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Synthesis of Novel Cyclic Nitrones with gem-Difluoroalkyl Side Chains Through Cascade Reactions

22 Sep 2020-European Journal of Organic Chemistry (John Wiley & Sons, Ltd)-Vol. 2020, Iss: 35, pp 5741-5751

About: This article is published in European Journal of Organic Chemistry.The article was published on 2020-09-22 and is currently open access. It has received 1 citation(s) till now.

Summary (1 min read)

Introduction

  • Nitrones are presently the most used spin traps to characterize free radicals in biological systems,[1-5] with Phenyl-N-tertiobutyl Nitrone (PBN) and Dimethyl-Pyrrolidine-N-oxide being the most representative examples for such uses.
  • On the other hand, it is well recognized that introduction of fluorine in organic molecules can be used for a fine tuning of their physical, chemical and biological properties. [17].
  • Then, the authors will extend it to molecules B with functional groups in terminal position of the alkyl chains.
  • Further, these groups could be also employed to graft easily various types of labels eventually required for in depth in vivo biological studies.
  • All these new nitrones will be prepared in short sequences (2-3 steps) from the easily available type-D gemdifluoroalkyl propargylic alcohols.[21].

Results and Discussion

  • In order to prepare the first series of representative nitrones, the authors started from the known [21, 22] gem-difluoro propargylic derivative 1.
  • After reaction with n-BuLi at -90 °C, followed by addition of different aldehydes 2a-e, the gem-difluorinated alcohols 3a-e were obtained (Scheme 1, Table 1).
  • The reactions with nitromethane, or 2-nitropropane, in the presence of DBU afforded in fair to good yields the nitro intermediates 4a-e and 5a-e respectively.
  • In agreement with previous results, the first step of this domino process is likely the base-mediated isomerization of the propargylic alcohols into the corresponding (non-isolated) enones 3’a-e which are trapped in situ by the nitroalkane anions to give the desired molecules 4 or 5. [22].

FULL PAPER

  • 4JC-F = 1.0 Hz), 21.2 (d, 3JC-F = 9.6 Hz).
  • 19F {H} NMR (282 MHz, CDCl3) δ - 99.8 (AB system, 2JF-F = 234.7 Hz), -113.7 (AB system, 2JF-F = 234.7 Hz).
  • HRMS (ESI): calcd. for [M+Na]+ (C12H13NO2F2Na) = 264.0807; found: 264.0810 (1 ppm).
  • Rf = 0.1 (Petroleum Ether / Ethyl Acetate: 5/5). mp = 201 °C. 1H NMR (500 MHz, CDCl3) δ 8.44 – 8.25 (m, 2H), 7.06 – 6.78 (m, 2H), 4.05 – 3.78 (m, 1H), 3.86 (s, 3H), 3.33 – 2.97 (m, 2H), 2.75 – 2.48 (m, 1H), 2.40 – 2.03 (m, 3H), 1.92 – 1.49 (m, 3H).

Conclusion

  • Novel mono- and bicyclic nitrones with a CF2R group in position have been efficiently prepared from gem-difluoro propargylic alcohols.
  • Biological properties of these new nitrones are under active study and corresponding results will be reported in due course.
  • A cc ep te d M an us cr ip t European Journal of Organic Chemistry.

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Synthesis of Novel Cyclic Nitrones
withgem-Diuoroalkyl Side Chains Through Cascade
Reactions
Ali Soulieman, Rima Ibrahim, Zeinab Barakat, Nicolas Gouault, Thierry
Roisnel, Joël Boustie, René Grée, Ali Hachem
To cite this version:
Ali Soulieman, Rima Ibrahim, Zeinab Barakat, Nicolas Gouault, Thierry Roisnel, et al.. Syn-
thesis of Novel Cyclic Nitrones withgem-Diuoroalkyl Side Chains Through Cascade Reactions.
European Journal of Organic Chemistry, Wiley-VCH Verlag, 2020, 2020 (35), pp.5741-5751.
�10.1002/ejoc.202000972�. �hal-02957740�

