Direct Sulfenylation of the Purine C8-H Bond with Thiophenols

Article abstract of DOI:10.1021/acs.joc.9b03115

The one-step copper-mediated regioselective formation of the C₈-S bond for purine derivatives with arylthiols was achieved using air as the green oxidant in the presence of 1.0 equiv of Na₂CO₃ and stoichiometric CuCl and 1,10-phenanthroline monohydrate. This method provides an economical, easy-to-handle, and effective method for the synthesis of 8-sulfenylpurine derivatives in moderate to excellent yields. The reaction is selective for C8 over C2 and C6. It also tolerates a free amine on the purine, and it has a wide substrate scope.

Full text of DOI:10.1021/acs.joc.9b03115

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Article
Direct Sulfenylation of the Purines C8-H Bond with Thiophenols
Wei Jiang, Juanping Zhuge, Jianxiao Li, Gary Histand, and Dongen Lin
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b03115 • Publication Date (Web): 03 Jan 2020
Downloaded from pubs.acs.org on January 3, 2020
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Direct Sulfenylation of the Purines C8-H Bond with Thiophenols
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†
Wei Jiang,† Juanping Zhuge,† Jianxiao Li,† Gary Histand,‡ and Dongen Lin*,
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†Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou 510641, P. R. China
‡International School of Advanced Materials, South China University of Technology, Guangzhou 510640, P. R. China.
*E-mail: denlin@scut.edu.cn
Supporting Information
ABSTRACT: The one-step copper-mediated regioselective formation of the C8-S bond for purine derivatives with arylthiols was
achieved using air as the green oxidant in the presence of 1.0 equivalent of Na2CO3 and stoichiometric CuCl and 1,10-phenanthroline
monohydrate. This method provides an economical, easy-to-handle and effective method for the synthesis of 8-sulfenylpurine
derivatives in moderate to excellent yields. The reaction is selective for C8 over C2 and C6. It also tolerates a free amine on the
purine, and it has a wide substrate scope.
INTRODUCTION
The purine heterocyclic framework, an important pharmaceutical intermediate with a broad range of functions, is widely used in the
field of biological and medicinal chemistry.1 The derivatives with the arylthio group on the purine’s C8 atom have attracted the
interest of synthetic chemists due to their important roles in antitumor and anticancer efforts.2 PU-H71, MPC-3100 and CUDC-305
(Figure 1) are effective Hsp90 inhibitors3 which can lead to cell- specific growth arrest or apoptosis in cancer cells, as well as
inhibition or regression of tumor growth. Therefore, the synthesis of such compounds by the direct sulfenylation of purine’s C8 with
various sulphur sources is of great interest.
Figure 1. Examples of purine analogues possessing biological activities.
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The C-S bond is an important structural unit found in a large number of biologically active molecules and functional materials.4 The
direct sulfenylation of purines C8-H bond to synthesize a series of 8-sulfenylpurine derivatives is difficult due to the low activity of
C8-H bond. Therefore, the conventional method for synthesizing 8-sulfenylpurine derivatives was by the nucleophilic substitution
reaction of arylthiols with 8-bromopurines, and the 8-bromopurines were formed by bromination of the purines’ C8-H bond. The total
yield of this method was less than 70% (Scheme 1a).5 In the past few decades, many efforts have been made in the C(sp2)-H bonds
direct functionalization which enabled the efficient construction of carbon-heteroatom bonds as a highly atom-economy. In 2013,
Hocek’s group6 firstly reported the direct C8-H sulfenylation reaction of 6-phenyl-9-benzyl purine with diphenyl disulfide in the
presence of tBuOLi (Scheme 1b). However, this reaction required 2.5 equiv of disulfide together with a long reaction time (120 h),
and two products were obtained with yields of 60% and 56%. Thus, further development for direct sulfenylation of purines C8-H
bond is strongly desired.
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The formation of a C-S bond through metal-catalyzed/mediated nitrogen heterocyclic compound C-H bond has been a subject of
particular interest.7 Pd,8 Ru,9 Ag10 and other transition metals-catalyzed11 the C-H to intramolecular or intermolecular C-S bond
transformation. This usually required other metal additives or other special requirements. Moreover, on the basis of the literature12
and our previous work, these methods have no significant effect on purine and its derivatives. The failure may be due to the four N
atoms of the purine being easily chelated or coordinated with these metals causing catalyst poisoning. In recent years, due to their
low cost and as alternative catalysts for C-H bond functionalization, copper salts were used in a large number of studies for the direct
functionalization the C-H bond of heterocyclic compounds (benzothiazole, benzoxazole, etc.).13 In 2013, Zhu and co-workers
described copper-catalyzed direct thiolation of xanthines and related heterocycles with disulfides using Cu(OAc)2·H 2O as the catalyst
under oxygen atmosphere.14 But it also required AgOAc as an additive and there was no mention that purines could be applied into
this catalytic system. Therefore, it is necessary to develop a highly efficient and novel method for synthesizing 8-sulfenylpurine
derivatives. Herein, we report the first one-step air-oxidized copper-mediated C8-H thiolation protocol for the coupling of purine
derivatives with thiophenols in the presence of base (Scheme 1c).
Scheme 1. Synthesis Routes of 8-Arylsulfanyl Purines
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RESULTS AND DISCUSSION
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In our preliminary experiments, the coupling of 6-methylthio-9-ethylpurine (1a) with p-toluenethiol (2a) was chosen as the model to
determine the optimal reaction conditions, and the results are summarized in Table 1. Initially, in the absence of a metal salt or ligand,
only trace amounts of desired products were obtained (entries 1 and 2). However, to our surprise, upon adding 2,2’-bipyridine ligand,
the desired product 3a was obtained in 58% yield (entry 3). Then, the nitrogen-based bidentate ligands were examined to explore the
ligand effect on the C8-S cross-coupling reaction, which revealed that 1,10-phenanthroline monohydrate was the best ligand (entries
4 and 5). Subsequently, several additives including CuBr, CuCl, CuCl2, Cu(OAc)2 and CuSO4 were tested, and CuCl exhibited the
highest reactivity (entries 6-10). Among them, the reason that Cu(II) promoted the reaction to proceed successfully may be that Cu(I)
was oxidized to Cu(II) in the presence of air during the reaction. Next we investigated a series of bases including K2CO3, KOtBu,
Na3PO4, NaOAc and K3PO4, but the desired product 3a was obtained in moderate to low yields (entries 11-15). And no product 3a
was detected when Cs2CO3 and NaOH were used as bases (entries 16 and 17). It is worth noting that the reaction did not occur in the
absence of base (entry 18). In the subsequent screening of various solvents, we found that this C8-S cross-coupling reaction was
effective in a range of polar aprotic solvents such as DMF, NMP, DMSO, and DMA (entries 19-21). In sharp contrast, lower yields
of 3a were obtained when a polar protic solvents (EG, PEG-400, PEG-200, HFIP) or a nonpolar solvent (dioxane) were used as
solvents (entries 22-26). In addition, studies on the temperature and the amount of CuCl or p-toluenethiol indicated that before the
optimum conditions was reached, the product yield was significantly improved with an increased reaction temperature or an increased
amount of CuCl or p-toluenethiol (entries 27-32). Remarkably, no product 3a was obtained when the reaction was conducted under
N2 (entry 33), but a large amount of di-p-tolylsulfane was obtained. Finally, when the reaction was performed under a pure oxygen
atmosphere, the yield was lowered to 67% (entry 34). The reduction in yield may be due to the facile formation of the di(4-
methylphenyl)thioether from the oxidation of p-toluenethiol at high oxygen concentrations.
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Table 1. Optimization of the Reaction Conditions a
yield
entry
additive
ligand
base
solvent
(%) b
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3
4
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DMF
DMF
DMF
DMF
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5
CuI
CuI
CuI
Bpy
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65
Phen
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9
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12
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15
CuI
CuBr
CuCl
CuCl2
Cu(OAc)2
CuSO4
CuCl
CuCl
CuCl
CuCl
CuCl
TMEDA
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
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88
99(94)
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85
73
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KOtBu
Na3PO4
NaOAc
K3PO4
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Cs2CO3
NaOH
DMF
DMF
DMF
N.D.
