Direct C-H amination of arenes with alkyl azides under rhodium catalysis

Article abstract of DOI:10.1002/anie.201302784

New horizons in the utility of azides: The rhodium-catalyzed intermolecular direct C-H amination of arenes with alkyl azides provides a convenient route to N-alkyl anilines (see scheme; DG=directing group). Alkyl azides with a wide range of functional groups reacted readily with various substrates, including benzamides, aromatic ketones, and flavones. Copyright

Full text of DOI:10.1002/anie.201302784

Angewandte
Chemie
Communications
Catalytic Amination
K. Shin, Y. Baek,
S. Chang*
&&&& — &&&&
New horizons in the utility of azides: The
ing group). Alkyl azides with a wide range
À
Direct C H Amination of Arenes with
Alkyl Azides under Rhodium Catalysis
rhodium-catalyzed intermolecular direct
of functional groups reacted readily with
various substrates, including benz-
amides, aromatic ketones, and flavones.
À
C H amination of arenes with alkyl
azides provides a convenient route to N-
alkyl anilines (see scheme; DG=direct-
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DOI: 10.1002/anie.201302784
Catalytic Amination
À
Direct C H Amination of Arenes with Alkyl Azides under Rhodium
Catalysis**
Kwangmin Shin, Yunjung Baek, and Sukbok Chang*
Dedicated to Professor Chul-Ho Jun on the occasion of his 60th birthday
Since the seminal study by Curtius on the use of alkyl azides in
À
organic chemistry, particularly in C N bond-forming reac-
tions, these readily available compounds have been widely
used as one of the most convenient amino sources.[1] The four
most notable examples of such reactions are the Schmidt
rearrangement,[2] the aza-Wittig reaction,[3] cycloaddition
with alkynes,[4] and the Staudinger ligation[5] (Scheme 1).
Whereas an amide bond is readily generated in the Schmidt
reaction, imine formation is facile under the aza-Wittig
conditions. The copper-mediated reaction of alkyl azides
with 1-alkynes has been well developed as a connecting tool in
various fields of research. Furthermore, alkyl azides are a key
component of the Staudinger ligation for the formation of
amides even in vivo.[6]
Despite the significant advances made in the use of alkyl
À
azides as the nitrogen source for C N bond formation, the use
of these widely available compounds in metal-mediated direct
C H amination has rarely been investigated.[7–9] Although N-
À
alkylimido (nitrenoid) metal complexes are known to be
generated,[10] the alkyl groups used are very limited even with
specially designed ligand systems. Moreover, only a few
À
examples of C N bond formation upon treatment of the
corresponding N-alkylimido metal species with hydrocarbons
have been reported.[10e,f,h] When compared to the Buchwald–
À
Scheme 1. a) Previously developed C N bond-forming reactions with
alkyl azides. b) The reaction developed in this study: a rhodium-
Hartwig amination procedure, in which (hetero)aryl halides
are treated with amines,[11] the direct C H amination of
À
À
catalyzed direct C H amination with alkyl azides. DG=directing
group, LA=Lewis acid.
(hetero)arenes displays notable advantages as
a more
À
straightforward route to C N bond formation. As a result,
À
extensive studies on direct C H amination have been carried
out, mainly with palladium[12] and copper catalysts.[13] How-
ever, amino sources are limited largely to amides, although
reaction conditions have been improved to enable the use of
During our continuing efforts to develop the direct
introduction of amino groups into (hetero)arenes with high
synthetic utility,[16] we recently reported rhodium-catalyzed
À
À
a broader range of substrates. Direct C H amination with N-
C H amination procedures with sulfonyl and aryl azides as
hydroxy-[14] and N-chloroamines has also been investiga-
ted,[13e,15] but its scope is still limited to the use of secondary
amine precursors to afford tertiary amine products.
unique amino sources.[17,18] The reactions proceed without an
external oxidant to release molecular nitrogen as the only by-
product. Although they feature broad substrate generality
with high functional-group tolerance, the installation of an
alkylamino group was also envisioned to be highly desirable,
as synthetically more important and diverse N-alkylaniline
products could be accessed directly by such an approach.
Furthermore, owing to the development of click cycloaddition
chemistry,[4] a wide range of alkyl azides are available,
including biologically relevant compounds, such as sugars
and peptides. In this context, we report herein the first
[*] K. Shin, Y. Baek, Prof. Dr. S. Chang
Center for Catalytic Hydrocarbon Functionalizations (IBS) and
Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 305-701 (Korea)
E-mail: sbchang@kaist.ac.kr
Homepage: http://sbchang.kaist.ac.kr/
À
rhodium-catalyzed direct C H amination of arenes with alkyl
azides.
