Naphthalenes and Quinolines by Domino Reactions of Morita–Baylis–Hillman Acetates

molecules

Article Naphthalenes and Quinolines by Domino Reactions of Morita–Baylis–Hillman Acetates

Joel K. Annor-Gyamﬁ, Ebenezer Ametsetor, Kevin Meraz and Richard A. Bunce * Department of Chemistry, Oklahoma State University, Stillwater, OK 74078–3071, USA; [email protected] (J.K.A.-G.); [email protected] (E.A.); [email protected] (K.M.) * Correspondence: [email protected]; Tel.: +1-405-744-5952

Academic Editor: Antonio Massa Received: 12 October 2020; Accepted: 27 October 2020; Published: 6 November 2020 Abstract: An eﬃcient synthetic route to highly functionalized naphthalenes and quinolines has been developed using domino reactions between Morita–Baylis–Hillman (MBH) acetates and active methylene compounds (AMCs) promoted by anhydrous K2CO3 in dry N,N-dimethylformamide (DMF) at 23 ◦C. The substrates incorporate allylic acetates positioned adjacent to a Michael acceptor as well as an aromatic ring activated toward a SNAr ring closure. A control experiment indicated that the initial reaction was an SN2’-type displacement of a side chain acetoxy by the AMC anion to aﬀord the alkene product bearing the added nucleophile trans to the SNAr aromatic ring acceptor. Thus, equilibration of the alkene geometry of the initial product was required prior to cyclization. Products were isolated in good to excellent yields. Numerous cases (24) are reported, and several mechanistic possibilities are discussed.

Keywords: Morita–Baylis–Hillman acetates; active methylene compounds; domino reactions; naphthalenes; quinolines

1. Introduction One facet of our research program has focused on domino reactions for the rapid assembly of molecules with potential use in drug synthesis. This requires highly functionalized compounds with reactive sites strategically positioned to capture intermediates from an initial reaction in one or more subsequent reactions to produce targets of high value in an efficient, eco-friendly manner. Among the compounds meeting these requirements are the products of the Morita–Baylis–Hillman (MBH) reaction. These highly functionalized adducts have proven quite useful in drug synthesis [1,2]. Additionally, the naphthalenes [3] and quinolines [4,5] targeted in this work could have immense value in medicinal chemistry. Previous work by others has appeared in this area, but details were lacking, and the diversity of examples reported was limited. One article outlined the formation of a number of naphthalene derivatives [6] from MBH acetates and active methylene compounds (AMCs) (Figure1A), but the initial adduct was assumed to have the correct geometry for ring closure, and the only molecule eliminated during the final aromatization was benzenesulfinic acid (PhSO2H). A second report described a synthesis of 3-quinolinecarboxylic esters [7] involving the reaction of ethyl 2-((2-chlorophenyl)((tosylsulfonamido)methyl)acrylate acrylate with tosylsulfonamide (Figure1B). A third study [8] advanced a synthesis of dihydroacridines from MBH acetates derived from 2-chloroquinoline-3-carboxaldehyde and AMCs to fuse a substituted benzene ring to the heterocycle (Figure1C). The final account detailed the AMC-dependent annulation of substituted benzene rings by reaction of this same MBH precursor to give acridines and phenanthridines [9] (Figure1D). The current work describes the synthesis of naphthalenes and quinolines with a broader range of functionality, evaluates a selection of different leaving groups, and discusses several mechanistic possibilities.

Molecules 2020, 25, 5168; doi:10.3390/molecules25215168 www.mdpi.com/journal/molecules Molecules 2020, 25, x 2 of 17

Moleculesof functionality,2020, 25, 5168 evaluates a selection of different leaving groups, and discusses several mechanistic2 of 17 possibilities.

OAc

CO2Et CO2Et PhSO2CH2CO2Et A. K CO , DMF F 2 3 92% 60 oC, 2-36 h CO2Et Cl NHTs Cl

CO2Et CO2Et TsNH2 B. K CO , DMF Cl 2 3 N 76% 80-90 oC, 1-10 h OAc

CO2Me CO2Me CH3C(O)CH2CO2Me C. N Cl K2CO3, DMF N 82% room temp, 3.5 h H CO2Me OAc MeO2C CO2Me CO Me CO Me 2 AMC 2 D. or K CO , DMF N Cl 2 3 N room temp, 0.5-5 h N Cl CO2Me O NCH CO Me, 59% AMC: NCCH2CO2Et, 78% 2 2 2 FigureFigure 1.1. Previous cyclizations to generategenerate aromaticaromatic systemssystems usingusing Morita–Baylis–HillmanMorita–Baylis–Hillman (MBH)(MBH) acetates.acetates. (A (A):): Formation Formation of of naphthalenes; naphthalenes; ( (BB):): Formation Formation of quinolines; ( C): FormationFormation ofof dihydroacridines;dihydroacridines; ((DD):): FormationFormation ofof acridinesacridines and and phenanthridines. phenanthridines.

2. Results and Discussion 2. ResultsThe MBH and reactionDiscussion was first reported in 1968 [10] and has undergone many modifications [11–13] to improveThe MBH its outcome.reaction was The first generally reported accepted in 1968 procedure [10] and has calls undergone for 1 equiv. many of modifications the aldehyde and[11– 1.213] equiv.to improve of the its electron-poor outcome. The alkene generally in the accepted presence procedure of 1.5 equiv. calls offor 1,4-diazabicyclo 1 equiv. of the aldehyde [2.2.2]octane and (DABCO)1.2 equiv. inof acetonitrilethe electron (ACN)‐poor alkene at room in temperaturethe presence (23of 1.5◦C) equiv. [14]. For of 1,4 the‐diazabicyclo current project, [2.2.2]octane we have generated(DABCO) thesein acetonitrile adducts by(ACN) the reaction at room of temperature polarized alkenes (23 °C) with [14]. aromatic For the aldehydescurrent project, incorporating we have functionalitygenerated these that furtheradducts activates by the the aromaticreaction ringof towardpolarized a S NalkenesAr reaction with using aromatic a 2:1 stoichiometry aldehydes ofincorporating alkene:aldehyde functionality with 1.2 that equiv. further of DABCO activates (Scheme the aromatic1). Thus, ring 2-fluoro-5-nitrobenzaldehyde toward a SNAr reaction using ( 1a ),a 2-fluoro-5-cyanobenzaldehyde2:1 stoichiometry of alkene:aldehyde (1b), and with 2-fluoronicotinaldehyde 1.2 equiv. of DABCO (1c )(Scheme were each 1). treatedThus, with2‐fluoro ethyl‐5‐ acrylatenitrobenzaldehyde (2a) and acrylonitrile (1a), 2‐fluoro (2b)‐ in5‐cyanobenzaldehyde ACN at 23 ◦C for 2 days (1b to), and give 2 the‐fluoronicotinaldehyde MBH alcohols (3a–e) in(1c 86–98%) were yields.each treated Attempts with to ethyl acylate acrylate the alcohol (2a) and adduct acrylonitrile3b with acetic(2b) in anhydride ACN at 23 at °C reflux for led2 days to acylation to give the of theMBH alcohol alcohols and ( allylic3a–e) inversionin 86–98% of yields. the acetate Attempts to aff ordto acylate (E)-2-cyano-3-(2-fluoro-5-nitrophenyl)allyl the alcohol adduct 3b with acetic acetateanhydride (4). at Interestingly, reflux led to an acylation X-ray structure of the alcohol of this and product allylic showed inversion the of acetoxymethyl the acetate to groupafford of(E the)‐2‐ rearrangedcyano‐3‐(2‐fluoro acetate‐5 to‐nitrophenyl)allyl be trans to the substrate acetate ( aromatic4). Interestingly, ring (see an Scheme X‐ray1 structure and the Supplementaryof this product Materials).showed the Acylation acetoxymethyl of the group MBH adductsof the rearranged without rearrangement acetate to be trans was to achieved the substrate using trimethylsilylaromatic ring trifluoromethanesulfonate(see Scheme 1 and the Supplementary (TMSOTf) as an Materials). acylation Acylation catalyst [ 15of] inthe dichloromethane MBH adducts without (DCM). Thisrearrangement catalyst permitted was achieved the acylation using oftrimethylsilyl3a–e at 0 ◦C trifluoromethanesulfonate in 30 min and delivered the(TMSOTf) unrearranged as an acetatesacylation5 –catalyst9, respectively, [15] in dichloromethane in 95–98% yields. (DCM). This catalyst permitted the acylation of 3a–e at 0 °C inThe 30 min results and of delivered our study the are unrearranged summarized in acetates Tables1 5 and–9, 2respectively,. The reaction in of 95–98% substrates yields.5– 8 (1 equiv.) withThe AMCs results10–14 of (1.5our equiv.)study are yielded summarized 1,3,6-trisubstituted in Tables 1 and naphthalenes 2. The reaction15–18 ,of while substrates precursor 5–8 (19 aequiv.)fforded with 6,8-disubstituted AMCs 10–14 quinolines (1.5 equiv.)19 with yielded the same 1,3,6 panel‐trisubstituted of nucleophiles. naphthalenes Naphthalene 15– formation18, while wasprecursor promoted 9 afforded by K2CO 3 (1.56,8‐disubstituted equiv.) in N,N -dimethylformamidequinolines 19 with (DMF) the same at 23 ◦ Cpanel in 1 h, of while nucleophiles. quinolines wereNaphthalene similarly formation prepared butwas required promoted heating by K at2CO 903 ◦(1.5C for equiv.) 6 h. Yields in N, wereN‐dimethylformamide uniformly good to (DMF) excellent, at with23 °C the in 2-fluoro-5-nitrophenyl1 h, while quinolines were SNAr similarly acceptor prepared giving the but most required efficient heating ring closure, at 90 °C followed for 6 h. byYields the 2-fluoro-5-cyanowere uniformly good compound to excellent, and finally with 2-fluoropyridine.the 2‐fluoro‐5‐nitrophenyl The overall SNAr process acceptor appears giving to the involve most diastereoselectiveefficient ring closure, addition followed of the by nucleophile the 2‐fluoro to‐ the5‐cyano double compound bond methylene and finally of the 2‐ MBHfluoropyridine. substrate with The lossoverall of the process acetoxy appears group. to Following involve diastereoselective this addition, deprotonation addition of the of thenucleophile methine hydrogento the double from bond the addedmethylene nucleophile, of the SMBHNAr cyclization, substrate andwith elimination loss of the fuses acetoxy a disubstituted group. benzeneFollowing ring this to the addition, original

Molecules 2020, 25, x 3 of 17 Molecules 2020, 25, 5168 3 of 17 deprotonation of the methine hydrogen from the added nucleophile, SNAr cyclization, and elimination fuses a disubstituted benzene ring to the original aromatic nucleus. The exact sequence aromatic nucleus. The exact sequence of events for this process is unclear and is discussed in more detail of events for this process is unclear and is discussed in more detail below. In the current reactions, below. In the current reactions, the ﬁnal aromatization occurred by the elimination of benzenesulﬁnic the final aromatization occurred by the elimination of benzenesulfinic acid (PhSO2H) [6,16], nitrous acid (PhSO2H) [6,16], nitrous acid (HNO2)[9,17], or ethoxycarbonyl (CO2Et, presumably by hydrolysis acid (HNO2) [9,17], or ethoxycarbonyl (CO2Et, presumably by hydrolysis and decarboxylation) and decarboxylation) [9,18], all of which have precedent in the literature, although the loss of CO2Et in [9,18], all of which have precedent in the literature, although the loss of CO2Et in preference to the preference to the CN group was not expected. Aromatization by the elimination of CN is known [19,20], CN group was not expected. Aromatization by the elimination of CN is known [19,20], but it but it appears to be quite rare. appears to be quite rare.

H OH 3a (W = CH, X = CO2Et, Z = NO2) 3b (W = CH, X = CN, Z = NO2) Z X Z X O DABCO 3c (W = CH, X = CO Et, Z = CN) + 2 3d (W = CH, X = CN, Z = CN) W F CH3CN, 48 h, rt W F 86-98% 3e (W = N, X = CO2Et, Z = H) 1a (W = CH, Z = NO2) 2a (X = CO2Et) 1b (W = CH, Z = CN) 2b (X = CN) 1c (W = N, Z = H)

O H F O Ac2O 3b C reflux N NO 4 2

5 (W = CH, X = CO Et, Z = NO ) OAc 2 2 Ac O 6 (W = CH, X = CN, Z = NO ) 3a-e 2 Z X 2 TMSOTf, DCM 7 (W = CH, X = CO2Et, Z = CN) 0 oC, 30 min 8 (W = CH, X = CN, Z = CN) W F 95-98% 9 (W = N, X = CO2Et, Z = H) SchemeScheme 1. SynthesisSynthesis of of MBH MBH acetates acetates for for cyclization cyclization and rearranged product 4 (CCDC 2035023).

