Synthesis of cyclic guanidines: 2-arylamino-1,4,5,6-tetrahydropyrimidines

Considering the biological and chemical relevance of guanidine containing derivatives, we have devised a novel and efficient two-step synthesis of 2-arylamino-1,4,5,6-tetrahydropyrimidines. We have found that the coupling of aryl bromides with 2-aminopyrimidine is a very effective method for the high yielding synthesis of 2-arylaminopyrimidines. Moreover, the employment of Pd-catalysed hydrogenation to selectively reduce the pyrimidine ring generates a very high-yielding pathway to 2-arylamino-1,4,5,6-tetrahydropyrimidines of biological interest.


Introduction
Compounds embodying the guanidine functional group are prevalent throughout chemistry 1 and their synthesis has been of interest for many years. 2Many biologically active molecules containing guanidine or cyclic guanidine functionalities (e.g. the 2-aminoimidazoline system) exhibit a wide range of applications from minor groove binders 3 to potential antidepressant agents. 4Continuing with our interest in the guanidine system 4 and, in particular, in guanidines embedded in aliphatic rings, the synthesis of 2-arylamino-1,4,5,6-tetrahydropyrimidines, which are compounds that incorporate a cyclic guanidine moiety in a six-membered ring was highly interesting to us.We now present a flexible, two-step synthesis of these compounds, using either aryl bromides or anilines as starting materials.
Literature methods for the formation of 2-arylamino-1,4,5,6-tetrahydropyrimidines are often dated and low-yielding.These include formation of 2-chlorotetrahydropyrimidine followed by nucleophilic displacement of the chlorine by an aniline to form the C-N bond, 5 or reduction of the pyrimidine moiety of 2-aminopyrimidines using an excess of triethylsilane under acidic conditions. 6We aimed to find a more efficient, high-yielding synthetic method for the production of the required 2-arylamino-1,4,5,6-tetrahydropyrimidines.
Our approach consists in the initial preparation first of 2-arylaminopyrimidines with the intention of later transforming them into the corresponding 2-arylamino-1,4,5,6tetrahydropyrimidines as presented in Scheme 1.

Scheme 1.
Possible approaches to the synthesis of 2-arylaminopyrimidines.

Results and Discussion
We began our investigation by examining complementary methods for the formation of the C-N bond, by reacting either an aryl bromide with 2-aminopyrimidine or an aniline with 2chloropyrimidine, using the Buchwald-Hartwig reaction as a tool in each case (Scheme 1).Publications dealing with these particular couplings are scarce 7 and there have been no investigations into the effects of substituted aryl groups on the coupling process.As the 2aminopyrimidine moiety is also found throughout many therapeutically-active compounds 8 a comparative study on each of the complementary routes to the formation of 2arylaminopyrimidines (Scheme 1) was undertaken to determine the most effective and flexible synthetic pathway.
Initially, the coupling of 4-bromoanisole with 2-aminopyrimidine was investigated using chemistry developed in the laboratories of Buchwald 9 and Hartwig. 10Pd2(dba)3 was chosen as the source of catalytic Pd and different bases, solvents and temperatures were examined for their effect on the reaction.A range of ligands 1 -5 (Figure 1) was investigated but, as previously discovered, 7 we found that Xantphos 5 was the most successful ligand for this coupling process.Different combinations of base, solvent and temperature were explored and the results obtained are gathered in Table 1.The highest yields were obtained by using NaO t Bu as base and toluene as solvent (Table 1, entry 13).These optimised conditions were then applied to a range of aryl bromides possessing different electronic and steric features to yield a variety of 2-arylaminopyrimidines 6-16 (Table 2).The reagent combination was tolerant of most functional groups.However, when strongly electron-withdrawing substituents were present on the aryl halide, the use of K3PO4 as base gave optimal results.The presence of sterically bulky groups adjacent to the displaced halogen atom had no detrimental effects on the reaction, and in nearly all cases very good to excellent yields were obtained.The presence of electron-withdrawing substituents gave slightly lower yields than expected but the yields obtained were still acceptable.These results were very satisfactory and were replicable on a multi-gram scale.Next, the 'inverse' reaction of N,N-dimethyl-p-aminoaniline with 2-chloropyrimidine to give compound 17 under Buchwald-Hartwig conditions was investigated (Table 3).This reaction is known to occur without the use of Pd catalysis. 12However, in our experience, the yields varied greatly and harsh reaction conditions were required.A zinc-promoted version of this reaction has recently been published. 13The Pd-mediated cross-coupling reaction was optimised and it was found that satisfactory yields could be obtained under the same conditions that we earlier found to be successful for the coupling of aryl bromides with 2-aminopyrimidine (Table 3, entry 12).This reagent combination and conditions were then applied to the coupling of 2-chloropyrimidine to a selection of anilines containing both electron-withdrawing and -donating groups to produce the corresponding 2arylaminopyrimidines (Table 4).It was found that the more nucleophilic anilines were the most effective coupling partners with 2-chloropyrimidine, but that reaction still occurred with electron-deficient anilines.Overall, in the synthesis of 2-arylaminopyrimidines, we have found that the coupling of aryl bromides with 2-aminopyrimidine is a much more efficient method than the 'inverse' coupling of anilines with 2-chloropyrimidine.
With an efficient and robust method for the synthesis of 2-arylaminopyrimidines in hand, we turned our attention towards an effective method for the reduction of the pyrimidine ring to generate the desired tetrahydropyrimidines.Hydrogenation of the pyrimidine ring as described by Ajito et al. 14 offered a particularly attractive pathway to the desired compounds.
Gratifyingly, after some optimisation of the reaction conditions, a slightly modified version of Ajito's procedure gave 2-anilino-1,4,5,6-tetrahydropyrimidinium salts (19-29, Table 5) in high yields with very little purification required.Ajito's hydrogenation involved the use of acetic acid but with our systems these conditions did not result in an increase in yields.However, the use of methanol as a co-solvent in conjunction with aqueous HCl led to higher yields and allowed for a more facile purification of our target compounds.Optimum reactions times varied between 10 and 13 hours, depending on the substrate.Hydrogenation of the brominated 2-anilinopyrimidine not surprisingly resulted in dehalogenation of the aryl ring to leave the unsubstituted compound 19 (entry 7, Table 5).Interestingly, hydrogenation of the nitrile substituted 2-arylaminopyrimidines resulted in reduction of the nitrile moiety to the corresponding primary amine (entries 9 and 10, Table 5) except in the case of the ortho-substituted compound where the nitrile remained intact throughout the acid-promoted reduction (entry 8, Table 5).

