key: cord-0063139-2elz703t
authors: Mamedov, Vakhid А.; Zhukova, Nataliya А.; Kadyrova, Milyausha S.
title: The Dimroth Rearrangement in the Synthesis of Condensed Pyrimidines – Structural Analogs of Antiviral Compounds
date: 2021-05-15
journal: Chem Heterocycl Compd (N Y)
DOI: 10.1007/s10593-021-02913-7
sha: 96e7b2ee890cc9408a7afcc5aff81066f5a62f1b
doc_id: 63139
cord_uid: 2elz703t

[Image: see text] The review discusses the use of the Dimroth rearrangement in the synthesis of condensed pyrimidines which are key structural fragments of antiviral agents. The main attention is given to publications over the past 10 years. The bibliography includes 107 references.

The Dimroth rearrangement represents the isomerization of heterocycles which involves relocation of two heteroatoms in heterocyclic systems or in their substituents via the processes of ring opening and ring closure. This rearrangement can be subdivided into two types: relocation of heteroatoms within the rings of condensed systems (Type I) and migration of exo-and endocyclic heteroatoms in heterocyclic systems (Type II) (Fig. 1) . The second type of rearrangement, a particular case of which is the isomerization of 1-substituted 2-imino-1,2-dihydropyrimidines to 2-substituted aminopyrimidines by the action of bases (amidine rearrangement), is more common.

The rearrangement bearing the name of Dimroth was first observed by B. Rathke on a triazine derivative, but he did not provide any explanation for this phenomenon. 1 In 1909, O. Dimroth proposed a mechanism for the rearrangement of triazole. 2 The generality of this process for pyrimidines was recognized in the mid-1950s, 3, 4 and later it turned out that this is an even more general process characteristic of many nitrogen-containing heterocyclic systems. 5 The term "Dimroth rearrangement" was introduced in 1963 by D. J. Brown and J. S. Harper. 6 The Dimroth rearrangement is catalyzed by acids, 7,8 bases (alkali), 9, 10 is accelerated by heat or light. 11, 12 Numerous factors affect the course of the Dimroth rearrangement in heterocyclic systems: 1) the degree of aza-substitution in rings (more nitrogen atoms in the ring facilitates a nucleophilic attack); 13 2) pH of the reaction medium (affects the rate of the rearrangement); 14 3) the presence of electronwithdrawing groups (facilitates the opening of the ring); 13 4) the thermodynamic stability of the starting compound and the product. 15 The nature of functional groups, electronic and steric effects also affect the possibility of the Dimroth rearrangement and its course. 13, [16] [17] [18] Despite the fact that the specific route by which the Dimroth rearrangement takes place depends on many factors, in general, three fundamentally different stages can be identified: 1) formation of an adduct by an attack of the heterocyclic ring by a nucleophile, 2) electrocyclic ring opening in the adduct followed by rotation around the single bond, and 3) closure of the ring with the participation of other structural units. In total, these stages are known as the ANRORC mechanism (addition of nucleophile, ring opening, and ring closure). If the rearrangement occurs as a result of heating or irradiation, the first step is electrocyclic opening of the ring followed by ring closure. The presented mechanism illustrates the rearrangement of 2-imino-1-methyl-1,2-dihydropyrimidine (1-methylpyrimidin-2(1H)-imine) into 2-(methylamino)pyrimidine 19 (Scheme 1).

Primary information on the Dimroth rearrangement can be obtained from reference books on name reactions, 20, 21 whereas review articles devoted to its individual aspects provide more detailed information. There is, for example, a 1998 review article by Fujii and Itaya concerned with the rearrangement of adenine derivatives. 22 Other reviews on this topic date from 1965-1998 and require substantial additions, [23] [24] [25] [26] [27] as do sections in the review articles by L'аbbé 28 and by Maiboroda and Babaev. 29 More recent advances in the Dimroth rearrangement are reflected in relatively recent reviews. 5, 15, 30 Their authors have clearly demonstrated that although the Dimroth rearrangement is old, it is not obsolete.

