Functionalization of indazoles by means of transition metal-catalyzed cross-coupling reactions

Tetrahedron 72 (2016) 6711e6727

Contents lists available at ScienceDirect

Tetrahedron journal homepage: www.elsevier.com/locate/tet

Tetrahedron report 1125

Functionalization of indazoles by means of transition metal-catalyzed cross-coupling reactions rald Guillaumet b, * Saïd El Kazzouli a, *, Ge a b

EuroMed Research Institute, Euro-Mediterranean University of Fes, Route de Meknes, 30000 Fes, Morocco Institut de Chimie Organique et Analytique (ICOA), Universit e d’Orl eans, UMR CNRS 7311, BP 6759, Orl eans Cedex, 2 45067, France

a r t i c l e i n f o Article history: Received 14 April 2016 Available online 24 August 2016 Keywords: Indazole Cross-coupling Sonogashira Heck SuzukieMiyaura Stille N-arylation CeH activation Direct arylation Oxidative alkenylation ̀

Contents 1. 2.

3.

4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6711 Functionalization by cross-coupling reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6712 2.1. Suzuki . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6712 2.2. Heck . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6716 2.3. Sonogashira . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6717 2.4. Stille . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6718 Functionalization by CeH activation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6718 3.1. Direct arylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6718 3.2. Oxidative alkenylation and oxidative heteroarylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6720 N-arylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6721 Sequential coupling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6723 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6724 References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6725 Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6727

1. Introduction The indazole system was found in various biologically active molecules. For very recent applications, indazole was reported as e.g., selective estrogen receptor degraders,1 selective 5-HT2 receptor

* Corresponding authors. E-mail address: [email protected] (S. El Kazzouli). http://dx.doi.org/10.1016/j.tet.2016.08.031 0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.

agonist,2 anticancer agents mostly as kinase inhibitors,3 inhibitors of Aurora A (kinase involved in cell cycle),4 selective CRAF inhibitors,5 FGFR inhibitors6 as well as inhibitors of other kinases.6e10 It was described also as bacterial gyrase B inhibitors11 and as highly potent and selective human beta(3)-adrenergic receptor agonists.12 Indazole is also present in various drugs and drug candidates including bendazac13e15 (compound I), benzydamine16 (compound II), pazopanib (VotrientÒ)17 (compound III), granisetron (KytrilÒ)18,19 (compound

6712

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

IV) and gamendazole20,21 (compound V) (Fig. 1). For more details on biological applications of indazoles, a very interesting review has been recently published.22 Other relevant reviews focused on indazoles synthesis, properties and applications have also been reported.23,24 However, none of these reviews has been dedicated to the results achieved in the field of metal-catalyzed cross-coupling reactions. In this review paper, we wish to discuss and summarize the advances made since 1999 in this field toward indazoles functionalization (e.g., Sonogashira, Heck, SuzukieMiyaura, Stille, direct arylation, oxidative alkenylation, oxidative heteroarylation, N-arylation and sequential double functionalization). Procedures in which metal-based catalysis is not involved in the functionalization of indazoles are not included.

Scheme 1. The first example of SuzukieMiyaura cross-coupling.

2. Functionalization by cross-coupling reactions 2.1. Suzuki In 1999, Rault et al. reported the first example of SuzukieMiyaura cross-coupling reaction toward the preparation of 3arylindazoles.25 The presence of the NH free group of 3haloindazoles was a limiting factor, especially in the case of 3bromoindazole. In contrast, when 3-iodoindazole 1, protected by a benzyl group, was treated by 2-furylboronic acid, the expected product 2 was isolated in acceptable yield (79%). The reaction was conducted under the following conditions [1.1 equiv of 2furylboronic acid, 5 mol % of Pd(PPh3)4, 3 equiv of NaHCO3 in DME at reflux for 3 h] (Scheme 1). Authors showed that the use of NH free iodoindazole as starting material led to the expected products but in lower yields. In 2005, our group prepared 3-heteroarylated indazole 4 by treatment of 3-iodo-1-methyl 4,7-disubstituted indazole 3 under standard SuzukieMiyaura conditions [3-thiophenylboronic acid, Pd(PPh3)4 and Na2CO3 in refluxing DME].26 This procedure led to desired 3,4,7 trisubstituted indazole 4 in 81% yield (Scheme 2). In the same year, two other examples of C4-(hetero)arylated indazoles using SuzukieMiyaura cross-coupling reaction have been synthesized. Both compounds were obtained in good yields after the treatment of 4-iodoindazole 5 by either 4-methoxyphenyl- or 3-thiophenylboronic acid in the presence of a catalytic amount of Pd(PPh3)4 and Na2CO3 in refluxing DME.27 The desired products 6 and 7 were isolated in 85 and 80% yield, respectively (Scheme 3).

Scheme 2. SuzukieMiyaura reaction on 4, 7 disubstituted indazole 3.

One year later, we applied SuzukieMiyaura reaction for the synthesis of bioactive indazoles.28 The starting materials 8 and 11 were treated under standard reaction conditions [1.1 equiv of pMeOeC6H4eB(OH)2, 5 mol % of Pd(PPh3)4, 3 equiv of NaHCO3, DME at reflux for 3 h]. This procedure led to desired product 12 in good yield (Scheme 4). In contrast, we noticed that the reaction between 8 and p-methoxyphenyl boronic acid gave the desired product 9 in only 45% yield (36% of N-deprotected indazole 10 was isolated). The cleavage of the tosyl protecting group was observed under the basic conditions required for SuzukieMiyaura coupling. This phenomenon was behind of the low yield observed for compound 9. In 2009, Rault and his group reported the synthesis of protected indazolylboronic esters and their applications in SuzukieMiyaura cross-coupling.29 So, in a representative example, starting from NSEM 5-bromoindazole 13 and bis(pinacolato)diboron (1.15 equiv) in the presence of KOAc (4.6 equiv), PdCl2(dppf)-CH2Cl2 (0.08 equiv) under argon, intermediate 14 was obtained in 67% yield. Then, the treatment with 4-iodoanisole (1.2 equiv), K3PO4 (1 equiv),

Fig. 1. Chemical structures of some drugs containing indazole.

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

6713

Scheme 3. SuzukieMiyaura cross-coupling at position 4 of indazole 5.

Scheme 6. The SuzukieMiyaura cross-coupling/N-deprotection sequence.

coupling partner, Loreto et al.31 achieved the synthesis of pyrrolyl indazoles 19 and 21. The cross-coupling reactions were conducted using either 18 or 20 as starting material, N-Boc-2-pyrrole boronic acid as coupling partner in the presence of Pd(dppf)Cl2 as catalyst and K2CO3 as base in DME at 80
C. Under these conditions, the desired products 19 and 21 were isolated in 84 and 92% yield, respectively (Scheme 7).

Scheme 4. SuzukieMiyaura cross-coupling of 7-nitroindazoles 8 and 11.

Pd(PPh3)4 (0.08 equiv), under argon in DMF at 60
C afforded the desired product 15 in 65% yield (Scheme 5). Hopkins and co-workers30 developed SuzukieMiyaura crosscoupling of N-Boc-3-iodo-5-methoxyindazole 16. The sequence was carried out using phenyl boronic acid and Pd(PPh3)4 catalyst in the presence of Na2CO3 (2N) in dioxane at 140
C for 10 min under microwave irradiation. Compound 17 resulting of the crosscoupling and ‘in situ’ deprotection was isolated in a very good yield (96%) (Scheme 6). Using either 5-bromo (1H)-indazole or 5-bromo (2H)-indazole as starting substrates with N-Boc-2-pyrrole boronic acid as

Scheme 7. SuzukieMiyaura cross-coupling of 5-bromo (1H)-indazole 18 and 5-bromo (2H)-indazole 20.

