Radical route for the Alkylation of Purine Nucleosides at C6 via Minisci reaction

Article abstract of DOI:10.1021/ol4033336

A highly regioselective Minisci reaction with the decarboxylative alkylation of purine nucleosides under mild conditions was developed. With 5 mol % AgNO₃ as a catalyst and (NH₄)₂S ₂O₈ as an oxidant, a series of purine nucleosides including ribosyl, deoxyribosyl, arabinosyl purine nucleosides worked well with primary, secondary, and tertiary aliphatic carboxylic acids.

Full text of DOI:10.1021/ol4033336

Letter
pubs.acs.org/OrgLett
Radical Route for the Alkylation of Purine Nucleosides at C6 via
Minisci Reaction
Ran Xia,†,‡ Ming-Sheng Xie,‡ Hong-Ying Niu,‡ Gui-Rong Qu,*,†,‡ and Hai-Ming Guo*,†,‡
†School of Environment, Henan Normal University, Xinxiang, Henan Province 453007, China
‡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 Province453007, P. R. China
S
* Supporting Information
ABSTRACT: A highly regioselective Minisci reaction with the
decarboxylative alkylation of purine nucleosides under mild
conditions was developed. With 5 mol % AgNO3 as a catalyst
and (NH4)2S2O8 as an oxidant, a series of purine nucleosides
including ribosyl, deoxyribosyl, arabinosyl purine nucleosides
worked well with primary, secondary, and tertiary aliphatic
carboxylic acids.
urine bases and nucleosides, as the basic structural units in
RNA and DNA, have found broad applications in
Scheme 1. Synthetic Routes to 6-Alkylpurines
P
biological and pharmaceutical chemistry. In particular, C6-
alkylated purine analogues possess unique biological effects
such as cytostatic,1 antiviral, and antimicrobial activities2 or
receptor modulation.3 For example, 6-methylpurine and 6-
ethylpurine ribonucleoside (Figure 1, A and B) have highly
efforts have been devoted to the synthesis of 6-alkylpurines and
remarkable progress has been made, there are still some
problems unsolved. For instance, the current methods suffer
from either expensive reagents/catalysts/ligands, harsh reaction
conditions, limited substrate scope, low regioselectivities, or
multiple-step procedures. Thus, developing an efficient route to
obtain C6-alkylated purines from cheap and easily available
alkylating reagents under mild condition is challenging and
fascinating.
On the other hand, the radical process, as a powerful method
for alkylation reaction, always proceeds under mild reaction
conditions.16 The only example of radical alkylation for C6-H
purines was acomplished with iodoalkane promoted by FeSO4
and t-BuOOH under acidic conditions.17 It is well-known that
the Minisci reaction using carboxylic acid as alkyl precursor has
the advantages of low cost, effectiveness, and ease of use in
organic synthesis;18 however, its application on the modifica-
tion of purine is still unexplored. In the context of projects in
the modification of purines,19,20 herein we report the silver-
catalyzed radical decarboxylative alkylation of C6-H purine
Figure 1. Selected examples of C6-alkylated purine analogues with
biological activities.
cytotoxic and antitumor activities,4 and 6-cyclopropylpurine
ribonucleosides (Figure 1, C and D) exert interesting cytostatic
activities.4 Furthermore, modification of purine derivatives at
C6 can adjust the number of hydrogen bonds in the purine
moiety5 and thus improve the biological activities of the purine
compounds.6−8 Therefore, searching for an efficient alkylation
method of purine derivatives at C6 is of great interest.
Conventional methods of introducing the alkyl group into
C6 of purines include the following: (1) classical metal-
catalyzed coupling reactions such as Negishi,9 Kumada,10 and
Suzuki reactions,11 which require alkylzinc reagents, Grinard
reagents, and alkylboronic reagents, respectively (Scheme 1a);
(2) the nucleophilic aromatic substitution (SNAr) reaction of 6-
halopurines with 3-alkylacetylacetone in the presence of base or
microwave irradiation (Scheme 1b);12−14 (3) the displacement
of a suitable leaving group on the purines by alkylidenephos-
phorane (Wittig reagent) and subsequent hydrolysis to give
C6-alkylated products (Scheme 1c).15 Although numerous
Received: November 18, 2013
Published: December 16, 2013
© 2013 American Chemical Society
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dx.doi.org/10.1021/ol4033336 | Org. Lett. 2014, 16, 444−447

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst (x)
none
oxidant (y)
solvent
DCM
temp (°C)
time (h)
yield (%)
1
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
K2S2O8 (1.5)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
none
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
50
2
2
2
2
2
6
6
6
6
6
6
6
0
0
2
FeSO4 (10)
DCM
3
CuSO4 (10)
CF3CO2Ag (10)
CF3CO2Ag (10)
CF3CO2Ag (10)
AgNO3 (10)
AgNO3 (10)
AgNO3 (5)
DCM
0
4
DCM
25
39
68
72
93
93
63
0
5
DCM:H2O (1:1)
DCM:H2O (1:1)
DCM:H2O (1:1)
DCM:H2O (1:1)
DCM:H2O (1:1)
DCM:H2O (1:1)
DCM:H2O (1:1)
DCM:H2O (1:1)
6
7
8
9
10
11
12
AgNO3 (2)
AgNO3 (5)
AgNO3 (5)
(NH4)2S2O8 (2)
47
a
b
Reaction conditions: 1a (0.25 mmol), 2a (2.0 equiv). Isolated yields.
