Rhodium(III)-Catalyzed Activation of Csp3 -H Bonds and Subsequent Intermolecular Amidation at Room Temperature

Article abstract of DOI:10.1002/anie.201504507

Disclosed herein is a Rh^III-catalyzed chelation-assisted activation of unreactive Csp3-H bonds, thus enabling an intermolecular amidation to provide a practical and step-economic route to 2-(pyridin-2-yl)ethanamine derivatives. Substrates with other N-donor groups are also compatible with the amidation. This protocol proceeds at room temperature, has a relatively broad functional-group tolerance and high selectivity, and demonstrates the potential of rhodium(III) in the promotive functionalization of unreactive Csp3-H bonds. A rhodacycle having a SbF₆^- counterion was identified as a plausible intermediate. Giving direction: The title reaction leads to the successful functionalization of unreactive Csp3-H bonds in the presence of directing groups (DGs). A rhodacycle having a SbF₆^- counterion was isolated and is proposed to be a plausible intermediate.

Full text of DOI:10.1002/anie.201504507

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Angewandte
Communications
International Edition: DOI: 10.1002/anie.201504507
À
C H Activation
German Edition:
DOI: 10.1002/ange.201504507
À
Rhodium(III)-Catalyzed Activation of Csp3 H Bonds and Subsequent
Intermolecular Amidation at Room Temperature**
Xiaolei Huang, Yan Wang, Jingbo Lan, and Jingsong You*
Abstract: Disclosed herein is a RhIII-catalyzed chelation-
catalytic systems are difficult to find. As part of our ongoing
assisted activation of unreactive Csp3 H bonds, thus enabling
efforts in rhodium(III)-catalyzed C H activation,[5] we herein
À
À
an intermolecular amidation to provide a practical and step-
economic route to 2-(pyridin-2-yl)ethanamine derivatives.
Substrates with other N-donor groups are also compatible
with the amidation. This protocol proceeds at room temper-
ature, has a relatively broad functional-group tolerance and
high selectivity, and demonstrates the potential of rhodium(III)
illustrate a solution to this challenge through a rhodium-
À
catalyzed chelation-assisted amidation of unactivated Csp3
bonds as a representative example.
H
À
Recently, the approach toward direct Csp3 H amination
À
involving a C H activation process has attracted much
attention.[6–8] Despite significant advantages, such as high
selectivity and atom efficiency, most of the precedented
À
in the promotive functionalization of unreactive Csp3 H bonds.
A rhodacycle having a SbF6 counterion was identified as
À
À
examples have been restricted to Csp3 H activation/intra-
a plausible intermediate.
molecular amination,[9] and intermolecular amination was
developed initially.[10] Palladium has been established to
À
O
ver the past decades, the development of rhodium(III)-
catalysis has been an area of intense research in the synthetic
organic community. Recently, rhodium(III) has exhibited
enable unreactive Csp3 H bond activation/intermolecular
amination.[10a,b] Very recently, Chang and co-workers reported
the first iridium-catalyzed ketoxime-assisted intermolecular
À
À
great potential in the promotion of Csp2 H bond activation for
the construction of carbon–carbon and carbon–heteroatom
amidation of unactivated Csp3 H bonds with azides as the
amino source (Scheme 2a).[10c,d] Notably, the majority of the
amination reactions require relatively harsh reaction condi-
tions, especially elevated temperatures, which may be incom-
patible with sensitive functional groups. Thus, it would be
bonds.[1,2] Undoubtedly, expanding this chemistry to unreac-
tive Csp3 H sites is an appealing, yet conceptual and practical
challenge (Scheme 1). Although a few rhodium-catalyzed
À
À
valuable to discover an unreactive Csp3 H bond activation/
amination at room temperature.
À
Scheme 1. Evolution of rhodium(III)-catalyzed C H activation/func-
tionalization.
À
functionalizations of reactive Csp3 H bonds, such as those
which are acidic, adjacent to N, allylic, and benzylic have been
reported recently,[3] the activation of unreactive and remote
À
Csp3 H bonds with subsequent functionalization still remains
unsolved.[4] Several factors may be responsible for this
significant challenge, including: 1) Cleavage of inert, aliphatic
À
Scheme 2. Transition-metal-catalyzed activation of unreactive Csp3
bonds and subsequent amidation.
