DECARBOXYLATION OF AMINO ACIDS

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63/199,386, filed December 22, 2020, which is incorporated herein by reference in its entirety.

FIELD OF THE DISCLOSURE

[0002] The present disclosure relates to methods and systems for decarboxylation of amino acids. In particular, such methods and systems can employ an organocatalyst to provide favorable reaction conditions.

BACKGROUND

[0003] Chemical transformation of amino acids can provide useful bio-based starting materials. Yet such transformations can include difficult reaction conditions, such as high temperatures, long reaction times, and use of expensive catalysts.

SUMMARY

[0004] The present disclosure relates to methods for decarboxylating an amino acid to provide the corresponding amine. In particular embodiments, the methods herein provide high yield with reproducible synthetic results.

[0005] In a first aspect, the present disclosure encompasses a method of decarboxylating an amino acid, the method including: combining an amino acid, a solvent, and a catalyst in a vessel to provide a reaction mixture; and promoting formation of an ammonium carbamate salt of an amine to recover the catalyst within the reaction mixture. In particular embodiments, the amine is a decarboxylated form of the amino acid, and the ammonium carbamate salt is a reaction product produced between the amine and in situ generated carbon dioxide.

[0006] In some embodiments, the solvent includes a polar solvent, the catalyst includes a ketone or an aldehyde, and the vessel is an open vessel. In particular, said promoting can include dissolution of the ammonium carbamate salt of the amine within the polar solvent.

[0007] In other embodiments, the solvent includes a hydrocarbon solvent, the catalyst includes an aromatic ketone, and the vessel is a sealed vessel. In particular, said promoting can include dissolution of the in situ generated carbon dioxide within the hydrocarbon solvent.

[0008] In some embodiments, said promoting further includes: bubbling carbon dioxide into the reaction mixture, thereby facilitating formation of the ammonium carbamate salt of the amine. In other embodiments, the method further includes (e.g., after said promoting): isolating the amine or the ammonium carbamate salt of the amine. In some embodiments, said isolating includes distilling the reaction mixture, thereby removing the solvent and isolating the amine as a distillate. In other embodiments, said isolating includes precipitating the ammonium carbamate salt of the amine from the reaction mixture, thereby isolating the ammonium carbamate salt of the amine as a precipitate. Precipitating can include, e.g., cooling the reaction mixture.

[0009] In some embodiments, the method further includes (e.g., after said promoting or isolating): decomposing the precipitate, thereby releasing carbon dioxide and regenerating the amine. Decomposing can include, e.g., heating the precipitate.

[0010] In a second aspect, the present disclosure encompasses a method of decarboxylating an amino acid, the method including: combining an amino acid, a polar solvent, and a catalyst in an open vessel to provide a reaction mixture; and heating the reaction mixture to a temperature of about 150°C or greater, thereby decarboxylating the amino acid to form an amine. In some embodiments, said heating includes a temperature from about 150°C to 190°C, 150°C to 180°C, or 155°C to 180°C.

[0011] In some embodiments, the polar solvent includes a lower boiling point than the amine. In particular embodiments, the polar solvent includes a secondary alcohol. In further embodiments, the catalyst includes a ketone, an aromatic ketone, an unsaturated ketone, an a,P-unsaturated ketone, an a,P-unsaturated cyclic ketone, a ketone lacking an a-hydrogen, an aldehyde, or an aromatic aldehyde.

[0012] In a third aspect, the present disclosure encompasses a method of decarboxylating an amino acid, the method including: combining an amino acid, a hydrocarbon solvent, and a catalyst in a sealed vessel to provide a reaction mixture; and heating the reaction mixture to a temperature of about 150°C or greater, thereby decarboxylating the amino acid to form an amine. In some embodiments, said heating includes a temperature from about 150°C to 190°C, 150°C to 180°C, or 155°C to 180°C. [0013] In some embodiments, the hydrocarbon solvent includes an optionally substituted aromatic. In particular embodiments, the catalyst includes a ketone lacking an a-hydrogen or an aromatic ketone. [0014] In some embodiments (e.g., of any methods herein), the method further includes (e.g., during or after said heating): bubbling carbon dioxide into the reaction mixture, thereby facilitating formation of an ammonium carbamate salt of the amine. In other embodiments, the method further includes (e.g., after said heating): distilling the reaction mixture, thereby removing the solvent and/or the catalyst and isolating the amine as a distillate. In yet other embodiments, the method further includes (e.g., after said heating): precipitating an ammonium carbamate salt of the amine from the reaction mixture, thereby isolating the ammonium carbamate salt of the amine as a precipitate; filtering the reaction mixture to separate the precipitate and remove the solvent and/or the catalyst; and decomposing the precipitate, thereby releasing carbon dioxide and regenerating the amine.

[0015] In some embodiments (e.g., of any methods herein), the method further includes (e.g., after said distilling or said filtering): recycling the removed solvent and/or removed catalyst by delivery to the vessel to provide a further reaction mixture. In other embodiments (e.g., of any methods herein), the method further includes (e.g., after said isolating): recycling the component of the reaction mixture by delivery to the vessel to provide a further reaction mixture.

[0016] In some embodiments (e.g., of any methods herein), the method further includes (e.g., after said heating): isolating the amine or an ammonium carbamate salt of the amine. Isolating can include, e.g., vacuum distilling, precipitating, decomposing, filtering, and/or evaporating the reaction mixture or a component thereof.

[0017] In a fourth aspect, the present disclosure encompasses a system including: a reactor and a distillation unit.

[0018] In some embodiments, the reactor includes a vacuum rated vessel having an inlet, a first outlet, and a second outlet, wherein the inlet is configured to receive an amino acid, a solvent, and a catalyst to provide a reaction mixture within the vessel. In particular embodiments, the reactor is configured to promote formation of an ammonium carbamate salt of an amine to recover the catalyst within the reaction mixture, in which the amine is a decarboxylated form of the amino acid, and in which the ammonium carbamate salt is a reaction product produced between the amine and in situ generated carbon dioxide. In further embodiments, the first outlet is configured to convey the in situ generated carbon dioxide out of the vessel; and the second outlet is configured to convey the reaction mixture. [0019] In some embodiments, the distillation unit includes an inlet, a first outlet, a second outlet, and a third outlet, wherein the inlet of the distillation unit is configured to receive the reaction mixture by way of the second outlet of the reactor. In particular embodiments, the distillation unit is configured to distill the reaction mixture to separate the solvent, catalyst, unreacted amino acid, and amine. In further embodiments, the first outlet is configured to convey the separated solvent to the reactor; the second outlet is configured to convey the separated catalyst and the unreacted amino acid to the reactor; and the third outlet is configured to convey the amine and/or the ammonium carbamate salt of the amine to a receptable.

[0020] In some embodiments, the solvent includes a polar solvent, the catalyst includes a ketone or an aldehyde, and the vessel is an open vessel. In other embodiments, the solvent includes a hydrocarbon solvent, the catalyst includes an aromatic ketone, and the vessel is a sealed vessel.

[0021] In some embodiments, the system further includes: one or more controllers configured to cause the reactor to promote formation of the ammonium carbamate salt of the amine. In particular embodiments, the one or more controllers is configured to perform any method described herein.

[0022] In a fifth aspect, the present disclosure encompasses a system including: a first reactor, a bubbler, a separation unit, a second reaction, and an evaporation unit. [0023] In some embodiments, the first reactor includes a vessel having an inlet, a first outlet, and a second outlet, wherein the inlet is configured to receive an amino acid, a first solvent, and a catalyst to provide a reaction mixture within the vessel. In particular embodiments, the first reactor is configured to promote formation of an ammonium carbamate salt of an amine to recover the catalyst within the reaction mixture, in which the amine is a decarboxylated form of the amino acid, and in which the ammonium carbamate salt is a reaction product produced between the amine and in situ generated carbon dioxide. In further embodiments, the first outlet is configured to convey the in situ generated carbon dioxide out of the vessel; and the second outlet is configured to convey the reaction mixture.

[0024] In some embodiments, the bubbler is configured to deliver carbon dioxide to the first reactor, thereby promoting formation of the ammonium carbamate salt of the amine in the reaction mixture.

[0025] In some embodiments, the separation unit includes an inlet, a first outlet, and a second outlet, wherein the inlet of the separation unit is configured to receive the reaction mixture by way of the second outlet of the reactor. In particular embodiments, the separation unit is configured to form a precipitate including the ammonium carbamate salt of the amine and to filter the precipitate from the reaction mixture. In further embodiments, the first outlet is configured to convey the filtered catalyst and/or filtered solvent to the reactor; and the second outlet is configured to convey the precipitate.

[0026] In some embodiments, the second reactor includes a vessel having an inlet, a first outlet, and a second outlet, wherein the inlet is configured to receive the precipitate from the second outlet of the separation unit. In particular embodiments, the second reactor is configured to decompose the precipitate to the amine in the presence of a second solvent. In particular embodiments, the first outlet is configured convey in situ generated carbon dioxide out of the vessel; and the second outlet is configured to convey the amine and the second solvent.

[0027] In some embodiments, the evaporation unit includes a vessel having an inlet, a first outlet, and a second outlet, wherein the inlet is configured to receive the amine and the second solvent from the second reactor. In particular embodiments, the evaporation unit is configured to evaporate the second solvent. In further embodiments, the first outlet is configured to convey the evaporated solvent out of the vessel; and the second outlet is configured to convey the amine to a receptacle.

[0028] In some embodiments, the solvent includes a polar solvent, the catalyst includes a ketone or an aldehyde, and the vessel of the first reactor is an open vessel. In other embodiments, the solvent includes a hydrocarbon solvent, the catalyst includes an aromatic ketone, and the vessel is a sealed vessel.

[0029] In some embodiments, the system further includes: one or more controllers configured to cause the reactor to promote formation of the ammonium carbamate salt of the amine. In particular embodiments, the one or more controllers is configured to perform any method described herein.

[0030] In any embodiment herein, the reaction mixture is maintained at a temperature of about 150°C to 190°C, 150°C to 180°C, or 155°C to 180°C.

[0031] In any embodiment herein, the solvent is a hydrocarbon solvent, a non-protic solvent, a polar solvent, or a secondary alcohol solvent.

