Synthesis of 2,5-disubstituted 3-iodofurans via palladium-catalyzed coupling and iodocyclization of terminal alkynes

Article abstract of DOI:10.1021/jo1023987

2,5-Disubstituted 3-iodofurans are readily prepared under very mild reaction conditions by the palladium/copper-catalyzed cross-coupling of (Z)-β-bromoenol acetates and terminal alkynes, followed by iodocyclization. The useful intermediates conjugated eny

Full text of DOI:10.1021/jo1023987

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Synthesis of 2,5-Disubstituted 3-Iodofurans via Palladium-Catalyzed
Coupling and Iodocyclization of Terminal Alkynes
Zhengwang Chen, Gao Huang, Huanfeng Jiang,* Huawen Huang, and Xiaoyan Pan
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received December 4, 2010
2,5-Disubstituted 3-iodofurans are readily prepared under very mild reaction conditions by the
palladium/copper-catalyzed cross-coupling of (Z)-β-bromoenol acetates and terminal alkynes,
followed by iodocyclization. The useful intermediates conjugated enyne acetates are obtained in
high yields in the transformation. Aryl- and alkyl-substituted alkynes undergo iodocyclization in
good yields. The resulting iodine-containing furans can be readily elaborated to 2,3,5-trisubstituted
furans.
Introduction
furan synthesis is the Paal-Knorr method in which 1,4-dicar-
bonyl compounds are converted to furan derivatives.3 Re-
cently, several studies have focused on the development of
metal-catalyzed transformation, including the cyclization of
alkynyl,4 allenyl,5 cyclopropyl,6 and cyclopropenyl7 ketone
derivatives. Alternative strategies involve the cyclization of
functionalized oxirane,8 alkynols,9 (Z)-2-en-4-yn-1-ols,10 sub-
stituted propargyl vinyl ethers,11 and others.12
The synthesis of furans has attracted extensive interest,
because they are found as key structural elements in numerous
bioactive natural products and synthetic materials.1 Moreover,
they are useful intermediates for the preparation of a variety of
heterocyclic and acyclic compounds.2 Classical approaches to
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1134 J. Org. Chem. 2011, 76, 1134–1139
Published on Web 01/14/2011
DOI: 10.1021/jo1023987
r
2011 American Chemical Society

Chen et al.
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TABLE 1. Sonogashira Coupling of (Z)-β-Bromoenol Acetates and Terminal Alkynesa
aReaction conditions: (Z)-β-bromoenol acetate (0.5 mmol), terminal alkyne (1.0 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), CuI (5 mol %), TEA
(1 mmol) and THF (2 mL) solvent at 50 °C for 6 h.
Electrophilic cyclization of functionalized acetylene is one of
the most attractive methods for constructing heterocycles, espe-
cially the iodo- and bromoheterocycles, which provide an
opportunity for further functionalization through the transi-
tion-metal-catalyzed reactions. For example, a variety of hetero-
cycles, including furans,13 furanones,14 benzofurans,15 indoles,16
benzothiophenes,17 benzoselenophenes and selenophenes,18 qui-
nolines and isoquinolines,19 isoxazoles,20 etc.,21 were obtained
through the electrophilic cyclization in the past decades.
Very recently, we have communicated a convenient and
expedient method for the synthesis of (Z)-β-haloenol acetates
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from terminal alkynes using silver tetrafluoroborate as the
catalyst.22 Here we developed a two-step approach for the
synthesis of 2,5-disubstituted 3-iodofurans involving the So-
nogashira cross-coupling of terminal alkynes and (Z)-β-ha-
loenol acetates, followed by iodocyclization. Although 2,5-
disubstituted 3-iodofurans have been obtained previously
from but-3-yn-1-ones13a or alk-3-yn-1,2-diols,13b readily ac-
cessible starting materials, the high efficiency and compat-
ibility made our strategies attractive for furan synthesis.
