Diversity Oriented Syntheses of Conventional Heterocycles by Smart Multi Component Reactions (MCRs) of the Last Decade

A collection of smart multicomponent reactions (MCRs) with continuative post condensation cyclizations (PCCs) is presented to construct conventional three- to seven-membered heterocyclic compounds in diversity oriented syntheses (DOS). These will provide a high degree of applying economical and ecological advantages as well as of practicability. Water, ionic liquids, and solvent-less syntheses as well as use of various forms of energy as microwave and ultrasonic irradiation are examined and discussed.


Times and Progress
First of all, three syntheses of indole/indole derivatives, according to (1) [9], (2) [10], and (3) [11] in Scheme 1, shall demonstrate the course of time and progress in research, how reactions and their conditions became better in terms of ecology and economy, i.e., reaction temperatures fell from 360 °C to r.t. (room temperature) and −78 °C, reaction times decreased from 16 h to 30 min and product yields increased from 60% to 100% (Table 1) To compare data of not exactly identical products is problematic, but the principal trend in the different data is evident. Beyond this, (3) shows, that using an isocyanide function the reaction becomes faster. This advantage of highly reactive isocyanide reagents is also evident for isocyanide-based MCRs (I-MCRs) such as the Passerini-and Ugi-reactions [6] as well as novel I-MCRs presented in sub-section 3.2.

Nomenclature
Due to the rapid progression of MCRs by processing additional functions and its extensions into domino-and post-condensation-cyclisations (PCCs) (sub-sections 3.4 and 3.5), the hitherto existing nomenclature is no longer sufficient for many cases and becomes sometimes unwieldy and imprecise. A consequence of these impacts is a different counting of components and active functions. The latter can be emcompassed within the phrase "Multi-Function-Component-Reaction" or "MFCR", respectively [2], and is so used in this article. i.e., when the number of functions in the reaction involved exceeds the number of components, the former will be prefixed to the latter. For example, U-5F4CR means an Ugi four component reaction with five participating functions, as is in following sub-section 2.1. Often the extension of functions will cause a domino-reaction.

High Diversity in Heterocycle Syntheses with MCRs
Nowadays nearly all heterocycles can be constructed using MCRs. Here, a survey of recent developments on Diversity Oriented Syntheses (DOS) will be reported [7,8]. Diversity of products is increasing by both versatile and smart MCRs and many consecutive further reactions like versatile domino-reactions and post-condensation-cyclisations (PCCs) [12,13]. This can also be achieved by an increase of the number of components, as in 5CR [14], 7CR [15], and 8CR [16], transition metal catalysed MCRs [17], and evolutionary chemistry aided MCRs [18]. Several recent diversity oriented reviews [19][20][21][22][23][24][25][26] demonstrate the high innovation and creativity in this seminal field of chemistry. [27] Compound 1 is the bi-functional carbonyl component in the Ugi-four component reaction (U-4CR) in addition to carboxylic acid, isocyanide, and primary amine. After forming the α-adduct 2, the generated sec. amine substitutes the vicinal alkoxy-group (formerly the second function of 1). The latter reacts with the acyl function of the aza-anhydride moiety forming the carboxylic acid ester by-product. The Ugi-reaction goes on to form the target molecule, the tetra-substituted aziridine derivative 3 (Scheme 2). Yields are moderate to good (38-84%) [27]. Scheme 2. Synthesis of aziridine 3 by U-5F4CR.
Further furan syntheses are a 3CR of salicylaldehyde + amine + alkyne, [45] and a 3CR performed with an imidazolium salt + alkyne + aldehyde [46]. [47] The reaction of the ketone with the sulfonium ylide forms the epoxide intermediate 14 by elimination of dimethylsulfide. Compound 14 reacts with a primary amine in a microwave assisted Corey-Chaykovsky reaction affording the indole derivative 15 in 40-92% yield (Scheme 9) [47]. Last step is the thermodynamically driven aromatisation by β-elimination of water.

Scheme 9. Synthesis of indole 15 by Corey-Chaykovsky 3CR.
Further indole syntheses by multi-component reactions are a new 3CR Fischer indole syntheses based on new reactions of organometallic reagents with nitriles and carboxylic acids, which extend scope and synthetic utility of these syntheses [48], MCR of indoles from 2-iodobenzoic acid [49], and highly diversified indole scaffolds by U-4CR [50].

