Control over Organometallic Intermediate Enables Cp?Co(III) Catalyzed Switchable Cyclization to Quinolines and Indoles

Article abstract of DOI:10.1021/acscatal.6b00367

Achieving controllable C-H functionalization to elaborate valuable compounds from simple chemicals is attractive and highly desirable, especially if nonprecious transition metal catalysts can be used. However, controlling selectivity in these transformations remains a continuous challenge to synthetic chemists. Herein, we show for the first time that control over the reactive organometallic intermediate enables the switchable synthesis of quinoline and indole from amides and alkynes through C-H activation using Cp?Co(III). The keys to this strategy are (1) introducing a Lewis acid to greatly accelerate the dehydrative cyclization, which can outcompete dehydrogenative cyclization, and (2) tuning the directing group to facilitate the dehydrogenative cyclization and inhibit dehydrative cyclization.

Full text of DOI:10.1021/acscatal.6b00367

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Letter
Control Over Organometallic Intermediate Enables Cp*Co(III)
Catalyzed Switchable Cyclization to Quinolines and Indoles
Qingquan Lu, Suhelen Vásquez-Céspedes, Tobias Gensch, and Frank Glorius
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00367 • Publication Date (Web): 01 Mar 2016
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Control Over Organometallic Intermediate Enables Cp*Co(III)
Catalyzed Switchable Cyclization to Quinolines and Indoles
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Qingquan Lu, Suhelen Vásquez-Céspedes, Tobias Gensch, and Frank Glorius*
Organisch-Chemisches Institut Westfälische Wilhelms-Universität Münster Corrensstraße 40, 48149 Münster
(Germany)
quinolines and indoles has not been accomplished.11-12 The
major difficulty of this transformation is the high reactivity of
ABSTRACT: Achieving controllable C–H functionalization
to elaborate valuable compounds from simple chemicals is
the organometallic intermediate II generated in situ, render-
attractive and highly desirable, especially if non-precious
ing the following cyclization processes uncontrollable.
transition metal catalysts can be used. However, controlling
selectivity in these transformations remains a continuous
challenge to synthetic chemists. Herein, we show for the first
time that control over the reactive organometallic intermedi-
ate enables the switchable synthesis of quinoline and indole
from amides and alkynes through C–H activation using
Cp*Co(III). The keys to this strategy are: 1) introducing a
Lewis acid to greatly accelerate the dehydrative cyclization,
which can out-compete dehydrogenative cyclization; 2) tun-
ing the directing group to facilitate the dehydrogenative cy-
clization and inhibit dehydrative cyclization.
KEYWORDS: cobalt catalysis, C−H bond activation, switch-
able selectivity, dehydrative cyclization, dehydrogenative
cyclization
Scheme 1. Retrosynthetic analysis of quinolines and
indoles from amides and alkynes through C–H acti-
vation
Recent reports showed that cationic Cp*Co(III) complexes
might be more oxophilic than other transition metal com-
Catalysis is a key technology for organic synthesis, and the
plexes such as Cp*Rh(III) and can be utilized to achieve un-
conventional cyclization or oxidative coupling reactions.4a
development of more sustainable, efficient catalysts has be-
come particularly important in modern chemistry.1 More
We questioned whether a well-defined Cp*Co(III) system
recently, first row transition-metal catalysts have attracted
could offer the possibility to address the above-mentioned
more organic chemists not only due to their unique reactivi-
issues through identification of the selective cyclization pro-
ty, but also their lower toxicity, low cost, and abundant re-
cesses. A proposed pathways for the switchable synthesis of
serves.2 In this regard, cobalt catalysis has gained prominent
quinolines and indoles is outlined in Scheme 2. After initial
attention,3 and of particular interest is the high-valent cobalt
cyclometalation and alkyne insertion, an eight-membered
catalyst Cp*Co(III).3c,3d The high valence of the cobalt cata-
lyst has proven to be effective for enabling cascade bond
organometallic intermediate II is generated. It is well known
that the eight-membered organometallic intermediate II is
highly reactive,13 which could undergo intramolecular nucle-
construction reactions that are usually elusive and difficult to
achieve by other transition metals, as demonstrated by the
ophilic addition to C=O and further dehydration to furnish
groups of Matsunaga and Kanai,4 Ackermann,5 Ellman,6
quinoline. In contrast, a six-membered organometallic in-
Chang,7 Glorius8 and others.9 On this basis, we speculated
that this innovative catalysis might serve as an alternative
termediate IV can be formed through isomerization of II,
which then undergoes a C–N reductive elimination to form
route to address some formidable issues faced in C–H bond
indole. Ultimately, the relative reaction rates of dehydrative
functionalization.
