Application of New Efficient Hoveyda–Grubbs Catalysts Comprising An

molecules

Article Application of New Eﬃcient Hoveyda–Grubbs Catalysts Comprising an N→Ru Coordinate Bond in a Six-Membered Ring for the Synthesis of Natural Product-Like Cyclopenta[b]furo[2,3-c]pyrroles

Alexandra S. Antonova 1, Marina A. Vinokurova 1, Pavel A. Kumandin 1, Natalia L. Merkulova 1, Anna A. Sinelshchikova 2 , Mikhail S. Grigoriev 2 , Roman A. Novikov 3, Vladimir V. Kouznetsov 4 , Kirill B. Polyanskii 1,* and Fedor I. Zubkov 1,*

1 Organic Chemistry Department, Faculty of Science, Peoples’ Friendship University of Russia (RUDN University), Miklukho-Maklaya St., 6, 117198 Moscow, Russia; [email protected] (A.S.A.); [email protected] (M.A.V.); [email protected] (P.A.K.); [email protected] (N.L.M.) 2 A. N. Frumkin Institute of Physical Chemistry and Electrochemistry, Russian Academy of Sciences, Leninsky pr. 31, bld. 4, 119071 Moscow, Russia; [email protected] (A.A.S.); [email protected] (M.S.G.) 3 V. A. Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Vavilov Street, 32, 119991 Moscow, Russia; novikovﬀ[email protected] 4 Laboratorio de Química Orgánica y Biomolecular, CMN, Universidad Industrial de Santander, Parque Tecnológico Guatiguara, Km 2 vía refugio, Piedecuesta A.A. 681011, Colombia; [email protected] * Correspondence: [email protected] (K.B.P.); [email protected] (F.I.Z.); Tel./Fax: +7-(495)-952-26-44 (F.I.Z.)

Academic Editors: Igor V. Trushkov and Maxim G. Uchuskin Received: 3 November 2020; Accepted: 14 November 2020; Published: 17 November 2020

Abstract: The ring rearrangement metathesis (RRM) of a trans-cis diastereomer mixture of methyl 3-allyl-3a,6-epoxyisoindole-7-carboxylates derived from cheap, accessible and renewable furan-based precursors in the presence of a new class of Hoveyda–Grubbs-type catalysts, comprising an N Ru → coordinate bond in a six-membered ring, results in the diﬃcult-to-obtain natural product-like cyclopenta[b]furo[2,3-c]pyrroles. In this process, only one diastereomer with a trans-arrangement of the 3-allyl fragment relative to the 3a,6-epoxy bridge enters into the rearrangement, while the cis-isomers polymerize almost completely under the same conditions. The tested catalysts are active in the temperature range from 60 to 120 ◦C at a concentration of 0.5 mol % and provide better yields of the target tricycles compared to the most popular commercially available second-generation Hoveyda–Grubbs catalyst. The diastereoselectivity of the intramolecular Diels–Alder reaction furan (IMDAF) reaction between starting 1-(furan-2-yl)but-3-en-1-amines and maleic anhydride, leading to 3a,6-epoxyisoindole-7-carboxylates, was studied as well.

Keywords: furan; Hoveyda–Grubbs catalysts; nitrogen–ruthenium coordinate bond; ring-rearrangement metathesis; cyclopenta[b]furo[2,3-c]pyrroles; 3-allyl-3a,6-epoxyisoindoles; IMDAF reaction

1. Introduction The discovery of metathesis reactions has allowed the noticeable expansion of possibilities for the transformation of diﬀerent unsaturated substrates, including those aimed at obtaining complex naturally occurring compounds and pharmacologically meaningful molecules, which is reﬂected in a number of recent reviews [1–8]. In particular, the ring-rearrangement metathesis (RRM) of bi- and polycyclic alkenes has made it possible to obtain systems that are practically inaccessible by

Molecules 2020, 25, 5379; doi:10.3390/molecules25225379 www.mdpi.com/journal/molecules Molecules 2020, 25, x FOR PEER REVIEW 2 of 15 Molecules 2020, 25, x FOR PEER REVIEW 2 of 15 Molecules 2020, 25, 5379 2 of 15 a number of recent reviews [1–8]. In particular, the ring-rearrangement metathesis (RRM) of bi- and a number of recent reviews [1–8]. In particular, the ring-rearrangement metathesis (RRM) of bi- and polycyclic alkenes has made it possible to obtain systems that are practically inaccessible by means polycyclic alkenes has made it possible to obtain systems that are practically inaccessible by means meansof other of synthetic other synthetic pathways pathways [9–18]. [9 –Most18]. Mostoften, often,for the for rearrangement the rearrangement of bridged of bridged alkenes, alkenes, the of other synthetic pathways [9–18]. Most often, for the rearrangement of bridged alkenes, the thecommercially commercially available available Grubbs Grubbs (G) and (G) Hoveyda–Grubbs and Hoveyda–Grubbs (HG) (HG)ruthenium ruthenium catalysts catalysts are used, are which used, commercially available Grubbs (G) and Hoveyda–Grubbs (HG) ruthenium catalysts are used, which whichpermits permits the reliable the reliable production production of scaffolds of sca possessingﬀolds possessing a wide arange wide of range potential of potential biological biological activity permits the reliable production of scaffolds possessing a wide range of potential biological activity activitydue to the due characteristics to the characteristics of their ofcarbon their carbonskeletons skeletons [19–23]. [ 19Representative–23]. Representative examples examples of the above- of the due to the characteristics of their carbon skeletons [19–23]. Representative examples of the above- above-mentionedmentioned metathesis metathesis reactions reactions clearly clearly demonstrate demonstrate a variety a variety of possible of possible transformation transformation routes routes that mentioned metathesis reactions clearly demonstrate a variety of possible transformation routes that thatgive give the thestructural structural diversity diversity of the of the available available final ﬁnal products products (Scheme (Scheme 1).1). As As can be seen,seen, thethe directiondirection give the structural diversity of the available final products (Scheme 1). As can be seen, the direction ofof thethe reaction reaction may may depend depend not not only only on the on structure the struct of theure substrate,of the substrate, but also onbu thet also reaction on the conditions reaction of the reaction may depend not only on the structure of the substrate, but also on the reaction selectedconditions and selected the chosen and catalyst.the chosen catalyst. conditions selected and the chosen catalyst.

SchemeScheme 1.1.Selected Selected examples examples of theof the ring-rearrangement ring-rearrangement metathesis metathesis (RRM) (RRM) of tri- andof tri- tetracyclic and tetracyclic bridged Scheme 1. Selected examples of the ring-rearrangement metathesis (RRM) of tri- and tetracyclic systemsbridged closestsystems to closest the topic to the of this topic study. of this study. bridged systems closest to the topic of this study. Moreover,Moreover, amongamong allall thethe varietyvariety ofof metathesismetathesis productsproducts knownknown toto date,date, therethere isis aa solesole successfulsuccessful Moreover, among all the variety of metathesis products known to date, there is a sole successful exampleexample ofof thethe HG-catalyzedHG-catalyzed RRMRRM ofof 3a,6-epoxyisondole3a,6-epoxyisondole 11 whichwhich hashas producedproduced thethe previouslypreviously example of the HG-catalyzed RRM of 3a,6-epoxyisondole 1 which has produced the previously unknownunknown heterocyclicheterocyclic systemsystem ofof cyclopenta[cyclopenta[bb]furo[2,3-]furo[2,3-c]pyrrole]pyrrole 2,, butbut inin modestmodest yieldyield (31%)(31%) [[24]24] unknown heterocyclic system of cyclopenta[b]furo[2,3-c]pyrrole 2, but in modest yield (31%) [24] (Scheme(Scheme2 ).2). (Scheme 2).

