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Proceeding Paper

Synthesis of Amidines and Its Application to Pyrimidouracil Synthesis †

Department of Chemistry, Maharaja Bir Bikram College, Agartala, Tripura 799004, India
Presented at the 24th International Electronic Conference on Synthetic Organic Chemistry, 15 November–15 December 2020; Available online: https://ecsoc-24.sciforum.net/.
Chem. Proc. 2021, 3(1), 132; https://doi.org/10.3390/ecsoc-24-08503
Published: 20 November 2020

Abstract

:
An efficient and sustainable copper-catalyzed protocol has been developed for the preparation of amidines via nucleophilic addition of amines into nitriles. The reaction proceeded smoothly at 100 °C in the presence of CuCl, Cs2CO3, and 2,2/-bipyridine under oxygen (O2) atmosphere in 2,2,2-trifluoroethanol (TFE) solvent. Moreover, a straightforward synthetic method for the synthesis of substituted pyrimidouracils via PhI(OAc)2-mediated oxidative coupling of N-uracil amidines and methylarenes has been developed. The starting materials N-uracil amidines were synthesized from 6-chlorouracil and amidines via nucleophilic substitution reactions.

1. Introduction

Amidines are important structural motifs, which have been widely used as antibiotics, diuretics, antiphogistic drugs, anthelmintics, and acaricides [1,2]. They represent an important pharmacophore in modern drug discovery [3]. It can be found in DNA and RNA binding diamidine diminazene [4], Acid Sensing Ion Channel (ASIC) inhibitor [5], muscarinic receptor agonists for the treatment of Alzheimer’s disease [6], and recently, serine protease inhibitors [7]. Many N-arylamidines containing compounds have been used for the treatment of inflammation and pain [8,9,10]. In addition, they were also used as ligands for the preparation of transition metal complex [11,12]. Recent studies revealed that amidine substrates also can fix carbon dioxide [13]. In synthetic chemistry, amidines have been used as valuable precursors for the preparation of azaheterocycles of biological interest [14] like imidazoles [15], benzimidazoles [16,17], quinazolines [18], quinazolinones [19], triazine [20], triazoles [21] etc. These enormous significant applications have attracted the research community toward the development of simple and economically viable methods for the synthesis of amidines. Several synthetic methods have been developed for the preparation of amidines. Amongst these, the direct nucleophilic addition of an amine to nitrile is the most suitable and atom-economic method [22]. This one-step protocol for the synthesis of N-substituted amidines from nitriles and amines can be realized only if the nitriles are activated either by electron-withdrawing groups or by employing harsh conditions such as high temperature or pressure in the presence of Lewis acids [23] such as anhydrous AlCl3 [23], ZnCl2 [23], CaCl2 [24], SmI2[25], Ln(III) salt [26], and Ytterbium amide [27], or with aluminum amides [28] or stoichiometric amounts of CuCl [29] for unactivated nitriles. Alternatively, N-substituted amidines can also be accessed by nucleophilic amino substitution of thioamides or imidates [30]. Recently, new synthetic protocols based on a transition metal catalyst were developed that eliminates the activation of nitrile with a stoichiometric reagent [31,32,33,34]. Larhed and co-workers [31] have reported the palladium catalyzed synthesis of N-arylamidines from aryltrifluoroborates and cyanamides under microwave irradiation