Intermolecular C(sp3)?H Amination Promoted by Internal Oxidants: Synthesis of Trifluoroacetylated Hydrazones

Article abstract of DOI:10.1002/anie.201810502

An intermolecular C(sp³)?H amination reaction is reported that is promoted by internal oxidants and occurs via a C=N bond formation step. This intermolecular C(sp³)?H amination reaction of trifluoromethyl ketones and aryldiazonium tetrafluoroborates affords various valuable trifluoroacetylated hydrazones in high yields with excellent E/Z selectivities. The salient features of this reaction type is that it is free of metal, catalyst, directing groups, and azides, and that it can be carried out under mild conditions, is operationally simple and efficient, gram-scalable, and it tolerates various functional groups. Remarkably, an ectoparasites-controlling agent was smoothly synthesized on a gram scale using our method. Aryldiazonium tetrafluoroborates served as the aminating reagents as well as an internal oxidant.

Full text of DOI:10.1002/anie.201810502

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Intermolecular C(sp3)-H Amination Promoted by Internal
Oxidants: Synthesis of Trifluoroacetylated Hydrazones
Authors: Huanfeng Jiang, Chuanle Zhu, Hao Zeng, Fulin Chen, Zhiyi
Yang, and Yingying Cai
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201810502
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Angewandte Chemie International Edition
DOI: 10.1002/anie.201((will be filled in by the editorial staff))
Catch Phrase
Intermolecular C(sp3)-H Amination Promoted by Internal Oxidants:
Synthesis of Trifluoroacetylated Hydrazones**
Chuanle Zhu,* Hao Zeng, Fulin Chen, Zhiyi Yang, Yingying Cai, and Huanfeng Jiang*
Abstract: An internal oxidants-promoted intermolecular C(sp3)-H
amination reaction via C=N bond formation is reported. This
intermolecular C(sp3)-H amination reaction of trifluoromethyl
ketones and aryldiazonium tetrafluoroborates affords various
valuable trifluoroacetylated hydrazones in high yields with excellent
E/Z selectivities. The salient features of this reaction were metal-
free, catalyst-free, directing group-free, azides-free, mild conditions,
operational-simple, efficient, gram-scalable, and valuable
functional group tolerance. Remarkably, an ectoparasites-
controlling agent was smoothly synthesized on gram-scale with our
protocol. Aryldiazonium tetrafluoroborates served as the aminating
reagents as well as an internal oxidant.
D
ue to the ubiquity of nitrogen-containing molecules in many
Scheme 1. Internal Oxidants-Promoted Intermolecular Amination of Activated
C(sp3)-H Bond.
natural and bioactive synthetic compounds, the development of
efficient methods to construct carbon-nitrogen bonds plays a central
role in chemical synthesis.[1] The installment of carbon-nitrogen
bonds by direct C(sp3)-H functionalization represents one of the
most attractive and yet challenging strategies.[2-4, 6-7] In this context,
great efforts have been devoted to develop new and efficient
methods for intra-[3] and intermolecular[4] C(sp3)-H amination.
Generally, these reactions need stoichiometric amounts of strong
external oxidants such as toxic transition-metal salts, BQ
(benzoquinone), hypervalent iodine derivatives, or employ potential
explosive organic azides as the aminating reagents. Internal oxidant
is an idea oxidant, which serves as both a substrate and an oxidant in
reactions.[5] Thus, internal oxidants-promoted C(sp3)-H amination is
quite attractive but still underdeveloped.[6]
and selectivity, and led to the formation of C-N single bond
(Scheme 1, a). Despite this progress, we envisioned that if the
C(sp3)-H bond was sufficiently activated by an valuable group,
novel internal oxidants-promoted intermolecular C(sp3)-H amination
reactions might be efficiently realized under metal-free, catalyst-free,
directing group-free, and mild conditions.
