Cyclopropylamines from N,N-Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide
Cyclopropylamines from N,N-Dialkylcarboxamides and Grignard Reagents in the Presence of Titanium Tetraisopropoxide or Methyltitanium Triisopropoxide
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DOI：
10.1002/chem.201001550
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发表时间：
2010-12-01
影响因子：
4.3
通讯作者：
Schill (Nee Brackmann), Farina
中科院分区：
文献类型：
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作者：
de Meijere, Armin;Chaplinski, Vladimir;Schill (Nee Brackmann), Farina
在化学计量的四异丙氧基钛或三异丙氧基甲基钛存在下，用未取代的以及2-烷基、2，2-二烷基和3-链烯基取代的乙基溴化镁6处理33种不同的N，N-二烷基-和N-烷基-N-磷酰基烷基取代的羧酰胺9-17，得到取代的环丙胺20-25，产率为20-98%，这取决于具有NO（1：1）至优异（>25：1）非对映选择性的取代基。通常，用甲基三异丙氧基钛作为钛介体得到环丙胺20-28的较高产率（高达98%）而不损失非对映选择性。在这些条件下，甚至二氧戊环保护的酮和卤素取代的和手性的以及非手性的烷氧基烷基取代的甲酰胺也可以用未取代的以及苯基取代的和各种烷基取代的乙基溴化镁以及许多含杂原子的（例如，卤素-、三苯甲氧基-、四氢吡喃氧基-取代的）格氏试剂（共62个实施例）。N，N-二甲酰基烷基胺54在三异丙氧基甲基钛存在下用乙基溴化镁转化成N，N-二环丙基-N-烷基胺55，产率可高达82%（6个实施例）。通过应用分别由化学计量的四异丙氧基钛和手性二氨基或二醇配体产生的手性钛介体，开发了钛介导的N，N-二烷基甲酰胺环丙烷化的不对称变体。最有效的手性介质原来是钛bistaddolates，提供相应的环丙胺与对映体过量（ee）高达84%。对几种甲硅烷基添加剂的评价表明，只要使用2-芳基-或2-乙烯基-取代的乙基卤化镁，反应也可以用亚化学计量量（低至25摩尔%）的钛试剂有效地进行，并且可以接受伴随的产率轻微降低。新开发的方法已成功应用于制备已知药物和天然产物（如尼古丁代谢物（S）-可替宁以及杀虫剂呋虫胺和吡虫啉）的环丙胺类似物。
Thirty-three different N,N-dialkyl- and N-alkyl-N-phosphorylalkyl-substituted carboxamides 9-17 were treated with unsubstituted as well as with 2-alkyl-, 2,2-dialkyl-, and 3-alkenyl-substituted ethylmagnesium bromides 6 in the presence of stoichiometric amounts of titanium tetraisopropoxide or methyltitanium triisopropoxide to furnish substituted cyclopropylamines 20-25 in 20-98% yield, depending on the substituents with no (1:1) to excellent (>25:1) diastereoselectivities. Generally higher yields (up to 98%) of the cyclopropylamines 20-28 without loss of the diastereoselectivity were obtained with methyltitanium triisopropoxide as the titanium mediator. Under these conditions, even dioxolane-protected ketones and halogen-substituted and chiral as well as achiral alkyloxyalkyl-substituted carboxamides could be converted to the correspondingly substituted cyclopropylamines with unsubstituted as well as phenyl-and a variety of alkyl-substituted ethylmagnesium bromides in addition to numerous heteroatom-containing (e.g., halogen-, trityloxy-, tetrahydropyranyloxy-substituted) Grignard reagents (62 examples altogether). The transformation of N,N-diformylalkylamines 54 with ethylmagnesium bromide in the presence of methyltitanium triisopropoxide to N,Ndicyclopropyl-N-alkylamines 55 can be brought about in up to 82% yield (6 examples). An asymmetric variant of the titanium-mediated cyclopropanation of N,N-dialkylcarboxamides has been developed by applying chiral titanium mediators generated from stoichiometric amounts of titanium tetraisopropoxide and chiral diamino or diol ligands, respectively. The most efficient chiral mediators turned out to be titanium bistaddolates that provided the corresponding cyclopropylamines with enantiomeric excesses (ee) of up to 84%. Evaluation of several silyl-based additives revealed that the reaction can also efficiently be carried out with substoichiometric amounts (down to 25 mol%) of the titanium reagent, as long as 2-aryl- or 2-ethenyl-substituted ethylmagnesium halides are used and a concomitant slight decrease in yields is accepted. The newly developed methodology was successfully applied for the preparation of analogues with cyclopropylamine moieties of known drugs and natural products such as the nicotine metabolite (S)-Cotinine as well as the insecticides Dinotefuran and Imidacloprid.