Rhodium(III)-catalyzed Intermolecular Unactivated Secondary C(sp3)?H Bond Amidation Directed by 3,5-dimethylpyrazole

Article abstract of DOI:10.1002/adsc.201801592

A Rh(III)-catalyzed intermolecular unactivated secondary C(sp³)?H bond amidation via nitrene insertion directed by 3,5-dimethylpyrazole is reported. This procedure tolerates a broad substrate scope including chain and cyclic N-alklyamides. Notably, the directing group 3,5-dimethylpyrazole of chain N-alkylamide substrates could be easily removed via cascade intermolecular amidation and intramolecular cyclization in one-pot affording the sulfonylureas by increasing the reaction temperature. (Figure presented.).

Full text of DOI:10.1002/adsc.201801592

Title: Rhodium(III)-catalyzed intermolecular unactivated secondary
C(sp3)-H bond amidation directed by 3,5-dimethylpyrazole
Authors: Yanwei Wang, Hongxin Liu, Bin Li, and Baiquan Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201801592
Link to VoR: http://dx.doi.org/10.1002/adsc.201801592

10.1002/adsc.201801592
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Rhodium(III)-catalyzed intermolecular unactivated secondary
C(sp3)H bond amidation directed by 3,5-dimethylpyrazole
Yanwei Wang,a Hongxin Liu,a Bin Li,a and Baiquan Wanga,b,c,
*
a
State Key Laboratory of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071,
People’s Republic of China
Fax: (+86)-22-23504781
E-mail: bqwang@nankai.edu.cn
Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, People’s Republic of
China
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, People’s Republic of China
b
c
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
functionalizations.[7] Notably, C(sp3)H bond
Abstract: A Rh(III)-catalyzed intermolecular unactivated
secondary C(sp3)H bond amidation via nitrene insertion
activation has been increasingly explored using
directed by 3,5-dimethylpyrazole is reported. This
versatile Rh(III) catalysts for the construction of CC
procedure tolerates a broad substrate scope including chain
and CN bonds.[5,8-9] Despite these attractive
and cyclic N-alklyamides. Notably, the directing group 3,5-
successes, among them, there are only a few
examples on the construction of CN bond via
Rh(III)-catalyzed inert C(sp3)H bond activation, and
all these processes are limited to the primary
C(sp3)H bonds (Scheme 1b).[5a-d] Consequently,
dimethylpyrazole of chain N-alkylamide substrates could
be easily removed via cascade intermolecular amidation
and intramolecular cyclization in one-pot affording the
sulfonylureas by increasing the reaction temperature.
Keywords: Rh(III)-catalyzed; amidation; C(sp3)−H bond;
nitrene insertion
developing
Rh(III)-catalyzed
intermolecular
unactivated secondary C(sp3)H bond amination
remains highly challenge. As part of our ongoing
efforts in Rh(III)-catalyzed C(sp3)H bond
functionalization,[5e,9] herein we report the chelation-
The construction of CN bond has been one of hot
topics in synthetic chemistry, because the nitrogen is
a key component of many natural products, drug
molecules, and materials.[1] In recent years,
transition-metal-catalyzed CH bond amination as a
straightforward protocol to construct CN bond has
been well-established.[2,3] However, most efforts were
made on the C(sp2)H bonds and intramolecular or
activated C(sp3)H bonds,[3] and researches on the
intermolecular unactivated C(sp3)H bond amination
are still rare.[4,5a-d] Recently, notable achievements
have been also made in Rh(II)-catalyzed C(sp3)H
bond amination via a nitrene C-H insertion,[6]
however, intermolecular reactions based on this
strategy are often designed toward activated
methylene C−H bonds which generally at the allylic,
benzylic, or -heteroatomic positions (Scheme 1a).
The recent years have witnessed the significant
assisted Rh(III)-catalyzed selectively C(sp3)H bond
amidation of unactivated secondary chain or cyclic
aliphatic substrates via nitrene insertion (Scheme 1c).
