Process for the transition metal catalyzed cyanation of aryl/vinyl halides

Abstract

The present invention refers to a process for a transition metal, particularly nickel-catalyzed cyanation reaction of aryl/vinyl halide using organic nitrile compounds. This new reaction provides a strategically distinct approach to the safe preparation of aryl/vinyl cyanides, which are essential compounds in agrochemistry and medicinal chemistry.

Claims

1. A process comprising converting an aryl/vinyl halide/triflate (I) into an aryl/vinyl nitrile (III) using an alkylnitrile (II) as reagent in the presence of a transition metal coordinated to a ligand and a Lewis acid co-catalyst, and a base, optionally in a solvent, as represented in the following scheme: ##STR00010## Wherein: R.sup.c represents a C.sub.3 to C.sub.6 hydrocarbon chain which forms a five to eight-membered optionally substituted hydrocarbon ring system with the vinyl moiety; X represents halogen or triflate, R.sup.n represents a C.sub.3 to C.sub.12 alkyl group; the coordinated transition metal catalyst comprises a metal selected from a metal of the Iron-group, Cobalt-group, Nickel-group or Copper group; the ligand is selected from compounds having the ability to coordinate to said transition metal; the Lewis acid co-catalyst is selected from compounds of aluminum, boron, zinc, titanium, scandium, and the base is selected from common inorganic or organic bases having 5<pKa conjugated acid <35.

2. Process according to claim 1 wherein R.sup.c represents a C.sub.3 to C.sub.6 hydrocarbon chain which forms a five to eight-membered optionally substituted hydrocarbon ring system with the vinyl moiety which ring system may be a cycloalkyl, heterocycloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl hydrocarbon, which may be part of a hydrocarbon ring system having up to 30 carbon atoms and which may optionally be substituted by one or more groups selected from alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or a heterosubstituent.

3. Process according to claim 1 wherein R.sup.c represents a C.sub.3 to C.sub.4 hydrocarbon chain which forms a five to six membered optionally substituted aromatic or heteroaromatic hydrocarbon ring system with the vinyl moiety, which may be part of a hydrocarbon ring system having up to 30 carbon atoms and which may optionally be substituted by one or more groups selected from alkyl, cycloalkyl, heterocycloalkyl, alkenyl, alkynyl, aryl, aralkyl, heteroaryl, heteroaralkyl or a heterosubstituent.

4. Process according to claim 1 wherein R.sup.n is a R.sup.n represents a straight chain C.sub.6 to C.sub.9 alkyl group.

5. Process according to claim 1, wherein the coordinated transition metal catalyst is obtained from a transition metal catalyst precursor selected from Ni(COD).sub.2, Ni(acac).sub.2, Ni(CO).sub.4, Pd(dba).sub.2, Pd(OAc).sub.2, Co.sub.2(CO).sub.8.

6. Process according to claim 1 wherein the ligand of the coordinated transition metal catalyst is selected from compounds having the ability to coordinate to said transition metal selected from phosphorous-, nitrogen-, As-, Sb- or N-heterocyclic based ligands.

7. Process according to claim 1, wherein the ligand is selected from the group consisting of phosphine ligands, particularly PPh.sub.3, PCy.sub.3, P(OPh).sub.3, PEt.sub.3, BINAP, Xanthphos, DuPhos, DPEPhos, dppf, dppe, and mixtures thereof.

8. Process according to claim 1, wherein the Lewis acid co-catalyst is selected from AlMe.sub.3, Al(isobutyl).sub.3, AlMe.sub.2Cl, AlMeCl.sub.2, AlCl.sub.3, BPh.sub.3, B(C.sub.6F.sub.5).sub.3, Zn(OTf).sub.2, ZnCl.sub.2, TiCl.sub.4, Sc(OTf).sub.3.

Description

(1) The invention is further illustrated in the attached drawings and the following experimental section below.

(2) In the attached drawings:

(3) FIG. 1 illustrates options for the optimization of reaction conditions;

(4) FIG. 2 illustrates the scope of nickel-catalyzed transfer cyanation of aryl chlorides; and

(5) FIG. 3 illustrates Nickel-catalyzed transfer cyanation of aryl and vinyl triflates.

