WO2007007084A2

WO2007007084A2 - Copper (ii) catalysed additions to alkenes

Info

Publication number: WO2007007084A2
Application number: PCT/GB2006/002558
Authority: WO
Inventors: King Kuok HII (Mimì)
Original assignee: Ic Innovations Limited
Priority date: 2005-07-12
Filing date: 2006-07-10
Publication date: 2007-01-18
Also published as: WO2007007084A3

Abstract

The present invention relates to a process for the addition of a nucleophile to a substrate comprising an alkene, in the presence of a copper (II) catalyst, wherein the nucleophile is preferably a compound having the formula R1-XH wherein X is NR6, O, C(O)O, OCONH2, SO2NH2, CONH2, S, P or Si.

Description

Copper (II) catalysed additions to alkenes

The present invention provides a process for the addition of a nucleophile to an alkene in the presence of a Cu(II) catalyst.

The direct addition of H-X bonds across unsaturated carbon-carbon bonds represents one of the most atom-economical processes for the synthesis of functionalised molecules. In recent years, there have been several reports of novel catalysts that can facilitate the addition of N-H bonds to alkenes and alkynes (hydroamination reaction).

Uncatalysed addition of N-H bonds to alkenes and alkynes is inherently prohibited by a large activation energy barrier and such reactions are generally inert under ambient conditions, especially with electronically neutral alkene and/or non-nucleophilic NH substrates. As the reaction utilises readily available feedstock and is 100% atom-economical, it is an extremely attractive process for the production of amines.

With unsymmetrical alkenes, the hydroamination reaction poses additional selectivity issues. For example, the addition to vinylarenes can proceed with different regioselectivities, depending on the catalyst employed. Anti- Markovnikov addition of aryl/alkylamines occurs in the presence of strong Brønsted bases, organolanthanide, rhodium or ruthenium catalysts to furnish the linear product. On the other hand, the branched regiomer results from the (Markovnikov) addition of aromatic amines effected by Pd(TFA)₂/diphosphine/triflic acid or TiCl₄, whilst Pt(II)-PR₃ complexes catalysed the (reversible) addition of carboxy amides. Thus far, metal-catalysed intermolecular additions of sulfonamides to vinylarenes are rare. There are very few reports of similar additions of O-H bonds to alkenes. The development of a process for the addition of O-H bonds to alkenes is therefore an important target in chemical synthesis.

For non-activated alkenes, the electrophilic addition of some alcohols may be catalysed by Brønsted acids. However, the regioselectivity of this electrophilic addition process can be difficult to control as regioselectivity is dependent on the stability of the carbocation intermediate(s) formed during the addition process. In addition, competitive alkene polymerisation and rearrangement processes may also occur during the Brønsted acid catalysed addition.

Transition metal catalysis can offer alternative reaction pathways. Intramolecular hydroalkoxylation (addition of alcohols) has been largely achieved by the use of late transition metal catalysts such as [PtCl₂(C₂H₄)J₂ZPR₃, IrCl₃/AgOTf and, more recently, Sn(OTf)₄. Currently, however, there are only two known examples of intermolecular metal-catalysed O-H addition to alkenes. Firstly, the addition of 2-phenylethylethanol to styrene, 1-octene and norbornene has been carried out using a catalyst generated from a mixture of Cp*RuCl₂(PPh₃)₂/2AgOTf/diphosphine. This catalyst is also effective for the addition of aromatic carboxylic acids to certain olefins (hydroacyloxylation). The addition of phenolic and carboxylic acid nucleophiles to various alkenes has been reported employing a (Ph₃P)AuCl/AgOTf catalytic system. These methods use expensive transition metal catalysts to carry out the hydroalkoxylation and hydroacyloxylation reactions. Furthermore, they require a pre-activation step using silver salts. The use of such metals as silver is costly and requires time consuming purification steps to remove silver residues from the resulting product. Furthermore, the transition metal catalysts set out above are sensitive to air and moisture. They therefore need to be used under an inert atmosphere and require the use of specially dried solvents, reagents, etc.

There is therefore a need in the art for a process of hydroamination, hydroalkoxylation and/or hydroacyloxylation which is efficient and cost effective.

The first aspect of the invention provides a process for the addition of a nucleophile to an alkene in a substrate comprising adding said nucleophile to an alkene in the presence of a copper (II) catalyst to form a product having a covalent bond between the nucleophile and a carbon of the alkene, wherein the nucleophile is an acid, alcohol, amine or thiol.

The nucleophile preferably has the formula R²-XH, wherein X is NR⁶, O, C(O)O, S, P or Si and R¹ and R⁶ are any group. The first aspect of the invention therefore relates to a process for the addition of R¹ -XH to a substrate comprising an alkene, comprising adding R^!-XH to an alkene in the presence of a copper (II) catalyst to form a product having a covalent bond between the

-X-H bond of R*-XH and a carbon of the alkene, wherein X is NR⁶, O, C(O)O or S and R¹ and R⁶ are any group.

The use of a Cu(II) catalyst to catalyse the nucleophilic addition to an alkene provides an efficient and effective process for in particular hydroamination, hydroalkoxylation and/or hydroacyloxylation reactions. The Cu(II) salt for example Cu(OTf)₂ is easily procured, stored and handled without recourse to specifically purified reagents or solvents. Furthermore, its residue does not present any toxicity issues. The first aspect relates to a process for the production of a compound of formula (I)

(D comprising the addition of a compound of formula (II)

R-XH

(H) to a compound of formula (III)

(III)

in the presence of a copper (II) catalyst; wherein R¹, R², R³, R⁴, R⁵, and R⁶ can be any group and X is NR⁶, O, C(O)O, OCONH₂, SO₂NH₂, CONH₂, S, P or Si.

