Chemoselective Cobalt(I)-Catalyzed Cyclotrimerization of (Un)Symmetrical 1,3-Butadiynes for the Synthesis of 1,2,4-Regioisomers

Article abstract of DOI:10.1021/acs.orglett.9b01281

The cobalt(I)-catalyzed cyclotrimerization of (un)symmetrical 1,4-disubstituted 1,3-butadiynes is presented. In the case of unsymmetrical 1,3-butadiynes, this reaction can generate eight 1,2,4-substituted and four 1,3,5-substituted isomers. A single 1,2,4-substituted isomer was formed in excellent yields (up to 99%) and exclusive regioselectivities (>99:1) when symmetrical or a 1,3-butadiyne with an aryl or alkyl substituent and a trimethylsilyl group were applied. A large number of products accepting a wide variety of functional groups were synthesized.

Full text of DOI:10.1021/acs.orglett.9b01281

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chemoselective Cobalt(I)-Catalyzed Cyclotrimerization of
(Un)Symmetrical 1,3-Butadiynes for the Synthesis of 1,2,4-
Regioisomers
Sebastian M. Weber†,‡ and Gerhard Hilt*,†,‡
†
̈
Fachbereich Chemie Philipps Universitat Marburg, Hans-Meerwein Strasse 4, D-35032 Marburg, Germany
‡Institut fu
̈
r Chemie, Universitat Oldenburg, Carl-von-Ossietzky-Strasse 9-11, D-26111 Oldenburg, Germany
̈
S
* Supporting Information
ABSTRACT: The cobalt(I)-catalyzed cyclotrimerization of
(un)symmetrical 1,4-disubstituted 1,3-butadiynes is presented.
In the case of unsymmetrical 1,3-butadiynes, this reaction can
generate eight 1,2,4-substituted and four 1,3,5-substituted
isomers. A single 1,2,4-substituted isomer was formed in
excellent yields (up to 99%) and exclusive regioselectivities
(>99:1) when symmetrical or a 1,3-butadiyne with an aryl or
alkyl substituent and a trimethylsilyl group were applied. A
large number of products accepting a wide variety of
functional groups were synthesized.
he transition-metal-catalyzed cyclotrimerization of termi-
which generated the catalytically active cobalt(I) species in situ
in acetonitrile as solvent.
This catalyst system gave very good yields and an excellent
regioselectivity where the unsymmetrical product 4 was
formed in a regioisomeric ratio of >95:5 (Scheme 1).6
T
nal and internal alkynes is a well-known method in
organic synthesis for the formation of aromatic compounds.
Since its discovery by Berthelot and Reppe, many transition
metals (e.g., Fe, Ru, Co, Rh, Ir, Ni, Pd, Au) could be identified
as suitable catalysts for this transformation.1 A large number of
different cobalt-based catalysts could be identified for this
reaction and in addition to mechanistic investigations
performed by Vollhardt, Malacria, Aubert, Gandon, Dahy,
Koga, and many others,2 this method was also successfully
applied in several natural product syntheses (e.g., vitamin B6 or
( )-allocolchicine).3 For the cyclotrimerization of alkynes,
most often, cyclopentadienyl-cobalt-based catalysts have been
used while the number of in situ generated cobalt(I) catalysts
with phosphine- and imine-type ligands has been reported in
increasing numbers over the last few years.4
Scheme 1. Regioselective Cobalt(I)-Catalyzed
Cyclotrimerization of Alkynes
Besides this, we were able to alter the regioselectivity by
using disulfide-based ligands (e.g., 1,2-bis(phenylthio)ethane)
in THF as solvent to favor the symmetrical cyclotrimerization
product 5.6b
Interestingly, bench-stable cyclopentadienylcobalt catalysts
1−3 (selected examples, Figure 1) also have been reported by
In a recent study toward the regioselective Alder−ene
reaction of unsymmetrical 1,4-substituted 1,3-butadiynes, the
cyclotrimerization of the diynes was observed as a side
reaction.7 Interestingly, up to 12 regioisomers, eight unsym-
metrical and four symmetrical regioisomers (see Supporting
Information) are possible when starting from unsymmetrical
disubstituted 1,3-butadiynes.
