An improved synthesis of pyrimidine- and pyrazole-based acyclo-C-nucleosides as carbohybrids

Article abstract of DOI:10.1016/j.tetlet.2008.06.032

The synthesis of pyrimidine- and pyrazole-based acyclo-C-nucleosides as carbohybrids was optimized and developed. The synthesis of acyclic polyol-fused pyrimidines was achieved in good to excellent yield with high purity by the cyclocondensation of 2-C-fo

Full text of DOI:10.1016/j.tetlet.2008.06.032

Tetrahedron Letters 49 (2008) 5080–5083
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
An improved synthesis of pyrimidine- and pyrazole-based
acyclo-C-nucleosides as carbohybrids
*
Ram Sagar, Moon-Ju Kim, Seung Bum Park
Department of Chemistry, Seoul National University, Seoul 151-747, South Korea
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of pyrimidine- and pyrazole-based acyclo-C-nucleosides as carbohybrids was optimized
and developed. The synthesis of acyclic polyol-fused pyrimidines was achieved in good to excellent yield
with high purity by the cyclocondensation of 2-C-formyl glycals and various amidines using K2CO3 as
inorganic base in co-solvent system. In comparison, the syntheses of pyrazole-based acyclo-C-nucleo-
sides were accomplished simply by the cyclocondensation of 2-C-formyl glycals with hydrazine hydrate
at room temperature and with phenyl hydrazine at refluxing temperature in ethanol.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 7 May 2008
Revised 4 June 2008
Accepted 6 June 2008
Available online 12 June 2008
Keywords:
Pyrimidine
Pyrazole
2-C-Formyl glycals
Carbohybride
Acyclo-C-nucleoside
The development of practical and efficient route for the synthe-
sis of drug-like small molecules is of considerable interest to
medicinal chemists and chemical biologists.1 Pyrimidines and pyr-
azoles have been recognized as important heterocyclic compounds
due to their frequent use in bioactive natural products and in var-
ious pharmaceutical agents.2,3 The molecules with a pyrimidine
core structure exhibit diverse biological activities such as Tie-2
kinase inhibitor,2b HIV-1 inhibitor,2c antimalarial,2d secretive aden-
osine A1 receptor antagonist,2e antibacterial,2f and anticancer
activities.2h Pyrazole derivatives are also known as modulators in
biology; for example, they possess anti-obesity,3a anti-inflamma-
tory,3c estrogen receptor agonist,3d,e HIV-1 reverse transcriptase
inhibitor,3f and anti-hyperglymic activities.3g Some bioactive small
molecules with pyrimidine or pyrazole substructure are currently
used as therapeutic agents (Fig. 1). Therefore, continuous efforts
are being made to develop a more efficient and generally applica-
ble synthetic protocol for the synthesis of diversified pyrimidine
and pyrazole derivatives.
Figure 1. Bioactive small molecules with pyrimidine- and pyrazole-based core
skeleton (I–VI). (I) Trimethoprim, antibacterial drug in combination with Sulfa-
methoxazole; (II) Minoxidil, peripheral vasodilator; (III) Epiroprim, antibacterial;
(IV) Celebrex, anti-inflammatory drug; (V) PNU-32945, non-nucleoside reverse
transcriptase inhibitors; (VI) Rimonabant, CB1 receptor inverse agonist.
Peseke and co-workers utilized ‘push–pull activation’ ability of
2-C-formyl glycals and synthesized various molecules in the form
of acyclo-C-nucleoside containing pyridine/pyridone4a,b and pyr-
azoles.4c,d Peseke also reported three examples of the synthesis
of pyrimidine-based acyclo-C-nucleoside from 2-C-formyl galactal
in poor yield (24–32%); his approach, however, requires the use of
strong organic bases (NaOMe) and the reaction time is long (15–
20 h).5 Similarly, Yadav and coworkers reported the synthesis of
various pyrazoles from 2-C-formyl glucal under microwave condi-
tions and conventional thermal condition.6
In continuation of our research on diversity-oriented synthesis
(DOS) of drug-like small molecules,7 we investigated the incorpo-
ration of pyrimidine or pyrazole into novel core skeletons since
pyrimidine and pyrazole possess interesting biological activities.7a
Our research campaign came to fruition through our recently
reported efficient synthesis of acyclic polyols fused with pyr-
azolo[1,5-a]pyrimidines and 1,2,4-triazolo[1,5-a]pyrimidines.8 In
* Corresponding author. Tel.: +82 02 8809090; fax: +82 02 8844025.
