Letter pubs.acs.org/OrgLett
A One-Pot Synthesis of Highly Functionalized Purines Renaud Zelli,† Wael̈ Zeinyeh,†,‡ Romain Haudecoeur,† Julien Alliot,† Benjamin Boucherle,† Isabelle Callebaut,§ and Jean-Luc Décout*,† †
Univ. Grenoble Alpes, CNRS, DPM, 38000 Grenoble, France Univ. Grenoble Alpes, CEA, CNRS, BIG-LCBM, 38000 Grenoble, France § IMPMC, Sorbonne Universités, UPMC Univ. Paris 06, UMR CNRS 7590, Muséum National d’Histoire Naturelle, IRD UMR 206, IUC, Case 115, 4 Place Jussieu, 75005 Paris Cedex 05, France ‡
S Supporting Information *
ABSTRACT: Highly substituted purines were synthesized in good to high yields through a one-pot straightforward metal-free scalable method, using the Traube synthesis adapted to Vilsmeier-type reagents. From 5-amino-4-chloropyrimidines, new 9-aryl-substituted chloropurines and intermediates for peptide nucleic acid synthesis were prepared. Variant procedures allowing a rapid synthesis of ribonucleosides and 7-benzylpurine from 5-amidino-6-aminopyrimidines are also reported to illustrate the high potential of this versatile toolbox. This route appears to be particularly interesting in the field of nucleic acids for a direct and rapid access to various new 8alkylpurine nucleosides.
I
substituted purines using various electrophiles (see Supporting Information, SI).4 9H-Purines were also extensively modified, especially chloropurines, for further functionalization. However, access to some chemical spaces remains challenging, jeopardizing the development of pertinent analogues in structure− activity relationship processes. 9-Arylation of purines is an emblematic example of such difficulties, as chemists still struggle with inefficient reactions and narrow substrate scopes. The 9-arylation is indeed usually performed through either (1) copper-catalyzed C−N cross-coupling reaction of purines5 or (2) reaction of an arylamine with a 5-amino-4-chloropyrimidines before ring closure by an orthoester derivative,6 an acyl chloride,7 or more recently via an additional prior formylation step.8 These pathways present drawbacks, such as restricted substrate scope, low yields, and multiple steps, especially for Chan−Lam reactions. Beyond the case of aryl groups, the synthesis of 9-alkylpurines or purine-based nucleosides via direct substitution also causes difficulty, as the reaction leads to mixtures of N3-, N7-, and N9-substitutions, with a loss of yield and purification issues. In addition, all these methods do not provide a concomitant easy access to diversity at position 8, and a bromination/substitution sequence is generally needed for reaching 8-substituted purines of interest. The Vilsmeier’s reagent, i.e. (chloromethylene)dimethyliminium chloride, has been used for generating formamidine groups, often as an amino protecting group,9 or to generate formamido groups10 and also sporadically as intermediates for the synthesis of various 1,3-diazole hetero-
n recent decades, the purine scaffold has contributed intensively to the development of both biotechnological tools and bioactive compounds.1 Purine-based analogues have also been extensively used in clinics since the approval of the antiviral drug, Vidarabine, in 1976. Many drugs have been designed from analogy with natural purine-based nucleosides and nucleobases.2 They traditionally come with structural diversity at position 9 that is often linked to various carbohydrates, carbocycles, or alkyl groups (Figure 1). Since the preparation of purine itself by Fisher in 1898 and the first general synthesis of purines from 4,5-diaminopyrimidines and formic acid by Traube, many variants of the original synthesis3 were developed that led to diversely
Figure 1. Examples of bioactive purine-based compounds with various structures and activities. © 2017 American Chemical Society
Received: October 14, 2017 Published: November 10, 2017 6360
DOI: 10.1021/acs.orglett.7b03209 Org. Lett. 2017, 19, 6360−6363
Letter
Organic Letters
