An efficient and rapid solution phase combinatorial synthesis of a 3-substituted 5-arylidene-1-methyl-2-thiohydantoin library was developed. The salient feature for this library production procedure is the addition of the Lewis acid catalyst, indium(III) trifluoromethanesulfonate, which serves to facilitate the direct condensation of aldehydes with 3-substituted 1-methyl-2-thiohydantoins. Use of this Lewis acid catalyst has resulted in faster reaction times, higher conversions and better purity profiles for these condensation reactions as compared to traditional uncatalyzed reactions. The resulting 315 member library of 3-substituted 5-arylidene-1-methyl-2-thiohydantoin is described.

A one-pot method for the preparation of 1,8-naphthyridine derivatives is reported. The method involves the dimetalation of an appropriate N-2-pyridylpivalamide or tert-butylcarbamate followed by reaction with a b-dimethylamino or b-alkoxyacrolein derivative. This method is also applicable to 1,6-naphthyridines.Recently there has been increased interest in the synthesis of 1,8-naphthyridines and their application in medicinal chemistry as quinoline bioisosteres. 1 Traditionally, the cyclocondensation of amino pyridines with diethyl methoxymethylenemalonate or similar derivatives (EMME synthesis) has provided entry into the naphthyridine core. 2 In order to prepare even the simplest mono-and disubstituted 1,8-naphthyridines, it was necessary to subject the products derived from EMME synthesis to a lengthy and low-yielding series of tranformations. 3 A more direct method of naphthyridine preparation is the reaction of amino pyridines with an a,b-unsaturated ketones or aldehydes (Skraup or Doebner-Miller syntheses). This cyclization is carried out in hot sulfuric acid and affords poor yields with all but strongly activated pyridines. 4 The most efficient method of construction of naphthyridine ring appears to be the extension of the Friedländer quinoline synthesis pioneered by Hawes. 5,6 In this method, an amino pyridine containing an ortho-carbonyl functionality is reacted with an enolizable carbonyl compound. However, a significant disadvantage of this approach is the limited commercial availability of ortho-carbonyl substituted amino pyridines. In most cases these starting materials have to be prepared from the corresponding amino pyridines in 3-4 steps with only a moderate yield in the crucial ortho-metalation-functionalization step. 6a,7As part of a recent research program, we required a general route to variously substituted 1,8-naphthyridines. Multiple attempts to reproduce yields obtained by Hamada 8 following his modified Skraup synthesis procedure were not successful in our hands. 9 The regular Friedländer condensation using ortho-formyl substituted amino pyridines was considered and rejected due to its lengthiness and mediocre yield (vide supra). At this point our attention was attracted by an earlier published synthesis of quinolines via a modification of the Friedländer reaction. 10 This synthesis employed a one-pot reaction of the ortho-metalated anilides with a masked malondialdehyde species followed by an acid-mediated cyclization. We expected that extension of this methodology to naphthyridines would allow an efficient two-step preparation of 1,8-naphthyridines from commercially available amino pyridines.We were, therefore, pleased to find out that the unsubstituted 1,8-naphthyridine 3a can be obtained in high yield from pivalamide 1a derived in turn from 2-amino pyridine (R = H, R¢ = Pv). The dianion of 1a could be formed by treatment of a THF solution of the pivalamide with 2.2 equivalents of n-butyllithium. 7a Subsequent reaction with b-dimethylaminoacrolein (2) followed by heating to reflux in a...

A survey of Lewis acids was conducted to facilitate the formation of arylidenethiohydantoins. The use of indium(III) triflate shows significant advantages in facilitating this reaction. In most examples, the Lewis acid promoted catalysis gave shorter reaction times, higher conversion, and better purity profiles as compared to the traditional uncatalyzed reactions.The 3-substituted 5-arylidene-1-methyl-2-thiohydantoin moiety 3 is known to be a biologically active heterocycle in areas of antimycobacterial, 1 antiviral 2 and potentially anticonvulsant indications. 3 As part of our efforts to generate libraries of medicinally relevant compounds, we set out to prepare a focused library of approximately 400 compounds elaborating this interesting core. Most recently Nielsen 4 reported the preparation of a small 28-member library of 3-substituted 5-arylidene-1-methyl-2-thiohydantoins 3 via microwave-mediated and traditional reflux conditions with good results. Our initial approach for the preparation of 3-substituted 5-arylidene-1-methyl-2-thiohydantoins involved the direct condensation of aldehydes with 3-substituted 1-methyl-2-thiohydantoins 2 in the presence of an organic base and a solvent such as toluene or 1,4-dioxane (Scheme 1). Our observations showed that, in general, uncatalyzed reactions give modest to good yields of 40% to 80% with unhindered aldehydes and that sterically hindered aldehydes typically gave very poor results. Similar results (Scheme 2) are found in the literature for other carbonyl compounds including 1,3-dihydroindol-2-one (4, oxindole), 5 a,b-unsaturated ketones, 6,7 3-phenylisoxazol-5-one (5), 8 benzofuran-2(3H)-one (6), 9 pyrazol-5-one (7), 10 and 2-phenyl-3-thiazolin-5-one (8). 11 The use of catalysts (AlCl 3 , TsOH and KF/alumina) has been reported for other similar substrates, in particular oxindole, with good results for a limited number of examples. We envisaged using a large diversity of the library ligand sets; however, the microwave-assisted synthesis would not be viable for a two-dimensional library consisting of several hundred compounds. Hence we sought to develop a reaction protocol which generated the target 3-substituted 5-arylidene-1-methyl-2-thiohydantoins 3 in good yield for a wide variety of R and R¢ groups. We herein report our findings for the protocol validation phase of our compound library synthesis. A number of potential Lewis acid catalysts were surveyed to efficiently and reproducibly generate a library of previously unreported 3-substituted 5-arylidene-1-methyl-2-thiohydantoins 3. Scheme 1 General synthetic sequence for the preparation of 3-substituted 5-arylidene-1-methyl-2-thiohydantoins.

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N,N-Dimethylformamidine and novel N,N-diisopropylformamidine protecting groups were used to carry out a one-pot conversion of aminobenzoic acids into the corresponding amides. General conditions for an in situ transformation of aminobenzoic acids and their heterocyclic analogues into the corresponding formamidine-protected acid chlorides were developed. These chlorides were used in reactions with amines, including poorly reactive anilines. The protected amides were then smoothly deprotected by heating with ethylenediamine derivatives, resulting in a general procedure for the one-pot transformation of aminobenzoic acids into their amides. Our one-pot procedure was successfully applied to the preparation of several compounds of pharmaceutical interest.