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  • B01J31/2452—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom
  • B01J31/2457—Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring comprising condensed ring systems and phosphine-P atoms as substituents on a ring of the condensed system or on a further attached ring with more than one complexing phosphine-P atom comprising aliphatic or saturated rings, e.g. Xantphos
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  • C07D209/58—[b]- or [c]-condensed
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Definitions

• the present invention refers to processes for catalytic reversible unsaturated carbon-carbon bond-nitrile interconversion through controllable HCN-free transfer hydrocyanation wherein unsaturated carbon-carbon bond stands for a double carbon carbon bond or triple carbon carbon bond.
• Organonitriles and alkenes are important synthetic intermediates with orthogonal reactivity that play a central role in the preparation of polymers, pharmaceuticals, cosmetics and agrochemicals.
• a process to construct or deconstruct nitrile compounds through reversible interconversion with alkenes as desired would provide an exceptionally powerful synthetic tool.
• nitrile group is among the most versatile polar functionalities and is widely encountered in the preparation of polymers, pharmaceuticals, cosmetics and agrochemicals, both on industrial and laboratory scale.
• Organonitriles can serve as precursors for aldehydes, acids, esters, ketones, amides, amines and heterocydes. Additionally, the electron withdrawing nature of nitriles alters the reactivity profile of a molecule and enables functionalization of neighboring positions (a, but also ⁇ in the case of conjugated systems).
• the alkene group is a nonpolar functional group that has a distinct and complementary reactivity profile when compared to nitriles.
• Alkenes are tolerant to a wide range of reaction conditions commonly used to transform polar functional groups. Additionally, they can engage in a number of bond forming reactions (e.g. alkene metathesis reaction) not accessible using polar functional groups.
• bond forming reactions e.g. alkene metathesis reaction
• HCN hydrogen cyanide
• reaction pathway can possibly be favored on demand by shifting the equilibrium of the reaction using simple driving forces.
• the present invention provides an HCN-free transition metal, particularly Ni, - catalyzed reversible transfer hydrocyanation between alkyl nitriles and alkenes with tunable control over product selectivity (Figure 1 C).
• the present invention refers to a process for the catalytic reversible alkene-nitrile interconversion wherein an unsaturated hydrocarbon (I) is reacted with an alkylnitrile (II) in the presence of a transition metal coordinated to a ligand, as a coordinated transition metal catalyst, and a Lewis acid co-catalyst, preferably in a solvent, to yield an alkylnitrile (III) and an unsaturated hydrocarbon (IV), each being different from the starting compounds, as represented in the following reaction scheme:
• R 1 , R 2 , R 3 and R 4 can be the same or different and each independently represents H, straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyi, aryl, aralkyi, heteroaryl, heteroaralkyi, each being optionally substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyi, alkenyl, alkynyl, aryl, aralkyi, heteroaryl, heteroaralkyi or a heterosubstituent; or a heterosubstituent, or at least two of R 1 , R 2 , R 3 and R 4 may each form a cyclic 3 to 20 membered ring structure which may further be substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyi, aryl, aralkyi, heteroaryl, heteroaralkyi or a hetero
• R 5 , R 6 , R 7 and R 8 can be the same or different and each independently represents H, straight chain or branched chain alkyl, cycloalkyl,
• heterocycloalkyi, aryl, aralkyi, heteroaryl, heteroaralkyi each being optionally substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyi, alkenyl, alkynyl, aryl, aralkyi, heteroaryl, heteroaralkyi, or a heterosubstituent, or a heterosubstituent; or at least two of R 5 , R 6 , R 7 and R 8 may each form a cyclic 3 to 20 membered hydrocarbon ring structure which may further be substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyl, heterocycloalkyi, aryl, aralkyi, heteroaryl, heteroaralkyi or a heterosubstituent, and optionally including any of O, S, N in the straight chain, branched chain or cyclic structure; wherein preferably at least one of R
• the metal of the coordinated transition metal catalyst is selected from a metal of the Iron-group, Cobalt-group, Nickel-group or Copper group;
• the ligand of the coordinated transition metal catalyst is selected from compounds having the ability to coordinate to said transition metal, including phosphorous-, nitrogen- , As-, Sb- or N-heterocyclic based ligands; and the Lewis acid co-catalyst is selected from compounds of aluminum, boron, zinc, titanium, scandium.
