Room temperature zinc chloride-catalyzed cycloisomerization of alk-3-yn-1-ones: Synthesis of substituted furans

Article abstract of DOI:10.1021/ol062539t

5-Endo-dig cycloisomerization of 1,4-di- and 1,2,4-trisubstituted but-3-yn-1-ones in the presence of a catalytic amount of zinc chloride (10 mol %) in dichloromethane at room temperature (22 °C) provides 2,5-di- and 2,3,5-trisubstituted furans in high yie

Full text of DOI:10.1021/ol062539t

ORGANIC
LETTERS
2007
Vol. 9, No. 7
1175-1178
Room Temperature Zinc
Chloride-Catalyzed Cycloisomerization
of Alk-3-yn-1-ones: Synthesis of
Substituted Furans
Adam Sniady,† Audrey Durham,† Marco S. Morreale,† Kraig A. Wheeler,‡ and
Roman Dembinski*,†
Department of Chemistry, Oakland UniVersity, 2200 North Squirrel Road, Rochester,
Michigan 48309-4477, and Department of Chemistry, Eastern Illinois UniVersity,
600 Lincoln AVenue, Charleston, Illinois 61920-3099
dembinsk@oakland.edu
Received October 15, 2006
ABSTRACT
5-Endo-dig cycloisomerization of 1,4-di- and 1,2,4-trisubstituted but-3-yn-1-ones in the presence of a catalytic amount of zinc chloride (10 mol %)
in dichloromethane at room temperature (22 C) provides 2,5-di- and 2,3,5-trisubstituted furans in high yields (85 97%).
°
−
Attracting interest for well over a century, the field of furan
syntheses is continuously and rapidly developing.1,2 In
general, substituted furans are accessed via ring derivatization
or cyclization of acyclic precursors.1-3 Among the variety
of compounds that can be subjected to cyclization, unsatu-
rated alcohols or ketones are substrates of major interest.1,3
Intramolecular cycloisomerization reactions that involve
an acetylenic functionality are reportedly in the frontiers of
the synthesis, in part due to perfect atom economy. Oxygen-
containing internal nucleophiles have been used in this
regard.4 Most works in this area report elevated temperatures
up to refluxing solvents, although some, mostly gold-
catalyzed reactions can be carried out at room temperature.
Base- and acid-catalyzed reactions of alkynyl ketones have
been reported to yield furans.5,6 These approaches are rather
incongruous with sensitive functional groups. Relevant
reactions have also been reported with the aid of transition-
metal catalysts.7 In general, gold, mainly as AuCl3, is the
† Oakland University.
(3) (a) Eicher, T.; Hauptmann, S.; Speicher, A. The Chemistry of
Heterocycles, 2nd ed.; Wiley-VCH: Weinheim, Germany, 2003; pp 57-
62. (b) Jeevanandam, A.; Ghule, A.; Ling, Y.-C. Curr. Org. Chem. 2002,
6, 841-864. (c) Cacchi, S.; Fabrizi, G.; Goggiomani, A. Heterocycles 2002,
56, 613-632. (d) Ko¨nig, B. Furan. In Hetarenes and Related Ring Systems;
Science of Synthesis; Maas, G., Ed.; George Thieme Verlag: Stuttgart,
Germany, 2001; Category 2, Vol. 9, pp 183-285. (e) Hou, X. L.; Cheung,
H. Y.; Hon, T. Y.; Kwan, P. L.; Lo, T. H.; Tong, S. Y.; Wong, H. N. C.
Tetrahedron 1998, 54, 1955-2020. (f) Eberbach, W. Furan. In Houben-
Weyl; George Thieme Verlag: Stuttgart, Germany, 1994; E6a, Teil I, pp
16-185d. (g) Hou, X. L.; Yang, Z.; Wong, H. N. C. Furans and benzofurans.
In Progress in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L.,
Eds.; Pergamon Press: Oxford, UK, 2003; Vol. 15, pp 167-205. (h)
Friedrichsen, W. Furans and Benzo Derivatives: Synthesis. In Compre-
hensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W., Scriven,
E. F. V., Eds.; Pergamon Press: Oxford, UK, 1996; Vol. 2, pp 351-394.
‡ Eastern Illinois University.
(1) (a) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076-2080. (b) Brown,
R. C. D. Angew. Chem., Int. Ed. 2005, 44, 850-852.
(2) Selected recent examples: (a) Kawai, H.; Oi, S.; Inoue, Y. Hetero-
cycles 2006, 67, 101-105. (b) Ma, S.; Gu, Z.; Yu, Z. J. Org. Chem. 2005,
70, 6291-6294. (c) Duan, X.-h.; Liu, X.-y.; Guo, L.-n.; Liao, M.-c.; Liu,
W.-M.; Liang, Y.-m. J. Org. Chem. 2005, 70, 6980-6983. (d) Suhre, M.
H.; Reif, M.; Kirsch, S. F. Org. Lett. 2005, 7, 3925-3927. (e) Casey, C.
P.; Strotman, N. A. J. Org. Chem. 2005, 70, 2576-2581. (f) Sromek, A.
W.; Rubina, M.; Gevorgyan, V. J. Am. Chem. Soc. 2005, 127, 10500-
10501. (g) Aurrecoechea, J. M.; Pe´rez, E. Tetrahedron 2004, 60, 4139-
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126, 4118-4119. (i) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Milton,
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10.1021/ol062539t CCC: $37.00
© 2007 American Chemical Society
Published on Web 03/01/2007

