A novel iodine-promoted tandem cyclization: An efficient synthesis of substituted 3,4-diiodoheterocyclic compounds

Article abstract of DOI:10.1002/chem.201000518

(Figure Presented) Iodine sets allenes ringing: A novel iodine-promoted tandem cyclization reaction of but-2-yne-1,4-diol and 4aminobut-2-yn-l-ol derivatives leading to substituted 3, 4-diiodoheterocyclic compounds has been developed (see scheme). In this

Full text of DOI:10.1002/chem.201000518

COMMUNICATION
DOI: 10.1002/chem.201000518
A Novel Iodine-Promoted Tandem Cyclization: An Efficient Synthesis of
Substituted 3,4-Diiodoheterocyclic Compounds
Ke-Gong Ji, Hai-Tao Zhu, Fang Yang, Xing-Zhong Shu, Shu-Chun Zhao, Xue-Yuan Liu,
Ali Shaukat, and Yong-Min Liang*[a]
Five- and six-membered heterocyclic rings occur as key
structural subunits in numerous natural products, such as
polyacetylenic esters,[1] phytane-type diterpenedilactones,[2]
cylindriline C, and lepadiformine.[3] Thus, the development
of novel methods for the annulation of five- and six-mem-
bered heterocyclic rings is necessary, including metal-free,
mild, environmentally friendly, and atom-economic condi-
tions.
Many important heterocycles, such as benzo[b]thiophenes,[4]
benzofurans,[5] 2,3-dihydropyrroles,[6] pyrroles,[6] furans,[7] in-
doles,[8] isochromenes,[9] isocoumarins,[10] a-pyrones,[10] iso-
quinolines,[11] quinolines,[11] isoxazoles,[12] and oxazoles,[13]
have syntheses based on this strategy. Thus, electrophilic
cyclization reactions continue to be an area of active re-
search in the field of synthetic chemistry.
In the context of our ongoing efforts to construct func-
tionalized heterocyclic structures,[14] we have found that
propargyl carbocations,[15] which may be in equilibrium with
allene cations (Scheme 1a), are perfect intermediates for a
Scheme 1. a) Possible equilibrium. b) Design of the domino process.
Recently, the electrophilic cyclization of heteroatomic nu-
cleophiles, such as oxygen, nitrogen, and sulfur, with alkynes
has proven to be an effective method for the synthesis of
these heterocyclic compounds.[4–13] Due to the excellent al-
kynophilicity of molecular iodine, much attention has been
paid to iodine-based alkyne activation as an attractive pro-
tocol for developing new and efficient iodocyclizations.[6–8]
domino process. We envisioned that this type of propargyl
alcohol (1) could undergo the isomerization process in the
presence of I2 and then cyclize to give 3,4-diiodoheterocyclic
compounds 2 (Scheme 1b). Herein, we report example reac-
tions of but-2-yne-1,4-diol and 4-aminobut-2-yn-1-ol deriva-
tives towards the synthesis of 3,4-diiodoheterocyclic com-
pounds in the presence of I2. In this reaction, both the
iodine anion and cation generated from I2 are used effec-
tively.
Initially, we used 1-phenylbut-2-yne-1,4-diol (1a;
0.3 mmol) and I2 (1.2 equiv) in CH2Cl2 (3 mL) at room tem-
perature; to our delight, the desired product, 3,4-diiodo-2-
phenyl-2,5-dihydrofuran (2a) was isolated in 62% yield,
after 12 h (Table 1, entry 1). On increasing the amount of I2
[a] Dr. K.-G. Ji, H.-T. Zhu, F. Yang, X.-Z. Shu, S.-C. Zhao, X.-Y. Liu,
A. Shaukat, Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University
Lanzhou 730000 (China)
Fax : (+86)931-8912582
E-mail: liangym@lzu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201000518.
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6151

