Iterative C?H Functionalization Leading to Multiple Amidations of Anilides

Article abstract of DOI:10.1002/anie.201701138

Polyaminobenzenes were synthesized by the ruthenium-catalyzed iterative C?H amidation of anilides using dioxazolones as an amino source. This strategy could be implemented by the sequential activation of C?H bonds of formerly generated compounds by cascade chelation assistance of newly installed amide groups. Computational studies provided a rationale.

Full text of DOI:10.1002/anie.201701138

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International Edition: DOI: 10.1002/anie.201701138
German Edition: DOI: 10.1002/ange.201701138
CÀH Activation
À
Iterative C H Functionalization Leading to Multiple Amidations of
Anilides
+
+
Juhyeon Park , Jia Lee , and Sukbok Chang*
Abstract: Polyaminobenzenes were synthesized by the ruthe-
nium-catalyzed iterative CÀH amidation of anilides using
dioxazolones as an amino source. This strategy could be
implemented by the sequential activation of CÀH bonds of
formerly generated compounds by cascade chelation assistance
of newly installed amide groups. Computational studies
provided a rationale.
T
he demand for the selective synthesis of polysubstituted
benzenes has increased because of their versatile utility in
[
1]
synthetic, medicinal, and materials chemistry. In this con-
text, two synthetic approaches can be conceived: 1) construc-
tion of a benzene skeleton with the simultaneous introduction
of substituents, and 2) selective CÀH functionalization of
benzenes. In fact, various methods based on the former
Scheme 1. Iterative C
FG=functional group.
ÀH functionalization. DG=directing group,
[2]
strategy are known, including [2+2+2] and [4+2] cyclo-
addition.
Direct functionalization of benzenes is more attractive
[
3]
[4]
considering the availability of arene feedstocks. While the
chelation-assisted strategy has been remarkably successful for
the single derivatization of chelation-group-containing
arenes, double CÀH functionalization is often nonselective
benzene derivatives. Computational studies provided a ration-
ale on the extent of the cascade CÀH amidation.
[9]
We have recently disclosed that 1,4,2-dioxazol-5-ones
can work as a highly efficient and robust amino source in
[
5]
[10]
and/or uncontrollable (Scheme 1a). Indeed, it is challenging
transition metal catalyzed CÀH amidation reactions. This
to drive the CÀH functionalization in one direction: either
attractive feature of dioxazolones has been utilized subse-
quently by several research groups for the development of
[6]
effective suppression of the second installation or complete
[7]
[11]
conversion to the double functionalization. In this regard,
their own CÀH amidation reactions. We were intrigued by
[
8b,10b,12]
we wondered about the feasibility of an iterative CÀH
the use of anilides as a substrate
in a reaction with
functionalization of using a single mechanistic platform. For
this goal, several issues can be considered: 1) can newly
introduced functional groups work as an additional chelation
unit to drive the subsequent CÀH activation? and 2) how
many iterations of CÀH functionalization would proceed in
dioxazolones to lead to an iterative CÀH amidation, based on
a postulate that a newly installed amido group could also
work as a directing group for subsequent and iterative CÀN
bond formations.
We commenced our study by examining several transi-
tion-metal catalysts in the CÀH amidation of acetanilide to
one pot under the same catalyst system? (Scheme 1b).
In continuing our efforts on the development of direct
react with 1.1 equivalents of 3-phenyl-1,4,2-dioxazol-5-one
(Table 1; see the Supporting Information for details). As we
[
8]
CÀH amination reactions, described herein is the realization
of an iterative CÀH amidation of anilides to afford multi-
[10b]
recently revealed,
the cobalt precatalyst [{Cp*CoCl } ], in
2 2
amidated benzenes. To the best of our knowledge, this is the
combination with silver salts, was most efficient in this CÀH
amidation among group 9 metal congeners (entries 1–3).
More significantly, a cationic ruthenium catalyst generated
first demonstration of an iterative one-pot CÀH amidation of
[
13]
from [{Ru(p-cymene)Cl } ] and AgSbF
6
exhibited notable
2
2
efficiency (entry 4).
