Efficient palladium-mediated or base-induced 5-endo-dig cyclisation of C5-alkynylated pyrimidine derivatives: Conventional and microwave-assisted synthesis of novel furo[2,3-d]pyrimidines

Article abstract of DOI:10.1016/j.tetlet.2012.07.068

A series of the novel 5-alkynyl- and furo[2,3-d]pyrimidine derivatives in which the sugar moiety is replaced by a methoxymethyl (MOM) group is synthesised using the Sonogashira cross-coupling reaction under both conventional and microwave conditions, in g

Full text of DOI:10.1016/j.tetlet.2012.07.068

Tetrahedron Letters 53 (2012) 5144–5147
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient palladium-mediated or base-induced 5-endo-dig cyclisation of
C5-alkynylated pyrimidine derivatives: conventional and microwave-assisted
synthesis of novel furo[2,3-d]pyrimidines
a,
⇑
a
a
b
b
´
´
´
´
´
´
Tatjana Gazivoda Kraljevic , Andrea Bistrovic , Matea Dedic , Sandra Kraljevic Pavelic , Mirela Sedic ,
a,
⇑
´
´
Silvana Raic-Malic
a Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Maruli´cev trg 19, HR-10000 Zagreb, Croatia
Department of Biotechnology, University of Rijeka, Trg bra´ce Mazurani´ca 10, HR-51000 Rijeka, Croatia
b
ˇ
a r t i c l e i n f o
a b s t r a c t
Article history:
A series of the novel 5-alkynyl- and furo[2,3-d]pyrimidine derivatives in which the sugar moiety is
replaced by a methoxymethyl (MOM) group is synthesised using the Sonogashira cross-coupling reaction
under both conventional and microwave conditions, in good to excellent yields. The 5-endo-dig cyclisa-
tion of 5-alkynylpyrimidine derivatives promoted by a Pd-catalyst or base gives the corresponding
furo[2,3-d]pyrimidines in good yields.
Received 28 March 2012
Revised 29 June 2012
Accepted 12 July 2012
Available online 20 July 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
5-Alkynylpyrimidines
Furo[2,3-d]pyrimidines
N-Methoxymethylated pyrimidine
derivatives
Sonogashira cross-coupling reaction
5-Endo-dig cyclisation
Nucleoside analogues continue to dominate the area of antiviral
therapy and make a significant contribution to cancer chemother-
apy. Furthermore, the structural diversity and biological impor-
tance of pyrimidines have made them attractive targets for
synthesis. For this reason, numerous analogues and derivatives of
pyrimidines have been synthesised and developed as pharmaco-
logically active compounds or drugs.1 In particular, a number of
pyrimidine nucleoside analogues with potent biological properties
have been prepared by substitution at the 5-position of the pyrim-
idine ring.2 Moreover, functionalised alkynes are found to be
important building blocks for the synthesis of biologically active
pyrimidine derivatives.3 Bicyclic pyrimidine nucleosides such as
oxazole-, thieno- or imidazopyrimidines have demonstrated
pronounced antiviral and antileukemic activities.4,5 Based on the
potent bioactivities of compounds with a furo[2,3-d]pyrimidine
core, the development of efficient syntheses of novel N-alkylated
furo[2,3-d]pyrimidine derivatives has attracted our attention. We
considered position C6 of the furopyrimidine scaffold an interest-
ing target for the synthesis of the corresponding N-MOM deriva-
tives, and employed the Sonogashira cross-coupling reaction
Pd/CuI
base
Nu
Nu
R
R
base
Nu = O, N, S
R = H, alkyl, aryl, vinyl
Scheme 1. Overview of the 5-endo-dig mode of cyclisation.
under both conventional and microwave conditions6 as the key
step.
