Three-component one-pot

Thepreparadonof resin-bound nitroalkenes via a micro wave-assisted Knoevenagel reacdon of resin-bound nitroacedc acid v/ith aryl and alkyl subsdnited Mdehydes is reported. The potendiil of these resin-bound nitroalkenes for apphcadon in combmatorlM chemistry is demonstratedby a Diels-Alder reacdon v/ith 2,3-dimethylbutadienefScheme 8 9) Iris Mso used for one-pot three-component tandem [4t-2 /[3t-2 reacdons v/ith ethyl vinyl ether and styrene... 

Scheme 21 One-pot three-component synthesis of cUhydro-s-triazines...

The one-pot, three-component synthesis of a 20-membered dihydrotri-azine hbrary was also dramatically accelerated through the use of microwave irradiation [79]. Heating a subset of substituted anilines, cyanoguanidine and acetone in the presence of concentrated hydrochloric acid for 35 min at 90 °C in a single-mode microwave reactor gave the corresponding 2,2-dimethyl-1,2-dihydro-s-triazine hydrochloride 51 in comparable yield to conventional conductive heating methods but in a much shorter reaction time and increased purity (Scheme 21). 

Allylsilane additions were used in a formal synthesis of roflamycoin [51] (Eq. 24). A one-pot, three-component sequential coupling of bis-allylsilane 138 with 4-acetoxy-l,3-dioxanes 137 and 139 provided the C11-C22 polyol chain (140) in moderate yield. 

In analogy, Ugi et al. reported on a lactam formation by running a one-pot three components reaction the condensation of L-lysine 7, isobutyraldehyde and methyl isocyanide led to the corresponding a-amino-c-caprolactam 9, but the yield was not given. The authors presumed either a nucleophilic substitution of the ester 8 as the primary Ugi product by the amino function of the side chain or, alternatively, the nucleophilic attack of the NH2-group on an intermediately formed 0-acylamide and a subsequent rearrangement (Scheme 1) [4]. 

The preparation of resin-bound nitroalkenes via a microwave-assisted Knoevenagel reaction of resin-bound nitroacetic acid with aryl and alkyl substituted aldehydes is reported. The potential of these resin-bound nitroalkenes for application in combinatorial chemistry is demonstrated by a Diels-Alder reaction with 2,3-dimethylbutadiene (Scheme 8.9). It is also used for one-pot three-component tandem [4+2]/[3+2] reactions with ethyl vinyl ether and styrene 46... 

Reaction of pyridines with dialkyl acetylenedicarboxylates in the presence of isocyanates in dry CH2C12 at room temperature produced 1-substituted 2-oxo-l,9a-dihydro-2/7-pyrido[l,2-tf]pyrimidine-3,4-dicarboxylates <2004TL1803>. One-pot, three-component synthesis of 1-substituted 2-oxo-l,llb-dihydro-2//-pyrimido[2,l- ]iso-quinoline-3,4-dicarboxylates and 4-(3-chloro-4-methylphenyl)-3-oxo-4,4a-dihydro-3/7-pyrimido[l,2-tf]quinoline-l,2-dicarboxylate was realized by the reaction of isoquinoline and quinoline with isocyanates and dialkyl acetylenedicarboxylates <2004S861>. Diastereomeric mixtures of l-tosyl-2-aryl-l,llb-dihydro-2/7-pyrimido[2,Ttf]isoquinoline-3,4-dicarboxylates were obtained from isoquinoline, iV-tosyl-benzaldehyde imines, and DMAD <2002OL3575>. 

Oxidation of the tetrahydroindolizine 338 with sodium chlorite gives the lactam 339, which rapidly lactonizes to give the pyranoindolizine 340 (Equation 122) <2001T8647>, and the one-pot , three-component reaction between the keto ester 235, acrolein, and o-aminophenol (formally analogous to that of Equation 63) gives the benzoxazolo-naphthyridine 341 (Equation 123) <20010L2145>. 

A recent total synthesis of tubulysin U and V makes use of a one-pot, three-component reaction to form 2-acyloxymethylthiazoles <06AG(E)7235>. Treatment of isonitrile 25, Boc-protected Z-homovaline aldehyde 26, and thioacetic acid with boron trifluoride etherate gives a 3 1 mixture of two diastereomers 30. The reaction pathway involves transacylation of the initial adduct 27 to give thioamide 28. This amide is in equilibrium with its mercaptoimine tautomer 29, which undergoes intramolecular Michael addition followed by elimination of dimethylamine to afford thiazole 30. The major diastereomer serves as an intermediate in the synthesis of tubulysin U and V. 

Scheme 12.15 Microwave-mediated one-pot, three-component Wittig olefinations utilizing polymer-supported triphenylphosphine.

The cyclizations to obtain cyclic thioureas have been performed using thiocarbonyldiimidazole.232 Reaction of methyl acetoacetate, thiourea and an aliphatic aldehyde in the presence of the zinc iodide (Znl2) was studied. Under the normal pressure, reaction has not been occurred whereas at high pressure (300 MPa) conditions 3,4-dihydropyrimidine-2-thione was obtained only in 10% yield.233 The same one-pot three-component cyclocondensation reaction in the presence of iodide (I2) provides a variety of 3,4-dihydropyrimi-dine-2-thione in high yields.234 Condensation reaction of thioureas with a,p-unsaturated ketones in the presence of the sodium methoxide in methanol affords 3,4-dihydropyrimidine-2-thione derivatives.235,236 Acylation of N,N -disubstituted thioureas with methyl malonyl chloride followed by base-catalysed cyclization leads in the formation of l,3-disubstituted-2-thiobarbituric acids (Scheme 78).237... 

