Zinc-catalyzed cycloisomerizations. Synthesis of substituted furans and furopyrimidine nucleosides

Article abstract of DOI:10.1021/jo8007995

(Chemical Equation Presented) 5-Endo-dig cycloisomerization of 1,4- and 1,2,4- mostly aryl-substituted but-3-yn-1-ones in the presence of a catalytic amount of zinc chloride etherate (10 mol %) in dichloromethane at room temperature gave 2,5-di- and 2,3,5

Full text of DOI:10.1021/jo8007995

Zinc-Catalyzed Cycloisomerizations. Synthesis of Substituted Furans
and Furopyrimidine Nucleosides
Adam Sniady,† Audrey Durham,† Marco S. Morreale,† Andrzej Marcinek,‡
Slawomir Szafert,§ Tadeusz Lis,§ Krystyna R. Brzezinska, Takanori Iwasaki,¶
Takashi Ohshima,¶ Kazushi Mashima,¶ and Roman Dembinski*,†
Department of Chemistry, Oakland UniVersity, 2200 N. Squirrel Rd., Rochester, Michigan 48309-4477,
Institute of Applied Radiation Chemistry, Technical UniVersity of Lodz, Zeromskiego 116, 90-924 Lodz,
Poland, Department of Chemistry, UniVersity of Wroclaw, F. Joliot-Curie 14, 50-383 Wroclaw, Poland,
Materials Research Laboratory, UniVersity of California, Santa Barbara, California 93106, and
Department of Chemistry, Graduate School of Engineering Science,
Osaka UniVersity, Toyonaka, Osaka 560-8531, Japan
dembinsk@oakland.edu
ReceiVed April 9, 2008
5-Endo-dig cycloisomerization of 1,4- and 1,2,4- mostly aryl-substituted but-3-yn-1-ones in the presence
of a catalytic amount of zinc chloride etherate (10 mol %) in dichloromethane at room temperature gave
2,5-di- and 2,3,5-trisubstituted furans in high yields (85-97%). DSC studies confirmed that a solely
thermal process does not take place. A relevant catalytic process, employing µ-oxo-tetranuclear zinc
cluster Zn4(OCOCF3)6O, yielded bicyclic furopyrimidine nucleosides, when starting from acetyl-protected
5-alkynyl-2′-deoxyuridines (85-86%). Furopyrimidine was deprotected or simultaneously converted into
pyrrolopyrimidine nucleoside. The time/concentration dependence for the reaction of 1-phenyl-4-(4-
methylphenyl)butynone to 2-(4-methylphenyl)-5-phenylfuran displayed first-order kinetics with the rate
dependent on catalyst concentration. The plot of ln kobs versus ln[ZnCl2] indicated first-order cycloi-
somerization, as referred to ZnCl2 concentration, using both NMR and UV-vis reaction monitoring.
The crystal structure of propyl furopyrimidine nucleoside (orthorhombic, P212121, a/b/c ) 5.684(2)/
6.682(2)/36.02(2) Å, Z ) 4) shows C2′-endo deoxyribose puckering, and the base is found in the anti
position in crystalline form.
Introduction
carbonyl compounds have been successfully used for furan
formation. A variety of catalysts have been applied for the
cycloisomerization of oxo-alkynyl/allenyl compounds. Reactions
of alkynyloxiranes,3–6 (Z)-alk-2-en-4-yn-1-ols,7–11 alka-2,3-dien-
The furan unit can be found in biologically active compounds
and natural products and is a useful synthetic intermediate. Thus,
development of synthetic methods that provide access to highly
substituted furans is an active area of investigation, despite
existing significant achievements.1,2
Partly due to perfect atom economy, intramolecular cycloi-
somerization reactions involving unsaturated functional groups
are at the frontiers of the synthetic schemes. Internal nucleo-
philes, containing oxygen, derived from alcohols, oxiranes, or
(1) (a) Patil, N. T.; Yamamoto, Y. ArkiVoc 2007, x, 121–141. (b) Kirsch,
S. F. Org. Biomol. Chem. 2006, 4, 2076–2080. (c) Brown, R. C. D. Angew.
Chem., Int. Ed. 2005, 44, 850–852. (d) Graening, T.; Thrun, F. Furans and their
benzo derivatives: Synthesis. In ComprehensiVe Heterocyclic Chemistry III;
Katritzky, A. R., Ed.; Elsevier: New York, 2008; Vol. 3, pp 497-569.
(2) Selected recent examples: (a) Sanz, R.; Miguel, D.; Mart´ınez, A.; Álvarez-
Gutie´rrez, J. M.; Rodr´ıguez, F. Org. Lett. 2007, 9, 727–730. (b) Hayes, S. J.;
Knight, D. W.; Menzies, M. D.; O’Halloran, M.; Tan, W.-F. Tetrahedron Lett.
2007, 48, 7709–7712. (c) Miyagawa, T.; Satoh, T. Tetrahedron Lett. 2007, 48,
4849–4853. (d) Babudri, F.; Cicco, S. R.; Farinola, G. M.; Lopez, L. C.; Naso,
F.; Pinto, V. Chem. Commun. 2007, 3756–3758. (e) Dudnik, A. S.; Sromek,
A. W.; Rubina, M.; Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. J. Am. Chem. Soc.
2008, 130, 1440–1452. (f) Tamaso, K.-i.; Hatamoto, Y.; Obora, Y.; Sakaguchi,
S.; Ishii, Y. J. Org. Chem. 2007, 72, 8820–8823.
† Oakland University.
‡ Technical University of Lodz.
§ University of Wroclaw.
University of California, Santa Barbara.
¶ Osaka University.
10.1021/jo8007995 CCC: $40.75
Published on Web 07/03/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 5881–5889 5881

Sniady et al.
1-ones,8,12–16 alk-2-yn-1-ones,17–19 alk-4-yn-1-ones,20–24 2-(1-
alkynyl)-2-alken-1-ones,8,25,26 and alka-2,3,4-trien-1-ols27 all
furnished furans.
We have focused attention on starting materials containing
but-3-yn-1-one (homopropargylic ketone) moiety.28 Similarly,
several catalysts have been used for the conversion of alk-3-
yn-1-ones to furans. In addition to Brønstedt bases,29 derivatives
of metals such as silver,12 palladium,30 gold,14,31 or mercury32
have been applied for furans or related heterocycles33 formation.
Those methods offer useful routes, but moderate yields, elevated
reaction temperatures, or costs are currently challenging some
of these procedures. Also important, when considering potential
biological activity, is the cytotoxicity of the metal and its
residues in the final product. This concern requires the use of
scavengers. Therefore, in an effort to continue method develop-
ment, we have investigated easy-to-handle, inexpensive, and
readily available zinc derivatives that also provide catalytic
behavior similar to the currently available systems, without
affecting the bioactivity of the products.34
Flexibility of coordination combined with soft Lewis acidity
makes zinc centers useful for catalysis. However, the formation
of ring systems with the use of zinc halides has not been
extensively explored.35 For example, ZnI2-catalyzed cyclization
of propargylic N-hydroxylamines to 2,3-dihydroisoxazoles has
been observed in DMAP.36 Synthesis of furans from alk-2-yn-
1-ones in the presence of ZnBr2 and i-Pr2NEt (MeCN, 40-50
°C, 24 h) has also been reported.19 Relatively few cyclization
reactions have been pursued with the aid of ZnCl2. The protocol
usually includes stoichiometric use of the zinc reagent. For
instance, 2-alkynylphenols are converted into benzofurans with
the use of n-BuLi/ZnCl2 in refluxing toluene.37 Cycloconden-
sation of 1-hydroxy-2-methoxyalk-3-yne in the presence of
ZnCl2 in refluxing CCl4 has produced furan ring.38 Thus, we
further explored the potential of Zn-catalyzed procedures.
(3) Base-catalyzed: Marshall, J. A.; DuBay, W. J. J. Am. Chem. Soc. 1992,
114, 1450–1456.
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1084. (b) Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687–
7692.
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1995, 51, 13089–13102.
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59, 7169–7171. (b) Marshall, J. A.; Wang, X. J. Org. Chem. 1991, 56, 960–
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1990, 55, 3450–3451.
