Synthesis of novel C6-phosphonated purine nucleosides under microwave irradiation by SNAr-arbuzov reaction

Article abstract of DOI:10.1021/jo702680p

(Chemical Equation Presented) Novel C6-phosphonated purine nucleosides were obtained in good to excellent isolated yields by the simple and catalyst-free SNAr-Arbuzov reaction of trialkyl phosphite with 6-choloropurine nucleosides, including a series of n

Full text of DOI:10.1021/jo702680p

reactions.6 Many carbon-, nitrogen-, oxygen-, and sulfur-linked
substituents have been introduced at C6 by these reactions with
6-halopurine nucleosides.
Synthesis of Novel C6-Phosphonated Purine
Nucleosides under Microwave Irradiation by
SNAr-Arbuzov Reaction
Organphosphorus compounds are remarkable for their diverse
and potent biological activities.7 Their efficacy is often enhanced
by their association with various heterocycles. Phosphonated
azaheterocycles are an important class of compounds with high
biological potential as conformationally restricted bioisosteres
of amino acids.8 Very recently, the heterocycles bearing the
phosphorus functionalities have been synthesized, which would
serve in further functionalizations to produce molecular diversity
and produce biologically active compounds.9 However, there
is no report on the purine containing phosphorus substituents
up to date.
Gui-Rong Qu,* Ran Xia, Xi-Ning Yang, Jian-Guo Li,
Dong-Chao Wang, and Hai-Ming Guo*
College of Chemistry and EnVironmental Science, Henan
Normal UniVersity, Xinxiang 453007, Henan, P. R. China
ghm@henannu.edu.cn
ReceiVed December 18, 2007
Phosphonation reactions can be carried out in a number of
ways,10 the Arbuzov reaction probably being the most classical
one,10a,b together with SNAr10c or the Pd-coupling reaction on
unsaturated halides,10d-f and especially on electron-deficient
aromatic systems.10g,h As far as Arbuzov-catalyzed10i or catalyst-
free reaction is concerned, alkyl halides (mostly primary) and
acyl halides are commonly used as substrates,11 and aromatic
halides as well as heteraromatic halides can also undergo this
reaction at certain conditions.12
Microwave irradiation is used as an alternative thermal energy
source to conventional heating in organic synthesis. The use of
microwave irradiation has been applied to a wide range of
reaction types, including SNAr, cycloaddition, and organome-
tallic reactions. Many of these reactions have been demonstrated
to result in higher yield and/or selectivity under microwave
irradiation compared with using a heating bath.13
Herein, during the ongoing course of our study on the
development of new methods for the synthesis of nucleoside
analogues under microwave irradiation,14 we applied microwave-
Novel C6-phosphonated purine nucleosides were obtained
in good to excellent isolated yields by the simple and catalyst-
free SNAr-Arbuzov reaction of trialkyl phosphite with
6-choloropurine nucleosides, including a series of nonsugar
carbon nucleosides. Shorter reaction times were needed, and
substantially higher yields were obtained under microwave
irradiation conditions compared with conventional heating
conditions.
(4) (a) Hocek, M.; Masoj´ıdkova´, M.; Holy, A. Tetrahedron 1997, 53,
2291. (b) Langli, G.; Gundersen, L.-L.; Rise, F. Tetrahedron 1996, 52, 5625.
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Y. Q. V.; Ngassa, F. N.; Russon, L. M. J. Am. Chem. Soc. 2001, 123, 7779.
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Tunney, S. E.; Stille, J. K. J. Org. Chem. 1987, 52, 748. (e) Hirao, T.;
Masunaga, T.; Obshiro, Y.; Agawa, T. Synthesis 1981, 56. For an overview.
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Charbonniere, L. J.; Mameri, S.; Camerel, F. J. Org. Chem. 2005, 70, 9835.
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J.; Perigaud, C. Tetrahedron Lett. 2006, 47, 7719.
Natural purine nucleobases play important roles in many
biological processes. Purine derivatives with various substituents
at C6 have received considerable attention due to their broad
spectrum of biological activities.1 From a biological standpoint,
modification at C6 could adjust the number of H-bond in the
purine moiety.2 Advances in the synthesis of purines modified
at C6 include the use of SNAr (nucleophilic aromatic substitu-
tion),3 Stille coupling,4 Suzuki-Miyaura,5 and Sonogashira
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Hauser, D. R. J. J. Med. Chem. 2005, 48, 710. (f) Wang, J.-Q.; Kreklau, E.
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10.1021/jo702680p CCC: $40.75 © 2008 American Chemical Society
Published on Web 02/29/2008
2416
J. Org. Chem. 2008, 73, 2416-2419

