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Keywords:

  • alcohols;
  • amination;
  • homogeneous catalysis;
  • iridium;
  • pincer complexes

Catalytic transformation of alcohols to amines is a fundamental transformation in synthetic organic chemistry.1 Since a variety of amines play an important role as precursors and final products employed in pharmaceuticals such as anticancer agents and DNA alkylators, agrochemicals, flavors and fragrances, cosmetics and toiletries, polymers, dyes, and other fine chemicals, the development of versatile and efficient amination methods is still an area of vital research.2

In recent years, a number of transition metal-catalyzed reactions for the synthesis of aliphatic and aromatic amines, such as hydroamination of alkenes or alkynes3, 4 and aryl halides,5 has been developed. Moreover, N-alkylation with alkyl halides is a well-known procedure,6 but the use of alkyl halides is undesirable from an environmental point of view, since it generates wasteful salts as byproducts. Another useful approach in the synthesis of amines is the reductive amination of aldehydes and ketones.7 However, this method requires the use of strong reducing reagents or dangerous hydrogen gas and is not always selective for monoalkylation of primary amines.8

Catalytic amination of alcohols is an alternative method for the preparation of amines (Scheme 1) and it is attractive from several points of view. Firstly, it does not generate any harmful and/or wasteful byproducts, as the only byproduct is H2O. Secondly, alcohols are more readily available than the corresponding halides or carbonyl compounds, and if the reaction proceeds with equimolar amounts of starting compounds, extremely high efficiency can be realized.9

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Scheme 1. Catalytic amination of alcohols.

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Although several catalytic systems for the amination of alcohols have been studied using ruthenium10 and other transition metal complexes,11 as well as some heterogeneous catalysts,12 most of them require high reaction temperatures (>150 °C) and/or an excess of alcohols to obtain high yields of the product.

Quite recently, Beller et al. suggested a ruthenium-catalyzed system with primary and secondary amines under mild conditions.13 However, in most cases an excess of alcohol (up to 5 equivalents)13c or high catalyst loading13d (2 mol % of Ru precursor and 6 mol % of phosphine ligands) were required and, for some aliphatic amines, transalkylation took place.13c

The Ru-catalyzed amination of ethylene glycol and, to a lesser extent, 1,2-propanediol by secondary and primary amines was studied by Marsella.14 In particular, this worked established that the reaction of ethylene glycol with amines in the presence of [(Ph3P)3RuCl2] at 120 °C is highly dependent on the steric nature of the amine. Selective diamination was favored by small N-alkyl groups, whereas bulky amines preferably yielded ethanolamines. Application of a catalyst generated in situ from IrCl3n H2O/3 PPh3 for the amination of ethylene glycol under the same conditions proceeded only with moderate conversions but rather good selectivity toward the formation of the bis-aminated product.14a

Herein, we report on the selective monoamination of diols with secondary amines in the presence of the chlorodihydride complex [IrH2Cl{(iPr2PC2H4)2NH}] (2). Complex 2 was originally developed by Abdur-Rashid and co-workers for the transfer hydrogenation of ketones.16 The complex is air-stable and can be prepared by the reaction of [{IrCl(coe)2}2] (coe=cyclooctene) with the pincer ligand (iPr2PC2H4)2NH (1) in 2-propanol at 80 °C (Scheme 2).16, 17

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Scheme 2. Synthesis of iridium chlorodihydride complex 2.

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In a first screening, simple monoalcohols were treated as substrates to give corresponding amines. Firstly, methanol, as the simplest alcohol, was treated with amines in the presence of complex 2 (Table 1). The reactions were performed at 120 °C with 1 mol % of the catalyst. After 24 h, the reaction was stopped and the products were analyzed by GC.

Table 1. Amination of methanol in the presence of Ir catalyst 2.[a]
EntryAmineProductYield [%][b]
  1. [a] Reaction conditions: MeOH (1 mmol), Ir complex 2 (1 mol %), molar ratio of alcohol/amine=1:3, T=120 °C, t=24 h; [b] GC yield was determined with N-methylpyrrolidone as an internal standard; [c] ratio of tertiary amine/secondary amine=>99:<1; [d] ratio of N,N-dimethyl-1-phenylmethylamine to N-methyl-1-phenylmethylamine=87:13.

