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Catalyst-Free Reductive Amination of Aromatic Aldehydes with Ammonium Formate and Hantzsch Ester Pan-Pan Zhao,[a] Xin-Feng Zhou,[a] Jian-Jun Dai,*[a] Hua-Jian Xu*[a,b] 5
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Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x The protocol of the reductive amination of aromatic aldehydes using ammonium formate and Hantzsch Ester is described. It’s a mild, convenient, acid- and catalyst-free system applied for the synthesis of both symmetric and asymmetric aromatic secondary amines.
40
amination of aldehydes with the use of ammonium formate and HEH. The present study not only shows a new reductive amination system but also provides a convenient procedure for the synthesis of dibenzylamine and its derivatives. Table 1. Optimization of the Reaction Conditionsa
Introduction
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Dibenzylamines motifs are found in many important chemical materials, dyes and drug candidates (Figure 1).1 In this context, many efforts have been dedicated to developing new methods for the synthesis of these compounds.2 Among them, reductive amination reactions have emerged as powerful tool for forming dibenzylamines. Early methods for reductive amination commomly by the use of active borane, Raney-Ni or tin compounds suffer from high hydrogen pressure, poor stability and the environmental problems.3 In order to solve these problems, transition-metal based homogenous and/or heterogeneous Ru, Ir and Pt catalysts system were developed. 4 For example, Gross et al. reported the reductive amination of carbonyl compounds with aqueous ammonia by the use of a homogeneous Rh-catalyst.5 Lai et al. discovered a hydrioiridium (III) complex for the reductive amination of alhehydes in aqueous medium.6 Qi et al. used a Pt nanowire for the preparation of dibenzylamine under 1 bar hydrogen pressure.7
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Entry 1 2 3 4 5 6b 7c 8d 9e 10f 11g 12 13 14 15 16 17 18 19 20 21 22
a (1 equiv) (NH4)2SO4 NH4HCO3 (NH4)2CO3 HCOONH4 / HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4
Solvent MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH dioxane toluene EtOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH
Time (h) 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 4 12 16 20
T (oC) 60 60 60 60 60 60 60 60 60 60 60 60 60 60 r.t. 40 50 70 60 60 60 60
Yield [%] trace trace trace 86 0 0 60 86 69 85 61 13 25 41 47 55 67 78 62 90 97 97
30
Figure 1. Representative chemicals containing dibenzylamine motifs.
Reaction conditions: a Yield was determined by GC using diphenyl as the internal standard. All reactions were performed using benzaldehyde (0.5 mmol), HEH (1 equiv), and the solvent (2 mL). b No HEH was added. c HEH (0.5 equiv). d HEH (2 equiv). e HCOONH4 (0.5 equiv). f HCOONH4 (2 equiv). g HCOONH4 (4 equiv).
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On the other hand, small organic molecules such as Hantzsch Ester (HEH) have also been widely used in the reductive amination.8 Note that HEH is an easy-to-handle and safe reducing reagent in organic transformations. However, the reductive amination by HEH relies on Lewis acid, thiourea and so on as a catalyst.9 Despite these important advances, developing milder and more efficient environmental benign reductive amination remains a distinct challenge. Herein, we report a novel, mild and catalyst-free reductive
We started our study by examining the reductive amination of benzaldehyde 1 to dibenzylamine 2 in the presence of HEH (Table 1). Different inorganic ammonium salts were tested first (Table 1, entries 1-4). When inorganic ammonium salts such as (NH4)2SO4, NH4HCO3 and (NH4)2CO3 were employed only trace amount of the desired product could be obtained (Table 1, entries 1-3). To our delight, the use of HCOONH4 resulted in a significant improvement providing the dibenzylamine 2 in 86% yield (Table 1, entry 4). It is found that no desired product was
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obtained with the absence of HEH or HCOONH4 (Table 1, entries 5 and 6). To improve the yield, different amounts of HEH and ammonium formate were tested. Initially, we investigated the amount of ammonium formate at 60 oC in methanol (Table 1, entries 7-8). Use of more HEH improved the yield very slightly (Table 1, entry 8). By comparison of different amount of ammonium formate, the highest yield 86% was observed with 1.0 equivalent of ammonium formate. Next, we optimized the solvent, temperature, and reaction time. More solvents such as dioxane, toluene, and EtOH were tested (Table 1, entries 12-14), and MeOH was proven to be optimal. Accordingly, the activity of reaction at different temperatures was also investigated. The optimal reaction temperature was 60 oC, because the yield decreased at both lower and higher temperatures (Table 1, entries 15-18). Furthermore, different reaction times were tested. As for the reaction time, the highest 97% yield of dibenzylamine 2 was obtained with the reaction time being prolonged to 16 hours (Table 1, entry 21).
