Direct access to fully substituted 3-formyl-4-iodofurans through iodocyclization of α-alkynyl β-alkoxy enones

Article abstract of DOI:10.1002/ejoc.201201203

A facile access to 3-formyl-4-iodofurans is presented. This protocol consists of a Sonogashira cross-coupling of an α-iodo β-alkoxy enone with a terminal alkyne and the subsequent iodonium-promoted heteroannulation- dealkoxylation of the resulting α-alkynyl β-alkoxy enone by treatment with N-iodosuccinimide in aqueous medium. Fully substituted 3-formyl-4-iodofurans are easily accessible under mild reaction conditions from readily available α-iodo β-alkoxy enones and terminal alkynes. The proposed two-step protocol combines a Sonogashira cross-coupling reaction and subsequent iodocyclization without the need to isolate the intermediate α-alkynyl β-alkoxy enone. Copyright

Full text of DOI:10.1002/ejoc.201201203

FULL PAPER
DOI: 10.1002/ejoc.201201203
Direct Access to Fully Substituted 3-Formyl-4-iodofurans through
Iodocyclization of α-Alkynyl β-Alkoxy Enones
Guillaume Raffa,[a] Geneviève Balme,[a] and Nuno Monteiro*[a]
Keywords: Synthetic methods / Homogeneous catalysis / Cross-coupling / Cyclization / Oxygen heterocycles / Alkynes
A facile access to 3-formyl-4-iodofurans is presented. This
protocol consists of a Sonogashira cross-coupling of an α-iodo
β-alkoxy enone with a terminal alkyne and the subsequent
iodonium-promoted heteroannulation–dealkoxylation of the
resulting α-alkynyl β-alkoxy enone by treatment with N-
iodosuccinimide in aqueous medium.
access to 3-formyl-4-iodofurans II after in situ dealkyl-
ation – or hydrolysis – of the putative oxonium intermediate
(see Scheme 1). Surprisingly, despite their considerable po-
tential synthetic value, no practical and flexible method is
currently available to access such compounds, and only rare
examples of them have been reported so far in the litera-
ture.[7] Indeed, they are expected to be versatile synthetic
intermediates, given the great variety of chemical transfor-
mations available for each of the halogen and formyl func-
tional groups.[8] Herein, we report the successful develop-
ment of a two-step, semi-one-pot protocol for such com-
pounds from readily available α-iodo β-alkoxy enones and
terminal alkynes.
Introduction
The furan structure is a ubiquitous subunit in a variety
of bioactive natural products and synthetic materials, in-
cluding important agrochemicals and pharmaceuticals. Ad-
ditionally, furan derivatives can serve as versatile building
blocks in the construction of highly complex target struc-
tures.[1] Thus, the value and utility of this heterocycle con-
tinue to stimulate research directed toward its construc-
tion.[2] In this area, the development of synthetic strategies
that allow the flexible and rapid assembly of furan deriva-
tives with specific substitution patterns, prepared from
readily available starting materials and under mild reaction
conditions, remains an important goal. Today, electrophilic
heteroannulation processes that involve acetylenic com-
pounds bearing a tethered nucleophilic substituent are
among the most versatile and efficient synthetic methods to
rapidly elaborate highly substituted heterocyclic systems.[3]
In particular, furan derivatives have been accessed recently
though halonium-promoted heteroannulations of α-alkynyl
carbonyl compounds.[4,5] The ready accessibility of the lat-
ter compounds combined with the synthetic utility of the
halide functional group, thereby installed on the newly
formed heterocyclic ring, makes this approach particularly
attractive.
Scheme 1. Planned strategy toward 3-formyl-4-iodofurans.
Results and Discussion
To test the feasibility of the proposed concept, we first
We recently demonstrated the high versatility of alkyl β- needed a reliable procedure for the preparation of a series
keto enol ethers for use as masked β-dicarbonyl nucleo- of α-alkynyl ketones 3. We expected these to be accessible
philes in the direct construction of the 3-ketofuran unit by a Sonogashira cross-coupling of α-iodo β-alkoxy enones
through an alkynyl cyclization reaction.[6] Along the same 2, which in turn may be easily prepared by iodination[9] of
line, we envisioned that the iodonium-promoted heteroan- the corresponding and readily available β-alkoxy enones 1.
nulation of α-alkynyl β-alkoxy enones I would give direct Preliminary studies were conducted using iodo enone 2a
and phenylacetylene as model substrates. Initially, the cross-
coupling reaction was probed using reaction conditions pre-
viously developed in our laboratory for the alkynylation of
structurally related compounds [cat. PdCl2(PPh3)2, cat.
CuI, K2CO3, THF (tetrahydrofuran), 40 °C].[6c] Interest-
ingly, the desired alkynyl enone 3aaЈ proved relatively un-
stable under these conditions and exhibited a marked pro-
pensity to undergo gradual cyclization to 3-formylfuran 4
[a] Institut de Chimie et Biochimie Moléculaires et
Supramoléculaires (ICBMS, UMR 5246 du CNRS), Université
Lyon 1,
CPE Lyon 43, Blvd. du 11 Novembre 1918, 69622 Villeurbanne,
France
E-mail: monteiro@univ-lyon1.fr
Homepage: www.icbms.fr
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201203.
