JAYE JOSEPH A (US)
MCCORMICK GRANT M (US)
BERGER KRISTEN E (US)
US20110278556A1 | 2011-11-17 | |||
US20140252318A1 | 2014-09-11 |
SEIJAS ET AL.: "Microwave enhanced synthesis of acridines. A new aspect in the Bernthsen reaction", FOURTH INTERNATIONAL ELECTRONIC CONFERENCE ON SYNTHETIC ORGANIC CHEMISTRY (ECSOC-4), September 2000 (2000-09-01), pages 1 - 2, XP055554326
CLAIMS What is claimed is: 1. A method of making substituted acridities, the method comprising: reacting a bis(halophenyl) amine with an alkyne for a time and at a temperature to yield a substituted acridine. 2. The method of claim 1, wherein the bis(halophenyl)amine is a bis(bromophenyl) amine. 3. The method of claim 1, wherein the bis(halophenyl)amine is a bis(2- bromophenyl)amine. 4. The method of claim 1, wherein the bis(halophenyl)amine is bis(2- bromophenyl)amine. 5. The method of claim 1, wherein the alkyne is selected from the group consisting of R-C≡CH, wherein R is phenyl, substituted phenyl, C1-12-linear, branched, or cyclic alkyl, and Ci- 12- linear, branched, or cyclic alkoxy. 6. The method of claim 1 , wherein the reaction is conducted in a solvent comprising an amine group. 7. The method of claim 6, wherein the solvent comprises a di(alkyl)amine. 8. A method of making 9-substituted acridines, the method comprising: reacting a bis(2-bromophenyl) amine with an alkyne for a time and at a temperature to yield a 9-substituted acridine. 9. The method of claim 8, wherein the alkyne is selected from the group consisting of R-C≡CH, wherein R is phenyl, substituted phenyl, C1-12- linear, branched, or cyclic alkyl, and C1- 12- linear, branched, or cyclic alkoxy. 10. The method of claim 8, wherein the reaction is conducted in a solvent comprising an amine group. 11. The method of claim 10, wherein the solvent comprises a di(alkyl)amine. 12. A 9-substituted acridine of Formula I: wherein, R1 through R8 are the same or different and are independently selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteraryl, R9 is selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteraryl, carboxy, alkanoyl, alkanoyloxy, amido, cyano, isocyano, thiocyano, and isothiocyano; R10 is absent or, when R10 is present, R10 is independently selected form the substituents noted above for R1 thorugh R8, and the nitrogen atom to which R10 is bound bears a positive charge; and "n" is an integer of from 1 to 16; produced by reacting a bis(halophenyl) amine with an alkyne for a time and at a temperature to yield a 9-substituted acridine of Formula I. 13. The acridine of Claim 12, wherein R9 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl. 14. The acridine of Claim 13, having a formula as shown in Formula II: wherein R11 is selected from hydrogen, hydroxy, halogen, alkyl, substituted alky], alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteraryl. 15. The acridine of Claim 14, having a formula as shown in Formula ΙΠ: wherein R1 ', R2 , R3 , R4 , R5 , R6 , R7 , and R8 are the same or different and are selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteraryl; and "m" is an integer of from 1-16. |
CROSS-REFERENCE TO RELATED APPLICATIONS
Priority is hereby claimed to provisional application Serial No. 62/509,804, filed May 23, 2017, which is incorporated herein by reference.
FIELD OF THE INVENTION
Disclosed is a novel synthesis of substituted acridines. The synthesis is achieved by the palladium catalyzed closure of terminal acetylenes with bis(2-bromophenyl)amine. By including a diamine base and elevating temperatures, the reaction pathway favors the formation of acridine. The method works with aryl-alkynes containing donating and withdrawing groups as well as alkyl-alkynes.
BACKGROUND
Acridines are characterized by the linear fusing of three aromatic 6-membered rings with a nitrogen atom included in the center ring. 11 Acridines were first isolated from coal tar by Graebe in 1870. 12 The ability of acridine to bind DNA has made it a target for anticancer and
antimicrobial uses. However, current industrial uses for acridine include organic dyes and staining agents for microscopy. 13"16 More recently, acridines have been used for their electronic properties as hole transporting layers in organic light-emitting diodes (OLEDs) and as photo- redox catalysts. 16, 17
Acridine has the following structure and numbering scheme:
It is a mildly basic, colorless solid. Conventionally, acridine and 9-substituted acridines are formed via the Bernthsen acridine synthesis. Here, diphenylamine is condensed with a carboxylic acid in the presence of zinc chloride. When formic acid is used as the carboxylic acid, the reaction yields the parent acridine. When longer carboxylic acids are used, the reaction yields 9-substituted acridines.
SUMMARY OF THE INVENTION
In synthesizing new precursors for study, new cross-coupling pathways were used to produce a variety of polycylic aromatic molecules, particularly substituted acridines. This approach to acridine synthesis has not been observed previously, and it holds a great deal of potential for future synthetic and mechanistic insight. It is also highly useful for the production of acridine and substituted acridines.
