# US 10,865,163 B2 · Carbon dioxide as a directing group for C—H functionalization reactions involving Lewis basic amines, alcohols, thiols, and phosphines for the synthesis of compounds

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- Number: US 10,865,163 B2
- Document ID: US10865163B2
- Status: Granted
- Kind: B2
- Application number: 16/223,467
- Filed: 2018-12-18
- Published: 2019-06-20
- Granted: 2020-12-15
- Earliest claimed: 2017-12-20
- Assignees: The University of Toledo
- Applicants: The University of Toledo
- Inventors: Michael C. Young; Mohit Kapoor
- Web page: https://patentgrep.com/patent/US10865163B2

## CPC

- C07B 37/02: Addition
- C07B 37/04: Substitution
- C07B 43/00: Formation or introduction of functional groups containing nitrogen
- C07B 47/00: Formation or introduction of functional groups not provided for in groups C07B39/00 - C07B45/00
- C07C 209/68: from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
- C07C 211/08: containing alkyl groups having a different number of carbon atoms
- C07C 211/52: the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
- C07C 213/08: by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
- C07C 227/16: by reactions not involving the amino or carboxyl groups
- C07C 231/12: by reactions not involving the formation of carboxamide groups
- C07D 209/08: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
- C07D 311/76: Benzo[c]pyrans
- B01J 31/04: containing carboxylic acids or their salts {(B01J31/0277 - B01J31/0298 take precedence; multi-metal carboxylate complexes like Pd (II) acetate, i.e. Pd3 (OAc) 6 or Cr(II)acetate, i.e. Cr2(OAc)4 B01J31/2226)}
- B01J 31/4038: {containing noble metals}
- B01J 2231/42: Catalytic cross-coupling, i.e. connection of previously not connected C-atoms or C- and X-atoms without rearrangement
- B01J 2231/46: C-H or C-C activation
- B01J 2531/17: Silver
- B01J 2531/824: Palladium
- C07B 51/00: Introduction of protecting groups or activating groups, not provided for in the preceding groups
- C07C 2601/08: the ring being saturated
- C07C 2601/14: The ring being saturated
- C07C 2601/18: with a ring being at least seven-membered
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS

## Abstract

Methods of synthesizing compounds using CO2 as a directing group for C—H functionalization, and compounds made thereby, are described.

## Claims

### Claim 1

A method of functionalizing a C—H bond, the method comprising using CO2 as a directing group to convert a C—H bond in a substrate compound into a C—C bond by reacting the substrate compound with an aryl halide in the presence of a transition metal catalyst and CO2 as a gas or a solid, wherein the substrate compound comprises a primary or secondary amine functional group and the C—H bond is in a gamma position relative to the amine functional group.

### Claim 2 (depends on 1)

The method of claim 1, wherein the transition metal catalyst comprises palladium.

### Claim 3 (depends on 1)

The method of claim 1, wherein the amine is a primary amine.

### Claim 4 (depends on 3)

The method of claim 3, wherein the primary amine is selected from the group consisting of: 1-ethylcyclopentan-1-amine (S-1), 1-ethylcyclohexan-1-amine (S-2), 1-ethylcycloheptan-1-amine (S-3), 4-(tert-butyl)-1-ethylcyclohexan-1-amine (S-4), 9-ethyl-9H-fluoren-9-amine (S-5), 3-methylheptan-3-amine (S-6), 3-methylnon-3-amine (S-7), 3-methylpentan-3-amine (S-8), 3-ethylpentan-3-amine (S-9), and heptan-3-amine (5-10).

### Claim 5 (depends on 1)

The method of claim 1, wherein the amine is a secondary amine.

### Claim 6 (depends on 5)

The method of claim 5, wherein the secondary amine is selected from the group consisting of: N-(tert-pentyl)propan-1-amine (5-12), N-(tert-pentyl)butan-1-amine (5-13), N-(tert-pentyl)pentan-1-amine (5-14), 2-methyl-N-phenethylbutan-2-amine (S-15), N-benzyl-2-methylbutan-2-amine (S-16), N-(4-methoxybenzyl)-2-methylbutan-2-amine (5-17), N-(3-methoxybenzyl)-2-methylbutan-2-amine (5-18), N-(4-tolyl)-2-methylbutan-2-amine (5-19), N-(3-tolyl)-2-methylbutan-2-amine (S-20), and N-propylpentan-2-amine (S-22).

