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WO2004031134A1 - Process for making substituted aryl sulfonamides using an indium based catalyst system - Google Patents

Process for making substituted aryl sulfonamides using an indium based catalyst system Download PDF

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Publication number
WO2004031134A1
WO2004031134A1 PCT/GB2003/004234 GB0304234W WO2004031134A1 WO 2004031134 A1 WO2004031134 A1 WO 2004031134A1 GB 0304234 W GB0304234 W GB 0304234W WO 2004031134 A1 WO2004031134 A1 WO 2004031134A1
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indium
optionally substituted
compound
alkyl
alkoxy
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PCT/GB2003/004234
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French (fr)
Inventor
David Alan Griffin
Christopher Gregory Frost
Joseph Patrick Hartley
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Syngenta Limited
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Priority to AU2003267664A priority Critical patent/AU2003267664A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D279/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one sulfur atom as the only ring hetero atoms
    • C07D279/02—1,2-Thiazines; Hydrogenated 1,2-thiazines
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J31/00—Catalysts comprising hydrides, coordination complexes or organic compounds
    • B01J31/02—Catalysts comprising hydrides, coordination complexes or organic compounds containing organic compounds or metal hydrides
    • B01J31/0201—Oxygen-containing compounds
    • B01J31/0211—Oxygen-containing compounds with a metal-oxygen link

Definitions

  • the present invention relates to a process for the preparation of aryl sulfonamides and to catalysts useful in such a process.
  • Aromatic sulfonamides are of significant interest because of their bioactive nature, most notably as pharmaceuticals. Over thirty products containing this functionality are in clinical use, including antibacterials, diuretics, anticonvulsants, hypoglycemics and HTV protease inhibitors. Examples of such aromatic sulfonamides used in commercial products are sildenafil, acetazolamide, dichlorophenamide, sulphanilamide and sulfamethoxazole.
  • an activated aromatic compound is an aromatic compound substituted by one or more activating groups. Suitable activating groups are halogen or any electron-donating group.
  • aryl encompasses carbocyclic aromatic rings (such as phenyl, naphthyl, anthracyl, fluorenyl and indenyl) and heteroaromatic rings (also referred to as heteroaryl groups) which are aromatic ring systems containing at least one heteroatom and consisting either of a single ring or of two or more fused rings.
  • single rings will contain up to three and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulphur.
  • Examples of such groups include furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrimidinyl, 1,2,3-triazinyl, benzofuryl, benzisofuryl, benzothienyl, benzisothienyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl,
  • Halogen is fluorine, chlorine, bromine or iodine.
  • the substituents on the amino group maybe independently C ⁇ - ⁇ o alkyl groups which may themselves be optionally substituted.
  • Preferred catalysts are indium (DI) chloride, indium (HI) acetate, indium (ID) acetylacetonate, indium (HI) nitrate, indium (HI) perchlorate, indium (El) sulfate, indium (ITJ) trifluoroacetate, indium (El) trifluoroacetylacetonate, indium tris(trifluoromethanesulfonate) [also known as indium (ID) Inflate] and indium (in) triflamide.
  • One particularly suitable catalyst is indium (111) triflate.
  • the sulfamoylation is an intramolecular sulfamoylation reaction in which an aromatic compound carrying an electron-donating substituent and a sulphonamide is converted to a compound in which a 5-7 membered ring containing N and S (the S atom carrying two oxygen atoms) is fused onto the aromatic ring.
  • the aromatic compound may be substituted by a group that is both electron donating and sulphonamide-containing.
  • Ar-H (H) where Ar is as defined in relation to formula (I) with a compound of formula (IH) Z-SOz-NR ⁇ 2 (HI) where R 1 and R 2 are as defined in relation to formula (I) and Z is a leaving group, in the presence of an indium compound.
  • Suitable optional substituents for Ar in formula (I) are halogen or an electron- donating group.
  • Examples of a compound of formula (I) are sildenafil, acetazolamide, dichlorophenamide, sulphanilamide and sulfamethoxazole.
  • Z is halo, more preferably chloro.
