銅鹽催化β-雙羰基化合物α-位氮賓轉(zhuǎn)移反應(yīng)

辜玲慧, 田　雯, 何　菱

(四川大學(xué) 華西藥學(xué)院，四川 成都　610041)

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·快遞論文·

銅鹽催化β-雙羰基化合物α-位氮賓轉(zhuǎn)移反應(yīng)

辜玲慧, 田雯, 何菱*

(四川大學(xué) 華西藥學(xué)院，四川 成都610041)

摘要：以對氯苯磺酰胺為氮源，PhI(OAc)2為氧化劑，Cu(CF3SO3)2為催化劑，β-雙羰基衍生物為底物，于35 ℃用“一鍋法”合成了6個α-氨基-β-雙羰基化合物(3a～3f, 3b～3f為新化合物)，其結(jié)構(gòu)經(jīng)1H NMR，13C NMR和HR-ESI-MS表征。

關(guān)鍵詞：對氯苯磺酰胺; α-氨基-β-雙羰基化合物; 銅鹽催化; 氮賓轉(zhuǎn)移反應(yīng)

α-氨基-β-雙羰基化合物是一種常用的結(jié)構(gòu)模塊，可用于合成雜環(huán)化合物[1]，模擬肽[2]，α-氨基酸[3]和β-羥基α-氨基酯[4]化合物。此外，該結(jié)構(gòu)模塊在某些天然產(chǎn)物[5]和藥物分子[6]的合成中也有較關(guān)鍵的作用。氨基酸和生物活性肽均具有良好的生物活性,如免疫調(diào)節(jié)、抗血栓、抗高血壓、降膽固醇、抑制細(xì)菌、病毒和抗癌作用,抗氧化作用等[7]。

目前，合成α-氨基-β-雙羰基化合物的方法主要有：強堿介導(dǎo)的酮亞胺衍生物?；磻?yīng)[8]，特定底物的N—C?；w移反應(yīng)[9]，α-肟[10]和苯偶氮β-雙羰基化合物[11]還原反應(yīng)，噁唑-4-羧酸衍生物水解反應(yīng)[12]，金屬碳烯N-H插入反應(yīng)[13]及高氯酸鋅催化β-雙羰基化合物反應(yīng)[14]。以上方法的缺點主要在于：需使用強堿，底物局限性大和反應(yīng)步驟繁雜等。

本文以對氯苯磺酰胺(2)為氮源，PhI(OAc)2為氧化劑，Cu(CF3SO3)2為催化劑，β-雙羰基衍生物(1a～1f)為底物，于35 ℃用“一鍋法”合成了6個α-氨基-β-雙羰基化合物(3a～3f, 3b～3f為新化合物)，其結(jié)構(gòu)經(jīng)1H NMR，13C NMR和HR-ESI-MS表征。該方法具有反應(yīng)條件溫和，不需使用強堿，操作簡單等優(yōu)點。

Scheme 1

1實驗部分

1.1儀器與試劑

Varian Mercury 400 MHz型核磁共振儀(CDCl3為溶劑，TMS為內(nèi)標(biāo))；Bio ToF-Q型高分辨質(zhì)譜儀。

所用試劑均為分析純。

1.23a～3f的合成通法

氮氣保護下，在干燥的反應(yīng)瓶中依次加入1a～1f 1 mmol， 2 1.5 mmol， PhI(OAc)21.5 mmol， Cu(CF3SO3)20.2 mmol, 分子篩0.2 mmol和干燥CH2Cl230 mL，攪拌下于35 ℃反應(yīng)完全(TLC監(jiān)測)。濃縮，殘余物經(jīng)硅膠柱層析[洗脫劑：V(石油醚) ∶V(乙酸乙酯)=10 ∶1]純化得白色固體3a和淡黃色油狀液體3b～3f。