conditions. Recently, Bert et al. [32] have developed a new procedure for the synthesis of N-substituted amidines from arylboronic acids, isocyanides, and anilines catalyzed by palladium-catalyst under oxidative reaction conditions. Alternatively, N-substituted amidines can also be prepared via arylation of amidines with aryl halides or aryl triflates under transition metal catalysis conditions [33]. Other transition metal-catalyzed approaches such as palladium-catalyzed isocyanide insertion have also been explored in amidine synthesis [34]. However, such Pd(0)-initiated protocol typically requires phosphorus containing ligands, inert gas atmosphere, and basic reaction conditions, and hence, prevents the usage of substrates having base sensitive functional groups. Thus, the search for a new protocol for the synthesis of amidines via transition metal-catalyzed strategy under sustainable reaction conditions would be of high importance. Under these backgrounds, we have developed a new synthetic protocol for the preparation of N-substituted amidines using copper-salt as catalyst and O2 as green oxidant. Under the oxidative conditions, various N-substituted amidines were obtained in good to excellent yields from nitriles and amines.
Of late, several research groups have given attention to the oxidative transformation of amidine derivatives toward azaheterocycles. In this regard, Brasche and Buchwald reported the synthesis of benzimidazoles via copper-catalyzed C–H amination of amidines [17]. Similarly, Sheng et al. [35] utilized 3-iodochromones and amidines as the substrates for the synthesis of chromento[2,3-d]imidazol-9(1H)-ones. Chiba and co-workers also carried out the molecular transformation of aliphatic amidines to imidazoles via Cu-catalyzed oxidation of amidine moieties [36,37,38,39]. Recently, Zhu and co-workers also reported the synthesis of 2-alkyl substituted benzimidazoles through the hypervalent iodine(III)-promoted intramolecular oxidative C-H imidation of N-arylamidines [16]. Very recently, we also observed that pyrimidopyrimidines could be prepared starting from N-uracil amidines and benzaldehydes under metal free conditions [16]. However, the use of aldehydes as the coupling partner has several limitations such as (i) the oxidation of some reactive aldehyde groups under the reaction conditions, and therefore, to prevent this, the inert atmosphere is required [40]; (ii) decarbonylation of some reactive aldehydes under the high reaction temperature [41]; and (iii) moreover, some aldehydes such as heteroaryl ones are costly and not easily available. For these reasons, the synthesis of variable products using aldehyde as a coupling partner is restricted. To alleviate these shortcomings, we have developed another synthetic protocol for the preparation of tetrasubstituted pyrimidopyrimidines via TBHP-mediated direct oxidative coupling of N-uracil amidines and methyl arenes [42]. Very recently, we observed that pyrimidouracil synthesis could also be accomplished by ruthenium-catalyzed oxidative insertion of aryl methanols into N-uracil amidines [43]. In the continuation of our efforts toward the synthesis of nitrogen heterocycles (Scheme 1), an efficient synthetic procedure for the synthesis of pyrimidouracils via PhI(OAc)2 mediated oxidation insertion of methylarenes into N-uracil amidines was developed. The preliminary findings on the preparation of amidines and its application toward the synthesis of pyrimidouracils are presented in this communication.

