Rh[III]-catalyzed direct C-H amination using N -chloroamines at room temperature

Article abstract of DOI:10.1021/ol203353a

An efficient Rh(III)-catalyzed direct C-H amination of N-pivaloyloxy benzamides with N-chloroamines proceeding at room temperature was achieved. The versatile directing group allows for selective mono- and diamination and can be readily converted to give valuable benzamide or aminoaniline derivatives. Mechanistic studies have been carried out to elucidate the reaction pathway.

Full text of DOI:10.1021/ol203353a

ORGANIC
LETTERS
2012
Vol. 14, No. 2
656–659
Rh[III]-Catalyzed Direct CÀH Amination
Using N-Chloroamines at Room
Temperature
Christoph Grohmann, Honggen Wang, and Frank Glorius*
€
€
€
Westfalische Wilhelms-Universitat Munster, Organisch-Chemisches Institut,
Corrensstrasse 40, 48149 Mu€nster, Germany
glorius@uni-muenster.de
Received December 15, 2011
ABSTRACT
An efficient Rh(III)-catalyzed direct CÀH amination of N-pivaloyloxy benzamides with N-chloroamines proceeding at room temperature was
achieved. The versatile directing group allows for selective mono- and diamination and can be readily converted to give valuable benzamide or
aminoaniline derivatives. Mechanistic studies have been carried out to elucidate the reaction pathway.
The field of CÀH activation has seen considerable progress,
providing new transformations and improved efficiency.1
However, many of the developed processes require harsh
reaction conditions, thereby restricting their applicability in
synthesis. Consequently, the necessity for the design of mild
and powerful CÀH functionalization methods has become
evident.2 Among the desired transformations, the valuable
transition metal catalyzed CÀH amination reaction has been
unraveled only with limitations.3 As an alternative to the
established BuchwaldÀHartwig amination,4 the correspond-
ing direct transformation of aromatic CÀH bonds has been
predominantly reported in an intramolecular fashion,
mostly using Pd or Cu catalysts.5 The more challenging
intermolecular version had in most cases been limited
(4) (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.
(5) For examples of intramolecular Pd-catalyzed CÀH amination
reactions, see: (a) Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am.
Chem. Soc. 2005, 127, 14560. (b) Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc.
2008, 130, 14058. (c) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias,
M.; Beck, E. M.; Gaunt, M. J. Am. Chem. Soc. 2008, 130, 16184. (d) Mei,
T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 10806. (e)
(1) Recent reviews on CÀH functionalization using transitionmetals:
(a) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147. (b) Colby,
D. A.; Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (c) Xu,
L.-M.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712. (d)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792. (e) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2009, 48, 5094. (f) Giri, R.; Shi, B.-F.; Engle,
K. M.; Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (g) Li,
B.-J.; Yang, S.-D.; Shi, Z.-J. Synlett 2008, 949. (h) Kakiuchi, F.; Kochi,
T. Synthesis 2008, 3013. (i) Satoh, T.; Miura, M. Top. Organomet. Chem
2008, 24, 61. (j) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007,
107, 174. (k) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 46,
677.
€
Neumann, J.; Rakshit, S.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed.
2009, 48, 6892. (f) Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132,
3676. For recent Cu-catalyzed examples, see: (g) Brasche, G.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2008, 47, 1932. (h) Wang, H.; Wang, Y.;
Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem. Soc. 2010, 132, 13217. (i) Cho,
S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133, 5996.
(6) For intermolecular CÀH amination of heteroaromatics and
polyfluorinated aromatics, see: (a) Monguchi, D.; Fujiwara, T.;
Furukawa, H.; Mori, A. Org. Lett. 2009, 11, 1607. (b) Wang, Q.;
Schreiber, S. L. Org. Lett. 2009, 11, 5178. (c) Cho, S. H.; Kim, J. Y.;
Lee, S. Y.; Chang, S. Angew. Chem., Int. Ed. 2009, 48, 9127. (d) Kim,
J. Y.; Cho, S. H.; Joseph, J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49,
9899. (e) Kawano, T.; Hirano, K.; Satoh, T.; Miura, M. J. Am. Chem.
Soc. 2010, 132, 6900. (f) Zhao, H.; Wang, M.; Su, W.; Hong, M. Adv.
