Electrophilic carbocyclization of hydroxylated enynes

Article abstract of DOI:10.1002/chem.201003759

Mild, efficient, and clean! Six-membered cyclic products including diiodocyclohexadiene and 2,3-diiodobenzene have been prepared in a iodonium-induced internal carbocyclization of hydroxylated enynes (see scheme). This reaction proceeds smoothly under mild reaction conditions, and all the halogen atoms (I and Br) generated from the electrophiles are used effectively.

Full text of DOI:10.1002/chem.201003759

DOI: 10.1002/chem.201003759
Electrophilic Carbocyclization of Hydroxylated Enynes
Fang Yang,[a, b] Ke-Gong Ji,*[a, b] Hai-Tao Zhu,[b] Ali Shaukat,[b] Xue-Yuan Liu,[b] and
Yong-Min Liang*[b]
The electrophilic cyclization
of nucleophiles, such as oxygen,
nitrogen, sulfur, and carbon
with alkynes was studied in
detail by Barluenga, Larock,
Kirsch, and others and has
proved to be an effective
method for the construction of
cyclic compounds.[1,2] However,
electrophilic additions to al-
lenes have often been consid-
ered to be synthetically less at-
tractive because of to the lack
of efficient control of the regio
and stereoselectivity. Examples
of electrophilic cyclization of al-
lenes with nucleophiles for the
À
construction of C X (C, N, and
O) bonds include the cycliza-
tion of oxygen nucleophiles
with allenes for the direct for-
À
mation of
a
C O bond
(Scheme 1a).[3] Some important
Scheme 1. The domino process. E=electrophile, Py=pyridine.
4-iodofuran-2ACHTUNGTRENNUNG(5H)-ones, most
of which employ iodine to trig-
ger the cyclization, have been
developed using this method, while in an early report, Bar-
luenga et al. have used IPy2BF4/HBF4 to promote the aryla-
tion of allenes at À908C (Scheme 1b).[4] However, the reac-
tion conditions still need further improvement as the expen-
sive IPy2BF4 electrophile is now used and low temperatures
are still required.
alkynes with nucleophiles in domino reactions,[6] we found
that several transition metals, such as gold and platinum,
show similar behavior with electrophiles as I+.[6c,f,7] The
gold-catalyzed cycloisomerization of 1,n-enynes has become
an effective way to construct various carbocyclic products.[8]
However, the electrophilic cyclization of simple hydroxylat-
ed enynes is a particularly challenging chemical transforma-
tion. According to our previous work,[6] we envisioned that
this type of propargyl alcohols A could eliminate the hy-
droxyl group to give the intermediate B in the presence of I2
(A–F, Scheme 1). Herein, we present preliminary results of
a metal-free preparation of diiodocyclohexadienes and 2,3-
diiodobenzenes, in which the key cyclization step is the
attack of unactivated olefins on allenes promoted by the
iodonium ion at room temperature.
Simple olefins have not been used as internal carbon nu-
cleophiles in this manner.[2d,5] In the context of our ongoing
À
efforts to construct C X (C, N, and O) bonds by the use of
[a] Dr. F. Yang, K.-G. Ji
These authors contributed equally to this work.
[b] Dr. F. Yang, K.-G. Ji, H.-T. Zhu, A. Shaukat, X.-Y. Liu,
Prof. Dr. Y.-M. Liang
State Key Laboratory of Applied Organic Chemistry
Lanzhou University, Lanzhou 730000 (P.R. China)
Fax : (+86)931-8912582
Initially, we started by using the hydroxylated enyne 1a
(0.2 mmol) and I2 (1.2 equiv) in CH3NO2 at room tempera-
ture. To our delight, the desired products diiodocyclohexa-
diene (2a and 3a) were isolated in 70% yield after 24 h
(Table 1, entry 1). On increasing the amount of I2
E-mail: jikg08@gmail.com
liangym@lzu.edu.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201003759.
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Chem. Eur. J. 2011, 17, 4986 – 4990

