Copper mediated C-H amination with oximes: En route to primary anilines

Article abstract of DOI:10.1039/c8sc01256c

Here we report an efficient Cu(i)-mediated C-H amination reaction with oximes as amino donors to introduce NH₂ groups directly. Various strongly coordinating heterocycles including quinoline, pyrimidine, pyrazine, pyrazole and triazole were tolerated well. The potential utility was further demonstrated in a late-stage modification of telmisartan (an antagonist for the angiotensin II receptor).

Full text of DOI:10.1039/c8sc01256c

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Copper Mediated C–H Amination with Oximes: En Route
to Primary Anilines
Received 00th January 20xx,
Accepted 00th January 20xx
Lin-Lin Xu,+ b Xing Wang, + a Biao Ma, a Ming-Xing Yin, a Hai-Xia Lin, b Hui-Xiong Dai, * a Jin-Quan Yu c
Here we report an efficient Cu(I)-mediated C−H aminaꢀon reacꢀon with oximes as amino donor to introduce NH2 group
directly. Various strongly coordinating heterocycles including quinoline, pyrimidine, pyrazine, pyrazole and triazole were
well tolerated. The potential utility was further demonstrated in a late-stage modification of Telmisartan (an antagonist for
the angiotensin II receptor).
DOI: 10.1039/x0xx00000x
www.rsc.org/
Recently, C–H amination via transition-metal catalyzed C–H
activation process has attracted considerable attention and has been
proved to be a useful method to prepare amine molecules.7 Among
Introduction
Primary anilines are important structural motif present in many natural
and pharmaceutical compounds (Figure 1).1 For example, Retigabine is
an anticonvulsant used as an adjunctive treatment for partial epilepsies
in treatment-experienced adult patients.2 Anileridine as a member of
the piperidine class of analgesic agents is used be analgesic drug.3
Mesalazine is an aminosalicylate anti-inflammatory drug for treating
inflammatory bowel disease,4 and lenalidomide is a tumour necrosis
factor (TNF) inhibitors and can be used to treat multiple myeloma.5 The
development of efficient and practical approaches to access this type of
compounds is highly in demand and remains a challenge in organic
synthesis.6
these C–H amination reactions, only a few examples were able to
directly introduce an unprotected amino group to form primary
anilines.8 These reactions can be classified into two approaches:
nondirected and directed (Scheme 1). The former exploites the innate
reactivity of the substrates. For examples, nondirected amination of
arenes involving photocatalysis were realized by the Tung9a and
Nicewicz9b groups independently.
Fig. 1 Selected drug molecules containing primary anilines.
a.Department of Medicinal Chemistry, Shanghai Institute of Materia Medica,
University of Chinese Academy of Sciences, Chinese Academy of Sciences, 555 Zu
Chong Zhi Road, Shanghai, 201203, China. E-mail: hxdai@simm.ac.cn
b.
Department of Chemistry, Innovative Drug Research Center, Shanghai University
99 Shangda Road, Shanghai, 200444 (China)
c. Department of Chemistry, The Scripps Research Institute, 10550N. Torrey Pines
Scheme 1 The direct synthesis of primary anilines by C–H amination
Road, La Jolla, California 92037, USA
+ These authors contributed equally to this work.
Transition metal-catalyzed C–H aminations of arenes were also
reported by two groups of Falck9c and Morandi9d. However, controlling
the positional selectivity effectively remains to be a great challenge in
these reactions. In recent years, the use of directing group has become
a reliable approach to realize selective C–H functionalization.10 However,
d.
†Electronic Supplementary Informaꢀon (ESI) available: Data for new compounds
And experimental procedures. See DOI: 10.1039/x0xx00000x
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few examples on C–H amination to prepare the primary anilines are substrate was decomposed partially at this temperature. Finally, we
known. The use of chacogenide amine donors are largely limited to alkyl screened the temperature (Table 1, entries 14-16), and found that a
amines11. In 2014, Zhu group reported an example on employing the satisfactory yield of 78% could be obtained at 90 oC (entry 14).
