Efficient synthesis of halohydroxypyridinesby hydroxydeboronation

Anne Sophie Voisin, Alexandre Bouillon, Jean-Charles Lancelot and Sylvain Rault*

Centre d’Etudes et de Recherche sur le Medicament de Normandie (CERMN), UPRES EA-2126, U.F.R. des Sciences Pharmaceutiques,

5, rue Vaubenard, 14032 CAEN Cedex, France

Received 30 September 2004; revised 1 December 2004; accepted 2 December 2004

Available online 23 December 2004

Abstract—This paper describes a general method for the synthesis of halohydroxypyridines from novel halopyridinylboronic acids andesters recently described by some of us. Halopyridinylboronic acids and esters have been efficiently hydroxydeboronated under mildconditions by employing hydrogen peroxide or meta-chloroperbenzoic acid. These hydroxylations take place regioselectively without otheroxidation (N-oxide formation).q 2004 Elsevier Ltd. All rights reserved.

1. Introduction

Polyfunctional pyridines have become very useful com-pounds which have found applications as precursors ofpharmacological compounds or in the synthesis of liquidcrystals and polymers.1 Indeed, many products incorporatepyridine units bearing hydroxyl functions.

On the one hand, for instance, halohydroxypyridines areparticularly useful key intermediates in the synthesis ofanalogs of ABT-594,2 a potent non-opioid analgesic agent(Scheme 1).

Scheme 1.

Scheme 2.

On the other hand, halohydroxypyridines constitute appro-priate starting materials for the synthesis of orellanine, themost potent nephrotoxin found in some cortinarius mush-rooms species.3 Halohydroxypyridines have although agreat interest as precursors for new and highly activeherbicides and insecticides. Indeed, pyridine derivativeshave been shown as suitable compounds for combating

0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.doi:10.1016/j.tet.2004.12.006

Keywords: Pyridine; Hydroxydeboronation; Boronic acids.* Corresponding author. Tel.: C33 2 31 93 4169; fax: C33 2 31 93 1188;

e-mail: rault@pharmacie.unicaen.fr

noxious insects, acarides, nematodes or mollusks4

(Scheme 2).

The two methodologies allowing the preparation ofhalohydroxypyridines are the following ones: either theelectrophilic halogenation of hydroxypyridines or thehydroxylation of appropriate halopyridines.

Concerning the electrophilic halogenation of hydroxy-pyridines, numerous studies have been published. Thesemethodologies are drastic,5 yield mixtures of isomers6–8 andare often accomplished in several steps.9

Hydroxylation of halopyridines often uses the diazotation ofaminopyridines as the key step. The preparation of somechlorohydroxypyridines10 and iodohydroxypyridines11 havebeen described by this route. More recently, an originalsynthesis of fluorohydroxypyridines12 using acetyl hypo-fluorite has been reported. Finally, 2-chloropyridine hasbeen efficiently hydroxylated under mild and neutralconditions by employing cupric nitrate/phosphate buffer/

Tetrahedron 61 (2005) 1417–1421

Scheme 6. Reagents: (a) (1) n-BuLi, B(OiPr)3, K78 8C, (2) hydrolysis orpinacol, AcOH, hydrolysis; (b) (1) LDA, B(OiPr)3, K60 8C, (2) hydrolysisor pinacol, AcOH, hydrolysis.

A. S. Voisin et al. / Tetrahedron 61 (2005) 1417–14211418

30% hydrogen peroxide system in 78% yield.13 In fact, nogeneral method exists and reactivity often depends on initialsubstrate, on the nature and the position of the substituents.Therefore, there is a need to carry out direct hydroxylationof pyridines under mild reaction conditions.14

An alternative convenient and efficient route to synthetizehalohydroxypyridines II stands in the hydroxy-deborona-tion, originally described for the synthesis of phenol,consisting in the oxidation of the C–B bond by variousreactants15 (Scheme 3).

Scheme 3. Reagents: (a) aq H2O2, CH2Cl2, rt, 12 h; (b) 1.2 equiv m-CPBA,CHCl3, 6, 5 h.

2. Results and discussion

The hydroxydeboronation of halopyridinylboronic acids hasonly been described twice. 2-Chloro-5-iodopyridine under-goes a halogen–metal exchange (Scheme 4). The resultingunstable boron-ate complex is in situ converted into2-chloro-5-hydroxypyridine by action of hydrogenperoxide.2

Scheme 4. Reagents: (a) (1) BuLi, cyclohexane, THF, K78 8C, (2)B(OMe)3, K10 8C; (b) 30% aq H2O2, AcOH, 0–25 8C.