[0032] In any embodiment herein, the catalyst is a ketone, an aromatic ketone, an unsaturated ketone, an a,P-unsaturated ketone, an a,P-unsaturated cyclic ketone, a ketone lacking an a-hydrogen, an aldehyde, or an aromatic aldehyde. In some embodiments, the catalyst is an aromatic ketone, an a,p-unsaturated ketone, a a,p-unsaturated cyclic ketone, or an aromatic aldehyde. In particular embodiments, the catalyst is present at a concentration of about 0.5 mol.% to about 10 mol.%.

[0033] In any embodiment herein, a yield of the amine is greater than about 70%, 80%, 85%, 90%, or more or a yield from about 60% to 99.99% (e.g., from 60% to 99%, 70% to 99%, 80% to 99%, 85% to 99%, 90% to 99%, or 95% to 99%).

[0034] Additional details follow.

Definitions

[0035] The term “acyl,” or “alkanoyl,” as used interchangeably herein, represents an alkyl group, as defined herein, or hydrogen attached to the parent molecular group through a carbonyl group, as defined herein. This group is exemplified by formyl, acetyl, propionyl, butanoyl, and the like. The alkanoyl group can be substituted or unsubstituted. For example, the alkanoyl group can be substituted with one or more substitution groups, as described herein for alkyl. In some embodiments, the unsubstituted acyl group is a C2-7 acyl or alkanoyl group. In particular embodiments, the alkanoyl group is -C(O)-Ak, in which Ak is an alkyl group, as defined herein.

[0036] By “aliphatic” is meant a hydrocarbon group having at least one carbon atom to 50 carbon atoms (C1-50), such as one to 25 carbon atoms (C1-25), or one to ten carbon atoms (Ci- 10), and which includes alkanes (or alkyl), alkenes (or alkenyl), alkynes (or alkynyl), including cyclic versions thereof, and further including straight- and branched- chain arrangements, and all stereo and position isomers as well. Such an aliphatic can be unsubstituted or substituted with one or more groups, such as groups described herein for an alkyl group.

[0037] By “alkaryl” or “alkylaryl” is meant an alkyl group, as defined herein, attached to the parent molecular group through an arylene group, as defined herein. In some embodiments, the alkaryl group is -Ar-Ak, in which Ar is an optionally substituted arylene, as defined herein, and Ak is an optionally substituted alkyl, as defined herein. The alkaryl group can be substituted or unsubstituted. For example, the alkaryl group can be substituted with one or more substitution groups, as described herein for alkyl and/or aryl. Exemplary unsubstituted alkaryl groups are of from 7 to 16 carbons (C7-16 alkaryl), as well as those having an alkyl group with 1 to 6 carbons and an arylene group with 4 to 18 carbons (i.e., (C1-6 alkyl)C4-is aryl). [0038] By “alkenyl is meant an optionally substituted C2-24 alkyl group having one or more double bonds. The alkenyl group can be cyclic (e.g., C3-24 cycloalkenyl) or acyclic. The alkenyl group can also be substituted or unsubstituted. For example, the alkenyl group can be substituted with one or more substitution groups, as described herein for alkyl. Exemplary alkenyl groups include, e.g., vinyl (-CH=CH2), vinylidene (e.g., =C=CH2), ethylidene (e.g., =CH-CH3), allyl (-CH2-CH=CH2), 1-propenyl (-CH=CH-CH ₃ ), methylallyl (-CH ₂ -C(CH ₃ )=CH ₂ ), allylidene (e.g., =CH-CH=CH ₂ ), homoallyl (e.g., -CH2-CH ₂ -CH=CH ₂ ), 1-butenyl (-CH=CH-CH ₂ -CH ₃ ), 2-butenyl (-CH ₂ - CH=CH-CH3), 3-methyl-2-butenyl or prenyl (-CH2-CH=C(CH3)2), 3-butenyl (-CH2- CH2-CH=CH2), 4-methyl-3 -pentenyl (-CH2-CH2-CH=C(CH3)2), and the like.

[0039] By “alkoxy” is meant an -O-Ak group, in which Ak is an alkyl group, as defined herein.

[0040] By “alkoxycarbonyl“ is meant -C(O)-OAk, in which Ak is an alkyl group, as described herein. In some embodiments, an unsubstituted alkoxycarbonyl group is a C2-7 alkoxycarbonyl group.

[0041] By “alkyl” and the prefix “alk” is meant a branched or unbranched saturated hydrocarbon group of 1 to 24 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s-pentyl, neopentyl, hexyl, heptyl, octyl, nonyl, decyl, dodecyl, tetradecyl, hexadecyl, eicosyl, tetracosyl, and the like. The alkyl group can be cyclic (e.g., C3-24 cycloalkyl) or acyclic. The alkyl group can be branched or unbranched. The alkyl group can also be substituted or unsubstituted. For example, the alkyl group can be substituted with one, two, three or, in the case of alkyl groups of two carbons or more, four substituents independently selected from the group consisting of: (1) C1-6 alkoxy (e.g., -O-Ak, wherein Ak is optionally substituted C1-6 alkyl); (2) C1-6 alkylsulfinyl (e.g., -S(O)-Ak, wherein Ak is optionally substituted C1-6 alkyl); (3) C1-6 alkylsulfonyl (e.g., -SO2-Ak, wherein Ak is optionally substituted C1-6 alkyl); (4) amino (e.g., -NR ^N1 R ^N2 , where each of R ^N1 and R ^N2 is, independently, H or optionally substituted alkyl, or R ^N1 and R ^N2 , taken together with the nitrogen atom to which each are attached, form a heterocyclyl group); (5) aryl; (6) hydroxyaryl (e.g., -Ar- OH, wherein Ar is a bivalent form of optionally substituted aryl group); (7) arylalkoxy (e.g., -O-L-Ar, wherein L is a bivalent form of optionally substituted alkyl and Ar is optionally substituted aryl); (8) aryloyl (e.g., -C(O)-Ar, wherein Ar is optionally substituted aryl); (9) azido (e.g., -N3); (10) cyano (e.g., -CN); (11) guanidino;

(12) carboxyaldehyde (e.g., -C(O)H); (13) C3-8 cycloalkyl (e.g., a monovalent saturated or unsaturated non-aromatic cyclic C3-8 hydrocarbon group); (14) halo (e.g., F, Cl, Br, or I); (15) heterocyclyl (e.g., a 5-, 6- or 7-membered ring, unless otherwise specified, containing one, two, three, or four non-carbon heteroatoms, such as nitrogen, oxygen, phosphorous, sulfur, or halo, such as indolyl, imidazolyl, or any described herein);

(16) heterocyclyloxy (e.g., -O-Het, wherein Het is heterocyclyl, as described herein);

(17) heterocyclyloyl (e.g., -C(O)-Het, wherein Het is heterocyclyl, as described herein);

(18) hydroxyl (e.g., -OH); (19) N-protected amino; (20) nitro (e.g., -NO2); (21) oxo (e.g., =0); (22) C3-8 spirocyclyl (e.g., an alkylene or heteroalkylene diradical, both ends of which are bonded to the same carbon atom of the parent group); (23) C1-6 thioalkoxy (e.g., -S-Ak, wherein Ak is optionally substituted C1-6 alkyl); (24) thiol (e.g., -SH); (25) C1-6 selenoalkoxy (e.g., -Se-Ak, wherein Ak is optionally substituted C1-6 alkyl); (26) - CO2R ^A , where R ^A is selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C4-18 aryl, and (d) (C4-18 aryl) C1-6 alkyl (e.g., -L-Ar, wherein L is a bivalent form of optionally substituted alkyl group and Ar is optionally substituted aryl);

(27) -C(O)NR ^B R ^C , where each of R ^B and R ^c is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C4-18 aryl, and (d) (C4-18 aryl) C1-6 alkyl (e.g., -L-Ar, wherein L is a bivalent form of optionally substituted alkyl group and Ar is optionally substituted aryl); (28) -SChR ⁰ , where R ^D is selected from the group consisting of (a) C1-6 alkyl, (b) C4-18 aryl, and (c) (C4-18 aryl) C1-6 alkyl (e.g., -L-Ar, wherein L is a bivalent form of optionally substituted alkyl group and Ar is optionally substituted aryl); (29) -SO2NR ^E R ^F , where each of R ^E and R ^E is, independently, selected from the group consisting of (a) hydrogen, (b) C1-6 alkyl, (c) C4-18 aryl, and (d) (C4-18 aryl) C1-6 alkyl (e.g., -L-Ar, wherein L is a bivalent form of optionally substituted alkyl group and Ar is optionally substituted aryl); and (30) -NR ^G R ^H , where each of R ^G and R ^H is, independently, selected from the group consisting of (a) hydrogen, (b) an N-protecting group, (c) C1-6 alkyl, (d) C2-6 alkenyl (e.g., optionally substituted alkyl having one or more double bonds), (e) C2-6 alkynyl (e.g., optionally substituted alkyl having one or more triple bonds), (f) C4-18 aryl, (g) (C4-18 aryl) C1-6 alkyl (e.g., L-Ar, wherein L is a bivalent form of optionally substituted alkyl group and Ar is optionally substituted aryl), (h) C3-8 cycloalkyl, and (i) (C3-8 cycloalkyl) C1-6 alkyl (e.g., -L-Cy, wherein L is a bivalent form of optionally substituted alkyl group and Cy is optionally substituted cycloalkyl, as described herein), wherein in one embodiment no two groups are bound to the nitrogen atom through a carbonyl group or a sulfonyl group. The alkyl group can be a primary, secondary, or tertiary alkyl group substituted with one or more substituents (e.g., one or more halo or alkoxy). In some embodiments, the unsubstituted alkyl group is a Cl-3, Cl-6, Cl-12, Cl-16, Cl-18, Cl-20, Cl-24, C2-3, C2-6, C2-12, C2-I6, C2-I8, C2-20, C2-24, C3-6, C3-12, C3-16, C3-18, C3-20, C3-24, C4-6, C4-12, C4-16, C4-18, C4-20, C4-24, C5-6, C5-12, C5-16, C5-18, C5-20, C5-24, C6-12, Ce-i6, Ce-i8, C6-20, Ce-24, C7-12, C7-16, C7-18, C7-20, C7-24, Cs-i2, Cs-i6, Cs-is, Cs-20, Cs-24, C9-12, C9-16, C9-18, C9-20, C9-24, Cio-12, C10-16, Cio-18, C10-20, or Ci-24 alkyl group.

