Fluorinated Triazines

Abstract

In this chapter data on structure, synthetic routes, reactivity of derivatives of 1,2,3-triazines, 1,2,4-triazines and 1,3,5-triazines − bearing one or several fluorine atoms in heterocyclic ring as well as trifluoromethyl substituted triazines are considered and analyzed, and also their certain representatives are discussed. The bibliography – 119 references.

1 Introduction

A growing interest to fluorinated derivatives of triazines which is observed for the recent two decades has undoubtedly stimulated the development of new synthetic methods, as well as studying of their reactivity and elucidation of areas of their plausible applications.

2 Structure

In this section the data of theoretical studies reflecting the effects of fluorine atom(s) on geometrical characteristics of fluorine-containing triazines will be discussed. Selected examples of the X-ray crystallography analysis of 1,3,5-triazines, 1,2,4-triazines and 1,2,3-triazines as well as the data of ¹⁹F NMR spectroscopy elucidations will be considered.

2.1 Quantum-Chemical Calculations

The effects of incorporating of a fluorine atom in the position 2 of 1,3,5-triazine ring have been estimated by ab initio gradient method [1]. According to the data of quantum chemical calculations (Table 1), the angle of N¹C²N³ increases of 1.6°, the bonds C²-N¹ and C²-N³ become shorter of 0.0017 nm. It should be noted that the C-F bond in 2-fluoro-1,3,5-triazine is shortest one relative to 2-fluoropyridine (the difference is −0.003 nm) and 2-fluoropyrimidine (−0.001 nm) (Fig. 1). Calculations using HF//6-31G*//6-31G* gave following values of the N-F bond distances in 1-fluoro-2,4,6-trichloro-s-triazinium hexafluoroarsenate and 1-fluoro-s-triazinium hexafluoroarsenate: 0.1314 nm and 0.1317 nm respectively [2].

Table 1 Characteristics of 1,3,5-triazine and 2-monofluoro analogue

Fig. 1

Bond lengths (nm) and angles for 2-fluoropyridine, 2-fluoropyrimidine and 2-fluoro-1,3,5-triazine

2.2 X-ray Crystallography Analysis Data

Research of fluorinated derivatives of triazine by the X-ray method has fragmentary character. Fluorinated 1,3,5-triazines are most in detail considered. The X-ray data for 2,4-difluoro-6-bis(trimethylsilylphosphino)-1,3,5-triazine (Fig. 2) have been obtained [3]. The P(CN)₃ fragment of the molecule is practically planar, however the angles in the 1,3,5-triazine ring proved to differ considerably from those of the correct hexagon figure. The C¹–N¹–C² angle is 112.3°, while the opposite angle N²–C³–N³ has a much higher value of 132.0°. The C-N bond lengths have value which are typical for the corresponding double bond (0.131–0.135 nm), whereas C-P bond is significantly longer (0.181 nm), but keeps within an interval of typically C-P bond.

Fig. 2

X-ray data for 2,4-difluoro-6-bis(trimethylsilylphosphino)-1,3,5-triazine (Reproduced with permission of ACS [3])

Also fluorinated anionic triazine systems with TAS⁺ [(Me₂N)₃S⁺] cation have been studied by the X-ray crystallography (Figs. 3, 4, 5 and 6) [4]. It has been shown that values of the C¹–N¹ and C¹–N³ bonds in the anion C₃N₃F₄ ⁻ correspond to those of the ordinary bond, the N¹–C² and C³–N³ bonds are double, while the C²–N² and N²–C³ bonds proved to have intermediate values between ordinary and double bonds. The ring C₃N₃ fragment of compound TAS⁺ C₃N₃F₄ ⁻ is a planar one with the C¹ carbon atom to be in a tetrahedral configuration.

Fig. 3

X-ray data for TAS⁺ C₃N₃F₄ ⁻ (Reproduced with permission of RCS [4])

Fig. 4

X-ray data for РСА TAS⁺ C₃N₃F₂O⁻ (With permission of RCS [4])

Fig. 5

X-ray data for TAS⁺ C₃N₃F(CF₃)₃ ⁻ (Reproduced with permission of RCS [4])

Fig. 6

X-ray data for TAS⁺ C₃N₃F(CF₃)₃ ⁻ (Reproduced with permission of RCS [4])

X-ray data for 2-tris(trimethylstannyl)amino-4,6-difluoro-1,3,5-triazine (Fig. 7) show that the triazine ring is a little distorted, the molecule is nearly planar with the exception of methyl groups. The maximum deviation from the plane is exhibited by tin atoms (0.009 nm). The enlarged angle N²–C³–N³ (130.0°) is resisted by the angle C²–N¹–C¹ (114.7°). The C-N bond attached to the triazine ring is unusually small and its length is very close to values of three other C-N bonds of the ring, thus indicating at a considerable π-linkage of the ring with the exocyclic nitrogen atom [5].

Fig. 7

X-ray data for 2-tris(trimethylstannyl)amino-4,6-difluoro-1,3,5-triazine (Reproduced with permission of ACS [5])

The N-F bond length (0.11 nm) in 1-fluoro-2,4,6-trichloro-s-triazine hexafluoroarsenate is shorter than its calculated value of 0.0214 nm [2]. Also perfluorinated hexahydro-1,3,5-triazin-2,6-dione has been studied by X-ray crystallography method (Fig. 8) [6].

Fig. 8

X-ray data for perfluorinated hexahydrotriazindione (Reproduced with permission of Elsevier [6])

2.3 NMR Spectroscopy

Existence of three nitrogen atoms in a ring and such substituents as fluorine atoms in molecules of considered group of compounds does the most informative for the analysis of structure and properties NMR ¹³C and ¹⁹F spectroscopy.

2.3.1 NMR ¹³C Spectroscopy

The data on NMR ¹³C spectroscopy of 6-substituted fluorinated 1,3,5-triazines have been analyzed [3, 5, 7, 8]. Replacement of fluorine atom by CF(CF₃)₂ group leads to upfield shift of signals of triazine carbons in NMR ¹³C spectra. NMR ¹³C spectra of perfluorinated hexahydrotriazinedione have been also studied (Scheme 1) [6].

