New synthetic approach for the construction of multisubstituted 2-acyl furans by the IBX-mediated cascade oxidation/cyclization of cis-2-En-4-yn-1-ols (IBX = 2-iodoxybenzoic acid)

Article abstract of DOI:10.1002/chem.200801561

A new approach for the construction of multisubstituted 2-acyl furans through cis-2-En-4-yn-1-ols (IBX=2-iodoxybenzoic acid)-mediated oxidation/cyclization in dimethyl sulfoxidse (DMSO) was developed. The results show that the introduction of an alkyl group at Cl provided a satisfactory yield of furan of 60% at 90°C. It is seen that IBX act as an electrophile to promote the cycloaddition of carbonyl group to the alkyne moiety. The furan derivatives are found to be useful synthetic intermediates for access to the compounds bearing biological activity. The studies also elucidate this reaction mechanism and extend the scope of synthetic utility of multisubstituted 2-acyl furans.

Full text of DOI:10.1002/chem.200801561

COMMUNICATION
DOI: 10.1002/chem.200801561
New Synthetic Approach for the Construction of Multisubstituted 2-Acyl
Furans by the IBX-Mediated Cascade Oxidation/Cyclization of cis-2-En-4-
yn-1-ols (IBX=2-Iodoxybenzoic Acid)
Xiangwei Du, Haoyi Chen, and Yuanhong Liu*[a]
Hypervalent iodine compounds have been proved to be
mild and selective oxidizing agents in an impressive array of
synthetic methodologies and have received much attention
in recent years.[1] 2-Iodoxybenzoic acid (IBX, 1-hydroxy-1,2-
time of IBX-promoted cascade oxidation/cyclization of cis-
2-en-4-yn-1-ols, which represents an efficient and diversity
oriented protocol for the convergent construction of substi-
tuted 2-acyl furans. 2-Acyl furans and furfurals are of signifi-
cant synthetic interest, since they can be applied as flavour-
ing agents, perfume components, or as useful and versatile
synthetic intermediates for access to the condensed furanic
ring systems that shows widespread biological activity,[7]
such as Dantrolene analogues,[7a] anti-malarial agents,[7b]
Phosphoinositide 3-Kinase g inhibitors,[7c] HIV-1 integrase
binding inhibitors,[7d] and so forth. However, the synthetic
route for multisubstituted 2-acyl furans in a regioselective
manner is rare (Scheme 1).[8]
benziodoxol-3(1H)-one 1-oxide) was first synthesized in
G
1893; however, it was rarely used in organic synthesis until
1983 when Dess and Martin transformed IBX into the
highly soluble Dess–Martin periodinane (DMP).[2] In 1994,
Frigero and Santagostino reported that IBX could be readily
dissolved in dimethyl sulfoxide (DMSO) and served as val-
uable oxidant toward a variety of alcohols.[3] Since then, a
great deal of work has been done in IBX-mediated transfor-
mations with regards to mechanistic and synthetic as-
pects.[1,4] Generally, IBX is used as an efficient and mild oxi-
dizing reagent, for example, for the mild oxidative cleavage
of oximes and tosyl hydrazones,[4a] oxidation of amines to
imines,[4b] oxidative rearrangement of tertiary allylic alco-
hols,[4c] oxidation of silyl enol ethers to enones,[4d] a-hydrox-
ylation of carbonyl compounds,[4e] oxidative multicomponent
reactions,[4f–h] and so forth. IBX also operates as a single-
electron-transfer oxidant, such as in benzylic oxidation.[5a]
However, IBX-induced annulation strategies are quite limit-
ed. A remarkable work has been reported by Nicolaou
et al.; they have shown that IBX can promote the cycliza-
tion of unsaturated anilides, carbamates, and ureas via
amide-centered radicals to form novel and biologically im-
portant N-heterocyclic compounds.[5b–d] Nevertheless, there
is no report for IBX-assisted cyclization of alkynes,[6] to the
best of our knowledge. In this paper, we report for the first
Scheme 1. IBX-mediated formation of 2-acyl furans from cis-enynols.
Recently, we have reported an efficient synthetic ap-
proach to furans and stereo-defined dihydrofurans via gold-
catalyzed cyclization of (Z)-2-en-4-yn-1-ols.[9] During our
studies of new processes for heterocycle formation, we
found that (Z)-enynol 1a reacted with IBX in DMSO at
room temperature to afford the normal oxidation product
2a in 81% yield (Scheme 2). To our delight, when the reac-
tion temperature was increased to 908C, 2-benzoyl-5-phenyl-
furan (3a) was formed in 79% yield, while the intermediate
of 2a was completely consumed. Decreasing the reaction
temperature to 508C resulted in an incomplete transforma-
tion to 3a (26 h, 2a/3a=3.6:1). Addition of five equivalents
of H2O resulted in a decreased yield of 3a (NMR yield:
[a] X. Du, H. Chen, Prof. Dr. Y. Liu
State Key Laboratory of Organometallic Chemistry
Shanghai Institute of Organic Chemistry
Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (P. R. China)
Fax : (+86)021-64166128
E-mail: yhliu@mail.sioc.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200801561.
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9495

