Copper-catalyzed N-formylation of amines with CO₂ under ambient conditions

Abstract

We carried out work on N-formylation of amines with CO₂ and PhSiH₃ to produce formamides catalyzed by a copper complex. It was found that the Cu(OAc)₂–bis(diphenylphosphino)ethane (dppe) catalytic system was very efficient for these kind of reactions at room temperature and 1 atm CO₂ with only 0.1 mol% catalyst loading.

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Carbon dioxide (CO₂) chemistry is attracting increasing attention in both academia and industry because CO₂ is a cheap, non-toxic and abundant C1 building block.^1,2 Various approaches have been explored for the conversion of CO₂, and the catalytic reduction of CO₂ to value-added compounds is one of the most attractive routes. Various commodity chemicals such as formic acid derivatives,³ methane,⁴ methanol⁵ and formaldehyde⁶ can be produced.

Formamides are a class of chemicals with wide applications in industry as solvents and raw materials for synthesis of other chemicals. An interesting route for the synthesis of formamides is the N-formylation of amines with CO₂ in the presence of reducing agent. Hydrogen gas is the cleanest and most atom-economical reductant, but harsh reaction conditions, such as high reaction pressure and temperature, often prevents its broad application.⁷ Moreover, it is known that the activity of aromatic amines is poor when using H₂ as the reducing agent. Hydrosilanes possess a reduction potential similar to H₂ and a Si–H bond that is kinetically more reactive because of its polarity and lower bond dissociation energy. In addition, they circumvent the air and moisture sensitivity of aluminium and boron hydrides and so hydrosilanes are a kind of mild and easily handling reducing agent. Various organocatalysts⁸ and organometallic complexes⁹ have been utilized to catalyze the N-formylation of amines with CO₂ using hydrosilanes as the reductant. This kind of transformation was first reported in 2012 using organic base 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) as the catalyst at a reaction temperature of 100 °C.^2b Other organic catalysts such as N-heterocyclic carbenes (NHCs)^8a and ionic liquid 1-butyl-3-methylimidazolium chloride ([BMIm]Cl)^8b were also used to catalyze this reaction. However, N-heterocyclic carbenes (NHCs) is sensitivity to moisture and the catalyst loading was high (5 mol%). The [BMIm]Cl loading was 100% and high CO₂ pressure (1 MPa) was required for this transformation. 1,3,2-Diazaphospholene could catalyze the N-formylation reaction at room temperature and 1 atm CO₂, but the catalyst loading was high (5 mol%).^8c Alkyl bridged chelating bis(NHC) rhodium complexes (NHC = N-heterocyclic carbene) was highly effective for the reaction at a low catalyst loading and ambient temperature,^9a but at high pressure. In addition, the metal rhodium is expensive. Fe(acac)₂ with PP₃ catalyst system could catalyze the N-formylation reaction with 5 mol% catalyst loading at room temperature.^9b Copper with diphosphine ligand 1,2-bis(diisopropylphosphino)benzene catalyst has been widely used to catalyze the reduction of CO₂.¹⁰ Copper with 1,2-bis(diisopropylphosphino)benzene catalyzed the N-formylation using polymethylhydrosiloxane (PMHS) as the reducing agent,^9a and the TON is up to 11 700 at 80 °C. However, the value of TON is lower at room temperature.¹¹ It was well known that ligand is very important for catalytic reaction. Considering copper is cheaper, more efficient copper complex catalytic system for N-formylation of amines with CO₂ should be explored. Up to now, the formylation reaction at ambient temperature and atmospheric pressure with a low catalyst loading has not been achieved due mainly to the inherent kinetic stability of CO₂.

Herein, we conducted the first work to use Cu-based catalysts in the N-formylation of amines with CO₂ and PhSiH₃. It was found that the N-formylation reactions could be catalyzed efficiently by 1,2-bis(diphenylphosphino)ethane (dppe)–Cu(II) complex at room temperature and 1 atm CO₂ with only 0.1 mol% catalyst loading for the conversion of a wide range of aliphatic and aromatic amines, and the yields of the desired products were very high.

We check the effect of different ligand–Cu(II) catalysts in the N-formylation of amines with CO₂ and PhSiH₃. It was found that the bite angles of the ligands can affect significantly the yields of the desired product. The angle bite β° is bigger, the yield of the desired product is lower. The N-formylation reactions could be catalyzed efficiently by (dppe)–Cu(II) complex at room temperature and 1 atm CO₂ with only 0.1 mol% catalyst loading for the conversion of a wide range of aliphatic and aromatic amines, and the yields of the desired products were very high. And the TON can be reached to about 14 500 at room temperature with 1 atm CO₂ for 4 h and the TOF is about 3625 h⁻¹.

