Inspired by the suitability of quinoline N-oxides as electrophiles for alkylcopper nucleophiles, we envisioned that quinoline N-oxides could serve as proper electrophiles to react with allenyl copper species to form chiral allene products through a five-membered, rather than seven-membered, transition state Fig. Herein, we report our studies toward the development of an enantioselective synthesis of quinolinyl-containing chiral allenes.
Results Evaluation of reaction conditions We began our studies on this asymmetric allenylation by identifying an effective and selective chiral copper catalyst for the reaction between butenynylbenzene 2a and quinoline N-oxide 1a.
We tested copper complexes generated in situ from CuOAc and various chiral bisphosphine ligands as catalysts. The results are summarized in Fig.
Similar results were obtained for the reactions when catalysts generated from CuOAc and chiral ligands L2—L5 were employed.
Reaction conditions: quinoline N-oxide 1a 0. Enynes bearing reactive groups, such as ester 3f and 3j , benzyl ether 3g , siloxy 3h , and imide 3k , are compatible with the reaction conditions. The data in Fig. Reaction conditions: quinoline N-oxide 0.
CuOAc In addition, 1,3-enynes with substitution at the olefenic terminus of the enynes Z -2af and Z -2ag also reacted to afford the corresponding allenes 3af and 3ag in high isolated yields and good enantioselectivities. Z Alkenynoate 2ah , an activated 1,3-enyne, also reacted to give the allene product 3ah in high yield, albeit with a modest enantioselectivity.
However, Z -octenyne, a 1,3-enyne containing two alkyl groups at 1,4-positions, does not undergo this Cu-catalyzed asymmetric reaction. Scope of quinoline N-oxides Fig. In general, quinoline N-oxides with substituents at various positions reacted smoothly with the enyne 2a to yield the corresponding allenes 3ai—3ar in high yields and high enantioselectivities. However, 8-methyl and 8-methoxyquinoline N-oxides reacted with decreased enantioselectivities 3as and 3at , which might be due to the increased steric hindrance around the N—O bond.
However, the allenylation reactions of N-oxides of pyridines and isoquinolines do not occur under identified conditions. The enantioselectivity of this gram-scale reaction is comparable to that of a 0. In addition, we also showed that the quinoline-substituted allene products 3a and 3d underwent NIS-initiated cyclization to generate the corresponding 2-iodo-pyrrolo[1,2-a]quinolones in good yields Fig.
Yields are reported for isolated materials after column chromatography on silica gel Full size image This copper-catalyzed asymmetric allenylation was utilized for the modification of complex molecules. The results of this experiment indicate a mechanism involving catalyst control rather than substrate control when enantiometrically pure 1,3-enynes are used. Mechanistic considerations To gain some mechanistic insights into this Cu-catalyzed asymmetric allenylation of quinoline N-oxides, we conducted a series of deuterium-labeling experiments Fig.
The reaction of quinolineD N-oxide 1a-d1 with 1,3-enyne 2a under standard conditions afforded 3a in high isolated yield after purification with flash chromatography on silica gel, but no deuterium was incorporated into the product Fig.
When conducted with Ph2SiD2, the reaction of quinoline N-oxide 1a with 1,3-enyne 2a produced 3a-d1 in high isolated yield after purification with flash chromatography on silica gel, and the deuterium was located in the methyl group of 3a Fig. Upon workup by column chromatography on silica gel, both intermediates I-3a and I-3a-d1 underwent re-aromatization to yield 2-allenyl quinoline 3a in high yields.
Here, we present a review of this topic, focusing on describing the key transformations that can be observed at a transition-metal centre, as well as the use of well-defined organometallic complexes in the solid state as catalysts.
Keywords: solid state, organometallic, reactivity, catalysis 1. Introduction Organometallic chemistry, rigorously defined by the chemical synthesis and reactivity of molecules with metal—carbon bonds, is a vibrant area of research with a large variety of practical applications [ 1 ]. For example, organometallic complexes are commonly used as catalysts for the production of commodity chemicals, materials such as polymers, and in fine chemical synthesis and medicinal chemistry discovery [ 1 , 2 ].
The majority of discoveries in the area have been performed in the solution phase, with studies in the solid state generally often reserved only for structural analysis; for example, single-crystal X-ray crystallography and, to a significantly lesser extent, solid-state nuclear magnetic resonance spectroscopy. By contrast to the solution phase, studies on the synthesis of, and catalysis using, organometallic complexes in the solid phase have attracted significantly less attention, even though there are potential benefits to this approach, such as: improved selectivities in synthesis that comes from spatially confined environments, improved isolated yields of products and the attenuation of decomposition pathways allowing for products that might be kinetically unstable in solution to be observed in the solid state.
In fact, we ruled out that such azirines are viable intermediates in this catalytic cycle since independently synthesized 2H-azirine 4 was demonstrated to not react with 1f in the presence of RhS and visible light Fig. Computational studies revealed that there is a significant difference between the spin distribution of excited RhS—1f and IrS—1f.
As shown in Fig. This distinct difference in the nature of the excited state might account for the reactivity differences. Heteroaryl frameworks were proved to be compatible as demonstrated by the effective formation of thienyl- and indolyl- substituted 1-pyrrolines 3o, p. Notably, this protocol is amenable to the construction of complex 1-pyrrolines bearing a quaternary stereocenter 3q—s , including a spiro center 3s , reflecting the robustness of this single rhodium catalysis. To our delight, various functionalized vinyl azides were readily accommodated, including not only aryl vinyl azides 3t—x but also more challenging alkyl vinyl azides 3z—ab.
Reaction conditions: 1 0. Configurations were assigned with crystal structure of 3k Full size image Synthetic applications With the practical conditions and broad substrate scope in hand, we next evaluated the synthetic potential of this protocol Fig. Besides, a gram scale synthesis without loss of efficiency under air conditions highlights the practicality of this developed transformation without the requirement of inert conditions Fig.
Although the present methodology relies on a bidentate coordination mode, N-acylpyrazoles constitute very desirable synthons which can easily be transformed into other functionalities as shown in Fig. Importantly, the auxiliary 3- 4-methoxyphenyl pyrazole was fully recovered in these conversions.
From int3, the stereospecific 1,3-isomerization via TS4 to form int5 is facile. As shown in Fig. Furthermore, quinoline-substituted allenes, which are important but synthetically challenging, are unprecedented to the best of our knowledge. DFT calculations suggest that this Cu-catalyzed allenylation occurs through a nucleophilic attack of quinoline N-oxide with an allenyl copper intermediate via a five-membered transition state, thereby providing a rationale to explain the obtained chemoselectivity toward an allene rather than a propargylic product. Subsequently, we found that substituents within the pyrazole auxiliary have a profound influence on the reaction performance entries 1—3.
Accordingly, substantial endeavors have been made to develop methodologies for the asymmetric synthesis of chiral allenes. Introduction Chiral allene moieties are present in a variety of natural products, molecular materials, and a few marketed drugs due to their unique structural features, chemical reactivity, and biological properties 1 , 2.
The enantioselectivity of this gram-scale reaction is comparable to that of a 0.