Iodine-catalyzed oxidative functionalization of purines with (thio)ethers or methylarenes for the synthesis of purin-8-one analogues

Article abstract of DOI:10.1039/d1ob00118c

An efficient oxidative functionalization of purine-like substrates with (thio)ethers or methylarenes under mild conditions is described. Using I₂as the catalyst, and TBHP as the oxidant, this protocol provides a valuable synthetic tool for the assembly of a wide range of 9-alkyl(benzyl)purin-8-one derivatives with high atom- and step-economy and exceptional functional group tolerance.

Full text of DOI:10.1039/d1ob00118c

Organic &
Biomolecular Chemistry
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Iodine-catalyzed oxidative functionalization of
purines with (thio)ethers or methylarenes for the
synthesis of purin-8-one analogues†
a
Cite this: Org. Biomol. Chem., 2021,
19, 5121
Juanping Zhuge,a Ziyang Jiang,a Wei Jiang,a Gary Histandb and Dongen Lin
*
Received 22nd January 2021,
Accepted 22nd March 2021
An efficient oxidative functionalization of purine-like substrates with (thio)ethers or methylarenes under
mild conditions is described. Using I2 as the catalyst, and TBHP as the oxidant, this protocol provides a
valuable synthetic tool for the assembly of a wide range of 9-alkyl(benzyl)purin-8-one derivatives with
high atom- and step-economy and exceptional functional group tolerance.
DOI: 10.1039/d1ob00118c
rsc.li/obc
The purine skeleton, is widely found in many natural com- nated alkane (Scheme 1C).10c The copper salt is economical
pounds.1 Among them, purin-8-ones are well-known as but may be a biological toxin and the halogenated substrates
scaffolds to form target drugs against immune disease,2 as are environmentally unfriendly. In the literature11 and in our
bioreceptor agonists or antagonists,3 and cancer cell inhibi- previous work,12 a cross dehydrogenation coupling reaction
tors.4 The purin-8-ones Loxoribine,5 XBD1736 and GRC03214a occurred linking the nitrogen heterocycle or purine with the
are used as active pharmaceutical ingredients (Fig. 1). ether or toluene derivative via a new C–N bond. This paper
Research on such analogues is of great interest to organic che- extends that work to a bifunctionalization process with both a
mists.7 Traditionally, C–N and C–O bonds8,9 are constructed coupling and an oxidation occurring in one pot. In addition,
using a metal catalyst through an oxidative dehydrogenation sulfur analogues of the ethers were investigated. Herein, we
cross coupling process. However, problems with transition developed a novel method to construct new C–N and CvO
metal catalysts are increasingly apparent. They are expensive, bonds in a one-pot synthesis of 9-alkyl(benzyl)purin-8-one ana-
require special conditions (anhydrous and/or oxygen free, etc.) logues using I2 as the catalyst.
and are environmental pollutants. Therefore, metal-free
Initially, the reaction conditions for the model substrates,
methods of purin-8-one synthesis are desired. Recently, to 7-benzyl-6-chloro-7H-purine (1a) and tetrahydrofuran (THF)
investigate pharmaceutical applications, diverse methods were (2a), were investigated. The reaction of 1a in the presence of
developed for the synthesis of purin-8-one analogues.10 Maki’s the oxidant, TBHP, the base, K2CO3, and the solvent/reactant,
group used a quaternary ammonium iodide salt intermediate 2a, in air at 90 °C provided no desired product (Table 1, entry
to obtain purin-8-one derivatives (Scheme 1A).10a However, 1). Different commercially available transition metal salts
this iodide salt intermediate severely limited the range of CuCl2, FeCl2 and Pd(OAc)2 were examined, but they gave unsa-
8-oxo-purine nucleosides. Sugimura’s group reported the tisfactory results (entries 2–4). Instead of metal catalysts, the
regio- and stereo controlled synthesis of 8-oxo-purine nucleo- iodine catalysts, TBAI, KI and I2 were used and provided the
sides based on intramolecular glycosylation (Scheme 1B).10b desired product 3a in 54%, 50% and 75% yield (entries 5–7).
