Facile synthesis of 3,4-dihalofurans via electrophilic iodocyclization

Article abstract of DOI:10.1039/c1cc10584a

A facile, efficient, and general synthetic method for 3,4-dihalofurans has been developed via the electrophilic iodocyclization of various 4-hydroxy-2-but-2-yn-1-ones. The use of MeOH as a solvent is crucial for the efficient chemoselective synthesis of t

Full text of DOI:10.1039/c1cc10584a

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COMMUNICATION
Facile synthesis of 3,4-dihalofurans via electrophilic iodocyclizationw
Fan Yang,a Tienan Jin,*ab Ming Baoc and Yoshinori Yamamoto*ab
Received 29th January 2011, Accepted 18th February 2011
DOI: 10.1039/c1cc10584a
A facile, efficient, and general synthetic method for 3,4-dihalo-
furans has been developed via the electrophilic iodocyclization of
various 4-hydroxy-2-but-2-yn-1-ones. The use of MeOH as a
solvent is crucial for the efficient chemoselective synthesis of the
corresponding 3,4-dihalofurans.
ð2Þ
ð3Þ
Polysubstituted furans are of great interest as natural products
as well as synthetic building blocks.1 Owing to their wide
applications, the synthetic method for furans has been inten-
sively developed.1 Electrophilic iodocyclization of alkyne or
allene bound substrates is one of the most efficient strategies
In continuation of our interest in the development of
efficient synthetic methods of heterocycles,5 and in iodocycli-
zation chemistry,6 we attempted to synthesize 3,4-diiodofurans
through a simple iodine mediated electrophilic cyclization.
However, when 4-hydroxy-1,4-diphenylbut-2-yn-1-one 1a
was treated with I2 under the ordinary conditions, a mixture
of the corresponding furan 2a and the diiodinated acyclic
olefin 3a was obtained (Table 1, entry 1). This is not a
surprising result, since the addition of I2 to a triple bond takes
place rather easily. We thought that the coexistence of a protic
source may produce the corresponding diiodofuran 2a
selectively without formation of 3a, because the presence of
p-TosOH might be key for eqn (2).
for the construction of furans having a b-iodo-substituent under
very mild conditions (eqn (1)).2 Furthermore, the resulting
iodine-containing products can be readily converted to the
structurally elaborated polysubstituted furans regioselectively
using transition metal-catalyzed coupling reactions. On the
other hand, electrophilic iodocyclization for the synthesis of
the dihalogenated furans has been rarely reported,2h,3,4 although
it provides an opportunity to produce the b,b0-disubstituted
furans. Recently, Muller and co-workers reported a facile one-
¨
pot three-component reaction for the synthesis of 3-chloro-
4-iodofurans with moderate yields (eqn (2)).2h However, it seems
to be difficult to carry out the cross-coupling reaction of the two
C–X bonds of the resulting furans, since C–Cl bonds generally
exhibit low reactivity toward transition metal-catalyzed reac-
tions. Therefore, the development of an efficient and general
approach to iodo- or bromo-substituted dihalofurans is desir-
able. Herein, we wish to report a facile, efficient and general
synthetic method for 3,4-dihalofurans 2 (X = Br, I) from
4-hydroxy-but-2-yn-1-ones 1 (eqn (3)).
The use of CH2Cl2 with proton sources, such as H2O and
TfOH, did not improve the yield of 2a (entries 2 and 3). The
presence of MeOH (1.0 equiv.) slightly improved the yield of
2a (entry 4). The use of other aprotic solvents, such as THF,
CH3NO2, CHCl3, CCl4, and benzene, did not increase the
selectivity (entries 5–9). Fortunately, when MeOH or EtOH
was used as a solvent, the yield of 2a was dramatically
increased and formation of 3a was not detected (entries 10
and 11). These results indicate that such aprotic solvents are
indispensable for the selective formation of 2a.
The scope and limitations of iodine mediated electrophilic
cyclization of various substituted 4-hydroxy-but-2-yn-1-ones
are summarized in Table 2. The reactions of 4-hydroxy-
4-phenylbut-2-yn-1-ones 1b and 1c bearing an electron-donating
and an electron-withdrawing aromatic group at R2 produced
the corresponding diiodofurans 2b and 2c in 83% and 91%
yields, respectively (entries 1 and 2). Not only a naphthyl
substituent (1d), but also a tosyl-protected pyrrolyl (1e) group
at R2 afforded the desired products in good to high yields
(entries 3 and 4). The reaction also worked well with the
substrate 1f having an alkyl substituent at R2, furnishing the
expected tetrasubstituted diiodofuran 2f in good yield (entry 5).
ð1Þ
a Department of Chemistry, Graduate School of Science, Tohoku
University, Sendai 980-8548, Japan. E-mail: tjin@m.tohoku.ac.jp,
yoshi@m.tohoku.ac.jp; Fax: +81-22-795-6784;
Tel: +81-22-795-6581
b WPI-AIMR (WPI-Advanced Institute for Materials Research),
Tohoku University, Sendai 980-8577, Japan
c State Key Laboratory of Fine Chemicals, Dalian University of
Technology, Dalian 116012, China
w Electronic supplementary information (ESI) available: Experimental pro-
cedures and characterization data. CCDC 804042. For ESI and crystal-
lographic datain CIF orotherelectronic format see DOI: 10.1039/c1cc10584a
c
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Chem. Commun., 2011, 47, 4541–4543 4541

