Categories: Synthesis of N-Heterocycles >
Synthesis of pyrimidines
An oxidative annulation involving anilines, aryl ketones, and DMSO as a methine (=CH−) equivalent promoted by K2S2O8 provides 4-arylquinolines, whereas activation of acetophenone-formamide conjugates enables the synthesis of 4-arylpyrimidines.
S. D. Jadhav, A. Singh, Org. Lett., 2017, 19, 5673-5676.
A ZnCl2-catalyzed three-component coupling reaction allows the synthesis of various 4,5-disubstituted pyrimidine derivatives in a single step from functionalized enamines, triethyl orthoformate, and ammonium acetate. The procedure can be successfully applied to the efficient synthesis of mono- and disubstituted pyrimidine derivatives, using methyl ketone derivatives instead of enamines.
T. Sasada, F. Kobayashi, N. Sakai, T. Konakahara, Org. Lett., 2009, 11, 2161-2164.
An operationally simple, regioselective reaction of ketones, aldehydes, or esters with amidines in the presence of TEMPO and an in situ prepared recyclable iron(II)-complex provides various pyrimidine derivatives with broad functional group tolerance. The reactions are likely to proceed through a TEMPO complexation/enamine addition/transient α-occupation/β-TEMPO elimination/cyclization sequence.
X.-Q. Chu, W.-B. Cao, X.-P. Xu, S.-J. Ji, J. Org. Chem., 2017, 82, 1145-1154.
A base-promoted intermolecular oxidation C-N bond formation of allylic C(sp3)-H and vinylic C(sp2)-H of allyllic compounds with amidines enables the smooth formation of polysubstituted pyrimidines in the presence of O2 as the sole oxidant. This protocol features protecting group free nitrogen sources, good functional group tolerance, high atom economy, and environmental advantages.
W. Guo, C. Li, J. Liao, F. Ji, D. Liu, W. Wu, H. Jiang, J. Org. Chem., 2016, 81, 5538-5546.
A Cu-catalyzed and 4-HO-TEMPO-mediated [3 + 3] annulation of commercially available amidines with saturated ketones enables an efficient and facile synthesis of structurally important pyrimidines via a cascade reaction of oxidative dehydrogenation/annulation/oxidative aromatization.
J.-L. Zhang, M.-W. Wu, F. Chen, B. Han, J. Org. Chem., 2016, 81, 11994-12000.
A copper-catalyzed cyclization of ketones with nitriles enables a facile, general, and economical synthesis of diversely functionalized pyrimidines under basic conditions. The reaction shows broad substrate scope and tolerates many important functional groups.
L. Su, K. Sun, N. Pan, L. Liu, M. Sun, J. Dong, Y. Zhou, S.-F. Yin, Org. Lett., 2018, 20, 3399-3402.
An efficient, facile, and eco-friendly synthesis of pyrimidine derivatives involves an oxidative [3 + 2 + 1] three-component annulation of amidines, ketones, and N,N-dimethylaminoethanol as the one carbon source. The reaction tolerates many important functional groups.
Z. Qin, Y. Ma, F. Li, J. Org. Chem., 2021, 86, 13734-13743.
A regioselective, iridium-catalyzed multicomponent synthesis of pyrimidines from amidines and up to three (different) alcohols proceeds via a sequence of condensation and dehydrogenation steps. While the condensation steps deoxygenate the alcohol components, the dehydrogenations lead to aromatization. PN5P-Ir-pincer complexes catalyze this sustainable multicomponent process most efficiently.
N. Deibl, K. Ament, R. Kempe, J. Am. Chem. Soc., 2015, 137, 12804-12807.
A NaOH catalyzed rearrangement of propargylic hydroxylamines allows a highly stereoselective access to Cbz-protected β-enaminones. A subsequent synthesis of pyrimidines shows the synthetic potential of these β-enaminones.
E. Gayon, M. Szymczyk, H. Gérard, E. Vrancken, J.-M. Campagne, J. Org. Chem., 2012, 77, 9205-9220.
The direct condensation of cyanic acid derivatives with N-vinyl/aryl amides affords the corresponding C4-heteroatom substituted pyrimidines. The use of cyanic bromide and thiocyanatomethane in this chemistry provides versatile azaheterocycles poised for further derivatization.
O. K. Ahmad, M. D. Hill, M. Movassaghi, J. Org. Chem., 2009, 74, 8460-8463.
A novel and efficient synthesis of pyrimidine from β-formyl enamide involves samarium chloride catalysed cyclisation of β-formyl enamides using urea as source of ammonia under microwave irradiation.
M. G. Barthakur, M. Borthakur, P. Devi, C. J. Saikia, A. Saikia, U. Bora, A. Chetia, R. C. Boruah, Synlett, 2007, 223-226.