Results and Discussion
In pursuit of an inexpensive, mild, and efficient synthesis of
2,5-di- and 2,3,5-trisubstituted furans, a variety of commercially
available zinc salts was selected for examination (Table 1). In
a glovebox, 0.1 M solutions of ZnI2, ZnBr2, or ZnCl2 in ether
(14) Au-catalyzed: (a) Hashmi, A. S. K.; Schwarz, L.; Choi, J.-H.; Frost,
T. M. Angew. Chem., Int. Ed. 2000, 39, 2285–2288. (b) Hashmi, A. S. K.;
Schwarz, L.; Rubenbauer, P.; Blanco, M. C. AdV. Synth. Catal. 2006, 348, 705–
708.
(15) Au-catalyzed: Zhou, C.-Y.; Chan, P. W. H.; Che, C.-M. Org. Lett. 2006,
8, 325–328.
(16) Pd-catalyzed: Ma, S.; Zhang, J.; Lu, L. Chem. Eur. J. 2003, 9, 2447–
2456.
TABLE 1. Effect of Catalyst on the Cycloisomerization of 1a to 2a
(R ) Ph, R′ ) H, R′′ p-MeC6H4)a
(17) Cu-catalyzed: Kel’in, A. V.; Gevorgyan, V. J. Org. Chem. 2002, 67,
95–98.
catalyst
time (h)
yield (%)b
(18) Pd-catalyzed: Sheng, H.; Lin, S.; Huang, Y. Z. Tetrahedron Lett. 1986,
27, 4893–4894.
c
ZnI2
24
24
24d
1
24
24
24
2g
41
54
>99
>99
<2
7
(19) Zn-catalyzed: Lee, K. Y.; Lee, M. J.; Kim, J. N. Tetrahedron 2005, 61,
8705–8710.
c
ZnBr2
ZnCl2
ZnCl2
Zn(OAc)2
Zn(OTf)2
c
(20) Acid-catalyzed: Gelin, R.; Gelin, S.; Poimboeuf, J. C. Compt. Rend.
1964, 258, 5663–5665.
e
f
(21) Acid-catalyzed: Brown, C. D.; Chong, J. M.; Shen, L. Tetrahedron 1999,
55, 14233–14242.
f
(22) Base-catalyzed: MaGee, D. I.; Leach, J. D.; Setiadji, S. Tetrahedron
1999, 55, 2847–2856.
Zn phthalocyanine
Zn4(OCOCF3)6O
<2
>99
(23) Hg(OTf)2 · tetramethylurea catalyzed: (a) Imagawa, H.; Kurisaki, T.;
Nishizawa, M. Org. Lett. 2004, 6, 3679–3681. (b) Imagawa, H.; Kotani, S.;
Nishizawa, M. Synlett 2006, 642–644.
a Reactions were carried out on a 0.213 mmol scale using 0.11 M
solution of 1a in CH2Cl2 in drybox with 10 mol % of Zn catalyst unless
referenced otherwise. b As determined by 1H NMR after quenching the
reaction with water. c 0.1 M Et2O solution (prepared). d Incomplete
conversion after 20 h. e 1.0 M Et2O solution (commercial). f Suspension.
g 2.5 mol % (10 mol % based on atomic zinc); incomplete conversion
after 1 h.
(24) Pd-catalyzed: Picquet, M.; Bruneau, C.; Dixneuf, P. H. Tetrahedron
1999, 55, 3937–3948.
(25) Au-catalyzed: (a) Yao, T.; Zhang, X.; Larock, R. C. J. Org. Chem. 2005,
70, 7679–7685. (b) Yao, T.; Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2004,
126, 11164–11165. (c) Liu, X.; Pan, Z.; Shu, X.; Duan, X.; Liang, Y. Synlett
2006, 1962–1964.
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70, 4531–4534.
(27) Pd-catalyzed: Aurrecoechea, J. M.; Pe´rez, E. Tetrahedron 2004, 60,
4139–4149.
(33) See, for example: (a) Ermolat’ev, D. S.; Mehta, V. P.; Van der Eycken,
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Y. Tetrahedron 2007, 63, 1931–1936.
(28) For electrophilic cyclizations leading to of 3-halofurans and 5-halofu-
ropyrimidine nucleosides, see: (a) Sniady, A.; Morreale, M. S.; Wheeler, K. A.;
Dembinski, R. Eur. J. Org. Chem. 2008, 3449–3452. (b) Sniady, A.; Wheeler,
K. A.; Dembinski, R. Org. Lett. 2005, 7, 1769–1772. (c) Rao, M. S.; Esho, N.;
Sergeant, C.; Dembinski, R. J. Org. Chem. 2003, 68, 6788–6790.
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(b) Arcadi, A.; Marinelli, F.; Pini, E.; Rossi, E. Tetrahedron Lett. 1996, 37,
3387–3390. (c) Arcadi, A.; Rossi, E. Tetrahedron 1998, 54, 15253–15272.
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Lin, S.; Huang, Y. Synthesis 1987, 1022–1023. (c) Fukuda, Y.; Shiragami, H.;
Utimoto, K.; Nozaki, H. J. Org. Chem. 1991, 56, 5816–5819.
(31) (1-Ethynylcyclopropyl)alkynones: Zhang, J.; Schmalz, H.-G. Angew.
Chem., Int. Ed. 2006, 45, 6704–6707.
(34) Preliminary communication: Sniady, A.; Durham, A.; Morreale, M. S.;
Wheeler, K. A.; Dembinski, R. Org. Lett. 2007, 9, 1175–1178.
(35) (a) Gossage, R. A. Curr. Org. Chem. 2006, 10, 923–936. (b) McGarvey,
G. J. Zinc chloride. In The Electronic Encyclopedia of Reagents for Organic
Synthesis, http://mrw.interscience.wiley.com/eros/, doi: 10.1002/047084289X.
rz007.pub2. (c) Jacobi von Wangelin, A.; Frederiksen, M. U. Zinc-mediated
reactions. In Transition Metals for Organic Synthesis; Beller, M., ; Bolm, C.,
Eds.; Wiley-VCH: Weinheim, 2003; Chapter 3.7, pp 519-551.
(36) Aschwanden, P.; Frantz, D. E.; Carreira, E. M. Org. Lett. 2000, 2, 2331–
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5882 J. Org. Chem. Vol. 73, No. 15, 2008

Zinc-Catalyzed Cycloisomerizations
SCHEME 1. Synthesis of Furans 2a
a For catalyst and substrate structures, see Tables 1 and 2.
were added to ketone 1a (R ) Ph, R′ ) H, R′′ ) p-MeC6H4;
Scheme 1). Despite stirring at room temperature for 24 h,
significant but not complete conversion to 2a was observed with
ZnBr2 and ZnI2. On the other hand quantitative formation of
2a was achieved with ZnCl2. Interestingly, the order of reactivity
was ZnCl2 > ZnBr2 > ZnI2 (Table 1).39,40
The catalytic properties of the ZnCl2/ether combination have
been investigated by Mayr’s group for the addition of chlo-
rodiphenylmethane to methylpentene.41 The highest activity was
observed at a ZnCl2/ether ratio that optimized homogenity with
a minimum amount of ether. An increased amount of ether
resulted in slower conversion. Thus, following this lead, we
turned our attention to 1.0 M ZnCl2 etherate,42 an inexpensive
commercially available reagent that provided homogenity in the
reactions and complete conversion within 1 h at a ZnCl2/ether
molar ratio of 1:9.6.
Zinc acetate, triflate, and phthalocyanine all gave negligible
conversion after 24 h. The zinc tetranuclear cluster Zn4-
(OCOCF3)6O (3, Figure 1; discussed below) yielded a homo-
geneous system and was very effective for conversion of 1a to
2a (Table 1). However, this reagent was not pursued for
preparative scale reactions leading to furans 2 as it did not offer
a distinctive advantage over the readily available ZnCl2.
After catalyst selection, preparative reactions were attempted.
Alk-3-yn-1-ones (1a-h) were prepared from the respective alk-
3-yn-1-ols, which are available via alkynylation of oxiranes;
procedures in DMSO,43 or with BF3 in THF44 were both
effective. The oxidation of alk-3-yn-1-ols was carried out with
the Dess-Martin reagent45 or with the Jones reagent,46–48 at
up to a 5 g scale (1c).49 Alk-3-yn-1-ones are prone to isom-
erization to the corresponding allenes,50,51 but this was not
pertinent for the procedures for 1a-f,h. In most cases triple
bond stabilization by conjugation to an aromatic ring most likely
FIGURE 1. Molecular structure of µ-oxo-zinc tetranuclear cluster 3.
precluded isomerization.52 During attempted purification, contact
with silica gel led to complex mixtures, which is most likely
the reason that a silica-gel-supported Jones reagent53 was not
effective. Although the Dess-Martin procedure requires separate
preparation of the oxidant, it offered milder conditions and was
superior for the synthesis of labile methoxymethyl alkynone 1g.
