Domino Reactions in Organic Synthesis

Tietze, Lutz F.

doi:10.1021/cr950027e

Cited by 3,867 publications

(1,304 citation statements)

References 315 publications

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“…Following a reported procedure [8] , dry DMF (1.88 mL, 24.3 mmol, 1.2 equiv) was added into a solution of oxalyl dichloride (1.82 mL, 22.3 mmol, 1.1 equiv) in DCM (50 mL) slowly at 0 ˚C. After 15 minutes, the solution turned cloudy.…”

Section: -Methyl-1h-pyrrole-3-carbaldehyde (29)mentioning

confidence: 99%

“…13 C NMR (101 MHz, CDCl3) δ 129. 8,126.8 (q,J = 276.6 Hz),121.8,108.7,107.4,80.5,73.3,70.1,54.2,45.3,30.9 (q,J = 29.3 Hz), 23.9 (q, J = 2.9 Hz). 23.…”

Section: -(1-mentioning

confidence: 99%

“…With aromatic substituents, formation of the C6-alkynylated product 10 was observed for the first time. The C5-alkynylated product 8 was still the major product with a phenyl, a tolyl or a para-bromophenyl substituent (entries [7][8][9]. The latter case also demonstrated that halogen substituents were tolerated under the reaction conditions, allowing further functionalization of the products via classical cross-coupling chemistry.…”

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confidence: 96%

“…As C-H metalation of the arene ring of indoles is extremely difficult in presence of the more reactive C2 and C3 C-H bonds, we wondered if the desired reactive intermediate could be generated in situ during a metal-catalyzed cyclization step (Scheme 1). The use of such "domino" or "cascade" processes is one of the most efficient ways to increase molecular complexity in organic synthesis, [8] but it had not yet been applied to the synthesis of benzene alkynylated indoles. In fact, reported cascade approaches by the group of Cacchi and Zhu for the synthesis of alkynylated indoles have focused on the construction of the pyrrole ring using palladium catalysis (Scheme 1, A).…”

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confidence: 99%

“…In contrast, changing the base to sodium bicarbonate allowed increasing the yield to 40% (entry 5). Investigation of solvents showed that CH3CN was best (entries [6][7][8]. Neither the use of other hypervalent iodine reagents, such as TIPS-EBX (4b) or alkynyliodonium salt 4c (entries 9-10), nor platinum(IV) or (0) catalysts (entries 11-12) led to improved results.…”

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confidence: 99%

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Platinum‐Catalyzed Domino Reaction with Benziodoxole Reagents for Accessing Benzene‐Alkynylated Indoles

Waser

2015

Angew Chem Int Ed

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Indoles are omnipresent in natural products, bioactive molecules and organic materials. Consequently, their synthesis or functionalization are important fields of research in organic chemistry. Most works focus on installation or modification of the pyrrole ring. To access benzene ring-functionalized indoles with an unsubstituted pyrrole ring remains more challenging. Herein we report a platinumcatalyzed cyclization-alkynylation domino process to obtain selectively C5-or C6-functionalized indoles starting from easily available pyrroles. Our work combines for the first time a platinum catalyst with EthynylBenziodoXole (EBX) hypervalent iodine reagents in a domino process for the synthesis of polyfunctionalized arene rings and gives access to important building blocks for the synthesis of bioactive compounds and organic materials.Functionalized indoles occupy a privileged position in organic chemistry, as they can be found in biomolecules, drugs, agrochemicals and materials. [1] To access these important building blocks, a first approach consists in the introduction of functional groups onto simple, commercially available indoles. In order to have a more efficient alternative to well-established cross-coupling reactions, the transition metal-catalyzed direct functionalization of C-H bond on indoles has been intensively investigated in the last two decades. Nevertheless, this approach is mostly limited to the modification of the more reactive pyrrole ring (innate reactivity, Figure 1, A). [2] The functionalization of the benzene ring has been only rarely achieved and is limited to C2,C3-disubstituted indoles. [3] One notable exception is the selective iridiumcatalyzed C7-borylation of indoles reported by Hartwig and coworkers. [4] We were particularly interested by the introduction of an alkyne onto the benzyl ring of indoles, as alkynes are key building blocks in medicinal, synthetic and material chemistry. [5] Direct alkynylation approaches can be used only to access 2-and 3-substituted indoles. [6] This is an important limitation, as 5-or 6-alkynylated indoles can be found in bioactive compounds such as 5-LOX (5-lipoxygenase) inhibitor 1, [7a] or NMDA (N-Methyl-DAspartate Receptor) antagonist 2. [7b] Alkynylated carbazoles are especially important for organic materials, such as macrocycle 3, an organic sensor for the detection of TNT. [7c] If an efficient method for the synthesis of benzene-alkynylated indoles can be developed, more complex compounds could then be easily obtained by using wellestablished C-H functionalization at the C2 or C3 positions or transformations of the triple bond. As C-H metalation of the arene ring of indoles is extremely difficult in presence of the more reactive C2 and C3 C-H bonds, we wondered if the desired reactive intermediate could be generated in situ during a metal-catalyzed cyclization step (Scheme 1). The use of such "domino" or "cascade" processes is one of the most efficient ways to increase molecular complexity in organic synthesis, [8] but it had not y...