2. Materials and Methods

Initially, we have selected benzonitrile and benzylamine as a model substrate to examine the possibility of amidine synthesis by using commercially available Cu-salts as the catalyst (Scheme 2). The reactions were performed at 100 °C for 15 h using 15 mol % of different Cu-salts in the presence of Cs2CO3 (2 equiv) as a base and 2,2/-bipyridine (30 mol%) as the ligand in DMSO solvent. Amongst the tested copper catalysts, CuCl gave the best results and the desired N-benzylbenzamidine was obtained in 58% yield. Looking at the scope for improvement in the yield, screening of solvents, ligands, and bases was carried out. No improvement in the yield of the product was observed when the reaction was carried out either in DMF or THF, whereas only a small quantity of desired product was obtained in less polar toluene. Surprisingly, changing the solvent system to high polar ethanol gave the amidine product in 75% yield, and more polar TFE showed an increased yield (83%) of the product. This result encouraged us to choose this TFE as a solvent. Next, we examined the effect of temperature on this transformation, and it was observed that the optimum reaction temperature was 100 °C. The reaction at a higher temperature did not have any noticeable effect on the yield of the product. Furthermore, the reaction did not occurred without the copper catalyst.

3. Results and Discussion

We then explored the substrate scope and limitations of the present protocol by performing the reactions of various benzonitriles and amines. From Scheme 3, it is clear that this protocol is effective for the synthesis of various N-substituted benzamidines in high yields (Scheme 3). It was observed that benzonitriles with electron-donating substituents produced respective amidines in lower yields compared to the benzonitriles bearing electron-withdrawing substituents such as p-CF3 (89%) and p-CO2Et (93%). Two representative heteroaromatic nitriles such as 3-pyridinecarbonitrile and 3-thiophenecarbonitrile were also tested. Delightfully, both reactions proceeded smoothly, producing the corresponding amidines in good yields. Interestingly, aliphatic amines such as n-hexylamine, secondary cyclohexylamine, and tertiary butylamine were also well tolerated with benzonitrile, giving corresponding benzamidines in good yields.
Next, we developed a synthetic protocol for the preparation of pyrimidouracils starting from 6-chlorouracil by using amidines as a reaction partner. For this purpose, we prepared the starting materials N-uracil amidines by the nucleophilic substitution reaction between 6-chlorouracil and amidines. These starting materials were applied for the preparation of structurally diverse pyrimidouracils via hypervalent iodine-mediated oxidative insertion of methylarenes into N-uracil amidine. The reaction proceeded smoothly at 100 °C in the presence of PhI(OAc)2 (2 equiv.), Cs2CO3 (2 equiv.), and toluene for 15 h under an O2 atmosphere. A variety of pyrimidouracils were obtained in good to excellent yields under the optimal reaction conditions (Scheme 4). The electron-withdrawing group (F and CN) substituted methylarenes gave the lower yield of the products compared to the methylarenes having electron-donating group (OMe, Me) and halogens (Cl, Br). Interestingly, 2-methylnaphthalene could also well tolerated under the reaction conditions, giving the corresponding pyrimidouracil in excellent yield.
A proposed reaction pathway for the formation of the product is predicted in Scheme 5. At the beginning of the reaction, an aldehyde (A) is formed by the oxidation of methylearene in the presence of hepervalent iodine reagent. The insitu generated aldehyde on condensation with amidine to form azadiene B [44,45]. The intermediate azadiene undergoes an intramolecular Aza-Diel’s Alder type reaction, followed by a [1,5]-hydrogen transfer to give the isolable intermediate 5,6-dihydropyrimidopyrimidine (C). Finally, the pyrimidouracil is obtained by the oxidation of intermediate C with aerial oxygen.

4. Conclusions

In conclusion, we have developed an efficient and more sustainable protocol for the preparation of N-substituted benzamidines from aromatic/aliphatic nitriles and amines using CuCl as the catalyst in the presence of Cs2CO3, and 2,2/-bipyridine under O2 atmosphere in TFE solvent at 100 °C. Various N-substituted benzamidines were obtained in high yields under oxidative reaction conditions. Moreover, we developed an efficient and operationally simple method for the preparation of substituted pyrimidopyrimidines from N-uracil amidines and methylarenes using PhI(OAc)2 as an oxidative reagent. In this transformation, methylarenes are acted as the precursor of aldehyde. The main advantages of the protocol are that (i) it is operationally simple, (ii) methylarenes are cheap and more stable compared to aldehydes, and (iii) the use of green oxidant (O2). We believe that this protocol would be highly useful for the preparation of various pyrimidouracils of biological interest.