  • Each alkyl moiety is a straight or branched chain and unless otherwise stated is C ⁇ o alkyl, preferably C 1-6 alkyl, more preferably C 1-4 alkyl.
  • Typical examples of alkyl are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, is ⁇ -propyl, n-butyl, sec-butyl, ⁇ o-butyl, tert-butyl or n ⁇ o-pentyl.
  • Terms where alkyl is part of a larger grouping such as haloalkyl, alkylthio and alkoxy are to be construed accordingly.
  • alkenyl groups are straight or branched chains and unless otherwise stated are C 2-1 o alkenyl, preferably C 2-6 alkenyl, more preferably C 2-4 alkenyl and alkynyl groups are straight or branched chains and unless otherwise stated are C 2-10 alkynyl, preferably C 2-6 alkynyl, more preferably C 2-4 alkynyl.
  • Cycloalkyl groups are preferably C -7 cycloalkyl, more preferably Cs- ⁇ cycloalkyl.
  • the terms heterocycle or heterocyclic ring refer, unless otherwise stated, to a non- aromatic ring system of one or two rings containing up to 10 atoms including one or more (preferably one, two, three or four) heteroatoms selected from O, S and N. Examples of such rings include 1,3-dioxolane, tetrahydroftrran, morpholine and pipieridine; a further example is piperazine.
  • the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, NCS-, C -7 cycloalkyl (itself optionally substituted with C 1-6 alkyl or halogen), C 5-7 cycloalkenyl (itself optionally substituted with C--6 alkyl or halogen), C MO alkoxy, CM O alkoxy(C 1-10 )alkoxy, C 1-6 alkoxy-carbonyl(C 1 . 1 o)alkoxy, C ⁇ .
  • haloalkoxy aryl- (d- ⁇ alkoxy (where the aryl group is optionally substituted by halo, C 1-4 alkyl or C 1- alkoxy), C 3 - 7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with C 1-6 alkyl or halogen), C O alkenyloxy, CMO alkynyloxy, CM O alkylthio, CM O haloalkylthio, aryl(C 1-4 )-alkylthio (where the aryl group is optionally substituted by halo, CM alkyl or C 1-4 alkoxy), C 3-7 cycloalkylthio (where the cycloalkyl group is optionally substituted with C-.
  • the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, CM O alkoxy (itself optionally substituted by C MO alkoxy), aryl(C ⁇ - 4 )alkoxy, C O alkylthio, CM O alkylcarbonyl, C MO alkoxycarbonyl, d- 6 al lan inocarbonyl, di(C !
  • the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, C M O alkoxy (itself optionally substituted by C O alkoxy), aryl(d. 4 )alkoxy, C ⁇ - 10 alkylthio, CMO alkylcarbonyl, C 1-10 alkoxycarbonyl, C-.
  • alkenyl, alkynyl and cycloalkyl are as those listed above for , alkyl.
  • Preferred Ar groups are phenyl.
  • the optional substituents on aryl (including heteroaryl) and heterocyclic groups are as those for alkyl; in addition the optional substituent maybe C 1-10 alkyl.
  • heterocyclic groups may be substituted by one or more oxo groups.
  • the reaction is preferably carried out at a temperature of 50-200° C, preferably at a temperature of 100-200°C. Even more preferably the reaction is carried out at a temperature of lOO-120°C.
  • the reaction may be carried out at elevated pressure.
  • the reaction may be carried out in the presence of a solvent, such as an aromatic solvent (for example toluene), mtromethane, acetonitrile, an ether (such as tetrahydrofuran or dioxane) or a chlorinated alkane such as dichloroethane.
  • a solvent such as an aromatic solvent (for example toluene), mtromethane, acetonitrile, an ether (such as tetrahydrofuran or dioxane) or a chlorinated alkane such as dichloroethane.
  • a solvent such as an aromatic solvent (for example toluene), mtromethane, acetonitrile, an ether (such as tetrahydrofuran or dioxane) or a chlorinated alkane such as dichloroethane.
  • Preferred solvents are chlorinated alkanes and a more preferred solvent is dichloroethane.
