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WO2004096766A1 - A method of indole synthesis - Google Patents

A method of indole synthesis Download PDF

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Publication number
WO2004096766A1
WO2004096766A1 PCT/AU2004/000551 AU2004000551W WO2004096766A1 WO 2004096766 A1 WO2004096766 A1 WO 2004096766A1 AU 2004000551 W AU2004000551 W AU 2004000551W WO 2004096766 A1 WO2004096766 A1 WO 2004096766A1
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Prior art keywords
nitroarene
ort
enone
coupling
enal
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PCT/AU2004/000551
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French (fr)
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Martin Gerhardt Banwell
David William Lupton
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The Australian National University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/08—Indoles; Hydrogenated indoles with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/82—Carbazoles; Hydrogenated carbazoles
    • C07D209/88—Carbazoles; Hydrogenated carbazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the ring system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/80—[b, c]- or [b, d]-condensed
    • C07D209/94—[b, c]- or [b, d]-condensed containing carbocyclic rings other than six-membered

Definitions

  • the present invention relates generally to new synthetic methods for preparing indole compounds.
  • the invention relates to methods employing the step of coupling of an ⁇ -haloenone or ⁇ -haloenal with an ort ⁇ o-halonitroarene.
  • the invention also relates to methods employing the step of reductively cyclizing an ⁇ rt ⁇ o-(enone)nitroarene or ⁇ rt ? ⁇ -(enal)nitroarene .
  • the indole moiety represents a key substructure associated with many biologically active natural products and medicinal entities ((a) Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996. (b) Joule, J. A. Indole and its Derivatives. In Science of Synthesis: Houben-Weyl Methods of Molecular Transformations, Thomas, E. J., Ed.; Georg Thieme Verlag: Stuttgart, 2000; Category 2, Vol. 10, Chapter 10.13. (c) Gribble, G. W. J. Chem. Soc, Perkin Trans. 1 2000, 1045). As such, various methods have been developed for the construction of this ring system ((a) Sundberg, R. J. supra (b) Joule, J.A.
  • NPIF o-nitrophenylphenyliodonium fluoride
  • the NPIF employed in such conversions is produced over two steps from the corresponding ort ⁇ o-iodonitroarene whilst the TMS-enol ether can be generated through 1 ,4-reduction/enolate trapping of the relevant enone or enolisation of the appropriate ketone under conditions of kinetic or thermodynamic control followed by trapping with chlorotrimethylsilane.
  • TMS-enol ether can be generated through 1 ,4-reduction/enolate trapping of the relevant enone or enolisation of the appropriate ketone under conditions of kinetic or thermodynamic control followed by trapping with chlorotrimethylsilane.
  • the present invention provides a method for preparing an indole compound comprising the steps of:
  • the ⁇ rt ⁇ -(enone)nitroarene or ⁇ rt ⁇ -(enal)nitroarene resulting from step (i) may be subjected to a further step prior to the reductive cyclization:
  • the coupling of the ⁇ -haloenone or ⁇ -haloenal with the ⁇ rt ⁇ o-halonitroarene is carried out using copper (Cu), preferably in the presence of a Pd[0] catalyst.
  • reductive cyclization of the ⁇ rt/ ⁇ -(enone)nitroarene or ⁇ rt 2 ⁇ -(enal)nitroarene is carried out with dihydrogen (H 2 ) in the presence of Pd on carbon (Pd/C).
  • One particular aspect of the invention provides a method for preparing an ortho- (enone)nitroarene or ort/z ⁇ -(enal)nitroarene by coupling a ⁇ -haloenone or ⁇ -haloenal with an ort/zo-halonitroarene.
  • the present invention provides access to indole compounds via the reductive cyclization of an ⁇ rt ⁇ -(enone)nitroarene or ort ⁇ -(enal)nitroarene.
  • the present invention provides a 2-step procedure as a means of gaining access to indole compounds.
  • the first step involves coupling of an ⁇ -haloenone or an ⁇ -haloenal with an ⁇ rt/r ⁇ -halonitroarene, such that a single covalent bond is formed between the two carbon atoms which bore the halo groups, to form an ⁇ rt ⁇ o-(enone)nitroarene or ort ⁇ o-(enal)nitroarene respectively.
  • the second step involves a reductive cyclization of an ⁇ rt/? ⁇ -(enone)nitroarene or ⁇ rt ; ⁇ -(enal)nitroarene obtained therefrom to form the five-membered N-containing ring of the indole compound.
  • an indole compound refers to a compound (or molecule) which contains the indole moiety or indole core, ie
  • Indole compounds prepared by the methods of the present invention include the indole core substituted with a substituent at one or more of the 2-, 3-, 4-, 5-, 6-, or 7-positions. Two adjacent positions may be substituted so as to form a further ring fused to the indole core. Where multiple substituents are present, they may be the same or different.
  • halo is intended to include iodo, bromo and chloro, preferably iodo or bromo.
  • ⁇ -haloenone refers to a molecule containing an ⁇ , ⁇ -unsaturated ketone moiety having a halo substituent at the ⁇ -position (of the ⁇ , ⁇ -double bond).
  • the ⁇ , ⁇ -unsaturated ketone moiety may be part of a cyclic or acyclic molecule.
  • Cyclic ⁇ -haloenones may be monocyclic or polycyclic (fused or non-fused).
  • the ⁇ , ⁇ -unsaturated ketone moiety may be separate to or part of a ring system.
  • Suitable cyclic ⁇ -haloenones wherein the ⁇ , ⁇ -unsaturated ketone moiety is part of a ring include ⁇ -halocyclopentenones, ⁇ - halocyclohexenones, ⁇ -halocycloheptenones and ⁇ -halocycloocteneones.
  • ⁇ -haloenone is an ⁇ -halocyclohexenone
  • the present invention affords access to the tetrahydrocarbazole framework.
  • the ⁇ -haloenone is acyclic, ie open-chain, this provided access to non-annulated indoles.
  • ⁇ -haloenal refers to a molecule containing an ⁇ , ⁇ -unsaturated aldehyde moiety having a halo substituent at the ⁇ -position.
  • ⁇ -haloenals also affords access to non-annulated indoles.
  • ⁇ rt ⁇ o-halonitroarene is intended to refer to a molecule containing a nitro substituted benzene ring further substituted by a halo group ortho- to the nitro group.
  • the benzene ring may be fused to one or more mono- or poly-cyclic (aromatic or non- aromatic) groups, eg to form ⁇ rt ?o-halonitronaphthalenes, ⁇ rt ⁇ -halonitroindenes, ort 20-halonitroanthracenes, and ort& ⁇ -halonitrofluorenes.
  • ort/r ⁇ -(enone)nitroarene refers to a molecule containing a nitro-substituted benzene ring (which may be fused to one or more mono or polycyclic groups as described above) bearing an ⁇ , ⁇ -unsaturated ketone moiety ortho- to the nitro group wherein a single covalent bond is present between an ort/r ⁇ -carbon atom of the nitroarene and the ⁇ -carbon of the ⁇ , ⁇ -unsaturated ketone.
  • ort/r ⁇ -(enal)nitroarene refers to a molecule containing a nitro-substituted benzene ring (which may be fused to one or more mono- or polycyclic groups as described above) bearing an ⁇ - ⁇ -unsaturated aldehyde moiety ortho- to the nitro group wherein a single covalent bond is present between an ortfto-carbon atom of the nitroarene and the ⁇ - carbon (of the ⁇ , ⁇ -double bond) of the ⁇ , ⁇ -unsaturated aldehyde.
  • Substituents at any of the 2-, 3-, 4-, 5-, 6-, or 7-positions of the formed indole compound may arise from appropriate substitution of the starting ⁇ -haloenone, ⁇ -haloenal or ort 20-halonitroarene, or subsequent substitution of the ⁇ rt/r ⁇ -(enone)nitroarene or ort ? ⁇ -(enal)nitroarene formed directly therefrom (eg via cross-coupling processes known in the art).
  • the ⁇ rt ⁇ -(enone)nitroarene or ort r ⁇ -fenal)nitroarene which is subjected to reductive cyclization is intended to include ⁇ rt ⁇ o-(enone)nitroarenes and ort ⁇ o-(enal)nitroarenes formed or obtained directly from appropriately substituted or protected ⁇ -haloenones, ⁇ -haloenals and/or ort ⁇ o-halonitroarenes as well as ort/jo-(enone)nitroarenes and ort/r ⁇ -(enal)nitroarenes which are indirectly obtained or formed therefrom e.g.
  • the resulting indole compound bears a substituent at the 2-position.
  • the indole compound bears a substituent at the 3-position.
  • the indole compound bears the same or different substituents at both the 2- and the 3-position (2,3-disubstitution).
  • a further example of such disubstitution is where the 2- and 3-positions form part of an additional ring, such as a 5-, 6- or 7-membered ring, fused to the indole core (annulated indoles).
  • the indole compound bears a substituent at one, two, three or four of the 4-, 5-, 6- or 7-positions, particularly the 5- or 6-position.
  • ⁇ -haloenone, ⁇ -haloenal, ort ⁇ o-halonitroarene and ort ⁇ o-(enone)nitroarenes and ⁇ rt/r ⁇ -(enal)nitroarenes formed directly or indirectly therefrom may bear any other type of substituent or fused group provided that the substituents or fused groups do not substantially interfere with the coupling or reductive cyclization process.
  • Substituents that may potentially interfere with the coupling or cyclization process may be protected by a suitable protecting group and deprotected as required. Suitable protecting groups for various substituents are known in the art and are described in standard reference texts such as Protective Groups in Organic Chemistry, T.W. Greene and P.G.M.
  • Substituents present on the ⁇ -haloenone, ⁇ -haloenal, ort ⁇ o-halonitroarene, ⁇ rt/r ⁇ -(enone)nitroarene or ort ⁇ o-(enal)nitroarene, and accordingly, the indole compound formed directly or indirectly therefrom may, where appropriate, include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, acyl, halogen (F, Cl, Br, I), hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, acyloxy, amino, cyano, nitro, thio, thioalkyl, carboxyl, carboxy ester and amido, each of which may be further optionally substituted, where appropriate, as defined herein.
  • substituents which may be contemplated include alkyl, (eg C 1-6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (eg hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (eg methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (eg C 1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halogen (F, Cl, Br, I), trifluoromethyl, trichloromethyl, tribromomethyl.
  • alkyl eg C 1-6 alkyl such as methyl, ethyl, propyl, butyl,
  • alkyl denotes saturated straight chain, branched or cyclic hydrocarbon groups, preferably C ⁇ . 20 alkyl, eg Ci-io or C ⁇ - 6 .
  • straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl and branched isomers thereof, n-hexyl and branched isomers thereof, n-heptyl and branched isomers thereof, n-octyl and branched isomers thereof, n-nonyl and branched isomers thereof, and n-decyl and branched isomers thereof.
  • cyclic alkyl examples include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like.
  • An alkyl group may be further optionally substituted by one or more optional substituents as herein defined.