An analysis of the literature over the past 10 years has identified several studies that were not included in the 2017 review on the Dimroth rearrangement. 30 In addition, in the last three years, a number of new publications have been published on the synthesis of a wide variety of heterocyclic systems, namely, 2-aminoimidazolotriazoles (2-substituted triazoles), 31 [1, 2, 4] triazolo [1,5-a] pyridines, 32 7,8,9, 10-tetrahydro [1, 2, 4] triazolo [5,1-a] [2, 7] naphthyridines, 33 [1, 2, 4] triazolo [1,5-d] [1, 2, 4] triazines, 34 4-diazo-1,4-dihydroisoquinolin-3(2H)-ones, 35 2-sulfido-1,2,3,5-tetrahydro-4H [1, 2] oxazolo- [4',5':5,6] pyrano [2,3-d] [1, 3, 2] diazaphosphinines, 36 and thieno- [2,3-d] [1, 3, 2] diazaphosphorin-6-thione 2-sulfides 37 relying the Dimroth rearrangement, indicating its enormous potential.

This review is devoted to methods for the synthesis of benzo-and hetero-annulated pyrimidine derivatives which are the structural basis of many biologically active compounds and drugs with antiviral activity based on the Dimroth rearrangement. The synthesis methods are grouped depending on the type of the starting heterocyclic systems undergoing rearrangement. Before proceeding to the methods of synthesis, let us briefly analyze condensed pyrimidine derivatives with antiviral activity.

Benzo-annulated pyrimidine derivatives shown in Figure 2 , namely, 4-sulfanylquinazolines 1a,b exhibit an inhibitory effect against the tobacco mosaic virus (TMV), 38 2,4-disubstituted quinazoline derivatives 2a,b containing amide fragments show high inhibitory activity against influenza A/WSN/33 virus (H1N1). 39 Pyrimidine derivative 3 (BIX-01294), which is known as a methyltransferase inhibitor, entered the ranks of the most effective published Ebola virus inhibitors after a virtual screening. 40 Scheme 1 Figure 2 . Benzo-annulated pyrimidine derivatives (quinazolines) with antiviral activity. Figure 3 shows the structures of a number of heteroannulated pyrimidine derivatives with antiviral activity: pyrrolo [2,3-d] Compounds with antiviral activity were also found among hetero-annulated pyrimidine derivatives containing a bridgehead nitrogen atom. For example, imidazo[1,2-a]pyrimidine 20 exhibits specific activity against cytomegalovirus (CMV), 54 [1, 2, 4] triazolo[1,5-a]pyrimidine 21 is active in inhibiting hepatitis B virus surface antigen HBsAg, 50 preladenant (22) (Fig. 4) , known as a selective inhibitor of 2α-adenosine receptors and used in the treatment of Parkinson's disease, exhibits high inhibitory activity against Zika virus. 55

containing five-membered rings with two nitrogen atoms A special feature of aza-heterocycles such as imidazo-[1,2-a]pyrimidines is that they can undergo the Dimroth rearrangement under appropriate reaction conditions. This transformation is described as the migration of heteroatoms in heterocyclic system 23 with changes in the ring structure (compound 24) or without them (compound 23') ( Fig. 5) , and this is often an unwanted side reaction that usually occurs in basic media. Many factors influence the propensity of aza-heterocycles to undergo the Dimroth rearrangement. Typically, decreasing the π-electron density of the condensed 6-membered ring increases the rate of the rearrangement. Thus, aza-substitution in the imidazo[1,2-a]pyrimidine system with the formation of the corresponding imidazo[1,2-a]pyrimidine 23 leads to an easier nucleophilic attack at position 5 (Fig. 5) ; the same is observed in the imidazo[1,2-a]pyridine system with electron-withdrawing substituents. As a result, 2-phenylimidazo[1,2-a]pyridine does not undergo rearrangement under alkaline conditions; however, the same ring system undergoes rearrangement in the presence of electron-withdrawing substituents such as the nitro group at the C-6 or C-8 position. 56 The rearrangement rate depends on pH of the reaction medium, and the ratio of the products usually depends on the nature of the substituents. 5, 13 For the rearrangements described for the imidazo[1,2-a]pyrimidine system, 13,57-60 the use of hydrolytic [58] [59] [60] or haloform reaction conditions is typical. 57, 59 The Dimroth rearrangement can also occur under acidic conditions or upon photoactivation in other aza-heterocycles, especially in triazolo[4,3-a]pyrimidines and triazolo [4,3-c] pyrimidines, although such transformations were not observed in imidazo[1,2-a]pyrimidine system.