good yields of 3i–3k (68–85%, Table 1, entries 9–11). The
structure of the 2-acyl furans was further confirmed by X-
ray crystallographic analysis of 3c[10] and 2D NMR spectrum
of 3k.
(Z)-Enynols bearing a substituent at the C3 position were
prepared by the Sonogashira coupling reaction of iodinated
allylic alcohols with terminal alkynes. The iodide precursors
were conveniently synthesized from the corresponding prop-
argylic alcohols by their reaction with Red-Al (Red-Al=
sodium bis(2-methoxyethoxy)aluminumhydride) followed by
iodination of the organoaluminum intermediate.[11] Thus
enynols 1l–1q can be easily constructed by three steps from
two alkynes and one aldehyde. The following IBX-mediated
cyclization represents a diversity oriented protocol for the
convergent construction of 3,5-disubstituted-2-acyl furans.
As shown in Table 2, the aryl, alkyl, and TMS groups at C3
Scheme 2. Reactions of (Z)-enynol 1a with IBX.
53%, 9 h). The use of DMP instead of IBX only afforded a
complicated reaction mixture as observed by H NMR spec-
troscopy at 08C for 1.5 h in CH2Cl2.
As illustrated in Tables 1 and 2, the present method could
be applied successfully to a wide range of cis-enynols bear-
ing various substituents at C1–C5. The cyclization of enynols
1a–1 f, which were not substituted at C2 and C3, were inves-
1
Table 2. Formation of 3,5-disubstituted 2-acyl furans mediated by IBX.
Table 1. Formation
of
2-acyl
furans
mediated
by
IBX.
Enynol
R1
R2
Ph
u
Ph
Ph
R3
Ph
t [h]
Product
Yield [%][a]
1
2
3
4
5
6
1l
Ph
B
TMS
Ph
B
3
Ph
4
3
H
3
3l
4 3m
3n
3o
3 3p
3q
59
70
70
78
76
40
Enynol R1
R2 R3 R4
t
Prod- Yield
1m
1n
1o
1p
1q
Ph
Ph
[h] uct
[%][a]
Ph
H
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
Ph
4.5 3a
18 3b
15 3c
79[b]
64[c]
72
67
86
u
p-BrC6H4
p-MeOC6H4
p-ClC6H4
p-ClC6H4
Et
Ph
Et
Ph
H
H
Ph
p-ClC6H4
H
[a] Isolated yields.
H
p-MeOC6H4 15 3d
H
H
p-ClC6H4
Ph
15 3e
4
4
7
3 f
60[b]
–[d]
Et
Et
Et
Et
Bu
Ph
Ph
Ph
in enynol 1 are all compatible with this cyclization reaction,
furnishing the corresponding products 3l–3q in 40–78%
yields. It should be noted that in the case of 3l, a decreased
yield of 31% was observed at a prolonged reaction time
(6.5 h). Interestingly, when terminal alkynes of 1o–1q were
used, 3,5-disubstituted-2-furaldehydes 3o–3q were formed
in 40–78% yields (Table 2, entries 4–6). However, for eny-
nols substituted both at C2 and C3, for example, in the case
of (Z)-2,3-diethyl-5-(4-methoxy-phenyl)-1-phenyl-pent-2-en-
4-yn-1-ol (1r), only a mixture of 2-acyl furan 3r and oxida-
tion product of ketone 2r with a ratio of 1:1.8 (908C, 13 h)
was isolated in a combined yield of 72%.
Although further investigations to clarify the reaction
mechanism are needed, a tentatively suggested reaction
pathway is shown as follows (Scheme 3): first, an enynone
2a is formed by oxidation of 1a. In the next step, IBX may
act as an electrophile to promote the cycloaddition of car-
bonyl group to the alkyne moiety. Thus, an anti-5-exo-dig
cyclization is resulted to give 4. This is followed by addition
of hydroxyl group to the exocyclic double bond to form 5,
which subsequently decomposes to give 2-acyl furan 3a and
1-iodosobenzoic acid (IBA).
3h
41
68
85
81
10 3i
12 3j
12 3k
10 1j
11 1k
p-ClC6H4
p-MeOC6H4 Et
Ph
[a] Isolated yields. Unless otherwise noted, 3.0 equiv IBX was used. [b]