• equilibrium can be shifted from one side to the other. This can be preferably done by reacting the starting compounds to yield a reaction mixture from which one of the formed products is removed from the reaction system, for example by evaporation of a side-product (eg gas). Alternatively, the introduction of strain (eg ring strain) or steric constraints in one of the reactants can also be used to drive the reaction.
• a side-product eg gas
• strain eg ring strain
• steric constraints in one of the reactants can also be used to drive the reaction.
• R 1 , R 2 , R 3 and R 4 can be the same or different and each independently represents aryl, heteroaryl, aralkyi, or heteroaralkyi, each being optionally substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyi, heterocycloalkyi, alkenyl, alkynyl, aryl, aralkyi, heteroaryl, heteroaralkyi or a heterosubstituent, or a heterosubstituent, or R 2 and R 4 form a bond; wherein at least one of R 1 , R 2 , R 3 and R 4 is not hydrogen.
• R 5 , R 6 , R 7 and R 8 can be the same or different and each independently represents H, straight chain or branched chain alkyl, cycloalkyi, heterocycloalkyi, each being optionally substituted by one or more groups selected from straight chain or branched chain alkyl, cycloalkyi, heterocycloalkyi, alkenyl, alkynyl, aryl, aralkyi, heteroaryl, heteroaralkyi or a heterosubstituent, or a heterosubstituent, or at least two of R 5 , R 6 , R 7 and R 8 may each form a cyclic 3 to 20 membered hydrocarbon ring structure which may further be substituted by one or more groups selected from alkyl, cycloalkyi, heterocycloalkyi, aryl, heteroaryl or heterosubstituent, and optionally including any of O, S, N in the straight chain, branched chain or cyclic structure, wherein
• R 5 , R 6 , R 7 and R 8 can be the same or different and each independently represents H, straight chain or branched chain alkyl, or cycloalkyi, or at least two of R 5 , R 6 , R 7 and R 8 may each form a cyclic 3 to 20 membered aliphatic hydrocarbon ring structure which may further be substituted by one or more groups selected from alkyl, cycloalkyi, heterocycloalkyi, or heterosubstituent, and optionally including any of O, S, N in the straight chain, branched chain or cyclic structure, wherein at least one of R 5 , R 6 , R 7 and R 8 is not hydrogen.
• the compound of formula (II) is a lower alkyl nitrile having 1 to 6 carbon atoms, optionally substituted by one or more heterosubstituents.
• the compound of formula (I) is preferably a cyclic unsaturated hydrocarbon having 4 to 20, preferably 4 to 12 carbon atoms optionally substituted by one or more heterosubstituents.
• Unsaturated includes at least one of a double or triple bond.
• the inventors have evaluated a range of metals for use as coordinated metalcatalysts to develop the transfer hydrocyanation reaction.
• transition metal catalysts transition metals and compounds thereof, selected from the Iron-group, Cobalt-group, Nickel-group or Copper group, the groups 8 to 1 1 of the periodic table, particularly Nickel, Cobalt and Palladium, are preferred. Examples are Ni(COD) 2 , Ni(acac) 2 , Ni(CO) 4 , Pd(dba) 2 , Pd(OAc) 2 , Co 2 (CO) 8 and preferred examples are Ni(COD) 2 .
• Nickel was initially chosen as a metal because Nickel(O) complexes have been shown to be the active species in the oxidative addition of inert bonds, including aliphatic C-CN bonds.
• initial experiments using simple Nickel catalysts alone failed to afford any product formation.
• Lewis Acids can both accelerate some Nickel-mediated reactions, the inventors made use of the addition of a Lewis Acid co-catalyst for facilitating the desired reversible transfer hydrocyanation mechanism.
• the inventors also evaluated a range of ligands to increase the activity of the coordinated metal catalyst in the transfer hydrocyanation reaction.
• the ligand can be selected from compounds having the ability to coordinate to a transition metal, including phosphorous-, nitrogen-, As-, Sb- or N-heterocyclic based ligands.
• Examples are from the group consisting of phosphine ligands, particularly PPh 3 , PCy 3 , P(OPh) 3 , PEt 3 , BINAP, Xanthphos, DuPhos, DPEPhos, dppf, dppe, further preferred PPh 3 and DPEPhos, and mixtures thereof.
• Preferred examples are phosphine ligands, examples of which are DPEPhos, PPh 3 or mixtures thereof with the following meanings:
• BINAP 2,2'-Bis(diphenylphosphino)-1 ,1 '-binaphthalene
• the coordinated transition metal catalyst can be prepared in situ by addition of said ligands to a solution of the transition metal compound, said metal being selected from the Iron-group, Cobalt-group, Nickel-group or Copper group, the groups 8 to 1 1 of the periodic table, whereby coordinated transition metal catalysts with the metal Nickel, Cobalt or Palladium are preferred.
