PdII-Catalyzed Purine-Directed Ortho Nitration of 6-Arylpurines by C(sp2)–H Activation: A Practical Approach to Synthesize 6-(2-Nitroaryl)-Purine Derivatives

Article abstract of DOI:10.1002/ejoc.201800567

Herein we report a method for Pd^II-catalyzed purine-directed ortho nitration of 6-arylpurines via C(sp²)–H activation by using tBuONO/O₂ as nitration agent. This procedure is highly efficient and produces a range of 6-(2-nitroaryl)-purine derivatives with good chemoselectivity and functional-group tolerance. The utility of the method is further illustrated in the synthesis of antibacterial agent.

Full text of DOI:10.1002/ejoc.201800567

DOI: 10.1002/ejoc.201800567
Communication
Nitration
PdII-Catalyzed Purine-Directed Ortho Nitration of 6-Arylpurines
by C(sp2)–H Activation: A Practical Approach to Synthesize
6-(2-Nitroaryl)-Purine Derivatives
Quan Gou,[b] Wenxi Li,[c][‡] Qingsheng Zhao,[a][‡] Jia Xie,[a] Ping Luo,[a] Guang Cao,[a]
Suiyun Chen,*[b] and Jun Qin*[a]
Abstract: Herein we report a method for PdII-catalyzed purine- tives with good chemoselectivity and functional-group toler-
directed ortho nitration of 6-arylpurines via C(sp2)–H activation
by using tBuONO/O2 as nitration agent. This procedure is highly
efficient and produces a range of 6-(2-nitroaryl)-purine deriva-
ance. The utility of the method is further illustrated in the syn-
thesis of antibacterial agent.
Introduction
Nevertheless, ortho nitration of 6-arylpurines by C(sp2)–H acti-
vation has never been disclosed. Herein, we report a method
of PdII-catalyzed purine-directed ortho nitration of 6-arylpurines
by C(sp2)–H activation. This method is operated under mild
conditions by using tBuONO/O2 as nitration source. It is highly
efficient and produces a variety of 6-(2-nitroaryl)-purine deriva-
tives with good chemoselectivity and functional group toler-
ance.
Aromatic nitro compounds are widespread in the field of mate-
rial and pharmaceutical science.[1] They are important synthetic
precursors for other useful functional groups.[2] The classical
electrophilic aromatic nitration to prepare aromatic nitro com-
pounds uses corrosive nitric acid as nitration agent and suffers
from poor chemoselectivity and functional-group tolerance.[3]
Direct C(sp2)–H bond activation/nitration have become attract-
ive synthetic solution to this problem and many excellent exam-
ples have been reported in the literature.[4]
The purine skeleton, which is an inherent scaffold of RNA
and DNA, has received much attention of scientists due to its
importance in biochemistry and pharmaceutical industry.[5] Par-
ticularly, the arylpurine derivatives have exhibited broad biolog-
ical activities as antiviral (Hepatitis C), anticancer, and antimyco-
bacterial agents (Scheme 1).[6] Due to their biological signifi-
cance and applications, chemists have developed synthetic
methods to functionalize arylpurines. An important method is
the metal-catalyzed C(sp2)–H activation/functionalization be-
cause it simplifies the overall synthetic procedure.[7] Functionali-
zation of arylpurines by C(sp2)–H acetoxylation, acylation, allyl-
ation, arylation, cyanation, halogenation, trifluoromethylthiol-
ation, olefination, and amination have been reported recently.[8]
[a] Key Laboratory of Medicinal Chemistry for Natural Resource,
Ministry of Education, Yunnan University,
Kunming 650091, P. R. China
Scheme 1. Purine-based bioactive molecules.
