Expedient synthesis of 2-alkylthio-N6-aryladenosines from guanosine

Article abstract of DOI:10.1080/17415993.2017.1391812

A general approach for the synthesis of 2-alkylthio-N⁶-aryladenosine was developed from the commercially available guanosine through the acetyl protection, chlorination, diazotization-alkylthionation, aromatic nucleophilic substitution and deacetylation. Two approaches were designed for the transformation of 2-amino-6-chloroguanosine to 2-alkylthio-N⁶-aryladenosines but only the one with diazotization-alkylthionation first could afford the target molecules. Both electron-rich and deficient anilines can afford the desired products in moderate to good yield. Finally, under the optimized condition, 20 2-alkylthio-N⁶-aryladenosines were synthesized, 5 of which exhibit poor antiplatelet aggregation activities.

Full text of DOI:10.1080/17415993.2017.1391812

Journal of Sulfur Chemistry
ISSN: 1741-5993 (Print) 1741-6000 (Online) Journal homepage: http://www.tandfonline.com/loi/gsrp20
Expedient synthesis of 2-alkylthio-N6-
aryladenosines from guanosine
Miao Tian, Ning Chen, Fangming Xu, Xiuxiu Li, Shunlai Li & Hongguang Du
To cite this article: Miao Tian, Ning Chen, Fangming Xu, Xiuxiu Li, Shunlai Li & Hongguang Du
(2017): Expedient synthesis of 2-alkylthio-N6-aryladenosines from guanosine, Journal of Sulfur
Chemistry, DOI: 10.1080/17415993.2017.1391812
To link to this article: http://dx.doi.org/10.1080/17415993.2017.1391812
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Date: 27 October 2017, At: 15:55

JOURNAL OF SULFUR CHEMISTRY, 2017
https://doi.org/10.1080/17415993.2017.1391812
SHORT COMMUNICATION
Expedient synthesis of 2-alkylthio-N6-aryladenosines from
guanosine
Miao Tian, Ning Chen , Fangming Xu, Xiuxiu Li, Shunlai Li and Hongguang Du
Faculty of Science, Beijing University of Chemical Technology, Beijing, People’s Republic of China
ABSTRACT
ARTICLE HISTORY
A general approach for the synthesis of 2-alkylthio-N6-aryladenosine
was developed from the commercially available guanosine through
the acetyl protection, chlorination, diazotization-alkylthionation,
aromatic nucleophilic substitution and deacetylation. Two appro-
aches were designed for the transformation of 2-amino-6-chloro-
guanosine to 2-alkylthio-N6-aryladenosines but only the one with
diazotization-alkylthionation first could afford the target molecules.
Both electron-rich and deficient anilines can afford the desired prod-
ucts in moderate to good yield. Finally, under the optimized condi-
tion, 20 2-alkylthio-N6-aryladenosines were synthesized, 5 of which
exhibit poor antiplatelet aggregation activities.
Received 7 July 2017
Accepted 2 October 2017
KEYWORDS
Adenosine; guanosine;
purine riboside;
diazotization-
alkylthionation; antiplatelet
aggregation
1. Introduction
Adenosine derivatives, with various substituents at C2, C6, C8 and N9 positions, have
,
attracted much attention due to their broad spectrum of biological activities [1–6]. In 1999,
2-alkylthio-6-aminopurine riboside derivatives were first reported as inhibitors for P2Y12
CONTACT Ning Chen
chenning@mail.buct.edu.cn; Hongguang Du
dhg@mail.buct.edu.cn
Faculty of
Science, Beijing University of Chemical Technology, Beijing 100029, People’s Republic of China
This article makes reference to supplementary material available on the publisher’s website at
http://dx.doi.org/10.1080/17415993.2017.1391812.
© 2017 Informa UK Limited, trading as Taylor & Francis Group

2
M. TIAN ET AL.
receptor [7]. Since then, great endeavors have been devoted to developing various out-
standing antiplatelet inhibitors through the modification of the substituents on the purine
moiety [8–11]. In particular, adenosine derivatives with various substituents on the purine
motif, including the alkylthio group at the C2 position, the alkyl substituent at the N6 posi-
tion and the triphosphate side chain at the 5ꢀ position, possess unique biological effects,
such as Cangrelor [7] (Figure 1, I) and Ticagrelor [12] (Figure 1, II). In view of the sig-
nificant antiplatelet activities exhibited by purine derivatives, it is still highly desirable to
search for more effective antiplatelet aggregation molecules from purine derivatives.
General methods to produce adenosine derivatives varied from guanosine or 6-
halopurine riboside through alkylation, amination, and Buchwald–Hartwig amination
[9,13–15]. In recent years, our research group synthesized a series of adenosine deriva-
tives with alkoxy or alkylthio groups at position 2 and alkylamine at position 6 using
guanosine as a raw material [16,17]. Meanwhile, we also studied the antiplatelet activi-
ties of these compounds and found that molecules BF061 and BF081 (Figure 1, III and IV)
show excellent antiplatelet activities [16,18]. As the ongoing work, we planned to shorten
the N6-arylalkyl substituent to an aryl group in adenosine derivatives to investigate their
bioactivities. Herein, we report our recent progress for the synthesis and the antiplatelet
aggregation evaluation of various substituted 2-alkylthio-N6-aryladenosines.
2. Results and discussion
Following our previous method [16], commercially available guanosine (1) was used as a
starting material (Scheme 1). Initially, after acetylation with acetyl anhydride, 1 afforded
the corresponding acetyl guanosine 2 with 85% yield and the following chlorination
with POCl3 provided key intermediates 6-chlordine purine nucleoside 3 in 78% yield
(Scheme 1).
Figure 1. Structures of Cangrelor, Tricagrelor, BF061, and BF0801.

JOURNAL OF SULFUR CHEMISTRY
3
Scheme 1. The synthesis of 6-chloropurine nucleoside 3.
Scheme 2. Two approaches for the synthesis of 6-arylamino-2-alkylthiopurines.
In order to afford 2-alkylthio-N6-arylpurine riboside 5 (Scheme 2), two possible ways
were designed: C6-amination first (route 1) or C2-arylthio-substitution first (route 2).
Both approaches were examined, but only the latter one produced the target molecule.
Take 2-ethylthio-N6-phenylamino-purine acetyl nucleoside 5ꢀa as an example; in route 1,
amination of 3a from aniline gave corresponding 6-arylaminopurine riboside 4a in 44%
yield, but only trace yields of the target 5ꢀa was detected from thin-layer chromatogra-
phy (TLC) in the followed diazotization-alkylthionation process with iso-amylnitrite and
diethyl disulfide [17]. The result demonstrates that electron-donating group (alkylamino)
on purine motif makes the purine too electron-rich to stabilize the followed aryl radical
[19], thus inhibiting the further radical alkylthio coupling. We thus switched the sequences
of the reactions. First, the diazotization-alkylthionation approach of 3 was carried out with
65% yield of isolated4ꢀa, which further demonstrated that electron-withdrawing group C6-
position facilitated the radical coupling. To our gratification, the subsequent amination of
4ꢀa with aniline in the presence of triethylamine afforded the substitution product 5ꢀa in
81% yield.
Having obtained the model molecule 5bꢀ, we next examined the application of this
method. During the diazotization-alkylthionation process, we have exploited that ultra-
sound irradiation highly facilitated the radical coupling, which not only promoted the
reaction efficiency but also avoid the use of inert gas [17]. Herein, beside the diethyl disul-
fide, dimethyl- and dipropyl disulfide could also convert the muriatic purine nucleoside

