DOI: 10.1002/chem.201101091

Nickel-Catalyzed C�H Arylation of Azoles with Haloarenes: Scope,Mechanism, and Applications to the Synthesis of Bioactive Molecules

Takuya Yamamoto,[a] Kei Muto,[a] Masato Komiyama,[b] J�r�me Canivet,[a]

Junichiro Yamaguchi,[a] and Kenichiro Itami*[a]

Introduction

Heterobiaryl compounds represent a predominant structuralmotif in many natural products and bioactive molecules.[1]

The construction of these motifs has been established bypalladium- or nickel-catalyzed cross-coupling reactions ofaryl–metal compounds with aryl halides, namely theKumada–Tamao–Corriu, Negishi, Migita–Kosugi–Stille,Suzuki–Miyaura, and Hiyama cross-coupling reactions.[2]

Meanwhile, a transition-metal-catalyzed direct C�H bondarylation[3] that avoids the need to prepare stoichiometricamounts of aryl–metal reagent is finding increased use inthe preparation of heterobiaryl compounds. We have alsocontributed to this area of research by developing variousdirect C�H bond arylation reactions that are catalyzed byRh, Ir, Cu, and Pd complexes.[4]

Functionalized 2-arylazoles are a class of heterobiarylcompounds present in many biologically active natural prod-ucts and pharmaceuticals (Scheme 1).[5–12] In 1992, Ohta andco-workers first reported a direct C�H bond arylationmethod that used a palladium catalyst. However, the meth-odology was somewhat limited in substrate scope.[13] In1998, Miura and co-workers made a breakthrough in thisarea by devising a more general palladium-catalyzed directarylation protocol of azoles with haloarenes [Eq. (1)].[14]

Since these pioneering works in direct C�H coupling, manyresearch groups have been involved in finding new methodsfor the synthesis of 2-arylazoles using palladium catalysts.[15]

Ellman, Bergman, and co-workers reported a rhodium-cata-lyzed arylation of azoles with aryl bromides that is likely toproceed through a different mechanism.[16]

In spite of their utility, palladium and rhodium catalystsare expensive, even when used in catalytic amounts. In 2007,Daugulis and co-workers described a copper-catalyzed C�Harylation of azoles with haloarenes that was an importantbreakthrough in terms of catalyst cost.[17a] Subsequently,Miura and co-workers reported similar results.[17b] Our goalhas been to develop this type of C�H arylation reaction inan inexpensive and operationally simple manner, whilemaintaining high reactivity and broad substrate scope. Con-

[a] T. Yamamoto, K. Muto, Dr. J. Canivet, Dr. J. Yamaguchi,Prof. Dr. K. ItamiDepartment of ChemistryGraduate School of ScienceNagoya University, ChikusaNagoya 464-8602 (Japan)Fax: (+81) 52-788-6098E-mail : itami.kenichiro@a.mbox.nagoya-u.ac.jp

[b] M. KomiyamaPharmaceutical Development Research LaboratoriesTeijin Pharma Limited3-2, Asahigaoka 4-chomeHino, Tokyo 191-8512 (Japan)

Supporting information for this article is available on the WWWunder http://dx.doi.org/10.1002/chem.201101091.

Abstract: Novel nickel-based catalyticsystems for the C�H arylation ofazoles with haloarenes and aryl triflateshave been developed. We have estab-lished that Ni ACHTUNGTRENNUNG(OAc)2/bipy/LiOtBuserves as a general catalytic system forthe coupling with aryl bromides and io-dides as aryl electrophiles. For cou-plings with more challenging electro-philes, such as aryl chlorides and tri-flates, the Ni ACHTUNGTRENNUNG(OAc)2/dppf (dppf= 1,1’-bis(diphenylphosphino)ferrocene)system was found to be effective. Thi-

ACHTUNGTRENNUNGazoles, benzothiazoles, oxazoles, ben-zoxazoles, and benzimidazoles can beused as the heteroarene coupling part-ner. Upon further investigation, we dis-covered a new protocol for the presentcoupling using Mg ACHTUNGTRENNUNG(OtBu)2 as a milderand less expensive alternative to

LiOtBu. Attempts to reveal the mecha-nism of this nickel-catalyzed hetero-biaryl coupling are also described. Thisnewly developed methodology hasbeen successfully applied to the synthe-ses of febuxostat (a xanthine oxidaseinhibitor that is effective for the treat-ment of gout and hyperuricemia), tafa-midis (effective for the treatment ofTTR amyloid polyneuropathy), andtexaline (a natural product having anti-tubercular activity).