Scheme 10. Synthesis of pyrazol 17 by I-3CR.
A new and environmentally-friendly method for preparing dihydropyrano[2,3-c]pyrazoles in water as solvent and under ultrasound irradiation has been developed [52]. [53] Cyclopropylphenylketone and p-chlorobenzaldehyde react to form the aldol addition product. This undergoes with diethylamine β-elimination of H 2 O affording the 3-CR product Michael acceptor 18. Methylhydrazine reacts regioselectively with 18 according to the HSAB-concept in a PCC forming the pyrazoline derivative 19 with 72% yield and an anti/syn ratio of 3 (Scheme 11) [53]. Scheme 11. Synthesis of pyrazoline 19 by 3CR/PCC.

Imidazolium Salt 25, I-3CR, N-methyldihydropyridin + 2 x Isocyanide + Iodine [60]
A direct access to benzimidazolium salts has been achieved by a 3CR with N-methyldihydropyridine-3-carboxylate, two cyclohexyl isocyanides and iodine. The proposed reaction mechanism is rather complex. Core steps of the reaction are the double α-addition of isocyanides forming 22, the rearrangement of the dihydropyridine into the aza-bicyclo[2.2.2]octadiene structure 23. Ring-opening of 23 and ring-closure furnish the benzimidazolic zwittwerionic structure 24. Full aromatisation of 24 is thermodynamically driven and affords finally the benzimidazolium iodide 25 in a high yield of 85% (Scheme 13) [60].
2.14. Thiazole 30, Domino U-4CR / PCC, Thioacid + Amine + Isocyanide + Aldehyde [64] A U-4CR reaction effects the transfer of the thiol group onto the isocyanide carbon atom. After tautomerization of the thio group in the Ugi product 29 into a thiol function, this adds to the Michael acceptor of the former Schöllkopf isocyanide 28 to form the 2,4-disubstituted thiazole derivative 30 in 74% yield via elimination of dimethylamine (Scheme 15) [64].

Scheme 25. Synthesis of tetrazinane 57 by 3CR.
The proposed mechanism is favored by the lack of any solvent, so that N-H moieties are in direct contact with each other and are strongly activated by microwave irradiation (MW). A strong evidence for the proposed mechanism is given by comparing the data of the MW-supported reaction with the conventionally heated reaction. The MW-supported reaction rate is 15 fold and the product yield twice that of the conventionally heated process. [93] In an U-4CR wherein two components with two functions each, 2-aminobenzophenone, 2-azido-3phenylpropionic acid, benzaldehyde, and cyclohexyl isocyanide react forming the Ugi product 58 in 57-75% yield. A Staudinger-aza-Wittig sequence effects the ring closure furnishing the (S)-3-benzyl-2-oxo-1,4-benzodiazepines 59, yields are 65-84% (Scheme 26) [93]. The ketone carbonyl oxygen atom is removed by triphenylphosphane.

Strategies in Designing Novel MCRs
Several thermodynamic and reaction chemical effects as well as new strategies and new developed synthetic methods are smart and very advantageous ways to create novel MCRs.

Thermodynamic Effects
The well-known strategy to effect an easy forming of heterocyclic compounds by aromatising them has been often applied in syntheses, as illustrated by almost half the reactions in this paper. There, a resonance energy in the range of 100 kJ/mol is released. Particularly in the last step of a synthesis, the exergonic behavior makes this an irreversible one and affords good product yields. This is demonstrated by reactions with tautomerisations as the last step in sub-sections 2.7 and 2.20.
Another strategy to facilitate a reaction course is to accelerate the number of molecules on the product site of the syntheses. Thus, reaction entropy increases and facilitates cyclization. This can be done by introduction of appropriate substructures into the reaction paths, which will later become leaving groups to push the progress of the reactions, preferably in the last step. These are H 2 O in sub-sections 2.8, 2.11 and 2.19, MeOH in 2.17, N 2 in 2.16., CO 2 in 3.1.1, carboxylic acid ester in 2.1, dimethyl sulfide in 2.8, formamide in 2.9, dimethylamine in 2.14, isobutene in 2.21, isocyanate in 3.1.1, and even ketene in 3.1.2. The latter two by-products are somewhat unusual as leaving groups, so their reaction pathways will be discussed.

