Past, present and future of the Biginelli reaction: a critical perspective

This review covers up to 2010 and some available references of 2011 of synthetic advances in the Biginelli reaction, including recent mechanistic advances, new building blocks, new pharmacological disclosures and asymmetric syntheses. Also present account is covering all aspects of the reaction whereas some of previous ones emphasized one aspect and others had passing reference.


Introduction
Hantzsch, 1 Knoevenagel, 2 and Biginelli reactions, 3 have some similarity; as each one of these employs aldehyde, acetoacetic ester (active methylene compound). The earliest of these seems to be the discovery of the Hantzsch reaction which was reported in 1881, 1 wherein Hantzsch heated acetoacetic ester, an ammonia source, and an aldehyde, to obtain the now well-known dihydropyridines or Hantzsch pyridines 1. A decade later the Italian chemist P. Biginelli, 3 reacted same two components in equimolar ratio viz. acetoacetic ester, aldehyde and third component as urea in acidic alcoholic solution to obtain a new compound, the now well-known 3,4-dihydropyrimidin-2(1H)-ones or Biginelli compounds, 4 2 which are obvious aza-analogues of the Hantzsch dihydropyridines. Biginelli did not detect any Hantzsch dihydropyridines 1 as byproducts. 5 Hantzsch pyridines Biginelli compound (Dihydropyridine) (Dihydropyrimidine) He apparently did this reaction in a multicomponent way, and currently the development of multicomponent reactions (MCRs) is an integral part of numerous research efforts around the world involved in the drug development programs to achieve synthetic targets in expeditious way. It seems old discoveries are new fashions of the present times. Subsequent investigators have tried to understand the course of reaction and they invoke the participation of the Knoevenagel reaction.
In the initial years there was not much synthetic activity in this reaction but during last 100 years or so this reaction received much attention and as a result there were nearly five hundred research publications, mostly involving catalyst changes. During these years from its discovery emphasis was on understanding the course of reaction, with some emphasis on structural variants. Subsequent to these academic developments the Biginelli scaffold was shown to be of great value from a pharmaceutical point of view; because of this importance, investigations were very fast, and virtually every major journal was flooded with papers on the Biginelli reaction. 6 Major emphasis being on process streamlining mainly Lewis acid catalyst etc. In this account, update on catalyst variations, asymmetric synthesis, scaffold variations and Biginelli like reactions aspect of this reaction is presented. During the past decade or so publications have been so fast and numerous, some of these may get missed incidently so authors feel sorry for that if it happens.

Pharmacology
In this part of this account biological aspects of this motif are discussed. A biologist needs readily available, stable molecules for evaluation/study which this scaffold fulfills. In 1930, wool protection activity of these molecules was patented. 21 There followed further intensive investigation because of their resemblance to clinically used nifedipine 14- 16 Biginelli being their aza-analogue 17-18 further they had resemblance to marine natural alkaloids batzelladine B 19 (for this complete comparison see below). 22,23 Variation of all three building blocks, viz. active methylene, ureas, aldehyde component lead to extension of the scope original multi-component resulting in large molecular diversity of dihydropyrimidines. The biological investigation of these various molecules via molecular manipulation showed activities like antiproliferative, antiviral, antitumor, anti-inflammatory, antibacterial, antifungal, and antitubercular activity. Similarly, the structural core of quinoline is frequently associated with medicinal applications such as anticancer, antimicrobial, HIV-1 integrase inhibition, HIV protease inhibitors, antileishmanial activity, NK-3 receptor antagonists, PLT antagonists, and antimalarial activity.
In search of more potent and effective medicinal important molecules numerous Biginelli dihydropyrimidine related annulated or multifunctionallized pyrimidines heterocyclic have been investigated or tested against different dangerous diseases which is arise due to stress or pollution. It is worth mentioning here that these new dihydropyrimidines are synthesized in classical fashion or employing different reaction condition which are discussed in the catalyst section. In the following paragraphs only selective molecules are presented which are have significant activity and they are examined with clinically used drugs in vivo/in vitro and establishing QSAR. Pyrimidinone-peptoid hybrid molecules 37 are also identified as Hsp70 modulators that inhibit cell proliferation. Trifluoromethylated hexahydropyrimidine and tetrahydropyrimidine derivatives 38-42 represent promising new leads for the development of highly potent and selective anticancer compounds and also their in vitro cytotoxic activities were determined in colon cancer cell line.

Miscellaneous activities
Since our major objective in this account is to keep present description brief following structure are presented and given below them is given their activities.

Scope of reaction/developments in structural variants
To develop/explore Biginelli chemistry all commonly available as well as other variants of typical reactants aldehydes, ureas and active hydrogen components have been used so far.

