3-Aminopyrroles and their application in the synthesis of pyrrolo[3,2-d ]pyrimidine (9-deazapurine) derivatives

3-Aminopyrrole derivatives have been synthesized from 3-anilino-2-cyanoacrylonitrile using Thorpe-Ziegler cyclization. These substituted pyrroles are readily converted into 5 H -pyrrolo[3,2-d ]pyrimidine (9-deazapurines)


Results and Discussion
β,β-Enaminonitrile 2 was readily synthesized by the reaction of ethoxymethylene malononitrile 1 with p-anisidine in ethanol at room temperature. 20Enaminonitriles 2 were found to be good candidates to obtain 3-aminopyrrole based on a Thorpe-Ziegler cyclization. 15,16In this method, N-alkylation of a β,β-enaminonitrile was carried out using α-haloketones in anhydrous DMF in the presence of K 2 CO 3 as the base.Moreover, compounds having an aryl substituent on the amino moiety of the enamine group were the most convenient for alkylation and spontaneous intramolecular cyclization.The presence of this group facilitates the formation of the N-anion required for alkylation and subsequent carbanion formation for the cyclization involving the cyano group.
The reaction of enaminonitrile 2 with chloroacetonitrile, chloroacetone, ethyl bromoacetate and α-bromoacetophenone in DMF/K 2 CO 3 afforded the corresponding 3-aminopyrrole derivatives 4a-d in low yield (24-45 %) via intermediate 3. We prepared compound 4 by a modification of the method used by Gewald et al. 15,16 using triethylamine as alkaline reagent.When the reaction was carried out in an excess of triethylamine solution, the desired 3aminopyrrole derivatives 4a-d are obtained in a satisfactory yield (74-91 %).The structure of compounds 4a-d was established on the basis of elemental analysis, IR, mass, 1 H and 13 C NMR spectral data studies (cf.Experimental Section).For example, the 1 H NMR spectrum of compound 4a showed the absence of a signal for a methylene function and the presence of a two protons D 2 O exchangeable signal at δ = 6.11 ppm for the amino function and a singlet for the pyrrole 5-H proton at δ = 7.84 ppm. 13C NMR and mass spectra of compound 4a are in agreement with the proposed structure.When the reaction was carried out in excess of chloroacetonitrile, the N-substituted product 5 was obtained (Scheme 1).
The 3-amino-2-cyanopyrrole 4a is a polyfunctional compound containing an interesting set of substituents.Although the 3-amino group has an electronegative substituent in the neighboring ortho position, it retains its basic properties and is readily acylated in refluxing acetic anhydride to afford the monoacetyl derivative 6.
The most generally used approach to pyrrolo [3,2-d]pyrimidines has so far involved elaboration of the pyrrole ring onto a preformed pyrimidine bearing reactive functionalities at C-4 and C-5. 18,19,21Another strategy has involved the formation of the pyrimidine ring onto a preformed 3-aminopyrrole intermediate 22 as we describe herein.
Compound 4a,b reacted with triethyl orthoformate or dimethyl formamide dimethylacetal (DMFDMA) to give the corresponding imidocarboxylate derivatives 7 and amidine derivatives 8 respectively, which are the key compounds for the preparation of pyrrolo [3,2-d]pyrimidine derivatives.Thus, compound 7a was stirred at room temperature in methanolic ammonia to produce 4-aminopyrrolopyrimidine 9 and not the isomeric form 10 (Scheme 2).Attempts to obtain 9 from 8a according to literature methods 17 failed.The identity of pyrrolopyrimidine 9 was confirmed by 1 H NMR, NOE experiment and elemental analysis.Thus, the presence or absence of an Nuclear Overhauser Enhancement between specific protons allowed establishing the structure of compound 9. Compound 9 was also obtained on heating compound 4a in a mixture of HCO 2 H/HCONH 2 /DMF.Following the behavior that was observed with ammonia solution, compounds 7a and 8a reacted with aniline under reflux to produce the Dimroth rearrangement product, 4-substituted aminopyrrolopyrimidine 12, via the intermediate 11 (Scheme 3). 14,23ased on NMR data the alternative structure 11 was excluded.The 1 H NMR spectra of compound 12 showed all the expected signals for aromatic protons and four singlets signals at δ = 3.86 (OCH 3 ), 6.98 (NH), 8.52 (2-H) and 8.62 (6-H), which was not sufficient to differentiate between structures 11 and 12.For this reason, we obtained the HMQC and HMBC NMR spectra and made an unambiguous assignment in the 1 H and 13 C NMR spectrum (see Experimental Section).
In the HMBC spectrum, we observe an intense correlation peak for the NH proton at δ = 6.98 with the carbons peak at δ = 120.68ppm (C-2´´, 6´´), which is characteristic only for structure 12 but not for 11, where the indicated proton and carbon atoms are separated by five bonds.To confirm the structure of compound 12 an independent route was followed, compound 4a was refluxed in boiling formic acid to produce pyrrolopyrimidinone-7-carboxamide 13.Compound 13 was refluxed in phosphorus oxychloride to obtain 4-chloropyrrolopyrimidines 14 24 , then reacting compound 14 with aniline, the pyrrolo[3,2-d]pyrimidine 12 (65 %) was isolated, whose spectral characteristics were completely coincident with the samples obtained before (Scheme 3).
Under the same reaction conditions, the amidines 7b and 8b reacted with aniline to afford the bicyclic compound 4-oxo-3-phenylpyrrolo[3,2-d]pyrimidine 15.Also in these cases the ester group in position 2 of the pyrrole ring but not the 4-cyano group participates in the cyclization, as shown in the 1 H NMR spectra which revealed the absence of the ester groups (no triplet and quartet signals are found) and the presence of CN signal in the IR at 2232 cm -1 and at δ 117.02 ppm in the 13 C NMR spectra.

