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Letter
Palladium–Catalyzed Regioselective C–H Bond Arylations of Benzoxazoles and Benzothiazoles at the C7 Position Fatma Abdellaoui, Chiraz Youssef, Hamed Ben Ammar, Thierry Roisnel, Jean-François Soulé, and Henri Doucet ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00678 • Publication Date (Web): 31 May 2016 Downloaded from http://pubs.acs.org on June 2, 2016
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Palladium–Catalyzed Regioselective C–H Bond Arylations of Benzoxazoles and Benzothiazoles at the C7 Position Fatma Abdellaoui, a, b Chiraz Youssef,b Hamed Ben Ammar,b Thierry Roisnel,a Jean-François Soulé,a* and Henri Douceta* a
Institut des Sciences Chimiques de Rennes, UMR 6226 CNRS-Université de Rennes "Organométalliques : Matériaux et Catalyse", Campus de Beaulieu, 35042 Rennes, France. bLaboratoire de Synthèse Organique Asymétrique et Catalyse Homogène, (UR 11ES56) Université de Monastir, Faculté des Sciences de Monastir, avenue de l’environnement, Monastir 5000, Tunisia ABSTRACT: We report herein, a very simple catalytic system for the direct arylation of benzoxazole and benzothiazole derivatives at C7 position, namely, phosphine-free PdCl2 associated to PivOK in NMP at 150 ºC. (Thio)phenoxy chelation-assisted Pd-catalyzed C–H bond cleavage, from an opened intermediate, was proposed to explain this unique regioselectivity. This reaction allows the synthesis of 2-amino-6arylphenols through the ring opening of the benzoxazole. KEYWORDS . Arylation – Catalysis – C–H Activation – Palladium – Benzoxazole
Over the past decades, transition metal-catalyzed regioselective C–C bond formation methodologies led to a radical change in the synthesis of complex organic molecules such as pharmaceuticals or materials.1 Among them, C–H bond arylation reactions have emerged as one of the most powerful tools for the direct C–C bond formation with greater atom economy.2 In addition, such methodology allows in some cases novel regioselectivities affording products which were not easily accessible using more conventional methods. Most of the regioselective C–H bond arylations required the presence of an ortho-directing group such as amides, carboxylic acids, imines, pyridine, etc.3 Other methods for the control of the regioselectivity of arylations rely on the proton acidity via a concerted-metalation-deprotonation (CMD) pathway.4 Usually arylations of 2-phenylbenzothiazoles or 2-phenylbenzazoles via C–H bond activation would take place preferentially at the orthoposition of the phenyl ring, due to a directing effect of the benzoxazolyl or benzothiazolyl groups (Fig. 1a).5 To overcome this regioselectivity and provide an original access to C7 arylated benzoxazole the presence of an additional directing group is required. As example, in the course of their study on the synthesis of c-Met kinase inhibitors, Cho et al. reported a direct arylation of a 2arylbenzoxazole at C7 position through palladium catalysis (Fig. 1b).6 This uncommon regioselectivity could arise from the presence of the hydroxy group at the C6 position, which acts as an ortho-directing group. Phenoxy group has been firstly introduced as directing group by Miura for palladium-promoted C–H bond arylation of 2-arylphenols through a aryl(aryloxy)palladium intermediate.7 Moreover, when a larger excess of aryl iodide (4 eq.) was used, diarylation was also possible. However, to the best of our knowledge, there is no other example of transition metal-catalyzed C7 arylation of benzoxazoles or benzothiazoles, especially without the use of an additional directing group. On the other hand, during their investigations on palladium-catalyzed C2 direct arylation of
benzoxazole, Zhuravlev and co-worker have demonstrated a ring opening pathway (Fig. 1c).8 Based on this equilibrium between an opened and a closed form of benzoxazole –which is also found at high temperature with 2-substituted benzoxazoles–9 we postulate that 2-phenylbenzoxazole could be transitorily opened, under proper conditions, leading to a phenoxy group, which could act as directing group in palladium catalysis promoting a regioselective direct C7 arylation of benzoxazole (Fig 1d). Similar intermediate should be operative with 2-substituted benzothiazole. a. Pd-Catalyzed Direct Arylation of 2-Phenylbenzoxazole (Wu and Zhang).[5] H7
C4 or C7 no reactive position
H4 Z
N
R1
+
I
H
(4 equiv.)
