PMes3-Promoted Ruthenium-Catalyzed Meta C-H Nitration of 6-Arylpurines

Article abstract of DOI:10.1021/acs.joc.8b00149

To address the challenge of meta nitration of 6-arylpurine substrates, a versatile ruthenium catalyzed meta C-H nitration is developed. The use of a sterically hindered phosphine ligand is crucial for the catalytic efficiency, and a broad class of 6-arylpurines and nucleosides were found suitable for this process providing corresponding exclusively meta nitrated products in good yields.

Full text of DOI:10.1021/acs.joc.8b00149

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Article
PMes3-Promoted Ruthenium-Catalyzed Meta C-H Nitration of 6-Arylpurines
Zhoulong Fan, Heng Lu, and Ao Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00149 • Publication Date (Web): 27 Feb 2018
Downloaded from http://pubs.acs.org on February 27, 2018
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PMes3-Promoted Ruthenium-Catalyzed Meta C-H Nitration
of 6-Arylpurines
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Zhoulong Fan,†,‡ Heng Lu,§ and Ao Zhang*,†,‡,§
†CAS Key Laboratory of Receptor Research and the State Key Laboratory of Drug
Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences,
Shanghai 201203, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
§ShanghaiTech University, Shanghai 201210, China
ABSTRACT: To address the challenge of meta nitration of 6ꢀarylpurine substrates, a
versatile ruthenium catalyzed meta CꢀH nitration is developed. The use of sterically
hindered phosphine ligand is crucial for the catalytic efficiency, and a wide class of 6ꢀ
arylpurines and nucleosides were found suitable for this process providing
corresponding exclusively meta nitrated products in good yields.
INTRODUCTION
Purine and nucleoside analogues possess a wide range of biological activities, and are
used as prototypes for the development of antiꢀHIV, antiꢀinflammatory and anticancer
agents (Figure 1).1 Among them, 6ꢀarylpurine derivatives represent an important class
and have attracted great interest for their synthesis and diverse functionalization.
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Generally, Suzuki crossꢀcoupling reaction of 6ꢀchloropurine with various arylboronic
acids represents the universal method for the construction of 6ꢀarylpurines.2 However,
each analogue has to be accessed by means of de novo synthesis in the case of
polysubstituted 6ꢀarylpurine through multiple steps. Therefore, development of
methods for direct lateꢀstage modifications of 6ꢀarylpurines is daunting.
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Figure 1. Representative Biologically Active Purine Derivatives.
In the past decades, directing group (DG)ꢀassisted siteꢀselective CꢀH
activation/functionalization has achieved great progress for construction or
modification of complex natural products and pharmaceutical molecules.3ꢀ4 In contrast
to the widely used pyridyl DG, the purine scaffold as an intrinsic DG is rather
challenging due to: 1) multiple potential chelating sites (three additional nitrogen
atoms) that may deactivate the catalyst; and 2) easily generation of undesired CꢀH
functionalization at the highly nucleophilic C8 position of the purine core. Despite
these limitations, several ortho CꢀH functionalizations on the aryl component of 6ꢀ
arylpurines have been accomplished (Scheme 1a).5 In 2011, Guo5a and Lakshman5b
respectively developed Pd and Ru catalysis for ortho CꢀH arylation of 6ꢀarylpurines.
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Subsequently, the two research groups also described ortho CꢀH oxidation using
purine as the DG.5c,e Recently, Pd(II) or Co(III)ꢀcatalyzed CꢀH halogenations were
accomplished using Nꢀhalosuccinimide as the halogenating agent by the Guo5c and
Pawar5i groups, respectively. In addition, Chang et al reported ortho cyanation5h and
monoꢀamination5d,f of 6ꢀarylpurines. In the meantime, Nꢀheterocycleꢀassisted orthoꢀ
ruthenation strategy has been successfully established for the meta CꢀH
functionalization of arenes.6 Very recently, Ackermann developed the first meta CꢀH
bromination of 6ꢀarylpurine bases using the heterogeneous Ru@SiO2 catalyst,7 and
subsequently they also found that metaꢀselective alkylation was achieved by
ruthenium(II/III) catalysis (Scheme 1b).8
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Scheme 1. Site-Selective C-H Functionalizations of 6-Arylpurines.
Using the catalytic CꢀH nitration to readily construct the CꢀN bond with high
siteꢀselectivity by avoiding the use of strong acid condition remains an important
strategy in modern organic synthesis.9 Although ortho and meta CꢀH
functionalizations of 6ꢀarylpurines have achieved success in the past few years, to the
best of our knowledge, methods for meta CꢀH nitration of 6ꢀarylpurines have not been
established yet. Recently, we developed the first Ru(0)ꢀcatalyzed meta CꢀH nitration
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of arenes,10 unfortunately, this protocol is inapplicable to meta nitration of 6ꢀ
arylpurines. Subsequently, we also established the secondꢀgeneration ruthenium
catalytic system for metaꢀselective nitration of acetophenone oxime substrates,11
however, only a small amount of meta product was observed in the case of 6ꢀ
arylpurine. Therefore, a more versatile approach for meta nitration of the challenging
substrate 6ꢀarylpurines is needed. Herein, we described a tertiary phosphine ligand
promoted rutheniumꢀcatalyzed meta CꢀH nitration strategy (Scheme 1b), which
allows selective meta nitration of 6ꢀarylpurines and nucleosides.