E-mail address: sbpark@snu.ac.kr (S. B. Park).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.06.032

R. Sagar et al. / Tetrahedron Letters 49 (2008) 5080–5083
5081
addition, we identified that pyrimidine- and pyrazole-based acy-
clo-C-nucleosides can serve as key intermediates in the formation
of various novel core skeletons through further modifications.
However, the synthetic protocols reported by Peseke4c,d,5 cannot
satisfy the demands of efficient synthesis of these key intermedi-
ates. To satisfy this unmet demand, we systematically monitored
the reaction patterns to optimize the reaction conditions in order
to improve reaction yield and to shorten the reaction time. In this
Letter, we provide a detailed description of reaction optimization
for the synthesis of pyrimidine- and pyrazole-based acyclo-C-
nucleosides as carbohybrids.
The synthetic protocol was as follows: 2-C-formyl glucal 1 was
obtained from 3,4,6-tri-O-benzyl glucal via the Vilsmeier-Haack
reaction.9 Initially, we attempted to synthesize pyrimidine deriva-
tives by the condensation of 2-C-formyl glucal 1 and guanidinium
salt 3 in the presence of NaOMe in methanol, based on the previ-
ously reported procedure;5 however, we obtained the desired
pyrimidine 10 in very poor yield along with unidentifiable polar
byproducts. From the reaction mechanism of push–pull activation,
it is apparent that an appropriate base is necessary to activate the
dinucleophiles in order to perform the cyclocondensation reaction
for the formation of pyrimidines. Therefore, we screened other
organic bases (NaH and t-BuOK) instead of NaOMe to determine
their suitability as agents that can bring about this transformation;
however, all these bases failed to improve the reaction yields or
shorten the completion time. In all studied cases, we obtained very
poor yields (20%) along with some polar mass formed at the bot-
tom of TLC, which led us to believe that the poor yield of pyrimi-
dine 10 might be due to the instability of 2-C-formyl glucal 1
against strong organic bases in a polar solvent under the conven-
tional thermal condition.
In order to test our hypothesis, we tested this reaction by using
the above-mentioned bases—NaH and t-BuOK—in a co-solvent sys-
tem, that is, ethanol/THF (1:1); however, we only observed a sim-
ilar or slightly higher yield in all the cases without any significant
improvements. We also screened various bases for the appropriate
activation of guanidine 3 in a salt-free form without any destabili-
zation of our substrate 1. As shown in entry 1 of Table 1, this trans-
formation can be completed within 12 h at 80 °C by using K2CO3 as
the base in a co-solvent system of ethanol/THF (1:1) in an im-
proved yield (45%). As shown in entry 2 of Table 1, the desired
pyrimidine 10 was obtained in acceptable yield (60%) after stirring
for 17 h through the cyclocondensation of 2-C-formyl glucal 1 with
guanidinium salt 3 using n-BuLi as the base in THF at temperature
ranging from 0 °C to room temperature.
idinium salt 4, we observed further improvements in the yields of
desired pyrimidine 11 (Table 1, entries 4 and 5) at room tempera-
ture only when compared to the guanidinium salt case (Table 1,
entries 1 and 2); this improvement can be explained on the basis
of relative nucleophilicity, that is, 1,10-dimethylguanidine is more
nucleophilic than unsubstituted guanidine. In comparison, the
same transformation with trifluoroacetamidine 5, which is less
nucleophilic than guanidine, without any base under conventional
thermal condition in refluxing ethanol was not very clean and gave
only 25% isolable yield of desired pyrimidine 12 (data not shown)
even after 12 h. However, by microwave irradiation of 2-C-formyl
glucal 1 at 90 °C with trifluoroacetamidine 5 under neat condition,
the intrinsically lower nucleophilicity of dinucleophiles could be
overcome, and we were able to obtain the pyrimidine derivative
12 in good yield (70%) within 10 min (Table 1, entry 6). This was
only possible because trifluoroacetamidine 5 was supplied as an
acid-free liquid. Therefore, the reaction can be carried out under
neat conditions and microwave irradiation in the absence of a base.