The syntheses are quite efficient, requiring only three steps and one chromatographic purification for the final products 15–19. The products were isolated in good to excellent yields (75–96%) and were fully characterized by spectroscopic methods. The IR spectra indicated the presence of the expected functional groups (conjugated CO2Et or CN, polarized conjugated double bonds, and NO2). The naphthalenes showed three one-proton doublets (J1,3 < 3 Hz or apparent singlets) for the isolated protons at C2, C4, and C5, a doublet of doublets (J1,2 and 1,3 = large and small) for the proton at C7, and a doublet (J1,2 > 8 Hz) for the proton at C8. The chemical shifts were in accordance with those expected for an electron-deficient aromatic system. The quinolines exhibited two doublets (J1,3 < 3 Hz) for the protons at C2 and C4 as well as characteristic chemical shifts and couplings for the protons on C5–C7 of the system. The 13C-NMR were appropriate with respect to the number of carbonyl, aromatic, and aliphatic carbons. The mass spectra showed an ion corresponding to the molecular weight of the compound, and elemental analyses confirmed the formulas and purity. Two basic mechanisms are possible for this domino transformation: (1) initial SNAr attack by the AMC anion on the aromatic ring, followed by conjugate addition to the side chain double bond with an elimination of acetoxy or (2) initial SN20-type displacement of acetoxy from the side chain, followed by a SNAr cyclization. Option 1 would unquestionably predict the final product of the reaction and would not depend on the selective formation of a single alkene from the SN20 process. Option 2 would require a diastereoselective addition to give the double bond geometry that positions the active methylene fragment cis to the SNAr acceptor ring. To probe this aspect of the transformation, a control experiment was performed wherein the anion of methyl phenylsulfonylacetate was generated in the presence of a mixture of 2-fluoro-5-nitrotoluene (20) and 2-cyano-1-(2-fluorophenyl)allyl acetate (21) to determine

Molecules 2020, 25, 5168 4 of 17 the relative reactivity of the side chain versus the aromatic ring. If the side chain reacted preferentially, we were also interested in assessing any E-Z diastereoselectivity in the allylically rearranged double bond. Under the standard conditions, a reaction occurred exclusively at the side chain of the MBH acetateMolecules and 2020 also, 25 aff, xorded only methyl (Z)-4-cyano-5-(2-fluorophenyl)-2-(phenylsulfonyl)-4-pentenoate4 of 17 Molecules 2020, 25, x 4 of 17 (22, 70%) having the added active methylene nucleophile positioned trans to the aromatic SNAr acceptor ring. This was confirmed by an X-rayTable structure 1. Formation of adduct of naphthalenes.22 (see Scheme 2 and the Supplementary Materials).Molecules 2020 Compound, 25, x 20 (93%) wasTable recovered 1. Formation unchanged of naphthalenes. from this experiment. Thus, the overall4 of 17 Molecules 2020, 25, x 4 of 17 Moleculessequence 2020 must, 25, x proceed via OptionOAc 2 above, followed by double bond equilibration prior to4 S NofAr 17 OAc Table 1. Formation of naphthalenes. 5 4 ring closure. Z X Z 6 5 4 3 X Table 1. FormationL Y of naphthalenes. Z 6 3 X Z X L Y Table 1. Formation of naphthalenes.o 7 2 OAc Table 1. FormationK2CO3, DMF, ofnaphthalenes. 23 C, 1 h F K CO , DMF, 23 oC, 1 h 7 58 4 1 2 OAc 2 3 Z 6 3 X Z F X 10 (L = COL 2Et,Y Y = CN) 85 Y4 1 OAc 10 (L = CO Et, Y = CN) Z 6 3 X Z X 11 (L = SOL 22Ph,Y Y = CO2Me) 5 4 Y 5-8o Z 6 7 15-183 X 2 Z 5-8X 1112K2 (LCO(LL ==3 , SO NODMF,Y2Ph,, Y 23 Y= =COC, CO 1Et) 2hMe) 15-18 F K CO , DMF,2 23 oC, 21 h 7 8 1 2 12102 (L =3 NOCO2Et,, Y Y= CO= CN)2Et) F 13 (L = SO2Ph,o Y = COPh) 7 8 Y2 1 K2CO13103 (L, DMF, = SOCO 23Ph,Et, C, Y 1= hCN)COPh) F5-81114 (L(L == SOSO22Ph,Ph, Y = COCOMe)2Me) 8 15-181 Y 10 (L1411 = (L CO = SOEt, YPh, = YCN) = COCOMe)Me) 5-812 (L =2 NO22, Y = CO2Et)2 15-18Y 11 (L12 = (L SO = Ph,NO Y, Y= CO= COMe)Et) Substrate5-8 AMC13 (L a =2 SO22Ph,L b Y =2 COPh)2 X 15-18Y Z Pdt (%Yield) 12 (L13 = (L NOa = SO, Y =Ph, COb Y =Et) COPh) Substrate AMC14 (L = 2SO2Ph,L Y2 = COMe)X Y Z Pdt (%Yield) 13 (L = SO Ph, Y = COPh) 1410 (L =2 SOCO2Ph,2 EtY = COMe)CO2Et CN NO2 15a (90) 14 (L10 = SO Ph,CO Y =2Et COMe) CO2Et CN NO2 15a (90) SubstrateOAc AMC a 2 L b X Y Z Pdt (%Yield) OAc 11 SO2Ph CO2Et CO2Me NO2 15b (91) Substrate AMC a L b X Y Z Pdt (%Yield) O2N CO2Et 11a SOb 2Ph CO2Et CO2Me NO2 15b (91) O N SubstrateCO Et AMCa Lb X Y Z Pdt (%Yield) 2 Substrate 2 AMC 1012 L CO NO2Et2 XCO 2Et Y COCN2Et Z NO2 Pdt (%Yield)15a15c (90)(94) OAc 1210 CONO2Et2 CO2Et COCN2Et NO2 15c15a (94)(90) 10 CO Et CO Et CN NO 15a (90) OAcF 10 1113 CO2SO2Et 2Ph CO2COEt 2Et CNCOCOPh 2Me NO2 2NO 2 15a 15b15d(90) (91)(96) O2N F CO2Et OAc5 11 1311 SO SOPh2Ph CO COEt 2EtCO MeCOCOPh2Me NO NO2 15b (91)15d15b (96)(91) O N CO Et 2 2 2 2 2 2 2 2 2 5 2 12 2 NO 2CO Et 2 CO Et 2NO 15c (94) O N CO Et 11 14 SO PhSO 2Ph CO COEt 2Et CO MeCOMe NONO 2 15b 15e(91) (92) 2 2 12 1412 NOSONO2 2Ph2 CO2COEt2Et CO2EtCOMeCO2Et NO 2 NO2 15c (94)15e15c (92)(94) F 13 SO2Ph CO2Et COPh NO2 15d (96) 12 10 NOCO2 2Et CO2EtCN CO2EtCN NO2NO 2 15c (94)16a (80) F 13 13 SO SOPh2Ph CO COEt2Et COPhCOPh NO NO2 15d (96)15d (96) 5 OAc 10 2CO2Et 2 CN CN 2 NO2 16a (80) F 2 2 2 5 OAc 13 1411 SO2PhSO 2Ph CO2COEtCN Et COPhCOCOMe 2Me NO2NO 2 15d 16b15e(96) (92) (86) O N CN 14 SO2Ph CO2Et COMe NO2 15e (92) 2 5 1114 SO2Ph COCN2Et COCOMe2Me NO2 16b15e (92)(86) O N CN 2 14 1012 SO2PhCONO 2Et2 CO2EtCN COMeCOCN 2Et NO2NO 2 15e 16a(92)16c (80)(88) 10 CO Et CN CN NO 16a (80) OAc 1210 CO2NO2Et2 CN COCN2Et 2 NO2 16c16a (88)(80) F 11 SO2Ph CN CO2Me NO2 16b (86) OAc 1011 13 COSO2SOEtPh 2Ph CN CN COCNMeCOPh NO NO2NO 2 16b16a(86) 16d(80) (90) O2N F CN 2 2 2 O N OAc6 CN 1311 SO2Ph CN COCOPh2Me NO2 16d16b (90)(86) 2 6 12 12 NONO2 CNCN CO EtCO2Et NO NO2 16c (88)16c (88) O N CN 11 SO2Ph2 CN CO22Me NO2 2 16b (86) 2 1214 SONO2Ph2 CN COMeCO2Et NO2 16c16e (88) F 13 2 2 16d 12 1413 SONO2SOPh2 2Ph CN CN COPhCO2COMeCOPhEt NO NO2 2NO 2 16c(90) 16d16e(88) (88)(90) F 6 13 SO2Ph CN COPh NO2 16d (90) F 14 10 SO2COPh2Et CNCO2Et COMeCN NO2 CN 16e (88)17a (80) 6 13 10 SO2PhCO 2Et CNCO 2Et COPhCN NO2CN 16d 17a(90) (80) 14 SO2Ph CN COMe NO2 16e (88) 6 OAc 11 SO2Ph CO2Et CO2Me CN 17b (82) OAc 10 14 COSO2Et2Ph CO2EtCN CNCOMe CN NO2 17a (80)16e (88) 11 SO2Ph CO2Et CO2Me CN 17b (82) NC CO2Et 14 SO2Ph CN COMe NO2 16e (88) 11 1012 SO COPhNO2Et2 CO COEt 2EtCO MeCOCN2Et CN CN 17b (82)17a17c (80)(83) NC CO2Et 2 2 2 1210 CONO2Et2 CO2Et COCN2Et CN 17c17a (83)(80) OAc 2 2 2 1012 1113 CONO2SOEt2 2Ph CO2COEt 2Et COCN2EtCOCOPh Me CN CN CN 17c17a(83) 17b17d(80) (82)(85) OAcF 11 SO2Ph CO2Et CO2Me CN 17b (82) NC CO2Et 13 SO2Ph CO2Et COPh CN 17d (85) OAc7 F 13 12 SO2PhNO2 CO2COEt2Et COPhCO2Et CN CN 17d (85)17c (83) NC CO Et 11 14 SO2PhSO 2Ph CO2COEt 2Et CO2MeCOMe CN CN 17b 17e(82) (84) 7 2 12 NO2 CO2Et CO2Et CN 17c (83) NC CO Et 14 14 SO2SOPh2Ph CO2COEt2Et COMeCOMe CN CN 17e (84)17e (84) 2 12 13 NOSO2 2Ph CO2COEt 2Et CO2COPhEt CN CN 17c 17d(83) (85) F 10 CO2Et CN CN CN 18a (75) 1013 SOCO22PhEt COCN2Et COPhCN CN 17d18a (75)(85) 7 FOAc 10 CO2Et CN CN CN 18a (75) 13 1411 SO2PhSO 2Ph CO2COEtCN 2Et COPhCOCOMe 2Me CN CN 17d 18b17e(85) (84) (78) F 7 OAc 11 1114 SO SOPh2Ph CNCOCN2Et CO MeCOCOMe2Me CN CN 18b (78)18b17e (84)(78) NC 7 CN 2 2 NC CN 14 1012 SO2PhCONO 2Et2 CO2EtCN COMeCOCN 2Et CN CN 17e 18a(84)18c (75)(80) 12 NO CN CO Et CN 18c (80) OAc 1210 CONO2 2Et2 CN 2 COCN2Et CN 18c18a (80)(75) 2 2 10 1113 CO2SOEt 2Ph CN CN CNCOCOPh Me CN CN 18a 18b18d(75) (78)(80) OAcF 13 SO2Ph CN COPh CN 18d (80) NC CN 1311 SO2Ph CN COCOPh2Me CN 18d18b (80)(78) 8 F OAc8 1214 SONO2Ph2 CN COMeCO2Et CN 18c18e (80)(79) NC 8 CN 1114 SOSO22PhPh CN COMeCO2Me CNCN 18e18b(79) (78) 1412 SONO2Ph2 CN COMeCO2Et CN 18e18c (79)(80) NC CN a b AMC = active12 methylene13 NO SOcompound.2 2Ph CN CNL = leavingCO2COPhEt group. CN CN 18c 18d(80) (80) F a a b b AMCAMC= active= active methylene methylene13 compound. SOcompound.2Ph L = leavingCNL = leaving group.COPh group. CN 18d (80) 8 F 13 14 SO2PhSO 2Ph CN CN COPhCOMe CN CN 18d 18e(80) (79) F8 The syntheses are quite efficient,14 requiringSO2Ph only CNthree stepsCOMe and oneCN chromatographic18e (79) 8 a AMC = active methylene compound. b L = leaving group. The syntheses are quite efficient,14 requiringSO2Ph onlyCN threeCOMe steps andCN one chromatographic18e (79) purification for the finala productsAMC = active 15– 19methylene. The products compound. were b L isolated = leaving in group. good to excellent yields (75– purification96%) and were for fullythe final acharacterized AMC products = active 15methylene by–19 spectroscopic. The compound. products methods. wereb L = leaving isolated The group.IR in spectra good toindicated excellent the yields presence (75– 96%)The and weresyntheses fully characterizedare quite efficient, by spectroscopic requiring methods.only three The steps IR spectra and indicatedone chromatographic the presence of theThe expected syntheses functional are quite groups efficient, (conjugated requiring CO2 Etonly or CN,three polarized steps and conjugated one chromatographic double bonds, ofpurification the expected for thefunctional final products groups 15 (conjugated–19. The products CO2Et wereor CN, isolated polarized in good conjugated to excellent double yields bonds, (75– purificationandThe NO syntheses2). The for naphthalenes the are final quite products efficient,showed 15– 19threerequiring. The one products‐proton only weredoubletsthree isolated steps (J1,3 8 Hz) for the proton at C8. The chemical shifts were in accordance 96%)of andthe wereexpected fully functional characterized groups by spectroscopic(conjugated CO methods.2Et or CN,The polarizedIR spectra conjugatedindicated the double presence bonds, protonandwith NO those at2). C7, The expected and naphthalenes a doublet for an ( Jshowed 1,2electron > 8 Hz) three‐ deficientfor theone proton‐proton aromatic at doublets C8. system. The (chemicalJ1,3 8 Hz) atfor C2 the and proton C4 asat C8.well The as chemicalcharacteristic shifts chemical were in accordance shifts and the isolated protons at C2, C4, and C5, a doublet of doublets (J1,2 and 1,3 = large and small) for the withproton those at C7, expected and a doublet for an (J 1,2electron > 8 Hz)‐ deficientfor the proton aromatic at C8. system. The chemical The quinolines shifts were exhibited in accordance two protonwith at thoseC7, and expected a doublet for (J 1,2an > 8electron Hz) for‐ deficientthe proton aromatic at C8. The system. chemical The shifts quinolines were in accordanceexhibited two doublets (J1,3 < 3 Hz) for the protons at C2 and C4 as well as characteristic chemical shifts and with doublets those expected(J1,3 < 3 Hz) for foran theelectron protons‐deficient at C2 andaromatic C4 as system. well as Thecharacteristic quinolines chemical exhibited shifts two and doublets (J1,3 < 3 Hz) for the protons at C2 and C4 as well as characteristic chemical shifts and

