Mono- and Diamination of 4,6-Dichloropyrimidine, 2,6-Dichloropyrazine and 1,3-Dichloroisoquinoline with Adamantane-Containing Amines †

N-heteroaryl substituted adamantane-containing amines are of substantial interest for their perspective antiviral and psychotherapeutic activities. Chlorine atom at alpha-position of N-heterocycles has been substituted by the amino group using convenient nucleophilic substitution reactions with a series of adamantylalkylamines. The prototropic equilibrium in these compounds was studied using NMR spectroscopy. The introduction of the second amino substituent in 4-amino-6-chloropyrimidine, 2-amino-chloropyrazine, and 1-amino-3-chloroisoquinoline was achieved using Pd(0) catalysis.

In order to search for novel perspective biologically active compounds on the basis of amino substituted heterocycles a convenient method for the synthesis of ample series of such molecule bearing versatile groups is needed. Known approaches are often limited by harsh reaction conditions, thus diminishing the scope of available substrates, e.g., unsymmetrical 4,6-diaminopyrimidines were obtained using Pd-catalyzed reactions in low yields (5-27%) [11]. Another study revealed the formation of many by-products in these processes and a strong demand for a fine adjustment of the reaction conditions [27]. The methods for 1,3-diaminoisoquinolines preparation are also limited. One of the best methods envisages α-cyano-o-tolunitrile cyclization by the action of organolithium compounds [28]. They can be also synthesized by a two-step non-catalytic amination of 1,3-dichloroisoquinoline under harsh conditions, which provides quite moderate yields (up to 31%) [12]. Fluorescent 1-morpholinoisoquinoline-3-amines were synthesized from 1-bromoisoquinoline-3-amine by heating with excess morpholine [29]. Recently, an original approach has been proposed for diamino derivatives of isoquinoline and pyrimidine, consisting of the catalytic cyclization of cyanamides and ynamides in the presence of gold complexes [30].
For the aforementioned reasons, the aim of this work is the elaboration of the approach to adamantane-containing 4,6-diaminopyrimidines, 2,6-diaminopyrazines, and 1,3-diaminoisoquinolines. Selective monoamination of the corresponding dichloroheteroarenes can be accomplished in high yields under catalyst-free conditions [31]. Non-catalytic introduction of the second amino group is seriously hindered by the electron donor effect of the first amino group. It is rational to use the Pd-catalyzed amination at the second step as it is depicted on Scheme 1. Earlier we demonstrated Pd-catalyzed diamination to be useful in one-step syntheses of symmetrical adamantane-containing diamino derivatives of pyridines [32], quinolines [33], and 1,10-phenanthrolines [34]. Scheme 1. A two-step approach to adamantane-containing diamino heteroarenes studied in this work.
The heteroarylation of a sterically unhindered amine 4a proceeded smoothly and resulted in almost quantitative yield of the product 5a. Amines 4c,g with a closer position of the adamantane core to the amino group produced the target compounds in 76 and 77% yields, respectively. An increase in the steric hindrances in 4b,f resulted in lower yields of the amination products 5b,f (65 and 60%). The diamine 4d reacted selectively and not surprisingly only the primary amino group participated in the heteroarylation affording compound 5d in 60% yield. Initially, 55% yield was obtained in the reaction with the secondary amine 5e, but the result was improved (75%) by taking 3 equiv. 4,6dichloropyrimidine.