With the available optimized conditions, we investigated the
scope of the cyclocondensation of 2-C-formyl galactal9 2 with
guanidinium salt 3, 1,10-dimethyl guanidinium salt 4 and trifluoro-
acetamidine 5. As shown in entries 7–9 of Table 1, 2-C-formyl
galactal 2 was successfully coupled with all three nucleophiles
3–5 under optimized reaction conditions, and the respective
pyrimidines 13–15 were obtained in excellent yields (72–87%). It
is worth mentioning that compound 13 was obtained in 32% yield
using the reported procedure,5 whereas our optimized reaction
condition can provide compound 13 in 86% isolable yield (Table
1, entry 7).
After the synthesis of acyclic polyol-fused pyrimidines using
guanidinium salt, we further expanded the scope of this transfor-
mation with respect to both 2-C-formyl glycals (1–2) and benz-
amidines (6–7) to synthesize pyrimidine-based hetero-biaryl
compounds.10 Benzamidines (6–7) in the salt form were initially
treated with 2-C-formyl glucal 1 in the presence of K2CO3 in a
co-solvent system (EtOH/THF, 1:1) at room temperature; in this
reaction, no desired products were identified (Table 2, entries 1
and 3). In comparison, 2-C-formyl glucal 1 was successfully cou-
pled with benzamidines (6–7) under the reflux condition, and
the respective pyrimidine-based hetero-biaryl compounds 16 and
17 were produced in excellent yields (Table 2, entries 2 and 4).
Based on this efficient transformation, the molecular diversity on
these hetero-biaryl skeletons could be introduced simply by using
differently substituted benzamidines under identical reaction
conditions.
At this juncture, we expanded the scope of dinucleophiles to
demonstrate the generality of this transformation. In the case of
cyclocondensation of 2-C-formyl glucal 1 with 1,10-dimethylguan-
Under microwave irradiation, 2-C-formyl glucal 1 was success-
fully condensed with the salt-free form of benzamidines 6–7 in the
neat condition at 110 °C and the desired hetero-biaryl compounds
Table 1
Reaction optimization for the synthesis of pyrimidine derivatives
Entry
Substrate
Amidines
Reaction condition
R
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
2
2
2
3
3
4
4
4
5
3
4
5
EtOH/THF (1:1), K2CO3, 80 °C, 12 h
THF, n-BuLi, 0 °C to rt, 17 h
MeOH, K2CO3, rt, 6 h
EtOH/THF (1:1), K2CO3, rt, 7 h
THF, n-BuLi, 0 °C to rt, 19 h
NH2
NH2
NMe2
NMe2
NMe2
CF3
NH2
NMe2
CF3
H
H
H
H
H
H
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
H
10
10
11
11
11
12
13
14
15
45
60
46
59
65
70
86
87
72
l
W, 200 W, 90 °C, 10 min
EtOH/THF (1:1), K2CO3, 80 °C, 12 h
EtOH/THF (1:1), K2CO3, rt, 10 h
H
H
l
W, 200 W, 90 °C, 10 min

5082
R. Sagar et al. / Tetrahedron Letters 49 (2008) 5080–5083
Table 2
Improved synthesis of pyrimidine-based hetero-biaryls
Entry
Substrate
Benzamidinesa
Reaction condition
R
R1
R2
Product
Yield (%)
1
2
3
4
1
1
1
1
1
1
2
2
6
6
7
7
6
7
6
7
EtOH/THF (1:1), K2CO3, rt, 4 h
EtOH/THF (1:1), K2CO3, 80 °C, 2 h
EtOH/THF (1:1), K2CO3, rt, 4 h
EtOH/THF (1:1), K2CO3, 80 °C, 12 h
Cl
Cl
H
H
H
H
H
H
OBn
OBn
OBn
OBn
OBn
OBn
OBn
OBn
H
NR
16
NR
17
16
17
18
19
—
85
—
80
79
77
87
82
Me
Me
Cl
Me
Cl
5b
6b
7
l
l
W, 200 W, 110 °C, 10 min
W, 200 W, 110 °C, 10 min
EtOH/THF (1:1), K2CO3, 80 °C, 2 h
EtOH/THF (1:1), K2CO3, 80 °C, 11 h
8
Me
H
a
HI salt of 6 and HCl salt of 7 is used.