[0042] By “alkylene“ is meant a multivalent (e.g., bivalent) form of an alkyl group, as described herein. Exemplary alkylene groups include methylene, ethylene, propylene, butylene, etc. In some embodiments, the alkylene group is a C1-3, C1-6, C1-12, C1-16, Ci-is, Ci-20, Ci-24, C2-3, C2-6, C2-12, C2-16, C2-18, C2-20, or C2-24 alkylene group. The alkylene group can be branched or unbranched. The alkylene group can also be substituted or unsubstituted. For example, the alkylene group can be substituted with one or more substitution groups, as described herein for alkyl.

[0043] By “alkynyl” is meant an optionally substituted C2-24 alkyl group having one or more triple bonds. The alkynyl group can be cyclic or acyclic and is exemplified by ethynyl, 1-propynyl, and the like. The alkynyl group can also be substituted or unsubstituted. For example, the alkynyl group can be substituted with one or more substitution groups, as described herein for alkyl.

[0044] By “amino” is meant -NR ^N1 R ^N2 , where each of R ^N1 and R ^N2 is, independently, H, optionally substituted alkyl, or optionally substituted aryl, or R ^N1 and R ^N2 , taken together with the nitrogen atom to which each are attached, form a heterocyclyl group, as defined herein.

[0045] By “aminoalkyl” is meant an alkyl group, as defined herein, substituted by an amino group, as defined herein. Non-limiting aminoalkyl groups include -E-NR ^N1 R ^N2 , where E is a multivalent alkyl group, as defined herein; each of R ^N1 and R ^N2 is, independently, H, optionally substituted alkyl, or optionally substituted aryl; or R ^N1 and R ^N2 , taken together with the nitrogen atom to which each are attached, form a heterocyclyl group, as defined herein.

[0046] By “aralkyl” or “arylalkyl” is meant an aryl group, as defined herein, attached to the parent molecular group through an alkylene group, as defined herein. In some embodiments, the aralkyl group is -Ak-Ar, in which Ak is an optionally substituted alkylene, as defined herein, and Ar is an optionally substituted aryl, as defined herein. The aralkyl group can be substituted or unsubstituted. For example, the aralkyl group can be substituted with one or more substitution groups, as described herein for aryl and/or alkyl. Exemplary unsubstituted aralkyl groups are of from 7 to 16 carbons (C7-16 aralkyl), as well as those having an aryl group with 4 to 18 carbons and an alkylene group with 1 to 6 carbons (i.e., (C4-18 aryl)Ci-6 alkyl).

[0047] By ‘ ‘aromatic” is meant a cyclic, conjugated group or moiety of, unless specified otherwise, from 5 to 15 ring atoms having a single ring (e.g., phenyl) or multiple condensed rings in which at least one ring is aromatic (e.g., naphthyl, indolyl, or pyrazolopyridinyl); that is, at least one ring, and optionally multiple condensed rings, have a continuous, delocalized ^-electron system. Typically, the number of out of plane ^-electrons corresponds to the Huckel rule (4n+2). The point of attachment to the parent structure typically is through an aromatic portion of the condensed ring system. Such an aromatic can be unsubstituted or substituted with one or more groups, such as groups described herein for an alkyl or aryl group. Yet other substitution groups can include aliphatic, haloaliphatic, halo, nitrate, cyano, sulfonate, sulfonyl, or others.

[0048] By “aryl” is meant a group that contains any carbon-based aromatic group including, but not limited to, phenyl, benzyl, anthracenyl, anthryl, benzocyclobutenyl, benzocyclooctenyl, biphenylyl, chrysenyl, dihydroindenyl, fluoranthenyl, indacenyl, indenyl, naphthyl, phenanthryl, phenoxybenzyl, picenyl, pyrenyl, terphenyl, and the like, including fused benzo-C4-8 cycloalkyl radicals (e.g., as defined herein) such as, for instance, indanyl, tetrahydronaphthyl, fluorenyl, and the like. The term aryl also includes heteroaryl, which is defined as a group that contains an aromatic group that has at least one heteroatom incorporated within the ring of the aromatic group. Examples of heteroatoms include, but are not limited to, nitrogen, oxygen, sulfur, and phosphorus. Likewise, the term non-heteroaryl, which is also included in the term aryl, defines a group that contains an aromatic group that does not contain a heteroatom. The aryl group can be substituted or unsubstituted. The aryl group can be substituted with one, two, three, four, or five substituents described herein for alkyl.

[0049] By “arylene” is meant a multivalent (e.g., bivalent) form of an aryl group, as described herein. Exemplary arylene groups include phenylene, naphthylene, biphenylene, triphenylene, diphenyl ether, acenaphthenylene, anthrylene, or phenanthrylene. In some embodiments, the arylene group is a C4-18, C4-14, C4-12, C4-10, Ce-18, Ce-14, C6-12, or Ce-io arylene group. The arylene group can be branched or unbranched. The arylene group can also be substituted or unsubstituted. For example, the arylene group can be substituted with one or more substitution groups, as described herein for aryl. [0050] By “aryloxy is meant -OAr, where Ar is an optionally substituted aryl group, as described herein. In some embodiments, an unsubstituted aryloxy group is a C4-18 or Ce-i8 aryloxy group.

[0051] By “aryloxycarbonyl“ is meant -C(O)-OAr, in which Ar is an aryl group, as described herein. In some embodiments, an unsubstituted aryloxycarbonyl group is a C5- 18 or C7-19 aryloxycarbonyl group.

[0052] By “aryloyl” is meant -C(O)-Ar, where Ar is an optionally substituted aryl group, as described herein. In some embodiments, an unsubstituted aryloyl group is a C7-11 aryloyl or C5-19 aryloyl group.

[0053] By “carbocycle” is meant a compound having one or more cyclic aliphatic moieties. Non-limiting carbocycles include aromatic and non-aromatic compounds, such as cyclopentane, cyclohexane, cyclohexene, decalin, benzene, fluorene, naphthalene, acenaphthene, anthracene, phenanthrene, etc. The carbocycle can also be substituted or unsubstituted. For example, the carbocycle can be substituted with one or more groups including those described herein for alkyl. Exemplary carbocycle groups include C5-16 carbocycle.

[0054] By “carboxyl” is meant a -CO2H group.

[0055] By “cycloalkyl” is meant a monovalent saturated or unsaturated non-aromatic cyclic hydrocarbon group of from three to eight carbons, unless otherwise specified, and is exemplified by cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo[2.2.1.]heptyl, and the like. The cycloalkyl group can also be substituted or unsubstituted. For example, the cycloalkyl group can be substituted with one or more groups including those described herein for alkyl. Exemplary cycloalkyl groups include C3-6 cycloalkyl and C3-8 cycloalkyl.

[0056] By “cycloalkenyl” is meant a non-aromatic carbon-based ring composed of three to ten carbon atoms and containing at least one double bound, i.e., C=C. Examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, and the like.

[0057] By “halo” is meant F, Cl, Br, or I.

[0058] By “heteroaliphatic” is meant an aliphatic group, as defined herein, including at least one heteroatom to 20 heteroatoms, such as one to 15 heteroatoms, or one to 5 heteroatoms, which can be selected from, but not limited to oxygen, nitrogen, sulfur, silicon, boron, selenium, phosphorous, and oxidized forms thereof within the group. [0059] By ‘ ‘heteroaromatic is meant an aromatic group, as defined herein, containing one, two, three, or four non-carbon heteroatoms (e.g., independently selected from the group consisting of oxygen, nitrogen, sulfur, silicon, boron, selenium, phosphorous, and oxidized forms thereof).

[0060] By “heterocycle” is meant a compound having one or more heterocyclyl moieties. Non-limiting heterocycles include pyridine, piperidine, pyridazine, pyrimidine, pyrazine, triazine, pyrrole, pyrrolidine, pyrroline, pyrazole, imidazole, triazole, indole, indoline, indene, isoindole, benzimidazole, purine, etc. The heterocycle can also be substituted or unsubstituted. For example, the heterocycle can be substituted with one or more groups including those described herein for alkyl. Exemplary heterocycles can include any heterocyclyl groups described herein.