  • alkenyl denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C 2- 0 alkenyl (eg C 2 . 10 or C 2-6 ).
  • alkenyl examples include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3- decenyl, 1,3-butadienyl, 1 -4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4- hexadienyl, 1,3-cyclohexadienyl, 1 ,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5- cycl
  • alkynyl denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethynically mono-, di- or poly- unsaturated alkyl or cycloalkyl groups as previously defined.
  • the term preferably refers to C ⁇ - 20 alkynyl. Examples include ethynyl, 1- propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers.
  • An alkynyl group may be further optionally substituted by one or more optional substituents as herein defined.
  • aryl used either alone or in compound words denotes single, polynuclear, conjugated or fused residues of aromatic hydrocarbons.
  • aryl include phenyl, biphenyl, te ⁇ henyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl and chrysenyl.
  • Preferred aryl groups include phenyl and naphthyl.
  • aryl group may be further optionally substituted by one or more optional substituents as herein defined.
  • heteroaryl refers to aromatic heterocyclic ring systems, wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) of a cyclic hydrocarbon residue are replaced with a heteroatom to provide an aromatic residue. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. Suitable heteroatoms include O, N, S and Se.
  • heteroaryl examples include pyridyl, thienyl, furyl, pyrrolyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benoxazolyl, benzothiazolyl and the like.
  • Preferred heteroaryl groups include pyridyl, thienyl, furyl, pyrrolyl.
  • a heteroaryl group may be optionally substituted by one or more optional substituents as herein defined.
  • heterocyclyl when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C 3-20 (eg C 3-10 or C 3-6 ) wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue.
  • Suitable heteroatoms include, O, N, S, and Se. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms.
  • heterocyclic groups may include pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, mo ⁇ holino, indolinyl, imiazolidinyl, pyrazolidinyl, thiomo ⁇ holino, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl etc.
  • a heterocyclyl group may be further optionally substituted by one or more optional substituents as herein defined.
  • Preferred acyl includes C(O)-R, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, residue, preferably a C ⁇ -2 o residue.
  • acyl examples include formyl; straight chain or branched alkanoyl such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, tolu
  • phenylacetyl phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl
  • naphthylalkanoyl e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]
  • aralkenoyl such as phenylalkenoyl (e.g.
  • phenylpropenoyl e.g., phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g.
  • aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl
  • arylthiocarbamoyl such as phenylthiocarbamoyl
  • arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl
  • arylsulfonyl such as phenylsulfonyl and napthylsulfonyl
  • heterocycliccarbonyl heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl
  • alkoxy, alkenoxy alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy and acyloxy respectively denote alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and acyl groups as hereinbefore defined when linked by oxygen.
  • thioalkyl refers to an alkyl group when linked by sulfur.
  • Carboxyl refers to the group CO 2 H and “carboxy ester” refers to the group CO 2 R wherein R is any group not being H.
  • R includes alkyl and aryl.
  • amino and “amido” refer to groups NRR' and CONRR' respectively, wherein R and R" can independently be H, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaryl, heterocyclyl.
  • a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkenylacyl, alkenylacyl,
  • optional substituents include alkyl, (eg C 1-6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (eg hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (eg methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (eg C 1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halogen (F, Cl, Br, I), trifluoromethyl, trichloromethyl, tribromomethyl.
  • alkyl eg C 1-6 alkyl such as methyl, ethyl, propyl, butyl, cyclopropy
  • benzyl (wherein benzyl itself may be further optionally substituted), phenoxy (wherein phenyl itself may be further optionally substituted), benzyloxy (wherein benzyl itself may be further optionally substituted), amino, alkylamino (eg Ci- ⁇ alkyl, such as methylamino, ethylamino, propylamino etc), dialkylamino (eg C ⁇ -6 alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (eg NHC(O)CH 3 ), phenylamino (wherein phenyl itself may be further substituted), nitro, formyl, -C(O)-alkyl (eg Cj- alkyl, such as acetyl), O-C(O)-alkyl (eg C ⁇ _ 6 alkyl, such as acety
  • the coupling of the ort ⁇ o-halonitroarene with the ⁇ -haloenone or ⁇ -haloenal to form the indole compound is carried out in the presence of a suitable metal coupling agent such as Ni[0] or Cu[0], preferably with Cu[0] (eg Cu powder).
  • a suitable metal coupling agent such as Ni[0] or Cu[0]
  • the coupling is carried under Pd[0] catalysis which may afford the advantage of higher yields and/or shortened reaction times. Any active Pd[0] species may be used.
  • Suitable examples of a Pd[0] catalyst include Pd 2 (dba) 3 and Pd(PPh 3 ) 4 .
  • a Pd[0] catalyst may be generated in situ, eg through reduction by the Cu, from a suitable Pd[II] catalyst.
  • suitable Pd[II] catalyst examples thereof include PdCl 2 (dppf), Pd(OAc) 2 , PdCl 2 (CH 3 CN) 2 , Pd(C 6 H 5 CN) 2 Cl 2 and PdCl 2 (PPh 3 ) 2
  • the coupling process is carried out for a time and under conditions suitable for the formation of the desired ort/r ⁇ -(enone)nitroarene or ort /o-(enal)nitroarene.
  • the person skilled in the art would readily be able to determine appropriate conditions by routine experimentation.
  • the coupling process may be carried out in any suitable solvent, such as dimefhylformamide, dimethoxyethane, dimethylsulfoxide, or N-methylpyrrolidinone.
  • a particularly preferred solvent is dimethylsulfoxide.
  • the coupling process may be carried out at any suitable temperature, preferably from about 30°-100°, more preferably about 50°- 90°, even more preferably from about 50°-70°.
  • Reductive cyclization of the ort ⁇ o-(enone)nitroarene or ort/ ⁇ -(enal)nitroarene may be performed under any suitable reducing conditions known in the art.
  • the reductive cyclization is carried out using H 2 in the presence of a suitable catalyst such as PtO 2 , RI1/AI 2 O 3 , Pd(OH) 2 , Raney Nickel or Pd/C.
  • a suitable catalyst such as PtO 2 , RI1/AI 2 O 3 , Pd(OH) 2 , Raney Nickel or Pd/C.
  • a preferred catalyst is Pd/C.
  • Requisite ⁇ -haloenones or ⁇ -haloenals may be readily obtained by halogenation of the corresponding enone or enal according to known procedures (see for example, Johnson, C.R. et al, Tetrahedron Lett. 1992, 33, 917; Smith, A.B. et al J. Org. Chem., 1982, 47, 1855; and Ramanarayanan, G.V. et al, Synlett., 2002, 2059).
  • Table 1 illustrates the ⁇ rt/z ⁇ -(enone)nitroarene or ort/zo-(enal)nitroarene and corresponding indole compounds formed from 2-iodonitrobenzene or 2- bromonitrobenzene and the illustrated ⁇ -haloenone or ⁇ -haloenal.
  • Table 2 illustrates ort ⁇ o-(enone)nitroarenes and the corresponding indole compounds formed from 2-iodo-2-cyclohexen-l-one and the illustrated ort ⁇ o-halonitroarene.
  • halogenated or appropriately substituted ort ⁇ o-halonitroarenes may be particularly useful substrates in the present invention as they allow for other cross-coupling reactions to introduce additional ie replacement substitution on the benzene ring.
  • This is illustrated in Entry 2c of Table 2.
  • the dibromonitrobenzene 24 regioselectively coupled with 2- iodo-2-cyclohexen-l-one to form the bromo-ort ?o-enonenitroarene 25.
  • Suzuki-Miyaura coupling of 25 with l,3-benzodioxol-5-ylboronic acid afforded 26.
  • Compound 26 underwent reductive cyclization to afford the indole 28 (under shorter reaction times the cyclohexanone analogue of 26 was also produced).
  • the methods described herein may find utility in the preparation of indole compounds having biological importance.
  • examples of two such classes of compounds are the tryptamines (Spandoni, G., J. Med. Chem., 1997, 40, 1990 and Marias W. and Holzapfel, C.W., Synth. Commun., 1998, 28, 3681) and the carbazoles (Moody, C.J., Synlett., 1994, 681).
  • Table A illustrates a variety of conditions ("halo", solvent, catalyst, reaction temperature) which may be employed in the coupling of an ort ⁇ o-halonitroarene and an ort/*o-haloenone to form the desired ort/zo-(enone)nitroarene.
  • the by-product arising from the homocoupling of 1 can be suppressed by reducing the amount of haloarene employed and/or by slow addition of compound 1 to the reaction mixture. Formation of the byproduct can also be suppressed by judicious choice of coupling partners eg. by coupling the ort ⁇ o-bromonitroarene with the relevant ⁇ -iodoenal or enone.
  • a magnetically stirred mixture of the appropriate 2-halonitroarene (10 mmol), the appropriate ⁇ -halo-enone or -enal (5 mmol), copper powder (1.59 g of 99% material, 25 g.atom, CAS No. 7440-50-8) and Pd 2 (dba) 3 (260 mg, 0.25 mmol) in DMSO (15 mL) was heated at 70°C for 1 h under a nitrogen atmosphere then cooled and diluted with diethyl ether (150 mL). The resulting mixture was then filtered through a pad of Celite and the solids thus retained washed with ether (50 mL).
  • the title compound was prepared by Suzuki-Miyaura cross-coupling of bromo-arene 25 with 1 ,3-benzodioxol-5-ylboronic acid (Banwell, M.G., and Cowden, C.J. Aust. J. Chem., 1994, 47, 2235).
  • a magnetically stirred mixture of compound 25 225 mg, 0.76 mmol
  • the above-mentioned acid, Pd(PPh 3 ) 4 27 mg, 0.02 mmol
  • K 2 CO 3 1.8 mL of a 2 M aqueous solution
  • benzene (10 mL) and ethanol (3.75 mL) was heated at reflux for 16 h.

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Abstract

The present invention relates to methods for the synthesis of indoles. In particular, the invention relates to the coupling of an a-haloenone or a-haloenal with an ortho-halonitroarene to form an ortho-(enone)nitroarene or ortho-(enal)nitroarene. Reductive cyclization of an ortho-(enone)nitroarene or ortho-(enal)nitroarene affords access to indole compounds.

Description

A METHOD OF INDOLE SYNTHESIS
FIELD OF THE INVENTION
The present invention relates generally to new synthetic methods for preparing indole compounds. In particular, the invention relates to methods employing the step of coupling of an α-haloenone or α-haloenal with an ortΛo-halonitroarene. The invention also relates to methods employing the step of reductively cyclizing an σrtΛo-(enone)nitroarene or ørt ?ø-(enal)nitroarene .