Figure 1. Air-stable cyclopentadienylcobalt(I) catalysts.
Based on these results, our approach for this study was the
(a) identification of the formed regioisomers, (b) optimization
of the reaction conditions, and if possible, (c) regioselective
Gandon and Hapke, who were able to catalyze the
cocyclotrimerization reaction of alkynes and nitriles for the
synthesis of pyridine derivatives under relatively mild
conditions with good to excellent yields and regioselectivities.5
Our group has reported a “low-budget” cobalt catalyst
system, composed of cobalt(II) bromide, zinc, and zinc iodide,
Received: April 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01281
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
formation of only one regioisomer by altering the ligands and
solvents. Our initial optimization started with 1,3-butadiyne 6
as the test substrate, and fortunately, out of the 12 possible
isomers, only two isomers, 7 and 8, were formed, luckily
because the cyclotrimerization took place exclusively at the
triple bond adjacent to the arene moiety and not at the triple
bond next to the trimethylsilyl group. The results of the
optimization process are summarized in Table 1, and the
increasing the reaction temperature to 60 °C resulted in
complete conversion of the starting material combined with a
very good regioselectivity of rr (7/8) = 97:3 (entry 7). The
ligand dppm was also tested but gave inferior results (entry 5).
Eventually, we identified THF as the solvent of choice because
complete conversion and an exclusive regioselectivity were
observed (entry 8), which led to the product 7 in 97−99%
isolated yield, the latter on a 2.0 g scale. Unfortunately, the
solvent effect obtained for simple alkynes could not be
reproduced with unsymmetrical 1,3-diynes when diamine or
disulfide ligands were applied in THF (entries 9 and 10) and
remains an unsolved problem for the future to generate one of
the symmetrical isomers as the main product (for further
information, see the SI).
Table 1. Optimization of the Reaction Conditions
With the optimized reaction conditions in hand, the steric
effects of the trimethylsilyl residue on the starting material 6
were investigated next. The trimethylsilyl residue was altered
to contain simple alkyl substituents (9a−c) with increasing
steric hindrance (Table 2).
Table 2. Sterical Effects of the Alkyne Residue toward the
Chemo- and Regioselectivity of the Cyclotrimerization
a
conversion (%)
no.
ligand
none
Cy2(diimine)
py-imine
dppe
dppm
dppe
dppe
dppe
solvent, temp., time
(ratio 7/8)
1
2
3
4
5
6
7
8
9
CH3CN, 25 °C 18 h
CH3CN, 25 °C 18 h
CH3CN, 25 °C 18 h
CH3CN, 25 °C 18 h
CH3CN, 60 °C 18 h
CH2Cl2, 40 °C 72 h
CH3CN, 60 °C 18 h
THF, 60 °C 18 h
99 (69:31)
90 (63:37)
86 (65:35)
0, −
69 (74:26)
30 (nd)
99 (97:3)
99 (99:1) isolated: 99%
99 (64:36)
0, −
a
no. 1,3-diyne
R
conv (%) yield (%) detectable isomers
b
1
2
3
9a
9b
9c
Et
i-Pr
t-Bu
>99
>99
>99
99
98
99
7
7
1
Cy2(diimine)
disulfide
THF, 60 °C 72 h
THF, 60 °C 72 h
b
10
a
Reaction conditions: cobalt catalyst (5 mol %), Zn, ZnI2 (10 mol %
a
Reaction conditions: CoBr2(dppe) (5 mol %), Zn, ZnI2 (10 mol %
each), 1,3-butadiyne (0.30 mmol, 1.0 equiv), solvent (0.3 mL).
Conversion and ratio were determined by 19F NMR spectroscopy. For
a detailed table of optimization, see the SI. Cy2(diimin) =
dicyclohexylethane-1,2-diimine; py-imine = N-mesityl-1-(pyridin-2-
yl)methanimine, dppe = 1,2-bis(diphenylphosphino)ethane, dppm =
1,1-bis(diphenylphosphino)methane, disulfide = 1,2-bis(4-
methoxyphenyl)thio)ethane.
each), 1,3-diyne 9a−c (3.0 mmol), THF (3.0 mL).The conversion
b
was detected by 19F NMR spectroscopy. The number of isomers
were detected by 19F NMR spectroscopy. The products were obtained
as an inseparable mixture of regioisomers.