Conclusions
We have found that the coupling of aryl bromides with 2-aminopyrimidine is a more effective method for the high yielding synthesis of 2-arylaminopyrimidines than the coupling of anilines with 2-chloropyrimidine.
In addition, the employment of Pd-catalysed hydrogenation to selectively reduce the pyrimidine ring generates a very high-yielding pathway to 2-arylamino-1,4,5,6-tetrahydropyrimidines that are potentially of biological interest.

Experimental Section
General.All commercial chemicals were obtained from Sigma-Aldrich or Fluka and used without further purification.Deuteriated solvents for NMR use were purchased from Apollo.Dry solvents were prepared using standard procedures, according to Vogel, with distillation prior to use.Chromatographic columns were run using a Biotage SP4 flash purification system with Biotage SNAP silica cartridges.Solvents for synthesis purposes were used at GPR grade.Analytical TLC was performed using Merck Kieselgel 60 F254 silica gel plates or Polygram Alox N/UV254 aluminium oxide plates.Visualisation was by UV light (254 nm).NMR spectra were recorded on Bruker DPX-400 Avance spectrometers, operating at 400.13 MHz for 1 H NMR and at 150.9 MHz for 13 C-NMR.Shifts are referenced to the internal solvent signals.NMR data were processed using Bruker TOPSPIN software.HRMS spectra were measured on a Micromass LCT electrospray TOF instrument with a WATERS 2690 autosampler and methanol/acetonitrile as carrier solvent.Melting points were determined using a Stuart Scientific Melting Point SMP1 apparatus and are uncorrected.Infrared spectra were recorded on a Perkin Elmer Spectrum One FT-IR Spectrometer equipped with a Universal ATR sampling accessory.
The mixture was heated to 95 °C.Once deemed complete (TLC) the reaction mixture was cooled, filtered through a pad of Celite, washed with EtOAc (20 mL) and diluted with water (20 ml), then extracted with EtOAc (3 x 20 mL).The organic layers were then combined, washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure.The product was then purified using column chromatography (hexanes: ethyl acetate, gradient from 20-70% ethyl acetate).
The mixture was heated to 90 °C.Once deemed complete (TLC) the reaction mixture was cooled, filtered through a pad of Celite, washed with EtOAc (20 mL) and diluted with water (50 mL).The product was extracted with EtOAc (3 x 50 mL).The organic layers were combined, washed with brine (50 mL), dried over MgSO4 and concentrated under reduced pressure.The product was then purified using column chromatography (hexane: ethyl acetate 20-70%).
General method C. Hydrogenation of 2-arylaminopyrimidines.To 2-arylaminopyrimidine (1 mmol) in MeOH (4 mL) was added 10% Pd/C (150 mg).To this was added aqueous HCl (1M, 1 mL).The mixture was then hydrogenated at atmospheric pressure for 10-12 hrs with vigorous stirring.If the reaction had not gone to completion after said time another equivalent of aqueous HCl acid was added and the vessel resubmited to the hydrogenation conditions previously mentioned.It was then filtered through a pad of Celite and concentrated.The residue was then purified by passing through a reverse phase silica plug, by diluting the compound in the minimum amount of H2O then using 95/5 H2O-MeCN as the eluent.This yielded the title compounds as the tetrahydropyrimidinium hydrochloride salts.

Figure 1 .
Figure 1.Ligands used in the optimisation process.

Table 5 .
Hydrogenation of the 2-aminopyrimidine ring a b Concomitant debromination.c Concomitant reduction of the nitrile moiety.© ARKAT-USA, Inc.