SYNTHESIS OF COMPOUNDS CONTAINING 8-OXA-3-AZABICYCLO (3.2.1)OCTANE RING Technical Field

[0001] The present invention pertains to a process for manufacturing compounds containing the 8-oxa-3-azabicyclo (3.2.1 ) octane ring, and more

particularly, to the catalytic amination of 2,5-bis(hydroxymethyl)

tetrahydrofuran for the manufacture of compounds containing the 8-oxa-3- azabicyclo (3.2.1 ) octane ring.

Background Art

[0002] It has been long known in the art that various compounds containing the 8- oxa-3-azabicyclo (3.2.1 ) octane ring exhibit desirable pharmaceutical effects, such as analgesic, anti-inflammatory, and anti-cancer effects, and are extensively used in drugs and clinical trails. These physiologically active compounds are illustrated by the following general formula (I) with R being hydrogen or a hydrocarbon group having 1 to 36 carbon atoms, and are hereinafter referred to as "bicyclic compound (N)".

(I)

The immediate precursor for making most of the bicyclic compounds (N) 8-oxa-3-azabicyclo (3.2.1 ) octane (I, R = H). Over the years, different approaches have been developed for manufacturing this important immediate precursor. An early method, disclosed in NEWTH, F.H., et al. The conversion of sucrose into furan compounds. J. Chem. Soc. 1948, p.155-158. and US 3953596 (ICI UNITED STATES) 27/04/1976 , was to form the 8-oxa-3-azabicyclo (3.2.1 ) octane compound by a two-step process. This two-step process includes: firstly, reacting 2,5- bis(hydroxymethyl) tetrahydrofuran (represented by formula (II) below, hereinafter referred to as "TMF-diol (II)") with -toluenesulfonyl chloride in pyridine, within a three-neck flask equipped with a thermometer to allow specific temperature control, to produce an unstable intermediate

compound of 2,5-bis-(hydroxymethyl)-tetrahydrofuran ditosylate

(represented by formula (III) below, hereinafter referred to as "ditosylate (III)"); and secondly, heating the thus obtained ditosylate (III) compound with liquid ammonia in absolute ethanol, at a temperature of about 150°C.

(II)

CH ₂ OS0 ₂ C ₆ H ₄ CH ₃ -p

CH ₂ OS0 ₂ C ₆ H ₄ CH ₃ -p

(Ml)

Despite the reported good yield, the above-mentioned two-step synthesis process has its limited use in the laboratory scale, as those conditions were not acceptable for scale up in a pharmaceutical facility. Intending to solve this scale-up problem, CONNOLLY, T.J., et al. Efficient Synthesis of 8-Oxa-3-aza-bicyclo[3.2.1]octane Hydrochloride. Organic Process

Research . 2010, vol.14, p.459-465. proposed a complicated four-step process to generate 8-oxa-3-azabicyclo (3.2.1 ) octane starting with 5- hydroxymethyl-2-furfuraldehyde. According to Connolly's four-step process, a TMF-diol (II) compound obtained from Raney nickel-mediated reduction of 5-hydroxymethyl-2-furfuraldehyde is converted to a ditosylate (III) compound (using similar conditions reported by Newth), and the ditosylate (III) compound is then cyclized with benzylamine to generate a bicyclic compound (N) with R = Ph, which eventually offers a 8-oxa-3-azabicyclo (3.2.1 ) octane compound through hydrogenolysis, using the reaction conditions as illustrated by the following scheme. [0005] Nevertheless, similar to the method reported by Newth, Connolly's four- step process also relies on a toxic TsCI reactant to convert TMF-diol (II) into ditosylate (III) compound. Moreover, as much as four moles of BnNh is needed for the cyclization of each mole of ditosylate (III), which also unfavourably leads to the necessity of Bn cleavage from the product.

[0006] There is thus a need to develop a novel, efficient, and environmentally

benign process for producing the abovementioned bicyclic compounds (N), which overcomes all the prior art disadvantages and also gives a high yield in industry application.

Summary of invention

[0007] Hence, the present application provides a process for manufacturing a

bicyclic compound (N) having the formula (I)

(I)

wherein the process comprises reacting c/s-2,5- bis(hydroxymethyl)tetrahydrofuran with at least one amine of formula NH2R' in a liquid reaction medium and in the presence of a catalytic system selected from the group consisting of:

- a homogenous catalyst which is a complex comprising at least one element selected from the group consisting of Iridium or Ruthenium and at least one donor ligand [Catalyst (H1 )] ; and

- a heterogeneous catalyst [Catalyst (H2)] comprising at least one Group 8-1 1 transition metal element and one poor metal element in the p-block of the period table,

wherein R and R' are the same or different and represent hydrogen or a hydrocarbon group having 1 to 36 carbon atoms.

For the purpose of the present invention, the term "poor metal" is used to describe a metallic element selected from aluminium, gallium, indium, thallium, tin, lead, bismuth and polonium. [0009] Advantageously, the aforementioned catalytic process of the present invention produces the desired bicyclic compound (N) through direct amination of c/ -2,5-bis(hydroxymethyl)tetrahydrofuran and generates only H2O as the only co-product, using no complex synthesis route or toxic reactants and eliminating the intermediate compound purification process. Thus, compared to the existing prior art processes, the catalytic process of the present invention is more environmental friendly, and further

characterized by an improved working efficiency and reduced production cost.

[0010] For the purpose of the present invention, the term "hydrocarbon group" used herein refers to any chemical group comprising hydrogen and carbon.

[001 1] Specifically, R and R' may be same or different and represent hydrogen or a radical selected from the group consisting of aryl, aralkyl, aminoalkyl, arylalkanoyi, heteroaroyl, alkoxy substituted aroyl, alkenyl (C2 to C ₄ ), halogen substituted aralkyl, guanadinoalkyl, halogen substituted aroyl, alkyl substituted aroyl, halogen substituted arylalkanoyi, hexahydrobenzoyi, arylalkenoyl, o- and p-alkyl substituted phenylalkanoyl, alkyl substituted naphthylalkanoyl, alkanoyl (C3 to C20), haloalykl substituted aroyl, alkoxy substituted aralkyl, heteroaralkyl, anilinocarbonyl, adamantanecarbonyl, arylsulfonyl, carboxyl substituted aroyl, hydroxyl substituted aroyl, alkanoyloxy substituted aroyl, arylglyoxylyl, alicyclic, arylene dicarbonyl-8- oxa-3-azabicyclo (3.2.1 ) octane, alkylene-8-oxa-3-azabicyclo (3.2.1) octane, alkylene dicarbonyl-8-oxa-3-azabicyclo(3.2.1 ) octane, and the pharmacologically acceptable acid addition salts thereof.

