WO2013108024A1 - Composés aromatiques et procédés de fabrication desdits composés - Google Patents

Composés aromatiques et procédés de fabrication desdits composés Download PDF

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Publication number
WO2013108024A1
WO2013108024A1 PCT/GB2013/050090 GB2013050090W WO2013108024A1 WO 2013108024 A1 WO2013108024 A1 WO 2013108024A1 GB 2013050090 W GB2013050090 W GB 2013050090W WO 2013108024 A1 WO2013108024 A1 WO 2013108024A1
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group
alkyl
substituted
compound
independently selected
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PCT/GB2013/050090
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English (en)
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Joseph P.A. HARRITY
James D. KIRKHAM
Damien F. CREPIN
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The University Of Sheffield
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
    • C07F5/02—Boron compounds
    • C07F5/04—Esters of boric acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages

Definitions

  • Aromatic compounds and methods of making the same
  • This invention relates to a process of making aromatic compounds, products thereof and to a process of making benzoxaboroles.
  • Benzoxaboroles have emerged as promising bioactive small molecule therapeutics (F. L. Rock et al. Science 2007, 316, 1759).
  • Traditional approaches to these compounds have involved functionalization of a benzene ring by metallation followed by borylation (D. Ding et. al. J. Med. Chem. 2011 , 54, 1276).
  • this approach uses very reactive organometallic reagents that lead to functional group incompatibility issues.
  • a palladium catalyzed borylation of aromatic bromides and triflates is also known (Y.K. Zhang et al. Bioorg. Med. Chem. Lett. 2011 , 21, 644).
  • This process also has disadvantages in that it requires an appropriately substituted precursor that can only be accessed after multistep operations.
  • An alternative approach that employs a metal catalysed alkyne trimerisation is limited to providing restricted substitution patterns and very lipophillic molecules (Y.
  • an improved cycloaddition process is desired to provide an optimized route to organoboron compounds and specifically to organoboron compounds with uses in bioactive small molecule therapeutics, such as benzoxaboroles.
  • the inventors of the present invention have developed a novel cycloaddition process for making aromatic compounds.
  • the novel method facilitates the production of a range of aromatic compounds which were previously very difficult to access using traditional synthetic approaches.
  • the novel method increases the rate of the cycloaddition reaction leading to a significantly reduced reaction time compared to techniques of the prior art.
  • the method of the invention can also be successfully performed at lower temperatures than cycloaddition reactions of the prior art.
  • the novel method also provides a high level of regiocontrol.
  • the novel method generates a series of products from precursor compounds containing group 13 and group 14 elements which are themselves novel and have useful applications.
  • a further aspect of the present invention is therefore a process directed to the synthesis of boron-containing aromatic compounds using the novel method disclosed herein and the subsequent transformation of these compounds to benzoaxoboroles or derivatives thereof.
  • the present invention provides a process of making an aromatic compound or derivative thereof comprising: reacting an alkynyl moiety containing an element selected from group 13 or 14 with a 2-pyrone moiety substituted with a Lewis base in the presence of a Lewis acid to form a six-membered ring fused with a five- membered ring.
  • the present invention provides a compound having the structure of Formula (I):
  • Q is not bonded to M and represents a N R R group wherein R and R may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group, substituted and unsubstituted hydrocarbyloxy groups or R and R are linked to each other to form a nitrogen-containing heterocycle, or wherein Q represents carbon or heteroatoms selected from N, S or O necessary to form a five or six membered heterocyclic ring by bonding to M, wherein, when Q represents a N R R group M is O or S and when Q represents carbon or heteroatoms selected from N, S or O necessary to form a five or six membered heterocyclic ring by bonding to M, M is N; Y is an element selected from group 13 or 14;
  • X is a halogen
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and a substituent;
  • R 4 is H or a substituent.
  • the present invention provides a process of making a benzoxaborole or a derivative of such a benzoxaborole comprising the steps of:
  • FIGS 1 to 22 illustrate the 1 H and 13 C NMR of the compounds of the present invention as depicted on the figures.
  • Ci -6 means a moiety having 1 , 2, 3, 4, 5 or 6 carbon atoms
  • Ci -4 means a moiety having 1 , 2, 3 or 4 carbon atoms
  • C 3 . 6 means a moiety having 3, 4, 5 or 6 carbon atoms
  • Ci- 3 means a moiety having 1 , 2 or 3 carbon atoms.
  • each independently selected from the group comprising or “each independently selected from the group consisting of” is intended to mean that each of the listed 'R' groups may be selected from the group independently of the other 'R' groups (here the term 'R' group refers to any group R, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 etc). Therefore, each 'R' group may be the same or different from each other.
  • R 1 and R 2 are each independently selected from the group consisting of: H and a substituted” covers the following cases in which (1 ) R 1 is H and R 2 is a substituent, (2) R 2 is H and R 1 is a substituent, (3) R 1 is H and R 2 is H and (4) R 1 is a substituent and R 2 is a substituent.
  • R 1 and R 2 may be the same substituents or may be different substitutents since they are each "independently selected” R groups. The same applies to other pairs of 'R' groups.
