Isocyanide-Based Multicomponent Reactions for the Synthesis of Heterocycles

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Review Isocyanide-Based Multicomponent Reactions for the Synthesis of Heterocycles

András Váradi, Travis C. Palmer, Rebecca Notis Dardashti and Susruta Majumdar *

Received: 10 October 2015 ; Accepted: 17 December 2015 ; Published: 23 December 2015 Academic Editor: Romano V. A. Orru

Department of Neurology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; [email protected] (A.V.); [email protected] (T.C.P.); [email protected] (R.N.D.) * Correspondence: [email protected]; Tel.: +1-646-888-3669

Abstract: Multicomponent reactions (MCRs) are extremely popular owing to their facile execution, high atom-efﬁciency and the high diversity of products. MCRs can be used to access various heterocycles and highly functionalized scaffolds, and thus have been invaluable tools in total synthesis, drug discovery and bioconjugation. Traditional isocyanide-based MCRs utilize an external nucleophile attacking the reactive nitrilium ion, the key intermediate formed in the reaction of the imine and the isocyanide. However, when reactants with multiple nucleophilic groups (bisfunctional reactants) are used in the MCR, the nitrilium intermediate can be trapped by an intramolecular nucleophilic attack to form various heterocycles. The implications of nitrilium trapping along with widely applied conventional isocyanide-based MCRs in drug design are discussed in this review.

Keywords: Ugi reaction; heterocycles; nitrilium trapping

1. Introduction Multicomponent reactions are powerful tools for the rapid generation of molecular diversity and complexity. In a typical multicomponent process, more than two components are combined in a single reaction, thereby providing an operationally effective and highly modular approach towards the synthesis of structurally diverse molecular entities. Multicomponent reactions (MCRs) represent an excellent tool for the generation of libraries of small-molecule compounds and are indispensable for structure–activity relationship (SAR) studies. Some MCRs generate uncommon, if not unique, scaffolds so the ability to further functionalize or modify them is key to exploring the utility of the scaffold in the biological realm. The unusual structure of many of these scaffolds makes them suited for exploring biological targets that traditional scaffolds do not target. Novel scaffolds are becoming more and more sought after as pathogens mutate to become resistant to current medications, and anti-aging agents are needed to tackle diseases such as Alzheimer’s, Parkinson’s, diabetes, and cancer. While MCRs may not be directly responsible for the drugs that treat these diseases in the future, they will certainly be involved as scientists search for tomorrow’s remedies. Some of the classic MCRs include the Passerini, Ugi, Mannich, Kabachnik-Fields, Biginelli, Hantzsch, Bucherer-Bergs, van Leusen and Strecker reactions. Isocyanide-based reactions form the backbone of today’s MCR chemistry, and the most common examples are: the Passerini reaction and the Ugi reaction. This review will cover some aspects of isocyanide chemistry with particular emphasis on nitrilium trapping.

Molecules 2016, 21, 19; doi:10.3390/molecules21010019 www.mdpi.com/journal/molecules Molecules 2016, 21, 19 2 of 22

1.1. Passerini Reaction The Passerini reaction is named after Mario Passerini, who discovered this reaction in 1921. It is the ﬁrst isocyanide based MCR and plays a central role in combinatorial chemistry today. It involves anMolecules aldehyde 2016, 21 or, 0019 ketone, an isocyanide, and a carboxylic acid and offers direct access to α-hydroxy2 of 21 Molecules 2016, 21, 0019 2 of 21 carboxamides (Scheme1). The exact mechanism is a subject of some uncertainty; the mechanism postulated by Ugi suggests a non-ionicnon-ionic pathway, sincesince the reaction is accelerated in aprotic solvents postulated by Ugi suggests a non-ionic pathway, since the reaction is accelerated in aprotic solvents (Scheme(Scheme2 2))[ [1].1]. TheThe electrophilicelectrophilic activationactivation ofof thethe carbonylcarbonyl groupgroup isis followedfollowed byby aa nucleophilicnucleophilic attackattack (Scheme 2) [1]. The electrophilic activation of the carbonyl group is followed by a nucleophilic attack by the isocyanide. This creates a nitrilium intermediate,intermediate, whichwhich isis thenthen attackedattacked byby thethe carboxylate.carboxylate. by the isocyanide. This creates a nitrilium intermediate, which is then attacked by the carboxylate.

Scheme 1. A general Passerini reaction yielding an α-acyloxy amide. Scheme 1. A general Passerini reaction yielding an α-acyloxy amide.

Scheme 2. Possible mechanism of the Passerini reaction. Scheme 2. Possible mechanism of the Passerini reaction. Asymmetric Passerini reactions are now known using a tridentate indan (pybox) Cu(II) Lewis Asymmetric Passerini reactions are now known using a tridentate indan (pybox) Cu(II) Lewis acid Asymmetriccomplex developed Passerini by reactionsSchreiber are[2] and now other known enantioselective using a tridentate catalysts indan (a combination (pybox) Cu(II) of silicon Lewis acid complex developed by Schreiber [2] and other enantioselective catalysts (a combination of silicon acidtetrachloride complex and developed a chiral bisphosphoramide) by Schreiber [2] and developed other enantioselective by Denmark [3] catalysts. Recently, (a Wang combination et al. used of tetrachloride and a chiral bisphosphoramide) developed by Denmark [3]. Recently, Wang et al. used siliconcommercially tetrachloride available and chiral a chiral Lewis bisphosphoramide) acids to achieve asymmetric developed byreactions Denmark [4]. [ 3Passerini]. Recently, reactions Wang etwith al. commercially available chiral Lewis acids to achieve asymmetric reactions [4]. Passerini reactions with usedalcohols, commercially isocyanides availableand carboxylic chiral acids Lewis have acids been to reported achieve by asymmetric the Zhu lab, reactions thereby extending [4]. Passerini the alcohols, isocyanides and carboxylic acids have been reported by the Zhu lab, thereby extending the reactionspotential utility with of alcohols, this reaction isocyanides beyond andcarbonyl carboxylic containing acids compounds. have been The reported methodology by the utilizes Zhu lab,the potential utility of this reaction beyond carbonyl containing compounds. The methodology utilizes the therebyconversion extending of an alcohol the potential to an aldehyde utility of using this catalytic reaction beyondTEMPO, carbonyl CuCl2 and containing NaNO2 [5]. compounds. In the presence The conversion of an alcohol to an aldehyde using catalytic TEMPO, CuCl2 and NaNO2 [5]. In the presence methodologyof In(III), Passerini-type utilizes the reaction conversions have of been an alcoholreported to between an aldehyde free alcohols using catalytic(isopropanol), TEMPO, aldehydes CuCl2 of In(III), Passerini-type reactions have been reported between free alcohols (isopropanol), aldehydes and(unsaturated NaNO2 [and5]. Inaryl) the and presence isocyanides of In(III), such Passerini-typeas t-butyl isocyanide reactions [6]. have Pioneering been reported work by betweenEl Kaïm (unsaturated and aryl) and isocyanides such as t-butyl isocyanide [6]. Pioneering work by El Kaïm freeand Grimaud alcohols led (isopropanol), to the discovery aldehydes of what (unsaturatedis now known and as the aryl) Passerini–Smiles and isocyanides reaction. such In as thist-butyl case, and Grimaud led to the discovery of what is now known as the Passerini–Smiles reaction. In this case, isocyanidean electron [ 6deficient]. Pioneering phenol work such by as El Kaïm2-nitropheno and Grimaudl (or other led to nitrogen the discovery heteroaromatic of what is but now electron known an electron deficient phenol such as 2-nitrophenol (or other nitrogen heteroaromatic but electron asdeficient the Passerini–Smiles phenols) replaces reaction. the carboxylic In this acid. case, The an mechanism electron deﬁcient is believed phenol to in suchvolve as activation 2-nitrophenol of the deficient phenols) replaces the carboxylic acid. The mechanism is believed to involve activation of the (oraldehyde other nitrogenby the weakly heteroaromatic acidic phenol but (pK electrona ~ 4.2) deﬁcient which makes phenols) the carbonyl replaces electrophilic the carboxylic vulnerable acid. The to aldehyde by the weakly acidic phenol (pKa ~ 4.2) which makes the carbonyl electrophilic vulnerable to mechanismattack by the is isocyanide. believed to The involve incipient activation nitrilium of the ion aldehyde formed is by attacked the weakly by the acidic phenol phenol followed (pKa ~by 4.2) an attack by the isocyanide. The incipient nitrilium ion formed is attacked by the phenol followed by an whichSNAr leading makes to the an carbonyl α-aryloxy electrophilic amide. The vulnerablekey step is tobelieved attack to by be the the isocyanide. irreversible The Smiles incipient rearrangement nitrilium SNAr leading to an α-aryloxy amide. The key step is believed to be the irreversible Smiles rearrangement ionof the formed intermediate is attacked phenoxyimi by the phenoldate adduct followed (Scheme by an3) [7]. SNAr leading to an α-aryloxy amide. The of the intermediate phenoxyimidate adduct (Scheme 3) [7]. Some other variations of the Passerini reaction with surrogates of carboxylic acid involved in Some other variations of the Passerini reaction with surrogates of carboxylic acid involved in the intramolecular trapping of the nitrilium will be discussed later in the review. The Passerini the intramolecular trapping of the nitrilium will be discussed later in the review. The Passerini reaction has recently been used to synthesize a library of monomers for the synthesis of polymers. reaction has recently been used to synthesize a library of monomers for the synthesis of polymers. By varying the R groups in the Passerini reaction, the group was able to tune the properties of the By varying the R groups in the Passerini reaction, the group was able to tune the properties of the resulting polymer [8]. It also found use in the synthesis of depsipeptides on a dihydropyridinone resulting polymer [8]. It also found use in the synthesis of depsipeptides on a dihydropyridinone core [9], dendrimers [10], photocaged compounds [11], cytotoxic/anticancer agents [12,13], imaging core [9], dendrimers [10], photocaged compounds [11], cytotoxic/anticancer agents [12,13], imaging agents [14], and HCV NS3 protease inhibitors [15]. agents [14], and HCV NS3 protease inhibitors [15].