Intramolecular 5-endo-dig cyclisation of 5-alkynylpyrimidines
is a powerful strategy for the construction of furo[2,3-d]pyrimi-
dines and other heterocycles (Scheme 1).7 Only limited examples
of the endo-mode of cyclisation under basic conditions using KOt-
Bu, Bu4NOAc, Et3N or K2CO3, and in the absence of transition met-
als, have led to functionalised cyclised products.8
As part of our ongoing research directed towards economical
and environmentally friendly cyclisations of acetylenic com-
pounds, we investigated the O-heteroannulation of 5-ethynylpy-
rimidine derivatives using microwave irradiation. Herein, we
describe the K2CO3-mediated cyclisation of 5-alkynylpyrimidine
⇑
Corresponding authors. Tel.: +385 1 4597 213; fax: +385 1 4597 250.
E-mail addresses: tatjana.gazivoda@fkit.hr (T.G. Kraljevic´), sraic@fkit.hr, silvana.
raic@fkit.hr (S. Raic´-Malic´).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.068

´
5145
T. G. Kraljevic et al. / Tetrahedron Letters 53 (2012) 5144–5147
3'-9'
R
R
1'-7'
O
O
4
2'
alkyne, base,
Pd(PPh3)4,
CuI, DMF
O
6
1'
I
7a
5
HN
HN3
5
6
N1
4a
+
conventional
(method A)
or MW
2
1
2
4
3
O
N
H
O
N
O
N
H
(method B)
H
1-10a
1-6b
R
R
1a
CH2OH
1b CH2OH
2a (CH2)3CH3
2b (CH2)3CH3
3b (CH2)4CH3
4b (CH2)5CH3
3a
4a
5a
(CH2)4CH3
(CH2)5CH3
(CH2)6CH3
5b (CH2)6CH3
6b (CH2)7CH3
6a (CH2)7CH3
7a
8a
9a
CH3
(CH2)3CH3
(CH2)4CH3
10a
Scheme 2. Conventional and microwave-assisted Sonogashira cross-coupling reactions.
derivatives, as the first example of base-induced 5-endo-dig cycli-
sation of simple unactivated alkynes in the absence of activating
and furo[2,3-d]pyrimidines 1–6b (Scheme 2). In general, the micro-
wave-assisted Sonogashira reaction gave 5-alkynylated 1–10a and
furo[2,3-d]pyrimidines 1–6b in good to excellent yields in short
reaction times. The reaction conditions and yields for the conven-
tional and microwave-assisted syntheses of compounds 1–10 are
summarised in Table 1. In comparison to reactions under micro-
wave irradiation, conventional syntheses provided 5-alkynylated
pyrimidine derivatives 1–10a in higher yields, while microwave
synthesis gave increased yields (2- to 28-fold) of bicyclic products
1–6b (Table 1). The only exception was the reaction of 5-iodouracil
with propargyl alcohol (entry 1, Table 1). It should be noted that
the microwave-assisted reaction of 5-iodouracil with (p-alkyla-
ryl)acetylenes gave only the 5-alkynylated pyrimidine derivatives
7–10a. The 5-endo-dig-cyclisation of 7–10a under both conven-
tional and microwave conditions was not detected. In contrast,
the one-step palladium-copper catalysed reaction of 5-iodouracil
with terminal alkylacetylenes gave both C5-alkynylated 1–6a and
bicyclic products 1–6b (Scheme 2).
reagents towards the alkynyl
p bond. A simple and general
approach for the synthesis of N-methoxymethylated furo[2,3-
d]pyrimidine derivatives 11–16 and 5-alkynylpyrimidine
derivatives 17–20 is presented. Sonogashira cross-couplings9 of
5-iodouracil with various alkylacetylenes and (p-alkylaryl)acety-
lenes in the presence of catalytic amounts of tetrakistriphenyl-
phosphine palladium(0) [Pd(PPh3)4], and copper(I) iodide (CuI) as
the co-catalyst and a base (Et3N) in DMF at room temperature
overnight gave the corresponding 5-alkynylated pyrimidine deriv-
atives 1–10a in good yields and furo[2,3-d]pyrimidines 1–6b as the
products of 5-endo-dig cyclisation (Scheme 2).10
To the best of our knowledge, microwave-assisted Sonogashira
cross-coupling to introduce long alkynyl and (p-alkylaryl)ethynyl
groups at position C5 of the pyrimidine moiety has never been re-
ported. Both conventional (method A) and microwave-assisted
(method B) Sonogashira reactions gave the 5-alkynylated 1–10a
Table 1
Conventional and microwave-assisted syntheses of compounds 1–10
Compd.
