A Bu4N[Fe(CO)3(NO)]-Catalyzed Hemetsberger–Knittel Indole Synthesis

Article abstract of DOI:10.1002/ejoc.201901864

The nucleophilic Fe complex Bu₄N[Fe(CO)₃(NO)] (TBA[Fe]) catalyzes the direct intramolecular amination of aryl vinyl azides to give the corresponding indole derivatives in good to excellent yields.

Full text of DOI:10.1002/ejoc.201901864

A Journal of
Accepted Article
Title: The Bu4N[Fe(CO)3(NO)]-catalyzed Hemetsberger-Knittel-indole
synthesis
Authors: Aslihan Baykal and Bernd Plietker
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10.1002/ejoc.201901864
European Journal of Organic Chemistry
COMMUNICATION
A Bu4N[Fe(CO)3(NO)]-catalyzed Hemetsberger-Knittel-indole
synthesis
Aslihan Baykal[a] and Bernd Plietker[a]*
Abstract: The nucleophilic Fe-complex Bu4N[Fe(CO)3(NO)]
(TBA[Fe]) catalyzes the direct intramolecular amination of aryl vinyl
azides to give the corresponding indole derivatives in good to
excellent yields.
Azides are useful synthetic building blocks that, after either
photochemical or thermal denitrogenation to the corresponding
nitrene, undergo a plethora of interesting transformations such
as the Curtius rearrangement of carboxylic acid azides to the
corresponding isocyanates/amines.[1,2] Although the formation of
a stable nitrene as an intermediate is under debate, the addition
of transition metal complexes leads to the formation of stable
metal nitrene complexes that were shown to be reactive in a
variety of amination reactions.[3] Aryl or alkyl azides can undergo
C-H- and C-C-bond aminations under thermal or photochemical
conditions[4], however, the field of transition metal catalyzed
activation of aryl or alkyl azides as compared to the activation of
acyl azides is comparably less developed.[3,5,6] Most recently,
iron complexes were shown to be potent catalysts for
intramolecular C-H-aminations using aryl or alkyl azides.[5,6]
Depending on the nature of the catalyst open-shell- or closed-
shell-type C-H-insertions are realized, which might open up new
ventures in the field of C-H-aminations.[6] Despite these efforts, it
Figure 1. C(sp2)-H-bond amination using azido aryl acrylates – state of
research and content of this work.
is somewhat surprising that a third class of azides, the vinyl
azides, have rarely been used in catalytic C-H-aminations.[7] This
is somewhat surprising given the fact that the starting materials
We initiated this project by employing the reaction conditions
like 1 are accessible in a straightforward manner and are known
that proved successful in the intramolecular C-H-aminations
to react under comparably mild conditions via a two-step
using aryl azides.[11]
reaction, i.e. the formation of an azirine 2 followed by its
rearrangement to the corresponding indole 3. Both reactions
differ in their temperature profile with the azirine-to-indole
rearrangement being the more endothermic one (eq. (1), Figure
1).[8] Till date only three examples for the direct conversion of
vinyl azides are reported (eq. (2), Figure 1),[9] however, several
reports on the C-H-amination using azide-derived azirines are
known.[10] Herein we report that the nucleophilic Fe-complex
Bu4N[Fe(CO)3(NO)] (TBA[Fe]) catalyzes the intramolecular
C(sp2)-H-amination of vinyl azides under mild conditions. Control
experiments indicate that we can exclude the in-situ formation of
azirines (eq. (3), Figure 1).
Much to our surprise, these conditions did not give the
desired product in good yields (entries 1 – 7, Table 1),
conversion of 1 was not complete and varying mixtures of indole
3 and amine 4 were isolated in moderate yields. Given the fact
that the reaction of azide 1 to 3 occurs via a two-step
mechanism of azirine formation at 80 °C and subsequent
thermal rearrangement at 140 °C (eq. (1), Figure 1)[8] we
decided to keep a moderate temperature of 80 °C. In the
absence of TBA[Fe], a clean formation of the azirine 2 was
observed, however, only traces of indole 3 could be isolated.