[0061] By “heterocyclyl” is meant a 3-, 4-, 5-, 6- or 7-membered ring (e.g., a 5-, 6-, or 7-membered ring), unless otherwise specified, containing one, two, three, or four noncarbon heteroatoms (e.g., independently selected from the group consisting of nitrogen, oxygen, phosphorous, sulfur, selenium, or halo). The 3-membered ring has zero to one double bonds, the 4- and 5-membered ring has zero to two double bonds, and the 6- and 7-membered rings have zero to three double bonds. The term “heterocyclyl” also includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocyclic rings is fused to one, two, or three rings independently selected from the group consisting of an aryl ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring, and another monocyclic heterocyclic ring, such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl and the like. Heterocyclics include acridinyl, adenyl, alloxazinyl, azaadamantanyl, azabenzimidazolyl, azabicyclononyl, azacycloheptyl, azacyclooctyl, azacyclononyl, azahypoxanthinyl, azaindazolyl, azaindolyl, azecinyl, azepanyl, azepinyl, azetidinyl, azetyl, aziridinyl, azirinyl, azocanyl, azocinyl, azonanyl, benzimidazolyl, benzisothiazolyl, benzisoxazolyl, benzodiazepinyl, benzodiazocinyl, benzodihydrofuryl, benzodioxepinyl, benzodioxinyl, benzodioxanyl, benzodioxocinyl, benzodioxolyl, benzodithiepinyl, benzodithiinyl, benzodioxocinyl, benzofuranyl, benzophenazinyl, benzopyranonyl, benzopyranyl, benzopyrenyl, benzopyronyl, benzoquinolinyl, benzoquinolizinyl, benzothiadiazepinyl, benzothiadiazolyl, benzothiazepinyl, benzothiazocinyl, benzothiazolyl, benzothienyl, benzothiophenyl, benzothiazinonyl, benzothiazinyl, benzothiopyranyl, benzo thiopyronyl, benzotriazepinyl, benzotriazinonyl, benzotriazinyl, benzotriazolyl, benzoxathiinyl, benzotrioxepinyl, benzoxadiazepinyl, benzoxathiazepinyl, benzoxathiepinyl, benzoxathiocinyl, benzoxazepinyl, benzoxazinyl, benzoxazocinyl, benzoxazolinonyl, benzoxazolinyl, benzoxazolyl, benzylsultamyl benzylsultimyl, bipyrazinyl, bipyridinyl, carbazolyl (e.g., 4H-carbazolyl), carbolinyl (e.g., P-carbolinyl), chromanonyl, chromanyl, chromenyl, cinnolinyl, coumarinyl, cytdinyl, cytosinyl, decahydroisoquinolinyl, decahydroquinolinyl, diazabicyclooctyl, diazetyl, diaziridinethionyl, diaziridinonyl, diaziridinyl, diazirinyl, dibenzisoquinolinyl, dibenzoacridinyl, dibenzocarbazolyl, dibenzofuranyl, dibenzophenazinyl, dibenzopyranonyl, dibenzopyronyl (xanthonyl), dibenzoquinoxalinyl, dibenzothiazepinyl, dibenzothiepinyl, dibenzothiophenyl, dibenzoxepinyl, dihydroazepinyl, dihydroazetyl, dihydrofuranyl, dihydrofuryl, dihydroisoquinolinyl, dihydropyranyl, dihydropyridinyl, dihydroypyridyl, dihydroquinolinyl, dihydrothienyl, dihydroindolyl, dioxanyl, dioxazinyl, dioxindolyl, dioxiranyl, dioxenyl, dioxinyl, dioxobenzofuranyl, dioxolyl, dioxotetrahydrofuranyl, dioxothiomorpholinyl, dithianyl, dithiazolyl, dithienyl, dithiinyl, furanyl, furazanyl, furoyl, furyl, guaninyl, homopiperazinyl, homopiperidinyl, hypoxanthinyl, hydantoinyl, imidazolidinyl, imidazolinyl, imidazolyl, indazolyl (e.g., IH-indazolyl), indolenyl, indolinyl, indolizinyl, indolyl (e.g., IH-indolyl or 3H-indolyl), isatinyl, isatyl, isobenzofuranyl, isochromanyl, isochromenyl, isoindazoyl, isoindolinyl, isoindolyl, isopyrazolonyl, isopyrazolyl, isoxazolidiniyl, isoxazolyl, isoquinolinyl, isoquinolinyl, isothiazolidinyl, isothiazolyl, morpholinyl, naphthindazolyl, naphthindolyl, naphthiridinyl, naphthopyranyl, naphthothiazolyl, naphthothioxolyl, naphthotriazolyl, naphthoxindolyl, naphthyridinyl, octahydroisoquinolinyl, oxabicycloheptyl, oxauracil, oxadiazolyl, oxazinyl, oxaziridinyl, oxazolidinyl, oxazolidonyl, oxazolinyl, oxazolonyl, oxazolyl, oxepanyl, oxetanonyl, oxetanyl, oxetyl, oxtenayl, oxindolyl, oxiranyl, oxobenzoisothiazolyl, oxochromenyl, oxoisoquinolinyl, oxoquinolinyl, oxothiolanyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, phenothienyl (benzothiofuranyl), phenoxathiinyl, phenoxazinyl, phthalazinyl, phthalazonyl, phthalidyl, phthalimidinyl, piperazinyl, piperidinyl, piperidonyl (e.g., 4-piperidonyl), pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl, pyrazolopyrimidinyl, pyrazolyl, pyridazinyl, pyridinyl, pyridopyrazinyl, pyridopyrimidinyl, pyridyl, pyrimidinyl, pyrimidyl, pyronyl, pyrrolidinyl, pyrrolidonyl (e.g., 2-pyrrolidonyl), pyrrolinyl, pyrrolizidinyl, pyrrolyl (e.g., 2H-pyrrolyl), quinazolinyl, quinolinyl, quinolizinyl (e.g., 4H-quinolizinyl), quinoxalinyl, quinuclidinyl, selenazinyl, selenazolyl, selenophenyl, succinimidyl, sulfolanyl, tetrahydrofuranyl, tetrahydrofuryl, tetrahydroisoquinolinyl, tetrahydroisoquinolyl, tetrahydropyndinyl, tetrahydropyridyl (pipendyl), tetrahydropyranyl, tetrahydropyronyl, tetrahydroquinolinyl, tetrahydroquinolyl, tetrahydrothienyl, tetrahydrothiophenyl, tetrazinyl, tetrazolyl, thiadiazinyl (e.g., 6H-l,2,5-thiadiazinyl or 2H,6H-1,5,2- dithiazinyl), thiadiazolyl, thianthrenyl, thianyl, thianaphthenyl, thiazepinyl, thiazinyl, thiazolidinedionyl, thiazolidinyl, thiazolyl, thienyl, thiepanyl, thiepinyl, thietanyl, thietyl, thiiranyl, thiocanyl, thiochromanonyl, thiochromanyl, thiochromenyl, thiodiazinyl, thiodiazolyl, thioindoxyl, thiomorpholinyl, thiophenyl, thiopyranyl, thiopyronyl, thiotriazolyl, thiourazolyl, thioxanyl, thioxolyl, thymidinyl, thyminyl, triazinyl, triazolyl, trithianyl, urazinyl, urazolyl, uretidinyl, uretinyl, uricyl, uridinyl, xanthenyl, xanthinyl, xanthionyl, and the like, as well as modified forms thereof (e.g., including one or more oxo and/or amino), and salts thereof. The heterocyclyl group can be substituted or unsubstituted. For example, the heterocyclyl group can be substituted with one or more substitution groups, as described herein for aryl.

[0062] By “hydroxyl” is meant -OH.

[0063] By “hydroxyalkyl” is meant an alkyl group, as defined herein, substituted by one to three hydroxyl groups, with the proviso that no more than one hydroxyl group may be attached to a single carbon atom of the alkyl group and is exemplified by hydroxymethyl, dihydroxypropyl, and the like.

[0064] By “oxo” is meant an =0 group.

[0065] By ‘ ‘salt” is meant an ionic form of a compound or structure (e.g., any formulas, compounds, or compositions described herein), which includes a cation or anion compound to form an electrically neutral compound or structure. Salts are well known in the art. For example, non-toxic salts are described in Berge S M et al., “Pharmaceutical salts,” J. Pharm. Sci. 1977 January; 66(1): 1-19; and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use,” Wiley-VCH, April 2011 (2nd rev. ed., eds. P. H. Stahl and C. G. Wermuth. The salts can be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting the free base group with a suitable organic acid (thereby producing an anionic salt) or by reacting the acid group with a suitable metal or organic salt (thereby producing a cationic salt). Representative anionic salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, butyrate, camphorate, camphorsulfonate, chloride, citrate, cyclopentanepropionate, digluconate, dihydrochloride, diphosphate, dodecylsulfate, edetate, ethanesulfonate, fumarate, glucoheptonate, gluconate, glutamate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, hydroxyethanesulfonate, hydroxynaphthoate, iodide, lactate, lactobionate, laurate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, polygalacturonate, propionate, salicylate, stearate, subacetate, succinate, sulfate, tannate, tartrate, theophyllinate, thiocyanate, triethiodide, toluenesulfonate, undecanoate, valerate salts, and the like. Representative cationic salts include metal salts, such as alkali or alkaline earth salts, e.g., barium, calcium (e.g., calcium edetate), lithium, magnesium, potassium, sodium, and the like; other metal salts, such as aluminum, bismuth, iron, and zinc; as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, pyridinium, and the like. Other cationic salts include organic salts, such as chloroprocaine, choline, dibenzylethylenediamine, diethanolamine, ethylenediamine, methylglucamine, and procaine. Yet other salts include ammonium, sulfonium, sulfoxonium, phosphonium, iminium, imidazolium, benzimidazolium, amidinium, guanidinium, phosphazinium, phosphazenium, pyridinium, etc., as well as other cationic groups described herein (e.g., optionally substituted isoxazolium, optionally substituted oxazolium, optionally substituted thiazolium, optionally substituted pyrrolium, optionally substituted furanium, optionally substituted thiophenium, optionally substituted imidazolium, optionally substituted pyrazolium, optionally substituted isothiazolium, optionally substituted triazolium, optionally substituted tetrazolium, optionally substituted furazanium, optionally substituted pyridinium, optionally substituted pyrimidinium, optionally substituted pyrazinium, optionally substituted triazinium, optionally substituted tetrazinium, optionally substituted pyridazinium, optionally substituted oxazinium, optionally substituted pyrrolidinium, optionally substituted pyrazolidinium, optionally substituted imidazolinium, optionally substituted isoxazolidinium, optionally substituted oxazolidinium, optionally substituted piperazinium, optionally substituted piperidinium, optionally substituted morpholinium, optionally substituted azepanium, optionally substituted azepinium, optionally substituted indolium, optionally substituted isoindolium, optionally substituted indolizinium, optionally substituted indazolium, optionally substituted benzimidazolium, optionally substituted isoquinolinum, optionally substituted quinolizinium, optionally substituted dehydroquinolizinium, optionally substituted quinolinium, optionally substituted isoindolinium, optionally substituted benzimidazolinium, and optionally substituted purinium).

[0066] By ‘ ‘stereoisomer” is meant any of the various stereoisomeric configurations that may exist for a given compound of the present invention and includes geometric isomers. It is understood that a substituent may be attached at a chiral center of a carbon atom. The term “chiral” refers to molecules which have the property of nonsuperimpos ability on their mirror image partner, while the term “achiral” refers to molecules which are superimposable on their mirror image partner. Therefore, the disclosure includes enantiomers, diastereomers or racemates of the compound.

“Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term is used to designate a racemic mixture where appropriate. “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other. The absolute stereochemistry can be specified according to the Cahn- Ingold-Prelog R-S system.

[0067] By “attaching,” “attachment,” or related word forms is meant any covalent or non-covalent bonding interaction between two components. Non-covalent bonding interactions include, without limitation, hydrogen bonding, ionic interactions, halogen bonding, electrostatic interactions, n bond interactions, hydrophobic interactions, inclusion complexes, clathration, van der Waals interactions, and combinations thereof.

[0068] As used herein, the term “about” means +/-10% of any recited value. As used herein, this term modifies any recited value, range of values, or endpoints of one or more ranges.

[0069] As used herein, the terms “top,” “bottom,” “upper,” “lower,” “above,” and “below” are used to provide a relative relationship between structures. The use of these terms does not indicate or require that a particular structure must be located at a particular location in the apparatus.

[0070] As used herein, the terms “comprises,” “comprising,” “includes,” “including,” “has,” “having” or any other variation thereof, are intended to cover a nonexclusive inclusion. For example, a process, method, article, or apparatus that comprises a list of features is not necessarily limited only to those features but may include other features not expressly listed or inherent to such process, method, article, or apparatus. Further, unless expressly stated to the contrary, “or” refers to an inclusive-or and not to an exclusive-or. For example, a condition A or B is satisfied by any one of the following: A is true (or present) and B is false (or not present), A is false (or not present) and B is true (or present), and both A and B are true (or present).

