A Copper-Catalyzed Synthesis of Pyrroles through Photochemically Generated Acylazirines

Article abstract of DOI:10.1002/ejoc.201901176

A synthesis of highly substituted 2,4-diacylpyrroles through a Cu-catalyzed dimerization of acylazirines generated in situ by a photochemical valence isomerization is described. The shown methodology allows the use of simple precursors and a readily avail

Full text of DOI:10.1002/ejoc.201901176

A Journal of
Accepted Article
Title: A Copper-Catalyzed Synthesis of Pyrroles through
Photochemically Generated Acylazirines
Authors: Jan Paternoga and Till Opatz
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10.1002/ejoc.201901176
European Journal of Organic Chemistry
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A Copper-Catalyzed Synthesis of Pyrroles through
Photochemically Generated Acylazirines
Jan Paternoga[a] and Till Opatz*[a]
Abstract: A synthesis of highyl substituted 2,4-diacylpyrroles through
a Cu-catalyzed dimerization of acylazirines generated in situ by a
photochemical valence isomerization is described. The shown
methodology allows the use of simple precursors and a readily
available copper(II)-catalyst. Since the reaction is best performed at
elevated temperatures, a method to adjust the temperature in the
reaction mixture during this dual light and metal-induced process was
established. Additionally, mechanistic studies of the reaction were
performed in order to provide a deeper understanding of the chemistry
of 2-acylazirines.
Besides, isoxazoles bearing electron donating substituents such
as alkoxy or amino groups were found by Auricchio and
coworkers to be converted into the corresponding 2-
alkoxycarbonyl-2H-azirines under iron dichloride catalysis. In the
same publication, the authors reported a dimerization reaction of
the formed 2H-azirines at elevated temperatures yielding in
tetrasubstituted pyrroles 2.[7] A similar observation was made by
Komendantov and Bekmukhametov, who had presumably found
the same kind of dimerization on 2-alkoxycarbonylazirines under
copper(II)-stearate catalysis, but reported
regioselectivity (2,3-dialkoxycarbonylpyrroles
2,4-dialkoxycarbonylpyrroles).[8]
a
different
instead of
Introduction
The utilization of light-induced ring strain as a driving force in the
synthesis of heterocycles can serve as an attractive and
eco-friendly alternative to schemes associated with the formation
of low-energy co-products such as borate salts or metal halides
as frequently seen in traditional C‒C or C‒heteroatom bond
formations. Small-ring systems often exhibit a high reactivity but
also a certain sensitivity.[1] The ideal strained intermediate
therefore can be generated in situ from stable precursors and is
directly transformed into the desired heterocyclic product under
the conditions of its formation. If the subsequent step is faster than
competing side reactions, highly reactive short-lived
intermediates can also be employed. Small-ring systems can be
prepared via UV photochemistry, as the energy injected into the
molecule by absorption of a photon of short wavelength can lead
to valence isomerizations or other processes providing products
of high energy content.[2] The chemistry of the 2H-azirines is
attractive in this context, as these intermediates can be used as
substrates in cycloadditions as well as for other syntheses of
various heterocyclic compounds.[3] They are most commonly
synthesized using the Neber rearrangement[4] or by a thermal or
photochemical conversion starting from vinyl azides.[5] Another
type of precursors for 2H-azirines are isoxazoles bearing at least
one aromatic substituent, that can be converted into the
corresponding 2-acylazirines under irradiation with UV-light.[6]
Unfortunately, the formation of the 2-acylazirines competes with
further isomerization to the thermodynamically stable oxazoles,
limiting the maximum isolated yield of the strained intermediate.[6]
Scheme 1. a) iron dichloride catalyzed dimerization of isoxazoles forming
2,4-alkoxycarbonylpyrroles b) photochemically in situ-generated 2-acylazirines
in the synthesis of imidazoles and 2,4-diacylpyrroles c) copper(II)-2-
ethylhexanoate catalyzed dimerization of in situ generated 2-acylazirines.[7-9]
Recently, our group has reported methodologies for the synthesis
of imidazoles and 2,4-diacylpyrroles starting from 2-acylazirines
generated in situ employing the photoisomerization of the
corresponding isoxazoles (scheme 1).[9] In these cases, the
subsequent step could conveniently be carried out at room
temperature and did not interfere with any photochemically or
thermally induced competing reactions such as oxazole formation.