BACKGROUND
The indole moiety represents a key substructure associated with many biologically active natural products and medicinal entities ((a) Sundberg, R. J. Indoles; Academic Press: San Diego, CA, 1996. (b) Joule, J. A. Indole and its Derivatives. In Science of Synthesis: Houben-Weyl Methods of Molecular Transformations, Thomas, E. J., Ed.; Georg Thieme Verlag: Stuttgart, 2000; Category 2, Vol. 10, Chapter 10.13. (c) Gribble, G. W. J. Chem. Soc, Perkin Trans. 1 2000, 1045). As such, various methods have been developed for the construction of this ring system ((a) Sundberg, R. J. supra (b) Joule, J.A. supra (c) Gribble, G. W. supra (d) Robinson, B. The Fischer Indole Synthesis; Wiley-Interscience: New York, 1982. (e) Hughes, D. L. Org. Prep. Proced. Int. 1993, 25, 607). The most well known and venerable method is the Fischer indole synthesis wherein an arylhydrazine is condensed with a enolisable ketone to give, after loss of ammonia, the corresponding 2,3- disubstituted indole. Whilst being an enormously important procedure, this approach suffers from a number of drawbacks, not the least being the rather harsh reaction conditions required to effect [3,3]-sigmatropic rearrangement of the initially produced hydrazone and the lack of regiocontrol available when employing ketones that can exist in more than one enolic form. One approach to addressing these difficulties (Iwama, T. et al; Org. Lett. 1999, 1, 673) is through the coupling of o-nitrophenylphenyliodonium fluoride (NPIF) with various trimethylsilyl enol ethers followed by TiCl3-induced reductive cyclization of the resulting α-(ortΛo-nitrophenyl)ketone to give 2,3-disubstituted indoles. The NPIF employed in such conversions is produced over two steps from the corresponding ortΛo-iodonitroarene whilst the TMS-enol ether can be generated through 1 ,4-reduction/enolate trapping of the relevant enone or enolisation of the appropriate ketone under conditions of kinetic or thermodynamic control followed by trapping with chlorotrimethylsilane. In other recent and related work, it was reported (Scott, T. L. and Soderberg, B. C. G. Tetrahedron Lett. 2002, 43, 1621) that the products of Stille-cross coupling of ortΛo-(tri-«-butylstannyl)nitrobenzene with various α-iodocycloalkenones engage in a novel metal-catalysed reductive N-heteroannulation in the presence of 6 atmospheres of CO to give l,2-dihydro-4(3H)-carbazolones. Further recent work (Ohshima, T. et al., J. Am. Chem. Soc. 2002, 124, 14546) has described the synthesis of (-)-strychnine, the indole residue of which is assembled via Stille cross-coupling of an α-iodocyclohexenone with ort zo-(tri-«-methylstannyl)nitrobenzene then reductive cyclization of the coupling product with zinc in methanolic aqueous ammonium chloride. In an especially important development, Buchwald and co-workers (Rutherford, J. L. et al., J. Am. Chem. Soc. 2002, 124, 15168) have demonstrated that methyl and certain other enolisable ketones can couple with ortΛo-chloro- or -bromonitrobenzenes in the presence of Pd (dba)3 and phenolic additives to give α-(ørt zø-nitroaryl)ketones that undergo reductive cyclization to the corresponding indoles on exposure to TiCl /ΝΗ4OAc.
Notwithstanding the existing methods for preparing indole compounds, the disadvantages associated therewith, eg, harsh conditions, lack of regiocontrol, use of stannanes or multiple/expensive reagents, indicate a continuing need for further processes which may circumvent one or more such shortcomings.
SUMMARY OF THE INVENTION
It has now been found that access to indole compounds may be achieved by a two-step process which may advantageously allow for the use of mild conditions and relatively simple, readily accessible and/or inexpensive reagents. Accordingly, in a first aspect, the present invention provides a method for preparing an indole compound comprising the steps of:
(i) coupling an α-haloenone or an α-haloenal with an ort/rø-halonitroarene to form an ørt/ϊø-(enone)nitroarene or ørtΛø-(enal)nitroarene respectively; and
(ii) reductively cyclizing the ørt/zø-(enone)nitroarene or ørtΛo-(enal)nitroarene.
Optionally, the ørtΛø-(enone)nitroarene or ørtΛø-(enal)nitroarene resulting from step (i) may be subjected to a further step prior to the reductive cyclization:
(i-a) protecting or deprotecting one or more substituents; and/or introducing one or more additional substituents; and/or replacing one or more substituents with another on the ørtΛø-(enone)nitroarene or ørtΛø-(enal)nitroarene.
In one embodiment of the invention, there is provided a method for preparing an indole compound comprising the steps of:
(i) coupling an α-haloenone or an α-haloenal with an ortΛø-halonitroarene to form an ørt/zø-(enone)nitroarene or ørt/?o-(enal)nitroarene respectively;
(ii) performing a cross-coupling step to introduce replacement substitution on the benzene ring of the ørtΛø-(enone)nitroarene or ørt 2θ-(enal)nitroarene; and
(iii) reductively cyclizing the ørt/iø-(enone)nitroarene or ørtΛø-(enal)nitroarene.
In a preferred embodiment, the coupling of the α-haloenone or α-haloenal with the ørtλo-halonitroarene is carried out using copper (Cu), preferably in the presence of a Pd[0] catalyst. In another preferred embodiment, reductive cyclization of the ørt/ ø-(enone)nitroarene or ørt 2ø-(enal)nitroarene is carried out with dihydrogen (H2) in the presence of Pd on carbon (Pd/C).
One particular aspect of the invention provides a method for preparing an ortho- (enone)nitroarene or ort/zø-(enal)nitroarene by coupling a α-haloenone or α-haloenal with an ort/zo-halonitroarene.
DETAILED DESCRIPTION OF THE INVENTION
Throughout this specification and the claims which follow, unless the context requires otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.
The reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that that prior art forms part of the common general knowledge in Australia.
The present invention provides access to indole compounds via the reductive cyclization of an ørtΛø-(enone)nitroarene or ortΛø-(enal)nitroarene. In one form, the present invention provides a 2-step procedure as a means of gaining access to indole compounds. The first step involves coupling of an α-haloenone or an α-haloenal with an ørt/rø-halonitroarene, such that a single covalent bond is formed between the two carbon atoms which bore the halo groups, to form an ørtΛo-(enone)nitroarene or ortΛo-(enal)nitroarene respectively. The second step involves a reductive cyclization of an ørt/?ø-(enone)nitroarene or ørt ;ø-(enal)nitroarene obtained therefrom to form the five-membered N-containing ring of the indole compound.
As used herein, an indole compound refers to a compound (or molecule) which contains the indole moiety or indole core, ie
Figure imgf000006_0001
Indole compounds prepared by the methods of the present invention include the indole core substituted with a substituent at one or more of the 2-, 3-, 4-, 5-, 6-, or 7-positions. Two adjacent positions may be substituted so as to form a further ring fused to the indole core. Where multiple substituents are present, they may be the same or different.
As used herein the term "halo", whether used alone or as part of a compound term, is intended to include iodo, bromo and chloro, preferably iodo or bromo.
An "α-haloenone" refers to a molecule containing an α,β-unsaturated ketone moiety having a halo substituent at the α-position (of the α,β-double bond). The α,β-unsaturated ketone moiety may be part of a cyclic or acyclic molecule. Cyclic α-haloenones may be monocyclic or polycyclic (fused or non-fused). The α,β-unsaturated ketone moiety may be separate to or part of a ring system. Examples of suitable cyclic α-haloenones wherein the α,β-unsaturated ketone moiety is part of a ring include α-halocyclopentenones, α- halocyclohexenones, α-halocycloheptenones and α-halocycloocteneones. Where the α- haloenone is an α-halocyclohexenone, the present invention affords access to the tetrahydrocarbazole framework. Where the α-haloenone is acyclic, ie open-chain, this provided access to non-annulated indoles.
An "α-haloenal" refers to a molecule containing an α,β-unsaturated aldehyde moiety having a halo substituent at the α-position. The use of α-haloenals also affords access to non-annulated indoles.
The term "ørtΛo-halonitroarene" is intended to refer to a molecule containing a nitro substituted benzene ring further substituted by a halo group ortho- to the nitro group. The benzene ring may be fused to one or more mono- or poly-cyclic (aromatic or non- aromatic) groups, eg to form ørt ?o-halonitronaphthalenes, ørtΛø-halonitroindenes, ort 20-halonitroanthracenes, and ort&ø-halonitrofluorenes.
The term "ort/rø-(enone)nitroarene" refers to a molecule containing a nitro-substituted benzene ring (which may be fused to one or more mono or polycyclic groups as described above) bearing an α,β-unsaturated ketone moiety ortho- to the nitro group wherein a single covalent bond is present between an ort/rø-carbon atom of the nitroarene and the α-carbon of the α,β-unsaturated ketone.
The term "ort/rø-(enal)nitroarene" refers to a molecule containing a nitro-substituted benzene ring (which may be fused to one or more mono- or polycyclic groups as described above) bearing an α-β-unsaturated aldehyde moiety ortho- to the nitro group wherein a single covalent bond is present between an ortfto-carbon atom of the nitroarene and the α- carbon (of the α,β-double bond) of the α,β-unsaturated aldehyde.
Substituents at any of the 2-, 3-, 4-, 5-, 6-, or 7-positions of the formed indole compound may arise from appropriate substitution of the starting α-haloenone, α-haloenal or ort 20-halonitroarene, or subsequent substitution of the ørt/rø-(enone)nitroarene or ort ?ø-(enal)nitroarene formed directly therefrom (eg via cross-coupling processes known in the art). Accordingly, as used herein, the ørtΛø-(enone)nitroarene or ort rø-fenal)nitroarene which is subjected to reductive cyclization is intended to include ørtΛo-(enone)nitroarenes and ortΛo-(enal)nitroarenes formed or obtained directly from appropriately substituted or protected α-haloenones, α-haloenals and/or ortΛo-halonitroarenes as well as ort/jo-(enone)nitroarenes and ort/rø-(enal)nitroarenes which are indirectly obtained or formed therefrom e.g. by further substitution prior to the reductive cyclization step (either by incorporating one or more additional substituents and/or replacing a substituent with another, and/or protecting a substituent with a protecting group and/or deprotecting a protected substituent and/or removing (i.e. replacing with H) a substituent). Indoles formed by further substitution, protection, deprotection or replacement or removal of a substituent after the reductive cyclization step are also contemplated by the invention.
In certain embodiments of the invention, the resulting indole compound bears a substituent at the 2-position. In alternative embodiments, the indole compound bears a substituent at the 3-position. In other embodiments the indole compound bears the same or different substituents at both the 2- and the 3-position (2,3-disubstitution). A further example of such disubstitution is where the 2- and 3-positions form part of an additional ring, such as a 5-, 6- or 7-membered ring, fused to the indole core (annulated indoles). In another embodiment of the invention, the indole compound bears a substituent at one, two, three or four of the 4-, 5-, 6- or 7-positions, particularly the 5- or 6-position.
