Fluoroform: an Efficient Precursor for the Trifluoromethylation of Aromatic Esters by Sodium Diisopropylamide with Trialkylamines

Article abstract of DOI:10.1002/ejoc.201900250

The trifluoromethanide anion is the postulated key intermediate in nucleophilic trifluoromethylation reactions. It is believed to be incompatible with Na⁺ cation due to the strong Na–F bond. However, herein we demonstrate that it could be prepared for the first time. Trialkylamines can be used as cation chelating agents to stabilize the isolated ^–CF₃ ion to realize trifluoromethylation reaction. With this strategy, trifluoromethyl aromatic ketones could be effectively synthesized from fluoroform and aromatic esters with diisopropyl aminosodium (NaDA) and trialkylamines.

Full text of DOI:10.1002/ejoc.201900250

A Journal of
Accepted Article
Title: Fluoroform: an Efficient Precursor for the Trifluoromethylation of
Aromatic Esters by Sodium Diisopropylamide with Trialkylamines
Authors: Zhaomeng Han, Sihan Chen, Yongjun Tu, Xiongdong Lian,
and Gongyong Li
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900250
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900250
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10.1002/ejoc.201900250
European Journal of Organic Chemistry
COMMUNICATION
Fluoroform: an Efficient Precursor for the Trifluoromethylation of
Aromatic Esters by Sodium Diisopropylamide with Trialkylamines
Zhaomeng Han*, Sihan Chen, Yongjun Tu, Xiongdong Lian*, and Gongyong Li
Abstract: The trifluoromethanide anion is the postulated key
intermediate in nucleophilic trifluoromethylation reactions. It is
believed to be incompatible with Na+ cation due to the strong Na-F
bond. However, herein we demonstrate that it could be prepared for
the first time. Trialkylamines can be used as cation chelating agents
for stabilizing the isolated −CF3 ion to realize trifluoromethylation
reaction. With this strategy, trifluoromethyl aromatic ketones could
be effectively synthesized from fluoroform and aromatic esters with
diisopropyl aminosodium (NaDA) and trialkylamines.
et al. reported a more stable trifluoromethyl covalent compound
Ruppert-Prakash reagent, TMSCF3, which is a commercialized
8h]
reagent.[8g,
It has been applied to trifluoromethylation of
various electrophiles. In 2013, Shibata et al. reported N'''-(1,1-
Dimethylethyl)-N,N',N''-tris [tris (dimethylamino) phosphorany-
lidene] phosphorimidic triamide(tert-Butylimino)tris((tris(dimethyl-
amino)phosphoranylidene)amino)phosphorane (P4-t-Bu), as an
-
organocatalyst, could function as a base and CF3 ion stabilizer.
[8i, 8j]
It can react with aromatic ketones and aldehydes including
naphthaldehydes, anthraldehydes, 2-thienylaldehydes. In 2014,
Prakash et al. reported a new strategy, introducing stoichio-
metric cation scavenger agent, 18-crown-6, into the trifluoro-
methylation using HCF3. It inhibited the process of
trifluoromethyl metamorphism by binding K+ (Scheme 1).[8k] It
has an effect on the nucleophilic substitution reactions of
fluorosulfonamides, thioethers and haloalkanes, nucleophilic
addition reactions of aromatic aldehydes, ketones and carbon
dioxide, aromatic nucleophilic substitution reactions of
fluorobenzenes.
Introduction
The widespread applications of fluorinecontaining com-
pounds in chemistry, biology and materials science,[1] has made
incorporation of fluorine into organic compounds a hot research
topic in synthetic organic chemistry.[2] Among various fluorinated
substituents, the trifluoromethyl group stands out because of
strong electron absorption, high stability and lipophilicity,
which could significantly change the acidity, dipole moment,
metabolism and chemical stability of trifluoromethylated
compounds. So the compounds with stronger biological activity
and special performance, are widely used in the field of
pesticides, dyestuff and pharmaceutics. [1a, 1d, 2a, 3]
Herein, we disclose a new strategy that trialkylamines could
be used as new more convenient cationic chelating agents,
stabilizing the -CF3 ion efficiently through liganation of Na+
(Scheme 1). It offers a new strategy to synthesize trifluoro-
aromatic ketones using the corresponding esters.