Mechanistic aspects of the rearrangement including some important kinetic parameters, electronic and steric factors have been described (Guerret et al.) , 13 identifying the minimum characteristics of aza-heterocycles to undergo the Dimroth rearrangement. In this study, the authors acknowledge the possibility of H 2 O recruitment by other mechanisms, such as 1,4-addition or tautomerism, but conclude that their data best support a mechanism involving a nucleophilic attack on the C-5 atom with the opening of the pyrimidine ring as shown in Figure 5 .

Russell et al. has shown 61 that the reactions of ethyl 6-arylimidazo[1,2-a]pyrimidine-2-carboxylates 25а-с obtained from 2-amino-5-iodopyrimidine (26a) by condensation with ethyl bromopyruvate to form 6-iodoimidazo[1,2-a]pyrimidine-2-carboxylate 27 at the first step and its subsequent Suzuki cross coupling with variously substituted arylboronic acid derivatives, depending on the amidation method, either lead to amides of imidazo[1,2-a]pyrimidine-2-carboxylic acid 28a-c (Scheme 2, route a), or via intermediates 29a-c to isomeric imidazo[1,2-a]pyrimidine-3-carboxylic acid amides 30a-e (route b). In this case, the direct amidation of the ethyl ester of 6-arylimidazo[1,2-a]pyrimidine-2-carboxylic acid 25a leads to the formation of the corresponding 2-carboxylic acid amides 28a-c (route a). However, when an alternative route was used for this purpose involving hydrolysis of esters 25a-c with subsequent amidation of the resulting carboxylic acids 29a-c, the formation of imidazo[1,2-a]pyrimidine-3-carboxylic acid amides 30a-e (route b) as a result of the Dimroth rearrangement took place. Obviously, isomerization should occur either at the hydrolysis step or at the amide formation step, and the step of ester hydrolysis proceeding under aqueous basic conditions is more likely for this process.

The authors of a study 61 performed a thorough analysis of structures 25a-c and 29a-с using a set of NMR methods, including 15 N-labeled derivatives 34c,d, 35b, 36b and 14 N-labeled derivatives 34а,b, 35a, 36a of imidazo[1,2-a]pyrimidines specially synthesized from compounds 31-33 for this purpose (Schemes 3 and 4). As a result, it was 

Wang's group showed 64 Thus, the authors of a study 64 proposed a general and convenient method for the synthesis of new derivatives of [1, 2, 4] triazolo [1,5-c] pyrimidines. The process has several advantages, including good yields, ease of operation, environmental benignness, relatively short reaction times, and the possibility to use a wide range of substrates which makes it a useful and attractive process for the synthesis of structurally diverse triazolopyrimidines.

Chernyshev and Astakhov showed 65 that 3-amino-2-benzyl [1, 2, 4] [4,3-c] pyrimidine 52а (R = H, 1 equiv) with NaOAc (2 equiv) in EtOH under reflux for 5 h led to only a single product, compound 53а (R = H) in 76% yield. In particularly, each isomer 52 and 53 was distinguished by their 1 H NMR spectra. For example, the most prominent peak in the spectrum of compound 52а was observed at 9.02 ppm as a singlet attributed to the pyrimidine proton, while a similar singlet in the spectrum of isomer 53а was observed downfield at 9.27 ppm. The relatively downfield region of the pyrimidine proton in the Scheme 10 Lauria's group showed 72 that the reaction of 3-phenylbenzo [4, 5] In the reaction of the angular tetracyclic compound 54b with 1-bromo-3-chloropropane in DMF in the presence of K 2 CO 3 , along with the formation of the expected chloropropyl derivative 61, rearrangement was again observed with the competitive formation of the linear isomer 62 as the main product. As a result of heating compound 62 in 1-methylpiperazine under reflux, derivative 63 73 was obtained (Scheme 15).

