Rhodium-catalyzed intermolecular amidation of arenes with sulfonyl azides via chelation-assisted C-H bond activation

Article abstract of DOI:10.1021/ja303527m

We report the direct amidation of arene C-H bonds using sulfonyl azides as the amino source to release N₂ as the single byproduct. The reaction is catalyzed by a cationic rhodium complex under external oxidant-free conditions in the atmospheric environment. A broad range of chelate group-containing arenes are selectively amidated with excellent functional group tolerance, thus opening a new avenue to practical intermolecular C-N bond formation.

Full text of DOI:10.1021/ja303527m

Communication
pubs.acs.org/JACS
Rhodium-Catalyzed Intermolecular Amidation of Arenes with
Sulfonyl Azides via Chelation-Assisted C−H Bond Activation
Ji Young Kim,† Sae Hume Park,† Jaeyune Ryu, Seung Hwan Cho, Seok Hwan Kim, and Sukbok Chang*
Department of Chemistry and Molecular-Level Interface Research Center, Korea Advanced Institute of Science & Technology
(KAIST), Daejeon 305-701, Republic of Korea
S
* Supporting Information
strategy is to use parent amines in the presence of external
ABSTRACT: We report the direct amidation of arene C−
H bonds using sulfonyl azides as the amino source to
release N2 as the single byproduct. The reaction is
catalyzed by a cationic rhodium complex under external
oxidant-free conditions in the atmospheric environment. A
broad range of chelate group-containing arenes are
selectively amidated with excellent functional group
tolerance, thus opening a new avenue to practical
intermolecular C−N bond formation.
oxidants, and there are several examples reporting the direct
amination of azoles,6 polyfluorobenzenes,6c and chelate group-
containing arenes.7 An alternative strategy is to employ pre-
activated amino precursors, which successfully led to the direct
amination of various (hetero)arenes.8,9 However, in these direct
amination reactions employing arenes, generation of stoichio-
metric byproducts still cannot be avoided under the conditions
used.10
These considerations led us to envision an environmentally
benign direct C−H amidation of arenes that does not generate
hazardous byproducts. In this context, we have successfully
developed a Rh-catalyzed direct N-arylation using sulfonyl
azides as an amino source and releasing N2 as the single
byproduct (Scheme 1c). Importantly, the chelation-assisted
direct C−N amidation proceeds in the absence of external
oxidants with high functional group tolerance. Although metal-
catalyzed intramolecular sp2 or sp3 C−H amination was
previously shown to annulate vinyl or aryl azides, giving rise
to heterocycles,11,12 azides have rarely been utilized for
intermolecular reactions with arene C−H bonds. In fact, only
limited examples are known wherein certain metal species
catalyze N-atom transfer of aryl azides to the allylic or benzylic
C−H bonds.13
ryl amines are a key component in numerous natural
A
products and synthetic compounds displaying important
chemical, biological, and medicinal properties.1 As a result,
there have long been extensive efforts toward the development
of efficient reactions to introduce nitrogen-containing groups
into arene molecules. Metal-mediated N-arylation of aryl
(pseudo)halides with amines or amides has been developed
as an attractive route to aminoarenes under various conditions,
pioneered by Ullmann and Goldberg employing stoichiometric
copper species.2 Important advances in transition metal-
catalyzed amination were made later, mainly by the Hartwig
and Buchwald groups (Scheme 1a),3 wherein palladium or
Based on previous observations that Rh(I),14 Rh(II),15 and
Rh(III)16 species are highly reactive in the oxidative C−H bond
funtionalizations of arenes, we initially examined the prospec-
tive C−H amidation of 2-phenylpyridine (1a) with sulfonyl
azides using available rhodium species (Table 1). Upon the
extensive screening of reaction conditions,17 we found that a
cationic Rh(III) species, [Cp*Rh(III)](SbF6)2, displayed a
significant catalytic activity while other rhodium precursors
were less effective (entries 1−5). Interestingly, this effect of
cationic catalyst was especially dramatic with the [RhCp*Cl2]2
complex, and the cationic rhodium species were readily
prepared in situ upon treatment of rhodium precursors with
silver salts.
Scheme 1. C−N Bond Formation Routes to Aryl Amines
The reaction proceeded smoothly at 110 °C in toluene to
give 4-methyl-N-[2-(pyridin-2-yl)phenyl]benzenesulfonamide
(4aa) in 77% yield after 12 h when p-toluenesulfonyl azide
was used as the amido source (entry 5). While the product
yield was decreased at lower temperature in toluene (entry 6),
the highest product yields were obtained in 1,2-dichloroethane
(DCE), even at 80 °C (entry 7), and other solvents gave
copper catalysts were used in combination with suitable ligands
under basic conditions.4 However, this procedure generates
stoichiometric amounts of byproducts such as hydrogen halides
or their base salts. The development of a direct amination of
arene C−H bonds is highly desirable.