Scheme 2. Synthesis of cyclopenta[b]furo[2,3-c]pyrrole core 2 via ring-rearrangement metathesis (HG- Scheme 2. Synthesis of cyclopenta[b]furo[2,3-c]pyrrole core 2 via ring-rearrangement metathesis (HG- SchemeII—the second-generation 2. Synthesis of cyclopenta[ Hoveyda–Grubbsb]furo[2,3- catalyst,c]pyrrole TBME—methyl core 2 via ring-rearrangement tert-butyl ether) [24]. metathesis (HG-II—theII—the second-generation second-generation Hoveyda–Grubbs Hoveyda–Grubbs catalyst, catalyst, TBME—methyl TBME—methyl tert-butyltert-butyl ether) ether) [24]. [24]. Hence, further investigations of the influence of catalysts and the structure of unsaturated Hence, further investigations of of the influence inﬂuence of catalysts and the structure of unsaturated substrates on the selectivity of metathesis reactions remain an ongoing trend in modern organic substrates on the selectivity of metathesis reactions remain an ongoing trend in modern organic synthesis. The selection of main starting materials for the suitable unsaturated substrates like 1 is also synthesis. The The selection selection of ofmain main starting starting materi materialsals for the for suitable the suitable unsaturated unsaturated substrates substrates like 1 is like also1 an important task. In this context, it should be noted that the starting material for 1 is furfural, which anis alsoimportant an important task. In this task. context, In this it shou context,ld be it noted should that be the noted starting that material the starting for 1 is material furfural, for which1 is is a renewable chemical and one of the most available agricultural byproducts from biomass [25,26]. isfurfural, a renewable which chemical is a renewable and one chemical of the most and available one of the agricultural most available byproducts agricultural from byproducts biomass [25,26]. from In regard to design of new catalysts for RRM, our group recently prepared a new class of effective Inbiomass regard [25 to, 26design]. In regard of new to catalysts design of for new RRM, catalysts our group for RRM, recently our group prepared recently a new prepared class of a neweffective class ruthenium catalysts comprising an N→Ru coordinate bond in a six-membered ring (Cat.1 and Cat.2) rutheniumof eﬀective catalysts ruthenium comprising catalysts comprisingan N→Ru coordinate an N Ru coordinatebond in a six-membered bond in a six-membered ring (Cat.1 ringand Cat.2 (Cat.1) (Figure 1) and found that they revealed a high level of activity (up to 10−2 mol%) in standard models → −2 2 (Figureand Cat.2 1)) and (Figure found1) and that found they thatrevealed they revealeda high level a high of activity level of activity(up to 10 (up mol%) to 10 − inmol%) standard in standard models

Molecules 2020, 25, 5379 3 of 15

Molecules 2020, 25, x FOR PEER REVIEW 3 of 15 Molecules 2020, 25, x FOR PEER REVIEW 3 of 15 models for the oleﬁn metathesis (styrene, allylbenzene, diethyl diallylmalonate, diallyltosylamide, for the olefin metathesis (styrene, allylbenzene, diethyl diallylmalonate, diallyltosylamide, norbornenfor the olefin/hex-1-ene, metathesis etc.) [27 ,(styrene,28]. allylbenzene, diethyl diallylmalonate, diallyltosylamide, norbornen/hex-1-ene, etc.) [27,28].

Figure 1.1. Hoveyda–Grubbs-type catalysts [[27]27] used for metathesismetathesis reactionsreactions inin thethe presentpresent work.work.

AccordingAccording toto thethe statementsstatements above and with thethe knowledgeknowledge that there are no reportsreports onon thethe eefficientfficient syntheticsynthetic methodsmethods forfor diverselydiversely polyfunctionalizedpolyfunctionalized cyclopenta[cyclopenta[bb]furo[2,3-]furo[2,3-cc]pyrroles]pyrroles usingusing easilyeasily availableavailable 3-allyl-3a,6-epoxyisoindoles 3-allyl-3a,6-epoxyisoindoles derived derived from 1-(furan-2-yl)-N-arylmethaniminesfrom 1-(furan-2-yl)-N-arylmethanimines through thethrough intramolecular the intramolecular Diels–Alder Diels–Alder furan (IMDAF) furan reaction, (IMDAF) our reaction, research our was research focused was on: (i)focused Establishing on: (i) theEstablishing optimal conditions the optimal for the conditions diastereoselective for the preparation diastereoselective of 3-allyl-3a,6-epoxyisoindoles, preparation of 3-allyl-3a,6- according toepoxyisoindoles, the variables: according solvent, acid to the catalysts, variables: reaction solvent, time acid and catalysts, temperature; reaction (ii) time With and the temperature; determined conditions(ii) With the in determined hand, preparing conditions diverse in 3a,6-epoxyisondol-7-carboxylichand, preparing diverse 3a,6-epoxyisondol-7-carboxylic acids and their methyl esters; acids (iii)and Corroboratingtheir methyl esters; the spatial (iii) Corroborating structure of isomeric the spatia acidsl structure and their of isomeric esters; (iv) acids Studying and their the esters; catalytic (iv) activityStudying of the ruthenium catalytic catalysts activity1 ofand ruthenium2 in the RRM catalysts of 3a,6-epoxyisoindole-7-carboxylates 1 and 2 in the RRM of 3a,6-epoxyisoindole-7- in comparison withcarboxylates HG-II catalyst;in comparison and (v) with With HG-II the catalyst; established and conditions(v) With the in established hand, preparing conditions the in desired hand, cyclopenta[preparing theb]furo[2,3- desired ccyclopenta[]pyrroles. Allb]furo[2,3- this is inc]pyrroles. order to developAll this is new, in order short to and develop efficient new, synthesis short and of naturalefficient product-like synthesis of scanaturalffolds product-like from renewable scaffolds furan-based from renewable precursors. furan-based precursors.

2.2. Results and Discussion TheThe principalprincipal syntheticsynthetic schemescheme forfor thethe requiredrequired 3-allyl-3a,6-epoxyisoindole-7-carboxylic3-allyl-3a,6-epoxyisoindole-7-carboxylic acidsacids 55 preparationpreparation includes includes two two key key steps steps and is and based is on based readily on available readily starting available materials. starting The materials. condensation The ofcondensation aryl amines of (oraryl benzyl amines amines) (or benzyl and amines) furfural and gives furfural the gives corresponding the corresponding Schiﬀ bases Schiff3, bases which, 3, beingwhich, treated being withtreated Grignard with Grignard reagents reagents (allyl magnesium (allyl magnesium bromide orbromide methallyl or methallyl magnesium magnesium chloride), givechloride), rise to give homoallylamines rise to homoallylamines4 in multigram 4 in multigram quantities (Schemequantities3)[ (Scheme29–32]. 3) [29–32].

Scheme 3. Synthesis of the starting 3a,6-epoxyisoindole-7-carboxylic acids 5 [29–32]. Scheme 3.3. Synthesis of the starting 3a,6-epoxyisoindole-7-carboxylic3a,6-epoxyisoindole-7-carboxylic acidsacids 55 [[29–32].29–32]. The subsequent reaction of furfurylamines 4 with maleic anhydride easily provides the TheThe subsequentsubsequent reactionreaction ofof furfurylaminesfurfurylamines 4 withwith maleicmaleic anhydrideanhydride easilyeasily providesprovides thethe corresponding isoindolocarboxylic acids 5, which were isolated in good overall yields. The IMDAF correspondingcorresponding isoindolocarboxylicisoindolocarboxylic acids 5,, whichwhich werewere isolatedisolated inin goodgood overalloverall yields.yields. TheThe IMDAFIMDAF reaction is highly stereoselective [33,34]; in the course of the tandem N-acylation/[4+2] cycloaddition reactionreaction isis highlyhighly stereoselectivestereoselective [[33,34];33,34]; inin thethe coursecourse ofof thethe tandemtandem N-acylationN-acylation/[4+2]/[4+2] cycloadditioncycloaddition sequence, only exo-adducts form as a mixture of two diastereomers (trans-5A and cis-5B) based on sequence,sequence, onlyonlyexo exo-adducts-adducts form form as as a a mixture mixture of of two two diastereomers diastereomers (trans (trans-5A-5Aand andcis- 5Bcis)-5B based) based on theon the orientation of the 3-allyl (or 3-methallyl) substituent relative to the 3a,6-epoxy-bridge (Figure 2). orientationthe orientation of the of 3-allylthe 3-allyl (or 3-methallyl)(or 3-methallyl) substituent substituent relative relative to the to 3a,6-epoxy-bridgethe 3a,6-epoxy-bridge (Figure (Figure2). 2). As we showed earlier [29–32], the synthesized 3-allyl-3a,6-epoxyisoindole-7-carboxylic acids 5 are excellent precursors for heterocyclization into the corresponding isoindoloquinolines and isoindolobenzazepines. In this process, the isomeric composition of adducts 5A/5B had no strong inﬂuence on the yield and stereochemistry of the target heterocycles. In contrast, as was demonstrated in the ﬁrst experiments in this study, only derivatives of the trans-isomer 5A are capable of further

Figure 2. Structures of the cis and trans diastereoisomers of 3a,6-epoxyisoindole-7-carboxylic acids 5.