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Table 2. Scope of aromatic aldehydes for reductive aminationa
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DOI: 10.1039/C4OB01590H
suppressed the selectivity of the reaction. We hardly got target product with ortho-substituted benzaldehyde in this system due to the steric congestion. For example, o-chlorobenzaldehyde failed to give any desired product (2u) under the above experimental conditions. In order to expand the scope of the reaction and get asymmetric secondary amine, we carried out further studies on the reaction of two different aromatic aldehydes (Table 3). Orthosubstituted benzaldehyde was added as another substrate. Accordingly, we increased the amount of HEH and HCOONH4 to improve the yield of the reaction. As shown in Table 3, a variety of substituted electron-rich and electron-deficient benzaldehydes could be successfully coupled. As the process became more complex, self-coupling products of 1 were also observed at the yield less than 20%. In addition, two different non-orthosubstituted benzaldehydes were also tried in this system. For example, p-methylbenzaldehyde and p-chloro-benzaldehyde were added as reactants, unfortunately, only 12% yield of asymmetric secondary amine was observed by GC analysis, the two symmetrical secondary amines were the main products. Table 3. Synthesis of asymmetric secondary aminesa
20 a
All reactions were performed using aromatic aldehyde (0.5 mmol), MeOH (2 mL). Isolated yields.
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With this optimal reaction conditions in hand, we next extended the scope of various aromatic aldehydes (Table 2). We found that the reaction was applicable to a wide range of substrates. Moreover, it was not influenced obviously by electron-donating or electron-withdrawing groups. Aromatic secondary amines were obtained in good to excelent yields. 3,4dichlorobenzaldehyde and 3,4-dimethylbenzaldehyde provided the corresponding products in 75% and 65% yield, respectively (Table 2, 2q and 2t). Naphthaldehydes were also tolerated in this process (Table 2, 2o-2p). However, the steric hindrance 2 | Journal Name, [year], [vol], 00–00
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a
All reactions were performed using 1 (0.25 mmol) and 3 (2 equiv), MeOH (2 mL). Isolated yields. b HEH (1 equiv), HCOONH4 (1 equiv).
As shown in Scheme 1, to highlight the utility of our reactions, the reductive amination of benzaldehyde was successfully scaled to 20 mmol, a 82% isolated yield was achieved.
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Scheme 1. Gram-scale synthesis of dibenzylamine.
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On the mechanism, some control experiments were carried out. As revealed in Scheme 2, we proposed there should involve an equilibrium of formic acid 7, ammonia 6 with ammonium formate 5 (Scheme 2, Eq 1). Dibenzylimine 8 was a key reaction intermediate, which had been reported in previous works.7,9b The transformation of dibenzylimine 8 to dibenzylamine 2 was the key in the research. In our experiments, no product was gotten when dibenzylimine 8 reacted with HEH under the reaction conditions (Scheme 2, Eq 2). However, 76% yield of dibenzylamine 2 was observed with adding ammonium formate 5 (Scheme 2, Eq 3). About 20% yield of dibenzylamine was also observed with formic acid 7 being added (Scheme 2, Eq 4). No product was gotten by adding ammonium formate 5 alone (Scheme 2, Eq 5). The results indicated that dibenzylamine was generated under the combined action of ammonium formate and formic acid with HEH.
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DOI: 10.1039/C4OB01590H
As shown in Scheme 4, when 1,4-phthalaldehyde I was used as substrate for reductive amination, to our surprise, light yellow suspended solid can be separated out from the solution within 6 hours.
Scheme 4. Further Research.
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After examination, we found that 1,4-phthalaldehyde I was successfully converted into a nitrogen-containing polymer II.11 The polymer II could be named as polybenzylamine. The structure of the polybenzylamine is similar to the polyaniline. Polyaniline (PAN) is a particularly promising material, which is widely used and studied.12 The polybenzylamine may potentially be applied to polymeric materials such as PAN. Thus, our developed method provides a new channel for the preparation of polymers.