  • the molar ratio of the compound of formula (H) to the compound of formula (ID) is from 1:1 to 100:1 and more preferably from 1:1 to 10:1; a ratio of 5:1 gives the highest yields in the shortest time.
  • the invention is illustrated by the following Examples.
  • EXAMPLE 1 This Example illustrates the preparation of dimethyl-p-toluenesulfonamide by reacting toluene with N,N-dimethylsulfamoyl chloride in the presence of various catalysts.
  • This Example illustrates an indium catalysed intramolecular sulfamoylation reaction.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

A process for making substituted aryl sulfonamides by sulfamoylation of an activated aromatic compound using an indium compound as a catalyst.

Description

PROCESS FOR MAKING SUBSTITUTED ARY SULFONAMIDES USING AN INDIUM BASED
CATALYST SYSTEM
The present invention relates to a process for the preparation of aryl sulfonamides and to catalysts useful in such a process. Aromatic sulfonamides are of significant interest because of their bioactive nature, most notably as pharmaceuticals. Over thirty products containing this functionality are in clinical use, including antibacterials, diuretics, anticonvulsants, hypoglycemics and HTV protease inhibitors. Examples of such aromatic sulfonamides used in commercial products are sildenafil, acetazolamide, dichlorophenamide, sulphanilamide and sulfamethoxazole. The most popular route to aromatic sulfonamides involves the chlorosulfonation of an arene, to give the sulfonyl chloride, and subsequent reaction with an amine. However this approach is marred either by the need to employ a large excess of chlorosulfonic acid that leads to acidic waste or the undesirable formation of the diaryl sulfone. The reaction of trialkylarylstannanes and sulfonyl isocyanates has also been employed. Electrophilic substitution reactions introducing the sulfonamide moiety directly are less well known but an aluminium chloride promoted thia-Fries rearrangement has been reported in Tetrahedron Lett. 2001, 42, 8729 and a sulfamoylation reaction has been disclosed in Synthesis, 1977, 39. However the use of stoichiometric Lewis acids or tin reagents is undesirable, particularly on an industrial scale, due to serious waste problems. Thus a cleaner alternative to existing methodologies for making aryl sulfonamides is required. The applicants have now successfully synthesised aryl sulfonamides using a catalysed sulfamoylation process.
According to the invention there is therefore provided a process for making substituted aryl sulfonamides by sulfamoylation of an activated aromatic compound using an indium compound as a catalyst. The reaction is suitable for the production a wide range of substituted aryl sulfonamides. An activated aromatic compound is an aromatic compound substituted by one or more activating groups. Suitable activating groups are halogen or any electron-donating group. The skilled person would readily be familiar with groups that are known to be electron-donating but typical examples are optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthio and optionally substituted alkylcarbonyloxy.
The term aryl encompasses carbocyclic aromatic rings (such as phenyl, naphthyl, anthracyl, fluorenyl and indenyl) and heteroaromatic rings (also referred to as heteroaryl groups) which are aromatic ring systems containing at least one heteroatom and consisting either of a single ring or of two or more fused rings. Preferably, single rings will contain up to three and bicyclic systems up to four heteroatoms which will preferably be chosen from nitrogen, oxygen and sulphur. Examples of such groups include furyl, thienyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, pyrimidinyl, 1,2,3-triazinyl, benzofuryl, benzisofuryl, benzothienyl, benzisothienyl, indolyl, isoindolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, benzotriazinyl, purinyl, pteridinyl and indolizinyl. Preferred examples of heteroaromatic rings include thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl and 1 ,3 ,4-thiadiazolyl.
Halogen is fluorine, chlorine, bromine or iodine.
The substituents on the amino group maybe independently Cι-ιo alkyl groups which may themselves be optionally substituted.
Preferred catalysts are indium (DI) chloride, indium (HI) acetate, indium (ID) acetylacetonate, indium (HI) nitrate, indium (HI) perchlorate, indium (El) sulfate, indium (ITJ) trifluoroacetate, indium (El) trifluoroacetylacetonate, indium tris(trifluoromethanesulfonate) [also known as indium (ID) Inflate] and indium (in) triflamide. One particularly suitable catalyst is indium (111) triflate.