N.D.
trace
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72
90
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
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8
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
NMP
DMSO
DMA
dioxane
EG
PEG-400
PEG-200
HFIP
DMF
DMF
DMF
DMF
5
trace
trace
trace
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87
49
68
93
78
95
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9
27c
28d
29e
30f
31g
32h
33i
34j
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DMF
DMF
DMF
DMF
trace
67
aReactions conditions: 1a (0.20 mmol), 2a (0.30 mmol), Additive (1.0 equiv), ligand (1.0 equiv), base (1.0 equiv), solvent (1.0 mL), under
air at 140°C for 18 h. Phen: 1,10-Phenanthroline monohydrate. TMEDA: N,N,N',N'-Tetramethylethylenediamine. EG: Ethylene glycol.
HFIP: 1,1,1,3,3,3-Hexafluoro-2-propanol N.D. = not determined. b Determined by GC using dodecane as the internal standard. c at 120°C. d
at 100°C. e 0.5 equiv CuCl was used. f 1.5 equiv CuCl was used. g 1 equiv p-toluenethiol was used. h 2 equiv p-toluenethiol was used. i under
N2 atomosphere. j under O2 atomosphere.
With the optimized reaction conditions in hand, the scope of this C8-S cross-coupling was investigated by reacting p-toluenethiol (2a)
with a series of purine derivatives. As shown in Table 2, many substrates with substituents at the C2, C6, N7 and N9 positions were
applied to the reaction system to further synthesize a series of purine derivatives. Purine derivatives with strong electron-donating
groups (−SMe, −OMe) at the C2 or C6 position formed the corresponding products with good yields (3a-3d, 89-94%). Gratifyingly,
substrate 1e and 1f bearing the reactive amino group (−NH2) at C2 or C6 position were an exception, and the desired products were
obtained in rather modest yield (3e-3f, 50-58%). When the substitutent at the N9 position of the purines was the benzyl group, the
products were obtained in high yields (3g-3i). Comparitively, the N9 alkyl-substituted substrates gave higher yields, whereas the N7
alkyl-substituted substrates gave slightly lower yields (3b vs 3j, and 3c vs 3k). It is especially noteworthy that the coupling reaction
of substrate 1l with 2a afforded only 3l in 93% yield under the standard conditions. The structure of 3l was confirmed by comparison
with the 1H and 13C NMR spectra of 9-ethyl-6-(p-tolylthio)-9H-purine (1pa). That is to say, the C8-S cross-coupling reaction occurred
on the C8 position of the purine derivatives, not on C2, C6 or other functional groups, indicating excellent regioselectivity.
Furthermore, caffeine 1m, one of the plant alkaloids, provided product 3m in 92% yield. Similarly, 1-methylbenzimidazole gave 3n
in 84% yield. However, no product was detected for 1o because of the steric hinderance (3i vs 3o). Moreover, in the reactions of the
hypoxanthine and guanine with p-toluenethiol under the optimized conditions, there were no corresponding products (3p-3q) detected.
Table 2. Substrate Scope of Various Purines a, k
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aReaction conditions: 1 (0.20 mmol), 2a (0.30 mmol), CuCl (1.0 equiv), Phen (1.0 equiv), Na2CO3(1.0 equiv), DMF (1.0 mL), under air at
140°C for 18 h. k Isolated yield.
To further expand the scope of the coupling reaction, a number of 6-chloropurine derivatives with various substituents, including
alkyl substituents at N7 or N9 position and halide or reactive amino substituents at C2, were examined under the further optimized
reaction conditions, providing the disubstituted or trisubstituted purine derivatives in moderate to excellent isolated yields (3r-3v, 52-
94%) (Table 3). The carbon-halogen bond cleavage reactions were subsequently studied. In the absence of CuCl and 1,10-
phenanthroline monohydrate, 2-chloro-9-ethylpurine was reacted at 80 °C for 6 h with 2a to form 6-(p-tolylthio)purine 1ra in 96%
yield (Scheme 2). Previous literature15 on the reaction of 6-halogenated purine derivatives with thiophenols has shown that the
reaction was carried out through a nucleophilic substitution mechanism.
Table 3. Substrate Scope of Various 6-Chloropurines a, k
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Reaction conditions: 1 (0.20 mmol), 2a (0.5 or 0.7mmol), CuCl (1.0 equiv), Phen (1.0 equiv), Na2CO3(2.0, 3.0 equiv), DMF (1.0 mL),
under air at 140°C for 18 h. k Isolated yield.
Scheme 2. Nucleophilic Substitution Reaction of 6-Chloropurine with 2a
Encouraged by the above results, the scope with respect to thiophenols was also investigated (Table 4). The coupling reactions
proceeded smoothly and gave the products in low to good yields (4a-4n, 0%-93%). Thiophenols with tert-butyl, methyl and methoxy
groups (electron withdrawing) provided better yields than those substituted with halides and nitro group (electron-withdrawing) (4a-
4e vs 4f-4n). In addition, the structure of 4g was clearly certified by single-crystal X-ray diffraction analysis.16 When the substituent
was in the meta or ortho position of thiophenols, the yield of the products was lower compared with the substituents in the para
position, and the yield was the lowest in the ortho position (4c vs 4d, 4i vs 4h and 4l vs 4m). Moreover, the coupling reaction was
also successful with the substrate 2-naphthothiophenol (4o, 85%).
Table 4. Substrate Scope of Various Thiophenols a, k
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aReaction conditions: 1a (0.20 mmol), 2 (0.30 mmol), CuCl (1.0 equiv), Phen (1.0 equiv), Na2CO3(1.0 equiv), DMF (1.0 mL), under air at
140°C for 18 h. kIsolated yield.
In addition to the thiophenols, the scope and generality of the approach for the direct thiolation of 6-methylthiopurine with
alkylthiols under the optimized reaction conditions was examined (Scheme 3). The results showed that the reaction of the alkylthiols
with 1a did not occur at the C8 position, but the methylthio group at the C6 position was replaced by the alkylthio groups (5a-5b).
The products were identical to those obtained by the reaction of 6-chloropurine with alkylthiols. Furthermore, in the absence of CuCl
and ligand, this reaction was successful using the same conditions (80°C, 6 h) as the reactions of 6-chloropurines with thiophenols.
The failure of the sulfenylation of the purines C8-H bond with alkylthiols may be that alkylthiols have a lower nucleophilicity than
thiophenols.
Scheme 3. Substrate Scope of Alkylthiols a, k
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aReaction conditions: 1a (0.20 mmol), 2a (0.30 mmol), CuCl (1.0 equiv), Phen (1.0 equiv), Na2CO3(1.0 equiv), DMF (1.0 mL), under air at
140°C for 18 h. l R1=MeS-. m R1=Cl. k Isolated yield.
In recent years, a Cu-mediated methylthiolation of heterocyclic compounds using DMSO as a simple, inexpensive and easy-to-handle
methylthiolation reagent was reported.17 Therefore, we explored the reaction of DMSO as the methylthiolation reagent and solvent
with 6-methylthio-9-ethylpurine and obtained a low yield (35%) of 6a under our reaction conditions (Scheme 4). Importantly, caffeine
1l reacted successfully to give the products 6b in moderate yield (50%).
Scheme 4. Substrate Scope of Two Purines a, k
aReaction conditions: 1a (0.20 mmol), DMSO (1.0 mL), CuCl (1.0 equiv), Phen (1.0 equiv), Na2CO3(1.0 equiv), under air at 140°C for 18
h. k Isolated yield.
To demonstrate the practicality of the method for the synthesis of 8-sulfenylpurine derivatives in organic synthesis, we scaled up the
reaction to the gram scale (Scheme 5). The target products 9-ethyl-6-(methylthio)-8-(p-tolylthio)-9H-purine (3a) and 9-benzyl-N,N-
dimethyl-8-(p-tolylthio)-9H-purin-6-amine (3i) were successfully obtained in 85% yield and 73% yield, respectively. The results
indicate that the method is applicable.