Conclusions
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In summary, a facile procedure for the synthesis of aromatic secondary amines through direct reductive amination of aldehydes and ammonium formate without catalyst has been developed. Both symmetric and asymmetric secondary amines could be obtained. The reaction conditions were mild and applicable to sensitive substrates. Furthermore, no heavy metals were introduced into the system.
Scheme 2. Control experiments. 60
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According to the results of the control experiments and previous reports, we proposed the mechanism of our reaction. The pathway was shown in Scheme 3. First, aromatic aldehyde 1 is converted to aryliminium 9 under the action of ammonium formate and HEH. Subsequently, aryliminium 9 is reduced to aromatic primary amine 10 by HEH providing the hydrogen source.7,8 Then, an imine 8, the key reaction intermediate, is obtained by aromatic primary amine 10 reacting with aromatic aldehyde.7,10 The intermediate 8 is stable in the reaction system, and it had been detected successfully by GC. After that, in the combined affect of ammonium formate and formic acid, the C＝ N moiety of intermediate 8 can be hydrogenated by HEH.10 Finally, the aromatic secondary amine 2 is obtained as the major product.
Experimental General experimental procedure aromatic secondary amines.
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the
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Aromatic aldehyde 1 (0.5 mmol) was blended with HEH (127 mg, 0.5 mmol) and HCOONH 4 (32 mg, 0.5 mmol) into a reaction tube, to which 2 mL MeOH was added. The tube was stirred at 60 oC for 16 hours. Product was separated using forced-flow chromatography on Silica Gel (acetic ether /light petroleum 1:10 or 1:8, and 1% triethylamine). General experimental procedure for the asymmetric aromatic secondary amines. Meta-Substituted or para-substituted benzaldehyde 1 (0.25 mmol) and ortho-substituted benzaldehyde 3 (0.5 mmol) were mixed with HEH (191 mg, 0.75 mmol) and HCOONH 4 (48 mg, 0.75 mmol) into a reaction tube, to which 2 mL MeOH was added. The reaction carried out at 60 oC for at least 16 hours. Product was separated using forced-flow chromatography on Silica Gel (acetic ether /light petroleum 1:8, and 1% triethylamine).
Acknowledgements 35
Scheme 3. Proposed Mechanism of the Reductive Amination of Aromatic Aldehyde.
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We gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 21272050, 21472033)
Finally, polymer was obtained accidently in our further research. This journal is © The Royal Society of Chemistry [year]
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and the Program for New Century Excellent Talents in University of the Chinese Ministry of Education (NCET-11-0627).
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Notes and references a
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School of Medical Engineering, School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, China. Email: [email protected] b Key Laboratory of Advanced Functional Materials and Devices, Anhui Province † Electronic Supplementary Information (ESI) available. See DOI: 10.1039/b000000x/ 1
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10 (a) S. Gomez, J. A. Peters, J. C. Waal and T. Maschmeyer, Appl. Catal., A, 2003, 254, 77; (b) S. Gomez, J. A. Peters, J. C. Waal, P. J. Brink and T. Maschmeyer, Appl. Catal., A, 2004, 261, 119; (c) Q. P. B. Nguyen and T. H. Kim, Tetrahedron, 2013, 69, 4938; (d) B. Li, J. B. Sortais and C. Darcel, Chem. Commun., 2013, 49, 3691. 11 For details, see supporting information. 12 (a) W.-S. Huang, B. D. Humphrey and A. G. MacDiarmid, J. Chem. Soc., 1986, 82, 2385; (b) J.-X. Huang, J. A. Moore, J. H. Acquaye and R. B. Kaner, Macromolecules, 2005, 38, 317; (c) K. Zhang, L.-L. Zhang, X.-S. Zhao and J.-S. Wu, Chem. Mater., 2010, 22, 1392; (d) T. Hibbard, K. Crowley and A. J. Killard, Anal. Chim. Acta, 2013, 779, 56.
