Nucleophilic tetrafluoroethylation employing in situ formed organomagnesium reagents

Article abstract of DOI:10.1021/acs.orglett.6b02890

Tetrafluoroalkyl bromides are metalated with equimolar iPrMgCl·LiCl (Turbo Grignard) to form organomagnesium compounds which are stable at low temperatures and react with various electrophiles (aldehydes, ketones, CO₂, cyclic sulfate and sulfamidate, N-sulfonylimines, nitrone, chlorophosphate, nonaflyl azide) to afford novel functionalized tetrafluoroethylene-containing products. Ease of operation, excellent selectivity, high nucleophilicity, and enhanced stability of the reactive species together with a broad substrate scope comprise a highly attractive nucleophilic tetrafluoroethylation protocol affording unique synthetic building blocks.

Full text of DOI:10.1021/acs.orglett.6b02890

Letter
pubs.acs.org/OrgLett
Nucleophilic Tetrafluoroethylation Employing in Situ Formed
Organomagnesium Reagents
Alena Budinska,† Jirí Vaclavík,†,‡ Vaclav Matousek,§ and Petr Beier*,†
́
̌
́
́
̌
†The Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam
Republic
‡Laboratory of Molecular Structure Characterization, Institute of Microbiology, Academy of Sciences of the Czech Republic, Víden
1083, 142 20 Prague 4, Czech Republic
§CF Plus Chemicals s.r.o., Kamenice 771/34, 625 00 Brno, Czech Republic
́ ̌
estí 2, 166 10 Prague 6, Czech
̌
ska
́
S
* Supporting Information
ABSTRACT: Tetrafluoroalkyl bromides are metalated with equi-
molar iPrMgCl·LiCl (Turbo Grignard) to form organomagnesium
compounds which are stable at low temperatures and react with
various electrophiles (aldehydes, ketones, CO2, cyclic sulfate and
sulfamidate, N-sulfonylimines, nitrone, chlorophosphate, nonaflyl
azide) to afford novel functionalized tetrafluoroethylene-containing products. Ease of operation, excellent selectivity, high
nucleophilicity, and enhanced stability of the reactive species together with a broad substrate scope comprise a highly attractive
nucleophilic tetrafluoroethylation protocol affording unique synthetic building blocks.
Scheme 1. Reagents for Radical, Nucleophilic, and
Electrophilic Tetrafluoroethylene Group Transfer
he incorporation of a difluoromethylene (CF2) group or
perfluoroalkylidene groups [(CF2)n] into organic mole-
T
cules is a popular strategy for modification of various properties
of molecules in life science and material science applications.1−6
For instance, the difluoromethylene group can act as a
bioisostere of ethereal oxygen, carbonyl, or CHOH groups,
and the difluoromethyl group can also serve as a lipophilic
hydrogen bond donor.5,7−9 In carbohydrates, the replacement of
CHOH groups with CF2 units causes only minimal steric and
ring conformation perturbation, but because of attractive dipolar
interactions of C−F bonds and hydrophobic desolvation, there
is, in some cases, such as in a hexafluorinated sugar derivative, a
dramatic improvement of transmembrane transport ob-
served.10,11 In addition, tetrafluorinated sugar analogues are
currently being investigated as enzyme inhibitors.12−14 For these
reasons, there is a high demand for new synthetic methods
enabling the incorporation of CF2CF2 groups.
Approaches to tetrafluoroethylene-containing compounds can
be divided into fluorination methods, such as deoxofluorination
of 1,2-dicarbonyl compounds,15,16 and fluoroalkyl-transfer
methods.17−22 The latter approach is based on functionalization
of suitable CF2CF2 precursors including tetrafluoroethylene or
1,2-dihalotetrafluoroethanes.23,24 We have recently reported
heteroatom-substituted radical,25 nucleophilic,26−29 and electro-
philic30 tetrafluoroethylene synthons starting from BrCF2CF2Br
(Scheme 1). However, the preparation of the nucleophilic
reagent silane from the bromide required an extra synthetic step
and displayed limited reaction scope.26−29 The strategy used for
the preparation of tetrafluorinated sugars and azasugars
employed metal−halogen exchange followed by intramolecular
cyclization.31−36 One report described metalation of 4-bromo-
3,3,4,4-tetrafluorobut-1-ene with an excess of MeLi and addition
to carbonyl compounds under Barbier conditions.37 Given the
considerable body of literature on perfluoroalkyl organo-
metallics,38−43 we were curious to see whether metalation of
R1CF2CF2Br provides stable metalated species and to explore
their reactivity with electrophiles in a one-pot fashion. If
successful, this methodology could serve as a tool for the
synthesis of a variety of CF2CF2-containing compounds.
