Iron catalyzed cross-coupling reactions of imidoyl derivatives

• US 20070106074A1
• Filed: 10/17/2006
• Published: 05/10/2007
• Est. Priority Date: 10/17/2005
• Status: Abandoned Application

• Current Assignee: Acadia Pharmaceuticals Inc.
• Original Assignee: Acadia Pharmaceuticals Inc.
• Inventors: Olsson, Roger, Ek, Fredrik, Ottesen, Lars
• Application Number:
  US11/582,729
• Publication Number:
  US 20070106074A1
• Time in Patent Office: Days
• US Class Current: 540/547
• CPC Class Codes: C07B 37/04 Substitution
• CPC Class Codes: C07D 243/38 [b, e]- or [b, f]-condensed with six-membered rings
• CPC Class Codes: C07D 267/20 [b, f]-condensed
• CPC Class Codes: C07D 281/16 [b, f]-condensed
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

Disclosed is a process for preparing a compound of formula A-N═C(D)(B), from a compound of formula A-N═C(E)(B) and a compound of formula D-M using an iron catalyst, where the process has is represented by Equation (I)

Claims

1. A process for preparing a compound of formula A-N═

C(D)(B), from a compound of formula A-N═

C(E)(B) and a compound of formula D-M using an iron catalyst, where the process is represented by Equation (I)

Wherein;

A and B are independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, —

C(=Z)R₁, —

C(=Z)OR₁, —

C(=Z)NR_1aR_1b, —

C(R₁)═

NR_1a, —

NR_1aR_1b, —

N═

CR_1aR_1b, —

N(R₁)—

C(=Z)R₁, —

N(R₁)—

C(=Z)NR_1aR_1b, —

S(O)NR_1aR_1b, —

S(O)₂NR_1aR_1b, —

N(R₁)—

S(═

O)R₁, —

N(R₁)—

S(═

O)₂R₁, —

OR₁, —

SR₁, and —

OC(=Z)R₁, or A and B taken together, along with the nitrogen atom to which A is attached and the carbon atom to which B is attached, form a ring;

E is selected from the group consisting of halide, sulfonate (—

OSO₃R₂), and phosphonate (—

OP(O)(OR_2a)(OR_2b));

D is selected from group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl;

M is selected from the group consisting of MgY, CaY, ZnY, MnY, and Mg derived metal reagents formed from reaction of MgY and other metal salts, such as Cu(CN)MgCl and Mn(Cl₂)MgCl;

Y is an anionic ligand

R₁, R_1a and R_1b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl;

R₂, R_2a and R_2b are independently selected from the group consisting of haloalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl; and

Z is O (oxygen) or S (sulfur).

2. The process of claim 1, wherein iron catalyst is selected from the group consisting of finely dispersed metallic iron, FeF₂, FeF₂ 4H₂O, FeF₃ H₂O, FeCl₂, FeCl₂ 4H₂O, FeCl₃, FeCl₃ 6H₂O, FeCl₃(PPh₃), Fe(OEt)₂, Fe(OEt)₃, FeCl₂(PPh₃)₂, FeCl₂(dppe) [dppe=1,2-bis-(diphenylphosphino)ethane], Fe(acac)₂ [acac=acetylacetonate], Fe(acac)₃, tris-(trifluoroacetylacetonato)iron (III), tris-(hexafluoroacetylacetonato)iron (III), tris-(dibenzoylmethido)iron (III), tris-(2,2,6,6-tetramethyl-3,5-diheptanedionate)iron (III), FeBr₂, FeBr₃, FeI₂, Fe(II)acetate, Fe(II)oxalate, Fe(II)stearate, Fe(III)citrate hydrate, Fe(III)pivalate, Fe(II)-D-gluconate 2 H₂O, Fe(OSO₂C₆H₄Me)₃, Fe(OSO₂C₆H₄Me)₃ hydrate, FePO₄, Fe(NO₃)₃, Fe(NO₃)₃ 9 H₂O, Fe(ClO₄)₃ hydrate, FeSO₄, FeSO₄ hydrate, Fe₂(SO₄)₃, Fe₂(SO₄)₃ hydrate, K₃Fe(CN)₆, ferrocene, bis(pentamethylcyclopentadienyl)iron, bis(indenyl)iron, Fe(II)phtalocyanin, Fe(III)phtalocyanin chloride, Fe(CO)₅, Fe(salen)X [salen=N,N-ethylenebis(salicylidenamidato), X=Cl, Br, I], 5,10,15,20-tetraphenyl-21H,23H-porphin-iron(III) halide, 5,10,15,20-tetrakis(pentafluorophenyl)-21H,23H-porphin-iron(III) halide, activated Fe, and iron-magnesium intermetallic compounds.

