Synthesis of cycloalkyl substituted purine nucleosides: Via a metal-free radical route

Article abstract of DOI:10.1039/c6ob00596a

An efficient route to synthesize cycloalkyl substituted purine nucleosides was developed. This metal-free C-H activation was accomplished by a tBuOOtBu initiated radical reaction. By adjusting the amount of tBuOOtBu and reaction time, the selective synthe

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Synthesis of Cycloalkyl Substituted Purine Nucleosides via a
Metal‐Free Radical Route
Dong‐Chao Wang,a,b Ran Xia,a,c Ming‐Sheng Xie,b Gui‐Rong Qu*b, Hai‐Ming Guo*a,b
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Abstract: An efficient route to synthesize cycloalkyl substituted
purine nucleosides was developed. This metal‐free C‐H activation
was accomplished by tBuOOtBu initiated radical reaction. By
adjusting the amount of tBuOOtBu and reaction time, the
selective synthesis of C6‐monocycloalkyl or C6,C8‐dicycloalkyl
substituted purine nucleosides could be realized. Furthermore,
uracil and related nucleosides were also suitable substrates, giving
the C5‐cyclohexyl substituted uracil derivatives in good yields with
excellent regioselectivities.
Introduction
In recent years, the humanity infectious diseases, which are
caused by viruses, increased progressively because the
reproduction and propagation of viruses guest in human
beings.1 Therefore, the modification of purine and pyrimidine
analogues have displayed extremely important due to their
outstanding antiviral activities.2 Subsequently, great endeavors
have been devoted to search various purine or pyrimidine
analogues to study their biological activities.3 In particular,
cycloalkyl substituted purine and pyrimidine derivatives
possess unique biological effects, such as antifolate (Figure 1,
Figure 1. Selected examples of the cycloalkyl substituted purine and pyrimidine
analogues with biological activities
a) Metal catalyzed coupling reactions
(4.0 equiv)
(1.5 equiv)
MgCl
CuI
N
N
LG
N
N
ZnBr
N
N
N
N
+
Bn
Ni(acac)2
Bn
A
),4a adenosine receptor antagonists (Figure 1,
B
),4b cytostatic
),4d and
LG = Cl, Br, I
N
N
BF3K (1.2 equiv)
Pd(OAc)2
),4c against herpes simplex (Figure 1,
N
(Figure 1, and E
C
D
receptor modulation.4e‐4g In view of the significant biological
activities exhibited by cycloalkyl substituted purine and
pyrimidine derivatives, searching for a useful method to
construct cycloalkyl substituted purine and pyrimidine
analogues is highly desirable.
N
Bn
b) Metal catalyzed radical alkylation
H
N
N
N
FeSO4, tBuOOH
N
+
I
H2SO4
N
N
N
N
Bn
Bn
c) This work
H
H
a. School of Environment, Henan Normal University, Xinxiang, Henan province,
453007, P. R. China.
N
N
N
N
R2
N
N
+
R1
N
R1
N
b. School of Chemistry and Chemical Engineering, Key Laboratory of Green Chemical
Media and Reactions of Ministry of Education, Henan Normal University, 46
Jianshe Road, Xinxiang, 453007 (P. R. China); Fax: (+86) 373‐3329276; E‐mail:
quguir@sina.com; ghm@htu.edu.cn.
[2H]
R2
Scheme 1. Synthetic routes to cycloalkyl substituted purine derivatives.
c. School of Chemistry and Chemical Engineering, Xinxiang University, Xinxiang
453003, China.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
Considering the importance of cycloalkyl substituted purine
analogues, numerous routes have been developed to
construct this class of heterocyclic compounds (Scheme 1). The
classic strategy is metal catalyzed coupling reactions, including:
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Table 1. The optimization of reaction conditions.[a]
a) Copper mediated reactions of Grignard reagents with 6‐
halopurines;5 b) Nickel catalyzed Negishi coupling reactions of
organozinc halides with 6‐halopurines;6 c) Palladium catalyzed
coupling reactions of alkyl trifluoroborates with 6‐halopurines7
(Scheme 1a). Whereas these reactions always need expensive
noble metals which would have residual toxic metals in the
final products. Meanwhile, these reactions also need leaving
groups at the C6 position of purine derivatives. The only
example of radical alkylation for C6‐H purines was
accomplished with cycloalkyl iodo as an alkylating reagent
promoted by FeSO4 and tBuOOH under strong acidic
conditions.8 However, the current methods always suffered
from either expensive metal catalysts or harsh reaction
conditions. In the context of ongoing projects in modifying
purine and pyrimidine derivatives,9,10 thus, we wish to develop
a direct method to construct cycloalkyl substituted purine and
pyrimidine analogues with metal‐free under mild conditions.
