl substituents the desired product 6 could still be obtained. As expected, when substrates 3a-1, 3a-3, and 3a-7 were mixed in a 2:1:1 ratio, product 6aa was obtained in moderate yield (Scheme 7, eq 10). Similarly, the dissymmetric azoxyarene could also be obtained from cross-coupling of mixed starting materials. For example, when substrates 3j, 3j-2, 3g-1, and 3g2 were utilized in the reaction as a 1:1:2:2 mixture (Scheme 7, eq 11), product 6gj could be isolated in moderate yield. Furthermore, although the starting material was a mixture of N-alkylanilines in different oxidation states, the desired products could still be obtained. For instance, the mixture of aniline, N-hydroxylaniline, and nitrone (3a-3:11a-1:9a:10a:1a = 1:1:1:5:2) could also transfer into the product 6aa smoothly under the standard reaction conditions (Scheme 7, eq 12). The intramolecular coupling from two different N-alkylaniline motifs worked as well. For example, product 8a was obtained from substrate 7a, in comparison with previously reported cyclic-azodioxide product.9g Although the reaction proceeded smoothly as observed by thin-layer chromatography (TLC), the isolated yield was low probably due to its instability during the isolation (Scheme 7, eq 13). As illustrated in the beginning of this report, the azoxy group can be viewed as bioisostere of alkene and amide in medicinal

chemistry. To prove this hypothesis, several “azoxy analogues” of bioactive molecules bearing alkene and amides motifs were synthesized, and their bioactivities were evaluated. For example, the azoxyarene analogues of pterostilbene,14 a stilbene-type product with diverse bioactivities including anticancer and antioxidation, showed comparable proliferation inhibition properties against A549 human lung cancer cells (compounds 6jw and 6jx inhibited A549 cell proliferation by 76.9% and 77.7%, respectively, after 72 h treatment, Scheme 8A). Similarly, compounds 6qz and 19,15 azoxyarene analogues of tamibarotene,16 a drug for acute progranulocytic leukemia Scheme 8. Azoxyarenes in Medicinal Chemistry

a

Taxol was used as a positive control; bInhibitory rate of growth at 100 μm or 25 nM (Taxol).

