Tandem reactions leading to bicyclic pyrimidine nucleosides and benzopyran-4-ones

Article abstract of DOI:10.1021/jo102131y

A novel, rapid, and efficient synthesis of bicyclic pyrimidine nucleosides and benzopyran-4-ones through oxidation of homopropargyl alcohols and subsequent isomerization, intramolecular addition of enol to allenic ketone has been developed. This methodology provides an efficient and promising approach to the structurally and pharmaceutically interesting pyrano[2,3-d]pyrimidine-2,5-dione nucleoside and benzopyran-4-one derivatives.

Full text of DOI:10.1021/jo102131y

pubs.acs.org/joc
antiviral and antimicrobial agents by exploiting the versatile
Tandem Reactions Leading to Bicyclic Pyrimidine
Nucleosides and Benzopyran-4-ones
aldehyde synthon 5-formyl-20-deoxyuridine (1).3 As a continua-
tion of our efforts, we were interested in pyrimidine nucleoside
with a propargyl ketone moiety on the 5-position of the
pyrimidine unit (3). The rationale behind this strategy is that
many pyrimidine nucleosides substituted at the 5-position are
known to have potent biological activities and SAR studies
indicate that the type of C-5 substituents likely to confer activity
are electron-withdrawing groups conjugated to the pyrimidine
ring.1 Moreover, considering the diverse reactivity shown by
propargyl ketones, the proposed hybrid compound combining
a pyrimidine nucleoside and a propargyl ketone moiety is a
good point of departure for further structural elaborations.
Our envisioned route to the proposed propargyl ketone 3 is
based on a known oxidation of homopropargyl alcohol with
Jones reagent.4 Thus, 2a was prepared from 5-formyl-30,50-di-
O-acetyl-20-deoxyuridine (1a)5 and then treated with Jones
reagent at 0 °C in acetone (Scheme 1). It turned out that 2a
was consumed completely in 10 min to give a product whose 1H
NMR spectra did not support the formation of 3. Upon
analysis of its 1H, 13C NMR, COSY, NOESY, and mass spec-
tra, the product was identified as a pyrano[2,3-d]pyrimidine-2,5-
dione nucleoside (4a). To confirm this structure, single crystals
of 4a suitable for X-ray diffraction characterization were ob-
tained by recrystallization from CH2Cl2/MeOH (2:1), and the
molecular structure clearly shows the six-membered pyran-4-
one ring.
Xuesen Fan,* Yangyang Wang, Yingying Qu, Haiyun Xu,
Yan He, Xinying Zhang,* and Jianji Wang
School of Chemistry and Environmental Science, Key
Laboratory of Green Chemical Media and Reactions,
Ministry of Education, Henan Key Laboratory for
Environmental Pollution Control, Henan Normal University,
Xinxiang, Henan 453007, People’s Republic of China
xuesen.fan@henannu.edu.cn; xinyingzhang@henannu.edu.cn
Received October 31, 2010
A novel, rapid, and efficient synthesis of bicyclic pyrimi-
dine nucleosides and benzopyran-4-ones through oxidation
of homopropargyl alcohols and subsequent isomerization,
intramolecular addition of enol to allenic ketone has been
developed. This methodology provides an efficient and
promising approach to the structurally and pharmaceuti-
cally interesting pyrano[2,3-d]pyrimidine-2,5-dione nucleo-
side and benzopyran-4-one derivatives.
SCHEME 1. Unexpected Formation of 4a
Although the modification of pyrimidine nucleosides and
nucleotides has resulted in a plethora of therapeutic agents
for a variety of diseases,1 the hunt for novel nucleoside
analogues as new drug candidates is still intense. It is not
only because there are still many diseases without an effective
remedy, but also due to the fact that many of the current
agents have been found to show such limitations as adverse
effects, insufficient selectivity for drug targets, and high
propensity for drug resistance.2
Further studies showed that with CrO3 alone (1.2 equiv) as
the oxidant, the reaction was reluctant to proceed. Over as
long as 3 h, 4a was only obtained in 15% yield. Increasing the
amount of CrO3 to 2.4 equiv did not improve the reaction.
With sulfuric acid alone, however, the reaction gave a black-
ish mixture beyond identification over stirring for 3 h. As
In recent years, we have conducted an ongoing study on the
design and synthesis of novel nucleoside analogues as potential
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M. N.; Kern, E. R.; Torrence, P. F. J. Med. Chem. 2006, 49, 4052. (b) Fan,
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Torrence, P. F. J. Med. Chem. 2006, 49, 3377. (c) Fan, X. S.; Feng, D.; Qu,
Y. Y.; Zhang, X. Y.; Wang, J. J.; Loiseau, P. M.; Andrei, G.; Snoeck, R.; De
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982 J. Org. Chem. 2011, 76, 982–985
Published on Web 01/07/2011
DOI: 10.1021/jo102131y
r
2011 American Chemical Society