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RESULTS AND DISCUSSION
We initiated our optimization studies with 9ꢀisopropylꢀ6ꢀphenylpurine (2a) as the
model substrate and AgNO3 as the nitrating agent, the desired meta nitration product
3a was obtained only in 35% yield (Table 1, entry 1). In order to improve the catalytic
efficiency, we firstly investigated various monodentate phosphorous ligands.8,12 To
our delight, tris(2,4,6ꢀtrimethylphenyl)phosphine (PMes3) was found to increase the
yield of meta nitrated product 3a up to 57% (entry 7). We then tested several NHC
ligands, but unfortunately, no better result was obtained (entries 11ꢀ12). Through
screening the loadings of PMes3, we found that using 0.3 equivalent of ligand gave 3a
in slightly higher yield (entry 13). To increase the solubility of the reaction mixture,
we tried to add a number of alcohols as the coꢀsolvent (entries 15ꢀ17). The results
showed that the use of DCE/HFIP as the mixture solvent improved the yield of 3a up
to 64%. Through prolonging the reaction time to 48 h, the yield of 3a was further
increased (74%, entry 18). It is worth noting that 3a was not detected in the presence
of RuCl2(PPh3)4 as the catalyst (entry 19). When the reaction was carried out under O2
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or N2 atmosphere, the yield of 3a significantly dropped (entries 20ꢀ21). Therefore, the
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reaction conditions in entry 18 were selected as the standard condition.
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Table 1. Optimization of the Reaction Conditionsa
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entry ligand (x equiv)
solvent
DCE
yieldb (%)
35
1
ꢀ
2
PPh3 (0.2)
DCE
41
3
P(oꢀtol)3 (0.2)
P(oꢀfuryl)3 (0.2)
P(pꢀOMeC6H4)3 (0.2)
P(pꢀCF3C6H4)3 (0.2)
PMes3 (0.2)
DCE
55
4
DCE
11
5
DCE
39
6
DCE
50
7
DCE
57
8
PCy3 (0.2)
DCE
21
9
XꢀPhos (0.2)
BrettPhos (0.2)
IMes.HCl (0.2)
IPr.HCl (0.2)
PMes3 (0.3)
DCE
25
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18c
19c,d
20c,e
21c,f
DCE
25
DCE
trace
24
DCE
DCE
60
PMes3 (0.4)
DCE
57
PMes3 (0.3)
PMes3 (0.3)
PMes3 (0.3)
PMes3 (0.3)
PMes3 (0.3)
PMes3 (0.3)
PMes3 (0.3)
DCE/tBuOH
DCE/HFIP
DCE/MeOH
DCE/HFIP
DCE/HFIP
DCE/HFIP
DCE/HFIP
14
64
n.d.
74
n.d.
62
53
aReaction conditions: 2a (0.10 mmol), AgNO3 (0.18 mmol),
Ru3(CO)12 (7.5 mol%), PhI(TFA)2 (1.1 equiv) in solvent (1
mL DCE, 100 ꢁL alcohol) at 100 oC for 24 h. bIsolated yield.
d
e
cFor 48 h. Using RuCl2(PPh3)4 as the catalyst. Under O2
protection. fUnder N2 protection. n.d. = not detected.
With the optimized reaction condition for meta nitration of 6ꢀarylpurines in
hand, we then explored a variety of substituted arylpurines in Scheme 2. For the para
substituted substrates, electronꢀneutral arylpurines gave the desired meta nitrated
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products 3b-d in 61ꢀ78% yields, whereas both electronꢀrich and electronꢀdeficient
ones were found to react sluggishly and afforded the corresponding products 3e-g in
slightly lower yields (48ꢀ53%). It was found that when one of the two meta positions
was substituted, the nitration reaction exclusively proceeded on the other meta
position and products 3h-3k were afforded in 32ꢀ64% yields. For orthoꢀmethyl
substituted substrate, the meta nitration prefers the sterically bulkier position and gave
the products in total 34% yield. Regrettably, only trace of corresponding meta
products were obtained in the cases of orthoꢀchloro or methoxy substituted substrates.
In addition, the present nitration approach was also applicable to naphthyl purine and
the exclusive meta nitration product 3m was obtained in 63% yield.
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Scheme 2. Scope of Substituted Arylpurinesa
iPr
iPr
N
N
N
N
N
N
N
N
Ru3(CO)12, PMes3
AgNO3
PhI(TFA)2
R1
R1
DCE/HFIP, 100 o
C
H
NO2
2b-m
iPr
3b-m
iPr
iPr
iPr
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NO2
NO2
NO2
NO2
Me
tBu
OMe
Ph
3b, 61%
3c, 64%
3d, 78%
3e, 48%
iPr
iPr
iPr
N
iPr
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
NO2
NO2
NO2
Me
NO2
Me
Cl
CO2Me
3f, 51%
3g, 53%
3i, 44%
3h, 42%
iPr
iPr
iPr
N
N
iPr
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Me
m
NO2
O2N
m'
Cl
NO2
EtO2C
NO2
3k, 32%(55%)b
3l, 34%
(m/m' = 8:1)
3j, 64%
3m, 63%
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aReaction conditions: 2b-m (0.10 mmol), AgNO3 (0.18 mmol), Ru3(CO)12 (7.5 mol%), PMes3 (30 mol%),
o
b
PhI(TFA)2 (1.1 equiv) in DCE/HFIP (1.1 mL, 10/1, v/v) at 100 C for 48 h in a sealed tube. Yield based
on the recovered starting material is listed in parenthesis.
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Subsequently, diverse Nꢀsubstituted purines were investigated under the standard
conditions (Scheme 3). In the case of Nꢀmethyl, ꢀbutyl, ꢀcyclopentyl and ꢀbenzyl 6ꢀ
phenylpurines, the yields of corresponding products 3n-q were lower than that of Nꢀ
isopropyl analog 3a (43ꢀ63% vs 74%). More appealingly, we found that nucleoside
analogues protected by acetylation were also suitable for current meta CꢀH nitration
and provided the corresponding products 3r-s in 31ꢀ42% yields, which would be
potentially useful for antiviral or anticancer drug screening.13 It should be noted that
the unprotected acyclovir side chain and 2’ꢀdeoxyribose of 6ꢀarylpurines are not
tolerated under present standard conditions.
