applied sciences 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 “privilegedthe “privileged structures” structures” of the mainof the sca mainffolds scaffolds for the discovery for the ofdiscovery new drug of candidatesnew drug [1candidates,2]. For all these[1,2]. reasons,For all athese growing reasons, number a growing of synthetic number approaches of synthetic for its preparationapproaches andfor derivatizationits preparation have and been derivatization reported in the have literature been [reported3–5]. Nowadays, in the notwithstandingliterature [3–5]. theNowadays, development notwithstanding of new methodologies the development concerning of thenew ex-novo methodologies preparation concerning of indoles, thethe 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 directedhave 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,software.equipped 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