Silver-Catalyzed Direct C6–H Arylation of Purines and Purine Nucleosides with Arylboronic Acids

Article abstract of DOI:10.1002/ejoc.201700406

A practical and operationally simple protocol for the assembly of 6-aryl-substituted purines through the direct C6–H arylation of purines and 8-azapurine and purine nucleosides from arylboronic acids was developed. This reaction was performed under ambient conditions with ammonium persulfate as the oxidant in the presence of silver(I). The reaction was found to be regioselective with the arylation occurring predominantly at the C6 position, and a large variety of functional groups, including halides, esters, hydroxy groups, and heterocycles, were tolerated.

Full text of DOI:10.1002/ejoc.201700406

A Journal of
Accepted Article
Title: Silver Catalyzed Direct C6-H Arylation of Purines and Purine
Nucleosides with Arylboronic Acid
Authors: Miao Tian, Mingwu Yu, Tingting Shi, Junbin Hu, Shunlai Li,
Jiaxi Xu, Ning Chen, and Hongguang Du
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700406
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700406
Supported by

10.1002/ejoc.201700406
European Journal of Organic Chemistry
COMMUNICATION
Silver Catalyzed Direct C6-H Arylation of Purines and Purine
Nucleosides with Arylboronic Acid
Miao Tian,a Mingwu Yu,a Tingting Shi,a Junbin Hu,a Shunlai Li,a Jiaxi Xu,a Ning Chen,a* and
Hongguang Dua*
Dedication ((optional))
Abstract: A practical and operationally protocol for assembling of 6-
coupling procedures need expensive noble metal catalysts,
aryl substituted purines has been described through the direct C6-H
require non-natural aryl halides as substrates, and bear strict
arylation of purines, 8-azapurine and purine nucleosides from
exclusion of moisture and air condition in many cases. An
arylboronic acid. This reaction carries out at ambient condition under
alternative strategy to furnish the coupling was achieved by
the oxidation of ammonium persulfate in the presence of silver (I),
traditional radical reaction through the ultraviolet irradiation from
featuring the regioselectivity predominantly at C6 position and
[8]
6-iodopurine
or the reaction with alkyl nitrite from 6-
tolerating a broad functional group compatibility scope such as
halides, esters, hydroxyls and heterocycles.
[9]
aminopurine (Scheme 1, b). However, low reactivity and poor
regioselectivity in such radical reactions also limit their
application. In recent decade, the direct C-H functionalization
represented a new, efficient, and atom-economic protocol for C-
C bonding formation,[10] but seldom literature exploited the direct
C6-H arylation of purines and purine nucleosides.[11] Recently,
our continuous interests focused on developing versatile
methods for the synthesis of various functionalized purine
nucleosides to study their diverse bioactivities.[12] Herein, we
describe an efficient way for the direct C-H arylation of purines
and purine nucleosides under the catalysis of silver nitrate in
room temperature (Scheme 1, c).
Introduction
Purines and purine nucleosides are one of the most widely
occurring N-heterocycles in nature,[1] constituting many brand-
name drugs.[2] Particularly, 6-aryl purines and purine
nucleosides also represent a plenty of important bioactive
molecules, providing various applications in anticancer, antivirus,
cytostatic and anti-HCV, such as the cytotoxicity inhibitor I,
nanomolar ligand for the bromodomain of human BRD9 II,
DNPH1 inhibitor III and cytostatic agent IV/V. [3](Figure 1) Owing
to the widespread in bioactivities, the syntheses and
modification of 6-purines and purine nucleosides are of great
significance today. However, most reported methods are based
upon
cross-coupling
between
6-purine
halides
(or
pseudohalides) and various coupling reagents, such as aryl
boric acid (Suzuki-Miyaura reaction),[4] aryl tin reagents (Stille
coupling),[5] aryl zinc reagents (Negeshi coupling),[6] and aryl
Grignard reagents (Kumada coupling).[7] (Scheme 1, a) Despite
the robust efficiency of reactivity in such reactions, most
Scheme 1. The synthesis of 6-aryl purines/purine nucleosides.