[
+]
[+]
[
*] J. Park, J. Lee, Prof. Dr. S. Chang
In our previous study of CÀH amidation of anilides with
Department of Chemistry, Korea Advanced Institute of Science and
Technology (KAIST), Daejeon 34141 (Republic of Korea)
and
Center for Catalytic Hydrocarbon Functionalization, Institute for
Basic Science (IBS), Daejeon 34141 (Republic of Korea)
[10b]
dioxazolones,
substituents in both reactants were found to
be sensitive to the reaction efficiency. Therefore, various
combinations of substrates and amidating precursors were
examined. For this purpose, acetanilide (1a), N-phenylpival-
amide (1b), and N-phenylbenzamide (1c) were reacted with
a range of dioxazolone derivatives (2a, 2b and 2c; Table 1).
E-mail: sbchang@kaist.ac.kr
+
[
] These authors contributed equally to this work.
III
The [Cp*Co ] system did not exhibit notable reactivity in
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201701138.
these amidation reactions (entries 5–7). We were pleased to
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[
a]
Table 1: Optimization studies.
1
2
[b]
Entry
Catalyst
R
R
Yield [%]
1
2
3
4
5
6
7
8
[{CoCp*Cl } ]
Me
Me
Me
Me
Me
tBu
Ph
Me
tBu
Ph
Ph
Ph
Ph
Ph
Me
tBu
Ph
Me
tBu
Ph
44 (3a)
<1 (3a)
31 (3a)
51 (3a)
20 (3b)
<1 (3c)
22 (3d)
12 (3b)
52 (3c)
<5 (3d)
<1 (4a)
<1 (4a)
<1 (4a)
<1 (4a)
<1 (4b)
<1 (4c)
<1 (4d)
<1 (4b)
17 (4c)
2
2
[{RhCp*Cl } ]
2
2
[{IrCp*Cl
2
}
2
]
[{Ru(p-cymene)Cl } ]
2
2
[{CoCp*Cl } ]
2
2
[{CoCp*Cl } ]
2
2
[{CoCp*Cl } ]
2
2
[{Ru(p-cymene)Cl } ]
[{Ru(p-cymene)Cl } ]
2 2
[{Ru(p-cymene)Cl } ]
2
2
[
c]
9
1
0
<1 (4d)
2
2
[
(
a] 1 (0.2 mmol), 2 (1.1 equiv), catalyst, and additive in ClCH CH Cl
0.5 mL). [b] Determined by H NMR analysis of the crude reaction
2 2
1
mixture (internal standard: dibromomethane). [c] Tris-amidated product
c was also obtained (6%). Cp*=C Me .
5
5
5
observe that the reactivity was greatly improved when 1b was
employed under the ruthenium catalysis conditions. Indeed,
almost full conversion of 2b was achieved in the amidation of
1
b (entry 9). Moreover, noticeable amounts of bis-amidation
(
4c, 17%) and tris-amidation (5c, 6%) took place. The CÀH
amidation of either 1a or 1c with dioxazolones resulted in low
efficiencies (entries 8 and 10).
Figure 1. a) ORTEP of 3c with selected bond lengths and angles.
Thermal ellipsoids shown at 50% probability level (solvent molecules
and several hydrogen atoms are omitted for clarity). b) Removal of
Taking this pattern into consideration, it was concluded
that the amidation of 1b with 2b is the best combination to
furnish the CÀH amidated products (3c, 4c, and 5c) under the
pivaloyl groups of 3c. c) C
presence and absence of H-bond.
ÀH Bond activation process of 3c in the
ruthenium-catalyzed conditions at 408C. Moreover, the for-
mation of a multi-amidated product, even using 1.1 equiv-
alents of amidating reagent, led us to anticipate that multiple
amidations would indeed be possible when larger amounts of
the amino source are employed.
cycle A-3c by a second CÀH activation of 3c, where L is p-
cymene and X is deprotonated 3c in an anionic amido form.
Extended calculations on the CMD step from 3c to A-3c
revealed that the TS-CMD with H-bond is energetically
À1
The structure of 3c was confirmed by an X-ray crystallo-
favored by 2.4 kcalmol when compared to that without
[
17]
graphic analysis (Figure 1a). Two amide groups form an
intramolecular hydrogen bond (H-bond) with one carbonyl
oxygen pointing towards the NÀH bond of the other amide
having such H-bond. This result suggests that an intra-
molecular H-bond is maintained to drive the ruthenium-
mediated CÀH bond activation more favorably.