Molecules 2020, 25, x 5 of 17 Molecules 2020, 25, x 5 of 17 couplings for the protons on C5–C7 of the system. The 13C‐NMR were appropriate with respect to thecouplings number for of the carbonyl, protons aromatic,on C5–C7 andof the aliphatic system. Thecarbons. 13C‐NMR The weremass appropriate spectra showed with respectan ion to correspondingthe number ofto thecarbonyl, molecular aromatic, weight and of thealiphatic compound, carbons. and Theelemental mass analysesspectra showedconfirmed an the ion formulascorresponding and purity. to the molecular weight of the compound, and elemental analyses confirmed the Molecules 2020, 25, 5168 5 of 17 formulas and purity. Table 2. Formation of quinolines. OAc TableTable 2. 2. FormationFormation of of quinolines. quinolines. 5 4 OAcCO Et 3 CO2Et 2 L Y 6 5 4 CO Et 3 CO2Et 2 L Yo 7 6 2 K2CO3, DMF, 23 C, 1 h N N F K CO , DMF, 23 oC, 1 h 78 1 2 10 (L2 = CO3 2Et, Y = CN) N N F 8 Y 1 9191110 (L (L = =SO CO2Ph,2Et, Y Y= =CO CN)2Me) Y 9191211 (L (L = =NO SO2,2 YPh, = YCO = 2COEt)2Me) 1312 (L (L = =SO NO2Ph,2, YY == COCOPh)2Et) 1413 (L (L = =SO SO2Ph,2Ph, Y Y= =COMe) COPh) 14 (L = SO2Ph, Y = COMe) Substrate AMC a L b Y Pdt (%Yield) SubstrateSubstrate AMC AMCa a L bL b YY Pdt Pdt (%Yield) (%Yield) 10 CO2Et CN 19a (75) OAc 10 10 COCO2Et2Et CNCN 19a19a (75)(75) 11 SO2Ph CO2Me 19b (82) OAc CO2Et 11 11 SO2SOPh2Ph COCO22Me 19b19b (82)(82) 12 NO2 CO2Et ND c CO2Et 12 NO CO Et ND c 12 NO2 2 CO22Et ND c 13 SO2Ph COPh 19d (80) N F 13 SO2Ph COPh 19d (80) 13 SO2Ph COPh 19d (80) N 99F 14 SO2Ph COMe 19e (76) 14 SO2Ph COMe 19e (76) 9 14 SO2Ph COMe 19e (76) a AMC = active methylene compound. b L = leaving group. c ND = not done. a AMCa AMC = active= active methylene methylene compound. compound. bb L = leaving group. group.c NDc ND= =not not done. done. MoleculesTwo basic2020, 25 mechanisms, x are possible for this domino transformation: (1) initial SNAr attack 6by of 17 the AMCTwo anion basic on mechanisms the aromatic are ring, possible followed for thisby conjugate domino transformation: addition to the side(1) initial chain S doubleNAr attack bond by withthe AMCan elimination anion on ofthe acetoxy aromatic or ring,(2) initial followed SN2′‐ bytype conjugate displacement addition of acetoxyto the side from chain the doubleside chain, bond followedwith an byelimination a SNAr cyclization. of acetoxy orOption (2) initial 1 would SN2′‐ typeunquestionably displacement predict of acetoxy the final from product the side of chain, the reactionfollowed and by would a SNAr not cyclization. depend on Option the selective 1 would formation unquestionably of a single predict alkene the from final the product SN2′ process. of the Optionreaction 2 andwould would require not dependa diastereoselective on the selective addition formation to giveof a singlethe double alkene bondfrom thegeometry SN2′ process. that PhSO2 positionsOption 2the would active requiremethylene a diastereoselective fragment cis to the addition SNAr acceptor to give ring.the doubleTo probe bond this geometryaspect of thethat OAc MeO2C N transformation,positionsO the2N active a CH controlmethylene3 experiment fragmentCN ciswas to theperformed S Ar acceptor wherein ring. Tothe probe anion this aspectof methyl of the PhSO2 CO2Me H phenylsulfonylacetatetransformation, a wascontrol+ generated experiment in the presencewas performed of a mixture whereinC of 2‐ fluorothe ‐5anion‐nitrotoluene of methyl (20) o F F K2CO3, DMF, 23 C, 1 h N andphenylsulfonylacetate 2‐cyano‐1‐(2‐fluorophenyl)allyl was generated acetate in the (21 )presence to determine of a themixture relativeF of reactivity2‐fluoro‐5 of‐nitrotoluene the side chain (20 ) 20 21 versusand 2 ‐thecyano aromatic‐1‐(2‐fluorophenyl)allyl ring. If the side acetate chain ( 21reacted) to determine preferentially, the relative we reactivitywere also of interested the side chain in assessingversus theany aromatic E‐Z diastereoselectivity ring. If the side inchain the reactedallylically preferentially, rearranged22 wedouble were bond. also interestedUnder the in standardassessing conditions, any E‐Z adiastereoselectivity reaction occurred exclusively in the allylically at the side rearranged chain of thedouble MBH bond.acetate Under and also the affordedstandard only conditions, methyl a (reactionZ)‐4‐cyano occurred‐5‐(2‐fluorophenyl) exclusively at‐2 ‐the(phenylsulfonyl) side chain of ‐the4‐pentenoate MBH acetate (22 and, 70%) also havingafforded the addedonly methyl active methylene(Z)‐4‐cyano nucleophile‐5‐(2‐fluorophenyl) positioned‐2‐ trans(phenylsulfonyl) to the aromatic‐4‐pentenoate SNAr acceptor (22, ring.70%) SchemeScheme 2.2. ControlControl experiment: experiment: Selective Selective reaction reaction of of the the MBH MBH acetate acetate and and formation formation of theof theZ alkene Z alkene22 Thishaving was the confirmed added active by an methylene X‐ray structure nucleophile of adduct positioned 22 (see trans Scheme to the aromatic2 and the SN ArSupplementary acceptor ring. (CCDC22 (CCDC 2035022). 2035022). Materials).This was Compoundconfirmed by20 (93%)an X‐ raywas structure recovered of unchanged adduct 22 from (see thisScheme experiment. 2 and the Thus, Supplementary the overall

Materials). Compound 20 (93%) was recovered unchanged from this experiment. Thus, the overallN sequenceAnalysisAnalysis must ofproceed of the the reactant viareactant Option in the in S N2the 2above,0 reaction SN2′ followedreaction (Option by(Option 2 above) double demands2 bondabove) equilibration that demands the starting that prior conformation the to startingS Ar ringsequenceminimizesconformation closure. must the stericminimizesproceed interaction via the Option steric between 2 interactionabove, the followed aryl, between the acetoxy,by doublethe andaryl, bond the the electron-withdrawing equilibrationacetoxy, and prior the electronto groupSNAr ‐ ring closure. (EWGwithdrawing= CO2Et group or CN) (EWG (Scheme = CO2).2 AnEt or earlier CN) study (Scheme describing 2). An theearlier reaction study of describing an acrylate-derived the reaction MBH of alcoholan acrylate with‐derived HBr proposed MBH alcohol conformation with HBr23 (Figure proposed2), which conformation has an additional 23 (Figure stabilizing 2), which H-bond has an betweenadditional the stabilizing OH and the H‐ EWG,bond between to rationalize the OH the and products the EWG, [20]. Thisto rationalize model would the products favor formation [20]. This of themodel alkene would that favor places formation the incoming of the active alkene methylene that places fragment the incoming cis to the active 2-fluoro-5-nitrophenyl methylene fragment moiety cis into thethe product. 2‐fluoro‐ With5‐nitrophenyl the current moiety substrates, in the H-bonding product. With is not the possible, current and substrates, so the large H‐bonding acetoxy group is not waspossible, expected and toso orient the large away acetoxy from thegroup EWG was (perhaps expected more to orient so for away CO2Et from than the CN) EWG to minimize (perhaps steric more crowdingso for CO (Scheme2Et than3). CN) Then, to an minimize initial S N steric20 reaction crowding involving (Scheme a syn 3). orientation Then, an of initial the nucleophile SN2′ reaction and leavinginvolving group a syn invoked orientation in some of earlierthe nucleophile work [21, 22and] would leaving give group an adduct invoked with in thesome AMC earlier fragment work trans[21,22] to would the SNAr give acceptor an adduct ring aswith in thethe aforementioned AMC fragment competitive trans to the reaction. SNAr acceptor Thus, in ring order as for in thethe cyclizationaforementioned to occur, competitive the initial reaction. Michael Thus, adduct in order22 must for equilibrate the cyclization to bring to occur, the nucleophilic the initial Michael center cisadduct to the 22 activated must equilibrate aromatic ringto bring to allow the nucleophilic cyclization by center an intramolecular cis to the activated SNAr reaction. aromatic Possible ring to mechanisms for this isomerization are discussed below. allow cyclization by an intramolecular SNAr reaction. Possible mechanisms for this isomerization are discussed below.

H O OEt H O

Ar 23

Figure 2. Conformation of an MBH alcohol with a stabilizing H‐bond.

In reactions at the side chain allylic moiety, there are two possible scenarios to explain the addition to the MBH acetate. The first [22] invokes an SN2′ process where a nucleophile attacks C1 (unsubstituted) of the allylic moiety, resulting in an accumulation of electron density on the opposite face of the molecule at C2. Then, this electron density is responsible for assisting in the departure of the acetoxy leaving group at C3. This process has been used to rationalize the reported preference for a syn orientation between the incoming nucleophile and the leaving group often seen in the reaction [23–25], although exceptions are known [26] with certain Nu–/L– combinations. The second scenario [27] claims that there is no justification for a syn orientation between the nucleophile and the leaving group. In fact, in highly substituted derivatives, such as 5–9, it has been suggested that the formation of a stabilized carbocation is more likely, in which case the avoidance of steric interactions guides the transformation to give the final product stereochemistry. The SN2′ initiated mechanism is depicted in Scheme 3 for the reaction of 6 with 11 to give 16b. The initial conformation of 6 would allow minimal steric interaction between the groups on the

Molecules 2020, 25, x 6 of 17

PhSO2

OAc MeO2C O2N CH3 CN PhSO2 CO2Me H + C o F F K2CO3, DMF, 23 C, 1 h N F 20 21

Scheme 2. Control experiment: Selective reaction of the MBH acetate and formation of the Z alkene 22 (CCDC 2035022).

Analysis of the reactant in the SN2′ reaction (Option 2 above) demands that the starting conformation minimizes the steric interaction between the aryl, the acetoxy, and the electron‐ withdrawing group (EWG = CO2Et or CN) (Scheme 2). An earlier study describing the reaction of an acrylate‐derived MBH alcohol with HBr proposed conformation 23 (Figure 2), which has an additional stabilizing H‐bond between the OH and the EWG, to rationalize the products [20]. This model would favor formation of the alkene that places the incoming active methylene fragment cis to the 2‐fluoro‐5‐nitrophenyl moiety in the product. With the current substrates, H‐bonding is not possible, and so the large acetoxy group was expected to orient away from the EWG (perhaps more so for CO2Et than CN) to minimize steric crowding (Scheme 3). Then, an initial SN2′ reaction involving a syn orientation of the nucleophile and leaving group invoked in some earlier work [21,22] would give an adduct with the AMC fragment trans to the SNAr acceptor ring as in the aforementionedMolecules 2020, 25, xcompetitive reaction. Thus, in order for the cyclization to occur, the initial Michael7 of 17 adduct 22 must equilibrate to bring the nucleophilic center cis to the activated aromatic ring to allow cyclization by an intramolecular SNAr reaction. Possible mechanisms for this isomerization Moleculesallylic side2020 ,chain.25, 5168 In this conformation, the acetoxy substituent should hinder approach to the6 oftop 17 are discussed below. face while the planar aromatic ring does not significantly block the bottom face. Introduction of the nucleophile to the bottom face would result in an accumulation of negative charge on the top face of the allylic system, as shown in A. RotationH of the acetoxy group 120° would position it anti to the accumulated negative charge and move theO substrateOEt H 2‐fluoro‐5‐nitrophenyl (Ar) moiety away O from the newly added nucleophile to give B. Then, the elimination of acetoxy would deliver the Z alkene 22. Subsequent equilibration of the double bond geometry to generate 24 and deprotonation of the residual active methine proton to give C wouldAr be followed by ipso attack at the fluorine‐ bearing aromatic carbon to afford Meisenheimer23 intermediate D. Rearomatization by loss of fluoride should then lead to 25. After ring closure, a conformation aligned for the elimination of benzenesulfinic acidFigureFigure by an2. 2. Conformation E2Conformation process would of of an an MBH afford MBH alcohol alcohol the fused with with aaromatic a stabilizing stabilizing compound H H-bond.‐bond. 16b.