Molecules 2016, 21, 19 3 of 22 key step is believed to be the irreversible Smiles rearrangement of the intermediate phenoxyimidate adduct (Scheme3)[7]. Some other variations of the Passerini reaction with surrogates of carboxylic acid involved in the intramolecular trapping of the nitrilium will be discussed later in the review. The Passerini reaction has recently been used to synthesize a library of monomers for the synthesis of polymers. By varying the R groups in the Passerini reaction, the group was able to tune the properties of the resulting polymer [8]. It also found use in the synthesis of depsipeptides on a dihydropyridinone core [9], dendrimers [10], photocaged compounds [11], cytotoxic/anticancer agents [12,13], imaging agentsMolecules [ 142016],, and21, 0019 HCV NS3 protease inhibitors [15]. 3 of 21 Molecules 2016, 21, 0019 3 of 21

Scheme 3. Passerini-Smiles reaction and its possible mechanism. Scheme 3. Passerini-Smiles reaction and its possible mechanism. A more recent but relevant addition by Soeta et al. is use of silanols instead of carboxylic acids A more more recent recent but but relevant relevant addition addition by by Soeta Soeta et al.et al.is useis of use silanols of silanols instead instead of carboxylic of carboxylic acids in the Passerini Reaction, which allows the synthesis of α-siloxyamides. The mechanism entails acidsin the inPasserini the Passerini Reaction, Reaction, which whichallows allowsthe synthesis the synthesis of α-siloxyamides. of α-siloxyamides. The mechanism The mechanism entails coordination of the silyl group to the oxygen of the carbonyl. This renders it susceptible to nucleophilic entailscoordination coordination of the silyl of thegroup silyl to groupthe oxygen to the of oxygen the carbonyl. of the This carbonyl. renders This it susceptible renders it to susceptible nucleophilic to attack by an isocyanide, followed by intramolecular trapping of the nitrilium ion by the alcoholic nucleophilicattack by an attackisocyanide, by an followed isocyanide, by followed intramolecular by intramolecular trapping of trapping the nitrilium of the ion nitrilium by the ion alcoholic by the functional group of the silanol (Scheme 4) [16]. alcoholicfunctional functional group of the group silanol of the (Scheme silanol 4) (Scheme [16]. 4)[16].

Scheme 4. Mechanism of α-siloxyamide-forming Passerini reaction. Scheme 4. Mechanism of α-siloxyamide-forming Passerini reaction. Soeta et al. also reported the one-pot synthesis of α-(sulfonyloxy)amide derivatives using an Soeta et al. also reported the one-pot synthesis of α-(sulfonyloxy)amide derivatives using an oxidativeSoeta Passeriniet al. also reaction. reported An the aldehyde, one-pot an synthesis isocyanide of αand-(sulfonyloxy)amide sulfinic acid were derivativesreacted, followed using by an oxidative Passerini reaction. An aldehyde, an isocyanide and sulfinic acid were reacted, followed by oxidativethe addition Passerini of meta-chloroperoxybenzoic reaction. An aldehyde, anacid isocyanide giving the and products sulﬁnic in acid high were yields reacted, (Scheme followed 5). The by the addition of meta-chloroperoxybenzoic acid giving the products in high yields (Scheme 5). The thereaction addition has a of wide meta-chloroperoxybenzoic scope on aldehydes and acid isocyanides giving the [17]. products in high yields (Scheme5). The reaction has a wide scope on aldehydes and isocyanides [17]. reaction has a wide scope on aldehydes and isocyanides [17].

Scheme 5. Passerini reaction yielding α-(sulfonyloxy)amides. Scheme 5. Passerini reaction yielding α-(sulfonyloxy)amides.

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Scheme 3. Passerini-Smiles reaction and its possible mechanism.

A more recent but relevant addition by Soeta et al. is use of silanols instead of carboxylic acids in the Passerini Reaction, which allows the synthesis of α-siloxyamides. The mechanism entails coordination of the silyl group to the oxygen of the carbonyl. This renders it susceptible to nucleophilic attack by an isocyanide, followed by intramolecular trapping of the nitrilium ion by the alcoholic functional group of the silanol (Scheme 4) [16].

Scheme 4. Mechanism of α-siloxyamide-forming Passerini reaction.

Soeta et al. also reported the one-pot synthesis of α-(sulfonyloxy)amide derivatives using an oxidative Passerini reaction. An aldehyde, an isocyanide and sulfinic acid were reacted, followed by theMolecules addition2016, 21 of, 19meta-chloroperoxybenzoic acid giving the products in high yields (Scheme 5).4 ofThe 22 reaction has a wide scope on aldehydes and isocyanides [17].

Scheme 5. Passerini reac reactiontion yielding α-(sulfonyloxy)amides. Molecules 2016, 21, 0019 4 of 21

The same group reportedreported aa Passerini/PudovikPasserini/Pudovik type reaction between aldehydes, isocyanides and phosphinic acids leading to α-(phosphinyloxy)amide derivatives. Th Thisis report is the first ﬁrst instance of an isocyanide-based MCR using phosphinicphosphinic acidacid insteadinstead ofof aa carboxyliccarboxylic acidacid asas aa reactant.reactant. The nucleophilic phosphinate group undergoesundergoes a subsequent catalytic Pudovik-type reaction, affording the products inin goodgood yieldsyields (Scheme(Scheme6 6))[ 18[18].].

SchemeScheme 6. Passerini/Pudovik type type reaction reaction leading leading to to highly highly functionalized functionalized α-(phosphinyloxy)amides.α-(phosphinyloxy)amides.

1.2. Ugi Reaction 1.2. Ugi Reaction A traditional Ugi four component reaction (U4CR, Scheme 7) employs a ketone or aldehyde, a A traditional Ugi four component reaction (U4CR, Scheme7) employs a ketone or aldehyde, a carboxylic acid, an isocyanide, and an amine. The reaction is typically carried out in methanol or carboxylic acid, an isocyanide, and an amine. The reaction is typically carried out in methanol or 2,2,2-trifluoroethanol in high reactant concentrations. The initial step is the formation of an imine 2,2,2-triﬂuoroethanol in high reactant concentrations. The initial step is the formation of an imine from the amine and the carbonyl compound. This is followed by the nucleophilic attack of the from the amine and the carbonyl compound. This is followed by the nucleophilic attack of the isocyanide, resulting in the formation of the highly reactive nitrilium intermediate. The nitrilium is isocyanide, resulting in the formation of the highly reactive nitrilium intermediate. The nitrilium then attacked by the carboxylic acid, and as a result of intramolecular Mumm rearrangement, the is then attacked by the carboxylic acid, and as a result of intramolecular Mumm rearrangement, the reaction yields a central bis-amide (Scheme 8). reaction yields a central bis-amide (Scheme8).

Scheme 7. A standard U4CR. The reaction can tolerate a wide variety of R groups.

Scheme 8. Mechanism of the Ugi 4-component reaction.

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Molecules 2016, 21, 0019 4 of 21 The same group reported a Passerini/Pudovik type reaction between aldehydes, isocyanides and phosphinicThe same group acids leadingreported to aα -(phosphinyloxy)amidePasserini/Pudovik type derivatives.reaction between This report aldehydes, is the first isocyanides instance andof an phosphinic isocyanide-based acids leading MCR tousing α-(phosphinyloxy)amide phosphinic acid instead derivatives. of a carboxylic This report acid isas the a reactant.first instance The ofnucleophilic an isocyanide-based phosphinate MCR group using un dergoesphosphinic a subsequent acid instead catalytic of a carboxylic Pudovik-type acid reaction,as a reactant. affording The nucleophilicthe products phosphinatein good yields group (Scheme undergoes 6) [18]. a subsequent catalytic Pudovik-type reaction, affording the products in good yields (Scheme 6) [18].

Scheme 6. Passerini/Pudovik type reaction leading to highly functionalized α-(phosphinyloxy)amides. Scheme 6. Passerini/Pudovik type reaction leading to highly functionalized α-(phosphinyloxy)amides. 1.2. Ugi Reaction 1.2. UgiA traditional Reaction Ugi four component reaction (U4CR, Scheme 7) employs a ketone or aldehyde, a carboxylicA traditional acid, an Ugi isocyanide, four component and an reactionamine. The (U4CR, reaction Scheme is typically 7) employs carried a ketone out in or methanolaldehyde, or a carboxylic2,2,2-trifluoroethanol acid, an isocyanide, in high reactant and an concentratioamine. The ns.reaction The initial is typically step is carried the formation out in methanol of an imine or 2,2,2-trifluoroethanolfrom the amine and inthe high carbonyl reactant compound. concentratio Thisns. is The followed initial stepby the is thenucleophilic formation attack of an ofimine the isocyanide, resulting in the formation of the highly reactive nitrilium intermediate. The nitrilium is Molecules 2016, 21from, 19 the amine and the carbonyl compound. This is followed by the nucleophilic attack of the 5 of 22 isocyanide,then attacked resulting by the incarboxylic the formation acid, andof the as highly a result reactive of intramolecular nitrilium intermediate. Mumm rearrangement, The nitrilium the is thenreaction attacked yields by a centralthe carboxylic bis-amide acid, (Scheme and as 8). a result of intramolecular Mumm rearrangement, the reaction yields a central bis-amide (Scheme 8).

Scheme 7. A standard U4CR. The reaction can tolerate a wide variety of R groups. Scheme 7. A standard U4CR. The reaction can tolerate a wide variety of R groups. Scheme 7. A standard U4CR. The reaction can tolerate a wide variety of R groups.

Scheme 8. Mechanism of the Ugi 4-component reaction. Scheme 8. Mechanism of the Ugi 4-component reaction. Scheme 8. Mechanism of the Ugi 4-component reaction.