Eur. J. Org. Chem. 2013, 105–110
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
105

G. Raffa, G. Balme, N. Monteiro
FULL PAPER
as the main reaction product. For instance, the latter was Table 1. Optimization of the iodocyclization process.[a]
isolated in 50% yield after 16 h of reaction time, aside from
other unidentified side products.[10] Gratifyingly, after fur-
ther experiments, we found that the use of Et3N/toluene as
a base/solvent pair enabled rapid and clean formation of
the cross-coupled product and retarded formation of the
side products. Under the optimized reaction conditions
[alkyne (1.25 equiv.), PdCl2(PPh3)2 (5 mol-%), CuI
(2.5 mol-%), Et3N/toluene (1:1), 40 °C], 3aaЈ was isolated in
83% yield, after only 1 h of reaction time. Accordingly, α-
alkynyl β-alkoxy enone 3bbЈ was obtained in 75% isolated
yield, following the same procedure (see Scheme 2).
Entry
I+ Source [equiv.] Solvent
Time [h]
% Yield 5a
1
2
3
4
5
6
7
I2 (1.1)
I2 (2.0)
DCM
DCM
0.25
0.25
22
6
6
6
28
25
NIS (1.1)
NIS (1.1)
NIS (1.1)
NIS (1.1)
NIS (1.1)
DCM
24 (+ 35% 6)
DCM/H2O
Et2O/H2O
MeCN/H2O
PhMe/H2O
75
48
[b]
–
6
45
[a] All reactions were carried out on a 0.2 mmol scale. [b] Complex
mixture.
Given the effectiveness and cleanliness of the Sonoga-
shira cross-coupling step and owing to the somewhat fragile
nature of the α-alkynyl β-alkoxy enones (see Exp. Section),
we next focused on establishing a rapid and effective proto-
col for formyl iodofuran formation that would avoid isolat-
ing and purifying the acetylenic precursors. A convenient
experimental procedure for the conversion of α-iodo enone
Scheme 2. Synthesis of α-alkynyl enones 3.
Next, the reactivity of alkynyl enone 3bbЈ, selected as the 2b into iodofuran 5a was thus conducted. Compound 2b
model substrate, was investigated with regard to various (1.0 equiv.) and phenylacetylene (1.25 equiv.) underwent a
iodonium-donating systems. The cyclization process was Sonogashira coupling reaction under the previously estab-
first probed at 20 °C with iodine as the I+ source and lished conditions [cat. PdCl2(PPh3)2, cat. CuI, toluene/
CH2Cl2 (DCM) as the solvent. Pleasingly, a fast reaction Et3N, 40 °C]. After the disappearance of the starting mate-
took place under these conditions to give the expected iodo- rial, as monitored by thin layer chromatography (approxi-
furan 5a, albeit in a disappointing 28% yield (see Table 1, mately 1 h), the reaction mixture was diluted with EtOAc,
Entry 1). Employing a large excess amount of I2 did not and the resulting solution was washed with brine to remove
improve the yield (see Table 1, Entry 2). When iodine was ammonium salts and then concentrated in vacuo. The crude
replaced with N-iodosuccinimide (NIS),[11] the outcome of alkynyl enone was then subjected to iodocyclization with
the reaction proved interesting, despite the longer reaction NIS (1.1 equiv.) under our optimized conditions (DCM/
time and the still poor yield (24%) obtained for 5a. Indeed, H2O, room temp.), and the reaction was complete within
under these conditions, 5a was accompanied, aside from 6 h. This resulted in an improved 62% overall yield for the
other minor unidentified side products, by another iodo- production of 5a, after the usual workup and silica gel
furan. The structure of this product, having incorporated a chromatography as the only and final purification step.
succinimide fragment, was assigned as hemiaminal ether 6 With this mild, practical protocol in hand, we set out to
(35% yield) and confirmed by X-ray crystal structure analy- screen the scope and limitation of this reaction with various
sis[12] (see Table 1, Entry 3). Unfortunately, this latter com- α-iodo β-alkoxy enones and terminal alkynes (see Table 2).
pound, which can be rationalized as the consequence of the
The best results were achieved with aryl-substituted al-
liberation of the succinimide anion in the reaction medium kynes, which provided the corresponding iodofurans in
(vide infra), showed remarkable stability and withstood the good overall yields. As illustrated by the reactions with
usual acidic work-up procedures (i.e., 1 n HCl). With the alkyl ketones 2b and 2c (see Table 2, Entries 1–7), the elec-
aim of minimizing the interference of the succinimide tronic nature of the arene attached to the triple bond had
anion, the same experiment was then repeated in the pres- a noticeable impact on the yield of the reaction, and the
ence of water as a cosolvent. Gratifyingly, the aqueous sol- presence of electron-donating groups gave better yields.
vent system enabled a noticeable improvement in the effi- Alkyl-substituted alkynes participated less efficiently in the
ciency of the reaction, not only by giving rise to the desired cyclization process (see Table 2, Entry 5). Phenyl and 2-fur-
formylfuran 5a as the sole reaction product in a satisfying yl ketones 2a and 2d also participated in the process to
75% overall isolated yield, but also by accelerating the rate give the corresponding 2,5-(hetero)arylfurans in acceptable
of reaction (see Table 1, Entry 4).[13] Other aqueous solvent isolated yields (see Table 2, Entries 8–11). It is noteworthy
systems were screened, but they did not lead to any further that 2,5-diphenylfuran 5h (see Table 2, Entry 8) was ac-
improvements (see Table 1, Entries 5–7).
companied by another furan derivative that was tentatively
106
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 105–110

Direct Access to Fully Substituted 3-Formyl-4-iodofurans
Table 2. Two-step synthesis of 3-formyl-4-iodofurans 5.[a]
assigned as the structural isomer 3-benzoyl-4-iodo-5-phen-
ylfuran (not shown). The mechanism involving the forma-
tion of this regioisomeric compound remains unclear. Im-
portantly, this process was successfully applied to the pre-
parative scale (2 mmol) synthesis of furan 5b (74% isolated
yield). The structure of the iodofuraldehydes was confimed
by the X-ray crystal structure analysis of 5k (see Fig-
ure 1).[12]
Figure 1. X-ray representation of crystal structure 5k.
