Addition of purines to N-Boc imines generated in situ in water: Efficient synthesis of novel acyclic purine azanucleosides

Article abstract of DOI:10.1055/s-0031-1291043

A mild, efficient and highly regioselective addition of purine derivatives to N-Boc imines generated in situ in water was developed for the first time. A wide range of novel acyclic purine azanucleosides were synthesized in moderate to high yields through this transformation. This methodology was also appropriate for some other N-heterocycles. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1291043

LETTER
▌1339
lAettder dition of Purines to N-Boc Imines Generated in Situ in Water: Efficient
Synthesis of Novel Acyclic Purine Azanucleosides
Efficient Synthesis of Novel Acyclic Purine Azanucleosides
Hui Zhang,a,b Chun-Xia Lian,a Wei-Cheng Yuan,a Xiao-Mei Zhang*a
a
Key Laboratory for Asymmetric Synthesis & Chirotechnology of Sichuan Province, Chengdu Institute of Organic Chemistry,
Chinese Academy of Sciences, Chengdu 610041, P. R. of China
Fax +86(28)85257883; E-mail: xmzhang@cioc.ac.cn
b
Graduate School of Chinese Academy of Sciences, Beijing 100049, P. R. of China
Received: 19.01.2012; Accepted after revision: 26.03.2012
broad scope of reactions to construct numerous com-
Abstract: A mild, efficient and highly regioselective addition of
pounds.9 Herein, we report a remarkably mild, efficient
purine derivatives to N-Boc imines generated in situ in water was
and highly N-9 regioselective addition of purine deriva-
tives to N-Boc-α-amido sulfones, through which a wide
developed for the first time. A wide range of novel acyclic purine
azanucleosides were synthesized in moderate to high yields through
this transformation. This methodology was also appropriate for variety of novel acyclic purine azanucleosides were syn-
some other N-heterocycles.
thesized in good yields for the first time.
Key words: addition, nucleobases, sulfones, imines, nucleosides
First, we investigated the addition of 2,6-dichloropurine
(1a) to N-Boc imine generated in situ from α-amido sul-
fone 2a in several organic solvents at room temperature,
Purines play important roles in regulation of many biolog-
ical processes. Modification of purine nucleoside has pro-
vided plenty of biologically active compounds, some of
which exhibit remarkable antiviral (ACV, ganciclovir
etc.)1 or anticancer (F-araA, araG, etc.)2 properties. How-
ever, their clinical application can be sometimes limited
by the toxic side effects or emergence of drug resistance.3
Therefore, much attention is still focused on the synthesis
of novel purine nucleoside analogues.
employing 1.5 equivalents of Na2CO3 as the base. As
shown in Table 1, when toluene, Et2O or EtOH were em-
ployed as the solvents, almost no reaction was observed
(Table 1, entries 1–3). When CH2Cl2 and DMF were used
as the solvents, poor yields were obtained (Table 1, entries
4 and 5; 28% and 21%, respectively). When THF was
used as the solvent, the yield increased to 88% (Table 1,
entry 6), but many side products were produced in this re-
action medium. Finally, we tried to perform the reaction
in neat water. To our delight, the reaction proceeded
smoothly to give product 3a in excellent yield of 97% (Ta-
ble 1, entry 7). It is significant because we have found
such a ‘green’ process to provide novel valuable acyclic
purine azanucleosides. Furthermore, it is noteworthy that
2,6-dichloropurine was absolutely regioselectively alkyl-
ated at N-9 position rather than at N-7 position in this
transformation. The site of N-alkylation was determined
by assigned HMBC spectra analysis (see the supporting
information). Afterwards, we examined the effects of var-
ious bases and found that Na2CO3 was ideal for this reac-
tion.
Acyclic azanucleosides represent a unique kind of unnat-
ural nucleosides. Owing to their various potent pharma-
ceutical activities, synthesis and application of acyclic
azanucleosides has attracted much attention.4–6 Up to
now, there are mainly two classes of acyclic azanucleo-
sides. One class is the amino acid or peptide derivatives of
pyrimidines.4 The other is the aza-analogues of ganciclo-
vir/penciclovir or acyclovir.5 Many efficient processes
have been developed to prepare these acyclic azanucleo-
sides and their biological activities have been extensively
studied. However, to the best of our knowledge, synthesis
of acyclic purine azanucleosides via amidoalkylation of
purines has not been systematically researched. Mean-
while, alkylation of purine analogues is rarely regiospecif-
ic and often provides the mixtures of N-9 and N-7
isomers.7 Therefore selective methods for the amidoalkyl-
ation of purines at the N-9 position are highly desirable.
Having established the optimal reaction conditions, we
applied this transformation to a number of purine deriva-
tives with various substituents. As indicated in Table 2, 6-
chloropurine derivatives 1a, 1c and 1d underwent the re-
action to give the desired products in excellent yields irre-
spective of the substituents on C2 in purines (Table 2,
entries 1, 3 and 4). 6-Unsubstituted purine derivatives 1b
and 1e resulted in slightly inferior yields of the corre-
sponding products (Table 2, entries 2 and 5). Meanwhile,
reaction of 2-chloro-6-methoxypurine (1f) only afforded
the product in poor yield after 30 hours (Table 2, entry 6).
It seems that electron-withdrawing substituent on C6 in
purine derivatives accelerates the reaction. On the other
hand, electron-donating substituent on C6 in purine deriv-
atives hinders the reaction. Whereas the substituents on
C2 position in purine derivatives have little influence on
Most of the aliphatic enolizable aldehyde derived imines
are unstable and even hard to isolate, thus resulting in a
considerable limitation to the generality of their applica-
tion. Gratifyingly, this problem can be circumvented by in
situ generation of N-acylimines from bench stable α-ami-
do sulfones8 and this strategy has been carried out in a
SYNLETT 2012, 23, 1339–1342
Advanced online publication: 14.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1291043; Art ID: ST-2012-W0053-L
© Georg Thieme Verlag Stuttgart · New York