4
M. TIAN ET AL.
Scheme 3. The reaction of 6-chloropurine 3 and dialkyl disulfide, and the radical trapping experiment
with TEMPO.
3 to the corresponding 2-alkylthiopurine derivatives in 66% (4ꢀa) and 60% (4ꢀc) isolated
yield under ultrasound irradiation at 65°C in acetonitrile (Scheme 3, a). When TEMPO, a
common radical scavenger, was added to the model reaction, both TEMPO-trapping prod-
uct 6 (35%) and target product 4ꢀb (28%) were isolated (Scheme 3, b), revealing that the
reaction was a radical process.
In our previous work, alkyl amine could directly react with 6-chloropurines to afford
the corresponding substitution molecules in excellent yield under the catalysis of Et3N in
EtOH (b.p. 78°C) [16]. However, in the current system, only 61% yield of 5ꢀa was obtained
(Table 1, entry 1). As is generally known, the nucleophicity of arylamine (aniline) is much
lower than that of alkylamine. We thus changed the solvent to n-propanol (b.p. 97°C), and
to our gratification the yield of 5ꢀa was promoted to 81% under refluxing. Further screening
of the organic bases (Table 1, entries 2−8) indicated that trimethylamine, pyridine, and
diisopropylethylamine (DIPEA) prompted the reaction with high efficiency, and DIPEA
was the best one (Table 1, entry 6), while DMAP and DBU showed no catalytic activity.
Moreover, focused on the DIPEA, ethanol and n-butanol were also investigated as solvents
but the reaction yields were diminished (Table 1, entries 7 and 8).
Under the optimized conditions, a series of substituted anilines, including electron-
donating (methyl and methoxy) and electron-withdrawing (fluoro-, cholro-, and nitro-)
substituents, were investigated. Moreover, 4ꢀa could be easily deacetylation by adding 3.0
equiv. of sodium methoxide [17]. To simplify the reaction operation, we tried the one-pot
strategy. Followed by the substitution, sodium methoxide was added to the reaction solu-
tion directly, and to our gratification, the target deacetylation 2-ethylthio-6-phenylamino-
purine nucleoside 5a was obtained in 66% yield (Table 2, 5a). On the further scope for
para-substituted anilines, we found that electron-rich anilines shows better reactivity than
that of electron-withdrawing ones probably due to their nucleophilicity nature (5b, 5c vs.
5d, 5e). However, all meta-substituted anilines provided moderate to good yield (5f–5i).
It is noteworthy that para-nitroaniline shows no reactivity in the current condition even
though we made every endeavor to develop it, but meta-nitroaniline could produce the tar-
get 5j in 45% yield because of the great difference in electronic influence between the para-
and meta-substituents. Furthermore, other purine substrates with 2-methylthio- (4ꢀb) and

JOURNAL OF SULFUR CHEMISTRY
5
Table 1. Optimization of substitution of aniline and 6-purine 4ꢀa.
Entry
Base
Et3N
Et3N
DMAP
DBU
Pyridine
DIPEA
DIPEA
DIPEA
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
EtOH
61
81
Trace
Trace
80
85
62
59
n-PrOH
n-PrOH
n-PrOH
n-PrOH
n-PrOH
EtOH
n-BuOH
aReaction condition: 4ꢀa (0.2 mmol), PhNH2 (0.4 mmol), base (0.4 mmol) solvent (4.0 mL), reflux 3 h; yields were determined
by 1H NMR obtained by using dimethyl maleate as an internal standard.
2-propylthio- (4ꢀc) substituents also investigated and the results were in line with 4ꢀa
(5k–5t).
Finally, the antiplatelet aggregation of all synthetic compounds was assayed by
adenosine-5ꢀ-diphosphate (ADP) and arachidonic acid (AA) with Ticagrelor and Can-
grelor as positive controls (see Supplemental Materials, Table S1, http://dx.doi.org/10.1080/
17415993.2017.1391812) [20]. Generally, most of them show poor antiplatelet aggregation
compared with Ticagrelor and Cangrelor.
3. Conclusion
Herein, we have developed a general approach for the synthesis of 2-alkylthio-N6-
aryladenosine from the commercially available guanosine. After acetyl protection and
chlorination, a key intermediate 2ꢀ,3ꢀ,5ꢀ-tri-O-acetyl-2-amino-6-chloropurine riboside 3
was obtained. Two approaches were designed for the transformation of 3 to 2-alkylthio-
N6-aryladenosines 5 but only the one with diazotization-alkylthionation first could afford
the target molecules. The result demonstrates that electron-rich purine prohibits the
diazotization-alkylthionation reaction. In the aromatic substitution, DIPEA can highly
prompt the aromatic nucleophilic substitution of 6-chloropurine with arylamines and both
electron-rich and deficient anilines afford the desired products in moderate to good yield.
Moreover, a wide array of functional groups, such as halogens, ethers, esters, hydroxyl, and
nitro, are also tolerated in this strategy.
4. Experimental section
4.1. General
Commercially available reagents were used without further purification. Melting points
were determined on a hot-stage melting point apparatus (uncorrected). Nuclear mag-
netic resonance (NMR) spectra were recorded in the CDCl3 or DMSO-d6 with TMS as
an internal standard (1H: 400 MHz, 13C: 100 MHz). The chemical shifts (δ) are reported

6
M. TIAN ET AL.
Table 2. Synthesis of target molecules 5.a
in parts per million (ppm) and coupling constants J are in Hz. The signal multiplici-
ties were distinguished with the common abbreviations with s (singlet), d (doublet), dd
(doublet of doublets), t (triplet), q (quartet), br s (broad singlet), and m (multiplet). IR