[0012] "Aryl" as used herein means a 6-carbon monocyclic or 10-carbon bicyclic aromatic ring system wherein 0, 1 , 2, 3, or 4 atoms of each ring are optionally substituted. "Alkyl" as used herein means a straight chain or branched saturated aliphatic hydrocarbon residue. Examples of aryl groups include phenyl, naphthyl and the like. The term "aralkyl" refers to alkyl substituted with an aryl, and the term "alkaryl" as used herein refers to aryl substituted with an alkyl. As used herein, "alkenyl" refers to a straight chain or branched aliphatic hydrocarbon residue having at least one carbon-carbon double bond, and "alkoxyl" refers to the group "alkyl-O- ", wherein alkyl is as defined above.

For the purpose of exemplification and not limitation, the above radicals designated R and R' include the following within their scope. The term "aralkyl" includes, for example, benzyl, phenethyl, a-methylphenethyl, o-, m-, and p-methylbenzyl, naphthylethyl, and phenylpropyl, wherein the alkyl portion of said radical is straight or branch chained and contains from 1 to 10 carbon atoms and the aryl portion is phenyl or naphthyl. Alkylene-8- oxa-3-azabicyclo (3.2.1 ) octane and alkylene dicarbonyl-8-oxa-3- azabicyclo (3.2.1 ) octane include such radicals wherein the alkylene portion thereof contains from 1 to 10 carbon atoms. The term "aryl" by itself or in combination with other radicals is used herein to denote radicals, such as phenyl and naphthyl. Aminoalkyl represents an amine group substituted with 1 to 3 alkyl groups having from 1 to 10 carbon atoms.

"Alkanoyl" as used herein by itself or in combination with other radicals includes such radicals having from 3 to 20 carbon atoms, for example, isobutyroyl, propionyl, caproyl, stearoyl, and heptanoyl. "Alkanoyl" when used herein in combination with other radicals includes such radicals having from 2 to 20 carbon atoms. Therefore, the term "arylalkanoyl" includes radicals, such as for example, phenylacetyl, phenylcaproyl, phenylstearoyi, and naphthylheptanoyl. The radical "heteroaroyl" includes, for example, nicotinoyl, thenoyl, and quinoxaloyl. When the term "alkyl" is used herein by itself or in combination with other radicals, it denotes both straight and branched chain alkyl radicals containing from 1 to 10 carbon atoms. For example, the alkyl portion of an alkyl substituted aroyl radical can contain from 1 to 10 carbon atoms and the aroyl radical can be substituted with at least 1 and no more than 5 such alkyl groups,

preferably 1 to 3. Further, for example, the alkyl portion of a

guanadinoalkyl radical includes alkyl radicals containing from 1 to 10 carbon atoms. "Aroyl" as used herein by itself or in combination with other radicals includes unsubstituted radicals, for example, naphthoyl and benzoyl. "Haloalkyl substituted aroyl" radicals include aroyl radicals substituted with at least 1 and no more than 3 haloalkyl radicals each of which contains from 1 to 10 carbon atoms and at least 1 and no more than 6 halogen atoms. When halogen is referred to in relation to any of the radicals represented by R or R', all halogens are intended and thus fluorine, chlorine, iodine, and bromine are included; however, flourine, chlorine, and bromine are preferred. "Alkoxy substituted aroyl" as used herein includes aroyl radicals substituted with at least 1 and no more than 3 alkoxy groups which each contains from 1 to 10 carbon atoms and includes radicals, such as methoxybenzoyl, pentoxybenzoyl, and 3,5- dibutoxynaphthoyl. The radical "arylsulfonyl" includes, for example, benzenesulfonyl and naphthalenesulfonyl. For example, "alicyclic" includes cycloalkyl radicals having from 3 to 8 ring carbon atoms, such as cyclopropyl, cyclopentyl, cyclohexyl, and cycloheptyl. By "alkenyl" is included, for example, straight and branched chain radicals containing from 2 to 4 carbon atoms. The term "arylalkenoyl" as used herein includes radicals, such as cinnamoyl and other such radicals, wherein the alkenoyl portion of the radical contains from 3 to 10 carbon atoms. The term

"alkanoyloxy substituted aroyl" as used herein includes radicals, such as acetoxybenzoyl and acetoxynaphthoyl, wherein the alakanoyloxy portion of the radicals contains from 2 to 10 carbon atoms and the aroyl radical is substituted with at least 1 and no more than 3 alkanoyloxy radicals. The terms "halogen substituted aralkyl, " "halogen substituted aroyl," and "halogen substituted arylalkanoyl" are used to indicate such radicals which are substituted with at least 1 and no more than 5 halogen atoms, preferably 1 to 3 halogen atoms. "Heteroaralkyl" includes, for example, radicals, such as thienylethyl, thienylhexyl, a-methylthienylethyl, and pyridylbutyl. "o- and p-Alkyl substituted phenylalkanoyl" includes radicals which are substituted with 1 to 3 (Ci to do) alkyl radicals. "Alkyl substituted naphthylalkanoyl" radicals include such radicals substituted on the aromatic ring with up to 5 (Ci to Cio) alkyl radicals. "Alkoxy substituted aralkyl" includes aralkyl radicals substituted with at least 1 and no more than 5 alkoxy groups (Ci to Cio), preferably 1 to 3 such alkoxy groups. "Carboxyl substituted aroyl" and "hydroxyl substituted aroyl" includes aroyl radicals suitably substituted with at least 1 and no more than 5 carboxyl or hydroxyl groups, as the case may, preferably substituted with 1 to 3 of such groups.