A plausible mechanism for the formation of the formyl
iodofurans is shown in Scheme 3. The cyclization reactions
are believed to proceed through activation of the carbon–
carbon triple bond by coordination to I+, and then subse-
quent intramolecular attack of the carbonyl oxygen (A)
gives the corresponding oxonium cation B. Subsequent hy-
drolysis furnishes the desired formylfuran. In the absence
of water, nucleophilic attack by the succinimide anion on B
may occur to form hemiaminal ether 6. Importantly, the
present reaction conditions should avoid the formation of
carcinogenic and volatile monohaloalkanes that are gen-
erally produced in iodocyclization–dealkylation process-
es.[4a,14]
Scheme 3. Mechanistic proposal.
Conclusions
[a] All reactions were single runs conducted on a 0.4 mmol scale.
Reagents and conditions: alkyne (1.25 equiv.), PdCl2(PPh3)2
(5 mol-%), CuI (2.5 mol-%), Et3N/toluene (1:1), 40 °C, 1 h (Step 1);
NIS (1.1 equiv.), DCM/H2O (1:1), room temp., 6 h (Step 2). [b] Iso-
lated yields (two steps). [c] This experiment was also performed on
a 2 mmol semipreparative scale (74% yield), see Exp. Section.
[d] The reaction produced a 4:1 mixture of 5h and its structural
isomer 3-benzoyl-4-iodo-5-phenylfuran (70% combined yield).
In summary, we have developed a flexible and practical
protocol to produce fully substituted 3-formyl-4-iodofurans
starting from terminal alkynes and readily accessible α-iodo
β-alkoxy enones, which are used as β-ketoaldehyde equiva-
lents. These compounds, which are not easily accessible by
other means, are poised for subsequent functionalization
Eur. J. Org. Chem. 2013, 105–110
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
107

G. Raffa, G. Balme, N. Monteiro
FULL PAPER
and 0.7 Hz, 1 H, Ar), 7.58 (dd, J = 1.7 and 0.7 Hz, 1 H, Ar), 7.95
(s, 1 H, =CHO) ppm. 13C NMR (100 MHz, CDCl3): δ = 62.5
(CH3), 82.2 (C–I), 112.3, 118.8, 145.8 (CH Ar), 150.3 (C Ar), 166.6
(=CHO), 176.0 (CO) ppm. GC–MS: m/z = 278.
and should offer great opportunities as unique building
blocks in synthesis, and particularly in the elaboration of
chemical libraries.
Representative Procedure for the Syntheses of α-Alkynyl β-Alkoxy
Enones 3: Caution! Because of the somewhat acid-sensitive nature
of the title compounds, special care should be taken during the
isolation and characterization processes. Although the compounds
normally withstand classic workup and purification by flash
chromatography on silica gel, leaving them in contact with silica
gel (or CDCl3) for prolonged periods of time resulted in gradual
degradation. In a glass tube fitted with a Teflon® screw seal, the
α-iodo enone (0.2 mmol) and the selected alkyne (0.25 mmol) were
Experimental Section
General Methods: All reactions were performed under an open at-
mosphere, using commercial grade solvents, with the exception that
reactions catalyzed by palladium were carried out under argon. An-
alytical thin layer chromatography was carried out on Merck silica
60/F-240 aluminium-backed plates. The developed chromatograms
were visualized by UV absorbance. Flash chromatography was per-
formed with Merck silica gel 60 (40–63 μm). The NMR spectro-
scopic data were recorded in the indicated solvent with either a 300
or 400 MHz spectrometer. Chemical shifts (δ) are given relative to
TMS (δ = 0.00 ppm) in parts per million (ppm) with the residual
signals of the deuterated solvent used as the standards [1H NMR
(CDCl3): δ = 7.26 ppm (s) and 13C NMR (CDCl3): δ = 77.16 ppm
(t)]. Coupling constants (J) are expressed in Hertz (Hz), and spin
multiplicities are given as s (singlet), d (doublet), t (triplet), q (quar-
tet), quint (quintet), sext (sextet), m (multiplet) and br. (broad).
Commercially available reagents, including alkoxy enone 1b, were
used as purchased. Alkoxy enones 1a, 1c, and 1d were prepared
from the corresponding methyl ketones according to published pro-
cedures.[15]
successively added to
a solution of PdCl2(PPh3)2 (7.5 mg,
0.01 mmol) and CuI (1 mg, 0.005 mmol) in a mixture of degassed
Et3N/toluene (1:1; 1 mL). The reactor was flushed with argon, and
the reaction mixture was stirred at 40 °C for 1 h and then diluted
with ethyl acetate (10 mL). The resulting solution was washed with
brine (2ϫ10 mL), and the organic layer was dried with MgSO4 and
concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, appropriate mixture of cyclohexane/
ethyl acetate) to afford the corresponding α-alkynyl enone. The (E)
configuration was assigned on the basis of NOE spectroscopy.
(E)-3-Ethoxy-1-phenyl-2-(phenylethynyl)prop-2-en-1-one (3aaЈ): Tan
oil (46 mg, 83%). 1H NMR (300 MHz, CDCl3): δ = 1.46 (t, J =
7.1 Hz, 3 H, CH3), 4.28 (q, J = 7.1 Hz, 2 H, CH2), 7.26–7.30 (m,
3 H, Ar), 7.36–7.41 (m, 2 H, Ar), 7.45 (d, J = 7.6 Hz, 2 H, Ar),
7.50–7.56 (m, 1 H, Ar), 7.94 (dd, J = 8.4 and 1.7 Hz, 2 H, Ar) ppm.
