Dual Roles of tert-Butyl Nitrite in the Transition Metal- and External Oxidant-Free Trifluoromethyloximation of Alkenes

Article abstract of DOI:10.1002/cssc.201901856

By employing tert-butyl nitrite as both nitrogen source and oxidant, the trifluoromethyloximation of alkenes proceeds smoothly in a free-radical process. The developed difunctionalization reaction enables practical and efficient synthesis of a wide range of α-CF₃ ketoximes in moderate yields with excellent regioselectivity. This method features the use of readily available and stable alkenes as substrates and inexpensive CF₃SO₂Na as a CF₃ reagent, no involvement of transition metals or external oxidant, and room-temperature conditions. Moreover, a scale-up of the reaction, further transformation of the products into various valuable CF₃-containing compounds, and removal of the trifluoromethyl group are readily achieved.

Full text of DOI:10.1002/cssc.201901856

Accepted Article
Title: Dual Roles of tert-Butyl Nitrite in the Transition Metal- and
External Oxidant-Free Trifluoromethyloximation of Alkenes
Authors: Ya Wu, Yanli Zhang, Zhen Yang, Jingchao Jiao, Xiaoke
Zheng, Weisheng Feng, Mengsha Zhang, Hao Cheng, and
Lin Tang
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10.1002/cssc.201901856
ChemSusChem
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Dual Roles of tert-Butyl Nitrite in the Transition Metal- and
External Oxidant-Free Trifluoromethyloximation of Alkenes
Ya Wu,[a] Yanli Zhang,[a] Zhen Yang,[b] Jingchao Jiao,[b] Xiaoke Zheng,[a] Weisheng Feng,[a] Mengsha
Zhang,[a] Hao Cheng,[b] and Lin Tang*[b]
Abstract: By employing tert-butyl nitrite as both nitrogen source and
oxidant, the first example of alkene trifluoromethyloximation is
reported. The developed difunctionalization reaction provides
practical and efficient synthesis of a wide range of α-CF3 ketoximes
in moderate yields with excellent regioselectivity. This protocol
features the use of inexpensive CF3SO2Na as a CF3 reagent, no
involvement of transition metal and external oxidant, and room
temperature conditions. Moreover, a scale-up reaction, further
transformation of the products to various valuable CF3-containing
compounds, and removal of trifluoromethyl are readily achieved.
Encouraged by the recent remarkable achievement of the C-N
bond formation reactions with tert-butyl nitrite as a nitrogen
source[15] and our interest in the exploration of metal-free radical
reactions,[16] we envisioned that the tert-butyl nitrite-mediated
radical aminotrifluoromethylation of alkenes with readily
available and inexpensive CF3SO2Na might afford α-CF3
ketoximes. Although it was challenging to explore a new method
of
transition
metal-
and
external
oxidant-free
aminotrifluoromethylation of alkenes, the proposed protocol was
successfully achieved by employing tert-butyl nitrite as both the
-
nitrogen source and the oxidant because the redox of CF3 and
tert-butyl nitrite could efficiently take place without a transition
metal catalyst via a free-radical pathway (Scheme 1d).
The trifluoromethyl incorporation into organic molecules
dramatically leads to a unique influence on chemical and
biological properties such as metabolic stability, bioavailability
and membrane permeability.[1] During the past decade, great
endeavors have been spurred in the development of a variety
of synthetic approaches for the introduction of the trifluoromethyl
into alkenes.[2] In particular, trifluoromethyl-containing alkene
difunctionalization, mainly relying on carbotrifluoromethylation,[3]
oxytrifluoromethylation,[4]
halotrifluoromethylation,[5]
and
aminotrifluoromethylation,[6,7,8] reveals the most straightforward
and practical synthetic strategy for the simultaneous introduction
of trifluoromethyl and
a second vicinal functionality. The
aforementioned aminotrifluoromethylation of alkenes was
successfully achieved under the catalysis of transition metals or
electrochemical oxidation , however, the reported nitrogen
sources (nucleophiles) were restricted to amines (protected
amines) (Scheme 1a),[6] azides (Scheme 1b)[6a,7] and nitrile
(Scheme 1c).[8] To date, aminotrifluoromethylation of alkenes
with other types of nitrogen sources is still undiscovered. Given
the significance of these studies, it is highly desirable to exploit a
new and efficient approach to extend the scope of
aminotrifluoromethylation of alkenes.