In a preferred subclass of the present invention, R and R' are

independently selected from the group consisting of: hydrogen, phenyl; aminoalkyl (Ci to Ce) where the amino group is primary, secondary, or tertiary; phenylacetyl; quinoxaloyl; mono-, di-, or tri-alkoxy (Ci to C ₄ ) substituted benzoyl; phenylalkyi where the alkyi constituent thereof contains from 1 to 4 carbon atoms such as benzyl, phenylpropyl, and phenethyl; alkenyl (C3 and C ₄ ); mono-, di-, or tri-halogen substituted phenylalkyi where the alkyi group contains from 1 to 4 carbon atoms and the halogen is substituted on the phenyl ring; guanadinoalkyl (Ci to C ₄ ); mono-, di-, or tri-halogen substituted benzoyl; mono-, di-, or tri-alkyl (Ci to C ₄ ) substituted benzoyl; mono-, di-, or trihalogen substituted

phenylalkanoyl wherein the alkanoyi group contains from 2 to 4 carbon atoms and the halogen is on the phenyl ring; hexahydrobenzoyl;

phenylalkenoyl wherein the alkenoyl group is a lower alkenoyl containing from 3 to 5 carbon atoms; phenylalkanoyl wherein the alkanoyi group contains from 2 to 4 carbon atoms; o- and p-alkyl (Ci to C ₄ ) substituted phenylalkanoyl where the alkanoyi group contains 2 to 4 carbon atoms and the alkyi group is substituted on the phenyl ring; alkyi (Ci to C ₄ ) substituted naphthylalkanoyl where the alkanoyi group contains 2 to 4 carbon atoms and the alkyi group or groups, preferably 1 to 3 alkyi groups, are attached to the naphthyl ring; alkanoyi (C3 to Cis); haloalkyi (Ci to C ₄ ) mono-, di-, or tri-substituted benzoyl wherein the haloalkyi group contains from 1 to 5 halogen atoms; mono-, di-, or tri-alkoxy (Ci to C ₄ ) substituted phenylalkyi wherein the alkyi group contains 1 to 4 carbon atoms and the alkoxy is substituted on the phenyl ring; thienylalkyl wherein the alkyi group contains from 1 to 4 carbon atoms; anilinocarbonyl;

adamantanecarbonyl; phenylsulfonyl; mono- or di-carboxyl substituted benzoyl; mono- or di-hydroxyl substituted benzoyl; nicotinoyl; mono-or di- alkanoyloxy (Ci to C ₄ ) substituted benzoyl; thenoyl; phenylglyoxylyl;

cycloalkyl (C ₄ to Cs), terephtholoyl-8-oxa-3-azabicyclo(3.2.1 )octane;

alkylene (Ci to C8)-8-oxa-3-azabicyclo(3.2.1 )octane; and alkylene (Ci to Ce) dicarbonyl-8-oxa-3-azabicyclo(3.2.1 )octane. When halogen is referred to in this subclass, all halogens are intended; however, fluorine, chlorine, and bromine are preferred. In this preferred subclass, the above radicals, representing R and R' above, can be substituted suitably in any of the ortho, meta, or para positions on the ring or any combination thereof unless otherwise directly indicated. For example, ring structures of the present preferred species of radicals R and R' may be substituted in two ortho positions or two meta positions and/or the para position, or one ortho and one para position or any desired position combinations thereof.

[0015] The terms "lower alkyl," "lower alkoxy," "lower haloalkyl," "lower alkanoyl," and "lower alkanoyloxy" can be used to describe such radicals as referred to above in the preceding paragraph when they contain up to four carbon atoms.

[0016] In one specific embodiment of the present invention, R and R' are both hydrogen.

[0017] In another preferred subclass of the present invention, R and R' above are independently selected from the group consisting of benzyl, phenyl, aminohexyl, phenylacetyl, quinoxaloyl, m-methoxybenzoyl, a- methylphenethyl, aminoethyl, propenyl, a-methyl p-chlorophenethyl, dimethylaminopropyl, phenethyl, 2-guanadinoethyl, p-chlorobenzoyl, p- toluoyl, m-chlorobenzoyl, o-chlorobenzoyl, o-toluoyl, m-chlorophenylacetyl, p-chlorophenylacetyl, m-toluoyl, ethylene-8-oxa-3-azabicyclo(3.2.1 )octane, β-methylphenethyl, β,β-dimethylphenethyl, p-chlorophenethyl,

hexahydrobenzoyl, o-chlorophenylacetyl, cinnamoyl, phenethylcarbonyl, o- methylphenylacetyl, heptnoyl, m-trifluoromethylbenzoyl, o- methoxyphenethyl, a-methylthienylethyl, anilinocarbonyl,

adamantanecarbonyl, phenylsulfonyl, o-carboxybenzoyl, stearoyl, propanoyl, o-hydroxybenzoyl, nicotinoyl, o-acetoxybenzoyl, thenoyl, phenylglyoxylyl, cyclohexyl, 3,4-dimethoxyphenethyl, hexamethylene-8- oxa-3-azabicyclo(3.2.1 )octane, adipyl-8-oxa-3-azabicyclo(3.2.1 ) octane, terephtholoyl-8-oxa-3-azabicyclo(3.2.1 )octane, and the pharmacologically acceptable acid addition salts thereof. Examples of the bicyclic compounds (N) in accordance with the present invention include: 8-oxa-3-azabicyclo (3.2.1 ) octane; 3-phenylacetyl-8-oxa 3-azabicyclo(3.2.1 )octane; 3-(p-chlorobenzoyl)-8-oxa-3- azabicyclo(3.2.1 )octane; 3-heptanoyl-8-oxa-3-azabicyclo(3.2.1 )octane; 3- nicotinoyl-8-oxa-3-azabicyclo (3.2.1 )octane; 3(m-chlorobenzoyl)-8-oxa-3- azabicyclo(3.2.1 ) octane; 3(o-chlorobenzoyl)-8-oxa-3- azabicyclo(3.2.1 )octane; 3-(p-toluoyl)-8-oxa-3-azabicyclo(3.2.1 )octane; 3- (m-chlorophenylacetyl)-8-oxa-3-azabicyclo(3.2.1 )octane; 3-(o- chlorophenylacetyl)-8-oxa-3-azabicyclo(3.2.1 )octane; 3-cinnamoyl-8-oxa- 3-azabicyclo (3.2.1 )octane; 3-(p-tolylacetyl)-8-oxa-3- azabicyclo(3.2.1 )octane; 3-(p-chlorophenylacetyl)-8-oxa-3- azabicyclo(3.2.1 )octane; 3-(o-tolylacetyl)-8-oxa-3-azabicyclo(3.2.1 )octane 3-(2-quinoxaloyl)-8-oxa-3-azabicyclo(3.2.1)octane; 3-(m- trifluoromethylbenzoyl)-8-oxa-3-azabicyclo(3.2.1 )octane; 3-(a-thenoyl)-8- oxa-3-azabicyclo(3.2.1 )octane; 3-heptanoyl-8-oxa-3-azabicyclo(3.2.1 ) octane; 3-hydrocinnamoyl-8-oxa-3-azabicyclo(3.2.1 )octane; 3-(o-toluoyl)- 8-oxa-3-azabicyclo(3.2.1 )octane; 3-(m-toluoyl)-8-oxa-3- azabicyclo(3.2.1 )octane; 3-hexahydrobenzoyl-8-oxa-3- azabicyclo(3.2.1 )octane; 3-(m-methoxybenzoyl)-8-oxa-3-azabicyclo (3.2.1 )octane; 3-stearoyl-8-oxa-3-azabicyclo(3.2.1 )octane; 3-propionyl-8- oxa-3-azabicyclo(3.2.1)octane; 3-nicotinoyl-8-oxa-3- azabicyclo(3.2.1 )octane; 3-(acetylsalicyloyl)-8-oxa-3- azabicyclo(3.2.1 )octane; 3-(o-carboxybenzoyl)- 8-oxa-3-azabicyclo (3.2.1 )octane; 3-( 1 -adamantanecarbonyl)-8-oxa-3-azabicyclo(3.2.1 ) octane; 3-(phenylglyoxylyl)-8-oxa-3-azabicyclo(3.2.1 )octane; 3-(o- hydroxybenzoyl)-8-oxa-3-azabicyclo(3.2.1 )octane; 3-benzenesulfonyl-8- oxa-3-azabicyclo(3.2.1 )octane; 3-(N-phenylcarbamoyl)-8-oxa-3- azabicyclo(3.2.1 )octane; 3-allyl-8-oxa-3-azabicyclo (3.2.1 )octane hydrochloride; 3-cyclohexyl-8-oxa-3-azabicyclo (3.2.1)octane

