Difluoromethyl Nitrile Oxide (CF2HCNO): A Neglected Chemical Reagent

Article abstract of DOI:10.1002/ejoc.201700764

A novel chemical reagent – difluoromethyl nitrile oxide, CF₂HCNO – was generated in situ for the first time. The synthesis commenced with ethyl difluoroacetate and included only two chemical steps. The difluoromethyl nitrile oxide smoothly participated in [3+2]-cycloaddition reactions with alkynes and enamines to give CF₂H-isoxazoles; these products are promising cores for agrochemistry. A representative CHF₂-isoxazole was incorporated into the known fungicide Fluxapyroxad (BASF), and the synthesized analogue showed higher antifungal activity than the parent fungicide.

Full text of DOI:10.1002/ejoc.201700764

DOI: 10.1002/ejoc.201700764
Communication
Novel Reagents
Difluoromethyl Nitrile Oxide (CF HCNO): A Neglected Chemical
2
Reagent
[
a,b,c]
[a]
[a]
[a]
Andrii Khutorianskyi,
Bohdan Chalyk, Petro Borysko, Anna Kondratiuk, and
Pavel K. Mykhailiuk*[
b]
Abstract: A novel chemical reagent – difluoromethyl nitrile alkynes and enamines to give CF H-isoxazoles; these products
2
oxide, CF HCNO – was generated in situ for the first time. The are promising cores for agrochemistry. A representative CHF2-
2
synthesis commenced with ethyl difluoroacetate and included isoxazole was incorporated into the known fungicide Fluxa-
only two chemical steps. The difluoromethyl nitrile oxide pyroxad (BASF), and the synthesized analogue showed higher
smoothly participated in [3+2]-cycloaddition reactions with antifungal activity than the parent fungicide.
Introduction
Derivatization of organic compounds with fluorinated units of-
[
1,2]
ten affects their physicochemical and biological properties.
Consequently, ca. 20 % of pharmaceuticals and agrochemicals
contain at least one fluorine atom. Especially prevalent are the
[
3]
trifluoromethyl and difluoromethyl groups.
The difluoro-
methyl group possesses lower lipophilicity and higher polarity
than the trifluoromethyl group. Moreover, it often mimics the
alcohol and thiol moieties by acting as a hydrogen-bond do-
nor.[ In recent years, however, chemists have opted to incorpo-
rate the difluoromethyl group by direct difluoromethylation[5,6]
and have highly underestimated the corresponding building
4]
[
7]
blocks. Hence, novel reagents to synthesize CF H-substituted
2
compounds are of value.
In 2015, we developed a novel chemical reagent – difluoro-
2 2 2
Scheme 1. Novel reagents: CF HCHN (1, 2015) and CF HCNO (2).
[
8]
methyldiazomethane, CF HCHN2 (1). During the past two
2
years, reagent 1 has already gained much popularity in chemis-
[
9]
try. For unclear reasons its isoelectronic analogue – difluoro-
ynes towards isoxazoles.[14,15] The isoxazole core occurs in at
least 17 FDA-approved drugs.
methyl nitrile oxide, CF HCNO (2) – remains unknown so far
Scheme 1).
The history of substituted nitrile oxides goes back to 1907,
when Wieland obtained the first stable benzonitrile oxide (3) in
pure form and studied some of its properties (Scheme 2).
Nowadays, nitrile oxides play an important role in chemistry as
useful starting materials,
[3]
2
(
In 1971, Deltsova, Ananyan, and Ganbaryan reported on the
[16]
in situ generation of trifluoromethyl nitrile oxide (4).
Since
then, reagent 4 has been blossoming in chemistry: it has al-
[
10,11]
ready been used in more than 50 research manuscripts and
[17]
patents.
Apart from academic applications, reagent 4 has
[
12,13]
especially in reactions with alk-
also been applied in drug-discovery projects by well-known
[
17k]
[18a]
pharmaceutical companies such as Abbott,
Pfizer,
Novar-
[
18b]
[18c]
tis,
and Amgen.
At the same time, conceptually attract-
[
[
[
a] Enamine Ltd./Bienta,
ive reagent 2 still remains unknown (Scheme 2).
Chervonotkatska 78, 02094 Kyiv, Ukraine
www.enamine.net
b] Taras Shevchenko National University of Kyiv, Chemistry Department,
Volodymyrska 60, 01601 Kyiv, Ukraine
E-mail: Pavel.Mykhailiuk@gmail.com
c] Taras Shevchenko National University of Kyiv,
Institute of High Technologies,
One might argue, how, in the 21st century, in the blossom
of organic chemistry, when scientists can already synthesize ex-
tremely complex compounds in more than 100 chemical
[
19]
steps,
we still do not have a tiny reagent (only two carbon
atoms in 2) with true high potential for the pharmaceutical and
agrochemical industries. In strict contrast to 4, no one can
therefore use reagent 2. In our opinion, this unallowable gap in
Volodymyrska 60, 01601 Kyiv, Ukraine
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.201700764.