The coupling of acid chlorides with terminal alkynes using one equivalent of triethylamine under Sonogashira conditions followed by subsequent addition of amines or amidinium salts to the intermediate alkynones allows a straightforward access to enaminones and pyrimidines under mild conditions and in excellent yields.
A. S. Karpov, T. J. J. Müller, Synthesis, 2003, 2815-2826.
A single-step conversion of various N-vinyl and N-aryl amides to the corresponding pyrimidine and quinazoline derivatives involves amide activation with 2-chloropyridine and trifluoromethanesulfonic anhydride followed by nitrile addition into the reactive intermediate and cycloisomerization.
M. Movassaghi, M. D. Hill, J. Am. Chem. Soc., 2006, 128, 14254-14255.
Ultrasound irradiation promoted the cyclocondensation of β-keto esters and amidines in good to excellent yields to form highly substituted 4-pyrimidinols. A subsequent ultrasound-promoted tosylation followed by a Suzuki-Miyaura cross-coupling provides 4-arylpyrimidines.
M. Vidal, M. García-Arriagada, M. C. Rezende, M. Domínguez, Synthesis, 2016, 48, 4246-4252.
Methyl 1,2,3-triazine-5-carboxylate reacts with alkyl and aryl amidines at room temperature at remarkable rates (<5 min, 0.1 M in CH3CN) nearly 10000-fold faster than that of unsubstituted 1,2,3-triazine to provide product pyrimidines in high yields. C4 Methyl substitution of the 1,2,3-triazine had little effect on the rate of the reaction, whereas C4/C6 dimethyl substitution slowed the reaction.
R. E. Quiñones, Z.-C. Wu, D. L. Boger, J. Org. Chem., 2021, 86, 13465-13474.
A method for the synthesis of 2-substituted pyrimidine-5-carboxylic esters is described. The sodium salt of 3,3-dimethoxy-2-methoxycarbonylpropen-1-ol has been found to react with a variety of amidinium salts to afford the corresponding 2-substituted pyrimidine-5-carboxylic esters.
P. Zhichkin, D. J. Fairfax, S. A. Eisenbein, Synthesis, 2002, 720-722.
TFA-catalyzed inverse electron demand Diels-Alder (IEDDA) reactions of electron-deficient 1,3,5-triazines and electron-deficient aldehydes/ketones provide highly functionalized pyrimidines as products in good yields. The reactions involve a cascade of stepwise inverse electron demand hetero-Diels-Alder (ihDA) reactions, followed by retro-Diels-Alder (rDA) reactions and elimination of water. An acid is required for both ihDA and rDA reactions.
K. Yang, Q. Dang, P.-J. Cai, Y. Gao, Z.-X. Yu, X. Bai, J. Org. Chem., 2017, 82, 2336-2344.
A metal-free method provides a very practical and efficient approach to 2,6-disubstituted 4-fluoropyrimidines in very good yields from readily accessible α-CF3 aryl ketones and different amidine hydrochlorides under mild conditions.
F. Liu, X. Zhang, Q. Qian, C. Yang, Synthesis, 2020, 52, 273-280.
The reaction of trifluorinated 2-bromoenones with aryl- and alkylamidines provides trifluoromethylated pyrimidines in very good yields via an aza-Michael addition-intramolecular cyclization-dehydrohalogenation/dehydration cascade reaction. This strategy offers high selectivity and mild reaction conditions.
A. R. Romanov, A. Yu. Rulev, A. V. Popov, E. V. Kondrashov, S. V. Zinchenko, Synthesis, 2020, 52, 1512-1522.
An easy to prepare, tridentate arylazo pincer iron complex catalyzes an eco-friendly construction of trisubstituted pyrimidines under mild aerobic conditions via dehydrogenative functionalization of alcohols with alkynes and amidines.
R. Mondal, G. Chakraborty, A. K. Guin, S. Sarkar, N. D. Paul, J. Org. Chem., 2021, 86, 13186-13197.
An efficient reaction of readily available substituted 2-benzylidenemalononitriles and substituted benzamidines provides 2-aryl-5-benzylpyrimidine-4,6-diamines in good yields under simple reaction conditions. This approach also enables some modifications of structurally complex bioactive molecules.
C. Wu, X. Bian, L. Wang, Y. Zhang, C. Wang, Synthesis, 2023, 55, 457-464.
An array of tetrasubstituted saturated fused pyrimidines has been synthesized through a simple and efficient one-pot operation. The strategic utilization of the N-PMB group enabled the construction of a broad range of N-vinyl tertiary enamide starting materials. This stands as a flexible approach to functionalized pyrimidines with the capability of manipulating either ketone, acid chloride, or nitrile reaction partners.
A. A. Estrada, J. P. Lyssikatos, F. St-Jean, P. Bergeron, Synlett, 2011, 2387-2391.