hydrochloride; 3-phenyl-8-oxa-3-azabicyclo(3.2.1 ) octane; 3-phenyl-8-oxa- 3-azabicylo(3.2.1 )octane hydrochloride; 3-(p-chlorophenethyl)-8-oxa-3- azabicyclo(3.2.1 )octane hydrochloride; 3-(a-methylphenethyl)-8-oxa-3- azabicyclo(3.2.1 )octane hydrochloride; 3-(a-methylphenethyl)-8-oxa-3- azabicyclo(3.2.1 ) octane; 3-(3,4-dimethoxyphenethyl)-8-oxa-3- azabicyclo(3.2.1 ) octane; 3-(3,4-dimethoxyphenethyl)-8-oxa-3- azabicyclo(3.2.1 ) octane hydrochloride; 3-benzyl-8-oxa-3- azabicyclo(3.2.1 )octane hydrochloride; 3-phenethyl-8-oxa-3- azabicyclo(3.2.1 )octane hydrochloride; 3(p-chlorophenethyl)-8-oxa-3- azabicylo(3.2.1 ) octane hydrochloride; 3-(p-methoxyphenethyl)8-oxa-3- azabicyclo (3.2.1 )octane hydrochloride; 3-(a,a-dimethylphenethyl)-8-oxa- 3-azabicyclo(3.2.1 )octane hydrochloride; 3-( -methylphenethyl)-8-oxa-3- azabicyclo(3.2.1 )octane hydrochloride; 3-(a-methyl-p-chlorophenethyl)-8- oxa-3-azabicyclo(3.2.1 )octane hydrochloride; 3-[1 -(2-thienyl)isopropyl]-8- oxa-3-azabicyclo(3.2.1 )octane hydrochloride; 3-(3-dimethylaminopropyl)-8- oxa-3-azabicyclo (3.2.1 )octane dihydrochloride; 3-(2-aminoethyl)-8-oxa-3- azabicyclo(3.2.1 )octane dihydrochloride; 3,3'-ethylene-bis [8-oxa-3- azabicyclo(3.2.1 )octane]; 3-(6-aminohexamethylene)-8-oxa-3- azabicyclo(3.2.1 )octane; 3,3'-hexamethylene-bis[8-oxa-3- azabicyclo(3.2.1 )octane]; and 3-(2-guanadinoethyl)-8-oxa-2- azabicyclo(3.2.1 )octane hydrosulfate monohydrate.

[0019] Regarding the Homogeneously Catalytic Process using Catalyst (H1)

[0020] The homogenous Catalyst (H1 ) used in the process of the present

invention, as aforementioned, is a complex comprising at least one element of Iridium (Ir) or Ruthenium (Ru) and also a donor ligand.

[0021] For the purpose of the present invention, a "homogenous catalyst" means that the catalytically active part of the catalyst is at least partly present in solution in the liquid reaction medium. Preferably, at least 90% of the homogenous catalyst is present in the solution in the liquid reaction medium.

[0022] In a preferred embodiment of the homogeneously catalytic process of the present invention, at least 95% of the Catalyst (H1 ) is soluble in the liquid reaction medium.

[0023] Unlimited examples of the Catalyst (H1 ) include: [Ru(p-cymene)Cl2]2,

[Ru(benzene)CI ₂ ] ₂ , [Ru(CO) ₂ CI ₂ ]2, [Ru(CO) ₃ CI ₂ ]2, [Ru(CO)CIH(PPh ₃ ) ₃ ], [Ru(COD)(allyl)], [RuCI ₃ H ₂ O], [Ru(acetylacetonate) ₃ ], [Ru(DMSO) ₄ CI ₂ ], [Ru(PPh ₃ ) ₃ (CO)(H)CI], [Ru(PPh ₃ )3(CO)CI ₂ ], [Ru(PPh ₃ )3(CO)(H) ₂ ],

[Ru(PPh ₃ )3CI ₂ ], [Ru(cyclopentadienyl)(PPh ₃ )2CI],

[Ru(cyclopentadienyl)(CO)2CI], [Ru(cyclopentadienyl)(CO)2H],

[Ru(cyclopentadienyl)(CO)2]2, [Ru(pentamethylcyclopentadienyl)(CO)2CI], [Ru(penta-methylcylcopentadienyl)(CO)2H],

[Ru(pentamethylcyclopentadienyl)(CO)2]2, [Ru(indenyl)(CO)2CI],

[Ru(indenyl)(CO) ₂ H], [Ru(indenyl)(CO) ₂ ]2, ruthenocene, [Ru(binap)CI ₂ ], [Ru(bipyridine) ₂ Cl2-2H ₂ O], [Ru(COD)CI ₂ ]2, [Ru(pentamethylcyclo- pentadienyl)(COD)CI], [Ru ₃ (CO)i ₂ ],