cyclization and dehydrogenative cyclization will determine
the final product distribution. Thus, control over the selec-
tivity would be accomplished if the reactivity of the interme-
diate II can be adjusted by elegant methods. On this basis,
Selectivity control has always been an essential issue in or-
ganometallic chemistry,10 and the sometimes uncontrolled
reactivity of organometallic intermediates makes it more
challenging to develop highly selective and efficient C–H
we reasoned that the cooperation of Cp*Co(III) and Lewis
functionalizations. An ambitious goal is the controlled syn-
acids (LA) would improve the electrophilicity of the carbonyl
thesis of quinolines and indoles, which are privileged struc-
group and further facilitate the nucleophilic addition process.
tures in medicinal chemistry and widely present in natural
Moreover, modulation of the electronic and steric properties
products.11-12 As shown in Scheme 1, both types of molecules
of the directing group would also enable the dehydrogena-
tive process and suppress the nucleophilic attack.14 If this
can be envisioned to arise retrosynthetically from the com-
bination of amides and alkynes. Although great progress has
strategy is successful, we recognized that this new catalytic
been made in transition metal catalysis, up to date, the ex-
system might provide (1) a demonstration of a new strategy
ploration of a switchable strategy for the synthesis of both
to switch the elusive organometallic intermediate between
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dehydrative cyclization and dehydrogenative cyclization
tained with high regioselectivity. Nevertheless, aliphatic al-
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processes, (2) a direct access to quinolines by employing
simple amides and alkynes through C–H activation,15 and (3)
an undeveloped Cp*Co(III) catalyzed oxidative dehydrogena-
tive C–C/C–N cyclization reaction.
kynes or terminal alkynes, such as octyne and
phenylacetylene, were not amenable to this protocol. Fur-
thermore, a series of acetanilides substituted with electron-
donating groups (MeO, Me, n-Bu,) and electron-withdrawing
groups (F, Cl, I) proved to be well tolerated and converted to
the expected quinolines 3f-3m in moderate to good yields.
The tolerance of halides, in particular the iodo, demonstrat-
ed the potential utility of the present protocol. For meta-
substituted acetanilide, as exemplified by fluoro, the reaction
gave two regioisomers with moderate selectivity. When the
sterically hindered ortho-methyl substituted acetanilide was
employed, only trace amounts of the desired product could
be detected. Variation of the N-acyl moiety of the anilide
substrate was found to be feasible as well. Anilides bearing
not only ethyl group, but also a hydrogen, proceeded to give
the expected products 3n and 3o in moderate to good yields.
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Scheme 2. Proposed pathways for switchable cycliza-
tion to quinolines and indoles from amides and al-
kynes through C–H activation
Table 1. Substrate scope for dehydrative cyclization to
quinolinesa
[Cp*Co(CO)I2] (10 mol%)
N
R1
R3
H
N
AgSbF6 (20 mol%)
Fe(OAc)2 (10 mol%)
R1
To validate our proposed assumption, we started our in-
vestigation by reacting acetanilide (1a) with diphenylacety-
lene (2a) as the model reaction. As expected, a mixture of
quinoline 3a and indole 4a was obtained in low selectivity
and low yield when 1a and 2a were directly reacted in the
presence of [Cp*Co(CO)I2] and AgSbF6. To improve the reac-
tion efficiency, we next screened an array of bases and the
yield of quinoline 3a slightly increased to 25% employing
Fe(OAc)2. (for details, see table S1 in the supporting infor-
mation). The low reaction efficiency is attributed to the de-
activation of Cp*Co(III) through C–N reductive elimination
to form indole 4a. On the basis of our above-mentioned hy-
pothesis, the feasibility of this strategy relies on the selectivi-
ty after the alkyne insertion step. To facilitate the nucleo-
philic addition, we next attempted to use a Lewis acid to
activate the C=O bond. Accordingly, the yield of quinoline 3a
increased to 72% when BF3•OEt2 was employed. The yield of
3a further improved to 76% with high selectivity by increas-
ing the temperature to 135 oC. Subsequently, to switch the
reaction selectivity from quinoline to indole, we utilized an
external oxidant, silver oxide, to close the dehydrogenative
catalytic cycle. However, the desired indole product 4a was
obtained only in 41% yield, together with 38% yield of the
quinoline. To solve this problem, we further aimed to inhibit
the nucleophilic addition and facilitate the isomeriza-
tion/reductive elimination process by tuning the directing
group.14 Delightfully, when the methyl group in the acetani-
lide (1a) was replaced by dimethylamino group, the corre-
sponding indole product 4c was isolated in 85% yield and no
quinoline was detected by GC-MS analysis. Moreover, nei-
ther indole nor quinoline was detected when [Cp*Co(CO)I2]
was absent, revealing the vital role of Cp*Co(III) in this trans-
formation.