Keywords: C�H functionalization ·cross-coupling · drug discovery ·heterocycles · natural products ·nickel

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sidering these factors, we searched for a novel catalyst, andfinally developed the nickel-catalyzed C�H arylation ofazoles with aryl halides and triflates in 2009.[4e] It should bementioned that the group of Miura also came to a similarconclusion almost simultaneously.[18] Since these discoveries,nickel-catalyzed direct heterobiaryl couplings using arylsi-lanes or arylboronic acids have been reported.[19,20]

In this article, we disclose: 1) a broad evaluation of sub-strate scope and limitations of Ni-catalyzed C�H arylationof azoles with haloarenes; 2) the establishment of a newprotocol using MgACHTUNGTRENNUNG(OtBu)2 as a milder and less expensive al-ternative to LiOtBu; 3) our attempts to reveal the mecha-nism of this nickel-catalyzed coupling; and 4) the applicationof Ni-catalyzed C�H arylation to the synthesis of febuxostat(a xanthine oxidase inhibitor that is effective for the treat-ment of gout and hyperuricemia),[5] tafamidis (effective forthe treatment of TTR amyloid polyneuropathy),[6] and texa-line (a natural product having antitubercular activity).[12]

Results and Discussion

Discovery of Ni-catalyzed C�H arylation of azoles withhalo ACHTUNGTRENNUNGarenes : We began our studies by examining variousnickel salts, ligands, and alkalinic additives in the reaction ofbenzothiazole (1 A) and iodobenzene (2 a). After extensivescreening, we found that Ni ACHTUNGTRENNUNG(OAc)2/2,2’-bipyridyl (bipy)could serve as an efficient catalyst in the presence ofLiOtBu. For example, the cross-coupling product 2-phenyl-benzothiazole (3 Aa) was obtained in 64 % yield when thereaction was carried out in THF at 85 8C for 18 h, represent-ing our “early” conditions (Scheme 2). Listed in Scheme 2

are some examples of variations from these early condi-tions.[21]

In the absence of a nickel source, almost none of the de-sired coupling was observed. Nickel complexes such as [Ni-ACHTUNGTRENNUNG(cod)2] (55 %) and NiCl2 (55 %) were moderately effective,but Ni ACHTUNGTRENNUNG(NO3)2·6 H2O and NiSO4·6 H2O were much less effec-tive. We have also determined that bidentate nitrogen-basedligands furnish efficient catalysts. Whereas bipy (64 %), 4,4’-(tBu)2bipy (70 %), and phenanthroline (52 %) promoted thecoupling, diphosphanes such as 1,2-bis(diphenylphosphino)-ethane (dppe) and 1,1’-bis(diphenylphosphino)ferrocene(dppf) were less efficient under these conditions. The cou-pling proceeded in various ether solvents, with 1,4-dioxanegiving the best yield (72 %), whereas toluene, N,N-dimethyl-formamide (DMF), and N-methyl-2-pyrrolidinone (NMP)

Scheme 1. 2-Arylated azoles in biologically active compounds.

Scheme 2. Ni-catalyzed C�H arylation of azoles with haloarenes.

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were unsuitable solvents. The choice of base additive turnedout to be most critical: when LiOtBu was replaced by otherbases such as NaOtBu, KOtBu, Mg ACHTUNGTRENNUNG(OtBu)2, NaOMe, LiOH,Li2CO3, Cs2CO3, K3PO4, or 1,8-diazabicycloACHTUNGTRENNUNG[5.4.0]undec-7-ene (DBU), almost none of the target product was pro-duced. A dramatic difference between LiOtBu and itssodium, potassium, and magnesium analogues is notable. Inview of efficiency, cost, simplicity, and stability, at this point,we identified Ni ACHTUNGTRENNUNG(OAc)2/bipy/LiOtBu/1,4-dioxane/85 8C asour “standard” conditions for the coupling reaction usingaryl iodides and bromides. Upon further optimization of thereaction, we found that the best conditions involved1.5 equivalents of benzothiazole, 1.0 equivalent of iodoben-zene, 10 mol % of Ni ACHTUNGTRENNUNG(OAc)2/bipy, and 1.5 equivalents ofLiOtBu in 1,4-dioxane at 85 8C for 36 h (80 % yield).

Scope of Ni-catalyzed C�H arylation of azoles with halo-ACHTUNGTRENNUNGarenes : We next examined the direct arylation of benzothi-ACHTUNGTRENNUNGazole with various haloarenes (Table 1). Bromobenzene andsubstituted bromoarenes reacted with benzothiazole (1 A) togive the corresponding 2-arylated benzothiazoles 3 Aa–Adin slightly lower yields compared with the iodoarene series(Table 1, entries 3, 5, 7, and 9). For a series of monomethyl-ACHTUNGTRENNUNGated iodo- or bromobenzenes, the ortho-methyl substitutedsubstrates generally afforded higher product yields thantheir meta- and para-substituted counterparts (Table 1, en-tries 4, 6, and 8).[22] ortho-Phenyliodobenzene also displayedhigh reactivity, giving the corresponding product 3 Ae in ex-cellent yield (Table 1, entry 10). Sterically more hindered 1-iodo-2,6-dimethylbenzene also gave the corresponding prod-uct 3 Ag in good yield (Table 1, entry 12). Both electron-richand electron-deficient aryl iodides and bromides can beused as aryl electrophiles (Table 1, entries 13–23). The cou-pling of ester-containing iodoarenes, such as ethyl 4-iodo-