In reactions at the side chainSO2Ph allylic moiety, there are two possible scenarios to explain the H OAc H OAc Ar H addition to the MBH acetate. The first [22] invokes an SN2′ processo where a nucleophile attacks C1 NC CO2Me NC SO2Ph 120 NC SO2Ph (unsubstituted) of the allylic moiety, resulting in an accumulation of electron density on the Ar bond opposite face of the molecule at C2. Then, thisAr electronCO Me density is responsibleOAc for COassisting2Me in the B: 2 rotation departure of the6 acetoxy11 leaving group at C3. AThis process has been used to rationalizeB the reported preference for a syn orientation between the incoming nucleophile and the leaving group often seen – in the reaction [23–25], althoughSO2Ph exceptions are known [26] with certain Nu–/L–OAc– combinations. The NC double second scenario [27] claims COthat2Me there is no justification for a syn orientation between the F bond SNAr B: NC SO2Ph NC SO2Ph nucleophile and theH leaving group. In fact, in highly substituted derivatives, such as 5–9, it has been addn H Ar Ar H suggested that the formation of a stabilized carbocationCO 2isMe more equillikely, in which caseCO the2Me avoidance of steric interactions guidesO N the transformation to give the final product stereochemistry. 2 C 24 22 The SN2′ initiated mechanism is depicted in Scheme 3 for the reaction of 6 with 11 to give 16b. The initial conformation ofSO 26Ph would allow minimalH stericSO2Ph interaction between the groups on the NC NC elim elim CO2Me H CO2Me 16b H – H –PhSO H F –F B: 2

O N O N 2 D 2 25

Scheme 3. SN2 mechanism leading to the formation of naphthalenes from MBH acetates. Scheme 3. SN2′0 mechanism leading to the formation of naphthalenes from MBH acetates.

InThe reactions second mechanistic at the side scenario, chain allylic illustrated moiety, in there Scheme are 4, two begins possible with loss scenarios of the toacetoxy explain group the additionto form stabilized to the MBH 3‐arylallylic acetate. The cations first [E22 and] invokes F [27]. an At SN this20 process point, whereit may aappear nucleophile that addition attacks C1to (unsubstituted)carbocation F should of the allylicbe easier, moiety, since resulting the alkene in an terminus accumulation is less of hindered. electron densityFurthermore, on the since opposite the faceEWG of should the molecule not be at coplanar C2. Then, with this electronthe allylic density cation, is responsible it should forhave assisting less steric in the influence departure on of the acetoxyreaction, leaving and the group larger at bond C3. This angles process around has beenthe carbocation used to rationalize should thepermit reported the formation preference of for both a syn E orientationand F. Addition between of thethe incomingactive methylene nucleophile nucleophile and the leaving would group then oftenlead seento both in the 22 reaction and 24, [ 23which–25], althoughcould cyclize exceptions as above. are In known both [examples26] with certain cited in Nu this–/L paper,– combinations. the alkene The with second the nucleophile scenario [27 trans] claims to thatthe S thereNAr isaromatic no justification system forwas a synisolated orientation with no between contamination the nucleophile by the and cis. the This leaving observation group. Incould fact, indisqualify highly substituted this mechanism, derivatives, but if such24 cyclizes as 5–9 ,very it has rapidly, been suggested it may not that be the possible formation to detect of a stabilizedor isolate carbocationthis short‐lived is more intermediate. likely, in which case the avoidance of steric interactions guides the transformation to give the final product stereochemistry. The S 2 initiatedH mechanismOAc is depicted in Scheme3 for the reaction of 6 with 11 to give 16b. N 0 –OAc– The initial conformationNC of 6 would allow minimalNC steric interactionor betweenNC the groups on the allylic H Ar Ar H side chain. In this conformation,Ar the acetoxy substituent should hinder approach to the top face while the planar aromatic ring6 does not significantly block theE bottom face. IntroductionF of the nucleophile to the bottom face would result in an accumulation of negativeSO2Ph charge on the topSO2Ph face of the allylic system, as shown in A. Rotation of the acetoxy group 120CO◦ 2wouldMe position it antiCO2Me to the accumulated negative charge and moveelim the substrateSNAr 2-fluoro-5-nitrophenylB: (Ar)equil moiety away from the newly added nucleophile to give16b B. Then,25 the elimination of acetoxy24 would deliver the22Z alkene 22 . Subsequent equilibrationScheme of4. Carbocation the double mechanism bond geometry leading to to generate the formation24 and of naphthalenes deprotonation from of MBH the residual acetates. active methine proton to give C would be followed by ipso attack at the fluorine-bearing aromatic carbon to afford Meisenheimer intermediate D. Rearomatization by loss of fluoride should then lead to 25.

Molecules 2020, 25, x 7 of 17 allylic side chain. In this conformation, the acetoxy substituent should hinder approach to the top face while the planar aromatic ring does not significantly block the bottom face. Introduction of the nucleophile to the bottom face would result in an accumulation of negative charge on the top face of the allylic system, as shown in A. Rotation of the acetoxy group 120° would position it anti to the accumulated negative charge and move the substrate 2‐fluoro‐5‐nitrophenyl (Ar) moiety away from the newly added nucleophile to give B. Then, the elimination of acetoxy would deliver the Z alkene 22. Subsequent equilibration of the double bond geometry to generate 24 and deprotonation of the residual active methine proton to give C would be followed by ipso attack at the fluorine‐ bearing aromatic carbon to afford Meisenheimer intermediate D. Rearomatization by loss of fluoride should then lead to 25. After ring closure, a conformation aligned for the elimination of benzenesulfinic acid by an E2 process would afford the fused aromatic compound 16b.

SO2Ph H OAc H OAc Ar H o NC CO2Me NC SO2Ph 120 NC SO2Ph Ar bond Ar CO Me OAc CO2Me B: 2 rotation 6 11 A B

– SO2Ph –OAc NC double CO2Me F bond SNAr B: NC SO2Ph NC SO2Ph H addn H Ar Ar H CO2Me equil CO2Me O N 2 C 24 22

SO2Ph H SO2Ph NC NC elim elim CO2Me H CO2Me 16b H – H –PhSO H F –F B: 2

O N O N 2 D 2 25 Molecules 2020, 25, 5168 7 of 17 Scheme 3. SN2′ mechanism leading to the formation of naphthalenes from MBH acetates.

AfterThe second ring closure, mechanistic a conformation scenario, aligned illustrated for the elimination in Scheme of 4, benzenesulfinic begins with loss acid of by the an acetoxy E2 process group to formwould stabilized afford the 3 fused‐arylallylic aromatic cations compound E and16b F. [27]. At this point, it may appear that addition to The second mechanistic scenario, illustrated in Scheme4, begins with loss of the acetoxy group carbocation F should be easier, since the alkene terminus is less hindered. Furthermore, since the to form stabilized 3-arylallylic cations E and F [27]. At this point, it may appear that addition to EWG should not be coplanar with the allylic cation, it should have less steric influence on the carbocation F should be easier, since the alkene terminus is less hindered. Furthermore, since the EWG reaction,should and not the be coplanar larger bond with theangles allylic around cation, itthe should carbocation have less stericshould influence permit on the the formation reaction, and of the both E and largerF. Addition bond angles of the around active the methylene carbocation nucleophile should permit would the formation then lead of both to bothE and 22F. Additionand 24, ofwhich couldthe cyclize active as methylene above. In nucleophile both examples would cited then in lead this to paper, both 22 theand alkene24, which with could the nucleophile cyclize as above. trans to the SInNAr both aromatic examples system cited in thiswas paper, isolated the alkenewith no with contamination the nucleophile by trans the to thecis. SThisNAr aromaticobservation system could disqualifywas isolated this mechanism, with no contamination but if 24 cyclizes by the cis.very This rapidly, observation it may could not be disqualify possible this to detect mechanism, or isolate this shortbut if‐24livedcyclizes intermediate. very rapidly, it may not be possible to detect or isolate this short-lived intermediate.

H OAc –OAc– NC NC or NC H Ar Ar H Ar 6 E F SO2Ph SO2Ph

CO2Me CO2Me equil Molecules 2020, 25, x elim SNAr B: 8 of 17 16b 25 24 22

SchemeScheme 4. Carbocation 4. Carbocation mechanism mechanism leading leading to to the the formation of of naphthalenes naphthalenes from from MBH MBH acetates. acetates. Two pathways can be envisioned for the equilibration of 22 to 24 that must occur before SNAr cyclization: (1) a well‐precedented Michael‐reverse Michael process [28–32] involving the excess Two pathways can be envisioned for the equilibration of 22 to 24 that must occur before SNAr AMCcyclization: or perhaps (1) a well-precedented (2) an intramolecular Michael-reverse addition–elimination Michael process [ 28reaction–32] involving (Scheme the 5). excess This AMC alternative processor perhaps would (2) an involve intramolecular loss of the addition–elimination acidic methine proton reaction from (Scheme 22 and5). addition This alternative of the processresulting anion Gwould to the involve benzylic loss double of the acidic bond methine to give protonH. This from may22 beand possible, addition since of the the resulting electron anion‐deficientG to the aromatic ringbenzylic should double stabilize bond to the give benzylicH. This may anion. be possible, Then, bond since the rotation electron-deﬁcient to give I aromaticand ring ring opening should would deliverstabilize the the benzylicanion needed anion. Then, for bondcyclization. rotation Once to give equilibrationI and ring opening occurs, would ring deliver closure the anion to 25 and eliminationneeded for cyclization.to generate Once 16b equilibration should be occurs,facile. Even ring closure if the toequilibrium25 and elimination does not to generate strongly16b favor the requiredshould be alkene facile. Evengeometry, if the equilibrium product formation does not strongly should favor gradually the required siphon alkene the initial geometry, adduct product over to the formation should gradually siphon the initial adduct over to the fused aromatic target. fused aromatic target.

SO2Ph

O2N CN excess CO2Me B: 22 SO Ph Michael-reverse Michael F 2

B: 24 CO2Me

O N CN O N SO Ph 2 O2N SO2Ph 2 2 CN CO Me F CN CO2Me F 2 F PhO2S CO2Me G H I

O2N CN B: SNAr 16b – –PhSO2H –F

PhSO2 CO2Me 25

SchemeScheme 5. 5.Possible Possible mechanisms mechanisms for double for double bond bond equilibration. equilibration.

Addition to the substrates with formation of the Z alkene (EWG and added AMC trans) was confirmed by both a side reaction observed during the synthesis to form acetate 4 and a control experiment to form 15 (Scheme 2). The formation of a single product has significant precedent in the case of EWG = CO2Et, but it is less probable for the sterically smaller EWG = CN group [33]. Unfortunately, the ester intermediate, while a single isomer, was not a solid and could not be subjected to X‐ray structure analysis. Additionally, Nuclear Overhauser enhancement (NOE) measurements were inconclusive. Nevertheless, products incorporating both EWGs formed in high yields. In cases where the initial addition yields the Z alkene, a reversible Michael reaction [28–32] or intramolecular isomerization could establish an E–Z equilibrium that would eventually cyclize and eliminate H–L to afford the aromatic products. A similar rationale can be applied to the pyridine‐containing substrates that lead to quinolines. The stereoselective formation of the alkenes with the added nucleophile cis to the aromatic ring has been observed in the past with small nucleophiles [21,34–40]. This has been confirmed by spectral characterization, and in one instance, X‐ray analysis [41]. However, our results, using large stabilized nucleophiles, appear to differ from these earlier findings.

3. Material and Methods

3.1. General Methods

Unless otherwise indicated, all reactions were carried out under dry N2 in oven‐dried glassware. All reagents and solvents were used as received. Reactions were monitored by thin layer chromatography on silica gel GF plates (Analtech No 21521, Newark, DE, USA). Preparative separations were performed by flash chromatography on silica gel (Davisil®, grade 62, 60–200 mesh, Sorbent Technologies, Norcross, GA, USA) containing UV‐active phosphor (Sorbent Technologies No. UV‐05) slurry packed into quartz columns. Band elution for all chromatographic

Molecules 2020, 25, 5168 8 of 17

Addition to the substrates with formation of the Z alkene (EWG and added AMC trans) was confirmed by both a side reaction observed during the synthesis to form acetate 4 and a control experiment to form 15 (Scheme2). The formation of a single product has significant precedent in the case of EWG = CO2Et, but it is less probable for the sterically smaller EWG = CN group [33]. Unfortunately, the ester intermediate, while a single isomer, was not a solid and could not be subjected to X-ray structure analysis. Additionally, Nuclear Overhauser enhancement (NOE) measurements were inconclusive. Nevertheless, products incorporating both EWGs formed in high yields. In cases where the initial addition yields the Z alkene, a reversible Michael reaction [28–32] or intramolecular isomerization could establish an E–Z equilibrium that would eventually cyclize and eliminate H–L to afford the aromatic products. A similar rationale can be applied to the pyridine-containing substrates that lead to quinolines. The stereoselective formation of the alkenes with the added nucleophile cis to the aromatic ring has been observed in the past with small nucleophiles [21,34–40]. This has been confirmed by spectral characterization, and in one instance, X-ray analysis [41]. However, our results, using large stabilized nucleophiles, appear to differ from these earlier findings.

