Rhodium(III)-catalyzed intermolecular N-chelator-directed aromatic C-H amidation with amides

Article abstract of DOI:10.1021/ol4024776

Rh(III)-catalyzed intermolecular direct aromatic C-H bond amidation with amides has been accomplished under mild reaction conditions. This protocol is applicable to a broad range of N-chelator-containing arenes amidated with aromatic and aliphatic sulfonamides. A possible mechanism is proposed according to the experimental results.

Full text of DOI:10.1021/ol4024776

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Rhodium(III)-Catalyzed Intermolecular
N‑Chelator-Directed Aromatic CꢀH
Amidation with Amides
Huaiqing Zhao, Yaping Shang, and Weiping Su*
State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the
Structure of Matter, Chinese Academy of Sciences, Fuzhou, Fujian 350002, China
wpsu@fjirsm.ac.cn
Received August 28, 2013
ABSTRACT
Rh(III)-catalyzed intermolecular direct aromatic CꢀH bond amidation with amides has been accomplished under mild reaction conditions. This
protocol is applicable to a broad range of N-chelator-containing arenes amidated with aromatic and aliphatic sulfonamides. A possible mechanism
is proposed according to the experimental results.
Although the BuchwaldꢀHartwig amination reactions1
and the UllmannꢀGoldberg coupling reactions2 have
provided powerful tools for the syntheses of aryl amines,
the ubiquity of (hetero)arylꢀnitrogen bonds in natural
products, pharmaceuticals, agrochemicals, and organic
materials3 continues to be the great impetus to the devel-
opment of efficient methods for constructing (hetero)-
arylꢀnitrogen bonds. From the standpoint of atom- and
step-economy, transition-metal catalyzed direct CꢀH ami-
nation with amines or amides would be the ideal approach
to aryl amines or N-arylated amides. However, the
achievement of direct CꢀH amination starting from
amines or amides represents a challenging goal because
of the coordination of amines or amides to catalyst centers
that may lead to catalyst poisoning or a decrease in cata-
lytic activity for CꢀH activation, and the lack of stability
of certain amines under oxidative conditions. A strategy to
effect the direct amination of (hetero)arenes is the use of
the amino or amido precursors such as oxime derivatives,4
chloroamines,5 N-fluorobenzenesulfonimide,6 andazides.7
Recently, much effort has been made to achieve the direct
CꢀH amination of (hetero)arenes with amines or amides,
successfully establishing some methods that enable the use
ofaminesoramidesfor the aminationof CꢀH bonds,8 and
the groups of Yu and Che have contributed to the pioneer-
ing work.9a Despite these advances, intermolecular CꢀH
amination with amines or amides is still limited to specific
substrates.9
(5) (a) Kawano, T.; Hiranoo, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900. (b) Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2012,
14, 272. (c) Grohmann, C.; Wang, H.; Glorius, F. Org. Lett. 2012, 14, 656.
(6) (a) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. J. Am. Chem.
Soc. 2011, 133, 1694. (b) Tang, R.-J.; Luo, C.-P.; Yang, L.; Li, C.-J. Adv.
Synth. Catal. 2013, 355, 869.
(7) (a) Stokes, B. J.; Dong, H.; Leslie, B. E.; Pumphrey, A. L.; Driver,
T. G. J. Am. Chem. Soc. 2007, 129, 7500. (b) Kim, J. Y.; Park, S. H.; Ryu,
J.; Cho, S. H.; Kim, S. H.; Chang, S. J. Am. Chem. Soc. 2012, 134, 9110.
(c) Ryu, J.; Shin, K.; Park, S. H.; Kim, J. Y.; Chang, S. Angew. Chem.,
Int. Ed. 2012, 51, 9904. (d) Shin, K.; Baek, Y.; Chang, S. Angew. Chem.,
Int. Ed. 2013, 52, 8301. (e) Kim, J.; Kim, J.; Chang, S. Chem.;Eur. J.
2013, 19, 7328. (f) Yadav, M. R.; Rit, R. K.; Sahoo, A. K. Org. Lett.
2013, 15, 1638. (g) Zheng, Q.-Z.; Liang, Y.-F.; Qin, C.; Jiao, N. Chem.
Commun. 2013, 49, 5654. (h) Thirunavukkarasu, V. S.; Raghuvanshi, K.;
Achermann, L. Org. Lett. 2013, 15, 3286.
(8) For selected reviews on CꢀH amination/amidation, see: (a)
Beccalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem.