In conclusion, the obtained experimental data contributed to the synthesis of new linear isomers of derivatives of benzo-and pyridine-annulated thieno[2,3-e]-[1,2,3]triazolo[1,5-a]pyrimidines 60 and 63 possessing antitumor activity, analogs of angular isomers 64 and 65 73 (Fig. 6) .

containing six-membered rings with nitrogen and oxygen atoms Li et al. 76 

Davoodnia's group revealed 80 that the reaction of 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4Hchromene-3-carbonitriles 76 with an excess of aliphatic carboxylic acids 77а,b in the presence of POCl 3 leads to new 2-alkyl-5-aryl-8,8-dimethyl-8,9-dihydro-3Н-chromeno-[2,3-d]pyrimidine-4,6(5Н,7Н)-diones 78a-h in high yields (Scheme 21). The optimal conditions for the reaction are heating of 2-amino-4-aryl-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitriles 76 in an excess of AcOH (77а) under reflux in the presence of POCl 3 as a chlorinating agent for 150 min. A decrease in the reaction temperature to 100°C led to a decrease in the product yield from 90 to 78%, all other parameters being equal. For comparison, the synthesis of compound 78а was also carried out using SOCl 2 . Under these conditions, product 78a was obtained in 82% yield. Therefore, all subsequent synthesis reactions of compounds 78b-h were carried out in the presence of POCl 3 at reflux in AcOH (77а) or propanoic acid (77b). Davoodnia's group 81 also synthesized some 9-alkyl-12-aryl-10,12-dihydro-11H-benzo[f]chromeno[2,3-d]pyrimidin-11-ones 79 via the intramolecular Pinner reaction of 3-amino-1-aryl-1H-benzo[f]chromene-2-carbonitriles 80 with aliphatic carboxylic acids 77a,b in the presence of POCl 3 followed by the Dimroth rearrangement (Scheme 23).

The proposed mechanism for the formation of compounds 78 includes the tandem intramolecular Pinner reaction and the Dimroth rearrangement. Chlorination of carboxylic acid 77 with POCl 3 leads to the formation of In terms of the sequence of transformations, the mechanism of formation of tetracyclic compounds 79a-g is identical to the mechanism of formation of compounds 78a-h 80 

Li et al. 82 group developed a method for the synthesis of 2,3-dihydropyrimido[4,5-d]pyrimidine, catalyzed by N-heterocyclic carbene (NHC-PPIm -in this case, it was generated by concentrating an aqueous solution of 1,3-dipropylimidazolium hydroxide) method of synthesis of 2,3-dihydropyrimido[4,5-d]pyrimidin-4(1H)-ones 81 based on the three-component reaction of 2-(ethoxymethylene)malononitrile (82), guanidines 83 (or amidines 84), and ketones 85 (or aldehydes 67) 83 (Scheme 24). This highly efficient method incorporates a cascade of transformations such as the Michael reaction, cyclization, isomerization, aromatization followed by nucleophilic attack and the Dimroth rearrangement. The method avoids the use of expensive reagents and multistep processes. A series of ketones 85 (or benzaldehydes 67) and guanidines 83 (or amidines 84) were investigated (Scheme 24). Theoretically, various carbonyl compounds could adversely affect this reaction due to steric hindrance and ring loading, but the reactions of all carbonyl compounds with guanidine 83a (R 3 = NH 2 ) led to products 81 in good and high yields (75-92%); reactions with N,N-dimethylguanidine 82b (R 3 = NMe 2 ) also led to the corresponding compounds 81 in good yields (79-86%). To broaden the scope of this onepot methodology, a specific series of guanidines 83 (compounds 83c (R 3 = NHPh), 83d (R 3 = NHMe), 83e (R 3 = NHEt)) and amidines 84 (compounds 84a (R 3 = Me), 84b (R 3 = Ph)) was chosen, and the corresponding compounds 81 were obtained in good or high yields (75-92%). These results illustrate the versatility of the NHC-PPIm catalyst and the advantages of this one-pot method. The reaction mechanism involves a cascade process similar to the synthesis of compounds 78a-h 80 compounds were unsuccessful even after careful monitoring of the reactions.