For all starting materials, complete conversions could be
observed, and the isolated yields were excellent as well.
However, the ethyl and isopropyl residues in 9a and 9b gave a
complex mixture of regioisomers, consisting of up to seven
isomers which could be detected by 19F NMR spectroscopy
(see the SI) (entries 1 and 2). Nevertheless, when a tert-butyl
residue was used (9c), again, only a single regioisomer was
observed and the unsymmetrical product 10c could be isolated
in an excellent yield of 99% (entry 3). Accordingly, we
rationalized that only steric interactions of the substituents on
the 1,3-butadiyne are responsible for the chemoselectivity
(reaction on the less hindered triple bond) as well as for the
regioselectivity, which prohibits the formation of a cobaltacycle
intermediate with a steric bulky substituent bonded directly to
the cobaltacycle.
choice for a 4-fluorophenyl substituent in 6 proved to be of
high value as the ratios of starting material to products as well
as the ratios of the products (7/8) could be easily evaluated by
19F NMR on the crude reaction mixture as well as for the
purified compounds.
Based on the previous study for the cyclotrimerization of
alkynes, we tested a number of solvents to investigate if the
solvent effect (see Tables S1 and S2) to alter the
regioselectivity could also be seen in the present reactions.
In the ligand-free reaction in acetonitrile, already complete
conversion could be observed, although the regioselectivity was
only moderate in favor of 7. The use of imine-type ligands
(entries 2 and 3) improved neither the yield nor the
regioselectivity. Surprisingly, the standard conditions for the
Alder−ene reaction with dppe as ligand gave no conversion in
acetonitrile (entry 3), while in dichloromethane as solvent only
30% conversion could be observed (entry 6). However,
After these preliminary investigations concerning the most
efficient catalyst and the steric hindrance effect, we investigated
several unsymmetrical 1,3-butadiynes as reactants, and the
results are summarized in Scheme 2.
B
DOI: 10.1021/acs.orglett.9b01281
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Organic Letters
Letter
Scheme 2. Unsymmetrical 1,3-Butadiynes Applied in the Cobalt-Catalyzed Cyctotrimerization
Scheme 3. Symmetrical 1,3-Butadiynes in the Cobalt-Catalyzed [2 + 2 + 2] Cyclotrimerization Reaction
C
DOI: 10.1021/acs.orglett.9b01281
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
First, the cobalt-catalyzed cyclotrimerization reaction was
performed on a larger scale to illustrate that this method can be
applied for the synthesis of gram amounts of the product 7a,
which was isolated in an undiminished yield of 99%.
Thereafter, as an alteration of the previous study, the 4-
fluorobenzene substituent in the 1,3-butadiyne 6a was varied
toward the three possible methoxybenzene-substituted diynes
to generate the products 12a−c. All of these reactions
proceeded well and gave yields between 86 and 97%. If the
4- and 3-methoxybenzene residues were used, an excellent
yield of 97% and a somewhat lower yield of 87% were
obtained, respectively. In case of the 2-methoxybenzene
derivative 12c, a product mixture consisting of different
isomers was observed (87% yield of all isomers). For once, due
to its increased steric hindrance at the 2-position, the alkyne
subunit next to the trimethylsilyl-substituted alkyne could be
involved in the [2 + 2 + 2] cycloaddition process leading to
other chemoisomers. On the other hand, the free rotation of
the 2-methoxybenzene substituent is hindered, leading to a
number of diastereomers (see the SI). Unfortunately, it was
neither possible to separate the chemo- or regioisomers via
column chromatography nor to obtain a significantly reduced
number of NMR signals for the methoxy protons at elevated
temperatures. Because of this observation, the 1,3-butadiyne
with a triisopropylsilane group was reacted under the
optimized reaction conditions. In addition, in this reaction,
the chemo- and/or regioselectivity could not be forced toward
the formation of a single isomer. Nevertheless, in this case, a
separation of the desired isomer was possible so that the
product 12d could be isolated in 15% yield (total yield of all
isomers: 78%).
