Letter pubs.acs.org/OrgLett
A New Strategy To Construct Acyclic Nucleosides via Ag(I)-Catalyzed Addition of Pronucleophiles to 9‑Allenyl‑9H‑purines Tao Wei,† Ming-Sheng Xie,† Gui-Rong Qu,*,† Hong-Ying Niu,‡ and Hai-Ming Guo*,† †
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China ‡ School of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang 453003, China S Supporting Information *
ABSTRACT: A new strategy to construct acyclic nucleosides with diverse side chains was developed. With Ag(I) salts as catalysts, the hydrocarboxylation, hydroamination, and hydrocarbonation reactions proceeded well, affording acyclic nucleosides in good yields (41 examples, 60−98% yields). Meanwhile, these reactions exhibited high chemoselectivities and Eselectivities.
I
method to synthesize purine nucleosides with different side chains is of great significance. Conventional methods of introducing diverse side chains into the N9 of purines are based on the nucleophilicity of the N9 in purines, such as (1) the alkylation reaction of purines with halogenated hydrocarbons to link an alkoxy substituent in the side chains (Scheme 1a);7 (2) the aza-Michael addition/ reduction reactions of purines with Michael acceptors such as
n recent years, human infectious diseases which are caused by viruses have increased rapidly due to the reproduction and propagation of virus guests in living body cells.1 Thus, the synthesis of nucleoside compounds has attracted much more attention owing to their excellent antiviral activities.2 In 1977, Acyclovir was first reported as a potent antiherpes drug, when various acyclic nucleosides with diverse side chains were found to exhibit outstanding antiviral activities.3 As shown in Figure 1,
Scheme 1. Synthesis of Acyclic Nucleosides with Diverse Side Chains
Figure 1. Selected examples of acyclic nucleosides with biological activities.
S-DHPA and R-PMPDAP, containing three carbon atoms in the side chains, exhibit strong antiviral activities against vaccinia and feline immunodeficiency virus infection, respectively.4 Famciclovir, containing ester groups in the side chains, has been approved by the FDA as an antiviral drug.5 Abacavir, comprising a carbon−carbon double bond in the side chain, is a reverse transcriptase inhibitor used to treat HIV.6 Because purine nucleosides with different side chains possess a broad spectrum of activities, the search for an efficient © 2014 American Chemical Society
Received: December 17, 2013 Published: January 17, 2014 900
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Scheme 2. Hydrocarboxylation Reactionsa,b
α,β-unsaturated aldehydes to link a hydroxyl group at C3′ of the side chains (Scheme 1b);8 and (3) the ring-opening reaction of purines with propylene oxides to introduce an alkoxy group at C3′ of the side chains (Scheme 1c).9 However, these methods could only introduce a single type of side chain.10 As we know, allenamines are versatile building blocks in organic synthesis.11 In the context of ongoing projects for the synthesis of purine analogues,12 we wish to develop a new strategy to construct purine acyclic nucleosides with diverse side chains by utilizing pronucleophiles to react with 9-allenyl9H-purines (Scheme 1d). Initially, we selected 9-allenyl-9H-purine (1a) and acetic acid (2a) as model substrates to optimize the reaction conditions (Table 1). With Pd salts as catalysts, the reaction did not occur Table 1. Optimization of Reaction Conditionsa
entry
catalyst
x
temp (°C)
time (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10c
Pd2(dba)3·CHCl3 Pd2(dba)3 AgNO3 AgOCOCF3 AgF Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3
5 5 5 5 5 5 2 1 2 2
80 80 80 80 80 80 80 80 70 80
8 8 8 8 8 8 8 8 8 8
N.R. N.R. 61 58 67 83 84 42 75 85
a
Reaction conditions: 1 (0.1 mmol), 2a (1.2 equiv), CH3CN (1.0 mL) in the air atmosphere. b Isolated yield based on 1. c E/Z = 1:1 determined by 1H NMR.
a
Unless otherwise noted, the reaction conditions were: 1a (0.1 mmol), 2a (1.2 equiv), CH3CN (1.0 mL) under an air atmosphere. bIsolated yield based on 1a. cIn the presence of N2. N.R. = No Reaction.