[a]
Jan Paternoga, Prof. Dr. Till Opatz
Institute of Organic Chemistry, Johannes Gutenberg University,
Duesbergweg 10-14, 55128 Mainz, Germany
E-mail: opatz@uni-mainz.de
https://ak-opatz.chemie.uni-mainz.de
Supporting information for this article is given via a link at the end of
the document.
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To ensure a sufficiently fast rate of the metal-catalyzed step which
matches the mostly temperature independent UV-driven
isomerization, it might be necessary to control the temperature of
the reaction vessel during the irradiation. To avoid the use of
expensive and sensitive immersion lamps, we opted for
immersion temperature control in combination with external
irradiation in a rayonet-type circular lamp array (vide infra). This
should allow to match the kinetics of the two subsequent steps in
order to minimize undesired side reactions. As a test case, the
well-known UV isomerization of isoxazoles was combined with a
subsequent step, which we found to require elevated
temperatures. As the reported dimerization reaction of Auricchio
and coworkers (see Scheme 1) is limited to azirines containing
alkoxycarbonyl substituents, a Lewis acid able to perform the
same transformation on the photochemically generated azirines
bearing an arylmethanone moiety had to be found.
Table 1. Catalyst screening for the dimerization reaction.
Entry
Catalyst
Yield[b]
c
1
2
None
AlCl3
-
c
-
c
3
ZnCl2
-
4
FeCl2
7
8
5
FeCl3
6
CuI
59
c
7
CuCl
-
c
8
CuO
-
c
9
Cu[N(SO2CF3)2]
Cu(OtBu)
-
Results and Discussion
10
11
12
13
14
15
16
27
47
46
57
55
65
The initial task was the identification of a suitable catalyst for the
dimerization of the model azirine 1a.
Cu(OAc)
Cu(OAc)2
Cu(II)-benzoate
Cu(II)-laurate
Cu(II)-2-ethylhexanoate
Cu(II)-2-ethylhexanoate
Scheme 2. Catalyst screening with model azirine 1a
cd
-
Therefore, several inexpensive and earth-abundant Lewis acids
were screened (see scheme 2 and table 1). In the absence of a
catalyst, no product formation was observed (see entry 1). When
frequently used Lewis acids such as aluminium chloride and zinc
chloride were tested, no turnover of the azirine was observed. Iron
chloride catalysts (as used by Auricchio and coworkers) only
afforded smaller amounts of the desired product (see
entries 4 + 5).[7] Significant catalytic activity was only found for
copper catalysts containing carboxylate, alkoxide or iodide
counterions. Surprisingly, the outcome of the reaction was not
affected by the initial oxidation state of the copper salt: Both
cuprous acetate and cupric acetate furnished pyrrole 2a in ca.
45% yield (see entries 11 + 12). When the lipophilicity of the
carboxylate counterion was increased by adding branching or
increasing the chain length, the isolated yield of the pyrrole could
be improved to 65 % with Cu(II)-2-ethylhexanoate (entries
12 - 15). As assumed, no product formation was observed when
the reaction was carried out at room temperature (see entry 16).
[a] Reaction conditions: 1a (0.45 mmol), catalyst (10 mol%), MeCN (4.5 mL,
0.1 M substrate concentration), 70 °C, 20 h [b] Isolated yields after
chromatography [c] not determined; no product formation observed by
LC/MS [d] reaction was carried out at room temperature
With the optimum catalyst in hand, it was attempted to combine
the photoisomerization of isoxazoles with the subsequent
dimerization reaction in
a one-pot procedure. Since the
photoisomerization (with wavelengths of 300 nm) is beyond the
spectral window of the frequently used thermofluids, no classic
external heating bath could be employed for tempering the
reaction mixture. Instead, the temperature was adjusted with an
external circulator connected to a “cold finger” placed inside the
reaction vessel during irradiation (see the SI for a more detailed
description).
