C-H amination of purine derivatives via radical oxidative coupling

Article abstract of DOI:10.1021/acs.joc.8b00066

An oxidative coupling reaction between purines and alkyl ethers/benzyl compounds was developed to synthesize a series of N9 alkylated purine derivatives using n-Bu₄NI as a catalyst and t-BuOOH as an oxidant. This protocol uses commercially available, inexpensive catalysts and oxidants and has a wide range of substrates with a simple operation.

Full text of DOI:10.1021/acs.joc.8b00066

Subscriber access provided by - Access paid by the | UCSB Libraries
C-H Amination of Purine Derivatives via Radical Oxidative Coupling
Zheng Luo, Ziyang Jiang, Wei Jiang, and Dongen Lin
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 06 Mar 2018
Downloaded from http://pubs.acs.org on March 6, 2018
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a service to the research community to expedite the dissemination
of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in
full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully
peer reviewed, but should not be considered the official version of record. They are citable by the
Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore,
the “Just Accepted” Web site may not include all articles that will be published in the journal. After
a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web
site and published as an ASAP article. Note that technical editing may introduce minor changes
to the manuscript text and/or graphics which could affect content, and all legal disclaimers and
ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or
consequences arising from the use of information contained in these “Just Accepted” manuscripts.
is published by the American Chemical Society. 1155 Sixteenth Street N.W.,
Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
C-H Amination of Purine Derivatives via Radical Oxidative Coupling
7
8
Zheng Luo, Ziyang Jiang, Wei Jiang, Dongen Lin*
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou
510640, People’s Republic of China
eꢀmail: denlin@scut.edu.cn
ABSTRACT: An oxidative coupling reaction between purines and alkyl ethers/benzyl compounds was
developed to synthesize a series of Nꢀ9 alkylated purine derivatives using nꢀBu4NI as a catalyst and
tꢀBuOOH as an oxidant. This protocol uses commercially available, inexpensive catalysts and oxidants,
and has a wide range of substrates with simple operation.
Introduction
The purine ring skeleton, a basic framework for many biologically important compounds, is actively
investigated in biological and pharmaceutical chemistry. The purine pharmacophore is found in many
antiviral and antitumor drug molecules.1 Therefore, the synthesis of nucleoside drug molecules and the
further modification of a diverse range of purines and nucleosides with potential pharmaceutical
activity has attracted the interest of synthetic chemists. For example, substitution at the N9 of purine by
pentose rings and alkyl derivatives via a CꢀN glycosidic linkage, affords nonꢀnatural nucleosides,
which can interfere with the expression of viral genes and obstruct tumor cell replication.2 Many
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 27
1
2
3
4
5
6
7
8
9
modified or functionalized purine nucleosides exhibit important effect in the aspect of biological
medicine including the antivirals, Aciclovir and Penciclovir, and anticancer agents, Fludarabine and
Cladribine.3 9ꢀ (Tetrahydrofuryl)adenine (9ꢀTHFꢀAde) is an inhibitor of adenylyl cyclase (Figure 1).4
Figure 1. Nucleosideꢀbased bioactive compounds
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
The synthesis of purine nucleoside derivatives has always been an important research topic in
organic chemistry due to its marvelous bioꢀand pharmacological activities. Traditionally, Nꢀalkylation
of purines are realized by nucleophilic substitution of alkylating agents, such as halogenated
compounds, mesylate or tosylate.5 Although these alkylating partners have proven to be efficient, they
often need multistep preꢀsynthesis, which leads to a lower atom economy and limited application. For
example, 9ꢀTHFꢀAde was obtained through 4 steps using adenine and 1,4ꢀdichloroꢀ2ꢀbutyne as starting
material.6 The reaction steps are rather tedious.
Developing a simple and convenient route to synthesize purine derivates, will help people synthesize
drugs containing the purine skeleton, and provide a protocol to obtain purine structures with potential
medicinal application. In the past decades, CꢀN bond formations via crossꢀdehydrogenative coupling of
CꢀH and NꢀH bonds have been developed under transition metal catalyzed conditions.7 However,
heavy metal residues in pharmaceutical products and its impact on health have caused public concern.
Therefore, metalꢀfree catalysts have received significant attention.
2
ACS Paragon Plus Environment

Page 3 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
In recent years, with the rapid developments of free radical chemistry, radical oxidative coupling
reactions have emerged as a powerful tool in organic synthesis.8 Remarkably, iodide ions can catalyze
the radical oxidative coupling reactions.9 Many groups have reported the CꢀN formation of the azole
compounds via radical oxidative coupling reaction.10 Moreover, substituents such as amino could be
tolerated under certain radical oxidative coupling conditions.11
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Hence, the application of the radical oxidative coupling strategy in the study of purine derivatives
has attracted much attention by organic chemists. For example, in 2011, Guo’s group reported an
efficient and elegant synthesis of Nꢀ9 alkylated purine derivatives using a DIB/I2 catalyzed reaction via
an intermolecular hydrogen abstraction reaction between the purine ring and an alkyl ether.12 In 2013,
Liu’s group discovered a novel route to Nꢀalkoxyalkylated nucleobases by the direct coupling of
saturated ethers employing a copper catalyst regulated by the ligand 2,2'ꢀbipyridine.13 Both of them
synthesized a series of purine N9 alkylated derivatives with good yield. Despite the undisputable
advances in these papers, there is no mention that the natural purines, such as adenine, could be applied
into their catalyzed system to provide the corresponding Nꢀ9 alkylated products. In these two reports,
adenine’s –NH2 was protected by BOC. Therefore, development of a novel protocol to alkylate purine
derivatives is necessary. Based on the literature9,10 and our previous work,14 we proposed that radical
oxidative coupling with iodide ions as a catalyst could be an efficient way to synthesize purine
derivatives containing nonꢀprotected functional groups. Herein, we report a novel method for the
metalꢀfree amination of alkyl ethers or benzyl compounds to form 9ꢀalkylpurine derivatives by using
nꢀBu4NI as the catalyst and tꢀBuOOH as the affordable and nontoxic oxidant (Scheme 1).
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 27
1
2
3
4
Scheme 1. Previous and present approaches for the alkylation of 9Hꢀpurine derivatives
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Results and Discussion
We initially investigated the oxidative coupling reaction between commercially available
6ꢀchloropurine and tetrahydrofuran (THF) under various catalytic conditions. Purines when treated
o
with tetrahydrofuran in the presence of nꢀBu4NI (20%) and TBHP in aqueous (3 equiv.) at 80 C
produced the desired product in 68% yield (Table 1, entry 1). Encouraged by this result, we examined
different organic catalysts. Substituting nꢀBu4NI with nꢀBu4NBr or nꢀBu4NCl gave unsatisfactory
results (entries 2 and 3). Other iodine catalysts, KI and I2 when used instead of nꢀBu4NI, afforded,
respectively, (61%) and (4%) yields (entries 4 and 5). Further optimization showed that a lower yield
was obtained by reducing the catalyst amount to 5 or 10 mol% (entry 6 or 7). The use of other oxidants,
K2S2O8, diꢀtertꢀbutyl peroxide (DTBP) and 2, 3ꢀdichloroꢀ5, 6ꢀdicyanoꢀ1, 4ꢀbenzequinone (DDQ), was
completely unproductive (entries 8ꢀ11). Moreover, increasing the quantity of oxidant TBHP from 3 to
5 equiv., reduced the yield slightly to 66% (entry 12). A much lower yield was obtained when 8 equiv.
4
ACS Paragon Plus Environment

