Hypervalent iodine-mediated regioselective cyclization of acetylenic malonates: Facile synthesis of 1-diiodomethylene indane and cyclopentane derivatives

Article abstract of DOI:10.1039/c1cc15529f

A facile synthesis of potentially useful 1-diiodomethylene indanes and cyclopentanes from the regioselective cyclization of acetylenic malonates with the combination of iodosobenzene with tetrabutylammonium iodide in 2,2,2-trifluoroethanol is reported. Th

Full text of DOI:10.1039/c1cc15529f

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COMMUNICATION
Hypervalent iodine-mediated regioselective cyclization of acetylenic
malonates: facile synthesis of 1-diiodomethylene indane and cyclopentane
derivativesw
Chen Zheng and Renhua Fan*
Received 7th September 2011, Accepted 28th September 2011
DOI: 10.1039/c1cc15529f
A facile synthesis of potentially useful 1-diiodomethylene indanes
and cyclopentanes from the regioselective cyclization of acetylenic
malonates with the combination of iodosobenzene with tetrabutyl-
ammonium iodide in 2,2,2-trifluoroethanol is reported.
In the last few decades, hypervalent iodine compounds have found
broad application in organic synthesis because of their versatility,
ready availability, and environmentally friendly nature.1 As the
result of their enhanced electrophilic properties, the reactions of
hypervalent iodine compounds with alkynes have been widely
investigated.1,2 Nonterminal alkynes are usually oxidized to the
corresponding carbonyl derivatives.3 The reaction of terminal
alkynes gives rise to two potentially useful products: alkynyl- and
Scheme 1
alkenyl-iodonium salts.4 Both of them are highly reactive to
various nucleophiles.5,6 On the other hand, the groups of Taguchi,7
Liang,8 Barluenga,9 and Wirth10 reported the iodine-induced
PhI(OAc)2 (DIB), PhI(OCOCF3)2 (BTI), and PhIO. Complicated
reactions were observed, and no desired cyclization products
electrophilic cyclizations of acetylenic malonates or b-ketoesters
to afford iodo-substituted indene or cyclopentene derivatives with
were isolated from the reactions. The analysis of the isolated
compounds indicated that compound 1a was oxidized to some
the aid of a base or a Lewis acid. The elegance of these tactics
unidentified carbonyl compounds. Some of our recent efforts
malonates in the presence of a hypervalent iodine compound.11
have been addressed in the oxidative cyclizations with the
leads us to examine the electrophilic cyclization of acetylenic
combination of iodosobenzene with tetrabutylammonium
As shown in Scheme 1, the reaction might proceed in two
iodide (PhIO/Bu4NI), and the in situ generated PhI(ONBu4)I
pathways. In path a, alkenyl-iodonium salt I generated from
was proposed to be the reactive iodine(III) species.12 Hence,
the iodine(III)-induced 5-exo-carbocyclization will be ready to
this combination was employed to induce the cyclization of
undergo the nucleophilic attack to provide product 2. In path b,
substrate 1a. The reaction using 2 equiv. of PhIO and 2 equiv.
the ligand exchange of the hypervalent iodine compound with
of Bu4NI in dichloromethane gave rise to an iodo-substituted
the terminal alkyne group will provide an alkynyl-iodonium
5-exo-carbocyclization product 2a in 46% yield (Table 1, entry 1).
salt II, and this intermediate will react with the nucleophile to
The stereochemistry of compound 2a was determined by the
form a Nu-substituted alkyne III. Besides the direct cyclization to
NOE spectrum. Interestingly, in the solvent screening experiments
access product 2, intermediate III might undergo an iodine(III)-
(Table 1, entries 2–10), we found that the formation of compound
induced 5-exo-carbocyclization followed by the second nucleo-
2a was not observed when 2,2,2-trifluoroethanol was used as
philic substitution to afford product 4.z
the solvent. Instead, a diiodo-substituted 5-exo-carbocyclization
To test our hypothesis, we selected diethyl 2-(2-ethynylbenzyl)-
product 4a was isolated in 59% yield. The best ratio of substrate,
malonate 1a as the model substrate for reaction condition
PhIO, and Bu4NI for the formation of compound 4a was 1 : 3 : 3,
screening. First, we examined a variety of hypervalent iodine
with which the yield increased to 83% (Table 1, entry 12). The
compounds, such as PhI(OH)OTs (HTIB), PhI(OH)OPO(OPh)2,
reaction proceeded sluggishly at 0 1C, and the higher temperature
shortened the reaction time from 24 h to 10 h with a slightly
lower yield.
Department of Chemistry, Fudan University, 220 Handan Road,
Shanghai 200433, China. E-mail: rhfan@fudan.edu.cn;
Fax: +86-21-6510-2412; Tel: +86-21-6564-2019
1,1-Diiodoalkene derivatives are of increasing importance
because they are versatile intermediates to undergo various
selective bond forming reactions in a sequential manner to
construct complex carbon frameworks.13 Although a wide series
w Electronic supplementary information (ESI) available: Experimental
1
procedures, characterization data, copies of H NMR and 13C NMR
of new compounds. See DOI: 10.1039/c1cc15529f
c
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Chem. Commun., 2011, 47, 12221–12223 12221