For the purposes of the invention, R¹ is preferably optionally substituted Ci_-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl;

The C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-I2 heteroaryl groups for R¹ can be optionally substituted with one of more of C_1-10 alkyl, C_2-I0 alkenyl, C_1-I0 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl.

The Ci_-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl groups are preferably optionally substituted with one or more of halo, Ci_-4 alkoxy, Ci_-4 alkyl, Ci_-4 alkyl-SO₂, SO₂, and phenyl. Preferably, R¹ is an alkyl group having 1 to 10 carbon atoms or a phenyl group. The alkyl or phenyl group are preferably optionally substituted with one or more of methoxy, SO₂, NO₂, MeSO₂, chloride, methyl, ethyl, propyl, butyl, pentyl or PhCH=CH. When R¹ is a phenyl group the substituents can be in the ortho, meta or para positions, preferably in the para positions.

For the purposes of this invention, a compound comprising an alkene can be any compound comprising a carbon-carbon double bond. The alkene can be represented by the general formula (III)

(HI) wherein R², R³, R⁴ and R⁵ can be any group.

Preferably R², R³, R⁴, R⁵ and R⁶ are independently hydrogen or optionally substituted C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or Cs_-12 heteroaryl, or wherein two of R², R³, R⁴ or R⁵ can together form a C_5-12 cycloalkyl ring.

The C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl groups for R², R³, R⁴ or R⁵ can be optionally substituted with one of more of Ci_-I0 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-I2 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano,

=0, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-I2 aryl. The Ci_-20 alkyl, C_2-20 alkenyl,

C_6-12 aryl or C_5-12 heteroaryl groups are preferably optionally substituted with one or more of halo, C_1-4 alkoxy, C_1-4 alkyl, C_1-4 alkyl-SO₂, SO₂, and phenyl.

Preferably R² and R⁴ together form a five or six membered aryl or cycloalkyl group, wherein said cycloalkyl group can be bridged by an alkyl moiety containing one, two or three carbon atoms. More preferably, R² and R⁴ together form a norbornene moiety or a substituted analogue thereof.

One or more of R and R is preferably hydrogen.

In one feature of the first aspect of the invention, the alkene is a compound of formula (III) wherein R² is preferably C_6-12 aryl optionally substituted with one or more of C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl. Preferably R² is phenyl or naphthyl, optionally substituted with one or more of C_1-10 alkyl, halo or C_1-10 alkoxy, more preferably with one or more of methyl, chloride, fluoride or methoxy.

As discussed above, R² and R⁴ can together form a norbornene moiety or a substituted analogue thereof. In particular, the alkene is a compound of formula (Ilia) wherein

(Ilia) R³ and R⁵ are as defined above and R¹⁰, R¹¹, R¹² and R¹³ are independently C_1- io alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl.

The compound of formula (Ilia) is preferably

The compound comprising an alkene may comprise one or more functional groups. For example, the alkene may be a compound of formula (HIb)

(HIb)

wherein R₁ is as defined above; and R⁸ is independently hydrogen or C_1-2O alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl, optionally substituted with one of more of C_1-10 alkyl, C_2-io alkenyl, Ci_-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷ wherein R is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl and where

R⁸ is preferably a group -NR⁹-C(O)-R¹⁰ wherein R¹⁰ is independently hydrogen or C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or

C_5-12 heteroaryl, optionally substituted with one of more of Ci_-10 alkyl, C_2-I0 alkenyl, C_1-I0 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-I2 heterocyclyl, halo, cyano,

=O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷ wherein R⁷ is absent or is one or more of C_1-I0 alkyl, halo or C_6-12 aryl and wherein R⁹ is hydrogen or can form with R¹⁰ a 4, 5 or 6-membered ring comprising one or more heteroatom such as an oxazolidinone ring.

In an alternative feature of the first aspect, compound comprising an alkene may comprise two or more alkene functionalities. Preferably, the alkene is a diene of formula (IIIc)

wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸and R¹⁹ can be any group.

Preferably R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸and R¹⁹ are independently hydrogen or optionally substituted C_1-2O alkyl, C_2-20 alkenyl, C_6-I2 aryl or C_5-12 heteroaryl, or wherein two of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸and R¹⁹ can together form a C_5-12 cycloalkyl ring.

The C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl groups for R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸and R¹⁹ can be optionally substituted with one of more of C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl. The C_1-20 alkyl, C_2- ₂₀ alkenyl, C_6-12 aryl or C_5-I2 heteroaryl groups are preferably optionally substituted with one or more of halo, C_1-4 alkoxy, C_1-4 alkyl, C_1-4 alkyl-SO₂, SO₂, and phenyl.

Preferably the diene can be a cyclic diene, for example a diene of formula (HId)

(HId) wherein n is 0, 1, 2, 3 or 4 and any position on the ring can be substituted with one or more of C_1-10 alkyl, C_2-10 alkenyl, Ci_-10 alkoxy, C_6-12 aryloxy, C_6-I2 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-1O alkyl, halo or C_6-12 aryl.

The diene is preferably optionally substituted cyclohexadiene.

In a particularly preferred feature of the first aspect of the invention, the nucleophile is an alcohol or an acid. The invention therefore relates to a process for the addition of an alcohol or a carboxylic acid to a carbon-carbon bond in a substrate comprising adding an alcohol or carboxylic acid to an alkene in the presence of a copper catalyst to form a product having a covalent bond between the -O-H bond of the alcohol or the carboxylic acid and a carbon of the alkene.

