Manganese(I)-Catalyzed C-H Aminocarbonylation of Heteroarenes

Article abstract of DOI:10.1002/anie.201507087

A versatile manganese(I) catalyst was employed in C-H aminocarbonylation reactions of heteroarenes with aryl as well as with alkyl isocyanates using a removable directing group approach. Detailed experimental mechanistic studies were suggestive of an organometallic C-H manganesation step, followed by a rate-determining migratory insertion. Heteroaromatic amides were obtained by a step-economical, manganese(I)-catalyzed C-H aminocarbonylation reaction between heteroarenes and aryl and alkyl isocyanates. The catalytic cycle was initiated by a facile organometallic C-H manganesation step, followed by a rate-determining migratory insertion.

Full text of DOI:10.1002/anie.201507087

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201507087
German Edition: DOI: 10.1002/ange.201507087
À
C H Activation
Manganese(I)-Catalyzed C–H Aminocarbonylation of Heteroarenes
Weiping Liu, Jonas Bang, Yujiao Zhang, and Lutz Ackermann*
Dedicated to Professor Paul Knochel on the occasion of his 60th birthday
Abstract: A versatile manganese(I) catalyst was employed in
At the outset of our studies, we tested reaction conditions
À
À
C H aminocarbonylation reactions of heteroarenes with aryl
for the C H aminocarbonylation of indole 1a with isocyanate
as well as with alkyl isocyanates using a removable directing
group approach. Detailed experimental mechanistic studies
2a (Table 1). The desired product 3aa could be obtained with
[Mn2(CO)10] as the catalyst using toluene as the solvent
(entry 1). In contrast to recent cobalt-catalyzed
À
were suggestive of an organometallic C H manganesation step,
approaches,[4,5] the manganese-catalyzed C H aminocarbo-
À
followed by a rate-determining migratory insertion.
nylation also occurred in the absence of any additional ligands
or additives. Although the catalytic efficacy was only slightly
À
T
he direct utilization of otherwise inert C H bonds as latent
functional groups has received considerable attention,
because it avoids the use of prefunctionalized substrates.[1]
In this context, over the last decade powerful transition-metal
À
catalysts for C H activation have been developed, which have
enabled a streamlining of organic synthesis.[1] For instance, the
step-economical assembly of aryl amides proved viable
À
through C H functionalizations using easily accessible iso-
cyanates,[2] with key contributions by the groups of Kuninobu/
Takai, Bergman/Ellman, Cheng, Li, and our group.[3] Reac-
tions of this type could be successfully achieved using
catalysts derived from the versatile, yet rather expensive, 4d
or 5d transition metals rhodium, rhenium, or ruthenium. In
contrast, only two very recent reports by us[4] and Ellman
et al.[5] highlighted the potential of more naturally abundant
À
Figure 1. Manganese-catalyzed C H aminocarbonylation.
À
Table 1: Optimization of the manganese-catalyzed C H aminocarbony-
lation.[a]
À
3d cobalt complexes for C H aminocarbonylation reactions.
Despite this considerable advance, the approach was limited
to complexes employing the relatively expensive Cp*CoIII
motif (Cp* = pentamethylcyclopentadienyl).
Although manganese is the third most abundant transition
Entry
Catalyst
Additive
Solvent
T [8C]
Yield [%][b]
metal, organometallic[6–8] C H functionalization reactions
À
1
2
3
4
5
6
7
8
[Mn2(CO)10]
[Mn2(CO)10]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[Mn2(CO)10]
[Mn2(CO)10]
[Mn2(CO)10]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[MnBr(CO)5]
[Mn2(CO)10]
–
–
PhMe
PhMe
PhMe
PhMe
PhMe
Et2O
1,4-dioxane
DME
Et2O
PhMe
THF
MTBE
nBu2O
Et2O
120
120
120
120
120
100
100
100
100
120
100
100
100
100
100
100
100
100
100
56[c]
47[c]
70[c]
79[c]
<3[c]
76
with manganese complexes are unfortunately scarce,[9]
despite notable recent progress from the groups of Kuni-
nobu/Takai[10] and Wang[11] as well as from our group.[12]
Within our program on sustainable catalysis,[13] we have now
developed an expedient chelation-assisted manganese-cata-
NaOAc
NaOAc
NEt3
PPh3
NaOAc
NaOAc
NaOAc
NaOAc
–
–
–
–
–
–
–
–
–
–
33[d]
14[d]
84
61
78
80
91
95
83
89
–
–
–
À
lyzed C H aminocarbonylation, on which we report herein.
Notable features of our findings include: i) an unusually
broad substrate scope featuring challenging sterically bulky
alkyl isocyanates; ii) the use of synthetically useful removable
directing groups (rDG);[14,15] and iii) a detailed mechanistic
insight into the working mode of the catalysts (Figure 1).
9
10
11
12
13
14
15
16
17
18
19
–
Et2O
Et2O
Et2O
[*] W. Liu, J. Bang, Y. Zhang, Prof. Dr. L. Ackermann
Institut für Organische und Biomolekulare Chemie
Georg-August-Universität Gçttingen
MnCl2
Mn(OAc)2
Et2O
Tammannstrasse 2, 37077 Gçttingen (Germany)
E-mail: Lutz.Ackermann@chemie.uni-goettingen.de
Homepage: http://www.ackermann.chemie.uni-goettingen.de/
[a] Reaction conditions: 1a (0.50 mmol), 2a (0.55 mmol), [Mn]
(10 mol%), additive (20 mol%), solvent (1.0 mL), 1008C, 16 h. [b] Yield
of isolated product. [c] 2a (1.0 mmol). [d] NMR conversion with CH2Br2
as the internal standard. DME=1,2-dimethoxyethane; MTBE=methyl-
tert-butyl ether; py=pyridyl.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201507087.
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improved with [MnBr(CO)5] as the catalyst in the presence of
À
a tertiary amine (entries 2–5), the most effective C H amino-
carbonylations were achieved with ethereal solvents
(entries 6–13. Optimal results were, hence, obtained in
ethers as the solvent with [MnBr(CO)5] as the catalyst of