Depending upon the R groups, post Ugi reactions have been reported. Most notable are the Ugi-Heck [19], Ugi-Diels-Alder [20], Ugi-click [21] and Ugi-Buchwald-Hartwig [22] reactions, whereby theMolecules Ugi 2016 bis-amide, 21, 0019 with reactive functional groups undergoes secondary reactions5 of 21 to form a ring. Linear bis-amides on the other hand are useful in the synthesis of peptides (linear and cyclic) and peptidomimeticsDepending [23 upon]. the R groups, post Ugi reactions have been reported. Most notable are the Ugi-Heck [19], Ugi-Diels-Alder [20], Ugi-click [21] and Ugi-Buchwald-Hartwig [22] reactions, whereby In the case of Ugi and Passerini reactions, an important intermediate in the mechanism is the Ugi bis-amide with reactive functional groups undergoes secondary reactions to form a ring. the reactiveLinear nitrilium. bis-amides The on the mechanism other hand are of useful the Ugi in the reaction synthesis involves of peptides the (linear nucleophilic and cyclic) and attack of the isocyanidepeptidomimetics on the imine [23]. species (A) formed by the condensation of the amine and the ketone or In the case of Ugi and Passerini reactions, an important intermediate in the mechanism is aldehyde (Scheme9). Lewis acids (such as TiCl 4) are effective in aiding the formation of the imine the reactive nitrilium. The mechanism of the Ugi reaction involves the nucleophilic attack of the by activating the aldehyde or ketone, thereby facilitating a nucleophilic attack by an amine [24]. isocyanide on the imine species (A) formed by the condensation of the amine and the ketone or The resultingaldehyde nitrilium (Scheme intermediate9). Lewis acids (such (B) as itself TiCl4) is are highly effective reactive in aiding the as formation well and of the readily imine by reacts with nucleophiles.activating In a the traditional aldehyde or U4CR, ketone, the thereby reaction facilita partnerting a nucleophilic of the nitrilium attack by (anB )amine is the [24]. carboxylic The acid. Besides beingresulting a nucleophilic nitrilium intermediate partner ( inB) itself the Ugiis highly reaction, reactive the as carboxylic well and readily acid alsoreacts plays with a part in nucleophiles. In a traditional U4CR, the reaction partner of the nitrilium (B) is the carboxylic acid. activating the nitrilium ion. Metal triﬂates have been shown to activate this nitrilium intermediate Besides being a nucleophilic partner in the Ugi reaction, the carboxylic acid also plays a part in making themactivating more the susceptible nitrilium ion. toMetal nucleophilic triflates have attackbeen shown by carboxylicto activate this acids nitrilium and intermediate therebyincreasing rates of U4CRmaking product them more formation susceptible by to aboutnucleophilic two- attack to seven-fold by carboxylic [25 acids]. However, and thereby when increasing reactants with multiple nucleophilicrates of U4CR product groups formation (bisfunctional by about components) two- to seven-fold are [25]. used However, in the when Ugi reaction,reactants with the nitrilium multiple nucleophilic groups (bisfunctional components) are used in the Ugi reaction, the nitrilium intermediateintermediate can be trappedcan be trapped by an by intramolecular an intramolecular nucleophilic attack attack (Scheme (Scheme 9). 9).

O R5

Traditional U4CR R1 R4 N HN R4 R2 R3 N B C R1 H N

2 3 R R R1 R4 N A HN R2 R3 Intramolecular nitrilium trapping B Scheme 9. In nitrilium trapping reactions, an external or intramolecular nucleophile attacks the Scheme 9. In nitrilium trapping reactions, an external or intramolecular nucleophile attacks the nitrilium species (B). nitrilium species (B). 1.3. Nitrilium Trapping by an External Nucleophile The traditional Ugi reaction utilizes a carboxylic acid as the fourth component in trapping the nitrilium ion. In the absence of a carboxylic acid, water can act as the nucleophilic partner too. One well-known example of utilizing the Ugi reaction in bioactive molecule synthesis is the synthesis of the local anesthetic lidocaine (Scheme 10) [26]. Trapping of nitrilium ion by water is usually carried out under acidic conditions [27,28].

Scheme 10. Lidocaine is a local anesthetic on the WHO Model List of Essential Medicines, which can be synthesized in one step via an U3CR.

Besides carboxylic acids, hydrazoic acid, HOCN, HSCN, and H2Se are some other external nucleophiles which participate as the fourth component in a U4CR (Scheme 11) [29].

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O R5

Traditional U4CR R1 R4 N HN R4 R2 R3 N B C R1 H N

2 3 R R R1 R4 N A HN R2 R3 Intramolecular nitrilium trapping B Molecules 2016, 21, 19 6 of 22 Scheme 9. In nitrilium trapping reactions, an external or intramolecular nucleophile attacks the nitrilium species (B). 1.3. Nitrilium Trapping by an External Nucleophile 1.3. Nitrilium Trapping by an External Nucleophile The traditional Ugi reaction utilizes a carboxylic acid as the fourth component in trapping the The traditional Ugi reaction utilizes a carboxylic acid as the fourth component in trapping the nitrilium ion. In the absence of a carboxylic acid, water can act as the nucleophilic partner too. One nitrilium ion. In the absence of a carboxylic acid, water can act as the nucleophilic partner too. One well-known example of utilizing the Ugi reaction in bioactive molecule synthesis is the synthesis of well-known example of utilizing the Ugi reaction in bioactive molecule synthesis is the synthesis of the localthe local anesthetic anesthetic lidocaine lidocaine (Scheme (Scheme 10 10))[ 26[26].]. Trapping of of nitrilium nitrilium ion ion by bywater water is usually is usually carried carried out underout under acidic acidic conditions conditions [27 [27,28].,28].

SchemeScheme 10. Lidocaine 10. Lidocaine is ais local a local anesthetic anestheticon on thethe WHO Model Model List List of ofEssential Essential Medicines, Medicines, which which can can be synthesized in one step via an U3CR. be synthesized in one step via an U3CR.

Besides carboxylic acids, hydrazoic acid, HOCN, HSCN, and H2Se are some other external Besidesnucleophiles carboxylic which participate acids, hydrazoic as the fourth acid, component HOCN, in HSCN, a U4CR and (Scheme H2Se 11) are [29]. some other external nucleophilesMoleculesMolecules 2016 ,2016 21 which, 0019, 21, 0019 participate as the fourth component in a U4CR (Scheme 11)[29]. 6 of 216 of 21

SchemeScheme 11. 11.Replacement Replacement ofof the carboxylic carboxylic acid acid in inanan U4CR. U4CR. Scheme 11. Replacement of the carboxylic acid in an U4CR. Nitrilium trapping by primary amines leads to the synthesis of amidines [30] (Scheme 12A), while Nitriliumwith electron trapping deficient byphenols primary leads aminesto N-aryl leads amines to [31,32] the synthesis (Ugi-Smiles of coupling, amidines Scheme [30] (Scheme12B). 12A), whileNitrilium with electron trapping deﬁcient by primary phenols amines leadsleads to to theN -arylsynthesis amines of amidines [31,32] [30] (Ugi-Smiles (Scheme 12A), coupling, while Schemewith electron 12B). deficient phenols leads to N-aryl amines [31,32] (Ugi-Smiles coupling, Scheme 12B).

Scheme 12. (A) Reaction of amines with the nitrilium yields amidines; (B) trapping with phenols leads to N-aryl amines (Ugi-Smiles reaction).

2. Intramolecular Trapping of Nitrilium Ion Scheme 12. ((AA)) Reaction Reaction of of amines amines with with the nitrilium yields amidines; ( B) trapping with phenols This review will focus on the chemistry of nitrilium trapping, and its possible application in the leads toto N-arylN-aryl aminesamines (Ugi-Smiles(Ugi-Smiles reaction).reaction). synthesis of biologically active heterocyclic compounds. For excellent reviews on the usefulness of 2. IntramolecularMCRs in drug Trappingdevelopment, of Nitriliumsee the papers Ion by Dömling and Hulme [26,33,34]. In the absence of an external nucleophile, the reactive nitrilium species can be trapped intramolecularly by a bisfunctional nucleophilicThis review component. will focus onThis the component chemistry could of nitril be anium amine, trapping, carboxylic and acid, its possible phenol, amide,application imine, in the synthesishydrazide, of biologically activated carbon active or heterocyclic oxime. compounds. For excellent reviews on the usefulness of MCRs in drug development, see the papers by Dömling and Hulme [26,33,34]. In the absence of an external2.1. Trappingnucleophile, by a Carboxylic the reactive Acid nitrilium species can be trapped intramolecularly by a bisfunctional nucleophilicIn the component. case where Thisboth ancomponent aldehyde andcould a carboxylic be an amine, acid arecarboxylic present onacid, the phenol,same molecule, amide, as imine, hydrazide,in 2-formylbenzoic activated carbon acid, it or has oxime. been shown that the carboxylic acid will trap the nitrilium ion [35]. Whereas an U4CR yields a linear scaffold, this trapping generates a cyclic product. This has been 2.1. Trappingutilized forby athe Carboxylic rapid and Acid high-yielding synthesis of functionalized isocoumarins, such as the anticoagulant warfarin (Scheme 13). Treatment of the product with a catalytic amount of acid led to anIn isomerizationthe case where to theboth expected an aldehyde product. and a carboxylic acid are present on the same molecule, as in 2-formylbenzoic acid, it has been shown that the carboxylic acid will trap the nitrilium ion [35]. Whereas an U4CR yields a linear scaffold, this trapping generates a cyclic product. This has been utilized for the rapid and high-yielding synthesis of functionalized isocoumarins, such as the anticoagulant warfarin (Scheme 13). Treatment of the product with a catalytic amount of acid led to an isomerization to the expected product.

Molecules 2016, 21, 19 7 of 22

2. Intramolecular Trapping of Nitrilium Ion This review will focus on the chemistry of nitrilium trapping, and its possible application in the synthesis of biologically active heterocyclic compounds. For excellent reviews on the usefulness of MCRs in drug development, see the papers by Dömling and Hulme [26,33,34]. In the absence of an external nucleophile, the reactive nitrilium species can be trapped intramolecularly by a bisfunctional nucleophilic component. This component could be an amine, carboxylic acid, phenol, amide, imine, hydrazide, activated carbon or oxime.

2.1. Trapping by a Carboxylic Acid In the case where both an aldehyde and a carboxylic acid are present on the same molecule, as in 2-formylbenzoic acid, it has been shown that the carboxylic acid will trap the nitrilium ion [35]. Whereas an U4CR yields a linear scaffold, this trapping generates a cyclic product. This has been utilized for the rapid and high-yielding synthesis of functionalized isocoumarins, such as the anticoagulant warfarin (Scheme 13). Treatment of the product with a catalytic amount of acid led to an isomerization to the expected product. Molecules 2016, 21, 0019 7 of 21

Scheme 13. Intramolecular trapping with a carboxylic acid.