EXPERIMENTAL PART

(6) To test their hypothesis, the inventors selected butyronitrile 2a as an inexpensive reagent (˜80€/L) to cyanate aryl chloride 1a (Table 1). The choice of 2a as cyanating agent is accounted for its low price, low-molecular weight and high volatility of the corresponding alkene by-product. After careful evaluation of reaction parameters, the inventors found that a combination of inexpensive and bench-stable Ni(acac).sub.2, Xantphos, Al(isobutyl).sub.3 as co-catalyst, Zn as reducing agent to generate Ni(0) and K.sub.3PO.sub.4 as base in toluene at 120° C. gave the best result within 12 hours, delivering 3aa in 88% GC yield (entry 1). It is noteworthy that undesired homodimerization or Heck-type reactions were not observed under the reaction conditions. The results of ligand optimization showed that the use of a bidentate ligand with a smaller bite angle hampered the reactivity of this cyanation reaction, and no product was detected when the reaction was treated with a monodentate phosphine ligand (entries 2 and 3). As shown in entries 4-8, the use of other precatalysts or co-catalysts resulted either in lower yields of 3aa or no product formation, indicating that an aluminium Lewis acid plays a critical role in the activation of the C—CN bond. Likewise, other bases or reducing agent had a deleterious effect on the outcome of the reaction (entries 9-11). Lower yields of 3aa were obtained when the reaction was treated with fewer equivalents of 2a (entry 12), probably reflecting the slower rate of retro-hydrocyanation relative to the oxidative addition of the aryl chloride.

(7) With optimized conditions in hand, the inventors examined the substrate scope of this nickel-catalyzed transfer cyanation of aryl chlorides. As shown in table 2 illustrating the scope of nickel-catalyzed transfer cyanation of aryl chlorides, substrates bearing electron donating or withdrawing substituents, whether they were at the para, meta or even ortho position, reacted well under our optimized reaction conditions (3ba-3ja), revealing a good tolerance to steric and electronic effects. Naphthyl and 9-phenanthryl chlorides can also be converted to the corresponding aryl nitriles in good yields (3la, 3ma). Several nitrogen and oxygen heterocycles relevant to the drug discovery process, such as pyrrole, morpholine, dioxole and indole, could be efficiently tolerated by the catalytic system (3oa-3sa).

(8) To demonstrate the robustness and generality of the inventive method, the inventors extended the scope to aryl and vinyl triflates as another important class of electrophiles. Despite the fact that triflate electrophiles, which can be easily accessed from phenols or aliphatic ketones, are retrosynthetically complementary to halides, they have not been frequently used in transition-metal catalyzed cyanation reactions. In particular, few examples of nickel-catalyzed cyanation of aryl triflates have been reported, and these protocols all rely on highly toxic KCN as cyanating reagent.

(9) After a slight modification of the reaction conditions, the inventors found that several aryl and vinyl triflates can be successfully converted to the corresponding cyano products in good to excellent yields (62-97%) under mild reaction conditions (Ni(cod).sub.2, Xantphos, AlCl.sub.3, Et.sub.3N in toluene at 50-110° C. for 3-12 hours).

(10) As shown in Table 3, substrates bearing either electron deficient (3ta, 3ua) or electron donating groups (3fa, 3ca, 3ea, 3va) can be efficiently converted to aryl nitriles in excellent yields. Ortho substituted substrates reacted well under our reaction conditions, even though slightly lower yields were obtained (3ea, 3xa).

(11) A chemoselective reaction of the triflate electrophile could be realized in the presence of a chloride, furnishing the desired products in good yields (3ya, 3za). Heterocycles such as pyrrolidine, dioxole, carbazole, pyrazole and quinoline were well tolerated under our conditions (3ab, 3qa, 3bb, 3cb, 3db). Even unprotected indole and carbazole substrates could be well tolerated (3eb, 3fb). Interestingly, vinyl triflates efficiently afforded synthetically versatile vinyl nitriles in excellent yields (3gb). To further demonstrate the diversity and practicability of this developed method, a few natural products, such as 5-tocopherol, cholesterol and estrone, were transformed into the corresponding triflates before being subjected to the transfer cyanation conditions to obtain excellent yields of the desired products (3hb-3jb).

(12) Notably, the amount of the reagent can be reduced from 10 equiv. to 2 equiv. when the electrophile is slowly added to the reaction mixture (3aa).

(13) The method could also be employed on a preparative scale when the reaction was performed in an open system to facilitate the rapid release of the propene side-product (Scheme 2).