R
Conventional synthesis
Microwave-assisted synthesis
Base
Time (h)
Yield (%)
Base
Time (h)
Yield (%)
a
b
a
b
1
CH2OH
Et3N
(iPr)2EtN
Et3N
Et3N
Et3N
15
15
15
15
15
15
15
56
29
76
85
33
42
68
—
58
1
1
23
2
Et3N
(iPr)2Et
Et3N
Et3N
Et3N
Et3N
Et3N
0.5
2
0.5
0.5
2
71
37
25
32
18
33
8
2
—
3
25
52
7
2
3
4
5
6
(CH2)3CH3
(CH2)4CH3
(CH2)5CH3
(CH2)6CH3
(CH2)7CH3
Et3N
Et3N
2
2
12
52
7
8
Et3N
Et3N
Et3N
Et3N
24
24
24
24
55
60
78
64
—
—
—
—
Et3N
Et3N
Et3N
Et3N
10
10
10
10
14
29
48
34
—
—
—
—
CH3
(CH2)3CH3
(CH2)4CH3
9
10

´
T. G. Kraljevic et al. / Tetrahedron Letters 53 (2012) 5144–5147
5146
Compounds 1–10a were subsequently submitted to N-meth-
furo[2,3-d]pyrimidine derivatives 11–16 were also obtained from
the corresponding furopyrimidines 1–6b in methoxymethylation
reactions with K2CO3 in good to excellent yields (58–83%) (method
D, Scheme 3).12
Moreover, N,N-1,3-diMOM 5-alkynylated pyrimidine deriva-
tives (22–25) were prepared by Sonogashira cross-coupling
reactions of aliphatic acetylenes with 5-iodo-1,3-bis(methoxy-
methyl)pyrimidine (21a) using both conventional and microwave
conditions (see Supplementary data).
The structures of the newly synthesised compounds 1–20 were
deduced by analysis of their 1H and 13C NMR and mass spectra as
well as elemental analyses. The assignments of the 1H NMR spectra
were performed on the basis of the chemical shifts, signal intensi-
ties and the magnitudes and multiplicities of H–H coupling con-
stants (see Supplementary data).
oxymethylation reactions. As the literature attests, there are only
a few reports on the MOM protection of nitrogen in a pyrimidine
ring,11 and no reports of N-MOM pyrimidines with long 5-alkynyl
side chains or 6-alkylfuro[2,3-d]pyrimidines. N-methoxymethyla-
tion reactions of 5-alkynylated pyrimidine derivatives 1–10a were
performed with K2CO3 (2.5 equiv) and methoxymethyl chloride
(MOMCl, 2 equiv) in DMF at room temperature. We found that
5-alkynylpyrimidines 1–6a underwent smooth base-catalysed
5-endo-dig cyclisation, leading to the formation of furo[2,3-
d]pyrimidines 11–16 in good yields (42–59%, method C). On the
other hand, the methoxymethylation reaction of 5-[(p-alkyla-
ryl)ethynyl]pyrimidines 7–10a gave N-1-MOM 17–20a and N,N-
1,3-diMOM 17–20b 5-alkynylated pyrimidine derivatives (method
C, Scheme 3).12 Pyrimidine derivatives 7–10a bearing (p-alkyla-
ryl)acetylenes at C5 did not afford bicyclic products, even after
prolonged reaction times (method C, Scheme 3). N-3-MOM-
The 5-alkynylated and furo[2,3-d]pyrimidine derivatives 1–20
were evaluated for their cytostatic activities against human
R
O
HN
O
N
H
1-10a
K2CO3,
MOMCl,
DMF
method C
1-6a
7-10a
R
R
R
+
O
O
O
MOM
O
N
HN
O
N
R
3
1
N
1
N
3
N
O
MOM
MOM
MOM
a
b
Yield (%)
Method C Method D
Yield (%)
18, 4
R
11 CH2OH
17a,b
46
64
12 (CH2)3CH3
13 (CH2)4CH3
14 (CH2)5CH3
15 (CH2)6CH3
16 (CH2)7CH3
44
47
59
42
48
58
58
83
58
66
18a,b
19a,b
44, 17
53, 3
CH3
(CH2)3CH3
(CH2)4CH3
20a,b
23, 6
K2CO3, MOMCl,
DMF
method D
R
O
N
O
N
H
1-6b
Scheme 3. N-Methoxymethylation reactions.