  • the temperature, pressure or time quoted is approximate rather than the precise temperature, amount of pressure or amount of time.
  • aromatic compound or derivative thereof includes compounds with fused ring systems. More particularly, the term refers to a compound with a six-membered aromatic ring fused with a five-membered heterocycle. The five-membered ring may contain more than one heteroatom.
  • Lewis acid refers to a molecular entity (and the corresponding chemical species) that is an electron-pair acceptor.
  • Lewis base refers to a molecular entity (and the corresponding chemical species) able to donate a pair of electrons.
  • group 13 or group 14 element refers to any element in group 13 or group 14 of the periodic table.
  • substituted means a non-hydrogen moiety, for example a hydroxy, carboxy, carboxamido, imino, alkanoyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), Ci -6 haloalkyl (e.g. trifluoromethyl), d- 6 alkoxy (e.g. methoxy, ethoxy or propoxy), Ci -6 haloalkoxy (e.g. trifluoromethoxy), hydrocarbyl or hydrocarbyloxy group.
  • halogen e.g. fluoro, chloro or bromo
  • Ci -6 haloalkyl e.g. trifluoromethyl
  • d- 6 alkoxy e.g. methoxy, ethoxy or propoxy
  • Ci -6 haloalkoxy e.g. trifluoromethoxy
  • substituted may be each independently unsubstituted or substituted (wherever chemically possible) with from 1 to 5 substituents selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), Ci -6 alkyl (e.g. methyl, ethyl or propyl), Ci -6 haloalkyl (e.g. trifluoromethyl), d- 6 alkoxy (e.g. methoxy, ethoxy or propoxy), Ci -6 haloalkoxy (e.g.
  • C 3 . 6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-C 1-6 alkyl e.g. benzyl
  • C 1-6 alkyl aryl e.g. trifluoromethoxy
  • C 3 . 6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-C 1-6 alkyl e.g. benzyl
  • C 1-6 alkyl aryl e.g. benzyl
  • Hydrocarbyl and hydrocarbyloxy groups disclosed herein may have, for example, from 1 to 10, e.g. from 1 to 6 carbon atoms.
  • hydrocarbyl groups include those consisting of one or a combination of moieties selected from: alkyl, cycloalkyl, alkenyl, cycloalkenyl and aryl (e.g. phenyl), as is the case of phenylalkyl groups.
  • hydrocarbyl may be a non- hydrogen group selected from the group consisting of: alkyl (e.g. C i-6 alkyl); alkenyl (e.g. C2-6 alkenyl); aryl (e.g. phenyl); cycloalkyl (e.g. C 3- 6 cycloalkyl); cycloalkenyl (e.g.
  • alkyl alkenyl e.g. C i-6 alkyl c2-6 alkenyl
  • alkenyl alkyl e.g. C 2-6 alkenyl c1-6 alkyl
  • aryl alkyl e.g. phenyl c1-6 alkyl, such as benzyl
  • alkyl aryl e.g. C i-6 alkyl phenyl
  • alkyl cycloalkyl e.g. C i-6 alkyl C 4- 6 cycloalkyl
  • cycloalkyl alkyl e.g.
  • C 3- 6 cycloalkyl c1-6 alkyl cycloalkenyl alkyl (e.g. C 4-6 cycloalkenyl C i-6 alkyl), and alkyl cycloalkyl (e.g. C i-6 alkyl C 3- 6 cycloalkyl).
  • the above mentioned C i -6 alkyl may be optionally interrupted by -0-, -S- or - NR-.
  • the present invention provides a process of making an aromatic compound or derivative thereof comprising: reacting an alkynyl containing an element selected from group 13 or 14 with a 2-pyrone substituted with a Lewis base in the presence of a Lewis acid to form a six-membered ring fused with a five- membered ring.
  • the process involves the following reaction scheme:
  • Q is not bonded to M and represents a N R R group wherein R and R may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group, substituted and unsubstituted hydrocarbyloxy groups or R and R are linked to each other to form a nitrogen-containing heterocycle, or wherein Q represents carbon or heteroatoms selected from N, S or O necessary to form a five or six membered heterocyclic ring by bonding to M, wherein, when Q represents a N R R group M is O or S and when Q represents carbon or heteroatoms selected from N, S or O necessary to form a five or six membered heterocyclic ring by bonding to M, M is N;
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and a substituent;
  • Y is an element selected from group 13 or 14;
  • L is a cation
  • X is a halogen
  • R 4 is H or a substituent.
  • Y is an element selected from the group consisting of Boron,
  • Y is Boron
  • X is selected from the group consisting of fluorine, bromine or chlorine. In a preferred embodiment, X is fluorine.
  • L is a metal cation or an ammonium cation.
  • L is a metal cation selected from the group consisting of potassium or caesium.
  • L is an ammonium cation comprising a substituted tetraalkylammonium group.
  • L is tetraethylammonium
  • L is potassium
  • R 4 is selected from the group consisting of: H, halogen, trialkylsilyl, substituted and unsubstituted hydrocarbyl group, and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: Ci -6 alkyl, -6 alkenyl, -6 cycloalkyl, -6 cycloalkyl d- 6 alkyl, aryl (e.g. phenyl), aryl-d-6 alkyl (e.g.