It will be recognised that the α-haloenone, α-haloenal, ortΛo-halonitroarene and ortΛo-(enone)nitroarenes and ørt/rø-(enal)nitroarenes formed directly or indirectly therefrom, may bear any other type of substituent or fused group provided that the substituents or fused groups do not substantially interfere with the coupling or reductive cyclization process. Substituents that may potentially interfere with the coupling or cyclization process may be protected by a suitable protecting group and deprotected as required. Suitable protecting groups for various substituents are known in the art and are described in standard reference texts such as Protective Groups in Organic Chemistry, T.W. Greene and P.G.M. Wutz, (1999), Wiley Interscience, as are methods for their installation and removal. Substituents which do not substantially affect the coupling or reductive cyclization processes but which themselves may be affected by the coupling or reductive cyclization conditions may also be protected by a suitable protecting group and subsequently deprotected as required.
Substituents present on the α-haloenone, α-haloenal, ortΛo-halonitroarene, ørt/rø-(enone)nitroarene or ortΛo-(enal)nitroarene, and accordingly, the indole compound formed directly or indirectly therefrom, may, where appropriate, include, but are not limited to, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, acyl, halogen (F, Cl, Br, I), hydroxy, alkoxy, alkenyloxy, alkynyloxy, aryloxy, heteroaryloxy, heterocyclyloxy, acyloxy, amino, cyano, nitro, thio, thioalkyl, carboxyl, carboxy ester and amido, each of which may be further optionally substituted, where appropriate, as defined herein. Some examples of substituents which may be contemplated include alkyl, (eg C1-6alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (eg hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (eg methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (eg C1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halogen (F, Cl, Br, I), trifluoromethyl, trichloromethyl, tribromomethyl. hydroxy, phenyl (which itself may be further optionally substituted), benzyl (wherein benzyl itself may be further optionally substituted), phenoxy (wherein phenyl itself may be further optionally substituted), benzyloxy (wherein benzyl itself may be further optionally substituted), amino, alkylamino (eg Cι.6alkyl, such as methylamino, ethylamino, propylamino etc), dialkylamino (eg Cι-6alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (eg NHC(O)CH3), phenylamino (wherein phenyl itself may be further substituted), nitro, formyl, -C(O)-alkyl (eg Cι-6 alkyl, such as acetyl), O-C(O)-alkyl (eg C1-6alkyl, such as acetyloxy), benzoyl (wherein the phenyl group itself may be further optionally substituted), replacement of CH2 with C=O, CO2H, CO2alkyl (eg Cι-6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester), CO2ρhenyl (wherein phenyl itself may be further substituted), CONH2, CONHphenyl (wherein phenyl itself may be further substituted), CONHbenzyl (wherein benzyl itself may be further substituted),CONHalkyl (eg Cι-6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl amide), CONHdialkyl (eg
Figure imgf000009_0001
and methylenedioxy.
As used herein, the term "alkyl", used either alone or in compound words, denotes saturated straight chain, branched or cyclic hydrocarbon groups, preferably Cι.20 alkyl, eg Ci-io or Cι-6. Examples of straight chain and branched alkyl include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, n-pentyl and branched isomers thereof, n-hexyl and branched isomers thereof, n-heptyl and branched isomers thereof, n-octyl and branched isomers thereof, n-nonyl and branched isomers thereof, and n-decyl and branched isomers thereof. Examples of cyclic alkyl include mono- or polycyclic alkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and the like. An alkyl group may be further optionally substituted by one or more optional substituents as herein defined.
The term "alkenyl" as used herein denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon to carbon double bond including ethylenically mono-, di- or poly-unsaturated alkyl or cycloalkyl groups as previously defined, preferably C2- 0 alkenyl (eg C2.10 or C2-6). Examples of alkenyl include vinyl, allyl, 1-methylvinyl, butenyl, iso-butenyl, 3-methyl-2-butenyl, 1-pentenyl, cyclopentenyl, 1-methyl-cyclopentenyl, 1-hexenyl, 3-hexenyl, cyclohexenyl, 1-heptenyl, 3-heptenyl, 1-octenyl, cyclooctenyl, 1-nonenyl, 2-nonenyl, 3-nonenyl, 1-decenyl, 3- decenyl, 1,3-butadienyl, 1 -4,pentadienyl, 1,3-cyclopentadienyl, 1,3-hexadienyl, 1,4- hexadienyl, 1,3-cyclohexadienyl, 1 ,4-cyclohexadienyl, 1,3-cycloheptadienyl, 1,3,5- cycloheptatrienyl and 1,3,5,7-cyclooctatetraenyl. An alkenyl group may be optionally substituted by one or more optional substituents as herein defined.
As used herein the term "alkynyl" denotes groups formed from straight chain, branched or cyclic hydrocarbon residues containing at least one carbon-carbon triple bond including ethynically mono-, di- or poly- unsaturated alkyl or cycloalkyl groups as previously defined. The term preferably refers to Cι-20 alkynyl. Examples include ethynyl, 1- propynyl, 2-propynyl, and butynyl isomers, and pentynyl isomers. An alkynyl group may be further optionally substituted by one or more optional substituents as herein defined.
The term "aryl" used either alone or in compound words denotes single, polynuclear, conjugated or fused residues of aromatic hydrocarbons. Examples of aryl include phenyl, biphenyl, teφhenyl, quaterphenyl, naphthyl, tetrahydronaphthyl, anthracenyl, dihydroanthracenyl, benzanthracenyl, dibenzanthracenyl, phenanthrenyl, fluorenyl, pyrenyl, idenyl, azulenyl and chrysenyl. Preferred aryl groups include phenyl and naphthyl. An aryl group may be further optionally substituted by one or more optional substituents as herein defined. The term "heteroaryl" refers to aromatic heterocyclic ring systems, wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) of a cyclic hydrocarbon residue are replaced with a heteroatom to provide an aromatic residue. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. Suitable heteroatoms include O, N, S and Se. Examples of heteroaryl include pyridyl, thienyl, furyl, pyrrolyl, indolyl, pyridazinyl, pyrazolyl, pyrazinyl, thiazolyl, pyimidinyl, quinolinyl, isoquinolinyl, benzofuranyl, benzothienyl, purinyl, quinazolinyl, phenazinyl, acridinyl, benoxazolyl, benzothiazolyl and the like. Preferred heteroaryl groups include pyridyl, thienyl, furyl, pyrrolyl. A heteroaryl group may be optionally substituted by one or more optional substituents as herein defined.
The term "heterocyclyl" when used alone or in compound words includes monocyclic, polycyclic, fused or conjugated hydrocarbon residues, preferably C3-20 (eg C3-10 or C3-6) wherein one or more carbon atoms (and where appropriate, hydrogen atoms attached thereto) are replaced by a heteroatom so as to provide a non-aromatic residue. Suitable heteroatoms include, O, N, S, and Se. Where two or more carbon atoms are replaced, this may be by two or more of the same heteroatom or by different heteroatoms. Suitable examples of heterocyclic groups may include pyrrolidinyl, pyrrolinyl, piperidyl, piperazinyl, moφholino, indolinyl, imiazolidinyl, pyrazolidinyl, thiomoφholino, dioxanyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydropyrrolyl etc. A heterocyclyl group may be further optionally substituted by one or more optional substituents as herein defined.
The term "acyl" either alone or in compound words such denotes a group containing the moiety C=O (and not being a carboxylic acid, ester or amide) Preferred acyl includes C(O)-R, wherein R is hydrogen or an alkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, residue, preferably a Cι-2o residue. Examples of acyl include formyl; straight chain or branched alkanoyl such as, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl and icosanoyl; cycloalkylcarbonyl such as cyclopropylcarbonyl cyclobutylcarbonyl, cyclopentylcarbonyl and cyclohexylcarbonyl; aroyl such as benzoyl, toluoyl and naphthoyl; aralkanoyl such as phenylalkanoyl (e.g. phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutylyl, phenylpentanoyl and phenylhexanoyl) and naphthylalkanoyl (e.g. naphthylacetyl, naphthylpropanoyl and naphthylbutanoyl]; aralkenoyl such as phenylalkenoyl (e.g. phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl and phenylhexenoyl and naphthylalkenoyl (e.g. naphthylpropenoyl, naphthylbutenoyl and naphthylpentenoyl); aryloxyalkanoyl such as phenoxyacetyl and phenoxypropionyl; arylthiocarbamoyl such as phenylthiocarbamoyl; arylglyoxyloyl such as phenylglyoxyloyl and naphthylglyoxyloyl; arylsulfonyl such as phenylsulfonyl and napthylsulfonyl; heterocycliccarbonyl; heterocyclicalkanoyl such as thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, thiazolylacetyl, thiadiazolylacetyl and tetrazolylacetyl; heterocyclicalkenoyl such as heterocyclicpropenoyl, heterocyclicbutenoyl, heterocyclicpentenoyl and heterocyclichexenoyl; and heterocyclicglyoxyloyl such as thiazolyglyoxyloyl and thienylglyoxyloyl.
The terms alkoxy, alkenoxy alkynoxy, aryloxy, heteroaryloxy, heterocyclyloxy and acyloxy respectively denote alkyl, alkenyl, alkynyl aryl, heteroaryl, heterocyclyl and acyl groups as hereinbefore defined when linked by oxygen.
The term thioalkyl refers to an alkyl group when linked by sulfur.
Ther term "carboxyl" refers to the group CO2H and "carboxy ester" refers to the group CO2R wherein R is any group not being H. Preferred R includes alkyl and aryl.
The terms "amino" and "amido" refer to groups NRR' and CONRR' respectively, wherein R and R" can independently be H, alkyl, alkenyl, alkynyl, aryl, acyl, heteroaryl, heterocyclyl.
In this specification "optionally substituted" is taken to mean that a group may or may not be further substituted or fused (so as to form a condensed polycyclic group) with one or more groups selected from alkyl, alkenyl, alkynyl, aryl, halo, haloalkyl, haloalkenyl, haloalkynyl, haloaryl, hydroxy, alkoxy, alkenyloxy, aryloxy, benzyloxy, haloalkoxy, haloalkenyloxy, haloaryloxy, nitro, nitroalkyl, nitroalkenyl, nitroalkynyl, nitroaryl, nitroheterocyclyl, amino, alkylamino, dialkylamino, alkenylamino, alkynylamino, arylamino, diarylamino, benzylamino, dibenzylamino, acyl, alkenylacyl, alkynylacyl, arylacyl, acylamino, diacylamino, acyloxy, alkylsulphonyloxy, arylsulphenyloxy, heterocyclyl, heterocycloxy, heterocyclamino, haloheterocyclyl, alkylsulphenyl, arylsulphenyl, carboalkoxy, carboaryloxy mercapto, alkylthio, benzylthio, acylthio, cyano, nitro , sulfate and phosphate groups.
