Vinylation of a Secondary Amine Core with Calcium Carbide for Efficient

molecules

Article Vinylation of a Secondary Amine Core with Calcium Carbide for Efﬁcient Post-Modiﬁcation and Access to Polymeric Materials

Konstantin S. Rodygin 1, Alexander S. Bogachenkov 1 and Valentine P. Ananikov 1,2,* ID

1 Saint Petersburg State University, Universitetsky Prospect, 26, St. Petersburg 198504, Russia; [email protected] (K.S.R.); [email protected] (A.S.B.) 2 Zelinsky Institute of Organic Chemistry, Russian Academy of Science, Leninsky Prospect, 47, Moscow 119991, Russia * Correspondence: [email protected]

Received: 16 February 2018; Accepted: 9 March 2018; Published: 13 March 2018

Abstract: We developed a simple and efﬁcient strategy to access N-vinyl secondary amines of various naturally occurring materials using readily available solid acetylene reagents (calcium carbide, KF, and KOH). Pyrrole, pyrazole, indoles, carbazoles, and diarylamines were successfully vinylated in good yields. Cross-linked and linear polymers were synthesized from N-vinyl carbazoles through free radical and cationic polymerization. Post-modiﬁcation of olanzapine (an antipsychotic drug substance) was successfully performed.

Keywords: acetylene; calcium carbide; vinylation; olanzapine; functionalization

1. Introduction Nitrogen-containing compounds are one of the most important functional molecules in modern chemistry, biology, and drug development. Nucleic acids, N-heterocyclic compounds, amines, amino-acids, and their biopolymers are pivotal to a vast majority of biochemical processes. Effective modification of secondary amines by the insertion of a vinyl group leads to demanded N-vinyl derivatives with a variety of new applications. Vinylated products are interesting both as biologically active cores [1] and as versatile building blocks for polymerization [2]. At the same time, carbazole-based compounds are considered promising as photoconductors and charge-transporting materials [3] in the aftermath of the discovery of photoconductivity in poly(N-vinylcarbazole) [4]. The unique properties of vinyl amines are exemplified by their ability to polymerize under both cationic [5] and free radical conditions [6]. Polymer synthesis with N-heterocyclic moieties like diazepine has great potential for application. The biologically active core can be converted into a polymeric form, which is capable of gradual depolymerization and release under specific conditions. Current methods for preparing N-vinyl derivatives of secondary amines involve the vinyl exchange reaction (Scheme1, route a), which requires a source of vinyl group (in most cases represented by vinyl acetate) and a metal catalyst. Enamines from nitrogenous bases [7], imidazole [8], triazoles [9], carbazole [10], and pyrrolidone [11] can be successfully obtained by this approach.

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SchemeScheme 1. 1.SyntheticSynthetic procedures procedures to accessaccessN N-vinyl‐vinyl derivatives. derivatives.