Pd(OAc) 2 (5 mol%) AgOAc (1.2 equiv.) tfa, reflux
Z
N R1
Z = O or S
most reactive position b. Pd-Catalyzed Regioselective C7 Arylation of 2-Arylbenzoxazol-6-ol (Cho).[6] Phenoxy directing group OH OH most reactive position H7 Pd 2(dba) 3 X-Phos + Br N O K 3PO 4 N O 45% toluene, 100 ºC, 13 h Ar (1.5 equiv.) Ar 1 example c. Ring-Opening Pathway in the Pd-Catalyzed Direct Arylation of Benzoxazoles (Zhuravlev).[8] Pd(OAc) 2 PPh 3 + I N+ OCs2CO 3 N O N O N O DMF (1.5 equiv.) via ring opening Ph H2 d. Pd-Catalyzed Regioselective C7 Arylation of Benzoxazoles and Benzothiazoles via a Ring-Opening Pathway (this work) H7 + Br
N R1
R 2 X = O or S; N X (1.5 equiv.) R1 = Ar or Alkyl (Thio)phenoxy as temporary directing group R1
N+
X R1
[Pd] Base
X-
Figure 1. Pd-Catalyzed C–H Arylation of Benzoxazoles.
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It is important to note that C7-arylated benzoxazole could be further easily deprotected to give a general access to 2-amino-6arylphenols. This motif is very interesting because it forms the core of a range of marketed biologically active compounds (Fig. 2). For examples, Eltrombapag is an oral medication commercialized by GSK for the treatment of chronic hepatic C infection.10 Totrombopag, also developed by GSK, is a back-up compound for eltrombopag. Garenoxacin is a quinolone antibiotic for the treatment of some bacterial infections. However, the synthesis of the 2-amino6-arylphenols, which are key intermediates of these drugs remain challenging. They are generally obtained in 5 steps, with poor overall yields, from 2-bromophenol via nitration reaction and Suzuki cross-coupling.11 NH N NH
O
CO2H
OH O
N
N
N NH
OH
N NH N N O O
N N
OH
N
HO Eltrombopag
Garenoxacin
Totrombopag
Figure 2. Marketed Drugs Containing 2-Amino-6-arylphenols. Recently, we reported the palladium-catalyzed direct arylation of benzoxazole or benzothiazole derivatives, in which such functional groups had not displayed any ortho-directing effect.12 In the course of our investigation on the reactivity of 2-arylbenzoxazole, we also employed 2-phenylbenzoxazole as starting material using our previous optimized reaction conditions (i.e., Pd(OAc)2, 2 eq. of KOAc, in DMA at 150 ºC) (Scheme 1). To our surprise, we obtained the unexpected C7 arylation product 1 as unique product in 31% yield.13 This result was quite remarkable, as the previously reported conditions only afforded the arylated product 2, resulting from the benzoxazoyl directed arylation (Fig. 1a).5a, 5b In addition other synthetic approaches generally involved multistep synthesis or/and poor regioselectivities.14 Only a few heterocycles display reactive C7–H or C4–H bonds using palladium catalysis (i.e., indazoles,15 pyrazolo[1,5-a]pyrimidines,16). + N
O
CHO
Pd(OAc) 2 (2 mol%)
Br (1 mmol)
KOAc (2 mmol) DMA, 150 ºC
N
O CHO Ph
1 31%
N
(1.5 mmol)
O
x-ray structure of 1
OHC
2 not detected
Scheme 1. Preliminary Result Then, we chose 1-bromo-4-(trifluoromethyl)benzene as more reactive coupling partner to screen the influence of several parameters of this reaction (Table 1). The same reaction conditions allowed the synthesis of C7 arylated benzoxazole 3 in 35% yield (entry 1). First, the influence of other solvents was evaluated (entries 2-5). Lower yields were obtained when the reaction was performed in DMSO or DMF and no reaction occurred in a nonpolar solvent such as xylene. Interestingly, when NMP was used as solvent, a higher yield of 56% in 3 was obtained (entry 5). We also examined other palladium sources (entries 6-8). PdCl2 affords a higher 68% yield in 3, whereas both PdCl(C3H5)(dppb) and Pd2(dba)3 led to lower yields. The use of PivOK improved the yield in 3 to 79% (entry 9). As proposed by Fagnou and coworkers, the superior activity of PivOK could come from its better
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proton-shuttle character in CMD mechanism, which makes the C– H bond cleavage easier. No yield improvement was observed using other bases such as K2CO3, Cs2CO3, t-BuOK, or AdOK (entries 1013). The change of the stoichiometry of the reaction, namely, 1 eq. of 2-phenylbenzoxazole and 1.5 eq. of 1-bromo-4(trifluoromethyl)benzene allowed the formation of desired product 3 in higher 85% yield (entry 14). When dried conditions were used, no reaction occurred; whereas the addition of 4 eq. of water promoted the reaction (entries 14-17).17, 18 Table 1. Optimization of the Reaction Conditions.