nucleosides with alkyl carboxylic acids under mild conditions
(Scheme 1d).
Scheme 2. Silver-Catalyzed Decarboxylative Alkylation of
Various Alkyl Carboxylic Acids
a
Initially, we began our study by using 6-H-2′,3′,5′-tri-O-
acetylpurine riboside (1a) and cyclohexylcarboxylic acid (2a) as
model substrates to optimize the reaction conditions (Table 1).
With K2S2O8 as an oxidant, several catalysts including FeSO4,
CuSO4, and CF3CO2Ag were tested in DCM at rt for 2 h, and
only CF3CO2Ag could afford the desired decarboxylative
alkylation product 3a with 25% yield (Table 1, entries 1−4).
It is worth mentioning that the alkylation exclusively happened
at the C6 position of riboside, which was proved by HSQC,
HMBC, and COSY spectra (see the Supporting Information for
details). That is to say, the reaction showed high regioselectivity
at C6 of riboside. Considering that the poor solubility of
K2S2O8 in DCM was unfavorable for the reaction, water was
added as a cosolvent, and the yield of 3a was improved to 39%
(Table 1, entries 4 and 5). To our delight, the yield of 3a could
reach to 68% when the reaction time was prolonged to 6 h
(Table 1, entry 6). Further experiments showed that AgNO3
was better than CF3CO2Ag, and (NH4)2S2O8 showed higher
efficiency than K2S2O8 (Table 1, entries 6−8). When the
catalyst loading decreased from 10 to 5 mol %, the yield
remained unchanged (Table 1, entries 8 and 9), while further
reduction of catalyst loading to 2 mol % led to lower yield
(Table 1, entry 10). The oxidant was proved to be crucial for
the reaction because no product was obtained in the absence of
(NH4)2S2O8 even when excess amounts of AgNO3 were used
(Table 1, entry 11). Meanwhile, the yield of 3a was decreased
greatly when the reaction temperature was increased, and room
temperature was the better choice (Table 1, entries 9 vs 12).
Under the optimized reaction conditions, a series of
carboxylic acids were subjected to the reaction (Scheme 2).
To our delight, all primary and secondary acyclic alkyl
carboxylic acids gave the corresponding 6-alkylpurine nucleo-
sides in satisfactory yields, and the length of the carbon chain
had little impact on the yields (3a−j). The carboxylic acids with
small rings were less reactive than larger ones (3a vs 3b).
Surprisingly, when 3-methylbutyric acid 2j was tested, the
product 3j was obtained with the migration of methyl group
form β position to α position (3j). For the tertiary alkyl
a
Reaction conditions: 1a (0.25 mmol), carboxylic acid 2 (2.0 equiv),
AgNO3 (5 mol %), (NH4)2S2O8 (2.0 equiv), DCM (1.0 mL), H2O
(1.0 mL), and isolated yields based on 1a.
carboxylic acids, the catalytic system was highly efficient,
affording the desired products with 97−99% yields (3k,l).
Furthermore, the carboxylic acid bearing O or N atom, such as
phenoxyacetic acid and phthalimidoacetic acid also furnished
the reaction smoothly (3m,n). In all cases, the reaction
exhibited high level of regioselectivities and exclusively occurred
on the C6 position of purine nucleosides.
