1,4-Diazabicyclo[2.2.2]octane (DABCO)-catalysed hydrolysis and alcoholysis reactions of 2-amino-9-benzyl-6-chloro-9H-purine

Abstract

2-Amino-9-benzyl-6-chloro-9H-purine 1 is hydrolysed in refluxing water in the presence of 1,4-diazabicyclo[2.2.2]octane (DABCO) to give 2-amino-9-benzyl-I ,6-dihydro-6-oxo-SH-purine 3; however, 1 reacts with hydroxide ion at ambient temp., or an alcohol and potassium carbonate at elevated temperatures, in the presence of DABCO to give 3 or 6-alkoxy-2-amino-9-benzyl-9H-purines 4-8, respectively.The development of efficient methods for the synthesis of N(9)-substituted guanines (2-amino-6-oxopurines) continues to receive much attention, in part due to the pivotal role of acyclovir and ganciclovir in the treatment of herpes virus infections. 1 Synthetic routes to N(9)-substituted guanines often proceed via 9-substituted 2-amino-6-chloropurines. Conversion of the 6-chloro moiety to the 6-0x0 function of guanine usually requires treatment with acid or base at elevated temp.2 Milder conditions for the conversion of 9-substituted 2-amino-6-chloropurines to 9-substituted guanines include the use of alkaline 2-hydroxyethanethiol3 and 6-pyridinium salts.4Ashwell et al., recently reported a two-stage procedure for the preparation of guanines from 2-amino-6-chloropurines.5The 6-chloro group was displaced with trimethylamine at 0°C to give a 2-amino-6-trimethylammonium purine salt. This salt was treated with 3-hydroxypropionitrile in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) to give 9-(substituted)guanine derivatives. We applied this method to the preparation of 2-amino-6-oxopurines but the method was problematic owing to the high volatility of trimethylamine. Substitution of the less volatile triethylamine for trimethylamine was not successful; a triethylammonium salt did not form. However, the bicyclic tertiary amine 1,4-diazabicyclo-[2.2.2]octane (DABCO), which has a high melting point, worked very well to form an in situ ammonium salt from 2-amino-9-benzyl-6-chloropurine 1 (see Scheme 1). The CI cr G I +N R Scheme 1Table 1~' Compound R Yieldh (YO) mpPC 3c OH(oxo) 40d, 34e 302-304 Compounds 3-8 were homogeneous by TLC [silica gel 60 (40-63 pm); ethyl acetate-hexanes]; 2 was an origin spot. All compounds gave combustion C, H and N analyses data to within 0.4% of theoretical values. Mass spectra and IH NMR spectra were consistent with the assigned structures. h The reported yields are for recrystallized material and are non-optimized. c See ref. 6. d Recrystallized from 80% aq. propan-2-01; 75% crude yield before recrystallization. See footnote 7 . c' Recrystallized from ethanol; 57% crude yield before recrystallization. See footnote Q . f Recrystallized from ethyl acetatehexanes. R See ref. 8 (lit.8 mp 95.5-99 "C non-recrystallized; purified by silica gel chromatography).DABCO moiety was easily hydrolysed in refluxing water or by using aqueous sodium hydroxide in dichloromethane at ambient temp. to provide the 9-substituted guanine. In addition, the DABCO-purine salt could be displaced with alcohols to give 6-alkoxy-2-aminopurines. This method represents a mild and efficient process for the synthesis of 9-su...

Syntheses of O6‐Alkyl‐ and Arylguanine Derivatives: Nucleobase Adducts Derived from Styrene 7,8‐ and 3,4‐Oxides

“…The reaction of DABCO-purine 9 with 4-vinylphenol (18) in DMF with sodium hydride as base yielded a complex mixture of prod-ucts. HPLC-MS analysis showed a number of peaks with quasi-molecular ions at m/z = 254, 366, 374, 484, 494 and 606 corresponding to a purinyl or DABCO-purinyl moiety with one to three vinylphenol molecules added.…”

“…Position 6 in 5 was activated for nucleophilic attack by displacement of chlorine by trimethylamine [17] or 1,4-diazabicyclo[2.2.2]octane (DABCO). [18,19] The ammonium salts formed react readily with alkoxides and aryloxides in polar aprotic solvents. [17][18][19] Moreover, they can be converted to 6-aryloxypurinyl derivatives when 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) is used as a base.…”

“…[18,19] The ammonium salts formed react readily with alkoxides and aryloxides in polar aprotic solvents. [17][18][19] Moreover, they can be converted to 6-aryloxypurinyl derivatives when 1,8-diazabicyclo [5.4.0]undec-7-ene (DBU) is used as a base. [20] We decided to use this synthetic approach to prepare O 6 -alkylguanine derivatives derived from styrene 7,8-oxide as well as O 6 -arylguanines derived from styrene 3,4-oxide.…”

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

“…Thus, 7-deazapurine compounds 10, 11 and 31, 32 were hydrolysed by the reaction with potassium carbonate and DABCO in water 30,31 to form 6-oxo-7-deazapurine derivatives 16, 17 and 37, 38. 32 was also tried.…”

A Simple and Straightforward Synthesis of Cinnamic acids and Ylidene Malononitriles via Knoevenagel Condensation Employing DABCO as Catalyst

“…It has also been employed as a catalyst for the substitution of chloropurine with alcohols [12], isothiocynation of amines, isoxazoline derivatives from activated primary nitro compounds and tertiary diamines, synthesis of naphthopyrans. Recently DABCO was used in addition of selenosulfonates to α,β-unsaturated ketones and in Sonogashira coupling reaction [13]. To aromatic aldehyde (500 mg, 1.0 equiv) and malonic acid (981 mg, 2.0 equiv) was added DABCO (105 mg, 2 equiv) in dimethyl formamide (5 mL) and the reaction mixture was stirred at 100-110 °C for 60-90 min.…”