Highly efficient AgNO3-catalyzed preparation of substituted furano-pyrimidine nucleosides

Article abstract of DOI:10.1055/s-2004-831330

An efficient method for the synthesis of substituted furanopyrimidine nucleosides is described. Upon treatment with catalytic AgNO₃, 5-alkynyl uracil derivatives were almost quantitatively converted into their corresponding bicyclic nucleoside

Full text of DOI:10.1055/s-2004-831330

2406
LETTER
Highly Efficient AgNO3-Catalyzed Preparation of Substituted Furano-
pyrimidine Nucleosides
Preparation of
S
ub
i
stituted
n
F
uranopyrim
c
idine
N
uc
e
leosides nt Aucagne, Franck Amblard, Luigi A. Agrofoglio*
ICOA UMR CNRS 6005, BP 6759, 45067 Orleans Cedex 2, France
Fax +33(2)38510728; E-mail: luigi.agrofoglio@univ-orleans.fr
Received 19 June 2004
The most common synthetic pathway for cyclization to
the target bicyclic nucleosides 1, as reported by Robins
and Barr,4 consists of the base and copper-catalyzed 5-
endo-dig cyclization of alkynyluridines 3 with CuI in tri-
ethylamine/methanol at reflux, between the C-4 pyrimi-
dine oxygen and acetylenic bond (Scheme 1). Similar
cyclization was noted in Stephens–Castro couplings of o-
iodoanilines with copper(I) acetylides5 by Bleackley et
al.6 Considerable amounts of this cyclized by-product
were isolated when longer reaction times were employed
or when an electron-withdrawing group was present on
the alkyne moiety. Homocoupling was found to compete
with cross-coupling, depending upon the steric hindrance
around the catalyst.
Abstract: An efficient method for the synthesis of substituted
furanopyrimidine nucleosides is described. Upon treatment with
catalytic AgNO3, 5-alkynyl uracil derivatives were almost quanti-
tatively converted into their corresponding bicyclic nucleoside
analogues.
Key words: AgNO3, cyclization, furanopyrimidines
Various C-5-alkynyl nucleosides can be obtained in high
yields (70–97%) by the cross-coupling of halogenated de-
rivatives with terminal alkynes under Pd(0)-catalyzed
Sonogashira coupling conditions.1 In most cases, a strong-
ly fluorescent furanopyrimidine derivative by-product
could be isolated with a <7% yield, or just detected by
TLC. Recently, McGuigan et al.2 reported that com-
pounds such as 1 displayed important potency and exclu-
sive selectivity against varicella zoster virus (VZV).
Structurally-related imidazo[1,2-c]pyrimidin-5(6H)-one
heterosubstituted nucleoside analogs 2 were discovered
by Mansour et al.3 to have anti-HBV (hepatitis B virus)
activity (Figure 1). Despite their biological importance,
the synthetic methodology used for the O-hetero-annula-
tion process is limited and suffers from poor to moderate
yields (8–73%). A more versatile and efficient procedure
remains a challenge.
Scheme 1
Motivated by our recent work concerning the palladium-
catalyzed synthesis of uridines on polystyrene based solid
supports,7 we explored a 5-endo-dig electrophilic cycliza-
tion catalyzed by AgNO3.8 The Lewis acid nature of
AgNO3 enables it to complex with alkynes and allenes,
thus permitting an intramolecular cycloaddition to pro-
ceed. This procedure has already been used, for instance,
on various phenolic keto-ynes9 and a-hydroxyallenes.10
Nevertheless, no systematic application to a-alkynyl car-
bonyl compounds, especially in the field of nucleosides,
has been explored. We describe herein the use of AgNO3,
as a clean, efficient and improved method for the synthe-
sis of known or new alkyl furanopyrimidine nucleosides
(Figure 2). In all cases, the cyclization yields were >95%,
with no need for purification.