[Ru(tetraphenylhydroxycyclopentadienyl)(CO)2H], [Ru(PMe ₃ ) ₄ (H)2],

[Ru(PEt ₃ ) ₄ (H) ₂ ], [Ru(PnPr ₃ ) ₄ (H) ₂ ], [Ru(PnBu ₃ ) ₄ (H) ₂ ], [Ru(PnOctyl ₃ ) ₄ (H) ₂ ],

[lrCI ₃ -H ₂ O], KlrCU, K ₃ lrCI ₆ , [lr(COD)CI] ₂ , [lr(cyclooctene) ₂ CI] ₂ ,

[lr(ethene)2CI]2, [lr(cyclopentadienyl)Cl2]2,

[lr(pentamethylcyclopentadienyl)Cl2]2, [lr(cylopentadienyl)(CO)2],

[lr(pentamethylcyclopentadienyl)(CO) ₂ ], [lr(PPh ₃ ) ₂ (CO)(H)],

[lr(PPh ₃ ) ₂ (CO)(CI)], [lr(PPh ₃ ) ₃ (CI)].

[0024] As used above and throughout the specification, "COD" refers to 1 ,5-

Cyclooctadiene, "Et" represents ethanol, "Me" represents methanol, and

"Ph" represents phenol.

[0025] One particularly preferred Ru-based Catalyst (H1 ) is [Ru(CO)CIH(PPh ₃ ) ₃ ], which is preferably used in situ in the form of

[Ru(CO)CIH(PPh ₃ ) ₃ ]/Xantphos system as described in M.BELLER, et al. Improved Rhthenium-Catalyzed Amniation of Alcohols with Ammonia: Synthesis of Diamines and Amino Esters. Angew. Chem., Int. Ed. Engl.. 201 1 , vol.50.

[0026] One preferred group of the Ir-based Catalysts (H 1) includes compounds of formula (IV) or (V) below:

[CpIrX ₂ ] ₂ (IV)

[CpIr(NH ₃ ) ₃ ][X] ₂ (V) wherein: Cp represents a cyclopentadienyl group which is optionally substituted by from 1 to 5 independently selected hydrocarbon groups; and X is a halogen atom selected from CI, Br, and I.

[0027] Among particularly preferred Catalyst (H1 ) compounds of formula (IV) or

(V), are [CplrCI ₂ ] ₂ , [Cplrl ₂ ] ₂ and [Cplr(NH ₃ ) ₃ ][l] ₂ .

[0028] Yet another group of preferred Catalysts (H1 ) includes the complex

catalyst described in US 20120232293 A , particularly, those of the following general formula (VI) :

wherein:

R ^a and R ^b are each, independently of one another, selected from a group consisting of: optionally substituted Ci-Cio alkyl, C3-C10 cycloalkyl, C3-C10 heterocyclyl comprising at least one heteroatom selected from N, O and S, C5-Cio aryl and C5-C10 heteroaryl comprising at least one heteroatom selected from N, O and S;

Y is a monoanionic ligand selected from the group consisting of H, F, CI, Br, I, OCOR, OCOCF3, OSO ₂ R, OSO ₂ CF ₃ , CN, OH, OR and N(R) ₂ or an uncharged molecule selected from the group consisting of NH3, N(R)3 and R ₂ NSO ₂ R;

X ¹ represents one, two or three substituents on one or more atoms of the acridinyl unit or one or two substituents on one or more atoms of the quinolinyl unit, wherein the radicals X ¹ are independently selected from the group consisting of H, F, CI, Br, I, OH, NH ₂ , NO ₂ ,— NC(O)R, C(O)NR ₂ ,— OC(O)R,— C(O)OR, CN, unsubstituted Ci-Cio alkoxy, alkyl, C3-C10 cycloalkyl, C3-C10 heterocyclyl comprising at least one heteroatom selected from N, O and S, Cs-C-m aryl and C5-C10 heteroaryl comprising at least one heteroatom selected from N, O and S; and,

M is Ir or Ru, preferably Ru.

In preferred Catalysts (H1 ) of formula (VI), R ^a and R ^b are each,

independently of one another, methyl, ethyl, isopropyl, tert-butyl, cyclohexyl, cyclopentyl, phenyl or mesityl; Y is a monoanionic ligand selected from the group consisting of H, F, CI, Br, I, OCOCH3, OCOCF3, OSO2CF3, CN and OH; X ¹ is H; and M is Ru.

[0030] The amount of the metal component of the homogenous Catalyst (H 1 ), preferably Ir or Ru, is generally from 0.1 to 5000 ppm by weight, based on the total liquid reaction medium.

[0031] In the homogenously catalytic process of the present invention, the

reaction between amine and the bis(hydroxymethyl)tetrahydrofuran compound generally occurs at a temperature of from 20 to 250°C, preferably from 100 to 200°C, and more preferably from 120 to 180°C. The absolute pressure of said reaction is generally controlled to be within the range of 0.1 to 10 MPa, preferably from 0.2 to 5 MPa, and more preferably from 0.2 to 3 MPa, which can be either the autogenous pressure of the liquid reaction medium at the reaction temperature or the pressure of a gas such as nitrogen, argon, or hydrogen.

[0032] The average reaction time is generally from 15 minutes to 100 hours,

preferably from 30 minutes to 50 hours.

[0033] In the homogenously catalytic process, the amine compound of formula NH2R' can be used in stoichiometric, substoichiometric or

superstoichiometric amounts based on the hydroxyl groups of the bis(hydroxymethyl)tetrahydrofuran reactant. In a preferred embodiment, the amine compound is used in an amount from 1- to 250-fold, preferably from 1 - to 100-fold, in particular in from 2- to 10-fold, molar excess per mole of hydroxyl groups in the bis(hydroxymethyl)tetrahydrofuran reactant. Higher excesses of amine compound are also possible.

[0034] In a specific embodiment of the homogenously catalytic process, the

amine compound is ammonia.

[0035] The liquid reaction medium for the homogenously catalytic process

optionally comprises a solvent. Suitable solvents are polar and nonpolar solvents which can be used in pure form or in mixtures.