Commercially available 1a was selected for the initial screening
aimed at identification of a suitable metalation reagent R2M
(Table 1). The in situ produced organometallic species
underwent reaction with the subsequently added electrophile
(4-nitrobenzaldehyde, 2a) to provide 3aa. Side reactions
included protonation to 4a, fluoride elimination to 5a, and
reaction with R2Br to give 6a. It was found that MeLi and n-BuLi
metalated 1a rapidly at −78 °C; however, the main products
were 6a and 5a, respectively (Table 1, entries 1 and 2). Under
Barbier conditions the formation of 3aa increased dramatically.
Unfortunately, adduct 7a arising from the reaction of R2 M with
2a formed in about 10% yield, and some unreacted 1a was still
present in the crude reaction mixture (Table 1, entries 3 and 4).
Received: September 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02890
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Metalation of 1a and Addition of the in Situ Formed
Organometallic Species to 4-Nitrobenzaldehyde (2a)
Table 2. Metalation Times of 1 with Grignard Reagents
a
b
yield (%)
time
entry
R2 M
MeLi
(min)
1a
3aa
4a
5a
6a
1
2
3
4
5
6
2
2
0
0
5
6
0
1
50
0
82
0
nBuLi
traces
59
MeLi
c
11
15
0
19
17
15
12
9
nBuLi
c
65
1
0
iPrMgCl
iPrMgCl·LiCl
10
64
12
0
45
0
85 (80)
0
0
a
Reaction conditions: 1a (0.1 mmol), c(1a) = 0.2 M, R2 M (1.05
equiv), THF, −78 °C, time; then 2a (2 equiv), THF, −78 °C to rt, 3
b
h. 19F NMR yield using PhCF3 as an internal standard, isolated yield
c
in parentheses. Barbier conditions (R2 M added at −78 °C to the
mixture of 1a and 2a).
With iPrMgCl and its LiCl complex, known as the Turbo
Grignard reagent, the metalation required a longer time than
with organolithiums. On the other hand, fewer side products
were formed, and the best result was obtained using Turbo
Grignard (Table 1, entry 6). The organomagnesium formed from
1a and the Turbo Grignard reagent was stable for 4 h at −78 °C,
at −50 °C decomposed to 5a with a half-life of 1.5 h, and fully
decomposed within 50 min at −40 °C. Thus, iPrMgCl·LiCl
outperformed other metalation reagents in terms of stability of
the resulting fluorinated metalated species while maintaining
their good nucleophilicity.
a
Reaction conditions: 1 (0.03 mmol), R2 M (1.05 equiv), THF, c(1) =
0.2 M, −78 °C, time; then 10% AcOH in THF (1 mL), −78 °C, 5
b
min. Time to reach >95% conversion of 1 to 4, determined by 19F
c
d
NMR. Tetrafluoroethylene formed instead of 4g. Metalation was
conducted at −90 °C.
Scheme 2. Metalation of 1l and the Reaction with D2O or 2a
The observed differences in metalation times for 1a prompted
us to investigate in more detail the effect of structure of 1 on
metalation rates at −78 °C in THF using iPrMgCl·LiCl. 19F
NMR analyses of the reaction mixture after addition of acetic acid
at different reaction times allowed us to determine the minimal
metalation times needed for complete conversion of 1 to 4
(Table 2). In general, metalation using LiCl-free Grignard
reagent was faster than with the Turbo Grignard reagent, which is
surprising since LiCl is known to break aggregates and make the
organomagnesium species more reactive.44,45 With Turbo
Grignard, the metalation times varied from <5 min for 1f and
aliphatic bromides 1h−j to 1 h for some of the aryloxy
derivatives. Sulfone 1g quickly eliminated phenylsulfinate to give
tetrafluoroethylene and was thus excluded from further reactions
with electrophiles. Bromide 1i and 1i reacted with the Turbo
Grignard reagent regioselectively on the CF2 group bearing the
bromine atom. Metalated species derived from bromide 1i and
tosylate 1j mostly eliminated fluoride to form the trifluorovinyl
compounds 5; however, at −90 °C this side reaction was
reasonably suppressed. In the case of 1l, further experiments with
D2O and 2a revealed a rearrangement of the metal species due to
appreciable acidity of the hydrogen atom on the imidazole ring,
affording a mixture of products 3la, 3l′a, and 4l as shown in
Scheme 2.