COMMUNICATION
Table 1. Carbocyclization of hydroxylated enynes for the synthesis of 1,2-
diiodo-4-methylcyclohexadiene.[a]
Entry Substrates
R
Solvent
I2
ACTHNUGTRNENUG
Products Yield
[equiv] 2/3[b] [%][c]
[d]
1
2
3
4
5
6
7
8
9
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH3NO2
CH2Cl2
DCE
1.2
1.5
1.8
2.0
2.5
1.8
1.8
1.8
1.8
35:1
40:1
50:1
35:1
20:1
30:1
30:1
–
70
84
90
81
76
82
80
Figure 1. X-ray structure of 2c. Ellipsoids set at 40% probability. Carbon:
[d]
THF
DMF
–
0
black; iodine: light gray; hydrogen atoms omitted for clarity.[9]
–
R
strates were effectively converted into the corresponding
2,3-diiodobenzenes 4 in moderate to good yield, as depicted
in Table 2. The molecular structure of the representative
product 4a was determined by X-ray crystallographic analy-
sis (Figure 2).[10] The reaction tolerates the presence of dif-
ferent electron-rich and electron-withdrawing aryl groups.
The steric effect was also tolerated in this reaction. Unfortu-
nately, substrate 1t with a heteroaromatic R group (a furan
nucleus), did not lead to the desired product. This might be
resulting from the fact that the furan nucleus is not stable in
this reaction system. Also, substrates 1v, which lacks a sub-
stituent at C5 (i.e., R1 =H) turned out to be unreactive
under the given reaction conditions, thus demonstrating that
the substituent at C5 is required to stabilize the positive
charge in the cyclic intermediate D.
85% 2c/3c (9:1)
90% 2d/3d
(6:1)
89% 2i/3i (6:1)
84% 2j/3j
(9:1)
R
65% 2m/3m (11:2)[e]
52% 2p/3p
(5:1)
53% 2q/3q (5:1) 70% 2af/3af
(5:1)
[a] Reaction conditions: 1a (0.2 mmol), I2 (1.8 equiv) in solvent (3.0 mL)
at room temperature. [b] The ratio of 2/3 is determined by NMR analysis.
[c] Yield of isolated product. [d] The CH3NO2 is untreated. [e] I2
(1.5 equiv).
(1.8 equiv), a 90% yield was obtained after 2 h, the ratio of
2a/3a was 50:1 (Table 1, entry 3). A further increase of the
amount of I2 gave no better results (Table 1, entries 4 and
5). Changing the reaction media was also not fruitful
(Table 1, entries 6–9). Various representative hydroxylated
enynes with different R groups were then subjected to the
optimized conditions, as depicted in Table 1. Thus, a tandem
carbon–carbon bond formation of hydroxylated enynes pro-
ceeded smoothly to give the corresponding products in mod-
erate to excellent yields. The reaction worked well with aro-
matic R groups. Unfortunately, substrates with only one ali-
phatic group at C1 did not react owning to the poor stabili-
zation of the intermediate B, as delineated in Scheme 1.
Electron-rich aryl groups showed better results than those
with electron-withdrawing groups (1c versus 1p). The mo-
lecular structure of the representative product 2c was deter-
mined by X-ray crystallographic analysis (Figure 1).[9] Inter-
estingly, it was found that substrate 1m with an o-(allyloxy)-
benzene group gave the corresponding product in the pres-
ence of I2 (1.5 equiv), and the double bond in the R group
was selectively retained in this reaction.
Fortunately, in the case of hydroxylated enynes 1w,x,
which contain styrene as R group and two olefin groups, the
styrene group was selectively retained and a good yield of
corresponding 4w,x was obtained (Scheme 2) at the above
reaction conditions at 08C.
Knowing the importance of multi-iodo-terphenyl deriva-
tives in organic materials,[11] which are used for the prepara-
tion of many optical and conductive materials through palla-
dium-catalyzed Sonagashira coupling, Suzuki coupling, and
Heck coupling reactions, we also prepared hydroxylated
enyne 1y, and it was found that under the optimized condi-
tions, the corresponding tetraiodo-1,1’:4’,1’’-terphenyl 4y was
obtained in 51% yield (Scheme 3).
Additionally, hydroxylated enyne 1z with an electron-
withdrawing aryl group was also subjected to the above con-
ditions (Scheme 4). To our delight, the corresponding prod-
uct 4’-bromo-2,3-diiodo-5-methyl-1,1’-biphenyl (4z) was ob-
tained in 52% yield. Then, we thought that if the olefin
group was changed into an aryl group such as 1-(4-bromo-
phenyl)-4-phenylbut-2-yn-1-ol (1aa), the corresponding 2,3-
diiodo-1,4-dihydronaphthalene 4aa could also be obtained.
To our surprise, only (E)-1-(4-bromophenyl)-2,3-diiodo-4-
phenylbut-2-en-1-ol (5aa) was selectively obtained in 56%
yield.
We also investigated a wide range of hydroxylated enynes
(1a–v) with different R and R2 substituents in the presence
of I2 with DDQ as oxidant. It was found that these sub-
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4987