Synth. Catal. 2010, 352, 1301. (g) Miyasaka, M.; Hirano, K.; Satoh, T.;
Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett. 2011, 13, 359. (h)
Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13,
2860. (i) Liu, X.-Y.; Gao, P.; Shen, Y.-W.; Liang, Y.-M. Org. Lett. 2011,
13, 4196. (j) For a recent transition-metal-free CÀH amination of
benzoxazoles, see: Wertz, S.; Kodama, S.; Studer, A. Angew. Chem.,
Int. Ed. 2011, 50, 11511.
(2) Critical review on mild metal-catalyzed CÀH activation:
€
Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740.
(3) For reviews of CÀH amination, see: (a) Mueller, P.; Fruit, C.
Chem. Rev. 2003, 103, 2905. (b) Davies, H. M. L.; Long, M. S. Angew.
Chem., Int. Ed. 2005, 44, 3518. (c) Dick, A. R.; Sanford, M. S. Tetra-
hedron 2006, 62, 2439. (d) Davies, H. M. L.; Manning, J. R. Nature 2008,
451, 417. (e) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009,
5061. (f) Armstrong, A.; Collins, J. C. Angew. Chem., Int. Ed. 2010, 49,
2282.
r
10.1021/ol203353a
Published on Web 12/23/2011
2011 American Chemical Society

to activated systems such as azoles or polyfluorinated
aromatics.6 Only a few examples of the direct amination of
unactivated aromatic CÀH bonds have been reported: Pd-
catalyzed oxidative amidation of oximes7a or anilides7b
with amides (via reactive nitrene intermediates) or
sulfonamides.7c,d Yu et al.8 recently communicated the Pd-
catalyzed CÀH amination of aromatic CÀH bonds using an
electron-deficient amide directing group and secondary
N-benzoyloxyamines. However, the reported Pd-catalyzed
methods involve oxidizing conditions at elevated tempera-
tures. Accounting for the need to design more benign and
generally applicable processes, it is desirable to develop
a mild CÀH amination of aromatic substrates using an
efficient and versatile directing group, which is (1) readily
accessible and (2) easily converted to different valuable
functionalities. Herein, we report on a Rh-catalyzed direct
CÀH amination of aromatic CÀH bonds9 proceeding at rt
by usage of the easily installed and versatile N-pivaloyloxy
amide directing group (DG) CONHOPiv and N-chloroalk-
ylamines as a readily accessible nitrogen source.
Table 1. Reaction Optimizationa
yield
(%)b
entry substrate amine catalyst
base
1
1a
1a
1a
1b
1b
1b
1b
1b
1b
2a [RhCp*Cl2]2 CsOAc
2a [RhCp*Cl2]2 CsOAc
2a Pd(OAc)2 CsOAc
27, 3aa
35, 3aa
<5, 3aa
80, 3ba
83, 3ba
2c
3c
4
2a [RhCp*Cl2]2 CsOAc
2a [RhCp*Cl2]2 CsOPiv
5
6d
7
2a [RhCp*Cl2]2 CsOAc, PivOH 85 (80), 3ba
5
[RhCp*Cl2]2 CsOAc
56, 3ba
(75), 4a
72, 3ba
8
9e
2a [RhCp*Cl2]2 AgOAc
2a [RhCp*Cl2]2 CsOAc
We10 and others11 have previously reported on Rh(III)-
catalyzed CÀH functionalization reactions proceeding
under mild conditions by application of benzhydroxamic
acid derived DGs.12 Encouraged by these results, we
approached the CÀH amination to build up important
a Reaction conditions: substrate 1a or 1b (0.2 mmol), N-substituted
morpholine (0.4 mmol), catalyst (5 mol %), base (0.4 mmol), dry MeOH
(1 mL), rt, 16 h. b Determined by 1H NMR of crude product using
CH2Br2 (7.04 μL) as internal standard; isolated yields in parentheses.
c 100 °C, 0.2 mmol of CsOAc. d 0.4 mmol of CsOAc, 0.1 mmol of PivOH.
e 0.6 mmol of 2a, 1 mol % [RhCp*Cl2]2, 0.6 mmol of CsOAc, 40 °C.
(7) For Pd-catalyzed intermolecular oxidative CÀH amidation, see:
(a) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc. 2006, 128,
9048. (b) Ng, K.-H.; Chan, A. S. C.; Yu, W.-Y. J. Am. Chem. Soc. 2010,
132, 12862. (c) Xiao, B.; Gong, T.-J.; Xu, J.; Liu, Z.-J.; Liu, L. J. Am.
Chem. Soc. 2011, 133, 1466. (d) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.;
Zhang, Q. J. Am. Chem. Soc. 2011, 133, 1694.