most effective catalyst for cycloisomerizations leading to
furans.8-13 Figure 1 schematically illustrates representative
are sometimes moderate,15a elevated reaction temperatures
are required,15,16 or rather expensive catalysts.10,12,13 Although
most reported gold-catalyzed reactions are carried out under
mild conditions (room temperature) and with a low catalyst
load (usually 1-5 mol %), we were drawn to the investiga-
tion of a less expensive and readily available metal derivative
that would provide parallel catalytic behavior to that of gold.
Coordinative flexibility combined with soft Lewis acidity
makes the zinc center useful for catalysis. Participation of
zinc bromide in synthesis is known and was summarized
recently.18 However, the formation of ring systems with the
use of zinc halides has not been extensively reported.18-22
Few cyclizations, leading to other than furan heterocycles,
were pursued with the aid of ZnCl2.23
We have reported electrophilic cyclizations leading to a
family of 3-halofurans24 and furopyrimidine nucleosides25
with the aid of N-bromo- and N-iodosuccinimide. Presently,
in pursuit of an inexpensive, mild, and efficient synthesis of
2,5-di- and 2,3,5-trisubstituted furans, we have selected the
furan acyclic precursor core (but-3-yn-1-one) with various
groups that remain as ring substituents of its furan derivative.
The alkyl (propyl), cycloalkyl (cyclopropyl, fused cyclo-
hexyl), ether (methoxymethyl), and aryl (phenyl, p-alkyl-
phenyls, p-halophenyls) groups were elected.
Figure 1. Representative gold-catalyzed cycloisomerizations lead-
ing to furans.
examples of gold-catalyzed cycloisomerizations of oxo-
alkynyl compounds: (Z)-alk-2-en-4-yn-1-ols,8 alkynyloxi-
ranes,9 alka-2,3-dien-1-ones,10,11 and alk-3-yn-1-ones,10,12,13
that lead to substituted furans. Among the starting materials
above, homopropargylic ketones are favored due to avail-
ability. Analysis of catalysts that have been examined for
cycloisomerization of alk-3-yn-1-ones revealed, in addition
to Au, derivatives of metals such as Pd14,15 and Cu.16
Recently, the list was expanded to include a mercury(II)
derivative, Hg(OTf)2‚(tetramethylurea)2.17 The reported yields
To prepare starting materials, respective alk-3-yn-1-ols
(1a-h), available by alkynylation of oxiranes,24,26 were
treated with Dess-Martin reagent27 (1.2 equiv) in dichlo-
romethane at room temperature or, except for 1g, with Jones
reagent24b,28-30 (3.0 M) in acetone at 0 °C, to yield but-3-
yn-1-ones (2a-h) (Scheme 1).24
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(19) (a) Jacobi von Wangelin, A.: Frederiksen, M. U. Zinc-Mediated
Reactions. In Transition Metals for Organic Synthesis; Beller, M., Bolm,
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2331-2333.
(21) For synthesis of furans from alk-2-yn-1-ones with the use of ZnBr2
and i-Pr2NEt (MeCN, 40-50 °C, 24 h) see: Lee, K. Y.; Lee, M. J.; Kim,
J. N. Tetrahedron 2005, 61, 8705-8710.
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to benzofurans at reflux in toluene see: Nakamura, M.; Ilies, L.; Otsubo,
S.; Nakamura, E. Org. Lett. 2006, 8, 2803-2805.
(24) (a) Sniady, A.; Wheeler, K. A.; Dembinski, R. Org. Lett. 2005, 7,
1769-1722. (b) Sniady, A.; Morreale, M. S.; Dembinski, R. Org. Synth.
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1176
Org. Lett., Vol. 9, No. 7, 2007

Albeit not catalytically active, their presence did not seem
to affect the reaction progress. Although strict anhydrous
conditions are not mandatory, the catalyst load can be
diminished by using freshly distilled anhydrous CH2Cl2 and
monitoring the reaction progress. If necessary, an extra
amount of ZnCl2 can be added to bring the reaction to
completion.
Scheme 1. Synthesis of Furans 3a
Other alkynyl ketones 2b-h (0.1-0.3 mmol) with cy-
cloalkyl/aryl (entry 2), aryl/aryl (entries 3-6), aryl/alkyl ether
(entry 7), and alkyl/fused cycloalkyl (entry 8) groups were
subjected to the reaction with ZnCl2 at room temperature in
a similar manner as 2a.32 To maximize the effectiveness of
the preparative experiments, we extended the time to 2 h to
ensure full completion of the reactions. 1H NMR examination
of postreaction mixtures indicated quantitative conversion
to the furans 3. The straightforward workup of the reaction,
by a simple filtration through a silica gel pad, allowed
separation of the product from the Zn(II) catalyst to render
furans with 85-97% yield.32 The isolation procedure facili-
tates a complete removal of ZnCl2, which was confirmed
based upon a AgNO3 test of the filtrate. The results are
summarized in Table 1.
a For full structures see Table 1.
When 1-phenyl-4-(p-tolyl)butynone 2a (0.1 mmol) was
treated with ZnCl2 (10 mol %) in dichloromethane, complete
conversion into 3a was noticed after 2 h by TLC. To maintain
mild conditions, the reaction was carried out at room
temperature and in the absence of base. Furan 3a was
isolated, after workup by simple filtration through a silica
gel pad, in 97% yield (Table 1, entry 1). Quantitative
1
The new furans 3b-h were characterized by H and 13C
NMR spectroscopy. The characteristic NMR (CDCl3) fea-
tures for furans33 3a-g include the 1H H-3/H-4 signals (AB,
6.00-6.77 ppm) and 13C C-3/C-4 signals (105.7-111.7
ppm). Mass spectra for 3a-h exhibited intense molecular
ions. Most of the furans 3 gave highly accurate ((0.1%)
elemental analyses without recrystallization.
Table 1. Preparation of Furans 3 via Cycloisomerization of 2
with the Use of Zinc Chloride
entry ynone
R
R′
R′′
furan yield (%)a
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
C6H5
C6H5
H
H
H
H
H
H
H
p-CH3C6H4
c-C3H5
3a
3b
3c
3d
3e
3f
97
85
90
96
89
85
65b
89c
A molecular structure of a representative furan was
confirmed by X-ray crystallography. The crystallization of
compound 3d from ether gave single crystals suitable for
X-ray analysis. Figure 2 illustrates the molecular structure
of the expected 2,5-disubstituted furan.34 Excluding the
methyl groups of the disordered tert-butyl substituent, the
entire molecule of 3d is planar. The maximum atom
deviations from the average plane are 0.31(1) and 0.27(1)
Å for C10 and C11, respectively.
p-BrC6H4
p-BrC6H4
p-ClC6H4
p-ClC6H4
p-ClC6H4
(CH2)4
p-CH3C6H4
p-t-BuC6H4
p-CH3C6H4
p-t-BuC6H4
CH3OCH2
CH3(CH2)2
2g
2h
3g
3h
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
1
A relevant cycloisomerization, a ZnI2-catalyzed formation
of 2,3-dihydroisooxazoles from propargylic N-hydroxyl-
2g was used as a substrate. c 3.2 mmol scale.
(32) Representativeprocedure: 2-(4-methylphenyl)-5-phenylfuran(3a).15a
A round-bottom flask was charged with 2a (0.234 g, 1.00 mmol) and CH2-
Cl2 (10 mL). Zinc chloride (1.0 M in ether, 0.10 mL, 0.10 mmol) was added
dropwise with a syringe. The solution was stirred at room temperature (22
°C) for 2 h. 1H NMR showed complete conversion of substrate. The reaction
mixture was passed through a short path silica gel column (2.5 × 15 cm;
CH2Cl2). The solvent was removed by rotary evaporation and the residue
was dried by an oil pump vacuum for 3 h to give 3a as a white solid (0.227
g, 0.970 mmol, 97%), mp 97-99 °C. Calcd for C17H14O: C, 87.15; H,
6.02. Found: C, 87.05; H, 6.03. IR (ν, cm-1, KBr) 1498 m, 1482 m, 821
m, 794 s, 757 s, 691 m. UV-vis (ꢀ, M-1 cm-1; ether; 4.7 × 10-5 M) 227
(11 000), 326 (28 000). MS 234 (M+, 100%); no other peaks of >20%.
NMR (CDCl3): 1H 7.83-7.64 (m, 4H), 7.50-7.20 (m, 5H), 6.77 (d, 1H,
J ) 3.3 Hz), 6.72 (d, 1H, J ) 3.3 Hz), 2.42 (s, 3H); 13C 153.7, 153.1,
137.4, 131.0, 129.5, 128.8, 128.2, 127.3, 123.8, 107.3, 106.6, 21.5.
(33) Alvarez-Ibarra, C.; Quiroga-Feijo´o, M. L.; Toledano, E. J. Chem.
Soc., Perkin Trans. 2 1998, 679-689.
(34) 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-621939. These data
can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif,
by e-mailing data_request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK;
fax: +44(0)1223-336033.
formation of 3a was also observed in an NMR tube when
an anhydrous atmosphere was maintaned (CDCl3, ZnCl2 6
mol %, 10 min). Thus, preparative reactions can likely be
carried out with a lower catalyst load.
The effect of the presence of water was also examined
for the cycloisomerization of 2a. The reaction conditions
included CH2Cl2 and 1.7 equiv of H2O. While the reaction
was sluggish, the furan 3a can be isolated with a comparable
yield at room temperature. However, the presence of water
required an additional quantity of ZnCl2. It is known that
Zn halides form oxy derivatives when mixed with water.31
(29) Padwa, A.; Crumrine, D.; Hartman, R.; Layton, R. J. Am. Chem.
Soc. 1967, 89, 4435-4442.
(30) Due to the presence of a labile propargylic ether function, the ketone
2g was not purified and was used as crude material for the reaction.
However, the furan 3g is stable.
(31) (a) Duffy, J. A.; Ingram, M. D. Inorg. Chem. 1978, 17, 2798-
2802. (b) See, also: McDaniel, D. H. Inorg. Chem. 1979, 18, 1412.
Org. Lett., Vol. 9, No. 7, 2007
1177

