Iron-Catalyzed Intramolecular C(sp2)-H Amination

Article abstract of DOI:10.1002/anie.201510045

The nucleophilic iron complex Bu₄N[Fe(CO)₃(NO)] (TBA[Fe]) catalyzes the direct intramolecular C-H amination of α-azidobiaryls and (azidoaryl)alkenes into the corresponding carbazoles and indoles, respectively, under mild conditions and with low catalyst loadings. These features and the broad functional-group tolerance render this method a particularly attractive alternative to established noble-metal-based procedures.

Full text of DOI:10.1002/anie.201510045

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International Edition: DOI: 10.1002/anie.201510045
German Edition: DOI: 10.1002/ange.201510045
Heterocycle Synthesis Very Important Paper
2
À
Iron-Catalyzed Intramolecular C(sp ) H Amination
Isabel T. Alt and Bernd Plietker*
In memory of Peter Hofmann
Abstract: The nucleophilic iron complex Bu4N[Fe(CO)3-
À
(NO)] (TBA[Fe]) catalyzes the direct intramolecular C H
amination of a-azidobiaryls and (azidoaryl)alkenes into the
corresponding carbazoles and indoles, respectively, under mild
conditions and with low catalyst loadings. These features and
the broad functional-group tolerance render this method
a particularly attractive alternative to established noble-
metal-based procedures.
À
D
espite significant progress, direct C H activation remains
to be one of the most challenging transformations in the field
of organometallic catalysis.[1] Apart from oxidative proce-
dures, the activation of diazo compounds or azides represents
an interesting alternative. Whereas the former processes
commonly require significant amounts of a stoichiometric
oxidant, N2 is formed as the sole by-product in the latter. A
variety of transition-metal-catalyzed processes for the activa-
tion of organic diazo compounds have been published;[2]
however, the corresponding electrophilic azide activation as
À
part of a C H amination has mainly been limited to noble-
metal catalysts.[3–5] Recently, the groups of Driver[4] and
Betley[5] reported efficient and elegant processes based on
(RhII)2 and FeI catalysts.
2
À
Figure 1. TBA[Fe]-catalyzed C(sp ) H amination.
For a couple of years, our group has been interested in
exploring the catalytic portfolio of the nucleophilic iron
complex Bu4N[Fe(CO)3(NO)] (TBA[Fe]).[6] We were able to
show that this electron-rich complex activates diazoesters for
catalytic carbene transfer reactions [Eq. (1), Figure 1],[6k]
a class of transformations that is commonly catalyzed by
oxidized metal salts.[2] In this context, we initiated a research
benchmark our catalytic transformation. We used the con-
ditions of the TBA[Fe]-catalyzed carbene transfer reaction[6k]
as the starting point for the reaction of azide 1 (Table 1).
Initial results were rather poor: The reaction resulted in at
least two different products, that is, the desired carbazole 2
and amine 3 (Table 1, entry 1). Further studies revealed that
solvent and ligand significantly affected the product distribu-
tion. Whereas the addition of ligands led to a decrease in
conversion, changing the solvent and adjusting the temper-
ature shifted the product distribution towards the formation
of the desired carbazole 2. The best results were obtained with
only 5 mol% of TBA[Fe] and 1,2-dichloroethane as the
solvent at a temperature of 1008C for 68 h. Importantly, only
little conversion was observed in the absence of the Fe
complex under otherwise identical reaction conditions. At
this point, we envisioned microwave irradiation to be a useful
method to accelerate the reaction through more efficient
energy transfer. Indeed, after only 1 h of microwave irradi-
ation (200 W, 1008C) at a decreased catalyst loading of
2.5 mol% under otherwise identical conditions, 1 was fully
converted, and carbazole 2 was isolated in 78% yield. Amine
3 and the diazo-coupling product that is formed by dimeriza-
tion of the nitrene ligand were observed as minor side
products. However, these products were only visible in the
1H NMR spectrum of the crude reaction mixture. Impor-
À
program aiming to develop C H activations using nucleo-
philic Fe complexes. Considering the previously reported, but
otherwise unprecedented, mode of diazoester activation, we
wondered whether this mode of action could also enable the
activation of azides. Herein, we present the successful
realization of this concept of a metal-catalyzed nucleophilic
azide activation and its application in catalytic intramolecular
2
À
C(sp ) H amination to give a variety of substituted carba-
zoles and indoles [Eq. (2), Figure 1].
Following Driverꢀs landmark reports on Rh-catalyzed
carbazole[4c] and indole[4a,b] synthesis, we chose a-azidobiaryls
as substrates in order to develop and, if successful, to
[*] M. Sc. I. T. Alt, Prof. Dr. B. Plietker
Institut für Organische Chemie, Universität Stuttgart
Pfaffenwaldring 55, 70569 Stuttgart (Germany)
E-mail: bernd.plietker@oc.uni-stuttgart.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201510045.
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Table 1: Optimization of the TBA[Fe]-catalyzed aryl C(sp ) H amina-
tion.[a]
Entry Cat. [mol%] Solvent
t [h]
T [8C] Conv. [%][b] (2/3)
1
2
3
4
5
6
7
8
9
10
10
10
10
5
5
5
2.5
1.25
0
CH2Cl2
CHCl3
1,2-DCE 16
1,2-DCE 16
1,2-DCE 16
16
16
80
80
80
100
100
100
100
100
100
100
5/5
5/5
28/5