In particular, the first aspect provides a process for the production of a compound of formula (Ia)

(Ia) comprising the addition of a compound of formula (Ha)

RtVrPH

(Ha) to a compound of formula (III)

(III) in the presence of a copper (II) catalyst; wherein R¹, R², R³, R⁴ and R⁵ can be any group, preferably a group as defined above; and n is zero or one. In a particularly preferred feature of the first aspect of the invention the nucloephile is an amine. The invention therefore relates to a process for the addition of an amine to a carbon-carbon bond in a substrate comprising adding an amine to an alkene in the presence of a copper catalyst to form a product having a covalent bond between the -N-H bond of the amine and a carbon of the alkene.

In particular, the first aspect provides a process for the production of a compound of formula (Ib)

(Ib) comprising the addition of a compound of formula (lib)

R-NR⁶H (lib) to a compound of formula (III)

(HI) in the presence of a copper (II) catalyst; wherein R¹, R², R³, R⁴, R⁵ and R⁶ can be any group.

Preferably R¹ is a group R^la -SO₂-, ^la CO₂, R^la OCO or R^la SO₂ wherein R^la is C_1-20 alkyl, C_2-2O alkenyl, C_6-12 aryl or C_5-12 heteroaryl, optionally substituted with one or more of C_1-10 alkyl, C_2-I0 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocycyl, halo, cyano, =0, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ ₈ or SO₂R⁷ wherein R⁷ is as defined above. When R^la is an aryl group, it is preferably phenyl.

In a particular feature of the first aspect, the alkene functionality and the group -XH may be present in the same molecule. The process of the first aspect of the invention is therefore an intramolecular process and in particular provides a process for the addition of a group -XH to an alkene in the presence of a copper (II) catalyst to form a cyclised product having a covalent bond between the group -X and a carbon of the alkene. For this feature of the invention, the compound comprising a group -XH and an alkene can be a compound of formula (IV)

(IV) wherein R , R²¹, R²², R²³ and R²⁴ < :an be any group and n is 2, 3, 4 or 5, preferably 2 or 3.

Preferably R²⁰, R²¹, R²², R²³ and R²⁴ are independently hydrogen or optionally substituted C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl, or wherein two of R²⁰, R²¹, R²², R²³ and R²⁴ can together form a C_5-12 cycloalkyl ring.

The C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl groups for R²⁰, R²¹, R²², R²³ and R²⁴ can be optionally substituted with one of more of C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of Cj_-10 alkyl, halo or C_6-12 aryl. The C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl groups are preferably optionally substituted with one or more of halo, C_1-4 alkoxy, C_1-4 alkyl, Ci_-4 alkyl-SO₂, SO₂, and phenyl.

In a further feature, the first aspect provides a process for the addition of a compound of formula (II) to an alkene of formula (Ilia), preferably to norbomene:

in the presence of a copper (II) catalyst.

The copper (II) catalyst can be provided by any copper (II) salt. Preferably the coppper (II) catalyst is provided from one or more of copper (II) trifluoromethane sulfonate, copper (II) acetate, copper (II) bromide, copper (II) chloride, copper (II) fluoride, copper (II) formate, copper (II) hydroxide, copper (IΙ)acetyl acetonate and derivatives thereof, copper (II) perchlorite, copper (II) sulfate or copper (II) thiocyanate. The copper (II) catalyst can be generated and then used in the process of the first aspect. Alternatively, the catalyst can be generated in situ. More preferably, the copper (II) catalyst is copper (II) trifluoromethane sulfonate.

The copper (II) catalyst can be generated in situ. In particular, the copper (II) catalyst is preferably Cu(OTf)₂ which can be generated in situ for example by the reaction of CuCl₂ with AgOTf.

The copper(II) catalyst of the first aspect preferably has a minimum catalyst loading of 10% to 0.5%, alternatively 5% to 1%, alternatively 3% to 1.5%, alternatively 2.5% to 2%. The process of the first aspect is preferably carried out in solvent such as water, protic and aprotic organic solvents and hydrocarbons, preferably dioxane. The process is preferably carried out at 25 to 150 ⁰C, alternatively at 50 to 100 ⁰C, alternatively at 80 ⁰C. The process can be carried out for 1 to 40 hours, alternatively for 10 to 30 hours, alternatively for 15 to 20 hours, alternatively for 18 hours.

In a particular preferred feature of the first aspect of the invention therefore provides a process for the addition of a nucleophile to a carbon-carbon bond in a substrate comprising incubating a Cu (II) catalyst with a diphosphine ligand comprising one or more chiral biaryl groups to form an asymmetric catalyst in situ; adding said nucleophile and an alkene to the in situ generated catalyst, to form a product having a covalent bond between the nucleophile and a carbon of the alkene, wherein the nucleophile is an acid, alcohol, amine or thiol.

For the purposes of the first aspect of the invention, the diphosphine ligand contains axial chirality and is preferably one or more of BINAP, ToI-BINAP, SYNPHOS, Cl-MeO-BIPHEP, MeO-BIPHEP, C3-Tunephos, Difluorphos or CTH- P-Phos.

The catalyst can be [(BINAP)₂Cu(solvent)₂]²⁺[TfO]^" ₂, preferably [(BINAP)₂Cu(OH₂)₂]²⁺[TfOr₂.