Table 1. Scope of iodo- and bromoarenes in Ni ACHTUNGTRENNUNG(OAc)2/bipy-catalyzedazole arylation.[a]

Substrate 2 Product 3 Yield[%][b]

1 X = I 3Aa 802[c] X = I 3Aa 513 X =Br 3Aa 624 X = I 3Ab 905 X =Br 3Ab 82

6 X = I 3Ac 717 X =Br 3Ac 63

8 X = I 3Ad 699 X =Br 3Ad 48

10 3Ae 91

11[d] 3Af 68

12[d] 3Ag 71

13 o- 3Ah 6514 m- 3Ai 5315 p- 3Aj 7016[d] o- 3Ak 7217 m- 3Al 7518 p- 3Am 68

19[d] 3An 65

20[d] m- 3Ao 4721 p- 3Ap 78

22 3Aq 51

23 3Ar 61

24[d] 3As 61

25 3At 91

26[d] 3Au 73

27[d] 3Av 62

Table 1. (Continued)

Substrate 2 Product 3 Yield[%][b]

28[d] 3Aw 96

29 3Ax 57

30[d] 3Ay 45

31 3Az 74

32 3Aaa 58

33[d] 3Aab 49

[a] Reagents and conditions: 1 A (0.75 mmol), 2 (0.50 mmol), Ni ACHTUNGTRENNUNG(OAc)2

(0.05 mmol), bipy (0.05 mmol), LiOtBu (0.75 mmol), 1,4-dioxane (2 mL),85 8C, 36 h. [b] Isolated yield of 3. [c] 1 mol % Ni ACHTUNGTRENNUNG(OAc)2 and bipy wereused. [d] LiOtBu (1.00 mmol) was used. The reaction was carried out at120 8C.

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benzoate, proceeded sluggishly to afford a mixture of thetarget product and tert-butylated product in less than 5 %yield. This is most likely due to a transesterification reactionwith LiOtBu, which generates an ethoxide that inhibits thecoupling reaction. On the other hand, an iodoarene with anamide moiety at the 4-position reacted smoothly with 1 A(Table 1, entry 24). Unfortunately, acylated and nitratedhalo ACHTUNGTRENNUNGarenes were ineffective aryl electrophiles under thesecatalytic conditions, giving less than 5 % yield. Presumably,substrates having highly sensitive functional groups reactwith LiOtBu and decompose under these conditions. Forsome substrates, more forcing conditions, such as highertemperatures and the use of 2.0 equivalents of LiOtBu, wererequired to reach high levels of substrate conversion(Table 1, entries 11, 12, 16, 19, 20, 24, 26–28, 30, and 33).Heteroaryl iodides and bromides were also reactive(Table 1, entries 29–33). Finally, this reaction can take placewith a catalyst loading as low as 1 mol % nickel (Table 1,entry 2).

On the basis of these findings, we next aimed to extendthe scope of the reaction to include more challenging arylelectrophiles such as aryl chlorides and triflates (Table 2).Various nitrogen bidentate ligands, such as bipyridyls andphenanthrolines, proved to be ineffective when using arylchlorides as haloarenes (Table 2, entry 1). Monodentatephosphane ligands such as Ph3P, Cy3P, (tBu)3P, and XPhoswere also not effective. The application of bidentate phos-phane ligands drastically increased the reaction yield; forexample, the use of bis(diphenylphosphino)butane (dppb)gave 2-phenylbenzothiazole (3 Aa) in 50 % yield. Upon fur-ther screening of ligands, it was found that the use of dppfas the ligand slightly increased the yield, and 3 Aa was gen-erated in 53 %, even though the Ni ACHTUNGTRENNUNG(OAc)2/dppf system hadbeen found to be less effective (26 % yield) with iodoben-zene at 85 8C (see Scheme 2). Finally, when the amount ofLiOtBu was decreased from 3.0 to 1.5 equivalents and thereaction was performed at 140 8C for 40 h, 3 Aa was isolatedin 74 % yield.

Using these optimized conditions, the direct arylation ofbenzothiazole (1 A) with various aryl chlorides and triflateswas performed (Table 3). Compared with unsubstituted

chlorobenzene (Table 3, entry 1), o-methylchlorobenzene re-acted with benzothiazole in a slightly higher yield (Table 3,entry 3). This reactivity trend is similar to that observedwith iodo- and bromoarenes as haloarene substrates. Elec-tron-poor and electron-rich aryl chlorides containing tri-fluoromethyl, fluoride, and methoxy groups also participatedin this coupling (Table 3, entries 4–6). Heteroaryl chloridesalso reacted smoothly under the action of Ni ACHTUNGTRENNUNG(OAc)2/dppfcatalyst (Table 3, entries 7–11).