Molecules 2020, 25, x FOR PEER REVIEW 3 of 15 for the olefin metathesis (styrene, allylbenzene, diethyl diallylmalonate, diallyltosylamide, norbornen/hex-1-ene, etc.) [27,28].

Figure 1. Hoveyda–Grubbs-type catalysts [27] used for metathesis reactions in the present work.

According to the statements above and with the knowledge that there are no reports on the efficient synthetic methods for diversely polyfunctionalized cyclopenta[b]furo[2,3-c]pyrroles using easily available 3-allyl-3a,6-epoxyisoindoles derived from 1-(furan-2-yl)-N-arylmethanimines through the intramolecular Diels–Alder furan (IMDAF) reaction, our research was focused on: (i) Establishing the optimal conditions for the diastereoselective preparation of 3-allyl-3a,6- epoxyisoindoles, according to the variables: solvent, acid catalysts, reaction time and temperature; (ii) With the determined conditions in hand, preparing diverse 3a,6-epoxyisondol-7-carboxylic acids and their methyl esters; (iii) Corroborating the spatial structure of isomeric acids and their esters; (iv) Studying the catalytic activity of ruthenium catalysts 1 and 2 in the RRM of 3a,6-epoxyisoindole-7- carboxylates in comparison with HG-II catalyst; and (v) With the established conditions in hand, preparing the desired cyclopenta[b]furo[2,3-c]pyrroles. All this is in order to develop new, short and efficient synthesis of natural product-like scaffolds from renewable furan-based precursors.

2. Results and Discussion The principal synthetic scheme for the required 3-allyl-3a,6-epoxyisoindole-7-carboxylic acids 5 preparation includes two key steps and is based on readily available starting materials. The condensation of aryl amines (or benzyl amines) and furfural gives the corresponding Schiff bases 3, which, being treated with Grignard reagents (allyl magnesium bromide or methallyl magnesium chloride), give rise to homoallylamines 4 in multigram quantities (Scheme 3) [29–32].

Scheme 3. Synthesis of the starting 3a,6-epoxyisoindole-7-carboxylic acids 5 [29–32].

MoleculesThe2020 subsequent, 25, 5379 reaction of furfurylamines 4 with maleic anhydride easily provides4 ofthe 15 corresponding isoindolocarboxylic acids 5, which were isolated in good overall yields. The IMDAF reaction is highly stereoselective [33,34]; in the course of the tandem N-acylation/[4+2] cycloaddition transformation under RRM conditions. Thus, in the second stage of this investigation, we tried to sequence, only exo-adducts form as a mixture of two diastereomers (trans-5A and cis-5B) based on resolve the problem of the diastereoselectivity of the IMDAF reaction. the orientation of the 3-allyl (or 3-methallyl) substituent relative to the 3a,6-epoxy-bridge (Figure 2).

Figure 2. Structures of the cis and trans diastereoisomers of 3a,6-epoxyisoindole-7-carboxylic acids 5. Figure 2. Structures of the cis and trans diastereoisomers of 3a,6-epoxyisoindole-7-carboxylic acids 5.

Considering the fact that reversible Diels–Alder reactions are most influenced by the reaction temperature and the polarity of the solvent [35–38], we compared the isomeric composition of the most diverse acids 5a,b,g,i,m formed under the conditions indicated in Table1. The application of Lewis acids (10–25 mol % of AlEt , BF OEt , TiCl ) as catalysts in MeCN, PhH, PhMe, or CH Cl turned out 3 3· 2 4 2 2 to be ineffective, probably due to their fast binding by a free carboxyl group of the products and due to the difficulties associated with the purification of the resulting reaction mixtures. Without catalyst addition, the pure target products precipitated from all tested solvents after the period of reaction time indicated in Table1, wherein acetonitrile showed the worst results both at room and at elevated temperatures, apparently due to the partial dissolution of the target acids. As a result, it was found that according to 1H-NMR analysis, the cis-isomer B, inactive in the metathesis reaction, mainly forms at r.t in CH2Cl2 (average predominance 92%), while the desired trans-isomer A is mainly produced at 16 C in the same solvent (average predominance 68%). − ◦ Table 1. Influence of solvents and temperature on the yields and ratios of trans-5A/cis-5B isomers of 3-allyl-1-oxo-3a,6-epoxyisoindole-7-carboxylic acids (5).

Compd. Substituents Conditions, Ratios of Trans-5A/cis-5B Isomers a, and Total Yields (%) CH Cl CH Cl MeCN MeCN PhH PhMe PhMe R1 R2 2 2 2 2 16 C, 3 d r.t, 3 d r.t, 3 d ∆, 3 h ∆, 3 h r.t, 3 d ∆, 3 h − ◦ 76/24 7/93 47/53 44/56 59/41 48/52 59/41 5a H Ph (43) (58) (45) (15) (82) (85) (90) 63/37 6/94 59/44 52/48 58/42 55/45 57/43 5b H 3-MeC H 6 4 (49) (65) (41) (25) (85) (90) (92) 75/25 0/100 24/75 28/72 52/48 78/22 71/29 5g H 4-IC H 6 4 (52) (67) (38) (23) (86) (90) (91) 68/32 23/77 53/47 50/50 59/41 67/33 67/33 5i Me Ph (63) (75) (62) (47) (95) (97) (98) 60/40 4/96 55/45 58/42 59/41 59/41 56/44 5m Me Bn (64) (77) (65) (54) (96) (98) (99) 68/32 8/92 48/52 46/54 57/43 61/39 62/38 Average values (54) (68) (50) (33) (89) (92) (94) a The ratios of the trans-5A/cis-5B isomers were established by 1H-NMR analysis of the isolated solids.

Decreasing the temperature to below 30 C sharply slowed down the rate of interaction between − ◦ maleic anhydride and secondary amines 4; however, at the same time, analysis of the data in Table1 shows that the yields of the isomer 5A/5B mixtures obtained in CH2Cl2 are 1.5–2 times lower compared to the mixtures isolated from benzene or toluene. Besides, the last two solvents provide a slight predominance of the isomer 5A at both r.t and heating. It is also important to note that the reaction time was the shortest in boiling toluene (~1 h); nevertheless, for a reasonable comparison of the results in Table1, all reactions were carried out in boiling solvents for 3 h. Thus, for further experiments, we synthesized mixtures of the trans-5A/cis-5B isomers either in dichloromethane at 16 C or in PhMe − ◦ at 3 h reﬂux, as indicated in Table2. Molecules 2020, 25, x FOR PEER REVIEW 4 of 15