This method suffered from a limited substrate scope and An increased or decreased amount of I2 did not improve the
required the activation of C8–H via bromination. In addition, yield (entries 8 and 9). Next, the reaction was carried out with
Guo’s group developed a one-pot copper catalyzed method for different oxidants: TBHP (in decane), DTBP, H2O2, K2S2O8,
the N-7 alkylation of 9-alkylpurin analogues using a haloge- DDQ, BPO, TBPB and no oxidant (entries 10–17). TBHP pro-
aKey Laboratory of Functional Molecular Engineering of Guangdong Province, School
of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, China. E-mail: denlin@scut.edu.cn
bInternational School of Advanced Materials, South China University of Technology,
Guangzhou 510640, China
†Electronic supplementary information (ESI) available: Synthesis details,
additional spectroscopic data, and characterization of new compounds. CCDC
2041079. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/d1ob00118c
Fig. 1 Examples of biologically active purin-8-one.
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Table 1 Optimization of the reaction parametersa
Entry Catalyst (mol%) Oxidantb (equiv.) Base (equiv.) Yieldc (%)
1
2
3
4
5
6
7
8
—
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
DTBP (2)
H2O2 (2)
K2S2O8 (2)
DDQ (2)
BPO (2)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
0
0
0
0
54
50
75
70
40
71
0
0
0
0
40
15
0
82
59
CuCl2 (20)
FeCl2 (20)
Pd(OAc)2 (20)
TBAI (20)
KI (20)
I2 (20)
I2 (30)
I2 (10)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
I2 (20)
9
10d
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25e
26f
27g
28h
29i
30j
31k
32l
33m
34n
TBPB (2)
—
TBHP (3)
TBHP (4)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
Na2CO3 (1.5) 32
Cs2CO3 (1.5) 55
—
10
86
80
89
84
90
63
51
5
K2CO3 (2)
K2CO3 (3)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
K2CO3 (2)
Scheme 1 Synthesis methods for purin-8-one analogues.
vided the best yield. Increasing the amount of oxidant, TBHP,
from 2 to 3 equiv., improved the yield to 82% (entry 18), but
using 4 equiv. lowered the yield (entry 19). The reaction was
further explored using the bases Na2CO3 and Cs2CO3, but the
yield did not improve (entries 20 and 21). When no base was
added, the yield was only 10% (entry 22). Increasing the
amount of base provided a similar yield (86% to 80%, entries
23 and 24). While slightly extending the reaction time (12 h)
provided a better yield of 89% (entry 25), but a longer reaction
time (24 h) reduced the yield (entry 26). Furthermore, the N2
atmosphere had little influence on the yield (entry 27). Raising
or lowering the temperature did not give better results (entries
8
26
58
77
a Reaction conditions: 1a (0.1 mmol), 2a (4 mmol), catalyst (20 mol%),
oxidant (2 equiv.) and base (1.5 equiv.) were heated in a sealed tube,
90 °C, 8 h. b TBHP (70% aq. solution). c GC yield. d TBHP (in decane).
e Reaction time 12 h. f Reaction time 24 h. g Under a N2 atmosphere.
h Reaction temperature 60 °C. i Reaction temperature 120 °C. j 2a (1
equiv.), CH3CN (1 mL). k 2a (2 equiv.), CH3CN (1 mL). l 2a (3 equiv.),
CH3CN (1 mL). m 2a (20 equiv.), CH3CN (1 mL). n 2a (30 equiv.).
28 and 29). In addition, experiments on the amounts of reac- the scope of the alkyl ether substrates with 7-benzyl-6-chloro-
tant 2a were carried out (entries 30–34). The results indicated 7H-purine (1a) under the optimized conditions was explored.
that the use of excess 2a as the reactant and solvent helps Cyclic and straight chain ethers were found to be suitable sub-
ensure the solubility of the other reactant and makes the reac- strates for this transformation (3g–3l). When 2-methyl-
tion more complete. Based on the above results, the optimized tetrahydrofuran was used, the product 3g, with two chiral
conditions were set as 0.1 mmol 1a, 20 mol% I2, 3 equiv. carbon atoms, was obtained in 65% yield, but 3g′ was not
TBHP and 2 equiv. K2CO3 in 4 mmol 2a, at 90 °C for 12 h.