CrossCross-coupling‐coupling reactions, reactions, catalyzed catalyzed by by copper copper [12] [12] andand iron iron [ 13[13],], or or palladium palladium complexes complexes [14], [14], requirerequire a partner: a partner: trimethyloxyvinylsilane trimethyloxyvinylsilane [ 15[15],], potassium potassium vinyltrifluoroborate vinyltrifluoroborate [16], or [16], vinyl or halide vinyl [17 halide] [17] (Scheme1 ,1, route route b). Anotherb). Another non-atom non‐ economicatom economic strategy, strategy, elimination, elimination, is based on ais two-step based on sequence, a two‐step sequence,which which is carried is carried out under out basic under conditions basic conditions (Scheme1 ,(Scheme route c). 1, The route Clemo-Perkin c). The Clemo method‐Perkin [ 18] andmethod [18] dehydrohalogenationand dehydrohalogenation in the presence in the ofpresence phase transfer of phase catalyst transfer [19] lead catalyst to N-vinyl [19] derivativeslead to N of‐vinyl derivativesindoles of [20 indoles], carbazoles [20], [carbazoles21], imidazoles [21], [ 22imidazoles], pyrazoles, [22], triazoles, pyrazoles, or tetrazoles triazoles, [23 or] and tetrazoles nitrogenous [23] and nitrogenousbases [24 ].bases Several [24]. other Several transformations other transformations leading to N-vinyl leading derivatives, to suchN‐vinyl as dehydrogenation derivatives, [such25], as ethylene insertion [26], and amine/aldehyde condensation could be also mentioned [27]. dehydrogenation [25], ethylene insertion [26], and amine/aldehyde condensation could be also An excellent atom-economic opportunity is provided by the addition reaction of acetylene, mentioned [27]. proceeding without by-product formation, which is to say that all atoms of starting materials become incorporatedAn excellent into atom products.‐economic This opportunity reaction (Scheme is provided1, route by d) the was addition originally reaction implemented of acetylene, by proceedingReppe [without28], and by it is‐product still used formation, with several which optimizations is to say that [29 all]. atoms Arylamines of starting can be materials successfully become incorporatedvinylated into according products. to this This procedure reaction [ 30(Scheme]. However, 1, route using d) andwas handlingoriginally pressured implemented acetylene by Reppe is [28], technicallyand it is still difficult used and with requires several dedicated optimizations hardware [29]. [31, 32Arylamines]. Not surprisingly, can be thissuccessfully atom-economic vinylated accordingapproach, to this despite procedure being efficient [30]. However, in terms ofusing chemistry, and handling has not found pressured widespread acetylene application is technically in difficultsynthetic and requires practice. dedicated hardware [31,32]. Not surprisingly, this atom‐economic approach, despite beingAs an alternativeefficient in to terms high pressure of chemistry, acetylene, has calcium not found carbide widespread has demonstrated application a very impressive in synthetic practice.potential in organic transformations [32–40]. Calcium carbide is inexpensive and readily available at the large-scale commercial production level. Currently, a carbide-based synthesis is underestimated in As an alternative to high pressure acetylene, calcium carbide has demonstrated a very its potential to provide not only useful intermediates for lab chemistry, but also materials and polymers impressive potential in organic transformations [32–40]. Calcium carbide is inexpensive and readily for fine technology [32,40]. As representative examples, the vinylation of O-H and S-H groups has availablebeen reportedat the large [36–‐40scale]. However, commercial the vinylation production of the level. N-H Currently, group is challenging, a carbide‐ andbased only synthesis indole is underestimatedderivatives have in its been potential studied to [ 41provide]. Recently, not only we developed useful intermediates a concept involving for lab a chemistry, solid acetylene but also materialsreagent, and where polymers the reactivity for fine oftechnology calcium carbide [32,40]. and As in representative situ generated examples, acetylene was the tunedvinylation by the of O‐ H andaddition S‐H ofgroups KF [38 ].has been reported [36–40]. However, the vinylation of the N‐H group is challenging,In this and work, only weindole developed derivatives a synthetic have been methodology studied [41]. for preparing Recently,N we-vinyl developed derivatives a concept of involvingsecondary a solid amines acetylene by utilizing reagent, a solid where acetylene the reactivity reagent (Schemeof calcium1, route carbide e). Fluoride-mediatedand in situ generated acetylene was tuned by the addition of KF [38]. In this work, we developed a synthetic methodology for preparing N‐vinyl derivatives of secondary amines by utilizing a solid acetylene reagent (Scheme 1, route e). Fluoride‐mediated vinylation is a powerful and new approach not addressed previously for the functionalization of amines. The vinylation of pyrrole, pyrazole, carbazoles, and diarylamines is reported here for the first time. This method has a number of key advantages from the standpoint of green chemistry (Scheme

Molecules 2018, 23, 648 3 of 11 Molecules 2018, 23, x 3 of 11 vinylation1, route is e) a powerfuland a very and newsimple approach practical not procedure addressed was previously developed for the using functionalization a combination of of amines.CaC2 The/KOH/KF. vinylation of pyrrole, pyrazole, carbazoles, and diarylamines is reported here for the first time. This method has a number of key advantages from the standpoint of green chemistry (Scheme1, route2. Results e) and a and very Discussion simple practical procedure was developed using a combination of CaC2/KOH/KF. Optimization of the proposed system was carried out to find the optimal conditions, particularly 2. Results and Discussion the solvent and the temperature. First, a dedicated experiment was performed to choose a solvent: piecesOptimization of calcium of the carbide proposed were system exposed was to carried a solvent/water out to find the mixture optimal under conditions, stirring. particularly In cases of thehydrophobic solvent and thesolvents temperature. (e.g., hexane First, or a dedicatedtoluene), two experiment phases appeared, was performed and calcium to choose carbide a solvent: reacted piecesmuch of faster calcium when carbide the water were was exposed heavier to than a solvent/water the solvent. In mixture both cases, under the stirring. release of In acetylene cases of did hydrophobicnot match solventsthe rate of (e.g., nucleophilic hexane or addition toluene), to twothe triple phases bond, appeared, and the and product calcium yields carbide were reactedlow (Table much1, entries faster when 1 and the 2). water In cases was heavierof dimethyl than thesulfoxide solvent. (DMSO) In both cases,and dimethyl the release formamide of acetylene (DMF), did a notsufficiently match the rate slow of release nucleophilic of gaseous addition acetylene to the triple allowed bond, us and to obtain the product and utilize yields wereits constant low (Table flow.1, To entriesminimize 1 and 2).losses, In cases we offinally dimethyl chose sulfoxide to employ (DMSO) DMSO, and avoiding dimethyl DMF formamide for its (DMF), partial a decomposition sufficiently slowduring release the of reaction. gaseous acetyleneFurthermore, allowed acetylene us to obtainhas good and solubility utilize its in constant DMSO, flow. and inorganic To minimize salts losses, are also wesoluble finally chosein DMSO. to employ DMSO, avoiding DMF for its partial decomposition during the reaction. Furthermore,Reaction acetylene in DMSO has gave good the solubility product in in DMSO, 38% yield and (Table inorganic 1, entry salts 3), are which also solublewas further in DMSO. improved toReaction 80% (Table in DMSO 1, entry gave 4). theIncreasing product loads in 38% of yield CaC (Table2 and 1water, entry did 3), not which improve was further the yields improved (Table 1, to 80%entries (Table 5, 6).1, entryDifferent 4). Increasingbases were loads probed of CaC(NaOH,2 and TEA, water K2CO did3, notNa2 improveCO3, pyridine), the yields and (Table potassium1, entrieshydroxide 5, 6). Different turned out bases to be were the probed most suitable. (NaOH, It TEA, was also K2CO important3, Na2CO to3, use pyridine), both components—KOH and potassium hydroxideand KF—simultaneously, turned out to be the since most using suitable. them It was separately also important significantly to use decreased both components—KOH the yields (Table and 1, cf. KF—simultaneously,entries 7, 8, and 4). since Interesting using them to note, separately the usage significantly of KF provided decreased a higher the yields yield (Tableas compared1, cf. entries to KOH 7, 8,(Table and 4). 1, Interestingentries 7, 8). to note, the usage of KF provided a higher yield as compared to KOH (Table1, entries 7, 8). Table 1. Optimization of the reaction conditions. 1 Table 1. Optimization of the reaction conditions. 1