Results and Discussion
Figure 1. Representative bioactive molecules with 6-aryl purine framework
One challenge in achieving the direct arylation of purines is to
overcome the regioselectivity imparted by three potential
reactive sites in purine: C2, C6 and C8. As is generally known,
the charge distribution of purine features the pyrimidyl moiety
electron deficient and the imidazyl moiety electron rich.[13] In
order to obtain the C6-arylation product, we turned our attention
to Minisci-type reaction,[14] a typical C-H alkylation reaction
towards electron-deficient heterocycles. In 2014, Qu and Guo
group developed an powerful strategy for C6-H alkylation of
[a]
Faculty of Science, Beijing University of Chemical Technology,
Beijing 100029, People’s Republic of China
E-mail: chenning@mail.buct.edu.cn
dhg@mail.buct.edu.cn
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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10.1002/ejoc.201700406
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COMMUNICATION
purine nucleosides from alkyl carboxylic acid via
a
much more complicated. Generally, among the three potential
coordinated nitrogen (N1, N3 & N7), N1 is prone to be the first
site being protonated according to literatures,[20] and N7 has yet
been identified to be potentially coordinated with silver.[15] We
therefore anticipated that the addition of 1 equiv. acid would
facilitate the radical addition upon not only accelerating the
reaction efficiency through reducing the whole electron density
of purine, but also improving the regioselectivity through the
protonation at N1 as the postulated intermediates VI or VII
(Scheme 2, b).
decarboxylation process.[15] In our case, however, no desired
product was detected by investigating benzoic acid as an aryl
fragment when it coupled with purine nucleosides 1.
We were inspired by the seminal work described from Baran
group who used aryl radicals, resulted from arylboronic acids, to
functionalize the electron-poor heteroarenes, such as pyridines
(Scheme 2, a).[16] Phenylboronic acid was therefore evaluated as
the coupling reagent, and to our gratification, 34% yield of
desired C6-phenyl purine nucleoside 3a was obtained in
o
DCM/H2O at 60 C (Table 1, entry 1). By simply modifying the
solvent from dichloromethane (DCM) to 1,2-dichloroethane
(DCE), the reaction efficiency was significantly promoted to 70%
yield (entry 2). It should be mentioned that C2- and C8-
phenylation products were observed in this reaction albeit with
very low yield (10%, 1:1).[17] No or only trace desired product
was generated by investigating miscible solvents, such as
DMF/H2O, MeCN/H2O, and THF/H2O (entries 35). The results
demonstrated that biphasic solvent was essential to facilitate the
solubility of both organic reactants and inorganic salts. Moreover,
the yield was obviously dropped by replacing ammonium
persulfate to potassium persulfate as oxidant (entry 6). It is
noteworthy that FeSO4, an efficient catalyst in C-H arylation of
benzoquinones,[18] only proceeded with moderate efficiency in
the current reaction albeit we made our every endeavour on
improving it (entries 710).
Scheme 2. [a] Proposed mechanism of direct arylation of pyridines on Baran’s
work; [b] Hypothesis of the influence of acid and silver with purine framework
Table 1. Optimization for the reaction between purine nucleoside (1a) and
phenyl boronic acid (2a).[a]
As we expected, a relatively higher yield was observed when
TFA was added to the system with the reaction time even
lessened to 1 h, and more significantly, the yield of mixture of
C2- and C8-phenyl purines was depressed to only 5% (Table 1,
entry 11). The result from TFA enlightened us to lower the
temperature to room temperature (around 20 oC) and finally, the
best result was obtained with 77% yield in 3 h (entry 12). By
contrast, without adding TFA the yield was yet diminished to 66%
in r.t. (entry 13).
Entries
Cat.
Solvents
(1:1)
Add.
Temp
. (oC)
Time.
(h)
Yields[b]
(%)
34
70[c]
trace
trace
0
32
42
43
53
1
2
3
4
5
6
7
8
9
10
11
12
13
AgNO3
AgNO3
AgNO3
AgNO3
AgNO3
DCM:H2O
DCE:H2O
DMF:H2O
MeCN:H2O
THF:H2O
DCE:H2O
DCE:H2O
DCE:H2O
DCE:H2O
DCE:H2O
DCE:H2O
DCE:H2O
DCE:H2O
-
-
-
-
-
-
-
-
-
60
60
60
60
60
60
60
80
80
80
60
rt
2
2
2
2
2
2
6
4
4
4
1
3
3
With optimized reaction conditions in hand, we sought to
explore the scope of purines (Table 2). Performing with phenyl
boronic acid (2a), various purine derivatives 1 could afford the
desired coupling products in moderate to good yields under the
standard condition. It is worth mentioning again that TFA is of
great significance in survey of reaction scope though there were
only 7% yield variation in the addition of either TFA or not (Table
1, entries 2 and 12). In general, despite there are three reactive
sites in its ring (C2-, C6-, and C8-), all purine and its analogues
predominately performed at the C-6 position. Both aryl and alkyl
substituted purines in 9 position gave the corresponding 6-
phenyl products in satisfactory yields (3b3l), but elevated
temperature was essential for aryl purines (3b & 3i) to undergo
the transformation probably due to its low solubility in DCE. We
found that the reaction was well tolerated with ester group (3a &
3e) and free hydroxyl group (3f & 3g) though the latter one with
relatively poor efficiency. To our gratification, 8-azapurine, a five-
membered nitrogen-containing bioactive heterocycle, is well
accommodated in this transformation. The same result was
obtained with the purine bearing a methyl in its 8-position (3i).