As a byproduct of the fluorochemical industry and also
greenhouse gas, fluoroform is available in large quantity at a
very low price and has drawn intensive attention as a fluorinated
building block. Currently, fluoroform are used for manufacturing
freezing medium, liquid plasma, fluorinated compounds and so
on.[4] The low acidity of CHF3 (pKa = 27 in H2O)[5] requires its
deprotonation by strong bases such as organometallic reagents.
However, isolated −CF3 ion is only stable at low temperature and
is exceedingly labile and undergoes facile decomposition in the
presence of main group metal ions such as Na+ , Li+ , Mg2+ etc.,
to yield M-F and difluorocarbene (:CF2).[1e-f,
To
2c, 6, 7, 8, 9–16]
develop the practicality of trifluoromethylation with fluoroform
remains a great challenge.
Trifluoromethylation of carbonyl compounds with CHF3 was
-
first reported in 1991 by Shono et al.[7] It was suggested that
CF3 ion could attack carbonyl group on DMF to form a key
intermediate 1, which can react with some aromatic aldehydes,
acidamides, aromatic esters and sulfurcontaining compounds
such as thioethers, sulfenyl chlorides and thiosulfonyl esters to
deliver the corresponding trifluoromethylation products. A series
of related works have addressed trifluoromethylated using
fluoroform in presence of strong bases and DMF at subambient
temperatures in the following several years.[8] In 2012, Prakash
[*]
Dr. Z. Han, Dr. S. Chen, Y. Tu, Dr. X. Lian, Dr. G. Li
Department of Research and Development
Shanghai Qixun medical technology co. LTD
4nd floor, Building 9, 500 Furonghua Road, Shanghai, 200321,
China
E-mail: han.zhaomeng@tianyupharm.com
lian.xiongdong@tianyupharm.com
Supporting information for this article is given via a link at the end
of the document.
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10.1002/ejoc.201900250
European Journal of Organic Chemistry
COMMUNICATION
Scheme 1. Three strategies for obtaining trifluoromethanide anion: 1.
6
2-Methoxy-N,N-dimethyl-
-60
5%
-
[8g,
Preparad stable covalent bond intermideates of CF3 ion like 1, [7] TMSCF3.
ethanamine
8h]
[8i, 8j]
2. Used organocatalyst 2 to catalyze HCF3.
3. Reacted with cation
[8k]
scavenger agents forming cation intermediates like 3
or 4 to inhibit the
7
8
9
Pentamethyldiethylenetriamine
Pentethyldiethylenetriamine
-60
-60
-60
83%
0
formation of M-F to stabilize -CF3 ion.
Tris(2-(2-methoxy-ethoxy)
ethyl)amine
<10%
Results and Discussion
We set out to use the reaction of m-chlorobenzoic acid ethyl
ester (5a) and CHF3, with diisopropyl aminosodium (NaDA) as
base in n-heptane. m-Chlorotrifluoroacetophenone (6a) could be
detected in -60oC temperature in two hours, but the yield was
less than 5% (Table 1, entries 1). Considering the amount of the
additive, co-solvent was more proper on stability of isolated −CF3
ion,[8, 15] various additive and temperature was examined. NaDA
with dimethyl ethylamine (DMEA) was examined next. The yield
increased to 24% (Table 1, entry 2), suggesting that amine
ligand has beneficial effect on the reaction. Further optimization
of addtives by varying the di-, tri-, and tetramine derivatives were
performed. When the additive was diamine, with TMEDA as
ligand, the rate of cationic chelating agent formation was fast
and the yield increased to 93% (Table 1, entry 3). When methyl
group was replaced with ethyl, the trend of cationic chelating
agent formation was disfavoured and the yield decreased to
60% (Table 1, entry 4). The trend was even more pronounced
with tetra-n-butyldiethylamine, where the formation of cationic
chelating agent was not observed (Table 1, entry 5). It was
worth noting that when 2-methoxy-N,N-dimethylethanamine was
used as the addtive, the rate of cationic chelating agent
formation was fast but the yield decreased to 5% (Table 1, entry
6). When pentamethyldiethylenetriamine and tritertiaryamine
were added in the reaction, the yield was also good (ca. 83%)
(Table 1, entry 7). The steric hindrance also appeared to play a
role, as pentethyldiethylenetriamine led to no product generation
(Table 1, entry 8). Addition of tris(2-(2-methoxyethoxy)ethyl)-
amine or N,N-bis[2-(dimethylamino)ethyl]-N,N-dimethyl-ethane-
1,2-diamine led to undesirable yields (Table 1, entries 9, 10).
