Acid-Catalyzed In Situ Generation of Less Accessible or Unprecedented N-Boc Imines from N-Boc Aminals
Acid-Catalyzed In Situ Generation of Less Accessible or Unprecedented N-Boc Imines from N-Boc Aminals
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DOI：
10.1002/anie.201300231
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发表时间：
2013-01-01
影响因子：
16.6
通讯作者：
Maruoka, Keiji
中科院分区：
文献类型：
--
作者：
Kano, Taichi;Yurino, Taiga;Maruoka, Keiji
亚胺是合成化学中能够通过加成反应、还原反应和环加成反应制备多种含氮化合物的有价值的试剂。[1-9]其中，具有容易处理的Boc基团的亚胺1（方案1）由于所得产物的高合成效用而经常用于有机合成。[10]然而，可用的Boc-保护的亚胺是有限的，因为它们的高反应性和它们的合成困难。虽然N-Boc-保护的亚胺1是通过三甲基甲硅烷基保护的亚胺2与二叔丁基二甲基亚砜（Boc 2 O;方案1，方法A）的反应制备的，但是该制备以低收率进行并且需要亚胺1和2的连续蒸馏。[11亚胺3的亚磺酸加合物由醛、氨基甲酸叔丁酯（BocNH 2）和亚磺酸钠盐（或亚磺酸）获得。这些亚胺前体3可以通过用碱如K2 CO 3处理（方法B）转化为亚胺1。该过程还能够原位生成反应性亚胺1，并且是合成化学中最常用的。[13醛和亚氨基膦4之间的氮杂-Wittig反应是N-Boc亚胺的替代方法（方法C）。[12然而，不幸的是，亚氨基膦4的前体叔丁氧羰基叠氮化物被认为是爆炸性的，因此不鼓励其使用。虽然在碳原子上具有芳族取代基的稍微稳定的N-Boc亚胺可通过任一方法获得，但具有烷基取代基的N-Boc亚胺较难获得，这是因为这样的亚胺容易异构化为相应的烯氨基甲酸酯。[16-21]据我们所知，仅报道了一种具有烯基取代基的N-Boc亚胺[22]，此外，具有炔基的N-Boc亚胺是前所未有的。[23]因此，开发生成反应性N-Boc亚胺1的一般方法在合成化学中具有重要意义。我们最近对在酸催化剂的影响下逐渐原位生成反应性N-叔丁氧羰基亚胺1，尤其是具有炔基的那些感兴趣。[14反应性亚胺的缓慢产生和快速消耗将避免它们的积累和分解。然后，我们专注于N-Boc胺醛5作为亚胺前体，其可以容易地通过醛和BocNH 2的缩合来制备。[19]所需的N-Boc亚胺将在酸催化剂的帮助下随着一个BocNH 2的离开而逐渐原位生成。在该反应体系中，中性副产物BocNH 2预计不会影响N-Boc亚胺与其他试剂的反应。实际上，N-Boc缩醛胺5（R= PhC C）仅通过在脱水剂、乙酸酐中在催化量的三氟乙酸存在下用BocNH 2处理3-苯基丙醛并随后过滤而获得，为白色固体（图1）。在三氟甲磺酸铜（II）（Cu（OTf）2）作为刘易斯酸催化剂的存在下，5与丙二酸二乙酯之间的反应以良好的产率进行，得到曼尼希型产物6（R= PhC C）（表1，条目1）。这一结果表明，
Imines are valuable reagents that are capable of producing a wide variety of nitrogen-containing compounds by addition reactions, reduction, and cycloaddition in synthetic chemistry.[1–9] Among them, imines 1 (Scheme 1) that have an easily handled Boc group are frequently used in organic synthesis owing to the high synthetic utility of the resulting product.[10] However, available Boc-protected imines are limited because of their high reactivity and the difficulty of their synthesis. While N-Boc-protected imines 1 are prepared by the reaction of trimethylsilyl-protected imines 2 with di-tert-butyl dicarbonate (Boc2O; Scheme 1, method A), this preparation proceeds in low yield and requires successive distillation of both imine 1 and 2.[11, 12] Sulfinic acid adducts of imines 3 are obtained from aldehydes, tert-butyl carbamate (BocNH2), and sulfinic acid sodium salt (or sulfinic acid). These imine precursors 3 can be converted into imines 1 by treatment with a base, such as K2CO3 (methodB). This procedure also enables in situ generation of reactive imines 1 and is the most commonly used in synthetic chemistry.[13, 14] The aza-Wittig reaction between aldehydes and iminophosphorane 4 is an alternative approach to N-Boc imines (methodC).[12, 15] Unfortunately, however, the precursor of iminophosphorane 4, tert-butoxycarbonyl azide, is recognized as being explosive, and its use is therefore discouraged. While somewhat stabilized N-Boc imines having an aromatic substituent on the carbon atom are obtainable by either methods, N-Boc imines with alkyl substituent are less accessible owing to the fact that such imines are readily isomerized to the corresponding enecarbamate.[16–21] To the best of our knowledge, only one N-Boc imine having an alkenyl substituent has been reported,[22] and furthermore, N-Boc imines with an alkynyl group are unprecedented.[23] Accordingly, development of the general method to generate reactive N-Boc imines 1 is of great significance in synthetic chemistry. We have recently become interested in the gradual in situ generation of reactive N-Boc imines 1, and especially those with an alkynyl group, under the influence of acid catalyst.[14, 16–21, 24] Slow generation and rapid consumption of reactive imines would avoid their accumulation and decomposition. We then focused on N-Boc aminals 5 as an imine precursor, which could be readily prepared by condensation of aldehydes and BocNH2.[19] The desired N-Boc imine would be gradually generated in situ with one BocNH2 departing with the aid of acid catalyst. In this reaction system, the neutral byproduct BocNH2 is not expected to affect the reaction of N-Boc imines with other reagents. Indeed, N-Boc aminal 5 (R= PhC C) was obtained as a white solid only by treatment of 3-phenylpropiolaldehyde with BocNH2 in a dehydrating agent, acetic anhydride in the presence of a catalytic amount of trifluoroacetic acid and subsequent filtration (Figure 1). In the presence of copper (II) trifluoromethanesulfonate (Cu (OTf) 2) as a Lewis acid catalyst, the reaction between 5 and diethyl malonate proceeded to give the Mannich-type product 6 (R= PhC C) in good yield (Table1, entry1). This result indicated that the hitherto