Y.-M. Liang, K.-G. Ji et al.
Table 2. Synthesis of 2,3-diiodobenzenes 4 from hydroxylated enynes 1.[a]
picted in Table 3. Notably, a
substrate similar to 1ae, with a
styrene as R group was also ob-
tained in 76% yield, whereas
the styrene group was selective-
ly retained in this reaction.
We next investigated the use
of the iodine bromide reagent
(IBr). To our surprise, IBr
(1.5 equiv) in CH3NO2 at
À258C converted hydroxylated
enyne 1u into 2u, which was
oxidized to 5’-bromo-4’-iodo-
1,1’:3’,1’’-terphenyl 5u in 30%
yield (Scheme 5). In this reac-
tion, both the halogen atoms (I
and Br) were used effectively.
In conclusion, we have re-
ported an iodonium-induced
carbocyclizations of alkenes
4a 80%[b]
4b 71%
4c 77%
4d 81%
4e 65%
4 f 60%
4g 70%
4h 80%
4i 78%
4j 80%
4k 68%
4l 69%
with
hydroxylated alkynes.
These transition-metal free re-
actions are mild, efficient,
clean, and simple to perform
and can convert hydroxylated
enynes
into
six-membered
4m 52%
4n 56%
4o 58%
4p 45%
4q 47%
4r 58%
cyclic products of high value in-
cluding diiodocyclohexadiene
and 2,3-diiodobenzene. In this
À
process, several C X (C, I, Br)
bonds are formed. The reaction
is atom economic and all the
halogen atoms (I and Br) gen-
erated from the electrophiles
are used effectively. The dihalo-
genated moiety can be readily
introduced into the benzene in
a position usually not easily to
functionalize.
[d]
4s 51%
4t trace[c]
4u 65%
4v
[a] Reaction conditions: 1a (0.2 mmol), I2 (1.8 equiv) in CH3NO2 (3.0 mL) at room temperature. [b] Yield of
isolated product. [c] Product 4u was observed only in trace amount. [d] No reaction was observed.
Scheme 2. Hydroxylated enynes 1w,x with styrene as R group.
Figure 2. X-ray structure of 4a. Ellipsoids set at 40% probability.
Carbon: black; iodine: light gray; hydrogen atoms omitted for clarity.[10]
Experimental Section
I2 (92 mg, 0.36 mmol, 1.8 equiv) was added to a solution of hydroxylated
alkynes 1 (0.20 mmol) in CH3NO2 (3.0 mL) at room temperature. When
the reaction was considered complete as determined by TLC analysis, the
reaction mixture was diluted with ethyl ether (40 mL), washed with
water, saturated brine, dried over Na2SO4, and evaporated under reduced
In the cases in which the aromatization process is blocked
by a substituent at the C1 position, hydroxylated enynes
1ab–ae gave the diene products in good yield as well, as de-
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Electrophilic Carbocyclization of Hydroxylated Enynes
COMMUNICATION
pressure. The residue was added in
CH2Cl2 (6 mL) without purification,
and then DDQ (90 mg, 0.40 mmol)
was added and the reaction was stirred
at room temperature. When the reac-
tion was considered complete as deter-
mined by TLC analysis, Na2S2O3 was
added and the reaction mixture was
diluted with ethyl ether (40 mL),
washed with water, saturated brine,
dried over Na2SO4, and evaporated
Scheme 3. Synthesis of 2,2’’,3,3’’-tetraiodo-5,5’’-dimethyl-1,1’:4’,1’’-terphenyl 4y. DDQ=2,3-dichloro-5,6-dicya-
no-1,4-benzoquinone.
under reduced pressure. The residue
was purified by chromatography on
silica gel to afford the corresponding
2,3-diiodobenzenes 4.
Acknowledgements
We are grateful to the National Science Foundation (NSF-21072080) for
financial support. We acknowledge the National Basic Research Program
of China (973 Program), 2010CB833203 and the Fundamental Research
Funds for the Central Universities.
Keywords: allenes
·
carbocyclization
·
electrophilic
cyclization · iodine · olefins
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Scheme 4. Comparison of the substrates 1z and 1aa.
Table 3. Synthesis of 1,2-diiodo-4-methylcyclohexadiene from hydroxy-
lated enynes1ab–ae.[a]
Entry
Substrates R, R1
2/3[b] Yield[%][c]
1
2
3
1ab R, R2 =CH3
5:2
2:1
5:2
55
88
88
1ac R=Ph, R2 =CH3
1ad R=CH3, R2 =Ph
4
1ae[d] R=styrene R2 =CH3 2:1
76
[a] Reaction conditions: 1a (0.2 mmol), I2 (1.8 equiv) in CH3NO2
(3.0 mL) at room temperature. [b] The ratio of 2/3 is determined by
NMR analysis. [c] Yield of isolated product. [d] This reaction was carried
out at 08C.
Scheme 5. Synthesis of 5’-bromo-4’-iodo-1,1’:3’,1’’-terphenyl 5u from hy-
droxylated enyne 1u.
Chem. Eur. J. 2011, 17, 4986 – 4990
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Y.-M. Liang, K.-G. Ji et al.
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Received: December 31, 2010
Published online: March 22, 2011
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