Page 5 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
of TBHP was used (entry 13). A cooperative combination of oxidant (TBHP) and catalyst (nꢀBu4NI ) is
essential for the success of this method, as the reaction failed in the absence of either of them (entries
7
8
9
o
o
14 and 15). When the reaction was performed at 70 oC, 90 C and 100 C, the desired products were
isolated in 60% , 82% and 50% yield (entries 16ꢀ18). THF served the dual role of a reactant and solvent.
Decreasing the quantity of the solvent, reduced the yield of product (entries 19 and 20). On the basis of
the above results, the best oxidative coupling conditions involved 4 mmol THF, 20 mol% nꢀBu4NI, and
3 equiv. TBHP at 90 oC.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1. Optimization of the Reaction Parametersa
entry
1
cat.( mol% )
nꢀBu4NI ( 20 )
nꢀBu4NCI ( 20 )
nꢀBu4NBr ( 20 )
KI (20 )
oxidantb ( equiv.. )
TBHP ( 3 )
TBHP ( 3 )
TBHP ( 3 )
TBHP ( 3 )
TBHP ( 3 )
TBHP ( 3 )
TBHP ( 3 )
K2S2O8( 3 )
DDQ ( 3 )
t(oC)
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
70
90
100
90
90
yield(%)c
68
0
2
3
0
4
61
<5
56
52
0
5
I2 ( 20 )
6
nꢀBu4NI ( 5 )
nꢀBu4NI ( 10 )
nꢀBu4NI ( 20 )
nꢀBu4NI ( 20 )
nꢀBu4NI ( 20 )
nꢀBu4NI ( 20 )
nꢀBu4NI ( 20 )
nꢀBu4NI ( 20 )
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
7
8
9
0
10
11
12
13
14
15
16
17
18
19d
20e
H2O2 ( 3 )
0
DTBP ( 3 )
TBHP ( 5 )
TBHP ( 8 )
TBHP ( 3 )
ꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀꢀ
0
66
40
<5
0
nꢀBu4NI ( 20 )
nꢀBu4NI ( 20 )
n-Bu4NI ( 20 )
nꢀBu4NI ( 20 )
nꢀBu4NI ( 20 )
nꢀBu4NI ( 20 )
TBHP ( 3 )
TBHP ( 3 )
TBHP ( 3 )
TBHP ( 3 )
60
82
50
45
62
TBHP ( 3 )
aReaction conditions: 1a (0.2 mmol), 2a (4 mmol), 90 C, 12 h, air. TBHP (70% in water), H2O2 (30% in
water), DTBP ( 98%). cIsolated yield. d2a (2 mmol). e2a (3 mmol).
o
b
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 27
1
2
3
4
5
6
7
8
9
With the optimized conditions in hand (Table 1, entry 17), we investigated the scope of this
oxidative coupling by reacting THF with a series of purines. As shown in Scheme 2, purine rings
bearing halide substituents (2ꢀF, 2ꢀCl and 2ꢀBr) all formed the corresponding purine products with
good yields (3b-3d, 80ꢀ87%). Purine rings substituted at the 6 position with electronꢀdonating groups
(ꢀOMe，ꢀNEt2, ꢀNBoc2) afforded moderate yields (3h, 3j-3k, 71ꢀ81%). Even the easily oxidized
methylthio group could be tolerated under the oxidative conditions (3e-3g, 84ꢀ89%). It is worth
mentioning that adenine, one of the natural purines, can also be used in these reaction conditions
yielding the desired product (3i, 86%). Gratifyingly, this direct oxidative coupling reaction occurred on
the N9 position of the purines, rarely on N7 or other functional groups of the purine, suggesting
excellent regioselectivity.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Next, scope studies were carried out between 6ꢀchloropurine and various ethers under the optimized
conditions. We noticed that both cyclic and chain ethers were suitable reaction substrates for this
transformation (3l-3p, 30ꢀ83%). It worth noting that the oxidative coupling reaction of
dimethoxyethane and 6ꢀchloropurine gave the coupled products in a separable regioisomeric mixture
with a total yield of 71% (3m and 3m'). From the result, we conclude that the secondary carbon is more
reactive than the primary carbon.10a,e
Scheme 2. Substrate Scope of the Purines and Ethers a
6
ACS Paragon Plus Environment

Page 7 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: 1 (0.2 mmol), 2 (4 mmol), TBAI (20 mol%), TBHP (3 equiv.), under air at 90 oC
for 12 h. Isolated yield are shown.
However, the reaction of 6ꢀchloropurine with anisole did not generate the corresponding product. To
our surprise, we obtained the product 5k from the reaction between pꢀmethyl anisole and
6ꢀchloropurine, which occurred at the benzyl site. Subsequently, we studied the scope of various
purines with toluene. As shown in Scheme 3, purine substrates bearing electronꢀdonating groups such
as 6ꢀSMe, 6ꢀOMe and electronꢀwithdrawing groups such as 2ꢀF, 2ꢀCl and 2ꢀBr all could be smoothly
converted to the corresponding products in moderate to good yields (5b-5h, 16ꢀ84%). Even the adenine
with NH2 could be used in the reaction system and generated the corresponding product (5i, 71%). In
addition, the structure of 5k was unambiguously assigned by its single crystal Xꢀray analysis (see SI for
more details).15 However some purine substrates yielded isomers of the desired products under these
oxidative coupling conditions. For example, products 5b and 5b' were obtained in 70% and 16% yield
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 27
1
2
3
4
5
6
when 2ꢀbromoꢀ6ꢀchloroꢀ9Hꢀpurine reacted with toluene. It worth noting that purine without any
substituent afforded isomers of the desired products 5j and 5j' in 52% and 27% yield.
7
8
9
To further explore the potential of our methodology, a variety of benzylic CꢀH bonds of substrates
were investigated. We were delighted to find that toluene derivatives with electronꢀdonating
substituents furnished higher yields of desired products than electronꢀwithdrawing substituents (5k-5n,
71ꢀ85%). Moreover, the coupling reaction proceeded successfully when employing benzylic substrates
with steric hinderance (5o-5p, 79ꢀ84%). However, in the reactions of the 6ꢀchloropurine with
2ꢀmethylpyridine and 2ꢀmethylfuran under the standard conditions, there were no coupling products
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
detected.
Scheme 3. Substrate Scope of the Purines and Aromatic Compoundsa
8
ACS Paragon Plus Environment

Page 9 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Cl
N
Cl
N
Cl
N
Cl
N
Cl
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
N
Cl
Br
Br
F
5d 84%
5a 81%
5b' 16%
5c 83%
5b 70%
S
N
S
N
S
O
N
NH2
N
N
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N
N
N
N
N
N
N
N
N
N
N
N
N
Cl
Br
N
N
5g 74%
5f 75%
5h 69%
5i 71%
5e 78%
Cl
N
N
N
N
N
N
N
N
N
N
OMe
5j 52%
5j' 27%
5k 85%
(5k X-ray)
Cl
N
N
Cl
N
Cl
N
Cl
Cl
N
N
N
N
N
N
N
N
N
N
N
N
Cl
N
N
N
N
Me
Me
Me
I
Br
5o 84%
5p 79%
5n 77%
5l 71%
5m 76%
Cl
N
Cl
N
N
N
N
N
N
N
N
O
5q 0%
5r 0%
aReaction conditions: 1 (0.2 mmol), 4 (4 mmol), TBAI (20 mol%), TBHP (3 equiv.), under air at 90 oC for 12
h. Isolated yield are shown.
In addition, the satisfactory results (78% yield or 72% yield) were obtained when the reaction was
performed on a gramꢀscale. We also conducted the reaction of adenine with THF on a gramꢀscale under
standard reaction conditions, producing 9ꢀTHFꢀAde in 80% yield, suggesting that 9ꢀTHFꢀAde could be
synthesized with no other wasteful byproducts except H2O and tꢀBuOH. It is the first example of a
oneꢀstep synthesis of 9ꢀTHFꢀAde in good yield with unprotected adenine and the readily accessible
starting material THF. It makes the method quite attractive for its economical and environmental
significance (Scheme 4).
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 27
1
2
3
Scheme 4. Gram-scale oxidative coupling reaction
4
5
Cl
Cl
6
7
8
9
N
N
N
O
N
N
n-Bu4NI (1.4 mmol)
N
H
t-BuOOH (21 mmol)
90 °C, 12 h
N
N
O
1a
3a
2a
1.08 g, 7 mmol
10.06 g, 140 mmol
1.22 g, 78%
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Cl
N
N
Cl
N
N
n-Bu4NI (1.4 mmol)
N
t-BuOOH (21 mmol)
90 °C, 12 h
N
N
N
H
1a
4a
5a
12.07 g, 140 mmol
1.08 g, 7 mmol
NH2
1.23 g, 72%
NH2
N
O
n-Bu4NI (2 mmol)
N
N
N
t-BuOOH (30 mmol)
90 °C, 12 h
N
N
N
N
O
H
1i
3i
2a
1.35 g, 10 mmol
14.37 g, 200 mmol
1.64 g, 80%
To elucidate the mechanism of this coupling reactions, several control experiments were carried out.
Initially, when
a
radical inhibitor, BHT (2,6ꢀdiꢀtertꢀbutylꢀ4ꢀmethylphenol) or TEMPO
(2,2,6,6ꢀtetraꢀmethylꢀpiperidineꢀNꢀoxyl) was added into the reaction, the formation of the desired
product was greatly supressed. We detected the radical trapped products by MS, isolated them by flash
chromatography, and obtained the THF−TEMPO and tolueneꢀTEMPO coupled products 6 and 7 in 62%
and 49% yield (Scheme 5). These results indicated that this oxidative coupling reaction involved a
radical pathway. Replacing nꢀBu4NI with I2 gave very little desired product, suggesting that nꢀBu4NI
plays an important role in the reaction. The mechanism of the oxidative coupling reaction has not been
fully explained but a plausible mechanism is proposed based on our above experimental results and
literature reported.10e,16 As shown in Scheme 6, initially, the oxidation of nꢀBu4NI by tꢀBuOOH
generates the tertꢀbutoxyl radical, iodine, and a hydroxyl anion.17 Then, tertꢀbutoxyl radical abstracts
hydrogen atoms from the ethers 2 or benzyl compounds 4 to give radical A and B, which were further
oxidized to an oxonium intermediate C or a benzyl cation D via a single electron transfer process.9e,16a,c
10
ACS Paragon Plus Environment