Ar
R2
R3
Ar
Lewis acid, DCE, 135 oC
O
R2
1
2
3
N
N
b
R = H, 3a 74%
R = Me, 3b 67%
R = Cl, 3c 56%
3d
66%
R = Me,
R = Et,
Ph
c
3e
72% (> 8:1)
R
R
F
N
R
3m 43% (5:1)d
3f
R = Me, 73%
Ph
3g
R = n-Bu,
78%
73%
R = I, 71%
N
Ph
3h
R = Ph,
3i
N
R
R
Ph
3j
R = Cl, 76%
R = F, 3k 79%
R = OMe, 3l 73%d
R = Et, 3n 63%
3o
Ph
R = H,
45%
Ph
Ph
aUnless otherwise specified, all reactions were carried out
using 1 (0.2 mmol), 2 (0.8 mmol), [Cp*Co(CO)I2] (10 mol%),
AgSbF6 (20 mol%), Fe(OAc)2 (10 mol%), and BF3•OEt2 (0.16
o
mmol) in DCE (1.0 mL) at 135 C under argon for 12 h, isolat-
ed yield. bSingle product was isolated. cMajor isomer was
shown. dB(C6F5)3 (0.16 mmol) was used and 24 h.
So far, most of the Cp*Co(III) catalyzed transformations
are limited to reactions known with established transition
metal catalysts. We next compared the reactivity of the state-
of-the-art precatalysts widely employed in C–H activation,
such as [(p-cymene)RuCl2]2, [Cp*RhCl2]2, Pd(OAc)2 and
[Cp*IrCl2]2, under otherwise identical conditions (see Table
S2 in the supporting information). All of these showed to be
inactive in this new challenging transformation and most of
the starting material remained inert after reaction, further
emphasizing the specificity of Cp*Co(III). The unique cata-
lytic efficiency of Cp*Co(III) might be attributed to its Lewis
acidity and the more nucleophilic alkenyl-Cp*CoIII species.4a
Subsequently, the generality of this protocol to synthesize
indoles was investigated. As shown in Table 2, the structure
of 4c was confirmed unambiguously by X-ray crystallograph-
ic analysis.16 Other N-phenylureas, such as, 1,1-diethyl-3-
phenylurea and N-phenylpiperidine-1-carboxamide, also dis-
play high reactivity in this protocol, affording the corre-
sponding indole products 4d and 4e in 84% and 66% yields,
respectively. Diphenylacetylenes substituted with methyl,
With the optimized reaction conditions in hand, the gen-
erality of this protocol to synthesize quinolines was first in-
vestigated and the results are given in Table 1. Diphenyla-
cetylenes bearing either electron-donating or electron-
withdrawing groups, such as p-methyl and p-chloro, effi-
ciently underwent dehydrative cyclization, giving good yields
of the desired quinolines 3b and 3c. Notably, when one of the
aromatic groups in diphenylacetylene was replaced with an
alkyl chain, the corresponding products (3d-3e) were ob-
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methoxy and chloro were viable in this transformation, fur-
indole product 4b was isolated in 53% yield while only about
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nishing the desired products 4f-4h in moderate to good
yields. The heterocyclic alkyne 1,2-bis(2-thienyl)acetylene
proved suitable for this dehydrogenative cyclization and gave
the desired product 4i in 80% yield. For unsymmetrical aryl-
alkyl substituted alkyne, the reaction proceeded smoothly
with high regioselectivity, delivering the expected product 4j
in 75% yield. Importantly, a diyne can also be successfully
utilized in this transformation, affording the corresponding
product 4k with highly selective monoannulation. Only trace
amount of the expected indole product was detected when
octyne or phenylacetylene was submitted. Furthermore, var-
ious ortho, meta and para-substituted N-arylureas were ex-
amined next. Methyl as an electron-donating group and fluo-
ro as an electron-withdrawing group did not alter the reac-
tivity of the N-arylureas, providing the desired products 4l
and 4m in 84% and 85% yields. It is particularly notable that
the meta-substituted N-arylurea gave the single product 4n
in 83% isolated yield. When methyl was located at the ortho-
position, 4o was isolated in 61% yield.
