Directed regioselective ortho,ortho'-magnesiations of aromatics and heterocycles using sBu2Mg in toluene.

Aryl azoles are ubiquitous as bioactive compounds and their regioselective functionalization is of utmost synthetic importance. Here, we report the development of a toluene-soluble dialkylmagnesium base sBu2Mg. This new reagent allows mild and regioselective ortho-magnesiations of various N-arylated pyrazoles and 1,2,3-triazoles as well as arenes bearing oxazoline, phosphorodiamidate or amide directing groups. The resulting diarylmagnesium reagents were further functionalized either by Pd-catalyzed arylation or by trapping reactions with a broad range of electrophiles (aldehydes, ketones, allylic halides, acyl chlorides, Weinreb amides, aryl halides, hydroxylamine benzoates, terminal alkynes). Furthermore, several double ortho,ortho'-magnesiations were realized in the case of aryl oxazolines, N-aryl pyrazoles as well as 2-aryl-2H-1,2,3-triazoles by simply repeating the magnesiation/electrophile trapping sequence allowing the preparation of valuable 1,2,3-functionalized arenes. This journal is © The Royal Society of Chemistry.

Introduction

The directed magnesiation of arenes and heteroarenes is an important synthetic tool for the preparation of polyfunctional aryl- and heteroaryl-magnesium organometallics.[1] Mixed magnesium and lithium amides R2NMgX·LiCl are usually the most efficient reagents for such metalations.[2] Recently, we have examined the regioselective metalation of various pharmaceutically relevant aryl azoles such as 1.[3] We found that standard metal amides such as LDA or TMPLi (TMP = 2,2,6,6-tetramethylpiperidyl) gave the lithiated products 2 with poor regioselectivity, due to a competitive deprotonation at the 5-position of the triazole ring of 1. The best result was achieved in toluene[4] using the alkylmagnesium amide TMPMgBu[5] prepared from commercial Bu2Mg, which provided after cross-coupling with aryl bromides various products of type 3. Although this base was highly regioselective in toluene, an excess of ArBr was required to compensate the formation of the Ar-nBu side-product, originating from a faster cross-coupling of the nBu moiety compared to the metalated azole 2 (Scheme 1).

Scheme 1

(a) Regioselective magnesiation and subsequent Negishi cross-coupling of aryl azoles (1) using TMPMgBu in toluene/hexane. (b) Regioselective magnesiation and ortho,ortho′-functionalization of arenes and heteroarenes using sBu2Mg in toluene.

While commercially available Bu2Mg contained a 60 : 40 mixture of nBu2Mg and sBu2Mg, we have found only small amounts of the branched coupling side-product Ar-sBu, suggesting that the secondary alkyl moiety was reacting much slower than the primary one.

Herein, we report the preparation of sBu2Mg,[6] which avoided these side reactions and significantly increased the metalation scope. Thus, we showed that sBu2Mg was an improved magnesiation reagent, which allowed a highly ortho-regioselective magnesiation of arenes 4 bearing various directing groups (DG), leading after trapping of the resulting diarylmagnesium species 5 with various electrophiles E1 to products of type 6. These polyfunctional arenes were in several cases magnesiated again using sBu2Mg producing, after addition of a second different electrophile E2, valuable 1,2,3-polyfunctional arenes of type 7.

Results and discussion

The reaction of sBuMgCl in diethyl ether with sBuLi (1.0 equiv.) in cyclohexane at 25 °C (2 h) gave, after solvent evaporation under vacuum, redissolution in toluene and filtration, a 0.43–0.48 M solution of sBu2Mg in 96% yield.[7,8]

In preliminary experiments, we have observed a smooth magnesiation of oxazoline 8a with a toluene solution of 0.6 equiv. of sBu2Mg leading to the diarylmagnesium 9a (Table 1). A full conversion to the diarylmagnesium species was achieved within 1 hour and the iodolyzed product 10a was isolated in 80% yield (entry 1). sBu2Mg gave also good results in cyclohexane or THF, albeit in lower yields (entries 2 and 3). cHex2Mg in toluene delivered the desired product 10a in only 46% yield and other bases such as Ph2Mg, (TMSCH2)2Mg and tBu2Mg or sBuMgCl[9] did not give any conversion (entries 4–8).

Magnesiation of oxazoline 8a using various magnesium reagents in various solvents at 25 °C

Entry	Reagent	Solvent	Yielda
1	sBu2Mg	Toluene	91% (80)c
2	sBu2Mg	THF	73%
3	sBu2Mg	Cyclohexane	64%
4	cHex2Mg	Toluene	46%
5	tBu2Mg	Toluene	0%
6	(TMSCH2)2Mg	Toluene	0%
7	Ph2Mg	Toluene	0%
8	sBuMgClb	Ether/toluene	0%

Calibrated GC-yield using undecane as internal standard.

