Rhodium(III)-catalyzed C(sp3)-H amidation of 8-methylquinolines with amides at room temperature

Article abstract of DOI:10.1246/cl.150848

Here we disclose a Rh(III)-catalyzed chelation-assisted C(sp³)-H activation of 8-methylquinolines, which can enable intermolecular amidation using commercially available, reliable amides as the amidating reagent to provide an efficient route to

Full text of DOI:10.1246/cl.150848

Received: September 9, 2015 | Accepted: September 21, 2015 | Web Released: September 29, 2015
CL-150848
Rhodium(III)-catalyzed C(sp3)-H Amidation of
8-Methylquinolines with Amides at Room Temperature
Xiaolei Huang and Jingsong You*
Key Laboratory of Green Chemistry and Technology of Ministry of Education, College of Chemistry,
Sichuan University, 29 Wangjiang Road, Chengdu 610064, P. R. China
(E-mail: jsyou@scu.edu.cn)
Previous work
Here we disclose
a Rh(III)-catalyzed chelation-assisted
C(sp3)-H activation of 8-methylquinolines, which can enable
intermolecular amidation using commercially available, reliable
amides as the amidating reagent to provide an efficient route to
quinolin-8-ylmethanamine derivatives. This amidation proceeds at
room temperature in moderate to excellent yields, and features
good functional group tolerance and complete mono-selectivity.
a)
b)
PhI NSO2R , R = 4-ClC6H4
80 °C
Pd(II),
F
N
RO2S
SO2R, R = Ph
100 °C
Pd(II),
N
N
R'
N
RSO2N3 , R = 4-MeC6H4
80 °C
c)
d)
SO2R
H
Ir(III),
Nitrogen-containing compounds are very important skeletons
that widely exist in natural products, pharmaceuticals, biologically
active substances, and diverse material molecules.1 Thus, the
formation of C-N bonds is a lasting hot topic, and has been
attracting significant attention in the synthetic organic community.2
In recent years, transition-metal-catalyzed C-H bond activation
and subsequent amination or amidation has been one of the most
important strategies for the construction of C-N bonds.3,4 Although
transition-metal-catalyzed C(sp2)-N formation4c has been well
established, reports on C(sp3)-N formation reactions via C-H
activation,4a,4b especially intermolecular amination or amidation
still remain underrepresented.5,6 In the existing C-H amidation
reactions, a variety of amidating reagents, such as amides,7 azides,8
nitrene precursors,6a N-fluorobis(phenylsulfonyl)imide (NFSI),6b
N-substituted hydroxylamines,9 and 1,4,2-dioxazol-5-ones10 have
been investigated. For safety and availability reasons, commer-
cially available, reliable amides could be an ideal amino source.
Quinolin-8-ylmethanamine derivatives are fundamental build-
ing blocks in medicinal chemistry and synthetic chemistry.11 In the
past years, 8-methylquinolines have been used as the preferential
substrates to afford quinolin-8-ylmethanamines through transition-
metal-catalyzed C(sp3)-H activation/intermolecular amidation
due to the conformational bias in favor of the construction of
the metallacycle.12 In 2006, Che and Yu reported the palladium-
catalyzed C(sp3)-H activation and subsequent nitrene insertion of
8-methylquinoline using a nitrene precursor as amidating reagent
(Scheme 1a).6a After that, palladium-catalyzed chelation-assisted
C(sp3)-H amidation of 8-methylquinolines with NFSI was
developed by Muñiz and co-workers (Scheme 1b).6b Recently,
iridium (Scheme 1c)6d and rhodium (Scheme 1d)13 demonstrated
catalysis in the amidation of 8-methylquinolines using azides as
the nitrogen atom source. Although the precedent examples feature
high chemoselectivity and efficiency, elevated temperatures are
necessary for the reaction to proceed. Undoubtedly, the develop-
ment of an efficient catalytic system for C(sp3)-H bond activation
of 8-methylquinolines and subsequent amidation under mild
reaction conditions, especially room temperature, would be highly
valuable and desirable.
R' = H or SO2R
RSO2N3 , R = Ar or Alkyl
100 °C
Rh(III),
This work
e)
Rh(III)
room temperature
+
RSO2NH2
N
N
NHSO2R
H
Readily available amidating reagents
Mild reaction conditions
Relatively high functionality tolerance
Entire mono-selectivity
Scheme 1. Transition-metal-catalyzed C(sp3)-H activation/intermo-
lecular amidation of 8-methylquinolines.
mild reaction conditions.15 In this work, the rhodium(III)-catalyzed
C(sp3)-H activation is successfully extended to the amidation of
8-methylquinolines at room temperature for the synthesis of
quinolin-8-ylmethanamine derivatives (Scheme 1e).
Our investigation was initiated with the reaction of 8-
methylquinoline (1a) and 4-methylbenzenesulfonamide (2a) as
the model reaction (Table S1 in Supporting Information). Initially,
3a was obtained in 59% yield in the presence of 5 mol % of
[Cp*RhCl2]2 and 20 mol % of AgSbF6, using 1.5 equiv of
PhI(OAc)2 as the oxidant in dichloromethane (DCM) at 90 °C for
24 h (Table S1, Entry 1). In the absence of [Cp*RhCl2]2 or AgSbF6,
no product was observed (Table S1, Entry 2). Decreasing the
catalyst loading gave a lower yield (Table S1, Entry 3). When an
excess of 2a was added, the yield of 3a was decreased to 26%, and
no bisamidated and triamidated products were observed (Table S1,
Entry 4). Among the various solvents examined, DCM proved to
be superior to 1,2-dichloroethane (DCE), toluene, methanol, and
N,N-dimethylformamide (DMF) (Table S1, Entries 1 and 5-8).
Other oxidants such as Cu(OAc)2, Ag2CO3, and AgOAc were
ineffective for the process (Table S1, Entries 9-11). To our delight,
this amidation could occur at room temperature, and 3a was
obtained in 60% yield (Table S1, Entries 12 and 13). Furthermore,
the addition of NaOAc as the additive turned out to benefit
amidation, and the desired product was obtained in 82% yield for
48 h (Table S1, Entries 14-17). Thus, the optimal conditions were
obtained by using PhI(OAc)2 (1.5 equiv) as the oxidant and NaOAc
Our group remains committed to rhodium(III)-catalyzed C-H
activation.14 Very recently, we reported rhodium(III)-catalyzed
chelation-assisted unreactive, aliphatic C-H bond amidation under
Chem. Lett. 2015, 44, 1685–1687 | doi:10.1246/cl.150848
© 2015 The Chemical Society of Japan | 1685