(a) J. S. Bradshaw, K. E. Krakowiak and R. M. Izatt, Tetrahedron, 1992, 48, 4475; (b) A. K. Ghose, V. N. Viswanadhan and J. J. Wendoloski, J. Comb. Chem., 1999, 1, 55; (c) T. Henkel, R. M. Brunne, H. Mueller and F. Reichel, Angew. Chem. Int. Ed., 1999, 38, 643; (d) M. Berger, B. Albrecht, A. Berces, P. Ettmayer and W. Neruda, J. Med. Chem., 2001, 44, 3031. (a) H. Greenfield, Ind. Eng. Chem. Prod. Res. Dev., 1976, 15, 156; (b) S. Galvagno, J. Mol. Catal., 1990, 58, 215; (c) C.-T. Yang, Y. Fu, Y.B. Huang, J. Yi, Q.-X. Guo and L. Liu, Angew. Chem. Int. Ed., 2009, 48, 7398; (d) O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden and J. M. Williams, Angew. Chem. Int. Ed., 2009, 48, 7375; (e) O. Y. Lee, K. L. Law and D. Yang, Org. Lett., 2009, 11, 3302; (f) M. Chatterjee, H. Kawanami, M. Sato, T. Ishizaka, T. Yokoyama and T. Suzuki, Green Chem., 2010, 12, 87; (g) M. Isiam, P. Mondal, A. S. Roy and K. Tuhina, J. Mater. Sci., 2010, 45, 2484; (h) J. Deng, L. P. Mo, F. Y. Zhao, L. L. Hou, L. Yang and Z. H. Zhang, Green Chem., 2011, 13, 2576; (i) R. Kawahara, K. I. Fujita and R. Yamaguci, Adv. Synth. Catal., 2011, 353, 1161; (j) X. J. Cui, Y. Zhang, F. Shi and Y. Q. Deng, Chem. Eur. J., 2011, 17, 2587. (a) C. F. Winans, J. Am. Chem. Soc., 1939, 61, 3566; (b) A. R. Surrey and G. Y. Lesher, J. Am. Chem. Soc., 1956, 78, 2573; (c) G. Grethe, H. L. Lee, M. Uskokovic and A. Brossi, J. Org. Chem., 1968, 33, 491; (d) M. D. Bomann, I. C. Guch and M. DiMare, J. Org. Chem., 1995, 60, 5995; (e) R. Apodaca and W. Xiao, Org. Lett., 2001, 3, 1745; (f) H. Kato, I. Shibata, Y. Yasaka, S. Tsunoi, M. Yasuda and A. Baba, Chem. Commun., 2006, 4189; (g) P. D. Pham, P. Bertus and S. Legoupy, Chem. Commun., 2009, 6207. (a) B. Miriyala, S. Bhattacharyya and J. S. Williamson, Tetrahedron, 2004, 60, 1463; (b) D. D. Dhavale, S. M. Jachak, N. P. Karche and C. Trombini, Tetrahedron, 2004, 60, 3009; (c) L. Hu, X.-Q. Cao, D.-H. Ge, H.-Y. Hong, Z.-Q. Guo, L. Chen, X.-H. Sun, J.-X. Tang, J.-W. Zheng, J.-M. Lu and H.-W. Gu, Chem. Eur. J., 2011, 17, 14283; (d) S. Enthaler, Catal. Lett., 2011, 141, 55; (e) F. Nador, Y. Moglie, A. Ciolino, A. Pierini, V. Dorn, M. Yus, F. Alonso and G. Radivoy, Tetrahedron Lett., 2012, 53, 3156. T. Gross, A. M. Seayad, M. Ahmad and M. Beller, Org. Lett., 2002, 4, 2055. R.-Y. Lai, C. I. Lee and S.-T. Liu, Tetrahedron, 2008, 64, 1213. F.-Q. Qi, L. Hu, S.-L. Lu, X.-Q. Cao and H.-W. Gu, Chem. Commun., 2012, 48, 9631. (a) R. I. Storer, D. E. Carrera, Y. Ni and D. W. C. MacMillan, J. Am. Chem. Soc., 2006, 128, 84; (b) D. Menche, F. Arikan, J. Li, S. Rudolph and F. Sasse, Bioorg. Med. Chem., 2007, 15, 7311; (c) S.-L. You, Chem. Asian J., 2007, 2, 820; (d) C. V. Voss, C. C. Gruber, K. Faber, T. Knaus, P. Macheroux and W. Kroutil, J. Am. Chem. Soc., 2008, 130, 13969; (e) G. Barbe and A. B. Charette, J. Am. Chem. Soc., 2008, 130, 18; (f) M. Zhang, H.-W. Yang, Y. Zhang, C.-J. Zhu, W. Li, Y.-X. Cheng and H.-W. Hu, Chem. Commun., 2011, 47, 6605; (g) C.-T. Cao, Y. Tan and X.-Q. Zhu, Sci. China Chem., 2012, 55, 2054; (h) W.-M. Du and Z.-K. Yu, Synlett, 2012, 23, 1300; (e) I. A. Khan and A. K. Saxena, J. Org. Chem., 2013, 78, 11656. (a) T. Itoh, K. Nagata, A. Kurihara, M. Miyazaki and A. Ohsawa, Tetrahedron Lett., 2002, 43, 3105; (b) D. Menche, J. Hassfeld, J. Li, G. Menche, A. Ritter and S. Rudolph, Org. Lett., 2006, 8, 741; (c) D. Menche, S. Böhm, J. Li, S. Rudolph and W. Zander, Tetrahedron Lett., 2007, 48, 365; (d) Q. P. B. Nguyen and T. H. Kim, Tetrahedron Lett., 2011, 52, 5004; (e) X.-W. Huang and J.-L. Liu, Chin. J. Org. Chem., 2013, 33, 1960.