Scheme 5. Scaled-Up Version of Synthesis of 8-Sulfenylpurine Derivatives
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To acquire insights into the mechanism of the reaction, control experiments were carried out (Scheme 6). Initially, the addition of a
known radical inhibitor of TEMPO (2.0 equiv) under standard conditions resulted in a reduction in yield to 30% and the rapid
production of large amounts of disulfide (Scheme 6a). Moreover, when p-tolyl disulfide was used instead of p-toluenethiol to react
with 6-methylthio-9-ethylpurine, only 20% of the product was obtained (Scheme 6b), indicating that the radical mechanism is not
possible and p-toluenethiol does not form p-tolyl disulfide to participate in the reaction. Subsequently, the reaction of 6-methylthio-
9-ethylpurine 1a with CuCl, Phen, and Na2CO3 dissolved in deuterated dimethylformamide upon heating at 140°C for 6 h based on
in situ 1H NMR analysis (Figure 2), showed no formation of the perceived C−H activated product 7a (Scheme 6c). However, upfield
shifts for the C2-H and C8-H protons resonances of 1a were observed. Thus, based on the experimental result, a previous literature18
and 3o product were not obtained, we proposed that the coordination step of the Cu complex and the N7 of purine derivatives occurs
during the reaction. For more insight, the reaction was carried out in the absence of 1a and Na2CO3 under air for 6 hours, then 1a was
added and the reaction was again carried out under air or N2 for 12 hours to give 98% of product (Scheme 6d). In addition, when
CuCl was replaced by CuCl2 to participate in the reaction under N2, the product 3a was obtained in 5% yield (Scheme 6e). The above
results show the importance of the formation of Cu-SAr complex as a key intermediate, which be obtained more quickly from the
reaction of the copper salt with thiophenol than from the corresponding disulfide under the optimized reaction conditions, and oxygen
from the air plays a critical role in the formation phase of the Cu-SAr complex and the base participates in the elimination of hydrogen
on the purine ring.
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Scheme 6. Control Experiments
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Figure 2. Interaction between 1a and Cu/Phen
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In accordance with the above evidence and some previous reports, a plausible mechanism is proposed as shown in Scheme 7. Starting
from the CuI-Phen complex I, the CuII-superoxo intermediate19 extracts the H-atom of the thiophenol in the presence of air, then
complexes with ArS¯ to form an ArS-CuII-OOH complex II.20 Subsequently, the purine-coordinated intermediate III formed by the
coordination of the ArS-CuII-OOH complex II with the N-atom on the five-membered ring of the purine skeleton undergoes migration
of the phenylthiolate group to the electrophilic sp2 C8 of the purine ring to create a HOO-Cu-mercaptopurine complex V via transition
state IV. Finally, the complex V undergoes the base-assisted deprotonation and dissociation of the N-Cu coordination bond to give
the desired product and CuI-hydropero complex. However, the CuI-hydropero complex is subsequently oxidized to the CuII species
and can’t be recycled to participate in the reaction.21
Scheme 7. Proposed Reaction Mechanism
CONCLUSIONS
In conclusion, we developed a general, highly regioselective and efficient protocol for the direct C-S cross-coupling between the
purine heterocyclic C8-H bond and aryl thiols along with a stoichiometric amount of copper(I) reagent and a N,N-type ligand. The
high regioselectivity was confirmed by the coupling reaction of 9-ethylpurine, which contains no substituents at C2 or C6, producing
3l as the only product. Also, the free amino group was tolerated in the reaction system (3e, 3f and 3t).
Mechanistic investigations revealed that oxygen played a critical role in the formation phase of the Cu-SAr complex, and the
coordination of the Cu complex and the N7 of purine derivatives was formed during the reaction. Purine derivatives constructed by
direct C-S cross-coupling have potential in medical applications. The synthetic utility of this reaction is currently being further studied.
EXPERIMENTAL SECTION
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General Information. All reactions were carried out in flame-dried sealed tubes with magnetic stirring under an air atmosphere
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unless otherwise noted. All reagents were purchased as analytical reagent grade and used without further purification, unless otherwise
state. C2 or C6 substituted purines was synthesized from 6-chloropurine and 2,6-dichloropurine according to Huang’s method.22 C2
and C6 substituted purines were synthesized from 2-amido-6-chloropurine according to Hu’s method.23 N7 and N9 substituted purines
were synthesized from N-9H-purines according to Kelley’s method and Çelik’s method.24 Purifications of reaction products were
carried out by flash chromatography using Qingdao Haiyang Chemical Co. Ltd silica gel (300-400 mesh). 1H, 13C and 19F NMR
spectra were recorded using the Bruker DRX-400 and Bruker AscendTM 500 spectrometer using CDCl3 or DMF-d6 as solvent and
TMS as an internal standard. The chemical shifts are referenced to signals at 7.26 and 77.0 ppm, respectively. Gas chromatograph
mass spectra analyses were performed on SHIMADZU model GCMS-QP5000 spectrometer. The data of HRMS was carried out on
a high-resolution mass spectrometer (LCMS-IT-TOF). IR spectra were recorded in KBr disks with a Bruker TENSOR 27 FTIR
spectrophotometer. Melting points were determined with a Büchi Melting Point B-545 instrument. Crystal data were obtained by
employing graphite monochromated Mo - Kα radiation (λ = 1.54178 Å) at 293(2) K and operating in the φ-ω scan mode. The structure
was solved by direct methods SHELXS-97.
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General procedure for the synthesis of starting purine derivatives 1
In a 100 mL single neck flash, the corresponding 6-chloropurine, 2,6-dichloropurine or 2-amido-6-chloropurine (10 mmol, 1.0
equiv) and 20% sodium methanethiol aqueous solution (50 mmol, 5 equiv or 100 mmol, 10 equiv) or sodium methoxide (12 mmol,
1.2 equiv or 24 mmol, 2.4 equiv) were dissolved in MT (20 mL). The mixture was stirred at 65 °C (oil bath) for 18 h. After completion
of the reaction, the reaction mixture was cooled to room temperature, and then concentrated under reduced pressure. The solid was
dissolved in water (20 mL). Then the PH value was adjusted to neutral with HCl. A large number of white solids was precipitated.
The solid obtained by filtration and drying was dissolved in CH3CN (25 mL), then K2CO3 (12 mmol, 1.2 equiv), and bromoethane
(12 mmol, 1.2 equiv) or benzyl chloride (12 mmol, 1.2 equiv) were added. The resulting solution was stirred at 75 °C (oil bath) for
18 h. After completion of the reaction, the reaction mixture was cooled to room temperature, and then concentrated under reduced
pressure. The solid was dissolved in ethyl acetate (30 mL), and then was filtered. The solvent was removed under reduced pressure
and the residue was purified by flash column chromatography (petroleum ether : ethyl acetate = 4 : 1) to obtain the starting purine
derivatives 1.
General procedure for the synthesis of 8-sulfenylpurine derivatives
To a solution of N,N-dimethylformamide (DMF) (1.0 mL) charged with purine derivatives (1, 0.2 mmol, 1.0 equiv) and thiols (2,
0.3, 0.5 or 0.7 mmol, 1.5, 2.5 or 3.5 equiv) was added CuCl (19.8 mg, 0.2 mmol, 1.0 equiv), 1,10-Phenanthroline hydrate (36.0 mg,
0.2 mmol, 1.0 equiv), and Na2CO3 (0.2, 0.4 or 0.6 mmol, 1.0, 2.0 or 3.0 equiv). The reaction mixture was stirred at 140°C (oil bath)
for 18 h. The mixture was cooled to room temperature and mixed with water (10.0 mL). The product was then extracted with
ethylacetate (3 × 8 mL). The combined organic phases were dried over anhydrous Na2SO4 and evaporated under a vacuum. The crude
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product was then purified by flash column chromatography on silica gel (petroleum ether : ethyl acetate = 10 : 1) to afford the desired
product 3, 4 and 5.
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General procedure for the synthesis of 8-methylthiopurine derivatives
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To a solution of dimethyl sulfoxide (DMSO) (1.0 mL) charged with purine derivatives (1, 0.2 mmol, 1.0 equiv) was added CuCl
(19.8 mg, 0.2 mmol, 1.0 equiv), 1,10-Phenanthroline hydrate (36.0 mg, 0.2 mmol, 1.0 equiv), and Na2CO3 (0.2 mmol, 1.0 equiv).