Figure 1 Structure of antiviral furano- (1) and imidazopyrimidine
(2) nucleosides
To confirm the viability of our method we treated differ-
ent substrates with a catalytic amount of AgNO3: 2¢-
deoxyribosyl nucleosides (series 1) and acyclonucleo-
sides (series 2 and 3), which were substituted at C-5 with
either alkyl- or alkylphenyl alkynes (Table 1). Thus ac-
cording to the literature, 5-alkynyluraciles derivatives
were first prepared from known iodinated protected
SYNLETT 2004, No. 13, pp 2406–2408
0
3
.1
1
.2
0
0
4
Advanced online publication: 31.08.2004
DOI: 10.1055/s-2004-831330; Art ID: D16304ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of Substituted Furanopyrimidine Nucleosides
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Scheme
2
Hypothesized mechanism for cyclization through
AgNO3
Figure 2 Structure of obtained furopyrimidines nucleosides
This hypothetical mechanism can be divided into two
steps: (1) initial activation of the triple bond through its
complexation with Ag+ and (2) intramolecular attack of
the oxygen across the activated carbon-carbon triple bond
with subsequent proton transfer and release of Ag+, to
give the target furanopyrimidine product C.
precursors 7,11 8,12 913 under Sonogashira cross-coupling
conditions14 at room temperature.15 The cyclization16 oc-
curred in the presence of a catalytic amount of AgNO3
(Table 1), affording the desired bicyclic furanopyrimidine
nucleosides 13, 14a,b, 15a,b17 with no purification neces-
sary other than an extraction to remove the catalyst. In all
cases, the isolated yields were >95%. After an appropriate
deprotection step18,19 (TFA–H2O, 2:1, v/v or MeOH–pyri-
dine–H2O–NaOH), the unprotected bicyclic nucleosides
1, 5a,b, 6a,b20 were isolated in quantitative yields. This
electrophilic 5-endo-dig cyclization with AgNO3 is be-
lieved to proceed through a catalytic mechanism involv-
ing a cationic intermediate (Scheme 2).
In summary, we have demonstrated that the electrophilic
cyclization using AgNO3 at room temperature is an im-
proved and useful alternative pathway for the cyclization
of a-alkynyl carbonyl compounds giving access to alkyl
furano pyrimidine in quantitative yields (>95%). Further
work is in progress to extend the present methodology to
the preparation of more complex molecular structures and
to its application to the synthesis of furanopyrimidine
nucleosides on solid support.
Table 1 Cyclization of Alkynylpyrimidines Derivatives Using Catalytic AgNO3
Entry
1
R
Iodo compound
R1
Alkynes Product
(Yield, %)
Cyclized Product
(Yield, %)
7
PhC5H11
10
13
(>98%)a,b
2
3
4
8
9
PhC5H11
C8H17
11a
11b
14a
(98%)a
14b
(98%)a
PhC5H11
12a
(78%)
15a
(95%)c
5
C8H17
12b
15b
(61%)
(98%)
a Yield calculated over 2 steps.
b <20% Cyclization yield using CuI–Et3N–MeOH.
c <50% Yield with CuI, Et3N, MeOH.
Synlett 2004, No. 13, 2406–2408 © Thieme Stuttgart · New York

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V. Aucagne et al.
LETTER
(CH2), 22.7 (CH2), 25.8 (CH3), 26.7 (CH3), 28.6 (CH2), 29.1
(CH2), 29.2 (CH2), 29.3 (CH2), 31.9 (CH2), 49.3 (CH2), 69.3
(CH2), 70.8, 75.9 (CH), 95.9, 101.3, 109.8, 126.6 (CH),
133.4 (CH), 145.4 (CH), 149.8, 162.2. HRMS (ESI): m/z
calcd for C22H32N2O4Na: 411.2260 [M + Na]+. Found:
411.2259.
Acknowledgment
We thank the CNRS and MENRT for financial support. F. Amblard
thanks the MENRT for a Ph.D. fellowship.
References
(16) General Procedure for Alkyne Cyclization Reactions:
Under dry nitrogen, the alkyne derivatives (0.047 mmol)
were dissolved in acetone (1 mL), then AgNO3 (0.009
mmol) was added. The reaction was stirred at r.t. until
complete conversion was reached. After evaporation of
volatiles, the crude residue was dissolved in EtOAc, washed
3 times with H2O, dried over MgSO4, filtered and concentred
in vacuo. The cyclized compound was pure enough (purity
determined by proton-decoupled 13C NMR) to be subjected
to the next reaction without further purification.