Examples of optional substituents include alkyl, (eg C1-6alkyl such as methyl, ethyl, propyl, butyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), hydroxyalkyl (eg hydroxymethyl, hydroxyethyl, hydroxypropyl), alkoxyalkyl (eg methoxymethyl, methoxyethyl, methoxypropyl, ethoxymethyl, ethoxyethyl, ethoxypropyl etc) alkoxy (eg C1-6 alkoxy such as methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy), halogen (F, Cl, Br, I), trifluoromethyl, trichloromethyl, tribromomethyl. hydroxy, phenyl (which itself may be further optionally substituted), benzyl (wherein benzyl itself may be further optionally substituted), phenoxy (wherein phenyl itself may be further optionally substituted), benzyloxy (wherein benzyl itself may be further optionally substituted), amino, alkylamino (eg Ci-βalkyl, such as methylamino, ethylamino, propylamino etc), dialkylamino (eg Cι-6alkyl, such as dimethylamino, diethylamino, dipropylamino), acylamino (eg NHC(O)CH3), phenylamino (wherein phenyl itself may be further substituted), nitro, formyl, -C(O)-alkyl (eg Cj- alkyl, such as acetyl), O-C(O)-alkyl (eg Cι_ 6alkyl, such as acetyloxy), benzoyl (wherein the phenyl group itself may be further optionally substituted), replacement of CH2 with C=O, CO2H, CO2alkyl (eg Cj.6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl ester), CO2phenyl (wherein phenyl itself may be further substituted), CONH2, CONHphenyl (wherein phenyl itself may be further substituted), CONHbenzyl (wherein benzyl itself may be further substituted),CONHalkyl (eg Cι-6 alkyl such as methyl ester, ethyl ester, propyl ester, butyl amide), CONHdialkyl (eg Cι-6alkyl) and methylenedioxy. The coupling of the ortΛo-halonitroarene with the α-haloenone or α-haloenal to form the indole compound is carried out in the presence of a suitable metal coupling agent such as Ni[0] or Cu[0], preferably with Cu[0] (eg Cu powder). Preferably the coupling is carried under Pd[0] catalysis which may afford the advantage of higher yields and/or shortened reaction times. Any active Pd[0] species may be used. Suitable examples of a Pd[0] catalyst include Pd2(dba)3 and Pd(PPh3)4. Alternatively, a Pd[0] catalyst may be generated in situ, eg through reduction by the Cu, from a suitable Pd[II] catalyst. Examples thereof include PdCl2(dppf), Pd(OAc)2, PdCl2(CH3CN)2, Pd(C6H5CN)2Cl2 and PdCl2(PPh3)2
The coupling process is carried out for a time and under conditions suitable for the formation of the desired ort/rø-(enone)nitroarene or ort /o-(enal)nitroarene. The person skilled in the art would readily be able to determine appropriate conditions by routine experimentation. The coupling process may be carried out in any suitable solvent, such as dimefhylformamide, dimethoxyethane, dimethylsulfoxide, or N-methylpyrrolidinone. A particularly preferred solvent is dimethylsulfoxide. The coupling process may be carried out at any suitable temperature, preferably from about 30°-100°, more preferably about 50°- 90°, even more preferably from about 50°-70°.
Reductive cyclization of the ortΛo-(enone)nitroarene or ort/ιø-(enal)nitroarene may be performed under any suitable reducing conditions known in the art. Preferably the reductive cyclization is carried out using H2 in the presence of a suitable catalyst such as PtO2, RI1/AI2O3, Pd(OH)2, Raney Nickel or Pd/C. A preferred catalyst is Pd/C.
Requisite α-haloenones or α-haloenals may be readily obtained by halogenation of the corresponding enone or enal according to known procedures (see for example, Johnson, C.R. et al, Tetrahedron Lett. 1992, 33, 917; Smith, A.B. et al J. Org. Chem., 1982, 47, 1855; and Ramanarayanan, G.V. et al, Synlett., 2002, 2059).
Table 1 below illustrates the ørt/zø-(enone)nitroarene or ort/zo-(enal)nitroarene and corresponding indole compounds formed from 2-iodonitrobenzene or 2- bromonitrobenzene and the illustrated α-haloenone or α-haloenal. Table 1
Figure imgf000015_0001
Figure imgf000016_0001
Thus reaction of either 2-iodo-2-cyclohexen-l-one (2, X=I) or 2-bromo-2-cyclohexen-l- one (2, X=Br) with 2-iodonitrobenzene or 2-bromonitrobenzene affords, under a variety of conditions (see Table A in Example 1) the desired ort/rø-enonenitroarene. Similarly, the lower homologue of 2-iodonitrobenzene, viz 6 (Johnson et al, supra; Smith et al, supra; and Ramanarayanan et al, supra) coupled with 2-iodonitrobenzene and the resulting product 7 was converted into the indole 8. An analogous sequence was applied to cycloheptenone (Scott, supra) to afford 11 via 10. Similarly, coupling of the enantiomerically pure 12 (Banwell, M.G., et al, J. Chem. Soc. Perkin Trans 1, 2000, 3555) with 2-iodonitrobenzene afforded 13 which underwent reductive cyclization to give the indole 14. An analogous sequence applied to 15 (Bowman, W.R., et al, J. Chem. Soc. Perkin Trans. 1, 2002, 58) afforded 17 via 16 and demonstrates that the invention is applicable in the preparation of non-annulated indoles. Further examples of the use of open chain (acyclic) enones is illustrated by the coupling of 29 (Johnson et al, supra) and 32 with 2-iodonitrobenzene to afford indoles 31 and 34 via the intermediates 30 and 33, respectively.
Table 2 below illustrates ortΛo-(enone)nitroarenes and the corresponding indole compounds formed from 2-iodo-2-cyclohexen-l-one and the illustrated ortΛo-halonitroarene.
TABLE 2
Figure imgf000018_0001
Thus, coupling of the 2,4-dinitrobromobenzene 18 with the iodoenone afforded 19 which underwent reductive cyclization with concomitant reduction of the second nitro-group to afford the amino-substituted indole compound 20 (Entry 2a). Similarly, reaction of the ørt/rø-iodonitrobenzene 21 with 2-iodo-2-cyclohexen-l-one afforded compound 22 which underwent reductive cyclization to provide the indole compound 23 (Entry 2b). Further halogenated or appropriately substituted ortΛo-halonitroarenes may be particularly useful substrates in the present invention as they allow for other cross-coupling reactions to introduce additional ie replacement substitution on the benzene ring. This is illustrated in Entry 2c of Table 2. Thus, the dibromonitrobenzene 24 regioselectively coupled with 2- iodo-2-cyclohexen-l-one to form the bromo-ort ?o-enonenitroarene 25. Suzuki-Miyaura coupling of 25 with l,3-benzodioxol-5-ylboronic acid afforded 26. Compound 26 underwent reductive cyclization to afford the indole 28 (under shorter reaction times the cyclohexanone analogue of 26 was also produced).
The methods described herein may find utility in the preparation of indole compounds having biological importance. Examples of two such classes of compounds are the tryptamines (Spandoni, G., J. Med. Chem., 1997, 40, 1990 and Marias W. and Holzapfel, C.W., Synth. Commun., 1998, 28, 3681) and the carbazoles (Moody, C.J., Synlett., 1994, 681).
Thus, coupling of the appropriately methoxy substituted ort/zo-halonitroarene with the appropriate α-haloenal may afford access to melatonin as illustrated in Scheme 1.
Figure imgf000019_0001
X=halogen
Scheme 1
Similarly, coupling of an appropriately substituted ort/zo-halonitroarene with a suitable α- halo-pαra-benzoquinone may afford access to carbazoles as illustrated in Scheme 2.
Figure imgf000020_0001
x = halogen
Scheme 2
Those skilled in the art will appreciate that the invention described herein is susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
The present invention will now be illustrated by the following Examples. It is to be understood that the Examples are provided for the puφose of illustration of certain embodiments only and are not intended to limit the generality hereinbefore described.
EXAMPLES
EXAMPLE 1
Table A illustrates a variety of conditions ("halo", solvent, catalyst, reaction temperature) which may be employed in the coupling of an ortΛo-halonitroarene and an ort/*o-haloenone to form the desired ort/zo-(enone)nitroarene. The by-product arising from the homocoupling of 1 can be suppressed by reducing the amount of haloarene employed and/or by slow addition of compound 1 to the reaction mixture. Formation of the byproduct can also be suppressed by judicious choice of coupling partners eg. by coupling the ortΛo-bromonitroarene with the relevant α-iodoenal or enone.
Table A: Coupling conditions for 1 + 2 -» 3
Figure imgf000022_0001
1. X = l, Br 2. X = I, Br
Entry Halide 1 Halide 2 Catalyst0'6/ Solvent Temp(°C)/ % Yield3 (mmol) (mmol) equiv.Cu)0 Time(h) (of 3)
1 X=I (1.0) X=I (0.5) A(lθ g.atom) DMSO 90/1 80
2 X=I (1.0) X=I (0.5) A(lθ g.atom) DMSO 70/1 74
3 X=I (1.0) X=I (0.5) A(lθ g.atom) DMSO 50/21 83
4 X=I (1.0) X=I (0.5) A(lθ g.atom) DMF 70/5 58
5 X=I (1.0) X=I (0.5) A (lθ g.atom) NMP 70/30 67
6 X=I (1.0) X=I (0.5) B(10 g. atom) DMSO 50/1 91
7 X=I (1.0) X=I (0.5) C(lθ g.atom) DMSO 50/3 85
8 X=I (1.0) X=I (0.5) D(lθ g.atom) DMSO 50/4 89
9 X=Br(1.0) X=Br (0.5) B (lθ g.atom) DMSO 70/2 88
10 X=I(5.0) X=Br(0.5) B(lθ g.atom) DMSO 70/6 72
1 1 X=Br(1.0) X=I (0.5) B (lθ g.atom) DMSO 70/1.5 88
12 X=I(1.0) X=I (0.5) B (5 g.atom) DMSO 70/1 87 "Catalysts: A = Pd(PPh3)4; B = Pd2(dba)3; C=PdCl2(dppf); D=Pd(OAc)2. "6 mol% catalyst loadings were used in these studies. Εquiv. wrt 2. "Yield calculations based on quantities of 2 employed.
Characterisation data for Compounds 3 and 4 (indole) is presented below.
2-(2-Nitrophenyl)-2-cyclohexen-l-one (3)
Rf 0.35 (silica, 3:7 v/v ethyl acetate/hexane), mp = 92-95 °C. Η NMR (CDC13, 300 MHz) δ 7.99 (dd, J= 8.1 and 1.5 Hz, IH), 7.58 (td, J= 7.5 and 1.5 Hz, IH), 7.45 (td, J= 8.1 and 1.5 Hz, IH), 7.24 (dd, J = 7.5 and 1.5 Hz, IH), 7.01 (t, J = 4.2 Hz, IH), 2.62-2.52 (complex m, 4H), 2.13 (p, J = 6.9 Hz, 2H); 13C NMR (CDC13, 75 MHz) δ 196.4, 148.4, 146.8, 139.2, 133.2, 131.9, 131.5, 128.6, 123.9, 38.1, 26.1, 22.4; IR, vmax (NaCl) 2942, 1674, 1519, 1345, 789, 749, 710, 562 cm-1; MS, m/z (El, 70 eV) 217 (M+\ 11%), 172 (46), 145 (47), 115 (69), 77 (75), 55 (100); HRMS, Found: M+', 217.0737. Cι2H„NO3 requires M+\ 217.0739.