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DOI: 10.1039/C6OB00596A
x
4a Yield
T
Time
3a Yield
[%][b]
Entry
Peroxide
[equiv]
[oC]
[h]
[%][b]
2.0
2.0
0
0
1
2
tBuOOtBu
tBuOOtBu
100
120
12
12
0
24
3
4
tBuOOtBu
tBuOOtBu
2.0
2.0
2.0
140
140
12
1
45
56
32
0
0
5
6
tBuOOtBu
tBuOOtBu
TBHP
140
140
140
140
140
2
3
2
2
2
91
85
26
66
73
2.0
2.0
2.0
1.0
3.0
5
0
7[c]
8
Initially, we used 6‐H‐2´,3´,5´‐tri‐O‐acetylpurine riboside (1a
)
and cyclohexane (2a) as model substrates to optimize the
reaction conditions (Table 1). When the reaction was
conducted with tBuOOtBu as a peroxide at 100 oC for 12 h, the
reaction did not occur and the substrates 1a was recovered
(entry 1). To our delight, increasing reaction temperature from
0
DCP
0
9
tBuOOtBu
10
10
11
tBuOOtBu
tBuOOtBu
140
140
2
4
83
74
o
100 oC to 120 C, the C6‐monocyclohexyl substituted purine
2.0
2.0
3.0
20
55
89
product 3a was obtained with 24% yield (entry 2). However, a
mixture of C6‐monocyclohexyl substituted purine 3a and C6,
C8‐dicyclohexyl substituted purine 4a was afforded with 77%
total yield when the reaction temperature increased from 120
oC to 140 oC (entry 3). Therefore, how to obtain a single
cyclohexyl substituted purine product was the focus for the
following optimization of the conditions. When the reaction
time was shortened from 12 h to 1 h, the yield of product 3a
was increased from 45% to 56% while the purine 4a was not
formed (entries 3‐4). Encouraged by the results, different
reaction times were further evaluated. When the reaction was
performed for 2 h, the product 3a was exclusively obtained
with 91% yield (entries 4‐6). When other peroxides including
tert‐butyl hydroperoxide (TBHP) and dicumyl peroxide (DCP)
were evaluated, no better results were obtained (entries 7‐8).
Thus, the optimal reaction time is 2 h for the selective
12
tBuOOtBu
tBuOOtBu
140
24
37
13
140
24
0
[a] Unless otherwise note, the reaction conditions were: 1a (0.25 mmol) and 2a
(2.5 mL) under air; [b] Isolated yields based on 1a; [c] 70% aqueous solution.
Subsequently, the substrate scope of the cycloalkylation
reaction was examined under the optimized conditions (Table
1, entry 5) for the selective generation of C6‐monocyclohexyl
substituted purine derivative. When purine nucleosides
bearing different ribosyl substitution were tested, the
corresponding
C6‐monocyclohexyl
substituted
purine
nucleosides were obtained with 78‐91% yields (Scheme 2, 3a
‐
3d). To our delight, purine nucleosides containing
arabinoribosyl substitutions also were suitable substrates to
afford the desired C6‐monocyclohexyl substituted purine
generation of C6‐monocyclohexyl substituted purine 3a
.
nucleosides with 75‐87% yields (Scheme 2, 3e‐3f). In the case
Subsequently, we wish to realize the selective synthesis of
purine 4a. Then, the amount of peroxide tBuOOtBu was
examined, and the yield of purine 4a was increased to 10%
yield when 3.0 equiv tBuOOtBu was used (entries 9‐10).
Prolonging the reaction time to 24 h, the yield of product 4a
increased greatly (entries 11‐12). Therefore, when the reaction
was performed with 3.0 equiv of tBuOOtBu at 24 h, the purine
3a disappeared completely and the C6,C8‐dicyclohexyl
substituted purine 4a was obtained with 89% yield (entry 13).
Therefore, by adjusting the amount of tBuOOtBu and the
reaction time, we can realize the selective synthesis of C6‐
monocyclohexyl or C6,C8‐dicyclohexyl substituted purine
nucleosides with excellent yields.
of purine nucleosides bearing deoxyribosyl substitution, the
reaction proceeded well giving the C6‐monocyclohexyl
substituted product 3g in 80% yield (Scheme 2, 3g).
Furthermore, 9‐benzyl‐9H‐purine worked well to furnish the
target product 3h in 83% yield (Scheme 2, 3h).
Next, various cycloalkanes were employed to construct C6‐
monocycloalkyl substituted purine nucleosides (Scheme 3).
Under the optimized conditions (Table 1, entry 5), the
cycloalkylation reactions worked well with different size of
rings in cycloalkanes, including cyclopentane
(
2b),
cycloheptane (2c), and cyclooctane (2d) (Scheme 3, 3a
‐3c). In
the case of decahydronaphthalene (2d), an inseparable
mixture was obtained (Scheme 3, 3d). When 1‐adamantane
(
2e
)
was used, the corresponding C6‐monocycloalkyl
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nucleosides were obtained with 82‐89% yield (Scheme 4, 4a
‐
substituted purine nucleoside 3e was obtained with 80% yield
(Scheme 3, 3e).