(Scheme 2, 3o−3s). Furthermore, when benzoic acid was tested, the product 3t was obtained with an 89% yield (Scheme 2, 3t). In the case of L-Boc-proline, the desired product 3u was afforded in an inseparable mixture of Z- and E-isomers (Scheme 2, 3u). Interestingly, in the absence of acetic acid (2a), the reaction proceeded well in the air atmosphere with AgOAc as a reactant (Scheme 3a). Meanwhile, when acetic acid was replaced by
(entries 1−2). Luckily, when AgNO3 was employed as a catalyst, the reaction proceeded well to afford product 3a (entry 3). Notably, the addition reaction had an excellent chemoselectivity and the carbon−carbon double bond in 3a has an exclusively E-configuration.13 Other Ag salts were tested, and Ag2CO3 was found to be the best one (entries 3−6). Next, the catalyst loading of the reaction was evaluated, and 2 mol % was the best choice (entries 6−8). When the reaction temperature was lowered from 80 to 70 °C, the yield decreased slightly (entry 9). When the reaction was carried out in the presence of N2, the yield of 3a was unchanged (entry 10). Under the optimized reaction conditions (Table 1, entry 7), several 9-allenyl-9H-purines with different substituents at the C2 or C6 position were subjected to the hydrocarboxylation reactions, giving the desired acyclic nucleosides in satisfactory yields (Scheme 2, 3a−3h). When 9-allenyl-9H-adenine was tested, the hydrocarboxylation reaction did not occur (Scheme 2, 3i). Then, the amino group of 9-allenyl-9H-adenine was protected by the Boc group, and the corresponding hydrocarboxylation reaction proceeded well, affording the desired product 3j in 95% yield. When carboxylic acids with different functional groups were tested, the reactions worked well, affording the corresponding products with good yields (Scheme 2, 3k−3n). To our delight, aliphatic carboxylic acids including primary, secondary, and cyclic carboxylic acids were also suitable substrates, giving acyclic nucleosides with good results
Scheme 3. Different Routes To Synthesize Acyclic Nucleoside 3a
PhI(OAc)2, the product 3a could still be obtained under an air atmosphere (Scheme 3b). In the two cases, these reactions did not occur when performed under an N2 atmosphere, which indicated that the hydrogen ions came from trace amounts of H2O in the air atmosphere. Subsequently, the hydroamination reactions of 9-allenyl-9Hpurine derivatives with different amines were further evaluated 901
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also suitable substrates, giving 5j−5m with 95−98% yields (Scheme 4, 5j−5m). Surprisingly, when benzylamine was tested, the product 5n was obtained with two moieties of purines (Scheme 4). Then, we examined the hydrocarbonation reactions of 9allenyl-9H-purine derivatives with carbon nucleophiles (Scheme 5). Under the optimal reaction conditions (Table 1, entry 7), the hydrocarbonation reaction between 1a and malononitrile (6a) exhibited low reactivity, and AgF (1.0 equiv) could afford the product 7a in 87% yield (Scheme 5a, 7a) (for the optimization of the reaction, see the Supporting Information for details). With AgF (1.0 equiv) as the catalyst, several representative purine substrates were evaluated, and the corresponding products were obtained in good yields (Scheme 5a, 7b−7d). Next, ethyl 2-cyanoacetate (6b) was explored, and the product 7e was obtained in 78% yield (Scheme 5b). When diethyl malonate was used, the reaction did not occur. Subsequently, structure derivatization of the acyclic nucleosides was tried (Scheme 6). Hydrolysis of acyclic nucleoside 3a
(Scheme 4). Under the optimal reaction conditions (Table 1, entry 7), the hydroamination reaction between 9-allenyl-9HScheme 4. Hydroamination Reactionsa,b
Scheme 6. Structure Derivatization of the Acyclic Nucleosides
a
Unless otherwise noted, the reaction conditions were: 1 (0.1 mmol), 4 (1.1 equiv), AgF (3 mol %), CH3CN (1.0 mL) in the air atmosphere for 4 h. b Isolated yield based on 1. c Reaction time: 2 h. d AgF (5 mol %).