Firstly, the effect of different ligand shown in Fig. 1 using Cu(OAc)₂ as the metal precursor was checked. The results were shown in Table 1. We found that mono-phosphine ligands (Cy₃P, Ph₃P, Tppi) are inactive for the N-formylation reaction. Bis-phosphine ligands are all active, and the yield of the desired product is related with the angle bite of the ligands. When the angle bite β° is bigger, the yield of the desired product is lower. The angle bite β° of dppm is 84°, while the yield of the desired is also very low because the dppm more easily forms dinuclear species complex. The angle bite of dppe and dppb is similar, while the yield of the desired of the product is higher for dppe, maybe because the ligand dppe is more flexible. It is obviously that dppe is the best ligand among the ligands checked (Table 1).

Fig. 1 Phosphine ligands employed for N-formylation reaction.

Table 1 The effect of bite angle of the ligands^a

Ligand	Bite angle, β°	Yield of formanilide (%)
a Reaction conditions: aniline (1 mmol), Si–H (6 mmol), Cu(OAc)2 (1 μmol), ligand (1.2 μmol); N.R. = No reaction.
Cy3P	—	N.R.
Ph3P	—	N.R.
TPPi	—	N.R.
Xantphos	102 (ref. 12)	11
dppb	87 (ref. 13)	23
dppm	84 (ref. 14)	59
dppe	89 (ref. 12)	96
dppbt	98 (ref. 13)	83

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The performances of different metal salts were evaluated for the N-formylation of aniline in the presence of dppe (Table 1). Among the salts studied, [Cu(OAc)₂] was very active, while other salts were not active (Table 2, entries 1–12 and 15). In addition, the reaction did not take place when only [Cu(OAc)₂] or dppe was used (Table 2, entries 13 and 14), indicating that both the Cu salt and ligand were necessary. Solvent also affected the reaction significantly. Toluene is the best solvent for the reaction and the yield of 2a could be as high as 96% (Table 2, entry 15). In THF and 1,4-dioxane the yields of 2a were 76% and 84%, respectively (Table 1, entries 16 and 17). The reaction did not take place in other solvents such as dichloromethane, hexane and CH₃CN (Table 2, entries 18 and 19). Finally, the reductant agents Ph₂SiH₂ and PMHS did not afford any desired product at the reaction conditions (Table 2, entries 20 and 21).

Table 2 Optimization of catalytic system and reaction condition^a

Entry	Metal precursor	Reducing agent	Solvent	Yield (%)
a Reaction conditions: aniline (1 mmol), Si–H (6 mmol), metal salt (1 μmol), ligand (1.2 μmol). b Without Cu(OAc)2·2H2O. c Without ligand.
1	AgCl	phSiH3	Toluene	<5%
2	AgOAc	phSiH3	Toluene	<5%
3	NiCl2·6H2O	phSiH3	Toluene	<5%
4	Ni(OAc)2	phSiH3	Toluene	<5%
5	FeCl2	phSiH3	Toluene	<5%
6	ZnCl2·6H2O	phSiH3	Toluene	<5%
7	Zn(OAc)2	phSiH3	Toluene	<5%
8	CuCl2·2H2O	phSiH3	Toluene	<5%
9	CuBr2	phSiH3	Toluene	<5%
10	CuBr	phSiH3	Toluene	<5%
11	CuI	phSiH3	Toluene	<5%
12	Cu(OTf)2	phSiH3	Toluene	<5%
13^b	—	phSiH3	Toluene	<5%
14^c	Cu(OAc)2·2H2O	phSiH3	Toluene	<5%
15	Cu(OAc)2·2H2O	phSiH3	Toluene	96
16	Cu(OAc)2·2H2O	phSiH3	THF	76
17	Cu(OAc)2·2H2O	phSiH3	1,4-Dioxane	84
18	Cu(OAc)2·2H2O	phSiH3	CH2Cl2	<5%
19	Cu(OAc)2·2H2O	phSiH3	Hexane	<5%
20	Cu(OAc)2·2H2O	Ph2SiH2	Toluene	<5%
21	Cu(OAc)2·2H2O	PMHS	Toluene	<5%