13C NMR (75 MHz, CDCl3): δ = 15.5 (CH3), 72.1 (CH2), 82.9,
98.5, 103.8 (=C–CϵC), 123.7 (C Ar), 128.0, 128.1, 128.3, 129.2,
131.3, 132.0 (CH Ar), 138.5 (C Ar), 167.3 (=CHO), 192.3
(CO) ppm. HRMS (CI): calcd. for C19H17O2 [MH]+ 277.1223;
found 277.1221.
3-Iodo-4-methoxybut-3-en-2-one (2b): Compound 2b was prepared
following a procedure reported in the literature.[9a]
Representative Procedure for the Syntheses of α-Iodo β-Alkoxy En-
ones
2-Iodo-3-ethoxy-1-phenylprop-2-en-1-one (2a): To a suspension of
N-iodosuccinimide (7.02 g, 31.2 mmol) in dichloromethane
(50 mL) were added acetic acid (2.68 mL, 46.8 mmol) and 3-
ethoxy-1-phenylprop-2-en-1-one (4.58 g, 26 mmol). The reaction
mixture was stirred at room temperature for 1 h and then cooled
to 0 °C (ice bath). Triethylamine (14.5 mL, 104.0 mmol) was then
added, and the reaction mixture was allowed to reach room tem-
perature (1 h). After this time, it was successively washed with an
aqueous Na2S2O3 solution (3ϫ20 mL) and then an aqueous
Na2CO3 solution (3ϫ20 mL). The organic layer was dried with
MgSO4 and concentrated in vacuo. The crude residue was purified
by flash chromatography on silica gel (cyclohexane/ethyl acetate)
(E)-4-Methoxy-3-[(4-methoxycarbonyl)phenylethynyl]but-3-en-2-one
(3bbЈ): Yellow solid (39 mg, 75%); m.p. 124–126 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.44 (s, 3 H), 3.92 (s, 3 H), 4.03 (s, 3 H),
7.53 (d, J = 8.5 Hz, 2 H), 7.71 (s, 1 H), 8.00 (d, J = 8.5 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.4, 52.3, 63.1, 85.2,
96.6, 103.5, 128.0, 129.5, 129.6, 131.2, 166.5, 196.0 ppm. HRMS
(CI): calcd. for C15H15O4 [MH]+ 259.0965; found 259.0965. The
same reaction was performed on a 2 mmol scale to give 3bbЈ
(408 mg, 79%).
1
to give 2a (5.34 g, 68% yield) as a white solid; m.p. 55–57 °C. H
General Procedure for Syntheses of 3-Formyl-4-iodofurans 5: In a
glass tube fitted with a Teflon® screw seal, α-iodo enone 2
(0.4 mmol) and the selected terminal alkyne (0.5 mmol) were suc-
cessively added to a solution of PdCl2(PPh3)2 (14 mg, 0.02 mmol)
and CuI (2 mg, 0.01 mmol) in a mixture of degassed Et3N/toluene
(1:1; 1 mL). The reactor was flushed with argon, and the reaction
mixture was stirred at 40 °C for 1 h and then diluted with ethyl
acetate (10 mL). The resulting solution was washed with brine
(2ϫ10 mL). The organic layer was concentrated in vacuo, and the
resulting residue was dissolved in a mixture of CH2Cl2/water (1:1;
4 mL). N-iodosuccinimide (100 mg, 0.44 mmol) was added, and the
reaction mixture was stirred at room temperature for 6 h and then
diluted with dichloromethane (10 mL). The resulting solution was
washed successively with an aqueous Na2S2O3 solution (2ϫ10 mL)
and then HCl (1 n solution, 3ϫ10 mL). The organic layer was
dried with MgSO4 and then concentrated in vacuo. The residue was
purified by flash column chromatography (silica gel, appropriate
NMR (300 MHz, CDCl3): δ = 1.40 (t, J = 7.1 Hz, 3 H, CH3), 4.21
(q, J = 7.1 Hz, 2 H, CH2), 7.31 (s, 1 H, =CHO), 7.41–7.45 (m, 2
H, Ar), 7.49–7.51 (m, 1 H, Ar), 7.54–7.58 (m, 2 H, Ar) ppm. 13C
NMR (75 MHz, CDCl3): δ = 15.2 (CH3), 71.7 (CH2), 83.6 (C–I),
128.5, 128.9, 131.5 (CH Ar), 137.8 (C Ar), 167.3 (=CHO), 191.0
(C=O) ppm. GC–MS: m/z = 302.
4-Iodo-5-methoxy-2-methylpent-4-en-3-one (2c): The reaction was
performed on 4.7 mmol scale to give 2c (766 mg, 64%) as an orange
solid; m.p. 68–69 °C (dec.). 1H NMR (300 MHz, CDCl3): δ = 1.07
[d, J = 6.8 Hz, 6 H, (CH3)2CH], 3.23 [quint, J = 6.8 Hz, 1 H,
(CH3)2CH], 3.98 (s, 3 H, OCH3), 7.50 (s, 1 H, =CHO) ppm. 13C
NMR (75 MHz, CDCl3): δ = 19.8 [(CH3)2CH], 36.0 [(CH3)2CH],
62.4 (OCH3), 82.1 (C–I), 163.4 (=CHO), 198.5 (CO) ppm. GC–
MS: m/z = 254.