2.2. Trapping byby AmideAmide Nitrilium ions can alsoalso bebe trappedtrapped byby isocyanidesisocyanides containingcontaining aa secondarysecondary amide.amide. The nitrilium isis trappedtrapped by by the the amide amide after after attacking attacking the imine,the imine, but contrary but contrary to what to one what would one expectwould the expect nitrogen the doesnitrogen not directlydoes not attack directly the attack isocyanide the isocyanide carbon. Instead, carbon. theInstead, electrons the electrons ﬂow from flow the from nitrogen the nitrogen through thethrough oxygen, the oxygen, and only and then only to thethen target to the atom target (Scheme atom (Scheme 14). The 14). reaction The reaction proceeds proceeds even wheneven when R1´4 1−4 areR1−4 bulkyare bulky substituents, substituents, showing showing that that the the scope scope of of the the reaction reaction is is not not limited limited by bythe the trappingtrapping when compared withwith aa traditionaltraditional UgiUgi [[36].36].

Scheme 14. The isocyanide attacks the nitrilium ion but is then trapped by the amide substituent Scheme 14.14. TheThe isocyanide isocyanide attacks the nitrilium ion bu butt is then trapped by the amide substituent before hydrolysis can occur. before hydrolysishydrolysis cancan occur.occur.

2.3. Trapping by an Imine The Groebke-Blackburn-Bienaymé reaction [37–39] yields 3-aminoimidizoles in a non-concerted [4 + 1] reaction between an imine formed by the reaction between an aldehyde and an amine, and an isocyanide. The heterocyclic nitrogen traps the nitrilium ion, which leads to the formation of an imidazole ring following a rearrangement (Scheme 15). This reaction is widely used for the generation of highly diverse small molecule libraries [40,41]; the bioactive compounds synthesized this way include kinase inhibitors [42], topoisomerase II inhibitors [43], antibacterials effective against methicillin-resistant Staphylococcus aureus [44], fluorescent probes [45] and HIV-1 reverse transcriptase inhibitors (Scheme 16) [46,47].

2.4. Trapping by a Secondary Amine When an aldehyde and 4-morpholinepropionitrile are combined in the presence of trimethylsilyltriflate, the aldehyde is trapped by the TMS group and the morpholino nitrogen stabilizes the nitrilium ion (Scheme 17). The trimethylsilyltriflate coordinates to and activates the aldehyde to attack by an isocyanide, similar to how the carboxylic acid normally activates the aldehyde through hydrogen bonding. If a ketone is present on the α-carbon of the isocyanide, the reaction can yield a cyclized product as well [48].

Molecules 2016, 21, 19 8 of 22

2.3. Trapping by an Imine The Groebke-Blackburn-Bienaymé reaction [37–39] yields 3-aminoimidizoles in a non-concerted [4 + 1] reaction between an imine formed by the reaction between an aldehyde and an amine, and an isocyanide. The heterocyclic nitrogen traps the nitrilium ion, which leads to the formation of an imidazole ring following a rearrangement (Scheme 15). This reaction is widely used for the generation of highly diverse small molecule libraries [40,41]; the bioactive compounds synthesized this way include kinase inhibitors [42], topoisomerase II inhibitors [43], antibacterials effective against methicillin-resistant Staphylococcus aureus [44], ﬂuorescent probes [45] and HIV-1 reverse transcriptase inhibitorsMolecules (Scheme 2016, 21 16, 0019)[ 46,47]. 8 of 21

+ Molecules 2016,O 21, 0019 H2N H N 8 of 21 + NC R R + 1 R2 2 + N R1 OH H2NN R MeOHH N NC3 + R + R1 R 2 HN N 2 R1 H N R3 MeOH R3 H+ HN R3 H+ H+ R N N 1 H+ R 1 R2 R N R2 N 1 N [4+1] R H N 1 R2 R2 C N [4+1] H N N NC N R3 R 4 N R3 R4 SchemeScheme 15. The 15. isocyanide The isocyanide in thein the Groebke–Blackburn–Bienaymé Groebke–Blackburn–Bienaymé reaction reaction is trapped is trapped by the bypresence the presence of anScheme imine-like 15. The moiety isocyanide [39]. in the Groebke–Blackburn–Bienaymé reaction is trapped by the presence of an imine-like moiety [39]. of an imine-like moiety [39].

Scheme 16. Bioactive compounds synthesized via the Groebke–Blackburn–Bienaymé reaction. SchemeScheme 16. Bioactive 16. Bioactive compounds compounds synthesized synthesized via the the Groebke–Blackburn–Bienaymé Groebke–Blackburn–Bienaymé reaction. reaction.

O OH O O + CN Zn(OTf) /TMSCl OH H O O + CN N Zn(OTf) /TMSCl2 HN O + CN OTMS 2.4. Trapping byPh aH SecondaryN Amine2 Ph N N + CN X TMSOTf OTMS Ph H O Ph N Ph H X TMSOTf O O O Ph H Ph O O O Ph OX X= OEt, morpholino N X X= OEt, morpholino When an aldehyde and 4-morpholinepropionitrileaqueous are combined in theN presence of aqueousworkup trimethylsilyltriﬂate,OTMS the aldehyde is trappedworkup by the TMS group and the morpholino nitrogen OTMS O Ph O stabilizes the nitriliumN+ ion (Scheme 17). The trimethylsilyltriﬂateOTMS coordinates toOTMS and activates the Ph TMSO + N N+ OTMS O OTMS+ N TMSO Ph Ph O aldehyde to attack byN anO isocyanide, similarPh N+ to how the carboxylicN+ O acid normallyX+ activates the N Ph X Ph N O O Ph N+ X N X α N aldehyde through hydrogen bonding. If a ketone is present on the -carbon of the isocyanide, the reaction canScheme yield 17. aA cyclizedmorpholino product isocyanide asyields well a linear [48 ].product, while an α-keto morpholino isocyanide cyclizes. Scheme 17. A morpholino isocyanide yields a linear product, while an α-keto morpholino isocyanide cyclizes. 2.5. Trapping by Amine 2.5. Trapping by Amine If the amine reagent is a diamine, one amino group will form an imine and the other will react withIf the the amine nitrilium reagent after isit aattacks diamine, that oneimine. amino This group trapping, will like form many an imineothers and shown the here,other forms will react a with the nitrilium after it attacks that imine. This trapping, like many others shown here, forms a

Molecules 2016, 21, 0019 8 of 21

+ O H2N H N NC + R + R1 R 2 N 2 R1 H N R3 MeOH HN R3 H+

H+ R1 N N R1 R R 2 N 2 [4+1] H N C N N R3 R4 Scheme 15. The isocyanide in the Groebke–Blackburn–Bienaymé reaction is trapped by the presence of an imine-like moiety [39].

Molecules 2016, 21, 19 9 of 22

Scheme 16. Bioactive compounds synthesized via the Groebke–Blackburn–Bienaymé reaction.

O OH O + CN Zn(OTf) /TMSCl H O N 2 N + CN OTMS Ph H Ph N X TMSOTf O Ph H O O Ph O X X= OEt, morpholino N aqueous workup OTMS O Ph OTMS N+ TMSO OTMS N N+ O + Ph Ph O O Ph N+ X N X N

Scheme 17. A morpholino isocyanide yields a linear product, while an α-keto morpholino isocyanide cyclizes. Scheme 17. A morpholino isocyanide yields a linear product, while an α-keto morpholino isocyanide cyclizes.2.5. Trapping by Amine If the amine reagent is a diamine, one amino group will form an imine and the other will react with the nitrilium after it attacks that imine. This trapping, like many others shown here, forms a 2.5. Trapping by Amine

If the amine reagent is a diamine, one amino group will form an imine and the other will react with the nitrilium after it attacks that imine. This trapping, like many others shown here, forms a highly substitutedMolecules heterocycle. 2016, 21, 0019 By using 1,2-diaminobenzenes, the reaction yields9 of 21 quinoxalinones in a single step (Schemehighly substituted18). As heterocycle. noted by By theusing authors,1,2-diaminobenzenes, several the quinoxalinone reaction yields quinoxalinones compounds in have afﬁnity for various centralMoleculesa single nervous 2016 step, 21, 0019(Scheme system 18). As (CNS) noted by receptors, the authors, several and quinoxalinone also may comp beounds useful have as affinity antidiabetic for9 of 21 agents and various central nervous system (CNS) receptors, and also may be useful as antidiabetic agents and antiretrovirals [highly49antiretrovirals]. substituted [49]. heterocycle. By using 1,2-diaminobenzenes, the reaction yields quinoxalinones in a single step (Scheme 18). As noted by the authors, several quinoxalinone compounds have affinity for various central nervous system (CNS) receptors, and also may be useful as antidiabetic agents and antiretrovirals [49].