1340
H. Zhang et al.
LETTER
the result of the reaction. 6-Chloro-7-deazapurine (1g) ex-
hibited lower activity to provide the product in moderate Generated from α-Amido Sulfone 2a10,11
Table 2 Addition of Various Purine Derivatives to N-Boc Imine
yield after a prolonged reaction time (Table 2, entry 7).
R2
X
Table 1 Screening of Solvents and Bases in the Addition of 2,6-Di-
N
chloropurine (1a) to N-Boc Imine Generated from α-Amido Sulfone
2a
R2
N
R1
N
N
H
1a–g
X
N
N
Cl
Na2CO3 (1.5 equiv)
r.t., H2O
+
R1
N
N
NHBoc
Ts
Cl
NHBoc
N
Cl
N
H
N
N
N
1a
base (1.5 equiv)
r.t., 12 h
3aa–ga
+
Cl
N
2a
NHBoc
Ts
NHBoc
Entrya
X
R1
R2
3
Time (h) Yield (%)b
3aa
1
2
3
4
5
6
7
N
N
N
N
N
N
C
Cl
H
Cl
H
3aa
3ba
3ca
3da
3ea
3fa
12
18
12
12
18
30
24
97
82
94
95
78
51
62
2a
Entrya
Solvent
Base
Yield (%)b
H
Cl
1
2
toluene
Et2O
EtOH
CH2Cl2
DMF
THF
H2O
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Li2CO3
K2CO3
Cs2CO3
NaOH
<5
<5
<5
28
21
88
97
62
60
51
61
47
33
45
NH2
Cl
Cl
H
Cl
H
3
OMe
Cl
4
3ga
5
a Unless indicated otherwise, the reaction was conducted with purine
derivatives 1 (0.24 mmol), α-amido sulfone 2a (0.20 mmol) and
Na2CO3 (0.30 mmol) in H2O (2.0 mL) at r.t.
b Isolated yield.
6
7
8
H2O
benzyl or 2,2-dimethyl-1,3-dioxolanyl, the reaction could
not complete so as to give the product in moderate yields
(Table 3, entries 8–10). Reaction of 2,6-dichloropurine
and chiral α-amido sulfone 2j afforded the product with
moderate yield and low diastereoselectivity. Meanwhile,
when less hindered 6-chloropurine (1c) reacted with 2j,
good yield as well as high diastereoselectivity were ob-
tained (Table 3, entry 11). It is noteworthy that the yield
and diastereoselectivity were influenced significantly by
the size of the substituent at C-2 on purine ring. This can
be explained by a proposed reaction model as outlined in
Scheme 1. Purine attacks (R)-2,2-dimethyl-1,3-dioxo-
lane-4-carbaldehyde derived imine from Si face which is
sterically more accessible. Meanwhile, the substituent at
C-2 on purine ring has steric influence on the methyl
group of imine. Small substituent such as H at C-2 exhib-
its little steric hindrance and provides the desired product
with high yield and diastereoselectivity (Table 3, entry
10). In contrast, larger group such as chloride makes it too
difficult for the purine to reach the imine and thus gives
the poor result (Table 3, entry 11). Owing to the instability
of N-(α-amido)nucleobases, we could not deprotect the
acetonide functional group in compounds 3aj and 3cj. Fi-
nally, the reaction of aryl α-amido sulfone was also inves-
tigated. However, the reaction proceeded sluggishly to
provide the product in poor yield (Table 3, entry 12).
9
H2O
10
11
12
13
14
H2O
H2O
H2O
KOH
H2O
NaOAc
KF
H2O
a Unless indicated otherwise, the reaction was conducted with 2,6-di-
chloropurine (1a; 0.24 mmol), α-amido sulfone 2a (0.20 mmol) and
base (0.30 mmol) in corresponding solvent (2.0 mL) at r.t.
b Isolated yield.
Furthermore, the generality of α-amido sulfones was also
investigated. Various α-amido sulfones were subjected to
the reaction with 2,6-dichloropurine. The results are sum-
marized in Table 3. As can be seen in Table 3, the yields
were highly dependent on the size of the R group in α-
amido sulfones. When R was ethyl, propyl, i-propyl, i-bu-
tyl or cyclohexyl, the reaction gave the corresponding
products with excellent yields (Table 3, entries 1 and 4–
7). When R was H or methyl, the reactions generated
some unidentified side products. Therefore, the yields of
the desired products decreased obviously (Table 3, entries
2 and 3). When R was a larger substituent such as hexyl,
Synlett 2012, 23, 1339–1342
© Georg Thieme Verlag Stuttgart · New York