FULL PAPER
1
Synthesis of novel cyclic nitrones with gem-difluoroalkyl side
chains through cascade reactions
Ali Souleiman
[a,b]
, Rima Ibrahim
[a]
, Zeinab Barakat
[a]
, Nicolas Gouault
[b]
, Thierry Roisnel
[b]
, Joel
Boustie
[b]
, René Grée*
[b]
, Ali Hachem*
[a]
[a] Lebanese University, Faculty of Sciences (I)
Laboratory for Medicinal Chemistry and Natural Products, and PRASE-EDST, Hadath, Lebanon
ahachem@ul.edu.lb
[b] Univ Rennes, CNRS (Institut for Chemical Sciences in Rennes), UMR 6226, 35000 Rennes, France
rene.gree@univ-rennes1.fr
Supporting information for this article is given via a link at the end of the document.
Abstract: New five-membered cyclic nitrones with gem-difluoroalkyl
groups in -position have been prepared by a 3-step sequence
starting from propargylic alcohols. This domino process involves a
base-mediated isomerization reaction to enones, which are trapped in
situ by nitroalkane anions. In a final step, starting from these key
precursors, a reduction-cyclization process affords the target
molecules. Mono- and bicyclic nitrones have been prepared by this
route which allows, as well, the synthesis of nitrones with functional
groups in terminal position of the side chain.
Introduction
Nitrones are presently the most used spin traps to characterize
free radicals in biological systems,
[1-5]
with Phenyl-N-tertiobutyl
Nitrone (PBN) and Dimethyl-Pyrrolidine-N-oxide (DMPO, Figure
1) being the most representative examples for such uses.
However, due to the variety of radical types to be studied with
large differences in physical, chemical and biological properties,
there is a constant need to design and develop novel nitrones.
[6]
Further, nitrones have been employed also as therapeutic
agents in the treatment of diseases related to oxidative stress
such as neurodegeneration,
[7,8]
ischemic stroke,
[9,10]
cardiovascular diseases,
[11]
and cancer.
[12-15]
In addition, nitrones
are valuable intermediates in organic synthesis affording
efficiently various types of useful heterocyclic, as well as acyclic
molecules.
[16]
On the other hand, it is well recognized that
introduction of fluorine in organic molecules can be used for a fine
tuning of their physical, chemical and biological properties.
[17]
Relatively few fluorinated nitrones have been described to date,
mostly with fluorine atoms on the phenyl group of PNB,
[18]
or with
CF
3
or CHF
2
groups on the nitrone.
[19]
In the case of fluorinated
nitrones,
19
F NMR could be also a very useful tool for monitoring
biophysical and biochemical studies.
[20]
Therefore, the goal of this
paper is to describe short and efficient syntheses of new nitrones
bearing gem-difluoroalkyl side chains in γ-position. More precisely,
we will first develop our strategy for the preparation of type A
model nitrones (Figure 1). Then, we will extend it to molecules B
with functional groups in terminal position of the alkyl chains. Such
groups (ester, azide, alcohol, tosylate, and protected alcohol)
could be of much use to adjust the physicochemical and biological
properties of these nitrones. Further, these groups could be also
employed to graft easily various types of labels eventually
required for in depth in vivo biological studies. Finally, starting
from the same intermediates, we will report the preparation of the
Figure 1. Our Target molecules starting from gem-difluorinated propargylic
alcohols D.
bicyclic analogues C. All these new nitrones will be prepared in
short sequences (2-3 steps) from the easily available type-D gem-
difluoroalkyl propargylic alcohols.
[21]
Results and Discussion
In order to prepare the first series of representative nitrones, we
started from the known
[21, 22]
gem-difluoro propargylic derivative 1.
After reaction with n-BuLi at -90 °C, followed by addition of
different aldehydes 2a-e, the gem-difluorinated alcohols 3a-e
were obtained (Scheme 1, Table 1). The reactions with
nitromethane, or 2-nitropropane, in the presence of DBU afforded
in fair to good yields the nitro intermediates 4a-e and 5a-e
respectively. In agreement with previous results, the first step of
this domino process is likely the base-mediated isomerization of
the propargylic alcohols into the corresponding (non-isolated)
enones 3’a-e which are trapped in situ by the nitroalkane anions
to give the desired molecules 4 or 5.
[22]
10.1002/ejoc.202000972
Accepted Manuscript
European Journal of Organic Chemistry

