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Article βArticle-Nitroacrylates: New Key Precursors of β-Nitroacrylates: New Key Precursors of Indole-2- Indole-2-Carboxylates via Fischer Indole Synthesis Carboxylates via Fischer Indole Synthesis Serena Gabrielli, Deepak Panmand, Roberto Ballini and Alessandro Palmieri * Serena Gabrielli, Deepak Panmand, Roberto Ballini and Alessandro Palmieri * Green Chemistry Group, Chemistry Division, School of Science and Technology, University of Camerino, Via Green Chemistry Group, Chemistry Division, School of Science and Technology, University of Camerino, Via S. Agostino n. 1, 62032 Camerino (MC), Italy; [email protected] (S.G.); [email protected] (D.P.); S. Agostino n. 1, 62032 Camerino (MC), Italy; [email protected] (S.G.); [email protected] [email protected] (R.B.) (D.P.); [email protected] (R.B.) * Correspondence: [email protected]; Tel.: +39-0737-402-262 * Correspondence: [email protected]; Tel.: +39-0737-402-262 Received: 5 November 2019 2019;; Accepted: 23 November 2019 2019;; Published: date 28 November 2019

Abstract: Indole 2-carboxylates2-carboxylates are very important scaffold scaﬀoldss that are widely investigated for their activities andand areare used used as as key key intermediates intermediate ofs of biologically biologically active active molecules. molecules Herein,. Herein, we reportwe report a new a procedurenew procedure for the for preparation the preparation of this of class this class of derivatives, of derivatives, via Fischer via Fis indolecher indole synthesis, synthesis, starting starting from βfrom-nitroacrylates β-nitroacrylates and arylhydrazines.and arylhydrazine Thes. The protocol protocol permits permits the the production production of of the the title title targetstargets in satisfactory overall yields,yields, avoids any wasteful aqueous work-up,work-up, and has with evident advantages from a sustainabilitysustainability point of view.

Keywords: Indoles;Indoles; β--nitroacrylates;nitroacrylates; Fis Fischercher indole indole synthesis synthesis;; heterocycles; c conjugateonjugate addition

1. Introduction The indolicindolic system is one of the most important and versatile nitrogen containing heterocycles heterocycles;; it is widely spread in nature nature,, such as in food, flowers, ﬂowers, in a multitude of of biologically biologically active active molecules, molecules, and isisprobably probably represented represented as oneas one of the of “privileged the “privileged structures” structures” of the main of the sca mainﬀolds scaffolds for the discovery for the ofdiscovery new drug of candidates new drug [1 candidates,2]. For all these[1,2]. reasons, For all a these growing reasons, number a growing of synthetic number approaches of synthetic for its preparationapproaches and for derivatization its preparation have and been derivatization reported in the have literature been [ reported3–5]. Nowadays, in the notwithstanding literature [3–5]. theNowadays, development notwithstanding of new methodologies the development concerning of the new ex-novo methodologies preparation concerning of indoles, the the historicalex-novo Fischerpreparation indole of synthesisindoles, the (introduced historical by Fis Emilcher Fischerindole synthesis in 1883) remains (introduced one of by the Emil pillars Fischer for the in direct1883) productionremains one of of functionalized the pillars for indolesthe direct (Scheme produc1)[tion6,7 of]. functionalized indoles (Scheme 1) [6,7].

Scheme 1. FisFischercher indole synthesis.synthesis.

This reactionreaction isis basedbased on on the the indolization indolization of of arylhydrazones arylhydrazones under under acidic acidic conditions, conditions and, and over over the years,the years, several several studies studies have have been been done done concerning concerning the discoverythe discovery and and use ofuse even-more of even-more eﬃcient efficient acid catalystsacid catalysts [8]. However, [8]. However only few, only eﬀorts few have efforts been directed have been toward directe thed preparation toward the of arylhydrazones, preparation of whicharylhydrazones, are mainly which prepared are mainly from ketones prepared and from arylhydrazines ketones and (Scheme arylhydrazines2)[9–11]. (Scheme 2) [9–11].