Synthesis of furans 2a-h was accomplished on a scale of
1-3 mmol. Examination of postreaction mixtures by 1H NMR
indicated quantitative conversions of 1 to the furans 2. Com-
pounds with combinations of substituents such as aryl (phenyl,
p-alkylphenyls, p-halophenyls), alkyl (propyl), cycloalkyl (cy-
clopropyl, fused cyclohexyl), and ether (methoxymethyl) were
produced with 85-97% yield (Table 2). Simple filtration
through a silica gel pad allowed for the effective isolation of
products. An AgNO3 test of the filtrate showed no trace of
chloride. Most of the furans gave highly accurate ((0.1%)
elemental analyses. Compounds 2a-h were characterized by
NMR, IR, MS, and UV-vis spectroscopy. The data agreed with
those previously reported for NMR54 and UV55 characterization
of substituted furans. The molecular structure of furan 2d was
also confirmed by X-ray crystallography.34
The most straightforward mechanistic outline of the
reaction includes activation of a triple bond by coordination
with a Zn atom. However, in a related cycloisomerization of
propargylic N-hydroxylamines to oxazoles (DMAP, CH2Cl2),
the requirement for base was explained by the coordination
of Zn to the oxygen atom of N-hydroxylamine.36 In addition,
coordination of zinc to oxygen is well documented in
structurally characterized enolates.56 Thus, we attempted to
gain more information about mechanistic features of the
reaction by kinetic measurements.
1
Kinetic Studies. The formation of 2a was monitored by H
(39) A similar trend was observed when finely ground solids of ZnI2, ZnBr2,
or ZnCl2 were added. Despite stirring at room temperature for 24 h, such systems
remained heterogeneous.
NMR to determine the effective reaction rate (CDCl3, 22.0 °C).
Yields were based upon spectra integration, since no byproduct
formation was observed and chemical shifts of reactant and
product are well separated.57 Figure 2 top illustrates the progress
of the reaction for a zinc chloride load of 3-7 mol %. The
reaction was essentially completed after 40 min at higher ZnCl2
concentrations. Thus, for preparative experiments, the reaction
can likely be carried out with less than 10% catalyst load and
shorter times than is reported. For example, full conversion was
reached within 10 min in the NMR tube at a higher concentra-
(40) For reaction leading to dihydroisoxazole ZnI2 was the most effective.36
(41) Mayr, H.; Striepe, W. J. Org. Chem. 1985, 50, 2995–2998.
(42) Mayr, H.; Hagen-Bartl, G. Zinc chloride etherate in dichloromethane.
In The Electronic Encyclopedia of Reagents for Organic Synthesis, http://
mrw.interscience.wiley.com/eros/, doi: 10.1002/047084289X.rz008.
(43) Brandsma, L. PreparatiVe Acetylenic Chemistry, 2nd ed.; Studies in
Organic Chemistry 34; Elsevier: Amsterdam, 1988; p 67.
(44) Yamaguchi, M.; Hirao, I. Tetrahedron Lett. 1983, 24, 391–394.
(45) (a) Boeckman, R. K.; Shao, P.; Mullins, J. J. Org. Synth. Coll. 2004,
10, 696-703; Org. Synth. 2000, 77, 141-152. (b) Ireland, R. E.; Liu, L. J.
Org. Chem. 1993, 58, 2899.
(46) Eisenbraun, E. J. Org. Synth. Coll. 1973, 5, 310-314; Org. Synth. 1965,
45, 28-32.
(47) Padwa, A.; Crumrine, D.; Hartman, R.; Layton, R. J. Am. Chem. Soc.
1967, 89, 4435–4442.
(52) Oxidation of alk-3-yn-1-ols to alk-3-yn-1-ones with the use of Dess-
Martin periodinane has been mentioned in ref 32, but no preparative protocol
was reported. For a workup leading mainly to alka-2,3-dien-1-ones see, for
example, ref 12a.
(48) Due to the ready formation of allene the ketone 1g was not purified
and was used as crude material for the reaction.
(49) Sniady, A.; Morreale, M. S.; Dembinski, R. Org. Synth. 2007, 84, 199–
208.
(53) Ali, M. H.; Wiggin, C. J. Synth. Commun. 2001, 31, 1389–1397.
(54) Alvarez-Ibarra, C.; Quiroga-Feijo´o, M. L.; Toledano, E. J. Chem. Soc.,
Perkin Trans. 2 1998, 679–689.
(50) (a) Krause, N.; Hashmi, A. S. K. Modern Allene Chemistry, Wiley:
Weinheim, 2004; pp 3-50. (b) Hashmi, A. S. K.; Choi, J.-H.; Bats, J. W. J.
Prakt. Chem. 1999, 341, 342–357. (c) Hashmi, A. S. K.; Ruppert, T. L.; Kno¨fel,
T.; Bats, J. W. J. Org. Chem. 1997, 62, 7295–7304.
(55) King, S. M.; Bauer, C. R.; Lutz, R. E. J. Am. Chem. Soc. 1951, 73,
2253–2256.
(56) See for example Greco, J. F.; McNevin, M. J.; Shoemaker, R. K.;
Hagadorn, J. R. Organometallics 2008, 27, 1948–1953, and references therein.
(57) See Supporting Information.
(51) Schmieder-van de Vondervoort, L.; Bouttemy, S.; Padro´n, J. M.; Le
Bras, J.; Muzart, J.; Alsters, P. L. Synlett 2002, 243–246.
J. Org. Chem. Vol. 73, No. 15, 2008 5883

Sniady et al.
TABLE 2. Preparation of Furans 2 via Cycloisomerization of 1 with the Use of ZnCl2
a Reactions were carried out on a 1.0 mmol scale with 10 mol % of ZnCl2, in CH2Cl2 at room temperature for 2 h, unless referenced otherwise.
Yields >99% as determined by H NMR. b 0.18 mol % of ZnCl2, crude 1g was used as a substrate. c 3.2 mmol scale.
1
at high catalyst load (12.5-170 equiv) by measuring the
absorbance at 255/330 nm (decay/growth, CH2Cl2, 24 °C; Figure
2 bottom).
All kinetic curves showed a very good fit to the pseudo-first-
order equation.57 The kinetics are first-order, since ZnCl2 acts
as a catalyst and the concentration can be assumed constant
over the course of the reaction. Thus, the rate of the reaction
can be expressed as V ) k[ZnCl2]x[1a], where x denotes an
unknown order of the reaction relative to ZnCl2, i.e., the number
of zinc atoms participating in the reaction. Simplifying the
reaction to pseudo-first-order gives V ) kobs[1a], where kobs
)
k[ZnCl2]x (kobs is the observed first-order rate constant, and k is
the rate of cycloisomerization in the presence of the catalyst).
Therefore the relationship of ln kobs versus ln[ZnCl2] should be
linear (ln kobs ) ln k + x ln[ZnCl2]) and indeed, a good linear
regression fit was found using x ) 0.84 ( 0.10 and ln k ) 1.58
( 0.54 for NMR, x ) 0.85 ( 0.10/0.95 ( 0.13 and ln k ) 1.43
( 0.59/1.94 ( 0.79 for UV-vis growth/decay (Figure 3). Thus,
despite the widely different concentrations and substrate/catalyst
ratios used, both NMR and UV-vis methods produced similar
results. For combined all data points the best linear regression
for the relationship of ln kobs versus ln[ZnCl2] was obtained with
x ≈ 1 (0.94 ( 0.07), which indicates a first-order reaction in
ZnCl2 and the participation of only one zinc atom in the reaction
mechanism. Therefore, assuming x ) 1, from the dependence
kobs ) k[ZnCl2], a rate constant for catalytic cycloisomerization
FIGURE 2. Progress of cycloisomerization of 1a with ZnCl2 in CDCl3
(1H NMR, 22.0 °C, [1a] ) 0.0854 M) (top) and in CH2Cl2 (132 equiv,
UV-vis, 24.0 °C, [1a] ) 3.35 × 10-5 M) (bottom).
tion of 1a. The aromatization reaction can also be readily
monitored by UV-vis spectroscopy, due to the well-separated
absorption maxima of the acyclic substrate 1a and the aromatic
product 2a. This allowed the collection of additional data points
can be estimated as k ) (11.50 ( 0.40) M-1 min-1 58 Supporting
.