TMSN3 as a nitrogen source to form primary anilines12a. Uchiyama and
Table 1 Optimization of reaction conditionsa
co-workers developed another aminated protocol which using BnONH2
OPiv
as aminated agent and involving the deprotonative cupration with a
stoichiometric amount of (TMP)2Cu(CN)Li212b. More recently, the Bolm
and coworkers developed a new reagent dibenzothiophene sulfoximine
as the NH3 surrogate to synthesize primary anilines.12c However, site
selective C–H amination in late-stage heterocycle drug discovery is
always a thorny problem, because that heterocycles competed with
directing groups for coordination to a metal catalyst, and may result in
the poisoning of a catalyst or the functionalization of an undesired C–H
bond. Herein, we first reported a facile Cu(I)-mediated Csp2–H amination
using the oximes derivatives as an aminated agent, in which the free
amine products can be easily obtained upon in-situ hydrolysis. The
potential use of this method in late-stage diversification for drug
discovery was exemplified in the directed amination of Telmisartan.
O
O
N
1) [Cu]
DG
DG
N
N
H
H
2) HCl (aq)
NH2
3a
H
1a
2a
temp, o
C
yield, %b
entry
DG
[Cu] (equiv)
base
1
2
A
A
A
A
B
C
D
E
F
CuOAc (0.2)
CuBr (0.2)
-
100
100
100
100
100
100
100
100
100
100
100
100
100
90
28
24
25
21
35
20
20
21
n.d.
40
49
52
58
-
3
CuCl (0.2)
-
Cu(OAc)2(0.2)
4
-
5
CuOAc (0.2)
CuOAc (0.2)
CuOAc (0.2)
CuOAc (0.2)
CuOAc (0.2)
CuOAc (0.3)
CuOAc (0.3)
CuOAc (1.0)
CuOAc (1.5)
CuOAc (1.5)
CuOAc (1.5)
CuOAc (1.5)
-
6
-
7
-
8
-
9
-
10
11
12
13
14
15
16
B
B
B
B
B
B
B
-
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
K2HPO4
Oximes derivatives as a class of versatile building blocks has been
applied in
a
number of transition metal-catalyzed C–H
functionalization.13 Due to the weaker N–O σ bond (∼57 kcal mol−1)
than normal σ C–X (X = C, N, O) bonds, oximes derivatives could not
only act as amino source but also as oxidants. Based on our previous
works14 and oximes chemistry reported by other groups,13 we proposed
a Cu(I) to Cu(III) catalytic cycle (Scheme 1): the first step is oxidative
insertion of Cu(I) species into the N-O bond to give the Cu(III)
intermediate A. After coordination of bidentate directing group
oxazoline-amide to Cu(III) complex A, C–H activation occurs to generate
the intermediate B. Subsequent reductive elimination affords imines
compound C and regenerates Cu(I). Finally, imines compound C can be
hydrolyzed to form primary amine 3 and ketone.
78 (73)c
66
80
70
59
O
A: R = H
O
Ph
N
B: R = Me
C: R = i-Pr
D: R = t-Bu
E: R = Ph
H
Ph
N
H
N
O
N
F
R
a
Reaction Conditions: 1) 1a (0.1 mmol), 2a (0.15 mmol), [Cu], base (0.1
b
mmol), DMSO (1 mL), N2, 8 h; 2) 2 M HCl (2 mL), rt. 20 mins. Yield
determined by 1H NMR analysis of crude reaction product using CH2Br2 as
internal standard. c Isolated yield is given in parentheses.
Results and discussion
Based on this hypothesis, we initiated studies by investigating the C–
H
amination of N-arylbenzamide substrate 1a with oxime 2a.
Encouragingly, we found that C–H amination of 1a-A with 1.5 equiv of
2a occurred in the presence of 20 mol % CuOAc in DMSO at 100 oC for
8 h, and the desired aminated product 3a-A was obtained in 28% yield
after acid hydrolysis. The structure of the product 3a-A was confirmed
by X-ray crystallography (Table 1). Other copper catalysts were also
investigated (Table 1, entries 1-4), and CuOAc was still the optimal one.
Subsequently, we investigated the influence of the directing groups (DG)
(Table 1, entries 5-9) on the efficiency of the amination reaction. We
found that the use of substrate 1a-B containing the methyl-substituted
oxazoline DG B afforded aminated product 3a-B in 35% yield.
