Ureas as new nucleophilic reagents for S NH amination and carbamoyl amination reactions in the 1,3,7-triazapyrene series

The ability of urea anions to react as nucleophiles with 1,3,7-triazapyrenes has been investigated. It was found that, against all expectations, the products of the substitution of hydrogen (S NH ) by an amino group were isolated in good yields. The reactions proceed in anhydrous DMSO solution at room temperature. However, when anions of mono substituted ureas containing bulky substituents were used, the products of previously unknown S NH reactions of alkyl carbamoyl amination were obtained.


Introduction
][9][10] In the case of electron-deficient substrates, such as azines and nitroarenes, the nucleophilic aromatic substitution of hydrogen (S N H ), 11,12 including its oxidative [13][14][15] and vicarious 16,17 versions, is an attractive alternative.An oxidative nucleophilic substitution of hydrogen enables one to carry out the process following the principles of green chemistry, such as atom efficiency, shorter synthesis, less hazardous chemicals, waste prevention, etc. 18,19 This methodology does not require any preliminary introduction of a classical leaving group into an aromatic substrate or reagent and does not need expensive catalysts or ligands.Mechanistically, it consists of σ H -adduct formation and its subsequent oxidative rearomatization (Scheme 1).

Scheme 1. Oxidative amination of azines.
As a rule, the second step is rate-limiting, because the hydride ion, which formally has to be lost, is a very poor leaving group.Numerous investigations have shown that spontaneous aromatization of such σ H -complexes occurs quite rarely.Usually, elimination of hydride ion is strongly facilitated by adding a special external oxidant.In spite of continuing discussion regarding hydride ion elimination, the stepwise mechanism involving successive electronproton-electron (EPE) transfer appears to be the most plausible pathway. 20In the presence of KMnO 4 electron-deficient azines and nitroarenes can be smoothly aminated by potassium amide in liquid ammonia or with liquid ammonia itself. 15n our previous reports, we have shown that 1,3,7-triazapyrene (1a) displays special properties due to the unique fusion of the carbocyclic and heterocyclic rings.These properties include an unusual ease of oxidative nucleophilic substitution of hydrogen, such as hydroxylation, 21 alkoxylation, 22,23 amination, 21 alkylamination, 24 arylation, 25,26 arylamination 27 and even amidation. 28Another unusual feature of 1,3,7-triazapyrenes is that the greater part of these transformations can be carried out in aqueous media.Note that peri-annelated azines, including 1,3,7-triazapyrene, are now of practical interest for electronic applications, especially as organic light-emitting diodes (OLEDs). 29,30t is known that the urea molecule is a weak electrophile and a weak ambident nucleophile.2][33][34] Ureas were used earlier as specific nitrogen nucleophiles in the palladium(II)catalyzed amino carbonylation of unsaturated amines, 35 in intramolecular cyclisation of ureido acids and esters, 36 in the synthesis of a di-and triarylamines by interaction with unactivated aryl halides under palladium catalysis 37 and in Biginelli reactions. 38n the course of this study, and taking into account the results of oxidative nucleophilic amidation of 1,3,7-triazapyrene, 28 we have tested the possibility of S N H carbamoyl amination of this heterocycle using urea as the nucleophilic reagent.