(14) ##STR00006##

(15) Several control reactions were then performed to gather preliminary information about the mechanism. The inventors demonstrated the occurrence of the proposed retro-hydrocyanation step through the detection of undecene isomers resulting from the retro-hydrocyanation of dodecanitrile (Scheme 3, eq. 1).

(16) The inventors also explored whether retro-hydrocyanation proceeds in the absence of electrophile. In this experiment, only small amounts of alkene isomers were observed, showing that retro-hydrocyanation cannot be performed efficiently in the absence of the electrophile. The normal reaction course resumed after addition of the electrophile, further suggesting that a direct transfer of the cyanide anion between two nickel(II)-species is the main pathway of the reaction (Scheme 3, eq. 2). Additional control experiments using a simple ammonium cyanide salt or acetone cyanohydrin as reagents did not give any conversion, further suggesting that our reaction is not proceeding through the in situ generation of an ammonium cyanide reagent (Scheme 3, eq. 3 and 4). Taken altogether, these experiments are best explained by a double catalytic cycle as presented in Scheme 2. Within this mechanistic context, the ability to drastically decrease the amount of butyronitrile reagent when the electrophile is slowly added to the reaction mixture (vide supra) highlights the critical importance of matching the rate of retro-hydrocyanation with that of aryl (pseudo)halide oxidative addition.

(17) ##STR00007##
General Procedure for the Cyanation of Aryl Chlorides

(18) ##STR00008##

(19) Under argon, to an 8.0 mL Screw-cap vial equipped with a magnetic stirring bar was added Ni(acac).sub.2 (2.6 mg, 5 mol %), Xantphos (5.8 mg, 5 mol %), Zn (2.0 mg, 15 mol %) and toluene (0.5 mL). The mixture was allowed to stir for 5 min. Then butyronitrile (138.2 mg, 2.0 mmol), aryl chloride (0.2 mmol), K.sub.3PO.sub.4 (84.9 mg, 0.4 mmol) and Al(isobutyl).sub.3 (25% in toluene, 31.7 mg, 20 mol %) were added sequentially to the resulting solution and the vial was sealed and placed on a heating plate (120° C.). After stirring for 12 hours, the reaction mixture was cooled to room temperature and quenched by adding two drops of water. The reaction mixture was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. Products were obtained after purification by flash column chromatography on silica gel. The scope of the obtainable products is illustrated in FIG. 2.

(20) General Procedure for the Cyanation of Aryl Triflates

(21) ##STR00009##

(22) Under argon, to an 16.0 mL Screw-cap vial equipped with a magnetic stirring bar was added Ni(COD).sub.2 (13.8 mg, 10 mol %), Xantphos (29.2 mg, 10 mol %) and toluene (0.5 mL). The mixture was allowed to stir for 5 min. Then butyronitrile (103.7 mg, 1.0 mmol), Et.sub.3N (139.0 μL, 1.0 mmol) and AlCl.sub.3 (40.0 mg, 60 mol %) were added sequentially to the resulting solution and the vial was sealed and placed to a heating plate (70° C.). Then a solution of aryl triflates (0.5 mmol) in toluene (1.5 mL) was slowly dosed into the stirring reaction mixture via syringe pump during 2-4 hours. Alternatively, the aryl triflate can in some cases also be directly added to the reaction mixture all at once. After an additional stirring for 1 hour at 50-70° C., the reaction mixture was cooled to room temperature and quenched by adding a few drops of water. The reaction mixture was dried over anhydrous Na.sub.2SO.sub.4 and concentrated under reduced pressure. Products were obtained after purification by flash column chromatography on silica gel. The scope of the obtainable products is illustrated in FIG. 3.

(23) In conclusion, a new transition metal, in particular nickel-catalyzed cyanation reaction has been developed, enabling the conversion of a broad range of aryl chlorides and aryl/vinyl triflates into aryl/vinyl nitriles using benign butyronitrile as reagent. The use of nontoxic and inexpensive butyronitrile as a cyanating agent not only addresses the safety issues encountered with most of the current cyanation reactions, but also overcomes other drawbacks by preventing catalyst deactivation and ensuring homogeneity of the reaction mixture. In a broader context, the inventors are convinced that the new concept delineated in this work, namely the merger of transfer functionalization and cross-coupling, will open new avenues in synthetic organic chemistry.