Trifluoromethyl group served as privileged moieties in the field
of medicinal chemistry because of its impressive impact on the
enhancement of the metabolic stability, bioavailability, and
lipophilicity of potential drugs.[8] Consequently, the synthesis and
application of novel trifluoromethyl group decorated compounds
have been extensively investigated in library design and drug
discovery.[9] Recently, we have reported a C(sp3)-H activation
reaction of trifluoromethyl ketones by internal oxidative oxime
acetates.[10a] As part of our continuous effort in internal oxidants-
promoted C(sp3)-H activations,[5] as well as recent interest in
trifluoromethyl decorated compounds,[10] herein, we report the
internal oxidants-promoted intermolecular C(sp3)-H amination
Recently, internal oxidants such as N-fluorobenzenesulfonimide
(NFSI), iminoiodinane, hydroxylamine derivatives, and anthranil
promoted intermolecular C(sp3)-H bond amination were investigated
by different groups,[6] especially for the attractive intermolecular
benzylic C(sp3)-H bond amination.[6b-h, 7] However, owing to the
insufficiently activated benzylic C(sp3)-H bond, these amination
reactions usually need transition-metal catalysts, directing groups,
high temperature, and/or long reaction time to ensure the reactivity
reaction of
trifluoromethyl ketones and aryldiazonium
tetrafluoroborates, delivering various useful trifluoroacetylated
hydrazones in high yields and excellent E/Z selectivities via C=N
bond formation (Scheme 1, b). Remarkably, aryldiazonium
tetrafluoroborates served as the aminating reagents as well as an
internal oxidant, and their C-N2 bond cleavage pathway is
completely inhibited in our process.[11]
On the basis of our previous works, the initial experiment of this
internal oxidants-promoted intermolecular C(sp3)-H amination
reaction was carried out with aryldiazonium tetrafluoroborate 1a and
trifluoromethyl ketone 2a in the presence of Cs2CO3 in toluene at
room temperature under N2 (Table 1, entry 1). We were pleased to
find that the desired trifluoroacetylated hydrazone 3a via C=N Bond
formation was isolated in 61% yield with excellent E/Z isomer
selectivity (E/Z > 20:1) in 5 minutes. To optimize the reaction
conditions, different types of inorganic bases such as K2CO3,
Na2CO3, Li2CO3, t-BuOLi, t-BuOK, and MeONa and organic bases
such as DBU, DABCO, and Et3N were examined (Table 1, entries
[] Dr. C. Zhu, H. Zeng, F. Chen, Z. Yang, Y. Cai, Prof. Dr. H. Jiang.
Key Laboratory of Functional Molecular Engineering of Guangdong
Province, School of Chemistry and Chemical Engineering, South
China University of Technology, Guangzhou 510640, P. R. China
Fax: (+86)20-8711-2906
E-mail: cechlzhu@scut.edu.cn; jianghf@scut.edu.cn
[] This work was supported by the National Program on Key Research
Project (2016YFA0602900), the National Natural Science Foundation
of China (21472051, 21420102003, and 21702064), the Pearl River
S&T Nova Program of Guangzhou (201806010138), and the
Guangdong Natural Science Foundation (2016A030310460).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
This article is protected by copyright. All rights reserved.

10.1002/anie.201810502
Angewandte Chemie International Edition
to be crystalline, then its structure and relative stereochemistry were
confirmed by the means of X-ray crystallographic analysis.[12]
Furthermore, different hetereo aromatic groups such as thienyl,
quinolyl, and pydridyl-bearing aryldiazonium tetrafluoroborates
were also found to be good substrates, and the corresponding
products 3ac-3ae were obtained in high yields.
Table 1. Optimization of the reaction conditions.[a]
Entry
1
Bases
Cs2CO3
K2CO3
Na2CO3
Li2CO3
t-BuOLi
t-BuOK
MeONa
DBU
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
DCE
Yield (%)[b]
63 (61)
64
2
3
44
4
13
5
trace
32
6
7
44
8
34
9
DABCO
Et3N
67
10
11
12
13
14
15
16
17
18
19[c]
20[d]
3
-
0
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
90
MeCN
99 (97)
83
1.4-dioxane
THF
74
DMF
98
DMSO
EtOH
98
80
MeCN
65
MeCN
0
[a] Unless otherwise noted, all reactions were carried out with 1a (0.2 mmol), 2a
(1.5 equiv), bases (1.5 equiv) and solvent (2 mL) in a 25 mL Schlenk tube at
room temperature for 5 min under N2. [b] The yields were determined by 19F
NMR spectroscopy of the crude product with PhCF3 as an internal standard,
and all of the E/Z isomer ratios
> 20:1. [c] 4-Methoxyphenyldiazonium
hexafluorophosphate was used instead of 1a. [d] 4-Methoxyphenyldiazonium 4-
methylbenzenesulfonate was used instead of 1a. The numbers in the
parentheses were isolated yields.
