Enantioselective Catalytic One-Pot Synthesis of Functionalized Methyleneindanes and Methylindenes Via a Michael/Conia-Ene Sequence
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SYNTHESIS0039-78811437-210X © Georg Thieme Verlag Stuttgart · New York 2017, 49, 1538–1546 1538 paper Syn thesis A. R. Philipps et al. Paper Enantioselective Catalytic One-Pot Synthesis of Functionalized Methyleneindanes and Methylindenes via a Michael/Conia-Ene Sequence Arne R. Philipps Marcus Blümel Simon Dochain O2N Daniel Hack NO NO2 2 1) Organocatalytic O 2 Dieter Enders* O O Michael addition R2 R + R1 R1 2 1 2 2 2) Indium-catalyzed R – ketene R R R O Conia-ene reaction (R2 = Me) Institute of Organic Chemistry, RWTH Aachen University, O Me Landoltweg 1, 52074 Aachen, Germany one pot 3–98% yield 23–99% yield [email protected] 76–99% ee 95–99% ee Received: 09.11.2016 tBu Accepted after revision: 11.11.2016 OH O NH NH2 Published online: 06.12.2016 O DOI: 10.1055/s-0036-1588113; Art ID: ss-2016-z0789-op N N NH O H Bn OH N Abstract An enantioselective one-pot Michael addition/Conia-ene re- action sequence catalyzed by the combination of a squaramide and in- I II N dium(III) triflate has been developed. Employing 2-ethynyl-β-nitrosty- indinavir indantadol renes and 1,3-dicarbonyl compounds as substrates, the functionalized HIV-1 protease inhibitor antiepileptic agent methyleneindanes and methylindenes are obtained in good to excellent CO2H Me enantiomeric excesses. For the indane/indene conversion a concerted HN Me fragmentation is proposed. O OH Key words organocatalysis, indium catalysis, Conia-ene reaction, in- Cl danes, indenes F Cl S O Me The importance of the indane and indene scaffolds in Cl 1 III IV V pharmaceutical chemistry cannot be overstated. There are sulindac indatraline clidanac numerous examples of successfully implemented mole- anti-inflammatory amine uptake inhibitor anti-inflammatory cules and the scope of their bioactivity is far reaching and Figure 1 Examples of indane and indene pharmaceuticals broad.2,3 In Figure 1 the structures of indinavir (I), an HIV-1 protease inhibitor,4 indantadol (II), an antiepileptic agent,5 the nonsteroidal anti-inflammatory drug sulindac (III),6 the economical approach towards cyclopentanes and cyclohex- amine uptake inhibitor indatraline (IV),7 and the anti-in- anes, as well as their heterocyclic counterparts.14 Due to its flammatory drug clidanac (V)8 are given as typical exam- great synthetic potential, the combination of organocataly- ples of bioactive indanes and indenes. At the same time, sis with the Conia-ene reaction has been the topic of sever- these scaffolds have gained enormous importance in mate- al investigations. There are novel opportunities for the in- rials science.9,10 troduction of stereoinformation into various important tar- Recently, there has been a lot of growth in the research get molecules.13,15 In addition to the mentioned Conia-ene field of organocatalysis in combination with transition- reactions, there have been further reports on the combina- metal catalysis,11 enabling a large number of new accessible tion of organocatalysis and indium catalysis for various transformations. Our group showed the possibility of ex- transformations, such as the α-alkylation of aldehydes,16 al- ploiting the versatile reactivity of 2-ethynyl-β-nitrosty- lylation reactions,17 1,2/1,4-additions to enones,18 and hete- renes 1 to form tetracyclic indole derivatives12 and spiropy- ro-Diels–Alder reactions.19 razolones13 using either gold or silver salts as the metal cat- To the best of our knowledge, there is only one example alyst. In particular, the Conia-ene reaction is an efficient of an asymmetric organocatalysis/Conia-ene sequence, em- tool which offers an easy, straightforward, and atom- ploying an indium salt as the metal catalyst, precedent in the literature.15c In contrast to our envisioned protocol, © Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 1538–1546 1539 Syn thesis A. R. Philipps et al. Paper which leads to compounds bearing a stereocenter at the β- higher catalyst loading. In toluene and in diethyl ether the position to the dicarbonyl moiety, the reported procedure reaction did not proceed as smoothly as in the chlorinated gives rise to cyclopentanes that feature the stereocenter at solvents and gave only mediocre yields. Overall, the choice the α-position. Herein, we present a novel catalytic se- of solvent did not have a stark influence on the asymmetric quence utilizing an enantioselective organocatalytic induction, as all isolated products had an enantiomeric ex- Michael addition of dicarbonyl compounds 2 to 2-ethynyl- cess of at least 98% ee. β-nitrostyrenes 1 and a subsequent cyclization via a Conia- ene reaction with an indium catalyst. This protocol allows Table 1 Optimization of the Reaction Conditions for the Michael Addi- for a direct one-pot access to methyleneindanes or methyl- tiona indenes, depending on the nature of the dicarbonyl com- NO NO pound 2.20 2 2 COMe cat. A (0.5 mol%) COMe Initially, we focused on the enantioselective Michael ad- + r.t. dition and thus treated 2-ethynyl-β-nitrostyrene (1a) with COMe COMe acetylacetone (2a) in the presence of different squaramide 21 and thiourea catalysts in dichloromethane (Scheme 1). 