Pd-Catalyzed Three-Component Reaction of Anilines, Ethyl Vinyl

Letter Cite This: Org. Lett. 2018, 20, 550−553

pubs.acs.org/OrgLett

Pd-Catalyzed Three-Component Reaction of Anilines, Ethyl Vinyl Ether, and Nitro-Paraffin: Assembly of β‑Nitroamines Lu Ouyang, Lingzhi Zhan, Jianxiao Li, Qiaoyu Zhang, Chaorong Qi, Wanqing Wu,* and Huanfeng Jiang* Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P. R. China S Supporting Information *

ABSTRACT: A novel palladium-catalyzed amination and nitration of ethyl vinyl ether for the construction of βnitroamine derivatives under mild conditions has been developed. This transformation provides a new strategy for the installation of amino and nitro from aromatic amines and nitro-paraffin into alkenes. Morpholine resulted in the azaHenry reaction, while DABCO led to the unexpected rearrangement.

M

Scheme 1. Pd-Catalyzed Oxidative Amination of Alkenes and aza-Henry Reaction

ulticomponent reactions (MCRs) are convergent, facile, and efficient reactions, in which a small set of starting materials react to build up the final product according to cascade chemical reactions with minimal workup, high atomeconomy, and experimental simplicity.1 Thus, they have been one of the most interesting and promising synthetic methods, and they provide a facile and efficient protocol to increasing molecular diversity and complexity. In recent decades, transition-metal-catalyzed MCRs have been explored intensively and gained outstanding achievements, especially for palladium catalysis.2 β-Nitroamines containing two nitrogenated functions represent a class of rather valuable synthons for the construction of various functional molecules which are important in bioactive molecules, pharmaceuticals agents, and natural products, such as 1,2-diamines and α-aminocarbonyls.3 Our strong interest in the Pd-catalyzed amination of alkenes for the formation of carbon−carbon and carbon−nitrogen bonds4 and the great value and usefulness of β-nitroamines prompted us to explore Pd-catalyzed amination and nitration of alkenes under mild conditions. The aza-Henry reaction (nitro-Mannich reaction) is a powerful synthetic transformation, which offers an entry to various functional compounds with amino and nitro groups (Scheme 1, eq 2).5 Despite significant progress made in this area in recent decades, most of the direct aza-Henry reactions started with imines (particularly for electron-deficient imines) which are ready-made or synthesized by the condensation of amines and aldehydes.6 To our knowledge, no studies have addressed the aza-Henry reactions which were conducted with imines generated in situ from a reaction between amines and vinyl ethers. Therefore, a new type of azaHenry reaction that proceeds with simple and readily available materials with high efficiency and step-economy is still in demand. Herein, we disclose a new Pd-catalyzed aza-Henry reaction between amines, ethyl vinyl ethers, and nitro-paraffin © 2018 American Chemical Society

to form β-nitroamines with simple operations (Scheme 1, eq 3). The imines serving as an intermediate were generated in situ by the reaction between anilines and ethyl vinyl ethers, which was seldom reported previously.7 To initiate our study, CH3NO2 3a masked as the nitro group, aniline 1a selected as the amino group, and ethyl vinyl ether 2a were examined as potential coupling partners. To our delight, a 29% yield of the desired product 4a was obtained when using 10 mol % of PdCl2 as the catalyst and 1 equiv of AgOAc in CH3NO2 at 60 °C for 12 h (Table 1, entry 1). We next Received: November 22, 2017 Published: January 25, 2018 550

DOI: 10.1021/acs.orglett.7b03631 Org. Lett. 2018, 20, 550−553

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

yieldb (%) entry

[Pd]

[Ag]

base

4a

5a

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22

PdCl2 Pd(PPh3)2Cl2 Pd(PhCN)2Cl2 [PdCl(allyl)]2 Pd(TFA)2 Pd(cy)3 Pd(PPh3)4 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2 [PdCl(allyl)]2

AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgNO3 Ag2O Ag2CO3 AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc AgOAc

− − − − − − − − − − KOAc KI K2CO3 Na2CO3 Cs2CO3 t-BuOK piperidine N,N-diisopropyl ethylamine morpholine morpholine DABCO DABCO

29 41 37 53 31 28 31 trace trace trace 36 31 21 44 trace trace 71 47 75 85 (83)c,e 9 7

n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d. n.d 29 29 22 23 trace trace 5 20 5 6 59 71 (65)d,e

a

Reaction conditions: all reactions were performed with 1a (0.25 mmol), 2a (2 equiv), palladium catalyst (10 mol %), Ag salts (1 equiv), base (1 equiv), CH3NO2 (3a, 1 mL), at 60 °C under air for 12 h. bYield was determined by GC with dodecane as internal standard based on 1a. c0.5 equiv of AgOAc and 0.5 equiv of morpholine were used for 2 h. d0.5 equiv of AgOAc and 0.2 equiv of DABCO were used for 12 h. eIsolated yield. n.d. = not determined.

shown in Scheme 2, this morpholine-controlled transformation was successfully performed on a 0.25 mmol scale to afford αalkyl-β-nitroamines. Various arylamines with electron-donating or -withdrawing groups such as fluoro, chloro, bromo, trifluoromethyl, isopropyl, and tert-butyl groups were well tolerated in this catalytic system, and the corresponding α-alkylβ-nitroamines 4b−4g were generated in moderate to good yields. In addition, disubstituted anilines such as 3,5-dimethyl (1h), 3,4-difluoro (1i), and 3-chloro-4-fluoro aniline (1j) were found to be compatible with the reaction in the yield of 72% and 71%. To further explore the steric-hindrance effect of this Pd-catalyzed amination and nitration, the methyl-substituted anilines (para-, meta-, and ortho-) were subjected to the reaction. Unfortunately, the yield was found to be decreased gradually (4k−4m), which indicated that the steric effect was obvious. Interestingly, when nitroethane 3b and 1-nitropropane (3c) were treated as the solvent with aniline under the standard conditions, the desired products 4n and 4o could be afforded in moderate yields with a dr ratio of about 1.8:1 and 4.4:1. However, no desired products were obtained when 2nitropropane (3d) and (nitromethyl)benzene 3e served as solvent. Moreover, enol ethers with different alkoxy groups were compliant with this reaction and yield the same product 4a. We next investigated the substrate scope of the [PdCl(allyl)]2/DABCO catalytic system (Scheme 3). Various anilines with fluoro, iPr, and 3,5-dimethyl substituents were subjected to the optimized reaction conditions, and the corresponding βmethyl-β-nitroamines 5a−5d were delivered in 60−72% yields.

examined the palladium catalysts, and [PdCl(allyl)]2 proved to be the most efficient, which offered 4a in 53% yield (Table 1, entries 2−7). Using [PdCl(allyl)]2 as the catalyst, different Ag salts (Table 1, entries 8−10) were examined and AgOAc was observed to be superior to AgNO3, Ag2O, and Ag2CO3. Interestingly, when different bases were added, the rearrangement product 5a was detected. Inorganic bases, such as KOAc, KI, K2CO3, and Na2CO3, gave moderate conversions, and the ratio of 4a and 5a was between 1:1 and 2:1 (Table 1, entries 11−14). Increasing the basicity by using Cs2CO3 and t-BuOK resulted in a dramatic drop in conversion as well as yields (Table 1, entries 15−16). Compared with inorganic bases, organic bases including piperidine, N,N-diisopropylethylamine, and morpholine, showed effective selectivity for 4a when subjected to the reaction conditions (Table 1, entries 17−19), and morpholine exhibited the highest conversion and selectivity. By decreasing the amount of AgOAc and morpholine to 0.5 equiv, 4a could be obtained in 85% yield (Table 1, entry 20). Moreover, it is worth noting that when DABCO was tested in the reaction, the rearrangement product 5a could be afforded in high selectivity and moderate yield (Table 1, entries 21−22), and conducting the reaction with 0.5 equiv of AgOAc and 0.2 equiv of DABCO resulted in a 71% yield. Finally, in the absences of silver salt, neither 4a nor 5a could be examined in this catalyst system, demonstrating the key role of Ag salts. With the optimal conditions in hand, a variety of βnitroamines were synthesized from amines, ethyl vinyl ether, and nitro-paraffin using the Pd-catalyzed intermolecular threecomponent amination and nitration reaction. Gratifyingly, as 551