with anilines 90 as a useful and fast tool for the synthesis of 4-anilinoquinazolines 91a-c and 92 (Scheme 28). In the case of the reaction of compound 89b with aromatic amine 90a (R 1 = 4-NO 2 , R 2 = H) with the strong electronwithdrawing nitro group, the process stops at the step of formation of amidine 93 (Scheme 28).

The formation of compounds 94a,b upon condensation of N-methylanilines 90b (R 1 = H, R 2 = Me) and 90c (R 1 = 4-MeO, R 2 = Me) with imine 89b (Scheme 28) confirms the reaction mechanism that has so far rarely been described in the literature. 85 The authors of the study 79 suggest that aromatic amine 90 attacks the carbon atom of 

Besson's group proposed a short and effective route to Azixa (EPi28495, MPC-6827), N-(4-methoxyphenylamino)-N,2-dimethylquinazoline (95) (Scheme 30), which is a low molecular weight microtubule formation inhibitor and has been identified as a potent inducer of apoptosis. [86] [87] [88] Moreover, Azixa (95) is able to cross the blood-brain barrier and accumulate in the brain. 88 This property makes Azixa (95) a good candidate for the treatment of primary and metastatic brain tumors the therapy of which is practically limited. The synthesis of 4-anilinoquinazoline 95 begins with the reaction of anthranilonitrile (66b) and N,N-dimethylacetamide dimethyl acetal (Scheme 30). Compared to the previously synthesized compounds 89a,b, the synthesis of amidine 96 requires more energy due to steric hindrance of the methyl substituents at the nitrogen atom. However, it was obtained in high yield (90%) after 2 min of microwave irradiation at 115°C. Condensation of 4-methoxyaniline (90d) with amidine 96 under the conditions described for the synthesis of products 91a-c and 92 required a longer reaction time (30 min) to obtain quinazoline 97 in 56% yield together with a significant amount of byproducts. However, heating amidine 96 by microwave irradiation in an MeCN-AcOH, 7:3 mixture leads to a high yield (88%) of N-(4-methoxyphenylamino)-2-methylquinazoline (97) which, after N-methylation, transforms into Azixa (95) in 55% yield based on the starting anthranilonitrile (66b) (Scheme 30).

Utilizing the Dimroth rearrangement, Smith et al. proposed 89 an alternative route involving sequential transformation of compounds 98-106 to obtain vandetanib (107) (Schemes 31-33). Vandetanib (107) , discovered by AstraZeneca, is an orally available tyrosine kinase inhibitor with activity against VEGFR/EGER/RET receptors and is currently used for the treatment of medullary thyroid cancer. 90 The 9-step method 89 (Schemes 31-33) made it possible to synthesize vandetanib (107) in 7% yield compared to the previously described 12-14-step methods involving compounds 108-110 (Scheme 34), which afford vandetanib (107) in 4-20% yield. 91-93 This method is easily carried out; chromatographic purification is required only at the fourth step for product 102 (Scheme 31).