5. Experimental

Instruments and reagents: All chemicals and reagents were purchased from Sigma-Aldrich, Alfa-Aesar, Spectrochem, TCI Chemicals and used as it received from company. Silica gel, 60–120 was used for normal chromatographic separation and silica gel 230–400 mesh was used for flash column chromatography. TLC plates were purchased from Merck and used for thin-layer chromatography (TLC). Silicon oil bath was used to determine the melting points of the synthesized compounds using open capillaries and are uncorrected. 1H and 13C NMR spectra were recorded at 400 MHz and 100 MHz, respectively using CDCl3 or DMSO-d6 solvents. Chemical shift values are given in parts per million (ppm, δ) with reference to tetramethylsilane (TMS) as the internal standard.
(a)
Procedure for the preparation of N-benzylbenzamidine from benzonitrile and benzylamine.
The benzonitrile (0.5 mmol, 1.0 equiv), benzylamine (0.6 mmol), Cs2CO3 (1.0 mmol), 2,2/-bipyridine (30 mol%), and CuCl (7.4 mg, 0.075 mmol) were taken in a dry vial (10 mL). Dry TFE (1 mL) was added using a syringe and then, oxygen (O2) gas was flushed into the vial for 1 min. Then, the vial was sealed and placed in a preheated oil bath at 100 °C. After 15 h stirring, the reaction mixture was cooled and then poured into NaOH (2M) solution. The aqueous layer was extracted with dichloromethane (3 × 10 mL). Finally, DCM was washed with brine and dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by chromatography using ethyl acetate–petroleum ether mixture (1:4) as eluent (ethyl acetate mixed with 7N NH3 in MeOH in the ratio 19:1) to give the title compounds.
N-Benzylbenzenecarboximidamide: Yield: 83% (87 mg), White solid, mp 69–71 °C. 1H NMR (400 MHz, DMSO): δ= 4.36 (s, 2H), 6.53 (br s, 2H), 7.20 (d, J = 7.2 Hz, 1H), 7.31 (t, J = 8.0 Hz, 2H), 7.38–7.43 (m, 5H), 7.82–7.84 (m, 2H). 13C NMR (100 MHz, DMSO): δ= 49.7, 126.5, 127.0, 127.9, 128.4, 128.5, 129.8, 137.7, 142.4. HRMS (ESI): m/z calcd for C14H15N2 [M++H]: 211.1236; found: 211.1235.
(b)
General procedure for the synthesis of N-uracil amidine derivatives
An oven-dried 10 mL pressure vial was loaded with 1,3-dimethyl-6-chlorouracil (349 mg, 2 mmol, 1.0 eq.), benzamidine hydrochloride (3.0 mmol, 1.5 equiv.), and 1,8-diazabicyclo[5.4.0]undec-7-ene (660 μL, 4.4 mmol, 2.2 equiv.). The anhydrous tert-butanol (0.5 mL) was added to the vial. Then, the vessel was flushed with N2 for 1 min. and sealed with a septum. The resulting mixture was placed in a preheated oil bath and stirred at 80 °C for 24 h. After completion of reaction, the reaction mixture was cooled to room temperature and then extracted with ethyl acetate. The combined ethyl acetate was washed with brine and the organic layer was dried (Na2SO4), filtered, and concentrated under reduced pressure. The resulting crude product was purified by column chromatography using the ethyl acetate/petroleum ether mixture as the eluent.
(c)
Procedure for PhI(OAc)2-mediated oxidative insertion of toluene into N-Uracil Amidines toward the synthesis of pyrimidouracils
N-Uracil amidine (0.5 mmol, 1.0 equiv.), toluene (1 mL), PhI(OAc)2 (1.0 mmol, 322 mg,) and Cs2CO3 (1.0 mmol, 325 mg) were added in a microwave vial. The vessel was flushed with O2 and then sealed with septum. The reaction mixture was placed in an oil bath and stirred for 15 h at 100 °C. After completion of the reaction, the reaction mixture was stirred with ethyl acetate (10 mL) and brine for 10–12 min. The aqueous layer was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine and dried (Na2SO4), and filtered. The crude products were purified by column chromatography using a mixture of hexane-ethyl acetate as the eluent.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