CaC2, base

H2O, additive N Solvent, T oC, h N H ◦ 2 Entry Solvent Base + Additive, equiv. CaC2, equiv. Water, equiv. T, C Time, h Yield, % 2 Entry1 HexaneSolvent BaseKOH+ (1.1), Additive, KF (1) equiv. CaC 22, equiv. Water, 4 equiv. 130T, °C Time, 4 h Yield, trace % 21 TolueneHexane KOHKOH (1.1), (1.1), KF (1)KF (1) 22 44 130130 44 tracetrace 32 DMSOToluene KOHKOH (1.1), (1.1), KF (1)KF (1) 22 44 130130 84 38trace 3 4 3 DMSODMSO KOHKOH (1.1), (1.1), KF (1)KF (1) 22 44 130130 48 80 38 5 DMSO KOH (1.1), KF (1) 2 8 130 4 62 4 3 DMSO KOH (1.1), KF (1) 2 4 130 4 80 6 DMSO KOH (1.1), KF (1) 4 8 130 4 57 75 DMSODMSO KOH KF (1.1), (1) KF (1) 22 48 130130 44 54 62 86 DMSODMSO KOH KOH (1.1), (1.1) KF (1) 24 48 130130 44 25 57 9 47 DMSODMSO KOH (1.1),KF KF (1) (1) 22 44 130130 44 88 54 108 DMSODMSO KOH (1.1),KOH KF (1.1) (1) 22 44 110130 44 66 25 11 DMSO KOH (1.1), KF (1) 2 4 150 4 50 9 4 DMSO KOH (1.1), KF (1) 2 4 130 4 88 12 DMSO KOH (1.5), KF (1.5) 2 4 130 4 52 13105 DMSODMSO KOH KOH, (1.1), KF KF (1) 22 -4 130110 44 trace66 11 DMSO KOH (1.1), KF (1) 2 4 150 4 50 1 Reaction12 DMSO conditions: substrateKOH (1.5), (1 equiv.), KF (1.5) CaC 2 (2 equiv.),2 KOH (1.1 equiv.),4 KF (1 equiv.),130 H2O4 (4 equiv.),52 2 3 4 DMSO13 5 (1 mL),DMSO 4 h; NMR yields;KOH, KFDMSO 3 mL; the2 yield ‐ after double vinylation,130 the yield4 after singletrace vinylation was 84%; 5 dry DMSO. 1 Reaction conditions: substrate (1 equiv.), CaC2 (2 equiv.), KOH (1.1 equiv.), KF (1 equiv.), H2O (4 equiv.), DMSO (1 mL), 4 h; 2 NMR yields; 3 DMSO 3 mL; 4 the yield after double vinylation, the yield Performing sequential vinylation by splitting the amount of calcium carbide into two parts after single vinylation was 84%; 5 dry DMSO. provided an excellent product yield of 88% (Table1, entry 9). The optimum temperature was estimated: lower temperaturesPerforming led sequential to incomplete vinylation conversion by splitting (Table1 ,the entry amount 10), while of calcium higher temperatures carbide into resulted two parts in theprovided decomposition an excellent and polymerizationproduct yield of of the88% product (Table (Table1, entry1, entry 9). The 11). optimum The optimal temperature amount of was baseestimated: was also established;lower temperatures further increasing led to itsincomplete amount led conversion to a decrease (Table in the 1, product entry 10), yields while (Table higher1, temperatures resulted in the decomposition and polymerization of the product (Table 1, entry 11). The optimal amount of base was also established; further increasing its amount led to a decrease in

