Synthesis of polysubstituted iodobenzene derivatives from alkynylsilanes and 1,3-dienes via diels-alder/oxidation/iodination reaction sequence

Article abstract of DOI:10.1021/acs.orglett.5b00306

The cobalt-catalyzed Diels-Alder reaction of trimethylsilyl-substituted alkynes with 1,3-dienes led to dihydroaromatic intermediates which were transformed into iodobenzene derivatives. For this transformation, the dihydroaromatic intermediates had to be oxidized and the trimethylsilyl-substituted arene had to undergo a silicon-iodine exchange reaction. For this purpose, a number of oxidizing agents and iodonium sources were tested in order to realize the desired two transformations in a single step. Eventually, the combination of tert-butyl hydroperoxide (TBHP), zinc iodide, and potassium carbonate led to the desired oxidation/iodination in good to excellent yields in a short reaction time at ambient temperatures.

Full text of DOI:10.1021/acs.orglett.5b00306

Letter
pubs.acs.org/OrgLett
Synthesis of Polysubstituted Iodobenzene Derivatives from
Alkynylsilanes and 1,3-Dienes via Diels−Alder/Oxidation/Iodination
Reaction Sequence
Robert Mockel and Gerhard Hilt*
̈
Fachbereich Chemie, Philipps-Universitat Marburg, Hans-Meerwein-Straße 4, D-35043 Marburg, Germany
̈
S
* Supporting Information
ABSTRACT: The cobalt-catalyzed Diels−Alder reaction of trimethylsilyl-
substituted alkynes with 1,3-dienes led to dihydroaromatic intermediates
which were transformed into iodobenzene derivatives. For this trans-
formation, the dihydroaromatic intermediates had to be oxidized and the
trimethylsilyl-substituted arene had to undergo a silicon−iodine exchange
reaction. For this purpose, a number of oxidizing agents and iodonium sources were tested in order to realize the desired two
transformations in a single step. Eventually, the combination of tert-butyl hydroperoxide (TBHP), zinc iodide, and potassium
carbonate led to the desired oxidation/iodination in good to excellent yields in a short reaction time at ambient temperatures.
odobenzene derivatives are excellent starting materials for
transition-metal-catalyzed cross-coupling under mild con-
Scheme 2. Desired Oxidation/Silicon−Iodine Exchange
I
Reaction
ditions based on the high reactivity of the carbon iodine bond in
the oxidative addition process.1 A drawback of the iodobenzene
derivatives is the high price for commercially available materials.
Nevertheless, the further need for simple synthesis of
polysubstituted iodobenzene derivatives with a predictable
incorporation of the iodine substituent at a precisely predictable
position is undisputable. In this respect, we envisaged the use of
alkynyl iodides as starting material in a cobalt-catalyzed Diels−
Alder reaction.2 However, under the reaction conditions of the
cobalt-catalyzed Diels−Alder reaction, the use of alkynyl iodides
led into oxidative insertions either of the metallic zinc or the low-
valent cobalt catalyst, which eventually resulted in a number of
undesired side reactions. Therefore, we alternatively envisaged
the use of alkynylsilanes (1) as building blocks for the synthesis
of more complex iodobenzene derivatives (Scheme 1).3 The use
are easy and the products are stable over a long period of time.
Second, the trimethylsilyl group is an excellent directing group
for the regioselective cobalt-catalyzed Diels−Alder reactions
when unsymmetrical starting materials are used.
Third, the silyl group can be substituted under relatively mild
conditions in an ipso-substitution by various iodonium sources
resulting in products of type 3.
In order to guarantee a high flexibility of substitution patterns,
we addressed the synthesis of different commercially unavailable
1,3-dienes via two methods. Either a Wittig reaction of an
aldehyde with allyltriphenylphosphonium bromide and a base
was used for the synthesis of 1-substituted 1,3-dienes5 or a
ruthenium-catalyzed enyne-metathesis reaction an of internal
alkyne with ethene was utilized to generate 2,3-disubstituted 1,3-
diene.6 However, at the early stage of the investigation the main
focus was set on commercially available 1,3-dienes, such as 2,3-
dimethyl-1,3-butadiene or isoprene.
Scheme 1. Outline of the Synthesis of Iodobenzene
Derivatives
In previous work, the silyl-substituted arenes (2) were isolated
after DDQ oxidation, which proved that the trimethylsilyl
substituent tolerates these reaction conditions.4 For this
investigation, oxidation of the primarily produced dihydroar-
omatic Diels−Alder product (4) to the aromatic compound and,
furthermore, silyl−iodine exchange should be realized in a single
transformation to yield 5 (Scheme 2). To achieve this goal, either
the iodonium source should be capable of oxidizing the
dihydroaromatic intermediate 4 or the oxidizing agent should
of alkynylsilanes (1) as dienophiles in a cobalt-catalyzed Diels−
Alder reaction for the synthesis of silyl-functionalized arenes (2)
has been disclosed before with simple 1,3-dienes.4 These cobalt-
catalyzed reactions were conducted under reductive conditions
utilizing zinc powder for the in situ reduction of the cobalt(II)
catalyst precursor to the reactive cobalt(I) complex. Under these
reaction conditions, the alkynyltrimethylsilanes were stable and
led to the desired dihydroaromatic intermediates in good yields
(compare 4 in Scheme 2).