Appl. Sci. 2019, 9, x; 5168; doi: doi: 10.3390/app9235168 wwwwww.mdpi.com.mdpi.com/journal//journal/applsci Appl. Sci. 2019, 9, x 2 of 7 Appl. Sci. 2019, 9, 5168 2 of 8 Appl. Sci. 2019, 9, x 2 of 7

Scheme 2. Synthesis of arylhydrazones. Scheme 2. Synthesis of arylhydrazones. Scheme 2. Synthesis of arylhydrazones. While simplesimple ketones ketones are are cheap cheap and and readily readily available, available, the functionalized the functionalized ones very ones often very require often a multisteprequireWhile a synthesismultistep simple andketones synthesis harsh are reaction andcheap hars conditions. andh reaction readily Among conditions.available, them, the αAmong-ketoesters functionalized them, are ofα-ketoesters particularones very interest areoften of sinceparticularrequire they a multistep areinterest key precursorssince synthesis they ofare and alkyl key hars indole-2-carboxylates,precursorsh reaction of conditions.alkyl indole-2-carboxylates, a very Among important them, class α -ketoestersa ofvery indole important thatare of is widelyclassparticular of investigatedindole interest that issince for widely its they activities investigated are key and precursors is for exploited its activities of asalkyl a strategicand indole-2-carboxylates, is exploited intermediate as a strategic of biologicallya very intermediate important active targets,ofclass biologically of indole such as thatactive the is NNRTI widelytargets, Delavirdineinvestigated such as the andfor NNRTI its its activities analogues Delavirdine and [12 is –and exploited17]. its Recently, analogues as a strategic following [12–17]. intermediate ourRecently, study concerningfollowingof biologically our the active usestudy of taβconcerningrgets,-nitroacrylates such theas the 1useas NNRTI aof useful β-nitroacrylates Delavirdine building block and 1 asits of heterocyclicaanalogues useful building [12–17]. systems Recently,block [18–21 of], weheterocyclicfollowing reported our systems a newstudy protocol [18–21], concerning forwe synthesizingreport the useed a ofnew 5β,-nitroacrylates startingprotocol from for synthesizing 11and as oa-bromoanilines, useful 5, starting building from based block 1 onand of a palladiumoheterocyclic-bromoanilines, catalyzed systems based Heck[18–21], on couplinga palladiumwe report [22] edcatalyzed (Scheme a new3 ,protocolHeck Way b).coupling for Now, synthesizing in[22] continuing (Scheme 5, starting3, this Way study b).from withNow, 1 and the in aimcontinuingo-bromoanilines, of avoiding this study the based use with ofon precious athe palladium aim metal of avoiding catalyzed (Pd), we the foundHeck use 1ofcouplingto precious be a valuable [22] metal (Scheme alternative(Pd), 3,we Way found of αb).-ketoesters 1Now, to be in a continuing this study with the aim of avoiding the use of precious metal (Pd), we found 1 to be a forvaluable the Fischer alternative indole of synthesis α-ketoesters (Scheme for the3, Way Fischer a). indole synthesis (Scheme 3, Way a). valuable alternative of α-ketoesters for the Fischer indole synthesis (Scheme 3, Way a).

