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Late-Stage Diversification of Imidazole-Based Pharmaceuticals Through Pd-Catalyzed Regioselective C–H Bond Arylations Amal Benzai, Xinzhe Shi, Fazia Derridj, Thierry Roisnel, Henri Doucet, and Jean-François Soulé J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01469 • Publication Date (Web): 23 Jul 2019 Downloaded from pubs.acs.org on July 23, 2019
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The Journal of Organic Chemistry
Late-Stage Diversification of Imidazole-Based Pharmaceuticals Through PdCatalyzed Regioselective C–H Bond Arylations Amal Benzai,‡, † Xinzhe Shi,‡ Fazia Derridj,† Thierry Roisnel,‡ Henri Doucet‡,* and JeanFrançois Soulé‡,* ‡Univ
Rennes, CNRS UMR6226, F-3500 Rennes, France
[email protected],
[email protected] †Laboratoire
de Physique et Chimie des Matériaux (LPCM), UMMTO University, BP 17 RP, 15000 Tizi-Ouzou, Algeria
Abstract: Palladium-catalyzed C–H bond arylation of imidazoles has been applied to pharmaceuticals such as Bifonazole, Climbazole and Prochloraz. In the presence of phosphine-free Pd(OAc)2 catalyst, aryl bromides are efficiently coupled at the C5 position of the imidazole units which are widely decorated. Under these conditions, only C–H bond arylation reaction occurred without affecting the integrity of chemical structure of the imidazole-based pharmaceuticals. Moreover, with Bifonazole Pd-catalyzed C–H bond diarylation at C2 and C5 positions of imidazole unit has also been performed.
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Since the pioneering work by Ohta and co-workers at early 90’s on Pd-catalyzed C–H bond arylation of heteroaromatics,1 such catalytic methods have become a powerful methodology for the straightforward synthesis of heterobiphenyl products.2 Besides the research to improve the regioselectivity of the C–H bond arylations,3 the functional group tolerance is an important issue to apply C–H bond arylation toward latestage modifications of complex molecules.4 In 2010, Alberico, Lavilla and co-workers reported the postmodification of peptides via Pd-catalyzed C–H bond arylation of tryptophan residues (Figure 1a).5 In the presence of 10 equivalents of aryl iodides, several tryptophan derivatives were arylated at the C2 position of the indole ring. Such late-stage modifications of tryptophans by Pd-catalyzed C–H bond arylation have been applied for the preparation of macropeptides.6 Ackermann and co-workers have reported direct arylations of tryptophans using metal-free conditions7 or using a ruthenium catalyst.8 Itami, Wünsh and coworkers applied regiodivergent C–H bond arylation of spirocyclic thiophenes to modulate their affinity with σ1 receptor surface (Figure 1b).9 However, only few methods for late-stage modification of pharmaceuticals have been reported in the literature.10
Imidazole ring is an important heterocycle present in many
pharmaceuticals or agrochemicals. As examples, Bifonazole is an imidazole antifungal drug used in the form of an ointment; while Climbazole is prescribed for the treatment of human fungal skin infections such as dandruff and eczema. Ketoconazole is also an antifungal medication used to treat a number of fungal infections. During the past decade, Pd-catalyzed regioselective C–H bond arylation of imidazole ring using aryl bromides,11 aryl chlorides,12 or the successive arylations13 has been intensively studied by several research groups including ours.14 However, to the best of our knowledge, there is no applications of Pdcatalyzed C–H bond arylation of imidazole ring to the late-stage modification of imidazole-based pharmaceuticals. The late-stage diversification of structurally complex imidazoles is a very appealing method for drug discovery. Therefore, herein, we decided to survey the reactivity of several imidazolebased pharmaceuticals such as Bifonazole, Climbazole and Ketoconazole in Pd-catalyzed C–H bond arylation (Figure 1c).
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The Journal of Organic Chemistry
Figure 1. Palladium-Catalyzed Late-Stage C–H Bond Arylations of Pharmaceuticals Containing an Heteroaromatic Unit.