Fan et al.
JOCNote
SCHEME 2. Plausible Pathway for the Formation of 4a
thieno-,12 oxazolo-,13 or pyridopyrimidine14 nucleoside analo-
gues, have been achieved and many of them have demonstrated
highly potent biological activities. To our knowledge, however,
there is still no report on the synthesis and biological study of
pyrano[2,3-d]pyrimidine-2,5-dione nucleoside. This prompted us
to investigate the scope and generality of this procedure and to
prepare more pyrano[2,3-d]pyrimidine-2,5-dione nucleoside deri-
vatives for biological studies.
Thus, a series of homopropargyl alcohols (2b-h) were
prepared and treated with Jones reagent (Table 1). This
showed that not only susbstrates in the 20-deoxyuridine series
underwent this procedure efficiently to give the bicyclic
nucleosides in high yields (entries 1 and 2), the 20,30-dideox-
yuridine (entry 3), ribonucleoside (entry 4), and acyclic
pyrimidine nucleoside substrates (entries 5-8) all afforded
the desired products in good yields. It was also shown that
several functional groups, such as acetyl, benzyl, homopro-
pargyl, and azido groups, were well tolerated under the
reaction conditions, thus resulting in a very efficient and
general methodology for the preparation of pyranopyrimi-
dine-2,5-dione nucleosides.
It is then noted that for substrates 2a-d, the 20-, 30-, or 50-
hydroxyl group(s) are protected with acetyl to avoid possible
side reactions and to facilitate purification in subsequent
reactions. Since the biological activity of nucleosides is often
correlated to their ability to be phosphorylated in vivo, and
nucleoside drugs are usually administered with free hydroxyl
group(s), efforts were then made to deprotect 4a-d. We were
able to find that the acetyls of 4a-d could be conveniently
removed with saturated ammonia in MeOH at room tem-
perature (Table 2).15
In a further aspect, based on the above results and taking
into account the proposed mechanism for the formation of 4,
we envisioned that 2-(1-hydroxybut-3-ynyl)phenol (6a), de-
rived from 2-hydroxybenzaldehyde and propargyl bromide,
if treated with Jones reagent, might follow the oxidation/
intramolecular cyclization cascade process to give benzopyr-
an-4-one (7a). Indeed, subsequent studies revealed that upon
treating with Jones reagent in acetone, 6a reacted rapidly to
give 7a in a yield of 88% in 5 min (Scheme 3).
It is well-known that the benzopyran-4-one moiety is a key
component for a number of natural products and clinically
used drugs by acting as one of the most powerful pharmaco-
phores. Compounds with this framework have shown various
pharmacological and biological activities.16-22 On the other
hand, benzopyran-4-ones are also important synthons in
a further aspect, Dess-Martin periodinane, a frequently
used oxidant for the preparation of allenic ketones from
homopropargyl alcohols,6 was tried. It followed that upon
treating with periodinane (1.2 equiv) for 3 h, 2a was con-
sumed and 4a was obtained in a yield of 65%.
On the basis of the above observations, a tentative path-
way for the formation of 4a is depicted in Scheme 2. First, 2a
was oxidized by Jones reagent to give a propargyl ketone (3),
which then isomerized into the corresponding 1,2-allenic ketone
(A). The allenic group conjugated to the carbonyl then under-
went an intramolecular nucleophilic addition with the in situ
formed enol unit (B) to form a pyran-4-one scaffold. The fact
that CrO3 alone is not as effective as Jones reagent or Dess-
Martin periodinane in the formation of 4a suggests that acids
(sulfuric acid in Jones reagent and acetic acid formed in the
oxidation process with Dess-Martin periodinane) play an im-
portant role, which is most likely attributed to their capability as
an acid in facilitating the keto-enol tautomerism. The acid may
also play a catalytic role in generating and activating the allene
and facilitating olefin isomerization. Moreover, it is possible to
give either R,β-unsaturated adduct (4a) orβ,γ-unsaturated adduct
(4a0) from B. According to literature results, the regio-selectivity
might be affected by the stability of products, the nature of
the nucleophile, and the reaction conditions.7 In our hands, only
the more stable R,β-unsaturated ketone (4a) was obtained.
This unexpected result turned out to be very interesting
and promising since bicyclic pyrimidine nucleosides have
long been of remarkable interest in both medicinal and
synthetic chemistry. To date, various bicyclic pyrimidine
nucleosides, such as furano-,8 pyrrolo-,9 imidazo-,10 thiazolo-,11
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J. Org. Chem. Vol. 76, No. 3, 2011 983