E-mail: qinjun@ynu.edu.cn
[b] School of Life Science, Yunnan University,
Kunming 650091, P. R. China
Results and Discussion
E-mail: chensuiyun@ynu.edu.cn
In a program directed to develop new C–H activation reac-
tions,[9] we have become interested in investigating of ortho
nitration of 6-arylpurines by using purine as intrinsic directing
group. If successful, this transformation could produce a variety
of 6-(2-nitroaryl)-purine derivatives in a straightforward manner.
Our study was commenced with nitration of 9-benzyl-6-phenyl-
www.ynu.edu.cn
[c] Institute of Agricultural Environment and Resource,
Yunnan Academy of Agricultural Science,
Kunming 650205, P. R. China
[‡] These authors contributed equally to this work.
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201800567.
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9H-purine 1a as the model reaction (Table 1). Treatment of 1a tions of substrates with either electron-donating or electron-
with NaNO2 in the presence of Cu(OAc)2 under air did not afford withdrawing ortho-substituted phenyl groups proceeded
the desired mono-nitrated product 2a (Table 1, entry 1). With smoothly to furnish the desired products in good yields
Pd(OAc)2 as catalyst, the reaction with either AgNO2 or NaNO2 (Table 2, 2ba–2ca). In addition, para-substituted 6-arylpurines
as nitration agent in the presence of K2S2O8 did not produce bearing either electron-deficient groups like F, Cl, Br, CO2Me,
any amount of 2a (Table 1, entries 2–4). However, when OCF3, or electron-rich groups such as tBu, MeO, Me, and TMS
tBuONO was used as nitration agent under O2, the reaction also performed well under the reaction conditions, affording
provided 2a in 30 % yield (Table 1, entry 5). Solvent effects the corresponding products in good to excellent yields (Table 2,
were then screened (Table 1, entries 6–11). It was found that 2da–2ha, 2ia–2la). Moreover, substrates with either electron-
benzotrifluoride was the best solvent, affording 2a in 90 % yield withdrawing or electron-donating meta-substitutions also af-
along with 5 % of the di-nitrated product 3a (Table 1, entry 9). forded the nitration products without incident under the reac-
Other solvents such as DCE, MeCN, anisole, PhCl or o-dichloro- tion conditions (Table 2, 2ma–2pa). The sterically hindered sub-
benzene were inferior to benzotrifluoride. Afterwards, we inves- strates were also tolerated to afford the product in good yield
tigated the effects of base additives on the reaction efficiency. (Table 2, 2qa–2ra). It is worth to note that the reaction condi-
It was shown that bases such as Na2CO3, K2CO3, KOAc or Cs2CO3 tions tolerated useful functional groups such as Br and CO2Me
were detrimental to the reaction (Table 1, entries 12–15). After that could be utilized as handles for further transformations.
that, we screened different palladium catalysts (Table 1, entries
16–18). We found that Pd(OAc)2 remained to be the best cata-
lyst. Ultimately, the optimal reaction conditions were Pd(OAc)2
(10 mol-%), tBuONO (2.0 equiv.) under 1 atm O2 in benzotri-
Afterwards, we examined the effect of N9-substitutions of 6-
phenylpurines on the nitration (Table 3). Nitrations of substrates
bearing N9-alkyl substitutions such as methyl, butyl and iso-
propyl groups were well tolerated to give the products in mod-
erate to good yields (Table 3, 2sa–ua). In addition, the nitration
of substrates that contained either aryl or benzyl group as N9-
substitution proceeded smoothly in moderate to good yields
(Table 3, 2va–wa). It is worth to note that the benzyl group of
fluoride (0.1 M) at 110 °C. It was worth to note that the reaction
conditions were highly chemoselective in that the nitration on
1a occurred exclusively on ortho position of phenyl group with-
out formation of C-2 or C-8 nitrated product.
