吡啶N-氧化物的合成及应用

1.前言

吡啶氮氧化物在有机合成中的应用也比较广泛，它可以进行许多吡啶类化合物无法或很难进行的反应，如卤代，碳氢键活化，硝化,腈基取代等。原因有可能是吡啶氮被氧化后，环上的电子云密度发生了很大的改变；吡啶相当于一个硝基苯，其邻位和对位碳原子上的电子云密度低于苯环，间位碳原子上电子云密度和苯环相当；当吡啶被氧化后就相当于一个氯苯，由于氧原子对氮原子的电负性进行了平衡，从而使环上其它位置的碳原子上电子云的密度发生改变。吡啶氮氧化物发生的碳-氢碱活化反应，多见于2-位,与三氯(溴)氧磷等试剂的氯(溴)代反应。当4位没有其它取代基时，同时会取代在2-位和4-位。吡啶氮氧化物还可以和氰化钠和氰化钾及TMSCN等氰化试剂反应，生成2-氰基吡啶氮氧化物。合成吡啶氮氧化物所用的氧化剂一般为：双氧水，间氯过氧苯甲酸，过氧乙酸等，oxone，MMPP等，化合物结构中的羧基，酯基，卤素，羟甲基，氨基，酰胺等基团，在氧化的过程中一般不受影响，可以放心去氧化。

2. 反应实例

2.1吡啶2位甲基氮氧化物的醇化

吡啶2-位甲基氮氧化物在TFAA或乙酸酐的作用下可以生成苄位醇

Step 1

A mixture of dimethyl 5-(6-methylpyridin-3-yl)isophthalate 2 (24 g, crude, 84.21 mmol) in 150 mL of dry DCM was added showly m-CPBA(22.68g,131.42 mmol) and stirred at 25 o C for 2.5h.TLC showed the reaction was completed. Na2SO3 (aq, 200 mL) and NaHCO3 (100 mL) was added to the mixture, and extracted with EtOAc (200 mL) 3 times.The organic layer was washed with water (200 mL) and brine (200 mL),dried over Na2SO4 and filtered, concentrated in vacuum to give a crude 3 (15g) which was used for the following step immediately.

Step 2

A mixture of crude 3 (15 g, crude, 49.8 mmol) in 100 mL of dry DCM was added showly TFAA(80 mL) at 0oC and stirred at 55 o Cfor 48h.TLC showed the reaction was completed. The reaction was concentrated and adjusted pH = 9 by added NaHCO3 (aq), and extracted with EtOAc (200 mL) ,The organic layer was washed with water (200 mL) and brine (200 mL), dried over Na2SO4 and filtered, concentrated in vacuum to give a residue was purified by silica chromatography with PE/EtOAc (100:1-2:1) to afford 4 (10.0 g, 66%) as a white solid.

Journal of Inorganic Biochemistry (2015), 144, 18-30

Step 1

35 mL of hydrogen peroxide (35% solution, 0.41 mol) was added to a solution of 5-ethyl-2-methyl-pyridine (21.76 mL, 0.17 mol) in glacial acetic acid (200 mL) and refluxed for 16 h (depicted in step c of Scheme 1). After evaporation of the majority of the solvent, the reaction mixture was neutralized with NaOH and Na2CO3 and the starting material was retrieved by extraction with petroleum ether.5-Ethyl-2-methyl-pyridine-N-oxide was extracted from the aqueous phase with CHCl3,dried over Na2SO4 and after removal of the solvent obtained as a bright yellow liquid in 99% yield

Step 2

a solution of the 5-ethyl-2-methylpyridine-N-oxide (22.28 g, 0.16 mol) andacetic anhydride (28 mL, 0.23 mol) in glacial acetic acid (7 mL) was refluxed for 3h, put on ice, neutralized, extracted with methylene chloride. After removal of the solvent, the extract was dissolved in diethyl ether, washed with a saturated solution of Na2CO3 and dried over Na2SO4 to give the product in 85% yield

Step 3

5-ethylpyridin-2-yl-methyl acetate (24.29 g, 0.14 mol) was dissolved in tetrahydrofuran (THF) and refluxed with an aqueous solution ofNaOH (8.1 g, 0.20 mol) for 5h. The reaction mixture was reboiled on activated charcoal and was neutralized with glacial acetic acid and filtered. After concentration of the crude product under reduced pressure, it was dissolved in a saturated solution of NaHCO3,extracted with diethyl ether and dried over sodium sulfate to give the product as a brown oil in 80% yield.

