Synthesis of substituted salicylaldehyde derivatives
Among other things, the present invention encompasses methods of synthesizing salicylaldehyde derivatives comprising the steps of: a) providing salicylaldehyde or a derivative thereof, b) forming an anhydro dimer of the provided salicylaldehyde compound, c) performing one or more chemical transformations on the anhydro dimer and d) hydrolyzing the anhydro dimer to provide a salicylaldehyde derivative different from that provided in step (a).
1. A method comprising the steps of:
a) providing a starting salicylaldehyde;
b) forming an anhydro dimer of the provided starting salicylaldehyde;
c) performing one or more chemical transformations on the anhydro dimer, wherein the step of performing one or more chemical transformations on the anhydro dimer comprises performing a carbon-carbon bond forming reaction on at least one aromatic ring of the anhydro dimer; and
(d) hydrolyzing the anhydro dimer to provide a salicylaldehyde different from that provided in step (a).
2. The method of claim 1 , comprising the steps of:
a) dehydrating the starting salicylaldehydes to form an anhydro dimer comprising two salicylaldehyde units;
b) alkylating at least one aromatic ring of the anhydro dimer in one or more positions; and
c) hydrolyzing the alkylated anhydro dimer to recover an alkylated salicyladehyde.
3. The method of claim 2 , wherein the step of alkylating the aromatic ring comprises reacting the anhydro dimer under Friedel Crafts alkylating conditions.
4. The method of claim 3 , wherein the Friedel Crafts alkylating conditions comprise reacting the anhydro dimer with at least one compound selected from the group consisting of: alkenes, alcohols, alkyl halides, and mixtures of two or more of these in the presence of a promoter selected from the group consisting of Lewis acids and proton acids.
5. The method of claim 2 , wherein the alkylation occurs equally on both salicylaldhyde units comprising the anhydro dimer.
6. The method of claim 2 , wherein:
the alkylation occurs at the aromatic ring position ortho to the hydroxyl group of the starting salicylaldehyde;
the alkylation occurs at the aromatic ring position para to the hydroxyl group of the starting salicylaldehyde; or
bis alkylation occurs at aromatic ring positions ortho and para to the hydroxyl group of the starting salicylaldehyde.
7. The method of claim 2 , wherein the method comprises a first alkylating step using a first alkylating reagent and a second alkylating step using a second alkylating reagent wherein the first and second alkylating reagents are different.
8. The method of claim 7 , wherein the first alkyating step introduces a substituent at the aryl position para to the phenol hydroxy group of the starting salicylaldehyde and the second alkylating step introduces a different substituent at the aryl position ortho to the phenol hydroxy group of the starting salicylaldehyde.
9. The method of claim 2 , wherein:
the starting salicylaldehyde is substituted at the aryl position ortho to the phenol and the alkylation step introduces a substituent at the aryl position para to the phenol hydroxyl group of the starting salicylaldehyde; or
the starting salicylaldehyde is substituted at the aryl position para to the phenol and the alkylation step introduces a substituent at the aryl position ortho to the phenol hydroxyl group of the starting salicylaldehyde.
10. The method of claim 2 , wherein the anhydro dimer formed in step (a) of claim 4 has a formula:
wherein at least one of R 1 , R 2 , R 3 , and R 4 is —H, and the remainder are each independently selected from the group consisting of halogen, —NO 2 , —CN, —Si(R y ) 3 , —SR y , —S(O)R y , —S(O) 2 R y , —NR y C(O)R y , —OC(O)R y , —CO 2 R y , —NCO, —N 3 , —OR y , —OC(O)N(R y ) 2 , —N(R y ) 2 , —NR y C(O)R y , —NR y C(O)OR y ; or an optionally substituted radical selected from the group consisting of C 1-20 aliphatic; C 1-20 heteroaliphatic; phenyl; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle, a 7-14 carbon saturated, partially unsaturated or aromatic polycyclic carbocycle; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 12-membered polycyclic saturated or partially unsaturated heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where each occurrence of R y is independently —H, or an optionally substituted radical selected from the group consisting of C 1-6 aliphatic, 3- to 7-membered heterocyclic, phenyl, and 8- to 10-membered aryl, and where two or more adjacent R y groups can be taken together to form an optionally substituted saturated, partially unsaturated, or aromatic 5- to 12-membered ring containing 0 to 4 heteroatoms.