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Table 1 Optimization of reaction conditionsa
conditions, affording the trisubstituted furans 2l and 2m in
good yields (entries 11 and 12).
We further tested this cyclization with an IBr electrophile
instead of iodine. Fortunately, in the presence of two
equivalents of IBr, substrates 1b, 1g, and 1n underwent the
electrophilic cyclization smoothly to afford the corresponding
3-bromo-4-iodofurans in good yields (eqn (4)). The structure
of 2b0 was unambiguously confirmed by X-ray crystal-structure
analysis.7
Additive/
equiv.
2a,
3a,
Entry Solvent
Time/h Yieldb (%) Yieldb (%)
1
2
3
4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
0.5
0.25
0.5
3
3
3
45
40
38
65
21
45
41
43
50
60
14
30
69
49
58
55
70
0
H2O (0.5)
TfOH (0.1)
MeOH (1.0)
5
6
7
8
CH3NO2
CHCl3
CCl4
1
0.25
0.3
5
9
10
11
Benzene
MeOH
EtOH
30
96 (87)
92
ð4Þ
5
0
a
Reaction conditions: 1a (0.2 mmol), I2 (0.6 mmol), anhydrous
solvent (0.1 M), room temperature. b 1H NMR yield determined using
CH2Br2 as an internal standard. Isolated yield is shown in parentheses.
A plausible mechanism for the present cyclization is shown
in Scheme 1. Presumably, initial activation of butynone 1a
with a Lewis acidic iodine8 in the presence of MeOH leads to
the ketal intermediate A.9 Subsequent dehypoiodination gave
propargylic carbocation B or allene cation C10 along with an
unstable hypoiodous acid (HOI) and an iodine anion. Attack
of the iodine anion onto the g-position of B or the cation C
affords iodoallene D which will react with hypoiodous
acid to form an iodonium intermediate E.11 Subsequent
intramolecular nucleophilic addition of an oxygen atom to
the activated allene E followed by elimination of MeOH
produces 2a.
Table 2 Synthesis of 3,4-diiodofurans by electrophilic iodocyclizationa
Entry Substrates 1
Products 2
Yieldb (%)
We carried out the following control experiments to confirm
the proposed mechanism. From the reaction of E-configured
diiodo hydroxyl enone 3a with I2 under the standard
conditions in CH2Cl2, 2a was obtained in 40% yield together
with the recovered 3a in 50% yield (eqn (5)). 2a must be
formed through a mechanism similar to the previously
1
2
3
4
5
1b R2 = 4-MeO–C6H4
2b
2c
2d
83
91
81
43
63
1c R2 = 4-Cl–C6H4
1d R2 = 1-naphthyl
reported one by Obrecht2a and Muller et al.,2g,h in which the
1e R2 = 2-(1-tosyl)pyrrolyl 2e
¨
1f R2 = n-C5H11
2f
interconversion of the (E)- and (Z)-isomers followed by
intramolecular cyclocondensation takes place. On the other
hand, the reaction of 3a in MeOH did not produce the
corresponding product 2a at all. Moreover, when the substrate
1o, without a proton at the propargyl alcoholic carbon, was
treated with I2 under the standard conditions, the methoxy
incorporated dihydrofuran 4o was obtained in 83% yield
(eqn (6)). These results indicate that the present cyclization
6
7
8
9
10
1g R2 = Ph
2f
2h
2i
2j
2k
89
80
88
75
68
1h R2 = 4-MeO–C6H4
1i R2 = 4-Cl–C6H4
1j R2 = 1-naphthyl
1k R2 = n-C5H11
11
12
1l R2 = Ph
2l
2m
85
60
1m R2 = n-C5H11
a
Reaction conditions: 1 (0.2 mmol), I2 (0.6 mmol), anhydrous MeOH
b