Scheme 3. Synthesis of alkyl indole-2-carboxylates starting from β-nitroacrylates. Scheme 3. Synthesis of alkyl indole-2-carboxylates starting from β-nitroacrylates. 2. Materials andScheme Methods 3. Synthesis of alkyl indole-2-carboxylates starting from β-nitroacrylates. 2. Materials and Methods 2.1.2. Materials General Section and Methods 2.1. General Section OXFORD NMR S400, Varian Mercury Plus 400, Oxford, UK, equipped with workstation Sun Blade 2.1. General Section 150,OXFORD software NMR VNMRJ S400, 1.1d, Varian and operating Mercury system Plus Solaris 400, 9.Oxford,1H NMR United analyses Kingdom, were recorded equipped at 400 MHzwith 13 andworkstationOXFORDC NMR NMR Sun analyses BladeS400, were150, Varian software recorded Mercury VNMRJ at 100 MHz.Plus 1.1d, 400 Ir and spectra, Oxford,operating were United recorded system Kingdom,Solaris with a Spectrum9. 1 Hequipped NMR Two analyses FT-IRwith spectrometer, Waltham, MA, USA equipped with ZnSe window, Dynascan Interferometer,1 detector wereworkstation recorded Sun at Blade 400 150,MHz software and 13C VNMRJ NMR analyses 1.1d, and were operating recorded system at Solaris100 MHz. 9. H Ir NMR spectra analyses were type LiTaO , and Spectrum 10 software. Microwave irradiations were performed by Biotage® Initiator. were recorded3 at 400 MHz and 13C NMR analyses were recorded at 100 MHz. Ir spectra were Microanalysesrecorded with werea Spectrum performed Two with FT-IR a CHNS-O spectromet analyzerer, Waltham, Model EA Massachusetts, 1108 from Fisons United Instruments. States recorded with a Spectrum Two FT-IR spectrometer, Waltham, Massachusetts, United States GS-MSequipped analyses with ZnSe were window, obtained Dynascan on an Agilent Interferometer, GC(6850N) detector/MS(5973N), type StevensLiTaO3, Creekand Spectrum Blvd, Santa 10 Clara,equippedsoftware. CA, withMicrowave USA, ZnSe EI technique window,irradiations (70 Dynascan eV), were GC / MSDperformedInterferometer, software, by andBiotagedetector an HP-5MS® typeInitiator. LiTaO column, Microanalyses3, and 30m, Spectrum Id 0.25 wereµ m,10 ® ﬁlmperformedsoftware. thichness Microwavewith 0.25 a CHNS-Oµm. Amberlystirradiations analyzer 15 were wasModel purchased performed EA 1108 from from by Sigma–Aldrich FisonsBiotage Instruments. Initiator. and was GS-MSMicroanalyses puriﬁed analyses by soaking were it in methanol for 24 h and then washing it with fresh methanol and THF and dried under a vacuum. obtainedperformed on with an Agilent a CHNS-O GC(6850N)/MS(5973N), analyzer Model EA 1108Stev ensfrom Creek Fisons Blvd, Instruments. Santa Clara, GS-MS CA, analysesUnited States, were obtainedEI technique on an (70 Agilent eV), GC/MSD GC(6850N)/MS(5973N), software, and an Stev HP-5MSens Creek column, Blvd, 30m, Santa Id Clara, 0.25 μCA,m, filmUnited thichness States, EI technique (70 eV), GC/MSD software, and an HP-5MS column, 30m, Id 0.25μm, film thichness Appl. Sci. 2019, 9, x 3 of 7

0.25μm. Amberlyst 15 was purchased from Sigma–Aldrich and was purified by soaking it in methanol for 24 h and then washing it with fresh methanol and THF and dried under a vacuum.