Scheme 1

NMR ¹³C spectra data of fluorinated triazines

Cyclic carbons with fluorine atom in NMR ¹³C spectra of boronfluoride salt of 2,4-difluoro-6-(1,3-diisopropyl-4,5-dimethylimidazolyl-2)-1,3,5-triazine are fixed in the form of a multiplet at 170.6–172.9 ppm [9]. NMR ¹³C spectra of difluoro-sulphonamido-1,3,5-triazines in THF-d ₈ at different temperatures (Table 2) reveal that at the room temperature C² and C³ atoms are equivalent, and at low temperatures rotation of the substituent round exocyclic C-N bond slows down so that C² and C³ atoms become magnetically nonequivalent [10].

Table 2 NMR ¹³C data of difluorosulphonamido-1,3,5-triazines in THF-d ₈ at different temperatures

2.3.2 ¹⁹F NMR Spectroscopy

The ¹⁹F NMR spectra of a number of fluorinated 1,3,5-triazines have been reported (solvent CDCl₃), the chemical shifts of fluorine are observed at -32-(-42) ppm [8]. As the information about spectra of fluorine-containing diazines in the same solvent is absent, it is difficult to compare ¹⁹F NMR spectra of fluorotriazines and fluorodiazines (Scheme 2).

Scheme 2

Chemical shifts in ¹⁹F NMR spectra of fluorinated 1,3,5-triazines

The NMR ¹⁹F spectra of the salts consisting of the anionic fluorine-containing triazine systems and TAS⁺ [(Me₂N)₃S⁺] as the cation have been elucidated, the chemical shifts of aromatic fluorine are equal −46.3 ppm (Scheme 3) [4]:

Scheme 3

The NMR ¹⁹F spectra data of the anionic fluorine-containing triazine systems and TAS⁺

The NMR ¹⁹F spectra data for the delocalized 1,3,5-triazinium cation which is formed on treatment of 3,5-trifluoromethyl-2,4,4,6,6-pentafluoro-3,4,5,6-tetrahydro-1,3,5-triazine with SbF₅ have been presented, the chemical shifts of aromatic fluorine are −13.5 ppm (Scheme 4) [6].

Scheme 4

The NMR ¹⁹F spectra data for the delocalized 1,3,5-triazinium cation

The data of ¹⁹F NMR spectroscopy show that chemical shifts of fluorine atoms attached to the ring in 1,2,3-triazines are varied greatly and lay in range from −79.5 to −166.0 ppm [11]. The data on ¹⁹F NMR spectra of fluorinated 1,2,4-triazines have recently been presented and discussed [12]. Coupling constants ⁵ J _F(3),F(6) lay in range from 35 to 37 Hz, constant ³ J _F(5),F(6) proved to be 24 Hz, whereas the ⁴ J _F(3),F(5) has smallest value (<4 Hz) (Scheme 5).

Scheme 5

Chemical shifts and coupling constants in ¹⁹F NMR spectra of fluorotriazines

3 Synthetic Methods

One of the most common synthetic approach to 1,2,3-, 1,2,4- and 1,3,5-triazines, bearing fluorine atoms as substituents in the ring, consists of the nucleophilic displacement of chlorine or bromine atoms with the fluoride anion in the corresponding haloderivatives, a direct fluorination, the Shimman reaction in addition to another synthetic strategies based on condensations and ring transformations.

3.1 Synthesis of Fluorine-Containing 1,2,3-Triazines

3.1.1 Nucleophilic Displacement of Bromine or Chlorine Atoms with the Fluoride Anion

The displacement of bromine or chlorine atoms in heteroaromatic compounds is certainly one of the most effective synthetic methods leading to fluorinated heterocyclic compounds [13]. For instance, heating 4,5,6-tribromo-1,2,3-triazine 1 with dry potassium fluoride at 550 °C in vacuum results in the formation of a mixture of 4,5,6-trifluoro-1,2,3-triazine 2 and 5-bromo-4,6-difluoro-1,2,3-triazine 3 in the ratio 1:1 (Scheme 6) [14].

Scheme 6

Nucleophilic displacement of bromine atoms with the fluoride anion

The reaction of 4,5,6-trichloro-1,2,3-triazine 4 with potassium fluoride at an elevated temperatures provides fully substituted 4,5,6-trifluoro-1,2,3-triazine 2 in addition to compounds 5 and 6 with partial displacement of chlorine atoms (Scheme 7) [11]. It is clear that yields of fluorinated products depend on the reaction conditions (Table 3) [11]. At temperatures of 150–200 °C replacement of one or two chlorine atoms take place. The polyfluorinated 1,2,3-triazines 2, 5 were obtained when using two-step process in 55–69 % yields.

Scheme 7

The reaction of 4,5,6-trichloro-1,2,3-triazine 4 with KF

Table 3 Fluorination of 4,5,6-trichloro-1,2,3-triazine [11]

Interaction of 4,5,6-trichloro-1,2,3-triazine 4 with hexafluoropropene in the presence of potassium and cesium fluorides leads to the formation of 4,6-di-(perfluoroisopropyl)-5-fluoro-1,2,3-triazine 7 in addition to small quantities of polyfluorinated alkyl-1,2,3-triazines 8 and 9 (Scheme 8) [11, 15]. Trifluoromethyl substituted 1,2,3-triazines are still unknown compounds.

Scheme 8

Interaction of 4 with hexafluoropropene in the presence of KF and CsF

3.2 Synthesis of Fluorine-Containing 1,2,4-Triazines

Fluorinated 1,2,4-triazines can be obtained by means of several synthetic approaches: the formation of 1,2,4-triazine ring through cyclocondensations of fluorine-containing synthones, a direct fluorination of the ring, replacement of chlorine atoms in chlorotriazines with the fluoride anion and other methods.