Scheme 7. Reagents: (a) aq H2O2, CH2Cl2, rt, 20 h.

The access to hydroxypyridines has also been recentlydescribed by Matondo16,17 from 2,6-dibromopyridine whichleads to the corresponding boronic acid, then to 2-bromo-6-hydroxypyridine via an oxidation reaction (Scheme 5).

Scheme 5. Reagents: (a) (1) iPrMgCl, 20 8C, 2 h, (2) [(CH3)3Si]3B, 0 8C tort, 24 h, (3) HCl/H2O, 0 8C to rt; (b) 3 N NaOH, 30% aq H2O2, THF, 0–5 8Cto 50 8C.

In our laboratory, the synthesis and the isolation of newhalopyridinylboronic acids and esters18–21 has been pub-lished (Scheme 6). These compounds are prepared takinginto account a regioselective halogen–metal exchange usingn-butyllithium or a regioselective ortholithiation usinglithium diisopropylamide and subsequent quenching withtriisopropylborate starting from appropriate mono- or di-halopyridines.

From these halopyridinylboronic acids and esters,22 wefocused on a general one-step method for the synthesis ofhalohydroxypyridines in aqueous or in anhydrousconditions.

2.1. Aqueous conditions

In this study, we chose to develop, in heterocyclic series, theprocedure described by Simon in aromatic series.23 Thereaction was carried out in a biphasic system (dichloro-methane/water) at room temperature from boronic acids oresters. The reaction is very mildly and totally regioselective.

Action of hydrogen peroxide on halopyridinylboronic acidsor esters lead to appropriate halohydroxypyridines in goodyields without base (Scheme 7 and Table 1).

Analytical data prove that only one product has beenformed. In agreement with Katritzky et al.,24 a singleb-halogen atom exerts a relatively small effect on thepyridone-hydroxypyridine equilibrum whereas a singlea-halogen atom has a much greater effect; our compoundsexist on an appreciable extent in the hydroxy-form.

Recently, we isolated two novel boronic acids, 2,6-dichloropyridin-3-yl boronic acid25 and 2,5-dichloro-pyridin-4-yl boronic acid. These compounds are preparedtaking into account a regioselective ortholithiation usinglithium diisopropylamide and subsequent quenching withtriisopropylborate starting from 2,6-dichloropyridine and2,5-dichloropyridine, respectively, (Scheme 8).

Extensive studies for the regioselectivity of lithiation of3-chloropyridine have been carried out by Queguiner’sgroup: LDA has been shown to be the most efficient in

Table 1. Synthesis of halohydroxypyridines 2 to 16 by action of hydrogen peroxide

Compounds B(OR)2 (position) X Hydroxy-pyridines Yields (%)a

1a 2 6-Br 2 491b 2 6-Br 23a 3 6-Br 4 853b 3 6-Br 45a 3 6-Cl 6 825b 3 6-Cl 67a 3 6-F 8 797b 3 6-F 89a 3 5-Br 10 839b 3 5-Br 1011a 3 4-Cl 12 5111b 3 4-Cl 1213a 3 2-Cl 14 8113a 3 2-Cl 1415a 4 2-Cl 16 7415a 4 2-Cl 16

a Best yields obtained, carrying out hydroxydeboronation either from halopyridinylboronic acids or esters. The deviation between these two reactants is notsignificant (!8%).

A. S. Voisin et al. / Tetrahedron 61 (2005) 1417–1421 1419

formation of the 4-lithio-species. But few studies have beencarried out on dihalopyridines and it seems that bothpositions can be deprotonated.26 In fact, the two regio-isomeric compounds were obtained without mutual con-tamination when 2,5-dichloropyridine was lithiated.Treatment with TMEDA-activated BuLi afforded 4-lithio-

Scheme 9.

Scheme 8. Reagents: (a) (1) LDA, B(OiPr)3, K80 8C, THF, (2) hydrolysis;(b) aq H2O2, CH2Cl2, rt, 20 h.

2,5-dichloropyridine whereas using t-BuLi afforded2-lithio-3,6-dichloropyridine.27 In our case, we assumethat only 4-substituted product is formed since an amide isused for deprotonation (Scheme 9).

