Research Article pubs.acs.org/acscatalysis
Catalytic Ynamide Oxidation Strategy for the Preparation of α‑Functionalized Amides Fei Pan,† Xin-Ling Li,† Xiu-Mei Chen,‡ Chao Shu,† Peng-Peng Ruan,† Cang-Hai Shen,† Xin Lu,*,‡ and Long-Wu Ye*,†,§
ACS Catal. 2016.6:6055-6062. Downloaded from pubs.acs.org by TULANE UNIV on 01/21/19. For personal use only.
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State Key Laboratory of Physical Chemistry of Solid Surfaces and Key Laboratory for Chemical Biology of Fujian Province, Department of Chemistry, Xiamen University, Xiamen 361005, China ‡ State Key Laboratory of Physical Chemistry of Solid Surfaces and Center for Theoretical Chemistry, Department of Chemistry, Xiamen University, Xiamen 361005, China § State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China S Supporting Information *
ABSTRACT: A Lewis acid-catalyzed alkyne oxidation strategy has been developed to produce diverse α-functionalized amides from readily and generally available ynamides. An efficient zinc(II)-catalyzed oxidative azidation and thiocyanation has been achieved, providing facile access to synthetically useful α-azido amides and α-thiocyanate amides, respectively. This chemistry can also be extended to oxidative halogenations by employing the 2-halopyridine N-oxide as both the oxidant and the halogen source, and its mechanistic rationale is also supported by density functional theory calculations. Moreover, NaBARF has been demonstrated to catalyze such an alkyne oxidation effectively, thus further excluding the metal carbene pathway in this cascade reaction. KEYWORDS: alkyne, oxidation, azidation, halogenation, homogeneous catalysis, synthetic methods
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INTRODUCTION The synthesis of α-functionalized carbonyl compounds always attracts considerable attention, because they are versatile building blocks and pivotal intermediates for the construction of a variety of biologically active natural products and medicinal compounds. In spite of the myriad methods available, most focus on the α-functionalization of carbonyl compounds1−3 such as the transition metal-catalyzed reaction of α-diazo carbonyl compounds1 and the α-functionalization of carbonyls that includes hypervalent iodine,2 which often suffer from multistep synthesis, limited substrate scope, and inaccessible starting materials. In particular, compared to the preparation of α-functionalized ketones and esters, successful examples of α-functionalized amide synthesis have been relatively scarce. Consequently, the development of novel methods for the construction of these skeletons is highly desirable, especially those based on assembling structures directly from readily available and easily diversified building blocks. Recently, gold-catalyzed intermolecular oxidation of alkynes by an N−O bond oxidant via a presumable α-oxo gold carbene4 pathway has attracted significant research attention, as this protocol renders readily available and safer alkynes as the replacement for hazardous, not easily accessible, and potentially explosive α-diazo carbonyls in accessing α-oxo metal carbenes.5 © 2016 American Chemical Society
As a result, this strategy has evolved into a robust and reliable methodology for C−C and C−X bond formation, especially in a highly stereoselective manner.6 Despite the fact that great achievements have been reached, examples of intermolecular alkyne oxidations with external nucleophiles are still very scarce7 mainly because of the competing background reaction of external nucleophiles with the activated alkynes and the overoxidation of the highly electrophilic carbene center by the same oxidant,8 thus generating the unwanted olefin and diketone byproducts, respectively (Scheme 1a). In other words, if external nucleophiles are stronger nucleophiles than N-oxides, the external nucleophiles would attack the alkynes directly to form olefin byproducts, while diketone byproducts would be obtained in the case in which N-oxides are stronger nucleophiles than external nucleophiles. Therefore, the ideal reaction pathway is one in which oxide attacks the alkyne first, followed by reaction with the external nucleophile rather than the second oxide. However, realizing this cascade reaction in such an orderly manner is highly challenging. In addition, it should be emphasized that no success has been achieved with external Received: June 8, 2016 Revised: August 1, 2016 Published: August 2, 2016 6055
DOI: 10.1021/acscatal.6b01599 ACS Catal. 2016, 6, 6055−6062
Research Article
ACS Catalysis
the most widely used method is the nucleophilic substitution of the α-substituted carbonyls bearing a good leaving group such as a halide or a sulfonyloxy unit (Scheme 2a).12c Notable is the
Scheme 1. Catalytic Alkyne Oxidation
Scheme 2. Initial Design
nucleophiles bearing strong coordinating groups (N3, NCS, Br, or Cl) in the gold-catalyzed intermolecular alkyne oxidation probably because these nucleophiles are able to deactivate the noble catalyst. In continuation of our work on ynamide chemistry,9,10 we recently disclosed that zinc could also effectively catalyze such an intermolecular alkyne oxidation and, importantly, the unwanted overoxidation could be completely suppressed in this oxidative zinc catalysis.11 It is worth noting that mechanistic studies revealed that the reaction presumably proceeds by a Lewis acidcatalyzed Friedel−Crafts-type pathway (SN2′ pathway) and that metal carbenes are not involved as reaction intermediates. Inspired by these results, we envisioned that the synthesis of α-functionalized amides might be accessed directly through such a Lewis acid-catalyzed reaction of ynamides with TMSX (Scheme 1b). Herein, we describe the realization of zinc-catalyzed oxidative azidation and thiocyanation, which constitutes a very practical approach to the generation of synthetically useful α-azido amides and α-thiocyanate amides, respectively. In addition, the challenging catalytic oxidative halogenation has also been achieved through such an alkyne oxidation by employing an oxidant as a source of halogen. Moreover, NaBARF has been shown for the first time to be a highly effective catalyst for the promotion of this cascade reaction.