In one aspect of the invention the sulfamoylation is an intramolecular sulfamoylation reaction in which an aromatic compound carrying an electron-donating substituent and a sulphonamide is converted to a compound in which a 5-7 membered ring containing N and S (the S atom carrying two oxygen atoms) is fused onto the aromatic ring. In one particular aspect of the invention the aromatic compound may be substituted by a group that is both electron donating and sulphonamide-containing.
In another aspect of the invention there is provided a process for preparing a compound of formula (I)
Ar-SOz-NP^R2 (1) where Ar is an optionally substituted aryl group and R1 and R2 are, independently H, optionally substituted C1-10 alkyl, preferably optionally substituted C1-6 alkyl, or optionally
1 substituted aryl; or R and R together with the N atom to which they are attached form an optionally substituted five-, six- or seven-membered heterocyclic ring, by reacting a compound of formula (IT)
Ar-H (H) where Ar is as defined in relation to formula (I) with a compound of formula (IH) Z-SOz-NR^2 (HI) where R1 and R2 are as defined in relation to formula (I) and Z is a leaving group, in the presence of an indium compound.
Suitable optional substituents for Ar in formula (I) are halogen or an electron- donating group. Examples of a compound of formula (I) are sildenafil, acetazolamide, dichlorophenamide, sulphanilamide and sulfamethoxazole. Preferably Z is halo, more preferably chloro.
Each alkyl moiety is a straight or branched chain and unless otherwise stated is C^o alkyl, preferably C1-6 alkyl, more preferably C1-4 alkyl. Typical examples of alkyl are methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, isσ-propyl, n-butyl, sec-butyl, ώo-butyl, tert-butyl or nβo-pentyl. Terms where alkyl is part of a larger grouping such as haloalkyl, alkylthio and alkoxy are to be construed accordingly.
Similarly alkenyl groups are straight or branched chains and unless otherwise stated are C2-1o alkenyl, preferably C2-6 alkenyl, more preferably C2-4 alkenyl and alkynyl groups are straight or branched chains and unless otherwise stated are C2-10 alkynyl, preferably C2-6 alkynyl, more preferably C2-4 alkynyl.
Cycloalkyl groups are preferably C -7 cycloalkyl, more preferably Cs-β cycloalkyl. The terms heterocycle or heterocyclic ring refer, unless otherwise stated, to a non- aromatic ring system of one or two rings containing up to 10 atoms including one or more (preferably one, two, three or four) heteroatoms selected from O, S and N. Examples of such rings include 1,3-dioxolane, tetrahydroftrran, morpholine and pipieridine; a further example is piperazine.
When present, the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, NCS-, C -7 cycloalkyl (itself optionally substituted with C1-6 alkyl or halogen), C5-7 cycloalkenyl (itself optionally substituted with C--6 alkyl or halogen), CMO alkoxy, CMO alkoxy(C1-10)alkoxy, C1-6 alkoxy-carbonyl(C1.1o)alkoxy, Cι.10 haloalkoxy, aryl- (d-^alkoxy (where the aryl group is optionally substituted by halo, C1-4 alkyl or C1- alkoxy), C3-7 cycloalkyloxy (where the cycloalkyl group is optionally substituted with C1-6 alkyl or halogen), C O alkenyloxy, CMO alkynyloxy, CMO alkylthio, CMO haloalkylthio, aryl(C1-4)-alkylthio (where the aryl group is optionally substituted by halo, CM alkyl or C1-4 alkoxy), C3-7 cycloalkylthio (where the cycloalkyl group is optionally substituted with C-.6 alkyl or halogen), arylthio (where the aryl group is optionally substituted by halo, C1-4 alkyl or C1- alkoxy), C1-6 alkylsulfonyl, d-6 haloalkylsulfonyl, C1-6 alkylsulflnyl, d-6 haloalkylsulfinyl, arylsulfonyl (where the aryl group is optionally substituted by halo, d- 4 alkyl or C1- alkoxy), CMO alkylcarbonyl, CMO alkoxycarbonyl, aminocarbonyl, C1-6 alkylaminocarbonyl, di(Cι_6 alkyl)-aminocarbonyl, N-(Cι-3 alkyl)-N-(C1-3 alkoxy)aminocarbonyl, C1-6 alkylcarbonyloxy, arylcarbonyloxy (where the aryl group is optionally substituted by halo, C1-4 alkyl or C1- alkoxy), di(C1-6)alkylaminocarbonyloxy, aryl (itself optionally substituted by halo, C1-4 alkyl or C1-4 alkoxy), heterocyclyl (itself optionally substituted by oxo, C1- alkyl, C1-4 alkoxy or halogen), aryloxy (where the aryl group is optionally substituted by halo, C1-4 alkyl or C1- alkoxy), heterocyclyloxy (where the heterocyclyl group is optionally substituted with oxo, C1-4 alkyl, Ci^ alkoxy or halogen), d-6 alkylamino, di(Cμ6)alkylamino, d-6 alkylcarbonylamino and
Figure imgf000005_0001
(C 1.6)alkylamino .