FULL PAPER
2
Scheme 1. The synthesis of nitro intermediates 4a-e and 5a-e
Table 1. The synthesis of nitro intermediates 4a-e and 5a-e
Yield (%)
[a]
Entry
SM
3
4
5
1
2a
3a: 73
[b]
4a : 72
5a : 69
2
2b
3b : 81
4b : 74
5b : 69
3
2c
3c : 60
4c : 69
5c : 73
4
2d
3d : 64
4d : 71
5d : 72
5
2e
3e : 67
4e : 76
5e : 60
[a] Isolated yields; [b] Reported previously.
[23]
Several attempts were done to reduce the nitro group in 4a using
Pd(OH)
2
and H
2
gas to afford the nitrone 6a but unfortunately the
yield was very low (15%). Similarly, NiCl
2
.6H
2
O in the presence of
NaBH
4
gave a poor yield (30%), and even lower yield (10%) was
obtained by using ammonium formate in the presence of Pd/C at
60°C. However, upon using Zn powder in the presence of NH
4
Cl
in water and THF at 0°C, the nitrones 6a-e and 7a-e were
successfully prepared, as shown in Scheme 2 and Table 2.
Scheme 2. Synthesis of the nitrones 6a-e and 7a-e
Table 2. Synthesis of the nitrones 6a-e and 7a-e
Yield (%)
[a]
Yield (%)
[a]
Entry
SM
6
SM
7
1
4a
6a : 65
5a
7a : 90
2
4b
6b : 61
5b
7b : 55
3
4c
6c : 71
5c
7c : 54
4
4d
6d : 73
5d
7d : 70
5
4e
6e : 69
5e
7e : 85
[a] Isolated yields
All these derivatives have spectral and analytical data in
agreement with the proposed structures (See experimental
section and SI). In addition, the structure of the nitrone 6e was
confirmed by X-Ray analysis (Figure 2).
[24]
Figure 2. X-Ray structure analysis of 6e.
Then, to expand the methodology to compounds having a
functional group on the terminal position of the side chain, we
started from the known
[25]
ynol 8 (Scheme 3). After oxidation with
Jones reagent at 0°C the ynone 9 was obtained in 75% yield and
it was reacted with Diethylaminosulfurtrifluoride (DAST) to give
the gem-difluoro propargylic intermediate 10 in 57% yield. The
same sequence of reactions as before allowed us to prepare the
alcohol 11a in 95% yield, the nitromethane adduct 12a with 76%
yield and finally the nitrone 13a in 77% yield. On the other hand,
the deprotection of 12a afforded the alcohol 14a in excellent yield,
and the final reduction gave in 60% yield the nitrone 15a with a
free primary alcohol group (Scheme 3).
Scheme 3. Synthesis of the nitrones 13a and 15a.
6e
10.1002/ejoc.202000972
Accepted Manuscript
European Journal of Organic Chemistry

FULL PAPER
3
Scheme 4. Synthesis of the nitrones, 18a, 20a, and 21a.
To complete this strategy and extend the range of functional
groups in the terminal position of the side chain, alcohol 14a was
first transformed into the acid 16a by Jones reagent. After Steglich
esterification of this acid, the ester 17a was obtained and the
reduction of the nitro group under the same conditions as above
gave the nitrone with a terminal ester group 18a, in 42% overall
yield from 14a. On the other hand, the tosylation of the alcohol
14a afforded compound 19a which was readily reduced to the
nitrone with a tosylate group 20a in 51% overall yield from 14a.
Then displacing this tosylate group with sodium azide afforded the
nitrone with a terminal azide 21a in 85% yield (Scheme 4). These
new nitrones, with different functional groups in the terminal
position of the side chain, offer many potentialities for further
applications in chemistry and in studies of biological problems.
In order to expand the strategy to fused bicyclic nitrones, we
started from the known,
[22]
gem-difluorinated propargylic
compound 22. After reaction with n-BuLi and different aromatic
aldehydes, the propargylic alcohols 23a-e were obtained in good
yields (Table 3). Substitution of the terminal primary alcohol by
bromine gave the derivatives 24a-e in fair to good yields. Then,
reaction with nitromethane in the presence of DBU gave directly
the cyclohexyl derivatives 25a-e, as single diastereoisomers
(control of the crude reaction mixture using
19
F NMR). Based on
our previous studies,
[22,26]
in this cascade process, three steps are
likely to occur sequentially: isomerization of the propargylic
alcohol to the enone then nucleophilic substitution of the bromine
by the nitromethane anion, and finally intramolecular Michael
addition of the nitro anion onto this enone to give 25a-e as trans
isomers (Scheme 5).
Scheme 5. Synthesis of the bicyclic nitrones 26a-e
Table 3. Synthesis of the bicyclic nitrones 26a-e
Yield (%)
[a]
Entry
SM
Ar
23
24
25
26
1
22a
Ph
72
[a]
72
[a]
76
56
2
22b
4-FC
6
H
4
70
88
66
70
3
22c
4-ClC
6
H
4
86
61
70
60
4
22d
2-furan
90
51
52
80
5
22e
4-(CH
3
O)C
6
H
4
95
77
49
75
[a] Isolated yields; [b] Reported previously
[22]
Figure 3. X-Ray structure analysis of 26a and 26b.
In a last step, the desired bicyclic nitrones were obtained using
the same reduction procedure as above to give compounds 26a-
e in good yields (Table 3). The structure of 26a and 26b, including
the trans ring junction, were unambiguously established using X-
Ray crystallography (Figure 3).
[24]
Conclusion
Novel mono- and bicyclic nitrones with a CF
2
R group in position
have been efficiently prepared from gem-difluoro propargylic
alcohols. Biological properties of these new nitrones are under
active study and corresponding results will be reported in due
course.
26a
26b
10.1002/ejoc.202000972
Accepted Manuscript
European Journal of Organic Chemistry