2-10). To our delight, a base of DABCO gave 3a in 67% 19F-NMR
yield with E/Z > 20:1. Without a base, no desired product 3a was
detected (Table 1, entry 11). Next, different types of solvent such as
DCE (1,2-dichloroethane), MeCN, 1,4-dioxane, DMF, DMSO, and
EtOH were screened (Table 1, entries 12-18). A solvent of MeCN
further enhanced the isolated yield of 3a to 97%. Additionally, other
types of aryldiazonium salts with different counterions such as
hexafluorophosphate and 4-methylbenzenesulfonate were also
investigated (Table 1, entries 19-20). The obtained results indicated
the suitable oxidative potential of aryldiazonium tetrafluoroborates
is very important to this transformation.
Under the optimized reaction conditions, we then turned our
attention to the generality of aryldiazonium tetrafluoroborates with
trifluoromethyl ketone 2a as the reaction partner in this internal
oxidants-promoted intermolecular C(sp3)-H amination reaction
(Scheme 2). In general, aryldiazonium tetrafluoroborates with
electron-donating, electron-neutral, and electron-withdrawing
groups on the different positions of the aryl ring all could afford the
desired trifluoroacetylated hydrazones smoothly with excellent E/Z
isomer selectivity (3a-3ab). It is worth mentioning that this mild and
efficient reaction system could tolerate diverse valuable functional
groups on the aryl ring of the aryldiazonium tetrafluoroborates, such
as alkoxyl, phenoxyl, alkyl, hydroxyl, morpholinyl, amino, aryl,
halo, trifluoromethyl, cyano, ester, acetyl, sulfonyl, nitro, and
ethynyl groups (products 3a-3ab), providing ample potential for
further synthetic applications. Significantly, product 3aa was proved
Scheme 2. Substrate scope of aryldiazonium tetrafluoroborates. Unless
otherwise noted, the reaction was run at 0.2 mmol scale under the standard
reaction conditions, and all the E/Z isomer ratios > 20:1. [a] The average
isolated yield of two parallel runs. [b] At 10 mmol scale, 0 oC to rt, 30 min, and
E/Z isomer ratio > 20:1. [c] ORTEP representation with 50% probability thermal
ellipsoids of a crystal structure of 3aa.
To further define the limitation of our protocol, the substrate
scope was extended to different trifluoromethyl ketones 2 (Scheme
3). Pleasingly, trifluoromethyl ketones with electron-donating group
such as methoxyl, and methyl groups and withdrawing groups such
as chloro, bromo, and iodo groups on the phenyl ring all could
undergo this reaction smoothly, providing the corresponding
trifluoroacetylated hydrazones in high yields with excellent E/Z
isomer selectivity (3af-3an). Especially, product 3al was obtained in
76% isolated yield, indicating that this reaction was not sensitive to
the steric hindrance. Additionally, 1,1,1-trifluoropentan-2-one also
gave the desired product 3ao in 29% yield.
Intrigued by this unique internal oxidants-promoted
intermolecular C(sp3)-H amination reaction, we further explored the
synthetic applications of these useful trifluoroacetylated hydrazones
(Scheme 4). Reduction the carbonyl group of 3a easily gave the
corresponding alcohol product 4 in 91% yield. N-protection of 3a
with propargyl bromide afforded trifluoroacetylated hydrazone 5 in
93% yield. On the other hand, diazo compound 6 was obtained in
67% yield via the selective O-protection of 3a with benzoyl chloride.
Next, various attractive but not easily accessible trifluoromethylated
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10.1002/anie.201810502
Angewandte Chemie International Edition
NMR yield, indicating our reaction was not air and moisture
sensitive (Scheme 5, a). Furthermore, the addition of radical
scavenger such as TEMPO, tert-butylhydroxytoluene (BHT) under
the standard reaction conditions almost has no influence on the
yields of 3a, indicating the reported C-N2 bond cleavage pathway of
aryldiazonium tetrafluoroborates is completely inhibited in our
process and a radical process might not be involved in this
transformation (Scheme 5, b)
Scheme 3. Substrate scope of trifluoromethyl ketones. Unless otherwise noted,
the reaction was run at 0.2 mmol scale under the standard reaction conditions,
and E/Z isomer ratios > 20:1. [a] The average isolated yield of two parallel runs.