Lastly, 1e, referred to its ester-bearing nature, was briefly
examined its scope with three arylboronic acids, and all arylation
reactions were carried out efficiently with both electron-deficient
(3j & 3k) and rich arylboronic acid (3l).
[d]
AgNO3
[d]
FeSO4
FeSO4
FeSO4
FeSO4
AgNO3
AgNO3
AgNO3
TFA
TFA
TFA
-
43
73[e]
77
rt
66
[a] Reaction conditions: 1a (0.25 mmol), 2a (0.375 mmol), AgNO3 or FeSO4
(0.2 equiv.), oxidant (4.0 equiv.), TFA (0.25 mmol), DCE/H2O (2.0 mL; 1:1,
v/v). [b] All yields are isolated products from column chromatography and the
trace yields were detected in Thin-Layer Chromatography (TLC). [c] Both
C2- and C8-phenyl purine were isolated as mixtures in 10% yield with ratio
of 1:1. [d] K2S2O8 instead of (NH4)2S2O8. [e] Both C2- and C8-phenyl purine
were isolated as mixtures in 5% yield with ratio of 1:1.
In Minisci reaction, acid (proton) could promote the aryl radical
addition reaction through activating the nitrogen to reduce the
electron density of the heteroarenes (Scheme 2, a).[14,16a,19]
However, boronic acid was generated concomitantly as soon as
the reaction proceeded, resulting in that the extra acid, like
trifluoroacetic acid (TFA), was not necessary in most cases,
especially for the reactions with mononitrogen substrates.[16a] In
our protocol, however, the tetranitrogen purine nucleoside 1a is
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European Journal of Organic Chemistry
COMMUNICATION
Table 3. Scope with respect to arylboronic acid [a]
Table 2. Scope with respect to purines and purine nucleosides [a]
[a] Reaction conditions: 1 (0.25 mmol), 2 (1.5 equiv), AgNO3 (0.2 equiv),
(NH4)2S2O8(4.0 equiv), TFA (1.0 equiv), DCE (1.0 mL), H2O (1.0 mL), room
temperature, and yields of isolated products are given. [b] Gram-scale reaction
from 1a (2.64 mmol, 1.00 g). [c] Modifying the reaction condition to: time, 3h;
temperature, 60 oC.
[a] Reaction conditions: 1a (0.25 mmol), arylboronic acid (1.5 equiv), AgNO3
(0.2 equiv), (NH4)2S2O8 (4.0 equiv), TFA (1.0 equiv), DCE (1.0 mL), H2O (1.0
mL) and yields of isolated products are given.
Having established the scope of purines, we next turned our
attention to aromatic boronic acids partner to react with purine
nucleoside 1a. First, comparing with para-, meta-ones (4c & 4d),
ortho-tolueneboronic acid (2b) displayed lower reactivity for its
higher steric hindrance (4b). Subsequently, the electron
influence of substituent on the phenyl ring was investigated. In
The reaction is then scaled up to evaluate its utility. On one
hand, 3a was obtained with 76% yield from 1.00 g of 1a (Table 2,
3a). On the other hand, featured bioactive compound IV (Figure
1), a typical cytostatic reagent,[4b] was prepared from 1a with 2g
under the standard condition followed by a methanolysis of
acetyl ester with 52% yields in total two steps (Scheme 3).
Compared with the classic Suzuki coupling which requires
precious palladium catalyst and relatively harsh conditions like
argon protection and high temperature,[3b] the current approach
is carried out at ambient condition with low-cost silver catalyst,
which thus could be utilized as an alternative and effective
method to construct 6-aryl purines.
general, both electron-donating (Me
withdrawing substituents (F, Cl
&
MeO, 4b4g) and
&
Br, 4h4m) were well
performed, but undoubtedly electron-rich arylboronic acid
provided better reactive efficiency owing to the reaction nature.
