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Synlett 2024; 35(02): 155-159
DOI: 10.1055/a-2103-9720
synpacts

Synthesis of Ynamides by C(sp)–H Amidation

Xiaolan Xie
a   College of Chemical Engineering and Materials Science, Quanzhou Normal University, Quanzhou 362000, P. R. of China
,
Na Hou
a   College of Chemical Engineering and Materials Science, Quanzhou Normal University, Quanzhou 362000, P. R. of China
,
Yan Lin
b   School of Special Education, Quanzhou Normal University, Quanzhou 362000, P. R. of China
,
Jian Lei  ∗
a   College of Chemical Engineering and Materials Science, Quanzhou Normal University, Quanzhou 362000, P. R. of China
› Author Affiliations

Financial support was received from the National Natural Science Foundation of China (21702120), the Natural Science Foundation of Fujian Province (2021J01965, 2018Y0073), Quanzhou City Science and Technology Program of China (2019C021R), and the Program for the Cultivation of Outstanding Young Scientific Talents in Fujian Province University.
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Abstract

Ynamides are versatile reactive building blocks in organic chemistry; consequently, synthetic methodologies to fabricate these compounds have received extensive attention. The construction of a C–N bond between an alkyne surrogate and an amide is a powerful and practical way to access ynamides, and has been widely studied. Recently, the amidation of terminal alkynes has emerged as a straightforward alternative. This Synpacts article briefly summarizes the use of C(sp)–H amidation strategies to form ynamides; it also highlights our recent work on the synthesis of ynehydrazides through the copper-catalyzed addition of terminal alkynes to dialkyl azodicarboxylates. Finally, some future directions in this field are outlined.


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Key words

ynamides - alkynes - copper catalysis - ynehydrazides - azodicarboxylates
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Jian Lei was born in Fujian province of the People’s Republic of China in 1988. He received his M.S. from the West China School of Pharmacy at Sichuan University under the supervision of Professor Zhenlei Song in 2012, In the period 2012–2015, he moved to Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, pursuing his Ph.D. under the guidance of Professors Qiang Zhu and Xiaoxing Wu. He is currently an associate professor at Quanzhou Normal University. His recent work focuses mainly on the development of novel catalytic reactions for the synthesis of N–N bond-containing-scaffolds and medicinal chemistry.

Ynamides are a class of N-alkynyl compounds with an electron-withdrawing group on the nitrogen atom or a structure containing an N=X (X = C, N, S) bond (Scheme [1a]).[1] [2] These compounds have been the focus of intensive research endeavors within the synthetic community owing to their distinct reactivities in the synthesis of nitrogen-containing scaffolds. Interested readers are encouraged to consult reviews on this topic.[3] Consequently, much effort has been made to develop robust methods for ynamide synthesis. In particular, the formation of C–N bonds by cross-coupling of alkyne derivatives with amide analogues is a prevalent method.[2] Recent reviews have summarized the use of alkynyl bromides, dihaloalkenes, alkynyl iodonium salts, ethynylbenziodoxolones, alkynyl copper derivatives, potassium alkynyltrifluoroborates, alkynylmagnesium bromides, alkynyllithium reagents, and alkynyl(triaryl)bismuthonium salts as alkyne surrogates participating in ynamide syntheses (Scheme [1b]).[2] However, these useful strategies suffer several disadvantages. For instance, alkyne surrogates require multistep syntheses, some are unstable, or harsh conditions may be necessary during their preparation. Starting from a terminal alkyne is an efficient complementary reaction owing to the abundance and availability of this class of compounds.[2] The following categories summarize some existing methods for synthesizing ynamides directly from terminal alkynes.

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Scheme 1 Classes of ynamides (a) and reported alkyne surrogates for their synthesis (b)

In 2008, Stahl and co-workers developed a novel copper-catalyzed oxidative coupling of terminal alkynes with amides to afford ynamides (Scheme [2a]).[4a] The optimized reaction conditions involved a combination of catalytic CuCl2 and 2.0 equivalents each of Na2CO3 and pyridine in toluene at 70 °C. The reaction exhibited a high atom economy and a wide amide scope. The authors proposed a tentative mechanism involving the formation of a CuII(alkynyl)(amidate) intermediate a-II through the reaction of the CuII acetylide species a-I with an activated amide nucleophile. Subsequent reductive elimination and aerobic oxidation provide the ynamides and regenerate the catalyst. During the process, bases and ligands inhibited the self-coupling of terminal alkynes. One drawback of this strategy is that it requires a significant excess of amide to achieve good results.

