CuI/L-proline-catalyzed coupling of substituted 3-iodoprop-2-en-1-ols with 1-alkynes and subsequent cyclization: A convenient approach for synthesizing polysubstituted furans

Article abstract of DOI:10.1002/asia.200900523

A new and convenient method to assemble polysubstituted furans from vinyl iodides and terminal alkynes, which involves a copper/l-proline- catalyzed cross-coupling and additive cyclization process, has been reported. The generality of this method has been demonstrated by preparing a wide range of substituted furans. The organic layer was washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified via column chromatography to provide the desired product. The structures of the present products were established based on NMR analysis. The electronic nature of the aromatic ring of aryl alkynes had little influence on the reaction yield. CuI/ L-proline as the catalyst, Cs₂CO₃ as the base, and dioxane as the solvent is an optimized combination for this cascade process.

Full text of DOI:10.1002/asia.200900523

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DOI: 10.1002/asia.200900523
CuI/l-Proline-Catalyzed Coupling of Substituted 3-Iodoprop-2-en-1-ols with
1-Alkynes and Subsequent Cyclization: A Convenient Approach for
Synthesizing Polysubstituted Furans
You Wang,[a] Lanting Xu,[a] and Dawei Ma*[b]
The synthesis of substituted furans is an old but still
active research area in organic chemistry.[1] The continuing
interest in this topic stems from the fact that these heterocy-
cles play an important role in many aspects. For example,
furan is the key structural subunit in an enormous number
of bioactive natural products and pharmaceutically impor-
tant substances, and forms the skeleton of many flavor and
fragrance compounds.[1] Additionally, substituted furans are
useful and versatile intermediates in synthetic organic
chemistry.[1] Among the existing methods for synthesizing
substituted furans, cycloisomerization of (Z)-2-en-4-yn-1-ols
is one of the most attractive approaches because of the po-
tential to form polysubstituted furans with great diversity.[2–4]
For this transformation, the often-used promoters or cata-
lysts are strong bases (such as KOtBu)[2] or transition-metal
(like ruthenium,[3a–c] palladium,[3d,e] and gold[3f,g]) complexes.
Scheme 1. Coupling/cycloisomerization cascade process to polysubstitut-
ed furans from substituted 3-iodoprop-2-en-1-ols and 1-alkynes.
In 1990, Vꢀgh and co-workers disclosed that copper(II)
could catalyze the conversion of (Z)-3-methyl-2-penten-4-
yn-1-ol into 3,3-dimethylfuran.[4] Although only this one ex-
ample has been examined, the potential of copper salts as
the catalysts for the cycloisomerization of (Z)-2-en-4-yn-1-
ols prompted us to develop a cascade process to synthesize
substituted furans from substituted 3-iodoprop-2-en-1-ols 2[5]
and 1-alkynes 1. As outlined in Scheme 1, we envisaged that
after CuI/amino acid catalyzed cross-coupling[6] of 1 and 2 to
afford substituted (Z)-2-en-4-yn-1-ols 3, the free hydroxyl
tance of the copper salt (complex 4) to give cyclization
products 5. From the intermediates 5, substituted furans 7
could be formed through two possible pathways. One is pro-
tonation of 5 and subsequent isomerization of the heterocy-
cles 6. The other possible pathway involves isomerization of
5, followed by protonation of the resultant intermediates
8.[7]
À
group would attack the C C triple bond under the assis-
With this idea in mind, we conducted a CuI/amino acid
catalyzed reaction of 1-ethynylbenzene 1a with (Z)-3-iodo-
2-phenylbut-2-en-1-ol 2a. It was found that under our previ-
ous reaction conditions for cross-coupling of vinyl iodides
and terminal alkynes (N,N-dimethylglycine as the ligand,
Cs2CO3 as the base, dioxane as the solvent, 808C)[6a] the de-
sired furan 7a was isolated in 70% yield (Table 1, entry 1).
Encouraged by this result, we attempted to improve the
yield by changing the reaction conditions. It was found that
a better yield could be obtained by using l-proline as a
ligand (Table 1, entry 2), which is consistent with results ob-
served in our indole formation.[6a] Switching the base to
K2CO3 and K3PO4 failed to give better results (Table 1, en-
[a] Y. Wang, L. Xu
Department of Chemistry
Fudan University
Shanghai 200433 (China)
[b] Prof. Dr. D. Ma
State Key Laboratory of Bioorganic & Natural Products Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
Fax : (+86)21-64166128
E-mail: madw@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.200900523.
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Chem. Asian J. 2010, 5, 74 – 76