Molecules 2018, 23, x 4 of 11 the product yields (Table 1, entry 12). The presence of water was necessary, as indicated by the control experiment,Molecules in 2018which, 23, 648 the reaction did not start without water in dry DMSO (Table 1, entry4 of 1113). The role of potassium fluoride in the studied system represents an interesting question. Microscopicentry examination 12). The presence of ofthe water solid was inorganic necessary, aspostreaction indicated by thewaste, control obtained experiment, in the in which absence the of KF, reaction did not start without water in dry DMSO (Table1, entry 13). indicated the formation of Ca(OH)2, as could be expected due to reaction of calcium carbide with The role of potassium fluoride in the studied system represents an interesting question. water. TheMicroscopic presence examination of KF promoted of the solid the inorganic formation postreaction of CaF waste,2 as a obtained predominant in the absence component of KF, of the inorganicindicated postreaction the formation residue. of Ca(OH) The 2,observed as could be difference expected due is to reactionexplained of calcium by the carbide lower with solubility water. and higher stabilityThe presence of CaF of2 KF [38]. promoted The presence the formation of potassium of CaF2 as fluoride a predominant in the component developed of system the inorganic importantly contributespostreaction to the reactivity residue. The of calcium observed carbide difference and is explained allows the by thecontrolled lower solubility release and of higheracetylene stability (Scheme 2). Another ofimportant CaF2 [38]. Therole presence may include of potassium the fluoride fluoride‐mediated in the developed functionalization system importantly of acetylene contributes (Scheme to 2). the reactivity of calcium carbide and allows the controlled release of acetylene (Scheme2). Another A similarimportant effect was role reported may include for the the fluoride-mediated concept of a functionalizationsolid acetylene of reagent acetylene in (Scheme the OH2). Abond similar vinylation process [38].effect was reported for the concept of a solid acetylene reagent in the OH bond vinylation process [38].

SchemeScheme 2. Plausible 2. Plausible mechanism mechanism of of vinylation of of secondary secondary amines. amines.

To assessTo the assess substrate the substrate scope scope of the of the developed developed vinylationvinylation protocol, protocol, it was it appliedwas applied to arylamines to arylamines (2b, 2c), (pyrrole2b, 2c), pyrrole(2d), pyrazole (2d), pyrazole (2e), (indoles2e), indoles (2f– (k2f),–k tetrahydrocarbazole), tetrahydrocarbazole ((2l2l),), bicarbazole bicarbazole (2m (),2m), and diazepineand (2n diazepine) (Schemes (2n) (Schemes 3–5). The3–5). vinylation The vinylation of ofaryl aryl amines amines was was ﬂawless flawless and producedand produced excellent excellent yields (2b, 2c). Pyrrole (2d) and pyrazole (2e) were also successfully vinylated. The vinylation of yields (2bindoles, 2c). delivered Pyrrole moderate(2d) and to pyrazole good product (2e yields) were (2f –alsok). Surprisingly, successfully despite vinylated.N-vinylindole The vinylation being of indoles delivereda well-known moderate compound to [good42], its product X-ray structure yields is ( considered2f–k). Surprisingly, obscure due despite to its low N melting‐vinylindole point being a well‐known(about 30compound◦C) [43]. Extraction [42], its with X‐ray hexane structure applied inis thisconsidered study allowed obscure the isolation due to of its pure low vinylated melting point (about 30derivatives, °C) [43]. Extraction which included withN -vinylindole,hexane applied and the in determinationthis study allowed their structures the isolation by means of ofpure X-ray vinylated derivatives,crystallography which included (Scheme N3).‐vinylindole, and the determination their structures by means of X‐ray The yield of vinyl indoles depended on the nature of a substituent in the aromatic ring. crystallographySubstituents (Scheme with an 3). electron-withdrawing effect, especially in the 2-position, substantially decreased Thethe yield yield of (2j ).vinyl This effectindoles was probablydepended due on to the the delocalization nature of ofa negativesubstituent charge in throughout the aromatic the ring. Substituentsmolecule with after an electron the proton‐withdrawing elimination and effect, corresponding especially decrease in the in2‐position, reactivity of substantially the nucleophile. decreased the yieldIsolated (2j). This vinylindoles effect was were probably air- and moisture-sensitive, due to the delocalization especially in presence of negative of trace charge amounts throughout of acids. the moleculeDevinylation after the proton occurred elimination as hydrolysis toand an initialcorresponding indole and acetic decrease aldehyde. in Simplicityreactivity of of the the synthetic nucleophile. procedure is noteworthy; the products can be thoroughly puriﬁed through extraction with hexane Isolated (othervinylindoles postreaction were components air‐ and are moisture insoluble‐ inorganicsensitive, molecules). especially in presence of trace amounts of acids. Devinylation occurred as hydrolysis to an initial indole and acetic aldehyde. Simplicity of the synthetic procedure is noteworthy; the products can be thoroughly purified through extraction with hexane (other postreaction components are insoluble inorganic molecules).

