Difluorocarbene Addition to Alkenes and Alkynes in Continuous Flow

Article abstract of DOI:10.1021/acs.orglett.6b00573

The first in-flow difluorocarbene generation and addition to alkenes and alkynes is reported. The application of continuous flow technology allowed for the controlled generation of difluorocarbene from TMSCF₃ and a catalytic quantity of NaI. Th

Full text of DOI:10.1021/acs.orglett.6b00573

Letter
pubs.acs.org/OrgLett
Difluorocarbene Addition to Alkenes and Alkynes in Continuous
Flow
Pauline Rulliere, Patrick Cyr, and Andre B. Charette*
̀
́
Universite
́
de Montrea
́
l, Centre in Green Chemistry and Catalysis, Department of Chemistry, Faculty of Arts and Science, P.O. Box
́
6128, Station Downtown, Quebec, Canada H3C 3J7
S
* Supporting Information
ABSTRACT: The first in-flow difluorocarbene generation and
addition to alkenes and alkynes is reported. The application of
continuous flow technology allowed for the controlled generation of
difluorocarbene from TMSCF3 and a catalytic quantity of NaI. The
in situ generated electrophilic carbene reacts smoothly with a broad
range of alkenes and alkynes, allowing the synthesis of the
corresponding difluorocyclopropanes and difluorocyclopropenes. The reaction is complete within a 10 min residence time at
high reaction concentrations. With a production flow rate of 1 mmol/min, continuous flow chemistry enables scale up of this
process in a green, atom-economic, and safe manner.
ifluorocyclopropanes have emerged as key substructures
in the construction of pharmaceutically relevant com-
dented, it is often tedious and applies nonenvironmentally
friendly conditions. Recently, greener and more facile methods
applying the thermal decarboxylative elimination of sodium
halodifluoroacetate have been used on a broad range of olefins.9
While effective, this procedure suffers from the high temper-
atures required for carbene generation (150−180 °C) and from
having a large excess of the precursor (5−10 equiv of
XCF2CO2Na). A second similar method also employs a
thermal decomposition of trimethylsilyl fluorosulfonyldifluoro-
acetate (TFDA).10 This strategy has the advantage of
generating carbenes that are more reactive toward electron-
poor alkenes. However, the reaction conditions remain harsh,
and the preparation of TFDA is tedious. To circumvent this,
one of the mildest ways involves the generation of
difluorocarbene from trimethylsilyl trifluoromethane
(TMSCF3). This reagent is safe, commercially available, and
inexpensive.11
D
pounds as well as in novel applications in material sciences
(Figure 1).1 The inclusion of fluorine atoms increases the
Figure 1. Integration of difluorocyclopropane scaffold into molecules
of interest.
Given the high temperatures, pressure, and volatility of the
reagents, we reasoned that a continuous flow strategy might be
applied to offer access to these privileged architectures. The
application of a flow chemistry setup would permit precise
temperature and pressure control as well as efficient heat
transfer (Figure 2). These features should allow us to scale up
this transformation under safe reaction conditions while
furnishing products in shorter reaction times.12
We began our studies by attempting traditional batch
conditions in a flow reactor. The carbene was generated in
the presence of the NaI activator upon heating (>60 °C).
Additionally, the reagents could be safely premixed with the
alkene in THF at room temperature (for solvent reoptimiza-
tion, see Supporting Information). The solution was introduced
into a Vapourtec system through an injection loop and passed
lipophilicity, bioavailability, metabolic stability, and, in some
cases, the potency of known biologically active molecules.2,3
Consequently, developing novel methods to incorporate
fluorine atoms to drug-like leads has become important to
drug design and discovery (Figure 1).1,4
As part of our ongoing research program toward developing
methods for halocyclopropane formation,5 we aim not only to
further develop methods to access these strained carbocycles
but also to do so in an efficient, safe, and sustainable way,
adhering to green chemistry principles.4 Herein we report our
efforts in this area, preparing gem-difluorocyclopropanes and
gem-difluorocyclopropenes from simple alkenes and alkynes.
