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Aminocatalyzed Synthesis of Enantioenriched Phenalene Skeletons through a Friedel-Crafts/Cyclization Strategy Maxime Giardinetti, Jerome Marrot, Christine Greck, Xavier Moreau, and Vincent Coeffard J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02629 • Publication Date (Web): 20 Dec 2017 Downloaded from http://pubs.acs.org on December 24, 2017

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The Journal of Organic Chemistry

Aminocatalyzed

Synthesis

of

Enantioenriched

Phenalene

Skeletons through a Friedel-Crafts/Cyclization Strategy Maxime Giardinetti,a Jérôme Marrot,a Christine Greck,a Xavier Moreaua* and Vincent Coeffarda,b* a

Institut Lavoisier de Versailles, UMR CNRS 8180, Université de Versailles-St-Quentin-en-Yvelines,

45 Avenue des États-Unis, 78035 Versailles cedex, France. b

Université de Nantes, CNRS, CEISAM, UMR 6230, Faculté des Sciences et des Techniques, 2 rue de

la Houssinière, BP 92208, 44322 Nantes Cedex 3, France.

ABSTRACT A series of enantioenriched phenalene-derived compounds were accessed by a FriedelCrafts/cyclization strategy. Starting from α,β-unsaturated aldehydes and 2-naphthol derivatives, high levels of enantioselectivity were obtained through iminium-enamine catalysis. The catalytic system composed of a diphenylprolinol silyl ether organocatalyst and triethylamine as a base was applied to a combination of diversely functionalized substrates. The obtained phenalene-derived architectures are promising building blocks for reaching natural products and exhibit fluorescence properties. TOC GRAPHIC

1 ACS Paragon Plus Environment

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The 1H-phenalene architecture 1 is a polycyclic aromatic hydrocarbon of molecular formula C13H10 which has been first prepared by Lock and Gergely in 1944 (Fig. 1).1 Fig. 1 Importance of the phenalene subunit

The electronic and molecular features of phenalene derivatives have been harnessed in a range of contexts. For instance, 9-hydroxyphenalenone compounds 2 have been successfully used as ligands in coordination chemistry due to their propensity to form chelates with several metal ions.2 In addition, phenalene derivatives are interesting building blocks for the preparation of stable π-conjugated cations and radicals with potential applications in photochemistry and materials science.3 Within the family of phenalene, the phenalenone subunit 3 is widely found in plants. Indeed, the phytoalexins phenalenones are secondary metabolites which are rapidly produced by the plant following a microbial attack or a stress situation.4 These phototoxins act as photosensitizers in the presence of environmental light and oxygen to produce cytotoxic species which allow the plants to counteract the threats.5 Therefore, phenalenone derivatives elicit antifungal,6 antimicrobial7 and anticancer activities.8 Optically active 1H-phenalene framework is also found in natural products such as monolaterol 4 which has been isolated from the roots of Monochoria elata, belonging to the plant family Pontederiaceae.9 This natural product represents the first isolated phenylphenalene-related compound with a chiral center at the phenyl-bearing atom. 2 ACS Paragon Plus Environment

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Another optically active member 5 of this family has been extracted from water hyacinth in 2011.10 As a part of our ongoing interest into organocatalytic functionalization of aromatic architectures,11

we

have

recently

developed

an

efficient

protocol

for

the

aminocatalyzed cascade synthesis of enantioenriched 1,7-annulated indoles and indazoles from α,β-unsaturated aldehydes (Scheme 1a).12 Taking advantage of the ability of aminocatalysts to promote iminium/enamine cascade sequences in the presence of α,β-unsaturated aldehydes,13 the synthetic strategy towards 1,7-annulated heterocycles involved an aza-Michael reaction followed by an intramolecular aldol condensation. The use of an aminocatalyst in conjunction with sodium acetate afforded diversely substituted enantioenriched tricyclic indole and indazole heterocycles. Asymmetric organocatalytic methods that would enable the synthesis of phenalenerelated compounds would be of great interest in light of the importance of such molecules in various fields of science. Our recent findings into organocatalytic formations of heterocycles prompted us to consider this strategy for reaching optically active phenalene derivatives. To this aim, a naphthalene ring decorated with an aldehyde and a functional group aiming at directing the Friedel-Crafts reaction is required to implement our methodology (Scheme 1b). Our strategy was based on the propensity of 2-naphthols to direct the Friedel-Crafts reaction at the 1-position, thus enabling the cyclization to proceed.14 Exquisite control of the regio-, diastereo- and enantioselectivities of the Friedel-Crafts alkylation of 2naphthols was described with different organocatalysts such as Cinchona derivatives,15 phosphoric acids,16 thioureas,17 aminocatalysts18 and other systems.19