### Claim 7 (depends on 1)

The method of claim 1, wherein the amine is 6-ethyl-3,3,9,9-tetraisopropyl-2,10-dimethyl-4,8-dioxa-3,9-disilaundecan-6-amine (5-11).

### Claim 8 (depends on 1)

The method of claim 1, wherein the aryl halide comprises an iodoaromatic compound.

### Claim 9 (depends on 8)

The method of claim 8, wherein the iodoaromatic compound is selected from the group consisting of: phenyl iodide, 3-iodoisocoumarin (S-23), 5-iodo-1-tosyl-1H-indole (S-24), 1-ethoxy-4-iodobenzene (S-25), and 1-benzyloxy-4-iodobenzene (S-26).

### Claim 10 (depends on 8)

The method of claim 8, wherein the aryl halide comprises a heterocycle.

### Claim 11 (depends on 1)

The method of claim 1, wherein the amine is a benzylamine.

### Claim 12 (depends on 1)

The method of claim 1, wherein the amine is an allylamine.

### Claim 13

A method of synthesizing a compound, the method comprising:
reacting a substrate having a primary or secondary amine functional group with a reactant in the presence of CO2 as a gas or a solid and a transition metal catalyst to produce a compound,
wherein the substrate is functionalized at a γ-C—H position relative to the primary or secondary amine functional group to produce the compound, and
wherein the reactant is an aryl halide.

### Claim 14 (depends on 13)

The method of claim 13, wherein the compound is a γ-arylated primary amine.

### Claim 15 (depends on 13)

The method of claim 13, wherein the compound is 2-methyl-4-phenylbutan-2-amine (1a), 4-(3-fluorophenyl)-2-methylbutan-2-amine (1b), 4-(4-fluorophenyl)-2-methylbutan-2-amine (1c), 2-methyl-4-[3-(trifluoromethyl)phenyl]butan-2-amine (1d), 2-methyl-4-[4-(trifluoromethyl)phenyl]butan-2-amine (1e), ethyl 2-(3-amino-3-methylbutyl)benzoate (1f), ethyl 3-(3-amino-3-methylbutyl)benzoate (1g), ethyl 4-(3-amino-3-methylbutyl)benzoate (1h), 2-methyl-4-(3-nitrophenyl)butan-2-amine (1i), 2-methyl-4-(4-nitrophenyl)butan-2-amine (1j), 4-[3,5-bis(trifluoromethyl)phenyl]-2-methylbutan-2-amine (1k), dimethyl 5-(3-amino-3-methylbutyl)isophthalate (1l), 4-(3-chloro-4-fluorophenyl)-2-methylbutan-2-amine (1m), 4-(4-bromophenyl)-2-methylbutan-2-amine (1n), 4-(4-iodophenyl)-2-methylbutan-2-amine (1o), 7-(3-amino-3-methylbutyl)-3,4-diphenyl-1H-isochromen-1-one (1p), 2-methyl-4-(N-tosyl-1H-indol-5-yl)butan-2-amine (1q), 4-(3-methoxyphenyl)-2-methylbutan-2-amine (1r), 4-(4-methoxyphenyl)-2-methylbutan-2-amine (1s), 4-(4-ethoxyphenyl)-2-methylbutan-2-amine (it), 4-(4-benzyloxyphenyl)-2-methylbutan-2-amine (1u), 2-methyl-4-(m-tolyl)butan-2-amine (1v), 2-methyl-4-(p-tolyl)butan-2-amine (1w), 4-(1,1′-biphenyl-4-yl)-2-methylbutan-2-amine (1x), 2-methyl-4-(naphthalen-1-yl)butan-2-amine (1y), 4-(2-fluorophenyl)-2-methylbutan-2-amine (1z), 2-(3-amino-3-methylbutyl)phenol (1aa), 4-(2-methoxyphenyl)-2-methylbutan-2-amine (1ab), 4,4′-(1,4-phenylene)bis(2-methylbutan-2-amine) (1ac), 1-phenethylcyclopentanamine (2a), 1-phenethylcyclohexanamine (2b), 1-phenethylcycloheptanamine (2c), 4-(tert-butyl)-1-phenethylcyclohexanamine (2d), 9-phenethyl-9H-fluoren-9-amine (2e), 3-methyl-1-phenylheptan-3-amine (2f), 3-methyl-1-phenylnonan-3-amine (2g), 2-amino-2-phenethylpropane-1,3-diol (2h), 3-methyl-1-phenylpentan-3-amine (2i-mono), 3-methyl-1,5-diphenylpentan-3-amine (2i-di), 3-ethyl-1-phenylpentan-3-amine (2j-mono), 3-ethyl-1,5-diphenylpentan-3-amine (2j-di), 4-(1,1′-biphenyl-4-yl)butan-2-amine (2k), 1-(1,1′-biphenyl-4-yl)pentan-3-amine (21), 1-(1,1′-biphenyl-4-yl)heptan-3-amine (2m), or 4-(1,1′-biphenyl-4-yl)-3,3-dimethylbutan-2-amine (2n).