For the purposes of this invention the term alkyl relates to both straight chain and branched chain alkyl radicals of 1 to 20 carbon atoms, preferably 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, n- pentyl, n-hexyl, n-octyl. In particular, alkyl relates to a group having 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 carbon atoms. The term alkyl also encompasses cycloalkyl radicals including but not limited to cyclopropyl, cyclobutyl, CH₂- cyclopropyl, CH₂-cyclobutyl, cyclopentyl or cyclohexyl. In particular, cycloalkyl relates to a group having 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms. Cycloalkyl groups can include briding atoms. In particular, the cycloalkyl group may have an alkyl bridging moiety have one, two or three carbon atoms. The carbon atoms of the bridging moiety may be substituted with for example one or more alkyl groups such as methyl. In particular, the bridged cycloalkyl group may be norbornene. The cycloalkyl groups can be optionally substituted or fused to one or more carbocycyl or heterocyclyl group.

Alkyl further encompasses haloalkyl groups wherein an alkyl radical as defined above is subsituted with one or more halide atoms such as F, Cl, Br, or I, such as CH₂CH₂Br, CF₃ or CCl₃.

The term alkenyl means a straight or branched alkylenyl radical of 2 to 20 carbon atoms, preferably 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms and containing one or more carbon-carbon double bons and includes but is not limited to ethylene, n-propyl-1-ene, n-propyl-2-ene, isopropylene, etc. In particular, alkenyl relates to a group having 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 carbon atoms.

Aryl means an aromatic 6 to 12 membered hydrocarbon containing one ring or being fused to one or more saturated or unsaturated rings including but not limited to phenyl, napthyl, anthracenyl or phenanthracenyl.

Heterocyclyl means a 5 to 12 membered ring system containing one or more heteroatoms selected from N, O or S and includes heteroaryl. In particular, the terms aryl, heteroaryl and heterocyclyl relate to a group having 5, 6, 7, 8, 9, 10, 11 or 12 ring atoms.

The heterocyclyl system can contain one ring or may be fused to one or more saturated or unsaturated rings. The heterocyclyl can be fully saturated, partially saturated or unsaturated and includes but is not limited to heteroaryl and heterocarbocyclyl. Examples of carbocyclyl or heterocyclyl groups include but are not limited to cyclohexyl, phenyl, acridine, benzimidazole, benzofuran, benzothiophene, benzoxazole, benzothiazole, carbazole, cinnoline, dioxin, dioxane, dioxolane, dithiane, dithiazine, dithiazole, dithiolane, furan, imidazole, imidazoline, imidazolidine, indole, indoline, indolizine, indazole, isoindole, isquinoline, isoxazole, iothiazole, morpholine, naphthyridine, oxazole, oxadiazole, oxathiazole, oxathiazolidine, oxazine, oxadiazine, phenazine, phenothiazine, phenoxazine, phthalazine, piperazine, piperidine, pteridine, purine, pyran, pyrazine, pyrazole, pyrazoline, pyrazolidine, pyridazine, pyridine, pyrimidine, pyrrole, pyrrolidine, pyrroline, quinoline, quinoxaline, quinazoline, quinolizine, tetrahydrofuran, tetrazine, tetrazole, thiophene, thiadiazine, thiadiazole, thiatriazole, thiazine, thiazole, thiomorpholine, thianaphthalene, thiopyran, triazine, triazole or trithiane.

For the purposes of the present invention, the term fused includes a polycyclic compound in which one ring contains one or more atoms preferably one, two or three atoms in common with one or more other ring.

Halogen means F, Cl, Br or I, preferably Br or Cl.

The second aspect of the invention relates to the use of a copper(II) catalyst in the addition of a micleophile to an alkene. In particular, the second aspect relates to the use of a copper (II) catalyst in the production of a compound of formula (I) by the addition of a compound of formula (II) to a compound of formula (III).

The third aspect of the invention provides a compound produced by the process of the first aspect.

All preferred features of each of the aspects of the invention apply to all other aspects mutatis mutandis.

The present invention will now be further illustrated by reference to one or more of the following non-limited examples.

EXAMPLES

Comparision of the activity of copper (II) trifluoromethanesulfonate with other catalysts.

Scheme 1. Catalysed addition of 4-methoxybenzoic acid to norbornene.

The addition of 4-methoxybenzoic acid to norbornene was initially examined in the presence of 10 mol% of triflic acid (dioxane, 80⁰C, 18 h). A very low yield of the product ester Ia was obtained (Table 1, entry 1), suggesting that electrophilic activation of the alkene by the strong Brønsted acid is fairly slow under these reaction conditions.

Several cationic metal catalysts were subsequently assessed as potential catalysts, chosen for their well-established Lewis acidity and for their stability to air and moisture (Scheme 1, Table 1). Cationic late-transition metal complexes (ruthenium and rhodium) failed to induce formation of any products, even at 5 mol% loading (entries 2 and 3). In turn, other Lewis acids such as silver, nickel and ytterbium triflate salts produced low to moderate conversions (entries 4-7). Ultimately, copper(II) trifluoromethanesulfonate proved to be a highly active catalyst, affording the norbornyl ester in high yield (entry 8).

Table 1 Addition of 4-methoxybenzoic acid to norbornene in the presence of different catalysts (Scheme l).^a Entry Catalyst catalyst loading (mol%) Yield/ %^b

1 TfOH 10 29

3 [Cp*Ru(NCCH₃)₃][PF₆] 5 -

4 AgOTf 2.5 9

5 AgBF₄ 2.5 -

6 Ni(OTf)₂ 2.5 5

7 Yb(OTf)₃ 2.5 45

8 Cu(OTf)₂ 2.5 95

" General reaction conditions: 4-methoxybenzoic acid (1.0 mmol), norbornene (1.5 mmol), dioxane, 80 ⁰C, 18 h. ^Isolated yield after column chromatography. The results were duplicated to within ±5%.

