# US 8,785,480 B2 · Functionalized pyridine N-oxides and processes for the preparation of the same

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- Number: US 8,785,480 B2
- Document ID: US8785480B2
- Status: Granted
- Kind: B2
- Application number: 13/917,030
- Filed: 2013-06-13
- Published: 2014-01-02
- Granted: 2014-07-22
- Earliest claimed: 2012-06-30
- Assignees: Dow AgroSciences LLC
- Applicants: Dow AgroSciences LLC
- Inventors: Douglas C. Bland; Ronald Ross, Jr.; Peter L. Johnson; Timothy C. Johnson
- Web page: https://patentgrep.com/patent/US8785480B2

## CPC

- C07D 213/89: with hetero atoms directly attached to the ring nitrogen atom
- C07D 409/04: directly linked by a ring-member-to-ring-member bond
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

In one embodiment, processes for the preparation of certain functionalized pyridine N-oxides are provided. In one form, the functionalized pyridine N-oxides include 2-substituted-5-(1-alkylthio)alkyl-pyridine N-oxides. Further embodiments, forms, objects, features, advantages, aspects, and benefits shall become apparent from the description.

## Claims

### Claim 1

A process for the preparation of a 2-substituted-5-(1-alkylthio)alkyl-pyridine N-oxide according to formula (I),
wherein
L represents a single bond or R1, S and L taken together represent a 4-, 5- or 6-membered ring;
R1 represents (C1-C4) alkyl;
R2 and R3 individually represent hydrogen, methyl, ethyl, fluoro, chloro or bromo;
n is an integer from 0-3; and
Y represents (C1-C4) haloalkyl;
in which:
i) an enamine according to formula (II)
wherein
R1, R2, R3, L, and n are as previously defined, and R4 and R5 independently represent C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl or R4 and R5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring is condensed with an α,β-unsaturated ketone according to formula (III)
wherein
Y is as previously defined; and
X1 represents halogen, OR6, OSO2R6, SR6, SOR6, SO2R6 or NR7R8, where R6 represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl, and R7 and R8 independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl or R7 and R8 taken together with N represent a 5- or 6-membered saturated or unsaturated ring;
to provide an intermediate compound according to formula (IV)
wherein
R1, R2, R3, R4, R5, L and n are as previously defined; and
ii) the intermediate compound according to formula (IV) is cyclized using an amine nucleophile according to formula (V)
H2N—X2 (V)
wherein X2 represents hydroxyl.

### Claim 2 (depends on 1)

The process of claim 1, wherein cyclization of the intermediate compound according to formula (IV) is performed under refluxing conditions.

### Claim 3 (depends on 2)

The process of claim 2, wherein the refluxing conditions include a temperature in the range of 50° C. to 90° C.

### Claim 4 (depends on 1)

The process of claim 1, wherein the amine nucleophile is hydroxylamine.

### Claim 5 (depends on 4)

The process of claim 4, wherein the hydroxylamine is in the form hydroxylamine hydrochloride.

### Claim 6 (depends on 5)

The process of claim 5, wherein the cyclization further includes using a non-nucleophilic base.

### Claim 7 (depends on 6)

The process of claim 6, wherein the non-nucleophilic base is triethylamine.

### Claim 8 (depends on 1)

The process of claim of claim 1, wherein the enamine according to formula (II) is condensed with the α,β-unsaturated ketone according to formula (III) at a temperature from −20° C. to 35° C.

### Claim 9 (depends on 1)

The process of claim 1, wherein the enamine according to formula (II) is condensed with the α,β-unsaturated ketone according to formula (III) at a temperature from −5° C. to 20° C.

### Claim 10 (depends on 1)

The process of claim 1, where the enamine according to formula (II) is condensed with the α,β-unsaturated ketone according to formula (III) in a non-polar solvent.

### Claim 11 (depends on 10)

The process of claim 10, wherein the non-polar solvent is toluene.

### Claim 12 (depends on 1)

The process of claim 1, wherein Y is CF3.

### Claim 13 (depends on 1)

The process of claim 1, wherein R2 and R3 independently represent hydrogen, methyl or ethyl.