Scheme 18. Synthesis of 3,4-dihydroquinoxalin-2-amine and a library of substituted analogs Scheme 18. Synthesisusing 1,2-diaminobenzenes. of 3,4-dihydroquinoxalin-2-amine and a library of substituted analogs using 1,2-diaminobenzenes. An intriguing way to ensure the generation of a heterocycle from a trapped MCR is to use a reactant that contains both the isocyanophile, which is an imine in a typical Ugi, and a nucleophile to Scheme 18. Synthesis of 3,4-dihydroquinoxalin-2-amine and a library of substituted analogs trap the nitrilium after its attack (Scheme 19). While similar to using a diamino reactant, this approach using 1,2-diaminobenzenes. An intriguinggoes way one step to further ensure and includes the generationthe “imine” with the of nucleophile a heterocycle rather than fromforming it a intrapped situ [50]. MCR is to use a reactant that containsAn intriguing both the way isocyanophile, to ensure the generation which of a is heterocycle an imine from in a trapped typical MCR Ugi, is to and use a nucleophile to O R trap the nitriliumreactant after that its1 contains attack bothN+ (Scheme the isocyanophile, 19). While which similaris an imine to inR1 usinga typical aUgi, diamino and a nucleophile reactant, to this approach - N trap the nitrilium after its attackN (Scheme 19). WhileNC similar to using a diamino reactant,N this approach + R goes one step furthergoes one step and further includes and includes the “imine”the “imine” with3 the the nucleophile nucleophile rather than rather forming thanit in situ forming [50]. it in situ [50]. R2 N O R 3 R O 2 R1 + R N 1 N N- + NC N R3 O R1 R2 N N O N- R3 R2 N+ R2 R3 O Scheme 19. [5 + 1] IsocyanideR cycloaddition yields six membered heterocycles. 1 N N- 2.6. Trapping by Enamide + R Lei and co-workers report a novel approach Nto synthesize pyridines2 [51]. The method features an unprecedented α-addition of aldehyde and enamideR3 to an isocyanide. While not an Ugi reaction, this cycloaddition is an intriguing example of nitrilium trapping outside the realm of isocyanide-based Scheme 19. [5 + 1] Isocyanide cycloaddition yields six membered heterocycles. SchemeMCRs. The 19. cascade[5 + 1] reaction Isocyanide involves cycloadditiona Zn(OTf)2-promoted yields [1 + 5] six cycloaddition membered of the heterocycles. isocyanide with a substituted enamide, followed by the aerobic oxidative aromatization and intramolecular acyl 2.6. Trapping by Enamide transfer and finally an acylation by an external acyl chloride to yield 2-substituted 4-acylamino-5- 2.6. Trapping by EnamideacyloxypyridinesLei and co-workers (Scheme report 20). aThe novel method approach provides to asynthesize straightforward pyridines route [51].to diversely The method substituted features an unprecedentedpyridines that are α -additionanalogues of of aldehydeacetylcholinesterase and enamide inhibitors to an [52].isocyanide. While not an Ugi reaction, Lei and co-workersthis cycloaddition report is an intriguing a novel example approach of nitrilium to synthesizetrapping outside pyridines the realm of isocyanide-based [51]. The method features MCRs. αThe cascade reaction involves a Zn(OTf)2-promoted [1 + 5] cycloaddition of the isocyanide an unprecedentedwith a substituted-addition enamide, of followed aldehyde by the aerobic and enamideoxidative aromatization to an isocyanide.and intramolecular While acyl not an Ugi transfer and finally an acylation by an external acyl chloride to yield 2-substituted 4-acylamino-5- acyloxypyridines (Scheme 20). The method provides a straightforward route to diversely substituted pyridines that are analogues of acetylcholinesterase inhibitors [52].

Molecules 2016, 21, 19 10 of 22 reaction, this cycloaddition is an intriguing example of nitrilium trapping outside the realm of isocyanide-based MCRs. The cascade reaction involves a Zn(OTf)2-promoted [1 + 5] cycloaddition of the isocyanide with a substituted enamide, followed by the aerobic oxidative aromatization and intramolecular acyl transfer and ﬁnally an acylation by an external acyl chloride to yield 2-substituted 4-acylamino-5-acyloxypyridines (Scheme 20). The method provides a straightforward route to diversely substituted pyridines that are analogues of acetylcholinesterase inhibitors [52]. Molecules 2016, 21, 0019 10 of 21

Molecules 2016, 21, 0019 10 of 21

Scheme 20. [1 + 5] cycloaddition with isocyanides and enamides yields substituted pyridines. Scheme 20. [1 + 5] cycloaddition with isocyanides and enamides yields substituted pyridines. 2.7. Trapping by Hydrazide 2.7. Trapping by HydrazideAchieving stereocontrol is among the current challenges of MCR chemistry. A recent example by Hashimoto et al. uses acyclic azomethine imines as prochiral electrophiles generated with Achievingcatalytic stereocontrolScheme amounts 20. of[1 is+axially 5] among cycloaddition chiral thedicarboxylic with current isocyanides acids challenges an[53].d enamides The nitrilium yields of MCR subsintermediatetituted chemistry. pyridines. following Atherecent example attack of the isocyanide is trapped intramolecularly by the oxygen of the hydrazide. The imine is by Hashimoto generated2.7.et Trapping al. fromuses by Hydrazidebenzaldehyde acyclic azomethineand N’-benzylbenzohydrazide imines as in prochiralthe presence of electrophiles a chiral carboxylic generated with acid. 2-benzoyloxyphenyl isocyanides [54] are used for this reaction, and a one-pot basic hydrolysis is catalytic amounts ofAchieving axially stereocontrol chiral dicarboxylic is among the current acids challenges [53]. of The MCR nitrilium chemistry. A intermediate recent example following the performed on the Ugi products to generate asymmetric benzoxazoles in high yield and ee (Scheme 21). attack of the isocyanideby Hashimoto is ettrapped al. uses acyclic intramolecularly azomethine imines by as theprochiral oxygen electrophiles of the generated hydrazide. with The imine is catalytic amounts of axially chiral dicarboxylic acids [53]. The nitrilium intermediate following the generated fromattack benzaldehyde of the isocyanide and is trappedN’-benzylbenzohydrazide intramolecularly by the oxygen in of the hydrazide. presence The of imine a chiralis carboxylic acid. 2-benzoyloxyphenylgenerated from isocyanidesbenzaldehyde and [54 N’]-benzylbenzohydrazide are used for this in reaction, the presence and of a chiral one-pot carboxylic basic hydrolysis is performed on theacid. Ugi 2-benzoyloxyphenyl products to isocyanides generate [54] asymmetric are used for this benzoxazoles reaction, and a one-pot in high basicyield hydrolysis and is ee (Scheme 21). performed on the Ugi products to generate asymmetric benzoxazoles in high yield and ee (Scheme 21).

Scheme 21. Chiral, acid-catalyzed, asymmetric Ugi reaction.

Scheme 21. Chiral, acid-catalyzed, asymmetric Ugi reaction. Scheme 21. Chiral, acid-catalyzed, asymmetric Ugi reaction.

Molecules 2016, 21, 19 11 of 22 Molecules 2016, 21, 0019 11 of 21

2.8. Trapping byby ActivatedActivated ArylAryl CarbonCarbon Nitrilium trapping can be utilizedutilized in the synthesis of natural product analogs as demonstrated by theMolecules work 2016 of Kim, Kim 21, 0019 etet al al [55].[55]. In In this this work, work, the the synthesis synthesis of of 11-methoxymitragynine 11-methoxymitragynine pseudoindoxyl, pseudoindoxyl,11 of 21 a aderivative derivative of the of opioid the opioid natural natural product product mitragynin mitragynine,e, is reported. is reported. The electron The donating electron properties donating 2.8. Trapping by Activated Aryl Carbon propertiesof the C-9 phenolic of the C-9 group phenolic are utilized group to are direct utilized the annulation to direct the reaction annulation through reaction the intramolecular through the intramoleculartrapping ofNitrilium the nitrilium trapping trapping species, of can the be nitriliumforming utilized thein species, the spirocyclic synthesis forming indoxylof natural the spirocyclicring product system. analogs indoxyl The Ugias ringdemonstrated three-component system. The Ugireaction three-componentby the is interruptedwork of Kim reaction etby al a [55]. Houben-Hoeis In interrupted this work,sch the bytype synthesis a Houben-Hoeschcyclization of 11-methoxymitragynine (Scheme type 22) cyclization [56]. pseudoindoxyl, (Scheme 22 )[a 56]. derivative of the opioid natural product mitragynine, is reported. The electron donating properties of the C-9 phenolic group are utilized to direct the annulation reaction throughR2 the intramolecular trapping of the nitrilium species, forming the spirocyclic indoxyl ring system.N The Ugi three-component MeO C reaction is interruptedOMe by a Houben-HoeO schN type cyclization (Scheme 22) [56]. R2 N ++H H N N Me H H R2 H Me 1 C H 1 R NH2 OMe R N H MeOOC MeO C OMe OMe O N MeOOC R2 2 N ++R H H N N Me H H H OMe N OMe Me 1 C H 1 O R NH2 hydrolysisOMe R H C MeOOC C OMe N MeOOC Me N Me 1 2 R NH R R1 N H HH OMe N OMe O HH hydrolysis HH C OMe C OMe N MeOOC Me MeOON C Me 1 R NH R1 N H HH Scheme 22. The interrupted Ugi approachHH to synthesize mitragynine pseudoindoxylHH analogs. Scheme 22. The interrupted Ugi approachOMe to synthesize mitragynine pseudoindoxylOMe analogs. MeOOC MeOOC Kysil et al. report a multicomponent reaction between ethylenediamines, isocyanides, ketones and Kysil etScheme al. 22.report The interrupted a multicomponent Ugi approach to reactionsynthesize mitragynine between ethylenediamines,pseudoindoxyl analogs. isocyanides, aldehydes that affords highly substituted 3,4,5,6-tetrahydropyrazin-2-amines, including spirocyclic ketones and aldehydes that affords highly substituted 3,4,5,6-tetrahydropyrazin-2-amines, including compoundsKysil (Scheme et al. report 23) a[57]. multicomponent The tetrahydropyrazine reaction between ring ethylenediamines, is formed as a isocyanides,result of the ketones intramolecular and spirocyclic compounds (Scheme 23)[57]. The tetrahydropyrazine ring is formed as a result trappingaldehydes of the thatnitrilium affords intermediate highly substituted by the 3,4,5,6-secondtetrahydropyrazin-2-amines ethylenediamine amino group, including and thespirocyclic subsequent of the intramolecular trapping of the nitrilium intermediate by the second ethylenediamine tautomerization.compounds (Scheme The reaction 23) [57]. is The promoted tetrahydropyrazine by Lewis acids, ring is particularly formed as a resulttrimethylchlorosilane. of the intramolecular aminotrapping group ofand the nitrilium the subsequent intermediate tautomerization. by the second ethylenediamine The reaction amino is group promoted and the by subsequent Lewis acids, particularlytautomerization. trimethylchlorosilane. The reaction is promoted by Lewis acids, particularly trimethylchlorosilane.

SchemeScheme 23. Synthesis23. Synthesis of of tetrahydropyrazines tetrahydropyrazines using ethylenediamine ethylenediamine and and Lewis Lewis acid acid catalysis. catalysis. Scheme 23. Synthesis of tetrahydropyrazines using ethylenediamine and Lewis acid catalysis.