Aldehyde
In case of aldehydes all the available aliphatic, aromatic, heterocyclic and rare aldehydes have been used including sugars aldoses. Biginelli reactions of formyl-and 1,10-diformylferrocene is also reported (see Table 1).

Urea
Regarding urea component, thiourea, and resin bonded urea and other related systems like guanidine are very successfully used. Various N-mono/di substituted ureas have been employed in this reaction to obtained pharmacologically potent molecules see Table 2.

Active hydrogen component
In active hydrogen family varies conventional and unconventional (which can be activated) active methylene compounds have been utilized in this reaction: see Table 3. Even then there are major gaps regarding this structural partner which will be discussed in an appropriate section. Now some cases are presented below for clarity and understanding of the readership.

Use of alcohols in place of aldehydes
Recently, alternative to the classical synthesis of Biginelli compounds has been reported directly from aromatic alcohols under mild conditions are also reported using ionic liquid 1methylimidazolium hydrogen sulfate [Hmim]HSO 4 . In this method aromatic aldehydes formed in situ via oxidation of aromatic alcohols with NaNO 3 (Scheme 11). 37 Scheme 11. Using alcohols instead of aldehydes; synthesis of 3,4-dihydropyrimidinones.
Classically the above mentioned three components are involved in this reaction and fourth is catalyst. Medium employed in this reaction in the original report is alcohol at reflux temperature. As a natural curiosity variations have been investigated to have access to these structurally diverse Biginelli compounds. All these variables are presented in the following pages.

Catalyst Variations
Because the "privileged" nature of this scaffold is of prime importance, academic institutions were busy keeping this property as a driving force in the generation of a large number of reports in pursuit of efficient processes and procedures for these molecules. Essentially, these reports reported catalyst variations only on the following types of catalysts so far. Since several workers reported catalyst variations for the effective production of this motif authors are presenting this aspect from the latest to the earlier ones over the past decade or so: see Table 4.  126 Silica-supported tin chloride and titanium tetrachloride, 127 Lewis acid, 128

Lewis acids
These catalysts leave scope for further mechanistic investigations. Authors are leaving to readers to think how fast these catalysts are reported details of each and every paper are omitted in this write-up. It may not the worth while to discuss each and every reagent here in this section it may not be possible to list all because while doing so such papers would exceed four hundered. In Biginelli chemistry Lewis acids halides, triflates and other salts of Li, Bi, Fe, Cu, Zn, Ru, Rh, W, Mo, Mg, Co, Ni, Sb, Yb, La, Zr, Ce, Sm, Sc, V, Cd, Al, Ag, Nd, Ca, I, B, Sr, Si, Nd, Nb, K, Na, Ga, Pb, Sn etc(sometimes even repeatedly in different journals) have been employed to achieve excellent yields and reduce reaction time as well (Table 4).

Ionic liquids
ILs are considered as the green solvent of present centaury which obey the twelve principles of the green chemistry and are extensively used as catalysts or solvent or both in the organic synthesis. 498 In this decade the use of ILs in Biginelli reaction have attracted much attention either to enhance rate of reaction or to make synthetic protocol greener. In the synthesis of DHPMs a variety of ILs viz task-specific, 263,415 Polymer-supported, 371 414 n-butyl pyridinium tetrafluoroborate, 354 tri-(2-hydroxyethyl) ammonium acetate 147 etc see Table  4.

Biocatalysts
Reports on an elegant use of fermenting yeast, 250 and enzyme, 181,500 for Biginelli reaction is described see table 4. Evidently more work is needed in the use of biocatalysts in this reaction.

Organocatalysts
For efficient production of Biginelli compound various organo catalysts like tartaric acid, oxalic acid, citric acid, lactic acid etc are also employed by authors and others. 55

Rate enhancements
In the past sonication and presently microwave irradiations are at the forefront of tools employed for time economy and rate enhancement of organic reactions.

Sonication
Though sonication of reaction mixture proved quite fruitful and there is a large amount of literature available on this topic, a detailed discussion on this topic is beyond the scope of this account as it is on general organic chemistry. As far as Biginelli reaction is concerned there are several reports, 80,190,201,452,527,530 using this technique and along with suitable catalysts systems.

Microwave irradiations
Gedye, 501 introduced the use of a domestic microwave oven in organic reaction in 1986. There after, there has been very fast investigation of organic reactions employing this technique and the use of microwave in Biginelli reaction is reported by Gupta and co-workers. 502 As far as our survey is concerned this seems to be first ever application in this reaction. Later on microwave is frequently used in this reaction and more then two dozen protocols are reported employing various solvents/solvent-free and catalysts/catalysts-free for detail see Table 4.