  • benzyl d-6 cycloalkenyl, d-6 cycloalkenyl d-6 alkyl, aryloxy d-6 alkyl, aryl d-6 alkyl oxy d-6 alkyl, d-6 cycloalkyl oxy d-6 alkyl, d-6 cycloalkyl d-6 alkyl oxy d-6 alkyl, -6 cycloalkenyl oxy d-6 alkyl, -6 cycloalkenyl d-6 alkyl oxy d-6 alkyl, d-6 alkoxy (e.g.
  • halogen e.g. F
  • d-6 haloalkyl e.g. d-6 fluoroalkyl
  • d-6 haloalkoxy e.g. -d-6 fluoroalkoxy
  • trimethylsilyl Any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), d-6 alkyl (e.g.
  • d-6 haloalkyl e.g. trifluoromethyl
  • d-6 alkoxy e.g. methoxy, ethoxy or propoxy
  • d-6 haloalkoxy e.g. trifluoromethoxy
  • -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d-6 alkyl aryl d-6 alkyl aryl.
  • R 4 is selected from the group consisting of d-6 alkyl, trimethylsilyl, aryl, d-6 alkyl substituted by aryl, d-6 alkoxy group, and d-6 cycloalkenyl.
  • R 4 is selected from the group consisting of phenyl, trimethylsilane, 1 - cyclohexenyl and n-Butyl.
  • Q is not bonded to M and represents a N R'R" group wherein R' and R" may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group, substituted and unsubstituted hydrocarbyloxy groups or R' and R" are linked to each other to form a nitrogen-containing heterocycle and M is O or S.
  • R and R may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: Ci -6 alkyl, -6 alkenyl, d-6 cycloalkyl, d-6 cycloalkyl d- 6 alkyl, aryl (e.g. phenyl), aryl-d-6 alkyl (e.g.
  • benzyl -6 cycloalkenyl, -6 cycloalkenyl d-6 alkyl, aryloxy Ci -6 alkyl, aryl d-6 alkyl oxy d-6 alkyl d-6 cycloalkyl oxy d-6 alkyl, -6 cycloalkyl d-6 alkyl oxy d-6 alkyl, -6 cycloalkenyl oxy d-6 alkyl, -6 cycloalkenyl d-6 alkyl oxy d-6 alkyl, d-6 alkoxy (e.g. methoxy, ethoxy or propoxy).
  • d-6 alkoxy e.g. methoxy, ethoxy or propoxy
  • any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), d-6 alkyl (e.g. methyl, ethyl or propyl), d-6 haloalkyl (e.g. trifluoromethyl), d-6 alkoxy (e.g. methoxy, ethoxy or propoxy), d-6 haloalkoxy (e.g.
  • d-6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d-6 alkyl aryl trifluoromethoxy
  • d-6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d-6 alkyl aryl e.g. benzyl
  • R' and R" are d-6 alkyl.
  • R' and R" are the same.
  • R' and R" are methyl.
  • R and R are linked to each other to form a nitrogen-containing heterocycle.
  • R and R are linked to each other to form a nitrogen-containing six- membered saturated heterocycle.
  • the nitrogen-containing six-membered saturated heterocycle may be selected from:
  • Q represents carbon or heteroatoms selected from N, S or O necessary to form a five or six membered heterocyclic ring by bonding to M and M is N.
  • said five or six membered heterocyclic ring is selected from the group consisting of:
  • W is S or O; Z is H or d- 6 alkyl; R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of: H and a substituent.
  • said five membered heterocyclic ring is selected from:
  • W is S or O and Z is H or Ci -6 alkyl.
  • W is S and Z is H.
  • W is O and Z is methyl.
  • said six membered heterocyclic ring is selected from
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of: H and a substituent.
  • R 5 , R 6 , R 7 and R 8 are selected from the group consisting of: H, halogen, trialkylsilyl, substituted and unsubstituted hydrocarbyl group, and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: Ci-6 alkyl, -6 alkenyl, -6 cycloalkyl, -6 cycloalkyl Ci -6 alkyl, aryl (e.g. phenyl), aryl-d-6 alkyl (e.g.
  • benzyl d-6 cycloalkenyl, d-6 cycloalkenyl d-6 alkyl, aryloxy Ci -6 alkyl, aryl d-6 alkyl oxy Ci -6 alkyl, -6 cycloalkyl oxy Ci -6 alkyl, -6 cycloalkyl Ci -6 alkyl oxy Ci -6 alkyl, -6 cycloalkenyl oxy Ci -6 alkyl, -6 cycloalkenyl d-6 alkyl oxy Ci -6 alkyl, d-6 alkoxy (e.g.
  • halogen e.g. F
  • d-6 haloalkyl e.g. Ci -6 fluoroalkyl
  • d-6 haloalkoxy e.g. -Ci -6 fluoroalkoxy
  • trimethylsilyl Any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), d-6 alkyl (e.g.
  • d-6 haloalkyl e.g. trifluoromethyl
  • d-6 alkoxy e.g. methoxy, ethoxy or propoxy
  • d-6 haloalkoxy e.g. trifluoromethoxy
  • C 3-6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d-6 alkyl aryl e.g. benzyl
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, d-6 alkyl and d-6 alkoxy.