4d). When decahydronaphthalene
(
D
2
O
d
I
)
: 10.
w
10aView Article Online
3
s
9/C
u
6Ose
B
d
0
,
0596A
a
n
inseparable mixture also was formed (Scheme 4, 4e). In the
case of 1‐adamantane (2e), the C6,C8‐dicycloalkyl substituted
purine nucleoside 4f was afforded with 70% yield (Scheme 4,
4f).
Scheme 2. Substrate scope of purine derivatives for the C6‐
monocycloalkylation.[a,b]
Scheme 4. The C6,C8‐dicycloalkylation of 1a with various cycloalkanes [a,b]
[a] Reaction conditions: 1 (0.25 mmol), tBuOOtBu (0.5 mmol) and 2a (2.5 mL)
under air; [b] The yield referred to isolated yield based on substrate 1.
Scheme 3. The C6‐monocycloalkylation of 1a with various cycloalkanes [a,b]
[a] Reaction conditions: 1a (0.25 mmol), tBuOOtBu (0.75 mmol) and 2 (2.5 mL)
under air; [b] The yield referred to isolated yield based on substrate 1a. [c]
Benzene (2.0 mL), 2f (2.5 mmol).
Scheme 5. The cycloalkylation of uracils derivatives 5 with cyclohexane 2a.[a,b]
O
O
H
O
R2
O
5
6
H
H
R2
O
R2
O
N
tBuOOtBu (2.0 equiv)
140 oC, 24 h
N
N
+
N
R1
N
R1
N
R1
2a
6a-6f
not formed
O
5a-5f
O
O
N
HN
HN
N
N
O
N
O
O
AcO
O
OAc OAc
6a, 95% yield
6b, 80% yield
6c
, 79% yield
O
O
O
HN
HN
HN
N
O
N
O
N
O
HO
BzO
AcO
O
O
O
AcO
[a] Reaction conditions: 1a (0.25 mmol), tBuOOtBu (0.5 mmol) and 2 (2.5 mL)
under air; [b] The yield referred to isolated yield based on substrate 1a. [c]
Benzene (2.0 mL), 2f (1.25 mmol).
O
O
CH3
OBz OBz
OAc
H3C
6d, 77% yield
6f, 78% yield
6e, 83% yield
[a] Reaction conditions: 5 (0.25 mmol), tBuOOtBu (0.50 mmol) and 2a (2.50 mL) under
air and the isolated yields were given.
Then, the substrate scope of the cycloalkylation reaction
was evaluated to afford C6,C8‐dicycloalkyl substituted purine
nucleosides under the optimized conditions (Table 1, entry 13).
When different size of rings in cycloalkanes were examined,
the corresponding C6,C8‐dicycloalkyl substituted purine
After a variety of cycloalkylated purine derivatives were
obtained, uracil and related nucleosides were evaluated in the
cycloalkylation reactions.11 As shown in Scheme 5, N1 or N3
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alkyl‐substituted uracil derivatives could afford C5‐cyclohexyl yields with excellent regioselectivities (6 examples, 77‐95%
View Article Online
DOI: 10.1039/C6OB00596A
substituted uracil products 6a
C6‐cyclohexyl substituted uracil products were not formed
(Scheme 5, 6a 6b). To our delight, uracil nucleosides bearing
‐6b with 80‐95% yields, while the yields).
‐
N1‐substitutions such as ribosyl and arabinoribosyl groups all
furnished the corresponding C5‐cyclohexyl substituted uracil
nucleosides with good yields (Scheme 5, 6c
mentioning that the cycloalkylation reactions could tolerate
free hydroxyl and amino groups (Scheme 5, 6b 6f). In all the
‐6f). It is worth
‐
case, the cycloalkylation reactions exclusively afforded the C5‐
cyclohexyl substituted uracil derivatives.