2,3,4, 9-Tetrahydro-lH-carbazole (4)
Rf 0.65 (silica, 1:4 v/v ethyl acetate/hexane), mp = 110-115 °C. 1H NMR (CDC13, 300 MHz) δ 7.63 (broad s, IH), 7.48 (m, IH), 7.28 (m, IH), 7.16-7.06 (complex m, 2H), 2.73 (m, 4H), 1.92 (m, 4H); 13C NMR (CDC13, 75 MHz) δ 135.5, 134.0, 127.7, 120.9, 119.0, 117.6, 110.2, 110.1, 23.4, 23.3(1), 23.2(8), 21.0.
EXAMPLE 2
The reaction conditions established above in Table A were applied to a range of coupling substrates, with the products then being reduced to the corresponding indoles. The outcomes of these two-step reaction sequences are presented in Table B.
Table B. Formation of indole compounds
Entry Nitroarene Enone/enal Coupling % Yield Indole % Yield product0
1 1 (X=I) 6 7 75 8 90
2 1 (X=I) 9 10 66 11 72
3 1 (X=I) 12 13 68 14 90
4 1 (X=I) 15 16 67 17 88
5 18 2 (X =D 19 82 20 80
6 21 2 (X=I) 22 80 23 97
7 24 2 (X=I) 25 71 4 90
8 - - 26* 77 28 77c
9 1 (X=I) 29 30 64 31 92
10 1 (X=I) 32 33 75 34 88 a The reaction conditions defined in Entry 12, Table A were employed for the couplings listed here. *Product obtained via Suzuki-Miyaura cross-coupling of compound 25 with 1.3-benodioxol-5- ylboronic acid. Υield after extended reaction time. General Procedure for Cu/PdfOJ-Catalysed Cross-Coupling Reactions for Formation of Compounds 3, 7, 10, 13, 16, 19, 22, 25, 26, 30 and 33.
A magnetically stirred mixture of the appropriate 2-halonitroarene (10 mmol), the appropriate α-halo-enone or -enal (5 mmol), copper powder (1.59 g of 99% material, 25 g.atom, CAS No. 7440-50-8) and Pd2(dba)3 (260 mg, 0.25 mmol) in DMSO (15 mL) was heated at 70°C for 1 h under a nitrogen atmosphere then cooled and diluted with diethyl ether (150 mL). The resulting mixture was then filtered through a pad of Celite and the solids thus retained washed with ether (50 mL). The combined filtrates were washed with water (2 x 150 mL) and brine (1 x 150 mL) then dried (MgSO4), filtered and concentrated under reduced pressure to give a brown oil which often solidified. Subjection of this material to flash chromatography (silica, ethyl acetate/hexane elution) and concentration of the appropriate fractions then afforded the coupling products.
General Procedure for Reductive Cyclisation Reactions for Formation of Compounds 4, 8, 11, 14, 17, 20, 23, 27, 28, 31 and 34
A mixture of the relevant substrate (0.11 mmol) and 10% Pd on C (20 weight% with respect to substrate) in methanol (5 mL) was stirred under an atmosphere of dihydrogen for 0.75 h then filtered through a pad of Celite. The solids thus retained were washed with methanol (ca. 5 mL) and the combined filtrates concentrated under reduced pressure. Subjection of the residue thus obtained to flash chromatography (silica, ethyl acetate/hexane elution) and concentration of the appropriate fractions then afforded the indole products.
Preparation of Compound 26
The title compound was prepared by Suzuki-Miyaura cross-coupling of bromo-arene 25 with 1 ,3-benzodioxol-5-ylboronic acid (Banwell, M.G., and Cowden, C.J. Aust. J. Chem., 1994, 47, 2235). Thus, a magnetically stirred mixture of compound 25 (225 mg, 0.76 mmol), the above-mentioned acid, Pd(PPh3)4 (27 mg, 0.02 mmol), K2CO3 (1.8 mL of a 2 M aqueous solution), benzene (10 mL) and ethanol (3.75 mL) was heated at reflux for 16 h. The cooled reaction mixture was partitioned between ethyl acetate (100 mL) and water (150 mL) and the separated organic phase dried (MgSO4), filtered and concentrated at reduced pressure. The resulting brown residue was subject to flash chromatography (silica, 1 :2 v/v ethyl acetate/hexane elution) and concentration of the appropriate fractions (Rf 0.2) then gave the title compound 26 (196 mg, 77%) as a yellow crystalline solid, mp 188-189 °C.
(L)-2-Iodocrotonaldehyde (32)
Following the protocol developed by Johnson C.R. et al (supra), a solution of iodine (4.06 g, 16 mmol) in 1:1 v/v CCLVpyridine (10 mL) was added, dropwise, to a magnetically stirred solution of crotonaldehyde (280 mg g, 4 mmol) in 1 :1 v/v CCl4/pyridine (10 mL) maintained at 0 °C (ice-water bath) under a nitrogen atmosphere. The resulting solution was stirred for a further 24 h during which time temperature was allowed to rise to 18 °C. After dilution with diethyl ether (250 ml) the reaction mixture was washed with water (3 x 75 mL), HC1 (2 x 50 mL of a 1 M aq. solution), water (1 x 40 mL) and Na2S2O3 (20 w/v% aq. solution) then dried (MgSO4) filtered and concentrated under reduced pressure to give the title aldehyde (463 mg, 62%) as an unstable light-yellow oil that was used immediately in the cross-coupling reaction with ort/zo-iodonitrobenzene.
Characterization data for prepared ort ?o-(enone)nitroarenes/ortΛo-(enal)nitroarenes and their corresponding indole compounds are presented below.
2-(2-Nitroph enyl)-2-cyclopenten-l-one (7)
Rf 0.3 (silica, 3:7 v/v ethyl acetate/hexane), mp = 90-94 °C. Η NMR (CDC13, 300 MHz) δ 7.97 (dd, J = 8.1 and 1.2 Hz, IH), 7.68 (t, J = 2.7 Hz, IH), 7.58 (dt, J = 8.1 and 1.5 Hz, IH), 7.46 (dt, J = 7.3 and 1.2 Hz, IH), 7.31 (dd, J = 7.3 and 1.5 Hz, IH), 2.80-2.76 (complex m, 2H), 2.56-2.52 (complex m, 2H); 13C NMR (CDC13, 75 MHz) δ 205.1, 158.8, 148.2, 143.7, 133.0, 131.1, 129.0, 127.1, 124.3, 34.6, 27.1 ; IR, vmax (KBr) 3072, 2927, 1700, 1631, 1576, 1519, 1472, 1438, 1400, 1343, 1318, 1140 cm"1; MS, m/z (El, 70 eV) 203 (M+\ 75%), 157 (60), 148 (90), 120 (82), 104 (98), 91 (62), 77 (87), 63 (61), 55 (100); HRMS, Found: M+\ 203.0581. CnH19NO3 requires M+', 203.0582. l,2,3,4-Tetrahydrocyclopentlb]indole (8)
Rf 0.6 (silica, 1 :4 v/v ethyl acetate/hexane), mp = 97-102 °C. 1H NMR (CDC13, 300 MHz) δ 7.73 (broad s, IH), 7.52 (m, IH), 7.30 (m, IH), 7.17 (m, 2H), 2.94-2.84 (complex m, 4H), 2.61 (m, 2H); 13C NMR (CDC13, 75 MHz) δ 143.5, 140.8, 124.5, 120.3, 119.5, 119.3, 118.3, 111.2, 28.7, 25.8, 24.4; MS, m/z (El, 70 eV) 157 (M+\ 100%), 156 (52), 130 (32), 128 (29).
2-(2-Nitrophenyl)-2-cyclohepten-l-one (10)
Rf 0.5 (silica, 2:3 v/v ethyl acetate/hexane), mp = 76-78 °C. Η NMR (CDCI3, 300 MHz) δ 8.05 (dd, J = 8.1 and 1.3 Hz, IH), 7.60 (td, J = 7.5 and 1.3 Hz, IH), 7.46 (td, J = 8.1 and 1.5 Hz, IH), 7.29 (dd, J= 7.5 and 1.5 Hz, IH), 6.72 (t, J= 6.3 Hz, IH), 2.79 (m, 2H), 2.59 (m, 2H), 1.92 (m, 4H); 13C NMR (CDC13, 75 MHz) δ 202.7, 143.1, 143.0, 135.2, 133.5, 132.7, 128.6, 124.4, 42.5, 27.9, 25.1, 21.1 (one signal overlapping or obscured); IR, vmax (KBr) 2940, 1670, 1523, 1349, 788, 747 cm-1; MS, m/z (El, 70 eV) 231 (M+\ 3%), 185 (70), 158 (60), 115 (61), 104 (64), 91 (56), 77 (79); HRMS, Found: M+', 231.0894. C13H13NO3 requires M+\ 231.0895.
5,6, 7,8,9,10-Hexahydrocyclohept/b/indole (11)
Rf 0.5 (silica, 1:4 v/v ethyl acetate/hexane), mp = 135-138 °C. 1H NMR (CDCI3, 300 MHz) δ 7.70 (broad s, IH), 7.47 (m, IH), 7.25 (m, IH), 7.08 (m, 2H), 2.81 (m, 4H), 2.00-
1.50 (complex m, 6H); 13C NMR (CDC13, 75 MHz) δ 137.4, 134.2, 129.2, 120.6, 119.0,
117.6, 113.7, 110.1, 31.8, 29.6, 28.7, 27.5, 24.6; IR, vmax (KBr) 3392, 2913, 1466, 1437, 740 cm-1; MS, m/z (El, 70 eV) 185 (M+\ 100%), 184 (62), 156 (76); HRMS, Found: M+\ 185.1201. Cι3H,5N requires M+\ 185.1204.
