PREPARATION OF BICYCLIC GUANIDINES BY THE IODOCYCLIZATION OF 3-ALKENYL-2-(SUBSTITUTED AMINO)- 1-IMIDAZOLIN-4-ONES1
PREPARATION OF BICYCLIC GUANIDINES BY THE IODOCYCLIZATION OF 3-ALKENYL-2-(SUBSTITUTED AMINO)- 1-IMIDAZOLIN-4-ONES1
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3-烯基-2-(取代氨基)-1-咪唑啉-4-酮碘环化制备双环胍1
DOI：
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发表时间：
1996
期刊：
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通讯作者：
A. Kakehi,
中科院分区：
文献类型：
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作者：
M. Noguchi;H. Okada;M. Watanabe;H. Moriyama;O. Nakamura;A. Kakehi,
研究了3-烯丙基-2-（取代氨基）-5-（未取代）和-5-（单取代）-咪唑啉-4-酮的碘代环化反应，其5-外环化产物咪唑并[1，2-a]咪唑与5，5-二甲基-1-咪唑啉-4-酮类似。并对这些环化反应的适用范围和局限性进行了讨论。在以前的论文中，我们报道了一种新的合成双环胍类化合物咪唑并[1，2-a]咪唑和咪唑并[1，2-a]嘧啶的方法，其中一些衍生物显示出降血糖活性。3-（2-烯基）-2-（取代氨基）-1-咪唑啉-4-酮经碘环化生成胍类化合物。碘环化反应的区域化学由相应的碘鎓离子中间体的LUMO的亲核试剂[fr（N）]的前线电子密度预测。本文报道了对这种氧化条件敏感的5-（未取代）和5-（单取代）-3-烯基-2-（取代氨基）-1-咪唑啉-4-酮的碘环化反应。这些环化的范围和限制也将被讨论。3-烯丙基-5-（未取代的）（13）和3-烯丙基-5-（单取代的）-2（取代的氨基）-1-咪唑啉-4-酮（14）和（15）的碘环化。在二甲氧基乙烷（DME）中于室温下反应，得到5-外环化产物，2-碘甲基-1-苯基-23-二氢-1H-咪唑并[1，2-a]咪唑-5（6 H）-酮（16 a），产率47%。用碳酸钾（K_2CO_3）作为碘化氢的清除剂，使产率提高到75%。16 a的结构是根据其光谱数据与以前报道的有关化合物的光谱数据相比较而确定的。5 3-烯丙基-2-苯胺基-5-甲基（14 a）和3-烯丙基-5-甲基-2-（对甲苯磺酰氨基）-咪唑啉-4-酮（14 B）与碘的类似反应也以良好的产率得到5-外型环化产物17 a，B。咪唑并咪唑17 a、B分别作为两种非对映异构体的混合物获得。环化反应的立体选择性不如预期的高。产物17 a不是那么稳定，并且用DBU（2.0当量）处理17 a是不可能的。在无水甲苯中以86%收率得到6-甲基-2-亚甲基-1-苯基-2，3-二氢-1H-咪唑并[1，2-a]咪唑5（6 H）-酮（18）。在3-烯丙基-2-氨基-5-苯基-1-咪唑啉-4-酮（15 a）与碘的反应中获得类似的结果;咪唑并咪唑19 a以两种非对映异构体的1：2混合物形式形成。
The iodocyclization of 3-allyl-2-(substituted amino)-5-(unsubstituted)and -5-(monosubstituted)-limidazolin-4-ones, which are suggested to be sensitive under such oxidative conditions, was examined; the 5-exo cyclization products, imidazo[l,2-a]imidazoles, were formed similarly to that of 5,5-dimethyl-l-imidazolin-4ones. The scope and limitations of these cyclization were also discussed. In previous papers, 1»we reported a novel synthetic route to bicyclic guanidines, imidazo[l,2-a]imidazole and imidazo[l,2-a]pyrimidine, some derivatives of which showed a hypoglycemic activity.^ The guanidines was formed by the iodocyclization of 3-(alk-2-enyl)-2-(substituted amino)l-imidazolin-4-ones. The regiochemistry of the iodocyclization was predicted by the frontier electron densities for nucleophile [fr(N)] of the LUMOs of the corresponding iodonium ion intermediates. The stereochemistry of the guanidines was interpreted in terms of the stereoselective formation of the iodonium ion and its successive opening by the intramolecular nitrogen nucleophile in an Sn 2 mode.We report here the iodocylization of some 5(unsubstituted)and 5-(monosubstituted)-3-alkenyl-2-(substituted amino)-l-imidazolin-4-ones, which are suggested to be sensitive to such oxidative conditions. The scopes and limitations of these cyclizations will be also discussed. Iodocyclizaion of 3-AIlyI-5-(unsubstituted)(13) and 3-AUyl-5-(monosubstituted)-2(substituted amino)-l-imidazolin-4-ones (14) and (15) The imidazolin-4-ones 13-15 were obtained according to the reported procedures in fair to good yields (Scheme 1 )2 ,4 The reaction of 3-allyl-2-anilino-l-imidazolin-4-one (13a) with iodine (3.0 equiv.) in dimethoxyethane (DME) at room temperature gave 5-exo cyclization product, 2-iodomethyl-l-phenyl-23dihydrolH-imidazo[l,2-a]imidazol-5(6/i)-one (16a), in 47% yield. Utilizing potassium carbonate (K2CO3) as a scavenger of hydrogen iodide afforded an improvement of its yield up to 75%. The structure of 16a was established on the basis of its spectroscopic data in comparison with those of the related compounds previously r e p o r t e d . 5 Similar reaction of 3-allyl-2-anilino-5-methyl(14a) and 3-allyl-5-methyl-2-(tosylamino)-limidazolin-4-ones (14b) with iodine gave also 5-exo cyclization products 17a,b in good yields. Imidazoimidazoles 17a,b were obtained as mixtures of two diastereomers, respectively. The stereoselectivity of the cyclization was not so high as expected. Product 17a was not so stable and the treatment of 17a with DBU (2.0 equiv.) in refluxing toluene gave 6-methyl-2-methylene-1 -phenyl-2,3-dihydro-l//-imidazo[ 1,2-a]imidazol5(6//)-one (18) in 86% yield. Similar results were obtained in the reaction of 3-allyl-2-amlino-5-phenyl-1imidazolin-4-ones (15a) with iodine; imidazoimidazole 19a was formed as a 1:2 mixture of two diastereomers.