JOURNAL OF SULFUR CHEMISTRY
7
spectra are recorded on an FT-IR instrument. HRMS measurements were carried out
on an Liquid Chromatography/Mass Spectrometer Detector QTOF mass spectrometer.
ADP, AA, and Aspirin were purchased from Sigma. Ticagrelor was purchased from Dalian
Meilun Biotech Co., Ltd. 2ꢀ,3ꢀ,5ꢀ-Tri-O-acetyl-2-amino-6-chloropurine riboside 3 were
synthesized according to the literature [21,22].
4.2. General procedure for the synthesis of 2-alkythio-6-chloro-9-(2ꢀ,3ꢀ,5ꢀ-tri-O-
acetyl-b-D-ribofuranosyl)-9H-purine (4ꢀa–4ꢀc)
2-Amino-6-chloropurine riboside 3 (3.0 g, 7.01 mmol) and dialkyl disulfides (21.04 mmol)
were suspended in 15 mL anhydrous acetonitrile in a 50-mL vial. Then, isopentylnitrite
(2.6 mL, 21.04 mmol) was then added to the mixture. The reaction was stirred at 65°C
under the condition of ultrasound for 30 min. Upon completion of the reaction, sol-
vent was evaporated in vacuo and the resulting residue was purified by silica gel column
chromatography (EtOAc/PE = 2:3, v/v) to afford corresponding product 4 as yellow oil.
4.2.1. 6-Chloro-2-ethylthio-9-(2ꢀ,3ꢀ,5ꢀ-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine (4ꢀa)
[16]
2.09 g, yield = 65%; a yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.11 (1H, s), 6.13 (1H, d,
J = 4.8 Hz), 5.95 (1H, t, J = 4.8 Hz), 5.61 (1H, t, J = 5.2 Hz), 4.45–4.42 (2H, m), 4.35–4.31
(1H, m), 3.23 (2H, q, J = 7.2 Hz), 2.15 (3H, s), 2.11 (6H, app s), 1.43 (3H, t, J = 7.2 Hz);
13C NMR (100 MHz, CDCl3): δ 170.3, 169.5, 169.3, 166.9, 152.0, 151.3, 142.1, 129.1, 86.9,
80.1, 73.0, 70.1, 62.7, 26.0, 20.7, 20.5, 20.4, 14.1.
4.2.2. 6-Chloro-2-methylthio-9-(2ꢀ,3ꢀ,5ꢀ-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine
(4ꢀb) [16]
2.18 g, yield = 66%; a yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.11 (1H, s), 6.12 (1H, d,
J = 4.4 Hz), 6.00 (1H, t, J = 5.2 Hz), 5.65 (1H, t, J = 5.2 Hz), 4.46–4.40 (2H, m), 4.35–4.30
(1H, m), 2.65 (3H, s), 2.16 (3H, s), 2.11 (3H, s), 2.10 (3H, s); 13C NMR (100 MHz, CDCl3):
δ 170.3, 169.5, 169.3, 167.4, 151.9, 151.3, 142.2, 129.1, 87.1, 80.1, 73.0, 70.2, 62.7, 20.7, 20.5,
20.4, 14.9.
4.2.3. 6-Chloro-2-propyllthio-9-(2ꢀ,3ꢀ,5ꢀ-tri-O-acetyl-β-D-ribofuranosyl)-9H-purine
(4ꢀc) [16]
2.05 g, yield = 60%; a yellow oil; 1H NMR (400 MHz, CDCl3): δ 8.10 (1H, s), 6.14 (1H, d,
J = 4.8 Hz), 5.92 (1H, t, J = 5.2 Hz), 5.59 (1H, t, J = 5.2 Hz), 4.47–4.41 (2H, m), 4.36–4.32
(1H, m), 3.20 (2H, t, J = 7.2 Hz), 2.15 (3H, s), 2.11 (3H, s), 2.10 (3H, s), 1.80 (2H, sext,
J = 7.2 Hz), 1.07 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δ 170.3, 169.5, 169.3,
167.1, 152.0, 151.2, 141.9, 129.1, 86.8, 80.1, 73.1, 70.2, 62.8, 33.6, 22.3, 20.7, 20.5, 20.4, 13.4.
4.3. General procedure for the synthesis of 2-alkylthio-N6-aryladenosines (5a–5t)
To a suspend solution of 4 (1.06 mmol) and 15 mL n-propanol, DIPEA (2.11 mmol) and
anilines (2.11 mmol) were added to the mixture. The reaction was stirred under the reflux-
ing condition till the disappearance of intermediate 4 (about 3−11 h). When the starting
material disappeared as monitored by TLC (EtOAc/PE = 2:3, v/v), the system was cooled