[0071] This written description uses examples to disclose the embodiments, including the best mode, and also to enable those of ordinary skill in the art to make and use the invention. The patentable scope is defined by the claims, and may include other examples that occur to those skilled in the art. Such other examples are intended to be within the scope of the claims if they have structural elements that do not differ from the literal language of the claims, or if they include equivalent structural elements with insubstantial differences from the literal languages of the claims.

[0072] Note that not all of the activities described above in the general description or the examples are required, that a portion of a specific activity may not be required, and that one or more further activities may be performed in addition to those described. The order in which activities are listed is not necessarily the order in which they are performed.

[0073] In this specification, the concepts have been described with reference to specific embodiments. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the invention as set forth in the claims below. Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of invention.

[0074] Benefits, other advantages, and solutions to problems have been described herein with regard to specific embodiments. However, the benefits, advantages, solutions to problems, and any feature(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential feature of any or all the claims.

[0075] After reading the specification, skilled artisans will appreciate that certain features are, for clarity, described herein in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be provided separately or in any subcombination. Further, references to values stated in ranges include each and every value within that range. BRIEF DESCRIPTION OF THE DRAWINGS

[0076] FIG. 1 shows an illustrative schematic of reacting a non-limiting amino acid (I) with a non-limiting catalyst (II) to form a corresponding amine (III) and a further ammonium carbamate salt (IV).

[0077] FIG. 2 shows an illustrative schematic of a catalytic cycle for reacting a nonlimiting amino acid (I) with a non- limiting catalyst (II).

[0078] FIG. 3 shows a schematic of a non- limiting method 300 to provide an amine 39.

[0079] FIG. 4 shows a schematic of another non-limiting method 400 to provide an amine 49.

[0080] FIG. 5 shows a schematic of yet another non-limiting method 500 to provide an amine 60.

[0081] FIG. 6 shows a gas chromatograph with flame-ionization detection (GC-FID) trace for a non-limiting phenethylammonium phenethylcarbamate salt (IVa), in which this trace is indiscernible from that of phenylalanine.

DETAILED DESCRIPTION

[0082] The present disclosure relates to methods of decarboxylating an amino acid. The method can include a reaction mixture having a combination of an amino acid, a solvent, and a catalyst (e.g., an organocatalyst, which can be metal-free in some instances). The amino acid, in turn, is decarboxylated to produce carbon dioxide (CO2) and the corresponding amine. By selecting particular solvents, catalysts, and reaction conditions (e.g., temperature, stirring conditions, and sealed/open vessel conditions), catalyst turnover and decarboxylation can be enhanced. One such condition can include those that promote the formation of an ammonium carbamate salt of an amine. Without wishing to be limited by mechanism, forming the salt provides concomitant release and recovery of the catalyst, which in turn can then participate in further decarboxylation of the amino acid. Salt formation, in turn, requires reactions between the produced amine and in situ generated CO2. While salt formation could appear to reduce recovery of the desired amine as a product, the salt provides an ionic form that can be readily separated from the reaction mixture and then be decomposed by simply heating the salt to regenerate the desired amine. In this way, also described herein are methods of isolating the ammonium carbamate salt of an amine (e.g., as a solid or a precipitate), which can be a storable and stabilized form of the amine. In other embodiments, reproducibility of decarboxylation conditions was improved by understanding the role of CO2 and the ammonium carbamate salt in amine synthesis.

[0083] Also described herein are mild reaction conditions for decarboxylation of amino acids. Such conditions can include reaction temperatures as low as about 180°C or even 160°C, at atmospheric pressure and without the addition of an acid. Furthermore, the reaction conditions herein can provide high reaction yield (e.g., greater than about 70%, 80%, 85%, 90%, or more). In some embodiments, a reduced organocatalyst loading from nearly 1 molar equivalent to 0.05 molar equivalents can afford high conversion and selectivity (e.g., a yield greater than about 80%, 85%, or even 90% in some instances). In particular embodiments, the amino acid is phenylalanine, and the corresponding amine is phenethylamine. In other embodiments, the amino acid is histidine, and the corresponding amine is histamine.

[0084] FIG. 1 shows a schematic of a non- limiting decarboxylation reaction. As can be seen, an amino acid (e.g., having structure (I)) is provided in the presence of a catalyst (e.g., having structure (II)), thereby providing a corresponding amine that is a decarboxylated form of the amino acid (e.g., having structure (III)) and in situ generated CO2. Under certain conditions, the amine (structures (III) and (III’) in FIG. 1) reacts with the in situ generated CO2 to produce an ammonium carbamate salt (structure (IV) in FIG. 1) of the amine. Such conditions include use of a solvent (e.g., a hydrocarbon solvent) in a closed vessel to maintain the generated gas within the solvent, thereby increasing the local reactant concentration of the CO2 gas that is required to provide the salt. Other conditions include use of a solvent (e.g., a polar solvent) in an open vessel to stabilize the formation of the salt, thereby releasing the catalyst from a reaction intermediate and recovering the catalyst for further conversion of amino acid molecules. [0085] FIG. 2 shows a schematic of a non- limiting catalytic cycle for a decarboxylation reaction. As can be seen, a non-limiting alpha-amino acid having structure (I) includes an amino group, a carboxyl group, and a side chain group (indicated by R ¹ ). Non-limiting R ¹ include H or optionally substituted alkyl (e.g., substituted with substituents described herein for alkyl). In the presence of a carbonylcontaining catalyst having structure (II), the amino acid and the catalyst forms a Schiff base adduct having structure (V). Further decarboxylation of the Schiff base adduct then releases CO2 and can form an azomethine ylide intermediate having structure (VI). Protonation provides a second Schiff base adduct having structure (VII), in which hydrolysis then releases the catalyst (II) and generates the corresponding amine having structure (HI).

[0086] The amine reaction product (III) can further react with another amine (III’) and CO2, at room temperature (r.t.), to form the ammonium carbamate salt having structure (IV). This competitive side reaction, while consuming the amine, can also release the catalyst (II) to further promote decarboxylation of remaining amine within the reaction mixture. Upon exposure to heat, the salt can decompose to regenerate the amine (III’) and release CO2.

[0087] Methods for decarboxylating an amino acid can include providing a reaction mixture (e.g., any described herein) within a vessel (e.g., an open vessel or a sealed vessel) and then heating the reaction mixture to a temperature of about 150°C or greater, thereby decarboxylating the amino acid to form the amine. In some embodiments, the reaction mixture includes an amino acid, a solvent (e.g., a polar solvent or a hydrocarbon solvent), and a catalyst.

[0088] The decarboxylation reaction conditions promote the decarboxylation of the amino acid, while minimizing the formation of unwanted contaminants or side products. The reaction conditions include those that promote formation of the ammonium carbamate salt. In one instance, the reaction condition includes bubbling carbon dioxide into the reaction mixture, thereby facilitating formation of the ammonium carbamate salt. [0089] In another instance, the reaction conditions includes combining an amino acid, a polar solvent, and a catalyst in an open vessel to provide a reaction mixture; and heating the reaction mixture to a temperature of about 150°C or greater. In particular, use of the polar solvent in an open vessel promoted formation of the ammonium carbamate salt, in which dissolution of the salt is improved within the polar solvent.

[0090] In yet another instance, the reaction conditions includes combining an amino acid, a hydrocarbon solvent, and a catalyst in a closed vessel to provide a reaction mixture; and heating the reaction mixture to a temperature of about 150°C or greater. In particular, use of the hydrocarbon solvent in a closed vessel promoted formation of the ammonium carbamate salt, in which dissolution of the in situ generated CO2 is improved within the hydrocarbon solvent.

[0091] Heating of the reaction mixture can include use of an oil bath, a microwave, or other heat source. Temperature conditions can include a range between about 145 °C to 190°C, 150°C to 190°C, 150°C to 180°C, 155°C to 180°C, 150°C to 165°C, or 160°C to 165 °C. [0092] A number of solvents are contemplated for use herein. The solvents in which certain steps of the reaction are conducted may affect the reaction time, reaction yield, and/or product purity. Useable solvents are disclosed herein and can include cyclohexanol, toluene, and others.

[0093] The reaction mixture can include any useful amount of catalyst, such as from about 0.5 mol.% to about 10 mol.%, including from 0.5 mol.% to 1 mol.%, 0.5 mol.% to 5 mol.%, 1 mol.% to 5 mol.%, or 1 mol.% to 10 mol.%.

[0094] In order to employ the stable ammonium carbamate salt for product isolation from the reaction mixture, isolation and purification processes are also described herein. In one embodiment, such processes can include vacuum distillation (e.g., to remove the solvent from the reaction mixture) or formation of the ammonium carbamate, previously deemed challenging with the prospect of enabling both solvent and organocatalyst recycling.

[0095] Methods can include operations to isolate the amine or an ammonium carbamate salt of the amine. In one embodiment, the method includes distilling the reaction mixture, thereby removing the solvent and/or the catalyst and isolating the amine as a distillate. In other embodiments, the method includes precipitating the ammonium carbamate salt of the amine from the reaction mixture, thereby isolating the ammonium carbamate salt as a precipitate; and filtering the reaction mixture to separate the precipitate and remove the solvent and/or the catalyst. Optionally, the precipitate can be decomposed (e.g., upon exposure to heat), thereby releasing carbon dioxide and regenerating the amine. Further methods of isolating the amine or the ammonium carbamate salt includes vacuum distilling, precipitating, decomposing, filtering, and/or evaporating the reaction mixture or a component thereof.

[0096] After isolating the product, the remaining separated fractions (e.g., catalyst, solvent, and/or unreacted amino acid) can be further recycled. Such recycling can include delivery of the fraction(s) to the vessel to provide a further reaction mixture. [0097] In particular embodiments, the decarboxylation methods herein lack acid hydrolysis as a final operation to promote for product and catalyst recovery. Without wishing to be limited by mechanism, understanding the role of carbon dioxide in the formation of an ammonium carbamate salt and its usefulness in organocatalyst turnover allowed for reducing catalyst loading and eliminating acid hydrolysis as a required step for product isolation. [0098] The method can further include purifying an isolated product. Such purification can include recrystallization, in which a process of repeated crystallization is used in order to purify a substance. A number of solvents are contemplated for use in this purification process. These solvents can include: methyl chloride, 2-propanol, methanol, ethanol (EtOH), methanol/acetone, water, methanol/ethyl acetate, water/acetone, methanol/ethanol, water/methanol, methanol/hexane, water/methanol/acetone, methanol/methylene chloride, 2-propanol/ethanol, methanol/2- propanol, acetone/2 -propanol, acetone/ethanol, and others.