Finally, we explored the use of other azoles in the aryl-ACHTUNGTRENNUNGation reactions (Table 4). Gratifyingly, thiazoles (1 A–E),benz ACHTUNGTRENNUNGoxazole (1 F), oxazoles (1 G and 1 H), and N-methylbenz ACHTUNGTRENNUNGimidazole (1 I) reacted smoothly under the influ-ence of Ni ACHTUNGTRENNUNG(OAc)2/bipy/LiOtBu to furnish the correspondingcoupling products in moderate yields. However, we foundthat the coupling of 1 F showed poor reproducibility. Afterreinvestigation of the catalyst precursor, we identified thatthe use of [NiACHTUNGTRENNUNG(cod)2]/bipy instead of Ni ACHTUNGTRENNUNG(OAc)2/bipy wouldprovide reproducible results. These experiments indicatethat the production of active Ni0 species from the Ni ACHTUNGTRENNUNG(OAc)2

precursor might be slower in the reaction with benzoxazole.

Table 2. Ligand screening for Ni-catalyzed C�H arylation of benzothi-ACHTUNGTRENNUNGazole with chlorobenzene.[a]

Ligand GC yield of 3 [%]

1 bipy 02 dppm 03 dppe 24 dppp 265 dppb 506 dppn 107 BINAP 68 Xantphos 439 dppf 53

[a] Reagents and conditions: 1A (0.75 mmol), chlorobenzene(0.50 mmol), Ni ACHTUNGTRENNUNG(OAc)2 (0.05 mmol), ligand (0.05 mmol), LiOtBu(1.5 mmol), 1,4-dioxane (2 mL), 140 8C, 10 h.

Table 3. Ni ACHTUNGTRENNUNG(OAc)2/dppf-catalyzed C�H arylation of benzothiazole witharyl chlorides and triflates.[a]

Substrate 2 Product 3 Isolatedyield [%]

1 X= Cl 3 Aa 742 X= OTf 3 Aa 48

3 3 Ab 85

4[b] 3 Am 32

5 3 An 65

6[b] 3 Aj 27

7[b] 3 Ax 54

8[b] 3 Ay 54

9[b] 3 Aac 44

10 3 Az 58

11[b] 3 Aad 63

[a] Reagents and conditions: 1 A (0.75 mmol), 2 (0.50 mmol), Ni ACHTUNGTRENNUNG(OAc)2

(0.05 mmol), dppf (0.05 mmol), LiOtBu (0.75 mmol), 1,4-dioxane (2 mL),140 8C, 40 h. [b] LiOtBu (1.5 mmol) was used.

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K. Itami et al.

We also found that the addition of one equivalent of zincpowder to our “standard” conditions gave reproducible re-sults, presumably due to the rapid formation of active Ni0

species.[23] In the case of thiazoles and oxazoles, only themonoarylated product was exclusively obtained. We also at-tempted the coupling reaction using imidazole, imidazoACHTUNGTRENNUNG[1,5-a]pyridine, and caffeine, but the corresponding couplingproducts were unfortunately obtained either in low yields orin trace amounts (less than 25 %).

A new protocol involving Mg ACHTUNGTRENNUNG(OtBu)2 : The studies men-tioned above clearly demonstrate the potential use of nickelcatalysis to rapidly access a range of arylazoles. However,we were not satisfied with the critical necessity of LiOtBu(base) and 1,4-dioxane (solvent), which might limit the syn-thetic applications of this approach. For example, the highbasicity and nucleophilicity of LiOtBu might be problematicfor some sensitive functional groups. In addition, 1,4-diox-ane might not be suitable for dissolving very polar sub-strates, which are often required during the syntheses ofpharmaceuticals and biologically active compounds. There-fore, we planned to explore the use of new base additivesfor the nickel-catalyzed C�H arylation in DMF (Table 5).Reactions were carried out using various alkaline additives(2 equiv) under the action of Ni ACHTUNGTRENNUNG(OAc)2/bipy catalyst inDMF at 100 8C for 18 h.[24] Similar to our previous screening

using 1,4-dioxane as a solvent, sodium and potassium tert-butoxides were again both ineffective. Interestingly, alkox-ides of alkaline earth metals such as barium, magnesium,and calcium were somewhat effective. Finally, we discoveredan acceptable solution in which the reaction was conductedwith two equivalents of Mg ACHTUNGTRENNUNG(OtBu)2 in DMF to furnish thecorresponding product 3 Aa in 35 % yield.

With new conditions in hand, we then compared the reac-tivity of aryl electrophiles under the action of Mg ACHTUNGTRENNUNG(OtBu)2 inDMF with those under LiOtBu in 1,4-dioxane. To this end,benzothiazole (3 A) was used as a fixed coupling partnerand various aryl electrophiles were classified as being “supe-rior”, “equal”, or “inferior” by comparing the yields underMg ACHTUNGTRENNUNG(OtBu)2-mediated conditions to those under LiOtBu-mediated conditions (Table 6). For example, in the case ofbromobenzene, further optimization (1.5 equiv MgACHTUNGTRENNUNG(OtBu)2