Rev. 2007, 107, 5318. (b) Collet, F.; Dodd, R. H.; Dauban, P. Chem.
Commun. 2009, 5061. (c) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010,
110, 1147. (d) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010,
49, 2282. (e) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev.
2011, 40, 5068.
(1) (a) Paul, F.; Patt, J.; Hartwig, J. F. J. Am. Chem. Soc. 1994, 116,
5969. (b) Guram, A. S.; Buchwald, S. L. J. Am. Chem. Soc. 1994, 116,
7901.
(2) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054.
(3) (a) Ricci, A. Amino Group Chemistry: From Synthesis to the Life
Sciences; Wiley-VCH: Weinheim, 2008. (b) Hili, R.; Yudin, A. K. Nat.
Chem. Biol. 2006, 2, 284. (c) Boaen, N. K.; Hillmyer, M. A. Chem. Soc.
Rev. 2005, 34, 267.
(4) (a) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc. 2010,
132, 12862. (b) Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.- Q.
J. Am. Chem. Soc. 2011, 133, 7652. (c) Matsuda, N.; Hiranoo, K.; Stoh,
T.; Miura, M. Org. Lett. 2011, 13, 2860. (d) Grohman, C.; Wang, H.;
Glorius, F. Org. Lett. 2013, 15, 3014. (e) Yu, S.; Wan, B.; Li, X. Org.
Lett. 2013, 15, 3706.
r
10.1021/ol4024776
XXXX American Chemical Society

Recently, the Rh(III) catalyst for CꢀH functionaliza-
tion has attracted more attention due to its high catalytic
activity and excellent functional group tolerance.10,11 In
the context of CꢀH amination, the Rh catalyst proved to
be very efficient for the transformation of allylic, benzylic,
and certain unactivated sp3 CꢀH bonds.8b,12 These elegant
studies led us to consider whether a Rh catalyst is applic-
able to the direct amination of aromatic CꢀH bonds with
amines or amides. Herein, we describe a mild, efficient
Rh(III)-catalyzed method for N-chelator-directed ortho
sp2 CꢀH bond amidation with sulfonamides.
Table 1. Optimization of the Rh-Catalyzed Amidationa
oxidant
(equiv)
temp
yield
(%)b
entry
solvent
DMSO
(°C)
1
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
Ag2CO3 (2.0)
AgOAc (4.0)
100
100
100
100
100
100
100
100
100
100
80
0
Recent advances in the Rh(III)-catalyzed CꢀH bond
activation10,11 have afforded valuable starting points for
our exploration in the direct amidation of arenes with
sulfonamides. Weselectedthe reactionof2-phenylpyridine
(1a) and p-toluenesulfonamide (2a) as the model reaction.
The [Cp*Rh(III)](SbF6)2, which can be generated in situ
from [Cp*RhCl2]2 in the presence of AgSbF6, was selected
as the catalyst. Initially, the model reaction that was
performed at 100 °C using Ag2CO3 as the oxidant in the
presence of 5 mol % of Rh(III) only generated a small
amount of the desired product 3a, in CH2Cl2 (Table 1,
entry 4). No desired product was obtained when the
2
DMF
0
3
1,4-dioxane
CH2Cl2
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
0
4
5
5
20
5
6
7
Cu(OAc)2 (2.0)
PhI(OAc)2 (2.0)
PhI(OAc)2 (2.0)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(TFA)2 (1.5)
PhI(OCOt‑Bu)2
(1.5)
5
8
20
60
74
74
76
71
0
9
10
11
12
13
14
15
60
40
60
60
58
(9) For the transition-metal catalyzed the amination/amidation of
(hetero)arenes with amines/amides, see: (a) Thu, H.-Y.; Yu, W.-Y.; Che,
C.-M. J. Am. Chem. Soc. 2006, 128, 9048. (b) Xiao, B.; Gong, T.-J.; Xu,
J.; Liu, Z.-J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 1466. (c) Shrestha, R.;
Mukherjee, P.; Tan, Y.; Litman, Z. C.; Hartwig, J. F. J. Am. Chem. Soc.
2013, 135, 8480. (d) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q.
J. Am. Chem. Soc. 2006, 128, 6790. (e) Monguchi, D.; Fujiwara, T.;
Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607. (f) Wang, Q.;
Schreiber, S. L. Org. Lett. 2009, 11, 5178. (g) Zhao, H.; Wang, M.; Su,
W.; Hong, M. Adv. Synth. Catal. 2010, 352, 1301. (h) Miyasaka, M.;
Hirano, K.; Satoh, T.; Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett.