[
20]
modern chemistry
must be urgently filled.
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Communication
3 2
Scheme 2. Nitrile oxides: PhCNO (3), CF CNO (4), and CF HCNO (2).
In this communication, therefore, novel chemical reagent 2
was generated, and its first representative reaction, the [3+2]
cycloaddition with alkynes towards CF H-isoxazoles, was stud-
2
ied. The products were shown to be useful starting materials
for organic synthesis, drug discovery, and agrochemistry.
Results and Discussion
Optimization
2
Scheme 3. Synthesis of CHF -isoxazole 8a.
The synthesis commenced from commercially available ester 5.
Reduction of 5 with LiAlH in diethyl ester at – 78 °C following a
4
[
21]
Importantly, the reaction was easily scaled up to obtain 25 g
of product 8a in one synthesis run.
literature protocol resulted in semiacetal CHF CH(OEt)OH (6).
2
Treatment of 6 with NH OH smoothly afforded the needed
2
oxime 7. Notably, compound 7 with only two C atoms has
never been previously reported in the literature.
3,5-Disubstituted Isoxazoles
In 2013, Crousse generated nitrile oxide 4 by oxidizing oxime
[
17n]
CF CHNOH with PhI(OAc) .
All our attempts, however, to Next, to study the scope of the developed reaction, electron-
treat oxime 7 with PhI(OAc) afforded complex mixtures, pre- deficient alkynes 10 and 12–14, unactivated alkynes 15–22,
3
2
2
sumably as a result of the side oxidation of the CHF group.
electron-rich alkyne 23, and aromatic/heteroaromatic alkynes
Therefore, we next challenged presumably the most com- 24–26 were tested (Table 1). Electron-deficient, electron-rich,
mon method to generate nitrile oxides from oximes: N-chloro- and unactivated alkynes 10 and 12–23 all afforded the CHF
2
-
2
[
22]
succinimide (NCS) followed by the addition of a base. Indeed, isoxazoles in 40–80 % yield. Instead of unavailable cyano acet-
formation of reagent 2 was observed, but in the first experi- ylene, we used alkene 11, which gave target isoxazole 11a
ments with alkyne 8, extensive dimerization into furoxan 9 was in 32 % yield. Aromatic alkynes 24–26 also underwent the
also observed. Also, a mixture of 3,4- and 3,5-disubstituted reaction, but the products were obtained in poor yields of
CHF -isoxazoles was formed. After extensive optimization of the 13–42 %.
2
ratio of reactants, solvent, base, and reaction time, we found
proper conditions to minimize the formation of both furoxan 9 (2) and alkynes belongs to type II [3+2]-cycloaddition reac-
These results suggest that the reaction between CF HCHO
2
[
12a]
and the 3,4-isomer and to avoid the use of a large excess tions,
in that the reaction proceeds well with electron-defi-
amount of reactants. In fact, after optimization, pure CHF -isox- cient, electron-rich, and unactivated alkynes.
2
azole 8a was obtained in 73 % yield as a colorless liquid
Scheme 3).
Enantiomerically pure alkynes 21 and 22 gave correspond-
ing products 20a and 21a without racemization.
(
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Communication
2
Table 1. Synthesis of 3,5- and 3,4-disubstituted CHF -isoxazoles.
[
a] Yield of isolated product. [b] 1. [3+2] cycloaddition, 2. trifluoroacetic acid (TFA), 3. Boc
2
O, Boc =tert-butoxycarbonyl.
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communication
Liquid isoxazole 15a was easily oxidized with CrO into corre- isoxazoles. In particular, we envisioned that they might be con-
3
[
23]
sponding crystalline acid 15b,
the structure of which was sidered as bioisosteres of CHF -NMe-pyrazoles, which are ex-
2
[
24]
[27]
proven by X-ray analysis (Figure 1).
tremely popular in agrochemistry.
8a to alcohol 37, followed by oxidation of the latter with CrO3
gave acid 38. Standard amide synthesis afforded compound 39
Scheme 5).
In fact, reduction of ester
2
(
Figure 1. X-ray analysis of CHF
2
-isoxazoles 15b, 32a, and 34a.[24]
This reaction in chloroform had high regioselectivity: it pre-
dominantly gave 3,5-disubstituted isoxazoles with less than 5 %
of the 3,4-disubstituted isomers. The pure products were ob-
tained in each case by column chromatography, crystallization,
or distillation.
3
,4-Disubstituted Isoxazoles
Scheme 5. Synthesis of compound 39. DIBAL = diisobutylaluminum hydride.