group. Moreover, a structural analysis of 3c by density
functional theory (DFT) calculations revealed that another
carbonyl oxygen is closely located in the direction of the
ortho-CÀH bond (2.3 ꢀ between O1 and H1 in Figure 1a) in
We were pleased to observe that the desired iterative
amidation indeed took place by using more equivalents of the
dioxazolone in a reaction with 1b (Figure 2). For instance, an
almost equal ratio of tris-amidation (5c, 36%) and tetra-
amidation (6c, 31%) was observed with the concomitant
decrease in mono-amidation (3c, 19%) and bis-amidation
(4c, 13%) when 3.1 equivalents of 2b were employed. Finally,
a quantitative formation of 6c was observed when 6.1 or more
equivalents of 2b were applied. Interestingly, the last CÀH
solution phase. This observation provides insight that the
subsequent CÀH activation of 3c would be highly plausible,
thus eventually enabling the iterative amidation. Pivaloyl
groups of 3c were readily removed upon acidic hydrolysis to
afford 1,2-phenylenediamine in satisfactory yield (Figure 1b).
The influence of the H-bond on the subsequent CÀH bond
bond of 6c was not reacted even when larger amounts of 2b
(> 8 equiv) were employed at 808C. This result suggests that
the amidation of the last CÀH bond in 6c is intrinsically
activation was next investigated (Figure 1c). We previously
elucidated, in rhodium-catalyzed CÀH amidation with
organic azides, that a substrate works as a proton source in
the final concerted metalation-deprotonation (CMD) step to
deliver the amidated product with the regeneration of
difficult to proceed under the present ruthenium catalysis (see
below).
The structures of 4c and 6c were confirmed by X-ray
[
8a]
[17]
a cyclometalated complex. By analogy, a cationic ruthe-
crystallographic analyses (Figure 3). These compounds also
+
nium species, [LRu-X] , was postulated in the present
show intramolecular H-bonds between the neighboring amide
groups.
amidation to be responsible for the formation of the ruthena-
2
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Figure 2. Synthesis of polyamidobenzenes. Conditions: 1b (0.1 mmol), 2b, catalyst, and additive in ClCH CH Cl (0.5 mL). Yields were determined
2
2
1
by H NMR analysis of the crude reaction mixture (internal standard: dibromomethane).
Figure 3. ORTEP of 4c and 6c with selected bond lengths and angles.
Thermal ellipsoid shown at 50% probability level (solvent molecules
and several hydrogen atoms are omitted for clarity).
The present iterative CÀH amidation was applied to
additional types of substrates (Scheme 2). When N-(o-tolyl)-
pivalamide was subjected to reaction with 2b (6.1 equiv), the
tris-amidated product 8 was obtained in excellent yield
(
Scheme 2a). Again, the last CÀH bond (ortho to methyl
Scheme 2. Iterative CÀH amidation of various anilides. Piv=pivaloyl,
Tf =trifluoromethanesulfonyl.
group) remained completely unreacted. A reaction of N-(m-
tolyl)pivalamide gave the bis-amidated compound 9 exclu-
sively, thus leaving two CÀH bonds, ortho to the methyl
substituent, intact (Scheme 2b). Interestingly, the same
product 9 could also be obtained from N-(p-tolyl)pivalamide.
When anilide derivatives bearing ortho halides were
reacted with 2b, the extent of multiple CÀH amidation was
the amidation at the last CÀH bond is sensitive to steric
factors.
The iterative CÀH amidation was convenient on even
varied depending on the halide groups present (Scheme 2c).
Tris-amidated products were formed exclusively from anilides
having chloro, bromo, or iodo groups (10, 11, and 12). In sharp
contrast, 2-fluoroanilide underwent the iterative CÀH ami-
gram scale (Scheme 2d). Significantly, nitration of 6c at the
last CÀH bond was smooth and afforded pentaamidonitro-
benzene (14) in good yield. It should be mentioned that since
hexaaminobenzenes are an important structural unit in
[14]
dation exhaustively to furnish the tetra-amidated product 13
materials science, preparative synthetic routes are highly
[
15]
(
Scheme 2c, right). This reaction result strongly suggests that
desirable.
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To gain further mechanistic insight, a kinetic isotope effect
KIE) study was performed (Scheme 3a). A significant KIE
to the 7-membered ruthenacycle D. Finally, protodemetala-
tion will take place by a CMD process by the interaction of D
with an anilide substrate to release an amidated product with
the regeneration of A.