In metal-catalyzed direct C−H amination of (hetero)arenes,
Received: April 12, 2012
two approaches can be conceived (Scheme 1b).5 The first
© XXXX American Chemical Society
A
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Communication
a
a
Table 1. Optimization of the Rh-Catalyzed Amidation
Table 2. Substrate Scope of 2-Phenylpyridine Derivatives
temp
(°C)
yield
b
entry
catalyst system (mol %)
solvent
(%)
1
Rh2(O2CCF3)4 (4)
toluene
toluene
toluene
toluene
toluene
toluene
1,2-DCE
t-amylOH
1,2-DCE
1,2-DCE
110
110
110
110
110
80
11
10
20
10
77
59
96
45
54
<1
84
27
64
n.r.
2
[Rh(cod)Cl]2 (4)
3
[Rh(cod)Cl]2 (4)/AgSbF6 (8)
[RhCp*Cl2]2 (4)
4
5
[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)/AgBF4 (16)
[RhCp*Cl2]2 (4)/KPF6 (16)
[RhCp*Cl2]2 (2.5)/AgSbF6 (10) 1,2-DCE
[RhCp*Cl2]2 (4)/AgSbF6 (16)
[RhCp*(MeCN)3][SbF6]2 (8)
6
7
80
8
80
9
80
10
11
12
13
14
80
80
1,2-DCE
1,2-DCE
1,2-DCE
50
80
[Ru(p-cymene)Cl2]2 (4)/
KPF6 (16)
80
15
Pd(OAc)2 (8)/PhI(OAc)2 (110) 1,2-DCE
80
n.r.
a
1a (0.2 mmol), 3a (1.1 equiv), catalyst, additive, and solvent (0.5
b
mL) at the indicated temperature for 12 h. NMR yield.
inferior yields (entry 8). Not surprisingly, the nature of the
cationic generator was also influential. While silver hexafluor-
oantimonate was most effective, alteration of the cationic or
anionic part of the additive gave reduced efficiency (entries 9
and 10). Although satisfactory product yield was obtained with
lower catalyst loading (entry 11), reactions at lower temper-
ature (e.g., 50 °C) became sluggish (entry 12). The fact that the
use of a pregenerated cationic rhodium species afforded 4aa,
albeit in slightly lower yield (entry 13), suggests that
[Cp*Rh(III)](SbF6)2 is indeed a catalytically active species.
Other transition metals such as ruthenium or palladium
complexes, which are known to be highly effective in direct
C−H bond functionalizations,18 were ineffective in the present
direct N-arylation (entries 14 and 15).
We next examined the substrate scope of various substituents
to react with sulfonyl azides under the optimized conditions.
Electronic variation of substituents at the arene moiety of 2-
phenylpyridines had little effect on the reaction efficiency. In
fact, ortho-amidated 2-phenylpyridine products having electron-
donating substituents such as methyl (4ba) or methoxy (4ca)
were obtained in good yields (Table 2).
a
b
In 1,2-DCE (0.5 mL) at 80 °C for 12 h (isolated yields). For 48 h.
c
Structure of the major product is shown.
slightly decreased the reactivity, presumably due to steric
reasons (4na). Although amidation of substrates substituted at
the meta-position with methyl (4oa) or acetyl (4pa) occurred
selectively at the sterically more accessible C−H bonds, a
substrate having a MeO group underwent the reaction to afford
two separable regioisomeric products in high ratio (4qa, 4qa′).
As anticipated, 2-(2-naphthalenyl)pyridine was amidated at the
sterically less hindered position in good yield (4ra).
Substrates substituted on the pyridine side were also readily
employed in the amidation process. The desired products were
obtained in good yields when a methyl group was substituted at
the 4- or 5-position of pyridine (4sa, 4ta). The amidation
occurred efficiently with 5-fluoro-2-phenylpyridine and 5-
acetyl-2-phenylpyridine to deliver 4ua and 4va, respectively.
The amidation of a substrate bearing a quinoline directing
group also proceeded in good yield (4wa).
While an unmasked hydroxyl group was compatible with the
present conditions (4da), substrates protected with acetyl or
benzyl groups underwent amidation with similar efficiency
(4ea, 4fa). The reaction was highly chemoselective in that
olefinic double bonds, a potential reacting site, were inert
(4ga). In addition, functional groups commonly used in organic
synthesis were totally tolerated. For example, substrates bearing
fluoro (4ha), chloro (4ia), ketone (4ja), ester (4ka), or
aldehyde (4la) groups were all smoothly amidated in high
yields. The amidation was highly selective, occurring exclusively
at the ortho-position relative to the 2-pyridyl, even in the
presence of other potential chelate groups such as ketone or
ester (4ja−4la).16e
A different heterocycle (e.g., pyrazole) other than pyridine
also worked well as an efficient directing group to facilitate the
amidation, albeit with a moderate yield (eq 1). In addition,
Substrates bearing electron-withdrawing groups such as
trifluoromethyl (4ma) underwent the amidation in high yield.