Derivatives with two a-halogen atoms displace thetautomeric equilibrium of pyridones significantly in favourof the hydroxypyridines form under all the conditionsinvestigated.24

2.2. Anhydrous conditions

The hydroxydeboronation can also be considered inanhydrous medium in the presence of meta-chloro-perbenzoic acid. The method is extremely regioselective(in the presence of 1.2 equiv of m-CPBA) and allows also

Scheme 10. Reagents: (a) 1.2 equiv m-CPBA, CHCl3, D, 5 h; (b) 2.4 equivm-CPBA, CHCl3, D, 5 h.

A. S. Voisin et al. / Tetrahedron 61 (2005) 1417–14211420

the preparation of hydroxy-N-oxides with 2.4 equiv ofm-CPBA (Scheme 10).

In conclusion, we have described a general method for thesynthesis of halohydroxypyridines obtained from novelhalopyridinylboronic acids and esters.

Halohydroxypyridines constitute very interesting key com-ponents likely to be engaged in various reactions and inparticular in cupro-catalyzed couplings like Chan Lam28

coupling leading, for example, to the formation ofdiarylethers.

We currently make profitable the reactivity of halo-pyridinylboronic acids and esters and halohydroxypyridinesin original reactions.

3. Experimental

3.1. General procedures

Commercial reagents were used as received withoutadditional purification. Melting points were determined ona Kofler melting point apparatus and are uncorrected. IRspectra were taken with a Perkin Elmer BX FT-IR. 1H NMR(400 MHz) and 13C NMR (100 MHz) were recorded on aJEOL Lambda 400 Spectrometer. Chemical shifts areexpressed in parts per million downfield from tetramethyl-silane as an internal standard. Thin-layer chromatography(TLC) was performed on 0.2 mm precoated plates of silicagel 60F-264 (Merck). Visualization was made withultraviolet light. Elemental analyses for new compoundswere performed at the ‘Institut de Recherche en ChimieOrganique Fine’ (Rouen).

Starting materials were purchased from Aldrich, AcrosOrganics and Lancaster and used without purification.

Analytical data for known compounds were always fullyconsistent with published data.

3.2. General procedure for the synthesis of dichloro-pyridinylboronic acids (17 and 19)

To a slurry of freshly distilled diisopropylamine (2 equiv) in100 mL of anhydrous tetrahydrofuran cooled to K40 8Cwas added dropwise a 2.5 M solution of n-BuLi in hexanes(2.2 equiv). The mixture was allowed to react at K40 8Cduring 30 min, and then cooled to K80 8C. A solution ofdichloropyridine (67.5 mmol, 1 equiv) in 50 mL ofanhydrous tetrahydrofuran was added dropwise in order tokeep the internal temperature at K80 8C. The resultingbeige mixture was allowed to react at this temperature over1 h. A solution of triisopropylborate (2.2 equiv) in 50 mL ofanhydrous tetrahydrofuran was then dropwise added,keeping the internal temperature at K80 8C. The mixturewas allowed to warm to room temperature and left to reactfor an additional hour. The resulting solution was quenchedby slow addition of 4% aqueous NaOH solution (200 mL).The resulting aqueous layer was collected and acidified topH 4 by dropwise addition of 6 N HCl (z60 mL), keepingthe internal temperature below 5 8C. Extraction with ethyl

acetate, evaporation of the organic layer and crystallizationfrom diethylether gave pure 17 and 19.

3.2.1. 2,6-Dichloro-3-pyridinylboronic acid (17). Paleorange solid, mp 150 8C. IR (KBr): 3362, 1568, 1417,1316, 1265, 1167, 1128, 1055, 830, 761, 691 cmK1. 1HNMR (d6-DMSO) d 8.60 (s, 2H), 7.90 (d, JZ7.8 Hz, 1H),7.49 (d, JZ7.8 Hz, 1H). 13C NMR (d6-DMSO) d 151.4,148.9, 146.1, 122.6. Anal. Calcd for C5H4BCl2NO2: C,31.31; H, 2.10; N, 7.30. Found: C, 31.94; H, 2.08; N, 7.05.

