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US-20260125340-A1 - METHOD FOR PREPARING AMIDES FROM ESTERS

US20260125340A1US 20260125340 A1US20260125340 A1US 20260125340A1US-20260125340-A1

Abstract

The present invention relates to a method for preparing of an amide of the formula (I-1) or a diamide of the formula (I-2) where the variables areas defined in the claims and the description, by reacting an ester with an aromatic or heteroaromatic amine in the presence of an alkali metal-containing base and a Lewis acid; where the reaction is carried out under essentially anhydrous conditions.

Inventors

  • Thomas Schaub
  • Christian Harald WINTER
  • Stefan Benson
  • Roland Goetz
  • Desislava Slavcheva Petkova
  • A. Stephen K. Hashmi
  • Nadja Elena Niggli

Assignees

  • BASF SE

Dates

Publication Date
20260507
Application Date
20231005
Priority Date
20221006

Claims (20)

  1. 1 . A method for preparing an amide of the formula (I-1) or a diamide of the formula (I-2) where R 1 is selected from the group consisting of hydrogen, C 1 -C 30 -alkyl which is unsubstituted or carries m radicals R a , C 1 -C 30 -haloalkyl which is unsubstituted or carries m radicals R a , C 2 -C 30 -alkenyl which is unsubstituted or carries m radicals R a , C 2 -C 30 -haloalkenyl which is unsubstituted or carries m radicals R a , C 2 -C 30 -alkynyl which is unsubstituted or carries m radicals R a , C 2 -C 30 -haloalkynyl which is unsubstituted or carries m radicals R a , C 3 -C 30 -cycloalkyl which is unsubstituted or carries m radicals R b , C 6 -C 22 -aryl which is unsubstituted or carries m radicals R b , and a 3- to 30-membered saturated, partially unsaturated, or maximally unsaturated heterocyclic ring containing 1, 2, 3, or 4 heteroatoms or heteroatom groups selected from, N, O, S, SO, and SO 2 as ring members, which is unsubstituted or carries m radicals R b ; R 2 is C 6 -C 22 -aryl which is unsubstituted or carries m radicals R b , or is a 5- to 30-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring members, where the heteroaromatic ring is unsubstituted or carries m radicals R b ; R 3 is selected from the group consisting of hydrogen, C 1 -C 30 -alkyl which is unsubstituted or carries m radicals R a , C 1 -C 30 -haloalkyl which is unsubstituted or carries m radicals R a , C 2 -C 30 -alkenyl which is unsubstituted or carries m radicals R a , C 2 -C 30 -haloalkenyl which is unsubstituted or carries m radicals R a , C 2 -C 30 -alkynyl which is unsubstituted or carries m radicals R a , C 2 -C 30 -haloalkynyl which is unsubstituted or carries m radicals R a , C 3 -C 30 -cycloalkyl which is unsubstituted or carries m radicals R b , C 6 -C 22 -aryl which is unsubstituted or carries m radicals R b , and a 3- to 30-membered saturated, partially unsaturated, or maximally unsaturated heterocyclic ring containing 1, 2, 3, or 4 heteroatoms or heteroatom groups selected from, N, O, S, SO, and SO 2 as ring members, which is unsubstituted or carries m radicals R b ; or R 3 forms a saturated or unsaturated 2-, 3-, or 4-membered linking group to a carbon or nitrogen ring atom of the aryl or heteroaromatic ring R 2 ; where the linking group may comprise 1 or 2 heteroatoms or heteroatom groups selected from, N, O, S, SO, and SO 2 ; where the linking group may carry 1, 2, or 3 radicals selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; A is a divalent aliphatic, cycloaliphatic, aliphatic-cycloaliphatic aromatic, aromatic-aliphatic, or heterocyclic moiety; each R a is independently selected from the group consisting of cyano, nitro, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C(═O)R c , amino, C 1 -C 4 -alkylamino, di-(C 1 -C 4 -alkyl)-amino, C 3 -C 20 -cycloalkyl, C 6 -C 22 -aryl which is unsubstituted or carries m radicals R d , and a 3- to 20-membered saturated, partially unsaturated, or maximally unsaturated heterocyclic ring containing 1, 2, 3, or 4 heteroatoms or heteroatom groups