3.2.1 Cyclocondensation Reactions

The synthesis of azoloannelated fluoro-1,2,4-triazines – 2-R-6-fluoro-1,2,4-triazolo[5,1-c][1,2,4]triazin-7(4H)-ones 10 has been recently described [16]. The coupling of 1,2,4-triazolyl-5-diazonium salts 11 with ethyl 2-fluoroacetate and the accompanied deacetylation leads to the formation of hydrazones 12 followed by cyclization on heating in aqueous alcohol in the presence of sodium acetate into the target fluoro compounds 10 (Scheme 9).

Scheme 9

Synthesis of triazolotriazin-7(4Н)-ones 10

3.2.2 Direct Fluorination Reactions

A rare example of the incorporation of a fluorine atom into azaaromatic compounds is the direct fluorination reaction of 6-azauracyl 13a and 2-(2,3,5-tri-O-acetyl-β-D-ribofuranozyl-1,2,4-triazin)-3,5(2H,4H)-dione 13b which takes place on passing of fluorine through a solution of azauracils 13a,b in acetic acid, thus giving 6-fluoro-1,2,4-triazin-3,5(2H,4H)-diones 14 in 20–55 % yields (Scheme 10) [17, 18].

Scheme 10

Direct fluorination reactions

3.2.3 Nucleophilic Displacement of Bromine or Chlorine Atoms with the Fluoride Ion

The reaction of bromo or chloro derivatives of triazines with the fluoride ion is one of the main methods for the synthesis of fluorinated 1,2,4-triazines [13]. For instance, 1,3-dimetyl-5-fluoro-6-azauracyl 16 was obtained by reacting dry potassium fluoride with the corresponding bromo precursor 15 (Scheme 11) [19].

Scheme 11

Synthesis of 1,3-dimetyl-5-fluoro-6-azauracyl 16

Another example illustrating utility of this approach is displacement of chlorine atoms in 3,5,6-trichloro-1,2,4-triazine which does occur in a melt of compound 17 with dry KF (Scheme 12) [20]. The conversion degree depends on the reaction conditions: at 450 °С the dominant product of the reaction proved to be 3,5,6-trifluoro-1,2,4-triazine 18, while 3-chloro-5,6-difluoro-1,2,4-triazine 19 was isolated as a minor product.

Scheme 12

Displacement of chlorine atoms in 3,5,6-trichloro-1,2,4-triazine

In order to obtain 3-fluoro-5-phenyl-1,2,4-triazine 22 from the corresponding 3-chloro derivative 20 the chlorine atom has to be displaced first with the trimethylammonium fragment (compound 21), which undergoes easily the fluorination reaction by action of potassium fluoride to give 3-fluoro-1,2,4-triazine 22 in addition to 3-dimethylamino-5-phenyl-1,2,4-triazine 23 [21] (Scheme 13).

Scheme 13

Reaction of compound 21 with KF

3.2.4 The Baltz-Schiemann Reaction

3-Fluoro-1,2,4-triazin-2-oxides 26 were obtained through diazotization of the corresponding amino derivatives 24 followed by thermolysis of the resulting diazonium tetrafluoroborates 25 (Scheme 14). It should be noted the salts 25 have been isolated first as rather stable heterocyclic diazonium species [22].

Scheme 14

The Baltz-Schiemann reaction

Two main synthetic approaches to trifluoromethyl substituted 1,2,4-triazines are known. They are cyclocondensation process based on (trifluoromethyl)carbonyl derivatives and transformation of 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine ring.

A synthesis of 3-methylthio-5-trifluoromethyl-1,2,4-triazine 30 was described using dibromotrifluoroaceton 3 and S-methylthiosemicarbazide 27 as starting materials (Scheme 15) [23]. The synthesis of 3-methylthio-6-trifluoromethyl-1,2,4-triazine 31 was achieved by using trifluoropyruvaldehyde 28 and S-methyl-thiosemicarbazide 27 as starting materials (Scheme 15) [24]. 3-Aminotriazine 33 was prepared by the condensation of aminoguanidine 32 with dibromoketone 29, this condensation was non-selective, and 6-trifluoromethyl-isomer as by-product was formed (Scheme 15) [25].

Scheme 15

Synthetic approaches to trifluoromethyl substituted 1,2,4-triazines

3-Hydrazono-1,1,1-trifluoroalkan-2-ones 35 prepared from 1,1,1-trifiuoroalkane-2,3-diones 34 reacted with several aldehydes in the presence of aqueous NH₄OH to afford 5-trifluoromethyl-2,3-dihydro-1,2,4-triazines, of which oxidation gave 5-trifluoromethyl-1,2,4-triazines 36 (Scheme 16) [26].

Scheme 16

Synthesis of 5-trifluoromethyl-1,2,4-triazines 36

Microwave assisted reaction of 2-diazo-4,4,4-trifluoro-3-oxobutanoate 37 with aryl hydrazides in the presence of copper(II)acetate, followed by reaction with ammonium acetate in acetic acid gave the 1,2,4-triazines 38 in modest yield (Scheme 17) [27].

Scheme 17

Synthesis of 1,2,4-triazines 38

The reaction of trifluoropyruvate 39 with 4-methylbenzoic acid amidrazone was carried out in refluxing ethanol to give 3-(p-tolyl)-6-trifluoromethyl-1,2,4-triazin-5(2H)-one 40 in 57 % yield. A 6-trfluoromethyl-1,2,4-triazine derivative 42 was synthesized in almost quantitative yield from 40 by chlorination followed by catalytic hydrogenation to remove chlorine substituent (Scheme 18) [28].

Scheme 18

Synthesis of triazine 42

Bis(trimethylsilyl) ether of 5-trifluoromethyl-6-azauracil 48 was obtained for the synthesis of the corresponding β-D-deoxyribonucleoside and nucleotide. α-Trifluoromethacrylic acid 43 has been converted with hydrogen peroxide to α,β-dihydroxy-α-trifluoromethylpropionic acid 44, which gave the hydrate of perfluoropyruvic acid 45 on treatment with sodium periodate. The semicarbazone 46 was cyclized using thionyl chloride to 5-trifluoromethyl-6-azauracil 47, compound 47 was heated under reflux in hexamethyldisilazane under nitrogen atmosphere thus resulting in the formation of 6-trifluoromethyl-1,2,4-triazine 48 (Scheme 19) [29].