The interest in acridine arose from the observation that the microwave-induced reaction of phenylacetylene with bis(2-bromophenyl)amine (3) in the presence of a diamine solvent unexpectedly resulted in a significant yield of an unknown molecule. Isolation and
characterization of this structure revealed that the reaction was producing 9-benzylacridine as the major product of the reaction. Acridines are typically synthesized by electrophilic aromatic substitution of pendant carboxylic acid derivatives or by adding groups on the edge of smaller rings. 18"24 Both of these methods typically require further processing to aromatize the acridine ring following closure. Though some tandem processes have been shown previously, none incorporate alkynes in a manner similar to the work disclosed herein. 25"27 Several methods use microwave chemistry to produce acridines. 28"29 The reaction described here was first observed in the microwave; it also proceeds via traditional heating methods.
Thus, the following methods are disclosed and claimed herein:
1. A method of making substituted acridines, the method comprising:
reacting a bis(halophenyl) amine with an alkyne for a time and at a temperature to yield a substituted acridine. 2. The method of claim 1, wherein the bis(halophenyl)amine is a bis(bromophenyl) amine.
3. The method of claim 1, wherein the bis(halophenyl)amine is a bis(2- bromophenyl)amine.
4. The method of claim 1, wherein the bis(halophenyl)arnine is bis(2- bromophenyl)amine.
5. The method of claim 1, wherein the alkyne is selected from the group consisting of R-C≡CH, wherein R is phenyl, substituted phenyl, C 1-12 -linear, branched, or cyclic alkyl, and Ci- 12- linear, branched, or cyclic alkoxy.
6. The method of claim 1, wherein the reaction is conducted in a solvent comprising an amine group.
7. The method of claim 6, wherein the solvent comprises a di(alkyl)amine.
8. A method of making 9-substituted acridines, the method comprising:
reacting a bis(2-bromophenyl) amine with an alkyne for a time and at a temperature to yield a 9-substituted acridine.
9. The method of claim 8, wherein the alkyne is selected from the group consisting of R-C≡CH, wherein R is phenyl, substituted phenyl, C 1-12 - linear, branched, or cyclic alkyl, and Ci- 12- linear, branched, or cyclic alkoxy.
10. The method of claim 8, wherein the reaction is conducted in a solvent comprising an amine group.
11. The method of claim 10, wherein the solvent comprises a di(alkyl)amine.
12. A 9-substituted acridine of Formula I:
wherein, R through R are the same or different and are independently selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteraryl,
R 9 is selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteraryl, carboxy, alkanoyl, alkanoyloxy, amido, cyano, isocyano, thiocyano, and isothiocyano;
R 10 is absent or, when R 10 is present, R 10 is independently selected form the subslituents noted above for R 1 thorugh R 8 , and the nitrogen atom to which R 10 is bound bears a positive charge; and
"n" is an integer of from 1 to 16; produced by
reacting a bis(halophenyl) amine with an alkyne for a time and at a temperature to yield a 9-substituted acridine of Formula I.
13. The acridine of Claim 12, wherein R 9 is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
14. The acridine of Claim 13, having a formula as shown in Formula Π:
wherein R is selected from hydrogen, hydroxy, halogen, alkyL, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaiyl, and substituted heteraryl. 15. The acridine of Claim 14, having a formula as shown in Formula HI:
wherein R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , and R 8' are the same or different and are selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteraryl; and
"m" is an integer of from 1-16.
DETAILED DESCRIPTION
Abbreviations and Definitions:
The following terms are used throughout as defined below.
As used herein and in the appended claims, singular articles such as "a" and "an" and "the" and similar referents in the context of describing the elements (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., "such as") provided herein, is intended merely to better illuminate the
embodiments and does not pose a limitation on the scope of the claims unless otherwise stated. No language in the specification should be construed as indicating any non-claimed element as essential.
As used herein, "about" will be understood by persons of ordinary skill in the art and will vary to some extent depending upon the context in which it is used. If there are uses of the term which are not clear to persons of ordinary skill in the art, given the context in which it is used, "about" will mean up to plus or minus 10% of the particular term.
Generally, reference to a certain element such as hydrogen or H is meant to include all isotopes of that element. For example, if an R group is defined to include hydrogen or H, it also includes deuterium and tritium. Compounds comprising radioisotopes such as tritium, C 14 , P 32 and S 35 are thus within the scope of the present technology. Procedures for inserting such labels into the compounds of the present technology will be readily apparent to those skilled in the art based on the disclosure herein. In general, "substituted" refers to an organic group as defined below (e.g., an alkyl group) in which one or more bonds to a hydrogen atom contained therein are replaced by a bond to non- hydrogen or non-carbon atoms. Substituted groups also include groups in which one or more bonds to a carbon(s) or hydrogen(s) atom are replaced by one or more bonds, including double or triple bonds, to a heteroatom. Thus, a substituted group is substituted with one or more substituents, unless otherwise specified. In some embodiments, a substituted group is substituted with 1, 2, 3, 4, 5, or 6 substituents. Examples of substituent groups include: halogens (i.e., CI. F, Br, and I); hydroxyls; alkoxy, alkenoxy, aryloxy, aralkyloxy, heterocyclyloxy, and
heterocyclylalkoxy groups; carbonyls (oxo); carboxyls; esters; methanes; oximes;
hydroxylamines; alkoxyamines; aralkoxy amines; thiols; sulfides; sulfoxides; sulfones; sulfonyls; sulfonamides; amines; N-oxides; hydrazines; hydrazides; hydrazones; azides; amides; ureas; amidines; guanidines; enamines; imides; isocyanates; isothiocyanates; cyanates; thiocyanates; imines; nitro groups; nitriles (i.e., CN); and the like.