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Scheme 3. Scope of N-Substituted Purinesa
R2
R2
N
N
N
N
N
N
N
N
Ru3(CO)12, PMes3
AgNO3
PhI(TFA)2
DCE/HFIP, 100 o
C
H
NO2
2n-s
3n-s
N
nBu
Me
Bn
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
NO2
3q, 45%
NO2
3n, 43%
NO2
3o, 61%
NO2
3p, 63%
NO2
NO2
N
N
N
N
N
N
N
N
AcO
AcO
O
O
OAc OAc
3r, 42%
OAc
3s, 31%
OAc
aReaction conditions: 2n-s (0.10 mmol), AgNO3 (0.18 mmol), Ru3(CO)12 (7.5 mol%), PMes3 (30 mol%),
PhI(TFA)2 (1.1 equiv) in DCE/HFIP (1.1 mL, 10/1, v/v) at 100 oC for 48 h in a sealed tube.
To demonstrate the utility of the current approach, we tried to shorten the route
for synthesis of the antiꢀinflammatory pꢀ38 kinase inhibitor 11d using the current meta
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nitration of arylpurines as the key step (Scheme 4). Firstly, the key intermediate 5 was
conveniently prepared through meta CꢀH nitration of phenylpurine 4 in 60% yield.
Subsequent hydrolysis with aqueous NaOH and condensation with cyclopropylamine
furnished the amide precursor 6 in 72% yield for two steps. Znꢀreduction followed by
sulfonylation completed the target inhibitor 1 in 58% overall yield in twoꢀstep. It is
worth noting that intermediate 6 could not be directly accessed through meta CꢀH
nitration method because of the intolerance of amide moiety. This concise fiveꢀstep
process with 25% overall yield (from 4) provides an alternative route for the synthesis
of antiꢀinflammatory agent 1 and would be conveniently used to generate more
derivatives.
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Scheme 4. Synthesis of p-38 Kinase Inhibitor 1
To gain more insight on the details of the meta nitration of 6ꢀarylpurines, we
firstly conducted the reaction with two model substrates 7 and 9, in which the N1 or
N7 nitrogen atom is removed. Only meta nitration product 8 was observed in 55%
yield under the standard condition, indicating that N1 is responsible for the reaction
(Scheme 5a). Furthermore, isotopeꢀlabelling experiments were also carried out with
substrates 2a and [D5]-2a, the ortho D/H exchanged products [Dn]-3a and [Dn]-3a’
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were isolated in 60% and 73% yield, respectively. These results disclosed that ortho
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CꢀH ruthenation process is reversible (Scheme 5b).
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Scheme 5. Primary Mechanism Studies
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Based on these results and our previous reports,11 a proposed mechanism is
shown in Scheme 6. Initially, the active Ru(II) catalyst was generated by the oxidation
of Ru(0) by PhI(TFA)2, then the resulting Ru(II) species was coordinated to the N1 of
the purine moiety and the ortho CꢀH bond of 2a was activated to provide the Ru(II)
species A, which could not be isolated and was proposed according to our previous
work.11 The nitrogen dioxide radical, produced by the oxidation of nitrate ion,
selectively attacked the para position of CꢀRu bond to form the species B. We have
tried to detect the possible TEMPOꢀNO2 product through TLC sprayed with
potassium permanganate, however, no relative product was isolated. The generation
of NO2 radical was proposed according to the previous literatures10,11. Subsequently,
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the reductive dehydrogenation occurred to deliver the Ru(II) complex C, which then
went through ligand exchange with CF3COOH to release the desired product 3a.
Meanwhile, the active Ru(II) catalyst was regenerated for the next catalytic cycle.
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Scheme 6. Proposed Mechanism
CONCLUSION
In conclusion, we have developed a versatile meta CꢀH nitration of 6ꢀarylpurines
under Ru3(CO)12/oxidant catalytic system. Notably, the reactivity was significantly
enhanced through employing the sterically hindered phosphine ligand. This protocol
could tolerate broad purine substrates as well as nucleosides. Moreover, it also
provides a convenient pathway for the synthesis of ongoing pꢀ38 kinase inhibitor and
its analogues.
EXPERIMENTAL SECTION
General Information. All reactions were performed in flameꢀdried glassware,
including sealed tubes or Schlenck tubes. Liquids and solutions were transferred with
syringes. All solvents and chemical reagents were obtained from commercial sources
and used without further purifications. H and 13C NMR spectra were recorded with
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tetramethylsilane as an internal reference. Low and highꢀresolution mass spectra were
recorded on EIꢀTOF (electrospray ionizationꢀtime of flight) or ESIꢀTOF. Flash
column chromatography on silica gel (200 ꢀ 300 mesh). The column output was
monitored by TLC on silica gel (100 ꢀ 200 mesh) precoated on glass plates (15 x 50
mm), and spots were visualized by UV light at 254 nM. The following starting
materials were synthesized according to previously described methods: 9ꢀisopropylꢀ6ꢀ
arylpurine,2b 9ꢀbutyl or benzylꢀ6ꢀchloropurine,14 9ꢀcyclopentylꢀ6ꢀchloropurine,15
(2R,3R,4R,5R)ꢀ2ꢀ(acetoxymethyl)ꢀ5ꢀ(6ꢀchloroꢀ9Hꢀpurinꢀ9ꢀyl)tetrahydrofuranꢀ3,4ꢀ
diyldiacetate.16
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General Procedure for Synthesis of Meta Nitrated Prodcucts. To a stirred
solution of substrates 2, 4 or 7 (0.10 mmol) in DCE/HFIP (1 mL/100 ꢁL), AgNO3 (31
mg, 0.18 mmol), PhI(TFA)2 (47 mg, 0.11 mmol), Ru3(CO)12 (4.8 mg, 7.5 mol%) and
o
PMes3 (12 mg, 30 mol%) were added. The mixture was stirred at 100 C for 48 h.
After cooled to room temperature, the reaction mixture was filtered and the filtrate
was concentrated. The residue was purified on a preparative TLC with petroleum
petroleum ether/ethyl acetate as the eluent to afford the nitrated products 3, 5 or 8.
