Difluoro- and trifluoro diazoalkanes-complementary approaches in batch and flow and their application in cycloaddition reactions

Article abstract of DOI:10.1039/c6gc03187k

Herein we report on applications of fluorinated diazoalkanes in cycloaddition reactions, with the emphasis on studying subtle differences between diverse fluorinated diazo compounds. These differences led to two major synthetic protocols in batch and flow that allow the safe and scalable synthesis of fluoroalkyl-, sulfone-substituted pyrazolines.

Full text of DOI:10.1039/c6gc03187k

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Difluoro- and Trifluoro diazoalkanes – complementary approaches
in batch and flow and their application in cycloaddition reactions
Katharina J. Hock,# Lucas Mertens,# Friederike K. Metze, Clemens Schmittmann, and Rene M.
Koenigs*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Herein we report on applications of fluorinated diazoalkanes in disubstituted pyrazoline (scheme 1a).7 This fascinating class of
cycloaddition reactions, with the emphasis on studying subtle heterocycles finds regular application,8 although current
differences between diverse fluorinated diazo compounds. These synthetic methodology does not allow an atom-economic,
differences led to two major synthetic protocols in batch and flow streamlined access to this class of compounds.8,9
that allow the safe and scalable synthesis of fluoroalkyl-, sulfone- Sulfone-substituted heterocycles are typically prepared by
substituted pyrazolines.
late-stage introduction of the sulfone moiety and more
importantly, the fluorinated analogues can only be accessed
using hazardous fluorinating reagents on decagram-scale,
which is far from being practical and scalable (scheme 1b).8c
Fluoroalkyl-substituted diazocompounds are a versatile class
of reagents for the introduction of fluorinated groups and their
synthetic potential has attracted significant interest in the past
decade.1 However, safe and scalable applications of
fluoroalkyl-substituted diazo compounds are still highly
desired, as this class of diazo compounds requires stringent
safety precautions.2
Trifluoro diazoethane is probably the best-studied reagent
among these diazo compounds and several groups reported its
application.3,4 Interestingly, difluoro diazoethane only recently
found its way into the organic synthesis repertoire, although it
differs only in a single fluorine atom from well-studied trifluoro
diazoethane.5 Additionally, fluoroalkyl-substituted donor-
acceptor diazo compounds are studied only to a very limited
extent.5b,6
As part of our continuous interest in fluorinated
diazocompounds, we decided to investigate the differences of
these diazoalkanes, which give important information on
potential synthetic routes, required synthesis technology and
subsequent scale-up of transformations using these versatile
reagents.
Against this background, we started our investigations by
studying the dipolar cycloaddition reaction of these
diazoalkanes with vinyl sulfones (scheme 1c). This
transformation is of particular importance as the reaction
product is
a highly valuable sulfone- and fluoroalkyl-
Scheme 1. Applications and synthetic approaches towards sulfonated pyrazoles.
We initiated our investigations towards fluorinated, sulfone-
substituted pyrazolines using a phase-transfer protocol for the
generation
of
trifluoro
diazoethane.10
Different
retrosynthetically feasible precursors were investigated,
though exclusively vinyl sulfones (7a and 7b) yielded the
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desired sulfonated heterocycles
(15a/b). We also tested
alkynyl sulfones (10) and vinyl sulfoxides (13) under the phase
transfer conditions, yet both failed to give the desired product.
Scheme 3. Preliminary investigations on sulfur-substituted pyrazolines.
In further investigations, we probed the closely related
difluoro diazoethane. The difluoromethyl group differs only in
a single fluorine atom from the well-studied trifluoromethyl
group; still, its introduction, physical-chemical and biological
properties are very much different.12
Hence, we investigated difluoro ethylamine hydrochloride as a
source of difluoro diazoethane. Yet, we could never observe
the formation of the desired reaction product (scheme 4).
Scheme 2. Preliminary investigations on sulfur-substituted pyrazolines.
Next, we examined a range of different organic solvents under
phase transfer conditions and were delighted to observe that
the desired trifluoromethyl substituted pyrazolines 15a and
15b could be obtained in different polar, and non-polar
solvents in good to excellent yield. Dichloromethane and three
equivalents of sodium nitrite proved to be the optimum
reaction conditions to yield both aryl- and alkyl- sulfone
substituted pyrazolines in excellent yield.11
Table 1. Substrate scope of trifluoromethyl substituted pyrazolines
Scheme 4. Attempts to the synthesis of difluoromethyl substituted pyrazolines.