purine (1a) and dibenzylamine (4a) could only afford product 5a with a 60% yield. Fortunately, when AgF (3 mol %) was employed as a catalyst, product 5a could be obtained with a 95% yield (Scheme 4, 5a) (for the optimization of the reaction, see the Supporting Information for details). Next, with AgF (3 mol %) as the catalyst, diisopropylamine (4b), pyrrolidine (4c), piperidine (4d), and morpholine (4e) were used as pronucleophiles, and the reactions worked well (Scheme 4, 5b−5e). In addition, aniline and substituted anilines were also tested, and the desired products were obtained with good yields (Scheme 5, 5f−5i). Besides, several 9-allenyl-9H-purines were
could generate product 8a with a hydroxyl group in quantitative yield. Next, the phosphine methylation of acyclic nucleoside 8a afforded the product 9a in 98% yield (Scheme 6a). Meanwhile, hydrogenation of 8a smoothly generated product 10a in 98% yield. As we know, an introduction of the fluorine atom into acyclic nucleosides often leads to remarkable changes in their pharmacokinetic properties.14 Thus, the fluoridation of acyclic nucleoside 7e was tried and the desired fluoride 11e was obtained with 95% yield, which could be further transformed to the acyclic nucleoside 12e by reduction (Scheme 6b). When the deuterium-labeled acetic acid (D-2a) was used to react with 9-allenyl-9H-purine (1a), the product (D-3a) was obtained with the deuterium atom at the C2′ of the side chain (Scheme 7a). Based on the above experiments and previous work,15 we proposed that, initially, the 9-allenyl-9H-purine (1a) was activated by the Ag+ cation through the coordination effect to form the intermediate A. Subsequently, attack by a nucleophile led to the vinyl-silver intermediate B. Finally, the intermediate B was quenched by a proton, which would generate the final product and release the Ag+ cation (Scheme 7b). In conclusion, we have developed an efficient method for the synthesis of acyclic nucleosides with diverse side chains. Compared with previous routes utilizing the nucleophilicity of the N9 in purines, this strategy made use of other pronucleophiles to react with 9-allenyl-9H-purines for introduc-
Scheme 5. Hydrocarbonation Reactionsa,b
a
Reaction conditions: 1 (0.1 mmol), 6 (1.1 equiv), AgF (1.0 equiv), CH3CN (1.0 mL) under an air atmosphere for 5 h. b Isolated yield based on 1. 902
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(3) Elion, G. B.; Furman, P. A.; Fyfe, J. A.; de Miranda, P.; Beauchamp, L.; Schaeffer, H. J. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 5716. (4) (a) De Clercq, E.; Descamps, J.; De Somer, P.; Holý, A. Science 1978, 200, 563. (b) Balzarini, J.; Aquaro, S.; Perno, C.-F.; Witvrouw, M.; Holý, A.; De Clercq, E. Biochem. Biophys. Res. Commun. 1996, 219, 337. (c) Šolínová, V.; Kašička, V.; Sázelová, P.; Holý, A. Electrophoresis 2009, 30, 2245. (5) Harnden, M. R.; Jarvest, R. L.; Boyd, M. R.; Sutton, D.; Vere Hodge, R. A. J. Med. Chem. 1989, 32, 1739. (6) (a) Crimmins, M. T.; King, B. W. J. Org. Chem. 1996, 61, 4192. (b) Bell, C. C.; Faulkner, L.; Martinsson, K.; Farrell, J.; Alfirevic, A.; Tugwood, J.; Pirmohamed, M.; Naisbitt, D. J.; Park, B. K. Chem. Res. Toxicol. 2013, 26, 759. (7) (a) Holý, A.; Votruba, I.; Masojídková, M.; Andrei, G.; Snoeck, R.; Naesens, L.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2002, 45, 1918. (b) Diederichsen, U.; Weicherding, D.; Diezemann, N. Org. Biomol. Chem. 2005, 3, 1058. (c) Harnden, M. R.; Jarvest, R. L.; Bacon, T. H.; Boyd, M. R. J. Med. Chem. 1987, 30, 1636. (d) Cheng, C.; Shimo, T.; Somekawa, K.; Baba, M. Tetrahedron 1998, 54, 2031. (8) (a) Gandelman, M.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2005, 44, 2393. (b) Guo, H.