and 1.5 equivalents benzothiazole were employed, and thereaction time was extended to 36 h) allowed the yield of3 Aa to be increased to 57 %, which is nearly as good as theyield obtained when LiOtBu was used. Therefore, bromo-benzene was classified as being “equal”. Haloarenes withelectron-neutral or electron-rich substituents, such as fluo-ride, methyl, and methoxy groups, were also identified asbeing “equal”. In contrast, ortho-substituted haloarenes,chlorobenzene, and phenyl triflate were found to be “inferi-or” substrates. On the other hand, electron-deficient haloar-enes, such as iodopyridine, iodonitrobenzene, and ester-sub-stituted iodobenzene, were found to be “superior” arylatingagents. Moreover, 4-nitroiodobenzene and ethyl 4-iodoben-zoate were effective only for Mg ACHTUNGTRENNUNG(OtBu)2-mediated reactions.As a result, we established two useful sets of coupling condi-tions for use with the Ni ACHTUNGTRENNUNG(OAc)2/bipy catalytic system.Whereas the LiOtBu/1,4-dioxane system generally workswell for robust substrates, the Mg ACHTUNGTRENNUNG(OtBu)2/DMF system is, inmany cases, superior for substrates with base-sensitive func-tional groups. It should also be mentioned that Mg ACHTUNGTRENNUNG(OtBu)2

is less expensive than LiOtBu.

Table 4. Scope of heteroarene coupling partners.[a]

Product 3 Isolatedyield [%]

Product 3 Isolatedyield [%]

80 61

69[b] 43

57 53[c]

73[b] 47

41

[a] Reagents and conditions: 1 (0.75 mmol), 2a (0.50 mmol), Ni ACHTUNGTRENNUNG(OAc)2

(0.05 mmol), bipy (0.05 mmol), LiOtBu (0.75 mmol), 1,4-dioxane (2 mL),85 8C, 36 h. [b] LiOtBu (1.00 mmol) was used. The reaction was carriedout at 120 8C. [c] Zn powder (0.50 mmol) was added.

Table 5. Effect of base on the Ni-catalyzed C�H arylation in DMF.[a]

Ligand GC yield of 3 Aa [%]

1 NaOtBu <12 KOtBu 03 CaACHTUNGTRENNUNG(OMe)2 64 BaACHTUNGTRENNUNG(OtBu)2 205 Mg ACHTUNGTRENNUNG(OMe)2 96 Mg ACHTUNGTRENNUNG(OEt)2 207 Mg ACHTUNGTRENNUNG(OtBu)2 358 Mg(OH)2 09 MgH2 0

[a] Reagents and conditions: 1 A (0.50 mmol), 2a (0.50 mmol), Ni ACHTUNGTRENNUNG(OAc)2

(0.05 mmol), bipy (0.05 mmol), base (1.0 mmol), DMF (2 mL), 100 8C,18 h.

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Mechanistic studies on the Ni-catalyzed C�H arylation ofazoles : Mechanistic studies on transition-metal-catalyzedazole–haloarene couplings using palladium, rhodium, andcopper catalysts had been performed by Ellman,[3h] Daugu-lis,[17c] and Zhuravlev.[25] According to these results, as wellas to our previous investigations, a likely mechanism fol-lowed in the present coupling involves Ni0/NiII redox cataly-sis (Scheme 3) and proceeds through: 1) oxidative additionof an aryl electrophile (Ar�X) to a Ni0 species generated in

situ; 2) nickelation of an azole(Het�H) with Ar�NiII�X togenerate an Ar�NiII�Het spe-cies; and 3) reductive elimina-tion of an arylazole product(Het�Ar) with the regenerationof Ni0 catalyst. It is quite clearthat a Ni0 species is involved incatalysis because the couplingalso proceeds well using [Ni-ACHTUNGTRENNUNG(cod)2] as a nickel source(Scheme 2). However, detailswere unclear regarding the ele-mentary steps in the assumedmechanism, such as 1) themanner in which the Ni0 speciesis produced from Ni ACHTUNGTRENNUNG(OAc)2

under the reaction conditions;2) whether or not an Ar�NiII�Xspecies is involved in the cata-lytic cycle; and 3) the way inwhich azole nickelation occursto give Ar�NiII�Het species.With these questions in mind,we performed a number of ex-periments to shed some light onthe mechanism of this reaction.

Generation of Ni0 species fromNi ACHTUNGTRENNUNG(OAc)2 : We initially pre-sumed that the active Ni0 spe-

cies could be generated from Ni ACHTUNGTRENNUNG(OAc)2 by the action of sac-rificial azole (in a catalytic amount). In other words, it mightbe possible that nickelation of two molar equivalents ofazole with Ni ACHTUNGTRENNUNG(OAc)2, followed by reductive elimination,could afford the necessary Ni0 species along with an azoledimer. To corroborate this hypothesis, we performed the ex-periments shown in Scheme 4. As anticipated, the dimeriza-

Scheme 3. A possible mechanism of nickel-catalyzed C�H arylation ofazoles with haloarenes.

