Copper-catalyzed carbonylative transformations of indoles with hexaketocyclohexane

Article abstract of DOI:10.1039/c8cc01784k

With hexaketocyclohexane octahydrate as the carbon monoxide source, a novel procedure for copper-catalyzed direct double carbonylation of indoles has been established. Using alcohols as reaction partners, moderate to good yields of the desired double carbonylation products have been obtained. Wide functional group tolerance and substrate scope can be observed.

Full text of DOI:10.1039/c8cc01784k

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Copper-Catalyzed Carbonylative Transformations of Indoles with
Hexaketocyclohexane
Zechao Wang, Zhiping Yin, and Xiao-Feng Wu*
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Straße 29a, 18059 Rostock (Germany).
Ag
2
CO
3
were variated (Table 1, entries 8-11). Surprisingly, 5 equiva-
CO gave the best result (Table 1, entry 10). In order to
ABSTRACT: With hexaketocyclohexane octahydrate as the carbon
monoxide source, a novel procedure on copper-catalyzed direct double
carbonylation of indoles has been established. Using alcohols as the
reaction partners, moderate to good yields of the desired double car-
bonylated products have been obtained. Wide functional groups toler-
ance and substrates scope can be observed.
lents of Ag
2
3
further improve the reaction outcome, the effects of acids were investi-
gated as well (Table 1, entries 12-16). TFA can improve the yield of the
double carbonylated to 40% (Table 1, entry 16), whereas HOAc,
PivOH, PhCOOH, and CH
3
SO H were all found to be inferior. In the
3
loading variation of TFA, 4 equivalents of TFA can give the highest
yield of 3a (Table 1, entries 17-19). In addition, a series of copper
catalysts and palladium catalysts were tested as well (Table 1, entries
Transition-metal-catalyzed carbonylation reactions have already be-
come one of the most powerful toolbox in modern organic chemis-
try.[ Up to date, most of the efforts were focused on the mono car-
bonylation processes. While the double carbonylation with introducing
two adjacent carbonyl groups into organic molecules has been less
explored.[ The challenge is come from the insertion of the second
molecular of carbon monoxide into the acyl-metal intermediate, which
is more trend to go reductive elimination or nucleophilic attract.
Hence, in the reported achievements, besides need palladium as the
catalysts, usually high CO pressure (> 50 bar) are necessary together
21-28). When using CuBr(Me S) as the catalyst and 1,10-Phen. as the
2
ligand (see the Supporting Information), we can obtain the highest
yield of 3a (69%; Table 1, entry 24). Subsequently, various commonly
applied solvents were tested as well, such as HFIP (hexafluoroisopro-
1]
panol), H O, HOAc, DMSO (dimethyl sulfoxide), toluene, DCE (1,2-
2
2]
dichloroethane), DMF (N,N-dimethylmethanamide), 1,4-dioxane, and
THF (tetrahydrofuran), no better results could be obtained (see the
Supporting Information). Then loading of catalyst system, methanol
and C
decreased (see the Supporting Information). Interestingly, Mo(CO)
and CO (1 bar) was applied instead of C ∙8H O in the model reac-
6
O
6
∙8H
2
O were variated as well, the yields of the target product
6
[
3]
with using aryl iodides as the substrates.
6
O
6
2
tion, but only trace amount of the desired product could be detected.
Additionally, although carbon monoxide is considered as one of the
cheapest C1 sources and hold non-replaceable advantages in industrial
scale applications, its special characters (eg., high toxicity, smell-less,
flammable, and etc.) limited its usage in laboratories. Those properties
also make special equipments (CO detector, autoclave, etc.) obligato-
ry. Hence, the developing of CO surrogates and explore their synthetic
applications become a new branch in chemistry research.[4] The known
CO surrogates have common problems including low efficiency, low
stability and/or high activating energy, etc. In our efforts on CO
a
Table 1. Optimization of the reaction conditions.
[
5]
b
sources research, hexaketocyclohexane octahydrate comes into our
Entry
1
Oxidant
Ag CO
Acid
-
Catalyst
Yield (%)
mind.[ Hexaketocyclohexane octahydrate (C
6]
O
∙8H O) is a kind of
6
6
2
[
7]
non-toxic stable solid. It was originally produced by oligomerization
of carbon monoxide, can be considered as six folds of carbon monoxide
2
3
Cu(OAc)
Cu(OAc)
2
2
23
2
3
4
5
6
7
8
9
K
2
S
2
O
8
-
0
0
(C
6
6
O ∙≈ 6 × CO) with 100% of atom efficiency as CO source. Due to
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
2
2
2
2
BQ
-
the ring of hexaketocyclohexane is highly strained; it can potentially
8
decompose to CO in the reaction solution. If it’s the case, the CO
O
2
-
0
concentration in the real solution can be significantly increased without
affecting the catalyst center. And new reactivities can potentially be
observed which are difficult in the case with pressurized carbon mon-
oxide gas.
AgOAc
AgOTf
AgTFA
-
trace
trace
trace
25
-
-
Our initial investigation was started with the reaction of indole (1a)
Ag
Ag
Ag
Ag
2
2
2
2
CO
CO
CO
CO
3
3
3
3
(3 eq.)
(4 eq.)
(5 eq.)
(6 eq.)
-
and methanol (2a), in the presence of C
of Cu(OAc) and Ag CO (1 equiv.) in CH
delight, 23% of the double carbonylation product 3a was formed after
0 hours (Table 1, entry 1). Based on this initial finding, various oxi-
dants such as K , BQ (1,4-benzoquinone), O , AgOAc, AgOTf,
6
O
6
∙8H
2
O (1 equiv.), 15 mol%
CN at 80 C. To our
-
30
o
2
2
3
3
1
0
-
36
2
11
-
35
2
S
2
O
8
2
1 c
2
Ag
Ag
2
CO
CO
3
HOAc
PivOH
26
AgTFA were tested subsequently. Unfortunately, none of them could
give improved results (Table 1, entries 2-7). Then the amounts of
1 c
3
30
2
3