-M.; Yuan, T.-F.; Niu, H.-Y.; Liu, J.-Y.; Mao, R.Z.; Li, D.-Y.; Qu, G.-R. Chem.Eur. J. 2011, 17, 4095. (c) Wu, H.; Tian, Z.-Q.; Zhang, L.-L.; Huang, Y.-D.; Wang, Y.-M. Adv. Synth. Catal. 2012, 354, 2977. (9) (a) Baumgartner, H.; Marschner, C.; Pucher, R.; Griengl, H. Tetrahedron Lett. 1991, 32, 611. (b) Zhang, L.; Peritz, A.; Meggers, E. J. Am. Chem. Soc. 2005, 127, 4174. (10) (a) Stanley, L. M.; Hartwig, J. F. J. Am. Chem. Soc. 2009, 131, 8971. (b) Guo, H.-M.; Wu, Y.-Y.; Niu, H.-Y.; Wang, D.-C.; Qu, G.-R. J. Org. Chem. 2010, 75, 3863. (c) Ullas, G. V.; Chu, C. K.; Ahn, M. K.; Kosugi, Y. J. Org. Chem. 1988, 53, 2413. (11) For selected examples on allenamines, see: (a) Hubert, A. J.; Viehe, H. G. J. Chem. Soc. C 1968, 228. (b) Wei, L.-L.; Xiong, H.; Hsung, R. P. Acc. Chem. Res. 2003, 36, 773. (c) Lu, T.; Lu, Z.; Ma, Z.X.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2013, 113, 4862. For selected reviews on allenes, see: (d) Zimmer, R.; Dinesh, C. U.; Nandanan, E.; Khan, F. A. Chem. Rev. 2000, 100, 3067. (e) Müller, T. E.; Hultzsch, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108, 3795. (f) Yu, S.; Ma, S. Angew. Chem., Int. Ed. 2012, 51, 3074. (g) Patil, N. T.; Kavthe, R. D.; Shinde, V. S. Tetrahedron 2012, 68, 8079. (12) (a) Guo, H.-M.; Xia, C.; Niu, H.-Y.; Zhang, X.-T.; Kong, S.-N.; Wang, D.-C.; Qu, G.-R. Adv. Synth. Catal. 2011, 353, 53. (b) Niu, H.Y.; Yuan, T.-F.; Qu, G.-R.; Li, D.-Y.; Mao, R.-Z.; Jin, X.; Yang, X.-N.; Guo, H.-M. Chin. J. Org. Chem. 2011, 10, 1613. (c) Meng, G.; Niu, H.Y.; Qu, G.-R.; Fossey, J. S.; Li, J.-P.; Guo, H.-M. Chem. Commun. 2012, 48, 9601. (d) Qu, G.-R.; Liang, L.; Niu, H.-Y.; Rao, W.-H.; Guo, H.M.; Fossey, J. S. Org. Lett. 2012, 14, 4494. (e) Li, J.-P.; Huang, Y.; Xie, M.-S.; Qu, G.-R.; Niu, H.-Y.; Wang, H.-X.; Qin, B.-W.; Guo, H.-M. J. Org. Chem. 2013, 78, 12629. (f) Wang, D.-C.; Niu, H.-Y.; Xie, M.-S.; Qu, G.-R.; Wang, H.-X.; Guo, H.-M. Org. Lett. 2014, 16, 262. (13) The carbon−carbon double bond in the side chain is an Econfiguration; see Supporting Information for details. (14) Shimizu, M.; Hiyama, T. Angew. Chem., Int. Ed. 2005, 44, 214. (15) (a) Arbour, J. L.; Rzepa, H. S.; Contreras-García, J.; Adrio, L. A.; Barreiro, E. M.; Hii, K. K. Chem.Eur. J. 2012, 18, 11317. (b) Marshall, J. A.; Bartley, G. S. J. Org. Chem. 1994, 59, 7169. (c) Lohse, A. G.; Hsung, R. P. Org. Lett. 2009, 11, 3430. (d) Sai, M.; Matsubara, S. Org. Lett. 2011, 13, 4676.
Scheme 7. (a) Deuterium-Labelling Experiment; (b) Proposed Mechanism for the Reaction
ing different side chains to the N9 of purines. With Ag(I) salts as catalysts, the reactions proceeded well, affording acyclic nucleosides with good results (41 examples, 60−98% yields). Meanwhile, these addition reactions exhibited high chemoselectivities and E-selectivities.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental details, optimization of the reaction conditions, copies of all spectral, and full characterization for all new compounds. This information is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: [email protected]. *E-mail: [email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (Nos. 21072047, 21172059, 21272059, 21202039, and 21372066), Excellent Youth Foundation of Henan Scientific Committee (No. 114100510012), the Program for Innovative Research Team from the University of Henan Province (2012IRTSTHN006), the Program for Changjiang Scholars and Innovative Research Team in University (IRT1061), Research Fund for the Doctoral Program of Higher Education of China (No.20124104110006), and the Program for Science & Technology Innovation Talents in Universities of Henan Province (No.13HASTIT013).