### Claim 16 (depends on 13)

The method of claim 13, wherein the compound is a γ-arylated secondary amine.

### Claim 17 (depends on 16)

The method of claim 16, wherein the γ-arylated secondary amine is selected from the group consisting of: 4-(1,1′-biphenyl-4-yl)-2-methyl-N-propylbutan-2-amine (3a), N-[4-(1,1′-biphenyl-4-yl)-2-methylbutan-2-yl]butan-1-amine (3b), N-[4-(1,1′-biphenyl-4-yl)-2-methylbutan-2-yl]pentan-1-amine (3c), 2-methyl-N-phenethyl-4-phenylbutan-2-amine (3d), N-benzyl-2-methyl-4-phenylbutan-2-amine (3e), N-(4-methoxybenzyl)-2-methyl-4-phenylbutan-2-amine (3f), N-(3-methoxybenzyl)-2-methyl-4-phenylbutan-2-amine (3g), 2-methyl-N-(4-methylbenzyl)-4-phenylbutan-2-amine (3h), 2-methyl-N-(3-methylbenzyl)-4-phenylbutan-2-amine (3i), 2-methyl-N-(naphthalen-2-ylmethyl)-4-phenylbutan-2-amine (3j), ethyl 4-(3-(benzylamino)-3-methylbutyl)benzoate (3k), and 1-(1,1′-biphenyl-4-yl)-N-propylpentan-3-amine (3l).

### Claim 18

A method of functionalizing a C—H bond, the method comprising using CO2 as a directing group to convert a C—H bond in a substrate compound into a C—C bond in the presence of a transition metal catalyst, wherein the substrate compound comprises a primary or secondary amine functional group, and the substrate compound is functionalized at a gamma C—H position relative to the primary or secondary amine functional group,
wherein the substrate compound is selected from the group consisting of: 1-ethylcyclopentan-1-amine (S-1), 1-ethylcyclohexan-1-amine (S-2), 1-ethylcycloheptan-1-amine (S-3), 4-(tert-butyl)-1-ethylcyclohexan-1-amine (S-4), 9-ethyl-9H-fluoren-9-amine (S-5), 3-methylheptan-3-amine (S-6), 3-methylnon-3-amine (S-7), 3-methylpentan-3-amine (S-8), 3-ethylpentan-3-amine (S-9), heptan-3-amine (S-10), N-(tert-pentyl)propan-1-amine (S-12), N-(tert-pentyl)butan-1-amine (S-13), N-(tert-pentyl)pentan-1-amine (S-14), 2-methyl-N-phenethylbutan-2-amine (S-15), N-benzyl-2-methylbutan-2-amine (S-16), N-(4-methoxybenzyl)-2-methylbutan-2-amine (S-17), N-(3-methoxybenzyl)-2-methylbutan-2-amine (S-18), N-(4-tolyl)-2-methylbutan-2-amine (S-19), N-(3-tolyl)-2-methylbutan-2-amine (S-20), N-propylpentan-2-amine (S-22), and 6-ethyl-3,3,9,9-tetraisopropyl-2,10-dimethyl-4,8-dioxa-3,9-disilaundecan-6-amine (S-11).