selected from, N, O, S, SO, and SO 2 as ring members, which is unsubstituted or carries m radicals R d ; each R b is independently selected from the group consisting of halogen, cyano, nitro, hydroxyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, amino, C 1 -C 4 -alkylamino, di-(C 1 -C 4 -alkyl)-amino, NR e R f , C(═O)NR e R f , C 1 -C 20 -alkyl, C 1 -C 20 -haloalkyl, C 2 -C 20 -alkenyl, C 2 -C 20 -haloalkenyl, C 2 -C 20 -alkynyl, C 2 -C 20 -haloalkynyl, C 3 -C 20 -cycloalkyl, C 6 -C 22 -aryl which is unsubstituted or carries m radicals R d , and a 3- to 20-membered saturated, partially unsaturated, or maximally unsaturated heterocyclic ring containing 1, 2, 3, or 4 heteroatoms or heteroatom groups selected from, N, O, S, SO, and SO 2 as ring members, which is unsubstituted or carries m radicals R d ; each R c is independently selected from the group consisting of C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkyl which carries a group NR e R f , C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; each R d is independently selected from the group consisting of halogen, cyano, hydroxyl, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; each R e is independently selected from the group consisting of hydrogen and C 1 -C 4 -alkyl; each R f is independently selected from the group consisting of —C(═O)-phenyl and phenyl which is unsubstituted or substituted by 1, 2, or 3 radicals selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; each m is independently 1, 2, 3, 4, or 5; comprising reacting an ester compound (II) of formula (II-1) or (II-2) wherein R 1 and A are as defined above; and R 4 is selected from the group consisting of C 1 -C 30 -alkyl, C 6 -C 14 -aryl, and C 6 -C 14 -aryl-C 1 -C 4 -alkyl; with an amine of formula (III) wherein R 2 and R 3 are as defined above, in the presence of an alkali metal-containing base and a Lewis acid; where the reaction is carried out under anhydrous conditions, where a water content in the reaction mixture is at most 0.15% by weight, relative to a total weight of the reaction mixture.
  2. 2 . The method according to claim 1 , where 1, 2, 3, or 4 of the following conditions a), b), c), and/or e); or 1, 2, 3, or 4 of the following conditions a), b), d), and/or e) apply: a) R 1 is selected from the group consisting of C 1 -C 20 -alkyl, C 1 -C 4 -alkyl which carries 1 or 2 radicals R a , C 2 -C 20 -alkenyl, C 2 -C 4 -alkenyl which carries a phenyl ring, C 3 -C 6 -cycloalkyl which is unsubstituted or carries m radicals R b , C 6 -C 10 -aryl which is unsubstituted or carries m radicals R b , and a 5- to 10-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms selected from, N, O, and S as ring members, which is unsubstituted or carries m radicals R b ; where each R a is independently C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, C(═O)R c , or phenyl; and each R b is independently halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, and a 5- or 6-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms selected from, N, O, and S as ring members, which is unsubstituted or carries m radicals R d ; where each R d is independently selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; b) R 2 is selected from the group consisting of C 6 -C 10 -aryl which is unsubstituted or carries m radicals R b , and a 5- to 10-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring members, which is unsubstituted or carries m radicals R b ; where each R b is independently selected from the group consisting of halogen, cyano, hydroxyl, nitro, C(═O)NR e R f , C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, and phenyl which is unsubstituted or carries m radicals R d ; each R d is independently selected from the group consisting of halogen, C 1 -C 4 -alkyl, and C 1 -C 4 -haloalkyl; each R e is independently selected from the group consisting of hydrogen and C 1 -C 4 -alkyl; and each R f is independently selected from the group consisting of —C(═O)-phenyl and phenyl which is unsubstituted or substituted by 1, 2, or 3 radicals selected from the group consisting of halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; c) R 3 is hydrogen or C 1 -C 4 -alkyl; d) R 3 forms a linking group —(CH 2 ) 2 —, —(CH 2 ) 3 —, or —CH═CH— to a carbon or nitrogen ring atom of the aryl or heteroaromatic ring R 2 ; e) A is C 1 -C 8 -alkanediyl, C 2 -C 8 -alkenediyl, C 3 -C 6 -cycloalkanediyl, or phenylene.