3.2.2. 2,5-Dichloro-4-pyridinylboronic acid (19). Beigesolid, dec 202 8C. IR (KBr): 3368, 1446, 1402, 1352, 1298,1194, 1119, 1041, 896, 670 cmK1. 1H NMR (d6-DMSO) d8.85 (s, 2H), 8.38 (s, 1H), 7.51 (s, 1H). 13C NMR (d6-DMSO) d 127.0, 121.1, 112.6, 102.0. Anal. Calcd forC5H4BCl2NO2: C, 31.31; H, 2.10; N, 7.30. Found: C, 30.98;H, 2.11; N, 7.01.

3.3. General procedure for synthesis of halohydroxy-pyridines in aqueous conditions (2, 4, 6, 8, 10, 12, 14, 16,18, 20)

To a stirred solution of boronic acid or ester (0.5 g) in 25 mLof dichloromethane was slowly added hydrogen peroxide(3 equiv). The reaction was then continued at roomtemperature during 20 h and 50 mL of water was added.The organic layer was collected, washed and dried overcalcium chloride/magnesium sulfate mixture, filtrated andconcentrated to dryness. Recrystallization from diethylethergave pure halohydroxypyridines.

3.3.1. 2,6-Dichloro-3-hydroxypyridine (18). Beige solid,mp 130 8C. IR (KBr): 3015, 1563, 1470, 1408, 1318, 1289,1234, 1086, 826, 731, 648 cmK1. 1H NMR (d6-DMSO) d11.14 (bs, 1H), 7.36 (AB system, JZ8.5 Hz, 2H). 13C NMR(d6-DMSO) d 149.5, 137.0, 136.2, 127.3, 124.2. Anal. Calcdfor C5H3Cl2NO: C, 36.62; H, 1.84; N, 8.54. Found: C,36.89; H, 1.61; N, 8.41.

3.3.2. 2,5-Dichloro-4-hydroxypyridine (20). Beige solid,mp 184 8C. IR (KBr): 2925, 1611, 1514, 1404, 1368, 1297,1259, 1104, 929, 731, 578 cmK1. 1H NMR (d6-DMSO) d12.23 (bs, 1H), 8.26 (s, 1H), 6.94 (s, 1H). 13C NMR (d6-DMSO) d 161.6, 153.0, 149.0, 118.7, 111.4. Anal. Calcd forC5H3Cl2NO: C, 36.62; H, 1.84; N, 8.54. Found: C, 36.94; H,1.60; N, 8.38.

3.4. General procedure for synthesis of halohydroxy-pyridines in anhydrous conditions (10)

To a stirred suspension of boronic acid (0.5 g) in 25 mL ofchloroform was slowly added meta-chloroperbenzoic acid(1.2 equiv). The reaction was refluxed for 5 h. The mixturewas allowed to warm to room temperature. The resultingsuspension was washed with 25 mL of sodium hydrogencarbonate. The organic layer was collected, dried overcalcium chloride/magnesium sulfate mixture, filtrated andconcentrated to dryness. Recrystallization from diethylethergave pure halohydroxypyridines.

A. S. Voisin et al. / Tetrahedron 61 (2005) 1417–1421 1421

3.5. General procedure for synthesis of halohydroxy-pyridine-N-oxides in anhydrous conditions (21)

To a stirred suspension of boronic acid (0.5 g) in 25 mL ofchloroform was slowly added meta-chloroperbenzoic acid(2.4 equiv). The reaction was refluxed for 5 h. The mixturewas allowed to warm to room temperature. The resultingsuspension was washed with 25 mL of sodium hydrogencarbonate. The organic layer was collected, dried overcalcium chloride/magnesium sulfate mixture, filtrated andconcentrated to dryness. Recrystallization from diethylethergave pure halohydroxypyridine-N-oxides.

3.5.1. 3-Bromo-5-hydroxypyridine-N-oxide (21). Beigesolid, mp 208 8C. IR (KBr): 3109, 2477, 1563, 1445, 1320,1226, 1151, 1004, 910, 845, 666, 595 cmK1. 1H NMR (d6-DMSO) d 11.06 (bs, 1H), 7.99 (s, 1H), 7.76 (s, 1H), 6.93 (s,1H). 13C NMR (d6-DMSO) d 155.9, 131.9, 129.9, 127.1,114.0. Anal. Calcd for C5H4BrNO2: C, 31.61; H, 2.12; N,7.37. Found: C, 31.68; H, 2.11; N, 7.21.

Acknowledgements

The authors thank Laboratoires Servier, Conseil Regionalde Basse-Normandie and FEDER (Fonds Europeens deDeveloppement Economique Regional) for their financialsupport.

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