Page 11 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Next, purines 1 is deprotonated by the hydroxyl anion to provide anionic species E,16a Finally, the
nucleophilic reaction of purine E with the oxonium intermediate C and the benzyl cation D forms the
corresponding desired product 3 or 5.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 5. Coupling in the Presence of a Freeꢀradical Scavenger
Scheme 6. Proposed Reaction Mechanism
Conclusions
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 27
1
2
3
4
5
6
7
8
9
In conclusion, an nꢀBu4NIꢀcatalyzed direct oxidative coupling reaction of alkyl ethers and benzyl
compounds with purine derivatives has been developed. The reactions of substrates containing various
functional groups proceeded smoothly to give the desired products in moderate to good yield. This
protocol provides an efficient and green way for the preparation of compounds containing the purine
ring structural unit. These compounds have potential in biological and pharmaceutical application.
Further investigations to study the synthetic utility of this reaction are currently in progress.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental Section
General Information. All reactions were carried out in flameꢀdried sealed tubes with magnetic
stirring under an air atmosphere unless otherwise noted. All alkyl ethers and benzyl compounds were
purchased from commercial suppliers and used without further purification, unless otherwise stated. C6
substituted purines were synthesized from 6ꢀchloropurine according to Huang’s method.18 C2 and C6
substituted purines were synthesized from 2ꢀamidoꢀ6ꢀchloropurine according to Hu’s method.19
Purifications of reaction products were carried out by flash chromatography using Qingdao Haiyang
Chemical Co. Ltd silica gel (300ꢀ400 mesh). Infrared spectra (IR) were recorded on a Brucker
TENSOR 27 FTIR spectrophotometer and are reported as wave number (cmꢀ1). Infrared spectra were
recorded by preparing a KBr pellet containing the title compound. 1H, 13C, 19F NMR spectra were
1
recorded on 400 MHz, 100 MHz and 376 MHz spectrometer, respectively. H NMR and 13C NMR
chemical shifts were determined relative to internal standard TMS at δ 0.0 and 19F NMR chemical
shifts were determined relative to CFCl3 as external standard. Chemical shifts (δ) are reported in ppm,
and coupling constants (J) are in Hertz (Hz). Splitting patterns are designated as singlet (s), broad
singlet (bs), doublet (d), triplet (t). Splitting patterns that could not be interpreted or easily visualized
12
ACS Paragon Plus Environment

Page 13 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
are designated as multiple (m). High resolution mass spectra (HRMS) were recorded on an IFꢀTOF
spectrometer (Micromass). Crystal data were obtained by employing graphite monochromated Mo ꢀ Kα
radiation (λ = 1.54178 Å) at 293(2) K and operating in the φꢀω scan mode. The structure was solved by
direct methods SHELXSꢀ97.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
General Procedure for the direct alkylation of purines. Purine substrates 1 (0.2 mmol), TBAI
(0.04 mmol, 14.77 mg), dried ethers 2 or benzyl compounds 4 (4 mmol) and TBHP (0.6mmol, 70% in
o
water) were successively added into a sealed tube. The reaction mixture was stirred at 90 C for 12
hours. After completion of reaction，the reaction tube was allowed to cool to room temperature and
quenched by the addition of a saturated solution of sodium bisulfite (3 mL). The mixture was extracted
with ethyl acetate (3×8 mL), the combined organic phases were dried over anhydrous Na2SO4 and
evaporated under vacuum. The crude product was then purified by flash column chromatography on
silica gel to afford the desired product 3 or 5.
6ꢀchloroꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3a. The product 3a was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a yellow solid (36.7 mg, 82% yield). H NMR
(400 MHz, CDCl3) δ 8.66 (s, 1H), 8.19 (s, 1H), 6.29 (dd, J=6.2, 3.0, 1H), 4.24 (dd, J=14.6, 6.8, 1H),
4.03 (q, J=7.6, 1H), 2.60 – 2.44 (m, 2H), 2.17 – 2.07 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 151.8,
151.0, 150.9, 143.4, 132.4, 86.6, 70.0, 32.5, 24.2. HRMS (ESI) calcd for [M + Na]+: C9H9ClN4NaO:
247.0357, found: 247.0359.
2ꢀbromoꢀ6ꢀchloroꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3b. The product 3b was purified with silica
gel chromatography (petroleum ether/ethyl acetate=3:1) as a light yellow solid (51.2 mg, 85% yield).
1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 6.29 (t, J = 4.7 Hz, 1H), 4.29 (dd, J = 13.9, 7.5 Hz, 1H),
4.07 (dd, J = 15.7, 7.6 Hz, 1H), 2.56 – 2.51 (m, 2H), 2.18 – 2.12 (m, 2H); 13C NMR (100 MHz, CDCl3)
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 27
1
2
3
4
5
6
δ 152.0, 151.4, 143.8, 142.9, 131.9, 86.8, 70.1, 32.7, 24.2. HRMS (ESI) calcd for [M + Na]+:
C9H8BrClN4NaO: 324.9462, found: 324.9460.
7
8
9
2,6ꢀdichloroꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3c. The product 3c was purified with silica gel
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
chromatography (petroleum ether/ethyl acetate=3:1) as a light yellow solid (41.4 mg, 80% yield). H
NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 6.29 (t, J = 4.7 Hz, 1H), 4.29 (dd, J = 13.9, 7.5 Hz, 1H), 4.07
(dd, J = 15.7, 7.6 Hz, 1H), 2.56 – 2.51 (m, 2H), 2.18 – 2.11 (m, 2H); 13C NMR (100 MHz, CDCl3) δ
152.8, 152.1, 151.7, 144.0, 131.5, 86.8, 70.1, 32.7, 24.1. HRMS (ESI) calcd for [M + Na]+:
C9H8Cl2N4NaO: 280.9967, found: 280.9964.
6ꢀchloroꢀ2ꢀfluoroꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3d. The product 3d was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a white liquid (42.1 mg, 87% yield). H NMR
(400 MHz, CDCl3) δ 8.22 (s, 1H), 6.33 – 6.27 (m, 1H), 4.32 (dd, J = 14.7, 6.7 Hz, 1H), 4.10 (dd, J =
15.8, 7.5 Hz, 1H), 2.61 – 2.53 (m, 2H), 2.23 – 2.16 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 157.0 (d, J
= 218 Hz), 152.7 (d, J = 10 Hz), 152.5 (d, J = 9 Hz), 144.1 (d, J = 3 Hz), 131.1 (d, J = 5 Hz), 86.8, 70.1,
32.5, 24.2; 19F NMR (376 MHz, CDCl3) δ ꢀ49.3. HR-MS (ESI) calcd for [M + Na]+: C9H8ClFN4NaO:
265.0263, found: 265.0270.
6ꢀ(methylthio)ꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3e. The product 3e was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a yellow solid (39.7 mg, 84% yield). H NMR
(400 MHz, CDCl3) δ 8.71 (s, 1H), 8.06 (s, 1H), 6.32 (dd, J = 6.4, 3.1 Hz, 1H), 4.28 (dd, J = 14.8, 6.6
Hz, 1H), 4.07 (dd, J = 15.6, 7.4 Hz, 1H), 2.72 (s, 3H), 2.57 – 2.46 (m, 2H), 2.18 – 2.11 (m, 2H); 13C
NMR (100 MHz, CDCl3) δ 161.6, 151.8, 147.4, 140.6, 132.1, 86.1, 69.7, 32.4, 24.3, 11.7. HRMS (ESI)
calcd for [M + H]+: C10H13N4OS: 237.0805, found:237.0803.
2ꢀchloroꢀ6ꢀ(methylthio)ꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3f. The product 3f was purified with
14
ACS Paragon Plus Environment

