Trifluoroacetaldehyde N-Tosylhydrazone as a Precursor of Trifluorodiazoethane in Reactions of Insertion into the Heteroatom-Hydrogen Bond

Article abstract of DOI:10.1021/acs.orglett.9b03471

Trifluorodiazoethane is a widely explored trifluoroethylating reagent, which is suitable for the preparation of a large number of fluorine-containing organic molecules. Nevertheless, CF₃CHN₂ has some disadvantages, such as volatility

Full text of DOI:10.1021/acs.orglett.9b03471

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Trifluoroacetaldehyde N‑Tosylhydrazone as a Precursor of
Trifluorodiazoethane in Reactions of Insertion into the
Heteroatom−Hydrogen Bond
Vladimir S. Ostrovskii, Irina P. Beletskaya, and Igor D. Titanyuk*
Department of Chemistry, Moscow State University, Leninskie Gory 1-3, Moscow 11999, Russian Federation
S
* Supporting Information
ABSTRACT: Trifluorodiazoethane is a widely explored
trifluoroethylating reagent, which is suitable for the prepara-
tion of a large number of fluorine-containing organic
molecules. Nevertheless, CF3CHN2 has some disadvantages,
such as volatility, storage instability, toxicity, and explosive-
ness. We report the application of trifluoroacetaldehyde N-
tosylhydrazone as a CF3CHN2 precursor capable of generating
in situ trifluorodiazoethane under mild basic conditions. Copper-catalyzed P−H, O−H, S−H, and C−H insertion reactions of
trifluoroacetaldehyde N-tosylhydrazone revealed its wide applicability in the synthesis of trifluoroethyl-containing substances.
he introduction of fluorine or fluoroalkyl substituents into
Tbiologically relevant compounds has become an
important tool in drug discovery.1 Special attention is paid
to trifluoromethyl-containing compounds due to the unique
properties of the trifluoromethyl group, such as the high
electronegativity, electron density, steric hindrance, and
hydrophobic properties. 2,2,2-Trifluorodiazoethane is a
versatile trifluoroethylating reagent for the preparation of a
wide range of fluoroorganic compounds.
It is employed in synthetic transformations such as
cyclopropanation,2 [3 + 2] cycloaddition,3 reactions with
carbonyl compounds4 and imines,5 heteroatom−hydrogen
bond insertions,6 carbon−hydrogen bond insertion,7 car-
bon−boron bond insertion,8 and some others. The most
valuable chemical syntheses are presented in Figure 1.
The preparation of 2,2,2-trifluorodiazoethane is rather
complicated. It is generated by the treatment of trifluoroethyl-
amine hydrochloride (CF3CH2NH2·HCl) with sodium nitrite
(NaNO2). Pure CF3CHN2 is gaseous at room temperature
(Mp = 12 to 13 °C) as well as explosive and toxic, so it is
usually explored as a stock solution. The application of 2,2,2-
trifluorodiazoethane commonly requires a large excess of
reagent and makes the synthetic method quite expensive.
These disadvantages remain a general limitation for the wider
synthetic use of this diazo compound, especially in a large-scale
synthesis.
To overcome the above drawbacks, we report here the
application of trifluoroacetaldehyde N-tosylhydrazone (1) as a
CF3CHN2 precursor that is capable of generating 2,2,2-
trifluorodiazoethane in situ under mild basic conditions. N-
Tosylhydrazones have been widely explored in organic
synthesis as precursors to diazo compounds.9 However,
trifluoroacetaldehyde-derived N-tosylhydrazone has been
used as an analog of CF3CHN2 in selected publications,
Figure 1. Some applications of 2,2,2-trifluorodiazoethane.
exclusively for the preparation of CF3-substituted pyrazolines10
and cyclopropanes11 (Scheme 1A).