´
5147
T. G. Kraljevic et al. / Tetrahedron Letters 53 (2012) 5144–5147
4. (a) Patil, V. D.; Wise, D. S.; Townsend, L. B.; Bloch, A. J. Med. Chem. 1974, 17,
1282–1285; (b) Patil, V. D.; Wise, D. S.; Wotring, L. L.; Bloomer, L. C.; Townsend,
L. B. J. Med. Chem. 1985, 28, 423–427; (c) Kifli, N.; De Clercq, E.; Balzarini, J.;
Simons, C. Bioorg. Med. Chem. 2004, 12, 4245–4252; (d) Amblard, F.; Aucagne,
V.; Guenot, P.; Schinazi, R. F.; Agrofoglio, L. A. Bioorg. Med. Chem. 2005, 13,
1239–1248.
5. (a) Miyazaki, Y.; Matsunaga, S.; Tang, J.; Maeda, Y.; Nakano, M.; Philippe, R. J.;
Shibahara, M.; Liu, W.; Sato, H.; Wang, L.; Nolte, R. T. Bioorg. Med. Chem. Lett.
2005, 15, 2203–2207; (b) Janeba, Z.; Balzarini, J.; Andrei, G.; Snoeck, R.; De
Clercq, E.; Robins, M. J. J. Med. Chem. 2005, 48, 4690–4696; (c) Foloppe, N.;
Fisher, L. M.; Howes, R.; Kierstan, P.; Potter, A.; Robertson, A. G. S.; Surgenor, A.
malignant tumour cell lines: cervical carcinoma (HeLa), breast epi-
thelial adenocarcinoma, metastatic (MCF-7), hepatocellular carci-
noma (HepG2), colorectal adenocarcinoma (SW620), pancreatic
carcinoma (MiaPaCa-2) and normal human fibroblasts (WI38).
However, the results indicated that the evaluated compounds did
not significantly inhibit any of the tested malignant tumour cell
lines.
In conclusion, we have described an efficient, experimentally
simple and attractive one-pot syntheses of 5-alkynylated pyrimi-
dines 1–10a and furo[2,3-d]pyrimidine derivatives 1–6b via a
Sonogashira cross-coupling/heteroannulation approach under
conventional and microwave conditions. While conventional syn-
thesis provided 5-alkynylpyrimidines 1–10a as the major products,
synthesis under microwave irradiation afforded bicyclic products
1–6b in considerably increased yields. We found that pyrimidine
derivatives with alkynyl side chains at C5, 1–6a, underwent smooth
base-promoted 5-endo-dig cyclisation during methoxymethylation
reactions leading to good yields of furo[2,3-d]pyrimidines 11–16.
However, pyrimidine derivatives bearing (p-alkylaryl)acetylenes
at C5 did not undergo the O-heteroannulation, thus affording N-1-
MOM 17–20a and N,N-1,3-diMOM 17–20b 5-[(p-alkylaryl)ethy-
nyl]pyrimidine derivatives. We believe this is the first report of an
alternative procedure for the synthesis of N-alkylated 5-alkynyl-
and furo[2,3-d]pyrimidine derivatives promoted by K2CO3. Further-
more, this synthetic procedure is potentially suitable for the
preparation of a variety of N-alkylated heterocyclic structural ana-
logues that could be developed as potential biologically active
compounds.
ˇ
´
E. J. Med. Chem. 2005, 48, 4332–4345; (d) Gazivoda, T.; Šokcevic, M.; Kralj, M.;
Šuman, L.; Pavelic´, K.; De Clercq, E.; Andrei, G.; Snoeck, R.; Balzarini, J.; Mintas,
´
´
M.; Raic-Malic, S. J. Med. Chem. 2007, 50, 4105–4112; (e) McGuigan, C.;
Balzarini, J. J. Antimicrob. Chemother. 2009, 64, 671–673.