Salt-free forms of benzamidines were used in this case. NR = no reaction.
b
16–17 were obtained in good yield (77–79%) within 10 min (Table
2, entries 5 and 6). The key feature of this transformation is that
benzamidines can be easily activated under microwave irradiation
and neat conditions. Using optimized reaction condition, 2-C-
formyl galactal 2 was also cyclocondensed with benzamidines
6–7, and the respective hetero-biaryl derivatives 18–19 were
obtained in excellent yields (Table 2, entries 7 and 8). On the basis
of the reported procedure, the hetero-biaryl-type compound 19
can only be obtained in 28% yield after 20 h of reaction,5 whereas
our optimized procedure can significantly improve the yield
(82%) with a shorter reaction time (Table 2, entry 8).
For the synthesis of acyclic polyol-fused pyrazole derivatives, 2-
C-formyl glycals (1–2) were subjected to cyclocondensation with
hydrazines (8–9).6 To our pleasant surprise, the desired pyrazole
derivative 20 was obtained in excellent yield (83%) at room tem-
perature after stirring 2-C-formyl glucal 1 and hydrazine hydrate
8 in ethanol for only 2 h (Table 3, entry 1). When the same trans-
formation of 2-C-formyl glucal 1 was tried with phenylhydrazine
9 at room temperature, no desired product was observed (Table
3, entry 2), whereas under the conventional thermal conditions
as well as microwave irradiation, the desired product 21 was
obtained in excellent yield (Table 3, entries 3 and 4). Similarly,
2-C-formyl galactal 2 was successfully condensed with hydrazine
8 at room temperature and with phenylhydrazine 9 under the
reflux condition, which yielded the desired pyrazole derivatives
22 and 23, respectively, in excellent yields (Table 3, entries 5 and
6). When 2-C-formyl galactal 2 was reacted with phenyl hydrazine
9 using microwave irradiation at 80 °C for 6 min, pyrazole deriva-
tive 23 was obtained in 82% isolable yield (Table 3, entry 7).
In summary, we have optimized and developed an improved,
practical, and environmentally friendly protocol for the synthesis
of pyrimidine- and pyrazole-based acyclo-C-nucleoside through
the cyclocondensation of 2-C-formyl glucal 1 and 2-C-formyl galac-
tal 2 into pyrimidines (10–15), pyrimidine-based hetero-biaryls
(16–19), and pyrazoles (20–23) in good to excellent yields. By
adopting our improved synthetic protocol, the desired pyrimidine
and pyrazole intermediates can be synthesized on a grams scale
without any risk of hazards, along with all possible combination
of skeletal, building block, and stereochemical diversity elements.
We successfully demonstrated this transformation with respect
to both 2-C-formyl glycals 1–2 and various dinucleophiles 3–9,
which were all successfully transformed into their respective
desired products under the optimized reaction condition. Further
modifications and diversifications as well as the associated biolog-
ical evaluations will be reported in due course.