To date pyrazole-directed CH functionalizations
have been mainly limited to C(sp2)H bonds,[10] only
a few examples of pyrazole-directed C(sp3)H bond
activations have been disclosed,[8g,11] probably due to
the weak coordinating ability of pyrazole.[11a]
Recently, Zhao’s group revealed that Rh(III)-
catalyzed trimethylpyrazole-directed C(sp3)H bond
arylation.[8g] Encouraged by this work, we postulated
that pyrazole may serve as the directing group to
assist Rh(III)-catalyzed nitrene insertion. After a
series attempts, the electron density exerts distinctly
influence on the amidation procedure, and the
electron-rich
3,5-dimethylpyrazole
or
3,4,5-
trimethylpyrazole could give the best results (For
details, see Table S1 in the ESI†). Notably, when the
temperature was increased to 100 °C, the directing
group could be removed in one-pot.
progress
in
Rh(III)-catalyzed
CH
bond
1
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10.1002/adsc.201801592
Advanced Synthesis & Catalysis
Table 1. Optimization of reaction conditions.[a,b]
Entry
1
2[d]
3[e]
4
Catalyst system
Additive
Solvent
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
DCE
Yield(%)[b]
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*Rh(MeCN)3](SbF6)2
[Cp*RhCl2]2/AgSbF6
-
68[c]
0
0
37
5
78
6
CHCl3
THF
63
7
19
8
NaOAc
KOAc
DCE
75
9
DCE
47
90(88)[c]
10
11
12[f]
13
14[g]
15[g]
16[f]
AgOAc
CsOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
DCE
DCE
trace
81
0
DCE
DCE
Rh2(OAc)4
DCE
0
Scheme 1. Transition-metal-catalyzed intermolecular
C(sp3)H bond amination.
[Rh(COD)Cl]2
DCE
0
[Cp*IrCl2]2/AgSbF6
Cp*Co(CO)I2/AgSbF6
DCE
0
17[h]
[a]
DCE
0
Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol),
To further optimize the reaction conditions, 3,5-
dimethyl-N-propyl-1H-pyrazole-1-carboxamide (1d)
and 4-chlorobenzenesulfonamide (2a) were chosen as
the model substrates. Other amide sources, p-
methylbenzenesulfonyl azide and 3-phenyl-1,4,2-
dioxazol-5-one, were also tested, but no desired
product was detected (Table 1, entries 2−3). The
effect of solvents was investigated (entries 4−7) and
DCE gave the best result as the yield of 3da was
increased to 78% (Table 1, entry 5). According to the
literature, the use of catalytic amount of an acetate
additive may lead to a dramatic improvement in the
reaction efficiency.[9a,12] Thus various acetate
additives were screened (Table 1, entries 8−11),
among which AgOAc was the most efficient that
could significantly improve the yield to 90% (Table 1,
entry 10). The use of [Cp*RhCl2]2/AgSbF6 catalyst
system instead of [Cp*Rh(MeCN)3](SbF6)2 afforded a
slightly lower yield (Table 1, entry 12). The control
experiment showed that [Cp*Rh(MeCN)3](SbF6)2
was essential for this transformation as its omission
led no formation of 3da (Table 1, entry 13). Notably,
Rh2(OAc)4, which could efficiently promote both the
intra- and intermolecular aliphatic C−H bond
amination reactions via a concerted asynchronous
C−H bond insertion pathway,[6] did not work in the
present direct amidation reaction conditions (Table 1,
entry 14). Several other transition metal catalysts
[Cp*Rh(MeCN)3](SbF6)2 (10 mol %), solvent (1.0 mL), 30 °C,
[b]
12 h, under Ar.
NMR yield, 1,1,2,2-tetrachloroehane as
[c]
[d]
internal standard.
Isolated yield.
Using p-
methylbenzenesulfonyl azide as amide source. [e] Using 3-phenyl-
[f]
1,4,2-dioxazol-5-one as amide source. [Cp*MCl2]2 (5 mol %),
AgSbF6 (20 mol %). [g] Catalyst (5 mol%).
mol %), AgSbF6 (20 mol %).
Cp*Co(CO)I2 (10
[h]
With the optimal reaction conditions in hand, we
explored the scope of N-alkyl-substituted amides (1)
and substituted benzenesulfonamides (2), as shown in
Table 2. First, we examined the applicability of the
scope of diverse benzenesulfonamides. The -
secondary amidation products could be obtained in
good to excellent yields (3da−3dk). It is noteworthy
that
the
halogen (F, Cl, Br)-substituted
benzenesulfonamides were well tolerated to afford
the corresponding products in 88-96% yields
(3da−3dc, 3dh). Substrates with strong electron-
withdrawing CF3 group gave 3df and 3dj in 90% and
92% yields, respectively, while 4-NO2 substituted
benzenesulfonamide afforded product 3dd in 75%
yield. Benzenesulfonamides bearing weak electron-
donating OCF3 group afforded the desired products
3de and 3dl in 84% and 91%, respectively. In
contrast, 4-Me substituted benzenesulfonamide gave
slightly
lower
yield
(3dk,
59%)
and
such
as
[Rh(COD)Cl]2,
[Cp*IrCl2]2,
and
Cp*Co(CO)I2 were also investigated, but no desired
benzenesulfonamide bearing
a
strong electron-
product was detected (Table 1, entries 15−17).
donating OMe group at 4-position could not work in
the reaction conditions. In addition, the alkyl
sulfonamides and benzamides were also tested, but
no desired amidation product was detected.