With the optimal reaction conditions in hands, we investi- the product 2wa could be removed to release the free nitrogen
gated the scope of 6-arylpurines (Table 2). To our delight, nitra- atom for further derivatizations. Purine nucleosides are a class
Table 1. Optimization of reaction conditions.[a]
Entry
Catalyst
Nitro source
Solvent
Yield[b]
2aa/3aa
1[c]
2[d]
3[d]
4[e]
5
6
7
8
9
10
11
12[g]
13[h]
14[i]
15[j]
16
17
18
Cu(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
NaNO2
MeOH
dichloroethane
toluene
toluene
toluene
dichloroethane
MeCN
anisole
benzotrifluoride
PhCl
o-dichlorobenzene
benzotrifluoride
benzotrifluoride
benzotrifluoride
benzotrifluoride
benzotrifluoride
benzotrifluoride
benzotrifluoride
0:0
0:0
0:0
0:0
30:0
41:15
0:0
AgNO2/K2S2O8
AgNO2/K2S2O8
NaNO2/K2S2O8
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
tBuONO/O2
0:0
90:5[f]
78:21
0:0
10:0
15:0
0:0
0:0
6:0
Pd(MeCN)2Cl2
Pd(PPh3)2Cl2
75:12
45:10
[a] General procedure: 1a (0.20 mmol), nitro source (0.40 mmol), and catalyst (10 mol-%) in solvent (2.0 mL) at 110 °C for 12–24 h with TLC control. [b]
Determined by analysis of crude mixture with CH2Br2 as internal standard by 1H NMR spectroscopy (400 MHz). [c] Cu(OAc)2: 3.0 equiv., NaNO2: 2.0 equiv.,
2.0 equiv. of K2HPO4 was added. [d] AgNO2: 2.0 equiv., K2S2O8: 2.0 equiv. [e] NaNO2: 2.0 equiv., K2S2O8: 2.0 equiv. [f] Isolated yield. [g] 2.0 equiv. of Na2CO3
was added. [h] 2.0 equiv. of K2CO3 was added. [i] 2.0 equiv. of KOAc was added. [j] 2.0 equiv. of Cs2CO3 was added.
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Table 2. Substrate scope of 9-benzyl-6-arylpurines.[a,b]
of important structures that have demonstrated important bio-
logical activity as anti-HIV/HBV agents.[10] We examined the
nitration of purine nucleoside substrate 1x under the reaction
conditions. We were pleased to find that the reaction afforded
the nitration product 2xa in 80 % yield.
Table 3. Substrate scope of N9-substituted 6-phenylpurines.[a,b]
[a] Reaction conditions: 1 (0.20 mmol), tBuONO (0.40 mmol), and Pd(OAc)2
(10 mol-%) under 1 atm O2 in benzotrifluoride (2.0 mL) at 110 °C for 12–24 h
with TLC control. [b] Isolated yield.
The utility of the method was successfully demonstrated in
the synthesis of antibacterial agent 5xa as shown in
Scheme 2.[11] Under the reaction conditions, nitration of 1x was
performed on a gram scale to give 2xa in 75 % yield. Then, an
additional nitro group was introduced at C2 position by treat-
ment of 2xa with TBAN/TFAA (TBAN = tetra-butylammonium
nitrate) to provide 3xa in 70 % yield. Afterwards, the C-2 nitro
group of 3xa was selectively replaced by 3-amino-1-propanol
to deliver 4xa, which was finally transformed into 5xa by a
two-step sequence including hydrogenative reduction and de-
glycosylation in 55 % overall yield.
To gain insights into the reaction mechanism, a series of con-
trol experiments was performed (Scheme 3). The nitration of 1a
was completely inhibited in the presence of radical scavengers,
such as BHT or TEMPO, implying that a radical process might
be involved for the reaction (Scheme 3, a). The kinetic isotope
[a] Reaction conditions: 1 (0.20 mmol), tBuONO (0.40 mmol), and Pd(OAc)2
(10 mol-%) under 1 atm O2 in benzotrifluoride (2.0 mL) at 110 °C for 12–24 h
with TLC control. [b] Isolated yield.
experiments (parallel intermolecular KIE
= 2.25, see the
Supporting Information) indicated that the cleavage of the
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2. Finally, a reductive elimination of B-1 or B-2 afforded 2 along
with regeneration of the PdII for the next catalytic cycle.
