Photochemical Cyclopropenation of Alkynes with Diazirines as Carbene Precursors in Continuous Flow

Article abstract of DOI:10.1021/acs.orglett.1c01750

An efficient synthesis of 3-trifluoromethyl-3-aryl-cyclopropenes via the cyclopropenation reaction of alkynes with photolytically generated carbenes from diazirine compounds is described. This reaction is performed in continuous flow using readily available LEDs under mild reaction conditions. This new and efficient method describes the synthesis of 25 examples of 3-trifluoromethyl-3-aryl-cyclopropenes with yields up to 97%, achieved in continuous flow with a 5 min residence time. Control experiments highlighted that diazirines are more efficient than diazo compounds for this transformation.

Full text of DOI:10.1021/acs.orglett.1c01750

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Letter
Photochemical Cyclopropenation of Alkynes with Diazirines as
Carbene Precursors in Continuous Flow
Nour Tanbouza,† Virginie Carreras,† and Thierry Ollevier*
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ABSTRACT: An efficient synthesis of 3-trifluoromethyl-3-aryl-cyclopropenes via the
cyclopropenation reaction of alkynes with photolytically generated carbenes from
diazirine compounds is described. This reaction is performed in continuous flow
using readily available LEDs under mild reaction conditions. This new and efficient
method describes the synthesis of 25 examples of 3-trifluoromethyl-3-aryl-
cyclopropenes with yields up to 97%, achieved in continuous flow with a 5 min
residence time. Control experiments highlighted that diazirines are more efficient
than diazo compounds for this transformation.
While exploring the reactivity of trifluoromethyl diazirines in
iazo compounds and diazirines, despite being structural
Disomers, have been developed in entirely separate a photochemical flow setup, we found that simple purple light-
areas.1,2 Both serve as carbene precursors;3,4 however, diazo
emitting diodes (LED) sufficed to generate carbenes from
trifluoromethyl diazirines for the formation of cyclopropenes
from alkynes. So, energy-consuming, expensive, and dangerous
mercury lamps could be replaced by simple LED lamps to
access cyclopropenes. Cyclopropenes are essential building
blocks in organic synthesis and are also valuable to the
pharmaceutical sector in drug discovery.31 However, studies
covering the synthesis of trifluoromethyl cyclopropenes have
only been recently reported via the cyclopropenation reaction
of alkynes using diazo compounds catalyzed by transition
metals.32−35
Only two reports on metal-free cyclopropenation have been
disclosed (Figure 1). The first involves the reaction of tosyl
hydrazones with a base to generate the diazo compound in situ
which is then decomposed thermally into the carbene species
for cyclopropenation in C6F6.36 The other uses diazo
compounds under blue LED irradiation which is applied for
the synthesis of a single example of a trifluoromethyl
cyclopropene.21,37 Hence, we disclose a new method that
will allow access toward versatile trifluoromethyl cyclopropene
motifs from diazirines in a straightforward, metal-free, green,
and scalable manner (Figure 1).
compounds have been regarded as essential building blocks in
synthetic chemistry,5,6 while diazirines are distinguished as
photolabeling and linking reagents.7,8 Trifluoromethyl diazir-
ines, in particular, have found a home in a wide variety of
applications from medicinal chemistry (i.e., as photoaffinity
probes)9,10 to surface chemistry (i.e., for analyte immobiliza-
tion),11,12 and polymer cross-linking.8,13 This divided interest
has led to diazirines becoming almost forgotten as building
blocks in organic synthesis despite their ability to generate
carbenes.14 Hence, it is worthwhile to better develop and
elaborate their utility for organic synthesis in the same sense as
diazo compounds. Another factor that encourages this
development is that, compared to diazo compounds, diazirines
exhibit higher bench stability, less toxicity, and less
explosibility.15−17 Diazirines are reported to generate free
carbenes by the loss of nitrogen gas (N2) under ultraviolet
(UV) irradiation (350−380 nm).18
Diazirines have only been studied for carbene insertion
reactions, using a mercury lamp as a UV source, with alcohols;
however low yields were obtained, and a limited scope was
demonstrated.19 Low yields are usually associated with the
high reactivity and instability of carbenes. Flow chemistry has
recently emerged as a useful tool for photochemical carbene
chemistry and has been gaining significant traction.20−22 For
this, we sought to generate them in continuous flow which
allows top control over reaction conditions.23−25 Flow
chemistry has been regarded as a tool that enables a safer
and more economical approach than traditional batch
chemistry which is being widely adopted by industries.23,26−29
In addition, photochemical reactions in flow have unmatched
efficiency compared to batch due to the enhanced and equal
distribution of light into a reaction mixture.22,30
During screening and optimization of the cyclopropenation
reaction (see Supporting Information (SI), p S-17) of 3-([1,1′-
biphenyl]-4-yl)-3-(trifluoromethyl)-3H-diazirine 1a with di-
phenyl acetylene in continuous flow, we found that visible-
Received: May 25, 2021
Published: July 6, 2021
https://doi.org/10.1021/acs.orglett.1c01750
© 2021 American Chemical Society
Org. Lett. 2021, 23, 5420−5424
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a
Scheme 2. Scope of Alkyne Substrates
Figure 1. State of the art: synthesis of trifluoromethyl cyclopropenes.
