Pyridylaminomethylenemalonates

From a study of the thermal ring closure of 2-pyridylaminomethylene-malonates (1001) by heating in diphenyl ether, Lappin found that pyri-do[l,2-a]pyrimidine-3-carboxylates (1002) were formed from those malo- 

Shur and Israelstam carried out the cyclization of 2-pyridylaminomethy-lenemalonates (1001) in polyphosphoric acid at 110°C for 4 hr (68JOC3015). They reported that pyrido[ 1,2-a]pyrimidine-3-carboxylates (1002) were obtained, even if they started from A/-(6-methyl- or 4,6-dimethyl-2-pyri-dyl)aminomethylenemalonates (1001, R = Me, R1 = H, 4-Me). However, it was later demonstrated that, in the case of the 6-methyl derivative (1001, R = Me, R1 = H), instead of the pyrido[ 1,2-a]pyrimidine-3-carboxylate (1002, R = Me, R1 = H), the ethyl, hydrogen Al-(6-methyl-2-pyridyl)ami-nomethylenemalonate (378, R = Me) was probably obtained. The latter 

Unsubstituted pyrido[ 1,2- i]pyrimidin-4-ones (1002,1005, R = H) could not be transformed even under fairly drastic conditions [77JCS(P 1)789). 

With respect to R2 (the substituent at position 3 of pyridopyrimidine), the transformation is influenced in the following sequence Me CH2COOEt H Ph CN COCH3 COCF3 = COOEt while with respect to R (the substituent at position 6), the following sequence applies COOEt = OH alkyl styryl NHAc [77JCS(P1)789  

Further investigation of the thermal ring transformation revealed that the length of the bond between C(4) and N(5), which must break in the 

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Ethyl 2-aminopyridinecarboxylates reacted smoothly with EMME at 120-130°C in 30 min, except the 3-carboxylate, which was reacted at 150-I70°C to give the corresponding 2-pyridylaminomethylenemalonate (49) in 78-92% yields (78MI5). 

Amino-3-(A,iV-dimethylcarbamoyl)thiopyridine was reacted with EMME or di-(4-methoxybenzyl) (4-methoxybenzyloxy)methylenemalo-nate at 100-120°C for 1 hr to afford 2-pyridylaminomethylenemalonates (50) in 76 and 80% yields, respectively (86EUP218423). 

After the reaction mixture of 4-amino-2-chloropyridine and EMME had been heated at 90°C for 10 hr, not only 4-pyridylaminomethylenemalonate (52), but also a malonamate derivative (53) was isolated (82CPB2399). 

Pyridylaminomethylenemalonates (262) were prepared in over 90% yields in the reactions of 2-aminopyridines, ethyl orthoformate, and dialkyl malonates at 130°C for 3-6 hr (73GEP2227651 87SC549). 

The reactions of ethyl 2-aminopyridine-4- and-5-carboxylates, ethyl orthoformate, and diethyl malonate in the presence of ZnCl, at 100-120°C for 15 min afforded 2-pyridylaminomethylenemalonates (264) in 53-71% yields (78MI5). 

Amino-3-[(dimethylamino)thiocarbonyloxy]pyridine was reacted with isopropylidene ethoxymethylenemalonate (422) under reflux for 2 hr to give isopropylidene 2-pyridylaminomethylenemalonate (426) in 44% yield (86EUP218423). 

Cyclopropylamino)-5-fluoro-6-(4-ethoxycarbonyl-l-piperazinyl)-pyridine was reacted with isopropylidene methoxymethylenemalonate (420) in methanol at ambient temperature for 4 hr to give isopropylidene 2-pyridylaminomethylenemalonate (428) in 67% yield (85EUPI53I63, 85EUP153828, 85EUP159I74 86EUP17265I 88EUP265230). 

The ring closure of 3-pyridylaminomethylenemalonates may lead to 1,5-naphthyridine or 1,7-naphthyridine, depending on which position of the pyridine ring (position 2 or 4) is involved in the cyclization (Scheme 45). Due to the higher reactivity of position 2 of 3-aminopyridine derivatives... 

This type of ring transformation occurs not only for pyrido[l,2-a]py-rimidines and in the cyclization of 2-pyridylaminomethylenemalonates, but also for other similar ring systems and (hetarylamino)methylenemalo-nates [e.g., 77JCS(P1)789 84JCS(P1)1795 also see later]. 

The ring closure of 2-pyridylaminomethylenemalonates (1008) in boiling diphenyl ether for 10-90 min afforded pyrido[l,2-a]pyrimidines (1009) in 52-57% yields (85EUP218423). 

The ring closure of 2-pyridylaminomethylenemalonates (1023, both 6-substituted and 6-unsubstituted) took place readily in phosphoryl chloride in the presence of a catalytic amount of polyphosphoric acid ( 1-10%) at reflux temperature. When hydrogen chloride gas evolution ceased, the reaction mixtures were treated with the appropriate alcohol, and hydrochloride salts of pyrido[l,2-a]pyrimidine-3-carboxylates (1024) were ob-... 

Cyclopenta[c]pyridylaminomethylenemalonate (1063) was cyclized by the action of a mixture of acetic anhydride and concentrated sulfuric acid at 90°C for 1 hr to give the tricyclic nitrogen bridgehead ring system (1064, R = CN) in 60% yield (83 KGS 1279). 

The reaction of diethyl 2-pyridylaminomethylenemalonate and hydrazine at room temperature gave 4-(2-pyridyl)-5-(2-pyridyl)amino-1,2,4-triazoline (1360) and diethyl malonate, while in boiling ethanol it afforded... 

Diethyl N-cyclopropyl(6-chloro-5-trifluoromethyl-2-pyridinyl)amino-methylenemalonate (1701, R = Cl, R1 = Et) was obtained in the reaction of sodium salt of diethyl cyclopropylaminomethylenemalonate and 2,6-dichoro-3-trifluoromethylpyridine in dimethyl sulfoxide at 50°C for 4 hr in 86% yield (90JHC1527). When 1701 (R = Cl, R1 = Et) was reacted with ethoxycarbonylpiperazine in dimethyl sulfoxide at 100°C for 16 hr, then a 1 1 mixture of 2-pyridylaminomethylenemalonate (1701, R = 4-eth-oxycarbonylpiperazinyl, R1 = Et) and 2-(cyclopropylamino)-6-ch oro-5-trifluoromethylpiridine were obtained in 40% yield. However, the 6-phe-nylthio derivative (1701, R = SPh, R1 = Et) was prepared in high yield in the reaction of the 6-chloro derivative (1701, R = Cl, R1 = Et) and sodium phenylsulfide in dimethyl sulfoxide at ambient temperature for 2.5 hr. 

The cyclization of isopropylidene 2-pyridylaminomethylenemalonates 147 in a mixture of phosphoryl chloride-polyphosphoric acid gave 4-oxo-4ff-pyrido[l,2-a]pyrimidine-3-carboxylic acids 131 (R1 = COOH) or their esters 131 (R1 = COOalkyl), depending upon whether the excess of phosphoryl chloride was reacted with water or an alcohol. In this way a mixed ester or a half-ester (e.g., 131 R = COOEt, R1 = COOR2, R2 = H, Me) was obtained from an ester derivative of isopropylidene aminomethyl-enemalonate 147 (R = COOEt) (84S152). The 6-ethoxycarbonyl derivative of isopropylidene 2-pyridylaminomethylenemalonate 147 (R = 6-COOEt) afforded triester 138 when the reaction mixture was treated with ethanol. 

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