Scheme 5. Control experiments
heterocycles in the field of medicinal chemistry, such as compounds
with 4-(trifluoromethyl)-pyrazole (7), 3-trifluoroacetyl indazol (8),
and 5-(trifluoromethyl)-2H-1,2,3-triazole (9) core skeletons, were
smoothly synthesized from 3a. Furthermore, a 5 mmol scale
reaction of aryldiazonium tetrafluoroborate 1ap and trifluoromethyl
ketone 2a was carried out in 30 minutes, providing the desired
trifluoroacetylated hydrazone 3ap in 73% yield (1.562 g). The
subsequent intramolecular dehydrogenative coupling of 3ar affords
3-trifluoroacetyl indazol derivative 10 in 63% yield (0.968 g). It is
worth to note that 3-trifluoroacetyl indazol derivative 10 is an
ectoparasites-controlling agent.[13]
On the basis of these experimental results as well as previous
10]
works,[5,
we tentatively proposed the reaction mechanism
illustrated in Scheme 6. Under the treatment of bases, 2a is likely to
deprotonating into its enolate anion 2a-E. The nucleophilic attack of
enolate intermediate 2a-E at the terminal N atom of aryldiazonium
tetrafluoroborate 1a provided an trifluoroacetylated azo intermediate
A,[15] which further converted to the desired trifluoroacetylated
hydrazone 3a via 1,3-hydragen atom transfer (1,3-HAT).
Aryldiazonium tetrafluoroborates not only served as the aminating
reagents but also as an internal oxidant in this transformation.
Scheme 6. Proposed mechanism.
In summary, we have reported an internal oxidants-promoted
intermolecular C(sp3)-H amination reaction via C=N bond formation.
This intermolecular C(sp3)-H amination reaction of trifluoromethyl
ketones and aryldiazonium tetrafluoroborates affords various
valuable trifluoroacetylated hydrazones in high yields with excellent
E/Z selectivities. This reaction features metal-free, catalyst-free,
directing group-free, azides-free, mild conditions, operational-
simple, efficient, gram-scalable, and valuable functional group
tolerance. Remarkably, an ectoparasites-controlling agent was
smoothly synthesized on gram-scale with our protocol.
Aryldiazonium tetrafluoroborates served as the aminating reagents
as well as an internal oxidant. The preliminary mechanism studies
indicated that a radical process might not be involved in this
transformation and the C-N2 bond cleavage pathway of
aryldiazonium tetrafluoroborates is completely inhibited in our
process. Efforts are currently underway in our laboratory to
investigate the mechanistic details and explore the synthetic
applications of our protocol, and the results of which will be
reported in due course.
Scheme 4. Synthetic applications. a) NaBH4, EtOH, rt, 2 h. b) NaH, DMF,30
min; propargyl bromide, rt, 12 h. c) Et3N, benzoyl chloride, CH2Cl2, rt, 12 h. d)
K2CO3, ethyl bromoacetate, DMF, rt, 12 h. e) Hexafluoroisopropanol (HFIP),
PhI(CF3CO2)2, rt, 12 h. f) CuBr2, NH4OAc, DMF/AcOH, 120 oC, O2, 12 h.
To cast some light on the mechanism details of this internal
oxidants-promoted intermolecular C(sp3)-H amination reaction,
1
some control experiments were performed. 19F-NMR and H-NMR
analysis experiments were conducted to monitor the reaction.
However, no signals of the possible intermediates were detected,
owing to the highly efficiency of the reaction.[14] Performing the
reaction under air and undried MeCN, 3a was obtained in 96%
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10.1002/anie.201810502
Angewandte Chemie International Edition
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Published online on ((will be filled in by the editorial staff))
Keywords: C(sp3)-H amination • internal oxidants • fluorine • synthetic
methods
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10.1002/anie.201810502
Angewandte Chemie International Edition
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Chuanle Zhu,* Hao Zeng, Fulin Chen,
Zhiyi Yang, Yingying Cai, Huanfeng
Jiang*
__________ Page – Page
An internal oxidants-promoted intermolecular C(sp3)-H amination reaction is realized
under mild conditions. The obtained trifluoroacetylated hydrazones via C=N bond
formation were further transformed into various useful trifluoromethyl group decorated
compounds.
Intermolecular C(sp3)-H Amination
Promoted by Internal Oxidants:
Synthesis
of
Trifluoroacetylated
Hydrazones
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