  • R 6 is a methoxy group.
  • R 8 is a methyl group.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, halogen, trialkylsilyl, substituted and unsubstituted hydrocarbyl group, and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: d-6 alkyl, d-6 alkenyl, C 3 - 6 cycloalkyl, C 3 -6 cycloalkyl d-6 alkyl, aryl (e.g. phenyl), aryl-d- 6 alkyl (e.g.
  • benzyl -6 cycloalkenyl, d-6 cycloalkenyl d-6 alkyl, aryloxy C 1-6 alkyl, aryl d-6 alkyl oxy d-6 alkyl, C 3 -6 cycloalkyl oxy d-6 alkyl, C 3 -6 cycloalkyl d-6 alkyl oxy d-6 alkyl, d-6 cycloalkenyl oxy d-6 alkyl, -6 cycloalkenyl d-6 alkyl oxy d-6 alkyl, d-6 alkoxy (e.g. methoxy, ethoxy or propoxy), halogen (e.g.
  • d-6 haloalkyl e.g. d-6 fluoroalkyl
  • d-6 haloalkoxy e.g. -d-6 fluoroalkoxy
  • trimethylsilyl Any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy,
  • d-6 alkoxy e.g. methoxy, ethoxy or propoxy
  • d-6 haloalkoxy e.g.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, d- 6 alkyl, trimethylsilyl, aryl, d- 6 alkyl substituted by aryl, d- 6 alkoxy, and C 4 -6 cycloalkenyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, d- 6 alkyl and d- 6 alkoxy.
  • R 2 is a methoxy group.
  • the novel method of the invention is performed in the presence of a Lewis acid.
  • Suitable Lewis acids are those which are sufficiently reactive to abstract a halide atom.
  • Examples of particularly suitable Lewis acids for the method of the invention include chlorotrimethyl silane (TMSCI), boron trifluoride ethyl etherate (BF 3 .OEt 2 ), fluoroboric acid (HBF 4 ), pentafluoroarsorane (AsF 5 ) and silicon tetrafluoride (SiCI 4 ).
  • Preferred Lewis acids are chlorotrimethyl silane (TMSCI) or boron trifluoride ethyl etherate (BF 3 .OEt 2 ).
  • a particularly preferred Lewis acid is boron trifluoride ethyl etherate (BF 3 .OEt 2 ).
  • boron trifluoride ethyl etherate (BF 3 .OEt 2 ) as the Lewis acid improves the selectivity for the desired product.
  • Suitable Lewis acids are those which are sufficiently reactive to abstract a halide atom and those skilled in the art will be aware of other suitable Lewis acids for this purpose and may be referred to the review of S. Darses et al., Chem. Rev., 2008, 108, 288-325.
  • the Lewis acid abstracts a halide atom from the alkyne to provide an alkynyl dihaloborane in situ.
  • the alkynyl dihaloborane acts itself as a Lewis acid and co-ordinates with the Lewis base attached to the substituted 2- pyrone moiety. Co-ordination of the alkynyl dihaloborane with the Lewis base of the substituted 2-pyrone moiety enables the rate of the ensuing cycloaddition to be increased.
  • reaction times for the method are substantially reduced compared to the reaction times of cycloaddition reactions of the prior art.
  • the reaction time is reduced to about 10 minutes.
  • the reaction time for known cycloaddition reactions of the prior art is typically over 16 hours.
  • the process is suitably performed in the presence of a solvent.
  • Suitable solvents include non-coordinating solvents, such as dichloromethane or 1 ,2- dichloroethane.
  • the process of the present invention can be carried out under mild conditions.
  • the process for synthesising compounds of Formula (I) is performed at a temperature from about 0°C to about 100 ⁇ .
  • the process of the invention can thus be successfully performed at temperatures lower than cycloaddition processes of the prior art which typically require temperatures of above ⁇ ⁇ 40°C.
  • the process of the invention can be performed at a temperature to enhance the level of regiocontrol for the desired product.
  • the process is performed at a temperature of about 25 °C to about 40 °C.
  • the process is performed at 40 °C.
  • the alkynyl moiety is reacted with the 2-pyrone moiety in the presence of a Lewis acid for a period of less than 1 hour.
  • the reaction time of the process is significantly reduced compared to the reaction times of cycloaddition reactions of the prior art.
  • the alkynyl moiety is reacted with the 2-pyrone moiety in the presence of a Lewis acid for a period of about 15 minutes and in other embodiments for a period of about 10 minutes.
  • Aromatic compounds and their derivatives are aromatic compounds and their derivatives:
  • Q is not bonded to M and represents a N R R group wherein R and R may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group, substituted and unsubstituted hydrocarbyloxy groups or R and R are linked to each other to form a nitrogen-containing heterocycle, or wherein Q represents carbon or heteroatoms selected from N, S or O necessary to form a five or six membered heterocyclic ring by bonding to M, wherein, when Q represents a N R R group M is O or S and when Q represents carbon or heteroatoms selected from N, S or O necessary to form a five or six membered heterocyclic ring by bonding to M, M is N;
  • Y is an element selected from group 13 or 14;
  • X is a halogen
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and a substituent;
  • R 4 is H or a substituent.
