Chelation-Assisted Rhodium-Catalyzed Direct Amidation with Amidobenziodoxolones: C(sp2)-H, C(sp3)-H, and Late-Stage Functionalizations

Article abstract of DOI:10.1021/acscatal.6b02015

Air-stable and convenient amidobenziodoxolones as an amidating reagent were disclosed to enable direct amidation on a wide range of C(sp²)-H bonds of (hetero)arenes and alkenes, as well as unactivated C(sp³)-H bonds under Rh^III catalysis. The approach to access 49 examples of structurally diverse amides is featured by mild conditions, complete chemoselectivity and regioselectivity, broad substrate scope (not limited to strongly heterocyclic coordinating groups), and tolerance of valuable functional substituents, such as unprotected amine and hydroxyl groups. The synthetic applicability of this protocol is also demonstrated by late-stage functionalization of biologically important scaffolds.

Full text of DOI:10.1021/acscatal.6b02015

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Letter
Chelation-Assisted Rhodium-Catalyzed Direct Amidation with
Amidobenziodoxolones: C(sp2)-H, C(sp3)-H and Late-Stage Functionalizations
Xu-Hong Hu, Xiao-Fei Yang, and Teck-Peng Loh
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02015 • Publication Date (Web): 03 Aug 2016
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ACS Catalysis
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Chelation-Assisted Rhodium-Catalyzed Direct Amidation with Am-
idobenziodoxolones: C(sp2)−H, C(sp3)−H and Late-Stage Functionali-
zations
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Xu-Hong Hu,†,‡ Xiao-Fei Yang,‡ and Teck-Peng Loh*,‡
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic In-
novation Center for Advanced Materials, Nanjing Tech University, Nanjing 211816, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Techno-
logical University, Singapore 637371, Singapore
ABSTRACT: Air-stable and convenient amidobenziodoxolones as an amidating reagent were disclosed to enable direct
amidation on a wide range of C(sp2)−H bonds of (hetero)arenes and alkenes, as well as unactivated C(sp3)−H bonds under
RhIII catalysis. The approach to access 49 examples of structurally diverse amides is featured by mild conditions, complete
chemo- and regioselectivity, broad substrate scope (not limited to strongly heterocyclic coordinating groups), and toler-
ance of valuable functional substituents such as unprotected amine, hydroxyl groups. The synthetic applicability of this
protocol is also demonstrated by late-stage functionalization of biologically important scaffolds.
KEYWORDS: C−H amidation, rhodium, hypervalent iodine reagents, amide, directing group
Direct catalytic C−H amination represents an efficient
and straightforward approach to synthesize a myriad of
nitrogen-containing compounds,1 which are ubiquitous in
the chemistry community as natural products and phar-
maceuticals. To date, several types of amino precursors
have been successfully employed in C−N bond-forming
process (Scheme 1a). Distinguished with the oxidative (an
external oxidant is required)2 and innate C−H amina-
tion,3,4 chelation-assisted C−H amination with the in-
volvement of preactivated amino sources5 and azides6
predominated in terms of high selectivity and efficiency.
Despite tremendous expansion regarding this field, the
demand for expedient construction of diversified C−N
bonds and safe manipulation calls for alternate new ami-
no sources. Very recently, the research groups of
Chang,7a,b Li,7c Jiao,7d Ackermann,7e and Glorius7f have
developed dioxazolones of nitrene equivalents8 as a pow-
erful amidating reagent in robust C−H amidation reac-
tions. In this respect, we wish to introduce a series of air-
stable amidobenziodoxolones as a complementary amide
source for efficient amidation of various C(sp2)−H and
C(sp3)−H bonds.
inert C−H bonds resulted in their synthetic utility beyond
electrophilic amination being challenging and largely un-
explored. Recently, DeBoef reported a single example of
Cu-mediated C−H amidation of 2-phenylpyridines with
phthalimide-derived iodane, albeit with modest reactivi-
ty.14 An alternative strategy is through in situ generation of
iminoiodinanes by employing a combination of the parent
amine with hypervalent iodine oxidants; nevertheless, it
suffers from harsh conditions, low regioselectivity, or lim-
ited substrate scope.2f,g,j,l,4a-c,g,h On the basis of Sanford’s
pioneering work on N-assisted stoichiometric amidation
with iminoiodinanes in a stepwise manner,15 we anticipat-
ed that competent hypervalent iodine reagents might ena-
ble a general strategy for C−N bond formation via a C−H
activation pathway. Inspired by the previous observation
that {Cp*RhIII} catalyst could facilitate C−H alkynylation
with trivalent iodine reagents,16 here we describe an un-
paralleled Rh-catalyzed C−H amidation of broadly defined
substrates bearing coordinating functional moieties by
using amidobenziodoxolones as a novel amidating reagent.