Biginelli scaffold variations and Biginelli-like reactions
Variations in the basic scaffold of classical Biginelli structure have attract much attention recently because these structural variations enhance the pharmacological activities of this motif. In this century, the desire for very effective drug molecules which have great pharmacological value, so in this search and to explore synthetic utility in case of Biginelli compound variation have been made at every position of the pyrimidine nucleus from N 1 to C 6 .

Asymmetric Biginelli reactions
During the past few decades there has been intensive researches started to develop methods for producing/ synthesizing one or other of the enantiomers because it is a common observation that individual enantiomers exhibit unlike or even opposite 84-85 biological activities. 6(d),6(i) Biginelli compounds contain a stereogenic center, 532 and the influence of the absolute configuration on the biological activity, 373,462,486,523,533 has been investigated e.g. in SQ 32926 the (R)-enantiomer 86 exhibits >400-fold more powerful antihypertensive activity than the (S)-isomer, 534  Therefore, enantio-control in the synthesis of DHPMs has been an objective of primary importance where significant pharmacological activity is concerned. Major achievements of synthetic chemists in the case of DHPMs are discussed here. In this investigation enantiomeric pure isomers has been reported employing chiral catalysts, chiral metal complexes, chiral substrate (one of three component viz. aldehydes, urea and active hydrogen component) and enzymatic resolution of a racemic mixture.
Recently, M. A. Blasco et al. reported biocatalytic highly enantioselective synthesis of (S)monastrol ofcourse they used enzymatic resolution employing enzymes lipase from Candida antarctica B and lipase from Candida rugosa yielding the (R) enantiomer in 48% yield (66% ee) and (S) in 31% yield (97% ee) Scheme 53. 537 Optically active DHPMs have also been synthesized through auxiliary assisted asymmetric Biginelli synthesis by Dondoni et al. using chiral starting materials such as C-glycosyl substrates 90, 91 and in this investigation the synthesis of two diastereomers of Monastrol analogs bearing the ribofuranosyl moiety has been successfully achieved via formation of diastereomeric N-3-ribofuranosyl amides from racemic Monastrol and separation of both diastereomers and subsequent amide hydrolysis of the desired diastereomer: Scheme 54. 538

Conclusions; Future Outlook
As may be seen in this account, initially there was slow activity in this reaction; later it picked up to understand the mechanism etc. In the past two decades or so after the disclosure that this structure is biologically significant, a spate of publications appeared virtually in all less known/regional and reputed international journals of organic chemistry using all types of catalysts variants, basic, acidic Lewis acids simple salts ionic liquids, nano-particles etc, and there are reports describing no catalysts is needed in this reaction. Also for optimizing the production of these compounds techniques like microwave, sonication, etc. are also reported. In these research publications quite often reference is made to C. O. Kappe's mechanism which is based on spectral data without going into actual details. Now some more mechanistic pathways/proposals are advanced which leaves a question mark on the mechanism followed in this reaction at least in the case of Lewis acids used. Certainly in each and every case there can not be single route adopted in this reaction. The real problem in this area was preparation of an optically pure Biginelli scaffold which was achieved recently and further refinements are being actively pursued by several groups. Now biological aspects of these molecules are being examind more intensively and several new activities are being observed, hopefully in near future some molecules in this class may be in clinical use which can lead to real commercial significance to these molecules.
Regarding, further synthetic advancements modification of this scaffold is being attempted and is suitably being tailored to suit the biological needs also there is a large scope of exploring cycloaddition chemistry on this molecule using the different substituents on this or using the double bond available it here is much wider scope of developments. No doubt some scattered efforts is in this direction is already there. We sincerely hope that our suggestions and this account as a whole will stimulate further serious research in this still fertile area. GaCl 3 is commercially available in sealed capsules and absorbs moisture as soon as it is exposed to air.     Heterocycles and also contribute to green chemistry namely functional group transformations based on catalysts developments, including enzymes, ionic liquids etc. using green techniques like ultrasound, microwave irradiation, grinding etc. as a result of these researches 27 Ph.D students received their degrees and are established in academic and industry institutions and abroad also. His broad area of research is heterocyclic chemistry, cycloadditions 1-3 (1,3 dipolar), 1-4, inter & intera molecular ones. He has published 255 research papers in reputed journals, apart from some, patents as well as reviews and Books. He is life member of several learnt bodies of this country like, chemical society, chemical research society of India and is Fellow of National Academy of science Allahabad (FNASc) and is also fellow of Indian Science Academy (FNA), New Delhi.