8
M. TIAN ET AL.
to room temperature, and sodium methoxide (3.0 equiv.) was added into the mixture. The
whole system was then heated to reflux for 1.5 h. The solvent was evaporated in vacuo.
Then, the mixture was dissolved with 12 mL EtOAc and H2O (1:1) and was neutralized
with dilute hydrochloric acid to pH = 7. The aqueous phase was extracted with EtOAc
(3 × 20 mL). The combined organic phase was dried over by anhydrous MgSO4. After fil-
trating and evaporating the solvent, the resulting residue was purified by silica gel column
chromatography (EtOAc/MeOH = 15:1, v/v) to afford corresponding product 5 as white
crystals.
4.3.1. (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(2-(ethylthio)-6-(phenylamino)-9H-purin-9-
yl)tetrahydrofuran-3,4-diol (5a)
282 mg, yield = 66%; white solid; m.p. = 171–172°C; Rf = 0.48 (EtOAc:MeOH = 15:1,
1
v/v). H NMR (400 MHz, DMSO-d6): δ 9.99 (1H, s), 8.42 (1H, s), 7.91–7.89 (2H, m),
7.37–7.33 (2H, m), 7.08–7.05 (1H, m), 5.90 (1H, d, J = 5.6 Hz), 5.48 (1H, d, J = 6.0 Hz),
5.22 (1H, d, J = 5.2 Hz), 5.06 (1H, t, J = 5.6 Hz), 4.66–4.62 (1H, m), 4.19–4.16 (1H, m),
3.98–3.95 (1H, m), 3.71–3.66 (1H, m), 3.53.60–3.55(1H, m), 3.16–3.11 (2H, m), 1.35 (3H,
t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 163.7, 151.5, 150.4, 139.6, 139.2, 128.3,
122.9, 120.9, 117.8, 87.4, 85.6, 73.4, 70.5, 61.5, 24.7, 14.9; FT-IR (film, cm−1): 3348, 3291,
2966, 2924, 1616, 1578, 1498, 1444, 1334, 1191, 1078, 748, 691. ESI-HRMS [M + H]+ calcd
for C18H22N5O4S+ m/z 404.1387, found 404.1388.
4.3.2. (2R,3R,4S,5R)-2-(2-(ethylthio)-6-(p-tolylamino)-9H-purin-9-yl)-5-
(hydroxy methyl)tetrahydrofuran-3,4-diol (5b)
301 mg, yield = 68%; white solid; m.p. = 182–183°C; Rf = 0.50 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 9.90 (1H, s), 8.40 (1H, s), 7.76 (2H, d, J = 8.4 Hz),
7.15 (2H, d, J = 8.0 Hz), 5.89 (1H, d, J = 6.0 Hz), 5.48 (1H, br s), 5.22 (1H, br s), 5.07
(1H, br s), 4.64 (1H, br s), 4.18 (1H, br s), 3.96 (1H, dd, J = 4.0, 7.6 Hz), 3.70–3.66
(1H, m), 3.58–3.56 (1H, m), 3.14–3.10 (2H, m), 2.29 (3H, s), 1.35 (3H, t, J = 7.6 Hz);
13C NMR (100 MHz, DMSO-d6): δ 163.7, 151.5, 150.3, 139.4, 136.6, 131.9, 128.7, 121.0,
117.7, 87.4, 85.5, 73.4, 70.5, 61.5, 24.7, 20.4, 14.9. FT-IR (film, cm−1): 3333, 3232, 3104,
2921, 2863, 1625, 1580, 1511, 1454, 1334, 1234, 1083, 811. ESI-HRMS [M + H]+ calcd for
C19H24N5O4S+ m/z 418.1544, found 418.1550.
4.3.3. (2R,3R,4S,5R)-2-(2-(ethylthio)-6-((4-methoxyphenyl)amino)-9H-purin-9-yl)-5-
(hydroxymethyl)tetrahydrofuran-3,4-diol (5c)
312 mg, yield = 68%; white solid; m.p. = 158–160°C; Rf = 0.44 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 9.85 (1H, s), 8.37 (1H, s), 7.75 (2H, d, J = 9.2 Hz),
6.93 (2H, d, J = 8.8 Hz), 5.88 (1H, d, J = 6.0 Hz), 5.47 (1H, d, J = 6.0 Hz), 5.21 (1H, d,
J = 4.8 Hz), 5.07 (1H, t, J = 5.6 Hz), 4.63 (1H, dd, J = 5.6, 11.2 Hz), 4.17 (1H, dd, J = 4.4,
8.4 Hz), 3.96–3.95 (1H, m), 3.76 (3H, s), 3.70–3.65 (1H, m), 3.60–3.55 (1H, m), 3.13–3.07
(2H, m), 1.33 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 163.7, 155.2, 151.5,
150.1, 139.3, 132.2, 122.7, 117.6, 113.5, 87.4, 85.5, 73.4, 70.5, 61.5, 55.2, 24.7, 15.0. FT-IR
(film, cm−1): 3381, 3352, 3110, 2927, 1619, 1582, 1509, 1455, 1334, 1243, 1118, 1038, 828.
ESI-HRMS [M + H]+ calcd for C19H24N5O5S+ m/z 434.1493, found 434.1495.

JOURNAL OF SULFUR CHEMISTRY
9
4.3.4. (2R,3R,4S,5R)-2-(2-(ethylthio)-6-((4-fluorophenyl)amino)-9H-purin-9-yl)-5-
(hydroxymethyl)-tetrahydrofuran-3,4-diol (5d)
161 mg, yield = 36%; white solid; m.p. = 208–210°C; Rf = 0.46 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 10.05 (1H, s), 8.41 (1H, s), 7.88 (2H, dd, J = 4.8,
8.8 Hz), 7.19 (2H, t, J = 8.8 Hz), 5.89 (1H, d, J = 6.0 Hz), 5.48 (1H, d, J = 6.0 Hz), 5.22
(1H, d, J = 4.8 Hz), 5.06 (1H, t, J = 5.6 Hz), 4.65–4.61 (1H, m), 4.19–4.16 (1H, m),
3.97–3.94 (1H, m), 3.71–3.58 (1H, m), 3.57–3.54 (1H, m), 3.13–3.08 (2H, m), 1.33 (3H, t,
J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 163.7, 158.0 (d, J = 238 Hz), 151.4, 150.4,
139.6, 135.6, 122.8, (d, J = 8 Hz), 117.7, 114.4 (d, J = 22 Hz), 87.4, 85.6, 73.4, 70.4, 61.5,
24.8, 14.9. 19F NMR (376 MHz, DMSO-d6): δ = −119.90. FT-IR (film, cm−1): 3342, 3277,
3125, 2964, 2927, 1620, 1580, 1506, 1448, 1335, 1220, 1073, 838. ESI-HRMS [M + H]+
calcd for C18H21FN5O4S+ m/z 422.1293, found 422.1293.
4.3.5. (2R,3R,4S,5R)-2-(2-(ethylthio)-6-((4-chlorophenyl)amino)-9H-purin-9-yl)-5-
(hydroxymethyl)-tetrahydrofuran-3,4-diol (5e)
200 mg, yield = 43%; white solid; m.p. = 188–190°C; Rf = 0.48 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 10.16 (1H, s), 8.43 (1H, s), 7.94 (2H, d, J = 9.2 Hz),
7.41 (2H, d, J = 8.8 Hz), 5.89 (1H, d, J = 6.0 Hz), 5.48 (1H, d, J = 6.0 Hz), 5.22 (1H, d,
J = 4.8 Hz), 5.05 (1H, t, J = 5.6 Hz), 4.63 (1H, dd, J = 6.0, 11.2 Hz), 4.17 (1H, dd, J = 4.8,
8.4 Hz), 3.96 (1H, dd, J = 4.0, 8.0 Hz), 3.70–3.65 (1H, m), 3.59–3.54 (1H, m), 3.16–3.11
(2H, m), 1.35 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 163.7, 151.2, 150.5,
139.8, 138.3, 128.2, 126.5, 122.3, 117.8, 87.4, 85.6, 73.4, 70.4, 61.5, 24.8, 14.8. FT-IR (film,
cm−1): 3342, 3288, 3122, 2961, 2928, 1614, 1573, 1491, 1443, 1334, 1192, 1069, 810. ESI-
HRMS [M + H]+ calcd for C18H21ClN5O4S+ m/z 438.0997, found 438.1003.
4.3.6. (2R,3R,4S,5R)-2-(2-(ethylthio)-6-(m-tolylamino)-9H-purin-9-yl)-5-
(hydroxymethyl)tetrahydrofuran-3,4-diol (5f)
381 mg, yield = 86%; white solid; m.p. = 168–170°C; Rf = 0.41 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 9.90 (1H, s), 8.40 (1H, s), 7.80 (1H, app s), 7.62 (1H,
d, J = 8.4 Hz), 7.21 (1H, t, J = 8.0 Hz), 6.88 (1H, d, J = 7.2 Hz), 5.88 (1H, d, J = 6.0 Hz),
5.47 (1H, d, J = 6.4 Hz), 5.20 (1H, d, J = 4.8 Hz), 5.06 (1H, t, J = 5.6 Hz), 4.61 (1H, dd,
J = 6.0, 11.2 Hz), 4.16 (1H, dd, J = 4.8, 8.4 Hz), 3.95 (1H, dd, J = 4.0, 7.6 Hz), 3.70–3.64
(1H, m), 3.59–3.53 (1H, m), 3.16–3.11 (2H, m), 2.31 (3H, s), 1.35 (3H, t, J = 7.2 Hz); 13
C
NMR (100 MHz, DMSO-d6): δ 163.6, 151.5, 150.4, 139.5, 139.2, 137.4, 128.2, 123.6, 121.4,
118.1, 117.8, 87.4, 85.6, 73.4, 70.5, 61.5, 24.7, 21.2, 15.0. FT-IR (film, cm−1): 3330, 3247,
3110, 2924, 2869, 1624, 1577, 1486, 1449, 1332, 1219, 1120, 1083, 779, 688. ESI-HRMS
[M + H]+ calcd for C19H24N5O4S+ m/z 418.1544, found 418.1548.
4.3.7. (2R,3R,4S,5R)-2-(2-(ethylthio)-6-((3-methoxyphenyl)amino)-9H-purin-9-yl)-5-
(hydroxymethyl)tetrahydrofuran-3,4-diol (5g)
299 mg, yield = 65%; white solid; m.p. = 95–96°C; Rf = 0.47 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 9.95 (1H, s), 8.42 (1H, s), 7.65 (1H, t, J = 2.0 Hz),
7.52–7.50 (1H, m), 7.24 (1H, t, J = 8.0 Hz), 6.6–6.63 (1H, m), 5.90 (1H, d, J = 2.0 Hz), 5.
44–5.15 (3H, m), 4.64 (1H, t, J = 7.2 Hz), 4.19–4.17 (1H, m), 3.96–3.98 (1H, m), 3.77 (3H,
s), 3.70–3.66 (1H, m), 3.59–3.55 (1H, m), 3.18–3.12 (2H, m), 1.36 (3H, t, J = 7.2 Hz); 13
C
NMR (100 MHz, DMSO-d6): δ 163.7, 159.4, 151.4, 150.3, 140.5, 139.6, 129.1, 117.9, 113.0,