The transformation provides a rapid and practical route to
monoamidation products with high chemo- and regiose-
lectivity and functional group tolerance (Scheme 1b).
Hypervalent iodine reagents9 containing I−N bonds
have been intensively studied in nitrogen-transfer reac-
tions in the past decades, whereby amidation preferential-
ly occurs at inherently electron-rich C−H bonds.10 In par-
ticular, notable contributions include the metal-free oxi-
dative amidation with a class of structurally defined triva-
lent iodine reagents bearing I−N single bonds, as elegantly
devised by the research groups of Zhdankin,11 Muñiz,12 and
Minakata.13 However, the relatively low reactivity of such
privileged reagents towards direct functionalization of
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Page 2 of 6
tion of the starting materials. We suspected that the acidic
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nature of the 2-iodobenzoic acid produced might be dele-
terious to heteroarenes. To our delight, introduction of
MgO as the base additive, as suggested by Du Bois,17 suc-
cessfully rendered the transformation to afford the desired
products in acceptable yields (3pa and 3qa). Meanwhile,
given the biologically relevant importance of indolines, a
range of indoline derivatives with varied substitution pat-
terns were employed and remarkably, valuable C-7 amidat-
ed indolines were produced in good to excellent yields
(3ra−wa).
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Of note, this catalytic protocol is not restricted to the
(hetero)arene substrates, but also enables olefinic C−H
amidation. Alkenes guided by strongly coordinating pyri-
dinyl group underwent exclusively Z-selective C−H ami-
dation. The transformation provides the unique access to a
variety of unprecedented enamides 4aa−4ea in 35−71%
yields, which overrides the potentially competing allylic
amination.12a
Scheme 1. Metal-catalyzed C−H amination/amidation
Our initial optimizations were undertaken with model
substrate 2-phenylpyridine (1a) with Zhdankin’s reagent11a
(2a) as a convenient amide source catalyzed by a cationic
RhIII species. Careful examinations revealed that treatment
of 1a and 1.2 equiv of 2a in the presence of [{Cp*RhCl2}2]
(2.5 mol%), AgSbF6 (10 mol%), KOAc (10 mol%) in 1,2-
DCE at 80 °C for 15 h gave an optimal 94% yield of mono-
amidated product 3aa (Table S1, See Supporting Infor-
mation). Other representative metal catalysts such as IrIII,
RuII, CoIII also displayed somewhat activity, but proved to
be less effective. Importantly, in stark contrast to the pre-
viously reported strategies using in situ-generated imi-
noiodinanes,2f,j,l,4a-c,g this protocol does not require an ex-
cess amount of the substrate or high catalyst loading,
thereby offering a potential opportunity for late-stage
functionalization of complex molecules.
[{Cp*RhCl2}2] (2.5 mol%)
AgSbF6 (10 mol%)
KOAc (10 mol%)
DG
DG
O
I
NHR
H
NHR
O
+
1,2-DCE, 80 °C, 15 h
1
2
3,4
(1.0 equiv)
(1.2 equiv)
Scope of amides and N-containing heterocyclic DGs
N
N
3aa
, 94%
R = Ts
N
N
NHTs
3ab
R = SO2(4-ClC6H4)
R = Ns
, 95%
NHTs
3ac, 85%a,b
NHR
a,b
3ad
, 51%
R = COMe
b
3ae
, 53%
CO2Me
R = CO(4-ClC6H4)
OMe
3ba
, 92%
3ca, 96%
O
N
N
N
N
N
NHTs
N
NHTs
NHTs
NHTs
NHTs
CN
3da, 80%c
The reactivity of differently decorated amidobenziodox-
olones (2) was subsequently evaluated in the amidation
reaction with 1a under this catalytic system (Scheme 2).
The results indicated that this protocol was applicable to
functionalized sulphonamides and simple amides. Then
we turned our attention to assess the substrate scope and
functional group compatibility for C(sp2)−H amidation
concerning 2a. As depicted in the formation of ortho-
amidated 2-phenylpyridine derivatives 3ba−3da, both
electron-donating and -withdrawing substituents were
well tolerated at the para position of the phenyl moiety.
While alteration of pyridine to additional heterocyclic co-
ordinating groups, including pyrimidine (3ea), oxazole
(3fa), and pyrazole (3ga), the amidation proceeded well to
furnish the corresponding products in moderate to good
yields. Furthermore, an excellent yield of 3ha was obtained
in the case of benzo[h]quinolone. The generality and limi-
tation of this approach was further defined with several
synthetically useful directing groups. The coupling reac-
tion of azobenzene with 2a took place to give mono- and
diamidation products 3ia and 3ia' in 71% combined yield.