• Examples of such compounds to be added are Ni(COD) 2 , Ni(acac) 2 , Ni(CO) 4 , Pd(dba) 2 , Pd(OAc) 2 , Co 2 (CO)s and preferred example is Ni(COD) 2 .
• the Lewis acid co-catalyst can be any known Lewis acid catalyst having sufficient Lewis acid strength and can be selected from compounds of aluminum, boron, zinc, titanium, scandium.
• Examples are AI(alkyl) 3-z Xz, wherein alkyl is Ci to C6, Z is 0 to 3 and X is halogen, preferred chlorine, such as AIMe 3 , AIMe 2 CI, AIMeCI 2 , AICIs, BPh 3 , B(C 6 F 5 ) 3 , Zn(OTf) 2 , ZnCI 2 , TiCI 4 , Sc(OTf) 3 , and preferred examples are AIMe 3 , AIMe 2 CI, AICI 3 , BPh 3 .
• the solvent is not critical and can be selected amongst those which are commonly used for such kind of catalysed reactions, such as aromatic solvents such as toluene, benzene, xylene, cumene, chlorobenzene, dichlorobenzene, or aliphatic hydrocarbon solvents, depending on the specific reaction system.
• the reaction temperature is usually in the range from 25 to 150 °C, preferably from 25 to 125°C. Definition for the substituents as used in the present formulae are given in the following.
• R S1 R S2 and R S3 each individually represent H, alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, sulfonyl, silyl, each being optionally substituted by one or more alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aralkyl, heteroaralkyl, sulfonyl or heterosubstituent.
• alkyl may be Ci-C2o-Alkyl which can be straight chain or branched or cyclic and has 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.
• Alkyl might particularly be Ci-C6-alkyl, in particular methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl, likewise pentyl, 1 -, 2- or 3-methylpropyl, 1 ,1 -, 1 ,2- or 2,2-dimethylpropyl, 1 - ethylpropyl, hexyl, 1 -, 2-, 3- or 4-methylpentyl, 1 ,1 -, 1 ,2-, 1 ,3-, 2,2-, 2,3- or 3,3- dimethylbutyl, 1 - or 2-ethylbutyl, 1 -ethyl-1 -methylpropyl, 1 -ethyl-2-methylpropyl, 1 ,1 ,2- or 1 ,2,2-trimethylpropyl.
• Cycloalkyl may be a cyclic alkyl group forming a 3 to 20 membered ring and might be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl.
• Heterocycloalkyl may be a cycloalkyl forming a 3 to 10 membered ring and incorporating one or more heteroatoms selected from N, O and S within the cycle.
• heterocycloalkyls can be preferentially selected from 2,3-dihydro-2-, - 3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4- or -5-furyl, tetrahydro-2- or -3-furyl, 1 ,3- dioxolan-4-yl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1 -, -2-, -3-, -4- or -5-pyrrolyl, 1 -, 2- or 3-pyrrolidinyl, tetrahydro-1 -, -2- or
• Halogen is F, CI, Br or I.
• Aryl might be phenyl, naphthyl or biphenyl and substituted derivatives thereof.
• Aralkyl might be benzyl, naphthylmethyl and substituted derivatives thereof.
• Heteroaryl may have one or more heteroatoms selected from N, O ,S and Si and is preferably 2- or 3-furyl, 2- or 3-thienyl, 1 -, 2- or 3-pyrrolyl, 1 -, 2-, 4- or 5- imidazolyl, 1 -, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, also preferably 1 ,2,3-triazol-1 -, -4- or -5-yl, 1 ,2,4-triazol-1 -, -3- or -5-yl, 1 - or 5- tetrazolyl, 1 ,2,3-oxadiazol-4- or -5-yl, 1 ,2,4-oxadiazol-3- or -5-yl, 1
• 5- , 6-, 7- or 8-quinazolinyl 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-, 7- or 8-2H-benzo-1 ,4- oxazinyl, also preferably 1 ,3-benzodioxol-5-yl, 1 ,4-benzodioxan-6-yl, 2,1 ,3- benzothiadiazol-4- or -5-yl or 2,1 ,3-benzoxadiazol-5-yl.
• Heteroaralkyl might be any of the aforementioned heteroaryl bound to an alkyl group, such as pyridinylmethyl.