Catalyst-free monoamination of 2,6-dichloropyrazine 2 and 1,3-dichloroisoquinoline 3 with a wide scope of adamantane-containing amines was studied earlier [31]. The known protocol [31] was employed for the synthesis of N-(2-(1-adamantyloxy)ethyl)-6chloropyrazin-2-amine 6 and N-[2-(1-adamantyloxy)ethyl]-3-chloroisoquinolin-1-amine 7 in 82 and 89% yields (Scheme 3) for further studies of the substitution of the chlorine in these compounds. The synthesis of adamantane-containing 4,6-diaminopyrimidines was studied using a model compound 5a with Pd(dba) 2 as a precatalyst (Scheme 4, Table 1). Classical phosphine ligands, like BINAP (2,2 -bis(diphenylphosphino)-1,1 -binaphthyl) and DavePhos (2-Dicyclohexylphosphino-2 -(N,N-dimethylamino)biphenyl) [35], were studied, as well as Ph-JosiPhos and Cy-JosiPhos (CyPF-t Bu), which were shown to be efficient in the amination of halosubstituted heterocycles [36,37], were also tested. Other donor phosphine ligands with bulky substituents (SPhos, XPhos, RuPhos BrettPhos) were not studied in this reaction as they earlier had been shown to be much less efficient in the heteroarylation of adamantane-containing amines with 2-bromopyridines [38]. The reaction of 5a with 1 equiv. of amine 4a in the presence of Pd(0)/BINAP (Table 1,   The use of bulky ligands (DavePhos, Ph-JosiPhos, and Cy-JosiPhos) did not lead to an increase in the product yield even in the presence of 2 equiv. amine (entries 2-4). The use of 4 equiv. amine allowed to obtain the target product in 60% yield (entry 5). The use of BINAP in this case gave the same yield, but with higher catalyst loading (entry 6). The reaction of more sterically hindered amines 4b and 4f with 5a in the presence of Pd(0)/DavePhos catalyst led to the formation of the unsymmetrical products 8b (40%) and 8f (46%), respectively (entries 7,8). N,N-diheteroarylation was also observed in all cases; however, corresponding products were always obtained as mixtures and could not be isolated in pure state. Such propensity for the diheteroarylation can be explained by the fact that 4-amino-6-chloropyrimidines exist as two tautomers A and B in equilibrium (Scheme 5). It may increase the NH-Het proton mobility and result in a faster N,N-diheteroarylation. Tautomeric equilibria of amine-imine type are natural for 2-aminoheterocycles and have been under investigation as it is a common form of isomerism for nucleobases. This phenomenon governs the ability of the heterocycles to form hydrogen bonds [41] and participate in redox processes [42]. In the case of the pyrimidine derivatives 5, the tautomers were observed in the 1 H NMR spectra. Line broadening was notable for NH, aliphatic CHN protons, as well for the protons of the heterocyclic ring. To get a deeper insight in the phenomenon, the influence of the steric hindrances at the amino group on the tautomerism was studied for the compounds 5b, 5c, 5f, and 5g. NMR spectra of these compounds were registered in CDCl 3 at different temperatures in the range 223-323 K to get activation energy characteristics presented in Table 2. The spectra were fitted using WinDNMR software and tautomers ratio was calculated (see Supplementary Materials). Reaction rate constants sum (k = k a + k b ) and equilibrium constant (K = k a /k b = [B]/[A]) were determined for each temperature. The activation energy characteristics (∆H = and ∆S = ) were calculated from the experiments using Eyring equation and are given in Table 2. While enthalpy and entropy of the activation of the processes differ substantially, the Gibbs energy does not show significant dependence on the structure of the compounds. With elevating the temperature, an increase in the imine ratio is observed and reaches 40% at 351-325 K. This could explain an easy formation of the palladium amide I complex from the imine form and, consequently, the tendency of the monoarylated product to participate in the second arylation step forming the N,N-diaryl derivative (Scheme 6). As it is known, the deprotonation of the palladium amine complex with its transformation into the amide complex is a rate-determining step of the catalytic cycle, and, in the present case, formation of the amide complex I is faster than amide complex II because of equilibrium between A and B forms.
