Featured Article Cite This: J. Org. Chem. 2019, 84, 7587−7605
pubs.acs.org/joc
Iodine-Catalyzed Nazarov Cyclizations Jonas J. Koenig, Thiemo Arndt, Nora Gildemeister, Jörg-M. Neudörfl, and Martin Breugst* Department of Chemistry, University of Cologne, Greinstraße 4, 50939 Köln, Germany
Downloaded via UNIV OF SOUTHERN INDIANA on July 17, 2019 at 08:25:23 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.
S Supporting Information *
ABSTRACT: The Nazarov cyclization is an important pericyclic reaction that allows the synthesis of substituted cyclopentenones. We now demonstrate that this reaction can be performed under very mild, metal-free reaction conditions using molecular iodine as the catalyst. A variety of different divinyl ketones including aromatic systems undergo the iodine-catalyzed reaction with moderate to very good yields in both polar and apolar solvents. Our mechanistic studies indicate that the Nazarov system is activated through a halogen bond between the carbonyl group and the catalyst, and other modes of action like Brønsted acid or iodonium ion catalysis are unlikely. Furthermore, addition of iodine to the double bond or a putative iodine-catalyzed cis−trans isomerization of the employed olefins seem not to be an important side reaction here.
■
INTRODUCTION
One of the simplest potential halogen-bond donors molecular iodineis known to be catalytically active in different reactions for more than 100 years.8 Different mechanisms had been suggested for the catalytic activity including a halogen-bond activation, Brønsted acid catalysis,9 and activation via the iodonium ion.10 Recently, we were able to show that molecular iodine acts as a halogen-bond donor in different Michael additions (Scheme 2, top). A hidden
Over the past decade, noncovalent interactions like halogen bonding have grown to become important concepts in different areas of chemistry.1 Halogen bonding is defined as the interaction between a Lewis acidic region of a halogen atom (typically iodine or bromine) and the lone pair of a Lewis base. Bolm and co-workers applied 1-iodoperfluoroalkanes as halogen-bond catalysts for the first time in 2008 in the reduction of 2-substituted quinolines with a Hantzsch ester.2 In the following years, systematic investigations, particularly by Huber and co-workers, identified polydentate iodinated azolium ions, perfluorinated iodobenzene derivatives, as well as hypervalent iodine(III) compounds as excellent catalysts for the activation of carbon−halogen bonds (Scheme 1).1d,e,3 Similar catalytic systems have also been employed in (hetero)-Diels−Alder reactions,4 imine reduction,5 Michael additions,6 or cross-enolate coupling reactions.7
Scheme 2. Recent Examples of Iodine-Catalyzed Reactions12,13
Scheme 1. Selected Halogen-Bond Donors Used in Catalysis2,3a,c,d,5
Brønsted acid catalysis by HI11 could be ruled out experimentally.12 Furthermore, experimental studies indicated that molecular iodine is equally or even more reactive than traditional Lewis acids like TiCl4 or AlCl3 in these reactions.12b Very recently, molecular iodine also turned out to be an excellent catalyst for the carbonyl-olefin metathesis Received: April 19, 2019 Published: June 6, 2019 © 2019 American Chemical Society
7587
DOI: 10.1021/acs.joc.9b01083 J. Org. Chem. 2019, 84, 7587−7605
The Journal of Organic Chemistry
Featured Article
Scheme 3. Selected Examples for Polarized Nazarov and a Related Iso-Nazarov Cyclizations15a−d,18
Scheme 4. Synthesis of the Nazarov Systemsa
(Scheme 2, bottom) and is comparable in reactivity to FeCl3.13 However, experimental and computational investigations indicate that in these reactions the catalytically active species might be the iodonium ion rather than a simple halogen-bond activation. We now wondered whether molecular iodine can also be used in other synthetically important reactions and replace traditional Lewis acids. In this regard, the Nazarov cyclization of divinyl ketones seemed to be the ideal candidate:14 Lewis acids catalyze this transformation very efficiently,15 but Brønsted acid catalyzed and organocatalytic variants are also known.16 In 2003, various groups simultaneously reported on polarized Nazarov cyclizations that can be performed under much milder conditions using different metallic Lewis acids like Cu(OTf)2, AlCl3, or Pd(OAc)2 (Scheme 3).15a−d Adding stoichiometric amounts of chiral bis(oxazoline) ligands also resulted in enantioselective transformations. As molecular iodine is an easy to handle solid that is soluble in many organic solvents, a replacement of traditional Lewis acids by I2 could allow milder reaction conditions or reduce potential environmental risks.9,17 Recently, iodine has already been applied as a catalyst in the related iso-Nazarov reactions with 5 mol % catalyst loading in boiling ethyl acetate (Scheme 3).18 In this mechanistically similar reaction, the alkene attacks the activated carbonyl group, and the final cyclopentenone is obtained after isomerization of the double bond. We now report on our results on iodine-catalyzed Nazarov cyclizations and their mechanistic investigations.
a
■
DMP: Dess−Martin periodinane; PTC: phase-transfer catalyst.