6. (a) Kabalka, G. W.; Wang, L.; Pagni, R. M. Tetrahedron 2001, 57, 8017–8028; (b)
Sørensen, U. S.; Pombo-Villar, E. Tetrahedron 2005, 61, 2697–2703; (c) Chen, Y.;
Markina, N. A.; Larock, R. C. Tetrahedron 2009, 65, 8908–8915.
7. (a) Cacchi, S. J. Organomet. Chem. 1999, 576, 42–64; (b) Rao, M. S.; Esho, N.;
Sergeant, C.; Dembinski, R. J. Org. Chem. 2003, 17, 6788–6790; (c) Palimkar, S.
S.; Kumar, P. H.; Lahoti, R. J.; Srinivasan, K. V. Tetrahedron 2006, 62, 5109–5115;
(d) Harkat, H.; Weibl, J. M.; Pale, P. Tetrahedron Lett. 2007, 48, 1439–1442; (e)
Palimkar, S. S.; More, V. S.; Kumar, P. H.; Srinivasan, K. V. Tetrahedron 2007, 63,
12786–12790; (f) Liu, Z.; Li, D.; Li, S.; Bai, D.; He, X.; Hu, Y. Tetrahedron 2007, 63,
1931–1936; (g) Heravi, M. M.; Sadjadi, S. Tetrahedron 2009, 65, 7761–7775.
8. (a) Hiroya, K.; Jouka, R.; Kameda, M.; Yasuhara, A.; Sakamoto, T. Tetrahedron
2001, 57, 9697–9710; (b) Motto, J. M.; Castillo, Á.; Greer, A.; Montemayer, L. K.;
Sheepwash, E. E.; Schwan, A. L. Tetrahedron 2011, 67, 1002–1010; (c) Chen, P.-
Y.; Wang, T.-P.; Huang, K.-S.; Kao, C.-L.; Tsai, J.-C.; Wang, E.-C. Tetrahedron
2011, 67, 9291–9297.
9. (a) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975, 44, 4467–
4470; (b) Sonogashira, K. J. Organomet. Chem. 2002, 653, 46–49; (c) Agrofoglio,
L. A.; Gillaizeau, I.; Saito, Y. Chem. Rev. 2003, 103, 1875–1916; (d) Sonogashira,
K. In Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Demeijere, A., Eds.;
Wiley-VCH: Weinheim, 2004; Vol. 1, p p.319; (e) Alonso, F.; Beletskaya, I. P.;
Yus, M. Chem. Rev. 2004, 104, 3079–3159; (f) Chinchilla, R.; Nájera, C. Chem.
Rev. 2007, 107, 874–922.
10. General procedure for the preparation of 1–10a and 1–6b. To a solution of 5-
iodopyrimidine (0.84 mmol) in anhydrous DMF (7 mL) were added the
terminal alkyne (2.5 mmol), Pd(PPh3)4 (0.08 mmol), CuI (0.08 mmol) and
Et3N [or (iPr)2EtN] (1.68 mmol). Method A: The reaction mixture was stirred
at room temperature overnight. The extent of the reaction was monitored by
TLC and the solvent was evaporated in vacuo and the residue purified by
column chromatography (initial eluent CH2Cl2, then CH2Cl2/MeOH = 40:1) to
afford 1–10a and 1–6b. Method B: The synthesis was carried out at 50 °C for
Acknowledgements
Support of this study by the Ministry of Science, Education and
Sports of the Republic of Croatia (projects #125-0982464-2925
and #335-0000000-3532) is gratefully acknowledged.
30 min under microwave irradiation (300 W, 1 bar, Milestone start
S
microwave oven). Purification by column chromatography (initial eluent
CH2Cl2, then CH2Cl2/MeOH = 40:1) afforded compounds 1–10a and 1–6b.
11. (a) Su, T.-L.; Huang, J.-T.; Burchenal, J. H.; Watanabe, K. A.; Fox, J. J. J. Med. Chem.