The proposed mechanism for the Dimroth rearrangement is shown in Scheme 35. 89 Proença's group has shown 94 that the reactions of anthranilonitrile (66b) and triethyl orthoformate (TEOF), depending on the experimental conditions, lead to various quinazoline derivatives in high and low yields both as individual compounds and in the form of mixtures. For 1 66b-TEOF, 1:1, AcOH (13 ml/mmol 66b), room temperature, 5 days 111 (75) pyrimidin-4-amines 118a-n based on compounds 115a-d and 116a-f using microwave irradiation. The reaction used readily available amines 116a-f and substituted N,N-dimethylformamidines 115a-d. The optimal reaction conditions for the synthesis of furo-and pyrrolo[2,3-d]pyrimidin-4-imino derivatives 117a-e were 110 or 140°C, 25-35 min, whereas for the preparation of structurally different furo-and thieno[2,3-d]pyrimidines 118a-n -180°C, 35 min ( Table 2 ). The proposed reaction mechanism 95 as shown in Scheme 37 involves the Dimroth rearrangement. First, the amino group of compound 116 attacks the carbon atom of formamidine 115 to produce intermediate E. Then, intramolecular ring closure takes place with the formation of intermediate F followed by removal of HNMe 2 to give product 117 (imino product 117 is the kinetic product). After that, H 2 O attacks the pyrimidine ring as a nucleophile and opens it with the formation of compound G in which the amidine fragment is rotated by 180° in comparison with the tautomeric form G'. Subsequent electrocyclization and elimination of H 2 O from compound H leads to thermodynamically stable product 118 (preferred at high * Yields of isolated and characterized products. with neutral amidines 131 was preliminarily carried out at room temperature in the presence of 1-4 equiv of TEOF and a catalytic amount of H 2 SO 4 but the reaction was very slow. When an excess of H 2 SO 4 (4 equiv) was added, a fast reaction took place (reaction time 5-10 min) with the formation of white products which were easily isolated by filtration and were identified as salts 132a·H 2 SO 4 (R 1 = 4-FC 6 H 4 , R 2 = 4-MeOC 6 H 4 , yields 64%) and 132b·H 2 SO 4 (R 1 = 4-MeOC 6 H 4 , R 2 = 4-MeC 6 H 4 , yield 76%). The free bases, adenines 132, were obtained in situ by treatment with DBU of the corresponding salts 132·H 2 SO 4 (Scheme 42).

The formation of adenines 132 is explained by the regioselective condensation of TEOF with the 5-amino group of imidazoles 131 as depicted in Scheme 43. The alternative condensation with the 4-carboxamidine group is unfavorable due to the formation of an amidinium salt in the presence of H 2 SO 4 . 99 Regioselective synthesis of С(6)-substituted adenines 133a-l occurs when the same precursors 131 are reacted with N,N-dimethylformamide diethyl acetal (DMF-DEA) in MeCN at 40°С. When the reaction was carried out for 1 day under these conditions, products 133a-i were isolated in good and high yields (61-93%). C(6)-Alkyladenines 133j-l were obtained using a one-pot two-step reaction of imidazoles 134 with benzylamine or 2-methoxyethylamine.

In the first step, imidazole 134 was reacted with an amine and 1 equiv TFA at room temperature. Then, DMF-DEA was added to the reaction mixture and the reaction was continued overnight which led to the formation of adenines 133j-l in 48-86% yields 99 (Table 3) . The formation of exclusively C(6)-isomer 133 by this route indicates regioselective condensation of DMF-DEA with the free amino group of the 4-carboxamidine substituent of imidazole 131 99 as shown in Scheme 44. Ben Jannet et al. 100 obtained the corresponding ethoxymethyleneamino derivative 136 by the reaction of 5-aminopyrazole-4-carbonitrile 135 with TEOF 101 and demonstrated that imidate 136 reacted at its two electrophilic centers with aliphatic amines 116 to form pyrazolopyrimidines 138a-c in two steps via intermediates 137a-c. In the first step, the condensation of imidate 136 with amines 116 in EtOH in the presence of a catalytic amount of AcOH leads to intermediate compounds 137a-c due to the nucleophilic attack of the amino group at the imide carbon atom. In the second step, the isolated amidines 137a-c undergo intramolecular cyclization with the in situ formation of intermediates I which are isomerized to thermodynamically more stable pyrazolopyrimidine derivatives 138a-c via tandem basecatalyzed opening and closure of the pyrimidine ring (Scheme 46). This rearrangement corresponds to those discussed in earlier studies. [102] [103] [104] The reaction of compounds 136 with aromatic amines 90 leads to N-aryl-3-methyl-1-phenyl-1H-pyrazolo [3,4- Borrell's group 105 developed two methods for the synthesis of 2-arylamino-5,6-dihydropyrido [2,3-d] pyrimidin-7(8H)-ones 140a-e. One of them relies on a multicomponent reaction between α,β-unsaturated ester 141, malononitrile (142), and arylguanidine 83 (obtained preliminary from the carbonate salt) in the presence of NaOMe in MeOH, whereas the other is based on the Dimroth rearrangement of 3-aryl-substituted pyridopyrimidines 143a-e, formed during the treatment of pyridones 144a-d with arylguanidines 83 in 1,4-dioxane, into 2-arylaminopyridopyrimidines 140a-e upon heating in MeOH in the presence of NaOMe (Scheme 47). For comparison, the yields (for each step and the combined yield) of a series of 2-arylamino-substituted pyridopyrimidines 140a-e using both methods are shown in Scheme 47.