3a: m.p.348～350 ℃;1H NMRδ: 7.81(d,J=8.8 Hz, 2H, ArH), 7.49(d,J=8.8 Hz, 2H, ArH), 5.67(d,J=8.4 Hz, 1H, NH), 4.67(d,J=8.4 Hz, 1H, CH), 4.18～4.11(m, 4H, OCH2), 1.25～1.19(m, 6H, CH3);13C NMRδ: 165.4, 139.5, 138.1, 129.3, 128.7, 62.9, 58.7, 13.8; HR-ESI-MSm/z: Calcd for C13H16NO6SClNa{[M+Na]+}372.028 5, found 372.029 7。

3b:1H NMRδ: 7.77(d,J=8.4 Hz, 2H, ArH), 7.41(d,J=8.4 Hz, 2H, ArH), 7.36～7.34 (m, 3H, ArH), 7.26～7.24(m, 2H, ArH), 5.99(s, 1H, NH), 5.10(s, 2H, OCH2), 4.77(s, 1H, CH), 3.65(s, 3H, CH3);13C NMRδ: 165.8, 165.3, 139.5, 137.9, 134.3, 129.3, 128.7, 128.6, 128.2, 68.4, 58.6, 53.6; HR-ESI-MSm/z: Calcd for C17H16NO6SClNa{[M+Na]+}420.028 5, found 420.029 8。

3c:1H NMRδ: 7.76(d,J=8.4 Hz, 2H, ArH), 7.46(d,J=8.4 Hz, 2H, ArH), 7.33～7.23(m, 3H, ArH), 7.17～7.15(m, 2H, ArH), 5.67(d,J=8.4 Hz, 1H, NH), 4.68(d,J=8.4 Hz, 1H, CH), 4.33～4.26(m, 2H, OCH2), 3.63(s, 3H, CH3), 2.91～2.88(m, 2H, a-H);13C NMRδ: 165.7, 165.2, 139.7, 137.8, 136.8, 129.4, 128.8, 128.7, 128.6, 126.8, 67.2, 58.4, 53.5, 34.6; HR-ESI-MSm/z: Calcd for C18H18NO6SClNa{[M+Na]+}434.044 1, found 434.044 2。

3d:1H NMRδ: 7.76(d,J=8.4 Hz, 2H, ArH), 7.42(d,J=8.4 Hz, 2H, ArH), 7.37～7.35(m, 2H, ArH), 7.31～7.27(m, 2H, ArH), 7.21～7.20(m, 3H, ArH), 6.96～6.94(d,J=6.4 Hz, 3H, ArH), 6.20(s, 1H, NH), 5.19～5.06(m, 2H, OCH2), 4.80～4.75(m, 1H, a-H), 4.63(d,J=5.2 Hz, 1H, CH), 3.56(s, 3H, CH3), 3.14～3.01(m, 2H, b-H);13C NMRδ: 170.4, 166.8, 162.9, 139.6, 137.6, 134.9, 134.7, 129.4, 129.2, 128.7, 128.6, 128.5, 127.3, 127.2, 67.6, 67.5, 58.9, 53.6, 37.3; HR-ESI-MSm/z: Calcd for C26H25N2O7SClNa{[M+Na]+}567.096 9 , found 567.098 6。

3e:1H NMRδ: 7.78(dd,J=8.8 Hz,J=3.2 Hz, 2H, ArH), 7.48(dd,J=8.4 Hz,J=2.0 Hz, 2H, ArH), 7.30～7.26(m, 3H, ArH), 7.10～7.02(m, 2H, ArH), 5.92(s, 1H, NH), 4.77～4.70(m, 1H, a-H), 4.57(s, 1H, CH), 3.75(s, 6H, CH3,CH3), 3.19～3.10(m, 2H, b-H);13C NMRδ: 170.9, 166.8, 162.8, 139.7, 137.6, 135.0, 129.4, 129.3, 129.2, 129.1, 128.7, 128.6, 127.3, 72.6, 72.4, 58.8, 53.6, 37.5; HR-ESI-MSm/z: Calcd for C20H21N2O7SClNa{[M+Na]+}491.065 6, found 491.063 7。