• Optionally substituted means unsubstituted or monosubstituted, disubstituted, trisubstituted, tetrasubstituted, pentasubstituted, or even further substituted on the respective group.
• a reaction pair of a coordinated transition metal catalyst and a Lewis acid co-catalyst can bes used for a nitrile transfer reaction from an hydrocarbon nitrile to an unsaturated hydrocarbon, wherein
• the metal of the coordinated transition metal catalyst is selected from a metal of the Iron-group, Cobalt-group, Nickel-group or Copper group;
• the ligand of the coordinated transition metal catalyst is selected from compounds having the ability to coordinate to said transition metal, including phosphorous-, nitrogen- , As-, Sb- or N-heterocyclic based ligands; and the Lewis acid co-catalyst is selected from compounds of aluminum, boron, zinc, titanium, scandium,
• Figure 1 shows the:
• alkyl nitrile product 2 formed in the forward reaction, can be used as test substrate to evaluate the efficiency of diverse alkene traps to drive the retro- hydrocyanation reaction to completion (Figure 2C).
• a control reaction using no acceptor alkene did not lead to any significant formation of product 1 .
• This result clearly shows that the formation of HCN and an alkene from an alkyl nitrile is thermodynamically disfavored, emphasizing the need to use an acceptor alkene to drive the process.
• Both norbornene (NBE, 7) and norbornadiene (NBD, 8) were then evaluated since they possess significant ring strain that should help to drive the retro-hydrocyanation reaction.
• Non-activated, terminal aliphatic alkenes were also very active substrates in the transformation and gave the linear product as the major product (up to 100% l/b selectivity in the case of sterically congested f Bu (30)).
• the inventors investigated 1 ,2-disubstituted substrates. Cycloalkenes (33, 35 and 37) and strained norbornenes (7 and 43) were well tolerated and afforded the cyanated products in high yields.
• Two renewable feedstocks, methyl oleate (45) and camphene (47) were subjected to the reaction conditions and high yields of the products were obtained.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), ⁇ -methylstyrene 1 (65 ⁇ , 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 mL, 2.50 mmol), 1 ,1 -diphenylethylene 19 (88 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 mL, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 mL) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), cyclopentene 33 (44 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 25 ml_ pressure tube under an argon atmosphere in a glove box. The pressure tube was taken out of the glove box and heated at 100 °C for 16 hours.
• reaction was cooled down to room temperature, and n-dodecane (100 ⁇ _) as internal standard was added to the solution.
• the reaction mixture was analyzed by GC and the yield of 34 determined by comparing their peak areas to that of the internal standard. (Retention time: 6.38 min, GC yield: 83%)
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), cyclohexene 35 (51 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 25 ml_ pressure tube under an argon atmosphere in a glove box. The pressure tube was taken out of the glove box and heated at 100 °C for 16 hours.
• reaction was cooled down to room temperature, and n-dodecane (100 ⁇ _) as internal standard was added to the solution.
• the reaction mixture was analyzed by GC and the yield of 36 determined by comparing their peak areas to that of the internal standard. (Retention time: 7.62 min, GC yield: 91 %)
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), cyclooctene 37 (65 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 mL, 2.50 mmol), norbornene 7 (47.1 mg, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 mL, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 mL) prepared in a 25 mL pressure tube under an argon atmosphere in a glove box. The pressure tube was taken out of the glove box and heated at 100 °C for 16 hours.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), 43 (126.7 mg, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 25 ml_ pressure tube under an argon atmosphere in a glove box. The pressure tube was taken out of the glove box and heated at 100 °C for 16 hours.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), styrene 9 (57.5 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), 2-methylstyrene 13 (65 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), 4-vinylanisole 15 (66.5 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 mL, 2.50 mmol), 4-fluorostyrene 17 (60 ⁇ , 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 mL, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 mL, 2.50 mmol), allyltriphenylsilane 27 (150.2 mg, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 mL, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 ⁇ / ⁇ ) in toluene (1 .0 mL) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• the Schlenk tube connected with a reflux condenser was taken out of the glove box, and was subsequently connected to a continuous flow of argon (positive pressure: 0.4 bar) and heated at 130 °C for 16 hours. After cooling to room temperature, the reaction mixture was analyzed by GC (Temperature program: 15°C/min to 180°C; 15°C/min to 300°C; 300°C (15 min)) and the regioselectivity of 28 determined by comparing their peak areas (l/b: 84/16).
• reaction was cooled down to room temperature, and n-dodecane (100 ⁇ _) as internal standard was added to the solution.