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Scheme 2 C(sp)–H amidation strategies for ynamide synthesis

To solve this problem, Mizuno and co-workers utilized Cu(OH)2 as a catalyst that could decrease the quantity of amide needed to complete the reaction (Scheme [2b]).[4b] Their aerobic oxidative C(sp)–H amidation was later expanded to the synthesis of ynimines[4c] and N-alkynylsulfoximines[4d] by using related imines and sulfoximines.

In 2012, the Muñiz group reported a reaction of aromatic terminal alkynes with PhI(OAc)N(SO2R)2 to afford ynamides under metal-free conditions (Scheme [2b]).[5] The reaction proceeds through the generation of adduct b-I, formed through initial dissociation of PhI(OAc)N(SO2R)2 followed by reversible coordination of the trivalent iodine to the terminal alkyne. With loss of HOAc by internal deprotonation, a σ-alkynyl iodine(III) intermediate b-II forms. Then, the corresponding amide anion attacks the alkynes at the β-position of iodine, and subsequent 1,2-migration leads to the formation of an ynamide.

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Scheme 3 Selected optimization experiments

Recently, Zhu’s group realized a copper-catalyzed aza-Sonogashira coupling reaction of terminal alkynes and O-acylimines to synthesize ynimines (Scheme [2c]).[6] When screening conditions for this transformation, they found that Cu(OAc)2 as a catalyst, 2,2′-biquinoline as a ligand, K2CO3 as a base, and DCE as a solvent at 110 °C were optimal. This protocol has wide practicality for substrates containing alkynes or imines. They proposed a possible mechanism involving the reaction of terminal alkynes, bases, and CuOAc, formed in situ, to afford a CuI acetylide intermediate c-I; a subsequent oxidative addition of CuI acetylide to the N–OAc bond produces the CuIII complex c-II. Then, reductive elimination of c-II furnishes the coordinated ynimine–CuI species c-III. Further ligand exchange with a terminal alkyne affords an ynimine and regenerates c-I. These elegant protocols provided straightforward routes to a series of ynamides; nevertheless, some ynamides still lack reliable synthetic routes and cannot be prepared through these methods.

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Scheme 4 Catalytic addition of terminal alkynes across azodicarboxylates

To address some synthesis issues associated with hydrazine-containing compounds,[7] we investigated the ynehydrazides, which were first synthesized by the Diederich group in 2003 and were later used as precursors to novel azacycles and azoheteroarene photoswitches.[8] [9] Previous synthesis routes to ynehydrazides involved an initial transformation of alkynes to alkynyllithium derivatives or ethynylbenziodoxolones, followed by an addition to azodicarboxylates or coupling with certain hydrazides.[10] We surmised that the direct catalytic addition of terminal alkynes to azodicarboxylates under suitable conditions might afford ynehydrazides. A precedent reaction provided a basis for our investigations on C(sp)–H hydrazidation: under catalytic conditions, arylboronic acids or arenes can form arylmetal species (e.g., with Cu or Au), which then add to azodicarboxylates, producing the related aryl hydrazides.[11] A similar reaction can also be achieved with an alkynylcopper species. On the other hand, alkynes are prone to undergo dimerization in the presence of copper catalysts, bases, and oxidants, i.e., the well-known Glaser–Hay coupling.[12] Diethyl azodicarboxylate has been reported to be an oxidant that can promote the dimerization of terminal alkynes.[13] Thus, appropriate tuning of the reaction conditions to avoid dimerization became an important problem to be addressed in this design. If successful, such a transformation would not only exhibit a very high atom economy and step economy, but might proceed under mild conditions to give ynehydrazides.[14]

Alkyne 1a and di-tert-butyl azodicarboxylate (DBAD; 2a) were investigated as model substrates (Scheme [3]). We found that the success of this unprecedented transformation largely relied on the choice of ligand. TMEDA led to a satisfactory yield of the ynehydrazide and kept the formation of dimer byproducts at a low level. In contrast to reports in the literature, we found that a catalytic amount of the weak base K2CO3 was enough to promote the reaction. Other solvents and copper salts were inferior to the optimized ones.