(
value (k /k = 2.0) was measured, thus implying that the CÀH
H
D
bond cleavage is rate limiting. Given the present reactivity
[10,13a,16]
pattern in addition to the previous mechanistic studies,
Computational calculations for the proposed catalytic
cycle on the formation of 3c from 1b with 2b were performed
(see the Supporting Information for details). The CÀH bond
a plausible catalytic cycle is presented in Scheme 3b. First,
a cationic ruthenium species induces the CÀH activation to
deliver the ruthenacycle A, where a dioxazolone will be
activation of 1b by D was calculated to have a barrier of
IV
À1
coordinated and lead to B. A Ru -imido species (C) is then
26.5 kcalmol to regenerate the ruthenacycle A (n = 0;
assumed to form upon the oxidative CO extrusion from B.
Subsequent migratory insertion of an imido moiety will lead
Scheme 3c). In addition, those in the subsequent CMD of
2
the second, third, and fourth CÀH bond activation to give the
corresponding ruthenacycles A (n = 1, 2, and 3) turned out to
À1
be similar (26.8, 27.6, and 27.0 kcalmol ). This result implies
that the cascade CÀH amidation occurs with similar efficiency
up to the fourth amidation. However, the fifth CÀH activation
À1
À1
barrier of 6c (32.0 kcalmol ) was 4–5 kcalmol higher than
those of the first to fourth CMD processes. Again, this result is
in a good agreement with the experimental observations that
the amidation at the last CÀH bond did not proceed under the
present reaction conditions.
In conclusion, we have proven that a cascade CÀH
functionalization is highly feasible by developing an iterative
ruthenium-catalyzed CÀH amidation of anilides in reaction
with dioxazolone amidating reagents. In this process, a newly
introduced amide serves as an effective directing group for
the successive CÀH bond activation with the help of intra-
molecular H-bonds. DFT calculations and mechanistic studies
rationalized the extent of the present cascade CÀH amidation
reactions. It showcases for the first time that an iterative CÀH
functionalization can be a powerful tool for introducing
multiple functional groups in one-pot cascade manner.
Acknowledgements
We thank Dr. Sung-Woo Park (IBS) for valuable discussions
and Dr. Jung Hee Yoon (IBS) for XRD analysis. This research
was supported by the Institute for Basic Science (IBS-R010-
D1).
Conflict of interest
The authors declare no conflict of interest.
Keywords: amidation · arenes · CÀH activation ·
reaction mechanisms · ruthenium
[
1] a) P. Bamfield, P. F. Gordon, Chem. Soc. Rev. 1984, 13, 441; b) V.
Snieckus, Chem. Rev. 1990, 90, 879; c) S. Saito, Y. Yamamoto,
Chem. Rev. 2000, 100, 2901; d) Modern Arene Chemistry (Ed.: D.
Astruc), Wiley-VCH, Weinheim, 2004; e) T. J. Donohoe, A. J.
Orr, M. Bingham, Angew. Chem. Int. Ed. 2006, 45, 2664; Angew.
Chem. 2006, 118, 2730; f) Marchꢀs Advanced Organic Chemistry,
6th ed.; (Ed.: M. B. Smith; J. March), Wiley, Weinheim, 2006;
g) W. A. L. van Otterlo, C. B. de Koning, Chem. Rev. 2009, 109,
Scheme 3. Mechanistic aspects of the iterative amidation.
3743.
4
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[
2] a) V. Gevorgyan, U. Radhakrishnan, A. Takeda, M. Rubina, M.
[11] a) Y. Liang, Y.-F. Liang, C. Tang, Y. Yuan, N. Jiao, Chem. Eur. J.
Rubin, Y. Yamamoto, J. Org. Chem. 2001, 66, 2835; b) A.
Jeevanandam, R. P. Korivi, I.-w. Huang, C.-H. Cheng, Org. Lett.
2015, 21, 16395; b) H. Wang, G. Tang, X. Li, Angew. Chem. Int.
Ed. 2015, 54, 13049; Angew. Chem. 2015, 127, 13241; c) R. Mei, J.
Loup, L. Ackermann, ACS Catal. 2016, 6, 793; d) X. Wang, A.
Lerchen, F. Glorius, Org. Lett. 2016, 18, 2090; e) B. Jeon, U.
Yeon, J.-Y. Son, P. H. Lee, Org. Lett. 2016, 18, 4610; f) N. Barsu,
M. A. Rahman, M. Sen, B. Sundararaju, Chem. Eur. J. 2016, 22,
9135; g) M. Jeon, N. K. Mishra, U. De, S. Sharma, Y. Oh, M.