Finally, the temperature was further screened. When the
temperature reached to -30oC, the yield decreased to 37%
(Table 1, entry 11).
10
11
N,N-bis[2-(dimethyl-amino)ethyl]-
N,N-dimethylethane-1,2-diamine
-60
-30
<5%
37%
Tetramethylethylenediamine
[a] Reaction conditions: 5a (10 mmol) in solvent (10 mL), nitrogen atmosphere.
[b] GC yields. [c] Reactions in a four-neck flask. [d] additive (6 mL). [e]
Reaction conditions: iPr2NH (50 mmol), addtive (6 ml), isoprene (50 mmol),
dispersion sodium (40 mmol), n-heptane (10 mL),
temperature in nitrogen atmosphere.
4 hours at room
Trialkylamines, especially TMEDA, can act as cationic
chelating agents toligated with Na+ to form a stable intermediate.
Lone pair electrons and electron-donating group on nitrogen
atom can strongly interact with Na+ cation, thus inhibiting the
-
formation of Na-F bond. The dissociated CF3 ion was active to
undergo carbonyl addition, rather than degradation to :CF2
(Scheme 2a). Oxygenated solvents such as THF, exhibit
stronger ligation capabilities than trialkylamines. The
intermediate 4 may undergo facile deaggregation in ethereal
solvents, such as THF. Thus, nonpolar solvent n-heptane was
found to be optimal (Scheme 2b).[8i]
Table 1. Optimization of reaction conditions
Scheme 2. Mechanism discussion.
Entry[a]
Additive [mL] [d]
-
Temp. [oC][c]
Yield [%][b]
<5%
24%
The scope of this reaction was investigated (Scheme 3). A
variety of esters, including substituted aromatic esters and
cinnamic ester were suitable reaction partners in this process.
Substrates with both electron-withdrawing groups like halogen
and general electron-donating groups worked well under
standard conditions (Scheme 3, 6b-6g). But the substrates with
strong electron-donating groups didn`t work well (Scheme 3, 6h-
6i). Naphthyl ester, ethyl nicotinoate and ethyl cinnamate could
be used to afford the target products in moderate yield (Scheme
1
2
3
4
5
-60
-60
-60
-60
-60
N,N-dimethylethanamine
Tetramethylethylenediamine
Tetraethylethylenediamine
Tetra-n-butyldiethylamine
93%
60%
0
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10.1002/ejoc.201900250
European Journal of Organic Chemistry
COMMUNICATION
Representative procedure: Into a flask, iPr2NH (50 mmol),
TMEDA (6 mL), isoprene (50 mmol), dispersion sodium (40
mmol), n-heptane (10 mL) were charged, the mixture was stirred
at 25oC for 4 hours under nitrogen atmosphere. Then the
reaction was cooled down to -60oC and m-chlorotrifluoroaceto-
phenone (10 mmol) was added, then fluoroform (20 mmol)
bubbled into the in the mixture slowly, the mixture was stirred at
-60oC for 2 hours. After the consumption of starting material, the
mixture was poured into aqueous citrate (10%) and the mixture
was extracted with dichloromethane. The organic phase was
concentrated and the residue was purified by flash
chromatography to yield 1-(3-chlorophenyl)-2,2,2-trifluoroethan-
1-one.
3, 6j-6l). When the substrates were ethyl para- or ortho-
chlorobenzoate, the yields were also good (Scheme 3, 6m-6n).
Because of the existence of active sites on aromatic aldehyde
and ketone which will react with NaDA, no corresponding
products can be obtained (Scheme 3, 6o-6p).
Acknowledgements
We are grateful to the Zhejiang Tianyu Pharmaceutical co. LTD,
the Shanghai Xinbu Medical Technology co. LTD, and the
Chemistry Department of Zhejiang University for support of this
research.
Keywords: fluoroform
•
trifluoromethylation
•
reactive
intermediates • cationic chelating agents
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COMMUNICATION
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This article is protected by copyright. All rights reserved.