• the reaction mixture was analyzed by GC and the yield of 26 determined by comparing their peak areas to that of the internal standard. (GC yield: 88%, ratio of regioisomers: 58/29/13, retention time:
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), 3,3-dimethyl-1 -butene 29 (65 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 25 ml_ pressure tube under an argon atmosphere in a glove box. The pressure tube was taken out of the glove box and heated at 100 °C for 16 hours.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), 1 -octene 31 (78.5 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• the Schlenk tube with a reflux condenser was taken out of the glove box, and was subsequently connected to a continuous flow of argon (positive pressure: 0.4 bar) and heated at 130 °C for 16 hours. After that time, the reaction was cooled down to room temperature, and n-dodecane (100 ⁇ _) as internal standard was added to the solution. The reaction mixture was analyzed by GC and the yield of desired product determined by comparing their peak areas to that of the internal standard. (GC yield: 90%, ratio of regioisomers: 48/32/1 1/9, retention time: 9.70, 8.95, 8.81 , 8.71 min respectively).
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), trans-4-octene 39 (78.5 ⁇ _, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• the Schlenk tube connected with a reflux condenser was taken out of the glove box, and was subsequently connected to a continuous flow of argon (positive pressure: 0.4 bar) and heated at 130 °C for 16 hours. After that time, the reaction was cooled down to room temperature, and n-dodecane (100 ⁇ _) as internal standard was added to the solution. The reaction mixture was analyzed by GC and the yield of desired product determined by comparing their peak areas to that of the internal standard. (GC yield: 98%, ratio of regioisomers: 46/30/12/12, retention time: 9.70, 8.95, 8.81 , 8.71 min respectively).
• Isovaleronitrile 5 (0.26 mL, 2.50 mmol), /V-vinylcarbazole 40 (96.6 mg, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 mL, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 mL) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), camphene 47 (68 mg, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 10 mL Schlenk tube under an argon atmosphere in a glove box.
• Isovaleronitrile 5 (0.26 ml_, 2.50 mmol), diphenylacetylene 23 (89 mg, 0.50 mmol) and 1 .0M solution of AIMe 2 CI in hexane (0.10 ml_, 0.10 mmol) were added sequentially to a solution of Ni(COD) 2 (6.9 mg, 5 mol%) and DPEphos (13.5 mg, 5 mol%) in toluene (1 .0 ml_) prepared in a 25 ml_ pressure tube under an argon atmosphere in a glove box. The pressure tube was taken out of the glove box and heated at 100 °C for 16 hours.
• Example 23 refers to a Scale-up experiment as illustrated in Figure 3B.
• Styrene 9 (4.58 ml_, 40 mmol) and 1 .0M solution of AIMe 2 CI in hexane (3.2 ml_, 3.2 mmol, 8 mol%) were added sequentially to a solution of Ni(COD) 2 (220.0 mg, 2 mol%) and DPEphos (430.8 mg, 2 mol%) in butyronitrile 4 (80 ml_) prepared in a 250 ml_ round bottle flask under an argon atmosphere in a glove box.
• the flask with a reflux condenser was taken out of the glove box, and was then connected to a continuous flow of argon (positive pressure: 0.4 bar) and heated at 130 °C for 16 hours. After cooling to room temperature, the reaction was quenched with methanol and the mixture was filtered through celite to remove the solid. The reaction mixture was analyzed by GC and the regioselectivity of 10 determined by comparing their peak areas (l/b: 82/18). The methanol and butyronitrile were distilled off under vacuum. The residue was directly purified by bulb-to-bulb distillation (Buchi Glass oven B-585) to give the desired product in 94% yield (4.95 g)-
• reaction mixture was stirred for 16 hours at 28 °C. After that time, the reaction mixture was concentrated under reduced pressure and the residue purified by flash column chromatography on silica gel (100% pentane) to 70 (49.0 mg, yield: 71 %).
• the inventors have shown in the above experimental results that a metal- catalyzed, in particular, Ni-catalyzed transfer hydrocyanation reaction between alkyl nitriles and alkenes can be fully manipulated to produce either product selectively using simple driving forces.
• This exceptionally powerful synthetic tool could be applied to the catalytic hydrocyanation and retro-hydrocyanation of a wide range of structurally different molecules (>40 examples) without relying on the use of highly toxic HCN.
• the functional group metathesis strategy delineated in this invention will likely be a milestone in the development of reversible hydrofunctionalization reactions of alkenes that do not rely on the use of hazardous gases.

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