Ruthenium-catalysed N-alkylation of anilines with primary carbohydrate alcohols via borrowing hydrogen strategy

Abstract

Ruthenium-catalysed N-alkylation of anilines with sugar derivatives proceeded via the borrowing hydrogen strategy. Primary carbohydrate alcohols were successfully applied to N-alkylation of aniline derivatives to give the corresponding aminosugars in high yields.

---

Transition-metal-catalysed N-alkylation of amines via the borrowing hydrogen strategy is a desirable process for the formation of carbon–nitrogen bonds, enabling alcohols to be employed directly as alkylating agents (Scheme 1a).¹ A variety of catalytic systems based on the late-transition metals have been developed for the N-alkylation of amines by using simple alcohols.^2–5 Biomass-derived alcohols, such as ethylene glycol, 1,3-propanediol, isohexides, and so on, have also been recognized as important reaction partners in the borrowing hydrogen strategy.⁶ However, carbohydrate alcohols have been scarcely used for the direct N-alkylation reaction. In this respect, in 2011, Cumpstey and Martín-Matute reported the first example of N-alkylation of alkylamines derived from sugars with primary carbohydrate alcohols catalysed by an Ir(III) complex, where amine-linked pseudodisaccharides are successfully synthesized in a single step through borrowing hydrogen strategy (Scheme 1b).⁷ In this context, we recently reported α-alkylation of methyl ketones with primary carbohydrate alcohols as alkylating agents (Scheme 1c).⁸ The reaction is efficiently catalysed by an Ir(III) complex in the presence of a strong base. During our studies on the catalytic functionalization of sugar derivatives,^8,9 it was found that a ruthenium complex was effective in catalyzing the borrowing hydrogen reaction between anilines and sugars (Scheme 1d). Here we describe that a ruthenium/dppf type ligand complex efficiently catalyses N-alkylation of anilines with primary carbohydrate alcohols, providing a new method for the synthesis of aminosugar derivatives.¹⁰ Aminosugars possess potential properties that take part in a variety of biological functions, and therefore, the development of the synthesis of the aminosugars is important for the understanding of their functions.¹¹

Scheme 1 Borrowing hydrogen reactions.

Our initial studies focused on the N-alkylation of aniline (1a) with 1,2 : 3,4-di-O-isopropylidene-α-D-galactopyranose (2a) in the presence of ruthenium complexes directed toward the catalytic synthesis of aminosugar 3aa (Table 1).¹² Treatment of 1a (1.2 equiv.) with 2a (1.0 equiv.) in the presence of [RuCl₂(p-cymene)]₂ (5 mol% of Ru), dppf (6 mol%), and K₂CO₃ (10 mol%) in toluene, which is one of the reaction conditions reported by Williams and co-workers,^2c at 110 °C for 21 h gave alkylated product 3aa in 31% yield (entry 1). The ligand and base were necessary to obtain 3aa (entries 2 and 3). The aryl groups on dppf ligands significantly influenced the reactivity. The use of ligand L1 substituted with p-(trifluoromethyl)phenyl groups improved the yield of 3aa up to 69% (entry 4). In contrast, methoxy-substituted L2 diminished the yield (entry 5), and ligand L3 inhibited the reaction, probably due to the bulkiness (entry 6). DPEphos, Xantphos, or Binap were not effective in catalyzing the present reaction (entries 7–9). The use of a slight excess (1.2 equiv.) of alcohol 2a toward aniline (1a) improved the yield up to 76% (entry 10). Na₂CO₃ and Cs₂CO₃ were less effective than K₂CO₃, thus giving 3aa in 45 and 53% yields, respectively (entries 11 and 12). The reaction in p-xylene at 140 °C gave 3aa in 87% yield (entry 13). The catalytic activity of [RuCl₂(benzene)]₂ was quite low (entry 14). Ru₃(CO)₁₂^2d and Ru-MACHO®^2j did not work as catalysts (entries 15–17).