Isocyanate 63 Elimination [95]
The reaction is mediated by tert.-butyl isocyanide. By-product of the pyrrole derivative synthesis is tert.-butyl isocyanate 63, which comes from the oxygenation of tert.-butyl isocyanide with oxygen from the acyl moiety (Scheme 28), which leaves back the strong azomethineylide 1,3-dipole 64. This reacts with the acetylenedicarboxylate in a [3+2] cycloaddition affording the pentasubstituted pyrrole derivative 65 in good yield of 84% [95]. Scheme 28. Isocyanate 63 formation as by-product in a pyrrole synthesis.
A highly interesting comparison of the same pyrrole synthesis by a 4F3CR catalyzed by Pd(0), but mediated by CO instead of isocyanide has been published in the same article [95]. In this case, CO 2 is formed by the oxygenation of CO.

Ketene 68 Elimination [96]
Nitrile and acylaminoketone react MW-assisted and fast to form 66. After eliminating the acyl residue the 3,5,6-trisubstituted 2-aminopyridine derivative 67 is formed in good yields. The side product of the synthesis is the high-energy-molecule ketene 68, which has been generated in an electrocyclic reaction of 63 and will further react (Scheme 29) [96]. Scheme 29. Ketene 68 formation as by-product in a pyridine synthesis.
Isocyanides 69, however, are typical MCR components [6,[103][104][105][106][107][108][109], and half of the reactions presented in this paper are based on isocyanides. Within the last decade, about a thousand papers on I-MCRs have been published. This outstanding position is the consequence of isocyanides' electronic structure as electron-rich carbenoids (Scheme 30). Whereas mesomer 69 I emphasises the nucleophilic character of the isocyanide, mesomer 69 II demonstrates the carbene nature of the isocyanide with its electron deficient sextet at the C-atom. This makes an isocyanide favored to react with a nucleophile and an electrophile simultaneously in an α-addition reaction, the I-3CR (as is P-3CR in sub-section 2.15). Thereby the transition of the divalent carbon C II of the carbenoid isocyanide into the sp 2 -hybridised tetravalent C IV of the α-adduct of the isocyanide with two reaction partners takes place. This is the irreversible step in the reaction of isocyanide-based MCRs and drives the reaction course to the product side.

Scheme 30. Resonance effect of isocyanide 69.
Since the pioneering and seminal research on isocyanide-based MCRs by Passerini and Ugi, who recognized their enormous potential and made this chemistry presentable, many extensions and some new I-MCRs have been created. Outstanding and recently intensively researched reactions are the combination of isocyanides with electron-deficient alkynes as are dialkyl acetylenedicarboxylates, generating the reactive zwitterionic intermediate (as 16 in sub-section 2.9), which could be trapped by a third component [108,109]. Several syntheses of this type are presented in sub-sections 2.7 [44], 2.9 [51], 2.20 [84], 2.22 [86], and 2.26 [94] of this paper.
Another important progress is the I-4CR from aldehyde + malodinitrile + imine + isocyanide [97]. Aldehyde and malodinitrile react in a Knoevenagel condensation forming a strong Michael acceptor, which adds as well as the imine to the isocyanide, according to the reaction in sub-section 2.6 [36], and 2.19 [79,83]. A reactive ylide-intermediate makes the reaction definite, achieving high product yields.

Scheme 31. Generation of isocyanides from formamides.
A new trend may sometimes help to solve an old problem, namely how to handle the disgusting odour of isocyanides. 1,3-Oxazoles can be easily transformed into isocyanide esters 71 by ring-opening with n-BuLi and acylating the hydroxylic group formed (Scheme 32) [113]. The odours of 71 depend on the acyl group, but are all likable. Scheme 32. Generation of isocyanides from 1,3-oxazoles.

Domino Reactions
Many MCRs are rather tolerant of most other functional groups and these may further react with the newly generated functions of the MCR product in a reaction cascade without additional operations. Thus a high degree of diversity can be achieved. Syntheses in sub-sections 2.14 [64], 2.15 [66], 2.18 [75], 2.19 [77], and 2.20 [84] contain domino reactions. Finally each MCR itself is a domino reaction. For nomenclature see sub-section 1.2.