1.2 equiv. of sBuMgCl were used.

Isolated yield.

Therefore, a range of oxazolines (8a–d) were magnesiated selectively on the aryl ring and the resulting diarylmagnesiums (9a–d) underwent Negishi cross-couplings,[10] copper-catalyzed allylation or acylation,[11]in situ Sonogashira cross-coupling[12] or trapping reactions with tetrachlorodibromoethane or dicyclopropylketone, leading to the mono–ortho substituted oxazolines 10b–j in 68–98% yield (Scheme 2).

Scheme 2

Regioselective magnesiation of oxazolines 8a–d with sBu2Mg leading, via diarylmagnesium species 9a–d, to functionalized oxazolines 10b–j. All yields refer to isolated compounds. Magnesiation conditions. The reaction was catalyzed by CuCN·2LiCl (20 mol%). Obtained after transmetalation with ZnCl2 (1.1 equiv.) and a palladium-catalyzed cross-coupling with [PdCl2(dppf)] (5 mol%, dppf = diphenylphosphinoferrocene) and an aryl halide (0.83 equiv.). Obtained after transmetalation with ZnCl2 (1.1 equiv.), subsequent iodine quench (1.1 equiv.) and Sonogashira cross-coupling with CuI (4 mol%), Pd(dba)2 (3 mol%, dba = dibenzylideneacetone), tri-(2-furyl)-phosphine (6 mol%) and phenylacetylene (1.3 equiv.).

Most of the C–H activation methods currently available for the arylation of aryl azoles were performed by using transition metal catalysts and suffered from the unwanted formation of symmetrical bis-arylated products and the selective preparation of unsymmetrical ortho–ortho′-bis-functionalized[13] aryl azoles remained challenging.[14] We have found that various oxazolines 10g–j were again magnesiated at 40–60 °C with sBu2Mg in toluene (Scheme 3).[15] The intermediate diarylmagnesium species were further functionalized by a copper-catalyzed allylation, Negishi cross-coupling, cobalt-catalyzed electrophilic amination[16] and iodolysis furnishing the desired products 11a–e in 74–93% yield. Interestingly, magnesiation of 10j followed by trapping with benzaldehyde and subsequent treatment with 6 M HCl provided lactone 11f in 56% yield.[17]

Scheme 3

Regioselective magnesiation of mono-functionalized oxazolines 10g–j, leading to ortho,ortho′-functionalized oxazolines 11a–f. All yields refer to isolated compounds. Magnesiation conditions. The reaction was catalyzed by CuCN·2LiCl (20 mol%). Obtained after transmetalation with ZnCl2 (1.1 equiv.) and a palladium-catalyzed cross-coupling with [PdCl2(dppf)] (5 mol%) and an aryl iodide (0.83 equiv.). Obtained after transmetalation with ZnCl2 (1.1 equiv.) and a cobalt-catalyzed electrophilic amination with CoCl2 (5 mol%) and morpholino benzoate (1.2 equiv.). Obtained after addition of benzaldehyde (1.2 equiv.) followed by treatment with 6 M HCl.

To demonstrate the versatility of the oxazoline directing group, the strongly sterical hindered ortho,ortho′-functionalized oxazoline 11b was successfully converted to the corresponding nitrile 11g using thionyl chloride and DMF[18] in 92% yield (Scheme 4).[19]

Scheme 4

Transformation of ortho,ortho′-functionalized oxazoline 11b to the corresponding nitrile 11g. Isolated yield.

We then turned our attention to the magnesiation of various N-aryl pyrazoles (12a–c). sBu2Mg proved also to be an excellent base for the regioselective magnesiation of N-aryl pyrazole 12a, affording the corresponding bis-arylmagnesium species 13a after 0.5 h at 40 °C. After addition of benzaldehyde or Weinreb amide MeCON(OMe)Me, alcohol 14a and ketone 14b were obtained in 74–86% yield (Scheme 5). Copper-catalyzed allylation with 3-bromocyclohex-1-ene produced the pyrazole 14c (90% yield). Interestingly, N-aryl pyrazoles 12b and 12c although bearing relatively acidic protons at the heterocyclic ring were selectively magnesiated at the ortho-position of the phenyl ring. In particular, unsubstituted pyrazole 12c was metalated in 94% yield and >98 : 1 : 1 selectivity, as determined by deuterolysis of a reaction aliquot.[20] These results further confirm the key role of the coordination at the N(2)-atom of the pyrazole to direct the metalation selectively on the aryl ring in a non-polar solvent like toluene. Thus, the functionalized pyrazoles 14d–f were obtained after Negishi cross-coupling with 5-bromopyrimidine, 5-bromobenzo[d][1,3]dioxole or addition of furfural in 64–90% yield. We also achieved an unsymmetrical ortho,ortho′-functionalization and mono-substituted pyrazole 14f was selectively magnesiated at 60 °C (0.5 h) and trapped by Negishi cross-coupling with 6-iodoquinoline and 4-iododibenzo[b,d]thiophene providing the products 15a–b in 67–84% yield (Scheme 6).