Table 6. Comparison between LiOtBu/1,4-dioxane and Mg ACHTUNGTRENNUNG(OtBu)2/DMF systems in Ni-catalyzed C�H aryl-ACHTUNGTRENNUNGation.[a]

Superior Equal Inferior2 3 ; yield [%][b] 2 3 ; yield [%][b] 2 3 ; yield [%][b]

3 Am ; 84 (68) 3Al ; 75 (75) 3Ak ; 33[d] (72)

3 Ax ; 85 (57) 3Aa ; 57[d] (62) 3Ae ; 26[d] (91)

3 Aae ; 29[c] (<1) 3 An ; 61 (65) 3Ab ; 58[d] (90)

3Ao ; 87 (47) 3 Ad ; 69 (69) 3Aat ; 63 (91)

3 Aaf ; 48[f] (<1) 3Af ; 57 (65) 3Aa ; <5 (74)

3 Ar ; 73[e] (61) 3Aa ; <5 (48)

[a] Reagents and conditions: 1A (0.75 mmol), 2 (0.50 mmol), Ni ACHTUNGTRENNUNG(OAc)2 (0.05 mmol), bipy (0.05 mmol), Mg-ACHTUNGTRENNUNG(OtBu)2 (0.75 mmol), DMF (2 mL), 100 8C, 36 h. [b] The first yield indicates the yield under the new protocolof Mg ACHTUNGTRENNUNG(OtBu)2 in DMF, and the second yield within parenthesis indicates the yield under the standard condi-tions. [c] The reaction was carried out at 85 8C. [d] The reaction was carried out at 120 8C. [e] DMSO was usedinstead of DMF as solvent. [f] The product was obtained as a mixture of 3Aaf (33 %) and tert-butyl ester3Aaf’ (15 %).

Scheme 4. Dimerization of benzothiazole by the action of Ni ACHTUNGTRENNUNG(OAc)2/bipyand LiOtBu. Reagents and conditions: 1 A (0.75 mmol), Ni ACHTUNGTRENNUNG(OAc)2

(0.05 mmol), bipy (0.05 mmol), LiOtBu (0.75 mmol), 1,4-dioxane (2 mL),120 8C, 36 h. The yield of 4 is based on Ni ACHTUNGTRENNUNG(OAc)2.

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K. Itami et al.

tion of benzothiazole (1 A) occurred through the agency ofNi ACHTUNGTRENNUNG(OAc)2/bipy and LiOtBu to give the dimer 4 in 74 % yield(based on nickel). Interestingly, further investigations led tothe conclusion that both Ni ACHTUNGTRENNUNG(OAc)2 and LiOtBu are requiredfor the dimerization to proceed.[24]

Deprotonation of azoles with LiOtBu : Having identifiedthat LiOtBu is critical for generating Ni0 species, we thenexplored another assumed role of LiOtBu as a deprotonat-ing agent of azoles within the catalytic cycle (nickelationstep). In early experiments, benzothiazole (1 A) was depro-tonated with n-butyllithium instead of LiOtBu and thenickel-catalyzed reaction with iodobenzene (2 a) was thenconducted. However, the expected coupling product 3 Aawas not obtained, and 1 A completely decomposed underthe coupling conditions. In line with this observation, Itohand co-workers reported that the C2-lithiated benzothiazole(Li-1 A) is very unstable even at �50 8C.[26] To evaluatewhether the deprotonation is taking place during nickel cat-alysis, we conducted the coupling in the presence of tBuOD(Scheme 5). When 1 A (1.5 equiv) was treated with 2 a

(1.0 equiv), Ni ACHTUNGTRENNUNG(OAc)2 (10 mol %), bipy (10 mol%), LiOtBu(2.0 equiv), and tBuOD (2.0 equiv), in 1,4-dioxane at 120 8Cfor 10 h, 42 % of recovered 1 A was deuterated at the C2 po-sition (coupling product 3 Aa was formed in 44 % yield). Al-though this result clearly indicates that the deprotonationoccurs under the coupling conditions, a more important im-plication may be the following. Taking the instability of C2-lithiated benzothiazole (Li-1 A) into account, one of the im-portant factors of the Ni-catalyzed coupling would be theexistence of a pre-equilibrium between 1 A and Li-1 A. Thisdeprotonation/protonation shuttle should help to preventdecomposition of Li-1 A. We believe that a similar effect isoperating in the generation of Ni0 species (Scheme 4).

Nickelation of azoles with Ar-NiII-X and subsequent reduc-tive elimination : In the mechanistic picture shown inScheme 3, nickelation of azoles with Ar-NiII-X is the nextstep after oxidative addition of Ar�X to Ni0 species. Thus,Ar-Ni ACHTUNGTRENNUNG(bipy)-Br complex 5 was prepared[27] and treated withbenzothiazole (1 A) in 1,4-dioxane at 120 8C (Scheme 6). Al-though the coupling product was not observed under theseconditions, we found that the addition of either LiOtBu orMg ACHTUNGTRENNUNG(OtBu)2 to the reaction of 1 A and 5 did produce 3 Aa in

72 % and 84 % yield, respectively (Scheme 6). This result al-ludes to the possibility of a sequence of 1) oxidative addi-tion, 2) azole nickelation, and 3) reductive elimination incatalysis.