Molecules 2018, 23, 648 5 of 11 Molecules 2018, 23, x 5 of 11 Molecules 2018, 23, x 5 of 11

Scheme 3. Structures of vinylated secondary amine products and yields (in %). Reaction Reaction conditions: conditions: Scheme 3. Structures of vinylated secondary amine products and yields (in %). Reaction conditions: 2 2 amine 11 (1(1 mmol), mmol), CaC CaC (22 (2mmol), mmol), KOH KOH (1.1 (1.1 mmol), mmol), KF (1 KF mmol), (1 mmol), H O H(42 mmol),O (4 mmol), DMSO DMSO (1 mL). (1 NMR mL). amine 1 (1 mmol), CaC2 (2 mmol), KOH (1.1 mmol), KF (1 mmol), H2O (4 mmol), DMSO (1 mL). NMR yieldsNMR yieldsare given are givenwithout without parentheses, parentheses, isolated isolated yields yields are given are givenin parentheses. in parentheses. yields are given without parentheses, isolated yields are given in parentheses. Upon the extraction of the vinylated carbazoles (2a, 2l), their low solubility in nonpolar solvents Upon the extraction of the vinylated carbazoles ( 2a, 2l), their low solubility in nonpolar solvents became evident, and hexane was replaced by ether for more efficient separation. became evident, and hexane was replaced by ether for more efﬁcientefficient separation.separation.

N HN 1l H 1l

CaC2, H2O KOH, KF CaC , H O KOH, KF DMSO,2 1302 oC DMSO, 130 oC

N AIBN (2 mol%) N Toluene N N AIBN (2 mol%) N Toluene N Toluene BF3 · O(C2H5)2 48Toluene h, 70 oC BF23 ·mol%O(C2H5)2 n 48 h, 70 oC n 242 h,mol% - 40 oC n n o 3l, 35 % 2l, 79 % 24 h, - 40 C 4l, 82 % 3l, 35 % 2l, 79 % 4l, 82 % Mn, SEC = 6600 [g/mol] Mn, SEC = 50000 [g/mol] M = 6600 [g/mol] M = 50000 [g/mol] n, SEC n, SEC Scheme 4. N‐vinyl‐1,2,3,4‐tetrahydrocarbazole synthesis and polymerization. Scheme 4. N‐-vinyl-1,2,3,4-tetrahydrocarbazolevinyl‐1,2,3,4‐tetrahydrocarbazole synthesis and polymerization. It was very interesting to probe the vinylated tetrahydrocarbazole (2l) in polymerization It was very interesting to probe the vinylated tetrahydrocarbazole (2l) in polymerization reactions (Scheme 4). To try the possibility of polymerization, we used N‐vinyl‐1,2,3,4‐ reactions (Scheme 4). To try the possibility of polymerization, we used N‐vinyl‐1,2,3,4‐ tetrahydrocarbazole (1l) as a monomer in either free radical or cationic conditions (Scheme 4). The 3l tetrahydrocarbazole (1l) as a monomer in either free radical or cationic conditions (Scheme 4). The 3l