light-emitting diodes (LEDs), purple LEDs (420 nm) in
particular, result in yields as high as 93% of the corresponding
cyclopropene 2a. Optimal flow reaction conditions required a
residence time of 5 min (10 mL reactor volume, 2 mL/min
flow rate) at 25 °C with reactants injected in a 0.4 M
concentration of diazirine 1a in CH2Cl2 (Scheme 1). Using
lamps with higher irradiation energies led to decreased yields
(see SI, pp S-17−18). So, irradiating at 420 nm targets the
lowest energy tail of the diazirine’s absorption peak (see SI, p
S-16).
a
Reaction conditions: 3-([1,1′-biphenyl]-4-yl)-3-(trifluoromethyl)-
3H-diazirine 1a (0.1 mmol) and the alkyne (1 mmol) in CH2Cl2
(0.25 mL) is injected through a 6-way valve (0.25 mL injection loop)
at 2 mL/min into the photoreactor (10 mL) equipped with 420 nm
a
Scheme 1. Optimized Reaction Conditions for the
Cyclopropenation of Diazirine 1a with Diphenyl Acetylene
light source set to 25 °C and 6 bar. Isolated yields. Yield determined
by 19F NMR using 3-fluoro-4-nitrotoluene as an internal standard.
insertion could be detected in the crude reaction mixture albeit
in low yields. When employing bis-alkynes 1,3-diethynylben-
zene and 1,4-diethynylbenzene, monocyclopropenes 2al and
2am were obtained in 53% and 14% yield, respectively, along
with products resulting from C−H insertion which was
isolated in the case of 2al′. In these cases, no bis-cyclopropenes
were obtained contrary to a previous report with trifluoro-
methyl metal carbenes.33
The scope of trifluoromethyl diazirine substrates was
investigated with diphenyl acetylene (Scheme 3). The reaction
of 3-(naphthalen-2-yl)-3-(trifluoromethyl)-3H-diazirine 1b
and 3-(4-(benzyloxy)phenyl)-3-(trifluoromethyl)-3H-diazirine
1c under irradiation at 420 nm resulted in cyclopropenes 2b
and 2c in 78% and 79% yield, respectively. In addition, the bis-
diazirine 1d yielded a separable mixture of both the
monocyclopropene diazirine 2d (30%) and the bis-cyclo-
propene 2d′ (54%). However, when 20 equiv of diphenyl
acetylene were used instead of 10 equiv, the yield of
monocyclopropene 2d decreased to 18% while that of bis-
cyclopropene 2d′ increased to 64%.