detected. This result shows that the primary carbon is more
Using the optimized conditions, the substrate scope of reactive than the secondary carbon, indicating that steric hin-
purines and alkyl ethers was investigated (Table 2). Purine sub- drance has a significant effect on the reaction. The desired
stituted at the 2 and 6 position with the weak electron-with- product 3m was not detected when using PhOMe as the sub-
drawing group (–Cl) and the electron-donating substituent strate. In addition to purines, 1-methylbenzimidazole as the
(–OMe) provided the desired products in good yield (3a–3c). In substrate provided 3n in 85% yield.
addition, a small non-bulky group at the 7 position (–Et) pro-
These results prompted us to investigate the reaction of het-
vided good yields of the corresponding products (3d–3f). Next, erocycle substrates with thioethers (Table 3). The corres-
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Table 2 Substrate scope of purines and alkyl ethersa
vided the THT adduct as the major product further confirming
the result (Scheme 2g).
To further explore the potential of this methodology,
toluene derivatives were investigated. The optimized con-
ditions showed that there was no requirement of a base.
Products from various substituted purines and toluene (7a13–
f) were formed in good yield (Table 4). Methylarenes bearing
electron-donating or withdrawing substituents such as
methoxy (7g), methyl (7h, m, p), halo (7i–k, n,14 o), nitro (7l)
were successfully transformed into the desired purin-8-one
products in good yield. When methylanisole (6g) was reacted
under both sets of optimized conditions, with and without a
base, the methylarene substituted product (7g) was obtained.
The structure of 7g was clearly certified by single-crystal X-ray
diffraction analysis.15 Ethylbenzene was also a suitable sub-
strate, producing the corresponding product (7q) in medium
yield. In addition to purines, the optimized reaction con-
ditions were also applied to other heterocycles, 1-methyl-
benzimidazole (7r) and 1-benzylbenzimidazole (7s) products
Table 4 Substrate scope of purines and methylarenesa
a Reaction conditions: 1 (0.1 mmol), 2 (4 mmol), I2 (20 mol%), TBHP
(70% aq. solution, 3 equiv.), and K2CO3 (2 equiv.) were heated in a
sealed tube under air at 90 °C for 12 h. Isolated yields are shown.
Table 3 Substrate scope of purines and thioethersa
a Reaction conditions: 1 (0.1 mmol), 4 (4 mmol), I2 (20 mol%), TBHP
(70% aq. solution, 3 equiv.), and K2CO3 (2 equiv.) were heated in a
sealed tube under air at 90 °C for 12 h. Isolated yields are shown.
ponding products (5a–5k) were generated in moderate yields.
An interesting result was found using 1,4-oxathiane as the sub-
strate. The product was determined using DEPT spectra to be
5j and not 5j′. A competition reaction using THF and THT pro-
a Reaction conditions: 1 (0.1 mmol), 6 (4 mmol), I2 (20 mol%), and
TBHP (70% aq. solution, 3 equiv.) were heated in a sealed tube under
air at 90 °C for 12 h. Isolated yields are shown.
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Scheme 3 Proposed reaction mechanism.
tion of 7-benzyl-6-chloro-7H-purine (1a) with equal amounts of
THF and THT under the optimized conditions was carried out,
products 3a and 5a in a 1 : 5 ratio were obtained, indicating that
thioethers are more reactive than alkyl ethers.
A possible reaction path based on previous literature
reports and our results is proposed (Scheme 3).10c,16 Initially,
tBuO-I A and HO-I B are generated by molecular iodine and
TBHP.17 The benzylic C(sp3)–H bond performs an iodination
t
reaction via BuO-I A or HO-I B to generate C. Then C under-
goes nucleophilic attack by purine 1a to provide the quaternary
ammonium salt D. Subsequently, the addition of TBHP gives
the peroxide E, which undergoes O–O bond cleavage to afford
the product 7a.16,18 The iodine is regenerated by TBHP, re-
cycling the catalyst.19
Scheme 2 Control experiments.
were obtained in high yields, but, benzothiazole (7t) and ben-
zoxazole (7u) products were only obtained in trace amounts.