Molecules 2018, 23, 648 6 of 11

MoleculesIt was 2018 very, 23, x interesting to probe the vinylated tetrahydrocarbazole (2l) in polymerization reactions6 of 11 (Scheme4). To try the possibility of polymerization, we used N-vinyl-1,2,3,4-tetrahydrocarbazole (1l) oligomer was isolated in low yield and moderate average mass after free radical polymerization in as a monomer in either free radical or cationic conditions (Scheme4). The 3l oligomer was isolated the presence of AIBN (2 mol %) in toluene medium. The electron‐donating and steric effects of in low yield and moderate average mass after free radical polymerization in the presence of AIBN methylene groups led to a decreased molecular mass of the 3l polymer as compared with polymers (2 mol %) in toluene medium. The electron-donating and steric effects of methylene groups led to a derived from completely aromatic carbazole. The presence of such substituents in carbazoles also led decreased molecular mass of the 3l polymer as compared with polymers derived from completely to decreasing molecular weight. Cationic polymerization worked better, leading to a polymer of a aromatic carbazole. The presence of such substituents in carbazoles also led to decreasing molecular greater mass (4l). Note that a simple protocol was utilized and reaction conditions were not weight. Cationic polymerization worked better, leading to a polymer of a greater mass (4l). Note that optimized. Both polymers were reprecipitated from methanol and characterized by NMR and size a simple protocol was utilized and reaction conditions were not optimized. Both polymers were exclusion chromatography (SEC). reprecipitated from methanol and characterized by NMR and size exclusion chromatography (SEC). Comparing monomers 2a and 2l, one may note that both N‐vinyl derivatives easily undergo Comparing monomers 2a and 2l, one may note that both N-vinyl derivatives easily undergo cationic polymerization and produce polymers of similar molecular mass range. However, different cationicbehavior polymerization was observed and in producethe case polymersof free radical of similar polymerization, molecular mass where range. the vinylated However, differenttetrahydrocarbazole behavior was (2l) observed gave shorter in the polymer case ofchains. free radicalThus, access polymerization, to both monomers where provides the vinylated good tetrahydrocarbazolepotential for material (2l) science gave shorter applications polymer as chains. an extension Thus, access of well to both‐known monomers carbazole provides‐containing good potentialsystems. for material science applications as an extension of well-known carbazole-containing systems. 0 3,33,3-bicarbazole′‐bicarbazole ((1m1m)) waswas chosen as as a a model model substrate substrate for for further further polymerization polymerization experiments experiments in inconnection connection with with the the promising promising potential potential of of polyvinyl polyvinyl carbazole carbazole (PVC) (PVC) in in optoelectronics. optoelectronics. One One-pot‐pot insertioninsertion of of two two vinyl vinyl groups groups is is challenging, challenging, sincesince spontaneousspontaneous oligomerization may may readily readily occur occur 0 duringduring the the synthetic synthetic procedure. procedure. Nevertheless, Nevertheless, thethe individualindividual double vinylated 3,3 3,3′‐-bicarbazolebicarbazole (2m (2m) ) waswas isolated isolated in 32%in 32% yield yield using using the developed the developed procedure procedure with calcium with calcium carbide carbide (Scheme (Scheme5). The presence 5). The ofpresence two vinyl of groupstwo vinyl in thegroups monomer in the monomer was clearly was conﬁrmed clearly confirmed by X-ray analysisby X‐ray (Scheme analysis5 (Scheme). 5).

SchemeScheme 5. 5.Double Double vinylation vinylation followed followed by by the the polymerization polymerization ofof bis(bis(NN-vinyl-3,3‐vinyl‐3,3′‐0-carbazole)carbazole) and and the the X-rayX‐ray structure structure of of2m 2m. .

Polymerization of the bis‐vinyl derivative in the presence of radical initiator (AIBN) resulted in highPolymerization yields (85%) of of the the insoluble bis-vinyl cross derivative‐linked polymer in the presence 3m. Comparison of radical of initiator the registered (AIBN) solid resulted‐state in highNMR yields‐spectra (85%) with of theliterature insoluble‐derived cross-linked NMR data polymer on PVC3m [44]. Comparison indicated the of thepolymeric registered nature solid-state of the NMR-spectraobtained material with (see literature-derived Supplementary NMR Materials data for on details). PVC [44 ] indicated the polymeric nature of the obtainedThe material developed (see vinylation Supplementary procedure Materials was successfully for details). utilized for post‐modification of a drug substance.The developed Olanzapine vinylation (Zyprexa) procedure is thienobenzodiazepine was successfully used utilized for forthe post-modiﬁcationtreatment of schizophrenia of a drug substance.and bipolar Olanzapine disorder (Zyprexa)[45]; it acts is thienobenzodiazepineby suppressing dopamine used and for the serotonin treatment receptor of schizophrenia activities. andCurrently bipolar available disorder [antipsychotic45]; it acts by suppressingdrugs have certain dopamine limitations. and serotonin Considerable receptor academic activities. efforts Currently are availableaimed at antipsychoticenhancing their drugs properties have (e.g., certain by chemical limitations. post Considerable‐modification), academic including effortsthe development are aimed atof enhancing new platforms their for properties drug delivery (e.g., [46]. by chemical The insertion post-modiﬁcation), of vinyl groups includingmodulates the the developmentfunctionality of of newa biologically platforms active for drug benzodiazepine delivery [46 core]. The and insertion creates novel of vinyl opportunities groups modulates for molecular the functionalitybinding. An olanzapine‐containing polymer, slowly releasing the active units by gradual depolymerization and/or devinylation upon delivery, could be of great therapeutic relevance. The vinylation of

Molecules 2018, 23, 648 7 of 11 of a biologically active benzodiazepine core and creates novel opportunities for molecular binding.

