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Catalytic Ynamide Oxidation Strategy for the Preparation of #-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., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01599 • Publication Date (Web): 02 Aug 2016 Downloaded from http://pubs.acs.org on August 2, 2016
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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*,†,§ †
State Key Laboratory of Physical Chemistry of Solid Surfaces & The 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 & 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.
ABSTRACT: 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 a 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‐halo pyridine N‐ oxide as both the oxidant and the halogen source, and its mechanistic rationale is also supported by DFT 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
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 my‐ riad methods available, most focus on the α‐ functionalization of carbonyl compounds1‐3 such as transi‐ tion metal‐catalyzed reaction of α‐diazo carbonyl com‐ pounds1 and hypervalent iodine participated α‐ functionalization of carbonyls,2 which often suffer from multistep synthesis, limited substrate scope and inaccess‐ ible starting materials. In particular, compared to the preparation of α‐functionalized ketones and esters, suc‐ cessful 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 diver‐ sified 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 of hazardous, not easily
accessible and potentially explosive α‐diazo carbonyls in accessing α‐oxo metal carbenes.5 As a result, this strategy has evolved into a robust and reliable methodology for the C−C and C−X bond formation, especially in a highly stereoselective manner.6 Albeit great achievements have been reached, examples of intermolecular alkyne oxida‐ tions with external nucleophiles are still very scarce7 mainly due to the competing background reaction of ex‐ ternal nucleophiles with the activated alkynes and the overoxidation of the highly electrophilic carbene center by the same oxidant,8 thus generating the unwanted ole‐ fin and diketone byproducts, respectively (Scheme 1a). In other words, if external nucleophiles are stronger nucleo‐ philes than N‐oxides, the external nucleophiles would attack the alkynes directly to form olefin byproducts, while diketone byproducts would be obtained in case that N‐oxides are stronger nucleophiles than external nucleo‐ philes. Therefore, the ideal reaction pathway is that oxide attacks the alkyne first, followed by reaction with the ex‐ ternal nucleophile rather than the second oxide. However, to realize this cascade reaction in such an orderly manner is highly challenging. In addition, it should be specially mentioned that no success has been achieved for external nucleophiles bearing strong coordinating groups (N3, NCS, Br, Cl) in the gold‐catalyzed intermolecular alkyne oxida‐
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tion probably due to the fact that 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 cata‐ lyze such an intermolecular alkyne oxidation and, impor‐ tantly, the unwanted overoxidation could be completely suppressed in this oxidative zinc catalysis.11 Of note, me‐ chanistic studies revealed that the reaction presumably proceeds by a Lewis acid‐catalyzed Friedel‐Crafts‐type pathway (SN2 pathway), and that metal carbenes are not involved as reaction intermediates. Inspired by these re‐ sults, 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 synthetical‐ ly useful α‐azido amides and α‐thiocyanate amides, re‐ spectively. In addition, the challenging catalytic oxidative halogenation has also been achieved through such an alkyne oxidation by employing oxidant as a source of ha‐ logen. Moreover, NaBARF has been shown for the first time to be highly effective catalyst to promote this cas‐ cade reaction.
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tion, the high value‐added α‐azido carbonyls can serve as direct precursors of α‐amino carbonyls14 and β‐azido alco‐ hols,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 have been reported on their synthe‐ sis. Among those, 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 sulfo‐ nyloxy unit (Scheme 2a).12c Notable is that this methodol‐ ogy generally suffers from drawbacks such as multistep synthesis, limited substrate scope, and low efficiency. In addition, α‐diazo carbonyls have also been used to pre‐ pare the corresponding α‐azido carbonyls, but relying on the stoichiometric use of CeCl3 (Scheme 2b).17 Therefore, novel catalytic approaches are still highly demanded for its construction, especially from readily and generally available precursors. We envisioned that using the above‐ mentioned zinc‐catalyzed oxidative approach,11 the prepa‐ ration of α‐azido amides might be achieved directly from the Lewis acid‐catalyzed oxidative reaction of ynamides with TMSN3 (Scheme 2c). Scheme 2. Initial Design. a) Most frequent used method for the synthesis of -azido carbonyls
Scheme 1. Catalytic Alkyne Oxidation.
O
O
O R2
1
R
R2
R1
R2
R1 N3
LG (LG = Cl, Br, I, OTs, OMs) b) Transformation of -diazo carbonyls into -azido carbonyls O N2
R
NaN3 CeX3 (stoichiometric) (X = Cl, OTf)
O N3
R
c) Zinc-catalyzed tandem alkyne oxidation/azidation (this work) PG N R1
R2 1
RESULTS AND DISCUSSION 1. Zn(OTf)2‐Catalyzed Tandem Alkyne Oxida‐ tion/Azidation. Organoazides are highly valuable and interesting compounds, and have been widely employed in organic and pharmaceutical synthesis, including 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 Particularly, compared with the simple alkyl or aryl azides, α‐azido carbonyls are ubiquitous structural motifs in organic molecules.12c Fea‐ turing of high potential chemical reactivity, these com‐ pounds demonstrate particular synthetic utility.13 In addi‐
TMSN3 [LA]/N-oxide
O PG
R2
N R1
N3 2
Our initial investigation focused on the reaction of ynamide substrate 1a with TMSN3 by the use of 8‐ ethylquinoline N‐oxide 3b as oxidant in DCE at 60 oC 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 dike‐ tone 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 all these cases.18 Somewhat surprisingly, NaBARF (10 mol %) alone could promote this oxidative azidation to give the correspond‐ ing 2a in 64% yield (Table 1, entry 8). Instead, Brønsted acids such as MsOH and TfOH were not effective in pro‐ moting this reaction,19 and only hydration byproduct 2ab was obtained (Table 1, entries 9‐10). In addition, the
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screening of other N‐oxides failed to improve the yield (Table 1, entries 11‐14). Delightedly, it was found that the use of 1.2 equiv of oxidant 3b minimized the formation of diketone 2aa and 78% yield of 2a could be achieved (Ta‐ ble 1, entry 15). Finally, it should be mentioned that only diketone 2aa was formed (>90% yield) if 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). Table 1. Optimization of Reaction Conditionsa
entry
catalyst
oxidant (R)
1
Zn(OTf)2
3b (Et)
72 15
