Mechanochemical Iridium(III)-Catalyzed C-H Bond Amidation of Benzamides with Sulfonyl Azides under Solvent-Free Conditions in a Ball Mill

Article abstract of DOI:10.1002/anie.201511689

Mechanochemical conditions have been applied to an iridium(III)-catalyzed C-H bond amidation process for the first time. In the absence of solvent, the mechanochemical activation enables the formation of an iridium species that catalyzes the ortho-selective amidation of benzamides with sulfonyl azides as the nitrogen source. As the reaction proceeds in the absence of organic solvents without external heating and yields the desired products in excellent yields within short reaction times, this method constitutes a powerful, fast, and environmentally benign alternative to the common solvent-based standard approaches.

Full text of DOI:10.1002/anie.201511689

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International Edition: DOI: 10.1002/anie.201511689
À
C H Amidations Very Important Paper
German Edition:
DOI: 10.1002/ange.201511689
À
Mechanochemical Iridium(III)-Catalyzed C H Bond Amidation of
Benzamides with Sulfonyl Azides under Solvent-Free Conditions in
a Ball Mill
Gary N. Hermann, Peter Becker, and Carsten Bolm*
Dedicated to Professor Dieter Enders on the occasion of his 70th birthday
Abstract: Mechanochemical conditions have been applied to
copper-catalyzed coupling of aryl boronic acids with amines
under mechanochemical conditions that was recently devel-
oped by Su and co-workers, which yielded the corresponding
products in a significantly shorter reaction times than the
solvent-based standard procedure.[9,10] Our group reported
À
an iridium(III)-catalyzed C H bond amidation process for the
first time. In the absence of solvent, the mechanochemical
activation enables the formation of an iridium species that
catalyzes the ortho-selective amidation of benzamides with
sulfonyl azides as the nitrogen source. As the reaction proceeds
in the absence of organic solvents without external heating and
yields the desired products in excellent yields within short
reaction times, this method constitutes a powerful, fast, and
environmentally benign alternative to the common solvent-
based standard approaches.
À
the first catalytic mechanochemical C H bond functionaliza-
tion process under solvent-free conditions that proceeds via
an active RhIII intermediate catalyzing an oxidative Heck-
type olefination process of acetanilides and olefins with
dioxygen as terminal oxidant (Scheme 1a).[11]
III
À
Inspired by the reports on Ir -catalyzed C H bond
functionalization[6] and encouraged by our previous work, we
wondered whether adequately substituted aromatic com-
pounds would undergo mechanochemically induced IrIII-
catalyzed amidation reactions in ball mills under solvent-
free conditions. Herein, we report the implementation of this
concept (Scheme 1b).
T
he introduction of nitrogen-containing moieties into
organic molecules is one of the key transformations of
modern organic synthesis,[1] as various nitrogen functional
groups are most common in natural products, agrochemicals,
and pharmaceutically relevant compounds.[2] In recent years,
À
direct transition-metal-catalyzed C H functionalization pro-
For our investigations, Changꢀs method for the amidation
of benzamides was chosen as the starting point.[6b] Thus,
N-(tert-butyl)benzamide (1a) and phenylmethanesulfonyl
azide (2a) were treated with a combination of [{Cp*IrCl2}2]
(2.5 mol%) and AgBF4 (10 mol%) as the catalyst and
AgOAc (20 mol%) as an additive in a mixer mill. Confirming
our hypothesis, after milling the reaction mixture with two
milling balls (0.5 cm diameter) for 99 min at 30 Hz, the
amidated product 3a had been formed in 38% yield
(determined by 1H NMR spectroscopy; Table 1, entry 1).
Next, the influence of the number and size of the milling balls
was investigated (entries 2–4). When only one large milling
ball (1.5 cm) was used instead of two smaller ones (0.5 cm),
the yield of 3a increased to 80% (entry 3). The use of an even
larger ball (2.0 cm) did not improve the yield further (entry 4;
72%). Next, the substrate amounts were varied. Using an
excess of benzamide 1a resulted in a slightly higher yield of
3a (entry 5; 87%). When the amount of 1a was increased
further, almost no change in yield was observed (entry 6;
cesses of unactivated aromatic compounds were established
as straightforward and elegant ways to form a great variety of
new carbon–carbon or carbon–heteroatom bonds. In this
context, Chang and others[3–6] have reported transition-metal-
À
catalyzed C N bond formation reactions using azides as the
nitrogen source where dinitrogen is formed as the sole
byproduct. For such transformations, IrIII catalysts were
particularly effective in activating aromatic compounds with
weakly coordinating directing groups in the ortho position.[6]
Unfortunately, however, most procedures involve the use of
significant amounts of solvents, which reduces the overall
sustainability of the processes.