Addition of para-substituted benzoic acid substrates to norbornene

The addition of a selection of pαrø-substituted benzoic acid substrates was examined subsequently (Table 2). Employing just 2.5 mol% of the copper catalyst, the addition of these acids proceeded smoothly to furnish the corresponding 2-norbornyl esters la-d in good yields (entries 1 to 4).

Compared to the cationic ruthenium system, these reactions appear to be relatively insensitive to the electronic property of the nucleophile, although the yield is slightly lower in the presence of electron- withdrawing substituents

(entries 3 and 4). As the copper catalyst precursor is employed in the higher oxidation state, it appears that the exclusion of air and moisture is unnecessary.

Indeed, the reaction can be performed in air with no noticeable decrease in yield (entries 1 vs 5).

Similarly, the addition of aliphatic and cinnamic acids was also accomplished — giving the corresponding esters 2a-c in good yields (entries 6-8). These results are in contrast to the catalytic activity of the cationic ruthenium system, which was ineffective for the addition of acetic acid.

Table 2 Cu(OTf)₂-catalysed addition of RCO₂H to norbomene.³

Entry RCO₂H Product Yield/%'

1 4-MeOC₆H₅CO₂H 95 (90)

Ia

Ib

Ic

Id

4-MeOC₆H₅CO₂H 97

Ia

2a

2b

2c ^α General reaction conditions: Cu(OTf)₂ (0.025 mmol), RCO₂H (1.0 mmol), norbornene (1.5 mmol), dioxane, 80 ⁰C, 18 h. ^Isolated yield based on acid after column chromatography, duplicated to within ±5%. Value in parenthesis corresponds to that reported using the cationic ruthenium catalyst (reference 8). ^cReaction carried out in air.

Addition of alcohols to norbornene

The copper (II) catalysed addition of alcohols to norbornene was investigated (Table 3). The electronic and steric properties of the phenolic species appear to exert little influence on the reaction outcome. Even at a reduced substrate ratio of 1:1, the addition of the aromatic alcohols proceeded smoothly to furnish aryl ethers 3a-c with excellent yields (entries 1-3). Correspondingly, the addition of benzyl and n-butanol afforded the alkyl ethers 4a and 4b in high yields (entries 4 and 5). The low isolated yield of the product ethers 4b and 4c may also be due partly to their volatility.

Table 3 Cu(OTf)₂-catalysed addition of ROH to norbornene.^a

Entry ROH Product Yield/%'

3a

3b

3c

4a

4b

4c

4d

^Ω General reaction conditions: Cu(OTf)₂ (0.025 mmol), ROH (1.0 mmol), norbornene (1.0 mmol), dioxane, 80 ⁰C, 18 h. ^Isolated yield based on alcohol after column chromatography, duplicated to within ±3%

All the reactions examined above proceeded with >95% exo- selectivity, as determined by ¹H NMR spectroscopy of crude product mixtures after column chromatography. These oily residues were subjected to Kugelrϋhr distillation to provide the exo- isomers as analytically pure samples.

Norbornyl esters and ether derivatives are important classes of compounds frequently employed in medicinal chemistry to enhance biological potency of drags. For example, Atizoram (CP80633), an aryl norbornyl ether, is a potent

PDE4 inhibitor that is highly effective as a topical treatment for atopic dematitis. Norbornyl esters and ethers are also important ingredients in the flavours and fragrances industry. Indeed, most of the products synthesised during the course of this invention possess rather pleasant odours.

The copper(II) catalysed reactions appear to be rather insensitive to the nature of the O-H bond. Without being bound by scientific theory, it is possible that the cationic copper(ϋ) catalyst activates the double bond of the strained alkene by ri-coordination, rendering it susceptible to attack by O-nucleophiles.

Copper catalysed hydroamination reactions

Catalytic reactions were conducted in parallel using a Radley's 12-placed reaction carousel. For a typical experiment, reaction tubes were loaded with the Cu(OTf)₂ (0.05 mmol), (±)-BINAP (0.05 mmol), a stirrer bar, and fitted with a teflon screw cap. The reaction tubes were placed on the carousel and its atmosphere purged under vacuum for 20 minutes and subsequently flushed with nitrogen. Vinylarene (1.0 mmol) and the requisite sulfonamide (2.0 mmol) was dissolved in anhydrous 1,4-dioxane (1 mL) and introduced into each reaction tube through the fitted PTFE septum via a syringe. The reaction temperature was then raised to 75 ⁰C and maintained (thermostat) for 18 h. After cooling, the reaction mixtures were adsorbed directly onto silica gel and purified by flash column chromatography (4:1 hexanes/ethylacetate), affording the products mostly as white crystalline solids.

Addition of toluenesulfonamide to styrene

Table 4. Reaction between styrene and toluenesulfonamide. ^[a]

Entry Catalyst Loading [mol%] Ia : 2^LDJ [%]

1 Cu(OTf)₂ 10 42 [C]

2 CuSO₄ 10 3 Cu(OAc)₂ 10 4 [Cu(NCMe)₄]PF₆ 10 5 CuBr 10 6 CuI 10 7 TfOH 20 14 :15 8 Cu(OTf)₂/(±)-BINAP 10 ₉₈[c] 9 Cu(OTf)₂/(±)-BINAP 5 9₇[[c] 10 Cu(OTf)₂/(±)-BINAP 1 ₉₃[c]

[a] TsNH₂ (2 mmol), styrene (1 mmol), solvent (1 mL), 75 ⁰C, 18 h. [b] Isolated yield after purification by column chromatography, duplicated to within ±3%. [c] Dimer 2 was not detected in the reaction mixture (¹H NMR).