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Scheme 1. Asymmetric synthetic strategies towards nitrogen-containing heterocycles (previous works) and phenalene derivatives (this work)

In particular, the group of Wang and Bencivenni showed that iminium ion catalysis was a powerful strategy to promote the Friedel-Crafts alkylation of 2-naphthol with α,β-unsaturated carbonyl compounds.18 A combination of 9-amino(9-deoxy)epi-quinine as the catalyst and 5nitrosalicylic acid turned out to be the best reaction conditions. The ability of aminocatalysts to promote high levels of stereoinduction in the Friedel-Crafts functionalization of 2naphthols is a solid foundation to embark on the asymmetric synthesis of phenalene derivatives through an iminium/enamine sequence. We began our studies by investigating the reaction of trans-cinnamaldehyde 7a and 2,7-dihydroxy-1-naphthaldehyde 6a, readily available from commercially available 2,7-dihydroxynaphthalene following a reported synthetic route.20 In analogy to the work of Jørgensen and co-workers about the aminocatalytic functionalization of 1-naphthol with 2,4-dienals, a combination of an aminocatalyst and 1,4-diazabicyclo[2.2.2]octane (DABCO) was chosen for the optimization studies (Table 1).21 The reaction of naphthol 6a with trans-cinnamaldehyde 7a in the presence of the Hayashi-Jørgensen catalyst 8a and DABCO afforded the desired product 9 in 38% 4 ACS Paragon Plus Environment

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yield and 91% ee (entry 1). The use of the 3,5-(CF3)2C6H3-derived catalyst 8b led to similar levels of yields albeit with a lower enantiomeric excess (74%, entry 2) whereas 8c possessing a bulkier OTBS-protecting group led to 9 in 28% yield with an excellent enantioselection (94%, entry 3). Increasing both the temperature and the reaction time led to a slightly better yield but the conditions were detrimental to the enantiomeric excess (entry 4). When the MacMillan imidazolidinone 8d was used to promote the transformation, no reaction occurred (entry 5). A screening of various solvents using the catalytic system 8c/DABCO enabled to select toluene as the best solvent (entries 6-8). Under these conditions, the desired target 9 was produced in 38% yield and 97% ee. Then, we investigated how bases affect the reaction outcome (entries 9-12). Regardless of the nature of the base, high levels of stereoinduction were obtained. However, the choice of the base influenced the reaction yields. Stronger bases gave higher levels of yields (36-38%) than weaker bases such as pyridine or N,Ndimethylaniline. These results corroborate previous findings which showed that the nucleophilicity of naphthol was increased by complexation with DABCO or deprotonation into the corresponding anionic form.21 In light of these results, triethylamine was chosen as a base for further studies. A better yield was obtained by changing the ratio of substrates. The reaction of 1 equivalent of naphthol 6a with 2 equivalents of aldehyde 7a in toluene led to 9 in 60% yield and 97% ee (entry 13). As previously discussed, the absence of a base is detrimental to the reaction and 9 was isolated in 40% yield (entry 14). Levels of stereoinduction dropped by screening other solvents even if a better yield of 82% was obtained by performing the reaction in a 7:3 mixture of toluene:EtOAc (entries 15-18). Finally, when the reaction was conducted without a base, Therefore, the use of the catalytic system 8c (20 mol%)/Et3N (5 mol%) in toluene at room temperature provided an effective balance between the level of yield and the enantiomeric excess (entry 13).



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Table 1 Optimization studies on the formation of chiral phenalene compoundsa

Entry

Ratio 6a:7a

8

Solvent

Base

Yieldb[%]

Eec[%]

1 2:1 8a CHCl3 DABCO 38 91 2 2:1 8b CHCl3 DABCO 31 74 3 2:1 8c CHCl3 DABCO 28 94 4d 2:1 8c CHCl3 DABCO 41 88 5 2:1 8d CHCl3 n.r n.d. 6 2:1 8c Toluene DABCO 38 97 7 2:1 8c MeCN DABCO

Aminocatalyzed Synthesis of Enantioenriched ... - ACS Publications

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