N
O
Ph (1.5 mmol)
+
Br
CF 3
(1 mmol)
CF 3
[Pd] (x mol%)
Base (2 mmol) Solvent, 140 ºC, 16 h
N
O Ph
3
Entry [Pd] (x mol%) Base Solvent Yield in 3 (%) 1 Pd(OAc)2 (2) KOAc DMA 38 2 Pd(OAc)2 (2) KOAc DMSO 14 3 Pd(OAc)2 (2) KOAc DMF 35 4 Pd(OAc)2 (2) KOAc xylene 0 5 Pd(OAc)2 (2) KOAc NMP 56 6 PdCl2 (2) KOAc NMP 68 7 PdCl(C3H5)(dppb) (2) KOAc NMP 14 8 Pd2(dba)3 (1) KOAc NMP 18 9 PdCl2 (2) PivOK NMP 79 10 PdCl2 (2) K2CO3 NMP 8 11 PdCl2 (2) Cs2CO3 NMP 34 12 PdCl2 (2) tBuOK NMP 21 13 PdCl2 (2) AdOK NMP 62 14[a] PdCl2 (2) PivOK NMP 85 15[b] PdCl2 (2) PivOK NMP 28 16[b, c] PdCl2 (2) PivOK NMP N.R. 17[b, c, d] PdCl2 (2) PivOK NMP 72 [a] 1 mmol. of 2-phenylbenzoxazole and 1.5 mmol. of 1-bromo-4(trifluoromethyl)benzene. [b] Dried NMP and PivOK. [c] Molecular sieves 4 Å (200 mg). [d] 4 mmol. of water.
With the optimized reaction conditions in hands, we turned our attention to the substrate scope for these direct C7 arylations of benzoxazole derivatives (Scheme 2). First, aryl bromides with 4nitrile, 4-formyl, 4-propionyl or 4-ester substituents have been successfully reacted with 2-phenylbenzoxazole to afford the C7 arylated benzoxazoles 4-7 in 62-85% yields. The reaction also proceeded in high yield using bromobenzene. 3Bromobenzonitrile afforded the desired product 9 in 66% yield. The reaction was found to be slightly steric factor dependent, as 2bromobenzaldehyde afforded the desired product 1 in 62% yield. 3-Bromopyridine and 5-bromopyrimidine were also successfully employed affording the C-7 arylated benzoxazoles 10 and 11 in 72% and 65% yields, respectively. Functional groups on the C2aryl of the benzoxazole were tolerated. Indeed, 2-(3-chloro-5fluorophenyl)benzoxazole was regioselectively arylated at C7 position with aryl bromides affording the desired products 12 and 13 in 59% and 64% yields, respectively. Direct arylation of a 3chloro-5-fluorobenzene moiety was not operative in NMP.18 Benzoxazoles substituted by an alkyl group at C2 position were also arylated at C7 position in very high yields. For example, from 2methybenzoxazole and a set of aryl bromides including heteroaryl bromides, the C7-arylated products 14-21 were obtained in 5389% yields. The electron-rich aryl bromide 4-bromoanisole was not reactive under these conditions. However, from 4-iodoanisole and in the presence of a diphosphine ligand, the desired coupling product 18 was isolated in 53% yield.18 A benzoxazole bearing a tert-butyl group at C2 position displayed a high reactivity, as 22 was obtained in very high yield, albeit an isopropyl substituent also afforded the C7-arylated product 23 but in 73% yield. It is im-
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portant to note that this reaction was not sensitive to the electronic properties of benzoxazole ring, as benzoxazoles substituted by methyl or nitro groups at C5 position afforded the desired C7 arylated products 24 and 25 in 69% and 65% yields, respectively. For reactions in which lower yields were obtained (i.e., products 9, 10, 20), aryl iodides instead of aryl bromides were also employed. However, similar yields were obtained showing that the lower yields obtained with these electron-deficient aryl bromides do not arise from a slow oxidative additive addition to palladium. R2 +
N
R= 4-CN R 4-CHO 4- COEt 4-CO2Et H 3-CN 2-CHO
O Ph
PivOK (2 eq.) NMP, 150 ºC, 16 h 4 5 6 7 8 9 10
R R= 4-CN 4-CF3 4-COEt H 4-OMe 3-CN 2-CN
N O O R= CN 12 59% Me CO2Et 13 64%
F
R
Cl CN N
O R
R3
N
76% 83% 65% 84% N O 71% 66%, 72%[a] Ph 62%, 58%[a] 10 72%
R N
R2
PdCl 2 (2 mol%)
(1.5 eq.)