1-(2-Furyl)-2-iodo-3-methoxyprop-2-en-1-one (2d): The reaction
performed on 2.4 mmol scale to give 2d (441 mg, 65%) as a yellow
1
solid; m.p. 70–72 °C. H NMR (300 MHz, CDCl3): δ = 4.10 (s, 3 mixture of cyclohexane/ethyl acetate) to afford the corresponding
H, CH3), 6.55 (dd, J = 3.6 and 1.7 Hz, 1 H, Ar), 7.23 (dd, J = 3.6 furan 5.
108
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 105–110

Direct Access to Fully Substituted 3-Formyl-4-iodofurans
4-Iodo-2-methyl-5-(4-methoxycarbonyl)phenylfuran-3-carbaldehyde (OCH3), 61.0 (OCH3), 61.1 (C–I), 104.4 (CH Ar), 120.0 (C Ar),
(5a): White solid (92 mg, 62%); m.p. 170–172 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.68 (s, 3 H, CH3), 3.94 (s, 3 H, OCH3),
8.04–8.12 (m, 4 H, Ar), 9.90 (s, 1 H, CHO) ppm. 13C NMR
(75 MHz, CDCl3): δ = 13.7 (CH3), 52.4 (OCH3), 63.6 (C–I), 122.2
(C Ar), 126.2 (CH Ar), 129.9 (CH Ar), 130.0 (C Ar), 133.3 (C
Ar), 150.0 (=CO), 161.7 (=CO), 166.6 (O=CO), 187.7 (CHO) ppm.
HRMS (CI): calcd. for C14H12IO4 [MH]+ 370.9775; found
370.9772.
124.7 (C Ar), 138.8 (=CO), 150.6 (=CO), 153.3 (=CO), 168.9
(=CO), 187.3 (CHO) ppm. HRMS (ESI): calcd. for C17H20IO5
[MH]+ 431.0350; found 431.0347.
4-Iodo-2,5-diphenylfuran-3-carbaldehyde (5h): The reaction pro-
duced a 4:1 mixture of the two hardly separable products 5h and
its structural isomer 3-benzoyl-4-iodo-5-phenylfuran (combined
yield of 70%). Data for 5h: Yellow solid (70 mg, 45%); m.p. 85–
1
87 °C. H NMR (300 MHz, CDCl3): δ = 7.40–7.53 (m, 6 H, Ar),
7.87–7.91 (m, 2 H, Ar), 8.06 (dd, J = 6.9 and 1.6 Hz, 2 H), 10.09
(s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 61.8 (C–I),
121.9 (C Ar), 127.4 (CH Ar), 128.2 (C Ar), 128.5 (CH Ar), 128.7
(CH Ar), 129.0 (CH Ar), 129.2 (C Ar), 129.4 (CH Ar), 130.9 (CH
Ar), 152.5 (=CO), 161.1 (=CO), 186.8 (CHO) ppm. HRMS (ESI):
calcd for C17H11INaO2 [M + Na]+ 396.9696; found 396.9697. Data
for 3-benzoyl-4-iodo-5-phenylfuran: This compound could not be
obtained in pure form. 1H NMR (300 MHz, CDCl3, deduced from
the crude mixture): δ = 7.39–7.51 (m, 4 H, Ar), 7.57–7.62 (m, 1 H,
Ar), 7.83 (s, 1 H, Hfuryl), 7.88 (dd, J = 8.3 and 1.5 Hz, 2 H, Ar),
7.99 (dd, J = 8.3 and 1.5 Hz, 2 H, Ar) ppm.
4-Iodo-2-methyl-5-phenylfuran-3-carbaldehyde (5b): Yellow solid
(109 mg, 87%); m.p. 74–75 °C. H NMR (400 MHz, CDCl3): δ =
1
2.67 (s, 3 H, CH3), 7.39 (m, J = 7.3 and 1.3 Hz, 1 H, Ar), 7.43–
7.47 (m, 2 H, Ar), 7.95 (dd, J = 7.3 and 1.3 Hz, 2 H, Ar), 9.91 (s,
1 H, CHO) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.6 (CH3),
61.4 (C–I), 121.9 (C Ar), 126.8 (CH Ar), 128.6 (CH Ar), 129.0 (CH
Ar), 129.3 (C Ar), 151.2 (=CO), 161.1 (=CO), 187.9 (CHO) ppm.
HRMS (ESI): calcd for C12H9INaO2 [M + Na]+ 334.9539; found
334.9532. The same reaction was performed on 2 mmol scale to
give 5b (462 mg, 74%).
4-Iodo-2-methyl-5-(4-methoxy)phenylfuran-3-carbaldehyde (5c): Yel-
low solid (120 mg, 88%); m.p. 70–72 °C. 1H NMR (300 MHz,
CDCl3): δ = 2.64 (s, 3 H, CH3), 3.85 (s, 3 H, OCH3), 6.97 (d, J =
8.7 Hz, 2 H, Ar), 7.87 (d, J = 8.7 Hz, 2 H, Ar), 9.88 (s, 1 H,
CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.5 (CH3), 55.5
(OCH3), 59.7 (C–I), 114.0 (CH Ar), 121.7 (C Ar), 121.9 (C Ar),
128.4 (CH Ar), 151.4 (=CO), 160.1 (=CO), 160.7 (=CO), 187.8
(CHO) ppm. HRMS (ESI): calcd. for C13H11INaO3 [M + Na]+
364.9645; found 364.9649.
