Preparation of Polyfunctionalized Aromatic Nitriles from Aryl Oxazolines.

A selective ortho,ortho'-functionalization of readily available aryl oxazolines by two successive magnesiations with sBu2 Mg in toluene followed by trapping reactions with electrophiles, such as (hetero)aryl iodides or bromides, iodine, tosyl cyanide, ethyl cyanoformate or allylic bromides (39 examples, 62-99 % yield) is reported. Treatment of these aryl oxazolines with excess oxalyl chloride and catalytic amounts of DMF (50 °C, 4 h) provided the corresponding nitriles (36 examples, 73-99 % yield). Conversions of these nitriles to valuable heterocycles are reported, and a tentative mechanism is proposed.

The preparation of highly substituted aromatic compounds is of great importance for pharmaceutical, agrochemical and material science applications. Especially, the selective preparation of ortho,ortho’‐trisubstituted aromatics are of importance. Various C−H activation methods allowed such ortho,ortho’‐functionalizations, however unsymmetrical ortho,ortho’‐derivatives were difficult to prepare. Recently, we have shown that the magnesiation of various N‐aryl azoles including aryl oxazolines may be achieved by selective metalation using the powerful base sBu2Mg in toluene. Although, such ortho,ortho’‐arylated heterocycles were useful on themselves but the generation of heterocycle‐free 1,2,3‐trisubstituted arenes would greatly enhance their synthetic potential. Thus, the preparation of newly ortho,ortho’‐functionalized aryl oxazolines would be much more relevant, if the oxazoline moiety could be converted to a carboxylate derivative. Such a conversion would valorize in general the chemistry of aryl oxazolines developed in pioneering work by Meyers, since this heterocycle is often difficult to cleave.

Aromatic nitriles are key intermediates for the preparation of various N‐heterocycles and represent valuable target molecules for various applications. They are usually prepared from various precursors such as aromatic aldehydes, hydrocarbons, carboxylic acid derivatives, halides or benzylic derivatives (see representative preparations in Scheme 1). In preliminary experiments, we have noticed that aryl oxazolines may be converted under harsh conditions (refluxing of a 2 : 1 mixture of thionyl chloride and DMF at 75 °C for 2 h) to the corresponding aromatic nitriles.

Scheme 1

a) Recent cyanation methods. b) Regioselective magnesiations of aryl oxazolines 1 using sBu2Mg in toluene furnishing ortho‐ and ortho,ortho’‐substituted oxazolines 2 and 3 and subsequent conversion to the corresponding nitriles 4 and 5.

Herein, we report the successive magnesiations of aryl oxazolines of type 1 providing ortho‐substituted aryl oxazolines of type 2 and ortho,ortho’‐substituted aryl oxazolines of type 3 and their conversion to the corresponding nitriles 4 and 5 (Scheme 1).

First, we have prepared a range of mono‐ortho‐substituted aryl oxazolines of type 2 starting from aryl oxazolines of type 1 by magnesiation with sBu2Mg[ , ] in toluene (0.48 M) prepared by the reaction of sBuMgCl with sBuLi (Scheme 2). In a typical experiment, we treated the phenyl oxazoline 1  a with sBu2Mg (0.6 equiv) for 1 h at 25 °C leading to the diarylmagnesium intermediate 6  a in toluene, which after transmetalation with ZnCl2 (1 M in THF, 1.1 equiv) and Negishi cross‐coupling with 1‐iodo‐3‐trifluorobenzene (0.83 equiv, 55 °C, 2 h) and PdCl2(dppf) (5 mol %, dppf=diphenylphosphinoferrocene) furnished the ortho‐substituted oxazoline 2  a in 73 % yield of analytically pure isolated product. Similarly, starting from 1  a and 1  b, we have prepared the related 2‐arylated oxazolines 2  b–f in 76–99 % yield.

Scheme 2

Regioselective magnesiation of oxazolines 1  a–i with sBu2Mg leading, via diarylmagnesium intermediates 6  a–i, to functionalized oxazolines 2  a–v. [a] All yields refer to analytically pure isolated compounds. [b] Magnesiation conditions. [c] Obtained after transmetalation with ZnCl2 (1.1 equiv) and a palladium‐catalyzed cross‐coupling with [PdCl2(dppf)] (5 mol%) and an aryl bromide or iodide (0.83 equiv). [d] Obtained after transmetalation with ZnCl2 (1.1 equiv) and a palladium‐catalyzed cross‐coupling with Pd(dba)2 (3 mol%), tfp (6 mol%) and an aryl bromide or iodide (0.83 equiv). [e] TMPMgCl⋅LiCl (2.0–3.0 equiv) was used for the magnesiation. [f] The reaction was catalyzed by CuCN⋅2LiCl (20 mol%).