We hypothesized this surprising observation with
a
significantly reduced stability in aqueous solution of difluoro
diazoethane and hydrolysis of the diazoalkane. Recently,
Mykhailiuk and our group reported on tert-butyl nitrite as an
efficient organic nitrite source for the formation of difluoro
diazoethane.5 We thus examined this transformation using a
purely organic medium (scheme 4) and both trifluoro and
difluoro ethylamine for comparison. We could observe
formation of the corresponding trifluoromethylated pyrazoline
15a only in moderate yield (48%), the difluoromethyl-
substituted pyrazoline 16a could be isolated in 8% yield.
entry
R
yield
entry
R
Yield
1
2
3
4
5
Phenyl
Methyl
Ethyl
84%
6
7
4-Fluorophenyl
4-Chlorophenyl
4-MeO-phenyl
3-Methylphenyl
2-Methylphenyl
93%
>99%
>99%
93%
91%
93%
8
Benzyl
9
>99%
94%
4-Methylphenyl
98%
10
reaction conditions: vinyl sulfone (0.5 mmol,
1 eq), trifluoroethyl amine
Thus, we focused our efforts for the dipolar cycloaddition
hydrochloride (2 eq) and NaNO2 (3 eq) in DCM (8 mL) / water (2 mL) was
vigourosly stirred for 14 h at room temperature; isolated yields.
reaction of difluoro diazoethane using continuous flow
technology.4j,
5b-c, 13
Using a 200 µL micromixer (Little Things
Factory, MR-LAB MST) and an 800 µL microreactor (PTFE
tubing) we were able to mix a stream of difluoroethyl amine
with a second stream of tert-butyl nitrite and catalytic
amounts of acetic acid providing a continuous access to
difluoro diazoethane. After optimization of the reaction
conditions, we were able to obtain the desired pyrazolines 16a
and 16b in excellent yield. Under these reaction conditions we
next probed trifluoro diazoethane but unexpectedly, the
desired pyrazoline 15a could only be obtained in significantly
decreased yield.11
We next studied the substrate scope of the reaction of
trifluoro diazoethane with vinyl sulfones under phase transfer
conditions. To our delight a range of different aromatic and
aliphatic vinyl sulfones (7a-j) could be converted to the
corresponding trifluoromethyl- and sulfone-substituted
pyrazolines (table 1) in excellent yield. The sulfone substituent
had only little influence on this transformation.
It should be noted, that we observed the initial formation of
both Δ1- and Δ2-pyrazoline, after purification on silica gel we
exclusively observed the Δ2-pyrazoline (scheme 3).
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Similarly, as in the phase-transfer protocol, we observed the We next investigated the substrate scope for this
formation of Δ1- and Δ2-pyrazoline and subsequent transformation and could demonstrate, that both the batch
isomerization to the Δ2-pyrazoline after chromatography.
and the continuous-flow protocol can be used to deliver the
Next, we examined the flow protocol in detail and evaluated desired pyrazolines in excellent yield. In general, different
different vinyl sulfones. Under the optimum flow conditions donor-acceptor substituted fluorinated diazoalkanes can be
for this transformation, we were able to show that prepared very efficiently using either batch or flow conditions.
difluoromethyl- and sulfone- substituted pyrazolines could be The advantages of the batch transformation being: no isolation
obtained in excellent yield. The effect of different linear of the diazo compound as well as fast and routine reaction
aliphatic, or differently substituted aromatic substituents had setup for small-scale transformations. The advantages of the
only a negligible effect on the yield of the desired pyrazolines.
flow protocol being: process safety and
performance in terms of yield.
a little better
Table 2. Substrate scope of difluoromethyl substituted pyrazolines.
Table 3. Fluorinated donor-acceptor diazo compounds in [2+3] cycloaddition reaction.