TABLE 1. Effect of Solvent and the Optimization of Reaction
Conditionsa
SCHEME 1. Reaction of 2,6-Dicholoro-9-(â-D-triacetoxy-
ribofuranosyl)purine Nucleoside with Triethyl Phosphate
entry
solvent
CH2Cl2
time (min)
T (°C)
yieldb (%)
1
2
3
4
5
6
25
25
25
10
8
41-42
81-82
120
120
150
no reaction
CH3CN
13
61
96
93
8
[bmim]BF4
solvent-free
solvent-free
solvent-freec
20 h
120
a The reaction was conducted with 0.15 mmol of 1a, 5.8mmol (1 mL)of
2a, and 5 mL of solvent under microwave irradiation. b Isolated yields based
on 1a. c The reaction was carried out in the convectional heating bath.
assisted SNAr-Arbuzov reaction to the synthesis of a novel
series of C6-phosphonated purine nucleosides, which opens a
new route for modification at C6 of purine nucleosides.
At first sight, the C6 chloride atom of 6-chloropurines appears
as an inactive and/or unexciting chemical entity for SNAr-
Arbuzov reaction compared with commonly used substrates,
such as primary alkyl halides or acyl halides. However, from
our experience with the facile synthesis of C6-substituted
aminopurine analogues under microwave irradiation,14b we knew
that the SNAr reaction of 6-choloropurines could be enhanced
by microwave irradiation, so we still envisioned that an SNAr-
Arbuzov reaction of 6-halide purines with trialkyl phosphite
could be carried out. With this idea in mind, we initiated the
study to generate the C6-phosphonated purine under microwave
irradiation. However, the reaction of 6-chloropurine and triethyl
phosphonite (2a) gave a complex mixture under several tem-
peratures from rt to 150 °C.
3), the yield was not higher than in neat conditions (entry 4),
so the solvent-free condition was selected for the reaction. At
room temperature or 50 °C, the substrate was not fully soluble
in P(OEt)3, and the yield was low. Increasing the temperature
to 120 °C, the reaction completed within 10 min in the yield of
96% (entry 4). Increasing the temperature to 150 °C, the reaction
completed within 8 min in 93% yield (entry 5). That is to say,
when the reaction temperature was lower than 120 °C, lower
yield was obtained. When the temperature was higher than 120
°C, significant change in yield was not observed. Therefore,
120 °C and 10 min were the optimized reaction conditions. It
is noteworthy that this method does not require the use of a
catalyst, whereas in most cases, the synthesis of (hetero)-
arylphosphonates cannot be performed without a suitable metal
complex.15
Although the side products in the above reaction were not
carefully analyzed, a possible postulation was that the unpro-
tected N-H at N9 position prevented the usual reaction. To
avoid this side reaction, we decided to use N9-substituted purine
nucleosides as substrates. We were pleased to find that the
reaction of 2,6-dicholoro-9-(â-D-triacetoxyribofuranosyl)purine
nucleoside (1a) with triethyl phosphite at 100 °C provided the
desired C6-phosphonated purine nucleoside (3a) in 92% yield
within 25 min (Scheme 1).
The reaction between 2,6-dicholoro-9-(â-D-triacetoxyribo-
furanosyl)purine nucleoside and triethyl phosphate under con-
vectional heating conditions and MWI heating conditions was
investigated to demonstrate the specific microwave effect. It
was found that under conventional heating conditions the
reaction gave a low yield (ca. 8.5%) within 20 h at 120 °C
(Table 1, entry 6). Microwave-assisted reaction exhibited several
advantages over the conventional heating by not only signifi-
cantly reducing the reaction time but also by improving the
reaction yield dramatically and, in the process, eliminating the
side reactions, implying the involvement of a specific nonther-
mal microwave effect.14b,16
Our first attempt to generate the C6-phosphonated purine
nucleoside using an SNAr-Arbuzov procedure was successful.
To evaluate the generality of the reaction, a number of 2,6-
dicholoropurines with various substituents, including a nonsugar
carbon substituent, at N9 were subjected to the optimized
reaction conditions (Table 2), affording the desired phosphonates
in good to excellent isolated yields (74-96%). The kind of
substituents at N9 had little impact on the yields of the products,
other than the triacylsugar- and allyl-substituted substrates giving
much higher yields.
Spectroscopic data were in agreement with the assigned
structure of the compound. High-resolution mass spectrometry
shows a clear molecular ion peak at m/e ) 549.1142, which
shows that only one chlorine atom was substituted. 31P NMR
indicated a single peak at δ ) 4.5 ppm. The C6 atom at δC )
152.6 ppm appears as a doublet with a coupling constant, 1JP-C
) 193.6 Hz. C4 and C5 also appear as a doublet with a smaller
2
3
coupling constant, JP-C ) 21.0 Hz and JP-C ) 11.6 Hz,
respectively. This demonstrated that phosphorus group was
attached to C-6 as expected.
Intriguing solvent effects were observed and the results are
shown in Table 1. No reaction was observed in CH2Cl2 (entry
1), a nonpolar solvent with low boiling point, while a higher
yield was obtained in CH3CN, a polar solvent (entry 2).
Although use of ionic liquid improved the yield to 61% (entry
To study the influence of substituent groups at C2, a series
of 6-chloropurines and 2-amino-6-choloropurines were em-
ployed as the substrates under optimized reaction conditions
(Table 3). In most cases, replacement of the chloride by H or
NH2 led to lower yields of the corresponding phosphonates after
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J. Org. Chem, Vol. 73, No. 6, 2008 2417