4-Iodo-2-phenyl-5-(4-methoxy)phenylfuran-3-carbaldehyde (5i): Yel-
low solid (123 mg, 74%); m.p. 117–120 °C. 1H NMR (300 MHz,
CDCl3): δ = 3.86 (s, 3 H, OCH3), 7.00 (d, J = 8.8 Hz, Ar), 7.49–7.52
(m, 3 H, Ar), 7.84–7.88 (m, 2 H, Ar), 10.06 (s, 1 H, CHO) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 55.5 (OCH3), 60.2 (C–I), 114.1 (CH
Ar), 121.8 (C Ar), 128.4 (CH Ar), 128.8 (CH Ar), 128.9 (CH Ar),
130.7 (CH Ar), 152.7 (=CO), 160.4 (=CO), 160.6 (=CO), 186.7
(CHO) ppm. HRMS (ESI): calcd. for C18H14IO3 [MH]+ 404.9982;
found 404.9968.
4-Iodo-2-methyl-5-(4-fluoro)phenylfuran-3-carbaldehyde (5d): Yel-
low solid (93 mg, 70%); m.p. 99–100 °C. 1H NMR (400 MHz,
CDCl3): δ = 2.66 (s, 3 H, CH3), 7.14 (t, J = 8.8 Hz, 2 H, Ar), 7.92
(dd, J = 8.8 and 5.1 Hz, 2 H, Ar), 9.89 (s, 1 H, CHO) ppm. 13C
NMR (100 MHz, CDCl3): δ = 12.4 (CH3), 60.0 (C–I), 114.6 (d,
2-Furyl-4-iodo-5-phenylfuran-3-carbaldehyde (5j): Solid (55 mg,
38%); m.p. 118–120 °C. 1H NMR (300 MHz, CDCl3): δ = 6.60 (dd,
J = 3.6, 1.7 Hz, 1 H, Ar), 7.39–7.50 (m, 4 H, Ar), 7.61 (d, J =
0.9 Hz, 1 H, Ar), 8.03 (dd, J = 7.0, 1.5 Hz, 2 H, Ar), 10.27 (s, 1 H,
CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 61.4 (C–I), 112.4
(CH Ar), 113.7 (CH Ar), 120.7 (C Ar), 127.3 (CH Ar), 128.6 (CH
Ar), 129.0 (C Ar), 129.4 (CH Ar), 144.3 (C Ar), 145.2 (CH Ar),
150.9 (=CO), 151.9 (=CO), 186.4 (CHO) ppm. HRMS (ESI): calcd.
for C15H10IO3 [MH]+ 364.9669; found 364.9678.
4
2JC,F = 21.8 Hz), 120.7 (C Ar), 124.4 (d, JC,F = 2.9 Hz), 127.7
3
1
(d, JC,F = 8.0 Hz), 149.4 (=CO), 160.0 (=CO), 161.8 (d, JC,F
=
248.6 Hz), 186.5 (CHO) ppm. HRMS (CI): calcd. for C12H9FIO2
[MH]+ 330.9626; found 330.9623.
4-Iodo-2-methyl-5-butylfuran-3-carbaldehyde (5e): CuI (10 mol-%)
and the alkyne (3 equiv.) were used to give 5e (61 mg, 47%) as a
tan oil. 1H NMR (300 MHz, CDCl3): δ = 0.93 (t, J = 7.3 Hz, 3 H,
CH3), 1.35 (sext, J = 7.3 Hz, 2 H, CH2), 1.60 (quint, J = 7.3 Hz, 2
H, CH2), 2.55 (s, 3 H, CH3), 2.65 (t, J = 7.3 Hz, 2 H, CH2), 9.79
(s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 13.4 (CH3),
13.9 (CH3), 22.2 (CH2), 26.8 (CH2), 30.05 (CH2), 62.2 (C–I), 120.5
(C Ar), 156.3 (=CO), 160.8 (=CO), 187.0 (CHO) ppm. HRMS
(ESI): calcd. for C10H14IO2 [M]+ 293.0036; found 293.0033.
2-Furyl-4-iodo-5-(3,4,5-trimethoxy)phenylfuran-3-carbaldehyde
(5k): Solid (103 mg, 55%); m.p. 159–160 °C. H NMR (300 MHz,
1
CDCl3): δ = 3.91 (s, 3 H, OCH3), 3.95 (s, 6 H, 2 OCH3), 6.60 (dd,
J = 3.6 and 1.7 Hz, 1 H, Ar), 7.27 (s, 2 H, Ar), 7.41 (d, J = 3.5 Hz,
1 H, Ar), 7.62 (d, J = 1.7 Hz, 1 H, Ar), 10.26 (s, 1 H, CHO) ppm.
13C NMR (75 MHz, CDCl3): δ = 56.4 (OCH3), 61.0 (C–I), 61.1
(OCH3), 104.9 (CH Ar), 112.4 (CH Ar), 113.7 (CH Ar), 120.8 (C
Ar), 124.2 (C Ar), 139.2 (=CO), 144.2 (C Ar), 145.2 (C Ar), 150.7
(=CO), 151.8 (=CO), 153.3 (=CO), 186.4 (CHO) ppm. HRMS
(ESI): calcd. for C18H16IO6 [MH]+ 454.9986; found 454.9980.