Page 15 of 27
The Journal of Organic Chemistry
1
2
3
4
silica gel chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (48.2 mg, 89% yield).
5
6
1
Mp 113ꢀ115 oC. H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 6.30 – 6.26 (m, 1H), 4.28 (dd, J = 14.9,
7
8
9
6.5 Hz, 1H), 4.07 (dd, J = 15.7, 7.5 Hz, 1H), 2.72 (s, 3H), 2.54 – 2.49 (m, 2H), 2.17 – 2.12 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 163.8, 153.5, 148.8, 141.1, 131.0, 86.2, 69.9, 32.7, 24.2, 12.1. HRMS
(ESI) calcd for [M + Na]+: C10H11ClN4NaOS: 293.0234, found: 293.0238. IR (KBr): 3131, 2903, 1698,
1555, 1480, 1389, 1319, 1211, 1079, 794 cmꢀ1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
2ꢀbromoꢀ6ꢀ(methylthio)ꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3g. The product 3g was purified with
silica gel chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (53.6 mg, 85% yield).
Mp 253ꢀ254 oC. 1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 6.28 (t, J = 4.7 Hz, 1H), 4.28 (dd, J = 14.8,
6.5 Hz, 1H), 4.07 (dd, J = 15.7, 7.6 Hz, 1H), 2.72 (s, 3H), 2.54 – 2.50 (m, 2H), 2.18 – 2.12 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 163.8, 148.7, 144.1, 140.9, 131.4, 86.2, 69.9, 32.7, 24.2, 12.1. HR-MS
(ESI) calcd for [M + Na]+: C10H11BrN4NaOS: 336.9729, found: 336.9730. IR (KBr): 3133, 2904, 1658,
1523, 1443, 1379, 1309, 1109, 1068, 673 cmꢀ1.
6ꢀmethoxyꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3h. The product 3h was purified with silica gel
chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (33.5 mg, 76% yield). Mp
170ꢀ172 oC. 1H NMR (400 MHz, CDCl3) δ 8.46 (s, 1H), 7.96 (s, 1H), 6.29 – 6.24 (m, 1H), 4.21 (dd, J
= 14.2, 7.2 Hz, 1H), 4.11 (s, 3H), 4.00 (dd, J = 15.6, 7.4 Hz, 1H), 2.51 – 2.42 (m, 2H), 2.14 – 2.03 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 161.0, 152.0, 151.2, 140.2, 122.2, 86.0, 69.7, 54.2, 32.4, 24.3.
HR-MS (ESI) calcd for [M + Na]+: C10H12N4NaO2: 243.0852, found: 243.0856. IR (KBr): 3224, 3130,
2904, 1600, 1560, 1434, 1343, 1201, 1106 cmꢀ1.
9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀadenine 3i. The product 3i was purified with silica gel chromatography
(petroleum ether/ethyl acetate/ammonium hydroxide=15:5:1) as a yellow solid (35.2 mg, 86% yield).
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 27
1
2
3
4
5
6
7
8
9
1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.85 (s, 1H), 6.23 (dd, J = 6.3, 3.1 Hz, 1H), 5.91 (s, 2H),
4.21 (dd, J = 14.6, 6.6 Hz, 1H), 3.99 (dd, J = 15.5, 7.5 Hz, 1H), 2.51 – 2.36 (m, 2H), 2.09 – 2.03 (m,
2H); 13C NMR (100 MHz, CDCl3) δ 155.5, 153.0, 149.3, 138.5, 120.3, 85.9, 69.6, 32.5, 24.3. HR-MS
(ESI) calcd for [M + H]+: C9H12N5O: 206.1036, found: 206.1037.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N, Nꢀdiethylꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurinꢀ6ꢀamine 3j. The product 3j was purified with silica
gel chromatography (petroleum ether/ethyl acetate/ammonium hydroxide=15:5:1) as a light yellow
1
liquid (37.1 mg, 71% yield). H NMR (400 MHz, CDCl3) δ 8.25 (s, 1H), 7.75 (s, 1H), 6.25 – 6.20 (m,
1H), 4.18 (dd, J = 14.8, 6.5 Hz, 1H), 3.99 – 3.92 (m, 5H), 2.45 – 2.37 (m, 2H), 2.07 – 2.00 (m, 2H),
1.21 (t, J = 7.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 153.6, 152.4, 149.7, 136.0, 120.1, 85.4, 69.4,
42.9, 32.3, 24.2, 13.5. HRMS (ESI) calcd for [M + H]+: C13H20N5O: 262.1662, found: 262.1666. IR
(KBr): 3208, 3126, 2930, 1676, 1588, 1449, 1384, 1285, 1070 cmꢀ1.
2ꢀ(diꢀtꢀbutyloxycarbonylamino)ꢀ6ꢀchloroꢀ9ꢀ(tetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3k. The product 3k
was purified with silica gel chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (71.3
mg, 81% yield). 1H NMR (400 MHz, CDCl3) δ 8.18 (s, 1H), 6.23 (dd, J = 6.4, 3.1 Hz, 1H), 4.22 (dd, J
= 14.9, 6.5 Hz, 1H), 4.01 (dd, J = 15.7, 7.4 Hz, 1H), 2.54 – 2.40 (m, 2H), 2.12 – 2.04 (m, 2H), 1.38 (s,
18H); 13C NMR (100 MHz, CDCl3) δ 151.7, 151.6, 151.1, 150.6, 144.3, 130.7, 86.8, 83.6, 70.0, 32.5,
27.9, 24.2. HR-MS (ESI) calcd for [M + Na]+: C19H26ClN5NaO5: 462.1515, found: 462.1524.
6ꢀchloroꢀ9ꢀ(1,4ꢀdioxanꢀ2ꢀyl)ꢀ9Hꢀpurine 3l. The product 3l was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (36.1 mg, 75% yield). H NMR
(400 MHz, CDCl3) δ 8.69 (s, 1H), 8.48 (s, 1H), 5.98 (dd, J = 5.2, 2.9 Hz, 1H), 4.15 (dd, J = 12.0, 2.7
Hz, 1H), 4.04 (dd, J = 12.0, 5.5 Hz, 1H), 3.87 – 3.80 (m, 4H). 13C NMR (100 MHz, CDCl3) δ 152.3,
151.5, 151.3, 143.8, 131.5, 77.7, 68.3, 66.3, 64.2. HR-MS (ESI) calcd for [M + Na]+: C9H9ClN4NaO2:
16
ACS Paragon Plus Environment