H
À
C H bonds with a metal is typically slow because of their high
bond strengths; and 2) comprehensive understanding of the
À
mechanistic aspects governing rhodium-catalyzed Csp3
activation remains obscure, and thus efficient rhodium
H
2-(Pyridin-2-yl)ethanamine derivatives are important
structural motifs widely found in pharmaceuticals and bio-
logically active molecules (Scheme 3).[11] Thus, their synthesis
has attracted considerable attention in the organic chemistry
community. Conventional routes to 2-(pyridin-2-yl)ethan-
amine derivatives usually require harsh reaction conditions
and multiple-step sequences.[11d,12] Undoubtedly, it would be
highly desirable to develop a rapid and concise strategy for
the synthesis of these prevalent skeletons. Considering that 2-
ethylpyridine derivatives are easily accessible synthetic pre-
cursors, we surmised that the selective amination or amida-
[*] X. Huang, Y. Wang, Prof. Dr. J. Lan, Prof. Dr. J. You
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, and State Key Laboratory of
Biotherapy, West China Medical School, Sichuan University
29 Wangjiang Road, Chengdu 610064 (PR China)
E-mail: jsyou@scu.edu.cn
[**] This work was supported by grants from the National NSF of China
(21432005, 21272160, and 21321061).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504507.
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Table 1: The scope with respect to the alkanes having different directing
groups.[a,b]
Scheme 3. Selected pharmaceutical and biologically active molecules
containing 2-(pyridin-2-yl)ethanamine derivatives.
À
tion of the inert methyl Csp3 H bond over the relatively
À
activated methylene Csp3 H bond would offer a practical,
step-economic route to 2-(pyridin-2-yl)ethanamine deriva-
tives through the direct use of the inherent pyridyl moiety as
the directing group (Scheme 2b).[13]
Our study commenced with the reaction of 2-(tert-
butyl)pyridine (1a) and 4-nitrobenzenesulfonamide (2a;
for detailed reaction optimization, see Table S1 in the
Supporting Information). After screening several parameters
(e.g., catalyst, oxidant, additive, solvent, and temperature),
3a (for structure see Table 1) was obtained in 75% yield
with the optimal catalytic system, which comprised
[Cp*Rh(MeCN)3][SbF6]2 (13 mol%; Cp* = pentamethyl
cyclopentadienyl), PhI(OAc)2 (1.5 equiv), and NaOAc
(30 mol%) in CH2Cl2 at room temperature for 48 hours. It
is worth noting that neither bis(amide) nor tri(amide)
compounds were observed when excess 2a was added (see
Table S1, entry 20).
[a] Reactions were performed with 1 (0.50 mmol) and 2a (0.25 mmol) in
0.75 mL of CH2Cl2. [b] Yields of isolated products. [c] [Cp*Rh(MeCN)3]-
[SbF6]2 (20 mol%), 72 h. [d] [{RhCp*Cl2}2] (8.0 mol%), AgNTf2
(32 mol%), and CH2Cl2 (0.5 mL). [e] [{RhCp*Cl2}2] (12 mol%), AgNTf2
(48 mol%), and CH2Cl2 (0.5 mL), 72 h. Tf =trifluoromethanesulfonyl.
Table 2: The scope with respect to the amides.[a,b]
With the optimal reaction conditions in hand, we explored
the scope with respect to the 2-ethylpyridine derivatives. As
summarized in Table 1, various 2-alkylpyridine derivatives
smoothly reacted with 2a, thus affording the desired products
in good yields (3a–c). Substrates with functional groups such
as alkoxy, phenyl, chloride, and ester on the alkane skeletons
were compatible with this reaction (3d–i). Moreover, elec-
tron-donating substituents on the pyridine ring resulted in
satisfactory yields (3j–l), whereas an electron-withdrawing
substituent disfavored the amidation (3m). When isoquino-
line was used as a directing group, the amidated product was
obtained in 66% yield (3n). Other kinds of alkanes with
different N-donor groups were also investigated. Cyclohex-
ane ketoximes, derived from tertiary alcohols, were compat-
ible with this amidation reaction in satisfactory yields (3o and
3p). 3-(tert-Butyl)-5,6-dihydro-1,4,2-dioxazine reacted with
2a to give the amidated product 3q in 61% yield. Moreover,
(E)-2-methylcyclohexanone O-methyl oxime could undergo
[a] Reactions were performed with 1a (0.50 mmol) and 2 (0.25 mmol) in
0.75 mL of CH2Cl2. [b] Yields of isolated products. [c] 1a (0.25 mmol)
and 2,2,2-trifluoroacetamide 2l (0.5 mmol).
By using PhSH and K2CO3 in MeCN, 3a was deprotected
to give 2-methyl-2-(pyridin-2-yl)propan-1-amine (5) in 90%
yield [Eq. (1)].[14] The amidated product 3q could also be
conveniently transformed into a b-amino acid in 68% yield
[Eq. (2)].[15]
À
b-amidation of a primary Csp3 H bond (3r).
Next, investigation of scope with respect to the amide
revealed that other aryl sulfonamides possessing an electron-
withdrawing group on the phenyl ring had similar reactivity
(4a–c; Table 2). Alkyl sulfonamides could also undergo the
amidation process in acceptable yields (4d–f). With an excess
of 2,2,2-trifluoroacetamide, 2-(tert-butyl)pyridine was trans-
formed into the amidated product 4g in 53% yield.
