Technical Field

[0001] The invention relates to a catalytic process for producing aromatic

formamides by formylation of aromatic amines. More particularly, it concerns preparation of aromatic formamide by the reaction of an aromatic amine with a formic acid ester in the presence of a metal sulfonimide salt catalyst.

Background Art

[0002] Preparation of formamides through formylation of amines has drawn great research interest, as the resulting formamides are often easily converted to industrially important chemical products such as isocyanides and formamidines, and their formyl groups can be conveniently utilized as protecting groups in peptide synthesis.

[0003] While syntheses of certain aliphatic formamides by formylating aliphatic amines with methyl formate in thermal conditions have been realized in an industrial scale with fairly good selectivies and yields, such as for the production of N, N-dimethylformamide (DMF), an analogous thermal transformation of aromatic amine to the corresponding formamides is less effective, judging by the harsh reaction condition and extended reaction times reported in the Examples of US 5053430 (BOEHRINGER

INGELHEIM KG) 9/22/1989 .

[0004] Intending to increase the efficiency of the amine formylation processes, US 2012/0253072 A (BASF SE) 12/1/2010 proposed a catalytic process for producing formamides in a relatively short reaction time, which requires reacting an aromatic amine with a formic acid ester using the catalyst of a phosphorus-comprising acid or a Lewis-acidic metal salt, and the metal of the Lewis-acidic metal salt is selected from zinc, lead and ytterbium.

Nevertheless, the metal catalysts used in US 2012/0253072 are either considered toxic (e.g. zinc, which is widely recognized as a source of environmental toxicity) or have limited availability (e.g, ytterbium), thus restricting their industrial use. Moreover, the application Examples in US 2012/0253072 were focused on aromatic amines with medium- to high- nucleophilicity, and relied on toxic solvents such as N,N- dimethylacetamide.

[0005] Thus, it is desirable to develop an economical and environmentally friendly formylation process for various aromatic amines with low nucleophilicity. Summary of invention

[0006] The present invention provides a catalytic process for preparing a

formamide, comprising reacting a formic acid ester with an aromatic amine carrying at least one electron withdrawing group (EWG) in the presence of a catalyst of fluorine-containing sulfonimide metal salt.

[0007] Preferably, said fluorine-containing sulfonimide metal salt comprises a metal element selected from the group consisting of alkaline earth metals and transition metals.

[0008] More preferably, said fluorine-containing sulfonimide metal salt comprises a metal element selected from the group consisting of Ca, Cu, Fe, and Al.

[0009] The Applicant has discovered that, surprisingly, by using a sulfonimide metal salt catalyst as above defined, the invented process enables effective formylation of aromatic amines of reduced nucleophilicity (given by their EWG substitutes). Further advantageously, the metal ions in the sulfonimide metal salt catalyst may be selected from inexpensive, nontoxic and abundant metals, which results in a more environmentally friendly formylation process.

[0010] As used herein, the term "aromatic amine" refers to a primary, secondary or tertiary amine containing an aryl moiety. In accordance with the present invention, the term "aryl" refers to a substituted or unsubstituted aromatic carbocyclic radical having 6 to 14 carbon atoms.

[0011] Preferably, the EWG-carrying aromatic amine used in the present

invention is a primary amine or a secondary amine. As used herein, the prefix "EWG-carrying" means that the associated molecule carries at least one EWG.

[0012] In specific embodiments of the present invention, the EWG-carrying

aromatic amine used is represented by the general formula of (EWG) _n -Ar- (NHR)m, wherein: n is an integer from 1 to 5, preferably from 1 to 2; m is an integer from 1 to 3, preferably 1 ; each R is independently a hydrogen atom or an alkyl radical having no more than 4 carbon atoms, and is preferably selected from the group consisting of hydrogen, methyl and ethyl; and Ar is an aryl moiety and is preferably a benzene ring that is optionally substituted.

[0013] As used herein, an "electron withdrawing group" or "EWG" refers to a

substituent that can withdraw electrons. Suitable examples of EWG include, but are not limited to, halogen, fluoroalkyl, O-fluoroalkyl, S- fluoroalkyl, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, halocarbonyl, formyl, carbonyl, sulfo, aryloxysulfonyl, perfluoroalkylsulfonyl, alkylsulfonyl, azo, alkenyl, alkynyl, acyl, dialkylphosphonato, diarylphosphonato, aminocarbonyl, primary ammonium, secondary ammonium, tertiary ammonium, nitro or combinations thereof.

[0014] The EWGs used in the scope of the present invention may be neutral, anionic or cationic.

[0015] Preferred examples of EWG for the present invention may be selected from a group consisting of halogen, peril uoroalkyl, O-perfluoroalkyl, S- perfluoroalkyl, and nitro.

[0016] The term "halogen" as used herein refers to F, CI, Br, and I, and is

preferably F and Br.