2011, 13, 359. (i) John, A.; Nicholas, K. M. J. Org. Chem. 2011, 76, 4158.
(j) Tran, L. D.; Roane, J.; Daugulis, O. Angew. Chem., Int. Ed. 2013, 52,
6043. (k) Xie, Y.; Qian, B.; Xie, P.; Huang, H. Adv. Synth. Catal. 2013,
355, 1315. (l) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S. Angew. Chem.,
Int. Ed. 2009, 48, 9127. (m) Kim, J. Y.; Cho, S. H.; Joseph, J.; Chang, S.
Angew. Chem., Int. Ed. 2010, 49, 9899.
16
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
PhI(OAc)2 (1.5)
ClCH2CH2Cl
CH2Cl2
60
60
60
60
60
59
54
69
0
17c
18d
19e
20f
CH2Cl2
CH2Cl2
CH2Cl2
62
a Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), [Cp*RhCl2]2
(2.5 mol %), AgSbF6 (10 mol %), oxidant, solvent (2 mL), 24 h.
b Isolated yield. c In absence of AgSbF6. d 1a (0.2 mmol), 2a (0.4 mmol).
e In absence of [Cp*RhCl2]2. f 1a (0.2 mmol), 2a (0.2 mmol); 3a was the
only product, and a diamidated product was not observed.
reaction was carried out in other solvents, such as DMSO,
DMF, and 1,4-dioxane (entries 1ꢀ3). When toluene was
used as the solvent, the yield of the transformation reached
20% (entry 5). We further tested other oxidants including
inorganic and organic compounds (entries 6ꢀ8) and found
that the effect of soluble PhI(OAc)2 was similar to that of
Ag2CO3 (entry 8). Satisfactorily, the change of solvent to
CH2Cl2 led to 3a in 60% yield (entry 9). Further investiga-
tions revealed that the reaction could occur under a milder
temperature (60 °C) with the improved yield (entries
10ꢀ13). Other hypervalent iodide (III) reagents with differ-
ent anions were inferior to PhI(OAc)2 (entries 14 and 15),
which presumably resulted from the effects of the different
anions generated from iodide reagents on CꢀH bond
activation.13 A control experiment showed that the Rh
catalyst was necessary for the reaction to occur (entry 19).
Using the optimized condition (Table 1, entry 12), we
first evaluated the substrate scope of arenes. As shown in
Scheme 1, the 2-arylpyridines containing electron-donating
groups such as a methyl or methoxy substituent in the
(10) For selected reviews on Rh(III)-catalyzed CꢀH activations, see:
(a) Satoh, T.; Miura, M. Chem.;Eur. J 2010, 16, 11212. (b) Colby,
D. A.; Tsai, A. S.; Bergman, R. G.; Ellman, J. A. Acc. Chem. Res. 2012,
45, 814. (c) Patureau, F. W.; Wencel-Delord, J.; Glorius, F. Aldrichimica
Acta 2012, 45, 31. (d) Song, G.; Wang, F.; Li, X. Chem. Soc. Rev. 2012,
41, 3651.
(11) For selected examples of Rh(III)-catalyzed CꢀH activations,
see: (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (b) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F.
J. Am. Chem. Soc. 2011, 133, 2350. (c) Tsai, A. S.; Tauchert, M. E.;
Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2011, 133, 1248. (d) Li,
Y.; Li, B.-J.; Wang, W.-H.; Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2011, 50, 2115. (e) Wencel-Delord, J.;
Nimphius, C.; Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2012,
€
51, 2247. (f) Schroder, N.; Wencel-Delord, J.; Glorius, F. J. Am. Chem.
Soc. 2012, 134, 8298. (g) Wang, H.; Grohmann, C.; Nimphius, C.;
Glorius, F. J. Am. Chem. Soc. 2012, 134, 19592. (h) Morimoto, K.; Itoh,
M.; Hirano, K.; Satoh, T.; Shibata, Y.; Tanaka, K.; Miura, M. Angew.
€
Chem., Int. Ed. 2012, 51, 5359. (i) Hyster, T. K.; Knorr, L.; Ward, T. R.;
Rovis, T. Science 2012, 338, 500. (j) Ye, B.; Cramer, N. Science2012, 338,
504. (k) Chan, W.-W.; Lo, S.-F.; Zhou, Z.; Yu, W.-Y. J. Am. Chem. Soc.