On the other hand, oximes are versatile structural motifs
because of their extensive applications as synthons in the
preparation of nitriles,[9] amides,[10] amines,[11] carbonyl
compounds,[12] N-containing heterocycles[13] and other
alternative compounds.[14] In this regard, the direct incorporation
of oxime and trifluoromethyl into organic molecules in a step-
economical manner demonstrates an ideal and valuable protocol.
Scheme 1. Aminotrifluoromethylation of alkenes.
The initial reaction conditions for tert-butyl nitrite-mediated
trifluoromethyloximation of alkenes were selected with 1-methyl-
4-vinylbenzene (1b, 0.25 mmol) as the model substrate in the
presence of tert-butyl nitrite (2a, 1.6 equiv) and CF3SO2Na (3a,
1.6 equiv) at room temperature for 4 h (Table 1). The reaction
was able to proceed smoothly in the solvent of DMSO, affording
the desired α-CF3 ketoxime 4b in 66% yield with an excellent
stereoselectivity (Entry 1). Relatively low yields (29-48%) were
offered when acetonitrile, tetrahydrofuran and ClCH2CH2Cl were
involved (Entries 2-4). Interestingly, the trifluoromethyloximation
reaction could hardly take place in the presence of water
because of the construction of 2-nitro-1-(p-tolyl)ethan-1-one
oxime via the nitration and oximation of 1b (Entry 5). Further
experiments reveal that the transition metal catalysts of CuBr,
FeSO4 and AgNO3 could not accelerate the radical
fragmentation in this reaction (Entries 6-8). Moreover, higher
temperature suppressed the formation of 4b (Entries 9 and 10).
The results obtained in Entries 11 and 12 indicate that
decreasing the amount of 2a or 3a had a negative influence on
this difunctionalization reaction. Additionally, the reaction was
not affected by the prolonged time (16 h) as shown in Entry 13.
[a]
[b]
Dr. Y. Wu, Dr. Y. Zhang, X. Zheng, Dr. W. Feng, M. Zhang
School of Pharmacy & Collaborative Innovation Center for
Respiratory disease Diagnosis and Treatment & Chinese Medicine
Development of Henan Province
Henan University of Chinese Medicine
Zhengzhou 450046 (P. R. China)
Dr. Z. Yang, J. Jiao, H. Cheng, Prof. Dr. L. Tang
College of Chemistry and Chemical Engineering
Xinyang Normal University
Xinyang 464000 (P. R. China)
E-mail: lintang@xynu.edu.cn
Supporting information for this article is given via a link at the end of
the document.
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COMMUNICATION
Therefore, the reaction conditions in Entry 1 were chosen as the
optimal for the next investigation.
Table 1. Optimization of reaction conditions.
Entry
1
Variation from the conditions
none
Yield [%][a]
66 (E/Z > 20:1)
48 (E/Z > 20:1)
29 (E/Z > 20:1)
39 (E/Z > 20:1)
trace
2
MeCN instead
3
THF instead
4
ClCH2CH2Cl instead
DMSO:H2O (1:1) instead
addition of 5 mol% CuBr
addition of 5 mol% FeSO4
addition of 5 mol% AgNO3
50 oC
5
6
62 (E/Z > 20:1)
65 (E/Z > 20:1)
49 (E/Z > 20:1)
62 (E/Z > 20:1)
54 (E/Z > 20:1)
58 (E/Z > 20:1)
52 (E/Z > 20:1)
67 (E/Z > 20:1)
7
8
9
10
11
12
13
80 oC
1b/2a/3a = 1:1.6:1
1b/2a/3a = 1:1:1.6
16 h
Scheme 2. Isolated yield; the mixed isomers were measured according to 1
H
NMR.
[a] Isolated yield; the mixed isomers were measured according to 1H NMR.
Furthermore, a series of aliphatic alkenes were successfully
converted to the α-CF3 ketoximes under the standard conditions
(Scheme 3). Allylbenzene 5a readily afforded the corresponding
product 6a in 51% yield with mixed isomers (Z/E = 2.74:1).