Appl.2.2. Preparation Sci. 2019, 9, 5168 of Starting Materials 3 of 8 β-Nitroacrylates 1 were synthesized by the Henry reaction–elimination process, starting from 2.2.nitroalkanes Preparation and of Startingalkyl glyoxalates Materials [23,24]. Arylhydrazines were purchased from Sigma–Aldrich as hydrochloride salts and were converted into the free bases by treatment with potassium carbonate in waterβ-Nitroacrylates [25]. 1 were synthesized by the Henry reaction–elimination process, starting from nitroalkanes and alkyl glyoxalates [23,24]. Arylhydrazines were purchased from Sigma–Aldrich as hydrochloride2.3. General Procedure salts and for werethe Preparation converted of into Compounds the free bases5 by treatment with potassium carbonate in water [25]. A mixture of β-nitroacrylate 1 (1 mmol) and arylhydrazine 2 (1 mmol) was stirred, under 2.3.solvent-free General Procedureand promoter-free for the Preparation conditions, of Compounds at room te5mperature for 2 h. Successively, acetonitrile (6 mL) and TMG (2 mmol, 0.230 mg) were added, and the resulting solution was stirred for a further 4 A mixture of β-nitroacrylate 1 (1 mmol) and arylhydrazine 2 (1 mmol) was stirred, under h. Then, the acetonitrile was removed under a vacuum, and for the purposes of removing the TMG, solvent-free and promoter-free conditions, at room temperature for 2 h. Successively, acetonitrile the reaction crude was filtered through a short pad of silica (3 g) and washed with ethyl acetate (25 (6 mL) and TMG (2 mmol, 0.230 mg) were added, and the resulting solution was stirred for a further mL). After evaporation under the vacuum of ethyl acetate, the mixture of tautomers 4, 4′, and 4′’ were 4 h. Then, the acetonitrile was removed under a vacuum, and for the purposes of removing the TMG, dissolved in 10 mL of the appropriate alcohol, treated with 2 g of Amberlyst 15, and irradiated by the the reaction crude was filtered through a short pad of silica (3 g) and washed with ethyl acetate (25 mL). Biotage® Initiator+ at 90 °C for 4 h. Finally, the resin was filtered off and it was washed with fresh After evaporation under the vacuum of ethyl acetate, the mixture of tautomers 4, 4 , and 4” were ethyl acetate (15 mL) and the crude product 5, which was obtained after removal of0 the solvent at dissolved in 10 mL of the appropriate alcohol, treated with 2 g of Amberlyst 15, and irradiated by the reduced pressure, and was purified by flash chromatography column (hexane–dichloromethane Biotage® Initiator+ at 90 C for 4 h. Finally, the resin was filtered off and it was washed with fresh 6:4). ◦ ethyl acetate (15 mL) and the crude product 5, which was obtained after removal of the solvent at reduced3. Results pressure, and Discussion and was purified by flash chromatography column (hexane–dichloromethane 6:4). 3. ResultsThis new and Discussionapproach (Scheme 3, Way a) involves two different steps: (i) A one-pot Michael addition/elimination process, in which the arylhydrazines 2 reacts with 1 to form adduct 3, which This new approach (Scheme3, Way a) involves two di fferent steps: (i) A one-pot Michael under basic conditions, eliminates nitrous acid and provides intermediate 4; and (ii) an acidic addition/elimination process, in which the arylhydrazines 2 reacts with 1 to form adduct 3, which under promoted indolization of 4 into the title target 5. basic conditions, eliminates nitrous acid and provides intermediate 4; and (ii) an acidic promoted indolization of 4 into the title target 5. 3.1. Optimization of the 1st Step 3.1. OptimizationIn order to optimize of the 1st Stepthe entire protocol, we first investigated the Michael addition/elimination one-potIn order process to optimize using phenylhydrazine the entire protocol, 2a weand first the investigated β-nitroacrylate the Michael1a as reagents. addition /Preliminaryelimination one-potstudies highlighted process using the phenylhydrazine almost quantitative2a and addition the β-nitroacrylate of 2a to 1a under1a as solvent-free reagents. Preliminary and promoter-free studies highlightedconditions theat room almost temperature quantitative addition(2 h). Further of 2a to investigations1a under solvent-free (in terms and promoter-freeof solvents, bases, conditions and atreaction room temperature temperatures) (2 h). were Further dedicated investigations to nitrous (in acid terms elimination, of solvents, and bases, the and best reaction result temperatures)was obtained wereusing dedicated two equivalents to nitrous of TMG acid elimination, in MeCN at androom the temp besterature result was (4 h, obtained entry f). usingInstead two of equivalents obtaining the of TMGpure inadduct MeCN 4a at, a room mixture temperature of tautomers (4 h, entry 4a, 4a’, f). Insteadand 4a” of were obtaining isolated the purein a ratio adduct of 4aapproximately, a mixture of 54:13:33. The ratio was calculated by 1H-NMR on the basis of the characteristic signal of each tautomers 4a, 4a0, and 4a” were isolated in a ratio of approximately 54:13:33. The ratio was calculated by 1tautomer,H-NMR on as the depicted basis of in the Figure characteristic 1. Nevertheless, signal of eachall tautomers tautomer, aswere depicted suitable in Figurefor the1 .Fischer Nevertheless, indole allsynthesis tautomers (Table were 1). suitable for the Fischer indole synthesis (Table1).

Figure 1. Characteristic 1H-NMR signal of tautomers 4a, 4a , and 4a” (tautomeric ratio 54:13:33). Figure 1. Characteristic 1H-NMR signal of tautomers 4a, 4a’,0 and 4a’’ (tautomeric ratio 54:13:33). Appl. Sci. 2019, 9, x 4 of 7

Appl. Sci. 2019, 9, 5168 4 of 8

Table 1. Optimization studies concerning the addition/elimination step. Table 1. Optimization studies concerning the addition/elimination step.