Preferably the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, CMO alkoxy (itself optionally substituted by CMO alkoxy), aryl(Cι- 4)alkoxy, C O alkylthio, CMO alkylcarbonyl, CMO alkoxycarbonyl, d-6 al lan inocarbonyl, di(C!-6 alkylaminocarbonyl, (C1-6)alkylcarbonyloxy, d-6 alkylcarbonylamino, phenyl (optionally substituted by halo, C1-4 alkyl or C1- alkoxy), heteroaryl (optionally substituted by halo, C1-4 alkyl or C1- alkoxy), phenoxy (optionally substituted by halo,
Figure imgf000005_0002
alkyl or C1-4 alkoxy), heteroaryloxy (optionally substituted by halo, d-4 alkyl or C1-4 alkoxy), heterocyclyl (optionally substituted by oxo, halo, Cι-4 alkyl or C1-4 alkoxy), heterocyclyloxy (optionally substituted by oxo, halo, C1-4 alkyl or C1-4 alkoxy), C3-7 cycloalkyl (itself optionally substituted with (C1-6)alkyl or halogen), C3-7 cycloalkyloxy, Cs_7 cycloalkenyl, Cι-6 alkylsulfonyl or C1-6 alkylsulfinyl.
More preferably the optional substituents on an alkyl moiety include one or more of halogen, nitro, cyano, CMO alkoxy (itself optionally substituted by C O alkoxy), aryl(d. 4)alkoxy, Cι-10 alkylthio, CMO alkylcarbonyl, C1-10 alkoxycarbonyl, C-.6 alkylaminocarbonyl, di(Cι-6 alkylaminocarbonyl, (C1-6)alkylcarbonyloxy, d-6
Figure imgf000005_0003
phenyl (optionally substituted by halo, C1- alkyl or C1-4 alkoxy), phenoxy (optionally substituted by halo, Cι-4 alkyl or C1-4 alkoxy), heteroaryl (optionally substituted by halo, C1- alkyl or C1-4 alkoxy), phenoxy (optionally substituted by halo, C1-4 alkyl or C1-4 alkoxy), heteroaryloxy (optionally substituted by halo, CM alkyl or CM alkoxy), heterocyclyl (optionally substituted by oxo, halo, Cl-4 alkyl or Cl-4 alkoxy), heterocyclyloxy (optionally substituted by oxo, halo, Cl-4 alkyl or Cl-4 alkoxy).
Optional substituents for alkenyl, alkynyl and cycloalkyl are as those listed above for , alkyl.
Preferred Ar groups are phenyl. When present, the optional substituents on aryl (including heteroaryl) and heterocyclic groups are as those for alkyl; in addition the optional substituent maybe C1-10 alkyl. In addition heterocyclic groups may be substituted by one or more oxo groups.