1a 2a 3 While the thiourea catalyst E did not show any catalytic ac- tivity in this reaction, all of the tested squaramide catalysts Entry Solvent Time (h) Yield (%)b ee (%)c showed very satisfying results. This might be due to the ter- 1d CH Cl 392 98 tiary amine moiety, which the tested thiourea catalyst does 2 2 not bear, assisting in deprotonation of the nucleophile. Cat- 2CH2Cl2 290≥99 alyst A derived from quinine showed the best asymmetric 3 CHCl3 393≥99 induction with 98% ee and an excellent yield of 92%. 4 toluene 3 44 99 5Et2O3 52 ≥99 NO2 NO2 a Reaction conditions: 1a (0.3 mmol), 2a (0.33 mmol), A (0.5 mol%), sol- COMe cat. A–E (2 mol%) COMe vent (1.5 mL). + b CH2Cl2, r.t., 3 h Yield of the isolated product 3. COMe COMe c Determined by HPLC on a chiral stationary phase. d 2 mol% of A was used. 1a 2a 3 In order to optimize the conditions for the Conia-ene R' O O cyclization of the Michael adduct 3 to form the methylene- N indane 4a, several metal salts were investigated (Table 2). F3C N N The selection of metal sources was based on prior reports in H H H R the literature of their successful application in similar Co- 22 nia-ene reactions. While 10 mol% of AgNTf2 in toluene CF3 N showed no catalytic activity, all of the tested gold sources A: R = OMe, R' = CH=CH2 92%, 98% ee led to decomposition of the starting material (entries 1–4). B: R = H, R' = CH=CH2 95%, 97% ee Irrespective of the phosphine ligand and the solvent, the re- C: R = H, R' = Et 87%, 97% ee action was very torpid and gave no isolable product but a O O complex mixture of compounds. When copper(I) chloride CF 3 in chloroform was used no reaction was observed, even N OH F3C S N N when the temperature was raised to 50 °C (entry 5). Zinc(II) H H H N N CF3 chloride showed some reactivity, but after 24 hours at 80 °C H H only a trace amount of 4a could be isolated (entry 6). In- CF3 N creasing the temperature to 100 °C for an hour did not im- D: 88%, –94% ee E: 0% prove the results. Scheme 1 Catalyst screening for the Michael reaction With indium(III) triflate in toluene at 80 °C, complete conversion was achieved after 3 hours with a surprising re- sult. In addition to the expected methyleneindane 4a, a sec- In the next step, the choice of solvent was investigated ond product was isolated and identified as methylindene 5a using a reduced amount of catalyst A of only 0.5 mol% (Ta- (Table 2, entry 7). When iron(III) chloride in chloroform was ble 1). The results in dichloromethane and chloroform were employed at room temperature, full conversion with a quite similar but, surprisingly, the lower catalyst loading strong preference towards methylindene 5a was observed had a beneficial effect on the stereoselectivity of this reac- after 5 hours and methyleneindane 4a was only isolated in tion. This may be due to a competing side reaction with a small amount (entry 8). © Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 1538–1546 1540 Syn thesis A. R. Philipps et al. Paper Table 2 Optimization of the Cyclization Reactiona O2N O2N O2N COMe COMe cat. (10 mol%) COMe COMe COMe + toluene Me R L1; R = Cy 3 R P AuCl 4a 5a L2; R = tBu Entry Catalyst Time (h) Temp Yield (%)b 4a/5a 1 AgNTf2 120 r.t. to 40 °C no reaction – 1 2 AgNTf2/AuL 120 r.t. to 40 °C decomposition – 2 3 AgNTf2/AuL 120 r.t. to 40 °C decomposition – c 1 4 AgNTf2/AuL 120 r.t. to 40 °C decomposition – 5c CuCl 120 r.t. to 50 °C no reaction – 6 ZnCl2 24 80–100 °C traces – 7 In(OTf)3 3 80 °C 99 1.4:1 c 8 FeCl3 5 r.t. 98 1:15 a Reaction conditions: 3 (0.1 mmol), catalyst (10 mol%), solvent (1.0 mL). b Yield of the isolated products. c CHCl3 as solvent. With these optimized conditions in hand, the reaction In the next step, different malonates were subjected to sequence was combined for a one-pot protocol and the these reaction conditions. Unfortunately, the catalyst load- scope of the reaction was explored (Table 3). When the ing of the first step had to be increased to 5 mol% as no re- diketone acetylacetone (2a) was employed in the reaction action with diesters occurred using a lower amount.