Subsequently, a variety of purine nucleosides were then
probed (Scheme 3). Arabinoribosyl purine nucleosides (1b,c),
deoxyribosyl purine nucleoside (1d), and ribosyl purine
nucleosides (1e−g) all proceeded well to give the correspond-
ing alkylation products with good to high yields (4b−g, 76−
90%). In addition, benzyl-substituted purine (1h) also
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Organic Letters
Letter
Scheme 3. Scope of Purines for the Silver-Catalyzed
a
Decarboxylative Alkylation
Figure 2. Interaction between 1a and AgNO3..
mechanism is shown in Scheme 5. First, Ag(I) cation was
oxidized to Ag(II) cation by peroxydisulfate ion, and sulfate
Scheme 5. Proposed Mechanism for the Minisci Reaction
a
Reaction conditions: 1 (0.25 mmol), 2a (2.0 equiv), AgNO3 (5 mol
%), (NH4)2S2O8 (2.0 equiv), DCM (1.0 mL), H2O (1.0 mL), room
temperature, and isolated yields based on 1.
proceeded smoothly to afford 4h with high yield (4h, 88%
yield). These results showed that this catalytic system could
tolerate various substituents at N9 in purine derivatives.
Next, some experiments were designed to study the
mechanism of the Minisci reaction. First, the kinetic isotope
effect (KIE) experiment was performed, and the KIE was
determined to be 1.07, which indicated that the C6−H bond
breaking event was not the rate-determining step (Scheme 4a).
radical anion was generated. Subsequently, the aliphatic
carboxylic acid was oxidized to alkyl radical by sulfate radical
anion. Finally, the alkyl radical reacted with C6-H rather than
C8-H to afford the corresponding product through radical
substitution reaction.21c
In summary, we have developed a highly regioselective
Minisci reaction for the synthesis of C6-alkylated purine
nucleosides using carboxylic acids as alkylation reagents. A
series of purine nucleosides including ribosyl, deoxyribosyl,
arabinosyl, and nonsugar purine nucleosides worked well.
Moreover, this catalytic system could tolerate a number of
readily available primary, secondary, and tertiary aliphatic
carboxylic acids. The mechanism studies showed that the
alkylation presumably involved the radical process. Further
synthetic applications of this reaction to biologically interesting
compounds are underway in our laboratory.
Scheme 4. (a) Kinetic Isotope Effect (KIE) Experiment; (b)
Radical-Trapping Experiments
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, optimization of the reaction conditions,
proposed mechanism, copies of all spectra, and full character-
ization for all new compounds. This information is available
free of charge via the Internet at http://pubs.acs.org.
Next, in the presence of radical scavenger TEMPO, the Minisci
reaction was completely inhibited and the radical-trapping
byproduct 5 was isolated in 87% yield (Scheme 4b). When
other radical precursors such as cyclohexane or cyclo-
propylboronic acid were tested, the corresponding alkylation
products were obtained with good yields, showing good
generality of the radical reactions for the functionation of C6-
H in purine derivatives (see the Supporting Information for
details).
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: quguir@sina.com.
*E-mail: guohm518@hotmail.com.
Notes
The authors declare no competing financial interest.
1
Subsequently, the H NMR studies between AgNO3 and 1a
ACKNOWLEDGMENTS
were carried out, and the downfield shifts of the resonances for
the C6-H and C8-H protons of 1a were observed. Meanwhile,
the peak of C6-H became broad and the peak of C8-H was still
sharp. However, no change of the C2 proton was found. Thus,
we proposed that the C6-H was activated by the Ag(I) cation
through the coordination with N7 of the purine derivative
(Figure 2). On the basis of the above experiments, a proposed
■
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21072047, 21172059,
21272059, 21202039 and 21372066), the Excellent Youth
Foundation of Henan Scientific Committee (No.
114100510012), the Program for Innovative Research Team
from the University of Henan Province (2012IRTSTHN006),
446
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Organic Letters
Letter
(c) Guo, H.-M.; Mao, Z.-J.; Niu, H.-Y.; Wang, D.-C.; Zhang, G.-S.; Qu,
G.-R. ARKIVOC 2010, ix, 300.
the Program for Changjiang Scholars and Innovative Research
Team in University (IRT1061), the Research Fund for the
Doctoral Program of Higher Education of China (No.2
0124104110006), and the Program for Science & Technology
Innovation Talents in Universities of Henan Province (No.
13HASTIT013).
(14) Nair, V.; Chamberlain, S. D. J. Am. Chem. Soc. 1985, 107, 2183.
(15) Taylor, E.; Martin, S. J. Am. Chem. Soc. 1974, 96, 8095.
(16) (a) Xia, R.; Niu, H.-Y.; Qu, G.-R.; Guo, H.-M. Org. Lett. 2012,
14, 5546. (b) He, T.; Yu, L.; Zhang, L.; Wang, L.; Wang, M. Org. Lett.