### Claim 19

A method of synthesizing a compound, the method comprising:
reacting a substrate having a primary or secondary amine functional group with a reactant in the presence of CO2 and a transition metal catalyst to produce a compound, wherein the substrate is functionalized at a γ-C—H position relative to the amine functional group to produce the compound, and
wherein the compound is a γ-arylated primary amine or a γ-arylated secondary amine selected from the group consisting of: 2-methyl-4-phenylbutan-2-amine (1a), 4-(3-fluorophenyl)-2-methylbutan-2-amine (1b), 4-(4-fluorophenyl)-2-methylbutan-2-amine (1c), 2-methyl-4-[3-(trifluoromethyl)phenyl]butan-2-amine (1d), 2-methyl-4-[4-(trifluoromethyl)phenyl]butan-2-amine (1e), ethyl 2-(3-amino-3-methylbutyl)benzoate (1f), ethyl 3-(3-amino-3-methylbutyl)benzoate (1g), ethyl 4-(3-amino-3-methylbutyl)benzoate (1h), 2-methyl-4-(3-nitrophenyl)butan-2-amine (1i), 2-methyl-4-(4-nitrophenyl)butan-2-amine (1j), 4-[3,5-bis(trifluoromethyl)phenyl]-2-methylbutan-2-amine (1k), dimethyl 5-(3-amino-3-methylbutyl)isophthalate (1l), 4-(3-chloro-4-fluorophenyl)-2-methylbutan-2-amine (1m), 4-(4-bromophenyl)-2-methylbutan-2-amine (1n), 4-(4-iodophenyl)-2-methylbutan-2-amine (1o), 7-(3-amino-3-methylbutyl)-3,4-diphenyl-1H-isochromen-1-one (1p), 2-methyl-4-(N-tosyl-1H-indol-5-yl)butan-2-amine (1q), 4-(3-methoxyphenyl)-2-methylbutan-2-amine (1r), 4-(4-methoxyphenyl)-2-methylbutan-2-amine (1s), 4-(4-ethoxyphenyl)-2-methylbutan-2-amine (1t), 4-(4-benzyloxyphenyl)-2-methylbutan-2-amine (1u), 2-methyl-4-(m-tolyl)butan-2-amine (1v), 2-methyl-4-(p-tolyl)butan-2-amine (1w), 4-(1,1′-biphenyl-4-yl)-2-methylbutan-2-amine (1x), 2-methyl-4-(naphthalen-1-yl)butan-2-amine (1y), 4-(2-fluorophenyl)-2-methylbutan-2-amine (1z), 2-(3-amino-3-methylbutyl)phenol (1aa), 4-(2-methoxyphenyl)-2-methylbutan-2-amine (1ab), 4,4′-(1,4-phenylene)bis(2-methylbutan-2-amine) (1ac), 1-phenethylcyclopentanamine (2a), 1-phenethylcyclohexanamine (2b), 1-phenethylcycloheptanamine (2c), 4-(tert-butyl)-1-phenethylcyclohexanamine (2d), 9-phenethyl-9H-fluoren-9-amine (2e), 3-methyl-1-phenylheptan-3-amine (2f), 3-methyl-1-phenylnonan-3-amine (2g), 2-amino-2-phenethylpropane-1,3-diol (2h), 3-methyl-1-phenylpentan-3-amine (2i-mono), 3-methyl-1,5-diphenylpentan-3-amine (2i-di), 3-ethyl-1-phenylpentan-3-amine (2j-mono), 3-ethyl-1,5-diphenylpentan-3-amine (2j-di), 4-(1,1′-biphenyl-4-yl)butan-2-amine (2k), 1-(1,1′-biphenyl-4-yl)pentan-3-amine (21), 1-(1,1′-biphenyl-4-yl)heptan-3-amine (2m), 4-(1,1′-biphenyl-4-yl)-3,3-dimethylbutan-2-amine (2n), 4-(1,1′-biphenyl-4-yl)-2-methyl-N-propylbutan-2-amine (3a), N-[4-(1,1′-biphenyl-4-yl)-2-methylbutan-2-yl]butan-1-amine (3b), N-[4-(1,1′-biphenyl-4-yl)-2-methylbutan-2-yl]pentan-1-amine (3c), 2-methyl-N-phenethyl-4-phenylbutan-2-amine (3d), N-benzyl-2-methyl-4-phenylbutan-2-amine (3e), N-(4-methoxybenzyl)-2-methyl-4-phenylbutan-2-amine (3f), N-(3-methoxybenzyl)-2-methyl-4-phenylbutan-2-amine (3g), 2-methyl-N-(4-methylbenzyl)-4-phenylbutan-2-amine (3h), 2-methyl-N-(3-methylbenzyl)-4-phenylbutan-2-amine (3i), 2-methyl-N-(naphthalen-2-ylmethyl)-4-phenylbutan-2-amine (3j), ethyl 4-(3-(benzylamino)-3-methylbutyl)benzoate (3k), and 1-(1,1′-biphenyl-4-yl)-N-propylpentan-3-amine (3l).