Cobalt-catalyzed [4+2+2] cycloaddition for the synthesis of 1,3,6-cyclooctatrienes

Article abstract of DOI:10.1002/anie.200800127

(Chemical Presented) After eight? Polysubstituted 1,3,6-cyclooctatrienes can be obtained in high regioselectivity and in good yields from a cobalt-catalyzed intermolecular cycloaddition reaction between two alkynes and a 1,3-diene (see example in scheme).

Full text of DOI:10.1002/anie.200800127

Angewandte
Chemie
DOI: 10.1002/anie.200800127
Cycloaddition Reactions
Cobalt-Catalyzed [4+2+2] Cycloaddition for the Synthesis of 1,3,6-
Cyclooctatrienes**
Gerhard Hilt* and Judith Janikowski
The atom-economical synthesis of carbocyclic eight-mem-
bered rings from double- and triple-bond systems is a forte of
organometallic catalysis. Nickel-catalyzed cyclotetrameriza-
tions of alkynes[1] and dimerizations of 1,3-butadienes with
nickel or iron catalysis[2] are among the most common
representatives of this class of reaction. One of the limiting
aspects of these intermolecular reactions is the required use of
identical starting materials. To our knowledge, a mild cobalt-
catalyzed method for the generation of eight-membered rings
in an intermolecular reaction utilizing different building
blocks has not been described previously.[3] In contrast to
the nickel-catalyzed cyclotetramerization of alkynes, cobalt-
catalyzed reactions predominantly lead to [2+2+2] cyclo-
trimerizations forming benzene derivatives.[4] In the presence
of 1,3-dienes alkynes react in the presence of cobalt catalysts
Scheme 2. Proposed pathways for the metal-catalyzed reactions lead-
ing to 1,4-cyclohexadiene (3) and 1,3,6-cyclooctatriene (2).
in a Diels–Alder reaction to yield 1,4-cyclohexadiene deriv-
atives.[5] A single report for the cobalt-catalyzed formation of
an eight-membered-ring side product was contributed by us
recently (Scheme 1). In this example the eight-membered
contrast the formation of eight-membered-ring products
when asymmetric alkynes are used cannot be rationalized
by formation of a cobaltacyclopentadiene intermediate
(path C) because the corresponding 3,4-disubstituted pattern
is disfavored for energetic reasons.[4] Under optimized con-
ditions for the formation of the eight-membered-ring prod-
ucts only traces of the cyclotrimerization product were
detected, leading to the assumption that the pathway which
proceeds via the cobaltacyclopentadienes (path C) can be
excluded as a plausible alternative.
Concerning the effect of the donor ligands on the
chemoselectivity of the cobalt catalysts, it was found that
the use of cobalt phosphine complexes preferentially leads to
cyclohexadienes 3 by reaction path A and no product of type
2 was observed.[5] Aliphatically substituted cobalt diimine
complexes in the absence of 1,3-dienes lead to a fast
cyclotrimerization of the applied alkynes.[7] In the presence
of 1,3-dienes regioselective Diels–Alder reactions are facili-
tated when pyridine–imine ligands are utilized with aromatic
substituents on the imine moiety.[8] Only when the aromatic
substituent is replaced by an aliphatic substituent in the imine
subunit of the ligand (7, Scheme 3) is the reductive elimi-
nation to 2 slow enough to permit further alkyne coordina-
tion, insertion, and finally reductive elimination to give the
Scheme 1. Products of the cobalt-catalyzed reaction of phenylacetylene
with isoprene.
cyclic product 1 was formed in 31% yield along with the
Diels–Alder and the cyclotrimerization products.[6]
A prerequisite for the formation of an eight-membered-
ring system 2 is a low-valent metal complex (Scheme 2) with
free sites for the coordination and activation of the substrates.
If the reductive elimination to the 1,4-cyclohexadiene product
(3) proceeds slowly (path A), further coordination and
insertion of an alkyne (path B) and subsequent reductive
elimination to the 1,3,6-cyclooctatriene (2) is possible. In
eight-membered-ring product
1
by reaction path B
(Scheme 2). In the context of the formation of the eight-
membered-ring [4+2+2] cyclization product from alkynes
with 1,3-dienes, the following points are remarkable:
1. An excess of the alkyne is not required.
2. The products are formed regioselectively with the two
substituents from the alkyne (Ph, Scheme 3) in a 1,2-
relation.
[*] Prof. Dr. G. Hilt, J. Janikowski
Fachbereich Chemie
Philipps-Universität Marburg
Hans-Meerwein-Strasse, 35043 Marburg (Germany)
Fax: (+49)6421-282-5677
E-mail: Hilt@chemie.uni-marburg.de
[**] This work was supported by the German Science Foundation.
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Communications
alized product 8b prepared from 1-hexyne and isoprene was
obtained in only 17% yield. On the other hand when an
oxygen-functionalised alkyne was applied up to 63% yield
could be obtained (8d). The reaction of phenylpropynylsul-
fone gave a moderate yield of 28% (8g) which is consistent
with the earlier findings of reduced activity of this alkyne in
cobalt-catalyzed Diels–Alder reactions.[9] When an acceptor-
substituted alkyne was used (Table 1, entry 8) the yield
increased considerably (8g, 78%). The yield of eight-mem-
bered-ring products was also increased when isoprene was