DOI: 10.1021/acs.orglett.7b03631 Org. Lett. 2018, 20, 550−553

Letter

Organic Letters Scheme 2. Morpholine Controlled Amination and Nitration of Ethyl Vinyl Ethera

Scheme 5. Control Experiments

alkyl-β-nitroamines 4 were generated in no more than 2 h, and β-methyl-β-nitroamines 5 were obtained after 2 h. Then we carried out further experiments to explain the transformation between 4 and 5. First, no reaction occurred in the absence of the Pd catalyst under condition B (Scheme 5, eq 1). When 4a was subjected to the standard condition B, 5a was produced in 43% yield (Scheme 5, eq 2). Moreover, when the reaction proceeded without an organic metal reagent or base, 45% yield of 5a was still achieved (Scheme 5, eq 3). It is worth noting that when 0.2 equiv of DABCO was added, the transformation efficiency improved (eq 4), which indicated that DABCO played an important role in rearrangement process. To further probe the transformation between 4 and 5, some control experiments were carried out under standard condition B (Figure 1). As the reaction time was prolonged, the yield of 4a

a

Reaction condition A: all reactions were performed with amines 1 (0.25 mmol), ethyl vinyl ether 2a (2 equiv), [PdCl(allyl)]2 (10 mol %), AgOAc (0.5 equiv), morpholine (0.5 equiv), nitro-pataffin (3, 1 mL), at 60 °C under air for 2 h. Yields refer to isolated yield. bReaction for 4 h.

Scheme 3. DABCO Controlled Amination and Nitration of Ethyl Vinyl Ethera

a

Reaction condition B: all reactions were performed with amines 1 (0.25 mmol), ethyl vinyl ether 2a (2 equiv), [PdCl(allyl)]2 (10 mol %), AgOAc (0.5 equiv), DABCO (0.2 equiv), CH3NO2 (3a, 1 mL), at 60 °C under air for 12 h. Yields refer to isolated yield.

Figure 1. Time course of controlling experiments.

was initially increased and began to decrease after 2 h (orange). But 2 h later, 5a was generated and the yield continued to increase to 79% (gray). These interesting results suggested that 4 could be converted to 5 under this catalytic system. Based on these interesting phenomena and findings, the proposed mechanistic pathway of this palladium-catalyzed amination and nitration is shown in Scheme 6. First, imine I

Simultaneously, steric hindrance clearly has an impact on the yield of β-methyl-β-nitroamines (5e−5g). To further highlight the applicability of this transformation, a gram-scale experiment was conducted (Scheme 4). The reaction proceeded effectively with 1a (8 mmol) in the presence of 10 mol % [PdCl(allyl)]2 for 2 h, and 1.15 g of 4a was obtained under the standard condition A. In order to gain insight into how the β-methyl-β-nitroamines 5 were generated, several mechanistic experiments were carried out (Scheme 5). According to previous experimental results, α-

Scheme 6. Proposed Mechanism

Scheme 4. Gram-Scale Experiment

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DOI: 10.1021/acs.orglett.7b03631 Org. Lett. 2018, 20, 550−553

