Hexahydropyrimidines

The definitive work is by I3C-NMR spectroscopy both conformers were detected289 at — 150°C and the ae conformer 321 was identified on the basis of the upheld (yai) shift of the NCH3 resonance (Section II,B,5). The results show the predominance of ee conformation 322 and are in line with the estimates based on dipole-moment measurements290 and Jgem comparisons with model compounds291 (323 model for 321 and 324 model for 322). Calculation of the equilibrium position from comparison of the chemical shift of the 2(ax) proton with the values in 323 and 324 is also in agreement with the predominance of 322,292 but a similar exercise291 based on Aae measurements favors the ae conformation 321 such chemical shift estimates are sensitive to the effect of the 5-substituents on the chemical shifts.279 

Estimates of the percentage ee conformation in other V,/V-dialkylhexahy-dropyrimidines are given in Table XXVI. Some disagreement exists between the positions of equilibria for the Af,Al-diisopropylhexahydropyrimidine based on dipole moment and on H-NMR chemical-shift measurements but in this case the higher (dipole moment) value is probably more representative of the true state of the equilibrium. 

Summary of Published Work on the Position of Conformational Equilibria in JV,JV-Dimethylhexahydropyrimidines 

Solvent Eq-eq conformation (322) (%) Method Reference Section of this review 

CH2C12 50 H NMR [comparison of 5 2(ax)-H with those in model systems] 292 II,B,1 

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Primary nitroparaffins react with two moles of formaldehyde and two moles of amines to yield 2-nitro-l,3-propanediamines. With excess formaldehyde, Mannich bases from primary nitroparaffins and primary amines can react further to give nitro-substituted cycHc derivatives, such as tetrahydro-l,3-oxa2iaes or hexahydropyrimidines (38,39). Pyrolysis of salts of Mannich bases, particularly of the boron trifluoride complex (40), yields nitro olefins by loss of the amine moiety. Closely related to the Mannich reaction is the formation of sodium 2-nitrobutane-1-sulfonate [76794-27-9] by warming 1-nitropropane with formaldehyde and sodium sulfite (41). 

There is an admirable summary of the stereochemistry of barbiturates and di- to hexahydropyrimidines Further information on reduced pyrimidines is collected <70HC 16-81)322) and some examples of the use of proton NMR spectra in elucidating the conformations of hydropyrimidines is given elsewhere (Section 2.13.1.3.1), based on the general principles of such work <65QR426). 

Tautomerism of 2-substituted hexahydropyrimidines has been studied (980PP53), and free energies, enthalpies, and entropies of activation for this ring-chain tautomeric equilibrium have been measured [97JCS(P2)169]. 

Nitroethane and formaldehyde are first reacted to give 2-methyl-2-nitro-1,3-propanediol. This is reacted with 2-ethylhexylamine and formaldehyde to give 5-nitro-1,3-bis(2-ethyl-hexyl)-5-methyl-hexahydropyrimidine. 

Lactame mit cyclischer Acyl-harnstoff-Struktur (z. B. 2,4-Dioxo-imidazolidin, S. 138f., 252f., 2,4-Dioxo- bzw. 2,4,6-Trioxo-hexahydropyrimidine) werden in der Regel an der Lactam-Struktur angegriffen, wahrend die Carbonyl-Funktion der Harnstoff-Gruppe nur z. Tl. reduziert wird (s. S. 135ff.). 

These synthetic pyrethroids mimic natural counterparts, of which the most important is pyrethrin 1 (10.265). Unfortunately, the natural products lack the photochemical and hydrolytic stability necessary for use as wool insect-resist agents. The synthetic products have the required stability, yet retain the low mammalian toxicity and low environmental retention of the natural products. Permethrin, however, is toxic to aquatic life and is therefore subject to increasingly severe discharge limits. There is some evidence that permethrin is less effective against larvae of a certain beetle. This can be compensated for by using a combination of permethrin with the hexahydropyrimidine derivative 10.264. Some possible alternative pyrethroids have been mentioned [517] as development products (10.266-10.269). 