Table 1 Ruthenium-catalysed N-alkylation of aniline 1a with galactopyranose 2a^a

Entry	Catalyst	Ligand	Yield^b (%)
a Reaction conditions: 1a (0.24 mmol), 2a (0.20 mmol), [RuCl2(p-cymene)]2 (0.0050 mmol, 5 mol% of Ru), and base (10 mol%) in toluene (0.30 mL) at 110 °C for 21 h. b Determined by ^1H NMR. c Without K2CO3. d Performed with 1a (0.20 mmol) and 2a (0.24 mmol). e With Na2CO3 instead of K2CO3. f With Cs2CO3 instead of K2CO3. g At 140 °C in p-xylene. h Isolated yield.
1	[RuCl2(p-cymene)]2	dppf	31
2	[RuCl2(p-cymene)]2	—	0
3^c	[RuCl2(p-cymene)]2	dppf	0
4	[RuCl2(p-cymene)]2	L1	69
5	[RuCl2(p-cymene)]2	L2	6
6	[RuCl2(p-cymene)]2	L3	0
7	[RuCl2(p-cymene)]2	DPEphos	15
8	[RuCl2(p-cymene)]2	Xantphos	6
9	[RuCl2(p-cymene)]2	Binap	0
10^d	[RuCl2(p-cymene)]2	L1	76
11^d^e	[RuCl2(p-cymene)]2	L1	45
12^d^f	[RuCl2(p-cymene)]2	L1	53
13^d^g	[RuCl2(p-cymene)]2	L1	87 (82)^h
14	[RuCl2(benzene)]2	L1	7
15^c^d	Ru3(CO)12	—	0
16^d	Ru3(CO)12	—	0
17^d	Ru-MACHO®	—	0

---

Scheme 2 summarizes the results obtained for the reaction of several primary carbohydrate alcohols. The reactions of O-methylated α-glucose 2b, β-glucose 2c, and β-galactose 2d with aniline (1a) gave the corresponding sugars 3ab–3ad in 42–53% yields. Alcohol 2e having benzyl ether moieties and 2f with a free hydroxy group reacted with 1a to give N-alkylated products 3ae and 3af in 25% and 35% yields, respectively. The reaction of C-glycoside 2g and deoxyglucose 2h also proceeded to give the corresponding aminosugars 3ag and 3ah.

Scheme 2 Scope of carbohydrate alcohols. Reaction conditions: 1a (0.10 mmol), 2 (0.12 mmol), [RuCl₂(p-cymene)]₂ (0.0025 mmol, 5 mol% of Ru), L1 (6 mol%) and K₂CO₃ (10 mol%) in p-xylene (0.15 mL) at 140 °C for 21 h.

A variety of aniline derivatives 1 participated in the reaction with carbohydrate alcohol 2a as summarized in Scheme 3. N-Alkylation of anilines having electron-donating and -withdrawing substituents (2a–2m) at the o-, m-, and p-positions proceeded to give the corresponding aminosugars in 18–97% yields, where anilines substituted with electron-withdrawing groups displayed the low reactivity. In particular, the loss of the catalytic activity was observed in reaction of p-bromoaniline (1f). Dimethyl (1n) and dimethoxyanilines (1o and 1p) reacted with 2a to give aminosugars 3na, 3oa, and 3pa, respectively, in high yields. Modest yields were observed for 3,4,5-trifluoroaniline (1q), 5-methoxy-1-naphthylamine (1r), and 6-methyl-2-aminopyridine (1s). In sharp contrast, N-methylaniline or aliphatic amines such as n-butylamine and piperidine were not alkylated under the present reaction conditions.

Scheme 3 Scope of anilines 1. Reaction conditions: 1 (0.10 mmol), 2a (0.12 mmol), [RuCl₂(p-cymene)]₂ (0.0025 mmol, 5 mol% of Ru), ligand (6 mol%), and K₂CO₃ (10 mol%) in p-xylene (0.15 mL) at 140 °C for 21 h. ^a0.20 mmol scale reaction. ^bFor 48 h.

In summary, we have developed ruthenium-catalysed N-alkylation of anilines with primary carbohydrate alcohols. A variety of aniline derivatives were applied to the reaction to give the corresponding aminosugars in high yields. Several O-protected sugar derivatives could be used as alkylating agents for N-alkylation of aniline derivatives.