Fan et al.
JOCNote
TABLE 1. Synthesis of Bicyclic Pyrimidine Nucleosides 4a
TABLE 2. Deprotection of Bicyclic Nucleosides 4a
aReaction conditions: 4 (0.5 mmol), sat. NH3/MeOH (5 mL), rt, 6 h.
bIsolated yields.
SCHEME 3. Synthesis of Benzopyran-4-one (7a)
bases,24 (ii) cyclocondensation of salicylate with dimethyl allene-
1,3-dicarboxylate in the presence of t-BuOK in t-BuOH,25 and
(iii) intramolecular Wittig reaction of acylphosphoranes.26 More
recently, Snieckus et al. reported that chromone deriva-
tives could be obtained by anionic carbamoyl transloca-
tion reactions.27 In spite of the success of the aforesaid methods,
(22) Hasan, S. M.; Alam, M. M.; Husain, A.; Khanna, S.; Akhtar, M.;
Zaman, M. S. Eur. J. Med. Chem. 2009, 44, 4896.
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M. A.; Ali, T. E.; Alnamer, Y. A.; Gabr, Y. A. Arkivoc 2010, 98.
(24) (a) Baker, W. J. Chem. Soc. 1933, 1381. (b) Hirao, I.; Yamaguchi,
M.; Hamada, M. Synthesis 1984, 1076.
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1983, 24, 597. (b) Nixon, N. S.; Scheinmann, F.; Suschitzky, J. L. J. Chem.
Res. (S) 1984, 380.
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(b) Lee, K. J.; Kim, S.; Park, H. Bull. Korean Chem. Soc. 1991, 12, 120.
(c) Bestmann, H. J.; Schade, G. Chem. Lett. 1983, 997. (d) Kumar, P.; Bodas,
M. S. Org. Lett. 2000, 2, 3821.
aReaction conditions: 2 (1.0 mmol), Jones reagent (1.2 mmol),
acetone (10 mL), 0 °C, 10 min. bIsolated yields.
organic synthesis.23 Generally, they are prepared through
(i) cyclodehydration of 1-(o-hydroxyaryl)-1,3-diketone or
equivalent intermediates catalyzed by strong acids or strong
(27) Macklin, T. K.; Panteleev, J.; Snieckus, V. Angew. Chem., Int. Ed.
2008, 47, 2097.
984 J. Org. Chem. Vol. 76, No. 3, 2011