were synthesized in Knoevenagel condensation reactions between suitable aldehydes and the β-keto ester obtained from 1-cyclohexene-1-carboxylic acid.15a,g,19 Typically, only the most stable E-configured diastereomer was obtained. We have furthermore synthesized the indole derivatives 7 and 9 as potential starting materials with aromatic character by modifying known procedures.20 While the corresponding Nazarov products obtained from 7 are key intermediates for the synthesis of germination stimulants for seeds of the parasitic plant Orobanche aegyptiaca,21 the Nazarov cyclization of 9b could result in the natural product bruceolline E.22
RESULTS AND DISCUSSION Starting Materials. The divinyl ketones used as the starting materials for the Nazarov cyclization were synthesized following literature-known procedures as summarized in Scheme 4. Lithiation of dihydropyran, reaction with α,βunsaturated aldehydes, and subsequent oxidation resulted in the Nazarov systems 1,15b while the more polarized structures 3 were obtained from the corresponding β-keto ester and the appropriate aldehyde.15a In addition, Nazarov systems 5 containing the cyclohexene instead of a dihydropyran ring 7588
DOI: 10.1021/acs.joc.9b01083 J. Org. Chem. 2019, 84, 7587−7605
The Journal of Organic Chemistry
Featured Article
Solvent Screening. To test our hypothesis of an iodinecatalyzed Nazarov cyclization, we combined the divinyl ketone 1a with 5 mol % iodine in different solvents (Table 1). After 30 min, the reaction mixture was deactivated by
according to NMR investigations (see the Supporting Information), no reaction occurs when ethyl acetate and molecular iodine are mixed in CD3CN within 90 min. In general, all substrates underwent the cyclization with complete regioselectivity and only one product could be observed under the experimental conditions. The obtained diastereomers were assigned on the basis of crystal structures (e.g., 2c, 4a, 4e)25 or on NMR spectroscopy. As observed before, the Nazarov systems 1 resulted in cis-configured products 2,15b while the systems derived from β-keto esters 3 and 5 were obtained as the thermodynamically more stable trans products.15a Alkyl and aryl substituents were well tolerated within the Nazarov systems 1, and good to excellent yields were obtained for most systems in less than 1 h. Only the phenyl-substituted system 1g afforded only moderate yields of the cyclization product 2g with full consumption of the starting material. In this case, unidentified side or decomposition products could be detected, however. For the β-keto esters 3 initially introduced by Frontier,15a the arylsubstituted systems 3a−e reacted significantly faster (1 min to 19 h) than the isopropyl-substituted analogue 4f (4 d). Although a direct comparison between the different motifs 1 and 3 is difficult, the reactivities of 1g and 3a indicate that the additional ester group of 3a slightly decelerates the reaction. In previous studies with Cu(OTf)2 as the catalyst, the esters cyclized slightly faster than the unsubstituted analogues.15a Furthermore, also the cyclohexenyl-derived systems 5 undergo the cyclization to yield 6 under these mild conditions in almost quantitative yields. In line with previous results by Frontier, the cyclohexenyl derivatives 5 reacted slightly slower than the dihydropyran systems 3 indicating that the enol substructure contributes to an activation of the Nazarov system. Even aromatic compounds like substituted indoles 7 and 9 can undergo the iodine-catalyzed Nazarov cyclization. While the 2-substituted indoles 7 afford the cyclization products 8 in almost quantitative yield within 5−16 h, the corresponding 3-substituted derivatives 9 required significantly longer reaction times and resulted in lower yields. The lower reactivity of 9 can be attributed to the better stabilization of the double bond within the aromatic system. While no competing reactivity was observed during the synthesis of 10a, the dimethylated analogue 10b could only be isolated in low yield. In this case, a competing intramolecular iodinecatalyzed Friedel−Crafts-type reaction12b,26 takes place leading to a potentially less strained six-membered ring system. In contrast to previous investigations by West and coworkers on the interrupted Nazarov cyclization with bromine,27 no addition products of molecular iodine to either double bond were observed in any case. This is in line with typically endergonic addition reactions of I2 to double bonds.10 A potential drawback of an iodine-catalyzed Nazarov cyclization could be an iodine-mediated cis−trans isomerization of the alkenes.28 These reactions are known to occur under different conditions, and different mechanisms have been suggested. In our experimental investigations, we had no evidence of any isomerization. As the synthetic procedures described in Scheme 4 resulted in the thermodynamically most stable divinyl ketones, a potential isomerization only plays a minor role for this study. However, we cannot completely exclude this isomerization. On the one hand, cis−
Table 1. Solvent Influence on the Iodine-Catalyzed Nazarov Cyclization of Divinyl Ketone 1a (a)
no.
solvent
yield (%)
no.
solvent
yield (%)
1 2 3 4 5 6 7 8
CH3CN CH2Cl2 CHCl3c Cl(CH2)2Cl Et2O THF 1,4-dioxane MTBE
87 (80)b 74 (66)b 85 (78)b 77 85 (82)b 64 (50)b 67% (60)b 55
9 10 11 12 13 14 15
EtOAc toluene benzene MeOH EtOH DMSO DMF
97 (94)b 71 79