WO2017006280 A1

Step 1

To a stirred solution of material compound (16g, 34 mmol) in DCM (170 ml) was added m-CPBA (11.7 g, 51.1 mmol)at rt over 5 min. After 4h, the reaction mixture was washed with Na2CO3 (3 x 5 mL),dried over Na2SO4,filtered and concentrated to give desired compound (14.6 g,).

Step 2

To a stirred solution of compound material (12.8g, 26.4 mmol) in anhydrous DCM (132 ml) was added, dropwise, trifluoroacetic anhydride (7.45ml, 52.7mmol) over 5 min at it.After 2h,sat NaHCO3 (50 mL) was slowly added, stirred for 10 min, aq layer separated, organic layer dried Na2SO4,filtered,concentrated,adsorbed onto celite and was purified on silica gel.The major peak was collected to afford desired compound (9.7 g, 76 % ).

A solution of 5 (0.54 g, 2.5 mmol) in 10 mLAc2O was stirred and heated at 110 ºC until the oxide was completely consumed (monitored by TLC).The mixture was cooled to room temperature and neutralized to PH ≥ 9 with a saturated aqueous solution of Na2CO3 and extracted with CH2Cl2. The remains after removal of CH2Cl2 by rotary evaporation was dissolved in an aqueous solution of HCl (1 mL conc. HCl in 8 mL water) and stirred at 70 ºC for 2h.The mixture was cooled to room temperature and neutralized to PH ≥ 9 with a saturated aqueous solution of Na2CO3.The product was taken up with CH2Cl2.The extract was dried over K2CO3 and concentrated.The crude product was purified by flash column chromatography to give 6 as a yellow solid in a 94% yield.

The N-oxide 2 (2.10 g, 9.3 mmol) was dissolved in dry chloroform (70 mL) at room temperature.Trifluoroacetic anhydride (TFAA) (25.9 mL, 186.0 mmol) was added and the solution was heated at 60 °C for 4.5h. After evaporation of solvent, the resultant yellow oil was dissolved in a mixture of ethanol (20 mL) and H2O (20 mL) and stirred for 3h at room temperature.The ethanol was evaporated and the aqueous phase was extracted with dichloromethane (3 x 7 125 mL).The organic phases were combined, dried over MgSO4 and evaporated under reduced pressure.The crude product was purified on a silica chromatography columnto afford compound 3 as a white solid (1.16 g, 55%).

2.2吡啶氮氧化物硝基化

吡啶氮氧化物的硝化反应就相对容易，一般硝化在4-位

J. Org. Chem.2009, 74, 939–942

To 40 mL of cold H2SO4.(0 ~ 10 ºC), the oxide 3 (0.93 g, 5 mmol) and then KNO3 (10.0 g, 100 mmol) was slowly added in portions. The mixture was heated to 80ºC and kept stirring at the temperature for 10h. The reaction was quenched by pouring the mixture onto cracked ice. The resulting solution was neutralized to PH ≥ 9 with a saturated aqueous solution of Na2CO3 and extracted with CH2Cl2.The extract was dried over K2CO3 and concentrated.The crude product was purified by flash column chromatography to give 4 as a yellow solid in a 74% yield

Chemical Communications (Cambridge, United Kingdom) (2016), 52(77), 11535-11538

Stir a mixture of (30.2 g) 2,6-dimethylpyridine 1-oxide in 40 mL H2SO4 and 30 mL fuming HNO3 at 110°C for 3 hours.Mix the solution with ice and H2O.Extract the solution with CH2Cl2.Wash the combined extract with 250 mL saturated K2CO3 solution.Extract the aqueous layer with CH2Cl2.Dry the combined extract over Na2SO4.Filter combined extract.Concentrate combined extract.