Table 1. The scope of 8-methylquinolinesa,b
Table 2. The scope of amidesa,b
[Cp*RhCl2]2 (5 mol%)
[Cp*RhCl2]2 (5 mol%)
AgSbF6 (20 mol%)
PhI(OAc)2 (1.5 equiv)
AgSbF6 (20 mol%)
PhI(OAc)2 (1.5 equiv)
R
R
SO2NH2
N
+
N
N
N
+
RNH2
NaOAc (30 mol%)
DCM, RT, 48 h
NaOAc (30 mol%)
DCM, RT, 48 h
NHTs
H
H
1a
NHR
2a
2
1
3
4
OMe
F
N
N
N
N
R1 = OMe (4a), 61%
N
N
NHTs
N
N
NHSO2
tBu (4b), 89%
NHSO2
NHSO2
NHSO2
NHTs
NHTs
NHTs
F
F3C
H (4c), 80%
3b, 83%
3a, 82%
3c, 63%
3d, 55%
Cl (4d), 84%
NO2 (4e), 82%
O2N
4h, 87%
Cl
Br
CF3
NO2
R1
4f, 91%
4g, 66%
N
N
N
N
N
N
N
NHTs
N
NHTs
NHTs
NHTs
3f, 81%
3e, 63%
3g, 79%
3h, 45%
NHSO2Et
4i, 64%
NHSO2Me
4j, 71%
NHCOCF3
NHSO2Bn
4k,77%
4l, 60%c
N
MeO
N
Br
N
N
aReactions were performed with 1a (0.50 mmol) and 2 (0.25 mmol) in
1.0 mL of DCM. bYields of isolated products. c1a (0.25 mmol) and
2,2,2-trifluoroacetamide (0.50 mmol).
NHTs
NHTs
3j, 76%
NHTs
NHTs
3i, 89%
3k, 88%
3l, 90%
aReactions were performed with 1 (0.50 mmol) and 2a (0.25 mmol) in
b
[Cp*RhCl2]2 (5 mol%)
AgSbF6 (20 mol%)
1.0 mL of DCM. Yields of isolated products.
a)
b)
CD3OD
(20 equiv)
N
+
N
PhI(OAc)2 (1.5 equiv)
NaOAc (30 mol%)
DCM, RT, 48 h or 45 min
H/D
1a-dn
no deuteration
1a
(30 mol %) as the additive in the presence of [Cp*RhCl2]2
(5.0 mol %) and AgSbF6 (20 mol %) in DCM at room temperature
for 48 h.
TsNH2
standard conditions
+
N
N
N
+
N
With the optimal conditions in hand, we examined the
reaction of 8-methylquinolines (1) with 4-methylbenzenesulfon-
amide (2a) (Table 1). Substrates with various commonly encoun-
tered functional groups, such as Me, MeO, X (X = F, Cl, Br), CF3,
and NO2, were compatible with this amidation reaction to afford
quinolin-8-ylmethanamine derivatives in moderate to good yields
(Table 1, 3b-3h). It is worth noting that 8-methylquinolines
bearing an electron-donating group on the C-5 position could well
undergo the amidation (Table 1, 3b and 3c), while the same
substrates gave lower yields in the work of Wang.13 The C-6- or C-
7-substituted 8-methylquinolines exhibited higher reactivity, and
the C(sp3)-amidated products were obtained in good to excellent
yields (Table 1, 3i-3l). Furthermore, no product was detected
when 8-ethylquinoline served as the coupling partner. This
observation indicated that steric hindrance could restrain the
formation of a five-membered rhodacycle that could offer
favorable driving force to promote the desired C-H activation.
Subsequently, the scope of amides was investigated. As
summarized in Table 2, a variety of aryl sulfonamides containing
electron-donating, electron-neutral, and electron-withdrawing
groups could undergo the amidation process, and the desired
products were obtained in satisfactory yields (4a-4h). Alkyl
sulfonamides could also be used as the amidating reagent in the
coupling reaction (4i-4k). When an excess of 2,2,2-trifluoroacet-
amide served as the substrate, 2,2,2-trifluoro-N-(quinolin-8-yl-
methyl)acetamide was produced in 60% yield (4l).
45 min
kH/kD = 5.7
CD3
D2C
NHTs
NHTs
3a
1a
1a-d3
3a-d2
Scheme 2. Deuterium-labeling experiments.
reacted with 4-methylbenzenesulfonamide in one vessel to afford a
notable primary kinetic isotopic effect (kH/kD = 5.7) (Scheme 2b),
indicating that C-H bond activation is likely related with the rate-
determining step.16
Treatment of 8-methylquinoline with [Cp*RhCl2]2 afforded
the neutral rhodium species 5 (eq 1),12d which could catalyze the
amidation of 8-methylquinoline in 64% yield in the presence of
AgSbF6 (eq 2). This result revealed the plausible intermediacy of a
cyclometalated Rh(III) complex in the catalytic cycle. In addition,
the reaction of 8-methylquinoline (1a) with N-tosyliminophenyl-
iodinane (6)17 was conducted in the absence of PhI(OAc)2 under
standard conditions to identify whether a nitrene precursor was
involved in the amidation. As a result, 3a was obtained in 38%
yield (eq 3), implying that a nitrene intermediate generated in situ
in the reaction of PhI(OAc)2 and sulfonamide might be related to
the amidation process.
NaOAc, MeOH
[Cp*RhCl2]2
+
ð1Þ
N
N
80 °C, 24 h
Rh Cl
Cp*
1a
5
, 23%
Deuterium-labeling experiments were conducted to explore
some preliminary insight into the mechanism of the C-H
amidation reaction. The H/D exchange experiments revealed that
the C(sp3)-H bond cleavage is irreversible (Scheme 2a). Then, the
intermolecular competition reaction was carried out. 1a and 1a-d3
5 (10 mol%)
AgSbF6 (10 mol%)
TsNH2
ð2Þ
+
N
PhI(OAc)2 (1.5 equiv)
NaOAc (30 mol%)
DCM, RT, 48 h
N
NHTs
3a, 64%
2a
1a
1686 | Chem. Lett. 2015, 44, 1685–1687 | doi:10.1246/cl.150848
© 2015 The Chemical Society of Japan