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Organic Letters

(4) (a) Wu, W.; Jiang, H. Acc. Chem. Res. 2012, 45, 1736. (b) Ouyang, L.; Wu, W. Curr. Opin. Green Sustain. Chem. 2017, 7, 46. (c) Ji, X.; Huang, H.; Wu, W.; Jiang, H. J. Am. Chem. Soc. 2013, 135, 5286. (d) Ji, X.; Huang, H.; Wu, W.; Li, X.; Jiang, H. J. Org. Chem. 2013, 78, 11155. (e) Ji, X.; Huang, H.; Xiong, W.; Huang, K.; Wu, W.; Jiang, H. J. Org. Chem. 2014, 79, 7005. (f) Ouyang, L.; Li, J.; Zheng, J.; Huang, J.; Qi, C.; Wu, W.; Jiang, H. Angew. Chem., Int. Ed. 2017, 56, 15926. (g) Ouyang, L.; Huang, J.; Li, J.; Qi, C.; Wu, W.; Jiang, H. Chem. Commun. 2017, 53, 10422. (5) (a) Henry, L. Bull. Acad. R. Belg. 1896, 32, 33. (b) Adams, H.; Anderson, J. C.; Peace, S.; Pennell, A. M. K. J. Org. Chem. 1998, 63, 9932. (c) Noble, A.; Anderson, J. C. Chem. Rev. 2013, 113, 2887. (d) Westermann, B. Angew. Chem., Int. Ed. 2003, 42, 151. (e) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (f) Palomo, C.; Oiarbide, M.; Laso, A. Eur. J. Org. Chem. 2007, 2007, 2561. (g) Anderson, J. C.; Koovits, P. J. Chem. Sci. 2013, 4, 2897. (h) Anderson, J. C.; Noble, A.; Torres, P. R. Tetrahedron Lett. 2012, 53, 5707. (6) (a) Nugent, B. M.; Yoder, R. A.; Johnston, J. N. J. Am. Chem. Soc. 2004, 126, 3418. (b) Yamada, K.; Harwood, S. J.; Groger, H.; Shibasaki, M. Angew. Chem., Int. Ed. 1999, 38, 3504. (c) Knudsen, K. R.; Risgaard, T.; Nishiwaki, N.; Gothelf, K. V.; Jorgensen, K. A. J. Am. Chem. Soc. 2001, 123, 5843. (d) Nishiwaki, N.; Knudsen, K. R.; Gothelf, K. V.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2001, 40, 2992. (e) Piscopo, C. G.; Sartori, G.; Mayoral, J. A.; Lanari, D.; Vaccaro, L.; Maggi, R. Synlett 2013, 24, 2596. (7) (a) Matsubara, Y.; Hirakawa, S.; Yamaguchi, Y.; Yoshida, Z. Angew. Chem., Int. Ed. 2011, 50, 7670. (b) Olmos, A.; Sommer, J.; Pale, P. Chem. - Eur. J. 2011, 17, 1907. (8) (a) Jang, T.-S.; Ku, W.; Jang, M. S.; Keum, G.; Kang, S. B.; Chung, B. Y.; Jia, Y. K. Org. Lett. 2006, 8, 195. (b) Jia, X.; Ren, Y.; Huo, C.; Wang, W.; Chen, X.; Wang, X. Chin. Chem. Lett. 2011, 22, 671. (c) Sridharan, V.; Avendano, C.; Menéndez, J. C. Tetrahedron 2007, 63, 673. (d) Verma, S.; Verma, D.; Jain, S. L. Tetrahedron Lett. 2014, 55, 2406. (9) (a) Okino, T.; Nakamura, S.; Furukawa, T.; Takemoto, Y. Org. Lett. 2004, 6, 625. (b) Gomez-Bengoa, E.; Linden, A.; López, R.; Múgica-Mendiola, I.; Oiarbide, M.; Palomo, C. J. Am. Chem. Soc. 2008, 130, 7955. (c) Tan, C.; Liu, X.; Wang, L.; Wang, J.; Feng, X. Org. Lett. 2008, 10, 5305. (d) Hu, Y.; Zhou, Z.; Gong, L.; Meggers, E. Org. Chem. Front. 2015, 2, 968. (10) (a) Berestovitskaya, V. M.; Makarenko, S. V.; Bushmarinov, I. S.; Lyssenko, K. A.; Smirnov, A. S.; Stukan’, A. E. V. Russ. Chem. Bull. 2009, 58, 1023. (b) Hao, F.; Asahara, H. A.; Nishiwaki, N. Org. Lett. 2017, 19, 5442.