The reaction exhibited broad functional-group tolerance, and a wide range of ynehydrazides could be generated containing either aryl- or alkyl-substituted acetylene derivatives (Scheme [4]). This copper-catalyzed process also permitted the synthesis of ynehydrazides that were difficult to prepare by previous methods. Examples include bromo-substituted or electron-deficient aryl alkynes. In addition to the broad scope of alkyne motifs, other dialkyl azodicarboxylates, such as DIAD and DEAD, were inferior to DBAD but nevertheless afforded the target products. This protocol could be scaled up to a 1 g scale without an obvious decrease in yield.

Regarding the reaction mechanism, the yield was almost unaffected by the presence of the radical scavenger 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) was added to the reaction system. This result showed that a radical reaction pathway can be excluded. We then performed the reaction with a commercially available dimer [Cu(OH)·TMEDA]2Cl2 (Cu-TMEDA). By investigating the reaction conditions, we figured out that the reaction conditions could be simplified, that is the use of Cu-TMEDA alone can provide good yields; extra ligands and bases are not necessary. Based on the results of control experiments and previous work, a tentative mechanism was proposed as follows (Scheme [5]). A (TMEDA)CuCl2 complex is formed in situ by the reaction of CuCl2 with TMEDA. This Cu complex coordinates with an alkyne to generate the π-complex A, deprotonation of which with a base affords the copper acetylide species B. Subsequent addition across the dialkyl azodicarboxylate affords a hydrazide–Cu species C. Another proton-transfer step produces an ynehydrazide and regenerates the catalyst, thereby completing the catalytic cycle. The reaction of B with a terminal alkyne to afford dimerization byproducts is inhibited under the optimized conditions.

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Scheme 5 Mechanistic proposal

In conclusion, the C(sp)–H amidation strategy, developed by Stahl, Muñiz, and Zhu and their co-workers provides a direct and efficient route to a range of ynamides. With our development of the first catalytic C(sp)–H hydrazidation to expand the practical methodologies, we envision that many unprecedented reactions might be possible. From our point of view, at least three perspectives deserve further endeavors in the future: (1) considering the hydrazide-Cu intermediate C in Scheme [5], further functionalization of the nitrogen might be realized, leading to tetrasubstituted hydrazines, i.e., the difunctionalization of azodicarboxylates; (2) The development of new catalytic additions to other N–N unsaturated motifs (e.g., arenediazonium salts) might provide other classes of ynamides;[15] and (3) more C(sp)–H amidation strategies are urgently required in addition to the abovementioned ones; for example, electrophilic amination with amide derivatives (e.g., N-halo amides, O-benzoylhydroxylamide) might be designed for the synthesis of less-accessible ynamides.[16]


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Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

J.L. thanks Professors Qiang Zhu, Shuang Luo (Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences), and Xiaoxing Wu (China Pharmaceutical University) for helpful discussions.


Corresponding Author

Jian Lei
College of Chemical Engineering and Materials Science, Quanzhou Normal University
Quanzhou 362000
P. R. of China   

Publication History

Received: 11 May 2023

Accepted after revision: 31 May 2023

Accepted Manuscript online:
31 May 2023

Article published online:
12 July 2023

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   Permissions and Reprints All articles of this category
Zoom Image
Jian Lei was born in Fujian province of the People’s Republic of China in 1988. He received his M.S. from the West China School of Pharmacy at Sichuan University under the supervision of Professor Zhenlei Song in 2012, In the period 2012–2015, he moved to Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, pursuing his Ph.D. under the guidance of Professors Qiang Zhu and Xiaoxing Wu. He is currently an associate professor at Quanzhou Normal University. His recent work focuses mainly on the development of novel catalytic reactions for the synthesis of N–N bond-containing-scaffolds and medicinal chemistry.
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Scheme 1 Classes of ynamides (a) and reported alkyne surrogates for their synthesis (b)
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Scheme 2 C(sp)–H amidation strategies for ynamide synthesis
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Scheme 3 Selected optimization experiments
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Scheme 4 Catalytic addition of terminal alkynes across azodicarboxylates
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Scheme 5 Mechanistic proposal