Scheme 19

Synthesis of 6-trifluoromethyl-1,2,4-triazine 48

Examples of synthesis of trifluoromethyl-substituted 1,2,4-triazines by transformation of 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine 49 ring are presented at Scheme 20. The anomeric C-glycosyl precursors 50, functionalized by an imidate group and appropriate for C-nucleoside synthesis were utilized as heterodienophiles in a Diels-Alder reaction with inverse electron demand to yield the O-benzyl protected 5-(β-d-ribofuranozyl)- and 5-(α-d-ribofuranosyl)-1,2,4-triazines 51 (Scheme 20) [30].

Scheme 20

Transformation of 3,6-bis(trifluoromethyl)-1,2,4,5-tetrazine 49 ring

Analogues synthesis of 3,6-bis(trifluoromethyl)-1,2,4-triasines bearing (2′,3′-dideoxy-β-D-ribofuranosyl)- or (2′-deoxy-β-D-ribofuranosyl)-residue at position 5 was reported [31, 32]. A new strategy for a straightforward synthesis of chiral 5-(2′-pyrrolidinyl)-1,2,4-triazines 53 starting from (S)- and (R)-proline iminoester 52 utilizing as the key steps the inverse electron demand Diels–Alder reaction of tetrazine 49 was achieved (Scheme 20) [33]. Electron-rich C = N bond of the hydrazone Me₂N-N = CH-CH = N-NH₂ proved to be effective dienophiles towards the electron-deficient tetrazine 49. The substituted 1,2,4-triazine 54 was formed by way of [4 + 2]cycloaddition and elimination of nitrogen [34].

3.3 Synthesis of Fluorine-Containing 1,3,5-Triazines

The most studied and widespread type of fluorinated triazines are 1,3,5-triazines. As well as their isomer compounds, fluorinated 1,3,5-triazines can be synthesized by several ways: (i) the formation of heterocyclic ring by means of cyclization reactions from fluorine-containing precursors; (ii) direct fluorination of triazines; (iii) nucleophilic displacement reactions of chlorinated triazines with the fluorine ion, and other synthetic procedures.

3.3.1 Cyclocondensation Reactions

Heating of a mixture of NaCN and NF₃ (or ClCN and NF₃) at 400–500 °C affords 2,4,6-trifluoro-1,2,3-triazine (cyanuric fluoride) 55 in a high yield (Scheme 21) [35]. The formation of triazine 55 is also observed on heating of chlorocyane with copper chloride at 300 °C [or on heating of chlorocyane with HgN(CF₃)₂ at 120 °C] [36], or by the reaction of trifluoroacetonitrile with cesium fluoride and NF₃ (Scheme 21) [37]. At room temperature, liquid cyanogen fluoride FCN is converted rapidly to polymeric materials, including cyanuric fluoride and a high-melting, water-sensitive solid polymer, but in the gas phase at atmospheric pressure it has been recovered partially after several weeks or under the conditions of polymerization [38].

Scheme 21

Synthesis of 2,4,6-trifluoro-1,2,3-triazine (cyanuric fluoride) 55

N-(4,6-Difluoro-1,3,5-triazin-2-yl)-N-ethyloctane-1-sulphonamide has been obtained from N-ethyloctane-1-sulphonamide and cyanuric fluoride [9]. The formation of 2,4-difluoro-1,3,5-triazine fragment has been exploited in the synthesis of dyes. The synthesis of triazine dyes has also been reported in a number of publications [39, 40] (Scheme 22). 2,4-Difluoro-6-arylamino-1,3,5-triazines 57 were obtained by the reaction of arylazoanilines 56 with cyanuric fluoride.

Scheme 22

Synthesis of 2,4-Difluoro-6-arylamino-1,3,5-triazines 57

3.3.2 Ring Transformations

Heating of 3,5,6-trifluoro-1,2,4-triazine 18 at a high temperature (approximately 500 °C) for many hours gave 2,4,6-trifluoro-1,3,5-triazine 55, as the ring transformation product, and perfluoropropylene (Scheme 23) [12].

Scheme 23

Transformation of 3,5,6-trifluoro-1,2,4-triazine 18 under heating

A rather complicated mixture of fluorinated compounds, including triazine 55, is formed on heating of 4-dichloroamino-2,3,5,6-tetrafluoropyridine at 550 °С [41]. Such transformations are supposed to occur due to decomposition of one fluorinated heterocycle into fluorocyane followed by the construction of a new fluorinated triazine system (Scheme 24).

Scheme 24

Transformation of 4-dichloroamino-2,3,5,6-tetrafluoropyridine

3.3.3 Direct Fluorination

Fluorination of the ring has been shown to take place on treatment of perfluoroalkyl-1,3,5-triazines 58 with fluorine, thus resulting in the formation of a mixture of cyanuric fluoride 55 in addition to mono- and difluoro-1,3,5-triazines 59 and 60 (Scheme 25) [42].

Scheme 25

Fluorination of perfluoroalkyl-1,3,5-triazines 58

3.3.4 Dehalogenation of Cyclic Halogenoamidines

Fluoroanhydride of cyanuric acid 55 was formed in a high yield by the defluorination reaction of perfluoro-1,3,5-triazacyclohexane 61a by action of ferrocene (Scheme 26) [43]. Dehalogenation of (NClCF₂)₃ 61b under the action of ClSC(O)CF₃ was reported (Scheme 26) [44].

Scheme 26

Dehalogenation of cyclic halogenoamidines

3.3.5 Replacement of Chlorine Atoms with Fluoride Ion

Replacement of chlorine atoms with fluoride ion is one of the main synthetic procedure to obtain fluorinated 1,3,5-triazines. Being depending on the reaction conditions and the nature of reagents, the reactions of cyanuric chloride with various fluorinating reagents lead to mono-, di- and trifluoro-1,3,5-triazines (Scheme 27, Table 4) [45–56]. A mixture of SbF₃, SbCl₃ and Cl₂ is an appropriate agent for total fluorination of cyanuric chloride 62. Formation of trifluoroderivative 55 proceeds selectively in high yield under reaction of 62 with HF and N(C₂H₅)₃ in 1-methyl-pyrrolidinone at room temperature.