exchanged for the sterically more hindered but more elec-
tron-rich 2,3-dimethyl-1,3-butadiene (8h, 88%). These results
indicate that acceptor-substituted alkynes and electron-rich
1,3-dienes are required for good results in the cycloaddition
process.
Scheme 3. Intermolecular cobalt-catalyzed [4+2+2] cycloaddition.
3. The addition of iron powder reduces the amount of side
products and increases the yield of the eight-membered-
ring products.
When internal alkynes were applied (Table 1, entries 11
and 12) the yields were somewhat diminished; however, a
complex pentasubstituted product (8j) was generated. In this
case the electronic effect of the 2,3-dimethyl-1,3-butadiene
also contributes to the higher yield, so that the hexasubsti-
tuted product 8k was isolated in 49% yield. Acceptor-
substituted internal alkynes as well as disubstituted 1,3-dienes
could be used.
Consequently, excellent results should be obtained when
acceptor-substituted terminal alkynes are reacted with an
electron-rich 1,3-diene. Accordingly, methyl acetylenecarbox-
ylic acid and 2-trimethylsilyloxy-1,3-butadiene were used in
the cobalt-catalyzed cyclization reaction (Scheme 4). Instead
of the direct isolation of intermediate 9, which was detected
by GCMS, hydrolysis with 2m HCl followed by column
chromatography gave the corresponding cyclooctadienone 10
in excellent 90% yield.
In most reactions the Diels–Alder reaction products are
observed as side products; they can be removed easily by
column chromatography.
The role of the iron powder remains unclear; however, the
addition of 10 mol% iron powder has a positive effect on the
chemoselectivity of the reaction (reaction path B is preferred)
and the purity of the products. The preparative results of the
cobalt-catalyzed intermolecular and atom-economical syn-
thesis of eight-membered-ring products from 1,3-dienes and
terminal as well as internal alkynes are summarized in
Table 1.
Table 1: Results of the cobalt-catalyzed synthesis of 1,3,6-cycloocta-
trienes.
Analogously, the acceptor-substituted internal alkyne 11
was
reacted
with
2-trimethylsilyloxy-1,3-butadiene
(Scheme 5), and in one synthetic operation a highly substi-
tuted cyclooctadienone product (12) with a high density of
functional groups was generated from two relatively simple,
commercially available starting materials with a good yield of
65%.
Entry
R1
R2
R3
Product
Yield
1
2
3
4
5
6
7
8
H
H
H
H
H
H
H
H
Ph
2-thienyl
nBu
H
H
H
H
H
H
H
H
H
H
Me
Me
1
65%
40%
17%
50%
63%[a]
56%[b]
28%
78%
88%
43%[c]
29%
49%
8a
8b
8c
8d
8e
8 f
8g
8h
8i
Utilizing a new cobalt-catalyzed reaction pathway we
have successfully coupled two alkynes with a 1,3-diene to
CH2OBn
CH2OAc
CH2CH(OAc)Me
CH2SO2Ph
CO2Me
CO2Me
CH2OAc
CO2Et
9
Me
Me
H
10
11
12
8j
8k
Me
CO2Me
[a] The product consists of a mixture of 80% 8e and 20% of the
regioisomer 1,3-bis(2-acetoxypropyl)-6-methylcycloocta-1,3,6-triene.
[b] The product was obtained in racemic form. [c] The product consists
of a mixture of 80% 8e and 20% of the regioisomer 1,3-bis(2-
acetoxypropyl)-6,7-dimethylcycloocta-1,3,6-triene.
The yield of the eight-membered-ring product 1 generated
from phenylacetylene and isoprene could be increased from
31%[6] to 65%, whereas product 8a generated from 2-
ethynylthiophene was obtained in 40% yield owing to the
deactivating effect of sulfur.[9] Surprisingly, the nonfunction-
Scheme 4. Cobalt-catalyzed synthesis of a cycloocta-3,5-dienone.
TMS=trimethylsilyl.
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Scheme 5. Cobalt-catalyzed synthesis of a tetrasubstituted cycloocta-
3,5-dienone.
generated eight-membered-ring systems in an unprecedented
fashion, thereby generating complex ring systems with a high
functional-group density. The electronic parameters respon-
sible high selectivity and yield were identified, thus opening
the way to an elegant method for the generation of
unsaturated medium-sized ring systems.
Experimental Section
Representative protocol for the cobalt-catalyzed [4+2+2] cycloaddi-
tion (Table 1, entry 1): A mixture of [Co(7)]Br2 (37 mg, 0.1 mmol,
5.0 mol%), zinc iodide (64 mg, 0.2mmol, 10.0 mol%), zinc powder
(13 mg, 0.2mmol, 10.0 mol%), and iron powder (11 mg, 0.2mmol,
10.0 mol%) was suspended in anhydrous dichloromethane (1 mL)
under a nitrogen atmosphere. Isoprene (136 mg, 2.0 mmol) and
phenylacetylene (204 mg, 2.0 mmol) were added, and the resulting
suspension was stirred for 16 h. (As the reaction times were longer
with other substrates, stirring was continued until complete con-
version was detected by GC/GCMS.) The solution was subsequently
filtered through a plug of silica gel (eluent: diethyl ether), the solvent
was removed under reduced pressure, and the residue was purified by
silica gel column chromatography (eluent: pentane/dichloromethane
100:1). The product was obtained as
a colorless oil (177 mg,
0.65 mmol, 65%). The analytical data are in accordance with the
literature values.[6]
Received: January 10, 2008
Revised: April 16, 2008
Published online: June 5, 2008
Keywords: alkynes · cobalt · cycloaddition ·
.
medium-ring compounds · regioselectivity
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