[0099] The method can further include removing the unreacted catalyst and solvent by washing with water and organic solvent (e.g. an ethyl solvent, such as, but not limited to, diethyl ether). The corresponding amine or salt (e.g., ammonium carbamate salt of the amine) can be recovered by distilling off the solvent and water. The washing and distillation step can be repeated as necessary. In embodiments, the reaction mixture can be washed three times with ether and water solvent. In embodiments, after washing and distilling off the water and solvent, the amine salt can be dried (e.g., in an oven).

[0100] It should be noted that ratios, concentrations, amounts, and other numerical data may be expressed herein in a range format. It is to be understood that such a range format is used for convenience and brevity, and thus, should be interpreted in a flexible manner to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. To illustrate, a concentration range of “about 0.1% to about 5%” should be interpreted to include not only the explicitly recited concentration of about 0.1 wt. % to about 5 wt. %, but also include individual concentrations (e.g., 1%, 2%, 3%, and 4%) and the subranges (e.g., 0.5%, 1.1%, 2.2%, 3.3%, and 4.4%) within the indicated range. In an embodiment, the term “about” can include traditional rounding according to significant figures of the numerical value. In addition, the phrase “about ‘x’ to ‘y’” includes “about ‘x’ to about ‘y’”.

Further methods, processes, and systems

[0101] The methods herein can be employed in any useful process. For instance, the process can include a decarboxylation operation to decarboxylate an amino acid to form an amine, an isolation operation to isolate the amine from the reaction mixture, and an optional recycle operation to recycle separated components for further reaction. These processes, in turn, can be performed within an apparatus (e.g., a reactor, a distillation unit, a bubbler, a separation unit, and/or an evaporation unit), which can be a part of a system.

[0102] FIG. 3 provides a non-limiting process 300 for providing an amine 39. The process can include providing a catalyst 30, an amino acid 31, and a solvent 32 (e.g., to a vessel) for a decarboxylation operation 302. Such an operation can include combining the catalyst 30, amino acid 31, and solvent 32 to form a reaction mixture; incubating the reaction mixture; and/or heating the reaction mixture with optional stirring. The decarboxylation operation can be conducted within a reactor, which can be an open vessel or a sealed vessel. During decarboxylation, CO233 can be released from the amino acid, in which the CO2 gas can be retained within the reactor or released from the reactor.

[0103] Any reactor described herein can include one or more inlets and/or outlets, in which an inlet can be configured to receive one or more components into the reactor and in which an outlet can be configured to convey one or more components out of the reactor. The reactor can be an open vessel or a closed vessel. The reactor can have one or more fluidic lines to fluidically communicate with other apparatuses. In one embodiment, the reactor is configured to promote formation of an ammonium carbamate salt of an amine, thereby recovering the catalyst within the reaction mixture.

[0104] As also seen in FIG. 3, the process 300 can include a distillation operation 304, in which the reaction mixture is distilled to remove the solvent, if the solvent has a lower boiling point than the amine, and then further increasing the temperature to remove the amine 39 as a distillate. Removed components of the reaction mixture, such as the solvent and/or the catalyst can be recycled 307, 309 back into the decarboxylation operation 302 to further increase process yield.

[0105] The distillation operation can be performed in a distillation unit having one or more inlets and/or outlets, in which an inlet can be configured to receive one or more components into the unit and in which an outlet can be configured to convey one or more components out of the unit. The unit can have one or more fluidic lines to fluidically communicate with other apparatuses. In one embodiment, the unit is configured to distill the reaction mixture to separate the solvent, catalyst, unreacted amino acid, and amine. Such configurations can include control of temperature and/or pressure within the vessel holding the reaction mixture within the distillation unit. [0106] Alternative processes are also described herein, such as amine isolation and purification via ammonium carbamate formation. FIG. 4 provides a non-limiting process 400 for providing an amine 49 by way of forming an ammonium carbamate salt 48. The process can include providing a catalyst 40, an amino acid 41, and a solvent 42 (e.g., to a vessel or a reactor) for a decarboxylation operation 402. The decarboxylation operation can be conducted within a first reactor (e.g., as described above), which can be an open vessel or a sealed vessel. During decarboxylation, CO243 can be released from the amino acid, in which the CO2 gas can be retained within the reactor or released from the reactor.

[0107] As also seen in FIG. 4, the process 400 can include a salt formation operation 404, in which CO244 can be introduced into the reaction mixture, thereby promoting formation of the ammonium carbamate salt 48 of the amine. CO2 can be introduced in any useful manner, such as by use of a bubbler in fluid communication with the reactor containing the reaction mixture. Salt formation can occur in the first reactor or in another apparatus (e.g., a separation unit having a chamber for holding the precipitate and a filter for filtering the reaction mixture). Upon forming the salt (e.g., as a precipitate), a recycle operation 409 can be conducted to provide the solvent, unreacted amino acid, and catalyst to the reaction mixture in the first reactor. Optionally, the process can include a filtration operation, in which a separation unit is employed to form a precipitate comprising the ammonium carbamate salt of the amine and to filter the precipitate from the reaction mixture.

[0108] To recover the amine, the ammonium carbamate 48 can undergo a decomposition operation 406 in a second reactor configured to decompose the precipitate to the amine. In one instance, decomposition can include heating the carbamate salt within the second reactor, which can result in CO2 evolution and leaving behind a solution including the amine 49.

[0109] FIG. 5 provides another non- limiting process 500 for providing an amine 60 by way of forming an ammonium carbamate salt 56. The process can include providing a catalyst 50, an amino acid 51, and a solvent 52 (e.g., to a vessel or a reactor) for a decarboxylation operation 502. The decarboxylation operation can be conducted within a first reactor (e.g., as described above), which can be an open vessel or a sealed vessel, and can release CO253.

[0110] The process 500 further includes a salt formation operation 504, in which CO254 can be introduced (e.g., by way of a bubbler) into the reaction mixture, thereby promoting formation of the ammonium carbamate salt of the amine. Salt formation can occur in the first reactor or in another apparatus (e.g., a separation unit having a chamber for holding the precipitate and a filter for filtering the reaction mixture).

[0111] Given the solubility of the ammonium carbamate, the salt can be precipitated by cooling the reaction mixture followed by filtration. Accordingly, the process 500 can further include a precipitation operation 514 for removing heat 55 or cooling the mixture, thereby forming a precipitate; as well as a filtration operation 524 to separate the components of the reaction mixture, thereby providing the ammonium carbamate salt 56. In some embodiments, the filtrate, containing the organocatalyst and solvent can be recycled, such as by way of a residual recycle operation 509, to promote other decarboxylation reactions. In some embodiments, the carbamate salt is stable and could potentially be used in further chemical reactions in this state.

[0112] To recover the amine, the ammonium carbamate 56 can undergo a decomposition operation 506 in a second reactor. The second reactor can be configured to decompose the precipitate to the amine in the presence of a second solvent 57, which can be the same or different as the first solvent 52 employed with the amino acid and the catalyst to provide the initial reaction mixture. In one instance, decomposition can include dissolving the carbamate salt in a second solvent 57 (e.g., a polar solvent with lower boiling point than the amine) and then heating. This would result in CO258 evolution, leaving behind a solution including the amine 60 and the second solvent 57/59.

[0113] In the second reactor or in another apparatus (e.g., an evaporation unit), the second solvent can be removed by way of evaporation. Thus, the method can further include an evaporation operation 508 in an evaporation unit. The evaporation unit can be configured to evaporate the second solvent 59, thereby providing a solution including the amine 60.

[0114] The system can include one or more controllers electrically connected to one or more apparatuses. The controller can include electronics to control various apparatuses (e.g., reactors, distillation units, bubblers, separation units, evaporation units, inlets, and/or outlets) or subparts of the system or systems. The controller, depending on the processing requirements and/or the type of system, may be programmed to control any of the processes disclosed herein, including delivering amino acids, catalysts, and solvents; conveying reactants, reaction products, salts, or reaction intermediates; providing reaction conditions, such as heating, cooling, mixing, stirring, vacuum distilling, precipitating, decomposing, filtering, and/or evaporating the reaction mixture or a component thereof; recycling separated components back into the reaction mixture, etc.

[0115] Non-limiting controller electronics include integrated circuits, logic, memory, and/or software that receive instructions, issue instructions, control operation, and the like. The integrated circuits may include chips in the form of firmware that store program instructions, digital signal processors (DSPs), chips defined as application specific integrated circuits (ASICs), and/or one or more microprocessors, or microcontrollers that execute program instructions (e.g., software).

[0116] In some embodiments, the one or more controllers can be configured to cause the reactor to promote formation of the ammonium carbamate salt of the amine. For instance, the controller can provide enhanced mixing within the reactor, thereby facilitating dissolution of CO2 and/or the ammonia carbamate salt within the solvent. In another instance, the controller is configured to perform any method or process described herein. In one example, the controller is configured to introduce CO2 into a reactor having a reaction mixture, thereby facilitating formation of the ammonium carbamate salt.

Amino acids and derivatives thereof

[0117] As described herein, the methods and systems herein can employ biomolecules, which can be decarboxylated. Non-limiting biomolecules include amino acids having an amino group and a carboxyl group, such as alpha amino acids, beta amino acids, gamma amino acids, delta amino acids, as well as L- or D- amino acids and combinations of any of these. As used herein the term “amino acid” refers to either natural and/or unnatural or synthetic amino acids, including glycine and both the D or L optical isomers, and amino acid analogs and peptidomimetics.

[0118] Examples of amino acids include glycine, alanine, valine, isoleucine, leucine, methionine, selenomethionine, phenylalanine, tyrosine, tryptophan, proline, cysteine, selenocysteine, serine, threonine, asparagine, glutamine, theanine, arginine, histidine, lysine, ornithine, pyrrolysine, aspartic acid, glutamic acid, allylglycine, 2-aminobutyric acid, P-alanine, P-cyanoalanine, allo-isoleucine, and salts, hydrates, and free base forms thereof. Such amino acids can include monomers, as well as a poly(amino acid) formed from a plurality of amino acids, such as in oligomers, homopolymers, multichain polymers, or copolymers. [0119] Yet other non-limiting biomolecules can include, e.g., derivatives of any amino acids including an alkenyl, alkenyloxy (e.g., -O-Ak, in which Ak is alkenyl), acetyl, carboxyl, or hydroxyl moiety. In particular embodiments, the biomolecule is an L-amino acid or a functionalized L-amino acid having an alkenyl, alkenyloxy (e.g., -O- Ak, in which Ak is alkenyl), carboxyl, or hydroxyl moiety.