Scheme 27

Fluorination of cyanuric chloride 62

Table 4 Fluorination of cyanuric chloride

It is worth to note that chlorine atoms both in the ring and in CCl₃ groups of compound 65 are subjected to the replacement reaction (Scheme 28) [47].

Scheme 28

Synthesis of fluorinated 1,3,5-triazines 66

Fluorination of 2,3-diamino-6-chloro-1,3,5-triazines 67 with anhydrous KF has been shown to proceed smoothly in the presence of catalytical amounts of dicyclohexano-18-crown-6 (Scheme 29). Fluoro-1,2,4-triazines 68 were obtained in 93–99 % yields [7]. 2-Isopropylamino-4-ethylamino-6-fluoro-1,2,4-triazine 68 (R¹ = NH(i-C₃H₇), R² = C₂H₅) was isolated in 66 % yield under similar reaction conditions with triethylpentadecylammonium bromide as the phase transfer catalyst [7].

Scheme 29

Synthesis of fluorinated 1,3,5-triazines 68

3.3.6 The Baltz-Schiemann Reaction

2,4-Difluoro-1,3,5-triazine 70 was obtained by diazotization of the corresponding diamino compound 69 followed by thermolysis of the resulting diazonium tetrafluoroborate (Scheme 30) [57].

Scheme 30

Synthesis of fluorinated 1,3,5-triazines 70

The main synthetic approaches to trifluoromethyl substituted 1,3,5-triazines are trimerization of CF₃CN [58], cyclocondensation process based on imidoylamidines [59], cyanoguanidines [60] or biguanides [61] and also fluorination of trichloromethyl-1,3,5-triazines [47, 62].

For example, trifluoroacetonitrile 73 trimerizes to give 2,4,6-tris(trifluo-romethyl)-1,3,5-triazine 74 [63]. Monomeric CF₃CN was generated by reaction of diisopropylcyanamide 71 and trifluoroacetic anhydride [58] or from perfluoroethyldimethylamine 72 [6] (Scheme 31).

Scheme 31

Synthesis of 2,4,6-tris(trifluoromethyl)-1,3,5-triazine 74

Di(pentafluorocyclopropanyl)-substituted triazine 76 was prepared from nitrile 75 by reaction with ammonia followed by acylation-cyclization with trifluoroacetic anhydride (Scheme 32) [64].

Scheme 32

Synthesis of fluorinated 1,3,5-triazine 76

By the method of acylation-cyclodehydration of imidoylamidines 77 1,3,5-triazines 78 have been prepared (Scheme 33) [59]. Synthesis of 2-trifluoromethyl-4,6-bis(2,3-dichloro-1,1,2,3,3-pentafluoro)-1,3,5-triazine from 3,4-dichloro-2,2,3,4,4-pentafluorobutyronitril, NH₃ and trifluoroacetic anhydride was reported [65].

Scheme 33

Synthesis of fluorinated 1,3,5-triazine 78

2-Amino-4-trifluoromethyl-6-methoxy-1,3,5-triazine 80 can be easily prepared starting from cyanoguanidine 79 by a zinc chloride-catalysed process (Scheme 34) [60].

Scheme 34

Synthesis of fluorinated 1,3,5-triazine 80

Cyclocondensation of substituted biguanides 81 with methyl trifluoroacetate in the presence of catalytic amounts of sodium ethylate gave 2-amino-4-(substituted amino)-6-trifluoromethyl sym-triazines 82 (Scheme 35) [66–72]. A rapid and efficient synthesis under microwave irradiation has been developed for various substituted 1,3,5-triazines that can serve as versatile building blocks for both supramolecular and medicinal chemistry [61, 73].

Scheme 35

Synthesis of fluorinated 1,3,5-triazines 82

2-Imino-1,3-thiazetidine 83 was used as precursor in the synthesis of triazine 85 (Scheme 36) [74]. Reaction of 83 with trifluoroacetic anhydride leads to 2-trifluoromethylimino-3-(4-chlorophenyl)-1,3-thiazetidine 84, the treatment of 84 with S-methylisothiourea sulfate results in trifluoromethyl substituted triazine 85.

Scheme 36

Synthesis of fluorinated 1,3,5-triazine 85

2,4,6-Tris(trichloromethyl)-1,3,5-triazine 86 was transformed to trifluoromethylderivative 74 under the action of SbF₅ (Scheme 37) [62].

Scheme 37

Synthesis of 2,4,6-tris(trifluoromethy1)-1,3,5-triazine 74

4 Chemical Properties

The main reactions of fluorine-containing triazines are connected with attack on the carbon atom bearing fluorine, which results to replacement of the fluorine atom or cycle transformation.

4.1 Chemical Properties of 1,2,3-Triazines

Aromatic amines are capable to displace fluorine atoms in trifluroro-1,2,3-triazine 2 to give 4-substituted products 87 (Scheme 38) [75–77].

Scheme 38

Amino-defluorination process in trifluroro-1,2,3-triazine 2

Being UV-irradiated 4,5,6-trifluoro-1,2,3-triazine 2 is transformed into trifluoroazet 88 (Scheme 39) [78].

Scheme 39

Transformation of 4,5,6-trifluoro-1,2,3-triazine 2 under UV-irradiation

4.2 Chemical Properties of 1,2,4-Triazines

A number of transformations involving the displacement of fluorine atoms in fluorinated 1,2,4-triazines have been described. In case of 3,5,6-trifluoro-1,2,4-triazine 18 the leaving mobility of fluorine atoms in these displacement reactions is decreasing as follows F⁵ > F³ > F⁶. In accordance with this sequence the hydrolysis of 1,2,4-triazine 18 results in the formation of 6-fluoro-1,2,4-triazine-3,5-(2Н,4Н)-dione 89 (Scheme 40) [20]. The reaction of compound 18 with methanol in a sealed tube afforded 3,5-dimethoxy-6-fluoro- and 5,6-dimethoxy-3-fluoro-1,2,4-triazines 90 and 91 in the ratio 1:2 in total yield of 46 % [20]. Reactivity of 3,5,6-trifluoro-1,2,4-triazine 18 towards N-nucleophiles can be illustrated by the reactions with ammonia (leading to 5-amino-3,6-difluoro-1,2,4-triazine 92), diethylamine and 4-chloroaniline. The reaction of 18 with diethylamine affords two products, 5-diethylamino-3,6-difluoro-1,2,4-triazine 93 and 3,5-bis(diethylamino)-6-fluoro-1,2,4-triazine 94 (Scheme 40) [20], while the only compound 95 was obtained from the reaction of 18 with 4-chloroaniline.