(17) 3-[(E)-3-(2,2-Dimethyl-1,3-dioxolan-4-yl)-2-propenyl]-6-
(4-pentylphenyl)furo[2,3-d]pyrimidin-2-(3H)-one (15a):
1H NMR (CDCl3): d = 0.90 (t, 3 H, J = 6.7 Hz), 1.21–1.41
(m, 4 H), 1.38 (s, 3 H), 1.42 (s, 3 H), 1.55–1.71 (m, 2 H), 2.64
(t, 2 H, J = 7.3 Hz), 3.61 (dd, 1 H, J = 8.0 Hz), 4.11 (dd, 1 H,
J = 6.1 Hz, J = 8.0 Hz), 4.50–4.76 (m, 3 H), 5.77 (dd, 1 H,
J = 7.0 Hz, J = 15.5 Hz), 6.01 (dt, 1 H, J = 6.0 Hz, J = 15.5
Hz), 6.64 (s, 1 H), 7.25 (d, 2 H, J = 8.1 Hz), 7.66 (d, 2 H,
J = 8.1 Hz), 7.89 (s, 1 H). 13C NMR (CDCl3): d = 14.1 (CH3),
22.6 (CH2), 25.9 (CH3), 26.7 (CH3), 31.0 (CH2), 31.5 (CH2),
35.9 (CH2), 52.4 (CH2), 69.3 (CH2), 76.1 (CH), 96.4 (CH),
108.9, 109.8, 125.1 (CH × 2), 125.7, 127.5 (CH), 129.2 (CH
× 2), 133.4 (CH), 138.9 (CH), 145.4, 155.2, 156.4, 171.9.
HRMS (ESI): m/z calcd for C25H30N2O4Na: 445.5186 [M +
Na]+. Found: 445.5182.
(1) Agrofoglio, L. A.; Gillaizeau, S.; Saito, Y. Chem. Rev. 2003,
103, 1875; and references cited therein.
(2) (a) McGuigan, C.; Yarnold, C. J.; Jones, G.; Velasquez, S.;
Barucki, H.; Brancale, A.; Andrei, G.; Snoeck, R.; De
Clercq, E.; Balzarini, J. J. Med. Chem. 1999, 42, 4479.
(b) McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.;
Erischen, J. T.; Andrei, G.; Snoeck, R.; De Clercq, E.;
Balzarini, J. J. Med. Chem. 2000, 43, 4993. (c) Srinivasan,
S.; McGuigan, C.; Andrei, G.; Snoeck, R.; De Clercq, E.;
Balzarini, J. Bioorg. Med. Chem. Lett. 2001, 11, 391.
(d) McGuigan, C.; Brancale, A.; Barucki, H.; Srinivasan, S.;
Jones, G.; Pathirana, R.; Blewett, S.; Alvarez, R.; Yarnold,
C. J.; Carangio, A.; Velazquez, S.; Andrei, G.; Snoeck, R.;
De Clercq, E. Drugs Future 2000, 25, 1151. (e) Carangio,
A.; McGuigan, C.; Andrei, G.; Snoeck, R.; De Clercq, E.;
Balzarini, J. Antivir. Chem. Chemother. 2001, 12, 187.
(3) Mansour, T. S.; Evans, C. A.; Charron, M.; Korba, B. E.
Bioorg. Med. Chem. Lett. 1997, 7, 303.
(4) (a) Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854.
(b) Robins, M. J.; Barr, P. J. Tetrahedron Lett. 1981, 22, 421.
(5) Castro, C. E.; Gaughan, E. J.; Owsley, D. C. J. Org. Chem.
1966, 31, 4071.
(6) Bleackley, R. C.; Jones, A. S.; Walker, R. T. Tetrahedron
1976, 32, 2795.
(18) General Procedure for Deprotection of Acetalic
Derivatives: The protected derivative (acetal, 0.22 mmol)
was stirred at r.t. for 3 h in a mixture of TFA–H2O (10 mL/
5 mL). After evaporation of volatiles the crude residue was
purified by flash chromatography.
(19) General Procedure for Deacetylation: Acetylated
nucleoside analogue (1 mmol) was dissolved in pyridine (10
mL) and EtOH (5 mL). The reaction mixture was cooled to
–10 °C and 5 mL of 1 M NaOH aq solution was added. The
resulting solution was stirred at this temperature until
completion (typically 1–4 h, followed by TLC). The reaction
mixture was neutralized with Dowex (H+ form) then filtered
through a fritted glass funnel. Solvents were evaporated in
vacuo and the oily residue was submitted to a flash column
chromatography using an appropriate eluent (typically
hexanes–EtOAc 25:75, EtOAc, and MeOH–EtOAc 1%) to
furnish the desired nucleosides.