TABLE 2. Reaction of Triethyl Phosphite with Various
2,6-Dicholoropurinesa
TABLE 3. Reaction of Triethyl Phosphite with Various
6-Chloropurines and 2-Amino-6-choloropurinesa
a The reaction was conducted with 0.15 mmol of 1 and 5.8 mmol (1
mL) of 2a under microwave irradiation. b Isolated yields based on 1.
SCHEME 2. Reaction of Triisopropyl Phosphite with
6-Chloropurines
a The reaction was conducted with 0.15 mmol of 1 and 5.8 mmol (1
mL) of 2a under microwave irradiation. b Isolated yields based on 1.
purification, indicating that the electron-donating effects on C2
could lead to decrease of the yields. Hydroxyl unprotected sugar
nucleosides were not suitable for this reaction under the
optimized conditions due to their poor solubility in P(OEt)3.
Interestingly, when 6-chloro-9-(â-D-2′,3′-isopropylribofurano-
syl)purine nucleoside was employed, the reaction could proceed
smoothly in good yield (entry 6). The exo-NH2 of guanosine
was also tolerated (entry 8).
These 6-chloropurine nucleosides can be easily obtained by
chlorination of protected inosine or guansine with POCl3 under
previously developed conditions in good yields.17 The nonsugar
carbon purine nucleosides can be synthesized by alkylation of
6-chloropurine with nonsugar carbon chains. Thus, the method
is a promising route for the synthesis of C6-phosphonated purine
nucleosides.
SCHEME 3. The Reaction of Triethyl Phosphite with
4-Chloropyrazolopyrimidine
Final confirmation for the structures of phosphonated products
was derived from an X-ray single crystal analysis. Furthermore,
the oxygen atom of PdO can interact with other molecules
through the H-bond, which can be applied to develop biologi-
cally active compounds.
We also extended triethyl phosphite to triisopropyl phosphate
(2b) to afford phosphonated products 3t-v with comparable
yields (Scheme 2).
razolopyrimidine18 using the same reaction conditions (Scheme
3). This further demonstrates the generality of this microwave-
assisted SNAr-Arbuzov reaction to generate phosphonated
hetercyclic scaffolds.
In conclusion, the first synthesis of purine nucleosides
containing a phosphonate group at C6 is developed, starting
from easily accessible 6-chloropurine nucleosides, via Abuzov-
type reaction. Microwaves can lead to dramatic reduction of
reaction times and substantial increase of the yields. It is
The use of microwave irradiation to generate phosphonated
purines was also tested on other hetercyclic scaffolds. For
example, 4-phosphonated pyrazolopyrimidine could also be
synthesized in good yield from the corresponding 4-chloropy-
(17) Janeba, Z.; Francom, P.; Robins, M. J. J. Org. Chem. 2003, 68,
989.
(18) Robins, R. K. J. Am. Chem. Soc. 1956, 78, 784.
2418 J. Org. Chem., Vol. 73, No. 6, 2008