47/<5
52/<5
71/<5
75/n.d.
79/n.d.
54/n.d.
<5/n.d.
1,2-DCE 68
1,2-DCE 1 (MW)
1,2-DCE 1 (MW)
1,2-DCE 1 (MW)
1,2-DCE 1 (MW)
10
[a] All reactions were performed on a 0.35 mmol scale in anhydrous
solvents (0.5m). [b] Conversions determined by analytical HPLC using
1,3,5-trimethoxybenzene as the internal standard. 1,2-DCE=1,2-
dichloroethane.
tantly, only traces of product were obtained under these
conditions in the absence of the Fe catalyst.
A subsequent evaluation of the scope and limitation of the
TBA[Fe]-catalyzed nitrene insertion reaction proved the
reaction to be broadly applicable (Scheme 1).
Various substituted carbazole derivatives were obtained
in good to excellent yields. Alkoxy, alkyl, and nitro groups as
well as halides were tolerated. Significant substitution effects
were observed. In particular, the position of the substituent
on the aryl moiety had a profound effect on the reactivity.
Scheme 1. TBA[Fe]-catalyzed intramolecular carbazole synthesis.
À
Whereas the azide with a methoxy group para to the C C
bond gave the desired carbazole 5 in 70% yield, the isomeric
meta-methoxy-substituted aryl azide was converted into
carbazole 8 in 35% yield. The latter product was formed as
a 7:1 mixture of regioisomers (para/ortho). These observa-
tions are in line with previous reports on similar rhodium-
catalyzed processes.[4b,c]
With these results in hand, we set out to expand the
reaction scope towards an intramolecular activation of vinyl
2
À
C(sp ) H bonds, which would lead to substituted indole
derivatives. We were pleased to find that this transformation
can be performed under essentially identical reaction con-
ditions (Scheme 2).
Various indole derivatives were obtained in a clean
cyclization reaction. Both electron-rich and electron-poor
(azidoaryl)alkenes were found to be reactive and transformed
into the corresponding indoles in good to excellent yields.
E- and Z-configured (azidoaryl)alkenes are equally reactive,
and indole 14 was isolated in 82% or 78% yield starting from
the corresponding E- or Z-configured (azidoaryl)alkene,
respectively. Moreover, even trisubstituted olefins were
reactive under these conditions.
À
The non-catalytic formal nitrene insertion into C H
bonds has been a matter of intense mechanistic investiga-
tions.[7] Most often, 2,6-(bisphenyl)arylazides were reacted,
Scheme 2. TBA[Fe]-catalyzed intramolecular indole synthesis.
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À
and the regioselectivity of the C N bond formation was
analyzed. Moderate kinetic isotope effects of about 1.9:1 were
reported.[7c] For the rhodium-catalyzed C H amination, the
À
same substrates were reacted, and a Hammett analysis was
conducted to establish a profound mechanistic proposal.[4c]
However, in our previous report on TBA[Fe]-catalyzed allylic
amination,[6c] additional ortho substitution on the aniline
derivative had been shown to inhibit the reaction, most likely
for steric reasons. Therefore, we decided to analyze potential
kinetic isotope effects by using monodeuterated aryl azide
D-1 (Scheme 3).
Figure 2. Mechanistic proposal.
which are mainly based on the use of oxidized transition-
metal catalysts. Investigations towards the amination of
3
3
À
À
C(sp ) H and C(sp ) N3 bonds are currently underway in
our laboratories.
Experimental Section
TBA[Fe] (0.009 mmol, 3.7 mg) and 1,2-dichloroethane (0.7 mL) were
added to a 10 mL microwave tube with a magnetic stir bar under N2
atmosphere. Subsequently, the azide (0.35 mmol) was added. The
reaction mixture was stirred under microwave conditions (200 W) at
1008C for 60 min. After cooling to ambient temperature and removal
of the solvent, the product was purified by column chromatography
on silica gel.
Scheme 3. Kinetic isotope effects of the TBA[Fe]-catalyzed (1), non-
catalyzed (2), and Rh-catalyzed (3) carbazole syntheses.
A moderate primary isotope effect of 1.63:1 was observed.
Interestingly, the same effect was found for the non-catalytic
thermal reaction, indicating the Fe-catalyzed process to have
a similar rate-determining step, for example, the activation or
migration of the H atom at the reactive aryl moiety. To
compare these results with the Rh-catalyzed amination
reaction developed by Driver and co-workers, we subjected
D-1 to Driverꢀs conditions and observed an isotope effect of
1.70:1. Based on the similarity of the results obtained for the
non-catalyzed and Rh- and Fe-catalyzed amination reactions,
we propose the following mechanism (Figure 2).
The [Fe(CO)3(NO)] anion I reacts with aryl azide II, with
release of N2, to iron nitrene intermediate III, which—owing
to the strong p-acceptor ligands on the metal center—
generates a partial positive charge on the ortho (or homo-
benzylic) carbon atom as visualized by the zwitterionic
mesomeric structure IV. Metal-to-ligand charge transfer sets
Acknowledgments
Financial support by the Landesgraduiertenstiftung Baden-
Württemberg (Ph.D. grant for I.A.) and the Deutsche
Forschungsgemeinschaft is gratefully acknowledged.
Keywords: azides · carbazoles · homogeneous catalysis ·
indoles · iron
How to cite: Angew. Chem. Int. Ed. 2016, 55, 1519–1522
Angew. Chem. 2016, 128, 1542–1545
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Received: October 28, 2015
Published online: December 9, 2015
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