Recently, our group reported a microwave-assisted SuzukieMiyaura cross-coupling of free (NH) 3-bromoindazoles.32 We have shown that SuzukieMiyaura coupling reaction under standard conditions [22, 4-MeOeC6H4eB(OH)2, Pd(PPh3)4, Cs2CO3 in a mixture of dioxane/EtOH] was not possible either at reflux or

Scheme 5. SuzukieMiyaura cross-coupling at position 5 of indazole 13.

6714

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

under microwave irradiations at 100
C. However, when the same reaction mixture was heated at 140
C under microwave irradiations, the desired product 23 was isolated in a low yield (48%). Interestingly, a total conversion and a good yield were achieved when the reaction was conducted in a mixture of dioxane/EtOH/ H2O (3/1/0.5) under similar reaction conditions at 140
C. In this case, compound 23 was isolated in 75% yield (Scheme 8). The reaction conditions were also effective when 3-chloroindazole was used as starting material; however, in this case, the desired product was isolated in a relatively low yield, in addition, a large amount of starting material was recovered.

Scheme 8. Microwave-assisted SuzukieMiyaura cross-coupling of free (NH) 3bromoindazole 22.

Independently, Buchwald et al. reported SuzukieMiyaura crosscoupling of unprotected indazoles33 by investigating the influence of the ligand and the palladium source (Scheme 9). In this study, the

entry Pd 1 Pd2dba3 2 Pd2dba3 3 Pd2dba3 4 Pd2dba3 5 Pd2dba3 6 Pd(OAc)2 7 Pd(OAc)2 8 P1 9 P2 10 P2 a b HPLC yield, GC yield.

SuzukieMiyaura cross-coupling of 3-chloroindazole33 24 was achieved and the best reaction conditions were found to be indole boronic acid 25 (2 equiv), 2.5 mol % of the palladium complex P2, 3 mol % of Sphos ligand, 2 equiv of K3PO4 in a mixture of dioxane/ H2O at 100
C. Using this procedure, the expected product 26 was isolated in a very good yield (Scheme 9). Thereafter, the utility of this new synthetic method was illustrated by the preparation of the c-Jun N-terminal kinase three inhibitor (compound 29). Thus, the treatment of indazole 27 under the optimized reaction conditions (in this case only 2 mol % of palladium source P2 was used) with phenyl boronic acid led to intermediate 28 in 95% yield (Scheme 10). Then, the treatment of 28 with bromobenzene in the presence of 1.5 mol % of the palladium complex P3, 1.5 mol % of BrettPhos and NaOt-Bu in dioxane at 100
C led to expected product 29 in 86% yield. In their anticancer and antimicrobial research programs, respectively, Wu group and Rao group34e36 have used SuzukieMiyaura coupling as a key step for the preparation of bioactive molecules. In selected examples, a series of c-met inhibitors was prepared by treatment of starting 6-bromoindazole 30 with substituted pyrazole boronic esters as coupling partners in the presence of Pd(PPh3)4 and K2CO3 in a mixture of DMF/H2O at 80
C. This procedure led to desired products 31, 32 and 33 in 68, 55 and 65% yield, respectively (Scheme 11). Recently, Abbott et al. developed new 4,6-disubstituted indazoles as PDK1 inhibitors using SuzukieMiyaura cross-coupling.37 For the representative example shown in Scheme 12, 4bromoindazole 34 was treated by 3 mol % of PdCl2(dppf),

ligand XPhos SPhos RuPhos Pt-Bu3 none XPhos SPhos XPhos SPhos SPhos

yielda 56 52 40 10 0 49 47 69 80 90b

Scheme 9. Influence of palladium source and ligand on SuzukieMiyaura cross coupling of unprotected 3-chloroindazole 24. Adapted from Buchwald et al.33

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

6715

Scheme 10. Preparation of c-Jun N-terminal kinase 3 inhibitor 29 by SuzukieMiyaura and BuchwaldeHartwig cross-coupling.

Scheme 11. Preparation of c-met inhibitors 31e33 by SuzukieMiyaura cross-coupling.

bis(pinacolato) diboron (1.4 equiv) and KOAc in refluxing MeOH. Under these conditions, the intermediate 35 was isolated in 77% yield. Then, 35 was treated by indole bromide 36 in the presence of 5 mol % of Pd2(dba)3 and Na2CO3 in a refluxing mixture of dioxane/H2O which afforded the desired product 37 in 70% yield (Scheme 12). Very recently, Reddy et al.38 reported the synthesis of 1H-pyridin-4-yl-3,5-disubstituted indazoles (Scheme 13) using indazole

38 as starting martial in the presence of Pd(OAc)2 as catalyst, CsF as base in a mixture of DMF/H2O at 95e100
C. Compounds 39e43, isolated in yields ranging between 72 and 80%, were evaluated for their activities as inhibitors of AKT.39,40 Burton and Egan reported the synthesis of new 3-arylated indazoles by iridium-catalysed CeH borylation and SuzukieMiyaura coupling reaction.41 In the first step, indazole 44 was treated by bis(pinacolato)diboron in the presence of [Ir(COD)(OMe)]2, 4,40 -di-tert-butyl-2,2’-bipyridyl (dtbpy) in TBME (methyl tert-butyl ether also known as MTBE) at 55
C for 1.5 h. This sequence gave the expected product 45 in 50%. Then, 45 was treated by iodobenzene in the presence of catalyst P4 and K3PO4 in TBME/H2O at 55
C for 16 h. This SuzukieMiyaura of boryl indazole 45 led to desired compound 46 in 72% yield (Scheme 14). Recently, Kallman et al. reported the preparation of indazole derivative 49 as a MET kinase inhibitor using SuzukieMiyaura coupling as a key step in their synthesis.42 The reaction was achieved starting from indazole derivative 47 and boronic ester in the presence of bis(di-tert-butylphosphino)ferrocene. PdCl2 (D-tBPF.PdCl2), K3PO4 and Boc2O in THF at 60
C. This sequence gave the intermediate 48 in 81% yield. Then, 49 was obtained in 99% yield by treatment of 48 by DBU in EtOH (Scheme 15).

Scheme 12. Synthesis of PDK1 inhibitor 37 using SuzukieMiyaura.

6716

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

Scheme 13. Synthesis of AKT inhibitors 39e43 by SuzukieMiyaura cross-coupling between substituted phenyl boronic acids and indazole 38.

Scheme 14. Synthesis of 3-arylated indazole 46 by iridium-catalysed CeH borylation and SuzukieMiyaura coupling reaction.

presence of Pd(dppf)Cl2, Cs2CO3 in DMF at 100
C for 2 h to led to expected products 46 and 52 in 43 and 44% yield, respectively (Scheme 16).

Scheme 15. Synthesis of MET kinase inhibitor 49 by SuzukieMiyaura cross-coupling.

