Synthesis and Crystallographic Characterization of a Maleimide
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crystals Technical Note TechnicalSynthesis Note and Crystallographic Characterization of a SynthesisMaleimide and Derivative Crystallographic of Tryptamine Characterization of a Maleimide Derivative of Tryptamine Jean Dubois 1,†, Melwin Colaço 2,†, Grégoire Rondelet 1 and Johan Wouters 1,* 1,† 2,† 1 1, Jean1 Department Dubois Chemistry,, Melwin Univer Colaçosity of, Grégoire Namur, 61 Rondelet rue de Bruxandelles, Johan B-5000 Wouters Namur, Belgium;* [email protected] (J.D.); [email protected] (G.R.) 1 Department Chemistry, University of Namur, 61 rue de Bruxelles, B-5000 Namur, Belgium; 2 Department Chemistry, St Joseph’s College, P O Box 27094, Bangalore 560 027, India; [email protected] (J.D.); [email protected] (G.R.) [email protected] 2 Department Chemistry, St Joseph’s College, P O Box 27094, Bangalore 560 027, India; [email protected] ** Correspondence:Correspondence: johan.wouter [email protected];[email protected]; Tel.: Tel.: +32-81-724550 +32-81-724550 † †Both Both authors authors contributed contributed equally. equally. Academic Editor: Helmut Cölfen Received: 4 October 2016; Accepted: 16 November 2016; Published: date 21 November 2016 Abstract: While mechanosynthesis of the target compound, 1-[2-(1 H-indol-3-yl)-ethyl]-pyrrole-2,5- dione, C14 HH1212 NN2 2OO2,2 did, did not not yield yield the the desired desired product, product, it it in insteadstead resulted resulted in in an an open open intermediate. intermediate. On the other hand, synthesis starting from thethe activated maleic anhydride yielded the finalfinal maleimide compound. The outcome of the mechanos mechanosynthesisynthesis has been evaluated by powder X-ray diffraction, and structures of both the finalfinal productproduct and open intermediate have been confirmedconfirmed using single-crystal crystallography. Keywords: mechanosynthesis; grinding; single-crystal structure; powder X-ray diffraction; maleic anhydride; tryptamine 1. Introduction Introduction This work forms a part of ourour studystudy onon epigeneticepigenetic modulationmodulation byby DNADNA methyltransferasesmethyltransferases (Mtases) [1[1,2].,2]. It It was was a consequence a consequence of attempting of attempting to synthesize to synthesize analogues analogues of N-phthalyl- of NL-tryptophan-phthalyl-L- (RG108),tryptophan which (RG108), are non-nucleosidic which are non-nucleosidic inhibitors of inhibitors Mtases [3 ,of4]. Mtases [3,4]. 1-[2-(1H-Indol-3-yl)-ethyl]-pyrrole-2,5-dione, C C1414HH1212N2OO22 (Scheme(Scheme 11,, compoundcompound 11)) is is a a potential potential Mtase inhibitor [4]. [4]. We report here ourour attemptattempt toto synthesizesynthesize thisthis compoundcompound byby mechanosynthesismechanosynthesis based onon a successfula successful approach approach adopted adopted for phthalimides for phthalimides using grinding using ofgrinding corresponding of corresponding anhydrides andanhydrides amines and [5]. amines [5]. This approach led to the corresponding openopen product,product, 1o1o.. Scheme 1. Chemical diagram of compounds under study. The crystal structure of N-phthalyl-L-tryptophan (RG108) has been obtained alone (CSD [6] The crystal structure of N-phthalyl-L-tryptophan (RG108) has been obtained alone (CSD [6] refcode OZITAT [7]) or as a salt with dicyclohexylamine (CSD refcode WADRAW [8]). The crystal refcode OZITAT [7]) or as a salt with dicyclohexylamine (CSD refcode WADRAW [8]). The crystal structure of a nitro-substituted analog of RG108 has also been determined (CSD refcode EVIWEM structure of a nitro-substituted analog of RG108 has also been determined (CSD refcode EVIWEM [9]). Crystals 2016, 6, 153; doi:10.3390/cryst6110153 www.mdpi.com/journal/crystals Crystals 2016, 6, 153; doi:10.3390/cryst6110153 www.mdpi.com/journal/crystals Crystals 2016, 6, 153 2 of 8 Crystals 2016, 6, 153 2 of 8 To theCrystals best 2016 of, 6 our, 153 knowledge, these are the only deposited crystal structures for this, otherwise2 of well8 documented,[9]). To the familybest of ofour compounds. knowledge, these are the only deposited crystal structures for this, otherwise [9]). To the best of our knowledge, these are the only deposited crystal structures for this, otherwise well documented, family of compounds. 2.well Results documented, and Discussion family of compounds. 