In the past decade, advanced ball-milling applications
have been established, enabling the mechanochemical acti-
vation of a large variety of organic transformations.[7]
Compared to common solvent-based methods, mechano-
chemically induced processes often have various advantages,
such as higher yields, shorter reaction times, lower catalyst
loadings, and the possibility of performing reactions in the
absence of organic solvents.[8] An illustrative example is the
[*] G. N. Hermann, P. Becker, Prof. Dr. C. Bolm
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: carsten.bolm@oc.rwth-aachen.de
Homepage: http://bolm.oc.rwth-aachen.de/
À
Supporting information for this article can be found under http://dx.
doi.org/10.1002/anie.201511689.
Scheme 1. C H bond functionalization under mechanochemical con-
ditions (DG=directing group).
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Table 1: Optimization of the IrIII-catalyzed amidation of benzamides
under mechanochemical conditions.[a]
Entry
Additive
(mol%)
1a
[equiv]
2a
[equiv]
Ball size
[cm]
3a[b]
[%]
1
2
3
4
5
6
7
8
9
AgOAc (20)
AgOAc (20)
AgOAc (20)
AgOAc (20)
AgOAc (20)
AgOAc (20)
–
AgOAc (10)
AgOAc (5)
NaOAc (10)
CsOAc (10)
Cu(OAc)2 (10)
1.0
1.0
1.0
1.0
1.7
1.8
1.7
1.7
1.7
1.7
1.7
1.7
1.5
1.5
1.5
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2”0.5
2”1.5
1.5
38
77
80
72
87
83
24
87
60
1
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
10
11
12
3
79
1.5
[a] Reaction conditions: [{Cp*IrCl2}2] (12.0 mg, 0.015 mmol, 2.5 mol%),
AgBF4 (12.0 mg, 0.06 mmol, 10 mol%), 30 Hz; the Retsch cryo mill,
vessel (25 mL), and balls were made of ZrO2. [b] Determined by 1H NMR
spectroscopy with 1,3,5-trimethoxybenzene as the internal standard.
Bn=benzyl, Cp*=pentamethylcyclopentadienyl.
83%). Performing the reaction in the absence of AgOAc
strongly affected the process, and 3a was formed in only 24%
yield (entry 7). However, decreasing the amount of AgOAc
from 20 mol% to 10 mol% did not affected the reaction
outcome, and 3a was obtained in 87% yield (entry 8).
However, with 5 mol% of AgOAc, the yield of 3a decreased
to 60% (entry 9). Replacing AgOAc with NaOAc or CsOAc
was not possible (entries 10 and 11). In contrast, the use of
Cu(OAc)2 led to product 3a in 79% yield (entry 12). These
results confirm observations by Ackermann and others,[12]
who found that the nature of the acetate plays an important
À
role in directed C H-bond functionalizations, and apparently,
this effect is also relevant in mechanochemically activated
processes performed under solvent-free conditions.
Three aspects of the IrIII-catalyzed amidation process
should be highlighted: First, because of the mechanochemical
activation, the reaction could be performed under solvent-
free conditions, generating the amidated products in high
yields. Second, the reaction time for full conversion of the
substrate was significantly shorter (99 min) than for the
standard method in an organic solvent (12 h), and third, no
external heating was required to form the desired products.[13]
Next, the substrate scope of the IrIII-catalyzed amidation
under mechanochemical conditions was investigated
(Scheme 2). Various sulfonyl azides performed well in the
reaction with 1a, affording the corresponding products 3a–3d
in yields ranging from 87% to 97%. Electronic effects played
only a minor role. Furthermore, butane-1-sulfonyl azide (2e)
and naphthalene-2-sulfonyl azide (2 f) reacted satisfyingly,
providing products 3e and 3 f, respectively, in 66% yield each.
To investigate the influence of substituents at the benzamide
core, sulfonyl azide 2a was reacted with substrates with an
electron-donating methyl or methoxy group in the para
III
À
Scheme 2. Substrate scope of the mechanochemical Ir -catalyzed C H
amidation. [a] Obtained as a 1.28:1 regioisomeric mixture.
position. Both transformations provided the corresponding
products in high yields (3g: 90%; 3h: 87%). The same was
true when tosyl azide was used in the reaction with the
4-methyl-substituted benzamide. Again, the product was
obtained in high yield (3i: 92%). A 1.28:1 regioisomeric
mixture of 3j was formed in 57% yield when 3-methoxy-
substituted benzamide 1j reacted with 2a. The analogous
transformation of a benzamide with a 3-bromo group
provided 3k as a single regioisomer in 42% yield. Starting
from 4-halogen-bearing benzamides and 2a, the correspond-
ing products 3l–3n were obtained in good yields of 79%,
72%, and 83%. In contrast, the reaction between 4-trifluoro-
methyl-substituted substrate 1o and 2a gave 3o in only
moderate yield (49%), which could be due to the strongly
electron-withdrawing effect of the CF3 substituent. Remark-
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ably, the reaction remained efficient when the substituent at
the amide nitrogen atom was changed from tert-butyl to
n-butyl, isopropyl, or cyclohexyl. In each case, the desired
product (3p–3r) was obtained in good yield (65–87%).
To gain insight into the mechanochemically promoted
reaction pathway, preliminary mechanistic studies were
carried out. First, the kinetic isotopic effect (KIE) was
determined in an intermolecular competition experiment
with [D5]-1a/[H5]-1a and 2a (Scheme 3a).[14] For the solvent-
free process presented here, a KIE of 1.2 was observed. This
value differs significantly from the KIE of 3.4 that was
determined for a similar reaction in solution.[6b,15] Apparently,
a change in mechanism has occurred, leading to fast, non-
Scheme 4. Formation of iridacycle complex 4 and its catalytic reactiv-
ity.
À
turnover-limiting C H bond cleavage under the applied
(solvent-free) mechanochemical conditions. Analyzing the
reasons for this unexpected behavior will be the focus of
future work.
mides in a mixer mill. The active catalyst is formed in situ, and
the amidated products were obtained in high yields and after
shorter reaction times than in solution.
Experimental Section
Representative procedure: Benzamide 1 (1.02 mmol, 1.7 equiv),
sulfonyl azide
2 (0.6 mmol, 1.0 equiv), [{Cp*IrCl2}2] (12.0 mg,
0.015 mmol, 2.5 mol%), AgBF4 (12.0 mg, 0.06 mmol, 10 mol%),
and AgOAc (10.0 mg, 0.016 mmol, 10 mol%) were transferred to
a ball-milling vessel (ZrO2, 25 mL) containing one grinding ball
(ZrO2, diameter: 1.5 cm). The ball-milling vessel was then transferred
to a mixer mill (RETSCH cryo mill), and the reaction mixture was
milled at 30 Hz for 99 min. The crude reaction mixture was extracted
by washing the vessel and the ball with EtOAc (5 ” 20 mL), and the
resulting mixture was filtered through a thin layer of SiO2 and
concentrated. The product was then isolated by flash column
chromatography on silica gel (n-pentane/EtOAc). To decrease the
amount of solvent used for the extraction of the reaction mixture
from the vessel, the crude product can alternatively be taken up by
adding sea sand (2 ” 1 g) to the ball-milling vessel and milling the
resulting mixture for 5 min (” 2). The amount of solvent utilized for
the purification can thus be reduced, and 3a was obtained in 83%
yield.[17]
Scheme 3. Intermolecular competition experiments performed under
mechanochemical conditions.
Acknowledgements
Intermolecular competition experiments with the differ-
ently substituted sulfonyl azides 2b/2c (Scheme 3b) and
benzamides 1h/1l (Scheme 3c) revealed a slightly lower
reactivity for electron-rich azide 2b than for 2c and a strong
preference for the more electron-rich benzamide 1h over 1l,
confirming that the cationic iridium species acts as an
electrophile in the activation process.[5b]
We thank RWTH Aachen University for support through the
Distinguished Professorship Program, which is funded by the
Excellence Initiative of the German federal and state govern-
ments.
À
Keywords: ball mill · C H amidations · iridium catalysis ·
mechanochemistry · solvent-free reactions
Taking the solvent-based procedure as a guideline,[16] the
stable cyclometalated iridium complex 4 was prepared in the
absence of solvent using a mixer mill (Scheme 4a). Complex 4
was then treated with AgSbF6 (20 mol%) and AgOAc
(10 mol%) and used as a catalyst (5 mol%) in the mecha-
nochemical ortho amidation of 1a with 2a. After 99 min,
product 3a was obtained in 94% yield, confirming the
cyclometalated iridium species (complex 4) to be an inter-
How to cite: Angew. Chem. Int. Ed. 2016, 55, 3781–3784
Angew. Chem. 2016, 128, 3845–3848
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Received: December 16, 2015
Published online: February 15, 2016
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