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Multicomponent Reaction Design Strategies: Towards Scaffold and Stereochemical Diversity

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Synthesis of Heterocycles via Multicomponent Reactions II

Part of the book series: Topics in Heterocyclic Chemistry ((TOPICS,volume 25))

Abstract

In the past decade, it has been extensively demonstrated that multicomponent chemistry is an ideal tool to create molecular complexity. Furthermore, combination of these complexity-generating reactions with follow-up cyclization reactions led to scaffold diversity, which is one of the most important features of diversity oriented synthesis. Scaffold diversity has also been created by the development of novel multicomponent strategies. Four different approaches will be discussed [single reactant replacement, modular reaction sequences, condition based divergence, and union of multicomponent reactions (MCRs)], which all led to the development of new MCRs and higher order MCRs, thereby addressing both molecular diversity and complexity.

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Notes

  1. 1.

    Small molecules are typically compounds with a molecular weight less than 500 Da: [1].

  2. 2.

    Molecules/interactions that are considered to be “undruggable”, comprise transcription factors, regulatory RNAs, interactions between proteins (especially intracellular) and between proteins and DNA. There are only about 500 “druggable” targets: [4].

  3. 3.

    The chemical space is a multidimensional area with each dimension defined by a descriptor which can be molecular weight, polarity, solubility, membrane permeability, binding constant. H-bonding properties etc. and encompasses all small carbon-based molecules that could in principle be created: [5].

  4. 4.

    The E factor is defined as the mass ratio of waste (everything but the desired product) to desired product. For a recent overview, see: [19].

  5. 5.

    Although the authors used a pre-formed imine, there are several examples known of proline catalyzed one-pot three component Mannich reactions. However, if aromatic aldehydes are used in this one-pot procedure, the obtained Mannich products had to be reduced (by NaBH4) to the corresponding alcohols to avoid epimerization: [38, 39].

  6. 6.

    This figure is a slightly modified figure as published in [40].

  7. 7.

    For more examples of the Build/Couple/Pair principle applied in DOS: [52–54].

  8. 8.

    It has to be noted that this reaction was first developed by Zhu and coworkers in 2001, even before the previous mentioned carbonyl variant of Ganem and co-workers: [58]. Later on, Ganem published a similar reaction with unsubstituted isocyanoamides: [59].

  9. 9.

    In addition to the examples reported here there are several other publications that apply SRR to achieve new scaffolds, thereby discovering new MCRs: [55, 75, 76].

  10. 10.

    The use of phosphonates with large R1 substituents resulted in a significant decrease in yield, 22–39% for R1 = Ph and i-pentyl.

  11. 11.

    Several other research groups have been involved in MCRs with aminoazoles, 1,3-diketones and aldehydes. For a recent overview see: [93].

  12. 12.

    Propagation of ultra sound waves into the liquid medium results in a series of high-pressure (compression) and low-pressure (rarefaction) cycles, with rates depending on the frequency. During the low-pressure cycle, high-intensity ultrasonic waves generate small vacuum bubbles in the liquid, which can reach a volume at which they are not stable anymore resulting in a violent collapse. This phenomenon is termed cavitation: [94, 95].

  13. 13.

    It has to be noted that the formation of oxazoles using isocyano amides has been well studied by Zhu and co-workers (see [58, 59]). With the work of Elders et al. the oxazole MCR has been expanded with a wide range of isocyano esters. The MCR with isocyano amides can now also be directed to the 2-imidazolines.

  14. 14.

    The directing properties of the MCR involving isocyano esters could exclusively be performed using α-aryl isocyano esters, since the use of α-alkyl isocyano esters always resulted in the formation of 2-imidazolines, in various solvents, even without AgOAc, see [96] and [97].

  15. 15.

    The α-isocyanide is α-acidic and will react in the 3CR to yield 2H-2-imidazolines, while the other isocyanide is an aliphatic isocyanide and remains unaffected.

Abbreviations

Ac:

Acetyl

Ar:

Aryl

BINAP:

2,2′-bis(diphenylphosphino)-1,1′-binaphthyl

Bn:

Benzyl

Bu:

Butyl

tBu:

Tert-butyl

CBD:

Condition-based divergence

Cp:

Cyclopentadienyl

CR:

Component reaction

3D:

Three dimensional

DA:

Diels-Alder

DCM:

Dichloromethane

de :

Diastereomer excess

DIPEA:

N,N-diisopropylethylamine

DMAD:

Dimethyl acetylenedicarboxylate

DMF:

Dimethylformamide

DMSO:

Dimethyl sulfoxide

DOS:

Diversity oriented synthesis

dppf:

1,1′-bis(diphenylphosphino)ferrocene

dr :

Diastereomer ratio

ee :

Enantiomer excess

Et:

Ethyl

EWG:

Electron withdrawing group

FG:

Functional group

HWE:

Horner-Wadsworth-Emmons

IMCR:

Isocyanide based multicomponent reaction

mCPBA:

m-chloroperoxybenzoic acid

MCR:

Multicomponent reaction

Me:

Methyl

MeCN:

Acetonitrile

min.:

Minute(s)

MRS:

Modular reaction sequences

MS:

Molecular sieves

MTBE:

Methyl tert-butyl ether

MW:

Microwave

n.d.:

Not determined

Nu:

Nucleophile

P-3CR:

Passerini 3-component reaction

Ph:

Phenyl

PMP:

p-methoxyphenyl

rt:

Room temperature

SRR:

Single reactant replacement

Tf:

Trifluoromethanesulfonyl (triflyl)

TFA:

Trifluoroacetic acid

THF:

Tetrahydrofuran

TMS:

Trimethylsilyl

Ts:

Tosyl, 4-toluenesulfonyl

U-4CR:

Ugi 4-component reaction

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Acknowledgment

This work was performed with financial support of the Dutch Science Foundation (NWO, VICI grant).

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Authors and Affiliations

  1. Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit Amsterdam, De Boelelaan 1083, 1081 HV, Amsterdam, The Netherlands

    Rachel Scheffelaar, Eelco Ruijter & Romano V. A. Orru

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  1. Rachel Scheffelaar
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  2. Eelco Ruijter
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  3. Romano V. A. Orru
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Correspondence to Romano V. A. Orru .

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Editors and Affiliations

  1. Fac. Sciences, Dept. Chemistry &, VU University Amsterdam, De Boelelaan 1083, Amsterdam, 1081 HV, Netherlands

    Romano V. A. Orru

  2. Faculty of Sciences, Section of Synthetic &, VU University Amsterdam, Amsterdam, 1081 HV, Netherlands

    Eelco Ruijter

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Scheffelaar, R., Ruijter, E., Orru, R.V.A. (2010). Multicomponent Reaction Design Strategies: Towards Scaffold and Stereochemical Diversity. In: Orru, R., Ruijter, E. (eds) Synthesis of Heterocycles via Multicomponent Reactions II. Topics in Heterocyclic Chemistry, vol 25. Springer, Berlin, Heidelberg. https://doi.org/10.1007/7081_2010_44

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