10
M. TIAN ET AL.
108.1, 106.7, 87.4, 85.5, 73.4, 70.4, 61.5, 55.0, 24.7, 14.9. FT-IR (film, cm−1): 3350, 3235,
3113, 2927, 1624, 1577, 1491, 1454, 1330, 1225, 1157, 1046, 768, 694. ESI-HRMS [M + H]+
calcd for C19H24N5O5S+ m/z 434.1493, found 434.1497.
4.3.8. (2R,3R,4S,5R)-2-(2-(ethylthio)-6-((3-fluorophenyl)amino)-9H-purin-9-yl)-5-
(hydroxymethyl)-tetrahydrofuran-3,4-diol (5h)
295 mg, yield = 66%; white solid; m.p. = 176–178°C; Rf = 0.48 (EtOAc:MeOH = 15:1,
1
v/v). H NMR (400 MHz, DMSO-d6): δ 10.24 (1H, s), 8.46 (1H, s), 7.98–7.94 (1H, m),
7.74–7.71 (1H, m), 7.40–7.34 (1H, m), 6.90–6.85 (1H, m), 5.91 (1H, d, J = 6.0 Hz), 5.50
(1H, d, J = 6.0 Hz), 5.23 (1H, d, J = 4.0 Hz), 5.06 (1H, br s), 4.64 (1H, dd, J = 5.6,
10.8 Hz), 4.18 (1H, m), 3.97 (1H, dd, J = 4.0, 7.6 Hz), 3.70–3.67 (1H, m), 3.59–3.56
(1H, m), 3.19–3.14 (2H, m), 1.38 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-
d6): δ 163.7, 162.0 (d, J = 239 Hz), 151.2, 150.6, 141.1, 139.9, 129.9, 117.9, 116.3, 109.0
(d, J = 21 Hz), 107.2 (d, J = 26 Hz), 87.4, 85.6, 73.4, 70.4, 61.5, 24.8, 14.9. 19F NMR
(376 MHz, DMSO-d6): δ = −112.59. FT-IR (film, cm−1): 3357, 3303, 3140, 2969, 2928,
1623, 1578, 1490, 1445, 1333, 1253, 1225, 1124, 1078, 810, 681. ESI-HRMS [M + H]+ calcd
for C18H21FN5O4S+ m/z 422.1293, found 422.1295.
4.3.9. (2R,3R,4S,5R)-2-(6-((3-chlorophenyl)amino)-2-(ethylthio)-9H-purin-9-yl)-5-
(hydroxymethyl)-tetrahydrofuran-3,4-diol (5i)
348 mg, yield = 75%; white solid; m.p. = 168–170°C; Rf = 0.47 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 10.23 (1H, s), 8.46 (1H, s), 8.24 (1H, t, J = 2.0 Hz),
7.82–7.80 (1H, m), 7.36 (1H, t, J = 8.0 Hz), 7.12–7.09 (1H, m), 5.91 (1H, d, J = 6.0 Hz),
5.50 (1H, d, J = 6.0 Hz), 5.23 (1H, d, J = 4.8 Hz), 5.07 (1H, t, J = 5.6 Hz), 4.63 (1H, dd,
J = 5.6, 11.2 Hz), 4.18 (1H, dd, J = 4.4, 8.0 Hz), 3.97 (1H, dd, J = 4.0, 7.6 Hz), 3.71–3.66
(1H, m), 3.61–3.55 (1H, m), 3.19–3.14 (2H, m), 1.38 (3H, t, J = 7.2 Hz); 13C NMR
(100 MHz, DMSO-d6): δ 163.7, 151.2, 150.6, 140.9, 139.9, 132.7, 130.0, 122.3, 120.0, 119.0,
117.9, 87.4, 85.6, 73.5, 70.4, 61.5, 24.8, 14.9. FT-IR (film, cm−1): 3324, 3232, 3119, 2964,
2927, 1623, 1573, 1480, 1447, 1331, 1120, 1082, 777, 706. ESI-HRMS [M + H]+ calcd for
C18H21ClN5O4S+ m/z 438.0997, found 438.0997.
4.3.10. (2R,3R,4S,5R)-2-(2-(ethylthio)-6-((3-nitrophenyl)amino)-9H-purin-9-yl)-5-
(hydroxymethyl)-tetrahydrofuran-3,4-diol (5j)
214 mg, yield = 45%; white solid; m.p. = 115–116°C; Rf = 0.34 (EtOAc:MeOH = 15:1,
1
v/v). H NMR (400 MHz, DMSO-d6): δ 10.56 (1H, s), 9.14 (1H, s), 8.49 (1H, app s),
8.25–8.23 (1H, m), 7.92–7.90 (1H, m), 7.66–7.62 (1H, m), 5.92 (1H, d, J = 6.0 Hz), 5.50
(1H, d, J = 6.0 Hz), 5.23 (1H, d, J = 4.8 Hz), 5.06 (1H, t, J = 5.6 Hz), 4.63 (1H, dd, J = 5.6,
11.2 Hz), 4.18 (1H, dd, J = 4.8, 8.4 Hz), 3.97 (1H, dd, J = 4.0, 7.6 Hz), 3.71–3.66 (1H,
m), 3.60–3.55 (1H, m), 3.24–3.19 (2H, m), 1.36 (3H, t, J = 7.6 Hz); 13C NMR (100 MHz,
DMSO-d6): δ 163.8, 151.1, 150.7, 147.9, 140.7, 140.2, 129.7, 126.4, 118.0, 117.0, 114.4,
87.4, 85.6, 73.5, 70.4, 61.5, 24.9, 14.6. FT-IR (film, cm−1): 3324, 3220, 3127, 2927, 1623,
1575, 1528, 1483, 1433, 1349, 1329, 1121, 1077, 789, 697. ESI-HRMS [M + H]+ calcd for
C18H21N6O6S+ m/z 449.1238, found 449.1233.