Page 17 of 27
The Journal of Organic Chemistry
1
2
3
4
263.0306, found: 263.0307.
5
6
7
8
9
6ꢀchloroꢀ9ꢀ(1,2ꢀdimethoxyethyl)ꢀ9Hꢀpurine 3m. The product 3m was purified with silica gel
chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (19.8 mg, 41% yield). Mp 62ꢀ63
oC. 1H NMR (400 MHz, CDCl3) δ 8.74 (s, 1H), 8.36 (s, 1H), 5.88 (t, J = 4.7 Hz, 1H), 3.90 (dd, J = 10.5,
5.1 Hz, 1H), 3.80 (dd, J = 10.5, 4.2 Hz, 1H), 3.36 (d, J = 11.1 Hz, 6H). 13C NMR (100 MHz, CDCl3) δ
152.2, 152.1, 151.2, 143.9, 131.5, 84.6, 72.8, 59.7, 57.3. HRMS (ESI) calcd for [M + Na]+:
C9H11ClN4NaO2: 265.0463, found: 265.0466. IR (KBr): 3123, 3112, 2916, 1648, 1592, 1453, 1393,
1223, 1108, 729 cmꢀ1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
6ꢀchloroꢀ9ꢀ((2ꢀmethoxyethoxy) methyl)ꢀ9Hꢀpurine 3m'. The product 3m' was purified with silica
gel chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (14.5 mg, 30% yield). Mp
1
54ꢀ56 oC. H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.23 (s, 1H), 5.69 (s, 2H), 3.68 – 3.63 (m, 2H),
3.47 – 3.43 (m, 2H), 3.27 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 152.5, 152.1, 151.4, 145.3, 131.5,
73.6, 71.5, 69.4, 59.1. HRMS (ESI) calcd for [M + Na]+: C9H11ClN4NaO2: 265.0463, found: 265.0459.
IR (KBr): 3214, 3068, 2927, 1623, 1562, 1438, 1379, 1212, 1100, 754 cmꢀ1.
9ꢀ(tertꢀbutoxymethyl)ꢀ6ꢀchloroꢀ9Hꢀpurine 3n. The product 3n was purified with silica gel
chromatography (petroleum ether/ethyl acetate=3:1) as a yellow solid (40.0 mg, 83% yield). Mp 63ꢀ64
oC. 1H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 8.27 (s, 1H), 5.64 (s, 2H), 1.18 (s, 9H). 13CNMR (100
MHz, CDCl3) δ 152.0, 151.2, 150.8, 145.3, 131.4, 76.2, 67.5, 27.7. HR-MS (ESI) calcd for [M + Na]+:
C10H13ClN4NaO: 263.0670, found: 263.0672. IR (KBr): 3136, 3014, 2879, 1639, 1573, 1462, 1365,
1238, 1100, 648 cmꢀ1.
6ꢀchloroꢀ9ꢀ(5ꢀmethyltetrahydrofuranꢀ2ꢀyl)ꢀ9Hꢀpurine 3o. The product 3o was purified with silica gel
chromatography (petroleum ether/ethyl acetate=3:1) as a yellow solid (33.4 mg, 70% yield), a mixture
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 27
1
2
3
4
5
6
7
8
9
1
of two diastereomers (dr=1:1). H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H), 8.30 (s, 0.5H), 8.24 (s,
0.5H), 6.36 (s, 0.5H), 6.30 (s, 0.5H), 4.66 – 4.57 (m, 0.5H), 4.40 – 4.27 (m, 0.5H), 2.68– 2.61 (m, 1H),
2.57 – 2.54 (m, 1H), 2.31 (dd, J = 12.8, 6.5 Hz, 0.5H), 2.21 (dd, J = 10.0, 4.7 Hz, 0.5H), 1.80 – 1.71 (m,
1H), 1.44 (d, J = 5.9 Hz, 1.5H), 1.33 (d, J = 5.9 Hz, 1.5H); 13CNMR (100 MHz, CDCl3) δ 151.8, 151.8,
151.0, 150.9, 150.9, 150.8, 143.6, 143.4, 132.4, 132.4, 86.5, 86.2, 78.7, 77.7, 33.4, 32.3, 31.8, 31.4,
20.9, 20.7. HR-MS (ESI) calcd for [M + Na]+: C10H11ClN4NaO: 261.0514, found: 261.0518.
6ꢀchloroꢀ9ꢀ(tetrahydroꢀ2Hꢀpyranꢀ2ꢀyl)ꢀ9Hꢀpurine 3p. The product 3p was purified with silica gel
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
chromatography (petroleum ether/ethyl acetate=3:1) as a green solid (37.7 mg, 79% yield). H NMR
(400 MHz, CDCl3) δ 8.67 (s, 1H), 8.28 (s, 1H), 5.72 (dd, J = 10.4, 2.4 Hz, 1H), 4.12 (dd, J = 12.7, 2.7
Hz, 1H), 3.72 (dd, J = 11.5, 8.8 Hz, 1H), 2.14 – 2.00 (m, 3H), 1.76 – 1.59 (m, 3H); 13C NMR (100
MHz, CDCl3) δ 152.0, 151.1, 151.0, 143.1, 131.7, 82.6, 68.9, 31.8, 24.8, 22.6. HRMS (ESI) calcd for
[M + Na]+: C10H11ClN4NaO: 261.0514, found: 261.0513.
9ꢀbenzylꢀ6ꢀchloroꢀ9Hꢀpurine 5a. The product 5a was purified with silica gel chromatography
(petroleum ether/ethyl acetate=3:1) as a white solid (39.6 mg, 81% yield). 1H NMR (400 MHz, CDCl3)
δ 8.53 (s, 1H), 8.07 (s, 1H), 7.13 – 7.05 (m, 5H), 5.29 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 151.9,
151.8, 150.6, 145.4, 134.6, 131.3, 129.0, 128.5, 127.8, 47.7. HRMS (ESI) calcd for [M + Na]+:
C12H9ClN4Na: 267.0408, found: 267.0412.
9ꢀbenzylꢀ2ꢀbromoꢀ6ꢀchloroꢀ9Hꢀpurine 5b. The product 5b was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (39.mg, 70% yield). H NMR
(400 MHz, CDCl3) δ 7.95 (s, 1H), 7.32 – 7.22 (m, 5H), 5.34 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
153.1, 151.6, 145.4, 143.3, 134.0, 131.0, 129.4, 129.1, 128.1, 48.1. HRMS (ESI) calcd for [M + Na]+:
C12H8BrClN4Na: 344.9513, found: 344.9519.
18
ACS Paragon Plus Environment