Information contains the results of the Levenberg-Marquardt
fitting procedure for all concentrations of ZnCl2 in the form of
(58) k ) (0.191 ( 0.007) M-1 s-1
.
5884 J. Org. Chem. Vol. 73, No. 15, 2008

Zinc-Catalyzed Cycloisomerizations
SCHEME 2. Synthesis of Furopyrimidine Nucleosides 5
TABLE 3. Optimization of the Cycloisomerization of Nucleoside
4a to 5a
FIGURE 3. Plot of ln kobs versus ln[ZnCl2] for 1H NMR and UV-vis
growth/decay observations.
catalyst
amount
time (h) solvent/temperature
yield
(%)a
(°C)
ZnCl2
ZnCl2
ZnCl2
ZnCl2
1.8 equiv
10 mol %
20 mol %
30 mol %
40 mol %
1 mol %
2 mol %
3 mol %
20
20
20
20
20
20
20
30
CH2Cl2/22
DCE/reflux
DCE/reflux
DCE/reflux
DCE/reflux
DCE/reflux
DCE/reflux
DCE/reflux
99 (89)
64
86
88
94
48
71
99 (86)
ZnCl2
Zn4(OCOCF3)6O
Zn4(OCOCF3)6O
Zn4(OCOCF3)6O
a
1H NMR yield; yield of isolated product in parenthesis.
virus (VZV).61 These bicyclic nucleosides are routinely pro-
duced via a cyclization of 5-alkynyl-2′-deoxyuridines.62,63
Commonly, copper/amine and/or palladium are used to catalyze
this reaction, frequently in a one-pot coupling/cyclization
procedure. However, residual traces of these metals may affect
biological activity determinations, and the reported yields are
often moderate.64 More recently, a silver catalyst was used
effectively for the cyclization,65 but difficulties in separating
silver from the furopyrimidines were reported.66 Considering
the importance of these bicyclic nucleosides, we decided to
examine the use of zinc catalysts to produce furopyrimidines.
Derivatives containing 4-alkylphenyl and n-alkyl substituents
are among the most active structures.61 Accordingly, a repre-
sentative nucleoside of each group was chosen to pursue
(Scheme 2).
Acyl protection of the ribose hydroxyl groups prevented
interaction of hydroxyl groups with the catalyst and afforded
greater solubility of the nucleosides in the reaction solvent.
Although preparative conversion of acetylated 5-p-tolylethynyl-
2′-deoxyuridine 4a (R ) p-MeC6H4)62,67 to furopyrimidine
nucleoside 5a was accomplished (89% yield), 1.8 equiv of ZnCl2
at room temperature (dichloromethane) or 0.4 equiv of ZnCl2
in refluxing DCE for 4a were required (20 h, Table 3). Thus,
we turned our attention to the µ-oxo-tetranuclear zinc cluster
3.68 This compound effectively catalyzes the direct conversion
FIGURE 4. DSC traces for alkynone 1a and (inset) for furan 2a.
figures that include the calculated kinetic parameters (final yield,
kobs), errors, and R2 values. The presence of an isosbestic point
in the UV-vis spectra can be used to support the contention
that the reaction proceeds with a limited number or no
intermediates that occur within the UV-vis time frame.
The possible noncatalytic process of cycloisomerization of
but-3-yn-1-ones59 was investigated by differential scanning
calorimetry (DSC), which has been shown to be helpful in
analyzing thermolytic reactions.60 The thermal cyclization of
1a in the absence of solvent and catalyst was studied by DSC
in the range between 0 and 250 °C. Figure 4 shows DSC data
that exhibit a melting peak of the alkynone 1a at 107.7 °C and
an exothermic process starting at about 128 °C. No melting or
recrystallization was observed when repeat scans were per-
formed, regardless of the heating or cooling rate in the repeated
runs. This included a melting point at 101.5 °C characteristic
for 2a (Figure 4 inset). In addition, weight loss was noticed
above 128 °C with the aid of thermogravimetric analysis (TGA).
Altogether, mass loss of 14% was observed in samples heated
up to 254 °C. Furthermore, 1H NMR monitoring of 1a preheated
in NMR tubes in the range of 140-180 °C confirmed the
degradation of 1a and did not indicate the formation of 2a. Thus,
it can be concluded that thermal cycloisomerization of but-3-
yn-1-ones is not a viable alternative to the catalyzed reaction.
Furopyrimidine nucleosides are potent and selective antiviral
agents with high specific activity against the varicella-zoster
(61) (a) McGuigan, C.; Balzarini, J. AntiViral Res. 2006, 71, 149–153. (b)
De Clercq, E. D. Med. Res. ReV. 2003, 23, 253–274.
(62) Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854–1862.
(63) For synthesis of 5-alkynyl-2′-deoxyuridines see: Meneni, S.; Ott, I.;
Sergeant, C. D.; Sniady, A.; Gust, R.; Dembinski, R. Bioorg. Med. Chem. 2007,
15, 3082–3088, and references therein.
(64) McGuigan, C.; Barucki, H.; Blewett, S.; Carangio, A.; Erichsen, J. T.;
Andrei, G.; Snoeck, R.; De Clercq, E.; Balzarini, J. J. Med. Chem. 2000, 43,
4993–4997.
(65) (a) Amblard, F.; Aucagne, V.; Guenot, P.; Schinazi, R. F.; Agrofoglio,
L. A. Bioorg. Med. Chem. 2005, 13, 1239–1248. (b) Aucagne, V.; Amblard, F.;
Agrofoglio, L. A. Synlett 2006, 2406–2408.
(59) Flash vacuum thermolysis reactions of allenyl ketones are known: (a)
Jullien, J.; Pechine, J. M.; Perez, F.; Piade, J. J. Tetrahedron 1982, 38, 1413–
1416. (b) Huntsman, W. D.; Yin, T.-K. J. Org. Chem. 1983, 48, 3813–3814.
(60) Kappe, T.; Stadlbauer, W. Molecules 1996, 1, 255–263, and references
therein.
(66) Hudson, R. H. E.; Moszynski, J. M. Synlett 2006, 2997–3000.
(67) Esho, N.; Davies, B.; Lee, J.; Dembinski, R. Chem. Commun. 2002,
332–333.
(68) Ohshima, T.; Iwasaki, T.; Mashima, K. Chem. Commun. 2006, 2711–
2713.
J. Org. Chem. Vol. 73, No. 15, 2008 5885

Sniady et al.
SCHEME 3. Deprotection of Furopyrimidine Nucleoside 5a and Its Conversion to Pyrrolopyrimidine 7a
of esters, lactones, and carboxylic acids to oxazolines in high
yield.68 It has also been found to be highly effective in a
transesterification reaction.69,70 Previously the cluster 3 was
shown to be highly effective for cyclization of butynone 1a.
Only 3 mol % of Zn4(OCOCF3)6O with the alkynyluridines 4a/b
in refluxing DCE for 30 h was needed to produce furopyrimidine
nucleosides 5a/b in 86%/85% yields. Purification was achieved
with column chromatography with the use of a low polarity
eluent, as a result of acetylated hydroxyl groups. Atomic
absorption spectrometry confirmed the absence of significant
amounts of Zn in the products 5a,b.