The author is thankful to Tripura University, Suryamaninar, Tripura, India for providing the Bruker-400 spectrometer facility for spectral analysis.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Aly, A.A.; Nour-El-Din, A.M. Functionality of amidines and amidrazones. ARKIVOC 2008, 153–194. [Google Scholar] [CrossRef]
  2. Dunn, P.J. Comprehensive Organic Functional Group Transformations II; Alan, R., Katritzky, R.J.K.T., Eds.; Elsevier: New York, NY, USA, 2005; Volume 5, p. 655. [Google Scholar]
  3. Drugs.com: Pharmaceutical Sales 2010. Available online: http://www.drugs.com/top200.html (accessed on 24 May 2012).
  4. Clement, B.; Immel, M.; Raether, W. Metabolic N-hydroxylation of diminazine in vitro. Arzneim. -Forsch. 1992, 42, 1497–1504. [Google Scholar]
  5. Chen, X.M.; Orser, B.A.; MacDonald, J.F. Design and screening of ASIC inhibitors based on aromatic diamidines for combating neurological disorders. Eur. J. Pharmacol. 2010, 648, 15–23. [Google Scholar] [CrossRef]
  6. Ojo, B.; Dunbar, P.G.; Durant, G.J.; Nagy, P.I.; Huzl, J.J.; Periyasamy, S.; Ngur, D.O.; ElAssadi, A.A.; Hoss, W.P.; Messer, W.S. Synthesis and biochemical activity of novel amidine derivatives as m1 muscarinic receptor agonists. Bioorg. Med. Chem. 1996, 4, 1604–1615. [Google Scholar] [CrossRef]
  7. Kotthaus, J.; Steinmetzer, T.; van de Locht, A.; Clement, B. Analysis of highly potent amidine containing inhibitors of serine proteases and their N-hydroxylated prodrugs (amidoximes). J. Enzym. Inhib. Med. Ch. 2011, 26, 115–122. [Google Scholar] [CrossRef] [PubMed]
  8. Kort, M.E.; Drizin, I.; Gregg, R.J.; Scanio, M.J.C.; Shi, L.; Gross, M.F.; Atkinson, R.N.; Johnson, M.S.; Pacofsky, G.J.; Thomas, J.B.; et al. Discovery and Biological Evaluation of 5-Aryl-2-furfuramides, Potent and Selective Blockers of the Nav1.8 Sodium Channel with Efficacy in Models of Neuropathic and Inflammatory Pain. J. Med. Chem. 2008, 51, 407–416. [Google Scholar] [CrossRef] [PubMed]
  9. Renton, P.; Green, B.; Maddaford, S.; Rakhit, S.; Andrews, J.S. NOpiates: Novel Dual Action Neuronal Nitric Oxide Synthase Inhibitors with μ-Opioid Agonist Activity. ACS Med. Chem. Lett. 2012, 3, 227–231. [Google Scholar] [CrossRef] [PubMed]
  10. Annedi, S.C.; Ramnauth, J.; Maddaford, S.P.; Renton, P.; Rakhit, S.; Mladenova, G.; Dove, P.; Silverman, S.; Andrews, J.S.; Felice, M.D.; et al. Discovery of N-(3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-6-yl) thiophene-2-carboximidamide as a Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) for the Treatment of Pain. J. Med. Chem. 2011, 54, 7408–7416. [Google Scholar] [CrossRef]
  11. Barker, J.; Kilner, M. The coordination chemistry of the amidine ligand. Coord. Chem. Rev. 1994, 133, 219–300. [Google Scholar] [CrossRef]
  12. Oakley, S.A.; Soria, D.B.; Coles, M.P.; Hitchcock, P.B. Structural diversity in the coordination of amidines and guanidines to monovalent metal halides. Dalton Trans. 2004, 537–546. [Google Scholar] [CrossRef]