[0120] Biomolecules can be formed in any useful manner. In one instance, the biomolecules are produced from yeast, gram positive bacteria, gram negative bacteria, or fungi. In other embodiments, amino acids, as well as derivatives thereof, are produced biologically by way of fermentation, acetylation, and/or prenylation. In particular embodiments, prenylation may involve feeding the organism the starting amino acid.

Solvents

[0121] The methods herein can employ a solvent, as well as mixtures of solvents. In particular embodiments, the solvent is selected to promote dissolution of the ammonium carbamate salt of the amine. Such solvents can include, e.g., polar solvents suitable for solvating ionic compounds. In other embodiments, the solvent is selected to promote dissolution of the in situ generated carbon dioxide. Such solvents can include, e.g., hydrocarbon solvents suitable for capturing this gas.

[0122] Non- limiting solvents include an alcohol, such as a primary alcohol (e.g., n- butanol, n-pentanol, ethanol, methanol, and n-propanol) or a secondary alcohol (e.g., isopropanol, cyclohexanol, and tert-butanol); a hydroxyether, such as 2-methoxyethanol; a hydrocarbon, such as an aromatic hydrocarbon (e.g., toluene, benzene, nitrobenzene); an aprotic solvent, such as tetrahydrofuran (THF), acetonitrile, N, A-dimethylformamide (DMF), AN-dimethylacetamide (DMAc), A-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide (DMSO), sulfolane, and acetone; etc. Yet other solvents can include In particular embodiments, the solvent has a boiling point of less than about 160°C, 150°C, 140°C, 130°C, or 120°C.

Catalysts

[0123] The methods herein can employ a catalyst, such as an organocatalyst. In particular embodiments, the catalyst is metal-free. In one embodiment, the catalyst includes a structure of formula (II):

O

^R '5 ^R "

' ' or a salt thereof, wherein: R is H or R ; each R" is, independently, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aromatic, or optionally substituted heteroaromatic; and wherein R' and R" can be taken together to form an optionally substituted aromatic, optionally substituted carbocycle, or optionally substituted heterocycle.

[0124] In some embodiments, R' is H; and R" is optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aromatic, or optionally substituted heteroaromatic. In other embodiments, each of R' and R" is, independently, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aromatic, or optionally substituted heteroaromatic. In yet other embodiments, R' and R" are taken together to form an optionally substituted aromatic, optionally substituted carbocycle, or optionally substituted heterocycle. In particular embodiments, the optionally substituted carbocycle includes optionally substituted cycloalkyl or optionally substituted cycloalkenyl.

[0125] In some embodiments, R' is H; and R" is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkanoyl, optionally substituted aryloyl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl. In other embodiments, each of R' and R" is, independently, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted alkanoyl, optionally substituted aryloyl, optionally substituted alkoxycarbonyl, optionally substituted aryloxycarbonyl, optionally substituted aryl, optionally substituted heterocyclyl, or optionally substituted heteroaryl.

[0126] In particular embodiments, the catalyst includes a structure of one of formulas (Ila)-(IIg): salt thereof, wherein:

R' is H or R" ^a ; each R" ^a is, independently, optionally substituted aliphatic, optionally substituted heteroaliphatic, optionally substituted aromatic, or optionally substituted heteroaromatic; n is 0, 1, or 2; and each of Ari and Cyl can be, independently, optionally substituted.

[0127] Optional substitutions for Ari and Cyl can include any described herein for alkyl. Non-limiting substitutions can include halo, hydroxyl, alkyl, alkenyl, oxo, amino, hydroxyalkyl, aminoalkyl, aryl, alkaryl, or aralkyl.

[0128] The catalyst can include any useful class, such as a ketone, an aromatic ketone, an unsaturated ketone, an a,P-unsaturated ketone, an a,P-unsaturated cyclic ketone, a ketone lacking an a-hydrogen, an aldehyde, or an aromatic aldehyde. In particular embodiments, the catalyst is a ketone lacking an a-hydrogen. In other embodiments, the catalyst is an enone or an enal.

[0129] Yet other examples of catalysts include benzophenone, 2-cyclohexene-l-one, 2-cyclopentene-l-one, isophorone (e.g., a-isophorone, P-isophorone, or mixtures thereof), acetophenone, carvone (e.g., R-carvone, S-carvone, or mixtures thereof), tetralone (e.g., 1-tetralone or 2-tetralone), indanone (e.g., 1-indanone), 9-fluorenone, benzaldehyde, salicylaldehyde, 4-formylbenzonitrile, 4-formyl benzoic acid, p- anisaldehyde, pyridinecarboxaldehyde (e.g., 2-, 3-, or 4-pyridinecarboxaldehyde), pyrrolecarboxaldehyde (e.g., 2-, 3-, or 4-pyrrolecarboxaldehyde), as well as substituted versions of any of these (e.g., having one or more substitutions as described for alkyl, such as hydroxyl, alkyl, alkoxy, halo, cyano, etc.). In other embodiments, the catalyst includes 3-penten-2-one, butanone, dihydrocarvone, citral, P-ionone, R-pulegone, carvenone, cinnamaldehyde, 3-methylcyclohex-2-enone, pentadione, acetone, piperitone, piperitenone, isopiperitenone, methyl vinyl ketone, butenones, 2-phenylpropenal, 2-ene- propanal, and other P-ene-aldehydes. Applications

[0130] The compositions herein can be employed as ingredients and/or monomers in any useful application. Exemplary, non-limiting applications include adhesives, coatings, films, and plastics. Such applications can include materials for use in constructing electronics, industrial adhesives, architectural adhesives and coatings, civil engineering adhesives and coatings, transportation adhesives and coatings, handheld devices, electronic devices, energy storage devices, energy generation devices, personal electronics (e.g., smart phones, laptops, or tablets), displays, sensors, semi-conductor materials (e.g., such as in chip patterning, manufacturing, and packaging), packages, and the like.

[0131] Yet other applications include use of the composition as a polymer curative, a resin (e.g., an ion free resin), a monomer for a polymer or a copolymer, and the like. The composition can be provided in any useful form, such as a film, a composite structure, a bulk structure, a fiber, or a particle.

[0132] In some embodiments, the present disclosure encompasses methods for manufacturing any use herein (e.g., an adhesive, a coating, a film, a plastic, a composite, an electronic device, an energy storage device, an energy generation device, and the like) by applying a composition herein (e.g., any foregoing compound) in the assembly of the adhesive, the coating, the film, the plastic, the composite, the electronic device, the energy storage device, or the energy generation device. In other embodiments, the composition is provided as a polymer curative.

EXAMPLES

Example 1: Decarboxylation of amino acids

[0133] Described herein are experimental and synthetic conditions for decarboxylation of amino acids in the presence of metal-free catalysts. Differing results were observed when reactions were performed in sealed versus open vessels. In particular, these conditions pointed to the potential role of liberated CO2 and ammonium carbamate salt in the decarboxylation reaction. Additional details follow.

Example 2: Decarboxylation of phenylalanine in a sealed vessel

[0134] Decarboxylation conditions were explored with an initial amino acid, phenylalanine, which should provide a corresponding phenethylamine (PEA) product material. Such conditions could be further extended to other amino acids (e.g., any described herein) to provide a corresponding decarboxylated reaction product, an amine. [0135] Initial screening of reaction parameters for phenylalanine decarboxylation was performed using the Biotage® Endeavor reactor (eight parallel overhead stirred reactions having a reaction volume of 1 - 4 mL) under sealed/closed conditions. A variety of reaction parameters including solvents, catalysts, and reaction temperatures and times were investigated. All initial experiments which involved temperatures less than about 110°C and/or alcohol solvents (particularly primary alcohol) and/or longer reaction times at higher temperatures (e.g., more than about 160°C) were generally unsuccessful. The phenethylamine (PEA) product material was not observed. Illustrative examples of these initial unsuccessful experiments are grouped in Table 1.

Table 1: Initial screening results for 200 mg of phenylalanine [0136] Subsequent screening experiments provided PEA formation in some instances. Screening conditions involved non-protic tetrahydrofuran (THF) and toluene solvents, shorter reaction times (e.g., 8 hours) at about 160 - 180°C, and use of benzophenone as the catalyst, which was chosen particularly because of the lack of a- hydrogen atoms. Conditions including this catalyst was further optimized to provide, in one instance, the desired PEA product material in 91% reaction assay yield. Reaction conditions include use of phenylalanine (200 mg, 1.0 equiv.), benzophenone (5 mol.%), and toluene (2 mL, 10 V) at 175 - 180°C for 8 hours under sealed/closed equipment.

The successful reactions under these optimum conditions exhibited a clear dark yellow homogeneous solution and a clean GC-FID trace as shown in FIG. 6. Further, larger scale synthesis can include mechanical mixing of the reaction mixture to improve solubility of the insoluble phenylalanine starting material in the toluene solvent.

Example 3: Decarboxylation of phenylalanine in an open vessel

[0137] With the identification of successful decarboxylation reaction conditions based on toluene solvent/benzophenone catalysts, further screening efforts focused on reaction conditions that could be moved from closed high pressure reactor equipment to more commercially viable traditional open glassware -based equipment. In particular, reaction conditions included lower reaction temperatures (lower than 180°C) or use of higher boiling solvents, as seen in Table 2. Table 2: Screening results for 200 mg of phenylalanine and 5 mol.% benzophenone catalyst [0138] As discussed in the pnor example, one optimized condition included use of toluene at 175 - 180°C for 8 hours, which provided PEA at 91% yield. Using a lower temperature (130 - 170°C) in the same solvent, the reaction appeared to proceed slowly as evidenced by yellow coloration of the liquid phase. Furthermore, the reaction remained incomplete after 8 hours, as evidenced by the presence of insoluble phenylalanine solid starting material at the bottom of the reaction tubes.

[0139] The reactions in higher boiling, commercially viable hydrocarbon solvents, similar to toluene, such as xylenes, tetralin and tri-isopropylbenzene (TIB) also exhibited presence of solid material and low PEA product assay yields (< 50 %) under comparable conditions to toluene. However, the solids present in these solvents appeared light and floating in the solvent rather than settling at the bottom of the reaction tube as in the case of other incomplete reactions with unconsumed phenylalanine starting material.

