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Multicomponent reactionsMCRs (multicomponent reactions) are a valuable strategy in the ‘green chemistry toolbox’when designing a synthetic approach with sustainability in mind and are increasinglygrowing in application in medicinal chemistry and drug discovery programmes,combinatorial chemistry, natural product synthesis, and polymer chemistry.[1] They alsoare ideally suited for diversity oriented synthesis and library generation. In 2014 R. C.Cioc, E. Ruijter & R. V. A. Orru published a review to promote the green process designopportunities available through the application of MCRs [1].

The benefits of MCRs are that they bring together at least three reactants in one-potbringing about an efficient and intrinsically atom economical reaction (generating aproduct that contains essentially all the atoms of the starting materials), generally undermild conditions and frequently using greener solvents.[1]

A major advantage of MCRs is waste reduction – due to their highly convergent nature,MCRs reduce waste generated by a process by incorporating a highly resource efficientstep in the synthesis and often shortening the overall number of steps. Their excellentchemo-and regio-selectivity minimises the generation of side-products, and by productsare typically simple, small molecules such as water, alcohols, amines or common salts,resulting in not only a reduced amount of waste, but the waste itself is generally benign(avoiding problems associated with the recovery and disposal of hazardous waste). Thework-up of these reactions is often straightforward via precipitation of the product,avoiding the use of more time consuming and resource intensive recovery andpurification methods. Solvent use is also generally significantly reduced due to reactiontelescoping and improved work-up.

This resource has been created as part of the IMI funded CHEM21 project (Chemical Manufacturing Methods for the 21st Century Pharmaceutical Industries). CHEM21 has receivedfunding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115360, resources of which are composed of financial contribution from the EuropeanUnion’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.

The educational material is licensed (unless otherwise specified) under Creative Commons license CC BY-NC 4.0, which gives permission for it to be shared and adapted for non-commercial purposes as long as attribution is given. For full details please see our legal statements.

The views expressed in regards to education and training materials represent the aspiration of the CHEM21 consortium, although may not always be the view of eachindividual organisation. Referencing of external sources does not imply formal endorsement by the CHEM21 consortium.

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Table 1 demonstrates some representative examples of MCRs and some indicative greenchemistry metrics.

This material is reproduced from R. C. Cioc, E. Ruijter and R. V. A. Orru, Multicomponentreactions: advanced tools for sustainable organic synthesis, Green Chem., 2014, 16,2958-2975..

It is copyright to the Royal Society of Chemistry (RSC) and is reproduced here with theirexpress permission. If you wish to reproduce it elsewhere you must obtain similarpermission from the RSC.

Table 1: Examples of MCRs

Reaction Year Scheme AE a, bEmwcWaste

Strecker 1850 80% 0.26 H2O

Biginelli 1891 84% 0.20 2H2O

Mannich 1912 89% 0.13 H2O

Passerini 1921 100% 0.00 None




http://dx.doi.org/10.1039/C4GC00013G

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Ugi 1959 91% 0.10 H2O

Petasis 1993 62% 0.55 B(OH)3

Groebke-Blackburn-Bienaymé

1998 90% 0.11 H 2 O

Passerini-Dömling 2000 84% 0.19 Me2NH

Orru 2003 86% 0.16 H2O

Reaction Year Scheme AE a, bEmwcWaste

One issue with the MCRs is that a number of the MCR strategies use a cyanide or anisocyanide as one of the reaction components, the synthesis of which are typicallythemselves atom-inefficient and tend to use hazardous reagents and problematicsolvents and as such the environmental implications of the preparation of these





compounds must be taken into consideration (as well as the toxicity of the cyanidecompounds). This reinforces the importance of looking upstream and downstream of aparticular reaction step and thinking holistically to ensure that methodologies aregenuinely greener. Research is underway to explore more environmentally acceptablemethods of generating cyanides, for example the use of potassium hexacyanoferrate (II)as an environmentally benign cyanide source.[2] [3]

1. R. C. Cioc, E. Ruijter and R. V. A. Orru , Multicomponent reactions: advanced toolsfor sustainable organic synthesis, Green Chem., 2014, 16, 2958–2975.

2. X. Hu, Y. Ma and Z. Li, Eco-friendly synthesis of α-aminonitriles from ketones inPEG-400 medium using potassium Hexacyanoferrate(II) as cyanide source,Journal of Organometallic Chemistry, 2012, 705, 70-74.