Very recently, Steel et al. reported a similar procedure to that developed by Burton and Egan41 for iridium-catalyzed CeH borylation followed by SuzukieMiyaura cross-coupling reaction under new reaction conditions.43 For a representative example, the starting indazoles 44 and 50 were treated by B2pin2 in the presence of 1.5 mol % of [Ir(cod)OMe]2 and 3 mol % of dtbpy in MTBE which afforded intermediates 45 and 51 in 67 and 100% yield, respectively (yields were determinated by 1H NMR). After the remove of volatiles, the reaction mixtures were treated by iodobenzene in the

Scheme 16. Iridium-catalyzed sequence.

CeH

borylation/SuzukieMiyaura

cross-coupling

2.2. Heck Functionalization of indazole by Heck cross-coupling was pioneered by Rault et al. providing thus the first example by using 3iodoindazoles and methyl acrylate as coupling partners.44 Authors showed that Heck cross-coupling was not effective when free (NH) indazoles were used as starting materials. In this case, only the Michael adducts were obtained. However, when Boc-protecting group was used, the treatment of the corresponding N-protected-

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

3-iodoindazole 53 by methyl acrylate in the presence of PdCl2(dppf), TEA and TBAI in DMF at 50
C for 2 h led to desired product 54 in an acceptable yield (62%). Under similar reaction conditions, a slightly lower yield was observed for the crosscoupled product 55 obtained when indazole 1 was used as starting material (Scheme 17).

6717

iodo-6-nitroindazole 58 in 97.7% HPLC yield. Then, intermediate 58 was treated by K2CO3 in DMF and Ac2O was added dropwise for 30 min. After 2 h, 1,10-phenanthroline, CuI and 2vinylpyridine were also added. The reaction mixture was stirred 8 h at 100
C to furnish the expected product 59 in 78% yield (Scheme 19). 2.3. Sonogashira Rault and co-workers reported also the first example of Sonogashira coupling of indazoles using various terminal alkynes as coupling partners under mild reaction conditions.49 Thus, indazole 53 was treated by 1-(pyrrolidin-1-yl)prop-2-yn-1-one under the following conditions (PdCl2(Ph3P)2, CuI, Et3N in DMF at room temperature), which led to alkynylated product 60 in 80% yield (Scheme 20).50

Scheme 17. The first example of Heck cross-coupling reaction.

In a notable application of Heck reaction on indazoles, our group have shown that this palladium-catalysed cross coupling can be used for C4-alkenylation of indazole 5.27 Thus, the treatment of 5 by methyl acrylate, under conditions similar to those developed by Rault’s group [PdCl2(dppf), TBAI and Et3N in DMF at 50
C], led to C4-alkenylated product 56 in 79% yield (Scheme 18). Very recently, Sun et al. reported the synthesis of axinitib, a selective inhibitor of vascular endothelial growth factor receptors (treatment of renal cell carcinoma45e47) using a new copper catalyzed Heck type coupling reaction.48 In a representative example, 6-nitroindazole 57 was first treated by K2CO3 and iodine in DMF at room temperature. This sequence led to 3-

Scheme 20. The first example of Sonogashira cross-coupling of indazole.

Recently, Mueller et al. reported an interesting one-pot Sonogashira couplingeTMS-deprotectioneCuAAC (copper(I)-catalyzed azideealkyne cycloaddition) sequence and its application to the

Scheme 18. Heck cross-coupling at position 4 of indazole 5.

Scheme 19. Synthesis of axinitib 59 using a copper catalyzed Heck type coupling reaction.

6718

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

Scheme 21. One-pot Sonogashira couplingeTMS-deprotectioneCuAAC sequence on indazole 53.

synthesis of kinase inhibitors.51 Iodoindazole 53 protected by a Boc group was treated under Sonogashira conditions using TMS acetylene in the presence of PdCl2(PPh3)2, CuI and Et3N in THF at room temperature. Then, intermediate 61 was treated by TBAF followed by BnN3 introduced in MeOH at room temperature. This sequence in one-pot Sonogashira couplingeTMS-deprotectioneCuAAC led to desired product 63 in 54% overall yield (Scheme 21). The Sonogashira approach was also investigated by our group toward C4-alkynylation of indazoles.27 So, the treatment of starting material 5 by phenyl acetylene in the presence of PdCl2(PPh3)2, CuI, and Et3N in DMF at room temperature was effective leading to expected C4-alkynylated indazole 64 in 71% yield (Scheme 22).

Scheme 23. Synthesis of compounds 66 and 67 by Stille cross-coupling of 65.

C4-Arylation using Stille cross-coupling has also been achieved by our group using indazole 5 and 2-(tributylstannyl)furan as coupling partners in the presence of Pd2(dba)3 and Ph3As in dioxane at 50
C. This procedure gave the expected coupling product 71 in 82% yield (Scheme 25).27 In another interesting application of Stille cross-coupling, Zhu et al. reported a new series of indazole derivatives as potent inhibitors of protein kinase B/Akt.54 The key intermediate 73 was prepared by treatment of indazole 72 by 5-bromopyridin-3-ol in the presence of Pd2(dba)3, (o-tol)3P and trimethylamine. This procedure led to 73 in 72% yield (Scheme 26). 3. Functionalization by CeH activation 3.1. Direct arylation

2.4. Stille Fraile et al. reported an efficient synthesis of novel 3-heteroaryl N1-functionalized indazoles via palladium cross-coupling reactions of ethyl (3-iodo-1H-indazol-1-yl)acetate 65 with either 3thiazolylstannane or 5-thiazolylstannane in the presence of Pd(PPh3)4 as catalyst in refluxing dioxane.52 The expected products 66 and 67 were isolated in 69 and 73% yields, respectively (Scheme 23). In 2005, Katzenellenbogen et al. reported the synthesis and biological evaluation of a new series of indazole derivatives as ligands for estrogen receptor b.53 These compounds were prepared using various palladium cross-coupling reactions, especially, Stille reaction. In a representative example, indazole 68 was functionalized at position three by treatment with PhSn(Me)3 in the presence of P(o-tol)3 and Pd2(dba)3 in DMF. This procedure led to expected compound 69 in 33% yield but also to methyl-substituted indazole 70 as a by-product in 30% yield (Scheme 24).

Direct arylation has attracted a lot of interest during the last decade and is considered nowadays as one of the most important realization in organic chemistry.23,55e60 In 2010, Greaney et al. have described the CeH arylation of substituted 2H-indazoles on water.61 Authors have shown that C-3 arylation of 2H-indazole 74 was effective using Pd(dppf)Cl2$DCM/ PPh3 as a catalytic system (catalyst/ligand) in the presence of Ag2CO3 on water. The desired product 75 was isolated in 76% yield when iodobenzene was used as coupling partner while it was slightly lower (71%) when bromobenzene was used instead of iodobenzene (Scheme 27). This method was successful when substituted iodoaryls or iodoheteroaryls were used (iodoaryls have shown to be slightly more reactive than iodoheteroaryls). Although the C3-arylation of substituted 2H-indazoles worked very well, no reaction was observed in the substituted 1H indazole series. Recently and independently, we and Itami group addressed in almost the same time the problem of the non-reactivity of C3

Scheme 22. C4-alkynylation of indazole 5.

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

6719

Scheme 24. Synthesis of new ligands for estrogen receptor b by Stille cross-coupling reaction.

Scheme 25. C4-arylation of indazole 5 using Stille cross coupling.

Scheme 28. The first example of C3 direct arylation of 1H-indazole 44.