Results and Discussion
Firstly, we studied the reaction of 1,3,7-triazapyrene (1a) with urea.It does not occur in a wide temperature range neither in polar (DMSO, ethanol, acetonitrile), or in non-polar solvents (toluene, xylene).The obvious reason for this is the low nucleophilicity of the reagent.As in the cases of aryl amination 27 and amidation 28 reactions, in order to increase its nucleophilicity we generated a urea anion by the action of sodium hydride in anhydrous dimethyl sulfoxide.
It is known that DMSO is a versatile and powerful solvent which provides maximum nucleophilicity of an anionic nucleophiles due to the absence of the solvate shell.The use of DMSO makes it possible to carry out this reaction at room temperature, without isolation from the air oxygen.
One can assume that the process progresses according to Scheme 2, but intermediate 2a enters then the conversion process into amine 3a, for example by alkaline hydrolysis during isolation.
Interestingly, though not being a strong nucleophile, the urea anion readily enters into an oxidative nucleophilic substitution of hydrogen with 1,3,7-triazapyrene.It appears that air oxygen is the oxidant for this reaction.
To confirm this, we performed the reaction in DMSO under argon.In this case only traces of product 3a were detected by TLC.Moreover a mixture of oligomerization products was obtained where the starting 1,3,7-triazapyrene has reacted completely under these conditions.Thus, one can conclude that 1,3,7-triazapyrene itself is not an effective acceptor of hydride ion and the decisive factor for rearomatization of σ H -adduct 4 is crucial access to air oxygen (Scheme 3).It is known that molecular oxygen is a very common oxidant for oxidation of σ Hadducts; it appears however that it operates efficiently only in the cases where anionic σ Hadducts can be further deprotonated by a base present in the system; thus, it is the corresponding dianion that is actually oxidized. 12n accordance with this it can be assumed that carbamoyl amination of 1,3,7-triazapyrene involves the formation of σ H -complex 4, its subsequent NH-deprotonation and oxidative aromatization of the dianion 5 to the anion 6 (Scheme 3).
It is relevant to ask whether alkaline hydrolysis during isolation is the reason for the subsequent transformation of the intermediate 2a into the final isolated product 3a?To test this, we analyzed a sample of the reaction mixture before isolation, by high resolution mass spectrometry (HRMS).This detected the presence mainly of a molecular ion corresponding to product 3a.The molecular ion of the intermediate 2a was also observed, but with a small content.Note, that in a separate experiment we showed that in the absence of 1,3,7-triazapyrene, urea anion in DMSO no change occurs at room temperature over a long period.
We believe that the final step in the synthesis of amine 3a includes the reversible conversion of anion 6 into anion 7 followed by elimination of 6-amino-1,3,7-triazapyrene anion 8 as a better leaving group in comparison with amide anion.Addition of water to the reaction mixture leads to protonation of the anion 8 to form product 3a (Scheme 3).Scheme 3. The postulated pathway for formation of compound 3a.
So, in the absence of oxygen, neither σ H -complex 4 nor dianion 5 are stable at room temperature and undergo oligomerization process.Repeated amination reaction does not occur because the anion 6 is not able to react further with nucleophiles.Thus the urea anion plays the dual role in this reaction acting as a nucleophilic agent and a base.
Amination of other 1,3,7-triazapyrenes in the system urea/NaH/DMSO produced similar results (Scheme 2, Table 1,   a In all experiments the use of six equivalents of the corresponding urea and six equivalents of NaH was found to be optimal for these procedures. The exception in this series was 2-methyl-1,3,7-triazapyren-6-amine (3g), which was obtained with a yield of only 5%.In our opinion, this was caused by deprotonation of the 2-CH 3 group of the starting compound 1g with subsequent oligomerization of the quinoid anion obtained.This process proceeds even faster in the absence of urea, i.e. in the system of compound 1g/DMSO/NaH.
Thus, according to the mechanism which is shown in Scheme 3 for the synthesis of compounds 3, this is a novel version of oxidative S N H reactions.Its distinguishing feature is the spontaneous transformation of a nucleophilic group of the S N H product obtained, i.e. in our case converting of the carbamoyl amino group into the amino group.Therefore, the urea anion may be viewed as a new useful amination reagent for some π-deficient substrates.
In contrast to the intermediates 2 (Scheme 2), compounds 9a,b proved to be more stable than their analogs.The probable cause of their comparative stability is spatial interference for the deprotonation of NHR groups which is necessary for the further conversions according to Scheme 3.However, they are unstable when heated in the crystalline state and in solution.For example, both these compounds under slow heating above the melting temperature were quantitatively converted into 1,3,7-triazapyren-6-amine (3a).Our attempts to recrystallize compound 9a from xylene, ethanol or benzene, as well as upon chromatographic separation on silica gel, led to partial transformation into amine 3a.So, when a solution of 1-tert-butyl-3-(1,3,7-triazapyren-6-yl)-urea (9a) in xylene was refluxed for one hour, it was converted into 1,3,7-triazapyren-6-amine (3a) in 91% yield.Probably the process proceeds in accordance with Scheme 3 wherein the the pyridine type nitrogen atoms of 1,3,7-triazapyrene ring function as base.
Note, that the compounds 9a,b represent the first example of the earlier unknown reaction of alkyl carbamoyl amination, i.e. the reaction of the direct oxidative nucleophilic substitution of hydrogen by an alkyl urea fragment.
The formation of compound 10 in the reaction with an anion of tert-butylurea indicates that it can react partly as O-nucleophile to form σ H -complex 11.As a result of the subsequent conversions, which are shown in Scheme 5, compound 10 is formed.Scheme 5.The suggested route for 7H-1,3,7-triazapyren-6-one (10) formation.
The different behavior of the two sterically hindered ureas is probably the result of their different spatial conformations which undergo the reaction with 1,3,7-triazapyrene.In any case, when the reaction of 1,3,7-triazapyrene (1a) with (1,1-dimethylpentyl)urea anion was carried out at 70-75 °C only traces of product 9b were detected by TLC and the sole isolated product was above-mentioned 7H-1,3,7-triazapyren-6-one (10) in 72% yield.Thus the chemoselectivity of the reactions involving the hindered ureas, i.e. whether they will react as N-or O-nucleophiles, depends upon the predominant conformer stability under the reaction conditions.
We have shown further that, as in the case of secondary benzamides, 28 1,3-dimethyl urea, containing two secondary amido groups does not react with 1,3,7-triazapyrene under the same conditions.This is due to spatial hindrance for S N H adduct formation as well as the impossibility to obtain its dianion which could then be oxidized by air oxygen at the aromatization stage (Scheme 3).
Reactions proceed in anhydrous DMSO solution at room temperature without protection from the air.When monosubstituted ureas with bulky substituents were used the first products of the earlier unknown S N H reactions of alkyl carbamoyl amination were obtained.