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Table 1 Evaluation of reaction conditions
Table 2 PhIO/Bu4NI mediated electrophilic cyclization
Entry Substrate
4a (%) Entry Substrate
4a (%)
4h (78)
Entry PhIO/equiv. Bu4NI/equiv. Solvent
2aa (%) 4aa (%)
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
2
2
3
3
3
4
2
2
2
2
2
2
2
2
2
2
2
3
4
3
CH2Cl2
THF
46
47
32
65
44
31
36
27
n.d.b
n.d.b
n.d.b
n.d.b
n.d.b
n.d.b
n.d.b
n.d.b
59
1
4a (83) 8
PhCH3
CH3CN
DMSO
EtOAc
MeOH
t-BuOH
2
3
4
5
6
4b (86) 9b
4c (68) 10
4d (75) 11
4e (74) 12
4f (76) 13
4i (81)
4j (0)
9
CF3CH2OH n.d.
10
11
12
13
14
H2O
50
n.d.b
49
CF3CH2OH n.d.b
CF3CH2OH n.d.b
CF3CH2OH n.d.b
CF3CH2OH n.d.b
83
35
25
4k (0)
4l (50)
a
b
Isolated yield based on substrate 1a. n.d. = not detected.
of 1,1-diiodoalkenes are easily prepared,14 only few methods for
the regiospecific synthesis of diiodomethylene cyclic compounds
are known. The group of Harada reported the preparation of
(diiodomethylene)cycloalkanes from the base-mediated cyclization
of 1, o-diiodo-1-alkynes.15 The group of Giacomini developed an
iododecarboxylation of 4-(carboxyalkylidene)azetidin-2-one
to synthesize diiodovinyl-b-lactams.16 McNelis and co-workers
described a ring expansion of 1-iodoethynyl-2-methyl-cyclo-
pentanols with iodine and HTIB to form 2-(diiodomethylidene)-
6-methylcyclohexanone.17
4m (52)
4n (73)
7
4g (78) 14b
a
b
Isolated yield based on substrate 1. Reaction at 50 1C.
Motivated by the synthetic potential of the possible method,
the generality of the present PhIO/Bu4NI induced cyclization
was then investigated under the established conditions (Table 2).
2-(2-Ethynylbenzyl)malonates were effective substrates, and
their reactions provided the expected products 4a–4i in good
yields (Table 2, entries 1–9). Additionally, the cyclization was
found to tolerate a range of different groups with different
electronic demands on the aromatic ring. No corresponding
diiodomethylene indane derivative was isolated from the
reaction of ethyl 2-(2-ethynylbenzyl)-3-oxobutanoate 1j or
2-(2-ethynylbenzyl)-1,3-diphenyl-propane-1,3-dione 1k (Table 2,
entries 10 and 11). The reactions of 4-pentynylmalonates afforded
diiodomethylene cyclopentanes 4l–4n in moderate to good yields
(Table 2, entries 12–14).
Scheme 2
Although, so far, we cannot be certain of the actual role of
CF3CH2OH in the formation of compound 4, a tentative
mechanism is depicted in Scheme 3. The reaction of acetylenic
malonate 1 with the generated active iodine(III) species A18 will
proceed in two different pathways dependent on the reaction
solvent. In path b, the reaction in 2,2,2-trifluoroethanol forms
an intermediate B, which can be attacked by the iodide ion via
a Michael addition—generation of alkylidene carbene—rear-
rangement sequence19 to generate 2-(2-(2-iodoethynyl)benzyl)-
malonate C. In the presence of another molecule A, compound
C is converted into an intermediate E via an iodine(III)-
mediated electrophilic 5-exo-carbocyclization. This is followed
by the second nucleophilic displacement with the iodide ion to
afford diiodomethylene indane derivative 4 accompanied by
the reductive elimination of PhI. In path a, iodine(III) com-
pound A activates the acetylene group to promote the intra-
molecular nucleophilic attack of malonate on the triple bond.
The annulation yields an intermediate G, which is ready to be
attacked by the iodide ion to generate product 2.
The treatment of compound 1a with iodine and a base
(t-BuOK8 or NaH10a) under the reported iodine-induced electro-
philic cyclization conditions gave rise to compound 2a in 39%
or 35% yield, respectively. The formation of compound 4a
was not observed. The replacement of PhIO with PhI(OAc)2
or PhI(OCOCF3)2 led to the failure in the formation of
compound 4a. When Bu4NBr or Bu4NCl was used instead
of Bu4NI, no corresponding dibromomethylene or dichloro-
methylene indane derivative was obtained. Under the standard
conditions, compound 2a or 1-methylene indane derivative 5
could not be converted to compound 4a. The reaction of
2-(2-ethynylbenzylidene)malonate 6 or 2-(2-ethynylphenyl)-
malonate 8 afforded the corresponding 2-iodoethynyl compound
7 or 9 in 95% or 75% yield, respectively (Scheme 2).
c
12222 Chem. Commun., 2011, 47, 12221–12223
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In conclusion, we have developed an efficient regioselective
cyclization of acetylenic malonates with the combination of
iodosobenzene with tetrabutylammonium iodide in 2,2,2-tri-
fluoroethanol to afford the synthetically useful 1-diiodomethylene
indane and cyclopentane derivatives in moderate to good
yields. Current dedication has also been made to extend its
scope, to explore its reaction mechanism and possible synthetic
applications, and these results will be reported in due course.
Financial support from National Natural Science Foundation
of China (21072033) is gratefully acknowledged.
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Notes and references
z Representative experimental procedure: the mixture of acetylenic
malonate (0.2 mmol) with Bu4NI (221 mg, 0.6 mmol) in CF3CH2OH
(2 mL) was treated with PhIO (132 mg, 0.6 mmol) at 25 1C, and the
reaction mixture was allowed to stir at 25 1C for 24 h. Upon
completion by TLC, the reaction was quenched with saturated
Na2S2O3, and extracted by ethyl acetate (50 mL ꢀ 3). The organic
layer was dried over anhydrated Na2SO4, and concentrated in vacuo.
The residue was purified by column chromatography on silica gel
(15% ethyl acetate in hexanes) to give the corresponding product 4.
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c
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Chem. Commun., 2011, 47, 12221–12223 12223