(8) For Pd-catalyzed intermolecular CÀH amination with alkyla-
mines, see: Yoo, E. J.; Ma, S.; Mei, T.-S.; Chan, K. S. L.; Yu, J.-Q. J. Am.
Chem. Soc. 2011, 133, 7652.
(9) (a) For a representative account on Rh-catalyzed CÀH amination
of saturated CÀH bonds, see: Du Bois, J. Org. Process Res. Dev. 2011,
15, 758. (b) During preparation of this manuscript, a related work
has been reported: Ng, K.-H.; Zhou, Z.; Yu, W.-Y. Org. Lett. 2011,
DOI: 10.1021/ol203046n.
(10) (a) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am.
Chem. Soc. 2011, 133, 2350. See also: (b) Willwacher, J.; Rakshit, S.;
Glorius, F. Org. Biomol. Chem. 2011, 9, 4736. (c) Patureau, F. W.;
Nimphius, C.; Glorius, F. Org. Lett. 2011, 13, 6346. (d) Patureau, F. W.;
Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1064. (e)
Patureau, F. W.; Besset, T.; Kuhl, N.; Glorius, F. J. Am. Chem. Soc.
2011, 133, 2154. (f) Besset, T.; Kuhl, N.; Patureau, F. W.; Glorius, F.
Chem.;Eur. J. 2011, 17, 7167. (g) Rakshit, S.; Patureau, F. W.; Glorius,
F. J. Am. Chem. Soc. 2010, 132, 9585. (h) Patureau, F. W.; Glorius, F.
J. Am. Chem. Soc. 2010, 132, 9982.
(11) (a) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (b) Guimond, N.; Gorelsky, S.; Fagnou, K. J. Am.
Chem. Soc. 2011, 133, 6449. For further important recent Rh(III)-
catalyzed CÀH activation/CÀC bond forming processes, see: (c) Ueura,
K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. (d) Umeda, N.;
Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74, 7094. (e) Tsai,
A. S.; Tauchert, M. E.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc.
2011, 133, 1248. (f) 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. (g)
Hyster, T. K.; Rovis, T. Chem. Sci. 2011, 1601. (h) Gong, T.-J.; Xiao, B.;
Liu, Z.-J.; Wan, J.; Xu, J.; Luo, D.-F.; Fu, Y.; Liu, L. Org. Lett. 2011, 13,
3235. (i) Mochida, S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem.
2011, 76, 3024. (j) Park, S. H.; Kim, J. Y.; Chang, S. Org. Lett. 2011, 13,
2372.
arylamines.13 Therefore, we commenced our study by
choosing benzhydroxamic acid derivative 1a as the sub-
strate, [RhCp*Cl2]2 as the catalyst, and CsOAc as the
base in methanol at rt (Table 1). As an aminating partner
we employed N-chloromorpholine 2a, which has been re-
ported to be efficient in the amination of azoles at rt.6e,14
To our delight, we observed the aminated product 3aa in
reasonable yield (entry 1). Further optimization revealed
the O-pivaloyl group of 1b to be effective at rt: using
CsOAc as the base and pivalic acid (PivOH) in substoi-
chiometric amounts, 80% of 3ba could be isolated
(entry 6). Notably, Pd(OAc)2 did not promote this reac-
tion (entry 3) and use of N-benzoyloxy morpholine 5
which was reported to be successful in Pd-catalyzed direc-
ted CÀH amination8 gave the product in a significantly
lower yield (entry 7). When AgOAc was used instead of
CsOAc, surprisingly the diamination product 4a was
obtained in 75% isolated yield (entry 8). In accordance
with a practical point of view, the catalyst loading can also
be lowered to 1 mol % [RhCp*Cl2]2 by increasing both the
amount of chloroamine to 3 equiv and the reaction tem-
perature to 40 °C (entry 9).
With these conditions in hand, the scope of the amine
partner was explored (Scheme 1). All of the present chloro-
amines are readily accessible from the corresponding
(12) For the pioneering use of O-methyl hydroxamic acids as DG in
CÀH activation chemistry, see: Wang, D.-H.; Wasa, M.; Giri, R.; Yu,
J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(13) (a) Lawrence, S. A. Amines: Synthesis, Properties and Applica-
tion; Cambridge University: Cambridge, U.K., 2004. (b) Amino Group
Chemistry: From Synthesis to the Life Sciences; Ricci, A., Eds.;
Wiley-VCH: Weinheim, 2007.