Entry Base Solvent Temp. Time (h) Yield (%) of 4a-a” Entry Base Solvent Temp. Time (h) Yield (%) of 4a-a” A ADBU DBU (1 eq.) (1 eq.) MeCN MeCN rt rt2 2 23 B TMG (1 eq.) MeCN rt 4 55 B TMG (1 eq.) MeCN rt 4 551 C KF/Al2O3 (1 eq.) MeCN rt 24 — 1 C DKF/Al PS-Carbonate2O3 (1 eq.) (1 eq.) MeCN MeCN rt rt 24 24 —--- 1 D E PS-Carbonate PS-TBD (1 eq.)eq.) MeCN MeCN rt rt 24 4 --- 35 1 E F PS-TBD TMG (1 (2eq.) eq.) MeCN MeCN rt rt 4 4 3575 F G TMG TMG (2 eq.) (2 eq.) MeCN MeCN 50rt ◦C 4 1 7560 H TMG (3 eq.) MeCN rt 4 71 G I TMG TMG (2 eq.) (2 eq.) MeCN THF 50 °C rt 1 4 6035 H J TMG TMG (3 eq.) (2 eq.) MeCN EtOAc rt rt 4 4 7149 I K TMG TMG (2 eq.) (2 eq.) THF DCM rt rt 4 4 3521 J TMG (2 eq.) EtOAc rt 4 49 1 No reaction occurs. K TMG (2 eq.) DCM rt 4 21 1 No reaction occurs. 3.2. Optimization of the 2nd Step 3.2. OptimizationSuccessively, of we the faced 2nd Step off the indolization of tautomers 4a-a” into the alkyl indole-2-carboxylate 5a. InSuccessively, this context, wewe first faced performed off the additionindolization/elimination of tautomers one-pot process, 4a-a” theninto the the TMG alkyl was removedindole-2-carboxylate by fast filtration 5a. Inthrough this context, a short we padfirst ofperformed Silica, and the finally, addition/elimination after the removal one-pot of the process, solvent underthen the a vacuum, TMG was the removed crude 4a-a” by werefast filtration subjected through to a variety a short of acidic pad conditions.of Silica, and Initially, finally, inspired after the by theremoval literature, of the we solvent tested PPA,under ZnCl a vacuum,2/AcOH, the SOCl crude2/EtOH, 4a-a” and werep-toluenesulfonic subjected to a acid variety/EtOH of [ 26acidic–29]. Onlyconditions. the latter Initially, system inspired was effi bycient the for literature, the indolization we tested reaction PPA, (3eq.ZnCl2p/AcOH,-TsOH, EtOH,SOCl2/EtOH, reflux, and 8 h, 32%).p-toluenesulfonic Based on this acid/EtOH result and [26–29]. following Only our the studies latter concerning system was the useefficient of heterogeneous for the indolization systems, wereaction repeated (3eq. the p reaction-TsOH, usingEtOH, 1g reflux,/mmol of8 Amberlysth, 32%). Based 15, a sulfonicon this acidresult type and based following upon a styrene-DVBour studies copolymerconcerning [the30]. use Under of heterogeneous these conditions, systems,5a waswe repeated recovered the in reaction a similar using yield 1g/mmol (30%), of but Amberlyst with the remarkable15, a sulfonic advantage acid type of based minimizing upon a thestyrene-DVB work-up step copolymer to an easy [30]. filtration, Under these thus avoidingconditions, the 5a classic was tediousrecovered and in wastefullya similar yield aqueous (30%), work-up. but with the Further remarkable tests permitted advantage the of optimizationminimizing the of work-up reaction conditionsstep to an easy (Table filtration,2), and thus the best avoiding yield ofthe 5aclassic(over tedious the two and steps) wastefully was recorded, aqueous underwork-up. microwave Further irradiationtests permitted at 90 the◦C foroptimization 4 h, using 2of g reaction/mmol of conditions Amberlyst (Table 15 (Entry 2), and k, 54%). the best yield of 5a (over the two steps) was recorded, under microwave irradiation at 90 °C for 4 h, using 2 g/mmol of Amberlyst 15 (Entry k, 54%).

Table 2. Optimization studies concerning the indolization step.

Entry Amberlyst 15 (g/mmol) Temp. (°C) Time (h) Yield (%) 1 of 5a a 1 reflux 8 30 b 1.5 reflux 8 34 c 2 reflux 8 38 d 2.5 reflux 8 39 Appl. Sci. 2019, 9, x 4 of 7

Table 1. Optimization studies concerning the addition/elimination step.