FULL PAPER
4
Experimental Section
General informations: see ref. 22
General procedure 1 for the synthesis of gem-
difluoropropargylic alcohols 3
To a solution of n-butyllithium 2.5 M (1.44 mL, 3.61 mmol) in anhydrous
THF (25 mL) cooled to -90°C, was added under nitrogen, a solution of 1
(500 mg, 2.77 mmol). The mixture was stirred for 30 min at -90°C. Then,
aldehyde 2 (1.3 equiv) in anhydrous THF (10 mL) was added at - 90°C,
stirred for 45 min, then the reaction mixture was allowed to warm to r.t.
within 2h. The mixture was then treated with a saturated ammonium
chloride solution and extracted with ethyl acetate (3x40 mL). The
combined organic phases were washed with water, dried over Na
2
SO
4
and
concentrated in vacuo. After purification by chromatography on silica gel,
the propargylic alcohols 3 were obtained.
4,4-difluoro-1-(4-fluorophenyl)-6-phenylhex-2-yn-1-ol 3b
Pale yellow oil, yield 684 mg (81%). R
f
= 0.5 (hexane / Ethyl Acetate: 8/2).
1
H NMR (300 MHz, CDCl
3
) δ 7.50 7.37 (m, 2H), 7.32 7.10 (m, 5H),
7.09 6.97 (m, 2H), 5.44 (t,
3
J
H-H
= 3.9 Hz, 1H), 2.90 2.76 (m, 2H), 2.45
2.24 (m, 2H), 2.32 2.10 (bs, 1H, OH).
13
C NMR (75 MHz, CDCl
3
) δ
163.1 (d,
1
J
C-F
= 247.9 Hz), 139.8, 134.9, 128.7, 128.6 (d,
3
J
C-F
= 8.4 Hz),
128.5, 126.6, 115.9 (d,
2
J
C-F
= 21.8 Hz), 114.2 (t,
1
J
C-F
= 233.6 Hz), 86.8 (t,
3
J
C-F
= 6.7 Hz), 79.6 (t,
2
J
C-F
= 41.0 Hz), 63.6, 41.0 (t,
2
J
C-F
= 26.2 Hz), 29.1
(t,
3
J
C-F
= 4.0 Hz).
19
F {H} NMR (282 MHz, CDCl
3
) δ -83.75 (s), -112.77 (s).
HRMS (ESI): calcd. for [M+Na]
+
(C
18
H
15
OF
3
Na) = 327.0967; found:
327.0970 (1 ppm).
1-(4-chlorophenyl)-4,4-difluoro-6-phenylhex-2-yn-1-ol 3c
Yellow oil, yield 534 mg (60%). R
f
= 0.2 (hexane / Ethyl Acetate: 9/1).
1
H
NMR (300 MHz, CDCl
3
) δ 7.48 – 7.35 (m, 4H), 7.35 7.27 (m, 2H), 7.26
7.16 (m, 3H), 5.49 (bs, 1H), 2.94 2.83 (m, 2H), 2.49 2.31 (m, 2H), 2.27
(bs, 1H, OH).
13
C NMR (75 MHz, CDCl
3
) δ 139.8, 137.5, 135.0, 129.2,
128.8, 128.5, 128.1, 126.6, 114.2 (t,
1
J
C-F
= 233.7 Hz), 86.6 (t,
3
J
C-F
= 6.7
Hz), 79.7 (t,
2
J
C-F
= 41.0 Hz), 63.6, 40.9 (t,
2
J
C-F
= 26.1 Hz), 29.1 (t,
3
J
C-F
=
4.0 Hz).
19
F {H} NMR {H} (282 MHz, CDCl
3
) δ -83.81 (s). HRMS (ESI):
calcd. for [M+Na]
+
(C
18
H
15
OF
2
35
ClNa) = 343.0671; 343.0672 (0 ppm).
4,4-difluoro-1-(furan-2-yl)-6-phenylhex-2-yn-1-ol 3d
Black oil, yield 490 mg (64%). R