Synthesis of Compound 4.2b,17 a) To a stirred solution of 3ꢀaminoꢀ4ꢀmethylbenzoic
acid (S1) (600 mg, 4 mmol) in isobutanol (20 mL), thionyl chloride (1.44 mL, 20
o
o
mmol) was added at 0 C. Then the mixture was stirred overnight at 80 C. After the
solvent was removed, the residue was purified on a silica gel column (PE/EA = 4/1)
to give compound S2; b) A microwave vial was charged with 4,6ꢀdichloropyrimidinꢀ
5ꢀamine (39 mg, 0.24 mmol), compound S2 (50 mg, 0.24 mmol), 37% HCl (12 ꢁL)
and isobutanol (0.5 mL). The vessel was sealed and heated in a microwave reactor at
150 oC for 1 h. After cooled to room temperature, the solvent was removed. The rude
product S3 and one drop of acetic acid were added in triethyl orthoformate (1 mL).
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The reaction vessel was placed in a microwave reactor at 120 oC for 15 min. After the
solvent was removed, The residue was purified on a silica gel column (PE/EA = 5/1)
to afford product S4; c) To a stirred solution of S4 (344 mg, 1 mmol) in toluene (20
mL), phenylboronic acid (244 mg, 2 mmol), K2CO3 (207 mg, 1.5 mmol), Pd(PPh3)4
(62 mg, 0.05 mmol) were added under N2 protection. Then the mixture was stirred at
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100 C for 16 h. After the solvent was removed, the residue was purified on a silica
gel column (PE/EA = 5/1) to afford compound 4.
Synthesis of Compound 6. To a stirred solution of compound 5 (43 mg, 0.1 mmol)
in dioxane (1 mL), 30% aqueous NaOH (0.5 mL) was added. Then the mixture was
o
stirred at 100 C for 1 h. HCl aqueous solution was added until pH = 3, the mixture
was extracted with DCM, and the combined organic phase was washed with brine,
dried over anhydrous sodium sulfate and concentrated. The residue was dissolved in
DMF (1 mL), EDCI (23 mg, 0.12 mmol), DMAP (1 mg, 0.01 mmol) and
cyclopropylamine (14 ꢁL, 0.2 mmol) were added. Then the mixture was stirred
overnight at room temperature. After the solvent was removed, the residue was
purified by silica gel column chromatography (PE/EA = 1/2) to give compound 6.
Synthesis of p-38 Kinase Inhibitor 1. A round flask was charged with compound 6
(29 mg, 0.07 mmol), zinc powder (46 mg, 0.7 mmol), saturated aqueous NH4Cl (1 mL)
and THF (1 mL). The mixture was stirred at 80 oC for 5 h. The solid was removed by
filtrated. 30% NaOH was added until pH = 9. The aqueous layer was extracted with
EtOAc, and the combined organic phase was washed with brine, dried over anhydrous
sodium sulfate and concentrated. The residue was used in the next step without further
purification. The crude product was dissolved in DCM (1 mL), pyridine (9 ꢁL, 0.11
o
mmol) and methylsulfonyl chloride (7 ꢁL, 0.08 mmol) were added at 0 C. The
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mixture was stirred at room temperature for 12 h. After the solvent was removed, the
residue was purified on a silica gel column (DCM/MeOH = 50/1) to give compound 1.
Spectroscopic Data of All New Compounds.
9
9-Isopropyl-6-(3-nitrophenyl)purine (3a): white solid (21 mg, 74%); mp = 171ꢀ173
oC; 1H NMR (300 MHz, CDCl3) δ 9.74 (s, 1H), 9.21 (d, J = 7.8 Hz, 1H), 9.06 (s, 1H),
8.36 (d, J = 8.2 Hz, 1H), 8.26 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 5.02 (p, J = 6.9 Hz,
1H), 1.71 (d, J = 6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 152.6, 152.1, 151.7,
148.7, 142.8, 137.6, 135.5, 131.7, 129.6, 125.2, 124.7, 47.6, 22.6; HRMS (EI): m/z
[M+] calcd for C14H13N5O2, 283.1069; found, 283.1068.
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9-Isopropyl-6-(4-methyl-3-nitrophenyl)purine (3b): white solid (18 mg, 61%); mp =
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179ꢀ181 C; 1H NMR (300 MHz, CDCl3) δ 9.51 (d, J = 1.8 Hz, 1H), 9.08 – 8.97 (m,
2H), 8.23 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.27 (s, 1H), 5.01 (p, J = 6.8 Hz, 1H), 2.70
(s, 3H), 1.70 (d, J = 6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 152.4, 152.0, 151.8,
149.7, 142.6, 135.9, 135.2, 133.6, 133.0, 131.5, 125.8, 47.5, 22.6, 20.6; HRMS (EI):
m/z [M+] calcd for C15H15N5O2, 297.1226; found, 297.1226.
9-Isopropyl-6-(2-nitro-[1,1'-biphenyl]-4-yl)purine (3c): white solid (23 mg, 64%);
mp = 144ꢀ146 oC; 1H NMR (300 MHz, CDCl3) δ 9.41 (d, J = 1.7 Hz, 1H), 9.13 (dd, J
= 8.2, 1.7 Hz, 1H), 9.06 (s, 1H), 8.25 (s, 1H), 7.65 (d, J = 8.1 Hz, 1H), 7.49 – 7.39 (m,
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5H), 5.01 (q, J = 6.8 Hz, 1H), 1.71 (d, J = 6.7 Hz, 6H); C NMR (126 MHz, CDCl3)
δ 152.5, 152.1, 151.4, 149.7, 142.7, 138.0, 137.0, 136.2, 132.9, 132.2, 131.7, 128.8,
128.5, 127.9, 125.2, 47.6, 22.6; HRMS (EI): m/z [M+] calcd for C20H17N5O2,
359.1382; found, 359.1382.