Likewise, commonly used amides, ketoxime, and N-oxide
were all found to facilitate ortho-selectivity efficiently
(3la−oa), whereas the use of ketone led to inferior conver-
sion (3ja). Exceptionally, subjecting heteroaromatic sub-
strates to the standard conditions resulted in decomposi-
a
3ga
, 84%
3fa
, 73%
3ha
, 94%
3ea
, 46%
Scope of other useful functional DGs
R'HN
OMe
O
NPh
i-Pr
O
Me
N
O
NHTs
N
N
NHTs
NHTs
NHTs
NHTs
R' = Me 3ka, trace
R' = i-Pr 3la, 70%b
c
3oa, 81%
3ia/3ia', 71%
(52% mono;
19% di)
3na
, 70%
3ja
, 18%
'
a,c
ma
, 63%
R = t-Bu
Substrates with respect to heterocycles
N
N
3ra
, 95%
R' = H
N
N
3sa
, 94%
R' = 2-Ph
NHTs
6
N
3ta
, 76%
R' = 4-Me
NHTs
N
NHTs
2
R' = 2-Me,5-OMe 3ua, 78%
R'
N
S
3va
R' = 5-Br
, 74%
, 88%
3wa
R' = 5-F
3pa, 62%d
d
3qa
4
, 58%
Substrates with respect to alkenes
N
N
N
N
NHTs
NHTs
NHTs
NHTs
NHTs
e
e
4da, 35%
4ea
, 63%
4aa
, 62%
4ca
, 64%
4ba
, 71%
Scheme 2. Substrate scope of C(sp2)−H amidation
Reaction conditions, unless otherwise noted: 1 (0.2 mmol), 2 (1.2
equiv), [{Cp*RhCl2}2] (2.5 mol%), AgSbF6 (10 mol%), and KOAc
(10 mol%) in 1,2-DCE (1.0 mL) at 80 °C for 15 h. Isolated yields are
a
b
c
given. At 100 °C. For 24 h. [{Cp*RhCl2}2] (4.0 mol%), AgSbF6
(16 mol%), and KOAc (16 mol%). MgO (1.2 equiv) was added. eAt
d
rt. Ts = 4-toluenesulfonyl. Ns = 4-nitrobenzenesulfonyl.
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ACS Catalysis
The established protocol for direct C(sp2)−H amidation
that the unprotected amine and hydroxyl groups survived
in this chemistry.
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with amidobenziodoxlones intrigued us to consider the
feasibility of applying our current catalytic system in the
unactivated C(sp3)−H amidation (Scheme 3). To this end,
substituted 8-methylquinolines18 were tested in this reac-
tion. Pleasingly, under the similar reaction conditions, a
set of electronically modified 8-methylquinolines readily
reacted at the benzylic position, despite the presence of
the potentially chelating ester and amino moieties
(6aa−6ga). It needs to be mentioned that the C−H ami-
dation of electron-rich 8-methylquinolines is thus far dif-
ficult to be realized by utilizing azides as the amidating
reagent.18d
Finally, some preliminary mechanistic experiments were
conducted to unravel the reaction mechanism. The obser-
vations that two well-defined rhodacyclic complexes C1
and C2 catalyzed the direct amidation instead of
[{Cp*RhCl2}2], giving essentially the same yields of the cor-
responding products 3aa and 6aa, respectively, therefore
indicate the potential intermediacy of a cyclometalated
species during the process (Schemes 5a and 5b). In addi-
tion, the intermolecular kinetic isotope effects (KIE) of
amidation with 2a have been determined. For C(sp2)−H
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2a
Having achieved the successful amidation of benzylic
C−H bond, we moved on to further expand the C(sp3)−H
substrate scope to more unactivated 2-alkylpyridines.19
Following slightly modified conditions (Table S2, see Sup-
porting Information), the amide group was successfully
installed at the primary C−H bond position assisted by an
inherent pyridinyl group, furnishing monoamidation
products 6ha−6na at room temperature. Several tethered
functional groups including phenyl, ethoxy, and alkene,
were well-tolerated in the amidation event. Analogously, 2-
alkylpyrimidine also proved to be a viable substrate (6oa).