Moreover, it is noteworthy that the conjugated enyne acetate
intermediates will be prove to have broad application.23
TABLE 2. Study of the Solvent Effect on the Iodocyclization Reactiona
entry
solvent
Et2O
THF
MeCN
hexane
MeOH
MeOH/CH2Cl2
CH2Cl2
yield of 41b (%)
recovery of 2 (%)
1
2
3
4
5
6c
7
15
28
75
82
tr
76
67
18
14
92
0
50
94
Results and Discussion
0
aReaction conditions: 2 (0.25 mmol), I2 (1.5 equiv), and NaHCO3 (1.5
equiv) in 2 mL of solvent at rt for 8 h. bYields of 41 are given for isolated
products. c1 mL of MeOH and 1 mL of CH2Cl2.
A two-step method to 2,5-disubstituted 3-iodofurans
has been examined involving (i) the Sonogashira coupling
of (Z)-β-bromoenol acetates with terminal alkynes to afford
the conjugated enyne acetates and (ii) a iodocyclization
reaction.
To test the scope of this overall approach, we first studied
the Sonogashira reaction of (Z)-β-bromoenol acetates with
terminal alkynes. Treatment of (Z)-β-bromoenol acetates
bearing different functionalities with a wide range of term-
inal alkynes under standard Sonogashira coupling condi-
tions (0.5 mmol of (Z)-β-bromoenol acetate, 2.0 equiv of
terminal alkyne, 5 mol % of Pd(OAc)2, 10 mol % of PPh3,
5 mol % of CuI, 1 mmol of Et3N, and 2 mL of THF at 50 °C
for 6 h) affords high yields of the target products (eq 1, Table 1).
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With the standard conditions in hand, the scope of both
(Z)-β-bromoenol acetates and terminal alkynes was explored
for the coupling reaction (Table 1). Initially, a variety of
terminal alkynes were investigated by reacting with (Z)-2-
bromo-1-phenylvinyl acetate (1) (entries 1-26). The results
showed that the aromatic alkynes with either an electron-
donating or electron-withdrawing group on the benzene ring
were able to generate the corresponding products in good to
excellent yields (entries 1-14). Substitution at the ortho
position of the aromatic ring had some impact on the yields
(entries 2-4, 11, and 12). It is noteworthy that ethynylferro-
cene and the 3-ethynylbenzenamine also afford the corre-
sponding coupling products in good yields (entries 8 and 9).
It should be pointed out that the carbon-halogen bonds
tolerated the substrate reactivity and the halogen-containing
products were afforded smoothly (entries 12 and 13). The
alkyl alkynes were also found to be suitable substrates for the
standard conditions (entries 15-26). When the aliphatic
alkynes bearing chloro, cyano, silyl, benzylic, cyclopropyl,
cyclohexyl, vinylic, and hydroxyl groups were employed, the
reaction proceeded in good to excellent yields. Subsequently,
some representative (Z)-β-bromoenol acetates were exam-
ined, and high yields were obtained in almost all case,
regardless of the nature of terminal alkynes (entries 27-36).
The starting conjugated enyne acetates were readily avail-
able through the Sonogashira coupling reaction, and we then
focused on the development of an optimum conditions of the
iodocyclization (Table 2). The reaction of (Z)-1,4-diphenyl-
but-1-en-3-ynyl acetate (2) with iodine and NaHCO3 was
chosen as a model system for this process. The reaction
showed a strong solvent dependence. Good yields were
~
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TABLE 3. Synthesis of 3-Iodofuransa
aReaction conditions: enyne acetate (0.25 mmol), I2 (1.5 equiv), and NaHCO3 (1.5 equiv) in 2 mL of CH2Cl2 at rt for 8 h. bReacted for 24 h.
obtained when MeCN and hexane were used; better results
were achieved using CH2Cl2, which furnished the desired
products 41 in 94% yield.
(entries 1-24). The results indicated that substituted aryl
groups were perfectly tolerated besides the substrate 8 and 9
(entries 1-14) . The alkyne 6 bearing a bulky tert-butyl
group afforded a high yield of the desired furan (entry 5).