Scheme 40

Displacement of fluorine atoms in fluorinated 1,2,4-triazines

It is worth to note that the replacement of fluorine atoms in 3,5,6-trifluoro-1,2,4-triazine 18 by action of bis(trifluoromethyl)amino anion (the latter can be obtained from perfluoro-2-azapropene and cesium fluoride) provides a mixture of mono-, di- and trisubstituted perfluorodimethylamino-1,2,4-triazines 96–98 (Scheme 41) [12].

Scheme 41

Interaction of 18 with bis(trifluoromethyl)amino anion

When 3,5,6-trifluoro-1,2,4-triazine 18 was kept in vacuo at -20 °C for 1 month in a Pyrex ampoule the dimeriration product, 3,6-difluoro-5-(3,5,5,6-tetrafluoro-4,5-dihydro-1,2,4-triazine-4-yl)-1,2,4-triazine 99, was shown to be formed (Scheme 42) [20]. The dimer 99 was passed over potassium fluoride at 250 °C to form triazine 18.

Scheme 42

Dimeriration of 3,5,6-trifluoro-1,2,4-triazine 18

Incorporation of perfluoroisopropyl groups into trifluoro-1,2,4-triazine takes place smoothly in the reaction of 18 with hexafluoropropene and cesium fluoride without of any solvent [12]. When the reaction is carried out at 125 °С for 25 min a mixture of 5-perfluoroisopropyl-derivative 100 and 3,5-di- and 3,5,6-tri (perfluoroisopropyl)-1,2,4-triazines 101, 102 are formed (Scheme 43), while the formation of trisubstituted derivative 102 (yield 52 %) takes place on heating at 110 °С for 2 h.

Scheme 43

Reaction of 18 with hexafluoropropene

A number of ring transformations and reactions involving the displacement of substituents such as SMe-group in trifluoromethyl containing 1,2,4-triazines have been described. N-substituted cyanamides participate in cycloaddition exclusively across C-5/N-2 of the 1,2,4-triazine nucleus 103 yielding the bicycle 104 as nonisolable intermediate. Elimination of trifluoroacetonitrile leads to the 1,3,5-triazines 105 as the main reaction products. Besides, the 1,2,4-triazines 106 are formed by loss of methyl thiocyanate (Scheme 44) [28].

Scheme 44

Transformations and displacement of SMe-group in trifluoromethyl containing 1,2,4-triazines

When the 5-methoxy derivative 107 was reacted with enamine in refluxing chloroform, pyridine 108 was obtained (Scheme 45) [28]. Diels-Alder reaction of triazine 5 with norbornadiene leads to formation of pyridine 109 (Scheme 45). Low yield of 109 clearly shows that this Diels-Alder reaction proceeds in an inverse electron demand manner [28].

Scheme 45

Diels-Alder reactions of triazine 107

Annulated pyridines 112 or 113 were formed on heating of triazines 110 or 111 bearing at position 3 NH-(CH₂)_n-C ≡ CH, O-(CH₂)_n-C ≡ CH or S-(CH₂)_n-C ≡ CH groups in chlorobenzene or diphenylether (Scheme 46) [23, 24]. This transformation is an example of intramolecular Diels-Alder reaction of 1,2,4 triazines accomplished with nitrogen elimination.

Scheme 46

Transformations of triazines 110 or 111

Nucleophilic displacement of the thiomethyl group in triazines 30 is described (Scheme 47) [23, 24, 80]. This reaction is valuable approach to broad variety of trifluoromethylated triazines.

Scheme 47

Nucleophilic displacement of the thiomethyl group in triazines 30

4.3 Chemical Properties of 1,3,5-Triazines

The chemistry of fluorinated 1,3,5-triazines is not as well studied as the chemistry of their chloro derivatives. In case of fluorotriazines the reactions directed on the ring nitrogen atoms, displacement of fluorine atoms and reactions on carbon atoms on the ring with retention of the fluorine atoms appear to be the most characteristic ones. In this section the N-alkylation and N-acylation reactions, as well as replacement of fluorine atoms by a variety of nucleophiles will be considered. Metallation of fluorotriazines and synthesis on the basis of organometallic compounds, as well as the cross-coupling reactions were described. Also several examples of photochemical reactions and transformations are presented.

4.3.1 Replacement of Fluorine Atoms

Nucleophilic replacement of fluorine atoms in azaaromatic compounds can be performed under rather mild reaction conditions, and this method is certainly one of the most effective approaches to their functionalization. Incorporation of perfluoroisopropyl groups into 2,4,6-trifluoro-1,3,5-triazine 55 proceeds smoothly by action of hexafluoropropene and cesium fluoride without of any solvent (Scheme 48, Table 5) [11, 81–83]. Trisubstituted derivatives 118 were formed in 52 % yield at 110 °С during 2 h. If reaction was carried out at 125 °С within 25 min the mixture of trisubstituted derivative 118 and 5-perfluoroisopropyl-1,2,4-triazine 115 and 3,5-di-(perfluoroisopropyl)-1,2,4-triazine 116 (Scheme 48) was isolated.