This means that the lowest energy lamp capable of
decomposing the diazirine results in better selectivity toward
the desired cyclopropenation reaction. Hence, this results in
the slow generation of the carbene species and thus mimics
slow addition in batch which is common practice in carbene
chemistry. The low yields could also be attributed to an inner
filter effect deriving from the cyclopropene product and could
be a reasonable explanation for the high yields with purple
LEDs. Control experiments involving the irradiation of pure
cyclopropene under 420 and 365 nm show no decomposition
(see SI p S34), and its UV−vis spectra show no absorbance
(see SI page S17). Also, an excess of the alkyne (10 equiv) was
required to achieve higher yields, but the remaining alkyne (9
equiv) was easily recovered (up to 98%).38
The cyclopropenation of 3-([1,1′-biphenyl]-4-yl)-3-(trifluor-
omethyl)-3H-diazirine 1a was then studied with various
alkynes (Scheme 2). Using internal aromatic alkynes, yields
ranged between 62% and 84% with alkynes bearing −NO2,
−CF3, or −F substituents on the Ar group (Scheme 2, 2ab,
2ad−2ae). When using an aliphatic alkyne, octan-4-yne led to
high yields (97%) of cyclopropene 2af. Then, in the case of
terminal alkynes, yields decreased overall as a result of carbene
insertion into the terminal C−H bond of the alkyne, but this
did significantly change with the type of substitution on the
alkyne (Scheme 2, 2ag−2ak). A detailed study by Koenigs et
al. showed the particularity of electron-rich diaryl carbenes,
generated by blue light irradiation of their diazo precursor, in
C−H insertion with terminal alkynes.39 However, in the case
of the donor−acceptor carbenes generated here, this C−H
Afterward, we sought to compare the effect of flow and
batch conditions on this reaction. The cyclopropenation
reaction of diphenylacetylene using 1a−1d was attempted in
batch under the same optimized conditions, but even after 24
h, the reaction remained incomplete due to reduced light
penetration. Batch conditions were found to be inefficient in
producing the cyclopropene in yields close to those obtained
under flow conditions, where they ranged between 42% and
<1% of 2a−2d. This emphasizes the utility of flow conditions
and their importance in achieving an efficient photochemical
cyclopropenation reaction with diazirines. These flow con-
ditions are superior to batch in terms of not only yields but
also reaction time which is shortened to 5 min instead of >24 h
and thus a higher output of cyclopropenes per hour. To
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a
conditions in flow (Scheme 4a). We observed that at 420 nm
the cyclopropene is obtained in only 5% yield which is
Scheme 3. Scope of Trifluoromethyl Diazirines
Scheme 4. Competition and Control Experiments
a
Reaction conditions: 3-(trifluoromethyl)-3H-diazirine 1a−1n (0.1
mmol) and the diphenyl acetylene (1 mmol) in CH2Cl2 (0.25 mL) is
injected through a 6-way valve (0.25 mL injection loop) at 2 mL/min
into the photoreactor (10 mL) equipped with the light source set to
b
25 °C and 6 bar. Yields are isolated. Yields determined by 19F NMR
c
using 3-fluoro-4-nitrotoluene as an internal standard. Twenty equiv
(2 mmol) of diphenyl acetylene were used.
demonstrate the ease of scale up with this method,
cyclopropene 2a was formed on a 10 mmol scale in 73%
yield within less than an hour (50 min).
Phenyl-3-(trifluoromethyl)-3H-diazirines with a −Me, −tBu,
or −OMe group in the para position of the aryl ring (1e−1g)
did not decompose under 420 nm (complete recovery of the
diazirine species), which was not surprising due to the absence
of any absorbance in that UV−vis region (see SI, p S-16). So, a
higher energy lamp was required. Using a 405 nm purple LED,
the corresponding cyclopropenes were obtained in moderate
yields (50−57%) (Scheme 3, 2e−2g). For 3-phenyl-3-
(trifluoromethyl)-3H-diazirine 1h and phenyl-3-(trifluoro-
methyl)-3H-diazirines substituted with a −F, −Br, or −CF3
group in either the para or meta position, an even higher
energy LED wavelength was required where a UV wavelength
of 380 nm allowed the decomposition of diazirines 1h−1l to
give the desired cyclopropenes, albeit in moderate and poor
yields (Scheme 3, 2h−2l). The low yields in cyclopropenes
(i.e., 12−51%) in these cases are due to side reactions of the
carbene intermediate under such high-energy irradiation. So,
even though these cyclopropenes are obtained in low yields, it
is a matter of the characteristic absorbance of their diazirine
precursors which necessitate harsher conditions, i.e., high
energy irradiation wavelengths. Then, when using 3-(2-
methoxyphenyl)-3-(trifluoromethyl)-3H-diazirine 1m and 3-
(2-fluoro)-3-(trifluoromethyl)-3H-diazirine 1n, even at 380
nm, the diazirine remained intact. This emphasizes the
significant influence of the decomposition of these diazirines
by electronic and steric factors.
significantly less than the yields obtained with the diazirine
substrate (93%). Then, when the energy of the irradiation was
lowered to better accommodate the diazo, the yields of the
cyclopropene 2a from the diazo substrate did slightly increase
to 12% and 14% when using LEDs at 450 and 470 nm,
respectively, while those derived from the diazirine remained
high, except at 470 nm where no diazirine decomposition was
observed. Thus, diazirines are, by far, better candidates as
carbene precursors for accessing trifluoromethyl cyclopropenes
by LED irradiation.
In a competition experiment for the cyclopropenation of
internal vs terminal alkynes (Scheme 4b), it was observed that
when using 5 equiv of each, cyclopropenes 2a and 2aj were
obtained in a 1:1 ratio (15%) with the major product being the
C−H insertion product from the terminal alkyne (1:1:2).