Scheme 47 demonstrates that a) the total yields of 4-amino-5,6-dihydropyrido[2,3-d]pyrimidin-7(8H)-ones 140a-e formed via 3-aryl-substituted pyridopyrimidines 143a-e, as a rule, are higher than those obtained as a result of the multicomponent reaction; b) when the α,β-unsaturated ester 141 has a substituent at the β-position (R 2 ), the yields are generally lower than when it is present at the α-position (R 1 ); and c) although the multicomponent reaction gives lower yields than the three-step procedure, in some cases it can be a good alternative as it allows the desired pyridopyrimidine 140 to be obtained in one step. The proposed mechanism for the formation of compounds 143a and 140a 105 is given in Scheme 48.

Wu's group 106 developed a highly selective and efficient temperature-dependent chemodivergent method for the synthesis of 4H-benzo[d] [1, 3] thiazin-4-ones and 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones from isothiocyanates 145 and isatins 146. The method incorporates a cascade of oxidation and decarboxylation processes followed by cyclization; carrying out the reaction at room temperature gives rise to 2-amino-4H-benzo[d] [1, 3] thiazin-4-one derivatives 147a-l (Scheme 49), while derivatives of 2-thioxo-4(3H)-quinozalinones 148a-l are formed at 80°С (Scheme 50).

As shown in Scheme 49, the use of halogenated (3-F, 3-Cl, 4-Cl, and 4-Br) isothiocyanatobenzenes 145 in the synthesis of 4H-benzo[d] [1, 3] thiazin-4-ones 147a-l leads to target products 147b-e in good yields (71-86%). The electron-withdrawing group (4-NO 2 ) had a positive effect on the reaction and the desired product 147f was obtained in good yield (85%). Electron-donating groups (4-Me, 3-MeO) also led to the corresponding compounds 147g,h in moderate yields (48 and 58%, respectively). Moreover, 3-isothiocyanopyridine underwent the reaction to form product 147i in good yield (86%). As for the substituents in the isatin fragment, electron-neutral and electron-donating groups do not affect the course of the reaction since products 147j-l were obtained in good yields (80-89%) in all of the variations of substituents. 106 In the case of the synthesis of 2-thioxo-2,3-dihydroquinozalin-4(1H)-one derivatives 148a-l, the reactions of isothiocyanatobenzenes containing halogen atoms and electron-withdrawing groups in the benzene ring proceeded with the formation of the target products 148b-e in high yields (65-78%). Electron-neutral and electron-donating groups in different positions had a minor effect on the yields of products 148b-e (51-65%). The sterically hindered 2-isothiocyanatonaphthalene also reacted with the formation of the target product 148i in 70% yield. In addition, isatin derivatives with electron-neutral and electron-donor groups showed good reactivity (compounds 148j-l, 72-81% yields) 106 (Scheme 50). A mechanism was proposed for the reaction of phenyl isothiocyanates with isatins based on the results of the following reactions of phenyl isothiocyanate (145a) with anhydride 149 at different temperature conditions with the formation of compounds 147a and 148a and treatment of 2-(phenylamino)-4H-benzo[d] [1, 3] thiazin-4-one (147а) with Na 2 CO 3 in DMSO at 100°С resulting in the Dimroth rearrangement with the formation of compound 148a (Scheme 51). 106 In the initial step of the process initiated by the nucleophilic attack of tert-butylperoxy anion on isatin 146a (R 2 = H), intermediate A is formed which is then converted into anhydride 149 by a mechanism similar to the Baeyer-Villiger oxidation. Then, cyclization of phenyl isothiocyanate (145а) with anhydride 149 with simultaneous decarboxylation leads to 2-(phenylamino)-4H-benzo[d]- [1, 3] thiazin-4-one 147а which in the presence of Na 2 CO 3 at high temperature undergoes the Dimroth rearrangement producing stable 2-thioxo-2,3-dihydroquinazolin-4(1H)one 148a 106 (Scheme 52).