The reaction is preferably carried out at a temperature of 50-200° C, preferably at a temperature of 100-200°C. Even more preferably the reaction is carried out at a temperature of lOO-120°C.
The reaction may be carried out at elevated pressure.
The reaction may be carried out in the presence of a solvent, such as an aromatic solvent (for example toluene), mtromethane, acetonitrile, an ether (such as tetrahydrofuran or dioxane) or a chlorinated alkane such as dichloroethane. Preferred solvents are chlorinated alkanes and a more preferred solvent is dichloroethane.
Preferably the molar ratio of the compound of formula (H) to the compound of formula (ID) is from 1:1 to 100:1 and more preferably from 1:1 to 10:1; a ratio of 5:1 gives the highest yields in the shortest time. The invention is illustrated by the following Examples.
EXAMPLE 1 This Example illustrates the preparation of dimethyl-p-toluenesulfonamide by reacting toluene with N,N-dimethylsulfamoyl chloride in the presence of various catalysts.
Figure imgf000007_0001
A stirring mixture of toluene (0.46g; 5mmol) dimethylsulfamoyl chloride (0.14g; lmmol) and indium triflate (0.112g; 20mol%) in dichloroethane [DCE] (5ml) was heated to
100°C for 24hours. The reaction mixture was then partitioned between dichloromethane and
1 M HCl. The aqueous layer was washed with dichloromethane three times and the combined organics were washed with brine, dried over MgSO (anhydrous) and concentrated to afford crude sulfonamide product which was purified by flash chromatography using petroleum ether
: ethyl acetate (4 : 1) as eluent to afford dimethyl-p-toluenesulfonamide as a white crystalline solid, mp 79-81°C.
1HNMR (CDC13) δ: 2.45(s,3H,Ar-Me), 2.68(s,6H,N-Me), 7.23-7.26(m,2H), 7.64-7.69(m,2H)ppm.
Expected: C 54.3; H 6.60; N 7.0%. Found: C 54.3; H 6.55; N 7.0%.
Results obtained with the same mol% of different catalysts are presented in Table 1
Table 1.
Figure imgf000007_0002
EXAMPLE 2
In this Example an aromatic compound was reacted with a sulfamoyl chloride using indium triflate as catalyst.
A stirring mixture of anisole (0.89ml; 8.25mmol), N,N-dimethyl sulfamoyl chloride (0.237g; 1.65mmol) and In(OTf)3 (0.184g; 20mol%) in dichloroethane (5ml) was heated to 100°C for 24hours. The reaction mixture was then partitioned between dichloromethane and 1 M HCl. The aqueous layer was washed with dichloromethane three times and the combined organics were washed with brine, dried over MgSO4 (anhydrous) and concentrated to afford crude sulfonamide product which was purified by flash chromatography using petroleum ether: ethyl acetate (4 : 1) as eluent.
The procedure was repeated for various other aromatic compounds and other sulfamoyl chlorides; the results are set out in Table 2.
Table 2
Figure imgf000008_0001
Table 2 (continued)
Aromatic Sulfamoyl Product Yield
(%) Compound Chloride
Toluene Diethyl /=\J r~Me 64 ' O — Me
(o.m.p; 0:0: 100)
Anisole Piperidyl 80
Figure imgf000009_0001
(o:m:p; 36:0:64)
Toluene Piperidyl 51
(p:m:p; 0:0:100)
Naphthalene Piperidyl 56
(a : β ; 24 : 76)
EXAM PLE3
This Example illustrates an indium catalysed intramolecular sulfamoylation reaction.
Figure imgf000009_0002
56% Yield
A stirring mixture of ethyl(phenethyl)sulfamoyl chloride (0.300g; 1.212mmol) and indium triflate (0.136g; 20mol%) in dichloroethane [DCE] (5ml) was heated to 100°C for 24 hours. The reaction mixture was then partitioned between dichloromethane and 1 M HCl. The aqueous layer was washed with dichloromethane three times and the combined organics were washed with brine, dried over MgSO4 (anhydrous) and concentrated to afford crude sulfonamide product which was purified by flash chromatography using petroleum ether : ethyl acetate (4 : 1) as eluent to isolate 2-ethyl-3,4-d y(fro-2H-benzo[e][l,2]thiazine 1,1- dioxide as a white crystalline solid, mp 59-60°C.