[**] This research was supported financially by the Institute of Basic
Science (IBS).
We first sought an optimal catalytic system for the direct
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201302784.
À
amination of arene C H bonds with a series of benzyl and
2
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Table 1: Optimization of the reaction parameters.[a]
Entry
R
n
Catalyst (mol%)
Yield[b]
1
2
3
4
5
NH2
NMe2
OEt
1
1
1
1
1
1
1
1
1
1
2
3
4
[{RhCp*Cl2}2] (4)/AgSbF6 (16)
[{RhCp*Cl2}2] (4)/AgSbF6 (16)
[{RhCp*Cl2}2] (4)/AgSbF6 (16)
[{RhCp*Cl2}2] (4)/AgSbF6 (16)
[{RhCp*Cl2}2] (4)/AgSbF6 (16)
Pd(OTf)2 (10)
[PdCl2(MeCN)2] (10)
[Rh2(O2CCF3)4] (4)
[Rh2(O2CCF3)4] (4)
[{Ru(p-cymene)Cl2}2] (4)/AgSbF6 (16) <5
11
N.R.
N.R.
15
65 (57)
N.R.
N.R.
N.R.
N.R.
NHMe
NHtBu
NHtBu
NHtBu
NHtBu
NHtBu
NHtBu
NHtBu
NHtBu
NHtBu
6[c]
7
8
9[d]
10
11
12
13
[{RhCp*Cl2}2] (4)/AgSbF6 (16)
[{RhCp*Cl2}2] (4)/AgSbF6 (16)
[{RhCp*Cl2}2] (4)/AgSbF6 (16)
85 (77)
50
45
[a] Reaction conditions: 1 (0.36 mmol), 2 (0.2 mmol), 1,2-dichloro-
ethane (0.5 mL). [b] The yield was determined by 1H NMR spectroscopy.
Where applicable, the yield of the isolated product is given in
parentheses. [c] Na2S2O8 (1 equiv) and HOTf (0.5 equiv) were added.
[d] PhI(OAc)2 (1 equiv) was added. Cp*=pentamethylcyclopentadienyl,
N.R.=no reaction, Tf=trifluoromethanesulfonyl.
alkyl azides (Table 1). With a cationic RhIII catalyst generated
in situ from [{RhCp*Cl2}2] and a silver additive,[19] no
significant conversion was observed when primary or tertiary
benzamides were treated with benzyl azide (n = 1; Table 1,
entries 1 and 2).[20] An ester was not an effective directing
group (Table 1, entry 3). In contrast, secondary N-alkyl
benzamides were aminated in varying yields, depending on
the N-alkyl group. For example, whereas the amination of N-
methylbenzamide was sluggish and gave the desired product
in low yield (Table 1, entry 4), N-tert-butylbenzamide under-
went more efficient amination with benzyl azide (Table 1,
entry 5). Other catalytic systems known to facilitate previ-
ously described amination or amidation reactions based on
a nitrenoid-insertion pathway[12b,g] were found to be ineffec-
tive (Table 1, entries 6–10). Not only benzyl azide but also
alkyl azides (n = 2 or higher) functioned as an effective amino
source in the rhodium-catalyzed reaction (Table 1, entries 11–
13).
Scheme 2. Scope of the reaction with respect to the alkyl azide
substrate: 1a (0.36 mmol), 2 (0.2 mmol), 1,2-dichloroethane (1,2-DCE;
0.5 mL). In each case, the yield of the isolated product is given. [a] The
reaction was carried out with 1a and 2 in a 1:2 ratio at 1108C for 24 h.
On the basis of these promising results, we further
À
investigated the scope of the direct C H amination of alkyl
azides with N-tert-butyl-4-nitrobenzamide (1a) as a standard
substrate (Scheme 2). Although the amination took place
smoothly in general, benzyl azides bearing electron-with-
drawing substituents afforded the corresponding products
3aa–3ad in slightly higher yields. An excess of the azide was
used in these cases (2 equiv with respect to 1); thus, the
procedure is flexible and can be adjusted readily for the
amination of more precious substrates. As anticipated, the
electronic influence was alleviated when phenethyl azides
were used (products 3af–3ai). Alkyl azides bearing acetyl and
phthalimido groups underwent the amination in good yield to
give 3aj and 3ak, respectively. We were pleased to observe
that aliphatic azides also participated in the reaction with
similar efficiency (products 3an and 3ao).