While this Letter was under preparation, the article of Bi and
coworkers12 appeared, reporting the successful exploration of
trifluoroacetaldehyde N-(2-trifluorophenylsulfonyl)hydrazone
as a trifluorodiazoethane surrogate. It was employed in the
difluoroalkenylation of X−H bonds (X = N, O, S, Se) along
with Doyle−Kirmse rearrangements and the cyclopropanation
of alkenes. Herein we propose hydrazone 1 as a masked 2,2,2-
trifluorodiazoethane, which under Cu(I) catalysis enables the
insertion into X−H bonds (X = P, O, S, C) to produce
trifluoroethyl-containing organic molecules (Scheme 1B).
Received: October 1, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
DBU, and Na3PO4 were found to be less effective. The optimal
reaction conditions therefore consist of reacting hydrazone 1
(1.0 equiv) with phosphonate (1.2 equiv) in THF at reflux
temperature in the presence of CuI (0.2 equiv) and
triethylamine (1.0 equiv). Under these conditions, diethyl
2,2,2-trifluorophosphonate (2a) was obtained in 95% NMR
yield (Table 1, entry 8).
Scheme 1. Synthetic Application of 2,2,2-
Trifluorodiazoethane from Hydrazone 1
After establishing the optimal conditions for the CuI-
catalyzed P−H bond insertion reaction, the reactivity of several
dialkyl phosphonates was examined, and the excellent
generality of this insertion process was found (Scheme 2).
a
Scheme 2. Scope of CuI-Catalyzed P−H Insertion of 1
This study was started with the preparation of trifluor-
oacetaldehyde N-tosylhydrazone (1) from commercially
available semiacetal CF3CH(OH)OEt by the modified
procedure disclosed by Ley.13 The widespread scope of
copper-catalyzed X−H insertion reactions of diazo compounds
prompted us to focus on this metal to probe the reactivity of 1.
Copper-catalyzed insertion into the P−H bond with
trifluorodiazoethane was reported in the literature by selected
examples.6b Thus we were interested in the elaboration of a
versatile methodology for the trifluoroethylphosphonates
synthesis. Diethyl phosphonate was taken as the model
substrate (Table 1).
Table 1. Reaction Condition Optimization for P−H
a
Yields given are for the isolated products (values in parentheses
a
Insertion
indicate the yield by 19F NMR spectroscopy).
The reaction proceeded smoothly, giving an outcome of
products 2a−f in up to 81% isolated yield. The yield was not
affected much by the alkyl moiety of the starting phosphonate
up to the C6 radical. Steric hindrance of the bulky substituents
prevented the formation of the desired product in the cases of
dinonyl phosphonate and diisopropyl phosphonate. The P−H
insertion reaction with diphenylphosphine oxide afforded a
complex mixture of products.
Having in mind the results of successful reactions with P−H
substrates, we supposed the formation of catalytic species
containing donating ligands (trialkyl phosphite) in a
coordinative sphere of copper(I) (Figure 2).
b
entry
catalyst (mol %)
base
solvent
yield
c
1
2
3
4
5
6
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
CuI (20)
pyridine
Et3N
pyridine
CH2Cl2
CH3CN
DME
THF
n.r.
n.r.
47
50
d
c
K2CO3
Na3PO4
NaH
d
tBuOK
THF
7
8
9
10
11
12
CuI (20)
CuI (20)
CuI (20)
Cu(OTf)2 (10)
Cu(acac)2 (10)
Cu(F3acac)2 (10)
DBU
Et3N
Et3N
Et3N
Et3N
Et3N
THF
THF
Et3N
THF
THF
37
95
77
17
35
46
THF
a
Reaction conditions: 1 (1.0 equiv), diethyl phosphonate (1.2 equiv),
b
70 °C or reflux (for THF and CH2Cl2). Yield was determined by 19
F
Figure 2. Suggested catalytic species containing donating ligands
(trialkyl phosphite) catalyzing P−H insertion reactions.
NMR spectroscopy with ethyl trifluoroacetate as an internal reference.
c
d
No reaction. Decomposition of 1 without the formation of 2a.