(14) For selected examples of N-chloroamines and N-chloroamides
as electrophilic nitrogen sources in metal-catalyzed amination reactions,
see: (a) He, C.; Chen, C.; Cheng, J.; Liu, C.; Liu, W.; Li, Q.; Lei, A.
Angew. Chem., Int. Ed. 2008, 47, 6414. (b) Barker, T. J.; Jarvo, E. R.
J. Am. Chem. Soc. 2009, 131, 15598. (c) For noncatalytic amination, see:
Hatakeyama, T.; Yoshimoto, Y.; Ghorai, S. K.; Nakamura, M. Org.
Lett. 2010, 12, 1516.
Org. Lett., Vol. 14, No. 2, 2012
657

Scheme 1. Substrate Scopea
Scheme 2. Derivatization of the N-Pivaloyloxy Amide Directing
Group
amount of chloromorpholine 2a. Also, meta (3la) and
ortho (3ka) substituents could be applied successfully in
this method. Interestingly, halide substituents (3ia, 3ja)
seem to hamper the reaction, although the reason for this
drop in reactivity remains to be elucidated.16 In contrast,
substrates bearing the strongly electron-withdrawing tri-
fluoromethyl group (3na) and the reactive C(aryl)ÀI
bond (3ma) could be aminated successfully using this
protocol. This is remarkable, since aryliodides represent
synthetically very useful moieties, allowing for further
transformation.
To get access to valuable amino benzamides 6, the NÀO
bond of the N-pivaloyloxy amide in 3ba can be easily
cleaved using SmI2 as a reductant (Scheme 2).17 Impor-
tantly, heating under basic conditions causes the N-piva-
loyloxy amide group to undergo a Lossen rearrangement.18
This fact might be particularly useful, since valuable 2-
aminoaniline derivatives can be readily obtained from the
aminated products 3, as could be demonstrated in the
synthesis of 1-morpholinoaniline 7 from 3ba. Furthermore,
by reaction of 3 with amines, urea functionalities can be
installed into the molecule, providing access to biologically
interesting structures (8).19
We then tried to gain some insight into the mechanism
by conducting a series of experiments.20 To check the re-
versibility of the CÀH activation step, a reaction using
substrate 1b was carried out in MeOH-d4 with omission of
N-chloromorpholine 2a (Scheme 3, I). The deuterium
incorporation was monitored by ESI-MS analysis and
revealed significant deuteration of 1b already after 30 min.
Furthermore, after 18 h only 2% undeuterated 1b was left,
displaying an efficient reversible cyclometalation of 1b
a Reaction conditions: 1b (1.0 mmol), N-chloroamine (2) (2.0 mmol),
[RhCp*Cl2]2 (5 mol %), CsOAc (2.0 mmol), PivOH (0.5 mmol), MeOH
(5 mL), rt, 16 h. Isolated yields. bAt 60 °C. cAgOAc (2.0 equiv) instead of
CsOAc and PivOH, 3 h, rt. dReaction conditions: N-pivaloyloxy benza-
mide 1 (0.5 mmol), 2a (1.5 mmol), CsOAc (1.5 mmol), PivOH
(0.25 mmol), [RhCp*Cl2]2 (5 mol %), MeOH (2.5 mL), rt, 16 h. e4 equiv
of CsOAc and 2a. f5 equiv of CsOAc and 2a. g10 equiv of CsOAc and 2a.
h10 mol % [RhCp*Cl2]2.
amines and bleach.15 The reaction proceeds smoothly for
secondary (hetero)cyclic N-chloroamines and gives the
monoaminated products in good to excellent yields. Grat-
ifyingly, ester and Boc protecting group are well tolerated
(3bc, 3be). However, a decrease in yield was observed, when
acyclic substrates were engaged (3bf), probably due to their
increased steric demand. Next, we examined the arene
partner for the influence of functional groups and the
substitution pattern of the aromatic ring on the reaction
course (Scheme 1). Alkyl (3ca, 3da) and phenyl substituents
(3ea) in the para position to the DG do not alter the
reaction outcome. Remarkably, the naphthamide de-
rived substrate (3fa) is aminated in the less sterically
hindered position in good yield. The methyl ester (3ga)
and methoxy group (3ha) in the para position are also
tolerated well, providing good yields with an excess
(16) In the cases of 3ia and 3ja, the reaction did not reach complete
conversion, even though an excess of N-chloromorpholine 2a was used.