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Section: -Methyl-1h-pyrrole-3-carbaldehyde (29)mentioning

confidence: 99%

“…13 C NMR (101 MHz, CDCl3) δ 129. 8,126.8 (q,J = 276.6 Hz),121.8,108.7,107.4,80.5,73.3,70.1,54.2,45.3,30.9 (q,J = 29.3 Hz), 23.9 (q, J = 2.9 Hz). 23.…”

Section: -(1-mentioning

confidence: 99%

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confidence: 96%

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confidence: 99%

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confidence: 99%

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Platinum‐Catalyzed Domino Reaction with Benziodoxole Reagents for Accessing Benzene‐Alkynylated Indoles

Waser

2015

Angew Chem Int Ed

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Optimization in organic synthesis

Snieckus

1999

Med. Res. Rev.

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Art is always a bonus to synthesis . . . . the artistic aspect of synthesis, beautiful and marvelous as it is, should not be a justification for carrying out a total synthesis. If your problem is truly essential then you don't care about the elegance. The more essential your first E is, the less important your last E becomes." 1 "Will we be able to recapture the many millions of presumed 'transient'natural products that were evolutionarily de-selected along the paths that eventually led to the natural products synthesized on Earth today? . . . I cannot imagine that in a young synthetic chemist's lifetime, it will not be accomplished." 2 Organic Synthesis, quo vadis? 3 has been a phrase, perhaps in a more modern language, on the lips of the practitioners of this demanding science-art, undoubtedly from the earliest times 4 but more vigorously in the last two decades. 5 Comparison of achievements of yesterday 6 and today 7 suggests progress in our abilities to construct molecules of complexity, with higher stereocontrol, faster analysis, and greater prediction of eventual success. However, the practical aspects, on any scale, of brevity, efficiency, safety, eco-consciousness, and energy-and resource-frugality remain, as noted by a major synthetic craftsman, 8 crudely addressed. The Y2K symbolism is perhaps also appropriate for urgently dedicating our efforts to making headway in the solution of these interrelated goals.Our central science 5a progresses on fronts of method development and total synthesis with a great deal of cross-talk and interdependency (see Fig. 1). The burgeoning literature of new methods suggests that 70% are not repeated, perhaps even in the original laboratories, a situation with dire consequences for ascertaining true yield ranges and reproducibility a la the Org. Syn. religion. Furthermore, as judged from a cursory glance of tables in recent journals, much is left to be desired in giving confidence to the user that a method has generality (substrate diversity, FG and steric tolerance, catalyst or reagent minimization, and temperature and solvent optimization). Although the beauty of judiciously modeled use of PGs is to be applauded, 9 FG protection is a continuing embarrassment and annoyance. Synthetic chemists are challenging the dogma by daring the multi-FG molecules to behave in the manner desired. Ugi multicomponent reactions 10 and combinatorial synthesis 11 will undoubtedly soon influence the PG-expediency problem. In industry, statistical programs 12 at times drive optimization of reactions thus meeting the normal intense time constraints to produce mulit-kg of commercial substances.Atom-economy, a term coined by another influential synthetic chemist, 13 has brought awareness of an issue to academic scientists which their industrial process and development colleagues un-

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