3-(2-Nitrophenyl)-4-oxo-2-cyclopentene-l-acetic acid Ethyl Ester (13)
Rf 0.3 (silica, 2:3 v/v ethyl acetate/hexane), mp = 85-87 °C, [α]D + 9.2 (c 2.7, CHC13); 1H
NMR (CDCI3, 300 MHz) δ 8.03 (dd, J = 8.1 and 1.2 Hz, IH), 7.62 (d, J = 2.7 Hz, IH),
7.61 (td, J= 7.5 and 1.2 Hz, IH), 7.51 (dt, J = 8.1 and 1.5 Hz, IH), 7.33 (dd, J = 7.5 and 1.5 Hz, IH), 4.18 (q, J = 7.0 Hz, 2H), 3.47 (m, IH), 2.86 (dd, J = 19.0 and 6.6 Hz, IH), 2.62 (m, 2H), 2.30 (dd, J = 19.0 and 2.7 Hz, IH), 1.28 (t, J = 7.0 Hz, 3H); 13C NMR (CDC13, 75 MHz) δ 203.8, 171.2, 160.0, 148.4, 144.2, 133.2, 131.3, 129.4, 126.9, 124.6, 60.9, 41.2, 38.7, 35.6, 14.2; IR, vmax (KBr) 2983, 1728 (sh), 1714, 1528, 1354, 1183, 1026, 788 cm-1.
l,2,3,4-Tetrahydrocyclopentfa]indole-2-acetic acid Ethyl Ester (14) Rf 0.25 (silica, 1 :4 v/v ethyl acetate/hexane), mp = 77-79 °C, [α]D -25.1 (c 0.8, CHC13); 1H NMR (CDCI3, 300 MHz) δ 7.84 (broad s, IH), 7.41 (m, IH), 7.30 (m, IH), 7.08 (m, 2H), 4.17 (q, J = 6.9 Hz, 2H), 3.38 (m, IH), 3.12 (m, 2H), 2.68-2.48 (complex m, 4H), 1.28 (t, J= 6.9 Hz, 3H); 13C NMR (CDCI3, 75 MHz) δ 172.9, 141.6, 140.7, 124.7, 120.7, 119.6, 118.4, 118.0, 111.3, 60.3, 41.2, 39.9, 32.4, 31.3, 14.3; IR, vmax (KBr) 3401, 2931, 2349, 1731, 1719 (sh), 1454, 1371, 1262, 1192, 1027, 741 cm"1; MS, m/z (El, 70 eV) 243 (M+\ 76%), 156 (38), 155 (100); HRMS, Found: M+\ 243.1260. C,5Hl7NO2 requires M+\ 243.1259.
)-2-(2-Nitrophenyl)-3-phenyl-2-propenal (16)
Rf 0.45 (silica, 1 :2 v/v ethyl acetate/hexane), mp = 73-75 °C. Η NMR (CDCI3, 300 MHz) δ 9.72 (s, IH), 8.23 (m, IH), 7.59 (m, 2H), 7.54 (s, IH), 7.36-7.22 (complex m, 3H), 7.22- 7.12 (complex m, 3H); 13C NMR (CDC13, 75 MHz) δ 191.8, 148.9, 148.7, 139.4, 133.9, 133.2, 131.9, 130.4, 130.4, 129.5, 129.4, 128.6, 124.8; IR, vmax (KBr) 3068, 1684, 1628, 1607, 1573, 1522, 1347, 1110, 1063, 857, 788, 746, 716, 694 cm-1; MS, m/z (El, 70 eV) 253 (M+\ <1%), 224 (76), 208 (40), 180 (43), 178 (46), 165 (48), 152 (72), 119 (74), 91 (100), 77 (52); HRMS, Found: M+\ 253.0733. C15H11NO3 requires M+\ 253.0739.
3-(Phenylmethyl)-m-indole (17)
Rf 0.4 (silica, 1:4 v/v ethyl acetate/hexane), mp = 104-106 °C. Η NMR (CDC13, 300 MHz) δ 7.94 (s, IH), 7.54 (d, J = 8.0 Hz, IH), 7.36 (dm, J = 8.0 Hz, IH), 7.34-7.16 (complex m, 6H), 7.10 (tm, J = 7.2 Hz, IH), 6.92 (broad s, IH), 4.14 (s, 2H); 13C NMR (CDCI3, 75 MHz) δ 141.2, 136.4, 128.7, 128.3, 127.4, 125.8, 122.3, 122.0, 119.3, 119.1, 115.8, 111.0, 31.6; IR, vmax (KBr) 3402, 1457, 1339, 1088, 1075, 1009, 743, 711 cm-1; MS, m/z (El, 70 eV) 207 (M+\ 100%),206 (80), 130 (85); HRMS, Found: M+\ 207.1043. C15H13N requires M+\ 207.1048.
2-(2,4-Dinitrophenyl)-2-cyclohexen-l-one (19) Rf 0.25 (silica, 2:3 v/v ethyl acetate/hexane), mp = 142-143 °C. 1H NMR (CDC13, 300 MHz) δ 8.86 (d, J = 2.4 Hz, IH), 8.44 (dd, J = 8.4 and 2.1 Hz, IH), 7.49 (d, J = 8.4 Hz, IH), 7.15 (t, J= 3.9 Hz, IH), 2.63 (m, 4H), 2.18 (p, J= 6.9 Hz, 2H); 13C NMR (CDC13, 75 MHz) δ 195.7, 148.8, 148.6, 147.3, 138.0, 137.9, 132.9, 127.4, 119.6, 38.0, 26.3, 22.3; IR, vmax (KBr) 3109, 1684, 1600, 1528, 1348, 1158, 1120, 907, 833, 734 cm-1; MS, m/z (El, 70 eV) 262 (M+#, 2%), 217 (24), 216 (32), 55 (100); HRMS, Found: M+", 262.0583. C12Hι0N2O5 requires M+\ 262.0590. "^
2,3,4, 9-Tetrahydro-lH-carbazol- 7-amine (20)
Rf 0.1 (silica, 2:3 v/v ethyl acetate/hexane), mp = 103-108 °C. 1H NMR (CDC13, 300 MHz) δ 7.43 (broad s, IH), 7.23 (d, J= 7.8 Hz, IH), 6.59 (broad s, IH), 6.53 (d J= 7.8 Hz,
IH), 3.45 (broad s, 2H), 2.65 (broad s, 4H), 1.86 (broad s, 4H); 13C NMR (CD3OD, 75
MHz) δ 151.6, 138.6, 133.4, 123.4, 118.5, 110.7, 109.6, 99.0, 24.7, 24.5, 24.0, 22.0; IR, vmax (KBr) 3392, 2928, 1631, 1504, 1470, 1328, 1151, 801 cm-1; MS, m/z (El, 70 eV) 186
( (MMτ+\ , 110000'%), 185 (30), 158 (100); HRMS, Found: M+\ 186.1157. C12H14N2 requires M+\ 186.1157.
2-(4-Methoxy-2-nitrophenyl)-2-cyclohexen-l-one (22)
Rf 0.3 (silica, 3:7 v/v ethyl acetate/hexane), mp = 64-66 °C. 1H NMR (CDC13, 300 MHz) δ 7.54 (d, J = 2.4 Hz, IH), 7.14-7.13 (complex m, 2H), 6.96 (t, J = 4.2 Hz, IH), 3.87 (s, 3H), 2.59-2.53 (complex m, 4H), 2.15-2.11 (complex m, 2H); 13C NMR (CDCI3, 75 MHz) δ 196.9, 159.5, 149.1, 146.1, 139.1, 132.5, 124.3, 119.6, 109.1, 55.9, 38.3, 26.3, 22.6; IR, vmax (KBr) 2913, 2847, 1678, 1613, 1523, 1494, 1454, 1346, 1230, 1035 cm-1; MS, m/z (El, 70 eV) 247 (M+#, 15%), 201 (100), 134 (20), 121 (17), 77 (17); HRMS, Found: M+", 247.0843. C13H13NO4 requires M+\ 247.0845. 2,3,4,9-Tetrahydro-7-methoxy-lH-carbazole (23)
Rf 0.2 (silica, 1 :9 v/v ethyl acetate/hexane), mp = 136-142 °C. Η NMR (CDC13, 300 MHz) δ 7.54 (broad s, IH), 7.33 (d, J= 8.4 Hz, IH), 6.80 (d, J= 2.1 Hz, IH), 6.76 (dd, J = 8.7 and 2.1 Hz, IH), 3.84 (s, 3H), 2.71-2.67 (complex m, 4H), 1.92-1.85 (complex m, 4H); 13C NMR (CDC13, 75 MHz) δ 155.8, 136.3, 132.8, 122.4, 118.2, 109.9, 108.2, 94.8, 55.8, 23.3, 23.2, 20.9 (one signal obscured or overlapping); IR, vmax (KBr) 3405, 2913, 2833, 1627, 1566, 1450, 1154, 1028 cm"1; MS, m/z (El, 70 eV) 201 (M+\ 100%), 186 (55), 173 (75); HRMS, Found: M+\ 201.1156. C13H15NO requires M+\ 201.1154.
2-(4-Bromo-2-nitrophenyl)-2-cyclohexen-l-one (25)
Rf 0.3 (silica, 1 :2 v/v ethyl acetate/hexane), oil. 1H NMR (CDCI3, 300 MHz) δ 8.16 (d, J = 2.1 Hz, IH), 7.72 (dd, J= 8.1 and 2.1 Hz, IH), 7.13 (d, J= 8.1 Hz, IH), 7.02 (t, J= 4.2 Hz, IH), 2.58 (m, 4H), 2.15 (m, 2H); 13C NMR (CDC13, 75 MHz) δ 196.2, 148.9, 147.1, 138.5, 136.2, 132.9, 130.9, 127.2, 121.9, 38.2, 26.3, 22.5; IR, vmax (KBr) 2984, 1681, 1529, 1351, 1095 876, 830, 741 cm"1; MS, m/z (El, 70 eV) 297 and 295 (M+\ 12 and 12%), 251 and 249 (68 and 68), 55 (100); HRMS, Found: M+\ 294.9847. C12H10 79BrNO3 requires M+\ 294.9844.
2-{{4-Benzo[l,3]dioxol-5-yl}-2-nitrophenyl}-2-cyclohexen-l-one (26) Rf 0.2 (silica, 1:2 v/v ethyl acetate/hexane), mp = 188-189 °C. 1H NMR (CDCI3, 300 MHz) δ 8.15 (d, J = 2.1 Hz, IH), 7.72 (dd, J = 8.1 and 2.1 Hz, IH), 7.28 (d, J = 8.1 Hz, IH), 7.08 (dd, J= 8.1 and 1.8 Hz, IH), 7.07 (s, IH), 7.04 (t, J= 4.2 Hz, IH), 6.90 (dm, J = 8.1 Hz, IH), 6.03 (s, 2H), 2.59 (m, 4H), 2.16 (p, J = 7.2 Hz, 2H); 13C NMR (CDC13, 75 MHz) δ 196.6, 148.8, 148.4, 148.0, 146.6, 141.8, 139.1, 132.5, 132.0, 131.1, 130.2, 122.3, 120.8, 108.8, 107.3, 101.4, 38.3, 26.3, 22.6; IR, vmax (KBr) 2953, 1680, 1531, 1509, 1480, 1356, 1250, 1229, 1109, 1038, 862, 812 cm"1; MS, m/z (El, 70 eV) 337 (M+\ 43%), 291 (38), 177 (100), 149 (71); HRMS, Found: M+\ 337.0951. Cι9H15NO5 requires M+\ 337.0950. 2-{{4-Benzo[l,3]dioxol-5-yl}-2-nitrophenyl}cyclohexanone (27)
Rf 0.3 (silica, 1 :4 v/v ethyl acetate/hexane), mp = 153-155 °C. 1H NMR (CDC13, 300 MHz) δ 8.13 (d, J = 2.1 Hz, IH), 7.72 (dd, J = 8.1 and 1.8 Hz, IH), 7.37 (d, J = 8.1 Hz, IH), 7.07 (dd, J- 7.2 and 2.1 Hz, IH), 6.90 (d, J= 6.9 Hz, IH), 6.03 (s, 2H), 4.31 (dd, J= 14.0 and 6.0 Hz, IH), 2.51 (m, 2H), 2.40 (m, IH), 2.20 (m, IH), 2.10 (m, 2H), 1.85 (m, 2H), 1.65 (broad s, IH); 13C NMR (CDCI3, 75 MHz) δ 208.3, 149.6, 148.5, 148.0, 140.9, 132.6, 132.2, 131.1, 130.7, 123.0, 120.9, 108.8, 107.4, 101.4, 53.2, 42.2, 33.8, 27.3, 25.4; IR, Vmax (KBr) 2933, 1712, 1532, 1509, 1481, 1351, 1229, 1039, 811 cm"1; MS, m/z (El, 70 eV) 399 (M+\ 100%), 322 915), 266 (45), 250 (30); HRMS, Found: M+\ 339.1100. Cι9H17NO5 requires M+\ 339.1107.