Prolonged reaction time and heating did not improve the yield.
(17) For NÀO cleavage using SmI2, see: (a) Keck, G. E.; Wager,
T. T.; McHardy, S. F. Tetrahedron 1999, 55, 11755.
(18) For Lossen rearrangement, see: (a) Lossen, H. Liebigs Ann.
Chem. 1869, 150, 314. (b) Lossen, W. Liebigs Ann. Chem. 1872, 161, 347;
1877, 186, 1; 1889, 252, 170; 1894, 281, 169. For review, see: (c) Bauer, L.;
Exner, O. Angew. Chem., Int. Ed. Engl. 1974, 13, 376.
(19) For AVE2865, a structurally related potent glycogen phosphor-
ylase inhibitor, see: Anderka, O.; Loenze, P.; Klabunde, T.; Dreyer,
M. K.; Defossa, E.; Wendt, K. U.; Schmoll, D. Biochemistry 2008, 47,
4683.
(15) Zhong, Y.-L.; Zhou, H.; Gauthier, D. R.; Lee, J.; Askin, D.;
Dolling, U. H.; Volante, R. P. Tetrahedron Lett. 2005, 46, 1099.
(20) See Supporting Information for further experimental details and
analytical data.
658
Org. Lett., Vol. 14, No. 2, 2012

Scheme 3. Deuteration Experiments Probing the Reversibility
of the CÀH Activation Step and the Kinetic Isotope Effect
Scheme 4. Proposed Mechanism
presence of N-chloroamine 2. The next steps in the catalytic
cycle are comparably fast but can only be presumed. N-Chloro
amine 2 might undergo an electrophilic amination14 of
rhodacycle A to give metalated species B, which upon
protodemetalation affords the amination product 3 and the
Rh(III)-catalyst.
In conclusion we have developed a Rh(III)-catalyzed
directed amination of aromatic CÀH bonds with N-chloro-
amines proceeding at rt. The use of a versatile N-pivaloyloxy
amide directing group is attractive, since it allows for further
diversification of the arylamine products into valuable
benzamide and 1-aminoaniline derivatives. Mechanistic stu-
dies revealed the CÀH activation event as the slow and
irreversible step of the catalytic cycle. This novel method
constitutes an extension to known Pd-catalyzed CÀH ami-
nation processes and benefits the design of new synthetic
approaches to important arylamine structures.
with the Rh-catalyst. When the same experiment was run
in the presence of 1 equiv of N-chloromorpholine 2a
(Scheme 3, II) and stopped after 30 min, 38% of 3ba
and 56% 1b could be isolated. Analysis by 1H NMR and
ESI-MS showed no deuterium incorporation in both
starting material and product, suggesting the CÀN bond
formation to be significantly faster than the back reaction
of the CÀH activation step.21 Next, in determining the
rate-determining step of the catalytic cycle, the deuterium
kinetic isotope effect was measured (Scheme 3, III). There-
fore, substrate d5-1b was synthesized and together with 1b
submitted to the Rh-catalyzed CÀH amination. After
15 min, the reaction was stopped and the products were
analyzed by 1H NMR and ESI-MS. A large kH/kD value
of 8.1 was observed, indicating the CÀH/CÀD bond
dissociation event as the rate-determining step of the
reaction pathway.
From these results, we would like to propose the following
mechanistic scenario (Scheme 4): After dissociation of the
rhodium dimer, ligand exchange of the monomer with the
present cesium salts provides a rhodium-carboxylate
species.22 Precomplexation to the directing N-pivaloyloxy
amide moiety is followed by CÀH activation to form
rhodacyle A; CÀH activation is the slow step in the catalytic
cycle and is reversible in the absence and irreversible in the
Acknowledgment. Generous financial support by the
€
DFG (IRTG Munster-Nagoya) and by the European
Research Council under the European Community’s Seven-
th Framework Program (FP7 2007-2013)/ERC Grant
Agreement No. 25936 is gratefully acknowledged. The
research of F.G. has been supported by the Alfried Krupp
Prize for Young University Teachers of the Alfried Krupp
von Bohlen und Halbach Foundation.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) For a related mechanistic investigation of an Rh-catalyzed
isoquinolone synthesis, see: Hyster, T. K.; Rovis, T. J. Am. Chem.
Soc. 2010, 132, 10565.
(22) Li, L.; Brennessel, W. W.; Jones, W. D. Organometallics 2009,
28, 3492.
Org. Lett., Vol. 14, No. 2, 2012
659