f
= 0.3 (hexane / Ethyl Acetate: 8/2).
1
H
NMR (300 MHz, CDCl
3
) δ 7.41 (dd,
3
J
H-H
= 1.9,
3
J
H-H
= 0.8 Hz, 1H), 7.33
7.24 (m, 2H), 7.23 7.14 (m, 3H), 6.44 (dd,
3
J
H-H
= 3.3 Hz,
3
J
H-H
= 0.8 Hz,
1H), 6.35 (dd,
3
J
H-H
= 3.3 Hz,
3
J
H-H
= 1.9 Hz, 1H), 5.49 (t,
5
J
H-F
= 3.9 Hz,
1H), 2.92 2.81 (m, 2H), 2.68 (bs, 1H, OH), 2.46 2.27 (m, 2H).
13
C NMR
(75 MHz, CDCl
3
) δ 151.4, 143.6, 139.9, 128.7, 128.5, 126.5, 114.2 (t,
1
J
C-
F
= 233.7 Hz), 110.7, 108.6, 84.7 (t,
3
J
C-F
= 6.8 Hz), 78.6 (t,
2
J
C-F
= 41.1
Hz), 57.9 (t,
4
J
C-F
= 1.8 Hz), 41.0 (t,
2
J
C-F
= 26.0 Hz), 29.1 (t,
3
J
C-F
= 4.0 Hz).
19
F {H} NMR (282 MHz, CDCl
3
) δ -84.02 (s). HRMS (ESI): calcd. for
[M+Na]
+
(C
16
H
14
O
2
F
2
Na) = 299.0854; found: 299.0857 (1 ppm).
4,4-difluoro-1-(4-methoxyphenyl)-6-phenylhex-2-yn-1-ol 3e
Pale yellow oil, yield 588 mg (67%). R
f
= 0.2 (Petroleum Ether / Ethyl
Acetate: 8/2).
1
H NMR (300 MHz, CDCl
3
) δ 7.47 7.40 (m, 2H), 7.35
7.27 (m, 2H), 7.26 7.17 (m, 3H), 6.96 6.89 (m, 2H), 5.47 (t,
5
J
H-F
= 3.9
Hz, 1H), 3.82 (s, 3H), 2.92 2.85 (m, 2H), 2.48 2.31 (m, 2H), 2.28 (bs,
1H).
13
C NMR (75 MHz, CDCl
3
) δ 160.1, 139.9, 131.4 (t,
5
J
C-F
= 1.6 Hz),
128.7, 128.5, 128.2, 126.5, 114.3, 114.2 (t,
1
J
C-F
= 233.4 Hz), 87.3 (t,
3
J
C-F
= 6.8 Hz), 79.2 (t,
2
J
C-F
= 40.9 Hz), 63.9 (t,
4
J
C-F
= 2.0 Hz), 55.5, 41.0 (t,
2
J
C-F
= 26.2 Hz), 29.1 (t,
3
J
C-F
= 4.0 Hz).
19
F {H} NMR (376 MHz, CDCl
3
) δ
-83.61 (s). HRMS (ESI): calcd. for [M+Na]
+
(C
19
H
18
O
2
F
2
Na) = 339.1167;
found: 339.1169 (1 ppm).
General procedure 2 for the synthesis of gem-difluoronitro-
ketones 4 and 5
Representative procedure: Synthesis of 4,4-difluoro-3-(nitromethyl)-
1,6-diphenylhexan-1-one 4a
To the difluoropropargylic alcohol 3a (150 mg, 0.52 mmol) was added
nitromethane (56 μL, 1.04 mmol) and DBU (310 μl, 2.10 mmol) in THF (3
ml). The reaction mixture was stirred at room temperature overnight. At the
end saturated NH
4
Cl (10 mL) was added and the reaction mixture was
extracted with ethyl acetate (3x20 mL). The organic layers were separated,
washed with water (1x10 mL), dried over Na
2
SO
4
and concentrated under
vacuum. After purification by chromatography on silica gel, 4a (131 mg,
72%) was obtained as white solid. R
f
= 0.2 (hexane / Ethyl Acetate: 9/1).
mp = 102 °C.
1
H NMR (300 MHz, CDCl
3
) δ 8.01 7.92 (m, 2H), 7.67