### Claim 14 (depends on 1)

The process of claim 1, wherein R2, R3, n, and Y are as previously defined, R1 represents CH3, L represents a single bond and the compound of formula (I) has the structure
wherein n=1-3.

### Claim 15 (depends on 14)

The process of claim 14, wherein Y represents (C1-C4) haloalkyl, R2 and R3 individually represent hydrogen, methyl, ethyl, fluoro, chloro or bromo, and n is an integer from 1-3.

### Claim 16 (depends on 15)

The process of claim 15, wherein Y represents CF3, R2 and R3 individually represent hydrogen, methyl or ethyl, and n is an integer from 1-3.

### Claim 17 (depends on 1)

The process of claim 1, which further includes the preparation of a compound according to formula (VI)
wherein
R1, R2, R3, L, n and Y are as previously defined;
X3 is optional and represents O when present;
X4 represents NNO2, NCN, NCOOR9 or NCONH2; and
R9 represents (C1-C3) alkyl;
in which:
a compound according to formula (I) is reacted with one or more reactants suitable for the addition of X4 and optionally X3.

### Claim 18

A process for the preparation of a compound according to formula (VI)
wherein
L represents a single bond or R1, S and L taken together represent a 4-, 5- or 6-membered ring;
R1 represents (C1-C4) alkyl;
R2 and R3 individually represent hydrogen, methyl, ethyl, fluoro, chloro or bromo;
n is an integer from 0-3; and
Y represents (C1-C4) haloalkyl;
X3 is optional and represents O when present;
X4 represents NNO2, NCN, NCOOR9 or NCONH2; and
R9 represents (C1-C3) alkyl;
in which:
a compound according to formula (I)
wherein R1, R2, R3, L, n and Y are as previously defined is reacted with one or more reactants suitable for the addition of X4 and optionally X3.

### Claim 19

A process for the preparation of a 2-substituted-5-(1-alkylthio)alkyl-pyridine N-oxide according to formula (I),
wherein
L represents a single bond or R1, S and L taken together represent a 4-, 5- or 6-membered ring;
R1 represents (C1-C4) alkyl;
R2 and R3 individually represent hydrogen, methyl, ethyl, fluoro, chloro or bromo;
n is an integer from 0-3; and
Y represents (C1-C4) haloalkyl;
in which a compound according to formula (IV)
wherein Y, R1, R2, R3, R4, R5, L and n are as previously defined is cyclized using an amine nucleophile according to formula (V)
H2N—X2 (V),
wherein X2 represents hydroxyl.

### Claim 20 (depends on 19)

The process of claim 19, in which:
an enamine according to formula (II)
wherein
R1, R2, R3, L, and n are as previously defined, and
R4 and R5 independently represent C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl or R4 and R5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring;
is condensed with an α,β-unsaturated ketone according to formula (III)
wherein
Y is as previously defined; and
X1 represents halogen, OR6, OSO2R6, SR6, SORE, SO2R6 or NR7R8, where R6 represents hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl, and R7 and R8 independently represent hydrogen, C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl or R7 and R8 taken together with N represent a 5- or 6-membered saturated or unsaturated ring to provide the compound according to formula (IV).

### Claim 21 (depends on 19)

The process of claim 19, in which:
an acetyl chloride compound according to formula (VII)
wherein Y represents C1-C4 haloalkyl is reacted with an alkyl vinyl ether according to formula (VIII)
wherein R10 represents C1-C4 alkyl to provide an intermediate compound according to formula (IX)
and the intermediate compound according to formula (IX) is condensed with an enamine according to formula (II)
wherein
R1, R2, R3, L, and n are as previously defined, and
R4 and R5 independently represent C1-C8 alkyl, C2-C8 alkenyl, C1-C8 arylalkyl, C1-C8 haloalkyl, C1-C8 alkoxyalkyl, C1-C8 alkylaminoalkyl, aryl or heteroaryl or R4 and R5 taken together with N represent a 5- or 6-membered saturated or unsaturated ring to provide the compound according to formula (IV).