Scheme 26. Synthesis of compound 73 using Stille cross-coupling.

2.0 equiv of K3PO4 as additive in DMA at 165
C for 12 h. This method led to expected product 78 in 60% yield (Scheme 29).63

Scheme 27. The first example of direct C3-arylation of substituted 2H-indazole 74.

position of 1H-indazoles by the development of new procedures based on the use of bidentate ligands.62,63 In our case, the C3 arylation of less reactive 1H-indazoles was feasible using 20 mol % of Pd(OAc)2 as catalyst and 40 mol % of 1,10-phenanthroline as ligand in the presence of 1.5 equiv of K2CO3 as base in refluxing DMA. This method, applied to starting material 44 in the presence of iodotoluene as coupling partner, was successful leading to desired product 76 in good yield, while, a moderate yield (51%) was isolated when bromotoluene was employed instead of iodotoluene (Scheme 28). In their case, Itami et al. used a closely related procedure for C3arylation of 1H-indazole, employing 1H-indazole 77 as starting material, 10 mol % of PdCl2 as calatyst, 10 mol % of 1,10phenanthroline as ligand, 1.5 equiv of Ag2CO3 as base and

Scheme 29. The first example of direct C3-arylation of 1H-indazole 77.

One year later, the Yu group reported similar procedure by reducing the catalyst and the ligand amounts (10 mol % of Pd(OAc)2 and 10 mol % of 1,10-phenanthroline). The reaction was conducted using starting material 44 in toluene at 160
C in the presence of 1 equiv of Cs2CO3. This procedure led to expected product 46 in 93% yield (1H NMR yield) (Scheme 30).64 It is noticed that the utility of C3-arylation of 1H-indazole was demonstrated by the total synthesis of the natural alkaloid nigellidine hyrdrobromide. Recently, in continuation of our investigation of this new procedure, we reported an original and regioselective C7 arylation of

6720

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

Scheme 32. The first example of C3 oxidative alkenylation of 1H-indazole 44.

candidate gamendazole in only three steps instead of the nine steps reported in the literature.20 The intermediate 83 was prepared from the commercially available indazole 82 in 87% yield. Then, 83 was treated by ethyl acrylate, Pd(OAc)2, Ag2CO3, AcOH/Ac2O in dioxane at 120
C for 18 h to afford 84 in 69% yield. Finally, 84 was subjected to LiOH in MeOH/THF/H2O at room temperature, which furnished gamendazole 85 in 91% yield (Scheme 33). Scheme 30. Direct C3-arylation of 1H-indazole 44.

substituted 1H-indazoles.65 Thus, starting material 79 was treated by 1.2 equiv of 4-iodotoluene, 10 mol % of Pd(OAc)2 as catalyst and 20 mol % of 1,10-phenanthroline as ligand in the presence of 1.5 equiv of K2CO3 as base in refluxing DMA. This procedure led to C7-arylated indazole 80 in 62% yield (Scheme 31). We thought that the C7 direct arylation reaction proceed via a coordination between Pd(OAc)2, 1H-indazole 79 and 1,10-phenanthroline (complex I) (Scheme 31).

Scheme 33. Synthesis of gamendazole by oxidative alkenylation.

Scheme 31. The first example of C7 direct arylation of 1H-indazole 79.

3.2. Oxidative alkenylation and oxidative heteroarylation The oxidative Heck-type reaction, also called the FujiwaraeMoritani reaction or CH/CH activation, has received considerable attention during the last decade and constitute now a key method for the achievement of CeC bond.66e68 Recently, oxidative (hetero) arylation has also emerged as a new and elegant method for the preparation of (hetero)aryl-(hetero)aryl linkages.69e74 Our group reported the first example of oxidative alkenylation of indazole system including both 1H-indazole and 2H-indazole series.75 For C3 alkenylation of 1-methylindazole 44, the reaction was carried out using ethyl acrylate, Pd(OAc)2 (5 mol %), Ag2CO3 (2.5 equiv), AcOH/Ac2O (1 equiv) in dioxane at 120
C for 18 h. The expected product 81 was isolated in 67% yield (Scheme 32). The utility of the oxidative alkenylation of 1H-indazole was successfully demonstrated by the total synthesis of the drug

The same reaction conditions were successfully applied for an original C7-alkenylation of substituted indazoles. In a representative example, the treatment of 3-phenyl indazole 79 under the conditions optimized for C3 alkenylation (see vide supra), led to C7 alkenylated indazole 86 in 61% (Scheme 34). It should be noticed that this achievement is the first example of oxidative alkenylation of the six-membered ring in the 6e5-biheterocyclic systems containing no heteroatom on the six-membered ring and at least one heteroatom on the five membered ring. Only two examples of C7alkenylation of indole using directing groups have been reported so far.76,77

Scheme 34. The first example of C7 oxidative alkenylation of 1H-indazole 79.

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

The same method was successful for C3 oxidative alkenylation of 2H-indazole 50. In this case, the desired product 87 was isolated in a very good yield (Scheme 35).

6721

Cu(OAc)2$H2O and pyridine in dioxane at 120
C for 24 h. This sequence gave the expected product 92 in 59% yield (Scheme 37). You and collaborators showed then that their library of indazoles containing heteroarenes exhibited full-color tunable fluorescence, high quantum yields and large Stokes shifts. Compound 93, prepared in one-step from 92, was found to be specific and photostable NIR probe for mitochondria (Scheme 37). 4. N-arylation

Scheme 35. The first example of C3 oxidative alkenylation of 2H-indazole 50.

Recently, Joo group reported similar method for oxidative alkenylation of (1H) indazole 44 and (2H) indazole 50 using 1 equiv of indazole, 1 equiv of alkene, 10 mol % of Pd(OAc)2 in the presence of 20 mol % of pyridine, 2 equiv of Cu(OAc)2$H2O in dioxane at 120
C.78 The desired products 88, 89 and 90 were isolated in moderate to acceptable yields (Scheme 36).

Scheme 36. C3-oxidative alkenylation of (1H) indazole 44 and (2H) indazole 50.

Very recently, You et al. reported a very interesting synthesis of biheteroaryl fluorophores using palladium-catalyzed oxidative CeH/CeH cross-coupling of 2H-indazoles with electron-rich heteroarenes.79 In a representative example, indazole 91 was treated by furan-2-carbaldehyde in the presence of Pd(PPh3)4,

N-arylation allowing the formation of CeN bond is one of the most important achievement in organic chemistry. This transformation is, mostly, catalyzed by either copper or palladium and has been extended studied by Buchwald group then by others.80e92 In this paragraph, we focus only on N-arylation taking place at the N1 position. In 2001, Buchwald et al. reported one example of N-arylation of indazole 94 using CuI as catalyst, (1R,2R)-cyclohexane-1,2diamine as ligand in the presence of K3PO4 in dioxane at 110
C for 24 h.93 This procedure led to expected product 95 in 96% yield (Scheme 38). In their development of novel bradykinin B1 receptor antagonists, Bodmer-Narkevitch et al. reported a similar procedure to Buchwald method93 for the synthesis of indazole derivatives employing N-arylation reaction.94 Thus, the treatment of indazole 24 as starting material and reactant 96 as partner with CuI as catalyst, (1R,2R)-cyclohexane-1,2-diamine as ligand in the presence of K3PO4 in dioxane followed by a treatment with HCl in MeOH at 70
C, led to expected product 97. From their library of compound, derivative 98, prepared after three steps from 97, was found to be a potent bradykinin B1 antagonist (Scheme 39). The groups of Lam and Chan reported one example of a successful N-arylation cross-coupling of 3-pyridyl boronate ester with indazole. The reaction was conducted using starting indazole 94 in the presence of 1 equiv of 3-pyridyl boronate ester, anhydrous Cu(OAc)2 (1.0 equiv) and pyridine (2.0 equiv) in CH2Cl2 at room temperature for 24 h. This sequence afforded the expected N-arylated indazole 99 in 63% yield (Scheme 40).95 In 2005, Aoyama et al. published a regioselective synthesis of 1arylindazoles via a copper(II) catalyzed N-arylation of 3trimethylsilylindazoles.96 In a representative example, indazole 100 was treated by phenylboronic acid in the presence of Cu(OAc)2, pyridine and 4  A molecular sieves in CH2Cl2 at room temperature under air. The expected product 101 was isolated in a good yield of 94% (Scheme 41).