Subsequently, some experiments were performed to
evaluate the mechanism of the cycloalkylation reaction. First,
when the TEMPO, a radical scavenger, was added, the
cycloalkylation reaction was completely inhibited. The radical
trapping by‐product 7a was isolated in 80% yield, which
Scheme 6. a) The radical trapping experiment; b) The kinetic isotope effect (KIE)
experiment
indicated that
a radical process was involved in the
cycloalkylation reaction (Scheme 6a). Next, when the crude
product of the reaction was analyzed by GC‐MS spectra, the
dimerization and three‐component coupling products of
cyclohexane were detected, which proved the existence of a
cyclohexyl radical in the cycloalkylation reaction (see
supporting information for detail). Besides, the kinetic isotope
effect experiment was performed and a significant isotope
effect was observed with KH/kD = 3.82, which suggested that
the C‐H bond cleavage of cyclohexane is the rate‐determining
step (Scheme 6b).9e
Based on the above experiments, a plausible mechanism for
the cycloalkylation reaction was proposed (Scheme 7).12 In the
initiation step, the tert‐butoxy radical was generated from
tBuOOtBu by heat. Then, the cyclohexyl radical was formed by
the hydrogen abstraction between tert‐butoxy radical and
cyclohexane (Scheme 7a). Subsequently, the radical addition of
cyclohexyl radical to C6 position of purine nucleoside 1a
Scheme 7. The proposed mechanism for the cycloalkylation reaction.
Experimental Section
afforded the intermediate A, followed by hydrogen abstraction
Monocycloalkylation reaction of 6‐H‐2’,3’,5’‐tri‐O‐acetylpurine riboside (1a)
with cyclohexane (2a)
with other radical to produce C6‐monocyclohexyl substituted
product 3a. By prolonging the reaction time and increasing the
amount of peroxide tBuOOtBu, the radical addition of
cyclohexyl radical to C6‐monocyclohexyl substituted purine
nucleoside 3a occurred, and the C6,C8‐dicyclohexyl
substituted purine nucleoside 4a was formed via hydrogen
abstraction reaction (Scheme 7b).
A reaction vessel was charged with 6‐H‐2’,3’,5’‐tri‐O‐acetylpurine
riboside (1a, 94.5 mg, 0.25 mmol), tBuOOtBu (0.095 mL, 0.5 mmol)
and cyclohexane (2.5 mL). Then, the reaction vessel was sealed and
o
the resulting solution was stirred at 140 C for 2 h. After cooling to
room temperature, the resulting mixture was removed in vacuo and
the residue was purified by column chromatography (SiO2, petro
ether/ethyl acetate = 1:2) to give 3a with 91% yield.
Conclusions
We have developed a metal‐free strategy for the synthesis of Dicycloalkylation reaction of 6‐H‐2’,3’,5’‐tri‐O‐acetylpurine riboside (1a)
cycloalkyl substituted purine and pyrimidine nucleosides. By with cyclohexane (2a)
adjusting the amount of tBuOOtBu and reaction time, the
selective synthesis of C6‐monocycloalkyl or C6,C8‐dicycloalkyl
riboside (1a, 94.5 mg, 0.25 mmol), tBuOOtBu (0.143 mL, 0.75 mmol)
substituted purine nucleosides could be realized. Meanwhile, a
variety of purine nucleosides containing ribosyl, arabinoribosyl,
and deoxyribosyl substitutions worked well with different size
of rings in cycloalkanes, affording the corresponding products
with good results (19 examples, 70‐92% yields). Furthermore,
uracil and related nucleosides also were suitable substrates,
giving the C5‐cyclohexyl substituted uracil derivatives in good
A reaction vessel was charged with 6‐H‐2’,3’,5’‐tri‐O‐acetylpurine
and cyclohexane (2.5 mL). Then, the reaction vessel was sealed and
o
the resulting solution was stirred at 140 C for 24 h. After cooling to
room temperature, the resulting mixture was removed in vacuo and
the residue was purified by column chromatography (SiO2, petro
ether/ethyl acetate = 2:1) to give 4a with 89% yield.
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M.‐S. Xie, H.‐Y. Niu, G.‐R. Qu and H.‐M. Guo, Org. Lett. 2014,
Acknowledgements
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16, 444.
DOI: 10.1039/C6OB00596A
10 H.‐M. Guo, S. Wu, H.‐Y. Niu, G. Song and G.‐R. Qu. Chemical
Synthesis of Nucleoside Analogues 3 (Ed.: Pedro Merino),
We are grateful for financial support from the National Natural
Science Foundation of China (Nos. 21372066 and 21472037),
the National Basic Research Program of China (973 Program,
No. 2014CB560713), the Plan for Scientific Innovation Talent of
Henan Province (164200510008), and Henan Normal
University National Outstanding Youth Cultivation Fund
(14JR003).
John Wiley
＆ Sons, New York, 2013, 103‐162.
11 For selected examples for regioselective substitution of
pyrimidine at position C5 or C6, see: a) A. Shmailov, L.
Alimbarova, I. Vatsouro, V. Tafeenko, E. Shokova and V.
Kovalev, Tetrahedron 2012, 68, 4765; b) A. Shmailov, L.
Alimbarova, E. Shokova, V. Tafeenko, I. Vatsouro and V.
Kovalev, Tetrahedron 2010, 66, 3058; c) K. Ulanenko, E. Falb,
H. E. Gottlieb and Y. Herzig, J. Org. Chem. 2006, 71, 7053; d)
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