After extensive optimization we found that indole 3 was formed
in good yields of about 70 % in the presence of 10 mol-%
TBA[Fe], a concentration of 0.25 mol/l and a temperature of
80 °C. For reasons of time, these reactions can be run under
microwave irradiation within 1 h or under thermal conditions
within 24 h with no significant change in yield or selectivity (entry
9, Table 1).
[a]
[*]
M.Sc. Aslihan Baykal, Prof. Dr. Bernd Plietker,
Institut für Organische Chemie, Universität Stuttgart, Pfaffenwaldring
55, DE-70569 Stuttgart (Deutschland)
corresponding author: Prof. Dr. Bernd Plietker,
e-mail: bernd.plietker@oc.uni-stuttgart.de
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201901864
European Journal of Organic Chemistry
COMMUNICATION
Table 2. Fe-catalyzed C(sp2)-H amination using aryl vinyl azides.[a]
Table 1. Optimization of Fe-catalyzed C(sp2)-H-amination.[a]
No
substrate
product[b]
yield[b]
no
1
solvent / conc. [M]
toluene / 0.5
TBA[Fe] [mol-%]
yield [%] (3 : 4)[b]
<5 : 10
- : 9
5
1
2
3
4
5
6
7
5 (X = F)
6
65
50
58
23
18
74
73
2
DMSO / 0.5
5
7 (X = Cl)
8
3
CH2Cl2 / 0.5
5
7 : 7
9 (X = Br)
10
12
14
16
18
4
CH3CN / 0.5
5
5 : 11
11 (X = CN)
13 (X = NMe2)
15 (X = OMe)
17 (X = t-Bu)
5
DMF / 0.5
5
9 : 20
6
1,2-dichlorobenzene / 0.5
1,2-dichloroethane / 0.5
CHCl3 / 0.5
5
9 : 16
7
5
30 : 7
8
5
38 : 5
9[c]
CHCl3 / 0.25
10
70 : -
8
46
(67 : -[d]
)
19
20
[a] All reactions were performed on a 0.5 mmol scale in dry solvents [0.5 M].
[b] Yields and product distributions were determined by 1H NMR with
mesitylene as internal standard. [c] Reaction was irradiated with 300 W [d]
Yield obtained under thermal conditions: 80 °C, 24 hours in a closed vessel.
9
21 (X = Br)
22
24
26
78
82
76
The optimized conditions are applicable for the C(sp2)-H-
amination of a variety of aryl vinyl azides (Table 2). The
substitution pattern on the aromatic moiety had a major impact
on the overall yield of the reactions, e.g. p- and o-bromo
substituents led to the desired products 10 and 22 in good yields,
upon shifting the bromo-substituent into the meta-position an
erosion of the isolated yield was observed (entries (3) and (9,
versus entry 8, Table 2). +I- and/or +M-substituents lead to
higher isolated yields (entries 12 and 13, Table 2). Although
various functional groups are tolerated, electronrich nitrogen
atoms lead to low yields (entry 5, Table 2). The reaction of
pyridyl-substituted vinyl azide 35 provided some indication that
might help to understand this limitation (entry 14, Table 2). Very
much to our surprise, the pyridyl-nitrogen atom proved to be the
most reactive structural motif, giving the corresponding 3-
azoindolizine 36 in 47 % yield (entry 16, Table 2). In light of this
result, it is reasonable to assume, that electronrich nitrogen
atoms are reactive towards the in-situ activated azide. To the
best of our knowledge, this is the only metal-catalyzed example
for a direct 3-azaindolizine derivative.[12] In contrast to pyridine
derivatives, the corresponding furan derivative 33 reacted to the
corresponding annelated furanopyrrol derivative 34 in moderate
yields. Moreover, aryl vinyl azides containing ketones 39 or
amides 41 are reactive (entries 18 and 19, Table 2).