Since the seminal synthesis of the difluorocyclopropane
scaffold,6 various methods toward this attractive core have been
delineated.7 The most common syntheses of difluorocyclopro-
panes and -cyclopropenes have relied on the [2 + 1]
cycloaddition of difluorocarbene to an alkene or alkyne.8
Although the preparation of difluorocarbene is well prece-
Received: February 29, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00573
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Letter
(from 0.5 to 0.9 mmol·L−1) and using a reduced amount of
catalyst NaI (0.1 equiv, entry 8). This was also consistent with
the low solubility of NaI in THF at high temperatures and the
fact that homogeneity is critical in continuous flow processes.
We next investigated the scope of the newly developed method.
Electron-rich styrenes led to almost quantitative yields of
difluorocyclopropanes (Scheme 1, products 1a−d). Styrenes
bearing electron-withdrawing substituents still provided the
difluorocyclopropanes with excellent yields (entries 1e−g).
a b
,
Scheme 1. Difluorocyclopropanation of Alkenes
Figure 2. Flow reactor setup.
through a heated perfluoroalkoxy (PFA) reactor equipped with
a back pressure regulator (BPR) to permit reaction temper-
atures above the boiling point of THF. At 110 °C, with 2.5
equiv of TMSCF3 and a catalytic amount of NaI (0.2 equiv),
the reaction proceeded within only 10 min with an 87% yield
(Table 1, entry 1). This is in contrast with the 2 h reaction
Table 1. Optimization of Reaction Temperature and
a
Residence Time
residence time
(min)
temp
(°C)
equivalent of
TMSCF3
NMR yield
b
entry
(%)
batch
120
10
10
15
20
10
10
10
10
65
110
120
120
120
120
150
200
120
2.5
2.5
2.0
1.5
1.5
1.5
1.5
1.5
100
87
98
92
91
88
96
52
1
2
3
4
a
b
c
Reactions were run on a 3.0 mmol scale, isolated yields. Yields in
5
1
parentheses were obtained by H NMR spectroscopy using triphenyl-
6
7
8
methane as the internal standard or 19F NMR spectroscopy using
c
fluorobenzene as the internal standard. Lower isolated yield than
d
2.0
99
NMR yield due to volatility of product.
a
b
1
Reactions run on a 1 mmol scale. Yields obtained by H NMR
spectroscopy of the crude reaction mixture using triphenylmethane as
c
The reaction allows various substitution patterns on the
alkene, affording the desired product in good to excellent yields
(Scheme 1, products 1h−j). The difluorocyclopropanation also
proceeded well with indene and in the presence of
functionalities, such as a silyl ether (products 1k and 1l).
When it comes to alkenes that are not derived from styrene,
the difluorocyclopropanation yields range from modest to
excellent. As expected, lower yields are observed with olefins
that are less nucleophilic. The difluorocyclopropanes were
obtained in good yields not only for highly substituted alkenes
(products m−n) but also with methacrylate (product 1o) and
cyclic alkenes (product 1p). Allenes afforded the difluorocy-
clopropane in moderate yield (product 1q). The yield
significantly decreased with the use of a monosubstituted
aliphatic alkene (product 1r).
the internal standard. Separated injection of a solution of TMSCF3 in
d
THF and styrene + NaI in THF in a T mixer. 0.9 M concentration
and 0.1 equiv of NaI was used.
times required for batch processes. Such an increase in
efficiency in the difluorocyclopropanation reaction can be
explained by the increased reaction pressure, a better heat
transfer through the high surface area of the PFA tubing, and
the controlled generation of carbene. Increasing the reaction
temperature to 120 °C allowed for a decrease in the amount of
TMSCF3 required (entry 2), affording the difluorocyclopro-
pane in a 98% yield. Increasing the residence time to 15 and 20
min resulted in no improvement (entries 3, 4). Separate
injection of a solution of the carbene precursor and of the
alkene premixed with the activator did not lead to any
improvement (entry 5 vs 3). A further increase of temperature
to 150 and 200 °C led to the formation of byproducts, since
styrene polymerization started to compete with the desired
difluorocyclopropanation (entries 6, 7). The optimal reaction
conditions were obtained under more concentrated conditions
This continuous flow method was also applied to
difluorocyclopropenation of alkynes. The exact same conditions
as those for alkenes were first used, and they were successful in
the quantitative transformation of pent-1-ynylbenzene into its
corresponding difluorocyclopropene (Scheme 2, product 2b).