Choi, H. Jo, R. Sachan, H. S. Kim, I. S. Kim, J. Org. Chem. 2016,
81, 9878; h) J. Wang, S. Zha, K. Chen, F. Zhang, C. Song, J. Zhu,
Org. Lett. 2016, 18, 2062.
2
002, 4, 807; c) S. Kotha, E. Brahmachary, K. Lahiri, Eur. J. Org.
Chem. 2005, 4741; d) P. R. Chopade, J. Louie, Adv. Synth. Catal.
006, 348, 2307.
2
[
3] a) V. Gevorgyan, A. Takeda, M. Homma, N. Sadayori, U.
Radhakrishnan, Y. Yamamoto, J. Am. Chem. Soc. 1999, 121,
6391; b) V. Gevorgyan, Y. Yamamoto, J. Organomet. Chem.
1999, 576, 232; c) N. Asao, H. Aikawa, J. Org. Chem. 2006, 71,
5249; d) N. Asao, Synlett 2006, 1645; e) M. Rubina, M. Conley, V.
Gevorgyan, J. Am. Chem. Soc. 2006, 128, 5818; f) S. Suzuki, Y.
Segawa, K. Itami, J. Yamaguchi, Nat. Chem. 2015, 7, 227.
[12] a) K.-H. Ng, A. S. C. Chan, W.-Y. Yu, J. Am. Chem. Soc. 2010,
132, 12862; b) K. Sun, Y. Li, T. Xiong, J. Zhang, Q. Zhang, J. Am.
Chem. Soc. 2011, 133, 1694; c) Q. Li, S. Y. Zhang, G. He, Z. Y.
Ai, W. A. Nack, G. Chen, Org. Lett. 2014, 16, 1764; d) ꢂ. M.
Martꢃnez, N. Rodrꢃguez, R. G. Arrayꢄs, J. C. Carretero, Chem.
Commun. 2014, 50, 2801.
[13] a) J. Kim, J. Kim, S. Chang, Chem. Eur. J. 2013, 19, 7328; b) V. S.
Thirunavukkarasu, K. Raghuvanshi, L. Ackermann, Org. Lett.
2013, 15, 3286; c) Q.-Z. Zheng, Y.-F. Liang, C. Qin, N. Jiao,
Chem. Commun. 2013, 49, 5654; d) C. Pan, A. Abdukader, J.
Han, Y. Cheng, C. Zhu, Chem. Eur. J. 2014, 20, 3606; e) M. R.
Yadav, R. K. Rit, A. K. Sahoo, Org. Lett. 2013, 15, 1638; f) K.
Raghuvanshi, D. Zell, K. Rauch, L. Ackermann, ACS Catal.
2016, 6, 3172.
[
4] a) H. M. D. Bandara, D. Jin, M. A. Mantell, K. D. Field, A.
Wang, R. P. Narayanan, N. A. Deskins, M. H. Emmert, Catal.
Sci. Technol. 2016, 6, 5304; b) G. B. Boursalian, M.-Y. Ngai, K. N.
Hojczyk, T. Ritter, J. Am. Chem. Soc. 2013, 135, 13278; c) T.
Kawakami, K. Murakami, K. Itami, J. Am. Chem. Soc. 2015, 137,
2460; d) H. J. Kim, J. Kim, S. H. Cho, S. Chang, J. Am. Chem.
Soc. 2011, 133, 16382.
[
5] a) T. W. Lyons, M. S. Sanford, Chem. Rev. 2010, 110, 1147; b) F.
Collet, C. Lescot, P. Dauban, Chem. Soc. Rev. 2011, 40, 1926;
c) L. McMurray, F. OꢁHara, M. J. Gaunt, Chem. Soc. Rev. 2011,
40, 1885; d) T. Newhouse, P. S. Baran, Angew. Chem. Int. Ed.
2011, 50, 3362; Angew. Chem. 2011, 123, 3422; e) P. B. Arockiam,
C. Bruneau, P. H. Dixneuf, Chem. Rev. 2012, 112, 5879; f) K. M.
Engle, T.-S. Mei, M. Wasa, J.-Q. Yu, Acc. Chem. Res. 2012, 45,
[14] a) J. J. Wolff, A. Zietsch, B. Nuber, F. Gredel, B. Speiser, M.