  13. Desset, S.L.; Cole-Hamilton, D.J. Carbon Dioxide Induced Phase Switching for Homogeneous-Catalyst Recycling. Angew. Chem. Int. Ed. 2009, 48, 1472–1474. [Google Scholar] [CrossRef]
  14. Rauws, T.R.M.; Maes, B.U.W. Transition metal-catalyzed N-arylations of amidines and guanidines. Chem. Soc. Rev. 2012, 41, 2463–2497. [Google Scholar] [CrossRef] [PubMed]
  15. Kuethe, J.T.; Childers, K.G.; Humphrey, G.R.; Journet, M.; Peng, Z. A Rapid, Large-Scale Synthesis of a Potent Cholecystokinin (CCK) 1R Receptor Agonist. Org. Process Res. Dev. 2008, 12, 1201–1208. [Google Scholar] [CrossRef]
  16. Huang, J.; He, Y.; Wang, Y.; Zhu, Q. Synthesis of benzimidazoles by PIDA-promoted direct C(sp2)-H imidation of N-arylamidines. Chem. Eur. J. 2012, 18, 13964–13967. [Google Scholar] [CrossRef]
  17. Brasche, G.; Buchwald, S.L. C–H Functionalization/C–N Bond Formation: Copper-Catalyzed Synthesis of Benzimidazoles from Amidines. Angew. Chem., Int. Ed. 2008, 47, 1932–1934. [Google Scholar] [CrossRef] [PubMed]
  18. Malakar, C.C.; Baskakova, A.; Conrad, J.; Beifuss, U. Copper-Catalyzed Synthesis of Quinazolines in Water Starting from o-Bromobenzylbromides and Benzamidines. Chem. Eur. J. 2012, 29, 8882–8885. [Google Scholar] [CrossRef] [PubMed]
  19. Ma, B.; Wang, Y.; Peng, J.L.; Zhu, Q. Synthesis of Quinazolin-4(3H)-ones via Pd(II)-Catalyzed Intramolecular C(sp2)–H Carboxamidation of N-arylamidines. J. Org. Chem. 2011, 76, 6362–6366. [Google Scholar] [CrossRef]
  20. Anderson, E.D.; Boger, D.L. Scope of the Inverse Electron Demand Diels–Alder Reactions of 1,2,3-Triazine. Org. Lett. 2011, 13, 2492–2494. [Google Scholar] [CrossRef]
  21. Castanedo, G.M.; Seng, P.S.; Blaquiere, N.; Trapp, S.; Staben, S.T. Rapid Synthesis of 1,3,5-Substituted 1,2,4-Triazoles from Carboxylic Acids, Amidines, and Hydrazines. J. Org. Chem. 2011, 76, 1177–1179. [Google Scholar] [CrossRef]
  22. Grivas, J.C.; Taurins, A. Further studies on the reaction between halogen-substituted nitriles and amines. Can. J. Chem. 1961, 39, 761–764. [Google Scholar] [CrossRef]
  23. Bower, J.D.; Ramage, G.R. Heterocyclic systems related to pyrrocoline. Part II. The preparation of polyazaindenes by dehydrogenative cyclisations. J. Chem. Soc. 1957, 4506–4510. [Google Scholar] [CrossRef]
  24. Meder, M.; Galka, C.H.; Gade, L.H. Bis(2-pyridylimino)isoindole (BPI) Ligands with Novel Linker Units: Synthesis and Characterization of Their Palladium and Platinum Complexes. Monatshefte fur Chemie 2005, 136, 1693–1706. [Google Scholar] [CrossRef]
  25. Xu, F.; Sun, J.; Shen, Q. Samarium diiodide promoted synthesis of N,N′-disubstituted amidines. Tetrahedron Lett. 2002, 43, 1867–1869. [Google Scholar] [CrossRef]
  26. Forsberg, J.H.; Spaziano, V.T.; Balasubramanian, T.M. Use of lanthanide(III) ions as catalysts for the reactions of amines with nitriles. J. Org. Chem. 1987, 52, 1017–1021. [Google Scholar] [CrossRef]