Experimental Section
General Procedures.Melting points were determined on a Gallenkamp melting point apparatus and are uncorrected.IR spectra were registered on a Perkin Elmer FTIR-1600 using Nujol emulsions between NaCl plates. 1 H NMR (300 or 400 MHz) and 13 C NMR (75.4 or 100.62 MHz) spectra were recorded in deuterated dimethylsulfoxide [D 6 ]DMSO or deuterated chloroform CDCl 3 on a Varian Unity Plus Spectrometer using tetramethylsilane (TMS) as an internal reference, and results are expressed as δ values.Double resonance, HMQC and HMBC experiments were carried out for complete assignment of proton and carbon signals in the NMR spectra, whenever possible.Mass spectra were performed on a Shimadzu GCMS-QP 1000 Ex mass spectrometer at 70 eV.Elemental analyses were obtained on a Leco CHNS-932 instrument.Compound 2 was prepared according to the literature. 20neral procedure for preparation of 3-aminopyrrole derivatives 4a-d Method A. A mixture of 2 (0.01 mol), the α-halo compound (chloroacetonitrile, chloroacetone, ethyl bromoacetate and α-bromoacetophenone) (0.011 mol), and potassium carbonate (2.0 g) in dimethylformamide (20 mL) was stirred for 1 h, at 90 °C, in an oil-bath.The reaction mixture was cooled and poured into water (60 mL).The precipitated solid products formed were filtered off, washed thouroughly with cold water and recrystallized from EtOH to afford the corresponding cyclized products 4a (45 %), 4b (24%), 4c (39%), 2d (35%).Method B. To a solution of the intermediate 2 (0.01 mol) the α-halo compound (chloroacetonitrile, chloroacetone, ethyl bromoacetate and α-bromoacetophenone) (0.011 mol) and triethylamine (4 mL) were added with external cooling.The reaction mixture was refluxed for 10-15 minutes, after cooling (50 mL) water was added, the solid product was filtered off, washed thoroughly with cold water and crystallized from ethanol (in case of 4a, 91 %).For derivatives 4b-c a brown oil was separated, the water was decanted and the oil was extracted with CH 2 Cl 2 (3 x 25 mL) and the combined organic layers were dried (Na 2 SO 4 ), filtered and the solvent was evaporated to give a solid which was crystallized from EtOH.

Reaction with acetic anhydride
To compound 4a,b (0.01 mol) was added acetic anhydride (10 mL), the reaction mixture was heated under reflux for 3 h, cooled and the precipitate was filtered off.

Reaction with triethyl orthoformate (7a,b)
A mixture of 3-aminopyrrole-4-carbonitrile, 4a,b (0.015 mol), triethyl orthoformate (20 mL) was heated under reflux for 7 h and then evaporated under reduced pressure.The residue was treated with ethanol and the solid product formed was collected by filtration, washed with ethanol and crystallized from EtOH.Reaction with DMFDMA DMFDMA (0.012 mol) was added to a solution of 3-aminopyrrole-4-carbonitrile 4a,b (0.01 mol), in dry toluene (40 mL) and the mixture heated under reflux for 7 h.the reaction mixture was cooled and the precipitated solid was filtered off and crystallized from EtOH.