Copper-promoted cycloaddition of diazocarbonyl compounds and acetylides.
Copper-promoted cycloaddition of diazocarbonyl compounds and acetylides.
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DOI：
10.1002/anie.200700069
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发表时间：
2007-04
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通讯作者：
X. Qi;J. Ready
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文献类型：
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作者：
X. Qi;J. Ready
1,3-偶极环加成为碳环和杂环5元环提供了方便在某些情况下，1,3偶极与亲偶极试剂反应而不激活任何组分。例如，烯烃的臭氧分解和腈氧化物向炔烃的加成通常不需要添加促进剂然而，对于许多底物组合，当偶极子和亲偶亲和剂简单混合时，不会形成环加合物。为了加速这些类型的反应，有两种互补的策略侧重于调节亲偶极试剂的反应性（方案1）。首先，加入路易斯酸来降低亲偶极试剂的LUMO在这种条件下，偶极子通过HOMO反应生成环加成产物。另外，增加亲偶极试剂电子密度的添加剂可以通过HOMO（亲偶极试剂）-LUMO（偶极子）相互作用加速环加成。这种方法不像基于路易斯酸的方法那样常见，但在铜催化炔和叠氮化物合成三唑的过程中最为有效在这里，我们报告了一个逆电按需偶极环加成的新例子：通过铜乙酰化与重氮羰基化合物的环加成合成吡唑（eq 1）。方案1：金属对1,3-偶极环加成中炔烃和烯烃的活化。吡唑亚结构出现在具有广泛生物活性的小分子中，因此是有机合成的一个有价值的靶标制备吡唑(1)的常用方法依赖于β-二酮与肼的缩合另外，重氮烯烃[9]或不饱和肼[10]的环化相对于二羰基/肼缩合提供了更好的区域化学控制，尽管前驱体的制备更具挑战性。吡唑的直接方法包括重氮化合物与炔烃的环加成。在这方面，富电子重氮化合物（如重氮甲烷）在温和的条件下与缺电子炔反应相反，需要路易斯酸来促进缺电子炔和重氮羰基化合物之间的环加成然而，简单的烷基乙炔或芳基乙炔在热条件下或在路易斯酸的存在下通常不能与重氮羰基化合物反应。寻找另一种激活模式，我们评估了金属乙酰基化合物与重氮羰基化合物的环加成。用不同的Cu(I)源和重氮乙酸苄酯(2)依次处理苯乙基锂时，与苯甲醇（BnOH，表1）形成吡唑1a。在所有情况下，重氮酯的转化都是完全的，除了一个例外，重氮酯的质量平衡的90%是由1a、BnOH和回收的炔烃组成的。富马酸酯和马来酸酯副产物经正己烷滴定纯度为90%；在所有情况下，分析纯的产品可以在硅胶柱层析后分离。图1铜促进乙酰化锂与重氮羰基化合物的反应。目前的环加成反应和两个已知反应之间的比较是惊人的。首先，Fu小组的一篇报告描述了Cu(I)催化的重氮酯烷基化反应（eq 2）在这些中性条件下，不形成吡唑。同样地，二氮乙酸乙酯与PhCCLi/CuCN·6LiCl的反应也没有产生明显的炔基酯。这两种体系之间的关键区别可能是在环加成中使用炔基阴离子而在Fu反应中使用中性炔。反应中铜的用量并不显着，因为即使催化CuI也促进了苯乙炔锂和重氮乙酸苄酯的环加成。(2)铜介导的炔基阴离子与重氮酯的环加成也与铜催化的末端炔与叠氮化合物的环加成相似因此，我们怀疑在这两种情况下都有类似的反应机制在起作用。铜可以作为给电子基团，提高炔HOMO的能量。涉及重氮羰基化合物LUMO的环加成生成（吡唑基）Cu中间体3，该中间体在反应条件下可发生互变异构。这个建议说明了几个重要的观察结果。首先，四氢呋喃、醚和甲苯的反应速率相似，这与协同环加成一致，而与逐步形成带电中间体不一致。其次，观察到的区域选择性与关于环加成的HOMO（亲偶极物）-LUMO（偶极子）相互作用的理论预测一致第三，炔上的吸电子基团定性地减缓了反应。这些基团会降低炔的HOMO，从而增加HOMO- lumo的间隙。第四，在反应条件下，重氮甲烷不与乙酰锂发生反应，这可能是重氮甲烷相对于重氮酯的高能LUMO的反映。最后，氘标记实验支持了所提出的互变异构化：铜介导的α- d -苄基重氮乙酸环加成（2-d）得到1 -d，吡唑环上含有大量氘（eq 3）。此外，回收的苯乙炔被部分氘化，可能反映了初始环加合物3被炔基阴离子去质子化苯甲醇副产物的来源目前尚不清楚，但可以排除其形成的几个明显机制。生成BnOH需要的是一般碱，而不是乙酰基或铜盐：重氮乙酸苄酯与丁基锂、Li2Cu(n-C4H9)2CN、苯乙酰锂或LDA反应完全，在温和条件下生成BnOH为主要产物。这一数据以及吡唑在反应条件下稳定的事实表明，重氮乙酸苄酯是BnOH的来源。从原理上讲，重氮乙酸苄酯中E2的直接消去可以解释BnOH的形成。如果是这样，降低2a的动态酸度可能会提高1a:BnOH比然而，在实践中，2或2-d的反应产生几乎相同的1a:BnOH比率（参见表1，条目8和公式3）。此外，回收的苯乙炔仅部分氘化，因此去质子化不能解释BnOH的全部形成。直接加入羰基可以释放BnOH，但这一途径尚无数据支持。特别是，反应后未反应的苯乙炔被回收，并且在粗反应混合物中没有观察到加成产物。此外，用小的（乙基）和大的（叔丁基）重氮酯得到的吡唑的产率相似，这表明不存在与羰基加成的竞争机制。最后，简单的酯水解似乎不太可能。具体来说，在不同亚化学计量量的水下进行的反应产生相似数量的BnOH，而过量的水会抑制反应。此外，BnOH的产生与反应混合物中含有的LiCl（一种可能的水源）的量成反比。(3)铜促进乙酰基与重氮羰基化合物的环加成反应为合成吡唑提供了一种直接有效的方法。该方法操作简单，并且可以容忍两个反应伙伴的实质性变化。此外，作为一个罕见的逆电按需环加成的例子，它代表了一种概念上新颖的方法来处理这类重要的杂环。正在进行的研究试图澄清负责吡唑和副产物形成的机制，目的是确定有利于前者而不是后者的反应参数。
1,3-Dipolar cycloadditions provide convenient access to carbocyclic and heterocyclic 5-membered rings.[1] In some cases, 1,3-dipoles react with dipolarophiles without activation of either component. For example ozonolysis of olefins and addition of nitrile oxides to alkynes often proceeds without added promoters.[2] With many substrate combinations, however, no cycloadduct is formed when dipole and dipoarophile are simply mixed. To accelerate these types of reactions, two complementary strategies focus on modulating the reactivity of the dipolarophile (Scheme 1). In the first, Lewis acids are included to lower the LUMO of the dipolarophile.[3] Under such conditions the dipole reacts through its HOMO to generate the cycloaddition product.