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N
NHSO2R
Path a
3
PhI(OAc)2
Cp*RhI
N
RhIIINHSO2R
3
-
Cp*
OAc
B
HOAc
N
2
N
RhIII
1a
2+
[Cp*RhIII
]
Path b
PhI(OAc)2
Cp*
A
PhI(OAc)2
RSO2NH2
RSO2N=IPh
Path c
4
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2
N
III
N
Rh
3 + OAc-
HOAc
RhV NSO2R
N
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Cp*
SO2R
D
Cp*
C
Scheme 3. Proposed mechanism.
[Cp*RhCl2]2 (5 mol%)
AgSbF6 (20 mol%)
+
TsN=IPh
N
N
NaOAc (30 mol%)
DCM, RT, 48 h
ð3Þ
NHTs
3a, 38%
6
1a
6
7
According to the experimental investigations and the previous
work on Rh(III)-catalyzed C-H bond amidation,7b,15 a plausible
mechanism is proposed (Scheme 3). First, N-chelator-assisted
C(sp3)-H activation affords the five-membered rhodacycle inter-
mediate A. Subsequently, intermediate A might undergo reaction
via three possible paths. In path a, treatment of A with a sulfamide
produces intermediate B, which could go through reductive
elimination to give the desired product 3. Meanwhile, the
generated Cp*Rh(I) species is reoxidized to the Cp*Rh(III)
species. In path b and c, a Rh(V)-nitrenoid intermediate C could
be obtained from either the oxidation of intermediate B or the
reaction of Awith a nitrene intermediate generated from PhI(OAc)2
and sulfonamide 2. Then, C is transformed into intermediate D,
and further releases product 3 in the presence of HOAc.
In summary, we have addressed a Rh(III)-catalyzed chelation-
assisted C(sp3)-H bond amidation of 8-methylquinolines using
commercially available amides as the amidating reagent at room
temperature in moderate to excellent yields. This protocol has
good functional group tolerance and complete mono-selectivity.
This strategy would represent a powerful route to quinolin-8-
ylmethanamine derivatives.
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We thank the financial support from the National NSF of
China (Nos. 21432005, 21272160, and 21321061).
Supporting Information is available electronically on J-STAGE.
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Chem. Lett. 2015, 44, 1685–1687 | doi:10.1246/cl.150848
© 2015 The Chemical Society of Japan | 1687