Scheme 48

Incorporation of perfluoroisopropyl groups into 1,3,5-triazine 55

Table 5 The reaction of cyanuric fluoride 55 with hexafluoropropene

It is worth noting that 2,4,6-trifluoro-1,3,5-triazine 55 is less active than cyanuric chloride in the reaction of with aniline (Scheme 49) [84]. N,N-Dimethylaniline and 1,8-bis(dimethylamino)naphthalene react with cyanuric fluoride 55 as C-nucleophiles to give 2,4-difluoro-6-(4-dimethylaminophenyl)-1,3,5-triazine 119 and 1,8-bis(dimethylamino)-4,5-(2,4-difluoro-1,3,5-triazinyl-6)naphthalene 123 (Scheme 49) [8]. Contrary to it, N,N-diethylaniline, and ortho- or para-substituted N,N-dimethylanilines react with trifluoro-1,3,5-triazine 55 as N-nucleophiles. These reactions are accompanied by elimination of N-alkyl group and the formation of 2,4-difluoro-6-arylamino-1,3,5-triazines 120–122 (Scheme 49).

Scheme 49

Reactions of cyanuric fluoride 55

In a similar way, on treatment of perfluoro-1,3,5-triazine 115 with dimethylaniline 2-fluoro-4-heptafluoroisopropyl-6-(4-dimethylaminophenyl)-1,3,5-triazine 124 was obtained in 36 % yield (Scheme 50) [8].

Scheme 50

Formation of triazine 124

Replacement of fluorine atoms in triazines 55, 115 and 115a take place also by action of pyrrole, N-methylpyrrole and N-methylindole resulting in the formation of the corresponding 1,3,5-triazines 125–130 (Scheme 51) [8].

Scheme 51

Replacement of fluorine atoms in triazines 55, 115 and 115a

In a similar manner, the reaction of cyanuric fluoride 55 with tris(trimethylstannyl)amine in dry ether at 0 °C leads to the formation of 2,4-difluoro-6-[di(trimethylstannyl)]-amino-1,3,5-triazine 131 (Scheme 52) [5].

Scheme 52

Reaction of cyanuric fluoride 55 with tris(trimethylstannyl)amine

Reaction pathway for substitution of fluorine atom in 2,4,6-trifluoro-1,3,5-triazine 55 under the action of trifluoromethyl anion has been studied [4] (Scheme 53). Since C ₃ N ₃ F ₄ ⁻ can act as a potential fluoride donor, initial reaction takes place between C ₃ N ₃ F ₄ ⁻ (A) and Me₃SiCF₃ forming a reactive silane, a source of the elusive CF₃ anion, which can then attack the neutral triazine (Scheme 53). Through A → B rearrangement, elimination, and further addition reactions the observed. As a result products 132, 133 and 134 are formed (Scheme 53).

Scheme 53

Substitution of fluorine atoms in 2,4,6-trifluoro-1,3,5-triazine 55

The anion C₃N₃F₄ (135) was prepared using TASF as the fluoride source via a simple fluoride addition to a carbon centre of C₃N₃F₃. After removal of the solvent and all volatile products in vacuo, a colourless solid was isolated in quantitative yield (Scheme 54). The compound shows two signals in the ¹⁹F NMR spectrum, due the presence of two magnetically nonequivalent fluorine groups. This indicates the absence of fast intramolecular fluorine exchange, which was found e.g. in cyclic fluorophosphazenates [4, 85].

Scheme 54

Fluoride addition to a carbon centre of C₃N₃F₃

2,4,6-Trifluoro-1,3,5-triazine 55 reacts with 2,3-dihydro-1,3-isopropyl-4,5-dimethylimidazol-2-ylidene tetrafluoroborate 136 resulting in replacement of one fluorine atom to yield difluoro-1,3,5-triazine 137 (Scheme 55) [8].

Scheme 55

Interaction of 55 with 2,3-dihydro-1,3-isopropyl-4,5-dimethylimidazol-2-ylidene tetrafluoroborate 136

The reaction of 2,4-difluoro-6-(1-methylpyrrolyl-2)-1,3,5-triazine 138 with iodpropargyl alcohol affords the product 139 due to replacement of one fluorine atom (Scheme 56) [86].

Scheme 56

Formation of fluorotriazine 139

Deoxygenative ability of cyanuric fluoride 55 for sulfoxides has been shown (Scheme 57) [87]. In contrast to cyanuric chloride no concomitant formation of undesired halogenated sulfides forms due to relatively low nucleophilicity of the fluoride ion.

Scheme 57

Deoxygenative ability of cyanuric fluoride 55

Replacement of fluorine atoms in 2,4-difluoro-6-heptafluoro-iso-propyl- and 2-fluoro-4,6-bis(heptafluoro-iso-propyl)-1,3,5-triazines 115 and 116 takes place quantitatively on reflux of 115 or 116 with methanol, isopropanol or phenols in acetonitrile (Scheme 58) [83].

Scheme 58

Replacement of fluorine atoms in compounds 115 and 116

Heating of compound 115 with cyclohexanol has been established to afford 2,4-dicyclohexyloxy-6-heptafluoro-iso-propyl-1,3,5-triazine 141, while 2-cyclohe-xyloxy-4,6-bis(heptafluoro-iso-propyl)-1,3,5-triazine 142 was formed from compound 116 (Scheme 59) [83].

Scheme 59

Synthesis of cyclohexyloxy-derivatives of fluorinated triazines

It is known [88] that replacement of fluorine atoms in cyanuric fluoride 55 with tetra-O-benzyl- or tetra-O-acetylglucose takes place consequently with the formation of di- and trisubstituted 1,3,5-triazines 143 and 144 (Scheme 60).

Scheme 60

Replacement of fluorine atoms in 55 with tetra-O-benzyl- or tetra-O-acetylglucose

The ability of fluorine atoms in cyanuric fluoride 55 to be replaced by action of O-nucleophiles can be exploited for the synthesis of calix[2]arene-[2]triazines 146 and 147 [89]. The reaction of 55 with 1,3-phenylenedimethanol leads to the formation of fluoro compound 145, and then to calix 146. Remaining fluorine atoms in the triazine fragments of calix 146 can be replaced easily by action of amines (Scheme 61).