Scheme 3. Comparison of the one-pot synthesis of tetrasubstituted pyrroles
from isoxazoles with a devided reaction setup.
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Applying this setup to isoxazole 3a, the corresponding pyrrole 2a
was obtained in 56% yield (see Scheme 3). As the
photoisomerization of isoxazole 3a to the corresponding
2-acylazirine 1a had been found to provide a maximum isolated
yield of around 50% in our laboratory, the theoretical maximum
substituents led to a reduction in yield most pronounced in the
case of bromine (entries 5 – 7), possibly due to a heavy atom
effect reducing the lifetime of the S1-state from which the
acylazirine is formed.[11] The incorporation of electron-withdrawing
groups resulted in a decreased yield of the dimerization products
overall yield of the separate reactions would amount to 31%. Thus, (see entries 8 – 9). Replacement of the phenyl with a naphthyl
it is advantageous to perform the two steps in a one-pot
photoreaction furnishing the dimerization product in an almost
doubled yield. Several control experiments were carried out and
the reaction parameters were varied (see the SI): In the absence
of the catalyst, only the formation of the 2H-azirine and the
oxazole was detected by LC/MS. Furthermore, the pure isoxazole
remained unchanged when it was stirred with the copper catalyst
at 70 °C in the dark. Thus, a direct condensation of two molecules
of isoxazole can be ruled out. Next, the influence of temperature,
solvent and concentration was investigated. Methanol,
cyclohexane or THF turned out to be inferior to 1,2-dichloroethane
and acetonitrile. Among those two, acetonitrile is the preferred
solvent regarding toxicity and eco-friendliness. Lowering the initial
catalyst loading of 10 mol% to 5 mol% resulted in a reduced yield,
while using 20 mol% did not increase the amount of pyrrole 2a. A
variation of the concentration was also not effective, increasing or
decreasing the solvent volume led to a reduction in yield. Finally,
the scalability was investigated using the threefold amount of
isoxazole 3a. Besides pyrrole 2a, which was again obtained in
56% yield, the primary byproducts could be isolated and
characterized. Chromatography afforded pyrazine 8a in 6%,
pyrimidine 9a (unambiguously determined by NMR spectroscopy
and X-ray crystallography) in 12% and enaminone 10a in 4% yield
(scheme 4).
group led to very long reaction times and poor yields. The same
observations were made when an electron-donating substituent
was attached to the phenyl group (entry 11). The
photoisomerization turned out to be very sluggish, possibly due to
extensive light absorption by the product formed. We were able to
overcome this problem by decreasing the concentration to 0.05 M,
which allows more photons to penetrate the reaction mixture
resulting in a faster isomerization rate.
Table 2. Substrate scope of the copper catalyzed dimerisation of in situ
generated 2-acylazirines.[a]
Entry
1
isoxazole
3a
R1
Ph
R2
Yield[b] (%)
Ph
56
51
46
2
3b
3c
4-Tol
Ph
3
3-Tol
Ph
c
4
3d
3e
2-Tol
Ph
-
5
4-F-C6H4
4-Cl-C6H4
4-Br-C6H4
4-CF3-C6H4
4-MeO2C-C6H4
2-naphthyl
4-MeO-C6H4
2-furanyl
Me
Ph
47
45
6
3f
Ph
7
3g
3h
3i
Ph
35
8
Ph
Ph
39
9
33
10
11
12
13
14
15
16
17
18
3j
Ph
48d
41d
43d
19
3k
Ph
3l
Ph
3m
3n
3o
3p
3q
3r
Ph
Scheme 4. Isolated compounds of the upscaled one-pot reaction.
Ph
4-tBu-C6H4
4-F-C6H4
4-MeO-C6H4
4-MeO2C-C6H4
pentyl
57
Under the improved reaction conditions, the substrate scope was
investigated by applying them to several isoxazoles bearing
mostly aromatic substituents on both the 3- and the 5-position,
which were previously synthesized using standard methods (see
Scheme 5 and table 2).[6b, 10]
Ph
54
Ph
73
Ph
46
Ph
28e
[a] Standard conditions: 3 (1.0 mmol), Cu(II)-2-ethylhexanoate (0.1 mmol),
MeCN (10 mL, 0.1 M substrate concentration), UV-B irradiation, 70 °C [b]
Isolated yields after chromatography [c] not determined; low product
formation observed by LC/MS [d] reaction was performed at c = 0.05 M
[e] reaction incomplete after 96 h, 43% yield b.r.s.m.