Scheme 37. Preparation of a compound 93 as a specific and photostable NIR probe for mitochondria by oxidative CeH/CeH cross-coupling.

6722

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

Scheme 38. CuI catalyzed N-arylation of indazole 94.

Scheme 39. Synthesis of compound 98 as a novel bradykinin B1 receptor antagonist by N-arylation.

Scheme 40. Cu(OAc)2 catalysed N-arylation of 94.

Scheme 41. Copper(II) catalyzed N-arylation of trimethylsilylindazole 100.

In 2011, Teo et al. reported three examples of CeN arylated indazoles using NH free indazole 94 (1.47 mmol), aryl iodide (2.21 mmol), KOH (2.94 mmol), CuI (10 mol %), MnF2 (30 mol %) and

trans-1,2-diaminocyclohexane (20 mol %) in H2O (0.75 mL) at 60
C for 24 h.97 The desired products 77, 102 and 103 were isolated in yields ranging between 84 and 94% (Scheme 42). In the same year, Teo group reported the N-arylation of indazoles by aryl iodides under ligand-free copper(I) oxide catalyzed conditions in water in a closed system at 130
C for 24 h.98 The reaction was conducted using indazole 94 and iodobenzene as coupling partners in the presence of Cu2O, TBAB, K3PO4 in water leading to expected product 77 in 79% yield (Scheme 43). Two years later, the same group described one example of a ligand-free Cu2O-catalyzed N-heteroarylation of indazole with iodopyridines using 10 mol % of Cu2O, in the presence of 2 equiv of Cs2CO3 in DMSO as the best reaction conditions.99 Under this procedure, the coupling reaction between indazole 94 and 3iodopyridine was achieved in 86% yield (the isolated product 104 contains 15% of 2H-indazole regioisomer) (Scheme 44). These conditions were then successfully applied to achieve the N-arylation of various nitrogen heterocycles (e.g., indole, 7-azaindole, imidazole, pyrrole and pyrazole) with 2-iodopyridine. Hopkins et al. developed a new method toward the N-arylation of 1H-indazole.30 In this case, indazole 105 was treated by iodobenzene in the presence of CuI, ligand L1 and K3PO4 in toluene at 110
C. This protocol led to expected product 106 in 86% yield (Scheme 45).

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

Scheme 42. CuI catalysed N-arylation of 94.

Scheme 43. Ligand-free copper(I) oxide catalyzed N-arylation of indazole 94.

Scheme 44. Ligand-free Cu2O-catalyzed N-heteroarylation of indazole 94.

Scheme 45. CuI-catalyzed N-arylation of indazole 105.

5. Sequential coupling In another interesting report, Rault et al.50 investigated sequential SonogashiraeSonogashira, SonogashiraeSuzuki, and SuzukieSonogashira reactions with 5-bromo-3-iodoindazole 107.

6723

In a representative example, a sequential SonogashiraeSonogashira cross-coupling was achieved using 107 as starting material in the presence of alkyne 108, PdCl2(PPh3)2 and CuI in Et3N/DMF at 20
C for 12 h. This first sequence led to C3-alkynylated product 109 in 88% yield. 109 was then subjected to a second Sonogashira cross-coupling reaction with alkyne 110 in the presence of PdCl2(PPh3)2, Ph3P and CuI in Et3N/DMF at 70
C for 24 h leading to bis-alkynylated indazole 111 in a good yield (Scheme 46). In another example50 a sequential SonogashiraeSuzuki crosscoupling was achieved using 5-bromo-3-iodoindazole 107. Intermediate 109, obtained during the first cross-coupling reaction, was subjected to SuzukieMiyaura cross-coupling reaction with 4methoxybenzeneboronic acid in the presence of Pd(PPh3)4 and Na2CO3 in a mixture of DME/H2O at 80
C for 24 h. This sequence led to desired product 112 in a good yield (Scheme 47). In a third example50 a sequential SuzukieSonogashira crosscoupling was achieved by subjecting 5-bromo-3-iodoindazole 107 to SuzukieMiyaura cross-coupling reaction [4methoxybenzeneboronic acid, Pd(PPh3)4, Na2CO3, DME/H2O at 80
C for 24 h]. This sequence furnished intermediate 113 in 89% yield. Then, the treatment of intermediate 113 by alkyne 108 in the presence of PdCl2(PPh3)4, CuI and PPh3 in Et3N/DMF at 70
C for 48 h, led to expected product 114 in 78% yield (Scheme 48). Rault and his group have shown that these procedures can also be used for sequential SonogashiraeSonogashira, SonogashiraeSuzuki, and SuzukieSonogashira reactions with 5-bromo-3-iodoindole as starting material. Our group decided to prepare 3-bromo-4-iodoindazole 115 in order to achieve unsymmetrical 3,4-diarylindazoles.27 Thus, starting material 115 was treated by 1 equiv of 4-methoxyphenylboronic acid under standard reaction conditions [Pd(PPh3)4, Na2CO3, DMF, reflux], giving exclusively the 4-monosubstituted product 116 in 78% yield. Then, this intermediate 116 was treated by 1-naphthyl boronic acid under similar SuzukieMiyaura conditions which led to expected unsymmetrical 3,4-diarylindazole 117 in a good yield (Scheme 49). In continuation of our investigation of C7 direct arylation of indazole, we developed a one-pot SuzukieMiyaura/C7 arylation to achieve C3, C7-bis-arylated indazoles (Scheme 50).65 For this aim, starting indazole 118 was first treated by benzene boronic acid under SuzukieMiyaura conditions [Pd(OAc)2, PPh3, K2CO3, K3PO4, DMA reflux for 24 h], then, iodotoluene and 1,10-phenanthroline were added and the reaction mixture was maintained at reflux for 24 h. This sequence afforded the expected bis-arylated indazole 119 in 58% yield (Scheme 50). In 2008, Lautens and Laleu reported a very interesting one-pot palladium-catalyzed alkylation/direct arylation reaction for the synthesis of annulated 2H-indazoles.100 In representative examples, indazoles 120 and 121 were treated by aryl iodide, Pd(OAc)2, tri-2-furylphosphine, Cs2CO3 and norbornene in acetonitrile at 90
C for 24 h while an acetonitrile solution of bromoethylindazole was added dropwise to the reaction mixture over 20 h. This one-pot sequence led to desired products 122 and 123 in very good yields (Scheme 51).