  • Y is an element selected from the group consisting of Boron
  • Y is Boron
  • X is selected from the group consisting of fluorine, bromine or chlorine. In a preferred embodiment, X is fluorine.
  • Q is not bonded to M and represents a N R'R" group wherein R' and R" may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group, substituted and
  • R' and R" are linked to each other to form a nitrogen-containing heterocycle and M is O or S.
  • R and R may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: Ci -6 alkyl, -6 alkenyl, d-6 cycloalkyl, d-6 cycloalkyl d- 6 alkyl, aryl (e.g. phenyl), aryl-d-6 alkyl (e.g.
  • benzyl -6 cycloalkenyl, -6 cycloalkenyl d-6 alkyl, aryloxy Ci -6 alkyl, aryl d-6 alkyl oxy d-6 alkyl d-6 cycloalkyl oxy d-6 alkyl, -6 cycloalkyl d-6 alkyl oxy d-6 alkyl, -6 cycloalkenyl oxy d-6 alkyl, -6 cycloalkenyl d_ 6 alkyl oxy d-6 alkyl, d_ 6 alkoxy (e.g. methoxy, ethoxy or propoxy).
  • d_ 6 alkoxy e.g. methoxy, ethoxy or propoxy
  • any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), d_ 6 alkyl (e.g. methyl, ethyl or propyl), d-6 haloalkyl (e.g. trifluoromethyl), d_ 6 alkoxy (e.g. methoxy, ethoxy or propoxy), d-6 haloalkoxy (e.g.
  • -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d_ 6 alkyl aryl e.g. trifluoromethoxy
  • -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d_ 6 alkyl aryl d_ 6 alkyl aryl
  • R' and R" are d_ 6 alkyl.
  • R' and R" are the same.
  • R' and R" are methyl.
  • R and R are linked to each other to form a nitrogen-containing heterocycle.
  • R and R are linked to each other to form a nitrogen-containing six- membered saturated heterocycle.
  • the nitrogen-containing six-membered saturated heterocycle may be selected from:
  • Q represents carbon or heteroatoms selected from N, S or O necessary to form a five or six membered heterocyclic ring by bonding to M and M is N.
  • said five or six membered heterocyclic ring is selected from the group consisting of:
  • W is S or O; Z is H or d- 6 alkyl; R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of: H and a substituent.
  • said five membered heterocyclic ring is selected from:
  • W is S or O and Z is H or Ci -6 alkyl.
  • W is S and Z is H.
  • W is O and Z is methyl.
  • said six membered heterocyclic ring is selected from:
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of: H and a substituent.
  • R 5 , R 6 , R 7 and R 8 are selected from the group consisting of: H, halogen, trialkylsilyl, substituted and unsubstituted hydrocarbyl group, and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: Ci-6 alkyl, d-6 alkenyl, d-6 cycloalkyl, d-6 cycloalkyl d- 6 alkyl, aryl (e.g. phenyl), aryl-d-6 alkyl (e.g.
  • benzyl d-6 cycloalkenyl, d-6 cycloalkenyl d-6 alkyl, aryloxy Ci -6 alkyl, aryl d-6 alkyl oxy Ci -6 alkyl, d-6 cycloalkyl oxy Ci -6 alkyl, -6 cycloalkyl d- 6 alkyl oxy d-6 alkyl, d-6 cycloalkenyl oxy d-6 alkyl, d-6 cycloalkenyl d-6 alkyl oxy d-6 alkyl, d-6 alkoxy (e.g.
  • halogen e.g. F
  • d-6 haloalkyl e.g. d-6 fluoroalkyl
  • d-6 haloalkoxy e.g. -d-6 fluoroalkoxy
  • trimethylsilyl Any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyi, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), d-6 alkyl (e.g.
  • d-6 haloalkyl e.g. trifluoromethyl
  • d-6 alkoxy e.g. methoxy, ethoxy or propoxy
  • d-6 haloalkoxy e.g. trifluoromethoxy
  • -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d-6 alkyl aryl d-6 alkyl aryl.
  • R 5 , R 6 , R 7 and R 8 are each independently selected from the group consisting of H, d-6 alkyl and d-6 alkoxy.
  • R 6 is a methoxy group.
  • R 8 is a methyl group.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, halogen, trialkylsilyl, substituted and unsubstituted hydrocarbyl group, and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: Ci -6 alkyl, d-6 alkenyl, -6 cycloalkyl, -6 cycloalkyl Ci -6 alkyl, aryl (e.g. phenyl), aryl-d-6 alkyl (e.g.
  • benzyl d-6 cycloalkenyl, d-6 cycloalkenyl d-6 alkyl, aryloxy Ci -6 alkyl, aryl d-6 alkyl oxy Ci -6 alkyl, -6 cycloalkyl oxy Ci -6 alkyl, -6 cycloalkyl Ci-6 alkyl oxy Ci -6 alkyl, -6 cycloalkenyl oxy Ci -6 alkyl, -6 cycloalkenyl d-6 alkyl oxy Ci -6 alkyl, halogen (e.g. F), d-6 haloalkyl (e.g. Ci -6 fluoroalkyl), d- 6 haloalkoxy (e.g.