Entry Base Solvent Temp. Time (h) Yield (%) of 4a-a” A DBU (1 eq.) MeCN rt 2 23 B TMG (1 eq.) MeCN rt 4 55 C KF/Al2O3 (1 eq.) MeCN rt 24 --- 1 D PS-Carbonate (1 eq.) MeCN rt 24 --- 1 E PS-TBD (1 eq.) MeCN rt 4 35 F TMG (2 eq.) MeCN rt 4 75 G TMG (2 eq.) MeCN 50 °C 1 60 H TMG (3 eq.) MeCN rt 4 71 I TMG (2 eq.) THF rt 4 35 J TMG (2 eq.) EtOAc rt 4 49 K TMG (2 eq.) DCM rt 4 21 1 No reaction occurs.

3.2. Optimization of the 2nd Step Successively, we faced off the indolization of tautomers 4a-a” into the alkyl indole-2-carboxylate 5a. In this context, we first performed the addition/elimination one-pot process, then the TMG was removed by fast filtration through a short pad of Silica, and finally, after the removal of the solvent under a vacuum, the crude 4a-a” were subjected to a variety of acidic conditions. Initially, inspired by the literature, we tested PPA, ZnCl2/AcOH, SOCl2/EtOH, and p-toluenesulfonic acid/EtOH [26–29]. Only the latter system was efficient for the indolization reaction (3eq. p-TsOH, EtOH, reflux, 8 h, 32%). Based on this result and following our studies concerning the use of heterogeneous systems, we repeated the reaction using 1g/mmol of Amberlyst 15, a sulfonic acid type based upon a styrene-DVB copolymer [30]. Under these conditions, 5a was recovered in a similar yield (30%), but with the remarkable advantage of minimizing the work-up step to an easy filtration, thus avoiding the classic tedious and wastefully aqueous work-up. Further tests permitted the optimization of reaction conditions (Table 2), and the best yield of 5a (over the two steps) was recorded, under microwave irradiation at 90 °C for 4 h, using 2 g/mmol of Amberlyst Appl.15 (Entry Sci. 2019 k, ,54%).9, 5168 5 of 8

Table 2. Optimization studies concerning the indolization step. Table 2. Optimization studies concerning the indolization step.

Appl. Sci. 2019, 9, x 5 of 7 1 EntryEntry Amberlyst Amberlyst 15 15(g/mmol) (g/mmol) Temp. Temp. (°C) (◦C) Time Time (h) Yield (%)(%) 1of of 5a 5a e 2 60 8 15 a 1 reflux 8 30 a 1 reflux2 8 30 f b 2 100 8 40 b 1.51.5 reflux reflux 8 8 3434 g c 2 2reflux reflux 16 8 3845 c 2 reflux 8 38 h d 2 2.5reflux reflux 24 8 3953 d 2.5 reflux 8 39 i e 2 2reflux 60 32 8 1551 f 2 100 2 8 40 3 j g 2 280 reflux 164 45 42 k h 2 290 reflux 3 244 53 54 l i 2 2100 reflux 3 324 51 49 3 1Overall yield jof the pure isolated2 product. 2Reaction 80 performed4 in a sealed 42 vessel. 3Reaction k 2 90 3 4 54 performed in a sealed vessel under microwave irradiation. l 2 100 3 4 49

3.3. Substrate1 Overall yield Scope of Investigation the pure isolated product. 2 Reaction performed in a sealed vessel. 3 Reaction performed in a sealed vessel under microwave irradiation. Lastly, to achieve the aim of verifying the generality of our protocol, we tested a variety of 3.3.β-nitroacrylates Substrate Scope and Investigation arylhydrazines under the optimized reaction conditions (Table 3). In all cases, the products were isolated from satisfactory to good overall yields (38%–55%), even in the presence of versatileLastly, toand achieve reactive the aimfunctionalities. of verifying theIn generalityparticular, ofit ourwas protocol, possible we to tested prepare a variety indoles of βfunctionalized-nitroacrylates on and the arylhydrazines C-3 chain that underwere suitable the optimized for further reaction manipulations, conditions (Table such 3as). 5e-g In all and cases, 5j, thewhich products contained were a isolatedphenyl ring, from a satisfactory double and to tr goodiple bond, overall and yields an ester (38–55%), group, evenrespectively. in the presence of versatileIt is andimportant reactive to functionalities. highlight that, Inin particular,order to pr itevent was possiblethe transesterificatio to prepare indolesn reaction functionalized at C-2, the onindolization the C-3 chain was thatconducted were suitable using the for same further alcohol manipulations, (R3OH) of suchthe ester as 5e-g moiety.and 5j , which contained a phenyl ring, a double and triple bond, and an ester group, respectively. Table 3. Synthesis of indoles 5a–m. Table 3. Synthesis of indoles 5a–m.