6-(4-(tert-Butyl)-3-nitrophenyl)-9-isopropylpurine (3d): white solid (26.5 mg, 78%);
mp = 119ꢀ121 oC; 1H NMR (300 MHz, CDCl3) δ 9.01 (d, J = 0.9 Hz, 1H), 8.92 (dd, J
= 8.5, 1.9 Hz, 1H), 8.88 (d, J = 1.9 Hz, 1H), 8.20 (s, 1H), 7.74 (d, J = 8.5 Hz, 1H),
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5.05 – 4.96 (m, 1H), 1.69 (d, J = 6.8 Hz, 6H), 1.47 (s, 9H); 13C NMR (126 MHz,
CDCl3) δ 152.4, 152.0, 151.6, 151.5, 143.6, 142.5, 134.9, 131.5, 131.4, 128.9, 125.0,
47.5, 35.9, 30.6, 22.6; HRMS (EI): m/z [M+] calcd for C18H21N5O2, 339.1695; found,
339.1692.
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9-Isopropyl-6-(4-methoxy-3-nitrophenyl)purine (3e): white solid (15 mg, 48%); mp
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= 201ꢀ203 C; 1H NMR (300 MHz, CDCl3) δ 9.46 (d, J = 2.2 Hz, 1H), 9.11 (dd, J =
8.9, 2.2 Hz, 1H), 8.99 (s, 1H), 8.21 (s, 1H), 7.24 (s, 1H), 4.99 (p, J = 6.8 Hz, 1H),
4.06 (s, 3H), 1.69 (d, J = 6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 154.5, 152.3,
152.0, 151.6, 142.3, 140.0, 135.2, 131.1, 128.6, 127.2, 113.3, 56.7, 47.4, 22.6; HRMS
(EI): m/z [M+] calcd for C15H15N5O3, 313.1175; found, 313.1174.
6-(4-Chloro-3-nitrophenyl)-9-isopropylpurine (3f): white solid (16 mg, 51%); mp =
139ꢀ141 oC; 1H NMR (300 MHz, CDCl3) δ 9.48 (d, J = 2.0 Hz, 1H), 9.08 (dd, J = 8.5,
2.0 Hz, 1H), 9.03 (s, 1H), 8.24 (s, 1H), 7.73 (d, J = 8.5 Hz, 1H), 5.01 (p, J = 6.8 Hz,
1H), 1.70 (d, J = 6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 152.6, 152.0, 150.4,
148.4, 142.9, 135.9, 133.7, 132.0, 131.6, 129.0, 126.6, 47.6, 22.6; HRMS (EI): m/z
[M+] calcd for C14H12ClN5O2, 317.0680; found, 317.0678.
Methyl 4-(9-isopropylpurinyl)-2-nitrobenzoate (3g): white solid (18 mg, 53%); mp =
126ꢀ128 oC; 1H NMR (300 MHz, CDCl3) δ 9.49 (d, J = 1.6 Hz, 1H), 9.23 (dd, J = 8.2,
1.6 Hz, 1H), 9.07 (s, 1H), 8.26 (s, 1H), 7.93 (d, J = 8.1 Hz, 1H), 5.08 – 4.98 (m, 1H),
3.97 (s, 3H), 1.71 (d, J = 6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 165.7, 152.8,
152.0, 150.3, 148.7, 143.2, 139.8, 133.6, 131.9, 130.1, 128.5, 124.9, 53.4, 47.7, 22.6;
HRMS (EI): m/z [M+] calcd for C16H15N5O4, 341.1124; found, 341.1125.
6-(3,4-Dimethyl-5-nitrophenyl)-9-isopropylpurine (3h): white solid (13 mg, 42%);
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mp = 164ꢀ166 C; H NMR (300 MHz, CDCl3) δ 9.19 (s, 1H), 9.02 (s, 1H), 8.84 (s,
1H), 8.22 (s, 1H), 5.04 – 4.96 (m, 1H), 2.50 (d, J = 13.0 Hz, 6H), 1.69 (d, J = 6.8 Hz,
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6H); 13C NMR (126 MHz, CDCl3) δ 152.4, 152.02, 151.95, 151.5, 142.5, 139.8, 134.0,
133.8, 133.2, 131.5, 123.1, 47.4, 30.9, 22.6, 20.8, 15.5; HRMS (EI): m/z [M+] calcd
for C16H17N5O2, 311.1382; found, 311.1381.
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9-Isopropyl-6-(3-methyl-5-nitrophenyl)purine (3i): white solid (13 mg, 44%); mp =
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139ꢀ141 C; H NMR (300 MHz, CDCl3) δ 9.56 (s, 1H), 9.05 (s, 1H), 8.97 (s, 1H),
8.26 (s, 1H), 8.18 (s, 1H), 5.02 (p, J = 6.8 Hz, 1H), 2.64 – 2.58 (m, 3H), 1.70 (d, J =
6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 152.5, 151.99, 151.96, 148.7, 142.8,
140.1, 137.3, 135.9, 131.7, 125.7, 122.2, 47.5, 22.6, 21.5; HRMS (EI): m/z [M+] calcd
for C15H15N5O2, 297.1226; found, 297.1227.
6-(3-Chloro-5-nitrophenyl)-9-isopropylpurine (3j): white solid (20.5 mg, 64%); mp
= 143ꢀ145 oC; 1H NMR (300 MHz, CDCl3) δ 9.73 – 9.69 (m, 1H), 9.25 (t, J = 1.7 Hz,
1H), 9.06 (s, 1H), 8.34 (t, J = 2.1 Hz, 1H), 8.27 (s, 1H), 5.08 – 4.98 (m, 1H), 1.71 (d,
J = 6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 152.7, 152.0, 150.1, 149.1, 143.2,
138.9, 135.7, 135.2, 131.7, 125.3, 122.9, 47.7, 22.6; HRMS (EI): m/z [M+] calcd for
C14H12ClN5O2, 317.0680; found, 317.0681.
