Synthesis of Unsymmetrical 5,5'-Disubstituted 2,2'-Bipyridines(1).
Synthesis of Unsymmetrical 5,5'-Disubstituted 2,2'-Bipyridines(1).
复制标题
不对称5,5-二取代2,2-联吡啶的合成(1)。
DOI：
10.1021/jo962398g
复制
发表时间：
1997
期刊：
影响因子：
--
通讯作者：
A. Patri
中科院分区：
文献类型：
--
作者：
G. Newkome;J. Gross;A. Patri
不对称6，6 ′-二取代2，2 ′-联吡啶的制备通常通过逐步单-N-氧化2，然后进行Boekelheide型还原3或通过不同吡啶前体的偶联4进行;这两种方法都有困难。然而，证明了5，在THF中，在-60 °C下，用1当量丁基锂，6，6 ′-双（羟甲基）-2，2 Mobibipyridine 2转化为单醇盐，其作为单甲磺酸盐被捕获，总收率为96%。该方法利用了中间体与起始材料不同的溶解度特性;该单锂醇盐在这些特定的反应条件下是不溶的。应用该一般程序6得到6-（溴甲基）-6′-（羟甲基）-2，2 ′-联吡啶，随后将其转化为官能化的寡联吡啶。由于我们需要不对称的5，5 ′-二取代的2，2 ′-联吡啶来合成树枝状基元内特异性定位的结合位点，我们在此描述了使用中间体的类似溶解度差异来从对称的2，2 ′-联吡啶-5，5 ′-二甲酸二乙酯以优异的总产率制备5′-氨基2，2 ′-联吡啶-5-甲酸。由2，2 ′-联吡啶-5，5 ′-二羧酸二乙酯（2）合成5，5 ′-二氨基-2，2 ′-联吡啶先前已由Whittle报道7。通过在部分真空下用钯/炭将纯烟酸乙酯1洗涤6天来制备所需的二酯2;除去催化剂和起始酯并再循环（方案1）。二酯2是在ca.第一次循环的产率为35%，其简单的NMR光谱支持该结构。通过利用碳酰肼的低溶解度，通过使用约1.5当量的肼并通过调节溶剂系统（乙醇/甲苯）的极性或反应温度（80 °C）来实现单碳酰肼3的排他性形成。单碳酰肼3在这些条件下沉淀，并以85%的产率获得。虽然3在许多有机溶剂中几乎不溶，但其在DMSO中的1H NMR谱清楚地显示了两个不同的6，6 ′-pyH分别在δ 9.1和9.2处的两个双峰（J）2 Hz），证实了不对称取代模式。在更剧烈的条件下用过量的水合肼处理2得到（100%）对称二碳酰肼4，其不溶于大多数常见的有机溶剂。单碳酰肼3与NaNO 2在浓盐酸中反应，得到（约. 100%）对应的碳酰肼5，其IR光谱清楚地表明在2181和2143 cm-1处存在特征碳酰肼伸缩以及支持转化的羰基从δ 163.8至171.0的位移（13 C NMR）。随后卡巴肼5的库尔修斯重排得到（82%）尿烷6; 6的13 C NMR显示尿烷部分的预期高场位移从δ 171.0变为153.3。6的皂化得到（89%）所需的5′-氨基-2，2 ′-联吡啶-5-羧酸盐酸盐7，其由δ 176.0处的羰基吸收和氨基甲酸酯羰基峰的消失支持。该亮黄色盐可溶于碱水溶液，但在除DMSO以外的有机溶剂中仅显示出非常低的溶解度。为了提高溶解度特性，使氨基酸7经受Fischer酯化条件，得到浅黄色固体形式的乙酯8。增强的有机溶解度和NMR光谱中典型的乙基吸收的出现支持指定的结构。由于溶解度差异而产生的选择性反应性的应用在不对称杂环的制备中具有巨大的潜力8，并且正在其他N-杂环官能化中进行。
The preparation of unsymmetrical 6,6′-disubstituted 2,2′-bipyridines has generally occurred by the stepwise mono-N-oxidation,2 followed by a Boekelheide-type rearrangement3 or by a coupling of different pyridine precursors;4 both procedures are plagued with difficulties. It was, however, demonstrated5 that, in THF at -60 °C with 1 equiv of butyllithium, 6,6′-bis(hydroxymethyl)-2,2′bipyridine2 was transformed to the monoalkoxide, which was trapped as the monomesylate in an overall 96% yield. This procedure takes advantage of the different solubility characteristics of the intermediates vs the starting material; this monolithium alkoxide is insoluble under these specific reaction conditions. Application of this general procedure was used6 to afford 6-(bromomethyl)-6′-(hydroxymethyl)-2,2′-bipyridine, which was subsequently converted to functionalized oligobipyridines. In that we needed unsymmetrical 5,5′-disubstituted 2,2′-bipyridines for the synthesis of specifically located binding loci within dendrons, we herein describe the use of similar solubility differences of the intermediate(s) to prepare 5′-amino2,2′-bipyridine-5-carboxylic acid in excellent overall yield from