3. Material and Methods

3.1. General Methods

Unless otherwise indicated, all reactions were carried out under dry N2 in oven-dried glassware. All reagents and solvents were used as received. Reactions were monitored by thin layer chromatography on silica gel GF plates (Analtech No 21521, Newark, DE, USA). Preparative separations were performed by flash chromatography on silica gel (Davisil®, grade 62, 60–200 mesh, Sorbent Technologies, Norcross, GA, USA) containing UV-active phosphor (Sorbent Technologies No. UV-05) slurry packed into quartz columns. Band elution for all chromatographic separations was monitored using a hand-held UV lamp (Fisher Scientific, Pittsburgh, PA, USA). Wash solutions used in work-up procedures were all aqueous. Melting points were obtained using a MEL-TEMP apparatus (Cambridge, MA, USA) and are uncorrected. FT-IR spectra were run using a Varian Scimitar FTS 800 spectrophotometer (Randolph, MA, USA) as thin films on NaCl disks. 1H- and 13C-NMR spectra were measured using a Bruker Avance 400 system (Billerica, MA, USA) in the indicated solvents at 400 MHz and 101 MHz, respectively, with (CH3)4Si as the internal standard; coupling constants (J) are given in Hz. Low-resolution mass spectra were obtained using a Hewlett-Packard Model 1800A GCD GC-MS system (Palo Alto, CA, USA). Details of the X-ray structure determinations are given in the Supplementary Materials. Elemental analyses ( 0.4%) were determined by Atlantic Microlabs ± (Norcross, GA, USA).

3.2. Representative Procedure for the Synthesis of MBH Alcohols (3a–e) To a stirred solution of the aldehyde 1a–c (1 equiv.) and DABCO (1.2 equiv.) in ACN (8 mL) under N2 was added ethyl acrylate (2a) or acrylonitrile (2b) (2 equiv.) at 23 ◦C. After 24–48 h, TLC analysis (10% EtOAc/hexane) indicated the reaction was complete. The solution was added to water, and the mixture was extracted with EtOAc (3 25 mL). The combined organic layers were washed with 0.5 M HCl × (2 10 mL), saturated NaHCO , and saturated NaCl and then dried (Na SO ). Removal of the solvent × 3 2 4 under vacuum resulted in pure MBH alcohols 3a–e, which were used without further puriﬁcation.

3.3. Synthesis of (E)-2-cyano-3-(2-fluoro-5-nitrophenyl)allyl acetate (4) A solution of the MBH alcohol 3b (1.11 g, 5 mmol) was dissolved in acetic anhydride (5.0 mL) and boiled for 6 h. The mixture was cooled, concentrated under vacuum, and the residue was dissolved in DCM (25 mL). The solution was washed with saturated NaHCO (3 50 mL) and water, dried 3 × (Na2SO4), and concentrated under vacuum to afford 4 (1.13 g, 4.3 mmol, 86%) as an off-white solid, m.p. 1 1 78–79 ◦C. IR: 2222, 1749, 1621, 1530, 1352 cm− ; H-NMR (400 MHz, CDCl3): δ 8.99 (dd, J = 6.3, 2.8 Hz, 1H), 8.35 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.43 (s, 1H), 7.33 (t, J = 9.0 Hz, 1H), 4.22 (d, J = 1.3 Hz, 2H), Molecules 2020, 25, 5168 9 of 17

13 2.19 (s, 3H); C-NMR (101 MHz, CDCl3): δ 170.1, 163.5 (d, J = 263.3 Hz), 144.4, 135.9 (d, J = 5.4 Hz), 127.8 (d, J = 10.7 Hz), 125.4 (d, J = 3.7 Hz), 122.1 (d, J = 14.3 Hz), 116.1 (d, J = 24.4 Hz), 115.5, 112.4, + (d, J = 2.1 Hz), 64.2, 20.7; MS (EI): m/z 264 [M] ; Anal. Calcd for C12H9FN2O4: C 54.55; H, 3.43; N, 10.60. Found: C, 54.58; H, 3.45; N, 10.53. The X-ray structure of 4 (CCDC 2035023) was obtained and the thermal elipsoid plot is shown in Scheme1 and the Supplementary Materials.

3.4. Representative procedure for the Synthesis of MBH Acetates (5–9) A solution of the MBH alcohol 3a–d (1 equiv.) in DCM (2 mL) was treated with acetic anhydride (1.5 equiv.) at 0 ◦C, followed by a 1 M solution of TMSOTf in DCM (20 µL/mmol substrate) [15]. The MBH alcohol 3e (1 equiv.) required acetic anhydride (3 equiv.) and 1 M TMSOTf in DCM (60 µL/mmol substrate). After 30 min, TLC analysis (10% ether in hexane) showed the reaction was complete. The reaction mixture was added to saturated NaHCO3, and the mixture was extracted with DCM (3 5 mL). The organic extracts were washed with water, dried (Na SO ), and evaporated under × 2 4 vacuum to afford clean MBH acetates 5–9, which did not require further purification. After optimization, this procedure was scaled up by a factor of five with no significant decrease in yield.

3.4.1. Ethyl 2-(acetoxy (2-ﬂuoro-5-nitrophenyl)methyl)acrylate (5)

1 1 Yield: 305 mg (0.98 mmol, 98%) as a colorless oil; IR: 1751, 1723, 1639, 1532, 1351 cm− ; H-NMR (400 MHz, CDCl3): δ 8.26 (dd, J = 6.0, 2.8 Hz, 1H), 8.23 (ddd, J = 8.9, 4.3, 2.9 Hz, 1H), 7.22 (t, J = 8.9 Hz, 2H), 6.91 (s, 1H), 6.54 (s, 1H), 4.18 (qd, J = 7.1, 1.3 Hz, 2H), 2.15 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 169.0, 164.2, 163.7 (d, J = 232.5 Hz ), 144.2 (d, J = 2.9 Hz), 137.4, 127.5, 127.4 (d, J = 3.1 Hz), 126.0 (d, J = 10.5 Hz), 125.1 (d, J = 5.4 Hz), 116.9 (d, J = 24.5 Hz), 66.6 (d, J = 2.8 Hz), 61.3, + 20.8 (d, J = 1.6 Hz), 14.0; MS: m/z 311 [M] ·; Anal. Calcd for C14H14FNO6: C, 54.02; H, 4.53; N, 4.50. Found: C, 53.94; H, 4.54; N, 4.39.

3.4.2. 2-Cyano-1-(2-ﬂuoro-5-nitrophenyl) allyl acetate (6)

Yield: 259 mg (0.98 mmol, 98%) as oﬀ-white crystals, m.p. 66–67 ◦C; IR: 2232, 1759, 1632, 1532, 1 1 1535, 1352 cm− ; H-NMR (400 MHz, CDCl3): δ 8.42 (dd, J = 6.1, 2.8 Hz, 1H), 8.31 (ddd, J = 9.0, 4.4, 2.8 Hz, 1H), 7.29 (t, J = 9.0 Hz, 1H), 6.64 (s, 1H), 6.19 (s, 1H), 6.18 (s, 1H), 2.26 (s, 3H); 13C-NMR (101 MHz, CDCl3): δ 168.8, 163.1 (d, J = 260.1 Hz), 144.7, 133.7, 126.8 (d, J = 10.3 Hz), 125.3 (d, J = 15.1 Hz), 124.1 + (d, J = 4.9 Hz), 120.9, 117.1 (d, J = 23.7 Hz), 115.2, 67.8 (d, J = 3.0 Hz), 20.8; MS: m/z 264 [M] ·; Anal. Calcd for C12H9FN2O4: C, 54.55; H, 3.43; N, 10.60. Found: C, 54.63; H, 3.45; N,10.52.

3.4.3. Ethyl 2-(acetoxy(5-cyano-2-ﬂuorophenyl)methyl)acrylate (7)

1 1 Yield: 285 mg (0.98 mmol, 98%) as a colorless oil; IR: 2234, 1752, 1729, 1637 cm− ; H-NMR (400 MHz, CDCl3): δ 7.69 (dd, J = 6.6, 2.1 Hz, 1H), 7.64 (ddd, J = 8.5, 4.7, 2.1 Hz, 1H), 7.19 (t, J = 9.3 Hz, 1H), 6.88 (s, 1H), 6.51 (s, 1H), 5.92 (s, 1H), 4.19 (q, J = 7.1 Hz, 2H), 2.15 (s, 3H), 1.25 (t, J = 7.1 Hz, 3H); 13 C-NMR (101 MHz, CDCl3): δ 169.0, 164.2, 162.6 (d, J = 260.3 Hz), 137.6, 134.4 (d, J = 9.8 Hz), 133.6 (d, J = 4.8 Hz), 127.7 (d, J = 14.9 Hz), 127.3, 117.8, 117.2 (d, J = 23.4 Hz), 108.7 (d, J = 4.0 Hz), 66.6 + (d, J = 2.9 Hz), 61.3, 20.8, 14.0; MS: m/z 291 [M] ·; Anal. Calcd for C15H14FNO4: C, 61.85; H, 4.84; N, 4.81. Found: C, 61.77; H, 4.86; N, 4.85.

3.4.4. 2-Cyano-1-(5-cyano-2-ﬂuorophenyl)allyl acetate (8)

1 Yield: 259 mg (0.98 mmol, 98%) as oﬀ-white crystals, m.p. 74–75 ◦C; IR: 2255, 2235, 1757, 1613 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 7.86 (dd, J = 6.6, 2.1 Hz, 1H), 7.72 (ddd, J = 8.4, 4.8, 2.1 Hz, 1H), 7.24 13 (t, J = 9.3 Hz, 1H), 6.60 (s, 1H), 6.16 (s, 1H), 6.15 (s, 1H), 2.24 (s, 3H); C-NMR (101 MHz, CDCl3): δ 168.8, 161.9 (d, J = 259.0 Hz), 135.2 (d, J = 9.8 Hz), 133.7, 132.3 (d, J = 4.3 Hz), 125.6 (d, J = 14.2 Hz), 120.9, 117.44 (d, J = 22.8 Hz), 117.41, 115.3, 109.6 (d, J = 4.0 Hz), 67.8 (d, J = 3.2 Hz), 20.8; MS: m/z 244 + [M] ·; Anal. Calcd for C13H9FN2O2: C, 63.93; H, 3.71; N, 11.47. Found: C, 63.81; H, 3.77; N, 11.35. Molecules 2020, 25, 5168 10 of 17

3.4.5. Ethyl 2-(acetoxy(2-ﬂuoropyridin-3-yl)methyl)acrylate (9)

1 1 Yield: 254 mg (0.95 mmol, 95%) as a colorless oil; IR: 1758, 1727, 1637 cm− ; H-NMR (400 MHz, CDCl3): δ 8.19 (m, 1H), 7.81 (ddd, J = 9.4, 7.4, 2.0 Hz, 1H), 7.20 (ddd, J = 6.5, 4.8, 1.6 Hz, 1H), 6.81 (s, 1H), 6.50 (s, 1H), 5.92 (s, 1H), 4.18 (q, J = 7.1 Hz, 2H), 2.14 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 169.1, 164.4, 161.0 (d, J = 241.9 Hz), 147.6 (d, J = 14.9 Hz), 140.1 (d, J = 4.3 Hz), 137.5, 127.2 (d, J = 1.2 Hz), 121.4 (d, J = 4.4 Hz), 120.5 (d, J = 27.9 Hz), 67.8, 61.2, 20.8, 14.0; MS: m/z 267 + [M] ·; Anal. Calcd for C13H14FNO4: C, 58.42; H, 5.28; N, 5.24. Found: C, 58.33; H, 5.25; N, 5.16.

3.5. Representative Procedure for the Synthesis of Naphthalene and Quinoline Analogs Using MBH Acetates and Active Methylene Compounds

A 50 mL, round-bottomed flask equipped with a condenser, stir bar, and N2 inlet, was charged with an MBH acetate (1 mmol) in DMF (2 mL). The corresponding active methylene compound (1.5 mmol) in DMF (1 mL) and K2CO3 (207 mg, 1.5 mmol) were added at room temperature with continued stirring. For naphthalenes 15–18, the reaction was complete in 1 h. For quinolines 19, the reaction was stirred at room temperature for 1 h and gradually heated to 90 ◦C with stirring for 6 h. In each case, TLC analysis (30% EtOAc in hexane) indicated the reaction was complete. The solution was poured into de-ionized water (15 mL), and the mixture was extracted with EtOAc (3 25 mL). The combined × organic layers were washed with saturated NaCl and dried (Na2SO4). Removal of the solvent under vacuum gave the crude product, which was purified by silica gel column chromatography to afford the pure naphthalene/quinoline derivatives.

3.5.1. Ethyl 4-cyano-7-nitro-2-naphthoate (15a) from 5 and ethyl cyanoacetate (10)

1 Yield: 243 mg (0.90 mmol, 90%) as an oﬀ-white solid, m.p. 77–79 ◦C; IR: 1716, 1536, 1349 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 8.91 (d, J = 2.3 Hz, 2H), 8.60 (d, J = 1.6 Hz, 1H), 8.48 (dd, J = 9.2, 2.3 HZ, 1H), 8.36 (d, J = 9.2 Hz, 1H), 4.42 (q, J = 7.1 Hz, 2H), 1.39 (t, J = 7.1 Hz, 3H); 13C-NMR: δ 163.9, 147.1, 136.8, 136.2, 135.2, 131.5, 129.7, 127.4, 126.2, 124.0, 116.1, 111.6, 62.4, 14.3; MS (EI): m/z 270; Anal. Calcd for C14H10N2O4: C, 62.22; H, 3.73; N, 10.37. Found: C, 62.26; H, 3.76; N, 10.28.