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DOI: 10.1039/C8CC01784K
a
1 c
1 c
1 c
1 c
1 c
1 c
4
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
Ag
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
CO
PhCOOH
CH SO
TFA
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
Cu(OAc)
2
2
2
2
2
2
2
36
Table 2. Double Carbonylation of Indole with Alcohols.
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
5
3
3
H
27
40
6
7
TFA (3 eq.)
TFA (4 eq.)
TFA (5 eq.)
TFA
41
8
46
9
40
2
2
2
2
2
2
2
2
0d
1d
2d
3d
4d
5d
6d
7d
8d
55
TFA
CuBr
2
52
TFA
CuCl
2
54
TFA
CuI
58 (57)
69 (67)
48
TFA
CuBr(Me
2
S)
TFA
Cu(acac)
Pd(OAc)
PdCl
Pd(TFA)
2
TFA
2
58
TFA
2
58
2
TFA
2
56
a
Reaction conditions: Indole 1a (0.2 mmol, 1 equiv.), methanol 2a (6
∙8H O (0.2 mmol, 1 equiv.), oxidant (0.2
mmol, 1 equiv.), acid (0.2 mmol, 1 equiv.), and catalyst (0.03 mmol, 15
mmol, 30 equiv.), C
6
O
6
2
o
mol %) in CH
3
CN (1 mL) for 20 h at 80 C in sealed tubes under air.
b
Yields were determined by GC using n-hexadecane as the internal
c
standard. Isolated yield is in parenthesis. Ag
2
CO
(1 mmol, 5 equiv.), TFA (0.8 mmol, 4 equiv.), and 1,10-phen
0.06 mmol, 30 mol%).
3
(1 mmol, 5 equiv.).
d
Ag
2
CO
3
(
With the optimized conditions in hand (Table1, entry 24), a screen-
ing of different alcohols was performed subsequently. As shown in
Table 2, various primary and secondary alcohols worked well under our
reaction conditions and gave the corresponding double carbonylation
products in moderate to good yields. However, tertiary alcohols such as
tert-butanol and tert-amyl alcohol gives only trace amount of the de-
sired double carbonylation products. To our delight, benzylic alcohols
can be applied under our reaction conditions as well to give the corre-
sponding products in moderate yields without any further optimiza-
tion.
Successively, various indoles were investigated for further extending
the substrates scope (Table 3). To our delight, a series of functional
groups, such as OMe, Ph, CF , Cl, and Br were compatible under our
3
conditions, which gave the desired double carbonylation products 4 in
moderate to good isolated yields. 2-Phenyl substituted indole can be
transformed as well, 42% yield of the desired methyl 2-oxo-2-(2-
phenyl-1H-indol-3-yl)acetate was isolated (4f). Unfortunately, no
target product could be detected when COOMe group substituted at
aReaction conditions: Indole 1a (0.2 mmol, 1 equiv.), alcohols 2 (6
mmol, 30 equiv.), C ∙8H O (0.2 mmol, 1 equiv.), Cu(Me S) (0.03
mmol, 15 mol %), 1,10-phen (0.06 mmol, 30 mol %), Ag CO (1
CN (1 mL), 20 h, 80
2
-position of indole. Comparing 4g with 4i, we found that the yield of
6
O
6
2
2
double carbonylation products could be decreased when 4-position of
indole substituted, which can be explained by the steric hindered
effects. Not only N-H free indoles, but also N-Me substituted indole
can be applied.
2
3
mmol, 5 equiv.), TFA (0.2mmol, 1 equiv.), CH
3
o
C, air, isolated yield.
In order to get some understandings of the reaction pathway, control
experiments were carried out. We found hexaketocyclohexane octahy-
o
drate is stable at 80 C in MeCN in the absence of catalyst (Scheme 1,
eq. a). Carbon monoxide gas can be detected after the addition of
Ag
2
CO (Scheme 1, eq. b). However, by performing the model system
3
under CO gas (1 bar) with standard conditions, only trace amount of
methyl 2-(1H-indol-3-yl)-2-oxoacetate could be detected (Scheme 1,
eq. c).