To gain insights into the mechanism of this methodology,
several control experiments were carried out. In Scheme 2a,
when a radical inhibitor, TEMPO (2,2,6,6-tetra-methyl-piper-
idine-N-oxyl) was added to the reaction, the formation of the
desired product 7r was not affected. It was obtained in 85%
yield. In Scheme 2b, the quaternary ammonium salt 8 was syn-
thesized by the reaction of 1-methylbenzimidazole and benzyl
chloride. In the absence of the iodine catalyst, 8 was trans-
formed into the product (7r) in 83% yield. The carbonylation
step did not require iodine, which implied that the function of
iodine was the conversion of benzyl C–H to benzyl C–I. In
Scheme 2c, the addition of H2O18 (2 equiv.) did not yield the
corresponding 7r-O18, indicating that the oxygen atom came
from TBHP, not from water. In Scheme 2d, using toluene under
the standard conditions, benzyl iodide was detected by GCMS
(see the ESI†), and subsequent addition of 1a provided 7a in a
yield of 73%. In Scheme 2e, similarly, using ethylbenzene,
(1-iodoethyl)benzene was detected by GCMS, and the addition
of 1a gave 7q in 65% yield. In Scheme 2f, when using cumene,
the (2-iodopropan-2-yl)benzene was detected by GCMS, and the
addition of 1a gave only trace amounts of the product. These
results may indicate that the reaction does not proceed through
a cation or radical intermediate, because cumene should
provide the most stable cation or radical. In Scheme 2g, a reac-
Conclusions
In conclusion, we have developed a concise, I2-catalyzed C–N
and CvO bifunctionalization protocol for the construction of
9-alkyl(benzyl)purin-8-one analogues via nucleophilic substi-
tution and sp2C–H oxidation. This method provides a simple
and direct way for the synthesis of C8vO/N9 substituted
purine compounds in one pot. These compounds have signifi-
cant potential as biological and pharmacological agents.
Moreover, the method is environmentally friendly since no pol-
lutant is generated in the reaction process. Further investi-
gations to understand the mechanism for this reaction are cur-
rently underway in our laboratory.
Author contributions
Juanping Zhuge – conceptualization, investigation, writing –
original draft; Ziyang Jiang – conceptualization, investigation;
Wei Jiang – investigation; Gary Histand – writing – review and
editing; Dongen Lin – conceptualization, project adminis-
tration, supervision, funding acquisition, writing – review and
editing.
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S.-H. Pan, J.-M. Fang and C.-H. Wong, Eur. J. Med. Chem.,
2019, 181, 111551–111567.
Conflicts of interest
There are no conflicts to declare.
5 D. E. Tuipulotu, N. E. Netzler, J. H. Lun, J. M. Mackenzie
and P. A. White, Antimicrob. Agents Chemother., 2018, 62,
e02417‐17.
6 L. Biswas, F. Farhan, J. Reilly, C. Bartholomew and X. Shu,
Int. J. Mol. Sci., 2018, 19, 3740–3755.
Acknowledgements
7 (a) Z. Li, H. Sun, H. Jiang and H. Liu, Org. Lett., 2008, 10,
3263–3266; (b) Q.-F. Zhong and L.-P. Sun, Tetrahedron,
2010, 66, 5107–5111; (c) M. E. A. Zaki and M. F. Proença,
Tetrahedron, 2011, 67, 755–762; (d) F. Lach and P. Koza,
ACS Comb. Sci., 2012, 14, 491–495; (e) T. Tobrman and
This work was supported by the Key Laboratory Open
Foundation of Functional Molecular Engineering of
Guangdong Province, China (2018kf09).
D.
Dvořák,
Synthesis,
2014,
46,
660–668;
(f) T. R. Mahajan, M. E. Ytre-Arne, P. Strøm-Andersen,
B. Dalhus and L. L. Gundersen, Molecules, 2015, 20,
15944–15965.
8 (a) Q. Xia, W. Chen and H. Qiu, J. Org. Chem., 2011, 76,
7577–7582; (b) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang,
Chem. Soc. Rev., 2011, 40, 5068–5083; (c) D. Wang, K. Zhao,
C. Xu, H. Miao and Y. Ding, ACS Catal., 2014, 4, 3910–3918;
(d) H. Kim and S. Chang, ACS Catal., 2016, 6, 2341–2351;
(e) Y. Park, Y. Kim and S. Chang, Chem. Rev., 2017, 117,
9247–9301.