3. Z. Li, G. Tian and Y. Ma, One-Pot Three-Component Solvent-Free Cyanoaroylationof Aldehydes Using Potassium Hexacyanoferrate(II) as an EnvironmentallyBenign Cyanide Source, Synlett, 2010, 2010, 2164-2168.




http://dx.doi.org/10.1039/C4GC00013G

http://www.sciencedirect.com/science/article/pii/S0022328X12000745


Case study 2

This case study was provided by Prof. Bert Maes' ORSY team at the University ofStuttgart.

With important medicinal properties, isothioureas are an important class of compoundsto the pharmaceutical industry; which have found use as anti-histamines, anti-bacterials,for treatment of peptic ulcers, HIV and influenza.[1][2][3][4][5] They are also crucialintermediates in the synthesis of guanidines[6] [7] (used in treatment of Lambert‑Eatonsyndrome), with many routes to their synthesis reporting the formation of isothioureas asintermediates.[6] [7] Beyond pharmaceutical applications isothioureas also haveapplications as agrochemicals as well as within the fine chemicals industry.

Scheme 1: Classical and novel MCR approaches to the synthesis of isothioureas [6][8]

Classically S-alkyl isothioureas are prepared from the corresponding thioureas by S-alkylation. The most common intermediates in the synthesis of guanidines, S-methylisothioureas are formed by reaction of the corresponding thioureas with the highlycarcinogenic and neurotoxic methyl iodide (MeI).[8] The use of alkyl halides to furnish S-This resource has been created as part of the IMI funded CHEM21 project (Chemical Manufacturing Methods for the 21st Century Pharmaceutical Industries). CHEM21 has receivedfunding from the Innovative Medicines Initiative Joint Undertaking under grant agreement n°115360, resources of which are composed of financial contribution from the EuropeanUnion’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind contribution.



https://www.uantwerpen.be/en/rg/orsy/

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alkyl isothioureas presents a variety of disadvantages including the associated healthrisks, flammability and reactivity of the reagents.

Given the industrial significance of isothioureas and relative lack of research into greenerapproaches to their synthesis, the CHEM21 researchers have developed amulticomponent reaction for the synthesis of isothioureas from isocyanides,thiosulfonates and amines,[8] the classical approach requires three synthetic steps withassociated chromatographic purification to achieve the alkylated isothiourea product,which the novel MCR approach can achieve in one step. It also circumvents the use of analkyl halide for the S-alkylation (Scheme 1).

The novel methodology allows access to a variety of novel isothioureas, including S-arylisothioureas which are difficult to achieve by other methods.[8] The method allows for theuse of readily available isocyanides, thiosulfonates and (hetero)aromatic amines toachieve the target molecules in a single synthetic step. The methodology operates using acopper based catalyst, does not require air exclusion and operates under mild reactiontemperatures.[8]

1. A. Nicholson, J. D. Perry, A. L. James, S. P. Stanforth, S. Carnell, K. Wilkinson, C.M. Anjam Khan, A. De Soyza and K. F. Gould, In vitro activity of S-(3,4-dichlorobenzyl)isothiourea hydrochloride and novel structurally relatedcompounds against multidrug-resistant bacteria, including Pseudomonasaeruginosa and Burkholderia cepacia complex, Int. J. Antimicrob. Ag., 2012, 39,27-32.

2. S. Harusawa, K. Sawada, T. Magata, H. Yoneyama, L. Araki, Y. Usami, K. Hatano, K.Yamamoto, D. Yamamoto and A. Yamatodani, Synthesis and evaluation of N-alkyl-S-[3-(piperidin-1-yl)propyl]isothioureas: High affinity and human/ratspecies-selective histamine H3 receptor antagonists, Bioorg. Med. Chem. Lett.,2013, 23, 6415-6420.

3. E. P. Istyastono, S. Nijmeijer, H. D. Lim, A. van de Stolpe, L. Roumen, A. J.Kooistra, H. F. Vischer, I. J. P. de Esch, R. Leurs and C. de Graaf, MolecularDeterminants of Ligand Binding Modes in the Histamine H4 Receptor: LinkingLigand-Based Three-Dimensional Quantitative Structure–Activity Relationship(3D-QSAR) Models to in Silico Guided Receptor Mutagenesis Studies, J. Med.Chem., 2011, 54, 8136-8147.




http://www.sciencedirect.com/science/article/pii/S0924857911003694


http://dx.doi.org/10.1021/jm201042n


4. G. Thoma, M. B. Streiff, J. Kovarik, F. Glickman, T. Wagner, C. Beerli and H. - G.Zerwes, Orally Bioavailable Isothioureas Block Function of the ChemokineReceptor CXCR4 In Vitro and In Vivo, J. Med. Chem., 2008, 51, 7915-7920.