In conclusion, a highly selective, base-catalyzed, temperature-controlled method has been developed for the synthesis of 4H-benzo[d] [1, 3] thiazin-4-ones and 2-thioxo-2,3-dihydroquinazolin-4(1H)-ones. The method involves a kinetically controlled tandem oxidation-cyclization process with decarboxylation in the reactions of isothiocyanates with isatins. Carrying out the reaction at room temperature yields access to 4H-benzo[d] [1, 3] thiazin-4-ones, whereas when the temperature is risen to 80°C, 2-thioxo-2,3dihydroquinazolin-4(1H)-ones can be obtained. 106 Wu et al. 107 employed 2-haloaryl isothiocyanates instead of isothiocyanobenzenes in the reaction with commercially available isatins resulting in the development of an efficient method for the synthesis of 12H-benzo [4, 5] quinazolin-12-one derivatives without the use of transition metals. A key step toward the synthesis of these compounds is the Dimroth rearrangement.

As shown in Scheme 53, the electronic properties and the position of the substituent on the phenyl ring of the 2-haloaryl isothiocyanate derivative 150 practically do not affect the course of the reaction. Compounds with fluorine atoms in positions 3, 4, and 6 react well forming target products 151a-c in good yields (64-81%) . The substituents at position 6 of the phenyl ring lead to a slight decrease in yield which can probably be attributed to steric hindrance. The presence of electron donor groups (4-MeO, 4-Me, and 5-Me) decreases the yields of products 151d-f (61-72%). The use of other halogens as substituents in the starting compounds 150 does not affect the course of the reaction and does not decrease the yields of products 151g-i (66-80%). 107 Based on the above results and literature data, a possible reaction mechanism was proposed using isatin 146a (R 2 = H) and 1-fluoro-2-isothiocyanatobenzene (150a) as To conclude, an analysis of the literature data made it possible to draw conclusions on the importance of pyrimidines and their condensed analogs and, in this regard, the need to develop new methods for their preparation, as well as the prospects of research of the directions of their practical use. The Dimroth rearrangement is a simple and efficient way of constructing condensed pyrimidines, often in a one-pot manner, from available starting reagents. An important positive aspect of the Dimroth rearrangement is the variability of the starting reagents which makes it possible to obtain various condensed systems with the pyrimidine ring with various substituents. At the same time, the dependence of the regional orientation and selectivity of reactions on many factors makes research in this direction interesting and unpredictable. The potential of condensed pyrimidine analogs as compounds with practically important properties, which has not yet been fully disclosed, guarantees in the future the constant interest of synthetic chemists both in this class of compounds in general and in methods of constructing the pyrimidine ring in combination with other carbo-and heterocyclic rings using also the Dimroth rearrangement. We hope that the systematization of literature data on the synthesis of various condensed pyrimidine analogs can serve as a foundation for the development of approaches to the synthesis of both natural compounds and their modified analogs with predictable biological activity.

Advances in Heterocyclic Chemistry

Advances in Heterocyclic Chemistry

Comprehensive Organic Name Reactions and Reagents

Strategic Applicatons of Named Reactions in Organic Synthesis

Organic Syntheses Based on Name Reactions

Pteridine Chemistry

Mechanism of Molecular Migrations

The Chemistry of Heterocyclic Compounds, The Pyrimidines

Proceedings of Voronezh State University. Series: Chemistry. Biology. Pharmacy