AnMolecules olanzapine-containing 2018, 23, x polymer, slowly releasing the active units by gradual depolymerization7 of 11 and/or devinylation upon delivery, could be of great therapeutic relevance. The vinylation of olanzapineolanzapine ((1n1n)) underunder thethe developeddeveloped conditionsconditions proceededproceeded smoothlysmoothly (Scheme(Scheme5 5),), and and the the vinyl vinyl derivativederivative ((2n2n)) was was isolated isolated in in a a pure pure form form as as a solida solid substance. substance. The The molecular molecular structure structure of productof product2n was2n was determined determined by X-rayby X‐ray analysis analysis (Scheme (Scheme6). 6).

Scheme 6. Vinylation of olanzapine andand X-rayX‐ray structurestructure ofof thethe vinylatedvinylated olanzapineolanzapine derivative.derivative.

3.3. Materials andand MethodsMethods GranulatedGranulated calcium calcium carbide carbide was was purchased purchased from from Sigma Sigma Aldrich Aldrich (St. (St.Louis, Louis, MO, USA) MO, ( USA)≥75% (volumetric).≥75% volumetric). NMR NMRspectra spectra of the of compounds the compounds were were recorded recorded using using a aBruker Bruker Avance Avance DRX DRX 400400 1 13 spectrometerspectrometer at at 298 298 K. K. The The1 H and 13CC-NMR‐NMR chemical chemical shifts are reported in ppm and were determined byby referencingreferencing thethe peakspeaks toto thethe residualresidual solventsolvent signals.signals. The data were processed usingusing MestReNovaMestReNova (version(version 6.0.2)6.0.2) desktopdesktop NMRNMR datadata processingprocessing software.software. High-resolutionHigh‐resolution mass spectra were registered onon aa Bruker Bruker Micro-TOF Micro‐TOF mass mass spectrometer spectrometer (ESI-MS). (ESI‐MS). All All melting melting points points (m.p.) (m.p.) were were measured measured in open in capillariesopen capillaries on an on electrothermal an electrothermal apparatus apparatus and are and uncorrected. are uncorrected. Liquid Liquid monomers monomers were were distilled distilled over calciumover calcium hydride hydride in vacuum in vacuum before before polymerization. polymerization. Size exclusion Size exclusion chromatography chromatography (SEC) was (SEC) carried was outcarried using out a Shimadzuusing a Shimadzu LC-20AD LC modular‐20AD modular system equipped system equipped with a TSKgel with a G5000HHR TSKgel G5000HHR column (7.8 column mm (7.8 mm × 300 mm) and an RID‐10A differential refractive index detector. The average molar mass ( × 300 mm) and an RID-10A differential refractive index detector. The average molar mass (MnSEC) and Mw molarMn SEC mass) and distribution molar mass (Mw distribution/Mn) values were( determined/ Mn ) values using were SEC indetermined tetrahydrofurane using (THF)SEC atin ◦ − 40tetrahydrofuraneC (flow rate = 1.0(THF) mL ·minat 401 )°C vs. (flow polystyrene rate = standards.1.0 mL∙min The−1) vs. unit polystyrene calibration wasstandards. conducted The using unit commerciallycalibration was available conducted narrow using molecular-weight-distribution commercially available narrow polystyrene molecular standards‐weight (0.5–1000‐distribution kDa, Polymerpolystyrene Laboratories). standards (0.5–1000 The chromatograms kDa, Polymer were Laboratories). processed using The chromatograms Shimadzu LCsolution were processed software. Theusing polymer Shimadzu samples LCsolution were initially software. filtered The through polymer a pulytetrafluoroethylene samples were initially (PTFE) filtered filter through (0.45 µm, a 13pulytetrafluoroethylene mm, Macherey-Nagel) (PTFE) and dissolved filter (0.45 in THF μm, (6 13 mg mm,·mL− Macherey1). Purification‐Nagel) via and column dissolved chromatography in THF (6 onmg silica∙mL−1 should). Purification be avoided via column due to chromatography the sensitivity of moston silica of the shouldN-vinyl be avoided amines due towards to the undergoing sensitivity rapidof most polymerization of the N‐vinyl or degradation. amines towards If purification undergoing via column rapid chromatographypolymerization isor required degradation. for some If reason,purification the silica via column should bechromatography neutralized with is required triethylamine. for some The reason, products the may silica be should sensitive be toneutralized light and shouldwith triethylamine. be stored in a The dark products place. Contact may be with sensitive acid or tracesto light of and metals should may initiatebe stored polymerization in a dark place. and shouldContact be with avoided. acid or traces of metals may initiate polymerization and should be avoided.