[ 4 ] Alternatively, additives that increase the electron density of the dipolarophile can accelerate cycloaddition via an HOMO(dipolarophile)-LUMO(dipole) interaction. This approach is less common than the Lewis acid-based methods,[5] but is most notably operative in the copper-catalyzed synthesis of triazoles from alkynes and azides.[6] Here we report a new example of inverse electron-demand dipolar cycloadditions: the synthesis of pyrazoles via cycloaddition of copper acetylides with diazocarbonyl compounds (eq 1). Scheme 1 Activation of alkynes and alkenes by metals for 1,3-dipolar cycloaddition. The pyrazole substructure appears in small molecules possessing a wide range of biological activities, and accordingly, represents a valuable target for organic synthesis.[7] A common tactic for the preparation of pyrazoles (1) relies on the condensation of β-diketones with hydrazines.[8] Alternatively, cyclization of diazo-alkenes[9] or unsaturated hydrazines[10] provides improved control of regiochemistry relative to the dicarbonyl/hydrazine condensation, although the precursors are more challenging to prepare. A direct approach to pyrazoles involves the cycloaddition of diazo compounds with alkynes. In this regard, electron-rich diazo compounds (e.g. diazomethane) react under mild conditions with electron-deficient alkynes.[11] In contrast, Lewis acids are required to promote the cycloaddition between electron deficient alkynes and diazocarbonyl compounds.[12] However, simple alkyl- or arylacetylenes generally fail to react with diazocarbonyl compounds under thermal conditions or in the presence of Lewis acids. Seeking an alternative mode of activation, we evaluated metal acetylides in cycloadditions with diazocarbonyl compounds. When lithium phenylacetylide was treated successively with various Cu(I) sources and benzyl diazoacetate (2), pyrazole 1a was formed along with benzyl alcohol (BnOH, Table 1). In all cases conversion of diazoester was complete, and, with one exception, >90% of the mass balance was accounted for by 1a, BnOH and recovered alkyne. Fumarate and maleate side products were observed in 90% purity by tituration with hexanes; in all cases analytically pure product can be isolated following column chromatography on silica gel. Figure 1 Copper-promoted reaction of lithium acetylides with diazo carbonyl compounds. Comparisons between the present cycloaddition and two known reactions are striking. First, a report from the Fu group described a Cu(I)-catalyzed alkynylation of diazoesters (eq 2).[15] Under these neutral conditions, no pyrazole is formed. Likewise, reaction of ethyl dizaoacetate with PhCCLi/CuCN·6LiCl generates no observable alkynyl ester. The critical difference between the two systems is likely the use of alkynyl anions in the cycloaddition versus the neutral alkyne in the Fu reaction. The amount of copper used in the reaction does not appear significant as even catalytic CuI promotes the cycloaddition of lithium phenylacetylene and benzyl diazoacetate. (2) The copper-mediated cycloaddition of alkynyl anions with diazoesters is also reminiscent of the copper-catalyzed cycloaddition of terminal alkynes with azides.