3% yield of the corresponding quinoline can be detected.
These results indicate that the bigger R1 group in cobaltacy-
cle intermediate II might hinder the dehydrative cyclization,
probably through supression of the nucleophilic addition
process. Moreover, the nucleophilic addition will be favored
for the amides due to the decreased electrophilicity of the
urea motif, as evidenced by the significant upfield shift of the
urea carbonyl carbon in 13C-NMR, relative to acetanilide. For
example, the chemical shift of the carbonyl group in N-(p-
tolyl)acetamide and 1,1-dimethyl-3-(p-tolyl)urea are 168.6 and
156.0 ppm, respectively.
To better understand the origin of the observed selectivity,
the mechanism of the alkyne insertion was studied computa-
tionally (Figure 1). Alkyne insertion in I occurs readily to
form the eight-membered cobaltacycle II. Nucleophilic at-
tack in this intermediate is favored to the acetamide (R = Me)
relative to the urea derivative (R = NMe2) by 1.7 kcal mol–1.
Isomerization to a 6-membered, N,O-chelating cobaltacycle
IV has a lower barrier by ca. 10 kcal mol–1 for either substrate.
Subsequent reductive elimination to the indole (V) is favored
for the more electron-rich urea derivative by 2.7 kcal mol–1
over the acetamide. Interestingly, from IV the acetamide
derivative has a slightly lower barrier for the isomerization
back to the 8-membered intermediate II (+31.5 kcal mol–1)
than the reductive elimination (+32.2 kcal mol–1), which
means that the overall lowest barrier for product formation is
the nucleophilic attack to the 6-membered ring III (+29.3
kcal mol–1). Based on these results, a slight preference for the
formation of quinolines over indoles should be expected
from acetanilide substrates, as opposed to a selective for-
mation of indole from arylurea. Importantly, the role of BF3
can be rationalized to decrease the high barrier for nucleo-
philic addition by coordination to II.
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Table 2. Substrate scope for dehydrogenative cyclization
to indolesa
R1
[Cp*Co(CO)I2] (10 mol%)
AgSbF6 (20 mol%)
Fe(OAc)2 (10 mol%)
O
H
N
R1
N
R2
R3
Ar
R3
Ar
O
Ag2O (1.0 equiv.)
DCE, 120 o
C
R2
1
2
4
R1 = Me,
i-Pr 4b
41%
53%
4c
4a
Me2N
O
R1
R1
=
,
O
4f
R = 4-Methoxyphenyl,
67%
R1 = NMe2,
85%
N
R
N
4i
R = 2-Thienyl, 80%
R1 = NEt2,
84%,
R = m-Methylphenyl,
4h
56%
Ph
4d
81%b, 11%c
R1 = Piperidyl,
R
Ph
4e
66%
Et2N
Et2N
O
O
N
N
R3
Cl
R2
4j
4g
77%
O
R2 = Et, R3 = Ph, 75% (> 8:1)
d
R2 = Ph, R3 = Phenylethynyl, 4k 55%
Cl
Me2N
O
Me2N
N
O
N
N
N
Ph
Ph
Ph
R
Ph
4l 84%
85%
Ph
4n 83%
Ph
4o 61%
R = Me,
R = F,
4m
aAll reactions were carried out using 1 (0.2 mmol), 2 (0.4
mmol), [Cp*Co(CO)I2] (10 mol%), AgSbF6 (20 mol%),
Fe(OAc)2 (10 mol%), and Ag2O (0.2 mmol) in DCE (1.0 mL) at
120 oC under argon for 12 h, isolated yield. b[Cp*RhCl2]2 (5
mol%) was used. c[Cp*IrCl2]2 (5 mol%) was used. dMajor
isomer was shown. The synthetic utility of this Cp*Co(III)-
catalyzed oxidative dehydrogenative cyclization strategy was
further illustrated by the removal of the carbamoyl moiety.