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Organic Letters

diverse N−O building blocks for high-performance energetic materials. J. Am. Chem. Soc. 2014, 136, 4437. (2) (a) Cottrell, T. L. The Strengths of Chemical Bonds; Academic Press: New York, 1956; pp 271−293. (b) Allen, F. H.; Kennard, O.; Watson, D. G. Tables of bond lengths determined by X-Ray and neutron diffraction. Part I. bond lengths in organic compounds. J. Chem. Soc., Perkin Trans. 2 1987, 2, S1−S19. (3) (a) Dugave, C. cis-trans Isomerization in Biochemistry; Wiley: 2006. For a typical example, see: (b) Arisawa, M.; Kasaya, Y.; Obata, T.; Sasaki, T.; Ito, M.; Abe, H.; Ito, Y.; Yamano, A.; Shuto, S. Indomethacin Analogues that Enhance Doxorubicin Cytotoxicity in Multidrug Resistant Cells without Cox Inhibitory Activity. ACS Med. Chem. Lett. 2011, 2, 353. (4) Remsberg, C. M.; Yanez, J. A.; Ohgami, Y.; Vega-Villa, K. R.; Rimando, A. M.; Davies, N. M. Pharmacometrics of pterostilbene: preclinical pharmacokinetics and metabolism, anticancer, antiinflammatory, antioxidant and analgesic activity. Phytother. Res. 2008, 22, 169. (5) (a) Rezaeifard, A.; Jafarpour, M.; Naseri, M. A.; Shariati, R. A rapid and easy method for the synthesis of azoxy arenes using tetrabutylammonium peroxymonosulfate. Dyes Pigm. 2008, 76, 840. (b) Kluge, R.; Schulz, M.; Liebsch, S. Sulfonic peracids-III. Heteroatom oxidation and chemoselectivity. Tetrahedron 1996, 52, 5773. (c) Neimann, K.; Neumann, R. A new non-metal heterogeneous catalyst for the activation of hydrogen peroxide: a perfluorinated ketone attached to silica for oxidation of aromatic amines and alkenes. Chem. Commun. 2001, 487. (d) Voutyritsa, E.; Theodorou, A.; Kokotou, M. G.; Kokotos, C. G. Organocatalytic oxidation of substituted anilines to azoxybenzenes and nitro compounds: mechanistic studies excluding the involvement of a dioxirane intermediate. Green Chem. 2017, 19, 1291. (e) Thorwirth, R.; Bernhardt, F.; Stolle, A.; Ondruschka, B.; Asghari, J. Switchable selectivity during oxidation of anilines in a ball mill. Chem. - Eur. J. 2010, 16, 13236. (f) Yang, F.; Wang, Z.; Zhang, X.; Jiang, L.; Li, Y.; Wang, L. A green chemosnzymatic process for the synthesis of azoxybenzenes. ChemCatChem 2015, 7, 3450. (g) Barak, G.; Sasson, Y. Effect of phase-transfer catalysis on the selectivity of hydrogen peroxide oxidation of aniline. J. Org. Chem. 1989, 54, 3484. (h) Murray, R. W.; Iyanar, K.; Chen, J.; Wearing, J. T. Oxidation of organonitrogen compounds by the methyltrioxorhenium-hydrogen peroxide system. Tetrahedron Lett. 1996, 37, 805. (i) Khatri, P. K.; Choudhary, S.; Singh, R.; Jain, S. L.; Khatri, O. P. Grafting of a rhenium-oxo complex on Schiff base functionalization graphene oxide: an efficient catalyst for the oxidation of amines. Dalton. Trans. 2014, 43, 8054. (j) Biradar, A. V.; Kotbagi, T. V.; Dongare, M. K.; Umbarkar, S. B. Selective N-oxidation of aromatic amines to nitroso derivatives using a molybdenum acetylide oxo-peroxo complex as catalyst. Tetrahedron Lett. 2008, 49, 3616. (k) Selvam, T.; Ramaswamy, A. R. Selective catalytic oxidation of aniline to azoxybenzene over titanium silicate molecular sieves. Catal. Lett. 1995, 31, 103. (l) Suresh, S.; Joseph, R.; Jayachandran, B.; Pol, A. V.; Vinod, M. P.; Sudalai, A.; Sonawane, H. R.; Ravindranathan, T. Catalytic selective oxidation of amines with hydroperoxides over molecular sieves: investigations into the reaction of alkylamines, arylamines, allylamines and benzylamines with H2O2 and TBHP over TS-1 and CrS-2 as the new catalyst. Tetrahedron 1995, 51, 11305. (m) Jagtap, N.; Ramaswamy, V. Oxidation of aniline over titania pillared montmorillonite clays. Appl. Clay Sci. 2006, 33, 89. (n) Tumma, H.; Nagaraju, N.; Reddy, K. V. Titanium (IV) oxide, an efficient and structure-sensitive heterogeneous catalyst for the preparation of azoxybenzenes in the presence of hydrogen peroxide. Appl. Catal., A 2009, 353, 54. (o) Chang, C.-F.; Liu, S.-T. Catalytic oxidation of anilines into azoxybenzenes on mesoporous silicas containing cobalt oxide. J. Mol. Catal. A: Chem. 2009, 299, 121. (p) Acharyya, S. S.; Ghosh, S.; Bal, R. Catalytic oxidation of aniline to azoxybenzene over CuCr2O4 spinel nanoparticle catalyst. ACS Sustainable Chem. Eng. 2014, 2, 584. (q) Shukla, A.; Singha, R. K.; Konathala, L. N. S.; Sasaki, T.; Bal, T. Catalytic oxidation of aromatic amines to azoxy compounds over a Cu-SeO2 catalyst using H2O2 as

(APL), were even more potent against HL-60 human leukemia cells (Scheme 8B). In summary, a catalytic, selective, and convenient approach to azoxyarene by oxidative coupling of secondary N-alkylaniline has been developed. The reaction features broad substrate scope and good functional group tolerance. Mechanistic studies suggested that the cleavage of (alkyl)C−(aryl)N bond took place first to release both primary aniline (or Nhydroxylaniline) and aldehyde/ketone, followed by (aryl)N− (aryl)N bond formation. Additionally, the azoxy can be viewed as the bioisostere of alkene and amide, and several azoxyarene products were discovered with anticancer activities.

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ASSOCIATED CONTENT

* Supporting Information S

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.9b01200. Experimental procedures, characterization data, kinetic studies, and 1H, 13C NMR, IR, and LC−MS analysis (PDF) Accession Codes

CCDC 1893754 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Hui Qian: 0000-0002-5606-9213 Qin Chen: 0000-0003-0278-6740 Zhilong Chen: 0000-0001-6312-4914 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We acknowledge financial support provided by the National Natural Science Foundation of China (21602011, 81572695). We also thank Prof. Guangming Yao, Prof. Chaomei Xiong, and Prof. Lingkui Meng (Huazhong University of Science and Technology (HUST)) as well as the Analytical and Testing Centre of HUST for NMR spectra and HRMS data collection. We thank Prof. Qihui Chen (Fujian institute of Research on the Structure of Matter, Chinese Academy of Science) for his help with X-ray analysis.

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REFERENCES

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