Conflicts of interest

There are no conflicts to declare.

Notes and references

1. For selected recent reviews, see: (a) E. Podyacheva, O. I. Afanasyev, D. V. Vasilyev and D. Chusov, ACS Catal., 2022, 12, 7142; (b) B. G. Reed-Berendt, D. E. Latham, M. B. Dambatta and L. C. Morrill, ACS Cent. Sci., 2021, 7, 570; (c) T. Irrgang and R. Kempe, Chem. Rev., 2019, 119, 2524; (d) B. G. Reed-Berendt, K. Polidano and L. C. Morrill, Org. Biomol. Chem., 2019, 17, 1595; (e) A. Corma, J. Navas and M. J. Sabater, Chem. Rev., 2018, 118, 1410; (f) Q. Yang, Q. Wang and Z. Yu, Chem. Soc. Rev., 2015, 44, 2305; (g) S. Bähn, S. Imm, L. Neubert, M. Zhang, H. Neumann and M. Beller, ChemCatChem, 2011, 3, 1853; (h) G. Guillena, D. J. Ramón and M. Yus, Chem. Rev., 2010, 110, 1611; (i) M. H. S. A. Hamid, P. A. Slatford and J. M. J. Williams, Adv. Synth. Catal., 2007, 349, 1555.
2. For selected examples using Ru catalysts, see: (a) Y. Watanabe, Y. Tsuji and Y. Ohsugi, Tetrahedron Lett., 1981, 22, 2667; (b) M. H. S. A. Hamid and J. M. J. Williams, Chem. Commun., 2007, 725; (c) M. H. S. A. Hamid, C. L. Allen, G. W. Lamb, A. C. Maxwell, H. C. Maytum, A. J. A. Watson and J. M. J. Williams, J. Am. Chem. Soc., 2009, 131, 1766; (d) D. Hollmann, A. Tillack, D. Michalik, R. Jackstell and M. Beller, Chem. – Asian J., 2007, 2, 403; (e) R. N. Monrad and R. Madsen, Org. Biomol. Chem., 2011, 9, 610; (f) A. B. Enyong and B. Moasser, J. Org. Chem., 2014, 79, 7553; (g) S. P. Shan, X. Xiaoke, B. Gnanaprakasam, T. T. Dang, B. Ramalingam, H. V. Huynh and A. M. Seayad, RSC Adv., 2015, 5, 4434; (h) M. Kaloğlu, Inorg. Chim. Acta, 2019, 498, 119163; (i) A. E. Putra, Y. Oe and T. Ohta, Eur. J. Org. Chem., 2013, 6146; (j) O. Ogata, H. Nara, M. Fujiwhara, K. Matsumura and Y. Kayaki, Org. Lett., 2018, 20, 3866; (k) M. Maji, K. Chakrabarti, B. Paul, B. C. Roy and S. Kundu, Adv. Synth. Catal., 2018, 360, 722; (l) X.-J. Yu, H.-Y. He, L. Yang, H.-Y. Fu, X.-L. Zheng, H. Chen and R.-X. Li, Catal. Commun., 2017, 95, 54; (m) S. Agrawal, M. Lenormand and B. Martín-Matute, Org. Lett., 2012, 14, 1456; (n) S. Demir, F. Coskun and I. Özdemir, J. Organomet. Chem., 2014, 755, 134; (o) Ö. Ulu, N. Gürbüz and I. Özdemir, Tetrahedron, 2018, 74, 645; (p) S. N. R. Donthireddy, P. M. Illam and A. Rit, Inorg. Chem., 2020, 59, 1835; (q) R. Savela, D. Vogt and R. Leino, Eur. J. Org. Chem., 2020, 3030; (r) F.-L. Yang, Y.-H. Wang, Y.-F. Ni, X. Gao, B. Song, X. Zhu and X.-Q. Hao, Eur. J. Org. Chem., 2017, 3481; (s) V. R. Jumde, L. Gonsalvi, A. Guerriero, M. Peruzzini and M. Taddei, Eur. J. Org. Chem., 2015, 1829; (t) K. O. Marichev and J. M. Takacs, ACS Catal., 2016, 6, 2205; (u) R. Ramachandran, G. Prakash, M. Nirmala, P. Viswanathamurthi and J. G. Malecki, J. Organomet. Chem., 2015, 791, 130; (v) S. Gayathri, P. Viswanathamurthi, R. Bertani and P. Sgarbossa, ACS Omega, 2022, 7, 33107; (w) F. V. Rossi, J. T. Starr, D. P. Uccello and J. A. Young, Org. Lett., 2020, 22, 5890.