9 (a) S. Gowrisankar, A. G. Sergeev, P. Anbarasan,
A. Spannenberg, H. Neumann and M. Beller, J. Am. Chem.
Soc., 2010, 132, 11592–11598; (b) B. Xiao, T.-J. Gong,
Z.-J. Liu, J.-H. Liu, D.-F. Luo, J. Xu and L. Liu, J. Am. Chem.
Soc., 2011, 133, 9250–9253; (c) S. Guin, S. K. Rout,
A. Banerjee, S. Nandi and B. K. Patel, Org. Lett., 2012, 14,
5294–5297; (d) N. Takemura, Y. Kuninobu and M. Kanai,
Org. Lett., 2013, 15, 844–847; (e) Y. Xiao, J. Li, Y. Liu,
S. Wang, H. Zhang and H. Ding, Eur. J. Org. Chem., 2018,
2018, 3306–3311; (f) J. Liu, Y. Wen, F. He, L. Gao, L. Gao,
J. Wang, X. Wang, Y. Zhang and L. Hu, Org. Chem. Front.,
2019, 6, 846–851.
Notes and references
1 (a) D. E. Verdugo, M. T. Cancilla, X. Ge, N. S. Gray,
Y.-T. Chang, P. G. Schultz, M. Negishi, J. A. Leary and
C. R. Bertozzi, J. Med. Chem., 2001, 44, 2683–2686;
(b) H. Rosemeyer, Chem. Biodivers., 2004, 1, 361–401;
(c) M. Legraverend and D. S. Grierson, Bioorg. Med. Chem.,
2006, 14, 3987–4006; (d) D. J. Newman and G. M. Cragg,
J. Nat. Prod., 2007, 70, 461–477; (e) M. E. Welsch,
S. A. Snyder and B. R. Stockwell, Curr. Opin. Chem. Biol.,
2010, 14, 347–361; (f) J. J. Araya, H. Zhang, T. E. Prisinzano,
L. A. Mitscher and B. N. Timmermann, Phytochemistry,
2011, 72, 935–941; (g) K. Yue, M. Ye, Z. Zhou, W. Sun and
X. Lin, J. Pharm. Pharmacol., 2013, 65, 474–493; (h) J. Yan,
M. Bi, A. K. Bourdon, A. T. Farmer, P.-H. Wang,
O. Molenda, A. T. Quaile, N. Jiang, Y. Yang, Y. Yin,
B. Simsir, S. R. Campagna, E. A. Edwards and F. E. Löffler,
Nat. Chem. Biol., 2018, 14, 8–14.
2 (a) A. B. Reitz, M. G. Goodman, B. L. Pope, D. C. Argentieri,
S. C. Bell, L. E. Burr, E. Chourmouzis, J. Come,
J. H. Goodman, D. H. Klaubert, B. E. Maryanoff,
M. E. McDonnell, M. S. Rampulla, M. R. Schott and
R. Chen, J. Med. Chem., 1994, 37, 3561–3578; (b) G. Jin, 10 (a) K. Kameyama, M. Sako, K. Hirota and Y. Maki,
C. C. N. Wu, R. I. Tawatao, M. Chan, D. A. Carson and
H. B. Cottam, Bioorg. Med. Chem. Lett., 2006, 16, 4559–
4563; (c) G. P. P. Gential, T. P. Hogervorst, E. Tondini,
M. J. v. d. Graaff, H. S. Overkleeft, J. D. C. Codée,
G. A. v. d. Marel, F. Ossendorp and D. V. Filippov, Bioorg.
Med. Chem. Lett., 2019, 29, 1340–1344.
Synthesis, 1983, 10, 849–850; (b) H. Sugimura and
D. Nitta, Tetrahedron Lett., 2012, 53, 4460–4463; (c) J.-P. Li,
Y. Huang, M.-S. Xie, G.-R. Qu, H.-Y. Niu, H.-X. Wang,
B.-W. Qin and H.-M. Guo, J. Org. Chem., 2013, 78, 12629–
12636.