[0140] Other solvents such as dimethylformamide (DMF) and ethylene glycol (EG) appeared to be reactive with reaction components as evident from very dark colored viscous reaction mixtures under otherwise similar reaction conditions to toluene.

[0141] Cyclohexanol was found to be suitable high boiling solvent affording the desired PEA product material in 88% assay yield. Further studies in open reaction conditions were conducted. Reactions were performed in traditional round-bottomed flasks equipped with reflux condensers under argon. In addition, reactions were stirred using magnetic stir bars and heated using an oil bath controlled by PARR 4848 controller. The glass equipment allowed for visual observation of the decarboxylation reaction for the first time and allowed for monitoring of the reaction progress. Reactions were carefully monitored for proper mixing of the heterogeneous reaction mixture and consumption of the insoluble phenylalanine starting material; and stopped at about two hours after disappearance of the solid phenylalanine starting material and appearance of clear homogeneous reaction solutions.

[0142] Several gram-scale reactions were performed with cyclohexanol solvent (10 V) under reflux conditions with the oil bath temperature maintained at 160 - 168°C (Table 3).

Table 3: Screening results for 5 mol.% catalyst in cyclohexanol solvent (10V)

[0143] Benzophenone in cyclohexanol provided high yield of the desired product. In particular, mild reaction conditions for decarboxylation of L-phenylalanine to produce 2- phenylethylamine (PEA) in high yield (88-92%) were determined: benzophenone (5 mol.%) as the catalyst, cyclohexanol (10V) as the solvent, in a reaction done at 162°C for 6-8 hours, under nitrogen, and at atmospheric pressure. Under these conditions, yield was higher (more than 80%) as compared to previously reported yields (14%).

Additionally, acid hydrolysis of the imine (to form the amine and/or to recover the catalyst) can be avoided during decarboxylation. Given this combination of reagents, the PEA product can be isolated in at least two ways with the option to recycle both solvent and organocatalyst: the first option is through vacuum distillation; and the second option is through formation of the ammonium carbamate of PEA, which can readily be achieved by providing carbon dioxide to the reaction mixture.

[0144] As also seen in Table 3, other carbonyl catalysts were explored and exhibited reasonable effectiveness in catalyzing the phenylalanine decarboxylation reaction. The carvone catalyst, in particular, exhibited a comparably faster decarboxylation reaction, as evidenced from the faster disappearance of the insoluble phenylalanine starting material under otherwise identical conditions. More importantly, this identification of alternate catalyst options offers opportunities for selecting and optimizing the most desirable catalyst based on economics, productivity, and compatibility to the ultimately chosen manufacturing solvent, scale-up, and product isolation strategies.

Example 4: Solvent studies for decarboxylation of phenylalanine

[0145] A variety of higher boiling solvents were screened in the glassware-based equipment to explore the feasibility of alternative solvents to cyclohexanol to support selection of future PEA product material isolation strategies (either based on distillation or aqueous product salt extraction). The phenylalanine decarboxylation reactions in the selected exploratory solvents were performed under otherwise identical conditions to cyclohexanol solvent but with minor adjustments to reaction temperature and time to aid reaction completion. The solvents explored included longer chain primary alcohols, cyclic amides, and higher hydrocarbons (Table 4).

Table 4: Solvent study of phenylalanine decarboxylation reaction (6-8 h reaction time) with 5 mol.% benzophenone catalyst nd: not determined

[0146] The primary alcohol and cyclic amide solvents appeared to be reactive under the decarboxylation reaction conditions evidenced by darker coloration of the reaction solutions, and afforded lower PEA product material assay yields. Additionally, the higher melting points (~ 50°C) of the longer chain primary alcohols resulted in some procedural problems in handling of these solvents and reactions. On the other hand, the hydrocarbons solvents appeared to slow the decarboxylation reaction presumably due to the lower solubility of the phenylalanine starting material and required higher reactions temperatures. The reaction coloration in hydrocarbon solvents remained light yellow (more desirable). Unfortunately, precipitation was observed upon cooling of the reaction solutions of these hydrocarbon solvents and PEA product assay yields were found to be comparatively lower. The observation of precipitate upon cooling of the phenylalanine decarboxylation reactions in higher hydrocarbon solvents was the second contributing factor in the initiation of further studies, as described below in the subsequent example. Example 5: Study of ammonium carbamate salts

[0147] As described herein, differing yields were observed for phenylalanine decarboxylation reaction under open reaction conditions (glassware equipment) in comparison to failure of identical reactions that were conducted under closed/sealed or open reaction conditions. Without wishing to be limited by mechanism, these differences could point to a previously undescribed role of the liberated carbon dioxide on the decarboxylation reaction. Such in situ generated CO2 could form of an alternate product, other than the desired amine. One such alternate product can be an ammonium carbamate salt, which is a reaction product that arises from the presence of both a basic primary amine and carbon dioxide.

[0148] For phenylalanine as the amino acid, the ammonium carbamate salt would be a phenethylammonium phenethylcarbamate salt (IVa), which is produced by reacting the amino acid (phenethylamine, PEA) in the presence of CO2 (Eq. 1):

PEA Salt (IVa)

Initial studies included the feasibility of the formation of salt (IVa) under the phenylalanine decarboxylation reaction conditions, which involve the presence of both PEA and CO2. Indeed, when a concentrated solution of PEA in TIB (tri-isopropyl benzene) was allowed to stand in air for few days or bubbled with dry carbon dioxide gas for few minutes, an insoluble white crystalline solid was produced. The solid was assigned the structure shown in Eq. 1 above. The white solid was collected by washing with diethyl ether (5V) and drying under vacuum.

[0149] The salt (IVa) was found to be sparingly soluble in non-polar solvents such as diethyl ether and hydrocarbon solvents (TIB), and more soluble in polar solvents such as IPA, acetonitrile and cyclohexanol. These solubility observations further support the experimental observations in phenylalanine decarboxylation reactions of some post reaction precipitation in hydrocarbon solvents under open conditions (glassware equipment with TIB solvent), significantly more post reaction precipitation in hydrocarbon solvents under closed conditions (PARR equipment with TIB solvent), and clear homogeneous post reaction solutions in polar solvents (glassware equipment with CH solvent). [0150] GC-FID analysis of a solution of salt (IVa) in acetonitrile was found to exhibit an identical GC-FID trace to PEA. This indicates that salt (IVa) readily reverts back to PEA product material under GC inlet temperature of 150°C, as shown in Eq. 2:

Salt (IVa) PEA

This further supports the formation of salt (IVa) under the phenylalanine decarboxylation reactions conditions including conditions which employ non-polar solvent such as TIB where solid precipitation and lower yields were observed, and conditions which employ polar solvents such as cyclohexanol, where precipitation and lower yields were not observed.

[0151] The inevitable formation of salt (IVa) under the decarboxylation reaction conditions can be expected to have significant influence on the decarboxylation reaction. For instance, salt (IVa) can be expected to influence the decarboxylation reaction both negatively and positively based on chosen reaction parameters. On the negative side, the formation of salt (IVa) likely results in the lower PEA product yields under reaction conditions involving primary alcohol, amide, and higher hydrocarbon solvents. In the case of the primary alcohol and amide solvents, salt (IVa) likely reacts with such solvents resulting in lower PEA product yields. In the case of higher hydrocarbon solvents, salt (IVa) most likely results in the formation of chemically reversible hydrogels or polymers (particularly under sealed conditions) resulting in lower PEA product yields due to potentially inaccurate analysis.

[0152] On the positive side, the formation of salt (IVa) likely results in facilitation of the decarboxylation reaction by preventing poisoning of carbonyl catalysts by the PEA product since it sequesters the basic PEA product in a reversible protected form (ensures catalyst turnover). The acid hydrolysis and molar quantities of organocatalyst for decarboxylation reactions done under pressure reported in literature are likely required because the catalyst is bound to the product as the imine.

[0153] Two side-by-side phenylalanine decarboxylation reactions were performed to test this hypothesis. Both reactions were performed using TIB solvent (10V) and benzophenone catalysts (5 mol.%) at 175°C. One reaction was performed with typical overhead inert gas (argon) conditions while the other was performed with in-solution inert gas (argon) bubbling. The phenylalanine starting material was completely consumed to afford a clear homogeneous light yellow reaction solution under normal conditions (8 hours), whereas the phenylalanine staring material remained significantly unconsumed to afford a heterogeneous reaction mixture under in-solution bubbling conditions (8 hours). This indicates that formation of salt (IVa) likely also facilitates the amino acid decarboxylation reaction by freeing up the carbonyl catalyst.

[0154] Based on this understanding, product isolation and purification can be possible by formation of CO2 salt which under certain conditions precipitates from the reaction mixture. This salt can subsequently and readily be converted to the free amine upon heating (Eq. 1 is reversible). Isolation of PEA (product) via formation of the ammonium carbamate, a white crystalline solid insoluble in various reaction solvents (e.g., tri-isopropyl benzene), is a strategy not previously used for decarboxylation of L- Phe.

Example 6: Formation and isolation of corresponding amines

[0155] The methods herein can be taken together to form and isolate the desired amine. In one instance, the amine is isolated as a distillate. As seen in FIG. 4, in a vacuum rated vessel, the decarboxylation reaction mixture can be heated under vacuum until the solvent (cyclohexanol, boiling point 161.8°C) is collected as distillate, with the option of being recycled in other decarboxylation reactions. The temperature is further increased until PEA (product, boiling point 197 - 200°C) is collected as distillate; the distillation bottoms contain benzophenone and any residual L-phenylalanine which could be recycled into the decarboxylation process to further increase process yield.

[0156] Alternatively, the amine can be isolated as the ammonium carbamate salt. As seen in FIG. 5, after performing the decarboxylation of phenylalanine to produce PEA, to ensure complete formation of the PEA ammonium carbamate, the reaction mixture is bubbled with CO2. Given the solubility of the ammonium carbamate, this salt can be precipitated by cooling the reaction mixture followed by filtration. The filtrate, containing the organocatalyst and solvent can be recycled in for other decarboxylation reactions. The carbamate solid is stable and could potentially be used in further chemical reactions in this state but to recover the PEA, the carbamate solid would need to be dissolved in a polar solvent (with lower boiling point than PEA) and heated. This would result in CO2 evolution, leaving behind a solution of pure PEA. Solvent removal via evaporation would produce pure PEA, a colorless liquid. Other embodiments

[0157] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features hereinbefore set forth, and follows in the scope of the claims.

[0158] Other embodiments are within the claims.