3.5.2. 3-Ethyl 1-methyl 6-nitronaphthalene-1,3-dicarboxylate (15b) from 5 and methyl phenylsulfonylacetate (11)

1 Yield: 276 mg (0.91 mmol, 91%) as an oﬀ-white solid, m.p. 203–204 ◦C; IR: 1707, 1527, 1350 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 9.20 (d, J = 9.5 Hz, 1H), 8.95–8.90 (complex, 3H), 8.45 (dd, J = 9.5, 2.5 Hz, 13 1H), 4.51 (q, J = 7.1 Hz, 2H), 4.07 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); C-NMR (101 MHz, CDCl3): δ 166.5, 164.9, 146.0, 137.0, 135.7, 133.0, 132.3, 129.0, 128.2, 127.9, 125.9, 122.9, 62.0, 52.8, 14.4; MS (EI): m/z 303 + [M] ·; Anal. Calcd for C15H13NO6: C, 59.41; H, 4.32; N, 4.62. Found: C, 59.48; H, 4.30; N, 4.51.

3.5.3. Diethyl 6-nitronaphthalene-1,3-dicarboxylate (15c) from 5 and ethyl nitroacetate (12)

1 Yield: 298 mg (0.94 mmol, 94%) as an oﬀ-white solid, m.p. 181–182 ◦C; IR: 1708, 1526, 1350 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 9.19 (d, J = 9.5 Hz, 1H), 8.95-8.90 (complex, 3H), 8.44 (dd, J = 9.5, 2.4 HZ, 1H), 4.53 (q, J = 7.1 Hz, 2H), 4.51 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13 C-NMR (101 MHz, CDCl3): δ 166.1, 165.0, 145.9, 136.8, 135.7, 132.8, 132.3, 129.0, 128.4, 128.2, 125.9, + 122.8, 62.0, 61.9, 14.4, 14.35; MS (EI): m/z 317 [M] ·; Anal. Calcd for C16H15NO6: C, 60.57; H, 4.77; N, 4.41. Found: C, 60.63; H, 4.73; N, 4.31.

3.5.4. Ethyl 4-benzoyl-7-nitro-2-naphthoate (15d) from 5 and 1-phenyl-2-(phenylsulfonyl) ethan-1-one (13)

1 Yield: 335 mg (0.96 mmol, 96%) as a white solid, m.p. 160–161 ◦C; IR: 1724, 1657, 1530, 1350 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 8.99 (d, J = 2.4 Hz, 1H), 8.93 (s, 1H), 8.36 (m, 2H), 8.27 (d, J = 9.3 Hz, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.67 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H), 4.48 (q, J = 7.1 Hz, 2H), 1.45 Molecules 2020, 25, 5168 11 of 17

13 (t, J = 7.1 Hz, 3H); C-NMR (101 MHz, CDCl3): δ 196.1, 165.0, 146.2, 137.2, 137.18, 135.3, 135.0, 134.1, + 132.1, 130.5, 130.0, 128.9, 128.8, 127.8, 126.0, 122.5, 62.0, 14.3; MS (EI): m/z 349 [M] ·; Anal. Calcd for C20H15NO5: C, 68.76; H, 4.33; N, 4.01. Found: C, 68.67; H, 4.35; N, 3.95.

3.5.5. Ethyl 4-acetyl-7-nitro-2-naphthoate (15e) from 5 and 1-(phenylsulfonyl)propan-2-one (14)

Yield: 262 mg (0.92 mmol, 92%) as a white ﬂaky solid, m.p. 152–153 ◦C; IR: 1714, 1690, 1526, 1 1 1351 cm− ; H-NMR (400 MHz, CDCl3): δ 9.01 (br t, J = 8.2 Hz, 1H), 8.90 (m, 2H), 8.73 (br s, 1H), 8.42 (br t, J = 8.4 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 2.84 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 200.3, 165.0, 146.1, 136.6, 135.6, 134.6, 132.5, 131.3, 128.7, 128.5, 125.7, 123.2, 62.1, 29.8, 14.4; + MS (EI): m/z 287 [M] ·; Anal. Calcd for C15H13NO5: C, 62.72; H, 4.56; N, 4.88. Found: C, 62.68; H, 4.55; N, 4.79.

3.5.6. 6-Nitronaphthalene-1,3-dicarbonitrile (16a) from 6 and 10

1 Yield: 178 mg (0.80 mmol, 80%) as a white solid, m.p. 224 ◦C (dec); IR: 2250, 1541, 1354 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 8.97 (d, J = 2.2 Hz, 1H), 8.67 (s, 1H), 8.65 (dd, J = 9.1, 2.2 Hz, 1H), 8.51 13 (d, J = 9.2 Hz, 1H), 8.26 (d, J = 1.6 Hz, 1H); C-NMR (101 MHz, CDCl3): δ 147.6, 139.7, 135.7, 135.5, + 131.4, 127.9, 125.3, 125.0, 116.0, 114.9, 113.2, 112.0; MS (EI): m/z 223 [M] ·; Anal. Calcd for C12H5N3O2: C, 64.58; H, 2.26; N, 18.83. Found: C, 64.52; H, 2.29; N, 18.74.

3.5.7. Methyl 3-cyano-6-nitro-1-naphthoate (16b) from 6 and 11

1 Yield: 220 mg (0.86 mmol, 86%) as a white solid, m.p. 219-220 ◦C; IR: 2254, 1708, 1534, 1350 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 9.26 (d, J = 9.5 Hz, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.54 13 (d, J = 1.7 Hz, 1H), 8.51 (dd, J = 9.5, 2.4 Hz, 1H), 4.08 (s, 3H); C-NMR (101 MHz, CDCl3): δ 165.3, + 146.5, 139.8, 135.0, 133.8, 132.2, 129.1, 128.6, 125.0, 123.8, 117.1, 111.3, 53.1; MS (EI): m/z 256 [M] ·; Anal. Calcd for C13H8N2O4: C, 60.94; H, 3.15; N, 10.93. Found: C, 60.87; H, 3.13; N, 10.87.

3.5.8. Ethyl 3-cyano-6-nitro-1-naphthoate (16c) from 6 and 12

Yield: 238 mg (0.88 mmol, 88%) as a white solid, m.p. 156–157 ◦C; IR: 2254, 1722, 1629, 1535, 1 1 1350 cm− ; H-NMR (400 MHz, CDCl3): δ 9.26 (d, J = 9.5 Hz, 1H), 8.89 (d, J = 2.4 Hz, 1H), 8.58 (s, 1H), 8.53 (s, 1H), 8.51 (dd, J = 9.5, 2.4 Hz, 1H), 4.54 (q, J = 7.1 Hz, 2H), 1.50 (t, J = 7.1 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 164.9, 146.5, 139.6, 135.0, 133.7, 132.1, 129.5, 128.7, 125.0, 123.7, 117.2, 111.3, 62.4, + 14.3; MS (EI): m/z 270 [M] ·; Anal. Calcd for C14H10N2O4: C, 62.22; H, 3.73; N, 10.37. Found: C, 62.18; H, 3.72; N, 10.31.

3.5.9. 4-Benzoyl-7-nitro-2-naphthonitrile (16d) from 6 and 13

1 Yield: 272 mg (0.90 mmol, 90%) as a white solid, m.p. 152–154 ◦C; IR: 2234, 1663, 1530, 1348 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 8.94 (d, J = 2.3 Hz, 1H), 8.58 (s, 1H), 8.42 (dd, J = 9.3, 2.3 Hz, 1H), 8.29 (d, J = 9.3 Hz, 1H), 7.90 (d, J = 1.6 Hz, 1H), 7.84 (dd, J = 8.4, 1.7 Hz, 2H), 7.71 (tt, J = 7.5, 1.4 Hz, 1H), 7.54 13 (t, J = 7.5 Hz, 2H); C-NMR (101 MHz, CDCl3): δ 194.7, 146.8, 138.5, 137.8, 136.6, 134.61, 134.55, 132.0, + 130.5, 130.4, 129.1, 128.2, 125.0, 123.4, 117.3, 111.1; MS (EI): m/z 302 [M] ·; Anal. Calcd for C18H10N2O3: C, 71.52; H, 3.33; N, 9.27. Found: C, 71.47; H, 3.31; N, 9.37.

3.5.10. 4-Acetyl-7-nitro-2-naphthonitrile (16e) from 6 and 14

1 Yield: 211 mg (0.88 mmol, 88%) as a white solid, m.p. 202–204 ◦C; IR: 2228, 1670, 1518, 1344 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 8.99 (d, J = 9.5 Hz, 1H), 8.88 (d, J = 2.4 Hz, 1H), 8.56 (s, 1H), 8.50 (dd, 13 J = 9.5, 2.4 Hz, 1H), 8.25 (d, J = 1.7 Hz, 1H), 2.82 (s, 3H); C-NMR (101 MHz, CDCl3): δ 198.9, 146.6, + 139.4, 136.8, 133.8, 132.3, 131.7, 128.8, 124.8, 124.0, 117.2, 111.1, 29.8; MS (EI): m/z 240 [M] ·; Anal. Calcd for C13H8N2O3: C, 65.00; H, 3.36; N, 11.66. Found: C, 64.93; H, 3.33; N, 11.59. Molecules 2020, 25, 5168 12 of 17

3.5.11. Ethyl 4,7-dicyano-2-naphthoate (17a) from 7 and 10

1 1 Yield: 200 mg (0.80 mmol, 80%) as a white solid, m.p. 209–210 ◦C; IR: 2229, 1720 cm− ; H-NMR (400 MHz, CDCl3): δ 8.87 (s, 1H), 8.66 (d, J = 1.5 Hz, 1H), 8.45 (s, 1H), 8.41 (d, J = 8.7 Hz, 1H), 7.96 (dd, 13 J = 8.7, 1.5 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 1.48 (t, J = 7.1 Hz, 3H); C-NMR (101 MHz, CDCl3): δ 164.0, 135.7, 135.6, 135.2, 134.8, 131.5, 131.2, 129.4, 126.8, 117.7, 116.1, 112.5, 111.5, 62.4, 14.3; MS (EI): m/z + 250 [M] ·; Anal. Calcd for C15H10N2O2: C, 71.99; H, 4.03; N, 11.19. Found: C, 72.04; H, 4.06; N, 11.12.

3.5.12. 3-Ethyl 1-methyl 6-cyanonaphthalene-1,3-dicarboxylate (17b) from 7 and 11

1 1 Yield: 232 mg (0.82 mmol, 82%) as a white solid, m.p. 181–182 ◦C; IR: 2224, 1707 cm− ; H-NMR (400 MHz, CDCl3): δ 9.13 (d, J = 9.0 Hz, 1H), 8.89 (d, J = 1.8 Hz, 1H), 8.77 (s, 1H), 8.38 (d, J = 0.9 Hz, 1H), 7.83 (dd, J = 9.0, 1.6 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 4.05 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 166.5, 165.0, 135.62, 135.55, 134.5, 132.4, 132.2, 130.1, 128.6, 127.8, 127.6, 118.3, + 111.0, 61.9, 52.7, 14.4; MS (EI): m/z 283 [M] ·; Anal. Calcd for C16H13NO4: C, 67.84; H, 4.63; N, 4.94. Found: C, 67.76; H, 4.62; N, 4.97.

3.5.13. Diethyl 6-cyanonaphthalene-1,3-dicarboxylate (17c) from 7 and 12

1 1 Yield: 247 mg (0.82 mmol, 83%) as a white solid, m.p. 159–160 ◦C; IR: 2223, 1714 cm− ; H-NMR (400 MHz, CDCl3): δ 9.12 (d, J = 9.1 Hz, 1H), 8.88 (d, J = 1.9 Hz, 1H), 8.77 (s, 1H), 8.37 (s, 1H), 7.83 (dd, J = 9.0, 1.5 Hz, 1H), 4.52 (q, J = 7.1 Hz, 2H), 4.50 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H), 13 1.48 (t, J = 7.1 Hz, 3H); C-NMR (101 MHz, CDCl3): δ 166.1, 165.1, 135.6, 135.4, 134.5, 132.21, 132.18, + 130.1, 128.6, 128.3, 127.6, 118.3, 110.9, 61.9, 61.8, 14.36, 14.35; MS (EI): m/z 297 [M] ·; Anal. Calcd for C17H15NO4: C, 68.68; H, 5.09; N, 4.71. Found: C, 68.62; H, 5.09; N, 4.63.

3.5.14. Ethyl 4-benzoyl-7-cyano-2-naphthoate (17d) from 7 and 13

1 Yield: 280 mg (0.85 mmol, 85%) as a white solid, m.p. 144–145 ◦C; IR: 2227, 1722, 1656 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 8.79 (s, 1H), 8.43 (s, 1H), 8.31 (s, 1H), 8.21 (d, J = 8.8 Hz, 1H), 7.85 (d, J = 7.7 Hz, 2H), 7.74 (d, J = 8.8 Hz, 1H), 7.66 (t, J = 7.5 Hz, 1H), 7.51 (t, J = 7.6 Hz, 2H), 4.47 (q, 13 J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H); C-NMR (101 MHz, CDCl3): δ 196.1, 165.1, 137.24, 137.15, 135.6, 134.2, 134.1, 133.6, 132.1, 130.4, 129.7, 129.4, 128.8, 128.5, 127.3, 118.3, 111.2, 61.9, 14.3; MS (EI): m/z 329 + [M] ·; Anal. Calcd for C21H15NO3: C, 76.58; H, 4.59; N, 4.25. Found: C, 76.60; H, 4.63; N, 4.17.