Substituted ring groups such as substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups also include rings and ring systems in which a bond to a hydrogen atom is replaced with a bond to a carbon atom. Therefore, substituted cycloalkyl, aryl, heterocyclyl and heteroaryl groups may also be substituted with substituted or unsubstituted alkyl, alkenyl, and alkynyl groups as defined below.
"Acridine" refers genetically to the unsubstituted compound:
"Acridines," when used genetically, refers to acridine and substituted acridines and acridines that have a quaternary nitrogen - i.e., quaternary salts of acridines:
The term "alkyl" refers to a branched or unbranched carbon chain having, for example, about 1-20 carbon atoms, and often 1-12, 1-10, 1-8, 1-6, or 1-4 carbons. Examples include, but are not limited to, methyl, ethyl, 1 -propyl, 2-propyl, 1 -butyl, 2-methyl-l -propyl, 2-butyl, 2- methyl-2-piopyl (t-butyl), 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3- methyl-1 -butyl, 2-methyl-l -butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2- pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3- dimethyl-2-butyl, hexyl, octyl, decyl, dodecyl, and the like. The alkyl can be unsubstituted or substituted. The alkyl can also be optionally partially or fully unsaturated.. As such, the recitation of an alkyl group optionally includes both alkenyl and alkynyl groups. The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., an alkylene).
The term "cycloalkyl" refers to cyclic alkyl groups of, for example, 3 to about 12, 3 to about 10, 3 to about 8, about 4 to about 8, or 5-6, carbon atoms having a single cyclic ring or multiple condensed rings. Cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantyl, and the like. The cycloalkyl can be unsubstituted or substituted. The cycloalkyl group can be monovalent or divalent, and can be optionally substituted as described for alkyl groups. The cycloalkyl group can optionally include one or more cites of unsaturation, for example, the cycloalkyl group can include one or more carbon-carbon double bonds, such as, for example, 1-cyclopent-l-enyl, l-cyclopent-2-enyl, l-cyclopent-3-enyl, cyclohexyl, 1- cyclohex-l-enyl, l-cyclohex-2-enyl, l-cyclohex-3-enyl, and the like. Bi- and tricyclic ring systems include both bridged cycloalkyl groups and fused rings, such as, but not limited to, bicyclo[2.1.1]hexane, adamantyl, decalinyl, and the like.
Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms. Aryl groups herein include monocyclic, bicyclic and tricyclic ring systems. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, fluorenyl, phenanthrenyl, anthracenyl, indenyl, indanyl, pentalenyl, and naphthyl groups. In some embodiments, aryl groups contain 6-14 carbons, and in others from 6 to 12 or even 6-10 carbon atoms in the ring portions of the groups. In some embodiments, the aryl groups are phenyl or naphthyl. Although the phrase "aryl groups" includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like), it does not include aryl groups that have other groups, such as alkyl or halo groups, bonded to one of the ring members. Rather, groups such as tolyl are referred to as substituted aryl groups. Representative substituted aryl groups may be mono-substituted or substituted more than once. For example, monosubstituted aryl groups include, but are not limited to, 2-, 3-, 4-, 5-, or 6-substituted phenyl or naphthyl groups, which may be substituted with substituents such as those listed above.
Aralkyl groups are alkyl groups as defined above in which a hydrogen or carbon bond of an alkyl group is replaced with a bond to an aryl group as defined above. In some embodiments, aralkyl groups contain 7 to 16 carbon atoms, 7 to 14 carbon atoms, or 7 to 10 carbon atoms. Substituted aralkyl groups may be substituted at the alkyl, the aryl or both the alkyl and aryl portions of the group. Representative aralkyl groups include but are not limited to benzyl and phenethyl groups and fused (cycloalkylaryl)alkyl groups such as 4-indanylethyl. Representative substituted aralkyl groups may be substituted one or more times with substituents such as those listed above.