Also, the 3,5‐dichlorophenyl oxazoline 1  c and the 3‐fluorophenyl oxazoline 1  d were magnesiated with sBu2Mg at 25 °C for 15 min furnishing the diarylmagnesium intermediates 6  c and 6  d. Trapping with various electrophiles such as iodine, tosyl cyanide, ethyl cyanoformate or (hetero)aryl iodides (Negishi cross‐coupling using Pd(dba)2 (3 mol %, dba=dibenzylideneacetone and tfp (6 mol %, tfp=tri(o‐furyl)phosphine) gave the expected products 2  g–m in 70–98 % yield. Electron‐rich substituted aryl oxazolines such as 1  e and 1  f as well as the 2‐naphthyl oxazoline 1  g were metalated with sBu2Mg as well as with TMPMgCl⋅LiCl[ , ] and were trapped with typical electrophiles providing the ortho‐substituted oxazolines 2  n–2  r in 65–98 % yield. Finally, the 1,4‐bisoxazolyl benzene 1  h or thienyl oxazoline 1  i were converted to the ortho‐substituted oxazolines 2  s–2  v in 92–98 % yield. With these oxazolines in hand, we have performed optimization experiments for their conversion to the corresponding nitriles. Thus, we have submitted the oxazoline 2  a to various conditions, leading to nitrile 4  a. We have noticed that thionyl chloride (used as solvent) was ineffective in the absence of DMF (entry 1 of Table 1) or in the presence of DMF (20 mol %) at 25 °C (entry 2). Heating to 50 °C, which presumably generates an intermediate immonium reagent (Me2N=C(H)Cl2); Vilsmeier reagent) led to the nitrile 4  a in 64 % calibrated GC‐yield (entry 3).

Table 1

Optimization of the dehydration reaction of oxazoline 2  a to nitrile 4  a.

Entry	Reagent	DMF [mol %]	T [°C]	Yield [%][a]
1	SOCl2	0	25	0
2	SOCl2	20	25	0
3	SOCl2	20	50	64
4	(COCl)2	0	25	traces
5	(COCl)2	20	25	47
6	(COCl)2	20	50	100 (98)[b]
7	(COCl)2 [c]	20	50	47

[a] Calibrated GC yield using undecane as internal standard. [b] Isolated yield. [c] 2.0 equiv of (COCl)2 in toluene were used.

Switching thionyl chloride to oxalyl chloride as solvent (0.2 M solutions) already provided 4  a at 25 °C (entries 4 and 5). Increasing the reaction temperature to 50 °C afforded the desired nitrile 4  a in quantitative GC‐yield (98 % isolated yield; entry 6). Using toluene as solvent and oxalyl chloride in small excess (2.0 equiv) was not satisfactory (entry 7). With these optimized conditions in hand, we have converted ortho‐substituted aryl oxazolines 2  a–b,d–l,n–v to the corresponding nitriles 4  a–u in 73–99 % yield (Scheme 3). Various functional groups like a CN, NO2, CO2Et, cyclohexenyl or thiopyridyl were compatible with the mild reaction conditions of this cyanation procedure.

Scheme 3

Transformation of ortho‐functionalized oxazolines 2  a–b,d–l,n–v to the corresponding nitriles 4  a–u. [a] All yields refer to isolated compounds. [b] SOCl2/DMF 2 : 1 (70 °C, 4 h) was used. [c] 5 h reaction time.

After these encouraging results, we have prepared various ortho,ortho’‐disubstituted oxazolines 3  a–i using sBu2Mg (0.6 equiv) in toluene between 40–70 °C with 0.5‐1 h reaction time in 64–93 % isolated yield. (Scheme 4). To our delight, the aryl oxazolines 3  a–i were readily converted in the corresponding nitriles 5  a–i in 82–99 % yield (Scheme 5). Remarkably, the scale‐up of this cyanation was performed in the case of 3  d providing the nitrile 5  d in multigram‐scale (3.1 g were prepared) in 97 % isolated yield.

Scheme 4

Regioselective magnesiation of ortho‐functionalized oxazolines 2  a–c,f,n with sBu2Mg leading to ortho,ortho’‐functionalized oxazolines 3  a–i. [a] All yields refer to isolated compounds. [b] Magnesiation conditions. [c] Obtained after transmetalation with ZnCl2 (1.1 equiv) and a palladium‐catalyzed cross‐coupling with [PdCl2(dppf)] (5 mol%) and an aryl halide (0.83 equiv). [d] Obtained after transmetalation with ZnCl2 (1.1 equiv) and a palladium‐catalyzed cross‐coupling with Pd(dba)2 (3 mol%), tfp (6 mol%) and an aryl halide (0.83 equiv). [e] Reaction was catalyzed by CuCN ⋅ 2LiCl (20 mol%).