Different allyl salicylaldehydes could be well compatible,
After confirmation of the optimized conditions, expanding the
scope of styrenes was carried out in the trifluoromethyloximation
reaction (Scheme 2). When the electron-donating groups of
methyl and tert-butyl (4b and 4c) and weakly electron-drawing
groups of halogen (4d-4i) appeared on the benzene ring, the
corresponding styrenes could afford the desired products in
good yields of 62-74%. The results obtained above show that
the substituent’s steric hindrance had little impact on the yields
(4e, 4f vs 4g). However, low stereoselectivity of the ortho-
substituted product 4g was obtained because of the steric
hindrance. Interestingly, the substrates bearing versatile groups
of carboxyl, chloromethyl and vinyl yielded the target products
4j-4l in moderate to good yields. Moreover, biphenyl and
naphthalene were commendably tolerated to provide 4m and 4n
in 78 and 61% yield, respectively. The N-heterocycle product 4o
was obtained with excellent stereoselectivity. When R was
methyl, 1p could also serve as an efficient substrate, leading to
4p in an acceptable yield, even though low stereoselectivity (E/Z
= 1.83:1) was observed.
affording the desired 6b-6f in
a regioselective manner
regardless of the electronic effect of the substituents, however,
low stereoselectivity was observed except 6c. The reason for
the stereoselective difference of 6c with other products is
unclear up to now. Relatively low yield of 6g was obtanied when
hydroxymethyl appeared on the benzene ring, which was
attributed to the construction of the byproduct 6b. The results
obtained in 6h and 6i indicate that the steric hindrance
immensely restrained the stereoselectivity. Moreover, reactions
involving acrylic esters, acrylic amides and malonic ester
smoothly proceeded to supply the desired products 6j-6n in
good yields. Similarly, low stereoselectivity was obtained due to
the steric hindrance (6l vs 6m). The single-crystal X-ray
diffraction analysis unambiguously established the E isomer of
6m.[17]
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compounds, was readily obtained through dehydration of 4b.
The versatile O-acetyl oxime 10b could also be efficiently
constructed by treating 4b with acetic anhydride.
Scheme 5. Transformations of the α-CF3 ketoxime 4b.
Additionally, the exchange of a hydrogen atom for a fluorine-
containing group is regarded as an essential strategy for
adjusting the physiochemical and metabolic properties of
candidate drugs.[18] In this context, the cesium carbonate-
promoted detrifluoromethylation of 10 was conducted in DMF,
affording the corresponding O-acetyl ketoximes 11b, 11d and
11e in satisfactory yields (Scheme 6).
Scheme 3. Isolated yield; the mixed isomers were measured according to 1
NMR.
H
In order to further assess the synthetic generality of this green
and efficient trifluoromethyloximation, a scale-up experiment
with 5 mmol of 1b as the substrate was carried out, which
leaded to 4b in 51% yield (Scheme 4a). Pleasingly, the bioactive
molecule of estrone derivative 5o was well tolerated to afford the
desired α-CF3 ketoxime 6o in 53% yield with a single E isomer
(Scheme 4b), revealing potential applications in pharmaceutical
synthesis.
Scheme 6. Removal of trifluoromethyl.
Several control experiments in Scheme 7 were conducted to
gain
a
mechanistic
insight
into
the
alkene
trifluoromethyloximation. With the addition of 2,2,6,6-tetramethyl-
1-piperidinyloxy (TEMPO) under the standard conditions, the
formation of 4b was absolutely suppressed, however, the
compounds 12, 13, 14 and 15 were detected by GC-MS
(Scheme 7a). Additionally, 16 was also detected when the
o
reaction temperature was increased to 60 C (Scheme 7b). The
results obtained in Scheme 7a and 7b suggest that a single
electron
transfer
process
was
involved
in
the
trifluoromethyloximation reaction through free-radicals of t-
BuO· and ·NO.[19] Upon conducting the reaction under air
atmosphere, the yield of 4b was decreased to 43% and 17 was
obtained in 28% yield via nitro-oximation of 1b, which again
implies the existence of ·NO that could be easily transformed
to ·NO2 in the presence of air (Scheme 7c). When a radical
scavenger 1,1-diphenyethylene was added to the reaction, the
alkene trifluoromethyloximation was suppressed, and the
radical ·CF3 could be trapped to offer the product 18 in 34%
yield (Scheme 7d). Furthermore, with the addition of a radical
Scheme 4. Examination of the synthetic utility.