Substitution at the 2-position of the aromatic ring had a
slight impact, and the alkyne 12 required prolonged reaction
time (entries 4 and 11). The chloro and bromoaryl group
were tolerated in this transformation and therefore available
for additional functionalization of the product at the C-Cl
or C-Br bond (entries 12 and 13). As the challenging
substrates, aliphatic terminal alkyne moieties were compa-
tible with the reaction system. The iodocyclization process
accommodates a variety of functional groups including
To test the scope of this iodocyclization reaction, we
subjected a number of enyne acetates to the reaction condi-
tions (eq 2, Table 3). In general, most of the substrates could
afford the corresponding 2,5-disubstituted 3-iodofurans in
excellent yields. Initially, a set of substituents at the terminal
alkyne moiety were evaluated in the standard conditions
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TABLE 4. Sonogashira Coupling of 3-Iodofurans and Terminal Alkynesa
aReaction conditions: 2,5-disubstituted 3-iodofuran (0.1 mmol), terminal alkyne (0.2 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), CuI (5 mol %),
TEA (1.2 mmol), and THF (1 mL) solvent at rt for 6 h.
halides, nitriles, cyclohexyl, and benzylic on the alkyne
moiety (entries 16, 17, 19, 21, and 22). Interestingly, the
nature of the R1 group on the double bond had very little
effect on the reaction rate or the product yield (entries
25-32). Unfortunately, some substrates failed to afford
the desired furans under our standard conditions (entries 8,
9, 18, 20, 23, and 24). It appeared that the nature of the
substituents attached to the triple bond has a major impact
on the success of the reaction.
of 2,5-disubstituted 3-iodofurans with terminal alkynes (eq 3,
Table 4). As shown in Table 4, all of the substrates reacted well
and provided excellent yields of the desired coupling products.
Moreover, compounds 74, 75, 76, and 79 were easily trans-
formed to the functionalized terminal alkynes.24,25
The resulting product 2,5-disubstituted 3-iodofurans ap-
peared attractive as intermediates for the preparation of more
highly functionalized furans. To further the utility of our
methodology, we studied the Sonogashira coupling reaction
A possible mechanism was proposed on the basis of
the previous work mechanism and our reaction results
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(Z)-1,4-Diphenylbut-1-en-3-ynyl Acetate (2). This product
SCHEME 1
1
was obtained as a yellow solid. H NMR (400 MHz, CDCl3):
δ 7.47-7.49 (m, 2H), 7.41-7.44 (m, 2H), 7.33-7.37 (m, 3H),
7.30-7.32 (m, 3H), 6.15 (s, 1H), 2.37 (s, 3H). 13C NMR (100
MHz, CDCl3): δ 167.2, 155.2, 133.0, 131.0, 129.1, 128.2, 127.9,
127.8, 124.1, 122.7, 97.3, 96.5, 83.6, 20.1. MS (EI) m/z: 77, 105,
115, 191, 220, 262. Anal. Calcd for C18H14O2: C, 82.42; H, 5.38.
Found: C, 82.27; H, 5.45.
General Procedure for Iodocyclization. A mixture of (Z)-1,4-
disubstitutedbut-1-en-3-ynyl acetate (0.25 mmol), I2 (1.5 equiv)
and NaHCO3 (1.5 equiv) in CH2Cl2 (2 mL) was stirred at rt for
8 h unless otherwise specified. The excess I2 was removed by
washing with a saturated aqueous solution of Na2S2O3. The
solution was extracted with ethyl acetate (3 Â 10 mL), and the
combined extract was dried with anhydrous MgSO4. Solvent
was removed, and the residue was separated by column chro-
matography to give the pure sample.
3-Iodo-2,5-diphenylfuran (41). This product was obtained as a
yellow solid: 1H NMR (400 MHz, CDCl3): δ 8.05 (d, J = 8.0 Hz,
2H), 7.68 (d, J = 7.6 Hz, 2H), 7.27-7.46 (m, 6H), 6.83 (s, 1H).