We started our investigations with the late-stage arylation of commercially available Bifonazole with 4bromobenzonitrile as the coupling partner (Scheme 1). Using our previously optimized reaction conditions for C–H bond arylation of imidazole at C5 position [namely, 2 mol% Pd(OAc)2 associated with KOAc as the base in DMA],14a the C5-arylated Bifonazole derivative was isolated in 61% yield. The reaction was very regioselective as other C–H bonds were not arylated. Interestingly, under these reaction conditions, the benzhydryl function was not cleaved. The use of more sophisticated palladium catalysts such as PdCl(C3H5)(dppb) or base (PivOK) failed to improve the yield. A lower catalyst loading of 1 mol% Pd(OAc)2 resulted in a lower yield in 1 of 57%. The reactions was carried out using 1.5 gram of Bifonazole with similar yields than on 1 mmol scale was obtained affording 1.13 g the 5-arylated product 1. To evaluate the potential of this method for the one-step diversification of Bifonazole, we turned our attention to the scope of aryl bromides. The reaction with aryl bromides substituted by electron withdrawing groups –such as nitro, propionyl, ethyl ester, formyl or trifluoromethyl– at para-position reacted smoothly to give a wide 3 ACS Paragon Plus Environment
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diversity of C5-arylated Bifonazole derivatives 2-6 in 43-70% yields. The aryl bromides substituted by an electron donating group, such as 1-bromo-4-(tert-butyl)benzene or 4-bromoanisole, can also be coupled with Bifonazole. However, the C5-arylated products 7 and 8 were isolated in lower yields due to a partial conversation of these less reactive aryl bromides. Meta-substituted aryl bromides efficiently underwent Pdcatalyzed C5–H bond arylation of Bifonazole.
As examples, from 3-bromobenzonitrile and 3-
bromobenzotrifluoride, 9 and 10 were obtained in 61% and 71% yield, respectively. Interestingly, this procedure also allowed to introduce a benzo[1,3]dioxolane, which is widely found in natural products, multitude of alkaloids as well as pharmaceutical drugs. The reaction is not very sensitive to the steric hindrance. Indeed, the reaction performed with 2-bromobenzonitrile or 2-bromobenzotrifluoride afforded the C5-arylated Bifonazole derivatives 12 and 13 in 58% and 45% yield, respectively. Naphthalene is an important chromophore which can be used as a suitable probe for biological investigations.15
The
Bifonazole congeners 14 and 15 containing naphthyl units have been prepared in average yields from 2-, or 1-bromonapthalene through Pd-catalyzed C5 direct arylation of the imidazole ring. Finally, heteroaryl bromides were evaluated. The reaction between Bifonazole and 4-bromoisoquinoline lead to the formation of the desired C5-heteroarylated imidazole 16 in 63% yield. The structures of 15 and 16 were also assigned by X-ray analysis. Moreover, 5-bromopyrimidine was coupled with Bifonazole to afford the product 17 in 40% yield. The reaction is not limited to the use of N-containing heteroaryl bromides as the reaction between Bifonazole and 2-acetyl-5-bromothiophene provided the 5-(thiophen-2-yl)-imidazole derivative 18 in 59% yield. Interestingly, heteroaryl chloride such as 3-chloropyridine can also be employed as aryl source for the C5 direct arylation of Bifonazole to afford the bis-heteroaryl product 19 in 45% yield.
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The Journal of Organic Chemistry
Ph
Ph N
Ph
N
Ph N N
+
Br Ar
R= CN
1 61% (58%)a (61%)b (57%)c (57%, 1.13g)d N NO2 2 43% Ph COEt 3 77% CO2Et 4 90% CHO 5 77% CF3 6 66% R t-Bu 7 34% OMe 8 35%
Ph
Ph N
Ph
N
Pd(OAc)2 (2 mol%)
Ph
N
N
Ph
N
N
Ph
Ph Ar
Ph
Ph Ph
N O
N
Ph
Ph
N
Ph N
N
Ph N
N
15 42%
16 63%
Ph
N
Ph
X-ray analysis of 15
N N
N
17 41%
Ph
R R= CN 12 58% CF3 13 45%
11 28%
S
N 14 39%
N N
O
R R= CN 9 61% CF3 10 71%
Ph
N
N
KOAc (2 equiv.) DMA, 150 ºC 16 h
Ph N
O Me
18 59%
19 45%e
X-ray analysis of 16
Scheme 1. Palladium-Catalyzed Late-Stage Arylations of Bifonazole at the C5-position of the Imidazolyl Unit. aUsing
2 mol% PdCl(C3H5)(dppb). bUsing PivOK as base. cUsing 1 mol% of Pd(OAc)2. [c] Reaction performed with 3-chloropyridine. d Reaction performed using 1.5 g of Bifonazole Based on our previous work on one-pot Pd(OAc)2-catalyzed 2,5-diarylation of N-methyl imidazole,14b we next also considered applying this transformation for the late-stage diversification of imidazole-based pharmaceuticals (Scheme 2). Using our previous optimized reaction conditions for the direct diarylation of imidazole derivatives, namely 2 mol% of Pd(OAc)2 associated with 4 equivalents of CsOAc as strong base in DMA at 150 ºC for 48 h, Bifonazole reacted with 4-bromotoluene to afford the C2,C5-diarylated imidazole 20 in 57% yield. Similar reactivities were observed with 4-bromoanisole and bromobenzene leading to the formation of C2,C5-diarylated Bifonazole congeners 21 and 22 in 58% and 55% yield, respectively. In all cases, we also observed the formation of C5-monoarylated product in the crude mixtures but in low yields (