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a
Table 3. Double Carbonylation of Indoles with Methanol.
Scheme 2. Control Experiments.
aReaction conditions: Indoles 1 (0.2 mmol, 1 equiv.), methanol 2a (6
mmol, 30 equiv.), C ∙8H O (0.2 mmol, 1 equiv.), Cu(Me S) (0.03
mmol, 15 mol %), 1,10-phen (0.06 mmol, 30 mol %), Ag CO (1
CN (1 mL), 20 h, 80
The possibility that involves glyoxal as the intermediate can be ex-
cluded by the experiment shown in Scheme 2, eq. d. In the absence of
indole, under standard conditions, butyl formate can be detected in
GC-MS (Scheme 2, eq. e). Based on our results, a possible reaction
pathway is proposed (Scheme 3). In the presence of catalyst and alco-
hol, hexaketocyclohexane octahydrate was transformed into CO and
the corresponding alkyl formate via carboalkoxy complex C intermedi-
ate. The presence of TFA can promote the formation of intermediate
6
O
6
2
2
2
3
mmol, 5 equiv.), TFA (0.2mmol, 1 equiv.), CH
3
o
C, air, isolated yield.
Here, it’s also important to mention that monocarbonylation prod-
uct can be detected in some cases during the optimization process. In
order to extend the usage of hexaketocyclohexane octahydrate as CO
source, we performed further studies to increase the yield of monocar-
bonylation product. To our delight, the monocarbonylation product 5a
9
A. Then the complex A reacted with CO to give the acyl intermediate
B. After transmetalation with carboalkoxy complex C, the key interme-
1
0
diate D will be formed, which can produce the final double carbonyla-
tion product after reductive elimination. As alkyl formate and the
carboalkoxy complex C further decomposed into CO and alcohol
under high temperature, hence only monocarbonylation product was
produced from the reaction between the complex B and alcohol.
can be obtained in 46% yield by using chlorobenzene as the solvent at
o
1
30 C for 20 hours (Scheme 1).
Scheme 1. Cu-catalyzed monocarbonylation of indole.
Scheme 3. Proposed reaction pathway.
In summary, a novel procedure on copper-catalyzed double car-
bonylation of indoles with alcohols via C-H bond functionalization has

ChemComm
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DOI: 10.1039/C8CC01784K
been developed. With hexaketocyclohexane octahydrate as the CO
source, moderate to good yields of the desired products were pro-
(6) Hexaketocyclohexane octahydrate, CAS Number: 527-31-1
(
7) a) G. Seitz, P. Imming, Chem. Rev. 1992, 92, 1227-1260; b) R. B. Wyrwas, C.
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duced. And monocarbonylation can be realized as well. C
been explored as an efficient CO source for the first time.
6
O
6
∙8H O has
2
(
Spectrometry, 1999, 188, 17-25; b) X. Bao, X. Zhou, C. F. Lovitt, A. Venkatra-
man, D. A. Hrovat, R. Gleiter, R. Hoffmann, W. T. Borden, J. Am. Chem. Soc.
2
012, 134, 10259-10270.
ASSOCIATED CONTENT
Supporting Information
(9) Z. Wang, Z. Yin and X.-F. Wu, Org. Lett., 2017, 19, 4680-4683.
General procedures, analytic data and NMR spectrums (PDF)
(10) a) P. L. Burk, D. Van Engen, and K. S. Campo, Organometallics, 1984, 3,
4
93-495; b) E. Amadio, Z. Freixa, P. W. N. M. van Leeuwen, L. Toniolo, Catal.
Sci. Technol., 2015, 5, 2856-2864.
AUTHOR INFORMATION
Corresponding Author
E-mail: xiao-feng.wu@catalysis.de
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the Chinese Scholarship Council for financial Support. We
thank the analytical department of Leibniz-Institute for Catalysis at the
University of Rostock for their excellent analytical service here. We
appreciate the general support from Professor Armin Bo r̈ ner and
Professor Matthias Beller in LIKAT.
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