Table 1. Coupling of 1a and 2a under different reaction conditions.[a]
Table 2. Synthesis of polysubstituted furans via a cascade coupling/cycloi-
somerization process.[a]
Entry
Vinyl
Product
Yield [%][b]
iodide
Amino acid[c]
Base
Solvent
Yield [%][b]
1
75
Entry
1
2
3
4
5
6
7
8
A
B
B
B
B
B
B
B
Cs2CO3
Cs2CO3
K2CO3
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
dioxane
dioxane
dioxane
dioxane
DMF
DMSO
toluene
iPrOH
70
83
55
70
75
55
10
50
2
3
4
5
6
7c: R=4-CH3OC6H4
7d: R=4-FC6H4
7e: R=(CH2)2OBn
7 f: R=(CH2)2OTBS
7q: R=CH2CH2CH3
77
81
72
74
0[c]
7
89
[a] Reaction conditions: 1a (0.3 mmol), 2a (0.25 mmol), 10 mol% CuI,
30 mol% amino acid, base (0.75 mmol), solvent (0.5 mL), under Ar at-
mosphere, 808C, 36 h. [b] Yield of isolated product. [c] A: N,N-dimethyl-
glycine hydrochloride salt; B: l-proline.
8
58
tries 3 and 4). Among the other solvents tested, DMF pro-
vided the product in 75% yield (Table 1, entry 5), while low
yields were observed in the cases of DMSO, toluene, and
iPrOH (Table 1, entries 6–8). Thus, we concluded that CuI/
l-proline as the catalyst, Cs2CO3 as the base, and dioxane as
the solvent is an optimized combination for this cascade
process.
9
73
65
10
After identification of the optimized reaction conditions,
the scope and limitations of this cascade process were exam-
ined by varying vinyl iodides and 1-alkynes. As indicated in
Table 2, substituted aryl alkynes were able to couple with
2a, providing the corresponding 2,3,4-trisubstituted furans
7b–d in good yields (entries 1–3). The electronic nature of
the aromatic ring of aryl alkynes had little influence on the
reaction yield (compare entry 1 and 3). Two O-protected
propargyl alcohols gave the desired products 7e and 7 f
(Table 2, entries 4 and 5), while a simple aliphatic alkyne
did not give any furan product (entry 6). In the latter case a
coupling product was isolated in about 70% yield, indicating
that further cycloisomerization of this (Z)-2-en-4-yn-1-ol did
not take place under the present conditions. These results
demonstrated that subtle changes in electron nature of the
aliphatic alkynes could alter the cycloisomerization process.
A similar phenomenon has been noticed in our indole syn-
thesis.[6a] More studies are required to solve this problem.
Further investigation revealed that changing the substitu-
ents at the 1- or 2-positions of furans is possible, as shown
from the results of entries 7–10 in which furans 7g–j were
assembled from different 1,2,2-trisubstituted vinyl iodides
(Table 2, entries 7–10). Next, we attempted to synthesize
2,3,5-trisubstituted furans, and were pleased to find that two
2,2-disubstituted vinyl iodides were compatible with the re-
action conditions, providing the desired furans 7k and 7l in
good yields (Table 2, entries 11 and 12). When vinyl iodides
2g and 2h were employed, the reaction became sluggish,
and increasing the reaction temperature was required to
ensure good conversion (Table 2, entries 13 and 14). In the
case of vinyl iodide 2i as a substrate, the reaction proceeded
smoothly at 808C to give 2,3,4,5-tetrasubstituted furans 7o
11
12
13
79
68
67[d]
14
15
63[d]
76
16
74
[a] Reaction conditions: vinyl iodide (0.25 mmol), 1-alkyne (0.3 mmol),
CuI (0.025 mmol), l-proline (0.075 mmol), Cs2CO3 (0.75 mmol), 1,4-diox-
ane (0.5 mL), under Ar atmosphere, 808C, 36–48 h. [b] Yield of isolated
product. [c] A coupling product was isolated in about 70% yield. [d] The
reaction was carried out at 1008C.
and 7p (Table 2, entries 15 and 16). These results illustrated
that the steric hindrance or electronic nature of vinyl iodides
might influence the reaction rate. The formation of these
Chem. Asian J. 2010, 5, 74 – 76
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www.chemasianj.org
75

D. Ma et al.
COMMUNICATION
four 2,3,4,5-tetrasubstituted furans further demonstrated the
capability of this process for preparing polysubstituted
furans. This method is a promising way to prepare furans
with variable substituents at all four positions by employing
suitable vinyl iodides and terminal alkynes.
The structures of the present products were established
based on NMR analysis. This conclusion was further con-
firmed by X-ray structural analysis of 2,3,4-trisubstituted
furan 7i, as illustrated in Figure 1.
Keywords: alkynes · catalysis · coupling · furan · heterocycle
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Figure 1. X-ray crystal structure of the furan 7i.
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In conclusion, we have developed a new and convenient
method to assemble polysubstituted furans from vinyl io-
dides and terminal alkynes, which involves a copper/l-pro-
line-catalyzed cross-coupling and additive cyclization pro-
cess. Our result gives an additional example for synthesis of
heterocycles via ligand-promoted Ullmann-type coupling re-
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demonstrated by preparing a wide range of substituted
furans. These features would make this method an attractive
choice for furan synthesis.
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Experimental Section
Typical procedure for assembly of polysubstituted furans: A Schlenk
tube was charged with substituted 3-iodoprop-2-en-1-ol (0.25 mmol), CuI
(5 mg, 0.025 mmol), l-proline (9 mg, 0.075 mmol), and Cs2CO3 (245 mg,
0.75 mmol). The tube was evacuated and backfilled with argon, and then
1-alkyne (0.3 mmol) and 1,4-dioxane (0.5 mL) were added via syringe.
After the reaction mixture was stirred at 80–1008C for 36–48 h, it was
partitioned between ethyl acetate and saturated NH4Cl. The organic
layer was washed with brine, dried over Na2SO4, and concentrated in va-
cuo. The residue was purified via column chromatography to provide the
desired product.
Received: October 5, 2009
Published online: December 10, 2009
Acknowledgements
We are grateful to the Chinese Academy of Sciences and the National
Natural Science Foundation of China (grant 20621062) for their financial
support.
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