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The reaction mixture was stirred at 140 C (oil bath) for 18 h. The mixture was cooled to room temperature and mixed with water
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(10.0 mL). The product was then extracted with ethylacetate (3 × 8 mL). The combined organic phases were dried over anhydrous
Na2SO4 and evaporated under a vacuum. The crude product was then purified by flash column chromatography on silica gel
(petroleum ether : ethyl acetate = 4 : 1) to afford the desired product 6.
General procedure for the synthesis of 9-ethyl-6-(p-tolylthio)-9H-purine
To a solution of N,N-dimethylformamide (DMF) (1.0 mL) charged with 6-chloropurine (1r, 0.2 mmol, 1.0 equiv) and p-
toluenethiol (2a, 0.2mmol, 1.0 equiv) was added Na2CO3 (0.2 mmol, 1.0 equiv). The reaction mixture was stirred at 80°C (oil bath)
for 6 h. The mixture was cooled to room temperature and mixed with water (10.0 mL). The product was then extracted with
ethylacetate (3 × 8 mL). The combined organic phases were dried over anhydrous Na2SO4 and evaporated under a vacuum. The crude
product was then purified by flash column chromatography on silica gel (petroleum ether : ethyl acetate = 5 : 1) to afford the desired
product 1ra.
9-ethyl-2,6-bis(methylthio)-9H-purine (1c): Yield: 51% (1.2 g) as yellow solid; mp = 69.4 - 69.9°C; 1H NMR (500 MHz, CDCl3)
δ 7.83 (s, 1H), 4.23 (q, J = 7.3 Hz, 2H), 2.70 (s, 3H), 2.63 (s, 3H), 1.51 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.8,
160.9, 149.1, 140.9, 128.7, 38.8, 15.3, 14.6, 11.7 ppm; νmax(KBr)/cm-1 3043, 2973, 1564, 1448, 1340, 1212, 1143, 945, 873, 782; HR-
MS (ESI) calcd for C9H13N4S2, [M + H]+: 241.0576, found: 241.0579.
9-ethyl-2,6-dimethoxy-9H-purine (1d): Yield: 67% (1.4 g) as a white solid; mp = 118.6 - 119.2°C; 1H NMR (500 MHz, CDCl3)
δ 7.78 (s, 1H), 4.22 (q, J = 7.3 Hz, 2H), 4.17 (s, 3H), 4.05 (s, 3H), 1.53 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.9,
161.6, 153.4, 140.2, 117.3, 54.9, 54.1, 38.7, 15.2 ppm; νmax(KBr)/cm-1 3095, 2960, 1736, 1600, 1524, 1476, 1358, 1073, 740, 648;
HR-MS (ESI) calcd for C9H13N4O2, [M + H]+: 209.1033, found: 209.1035.
6-ethoxy-7-ethyl-7H-purine (1j): Yield: 26% (0.5 g) as a yellow solid; mp = 119.2 - 119.7°C; 1H NMR (500 MHz, CDCl3) δ 8.52
(s, 1H), 7.96 (s, 1H), 4.55 (q, J = 6.9 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.46 (t, J = 7.1 Hz, 3H), 1.41 (t, J = 7.0 Hz, 3H); 13C{1H}
NMR (125 MHz, CDCl3) δ 161.8, 156.8, 152.0, 112.7, 62.8, 42.7, 16.8, 14.4 ppm; νmax(KBr)/cm-1 3081, 2976, 1616, 1557, 1482,
1380, 1216, 1133, 1012, 892, 789; HR-MS (ESI) calcd for C9H13N4O, [M + H]+: 193.1084, found: 193.1087.
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7-ethyl-2,6-bis(methylthio)-7H-purine (1k): Yield: 34% (0.8 g) as a yellow solid; mp = 105.0 -105.6°C; H NMR (500 MHz,
CDCl3) δ 7.98 (s, 1H), 4.40 (q, J = 6.6 Hz, 2H), 2.71 (s, 3H), 2.64 (s, 3H), 1.54 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3)
δ 165.0, 159.5, 153.6, 145.7, 120.2, 42.8, 17.4, 14.5, 12.1 ppm; νmax(KBr)/cm-1 3086, 2926, 1527, 1481, 1370, 1296, 1106, 999, 868,
787; HR-MS (ESI) calcd for C9H12N4NaS2, [M + Na]+: 263.0396, found: 263.0391.
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9-ethyl-6-(methylthio)-8-(p-tolylthio)-9H-purine (3a): Yield: 94% (59.4 mg) as a pale yellow solid; mp = 102.1 - 103.4°C; 1H
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NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.33 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.1 Hz, 2H), 4.18 (q, J = 7.2 Hz, 2H), 2.59 (s, 3H),
2.25 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8, 151.5, 149.9, 149.8, 139.0, 132.3, 131.8, 130.3,
125.9, 38.8, 21.2, 14.7, 11.9 ppm; νmax(KBr)/cm-1 3021, 2973, 2922, 1645, 1564, 1491, 1453, 1427, 1317, 1250, 1233, 1172, 1152,
952, 865, 806, 707, 575; HR-MS (ESI) calcd for C15H17N4S2, [M + H]+: 317.0889, found: 317.0886.
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9-ethyl-6-methoxy-8-(p-tolylthio)-9H-purine (3b): Yield: 91% (54.6 mg) as a white solid; mp = 122.8 - 124.3°C; 1H NMR (400
MHz, CDCl3) δ 8.46 (s, 1H), 7.41 (d, J = 7.8 Hz, 2H), 7.13 (d, J = 7.7 Hz, 2H), 4.29 (q, J = 7.2 Hz, 2H), 4.12 (s, 3H), 2.31 (s, 3H),
1.33 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.8, 153.3, 151.6, 149.2, 139.0, 132.5, 130.3, 126.1, 121.8, 54.1, 38.9,
21.2, 14.8 ppm; νmax(KBr)/cm-1 3055, 2988, 2936, 2857, 1593, 1491, 1469, 1351, 1309, 1209, 1064, 958, 889, 810, 721, 664; HR-
MS (ESI) calcd for C15H17N4OS, [M + H]+: 301.1118, found: 301.1123.
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9-ethyl-2,6-bis(methylthio)-8-(p-tolylthio)-9H-purine (3c)： Yield: 89% (64.4 mg) as a pale yellow solid; mp = 107.8 - 109.1°C;
1H NMR (400 MHz, CDCl3) δ 7.23 (d, J = 7.6 Hz, 2H), 6.99 (d, J = 7.7 Hz, 2H), 4.06 (q, J = 6.8 Hz, 2H), 2.52 (s, 3H), 2.47 (s, 3H),
2.17 (s, 3H), 1.14 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.7, 159.7, 150.6, 147.6, 138.6, 131.6, 130.3, 129.0,
126.8, 38.7, 21.2, 14.7, 11.8 ppm; νmax(KBr)/cm-1 3055, 2979, 2926, 1642, 1558, 1492, 1432, 1400, 1322, 1197, 1144, 958, 880, 805,
674, 581; HR-MS (ESI) calcd for C16H19N4S3, [M + H]+: 363.0766, found: 363.0769.
9-ethyl-2,6-dimethoxy-8-(p-tolylthio)-9H-purine (3d)： Yield: 90% (59.4 mg) as a pale yellow solid; mp = 109.2 - 110.5°C; 1H
NMR (400 MHz, CDCl3) δ 7.25 (d, J = 7.5 Hz, 2H), 7.00 (d, J = 7.5 Hz, 2H), 4.11 (q, J = 6.5 Hz, 2H), 4.03 (s, 3H), 3.91 (s, 3H),
2.19 (s, 3H), 1.18 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 161.5, 161.0, 154.6, 146.0, 138.3, 131.4, 130.2, 127.5,
117.6, 55.0, 54.2, 38.7, 21.0, 14.7 ppm; νmax(KBr)/cm-1 3017, 2935, 1588, 1494, 1454, 1391, 1353, 1306, 1242, 1220, 1089, 971, 952,
804, 789, 663; HR-MS (ESI) calcd for C16H19N4O2S, [M + H]+: 331.1223, found: 331.1221.