Scheme 5. Substrate scope of the copper catalyzed dimerisation of in situ
generated 2-acylazirines.
The obtained pyrroles are shown in table 2. The R1 group in the
isoxazole starting material was varied first by changing the
substitution pattern of the phenyl group. Replacement of the
unsubstituted phenyl group (1a) with both the p-tolyl (1b) and the
m-tolyl (1c) derivative furnished the corresponding dimerization
product in comparable yields, whereas the reaction failed with the
o-tolyl substituent (entries 2 – 4). The introduction of 4’-halogen
This modification increased the yield of the naphthyl derivative 2j
from 21% to 48%. The regioselectivity of the dimerization could
be unambiguously determined using X-ray crystallography of
p-methoxyphenyl substituted pyrrole 2k (see the SI). When a
methyl group was employed as the R1 substituent, the
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10.1002/ejoc.201901176
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chemoselectivity was changed and pyrazine 8m was obtained as
the main product in 38% yield (scheme 6). Thus, an aromatic
substituent as R1 is presumably crucial in order to stabilize the
formed intermediate 12 (vide infra) and to suppress the direct
dimerization yielding in the corresponding pyrazines 8.
Scheme 6. Isolated products of the dimerization reaction applying standard
conditions on isoxazole 3l.
Scheme 7. Isolated cross coupling products and determination of their structure
via NMR experiments.
Secondly, 15N labeled azirine 1s was prepared in two steps
starting from 15N-hydroxylamine and reacted with unlabeled
methyl derivative 1m to determine which of the two available
nitrogen atoms is integrated into the cross coupled pyrroles 2t and
2u. The structure of the formed isomers (shown in scheme 7 and
determined using 1H-1H-NOESY and 1H-13C-HMBC experiments)
are indicating two fundamental findings. First, the reaction
features the cleavage of the C‒N single bond, as an intermediate
similar to complex 14 has to be passed to explain the found
structures. Furthermore, the 15N labeling of the products indicates
the elimination of the nitrogen of the azirine, which is ring opened
to the complex 14. Additionally, a glovebox experiment with only
the labeled azirine 1r in dry deuterated acetonitrile revealed the
formation of enaminone 10 even under rigorous exclusion of
water (vide infra).Based on these findings, the following reaction
mechanism (shown in scheme 8) appears plausible: As stated
before, the reaction yields the same product distribution, both
when cuprous acetate and cupric acetate are used and an
oxidative addition of the copper(I)-species seems more
reasonable. Therefore, we assume a copper(I)-species is initially
generated. This catalyst should be able to reductively cleave the
C‒N σ bond of the 2H-azirine 1 resulting in the copper complex
12a-c.
Secondly, the R2-substituent of the isoxazole was varied. Both
alkyl and halogens on the phenyl ring were well tolerated (entries
14 + 15). By introducing an electron-withdrawing substituent, the
pyrrole was obtained in a slightly decreased yield (entry 17).
Aromatic substituents bearing an electron-donating moiety
produced an increased yield (entry 16). The replacement of the
aryl moiety in R2 position with an alkyl group resulted in very long
reaction times. Even after 96 h, only partial consumption of the
starting material was detected using LC/MS and pyrrole 2r was
obtained in 28% yield. The UV-Vis spectrum of isoxazole 3r
exhibits a noticeable hypsochromic shift of the absorption
maximum (λmax = 240 nm for 3r in comparison to 270 nm for 3a)
explaining the slow isomerization rate under UV-B irradiation. A
possible selective cross coupling between two azirines was tested
by applying the standard conditions on a 1:1 mixture of isoxazoles
3i and 3p. As the reaction provided an almost equimolar mixture
of the homocoupled pyrroles 2i and 2p and the two cross coupled
regioisomers 2w and 2x (see the SI), a selective cross coupling
of two isoxazoles under the applied conditions appears not to be
feasible.