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Having in hand an efficient catalytic system for the hydroformylation of 1a, the scope of reactive amines were explored utilizing Cu(OAc)₂·H₂O and dppe (0.1 mol%) as a catalytic system with PhSiH₃ as a reductant in toluene, and the results are listed in Table 3. It was demonstrated that different kinds of amines were formylated to the corresponding formamides in excellent yields at 25 °C and 1 atm CO₂. The yields of the corresponding products were 96% and 97% respectively for aniline, 4-methyl aniline in 4 hours (Table 3, entries 1 and 2). When the substituent group was chloride, the reaction time need to be prolonged to 5 hours to get 95% yield of N-(4-chlorophenyl)formamide (Table 3, entry 3). Longer reaction time (6 h) was required for achieving high yield of N-mesitylformamide (Table 3, entry 4) because of steric hindrance. Primary aliphatic amine also showed high activity, while aliphatic amine with alkyl chains showed lower activity compared to benzyl amine and cyclohexanamine (Table 3, entries 5–7). All the primary amines checked only yielded monoformylated products (Table 3, entries 1–7). We did not detect any diformylated products using N-phenylformamide as the starting material. The yield of the N,N-diphenylformamide was 91% in 6 hours (Table 3, entry 11). N-Methylaniline, indoline and morpholine exhibited the highest activity, and the yields of the corresponding products could reach 99% in 2 hours (Table 3, entries 8–10). Longer reaction time was needed to get high yield of the product for dihexylamine and the yield of N,N-dihexylformamide could be increased to 96% after a longer reaction time (Table 3, entry 13). Secondary amines with alkyl chains showed lower activity compared to N-methylanilines and aliphatic primary amines (Table 3, entries 6, 8 and 13).

Table 3 N-Formylation of various amines with CO₂^a

Entry	Substrate	Product	Time (h)	Yield (%)
a Reaction conditions: amine (1 mmol), PhSiH3 (2 mmol), Cu(OAc)2·2H2O (1 μmol), dppe (1.2 μmol).
1			4	96
2			4	97
3			5	95
4			8	92
5			4	99
6			5	95
7			4	92
8			2	99
9			2	99
10			2	99
11			6	91
12			4	99
13			6	96

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The possible reaction mechanism was shown in Scheme 1. The copper catalyst activated PhSiH₃ to form B and catalyzed the insertion of CO₂ into Si–H bond to form intermediate C, which further reacted with the amine, producing the final product. To get evidence for supporting this reaction mechanism, control experiment was performed. The reaction of PhSiH₃ and CO₂ was allowed to proceed for 1 h in the presence of the catalyst. The CO₂ was removed and aniline was added and stirred for 4 h, and N-phenylformamide was also produced. This indicates that an intermediate was formed in the N-formylation reaction. To identify the intermediate, the mixture of catalyst, PhSiH₃ and CO₂ after reaction for 1 h without aniline was analyzed by ¹H NMR and ¹³C NMR (Fig. 2 and 3). A signal appeared at δ = 163.0 ppm (Fig. 2), and a new one signal also appeared in the ¹H NMR spectrum at δ = 8.18 ppm (Fig. 3). These two signals were ascribed to formoxysilane (Fig. 3), indicating that the reaction of phenylsilane with CO₂ to form formoxysilane in the presence of the copper-based catalyst. After the addition of aniline, the formoxysilane intermediate transformed into the corresponding product. The mixture of catalyst, PhSiH₃ and CO₂ stirred 1 h, and then analyzed by GC-MS. Formoxysilane intermediate was detected (Fig. S1†).

Scheme 1 The possible reaction mechanism.

Fig. 2 ¹³C NMR spectra of catalyst, PhSiH₃ and CO₂ (DMSO-d₆, 298 K).

Fig. 3 ¹H NMR spectra of catalyst, PhSiH₃ and CO₂ (d₆-DMSO, 298 K).

Conclusions

In conclusion, Cu(II)–dppe complex can efficiently catalyze the N-formylation reactions of various amines with CO₂ and PhSiH₃ at ambient condition with only 0.1 mol% catalyst loading. The yields of the corresponding desired products range from 91% to 99%, and no by-product is formed in the reactions. In a reaction, phenylsilane reacts with CO₂ to form an intermediate formoxysilane, which reacts with the amine to yield the desired product. We believe that this route has great potential of application because the reactions proceed at ambient condition with very high efficiency, and the catalyst is cheap.

Acknowledgements

This work was supported by the Recruitment Program of Global Youth Experts of China, Chinese Academy of Sciences (KJCX2.YW.H30). National Natural Science Foundation of China (21533011, 21321063), and. The measurements of ¹H and ¹³C nuclear magnetic resonance (NMR) and high resolution mass spectrometry (HRMS) were performed at the Centre for Physicochemical Analysis and Measurements in ICCAS.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedures, spectroscopic data, and supporting figures and tables. See DOI: 10.1039/c6ra05199e

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