  • halogen e.g. F
  • d-6 haloalkyl e.g. Ci -6 fluoroalkyl
  • d- 6 haloalkoxy e.g.
  • -Ci -6 fluoroalkoxy and trimethylsilyl.
  • substituents wherever chemically possible
  • d-6 haloalkoxy e.g. trifluoromethoxy
  • C 3 -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d-6 alkyl aryl e.g. methoxy, ethoxy or propoxy
  • d-6 haloalkoxy e.g. trifluoromethoxy
  • C 3 -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, d-6 alkyl, trimethylsilyl, aryl, d-6 alkyl substituted by aryl, d-6 alkoxy, and -6 cycloalkenyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, d-6 alkyl and d-6 alkoxy.
  • R 2 is a methoxy group.
  • the present invention provides a process of making a benzoxaborole or a derivative of such a benzoxaborole comprising the steps of:
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H and a substituent;
  • R and R may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group, substituted and unsubstituted hydrocarbyloxy groups or wherein R and R are linked to eachother to form a nitrogen-containing heterocycle;
  • B is Boron
  • L is a cation
  • X is a halogen
  • R 4 is H or a substituent.
  • X is selected from the group consisting of fluorine, bromine or chlorine. In a preferred embodiment, X is fluorine.
  • L is a metal cation or an ammonium cation.
  • L is a metal cation selected from the group consisting of potassium or caesium.
  • L is an ammonium cation comprising a substituted tetraalkylammonium group.
  • L is tetraethylammonium
  • L is potassium
  • R 4 is selected from the group consisting of: H, halogen, trialkylsilyl, substituted and unsubstituted hydrocarbyl group, and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: Ci -6 alkyl, -6 alkenyl, -6 cycloalkyl, -6 cycloalkyl Ci -6 alkyl, aryl (e.g. phenyl), aryl-d-6 alkyl (e.g.
  • benzyl d-6 cycloalkenyl, d-6 cycloalkenyl Ci -6 alkyl, aryloxy d-6 alkyl, aryl d-6 alkyl oxy Ci-6 alkyl, -6 cycloalkyl oxy d-6 alkyl, -6 cycloalkyl Ci -6 alkyl oxy Ci -6 alkyl, -6 cycloalkenyl oxy Ci -6 alkyl, -6 cycloalkenyl d-6 alkyl oxy Ci -6 alkyl, halogen (e.g. F), d-6 haloalkyl (e.g. Ci -6 fluoroalkyl), d- 6 haloalkoxy (e.g.
  • halogen e.g. F
  • d-6 haloalkyl e.g. Ci -6 fluoroalkyl
  • d- 6 haloalkoxy e.g.
  • -Ci -6 fluoroalkoxy and trimethylsilyl. Any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), d-6 alkyl (e.g. methyl, ethyl or propyl), d-6 haloalkyl (e.g.
  • d-6 alkoxy e.g. methoxy, ethoxy or propoxy
  • d-6 haloalkoxy e.g.
  • C 3 -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d-6 alkyl aryl e.g. trifluoromethoxy
  • R 4 is selected from the group consisting of d-6 alkyl, trimethylsilyl, aryl, d-6 alkyl substituted by aryl, d_ 6 alkoxy group, and d-6 cycloalkenyl.
  • R 4 is selected from the group consisting of phenyl, trimethylsilane, 1 - cyclohexenyl and n-Butyl.
  • R' and R" may be the same or different and are each independently selected from the group consisting of: substituted and unsubstituted hydrocarbyl group and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: d-6 alkyl, d-6 alkenyl, C 3 - 6 cycloalkyl, C 3 -6 cycloalkyl d-6 alkyl, aryl (e.g. phenyl), aryl-d- 6 alkyl (e.g.
  • benzyl -6 cycloalkenyl, -6 cycloalkenyl d-6 alkyl, aryloxy d-6 alkyl, aryl d-6 alkyl oxy d-6 alkyl, C 3 -6 cycloalkyl oxy d-6 alkyl, d-6 cycloalkyl d-6 alkyl oxy d-6 alkyl, -6 cycloalkenyl oxy d-6 alkyl, -6 cycloalkenyl d-6 alkyl oxy d-6 alkyl, d_ 6 alkoxy (e.g. methoxy, ethoxy or propoxy).
  • d_ 6 alkoxy e.g. methoxy, ethoxy or propoxy
  • any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyl, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), d_ 6 alkyl (e.g. methyl, ethyl or propyl), d-6 haloalkyl (e.g. trifluoromethyl), d_ 6 alkoxy (e.g. methoxy, ethoxy or propoxy), d-6 haloalkoxy (e.g.
  • -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d_ 6 alkyl aryl e.g. trifluoromethoxy
  • -6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl-d- 6 alkyl e.g. benzyl
  • d_ 6 alkyl aryl d_ 6 alkyl aryl
  • R' and R" are d_ 6 alkyl.
  • R' and R" are the same.
  • R' and R" are methyl.