  3. 3 . The method according to claim 1 , where R 1 is selected from the group consisting of C 1 -C 20 -alkyl, C 1 -C 4 -alkyl which carries a phenyl ring, C 2 -C 20 -alkenyl, C 2 -C 4 -alkenyl which carries a phenyl ring, C 6 -C 10 -aryl which is unsubstituted or carries m radicals R b , and a 5- to 10-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms selected from, N, O, and S as ring members, which is unsubstituted or carries m radicals R b ; where each R b is independently halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy.
  4. 4 . The method according to claim 3 , where R 1 is selected from the group consisting of C 1 -C 4 -alkyl which carries a phenyl ring, C 2 -C 20 -alkenyl, C 2 -C 4 -alkenyl which carries a phenyl ring, phenyl which is unsubstituted or carries m radicals R b , and a 5- or 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms selected from, N, O, and S as ring members, which is unsubstituted or carries m radicals R b ; where each R b is independently halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; and m is 1, 2, or 3.
  5. 5 . The method according to claim 4 , where R 1 is selected from the group consisting of C 1 -C 2 -alkyl which carries a phenyl ring, C 2 -C 20 -alkenyl, C 2 -alkenyl which carries a phenyl ring, phenyl which is unsubstituted or carries m radicals R b , and a 5- or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members, which is unsubstituted or carries m radicals R b ; where each R b is independently halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; and m is 1, 2, or 3.
  6. 6 . The method according to claim 1 , where R 2 is selected from the group consisting of C 6 -C 10 -aryl which is unsubstituted or carries m radicals R b , and a 5- to 10-membered heteroaromatic ring containing 1, 2, 3, or 4 heteroatoms selected from N, O, and S as ring members, which is unsubstituted or carries m radicals R b ; where each R b is independently selected from the group consisting halogen, cyano, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -haloalkoxy, and phenyl; and m is 1, 2, or 3.
  7. 7 . The method according to claim 6 , where R 2 is selected from the group consisting of phenyl which is unsubstituted or carries m radicals R b , and 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members, which is unsubstituted or carries m radicals R b ; where each R b is independently selected from the group consisting halogen, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, and phenyl; and m is 1, 2, or 3.
  8. 8 . The method according to claim 1 , where R 4 is selected from the group consisting of C 1 -C 4 -alkyl, phenyl, and benzyl.
  9. 9 . The method according to claim 1 , where R 1 is selected from the group consisting of C 1 -C 2 -alkyl which carries a phenyl ring, C 2 -C 20 -alkenyl, C 2 -alkenyl which carries a phenyl ring, phenyl which is unsubstituted or carries m radicals R b , and a 5- or 6-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members, which is unsubstituted or carries m radicals R b ; where each R b is independently halogen, cyano, C 1 -C 4 -alkyl, C 1 -C 4 -haloalkyl, C 1 -C 4 -alkoxy, and C 1 -C 4 -haloalkoxy; and m is 1, 2, or 3; R 2 is selected from the group consisting of phenyl which is unsubstituted or carries m radicals R b , and 6- to 10-membered heteroaromatic ring containing 1 or 2 nitrogen atoms as ring members, which is unsubstituted or carries m radicals R b ; where each R b is independently selected from the group consisting halogen, nitro, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, and phenyl; and m is 1, 2, or 3; R 3 is hydrogen or C 1 -C 4 -alkyl; or —NR 2 R 3 stands for 2,3-dihydroindol-1-yl, 1,2,3,4-tetrahydroquinolin-1-yl or indol-1-yl; A is C 1 -C 4 -alkanediyl; and R 4 is C 1 -C 4 -alkyl or phenyl.