Wꢅrde, J. Org. Chem. 2001, 66, 2769; b) J. Mahmood, D. Kim, I.-
Y. Jeon, M. S. Lah, J.-B. Baek, Synlett 2013, 246; c) K. Hermann,
M. Nakhla, J. Gallucci, E. Dalkilic, A. Dastan, J. D. Badji c´ ,
Angew. Chem. Int. Ed. 2013, 52, 11313; Angew. Chem. 2013, 125,
11523; d) B. Speiser, M. Wꢅrde, C. Maichle-Mçssmer, Chem.
Eur. J. 1998, 4, 222; e) N. Lahiri, N. Lotfizadeh, R. Tsuchikawa,
V. V. Deshpande, J. Louie, J. Am. Chem. Soc. 2017, 139, 19.
[15] Flꢅrscheim and Holmes reported a reduction procedure of
explosive trinitrotriaminobenzene to hexaaminobenzene by
using phenylhydrazine as an excessive reducing reagent under
harsh conditions (120 – 2008C): B. Flꢅrscheim, E. L. Holmes, J.
Chem. Soc. 1929, 330.
788; g) N. Kuhl, M. N. Hopkinson, J. Wencel-Delord, F. Glorius,
Angew. Chem. Int. Ed. 2012, 51, 10236; Angew. Chem. 2012, 124,
10382; h) S. R. Neufeldt, M. S. Sanford, Acc. Chem. Res. 2012,
45, 936; i) J. L. Jeffrey, R. Sarpong, Chem. Sci. 2013, 4, 4092.
[
6] a) Q. Chen, L. Ilies, E. Nakamura, J. Am. Chem. Soc. 2011, 133,
28; b) Y. Ano, M. Tobisu, N. Chatani, Synlett 2012, 2763.
7] a) K. Gao, P.-S. Lee, T. Fujita, N. Yoshikai, J. Am. Chem. Soc.
010, 132, 12249; b) X. Sun, G. Shan, Y. Sun, Y. Rao, Angew.
4
[
2
Chem. Int. Ed. 2013, 52, 4440; Angew. Chem. 2013, 125, 4536;
c) F. Xie, Z. Qi, S. Yu, X. Li, J. Am. Chem. Soc. 2014, 136, 4780;
d) V. G. Landge, G. Jaiswal, E. Balaraman, Org. Lett. 2016, 18,
8
12; e) K. M. Engle, D.-H. Wang, J.-Q. Yu, Angew. Chem. Int.
[16] S. H. Park, J. Kwak, K. Shin, J. Ryu, Y. Park, S. Chang, J. Am.
Chem. Soc. 2014, 136, 2492.
Ed. 2010, 49, 6169; Angew. Chem. 2010, 122, 6305.
[
[
8] a) J. Y. Kim, S. H. Park, J. Ryu, S. Hwan, S. H. Kim, S. Chang, J.
Am. Chem. Soc. 2012, 134, 9110; b) J. Ryu, J. Kwak, K. Shin, D.
Lee, S. Chang, J. Am. Chem. Soc. 2013, 135, 12861; c) K. Shin, H.
Kim, S. Chang, Acc. Chem. Res. 2015, 48, 1040.
[17] CCDC 1526694 (3c), 1526695 (4c), and 1526696 (6c) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge
Crystallographic Data Centre.
9] V. Bizet, L. Buglioni, C. Bolm, Angew. Chem. Int. Ed. 2014, 53,
5639; Angew. Chem. 2014, 126, 5745.
[
10] a) Y. Park, K. T. Park, J. G. Kim, S. Chang, J. Am. Chem. Soc.
2
2
015, 137, 4534; b) J. Park, S. Chang, Angew. Chem. Int. Ed.
015, 54, 14103; Angew. Chem. 2015, 127, 14309; c) Y. Park, J.
Manuscript received: February 1, 2017
Heo, M.-H. Baik, S. Chang, J. Am. Chem. Soc. 2016, 138, 14020.
Final Article published: && &&, &&&&
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Communications
CÀH Activation
J. Park, J. Lee, S. Chang*
&&&& — &&&&
Iterative CÀH Functionalization Leading
to Multiple Amidations of Anilides
Repeat performance: A ruthenium-cata-
lyzed cascade amidation of multiple CÀH
additional directing groups to drive sub-
sequent CÀH activation. This reaction
bonds of anilide has been developed. By
using dioxazolone as amidating reagents,
newly installed amide groups serve as an
provides a simple and mild approach to
the preparation of polyaminobenzenes.
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
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