3. For pioneering examples using Rh catalysts, see: (a) R. Grigg, T. R. B. Mitchell, S. Sutthivaiyakit and N. Tongpeny, J. Chem. Soc., Chem. Commun., 1981, 611; (b) N. Tanaka, M. Hatanaka and Y. Watanabe, Chem. Lett., 1992, 575; (c) C. Liu, S. Liao, Q. Li, S. Feng, Q. Sun, X. Yu and Q. Xu, J. Org. Chem., 2011, 76, 5759.
4. For pioneering examples using Ir catalysts, see: (a) K. Fujita, Z. Li, N. Ozeki and R. Yamaguchi, Tetrahedron Lett., 2003, 44, 2687; (b) K. Fujita, Y. Enoki and R. Yamaguchi, Tetrahedron, 2008, 64, 1943; (c) R. Kawahara, K. Fujita and R. Yamaguchi, J. Am. Chem. Soc., 2010, 132, 15108; (d) G. Cami-Kobeci, P. A. Slatford, M. K. Whittlesey and J. M. J. Williams, Bioorg. Med. Chem. Lett., 2005, 15, 535; (e) O. Saidi, A. J. Blacker, M. M. Farah, S. P. Marsden and J. M. J. Williams, Chem. Commun., 2010, 46, 1541; (f) B. Blank, M. Madalska and R. Kempe, Adv. Synth. Catal., 2008, 350, 749.
5. For selected examples of catalytic N-alkylation by use of transition-metal catalysts other than Ru, Rh, and Ir, see: (a) R. Martínez, D. J. Ramón and M. Yus, Org. Biomol. Chem., 2009, 7, 2176; (b) A. Martínez-Asencio, D. J. Ramón and M. Yus, Tetrahedron Lett., 2010, 51, 325; (c) M. Peña-López, P. Piehl, S. Elangovan, H. Neumann and M. Beller, Angew. Chem., Int. Ed., 2016, 55, 14967; (d) S. Rösler, M. Ertl, T. Irrgang and R. Kempe, Angew. Chem., Int. Ed., 2015, 54, 15046; (e) M. Vellakkaran, K. Singh and D. Banerjee, ACS Catal., 2017, 7, 8152.
6. (a) N. K. Gupta, P. Reif, P. Palenicek and M. Rose, ACS Catal., 2022, 12, 10400; (b) S. Hameury, H. Bensalem and K. de Oliveira Vigier, Catalysts, 2022, 12, 1306.
7. I. Cumpstey, S. Agrawal, K. E. Borbas and B. Martín-Matute, Chem. Commun., 2011, 47, 7827.
8. K. Tsuge, S. Kubota, K. Sakamoto, K. Kitayama and T. Nishimura, Adv. Synth. Catal., 2023, 365, 971.
9. K. Sakamoto, M. Nagai, Y. Ebe, H. Yorimitsu and T. Nishimura, ACS Catal., 2019, 9, 1347.
10. For a review of the synthesis of aminosugar derivatives, see: R. Sangwan, A. Khanam and P. K. Mandal, Eur. J. Org. Chem., 2020, 5949.
11. L. Cipolla and F. Peri, Mini-Rev. Med. Chem., 2011, 11, 39.
12. For an example of the synthesis of 3aa by N-arylation of 6-amino-6-deoxy-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose, see: K. B. Pal, M. Mahanti and U. J. Nilsson, Org. Lett., 2018, 20, 616.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3cc01931d

---