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9-ethyl-8-(p-tolylthio)-9H-purin-6-amine (3e): Yield: 58% (33.1 mg) as a pale yellow solid; mp = 160.3 - 161.8°C; H NMR
(400 MHz, CDCl3) δ 8.21 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.40 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 2.21 (s,
3H), 1.23 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.9, 152.9, 151.2, 145.9, 138.6, 131.4, 130.3, 127.2, 120.1, 38.7,
21.1, 14.9 ppm; νmax(KBr)/cm-1 3338, 3162, 2967, 2929, 2359, 1658, 1597, 1568, 1489, 1465, 1309, 1205, 1016, 959, 798, 603, 569,
503; HR-MS (ESI) calcd for C14H16N5S, [M + H]+: 286.1121, found: 286.1123.
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9-ethyl-6-methoxy-8-(p-tolylthio)-9H-purin-2-amine (3f): Yield: 50% (31.5 mg) as a yellow solid; mp = 111.7 - 112.2°C; H
NMR (500 MHz, CDCl3) δ 7.30 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 5.00 (s, 2H), 4.12 (q, J = 7.2 Hz, 2H), 4.05 (s, 3H),
2.30 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 160.9, 159.3, 154.9, 143.7, 138.0, 130.8, 130.2, 128.4,
116.2, 53.9, 38.5, 21.1, 14.8 ppm; νmax(KBr)/cm-1 3476, 3315, 3189, 2926, 2854, 1629, 1578, 1492, 1480, 1419, 1319, 1251, 1068,
955, 808, 790, 500; HR-MS (ESI) calcd for C15H17N5NaOS, [M + Na]+: 338.1046, found: 338.1049.
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9-benzyl-6-(methylthio)-8-(p-tolylthio)-9H-purine (3g): Yield: 90% (68.1 mg) as a white solid; mp = 106.5 - 107.9°C; 1H NMR
(500 MHz, CDCl3) δ 8.64 (s, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.23 - 7.15 (m, 5H), 7.02 (d, J = 8.0 Hz, 2H), 5.34 (s, 2H), 2.59 (s, 3H),
2.21 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.6, 151.6, 150.8, 150.2, 139.1, 135.5, 132.8, 131.7, 130.2, 128.7, 128.0, 127.7,
125.4, 46.7, 21.2, 12.0 ppm; νmax(KBr)/cm-1 3048, 2919, 1572, 1493, 1451, 1428, 1320, 1256, 1186, 1147, 991, 918, 866, 805, 693,
612, 549, 504; HR-MS (ESI) calcd for C20H19N4S2, [M + H]+: 379.1046, found: 379.1049.
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9-benzyl-6-methoxy-8-(p-tolylthio)-9H-purine (3h): Yield: 94% (68.1 mg) as a pale yellow solid; mp = 114.6 - 116.0°C; H
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NMR (500 MHz, CDCl3) δ 8.38 (s, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.13 (s, 5H), 6.97 (d, J = 7.9 Hz, 2H), 5.31 (s, 2H), 4.00 (s, 3H),
2.17 (s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.7, 153.8, 151.8, 150.1, 139.1, 135.5, 132.8, 130.3, 128.7, 128.0, 127.7, 125.7,
121.7, 54.2, 46.9, 21.2 ppm; νmax(KBr)/cm-1 3032, 2933, 1574, 1492, 1419, 1402, 1304, 1240, 1180, 1068, 981, 902, 808, 728, 695,
571, 501; HR-MS (ESI) calcd for C20H18N4NaOS, [M + Na]+: 385.0586, found: 385.0585.
9-benzyl-N,N-dimethyl-8-(p-tolylthio)-9H-purin-6-amine (3i): Yield: 80% (59.4 mg) as a yellow solid; mp = 107.9 - 109.5°C;
1H NMR (500 MHz, CDCl3) δ 8.26 (s, 1H), 7.19 - 7.09 (m, 7H), 6.96 (d, J = 8.0 Hz, 2H), 5.29 (s, 2H), 3.43 (s, 6H), 2.21 (s, 3H);
13C{1H} NMR (125 MHz, CDCl3) δ 154.1, 152.7, 152.3, 143.2, 137.9, 136.1, 130.7, 130.0, 128.6, 128.1, 127.6, 127.5, 120.8, 46.5,
38.6, 21.1 ppm; νmax(KBr)/cm-1 3027, 2923, 2853, 1589, 1560, 1492, 1454,1428, 1376, 1325, 1295, 1170, 1052, 805, 731, 697; HR-
MS (ESI) calcd for C21H22N5S, [M + H]+: 376.1590, found: 376.1586.
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6-ethoxy-7-ethyl-8-(p-tolylthio)-7H-purine (3j): Yield: 85% (53.4 mg) as a yellow solid; mp = 82.2 - 83.5°C; H NMR (500
MHz, CDCl3) δ 8.41 (s, 1H), 7.41 (d, J = 8.1 Hz, 2H), 7.08 (d, J = 8.0 Hz, 2H), 4.51 (q, J = 7.1 Hz, 2H), 4.30 (q, J = 7.2 Hz, 2H),
2.25 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.29 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.0, 155.4, 154.2, 151.7, 139.4,
133.5, 130.3, 124.9, 114.5, 62.7, 41.9, 21.2, 16.0, 14.5 ppm; νmax(KBr)/cm-1 3036, 2924, 1613, 1551, 1491, 1465, 1398, 1260, 1180,
1139, 1122, 1019, 901, 810, 663, 502; HR-MS (ESI) calcd for C16H19N4OS, [M + H]+: 315.1274, found: 315.1275.
7-ethyl-2,6-bis(methylthio)-8-(p-tolylthio)-7H-purine (3k): Yield: 84% (60.8 mg) as a yellow solid; mp = 123.4 - 124.9°C; 1H
NMR (500 MHz, CDCl3) δ 7.40 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.56 (s, 3H), 2.46 (s, 3H),
2.24 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 164.6, 158.8, 156.2, 151.2, 139.8, 134.3, 130.4, 123.9,
122.2, 41.8, 21.3, 16.5, 14.4, 12.1 ppm; νmax(KBr)/cm-1 2980, 2932, 1563, 1529, 1465, 1374, 1284, 1206, 1094, 1014, 876, 833, 782,
503; HR-MS (ESI) calcd for C16H19N4S3, [M + H]+: 363.0766, found: 363.0764.
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9-ethyl-8-(p-tolylthio)-9H-purine (3l): Yield: 93% (50.2 mg) as a pale yellow solid; mp = 91.8 - 93.3°C; H NMR (500 MHz,
CDCl3) δ 8.90 (s, 1H), 8.85 (s, 1H), 7.53 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 4.32 (q, J = 7.2 Hz, 2H), 2.37 (s, 3H), 1.45 (t,
J = 7.3 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 155.1, 152.9, 151.5, 145.7, 140.1, 134.3, 130.5, 123.3, 38.2, 21.3, 14.6 ppm;
νmax(KBr)/cm-1 3046, 2951, 1648, 1580, 1474, 1428, 1339, 1299, 1240, 1115, 956, 914, 808, 790, 679, 618; HR-MS (ESI) calcd for
C14H15N4S, [M + H]+: 271.1012, found: 271.1012.
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1,3,7-trimethyl-8-(p-tolylthio)-3,7-dihydro-1H-purine-2,6-dione (3m): Yield: 92% (58.2 mg) as a white solid; H NMR (400
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(100 MHz, CDCl3) δ 154.7, 151.2, 147.9, 147.1, 138.6, 131.3, 130.2, 126.7, 109.2, 33.0, 29.7, 27.8, 21.1 ppm; HR-MS (ESI) calcd
for C15H17N4O2S, [M + H]+: 317.1067, found: 317.1065.