[0036] Examples of non-polar solvents are hexane, heptane, octane, cyclohexane, benzene, toluene, xylene and mesitylene and linear and cyclic ethers such as THF, diethyl ether, 1 ,4-dioxane, MTBE (tert-butyl methyl ether), diglyme and 1 ,2-dimethoxyethane, among which toluene, xylene or mesitylene is preferred.

[0037] Examples of polar solvents are water, dimethylformamide, formamide, tert- amylalcohol, tert-butanol and acetonitrile, among which water or tert- amylalcohol is preferred.

[0038] To carry out the reaction, the amine compound of formula Nh R' and the bis(hydroxymethyl)tetrahydrofuran reactant, optionally together with one or more solvents, together with the Catalyst (H1 ) are introduced into a reactor. The introduction of amine, bis(hydroxymethyl)tetrahydrofuran, optional solvent and Catalyst (H1 ) can be carried out simultaneously or separately. The reaction can be carried out continuously, in the semibatch mode, in the batch mode, admixed in product as solvent or without admixing in a single pass.

[0039] It is in principle possible to use all reactors which are basically suitable for gas/liquid reactions at the given temperature and the given pressure for the homogenously catalytic process of the invention.

[0040] The reaction output formed in the reaction generally comprises the

corresponding bicyclic compound (N) obtained by amination of

bis(hydroxymethyl)tetrahydrofuran, the one or more solvents if used, the Catalyst (H 1), possibly unreacted bis(hydroxymethyl)tetrahydrofuran and amine, and also the water co-product formed from the reaction.

[0041] Any excess amine present, any solvent present, the Catalyst (H1 ) and the water co-product are removed from the reaction output. The bicyclic compound (N) product obtained can be worked up further. The excess amine, the Catalyst (H1 ), any solvent and any unreacted

bis(hydroxymethyl)tetrahydrofuran can be recirculated to the amination reaction.

[0042] If the amination reaction is carried out without solvent, the homogeneous Catalyst (H1 ) used is dissolved in the product after the reaction. This can remain in the product or be separated off therefrom by a suitable method. Possibilities for separating off the Catalyst (H1 ) are, for example, scrubbing with a solvent which is not miscible with the product and in which the Catalyst (H1 ) dissolves better than in the product as a result of a suitable choice of the ligands. The concentration of homogeneous catalyst in the product is optionally reduced by multistage extraction. As extractant, preference is given to using a solvent which is also suitable for the target reaction, e.g. toluene, benzene, xylenes, alkanes such as hexanes, heptanes and octanes and acyclic or cyclic ethers such as diethyl ether and tetrahydrofuran, which can after concentration by evaporation be reused together with the extracted catalyst for the reaction. It is also possible to remove the Catalyst (H1 ) by means of a suitable absorbent.

[0043] The Catalyst (H1 ) can also be separated off by adding water to the product phase if the amination reaction is carried out in a solvent which is immiscible with water. If the Catalyst (H1) in this case dissolves

preferentially in the solvent, it can be separated off with the solvent from the aqueous product phase and optionally be reused. This can be brought about by selection of suitable ligands. It is also possible to separate the amination product from the Catalyst (H1 ) by distillation.

[0044] If the amination reaction is carried out in one or more solvents, the one or more solvents can be miscible with the amination product and be separated off by distillation after the reaction. It is also possible to use solvents which have a miscibility gap with the amination products or the starting materials. Suitable solvents for this purpose are, for example, toluene, benzene, xylenes, alkanes such as hexanes, heptanes and octanes and acyclic or cyclic ethers such as diethyl ether, tetrahydrofuran, tert-amylalcohol and dioxane. As a result of suitable choice of the ligands of Catalyst (H1 ), the Catalyst (H1 ) can preferentially dissolve in the solvent phase, i.e. in the phase not comprising product. The ligands of Catalyst (H1 ) can also be selected so that the Catalyst (H1 ) dissolves in the amination product. In this case, the amination product can be separated from the Catalyst (H1) by distillation.

[0045] The amination product may also be used as solvent. The solvent can also be miscible with the starting materials and the product under the reaction conditions and only form a second liquid phase comprising the major part of the Catalyst (H1 ) after cooling. As solvents which display this property, mention may be made by way of example of toluene, benzene, xylenes, alkanes such as hexanes, heptanes and octanes. The Catalyst (H1 ) can then be separated off together with the solvent and be reused. The product phase can also be admixed with water in this variant. The proportion of the Catalyst (H1 ) comprised in the product can be

subsequently separated off by means of suitable absorbents such as polyacrylic acid and salts thereof, sulfonated polystyrenes and salts thereof, activated carbons, montmorillonites, bentonites and zeolites or else be left in the product.

[0046] The amination reaction can also be carried out in a two-phase system. In the case of the two-phase reaction, suitable nonpolar solvents are, in particular, toluene, benzene, xylenes, alkanes such as hexanes, heptanes and octanes in combination with non-polar ligands on the Catalyst (H1 ), as a result of which the Catalyst (H1 ) accumulates in the nonpolar phase. In this embodiment, in which the amination product and the water co-product of reaction and any unreacted starting materials form a second phase enriched with these compounds, the major part of the Catalyst (H1 ) can be separated off from the product phase by simple phase separation and be reused.

[0047] It can also be advantageous for the water co-product formed in the

reaction to be removed continuously from the reaction mixture. The water co-product of reaction can be separated off from the reaction mixture directly by distillation or as azeotrope with addition of a suitable solvent (entrainer) and using a water separator or be removed by addition of water-withdrawing auxiliaries.

[0048] The addition of bases can have a positive effect on forming the desired amination product of bicyclic compound (N). Suitable bases which may be mentioned here are alkali metal hydroxides, alkaline earth metal hydroxides, alkaline metal alkoxides, alkaline earth metal alkoxides, alkali metal carbonates and alkaline earth metal carbonates, of 0.01 to 100 molar equivalents, based on the Catalyst (H1 ) used.

[0049] Regarding the Heterogeneously Catalytic Process using Catalyst (H2) [0050] The heterogeneous Catalyst (H2) used in the process of the present invention, as aforementioned, comprises at least one Group 8-1 1 transition metal element and one poor metal element in the p-block of the period table.

[0051] For the purpose of the present invention, a "heterogeneous catalyst" refers to a catalyst having a phase that is different from the liquid phase of the reaction medium.