11. The method of claim 10 , wherein R 3 is H in dehydrating step (a).
12. The method of claim 11 , wherein R 1 in dehydrating step (a) is selected from the group consisting of optionally substituted C 1-20 aliphatic, and optionally substituted aryl.
13. The method of claim 12 , wherein R 1 in dehydrating step (a) is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, isoamyl, tert-amyl, and substituted phenyl.
14. The method of claim 10 , wherein the alkylation at step (b) changes R 3 from —H to an optionally substituted aliphatic group.
15. The method of claim 1 , wherein the anhydro dimer formed in step (c) has a formula:
wherein at least one of R 1 , R 2 , R 3 , and R 4 is —H, and the remainder are each independently selected from the group consisting of halogen, —NO 2 , —CN, —Si(R y ) 3 , —SR y , —S(O)R y , —S(O) 2 R y , —NR y C(O)R y , —OC(O)R y , —CO 2 R y , —NCO, —N 3 , —OR y , —O C(O)N(R y ) 2 , —N(R y ) 2 , —NR y C(O)R y , —NR y C(O)OR y ; or is selected from the group consisting of C 1-20 aliphatic; C 1-20 heteroaliphatic; phenyl; a 3- to 8-membered saturated or partially unsaturated monocyclic carbocycle; a 7-14 carbon saturated, partially unsaturated or aromatic polycyclic carbocycle; a 5- to 6-membered monocyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 3- to 8-membered saturated or partially unsaturated heterocyclic ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur; a 6- to 12-membered polycyclic saturated or partially unsaturated heterocycle having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; or an 8- to 10-membered bicyclic heteroaryl ring having 1-5 heteroatoms independently selected from nitrogen, oxygen, or sulfur; where each occurrence of R y is independently —H, or is selected from the group consisting of C 1-6 aliphatic, 3- to 7-membered heterocyclic, phenyl, and 8- to 10- membered aryl, and where two or more adjacent R y groups can be taken together to form a saturated, partially unsaturated, or aromatic 5- to 12-membered ring containing 0 to 4 heteroatoms; and
wherein a chemical transformation at step (c) changes R 3 from —H to an optionally substituted C 1-20 aliphatic group, or an optionally substituted aryl group.
16. A method comprising the steps of:
a) providing a starting salicylaldehyde;
b) forming an anhydro dimer of the provided starting salicylaldehyde;
c) performing one or more chemical transformations on the anhydro dimer, wherein the step of performing one or more chemical transformations on the anhydro dimer comprises performing a carbon-heteroatom bond forming reaction selected from halogenation, oxidation, silylation, metalation on at least one aromatic ring of the anhydro dimer; and
(d) hydrolyzing the anhydro dimer to provide a salicylaldehyde different from that provided in step (a).
17. The method of claim 16 , wherein the carbon-heteroatom bond forming reaction is halogenation.
18. The method of claim 17 , wherein after halogenation, one or more addition chemical transformations are performed on the anhydro dimer.
19. The method of claim 16 , wherein the carbon-heteroatom bond forming reaction introduces a group linked via an atom selected from the group consisting of oxygen, nitrogen, sulfur, phosphorous, boron, tin, silicon, lithium, magnesium, and combinations of two or more of these.
20. A method comprising the steps of:
a) providing a starting salicylaldehyde;
b) forming an anhydro dimer of the provided starting salicylaldehyde;
c) performing one or more chemical transformations on the anhydro dimer, wherein the step of performing one or more chemical transformations on the anhydro dimer comprises one or more chemical reactions to manipulate functional groups already present on the dimer;
wherein the functional groups manipulated are attached to the aryl ring of the salicaldehyde or substituents attached to the aryl rings;
(d) hydrolyzing the anhydro dimer to provide a salicylaldehyde different from that provided in step (a).
21. The method of claim 20 , wherein the chemical reactions are selected from reductions, oxidations, additions, protections, cycloadditions, aminations, decarboxylation, halogenations, transition metal-catalyzed carbon-carbon bond couplings, click reactions, or ring-closing or cross metathesis reactions.
22. The method of claim 21 , wherein the chemical reaction is halogenation.
23. The method of claim 21 , wherein after halogenation, one or more addition chemical transformations are performed on the anhydro dimer.
24. The method of claim 1 , wherein the carbon-carbon bond forming reaction is selected from alkylations, arylations, or acylations.
25. The method of claim 21 , wherein the chemical reaction is amination.