  • R' and R" are linked to each other to form a nitrogen-containing heterocycle.
  • R and R are linked to each other to form a nitrogen-containing six- membered saturated heterocycle.
  • R' and R" may be selected from:
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, halogen, trialkylsilyl, substituted and unsubstituted hydrocarbyl group, and substituted and unsubstituted hydrocarbyloxy groups, e.g. a group selected from the group consisting of: Ci -6 alkyl, -6 alkenyl, d-6 cycloalkyl, d-6 cycloalkyl d- 6 alkyl, aryl (e.g. phenyl), aryl-d-6 alkyl (e.g.
  • benzyl -6 cycloalkenyl, -6 cycloalkenyl d-6 alkyl, aryloxy Ci -6 alkyl, aryl d-6 alkyl oxy Ci -6 alkyl, d-6 cycloalkyl oxy Ci -6 alkyl, -6 cycloalkyl d-6 alkyl oxy d_ 6 alkyl, d-6 cycloalkenyl oxy d-6 alkyl, d-6 cycloalkenyl d-6 alkyl oxy d-6 alkyl, halogen (e.g. F), d-6 haloalkyl (e.g.
  • d-6 fluoroalkyl d- 6 haloalkoxy (e.g. -d-6 fluoroalkoxy) and trimethylsilyl. Any of these groups may be unsubstituted or substituted with from 1 to 5 substituents (wherever chemically possible) selected from the group consisting of: hydroxy, carboxy, carboxamido, imino, alkanoyi, cyano, cyanomethyl, nitro, amino, halogen (e.g. fluoro, chloro or bromo), d-6 alkyl (e.g. methyl, ethyl or propyl), d-6 haloalkyl (e.g. trifluoromethyl), d-6 alkoxy (e.g.
  • d-6 haloalkoxy e.g. trifluoromethoxy
  • d-6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl- d-6 alkyl e.g. benzyl
  • d-6 alkyl aryl e.g. methoxy, ethoxy or propoxy
  • d-6 haloalkoxy e.g. trifluoromethoxy
  • d-6 cycloalkyl e.g. cyclohexyl
  • aryl e.g. phenyl
  • aryl- d-6 alkyl e.g. benzyl
  • d-6 alkyl aryl e.g. benzyl
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of: H, d-6 alkyl, trimethylsilyl, aryl, d-6 alkyl substituted by aryl, d-6 alkoxy, and -6 cycloalkenyl.
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of H, d-6 alkyl and d-6 alkoxy.
  • R 2 is a methoxy group.
  • the novel method of the invention to form aromatic borane compounds of Formula (IA) is performed in the presence of a Lewis acid.
  • Suitable Lewis acids are those which are sufficiently reactive to abstract a halide atom.
  • Examples of particularly suitable Lewis acids for the method of the invention include chlorotrimethyl silane (TMSCI), boron trifluoride ethyl etherate (BF 3 .OEt 2 ), fluoroboric acid (HBF 4 ), pentafluoroarsorane (AsF 5 ) and silicon tetrafluoride (SiCI 4 ).
  • Preferred Lewis acids are chlorotrimethyl silane (TMSCI) or boron trifluoride ethyl etherate (BF 3 .OEt 2 ).
  • a particularly preferred Lewis acid is boron trifluoride ethyl etherate (BF 3 .OEt 2 ).
  • the selection of boron trifluoride ethyl etherate (BF 3 .OEt 2 ) as the Lewis acid improves the selectivity for the product Formula (IA).
  • Suitable Lewis acids are those which are sufficiently reactive to abstract a halide atom and those skilled in the art will be aware of other suitable Lewis acids for this purpose and may be referred to the review of S. Darses et al., Chem. Rev., 2008, 108, 288-325.
  • the Lewis acid abstracts a halide atom from the alkyne to provide an alkynyl dihaloborane in situ.
  • the alkynyl dihaloborane acts itself as a Lewis acid and co-ordinates with the Lewis base attached to the substituted 2- pyrone moiety.
  • Co-ordination of the alkynyl dihaloborane with the Lewis base of the substituted 2-pyrone moiety enables the rate of the ensuing cycloaddition to be increased. Consequently the reaction times for the method are substantially reduced compared to the reaction times of cycloaddition reactions of the prior art.
  • the reaction time for the formation of the aromatic borane is reduced to about 10 minutes.
  • the reaction time for known cycloaddition reactions of the prior art is typically over 16 hours.
  • the process is suitably performed in the presence of a solvent.
  • Suitable solvents include non-coordinating solvents, such as dichloromethane or 1 ,2- dichloroethane.
  • the process for synthesising compounds of Formula (IA) is performed at a temperature from about 0 °C to about 100 ⁇ .
  • the process of the invention can thus be successfully performed at temperatures lower than cycloaddition processes of the prior art which typically require temperatures of above ⁇ 40 °C.
  • the process of the invention can be performed at a temperature to enhance the level of regiocontrol for the product Formula (IA).
  • the process for synthesising compounds of Formula (IA) is performed at a temperature of about 25 °C to about 40 °C.
  • the process is performed at 40 °C.
  • the alkynyl borate is reacted with the 2-pyrone moiety in the presence of a Lewis acid for a period of less than 1 hour.