3. The process of claim 1, in which said organometallic reagent D-M is a Grignard reagent, wherein

D is selected from group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl;

and

M is MgY, wherein Y is fluoride, chloride, bromide, iodide.

7. The process of claim 1 or claim 4, wherein said process is performed in a reaction medium containing one or more solvents selected from the group consisting of ethereal, hydrocarbon, aprotic dipolar, and protic.

8. The process of claim 7, in which said ethereal solvent or hydrocarbon solvent is selected from the group consisting of diethyl ether, tetrahydrofuran, tetrahydropyran, methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, dibutyl ether, di-isopropyl ether, dimethoxyethane, dimethoxymethane, pentane, hexane, heptane, octane, isooctane, cyclohexane, benzene, toluene, xylene, cymene, petrol ether, and decaline.

9. The process of claim 7, wherein said aprotic dipolar solvent is selected from the group consisting of dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidinone (NMP);

tetramethylurea, sulfolane, diethyl carbonate, 1,3-ethylphosphoric acid triamide (HMPA), N,N,N′

,N′

-tetramethylethylenediamine (TMEDA).

10. The process of claim 7, wherein said cross coupling reaction is performed in a reaction medium containing one or more ethereal or hydrocarbon solvents selected from the group consisting of diethyl ether, tetrahydrofuran, tetrahydropyran, methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, dibutyl ether, di-isopropyl ether, dimethoxyethane, dimethoxymethane, pentane, hexane, heptane, octane, isooctane, cyclohexane, benzene, toluene, xylene, cymene, petrol ether, decaline, as well as one or aprotic dipolar solvent chosen from:

dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidinone (NMP);

tetramethylurea, sulfolane, diethyl carbonate, 1,3-ethylphosphoric acid triamide (HMPA), and N,N,N′

,N′

-tetramethylethylenediamine (TMEDA).

11. The process of claim 7, wherein said protic dipolar solvent is selected from the group consisting of water, ethanol, methanol, tert-butanol, isopropanol, and acetic acid

12. The process of claim 7, wherein said cross coupling reaction is performed in a reaction medium containing one or more ethereal or hydrocarbon solvents, selected from the group consisting of diethyl ether, tetrahydrofuran, tetrahydropyran, methyl-tetrahydrofuran, 1,4-dioxane, tert-butyl methyl ether, dibutyl ether, di-isopropyl ether, dimethoxyethane, dimethoxymethane, pentane, hexane, heptane, octane, isooctane, cyclohexane, benzene, toluene, xylene, cymene, petrol ether, decaline, as well as one or aprotic dipolar solvent chosen from:

dimethylformamide, dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidinone (NMP);

tetramethylurea, sulfolane, diethyl carbonate, 1,3-ethylphosphoric acid triamide (HMPA), N,N,N′

,N′

-tetramethylethylenediamine (TMEDA) and/or as well as one or protic dipolar solvent chosen from;

water, ethanol, methanol, tert-butanol, isopropanol, and acetic acid.