2 3 1 EntryEntry R R2 R R3 GG SolventSolvent YieldYield (%) (%) 1 ofof 5 5 a a EtEt EtEt HH EtOHEtOH5a 5a 5454 b CH (CH ) Et H EtOH 5b 52 b 3CH3(CH2 4 2)4 Et H EtOH 5b 52 c CH3(CH2)8 Et H EtOH 5c 50 d c CHEt3(CH2)8 EtEt 7-Me H EtOHEtOH5d 5c 5550 e d Ph(CH2Et)2 EtEt H7-Me EtOH EtOH5e 5d 4355 f e CH2=CH(CHPh(CH2)22)2 EtEt 7-Me H EtOHEtOH5f 5e 4343 g CH C(CH ) Et H EtOH 5g 41 f CH≡ 2=CH(CH2 3 2)2 Et 7-Me EtOH 5f 43 h Et Me H MeOH 5h 42 i g CHEt≡C(CH2)3 MeEt 5-Br H MeOH EtOH5i 5g 4141 j h MeOOC(CHEt2 )4 MeMe HH MeOHMeOH5j 5h 3642 k i EtEt PrMe H5-Br PrOHMeOH5k 5i 4641 l j MeOOC(CHEt2)4 Pr Me 7-Me H PrOH MeOH5l 5j 4536 m CH (CH ) Pr H PrOH 5m 38 k 3 Et2 6 Pr H PrOH 5k 46 l 1EtOverall yieldPr of the7-Me pure isolated PrOH product. 5l 45 m CH3(CH2)6 Pr H PrOH 5m 38 1 Overall yield of the pure isolated product.

4. Conclusions In conclusion, we disclosed a new, important application of β-nitroacrylates as a valuable alternative of α-ketoesters for synthesizing alkyl indole-2-carboxylates, which were key and useful intermediates of biologically active molecules. The method involved two easy steps and afforded title targets with a good substrate scope generality and satisfactory overall yields. Moreover, thanks to the possibility of removing the TMG by an easy filtration through the silica (first step), and the use Appl. Sci. 2019, 9, 5168 6 of 8

It is important to highlight that, in order to prevent the transesteriﬁcation reaction at C-2, the indolization was conducted using the same alcohol (R3OH) of the ester moiety. Detailed spectroscopic data for compounds 5a-m are included in the Supplementary Materials.

4. Conclusions In conclusion, we disclosed a new, important application of β-nitroacrylates as a valuable alternative of α-ketoesters for synthesizing alkyl indole-2-carboxylates, which were key and useful intermediates of biologically active molecules. The method involved two easy steps and afforded title targets with a good substrate scope generality and satisfactory overall yields. Moreover, thanks to the possibility of removing the TMG by an easy filtration through the silica (first step), and the use of heterogeneous Amberlyst 15 in the second step, it was possible to avoid the typical tedious and wasteful aqueous work-up, with evident advantages from a sustainability point of view.

Supplementary Materials: The following are available online at http://www.mdpi.com/2076-3417/9/23/5168/s1, Spectroscopic Data. Author Contributions: Conceptualization, S.G. and D.P.; methodology, S.G.; investigation, D.P.; validation, S.G. and D.P.; data curation, S.G.; writing—original draft preparation, A.P.; writing—review and editing, A.P.; supervision, R.B.; project administration, A.P.; funding acquisition, A.P. Funding: This research received no external funding. Acknowledgments: The authors thank the University of Camerino for financial support. Conflicts of Interest: The authors declare no conflict of interest.

Abbreviations The following abbreviations are used in this manuscript:

TMG 1,1,3,3-Tetramethylguanidine DBU 1,5-Diazabiciclo[5.4.0]undec-5-ene 1,5,7-Triazabicyclo[4.4.0]dec-5-ene bound to polystyrene PS-TBD (Sigma-Aldrich code: 01961) PS-Carbonate Carbonate on polymer support (Sigma-Aldrich code: 21850) NNRTI Non-nucleoside reverse transcriptase inhibitor PPA Poly Phosphoric Acid

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