As we showed earlier [29–32], the synthesized 3-allyl-3a,6-epoxyisoindole-7-carboxylic acids 5 are excellent precursors for heterocyclization into the corresponding isoindoloquinolines and isoindolobenzazepines. In this process, the isomeric composition of adducts 5A/5B had no strong Moleculesinfluence2020 on, 25 , 5379the yield and stereochemistry of the target heterocycles. In contrast, as5 ofwas 15 demonstrated in the first experiments in this study, only derivatives of the trans-isomer 5A are capable of further transformation under RRM conditions. Thus, in the second stage of this Table 2. Substituents R, isomer ratios, and yields for compounds 5–7. investigation, we tried to resolve the problem of the diastereoselectivity of the IMDAF reaction. Trans-5A/Cis-5B Trans-6A/Cis-6B EntryConsideringR1 R 2the fact that reversibleYield ofDiels–Alder Acid 5, % reactions areYield most of Ester influenced 6, % Yield by of Tricyclethe reaction 7, % Ratio Ratio temperature and the polarity of the solvent [35–38], we79 /compared21 the85 isomeric composition68 c of the mosta diverseH acids Ph 5a,b,g,i,m76/ 24formed under90 b the conditions95/5 e indicated in53 eTable 1. The application83 c of 2/98 e 12 e 0 c Lewis acids (10–25 mol % of AlEt3, BF3·OEta2, TiCl4) as catalysts in MeCN, PhH, PhMe, cor CH2Cl2 b H 3-MeC6H4 57/43 95 69/31 63 57 turnedc outH to be Bn ineffective, 90/ 10probably due57 b to their fast85/ 15binding by a 85 free carboxyl group 65 c of the b c d H 3-ClC6H4 76/24 48 70/30 80 57 products and due to the difficulties associated with the purification70/30 of the72 resulting reaction73 c mixtures. a e e c Withoute Hcatalyst4-ClC addition,6H4 the80/20 pure target91 products precipitated98/2 from46 all tested solvents89 after the 8/92 e 18 e 0 c period of reaction time indicated in Table 1, wherein acetonitrile72/28 showed70 the worst results63 c both at a e e c roomf andH at elevated4-BrC6H4 temperatures,80/20 apparently92 due to the99/1 partial dissolution46 of the target87 acids. As a e e c 1 5/95 12 0 result, it was found that according to H-NMRb analysis, the cis-isomer B, inactive in the metathesisc g H 4-IC6H4 71/29 52 59/41 63 48 a c reaction,h Hmainly3-Cl,4-FC forms6H3 at r.t57 in/43 CH2Cl2 (average 90 predominance66/34 92%), while 86 the desired 54trans-isomer i Me Ph 68/32 63 b 55/45 53 50 d A is mainly produced at −16 °C in the same solventb (average predominance 68%). d j Me 3-MeC6H4 60/40 67 45/55 73 38 a d k DecreasingMe 4-MeC the6H 4temperature51/49 to below 93 −30 °C sharply50/50 slowed down 98 the rate of44 interaction a d betweenl Me maleic 4-iPrC anhydride6H4 and71/29 secondary 88amines 4; however,87/13 at the same 82 time, analysis62 of the data m Me Bn 56/44 64 a 42/58 57 39 d b d in Tablen Me1 shows 2-ClC that6H4 the yields71/29 of the isomer63 5A/5B mixtures75/25 obtained 95 in CH2Cl2 are59 1.5–2 times b d lowero comparedMe 3-ClC to6H 4the mixtures68/32 isolated69 from benzene83 /17or toluene. Besides, 78 the last two61 solvents 57/43 56 52 d p Me 4-BrC6H4 76/24 64 b provide a slight predominance of the isomer 5A at both65 /35r.te and heating.45 eIt is also important61 d to note a b c d that Conditions:the reactionPhMe, time∆, 3was h; Cat.1the ,shortest CH2Cl2, 16in◦ C,boilin 3 d; gCat.2 toluene, CHCl 3(~1, ∆, 30h); min, nevertheless, under argon; forCH 2aCl 2reasonable, MW, e − comparison120 ◦C, 10 min,of the under results argon; in InTable light grey—ratios1, all reactions and yields were are carried presented out after in separation boiling ofsolvents the above for indicated 3 h. Thus, isomer 6A/6B mixture (in dark gray) with methanol. for further experiments, we synthesized mixtures of the trans-5A/cis-5B isomers either in dichloromethane at −16 °C or in PhMe at 3 h reflux, as indicated in Table 2. The third part of the work is related to the study of the catalytic activity of ruthenium catalysts 1 The third part of the work is related to the study of the catalytic activity of ruthenium catalysts and 2 (Figure1) under the RRM protocol. According to the previous paper [ 27], the N,N-dimethyl 1 and 2 (Figure 1) under the RRM protocol. According to the previous paper [27], the N,N-dimethyl catalyst 2 is the most thermally stable, while the morpholine derivative catalyst 1 is the most active catalyst 2 is the most thermally stable, while the morpholine derivative catalyst 1 is the most active (as it has the longest coordination N Ru bond ~2.32 Å). (as it has the longest coordination N→→Ru bond ~2.32 Å). With this in mind, only two of these complexes were selected for the present study. The direct With this in mind, only two of these complexes were selected for the present study. The direct introduction of acids 5 into the RRM was obviously impossible due to their poor solubility in common introduction of acids 5 into the RRM was obviously impossible due to their poor solubility in common organic solvents and due to the presence of a free carboxylic group in their structure, which is destructive organic solvents and due to the presence of a free carboxylic group in their structure, which is to Hoveyda–Grubbs catalysts. Thus, methyl esters 6 of corresponding acids 5 were prepared according destructive to Hoveyda–Grubbs catalysts. Thus, methyl esters 6 of corresponding acids 5 were to the classical procedure (Scheme4, Table2). prepared according to the classical procedure (Scheme 4, Table 2).

SchemeScheme 4.4. EsteriﬁcationEsterification ofof 3a,6-epoxyisondol-7-carboxylic acidsacids5 5 withwith methanolmethanol aaffordingﬀording respectiverespective 3a,6-epoxyisoindole-7-carboxylates3a,6-epoxyisoindole-7-carboxylates (6(6).).

AsTable the 1. entries Influencea, h of, ksolvents, n in Table and temperat2 reveal,ure the ontrans the yields/cis isomeric and ratios ratio of trans of acids-5A/cis5-does5B isomers not change of noticeably3-allyl-1-oxo-3a,6-epoxyisoindole-7-carboxylic during the esteriﬁcation process, i.e., acids retro-DA (5). reaction or epimerization do not proceed underCompd. selected conditions.Substituents Esters 6 obtained Conditions, in thisRatios way of Trans are crystalline,-5A/cis-5B Isomers easily a, and isolated Total Yields substances (%) that are readily soluble in dichloromethane.CH2Cl2 CH2Cl2 MeCN MeCN PhH PhMe PhMe R1 R2 Elucidation of the spatial structure−16 °C, 3 d of isomericr.t, 3 d acidsr.t, similar 3 d to∆,5A 3 h/ 5B and∆, 3 h esters r.t, similar 3 d to∆6A, 3 h/6B has been previously done in the literature more than once [29–32,37,39–42], while as a rule, 2D NOE

NMR data have been used for evidence of their structures. Here we present X-ray structural information for a pair of isomeric methyl esters 6eA/6eB, which conﬁrms the preceding conclusions concerning the location of the substituent in the third position of the heterocyclic core (Figure3). Molecules 2020, 25, 5379 6 of 15

Molecules 2020, 25, x FOR PEER REVIEW 6 of 15

Figure 3. 3. X-rayX-ray crystal crystal structures structures of trans of trans-6eA-6eA (at the(at top) the andtop) cis and-6eBcis (at-6eB the(at bottom) the bottom methyl) 3-allyl- methyl 2-(4-chlorophenyl)-1-oxo-1,2,3,6,7,7a-hexa3-allyl-2-(4-chlorophenyl)-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylates.hydro-3a,6-epoxyisoindole-7-carboxylates.

Single crystals crystals of of diastereoisomers diastereoisomers 6e6e werewere grown grown from from an ether an ether solution, solution, and single-crystal and single-crystal XRD analysisXRD analysis revealed revealed that both that isomers both isomers comprised comprised 3a,6-epoxyisondolo-7-carboxylates 3a,6-epoxyisondolo-7-carboxylates with one molecule with one inmolecule an asymmetric in an asymmetric unit. Trans unit.-6eATrans isomer-6eA crystallizesisomer crystallizes in the tricli in thenic tricliniccrystal system crystal P-1 system space P-1 group, space whilegroup, the while cis-6eB the cis isomer-6eB isomer crystallizes crystallizes in the inorthorhombic the orthorhombic crystal crystal system system P2121 P221 1space2121 space group. group. The configurationThe configuration of the of thetricyclic tricyclic system system is identical is identical for for both both isomers isomers (see (see Tables Tables S2–S6 S2–S6 for for bond bond lengths lengths and angles, and Figure S1 for the overlay of the two molecules). molecules). The The substituents substituents in in the the third third position position of the heterocyclic heterocyclic core are located in transtrans oror ciscis positionspositions that that influence influence the the distance distance between between atoms, atoms, which are key for an NOE analysis (Table 3 3).). TheThe phenylphenyl ringsrings ofof 3a,6-epoxyisondolo-7-carboxylates3a,6-epoxyisondolo-7-carboxylates are twisted at different different angles with respect to the heterocycle due to the diffe differentrent orientations of the bulky substituent inin thethe thirdthird position.position. InIn the the case case of ofcis cis-isomer-isomer6eB 6eB, the, the angle angle between between the the C6 Cplane6 plane of ofphenyl phenyl atoms atoms and and the the C(1)N(2)C(3) C(1)N(2)C(3) plane plane is equal is equal to 44 to◦, 44°, while while for trans for trans-isomer-isomer6eA ,6eA this, anglethis angle is 125 is◦ . 125°.The orientation The orientation of the of methyl the methyl esters esters group group differs di onlyffers slightlyonly slightly for both for isomersboth isomers (Figure (Figure3). 3).