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REFERENCES
(1) (a) Francesco, R.; De Carfí, A. Adv. Drug. Delivery Rev. 2007, 59, 1242. (b) Guo, H.-M.; Wu, S.; Niu, H.-Y.; Song, G.; Qu, G.-R. Chemical Synthesis of Acyclic Nucleosides in Chemical Synthesis of Nucleoside Analogues 3; Merino, Pedro, Ed.; John Wiley & Sons: New York, 2013; pp 103−162. (2) (a) Parker, W. B. Chem. Rev. 2009, 109, 2880. (b) Mieczkowski, A.; Roy, V.; Agrofoglio, L. A. Chem. Rev. 2010, 110, 1828. 903
dx.doi.org/10.1021/ol4036566 | Org. Lett. 2014, 16, 900−903
A New Strategy To Construct Acyclic Nucleosides via Ag(I)-Catalyzed Addition of Pronucleophiles to 9‑Allenyl‑9H‑purines Tao Wei,† Ming-Sheng Xie,† Gui-Rong Qu,*,† Hong-Ying Niu,‡ and Hai-Ming Guo*,† †
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang, Henan 453007, P. R. China ‡ School of Chemistry and Chemical Engineering, Henan Institute of Science and Technology, Xinxiang 453003, China S Supporting Information *
ABSTRACT: A new strategy to construct acyclic nucleosides with diverse side chains was developed. With Ag(I) salts as catalysts, the hydrocarboxylation, hydroamination, and hydrocarbonation reactions proceeded well, affording acyclic nucleosides in good yields (41 examples, 60−98% yields). Meanwhile, these reactions exhibited high chemoselectivities and Eselectivities.
I
method to synthesize purine nucleosides with different side chains is of great significance. Conventional methods of introducing diverse side chains into the N9 of purines are based on the nucleophilicity of the N9 in purines, such as (1) the alkylation reaction of purines with halogenated hydrocarbons to link an alkoxy substituent in the side chains (Scheme 1a);7 (2) the aza-Michael addition/ reduction reactions of purines with Michael acceptors such as
n recent years, human infectious diseases which are caused by viruses have increased rapidly due to the reproduction and propagation of virus guests in living body cells.1 Thus, the synthesis of nucleoside compounds has attracted much more attention owing to their excellent antiviral activities.2 In 1977, Acyclovir was first reported as a potent antiherpes drug, when various acyclic nucleosides with diverse side chains were found to exhibit outstanding antiviral activities.3 As shown in Figure 1,
Scheme 1. Synthesis of Acyclic Nucleosides with Diverse Side Chains
Figure 1. Selected examples of acyclic nucleosides with biological activities.
S-DHPA and R-PMPDAP, containing three carbon atoms in the side chains, exhibit strong antiviral activities against vaccinia and feline immunodeficiency virus infection, respectively.4 Famciclovir, containing ester groups in the side chains, has been approved by the FDA as an antiviral drug.5 Abacavir, comprising a carbon−carbon double bond in the side chain, is a reverse transcriptase inhibitor used to treat HIV.6 Because purine nucleosides with different side chains possess a broad spectrum of activities, the search for an efficient © 2014 American Chemical Society
Received: December 17, 2013 Published: January 17, 2014 900
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Scheme 2. Hydrocarboxylation Reactionsa,b
α,β-unsaturated aldehydes to link a hydroxyl group at C3′ of the side chains (Scheme 1b);8 and (3) the ring-opening reaction of purines with propylene oxides to introduce an alkoxy group at C3′ of the side chains (Scheme 1c).9 However, these methods could only introduce a single type of side chain.10 As we know, allenamines are versatile building blocks in organic synthesis.11 In the context of ongoing projects for the synthesis of purine analogues,12 we wish to develop a new strategy to construct purine acyclic nucleosides with diverse side chains by utilizing pronucleophiles to react with 9-allenyl9H-purines (Scheme 1d). Initially, we selected 9-allenyl-9H-purine (1a) and acetic acid (2a) as model substrates to optimize the reaction conditions (Table 1). With Pd salts as catalysts, the reaction did not occur Table 1. Optimization of Reaction Conditionsa
entry
catalyst
x
temp (°C)
time (h)
yield (%)b
1 2 3 4 5 6 7 8 9 10c
Pd2(dba)3·CHCl3 Pd2(dba)3 AgNO3 AgOCOCF3 AgF Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3 Ag2CO3
5 5 5 5 5 5 2 1 2 2
80 80 80 80 80 80 80 80 70 80
8 8 8 8 8 8 8 8 8 8
N.R. N.R. 61 58 67 83 84 42 75 85
a
Reaction conditions: 1 (0.1 mmol), 2a (1.2 equiv), CH3CN (1.0 mL) in the air atmosphere. b Isolated yield based on 1. c E/Z = 1:1 determined by 1H NMR.