2011, 13, 5016. (c) Deng, G.-J.; Ueda, K.; Yanagisawa, S.; Itami, K.; Li,
C.-J. Chem.Eur. J. 2009, 15, 333. (d) Deng, G.-J.; Zhao, L.; Li, C.-J.
Angew. Chem., Int. Ed. 2008, 47, 6278. (e) Lubriks, D.; Sokolovs, I.;
Suna, E. J. Am. Chem. Soc. 2012, 134, 15436.
REFERENCES
■
(1) Montgomery, J. A.; Hewson, K. J. Med. Chem. 1968, 11, 48.
(2) (a) Bakkesteun, A. K.; Gundersen, L.-L.; Langli, G.; Liu, F.;
Nolsøe, J. M. J. Bioorg. Med. Chem. Lett. 2000, 10, 1207. (b) Andersen,
G.; Gundersen, L.-L.; Nissen-Meyer, J.; Rise, F.; Spilsberg, B. Bioorg.
Med. Chem. Lett. 2002, 12, 567. (c) Gundersen, L.-L.; Nissen-Meyer,
J.; Spilsberg, D. J. Med. Chem. 2002, 45, 1383. (d) Bakkestuen, A. K.;
Gundersen, L.-L.; Utenova, B. T. J. Med. Chem. 2005, 48, 2710.
(e) Brændvang, M.; Gundersen, L.-L. Bioorg. Med. Chem. 2005, 13,
6360. (f) Brændvang, M.; Gundersen, L.-L. Bioorg. Med. Chem. 2007,
15, 7144.
(17) Des
7875.
́
aubry, L.; Bourguignon, J.-J. Tetrahedron Lett. 1995, 36,
(18) (a) Gooßen, L. J.; Rodríguez, N.; Gooßen, K. Angew. Chem., Int.
Ed. 2008, 47, 3100. (b) Duncton, M. J. Med. Chem. Commun. 2011, 2,
1135. (c) Fontana, F.; Minisci, F.; Barbosa, M. N.; Vismara, E. J. Org.
Chem. 1991, 56, 2866.
(19) (a) Qu, G.-R.; Liang, L.; Niu, H.-Y.; Rao, W.-H.; Guo, H.-M.
Org. Lett. 2012, 14, 4494. (b) Xin, P.-Y.; Niu, H.-Y.; Qu, G.-R.; Ding,
R.-F.; Guo, H.-M. Chem. Commun. 2012, 48, 6717. (c) Meng, G.; Niu,
H.-Y.; Qu, G.-R.; Fossey, J. S.; Li, J.-P.; Guo, H.-M. Chem. Commun.
2012, 48, 9601.
(20) Guo, H.-M.; Wu, S.; Niu, H.-Y.; Song, G.; Qu, G.-R. In Chemical
Synthesis of Acyclic Nucleosides in Chemical Synthesis of Nucleoside
Analogues 3; Merino, P., Ed.; John Wiley & Sons: New York, 2013; pp
103−162.
(21) (a) Patel, N. R.; Flowers, R. A., II. J. Am. Chem. Soc. 2013, 135,
4672. (b) Seiple, I. B.; Su, S.; Rodriguez, R. A.; Gianatassio, R.;
Fujiwara, Y.; Sobel, A. L.; Baran, P. S. J. Am. Chem. Soc. 2010, 132,
13194. (c) Minisci, F.; Citterio, A.; Giordano, C. Acc. Chem. Res. 1983,
16, 27.
(3) (a) Cocuzza, A. J.; Chidester, D. R.; Culp, S.; Fitzgerald, L.;
Gilligan, P. Bioorg. Med. Chem. Lett. 1999, 9, 1063. (b) Chang, L. W.;
Spanjersberg, R. F.; von Frijtag Drabbe Kunzel, J. K.; Mulder-Krieger,
T.; Brussee, J.; Ijzerman, A. P. J. Med. Chem. 2006, 49, 2861.
(4) Kuchar,
Biomol. Chem. 2008, 6, 2377.
̌ ́ ̌ ́
M.; Pohl, R.; Klepetarova, B.; Votruba, I.; Hocek, M. Org.
(5) (a) Basu, A. K.; Essigmann, J. M. Chem. Res. Toxicol. 1988, 1, 1.
(b) Lakshman, M. K.; Ngassa, F. N.; Keeler, J. C.; Dinh, Y. V.; Hilmer,
J. H.; Russon, L. M. Org. Lett. 2000, 2, 927.
(6) (a) Gibson, A. E.; Arris, C. E.; Bentley, J.; Boyle, F. T.; N Curtin,
J. T.; Davies, G.; Endicott, J. A.; Golding, B. T.; Grant, H.; Griffin, R.
J.; Jewsbury, P.; Johnson, L. N.; Mesguiche, V.; Newell, D. R.; Noble,
M. M.; Tucker, J. A.; Whitfield, H. J. J. Med. Chem. 2002, 45, 3381.
(b) Hardcastle, I. R.; Arris, C. E.; Bentley, J.; Boyle, F. T.; Chen, Y.;
Curtin, N. J.; Endicott, J. A.; Gibson, A. E.; Golding, B. T.; Griffin, R.