[0017] The term "fluoroalkyl" as used herein refers to an alkyl group that has at least one hydrogen atom replaced with a fluorine atom. The term

"perfluoroalkyl", as used herein, refers to an alkyl group having all the hydrogen atoms replaced with fluorine atoms. A perfluoroalkyl is therefore a subset of a fluoroalkyl.

[0018] The term "alkyl", as used herein and recognized in the art, refers to a

monovalent radical of an alkane.

[0019] The term "cyano" as used herein refers to a monovalent group of formula - CN.

[0020] The term "carboxy" as used herein refers to a monovalent group of formula -COOH.

[0021] The term "alkoxycarbonyl" as used herein refers to a monovalent group of formula -(C=O)-O-R ¹ wherein R ¹ is an alkyl group, preferably an alkyl group having 1-6 carbon atoms. [0022] The term "aryloxycarbonyl" as used herein refers to a monovalent group of formula— (C=O)OAr.

[0023] The term "halocarbonyl" as used herein refers to a monovalent group of formula— (C=O)X where X is a halogen group.

[0024] The term "formyl" as used herein refers to a monovalent group of formula -

(C=0)H.

[0025] The term "carbonyl" as used herein refers to a divalent group of formula - (C=O)-.

[0026] The term "sulfo" as used herein refers to a monovalent group of formula - SO ₃ H.

[0027] The term "perfluoroalkylsulfonyl" as used herein refers to a monovalent group of formula -SO2Rf where Rf is a perfluoroalkyl.

[0028] The term "alkylsulfonyl" as used herein refers to a monovalent group of formula -SO2R ¹ , wherein R ¹ is as defined above.

[0029] The term "azo" as used herein refers to a divalent group of formula -N=N-.

[0030] The term "alkenyl" as used herein, same as the general understanding in the art, refers to a monovalent radical of an alkane.

[0031] The term "alkynyl" as used herein, same as the general understanding in the art, refers to a monovalent radical of an alkyne.

[0032] The term "acyl" as used herein refers to a monovalent group of formula -

COR ¹ , wherein R ¹ is as defined above.

[0033] The term "dialkylphosphonato" as used herein refers to a monovalent group of formula -(PO)(OR ¹ )2 where R ¹ is as defined above.

[0034] The term "diarylphosphonato" as used herein refers to a monovalent group of formula -(ΡΟ)(ΟΑ where Ar is an aryl moiety.

[0035] The term "aminocarbonyl" as used herein refers to a monovalent group of formula -(CO)N(R ² )2 where each R ² is independently hydrogen, alkyl, or aryl.

[0036] As used herein, the term "primary ammonium" refers to a cationic group of formula -[Nh R ¹ ] ^4" , the term "secondary ammonium" refers to a cationic group of formula -[NHR ¹ 2] ⁺ , and the term "tertiary ammonium" refers to a cationic group of formula -[NR ¹ 3] ⁺ , wherein R ¹ is as defined above. [0037] According to the present invention, the preferred examples of the EWG- carrying aromatic amines include EWG-carrying anilines, EWG-carrying /V- methylanilines and EWG-carrying diaminobenzenes, wherein the EWG is selected from a group consisting of F, Br, NO2, CF3, OCF3, and SCF3.

[0038] The catalyst used in the process of the present invention is preferably a sulfonimide salt represented by the formula (1),

A[RfSO ₂ -N-SO ₂ Rf ² ] (1)

wherein Rf ¹ and Rf ² ,each having 1 to 12 carbon atoms, are independently selected from the group consisting of perfluoroalkyl groups, fluoroalkyl groups, fluoroalkenyl groups and fluoroallyl groups, and wherein A is a metal selected from the group consisting of Ca, Cu, Fe, and Al.

[0039] In the preferred embodiments of the present invention, the sulfonimide salt catalysts used are those of formula (1) with Rf ¹ and Rf ² both being a perfluoroalkyl group. More preferably, the sulfonimide salt catalysts used in the invented process are selected from metal bis-triflimides, i.e. those of formula (1) with Rf ¹ and Rf ² both being CF3. Metal bis-triflimide is also known as metal bis-trifluoromethanesulfonimide, and will be used

interchangeably in the text of the application.

[0040] Specific Examples of sulfonimide salt catalysts used in the present

invention include calcium bis-triflimide, iron (III) bis-triflimide, copper bis- triflimide and aluminium bis-triflimide, among which calcium bis-triflimide and iron (III) bis-triflimide are preferred.

[0041] In specific embodiments of the present invention, the sulfonimide salt

catalyst is used in a molar ratio of from 0.001 to 0.3, preferably from 0.01 to 0.1 , based on the amino groups of the EWG-carrying aromatic amine used.