Guided by our previous work, 10 mol% of copper(II) triflate was initially used to catalysed the reaction between toluenesulfonamide and styrene. Under these conditions, the hydroamination reaction proceeded at 75 ⁰C (Table 1, entry I) - a much lower temperature than that required for the addition of other nitrogen nucleophiles (100- 140 ⁰C). Despite the modest yield obtained (42%), the branched 1-phenethyltosylamide Ia was obtained as the only product. To validate the unique reactivity of the catalyst, a set of control experiments were conducted in the presence of other copper salts, as well as triflic acid. The results show that the combination of the triflate counteranion (entries 2 and 3) and the +2 oxidation state (entry 4-6) is crucial for catalytic activity. Notably, triflic acid gave a very low yield of Ia under these conditions, with concomitant formation of a styrene dimer 2 (entry 7). Hence, we can ruled out a process catalysed solely by the Brønsted acid.

Significantly, the copper-catalysed process was found to be greatly enhanced in the presence of BINAP (entry 8). Consequently, the catalyst loading can be reduced to 1 mol% before any adverse effect in yield was noticeable (entries 9 and 10)

Investigation of hydroamination with electronically different alkenes

Table 5. Hydroamination of vinylarenes with arylsulfonamide.^[a5

mmol), vinylarene (1.0 mmol), 1,4-dioxane, 75 ⁰C, 18 h. [b] Isolated yield (based on vinylarene) after purification by column chromatography, duplicated to within ±3%. [c] Calculated by ¹H analysis of product mixtures. Value in parenthesis corresponds to the yield of dimer, based on amount of vinylarene used.

The scope of the reaction was examined by the introduction of electronically different substituents systematically (Table 5). 4-Nitrobenzenesulfonamide was also employed as a substrate, as the nosyl (Ns) moiety is often used as a protecting and activating group in the synthesis of secondary amines.

In most cases, the addition reactions proceeded smoothly to afford the corresponding branched regiomer in moderate to excellent yields. The reactions of TsNH₂ with styrene and electron-deficient 4-fluorostyrene gave the highest yields (entries 1 and 2), while the reaction of 4-chlorostyrene was somewhat slower (entry 3). The introduction of methyl groups retarded the reaction rate (entries 4 and 5), although moderate yields can be obtained. Similarly, the addition to 2-vinylnapthalene also proceeded with modest yield (entry 7). In comparison, the addition of the less nucleophilic arylsulfonamide is slower overall. Otherwise, the trend appears to be broadly similar; best yields were obtained with the unsubstituted and 4-fluoro-styrenes (entries 8 and 9), and moderate yields for 4-chloro and 4-methyl-styrenes (entries 10 and 11). Addition of sulfonamides to electron-rich 2,5-dimethylstyrene and 4- methoxystyrene are sufficiently slow. In the latter case, competitive dimerisation of the alkene is observable, leading to mixtures of products (entries 5, 6, 12 and 13).

The catalyst system has a much wider scope than NBS, reported to catalyse the addition of sulfonamides only to electron-rich styrenes (containing OMe or SMe groups).

Without being bound by scientific theory, a catalytic cycle is tentatively proposed based on the above observations (Scheme 2). Ligand exchange between the catalyst and arylsulfonamide is assumed to generate a copper- sulfonamide intermediate 4 with cocomittant release of triflic acid, which protonates the vinylarene. The TfO^" anion is envisaged to play an important role in the fusion of the reactive intermediates 4 and 5, either by enhancing the nucleophilicity of the amide anion through hydrogen bonding with N-H, and/or by stabilising the cationic intermediate by ion pairing. Dimerisation of the vinylarene becomes competitive when the addition of the sulfonamide is slow, as the result of employing an electron-deficient sulfonamide and/or electron- rich vinylarene, leading to a reduction in the reactivities of 4 and 5, respectively.

Scheme 2. Proposed catalytic cycle. Reversibility of the C-N bond formation

To verfiy the reversibility of the C-N bond formation process, the stability of optically active (S)-Ia was examine under two catalytic conditions; with and without the (±)-BINAP ligand (Scheme 3). Compound (S)-Ia was prepared by the tosylation reaction of commercially available (s)-(-)-l-phenylethyl- amine. Enantioplurity of Ia was assessed by chiral HPLC (conditions: Chiralcel Ob-N, i-Pr OH/hexane 10:90, flow rate 0.6 mL/min, t_R=16.8 min, t_s=20.4 min). The results are highly revealing: whilst no racemisation was observed in the absence of the catalyst (18 h), slow racemisation occurred in the presence of the diphosphine (75 ⁰C, 24h), where the compound loses its stereointegrity (84%ee). This suggests a competitive racemisation pathway in the presence of the diphosphine ligand.

NHTs NHTs NHTs

Y Catalyst A or B - + T

Phf ^ *^■ PrT^""^ Phf ^

(S)-Ia 75 °C, dioxane

Catalyst A: Cu(OTf)₂ (10 mol%) Catalyst B: Cu(OTf)₂ (5 mol%), (±)-BINAP (5 mol%)

Scheme 3. Probing the reversibility of the C-N bond formation.

Cu(OTf)₂ can also catalyse the addition of toluenesulfonamide to norbornene

(Scheme 4), furnishing the hydroamination product 4a in 95% yield. The efficiency of the system compares well with the reported use of 10 mol% of

[(COD)Pt(OTf)₂] to effect the same reaction under similar conditions, in o- dichlorobenzene. Additionally, the electron-deficient 4- nitrophenylsulfonamide and the presence of an N-benzyl moiety are also fairly well-tolerated, as products 4b and 4c can both be obtained in good yields. The reaction favours the formation of the exo- isomer exclusively, as indicated by the appearance of a distinctive ¹H NMR signal at ca. 3.3 ppm, corresponding to an endo-proton at C-I (broad singlet). 95% 83%

77%

Scheme 4. Copper-catalysed addition of arylsulfonamides to norbomene. Reaction conditions (unoptimised): Sulfonamide (1 mmol), norbomene (1.5 mmol), catalyst (0.1 mmol), 1, 4-dioxane (1 mL), 85 ⁰C, 18 h. Yields were calculated based on the product obtained after column chromatography.