3f:1H NMRδ: 7.82(d,J=8.8 Hz, 2H, ArH), 7.50(d,J=8.4 Hz, 2H, ArH), 7.11(s, 1H, NH), 6.24(s, 1H, NH), 4.68(s, 1H, CH), 4.04～4.01(m, 2H, CH2), 3.76(s, 3H,CH3), 3.67(s, 3H, CH3);13C NMRδ: 169.4, 167.0, 164.0, 139.7, 137.5, 129.4, 128.6, 58.9, 53.5, 52.6, 41.5; HR-ESI-MSm/z: Calcd for C13H16N2O7SCl{[M+H]+}379.036 7, found 379.035 7。

2結(jié)果與討論

2.1合成

以1a為底物,研究了催化劑，氧化劑和氮源對反應(yīng)的影響。

(1) 催化劑

1a 1 mmol, PhI(OAc)21.5 mmol, 2 1.5 mmol, 分子篩0.2 mmol, 其余反應(yīng)條件同1.2，研究催化劑對反應(yīng)的影響，結(jié)果見表1。

表1　催化劑對3a收率的影響*

*1a 1 mmol, PhI(OAc)21.5 mmol, 2 1.5 mmol,分子篩0.2 mmol, 其余反應(yīng)條件同1.2。

由表1可見，Rh2(O2CC7H15)4， Rh2(OAc)4和[Cu(MeCN)4]ClO4(Cat2～Cat4)對反應(yīng)無催化作用，不能合成相應(yīng)的胺化產(chǎn)物。Cu(CF3SO3)2(Cat1)催化性能最好，3a收率68%。

(2) 氧化劑

1a 1 mmol, Cu(CF3SO3)20.2 mmol, 2 1.5 mmol, 分子篩0.2 mmol, 其余反應(yīng)條件同2.1(1)，研究氧化劑對反應(yīng)的影響，結(jié)果見表2。由表2可見，以 PhIO，4-methyl-PhIO，4-chloro-PhI(OAc)2， 4-methoxy- PhI(OAc)2(Oxi2～Oxi5)為氧化劑，3a收率均低于PhI(OAc)2(Oxi1, 68%)。

表2　氧化劑對3a收率的影響*

*1a 1 mmol, Cu(CF3SO3)20.2 mmol, 2 1.5 mmol,分子篩0.2 mmol, 其余反應(yīng)條件同表1。

(3) 氮源

1a 1 mmol, PhI(OAc)21.5 mmol, Cu(CF3SO3)20.2 mmol, 分子篩0.2 mmol,其余反應(yīng)條件同2.1(1)，研究氮源對反應(yīng)的影響，結(jié)果見表3。由表3可見，2為氮源，3a收率最高(68%)。

表3　氮源對3a收率的影響*

*1a 1 mmol, Cu(CF3SO3)20.2 mmol, PhI(OAc)21.5 mmol,分子篩0.2 mmol,其余反應(yīng)條件同表1。

2.2底物拓展

以1b～1f替代1a,考察了反應(yīng)條件的普適性。結(jié)果表明：反應(yīng)條件具有較好的普適性，3b～3f收率26%～71%。

參考文獻

[1]Chai L L, Elix J A, Huleatt P B. The synthetic versatility of alkoxycarbonyl- and hydroxymethyl-piperazine-2,5-diones[J].Tetrahedron,2005,36(49):8722-8739.

[2]Chang L L, Yang G X, McCauley E,etal. Constraining the amide bond inN-sulfonylated dipeptide VLA-4 antagonists[J].Med Chem Lett,2008,18(5):1688-1691.

[3]Nemoto T, Harada T, Matsumoto T,etal. Pd-catalyzed enantioselective synthesis of quaternary α-amino acid derivatives using a phenylalanine-derived P-chirogenic diaminophosphine oxide[J].Tetrahedron Lett,2007,38(51):6304-6307.