1986, 29, 709–715; (b) Edstrom, E. D.; Feng, X.; Tumkevicius, S. Tetrahedron
Lett. 1996, 37, 759–762; (c) Heintzelman, G. R.; Fang, W.-K.; Keen, S. P.;
Wallace, G. A.; Weinreb, S. M. J. Am. Chem. Soc. 2001, 123, 8851–8853; (d)
Muschalek, B.; Weidner, I.; Butenschön, H. J. Organomet. Chem. 2007, 692,
2415–2424; (e) Zhang, F.; Kulesza, A.; Rani, S.; Bernet, B.; Vasella, A. Helv. Chim.
Supplementary data
Supplementary data (1H and 13C NMR, mass spectrometry and
elemental analysis data of compounds 1–20, synthesis and exper-
imental procedures of compounds 21–25) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2012.07.068.
´
´
Acta 2008, 91, 1201–1218; (f) Kraljevic, Gazivoda.; Petrovic, T.; Krištafor, M.;
Makuc, S.; Plavec, J.; Ross, L. T.; Ametamey, S. M; Raic´-Malic´, S. Molecules 2011,
16, 5113–5129; (g) Gazivoda .Kraljevic´, T.; Klika, M.; Kralj, M.; Martin-Kleiner,
I.; Jurmanovic´, S.; Milic´, A.; Padovan, J.; Raic´-Malic´, S. Bioorg. Med. Chem. Lett.
2012, 22, 308–312.
References and notes
12. Method C: a solution of 5-alkynylpyrimidine derivative 1–10a (0.4 mmol) and
K2CO3 (1 mmol) in anhydrous DMF (5 mL) was cooled to 0 °C, and after 10 min,
methoxymethyl chloride (MOMCl) (1.2 mmol) was added. The obtained
mixture was additionally stirred at room temperature overnight and the
solvent was then evaporated. Purification by column chromatography (CH2Cl2/
MeOH = 40:1) afforded compounds 11–20. Method D: a solution of furo[2,3-
d]pyrimidine derivative 1–6b (0.08 mmol) and K2CO3 (0.16 mmol) in
anhydrous DMF (1 mL) was cooled to 0 °C, and after 10 min, MOMCl
(0.16 mmol) was added. The obtained mixture was additionally stirred at
room temperature overnight and the solvent was then evaporated. Further
purification by column chromatography (CH2Cl2/MeOH = 40:1) afforded 11–
16.
1. (a) Girreser, U.; Heber, D.; Schütt, M. Tetrahedron 2004, 60, 11511–11517; (b)
Peng, Z.-H.; Journet, M.; Humphrey, G. Org. Lett. 2006, 18, 395–398; (c)
Braendvang, M.; Gundersen, L. L. Tetrahedron Lett. 2007, 48, 3057–3059; (d)
Choudhury, A.; Chen, H.; Nilsen, C. N.; Sorgi, K. L. Tetrahedron Lett. 2008, 49,
102–105; (e) Mishra, R.; Tomar, I. Int. J. Pharm. Sci. Res. 2011, 2, 758–771.
2. (a) Heidelberger, C. In Cancer Medicine; Holland, J. F., Frei, E., Eds.; Lea and
Febiger: Philadelphia, 1984; pp 801–824; (b) Sigmond, J.; Peters, G. J.
Nucleosides Nucleotides Nucleic Acids 2005, 24, 1997–2022; (c) Ibrahim, D. A.;
El-Metwally, A. M. Eur. J. Med. Chem. 2010, 45, 1158–1166.
3. (a) Bères, J.; Bentrude, W. G.; Balzarini, J.; De Clercq, E.; Otvös, L. J. Med. Chem.
1986, 29, 494–499; (b) Herdewijn, P. Antiviral Chem. Chemother. 1994, 5, 131–
146; (c) Fillastre, J. P.; Godin, M.; Legallicier, B.; Chretien, P.; Bidault, R.;
Gillotin, C.; Wooton, R.; Posner, J.; Peck, R. W. J. Antimicrob. Chemother. 1996, 37,
965–974.