  27. Wang, J.; Xu, F.; Cai, T.; Shen, Q. Addition of Amines to Nitriles Catalyzed by Ytterbium Amides: An Efficient One-Step Synthesis of Monosubstituted N-Arylamidines. Org. Lett. 2008, 10, 445–448. [Google Scholar] [CrossRef]
  28. Gielen, H.; Alonso-Alija, C.; Hendrix, M.; Niewohner, U.; Schauss, D. A novel approach to amidines from esters. Tetrahedron Lett. 2002, 43, 419–421. [Google Scholar] [CrossRef]
  29. Rousselet, G.; Capdevielle, P.; Maumy, M. Copper(I)-induced addition of amines to unactivated nitriles: The first general one-step synthesis of alkyl amidines. Tetrahedron Lett. 1993, 34, 6395–6398. [Google Scholar] [CrossRef]
  30. DeKorver, K.A.; Johnson, W.L.; Zhang, Y.; Hsung, R.P.; Dia, H.F.; Deng, J.; Lohse, A.G.; Zhang, Y.S. N-Allyl-N-sulfonyl Ynamides as Synthetic Precursors to Amidines and Vinylogous Amidines. An Unexpected N-to-C 1,3-Sulfonyl Shift in Nitrile Synthesis. J. Org. Chem. 2011, 76, 5092–5103. [Google Scholar] [CrossRef]
  31. Savmarker, J.; Rydfjord, J.; Gising, J.; Odell, L.R.; Larhed, M. Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates. Org. Lett. 2012, 14, 2394–2397. [Google Scholar] [CrossRef]
  32. Zhu, F.; Li, Y.; Wang, Z.; Orru, R.V.A.; Maes, B.U.W.; Wu, X.-F. Palladium-Catalyzed Construction of Amidines from Arylboronic Acids under Oxidative Conditions. Chem. Eur. J. 2016, 22, 7743–7746. [Google Scholar] [CrossRef]
  33. McGowan, M.A.; McAvoy, C.Z.; Buchwald, S.L. Palladium-Catalyzed N-Monoarylation of Amidines and a One-Pot Synthesis of Quinazoline Derivatives. Org. Lett. 2012, 14, 3800–3803. [Google Scholar] [CrossRef] [PubMed]
  34. Saluste, C.G.; Crumpler, S.; Furber, M.; Whitby, R.J. Palladium catalysed synthesis of cyclic amidines and imidates. Tetrahedron Lett. 2004, 45, 6995–6996. [Google Scholar] [CrossRef]
  35. Sheng, J.; Chao, B.; Chen, H.; Hu, Y. Synthesis of Chromeno[2,3-d]imidazol-9(1H)-ones via Tandem Reactions of 3-Iodochromones with Amidines Involving Copper-Catalyzed C–H Functionalization and C–O Bond Formation. Org Lett. 2013, 15, 4508–4511. [Google Scholar] [CrossRef]
  36. Chen, H.; Sanjaya, S.; Wang, Y.-F.; Chiba, S. Copper-Catalyzed Aliphatic C-H Amination with an Amidine Moiety. Org. Lett. 2013, 15, 212–215. [Google Scholar] [CrossRef]
  37. Wang, Y.-F.; Chen, H.; Zhu, X.; Chiba, S. Copper-Catalyzed Aerobic Aliphatic C–H Oxygenation Directed by an Amidine Moiety. J. Am. Chem. Soc. 2012, 134, 11980–11983. [Google Scholar] [CrossRef]
  38. Wang, Y.-F.; Zhu, X.; Chiba, S. Copper-Catalyzed Aerobic [3+2]-Annulation of N-Alkenyl Amidines. J. Am. Chem. Soc. 2012, 134, 3679–3682. [Google Scholar] [CrossRef] [PubMed]
  39. Sanjaya, S.; Chiba, S. Copper-catalyzed aminooxygenation of N-allylamidines with PhI(OAc)2. Org. Lett. 2012, 14, 5342–5345. [Google Scholar] [CrossRef] [PubMed]
  40. Sharama, G.V.R.; Robert, A. Oxidation of aromatic aldehydes with potassium bromate–bromide reagent and an acidic catalyst. Res. Chem. Intermed. 2013, 39, 3251–3254. [Google Scholar] [CrossRef]