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The amidation reaction of 1a with 2a by using neutral 6 as
the catalyst furnished the desired product 3a in only 15%
yield [Eq. (3)]. However, the yield of 3a increased to 50%
when AgSbF6 was introduced into the reaction mixture
[Eq. (4)]. Moreover, 7 also catalyzed the amidation of 1a to
afford 3a in 58% yield [Eq. (5)]. These results suggested the
possible intermediacy of a cationic five-membered rhodacycle
complex in the catalytic cycle.
To gain insight into the reaction mechanism, deuterium-
labeling experiments were conducted. The hydrogen–deute-
À
rium exchange experiments exhibited that the primary Csp3
H
bond cleavage was an irreversible process (Scheme 4a). The
intermolecular competition reaction between 1g and [D6]-1g
with 2a in one vessel gave a notable primary kinetic isotopic
effect (kH/kD = 6.0; Scheme 4b). This result revealed that the
À
C H bond cleavage might be related to the rate-determining
step.[16]
Given that a nitrene precursor might be generated in situ
from PhI(OAc)2 and sulfonamide, two experiments were
performed to confirm whether a nitrene intermediate was
involved in the catalytic cycle. The reaction of 1a with the
nitrene precursor 8[19] gave 3a in 12% yield [Eq. (6)]. A
further experiment afforded 3a in 55% yield by using 7 and 8
as substrates [Eq. (7)]. The facts imply that a nitrene inter-
mediate is likely involved in the amidation process.
Scheme 4. Deuterium-labeling experiments.
As the tert-butyl group has a conformational bias to favor
of the formation of cyclometalated species, 1a was used to
isolate rhodacycle intermediates. Surprisingly, 1a reacted
stoichiometrically with [{RhCp*Cl2}2] and AgSbF6 to afford
the neutral rhodium(III) complex 6 (Scheme 5a). Usually, the
rhodacycle formation reactions in the presence of
[{RhCp*Cl2}2]/AgSbF6 would give the corresponding cationic
À
five-membered rhodacycle complex with the SbF6 counter-
ion as a noncoordinating anion.[17] It is notable that 6 could
not be obtained without AgSbF6 (Scheme 5b). When 1a
reacted with [Cp*Rh(MeCN)3][SbF6]2, the cationic rhodium
species 7 could be obtained in an excellent yield (Scheme 5c).
Moreover, the neutral complex 6 could also be transformed
into 7 by using a stoichiometric amount of AgSbF6 to remove
chloride (Scheme 5d). The structures of the complexes 6 and
7 were confirmed by X-ray crystallographic analysis.[18]
Based on the above investigations and known rhodium-
(III)-catalyzed C H bond functionalizations,[2,3d,20] a plausible
À
mechanistic pathway is proposed (Scheme 6). First, the
intermediate IM1 is generated through chelation-assisted
À
Csp3 H activation. Next, the reaction has three possible
paths.[20] In path a, IM1 reacts with a sulfamide to produce
the intermediate IM2. After sequential reductive elimination
and reoxidation of the [Cp*RhI] species, the desired product
is obtained and [Cp*RhIII] is regenerated. In the other cases,
IM2 could be oxidized by PhI(OAc)2 to afford a rhodium(V)
nitrenoid intermediate (IM3; path b), which could also be
obtained from the reaction of IM1 with a nitrene precursor
generated in situ from PhI(OAc)2 and the sulfonamide 2
(path c). Subsequently, the sulfonamido unit inserts into the
Scheme 5. Synthesis of rhodium(III) complexes. ORTEP diagrams of 6
and 7. The SbF6À counterion of 7 in the ORTEP diagram is omitted.
Thermal ellipsoids are shown at 50% probability.
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À
C Rh bond to form the intermediate IM4. Finally, proto-
nolysis of IM4 gives the coupled product 3.
In summary, we have developed a rhodium(III)-catalyzed
À
chelation-assisted amidation of unactivated Csp3 H bonds by
using amides as the amino source at room temperature, thus
showing that rhodium(III) can activate unreactive, aliphatic
À
C H bonds under mild reaction conditions. Various sub-
À
strates containing inert Csp3 H bonds smoothly undergo this
coupling process with relatively broad functional-group
tolerance and complete monoselectivity. A cationic five-
membered rhodacycle complex has been established as
a possible intermediate. We believe that this strategy repre-
sents an efficient route to 2-(pyridin-2-yl)ethanamine deriv-
atives for medical and natural product chemistry studies.
À
Keywords: C H activation · heterocycles · rhodium ·
sulfonamides · X-ray diffraction
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9404–9408
Angew. Chem. 2015, 127, 9536–9540
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Received: May 18, 2015
Published online: July 14, 2015
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