1
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>99
2
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80
3
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>99[c]
4
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95[d]
5
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>99[c]

Piperidine and morpholine reacted with an excess of methanol to give methylated amines with yields of greater than 99 % and 80 %, respectively (Table 1, entries 1 and 2). Application of tert-butylamine under the same conditions afforded greater than 99 % yield of N,N-dimethyl-tert-butylamine (Table 1, entry 3). Benzylamine and (S)-1-phenylethanamine were also successfully applied (Table 1, entries 4 and 5). The amination with benzylamine led to the formation of both N-methyl- and N,N-dimethylamine in a 13:87 ratio (Table 1, entry 4). Reaction of (S)-1-phenylethylamine gave selectively (S)-N,N-dimethyl-1-phenylethylamine without racemization (Table 1, entry 5).18

Results of the amination of other aliphatic alcohols with diethylamine and piperidine are listed in Table 2. In general, moderate to good yields were obtained. Functionalized alcohols could also be converted. Olefinic groups in the substrate were not affected (Table 2, entries 4 and 9). The highest yield at 120 °C was that with β-hydroxypropanenitrile as substrate (74 %; Table 2, entry 8). Increasing the temperature to 140 °C led to improved yields (Table 2, entries 9–11), as did the addition of bases (Table 2, entries 3, 4, 6–8).19

Table 2. Application of Ir catalyst 2 for the amination of aliphatic alcohols.[a]
EntryAlcoholProductYield [%][b]
  1. [a] Conditions unless otherwise stated: alcohol (1 mmol), Ir complex 2 (1 mol %), molar ratio of alcohol/amine=1:3, T=120 °C, t=24 h; [b] GC yield was determined with N-methylpyrrolidone as an internal standard; [c] NaOtBu was used as an additive (molar ratio of 2 to NaOtBu=1:1.1); [d] NaHCO3 was used as an additive (molar ratio of 2 to NaHCO3=1:1.1); [e] up to 5 % of N,N-diethyl-3-hydroxypropanamide and 3-(diethylamino)-N,N-diethylpropanamide were formed as byproducts; [f] T=140 °C, t=24 h, catalyst loading=1 mol %; [g] molar ratio of alcohol/amine=1:12.

1
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35 40[c]
2
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35[f]
3
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39 40[c]
4
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60 79[c]
5
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6
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54 55[c]
7
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66 71[c]
8
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74[e] 82[d,e] 98[c,e]
9
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21 40[f]
10
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27 98[f,g]
11
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15 60[f]

We subsequently tested Ir catalyst 2 for the amination of diols (Scheme 3). Pleasingly, 2 converted ethylene glycol with diethylamine into N-diethylaminoethanol with excellent catalytic activity (conversions of greater than 99 %) and selectivity towards the formation of the targeted amino alcohol of type 3 (Scheme 3; R=-CH2-, R1, R2=Et; Table 3, entries 1–7).

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Scheme 3. Ir-catalyzed amination of aliphatic diols.

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Table 3. Ir catalyzed amination of ethylene glycol with diethylamine.[a]
EntryCatalystLoading [mol %]Time [h]Yield [%][e]Selectivity 3/4
  1. [a] Conditions: ethylene glycol (1 mmol), molar ratio of ethylene glycol/diethylamine=1:3, without solvents; [b] T=120 °C; [c] T=140 °C; [d] T=100 °C; [e] GC-yield was determined with N-methylpyrrolidone as an internal standard; [f]  up to 5 % unidentified byproducts were formed.

121.020[b]99>99/<1
221.06[b]97>99/<1
321.02[c]96>99/<1
420.320[b]84>99/<1
520.36[b]83>99/<1
620.36[d]69>99/<1
720.32[c]86>99/<1
8[{Ir(cod)Cl}2]0.320[b]3350/50
9[{Ir(cod)Cl}2]/3 PPh31.020[d]8921/79
10[{Ir(cod)Cl}2]/2 dppe1.020[d]94[f]19/81
11IrCl3n H2O1.06[b]87/93
12IrCl3n H2O/3 PPh31.020[b]20<1/>99

The reaction proceeded without any solvent and with an ethylene glycol/diethylamine molar ratio of 1:3 at 120 °C. In the presence of 1.0 mol % of catalyst, a yield of 99 % was achieved after 20 h (Table 3, entry 1). Conversions were dependent on the catalyst concentration and temperature. Thus the reaction after 6 h at 120 °C gave 97 % yield (Table 3, entry 2). Decreasing the catalyst loading to 0.3 mol % under the same conditions led to a decrease in activity (Table 3, entries 4 and 5). Similar results were recorded for the amination at 140 °C; after 2 h in the presence of 1.0 mol % of 2, the yield was 96 % (Table 3, entry 3), whereas the reaction in the presence of 0.3 mol % of catalyst gave 86 % only (Table 3, entry 7). The reaction proceeded in all cases without the formation of byproducts. In strong contrast, none of the other Ir catalysts tested showed comparable results (Table 3, entries 8–12). Neither [{Ir(cod)Cl}2] nor IrCl3n H2O gave sufficient conversions or displayed any selectivity towards the formation of N-diethylaminoethanol (Table 3, entries 8 and 11). Addition of triphenylphosphane or bis(diphenylphosphanyl)ethane (dppe) led to an improvement of the conversion of ethylene glycol and enhanced the selectivity towards the formation of the diaminated product (Table 3, entries 9, 10, and 12) but, in general, the results were inferior.