(20) 1-[(E)-4,5-dihydroxy-2-pentenyl]-5-[2-(4-pentyl-
phenyl)ethynyl]-2,4 (1H,3H)-pyrimidinedione (6a): 1H
NMR (DMSO-d6): d = 0.73–0.91 (m, 3 H), 1.18–1.37 (m, 4
H), 1.49–1.68 (m, 2 H), 2.57 (t, 2 H, J = 7.5 Hz), 3.22–3.33
(m, 2 H), 3.91–4.03 (m, 1 H), 4.25–4.39 (m, 2 H), 4.51–4.61
(m, OH), 4.86 (d, OH, J = 4.5 Hz), 5.69–5.85 (m, 2 H), 7.22
(d, 2 H, J = 8.0 Hz), 7.36 (d, 2 H, J = 8.0 Hz), 8.10 (s, 1 H)
11.64 (s, NH). 13C NMR (DMSO-d6): d = 13.9 (CH3), 21.9
(CH2), 30.3 (CH2), 30.8 (CH2), 34.9 (CH2), 48.9 (CH2), 65.7
(CH2), 71.4 (CH), 81.6, 92.0, 97.7, 119.6, 123.7 (CH), 128.7
(CH × 2), 131.0 (CH × 2), 135.8 (CH), 143.2, 148.3 (CH),
149.8, 161.9. HRMS (ESI): m/z calcd for C22H26N2O4Na:
405.1790 [M + Na]+. Found: 405.1791.
(7) Aucagne, V.; Berteina-Raboin, S.; Guenot, P.; Agrofoglio,
L. A. J. Comb. Chem. 2004, in press.
(8) For electrophilic cyclization using NIS or NBS, see:
(a) Rao, M. S.; Esho, N.; Sergeant, C.; Dembinski, R. J. Org.
Chem. 2003, 68, 6788. (b) Arcadi, A.; Cacchi, S.; Di
Giuseppe, S.; Babrizi, G.; Marinelli, F. Org. Lett. 2002, 4,
2409.
(9) Jong, T.-T.; Leu, S.-J. J. Chem. Soc., Perkin Trans. 1 1990,
423.
(10) Marshall, J. A.; Wang, X. J. J. Org. Chem. 1990, 55, 2995.
(11) Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854.
(12) Kelly, J. L.; Kelsey, J. E.; Hull, W. R.; Krochmal, M. P.;
Schaeffer, H. J. J. Med. Chem. 1981, 24, 753.
(13) Amblard, F.; Nolan, S. P.; Gillaizeau, I.; Agrofoglio, L. A.
Tetrahedron Lett. 2003, 44, 9177.
(14) Typical Procedure for Sonogashira Cross-Coupling.
Under dry nitrogen, the iodo derivatives (0.026 mmol) were
dissolved in DMF (0.5 mL), then alkyne (0.079 mmol), Et3N
(0.079 mmol), CuI (0.005 mmol), PdCl2 (PPh3)2 (0.003
mmol) were added. The reaction was stirred at r.t. until
complete conversion was reached. After evaporation of
volatiles the crude residue was purified by flash
chromatography.
(15) 5-(1-decynyl)-1-[(E)-3-(2,2-dimethyl-1,3-dioxolan-4-yl)-
2-propenyl]-2,4 (1H,3H)-pyrimidinedione (12b): 1H
NMR (CDCl3): d = 0.86 (t, 3 H, J = 6.9 Hz), 1.15–1.48 (m,
16 H), 1.50–1.63 (m, 1 H), 2.36 (t, 2 H, J = 6.9 Hz), 3.58 (dd,
1 H, J = 8.0 Hz), 4.10 (dd, 1 H, J = 6.3 Hz, J = 8.0 Hz), 4.22–
4.41 (m, 2 H), 4.48–4.61 (m, 1 H), 5.72 (dd, 1 H, J = 6.0 Hz,
J = 15.4 Hz), 5.83 (dt, 1 H, J = 5.7 Hz, J = 15.4 Hz), 7.31 (s,
1 H), 9.17 (s, 1 H). 13C NMR (CDCl3): d 14.2 (CH3), 19.7
Synlett 2004, No. 13, 2406–2408 © Thieme Stuttgart · New York