Heterocyclyl groups include aromatic (also referred to as heteroaryl) and non-aromatic ring compounds containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, and S. In some embodiments, the heterocyclyl group contains 1, 2, 3 or 4 heteroatoms. In some embodiments, heterocyclyl groups include mono-, bi- and tricyclic rings having 3 to 16 ring members, whereas other such groups have 3 to 6, 3 to 10, 3 to 12, or 3 to 14 ring members. Heterocyclyl groups encompass aromatic, partially unsaturated and saturated ring systems, such as, for example, imidazolyl, imidazolinyl and imidazolidinyl groups. The phrase "heterocyclyl group" includes fused ring species including those comprising fused aromatic and non-aromatic groups, such as, for example, benzotriazolyl, 2,3- dihydrobenzo[l,4]dioxinyl, and benzo[l,3]dioxolyl. The phrase also includes bridged polycyclic ring systems containing a heteroatom such as, but not limited to, quinuclidyl. However, the phrase does not include heterocyclyl groups that have other groups, such as alkyl, oxo or halo groups, bonded to one of the ring members. Rather, these are referred to as "substituted heterocyclyl groups". Heterocyclyl groups include, but are not limited to, aziridinyl, azetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrothiophenyl,
tetrahydrofuranyl, dioxolyl, furanyl, thiophenyl, pyrrolyl, pyrrolinyl, imidazolyl, imidazolinyl, pyrazolyl, pyrazolinyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, thiazolinyl, isothiazolyl, thiadiazolyl, oxadiazolyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, tetrahydropyranyl, tetrahydrothiopyranyl, oxathiane, dioxyl, dithianyl, pyranyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, dihydropyridyl, dihydrodithiinyl, dihydrodithionyl, homopiperazinyl, quinuclidyl, indolyl, indolinyl, isoindolyl, azaindolyl (pyrrolopyridyl), indazolyl, indolizinyl, benzotriazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, benzthiazolyl, benzoxadiazolyl, benzoxazinyl, benzodithiinyl, benzoxathiinyl, benzothiazinyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, benzo[l,3]dioxolyl, pyrazolopyridyl, imidazopyridyl (azabenzimidazolyl), triazolopyridyl, isoxazolopyridyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl, pteridinyl, thianaphthyl, dihydrobenzothiazinyl, dihydrobenzofuranyl, dihydroindolyl, dihydrobenzodioxinyl, tetrahydroindolyl,
tetrahydroindazolyl, tetrahydrobenzimidazolyl, tetrahydrobenzotriazolyl,
tetrahydropyiTolopyridyl, tetrahydropyrazolopyridyl, tetrahydroiniidazopyridyl,
tetrahydrotriazolopyridyl, and tetrahydroquinolinyl groups. Representative substituted
heterocyclyl groups may be mono-substituted or substituted more than once, such as, but not limited to, pyridyl or morpholinyl groups, which are 2-, 3-, 4-, 5-, or 6-substituted, or
disubstituted with various substituents such as those listed above.
Heteroaryl groups are aromatic ring compounds containing 5 or more ring members, of which, one or more is a heteroatom such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, thiophenyl,
benzothiophenyl, furanyl, benzofuranyl, indolyl, azaindolyl (pyrrolopyridinyl), indazolyl, benzimidazolyl, imidazopyridinyl (azabenzimidazolyl), pyrazolopyridinyl, triazolopyridinyl, benzotriazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl,
isoxazolopyridinyl, thianaphthyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl,
isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups. Heteroaryl groups include fused ring compounds in which all rings are aromatic such as indolyl groups and include fused ring compounds in which only one of the rings is aromatic, such as 2,3-dihydio indolyl groups. Although the phrase "heteroaryl groups" includes fused ring compounds, the phrase does not include heteroaryl groups that have other groups bonded to one of the ring members, such as alkyl groups. Rather, heteroaryl groups with such substitution are referred to as "substituted heteroaryl groups." Representative substituted heteroaryl groups may be substituted one or more times with various substituents such as those listed above.
Groups described herein having two or more points of attachment (i.e., divalent, trivalent, or polyvalent) within the compound of the present technology are designated by use of the suffix, "ene." For example, divalent alkyl groups are alkylene groups, divalent aryl groups are arylene groups, divalent heteroaryl groups are divalent heteroarylene groups, and so forth. Substituted groups having a single point of attachment to the compound of the present technology are not referred to using the "ene" designation. Thus, e.g., chloroethyl is not referred to herein as chloroethylene.
Alkoxy groups are hydroxyl groups (— OH) bonded to a carbon atom of a substituted or unsubstituted alkyl group as defined above. Examples of linear alkoxy groups include but are not limited to methoxy, ethoxy, propoxy, butoxy, pentoxy, hexoxy, and the like. Examples of branched alkoxy groups include but are not limited to isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, isohexoxy, and the like. Examples of cycloalkoxy groups include but are not limited to cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, and the like. Representative substituted alkoxy groups may be substituted one or more times with substituents such as those listed above.
The terms "alkanoyl" and "alkanoyloxy" as used herein can refer, respectively, to— C(=0)-alkyl groups and— O— C(=0)-alkyl groups, each containing 2-16 carbon atoms.
The terms "aryloxy" and "arylalkoxy" refer to, respectively, a substituted or
unsubstituted aryl group bonded to an oxygen atom and a substituted or unsubstituted aralkyl group bonded to the oxygen atom at the alkyl. Examples include but are not limited to phenoxy, naphthyloxy, and benzyloxy. Representative substituted aryloxy and arylalkoxy groups may be substituted one or more times with substituents such as those listed above.
The term "carboxylate" as used herein refers to a— COOH group.
The term "ester" as used herein refers to— COOR groups, in which R is a substituted or unsubstituted alkyl, cycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein.
The term "amide" (or "amido") includes C- and N-amide groups, i.e.,— C(=0)NRR', and— NRC(=0)R' groups, respectively. R and R' are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. Amido groups therefore include but are not limited to carbamoyl groups (— C(=0)NH 2 ) and formamide groups (— NHC(=0)H). In some embodiments, the amide is— NRC(=0)— (Ci-5 alkyl) and the group is termed "carbonylamino," and in others the amide is— NHC(=0)-alkyl and the group is termed "alkanoylamino." The term "nitrile" or "cyano" as used herein refers to the— C≡N group.