The favourably tolerance on carbon-halo bond also features
potential applications for the further functionalization. When
bearing the methoxyl group, meta-substituted aryl boronic acid
proceeded with better yield than ortho- and para-ones did
(4e4g). The result seems that very strong electron-rich
arylboronic acid might retard the coupling efficiency. To test our
hypothesis, 3,5-dimethyl boronic acid was carried out with the
yield slightly dropping to 55% (4n). What surprised us was the
coupling with 3,5-dimethoxylphenyl boronic acid, a very strong
electron-rich substrate, providing no reaction in current
conditions. To our delight, naththylboronic acid could generate
the desired product in a good yield (4o) and the reaction also
tolerated the thiophenyl group albeit with only serviceable yield
(4p).
Scheme 3. Large scale synthesis of cytostatic agent IV.
Finally, reaction mechanism was briefly investigated. The
radical trapping experiment that no desired coupling product was
observed in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyl
(TEMPO) strongly supports the current protocol which was
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[3]
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carried out with radical process (see supporting information). To
further understanding the influence of TFA, the reaction of 1e
and phenylboronic acid (2a) was examined with different loading
of TFA (See SI), the result that is in line with Flowers' report.[19]
Meanwhile, in the presence of 4 equivalents of TFA, double
arylation products 5 and 6 were discovered, verifying that upon
decreasing of electron density of purine framework, multiple
arylations could be proceeded through the over-protonation
control of TFA (Scheme 4).
[4]
[5]
[6]
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Scheme 4. Over arylation investigation in the presence of 4 equivalents of
TFA
Conclusions
In conclusion, we have developed an efficient and expedient
way to modify bioactive purines and purine nucleosides involving
a direct C6-H arylation of purines from arylboronic acid under
mild conditions. The current reaction is carried out in air under
the catalysis of inexpensive silver nitrate (less than $2 per gram)
and ammonium persulfate (less than $0.2 per gram) displaying a
broad scope for both purine and arylboronic acid coupling
partners. TFA was essential to the reaction not only promoting
the reaction efficiency, but improving the regioselectivity as well.
Finally, the reaction is scalable with various functional groups
tolerance, such as halides, esters, hydroxyls and heterocycles.
[8]
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Experimental Section
To a 15 mL vial, 94.6 mg 1a (0.25 mmol) and 45.7 mg phenylboronic acid
2a (0.38 mmol) were suspended in 1,2-dichloroethane (1 mL) and
followed by an addition of aqueous solution mixed with 8.5 mg AgNO3
(0.05 mmol), 228.2 mg (NH4)2S2O8 (1.00 mmol) and 28.5 mg TFA (0.25
mmol) in water (1 mL). After stirring at ambient atmosphere for 3h, the
mixture was filtered with silica gel and the filtrate was then diluted with
1,2-dichloroethane (10 mL) followed by a neutralization with 0.25 mL
triethylamine. The organic layer was then separated, dried with MgSO4,
filtered and concentrated. Further purification by column chromatography
gave rise to the pure 3a as colorless sticky oil, 87.5 mg (77%).
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Acknowledgements ((optional))
We are grateful for the financial support from the National
Natural Science Foundation of China (Grant 21272022).
Keywords: purine • purine nucleosides • silver catalysis • C-H
activation • arylboronic acid
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Blackwell, 2010.
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European Journal of Organic Chemistry
COMMUNICATION
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[17] Note: 1) C2- and C8-phenyl purine nucleosides are isolated as mixtures
which cannot be separated each other not only for the very low yields
but also for the almost same polarity. 2) The structures of all
compounds are verified by HSQC, HMBC and HRMS; 3) C2-phenyl
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10.1002/ejoc.201700406
European Journal of Organic Chemistry
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Miao Tian,a Mingwu Yu,a Tingting Shi,a
Junbin Hu,a Shunlai Li,a Jiaxi Xu,a Ning
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An efficient protocol for direct C6-H arylation of purines and purine nucleosides has
been described here under the catalysis of silver nitrate in ambient condition. A
wide assortment of purines and arylboronic acids can be employed in this process
to afford C6-aryl purines and purine nucleosides with high regioselectivity.
Silver Catalyzed Direct C6-H Arylation
of Purines and Purine Nucleosides
with Arylboronic Acid
*silver catalysis
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