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Fe-catalyzed esterification of amides via C–N bond activation

Authors:	Xiuling Chen Siying Hu Rongxing Chen Jian Wang Minghu Wu Haibin Guo Shaofa Sun

Affiliation:	Hubei University Of Science and Technology, China

Abstract:	An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols for the preparation of esters was performed. The esterification process was accomplished with FeCl₃·6H₂O, which is a stable, inexpensive, environmentally friendly catalyst with high functional group tolerance. An efficient Fe-catalyzed esterification of primary, secondary, and tertiary amides with various alcohols was performed. Esterification was accomplished with inexpensive, environmentally friendly FeCl₃·6H₂O, and with high functional group tolerance The amide bond is not only employed as an important natural peptide skeleton in biological systems, but also as a versatile functional group in organic transformations.^1,2 Among amide transformations,^3,4 transamidation and esterification of amides have attracted widespread attention from organic chemists.^5–11 In contrast to transamidation of amides, esterification of amides is relatively difficult because of the low nucleophilicity of alcohols compared with amines.¹² To overcome this shortcoming, various processes for the esterification of amides have been developed, such as using an activating agent,⁶ employing twisted amides,⁷ and forming intramolecular assisted groups.⁸ For increasing the synthetic flexibility of esterification of amides, new catalytic systems Zn(OTf)₂ and Sc(OTf)₃ were developed by Mashima and Williams for the esterification of amides.⁹ Shimizu et al. reported CeO₂ catalyzed esterification of amides.¹⁰ Off late, progress of the significant Ni-catalyzed esterification of amides has gained precedence.¹¹ Although this approach produces satisfactory yield, the drawbacks such as the use of an expensive catalyst, generation of reagent waste, high temperature and the limited scope of the substrate still persists. Herein, under mild reaction conditions, we report a novel and efficient Fe-catalyzed esterification of amides for the synthesis of esters (eqn (1)). Compared to conventional methods, this esterification procedure is distinguished by using a stable, inexpensive, environment-friendly catalyst, i.e., FeCl₃·6H₂O with a low toxicity solvent. The catalytic system has wide functional group compatibility. The reactions of several primary, secondary, and tertiary amides with various alcohols have been well tolerated in this process. Moreover, esters were also as effective as esterification reagents for the esterification of amides by the acyl–acyl exchange process. In the course of our present study, a Co-catalyzed amide C–N cleavage to form esters was reported by Danoun et al.¹³ However, an additional additive (Bipy) and Mn (3 equiv.) were needed and the scope of the reaction was limited to only tertiary amides; primary or secondary amides were not compatible with this catalytic oxidation system.1We initially selected benzamide 1a and ethanol 2a as model substrates to screen the reaction conditions, and the results are summarized in
Entry	Catalyst (20%)	Additive (40%)	Yield^b
1	FeCl₂	—	31
2	FeCl₃	—	31
3	FeBr₃	—	25
4	FeSO₄·7H₂O	—	20
5	Fe(NO₃)₃·9H₂O	—	20
6	FeCl₃·6H₂O	—	35
7	CuCl₂	—	Trace
8	PdCl₂	—	Trace
9	Ni₂Cl·6H₂O	—	Trace
10	—	—	—
12	FeCl₃·6H₂O	Pyridine	Trace
13	FeCl₃·6H₂O	1,10-Phenanthroline	Trace
14	FeCl₃·6H₂O	Formic acid	Trace
15	FeCl₃·6H₂O	l-Proline	Trace
16	FeCl₃·6H₂O	H₂SO₄	22
17	FeCl₃·6H₂O	HNO₃	25
18	FeCl₃·6H₂O	HCl	91
19	—	HCl	35
20^c	FeCl₃·6H₂O	HCl	Trace
21^d	FeCl₃·6H₂O	HCl	36
22^e	FeCl₃·6H₂O	HCl	28
23^f	FeCl₃·6H₂O	HCl	40

Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.1 mL), catalyst (0.04 mmol, 20 mol%), H₂SO₄ (concentrated, 0.24 mmol), HNO₃ (concentrated, 0.24 mmol), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bGC yield using hexadecane as internal standard.^cDMF was used as a solvent.^d1,4-Dioxane was used as solvent.^eToluene was used as solvent.^fCH₃CN was used as solvent.The substrate scope of esterification with alcohols was investigated under the optimized reaction conditions. As shown in