Finally, we carried out several control experiments regarding the
mechanism of the dimerization. As stated before, Auricchio and
coworkers found iron dichloride to promote the dimerization
reaction of 2H-azirines bearing an alkoxycarbonyl group.[7] In their
manuscript, the formation of the pyrrole was proposed to proceed
via the cyclization of the reduced enaminone 10 with remaining
azirine 1. Enaminone 10 was suggested to be formed via
reduction of the azirine with water and the iron salt. Nevertheless,
no detailed mechanistic studies were carried out regarding this
type of dimerization to the best of our knowledge. Based on this
mechanistic hypothesis, the influence of water on the dimerization
reaction was investigated first. Therefore, the dimerization of
model azirine 1a was reperformed under glove box conditions in
the presence of molecular sieves (MS 3 Å). The dimerization
product was obtained in comparable yield as under standard
conditions, so water as an external proton donor can be ruled out.
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involves the decomposition of the copper nitrene complex
generating a copper(0)-species and molecular nitrogen.
Scheme 9. Plausible reoxidation pathway for the active copper species.
We assume the copper(0) to be reoxidized in situ: The observed
enaminone byproduct 10 could arise from a reduction of the
remaining azirine 1, which regenerates the active
copper(I)-species (see scheme 9). The formed enaminone can
also contribute to the formation of the dimerized pyrrole 2 (see
scheme 11).
Scheme 8. Plausible mechanism for the formation of the tetrasubstituted
pyrroles 2. (For the simplicity, the ligands/conterions of the copper catalyst are
not shown).
Since the energy difference between the oxidation states of
copper are narrow and other ring opening reactions of 2H-azirines
are known to furnish both radical and ionic intermediates[12], the
addition complex 12c can also be described by resonance
structures of a stabilized dipole (12a) and imine radical (12b). The
formation of pyrazine byproduct 8 can be understood from the
dipole character of structure 12a, which allows
a direct
Scheme 10. Control experiments regarding the mechanism of the pyrrole
dimerization yielding in pyrazine 8 (Path A, scheme 8). Another
pathway for the formation of 8 might be the known dimerization of
nitrile ylide 11, which could arise from a thermal C‒C bond
scission of azirine 1 (Path B, scheme 8).[13] However, we never
observed formation of pyrazine 8 in the absence of copper.
formation
An attempt to use 1,4-Benzoquinone for the reoxidation of the
assumed copper(0)-complex resulted in a slightly decreased yield
(see scheme 10). Possible other mechanisms for the reoxidation
would for example involve the generation of diimide starting from
a formed copper-imido-complex, which could decompose to
furnish molecular nitrogen and hydrogen or ammonia and
nitrogen via a disproportionation reaction or itself reduce the
azirine 1 to the corresponding enaminone 10. In a control reaction
with cyclohexene (which is known to be reduced by diimide
quantitatively)[15] no cyclohexane formation was observed by
1H-NMR (see scheme 10 and the SI). Additionally no molecular
hydrogen or ammonia could be detected in this experiment
(yet the detection level has not been determined). Thus, we have
found no contradiction to the proposed mechanism so far.
As we found the 2,2,6,6-tetramethylpiperidinyloxyl (TEMPO)
radical to not to interfere with the pyrrole formation (vide infra), we
assume the reaction to involve an ionic mechanism. Therefore,
intermediate 12 presumably adds to the C=N-bond of another
molecule of azirine resulting in the aziridine anion 13, which
undergoes a 4-exo-trig-cyclization onto the copper-activated C=N
bond. Byproducts arising from the potentially competing addition
to the carbonyl of the former β-iminoketone were not found in our
experiments. The [2.1.0]-bicyclic system 14 was already
proposed as key intermediate in the synthesis of
2,4-diacylpyrroles by Khlebnikov and coworkers[14] and in our
former study[9b]. Via elimination of a proton and a copper nitrene
complex, we assume (2H)-pyrrole 16 to be formed which should
directly undergo a [1,5] sigmatropic H-shift yielding in the
(1H)-pyrrole 2. The regeneration of the active catalyst most likely
While a selective cross-coupling would be synthetically more
appealing than a dimerization, our attempts in the latter direction
have met with limited success so far. When applying the standard
conditions to a mixture of model azirine 1a and enaminone 10u,
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the copper-catalyst induced a formal intermolecular redox
reaction and formed the reduced enaminone 10a as the main
product along with only 22% (NMR) of the desired mixed pyrrole
2v (see scheme 11).