JOURNAL OF SULFUR CHEMISTRY
11
4.3.11. (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(2-(methylthio)-6-(phenylamino)-9H-
purin-9-yl)tetrahydrofuran-3,4-diol (5k)
281 mg, yield = 68%; white solid, m.p. = 185–186°C; Rf = 0.44 (EtOAc:MeOH = 15:1,
1
v/v). H NMR (400 MHz, DMSO-d6): δ 9.99 (1H, s), 8.41 (1H, s), 7.91–7.89 (2H, m),
7.36–7.32 (2H, m), 7.07–7.04 (1H, m), 5.90 (1H, d, J = 6.0 Hz), 5.47 (1H, d, J = 6.4 Hz),
5.21 (1H, d, J = 4.8 Hz), 5.04 (1H, t, J = 6.0 Hz), 4.66–4.62 (1H, m), 4.19–4.16 (1H, m),
3.96–3.94 (1H, m), 3.70–3.33 (2H, m), 2.54 (3H, s); 13C NMR (100 MHz, DMSO-d6): δ
164.3, 151.3, 150.4, 139.6, 139.2, 128.4, 122.8, 120.9, 117.7, 87.3, 85.6, 73.4, 70.5, 61.5, 14.0.
FT-IR (film, cm−1): 3327, 3286, 3095, 2907, 1618, 1578, 1498, 1444, 1339, 1298, 1076, 745,
691. ESI-HRMS [M + H]+ calcd for C17H20N5O4S+ m/z 390.1231, found 390.1239.
4.3.12. (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(6-(phenylamino)-2-(propylthio)-9H-
purin-9-yl)tetrahydrofuran-3,4-diol (5l)
279 mg, yield = 63%; white solid; m.p. = 159–160°C; Rf = 0.42 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 10.00 (1H, s), 8.42 (1H, s), 7.89 (2H, d, J = 8.0 Hz),
7.35 (2H, t, J = 8.0 Hz), 7.07 (1H, t, J = 7.2 Hz), 5.89 (1H, d, J = 6.0 Hz), 5.49 (1H,
d, J = 6.0 Hz), 5.22 (1H, d, J = 4.8 Hz), 5.07 (1H, t, J = 5.2 Hz), 4.66–4.62 (1H, m),
4.18–4.17 (1H, m), 3.97–3.95 (1H, m), 3.71–3.67 (1H, m), 3.60–3.55 (1H, m), 3.13–3.08
(2H, m), 1.69 (2H, sext, J = 7.2 Hz), 0.98 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-
d6): δ 163.8, 151.4, 150.3, 139.6, 139.2, 128.3, 122.9, 120.9, 117.8, 87.4, 85.6, 73.4, 70.5, 61.5,
32.3, 22.8, 13.3. FT-IR (film, cm−1): 3316, 3104, 2964, 2926, 1616, 1577, 1495, 1444, 1330,
1296, 1234, 1080, 750, 690. ESI-HRMS [M + H]+ calcd for C19H24N5O4S+ m/z 418.1544,
found 418.1552.
4.3.13. (2R,3R,4S,5R)-2-(6-((4-fluorophenyl)amino)-2-(propylthio)-9H-purin-9-yl)-5-
(hydroxymethyl)tetrahydrofuran-3,4-diol (5m)
291 mg, yield = 63%; white solid; m.p. = 171–173°C; Rf = 0.41 (EtOAc:MeOH = 15:1,
1
v/v). H NMR (400 MHz, DMSO-d6): δ 10.05 (1H, s), 8.41 (1H, s), 7.89–7.86 (2H,
m), 7.21–7.17 (2H, m), 5.88 (1H, d, J = 6.0 Hz), 5.48 (1H, d, J = 6.0 Hz), 5.21 (1H, d,
J = 4.8 Hz), 5.06 (1H, t, J = 5.6 Hz), 4.65–4.61 (1H, m), 4.17 (1H, dd, J = 4.8, 8.4 Hz),
3.96 (1H, dd, J = 4.0, 7.6 Hz), 3.71–3.65 (1H, m), 3.59–3.54 (1H, m), 3.10–3.06 (2H, m),
1.69 (2H, sext, J = 7.2 Hz), 0.98 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ
163.8, 158.0 (d, J = 238 Hz), 151.4, 150.3, 139.6, 135.5, 122.9 (d, J = 8 Hz), 117.7, 114.9
(d, J = 22 Hz), 87.4, 85.6, 73.4, 70.4, 61.5, 32.3, 22.7, 13.3. 19F NMR (376 MHz, DMSO-
d6): δ = −119.85. FT-IR (film, cm−1): 3313, 3268, 3125, 2961, 2925, 1621, 1581, 1506,
1450, 1332, 1222, 1123, 1081, 835. ESI-HRMS [M + H]+ calcd for C19H23FN5O4S+ m/z
436.1449, found 436.1451.
4.3.14. (2R,3R,4S,5R)-2-(6-((4-chlorophenyl)amino)-2-(propylthio)-9H-purin-9-yl)-5-
(hydroxymethyl)tetrahydrofuran-3,4-diol (5n)
273 mg, yield = 57%; white solid; m.p. = 175–177°C; Rf = 0.42 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 10.15 (1H, s), 8.42 (1H, s), 7.92 (2H, d, J = 8.8 Hz),
7.39 (2H, d, J = 8.8 Hz), 5.88 (1H, d, J = 6.0 Hz), 5.48 (1H, d, J = 6.0 Hz), 5.21 (1H, d,
J = 5.2 Hz), 5.05 (1H, t, J = 5.6 Hz), 4.65–4.61 (1H, m), 4.16 (1H, dd, J = 4.8, 8.4 Hz), 3.95
(1H, dd, J = 4.0, 7.6 Hz), 3.69–3.64 (1H, m), 3.59–3.54 (1H, m), 3.12–3.06 (2H, m), 1.71
(2H, sext, J = 7.2 Hz), 0.97 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 163.8,