Ethyl 3-(9-isopropylpurin-6-yl)-5-nitrobenzoate (3k): white solid (11.5 mg, 32%);
mp = 172ꢀ174 oC; 1H NMR (300 MHz, CDCl3) δ 9.97 (t, J = 1.9 Hz, 1H), 9.83 (t, J =
1.5 Hz, 1H), 9.09 (s, 1H), 8.99 (t, J = 1.9 Hz, 1H), 8.29 (s, 1H), 5.02 (q, J = 6.8 Hz,
1H), 4.51 (q, J = 7.1 Hz, 2H), 1.71 (d, J = 6.8 Hz, 6H), 1.48 (t, J = 7.1 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 164.5, 152.7, 152.1, 150.7, 148.8, 143.2, 138.1, 135.9,
132.7, 131.8, 128.4, 126.0, 62.1, 47.6, 22.6, 14.4; HRMS (EI): m/z [M+] calcd for
C17H17N5O4, 355.1281; found, 355.1284.
9-Isopropyl-6-(2-methyl-3-nitrophenyl)purine (3l): white solid (9 mg, 30%); mp =
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106ꢀ108 C; H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.19 (s, 1H), 7.97 (dd, J =
8.1, 1.4 Hz, 1H), 7.85 (dd, J = 7.7, 1.4 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 5.02 (p, J =
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6.8 Hz, 1H), 2.50 (s, 3H), 1.72 (d, J = 6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ
156.5, 152.0, 151.7, 151.4, 143.1, 138.2, 134.7, 132.8, 131.9, 126.5, 125.2, 47.7, 22.6,
16.9; HRMS (EI): m/z [M+] calcd for C15H15N5O2, 297.1226; found, 297.1219.
9-Isopropyl-6-(2-methyl-5-nitrophenyl)purine (3l’): colorless oil (1.2 mg, 4%); mp =
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117ꢀ119 C; H NMR (300 MHz, CDCl3) δ 9.08 (s, 1H), 8.62 (d, J = 2.5 Hz, 1H),
8.25 (dd, J = 8.5, 2.5 Hz, 1H), 8.20 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 5.02 (p, J = 6.8
Hz, 1H), 2.57 (s, 3H), 1.72 (d, J = 6.8 Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 156.0,
152.0, 151.9, 146.2, 145.3, 143.0, 136.2, 132.5, 132.1, 126.1, 124.1, 47.7, 22.6, 21.0;
HRMS (EI): m/z [M+] calcd for C15H15N5O2, 297.1226; found, 297.1226.
9-Isopropyl-6-(4-nitronaphthalen-2-yl)purine (3m): pale yellow solid (21 mg, 63%);
mp = 165ꢀ167 oC; 1H NMR (300 MHz, CDCl3) δ 9.72 (s, 2H), 9.05 (s, 1H), 8.57 (d, J
= 8.7 Hz, 1H), 8.27 (s, 1H), 8.16 (d, J = 8.2 Hz, 1H), 7.77 (t, J = 7.8 Hz, 1H), 7.66 (t,
J = 7.5 Hz, 1H), 5.03 (q, J = 6.7 Hz, 1H), 1.71 (d, J = 6.8 Hz, 6H); 13C NMR (126
MHz, CDCl3) δ 152.5, 152.0, 151.5, 147.0, 142.7, 136.3, 134.4, 132.2, 131.7, 130.6,
130.2, 127.7, 125.9, 124.2, 123.2, 47.5, 22.6; HRMS (EI): m/z [M+] calcd for
C18H15N5O2, 333.1226; found, 333.1233.
9-Methyl-6-(3-nitrophenyl)purine (3n): white solid (11 mg, 43%); mp = 245ꢀ247 oC;
1H NMR (300 MHz, CDCl3) δ 9.76 (s, 1H), 9.22 (d, J = 7.8 Hz, 1H), 9.10 (s, 1H),
8.38 (d, J = 10.0 Hz, 1H), 8.19 (s, 1H), 7.75 (t, J = 8.0 Hz, 1H), 3.99 (s, 3H); 13C
NMR (126 MHz, CDCl3) δ 152.5, 151.8, 148.7, 148.6, 145.6, 137.4, 135.5, 131.2,
129.6, 125.3, 124.8, 30.0; HRMS (EI): m/z [M+] calcd for C12H9N5O2, 255.0756;
found, 255.0760.
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9-Butyl-6-(3-nitrophenyl)purine (3o): white solid (18 mg, 61%); mp = 122ꢀ124 C;
1H NMR (300 MHz, CDCl3) δ 9.75 (t, J = 2.0 Hz, 1H), 9.22 (dt, J = 7.9, 1.3 Hz, 1H),
9.07 (s, 1H), 8.37 (ddd, J = 8.2, 2.4, 1.1 Hz, 1H), 8.19 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H),
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4.36 (t, J = 7.2 Hz, 2H), 1.95 (q, J = 7.5 Hz, 2H), 1.40 (dd, J = 14.9, 7.4 Hz, 2H), 1.00
(t, J = 7.3 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 153.0, 152.3, 151.7, 148.7, 145.1,
137.5, 135.4, 131.3, 129.6, 125.2, 124.7, 43.9, 31.9, 19.9, 13.5; HRMS (EI): m/z [M+]
calcd for C15H15N5O2, 297.1226; found, 297.1223.
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9-Cyclopentyl-6-(3-nitrophenyl)purine (3p): white solid (19.5 mg, 63%); mp = 151ꢀ
153 oC; 1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 9.21 (d, J = 7.8 Hz, 1H), 9.06 (s,
1H), 8.37 (d, J = 8.2 Hz, 1H), 8.24 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 5.14 – 5.03 (m,
1H), 2.37 (dt, J = 10.9, 5.1 Hz, 2H), 2.14 – 1.97 (m, 4H), 1.87 (dd, J = 10.2, 5.0 Hz,
2H); 13C NMR (126 MHz, CDCl3) δ 153.0, 152.1, 151.6, 148.7, 143.4, 137.6, 135.4,
131.7, 129.6, 125.2, 124.7, 56.4, 32.7, 23.9; HRMS (EI): m/z [M+] calcd for
C16H15N5O2, 309.1226; found, 309.1226.