Molecules 2016, 21, 19 12 of 22

Molecules 2016, 21, 0019 12 of 21 Xia and co-workers report an asymmetric Ugi-type reaction between α-isocyanoacetamides andXia chiral and imines co-workers catalyzed report by an phenylphosphilic asymmetric Ugi-type acid leading reaction to between 3-oxazolyl α-isocyanoacetamides morpholin-2-one or andpiperazin-2-one chiralMolecules imines 2016, 21 derivatives, 0019catalyzed [ 58by]. Thephenylphosphilic oxazol ring is formedacid leading following to 3-oxazolyl the intramolecular morpholin-2-one attack12 of 21 of theor piperazin-2-onecarbonyl oxygen derivatives of the isocyanoacetmide [58]. The oxazol amide ring is group. formed The following subsequent the intramolecular reaction of aminooxazoles attack of the carbonylwith maleic oxygenXia and anhydride of co-workers the isocyanoacetmide led report to fused an asymmetric heterocycles amide grou Ugi-typep. through The subsequentreaction a multiple between reaction domino α-isocyanoacetamides of aminooxazoles reaction sequence with maleic(Schemeand anhydride 24chiral). imines led to catalyzed fused heterocycles by phenylphosphilic through aacid multiple leading domino to 3-oxazolyl reaction morpholin-2-one sequence (Scheme or 24). piperazin-2-one derivatives [58]. The oxazol ring is formed following the intramolecular attack of the carbonyl oxygen of the isocyanoacetmide amide group. The subsequent reaction of aminooxazoles with maleic anhydride led to fused heterocycles through a multiple domino reaction sequence (Scheme 24).

Scheme 24. SynthesisSynthesis of of tetrahydropyrazines tetrahydropyrazines using ethylenediamine and Lewis acid catalysis. Scheme 24. Synthesis of tetrahydropyrazines using ethylenediamine and Lewis acid catalysis. 3. Intramolecular Intramolecular Nitrilium Nitrilium Trapping Trapping by by Aminophenols Aminophenols 3. Intramolecular Nitrilium Trapping by Aminophenols Heterocycles play an important role in the design and synthesis of bioactivebioactive small molecules: the Heterocycles play an important role in the design and synthesis of bioactive small molecules: the vast majority of marketed drugs contain at leastleast oneone heterocyclicheterocyclic ring.ring. NumerousNumerous nitrogen-containing heterocyclesvast majority including of marketed dihydrothiazoles, drugs contain atbenzoxaz least oneoles, heterocyclic benzothiazoles ring. Nume androus benzimidazoles nitrogen-containing possess heterocyclesheterocycles including including dihydrothiazoles, dihydrothiazoles, benzoxazoles, benzoxazoles, benzothiazoles benzothiazoles and and benzimidazoles benzimidazoles possess possess biological activity [59–63]. biologicalbiological activity activity [59 –[59–63].63].

Scheme 25. Synthesis of heterocyclic scaffolds using a three-component reaction. Scheme 25. Synthesis of heterocyclic scaffolds using a three-component reaction. We recentlyScheme reported25. Synthesis a novel of heterocyclic MCR between scaffolds α-ketones, using a2-aminophenol, three-component and reaction. isocyanide that Wetakes recently advantage reported of intramolecular a novel MCRnitrilium between trappingα-ketones, yielding benzoxazoles 2-aminophenol, and other and heterocycles isocyanide that takesWe(Scheme advantage recently 25) [64]. ofreported intramolecularThe reaction a novel proceeds nitriliumMCR via between a trappingbenzo[ bα][1,4]oxazine-ketones, yielding 2-aminophenol, benzoxazolesintermediate. Owing and and otherto isocyanidethe heterocyclesreactive that takes(Schemenature advantage 25 )[of64 the]. of Thetrapped intramolecular reaction intermediate, proceeds nitrilium the via ring a benzo[ trappican be bngopened][1,4]oxazine yielding by a secondbenzoxazoles intermediate. molecule and of Owing aminophenol other to heterocycles the reactive or (Schemenatureother of 25) thebis-nucleophiles [64]. trapped The reaction intermediate, yielding proceeds benz theoxazoles via ring a canbenzo[ and be otherb opened][1,4]oxazine diverse by aheterocyclic second intermediate molecule scaffolds.. Owing of Furthermore, aminophenol to the reactive or naturethe of reaction the trapped generates intermediate, two addition theal ring diversity can be handles opened that by werea second utilized molecule to synthesize of aminophenol various or other bis-nucleophiles yielding benzoxazoles and other diverse heterocyclic scaffolds. Furthermore, the reaction generates two additional diversity handles that were utilized to synthesize various

Molecules 2016, 21, 19 13 of 22 other bis-nucleophiles yielding benzoxazoles and other diverse heterocyclic scaffolds. Furthermore, the reaction generates two additional diversity handles that were utilized to synthesize various Molecules 2016, 21, 0019 13 of 21 substituted bis-heterocyclic derivatives. Synthesis of heterocycles is traditionally accomplished throughsubstituted multistep bis-heterocyclic routes and/or derivatives. harsh reaction Synthesi conditions,s of heterocycles particularly is traditionally of benzoxazoles accomplished [65], and whilethrough MCR multistep approaches routes can and/or also harsh be taken reaction [29 cond,66],itions, there particularly is a need of benzoxazoles for a more [65], resource-efﬁcient, and while preferablyMCR approaches one-pot method can also for be their taken synthesis [29,66], there [67,68 is]. a Metal need for catalyzed a more insertionresource-efficient, of isocyanides preferably leading to heterocyclesone-potMolecules method are 2016 known, 21for, 0019 their and synthesis usually [67,68]. utilize harshMetal conditionscatalyzed insertion and have of somewhatisocyanides limited 13leading of 21 scope to in termsheterocycles of diversity are [69 known,70]. and usually utilize harsh conditions and have somewhat limited scope in substituted bis-heterocyclic derivatives. Synthesis of heterocycles is traditionally accomplished Weterms discovered of diversity this [69,70]. reaction while performing a routine U4CR in 2,2,2-triﬂuoroethanol (TFE) Wethrough discovered multistep this routes reaction and/or whileharsh reaction performing conditions, a routine particularly U4CR of inbenzoxazoles 2,2,2-trifluoroethanol [65], and while (TFE) between 2-aminophenol, N-methyl-4-piperidone, 4-methoxyphenyl isocyanide and acetic acid at betweenMCR 2-aminophenol, approaches can N also-methyl-4-piperidone, be taken [29,66], there 4-me is athoxyphenyl need for a mo isocyanidere resource-efficient, and acetic preferably acid at 55 °C, ˝ one-pot method for their synthesis [67,68]. Metal catalyzed insertion of isocyanides leading to 55 C,we observed we observed an unusual an heterocy unusualclic heterocyclic (benzo[d]oxazol-2-yl)-1-methylp (benzo[d]oxazol-2-yl)-1-methylpiperidineiperidine product (benzoxazole, product 1) heterocycles are known and usually utilize harsh conditions and have somewhat limited scope in (benzoxazole,along with1 the) along expected with U4CR the expected product s U4CReen only product in trace seenamounts only (Scheme in trace 26). amounts (Scheme 26). terms of diversity [69,70]. We discovered this reaction while performing a routine U4CR in 2,2,2-trifluoroethanol (TFE) between 2-aminophenol, N-methyl-4-piperidone, 4-methoxyphenyl isocyanide and acetic acid at 55 °C, we observed an unusual heterocyclic (benzo[d]oxazol-2-yl)-1-methylpiperidine product (benzoxazole, 1) along with the expected U4CR product seen only in trace amounts (Scheme 26).

SchemeScheme 26. 26.Our Our MCR MCR yielded yielded an an unexpected unexpected benzox benzoxazoleazole instead instead of the ofthe U4CR U4CR product. product.

We investigated the scope of this heterocycle-forming MCR using various isocyanides. While We4-methoxyphenylisocyanide investigatedScheme the 26. scope Our MCRprovided of thisyielded heterocycle-forming thean unexpected best yields benzox, otherazole MCR isocyanidesinstead usingof the U4CRwere various product. also isocyanides.effective in the While 4-methoxyphenylisocyanidereaction. It should be pointed provided out that the the bestisocyanide yields, contributes other isocyanides only one carbon were atom also towards effective in the reaction.benzoxazole;We It shouldtherefore,investigated be the the pointed reacti scopeon of outoutcomethis heterocycle-forming that is the independent isocyanide MCR of theusing contributes nature various of isocyanides. isocyanide only one Whileused. carbon The atom scope 4-methoxyphenylisocyanideof this reaction was evaluated provided by the using best yieldsdifferent, other ketones isocyanides and substitutedwere also effective 2-aminophenols in the towards benzoxazole;reaction. It should therefore, be pointed the out reaction that the isoc outcomeyanide contributes is independent only one ofcarbon the atom nature towards of isocyanide (Scheme 27). The reaction was effective with a variety of ketones including the complex, multifunctional used. Thebenzoxazole; scope of therefore, this reaction the reacti wason outcome evaluated is independent by using of the differentnature of isocyanide ketones used. and The substituted semi-synthetic natural product-like naloxone (product 7), a clinically used opioid antagonist, 2-aminophenolsscope of (Schemethis reaction 27 was). The evaluated reaction by using was different effective ketones with and a varietysubstituted of 2-aminophenols ketones including the highlighting the good functional group tolerance of this reaction. complex, multifunctional(Scheme 27). The reaction semi-synthetic was effective with natural a variet product-likey of ketones including naloxone the complex, (product multifunctional7), a clinically used semi-synthetic natural product-like naloxone (product 7), a clinically used opioid antagonist, opioid antagonist,highlighting highlighting the good functional the good group functional tolerance of groupthis reaction. tolerance of this reaction.

Scheme 27. Scope of our MCR yielding benzoxazoles. Scheme 27. Scope of our MCR yielding benzoxazoles. Scheme 27. Scope of our MCR yielding benzoxazoles.