TableTable 3. SelectedSelected interatomic interatomic distances distances (Å) in esters 6eA and 6eB according to single-crystal XRD.

DistancesDistances (Å) (Å) Trans-6eATrans-6eA Cis-6eB Cis-6eB H(3)H(3)…H(7a)... H(7a) 3.781(1)3.781(1) 2.915(1) 2.915(1) H(3)H(3)…H(4)... H(4) 3.493(1)3.493(1) 2.871(1) 2.871(1) a ... C(10)C(10) a…H(4) H(4) 4.521(2)4.521(2) 3.772(5) 3.772(5) a a C(10)C(10) is the is the methylene methylene carbon carbon atom of of the the allyl allyl fragment. fragment.

The indicated X-ray parameters (for 6eA and 6eB)) are are in in good good agreement agreement with with the the data data from from 2D 2D NOESY NMR experiments carried out for transtrans- and and ciscis-isomers-isomers of of compounds compounds 5e,,k,,m,,p andand 6e6e,,kk,,mm,,pp (A/BA/B) (Figure 44).). All these compounds have a similar configuration of the tricyclic skeleton and side groups for different substituents and gave the same cross-peaks in the NOESY spectra. Key NOE interactions are indicated in Figure4. There are strong NOE interactions between H(4)–H(7a) and H(5)–H(7) for both diastereomers, indicating their identical endo-configurations for protons H(7) and H(7a). The difference lies in the side allyl/methallyl group, which is present in trans- or cis-form. There are

Molecules 2020, 25, 5379 7 of 15

strong resulting cross-peaks in the NOESY spectra between H(4)–H2C for trans-diastereomer A and H(4)–H(3) and H(3)–H(7a) for cis-diastereomer B (green arrows in Figure4), which indicates their spatial proximity (<3 Å) and fully corresponds to the XRD data (Table3). Cross-peaks between these protons but for other diastereomers (B and A, respectively)—between H(4)–H(3) and H(3)–H(7a) for trans-diastereomer A and H(4)–H2C for cis-diastereomer B—are absent in the NOESY spectra almost completely (crossed-out red arrows in Figure4). The side allyl /methallyl group is conformationally

Moleculesquite mobile 2020, 25 in, x solution,FOR PEER REVIEW and NOE data for it cannot be appropriately compared with XRD distances.7 of 15

FigureFigure 4. 4. ((AA.).) Key Key observed NOENOE interactions interactions in in 2D 2D NOESY NOESY NMR NMR spectra spectra for bothfor both representative representativetrans - transand-cis and-diastereomers cis-diastereomers5e,k,m 5e,p,andk,m,6ep ,andk,m ,6ep (,Ak,/mB).,p ( B(A/B.) Representative). (B.) Representative part of 2D part NOESY of 2D spectra NOESY for spectramixture for of mixturetrans-(violet of trans) and- (cisviolet-(red) and) diastereomers cis- (red) diastereomers of the allyl derivative of the allyl6e withderivative assignments 6e with of assignmentssignals and NOE.of signals and NOE.

1 13 AllH these and compoundsC-NMR spectra have a forsimilar series configuration5/6 of trans -of and the cistricyclic-diastereomers skeleton andA/B sidehave groups very for few differentcharacteristic substituents signals and by whichgave the they same could cross-pe be easilyaks in distinguished. the NOESY spectra. However, Key NOE they haveinteractions several arecharacteristic indicated in patterns Figure 4. of There correlation are strong peaks NOE in interactions 2D HSQC spectrabetween (Figure H(4)–H(7a)5 and and see H(5)–H(7) the ESI with for bothassignments diastereomers, data), indicating for example, their foridentical CH(4) en anddo-configurations CH(5) alkene for protons, protonsortho H(7)-CH and/meta H(7a).-CH The for differencepara-substituted lies in the aromatics side allyl/methallyl at N(2), and group, aliphatic which CH is2 present-groups in in trans allyl- or/methallyl cis-form. fragment.There are strong In the resultingwhole, the cross-peaks absolute values in the ofNOES chemicalY spectra shifts between are non-characteristic, H(4)–H2C for sincetrans-diastereomer there is a fairly A large and H(4)– scatter H(3)of chemical and H(3)–H(7a) shifts depending for cis-diastereomer on the substituents. B (green arrows However, in Figure for a number4), which of indicates protons their and carbons,spatial proximitythe sequence (<3 Å) of and the signalsfully corresponds and diﬀerence to the of XRD their data chemical (Table shifts 3). Cross-peaks are characteristic between and these the sameprotons for butall compounds.for other diastereomers The H(3), H(4),(B and H(7a), A, respectively)—between CH2 protons, and the CH(3),H(4)–H(3) C(3a), and CH H(3)–H(7a)2 carbons havefor trans such- diastereomerfeatures. Data A on and them H(4)–H2C are given for in Tablescis-diastereomer S12 and S13 B—are (see the absent ESI). in the NOESY spectra almost completely (crossed-out red arrows in Figure 4). The side allyl/methallyl group is conformationally quite mobile in solution, and NOE data for it cannot be appropriately compared with XRD distances. 1H and 13C-NMR spectra for series 5/6 of trans- and cis-diastereomers A/B have very few characteristic signals by which they could be easily distinguished. However, they have several characteristic patterns of correlation peaks in 2D HSQC spectra (Figure 5 and see the ESI with assignments data), for example, for CH(4) and CH(5) alkene protons, ortho-CH/meta-CH for para- substituted aromatics at N(2), and aliphatic CH2-groups in allyl/methallyl fragment. In the whole, the absolute values of chemical shifts are non-characteristic, since there is a fairly large scatter of chemical shifts depending on the substituents. However, for a number of protons and carbons, the sequence of the signals and difference of their chemical shifts are characteristic and the same for all compounds.

Molecules 2020, 25, x FOR PEER REVIEW 8 of 15

MoleculesThe H(3),2020 H(4),, 25, 5379 H(7a), CH2 protons, and the CH(3), C(3a), CH2 carbons have such features. Data8 of on 15 them are given in Tables S12 and S13 (see the ESI).