9-Benzyl-6-(3-nitrophenyl)purine (3q): white solid (15 mg, 45%); mp = 186ꢀ188 oC;
1H NMR (300 MHz, CDCl3) δ 9.75 (s, 1H), 9.22 (d, J = 7.8 Hz, 1H), 9.11 (s, 1H),
8.37 (d, J = 8.1 Hz, 1H), 8.17 (s, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.37 (q, J = 4.7 Hz,
5H), 5.52 (s, 2H); 13C NMR (126 MHz, CDCl3) δ 153.0, 152.6, 151.9, 148.7, 144.9,
137.4, 135.5, 134.9, 131.2, 129.6, 129.3, 128.8, 127.9, 125.3, 124.7, 47.5; HRMS (EI):
m/z [M+] calcd for C18H13N5O2, 331.1069; found, 331.1048. Spectral data matched
the previous report.18
(2R,3R,4R,5R)-2-(Acetoxymethyl)-5-(6-(3-nitrophenyl)purin-9-yl)tetrahydrofuran-
3,4-diyl diacetate (3r): white solid (21 mg, 42%); mp = 73ꢀ75 oC; 1H NMR (300 MHz,
CDCl3) δ 9.73 (s, 1H), 9.20 (d, J = 8.1 Hz, 1H), 9.08 (s, 1H), 8.44 – 8.34 (m, 2H),
7.75 (t, J = 8.0 Hz, 1H), 6.31 (d, J = 5.2 Hz, 1H), 6.02 (t, J = 5.4 Hz, 1H), 5.71 (t, J =
5.1 Hz, 1H), 4.54 – 4.36 (m, 3H), 2.17 (d, J = 7.0 Hz, 6H), 2.10 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 170.3, 169.6, 169.4, 152.7, 152.4, 148.7, 143.4, 137.1, 135.5,
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131.9, 129.7, 125.5, 124.8, 86.6, 80.5, 73.1, 70.6, 63.0, 20.8, 20.6, 20.4; HRMS (EI):
m/z [M+] calcd for C22H21N5O9, 499.1339; found, 499.1342.
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yl)tetrahydrofuran-3,4-diyl diacetate (3s): colorless oil (16 mg, 31%); mp = 162ꢀ164
oC; 1H NMR (300 MHz, CDCl3) δ 9.55 (s, 1H), 9.06 (s, 1H), 8.96 (s, 1H), 8.35 (s, 1H),
8.20 (s, 1H), 6.31 (d, J = 5.2 Hz, 1H), 6.02 (t, J = 5.4 Hz, 1H), 5.75 – 5.68 (m, 1H),
4.53 – 4.39 (m, 3H), 2.61 (s, 3H), 2.17 (d, J = 6.6 Hz, 6H), 2.10 (s, 3H); 13C NMR
(126 MHz, CDCl3) δ 170.3, 169.6, 169.4, 152.64, 152.61, 152.4, 148.7, 143.3, 140.3,
136.8, 135.9, 131.9, 126.0, 122.3, 86.6, 80.5, 73.1, 70.6, 63.0, 30.9, 21.5, 20.8, 20.5,
20.4; HRMS (EI): m/z [M+] calcd for C23H23N5O9, 513.1496; found, 513.1495.
Isobutyl 3-amino-4-methylbenzoate (S2): white solid (546 mg, 66%); mp = 33ꢀ35 oC;
1H NMR (300 MHz, CDCl3) δ 7.39 (dd, J = 7.7, 1.8 Hz, 1H), 7.35 (d, J = 1.7 Hz, 1H),
7.10 (d, J = 7.7 Hz, 1H), 4.07 (d, J = 6.6 Hz, 2H), 3.66 (s, 2H), 2.21 (s, 3H), 2.07 (dt, J
= 13.4, 6.7 Hz, 1H), 1.01 (d, J = 6.7 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 166.9,
144.5, 130.4, 129.3, 127.5, 119.9, 115.5, 70.8, 27.9, 19.3, 17.6; HRMS (ESI): m/z
[M+H]+ calcd for C12H18NO2, 208.1332; found, 208.1331.
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Isobutyl 3-(6-chloropurin-9-yl)-4-methylbenzoate (S4): white solid (47 mg, 57% for
two steps); mp = 132ꢀ134 oC; 1H NMR (300 MHz, CDCl3) δ 8.78 (s, 1H), 8.23 (s, 1H),
8.17 (d, J = 8.0 Hz, 1H), 8.00 (s, 1H), 7.56 (d, J = 8.0 Hz, 1H), 4.13 (d, J = 6.6 Hz,
13
2H), 2.21 (s, 3H), 2.09 (dd, J = 13.7, 7.1 Hz, 1H), 1.01 (d, J = 6.7 Hz, 6H); C NMR
(151 MHz, CDCl3) δ 165.1, 152.8, 152.2, 151.9, 145.0, 140.6, 132.5, 132.0, 131.5,
131.3, 130.2, 128.6, 71.5, 27.9, 19.2, 18.3; HRMS (ESI): m/z [M+H]+ calcd for
C17H18ClN4O2, 345.1113; found, 345.1106.
Isobutyl 4-methyl-3-(6-phenylpurin-9-yl)benzoate (4): white solid (332 mg, 86%);
mp = 94ꢀ96 oC; 1H NMR (300 MHz, CDCl3) δ 9.04 (s, 1H), 8.85 (d, J = 6.1 Hz, 2H),
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8.23 (s, 1H), 8.16 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H), 7.58 (p, J = 8.1, 7.1 Hz, 4H), 4.13
(d, J = 6.6 Hz, 2H), 2.24 (s, 3H), 2.12 – 2.00 (m, 1H), 1.01 (d, J = 6.7 Hz, 6H); 13C
NMR (151 MHz, CDCl3) δ 165.3, 155.6, 153.2, 152.9, 144.0, 140.9, 135.5, 133.1,
131.8, 131.3, 130.98, 130.70, 130.04, 129.87, 128.77, 71.44, 27.87, 19.20, 18.41;
HRMS (ESI): m/z [M+H]+ calcd for C23H23N4O2, 387.1816; found, 387.1816.