Scheme 5

Regioselective magnesiation of N-aryl pyrazoles 12a–c with sBu2Mg leading, via diarylmagnesium species 13a–c, to functionalized N-aryl pyrazoles 14a–f. All yields refer to isolated compounds. Magnesiation conditions. The reaction was catalyzed by CuCN·2LiCl (20 mol%). Obtained after transmetalation with ZnCl2 (1.1 equiv.) and a palladium-catalyzed cross coupling with [PdCl2(dppf)] (5 mol%) and an aryl bromide (0.83 equiv.).

Scheme 6

Regioselective magnesiation of mono-functionalized N-aryl pyrazole 14f with sBu2Mg leading to ortho,ortho′-functionalized N-aryl pyrazoles 15a–b. All yields refer to isolated compounds.

The functionalization of less common heterocycles is of key importance for pharmaceutical applications.[21] Thus, the metalation of symmetrical 2-aryl-2H-1,2,3-triazoles 16a–b was then investigated (Scheme 7).[22,23] After metalation of 16a with 0.6 equiv. of sBu2Mg for 15 min at 40 °C, the resulting bis-arylmagnesium species 17a was then trapped with furfural, affording the functionalized 1,2,3-triazole 18a in a 68% yield. Further trapping reactions such as Negishi cross-coupling, copper-catalyzed allylation and oxidative alkynylation with (phenylethynyl)lithium[24] lead to 2-aryl-1,2,3-triazoles 18b–d in 52–66% yield. Similarly, 1,2,3-triazole 16b was readily magnesiated at 25 °C (0.5 h) as shown by the quantitative formation of a single regioisomer by NMR-analysis of a deuterolyzed reaction aliquot.[20] Further quenching reactions of 17b like thiomethylation and allylation furnished triazoles 18e–f in 82–91% yield. A second functionalization was performed on N-aryl triazoles 18d–f using again sBu2Mg in toluene, followed by quench with a different electrophile (E2) (Scheme 8). We observed a complete magnesiation of 18d with sBu2Mg within 15 min at 40 °C and a subsequent reaction with benzaldehyde produced the mixed bis-functionalized 1,2,3-triazole 19a in 42% yield. Similarly, 18e and 18f were magnesiated under the standard conditions and the resulting bis-arylmagnesium species were trapped with a different electrophile (E2) leading to a range of unsymmetrical functionalized 1,2,3-triazoles 19b–f in 70–88% yield.

Scheme 7

Regioselective magnesiation of 2-aryl-2H-1,2,3-triazoles 16a–b with sBu2Mg leading, via diarylmagnesium species 17a–b, to functionalized 2-aryl-2H-1,2,3-triazoles 18a–f. All yields refer to isolated compounds. Magnesiation conditions. 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.). Obtained after transmetalation with CuCN·2LiCl (1.2 equiv.) and subsequent addition of (phenylethynyl)lithium (2.0 equiv.), followed by addition of chloranil (1.3 equiv.). The reaction was catalyzed by CuCN·2LiCl (20 mol%).

Scheme 8

Regioselective magnesiation of mono-functionalized 2-aryl-2H-1,2,3-triazoles 18d–f with sBu2Mg leading to ortho,ortho′-functionalized 2-aryl-2H-1,2,3-triazoles 19a–f. All yields refer to isolated compounds. Magnesiation conditions. The regioselectivity was determined by crystal structure analysis, see ESI.† The reaction was catalyzed by CuCN·2LiCl (20 mol%). The reaction was catalyzed by CuI (10 mol%). Obtained after transmetalation with ZnCl2 (1.1 equiv.) and a palladium-catalyzed cross-coupling with [PdCl2(dppf)] (5 mol%) and an aryl bromide (0.83 equiv.).