Finally,
we
chose
10
mol%
of
[Cp*Rh(MeCN)3](SbF6)2, 30 mol % of AgOAc, and
1.5 equiv of PhI(OAc)2 in DCE (1 mL) at 30 °C
under Argon for 12 h (Table1, entry 10) as the
standard conditions.
2
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10.1002/adsc.201801592
Advanced Synthesis & Catalysis
Table 2. Substrate scope.[a]
To further define the scope and limitation of this
reaction, N-cycloalkyl-substituted amides have also
been examined. N-cyclopentyl-, N-cyclohexyl-, N-
cycloheptyl-, and N-cyclooctyl-substituted amides
furnished the corresponding products in moderate to
good yields (3oa−3ta, 42−76%). The molecular
1
structure of 3pa was confirmed by its H and 13C
NMR spectra, mass spectra, and single-crystal X-ray
diffraction analysis (see the ESI†).[15] To illustrate the
C(sp3)−H
amidation
reactivity,
1,2,3,4-
tetrahydronaphthalen-1-amine based amide was
treated with 2a, affording the desire C(sp3)−H amide
product 3sa in 15% yield as the sole product.
Notably, when the reaction temperature was
increased to 100 °C, the directing group 3,5-
dimethylpyrazole of chain N-alkyl-substituted amides
could be removed in one-pot to afford the
corresponding sulfonylurea compounds 4a−4d in
high yields via cascade intermolecular amidation and
intramolecular
cyclization
(Table
3).
The
sulfonylureas, such as glibenclamide, glipizide,
glimepiride, gliclazide etc, are efficient hypoglycemic
agents. Thus, this transformation may have potential
application in the field of drug synthesis. The
sulfonyl group of sulfonylurea 4a can be removed
according to the literature procedure to furnish the
corresponding free urea 7 in 73% yield (Scheme 2).
Table 3. Removal the directing group in one-pot.[a]
[a]
Reaction conditions:
1 (0.4 mmol), 2 (0.2 mmol),
[Cp*Rh(MeCN)3](SbF6)2 (10 mol %), AgOAc (30 mol %),
PhI(OAc)2 (0.3 mmol), DCE (1.0 mL), 30 °C, 12 h, under
Ar; isolated yields are shown. [b] 1 (0.2 mmol),
2 (0.3 mmol),
PhI(OAc)2 (0.5 mmol).
Next, the scope with respect to N-alkyl-
substituted amides was examined in the coupling of
2a. By treating substituted 2-aryl-ethylamine based
amides with 2a, the transformation proceeded well to
furnish the corresponding -secondary amidation
products in 63-97% yields (3fa−3ja), among which
the yield of electron-rich 2-aryl-ethylamine based
amide declined (3ja, 63%). In addition to secondary
C−H bonds, the nitrene insertion procedure
proceeded smoothly on the tertiary C−H bond
affording the amidation product in good yield (3ka,
60%). The branched-chain N-alkylamide was also
tested but the corresponding product 3la was obtained
only in 27% yield, probably because that the steric
hindrance hampers the nitrene insertion. Notably,
when the straight chain was extended to n-butylamine
or N-amylamine based amides, the -secondary
amidation products could be also obtained in good
yield (3ma, 3na) along with small amount of -
secondary amidation products (3ma’, 3na’), which
indicated that the five-membered rhodacycle
intermediate was superior to the six-membered one in
this reaction system.
[a]
Reaction conditions:
1 (0.4 mmol), 2 (0.2 mmol),
[Cp*Rh(MeCN)3](SbF6)2 (10 mol %), AgOAc (30 mol %),
PhI(OAc)2 (0.3 mmol), DCE (1.0 mL), 100 °C, 12 h, under
Ar; isolated yields are shown.
Scheme 2. Removal the sulfonyl of sulfonylurea.