Scheme 11. Product distribution using the standard conditions with an
external enaminone; Yields were calculated using phenanthrene as an internal
standard (1H-NMR).
Further attempts to effect a cross-coupling in acceptable yields
are currently ongoing but will most probably require a different
metal catalyst.
Conclusions
In summary, a consecutive photochemical and metal-catalyzed
ring-contraction/dimerization sequence in
a
rayonet-type
photoreactor under internal temperature control was established.
Adjustment of the temperature allowed to match the rates of the
thermal and the photoinduced step. Aryl substituted isoxazoles
could be converted through the corresponding 2-acylazirine
intermediates to highly substituted 2,4-diacylpyrroles. A variety of
previously unknown pyrroles could be obtained from simple
precursors and using an inexpensive and readily available copper
catalyst.
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chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 97:3 → 85:15)
afforded the title compound (882 mg, 3.80 mmol, 45%) as a colorless solid.
Rf = 0.42 (4:1 cyclohexane/ethyl acetate). Mp: 131 – 132 °C. IR (ATR):
2920, 1573, 1469, 1450, 1416, 835, 787, 763, 690. 1H NMR (300 MHz,
CDCl3): δ 7.87 – 7.82 (m, 2H), 7.73 – 7.70 (m, 1H), 7.68 – 7.64 (m, 1H),
7.54 – 7.44 (m, 3H), 7.38 (t, 3JHH = 7.6 Hz, 1H), 7.30 – 7.25 (m, 1H), 6.83
(s, 1H), 2.44 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 170.3, 163.1, 138.7,
130.8, 130.2, 129.0, 128.8, 127.5, 127.4, 125.8, 124.0, 97.5, 21.4. MS
(ESI): m/z = 236.1 [M + H]+. The spectroscopic data are in accordance to
the literature.[18]
Experimental Section
Acetonitrile (MeCN), dichloromethane (DCM), 1,2-dichloroethane (DCE)
and cyclohexane were distilled from calcium hydride under an nitrogen
atmosphere. Solvents were degassed using freeze-pump-thaw cycles or
by bubbling argon through the liquid in an ultrasonic bath.
Deuterochloroform was stored over basic alumina (Brockmann activity I).
All reagents were purchased from commercial suppliers and used without
further purification. Water or oxygen sensitive reactions were performed
under an atmosphere of nitrogen in oven-dried glassware using standard
Schlenk technique. Photochemical reactions were performed in quartz
tubes using a photochemical reactor equipped with a circular array of 16
UV lamps (λ = 300 nm, power: 8 W per lamp), a magnetic stirrer and a
cooling fan. The temperature in the photochemical reactions were adjusted
using an external circulator connected to a cold finger, which was then
placed into the quartz tube. Thin layer chromatography was carried out on
silica gel 60 F254 plates and visualized using UV light. Preparative normal
phase chromatography was carried out on silica gel (35 – 70 µm) using
manual flash chromatography or an automatic flash purification system.
Preparative reversed-phase chromatography was performed on a HPLC
system with a C18PFP column (pore size: 5 µm, length: 15 cm, diameter:
30 mm) or on an automatic flash purification system with C18 modified silica
gel columns and by using mixtures of acetonitrile and water as eluent.