2012, 134, 13565. (l) Zhen, W.; Wang, F.; Zhao, M.; Du, Z.; Li, X.
Angew. Chem., Int. Ed. 2012, 51, 11819. (m) Li, B.-J.; Wang, H.-Y.; Zhu,
Q.-L.; Shi, Z.-J. Angew. Chem., Int. Ed. 2012, 51, 3948. (n) Dong, J.;
Long, Z.; Song, F.; Wu, N.; Guo, Q.; Lan, J.; You, J. Angew. Chem., Int.
Ed. 2013, 52, 580. (o) Neely, J. M.; Rovis, T. J. Am. Chem. Soc. 2013, 135,
€
66. (p) Wang, H.; Schroder, N.; Glorius, F. Angew. Chem., Int. Ed. 2013,
52, 5386. (q) Zhang, G.; Yang, L.; Wang, Y.; Xie, Y.; Huang, H. J. Am.
Chem. Soc. 2013, 135, 8850.
(12) (a) Zalatan, D. N.; Bios, J. D. In Topics in Current Chemistry; Yu,
J.-Q., Shi, Z.-J., Eds.; Springer: Berlin, 2010; Vol. 292, pp 364ꢀ370. (b)
Bois, J. D. Org. Process Res. Dev. 2011, 15, 758.
(13) (a) Davies, D. L.; Donald, S. M. A.; Macgregor, S. A. J. Am.
Chem. Soc. 2005, 127, 13754. (b) Lafrance, M.; Fagnou, K. J. Am. Chem.
Soc. 2006, 128, 16496. (c) Li, L.; Brennessel, W. W.; Jones, W. D.
Organometallics 2009, 28, 3492.
B
Org. Lett., Vol. XX, No. XX, XXXX

para or meta positions on the aryl moiety were efficiently
coupled with the amide, producing the desired products
with good yields (3b, 3c, 3g, and 3h). However, the sub-
stituent on the 2-position of the aromatic ring resulted in a
slightly lower yield probably due to the steric factor (3g).
Substrates bearing an electron-withdrawing group af-
forded an excellent yield (3d). Notably, the aldehyde and
bromide groups, which are versatile for chemical transfor-
mations, were also tolerated (3e and 3f). We next examined
the substituent effect of the pyridine moiety. Methyl and
fluoro substituents on the 50-position of pyridine furnished
the desired products in 74% and 71% yields (3i and 3j).
The amidations of 1-phenylisoquinoline and benzo-
[h]quinoline afforded the desired products, 3k and 3l, in
70% and 91% yields. Interestingly, the optimal conditions
are also applicable to other heterocycles besides pyridine.
Amidation of 1-phenylpyrazole afforded the desired pro-
duct (3m) in 62% yield. We also found that aryl oxazolines
underwent smoothly the amidation at the ortho-position,
affording the corresponding products (3nꢀ3q) in good to
excellent yields at the elevated temperature (100 °C).
electron-deficient amide (4o). Unfortunately, some amides
such as N-methyl arylsulfonamides, benzamides, and ani-
lines did not react with the arenes under the optimal or
modifiedreaction conditions. Wespeculatethat theamines
bearing strong electron-withdrawing groups can increase
the acidity of the NꢀH bond and assist the amides to
couple with arenes.
Scheme 2. Rh-Catalyzed Amidation of Different Amidesa
Scheme 1. Rh-Catalyzed Amidation of Different Arenesa
a Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), [Cp*RhCl2]2
(2.5 mol %), AgSbF6 (10 mol %), PhI(OAc)2 (0.3 mmol), CH2Cl2 (2 mL).
b Reactions were performed at 100 °C. c 1a (0.2 mmol), 2 (1.1 equiv).
To obtain some preliminary mechanistic insight into
the amidation reaction, we performed isotope labeling
experiments (Scheme 3). When CD3OD was added as the
mixed solvent, a significant H/D scrambling exclusively
in the ortho-position of the phenyl group was observed
(Scheme 3a). On top of that, the intermolecular com-
petition experiment between 2-phenylpyridine and 2-
(pentadeuteriophenyl)pyridine in one vessel was not in-
dicative of a notable primarykinetic isotope effect (kH/D
=
a Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), [Cp*RhCl2]2
(2.5 mol %), AgSbF6 (10 mol %), PhI(OAc)2 (0.3 mmol), CH2Cl2
(2 mL), isolated yield. b Reactions were performed at 100 °C.
1.67) (Scheme 3b).14 These data suggested that the Rh-
catalyzed ortho-CꢀH bond cleavage in the amidation
reaction is reversible.