F
50 ꢀL/min
NH2
O
O
O
O
F
S
N
N
S
R
11b
N
R
7a-j
HN
F
H
BPR
tR = 10 min
O
CHCl3
RT
O
F
N
F
F
16a-j
T = 55 °C
HOAc
50 ꢀL/min
entry[a]
substrate
yield
entry
sustrate
Yield[b]
entry
R1
R2 (diazo compound)
yield batch
yield flow
1
2
3
4
5
Phenyl
Methyl
Ethyl
93%
92%
99%
98%
95%
6
7
4-Fluorophenyl
4-Chlorophenyl
4-MeO-phenyl
3-Methylphenyl
2-Methylphenyl
97%
89%
1
2
3
4
5
6
Methyl
Methyl
Methyl
Methyl
Methyl
Phenyl
Phenyl
4-Methylphenyl
4-Fluorophenyl
-CH2-CH2-Ph
Methyl
97%
75%
80%
67%
96%
99%
99%
97%
98%
97%
99%
99%
8
83%
Benzyl
9
>99%
>99%
4-Methylphenyl
10
reaction conditions: a solution of amine (0.2 M in CHCl3, 4 eq.) and of tBuONO
plus AcOH (2.4 M / 0.08 M in CHCl3) were placed in two separate syringes and
added by syringe pump at a flow rate of 50 µL/min for each syringe into a
microreactor (residence time 10 min, temperature = 55 °C). The outlet was
connected via a back pressure regulator (20 psi) to a reaction flask containing the
vinyl sulfone (0.5 mmol) in CHCl3 and stirred for 14 h at room temperature.
Isolated yields.
Methyl
reaction conditions: For the batch reactions: the diazo compound is prepared by
heating the amine (4 eq), tBuONO (4.8 eq) and AcOH (1.6 eq) in CHCl3 to 55 °C for
3 h, then after cooling to RT, vinyl sulfone (0.5 mmol) is added; isolated yields
after chromatography. For the flow reactions: a solution of amine (0.2 M in CHCl3,
4 eq.) and of tBuONO plus AcOH (2.4 M / 0.8 M in CHCl3) were placed in two
separate syringes and added by syringe pump at a flow rate of 50 µL/min for each
syringe into a microreactor (residence time 10 min). The outlet was connected via
a back pressure regulator (20 psi) to a reaction flask containing the vinyl sulfone
(0.5 mmol) in CHCl3 and stirred for 14 h; isolated yields.
For a comprehensive evaluation of fluoroalkyl-substituted
diazoalkanes in this cycloaddition reaction, we next
investigated fluoroalkyl-aryl substituted diazoalkanes. These
diazoalkanes are closely related to donor-acceptor
diazoalkanes due to the strong electron-withdrawing nature of
the fluoroalkyl group (figure 1).14
In further experiments, we investigated the robustness and
scalability of these transformations. This is of particular
importance, as organic synthesis with diazo compounds needs
to be conducted with greatest care to prevent serious
incidents.
Firstly, we examined the phase transfer protocol for the
reaction of trifluoro diazoethane with vinyl sulfones on a gram-
scale reaction. To our delight, the sulfone-substituted
pyrazoline 15a could be isolated in excellent yield. Similarly,
difluoro diazoethane can be prepared in a continuous flow
fashion for more than 10 hours and the subsequent
cycloaddition reaction was scaled-up to gram scale yielding
1.08 g of the difluoromethyl substituted pyrazoline 16a
(scheme 5).
Figure 1. Donor-acceptor substituted diazoalkanes.
In initial experiments we examined both protocols described
above for the synthesis of fluorinated donor-acceptor diazo
compounds. Yet, the phase transfer protocol and the water-
free domino reaction protocol both failed to give the desired
product in acceptable yield.11 However, if the diazo compound
is prepared in situ and methyl vinyl sulfone is added
subsequently after three hours in a one-pot protocol, the
desired pyrazoline can be isolated in excellent yield.
This observation prompted us to examine the continuous-flow
protocol for these substrates. To our delight the desired
pyrazolines could be obtained in excellent yield (table 4, 21a).
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O
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O
O
O
NaNO2
S
F
N
Ph
NH2 . HCl
11a . HCl
S
Ph
HN
DCM, water
F
F
7a
F
F
6
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O
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NH2
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S
F
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Ph
11b
N
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H
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7
In summary, we have reported on robust and atom-economic
batch and flow protocols for the preparation of fluoroalkyl-
substituted, sulfonated pyrazolines in one synthetic step
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