4-Iodo-2-isopropyl-5-phenylfuran-3-carbaldehyde
(5f):
Solid
1
(101 mg, 75%); m.p. 44–46 °C. H NMR (300 MHz, CDCl3): δ =
1.36 [d, J = 6.9 Hz, 6 H, (CH3)2CH], 3.73 [quint, J = 6.9 Hz, 1 H,
(CH3)2CH], 7.36–7.48 (m, 3 H, Ar), 7.96 (d, J = 7.5 Hz, 2 H, Ar),
9.94 (s, 1 H, CHO) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6
[(CH3)2CH], 27.3 [(CH3)2CH], 61.5 (C–I), 120.0 (C Ar), 126.8 (CH
Ar), 128.6 (CH Ar), 128.9 (CH Ar), 129.4 (C Ar), 150.8 (=CO),
169.1 (=CO), 187.6 (CHO) ppm. HRMS (ESI): calcd. for
C14H14IO2 [MH]+ 341.0033; found 341.0039.
Characterization for Compound 6: Compound 6 was purified by
column chromatography (silica gel, appropriate mixture of cyclo-
hexane/ethyl acetate) to give a yellow solid; m.p. 131–133 °C. 1H
NMR (300 MHz, CDCl3): δ = 2.58 (s, 3 H, CH3), 2.72 [s, 4 H,
(CH2)2], 3.46 (s, 3 H, OCH3), 3.92 (s, 3 H, CO2CH3), 6.03 (s, 1 H,
NCHO), 7.99–8.07 (m, 4 H, Ar) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.4 (CH3), 28.2 (CH2), 52.3 (OCH3), 57.2 (OCH3),
65.4 (C–I), 80.7 (NCHO), 118.0 (C Ar), 125.6 (CH Ar), 129.1 (C
Ar), 129.8 (CH Ar), 134.3 (C Ar), 148.5 (=CO), 154.3 (=CO), 166.9
(OC=O), 176.1 (NC=O) ppm. HRMS (ESI): calcd. for C19H18-
INNaO6 [M + Na]+ 506.0071; found 506.0077.
4-Iodo-2-isopropyl-5-(3,4,5-trimethoxy)phenylfuran-3-carbaldehyde
(5g): Solid (132 mg, 76%); m.p. 91–93 °C. 1H NMR (300 MHz,
CDCl3): δ = 1.35 [d, J = 6.9 Hz, 6 H, (CH3)2CH], 3.69 [quint, J =
6.9 Hz, 1 H, (CH3)2CH], 3.88 (s, 3 H, OCH3), 3.92 (s, 6 H, 2 Supporting Information (see footnote on the first page of this arti-
1
OCH3), 7.17 (s, 2 H, Ar), 9.92 (s, 1 H, CHO) ppm. 13C NMR
cle): Crystal data for compounds 5k and 6 and H and 13C NMR
(75 MHz, CDCl3): δ = 20.6 [(CH3)2CH], 27.3 [(CH3)2CH], 56.4 spectra for compounds 5.
Eur. J. Org. Chem. 2013, 105–110
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
109

G. Raffa, G. Balme, N. Monteiro
FULL PAPER
2010, 51, 3417–3421; h) C.-H. Cho, F. Shi, D.-I. Jung, B. Ne-
uenswander, G. H. Lushington, R. C. Larock, ACS Comb. Sci.
2012, 14, 403–414.
Acknowledgments
This research was financially assisted by a grant to G. R. from the
French Ministry of Higher Education and Research (MESR). We
thank Dr. E. Jeanneau (Centre de Diffractométrie Henri Longch-
ambon, Université Lyon 1) for the X-ray crystallographic analyses.
[6] a) E. Bossharth, P. Desbordes, N. Monteiro, G. Balme, Org.
Lett. 2003, 5, 2441–2444; b) I. Aillaud, E. Bossharth, D. Con-
reaux, P. Desbordes, N. Monteiro, G. Balme, Org. Lett. 2006,
8, 1113–1116; c) G. Raffa, M. Rusch, G. Balme, N. Monteiro,
Org. Lett. 2009, 11, 5254–5257; d) D. Delaunay, D. Conreaux,
E. Bossharth, P. Desbordes, N. Monteiro, G. Balme, Synthesis
2010, 1741–1744; e) G. Raffa, S. Belot, G. Balme, N. Monteiro,
Org. Biomol. Chem. 2011, 9, 1474–1478.
[7] For iodo derivatives, see: a) M. C. Zaluski, M. Robba, M. Bon-
homme, Bull. Soc. Chim. Fr. 1970, 1838–1843; for other halo
compounds, see: b) S. Katsumura, K. Ichikawa, H. Mori,
Chem. Lett. 1993, 9, 1525–1528; c) A. M. Jones, A. J. Simpson,
S. P. Stanforth, J. Heterocycl. Chem. 1990, 27, 1843–1844; d)
N. D. Pearson, PCT Int. Patent Appl. WO 9402478, 1994.
[8] For a recent use of a 3-bromo-4-formylfuran in library pro-
duction around the furan motif, see: T. Lampe, R. Kast, F.
Stoll, J. Schuhmacher, PCT Int. Patent Appl. WO 2009/097991,
2009.
[9] a) S. A. Kozmin, T. Iwama, Y. Huang, V. H. Rawal, J. Am.
Chem. Soc. 2002, 124, 4628–4641; b) L. M. Kacharova, A. D.
Cacharov, I. I. Gerus, J. Fluorine Chem. 2001, 111, 29–31.
[10] During the course of our preliminary investigations, Li and co-
workers reported the formation of 3-formylfurans through the
Cu-catalyzed cyclization of α-alkynyl enaminones. J. Yang, C.
Wang, X. Xie, H. Li, E. Li, Y. Li, Org. Biomol. Chem. 2011, 9,
1342–1346.