3.5.15. Ethyl 4-acetyl-7-cyano-2-naphthoate (17e) from 7 and 14

1 Yield: 224 mg (0.84 mmol, 84%) as a white solid, m.p. 134–135 ◦C; IR: 2229, 1717, 1678 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 8.95 (d, J = 9.0 Hz, 1H), 8.76 (s, 1H), 8.68 (t, J = 1.6 Hz, 1H), 8.37 (s, 1H), 7.83 (dt, J = 8.9, 1.8 Hz, 1H), 4.51 (q, J = 7.1 Hz, 2H), 2.82 (s, 3H), 1.49 (t, J = 7.1 Hz, 3H); 13C-NMR (101 MHz, CDCl3): δ 200.4, 165.1, 135.5, 135.4, 135.3, 133.5, 132.4, 130.7, 130.5, 128.4, 127.9, 118.2, 111.2, + 62.0, 29.8, 14.4; MS (EI): m/z 267 [M] ·; Anal. Calcd for C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found: C, 71.84; H, 4.93; N, 5.28.

3.5.16. Naphthalene-1,3,6-tricarbonitrile (18a) from 8 and 10

1 1 Yield: 152 mg (0.75 mmol, 75%) as a white solid, m.p. 206–207 ◦C; IR: 2232 cm− ; H-NMR: δ 8.53 (br s, 1H), 8.45 (d, J = 8.7 Hz, 1H), 8.42 (br s, 1H), 8.22 (d, J = 1.6 Hz, 1H), 8.04 (dd, J = 8.7, 1.6 Hz, 1H); 13 C-NMR (101 MHz, CDCl3): δ 138.5, 135.2, 134.8, 134.4, 132.2, 131.3, 127.2, 117.1, 116.2, 114.8, 113.8, + 113.1, 111.7; MS (EI): m/z 203 [M] ·; Anal. Calcd for C13H5N3: C, 76.84; H, 2.48; N, 20.68. Found: C, 76.89; H, 2.51; N, 20.57.

3.5.17. Methyl 3,6-dicyano-1-naphthoate (18b) from 8 and 11

1 Yield: 184 mg (0.78 mmol, 78%) as an oﬀ-white solid, m.p. 235–236 ◦C; IR: 2228, 1719 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 9.18 (d, J = 9.0 Hz, 1H), 8.49 (s, 1H), 8.45 (s, 1H), 8.34 (s, 1H), 7.91 Molecules 2020, 25, 5168 13 of 17

13 (d, J = 8.9 Hz, 1H), 4.10 (s, 3H); C-NMR (101 MHz, CDCl3): δ 165.3, 138.5, 134.6, 133.8, 133.3, 132.0, + 131.1, 129.0, 127.9, 117.7, 117.2, 112.2, 110.9, 53.1; MS (EI): m/z 236 [M] ·; Anal. Calcd for C14H8N2O2: C, 71.18; H, 3.41; N, 11.86. Found: C, 71.09; H, 3.43; N, 11.79.

3.5.18. Ethyl 3,6-dicyano-1-naphthoate (18c) from 8 and 12

1 1 Yield: 200 mg (0.80 mmol, 80%) as a white solid, m.p. 185–186 ◦C; IR: 2228, 1704 cm− ; H-NMR (400 MHz, CDCl3): δ 9.18 (d, J = 9.0 Hz, 1H), 8.48 (s, 1H), 8.44 (s, 1H), 8.34 (s, 1H), 7.90 (d, J = 9.0 Hz, 1H), 4.53 (q, J = 7.1 Hz, 2H), 1.49 (t, J = 7.1 Hz, 3H); 13C-NMR: δ 164.9, 138.3, 134.6, 133.9, 133.2, 132.0, 131.0, + 129.3, 127.9, 117.8, 117.3, 112.1, 110.9, 62.3, 14.3; MS (EI): m/z 250 [M] ·; Anal. Calcd for C15H10N2O2: C, 71.99; H, 4.03; N, 11.19. Found: C, 72.05; H, 4.04; N, 11.07.

3.5.19. 4-Benzoylnaphthalene-2,7-dicarbonitrile (18d) from 8 and 13

1 1 Yield: 280 mg (0.80 mmol, 80%) as a white solid, m.p. 170–171 ◦C; IR: 2232, 1664 cm− ; H-NMR (400 MHz, CDCl3): δ 8.44 (s, 1H), 8.39 (s, 1H), 8.23 (d, J = 8.8 Hz, 1H), 7.88-7.77 (complex, 4H), 7.70 13 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.7 Hz, 2H); C-NMR (101 MHz, CDCl3): δ 194.7, 138.4, 136.6, 136.5, 134.59, 134.55, 133.4, 131.9, 130.6, 130.4, 130.0, 129.0, 127.6, 117.7, 117.4, 112.4, 110.7; MS (EI): m/z 282 + [M] ·; Anal. Calcd for C19H10N2O: C, 80.84; H, 3.57; N, 9.92. Found: C, 80.83; H, 3.54; N, 9.86.

3.5.20. 4-Acetylnaphthalene-2,7-dicarbonitrile (18e) from 8 and 14

1 1 Yield: 224 mg (0.79 mmol, 79%) as a white solid, m.p. 215–216 ◦C; IR: 2227, 1686 cm− ; H-NMR (400 MHz, CDCl3): δ 8.91 (d, J = 9.0 Hz, 1H), 8.43 (s, 1H), 8.34 (d, J = 1.7 Hz, 1H), 8.20 (d, J = 1.6 Hz, 13 1H), 7.89 (dd, J = 9.0, 1.7 Hz, 1H), 2.82 (s, 3H); C-NMR (101 MHz, CDCl3): δ 199.0, 138.1, 136.7, 134.4, + 132.7, 132.2, 131.3, 131.2, 128.1, 117.7, 117.3, 112.4, 110.7, 29.8; MS (EI): m/z 220 [M] ·; Anal. Calcd for C14H8N2O: C, 76.35; H, 3.66; N, 12.72. Found: C, 76.30; H, 3.63; N, 12.67.

3.5.21. Ethyl 8-cyanoquinoline-6-carboxylate (19a) from 9 and 10

1 1 Yield: 170 mg (0.75 mmol, 75%) as a yellow solid, m.p. 142–144 ◦C; IR: 2233, 1722 cm− ; H-NMR (400 MHz, CDCl3): δ 9.20 (m, 1H), 8.81 (s, 1H), 8.73 (d, J = 1.7 Hz, 1H), 8.38 (dd, J = 8.3, 1.7 Hz, 1H), 7.65 (dd, J = 8.3, 4.3 Hz, 1H), 4.50 (q, J = 7.1 Hz, 2H), 1.48 (q, J = 7.1 Hz, 3H); 13C-NMR) (101 MHz, CDCl3): δ 164.3, 154.4, 149.0,137.8, 135.3, 135.2, 128.3, 127.5, 123.5, 116.5, 113.8, 62.2, 14.3; MS (EI): m/z + 226 [M] ·; Anal. Calcd for C13H10N2O2: C, 69.02; H, 4.46; N, 12.38. Found: C, 69.07; H, 4.49; N, 12.27.

3.5.22. 6-Ethyl 8-methyl quinoline-6,8-dicarboxylate (19b) from 9 and 11

1 1 Yield: 212 mg (0.82 mmol, 82%) as an oﬀ-white solid, m.p. 75–77 ◦C; IR: 1722 cm− ; H-NMR (400 MHz, CDCl3): δ 9.14 (dd, J = 4.2, 1.8 Hz, 1H), 8.70 (d, J = 2.0 Hz, 1H), 8.62 (d, J = 2.0 Hz, 1H), 8.31 (dd, J = 8.4, 1.8 Hz, 1H), 7.54 (dd, J = 8.3, 4.2 Hz, 1H), 4.48 (q, J = 7.1 Hz, 2H), 4.08 (s, 3H), 1.46 13 (t, J = 7.1 Hz, 3H); C-NMR (101 MHz, CDCl3): δ 167.6, 165.3, 153.5, 147.2, 137.6, 133.9, 132.0, 129.9, + 127.8, 127.7, 122.3, 61.8, 52.9, 14.4; MS (EI): m/z 259 [M] ·; Anal. Calcd for C14H13NO4: C, 64.86; H, 5.05; N, 5.40. Found: C, 64.80; H, 5.03; N, 5.37.

3.5.23. Ethyl 8-benzoylquinoline-6-carboxylate (19d) from 9 and 13

1 Yield: 244 mg (0.80 mmol, 80%) as a light yellow solid, m.p. 146–147 ◦C; IR: 1718, 1671 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 8.93 (d, J = 4.2 Hz, 1H), 8.72 (d, J = 1.9 Hz, 1H), 8.36-8.30 (complex, 2H), 7.84 (d, J = 7.3 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.50 (dd, J = 8.4, 4.2 Hz, 1H), 7.42 (t, J = 7.7 Hz, 13 2H), 4.46 (q, J = 7.1 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H); C-NMR (101 MHz, CDCl3): δ 197.1, 165.5, 152.8, 147.9, 139.8, 137.4, 137.3, 133.5, 132.4, 130.2, 128.5, 128.0, 127.62, 127.55, 122.4, 61.7, 14.4; MS (EI): m/z + 305 [M] ·; Anal. Calcd for C19H15NO3: C, 74.74; H, 4.95; N, 4.59. Found: C, 74.71; H, 4.95; N, 4.52. Molecules 2020, 25, 5168 14 of 17

3.5.24. Ethyl 8-acetylquinoline-6-carboxylate (19e) from 9 and 14

1 1 Yield: 185 mg (0.76 mmol, 76%) as a white crystals, m.p. 103–104 ◦C; IR: 1704, 1689 cm− ; H-NMR (400 MHz, CDCl3): δ 9.06 (dd, J = 4.2, 1.8 Hz, 1H), 8.69 (d, J = 1.9 Hz, 1H), 8.50 (d, J = 1.9 Hz, 1H), 8.32 (dd, J = 8.4, 1.8 Hz, 1H), 7.54 (dd, J = 8.3, 4.2 Hz, 1H), 4.47 (q, J = 7.1 Hz, 2H), 2.94 (s, 3H), 1.46 13 (t, J = 7.1 Hz, 3H); C-NMR (101 MHz, CDCl3): δ 203.2, 165.5, 152.4, 147.2, 140.1, 137.6, 133.7, 128.6, + 128.1, 127.7, 122.2, 61.7, 32.6, 14.4; MS (EI): m/z 243 [M] ·; Anal. Calcd for C14H13NO3: C, 69.12; H, 5.39; N, 5.76. Found: C, 69.06; H, 5.37; N, 5.69.

3.6. Competitive Reaction Control Experiment. Formation of Methyl (Z)-4-cyano-5-(2-ﬂuorophenyl)-2-(phenylsulfonyl)-4-pentenoate (22)

A 50-mL, round-bottomed flask equipped with a condenser, stir bar, and N2 inlet was charged with a 2-fluoro-5-nitrotoluene (20, 155 mg, 1 mmol) and 2-cyano-1-(2-fluorophenyl)allyl acetate (21, 219 mg, 1 mmol) in DMF (2 mL) under N2. Methyl phenylsulfonylacetate (321 mg, 1.5 mmol) and K2CO3 (207 mg, 1.5 mmol) were added at room temperature with stirring. TLC analysis (20% EtOAc in hexane) indicated that the reaction was complete in 1 h. The solution was poured into de-ionized water (15 mL), and the mixture was extracted with EtOAc (3 25 mL). The combined organic layers × were washed with saturated NaCl and dried (Na2SO4). Removal of the solvent under vacuum gave the crude product, which was purified by silica gel column chromatography to afford 20 (144 mg, 1 93%) and 22 (261 mg, 0.7 mmol, 70%) as a white solid, m.p. 95–97 ◦C; IR: 2215, 1744, 1637, 1149 cm− ; 1 H-NMR (400 MHz, CDCl3): δ 7.98 (td, J = 7.8, 1.7 Hz, 1H), 7.92 (d, J = 7.8 Hz, 2H), 7.74 (tt, J = 7.5, 1.9 Hz, 1H), 7.62 (t, J = 8.2 Hz, 2H), 7.44–7.36 (complex, 1H), 7.31 (s, 1H), 7.20 (t, J = 7.8 Hz, 1H), 7.10 (t, J = 9.5 Hz, 1H), 4.34 (dd, J = 10.7, 4.4 Hz, 1H), 3.67 (s, 3H), 3.20 (dd, J = 14.3, 4.4 Hz, 1H), 13 3.14 (dd, J = 14.3, 10.7 Hz, 1H); C-NMR (101 MHz, CDCl3): δ 164.9, 160.4 (d, J = 253.0 Hz), 139.3 (d, J = 6.5 Hz), 136.8, 134.8, 132.6 (d, J = 8.7 Hz), 129.4, 129.2, 128.3 (d, J = 1.6 Hz), 124.6 (d, J = 3.7 Hz), 121.1 (d, J = 11.7 Hz), 117.0, 115.8 (d, J = 21.7 Hz), 107.2 (d, J = 2.0 Hz), 68.7, 53.3, 33.0; MS (EI): m/z + 373 [M] ·; Anal. Calcd for C19H16FNO4S: C, 61.12; H, 4.32; N, 3.75. Found: C, 61.22; H, 4.25; N, 3.68. The X-ray structure for compound 22 (CCDC 2035022) and the thermal elipsoid plot is shown in Scheme2 and the Supplementary Materials.