Isobutyl 4-methyl-3-(6-(3-nitrophenyl)purin-9-yl)benzoate (5): white solid (26 mg,
60%); mp = 107ꢀ109 oC; 1H NMR (300 MHz, CDCl3) δ 9.83 (t, J = 2.0 Hz, 1H), 9.28
(d, J = 7.8 Hz, 1H), 9.09 (s, 1H), 8.46 – 8.40 (m, 1H), 8.29 (s, 1H), 8.18 (dd, J = 8.1,
1.7 Hz, 1H), 8.04 (d, J = 1.7 Hz, 1H), 7.79 (t, J = 8.0 Hz, 1H), 7.57 (d, J = 8.1 Hz,
1H), 4.13 (d, J = 6.7 Hz, 2H), 2.25 (s, 3H), 2.08 (dt, J = 13.5, 6.7 Hz, 1H), 1.01 (d, J =
6.7 Hz, 6H); 13C NMR (151 MHz, CDCl3) δ 165.2, 153.3, 153.2, 152.6, 148.7, 144.9,
140.8, 137.2, 135.5, 132.8, 131.9, 131.2, 130.9, 130.2, 129.8, 128.8, 125.6, 124.9,
71.5, 27.9, 19.2, 18.4; HRMS (EI): m/z [M+] calcd for C23H21N5O4, 431.1594; found,
431.1584.
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N-Cyclopropyl-4-methyl-3-(6-(3-nitrophenyl)purin-9-yl)benzamide (6): white solid
(30 mg, 72% for two steps); mp = 208ꢀ210 oC; 1H NMR (300 MHz, CDCl3) δ 9.81 (t,
J = 2.0 Hz, 1H), 9.28 (d, J = 7.5 Hz, 1H), 9.07 (s, 1H), 8.42 (dd, J = 8.2, 1.3 Hz, 1H),
8.27 (s, 1H), 7.90 – 7.74 (m, 3H), 7.54 (d, J = 8.1 Hz, 1H), 6.30 (s, 1H), 2.91 (tt, J =
7.1, 3.6 Hz, 1H), 2.23 (s, 3H), 0.90 (q, J = 6.9 Hz, 2H), 0.69 – 0.58 (m, 2H); 13C
NMR (151 MHz, CDCl3) δ 167.1, 153.3, 153.2, 152.6, 148.7, 144.9, 139.2, 137.2,
135.6, 134.0, 133.0, 132.0, 130.9, 129.8, 128.1, 126.6, 125.6, 124.8, 23.3, 18.2, 6.9;
HRMS (ESI): m/z [MꢀH]ꢀ calcd for C22H17N6O3, 413.1368; found, 413.1363.
N-Cyclopropyl-4-methyl-3-(6-(3-(methylsulfonamido)phenyl)purin-9-yl)benzamide
(1): white solid (18.7 mg, 58% for two steps); mp = 214ꢀ216 oC; 1H NMR (300 MHz,
DMSOꢀd6) δ 10.03 (s, 1H), 9.00 (s, 1H), 8.91 (s, 1H), 8.74 – 8.68 (m, 2H), 8.51 (d, J
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= 4.2 Hz, 1H), 7.98 (dd, J = 10.5, 1.9 Hz, 2H), 7.61 (t, J = 7.7 Hz, 2H), 7.44 (d, J =
8.0 Hz, 1H), 3.08 (s, 3H), 2.89 – 2.82 (m, 1H), 2.16 (s, 3H), 0.72 – 0.64 (m, 2H), 0.59
– 0.52 (m, 2H); 13C NMR (151 MHz, DMSOꢀd6) δ 166.5, 153.4, 153.2, 152.9, 147.0,
139.4, 138.9, 136.8, 133.7, 133.3, 131.6, 130.6, 130.2, 128.8, 127.3, 125.8, 123.0,
120.6, 23.6, 18.0, 6.2; ESIꢀMS (m/z) 461 (MꢀH)ꢀ; HRMS (ESI): m/z [MꢀH]ꢀ calcd for
C23H21N6O3S, 461.1401; found, 461.1401. Spectral data matched the previous
report.1d
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7-Isopropyl-4-(3-nitrophenyl)pyrrolo[2,3-d]pyrimidine (8): white solid (15.5 mg,
55%); mp = 113ꢀ115 oC; 1H NMR (300 MHz, CDCl3) δ 9.01 (s, 1H), 8.99 (s, 1H),
8.51 (d, J = 7.8 Hz, 1H), 8.37 (dd, J = 8.2, 1.2 Hz, 1H), 7.74 (t, J = 8.0 Hz, 1H), 7.47
(d, J = 3.7 Hz, 1H), 6.85 (d, J = 3.7 Hz, 1H), 5.24 (p, J = 6.7 Hz, 1H), 1.59 (d, J = 6.8
Hz, 6H); 13C NMR (126 MHz, CDCl3) δ 154.3, 151.3, 151.1, 148.7, 140.2, 134.6,
129.8, 126.5, 124.4, 123.7, 116.0, 99.6, 46.2, 22.7; HRMS (EI): m/z [M+] calcd for
C15H14N4O2, 282.1117; found, 282.1109.
ASSOCIATED CONTENT
Supporting Information
H/D exchange experiments and 1H and 13C NMR spectra for all new compounds. This
material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: aozhang@simm.ac.cn
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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This work was supported by grants from Chinese NSF (81773565,81430080).
Supporting from the National Program on Key Basic Research Project of China
(2015CB910603), the International Cooperative Program (GJHZ1622) and Key
Program of the Frontier Science (QYZDJꢀSSWꢀSMC002) of the Chinese Academy of
Sciences, the Shanghai Commission of Science and Technology (16XD1404600) are
also highly appreciated.
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