General experimental procedure: (see Supplementary data for de-
tailed experimental procedure) Preparation of compounds 10 and 16
using K2CO3 in EtOH/THF (1:1): To a stirred suspension of K2CO3
(172.5 mg, 1.25 mmol, 5.0 equiv) and respective guanidinium salt
3 (2.0 equiv) in EtOH (2.0 mL), 2-C-formyl glucal 1 (110 mg,
0.250 mmol) in THF (2.0 mL) was added and resulting mixture
was heated at 80 °C until disappearance (TLC) of 2-C-formyl glucal
1 (12 h). The resulting reaction mixture was concentrated in vac-
uum and subjected to flash column chromatography purification
to obtain the respective pure product 10 in 45% isolable yield. A
similar reaction condition was applied for the synthesis of com-
pound 16 using benzamidine salt 6. Compound 10: Amorphous
solid, ½a 2D8
ꢁ42.74 (c 0.340, CH2Cl2); TLC: Rf = 0.20 (7:3, EtOAc/
ꢀ
Table 3
Improved synthesis of pyrazole derivatives
Entry
Substrate
Hydrazines
Reaction condition
R
R1
R2
Product
Yield (%)
1
2
3
4
5
6
7
1
1
1
1
2
2
2
8
9
9
9
8
9
9
EtOH, rt, 2 h
EtOH, rt, 8 h
EtOH, 80 °C, 10 h
H
H
H
H
H
OBn
OBn
OBn
OBn
OBn
OBn
OBn
H
20
NR
21
21
22
23
23
83
—
Ph
Ph
Ph
H
Ph
Ph
77
80
95
79
82
l
W, 250 W, 80 °C, 6 min
EtOH, rt, 2 h
EtOH, 80 °C, 10 h
H
H
l
W, 250 W, 80 °C, 6 min

R. Sagar et al. / Tetrahedron Letters 49 (2008) 5080–5083
5083
hexane, v/v); 1H NMR (500 MHz, CDCl3) d 8.28 (s, 2H), 7.34–7.10
References and notes
(m, 15H), 5.14 (br s, 2H, NH2), 4.56 (d, J = 3.0 Hz, 1H), 4.53 (d,
J = 12.0 Hz, 1H), 4.50 (br s, 2H), 4.39 (d, J = 11.0 Hz, 1H), 4.26 (d,
J = 11.0 Hz, 1H), 4.25 (d, J = 12.0 Hz, 1H), 4.00 (m, 1H), 3.60 (m,
2H), 3.55 (dd, J = 7.0 Hz and J = 3.5 Hz, 1H), 2.75 (d, J = 6.0 Hz
1H); 13C NMR (125 MHz, CDCl3) d 163.0, 158.4, 137.9, 137.5,
137.4, 128.8, 128.7, 128.6, 128.5, 128.2, 128.1, 121.5 81.6, 76.5,
74.7, 73.7, 71.3, 71.1, 70.2; FAB-HRMS m/z calcd for C29H31N3O4
[M+H]+: 486.2393; found: 486.2396. Compound 16: Sticky Oil,
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½
a 2D8
ꢀ
ꢁ48.47 (c 0.346, CHCl3); TLC: Rf = 0.49 (2:3, EtOAc/hexane,
v/v); 1H NMR (500 MHz, CDCl3) d 8.72 (s, 2H), 8.39 (d, J = 8.5 Hz,
2H), 7.48 (d, J = 8.5 Hz, 2H), 7.33–7.25 (m, 10H), 7.16–7.15 (m,
3H), 7.00 (dd, J = 7.0 Hz and 2.5 Hz, 2H), 4.76 (d, J = 2.5 Hz, 1H),
4.58 (d, J = 12.0 Hz, 1H), 4.52 (br s, 2H), 4.37 (d, J = 11.5 Hz, 1H),
4.32 (d, J = 11.5 Hz, 1H), 4.14 (d, J = 11.5 Hz, 1H), 4.04 (m, 1H),
3.64 (br d, J = 4.0 Hz, 2H), 3.61 (dd, J = 7.5 Hz and 2.5 Hz, 1H),
2.57 (d, J = 4.5 Hz 1H); 13C NMR (125 MHz, CDCl3) d 163.4, 157.0,
137.8, 137.2, 137.1, 137.0, 136.1, 130.1, 129.7, 129.1, 128.8,
128.7, 128.6, 128.5, 128.3, 81.2, 76.5, 74.6, 73.8, 72.0, 70.8, 70.1;
LRMS m/z calcd for C35H33ClN2O4 [M+H]+: 581.22; found: 581.25.
Acknowledgments
This work is supported by (1) the Korea Science and Engineer-
ing Foundation (KOSEF); (2) MarineBio Technology Program
funded by Ministry of Land, Transport, and Maritime Affairs, Korea;
and (3) the Research Program for New Drug Target Discovery grant
from the Ministry of Education, Science & Technology (MEST). R.S.
and M.J.K are grateful for the fellowship award of the Brain Korea
21 Program.
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Supplementary data
8. Sagar, R.; Park, S. B. J. Org. Chem. 2008, 73, 3270.
General experimental and synthetic procedures, complete spec-
tral data and the copies of 1H and 13C NMR spectra of all com-
pounds 10–23 are available. Supplementary data associated with
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j.tetlet.2008.06.032.
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