[4]Maeda T, Makino K, Iwasaki M,etal. Diastereo- and enantioselective hydrogenation ofα-amino-β-keto ester hydrochlorides catalyzed by an iridium complex with MeO-BIPHEP and NaBArF:Catalytic cycle and five-membered chelation mechanism of asymmetric hydrogenation[J].Chem Eur J,2010,16(39):11954-11962.

[5]Labeeuw O, Phansavath P, Genêt P. Total synthesis of sulfobacin A through dynamic kinetic resolution of a racemicβ-keto-α-amino ester hydrochloride[J].Tetrahedron:Asymmetry,2004,15(12):1899-1908.

[6]Phansavath P, Duprat de Paule S, Ratovelomanana-Vidal V,etal. An efficient formal synthesis of (-)-balanol by using ruthenium-catalyzed asymmetric hydrogenation[J].Eur J Org Chem,2000:3903-3907.

[7]孔毅，楊婉，吳梧桐. 我國氨基酸類藥物研究進展[J].藥物生物技術(shù),2007,14(3):230-234.

[8]Singh J, Gordon T D, Earley W G,etal. An efficient synthesis and acylation ofα-amino-β-keto-esters:Versatile intermediates in the synthesis of peptide mimetics[J].Tetrahedron Lett,1993,34(2):211-214.

[9]Makino K, Okamoto N, Hara O,etal. Efficient enantioselective synthesis of (2R,3R)- and (2S,3S)-3-hydroxyleucines and their diastereomers through dynamic kinetic resolution[J].Tetrahedron:Asymmetry,2001,32(51):1757-1762.

[10]Wiley R. H, Borum O H. Conversion of alpha-amino acids to acylamido ketones and oxazoles[J].J Am Chem Soc,1948,70(6):1666.

[11]Bolhofer W A.β-Phenylserine[J].J Am Chem Soc,1952,74(21):5459-5461.

[12]Suzuki M, Iwasaki T, Miyoshi M,etal. New convenient syntheses of alpha-C-acylamino acids and alpha-amino ketones[J].Org Chem,1973,38(20):3571-3575.

[13]Honey M A, Blake A J, Campbell B,etal. One-pot synthesis ofN-methylindoles fromN-methylanilines and of benzofurans from phenols using transition-metal carbene X-H insertion reactions[J].Tetrahedron,2009,65(44):8995-9001.

[14]Yu J, Liu S S, Cui J,etal. A mild and efficient directγ-amination ofβ-dicarbonyl compounds using iodosobenzene andp-toluenesulfonamide catalyzed by perchlorate zinc hexahydrate[J].Org Lett,2012,14(3):832-835.

Nitrene Transfer Reaction onα-H ofβ-dicarbonyl Compounds Catalyzed by Copper Salt

GU Ling-hui，TIAN Wen，HE Ling*

(West China School of Pharmacy, Sichuan University, Chengdu 610041, China)

Abstract：Six α-amino-β-dicarbonyl compounds(3a～3f, 3b～3f were novel compounds) were synthesized by “one-pot method” at 35 ℃, using chlorobenzene sulfonamide as nitrogen source, PhI(OAc)2 as oxidizing agent, Cu(CF3SO3)2 as catalyst and β-dicarbonyl compounds as substrate. The structures were characterized by1H NMR，13C NMR and HR-ESI-MS.

Keywords：p-chlorobenzene sulfonamide; α-amino-β-dicarbonyl compound; copper salt catalysis; nitrene transfer reaction

收稿日期：2015-04-22；

修訂日期：2016-03-20

基金項目：國家自然科學(xué)基金資助項目(21072131)

作者簡介：辜玲慧(1989-)，女，漢族，四川仁壽人，博士研究生，主要從事藥物化學(xué)的研究。 E-mail: 790369649@qq.com通信聯(lián)系人： 何菱，教授，博士生導(dǎo)師， E-mail: lhe2001@sina.com

中圖分類號：O625.75; O625.6

文獻標(biāo)志碼：A

DOI：10.15952/j.cnki.cjsc.1005-1511.2016.05.15175