Experimental Section
General.All melting points were determined in glass capillaries and are uncorrected.The 1 H and 13 C NMR spectra were recorded on a Bruker Avance HD 400 spectrometer in the solvent indicated.The chemical shifts are given in parts per million (ppm) relative to residual solvent signals. 39All coupling constants are in Hertz.High-resolution mass spectra (HRMS) were registered on a Bruker UHR-TOF Maxis TM Impact instrument using the ESI technique.IR spectra were recorded on a Shimadzu IRTracer-100 as thin films.Starting compounds 1a,g, 40 1b,c, 26 1d,e, 25 and 1f 41 were obtained by known procedures.Sodium hydride as a 60% w/w dispersion in mineral oil was used as such (Merck).Other commercially available chemicals were also used without additional purification.The progress of the reactions was monitored by thin-layer chromatography (TLC), using Silufol UV-254 silica gel plates.The identification of samples from different experiments was accomplished by mixed mps or by superposition their IR spectra.Copies of the 1 H NMR, 13 C NMR and IR spectra of all new compounds are available as supporting information.

General Procedures for the Synthesis of 1,3,7-triazapyren-6-amines 3a-g
The reaction vessel must be protected from the air moisture, but not from air oxygen.To a solution of the corresponding urea (3 mmol) in anhydrous DMSO (5 mL), NaH (3 mmol, based on active ingredient) was added at rt.When hydrogen bubbling ceased, the corresponding 1,3,7triazapyrene (1a-g; 0.5 mmol) was added.The mixture was stirred vigorously at rt during the time indicated in Table 1.Then H 2 O (20 mL) was added and the precipitate obtained was filtered off, washed with H 2 O and dried.1,3,7-Triazapyrene-6-amine (3a).Brown solid (97 mg, 88%, using urea and 63 mg, 57%, using phenylurea), subl.p. 250 °C (from EtOH), ref. 21 (1,1-Dimethylpentyl)-urea. Finely powdered urea (6 g, 0.1 mole) was added with stirring to concentrated H 2 SO 4 (19.3 g, 0.198 mole, d = 1.84), cooled in an ice bath, at such a rate that the temperature remained between 20-25 °C.Then 2-methylhexan-2-ol (23.2 g, 0.2 mol) was added dropwise maintaining the mixture temperature within the same range.After the addition was completed the mixture was stirred for an additional 30 minutes, allowed to stand at rt overnight, and then poured with stirring onto cracked ice (~ 150 g).Without removal of the precipitate, the mixture was made alkaline to Congo red indicator by adding slowly with stirring a solution of NaOH (16 g in 75 mL of H 2 O).The mixture was cooled with an ice bath to keep the temperature below 25 °C.The mixture was stirred in the ice bath until the temperature fell to about 15 °C, at which point the precipitate was filtered off and washed with cold H 2 O (2 x 100 mL).The crude product was recrystallized from H 2 O. White solid (7.2 g, 45%), mp 105-106 °C (from H 2 O). 1   (10).The reaction vessel must be protected from the air moisture, but not from air oxygen.To a solution of the tert-butylurea (174 mg, 3 mmol) in anhydrous DMSO (5 mL) NaH (120 mg, 3 mmol, based on active ingredient) was added at rt.When hydrogen bubbling ceased, 1,3,7-triazapyrene (1a) (103 mg, 0.5 mmol) was added.The mixture was stirred at rt for 7 h, poured onto crushed ice (50 g), and allowed to warm to rt.The precipitate obtained was filtered off, washed with cold H 2 O, and dried.The dry product was recrystallized from CH 2 Cl 2 (~ 50 mL) to form 1-(tert-butyl)-3-(1,3,7-triazapyren-6-yl)urea (9a).Pure 7H-1,3,7-triazapyren-6-one (10) was obtained by extracting the aqueous filtrate with 1-butanol (3x3 mL) and distilling off the solvent under reduced pressure followed by recrystallization from EtOH.