FigureFigure 5.5. Typical characteristiccharacteristic patternpattern ofof CH(4)CH(4) andand CH(5)CH(5) correlationcorrelation peakspeaks inin 2D2D HSQCHSQC spectraspectra 6k (mixture(mixture ofof transtrans andand ciscis diastereomersdiastereomers ofof 6kas asan an example) example) used used for for assignments assignments of of diastereomers. diastereomers. Therefore, the combination of the single-crystal XRD and NMR data allowed us to make an Therefore, the combination of the single-crystal XRD and NMR data allowed us to make an unambiguous assignment of isomers of all compounds 5 and 6 to the A or B series. unambiguous assignment of isomers of all compounds 5 and 6 to the A or B series. Considering that we were unable to achieve a noticeable predominance of the desired acids 5A by Considering that we were unable to achieve a noticeable predominance of the desired acids 5A varying the IMDAF reaction conditions (see Table1), we paid close attention to finding preparative by varying the IMDAF reaction conditions (see Table 1), we paid close attention to finding methods for the separation of isomeric esters 6A/6B. We failed to find a suitable chromatographic preparative methods for the separation of isomeric esters 6A/6B. We failed to find a suitable system for the separation of isomers 6A/6B on silica gel due to the closeness of their retention factors. chromatographic system for the separation of isomers 6A/6B on silica gel due to the closeness of their Mixtures of diastereomers 6aA/6aB (79/21), 6eA/6eB (16/84), 6fA/6fB (29/71) and 6pA/6pB (57/43) were retention factors. Mixtures of diastereomers 6aA/6aB (79/21), 6eA/6eB (16/84), 6fA/6fB (29/71) and used as model compounds, and mixtures of EtOAc/hexane, MeOH/THF and CHCl /MeOH were 6pA/6pB (57/43) were used as model compounds, and mixtures of EtOAc/hexane, MeOH/THF3 and applied as eluents. However, our attempts to separate the same esters by fractional crystallization were CHCl3/MeOH were applied as eluents. However, our attempts to separate the same esters by more fruitful. For this purpose, fine powders of the stereoisomer mixtures were stirred for a half-hour fractional crystallization were more fruitful. For this purpose, fine powders of the stereoisomer at 45–50 C in a methanol solution; then, the least soluble isomer 6B was filtered off and the mother mixtures◦ were stirred for a half-hour at 45–50 °C in a methanol solution; then, the least soluble isomer liquor was concentrated. After this treatment, the purity of individual isomers 6A and 6B exceeded 6B was filtered off and the mother liquor was concentrated. After this treatment, the purity of 92% (diastereomeric excess (de) > 84%) in total yields of more than 94%. Repeating this procedure one individual isomers 6A and 6B exceeded 92% (diastereomeric excess (de) > 84%) in total yields of more more time resulted in virtually pure isomers. According to the described protocol, the diastereomers than 94%. Repeating this procedure one more time resulted in virtually pure isomers. According to of 3-allyl substituted esters 6aA/6aB, 6fA/6fB and 6eA/6eB were separated and tested as metathesis the described protocol, the diastereomers of 3-allyl substituted esters 6aA/6aB, 6fA/6fB and 6eA/6eB objects (Scheme5), described in the third part of this manuscript. Separation of 3-methallyl substituted were separated and tested as metathesis objects (Scheme 5), described in the third part of this esters 6pA/6pB by this way was less efficient, resulting in the formation of a 65/35 mixture of isomers manuscript. Separation of 3-methallyl substituted esters 6pA/6pB by this way was less efficient, after one “recrystallization” from MeOH. resulting in the formation of a 65/35 mixture of isomers after one “recrystallization” from MeOH. The first experiments showed that solutions of the individual cis-isomers 6aB, 6eB and 6fB in CH2Cl2 at both room and elevated temperatures underwent polymerization with catalysts 1, 2 or HG-II (0.5–5 mol%). We were unable to isolate individual substances from metathesis product mixtures obtained under either an argon or an ethylene atmosphere (2 bar), except in two cases 6eB (R1 = H, 2 1 2 R = 4-ClC6H4) and 6fB (R = H, R = 4-BrC6H). In these tests under an argon atmosphere, divinyl furo[2,3-c]pyrroles 8, probably the products of a series of the sequenced intermolecular cross metathesis reactions, were localized in a very low yield (Scheme6). The formation of this product only occurs if the reaction is carried out for 15 min or less; upon longer heating, products 8 are completely transformed into a polymer.

Molecules 2020, 25, x FOR PEER REVIEW 9 of 15

Molecules 2020, 25, 5379 9 of 15 Molecules 2020, 25, x FOR PEER REVIEW 9 of 15

Scheme 5. Synthesis of cyclopenta[b]furo[2,3-c]pyrroles 7.

The first experiments showed that solutions of the individual cis-isomers 6aB, 6eB and 6fB in 2 2 CH2Cl2 at both room and elevated temperatures underwent polymerization with catalysts 1, 2 or HG- II (0.5–5 mol%). We were unable to isolate individual substances from metathesis product mixtures 1 2 obtained under either an argon or an ethylene atmosphere (2 bar), except in two cases 6eB (R1 = H, R2 6 4 1 2 6 = 4-ClC6H4) and 6fB (R1 = H, R2 = 4-BrC6H). In these tests under an argon atmosphere, divinyl furo[2,3- c]pyrroles 8, probably the products of a series of the sequenced intermolecular cross metathesis c]pyrroles 8, probably the products of a series of the sequenced intermolecular cross metathesis reactions, were localized in a very low yield (Scheme 6). The formation of this product only occurs if Scheme 5. Synthesis of cyclopenta[b]furo[2,3-c]pyrroles 7. the reaction is carried outScheme for 5.15Synthesis min or ofless; cyclopenta[ upon longerb]furo[2,3- heating,c]pyrroles products7. 8 are completely transformed into a polymer. The first experiments showed that solutions of the individual cis-isomers 6aB, 6eB and 6fB in CH2Cl2 at both room and elevated temperatures underwent polymerization with catalysts 1, 2 or HG- II (0.5–5 mol%). We were unable to isolate individual substances from metathesis product mixtures obtained under either an argon or an ethylene atmosphere (2 bar), except in two cases 6eB (R1 = H, R2 = 4-ClC6H4) and 6fB (R1 = H, R2 = 4-BrC6H). In these tests under an argon atmosphere, divinyl furo[2,3- c]pyrroles 8, probably the products of a series of the sequenced intermolecular cross metathesis reactions, were localized in a very low yield (Scheme 6). The formation of this product only occurs if the reaction is carried out for 15 min or less; upon longer heating, products 8 are completely transformed into a polymer. SchemeScheme 6. 6. ResultsResults of of metathesis metathesis of of ciscis-isomers-isomers 6B.6B.

InIn these these two two cases, cases, it it turned turned out out to to be be possible possible to to isolate isolate products products usin usingg column column chromatography. chromatography. TheThe spatialspatial structurestructure of of one one of them of them (8b) was(8b entirely) was entirely conﬁrmed confirmed by X-ray analysisby X-ray (Figure analysis6). Compounds (Figure 6). Compounds8a and 8b also 8a canand be8b obtainedalso can be by obtained reaction by of thereaction esters of6e theor esters6f with 6e ethyleneor 6f with (2 ethylene bar, 100 (2◦C, bar, 6h) 100 in °C,dichloromethane 6 h) in dichloromethane in presence in of presence catalyst of2 incatalyst 5–8% yields.2 in 5–8% yields.

Scheme 6. Results of metathesis of cis-isomers 6B.

In these two cases, it turned out to be possible to isolate products using column chromatography. The spatial structure of one of them (8b) was entirely confirmed by X-ray analysis (Figure 6). Compounds 8a and 8b also can be obtained by reaction of the esters 6e or 6f with ethylene (2 bar, 100 °C, 6 h) in dichloromethane in presence of catalyst 2 in 5–8% yields.

Figure 6. X-ray crystal structure of methyl (2RS,3SR,3aRS,6SR,6aSR)-6-allyl-5-(4-bromophenyl)-4- oxo-2,6a-divinylhexahydro-2H-furo[2,3-c]pyrrole-3-carboxylate (8b).

However, it was found that the pure trans-isomers 6aA, 6eA and 6pA are able to form tricyclic systems of cyclopenta[b]furo[2,3-c]pyrrole 7 in the RRM reaction (the last column of Tables2 and4). Moreover, in contrast to the communications [9–11,17,19,21,22], in our case, the ring-rearrangement metathesis does not require the supporting application of ethylene that facilitates practical synthesis.

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Table 4. Optimization of the RRM protocol using the test esters 6eA and 6pA.