conditions, dimethylamine released in the final cyclization/ aromatization step or formed under drastic conditions from DMF, if chosen as a solvent,8,12 could react in SNAr reactions from a chlorine atom carried by the starting or intermediate pyrimidines and/or the formed purines. The conditions of this reaction sequence thus appeared as fully compatible for building a one-pot strategy, directly from the starting pyrimidine to the final substituted purine. Adjustments were envisaged for reacting starting pyrimidines with electrophiles at positions 4 (Variant A) or 5 (Variant B), leading to a straightforward access to nucleosides and 7-substituted purines. In all cases, the 8-substitution of the purines could be managed by using modified Vilsmeier-type reagents generated in parallel. Thus, we report a new one-pot, metal-free reaction toolbox based on Vilsmeier’s reagent reactivity, dedicated to the synthesis of extensively substituted purines with high yields, an associated extremely wide directly reachable diversity at positions 2, 6, 7, 8 and/or 9, and a privileged access to 2- and/ or 6-halogenated purines that allow further fine-tuned structural modifications. A typical procedure involves 5-amino-4,6-dichloropyrimidines 1−3 and an amine refluxed in dioxane for 16 h. The reaction was monitored by TLC to follow the disappearance of the starting material and to witness aromatic nucleophilic substitution of the chloro group by the amine. The Vilsmeier’s
aromatic rings upon cyclization (e.g., imidazoles, benzimidazoles, 9H-purines).11 However, the few reported reactions were associated either with the formation of naked rings starting from o-diamino or amino-o-nitro derivatives, without simultaneous N-functionalization, or with extreme pressure, temperature, and reaction time conditions, incompatible with most of the classical functional groups. Using 5-amino-4-chloropyrimidines, we considered that an amidine group embedded in the amino substituent could easily undergo cyclization right after substitution of the chlorine atom by an amine, resulting in the formation of 9-substituted 6-chloropurines preferably under mild acidic conditions (Scheme 1). Indeed, under basic Scheme 1. A New Strategy for Purine Synthesis
Scheme 2. Substrate Scope of the One-Pot Substitution/Cyclization Sequence
a
Modified procedure via formation of 5-amidino-2,4,6-trichloropyrimidine; see ref 14 and Supporting Information (SI). bDIPEA (2.0 equiv) was used instead of p-toluenesulfonic acid. cConcomitant protection of the 2-amino group form occurred under the reported conditions. dModified procedure via prior formation of a Vilsmeier-type reagent; see ref 16 and SI. 6361
DOI: 10.1021/acs.orglett.7b03209 Org. Lett. 2017, 19, 6360−6363
Letter
Organic Letters
byproducts) while POCl3, SOCl2, and N,N-dimethylacetamide dimethyl acetal led mainly to lower yields with byproduct formation. The synthesis of modified nucleosides, a topic of high importance, can be accessible from aminosugars according to the developed Vilsmeier-based methodology. However, the preparation of aminosugars can be hard and lengthy. We thus addressed this hurdle by developing a first Variant “A” of the method (Scheme 3), mainly for rapid access to 8-substituted
reagent (2 equiv) was then added, immediately inducing the formation of the amidine group and the subsequent cyclization in less than 30 min at 25 °C. After rapid workup and purification, the reaction sequence afforded the desired purines in good to very good yields. Overall, although the three steps described above, i.e. nucleophilic substitution, formation of the amidine group, and cyclization, were conducted in one pot without any intermediate purification, very few byproduct formation was observed, leading to easy isolation of the purines through a final chromatography. Several experimental conditions were modulated in order to assess the robustness of the reaction. The influences of water traces and oxygen were evaluated using nonanhydrous solvents and an ambient atmosphere, resulting in no yield loss (2 equiv of Vilsmeier’s reagent). Comparative assays performed from 50 mg and 1 g of starting pyrimidine demonstrated the efficacy of the reaction at different operating scales. Overall, these results emphasized a low sensitivity to moisture, oxygen, and scale. The scope of the reaction was investigated using compound 1 and several aromatic amines carrying various substituents for synthesizing purines 4−17 (Scheme 2). 