Presynthesized cyclometalated Rh(III) complex 515 re-
acted with sulfonamide (2a) producing the amidating
product in 50% yield (Scheme 4a). We also observed
that complex 5 could catalyze the amidation of the CꢀH
bond and furnished the desired product in 74% yield
(Scheme 4b). These reactions indicate that 5 is a plausible
activated intermediate in the reaction. To identify whether
Additionally, the scope of sulfonamides was examined
under the established conditions (Scheme 2). The sulfon-
amides containing electron-withdrawing groups such as F,
Cl, Br, CF3, or NO2 on the arene moiety furnished good
yields (4dꢀ4j) while arylsulfoamide substrates bearing
electron-donating groups such as methyl (4b) or methoxy
(4c) resulted in slightly diminished yields. By increasing
the reaction temperature to 100 °C, alkyl-substituted
sulfonamides also reacted efficiently (4lꢀ4n). It is worth
mentioning that the methodology could also be applied to
(14) Simmons, E. M.; Hartwig, J. F. Angew. Chem., Int. Ed. 2012, 51,
3066.
(15) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008,
130, 12414.
Org. Lett., Vol. XX, No. XX, XXXX
C

amide transfers to the Rh(III) center with the aid of a base,
yielding the intermediate IV that undergoes reductive
elimination to form the CꢀN bond and Rh(I) intermediate
VI. Then, the Rh(I) intermediate is oxidized by PhI(OAc)2
to generate Rh(III) intermediate VII. In path b and c, the
intermediate nitrenoid V16 possessing a Rh(V) center11e,f,17
is generated via the intermediate IV or III, respectively.
The intermediate V undergoes reductive elimination to
form CꢀN bond Rh(III) species VII. Finally, the six-
membered rhodacycle is protonated by the acid generated
in situ, producing the desired product.
Scheme 3. Deuteration Experiments
Scheme 5. Proposed Mechanism
a nitrene intermediate (PhIdNꢀTs, 6) is generated from
the reaction of PhI(OAc)2 with sulfonamide, the reaction
of nitrene precursor 6 was carried out under identical
conditions (Scheme 4c), which afforded only an ∼10%
yield of the product. A further experiment (Scheme 4d)
gave the desired product in 56% yield. These results
suggested that the Rh-catalyzed CꢀH amidation likely
involved the nitrene intermediate.
Scheme 4. Mechanistic Experiments
In summary, a novel Rh-catalyzed method for the
N-chelator directed ortho-sp2 CꢀH bond amidation has
been developed for the first time, which allowed using
sulfonamides as the amidating reagents under mild reac-
tion conditions. This efficient method enables various
arenes to be amidated with both aromatic and aliphatic
sulfonamides with good functional group tolerance and
selectivity in good to excellent yields, providing a comple-
ment to the existing amidation methods. Our future work
is to expand the substrate scope of this protocol and get a
better understanding of the reaction mechanism.
Acknowledgment. Financial support from the 973 Pro-
gram (2011CB932404, 2011CBA00501), NSFC (20925102,
21202164), and National Key Technology R & D Program
(2012 BAE 06B08) is greatly appreciated.
Based on the experiments and related Rh-catalyzed
CꢀN bond formation reported by others,4d,7c,7d a plausi-
ble mechanism for this reaction is proposed in Scheme 5. A
highly electrophilic Rh(III) species I is generated from the
Rh precursor, which is stabilized by coordinating to the
nitrogen of 2-phenylpyridine. The N-directed CꢀH bond
activation occurs via a base-assisted concerted metalationꢀ
deprotonation process,11e,13c forming a five-membered-
rhodacycle III.11c,d Subsequently, the reaction may pro-
ceed via three possible paths. In the case of path a, the
Supporting Information Available. Detailed experimen-
tal procedures and characterization for products. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(17) For Rh(V) species, see: (a) Duckett, S. B.; Perutz, R. N. Orga-
nometallics 1992, 11, 90. (b) Brayshaw, S. K.; Sceats, E. L.; Green, J. C.;
Weller, A. S. Proc. Natl. Acad. Sci. U.S.A. 2007, 104, 6921. (c)
Vyboishchikov, S. F.; Nikonov, G. I. Organometallics 2007, 26, 4160.
(16) For Rh(V)-nitrenoid species, see: Xu, L.; Zhu, Q.; Huang, G.;
Cheng, B.; Xia, Y. J. Org. Chem. 2012, 77, 3017.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX