Silver-Catalyzed N-H Functionalization of Aryl/Aryl Diazoalkanes with Anilines

Article abstract of DOI:10.1021/acs.orglett.1c02289

Herein, we report on the N-H functionalization reaction of primary and secondary anilines with diaryldiazoalkanes using simple AgPF6 as catalyst. We demonstrated broad applicability in the reaction of diaryldiazoalkanes with different anilines (31 examples, up to 97% yield). Furthermore, we propose a possible reaction mechanism for the N-H functionalization.

Full text of DOI:10.1021/acs.orglett.1c02289

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Letter
Silver-Catalyzed N−H Functionalization of Aryl/Aryl Diazoalkanes
with Anilines
Feifei He,† Claire Empel,† and Rene M. Koenigs*
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ABSTRACT: Herein, we report on the N−H functionalization reaction of primary and secondary anilines with diaryldiazoalkanes
using simple AgPF6 as catalyst. We demonstrated broad applicability in the reaction of diaryldiazoalkanes with different anilines (31
examples, up to 97% yield). Furthermore, we propose a possible reaction mechanism for the N−H functionalization.
Our group reported on the metal-free reactions of aryl/aryl
arbon−nitrogen bonds are one of the most important
Ccarbon−heteroatom bonds and can be found in organic diazoalkanes, which allows access to three different reaction
pathways depending on the electronic properties of the
diazoalkanes under photochemical conditions (Figure 1a, 6−
8)8a or a benzhydryl cation under Brønsted acid-catalyzed
conditions that can be used in C−H functionalization.8b
Despite the significance of amination reactions in organic
synthesis, studies on the N−H functionalization of aniline
derivatives with aryl/aryl diazoalkanes are rare. In 2020, Che et
al. investigated Fe-porphyrin complexes in diaryl carbene
transfer reactions. Using a large excess (10 equiv) of the
reaction partner (9a), the corresponding N−H functionaliza-
tion products (10a) were obtained in moderate to excellent
yield and a good functional group tolerance after 12 h reaction
time.9a Apart from Che’s work, previous reports are frequently
limited to singular examplesoften as part of studies on
acceptor-only or donor/acceptor diazoalkanes (Figure 1b).9
Therefore, studies on the N−H insertion reaction of aryl/
aryl diazoalkanes are highly demanded as these would provide
insight into the reactivity of aryl/aryl diazoalkanes in X−H
functionalization reactions and provide applications for the
introduction of a benzhydryl amine protecting groups.10
Based on our interest in carbene chemistry11 and N−H
functionalization reactions via carbene intermediates,12 we
became intrigued in studying the N−H insertion reactions of
aryl/aryl diazoalkanes (Figure 1c). We therefore studied the
compounds across all disciplines, from natural products to
drugs and materials. The development of efficient methods for
the construction of this bond is thus of ongoing interest in
organic synthesis methodology.1 In particular, amination
reactions under mild and environmentally benign reaction
conditions are attractive as they bear the potential for the
direct amination of complex molecules.2 One approach toward
this goal harnesses reactive intermediates, such as carbenes that
allow for the direct amination of primary and secondary
amines.3 The carbene itself can be readily obtained by
decomposition reaction of diazoalkanes under metal-catalyzed,
thermal, or photochemical reaction conditions.5 In the
majority of studies, either acceptor or donor/acceptor type
diazoalkanes were employed,4,5 whereas aryl/aryl diazoalkanes
remained underexplored and underestimated. Only until
recently, applications of such aryl/aryl diazoalkanes remained
rare and often only single experiments were reported. First,
more general applications of these were reported in early 2020.
Aryl/aryl diazoalkanes are of particular interest as they allow
the introduction of a diarylmethylene unit onto organic
building blocks. In this context, the Davies group reported
on asymmetric Rh-catalyzed cyclopropanation reactions of
aryl/aryl diazoalkanes and uncovered a marked influence of the
substitution pattern of the aromatic rings on the stereo-
selectivity of the cyclopropanation reaction (Figure 1a, 4).6a
Furthermore, the Davies and Stahl groups reported on a
copper-catalyzed aerobic oxidation of hydrazones to the
corresponding aryl/aryl diazoalkanes and subsequent trapping
of the aryl/aryl diazoalkane with acetic acid.6b In a different
approach, the Zhou7a and the Franz7b groups studied Rh-
catalyzed asymmetric Si−H insertion reactions (Figure 1a, 5).
Received: July 8, 2021
https://doi.org/10.1021/acs.orglett.1c02289
© XXXX American Chemical Society
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Table 1. Reaction Optimization
a
b
entry
catalyst
yield
c
1
2
3
4
[Ru(p-cymene)Cl2]2
PdCl2
Rh2(OAc)4
CuOTf
JohnPhos(AuCl)
B(C6F5)3
AgPF6
no reaction
traces
dec of 1a
29%
20%
15%
d
5
6
7
8
84%
86%
e
AgPF6
9
aq. HPF6
no reaction
a
Reaction conditions: In an oven-dried test tube, catalyst (3 mol %)
was put under vacuum and flushed with Argon for three times. Dry,
degassed DCM (0.5 mL) was added. Aniline 9a (0.4 mmol) and aryl/
aryl-diazo 1a (0.2 mmol) was dissolved in 0.5 mL of dry, degassed
DCM and added to the reaction mixture in one portion. The reaction
mixture was stirred at rt until the aryl/aryl diazo 1a was consumed.
b
c
Isolated reaction yield of 10a. Both staring materials were
d
e
recovered. NaBArF4 (5 mol %) was used as an additive. A 1:1
stoichiometry of aniline 9a and aryl/aryl-diazo 1a was used. dec =
decomposition
rationalized by an acid base reaction between the Brønsted
acid catalyst and aniline 9a that shuts down catalytic activity of
the Brønsted acid (Table 1, entry 9).
With the optimized conditions in hand, we next studied
different anilines 9 in the reaction with diphenyl diazomethane
1a (Scheme 1). Different electron-donating, electron-with-
drawing substituents and halogens were well tolerated in all
positions of the aromatic ring of 9, and the corresponding N−
H functionalization products 10a−o were isolated in high
yield. We observed slightly reduced reaction yields in the case
of ortho-substituted anilines, which can be reasoned by
increased sterical hindrance due to the ortho substituent
(10k−o). Moreover, 1-naphtylamine and benzo[d][1,3]dioxol-
5-amine proved compatible with the present reaction
conditions and the products were formed in 68% and 56%,
respectively (10p,q). Additionally, we investigated the syn-
thesis of 10a on a 1 mmol scale, and to our delight we were
able to isolate 10a in slightly reduced yield (78%).
Next, we investigated different aryl/aryl diazoalkanes 1 in
the reaction with aniline 9a. Electron-donating and chloro
substituents were well tolerated in all positions of the aromatic
ring (10r−w). Overall, we observed slightly reduced yields
compared to the unsubstituted diazoalkane 1a. When
introducing electron-withdrawing substituents instead of
electron-donating substituents, we observed a strong depend-
ence of the position of the substituent, while a 3-nitro
substituent was well tolerated, a 4-nitro substituent reduced
the yield significantly (10x−z). This observation could be
reasoned by the mesomeric effect of the nitro group leading to
an activation of diphenyl diazomethane 1x and subsequent
higher reaction yield compared to unsubstituted diphenyl
diazomethane 1a (97% vs 86%, respectively). Furthermore, 4-
nitro substituted diphenyl diazomethanes 1y,z deactivated the
diazoalkane and longer reaction times and lower yields were
observed (Scheme 1).
Figure 1. Application of diaryl carbenes in organic synthesis.
reaction of diphenyl diazomethane 1a with aniline 9a in the
presence of different metal catalysts or under photochemical
conditions (for details, please see the Supporting Information
(SI), Table S1).
However, carbene transfer catalysts based on rhodium, gold,
copper, ruthenium or palladium did not provide the desired
product in reasonable yield (Table 1, entries 1−5). In the case
of JohnPhos(AuCl) and CuOTf, the N−H functionalization
product 10a was formed in low yield and the diazine was
formed as the major byproduct (Table 1, entries 4 and 5). In a
next step, we investigated the borane-catalyzed reaction, using
B(C6F5)3 as catalyst we isolated the N−H functionalization
product in 15% yield after reaction overnight (Table 1, entry
6). Unexpectedly, simple AgPF6 proved highly efficient and the
reaction was completed after only 10 min of reaction time at
ambient temperature and we were able to isolate 10a in 84%
yield (Table 1, entry 7). Intrigued by the promising results
using AgPF6 as catalyst, we further investigated different silver
salts, catalyst loadings, solvents and the stoichiometry of the
model reaction (for details, please see the SI, Table S1).13
However, no further improvement of the reaction yield was
obtained. A 1:1 stoichiometry of 1a and 9a in DCM as solvent
proved optimal to yield the product 10a in 86% yield (Table 1,
entry 8). To evaluate the participation of HPF6 as a hidden
Brønsted acid catalyst, we investigated HPF6 as a catalyst. Yet,
even after 24 h of reaction time, we did not observe any
reaction and both starting materials remained untouched. This
excludes the participation of HPF6 as catalyst, which can be
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substituted N-methyl aniline, the reaction yield decreased
significantly and the products were isolated in moderate yield
(12e,f) (Scheme 2).
Scheme 1. Scope of Different Primary Anilines and Aryl/
Aryl Diazoalkanes
Scheme 2. Scope of Different Secondary Anilines
When studying aliphatic primary and secondary amines,
indole, or carbazole in this silver-catalyzed transformation
(13a−e), we did not observe the desired reaction product.
Instead, we observed the decomposition of the diazoalkane 1a.
Furthermore, we investigated cyclohexanol (14a), phenol
(14b), thiophenol (15a), and allyl mercaptan (15b) in O−H
and S−H insertion reactions, respectively. However, we did
not observe any product formation and diazoalkane 1a
decomposed to a complex mixture of byproducts (Scheme 2).
Based on literature precedence,7,14 we propose a reaction
mechanism that involves stabilization of the silver salt by
Lewis-basic amine (I)15 that can undergo formation of a silver
carbene complex III. Hydrogen bonding of aniline to the
carbene carbon results in the formation of intermediate IV,
which can further react to intermediate V. It should be noted
that the aniline molecule can potentially be both delivered
intra- and intermolecularly in this reaction. In a last step, the
silver carbon bond is cleaved, releasing the desired product 10a
and the catalytically active species I (Scheme 3). Based on the
proposed mechanism longer reaction times for secondary
anilines 11 can be reasoned by a slower formation of the
hydrogen bonding complex IV and subsequent slower C−N
bond forming reaction to form intermediate V. Furthermore,
sterically demanding substituents suppress the formation of V,
especially when secondary anilines are investigated which is in
line with the experimental results.
a
NMR yield due to inseparable mixture of N−H functionalization
product and byproducts.
In further studies, we investigated secondary aniline
derivatives. However, N-methyl aniline 11a proved much less
reactive and gave a significantly lower yield of the N−H
functionalization product 12a under the optimized conditions
after 24 h reaction time. Byproducts arise from decomposition
of the diazoalkane 1a, and we therefore decided to use a slow
addition protocol (24 h addition time) and 2 equiv of aniline
11a. With this adapted procedure, we were able to isolate 12a
in 66% yield. We then investigated different N-alkyl and N-aryl
anilines in the reaction with diazoalkane 1a. Sterically less
demanding substituents were compatible with the reaction
conditions, and the corresponding products were isolated in
moderate to high yield (12b−d). When sterically more
demanding groups were introduced, e.g., ortho methyl
In summary, we developed a method for the efficient N−H
functionalization reaction of primary and secondary anilines
with aryl/aryl diazoalkanes using a simple silver salt as catalyst.
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Author Contributions
†F.H. and C.E. contributed equally to this work.
Scheme 3. Proposed Reaction Mechanism
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
R.M.K. thanks the German Science Foundation for financial
support. F.H. gratefully acknowledges the China Scholarship
Council for generous support. C.E. thanks the Fonds der
Chemischen Industrie for a Kekulé scholarship.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02289.
Full experimental data for all compounds, experimental
procedures, characterizations, and analytical data (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Rene M. Koenigs − Institute of Organic Chemistry, RWTH
Aachen University, D-52074 Aachen, Germany;
orcid.org/0000-0003-0247-4384; Email: rene.koenigs@
rwth-aachen.de
Authors
Feifei He − Institute of Organic Chemistry, RWTH Aachen
University, D-52074 Aachen, Germany
Claire Empel − Institute of Organic Chemistry, RWTH
Aachen University, D-52074 Aachen, Germany
Complete contact information is available at:
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