Page 19 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
7ꢀbenzylꢀꢀ2ꢀbromoꢀ6ꢀchloroꢀ7Hꢀpurine 5b'. The product 5b' was purified with silica gel
chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (8.9mg, 16% yield). Mp 145ꢀ148
7
8
9
1
oC. H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.41 (dd, J = 5.1, 2.0 Hz, 3H), 7.20 – 7.17 (m, 2H),
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
5.68 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 163.6, 150.2, 143.6, 143.5, 134.1, 129.5, 129.1, 127.1,
122.2, 50.9. HRMS (ESI) calcd for [M + Na]+: C12H8BrClN4Na: 344.9513, found: 344.9514. IR
(KBr): 3105, 2924, 1646, 1599, 1528, 1476, 1453, 1169, 796, 744, 703, 626 cmꢀ1.
9ꢀbenzylꢀ2,6ꢀdichloroꢀ9Hꢀpurine 5c. The product 5c was purified with silica gel chromatography
1
(petroleum ether/ethyl acetate=3:1) as a white solid (53.7 mg, 83% yield). H NMR (400 MHz, CDCl3)
δ 8.07 (s, 1H), 7.42 – 7.31 (m, 5H), 5.43 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 153.2, 153.2, 151.9,
145.6, 134.0, 130.7, 129.4, 129.1, 128.1, 48.1; HRMS (ESI) calcd for [M + Na]+: C12H8Cl2N4Na:
301.0018, found: 301.0014.
9ꢀbenzylꢀ6ꢀchloroꢀ2ꢀfluoroꢀ9Hꢀpurine 5d. The product 5d was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a white liquid (44 mg, 84% yield). H NMR
(400 MHz, CDCl3) δ 8.00 (s, 1H), 7.32 – 7.22 (m, 5H), 5.31 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
157.4 (d, J = 219 Hz), 153.7 (d, J = 17Hz), 152.8 (d, J = 18Hz), 145.6 (d, J = 3Hz), 134.0, 130.2 (d, J =
5Hz), 129.4, 129.1, 128.1, 48.1; 13F NMR (376 MHz, CDCl3) δ ꢀ49.2. HRMS (ESI) calcd for [M +
Na]+: C12H8ClFN4Na: 285.0314, found: 285.0312.
9ꢀbenzylꢀ6ꢀ(methylthio)ꢀ9Hꢀpurine 5e. The product 5e was purified with silica gel chromatography
1
(petroleum ether/ethyl acetate=3:1) as a light yellow solid (40.0 mg, 78% yield). H NMR (400 MHz,
CDCl3) δ 8.78 (s, 1H), 7.95 (s, 1H), 7.37 – 7.28 (m, 5H), 5.43 (s, 2H), 2.75 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 161.8, 152.2, 148.4, 142.4, 135.2, 131.3, 129.1, 128.6, 127.8, 47.4, 11.8. HRMS (ESI)
calcd for [M + Na]+: C13H12N4NaS: 279.0675, found: 279.0678.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 27
1
2
3
4
5
6
7
8
9
9ꢀbenzylꢀ2ꢀchloroꢀ6ꢀ(methylthio)ꢀ9Hꢀpurine 5f. The product 5f was purified with silica gel
chromatography (petroleum ether/ethyl acetate=3:1) as a yellow solid (43.6 mg, 75% yield). Mp
118ꢀ119 oC. 1H NMR (400 MHz, CDCl3) δ 7.79 (s, 1H), 7.28 – 7.19 (m, 5H), 5.28 (s, 2H), 2.64 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 164.0, 153.9, 149.8, 142.8, 134.7, 130.2, 129.2, 128.7, 128.0, 47.5,
12.1. HRMS (ESI) calcd for [M + Na]+: C13H11ClN4NaS: 313.0285, found: 313.0287. IR (KBr): 3099,
2924, 1634, 1579, 1490, 1426, 1409 , 1381, 1235, 1150, 803, 765, 707 cmꢀ1.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9ꢀbenzylꢀ2ꢀbromoꢀ6ꢀ(methylthio)ꢀ9Hꢀpurine 5g. The product 5g was purified with silica gel
chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (49.43 mg, 74% yield). Mp
130ꢀ133 oC. 1H NMR (400 MHz, CDCl3) δ 7.85 (s, 1H), 7.39 – 7.28 (m, 5H), 5.38 (s, 2H), 2.74 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 163.9, 149.8, 144.5, 142.6, 134.7, 130.6, 129.2, 128.8, 128.0, 47.5,
12.2. HRMS (ESI) calcd for [M + Na]+: C13H11N4BrNaS: 356.9780, found: 356.9784. IR (KBr): 3098,
2923, 1642, 1571, 1494, 1454, 1409 , 1378, 1144, 1079, 744, 705, 665 cmꢀ1
9ꢀbenzylꢀ6ꢀ(methoxy)ꢀ9Hꢀpurine 5h. The product 5h was purified with silica gel chromatography
1
(petroleum ether/ethyl acetate=3:1) as a light yellow solid (33.1 mg, 69% yield). H NMR (400 MHz,
CDCl3) δ 8.60 (s, 1H), 7.92 (s, 1H), 7.41 – 7.28 (m, 5H), 5.44 (s, 2H), 4.22 (s, 3H). 13C NMR (100
MHz, CDCl3) δ 161.1, 153.8, 152.3, 142.0, 135.2, 129.1, 128.6, 127.8, 121.4, 54.3, 47.5. HRMS (ESI)
calcd for [M + H]+: C13H13N4O: 241.1084, found: 241.1088.
9ꢀbenzylꢀ9Hꢀadenine 5i. The product 5i was purified with silica gel chromatography (petroleum
ether/ethyl acetate/ammonium hydroxide=15:5:1) as a white solid (31.9 mg, 71% yield). 1H NMR (400
MHz, DMSOꢀd6) δ 8.25 (s, 1H), 8.15 (s, 1H), 7.35 – 7.22 (m, 7H), 5.37 (s, 2H). 13C NMR (100 MHz,
DMSOꢀd6) δ 156.5, 153.1, 150.0, 141.3, 137.6, 129.1, 128.2, 128.0, 119.1, 46.6. HRMS (ESI) calcd
for [M + H]+: C12H12N5: 226.1087, found: 226.1085.
20
ACS Paragon Plus Environment

Page 21 of 27
The Journal of Organic Chemistry
1
2
3
4
9ꢀbenzylꢀ9Hꢀpurine 5j. The product 5j was purified with silica gel chromatography (petroleum
5
6
1
ether/ethyl acetate=3:1) as a white solid (21.8 mg, 52% yield). H NMR (400 MHz, CDCl3) δ 9.17 (s,
7
8
9
1H), 9.04 (s, 1H), 8.09 (s, 1H), 7.40 – 7.30 (m, 5H), 5.47 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 152.9,
151.5, 148.7, 145.1, 135.0, 134.0, 129.2, 128.7, 127.9, 47.2. HR-MS (ESI) calcd for [M + H]+:
C12H11N4: 211.0978, found: 211.0980.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9ꢀbenzylꢀ9Hꢀpurine 5j'. The product 5j' was purified with silica gel chromatography (petroleum
1
ether/ethyl acetate=3:1) as a white solid (11.3 mg, 27% yield). Mp 123ꢀ124 oC. H NMR (400 MHz,
CDCl3) δ 9.14 (s, 1H), 8.76 (s, 1H), 8.31 (s, 1H), 7.41 (dd, J = 5.1, 1.8 Hz, 3H), 7.27 (dd, J = 7.3, 4.2
Hz, 2H), 5.46 (s, 2H). 13C NMR (100 MHz, CDCl3) δ 161.1, 153.5, 148.0, 140.4, 133.6, 129.5, 129.2,
127.5, 125.3, 50.3. HRMS (ESI) calcd for [M + H]+: C12H11N4: 211.0978, found: 211.0979. IR (KBr):
3105, 2923, 1601, 1554, 1520, 1484, 1448, 1208, 731, 697 cmꢀ1.
6ꢀchloroꢀ9ꢀ(4ꢀmethoxybenzyl)ꢀ9Hꢀpurine 5k. The product 5k was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a white solid (46.7 mg, 85% yield). H NMR
(400 MHz, CDCl3) δ 8.80 (s, 1H), 8.08 (s, 1H), 7.29 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.6 Hz, 2H), 5.40
(s, 2H), 3.81 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.0, 151.1, 150.8, 150.1, 143.9, 130.6, 128.6,
125.4, 113.6, 54.3, 46.5. HRMS (ESI) calcd for [M + Na]+: C13H11ClN4NaO: 297.0514, found:
297.0519.
6ꢀchloroꢀ9ꢀ(4ꢀiodobenzyl)ꢀ9Hꢀpurine 5l. The product 5l was purified with silica gel chromatography
1
(petroleum ether/ethyl acetate=3:1) as a light yellow solid (52.6 mg, 71% yield). Mp 140ꢀ142 °C. H
NMR (400 MHz, CDCl3) δ 8.70 (s, 1H), 8.04 (s, 1H), 7.62 (d, J = 8.4 Hz, 2H), 6.99 (d, J = 8.3 Hz, 2H),
5.33 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.8, 151.3, 144.8, 138.4, 134.2, 131.5, 129.7,
94.7, 47.4. HR-MS (ESI) calcd for [M + Na]+: C12H8ClIN4Na: 392.9374, found: 392.9376. IR (KBr):
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 27
1
2
3
4
3120, 3081, 2924, 1643, 1592, 1559, 1487, 1442, 1008, 859, 809 , 583 cmꢀ1.
5
6
9ꢀ(4ꢀbromobenzyl)ꢀ6ꢀchloroꢀ9Hꢀpurine 5m. The product 5m was purified with silica gel
7
8
9
1
chromatography (petroleum ether/ethyl acetate=3:1) as a yellow solid (49.2 mg, 76% yield). H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(400 MHz, CDCl3) δ 8.79 (s, 1H), 8.12 (s, 1H), 7.51 (d, J = 8.4 Hz, 2H), 7.21 (d, J = 8.4 Hz, 2H), 5.43
(s, 2H); 13C NMR (100 MHz, CDCl3) δ 152.3, 151.8, 151.3, 144.8, 133.5, 132.5, 131.5, 129.6, 123.1,
47.3. HRMS (ESI) calcd for [M + Na]+: C12H8BrClN4Na: 344.9513, found: 344.9516.
6ꢀchloroꢀ9ꢀ(2ꢀchlorobenzyl)ꢀ9Hꢀpurine 5n. The product 5n was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a light yellow solid (43.4 mg, 77% yield). H
NMR (400 MHz, CDCl3) δ 8.78 (s, 1H), 8.20 (s, 1H), 7.45 (d, J = 9.0 Hz, 1H), 7.38 – 7.25 (m, 3H),
5.58 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 152.1, 151.9, 151.2, 145.2, 133.7, 132.1, 131.4, 130.7,
130.5, 130.2, 127.6, 45.6. HRMS (ESI) calcd for [M + H]+: C12H9Cl2N4: 279.0199, found: 279.0193.
6ꢀchloroꢀ9ꢀ(1ꢀphenylethyl)ꢀ9Hꢀpurine 5o. The product 5o was purified with silica gel
1
chromatography (petroleum ether/ethyl acetate=3:1) as a yellow liquid (43.0 mg, 84% yield). H NMR
(400 MHz, CDCl3) δ 8.75 (s, 1H), 8.14 (s, 1H), 7.38 – 7.32 (m, 5H), 5.99 (t, J = 7.2 Hz, 1H), 2.04 (d, J
= 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 151.9, 151.6, 151.0, 143.5, 139.1, 131.8, 129.2, 128.8,
126.6, 54.7, 20.7. HRMS (ESI) calcd for [M + Na]+: C13H11ClN4Na: 281.0564, found: 281.0567.
6ꢀchloroꢀ9ꢀ(2ꢀphenylpropanꢀ2ꢀyl)ꢀ9Hꢀpurine 5p. The product 5p was purified with silica gel
chromatography (petroleum ether/ethyl acetate=3:1) as a yellow solid (43.1 mg, 79% yield). Mp
120ꢀ124 oC. 1H NMR (400 MHz, CDCl3) δ 8.54 (s, 1H), 8.08 (s, 1H), 7.29 – 7.23 (m, 3H), 7.12 (d, J =
6.7 Hz, 2H), 2.14 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 152.0, 151.3, 151.2, 144.0, 143.5, 132.7,
128.9, 128.1, 125.0, 62.8, 29.7 29.2. HRMS (ESI) calcd for [M + Na]+: C14H13ClN4Na: 295.0721,
found: 295.0723. IR (KBr): 3119, 3068, 2924, 1647, 1592, 1553, 1485, 1433, 1389, 1084, 858, 766,
22
ACS Paragon Plus Environment