[0042] Generally, the formic acid ester used in the present invention is derived from a linear or branched aliphatic alcohol having 1 to 6 carbon atoms (e.g. methanol), or from a linear or branched 1-alkenyl formate having 2-6 carbon atoms in the alkenyl radical (e.g., vinyl formate or isoprenylformate). Preferably, the formic acid ester used is selected from linear or branched Ci-C6-alkyl formates, and can be used individually or as a mixture. Particular preference is given to methyl formate, which is also available on an industrial scale.

[0043] In preferred embodiments of the present invention, the formic acid ester is used in a molar ratio of from 1 :1 to 20:1 , preferably from 2:1 to 8:1 , based on the amino groups of the EWG-carrying aromatic amine used.

[0044] Advantageously, the process of the present invention may be carried out in the substantial absence of an additional solvent, which hereby means that no more than 10% by weight, based on the amount of starting materials in the process, of materials which act as solvents/diluents and inert to the starting materials, catalyst and end products are present during the process. Suitably not more than 5% by weight, and preferably not more than 2% by weight, of additional solvent, based on the starting materials, is used in the process.

[0045] Suitable additional solvent used in the process of the present invention may be selected from a group consisting of water, polar organic solvents, and dipolar aprotic organic solvents, of which polar organic solvents are preferred.

[0046] Specific examples of suitable additional solvent include nitromethane, dichloromethane, ethyl acetate, and amides (e.g. DMF). These solvents may be used individually or as a mixture.

[0047] Further advantageously, the process of the present invention may be

carried out in the complete absence of additional solvent, thus obviating the need for using explosive or toxic organic solvents while simplifying the product/catalyst recycle process.

[0048] In the process of the present invention, the reaction of the aromatic amine with the formic acid ester in the presence of the sulfonimide salt catalyst is preferably carried out at a reaction temperature of 20-160°C, more preferably 60-120°C.

[0049] The reaction time of the process is generally less than 5 hours, preferably from 0.5 to 4 hours, and more preferably from 0.5 to 2 hours.

[0050] The pressure conditions of the process are generally selected depending on the formic acid ester used and its boiling temperature. Specifically, the reaction of the process can be carried out at an autogenous pressure (pressure which is established during the reaction in the closed vessel at the reaction temperature) or, alternatively, at a higher pressure of from 1 to 100 bar absolute or a subatmospheric pressure of from 0.001 to 1 bar absolute.

[0051] Preferably, the reaction of the process is carried out under microwave irradiation. The microwave irradiation according to the invention can be carried out using commercially available microwave synthesizers, such as Biotage® Initiator Microwave Synthesizer (Biotage AB, Uppsala, Sweden). The microwave irradiation is generally in the range of 50-1000 W, preferably in the range of 100 to 600 W, for a period of 1-120 min.

[0052] Isolation of the aromatic formamide product can take place by

conventional separation methods known in the art, e.g., fractional distillation. Alternatively, the reaction discharge mixture can be evaporated to dryness and the resulted solid can be purified by washing with or recrystallization from a suitable solvent. Furthermore, the aromatic formamide product may be precipitated by adding a suitable solvent, isolated by filtration and then purified by washing or recrystallization.

[0053] The aromatic formamide product obtained can be further processed to industrially important aromatic isocyanates, e.g., by oxidative

dehydrogenation.

[0054] In line with the afore-described formylation process, the present invention also provides a reaction medium for preparing a formamide, the reaction medium comprising: a formic acid ester, an aromatic amine carrying at least one EWG, and a fluorine-containing sulfonimide metal salt.

Description of embodiments

[0055] The following general procedure and examples are provided to illustrate preferred embodiments of the invention and are not intended to restrict the scope thereof.

Examples 1-12

[0056] General Procedure

[0057] In a 5ml Biotage® microwave vial fitted with a magnetic stirrer, 600 mg of methyl formate (10 mmol, 5 equiv) was mixed with 60 mg Ca(NTf2)2 (0.1 mmol, 5 mol%), nitromethane (0.33 equiv) and a particular aromatic amine (2mmol, 1 equiv) as identified in Table 1. All chemicals were used as obtained from the supplier. Subsequently, the microwave vial was sealed and the mixture was stirred at 1 15°C for one hour, under microwave irradiation, to allow the formylation reaction to proceed.

58] Upon completion of the formylation reaction, the product was isolated after flash chromatography (eluent: cyclohexane/ethyl acetate = 1 :1 , V/V).

Analytical thin layer chromatography was then carried out on the separated product using glass-back plates coated with silica gel.

Components were visualized by UV light at 254 nm. ¹ H NMR was recorded at 300 MHz and ³ C NMR was recorded at 75 MHz in CDCI ₃ or DMSO-o¾. The isolated product yield of each Example is also recorded in Table 1.

Table 1

* "AA "in Table 1 refers to the EWG-carrying aromatic amine used in each Example