Ammonia is the commonly used reagent for the deprotection
of acyl groups from the ribose hydroxyl function.71 It is also
known that at elevated temperatures ammonia converts furo-
pyrimidines into pyrrolopyrimidines,72,73 which may form
unusual base pairs.74 This transformation is also observed during
classical deprotection of synthetic oligonucleotides, in which
incorporated furopyrimidines are quantitatively converted into
pyrrolopyrimidines.75 These observations prompted us to take
advantage of different reaction conditions. Accordingly, com-
bination of two reactions in a one-pot procedure gave unpro-
tected pyrrolopyrimidine 7a in 57% yield (50 °C, 16 h, Scheme
3). Although almost quantitative conversion was observed by
TLC, the presence of acetamide in the post reaction mixture
required careful chromatography for effective isolation of
pyrrolo nucleoside 7a. Alternatively, protected nucleoside 5a76
was deacetylated to yield furanopyrimidine 6a in 91% yield
when treated with ammonia/methanol at room temperature for
20 h (Scheme 3).77
molecular structure of nucleoside 6b that was obtained in a
similar manner as 6a (87% yield) was confirmed by X-ray
crystallography (Figure 5).78 In solid state, the ribose adopted
a C2′-endo conformation and the ribose-base distance, C1′-N3,
is 1.4850(19) Å. The C2 carbonyl group of 6b adopted an anti
orientation toward the ribose ring: the glycosidic bond torsion
angle ꢀ (O4′-C1′-N3-C2) is -153.26(13)°. The C5′-O5′
bond is +sc to the C4′-C3′ bond, which can be visualized by
the O5′-C5′-C4′-C3′ torsion angle γ ) 48.48(18)°. Packing
diagrams and a crystallographical table are available.57
In summary, we have demonstrated that ZnCl2 and the
Zn4(OCOCF3)6O cluster 3 are efficient, metallic catalysts for
quantitative cycloisomerization of the but-3-yn-1-ones 1 at room
temperature in the absence of base to furans 2 and also for
conversion of acylated 5-alkynyl-2′-deoxyuridines 4 to furan-
opyrimidines 5. The kinetics for ZnCl2-catalyzed conversion of
1a to 2a was shown to be pseudo-first-order. It was also
determined that the reaction could not be carried out in a
thermal, noncatalytic mode. The cluster 3 exceeds the reactivity
of ZnCl2 for nucleosides and equals its reactivity observed
during the synthesis of the furans. A relatively short reaction
time and inexpensive, easy to handle catalysts provide an
appealing alternative to currently available methods. Our
approach allows for the facile and effective preparation of
substituted furans and biologically active furopyrimidine nucleo-
sides. This method, with excellent atom economy, facilitates
the introduction of furans substituents, such as cyclopropyl, that
are not easily carried out by other methods79 and tolerates most
functional groups present in nucleosides.
The structure of nucleosides 5, 6, and 7 was confirmed by
NMR, IR, MS, and UV-vis spectroscopy. In addition, the
Experimental Section
General Procedure for Alk-3-yn-1-ones (1) with the Use of
Dess-Martin Periodinane.52,80 A round-bottom flask was charged
with Dess-Martin periodinane (3.54 mmol) and CH2Cl2 (22 mL).
(69) Iwasaki, T.; Maegawa, Y.; Hayashi, Y.; Ohshima, T.; Mashima, K. J.
Org. Chem. 2008, 73, 5147–5150.
(70) Ohshima, T.; Iwasaki, T.; Maegawa, Y.; Yoshiyama, A.; Mashima, K.
J. Am. Chem. Soc. 2008, 130, 2944–2945.
(71) See for example: Neilson, T.; Werstiuk, E. S. Can. J. Chem. 1971, 49,
493–499.
(72) (a) Woo, J.; Meyer, R. B.; Gamper, H. B. Nucleic Acids Res. 1996, 24,
2470–2475. (b) Hudson, R. H. E.; Ghorbani-Choghamarani, A. Synlett 2007,
870–873.
(73) MeONa can be used for deacylation of furanopyrimidines in solution.65b
(74) (a) Dash, C.; Rausch, J. W.; Le Grice, S. F. J. Nucleic Acids Res. 2004,
32, 1539–1547. (b) Liu, C.; Martin, C. T. J. Biol. Chem. 2002, 277, 2725–2731.
(75) (a) Liu, C.; Martin, C. T. J. Mol. Biol. 2001, 308, 465–475. (b)
Ranasinghe, R. T.; Rusling, D. A.; Powers, V. E. C.; Fox, K. R.; Brown, T.
Chem. Commun. 2005, 2555–2557.
(76) Esho, N.; Desaulniers, J.-P.; Davies, B.; Chui, H. M.-P.; Rao, M. S.;
Chow, C. S.; Szafert, S.; Dembinski, R. Bioorg. Med. Chem. 2005, 13, 1231–
1238.
(77) For deacetylation at 0 °C see: Robins, M. J.; Nowak, I.; Rajwanshi,
V. K.; Miranda, K.; Cannon, J. F.; Peterson, M. A.; Andrei, G.; Snoeck, R.; De
Clercq, E.; Balzarini, J. J. Med. Chem. 2007, 50, 3897–3905.
FIGURE 5. ORTEP view and a molecular structure of 6b with the
atom-labeling scheme. Thermal ellipsoids at the 50% probability level.
5886 J. Org. Chem. Vol. 73, No. 15, 2008

Zinc-Catalyzed Cycloisomerizations
A solution of alk-3-yn-1-ol (2.95 mmol) in CH2Cl2 (14 mL) was
added dropwise via syringe. The solution was stirred under nitrogen
atmosphere at room temperature. After 1 h TLC showed complete
conversion of the substrate. Sodium thiosulfate aqueous solution
(1.5 g) in saturated NaHCO3 (60 mL) was added to reaction mixture,
which was then stirred until two clear phases were formed. The
aqueous phase was extracted with ether (3 × 50 mL). The combined
organic layers were washed with saturated solution of NaHCO3
(30 mL). The organic phase was dried over Na2SO4, and solvent
was removed by rotary evaporation. The resulting solid was dried
for 6 h under oil pump vacuum (volatile liquid samples were treated
carefully at room temperature by rotary evaporator equipped with
a water pump) to give 1, which was used in the next step without
further purification.
General Procedure for Synthesis of Furans (2). A round-
bottom flask was charged with 1 (1.00 mmol) and CH2Cl2 (10 mL).
Zinc chloride (1.0 M in ether, 0.10 mL, 0.10 mmol) was added
dropwise via syringe. The solution was stirred at room temperature
for 2 h. 1H NMR/TLC showed complete conversion of the substrate.
Reaction mixture was passed through a silica gel column (2.5 cm
× 15 cm; CH2Cl2). The solvent was removed by rotary evaporation,
and the residue was dried by oil pump vacuum for 3 h to give 2.
Volatile liquid samples were treated carefully at room temperature
by a rotary evaporator equipped with a water pump.
2-(4-Bromophenyl)-5-(4-tert-butylphenyl)furan (2d). From 1-(4-
bromophenyl)-4-(4-tert-butylphenyl)but-3-yn-1-one (1d) (0.355 g,
1.00 mmol), CH2Cl2 (10 mL), and ZnCl2 (1.0 M in ether; 0.10 mL,
0.10 mmol). White solid of 2d (0.340 g, 0.957 mmol, 96%), mp
152-154 °C. Anal. Calcd for C20H19BrO: C, 67.61; H, 5.39. Found:
C, 67.60; H, 5.41. IR (cm-1, KBr) 1494 s, 1474 s, 834 s, 821 s,
792 s. UV-vis (ε, M-1 cm-1; ether, 3.1 × 10-5 M) 230 (12000),
332 (34000). MS 354 (M+, 87%), 339 ((M-Me)+, 100%); no other
1
peaks above 200 of >20%. NMR (CDCl3): H 7.67 (d, 2H, J )
8.5), 7.60 (d, 2H, J ) 8.7), 7.51 (d, 2H, J ) 8.7), 7.43 (d, 2H, J )
8.5), 6.73 (d, 1H, J ) 3.5), 6.69 (d, 1H, J ) 3.5), 1.36 (s, 9H); 13
C
154.1, 152.1, 150.9, 132.0, 129.9, 128.0, 125.8, 125.2, 123.8, 121.0,
107.9, 106.9, 34.8, 31.4.
2-(4-Chlorophenyl)-5-(4-methylphenyl)furan (2e). From 1-(4-
chlorophenyl)-4-(4-methylphenyl)but-3-yn-1-one (1e) (0.269 g, 1.00
mmol), CH2Cl2 (10 mL), and ZnCl2 (1.0 M in ether; 0.10 mL, 0.10
mmol). White solid of 2e (0.240 g, 0.893 mmol, 89%), mp 188-190
°C. Anal. Calcd for C17H13ClO: C, 75.98; H, 4.88. Found: C, 75.98;
H, 4.86. IR (cm-1, KBr) 1497 s, 1479 s, 827 s, 793 s. UV-vis (ε,
M-1 cm-1; ether; 4.1 × 10-5 M) 229 (11000), 330 (28000). MS
268 (M+, 100%); no other peaks above of >20%. NMR (CDCl3):
1H 7.66 (d, 2H, J ) 8.6), 7.63 (d, 2H, J ) 8.1), 7.36 (d, 2H, J )
8.6), 7.22 (d, 2H, J ) 8.1), 6.72 (d, 1H, J ) 3.5), 6.68 (d, 1H, J )
3.5), 2.38 (s, 3H); 13C 154.1, 152.0, 137.6, 132.9, 129.6, 129.0,
128.0, 125.0, 123.9, 107.8, 106.7, 21.5.