Table 1. Optimization of the iodine cyclization of 1-phenylbut-2-yne-1,4-
Table 2. Synthesis of 3,4-diiododihydrofurans 2 from but-2-yne-1,4-diol de-
rivatives 1.[a]
diol, 1a.[a]
Entry
Solvent
I2 [equiv]
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
dry CH2Cl2
DCE
DMF
MeOH
THF
1.2
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
12
8
4
12
6
12
12
12
12
62
95
99
2a, 99%[b] 2b, 96%
2c, 90%
2h, 82%
2d, 92%
2i, 93%
2e, 94%
2j, 92%
trace
90
nr[c]
nr[c]
41
2 f, 90%
2g, 70%[c]
CH3CN
72
[a] Conditions: 1a (0.3 mmol) and I2 in CH2Cl2 (3.0 mL), at room temper-
ature. [b] Isolated yield. [c] nr=no reaction.
2k, 92%
2p, 80%
2l, 87%[d]
2m, 83%[d]
2n, 82%[d]
2o, 83%[d]
2t, 82%[d]
2q, 75%
2r, 91%
2s, 88%
present to 1.5 equivalents, a 95% yield of 2a was obtained
after 8 h (Table 1, entry 2) and, on further increasing the
amount of I2 to 2.0 equivalents, an excellent yield of 2a was
obtained (up to 99%; Table 1, entry 3). The reaction was
also tested in dry CH2Cl2, in which case only trace amounts
of 2a were observed (Table 1, entry 4).
[a] All reactions were run under the following conditions, unless otherwise
indicated: 1 (0.30 mmol) and I2 (2.0 equiv) in CH2Cl2 (3 mL), at room tem-
perature. [b] Isolated yield. [c] 20% of the starting material was recovered.
[d] The reaction was carried out at 408C.
The reaction was also tested in other solvents. The use of
dichloroethene (DCE) gave an almost identical result, albeit
with a very slightly lower yield (Table 1, entry 5), whereas
DMF and MeOH proved to be ineffective and THF and
CH3CN were less effective (Table 1, entries 6–9). Thus, the
optimum reaction conditions employ 1.0 equivalent of 1a
and 2.0 equivalents of I2, in CH2Cl2, at room temperature.
With the optimized conditions in hand, various but-2-yne-
1,4-diol derivatives, 1a–t, were subjected to the above condi-
tions, as depicted in Table 2. Thus, the tandem carbon–het-
Table 3. Synthesis of 3,4-diiododihydropyrroles 2u–ac[b] from 4-amino-
but-2-yn-1-ol derivatives 1u–ac.[a]
2u, 86%
2v, 91%
2w, 87%
ACHTUNGTRENNUNGeroatom bond formation reactions of but-2-yne-1,4-diol de-
rivatives 1a–t proceeded smoothly to provide the corre-
sponding products 2a–t in moderate to excellent yields. The
reaction works well with aromatic R’ groups. Electron-rich
aryl groups showed better results than those with an elec-
tron-withdrawing group in this tandem reaction (e.g., 1a vs.
1g). Substrates 1h and 1i, with a styrene or heteroaromatic
R’ group, can also afford the desired products 2h and 2i in
83 and 93% yield, respectively. Interestingly, substrates like
1l–o, with aliphatic groups, can also gave the corresponding
3,4-diiodoheterocyclic compounds 2l–o in moderate yields.
Other substrates, like 1p–t, can also afford the correspond-
ing products 2p–t in moderate to excellent yield.
2x, 80%[c]
2y, 97%[c]
2z, 45%[c]
2aa, 85%[c]
2ab, 80%[c]
2ac, 70%[c]
[a] All reactions were run under the following conditions, unless other-
wise indicated: 1 (0.30 mmol) and I2 (3.0 equiv) in CH2Cl2 (3 mL), at
room temperature. [b] Isolated yield. [c] The reaction was carried out at
408C.
Furthermore, to expand the scope of this reaction, we also
investigated a range of 4-aminobut-2-yn-1-ol derivatives,
1u–ac. It was found that, under the optimized conditions,
substrates 1u–ac were transferred into 3,4-diiodo-dihydro-
pyrroles 2u–ac in moderate to excellent yields, as depicted
in Table 3. The molecular structure of the representative
product 2u was determined by X-ray crystallography
(Figure 1).[16] Substrates like 1x–ac, with aliphatic substitu-
ents, can also afford the desired spiro products in good
yield.
As we know, six-membered pyran rings are very impor-
tant in organic chemistry. Consequently, under the opti-
mized conditions, we also investigated the reaction of pent-
2-yne-1,5-diol derivative 1ad. Fortuitously, 4,5-diiodo-2,6-di-
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3,4-Diiodoheterocyclic Compounds
COMMUNICATION
Scheme 4. Proposed mechanism.
Figure 1. X-ray crystal structure of 2u.[16]
In conclusion, an efficient synthesis of highly substituted
3,4-diiodoheterocyclic compounds from but-2-yne-1,4-diol
and 4-aminobut-2-yn-1-ol derivatives has been developed. In
this reaction, trace amounts of water are necessary and both
the iodine anion and cation, generated from I2, are used ef-
fectively.
phenyl-3,6-dihydro-2H-pyran (2ad) was obtained in moder-
ate yield (Scheme 2).
A standard feature of this process is that the diiodohet-
ACHTUNGTRENNUNGerocyclic compounds produced by the iodocyclization can be
Experimental Section
General procedure–Synthesis of diiodoheterocyclic derivatives: I2
(152.4 mg, 0.6 mmol, 2 equiv) was added to a solution of 1 (0.30 mmol) in
wet CH2Cl2 (3.0 mL) and the resulting mixture was stirred at room tem-
perature. When the reaction was considered complete, as determined by
TLC analysis, the reaction mixture was diluted with diethyl ether
(40 mL), washed with water and brine, dried over Na2SO4, and evaporat-
ed under reduced pressure. The resulting residue was purified by column
chromatography on silica gel to afford the corresponding diiodoheterocy-
clic compound 2.
Scheme 2. Synthesis of 4,5-diiodo-2,6-diphenyl-3,6-dihydro-2H-pyran
(2ad).
further elaborated by using various palladium-catalyzed pro-
cesses. For example, the Sonogashira coupling[17] of 3,4-di-
ACHTUNGTRENNUNGiododihydrofuran 2p affords the corresponding product 3p
in excellent yield (Scheme 3).
Acknowledgements
We thank the NSF (NSF-20732002, NSF-20872052, and NSF-20090443)
for financial support.
Keywords: allenes · cyclization · heterocycles · iodine ·
propargyl carbocations
Scheme 3. An example of further elaboration of compounds 2.
On the basis of the observations above, we propose the
following mechanism for this iodine cyclization (Scheme 4).
In the CH2Cl2 used, trace amounts of water react with the I2
to produce protons, iodine anions, iodine cations, and hy-
droxide anions. In the presence of protons, substrate 1 loses
a hydroxide group to afford the intermediate allene cat-
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Received: February 27, 2010
Published online: April 26, 2010
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