Optimization studies indicated that CuI (10 mol %) was
This hypothesis is supported by the fact that some other
CuI-catalyzed X−H insertion reactions (X = O, N, S) failed
under similar conditions. It was found that thiols, anilines,
alcohols, and carboxylic acids gave low yields or traces of
trifluoroethyl-substituted compounds. We suggested that
copper catalysts possessing donating ligands could substantially
improve the outcome of the desired products. After a short
screening of Cu(I) catalytic systems, we figured out that
CuBr(SMe2) was the most effective catalyst for O−H and S−
superior to the other catalysts tested (Table 1, entries 1−9 vs
entries 10−12). The reaction was sensitive to the solvent and
base. No reaction occurred with CuI in pyridine (weak base)
or in dichloromethane (low reaction temperature) (Table 1,
entries 1 and 2). The strong bases like sodium hydride and
tBuOK caused the decomposition of 1 without the formation
of 2a (Table 1, entries 5 and 6). Triethylamine appeared to be
the best base for this reaction, whereas other bases like K2CO3,
B
DOI: 10.1021/acs.orglett.9b03471
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
H bond insertions with carboxylic acids and thiols,
respectively. Benzene was chosen as the optimal solvent for
these reactions.
Carboxylic acids, either aromatic or aliphatic, appeared to be
suitable substrates and were converted into the corresponding
trifluoroethyl esters 3a−h (Scheme 3). Aromatic and aliphatic
On the basis of the precedential work of Ma,7 we examined
the ability of 1 to react with 4-bromo-1-ethynylbenzene (5) in
the presence of CuI (10 mol %). A preliminary result was
obtained via the Cu/triethylamine/MeCN system to provide
the corresponding trifluoroethylated product 6 in 33% yield.
The method is currently under investigation, and the results of
further research will be published elsewhere.
In summary, we report the use of trifluoroacetaldehyde N-
tosylhydrazone (1) as a stable precursor of CF3CHN2. The
latter can be generated in situ under mild basic conditions that
avoid working with a hazardous diazo compound. We have
disclosed a direct, simple, and efficient copper(I)-catalyzed
trifluoroethylation of dialkyl phosphonates, carboxylic acids,
thiols, and terminal alkynes employing 1. The most significant
result is the easy execution of the synthesis, which enables the
rapid preparation of trifluoroethylated compounds.
a
Scheme 3. Scope of O−H and S−H Insertions of 1
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03471.
Procedures and characterization data (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: titanyuk@org.chem.msu.ru.
ORCID
Igor D. Titanyuk: 0000-0002-7519-5602
Author Contributions
The manuscript was written through contributions of all
authors.
Notes
a
The authors declare no competing financial interest.
Yields given are for the isolated products.
ACKNOWLEDGMENTS
■
This work was supported by the Russian Science Foundation
(grant 19-13-00223). The research work was carried out using
an Agilent 400-MR NMR spectrometer purchased under the
program of MSU development. We acknowledge Thermo
Fisher Scientific, Inc. and MS Analytica (Moscow, Russia), for
providing the mass spectrometry equipment for this work.
carboxylic acids reacted with 1 under CuBr(SMe2) catalysis to
afford products in 33−80% yield. Remarkably, the reaction
tolerates phenolic hydroxyl in salicylic acid, thus leading to the
trifluoroethyl salicylate (3e).
Electron-poor heteroaryl thiols reacted with 1 under the
same conditions, leading to the 2,2,2-trifluoroethyl-substituted
sulfides 4a−g in up to 80% yield. Fluorinated sulfides 4 can be
oxidized to sulfones, which are suitable substrates for the
synthesis of CF3-substituted terminal olefins via Julia−
Kocienski olefination.14 The product of the S−H insertion of
thiophenol was observed only in a trace amount, using either
CuI or CuBr(SMe2) as the catalyst.
The trifluoroethylation of terminal alkynes remains an
interesting challenge to date. Herein we report our first result
in developing the catalytic trifluoroethylation of terminal
alkynes applying N-tosylhydrazone 1 (Scheme 4).
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Org. Lett. XXXX, XXX, XXX−XXX