Scheme 61

Synthesis of calix[2]arene-[2]triazines 146 and 147

Reaction of 2,4,6-trifluoro-1,3,5-triazine 55 with 1-amino-8-naphthol-3,6-disulfonic acid provides 1-(4′,6′-difluoro-1′,3′,5′-triazyn-2′-yl)amino-8-naphthol-3,6-disulfonic acid in 95 % yield [90]. Substitution of fluorine atoms in fluorotriazine dye 148 with the alkoxides, generated from tetrahydropyran-2-methanol, α- and β-methylglucopyranoside, D-sorbitol, D-mannitol and D-glucose, has been found to lead to the corresponding conjugates 149 (Scheme 62) [91].

Scheme 62

Synthesis of derivatives 149

Replacement of one of fluorine atoms in 2,4-difluoro-6-(4-arylazophenyl)-amino-1,2,4-triazines 150 with methoxy or amino group is used for the synthesis of fluorotriazine dyes 151 and 152, which are effective for cotton coloring (Scheme 63) [39, 40].

Scheme 63

Synthesis of fluorotriazine dyes 151 and 152

The chemical process of replacement of fluorine atoms has found its practical application for fixing of yellow and dark blue fluorotriazine dyes 153 on cellulose (Scheme 64) [92–94].

Scheme 64

Fixing of yellow and dark blue fluorotriazine dyes 153 on cellulose

Replacement of three fluorine atoms in cyanuric fluoride 55 was applied for construction biologically active molecules of deazapurine type [95]. Cyanuric fluoride mediated reaction of chiral N^α-tritylamino acids leads to the corresponding acyl fluorides 155 which are powerful acylating agents for peptide synthesis (Scheme 65) [96].

Scheme 65

Acyl fluorides 155, powerful acylating agents for peptide synthesis

Reactions of replacement of SMe [79], trichloromethyl [97] or trifluoromethyl groups represent effective approaches for modifications of trifluoromethyl containing 1,3,5-triazines. Direct vapor-phase fluorination of tris-(trifluoromethy1)-s-triazine 74 has been studied and was found that the perfluoroalkyl groups of 74 were progressively replaced by fluorine to give mixture of 2,4-difluoro-6-trifluoromethyl-s-triazine 156 and 2,4-bis-(trifluoromethyl)-6-fluoro-s-triazine 157 (Scheme 66) [98]. Photoirradiation of tris-(trifluoromethy1)-s-triazine in cyclohexane leads to a mixture of adduct 158 and dihydrocompound 159 (Scheme 66) [99].

Scheme 66

Transformations of tris-(trifluoromethy1)-s-triazine

Diamine compound 161 was obtained in the reaction of tris(trifluoromethyl)-s-triazine 74 with ammonia. The reaction was presumed to proceed through addition-elimination mechanism as shown at Scheme 67 from the fact that 1,4-adduct was obtained, when ammonia gas was bubbled into the ether solution of the s-triazine [100].

Scheme 67

Reaction of tris(trifluoromethyl)-s-triazine 74 with ammonia

Transformation of diamino-derivative 161 to N-oxide 162 was reported via oxidation with peracetic acid [101]. 2,4,6-Tris-(trifluoromethyl)-1,3,5-triazine 74 reacts with ethanol an the presence of hydrochloric acid to form ethyl trifluoroacetate [62].

5 Application of Fluorinated Triazines

2-R-6-Fluoro-1,2,4-triazolo[5,1-c][1,2,4]triazin-7(4Н)-ones 10 were shown to be active against flu A virus [16], while 1′-substituted carbonucleosides 163 bearing the fragment of pyrrolo[5,1-f][1,2,4]triazine were reported to possess antiviral activity (Scheme 68) [102].

Scheme 68

Annelated fluorotriazines possessing antiviral activity

2,4,6-Trifluoro-1,3,5-triazines are widely used as starting materials for the synthesis of dyes, sensors, and biologically active compounds. A series of synthetic dyes containing one or two fluorine atoms, for example 148 [91], 151, 152 [39, 45], 54 [86, 92, 94] have been described. Also patents [103–112] are dedicated to fluorotriazine dyes. The reaction of cyanuric fluoride with amines has been used for the synthesis of analogs of the anticancer drug trimelamol which is 2,4,6-tris-[(hydroxymethyl)methylamino]-1,3,5-triazine. That is why cytotoxic properties of its analogs, such as 2-fluoro-4,6-bis[(2,2,2-trifluoroethyl)amino]-1,3,5-triazine and 2-fluoro-4,6-bis(propargylamino)-1,3,5-triazine, towards a variety of tumor cell lines in vitro have been studied. They revealed that 2,4,6-trisubstituted derivatives proved to be more active than 2-fluoro-4,6-disubstituted analogs [113]. Compound 164 was shown to inhibit enzyme Akt1-kinase [114], while aminotriazine 165 was found to act as 5-HT₇ receptor antagonist (binding affinity K_i = 10 nM) [115]. 6-(4-Bromobenzylamino)-2-methyl-4-trifluoromethyl-1,3,5-triazine 166 was found to possess strong pre- and post-emergence herbicidal activities (Scheme 69) [97].

Scheme 69

Structure of fluorotriazines 164–166

3-(4,6-Difluorotriazinyl)amino-7-methoxycoumarin (FAMC, 167) is useful for determination of antiviral drug amantadine by high-performance liquid chromatography. Amantadine was derivatized quantitatively into fluorescent compound through the amino group treatment with FAMC, this method gave satisfactory results with respect to recovery and precision to quantify amantadine spiked in urine [116]. 3-(Difluoro-1,3,5-triazinyl)-1-(ethylthio)-2-n-propylbenz[f]isoindole (168), which reacts with phenolic hydroxyl groups, can use as a fluorescence derivatization reagent for estrogens in high-performance liquid chromatography (Scheme 70) [117].

Scheme 70

Structure of fluorotriazines 167, 168

Receptor for naphthalene diimide guest with efficient quenching of prophyrin fluorescence was obtained by replacement of two fluorine atoms in compound 169 by n-pentylamine [118]. Perfluoroalkyl-s-triazines 170 can be used as high-temperature fluids (Scheme 71) [119].

Scheme 71

Structure of fluorotriazines 169, 170

6 Conclusion

It is worth to mention that triazines and their fluorinated derivatives continue to be important for applications in medicine as well as intermediates for dyes and sensors.