Melting points were determined in open capillary tubes and are not
corrected. NMR spectra were recorded on a 300, 400 or 600 MHz
3-(2-Methylphenyl)-5-phenylisoxazole (3d). Following the general
procedure using 2-tolualdehyde (8.32 mmol, 0.97 mL, 1.00 eq.) and
phenylacetylene (8.74 mmol, 0.96 mL, 1.05 eq.) after column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 97:3 → 85:15)
afforded the title compound (1.02 g, 4.34 mmol, 52%) as a colorless oil. Rf
= 0.50 (4:1 cyclohexane/ethyl acetate). IR (ATR): 2920, 1573, 1469, 1450,
1
1416, 835, 787, 763, 690. H NMR (300 MHz, CDCl3): δ 7.89 – 7.82 (m,
2H), 7.60 – 7.54 (m, 1H), 7.54 – 7.42 (m, 3H), 7.41 – 7.27 (m, 3H), 6.71 (s,
1H), 2.54 (s, 3H). 13C NMR (75 MHz, CDCl3) δ 169.5, 163.7, 136.9, 131.1,
130.2, 129.5, 129.0, 128.9, 127.5, 126.0, 125.9, 100.2, 21.1. MS (ESI):
m/z = 236.1 [M + H]+. The spectroscopic data are in accordance to the
literature.[19]
3-(4-Fluorophenyl)-5-phenylisoxazole (3e). Following the general
procedure using 4-fluorobenzaldehyde (8.32 mmol, 0.89 mL, 1.00 eq.) and
phenylacetylene (8.74 mmol, 0.96 mL, 1.05 eq.) after column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 97:3 → 80:20)
afforded the title compound (893 mg, 3.74 mmol, 45%) as a colorless solid.
Rf = 0.42 (4:1 cyclohexane/ethyl acetate). Mp: 165 – 166 °C. IR (ATR):
3054, 1605, 1526, 1448, 916, 845, 816, 766, 693, 534. 1H NMR (300 MHz,
CDCl3): δ 7.91 – 7.78 (m, 4H), 7.56 – 7.40 (m, 3H), 7.24 – 7.10 (m, 2H),
instrument at 23 °C using standard pulse sequences. The 1H and the 13
C
chemical shifts (δ) were referenced to the residual solvent signal as
internal standard (CDCl3: δ = 7.26 ppm and 77.16 ppm, MeCN-d3: δ = 1.94
ppm and 118.26 ppm for 1H and 13C NMR).[16] The 15N NMR and 19F NMR
were referenced to an external standard (15N: nitromethane in CDCl3 = 0.0
ppm; 19F: α,α,α-trifluorotoluene in CDCl3, δ = – 63.9 ppm). FT-IR spectra
(given in cm-1) were recorded using a diamond ATR unit. ESI-MS spectra
were recorded using an HPLC system with a UV diode array detector
coupled with a LC/MSD ion trap. Mixtures of water (with 0.1% formic acid)
and acetonitrile were used as eluent at a total flow rate of 1.0 mL/min. High
resolution masses (APCI-MS and ESI-MS) were recorded using a Q-ToF
instrument with dual source and suitable external calibrant.
1
6.80 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 170.6, 163.8 (d, JCF = 249.8
3
Hz), 162.1, 130.3, 129.0, 128.7 (d, JCF = 8.5 Hz), 127.3, 125.8, 125.4
2
(d, 4JCF = 3.3 Hz), 116.1 (d, JCF = 22.0 Hz), 97.3. 19F-NMR (282 MHz,
CDCl3) δ – (111.51 – 111.90). MS (ESI): m/z = 240.0 [M + H]+. The
spectroscopic data are in accordance to the literature.[9b]
Isoxazole Synthesis. Isoxazoles 3a and 3i-m were previously
synthesized using standard conditions.[9] The isoxazoles 1c-I and 1n-r
were synthesized applying an optimized method of Fokin and
coworkers[10]: To a solution of the corresponding aldehyde (1.00 eq.) and
hydroxylamine hydrochloride (1.05 eq.) in tert-butanol/water (1:1, c = 0.25
mmol/mL) was added sodium hydroxide (1.05 eq.) and the solution was
stirred at room temperature for 1 h. Chloramine-T trihydrate (1.05 eq.) was
added in small portions over 5 – 10 minutes. The corresponding terminal
alkyne (1.05 eq.), copper sulfate pentahydrate (0.03 eq.) and copper wire
(0.04 eq.) were added and the pH was adjusted to approximately 6 by
addition of aqueous NaOH (1N). The mixture was stirred over night and
poured into water (150 mL). Aqueous NaOH (1N, 10 mL) was added and
the mixture extracted with dichloromethane (3 × 50 mL). The combined
organic extracts were dried over Na2SO4 and the solvent was removed in
vacuo. The crude product was purified by automatic flash column
chromatography (eluent: cyclohexane/ethyl acetate) to afford the crude
isoxazoles 3c-q. Some of the isoxazoles were further purified by
recrystallization using mixtures of acetonitrile and water.