H
R
NHTs
[{RhCp*Cl2}2] (5 mol%)
AgSbF6 (20 mol%)
KOAc (20 mol%)
N
N
N
N
N
N
AcO
AcO
N
N
R
1,2-DCE, 80 °C, 24 h
O
O
R = NH2 7aa, 48% (48 h)
R = H 7ba, 75%
AcO OAc
AcO OAc
Guanosine derivatives
O
N
O
N
2a
standard
conditions
TsHN
N
N
O
H
O
O
O
OH
O
OH
O
8, 70%
Camptothecin N-oxide
H
NHR
O
I NHR
[{Cp*RhCl2}2] (2.5-5 mol%)
AgSbF6 (10-20 mol%)
KOAc (10-20 mol%)
Scheme 4. Late-stage C−H amidation
N
N
+
O
X
X
1,2-DCE, rt to 80
24-72 h
C
5
2
6
(1.0 equiv)
(1.2 equiv)
NHTs
NHTs
NHNs
NHR
N
N
N
N
EtO2C
R'
NHAc
Cl
6ga
R = Ts 6aa, 73%
6ba
a
6ca
6da
, 60%
R' = Br
R' = NO2
, 84%
6fa
, 70%
, 64%
R = Ns
, 78%
R' = OMe 6ea, 82%
Ph
N
N
N
N
NHTs
NHTs
NHTs
NHTs
b
b
b
b
6ia
, 64%
6ja
, 59%
6ha
6ka
, 41%
, 65%
O
N
N
N
N
NHTs
N
NHTs
NHTs
NHTs
b
b
b
b
6oa
, 62%
6la
, 60%
6na
, 27%
6ma
, 43%
Scheme 3. Substrate scope of C(sp3)−H amidation
Reaction conditions, unless otherwise noted: 5 (0.2 mmol), 2 (1.2
equiv), [{Cp*RhCl2}2] (2.5 mol%), AgSbF6 (10 mol%), and KOAc
(10 mol%) in 1,2-DCE (1.0 mL) at 80 °C for 24 h. Isolated yields
a
b
are given. At 60 °C. 5 (0.2 mmol), 2a (1.2 equiv), [{Cp*RhCl2}2]
(5.0 mol%), AgSbF6 (20 mol%), and KOAc (20 mol%) in 1,2-DCE
(1.0 mL) at rt for 72 h.
To showcase the applicability of the process, we per-
formed the direct amidation of complex bioactive mole-
cules bearing miscellaneous functional groups (Scheme
4). 6-Phenylpurinyl nucleosides, derived from guanosine,
were monoamidated on the expected phenyl ring efficient-
ly (7aa and 7ba). Moreover, treatment with camptothecin
N-oxide under the typical amidation conditions smoothly
furnished the desired product 8 in 70% yield, as confirmed
by X-ray crystallographic analysis. It should be pointed out
Scheme 5. Preliminary mechanistic experiments
amidation, a KIE value of 1.6 revealed that C–H cleavage
might not be the rate-limiting step (Scheme 5c).20 By con-
trast, a notable KIE for C(sp3)−H amidation suggests that
C–H cleavage is plausibly involved in the turnover-limiting
step (Scheme 5d). Interestingly, a rhodacyclic intermediate
C3, which was previously obtained with tosyl azide by
Chang,21 was also successfully isolated (Scheme 5e).
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gapore National Research Foundation (NRF2015NRF-
POC001-024). Dr. Rakesh Ganguly is acknowledged for X-ray
crystallographic analysis.
As exemplified with C−H amidation of 1a, a plausible
mechanism for the catalytic system is proposed on the
basis of the above mechanistic studies and additional con-
trol experiments (For details, see Supporting Information)
as well as previous reports (Figire 1).16,21 The amidation
pathway may involve prior coordination of active rhodacy-
cle A with 2a to form RhIII complex B. The structurally
defined intermediate C can be accessed through two pre-
sumptive routes: (a) oxidative addition to afford putative
RhV intermediate D, followed by reductive elimination to
release 2-iodobenzonic acid; (b) insertion of RhV-nitrenoid
species into Rh−C bond. It is also likely that dissociation of
2-iodobenzonic acid from D followed by reductive elimi-
nation leads to the same intermediate E. Proto-
demetallation of the resulting intermediate C delivers the
product 3aa, along with the regenerated {Cp*RhIII} species.
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Figure 1. Simplified mechanistic proposal
In summary, a robust Rh-catalyzed C–H amidation us-
ing cyclic trivalent iodine reagents as a new amide source
has been accomplished. The protocol is applicable to a
broad spectrum of DG-containing substrates, including
synthetically useful N-containing hetereocycles, azo, am-
ide, ketoxime, and N-oxide. Specifically, the utility of these
reagents allows direct amidation of both C(sp2)−H and
inert C(sp3)−H bonds to yield monoamidation products by
the release of environmentally benign 2-iodobenzonic ac-
id. Considering the high amidation efficiency and func-
tional group compatibility of the transformation, we envi-
sion that this newly developed method will pave a promis-
ing and complementary way for late-stage amidation of
complex molecules in medicine and material related areas.
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ASSOCIATED CONTENT
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.0000000.
Experimental procedures and characterization data (PDF)
Crystallographic data for compounds 8 and C3 (CIF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: teckpeng@ntu.edu.sg.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support was provided by the NNSFC (21432009),
the Singapore Ministry of Education Academic Research
Fund [MOE2014-T1-001-102, MOE2015-T1-001-070], and Sin-
(6) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040–
1052.
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