The range of possible benzamide substrates was then
studied in the reaction with 3,5-bis(trifluoromethyl)benzyl
azide (2a; 2 equiv; Scheme 3). The reaction proceeded
smoothly to afford ortho-aminated products in moderate to
good yields, although the use of benzamides bearing electron-
donating groups led to decreased yields (e.g. in the synthesis
of 3ea and 3 fa). 2-Naphthamide was aminated at the less
hindered position to give 3da in good yield. Various func-
tional groups commonly encountered in organic synthesis
were tolerated well, such as halide (products 3ga, 3ha),
acetate (product 3ia), and aldehyde groups (product 3ja).
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shows high value, as it offers the most straightforward route to
these compounds.
One of the most striking features of the use of alkyl azides
lies in the ready access to structurally diverse compounds,
Scheme 3. Scope of the reaction with respect to the benzamide
substrate: 1 (0.2 mmol), 2a (0.4 mmol), 1,2-DCE (0.5 mL). In each
case, the yield of the isolated product is given.
Notably, the amination was efficient regardless of the N-alkyl
moiety of the secondary benzamide (products 3ka–3ma).
Encouraged by these results, we turned our attention to
additional substrates bearing weak coordinating groups. To
our delight, we observed that aromatic ketones were readily
aminated to afford synthetically useful ortho-aminoaryl
ketones (Scheme 4).[21] Aryl alkyl ketones bearing primary,
secondary, and tertiary alkyl moieties all underwent the
amination in satisfactory yields (products 6a–6d). These
results suggest that the present reaction is not influenced by
the steric bulk of the substrates. Unlike in the benzamide
substrates (Scheme 3), electronic variation of the aromatic
substituent in the aryl ketones had little effect on the reaction
efficiency (products 6e–6k). The amination reaction could be
scaled up without difficulty, as demonstrated in the produc-
tion of 6i. Benzophenone and 1-tetralone were also smoothly
aminated to give 6l and 6m, respectively. Aryl ketoximes
were also good substrates for this amination under similar
conditions, irrespective of the electronic nature of substitu-
ents on the aromatic ring (products 7a–7c).
Scheme 4. Scope of the reaction for the amination of aryl ketones and
ketoximes: 4 or 5 (0.2 mmol), 2a (0.4 mmol), 1,2-DCE (0.5 mL). In
each case, the yield of the isolated product is given. [a] The reaction
was carried out on a 5 mmol scale (with 5 mmol of 4-methoxyaceto-
phenone). [b] The reaction was carried out at 1108C. Cy=cyclohexyl.
We were pleased to find that chromone and flavones were
also aminated in synthetically acceptable yields (Scheme 5).
Since 5’-aminochromones and their flavone derivatives are
known to exhibit interesting biological activity,[22] our method
À
Scheme 5. Direct C H amination of chromone and flavones: 8
(0.2 mmol), 2a (0.4 mmol), 1,2-DCE (0.5 mL). In each case, the yield
of the isolated product is given. [a] The reaction was carried out with
4 mol% of the Rh catalyst and 16 mol% of the Ag additive.
4
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Scheme 6. Application of biologically relevant alkyl azides: 1a
(0.2 mmol), 2 (0.4 mmol), 1,2-DCE (0.5 mL). In each case, the yield of
the isolated product is given. [a] The reaction was carried out at 858C.
Bn=benzyl.
mainly as a result of the remarkable advances that have been
made in click chemistry.[4] We successfully applied our
protocol to the introduction of biologically relevant sugar
and amino acid groups by using the corresponding alkyl
azides (Scheme 6).
Scheme 7. a) Catalytic amination of benzo[h]quinoline (10). b) Stoi-
chiometric reaction with the cyclometalated rhodium complex 12.
Ar=3,5-(CF3)2C6H3.
To shed light on the reaction
mechanism of this amination reac-
tion, we conducted isotope labeling
experiments with deuterium-la-
beled benzamides.[23] Significant
primary kinetic isotope effects
were observed on the basis of an
intermolecular competition experi-
ment in one vessel (PH/PD = 4.0)
and in a parallel experiment (kH/
kD = 1.7). Moreover, no H/D
scrambling was found to occur
between substrates. These results
À
suggest that the C H bond cleav-
age of arenes is irreversible and
rate-limiting with the present rho-
dium catalyst system.
À
Scheme 8. a) Proposed mechanism of the direct C H amination. b) Examples of isolated metal
alkylimido complexes. Ad=adamantyl.
Benzo[h]quinoline (10) was
aminated readily under the standard conditions to give 11
(Scheme 7a), and the treatment of a pregenerated cyclo-
metalated rhodium complex 12[24] with azide 2a also gave the
aminated product 11, albeit in moderate yield (Scheme 7b).