Moreover, the alkynyltrimethylsilanes have a number of
advantages. First, the syntheses of the alkynylsilane derivatives
Received: January 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00306
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Letter
also be able to generate iodonium ions from simple iodine
sources in situ.
conditions (TosOH) was applied for the formation of 5 (Scheme
5).10
The first attempt to realize the desired transformation was the
conversion of 4 with ICl (2.0 equiv) in dichloromethane.7
Surprisingly, after 15 min reaction time at room temperature only
17% of the desired product 5 could be isolated. In addition to 5,
also several HCl-addition products could be detected by GCMS
analysis and were isolated as a mixture of isomers (>50%).
Accordingly, these conditions were not useful for a clean
conversion of 4 to 5. Next, we investigated the use of NIS (N-
iodosuccinimide) as iodonium source and oxidizing agent
(Scheme 3).8 Although NIS has not been described as the
oxidizing agent for the synthesis of arenes from intermediates
such as 4, the first results were promising.
Scheme 5. m-CPBA/I2-Induced Oxidation/Iodination
Reaction
In this set of experiments, 4f was used as easily accessible
intermediate of type 4 and the corresponding iodobenzene 5f
was generated in only 5 min reaction time at ambient
temperatures. We then investigated different ratios of oxidizing
agent, acid, and iodonium source. The results of the m-CPBA/I2-
induced oxidation/iodination reaction sequence are summarized
in Table 1.
Scheme 3. NIS-Induced Oxidation/Iodination Reaction
Table 1. Results of the m-CPBA/I2 Reaction
a
a
no.
m-CPBA/TosOH/I2 (equiv)
6g/7g (%)
5g (%)
1
2
3
4
5
6
7
2.0/0.6/1.0
2.0/0.6/3.0
2.0/2.0/3.0
2.0/2.0/2.0
2.0/2.0/4.0
2.0/3.0/4.0
3.0/3.0/3.0
7/14
7/31
6/4
54
53
76
77
83
89
92
8/4
7/5
The NIS-induced protocol for the synthesis of products 5 led
to the desired iodobenzene derivatives in moderate yields. The
high conversion of material into unidentified side products, the
long reaction time, and the tendency of the products to
decompose, most likely by the unidentified side products which
were not separable from the products by simple column
chromatography, were unsatisfying. Nevertheless, the yield of
5a could be increased to 67% when the reaction was performed in
dichloromethane instead of acetonitrile utilizing 3.0 equiv of NIS
after 72 h, but still these conditions were not particularly
practical.
In a small set of experiments, we then investigated the use of a
combination of hydrogen peroxide as an inexpensive and readily
available oxidizing agent for dihydroaromatic intermediates of
type 4 in combination with zinc iodide as an easy to handle iodine
source (Scheme 4).9
7/2
6/2
a
Yields were obtained from GC analysis using decane as the internal
standard.
Under optimized reaction conditions, up to 92% of 5f was
obtained using an excess of each m-CPBA, TosOH, and iodine.
Nevertheless, under all tested conditions, the desired product
was accompanied by a small amount of proto-desilylated 6f and
varying amounts of epoxidized side product, whose structure was
tentatively assigned to 7f. The separation of the desired product
from the side products is very tedious which disfavors these
reaction protocols.
Although the overall results of the m-CPBA/TosOH/I2
process were already quite promising, we were not satisfied
with the encountered proto-desilylation side product. Therefore,
basic conditions were tested for the oxidation/iodination using
tert-butyl hydroperoxide (TBHP) as oxidant,11 and iodine or zinc
iodide were applied as iodonium source (Scheme 6).
Scheme 4. ZnI2/H2O2-Induced Oxidation/Iodination
Reaction
The results of the TBHP-induced oxidation/iodination
reaction sequence are summarized in Table 2.
While in the absence of base 80% of 5f was obtained using 2.0
equiv of I2, the addition of further amounts of I2 resulted in
decreased yields (entries 1−3). Organic bases such as NEt3,
While the yields of products 5a and 5b were increased, the
reaction time was quite long to obtain the desired products and
either DDQ or NIS had to be added at the end to achieve either
complete oxidation of dihydroaromatic intermediates or to
complete the silicon−iodine exchange.
Scheme 6. TBHP/I2- or TBHP/ZnI2-Induced Oxidation/
Iodination Reaction
Considerably better results were obtained when a combination
of m-CPBA (m-chloroperbenzoic acid) and iodine under acidic
B
DOI: 10.1021/acs.orglett.5b00306
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Letter
a
Table 2. Results of the TBHP/I2 and TBHP/ZnI2 Reaction
Scheme 7. Two-Step Synthesis of Iodobenzene Derivatives
a
no.