[1] a) X. L. Hou, Z. Yang, H. N. C. Wong, in: Progress in Hetero-
cyclic Chemistry (Eds.: G. W. Gribble, T. L. Gilchrist), Perga-
mon, Oxford, UK, 2003, vol. 15, pp. 167–205; b) B. A. Keay,
P. W. Dibble, in: Comprehensive Heterocyclic Chemistry II
(Eds.: A. R. Katritzky, C. W. Rees, E. F. V. Scriven), Elsevier,
Oxford, UK, 1997, vol. 2, pp. 395–436; c) D. M. X. Donnelly,
M. J. Meegan, in: Comprehensive Heterocyclic Chemistry (Eds.:
A. R. Katritzky, C. W. Rees), Pergamon, Oxford, UK, 1984,
vol. 4, pp. 657–712.
[2] For reviews of furan Synthesis see a) X. L. Hou, H. Y. Cheung,
T. Y. Hon, P. L. Kwan, T. H. Lo, S. Y. Tong, H. N. C. Wong,
Tetrahedron 1998, 54, 1955–2020; b) S. F. Kirsch, Org. Biomol.
Chem. 2006, 4, 2076–2080; c) G. Balme, D. Bouyssi, N. Mon-
teiro, Heterocycles 2007, 73, 87–124.
[3] For recent reviews on electrophilic cyclizations of alkynes, see:
a) F. Rodríguez, F. J. Fañanás, in: Handbook of Cyclization Re-
actions (Ed.: S. Ma), Wiley-VCH, Weinheim, Germany, 2010,
vol 2, pp. 951–990; b) K. C. Majumdar, P. Debnath, B. Roy,
Heterocycles 2009, 78, 2661–2728; c) P. Belmont, E. Parker,
Eur. J. Org. Chem. 2009, 6075–6089; d) N. T. Patil, Y. Yamam-
oto, Chem. Rev. 2008, 108, 3395–3442; e) R. C. Larock, in:
Acetylene Chemistry (Eds.: F. Diederich, P. J. Stang, R. R. Tyk-
winsky), Wiley-VCH, Weinheim, Germany, 2005, pp. 51–99; f)
R. C. D. Brown, Angew. Chem. 2005, 117, 872; Angew. Chem.
Int. Ed. 2005, 44, 850–852.
[11] For recent uses of N-halosuccinimides for the introduction of
halogens through electrophilic cyclizations, see: a) B. Crone,
S. F. Kirsch, J. Org. Chem. 2007, 72, 5435–5438; b) Y.-X. Xie,
Z.-Y. Yan, D.-Z. Wang, L.-Y. Wu, B. Qian, X.-Y. Liu, Y.-M.
Liang, Eur. J. Org. Chem. 2009, 2283–2288; c) T. Okitsu, K.
Sato, A. Wada, Org. Lett. 2010, 12, 3506–3509; d) Y. Zhu, G.
Yin, D. Hong, P. Lu, Y. Wang, Org. Lett. 2011, 13, 1024–1027;
[4] For reviews on the halocyclizations of alkynes, see: a) B. Go-
doi, R. F. Schumacher, G. Zeni, Chem. Rev. 2011, 111, 2937–
2980; b) M. Jacubert, A. Tikad, O. Provot, A. Hamze, J.-D.
see also ref.[5]
.
Brion, M. Alami, Eur. J. Org. Chem. 2010, 4492–4500; c) Y. [12] CCDC-856403 (for 6) and -872965 (for 5k) contain the supple-
Yamamoto, I. D. Gridnev, N. T. Patil, T. Jin, Chem. Commun.
2009, 5075–5087; d) M. J. Mphahlele, Molecules 2009, 14,
4814–4837; e) H. Togo, S. Iida, Synlett 2006, 2159–2175; for a
general review dealing with the syntheses of β-halofurans, see:
R. Dembinski, Y. Li, D. Gundapuneni, A. Decker, Top. Hetero-
cycl. Chem. 2012, 27, 65–100.
mentary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif;
see also the Supporting Information to this article.
[13] For another example of the beneficial effect of added water in
NIS-promoted iodocyclization reactions, see: S. Ma, L. Lu, J.
Org. Chem. 2005, 70, 7629–7633.
[14] T. Okitsu, D. Nakazawa, R. Taniguchi, A. Wada, Org. Lett.
2008, 10, 4967–4970.
[15] a) E. Stern, G. G. Muccioli, B. Bosier, L. Hamtiaux, R. Millet,
J. H. Poupaert, J.-P. Hénichart, P. Depreux, J.-F. Goossens,
D. M. Lambert, J. Med. Chem. 2007, 50, 5471–5484; b) J. C.
Jewett, V. H. Rawal, Angew. Chem. 2007, 119, 6622; Angew.
Chem. Int. Ed. 2007, 46, 6502–6504.
[5] For illustrative examples of halocyclizations of α-alkynyl carb-
onyl compounds, see: a) M. S. Rao, N. Esho, C. Sergeant, R.
Dembinski, J. Org. Chem. 2003, 68, 6788–6790; b) T. Yao, X.
Zhang, R. C. Larock, J. Org. Chem. 2005, 70, 7679–7685; c) Y.
Liu, S. Zhou, Org. Lett. 2005, 7, 4609–4611; d) A. Sniady,
K. A. Wheeler, R. Dembinski, Org. Lett. 2005, 7, 1769–1772;
e) Y. Xiao, J. Zhang, Angew. Chem. 2008, 120, 1929; Angew.
Chem. Int. Ed. 2008, 47, 1903–1906; f) A. Sniady, M. S. Morre-
ale, K. A. Wheeler, R. Dembinski, Eur. J. Org. Chem. 2008,
3449–3452; g) C.-H. Cho, R. C. Larock, Tetrahedron Lett.
Received: September 7, 2012
Published Online: November 12, 2012
110
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 105–110