2. Results and Discussion 2.1.2. Synthesis Results and and Discussion Crystallization 2.1. Synthesis and Crystallization 2.1.1.2.1. Mechanosynthesis Synthesis and Crystallization 2.1.1. Mechanosynthesis 2.1.1.Initial Mechanosynthesis attempts to obtain target maleimide 1 were based on our previous work where Initial attempts to obtain target maleimide 1 were based on our previous work where mechanosynthesisInitial attempts was to used obtain to preparetarget maleimide phthalimide 1 were compounds based on [5 ].our In previous brief, the work starting where solid mechanosynthesis was used to prepare phthalimide compounds [5]. In brief, the starting solid reactants,mechanosynthesis tryptamine was (2) andused maleicto prepare anhydride phthalimide (3) (Figure compounds1), were [5]. ground In brief, in anthe equimolarstarting solid ratio, reactants, tryptamine (2) and maleic anhydride (3) (Figure 1), were ground in an equimolar ratio, reactants, tryptamine (2) and maleic anhydride (3) (Figure 1), were ground in an equimolar ratio, eithereither manually manually using using a mortara mortar and and pestle pestle oror mechanicallymechanically using using a a vibration vibration ball ball mill mill Retsch Retsch MM400 MM400 either manually using a mortar and pestle or mechanically using a vibration ball mill Retsch MM400 (Retsch(Retsch GmbH, GmbH, Haan, Haan, Germany Germany ) (60 ) (60 min min at at 30 30 Hz, Hz, 2–10 2–10 balls balls added added to to a a 2 2 mLmL plasticplastic vial).vial). Progress of (Retsch GmbH, Haan, Germany ) (60 min at 30 Hz, 2–10 balls added to a 2 mL plastic vial). Progress reactionof reaction was monitored was monitored by powder by X-raypowder diffraction X-ray diffraction (Panalytical (Panalytical ProX’pres, ProX’pres, Almelo, the Almelo, Netherlands, the of reaction was monitored by powder X-ray diffraction (Panalytical ProX’pres, Almelo, the CuNetherlands, radiation) (Figure Cu radiation)2). (Figure 2). Netherlands, Cu radiation) (Figure 2). Figure 1. Synthetic route to 1, using a solvent-free mechanosynthetic approach. FigureFigure 1. 1.Synthetic Synthetic route route to to1 1,, usingusing aa solvent-free mech mechanosyntheticanosynthetic approach. approach. Figure 2. Powder X-ray diffractograms showing the outcome of the grinding experiment. Starting Figure 2. Powder X-ray diffractograms showing the outcome of the grinding experiment. Starting Figuresolids 2. Powder(maleic anhydrate X-ray diffractograms and tryptamine), showing solid the outcomeobtained ofafte ther grinding grinding (60 experiment. min at 30 Starting Hz), solid solids solids (maleic anhydrate and tryptamine), solid obtained after grinding (60 min at 30 Hz), solid (maleicobtained anhydrate after heating and tryptamine), (30 min at 140 solid °C). obtained Diffractogr afterams grinding simulated (60 minon the at basi 30 Hz),s of solidthe single obtained crystal after obtained after heating (30 min at 140 °C). Diffractograms simulated on the basis of the single crystal heatingstructures (30 min of 1 at and 140 1o◦ C).are Diffractogramspresented for comparison. simulated on the basis of the single crystal structures of 1 structures of 1 and 1o are presented for comparison. and 1o are presented for comparison. Crystals 2016, 6, 153 3 of 8 CrystalsUpon 2016 grinding,, 6, 153 characteristic diffraction peaks of the reactants were replaced by peaks associated3 of 8 to the new ground product (Figure2). Recrystallization of the ground solid from a saturated solution Upon grinding, characteristic diffraction peaks of the reactants were replaced by peaks in aassociated MeOH/toluene to the mixturenew ground led toproduct small (Figure single crystals2). Recrystallization useful for crystal of the structureground solid determination. from a X-raysaturated diffraction solution analysis in a MeOH/toluene revealed that the mixture compound led to small obtained single upon crystals grinding useful isfor the crystal open structure maleamide intermediatedetermination.1o (Section X-ray diffraction 2.2). This analysis result revealed is consistent that the withcompound similar obtained observations upon grinding that we is the made for phthalimidesopen maleamide [5 ].intermediate Powder diffractogram 1o (Section 2.2). simulated This result onis consistent the basis with of the similar single observations crystal structure that coordinateswe made (Figurefor phthalimides2) corresponds [5]. Powder to the diffractog experimentalram simulated data recorded on the onbasis the of solidthe single obtained crystal after grinding,structure confirming coordinates that (Figure the bulk2) corresponds powder correspondsto the experimental to 1o .data Conversion recorded on in the almost solid quantitativeobtained (>95%)after as grinding, judged fromconfirming NMR that and the powder bulk powder X-ray corresponds diffraction data. to 1o. Conversion in almost quantitative (>95%)We expected as judged to from get the NMR final, and closed powder maleimide X-ray diffraction1 on heating data. the intermediate [5]. Despite several attempts,We we expected were unable to get tothe convert final, closed intermediate maleimide1o 1 oninto heating the target the intermediate compound [5].1. Despite several attempts,