The amination of 2-amino-6-chloropyrazine 6 (Scheme 7) using 1 equiv. of 4a also led to a complex mixture of oligomers (Table 3, entries 1, 2), preventing the isolation of the target compound 9a in a pure state. The application of 2 equiv. amine in the presence of Pd(0)/Cy-JosiPhos catalytic system afforded 9a in 30% yield (entry 3) and the use of 4 equiv. amine with Ph-JosiPhos allowed the isolation of 9a in 90% yield (entry 4). Under analogous conditions, 9b, 9g, and 9h were synthesized in moderate yields 36-48% (entries 5,7,8). Indeed, the target products were obtained in much better yields in the reaction mixtures, but the losses during the separation from the oligomeric products badly decreased the isolated yields. Compound 9f could not be isolated in a pure state due to such problem; its yield was estimated as 47% by 1 H NMR spectrum (entry 6). Scheme 6. Proposed mechanism of the formation of mono-and di-heteroarylated products.
Scheme 7. Synthesis of adamantane-containing 2,6-diaminopyrazines. The amination of 2-amino-3-chloroisoquinoline 7 (Scheme 8) is also complicated by the formation of oligomers; however, in this case, it is somewhat less prominent, presumably due to more steric hindrances at the NH group. The application of 2 equiv. amine in the presence of Pd(0)/Cy-JosiPhos and Pd(0)/DavePhos catalytic systems gave only a mixture of oligomers (Table 4, entries 1,2). In the first case, the formation of the product 11 of C-Cl bond reduction was observed (entry 1). The use of 4 equiv. amine in the presence of Pd(0)/DavePhos afforded the desired compound 10a in 77% yield (entry 3). The test of the BINAP ligand, even at greater catalyst loading, did not lead to an increase in the product yield (entry 4). Under optimized conditions, 1,3-diaminoisoquinolines 10b, 10f and 10g were obtained in 43-67% yields (entries 5-7).

Materials and Methods
NMR spectra were registered using a Bruker Avance 400 spectrometer (Bruker Daltonics, Germany), MALDI-TOF spectra were obtained with a Bruker Autoflex II spectrometer (Bruker Daltonics, Germany) using 1,8,9-trihydroxyanthracene as a matrix and polyethylene glycols (PEGs) as internal standards. Dichloropyrimidine, dichloropyrazine, dichloroisoquinoline, BINAP, DavePhos and JosiPhos ligands, sodium tert-butoxide, and potassium carbonate were purchased from Aldrich (Daltonics, Germany) and Acros (Morris Plains, NJ, USA) and used without further purification. Amines 4a and 4b were prepared according to reported procedures of References [43,44], respectively. Amines 4c and 4e,g,h, were obtained according to a method described in Reference [45], amines 4d and 4f were obtained according to methods described in References [39,46]. Pd(dba) 2 was synthesized from PdCl 2 according to a known procedure [47]. Dioxane was distilled over NaOH followed by the distillation over sodium under argon. Dimethylformamide was distilled over sodium hydride under reduced pressure. Dichloromethane and methanol were used freshly distilled.

Conclusions
To sum up, we have investigated a synthetic approach to adamantane-containing 4,6-diaminopyrimidine, 2,6-diaminopyrazine, and 1,3-diaminoisoquinoline based on consequent substitution of chlorine atoms in the corresponding dichloroheterocycle by means of convenient nucleophilic substitution and Pd-catalyzed amination, respectively. Selective monoamination of 4,6-diaminopyrimidine proceeds under catalyst-free conditions with products yields from good to excellent. Synthesis of 4,6-diaminopyrimidine, 2,6-diaminopyrazine and 1,3-diaminoisoquinoline by Pd-catalyzed amination of aminochloroderivatives is complicated by N,N-diarylation, leading to formation of oligomers; therefore, to suppress the side products formation, 4-fold excess of amine is required. Adamantane-containing 4,6-dialkylaminopyrimidines and 1,3-dialkylaminoisoquinolines have been obtained in moderate to good yields (40-60%) using DavePhos as a ligand while the use of Ph-JosiPhos ligand is necessary for the synthesis of adamantylated 2,6-diaminopyrazines. It has been shown that adamantane-containing 6-chloro-4-aminopyrimidines exhibit prototropic tautomerism, which was observed and quantitatively characterized by NMR-spectroscopy. Tautomerism between amine and imine forms of the N-heteroarylated derivatives of adamantaneamines is held responsible to the formation of N,N-diarylated species.