fact that this methodology generally suffers from drawbacks such as multistep synthesis, limited substrate scope, and low efficiency. In addition, α-diazo carbonyls have also been used to prepare the corresponding α-azido carbonyls, but by relying on the stoichiometric use of CeCl3 (Scheme 2b).17 Therefore, novel catalytic approaches are still in great demand for its construction, especially from readily and generally available precursors. We envisioned that using the zinc-catalyzed oxidative approach mentioned above,11 the preparation of α-azido amides might be achieved directly from the Lewis acid-catalyzed oxidative reaction of ynamides with TMSN3 (Scheme 2c). Our initial investigation focused on the reaction of ynamide substrate 1a with TMSN3 by the use of 8-ethylquinoline N-oxide 3b as an oxidant in DCE at 60 °C in the presence of different Lewis acids (10 mol %). To our delight, these Lewis acids could catalyze the oxidative azidation smoothly to afford the desired α-azido amide 2a in 59−72% yields (Table 1, entries 1−7), and Zn(OTf)2 gave the best result (Table 1, entry 1). Of note, although diketone byproduct 2aa could be formed in a significant amount in such an intermolecular cascade reaction, no olefin byproduct formation via the direct reaction of TMSN3 with ynamide 1a was observed in any of these cases.18 Somewhat surprisingly, NaBARF (10 mol %) alone could promote this oxidative azidation to give the corresponding 2a in 64% yield (Table 1, entry 8). Instead, Brønsted acids such as MsOH and TfOH were not effective in promoting this reaction,19 and only hydration byproduct 2ab was obtained (Table 1, entries 9 and 10). In addition, the screening of other N-oxides failed to improve the yield (Table 1, entries 11−14). To our delight, we found that the use of 1.2 equiv of oxidant 3b minimized the formation of diketone 2aa and a 78% yield of 2a could be achieved (Table 1, entry 15). Finally, it should be mentioned that diketone 2aa was formed (>90% yield) only if the reaction was catalyzed by typical gold catalysts such as IPrAuNTf2, Ph3PAuNTf2, Cy-JohnPhosAuNTf2, and XPhosAuNTf2, and no 2a formation was observed in the absence of the catalyst (>95% of 1a remained unreacted). With the optimized reaction conditions in hand, the scope of this Zn-catalyzed oxidative azidation was then examined. A variety of different R1-substituted (R1 = alkyl or aryl) ynamides that were evaluated in this study reacted well with TMSN3,
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RESULTS AND DISCUSSION Zn(OTf)2-Catalyzed Tandem Alkyne Oxidation/Azidation. Organoazides are highly valuable and interesting compounds and have been widely employed in organic and pharmaceutical synthesis, including being used as amine precursors, potential sources of nitrenes, valuable dipoles in 1,3-dipolar cycloaddition, and starting materials of iminophosphoranes utilized in aza-Wittig reactions to construct various heterocycles.12 In particular, compared with the simple alkyl or aryl azides, α-azido carbonyls are ubiquitous structural motifs in organic molecules.12c Featuring high potential chemical reactivity, these compounds demonstrate particular synthetic utility.13 In addition, the high-value-added α-azido carbonyls can serve as direct precursors of α-amino carbonyls14 and β-azido alcohols,15 both of which are important building blocks and widely exist in pharmaceuticals or naturally occurring compounds.16 It is surprising, however, that only a few preparative methods for their synthesis have been reported. Among those, 6056
DOI: 10.1021/acscatal.6b01599 ACS Catal. 2016, 6, 6055−6062
Research Article
ACS Catalysis Table 1. Optimization of Reaction Conditionsa
Table 2. Reaction Scope for the Formation of α-Azido Amides 2a
NMR yield (%)b entry
catalyst
oxidant (R)
2a
2aa
2ab
1 2 3 4 5 6 7c 8 9d 10d 11 12 13 14 15e
Zn(OTf)2 Yb(OTf)3 Fe(OTf)2 In(OTf)3 Sm(OTf)2 Y(OTf)3 Zn(OTf)2/NaBARFf NaBARFf MsOH TfOH Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2 Zn(OTf)2
3b (Et) 3b (Et) 3b (Et) 3b (Et) 3b (Et) 3b (Et) 3b (Et) 3b (Et) 3b (Et) 3b (Et) 3a (Me) 3c (iPr) 3d (2,6-Br2) 3e (2,6-Cl2) 3b (Et)
72 66 62 63 61 59 71 64