The term "amine" (or "amino") as used herein refers to— NRR' groups, wherein R and R' are independently hydrogen, or a substituted or unsubstituted alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heterocyclylalkyl or heterocyclyl group as defined herein. In some embodiments, the amine is alkylamino, dialkylamino, arylamino, or alkylarylamino. In other embodiments, the amine is NH 2 , methylamino, dimethylamino, ethylamino, diethylamino, propylamino, isopropylamino, phenylamino, or benzylamino.
The term "halogen" or "halo" as used herein refers to chlorine, fluorine,, bromine, and iodine.
'Tautomers" refers to isomeric forms of a compound that are in equilibrium with each other. The presence and concentrations of the isomeric forms will depend on the environment the compound is found in and may be different depending upon, for example, whether the compound is a solid or is in an organic or aqueous solution. For example, in aqueous solution,
quinazolinones may exhibit the following isomeric forms, which are referred to as tautomers of each other:
Because of the limits of representing compounds by structural formulas, it is to be understood that all chemical formulas of the compounds described herein represent all tautomeric forms of compounds and are within the scope of the present technology.
Stereoisomers of compounds (also known as optical isomers) include all chiral, diastereomeric, and racemic forms of a structure, unless the specific stereochemistry is expressly indicated. Thus, compounds used in the present technology include enriched or resolved optical isomers at any or all asymmetric atoms as are apparent from the depictions. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be isolated or synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these stereoisomers are all within the scope of the present technology.
The term "solvent" refers to any liquid that can dissolve a compound to form a solution. Amme-containing solvents include, but are not limited to di(alkyl)amines, such as
dnsopropylamine, ethylene diamine, tetramemylemylenediamine, and the like. Numerical ranges as used herein are intended to include every number and subset of numbers contained within that range, whether specifically disclosed or not. Further, these numerical ranges should be construed as providing support for a claim directed to any number or subset of numbers in that range. For example, a disclosure of from 1 to 10 should be construed as supporting a range of from 2 to 8, from 3 to 7, from 1 to 9, from 3.6 to 4.6, from 3.5 to 9.9, and so forth.
All references to singular characteristics or limitations of the present invention shall include the corresponding plural characteristic or limitation, and vice- versa, unless otherwise specified or clearly implied to the contrary by the context in which the reference is made. The indefinite articles "a" and "an" mean "one or more," unless explicitly limited to the singular.
All combinations of method or process steps as used herein can be performed in any order, unless otherwise specified or clearly implied to the contrary by the context in which the referenced combination is made.
The methods of the present invention can comprise, consist of, or consist essentially of the essential elements and limitations of the method described herein, as well as any additional or optional ingredients, components, or limitations described herein or otherwise useful in synthetic organic chemistry.
The method:
The precursor bis(2-bromophenyl)amine 3 was synthesized in 68% yield from 2- bromoaniline 1 and bromoiodobenze 2 by a palladium catalyzed cross coupling reaction in the presence of bis(2-diphenylphosphino)phenyl)ether (DPEPhos). See Reaction Scheme 1. 30 This system allows for nearly complete reaction between the iodine and the aniline groups with little evidence for homocoupling between halides or bromo-iodo mixtures in the products. The dibromo product 3 can then be converted to bis(tolan)amine (i.e., bis(diphenylacetylene)amine) 4a in 63% yield by a double Sonogashira cross-coupling reaction with phenyl-acetylene and using diisopropylamine as a solvent. Reaction Scheme 1: Cross-Coupling Reactions to Produce Precursor 3 and Bis(tolan)amine 4a
The diisopropyl amine was replaced with ethylene diamine and raised the temperature of the reaction. The presence of the di-aryl amine and two halogen atoms makes 3 a multi-faceted molecule for synthesis. The amine group can be further functionalized by Buchwald-Hartwig type reactions, the halides are excellent handles for cross couplings, and inter- and intra-molecular homocoupling reactions are possible as well. 31 With the diamine solvent, we discovered that bis(tolan)amine 4a was no longer the major product of the reaction. Instead, 9-benzylacridine (5a) was present with small amounts of 4a and carbazole 6 from homocoupling of the ortho-bromides. See Table 1.
Table 1: Production of 9-Substituted Acridines 5a-5f
The above synthetic scheme can be used to fabricate a host of structurally related analogs, such as those having a structure as shown in Formula I:
wherein, R 1 through R are the same or different and are independently selected from hydrogen, hydroxy, halogen, alkyl, substituted alky], alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteraryl,
R 9 is selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, substituted heteraryl, carboxy, alkanoyl, alkanoyloxy, amido, cyano, isocyano, thiocyano, and isothiocyano;
R 10 is absent or, when R 10 is present, R 10 is independently selected form the substituents noted above for R 1 thorugh R 8 , and the nitrogen atom to which R 10 is bound bears a positive charge; and
"n" is an integer of from 1 to 16.
Specifically included within the above definition are 9-substituted acridines, and bis(9- substitued acridines) of Formula II and III, respectively:
wherein, R 1 -R 10 and "n" are as defined previously; Formula ΙII presents the same situation as in Formula I when R 9 is a substituted aryl (i.e., an aryl substituted with a 9-acridine);
R 11 is selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteraryl;
R 1' , R 2' , R 3' , R 4' , R 5' , R 6' , R 7' , and R 8' are the same or different and are selected from hydrogen, hydroxy, halogen, alkyl, substituted alkyl, alkoxy, substituted alkoxy, aryl, substituted aryl, aralkyl, substituted aralkyl, heterocyclyl, substituted heterocyclyl, heteroaryl, and substituted heteraryl; and
"m" is an integer of from 1-16.