2-(4-Methylphenyl)-5-phenylfuran (2a).18 From 4-(4-meth-
ylphenyl)-1-phenylbut-3-yn-1-one (1a) (0.234 g, 1.00 mmol),
CH2Cl2 (10 mL), and ZnCl2 (1.0 M in ether; 0.10 mL, 0.10 mmol).
White solid of 2a (0.227 g, 0.970 mmol, 97%). DSC (Tp) 101.5
°C. Anal. Calcd for C17H14O: C, 87.15; H, 6.02. Found: C, 87.05;
H, 6.03. UV-vis (ε, M-1 cm-1; ether; 4.7 × 10-5 M) 227 (11000),
326 (28000). MS 234 (M+, 100%); no other peaks of >20%. Other
spectral data matched those reported earlier.81
2-Cyclopropyl-5-phenylfuran (2b). From 4-cyclopropyl-1-
phenylbut-3-yn-1-one (1b) (0.184 g, 1.00 mmol), CH2Cl2 (10 mL),
and ZnCl2 (1.0 M in ether; 0.10 mL, 0.10 mmol). Colorless oil of
2b (0.156 g, 0.846 mmol, 85%). Anal. Calcd for C13H12O: C, 84.75;
H, 6.57. Found: C, 84.63; 6.79. IR (cm-1, neat) 1487 s, 1448 s,
781 s, 757 s, 690 s. UV-vis (ε, M-1 cm-1; ether; 7.6 × 10-5 M)
223 (14000), 291 (34000). MS 184 (M+, 100%), 157 (40%), 128
(22%), 115 (30%), 105 (34%); no other peaks above 100 of >20%.
NMR (CDCl3):82 1H 7.72-7.62 (m, 2H), 7.47-7.20 (m, 3H), 6.50
(d, 1H, J ) 3.3), 6.00 (d, 1H, J ) 3.4), 2.10-1.94 (m, 1H),
1.06-0.86 (m, 4H); 13C 157.3, 151.8, 131.3, 128.7, 126.8, 123.4,
105.9, 105.7, 9.2, 7.1.
2-(4-Bromophenyl)-5-(4-methylphenyl)furan (2c). From 1-(4-
bromophenyl)-4-(4-methylphenyl)but-3-yn-1-one (1c) (0.313 g, 1.00
mmol), CH2Cl2 (10 mL), and ZnCl2 (1.0 M in ether; 0.10 mL, 0.10
mmol). White solid of 2c (0.283 g, 0.904 mmol, 90%), mp 202-204
°C. Anal. Calcd for C17H13BrO: C, 65.19; H, 4.18. Found: C, 64.96;
H, 4.17. IR (cm-1, KBr) 1496 s, 1475 s, 826 s, 793 s. UV-vis (ε,
M-1 cm-1; ether; 3.5 × 10-5 M) 230 (13000), 332 (36000). MS
312 (M+, 100%); no other peaks above 150 of >20%. NMR
(CDCl3): 1H 7.63 (d, 2H, J ) 8.1), 7.60 (d, 2H, J ) 8.6), 7.51 (d,
2H, J ) 8.6), 7.22 (d, 2H, J ) 8.1), 6.73 (d, 1H, J ) 3.3), 6.68 (d,
1H, J ) 3.3), 2.38 (s, 3H); 13C 154.1, 152.0, 137.6, 132.0, 129.9,
129.6, 128.0, 125.2, 123.9, 121.0, 107.9, 106.7, 21.5.
2-(4-Chlorophenyl)-5-(tert-butylphenyl)furan (2f). From 1-(4-
chlorophenyl)-4-(4-tert-butylphenyl)but-3-yn-1-one (1f) (0.311 g,
1.00 mmol), CH2Cl2 (10 mL), and ZnCl2 (1.0 M in ether; 0.10 mL,
0.10 mmol). White solid of 2f (0.263 g, 0.846 mmol, 85%), mp
141-143 °C. Anal. Calcd for C20H19ClO: C, 77.28; H, 6.16. Found:
C, 77.07; H, 6.21. IR (cm-1, KBr) 1494 s, 1477 s, 835 s, 824 s,
791 s. UV-vis (ε, M-1 cm-1; ether; 3.5 × 10-5 M) 229 (10000),
331 (26000). MS 310 (M+, 73%), 295 ((M-Me)+, 100%); no other
1
peaks above 150 of >20%. NMR (CDCl3): H 7.69 (d, 2H, J )
8.5), 7.66 (d, 2H, J ) 8.6), 7.43 (d, 2H, J ) 8.5), 7.37 (d, 2H, J )
8.6), 6.72 (d, 1H, J ) 3.4), 6.69 (d, 1H, J ) 3.4), 1.35 (s, 9H); 13
C
154.0, 152.1, 150.9, 132.9, 129.6, 129.0, 128.0, 125.8, 125.0, 123.7,
107.8, 106.9, 34.8, 31.4.
2-(4-Chlorophenyl)-5-(methoxymethyl)furan (2g). From crude
1-(4-chlorophenyl)-5-methoxypent-3-yn-1-one (1g) (0.223 g, 1.00
mmol), CH2Cl2 (10 mL), and ZnCl2 (1.0 M in ether; 0.10 mL, 0.10
mmol). Yellow oil of 2g (0.145 g, 0.651 mmol, 65%). Anal. Calcd
for C12H11ClO2: C, 64.73; H, 4.98. Found: C, 64.67; 4.92. IR (cm-1
,
neat) 2927 s, 2821 s, 1482 s, 1205 s, 830 s, 789 s. UV-vis (ε,
M-1 cm-1; ether; 8.1 × 10-5 M) 221 (8000), 289 (27000). MS
222 (M+, 31%), 191 ((M - OMe)+, 100%); no other peaks above
1
150 of >20%. NMR (CDCl3): H 7.60 (d, 2H, J ) 8.6), 7.33 (d,
2H, J ) 8.6), 6.58 (d, 1H, J ) 3.3), 6.40 (d, 1H, J ) 3.3), 4.44 (s,
2H), 3.40 (s, 3H); 13C 153.2, 151.6, 133.1, 129.2, 128.9, 125.1,
111.7, 106.1, 66.5, 57.9.
2-Propyl-4,5,6,7-tetrahydro-1-benzofuran (2h). From 2-(pent-
1-yn-1-yl)cyclohexanone (1h) (0.527 g, 3.21 mmol), CH2Cl2 (15
mL), and ZnCl2 (1.0 M in ether; 0.32 mL, 0.32 mmol). Colorless
oil of 2h (0.468 g, 2.85 mmol, 89%). Anal. Calcd for C11H16O: C,
80.44; H, 9.82. Found: C, 80.27; H, 9.96. IR (cm-1, neat) 1573 s,
1445 s. UV-vis (ε, M-1 cm-1; ether; 1.3 × 10-4 M) 224 (10000).
MS 164 (M+, 77%), 135 (M - Et, 100%); no other peaks above
1
(78) Crystallographic data (excluding structural factors) for the structure
reported in this paper were also deposited with Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC-683563. These data can be
obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, by e-mailing,
or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44(0)1223-336033.
(79) Donohoe, T. J.; Fishlock, L. P.; Lacy, A. R.; Procopiou, P. A. Org.
Lett. 2007, 9, 953–956.
100 of >20%. NMR (CDCl3): H 5.76 (s, 1H), 2.52 (t, 4H, J )
7.3), 2.40-2.32 (m, 2H), 1.82-1.56 (m, 4H), 1.65 (p, 2H, J )
7.4), 0.95 (t, 3H, J ) 7.4); 13C 154.1, 148.7, 117.2, 105.7, 30.3,
23.4 (2C), 23.4, 22.3, 21.7, 13.9.