  10. 10 . The method according to claim 1 , where the compound of formula (II-1) and the compound of formula (III) are used in a molar ratio of from 5:1 to 1:5, and the compound of formula (II-2) and the compound of formula (III) are used in a molar ratio of from 2.5:1 to 1:10.
  11. 11 . The method according to claim 1 , where the Lewis acid is selected from the group consisting of the halides, nitrates, carboxylates where the anion has a formula R—COO − , where R is C 1 -C 10 -alkyl, C 3 -C 6 -cycloalkyl, or C 3 -C 6 -cycloalkyl-C 1 -C 10 -alkyl; acetylacetonates, C 1 -C 4 -alkoxides, and carbonyl complexes of metals of groups 4, 6 to 10, 12, 13, or 15 of the periodic table of elements.
  12. 12 . The method according to claim 11 , where the Lewis acid is selected from the group consisting of the halides, the carboxylates where the anion has the formula R—COO − , where R is C 1 -C 4 -alkyl, the carboxylates where the anion has the formula R—COO − , where R is C 3 -C 6 -cycloalkyl-C 1 -C 10 -alkyl, the acetylacetonates, the C 1 -C 4 -alkoxides and the carbonyl complexes of Mn, Co, Zn or Bi.
  13. 13 . The method according to claim 11 , where the Lewis acid is selected from the group consisting of MnCl 2 , MoCl 3 , CrCl 3 , BiCl 3 , SbCl 3 , ZnCl 2 , FeCl 3 , FeCl 2 , CoCl 2 , NiCl 2 , TiCl 4 , ZrCl 4 , HfCl 4 , MnBr 2 , Mn(NO 3 ) 2 , Co(NO 3 ) 2 , Mn(OAc) 2 , Mn(4-cyclohexylbutyrat) 2 , Fe(OAc) 3 , Bi(OAc) 3 , Mn(AcAc) 2 , Mn(AcAc) 3 , Fe(AcAc) 2 , Fe(AcAc) 3 , Ni(AcAc) 2 , Bi(OiPr) 3 , Ti(OiPr) 4 , AI(OiPr) 3 , Mn 2 (CO) 10 , Mn(CO) 5 Br, Cr(CO) 6 , Fe(CO) 4 , and CO 2 (CO) 8 ; where OAc means acetate, AcAc means acetylacetonate and OiPr means isopropoxide.
  14. 14 . The method according to claim 13 , where the Lewis acid is selected from the group consisting of MnCl 2 , MnBr 2 , BiCl 3 , CoCl 2 , ZnCl 2 , Mn(OAc) 2 , Mn(AcAc) 2 , Mn(AcAc) 3 , Mn(4-cyclohexylbutyrat) 2 , Bi(OiPr) 3 , Mn(CO) 5 Br and Mn 2 (CO) 10 .
  15. 15 . The method according to claim 1 , where the Lewis acid is used in an amount of from 0.00001 to 0.2 mol.
  16. 16 . The method according to claim 15 , where the Lewis acid is used in an amount of from 0.001 to 0.01 mol per mol of compound (II) or (III) which is not used in excess.
  17. 17 . The method according to claim 1 , where the alkali metal-containing base is selected from the group consisting of alkali metal alkoxides, amides, hydrides, borohydrides and, aluminiumhydrides.
  18. 18 . The method according to claim 1 , where the alkali metal-containing base is used in an amount of from 0.00001 to 0.1 mol per mol of that compound (II) or (III) which is not used in excess.
  19. 19 . The method according to claim 1 , where the Lewis acid is selected from the group consisting of the halides, the carboxylates where the anion has the formula R—COO − , where R is C 1 -C 4 -alkyl, the carboxylates where the anion has the formula R—COO − , where R is C 3 -C 6 -cycloalkyl-C 1 -C 10 -alkyl, the acetylacetonates, the C 1 -C 4 -alkoxides, and the carbonyl complexes of Mn, Co, Zn, or Bi; and the alkali metal-containing base is selected from the group consisting of alkali metal C 1 -C 10 -alkoxides, alkali metal amides of the formula M + [N(R g ) 2 ] − , where M + is an alkali metal cation and R g is hydrogen, C 1 -C 4 -alkyl, or Si(C 1 -C 4 -alkyl) 2 ; and alkali metal borohydrides of the formula M + [BH(C 1 -C 4 -alkyl) 3 ] − , where M + is an alkali metal cation.
  20. 20 . The method according to claim 1 , where the water content in the reaction mixture is less than 0.1% by weight relative to the total weight of the reaction mixture.