O R1
N
R3
Br
14 15 16 17 18 19 20
O R1
N N
N N
O Ph 11 67%
N
76% N 82% N O 89% 70% Me 0%, 53%[b] 21 75% 74% 65%, 68%[a]
R' 24 R = Me, R' = COEt 69% 25 R = NO 2, R' = H 65% N
R= t-Bu 22 91% i-Pr 23 73%
O Me
[a] ArI was used insed of ArBr. [b] 2 mol% of Xantphos was added and the reaction was performed from 4-iodoanisole instead of 4-bromoanisole.
Scheme 2. Scope of the Pd-Catalyzed Benzoxazoles C7 Arylations. We also investigated the reactivity of benzothiazoles (Scheme 3). We were pleased to find that the reaction proceeded well with 2-alkylbenzothiazoles. 2-Tert-butyl- or 2-iso-propylbenzothiazoles were arylated using 2 mol% of PdCl2 in the presence of KOAc as base in NMP to afford the C7 arylated products 26-29 in 54-63% yields. 2,5-Dimethylbenzothiazole was also arylated at the C7 position in good yield. However, 2-phenylbenzothiazole displayed no reactivity under these conditions, probably due to the formation of a chelate complex with the palladium species. R2
R3 + Br
N
S
R2
PdCl 2 (2 mol%)
PivOK (2 eq.) NMP, (1.5 eq.) 150 ºC, 16 h
R1 = t-Bu t-Bu i-Pr Me Me
R3
N
S
R2 = H H H Me Me
R3 = 4-CN 4-COEt 4-CO2Et 4-COEt 2-CN
O
26 27 28 29 30
8 or 3
R NH
(x eq.)
R
OH
H 2N
Ph
R = H 31 96% Ph i) NaBH 4 (2 eq.), AcOH (cat.), THF, rt, 16 h; ii) Pd/C (10 mol%), EtOH, H 2 (2 atm), rt, 12 h.
OH
R = H 32 97% R = CF 3 33 97% (over 2 steps)
Scheme 4. Deprotection of Benzoxazoles. The 2,7-diphenylbenzoxazole 8 has been deprotected using NaBH4 to furnish the N-benzyl-2-amino-6-phenylphenol 31 in 96% yield. Then, debenzylation using Pd/C under H2 atmosphere allowed the formation of the aminophenol 31 in excellent 97%
x eq. 34 8 1 43% traces 3 traces 46%
i) b.
+
Br
R3
N O R2
H 2N
CN
CN
(1.5 eq.)
OH N.R.
O R3 R1 N R2 O NH
H 2N
O N.R.
Ph CN
O
N.R.
CN O
ii)
i)
+ 8
Ph N 34
Ph
Br
N
54% 63% 67% 68% 57%
The potential of this methodology for the access to C6 arylated 2-aminophenols, which are useful building blocks in pharmaceuticals, was then investigated (Scheme 4).19 R
O
i)
+
a.
R1
Scheme 3. Scope of the Pd-Catalyzed Benzothiazoles C7 Arylations.