On the other hand, an ortho-substituent at the phenyl moiety
direct N-arylation took place at the ortho-position of an oxime
group, which is readily accessible and easily convertible to other
B
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Journal of the American Chemical Society
Communication
functional groups (eq 2), thus expanding the scope of the
present amidation method.
The scope of sulfonyl azides was then examined in the
amidation of 2-phenylpyridine. Arenesulfonyl azide substrates
substituted with methoxy (4ab), chloro (4ac), or trifluor-
omethyl (4ad) groups were readily amidated at the ortho-
position. Aliphatic variants worked equally well, and n-butane-,
phenylmethane-, and camphorsulfonyl azides reacted smoothly
(4ae, 4af, and 4ag, Table 3).
a
Table 3. Substrate Scope of Sulfonyl Azides
1a and 1a-d5 (Scheme 3a), suggesting that the C−H bond
cleavage is likely involved in the rate-limiting step.22 A stable
cyclometalated Rh(III) complex 9 was obtained upon treat-
ment of benzo[h]quinoline with [RhCp*Cl2]2,23 and amido
insertion into its cationic species occurred smoothly upon
reacting it with TsN3 within 3 h at room temperature (Scheme
3b). A sulfonamido rhodium 10 was isolated from this reaction
and its structure unambiguously characterized by X-ray
crystallographic analysis. Importantly, 9 catalyzed an amidation
reaction of 2-phenylpyridine to give 4aa in high yield (Scheme
3c), suggesting the plausible intermediacy of a cyclometalated
complex in the catalytic cycle.
a
b
Isolated yields. Carried out for 48 h.
The amidated products can be useful in various areas,
including organic synthesis, coordination chemistry, and the
pharmaceutical industry (Scheme 2). Benzo[h]quinoline read-
ily underwent direct C−H amidation using as low as 0.5 mol %
of the Rh catalyst precursor. The reaction was scaled-up
without difficulty, and the product 4xa was isolated by a simple
purification process (recrystallization) with N2 as the single
byproduct. Product 4xa has utility in coordination chemistry as
an effective bidentate ligand (6), as exemplified by Ritter’s
group in fluorination chemistry.19 Selective amidation took
place with 3-phenylisoquinoline using 1 mol % of the Rh
species to give 4ya in high yield, which was then used as an
intermediate in the synthesis of a bioactive compound, 7.20
Scheme 3. Preliminary Mechanistic Studies
Scheme 2. Potential Utilities of Amidated Products
Based on the above observed data, a mechanistic pathway
using 2-phenylpyridine (1a) and TsN3 is proposed in Scheme
4. First, treatment of the [RhCp*Cl2]2 precursor with AgSbF6
additive generates a cationic Rh(III) species, which facilitates
the key C−H bond activation to afford a five-membered
rhodacyclic intermediate I, an structural analogue of isolated 9
(Scheme 3b). Coordination of azide to I leading to II is
assumed to follow before the subsequent insertion of a
sulfonamido moiety into the rhodacycle.24 This amido transfer
will provide Rh(III) amido complex III, an analogue of the fully
characterized complex 10 (Scheme 3b). Finally, protonolysis of
III delivers the desired product 4.
In summary, we have developed a rhodium-catalyzed direct
amidation of arenes using sulfonyl azides as the amine source,
which is proposed to proceed via chelation-assisted C−H bond
activation. A range of arene substrates were selectively amidated
in high yields with excellent functional group tolerance. The
amidation requires no external oxidants and releases N2 as the
single byproduct, thus offering an environmentally benign C−N
arylation procedure that can be readily scaled-up. The synthetic
utility of amidated products is enormous in such areas as
organic synthesis, coordination chemistry, materials science,
and medicine.
Amidation of 9-alkyl-6-arylpurines proceeded smoothly and
with excellent selectivity to afford the corresponding products
(8aa, 8ba) in high yields using 1 mol % of the catalyst precursor
(eq 3). A 6-arylpurinyl nucleoside was amidated efficiently
(8ca, eq 4), but even a substrate bearing an unprotected aniline
group underwent the amidation in an acceptable yield (8da). 6-
Arylpurine derivatives are known to exhibit high anti-
mycobacterial, cytostatic, and anti-HCV activities.21
To obtain further insights into the present direct C−H
amidation, preliminary mechanistic experiments were carried
out. A notable primary kinetic isotope effect (KIE, kH/kD
=
2.01) was observed for two separate competition reactions with
C
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Journal of the American Chemical Society
Communication
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additives in those cases.
Scheme 4. Proposed Reaction Pathway
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures; data for new compounds,
1
including H, 13C NMR, and X-ray analysis. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
sbchang@kaist.ac.kr
■
Author Contributions
†J.Y.K. and S.H.P. contributed equally.
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(b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. 2010,
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A. J. Am. Chem. Soc. 2011, 133, 1248. (d) Rakshit, S.; Grohmann, C.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Korea Research Foundation (KRF-2008-C00024, Star Faculty
Program) and MIRC (NRF-2012-0000912) are appreciated.
■
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