a
Unless otherwise noted, the reaction conditions were: 1a (0.1 mmol), 2a (1.2 equiv), CH3CN (1.0 mL) under an air atmosphere. bIsolated yield based on 1a. cIn the presence of N2. N.R. = No Reaction.
(Scheme 2, 3o−3s). Furthermore, when benzoic acid was tested, the product 3t was obtained with an 89% yield (Scheme 2, 3t). In the case of L-Boc-proline, the desired product 3u was afforded in an inseparable mixture of Z- and E-isomers (Scheme 2, 3u). Interestingly, in the absence of acetic acid (2a), the reaction proceeded well in the air atmosphere with AgOAc as a reactant (Scheme 3a). Meanwhile, when acetic acid was replaced by
(entries 1−2). Luckily, when AgNO3 was employed as a catalyst, the reaction proceeded well to afford product 3a (entry 3). Notably, the addition reaction had an excellent chemoselectivity and the carbon−carbon double bond in 3a has an exclusively E-configuration.13 Other Ag salts were tested, and Ag2CO3 was found to be the best one (entries 3−6). Next, the catalyst loading of the reaction was evaluated, and 2 mol % was the best choice (entries 6−8). When the reaction temperature was lowered from 80 to 70 °C, the yield decreased slightly (entry 9). When the reaction was carried out in the presence of N2, the yield of 3a was unchanged (entry 10). Under the optimized reaction conditions (Table 1, entry 7), several 9-allenyl-9H-purines with different substituents at the C2 or C6 position were subjected to the hydrocarboxylation reactions, giving the desired acyclic nucleosides in satisfactory yields (Scheme 2, 3a−3h). When 9-allenyl-9H-adenine was tested, the hydrocarboxylation reaction did not occur (Scheme 2, 3i). Then, the amino group of 9-allenyl-9H-adenine was protected by the Boc group, and the corresponding hydrocarboxylation reaction proceeded well, affording the desired product 3j in 95% yield. When carboxylic acids with different functional groups were tested, the reactions worked well, affording the corresponding products with good yields (Scheme 2, 3k−3n). To our delight, aliphatic carboxylic acids including primary, secondary, and cyclic carboxylic acids were also suitable substrates, giving acyclic nucleosides with good results
Scheme 3. Different Routes To Synthesize Acyclic Nucleoside 3a
PhI(OAc)2, the product 3a could still be obtained under an air atmosphere (Scheme 3b). In the two cases, these reactions did not occur when performed under an N2 atmosphere, which indicated that the hydrogen ions came from trace amounts of H2O in the air atmosphere. Subsequently, the hydroamination reactions of 9-allenyl-9Hpurine derivatives with different amines were further evaluated 901
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also suitable substrates, giving 5j−5m with 95−98% yields (Scheme 4, 5j−5m). Surprisingly, when benzylamine was tested, the product 5n was obtained with two moieties of purines (Scheme 4). Then, we examined the hydrocarbonation reactions of 9allenyl-9H-purine derivatives with carbon nucleophiles (Scheme 5). Under the optimal reaction conditions (Table 1, entry 7), the hydrocarbonation reaction between 1a and malononitrile (6a) exhibited low reactivity, and AgF (1.0 equiv) could afford the product 7a in 87% yield (Scheme 5a, 7a) (for the optimization of the reaction, see the Supporting Information for details). With AgF (1.0 equiv) as the catalyst, several representative purine substrates were evaluated, and the corresponding products were obtained in good yields (Scheme 5a, 7b−7d). Next, ethyl 2-cyanoacetate (6b) was explored, and the product 7e was obtained in 78% yield (Scheme 5b). When diethyl malonate was used, the reaction did not occur. Subsequently, structure derivatization of the acyclic nucleosides was tried (Scheme 6). Hydrolysis of acyclic nucleoside 3a
(Scheme 4). Under the optimal reaction conditions (Table 1, entry 7), the hydroamination reaction between 9-allenyl-9HScheme 4. Hydroamination Reactionsa,b
Scheme 6. Structure Derivatization of the Acyclic Nucleosides
a
Unless otherwise noted, the reaction conditions were: 1 (0.1 mmol), 4 (1.1 equiv), AgF (3 mol %), CH3CN (1.0 mL) in the air atmosphere for 4 h. b Isolated yield based on 1. c Reaction time: 2 h. d AgF (5 mol %).