Page 23 of 27
The Journal of Organic Chemistry
1
2
3
4
703 cmꢀ1.
5
6
2,2,6,6ꢀTetramethylꢀ1ꢀ((tetrahydrofuranꢀ2ꢀyl)oxy)piperidine 6. The product 6 was purified with
7
8
9
1
silica gel chromatography (petroleum ether/ethyl acetate=15:1) as a white solid (62% yield). H NMR
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(400 MHz, CDCl3) δ 5.37 (s, 1H), 3.86 (dd, J = 13.8, 6.6 Hz, 2H), 2.04 – 1.87 (m, 3H), 1.79 (d, J = 9.8
Hz, 1H), 1.49 (s, 5H), 1.33 (s, 1H), 1.22 (s, 3H), 1.11 (s, 3H), 1.07 (s, 3H), 1.05 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 109.6, 66.6, 60.1, 58.6, 40.1, 39.7, 33.9, 33.4, 31.2, 23.9, 20.5, 20.1, 17.3. HRMS ( ESI)
Calculated for[ M+H]+: C13H26NO2, 228.1958, Found:228.1963
1ꢀ(benzyloxy)ꢀ2,2,6,6ꢀtetramethylpiperidine 7. The product 7 was purified with silica gel
chromatography (petroleum ether/ethyl acetate=20:1) as a white solid (49% yield). 1H NMR (400 MHz,
CDCl3) δ 7.43 – 7.30 (m, 5H), 4.88 (s, 2H), 1.70 – 1.40 (m, 6H), 1.31 (s, 6H), 1.20 (s, 6H). 13C NMR
(100 MHz, CDCl3) δ 138.3, 128.3, 127.5, 127.3, 78.8, 60.1, 39.8, 33.1, 20.3, 17.2. MS (EI) Calculated
for[ M]+ C16H25NO,247.19, Found:247.09
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: denlin@scut.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors thank the Science and Technology Program of South China University of Technology for
financial support. The authors also thank Professor Gary Histand from the International School of
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 27
1
2
3
4
5
6
Advanced Materials, South China University of Technology for helpful discussions.
Supporting Information
7
8
9
Copies of 1H and 13C NMR spectra of all the compounds, copies of 19F NMR spectra of 3d and 5d and
Xꢀray crystallography data of 5k are available in the Supporting Information. This material is available
free of charge via the Internet at http://pubs.acs.org.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
REFERENCES
(1) (a) Knapp, S. Chem. Rev. 1995, 95, 1859. (b) Huryn, D. M.; Okabe, M. Chem. Rev. 1992, 92,
1745. (c) Ichikawa, E.; Kato, K. Curr. Med. Chem. 2001, 8, 385. (d) Chen, X. C.; Kern, E. R.; Drach, J.
C.; Gullen, E.; Cheng, Y.ꢀC.; Zemlicka, J. J. Med. Chem. 2003, 46, 1531. (e) Mahony, W. B.; Domin, B.
A.; Daluge, S. M.; Zimmerman, T. P. Biochem. pharmacol. 2004, 68, 1797. (f) Ferrero, M.; Gotor, V.
Chem. Rev. 2000, 100, 4319. (g) Berecibar, A.; Grandjean, C.; Siriwardena, A. Chem. Rev. 1999, 99,
779.
(2) (a) Marquez, V. E.; Lim, M.ꢀI. Med. Res. Rev. 1986, 6, 1. (b) VivetꢀBoudou, V.; Didierjean, J.;
Isel, C.; Marquet, R. Cell. Mol. Life Sci. 2006, 63, 163. (c) Ueland, P. M. Pharmacol. Rev. 1982, 34,
223. (d) De Clercq, E.; Descamps, J.; De Somer, P.; Barr, P. J.; Jones, A. S.; Walker, R. T. Proc. Natl.
Acad. Sci. U. S. A. 1979, 76, 2947. (e) McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.; Erichsen,
J. T.; Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2000, 43, 4993.
(3) (a) De Clercq, E. Nucleos. Nucleot. Nucl. 2004, 23, 457. (b) Freeman, S.; Gardiner, J. M.; Mol.
Biotechnol. 1996, 5, 125. (c) Barrio, J. R., Bryant, J. D., Keyser, G. E. J. Med. Chem. 1980, 23, 572. (d)
Novosjolova, I.; Bizdēna, Ē.; Turks, M. Eur. J. Org. Chem. 2015, 17, 3629. (e) Zhou, X.ꢀX., Littler, E.
Curr. Top. Med. Chem. 2006, 6, 851. (f) Lin, T. S., Luo, M. Z., Liu, M. C.; Pai, B.; Dutschman, G. E.;
24
ACS Paragon Plus Environment