3-(3,5-Di-O-acetyl-2-deoxy-ꢀ-D-erythro-pentofuranosyl)-6-(4-me-
thylphenyl)furo[2,3-d]pyrimidin-2(3H)-one (5a).76 Method A (ZnCl2,
CH2Cl2, room temperature). A round-bottom flask was charged with
3′,5′-di-O-acetyl-2′-deoxy-5-p-tolylethynyluridine (4a) (0.380 g,
0.891 mmol) and CH2Cl2 (8 mL). ZnCl2 (1.0 M in ether; 1.60 mL,
1.60 mmol) was added dropwise via syringe in three equal parts
every 1 h. The solution was stirred at room temperature for 20 h.
1H NMR showed complete conversion of the substrate. Silica gel
(80) Freshly prepared Dess-Martin periodinane reagent was used at 1.2 equiv
stoichiometry. Prolonged storage of the reagent required the use of additional
amounts, up to 1.5 equiv.
(81) Koga, Y.; Kusama, H.; Narasaka, K. Bull. Chem. Soc. Jpn. 1998, 71,
475–482.
(82) The 1H and 13C NMR chemical shifts are in ppm, and J values are in
Hz.
J. Org. Chem. Vol. 73, No. 15, 2008 5887

Sniady et al.
column chromatography (2.5 cm × 15 cm; CHCl3 f CHCl3/MeOH,
99:1) gave a colorless fraction. The solvent was removed by rotary
evaporation, and the residue was dried by oil pump vacuum to give
5a as a white solid (0.340 g, 0.797 mmol, 89%). Method B
(Zn4(OCOCF3)6O,68 DCE, reflux). A round-bottom flask was
charged with Zn4(OCOCF3)6O (0.0185 g, 0.0194 mmol), 3′,5′-di-
O-acetyl-2′-deoxy-5-p-tolylethynyluridine (4a) (0.275 g, 0.645
mmol), and DCE (5 mL). The solution was stirred and refluxed
5b (0.270 g, 0.714 mmol), MeOH (10 mL), and ammonia (7.0 M
in MeOH; 3.0 mL, 21 mmol). The solution was stirred at room
temperature for 20 h. TLC showed complete conversion of the
substrate. The solvent was removed by rotary evaporation and the
residue was suspended in CHCl3 and sonicated; MeOH (0.20 mL)
was added (to dissolve acetamide, a byproduct). The solid was
filtered off and dried by oil pump vacuum to give 6b (0.128 g,
0.435 mmol, 61%). The solvent was removed from filtrate by rotary
evaporation and the solid residue was suspended in CHCl3 and
sonicated. Filtration and drying by oil pump vacuum gave additional
amount of white solid of 6b (0.055 g, 0.19 mmol, 26%; total 0.183
g, 0.622 mmol, 87%). Anal. Calcd for C14H18N2O5 ·1/2H2O: C,
55.44; H, 6.31. Found: C, 55.46; H, 6.13. IR (cm-1, KBr) 3371 br,
3263 br, 1672 s, 1624 s, 1578 s, 1385 s, 1104 s, 784 s. UV-vis (ε,
M-1 cm-1; MeOH; 3.7 × 10-5 M) 225 (9800), 244 (8900), 331
(5200). MS 317 ((M + Na)+, 27%), 295 (M+, 24%), 179 ((B +
1
for 30 h. H NMR showed complete conversion of the substrate.
Silica gel column chromatography (2.5 cm × 15 cm; CHCl3 f
CHCl3/MeOH, 99:1) gave a colorless fraction. The solvent was
removed by rotary evaporation and the residue was dried by oil
pump vacuum to give 5a as a white solid (0.237 g, 0.556 mmol,
86%). Anal. Calcd for C22H22N2O7: C, 61.97; H, 5.20. Found: C,
1
62.02; H, 5.26. NMR (CDCl3): H 8.28 (s, 1H, H4), 7.61 (d, J )
8.2, 2H, o-C6H4CH3), 7.21 (d, J ) 8.2, 2H, m-C6H4CH3), 6.67 (s,
1H, H5), 6.31 (dd, J ) 7.6, 5.6, 1H, H1′), 5.22 (d, J ) 6.4, 1H,
H3′), 4.39 (s, 3H, H4′, H5′), 2.92 (ddd, J ) 14.6, 5.6, 2.2, 1H,
H2′), 2.36 (s, 3H, C6H4CH3), 2.08 (s, 3H, COCH3), 2.11-2.03 (m,
1H, H2′), 2.05 (s, 3H, COCH3); 13C 171.8 (m, C7a), 170.4 and
170.3 (2m, 2 COCH3), 156.2 (t, J ) 4.2, C6), 154.5 (br s, C2),
140.1 (q, J ) 6.9, p-C6H4CH3), 134.5 (d, J ) 184.9, C4), 129.7 (d,
J ) 158.2, m-C6H4CH3), 125.6 (t, J ) 7.5, i-C6H4CH3), 124.9 (br
d, J ) 156.4, o-C6H4CH3), 108.4 (m, C4a), 96.7 (d, J ) 180.2,
C5), 88.5 (d, J ) 175.3, C1′), 83.3 (d, J ) 152.1, C4′), 74.2 (d, J
) 158.2, C3′), 63.7 (t, J ) 148.7, C5′), 39.3 (dd, J ) 139.7, 132.8,
C2′), 21.5 (q, J ) 126.8, C6H4CH3), 20.9 (q, J ) 130.0, 2 COCH3).
3-(3,5-Di-O-acetyl-2-deoxy-ꢀ-D-erythro-pentofuranosyl)-6-pro-
pylfuro[2,3-d]pyrimidin-2(3H)-one (5b). Method A: from 3′,5′-di-
O-acetyl-2′-deoxy-5-pent-1-yn-1-yluridine (4b) (0.247 g, 0.653
mmol), CH2Cl2 (6 mL), and ZnCl2 (1.0 M in ether; 1.20 mL, 1.20
mmol). White oil/foam of 5b (0.210 g, 0.555 mmol, 85%). Method
B: from 3′,5′-di-O-acetyl-2′-deoxy-5-pent-1-yn-1-yluridine (4b)
(0.530 g, 1.40 mmol), Zn4(OCOCF3)6O (0.040 g, 0.042 mmol), and
DCE (10 mL). White oil/foam of 5b (0.450 g, 1.19 mmol, 85%).
Anal. Calcd for C18H22N2O7: C, 57.14; H, 5.86. Found: C, 52.24;
H, 5.45. IR (cm-1, CH2Cl2) 1745 s, 1675 s, 1577 m, 1382 m,
1234 m. UV-vis (ε, M-1 cm-1; MeOH; 3.7 × 10-5 M) 244 (5400),
331 (10000). MS 379 ((M+H)+, 40%), 179.1 ((B+H)+, 100%).
NMR (CDCl3):83 1H 8.16 (s, 1H, H4), 6.33 (dd, J ) 7.6, 5.6, 1H,
H1′), 6.12 (s, 1H, H5), 5.22 (d, J ) 6.6, 1H, H3′), 4.39 (s, 3H,
H4′, H5′), 2.94 (ddd, J ) 14.4, 5.6, 2.3, 1H, H2′), 2.63 (t, J ) 7.5,
2H, H1′′), 2.11 (s, 3H, COCH3), 2.14-2.00 (m, 1H, H2′), 2.06 (s,
3H, COCH3), 1.72 (sextet, J ) 7.5, 2H, H2′′), 0.99 (t, J ) 7.5, 3H,
H3′′); 13C 171.9 (dd, J ) 9.4, 6.9, C7a), 170.4 and 170.2 (br s, 2
COCH3), 160.0 (br s, C6), 154.5 (d, J ) 5.5, C2), 133.8 (d, J )
184.7, C4), 107.9 (s, C4a), 98.9 (d, J ) 180.2, C5), 88.3 (d, J )
173.9, C1′), 83.1 (d, J ) 152.2, C4′), 74.0 (d, J ) 137.6, C3′),
63.7 (t, J ) 148.7, C5′), 39.1 (dd, J ) 140.0, 133.1, C2′), 30.1 (t,
J ) 126.0, C1′′), 20.8 (q, J ) 130.1, 2 COCH3), 20.1 (t, J ) 128.0,
C2′′), 13.5 (q, J ) 125.5, C3′′).