4. Conclusions We have investigated the synthesis of naphthalenes and quinolines from Morita–Baylis–Hillman acetates and active methylene compounds promoted by K2CO3 in DMF. The formation of naphthalenes occurs at 23 ◦C, while quinolines required heating to 90 ◦C. Substrates for the naphthalenes were MBH acetates bearing 2-ﬂuoroaromatic rings activated toward SNAr ring closure by C5 NO2 or CN groups. Quinoline precursors were activated only by the electron-withdrawing nitrogen in a 2-ﬂuoropyridine ring. The transformation most likely involves a domino SN20-SNAr process. A control experiment indicated that the initial reaction occurs by an SN20-type substitution of the side chain acetate to yield the alkene having the aromatic ring trans to the aromatic SNAr acceptor ring. Thus, under the reaction conditions, a reversible Michael addition or an intramolecular addition–elimination must occur to equilibrate the geometry of the double bond to yield the alkene isomer needed for ring closure. The isolation of intermediates from the reaction disputes an earlier report that the reaction directly delivers the alkene needed for cyclization. Once equilibrated, subsequent deprotonation of the active methine proton, SNAr ring closure, and the elimination of SO2Ph, NO2, or CO2Et then aromatizes the product. Much of the selectivity appears to be guided by steric considerations. The loss of SO2Ph or NO2 in the aromatization process has good precedent in the literature, but the loss of CO2Et in preference to CN was unexpected. Good to excellent yields were isolated for all examples.

Supplementary Materials: The following are available online, Copies of 1H-NMR and 13C-NMR spectra for all compounds and tables of crystal data for compounds 4 and 22. Molecules 2020, 25, 5168 15 of 17

Author Contributions: Formal analysis, R.A.B.; Investigation, J.K.A.-G., E.A. and K.M.; Methodology, J.K.A.-G., E.A. and K.M.; Project administration, R.A.B.; Writing—original draft, R.A.B.; Writing—review & editing, R.A.B., J.K.A.-G., E.A. and K.M. All authors have read and agreed to the published version of the manuscript. Funding: Financial support for this work was obtained from the Oklahoma State University Foundation and the College of Arts and Sciences at Oklahoma State University. The University of Oklahoma Chemical Crystallography Laboratory was upgraded with support from the NSF (CHE-1726630). The Oklahoma State University State-wide NMR Facility was established with funds from the NSF (BIR-9512269) the OSU Regents for Higher Education the W. M. Keck Foundation and Conoco, Inc. Acknowledgments: J.K.A.-G. and K.M. wish to thank K. Darrell Berlin and the OSU Foundation for Summer Scholarships. The authors also wish to thank Douglas Powell at the University of Oklahoma Chemical Crystallography Laboratory for obtaining the X-ray crystal structures. This facility was established with support from the NSF (CHE-1726630). Finally, the authors are indebted to the OSU College of Arts and Sciences for funds to purchase several departmental instruments including an FT-IR and a 400 MHz NMR unit for the State-wide NMR facility. The NMR facility was initially established with support from the NSF (BIR-9512269), the Oklahoma State Regents for Higher Education, the W. M. Keck Foundation, and Conoco, Inc. Conﬂicts of Interest: The authors declare no conﬂict of interest.

References

1. Narendar Reddy, T.; Jayathirtha Rao, V. Importance of Baylis-Hillman adducts in modern drug discovery. Tetrahedron Lett. 2018, 59, 2859–2875. [CrossRef] 2. Lima-Junior, C.G.; Vasconcellos, M.A.A. Morita Baylis-Hillman adducts: Biological activities and potentialities to the discovery of new cheaper drugs. Bioog. Med. Chem. 2012, 20, 3954–3971. [CrossRef][PubMed] 3. Makar, S.; Saha, T.; Singh, S.K. Naphthalene, a versatile platform in medicinal chemistry: Sky high perspective. Eur. J. Med. Chem. 2019, 161, 252–276. [CrossRef][PubMed] 4. Ofzal, O.; Kumar, S.; Haider, M.R.; Ali, M.R.; Kumar, R.; Jaggi, M.; Bawa, S. A review on anticancer potential of bioactive heterocycle quinoline. Eur. J. Med. Chem. 2015, 97, 871–910. [CrossRef] 5. Beena; Rawat, D.S. Antituberculosis drug research: A critical review. Med. Res. Rev. 2013, 33, 693–764. [CrossRef][PubMed] 6. Im, Y.J.; Chung, Y.M.; Gong, J.H.; Kim, J.N. Synthesis of naphthalenes from the reaction of Baylis-Hillman acetates and sulfonyl group-containing active methylene compounds. Bull. Korean Chem. Soc. 2002, 23, 787–788. [CrossRef] 7. Kim, J.N.; Lee, H.J.; Lee, K.Y.; Kim, H.S. Synthesis of 3-quinolinecarboxylic acid esters from the Baylis-Hillman adducts of 2-halobenzaldehyde N-tosylimines. Tetrahedron Lett. 2001, 42, 3737–3740. [CrossRef]

8. Gupta, T.; Bharadwaj, K.C.; Singh, R.M. Cascade SN2’-SNAr, Elimination and 1,5-hydride shift reactions by acetylacetone/acetoacetic esters: Synthesis of 9,10-dihydroacridines. Eur. J. Org. Chem. 2016, 4981–4984. [CrossRef] 9. Gupta, T.; Singh, J.B.; Mishra, K.; Singh, R.M. Active methylene compounds (AMCs)controlled facile synthesis of acridine and phenanthridine from morita Baylis-Hillman acetate. RSC Adv. 2017, 7, 54581–54585. [CrossRef] 10. Morita, K.; Suzuki, Z.; Hirose, H. A tertiary phosphine-catalyzed reaction of acrylic compounds with aldehydes. Bull. Soc. Chem. Jpn. 1968, 41, 2815. [CrossRef] 11. Baylis, A.B.; Hillman, M.E.D. Acrylic Compounds. German Patent 2155113, 1972. 12. Hillman, M.E.D.; Baylis, A.B. The reaction of acrylic type compounds with aldehydes and certain ketones. U.S. Patent 3,743,669, 3 July 1973. 13. Kürti, L.; Czakó, B. Strategic Applications of Named Reaction in Organic Chemistry; Elsevier: New York, NY, USA, 2005; pp. 48–49. 14. Singh, B.; Chandra, A.; Singh, R.H. Base-free amination of BH acetates of 2-chloroquinolinyl-3- carboxaldehydes: A facile route to the synthesis of N-substituted-1,2-dihydrobenzo[b][1.8]naphthyridines. Tetrahedron 2011, 67, 2441–2446. [CrossRef] 15. Procopiou, P.A.; Baugh, S.P.D.; Flack, S.S.; Inglis, G.G.A. An extremely powerful acylation reaction of alcohols with acid anhydrides catalyzed by trimethylsilyl triﬂuoromethanesulfonate. J. Org. Chem. 1998, 63, 2342–2347. [CrossRef] 16. Love, B.E.; Raje, P.S. Preparation of 1-aryl-carbolines. J. Org. Chem. 1994, 59, 3219–3222. [CrossRef] Molecules 2020, 25, 5168 16 of 17

17. Paredes, E.; Biolatta, B.; Kneetemen, M.; Mancini, P. One-step synthesis of 2,9-disubstituted phenanthrenes via Diels-Alder reactions using 1,4-disubstituted naphthalenes as dienophiles. Tetrahedron Lett. 2002, 43, 4601–4603. [CrossRef] 18. Schenck, L.W.; Kuna, S.K.; Frank, W.; Alber, A.; Kucklaender, U. Dialkyl quinone-2,3-dicarboxylates in the Nenitzescu reaction. Tetrahedron 2005, 61, 9129–9139. [CrossRef] 19. Kucukdisli, M.; Ferenc, D.; Heinz, M.; Wiebe, C.; Opatz, T. Simple two-step synthesis of 2,4-disubstituted pyrroles and 3,5-disubstituted pyrrole-2-carbonitriles from enones. BeilsteinJ. Org. Chem. 2014, 10, 466–470. [CrossRef] 20. Wang, Y.-W.; Fang, J.-M.; Wang, Y.-K.; Wang, M.-H.; Ko, T.-Y.; Cherng, Y.-J. Addition reactions of 2-amino-4-methoxypenta-2,4-dienenitrile with electrophiles containing electron-deﬁcient multiple bonds. J. Chem. Soc., Perkin Trans. 1992, 1, 1209–1213. [CrossRef] 21. Buchholz, R.; Hoﬀmann, H.M.R. α-Methylidene and α-Alkylidene-β-lactams from nonproteinogenic amino acids. Helv. Chim. Acta 1991, 74, 1213–1220. [CrossRef]

22. Stohrer, W.-D. On the stereochemistry of the SN2’ reaction. Angew. Chem. Int. Ed. 1983, 22, 613–614. [CrossRef]

23. Magid, R.M.; Fruchey, O.S. Stereochemistry of the SN2’ reaction of an acyclic allylic chloride with a secondary amine. J. Am. Chem. Soc. 1977, 99, 8368–8369. [CrossRef] 24. Oritani, T.; Overton, K.H. Stereochemistry of the SN2’ reaction with acyclic allylic esters. J. Chem. Soc. Chem. Commun. 1978, 454–455. [CrossRef] 25. Magid, R.M. Nucleophilic and organometallic displacement reactions of allylic compounds: Stereo- and regiochemistry. Tetrahedron 1980, 36, 1901–1930. [CrossRef]

26. Stork, G.; Kreft III, A.F. Concerning the stereochemistry of the SN2’ reaction. “Concerted” allylic displacement in an acyclic system: Anti displacement with thiolate anion. J. Am. Chem. Soc. 1977, 99, 3851–3852. [CrossRef]

27. Bach, R.D.; Wolber, G.J. Stereochemistry of the concerted SN2’ reaction of 3-chloropropene: A theoretical study. J. Am. Chem. Soc. 1985, 107, 1352–1357. [CrossRef] 28. Bergman, E.D.; Ginsburg, D.; Pappo, R. The Michael Reaction. Org. React. 1959, 10, 179–555. 29. Werner, R.M.; Williams, L.M.; Davis, J.T. The C-glycosyl analog of an N-linked glycoamino acid. Tetrahedron Lett. 1998, 39, 9135–9138. [CrossRef] 30. Shao, H.; Ekthawatchai, S.; Chen, C.-S.; Wu, S.-H.; Zou, W. 1,2-Migration of 2’-oxoalkyl group and concomitant synthesis of 2-C-branched O-, S-glycosides and glycosyl azides via 1,2-cyclopropanated sugars. J. Org. Chem. 2005, 70, 4726–4734. [CrossRef] 31. Henderson, A.P.; Bleasdale, C.; Delaney, K.; Lindstrom, A.B.; Rappaport, S.M.; Waidyanatha, S.; Watson, W.P.; Golding, B.T. Evidence for the formation of Michael adducts from reactions of [E,E]-muconaldehyde with glutathione and other thiols. Bioorg. Chem. 2005, 33, 363–373. [CrossRef] 32. Hintermann, L.; Dittmer, C. Asymmetric ion-pairing catalysis of the reversible cyclization of 2’-hydroxychalcone to flavanone: Asymmetric catalysis of an equilibrating reaction. Eur. J. Org. Chem. 2012, 5573–5584. [CrossRef] 33. McKenna, E.G.; Walker, B.J. Wittig reactions of ylide anions derived from stabilized ylides. J. Chem. Soc. Chem. Commun. 1989, 568–569. [CrossRef] 34. Hoffmann, H.M.R.; Rabe, J. DABCO-catalyzed coupling of aldehydes with activated double bonds. 4. Stereoselective synthesis of trisubstituted olefins and terpenoid building blocks via 2-(hydroxyalkyl)-2-propenoic esters. J. Org. Chem. 1985, 50, 3849–3859. [CrossRef] 35. Ameer, F.; Drewes, S.E.; Houston-McMillan, M.S.; Kaye, P.T. Necic acid synthons. Part 4. Regioselectivity in the reactions of chloro and iodo derivatives of selected 3-hydroxy-2-methylene-alkanoate esters with ethyl 3-methyl-3-oxobutanoate. J. Chem. Soc. Perkin Trans. 1985, 1, 1143–1145. [CrossRef] 36. Basavaiah, D.; Pandiaraju, S.; Padmaja, K. The Friedel-Crafts chemistry: Acetates of the Baylis-Hillman adducts as novel stereodefined-electrophiles. Synlett 1996, 393–395. [CrossRef] 37. Chavan, S.P.; Ethiraj, K.S.; Kamat, S.K. Facile synthesis of 2Z-2-chloromethyl aryl-2-enoates. Tetrahedron Lett. 1997, 38, 7415–7416. [CrossRef] 38. Yadav, J.S.; Subba Reddy, B.V.; Madan, C. Montmorillonite clay-catalyzed stereoselective synthesis of aryl-substituted (E)- and (Z)-allyl iodides and bromides. New J. Chem. 2001, 25, 1114–1117. [CrossRef]

39. Krishna, P.R.; Kannan, V.; Sharma, G.V.M. FeCl3 and Yb(OTf)3 mediated conversion of acetates of the Baylis-Hillman adducts into (Z) and (E) trisubstituted alkenes. Synth. Commun. 2004, 34, 55–64. [CrossRef] Molecules 2020, 25, 5168 17 of 17

40. Li, J.; Wang, X.; Zhang, Y. Direct and highly eﬃcient synthesis of (Z)-allyl iodides from Baylis-Hillman adducts promoted by TMSCl/NaI system. Synlett 2005, 1039–1041. [CrossRef]

41. Gohain, M.; Lin, S.; Bezuidenhoudt, B.C.B. Al(OTf)3-catalyzed SN2’ substitution of the-hydroxy group in Morita-Baylis-Hillman adducts with indoles. Tetrahedron Lett. 2015, 56, 2579–2582. [CrossRef]

Sample Availability: Samples of the compounds are not available from the authors.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional aﬃliations.

© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).