bis(trimethylsilyl)-1,3-butadiyne (13k) were used. The corre-
sponding products 14j and 14k were isolated in only 50 and
30% yield, respectively, but while 14k was generated as a single
regioisomer in a very slow reaction (after 72 h still
incomplete), the alkyl-substituted derivative 14j gave a 2:1
mixture of the two regioisomers. When substituents in the 2-
position of the aryl subunit were applied, the cyclotrimeriza-
tion products 14l and 14m were also obtained in good to
1
excellent yields. However, the H and 13C NMR data show a
large number of isomers which are most likely attributed to
diastereomers, as mentioned above. High-temperature NMR
spectra (up to 100 °C, see SI) were inconclusive because the
number of signals were reduced but still too high for all arene
subunits rotating unhindered (six signals for the methyl groups
1
in H NMR for 14l and six signals for the methoxy groups in
14m as was found for 14h and 14i). The formation of the
corresponding symmetrical 1,3,5-regioisomer 15l/15m is
possible but unlikely based on all other results obtained in
this study. In addition, the symmetrical isomers 15l and 15m
cannot account for the number of signals observed for the
methyl (14l) and the methoxy protons (14m).10
In conclusion, we were able to react symmetrical and
unsymmetrical 1,3-butadiynes toward the unsymmetrical
cyclotrimerization product as soon as the steric difference of
the substituents at position 1 and 4 of the 1,3-butadiyne were
significant toward the unsymmetrical chemo- and regioisomers
of type 12 and 14 in good to excellent yields. Fortunately, the
cobalt-catalyzed cyclotrimerization reaction of unsymmetrical
butadiynes generated a single isomer out of 12 possible
isomers; however, the alteration of the chemo- and
regioselectivity toward a 1,3,5-regioisomer could not be
accomplished.
Accordingly, we rationalize that the product mixture of 12c
most likely consisted of chemoisomers where both double
bonds are incorporated in the [2 + 2 + 2] cycloaddition
reaction. Thereafter, an alkyl-substituted 1,3-butadiyne was
reacted to generate the product 12e as a single chemo- and
regioisomer in 91% yield, which also indicates that the steric
hindrance is of high importance in these reactions.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01281.
Finally, we investigated symmetric substituted 1,3-diynes in
the cobalt-catalyzed cyclotrimerization reaction. As far as we
know, mostly symmetrical 1,4-diaryl-substituted 1,3-butadiyne
derivatives have been applied in cobalt-catalyzed [2 + 2 + 2]
cycloaddition reactions utilizing CpCo-type catalysts reported
in a small number of publications over the last decades.8 In the
present [2 + 2 + 2] cycloaddition reaction with diyne 13, only
two isomers (14 and 15) are possible (Scheme 3). At first, the
optimized reaction conditions were confirmed with 1,3-diyne
13b as test substrate. It could be shown by 19F NMR
spectroscopy that the optimized reaction conditions for
unsymmetrical diynes of type 3 also work well with
symmetrical substituted 1,3-diynes of type 13 (for a detailed
optimization, see the SI). Next, we examined different 1,3-
butadiynes in the cycloaddition reaction (Scheme 3).
A variety of unsymmetrical products of type 14 could be
obtained in good to excellent yields (73−99%) and excellent
regioselectivity (>99:1), outperforming the results obtained
with Co2(CO)8- or CpCo-type catalysts.8 While a large
number of functional groups on the aryl substituents in the
3- and 4-positions were well tolerated, it should be noted that
the nitro group inhibited the cyclotrimerization completely
(14g, 0%). One reason could be the very low solubility of the
starting material in organic solvents.9 The only drawback was
encountered when the substrates deca-4,6-diyne (13j) and 1,4-
Experimental procedures, analytical data, NMR spectra
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: gerhard.hilt@uni-oldenburg.de.
ORCID
Gerhard Hilt: 0000-0002-5279-3378
Notes
The authors declare no competing financial interest.
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