11 (a) W. Liu, C. Liu, Y. Zhang, Y. Sun, A. Abdukadera,
B. Wang, H. Li, X. Ma and Z. Zhang, Org. Biomol. Chem.,
2015, 13, 7154–7158; (b) G. Pandey, R. Laha and D. Singh,
J. Org. Chem., 2016, 81, 7161–7171; (c) L. Dian, Q. Xing,
D. Zhang-Negrerie and Y. Du, Org. Biomol. Chem., 2018, 16,
4384–4398; (d) M. Mondal, T. Begum and P. Bharali, Catal.
Sci. Technol., 2018, 8, 6029–6056; (e) F. Bao, Y. Cao, W. Liu
and J. Zhu, RSC Adv., 2019, 9, 27892–27895; (f) J. Frydrych,
L. P. Slavětínská, M. Dračínský and Z. Janeba, Molecules,
2020, 25, 4307–4329; (g) P. Qi, F. Sun, N. Chen and H. Du,
J. Org. Chem., 2020, 85, 8588–8596; (h) S.-Z. Song,
Y.-N. Meng, Q. Li and W.-T. Wei, Adv. Synth. Catal., 2020,
362, 2120–2134.
3 (a) J. P. Beck, A. G. Arvanitis, M. A. Curry, J. T. Rescinito,
L. W. Fitzgerald, P. J. Gilligan, R. Zaczek and G. L. Trainor,
Bioorg.
Med.
Chem.
Lett.,
1999,
9,
967–972;
(b) J. J. Weterings, S. Khanb, G. J. v. d. H. v. Noort,
C. J. M. Melief, H. S. Overkleeft, S. H. v. d. Burg,
F. Ossendorp, G. A. v. d. Marel and D. V. Filippov, Bioorg.
Med. Chem. Lett., 2009, 19, 2249–2251; (c) Y. Tadokoro,
T. Nishikawa, T. Ichimori, S. Matsunaga, M. J. Fujita and
R. Sakai, ACS Omega, 2017, 2, 1074–1080.
4 (a) T.-C. Kuo, L.-W. Li, S.-H. Pan, J.-M. Fang, J.-H. Liu,
T.-J. Cheng, C.-J. Wang, P.-F. Hung, H.-Y. Chen, T.-M. Hong,
Y.-L. Hsu, C.-H. Wong and P.-C. Yang, J. Med. Chem., 2016,
59, 8521–8534; (b) M.-R. Huang, Y.-L. Hsu, T.-C. Lin, 12 Z. Luo, Z. Jiang, W. Jiang and D. Lin, J. Org. Chem., 2018,
T.-J. Cheng, L.-W. Li, Y.-W. Tseng, Y.-s. Chou, J.-H. Liu,
83, 3710–3718.
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13 In this reaction, 1,9-disubstituted purine-6,8-dione bypro- 17 (a) K. Sun, Y. Lv, J. Wang, J. Sun, L. Liu, M. Jia, X. Liu, Z. Li
duct 7a′ was isolated in yield of 22%. Its structure was avail-
able in ESI.†
14 In this reaction, 1,9-disubstituted purine-6,8-dione bypro-
and X. Wang, Org. Lett., 2015, 17, 4408–4411; (b) D. Zhu,
W.-K. Luo, L. Yang and D.-Y. Ma, Org. Biomol. Chem., 2017,
15, 7112–7116.
duct 7n′ was isolated in yield of 15%. Its structure was 18 Y. Zi, Z.-J. Cai, S.-Y. Wang and S.-J. Ji, Org. Lett., 2014, 16,
available in ESI.† 3094–3097.
15 For details on the single crystal information of 7g, please 19 (a) D. Liu and A. Lei, Chem. – Asian J., 2015, 10,
see the ESI.†
806–823; (b) Y. Wu, Y. Yang, Y. Qi, S. Du, Y. Zhang,
L. Ding and Y. Zhao, Tetrahedron Lett., 2018, 59, 4216–
4220.
16 W. K. Luo, X. Shi, W. Zhou and L. Yang, Org. Lett., 2016, 18,
2036–2039.
5126 | Org. Biomol. Chem., 2021, 19, 5121–5126
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