J.; Jewsbury, P.; Menyerol, J.; Mesguiche, V.; Newell, D. R.; Noble, M.
M.; Pratt, D. J.; Wang, L.-Z.; Whitfield, H. J. J. Med. Chem. 2004, 47,
3710. (c) Chen, X.; Kern, E. R.; Drach, J. C.; Gullen, E.; Cheng, Y. C.;
Zemlicka, J. J. Med. Chem. 2003, 46, 1531.
(7) (a) Hocek, M.; Holy, A.; Votruba, I.; Dvorakova, H. J. Med. Chem.
2000, 43, 1817. (b) Gundersen, L. L.; Nissen-Meyer, J.; Rise, F.;
Spilsberg, B. J. Med. Chem. 2002, 45, 1383. (c) Bakkestuen, A. K.;
Gundersen, L. L.; Utenova, B. T. J. Med. Chem. 2005, 48, 2710.
(d) Hocek, M.; Naus,
Tharnish, P. M.; Otto, M. J. J. Med. Chem. 2005, 48, 5869.
(8) (a) Hocek, M.; Holy, A.; Votruba, I.; Dvora ova, H. J. Med. Chem.
2000, 43, 1817. (b) Hocek, M.; Holy, A.; Votruba, I.; Dvora ova, H.
Collect. Czech. Chem. Commun. 2001, 66, 483. (c) Hocek, M.; Holy, A.;
Dvora ova, H. Collect. Czech. Chem. Commun. 2002, 67, 325.
̌
P.; Pohl, R.; Votruba, I.; Furman, P. A.;
̌
k
́
́
̌
k
́
́
̌
k
́
́
̌
(9) (a) Capek, P.; Pohl, R.; Hocek, M. J. Org. Chem. 2004, 69, 7985.
(b) Wang, D.-C.; Niu, H.-Y.; Qu, G.-R.; Liang, L.; Wei, X.-J.; Zhang,
̌
Y.; Guo, H.-M. Org. Biomol. Chem. 2011, 9, 7663. (c) Silhar
́
, P.; Pohl,
, P.; Pohl,
̌
R.; Votruba, I.; Hocek, M. Org. Lett. 2004, 6, 3225. (d) Silhar
R.; Votruba, I.; Hocek, M. Synthesis 2006, 1848. (e) Silhar
Votruba, I.; Hocek, M. Org. Biomol. Chem. 2005, 3, 3001. (f) Hasník,
́
̌
́
, P.; Pohl, R.;
̌
Z.; Silhar
́
, P.; Hocek, M. Tetrahedron Lett. 2007, 48, 5589.
dez, M.; Krause, H. J. Am.
Chem. Soc. 2002, 124, 13856. (b) Tobrman, T.; Dvora , D. Org. Lett.
2006, 8, 1291. (c) Hocek, M.; Dvora ova, H. J. Org. Chem. 2003, 68,
5773. (d) Sugimura, H.; Takei, H. Bull. Chem. Soc. Jpn. 1985, 58, 664.
(e) Dvora ova, H.; Dvora , D.; Holy, A. Tetrahedron Lett. 1996, 37,
1285.
(10) (a) Furstner, A.; Leitner, A.; Men
́
̈
̌ ́
k
̌
k
́
́
̌
k
́
́
̌ ́
k
́
(11) Hasník, Z.; Pohl, R.; Hocek, M. Synthesis 2009, 1309.
(12) (a) Tan, K. L.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2002, 124, 13964. (b) Tan, K. L.; Park, S.; Ellman, J. A.; Bergman, R.
G. J. Org. Chem. 2004, 69, 7329.
(13) (a) Guo, H.-M.; Zhang, Y.; Niu, H.-Y.; Wang, D.-C.; Chu, Z.-L.;
Qu, G.-R. Org. Biomol. Chem. 2011, 9, 2065. (b) Qu, G.-R.; Mao, Z.-J.;
Niu, H.-Y.; Wang, D.-C.; Xia, C.; Guo, H.-M. Org. Lett. 2009, 11, 1745.
447
dx.doi.org/10.1021/ol4033336 | Org. Lett. 2014, 16, 444−447