Importantly, in a separate experiment, 12 catalyzed the
amination of 10 in 70% yield;[23] thus, the intermediacy of
a cyclometalated rhodium complex in the catalytic cycle is
plausible.
nitrenoids are known to be generated in reactions of alkyl
azides with Co,[10a,b,d] Ni,[10c,g,i] Cu,[10e] and Fe complexes,[10f,h]
and some of those species were indeed isolated (Scheme 8
b).[10a–d] In this context, we postulate that alkyl azides react
with the rhodacycle to furnish the corresponding nitrenoids,
as proposed in our previous studies with sulfonyl and aryl
azides.[17]
To further investigate electronic effects on the reaction
rates, we also performed intermolecular competition experi-
ments. The observation that amination was faster with both
benzamide and acetophenone[23] substrates bearing electron-
rich substituents strongly suggests that this amination does
not proceed through a nucleophilic aromatic substitution
(SNAr) pathway.[28] Furthermore, a competition experiment
between benzyl azide and an aryl azide in a reaction with
benzamide showed significantly higher reactivity of benzyl
azide over the aryl azide.[23] This result implies that the rate of
the final protonolysis step in the catalytic cycle closely reflects
the degree of nucleophilicity of the presumed rhodacyclic
intermediate IV (Scheme 8).
A plausible amination pathway based on these mecha-
nistic studies as well as previously reported studies[25–27] is
À
depicted in Scheme 8a. First, irreversible C H bond cleavage
by a cationic rhodium species leads to the formation of a five-
membered rhodacyclic intermediate I. Coordination of the
alkyl azide to I would form an intermediate II, and
subsequent insertion of the N-alkylamido group into the
rhodacycle would afford a RhIII amido species IV. In this
process, either a stepwise nitrenoid pathway (path a) or
concerted migratory insertion route (path b) would be
possible. Finally, protonolysis of complex IV would deliver
the N-alkylaniline product. In fact, a range of metal alkyl
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C. Piangiolino, Coord. Chem. Rev. 2006, 250, 1234; c) T. G.
Driver, Org. Biomol. Chem. 2010, 8, 3831.
In conclusion, we have developed a straightforward
procedure for the insertion of an amino group into arene
À
[8] For intramolecular C H amination with azides other than alkyl
À
C H bonds by the use of alkyl azides as the nitrogen source.
azides, see: a) B. J. Stokes, H. Dong, B. E. Leslie, A. L.
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Chem. Int. Ed. 2011, 50, 9884.
Both benzyl and aliphatic azides bearing a wide range of
functional groups of high biological interest reacted readily
with a range of substrates containing chelating groups under
RhIII catalysis. The excellent functional-group tolerance
observed will enable this transformation to be applied as
a convenient route to synthetically and medicinally important
amino compounds.
À
[9] For intermolecular C H amination with azides other than alkyl
azides, see: a) S. Cenini, E. Gallo, A. Penoni, F. Ragaini, S.
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2010, 29, 389; d) V. Lyaskovskyy, A. I. O. Suarez, H. Lu, H.
Jiang, X. P. Zhang, B. de Bruin, J. Am. Chem. Soc. 2011, 133,
12264; e) Y. Nishioka, T. Uchida, T. Katsuki, Angew. Chem.
2013, 125, 1783; Angew. Chem. Int. Ed. 2013, 52, 1739.
Experimental Section
Representative procedure: N-tert-Butyl-4-nitrobenzamide (1a;
80 mg, 0.36 mmol), phenethyl azide (2 f; 27 mL, 0.2 mmol),
[{RhCp*Cl2}2] (4.9 mg, 4 mol%), AgSbF6 (11.0 mg, 16 mol%), and
1,2-dichloroethane (0.5 mL) were placed in a screw-cap vial equipped
with a Spinvane triangular stir bar under atmospheric conditions. The
reaction mixture was stirred in a preheated oil bath at 858C for 24 h,
cooled to room temperature, filtered through a pad of Celite, and then
washed with CH2Cl2 (3 ꢀ 10 mL). Organic solvents were removed
under reduced pressure, and the residue was purified by silica-gel
chromatography (n-hexane/EtOAc, 10:1, v/v) to give 3af (52.6 mg,
77%).
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Received: April 4, 2013
Revised: May 20, 2013
Published online: && &&, &&&&
Keywords: alkyl nitrenoids · aniline derivatives · azides ·
.
À
C H amination · rhodium catalysis
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Angew. Chem. Int. Ed. 2013, 52, 1 – 7
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