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1-methyl-2-(p-tolylthio)-1H-benzo[d]imidazole (3n): Yield: 84% (42.7 mg) as a pale yellow solid; mp = 89.4 - 90.7°C; 1H NMR
(500 MHz, CDCl3) δ 7.76 - 7.71 (m, 1H), 7.27 (d, J = 8.2 Hz, 2H), 7.25 - 7.16 (m, 3H), 7.05 (d, J = 8.1 Hz, 2H), 3.61 (s, 3H), 2.25
(s, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 148.5, 143.2, 138.1, 136.6, 131.1, 130.3, 128.1, 123.1, 122.3, 119.7, 109.4, 30.7, 21.2
ppm; νmax(KBr)/cm-1 3049, 2924, 1596, 1492, 1446, 1417, 1362, 1279, 1183, 1087, 806, 744, 565; HR-MS (ESI) calcd for C15H15N2S,
[M + H]+: 255.0950, found: 255.0951.
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9-ethyl-6,8-bis(p-tolylthio)-9H-purine (3r): Yield: 89% (69.8 mg) as a white solid; mp = 130.8 - 132.4°C; 1H NMR (400 MHz,
CDCl3) δ 8.47 (s, 1H), 7.43 (d, J = 7.4 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 7.6 Hz, 2H), 4.20 (q,
J = 6.8 Hz, 2H), 2.32 (s, 3H), 2.29 (s, 3H), 1.26 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 151.8, 150.7, 150.3,
139.6, 139.2, 135.5, 132.6, 131.1, 130.4, 130.1, 125.6, 123.9, 38.8, 21.4, 21.3, 14.7 ppm; νmax(KBr)/cm-1 3045, 2982, 2933, 2914,
1594, 1559, 1490, 1434, 1319, 1251, 1222, 1146, 1016, 949, 859, 808, 576; HR-MS (ESI) calcd for C21H21N4S2, [M + H]+: 393.1202,
found: 393.1202.
7-ethyl-6,8-bis(p-tolylthio)-7H-purine (3s): Yield: 85% (66.7 mg) as a pale yellow solid; mp = 152.3 - 153.5°C; 1H NMR (400
MHz, CDCl3) δ 8.51 (s, 1H), 7.47 (d, J = 7.9 Hz, 2H), 7.38 (d, J = 7.9 Hz, 2H), 7.15 (dd, J = 11.3, 8.1 Hz, 4H), 4.49 (q, J = 7.0 Hz,
2H), 2.31 (s, 3H), 2.28 (s, 3H), 1.47 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 158.7, 158.0, 152.4, 150.2, 140.1, 139.9,
135.3, 134.4, 130.4, 130.3, 124.8, 123.6, 123.5, 42.0, 21.4, 21.3, 16.6 ppm; νmax(KBr)/cm-1 3038, 2967, 2917, 1594, 1560, 1541, 1490,
1467, 1413, 1377, 1335, 1279, 1223, 1179, 1091, 1016, 980, 805, 762; HR-MS (ESI) calcd for C21H20N4NaS2, [M + Na]+: 415.1022,
found: 415.1025.
9-ethyl-6,8-bis(p-tolylthio)-9H-purin-2-amine (3t): Yield: 52% (42.3 mg) as a pale yellow solid; mp = 94.5 - 95.8°C; 1H NMR
(400 MHz, CDCl3) δ 7.40 (d, J = 8.1 Hz, 2H), 7.24 (d, J = 8.2 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 8.1 Hz, 2H), 4.78 (s,
2H), 4.00 (q, J = 7.2 Hz, 2H), 2.28 (s, 3H), 2.24 (s, 3H), 1.12 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.4, 159.1,
152.2, 145.1, 139.1, 138.1, 135.5, 130.8, 130.2, 129.7, 128.1, 125.7, 124.3, 38.4, 21.4, 21.1, 14.7 ppm; νmax(KBr)/cm-1 3336, 3195,
2978, 2918, 1650, 1581, 1555, 1491, 1411, 1288, 1224, 1151, 1017, 914, 806, 504; HR-MS (ESI) calcd for C21H22N5S2, [M + H]+:
408.1311, found: 408.1315.
9-benzyl-6,8-bis(p-tolylthio)-9H-purine (3u): Yield: 94% (85.4 mg) as a pale yellow solid; mp = 149.9 - 151.2°C; 1H NMR (400
MHz, CDCl3) δ 8.47 (s, 1H), 7.41 (d, J = 7.4 Hz, 2H), 7.30 (d, J = 7.5 Hz, 2H), 7.19 - 7.11 (m, 7H), 7.04 (d, J = 7.6 Hz, 2H), 5.31 (s,
2H), 2.29 (s, 3H), 2.24 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.1, 152.0, 151.5, 150.8, 139.6, 139.2, 135.6, 135.3, 132.8,
131.1, 130.3, 130.1, 128.8, 128.1, 127.7, 125.3, 123.9, 46.8, 21.5, 21.3 ppm; νmax(KBr)/cm-1 3038, 2922, 1594, 1556, 1492, 1449,
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1430, 1317, 1255, 1189, 1147, 1006, 932, 862, 805, 731, 519; HR-MS (ESI) calcd for C26H23N4S2, [M + H]+: 455.1359, found:
455.1361.
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9-benzyl-2,6,8-tris(p-tolylthio)-9H-purine (3v): Yield: 87%, 86% and 84% (100.3 mg, 99.1 mg and 96.8 mg) as a pale yellow
solid; mp = 131.8 - 133.2°C; 1H NMR (400 MHz, CDCl3) δ 7.28 - 7.18 (m, 6H), 7.12 - 7.08 (m, 3H), 7.04 (dd, J = 6.6, 3.1 Hz, 2H),
7.00 - 6.93 (m, 6H), 5.05 (s, 2H), 2.25 (s, 6H), 2.19 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.1, 159.4, 151.5, 149.3, 138.9,
138.9, 138.6, 135.4, 135.2, 135.1, 132.1, 130.3, 129.7, 129.6, 128.8, 128.6, 128.4, 128.1, 126.9, 126.2, 123.8, 46.9, 21.5, 21.5, 21.3
ppm; νmax(KBr)/cm-1 3024, 2917, 1593, 1565, 1540, 1491, 1449, 1326, 1290, 1251, 1163, 1136, 1015, 929, 874, 801, 728, 695; HR-
MS (ESI) calcd for C33H29N4S3, [M + H]+: 577.1549, found: 577.1543.
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8-((4-(tert-butyl)phenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4a): Yield: 88% (63.0 mg) as a pale yellow solide; mp = 103.2
- 104.7°C; 1H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 7.37 (t, J = 2.0 Hz, 1H), 7.35 (t, J = 2.0 Hz, 1H), 7.26 (t, J = 2.0 Hz, 1H), 7.25
(t, J = 1.9 Hz, 1H), 4.16 (q, J = 7.2 Hz, 2H), 2.56 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H), 1.17 (s, 9H); 13C{1H} NMR (125 MHz, CDCl3) δ
159.8, 152.0, 151.4, 149.6, 131.9, 131.7, 126.6, 126.1, 119.3, 38.8, 34.6, 31.2, 14.7, 11.9 ppm; νmax(KBr)/cm-1 3050, 2962, 1553,
1488, 1453, 1368, 1310, 1263, 1220, 1169, 1148, 1111, 1012, 952, 863, 820, 679, 575, 549; HR-MS (ESI) calcd for C18H23N4S2, [M
+ H]+: 359.1359, found: 359.1353.
8-((3,5-dimethylphenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4b): Yield: 85% (56.1 mg) as a pale yellow solid; mp = 108.6
- 110.0°C; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.01 (s, 2H), 6.82 (s, 1H), 4.16 (q, J = 7.2 Hz, 2H), 2.59 (s, 3H), 2.16 (s, 6H),
1.20 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1, 151.5, 149.7, 149.2, 139.2, 131.8, 130.4, 129.4, 129.3, 38.8, 21.1,
14.7, 11.9 ppm; νmax(KBr)/cm-1 3041, 2928, 1601, 1567, 1453, 1432, 1321, 1263, 1224, 1151, 952, 851, 797, 686, 576; HR-MS (ESI)
calcd for C16H19N4S2, [M + H]+: 331.1046, found: 331.1047.