Then when looking at the preference of the reaction
conditions toward a cyclopropenation vs a cyclopropanation
reaction by using 5 equiv of diphenyl acetylene and 5 equiv of
(E)-1,2-diphenylethene under the optimized conditions
(Scheme 4c), the corresponding cyclopropene 2a was obtained
in 45% yield while the cyclopropane 2a′ was obtained in 36%
yield (i.e., 2a/2a′ = 1.25:1 ratio). Using propargyl alcohols
with the diazirine, the cyclopropene was never observed and
Photochemical cyclopropenation reactions of alkynes have
been reported to occur with diazo compounds using blue
LEDs (470 nm) but are limited to diazo esters.21,37,39 So, to
evaluate the usefulness of choosing to do a photochemical
cyclopropenation with diazirines instead of diazo compounds,
we compared the reactivity of the diazirine substrate 1a and its
linear isomer diazo substrate 1a′ under the same reaction
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the major products were the corresponding ethers after O−H
insertion (Scheme 4d). 4-(2,2,2-Trifluoro-1-(pent-4-yn-1-
yloxy)ethyl)-1,1′-biphenyl 3a was obtained in 58% yield, and
4-(2,2,2-trifluoro-1-(prop-2-yn-1-yloxy)ethyl)-1,1′-biphenyl
3b, in 70% yield. Then, as a proof of concept, the TMS-
cyclopropene 2ak was deprotected using TBAF (1 equiv)
which occurred in 70% yield after 18 h at room temperature.
To gain better insight into the mechanism of the LED-
mediated cyclopropenation of alkynes using trifluoromethyl
diazirines, the reaction was monitored in real time using IR
spectroscopy (see SI-31). The intermediate formation of the
linear isomer, i.e. the diazo compound, was detected in traces
(characteristic peak at 2093 cm−1) in addition to the
cyclopropene (at 1499 cm−1). So, it is most likely that, upon
irradiation, the diazirine generates both the carbene species
and traces of the diazo compound which in turn generates the
carbene. This observation is consistent with previous reports
with UV irradiation of diazirines.2,18,19,40
In conclusion, we have developed a streamlined approach for
the synthesis of new trifluoromethyl cyclopropenes starting
from diazirines as carbene precursors. This method proceeds
more efficiently under continuous flow conditions, and the
wavelength of irradiation needed depends on the diazirine
substrate. The generality of this efficient process was shown
over 25 examples. Excellent yields of 3-trifluoromethyl-3-aryl-
cyclopropenes were obtained in continuous flow with a 5 min
residence time. In situ reaction monitoring revealed that
isomerization of the diazirine into the diazo compound occurs
to some extent. This method adds to the examples of efficient
combination of photochemistry and flow chemistry which is
attracting the interest of both academics and industries.
ACKNOWLEDGMENTS
■
This work was supported by the Natural Sciences and
Engineering Research Council of Canada (NSERC) Discovery
Grant RGPIN-2017-04272, the FRQNT Centre in Green
Chemistry and Catalysis (CGCC) Strategic Cluster FRQNT-
2020-RS4-265155-CCVC, and Université Laval. N.T. thanks
the Natural Sciences and Engineering Research Council of
Canada (NSERC) for a PSG D award (PGSD3-546986-2020).
The authors thank Vanessa Kairouz (Université de Montréal)
for her training in continuous flow chemistry and mentorship
as part of the CGCC NSERC CREATE program. We thank
Prof. Frédéric-Georges Fontaine (Université Laval) for lending
the ReactIR 15. We thank Mettler Toledo for their generous
loan of the FlowIR cell.
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ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c01750.
Experimental procedures, characterization data of
starting material and target compounds, and copies of
1H, 13C, and 19F NMR spectra (PDF)
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Corresponding Author
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Thierry Ollevier − Département de chimie, Université Laval,
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Authors
Nour Tanbouza − Département de chimie, Université Laval,
Québec, QC G1V 0A6, Canada; orcid.org/0000-0002-
9729-0918
Virginie Carreras − Département de chimie, Université Laval,
Québec, QC G1V 0A6, Canada; orcid.org/0000-0002-
8440-2327
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c01750
Author Contributions
†N.T. and V.C. contributed equally.
Notes
The authors declare no competing financial interest.
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Furthermore, the use of 420 nm LED generates complete conversion
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https://doi.org/10.1021/acs.orglett.1c01750
Org. Lett. 2021, 23, 5420−5424