Further transformations of the resulting α-CF3 ketoxime 4b
were successfully achieved to offer many valuable building
blocks as depicted in Scheme 5. 7b were easily formed via the
Beckman rearrangement in the presence of BF3·Et2O. The
deoximation of 4b was smoothly performed to give α-CF3 ketone
8b in 71% yield. Moreover, the 2H-azirine, one of the most
important skeletal units for the preparation of heterocyclic
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clock 1-phenylvinylcyclopropane to the reaction,
a
ring
In summary, we have disclosed a convenient and precise
trifluoromethyloximation of alkenes for the first time. The
challenging conversion of unactivated and activated alkenes into
various α-CF3 ketoximes is achieved with excellent
regioselectivity, as well as excellent stereoselectivity for most of
styrenes, and good functional group tolerance under transition
metal- and external oxidant-free conditions. By use of
bifunctional tert-butyl nitrite as both nitrogen source and oxidant,
these transformations can proceed smoothly via a free-radical
process with readily available and stable alkenes as the
substrates, inexpensive CF3SO2Na as the CF3 reagent, and
DMSO as the green solvent under mild conditions. A gram-scale
reaction is successfully achieved to further demonstrate the
synthetic generality of the developed protocol. More interestingly,
the obtained α-CF3 ketoximes can be efficiently converted to
structurally important CF3-containing target molecules, and CF3
group can be readily removed in the presence of Cs2CO3.
expansion product 19 was detected by HRMS and 19F NMR,
which indicates the existence of the radical ·CF3 (Scheme 7e).
Experimental Section
General reaction procedures for the synthesis of 4 and 6
To a 10 mL schlenk tube was added CF3SO2Na (0.40 mmol), and the
tube was vacuumized and back-filled with nitrogen (this process was
repeated for three times). Alkenes 1 or 5 (0.25 mmol), dry DMSO (1.0
mL) and tert-butyl nitrite (0.40 mmol) were added to the tube via syring,
respectively. The resulting mixture was stirred at room temperature for 4
h. When the reaction was finished, appropriate ethyl acetate was added
to the mixture and DMSO was extracted by saturated NaCl solution. The
obtained organic phase was evaporated to remove the solvent and the
resulting residue was further purified by flash column chromatography
using petroleum ether/ethyl acetate to afford the products 4 or 6.
Acknowledgements
Scheme 7. Preliminary mechanistic experiments.
This work was supported by no. 21602190 and 21402044 from
the National Natural Science Foundation of China, no.
172102210456 from the Foundation of Department of Science
and Technology of Henan Province, no. 17A150049 and
18A150049 from the Henan Key Scientific Research Project,
and the Nanhu Scholars Program for Young Scholars of XYNU.
Based on the results described above, we proposed a
plausible mechanism for the trifluoromethyloximation reaction
(Scheme 8). Firstly, tert-butyl nitrite decomposes into radicals
tBuO· and ·NO. tBuO· then oxidizes CF3SO2Na to ·CF3 via a
SET (single electron transfer) process, along with the generation
of SO2 and tBuONa. The addition of ·CF3 to alkenes provides the
radical A that seizes ·NO to afford the intermediate B. Lastly, the
final products 4 or 6 are constructed through the tautomerization
of B. Nevertheless, the formation of products D is totally
suppressed, which represents an excellent regioselectivity.
Keywords: alkenes • trifluoromethylation • free-radical • tert-
butyl nitrite • metal-free
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[17] The CCDC number of 6m is 1912730 and the supplementary
crystallographic data for this manuscript can be gained free of charge
from
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif.
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For internal use, please do not delete. Submitted_Manuscript
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10.1002/cssc.201901856
ChemSusChem
COMMUNICATION
By use of bifunctional tert-butyl
nitrite as both nitrogen source and
oxidant, the trifluoromethyloximation
of alkenes proceeds smoothly via a
free-radical process with readily
available and stable alkenes as the
substrates, inexpensive CF3SO2Na
as the CF3 reagent, and DMSO as
the green solvent under mild
conditions. Moreover, a scale-up
reaction, further transformation of
the products to various valuable
CF3-containing compounds, and
removal of trifluoromethyl are
readily achieved.
Y. Wu, Y. Zhang, Z. Yang, J. Jiao,
X. Zheng, W. Feng, M. Zhang, H.
Cheng, and L. Tang*
Page No. – Page No.
Dual Roles of tert-Butyl Nitrite in
the Transition Metal- and External
Oxidant-Free
Trifluoromethyloximation of
Alkenes
For internal use, please do not delete. Submitted_Manuscript
This article is protected by copyright. All rights reserved.