Metalation times corresponded to values shown in Table 2 (5
min for 1f,h−j). Reactions of a random selection of bromides 1
with electron-rich or electron-poor aromatic aldehydes, enoliz-
able aliphatic aldehyde, or α,β-unsaturated aldehyde provided
adducts in high yields (Table 3, entries 1−9). Addition to
ketones also proceeded with good efficiency (Table 3, entries
10−14), which implies that the organomagnesium species
derived from 1 are more nucleophilic than the previously
reported PhSCF2CF2TMS with fluoride initiators.26 With CO2,
novel tetrafluoropropionic acids were synthesized (Table 3,
entries 15−17). Following a failed addition to unactivated imine
(N-(4-(trifluoromethyl)benzylidene)aniline), N-sulfonylaldi-
mine and cyclic ketimine yielded sulfonamides (Table 3, entries
18 and 19). Similarly, whereas reactions with epoxides (2-
ethyloxirane and 7-oxabicyclo[4.1.0]heptane) were unproduc-
tive, the ring opening of cyclic sulfate 2r and cyclic sulfamidate 2s
provided 2-fluoroalkyl-substituted ethanols and amines, respec-
Having identified suitable metalation conditions, reactions of
bromides 1 with a range of electrophiles leading to tetrafluoro-
ethylene-containing products 3 were examined (Table 3).
B
DOI: 10.1021/acs.orglett.6b02890
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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a
Table 3. One-Pot Nucleophilic Tetrafluoroethylation Starting from Bromides 1a−k
a
Reaction conditions: 1 (0.43−4.0 mmol), iPrMgCl·LiCl (1.05 equiv), THF, c(1) = 0.2 M, −78 °C, 5−60 min (see Table 2 for metalation times);
b
c
d
e
then 2 (2 equiv), THF, −78 °C to rt, 3 h. Isolated yield. Metalation was conducted at −90 °C. Using 1.05 equiv of 1 and 1 equiv of 2. dr 95:5
f
g
h
i
(HPLC). Using 1.2 equiv of 2. After treatment with 16% aqueous H2SO4, reflux, overnight. Using 0.95 equiv of 2. After treatment with 10%
j
k
aqueous H2SO4, rt, 1 h. Using 4 equiv of 2. 19F NMR yield using internal standard (PhCF3); 3ew was obtained together with 4e (24%) as an
inseparable mixture.
tively in high yields after acidic hydrolysis (Table 3, entries
20−22).46
Reaction with 3,4-dihydroisoquinoline 2-oxide (2t) resulted in
the formation of the respective products (Table 3, entry 23) and
with diethyl chlorophosphate (2u), moderate to good yields of
the corresponding fluoroalkyl phosphonates were obtained
(Table 3, entries 24−26). In the two latter cases, the reactions
with 1i and 1j led to considerable elimination to trifluorovinyl
compounds 5i and 5j both at −78 and −90 °C, causing reduced
yields of the products. A highly electrophilic azide 2v afforded the
corresponding fluoroalkyl azide 3av in good yield (Table 3, entry
27). Lastly, the formation of side product 6 in the metalation
experiments shown in Table 1 prompted us to investigate alkyl
halides as electrophiles. However, the reaction was only partially
C
DOI: 10.1021/acs.orglett.6b02890
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ASSOCIATED CONTENT
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S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02890.
(26) Chernykh, Y.; Hlat-Glembova,
Org. Chem. 2011, 2011, 4528.
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Experimental procedures, product characterization, and
1H, 13C, 19F, and 31P NMR spectra (PDF)
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AUTHOR INFORMATION
̌
k, V.; Vac
́
lavík, J.; Haj
A.; Togni, A.; Beier, P. Chem. - Eur. J. 2016, 22,
́
ek, P.; Charpentier, J.; Blastik, Z. E.;
■
́
Corresponding Author
*E-mail: beier@uochb.cas.cz.
Notes
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(34) Fontenelle, C. Q.; Tizzard, G. J.; Linclau, B. J. Fluorine Chem.
2015, 174, 95.
The authors declare the following competing financial
interest(s): CF Plus Chemicals s.r.o. (www.cfplus.cz) company,
an ETHZ spin-off, commercializes the CF2CF2 building blocks
used in this publication.
(35) Konno, T.; Hoshino, T.; Kida, T.; Takano, S.; Ishihara, T. J.
Fluorine Chem. 2013, 152, 106.
(36) Bonnac, L.; Lee, S. E.; Giuffredi, G. T.; Elphick, L. M.; Anderson,
A. A.; Child, E. S.; Mann, D. J.; Gouverneur, V. Org. Biomol. Chem. 2010,
8, 1445.
ACKNOWLEDGMENTS
■
This work was financially supported by the Academy of Sciences
of the Czech Republic (RVO: 61388963). We thank Prof.
Antonio Togni (ETH Zurich) for hosting A.B. and J.V. on
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(37) Konno, T.; Takano, S.; Takahashi, Y.; Konishi, H.; Tanaka, Y.;
Ishihara, T. Synthesis 2011, 2011, 33.
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(39) Burton, D. J.; Lu, L. Top. Curr. Chem. 1997, 193, 45.
(40) Guang, J.; Hopson, R.; Williard, P. G.; Fujiu, M.; Negishi, K.;
Mikami, K. J. Org. Chem. 2016, 81, 5922.
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D
DOI: 10.1021/acs.orglett.6b02890
Org. Lett. XXXX, XXX, XXX−XXX