2
72.6, 70.0, 63.9 (d, JC-P ) 6.0 Hz), 62.4, 20.2, 20.0, 19.8, 15.9
noteworthy that this method does not require the use of a
catalyst. The resulting phosphonated purine nucleosides are
important candidates for biologically active compounds. Our
report opens an effective new route for modification at C6 of
purine nucleosides. The pharmacological evaluation of these
compounds is undergoing in our laboratories.
(d, JC-P ) 6.0 Hz); 31P NMR (CDCl3, 100 MHz) δ 4.5; HRMS
3
calcd for C20H27ClN4O10P [M + H+] 549.1153, found 549.1142.
The reaction conditions described in the experimental section
were representative and all ratios and concentrations of reactants
remained constant for the other substrates.
Preparation of Diethyl 2-Chloro-9-(â-D-triacetoxyribofura-
nosyl)purinyl Phosphonate (3a) with Conventional Heating.
Purine nucleoside 1a (0.15 mmol) was put in a 5 mL glass vial
equipped with a small magnetic stirring bar. To this was added 1
mL of triethyl phosphite. The mixture was stirred in oil heating
bath at 120 °C for 20 h. Then the vial was cooled to room
temperature. After evaporation of the unreacted P(OEt)3, the resulted
residue was purified by column chromatography over silica gel
using neat ethyl acetate as the eluent, to give purine phosphonate
3a.
Experimental Section
Preparation of Diethyl 2-Chloro-9-(â-D-triacetoxyribofura-
nosyl)purinyl Phosphonate (3a). Purine nucleoside 1a (0.15 mmol)
was put in a 5 mL glass vial equipped with a small magnetic stirring
bar. To this was added 1 mL of triethyl phosphite. Then the mixture
was put into the cavity of the microwave synthesis apparatus and
irradiated at 400 W at 120 °C for 10 min. After completion of the
reaction, the vial was cooled to room temperature. After evaporation
of the unreacted P(OEt)3, the crude product was purified by column
chromatography over silica gel using neat ethyl acetate as the eluent,
to give purine phosphonate 3a. Light yellow oil. 1H NMR (CDCl3,
400 MHz) δ ppm 8.39 (s, 1H), 6.18 (d, J ) 5.2 Hz, 1H), 5.75 (t,
J ) 5.6 Hz, 1H), 5.51 (t, J ) 5.2 Hz, 1H), 4.38 (t, J ) 4 Hz, 1H),
4.35-4.28 (m, 6H), 2.06 (s, 3H), 2.02 (s, 3H), 1.98 (s, 3H), 1.32
(t, J ) 7.2 Hz, 6H); 13C NMR (CDCl3, 100 MHz) δ 169.8, 169.1,
168.9, 153.9, 153.7 (d, 1JC-P ) 193.6 Hz), 153.3-153.1 (d, 3JC-P
) 11.6 Hz), 145.4, 134.4-134.2 (d, 2JC-P ) 21.0 Hz), 85.8, 80.2,
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (20772024) for financial support.
Supporting Information Available: NMR data of all synthe-
sized compounds and full characterization of novel compounds as
well as X-ray crystallographic data. This material is available free
of charge via the Internet at http://pubs.acs.org.
JO702680P
J. Org. Chem, Vol. 73, No. 6, 2008 2419