Macrocyclization
The efficient access to macrocyclic structures is still rather difficult. Recent research in this field deals with MCR syntheses of macrocycles, on the approach "multiple multicomponent reaction using two bifunctional building blocks (MiBs)" [114,115].

New Methods in Performing Conditions to Modern Requirements
Many of the developments of the MCRs in Section 2 are impelled by modern requirements of green chemistry as using water or ionic liquids as solvents or applying solvent-less syntheses and running the reactions at r.t. as well as employing microwave, infrared, or ultrasound irradiation energy in the syntheses.

Water as Solvent
Most MCRs are tolerant of most reaction conditions and non-involved functional groups, so often water, which does not pollute the environment, can be used as solvent, as in sub-sections 2.9 [52], 2.15 [68], and 2.19 [78,80]. A review on this topic is given [116].

Ionic Liquids as Solvent
The main disadvantage of common solvents is their high vapor pressure, so that losses in the course of a synthesis can be quite substantial and this leakage may pollute the environment. Solvents with a very low vapor pressure could solve the problem. Two kinds of solvents have been proven, ionic liquids (ILs) [117] and long-chained polyethylene glycols. Both have been employed in syntheses of heterocyclic compounds by MCRs. Some syntheses in IL as solvent are described in sub-sections 2.11 [58], and 2.19 [81,82].

Solvent-Less Syntheses
From the ecological and economical points of view, it might be advantageous to run MCRs without any solvent. This will be of course supported by a high ratio of liquid components and their suitable properties. Several syntheses have been carried out with neat components, and detailed studies on this issue have been done in sub-sections 2.4 [33,34], 2.11 [59], 2.17 [74], 2.19 [79], and 2.24 [92].

Alternative Forms of Energy: Microwave, Infrared, Ultrasound Irradiation
Conventional thermal heat as a source of the required energy to bring reactions to run is generally and always employable, but this heat is not selective at all. Certain vibrations of bonds in common compounds, however, can be activated selectively and thus less energy input can achieve the same effect as by using conventional heat.
In the 3CR solvent-less synthesis of 6-aryl-1,2,4,5-tetrazinane-3-thione in sub-section 2.24 reaction times and product yields of both conventional heated and MW assisted reactions have been compared with each other [92]. The efficiency of MW on the reactions has been enormous: reaction times have been reduced to 1/15, whereas the yields doubled concurrently. This should be caused by highly polar reactants. A different effect has been observed in a 4CR synthesizing polyaryl-substituted imidazoles in the ionic liquid butylmethyl imidazolium bromide. Reaction time with heat has been half that of with MW, and yields have been similar in both cases [58]. Here the reactants have been highly non-polar. Reviews on the usage of MW in syntheses of heterocycles by MCRs are given [118][119][120][121]. An alternative energy source for reaction activation, even without solvents, is IR [122].
A novel and environmentally-friendly method for preparing dihydropyrano [2,3-c]pyrazoles in water as solvent and under ultrasound irradiation has been developed [52]. Syntheses of pyrazolopyridines have been performed by 3CRs from aldehyde + malodinitrile + 3-aminopyrazole activated with both conventional heat and ultrasound (sub-section 2.19) [83]. Product yields of ten ultrasound activated reactions are on average 60% higher than those of the same, conventionally heated reactions.

Conclusions
Figure 1 presents a sketch showing the deeper insight of this review, which demonstrates a nearly unlimited up-growth of novel MCRs forming complex heterocyclic structures. Several new smart strategies in combinations of reacting diverse functional groups have been developed and widened the reaction space of MCRs and thus the scope of their application. Particularly reactions of isocyanides with deactivated alkynes such as acetylenedicarboxylates are widely deployable and eagerly investiga-ted, and other smart MCRs are distinctly coming up. But isocyanide-based MCRs still account for a great part of multi-component reactions.
Also several environmentally-friendly new tools have been employed, referring to the use of solvents and energy source. These may offer economical advantages too. Water is useful as solvent for many syntheses by MCRs, because most of their involved functional groups are neutral against water. In special cases solvent-less syntheses provide great advantages from most points of view. Often the totally unselective conventional heat can be changed by selective microwave irradiation, which may use less energy. Thereby, components may react much faster, achieving very good product yields. This can also be performed in some cases by use of ultrasonic irradiation. Thus, also in the future further substantial and increasing growth in MCRs for performing heterocycle syntheses is to be expected.