5. C. Ma, A. Wu, Y. Wu, X. Ren and M. Cheng, Design and Synthesis of N-ArylIsothioureas as a Novel Class of Gastric H+/K+-ATPase Inhibitors, Archiv derPharmazie, 2013, 346, 891-900.

6. C. Alonso-Moreno, A. Antinolo, F. Carrillo-Hermosilla and A. Otero, Guanidines:from classical approaches to efficient catalytic syntheses, Chem. Soc. Rev., 2014,43, 3406-3425.

7. T. R. M. Rauws and B. U. W. Maes, Transition metal-catalyzed N-arylations ofamidines and guanidines, Chem. Soc. Rev., 2012, 41, 2463-2497.

8. P. Mampuys, Y. Zhu, T. Vlaar, E. Ruijter, R. V. A. Orru and B. U. W. Maes,Sustainable Three-Component Synthesis of Isothioureas from Isocyanides,Thiosulfonates, and Amines, Angew. Chem. Int. Ed., 2014, 53, 12849-12854.




http://dx.doi.org/10.1021/jm801065q

http://dx.doi.org/10.1002/ardp.201300276

http://dx.doi.org/10.1039/C4CS00013G

http://dx.doi.org/10.1039/C1CS15236J

http://dx.doi.org/10.1002/anie.201406717


Case study 3

The β-amino alcohol moiety is a privileged structural motif in the pharmaceuticalindustry. Salbutamol (1) and propranolol (2) are on the World Health Organization List ofEssential Medicines [1] and represent the most important examples of therapeutic agentsbearing this structural feature. Numerous others have been released on the market for thetreatment of various circulatory, respiratory and other diseases (Figure 1). In addition totheir high relevance in drug discovery,[2][3][4]N-substituted β-amino alcohols areimportant building blocks in the preparation of added value chemicals[5][6] and ligandsfor catalysis.[7][8]

Figure 1: Examples of drugs based on the N-substituted β-amino alcohol motif [9]

The construction of the β-amino alcohol fragment is almost invariably achieved by thenucleophilic attack of an amine on a suitable electrophilic reaction partner, such as anepoxide, α-haloketone or β-halohydrin (Scheme 1). Although robust, there are manydrawbacks associated with this synthetic strategy. First, the required starting materialsare typically not commercial and their multistep preparation is highly wasteful and time-consuming. Secondly, the substitution approach poses important selectivity issues (e.g.regioselectivity in the epoxide opening), double alkylation of the (unprotected) primaryamine and low reactivity of poorly nucleophilic and bulky amines which thus need to beemployed in large excess. A general alternative strategy circumventing these problemsand employing readily available building blocks would therefore be a valuable tool formedicinal as well as process chemistry.




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Scheme 1: Synthetic approaches towards N-substituted β-amino alcohols[9]

CHEM21 researchers designed a novel method for the construction of the N-substituted β-amino alcohol motif via a less straightforward central C-C bond retrosyntheticdisconnection through addition rather than substitution, using aldehydes andisocyanides as building blocks. Aldehydes, isocyanides and SiCl4 can be combined in aPasserini-type reaction to give α-trichlorosilyloxy imidoyl chlorides,[10][11] which areversatile intermediates towards the synthesis of valuable compounds like α-hydroxyamides and α‑hydroxy esters. For the synthesis of β-amino alcohols, the CHEM21researchers employed in the same pot the generation of the imidoyl chloride intermediatefrom aldehydes and isocyanides in combination with its reduction with a mild reducingagent (ammonia-borane). This approach furnishes the desired β‑amino alcoholderivatives in a faster, simpler and more general way than current methodology (Scheme2).

Scheme 2: Synthesis of N-substituted β-amino alcohols from aldehydes andisocyanides[9]




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The synthetic utility of this method was validated by the preparation of approx. 40 β-amino alcohols in good yields (44-93%). Importantly, high performance is achieved inchallenging circumstances for conventional approaches: oxidation-sensitive functionalgroups, bulky derivatives, nucleophilic substitution-sensitive substrates and non-nucleophilic amines. Furthermore, the method can be upgraded to a catalyticenantioselective synthesis by introducing a (commercial) chiral catalyst.

The good availability of the required building blocks, the reduced reaction time and thegeneral scope recommend this method for both combinatorial and medicinal chemistryapplications.[9]

1. WHO essential medicines, 18th edition (Last accessed: 2014).2. A. K. Verma, H. Singh, M. Satyanarayana, S. P. Srivastava, P. Tiwari, A. B. Singh, A.