Entry

Alcohol

Products

Yield^b

Ethanol 2a

3a, 85%

n-Propanol 2b

3b, 88%

n-Octanol 2c

3c, 82%

i-Propanol 2d

3d, 91%

t-Butyl alcohol 2e

3e, 81%

Cyclohexanol 2f

3f, 80%

Phenethanol 2g

3g, 83%

Phenethanol 2h

3h, 81%

Trifluoroethanol 2i

3i, 81%

Ethane-1,2-diol 2j

3j, 85%

Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.1 mL), 2b–2j (0.24 mmol), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.We then examined the generality of amides and the results are compiled in EntryAmidesProducts and yield^b1 3k, 86%2 3l, 85%3 3m, 78%4 3n, 75%5 3o, 86%6 3p, 84%7 3q, 90%8 3r, 86%9 3s, 84%10 3t, 55%11 3u, 88%12 3v, 85%13 3w, 81%Open in a separate window^aReaction conditions: 1b–1n (0.2 mmol), 2a (0.1 mL), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.In addition to alcohols, esters were also used as substrates for esterification of amides through the acyl–acyl exchange process under the optimal reaction conditions.¹⁴ As shown in EntryAmidesEstersProducts and yield^b11a 21a 31a 41a 51b 61c 71h Open in a separate window^aReaction conditions: 1a–1h (0.2 mmol), 2k, 2l (0.1 mL), 2m–2o (0.24 mmol), FeCl₃·6H₂O (0.04 mmol, 20 mol%), HCl (0.24 mmol, 36–38%), n-hexane (1.0 mL), 80 °C, 14 h.^bIsolated yield.The substrate scope of this iron-catalyzed esterification of secondary and tertiary amides with alcohols was investigated. Remarkably, when a secondary amide, viz., N-methylbenzamide (1o) and a tertiary amide, viz., N,N-diethylbenzamide (1p) were used as substrates, the corresponding esters 3a and 3v were afforded in high yield (Scheme 1).Open in a separate window Scheme 1Reaction of secondary and tertiary amides 1o and 1p with ethanol.In addition to aromatic primary, secondary and tertiary amides, the esterification of aliphatic primary, secondary and tertiary amides was also investigated under the optimal reaction conditions, the corresponding esters were afforded in good to excellent yield and the results are shown in Scheme 2. 2-Phenylacetamide (1q) participated in this catalytic reaction to form the ester 3y in 86% yield. N-Acetylaniline 1r and N,N-dimethylformamide 1s were also applicable to this catalytic system, and transformed into the corresponding esters 3z and 3z¹ in 79% and 82% yield respectively.Open in a separate window Scheme 2Reaction of aliphatic amides 1q, 1r and 1s with different alcohols.To demonstrate the effect of iron salt in the current catalytic system, several control experiments were carried out as shown in Scheme 3. When 1 equivalent FeCl₃·6H₂O was used as the catalyst in the absence of HCl, 3a was obtained in 90% yield. This result indicated that the catalytic cycle of the iron salt was hindered in the present reaction conditions. When the stronger bidentate ligands such as 2,2-bipyridine was used, 3a was not obtained and trace amounts of 3a were detected on using ferrocene as the catalyst, indicating that the iron salt catalyst showed low efficiency in the presence of the stronger ligand. Thus, it was deduced that free Fe(ii or iii) was effective for this reaction.Open in a separate window Scheme 3Control experiments.According to the reported literature^5d and our experimental results, the catalytic reaction pathways for the Fe-catalyzed esterification of amides by alcohols are proposed as shown in Scheme 4. The first step is the generation of the amidate complex A, which can be formed from free Fe(iii) and amide 1. The complex A reacts with alcohol 2 to produce an unstable intermediate B. The interaction between the alcohol oxygen and the carbonyl results in cyclic intermediate C, which is in equilibrium with its isomer D. Intermediate E can also be produced from Dvia C–N bond cleavage. Through the reaction of HCl and a new molecule amide, intermediate E produces the desired ester 3, ammonium chloride (colorless crystal, which was detected after the reaction), and the amidate complex A.Open in a separate window Scheme 4Plausible reaction mechanism for Fe-catalyzed esterification of amides by alcohols. Keywords:

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