Interestingly, the use of Daugulis’s 8-aminoquinoline DG under the
same conditions did not provide any desired product (entry 9). This
result is consistent with our early observation.14 The yield was improved
to 40% by further increasing the amount of CuOAc to 30 mol %. After
screening a series of bases (see SI), a higher yield of 49% was obtained
using 1 equiv of K2HPO4 as a base. Considering that the product binds to
the catalyst better than the starting material, increasing the amount of
copper may be beneficial to the reaction. Indeed, we found that when 1.5
equiv of CuOAc was used, the yield could be increased to 58% with full
conversion of substrate 1a (Table 1, entry 13), which implied that the
3a-A
After the optimal reaction condition was found, we proceeded to
examine the substrate scope. As shown in Table 2, a wide variety of
substituted benzamides were reactive. 2-Methyl substituted substrates
1b gave the aminated product in a moderated yield of 54%. Various
electron-donating and -withdrawing substituents including methyl 1c, t-
butyl 1d, methoxyl 1e, fluoro 1f, chloro 1g, bromo 1h, acetyl 1i,
trifluoromethyl 1j and phenyl 1k , vinyl 1l at 4-position on benzamides
were compatible in the reaction, affording the desired products in
moderate to good yields. When the 3-positions of on benzamides were
substituted with methyl, methoxyl or fluoro, the C–H activation took
place at both 2- and 6-positions to give two regioisomeric products,
with the less hindered 6-position-aminated product as a major. In the
case of the benzamide bearing 3-CF3 (3p), only 6-position-aminated
product was obtained. Gratifyingly, this copper-mediated C–H
amination protocol was compatible with a wide variety of heterocycles,
including pyridines, quinoline, and benzothiphene-derived substrates
2 | J. Name., 2012, 00, 1-3
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a
(3q-t). Notably, 0.3 equiv of CuOAc was sufficient go enable the
amination reaction (the yields were also shown in the parentheses), and
the yields were even higher than those obtained in the reactions using
1.5 equiv of CuOAc in some cases (3g, 3h and 3t).
Reaction Conditions: 1) 4a-4g (0.1 mmol), 2a (0.15 mmol), CuOAc ( 0.15
mmol), K2HPO4 (0.1 mmol), DMSO (1 mL), 90 oC, 6 h, N2. 2) 2 M HCl (2 mL),
rt. 20 mins. b Isolated yield. c 0.3 equiv of CuOAc was used in parentheses.
standard conditions, C–H amination proceeded exclusively at the
position ortho to the amide group, providing the desired product in 71%
isolated yield. The structure of 5a was confirmed by X-ray
crystallography. Furthermore, when the pyridine was replaced with
Table 2 The scope of C–H aminationa, b
O
O
OPiv
1) CuOAc, K2HPO4,
DMSO, 90 oC, N2
N
N
N
H
R
H
R
other medicinally important heterocycles, including a quinoline,
+
2) HCl (aq)
H
NH2
N
O
N
O
pyrimidine, pyrazine, pyrazole and triazole, the amide group was still an
effective directing group, and the desired aminated products were
formed in moderate to good yields (38-72%). Furthermore, the
reactions using 0.3 equiv of CuOAc as the catalyst were also examined
(the yields were also shown in the parentheses).
Me
1a-1t
Me
3a-3t
2a
O
Me
O
O
O
Oxa
Oxa
Oxa
Oxa
N
H
N
N
H
N
H
H
NH2
NH2
Me
NH2
t-Bu
NH2
3a, 73% (49%)c
3b, 54% (31%)
3c, 63% (44%)
3d, 56% (34%)
O
O
O
O
Oxa
Oxa
Oxa
Oxa
N
H
N
H
N
H
N
H
MeO
NH2
F
NH2
Cl
NH2
Br
NH2
3e, 61% (39%)
3f, 80% (45%)
3g, 35% (50%)
3h, 30% (48%)
O
O
O
O
Oxa
Oxa
Oxa
Oxa
Oxa
Oxa
N
H
N
H
N
H
N
H
Ac
NH2
F3C
NH2
Ph
NH2
NH2
3i, 56% (48%)
3j, 52% (52%)
3k, 58% (47%)
3l, 69% (44%)
O
2
O
2
O
2
O
Me
Oxa MeO
F
Oxa
F3C
N
N
N
H
N
H
H
6
H
6
6
NH2
NH2
NH2
NH2
3m,
3n
3o,
69% C2 : C6 = 9:60
, 78% C2:C6 = 15:63
(49% C2:C6 = 6:43)
72% C2:C6 = 23:49
(39% C2:C6 = 9:30)
3p, 54% (43%)
(39% C2 : C6 = 7:32)
H
H
O
O
N
O
N
O
Oxa
NH2
OXa
NH2
Oxa
S
OXa
N
N
H
H
Scheme 2 a) Intramolecular kinetic isotope effect (KIE); b) Intermolecular KIE
N
NH2
NH2
3t, 43% (53%)
N
N
To probe the reaction mechanism, we measured intra- and
intermolecular kinetic isotope effects. Significant isotope effects were
observed in both cases (Scheme 2). In addition, the addition of radical
scavenger 2,2,6,6-tetramethylpiperidine-N-oxyl (TEMPO) did not affect
the reaction efficiency under optimized conditions, which indicates that
a radical pathway is unlikely (Scheme 3). These combined data support
a mechanism which involves a copper-mediated C–H cleavage step
rather than an electrophilic aromatic substitution (SEAr) or radical
pathway. Therefore, we proposed a Cu(I) to Cu(III) mechanism as shown
in Scheme 1.