TBHP/I2
base
5g (%)
1
2
4.0/1.0
4.0/2.0
4.0/3.0
4.0/2.0
4.0/2.0
4.0/2.0
4.0/2.0
4.0/2.0
4.0/2.0
4.0/2.0
4.0/2.0
TBHP/ZnI2
62
80
3
56
4
NEt3 (4.0 equiv)
pyridine (4.0 equiv)
lutidine (4.0 equiv)
KOH (4.0 equiv)
KOAc (4.0 equiv)
Na3PO4 (4.0 equiv)
KOtBu (4.0 equiv)
K2CO3 (4.0 equiv)
base
0
5
50
6
64
7
43
8
77
9
87
10
11
no.
58
89
5g (%)
12
13
14
15
4.0/2.0
4.0/2.0
4.0/2.0
4.0/2.0
86
76
91
98
K2CO3 (1.0 equiv)
K2CO3 (2.0 equiv)
K2CO3 (4.0 equiv)
a
Yields were obtained from GC analysis using decane as internal
standard.
pyridine, and lutidine gave only moderate yields, but
considerably better results were obtained with inorganic bases,
such as sodium phosphate or potassium carbonate (entries 9 and
11). When the iodonium source ws changed to zinc iodide, the
yields could be further increased so that eventually the
combination of TBHP/ZnI2/K2CO3 in a ratio of 4:2:4 equiv
gave excellent results (entry 15) without any trace of proto-
desilylation or epoxidation side products.
Finally, the combination of the cobalt-catalyzed Diels−Alder
reaction and TBHP/ZnI2/K2CO3-oxidation/iodination were
tested without purification of the dihydroaromatic intermediates
of type 4 (Scheme 7). After complete conversion of the starting
materials in the cobalt-catalyzed Diels−Alder reaction, the
dihydroaromatic intermediates were filtered over a small plug
of silica gel and used in the oxidation/iodination reactions as
obtained. The use of symmetrical as well as unsymmetrical 1,3-
dienes could be achieved. The regioselectivity of the cobalt-
catalyzed Diels−Alder reaction was controlled by the ligand
(bidentate phosphine versus pyridine−imine ligand) as we
described in the past.12 The excellent control of the
regiochemistry of functionalized alkynes with unsymmetrical
1,3-dienes was only recently demonstrated with alkynylboro-
nates as functionalized building blocks for the synthesis of
complex monomers for the palladium-catalyzed Suzuki polymer-
ization reaction.13 The desired iodobenzene derivatives were
obtained in moderate to good yields, and several functional
groups were tolerated in both reactions.
The commercially available symmetrical 2,3-dimethyl-1,3-
butadiene could be utilized for the synthesis of the
trimethyliodobenzene derivative 5b in a good overall yield of
80%. As a prototype of an unsymmetrical 1,3-diene, isoprene was
converted to the corresponding iodobenzene derivatives 5g−m
with the Co(pyridine-imine)-type catalyst to generate products
with the methyl group of the isoprene and the iodine substituent
in a 1,3-relation. These iodine-containing products were isolated
in 58−83% yields for the Diels−Alder/oxidation/iodination
reaction sequence. Moreover, two different 1-aryl-substituted
1,3-dienes were converted to the desired products 5n and 5o in
very good yields of 75% and 79%, respectively. Finally, the
Co(dppe)-type catalyst led to the regioselective formation of 5p
a
Reaction conditions: CoBr2(ligand) (10 mol %), zinc powder (20
mol %), zinc iodide (20 mol %), alkyne (1.0 equiv) and diene (1.0
equiv), CH2Cl2, 24 h, rt, filtration through silica gel, then K2CO3 (4.0
equiv), TBHP (4.0 equiv), ZnI2 (2.0 equiv), CH2Cl2, rt, 24−48 h.
with the iodine substituent and the phenyl substituent of the
diene component in a 1,4-relation in moderate 47% yield.
In conclusion, we were able to generate the trimethylsilyl-
functionalized dihydroaromatic compounds in a regioselective
fashion and tested a number of oxidizing/iodination conditions.
Eventually, we were able to realize a mild and benign protocol for
the synthesis of multiple-substituted iodobenzenes from
dihydroaromatic intermediates in a single synthetic step. In
particular, we were able to generate interesting materials such as
the bromoiodo-substituted biaryl derivative (5n) as well as 2,3-
disubstituted iodobenzene derivative (5o). In addition, 2,5-
disubstituted products, such as the chloroiodobiphenyl 5m, and
also 2,4,5-trisubstituted iodobenzenes (5p) were synthesized.
Based on these results we are confident that we will be able to
generate highly interesting iodobenzene building blocks for
palladium-catalyzed cross-coupling reactions utilizing the
regiodiverse and powerful cobalt-catalyzed Diels−Alder reaction
of alkynyltrimethylsilanes with substituted 1,3-dienes in the
future.
ASSOCIATED CONTENT
■
S
* Supporting Information
Synthesis, analytical data, NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
C
DOI: 10.1021/acs.orglett.5b00306
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Letter
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hilt@chemie.uni-marburg.de. Fax: +49 6421 2825601.
Notes
The authors declare no competing financial interest.
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DOI: 10.1021/acs.orglett.5b00306
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