Intramolecular reactions

10 mol% of copper(II) triflate was initially used to catalysed the reaction between toluenesulfonamide and styrene. Under these conditions, the hydroamination reaction proceeded at 75 °C (Table 6, entry 1) - a much lower temperature than that required for the addition of other nitrogen nucleophiles (100-140⁰C). Despite the modest yield obtained (42%), the branched 1- phenethyltosylanαdde Ia was obtained as the only product. To validate the unique reactivity of the catalyst, a set of control experiments were conducted in the presence of other copper salts, as well as triflic acid. The results show that the combination of the triflate counteranion (entries 2 and 3) and the +2 oxidation state (entry 4-6) is crucial for catalytic activity. Notably, triflic acid gave a very low yield of Ia under these conditions, with concomitant formation of a styrene dimer 2 (entry 7). Hence, we can ruled out a process catalysed solely by the Brønsted acid.

Significantly, the copper-catalysed process was found to be greatly enhanced in the presence of BINAP (entry 8). Consequently, the catalyst loading can be reduced to 1 mol% before any adverse effect in yield was noticeable (entries 9 and 10).

Preliminary results showed that the intramolecular reactions are accelerated by diphosphine ligands, with BINAP being the best ligand. Table 6 Optimisation of catalytic conditions." Catalyst

Ligand

(CH₂CI)₂, reflux

Entry Catalyst Ligand Bite Loading t/h Conversion angle*/⁰ /mol% /%

1 Cu(OTf)₂ - - 5 20 84

2 Cu(OTf)₂ - 5 18 -

3 Cu(OTf)₂ P(o-tolyl)₃'ⁱ - 5 18 -

4 Cu(OTf)₂ dppe 85.8 5 18 100

5 Cu(OTf)₂ dppp 90.6 5 18 95

6 Cu(OTf)₂ dppb 94.3 5 18 35

7 Cu(OTf)₂ dppf 99.1 5 18 89

8 Cu(OTf)₂ Xantphos 110.0 5 18 100

9 Cu(OTf)₂ ±-BINAP 92.7 5 18 100

10 Cu(OTf)₂ dppe 85.8 2 18 88

11 Cu(OTf)₂ Xantphos 110.0 1 6 48

12 Cu(OTf)₂ Xantphos 110.0 1 24 92

13 Cu(OTf)₂ ±-BINAP 92.7 1 6 68

14 Cu(OTf)₂ ±-BINAP 92.7 1 24 100

"General reaction conditions: Cu(OTf)₂ (0.05 mmol), Ar SO₂NH₂ (2.0 mmol), vinylarene (1.0 mmol), 1,4-dioxane, 75 ⁰C, 18 h. From X-ray crystal structures of (diphosphine)PdCl₂ obtained using the Cambridge Crystallographic Database, except Xantphos.fref x] ^Determined by H NMR of crude reaction mixture. Value in parenthesis corresponds to isolated yield after purification. Metal-to-ligand ratio of 1: 2.

Further examples of intramolecular addition have been carried out to form lactones that are important to the fragrance and flavours. Some examples are given below:

Table 7 Copper-catalysed intramolecular acylalkoxylation of alkenoic acids."

Entry Substrate Product Yield^fc/%

3.5 : 1

^a Typical reaction: Cu(OTf)₂ (2 mol%), rac-BJNAP (2 mol%), 83 ⁰C, 18 h. ^Determined by ¹H NMR.

Also,

,OH

Cu(OTf)₂ (5 mol%)

O O ^;O Ligand (5 mol%)

Examples of additions to dienes

Table 8. Addition of N-H to 1,3-cyclohexadiene

Catalyst

1 ,4-dioxane

^α5 mol% catalyst.

Table 9. Addition to other dienes.^a

"Catalyst: Cu(OTf)₂ (5 mol%), dppe (5 mol%). Reaction temperature = 55 ⁰C, reaction time = 18 h.

Claims

1. A process for the addition of a rracleophile to an alkene in a substrate comprising adding said nucleophile to an alkene in the presence of a copper (II) catalyst to form a product having a covalent bond between the nucleophile and a carbon of the alkene, wherein the nucleophile is an acid, alcohol, amine or thiol.

2. The process as claimed in claim 1 wherein the nucleophile has the formula R¹ -XH, wherein X is NR⁶, O, C(O)O, S, P or Si and R¹ and R⁶ are any group.

3. The process as claimed in any one of claims 1 or 2 for the production of a compound of formula (I)

(D comprising the addition of a compound of formula (II)

R-XH

(H) to a compound of formula (III)

(HI)

in the presence of a copper (II) catalyst; wherein R¹, R², R³, R⁴, R⁵, and R⁶ can be any group and X is NR⁶, O, C(O)O, OCONH₂, SO₂NH₂, CONH₂ or S.

4. The process as claimed in claim 3 wherein R¹ is C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl optionally substituted with one of more of C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-J2 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl.

5. The process as claimed in any one of claims 1 to 4 wherein the compound comprising an alkene is a compound of general formula (III)

(III) wherein R², R³, R⁴, R⁵ and R⁶ are independently hydrogen or C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl optionally substituted with one of more of C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-J2 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl, or wherein two of R², R³, R⁴ or R⁵ can together form a C_5-12 cycloalkyl ring.