Without being limited to any mechanism or underlying chemical phenomena, it appears the terminal alkyne reacts with one of the bromides of bis(2-bromophenyl)amine and rather than the second bromide performing a Sonogashira cross-coupling, it proceeds to do an intramolecular cyclization at the terminal carbon. This closes the diarylamine into a three-ring system. Through proton transfers, the rings are aromatized and a benzylic methylene is formed adjacent to the imposition of the acridine. The reaction was screened the reaction at varying temperatures with one equivalent of phenyl acetylene to optimize the reaction for acridine. Though 180 °C did not have the highest yield of acridine it appeared that bis(tolan)amine 4a and carbazole 6 products were minimized. The equivalents of alkyne, solvent, and substituents on the alkyne were varied. The acridine yield using tetramethylenediamine (TMEDA) remained comparable to the yield obtained using ethylene diamine. Electron rich and poor terminal alkynes including alkyl substituted alkynes all produced acridine in varying amounts. We were able to produce a range of 9-substituted acridines including benzyl (5a), 4-methylbenzyl- (5b), 4-methoxybenzyl- (5c), 4- fluorobenzyl- (5d), heptylacridine- (5e), and 5-phenylpentyl-acridine (5f) were produced. Though electron-rich substituents produced higher yields, it was possible to obtain acridines with 4- fluorophenylacetylene and even alkynes with no conjugated aromatic groups such as 1-octyne and 6-phenyl-l-hexyne. The major side-products remained carbazoles from intramolecular homocoupling of the halides along with a variety of products with the terminal alkyne adding to the amine or alkyne degradation products. All of these side-products, though, formed to a lesser extent than the formation of the acridine.
The representative examples shown in Table 1 used microwave heating for the synthesis. A few methods for acridine synthesis in the literature use microwave reactors. 23, 28 ' 29 To ensure the reaction results were not related to the heat source, we tested the synthesis of molecules 5a-f under the same reaction conditions with conventional heating in round-bottomed flasks at 180 °C in an oil bath. The results were consistent with the microwave reactions and had similar yields. EXAMPLES:
The following examples are included to provide a more complete disclosure of the method described and claimed herein. The examples do not limit the scope of the claims in any fashion.
General Experimental:
Reagents and anhydrous solvents were purchased from Sigma-Aldrich (St. Louis, Missouri, USA). All other chemicals were used without purification unless otherwise noted. NMR spectra were acquired on a JEOL 400 MHz NMR spectrometer with chloroform-rfi (6H = 7.26 ppm 5c = 77.23 ppm) or acetone-ifc (6H = 2.05 ppm 6c = 206.26 ppm). All coupling constants were generated by the MestReNova program (Mestrelab Research, Escondido, California, USA, a wholly owned subsidiary of Mestrelab Research, S.L., Santiago de
Compostela, Spain) and were uncorrected. Chromatography was performed with Biotage KP- SIL™ or KP-NH™ cartridges (Biotage AB, Uppsala, Sweden) or SiliCycle-brand silica gel (porosity = 60 A, particle size 40-63 um) (SiliCycle Inc., Quebec, Canada). Microwave reactions were run on the Discover Microwave System by CEM Corporation (Matthews, North Carolina, USA). High-resolution mass spectrographic data were acquired with an Agilent 7200 GC/QTOF (Agilent Technologies, Santa Clara, California, USA) or a Bruker Bio TOF II with Electrospray Ionization (Bruker Company, Billerica, Massachusetts, USA). Synthesis of Bis(bromophenyl)amine 3 :
To a flame-dried 35 mL microwave vial with a teflon cap, 16 mL of anhydrous toluene was added followed by 3.176g (33.1 mmol) of sodium tert-butoxide then 2.63 mL (23.2 mmol) of 2-bromoaniline (1) and 2.98 mL (23.2 mmol) of 2-bromoiodobenzene dropwise and stirred. The ligand (oxydi-2,l-phenylene)bis(diphenylphosphine) ("DPEPhos"), 0.1026g (0.190 mmol), and 0.0298g (0.133 mmol) Pd(OAc)2 were added then heated 30 minutes at 150 °C in a microwave reactor. The product was extracted with 3 x 35 mL of dichloromethane and the combined organic layer was washed with water (3xl50mL). The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resulting product was recrystallized from ethanol to yield white or gray needles 67.7%.
MP 59.8-60.7 °C 1 H NMR (400 MHz, CDCb) δ: 7.58 (dd, J = 8.0 Hz, 1.6 Hz, 2H), 7.30 (dd, J = 8.0 Hz, 1.6 Hz, 2H), 7.22 (td, J = 8.4 Hz, 1.2 Hz, 2H), 6.84 (td, J = 7.6 Hz, 2.0 Hz, 2H), 6.44 (s, 1H). 13 C NMR (100 MHz, CDCb) δ: 140.13, 133.39, 128.23, 122.67, 118.08, 114.38. HRMS (EI) calc. for C 11 H 9 Br 2 N = 324.9102, found 324.9094. UV-Vis (CH 2 Ch) λ max (ε, cm- lM-1) 287 (39000).