Molecules 2016, 21, 19 14 of 22 Molecules 2016, 21, 0019 14 of 21

Isocyanides play an unusual role in this MCR, contributing only one carbon atom to the benzoxazole.Molecules 2016 The The, 21 ,aryl 0019 aryl or or alkyl alkyl amine amine moiety moiety acts acts as the as theleaving leaving group, group, leading leading to an to insertion an insertion14 of of21 only of onlythe isocyanide the isocyanide carbon carbon into intothe thebenzoxazole benzoxazole moiety. moiety. While While investigating investigating the the effect effect of of various Isocyanides play an unusual role in this MCR, contributing only one carbon atom to the isocyanides, we found that 2,6-dimethylphenyl isocyanide, instead of the expected benzoxazole, benzoxazole. The aryl or alkyl amine moiety acts as the leaving group, leading to an insertion of only yielded a spiro[benzo[b][1,4]oxazine]-imine (benzoxazine, 10) scaffold when reacted with NMP and yieldedthe aisocyanide spiro[benzo[ carbonb][1,4]oxazine]-imine into the benzoxazole (benzoxazine, moiety. While 10) investigatingscaffold when the reacted effect withof various NMP and 2-aminophenolisocyanides, (Schemewe found 2828). that). The The 2,6-dimethylphenyl isolation isolation and and structure structure isocyanide, elucidation instead of of the this expected benzoxazine benzoxazole, derivative providedyielded us a the spiro[benzo[ ﬁrstfirst cluesb][1,4]oxazine]-imine about the mechanism (benzoxazine, ofof thisthis reaction.reaction. 10) scaffold when reacted with NMP and 2-aminophenol (Scheme 28). The isolation and structure elucidation of this benzoxazine derivative provided us the first clues about the mechanism of this reaction.

Scheme 28. Sterically hindered isocyanide yields a [benzo[b][1,4]oxazine]-imine (10). Scheme 28. Sterically hindered isocyanide yields a [benzo[b][1,4]oxazine]-imine (10). Scheme 28. Sterically hindered isocyanide yields a [benzo[b][1,4]oxazine]-imine (10). We hypothesized that the benzoxazine 10 was an intermediate in the reaction route leading to the final Weproduct hypothesizedWe hypothesized benzoxazole that that 1. theWe the envisioned benzoxazine the1010 was reactionwas an intermediate an mechan intermediateism in thefor reactionthe inthe formation reactionroute leading of routebenzoxazoles to the leading toshown thefinal ﬁnalin productScheme product benzoxazole 29. benzoxazole 1. We envisioned1. We envisioned the reaction the mechan reactionism for mechanism the formation for of benzoxazoles the formation of benzoxazolesshown in Scheme shown 29. in Scheme 29.

H OH H OH HH O TfTf O O 1 OH 1 R1 R O O OH N R1 N NN C N R N C HNHN NHNH2 2 ~ H~ H

N N N NN N ABAB OH OH 1 O H NR1 O H NR HN R1 H NH C N HN NR1 NH C H N N H N N 2 N HO N H2N HO C N HO C HOR1 HNR1 H HO N HO O HN HN H HN HO HO ON NO HN HN N N O 1 N R -NH2 1 N R1-NH N SchemeScheme 29. 29.Proposed Proposed mechanism mechanism for the the2 formation formation of ofbenzoxazole benzoxazole 1. 1. 1 To test ourScheme proposed 29. mechanism Proposed mechanism that the benzoxazine for the formation C is an of intermediate benzoxazole in 1 .the synthesis of Tobenzoxazoles, test our proposedwe isolated mechanism the benzoxazine that obtain the benzoxazineed using 4-methoxyphenylisocyanide.C is an intermediate We in enhanced the synthesis of benzoxazoles, we isolated the benzoxazine obtained using 4-methoxyphenylisocyanide. We Tothe scopetest our of our proposed MCR by mechanismreacting the isolated that the benzoxazi benzoxazinene intermediate C is an with intermediate a series of bis-nucleophiles in the synthesis of enhancedincluding the scope1,2-diaminobenzene, of our MCR by2-aminothiophenol, reacting the isolated and cysteamine benzoxazine to synt intermediatehesize benzimidazole, with a series of benzoxazoles, we isolated the benzoxazine obtained using 4-methoxyphenylisocyanide. We enhanced bis-nucleophilesbenzothiazole including and dihydrothiazol 1,2-diaminobenzene,e derivatives, respectively. 2-aminothiophenol, and cysteamine to synthesize the scope of our MCR by reacting the isolated benzoxazine intermediate with a series of bis-nucleophiles benzimidazole, benzothiazole and dihydrothiazole derivatives, respectively. including 1,2-diaminobenzene, 2-aminothiophenol, and cysteamine to synthesize benzimidazole, benzothiazole and dihydrothiazole derivatives, respectively.

Molecules 2016, 21, 19 15 of 22

Molecules 2016, 21, 0019 15 of 21

To enhanceTo enhance the the diversity diversity and, and, thus, thus, the the possible possible bi biologicalological relevance relevance of ofthe the benzoxazole benzoxazole scaffold, scaffold, we decidedwe decided to exploitto exploit the the free free phenolic phenolic OHOH andand secondary aromatic aromatic amine amine of the of thebenzoxazole benzoxazole productsproducts to make to make second-generation second-generation derivatives derivatives (Figure(Figure 11).).

FigureFigure 1. 1.Diversiﬁcation Diversification of the benzoxazole benzoxazole scaffold. scaffold.

In summary, we discovered a convenient, Brønsted acid catalyzed, isocyanide based Inheterocycle-forming summary, we three-component discovered a reaction convenient, between Brønsted 2-aminophenols, acid catalyzed, isocyanides, isocyanide and ketones based heterocycle-formingthat leads to benzoxazoles three-component and other heterocyclic reaction between products. 2-aminophenols,The reaction progresses isocyanides, via a benzoxazine and ketones that leadsintermediate to benzoxazoles formed by and intramolecular other heterocyclic nucleophilic products. trapping The of reaction the reactive progresses nitrilium via intermediate a benzoxazine intermediateby an adjacent formed phenolic by intramolecular group. The reactivity nucleophilic of benzoxazine trapping to of bis-nucleophiles the reactive nitrilium was leveraged intermediate to by ansynthesize adjacent an phenolic array of group. heterocyclic The reactivity scaffolds ofincluding benzoxazine benzimidazoles, to bis-nucleophiles dihydrothiazoles was leveragedand to synthesizebenzothiazoles. an array The ofreaction heterocyclic showed scaffoldsgood functi includingonal group benzimidazoles, tolerance, and is dihydrothiazoles compatible with and different ketones and aminophenols, ideal for the generation of molecule libraries under mild reaction benzothiazoles. The reaction showed good functional group tolerance, and is compatible with conditions, without the use of transition metal catalysts. We have further exploited the reactivity of different ketones and aminophenols, ideal for the generation of molecule libraries under mild reaction the phenolic hydroxyl and the aromatic secondary amine to diversify the scaffolds. conditions, without the use of transition metal catalysts. We have further exploited the reactivity of the phenolic4. Synthesis hydroxyl of Opioids and theby the aromatic Ugi Reaction secondary amine to diversify the scaffolds.

4. SynthesisMorphine of Opioids and its semi-synthetic by the Ugi Reaction congeners are the most important agents used for the treatment of moderate to severe pain. The desired analgesic effect is accompanied by various dangerous adverse Morphineeffects, which and are its predominantly semi-synthetic mediated congeners by aremu theopioid most receptors important (MOR). agents One used possible for the way treatment to of moderateovercome toMOR-mediated severe pain. adverse The desiredeffects is analgesicto synthesize effect mixed is partial accompanied agonists or by compounds various dangerous with adversemixed effects, MOR whichagonist/delta are predominantly opioid receptor mediated (DOR) antagonist by mu opioidproperties receptors [71,72]. The (MOR). ability One of morphine possible way to overcometo induce MOR-mediatedtolerance and dependence adverse may effects be counte is tored synthesize by co-administering mixed partial DOR agonists antagonists or without compounds withsacrificing mixed MOR antinociception agonist/delta [73,74]. opioid Similarly, receptor partial ac (DOR)tivation antagonist of multiple propertiesopioid receptors, [71,72 for]. example The ability by a dual MOR-DOR partial agonist ligand, can alleviate these side effects. However, the previously of morphine to induce tolerance and dependence may be countered by co-administering DOR reported MOR/DOR mixed agonists are mostly peptides, therefore their clinical applicability is antagonistslow [75–77]. without sacriﬁcing antinociception [73,74]. Similarly, partial activation of multiple opioid receptors,Synthetic for example aryl anilido by a dualpiperidines MOR-DOR including partial fentanyl agonist and ligand,carfentanil can (19) alleviate are potent these analgesics side effects. However,acting theprimarily previously on MOR, reported and their MOR/DOR scaffold can be mixed accessed agonists by the Ugi are reaction. mostly Lofentanyl, peptides, structurally therefore their clinicalclosely applicability related to carfentanil, is low [75 –has77 ].been shown to possess high affinity for DOR as well [78]. The synthesis Syntheticof carfentanil aryl was anilido recently piperidines reported using including an U4CR fentanyl followed andby methanolysis carfentanil of (19) the arecarfentanil potent amide analgesics actingUgi primarily product (Scheme on MOR, 30) and[79]. The their same scaffold approach can has be been accessed used by by Portoghese the Ugi reaction.and co-workers Lofentanyl, to structurallyprepare carfentanil-based closely related bivalent to carfentanil, ligands for has the been treatment shown of opioid to possess withdrawal high [80,81]. afﬁnity for DOR as well [ 78]. The synthesis of carfentanil was recently reported using an U4CR followed by methanolysis of the carfentanil amide Ugi product (Scheme 30)[79]. The same approach has been used by Molecules 2016, 21, 19 16 of 22

Portoghese and co-workers to prepare carfentanil-based bivalent ligands for the treatment of opioid withdrawalMolecules [80,81 2016]., 21, 0019 16 of 21