3- and 4-Chloro, 3,5dichloro-, and 4-bromo-anilines and naked aniline were all proven effective substrates, yielding corresponding purines (respectively 4, 5, 7, 8, and 9) through the one-pot process. Unsurprisingly, 2-chloroaniline as the starting amine showed far less reactivity; however, the corresponding purine 6 was isolated with an acceptable yield in a development context. The reaction was then performed with a variety of anilines for testing the preparation of purines substituted by electrondonating (10−12) or electron-withdrawing groups (13−16) or heterocyclic moieties (17) at position 9. High yields were obtained, except for 6 for which it was limited by steric effect in the first step, indicating low influence of the nucleophilicity of the amine, even when considering Hammett constant extrema (e.g., p-NO2Ph and p-OMePh, 15 and 12, respectively).13 Diversely 2-substituted pyrimidines, with R2 = Me, NH2, Cl,14 were also reacted with p-substituted anilines and gave yields that remain good (18−23). Aliphatic amines reacted effectively under alkaline conditions during the first step to give purines 24−27. The use of glycine tert-butyl esters readily resulted in the production of building blocks (26 and 27) for peptide nucleic acid (PNA) synthesis. This shows the expected compatibility of the method with the presence of acid-labile groups since the release of dimethylamine during the cyclization/aromatization process limits the acidification of the medium. The preparation of a key intermediate 23 in the synthesis of SR 3029 (Figure 1), a commercially available kinase inhibitor with potent antiproliferative properties, aptly illustrates the potential of the present method. Compound 23 was obtained with 95% yield14 as compared to the 18% yield described for its synthesis from 2,6-dichloropurine by the Chan−Lam coupling reaction.15 For C8 functionalization, Vilsmeier-type reagents were prepared separately using oxalyl chloride and a suitable amide and were added at 35 °C to the reaction mixture right after the first step of the sequence.16 The cyclization step was then performed at 80 °C, as it appeared to be less reactive than for classical Vilsmeier’s reagent. Thus, the method was found tolerant to sterical hindrance, as methyl, dimethylamino, phenyl, and 4-chlorophenyl groups were all introduced with good yields (28−32). Oxalyl chloride presented the best characteristics in a one-pot context (i.e., formation of gaseous
Scheme 3. Substrate Scope of “Variant A” Sequence
ribonucleosides. The reaction of 6-amino-5-amidinopyrimidines 33−35 with electrophiles provided the purine N9-sugar, thereby opening a route to nucleosides. Precursors of adenosine, ascamycin, and guanosine derivatives 36−38 were synthesized in only one step from amidines 33−35, 1-O-acetyl-2,3,5-tri-Obenzoyl-β-D-ribose, and TMSOTf, with moderate yields through nonoptimized silyl-Hilbert−Johnson17 procedures (replacement of TMSOTf by SnCl4 led to similar yields). Interestingly, the method allowed the straightforward introduction of a substituent at position 8, as demonstrated with the synthesis of the 8-methyl nucleoside 37. This procedure of glycosylation was highly selective since only one ribonucleoside was detected by 1H NMR. In the presence of TMSOTf, pyrimidine 33 led exclusively to 6-chloropurine that appeared in additional experiments to be unreactive in the glycosylation reaction without silylation (SI). Thus, the formation of 9H-6-chloropurines can compete with the oxocarbenium formation necessary for pyrimidine glycosylation, thereby limiting the yields. Under the same conditions, pyrimidine 34 was converted to nucleoside 37, isolated in 42% yield as the sole detected nucleoside (NMR), and unreacted 34 was recovered (55%), showing in this case a weak yield limitation via 9H-purine formation. These results demonstrate that 5-amidino-4-aminopyrimidines can be used for preparing rapidly purine nucleosides via a highly selective one-pot glycosylation−cyclization process involving primarily the reaction of the silylated pyrimidine amino group with the activated sugar.18 Finally, 7-benzylpurine was prepared through a second Variant “B” involving (1) selective N5-alkylation of 5-amino4,6-dichloropyrimidines and amination, according to Liu et al.,19 and (2) addition of a Vilsmeier-type reagent resulting in a quantitative purine scaffold formation (SI). In summary, the versatile one-pot synthesis of highly substituted purines and its variant routes A and B reported herein highlight the large chemical potential of the method made of Vilsmeier-type reagents and pyrimidines. Such a toolbox should receive many applications in the search for new biological tools and drugs, strongly broadening the accessible 6362
DOI: 10.1021/acs.orglett.7b03209 Org. Lett. 2017, 19, 6360−6363
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Organic Letters