LETTER
Efficient Synthesis of Novel Acyclic Purine Azanucleosides
1341
to probe whether the addition could be easily accessed.
The results are shown in Figure 1. As expected, these re-
actions also proceeded smoothly to give the correspond-
ing products in high yields.
Cl
N
N
N
N
H
H
R
H
H
O
H
H
O
H
H
N
N
N
N
H
N
N
H
O
H
N
H
N
H
H
H
Si face attack
H
O
NHBoc
NHBoc
NHBoc
Scheme 1 Model for diastereoselective addition of purines to (R)-
2,2-dimethyl-1,3-dioxolane-4-carbaldehyde derived imine
3ha, 12 h, 96%
3ia, 12 h, 87%
3ja, 12 h, 92%
Table 3 Addition of Purine Derivative 1a or 1c to N-Boc Imines
Generated from α-Amido Sulfones 2a–2k
Figure 1 Products of addition of selected N-heterocycles to N-Boc
imine generated in situ from α-amido sulfone 2a
Cl
In summary, we have developed a remarkably mild, effi-
cient and highly regioselective addition of purine deriva-
tives to N-Boc imines generated in situ in water for the
first time. The reactions proceeded in aqueous medium at
room temperature without any catalyst. A wide range of
novel acyclic purine azanucleosides were synthesized in
moderate to high yields through this transformation. In
addition, this methodology was also appropriate for some
N-heterocycles. Further investigation of synthetic and bi-
ological utility of these products is ongoing in our labora-
tory.
N
N
R1
N
N
Cl
N
H
1a or 1c
N
N
N
Na2CO3 (1.5 equiv)
r.t., H2O
+
R1
NHBoc
R3
3aa–ak, cj
NHBoc
R3
Ts
2a–k
Entrya R1 (1)
R3 (2)
3
Time (h) Yield (%)b
1
2
3
4
5
6
7
8
9
Cl (1a) c-hexyl (2a) 3aa
12
18
18
12
12
12
12
24
18
97
72
74
87
91
95
90
71
81
Cl (1a) H (2b)
Cl (1a) Me (2c)
Cl (1a) Et (2d)
Cl (1a) Pr (2e)
Cl (1a) i-Pr (2f)
Cl (1a) i-Bu (2g)
3ab
3ac
3ad
3ae
3af
Acknowledgment
We are grateful for the financial support from the Sichuan Youth
Science & Technology Foundation.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
3ag
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1339–1342

1342
H. Zhang et al.
LETTER
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mmol, 1.5 equiv), and H2O (2 mL) were put in a 10-mL glass
vial equipped with a small magnetic stirring bar. To the
solution was added purine derivative (0.24 mmol, 1.2 equiv).
After stirring for the stipulated time at r.t., the mixture was
diluted with H2O (5 mL) and extracted with EtOAc (3 × 25
mL, for 3aa–3ak, 3ca and 3cj) or CHCl3 (3 × 25 mL, for
3ba, 3da, 3ea, 3fa and 3ga). The organic layers were
combined, dried over anhyd Na2SO4 and concentrated under
reduced pressure. The residue was subjected to silica gel
flash chromatography (EtOAc–hexanes, 1:5) to give the
pure product.
(11) tert-Butyl Cyclohexyl (2,6-Dichloro-9H-purin-9-
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1 H), 2.33 (br, 1 H), 1.65–2.02 (m, 4 H), 1.37 (s, 9 H), 0.83–
1.36 (m, 6 H).13C NMR (75 MHz, CDCl3): δ = 154.5, 152.6,
152.4, 151.8, 145.7, 131.3, 81.3, 69.4, 40.1, 29.4, 29.1, 28.1,
25.7, 25.2, 25.1. HRMS (ESI): m/z [M + Na]+ calcd for
C17H23Cl2N5NaO2: 422.1121; found: 422.1138.
Synlett 2012, 23, 1339–1342
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