Ir catalyst 2 also proved active and highly selective with other diols and amines (Table 4). Ethylene glycol reacted cleanly with dimethylamine, piperidine, and pyrrolidine (Table 4, entries 2–5). Similar results were obtained for the aminations of propane-1,3-diol and 2-methylpropane-1,3-diol (Table 4, entries 6–11). Up to 93 % yields and extremely high selectivities (up to >99 %) towards the formation of the desired monoaminated products were achieved. Decreases in both conversion and selectivity were recorded for the reaction of butane-1,4-diol with diethylamine (Table 4, entry 12). Raising the temperature to 140 °C led to an increase in yield up to 77 %, but the selectivity decreased (Table 4, entry 14). Amination of the same diol with dimethylamine in 1,2-dimethoxyethane (DME) at 140 °C gave 86 % yield and the formation of mono- and diaminated products in a ratio of 70:30 (Table 4, entry 15). Finally, amination of 2,2′-oxydiethanol by diethyl- and dimethylamine gave moderate yields in favor of the monoaminated product (Table 4, entries 16–18). Raising the temperature to 140 °C led to an increase in conversion, but again the selectivity was lowered (Table 4, entry 17).

Table 4. Ir-Complex 2 as catalyst for the amination of diols.[a]
EntryCatalystAmineYield [%][b]Selectivity 3/4
  1. [a] Conditions: Diol (1 mmol), catalyst (1 mol %), molar ratio of diol/amine=1:3, t=20 h; [b] GC yields were determined with N-methylpyrrolidone as an internal standard; [c] T=120 °C; [d] T=140 °C; [e] T=100 °C; [f] NaOtBu as additive (molar ratio of 2 to NaOtBu=1:1.1); [g] reaction was carried out in DME (concentration of diol=1.2 mol L−1).

1
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HNEt299[c]>99/<1
2HNMe297[c,g]>99/<1
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97[c]99/1
4 99[d,f]>99/<1
5
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96[e, f]99/1
6
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HNMe293[d,g]90/10
7HNEt286[c]>99/<1
8HNEt288[d]99/1
9HNEt291[c,f]98/2
10
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HNEt286[c]>99/<1
11HNEt287[d]99/1
12
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HNEt248[c]88/12
13HNEt256[c,f]84/16
14HNEt277[d]76/24
15HNMe286[d,g]70/30
16
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HNEt244[c]80/20
17HNEt262[d]75/25
18HNMe249[d,g]70/30

In conclusion, we have developed a general and highly selective Ir-catalyzed amination of aliphatic alcohols and diols. For the first time, it has been shown that an Ir–pincer chlorodihydride complex, usually applied for the transfer hydrogenation of ketones, can efficiently catalyze this transformation. Efforts to elucidate details of the mechanism20 are currently under way.

Experimental Section

  1. Top of page
  2. Experimental Section
  3. Acknowledgements

All reactions were carried out under an argon atmosphere. Chemicals were purchased from Aldrich, Fluka, Acros, and Strem and used without further purification. Amines were distilled under argon. IrH2Cl[(iPr2PC2H4)2NH] (2) was purchased from Strem (CAS 791629-96-4) or it was prepared according to the procedure of the literature.16 All compounds were characterized by 1H and 13C NMR spectroscopy, MS or GCMS, and HRMS. GC was carried out on a Hewlett–Packard HP 7890 A chromatograph with HP-INNOWax column (J&W Scientific, Agilent Technologies No. 19091N-136, 60 m×0.250 mm×0.25 μm). GC-MS was performed on a Hewlett–Packard HP 6890 chromatograph with HP-5 GC column (J&W Scientific, Agilent Technologies, No. 19091J-413, 30 m×0.320 mm×0.25 μm).

General procedure for the iridium-catalyzed amination of alcohols and diols

A 37 mL-ACE-pressure tube (Aldrich; Z181072) was charged with the corresponding alcohol or diol (1 mmol), amine (3 mmol), and catalyst 2 (5.4 mg, 0.01 mmol). The reaction mixture was stirred at 120 °C or 140 °C for 20 h and the reaction monitored by GC. After completion, excess amine was removed under vacuum and the residue was purified by column chromatography on silica (eluents: ethyl acetate/hexane 1:5 (or 1:10) or ethyl acetate/toluene 1:10, depending on the structures of the product).

Acknowledgements

  1. Top of page
  2. Experimental Section
  3. Acknowledgements

This research was financially supported by Taminco (Gent, Belgium). The authors are grateful to Prof. Dr. M. Beller for fruitful discussions. We thank also Mrs. K. Buchholz, Mrs. S. Buchholz, Mrs. S. Schareina and Mrs. Dr. C. Fischer for skilled technical assistance.