12
M. TIAN ET AL.
151.2, 150.5, 139.8, 138.3, 128.2, 126.5, 122.4, 117.9, 87.4, 85.6, 73.4, 70.4, 61.5, 32.4, 22.6,
13.3. FT-IR (film, cm−1): 3326, 3232, 3113, 2967, 2929, 2871, 1620, 1576, 1528, 1492, 1451,
1328, 1236, 1086, 825. ESI-HRMS [M + H]+ calcd for C19H23ClN5O4S+ m/z 452.1154,
found 452.1155.
4.3.15. (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(6-((4-methoxyphenyl)amino)-2-(propyl
thio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol (5o)
280 mg, yield = 59%; white solid; m.p. = 119–121°C; Rf = 0.38 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 9.85 (1H, s), 8.37 (1H, s), 7.73 (2H, d, J = 9.2 Hz),
6.93 (2H, d, J = 9.2 Hz), 5.87 (1H, d, J = 6.0 Hz), 5.47 (1H, d, J = 6.4 Hz), 5.20 (1H, d,
J = 4.8 Hz), 5.07 (1H, t, J = 5.6 Hz), 4.65–4.61 (1H, m), 4.16 (1H, dd, J = 4.8, 8.0 Hz),
3.95 (1H, dd, J = 4.0, 7.6 Hz), 3.69–3.65 (1H, m), 3.59–3.54 (1H, m), 3.11–3.03 (2H, m),
1.69 (2H, sext, J = 7.2 Hz), 0.98 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ
163.7, 155.3, 151.5, 150.1, 139.3, 132.1, 122.8, 117.6, 113.5, 87.4, 85.5, 73.3, 70.5, 61.5, 55.2,
32.3, 22.8, 13.3. FT-IR (film, cm−1): 3388, 3315, 3125, 2930, 2869, 1621, 1583, 1509, 1455,
1331, 1244, 1119, 1080, 828. ESI-HRMS [M + H]+ calcd for C20H26N5O5S+ m/z 448.1649,
found 448.1656.
4.3.16. (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(2-(propylthio)-6-(p-tolylamino)-9H-
purin-9-yl)tetra-hydrofuran-3,4-diol (5p)
306 mg, yield = 67%; white solid; m.p. = 179–181°C; Rf = 0.44 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 9.89 (1H, s), 8.38 (1H, s), 7.74 (2H, d, J = 8.8 Hz),
7.14 (2H, d, J = 8.4 Hz), 5.87 (1H, d, J = 5.6 Hz), 5.47 (1H, d, J = 6.0 Hz), 5.20 (1H, d,
J = 4.8 Hz), 5.06 (1H, t, J = 5.2 Hz), 4.64–4.60 (1H, m), 4.16–4.15 (1H, m), 3.95 (1H, dd,
J = 4.0, 7.6 Hz), 3.69–3.66 (1H, m), 3.59–3.53 (1H, m), 3.10–3.06 (2H, m), 2.28 (3H, s),
1.70 (2H, sext, J = 7.2 Hz), 0.99 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ
163.7, 151.5, 150.2, 139.4, 136.6, 131.9, 128.7, 121.1, 117.7, 87.4, 85.6, 73.4, 70.5, 61.5, 32.3,
22.8, 20.4, 13.3. FT-IR (film, cm−1): 3325, 3235, 3116, 2922, 2869, 1624, 1580, 1512, 1454,
1335, 1236, 1124, 1083, 812. ESI-HRMS [M + H]+ calcd for C20H26N5O4S+ m/z 432.1700,
found 432.1705.
4.3.17. (2R,3R,4S,5R)-2-(6-((3-fluorophenyl)amino)-2-(propylthio)-9H-purin-9-yl)-5-
(hydroxymethyl) tetrahydrofuran-3,4-diol (5q)
328 mg, yield = 71%; white solid; m.p. = 155–157°C; Rf = 0.44 (EtOAc:MeOH = 15:1,
1
v/v). H NMR (400 MHz, DMSO-d6): δ 10.23 (1H, s), 8.45 (1H, s), 7.96–7.91 (1H, m),
7.73–7.71 (1H, m), 7.40–7.34 (1H, m), 6.90–6.86 (1H, m), 5.90 (1H, d, J = 6.0 Hz), 5.49
(1H, d, J = 6.0 Hz), 5.22 (1H, d, J = 3.2 Hz), 5.06 (1H, br s), 4.65–4.61 (1H, m), 4.17 (1H,
br s), 3.97–3.94 (1H, m), 3.70–3.67 (1H, m), 3.59–3.56 (1H, m), 3.17–3.11 (2H, m), 1.73
(2H, sext, J = 7.2 Hz), 1.01 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 163.8,
162.0 (d, J = 239 Hz), 151.2, 150.5, 141.2 (d, J = 11 Hz), 139.9, 129.9 (d, J = 10 Hz), 117.9,
116.4, 109.0 (d, J = 21 Hz), 107.3 (d, J = 26 Hz), 87.4, 85.6, 73.4, 70.4, 61.5, 32.4, 22.7,
13.2. 19F NMR (376 MHz, DMSO-d6): δ = −112.45. FT-IR (film, cm−1): 3319, 3226, 3134,
2931, 2869, 1621, 1578, 1489, 1444, 1331, 1226, 1124, 1079, 770, 680. ESI-HRMS [M + H]+
calcd for C19H23FN5O4S+ m/z 436.1449, found 436.1451.