Starting Entry Catalyst (mol %) Conditions Target Tricycle Yield, % a Ester

1 6eA Cat. 1 (0.5) CHCl3, ∆, 3 h, Ar 7e 85 2 6eA Cat. 1 (0.5) CHCl3, ∆, 1.5 h, Ar 7e 80 3 6eA Cat. 1 (0.5) CHCl3, ∆, 1.0 h, Ar 7e 82 b 4 6eA Cat. 1 (0.5) CHCl3, ∆, 0.5 h, Ar 7e 80 5 6eA HG-II (0.5) CHCl3, ∆, 0.5 h, Ar 7e 74 6 6eA Cat. 1 (0.5) CHCl3, ∆, 0.25 h, air 7e 35 b 7 6eA Cat. 1 (0.5) CHCl3, ∆, 0.25 h, Ar 7e 83 8 6eA Cat. 1 (0.5) CH2Cl2, ∆, 3 h, Ar 7e 58 9 6eA Cat. 1 (0.5) CH2Cl2, ∆, 1.5 h, Ar 7e 52 10 6eA Cat. 1 (0.5) CH2Cl2, ∆, 0.5 h, Ar 7e 37 11 6eA Cat. 1 (1.0) CHCl3, ∆, 0.25 h, Ar 7e 85 12 6eA Cat. 1 (1.0) CHCl3, ∆, 0.5 h, Ar 7e 85 13 6eA Cat. 1 (0.1) CHCl3, ∆, 0.25 h, Ar 7e 32 14 6eA Cat. 1 (0.1) CHCl3, ∆, 1.0 h, Ar 7e 51 15 6eA Cat. 1 (0.1) CHCl3, ∆, 1.5 h, Ar 7e 54 16 6eA Cat. 1 (0.1) CHCl3, ∆, 3 h, Ar 7e 55 17 6pA Cat. 2 (0.5) CHCl3, ∆, 30 min, Ar, MW, 120 ◦C 7p 55 18 6pA Cat. 2 (0.5) CHCl3, ∆, 20 min, Ar, MW, 120 ◦C 7p 52 19 6pA Cat. 2 (0.5) CHCl3, ∆, 10 min, Ar, MW, 120 ◦C 7p 45 20 6pA Cat. 2 (0.5) CH2Cl2, ∆, 30 min, Ar, MW, 120 ◦C 7p 85 21 6pA Cat. 2 (0.5) CH2Cl2, ∆, 20 min, Ar, MW, 120 ◦C 7p 84 22 6pA Cat. 2 (0.5) CH2Cl2, ∆, 15 min, Ar, MW, 120 ◦C 7p 80 23 6pA Cat. 2 (0.5) CH2Cl2, ∆, 10 min, Ar, MW, 100 ◦C 7p 0 b 24 6pA Cat. 2 (0.5) CH2Cl2, ∆, 10 min, Ar, MW, 120 ◦C 7p 82 25 6pA HG-II (0.5) CH2Cl2, ∆, 10 min, Ar, MW, 120 ◦C 7p 42 26 6pA Cat. 2 (1.0) CH2Cl2, ∆, 10 min, Ar, MW, 120 ◦C 7p 83 25 6pA Cat. 2 (1.0) CH2Cl2, ∆, 15 min, Ar, MW, 120 ◦C 7p 85 26 6pA Cat. 2 (0.1) CH2Cl2, ∆, 10 min, Ar, MW, 120 ◦C 7p 43 27 6pA Cat. 2 (0.1) CH2Cl2, ∆, 15 min, Ar, MW, 120 ◦C 7p 47 a Isolated yields of products 7 after column chromatography. b In gray—the best conditions and yields (in bold) are highlighted.

To achieve the maximum yield of the target tricycles 7, the metathesis reaction was optimized in terms of solvent, temperature, duration and amount of catalyst. Due to the poor solubility of esters 6eA (3-allyl) and 6pA (3-methallyl) in benzene and o-dichlorobenzene, we chose not to use aromatic solvents; similarly, polar solvents such as THF or MeCN proved to be ineffective in view of their capacity to interact with the Hoveyda–Grubbs type catalysts at elevated temperatures. The best of the tested mediums turned out to be halogenomethanes (CH2Cl2 and CHCl3), and hence they were used as solvents in all further experiments. None of the selected catalysts exhibited activity at temperatures below 50 ◦C, and no rearrangement products 7e,p were fixed. Being the most active, the morpholine containing Cat. 1 started to work at the temperature of boiling chloroform (~60 ◦C), causing the rearrangement of the test 3-allyl isoindolone 6e. The more sterically demanding methallylic substrate 6pA are not recyclized under these conditions. An increase in temperature up to 100 ◦C under microwave irradiation led to a rapid decomposition of Cat. 1 (at 100 ◦C, the emerald-green color of the chloroform solution of Cat. 1 turned brown almost immediately), and accordingly to low yields of the product 7p. Obviously, higher temperatures and a more thermally stable catalyst should be used for a successful cyclization of methallyl derivatives 6i–p. N,N-Dimethylamino derivative (Cat. 2), with a shorter bond length between nitrogen and ruthenium (the N Ru bond is 2.24 Å [27]), is stable at least up to 140 C[27], and therefore turned out → ◦ to be effective for the preparation of cyclopenta[b]furo[2,3-c]pyrrole 7p at temperatures above 100 ◦C in microwave-assisted experiments (entries 17–26, Table4). It should be noted that the amount of catalysts 1 and 2 required for the complete conversion of the initial esters 6eA, 6pA did not exceed 0.5 mol % in both cases, while the reaction time was much shorter than in the papers cited above [9–23]. After all attempts, the following conditions were found to be optimal for the recyclizations of the allyl derivative (6eA): boiling chloroform, 0.5 mol % of Cat. 1, 30 min. For synthesis of the methyl substituted 6pA, the best results were achieved under microwave activation in CH2Cl2 at 120 ◦C, 10 min, Cat. 2 (0.5 mol %). Molecules 2020, 25, x FOR PEER REVIEW 11 of 15

20 6pA Cat. 2 (0.5) CH2Cl2, Δ, 30 min, Ar, MW, 120 °C 7p 85 21 6pA Cat. 2 (0.5) CH2Cl2, Δ, 20 min, Ar, MW, 120 °C 7p 84 22 6pA Cat. 2 (0.5) CH2Cl2, Δ, 15 min, Ar, MW, 120 °C 7p 80 23 6pA Cat. 2 (0.5) CH2Cl2, Δ, 10 min, Ar, MW, 100 °C 7p 0 24 6pA Cat. 2 (0.5) CH2Cl2, Δ, 10 min, Ar, MW, 120 °C 7p 82 b 25 6pA HG-II (0.5) CH2Cl2, Δ, 10 min, Ar, MW, 120 °C 7p 42 26 6pA Cat. 2 (1.0) CH2Cl2, Δ, 10 min, Ar, MW, 120 °C 7p 83 25 6pA Cat. 2 (1.0) CH2Cl2, Δ, 15 min, Ar, MW, 120 °C 7p 85 26 6pA Cat. 2 (0.1) CH2Cl2, Δ, 10 min, Ar, MW, 120 °C 7p 43 27 6pA Cat. 2 (0.1) CH2Cl2, Δ, 15 min, Ar, MW, 120 °C 7p 47 Moleculesa Isolated2020, 25 yields, 5379 of products 7 after column chromatography. b In gray—the best conditions and yields11 of 15 (in bold) are highlighted.

It was interesting to compare the potential of the commercially available HG-II catalyst with It was interesting to compare the potential of the commercially available HG-II catalyst with catalysts Cat.1 and Cat.2 (see entries 4, 5, 24 and 25 in light gray in Table4). Analysis of the isolated catalysts Cat.1 and Cat.2 (see entries 4, 5, 24 and 25 in light gray in Table 4). Analysis of the isolated yields of products 7e,p allows us to conclude that the most popular commercial catalyst (HG-II) is yields of products 7e,p allows us to conclude that the most popular commercial catalyst (HG-II) is less efficient. less efficient. The optimized protocols discussed above were planned to be extended to the recyclization of The optimized protocols discussed above were planned to be extended to the recyclization of the remaining esters 6 (Table2). However, the obvious disadvantage of the method is the need to the remaining esters 6 (Table 2). However, the obvious disadvantage of the method is the need to separate mixtures of diastereomers 6A/6B. We tried to get around this obstacle, taking into account separate mixtures of diastereomers 6A/6B. We tried to get around this obstacle, taking into account that cis-isomers 6aB–6pB can be considered as undesirable ballast in the target tricycles 7 synthesis, that cis-isomers 6aB–6pB can be considered as undesirable ballast in the target tricycles 7 synthesis, and that the proposed pathway is based on readily available starting materials and reliable synthetic and that the proposed pathway is based on readily available starting materials and reliable synthetic procedures, which allows the synthesis to be scaled up to kilogram quantities. Thereby, the developed procedures, which allows the synthesis to be scaled up to kilogram quantities. Thereby, the approaches were further applied to the metathesis of mixtures of isomers 6A/6B (Scheme5). To our developed approaches were further applied to the metathesis of mixtures of isomers 6A/6B (Scheme satisfaction, the admixtures of cis-isomers 6B had no significant impact on the reaction progress; 5). To our satisfaction, the admixtures of cis-isomers 6B had no significant impact on the reaction the polymerization products formed from them could be easily separated during purification by flash progress; the polymerization products formed from them could be easily separated during or column chromatography to provide the pure cyclopenta[b]furo[2,3-c]pyrroles 7 in good yields (based purification by flash or column chromatography to provide the pure cyclopenta[b]furo[2,3-c]pyrroles trans 6A on7 in the good yields-isomer (based). Thus,on the the trans majority-isomer of 6A the). RRMThus, reactions the majority presented of the in RRM Table reactions2 were carried presented out 6A/6B usingin Table mixtures 2 wereof carried isomers out usingas mixtures starting of materials. isomers 6A/6B as starting materials. ItIt worthworth mentioningmentioning herehere thatthat byby revisingrevising thethe ethylene-supportedethylene-supported transformationstransformations ofof thethe similarsimilar substratessubstrates [[9–23],9–23], thethe questionquestion ofof thethe sequencesequence ofof metathesismetathesis stagesstages arose.arose. In theory, twotwo pathspaths existexist 6 7 forfor thethe rearrangementrearrangement ofof 6 toto 7 inin anan ethyleneethylene atmosphere:atmosphere: ROMROM/RCM,/RCM, oror vicevice versa,versa, RCMRCM/ROM/ROM trans 6A successionssuccessions [[43].43]. We supposesuppose thatthat thethe plausibleplausible mechanismmechanism ofof thethe metathesismetathesis ofof trans-isomers-isomers 6A doesdoes notnot didifferffer fromfrom thethe generallygenerally acceptedaccepted one,one, asas itit isis representedrepresented in in Scheme Scheme7 .7.