Page 25 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
Cheng, Y. C. Biochem. Pharmacol. 1994, 47, 171. (g) Ivo, G.; Thomas, K.; Michael, S.; Francoise, H.
G.; Wolfgang, V.; Günther, K. J. Hepatol. 1998, 28, 504.
7
8
9
(4) (a) De Clercq, E. Rev. Med. Virol. 2009, 19, 287. (b) Wang, L.; Zhu, K.ꢀQ.; Wu, W.ꢀT.; Chen, Q.;
He, M.ꢀY. Catal. Sci. Technol. 2015, 5, 2891.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(5) (a) Borrmann, T.; Abdelrahman, A.; Volpini, R.; Lambertucci, C.; Alksnis, E.; Gorzalka, S.;
Knospe, M.; Schiedel, A. C.; Cristalli, G.; Müller, C. E. J. Med. Chem. 2009, 52, 5974. (b) Guo, H.ꢀM.;
Wu, Y.ꢀY.; Niu, H.ꢀY.; Wang, D.ꢀC.; Qu, G.ꢀR. J. Org. Chem. 2010, 75, 3863. (c) Chen, S.; Graceffa, R.
F.; Boezio, A. A. Org. Lett. 2016, 18, 16. (d) Arico, J. W.; Calhoun, A. K.; Salandria, K. J.; McLaughlin,
L.W. Org. Lett. 2010, 12, 120. (e) Holý, A.; Dvořáková, H.; Jindřich, J.; Masojídková, M.; Buděšínský,
M.; Balzarini, J.; Andrei, G.; De Clercq, E. J. Med. Chem. 1996, 39, 4073.
(6) Phadtare, S.; Zemlicka, J. J. Am. Chem. Soc. 1989, 111, 5925.
(7) (a) Wang, Q.; Su, Y.; Li, L.; Huang, H. Chem. Soc. Rev. 2016, 45, 1257. (b) Bariwal, J.; Van der
Eycken, E. Chem. Soc. Rev. 2013, 42, 9283. (c) Martinez, Á. M.; Rodríguez, N.; Arrayás, R. G.;
Carretero, J. C. Chem. Commun. 2014, 50, 2801. (d) Sadhu, P.; Punniyamurthy, T. Chem. Commun.
2016, 52, 2803. (e) Marchetti, L.; Kantak, A.; Davis, R.; DeBoef, B. Org. Lett. 2015, 17, 358.
(8) (a) Guo, S.; Kumar, P. S.; Yang, M. Adv. Synth. Catal. 2017, 359, 2. (b) Sun, J.; Zhang, Y.;
Mathan, S.; Wang, Y.; Pan, Y. J. Org. Chem. 2016, 81, 3380. (c) Okugawa, N.; Moriyama, K.; Togo, H.
J. Org. Chem. 2017, 82, 170. (d) Liu, S.; Liu, A.; Zhang, Y.; Wang, W. Chem. Sci. 2017, 8, 4044. (e)
Wang, L.; Cao, J.; Chen, Q.; He, M. J. Org. Chem. 2015, 80, 4743. (f) Xia, Q.; Chen, W.; Qiu, H. J.
Org. Chem. 2011, 76, 7577. (g) Yang, Q.; Choy, P. Y.; Fu, W. C.; Fan, B.; Kwong, F. Y. J. Org. Chem.
2015, 80, 11193. (h) Singh, M. K.; Akula, H. K.; Satishkumar, S.; Stahl, L.; Lakshman, M. K. ACS.
Catal. 2016, 6, 1921.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 27
1
2
3
4
5
6
7
8
9
(9) (a) Rajamanickam, S.; Majji, G.; Santra, S. K.; Patel, B. K. Org. Lett. 2015, 17, 5586. (b) Liu,
W.; Liu, C.; Zhang, Y.; Sun, Y.; Abdukadera, A.; Wang, B.; Li, H.; Ma, X.; Zhang, Z. Org. Biomol.
Chem. 2015, 13, 7154. (c) Liu, Z.; Zhang, X.; Li, J.; Li, F.; Li, C.; Jia, X.; Li, J. Org. Lett. 2016, 18,
4052. (d) Wu, X.ꢀF.; Gong, J.ꢀL.; Qi, X. Org. Biomol. Chem. 2014, 12, 5807. (e) Xue, Q.; Xie, J.; Li,
H.; Cheng, Y.; Zhu, C. Chem. Commun. 2013, 49, 3700. (f) Wei, W.; Zhang, C.; Xu, Y.; Wan, X. Chem.
Commun. 2011, 47, 10827.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10) (a) Dian, L.; Wang, S.; ZhangꢀNegrerie, D.; Du, Y.; Zhao, K. Chem. Commun. 2014, 50, 11738.
(b) Lv, Y.; Sun, K.; Wang, T.; Wu, Y.; Li, G.; Pu, W.; Mao, S. Asian. J. Org. Chem. 2016, 5, 325.
(c)Yang, Q.; Choy, P. Y.; Wu, Y.; Fan, B.; Kwong, F. Y. Org. Biomol. Chem. 2016, 14, 2608. (d) Aruri,
H.; Singh, U.; Kumar, M.; Sharma, S.; Aithagani, S. K.; Gupta, V. K.; Mignani, S.; Vishwakarma, R.
A.; Singh, P. P. J. Org. Chem. 2017, 82, 1000. (e) Aruri, H.; Singh, U.; Sharma, S.; Gudup, S.; Bhogal,
M.; Kumar, S.; Singh, D.; Gupta, V. K.; Kant, R.; Vishwakarma, R. A.; Singh, P. P. J. Org. Chem. 2015,
80, 1929.
(11) Xia, R.; Niu, H.ꢀY.; Qu, G.ꢀR.; Guo, H.ꢀM. Org. Lett. 2012, 14, 5546.
(12) Guo, H.ꢀM.; Xia, C.; Niu, H.ꢀY.; Zhang, X.ꢀT.; Kong, S.ꢀN.; Wang, D.ꢀC.; Qu, G.ꢀR. Adv. Synth.
Catal. 2011, 353, 53.
(13) Huang, R.; Xie, C.; Huang, L.; Liu, J. Tetrahedron 2013, 69, 577.
(14) Xu, S.; Luo, Z.; Jiang, Z.; Lin, D. Synlett 2017, 28, 868.
(15) Single crystal information of 5k, please see the SI for details.
(16) (a) Wang, L.; Zhu, K.; Chen, Q.; He, M. J. Org. Chem. 2014, 79, 11780. (b) Liu, Z.; Zhang, X.;
Li, J.; Li, F.; Li, C.; Jia, X.; Li, J. Org. Lett. 2016, 18, 4052. (c) Chen, L.; Shi, E.; Liu, Z.; Chen, S.; Wei,
W.; Li, H.; Xu, K.; Wan, X. Chem. Eur. J. 2011, 17, 4085. (d) Li, L.ꢀT.; Huang, J.; Li, H.ꢀY.; Wen, L.ꢀJ.;
26
ACS Paragon Plus Environment

Page 27 of 27
The Journal of Organic Chemistry
1
2
3
4
5
6
Wang, P.; Wang, B. Chem. Commun. 2012, 48, 5187. (e) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.;
Wan, X. Angew. Chem. Int. Ed. 2012, 51, 3231.
7
8
9
(17) (a) Wong, Y.ꢀC.; Tseng, C.ꢀT.; Kao, T.ꢀT.; Yeh, Y.ꢀC.; Shia, K.ꢀS. Org. Lett. 2012, 14, 6024. (b)
Li, H.; Xie, J.; Xue, Q.; Cheng, Y.; Zhu, C. Tetrahedron Lett. 2012, 53, 6479. (c) Wang, S.; Wang, J.;
Guo, R.; Wang, G.; Chen, S.ꢀY.; Yu, X.ꢀQ. Tetrahedron Lett. 2013, 54, 6233.
(18) Huang, L.ꢀK.; Cherng, Y.ꢀC.; Cheng, Y.ꢀR.; Jang, J.ꢀP.; Chao, Y.ꢀL.; Cherng, Y.ꢀJ. Tetrahedron
2007, 63, 5323.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(19) Hu, Y. L.; Liu, X.; Lu, M.; Ge, Q.; Liu, X. B. J. Korean Chem. Soc. 2010, 54, 429.
27
ACS Paragon Plus Environment