Inorganic Chemistry (2019), 58(5), 3015-3025

6-Methyl-pyridine-N[1]oxide-2-carboxylic acid (313 mg, 2.04 mmol) was dissolved in H2SO4 (11 mL, 204 mmol) at room temperature and the solution was placed in an ice bath. Concentrated nitric acid (9.7 mL, 153 mmol) was added slowly to the mixture and the solution was heated at 100 °C for 3 days. After cooling to room temperature, the solution was poured slowly onto ice (100 g) over 1 h and the ice allowed to melt. The mixture was filtered and the aqueous phase was extracted three times with CH2Cl2 (3 x 50 mL). All the organic layers were combined, dried over MgSO4, and the solvent reduced to small volume under reduced pressure. After 2 days, crystals appeared in the flask (following slow solvent evaporation). The crystals were filtered to give compound 1 as a colorless solid (144 mg, 36%). The filtrate was evaporated and purified under column chromatography (SiO2, CH2Cl2/acetic acid, 98/2) to yield additional material (80 mg, 20%).

Journal of Medicinal Chemistry (2003), 46(4), 461-473

To a solution of 25 (3.79 g, 19.7 mmol) inH2SO4 (65.8 mL)was added fuming nitric acid (32.9 mL) under ice cooling and the mixture was stirred at 100 C for 4 h. The reaction mixture was added dropwise to ice cooled water and extracted with CHCl3. The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to afford 26 as a pale yellow solid (3.72 g, 80%yield).

2.3 吡啶氮氧化物‍的碳-氢碱活化

吡啶氮氧化物发生的碳-氢碱活化反应，多见于2-位

WO2008044217 A2

A solution of bromobenzene (0.495 ml) in toluene (3 ml) was added under argon to K2CO3 (466 mg), palladium diacetate (62 mg),tri-tert-butylphosphonium tetrafluoroborate (52 mg)and intermediate (250 mg).The reaction mixture was stirred at 110°C overnight and filtered off through Celite. The resulting solution was evaporated off and the residue was purified by CC (Hept/EA 7/3) to afford 280 mg of the desired product.

Journal of Organic Chemistry (2013), 78(6), 2720-2725

A solution of 1l (10 mmol) in THF (250 mL) was treated with phenyl magnesium chloride (2a, 12 mmol)and then DDQ (15 mmol)as described in the general procedure. Upon completion of the reaction (monitored by TLC), the mixture was warmed to 0°C, and PCl3 (15 mmol) was added dropwise. The mixture was allowed to come to room temperature and stirred for 2 h. The mixture was treated with saturated aqueous Na2CO3 solution (80 mL), and THF was removed by distillation in vacuo. The aqueous phase was extracted with CH2Cl2 (5 × 80 mL), and the organic fractions were dried (Na2CO3) and concentrated in vacuo.The residue was purified by flash chromatography (petroleum ether/ethyl acetate = 10:1) to give 4 in 86% yield (2.30g): white solid

Journal of Organic Chemistry (2013), 78(6), 2720-2725

A dry argon-flushed 250-mL flask, equipped with a magnetic stirrer and a septum, was charged with 2-halopyridine Noxide (3.2 mmol). Dry THF (80 mL) was added, the resulting solution was cooled to −50 °C, and RMgX (3.8 mmol) was then added slowly using a syringe during 1 h. The mixture was stirred at that temperature for 1−1.5h until the 2-halopyridine Noxide was consumed (checked by TLC). DDQ (860 mg, 3.8 mmol) was added.The mixture was then allowed to come to room temperature and stirred for 4h.The reaction was quenched with a 20% solution of Na2CO3 (20 mL), and THF was removed by distillation in vacuo.The aqueous phase was extracted with CH2Cl2 (5 × 40 mL), and the organic fractions were dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by flash chromatography to yield the desired oxide.