SchemeScheme 7.7. PossiblePossible reactionreaction sequencesequence for for RRM RRM by by the the example example of of the the conversion conversion of oftrans trans--isomerisomer6aA 6aAto 7ato in7a thein the presence presence of Cat.of Cat. 1. 1.

We did not set ourselves the goal of investigating in detail the reaction mechanism; however, from general considerations, it can be assumed that the ring-closing metathesis (RCM) stage has to precede the opening of the 7-oxabicycloheptene cycle (ROM). This statement is supported by the observed behavior of trans-3-allyl derivatives 6aA–6hA, which regroup more quickly and under more mild conditions compared to their 3-methallyl analogs 6iA–6pA. This fact is probably related to the more rapid cycloaddition of the double bond of the allylic fragment to the Ru=CH-R center of the catalyst with the formation of structure I1 (Scheme 7). This statement is in good accordance with recentlyMolecules published2020, 25, 5379 data [43,44]. 12 of 15 During the metathesis of cis-isomers 6B, which are not capable of RCM, the polymer similar to D is apparently formed through the cross-metathesis intermediate C (Scheme 8). Although the exo- allylic double bond is more reactive, it is also possible to obtain the short-lived triene 8a which is cyclic allylic double bond is more reactive, it is also possible to obtain the short-lived triene 8a which generated in the course of the catalytic cleavage of the endo-cyclic double bond in the starting molecules is generated in the course of the catalytic cleavage of the endo-cyclic double bond in the starting 6B (ruthenium complexes E and F). molecules 6B (ruthenium complexes E and F).

SchemeScheme 8. 8. PossiblePossible behavior behavior of of ciscis-isomer-isomer 6aB6aB underunder metathesis metathesis reaction reaction conditions. conditions.

3.3. Materials Materials and and Methods Methods

3.1.3.1. General General Remarks Remarks AllAll reagents reagents were were purchased purchased from from commercial commercial suppliers suppliers (Acros (Acros Organi Organics,cs, Morris Morris Plains, Plains, NJ, NJ, USAUSA and and Merck Merck KGaA, KGaA, Darmstadt, Darmstadt, Germany) Germany) and and us useded without without further further purification. purification. Metathesis Metathesis reactions required solvents (CH Cl and CHCl ) pre-dried over anhydrous P O and an inert reactions required solvents (CH2Cl2 2 2and CHCl3)3 pre-dried over anhydrous P2O2 5 5and an inert atmosphereatmosphere (dry (dry Ar). Ar). Thin Thin layer layer chromatography chromatography was wascarried carried out on out aluminum on aluminum backed backed silica silicapre- pre-coated plates «Sorbfil» and «Alugram». The plates were visualized using a water solution of coated plates «Sorbfil» and «Alugram». The plates were visualized using a water solution of KMnO4 KMnO or UV (254 nm). After extraction, organic layers were dried over anhydrous MgSO . IR spectra or UV (2544 nm). After extraction, organic layers were dried over anhydrous MgSO4. IR spectra4 were obtainedwere obtained in KBr in pellets KBr pellets or in thin or in films thin using films usingan Infralum an Infralum FT-801 FT-801 IR-Fourier. IR-Fourier. NMRNMR spectra spectra were wererun 1 inrun deuterated in deuterated solvents solvents (>99.5 (> atom99.5 atom% D) %on D) Jeol on JNM-ECA Jeol JNM-ECA 600 (600.1 600 (600.1 MHz MHz for 1H for andH 150.9 and 150.9 MHz MHz for for 13C) spectrometer for 2–5% solutions in CDCl or DMSO-d6 at 22–23 C using residual solvent 13C) spectrometer for 2–5% solutions in CDCl3 or DMSO-d63 at 22–23 °C using◦ residual solvent signals signals (7.26/77.0 ppm for 1H/13C in CDCl and 2.50/39.5 ppm for 1H/13C in DMSO-d ) or TMS as an (7.26/77.0 ppm for 1H/13C in CDCl3 and 2.50/39.53 ppm for 1H/13C in DMSO-d6) or TMS6 as an internal internal standard. CFCl was used as an internal standard for 19F-NMR spectra. standard. CFCl3 was used3 as an internal standard for 19F-NMR spectra. 3.2. Experimental Procedures 3.2. Experimental Procedures The initial homoallylamines 4a–p were synthesized according to the previously described procedures [45,46]. Carboxylic acids 5a p were synthesized using the known methods [29–32]. − The detailed description of the preparation for all new compounds obtained in this work is given in the ESI section. Molecules 2020, 25, 5379 13 of 15

4. Conclusions Our systematic studies on furan chemistry and metathesis reactions resulted in the development of general, eﬀective method for the synthesis of natural product-like cyclopenta[b]furo[2,3-c]pyrroles from easily available, renewable furan-based precursors. The target tricyclic molecules were formed in high yields from esters of 3-allyl or 3-methallyl substituted 3a,6-epoxyisondolo-7-carboxylic acids in the presence of a new type of Hoveyda–Grubbs catalysts. The inﬂuence of the length of the N Ru → coordinate bond in the ruthenium complexes on the rate of the reaction was examined, and selective catalysts for the RRM of the allyl and methallyl derivatives were discovered. It was also proven that the recyclization is strictly stereoselective; only trans-isomer from two possible diastereoisomers of the initial methyl 3a,6-epoxyisondolo-7-carboxylates can be involved in the metathesis reaction.

Supplementary Materials: The following are available online, Figure S1: Structure of 6eA (296 K) C19H18ClNO4 (CCDC number 2023634), Figure S2: Structure of 6eB (296 K) C19H18ClNO4 (CCDC number 2023635), Figure S3: The overlay of molecules of trans-6eA (blue) and cis-6eB (red) methyl 3-allyl-2-(4-chlorophenyl)-1-oxo-1,2,3,6,7,7a-hexahydro-3a,6-epoxyisoindole-7-carboxylates according to the single crystal XRD, Figure S4: Structure of 8b (CCDC number is 2025199), Table S1: Crystal data and structure refinement for 6eA and 6eB, Table S2: Bond Lengths for 6eA, Table S3: Bond Angles for 6eA, Table S4: Hydrogen Bonds for 6eA, Table S5: Bond Lengths for 6eB, Table S6: Bond Angles for 6eB, Table S7: Hydrogen Bonds for 6eB, Table S8: Crystal data and structure refinement for 8b, Table S9: Bond Lengths for 8b, Table S10: Bond Angles for 8b, Table S11: Hydrogen Bonds for 8b, Table S12: Selected 1H-NMR chemical shifts for trans- and cis-isomers, Table S13: Selected 13C-NMR chemical shifts for trans- and cis-isomers. Author Contributions: A.S.A., M.A.V., P.A.K., and N.L.M. performed the synthesis and purification of the obtained compounds; A.A.S. and M.S.G. performed the X-ray diffraction experiments; K.B.P. conducted the NMR data analysis; R.A.N. performed the NMR experiments; V.V.K. organized the drafts’ preparation and participated in the editing; F.I.Z. conceived, designed the experiments and supervised all processes of this investigation. All authors have read and agreed to the published version of the manuscript. Funding: The authors extend their appreciation to the Russian Science Foundation (RSF) for funding this work through a general research project under grant number (project No. 18-13-00456). Conflicts of Interest: The authors declare no conflict of interest.

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Sample Availability: Samples of the compounds 5–7 are available from the authors.

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