(0.1 M), room temperature, 2–5 hours. Isolated yield.
Similarly, the 4-pentyl substituted 4-hydroxy-but-2-yn-1-ones
1g–k having various substituted phenyl groups, naphthyl
group, and alkyl group at R2 underwent the cyclization
smoothly to give the products in high yields (entries 6–10).
Substrates 1l and 1m having a primary propargyl alcohol
moiety were also compatible with the standard reaction
Scheme 1 Proposed reaction mechanism.
c
4542 Chem. Commun., 2011, 47, 4541–4543
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nane, 100 1C, 83%; (b) (i) Pd(PPh3)2Cl2 (5 mol%), CuI (10 mol%),
DIPA, THF, 60 1C, ethynyltrimethylsilane. (ii) K2CO3, MeOH/THF,
rt, 70% for 2 steps.
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ð5Þ
ð6Þ
4 For synthesis of 3,4-diiododihydrofurans, see: (a) A. A. Kruglov,
Zh. Obshch. Khim., 1937, 7, 2605; (b) K.-G. Ji, H.-T. Zhu, F. Yang,
X.-Z. Shu, S.-C. Zhao, X.-Y. Liu, A. Shaukat and Y.-M. Liang,
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(c) N. T. Patil and Y. Yamamoto, Chem. Rev., 2008, 108, 3395.
As shown in Scheme 2, diiodofuran 2a was readily converted
to the tetrasubstituted furans using various Pd-catalyzed
processes. For example, the double Stille couplings of 2a with
allyltributylstannane gave the bisallylated product 5a in 83%
yield. Similarly, the double Sonogashira couplings of 2a with
trimethylsilyl acetylene afforded the corresponding product 6a
in 70% yield after deprotection of TMS-groups.
6 For our recent iodine-mediated electrophilic cyclizations, see:
(a) D. Fischer, H. Tomeba, N. K. Pahadi, N. T. Patil and
Y. Yamamoto, Angew. Chem., Int. Ed., 2007, 46, 4764;
(b) D. Fischer, H. Tomeba, N. K. Pahadi, N. T. Patil, Z. Huo
and Y. Yamamoto, J. Am. Chem. Soc., 2008, 130, 15720;
(c) Z. Huo, H. Tomeba and Y. Yamamoto, TetrahedronLett.,
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In conclusion, we have developed a facile, efficient, and
general method for the synthesis of dihalofurans through
electrophilic iodocyclization. This methodology accommodates
a wide range of functional groups and affords various highly
substituted 3,4-diiodo- and 3-bromo-4-iodo-furans efficiently
under mild reaction conditions. The reaction proceeds through
ketals generated in situ in MeOH. The resulting diiodo compounds
can be readily transferred to the multi-p-system substituted
furans by Pd-catalyzed transformations. Application of the
present method to the synthesis of useful optoelectronic
materials is in progress.
7 CCDC-804042 contains the supplementary crystallographic data
for 2b0.
8 K. Rossen, R. A. Reamer, R. P. Volante and P. J. Reider, Tetrahedron
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substitution reactions of propargyl alcohols, see: (a) P. Srihari,
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F.Y. acknowledges the support of China Scholarship
Council (CSC).
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Notes and references
1 For selected reviews, see: (a) B. A. Keay, J. M. Hopkins
and P. W. Dibble, in Comprehensive Heterocyclic Chemistry III,
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 4541–4543 4543