purine (1a) and dibenzylamine (4a) could only afford product 5a with a 60% yield. Fortunately, when AgF (3 mol %) was employed as a catalyst, product 5a could be obtained with a 95% yield (Scheme 4, 5a) (for the optimization of the reaction, see the Supporting Information for details). Next, with AgF (3 mol %) as the catalyst, diisopropylamine (4b), pyrrolidine (4c), piperidine (4d), and morpholine (4e) were used as pronucleophiles, and the reactions worked well (Scheme 4, 5b−5e). In addition, aniline and substituted anilines were also tested, and the desired products were obtained with good yields (Scheme 5, 5f−5i). Besides, several 9-allenyl-9H-purines were
could generate product 8a with a hydroxyl group in quantitative yield. Next, the phosphine methylation of acyclic nucleoside 8a afforded the product 9a in 98% yield (Scheme 6a). Meanwhile, hydrogenation of 8a smoothly generated product 10a in 98% yield. As we know, an introduction of the fluorine atom into acyclic nucleosides often leads to remarkable changes in their pharmacokinetic properties.14 Thus, the fluoridation of acyclic nucleoside 7e was tried and the desired fluoride 11e was obtained with 95% yield, which could be further transformed to the acyclic nucleoside 12e by reduction (Scheme 6b). When the deuterium-labeled acetic acid (D-2a) was used to react with 9-allenyl-9H-purine (1a), the product (D-3a) was obtained with the deuterium atom at the C2′ of the side chain (Scheme 7a). Based on the above experiments and previous work,15 we proposed that, initially, the 9-allenyl-9H-purine (1a) was activated by the Ag+ cation through the coordination effect to form the intermediate A. Subsequently, attack by a nucleophile led to the vinyl-silver intermediate B. Finally, the intermediate B was quenched by a proton, which would generate the final product and release the Ag+ cation (Scheme 7b). In conclusion, we have developed an efficient method for the synthesis of acyclic nucleosides with diverse side chains. Compared with previous routes utilizing the nucleophilicity of the N9 in purines, this strategy made use of other pronucleophiles to react with 9-allenyl-9H-purines for introduc-
Scheme 5. Hydrocarbonation Reactionsa,b
a
Reaction conditions: 1 (0.1 mmol), 6 (1.1 equiv), AgF (1.0 equiv), CH3CN (1.0 mL) under an air atmosphere for 5 h. b Isolated yield based on 1. 902
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Organic Letters
Letter
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Scheme 7. (a) Deuterium-Labelling Experiment; (b) Proposed Mechanism for the Reaction
ing different side chains to the N9 of purines. With Ag(I) salts as catalysts, the reactions proceeded well, affording acyclic nucleosides with good results (41 examples, 60−98% yields). Meanwhile, these addition reactions exhibited high chemoselectivities and E-selectivities.
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ASSOCIATED CONTENT
S Supporting Information *
Experimental details, optimization of the reaction conditions, copies of all spectral, and full characterization for all new compounds. This information is available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
*E-mail: [email protected]. *E-mail: [email protected]. Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (Nos. 21072047, 21172059, 21272059, 21202039, and 21372066), Excellent Youth Foundation of Henan Scientific Committee (No. 114100510012), the Program for Innovative Research Team from the University of Henan Province (2012IRTSTHN006), the Program for Changjiang Scholars and Innovative Research Team in University (IRT1061), Research Fund for the Doctoral Program of Higher Education of China (No.20124104110006), and the Program for Science & Technology Innovation Talents in Universities of Henan Province (No.13HASTIT013).
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REFERENCES
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