is formed via the reaction between amines and ethyl vinyl ether with the aid of a Pd catalyst and the elimination of EtOH.7,8 Then the reaction includes aza-Henry reaction of imines with nitro-paraffin to give α-alkyl-β-nitroamines (4) in the presence of AgOAc.5,9 With the assistance of DABCO, aziridines (II) were generated, and then ring openning and rearrangement10 would occur to afford β-methyl-β-nitroamines (5). In summary, we have established a novel Pd-catalyzed threecomponent amination and nitration reaction with simple and readily available materials. Various important organic molecules β-nitroamines were achieved through this transformation. In addition, this strategy provides an elegant and efficient azaHenry reaction under mild conditions, and it may open up a new viewpoint in the synthesis of β-nitroamines. Further studies to investigate the synthetic applications of this reaction are in progress.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03631. Experimental procedures, condition screening table, characterization data, and copies of NMR spectra for all products (PDF)

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AUTHOR INFORMATION

Corresponding Authors

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

Huanfeng Jiang: 0000-0002-4355-0294 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS The authors thank the National Program on Key Research Project (2016YFA0602900), the National Natural Science Foundation of China (21420102003 and 21672072), and the Fundamental Research Funds for the Central Universities (2015ZY001 and 2017ZD062) for financial support.

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REFERENCES

(1) (a) Cioc, R. C.; Ruijter, E.; Orru, R. V. A. Green Chem. 2014, 16, 2958. (b) Brauch, S.; van Berkel, S. S.; Westermann, B. Chem. Soc. Rev. 2013, 42, 4948. (c) Zhu, J.; Bienaymé, H. Multicomponent Reactions; Wiley-VCH: Weinheim, 2005. (d) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602. (e) Zarganes-Tzitzikas, T.; Chandgude, A. L.; Dömling, A. Chem. Rec. 2015, 15, 981. (2) (a) Tsuji, J. Palladium Reagents and Catalysis: Innovations in Organic Synthesis; Wiley: Chichester, U.K., 1995. (b) Jiang, H.; Ji, X.; Li, Y.; Chen, Z.; Wang, A. Org. Biomol. Chem. 2011, 9, 5358. (c) Shen, C.; Wu, X.-F. Chem.Eur. J. 2016, 22, 1. (3) (a) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017. (b) Ruano, J. L. G.; Cantarero, J. L.-C.; de Haro, T.; Aleman, J.; Cid, M. B. Tetrahedron 2006, 62, 12197. (c) Czekelius, C.; Carreira, E. M. Angew. Chem., Int. Ed. 2005, 44, 612. (d) Johnson, H. G. J. Am. Chem. Soc. 1946, 68, 12. (e) Morris, M. L.; Sturgess, M. A. Tetrahedron Lett. 1993, 34, 43. (f) Ballini, R.; Petrini, M. Tetrahedron Lett. 1999, 40, 4449. (g) Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67, 101. (h) Rebollo, O.; Olmo, E. D.; Ruiz, G.; Lopez-Perez, J. L.; Gimenez, A.; Feliciano, A. S. Bioorg. Med. Chem. Lett. 2008, 18, 184. 553

DOI: 10.1021/acs.orglett.7b03631 Org. Lett. 2018, 20, 550−553