choice (entries 12–16). Furthermore, test reactions clearly
À
showed that the C H functionalization did not occur in the
absence of the catalyst or when employing simple manganese
salts (entries 17–19).
With the optimized catalytic system in hand (Table 1,
À
entries 13 and 14), we explored its versatility in the C H
functionalization of indole 1a (Scheme 1). Using these
À
Scheme 2. Manganese-catalyzed C H activation with indoles 1 and
pyrroles 4. [a] nBu2O used as solvent.
À
Scheme 1. Manganese-catalyzed C H aminocarbonylation with isocya-
nates 2. [a] nBu2O used as solvent.
the aminocarbonylation of substrate 4b chemoselectively
delivered the mono-functionalized pyrrole 5ba as the sole
product.
reaction conditions, a variety of substituted aryl isocyanates
2 was smoothly converted into the corresponding products 3.
The reaction conditions demonstrated considerable tolerance
of valuable functional groups, such as alkyl or aryl halides. It is
important to note that the manganese(I) catalyst also proved
applicable to more challenging electron-rich alkyl isocyanates
2. Intriguingly, in contrast to the cobalt(III)-catalyzed reac-
tion,[4,5] even isocyanate 2m bearing a sterically hindered
In light of the unique features of the manganese-catalyzed
À
C H aminocarbonylation reaction, we sought to delineate the
mode of action of the catalyst. To this end, we performed
reactions with isotopically-labeled substrates (Scheme 3).
First, we found that manganese-catalyzed H/D exchange
was facile in this system.[16] In agreement with this finding,
only a minor kinetic isotope effect (KIE) was found in
independent reactions using either substrate 1a or the
monolabeled analogue [D1]-1a (Scheme 3b). These observa-
À
secondary alkyl group underwent the C H functionalization,
with the product obtained in a synthetically useful yield.
Likewise, the congested ortho-substituted aryl isocyanate 2n
and the heteroaromatic substrate 2o were converted with
high catalytic efficacy.
À
tions are indicative of a fast and reversible C H mangane-
sation process.
Intermolecular competition experiments revealed elec-
tron-deficient isocyanates 2 and electron-rich indoles 1 to be
Moreover, diversely decorated indoles 1 proved to be
À
amenable for the site-selective C H functionalization process
À
(Scheme 2). The C H aminocarbonylation reaction was
shown to be highly chemoselective, as reflected by the
smooth conversion of indoles bearing bromo, iodo, ester, or
ketone groups, among others. Sterically encumbered sub-
strates 1j and 1k featuring substituents in the C3 position
were also found to be suitable substrates. Notably, the
manganese(I) catalyst was not limited to indole substrates,
À
but pyrroles 4 underwent the C H functionalization with
comparable levels of catalytic efficacy. It is noteworthy that
Scheme 3. Studies with isotopically labeled compounds.
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Scheme 4. Intermolecular competition experiments.
inherently most reactive (Scheme 4), which can be rational-
ized in terms of a rate-determining nucleophilic attack of the
metallated indole on the coordinated isocyanate electrophile
2.
Scheme 6. Proposed catalytic cycle.
Additionally, evidence for an organometallic activation
À
mode was gathered by successful manganese(I)-catalyzed C
H functionalizations under either an atmosphere of air or in
the presence of stoichiometric amounts of the radical
scavenger 2,2,6,6,-tetramethylpiperidine-N-oxide (TEMPO;
Scheme 5).
Scheme 5. Evidence supporting an organometallic activation mode for
À
the C H functionalization process.
Overall, our experimental mechanistic studies are sugges-
À
tive of a fast C H manganesation, which is followed by
coordination of the isocyanate 2 to the thus formed cyclo-
metalated complex 7 (Scheme 6). Thereafter, coordination
and rate-determining isocyanate insertion generates inter-
mediate 9. Finally, proto-demetalation liberates the desired
product 3 and regenerates the catalytically active manganese-
(I) complex.
À
Scheme 7. Diversification of C H activation products. Reagents and
conditions: i) 1-Fluoro-2-nitrobenzene, Cs2CO3, CH3CN, 908C, 12 h.
ii) CuI (cat.), l-proline (cat.), NaH, DMF, 1508C, mw, 5 min.
À
The synthetic utility of the manganese(I)-catalyzed C H
aminocarbonylation strategy was illustrated by devising
a powerful procedure for the traceless removal of the pyridyl
directing group (Scheme 7a). Moreover, the late-stage diver-
sification of amides 10 provided versatile access to valuable
quinoxalinones 11 in a step-economical manner (Scheme 7b).
In summary, we have reported the first manganese-
optimized manganese(I) catalyst was highly functional-group
À
tolerant and allowed for C H functionalizations on syntheti-
cally useful heteroarenes with ample scope. Detailed mech-
anistic studies provided strong evidence for an organometallic
À
C H manganesation, along with a rate-determining migra-
À
catalyzed aminocarbonylation by C H bond activation. The
tory isocyanate insertion step.
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(FP7 2007-2013)/ERC Grant agreement no. 307535, and the
Chinese Scholarship Program (fellowship to W.L.) is grate-
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Keywords: C–H activation · indoles · isocyanates · manganese ·
reaction mechanisms
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Angew. Chem. 2015, 127, 14343–14346
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Received: July 30, 2015
Published online: September 29, 2015
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