Finally, we examined the metalation of 1-aryl-1H-1,2,3-triazoles such as 20a–e and found that sBu2Mg led to a highly regioselective magnesiation at the ortho-position of the aryl ring in toluene (25–40 °C, 0.5–1 h), affording the bis-aryl-magnesium species 21a in 75% yield and 97 : 3 regioselectivity (Scheme 9).[20]

Scheme 9

Regioselective magnesiation of 1-aryl-2H-1,2,3-triazoles 20a–e with sBu2Mg leading, via diarylmagnesium species 21a–e, to functionalized 1-aryl-2H-1,2,3-triazoles 22a–h. All yields refer to isolated compounds. Magnesiation conditions. 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.). The reaction was catalyzed by CuCN·2LiCl (20 mol%). The regioselectivity was determined by crystal structure analysis, see ESI.†

This new metalation procedure occurred twice as fast as the previously reported TMPMgBu base.[3] 1,2,3-Triazoles 22a and 22b were isolated in 93% and 67% yields respectively after Negishi cross-couplings with only 0.83 equiv. of aryl bromide.[3] Copper-catalyzed acylation[11] with benzoyl chloride lead to products 22c and 22d in 55–58% yield and quenching with various aldehydes afforded compounds 22e–h in 69–80% yield.

Remarkably, sBu2Mg was also an excellent base for the magnesiation of various arenes bearing directing groups such as a tertiary amide or phosphorodiamidate (23a–j; Scheme 10).[25] The addition of sBu2Mg to the aromatic amide 23a in toluene led to a clean magnesiation within 0.5 h at room temperature. The resulting diarylmagnesium species 24a was then further allylated with allyl and cyclohexenyl bromides, leading to 25a and 25b in 62% and 71% yield respectively. Copper-catalyzed acylation of 23a with thiophene-2-carbonyl chloride or trapping with furfural furnished the ketone 25c (64% yield) and the lactone 25d (76% yield).[26] Similarly, the amides 23b–f afforded with the same magnesiation/trapping sequence the polyfunctional amides (25e–i) in 61–72% yield. Various phosphorodiamidates (23g–j) were also metalated with sBu2Mg at 40–60 °C (0.5–1 h) providing the diarylmagnesiums 24g–j, which were trapped with a range of electrophiles (MeSSO2Me, I2, cHexCHO and (BrCCl2)2) furnishing the phenol derivatives 25j–m in 68–98% yield. Removal of the phosphorodiamidate group[27] in 25m was achieved with a 2 M HCl treatment in dioxane (105 °C, 1 h) leading to phenol 25n in 88% yield. Interestingly, 1-propyl-1,2,4-triazole (23k) was magnesiated with sBu2Mg and allylated with cinnamyl bromide providing the N-heterocycle 25o in 86% yield.[28]

Scheme 10

Regioselective magnesiation of various arenes bearing an amide or a phosphorodiamidate directing group as well as 1-propyl-1,2,4-triazole 23a–k with sBu2Mg leading, via diarylmagnesium species 24a–k, to functionalized arenes 25a–o. All yields refer to isolated compounds. Magnesiation conditions. The reaction was catalyzed by CuCN·2LiCl (20 mol%). R = P(O)(NMe2)2. Obtained after treating 25m with 2 M HCl in dioxane (105 °C, 1 h).

We performed some further transformations leading to polyfunctionalized 1,2,3-trisubstituted arenes to show the utility of these magnesiations. The newly prepared amide 25b was thus selectively reduced with Cp2Zr(H)Cl[29] (25 °C, 15 min) to the aldehyde 26a in 90% yield. A two–step transformation consisting of a reduction with the complex borohydride LiH3BPyrr (Pyrr = pyrrolidino)[30] followed by a treatment with ethyl chloroformate[31] provided the benzylic chloride 26b in 85% overall yield (Scheme 11).

Scheme 11

Synthetic transformations of magnesiated product 25b. All yields refer to isolated compounds.

Conclusions

In summary, we have developed a new preparation of sBu2Mg in toluene and showed its utility for the directed magnesiation of various aromatic and heterocyclic systems including pharmaceutically relevant N-arylated pyrazoles as well as N-arylated 1,2,3-triazoles. This method provides a unique access to varius diarylmagnesium reagents in toluene. Furthermore, a range of arenes bearing various directing groups such as an oxazoline, phosphorodiamidate or an amide were magnesiated with sBu2Mg. Remarkably, a second unsymmetrical ortho,ortho′-functionalization was achieved in the case of aryl oxazolines, N-aryl pyrazoles as well as N-aryl triazoles, leading to valuable synthetic intermediates of potential pharmaceutical relevance. Further investigations of the use of sBu2Mg as metalating agent are currently underway in our laboratory.

Author contributions

A. H., J. P. P, S. B. D., F. T. and K. K. performed and analyzed the experiments. A. H., F. H. L., S. L., S. W. and P. K. designed the experiments. A. H., S. L., S. W., and P. K. prepared the manuscript with contributions of all authors.

Conflicts of interest

There are no conflicts to declare.