Scheme 5

Transformation of ortho,ortho’‐functionalized oxazolines 3  a‐i to the corresponding nitriles 5  a–i. [a] All yields refer to isolated compounds.

Furthermore, we have treated ortho‐methoxy substituted aryl oxazolines 7  a and 7  b with various nucleophiles, as previously described by Meyers, resulting in substituted products of type 8. Thus, the reaction of the reaction of 7  a with cHexMgCl or exo‐norbornylmagnesium bromide (25 °C, 1 h) produced the alkylated derivatives 8  a–8  b in 81–96 % yield (Scheme 6).

Scheme 6

Nucleophilic aromatic substitution on ortho‐(methoxy)aryl oxazolines 7  a‐c furnishing functionalized aryl oxazolines 8  a–e and subsequent transformation to the corresponding nitriles 9  a–c. Multiple functionalizations on aryl oxazolines 8  a and 8  e and subsequent transformation to the corresponding nitriles 11 and 14. [a] All yields refer to isolated compounds.

Treatment of 7  b with piperidyllithium or vinylmagnesium bromide provided the aminated and vinylated products 8  c and 8  d respectively (62‐90 % yield). Applying the cyanation procedure afforded the aryl nitriles 9  a–c in 90–97 % yield (Scheme 7). Treatment of the alkylated oxazoline 8  a with sBu2Mg (60 °C, 1 h) and subsequent Negishi cross‐coupling furnished the ortho,ortho’‐functionalized aryl oxazoline 10 in 80 % yield, which was converted to the corresponding aromatic nitrile 11 in 99 % yield. Reacting the readily available 2‐methoxy oxazoline 7  c with cHexMgCl (25 °C, 1 h) furnished the ortho‐substituted oxazoline (8  e) in 75 % yield. Br/Mg‐exchange with iPrMgCl⋅LiCl produced an intermediate functionalized aryl magnesium derivative, which after treatment with tosyl cyanide (25 °C, 1 h) gave the nitrile 12 in 68 % yield. Subsequent magnesiation with TMPMgCl⋅LiCl followed by an iodolysis of the intermediate Grignard species led to the polyfunctional aryl iodide 13 in 77 % yield, which was converted by the usual procedure into the penta‐substituted dinitrile 14 in 96 % yield demonstrating the versatility of this approach for preparing highly substituted aryl nitriles.

Scheme 7

Transformation of aryl nitriles 4  e and 4  j to cyclic derivatives 15  a and 15  b. All yields refer to isolated compounds.Reaction conditions: i) MeLi (2.0 equiv), THF, 0 °C, 15 min. ii) H2O, I2 (4.0 equiv), K2CO3 (3.0 equiv), THF, 60 °C, 2 h. iii) Ti(OiPr)4 (1.1 equiv), EtMgBr (2.0 equiv), Et2O, 25 °C, 1 h.

Some of these nitriles were converted to cyclized derivatives by diverse methods. Thus, the nitrile 4  e was converted to the phenanthridine 15  a by an imino radical cyclization in 74 % yield. Treatment of 4  j using the Kulinkovich procedure (Ti(OiPr)4 and EtMgBr) in ether (25 °C, 1 h) furnished a spirocyclic lactam 15  b in 79 % yield.

A tentative reaction mechanism was proposed in Scheme 8. Thus, DMF was first converted with oxalyl chloride to the Vilsmeier‐reagent 16. Its reaction with the aryl oxazoline 1 provided the oxonium ion 17 which by a fragmentation led to the aryl nitrile 4 and to the amino‐derivative 18 which gave the iminium chloride 19 regenerating DMF and methallyl chloride in a further fragmentation step. Interestingly, the use of an aryl oxazoline such as 20 missing the two methyl groups necessary in the fragmentation process leading to a nitrile, gave no reaction under our standard conditions.

Scheme 8

Tentative reaction mechanism of the conversion of aryl oxazoline 1 to the aromatic nitrile 4.

In summary, a new method for preparing highly functionalized tri‐, tetra‐ and penta‐substituted aromatic nitriles by using successive magnesiations with sBu2Mg in toluene followed by trapping with a broad range of electrophiles associated with an efficient conversion of the oxazolyl directing group to a nitrile using oxalyl chloride and catalytic amounts of DMF (50 °C, 4 h) is reported.

Conflict of interest

The authors declare no conflict of interest.

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