  41. Modak, A.; Deb, A.; Patra, S.; Rana, S.; Maity, S.; Maiti, D. A general and efficient aldehyde decarbonylation reaction by using a palladium catalyst. Chem. Commun. 2012, 48, 4253–4255. [Google Scholar] [CrossRef]
  42. Debnath, P. TBHP-mediated oxidative synthesis of substituted pyrimido[4,5-d]pyrimidines from N-uracil amidines and methylarenes under metal free conditions. RSC Adv. 2019, 9, 29831–29839. [Google Scholar] [CrossRef]
  43. Debnath, P.; Sahu, G.; De, U.C. Synthesis of Functionalized Pyrimidouracils by Ruthenium Catalyzed Oxidative Insertion of (Hetero)aryl Methanols into N-Uracil Amidines. Appl. Organomet. Chem. 2021, 35, e6087. [Google Scholar] [CrossRef]
  44. Wang, M.; Meng, Y.; Wei, W.; Wu, J.; Yu, W.; Changa, J. Iodine/Copper(I)-Catalyzed Direct Annulation of N-Benzimidazolyl Amidines with Aldehydes for the Synthesis of Ortho-Fused 1,3,5-Triazines. Adv. Synth. Catal. 2018, 360, 86–92. [Google Scholar] [CrossRef]
  45. Tiwari, A.R.; Bhanage, B.M. Oxidative Functionalization of Styrenes: Synthesis of 1,3,5-triazines from Styrenes via Tandem Cyclization with Amidines. ChemistrySelect 2016, 1, 343–346. [Google Scholar] [CrossRef]
Scheme 1. Direct oxidative and oxidative imidoylative amination of N-uracil-amidines.
Scheme 1. Direct oxidative and oxidative imidoylative amination of N-uracil-amidines.
Chemproc 03 00132 sch001
Scheme 2. Synthesis of N-benzylbenzamidine from benzylamine and benzonitrile catalyzed by copper salt.
Scheme 2. Synthesis of N-benzylbenzamidine from benzylamine and benzonitrile catalyzed by copper salt.
Chemproc 03 00132 sch002
Scheme 3. Synthesis of N-substituted amidines from amines and benzonitriles catalyzed by CuCl.
Scheme 3. Synthesis of N-substituted amidines from amines and benzonitriles catalyzed by CuCl.
Chemproc 03 00132 sch003
Scheme 4. PhI(OAc)2-mediated synthesis of pyrimidouracils from N-uracil amidines and arylmethanes.
Scheme 4. PhI(OAc)2-mediated synthesis of pyrimidouracils from N-uracil amidines and arylmethanes.
Chemproc 03 00132 sch004
Scheme 5. A plausible mechanism for the formation of pyrimidouracil.
Scheme 5. A plausible mechanism for the formation of pyrimidouracil.
Chemproc 03 00132 sch005
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Debnath, P. Synthesis of Amidines and Its Application to Pyrimidouracil Synthesis. Chem. Proc. 2021, 3, 132. https://doi.org/10.3390/ecsoc-24-08503

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Debnath P. Synthesis of Amidines and Its Application to Pyrimidouracil Synthesis. Chemistry Proceedings. 2021; 3(1):132. https://doi.org/10.3390/ecsoc-24-08503

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Debnath, Pradip. 2021. "Synthesis of Amidines and Its Application to Pyrimidouracil Synthesis" Chemistry Proceedings 3, no. 1: 132. https://doi.org/10.3390/ecsoc-24-08503

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