Organic Letters (2011), 13(22), 6102-6105

Under argon, a four-necked flask equipped with a magnetic stirrer was charged with 6-methyl-3-nitropyridine 1-oxide(500 mg, 3.2 mmol)and 80mL of THF. The mixture was cooled to -60°C,and EtMgBr( 4.0 mmol) was added slowly with a syringe while the reaction temperature was kept under -60°C.The mixture was stirred at -60°C until starting material was consumed (monitored by TLC).DDQ (900 mg, 4.0 mmol) was added. The mixture was then allowed to come to room temperature and stirred for 4 h. The reaction was quenched with a 20% solution of Na2CO3 (20 mL) and THF was removed by rotary evaporation in vacuo. The aqueous phase was extracted with CH2Cl2 (5 × 40 mL), and the organic fractions were dried (Na2SO4), and concentrated in vacuo. The crude residue was purified by flash chromatography (ethyl acetate/ethanol = 5:1; Rf = 0.35) to yield the oxide 3gm (542 mg, 92%).

2.3 吡啶氮氧化物的腈基取代

吡啶氮氧化物还可以和氰化钠和氰化钾及TMSCN等氰化试剂反应，生成2-氰基吡啶氮氧化物。

WO2018136887 A1

To a solution of 4-cyclopropyl-1 -oxido-pyridin-1 -ium (870 mg, 6.44 mmol) in MeCN (8 mL) was added TEA (1.04 g, 10.3 mmol, 1.43 mL) and TMSCN (1.66 g, 16.74 mmol, 2.1 mL).The mixture was stirred at 70°C for 1h.The reaction mixture was concentrated under reduced pressure.H2O (10 mL) was added and extracted with EtOAc (15 mL x 3), dried over Na2SO4,filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO2, from EtOAc 4% to 20% in Petroleum ether) to afford 4- cyclopropylpyridine-2-carbonitrile (190 mg, 1.32 mmol, 20% yield) as a yellow liquid.

WO2009125366 A1

To a solution of 4-phenylpyridine N-oxide (5 g) in DCM (50 mL) was added at rt trimethylsilylcyanide (11 mL),followed by acetyl chloride (3.1 mL) over 10 min. The reaction mixture was stirred overnight at RT.A solution of aq. 10% Na2CO3 was added and the mixture was extracted with EA.The combined org. phases were washed with brine, dried (Na2SO4) and evaporated off. Filtration over a plug of silica gel (Hept/EA 1/1) gave the desired compound (450 mg).

Journal of Medicinal Chemistry (2003), 46(4), 461-473

To a stirred solution of 0.95 g (7.48 mmol) of 3-fluoro-4-methylpyridine N-oxide in 20 mL of acetonitrile was added 1.14 g (11.2 mmol) of triethylamine followed by 1.48 g(15.0 mmol) of trimethylsilyl cyanide.This reaction mixture was heated at reflux for 48h, after which time the solution was concentrated at reduced pressure.The dark residue was dissolved in CHCl3,washed with saturated aqueous NaHCO3,and the aqueous layer back-washed with chloroform (4x).The combined organic layers were dried over MgSO4, and the solvents removed a reduced pressure to give an oil that was chromatographed on SiO2,using 75:25 hexane-EtOAc to giv0.67 g of the title compound as a yellow oil

2.4 吡啶氮氧化物的其他取代

吡啶氮氧化物4位的硝基容易被亲核试剂取代，也容易在某些试剂的作用下转换为卤素等其它基团。

WO2013144179 A1

2-Bromo-6-methyl-4-methoxy-pyridine 1-oxide 2-Bromo-6-methyl-4-nitro-pyridine 1-oxide (4 g, 17 mmol) was dissolved in methanol (anhydrous, 100 mL) and sodium methoxide (1.8g, 33mmol) was added.The mixture was stirred at room temperature for 90 minutes, diluted with water (90 mL) and concentrated under reduced pressure to half of its volume.The mixture was extracted with DCM, the combined organic phases were dried (sodium sulfate) and concentrated to dryness under reduced pressure. 3.3g of yellow crystals,15 mmol,88%).