A copper-catalyzed one-pot three-component atom-economical C-H functionalization process was used to form enantioenriched propargylamines. This protocol was also employed for the synthesis of the alkaloid (A)-(+)-coniine (Equation (196)).159 159a... 

A major advancement for the subfield of enamine catalysis was achieved with the identification of aldehydes as useful donors for similar Mannich reactions.In particular, the addition of mono- or disubstituted aldehydes to ketoi-mines or aldimines, respectively, represents an elegant and highly efficient approach to the enantioselective construction of quaternary a-amino acids (Scheme 11A one-pot, three-component variant of the aldehyde Mannich reaction has also been recently disclosed (Scheme i 296-300... 

In extending this concept to transformations that formally deliver Diels-Alder products, a one-pot three-component Mannich/Michael reaction pathway was developed in which simple cyclic enones, formaldehyde, and aryl amines were treated with catalytic amounts of proline (2) to provide regio-, diastereo-, and enantioselective bicyclic compounds in high yields (Scheme ll.lOb). Multicomponent domino... 

Jprgensen has also developed a one-pot three component coupling of 1,3-dicarbonyl compounds, a,P-unsaturated aldehydes and primary amines to give a series of Hantzsch ester analogues [99],... 

Adib M, Jahromi AH, Tavoosi N et al (2006) Microwave-assisted efficient, one-pot, three-component synthesis of 3, 5-disubstituted 1, 2, 4-oxadiazoles under solvent-free conditions. Tetrahedron Lett 47(17) 2965-2967... 

Shen L, Cao S, Liu NJ, Wu JJ, Zhu LJ, Qian XH (2008) Ytterbium(III) perfluorooctanoate catalyzed one-pot, three-component synthesis of fully substituted pyrazoles under solvent-free conditions. Synlett 1341-1344... 

Murai K, Nakatani R, Kita Y, Fujioka H (2008) One-pot three-component reaction providing 1,5-henzodiazepine derivatives. Tetrahedron 64 11034—11040... 

Nagarapu L, Bantu R, Mereyala HB (2009) TMSCl-mediated one-pot, three-component synthesis of 2H-indazolo 2, 1-b phthalazine-triones. J Heterocycl (Them 46 728-731... 

Dey S, Pal C, Nandi D, Giri VS, Zaidlewicz M, Krzeminski M, Smentek L, Hess BA, Gawronski J, Kwit M, Babu NJ, Nangia A, Jaisankar P (2008) Lewis acid-catalyzed one-pot, three-component route to chiral 3,3 -bipyrroles. Org Lett 10 1373-1376... 

The stereoselective synthesis of c/.v-fused pyrano and furanobenzopyran can be achieved through the one-pot three-component reaction of o-hydroxy benzaldehyde, aromatic amines, and cyclic enolethers in the presence of catalytic amounts of Bi(OTf)3 (10 mol%) in air and the moisture-stable ionic liquid [bmim]PF6 [116]. The reaction of salicilaldehyde, aniline and 2,3-dihydrofuran furnishes the c/.v-fused furanochroman. In a similar fashion, various substituted salicilaldehydes and... 

A facile one-pot synthesis of furopyrans takes place with aromatic aldehydes, cyclohexyl isocyanide, and 4-hydroxy-6-methyl-2-pyrone in the presence of a solid support such as Montmorillonite K-10 (Equation 62) <2005SC535>. The solvent-free reaction, which is enhanced by microwave irradiation, proceeds much more rapidly under these conditions than by conventional methods <2002TL2293>. The one-pot, three-component reaction is also reported to take place rapidly using water as solvent <2004M589>. 

Finally, a one-pot, three-component condensation reaction in water provides an efficient procedure for the synthesis of furo[2,3-r/ pyrimidine-2,4(1/7,3//)-diones 303 (Scheme 26). A, A -Dimethylbarbituric acid 301 and 4-nitrobenzaldehyde 302 are reacted with a series of isocyanides to give good yields of the 6-amino products 303 <2002TL9151, 2005SC535>. 

The use of a pyrimidine precursor continues to be the more popular approach to furo pyrimidines. The one-pot three-component condensation reactions of alkyl or aryl isocyanides with A[A -dimethylbarbituric acid in the presence of terephthaldialdehyde proceeded spontaneously at room temperature in DMF to give good yields of the corresponding l,4-bis(6-alkyl or arylamino-1,3-dimethylfurano[2,3-4]pyrimidin-2,4(l//,3//)-dione-5-yl)benzenes <2006BMCL3697>. 

Kappe et al. reported the microwave-assisted synthesis of pyrido[2,3-ri ]pyrimidines via a one-pot three component cyclocondensation of a,(3-unsaturated esters, amidines and malonitrile (or ethyl cyanoacetate) (Scheme 3.45)71. Quiroga et al. reported a similar three component cyclocondensation to synthesise regiospecif-ically 5,8-dihydropyrido[2,3-ri ]pyrimidines under solvent-free conditions, starting from a combination of aminopyrimidin-4-ones, benzoylacetonitrile and benzaldehyde (Scheme 3.45)72. 

In 2003, Balalaie and co-workers published a new paper in the area of imidazole synthesis39. In the above examples reported by Westman, ammonium acetate and primary amines act as the nitrogen source for the imidazole ring. In the Baladie novel one-pot three-component method, ammonium acetate was replaced by benzonitrile derivatives. Thus, benzil, primary amines and benzonitrile derivatives underwent a condensation reaction on acidic silica gel as the solid support, Scheme 5.23. The reaction mixtures were irradiated for 8 min in a domestic oven under solvent-free conditions to give the products in 58-92% yield. 

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