Scheme 46. Sequential SonogashiraeSonogashira on 5-bromo-3-iodoindazole 107.

6724

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

Scheme 47. Sequential SonogashiraeSuzuki on 5-bromo-3-iodoindazole 107.

Scheme 48. Sequential SuzukieSonogashira on 5-bromo-3-iodoindazole 107.

Scheme 49. Sequential SuzukieSuzuki reaction on 3-bromo-4-iodoindazole 115.

Scheme 50. One-pot SuzukieMiyaura/C7 arylation on indazole 118.

Recently, Chakrabarty et al.101 described a domino Sonogashira/ Cacchi coupling-heteroannulation of 4-iodoindazoles. In a representative example, 124 was treated by trimethylsilyl acetylene in the presence of Pd(Ph3P)2Cl2, CuI and Et3N in DMF at 110
C for 10 h. This sequence led to desired product 125 in 83% yield (Scheme 52). 6. Conclusion This short review highlighted the application of metal-catalyzed cross coupling reactions in the functionalization of indazoles by

Scheme 51. Synthesis of annulated 2H-indazoles 122 and 123 by one-pot alkylation/ direct arylation.

surveying the development of this chemistry from 1999 to date. The review point out the significant development in this field during this important period and showed how the classical crosscoupling methods (SuzukieMiyaura, Stille, Sonogashira and Heck reactions) was successfully and progressively supplemented by the interesting and more step-economical CeH and CeH/CeH activation procedures. We strongly believe that there is continuing interest in indazoles synthesis and functionalization by means of cross-coupling reactions, especially, CeH and CeH/CeH activation procedures (direct arylation, direct alkenylation, oxidative alkenylation and

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

Scheme 52. Synthesis of compound 125 by a domino Sonogashira/Cacchi couplingheteroannulation.

oxidative (hetero)arylation). Future challenges will be the development of regioselective functionalizations of the indazole system at either the five membered or the six membered rings. Another challenging goal will be the optimization of the existing methods in order to reduce the amount of the catalyst and ligand, avoid or limit, in some cases, the use of organic solvents and reduce the reaction times by employing microwave irradiation. It will be also an interesting task to find new low cost and environmentally friendly reaction conditions (low cost catalysts, green catalysts, recyclable catalysts, and catalyst-free conditions) for the achievement of biologically active indazole derivatives. References and notes 1. Govek, S. P.; Nagasawa, J. Y.; Douglas, K. L.; Lai, A. G.; Kahraman, M.; Bonnefous, C.; Aparicio, A. M.; Darimont, B. D.; Grillot, K. L.; Joseph, J. D.; Kaufman, J. A.; Lee, K.-J.; Lu, N.; Moon, M. J.; Prudente, R. Y.; Sensintaffar, J.; Rix, P. J.; Hager, J. H.; Smith, N. D. Bioorg. Med. Chem. Lett. 2015, 25, 5163. 2. May, J. A.; Sharif, N. A.; McLaughlin, M. A.; Chen, H.-H.; Severns, B. S.; Kelly, C. R.; Holt, W. F.; Young, R.; Glennon, R. A.; Hellberg, M. R.; Dean, T. R. J. Med. Chem. 2015, 58, 8818. 3. Lu, Y.-Y.; Wang, J.-J.; Zhang, X.-K.; Li, W.-B.; Guo, X.-L. J. Pharm. Pharmacol. 2015, 67, 1393. 4. Song, P.; Chen, M.; Ma, X.; Xu, L.; Liu, T.; Zhou, Y.; Hu, Y. Bioorg. Med. Chem. 2015, 23, 1858. 5. Aman, W.; Lee, J.; Kim, M.; Yang, S.; Jung, H.; Hah, J.-M. Bioorg. Med. Chem. Lett. 2016, 26, 1188. 6. Liu, J.; Peng, X.; Dai, Y.; Zhang, W.; Ren, S.; Ai, J.; Geng, M.; Li, Y. Org. Biomol. Chem. 2015, 13, 7643. 7. Furlotti, G.; Alisi, M. A.; Cazzolla, N.; Dragone, P.; Durando, L.; Magaro, G.; Mancini, F.; Mangano, G.; Ombrato, R.; Vitiello, M.; Armirotti, A.; Capurro, V.; Lanfranco, M.; Ottonello, G.; Summa, M.; Reggiani, A. J. Med. Chem. 2015, 58, 8920. 8. Dugar, S.; Hollinger, F. P.; Mahajan, D.; Sen, S.; Kuila, B.; Arora, R.; Pawar, Y.; Shinde, V.; Rahinj, M.; Kapoor, K. K.; Bhumkar, R.; Rai, S.; Kulkarni, R. ACS Med. Chem. Lett. 2015, 6, 1190. 9. Haile, P. A.; Votta, B. J.; Marquis, R. W.; Bury, M. J.; Mehlmann, J. F.; Singhaus, R.; Charnley, A. K., Jr.; Lakdawala, A. S.; Convery, M. A.; Lipshutz, D. B.; Desai, B. M.; Swift, B.; Capriotti, C. A.; Berger, S. B.; Mahajan, M. K.; Reilly, M. A.; Rivera, E. J.; Sun, H. H.; Nagilla, R.; Beal, A. M.; Finger, J. N.; Cook, M. N.; King, B. W.; Ouellette, M. T.; Totoritis, R. D.; Pierdomenico, M.; Negroni, A.; Stronati, L.; Cucchiara, S.; Ziolkowski, B.; Vossenkamper, A.; MacDonald, T. T.; Gough, P. J.; Bertin, J.; Casillas, L. N. J. Med. Chem. 2016, 59, 4867. 10. Shan, Y.; Dong, J.; Pan, X.; Zhang, L.; Zhang, J.; Dong, Y.; Wang, M. Eur. J. Med. Chem. 2015, 104, 139. 11. Zhang, J.; Yang, Q.; Romero, J. A. C.; Cross, J.; Wang, B.; Poutsiaka, K. M.; Epie, F.; Bevan, D.; Wu, Y.; Moy, T.; Daniel, A.; Chamberlain, B.; Carter, N.; Shotwell, J.; Arya, A.; Kumar, V.; Silverman, J.; Kien, N.; Metcalf, C. A.; Ryan, D., III; Lippa, B.; Dolle, R. E. ACS Med. Chem. Lett. 2015, 6, 1080. 12. Wada, Y.; Shirahashi, H.; Iwanami, T.; Ogawa, M.; Nakano, S.; Morirnoto, A.; Kasahara, K. i; Tanaka, E.; Takada, Y.; Ohashi, S.; Mori, M.; Shuto, S. J. Med. Chem. 2015, 58, 6048. 13. Yin, X.; Zhang, Y.; Shen, J.; Wu, H.; Zhu, X.; Li, L.; Qiu, J.; Jiang, S.; Zheng, X. Acta Pharmacol. Sin. 2005, 26, 721. 14. Shen, H.; Gou, S.; Shen, J.; Zhu, Y.; Zhang, Y.; Chen, X. Bioorg. Med. Chem. Lett. 2010, 20, 2115. 15. Saso, L.; Silvestrini, B. Med. Hypotheses 2001, 56, 114. 16. Baldock, G. A.; Brodie, R. R.; Chasseaud, L. F.; Taylor, T. J. Chromatogr.-Biomed. Appl. 1990, 529, 113. 17. Keisner, S. V.; Shah, S. R. Drugs 2011, 71, 443. 18. Chaturvedula, A.; Joshi, D. P.; Anderson, C.; Morris, R.; Sembrowich, W. L.; Banga, A. K. Pharm. Res. 2005, 22, 1313. 19. Bermudez, J.; Fake, C. S.; Joiner, G. F.; Joiner, K. A.; King, F. D.; Miner, W. D.; Sanger, G. J. J. Med. Chem. 1990, 33, 1924. 20. Veerareddy, A.; Surendrareddy, G.; Dubey, P. K. Synth. Commun. 2013, 43, 2236. 21. Tash, J. S.; Chakrasali, R.; Jakkaraj, S. R.; Hughes, J.; Smith, S. K.; Hornbaker, K.; Heckert, L. L.; Ozturk, S. B.; Hadden, M. K.; Kinzy, T. G.; Blagg, B. S. J.; Georg, G. I. Biol. Reprod. 2008, 78, 1139.