For example, 4c can be easily transformed into the
corresponding unprotected indole in 76% yield by a simple
operation (see Scheme S1 in the supporting information).
As mentioned above, the key cobaltacycle intermediate II,
determines the efficiency of the dehydrative cyclization or
dehydrogenative cyclization processes. When acetanilide (1a)
reacted with diphenylacetylene under the dehydrogenative
cyclization conditions, the corresponding indole 4a was iso-
lated in 41% yield while 38% yield of quinoline 3a was gener-
ated concurrently. However, when N-phenylisobutyramide
was submitted under identical condition, the corresponding
Figure 1. Free-energy profiles for two competitive reaction
pathways at the IEFPCM(1,2-DCE)/M06/6-311G**//M06-L/6-
31G**+LANL2DZ(Co) level. For details, please see the Sup-
porting Information.
In addition, a competition experiment between 1a and 1c
was conducted (Scheme 3). The result showed that the
reaction of 1c with 2a displayed a faster reaction rate than 1a
with 2a, and the ratio of the final indole products 4a and 4c
is 1:2.4. This result could serve as an experimental evidence
to support density functional theory calculations.
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AUTHOR INFORMATION
Corresponding Author
glorius@uni-muenster.de
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5
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ACKNOWLEDGMENT
This work was supported by the European Research Council
under the European Community’s Seventh Framework
Program (FP7 2007-2013)/ERC Grant agreement no 25936
and the Alexander von Humboldt Foundation (Dr. Q. Lu.).
We also thank Dr. Eric A. Standley and Dr. Christian Mück-
Lichtenfeld for helpful discussions and the ZIV
Münster/PALMA for computational resources.
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Scheme 3. Competition experiment between 1a and 1c
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Furthermore, for the dehydrative cycle, the KIE value from
the intermolecular competition experiment was 3.2 while a
kH/kD = 1.6 was observed from two parallel reactions. The KIE
results from the dehydrogenative cycle were 2.9 and 2.75,
respectively, from the corresponding intermolecular compe-
tition experiment and two parallel reactions (Scheme 4).
These results suggest that the cleavage of the C–H bond is
plausibly involved in the rate determining step.
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Scheme 4. The kinetic isotope effect (KIE)
experiments
In summary, we have successfully developed a general
strategy to control the reaction selectivity by tuning the reac-
tivity of the organometallic intermediate, in which an earth-
abundant metal catalyst and easily available chemicals are
utilized to synthesize valuable quinolines and indoles. The
significant aspects of our work are: (1) the strategy to switch
the elusive organometallic intermediate between dehydrative
cyclization or dehydrogenative cyclization processes is
demonstrated; (2) the discovery that the cooperation of
Cp*Co(III) and Lewis acid is feasible, which can efficiently
promote dehydrative cyclization reaction; (3) the vital role of
directing groups is uncovered by density functional theory
calculations and experiments; (4) the unique activity of
Cp*Co(III) is explored in comparison to other precious tran-
sition metal catalysts, which could provide useful clues for
further novel reaction design. These results provide not only
a solution for tuning the chemical-selectivity of C–H bond
transformations, and also offer valuable information for a
better understanding of Co(III) chemistry.
ASSOCIATED CONTENT
Supporting Information.
Experimental procedure, characterization data, computa-
1
tional details and copies of H and 13C NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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(16) CCDC 1441958 (4c) contains the supplementary
crystallographic data. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif since November 12. 2015.
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