10
11
23 (X = OMe)
25 (X = Me)
12
13
86
94
28
27
29
31
30
32
14
15
16
78
41
47
33
35
34
36
17
18
37 (X = OEt)
39 (X = Ph)
38
40
80
50
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10.1002/ejoc.201901864
European Journal of Organic Chemistry
COMMUNICATION
19[c]
41 (X = N-morpholine)
42
41
informations suggest that we can exclude the in-situ formation of
azirines under the reaction conditions reported in this manuscript.
mild C(sp2)-H-amination using
nucleophilic catalyst with aryl
[a] All reactions were performed on a 0.5 mmol scale in dry CHCl3 [0.25 M]
with TBA[Fe] [10 mol-%] using microwave irradiation for 1 h at 80 °C. [b]
Isolated yield after column chromatography. [c] Reaction was performed on
a 0.2 mmol scale.
Herein, we report
Bu4N[Fe(CO)3(NO)] as
a
a
acrylazides as starting materials. These materials are readily
accessible in one step via a Knoevenagel-condensation from -
azide alkylacetates and the corresponding aldehydes. A variety
of different substrates reacted smoothly to the corresponding
indole derivatives in good to excellent yields.
A Hammett-correlation for conversion of substrates 1, 5, 7, 9,
11, 15, and 17 clearly showed that more electronrich vinyl
azides are displaying a higher reactivity (Figure 2).
0,2
0,1
0
Acknowledgements
Financial support by the Deutsche Forschungsgemeinschaft (PL
300/14-1) is gratefully acknowledged.
-0,4
-0,2
0
0,2
0,4
0,6
0,8
-0,1
-0,2
-0,3
-0,4
-0,5
-0,6
Keywords: iron • C-H activation • C(sp2)-H-amination • indole •
metal-ligand cooperation • catalysis
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Figure 2. Hammett-correlation for TBA[Fe]-catalyzed C-H amination.
[2]
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In order to shed some light into a potential mechanism, control
experiments were performed (Figure 3). Azirine 2 was formed
following literature procedures[8] and subjected to our (condition
,
A), Driver´s (condition B)[9a] and Bolm´s (condition C)[9c]
[4]
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Figure 3. C-H-amination: control experiments (conditions A: TBA[Fe] [10 mol-
%], CHCl3 [0.25 M], 80 °C; conditions B: Rh2(O2CC3F7)4 [5 mol-%], PhMe [1 M],
60 °C; conditions C: Fe(OTf)2 [10 mol-%], THF [0.5 M], 80 °C.
While TBA[Fe] did not show any reactivity, both the Rh- and the
Fe(OTf)2-catalyzed
rearrangement product 3 in low to moderate yield, indicating that
the TBA[Fe]-catalyzed transformation follows distinctive
versions
gave
the
corresponding
a
different mechanistic scenario. Treatment of o-deuterated aryl
vinyl azide 1-(o-D1) with TBA[Fe] led to a clean formation of
indole 3-(o-D/H) in 70 % yield. A small kinetic isotope effect was
observed indicating that the C-H-bond scission process might
not be the rate limiting step (eq. (2), Figure 3). These
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2688-2690.
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10.1002/ejoc.201901864
European Journal of Organic Chemistry
COMMUNICATION
COMMUNICATION
Aslihan Baykal and Bernd Plietker*
Page No. – Page No.
The Bu4N[Fe(CO)3(NO)]-catalyzed
Hemetsberger-Knittel-indole
synthesis
The anionic Fe-complex Bu4N[Fe(CO)3(NO)] catalyzes the denitrogenative C(sp3)-
H-amination of a variety of aryl vinyl azides to the corresponding indoles in good to
excellent yields.
This article is protected by copyright. All rights reserved.