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This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains.
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Catalyst-Free Reductive Amination of Aromatic Aldehydes with Ammonium Formate and Hantzsch Ester Pan-Pan Zhao,[a] Xin-Feng Zhou,[a] Jian-Jun Dai,*[a] Hua-Jian Xu*[a,b] 5
10
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX DOI: 10.1039/b000000x The protocol of the reductive amination of aromatic aldehydes using ammonium formate and Hantzsch Ester is described. It’s a mild, convenient, acid- and catalyst-free system applied for the synthesis of both symmetric and asymmetric aromatic secondary amines.
40
amination of aldehydes with the use of ammonium formate and HEH. The present study not only shows a new reductive amination system but also provides a convenient procedure for the synthesis of dibenzylamine and its derivatives. Table 1. Optimization of the Reaction Conditionsa
Introduction
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Dibenzylamines motifs are found in many important chemical materials, dyes and drug candidates (Figure 1).1 In this context, many efforts have been dedicated to developing new methods for the synthesis of these compounds.2 Among them, reductive amination reactions have emerged as powerful tool for forming dibenzylamines. Early methods for reductive amination commomly by the use of active borane, Raney-Ni or tin compounds suffer from high hydrogen pressure, poor stability and the environmental problems.3 In order to solve these problems, transition-metal based homogenous and/or heterogeneous Ru, Ir and Pt catalysts system were developed. 4 For example, Gross et al. reported the reductive amination of carbonyl compounds with aqueous ammonia by the use of a homogeneous Rh-catalyst.5 Lai et al. discovered a hydrioiridium (III) complex for the reductive amination of alhehydes in aqueous medium.6 Qi et al. used a Pt nanowire for the preparation of dibenzylamine under 1 bar hydrogen pressure.7
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Entry 1 2 3 4 5 6b 7c 8d 9e 10f 11g 12 13 14 15 16 17 18 19 20 21 22
a (1 equiv) (NH4)2SO4 NH4HCO3 (NH4)2CO3 HCOONH4 / HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4 HCOONH4
Solvent MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH dioxane toluene EtOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH MeOH
Time (h) 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 8 4 12 16 20
T (oC) 60 60 60 60 60 60 60 60 60 60 60 60 60 60 r.t. 40 50 70 60 60 60 60
Yield [%] trace trace trace 86 0 0 60 86 69 85 61 13 25 41 47 55 67 78 62 90 97 97
30
Figure 1. Representative chemicals containing dibenzylamine motifs.
Reaction conditions: a Yield was determined by GC using diphenyl as the internal standard. All reactions were performed using benzaldehyde (0.5 mmol), HEH (1 equiv), and the solvent (2 mL). b No HEH was added. c HEH (0.5 equiv). d HEH (2 equiv). e HCOONH4 (0.5 equiv). f HCOONH4 (2 equiv). g HCOONH4 (4 equiv).