2.0 equiv IBX was used. [c] 49% yield when 2.0 equiv IBX was used. [d]
A mixture of structurally unidentified products was observed.
tigated first. We found that the substituents Br, OMe and Cl
on the aromatic rings at C1 and C5 were well tolerated
during the reaction, furnishing the corresponding furans 3b–
3e in 64%–86% yield with relatively long reaction times of
15–18 h (Table 1, entries 2–5). Introducing an alkyl group at
C1 also afforded furan 3 f in a satisfactory yield of 60% at
908C (Table 1, entry 6). When enynol 1g with an alkyl sub-
situent at C5 was employed, the desired 2-acyl furan was
not observed; instead a mixture of structurally unidentified
products were formed (Table 1, entry 7). The results of eny-
nols 1h–1k bearing an additional alkyl substituent at C2 are
highly dependent on the substituents on C1. Enynol 1h sub-
stituted both at C1 and C2 with alkyl groups resulted in a
lower yield of 3h (41%, Table 1, entry 8). We envisioned
that this may due to the lower stability of dialkyl-substituted
furan 3h under IBX oxidation conditions. However, chang-
ing the alkyl substituent at C1 to aryl groups resulted in
To support the reaction mechanism, the reaction of eny-
none 2a and IBX (1.2 equiv) was carried out. The desired
product 3a was obtained in 80% yield (Scheme 4, top). It is
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Cyclization Reactions
COMMUNICATION
ed in vacuo. The crude product was purified by chromatography on silica
gel to afford the 2-acyl furan derivative 3m in 70% yield. 1H NMR
(CDCl3, Me4Si): d=0.96 (t, J=7.4 Hz, 3H), 1.41–1.48 (m, 2H), 1.63–1.71
(m, 2H), 2.96 (t, J=7.7 Hz, 2H), 6.77 (s, 1H), 7.32–7.42 (m, 3H), 7.47–
7.56 (m, 3H), 7.69–7.72 (m, 2H), 8.06–8.09 ppm (m, 2H); 13C NMR
(CDCl3, Me4Si): d=13.90, 22.51, 26.08, 31.59, 109.73, 124.76, 128.09,
128.81, 128.92, 129.41, 129.48, 131.89, 138.24, 140.50, 147.18, 155.54,
183.21 ppm; IR (neat): n˜ =3064, 2957, 1637, 1476, 1291, 907, 691 cmÀ1
HRMS (EI): m/z calcd for C21H20O2: 304.1463; found: 304.1459.
;
Acknowledgements
We thank the National Natural Science Foundation of China (Grant No.
20732008), Chinese Academy of Science, Science and Technology Com-
mission of Shanghai Municipality (Grant Nos. 07JC14063, 08QH14030),
and the Major State Basic Research Development Program (Grant No.
2006CB806105) for financial support.
Scheme 3. Proposed reaction mechanism for the formation of 2-acyl
furans.
Keywords: cyclization · enynols · furans · iodoxybenzoic
acid · oxidation
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Experimental Section
A typical procedure for IBX-mediated cyclization of (Z)- 3-butyl-1,5-di-
phenyl-pent-2-en-4-yn-1-ol (1m): IBX (3.0 equiv, 296 mg, 1.05 mmol) was
added to a solution of (Z)-enynol 1m (102 mg, 0.35 mmol) in DMSO
(1.0 mL). The resulting solution was stirred at 908C until the reaction
was complete, as monitored by thin-layer chromatography. After the re-
action, the precipitate of IBA (probably) was removed by filtration, and
the filtrate was diluted with water and extracted with diethyl ether. The
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Chem. Eur. J. 2008, 14, 9495 – 9498
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Received: July 31, 2008
Published online: September 22, 2008
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