O
Based on Gorelsky calculations,20 the difference between the Gibbs free energies of activation (ΔG‡298K) for the cleavage of the C4–H and C7–H bonds of benzoxazole or benzothiazole via a CMD pathway does not explain the complete regioselectivity on this reaction. Nevertheless, we cannot completely deny a potential effect of the C2 benzoxazole substituent. Then, in order to have a better understanding of the reaction mechanism, a set of control experiments was carried out. As expected from the previous literature,21 unsubstituted benzoxazole in the presence of 1 equiv. of PhBr was arylated at C2 position affording 34 in 43% yield; however, in presence of 3 equiv. of PhBr, the diarylated product 8 was isolated in 46% yield (Scheme 5.a). No reaction occurred using unprotected 2-aminophenol, 2-methoxyaniline and N-(2methoxyphenyl)benzamide. Using N-benzoyl aminophenol as starting material, we found that the arylation occurred at the C–H bond adjacent to the OH function; however, a cyclization reaction also took place to give the benzoxazole 4 in 37% yield with trace amount of the arylated product 35. No arylation product arising from an amide directed reaction was detected. From 2-(piperidin1-yl)phenol, in which amine was protected (no cyclization to form a benzoxazole was possible) the arylated product 36 was regioselectively obtained in 27% yield (Scheme 5.b). All these control experiments seem to support a phenoxy directed arylation mechanism via an isomerization between opened and closed benzoxazole forms which may occur at high temperature.22 However, we cannot completely deny a SEAr mechanism, which has been proposed by Hartwig in the case of iridium-catalyzed C7 borylation of benzoxazoles.23 Finally, an intermolecular kinetic isotopic effect (KIE, kH/kD) of 1.8 was determined from two parallel reactions. This result suggest that the C–H bond cleavage is the “turnover-limiting step” of this catalytic reaction (Scheme 5.c).24
R1
R1
N
yield. This sequence reaction was also conducted from 3, without the isolation of the intermediate, to give the 2-amino-6-arylphenol 33 in 97% yield.
N NH
Ph
OH
OH
36 27%
35 traces + 4 (37%)
c.
H/D N
O Ph
+ Br
CN
i)
(1.5 eq.)
37-[D]
CN N
O 4
KIE = 1.8
Ph
i) PdCl 2 (2 mol%), PivOK (2 eq.), NMP, 150 ºC, 16 h.
Scheme 5. Control Experiments and Kinetic Isotopic Effect. Finally, a plausible catalytic cycle is shown in Fig. 3. We propose a catalytic cycle involving phenoxy chelation-assisted palladiumcatalyzed regioselective C–H bond cleavage (intermediate E), resulting from an equilibrium between the closed (C) and the opened (D) forms of benzoxazole.25 A similar mechanism might also be operative from benzothiazole with a sulfur chelationassisted C–H bond activation. Such opened transition states have
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been previously mentioned in the direct functionalization of benzoxazoles or azoles at the C2 positions.8, 26 Ar–Br
Pd 0
Ar Pd A Br
Ar OH O G
N H
R
Ar
- H 2O F
O
H
KBr
N H
O R
OH O
Ar
KOAc
Pd
Ar Pd OAc B
R
R N
H Pd O
Ar
N C + H 2O H OH O
O AcOH
H E
N H
R D
N H
Figure 3. Proposed Mechanism. In summary, we discovered that a simple catalytic system, namely, phosphine-free of PdCl2 with PivOK as base in NMP, allowed the regioselective arylation of both benzoxazoles and benzothiazoles at unexpected C7-position. Mechanistic studies suggest that an open form of benzoazoles with a palladium coordination to the phenoxy group is the key factor for the control of the regioselectivity. We believe that this methodology is the first one allowing a simple access to C7-arylated benzoazoles and 2-amino-6arylphenols. As this procedure tolerates a wide substrate scope, it should find further applications in drug and material designs.
ASSOCIATED CONTENT Supporting Information. Reaction procedure and spectra are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author *
[email protected],
[email protected] ACKNOWLEDGMENT F. A. is grateful to Université de Tunis El Manar.. We also thank the CNRS, “Rennes Metropole” and French Scientific Ministry of Higher Education for providing financial support.
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R
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26.(a) Zhang, F.; Greaney, M. F., Angew. Chem. Int. Ed. 2010, 49, 2768-2771; (b) Strotman, N. A.; Chobanian, H. R.; Guo, Y.; He, J.; Wilson, J. E., Org. Lett. 2010, 12, 3578-3581; (c) Joseph, J.; Kim, J. Y.; Chang, S., Chem. Eur. J. 2011, 17, 8294-8298.
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