incorporation of deuterium was observed into the essentially
quantitatively formed furan 3a, it may be suggested that the
mechanism involves an intramolecular H transfer.
In summary, we have demonstrated that ZnCl2 is an
efficient, non-transition metal catalyst for quantitative cyclo-
isomerization of the but-3-yn-1-one unit at room temperature
and in the absence of base. Simple isolation protocol
facilitates high yields. The relatively short reaction time and
an easy-to-handle catalyst provide an appealing alternative
to currently available methods. Our approach allows for facile
preparation of highly substituted furans. This route, with
perfect atom economy, tolerates sensitive functional groups,
as illustrated with the labile propargyl ether-containing
example. The investigation of an extension of this method
toward a preparation of potent antiviral furopyrimidine
nucleosides from 5-alkynyl-2′-deoxyuridines is in progress.
Figure 2. An ORTEP view of the 3d with the atom-labeling
scheme. Thermal ellipsoids at the 50% probability level. Selected
interatomic distances (Å): O1-C2 1.376(3); O1-C5 1.370(3); C2-
C3 1.358(4); C2-C6 1.442(3); C3-C4 1.392(4); C4-C5 1.361-
(4); C5-C13 1.450(3). Key angles (deg): C2-O1-C5 107.46(18);
O1-C2-C3 108.6(2); C3-C2-C6 133.9(2); O1-C2-C6 117.5-
(2); C2-C3-C4 107.7(2); C3-C4-C5 107.4(2); O1-C5-C4
108.8(2); O1-C5-C13 117.3(2); C4-C5-C13 133.8(2).
Acknowledgment is made to the donors of the Petroleum
Research Fund (ACS-PRF#46094), administered by the
American Chemical Society, for support of this research. We
also thank Oakland University, the Research Excellence
Program in Biotechnology for funding. A.S. is grateful for
the Provost’s Graduate Student Research Award. A.D. was
supported by a Dershwitz Summer Fellowship.
amines (DMAP, CH2Cl2, 23 °C), is postulated to proceed
via an intramolecular, stepwise mechanism involving an
organozinc intermediate.20 Carreira et al. determined that the
process is not proton-catalyzed, the presence of base is
essential for completion of the reaction, and suggested that
Zn(II) likely coordinates N-hydroxylamine.20
To gain insight into the mechanism we have carried out
two independent experiments of a zinc-catalyzed cyclization
of 2a in the presence of D2O (1.7 equiv; 35 mol % of ZnCl2)
and CD3OD (30 equiv; 1.7 equiv of ZnCl2). Since no
1
Supporting Information Available: H, 13C NMR spec-
tra for all furans (3a-h) and an X-ray table for 3d, and a
separate CIF file for 3d. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL062539T
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