To probe the mechanism of the reaction, a series
of insightful experiments were carried out. The H/D
exchange experiment of 1d with CD3CO2D was
3
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10.1002/adsc.201801592
Advanced Synthesis & Catalysis
performed under standard conditions in the absence
of 2a (Scheme 3, eq a), the degree of deuterium
incorporation into the alkyl chain of 1a was 0%,
indicating that the Rh(III)-catalyzed CMD pathway
could be ruled out.[4i] Subsequently, the deuterium
competition experiment between substrates 1f and d-
1f was conducted and a kinetic isotope effect (KIE)
was found to be kH/kD = 1.0, which indicated that the
cleavage of the C(sp3)−H bond might be not involved
in the rate-determining step (eq b). Furthermore, to
testify that the nitrene insertion pathway might be
involved in the catalytic cycle, another two
experiments were conducted (eqs c and d). Given that
a nitrene precursor might be generated in situ from
PhI(OAc)2 and sulfonamide, the nitrene precursor
iminoiodane 5 was synthesized. When 5 was used
instead of 2a and PhI(OAc)2 to react with 1d in the
standard reaction conditions product 3da was formed
in 53% NMR yield in the presence of 2 equiv of
AcOH; notably, the yield could be decreased to 15%
without AcOH (eq c).[5a] Moreover, after addition of
styrene (1 mL) in the reaction of 1d with 2d, the
aziridine derivative 6 was isolated in 4% yield (eq
d).13 Without the Rh(III) catalyst or substrate 1d, no
azacyclopane derivative 6 was observed (For details,
see the ESI†). These results suggested that the 3,5-
dimethylpyrazole assisted Rh(III)-catalyzed nitrene
insertion pathway is likely involved in the catalytic
cycle.
complex B via the reaction of intermediate A with a
nitrene precursor formed in situ from PhI(OAc)2 and
the sulfonamide 2. Subsequently, concerted Rh-
nitrene insertion into the C(sp3)−H bond yields the
intermediate C. Finally, protonation of intermediate
C with HOAc gives the amide product 3 and
regenerates the Rh(III) species for the next catalytic
cycle. When the temperature is increased to 100 °C,
the amide product undergoes intramolecular
cyclization to furnish the sulfonylurea compound 4
by elimination of 3,5-dimethylpyrazole (for details,
see the ESI†).
In conclusion, we have developed
a
rhodium(III)-catalyzed intermolecular unactivated
C−H bond amidation via Rh-nitrenoid insertion
assisted by 3,5-dimethylpyrazole. A broad scope of
substrates including chain and cyclic aliphatic
C(sp3)−H bonds has been established. The directing
group 3,5-dimethylpyrazole of chain substrates could
be easily removed by increasing the reaction
temperature to 100 °C in one-pot giving the
sulfonylureas. Further applications of this procedure
in the synthesis of other targets and a detailed
mechanistic investigation are currently under
investigation in our laboratory.
Scheme 4. Proposed mechanistic pathway.
Experimental Section
A mixture of amide 1 (0.4 mmol, 2.0 equiv.), sulfamide 2
(0.2 mmol, 1.0 equiv), [Cp*Rh(MeCN)3](SbF6)2 (16.7 mg,
0.02 mmol, 10.0 mol %), AgOAc (10.0 mg, 0.06 mmol, 30
mol%)， and PhI(OAc)2 (96.6 mg, 0.3 mmol, 1.5 equiv)
were weighed in a Schlenk tube equipped with a stir bar.
Dry 1,2-dichloroethane (1.0 mL) was added and the
mixture was stirred at 30 °C for 12 h under Ar atmosphere.
Afterwards, it was evaporated under reduced pressure and
the residue was absorbed to small amounts of silica. The
Scheme 3. The mechanism study experiments.
Based on the above experimental results and
purification
was
performed
by flash column
known
transition-metal-catalyzed
C−H
bond
chromatography on silica gel (eluent: EtOAc/petroleum
ether = 1:3).
functionalizations,[4i,5,6,14] a possible mechanism is
proposed for the present catalytic reaction (Scheme
4). First, Cp*Rh(III) reacts with the bidentate
directing group of 1d to form the intermediate A,
which is followed by the generation of Rh(V) nitrene
Acknowledgements
4
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10.1002/adsc.201801592
Advanced Synthesis & Catalysis
We thank the National Natural Science Foundation of China (No.
21672108) and the Natural Science Foundation of Tianjin (No.
16JCZDJC31700) for financial support.
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Advanced Synthesis & Catalysis
COMMUNICATION
Rhodium(III)-catalyzed intermolecular unactivated
secondary C(sp3)–H bond amidation directed by
3,5-dimethylpyrazole
Adv. Synth. Catal. Year, Volume, Page 1 - Page 5
Y. Wang, H. Liu, B. Li, and B. Wang*
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