9-ethyl-8-((4-methoxyphenyl)thio)-6-(methylthio)-9H-purine (4c): Yield: 93% (61.8 mg) as a white solid; mp = 152.4 - 153.9°C;
1H NMR (400 MHz, CDCl3) δ 8.63 (s, 1H), 7.52 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 7.9 Hz, 2H), 4.27 (m, J = 7.0 Hz, 2H), 3.80 (s, 3H),
2.67 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.5, 159.3, 151.2, 150.9, 149.8, 135.0, 131.8, 119.0,
115.1, 55.4, 38.6, 14.7, 11.9 ppm; νmax(KBr)/cm-1 3053, 2964, 2926, 1591, 1557, 1494, 1454, 1319, 1244, 1174, 1022, 951, 863, 832,
576; HR-MS (ESI) calcd for C15H17N4OS2, [M + H]+: 333.0838, found: 333.0838.
9-ethyl-8-((3-methoxyphenyl)thio)-6-(methylthio)-9H-purine (4d): Yield: 89% (59.1 mg) as a white solid; mp = 105.3 - 106.9°C;
1H NMR (400 MHz, CDCl3) δ 8.67 (s, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.11 (s, 1H), 7.04 (d, J = 7.7 Hz, 1H), 6.84 (dd, J = 8.3, 2.0 Hz,
1H), 4.28 (q, J = 7.2 Hz, 2H), 3.77 (s, 3H), 2.69 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.2, 160.1,
151.6, 149.6, 148.6, 131.7, 131.2, 130.2, 123.4, 116.6, 114.4, 55.4, 38.9, 14.8, 11.8 ppm; νmax(KBr)/cm-1 3054, 2971, 2930, 1590,
1567, 1476, 1456, 1422, 1324, 1237, 1152, 1033, 950, 864, 790, 679, 549; HR-MS (ESI) calcd for C15H17N4OS2, [M + H]+: 333.0838,
found: 333.0841.
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8-((3,4-dimethoxyphenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4e): Yield: 87% (63.0 mg) as a pale yellow solid; mp = 130.2
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- 131.7°C; 1H NMR (400 MHz, CDCl3)δ 8.54 (s, 1H), 7.12 (s, 1H), 7.06 (d, J = 8.1 Hz, 1H), 6.75 (d, J = 8.2 Hz, 1H), 4.19(q, J = 7.2
Hz, 2H), 3.78 (s, 6H), 2.58 (s, 3H), 1.26 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 159.4, 151.3, 150.5, 150.1, 149.7,
149.5, 131.7, 126.1, 119.3, 116.3, 111.7, 56.1, 56.0, 38.6, 14.7, 11.8 ppm; νmax(KBr)/cm-1 3063, 2932, 2839, 1569, 1504, 1462, 1401,
1317, 1235, 1017, 953, 863, 802, 764, 616, 589; HR-MS (ESI) calcd for C16H19N4O2S2, [M + H]+: 363.0944, found: 363.0941.
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9-ethyl-8-((4-fluorophenyl)thio)-6-(methylthio)-9H-purine (4f): Yield: 80% (51.3 mg) as a pale yellow solid; mp = 115.8 -
117.4°C; 1H NMR (400 MHz, CDCl3)δ 8.54 (s, 1H), 7.47 (dd, J = 8.6, 5.2 Hz, 2H), 6.98 (t, J = 8.6 Hz, 2H), 4.19 (q, J = 7.2 Hz, 2H),
2.57 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 164.4, 161.9, 159.7, 151.4, 149.8, 134.9, 131.8, 124.2,
116.8, 38.7, 14.8, 11.9 ppm; 19F NMR (471 MHz, CDCl3) δ -111.42 ppm; νmax(KBr)/cm-1 3063, 2972, 2922, 1586, 1568, 1489, 1434,
1319, 1223, 1168, 1087, 950, 864, 834, 679, 552; HR-MS (ESI) calcd for C14H14FN4S2, [M + H]+: 321.0638, found: 321.0636.
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8-((3,4-difluorophenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4g): Yield: 73% (49.4 mg) as a pale yellow solid; mp = 116.8 -
118.3°C; 1H NMR (400 MHz, CDCl3) δ 8.66 (s, 1H), 7.46 (ddd, J = 9.8, 7.3, 2.2 Hz, 1H), 7.32 (ddd, J = 9.0, 3.9, 1.9 Hz, 1H), 7.24 -
7.14 (m, 1H), 4.31 (q, J = 7.2 Hz, 2H), 2.69 (s, 3H), 1.39 (t, J = 7.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.1, 151.6, 149.6,
148.6, 131.7, 128.9, 125.3, 121.7, 121.6, 118.3, 118.2, 38.8, 14.9, 11.9 ppm; 19F NMR (471 MHz, CDCl3) δ -134.80, -135.83 ppm;
νmax(KBr)/cm-1 3056, 2923, 2856, 1603, 1568, 1504, 1461, 1370, 1318, 1273, 1200, 1150, 1117, 952, 902, 864, 773, 586; HR-MS
(ESI) calcd for C14H13F2N4S2, [M + H]+: 339.0544, found: 339.0547.
8-((2-chlorophenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4h): Yield: 51% (34.3 mg) as a pale yellow solid; mp = 66.8 -
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68.3°C; H NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 7.47 - 7.43 (m, 1H), 7.34 - 7.31 (m, 1H), 7.28 - 7.24 (m, 1H), 7.23 - 7.17 (m,
1H), 4.32 (q, J = 7.2 Hz, 2H), 2.70 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 160.7, 151.8, 149.6, 147.4,
134.7, 132.4, 132.0, 130.4, 130.2, 129.4, 127.7, 39.1, 14.9, 11.9 ppm; νmax(KBr)/cm-1 3080, 2980, 2928, 1564, 1447, 1425, 1319,
1221, 1152, 1035, 950, 865, 790, 740, 572; HR-MS (ESI) calcd for C14H14ClN4S2, [M + H]+: 337.0343, found: 337.0342.
8-((4-chlorophenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4i): Yield: 70% (47.0 mg) as a pale yellow solid; mp = 113.2 -
114.7°C; 1H NMR (500 MHz, CDCl3) δ 8.53 (s, 1H), 7.36 (d, J = 8.5 Hz, 2H), 7.20 (d, J = 8.5 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 2.55
(s, 3H), 1.23 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 159.9, 151.5, 149.6, 148.7, 135.0, 133.3, 131.7, 129.6, 128.0,
38.7, 14.8, 11.9 ppm; νmax(KBr)/cm-1 3068, 2924, 1565, 1475, 1426, 1317, 1250, 1222, 1173, 1151, 1090, 1012, 952, 865, 820, 578;
HR-MS (ESI) calcd for C14H14ClN4S2, [M +H]+: 337.0343, found: 337.0345.
8-((2,4-dichlorophenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4j): Yield: 47% (34.8 mg) as a pale yellow solid; mp = 139.3 -
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140.9°C; H NMR (500 MHz, CDCl3) δ 8.69 (s, 1H), 7.48 (d, J = 2.0 Hz, 1H), 7.37 (d, J = 8.5 Hz, 1H), 7.21 (dd, J = 8.5, 2.0 Hz,
1H), 4.33 (q, J = 7.3 Hz, 2H), 2.69 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 160.6, 151.8, 149.6, 147.1,
135.8, 135.1, 133.6, 131.9, 130.1, 128.5, 128.1, 39.0, 15.0, 11.9 ppm; νmax(KBr)/cm-1 3056, 2973, 2921, 1567, 1453, 1427, 1370,
1318, 1250, 1225, 1151, 1096, 1032, 952, 865, 813, 551; HR-MS (ESI) calcd for C14H13Cl2N4S2, [M + H]+: 370.9953, found: 370.9958.
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8-((3,4-dichlorophenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4k): Yield: 58% (42.9 mg) as a pale yellow solid; mp = 96.2 -
97.9°C; 1H NMR (500 MHz, CDCl3) δ 8.68 (s, 1H), 7.66 (d, J = 1.8 Hz, 1H), 7.44 (d, J = 8.4 Hz, 1H), 7.37 (dd, J = 8.4, 2.0 Hz, 1H),
4.31 (q, J = 7.2 Hz, 2H), 2.70 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 160.5, 151.8, 149.6, 147.8, 133.5,
133.3, 133.1, 131.8, 131.2, 130.9, 129.6, 38.9, 15.0, 11.9 ppm; νmax(KBr)/cm-1 3054, 2925, 2863, 1565, 1457, 1426, 1366, 1319, 1224,
1151, 1032, 952, 864, 810, 702, 549; HR-MS (ESI) calcd for [M + H]+: C14H13Cl2N4S2: 370.9953, found: 370.9951.