Synthesis of Bis(tolan)amine (4).
To a flame-dried 35mL microwave vial with a teflon cap, 25 mL of diisopropylamine was added via syringe and degassed with nitrogen for ten minutes. To this vessel 0.5095g (1.6 mmol) of bis(2-bromophenyl)amine 3, 0.140 g (0.74 mmol) Cul, and 0.1111 g Pd(PPh 3 )2Ch (0.16 mmol) were added sequentially while stirring under nitrogen. Subsequently 0.84 mL of phenyl acetylene was added dropwise via syringe over 30 min heating for 2.5 hours at 150 °C in a microwave reactor. Upon completion, the reaction was poured over ice and extracted into dichloromethane (3x50mL). The combined organic layer was washed with water (3xl00mL) then concentrated in vacuo. The reaction was then purified using a KP-NH™ flash column using hexanes and ethyl acetate to produce a yellow solid in 63% yield.
MP 136.6-137.1 °C Ή NMR (400 MHz, CDCb) δ: 7.53 (dd, J = 1.4 Hz, 7.7 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.38 (m, 5H), 7.28 (t, J = 7.3 Hz, 2H), 7.22-7.17 (m, 2H), 7.13 (t, J = 7.2 Hz, 4H), 6.90 (t, J = 7.6 Hz, 2H). 13 C NMR (100 MHz, CDCb) δ: 143.2, 132.9, 131.7, 129.4, 128.4, 128.3, 122.9, 120.1, 115.3, 112.2, 96.2, 85.6. HRMS (ESI) calc. for C 28 H 19 NNa [M+Na]+ = 392.141519, found 392.1433. UV-Vis (CH 2 C1 2 ) λ max (ε, cm-lM-1) 279 (160000), 312 (37000), 340 (44000).
General Procedure for Synthesis of 9-Substituted Acridine Derivatives 5a-5f:
To a flame-dried 35 mL microwave vial with a teflon coated cap, 25 mL of ethylene diamine was added via syringe and degassed with nitrogen for 20 minutes. To this vessel was added 0.5037 g (1.5 mmol) of bis(2-bromophenyl)amine, 0.0658 g (0.30 mmol) of copper iodide, and 0.2188 g (0.30 mmol) of bis(triphenylphosphine)palladium dichloride sequentially while stirring under nitrogen. Next 3.0 mmol of aryl acetylene was added drop wise via syringe. The reaction flask was heated for 1.5 hours at 180 °C in a microwave reactor. Upon completion, the reaction was then poured over ice, extracted into dichloromethane (3x 35 mL) and the combined organic layers were washed with water three times before purifying on an amine treated KP-NH™ silica flash column using hexanes and ethyl acetate as eluent.
Preparation of 9-(phenylmethyl)acridine (5a):
The general procedure for the synthesis of 9-substituted acridine derivatives above was followed with 0.33 mL (3.0 mmol) phenyl acetylene. The reaction produced a mustard yellow solid in 0.2170 g (53%) yield.
MP 160.6-163.6 °C. 1 H NMR (400 MHz, CDCb) δ: 8.25 (t, J = 8.0 Hz, 4H), 7.77 (t, J = 4.0 Hz, 2H), 7.53 (td, J = 8.0 Hz,1.2 Hz 2H), 7.24-7.16 (m, 3H), 7.11 (d, J = 6.8 Hz, 2H). 13 C NMR (100 MHz, CDCb) δ: 149.0, 143.6, 139.5, 130.5, 130.0, 128.9, 128.3, 126.2, 126.2 125.8, 124.9, 33.3. HRMS (ESI) calc. for CioHisN = 270.1283, found 270.1204. UV-Vis (CH2CI2) λ max (ε, cm-lM-1) 255 (120000), 280 (sh, 5100), 343 (5700), 361 (8600), 387 (38000). Preparation of 9-[(4-methylphenyl)methyl]acridine (5b):
The general procedure for the synthesis of 9-substituted acridine derivatives above was followed with 0.39 mL (3.0 mmol) 4-ethynyltoluene. The reaction produced a pale white solid in 0.2361 g (55%) yield.
MP 160.6-163.6 °C. 1 H NMR (400 MHz, CDCb) δ: 8.25 (dd J = 8.9 Hz, 9.1 Hz, 4H) 7.77 (ddd, J = 1.2 Hz, 8.8 Hz, 8.8 Hz, 2H), 7.52 (ddd, J = 1.2 Hz, 8.8 Hz, 8.9 Hz, 2H), 7.01 (aa'bb' J =
8.4 Hz, 8.4 Hz, 4.8 Hz, 4H), 4.99 (s, 2H), 2.26 (s, 2H). 13 C NMR (100 MHz, CDC13) δ: 149.04, 143.90, 136.42, 136.16, 130.49, 129.95, 129.52, 128.12, 126.16, 125.80, 124.94, 32.89, 21.11. HRMS (ESI) calc. For C 2 iHi 8 N [M+l]+ = 284.1439, found 284.1431. UV-Vis (CH2CI2) λ max (ε, cm-lM-1) 255 (130000), 247 (sh, 55000), 342 (6100), 362 (9100), 387 (3000).