JOURNAL OF SULFUR CHEMISTRY
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4.3.18. (2R,3R,4S,5R)-2-(6-((3-chlorophenyl)amino)-2-(propylthio)-9H-purin-9-yl)-5-
(hydroxymethyl) tetrahydrofuran-3,4-diol (5r)
307 mg, yield = 64%; white solid; m.p. = 137–139°C; Rf = 0.44 (EtOAc:MeOH = 15:1,
1
v/v). H NMR (400 MHz, DMSO-d6): δ 10.22 (1H, s), 8.45 (1H, s), 8.19–8.18 (1H, m),
7.83–7.80 (1H, m), 7.38–7.34 (1H, m), 7.12–7.09 (1H, m), 5.89 (1H, d, J = 6.0 Hz), 5.48
(1H, d, J = 6.0 Hz), 5.22 (1H, d, J = 4.8 Hz), 5.06 (1H, t, J = 5.6 Hz), 4.65–4.61 (1H, m),
4.17 (1H, dd, J = 5.2, 8.8 Hz), 3.96 (1H, dd, J = 4.0, 7.6 Hz), 3.70–3.65 (1H, m), 3.60–3.57
(1H, m), 3.16–3.12 (2H, m), 1.73 (2H, sext, J = 7.2 Hz), 0.99 (3H, t, J = 7.2 Hz); 13C NMR
(100 MHz, DMSO-d6): δ 163.8, 151.1, 150.6, 140.9, 139.9, 132.7, 130.0, 122.3, 120.1, 119.0,
117.9, 87.4, 85.6, 73.4, 70.4, 61.5, 32.4, 22.5, 13.2. FT-IR (film, cm−1): 3321, 3225, 3155,
2962, 2929, 2872, 1624, 1573, 1479, 1447, 1331, 1237, 1120, 1079, 774,702. ESI-HRMS
[M + H]+ calcd for C19H23ClN5O4S+ m/z 452.1154, found 452.1157.
4.3.19. (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(6-((3-methoxyphenyl)amino)-2-
(propylthio)-9H-purin-9-yl)tetrahydrofuran-3,4-diol (5s)
332 mg, yield = 70%; white solid; m.p. = 90–92°C; Rf = 0.40 (EtOAc:MeOH = 15:1,
1
v/v). H NMR (400 MHz, DMSO-d6): δ 9.94 (1H, s), 8.41 (1H, s), 7.61–7.60 (1H, m),
7.52–7.50 (1H, m), 7.25–7.21 (1H, m), 6.66–6.63(1H, m), 5.88 (1H, d, J = 6.0 Hz), 5.12
(3H, br s), 4.64–4.61 (1H, m), 4.17–4.15 (1H, m), 3.96–3.93 (1H, m), 3.76 (3H, s), 3.69–3.65
(1H, m), 3.58–3.54 (1H, m), 3.12 (2H, dt, J = 4.8, 7.2 Hz), 1.71 (2H, sext, J = 7.2 Hz), 0.99
(3H, t, J = 7.2 Hz); 13C NMR (100 MHz, DMSO-d6): δ 163.8, 159.3,151.4, 150.3, 140.4,
139.6, 129.1, 117.9, 113.1, 108.1, 106.9, 87.4, 85.5, 73.4, 70.4, 61.5, 55.0, 32.3, 22.7, 13.2. FT-
IR (film, cm−1): 3345, 3238, 3107, 2958, 2928, 2869, 1624, 1577, 1492, 1454, 1329, 1287,
1226, 1157, 1084, 776, 685. ESI-HRMS [M + H]+ calcd for C20H26N5O5S+ m/z 448.1649,
found 448.1648.
4.3.20. (2R,3S,4R,5R)-2-(hydroxymethyl)-5-(2-(propylthio)-6-(m-tolylamino)-9H-
purin-9-yl)tetrahydrofuran-3,4-diol (5t)
366 mg, yield = 80%; white solid; m.p. = 182–184°C; Rf = 0.40 (EtOAc:MeOH = 15:1,
v/v). 1H NMR (400 MHz, DMSO-d6): δ 9.89 (1H, s), 8.39 (1H, s), 7.75 (1H, br s), 7.66–7.64
(1H, m), 7.23–7.19 (1H, m), 6.90–6.88 (1H, m), 5.88 (1H, d, J = 6.0 Hz), 5.47 (1H, d,
J = 6.0 Hz), 5.20 (1H, d, J = 4.8 Hz), 5.07 (1H, t, J = 5.6 Hz), 4.64–4.61 (1H, m), 4.16
(1H, dd, J = 4.4, 8.0 Hz), 3.95 (1H, dd, J = 4.0,7.6 Hz), 3.69–3.65 (1H, m), 3.59–3.55 (1H,
m), 3.14–3.09 (2H, m), 2.31 (3H, s), 1.70 (2H, sext, J = 7.2 Hz), 0.98 (3H, t, J = 7.2 Hz);
13C NMR (100 MHz, DMSO-d6): δ 163.8, 151.5, 150.3, 139.5, 139.1, 137.4, 128.2, 123.6,
121.6, 118.2, 117.8, 87.4, 85.6, 73.4, 70.5, 61.5, 32.4, 22.6, 21.3, 13.3. FT-IR (film, cm−1):
3331, 3235, 3113, 2958, 2925, 2869, 1625, 1575, 1486, 1450, 1330, 1224, 1084, 779, 687.
ESI-HRMS [M + H]+ calcd for C20H26N5O4S+ m/z 432.1700, found 432.1705.
4.4. Radical trapping experiment procedure for 6-chloropurine 3a, diethyl
disulfide, and TEMPO
4.4.1. (2R,3R,4R,5R)-2-(acetoxymethyl)-5-(6-chloro-2-((2,2,6,6-tetramethylpiperidin-
1-yl)oxy)-9H-purin-9-yl)tetrahydrofuran-3,4-diyl diacetate (6)
211 mg, yield = 35%; colorless oil; Rf = 0.51 (EtOAc:PE = 1:1, v/v). 1H NMR (400 MHz,
CDCl3): δ 8.01 (1H, s), 6.12 (1H, t, J = 5.2 Hz), 6.06 (1H, d, J = 5.2 Hz), 5.63 (1H, t,

14
M. TIAN ET AL.
J = 4.8 Hz), 4.69–4.65 (1H, m), 4.52–4.43 (2H, m), 2.16 (3H, s), 2.11 (3H, s), 2.07 (3H,
s), 1.66–1.51 (6H, m), 1.31 (3H, s), 1.30 (3H, s), 1.11 (3H, s), 1.04 (3H, s); 13C NMR
(100 MHz, CDCl3): δ 170.4, 169.4, 169.1, 165.2, 152.7, 152.3, 142.5, 128.2, 87.4, 80.4, 72.4,
70.8, 63.2, 61.0, 60.8, 39.4, 39.3, 32.1, 31.8, 20.8, 20.7, 20.5, 20.3, 17.1. FT-IR (film, cm−1):
2975, 2936, 1751, 1608, 1565, 1506, 1436, 1381, 1225, 938. ESI-HRMS [M + H]+ calcd for
C25H35ClN5O8+ m/z 568.2169, found 568.2299
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
We are grateful for financial support from the National Natural Science Foundation of China [grant
21272022 and 21702014].
ORCID
Ning Chen http://orcid.org/0000-0001-6660-4892
Hongguang Du http://orcid.org/0000-0003-3237-4261
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