Fan et al.
JOCNote
TABLE 3. Synthesis of Benzopyran-4-ones 7a
also react smoothly to give 7g in 86% yield (entry 7). In
addition, 1-(1-hydroxybut-3-ynyl)naphthalen-2-ol (6h)
proved to be a suitable substrate for this reaction and
afforded 3-methyl-1H-benzo[f]chromen-1-one (7h) in good
yield (entry 8). These promising results allow the present
procedure to be used as a rapid and general protocol for the
preparation of benzopyran-4-ones.
In summary, a novel and efficient synthesis of bicyclic
pyrimidine nucleosides and benzopyran-4-ones is developed.
To the best of our knowledge, this is the first report of
pyrano[2,3-d]pyrimidine-2,5-dione nucleosides and the first
example in which benzopyran-4-one derivatives are prepared
via oxidation of homopropargyl alcohol derived from 2-hy-
droxyaromatic aldehyde. The synthetic procedure itself has
advantages such as high efficiency, readily obtainable start-
ing material, very cheap reagents, and extremely mild reac-
tion conditions. Current studies are in progress to extend the
synthetic potential of this novel procedure and to study the
biological activities of the bicyclic pyrimidine nucleosides
obtained in this work.
Experimental Section
5-Formylpyrimidine nucleosides (1a-h) were prepared
through oxidation of the corresponding 5-methylpyrimidine
nucleosides. Homopropargyl alcohols 2a-h were prepared
through zinc promoted propargylation of 5-formylpyrimidine
nucleosides (1a-h) with propargyl bromide based on literature
procedure.5 Homopropargyl alcohol substrates 6a-h were pre-
pared through zinc-promoted propargylation of 2-hydroxyben-
zaldehydes which are all commercially available.5
Typical Procedure for the Preparation of 4a. To a solution of
2a (380 mg, 1 mmol) in acetone (10 mL) cooled to 0 °C was added
Jones reagent (1.2 mmol) in a dropwise manner. Upon complete
consumption of the starting material as monitored by TLC, the
reaction mixture was quenched by addition of isopropanol. The
mixture was filtered and the filtrate was concentrated under
vacuum. The residue was purified by column chromatography
on silica gel with CH3OH/CH2Cl2 (0-2%) to give 4a as colorless
solids. 1H NMR (400 MHz, CDCl3) δ 2.11 (s, 3H), 2.17 (s, 3H),
2.23-2.30 (m, 1H), 2.35 (s, 3H), 2.86-2.92 (m, 1H), 4.37-4.45 (m,
3H), 5.20-5.23 (m, 1H), 5.98 (s, 1H), 6.28-6.31 (m, 1H), 9.15 (s,
1H). 13C NMR (100 MHz, CDCl3) δ 20.5, 20.6, 20.8, 39.5, 63.0,
73.2, 83.4, 88.5, 104.4, 110.3, 148.0, 153.3, 167.1, 168.3, 170.2,
170.4, 175.8. MS m/z 379 (MH)þ. HRMS (FAB) calcd for
C17H19N2O8 379.1142 [M þ H], found 379.1148.
aReaction conditions: 7 (1.0 mmol), Jones reagent (1.2 mmol),
acetone (10 mL), 0 °C, 5 min. bIsolated yields.
some of them still suffer from harsh reaction conditions, tedious
procedures, or low yields. This prompted us to investigate the
possibility of developing the present procedure into a general and
practical method for the synthesis of benzopyran-4-ones. Thus, a
variety of propargyl alcohols (6b-h) were prepared and treated
with Jones reagent. The results are summarized in Table 3.
From Table 3, it was concluded that for substrates with
either electron-withdrawing or electron-donating groups, the
reactions proceeded smoothly to give the desired products in
good yields. Functional groups, such as nitro, methoxy, and
halide, were well tolerated under these conditions. It is notable
that 6g with bulky tert-butyl groups on the phenyl ring could
Acknowledgment. We are grateful to the National Natural
Science Foundation of China (Nos. 20772025 and 20972042),
Innovation Scientists and Technicians Troop Construction
Projects of Henan Province (No. 104100510019), and the
program for Innovative Research Team in University of Henan
Province (2008IRTSTHN002) for financial support.
Supporting Information Available: Experimental details,
X-ray crystal structure of 4a, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 3, 2011 985