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8-((4-bromophenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4l): Yield: 54% (41.0 mg) as a yellow solid; mp = 58.8 - 60.3°C;
1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 7.37 - 7.34 (m, 1H), 7.32 - 7.26 (m, 1H), 7.20 (d, J = 8.1 Hz, 1H), 7.16 - 7.09 (m, 1H),
4.17 (q, J = 7.0 Hz, 2H), 2.56 (s, 3H), 1.24 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.0, 151.6, 149.6, 148.7, 135.0,
133.3, 132.5, 130.7, 129.7, 38.8, 14.9, 11.9 ppm; νmax(KBr)/cm-1 3054, 2988, 2926, 1565, 1473, 1434, 1321, 1251, 1223, 1152, 1089,
1010, 952, 864, 815, 502; HR-MS (ESI) calcd for C14H14BrN4S2, [M + H]+: 380.9838, found: 380.9841.
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8-((2-bromophenyl)thio)-9-ethyl-6-(methylthio)-9H-purine (4m): Yield: 43% (32.7 mg) as a yellow solid; mp = 193.2 - 194.5°C;
1H NMR (400 MHz, CDCl3) δ 8.61 (s, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 7.21 - 7.08 (m, 2H), 4.24 (q, J = 7.0
Hz, 2H), 2.61 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 160.7, 151.8, 149.6, 147.4, 134.6, 132.3, 132.0,
130.4, 130.2, 129.4, 127.7, 39.1, 15.0, 11.9 ppm; νmax(KBr)/cm-1 3076, 2981, 2931, 1563, 1446, 1425, 1319, 1253, 1221, 1152, 1034,
950, 865, 790, 764, 572; HR-MS (ESI) calcd for C14H14BrN4S2, [M + H]+: 380.9838, found: 380.9842.
9-ethyl-6-(methylthio)-8-(naphthalen-2-ylthio)-9H-purine (4o): Yield: 85% (55.3 mg) as a brick red solid; mp = 122.3 - 123.7°C;
1H NMR (500 MHz, CDCl3) δ 8.57 (s, 1H), 7.92 (s, 1H), 7.72 - 7.67 (m, 2H), 7.65 (dd, J = 6.1, 3.3 Hz, 1H), 7.45 - 7.41 (m, 1H), 7.38
(dd, J = 6.2, 3.2 Hz, 2H); 13C{1H} NMR (125 MHz, CDCl3) δ 160.2, 151.6, 149.7, 149.1, 133.6, 132.9, 131.9, 131.0, 129.3, 128.6,
127.8, 127.6, 127.1, 127.0, 126.9, 38.9, 14.8, 11.9 ppm; νmax(KBr)/cm-1 3051, 2978, 2925, 1691, 1560, 1498, 1452, 1427, 1319, 1252,
1218, 1151, 949, 863, 817, 757, 552; HR-MS (ESI) calcd for C18H17N4S2, [M + H]+: 353.0889, found: 353.0892.
9-ethyl-6-(octylthio)-9H-purine (5a): Yield: 96% and 95% (56.0 mg and 55.51mg) as a yellow oil; 1H NMR (500 MHz, CDCl3)
δ 8.70 (s, 1H), 8.03 (s, 1H), 4.32 (q, J = 7.3 Hz, 2H), 3.39 (t, J = 7.4 Hz, 2H), 1.79 (p, J = 7.5 Hz, 2H), 1.55 (t, J = 7.4 Hz, 3H), 1.49
(p, J = 7.2 Hz, 2H), 1.37 – 1.25 (m, 8H), 0.87 (t, J = 6.9 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.2, 151.5, 148.0, 142.0,
131.3, 38.8, 31.6, 29.3, 29.0, 29.0, 28.7, 28.5, 22.5, 15.3, 13.9 ppm; HR-MS (ESI) calcd for C15H25N4S, [M + H]+: 293.1794, found:
293.1790.
6-(dodecylthio)-9-ethyl-9H-purine (5b): Yield: 97% and 95% (67.6 mg and 66.2 mg) as a white solid; mp = 50.3 - 51.6°C; 1H
NMR (500 MHz, CDCl3) δ 8.70 (s, 1H), 8.01 (s, 1H), 4.31 (q, J = 7.3 Hz, 2H), 3.39 (t, J = 7.4 Hz, 2H), 1.79 (p, J = 7.5 Hz, 2H), 1.54
(t, J = 7.3 Hz, 3H), 1.49 (p, J = 7.3 Hz, 2H), 1.37 - 1.24 (m, 16H), 0.87 (t, J = 7.0 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.1,
151.5, 148.1, 141.9, 131.3, 38.8, 31.8, 29.5, 29.5, 29.5, 29.4, 29.3, 29.2, 29.1, 28.7, 28.5, 22.5, 15.3, 14.0 ppm; νmax(KBr)/cm-1 3048,
2936, 2847, 1567, 1467, 1421, 1393, 1326, 1215, 1167, 1148, 1079, 987, 932, 858, 792, 715, 644, 576; HR-MS (ESI) calcd for
C19H33N4S, [M + H]+: 349.2420, found: 349.2426.
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9-ethyl-6,8-bis(methylthio)-9H-purine (6a): Yield: 35% (16.8mg) as a white solid; mp = 130.3 - 131.8°C; 1H NMR (400 MHz,
CDCl3) δ 8.53 (s, 1H), 4.11 (q, J = 7.2 Hz, 2H), 2.74 (s, 3H), 2.65 (s, 3H), 1.33 (t, J = 7.2 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 157.2, 153.9, 150.6, 150.4, 131.9, 38.0, 14.4, 14.1, 11.8 ppm; νmax(KBr)/cm-1 3031, 2921, 2851, 1557, 1459, 1423, 1317, 1222,
1149, 951, 866, 796, 680, 553; HR-MS (ESI) calcd for C9H13N4S2, [M + H]+: 241.0576, found: 241.0579.
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1,3,7-trimethyl-8-(methylthio)-3,7-dihydro-1H-purine-2,6-dione (6b): Yield: 50% (24.0 mg) as a white solid; H NMR (400
9
MHz, CDCl3) δ 3.75 (s, 3H), 3.48 (s, 3H), 3.30 (s, 3H), 2.64 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 154.5, 151.9, 151.5, 148.5,
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108.6, 32.0, 29.7, 27.8, 14.7 ppm; HR-MS (ESI) calcd for C9H12N4NaO2S, [M + Na]+: 263.0573, found: 263.0578.
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9-ethyl-6-(p-tolylthio)-9H-purine (1ra): Yield: 96% (51.9 mg) as a white solid; mp = 113.8 - 115.1°C; H NMR (400 MHz,
CDCl3) δ 8.54 (s, 1H), 7.93 (s, 1H), 7.46 (d, J = 8.0 Hz, 2H), 7.19 (d, J = 7.8 Hz, 2H), 4.22 (q, J = 7.3 Hz, 2H), 2.32 (s, 3H), 1.47 (t,
J = 7.3 Hz, 3H); 13C{1H} NMR (125 MHz, CDCl3) δ 161.1, 152.3, 148.7, 142.5, 139.8, 135.6, 130.9, 130.2, 123.6, 39.1, 21.5, 15.5
ppm; νmax(KBr)/cm-1 3090, 2990, 2919, 1595, 1560, 1489, 1436, 1395, 1327, 1210, 1166, 932, 849, 817, 646, 501; HR-MS (ESI)
calcd for C14H15N4S, [M + H]+: 271.1012, found: 271.1014.
ASSOCIATED CONTENT
Supporting Information
1H NMR and 13C NMR spectra for all products, and crystallographic data for 4g (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: denlin@scut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by the financial support from the Key Laboratory Open Foundation of Functional Molecular Engineering of
Guangdong Province (2018kf09)
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