A Diversity‐Oriented, Microwave‐Assisted Synthesis of 4‐oxo and 4‐chloropyrido[2,3‐d]pyrimidin‐7(8H)‐ones

Abstract

A microwave-assisted protocol for the synthesis of 4-oxo and 4-chloropyrido [2,3-d]pyrimidin-7(8H)-ones, 13 and 9 respectively, bearing a carbon substituent at C2 and a chlorine atom at C4 is reported. The introduction of a wide range of substituents at C2 renders this methodology easily amenable to combinatorial chemistry applications. Two examples of further derivatization of compounds 9, substitution by amine and Suzuki coupling, under microwave irradiation are also described. IntroductionPyrido [2,3-d] Our group has actively been working in the development of synthetic strategies for the preparation of 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (2) from a,b-unsaturated esters (3) (Scheme 1). Thus, in the so called cyclic strategy 2-methoxy-6-oxo-1,4,5,6-tetrahydropyridin-3-carbonitriles (5) are obtained by reaction of an a,b-unsaturated ester (3) and malononitrile (4, G CN) in NaOMe/MeOH [11]. Treatment of pyridones 5 with guanidine or amidine systems (6, R 5 NH 2 , H, alkyl, aryl, heteroaryl) affords 4-aminopyrido[2,3-d]pyrimidines (2, R 4 NH 2 ) [12]. The 1,5-dinitrile systems 7 were obtained by reaction of the corresponding pyridine-3-carbonitriles (5) with sodium cyanamide [13]. Treatment of 7 with hydrogen bromide afforded both positional bromo-substituted isomers depending on the thermal level employed. Thus, when the reaction was carried out at low temperature the 2-amino-4-bromo-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (2, R 5 NH 2 , R 4 Br) were selectively formed, but when the process was run at high temperature the 4-amino-2-bromo-substituted compounds (2, R 5 Br, R 4 NH 2 ) were predominantly obtained [14]. This behaviour was found to be independent of the nature and position of the substituents present on the pyridone ring. On the other hand, we described an acyclic variation of the above protocol for the synthesis of pyridopyrimidines (2, R 4 NH 2 ) based on the isolation of the corresponding Michael adduct (8, G CN) [15], that also allowed us to obtain 4-oxopyrido [2,3-d] From the preceding discussion it is clear that, so far, we were only capable to synthesize 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (2) with a carbon substituent at position C2 by using an amidine (6), which causes the presence of an amino group or a carbonyl group at C4 of the resulting pyrido [2,3-d]pyrimidine. Now, as a part of our ongoing research in the area of combinatorial chemistry focused on the preparation of random libraries for High Throughput Screening (HTS), we decided to devise a strategy to synthesize 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (9) bearing a carbon substituent at C2 and a chlorine atom at C4 (R 4 Cl), susceptible of subsequent decoration chemistry (reduction, nucleophilic displacement with amines, C À C bond formation). The present paper deals with the results of this study. Results and discussionIn order to synthesize pyridopyrimidines (9) with a carbon substituent at position C2 and a chlorine atom at C4, we have developed a synthetic strategy based on the cyclization with anhydro...

Pyrido[2,3-d]pyrimidin-7(8H)-ones: Synthesis and Biomedical Applications

“…[36,76] In summary, the combinations of substituents apparently more widely explored in literature for both structures are a) In 14.08% of the 5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones (11): G 2 = nitrogen substituent, G 4 = oxygen substituent (in particular as a carbonyl group), R 5 = phenyl group, R 6 Thus, in the case of the structures 11 (C5-C6 single bond), 53.12% present at least a substituent at C5 and a CH2 at C6 (in most of them a carbon substituent [29,30] and, more precisely, a phenyl ring in one half of the structures [50,51]) while only 3.19% present a substituent at C6 and a CH2 at C5 (in this case most structures present a carbon substituent [52,53] which is a phenyl ring in also one half of them [31,42]). Finally, 20.86% of the structures do not present substituents at C5 or C6 [20,54]. These three substitution patterns cover 84.87% of the total diversity.…”

“…Such acyclic protocol was amenable to a multicomponent microwave-assisted cyclocondensation to afford compounds 50 and 51 via Michael adducts 48 [50,98]. We also achieved 4-unsubstituted 5,6-dihydropyrido[2,3-d]pyrimidines (55; R 4 = H) through the Michael addition of 2-aryl substituted acrylates (45; R 6 = aryl, R 5 = H) and 3,3-dimethoxypropanenitrile (52) which leads, depending on the reaction temperature (60 or −78 • C, respectively), to a 4-methoxymethylene substituted 4-cyanobutyric ester (54) or to a 4-dimethoxymethyl 4-cyanobutyric ester (53). These compounds are subsequently converted to the desired 4-unsubstituted compound (55; R 4 = H) upon treatment with a guanidine carbonate 49 under microwave irradiation [99].…”

Microwave‐Heated Transition Metal‐Catalyzed Coupling Reactions

“…The first example of a Suzuki-Miyaura reaction for the decoration of a 4-chloro[2,3-d]pyrimidin-7(8H)-one scaffold utilizing phenylboronic acid as the coupling partner furnished a good isolated yield (Scheme 15.24) [77].…”

Microwave-assisted multi-step synthesis of novel pyrrolo-[3,2-c]quinoline derivatives

“…Many organic reactions have been explored and adapted under microwave activation. 3,4 Examples of multi-step synthesis in which each step requiring heating performed under microwave are scarce in the literature. We report herein a new microwave-enhanced multi-step synthetic pathway for the preparation of pyrrolo-[3,2c]quinoline derivatives.…”