7-{4-Benzofl,3Jdioxol-5-yl}-2,3,4,9-tetrahydro-lH-carbazole (28)
Rf 0.5 (silica, 1 :4 v/v ethyl acetate/hexane), mp = 169-171 °C. 1H NMR (CDC13, 300 MHz) δ 7.71 (s, IH), 7.47 (d, J = 8.1 Hz, IH), 7.39 (m, IH), 7.26 (m, IH), 7.14-7.06 (complex m, 2H), 6.88 (d, J = 8.1 Hz, IH), 5.99 (s, 2H), 2.73 (m, 4H), 1.90 (m, 4H); 13C NMR (CDC13, 75 MHz) δ 147.9, 146.3, 137.1, 136.1, 134.8, 134.2, 126.9, 120.5, 118.7, 117.8, 110.1, 108.7, 108.4, 107.9, 100.9, 23.3, 23.2, 23.1, 20.9; IR, vmax (KBr) 3393, 2929, 1508, 1472, 1241, 1042, 927, 801 cm"1; MS, m/z (El, 70 eV) 291 (M+\ 100%), 263 (73); HRMS, Found: M+\ 291.1262. C19H17NO2 requires M+', 291.1259.
(3Z)-3-(2-Nitrophenyl)-4-phenyl-3-buten-2-one (30)
Rf 0.2 (silica, 1 :4 v/v ethyl acetate/hexane), yellow oil. 1H NMR (CDCI3, 300 MHz) δ 8.22 (m, IH), 7.69 (s, IH), 7.55 (m, 2H), 7.25-7.10 (complex m, 4H), 7.01 (m, IH), 6.98 (m, IH), 2.52 (s, 3H); 13C NMR (CDC13, 75 MHz) δ 197.3, 139.3, 139.0, 133.9(2), 133.9(0), 132.4, 130.2, 129.5, 129.1, 128.5, 124.8, 26.5 (two signals obscured or overlapping); IR, vmax (KBr) 3065, 1667, 1624, 1606, 1519, 1346, 1234, 1168, 851, 789 cm"1; MS, m/z (El, 70 eV) 267 (M+\ <1%), 266 (<1), 251 (<1), 208 (54), 198 (100), 180 (48), 168 (40), 152 (32), 119 (36), 105 (50); HRMS, Found: M+', 267.0903. C16H13NO3 requires M+', 267.0895. 2-Methyl-3-(phenylmethyl)-lH-indole (31)
Rf 0.35 (silica, 1 :4 v/v ethyl acetate/hexane), oil. Η NMR (CDC13, 300 MHz) δ 7.76 (broad s, IH), 7.42 (d, J = 7.8 Hz, IH), 7.30-7.14 (complex m, 6H), 7.13 (t, J = 7.2 Hz, IH), 7.05 (t, J = 6.9 Hz, IH), 4.10 (s, 2H), 2.38 (s, 3H); 13C NMR (CDC13, 75 MHz) δ 141.6, 135.2, 131.6, 128.8, 128.2(3), 128.2(2), 128.1(7), 125.6, 120.9, 119.2, 118.3, 110.5, 110.1, 30.0, 11.7 (one signal due to unidentified impurity); IR, vmax (KBr) 3405, 3057, 1458, 1302, 1241, 1075, 739, 695, 590 cm-1; MS, m/z (El, 70 eV) 221 (M+\ 93%), 220 (56), 206 (58), 144 (100); Found: M+\ 221.1206. Cϊ6Hι5N requires M+\ 221.1204.
( )-2-Iodocrotonaldehyde (32)
Rf 0.5 (silica, 3:7 v/v ethyl acetate/hexane), unstable oil. 1H NMR (CDC13, 300 MHz) δ 8.68 (s, IH), 7.28 (q, J = 6.9 Hz, IH), 2.20 (d, J = 6.9 Hz, 3H); 13C NMR (CDC13, 75 MHz) δ 187.7, 158.0, 113.3, 22.6.
( )-2-(2-Nitrophenyl)crotonaldehyde (33)
Rf 0.4 (silica, 3:7 v/v ethyl acetate/hexane), oil. Η NMR (CDCI3, 300 MHz) δ 9.56 (s, IH), 8.13 (dd, J = 7.8 and 1.5 Hz, IH), 7.64 (td, J = 7.8 and 1.5 Hz, IH), 7.55 (td, J= 7.8 and 1.5 Hz, IH), 7.19 (dd, J = 7.8 and 1.5 Hz, IH), 6.96 (q, J = 7.1 Hz, IH), 1.94 (d, J = 7.1 Hz, 3H); 13C NMR (CDCI3, 75 MHz) δ 191.6, 149.7, 143.3, 133.3, 132.1, 129.3, 129.1, 128.3, 124.8, 15.9; IR, vmax (KBr) 2827, 1687, 1644, 1522, 1347, 1225, 1133, 788, 743, 708 cm-1; MS, m/z (El, 70 eV) 191 (M+\ 6%), 198 (43), 162 (55), 135 (100), 115 (67), 104 (52), 91 (53), 77 (55); HRMS, Found: M+\ 191.0576. Cι0H9NO3 requires M+\ 191.0582.
3-Ethyl-m-indole (34) Rf 0.7 (silica, 1 :4 v/v ethyl acetate/hexane), oil. Η NMR (CDCI3, 300 MHz) δ 7.91 (broad s, IH), 7.62 (d, J= 7.3 Hz, IH), 7.36 (d, J= 7.8 Hz, IH), 7.19 (t, J= 7.8 Hz, IH), 7.12 (t, J = 7.3 Hz, IH), 6.98 (broad s, IH), 2.80 (q, J = 7.5 Hz, 2H), 1.34 (t, J = 7.5 Hz, 3H); 13C NMR (CDCI3, 75 MHz) δ 136.4, 121.8, 120.4, 119.0, 118.9, 118.8, 111.0, 18.3, 14.4 (one signal overlapping or obscured); IR, vmax (KBr) 3405, 2963, 1617, 1454, 1338, 1089, 739 cm"1; MS, m/z (El, 70 eV) 145 (M+\ 63%), 144 (30), 131 (30), 130 (100), 77 (25).

Claims

THE CLAIMS:
1. A method for preparing an indole compound comprising the steps of:
(i) coupling an α-haloenone or an α-haloenal with an ortΛo-halonitroarene to form an ort/rø-(enone)nitroarene or ort/*o-(enal)nitroarene respectively; and
(ii) reductively cyclizing the ortΛo-(enone)nitroarene or ort zo-(enal)nitroarene.
2. The method according to claim 1 wherein the coupling step is carried out using a metal coupling agent.
3. The method according to claim 2 wherein the metal coupling agent is Ni[0] or Cu[0].
4. The method according to claim 1 wherein the coupling is carried out in the presence of a Pd[0] catalyst.
5. The method according to claim 4 wherein the Pd[0] catalyst is Pd2(dba)3 or Pd(PPh3)4.
6. The method according to claim 4 wherein the Pd[0] catalyst is generated in situ from a Pd[II] catalyst.
7. The method according to claim 6 wherein the Pd[II] catalyst is selected from the group consisting of PdCl2(dppf), Pd(OAc)2, PdCl2(CH3CN)2, Pd(C6H5CN)2Cl2 and PdCl2(PPh3)2.
8. The method according to claim 1 wherein reductive cyclization step is carried out using H2 in the presence of a suitable catalyst.
9. The method according to claim 8 wherein the catalyst is selected from the group consisting of PtO2, Rh/Al2O3, Pd(OH)2, Raney Nickel and Pd/C.
10. The method according to claim 9 wherein the catalyst is Pd/C.
11. The method according to claim 1 wherein step (ii) is optionally preceeded by: (i-a) protecting or deprotecting one or more substituents; and/or introducing one or more substituents; and/or replacing one or more substituents with another on the ortho-
(enone)nitroarene or ortΛo-(enal)nitroarene.
12. A method for preparing an indole compound comprising the steps of:
(i) coupling an α-haloenone or an α-haloenal with an ort zo-halonitroarene to form an ort/?o-(enone)nitroarene or ort zo-(enal)nitroarene respectively; (ii) performing a cross-coupling step to introduce replacement substitution on the benzene ring of the ortΛo-(enone)nitroarene or ort/rø-(enal)nitroarene; and
(iii) reductively cyclizing the ortΛo-(enone)nitroarene or ort zo-(enal)nitroarene.
13. A method for preparing an ortΛo-(enone)nitroarene or ortΛo-(enal)nitroarene comprising the step of coupling an α-haloenone or an α-haloenal respectively with an ort/io-halonitroarene.
14. A method for preparing an indole compound comprising the step of reductively cyclizing an ortΛo-(enone)nitroarene or ort/?o-(enal)nitroarene which has been prepared by coupling an ort io-halonitroarene with an α-haloenone or α-haloenal respectively.
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US7767689B2 (en) 2004-03-15 2010-08-03 Ptc Therapeutics, Inc. Carboline derivatives useful in the treatment of cancer
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US8076352B2 (en) 2004-03-15 2011-12-13 Ptc Therapeutics, Inc. Administration of carboline derivatives useful in the treatment of cancer and other diseases
US8940896B2 (en) 2004-03-15 2015-01-27 Ptc Therapeutics, Inc. Tetra-cyclic carboline derivatives useful in the inhibition of angiogenesis
WO2006065480A3 (en) * 2004-11-23 2006-08-03 Ptc Therapeutics Inc Tetrahydrocarbazoles as active agents for inhibiting vegf production by translational control
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JP2008520742A (en) * 2004-11-23 2008-06-19 ピーティーシー セラピューティクス， インコーポレイテッド Carbazole derivatives, carboline derivatives and indole derivatives useful for inhibition of VEGF production
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