Possible pathways for azole nickelation and the importanceof the protonation/deprotonation shuttle : Although themechanism of nickel-catalyzed arylation of azoles with halo-ACHTUNGTRENNUNGarenes is not yet entirety clear, a number of experiments areconsistent with the proposed Ni0/NiII catalytic cycle shownin Scheme 3; namely, the Ni0/NiII redox catalysis consistingof: 1) oxidative addition of ArX to Ni0, 2) azole nickelationproducing Ar-Ni-Het, and 3) reductive elimination, generat-ing heterobiaryl product Het�Ar and Ni0. It is of note thatLiOtBu and Mg ACHTUNGTRENNUNG(OtBu)2 most likely play a critical role inthe azole nickelation step, which should be involved both inthe product-generating catalytic cycle as well as in the gen-eration of catalytically active Ni0 species from Ni ACHTUNGTRENNUNG(OAc)2.

We assume that the azole nickelation step might occurthrough a concerted metalation–deprotonation of azole withAr-Ni-OtBu, which could possibly be generated either fromAr-Ni-X and tert-butoxide (Path A in Scheme 7),[28] orthrough tert-butoxide-mediated deprotonation of azole fol-lowed by transmetalation of the generated azolyllithium (ormagnesium) with Ar-Ni-X (Path B in Scheme 7). If thelatter mechanism were operating, the current Ni-catalyzedheterobiaryl coupling would be tantamount to an in situKumada–Tamao–Corriu type coupling of metalated azolesand aryl electrophiles. However, we must stress that even ifthis is the case, the deprotonation/protonation shuttle ofazoles (which avoids azole substrate decomposition) is es-sential for achieving the heterobiaryl coupling.[29] In thisregard, the present Ni-catalyzed azole arylation is notmerely an in situ Kumada–Tamao–Corriu type coupling.

Applications of Ni-catalyzed C�H arylation to the synthesisof biologically active compounds : To illustrate the utility ofNi-catalyzed azole arylation in the preparation of biological-

Scheme 5. Protonation/deprotonation shuttle.

Scheme 6. Reaction of phenylnickel bromide complex and benzothiazole.[a] DMF was used as solvent.

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FULL PAPERArylation of Azoles

ly active compounds, we selected febuxostat, tafamidis andtexaline as aryl-substitutedazole targets.

Febuxostat is an inhibitor ofxanthine oxidase that has beendeveloped by Teijin Pharma asa new drug for the treatment ofgout and hyperuricemia(Scheme 8).[5] It has been 40years since a drug of this kind

has been developed, and febuxostat has gained a lot of pop-ularity; it has already been accepted for commercial use inEurope, USA, and Korea. Therefore, the development of anefficient synthesis of febuxostat is currently ongoing in pro-cess chemistry. Under the influence of Ni ACHTUNGTRENNUNG(OAc)2/bipy cata-lyst and LiOtBu, thiazole 6 andiodoarene 7 underwent cross-coupling in 1,4-dioxane at100 8C to furnish the corre-sponding coupling product(Scheme 8). The Mg ACHTUNGTRENNUNG(OtBu)2/di-methylsulfoxide (DMSO)system was equally effective forthe coupling. Subsequent treat-ment with CF3CO2H affordedfebuxostat in 62–67 % overallyield. The synthesis is extreme-ly efficient because both of the

coupling components (6 and 7) can be quickly derivatized inone step from commercially available 4-methyl-5-thiazole-carboxylic acid and 2-fluoro-5-iodobenzonitrile, respectively.

Tafamidis, which was first synthesized by Kelly and co-workers,[6] is effective for the treatment of TTR amyloidpolyneuropathy (Scheme 9), and is currently well intoPhase II and III clinical trials for treating these diseases. Weattempted to couple a benzoxazole ester with 1,3-dichloro-5-iodobenzene (9), expecting to achieve a more efficient syn-thesis, however, the coupling did not proceed at all. Aftersome investigation, we found that changing the ester of ben-zoxazole to an amide moiety solved this problem. The de-sired direct arylation was thus achieved, and subsequent hy-drolysis of the amide using HF/pyridine provided tafamidisin 70 % overall yield (Scheme 9).

As a third example in this project, the synthesis of a natu-ral product, texaline, which has antitubercular activity,[12a]

was undertaken. Piguel and co-workers had already report-ed the synthesis of texaline using a palladium-mediated

direct arylation method under microwave conditions in 57 %yield.[12c] We found that texaline could be obtained in a su-perior 84 % yield under the action of the Ni/bipy/LiOtBucatalytic system in 1,4-dioxane at 120 8C (Scheme 10).

Conclusion

We have developed an efficient nickel-catalyzed process forthe C�H bond arylation of azoles with aryl electrophiles.One of the important features of the present reactions is theutilization of inexpensive, air-stable Ni ACHTUNGTRENNUNG(OAc)2·4H2O as thecatalyst precursor.[30] We have established that Ni ACHTUNGTRENNUNG(OAc)2/bipy/LiOtBu serves as a general catalytic system for the cou-pling using aryl bromides and iodides as aryl electrophiles.

Scheme 7. Possible pathways of azole nickelation.