6725

22. Gaikwad, D. D.; Chapolikar, A. D.; Devkate, C. G.; Warad, K. D.; Tayade, A. P.; Pawar, R. P.; Domb, A. J. Eur. J. Med. Chem. 2015, 90, 707. 23. Rossi, R.; Bellina, F.; Lessi, M.; Manzini, C.; Perego, L. A. Synthesis 2014, 46, 2833. 24. Ila, H.; Markiewicz, J. T.; Malakhov, V.; Knochel, P. Synthesis 2013, 45, 2343. 25. Collot, V.; Dallemagne, P.; Bovy, P. R.; Rault, S. Tetrahedron 1999, 55, 6917. 26. Bouissane, L.; El Kazzouli, S.; Leger, J. M.; Jarry, C.; Rakib, E. M.; Khouili, M.; Guillaumet, G. Tetrahedron 2005, 61, 8218. 27. El Kazzouli, S.; Bouissane, L.; Khouili, M.; Guillaumet, G. Tetrahedron Lett. 2005, 46, 6163. 28. Bouissane, L.; El Kazzouli, S.; Leonce, S.; Pfeiffer, B.; Rakib, E. M.; Khouili, M.; Guillaumet, G. Bioorg. Med. Chem. 2006, 14, 1078. 29. Crestey, F.; Lohou, E.; Stiebing, S.; Collot, V.; Rault, S. Synlett 2009, 615. 30. Salovich, J. M.; Lindsley, C. W.; Hopkins, C. R. Tetrahedron Lett. 2010, 51, 3796. 31. Migliorini, A.; Oliviero, C.; Gasperi, T.; Loreto, M. A. Molecules 2012, 17, 4508. 32. Ben-Yahia, A.; Naas, M.; El Brahmi, N.; El Kazzouli, S.; Majoral, J. P.; Essassi, E. M.; Guillaumet, G. Curr. Org. Chem. 2013, 17, 304. 33. Duefert, M. A.; Billingsley, K. L.; Buchwald, S. L. J. Am. Chem. Soc. 2013, 135, 12877. 34. Ye, L.; Ou, X.; Tian, Y.; Yu, B.; Luo, Y.; Feng, B.; Lin, H.; Zhang, J.; Wu, S. Eur. J. Med. Chem. 2013, 65, 112. 35. Li, R.; Cui, B.; Li, Y.; Zhao, C.; Jia, N.; Wang, C.; Wu, Y.; Wen, A. Eur. J. Pharmacol. 2014, 724, 77. 36. Padmaja, P.; Yedukondalu, M.; Sridhar, R.; Busi, S.; Rao, M. V. B. Lett. Drug Des. Discov. 2013, 10, 625. 37. Brzozowski, M.; O’Brien, N. J.; Wilson, D. J. D.; Abbott, B. M. Tetrahedron 2014, 70, 318. 38. Gogireddy, S.; Kalle, A. M.; Dubey, P. K.; Reddy, A. V. J. Chem. Sci. 2014, 126, 1055. 39. Babu, S.; Dagnino, R. Jr.; Ouellette, M. A.; Shi, B.; Tian, Q.; Zook, S. E.; WO/ 2006/048745, PCT/IB2005/003300. 40. Babu, S.; Dagnino, R. Jr.; Haddach, A.; Mitchell, M. B.: Ouellette, M. A.; Saenz, J. E.; Srirangam, J. K.; Zook, S. E.; WO/2006/048761, PCT/IB2005/003348. 41. Egan, B. A.; Burton, P. M. RSC Adv. 2014, 4, 27726. 42. Kallman, N. J.; Liu, C.; Yates, M. H.; Linder, R. J.; Ruble, J. C.; Kogut, E. F.; Patterson, L. E.; Laird, D. L. T.; Hansen, M. M. Org. Biomol. Chem. 2014, 18, 501. 43. Sadler, S. A.; Hones, A. C.; Roberts, B.; Blakemore, D.; Marder, T. B.; Steel, P. G. J. Org. Chem. 2015, 80, 5308. 44. Collot, V.; Varlet, D.; Rault, S. Tetrahedron Lett. 2000, 41, 4363. 45. Singh, M.; Odusanya, O.; Wilmes, G. M.; Eitouni, H. B.; Gomez, E. D.; Patel, A. J.; Chen, V. L.; Park, M. J.; Fragouli, P.; Iatrou, H.; Hadjichristidis, N.; Cookson, D.; Balsara, N. P. Macromolecules 2007, 40, 4578. 46. Elly, R. J.; Rixe, O. Target. Oncol. 2009, 4, 297. 47. Kelly, R. J.; Rixe, O. Recent Results Canc. Res. 2010, 184, 33. 48. Zhai, L.-H.; Guo, L.-H.; Luo, Y.-H.; Ling, Y.; Sun, B.-W. Org. Process Res. Dev. 2015, 19, 849. 49. Arnautu, A.; Collot, V.; Ros, J. C.; Alayrac, C.; Witulski, B.; Rault, S. Tetrahedron Lett. 2002, 43, 2695. 50. Witulski, B.; Azcon, J. R.; Alayrac, C.; Arnautu, A.; Collot, V.; Rault, S. Synthesis 2005, 771. 51. Merkul, E.; Klukas, F.; Dorsch, D.; Graedler, U.; Greiner, H. E.; Mueller, T. J. J. Org. Biomol. Chem. 2011, 9, 5129. 52. Fraile, A.; Rosario Martin, M.; Garcia Ruano, J. L.; Antonio, D. J.; Arranz, E. Tetrahedron 2011, 67, 100. 53. De Angelis, M.; Stossi, F.; Carlson, K. A.; Katzenellenbogen, B. S.; Katzenellenbogen, J. A. J. Med. Chem. 2005, 48, 1132. 54. Zhu, G.-D.; Gandhi, V. B.; Gong, J.; Thomas, S.; Woods, K. W.; Song, X.; Li, T.; Diebold, R. B.; Luo, Y.; Liu, X.; Guan, R.; Klinghofer, V.; Johnson, E. F.; Bouska, J.; Olson, A.; Marsh, K. C.; Stoll, V. S.; Mamo, M.; Polakowski, J.; Campbell, T. J.; Martin, R. L.; Gintant, G. A.; Penning, T. D.; Li, Q.; Rosenberg, S. H.; Giranda, V. L. J. Med. Chem. 2007, 50, 2990. 55. Rossi, R.; Lessi, M.; Manzini, C.; Marianetti, G.; Bellina, F. Adv. Synth. Catal. 2015, 357, 3777. 56. Mercier, L. G.; Leclerc, M. Acc. Chem. Res. 2013, 46, 1597. 57. Lebrasseur, N.; Larrosa, I.; Katritzky, A. R., Ed. Adv. Heterocycl. Chem. 2012, Vol. 105, 309e351. 58. El Kazzouli, S.; Koubachi, J.; El Brahmi, N.; Guillaumet, G. RSC Adv. 2015, 5, 15292. 59. Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Synlett 2006, 3237. 60. Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. J. Org. Chem. 2007, 72, 7650. 61. Ohnmacht, S. A.; Culshaw, A. J.; Greaney, M. F. Org. Lett. 2010, 12, 224. 62. Ben-Yahia, A.; Naas, M.; El Kazzouli, S.; Essassi, E. M.; Guillaumet, G. Eur. J. Org. Chem. 2012, 7075. 63. Hattori, K.; Yamaguchi, K.; Yamaguchi, J.; Itami, K. Tetrahedron 2012, 68, 7605. 64. Ye, M.; Edmunds, A. J.; Morris, J. A. F.; Sale, D.; Zhang, Y.; Yu, J. Q. Chem. Sci. 2013, 4, 2374. 65. Naas, M.; El Kazzouli, S.; Essassi, E. M.; Bousmina, M.; Guillaumet, G. J. Org. Chem. 2014, 79, 7286. 66. Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170. 67. Kozhushkov, S. I.; Ackermann, L. Chem. Sci. 2013, 4, 886. 68. Koubachi, J.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Synthesis 2009, 271. 69. Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. 70. Stuart, D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.