6. The process as claimed in any one of claims 1 to 5 wherein the compound comprising an alkene is a compound of formula (Ilia)

(Ilia) wherein R³ and R⁵ are as defined for claim 5 and R¹⁰, R¹¹, R¹² and R¹³ are independently C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl.

7. The process as claimed in any one of claims 1 to 5 wherein the compound comprising an alkene is a compound of formula (HIb)

(HIb)

wherein R₁ is as defined in claim 4; and R⁸ is independently hydrogen or C_1-20 alkyl, C_2-2O alkenyl, Cg_-12 aryl or Cs_-I2 heteroaryl, optionally substituted with one of more of C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷ wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-12 aryl.

8. The process as claimed in any one of claims 1 to 5 wherein the compound comprising an alkene is a compound of formula (HIc)

(HIc) wherein R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸and R¹⁹ are independently hydrogen or C_1-20 alkyl, C_2-20 alkenyl, C_6-12 aryl or C_5-12 heteroaryl optionally substituted with one of more of C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-12 heterocyclyl, halo, cyano, =0, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-I2 aryl, or wherein two of R¹⁴, R¹⁵, R¹⁶, R¹⁷, R¹⁸and R¹⁹ can together form a C_5-12 cycloalkyl ring.

9. The process as claimed in any one of claims 1 to 5 wherein the compound comprising an alkene is a compound of formula (HId)

(HId) wherein n is 0, 1, 2, 3 or 4 and any position on the ring can be substituted with one or more of C_1-10 alkyl, C_2-10 alkenyl, C_1-10 alkoxy, C_6-12 aryloxy, C_6-12 aryl, C_5-I2 heterocyclyl, halo, cyano, =O, NO₂, COR⁷, CO₂R⁷, NR⁷R⁷, SR⁷, SOR⁷ or SO₂R⁷; wherein R⁷ is absent or is one or more of C_1-10 alkyl, halo or C_6-I2 aryl.

10. The process as claimed in any one of claims 1 to 9 for the addition of an alcohol or a carboxylic acid to a carbon-carbon bond in a substrate comprising adding an alcohol or carboxylic acid to an alkene in the presence of a copper catalyst to form a product having a covalent bond between the -O-H bond of the alcohol or the carboxylic acid and a carbon of the alkene.

11. The process as claimed in any one of claims 1 to 10 for the production of a compound of formula (Ia)

(Ia) comprising the addition of a compound of formula (Ha)

(Ha) to a compound of formula (III)

(HI) in the presence of a copper (II) catalyst; wherein R¹, R², R³, R⁴ and R⁵ can be any group and n is zero or one.

12. The process as claimed in any one of claims 1 to 9 for the production of a compound of formula (Ib)

(Ib) comprising the addition of a compound of formula (lib)

R-NR⁶H

(lib) to a compound of formula (III)

(III) in the presence of a copper (II) catalyst; wherein R¹, R², R³, R⁴, R⁵ and R⁶ can be any group.

13. The process as claimed in any one of claims 1 to 12 comprising an intramolecular process and in particular provides a process for the addition of a group -XH to an alkene in the presence of a copper (II) catalyst to form a cyclised product having a covalent bond between the group -X and a carbon of the alkene, wherein the group -X and the alkene group are in the same molecule.

14. The process as claimed in any one of claims 1 to 5 wherein the compound comprising an alkene is a compound of formula (IV)

(IV) wherein R²⁰, R²¹, R²², R²³ and R²⁴ can be any group and n is 2, 3, 4 or 5.

15. The process as claimed in any one of claims 1 to 6 for the addition of a compound of formula (II) to norbornene:

in the presence of a copper (II) catalyst.

16. The process as claimed in any one of claims 1 to 15 wherein the copper (II) catalyst is copper (II) trifluoromethane sulfonate.

17. The process as claimed in any one of claims 1 to 16 wherein the copper (II) catalyst is generated in situ.

18. The process as claimed in any one of claims 1 to 17 wherein the copper(II) catalyst has a minimum catalyst loading of 10% to 0.5%.

19. The process as claimed in any one of claims 1 to 18 for the addition of a nucleophile to an alkene in a substrate comprising incubating a Cu (II) catalyst with a diphosphine ligand comprising one or more chiral biaryl groups to form an asymmetric catalyst in situ; adding said nucleophile and an alkene to the in situ generated catalyst, to form a product having a covalent bond between the nucleophile and a carbon of the alkene, wherein the nucleophile is an acid, alcohol, amine or thiol.

20. The process as claimed in claim 19 wherein the diphosphine ligand is one or more of BINAP, ToI-BINAP, SYNPHOS, Cl-MeO-BIPHEP, MeO- BIPHEP, C3-Tunephos, Difluorphos or CTH- P-Phos.

21. The use of a copper(II) catalyst in the addition of a nucleophile to an alkene.

22. The use of a copper(II) catalyst in the addition of an alcohol or carboxylic acid to an alkene.

23. The use of a copper(II) catalyst in the addition of an amine to an alkene.

24. The use of a copper (II) catalyst as claimed in claim 21 or 22 in the production of a compound of formula (Ia)

by the addition of a compound of formula (Ha) to a compound of formula (Ilia) wherein R¹, R², R³, R⁴ and R⁵ can be any group.

25. A product as produced by the process of any one of claims 1 to 20.

26. A process as substantially described herein with reference to one or more of the examples.

27. A use as substantially described herein with reference to one or more of the examples.

28. A product as substantially described herein with reference to one or more of the examples.