[16] Accordingly, we suspect a similar reaction mechanism is operative in both cases. Copper may serve as an electron-donating group and raise the energy of the alkyne HOMO. Cycloaddition involving the LUMO of the diazocarbonyl compound generates a (pyrazolyl)Cu intermediate 3 which can tautomerize under the reaction conditions. This proposal accounts for several important observations. First, the fact that the reaction rate is similar in THF, ether and toluene is consistent with a concerted cycloaddition but not with stepwise formation of charged intermediates. Second, the observed regioselectivity is consistent with theoretical predictions regarding cycloaddition featuring HOMO(dipolarophile)-LUMO(dipole) interactions.[4] Third, electron withdrawing groups on the alkyne qualitatively slow the reaction. These groups should lower the HOMO of the alkyne and therefore increase the HOMO-LUMO gap. Fourth, diazomethane does not react with lithiumacetylides under the reaction conditions, presumably a reflection of its high-energy LUMO relative to diazoesters. Finally, deuterium labelling experiments support the proposed tautomerization: Copper-mediated cycloaddition with α-D-benzyl diazoacetate (2-d) yields 1a–d with substantial deuterium incorporation on the pyrazole ring (eq 3). Additionally, recovered phenyl acetylene was partially deuterated, likely reflecting deprotonation of the initial cycloadduct 3 by alkynyl anion.[17] The origin of the benzyl alcohol side product is not clear at present, although several obvious mechanisms for its formation can be ruled out. Generation of BnOH requires a general base and not acetylides or copper salts specifically: benzyl diazoacetate reacts completely with butyllithium, Li2Cu(n-C4H9)2CN, lithium phenylacetylide or LDA to yield BnOH as the major product under mild conditions. This data, and the fact that the pyrazole is stable under the reaction conditions, implicates benzyl diazoacetate as the source of BnOH. In principle, direct E2 elimination of alkoxide from benzyl diazoacetate could account for BnOH formation. If so, reducing the kinetic acidity of 2a might increase the 1a:BnOH ratio.[18] In practice, however, reactions with 2 or 2-d yield nearly identical 1a:BnOH ratios (cf. Table 1, entry 8 and eq 3). Additionally, recovered phenylacetylene was only partially deuterated, so deprotonation could not account for all of the BnOH formation. Direct addition to the carbonyl could release BnOH, yet such a pathway is not supported by the data. In particular, unreacted phenylacetylene is recovered after the reaction, and no addition products are observed in the crude reaction mixtures. Furthermore, the similar yields of pyrazole obtained with small (ethyl) and large (tert-butyl) diazoesters argues against a competing mechanism involving addition to the carbonyl. Finally, simple ester hydrolysis appears unlikely. Specifically, reactions performed with varying sub-stoichiometric amounts of water yield similar amounts of BnOH while excess water inhibits the reaction. Further, the production of BnOH is inversely related to the amount of LiCl (a possible source of water) included in the reaction mixture. (3) The copper-promoted cycloaddition of acetylides with diazocarbonyl compounds offers a direct and efficient approach to the synthesis of pyrazoles. The method is operationally simple and tolerates substantial variation in the two reacting partners. Furthermore, as a rare example of an inverse-electron-demand cycloaddition, it represents a conceptually novel approach to this important class of heterocycles. Ongoing studies seek clarification of the mechanisms responsible for pyrazole and side-product formation with an aim to identify reaction parameters which favor the former over the latter.