Journal of Organic Chemistry (2009), 74(19), 7441-7448

the mixture of 2-chloro-4-nitropyridine-N-oxide (11, 1.0 g, 5.7 mmol) and acetyl chloride (4 mL) for 40 min, poured to iced water, neutralized with NaHCO3 sat. extracted with CHCl3, extracts were dried (Na2CO3), solvents evaporated and the residue was purified on a silica gel plug giving 0.75 g (80% yield) of 4h as a colorless oil

Tetrahedron (2009), 65(36), 7474-7481

Acetyl bromide (34.6 mL, 0.46 mol) was added in small portions to a solution of 4-nitro-2-picoline N-oxide (2.47 g, 0.02 mol) in glacial AcOH (35 mL) at 55 oC. The resulting solution was heated to 120 oC with stirring for 2.5 h in air. After cooling to rt the solution was poured into crushed ice and made basic with K2CO3 and the product extracted with CH2Cl2.The combined organic phases were washed with brine, and dried over Na2SO4.The solvent was removed in vacuum resulting in a pale orange oil, which was used without further purification (2.75 g, 91%)

Organic Letters (2012), 14(21), 5618-5620

A dry argon-flushed flask equipped with a magnetic stirrer, was charged with 2-nitropyridine-N-oxide (1.0 mmol). Dry THF (50 mL) was added, the mixture was cooled to −50 °C, followed by the dropwise addition of RMgBr (1.0 mL, 1.2 M)in THF, 1.2 mmol) using a syringe.The mixture was stirred at −50°C until the reaction was completed (checked by TLC). The reaction was quenched by adding a 10% solution of Na2CO3 (20 mL) followed by removing THF in vacuo. The remaining aqueous phase was extracted with DCM (5 × 40 mL), and the organic fractions were combined and dried over Na2SO4.Evaporation of DCM left a crude residue that was purified by flash chromatography to give the desired products.

2.4 吡啶氮氧化物的卤代

Organic Letters (2018), 20(18), 5757-5761

Add a solution of (S)-6,6'-dimethoxy-1,1'-biisoquinoline N,N'-dioxide (136 mg, 0.39 mmol) in THF (53 mL) dropwise to a solution of LDA in THF (0.3 M, 7.8 mL) in a 250 mL round-bottom flask at -78°C by a cannula.Stir the reaction mixture for 4 hours at -78°C.Treat the mixture dropwise with a solution of 1,2-dibromotetrachloroethane (2.21 g, 6.79 mmol) in THF (11mL).Stir the mixture for an additional 15h at -78°C.Quench the reaction with anhydrous methanol (1mL) at -78 °C.Allow the mixture to warm up to room temperature.Concentrate the mixture in vacuo.redissolve the residue in DCM (10 mL).Wash the residue with saturated aqueous NH4Cl solution (10 mL).Back-extract the aqueous layer with DCM (10 mL x 3).Dry the combined organic layers over Na2SO4.Filter the mixture and concentrate in vacuo.Purify the resulting crude product by flash chromatography on silica gel (EtOAc with 0.5% Et3N) to afford (S)-3,3'-dibromo-6,6'-dimethoxy-1,1'-biisoquinoline N,N'-dioxide.

Organometallics (2011), 30(24), 6751-6765

In a 250 mL round-bottom flask open to the air, 4-tert-butylpyridine-N-oxide (15.3 g, 101 mmol) was dissolved in 61 mL of neat POCl3. The mixture was allowed to reflux under argon for 12−16h (refluxing can also be done under air, but the yield is somewhat lower). Excess POCl3 was removed by distillation, and the remaining liquid was washed with a saturated aqueous solution of sodium carbonate. The organic layer was extracted with ether, filtered, and evaporated to dryness, yielding a dark red oil (13.5 g, 79.3 mmol, 79% yield)