[0052] Desirably, the heterogeneous catalyst (H2) comprises one or more

catalytically active materials supported upon a suitable, solid substrate. The substrate may have various shapes or combinations such as, for example, powder, particle, pellet, granule, extrudate, fiber, shell, honeycomb, membrane, cloth, plate, or the like. The particles can be regular in shape, irregular, dendritic, dendrite-free, rounded, square, tetrahedral, or the like. Preferred supports are particulate in nature.

[0053] Preferably, the catalytically active portion of Catalyst (H2) comprises an oxide represented by the general formula (VII):

M _a M O _c (VII)

wherein:

M represents one or more transition metal elements selected from a group consisting of Cu, Zn, Ti, Zr, Hf, Rh, Ir, Ni, Pd and Pt, preferably from a group consisting of Cu, Ni, and Pt;

M' represents one or more poor metal elements selected from a group consisting of Al, Ga, In, Sn, Pb, TI, Bi, and Po, and is preferably Al;

a and b independently represent a number from 0.01 to 10; and

c is greater than zero and less than a number sufficient to satisfy the valence requirements of the other elements present when in a fully oxidized state.

[0054] When in use for the present invention, the oxide of formula (VII) is in a reduced state, thus containing less oxygen than necessary to satisfy the valence requirements of the metals present if in a fully oxidized state, as reflected in the definition of c in the formula (VII).

[0055] In the preferred embodiments of formula (VII), M represents Cu and/or Ni, M' represents Al, and the following formula (VIII) is complied: S iCu ... il . () (VIII)

wherein:

x is a number ranging from 0 to 3, preferably from 0 to 1 ; y is a number ranging from 0.1 to 2.5, preferably from 0.5 to 1.5; and z is greater than zero and less than a number sufficient to satisfy the valence requirements of the other elements present when in a fully oxidized state.

[0056] In one preferred embodiment of formula (VIII), x is around 1 , y is around 1.3, and z is larger than 2. In another preferred embodiment of formula (VIII), x is zero, y is around 1.3, and z is larger than 2.

[0057] The Applicant also found that, in addition to the oxides of formula (VII), Catalyst (H2) may further comprise at least one noble metal component, to enhance its catalytic activity. Specifically, the noble metal is preferably loaded onto a surface of the oxide of formula (VII), by doping or other conventional deposition means known in the art. Preferably, said noble metal is selected from Ru, Pt, and Pd.

[0058] The amount of noble metal, when used in combination with the oxide of formula (VII) in the Catalyst (H2), is from 0.1 to 10 wt%, preferably from 0.1 to 8 wt%, and more preferably from 0.1 to 5 wt% based on the weight of said oxide of formula (VII).

[0059] In one particularly preferred embodiment of the above category, the

catalytically active portion of Catalyst (H2) is essentially composed of a noble metal of Pd, Ru, or Pt and an oxide of formula (VIII), wherein x is zero or around 1 , y is around 1.3, and z is larger than 2.

[0060] The amount of the metal component in the heterogeneous Catalyst (H2) is generally used in a 5-200%, 10-150%, or 50-120% weight equivalent, based on the 2,5-bis(hydroxymethyl) tetrahydrofuran reactant.

[0061] Generally, the Catalysts (H2) are solid catalysts, and can be conveniently accommodated in the form of fixed catalyst beds with the reactor or in separate containers outside the reactor. The Catalysts (H2) can also be used as loose beds, e.g. as a loose bed in a distillation packing, be shaped to give dumped packings or moldings incorporated into filter fabric and shaped to give bales or column packings, or in other forms known in the art. [0062] A solid Catalyst (H2) can be prepared in various methods known in the art to produce a solid catalyst body. For instance, a co-precipitation method can be conveniently used.

[0063] The co-precipitation method to prepare a Catalyst (H2) normally comprises the following steps:

(i) preparation of a mixture comprising the metal elements of the Catalyst (H2) in ionic form;

(ii) adding a co-precipitating agent to the mixture to precipitate the metal elements of the Catalyst (H2), and obtain a slurry;

(iii) filtering, drying and thermally treating the slurry, to obtain a catalyst precursor; and

(iv) subjecting the catalyst precursor to reduction, to obtain the Catalyst (H2).

[0064] Typically, step (i) comprises dissolving more than one metal salts in a

solvent, e.g. water.

[0065] As the material used for co-precipitating agent in step (ii), basic solutions such as sodium carbonate, sodium bicarbonate, ammonium carbonate, ammonium bicarbonate, and ammonia water can be selected.

[0066] With regard to the thermal treatment means in step (iii), calcination is

preferably used. The calcination is typically carried out at temperatures in a range of 350 to 750°C, and preferably from 450 to 600°C, and under any suitable gas atmosphere, e.g. in the presence of hydrogen, nitrogen, helium, argon and/or steam or mixtures thereof.

[0067] Conveniently, the reduction step (iv) may be performed by contacting the catalyst precursor with hydrogen. Hydrogen is normally present as a gas at low to moderate pressure in contact with the catalyst precursor. Partial pressures of hydrogen of at least one atmosphere are preferred. The reduction temperature in step (iv) is suitably between 200 and 600°C, preferably between 300 and 500°C.

[0068] In the heterogeneously catalytic process of the present invention, the

reaction between amine and the bis(hydroxymethyl)tetrahydrofuran compound generally occurs at a temperature of from 100 to 500°C, preferably from 100 to 300°C, and more preferably from 150 to 200°C. The absolute pressure of said reaction is generally controlled to be within the range of 0.1 to 10 MPa, preferably from 0.2 to 5 MPa, and more preferably from 0.2 to 3 MPa.

[0069] The applicant has found that, a supply of hydrogen into the reactor for the heterogeneously catalytic process advantageously promotes the catalytic activity of the Catalyst (H2), and also desirably extends the catalyst life. Generally, the amount of hydrogen supplied is controlled to maintain a hydrogen pressure in a range of 0.05 to 3 MPa, preferably from 0.05 to 2 MPa in the reactor.

[0070] Inert gases such as nitrogen, helium, and methane can also be supplied to the reactor, to assist in reaction temperature control and help maintain the desired pressure conditions during the course of reaction.

[0071] In the heterogeneously catalytic process of the present invention, the

average reaction time is generally from 15 minutes to 100 hours,

preferably from 3 hours to 50 hours, and more preferably from 5 hours to 20 hours.