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On the other hand, small organic molecules such as Hantzsch Ester (HEH) have also been widely used in the reductive amination.8 Note that HEH is an easy-to-handle and safe reducing reagent in organic transformations. However, the reductive amination by HEH relies on Lewis acid, thiourea and so on as a catalyst.9 Despite these important advances, developing milder and more efficient environmental benign reductive amination remains a distinct challenge. Herein, we report a novel, mild and catalyst-free reductive
We started our study by examining the reductive amination of benzaldehyde 1 to dibenzylamine 2 in the presence of HEH (Table 1). Different inorganic ammonium salts were tested first (Table 1, entries 1-4). When inorganic ammonium salts such as (NH4)2SO4, NH4HCO3 and (NH4)2CO3 were employed only trace amount of the desired product could be obtained (Table 1, entries 1-3). To our delight, the use of HCOONH4 resulted in a significant improvement providing the dibenzylamine 2 in 86% yield (Table 1, entry 4). It is found that no desired product was
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obtained with the absence of HEH or HCOONH4 (Table 1, entries 5 and 6). To improve the yield, different amounts of HEH and ammonium formate were tested. Initially, we investigated the amount of ammonium formate at 60 oC in methanol (Table 1, entries 7-8). Use of more HEH improved the yield very slightly (Table 1, entry 8). By comparison of different amount of ammonium formate, the highest yield 86% was observed with 1.0 equivalent of ammonium formate. Next, we optimized the solvent, temperature, and reaction time. More solvents such as dioxane, toluene, and EtOH were tested (Table 1, entries 12-14), and MeOH was proven to be optimal. Accordingly, the activity of reaction at different temperatures was also investigated. The optimal reaction temperature was 60 oC, because the yield decreased at both lower and higher temperatures (Table 1, entries 15-18). Furthermore, different reaction times were tested. As for the reaction time, the highest 97% yield of dibenzylamine 2 was obtained with the reaction time being prolonged to 16 hours (Table 1, entry 21).
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Table 2. Scope of aromatic aldehydes for reductive aminationa
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DOI: 10.1039/C4OB01590H
suppressed the selectivity of the reaction. We hardly got target product with ortho-substituted benzaldehyde in this system due to the steric congestion. For example, o-chlorobenzaldehyde failed to give any desired product (2u) under the above experimental conditions. In order to expand the scope of the reaction and get asymmetric secondary amine, we carried out further studies on the reaction of two different aromatic aldehydes (Table 3). Orthosubstituted benzaldehyde was added as another substrate. Accordingly, we increased the amount of HEH and HCOONH4 to improve the yield of the reaction. As shown in Table 3, a variety of substituted electron-rich and electron-deficient benzaldehydes could be successfully coupled. As the process became more complex, self-coupling products of 1 were also observed at the yield less than 20%. In addition, two different non-orthosubstituted benzaldehydes were also tried in this system. For example, p-methylbenzaldehyde and p-chloro-benzaldehyde were added as reactants, unfortunately, only 12% yield of asymmetric secondary amine was observed by GC analysis, the two symmetrical secondary amines were the main products. Table 3. Synthesis of asymmetric secondary aminesa
20 a
All reactions were performed using aromatic aldehyde (0.5 mmol), MeOH (2 mL). Isolated yields.
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With this optimal reaction conditions in hand, we next extended the scope of various aromatic aldehydes (Table 2). We found that the reaction was applicable to a wide range of substrates. Moreover, it was not influenced obviously by electron-donating or electron-withdrawing groups. Aromatic secondary amines were obtained in good to excelent yields. 3,4dichlorobenzaldehyde and 3,4-dimethylbenzaldehyde provided the corresponding products in 75% and 65% yield, respectively (Table 2, 2q and 2t). Naphthaldehydes were also tolerated in this process (Table 2, 2o-2p). However, the steric hindrance 2 | Journal Name, [year], [vol], 00–00
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a
All reactions were performed using 1 (0.25 mmol) and 3 (2 equiv), MeOH (2 mL). Isolated yields. b HEH (1 equiv), HCOONH4 (1 equiv).
As shown in Scheme 1, to highlight the utility of our reactions, the reductive amination of benzaldehyde was successfully scaled to 20 mmol, a 82% isolated yield was achieved.
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Scheme 1. Gram-scale synthesis of dibenzylamine.