7.57 (m, 1H), 7.54 7.44 (m, 2H), 7.34 7.15 (m, 5H), 4.74 (dd,
2
J
H-H
=
13.6 Hz,
3
J
H-H
= 6.1 Hz, 1H), 4.52 (dd,
2
J
H-H
= 13.6 Hz,
2
J
H-H
= 5.5 Hz, 1H),
3.83 3.62 (m, 1H), 3.41 (dd,
2
J
H-H
= 18.5 Hz,
2
J
H-H
= 4.6 Hz, 1H), 3.24
(dd,
2
J
H-H
= 18.5 Hz,
2
J
H-H
= 8.1 Hz, 1H), 2.94 2.82 (m, 2H), 2.33 2.10
(m, 2H).
13
C NMR (75 MHz, CDCl
3
) δ 196.1, 140.0, 136.1, 134.0, 129.0,
128.8, 128.4, 128.3, 126.6, 124.1 (t,
1
J
C-F
= 245.7 Hz), 73.9 (t,
3
J
C-F
= 4.8
Hz), 39.3 (t,
2
J
C-F
= 24.5 Hz), 37.0 (t,
2
J
C-F
= 24.6 Hz), 35.4 (t,
3
J
C-F
= 3.6
Hz), 28.0 (t,
3
J
C-F
= 5.1 Hz).
19
F {H} NMR (282 MHz, CDCl
3
) δ -102.95 (AB
system,
2
J
F-F
= 248.9 Hz), -104.05 (AB system,
2
J
F-F
= 248.9 Hz). HRMS
(ESI): calcd. for [M+Na]
+
(C
19
H
19
NO
3
F
2
Na) = 370.1225; found: 370.1230
(1 ppm).
4,4-difluoro-1-(4-fluorophenyl)-3-(nitromethyl)-6-phenylhexan-1-one
4b
Yellow solid, yield 133 mg (74%) from 150 mg (0.49 mmol) of 3b. R
f
= 0.4
(hexane / Ethyl Acetate: 9/1). mp = 129 °C.
1
H NMR (300 MHz, CDCl
3
) δ
8.15 7.98 (m, 2H), 7.48 7.08 (m, 7H), 4.80 (dd,
2
J
H-H
= 13.6 Hz,
3
J
H-H
=
5.9 Hz, 1H), 4.58 (dd,
2
J
H-H
= 13.6 Hz,
3
J
H-H
= 5.6 Hz, 1H), 3.87 3.63 (m,
1H), 3.45 (dd,
2
J
H-H
= 18.5 Hz,
3
J
H-H
= 4.6 Hz, 1H), 3.29 (dd,
2
J
H-H
=18.4 Hz,
3
J
H-H
= 8.0 Hz, 1H), 3.09 2.81 (m, 2H), 2.39 2.16 (m, 2H).
13
C NMR (75
MHz, CDCl
3
) δ 194.5, 166.3 (d,
1
J
C-F
= 256.3 Hz), 139.9, 132.5 (d,
4
J
C-F
=
3.0 Hz), 131.0 (d,
3
J
C-F
= 9.5 Hz), 128.8, 128.4, 124.0 (t,
1
J
C-F
= 245.8 Hz),
116.2 (d,
2
J
C-F
= 22.1 Hz), 73.8 (t,
3
J
C-F
= 4.9 Hz), 39.3 (t,
2
J
C-F
= 24.5 Hz),
36.9 (t,
2
J
C-F
= 24.6 Hz), 35.2 (t,
3
J
C-F
= 3.7 Hz), 28.0 (t,
3
J
C-F
= 5.1 Hz).
19
F
{H} NMR (282 MHz, CDCl
3
) δ -103.00 (AB system,
2
J
F-F
= 248.8 Hz), -
103.52 (s), -139.95 (AB system,
2
J
F-F
= 248.8 Hz). HRMS (ESI): calcd. for
[M+Na]
+
(C
19
H
18
NO
3
F
3
Na) = 388.1131; found: 388.1131 (0 ppm).
1-(4-chlorophenyl)-4,4-difluoro-3-(nitromethyl)-6-phenylhexan-1-one
4c
White solid, yield 123 mg (69%) from 150 mg (0.47 mmol) of 3c. R
f
= 0.3
(hexane / Ethyl Acetate: 9/1). mp = 137 °C.
1
H NMR (300 MHz, CDCl
3
) δ
7.94 7.86 (m, 2H), 7.52 7.42 (m, 2H), 7.34 7.12 (m, 5H), 4.73 (dd,
2
J
H-H
= 13.6 Hz,
3
J
H-H
= 5.9 Hz, 1H), 4.51 (dd,
2
J
H-H
= 13.6,
3
J
H-H
= 5.6 Hz,
1H), 3.79 3.54 (m, 1H), 3.37 (dd,
2
J
H-H
= 18.5 Hz,
3
J
H-H
= 4.6 Hz, 1H),