K. Dwivedi, S. K. Singh, M. Srivastava, C. Nath, R. Raghubir, A. K. Srivastava and R.Pratap, Flavone-Based Novel Antidiabetic and Antidyslipidemic Agents, Journalof Medicinal Chemistry, 2012, 55, 4551-4567.

3. C. D. Smith, A. Wang, K. Vembaiyan, J. Zhang, C. Xie, Q. Zhou, G. Wu, S. R. WayneChen and T. G. Back, Novel Carvedilol Analogues That Suppress Store-Overload-Induced Ca2+ Release, Journal of Medicinal Chemistry, 2013, 56, 8626-8655.

4. A. Liu, L. Huang, Z. Wang, Z. Luo, F. Mao, W. Shan, J. Xie, K. Lai and X. Li, Hybridsconsisting of the pharmacophores of salmeterol and roflumilast orphthalazinone: Dual β2-adrenoceptor agonists-PDE4 inhibitors for the treatmentof COPD, Bioorganic & Medicinal Chemistry Letters, 2013, 23, 1548-1552.

5. W. Ang, W. Ye, Z. Sang, Y. Liu, T. Yang, Y. Deng, Y. Luo and Y. Wei, Discovery ofnovel bis-oxazolidinone compounds as potential potent and selectiveantitubercular agents, Bioorganic & Medicinal Chemistry Letters, 2014, 24, 1496-1501.

6. J. Ford Burns, B. Chen, C. - A. Chen, D. Doller, E. Edelmenky, Y. Jiang, J. M.Peterson, M. Sabio, J. Weiss, A. D. White, L. Wu, R. Bhardwaj, G. Chandrasena, N.J. Boyle and X. Huang, cis-1-Oxo-heterocyclyl-4-amido cyclohexane derivatives asNPY5 receptor antagonists, Bioorganic & Medicinal Chemistry Letters, 2014, 24,1458-1461.

7. D. Guijarro, Ó. Pablo and M. Yus, Achiral β-amino alcohols as efficient ligands forthe ruthenium-catalysed asymmetric transfer hydrogenation of sulfinylimines,Tetrahedron Letters, 2011, 52, 789-791.




http://www.who.int/iris/bitstream/10665/93142/1/EML_18_eng.pdf?ua=1

http://dx.doi.org/10.1021/jm201107g

http://dx.doi.org/10.1021/jm401090a




http://www.sciencedirect.com/science/article/pii/S0040403910022495


8. D. Isik Tasgin and C. Unaleroglu, Enantioselective addition of diethylzinc toaldehydes catalyzed by β-amino alcohols derived from (1R,2S)-norephedrine,Applied Organometallic Chemistry, 2010, 24, 33-37.

9. R. C. Cioc, D. J. H. van der Niet, E. Janssen, E. Ruijter and R. V. A. Orru, One-PotSynthesis of N-Substituted β-Amino Alcohols from Aldehydes and Isocyanides,Chemistry – A European Journal, 2015, 21, 7808-7813.

10. S. E. Denmark and Y. Fan, The First Catalytic, Asymmetric α-Additions ofIsocyanides. Lewis-Base-Catalyzed, Enantioselective Passerini-Type Reactions,Journal of the American Chemical Society , 2003, 125, 7825-7827.

11. S. E. Denmark and Y. Fan, Catalytic, Enantioselective α-Additions of Isocyanides: Lewis Base Catalyzed Passerini-Type Reactions, The Journal of Organic Chemistry,2005, 70, 9667-9676.




http://dx.doi.org/10.1002/aoc.1583

http://dx.doi.org/10.1002/chem.201500210

http://dx.doi.org/10.1021/ja035410c

http://dx.doi.org/10.1021/jo050549m


Case studies

Figure 1: 2 step route to Praziquantel devised by Cao et al. [1]

Cao et al. have developed a route incorporating a multicomponent reaction for thesynthesis of Praziquantel, a drug on the WHO list of essential medicines used for thetreatment of schistosomiasis.[1] An Ugi four component reaction is first applied toproduce an acylated intermediate which is subsequently cyclised via a Pictet-Spenglerreaction. This has been demonstrated on a small scale. This route shows promise as a




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mass efficient two-step synthesis of Praziquantel and additional benefits are that the by-products from the two steps are water and two equivalents of methanol, and the reactionconditions are mild.

1. H. Cao, H. Liu and A. Dömling, Efficient Multicomponent Reaction Synthesis ofthe Schistosomiasis Drug Praziquantel, Chemistry – A European Journal, 2010, 16,12296-12298.




http://dx.doi.org/10.1002/chem.201002046


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