[0072] In the heterogeneously catalytic reaction, the amine compound of formula NH2R' can be used in stoichiometric, substoichiometric or

superstoichiometric amounts based on the hydroxyl groups of the bis(hydroxymethyl)tetrahydrofuran reactant. In a preferred embodiment, the amine compound is used in an amount from 1- to 250-fold, preferably from 1 - to 100-fold, in particular in from 2- to 10-fold, molar excess per mole of hydroxyl groups in the bis(hydroxymethyl)tetrahydrofuran reactant. Higher excesses of amine compound are also possible.

[0073] Preferably, ammonia is used, in its gaseous or liquid phase.

[0074] The liquid reaction medium for the heterogeneous catalytic process

optionally comprises a solvent. Suitable solvents are polar and nonpolar solvents which can be used in pure form or in mixtures, and non-polar solvents are preferred.

[0075] Examples of non-polar solvents are hexane, heptane, octane, cyclohexane, benzene, toluene, xylene and mesitylene and linear and cyclic ethers such as THF, diethyl ether, 1 ,4-dioxane, MTBE (tert-butyl methyl ether), diglyme and 1 ,2-dimethoxyethane, among which toluene, xylene or mesitylene is preferred.

[0076] To carry out the desired amination reaction, the amine compound of

formula Nh R' and the 2,5-bis(hydroxymethyl)tetrahydrofuran reactant, together with the Catalyst (H2) and optionally with one or more solvents, are introduced into a reactor. The introduction of amine, 2,5- bis(hydroxymethyl)tetrahydrofuran, optional solvent(s) and Catalyst (H2) can be carried out simultaneously or separately.

[0077] The heterogeneously catalytic process of the present invention may be operated batchwise or continuously. In the continuous mode of operation, the catalyst (H2) may be conveniently placed in a flow reactor.

Description of embodiments

[0078] The following examples are provided to illustrate preferred embodiments of the invention and are not intended to restrict the scope thereof.

Examples

[0079] Example 1 : Homogeneously catalytic process using Ir-based Catalyst (H1)

In a nitrogen-purged sealed caroulsel tube, 2,5- bis(hydroxymethyl)tetrahydrofuran (132 mg, LOmmol) and

benzylamine(268 mg, 2.5 mmol.) in 0.5 ml of water containing 3.0 mol% of [Cp ^* lr(NH ₃ ) ₃ ][l]2 catalyst were heated at 120°C for 20 hours. The reaction mixture was then cooled and extracted with ethyl acetate (2ml x 3 times). The thus obtained product was then analysed by NMR and GC using biphenyl as the internal standard. The bicyclic product (I, R = benzyl) was obtained in 94% yield.

2.5 equiv. 94% yield

[0080] Example 2: Homogeneously catalytic process using Ru-based Catalyst (H1)

In a nitrogen-purged sealed autoclave (25 ml), 2,5- bis(hydroxymethyl)tetrahydrofuran (264 mg, 2.0 mmol), Xantphos (3 mol%) and [Ru(CO)CIH(PPh ₃ )3] (3mol%) were dissolved in 2 ml of tert-amyl alcohol and then charged with 5 bar NH ₃ . The mixture was heated at 150°C for 40 hours. The thus obtained product was then analysed by NMR and GC using biphenyl as internal standard. The bicyclic product (I, R = H) was obtained in 93% yield.

93% yield

[0081] Example 3: Preparation of a Cu-Ni-AI oxide catalyst (H2):

[0082] 1.16 g Ni(NO ₃ ) ₂ -6H ₂ O, 0.97 g Cu(NO ₃ ) ₂ -3H ₂ O and 2 g AI(NO ₃ ) ₃ -9H ₂ O were dissolved in 30 ml deionized water, to which 20 ml Na ₂ CO ₃ aqueous solution (0.95 mol/L) was dropwisely added in the next 30 minutes under rigorous stirring. The resultant slurry was further stirred for 5 hours and the catalyst precursors were separated by centrifugation and washed by deionized water until the pH value of the solution approached 7. The washed solid portion was dried at 100°C for 5 hours, calcined at 500°C for 5 hours and then reduced under a hydrogen flow at 400°C for 2 hours, and about 0.8 g sample of a Cu-Ni-AI oxide catalyst was obtained.

[0083] Example 4: Heterogeneously catalytic process using noble metal-free

catalyst (H2)

[0084] In a nitrogen-purged sealed autoclave (25 ml) were placedl OO mg of 2,5- bis(hydroxymethyl)tetrahydrofuran, 100mg of a Cu-Ni-AI oxide catalyst (Cu: Ni: Al = 1 : 1 : 1.3) and 2ml toluene. The vessel was pressurized withl bar H ₂ and7 bar NH ₃ , and then heated at 200°C for 1 1 hours. The thus obtained product was then analysed by GC using biphenyl as internal standard. The bicyclic product (I, R = H) was obtained in 50% yield.

cis/trans = 10/1

[0085] Example 5: Heterogeneously catalytic process using Ru-doped catalyst

In a nitrogen-purged sealed autoclave (25 ml) were placed 100 mg of 2,5- bis(hydroxymethyl)tetrahydrofuran, 100mg Ru-doped Cu-Ni-AI oxide catalyst (0.64wt% Ru, Cu:Ni:AI = 1 : 1 :1.3) and 2ml toluene. The vessel was pressurized withl bar H2 and 7 bar NH3, and heated at 200°C for 1 1 hours. The thus obtained product was then analysed by GC using biphenyl as the internal standard. The bicyclic product (I, R = H) was obtained in 57% yield.

[0086] Example 6: Heterogeneously catalytic process using Ru-doped Cu-AI

oxide catalyst (H2)

[0087] The procedure of Example 4 was essentially followed, except that the

catalyst was replaced by Ru doped Cu-AI oxide (0.64wt%, Cu: Al = 1 : 1.3). The bicyclic product (I, R = H) was obtained in 42% yield.

[0088] Example 7: Heterogeneously catalytic process using Pt-doped catalyst

(H2)

In a nitrogen-purged sealed autoclave (25 ml) were placedl OO mg of 2,5- bis(hydroxymethyl)tetrahydrofuran, 100mg of Pt-doped Cu-Ni-AI oxide catalyst (0.1 1wt% Pt, Cu:Ni:AI = 1 : 1 : 1.3) and 2ml toluene. The vessel was pressurized withl bar H ₂ and 7 bar NH3, and heated at 200°C for 1 1 hours. The thus obtained product was then analysed by GC using biphenyl as internal standard. The bicyclic product (I, R = H) was obtained in 58% yield.

cis/trans = 10/1