In 1997, the controversial mechanism of the Biginelli reaction was reinveshgated by Kappe using NMR spectroscopy and trapping experiments [94], and the current generally accepted process was elucidated (see Scheme 9.23). The N-acyliminium ion 9-112 is proposed as key intermediate this is formed by an acid-catalyzed reaction of an aldehyde with urea or thiourea via the semiaminal 9-111. Intercephon of 9-112 by the enol form of the 1,3-dicarbonyl compound 9-113 produces the open-chain ureide 9-114, which cyclizes to the hexahydropyrimidine 9-115. There follows an elimination to give the final product 9-116. 

The Mannich condensation between nitromethane, formaldehyde and t-butylamine, followed by nitrolysis of the resulting product (101), has been used to synthesize 1,3,5-trinitro-hexahydropyrimidine (102) (TNHP) treatment of the latter with formaldehyde in a Henry type methylolation, followed by 0-nitration with nitric acid, yields the nitrate ester (103). ... 

Preparative methods for dihydro-, tetrahydro-, and hexahydropyrimidines have been comprehensively illustrated and discussed [441, 483—485]. 

Scheme 14 Three-component synthesis of hexahydropyrimidine derivatives...

It is interesting to note that when the dicarbonyl partner is a trifluoromethyl-ketone derivative, the dehydration is not observed and the corresponding hexahydropyrimidine s are obtained in good yields [70,80-82], regardless of the reaction conditions involving various catalytic systems, different medium, and thermal activation modes (Scheme 14 and Table 1). The different observations based on the isolation of these hydroxylated products allowed to corroborate the acyliminium ion mechanism [62]. 

Putilova ES, Troitskii NA, Zlotin SG, Khudina OG, Burgart YV, Saloutin VI, Chupakhin ON (2006) One-step solvent-free synthesis of fluoroalkyl-substituted 4-hydroxy-2-oxo(thioxo) hexahydropyrimidines in the presence of l-butyl-3-methylimidazolium tetrafluoroborate. Russ J Org Chem 42 1392-1395... 

Dihydro- ", tetrahydro- " " and hexahydropyrimidines were synthesized from aminoamidoximes and carbonyl compounds too. 

Reduced pyrimidines are much less stable toward hydrolysis than the fully conjugated analogs, and this is often used synthetically to produce amino acids and diamines. The BH3 reduction of cyclic amidines (1,4,5,6-tetrahydropyr-imidines) to hexahydropyrimidines, and their subsequent hydrolysis was mentioned above <1999JFIC105>, but there are many more examples. For instance, m-cyclobutane /5-amino acids 544 can be prepared from the cyclobutane derivatives 542 formed by the [2-F2] photocycloaddition reaction between uracil and ethylene <2002TL6177, 2004TL7095, 2006SL1394>. 

In the currently accepted mechanistic pathway outlined in Scheme 7, the key step in the Biginelli sequence involves the acid-catalyzed formation of an Wacyliminium ion intermediate of type 719 from the aldehyde and urea precursors <1997JOC7201, 2000ACR879, 20040R1>. Interception of the iminium ion 719 by the CH-acidic carbonyl component 715, presumably through its enol tautomer, produces an open-chain ureide 720, which subsequently cyclizes to hexahydropyrimidine 721. Acid-catalyzed elimination of water from 721 ultimately leads to the... 

Cyclobutane-fused hexahydropyrimidine-2,4-dione 569 was converted to the corresponding l,3-oxazin-2-one derivative 571 in a two-step procedure (Scheme 109). Compound 569 was reduced with NaBH4 to give ureidoalco-hol 570 in excellent yield, the diazotization of which provided the cyclic carbamate derivative 571 <2006TL5981>. 

Halogen displacement from 2-halo-tetrahydropyrans and -hexahydropyrimidines is extremely easy, being assisted, in the SnI process, by the electron pairs on the heteroatom (equation 124). 3-Halohexahydropyridines can also show accelerated halogen displacement (anchimeric assistance from nitrogen equation 125). Apart from these and other (normal) substitutions, eliminations of H—Hal are also commonly found. 

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