B
DOI: 10.1021/acs.orglett.6b00573
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Organic Letters
Letter
propenes17 in flow were pursued. For example, our procedure
could be nicely coupled with Cossy’s difluorocyclopropene
cycloaddition conditions17b to produce 5-fluoropyridazine 5
with a good yield over two steps in an effective way with a
reduced reaction time (Scheme 5).
a b
,
Scheme 2. Difluorocyclopropanation of Alkynes
Scheme 5. Synthesis of 5-Fluoropyridazine in Continuous
Flow
a
b
Reactions were run on a 3.0 mmol scale, isolated yields. Yields
In conclusion, we have developed a protocol for the
TMSCF3-mediated difluorocyclopropanation of a broad range
of alkenes and alkynes using flow chemistry where catalytic NaI
generates the reactive carbene in situ. The reaction proceeded
cleanly with a 1 mmol·min−1 production rate and a 10 min
residence time, overcoming pressure and controlled carbene
generation issues while reducing the amount of carbene
precursor, carbene activator, and solvent. Moreover, the
difluorocyclopropanes and difluorocyclopropenes can be
further transformed into interesting fluorinated building blocks.
Extension of the use of this in flow generated difluorocarbene
for continuous flow synthesis is currently underway.
obtained by 19F NMR spectroscopy using fluorobenzene as the
internal standard are displayed in parentheses. Lower isolated yield
than NMR yield due to volatility of product.
c
Other phenylacetylene derivatives also reacted almost quanti-
tatively (products 2a−d). Under those conditions, terminal
aliphatic alkynes also undergo difluorocyclopropanation with
good yields (products 2e−i). Functionalities, such as ester or
unprotected alcohol, are tolerated, although the free alcohol
gets silylated during the reaction (2f was prepared from pentyn-
1-ol).
Difluorocyclopropenes are known for their instability13 and,
more specifically, for their ease of hydrolysis into the
corresponding stable cyclopropenone.14 Cyclopropenones
have been recently established as useful building blocks in
synthesis.15
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.6b00573.
During this work, it was shown that functionalized
difluorocyclopropenes could be converted into cycloprope-
nones upon stirring in wet chloroform overnight (Scheme 3).
For the more stable substrate 2f, addition of silica was required
to achieve the hydrolysis of the difluorocyclopropene (see
Supporting Information for more details).
Optimization tables, experimental procedures, character-
ization data, and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Scheme 3. Cyclopropenone Synthesis
*E-mail: andre.charette@umontreal.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Science and
Engineering Research Council of Canada (NSERC) under
the CREATE Training Program in Continuous Flow Science
and the Discovery Grant Program, the Canada Foundation for
Innovation, the Canada Research Chair Program, the FRQNT
Centre in Green Chemistry and Catalysis (CGCC) and
To further illustrate the versatility of the method, the
synthesis of gem-difluorophenylcyclopropanecarboxylic acid 4
was scaled up to produce 16 mmol of the intermediate 1k in
less than 35 min (Scheme 4). The reaction would have been
otherwise difficult to realize in batch under safe conditions due
to the gas evolution and pressure build-up as a function of time.
To further illustrate the usefulness of this process, other
applications of difluorocyclopropanes16 and difluorocyclo-
́ ́
Universite de Montreal. The authors would like to thank Dr.
Martial Bertrand and Dr. Francis Beaulieu from OmegaChem
for fruitful discussions. P.C. is grateful to NSERC, FRQNT,
Hydro-Queb
scholarships. P.R. would like to thank V. Kairouz (Center for
Continuous Flow Science, Universite de Montreal) for her help
with the flow equipment and E. Levesque (Charette group,
Universite de Montreal) for the flow schemes design.
́ ́ ́
ec and Universite de Montreal for postgraduate
́
́
Scheme 4. Scale-up Synthesis of Difluorocyclopropane
Building Block
́
́
́
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