Variations in the mechanisms of direct metallation of cyclic and acyclic aminals.
Variations in the mechanisms of direct metallation of cyclic and acyclic aminals.
复制标题
环状和无环缩醛胺直接金属化机制的变化。
作者：
Ina Kamps;Daniel Bojer;Stuart A. Hayes;R. J. Berger;B. Neumann;N. Mitzel
由于胺的直接非金属化的制备方案的开发是一项具有挑战性但有价值的任务，因为此类试剂对于合成来说非常重要。由于相邻氮原子上的电子密度积累和碳负离子功能，这些系统被视为不稳定甚至不稳定的碳负离子。通过金属转移、亚胺盐与低价金属卤化物的反应、C S 或 C Te 键断裂或通过 BF3 加合物形成活化胺 [5] 来制备 α-金属化胺的替代多步骤方法涉及巨大的准备工作，并且由于物质损失而效率低下。尽管过去几年取得了重大进展，但直接进行去质子化的胺系统的数量仍然很容易被忽视。正丁基锂单锂化物N,N,N-三甲基-1,4,7-三氮杂环壬烷的一个甲基；使用 Schlosser 碱将 N-甲基哌啶在 CH3 基团处去质子化；两个小组描述了 Me2NACHTUNGTRENNUNG(CH2)2NMe2 (TMEDA) 的去质子化，但从未大规模发生； MeNACHTUNGTRENNUNG[(CH2)2NMe2]2 (PMDTA) 可以被锂化，但产量也有限；手性二胺（(R,R)-四甲基-1,2-二氨基环己烷（(R,R)TMCDA）被发现在其末端 CH3 基团处进行直接金属化。[10]后三个例子很重要，因为底物广泛用作烷基锂化学中的辅助碱，而不是金属化它们。生成与两个氮原子相邻的碳负离子似乎更加困难。然而，我们最近发现并入缩醛胺单元饱和六元环中的 NCH2N 位置选择性锂化 1,3,5-三甲基-1,3,5-三氮杂环己烷 (TMTAC) 与正丁基锂的反应，甚至更好地与正丁基锂在己烷中的反应顺利进行，得到由与 TMTAC 交替链连接的锂化 TMTAC 二聚体组成的产物。 ACHTUNGTRENNUNG[CH2N(Me)]2CHLi}2·TMTAC]1。[11]后来我们发现在低温下进行较长时间的反应会产生完全锂化的化合物，1,3-二甲基-1,3-二氮杂环己烷（DMDAC）也被tBuLi在NCH2N位置锂化，这些化合物已被证明适用于Corey-Seebach锂化。二噻烷类似试剂，但具有无重金属后处理程序的优点，甚至具有通过亚甲基 H2CACHTUNGTRENNUNG[NCH2N(Me)ACHTUNGTRENNUNG(CH2)3]2 连接的两个二氮杂环己烷单元的系统也可以高产率双重去质子化，得到 H2C ACHTUNGTRENNUNG[NCH(Li)N(Me) 二聚体。 ACHTUNGTRENNUNG(CH2)3]2.[13] 这些结果与 Karsch 的报告相反，其中 RMeNCH2NMeR 类型的开链缩醛胺可以通过 tBuLi 处理同时在两个甲基上锂化（方案 1）。
The development of preparative protocols for direct ametallation of amines is a challenging but worthwhile task, due to the importance of such reagents for synthesis. Because of the electron-density accumulation on the adjacent nitrogen atom and carbanionic function, these systems are regarded as non-stabilised or even destabilised carbanions. Alternative multi-step approaches to a-metallated amines via transmetallation, reactions of iminium salts with lowvalent metal halides, C S or C Te bond cleavage or activation of amines by BF3 adduct formation [5] involve enormous preparative effort and are inefficient due to loss of substance. Despite substantial progress in the few last years, the number of amine systems directly accessible to deprotonation is still easy to overlook. n-Butyllithium mono-lithiates N,N ,N -trimethyl-1,4,7-triazacyclononane at one methyl group; N-methylpiperidine is deprotonated at the CH3 group using Schlosser s base; the deprotonation of Me2NACHTUNGTRENNUNG(CH2)2NMe2 (TMEDA) was described by two groups, but never occurs in large yield; MeNACHTUNGTRENNUNG[(CH2)2NMe2]2 (PMDTA) can be lithiated, but again in limited yield; and the chiral diamine ((R,R)-tetramethyl-1,2-diaminocyclohexane ((R,R)TMCDA) was found to undergo direct metallation—again at its terminal CH3 group. [10] The latter three examples are important due to the fact that the substrates are widely applied as auxiliary bases in alkyllithium chemistry, without the intention of metallating these. Generating a carbanion adjacent to two nitrogen atoms seemed even more difficult. However, we recently found that aminal units incorporated in saturated six-membered rings are selectively lithiated at the endocyclic NCH2N position. The reaction of 1,3,5-trimethyl-1,3,5-triazacyclohexane (TMTAC) with nBuLi and even better with tBuLi in hexane proceeds smoothly giving a product consisting of a dimer of lithiated TMTAC linked into chains alternating with TMTAC, [{MeN ACHTUNGTRENNUNG[CH2N(Me)]2CHLi}2·TMTAC]1.[11] Later we found that conducting the reaction for a longer time at low temperatures leads to the completely lithiated compound. A similar result was found for 1,3-dimethyl-1,3-diazacyclohexane (DMDAC), which is also lithiated at the NCH2N position by tBuLi. These compounds have been shown to be applicable as Corey–Seebach lithiated dithiane analogous reagents, but with the advantage of heavy-metal free workup procedures. Even a system that has two diazacyclohexane units joined via a methylene group H2CACHTUNGTRENNUNG[NCH2N(Me)ACHTUNGTRENNUNG(CH2)3]2 can be doubly deprotonated in high yields to give a dimer of H2C ACHTUNGTRENNUNG[NCH(Li)N(Me) ACHTUNGTRENNUNG(CH2)3]2.[13] These results are in contrast to reports by Karsch, in which open-chain aminals of the type RMeNCH2NMeR can be simultaneously lithiated at both methyl groups by treatment with tBuLi (Scheme 1). Obviously there are different mechanisms involved.