Description

The present invention relates to a method for preparing of an amide of the formula (I-1) or a diamide of the formula (I-2) as defined below derived from an aromatic or heteroaromatic amine by reacting an ester with an aromatic or heteroaromatic amine in the presence of an alkali metal-containing base and a Lewis acid; where the reaction is carried out under essentially anhydrous conditions. TECHNICAL BACKGROUND Amide functional groups are ubiquitous in biological, pharmaceutical, agrochemical and natural products. Efficient synthesis routes to amides are therefore of high importance. Aromatic amides are of great interest especially as pharmaceuticals and pesticides and as precursors of such active ingredients. The fungicides boscalid, fluxapyroxad or bixafen are prominent representatives, to name just a few examples. They are generally synthesized from the corresponding acid chlorides and amines in combination with stochiometric amounts of a base, such as triethylamine, to form the corresponding amide bond in these target molecules in sufficiently high yields (see for example Green Chemistry, 2021, 23, 8169-8180). The acid chlorides are usually formed from the corresponding acid with a chlorination agent, such as thionylchloride, whereas the acid is usually made by hydrolysis of the ester (esters are more common synthetic intermediates than the corresponding acids). A drawback of this route to the amide is the three steps generally required—ester hydrolysis, acid chloride formation, amidation—, the use of chlorinating agents and the amount of waste formed. Other established routes to amides involve the reaction of the corresponding acid with an amine using an activating agent, such as HATU or EDC. The drawbacks of this route are similar to those mentioned above—two steps required and the formation of stoichiometric amounts of waste byproducts. Therefore, synthetic routes to amides via the direct reaction of esters with amines without the use of halogenating agents or other stoichiometric activating agents and in less steps is desirable. Moreover, there is a special need for efficient amidation routes starting from (hetero)aromatic amines, which, given their weaker nucleophility as compared to aliphatic amines, is still challenging. As explained above, (hetero)aromatic amide moieties are widespread in many pharmaceuticals and pesticides. During the last years, several synthetic methods for preparing amides via direct reaction of esters with (aromatic) amines have been suggested. H. Moromoto et al. describe in Organic Letters, 2014, 16, 2018-2021 the La(OTf)3 (OTf=CF3SO3) catalyzed amidation of esters with different amines. For aromatic amines, catalyst loadings of 2-5 mol-% of the lanthanum catalyst are necessary. Moreover, the amidation was only carried out with very electron-rich and activated aromatic amines, such as 4-methoxyaniline. This route is thus viable for a limited substrate scope only. Moreover, lanthanum catalysts are expensive, and their production, given that lanthanum is a rare earth metal, involves polluting and hazardous processes. B. D. Mkhonazi et al. describe in Molecules, 2020, 25, 1040-1048 Lewis acid (e.g. FeCl3, FeBr3, AlCl3, BiCl3) catalyzed amidations of esters with different amines. For aromatic amines, catalyst loadings of 15 mol % of FeCl3 were necessary and the amidation with aromatic amines worked only if ethyl 2-pyridine-carboxylate was used as ester, the 2-pyridyl group being essential for the activation of the catalyst. Also this route is thus viable for a limited substrate scope only. T. B. Halima et al. describe in Angewandte Chemie, International Edition, 2018, 57, 12925-12929 the direct amidation of esters with aromatic amines by using Ni(COD)2 (COD=1,5-cyclooctadiene) in combination with the N-heterocyclic carbene IPr (1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) as the catalyst. Optimal results were reported at a loading of 10 mol % of the Ni complex with 20 mol % of the N-heterocyclic carbene. The system works for a variety of anilines. A drawback of this system is the use of relative large amounts of the sensitive and expensive Ni(COD)2 as well as the N-heterocyclic carbene (NHC) ligand. W. I. Nicholson et al. describe in Angewandte Chemie, International Edition 2021, 60, 21686-21874 the direct amidation of esters with aromatic amines by using ball mill technology in the presence of an alkoxide base like KOtBu (potassium tert-butanolate) as a mediator. The system works for a variety of different anilines. Unfortunately, high yields can only be obtained when stochiometric amounts of the alkoxide base are used. Moreover, ball milling equipment is not universally available and the technology is so far not applicable in organic syntheses on industrial scale. R. Zhang et al. describe in Green Chemistry 2021, 23, 3972-3982 the solvent-free direct amidation of esters with aromatic amines using an alkoxide base like NaOtBu (sodium tert-butanolate) as a mediator. The s