To synthesize the 3,4-disubstituted isoxazoles, we took 1,2-
“
push–pull” enamines 27–33 and enol 34 as substrates. Slight
We next experimentally measured the antifungal activity of
compound 39 and Fluxapyroxad, a fungicide commercialized
by BASF. On two strains of fungi, that is, Fusarium oxysporum
Schltdl. and Aspergillus ustus (Bainier) Thom & Church, com-
pound 39 showed activity that was 2–4 times higher than that
of Fluxapyroxad (Table 2). Both compounds had the same activ-
ity on Fusarium verticillioides (Sacc.) Nirenberg. Indeed, we do
not claim that patent-free compound 39 will definitely become
a commercialized fungicide, but these results practically dem-
onstrate the enormously high synthetic potential of both rea-
optimization of the reaction was needed: we first generated a
solution of the corresponding chloroxime, which was followed
by the addition of the enamine. Under these conditions, prod-
ucts 27a–34a were all obtained in 14–80 % yield. In these cases,
the reactions were regioselective, as the formation of the 3,5-
isomers was not observed. The structures of products 32a and
3
4a were proven by X-ray analysis (Figure 1).[
24]
Practical Applications
gent 2 and the synthesized CHF -isoxazoles.
2
[
3,25]
Indeed, given the high importance of both isoxazoles
the CHF group in medicinal chemistry (Figure 1) and organic
and
[
3]
2
Table 2. Antifungal activities of fluxapyroxad and compound 39.
synthesis, the synthesized CHF -isoxazoles seem to be very in-
2
[
26]
triguing building blocks.
For example, acidic hydrolysis of
isoxazole 21a into amino alcohol 35, followed by N-Boc protec-
tion and oxidation with CrO gave fluorinated α-amino acid 36
3
(
Scheme 4). This amino acid might also be considered an ana-
logue of the natural compound ibotenic acid (owing to bio-
[
4]
isosterism of the aromatic –CHF and –OH groups).
2
[
a] Minimal inhibitory concentration of a compound that inhibits the growth
of fungi.
Conclusions
In summary, we herein delineated three important findings:
one, the novel chemical reagent difluoromethyl nitrile oxide,
CF HCNO (2), was synthesized (generated in situ) for the first
2
Scheme 4. Synthesis of amino acid 36. PTSA = para-toluenesulfonic acid.
time; two, the synthesis of CHF -substituted 3,4- and 3,5-isox-
2
Apart from the purely synthetic work, we also wanted to azoles from 2 was elaborated; three, the obtained products
show the high practical potential of the synthesized CHF2- were shown to be useful in drug discovery and agrochemistry
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Communication
wig, J. Am. Chem. Soc. 2012, 134, 5524 (CHF
C. S. Thomoson, W. R. Dolbier Jr., Org. Lett. 2015, 17, 3528 (CHF
8] P. Mykhailiuk, Angew. Chem. Int. Ed. 2015, 54, 6558; Angew. Chem. 2015,
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[9] a) S. K. Riter, Chem. Eng. News 2015, 93, 3; b) J. Li, X.-L. Yu, J. Cossy, S.-Y.
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2
Cu); j) Z. Zhang, X. Tang,
as patent-free bioisosteres of N-Me pyrazoles. In fact, com-
pound 39 was more potent than the known pesticide Fluxa-
pyroxad (BASF).
We do believe that given the high availability of starting ma-
terials, chemists will also use reagent 2 in the synthesis of other
2
SO Cl).
2
[
1
2
66; c) A. Feraldi-Xypolia, G. Fredj, G. Tran, T. Tsuchiya, J.-P. Vors, P. My-
CF H-substituted compounds, such as isoxazolines, oximes, and
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oxadiazoles, as the chemistry of nitrile oxides has been known
[
10–13]
for more than a century.
We also envision that reagent 2
will soon become useful in medicinal chemistry, agrochemistry,
and organic synthesis in the very same way that the diazo rea-
gent CF HCHN (1) and the nitrile oxide CF CNO (4) already did.
[
[
10] PhCNO seems to have been first synthesized by Werner and Buss in
2
2
3
1
1
894 without even realizing it: A. Werner, H. Buss, Ber. Dtsch. Chem. Ges.
894, 27, 2193.
11] H. Wieland, Ber. Dtsch. Chem. Ges. 1907, 40, 1667.
Acknowledgments
[12]
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Synthesis (Ed.: H. Feuer), Wiley, Hoboken, NJ, 2008, pp. 1–128.
The authors are grateful to Prof. A. Tolmachev for financial sup-
port and to Dr. S. Shishkina for X-ray studies and Ms. K. V. Hre-
beniuk for the synthetic help.
[
[
13] Review on nitrile oxide: C. Grundmann, Synthesis 1970, 344.
14] The reaction of PhCNO (3) with alkynes towards isoxazoles was first re-
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Keywords: Heterocycles · Nitrile oxides · Fluorine · Alkynes ·
Bioisosterism
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3
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2
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Communication
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[
[
24] CCDC 1547614 (for 15b), 1547613 (for 32a), and 1548642 (for 34a) con-
tain the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallographic
Data Centre.
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984; c) S. Fustero, J. F. Sanz-Cervera, Org. Prep. Proced. Int. 2009, 41, 253.
Received: May 30, 2017
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