1H NMR (CDC13) δ: 1.25-1.32(t,3H, J=7.2 Hz), 3.00(t,2H, J=6.4Hz), 3.26(q,2H, J=7.2Hz), 3.89(t,2H, J-6.4 Hz), 7.21-7.86(m, aromatic protons, 4H)ppm.
Expected: C 56.8; N 6.6; H 6.20%. Found: C 56.5; N 6.5; H 6.15%.

Claims

CLATMS
1. A process for making substituted aryl sulfonamides by sulfamoylation of an activated aromatic compound using an indium compound as a catalyst.
2. A process according to claim 1 wherein the activated aromatic compound is an aromatic compound substituted by one or more activating groups selected from halogen or an electron-donating group.
3. A process according to claim 2 wherein the activated aromatic compound is an aromatic compound substituted by one or more activating groups selected from halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted amino, optionally substituted alkoxy, optionally substituted alkylthio and optionally substituted alkylcarbonyloxy.
4. A process for preparing a compound of formula (I)
Ar-SO2-NR1R2 (I) where Ar is an optionally substituted aryl group and R1 and R2 are, independently H, optionally substituted CMO alkyl or optionally substituted aryl; or R1 and R2 together with the N atom to which they are attached form an optionally substituted five-, six- or seven-membered heterocyclic ring, by reacting a compound of formula (II)
Ar-H (D) where Ar is as defined in relation to formula (I) with a compound of formula (ID)
Z-SOa-NR^2 (ID) where R1 and R2 are as defined in relation to formula (I) and Z is a leaving group, in the presence of an indium compound.
5. A process according to claim 1 wherein the substituted aryl sulfonamide is sildenafil, acetazolamide, dichlorophenamide, sulphanilamide or sulfamethoxazole.
A process according to any preceding claim wherein the indium compound is indium (ID) chloride, indium (ID) acetate, indium (ID) acetylacetonate, indium (DJ) nitrate, indium (DI) perchlorate, indium (Dl) sulfate, indium (HI) trifluoroacetate, indium (DI) trifluoroacetylacetonate, indium (ID) triflate or indium (DI) triflamide.
A process according to claim 6 wherein the indium compound is indium triflate.
PCT/GB2003/004234 2002-10-02 2003-09-30 Process for making substituted aryl sulfonamides using an indium based catalyst system WO2004031134A1 (en)

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CN103265505A (en) * 2013-05-24 2013-08-28 浙江工业大学 Preparation method of N-p-toluenesulfonyl piperidine
US8664411B2 (en) 2007-07-05 2014-03-04 Merck Sharp & Dohme Corp. Tetrahydropyranochromene gamma secretase inhibitors
US11787812B2 (en) 2020-12-11 2023-10-17 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[4,3-d]pyrimidines and imidazo[5,1 -f][1,2,4]triazines as androgen receptor and phosphodiesterase dual inhibitors

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C.G. FROST ET.AL: "INDIUM-CATALYSED ARYL AND ALKYL SULFONYLATION OF AROMATICS", SYNLETT, no. 6, 2001, pages 830 - 832, XP002268353 *
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8664411B2 (en) 2007-07-05 2014-03-04 Merck Sharp & Dohme Corp. Tetrahydropyranochromene gamma secretase inhibitors
CN103265505A (en) * 2013-05-24 2013-08-28 浙江工业大学 Preparation method of N-p-toluenesulfonyl piperidine
CN103265505B (en) * 2013-05-24 2016-03-09 浙江工业大学 A kind of preparation method of N-tosylpiperidine
US11787812B2 (en) 2020-12-11 2023-10-17 Ildong Pharmaceutical Co., Ltd. Substituted pyrazolo[4,3-d]pyrimidines and imidazo[5,1 -f][1,2,4]triazines as androgen receptor and phosphodiesterase dual inhibitors

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