  • the reaction time of the process is significantly reduced compared to the reaction times of cycloaddition reactions of the prior art.
  • the alkynyl borate is reacted with the 2-pyrone moiety in the presence of a Lewis acid for a period of about 15 minutes and in other embodiments for a period of about 10 minutes.
  • the novel method for synthesizing compounds of Formula (II) is performed in the presence of a reducing agent.
  • a mild reducing agent such as sodium borohydride can be used.
  • Other borohydride reducing agents may also be suitable. Further examples include lithium borohydride and sodium cyanoborohydride.
  • aluminium hydride reducing agents may be used. Examples of suitable aluminium hydride reducing agents include lithium aluminium hydride, sodium bis(2-methoxyethoxy)aluminumhydride (Red-AI) or diisobutylaluminium hydride (Dibal-H).
  • the process for synthesising compounds of Formula (II), by the reduction of compounds of Formula (IA), is performed at a temperature from about 0 °C to about 100 ⁇ .
  • the process is performed at ambient temperature.
  • the reduction step is performed in the presence of a suitable solvent, such as ethanol.
  • IR Infrared
  • Spectra were recorded on a Perkin Elmer Paragon 100 FTI R spectrophotometer, v max in cm "1 . Samples were recorded as thin films using sodium chloride plates, as a DCM solution. Bands are characterised as broad (br), strong (s), medium (m), and weak (w).
  • 1 H NMR spectra were recorded on a Bruker AC-250 (250 MHz) or AMX-400 (400 MHz) supported by an Aspect 3000 data system, unless otherwise stated. Chemical shifts are reported in ppm from tetramethylsilane with the residual protic solvent resonance as the internal standard (CHCI 3 : 57.27ppm).
  • Thin layer chromatography was performed on aluminium backed plates pre-coated with silica (0.2 mm, Merck DC-alufolien Kieselgel 60 F254) which were developed using standard visualizing agents: Ultraviolet light or potassium permanganate.
  • the reaction mixture was washed sequentially with saturated NaHC0 3 (40 mL), water (40 mL), and saturated brine (40 mL).
  • the organic layer was dried over MgS0 4 , filtered and evaporated to afford crude product.

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Abstract

Cette invention concerne un procédé de fabrication de composés aromatiques, de produits obtenus par celui-ci et un procédé de fabrication de benzoxaboroles. Selon un aspect, la présente invention concerne un procédé de fabrication d'un composé aromatique ou d'un produit dérivé de celui-ci consistant à : faire réagir une fraction alcynyle contenant un élément choisi parmi le groupe 13 ou 14 avec une fraction 2-pyrone contenant une base de Lewis en présence d'un acide de Lewis pour former un anneau à six chaînons fusionné à un anneau à cinq chaînons. Selon un autre aspect, la présente invention permet d'obtenir des composés en utilisant ledit procédé. Dans un autre aspect, la présente invention concerne un procédé de fabrication d'un benzoxaborole ou d'un dérivé dudit benzoxaborole comprenant les étapes consistant à : a) faire réagir un borate d'alcynyle avec une fraction 2-pyrone substituée par un amide en présence d'un acide de Lewis pour former un borane aromatique ; b) faire réagir ledit borane avec un agent réducteur.
PCT/GB2013/050090 2012-01-17 2013-01-16 Composés aromatiques et procédés de fabrication desdits composés WO2013108024A1 (fr)

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US9138002B2 (en) 2013-01-30 2015-09-22 Agrofresh Inc. Compounds and compositions
US9426996B2 (en) 2013-01-30 2016-08-30 Agrofresh Inc. Use of benzoxaboroles as volatile antimicrobial agents on meats, plants, or plant parts
US9585396B2 (en) 2013-01-30 2017-03-07 Agrofresh Inc. Volatile applications against pathogens
US10070649B2 (en) 2013-01-30 2018-09-11 Agrofresh Inc. Volatile applications against pathogens
US10765117B2 (en) 2013-01-30 2020-09-08 Agrofresh Inc. Volatile applications against pathogens
US11039617B2 (en) 2013-01-30 2021-06-22 Agrofresh Inc. Large scale methods of uniformly coating packaging surfaces with a volatile antimicrobial to preserve food freshness
US11202448B2 (en) 2013-01-30 2021-12-21 Agrofresh Inc. Volatile applications against pathogens
US11771089B2 (en) 2013-01-30 2023-10-03 Agrofresh Inc. Large-scale methods of uniformly coating packaging surfaces with a volatile antimicrobial to preserve food freshness
US11917997B2 (en) 2013-01-30 2024-03-05 Agrofresh Inc. Volatile applications against pathogens
WO2016153906A1 (fr) * 2015-03-20 2016-09-29 Board Of Regents Of The Nevada System Of Higher Education, On Behalf Of The University Of Nevada, Reno Procédés de fabrication de composés polycycliques à l'aide de séquences de réaction en tandem/à plusieurs composants
US10966429B2 (en) 2016-03-07 2021-04-06 Agrofresh Inc. Synergistic methods of using benzoxaborole compounds and preservative gases as an antimicrobial for crops

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