Molecules 2016, 21, 0019 16 of 21 Molecules 2016, 21, 0019 16 of 21

Scheme 30. Synthesis of carfentanil by the U4CR. Scheme 30. Synthesis of carfentanil by the U4CR. Interested in creating highly potent synthetic opioids acting as MOR and DOR dual agonists, Interestedour research in creating group recently highlyScheme reportedScheme potent 30. 30. the Synthesis synthetic Synthesis synthesis of opioidsof carfentanilcarfentanil carfentanil acting by by amidesthe the U4CR. as U4CR. using MOR the and U4CR DOR approach dual [82]. agonists, our We substituted the ester moiety with an amide using various isocyanides and determined if the amide research group recently reported the synthesis of carfentanil amides using the U4CR approach [82]. InterestedanalogsInterested were in analgesicscreating in creating highlywith highly improved potent potent sidesyntheti syntheti effectc profilesopioidsopioids comparedacting acting as asMOR to MOR morphine. and and DOR Previously,DOR dual dualagonists, only agonists, We substitutedour research the ester group moiety recently withreported an the amide synthesis using of carfentanil various isocyanidesamides using the and U4CR determined approach [82]. if the amide our researchthe primary group amide recently was reported [83,84].the synthesis Four-com of ponentcarfentanil Ugi reactionsamides using were thecarried U4CR out approachbetween [82]. analogs wereWeN-alkylpiperidones, substituted analgesics the withester aniline, moiety improved propionic with an sideacid amide and effect using an array proﬁlesvarious of aliphatic isocyanides compared isocyanides and to determined morphine. (Scheme 31).if the Previously, amide only We substituted the ester moiety with an amide using various isocyanides and determined if the amide the primaryanalogs amide were was analgesics reported with improved [83,84]. side Four-component effect profiles compared Ugi reactions to morphine. were Previously, carried only out between analogsthe wereprimary analgesics amide was with reported improved [83,84]. side Four-com effect profilesponent Ugi compared reactions to were morphine. carried outPreviously, between only N-alkylpiperidones,the primaryN-alkylpiperidones, amide aniline, was aniline, reported propionic propionic [83,84]. acid acid Four-comand and an an array arrayponent of aliphatic of Ugi aliphatic reactions isocyanides isocyanides were (Scheme carried 31). (Scheme out between 31). N-alkylpiperidones, aniline, propionic acid and an array of aliphatic isocyanides (Scheme 31).

Scheme 31. Synthesis of carfentanil amides by the Ugi reaction.

Piperidine-4-ones with N-phenylethyl and N-cyclopropylmethyl substituents were employed in the reactions. The Schemecarfentanil 31. Synthesis amides wereof carfentanil isolated amides in moderate by the Ugi to reaction. good yields. The use of Ugi Scheme 31. Synthesis of carfentanil amides by the Ugi reaction. reactions to access the carfentanil scaffold makes diversification library-friendly because of the commercialPiperidine-4-ones availabilityScheme with of the31. N Synthesissimple-phenylethyl building of carfentanil and blocks N-cyclopropylmethyl used amides in this by thereaction. Ugi substituents reaction. were employed Piperidine-4-onesin theThe reactions. synthesized withThe carfentanilderivativesN-phenylethyl amides(Figure were2, and20– 29isolatedN) were-cyclopropylmethyl incharacterized moderate to using good in substituentsyields. vitro receptor The use binding wereof Ugi employed Piperidine-4-onesreactionsand in vivo to analgesia access withthe assays carfentanil N -phenylethylin a mouse scaffold model. and makes OurN-cyclopropylmethyl leaddiversification compound, library-friendly the Nsubstituents-cycloheptyl because analogwere of employed (30the), in the reactions.commercial The availability carfentanil of the simple amides building were blocks isolated used in in this moderate reaction. to good yields. The use of in thewas reactions. subjected The to detailed carfentanil pharmacological amides were characterization. isolated in moderate to good yields. The use of Ugi Ugi reactionsThe to accesssynthesized the derivatives carfentanil (Figure scaffold 2, 20– makes29) were diversiﬁcationcharacterized using library-friendly in vitro receptor binding because of the reactions to access the carfentanil scaffold makes diversification library-friendly because of the commercialand availability in vivo analgesia ofthe assays simple in a mouse building model. blocks Our lead used compound, in this reaction.the N-cycloheptyl analog (30), commercialwas subjected availability to detailed of theO pharmacological simple buildingO characterization. blocks usedO in this reaction.O N N N N The synthesized derivativesN (Figure2, 20N –29) were characterizedN usingN in vitro receptor binding The synthesized derivativesH (Figure 2, H20–29) were characterizedH usingH in vitro receptor binding and in vivo analgesia assaysO in a mouseO model. Our leadO compound,O the N-cycloheptyl analog (30), and in vivo analgesia assaysN in a mouse Nmodel. Our leadN compound, theN N-cycloheptyl analog (30), O O O O was subjected to detailed pharmacological20 characterization.21 22 23 was subjected to detailedN pharmacologicalN characterization.N N N N N N H H H H O O O O N N N N O O O O N 20 N 21N 22N 23 O N O N N O N O H H H H NO ON O N O N N N N N N H N H N H N H O O O O O O O O N 24N 25 26N N27 N N N N N N N N H H H H O 20 O 21O 22O 23 N ON N O N N N 24N 25 26N 27 H H O O O O O O N N N N N N N O N O N N H 28 H H H O ON O N 29 O N N H H N O N O N N Figure 2. Structures of the synthesized carfentanilN amide analogs 20–29. 24N 25 26 27 28 29 Figure 2. Structures ofO the synthesized carfentanilO amide analogs 20–29. N N N N H H O O N N

28 29 Figure 2. Structures of the synthesized carfentanil amide analogs 20–29. Figure 2. Structures of the synthesized carfentanil amide analogs 20–29.

Molecules 2016, 21, 19 17 of 22

The synthesized compounds were characterized in in vitro radioligand binding assays in CHO cell lines stably transfected with murine MOR, DOR, and KOR (Table1). Analogs with N-cyclopropylmethyl (28, 29) displayed low affinity for opioid receptors (Ki > 100 nM), whereas analogs with N-phenylethyl substituents (20–27) showed moderate to high affinity, particularly for MOR. Most analogs had low affinity (Ki > 100 nM) for KOR. Three compounds, 22 (cyclohexyl), 23 (cycloheptyl) and 27 (adamantyl) had DOR affinity of less than 10 nM. Given our hypothesis that MOR-DOR compounds may be useful for overcoming side effects, we studied the pharmacology of compounds with affinity at MOR and DOR. We selected 23 for detailed pharmacological evaluation because its affinity for DOR was the highest in the series.

Table 1. Summary of in vitro receptor binding and in vivo tail-ﬂick analgesia.

Cmpd. MOR-CHO DOR-CHO KOR-CHO ED50 (mg/kg) 20 10.3 ˘ 5.1 >100 87.6 ˘ 29 0.78 ˘ 0.26 21 29.4 ˘ 15 90.7 ˘ 23 >100 9.92 ˘ 0.08 22 0.84 ˘ 0.34 2.65 ˘ 0.32 0.44 ˘ 0.05 3.10 ˘ 0.19 23 2.66 ˘ 1.3 8.90 ˘ 7.7 >100 10.0 ˘ 0.00 24 21.1 ˘ 11 87.9 ˘ 4.8 >100 >10 25 2.73 ˘ 2.2 71.2 ˘ 8.7 >100 1.09 ˘ 0.05 26 27.0 ˘ 20 27.0 ˘ 3.6 >100 >10 27 25.0 ˘ 9.8 8.83 ˘ 0.63 >100 >10 28 >100 >100 >100 >10 29 >100 >100 >100 >10

The compounds were evaluated in in vivo antinociception assays in mice. Analogs 20–23 and 25 showed analgesia at the highest given dose of 10 mg/kg. Three compounds in the series (20, 22, 25) were more potent than morphine (ED50 ~5 mg/kg, sc) [85]. The analgesic ED50 values of 21 and our lead compound 23 (ED50 = 10 mg/kg, sc) was about two-fold lower than that of morphine (Table1). Compound 23 was found to be a full agonist at MOR and a partial agonist at DOR in [35S]GTPγS binding assays. We looked at the side-effect profile of 23 in mouse models of respiratory depression (RD) and physical dependence. At doses 4 ˆ ED50 (40 mg/kg, sc), 23 did show some signs of RD. Repeated administration of traditional opioids leads to both tolerance and physical dependence, reducing the effectiveness of the drug over time and making it liable to cause addiction. Chronic dosing of 23 produced tolerance, however, 23-tolerant mice challenged with naloxone (a common opioid antagonist) demonstrated fewer withdrawal symptoms than morphine. Another serious side effect of MOR opioids is constipation. At doses 2ˆ ED50 (20 mg/kg) and 5ˆ ED50 (50 mg/kg), 23 showed no signs of inhibition of gastrointestinal motility, while morphine caused constipation at its ED50 dose. In summary, the cycloheptyl amide analog (23) of carfentanil may be useful in negating multiple major side effects seen with classic MOR analgesics. We hope to optimize the structure of this carfentanil amide scaffold to maintain receptor affinities and MOR agonism, while reducing the DOR efficacy to attain a MOR agonist/DOR antagonist based pharmacophore to address respiratory depression, which was observed with the current lead molecule. The utilization of Ugi chemistry to diversify the amine and carboxylic acid ends with commercially available reagents makes further derivatives readily accessible. The presented examples underline the greatest advantage of multicomponent reactions: the possibility to create diverse bioactive compounds from simple building blocks in just a few or even only one step. MCRs are an extremely useful and quickly evolving field of synthetic organic chemistry. In recent years, countless varieties of isocyanide-based MCRs have emerged, among which numerous intriguing reactions can be found that take advantage of nitrilium trapping, the nucleophilic attack on the extremely reactive nitrilium intermediate. These reactions have not only introduced us to novel Molecules 2016, 21, 19 18 of 22 chemical methodologies and reaction mechanisms, but also made new areas of chemical space easily accessible. Based on the diversity of structures that can be accessed by MCRs that involve nitrilium trapping, these methodologies will have a bright future in drug design and synthesis.

Acknowledgments: This work was supported by research grants from the National Institute on Drug Abuse (DA034106) to S.M. This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA008748. Author Contributions: SM conceived and designed the review article. AV, TP and RD did literature research on relevant articles for this review. AV, TP and SM wrote the review. Conﬂicts of Interest: The authors declare no conﬂict of interest.

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