13C NMR (100 MHz, CDCl3): δ 153.9, 151.0, 130.1, 129.5,
128.7, 128.4, 128.1, 128.0, 126.1, 123.8, 115.7, 62.7. MS (EI) m/z:
77, 105, 189, 191, 346. Anal. Calcd for C16H11IO: C, 55.51; H,
3.20. Found: C, 55.34; H, 3.28.
General Procedure for the Preparation of 2,3,5-Trisubstituted
Furans. To the mixture of 2,5-disubstituted 3-iodofuran
(0.1 mmol), Pd(OAc)2 (5 mol %) and PPh3 (10 mol %) in
THF (2 mL) solvent were added successively TEA (0.2 mmol)
and CuI (5 mol %), the mixture was stirred for 5 min at rt,
terminal alkyne (0.2 mmol) was added, the flask was then sealed,
and the mixture was stirred at rt for 6 h. The solution was
washed with water and extracted with ethyl acetate (3 Â 5 mL),
and the combined extract was dried with anhydrous MgSO4.
Solvent was removed, and the residue was separated by column
chromatography to give the pure sample.
(Scheme 1).16b,18b,21d In the first step, coordination of the
triple bond to the I2 generates the iodonium a, then an anti
attack of the electrophile forms b, and subsequently the
acetyl group can be removed from intermediate b with aid
of an nucleophile to afford the target produce 41.
Conclusions
A very efficient synthesis of 2,5-disubstituted 3-iodofurans
has been developed through the Sonogashira coupling of
(Z)-β-bromoenol acetates with terminal alkynes, followed by
intramolecular iodocyclization. The useful intermediates of
conjugate enyne acetates were obtained in high yields with
broad functional groups tolerated. We observed that the
iodocyclization was sensitive to the nature of the solvent and
the structure of conjugate enyne acetates. The 2,5-disubsti-
tuted 3-iodofurans appear attractive for the prearation of
more highly substituted furans. For example, the 2,3,5-
trisubstituted furans were prepared with excellent yields.
3-(2-(4-Methoxyphenyl)ethynyl)-2,5-diphenylfuran (73). This
product was obtained as a yellow solid. H NMR (400 MHz,
1
Experimental Section
CDCl3): δ 8.02 (d, J = 7.6 Hz, 2H), 7.73 (d, J = 7.6 Hz, 2H),
7.39-7.51 (m, 6H), 7.28-7.33 (m, 2H), 6.90 (d, J = 8.8 Hz, 2H),
6.82 (s, 1H), 3.83 (s, 3H). 13C NMR (100 MHz, CDCl3): δ 159.7,
153.6, 152.2, 132.9, 130.5, 130.0, 128.8, 128.6, 127.9, 127.9,
124.7, 123.9, 115.2, 114.1, 110.0, 105.2, 94.0, 81.3, 55.3. MS
(EI) m/z: 51, 77, 152, 199, 277, 350. Anal. Calcd for C25H18O2:
C, 85.69; H, 5.18. Found: C, 85.43; H, 5.25.
General Procedure for Synthesis of (Z)-1,4-Disubstitutedbut-
1-en-3-ynyl Acetates. To the mixture of (Z)-β-bromoenol ace-
tate (0.5 mmol), Pd(OAc)2 (5 mol %), and PPh3 (10 mol %) in
THF (2 mL) solvent, were added successively TEA (1 mmol) and
CuI (5 mol %), the mixture was stirred for 5 min at rt, terminal
alkyne (1.0 mmol) was added, the flask was then sealed, and the
mixure was stirred at 50 °C for 6 h. The solution was washed
with water and extracted with ethyl acetate (3 Â 15 mL), and the
combined extract was dried with anhydrous MgSO4. Solvent
was removed, and the residue was separated by column chro-
matography to give the pure sample.
Acknowledgment. We gratefully acknowledge the National
Natural Science Foundation of China (Nos. 20625205,
20772034, and 20932002), National Basic Research Program
of China (973 Program) (No. 2011CB808600), Doctoral
Fund of Ministry of Education of China (20090172110014),
and Guangdong Natural Science Foundation (No.
10351064101000000) for financial support.
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Supporting Information Available: Full experimental details
and copies of NMR spectral data. This material is available free
of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 76, No. 4, 2011 1139