3q, 60% (52%)
3r, 59% (35%)
3s, 58% (45%)
a
Reaction Conditions: 1) 1a-1t (0.1 mmol), 2a (0.15 mmol), CuOAc (0.15
mmol), K2HPO4 (0.1 mmol), DMSO (1 mL), N2, 90 oC, 8 h; 2) 2 M HCl (2 mL),
rt. 20 mins. b Isolated yield. c 0.3 equiv of CuOAc was used in parentheses.
Inspired by previous examples on overcoming the positional
selectivity with substrates containing strongly coordinating
heterocycles,15 we subsequently examined whether the C–H amination
system could override the heterocycle-directed cyclometalation (Table
3). We chose para-(2-pyridyl)benzamide as a test substrate. Under the
Table 3 Overcoming the limitation of heterocycles in C–H aminationa, b
Scheme 3 The effect of TEMPO.
We also conducted the reaction on a gram scale under 0.3 and 1.5
equiv of CuOAc, 3a was obtained in 45% and 62% yield respectively, and
most of benzophenone was recovered (see SI). Removal of this amide-
oxazoline DG was demonstrated by treating product 3a with 2 N
KOH/EtOH at 80 °C to release the corresponding carboxylic acid and
oxazolyamide DG in good yields (Scheme 4). Interestingly, when the
aminated products were treated with concentrated HCl at 190 oC, a
series of different substituted primary anilines were obtained with
complete removal of the amide-oxazoline part (Table 4).16 Especially
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primary anilines containing heterocycles are accessible via this
approach, a good complement to early reported nondirected C–H
aminations.9
Conclusions
In summary, we have developed a Cu(I)-mediated C–H amination
reaction for the synthesis of primary anilines. A catalytic cycle involving
Cu(I) to Cu(III) was proposed, and the oximes derivatives not only act as
the amino source but also as oxidant. This practical reaction is
compatible with various functional groups as well as diverse strongly
coordinating heterocycles. The potential utility of this method was
demonstrated by the late-stage diversification of the drug molecule
Telmisartan.
Scheme 4 Removal of the directing group
Table 4 The transformation of aminated producta, b
Conflicts of interest
The authors declare no conflict of interest.
Acknowledgements
We gratefully acknowledge Shanghai Institute of Materia Medica,
Chinese Academy of Sciences, NSFC-21472211, NSFC-21772211, Youth
Innovation Promotion Association CAS (NO.2014229), Institutes for
Drug Discovery and Development, Chinese Academy of Sciences
(NO.CASIMM0120163006), Science and Technology Commission of
Shanghai Municipality (17JC1405000) for financial support. We
gratefully acknowledge NSF under the CCI Center for Selective C–H
Functionalization, CHE-1205646 for financial support.
a Reaction Conditions: 3, 5 (0.03 mmol), Conc HCl (0.5 ml), 190 oC, 3 h, Air, b Isolated
yield.
To further demonstrate the viability of the C–H amination reactions
for late-stage diversification in drug discovery, we chose Telmisartan, an
antagonist for the angiotensin II receptor, for functionalization (Scheme
5). As we mentioned earlier,15f there are multiple reactive C–H bond in
this molecule, which significantly enhance the difficulty of selective
functionalization of the target C–H bond. By installing the directing
group amide oxazoline into the molecule, we were pleased to find that
C–H amination occurred exclusively at the amide-directed position,
while other C–H functionalization products were not observed.
Furthermore, the resulted aminated product were treated under acidic
or alkaline conditions respectively to afford two derivatives 8k and 6b.
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DOI: 10.1039/C8SC01256C