Andreasen, J.; Shimpukade, B.; Ulven, T. Green Chem. 2013, 15, 336− 340. (6) (a) Aguado, L.; Camarasa, M.-J.; Pérez-Pérez, M.-J. J. Comb. Chem. 2009, 11, 210−212. (b) Aguado, L.; Canela, M.-D.; Thibaut, H. J.; Priego, E.-M.; Camarasa, M.-J.; Leyssen, P.; Neyts, J.; Pérez-Pérez, M.-J. Eur. J. Med. Chem. 2012, 49, 279−288. (7) Yang, J.; Dang, Q.; Liu, J.; Wei, Z.; Wu, J.; Bai, X. J. Comb. Chem. 2005, 7, 474−482. (8) Dejmek, M.; Kovackova, S.; Zbornikova, E.; Hrebabecky, H.; Sala, M.; Dracinsky, M.; Nencka, R. RSC Adv. 2012, 2, 6970−6980. (9) Toste, D.; McNulty, J.; Still, I. W. J. Synth. Commun. 1994, 24, 1617−1624. (10) Daluge, S. M.; Martin, M. T.; Sickles, B. R.; Livingston, D. A. Nucleosides, Nucleotides Nucleic Acids 2000, 19, 297−327. (11) (a) Pawar, V. G.; De Borggraeve, W. M.; Robeyns, K.; Van Meervelt, L.; Compernolle, F.; Hoornaert, G. Tetrahedron Lett. 2006, 47, 5451−5453. (b) Dohle, W.; Staubitz, A.; Knochel, P. Chem. - Eur. J. 2003, 9, 5323−5331. (c) Stucky, G.; Griffiths, G. PCT WO96/21664, 1996. (12) Cechova, L.; Jansa, P.; Sala, M.; Dracinsky, M.; Holy, A.; Janeba, Z. Tetrahedron 2011, 67, 866−871. (13) The reaction of formamidine of 1 with 4-bromoaniline in a 1:1 ratio in the presence of benzenesulfonic acid led to the expected purine 8 and its 6-(bromophenyl)amino derivative in a 10:90 ratio. When using formamidine of 1 in excess (5 equiv), complete reaction was observed by 1H NMR to lead to 8 and 6-substituted 9-arylpurine in a 70:30 ratio. (14) This compound was prepared from N-(2-amino-4,6-dichloropyrimin-5-yl)-N′,N′-dimethylformamidine which was converted to the corresponding 2,4,6-trichloropyrimidine through diazotization (44% yield); procedure adapted from: (a) Krchnak, V.; Arnold, Z. Collect. Czech. Chem. Commun. 1975, 40, 1390−1395. (b) Nara, S. J.; Jha, M.; Brinkhorst, J.; Zemanek, T. J.; Pratt, D. A. J. Org. Chem. 2008, 73, 9326−9333. This compound showed high reactivity and selectivity in nucleophilic substitution with arylamines and allowed more efficient reactions with o-substituted anilines (21 vs 6). (15) (a) Bibian, M.; Rahaim, R. J.; Choi, J. Y.; Noguchi, Y.; Schürer, S.; Chen, W.; Nakanishi, S.; Licht, K.; Rosenberg, L. H.; Li, L.; Feng, Y.; Cameron, M. D.; Duckett, D. R.; Cleveland, J. L.; Roush, W. R. Bioorg. Med. Chem. Lett. 2013, 23, 4374−4380. (b) Roush, W. R.; Duckett, D. R.; Cleveland, J. L.; Rosenberg, L. H. PCT WO 2017/ 066055, 2017. (16) For 8-substituted purines, a rapid workup was performed after the alkylation step, and the crude product in glyme was reacted with the Vilsmeier-type reagent, prepared right before by adding oxalyl chloride in a solution of amide in 1,2-dichloroethane. (17) Niedballa, U.; Vorbrueggen, H. J. Org. Chem. 1976, 41, 2084− 2086. (18) The reaction of the anomeric isomer mixture of 2,3,5-tri-Obenzoyl-1-chlororibose and freshly silylated pyrimidine 33 led to the βribonucleoside 36 in 34% yield without formation of 9H-purine demonstrating purine formation from the silylated pyrimidine. (19) Liu, J.; Dang, Q.; Wei, Z.; Shi, F.; Bai, X. J. Comb. Chem. 2006, 8, 410−416.
chemical diversity. The one-pot synthesis is compatible with the presence of acid-labile groups and avoids the release of nucleophilic species able to substitute the 6-chlorine atom of the prepared purines in contrast to other methods of purine synthesis from pyrimidines that release water or alcohols. In the pyrimidine intermediates, the high reactivity of the primary 5or 6-amino group in comparison to that of the secondary 6- or 5-amino group introduced through SNAr reaction allows a highly selective Vilsmeier reaction.
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03209. Experimental procedures and spectral data (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Romain Haudecoeur: 0000-0002-6271-4717 Benjamin Boucherle: 0000-0002-1174-4449 Jean-Luc Décout: 0000-0001-7058-1304 Notes
The authors declare the following competing financial interest(s): R.Z., W.Z., R.H., B.B., and J.L.D. are co-inventors of the related patent application PCT/IB2017/000688 (mentioned in the manuscript).
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ACKNOWLEDGMENTS The authors are grateful to association “Vaincre La Mucoviscidose” (B.B., J.A., and R.Z. Grants RF20140501061, RF20150501421, RF20160501676) and ANR (Labex Arcane ANR-11-LABX-0003-01, J.A. and W.Z. grants) for financial support.
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REFERENCES
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DOI: 10.1021/acs.orglett.7b03209 Org. Lett. 2017, 19, 6360−6363