1
H)+, 100%). NMR (DMSO-d6): H 8.67 (s, 1H, H4), 6.43 (s, 1H,
H5), 6.16 (t, J ) 6.1, 1H, H1′), 5.28 (d, J ) 4.2, 1H, OH3′), 5.12
(t, J ) 5.1, 1H, OH5′), 4.36-4.16 (m, 1H, H3′), 3.99-3.82 (m,
1H, H4′), 3.78-3.51 (m, 2H, H5′), 2.62 (t, J ) 7.3, 2H, H1′′),
2.47-2.29 (m, 1H, H2′), 2.14-1.95 (m, 1H, H2′), 1.64 (sextet, J
) 7.3, 2H, H2′′), 0.93 (t, J ) 7.3, 3H, H3′′); 13C 171.2 (m, C7a),
158.1 (br s, C6), 153.8 (d, J ) 5.6, C2), 136.8 (d, J ) 187.0, C4),
106.4 (s, C4a), 99.9 (d, J ) 182.1, C5), 88.1 (d, J ) 149.7, C4′),
87.4 (d, J ) 173.4, C1′), 69.7 (d, J ) 148.7, C3′), 60.8 (t, J )
139.9, C5′), 41.3 (C2′),85 29.3 (t, J ) 130.3, C1′′), 19.86 (t, J )
125.8, C2′′), 13.4 (q, J ) 121.5, C3′′).
3-(2-Deoxy-ꢀ-D-erythro-pentofuranosyl)-6-(4-methylphenyl)-3,7-
dihydro-2H-pyrrolo[2,3-d]pyrimidin-2-one (7a). A pressure vial was
charged with 6a (0.106 g, 0.248 mmol), MeOH (4 mL), and am-
monia (30% aqueous solution; 4 mL). The vial was sealed, and
1
the mixture was stirred at 50 °C for 16 h. H NMR/TLC showed
a complete conversion of the substrate. The solvent was removed
by rotary evaporation. The residue was mixed with minimum
amount of CHCl3/MeOH and silica gel and, after evaporation, was
charged on column (5 cm × 30 cm; CHCl3 f CHCl3/MeOH, 92:
8) gave a colorless fraction. The solvent was removed by rotary
evaporation and the residue was dried by oil pump vacuum. The
solid was dissolved in the minimum amount of MeOH and
precipitated with excess of ether. Sonication of mixture for 10 min
followed by filtration gave, after drying by oil pump vacuum, 7a
as a pale-yellow solid (0.048 g, 0.14 mmol, 57%). Anal. Calcd for
C18H19N3O4 ·1.5 H2O: C, 58.69; H, 6.02. Found: C, 58.70; H, 5.73.
IR (cm-1, KBr) 3344 br, 1656 s, 1570 s, 1452 m, 1096 m, 776 m.
UV-vis (ε, M-1 cm-1; MeOH; 3.2 × 10-5 M) 268 (22000), 367
(6600). MS 381 ((M + K)+, 89%), 364 ((M + Na)+, 100%), 342
(M+, 6%). NMR (DMSO-d6):83 1H 11.72 (s, 1H, N7), 8.67 (s, 1H,
H4), 7.72 and 7.27 (2d, J ) 8.1, 2 × 2H, o- and m-C6H4CH3),
6.66 (s, 1H, H5), 6.27 (t, J ) 6.2, 1H, H1′), 5.27 (d, J ) 4.1, 1H,
OH3′), 5.14 (t, J ) 5.0, 1H, OH5′), 4.38-4.19 (m, 1H, H3′), 3.90
(q, J ) 3.4, 1H, H4′), 3.85-3.55 (m, 2H, H5′), 2.45-2.20 (m, 1H,
H2′), 2.33 (s, CH3), 2.17-1.96 (m, 1H, H2′); 13C 159.9 (t, J )
7.1, C6), 153.8 (d, J ) 4.8, C2), 139.5 and 137.9 (2s, p-C6H4CH3
and C7a), 136.0 (d, J ) 184.1, C4), 129.5 (d, J ) 160.3, m- or
o-C6H4CH3), 127.8 (s, p-C6H4CH3), 125.0 (d, J ) 159.2, o- or
m-C6H4CH3), 109.2 (s, C4a), 96.2 (d, J ) 178.7, C5), 87.9 and
87.0 (d, J ) 149.5 and d, J ) 174.0, C1′ and C4′), 69.9 (d, J )
145.9, C3′), 61.0 (t, J ) 140.9, C5′), 41.5 (t, J ) 133.5, C2′), 20.9
(q, J ) 126.7, C6H4CH3).
3-(2-Deoxy-ꢀ-D-erythro-pentofuranosyl)-6-(4-methylphenyl)fu-
ro[2,3-d]pyrimidin-2(3H)-one (6a).64 A round-bottom flask was
charged with 5a (0.106 g, 0.248 mmol), MeOH (5 mL), and
ammonia (7.0 M in MeOH; 1.2 mL, 8.4 mmol). The solution was
stirred at room temperature for 20 h. TLC showed complete
conversion of the substrate. The reaction mixture was filtered, and
the solid was dried by oil pump vacuum to give 6a (0.064 g, 0.19
mmol, 75%). The solvent was removed from the filtrate by rotary
evaporation, and the remaining product was suspended in CHCl3
and sonicated. Filtration and drying by oil pump vacuum gave an
additional amount of 6a as a white solid (0.014 g, 0.041 mmol,
16%; total 0.078 g, 0.23 mmol, 91%). The spectral data matched
those reported earlier.64
Kinetic Analysis was carried out using the Levenberg-Marquardt
algorithm implemented into the OriginPro 7.5 software. The first-
order rate constant values (kobs) were evaluated from the fitting
procedure of product build-up versus time to the first-order
exponential growth with two unknown parameters ([X]∞ and kobs):
3-(2-Deoxy-ꢀ-D-erythro-pentofuranosyl)-6-propylfuro[2,3-d]py-
rimidin-2(3H)-one (6b).84 A round-bottom flask was charged with
(84) Compound 6b has been reported but no spectral data were given: Rai,
D.; Johar, M.; Manning, T.; Agrawal, B.; Kunimoto, D. Y.; Kumar, R. J. Med.
Chem. 2005, 48, 7012–7017.
(83) The i/o/m/p positions were designated with respect to the pyrimidine
group.
(85) Multiplicity was not determined in the 13C NMR spectrum (peaks were
obscured).
5888 J. Org. Chem. Vol. 73, No. 15, 2008

Zinc-Catalyzed Cycloisomerizations
[X]t ) [X]∞ ·(1 - exp(-kobs ·t)), where [X]t is concentration of the
product at time t, [X]∞ is final concentration of the product, and
kobs is first-order rate constant of the product build-up; or if presented
as a yield of the product: [Y]t ) [Y]∞ ·(1 - exp(-kobs ·t)), where
[Y]t is yield of the product at time t, [Y]∞ is final yield of the
product, and kobs is first-order rate constant of the product build-
up. The substrate decay (UV-vis measurements, absorption at 255
Fellowship. A.S. is grateful for the Provost’s Graduate Student
Research Award. DSC measurements were performed at the
UCSB MRL Central Facilities supported by the MRSEC
Program of the National Science Foundation under award No.
DMR05-20415. We thank K. Oprza¸dek (University of Podlasie)
for AA measurements. The Polish State Committee for Scientific
Research Grants N204 140 31/3236 and N205 003 32/0258 are
acknowledged as well.
nm) followed the first-order exponential decay: [A]t
)
[A]0 ·exp(-kobs ·t) + y0, where [A]t is absorbance of the substrate
at 255 nm at time t, [A]0 is initial absorption of the substrate, y0 is
baseline absorbance and kobs is the first-order rate constant of the
substrate decay.
Supporting Information Available: Experimental proce-
dures and characterization data for compounds 1 and 4; kinetic
studies data; NMR spectra for compounds 1, 4b, 5, 6b, and 7a;
X-ray table and packing diagrams; and a separate cif file for
compound 6b. This material is available free of charge via the
Internet at http://pubs.acs.org.
Acknowledgment. The authors acknowledge the donors of
the Petroleum Research Fund (ACS-PRF no. 46094), admin-
istered by the American Chemical Society, the National Institute
of Health (NIH, CA111329), Oakland University, and its
Research Excellence Program in Biotechnology for support of
this research. A.D. was supported by the Dershwitz Summer
JO8007995
J. Org. Chem. Vol. 73, No. 15, 2008 5889