Scheme 2. Synthesis of antibacterial agent 5xa.
C(sp2)–H bond of the substrate occurred as the rate-limiting
step (Scheme 3, b).[12] The purine N1 and N7 atom of 1a were
involved in the reaction presumably as chelating group, be-
cause substrate 1y or 1z, which had either N1 or N7 absent
compared to 1a, afforded the nitration product 2ya and 2za in
much lower yield under the reaction condition (36 % and 67 %
respectively) (Scheme 3, c). Based on the limited data available,
a radical pathway involving PdII/PdIV catalysis was tentatively
proposed as shown in Scheme 4.[4j–4l] In the first step, either
the N1 or the N7 atom of substrate 1 coordinate to PdII followed
by cleavage of the C(sp2)–H bond to either form the six-mem-
bered or the five-membered cyclopalladated complex A-1 or A-
·
2. Then, an oxidative addition of A-1 and A-2 with NO2 gener-
ated by tBuONO/O2 produced an PdIII intermediate, which was
further oxidized by O2 to give the PdIV intermediates B-1 or B-
Scheme 3. Control experiments.
Scheme 4. Proposed reaction mechanism.
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Conclusion
In conclusion, we have developed an efficient protocol for the
ortho nitration of 6-arylpurines by PdII-catalyzed C(sp2)–H acti-
vation using purine as an intrinsic directing group. This ap-
proach is operated under mild conditions and uses tBuONO/O2
as nitration agent. It shows good chemoselectivity and func-
tional-group tolerance and produces a variety of 6-(2-nitroaryl)-
purine derivatives, which are useful scaffolds in medicinal
chemistry. The utility of the method is further illustrated in the
synthesis of an antibacterial agent. Further investigation of the
detailed reaction mechanism and expanding the reaction scope
is currently in progress.
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Experimental Section
A 15 mL Schlenk tube was charged with 1 (0.20 mmol), tBuONO
(2.0 equiv.), and Pd(OAc)2 (10 mol-%) in benzotrifluoride (0.1 M). The
Schlenk tube was purged with oxygen and then tightly capped. The
mixture was vigorously stirred at 110 °C and the progress of this
reaction was monitored by TLC. Upon completion of the reaction,
the mixture was filtered through a short pad of Celite. The filtrate
was concentrated in vacuo to give a residue, which was purified by
flash chromatography to furnish the title compounds 2.
Conflict of Interest
The authors declare no conflict of interest.
Acknowledgments
[7]
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We gratefully acknowledge financial support from Program of
High-End Science and Technology Talents of Yunnan Province
(2012HA003), Postdoctoral Science Foundation of China, Pro-
gram of Hundred Oversea High-Level Talents of Yunnan Prov-
ince (W8110305), Yunnan University (XT412003), and Program
for Changjiang Scholars and Innovation Research Team in Uni-
versity (IRT13095).
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Keywords: Palladium · Nitration · Nitrogen heterocycles ·
tert-Butyl nitrite · Radical reactions
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Received: April 11, 2018
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Nitration
Q. Gou, W. Li, Q. Zhao, J. Xie,
P. Luo, G. Cao, S. Chen,* J. Qin* .... 1–7
PdII-Catalyzed Purine-Directed Or-
tho Nitration of 6-Arylpurines by
C(sp2)–H Activation: A Practical Ap-
proach to Synthesize 6-(2-Nitroaryl)-
Purine Derivatives
6-(2-Nitroaryl)-purine can be obtained of tBuONO/O2. The purine substituent
through PdII-catalyzed C(sp2)–H activa- acts as an ortho directing group for the
tion of 6-arylpurines in the presence nitration.
DOI: 10.1002/ejoc.201800567
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