Scheme 8. Concise synthesis of febuxostat.

Scheme 9. Concise synthesis of tafamidis.

Scheme 10. Concise synthesis of texaline.

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For coupling more challenging electrophiles, such as arylchlorides and triflates, the Ni ACHTUNGTRENNUNG(OAc)2/dppf/LiOtBu systemturned out to be effective. Thiazoles, benzothiazoles, oxa-zoles, benzoxazoles, and benzimidazoles can be used as theheteroarene coupling partner. Upon further investigation,we discovered a new protocol for the present coupling usingMg ACHTUNGTRENNUNG(OtBu)2 as a milder and less expensive alternative toLiOtBu. A number of mechanistic experiments were in linewith the proposed Ni0/NiII redox catalysis proceedingthrough: 1) oxidative addition of an aryl electrophile to Ni0

species generated in situ, 2) nickelation of an azole with ar-ylnickel(II) species, and 3) reductive elimination of a hetero-biaryl product with the regeneration of Ni0 catalyst. The effi-cient and rapid syntheses of febuxostat, tafamidis, and texa-line speak well for the potential of the present nickel cataly-sis in a range of synthetic applications.

Experimental Section

General procedure for the nickel-catalyzed C�H arylation of azoles withhaloarenes and LiOtBu : A 20 mL glass vessel equipped with a J. YoungO-ring tap, containing a magnetic stirring bar and Ni ACHTUNGTRENNUNG(OAc)2·4H2O(10.6 mg, 0.05 mmol) was dried with a heatgun under vacuum and filledwith argon after cooling to RT. To this vessel were added bipy or dppf(0.05 mmol), LiOtBu (60.0 mg, 0.75 mmol), azole 1 (0.75 mmol), and hal-oarene 2 (0.50 mmol), followed by anhydrous 1,4-dioxane (2.0 mL). Thevessel was sealed and then heated (85–140 8C) in an eight-well reactionblock with stirring. After cooling to RT, the mixture was passed througha short silica gel pad (EtOAc), the filtrate was concentrated, and the resi-due was subjected to preparative thin-layer chromatography (hexane/EtOAc) to afford a coupling product 3.

Typical procedure for the nickel-catalyzed C�H arylation of azoles withhaloarenes and Mg ACHTUNGTRENNUNG(OtBu)2 : A 20 mL glass vessel equipped with J. YoungO-ring tap, containing a magnetic stirring bar and Ni ACHTUNGTRENNUNG(OAc)2·4H2O(10.6 mg, 0.05 mmol) was dried with a heatgun under vacuum and filledwith argon after cooling to RT. To this vessel were added bipy (7.8 mg,0.05 mmol), Mg ACHTUNGTRENNUNG(OtBu)2 (127.9 mg, 0.75 mmol), 1A (101.3 mg,0.75 mmol), and 2 a (102.0 mg, 0.50 mmol), followed by anhydrous DMF(2.0 mL) under a stream of argon. The vessel was sealed with an O-ringtap and then heated at 100 8C for 36 h in an 8-well reaction block withstirring. After cooling the reaction mixture to RT, the mixture was con-centrated under vacuum. The crude product was dissolved in EtOAc, fil-tered through Celite, the filtrate was concentrated, and the residue wassubjected to preparative thin-layer chromatography (hexane/EtOAc) toafford 3Aa (77.1 mg, 73 %) as a light-tan solid.

Acknowledgements

We thank Mr. Naoki Tsuchiya and Mr. Takumi Takeyasu for helpful dis-cussions on the synthesis of febuxostat. This work was supported by aGrant-in-Aid for Scientific Research from MEXT, and the Teijin PharmaAward in Synthetic Organic Chemistry, Japan to J.Y.

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[21] Typically, anhydrous Ni ACHTUNGTRENNUNG(OAc)2 is generated by the dehydration ofNi ACHTUNGTRENNUNG(OAc)2·4H2O, which is less expensive (see Experimental Section).When Ni ACHTUNGTRENNUNG(OAc)2·4 H2O was used without pretreatment, 3Aa was ob-tained in 23 % yield.

[22] Higher reactivity of ortho-substituted halobenzenes might be as-cribed to steric-induced acceleration in the product-forming reduc-tive elimination step in the catalytic cycle (Scheme 2).

[23] Miura and co-workers also indicated such a phenomenon; see refer-ence [18].

[24] See the Supporting Information for further details.[25] R. S. S�nchez, F. A. Zhuravlev, J. Am. Chem. Soc. 2007, 129, 5824 –

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[30] The price of representative catalyst precursors in arene arylation(Strem Chemicals, 2009): Ni ACHTUNGTRENNUNG(OAc)2·4H2O ($126 for 1 kg), CuI ($102for 500 g), [RuCl2 ACHTUNGTRENNUNG(p-cymene)]2 ($116 for 5 g), Pd ACHTUNGTRENNUNG(OAc)2 ($678 for25 g), [RhCl(CO)2]2 ($610 for 2 g).

Received: April 10, 2011Published online: July 8, 2011

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