6726 71. 72. 73. 74. 75. 76. 77. 78. 79. 80. 81. 82. 83. 84. 85. 86.

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727 Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904. Li, B.-H.; Tian, S.-L.; Fang, Z.; Shi, Z. J. Angew. Chem., Int. Ed. 2008, 47, 1115. Brasche, G.; Garcia-Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207. Yang, Z.; Qiu, F. C.; Gao, J.; Li, Z. W.; Guan, B. T. Org. Lett. 2015, 17, 4316. Naas, M.; El Kazzouli, S.; Essassi, E. M.; Bousmina, M.; Guillaumet, G. Org. Lett. 2015, 17, 4320. Lanke, V.; Prabhu, K. R. Org. Lett. 2013, 15, 2818. Shi, J.; Yan, Y.; Li, Q.; Xu, H. E.; Yi, W. Chem. Commun. 2014, 6483. Han, S. J.; Kim, H. T.; Joo, J. M. J. Org. Chem. 2016, 81, 689. Cheng, Y.; Li, G.; Liu, Y.; Shi, Y.; Gao, G.; Wu, D.; Lan, J.; You, J. J. Am. Chem. Soc. 2016, 138, 4730. Antilla, J. C.; Klapars, A.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684. Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 5578. Antilla, J. C.; Baskin, J. M.; Barder, T. E.; Buchwald, S. L. J. Org. Chem. 2004, 69, 6514. Altman, R. A.; Buchwald, S. L. Org. Lett. 2006, 8, 2779. Altman, R. A.; Koval, E. D.; Buchwald, S. L. J. Org. Chem. 2007, 72, 6190. Altman, R. A.; Hyde, A. M.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2008, 130, 9613. Strieter, E. R.; Bhayana, B.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 78.

87. Maiti, D.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 17423. 88. Hicks, J. D.; Hyde, A. M.; Cuezva, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2009, 131, 16720. 89. Ackermann, L.; Barfuesser, S.; Potukuchi, H. K. Adv. Synth. Catal. 2009, 351, 1064. 90. Watanabe, T.; Oishi, S.; Fujii, N.; Ohno, H. J. Org. Chem. 2009, 74, 4720. 91. Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13. 92. McGowan, M. A.; Henderson, J. L.; Buchwald, S. L. Org. Lett. 2012, 14, 1432. 93. Klapars, A.; Antilla, J. C.; Huang, X. H.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7727. 94. Bodmer-Narkevitch, V.; Anthony, N. J.; Cofre, V.; Jolly, S. M.; Murphy, K. L.; Ransom, R. W.; Reiss, D. R.; Tang, C.; Prueksaritanont, T.; Pettibone, D. J.; Bock, M. G.; Kuduk, S. D. Bioorg. Med. Chem. Lett. 2010, 20, 7011. 95. Chan, D. M. T.; Monaco, K. L.; Li, R. H.; Bonne, D.; Clark, C. G.; Lam, P. Y. S. Tetrahedron Lett. 2003, 44, 3863. 96. Hari, Y.; Shoji, Y.; Aoyama, T. Tetrahedron Lett. 2005, 46, 3771. 97. Teo, Y. C.; Yong, F. F.; Lim, G. S. Tetrahedron Lett. 2011, 52, 7171. 98. Yong, F. F.; Teo, Y. C.; Tay, S.-H.; Tan, B. Y. H.; Lim, K.-H. Tetrahedron Lett. 2011, 52, 1161. 99. Teo, Y. C.; Yong, F. F.; Sim, S. Tetrahedron 2013, 69, 7279. 100. Laleu, B.; Lautens, M. J. Org. Chem. 2008, 73, 9164. 101. Barik, S. K.; Rakshit, M.; Kar, G. K.; Chakrabarty, M. Arkivoc 2014, 5, 1.

S. El Kazzouli, G. Guillaumet / Tetrahedron 72 (2016) 6711e6727

6727

Biographical sketch

Saïd El Kazzouli was born in Beni Mellal in 1975. He received his Master’s degree then his Ph.D. in chemistry from the University of Orleans in 2004 under the supervision of Prof. G. Guillaumet and Prof. A. Mouaddib. He worked then at the same University as a postdoctoral fellow with Prof. L. Agrofoglio and with Prof. S. BerteinaRaboin from 2004 to 2006. In 2006, he joined the National Cancer Institute (NCI) at the National Institutes of Health (NIH) in USA as a postdoctoral fellow for 3 years with Dr V. E. Marquez. In 2009, he became a researcher (project leader) at INANOTECH, MAScIR Foundation in Rabat, Morocco. In 2013, he joined the EuroMediterranean University of Fes, Morocco as an Associate Professor. His main research interests are the drug design and delivery by nanoparticles, catalysis and green chemistry.

rald Guillaumet was born in France in 1946. He studied chemistry at the University of Ge re and received his Ph. D. Clermont-Ferrand (France). He joined the group of Prof. Caube in 1972 from the University of Nancy (France) in the field of arynic condensations. Working first as an assistant at the University of Clermont-Ferrand, he was appointed as Maître-Assistant, then as Maître de Conferences at the University of Nancy. Nominated ans in 1983, he became dias full professor in organic chemistry at the University of Orle rector of the Institute of Organic and Analytical Chemistry. President of the University of ans from 19th November 2004 to 18th November 2009, author of more than 370 sciOrle entific publications and 46 patents, he also supervised 78 Ph.D students. His current research interests focus on heterocyclic chemistry (synthesis an methodologies), medicinal chemistry (drug discovery for CNS, metabolic and cardiovascular diseases, anticancer chemotherapy), and enantioselective synthesis of natural and non-natural molecules.