13. The process of claim 1 or claim 4, in which said process is performed in a microwave reactor.

4. A process for preparing a compound of Formula IV as shown in Equation 2:

wherein;

C is selected from the group consisting of halide, sulfonate (—

OSO₃R₂), and phosphonate (—

OP(O)(OR_2a)(OR_2b));

D is selected from group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl;

M is MgY;

Y is an anionic ligand;

Q is selected from the group consisting of NR₁, N⁺—

O⁻

, O, S, S═

O, O═

S═

O, CR₁R₂, C═

O, and SiR₁R₂;

E, F, G, H, I, J and L are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, nitro, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, —

CN, —

C(=Z)R₁, —

C(=Z)OR₁, —

C(=Z)NR_1aR_1b, —

C(R₁)═

NR_1a, —

NR_1aR_1b, —

N═

CR_1aR_1b, —

N(R₁)—

C(=Z)R₁, —

N(R₁)—

C(=Z)NR_1aR_1b, —

S(O)NR_1aR_1b, —

S(O)₂NR_1aR_1b, —

N(R₁)—

S(═

O)R₁, —

N(R₁)—

S(═

O)₂R₁, —

OR₁, —

SR₁, and —

OC(=Z)R₁;

K is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, —

CN, —

C(=Z)R₁, —

C(=Z)OR₁, —

C(=Z)NR_1aR_1b, —

C(=Z)N(R₁)NR_1aR_1b, —

C(R₁)═

NR_1a, —

NR_1aR_1b, —

N═

CR_1aR_1b, —

N(R₁)—

C(=Z)R₁, —

N(R₁)—

C(=Z)NR_1aR_1b, —

S(O)NR_1aR_1b, —

S(O)₂NR_1aR_1b, —

N(R₁)—

S(═

O)R₁, —

N(R₁)—

S(═

O)₂R₁, —

OR₁, —

SR₁, and —

OC(=Z)R₁;

R₁, R_1a and R_1b are independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl;

R₂, R_2a and R_2b are independently selected from the group consisting of;

haloalkyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl; and

Z is O (oxygen) or S (sulfur).

5. The process of claim 4, wherein iron catalyst is selected from the group consisting of finely dispersed metallic iron, FeF₂, FeF₂ 4H₂O, FeF₃ H₂O, FeCl₂, FeCl₂ 4H₂O, FeCl₃, FeCl₃ 6H₂O, FeCl₃(PPh₃), Fe(OEt)₂, Fe(OEt)₃, FeCl₂(PPh₃)₂, FeCl₂(dppe) [dppe=1,2-bis-(diphenylphosphino)ethane], Fe(acac)₂ [acac=acetylacetonate], Fe(acac)₃, tris-(trifluoroacetylacetonato)iron (III), tris-(hexafluoroacetylacetonato)iron (III), tris-(dibenzoylmethido)iron (III), tris-(2,2,6,6-tetramethyl-3,5-diheptanedionate)iron (III), FeBr₂, FeBr₃, FeI₂, Fe(II)acetate, Fe(II)oxalate, Fe(II)stearate, Fe(III)citrate hydrate, Fe(III)pivalate, Fe(II)-D-gluconate 2 H₂O, Fe(OSO₂C₆H₄Me)₃, Fe(OSO₂C₆H₄Me)₃ hydrate, FePO₄, Fe(NO₃)₃, Fe(NO₃)₃ 9 H₂O, Fe(ClO₄)₃ hydrate, FeSO₄, FeSO₄ hydrate, Fe₂(SO₄)₃, Fe₂(SO₄)₃ hydrate, K₃Fe(CN)₆, ferrocene, bis(pentamethylcyclopentadienyl)iron, bis(indenyl)iron, Fe(II)phtalocyanin, Fe(III)phtalocyanin chloride, Fe(CO)₅, Fe(salen)X [salen=N,N-ethylenebis(salicylidenamidato), X=Cl, Br, I], 5,10,15,20-tetraphenyl-21H,23H-porphin-iron(III) halide, 5,10,15,20-tetrakis(pentafluorophenyl)-21H,23H-porphin-iron(III) halide, activated Fe, and iron-magnesium intermetallic compounds.

6. The process of claim 4, in which said organometallic reagent D-M is a Grignard reagent, wherein

D is selected from group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroalicyclyl;

and

M is MgY, wherein Y is fluoride, chloride, bromide, iodide.