3.1. Synthetic Procedures

Molecules 2018, 23, 648 8 of 11

3.1. Synthetic Procedures

3.1.1. General Procedure of Vinylation An amine (1.0 mmol), crushed KOH (1.1 mmol, 62 mg), anhydrous KF (1.0 mmol, 58 mg), and granulated calcium carbide (2.0 mmol, 130 mg) were added to a reaction tube (7 mL) with 1 mL of DMSO. After stirring at room temperature for 5 min, water (4.0 mmol, 72 µL) was added, the tube was sealed, and the mixture was heated at 130 ◦C for 4 h with vigorous stirring. After cooling to 25 ◦C, the mixture was extracted with hexane (4 × 4 mL). Combined extracts were treated with 5% aqueous NaOH, then with brine, with water, and finally dried over Na2SO4. Concentration under reduced pressure gave the target compound. All vinylated amines were obtained as oils except 9-vinyl-9H-carbazole (2a) (m.p. 64–65 ◦C, lit. 64 ◦C[42]), N,N-diphenylvinylamine (2b) (m.p. 53–54 ◦C, lit. 52–54 ◦C[47]), N-(β-naphthyl)-N-phenylvinylamine (2c) (m.p. 80–81 ◦C, lit. 70–82 ◦C[47]), 9,90-divinyl-9H,90H-3,30-bicarbazole (2m) (decomposes at 162 ◦C), and 2-methyl-4- (4-methylpiperazin-1-yl)-10-vinyl-10H-benzo[b]thieno[2,3-e][1,4]diazepine (2n) (m.p. 188–190 ◦C). In case of compounds 2m and 2n, methyl tert-butyl ether (MTBE) was used for extraction instead of hexane. N-vinyl derivatives were isolated by ﬂash column chromatography with system hexane/MTBE (5/1) as an eluent with gradient elution. Compounds characterization is reported in the Supplementary Materials. Caution: The experimental procedures described in the present study involve the evolution of gaseous acetylene upon the reaction of water with calcium carbide—the necessary safety requirements for experiments with gases, acetylene, and CaC2 should be implemented (see corresponding regulations).

3.1.2. Experimental Procedure for the Radical Polymerization of N-vinyl-1,2,3,4-tetrahydrocarbazole (1l) To start, 276 mg (1.4 mmol) of 1l and 5 mg (0.03 mmol) of AIBN were added to a Schlenk tube containing 1 mL of dry and degassed toluene. The tube was sealed, and the reaction was performed with stirring under an inert atmosphere at 70 ◦C for 48 h. Then, the reaction mixture was precipitated in methanol (20 mL). The crude product was dissolved in chloroform (1 mL) and again precipitated in methanol (20 mL). After the residue was washed with hexane (3 × 3 mL), the work-up procedure was repeated. The residue was dried under a reduced pressure for two days at 40 ◦C to obtain a yellow solid (97 mg, 35% yield, Mn,SEC = 6600 (g/mol), Đ = 1.50).

3.1.3. Experimental Procedure for the Cationic Polymerization of N-vinyl-1,2,3,4-tetrahydrocarbazole (1l) To start, 276 mg (1.4 mmol) of 1l was placed into a Schlenk tube under an inert atmosphere. Then, 1 mL of degassed dry toluene was injected into the tube. After three degassing cycles, a toluene solution of boron triﬂuoride diethyl etherate (2 mol %) was injected into the tube under stirring at −40 ◦C. After 24 h in a cryostat, the toluene solution was poured into methanol. The yellow solid was collected through a ﬁlter, washed with hexane, dissolved in chloroform, and precipitated in methanol again. The powder was dried under a reduced pressure for two days at 40 ◦C (226 mg, 82% yield, Mn,SEC = 50000 (g/mol), Đ = 1.61).

4. Conclusions In conclusion, a new strategy of vinylation was developed, and a variety of secondary amines were effectively converted into N-vinyl derivatives. Calcium carbide was utilized as a vinylation agent to avoid high pressure equipment when producing required amounts of acetylene and thereby simplify the synthetic procedure. The application of KF/KOH as a base was important for efﬁcient transformation. The reaction turned out to have a good substrate scope, and various pyrrole, pyrazole, indoles, aryl amines, and carbazoles were successfully involved in the transformation. Regular and cross-linked polymers were obtained by radical and cationic polymerization of the studied carbazole- Molecules 2018, 23, 648 9 of 11 and bicarbazole-containing substrates. N-vinyl olanzapine was synthesized, and its molecular structure was established for the ﬁrst time.

Supplementary Materials: Supplementary data are available online. Acknowledgments: We acknowledge the generous support of Russian Science Foundation (RSF), No. 16-13-10301. This research used resources of the ‘Magnetic Resonance Research Centre’, ‘Chemical Analysis and Materials Research Centre’, and ‘Centre for X-ray Diffraction Studies’ of Research Park of Saint Petersburg State University. Author Contributions: K.S.R. and A.S.B. performed the experiments, elaborated and interpreted the spectroscopy data; V.P.A. designed and supervised the project. All authors took part in the manuscript preparation. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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

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