the symmetrical diethyl 2,2′-bipyridine-5,5′-dicarboxylate. The synthesis of 5,5′-diamino-2,2′-bipyridine from diethyl 2,2′-bipyridine-5,5′-dicarboxylate (2) had been previously reported by Whittle.7 The desired diester 2 was prepared by refluxing neat ethyl nicotinate 1 with palladium on charcoal for 6 days under a partial vacuum; the catalyst and starting ester were removed and recycled (Scheme 1). Diester 2 was isolated in ca. 35% yield on the first cycle, and its simple NMR spectra supported the structure. By taking advantage of the low solubility of carbohydrazides, the exclusive formation of the monocarbohydrazide 3 was achieved by the use of approximately 1.5 equiv of hydrazine and by adjusting either the polarity of the solvent system (ethanol/toluene) or the reaction temperature (80 °C). The monocarbohydrazide 3 precipitated under these conditions and was obtained in 85% yield. Although 3 is nearly insoluble in many organic solvent, its 1H NMR spectrum in DMSO clearly showed two doublets (J ) 2 Hz) at δ 9.1 and 9.2 for the two different 6,6′-pyH, respectively, confirming the unsymmetrical substitution pattern. Treatment of 2 with excess hydrazine hydrate under more drastic conditions afforded (100%) the symmetrical dicarbohydrazide 4, which is insoluble in most common organic solvents. Reaction of monocarbohydrazide 3 with NaNO2 in concentrated HCl gave (ca. 100%) the corresponding carbazide 5, whose IR spectrum clearly demonstrates the presence of the characteristic carbazide stretch at 2181 and 2143 cm-1 as well as the shift (13C NMR) from δ 163.8 to 171.0 for the carbonyl groups supporting the conversion. Subsequent Curtius rearrangement of carbazide 5 provided (82%) urethane 6; the 13C NMR for 6 shows the expected upfield shift from δ 171.0 to 153.3 for the urethane moiety. Saponification of 6 afforded (89%) the desired 5′-amino-2,2′-bipyridine-5-carboxylic acid hydrochloride 7 supported by the carbonyl absorption at δ 176.0 and the disappearance of the peak for the urethane carbonyl. The bright yellow salt is soluble in aqueous base but shows only very low solubility in organic solvent other than DMSO. In order to enhance the solubility characteristics, the amino acid 7 was subjected to Fischer esterification conditions affording the ethyl ester 8, as a pale yellow solid. The enhanced organic solubility and the appearance of the typical ethyl absorption in the NMR spectra support the assigned structure. Application of the selective reactivity due to solubility differences has great potential in the preparation of unsymmetrical heterocycles8 and is being pursued in other N-heterocyclic functionalizations.