3.22 (dd,
2
J
H-H
= 18.5 Hz,
3
J
H-H
= 8.0 Hz, 1H), 2.93 2.77 (m, 2H), 2.33
2.09 (m, 2H).
13
C NMR (75 MHz, CDCl
3
) δ 195.0, 140.6, 139.9, 134.4,
129.7, 129.3, 128.8, 126.6, 124.0 (t,
1
J
C-F
= 245.7 Hz), 73.8 (t,
3
J
C-F
= 4.9
Hz), 39.3 (t,
2
J
C-F
= 24.5 Hz), 36.9 (t,
2
J
C-F
= 24.7 Hz), 35.3 (t,
3
J
C-F
= 3.6
Hz), 28.0 (dd,
3
J
C-F
= 5.8 Hz,
3
J
C-F
= 5.0 Hz).
19
F {H} NMR (471 MHz,
CDCl
3
) δ -103.0 (AB system,
2
J
F-F
= 249.2 Hz), -103.6 (AB system,
2
J
F-F
=
249.2 Hz). HRMS (ESI): calcd. for [M+Na]
+
(C
19
H
18
NO
3
F
2
35
ClNa) =
404.0835; found: 404.0832 (1 ppm).
4,4-difluoro-1-(furan-2-yl)-3-(nitromethyl)-6-phenylhexan-1-one 4d
Black solid, yield 130 mg (71%) from 150 mg (0.54 mmol) of 3d. R
f
= 0.4
(hexane / Ethyl Acetate: 8/2). mp = 79 °C.
1
H NMR (300 MHz, CDCl
3
) δ
7.68 (dd,
3
J
H-H
= 1.7 Hz,
4
J
H-H
= 0.8 Hz, 1H), 7.46 7.15 (m, 6H), 6.65 (dd,
3
J
H-H
= 3.6 Hz,
3
J
H-H
= 1.7 Hz, 1H), 4.80 (dd,
2
J
H-H
= 13.7 Hz,
3
J
H-H
= 6.1
Hz, 1H), 4.59 (dd,
2
J
H-H
= 13.7 Hz,
3
J
H-H
= 5.7 Hz, 1H), 3.90 3.59 (m, 1H),
10.1002/ejoc.202000972
Accepted Manuscript
European Journal of Organic Chemistry

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Abstract: A state-of-the-art method was developed for repurposing nitrone-containing compounds in the chemosensory field, the ability of the designed molecules to chelate metal cations was evaluated, and their unprecedented solubility in water was confirmed. A facile, rapid, and solvent-free method of synthesizing small molecular mass chemosensors was developed by using a modulative α-aryl-N-aryl nitrone template. α-(Z)-Imidazol-4-ylmethylen-N-phenyl nitrone (Nit1) and α-(Z)-2-pyridyl-N-phenyl nitrone (Nit2) were prepared in 15 min, isolated in less than 60 min with ca. 90% yield, and screened against nine metal cations. Nit1 is a small-molecular-mass compound (188 g mol−1) that is water-soluble and has specificity for sensing Cu2+ with an association constant of K = 1.53 x 1010 and a limit of detection (LOD) of 0.06 ppm. These properties make Nit1 a competitive chemosensor for the detection of Cu2+ in aqueous solution. The nitrone-containing template used in this study is a step forward for new and small chemosensory entities.

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Journal ArticleDOI
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