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On the mechanism, some control experiments were carried out. As revealed in Scheme 2, we proposed there should involve an equilibrium of formic acid 7, ammonia 6 with ammonium formate 5 (Scheme 2, Eq 1). Dibenzylimine 8 was a key reaction intermediate, which had been reported in previous works.7,9b The transformation of dibenzylimine 8 to dibenzylamine 2 was the key in the research. In our experiments, no product was gotten when dibenzylimine 8 reacted with HEH under the reaction conditions (Scheme 2, Eq 2). However, 76% yield of dibenzylamine 2 was observed with adding ammonium formate 5 (Scheme 2, Eq 3). About 20% yield of dibenzylamine was also observed with formic acid 7 being added (Scheme 2, Eq 4). No product was gotten by adding ammonium formate 5 alone (Scheme 2, Eq 5). The results indicated that dibenzylamine was generated under the combined action of ammonium formate and formic acid with HEH.
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DOI: 10.1039/C4OB01590H
As shown in Scheme 4, when 1,4-phthalaldehyde I was used as substrate for reductive amination, to our surprise, light yellow suspended solid can be separated out from the solution within 6 hours.
Scheme 4. Further Research.
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After examination, we found that 1,4-phthalaldehyde I was successfully converted into a nitrogen-containing polymer II.11 The polymer II could be named as polybenzylamine. The structure of the polybenzylamine is similar to the polyaniline. Polyaniline (PAN) is a particularly promising material, which is widely used and studied.12 The polybenzylamine may potentially be applied to polymeric materials such as PAN. Thus, our developed method provides a new channel for the preparation of polymers.
Conclusions
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In summary, a facile procedure for the synthesis of aromatic secondary amines through direct reductive amination of aldehydes and ammonium formate without catalyst has been developed. Both symmetric and asymmetric secondary amines could be obtained. The reaction conditions were mild and applicable to sensitive substrates. Furthermore, no heavy metals were introduced into the system.
Scheme 2. Control experiments. 60
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According to the results of the control experiments and previous reports, we proposed the mechanism of our reaction. The pathway was shown in Scheme 3. First, aromatic aldehyde 1 is converted to aryliminium 9 under the action of ammonium formate and HEH. Subsequently, aryliminium 9 is reduced to aromatic primary amine 10 by HEH providing the hydrogen source.7,8 Then, an imine 8, the key reaction intermediate, is obtained by aromatic primary amine 10 reacting with aromatic aldehyde.7,10 The intermediate 8 is stable in the reaction system, and it had been detected successfully by GC. After that, in the combined affect of ammonium formate and formic acid, the C＝ N moiety of intermediate 8 can be hydrogenated by HEH.10 Finally, the aromatic secondary amine 2 is obtained as the major product.
Experimental General experimental procedure aromatic secondary amines.
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Aromatic aldehyde 1 (0.5 mmol) was blended with HEH (127 mg, 0.5 mmol) and HCOONH 4 (32 mg, 0.5 mmol) into a reaction tube, to which 2 mL MeOH was added. The tube was stirred at 60 oC for 16 hours. Product was separated using forced-flow chromatography on Silica Gel (acetic ether /light petroleum 1:10 or 1:8, and 1% triethylamine). General experimental procedure for the asymmetric aromatic secondary amines. Meta-Substituted or para-substituted benzaldehyde 1 (0.25 mmol) and ortho-substituted benzaldehyde 3 (0.5 mmol) were mixed with HEH (191 mg, 0.75 mmol) and HCOONH 4 (48 mg, 0.75 mmol) into a reaction tube, to which 2 mL MeOH was added. The reaction carried out at 60 oC for at least 16 hours. Product was separated using forced-flow chromatography on Silica Gel (acetic ether /light petroleum 1:8, and 1% triethylamine).
Acknowledgements 35
Scheme 3. Proposed Mechanism of the Reductive Amination of Aromatic Aldehyde.
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We gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 21272050, 21472033)
Finally, polymer was obtained accidently in our further research. This journal is © The Royal Society of Chemistry [year]
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and the Program for New Century Excellent Talents in University of the Chinese Ministry of Education (NCET-11-0627).
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Notes and references a
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School of Medical Engineering, School of Chemistry and Chemical Engineering, Hefei University of Technology, Hefei 230009, China. Email: [email protected] b Key Laboratory of Advanced Functional Materials and Devices, Anhui Province † Electronic Supplementary Information (ESI) available. See DOI: 10.1039/b000000x/ 1
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