Preparation of 9-[(4-anisolephenyl)methyl]acridine (5c):
The general procedure for the synthesis of 9-substituted acridine derivatives above was followed with 0.39 mL (3.0 mmol) 4-ethnynlanisole. The reaction produced a light cream colored solid in 0.1550 g (35%) yield.
MP 135.9-138.7 °C. 1 H NMR (400 MHz, CDCb) δ: 8.25 (dd, J = 7.8 Hz, 8.0 Hz, 4H), 7.77 (ddd, J = .8 Hz, 8.5 Hz, 8.6 Hz, 2H), 7.53 (ddd, J = 1.1 Hz, 8.6 Hz, 8.5 Hz, 2H), 7.02 (d, J =
8.7 Hz, 2H), 6.75 (d, J = 8.8 Hz, 2H), 4.96 (s, 2H), 3.72 (s, 3H). 13 C NMR (100 MHz, CDCb) δ: 158.2, 149.0, 144.0, 131.5, 130.5, 130.0, 129.2, 126.1, 125.7, 124.9, 114.2, 55.4, 32.4. HRMS (ESI) calc. for C 2 iHi 8 NO = 300.1388, found 300.1381. UV-Vis (CH2CI2) λ max (ε, cm- lM-1) 255 (430000), 247 (sh, 180000), 344 (19000), 361 (28000), 387 (14000).
Preparation of 9-[(4-flurophenyl)methyl)acridine (5d):
The general procedure for the synthesis of 9-substituted acridine derivatives above was followed with 0.35 mL (3.0 mmol) l-ethynyl-4-flurobenzene. The reaction produced a toffee- colored solid in 0.1192 g (27%) yield.
MP 163.6-165.9 °C 1H NMR (400 MHz, DMSO) δ: 8.45 (d, J = 9.0 Hz, 2H), 8.18 (d, J =
8.5 Hz, 2H), 7.85 (dd, J = 7.7 Hz, 8.8 Hz, 2H), 7.64 (dd, J = 7.5 Hz, 8.8 Hz, 2H), 7.17 (dd, J =
8.8 Hz, 8.5 Hz, 2H), 7.04 (t, J = 8.8 Hz, 2H), 5.10 (s, 2H) 13C NMR (100 MHz, CDC13) δ: 149.1, 143.2, 130.7, 130.0, 129.7, 129.6, 126.3, 125.7, 126.4, 125.7, 124.7, 115.8, 115.6, 32.5 HRMS (EI) calc. for C20H14FN 287.1111, found 287.1108 UV-Vis (CH2C12) Xmax (ε, cm- 1M- 1) 255 (470000), 343 (23000), 360 (35000), 385 (16000). Preparation of 9-heptylacridine (5e):
The general procedure for the synthesis of 9-substituted acridine derivatives above was followed with 0.45 mL (3.0 mmol) 1-octyne. The reaction produced a light red oil in 0.0781 g (19%) yield.
1H NMR (400 MHz, CDC1 3 ) δ: 8.23 (dd, J = 8.8 Hz, 8.8 Hz, 2H), 7.76 (dd, J = 7.7 Hz, 8.6 Hz, 2H), 7.56 (dd, J = 8.4 Hz, 8.6 Hz, 2H), 3.61 (t, J = 8.0 Hz, 2H), 1.82 (p, J = 7.8 Hz, 2H), 1.57 (p, J = 7.2 Hz, 2H), 1.40 (p, J = 6.9 Hz, 2H), 1.33-1.29 (m, 4H), .89 (t, J = 6.7 Hz, 3H). 13 C NMR (100 MHz, CDCI3) δ: 148.9, 130.6, 129.8, 125.6, 125.0, 124.5, 32.0, 31.6, 29.3, 27.9, 22.8, 14.3. HRMS (EI) calc. for C20H23N = 277.1831, found 277.1817. UV-Vis (CH2C12) max (ε, cm-lM-1) 255 (320000), 247 (sh, 130000), 359 (190000), 388 (8500).
Preparation of 9-[(4-phenylbutane)methyl]acridine (5f):
The general procedure for the synthesis of 9-substituted acridine derivatives above was followed with 0.46 mL (3.0 mmol) 5-phenyl-l-pentyne. The reaction produced a pale green oil in 0.0496 g (10%) yield.
1H NMR (400 MHz, CDCI3) δ: 8.22 (d, J = 8.7 Hz, 2H), 8.21 (d, J = 8.6 Hz, 2H), 7.76 (ddd, J = 8.4 Hz, .7 Hz, 8.6 Hz, 2H), 7.55 (ddd, J = 8.6 Hz, 10.3 Hz, 1.0 Hz, 2H), 7.28 (t, 2H), 7.21- 7.16 (mp, 3H), 3.64 (t, J = 7.9 Hz, 2H), 2.70 (t, J = 6.9 Hz, 2H), 1.93-1.84 (brm, 4H). 13 C NMR (100 MHz, CDC13) δ: 148.8, 142.1, 136.6, 129.9, 128.5, 126.0, 125.7, 125.0, 124.5, 35.8, 32.0, 31.11, 31.04, 27.7. HRMS (EI) calc. for C23H21N = 311.1674, found 311.1685. UV- Vis (CH2C12) max (ε, cm-lM-1) 255 (89000), 247 (sh, 40000), 360 (5900), 386 (2600).
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