3-(4-Chlorophenyl)-5-phenylisoxazole (3f). Following the general
procedure using 4’-chlorobenzaldehyde (8,32 mmol, 1.17g, 1.00 eq.) and
phenylacetylene (8.74 mmol, 0.96 mL, 1.05 eq.) after column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 95:5 → 80:20)
afforded the title compound (869 mg, 3.41 mmol, 41%) as a colorless solid.
Rf = 0.42 (4:1 cyclohexane/ethyl acetate). Mp: 169 – 170 °C. IR (ATR):
3112, 1489, 1447, 1095, 950, 840, 815, 767, 693. 1H NMR (300 MHz,
CDCl3): δ 7.88 – 7.77 (m, 4H), 7.55 – 7.43 (m, 5H), 6.80 (s, 1H). 13C NMR
(75 MHz, CDCl3) δ 170.8, 162.0, 136.0, 130.4, 129.2, 129.1, 128.1, 127.6,
127.3, 125.9, 97.3. MS (ESI): m/z = 256.1 [M + H]+. The spectroscopic
data are in accordance to the literature.[20]
3-(4-Bromophenyl)-5-phenylisoxazole (3g). Following the general
procedure using 4-bromobenzaldehyde (8.32 mmol, 1.54 g, 1.00 eq.) and
phenylacetylene (8.74 mmol, 0.96 mL, 1.05 eq.) after column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 95:5 → 80:20)
afforded the title compound (949 mg, 3.18 mmol, 38%) as a colorless solid.
Rf = 0.41 (4:1 cyclohexane/ethyl acetate). Mp: 182 - 183 °C. IR (ATR):
3113, 1597, 1488, 1426, 918, 815, 767, 692, 507. 1H NMR (300 MHz,
CDCl3): δ 7.88 – 7.80 (m, 2H), 7.79 – 7.71 (m, 2H), 7.66 – 7.59 (m, 2H),
7.54 – 7.43 (m, 3H), 6.81 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 170.8, 162.1,
132.2, 130.4, 129.1, 128.3, 128.1, 127.3, 125.9, 124.3, 97.3. MS (ESI):
m/z = 300.1 [M(79Br) + H]+, 302.0 [M(81Br) + H]+. The spectroscopic data
are in accordance to the literature.[21]
3-(4-Methylphenyl)-5-phenylisoxazole (3b). Following the general
procedure using 4-tolualdehyde (8.32 mmol, 0.98 mL, 1.00 eq.) and
phenylacetylene (8.74 mmol, 0.91 mL, 1.05 eq.) after column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 97:3 → 85:15)
afforded the title compound (921 mg, 3.90 mmol, 47%) as a colorless solid.
Rf = 0.44 (4:1 cyclohexane/ethyl acetate). Mp: 123 – 124 °C. IR (ATR):
2916, 1612, 1569, 1494, 1448, 949, 829, 763, 686. 1H NMR (300 MHz,
CDCl3): δ 7.88 – 7.82 (m, 2H), 7.79 – 7.73 (m, 2H), 7.54 – 7.42 (m, 3H),
7.32 – 7.27 (m, 2H), 6.81 (s, 1H), 2.42 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 170.2, 162.9, 140.2, 130.2, 129.6, 129.0, 127.5, 126.7, 126.3, 125.8,
97.4, 21.5. MS (ESI): m/z = 236.1 [M + H]+. The spectroscopic data are in
accordance to the literature.[17]
3-(4-(Trifluoromethyl)phenyl)-5-phenylisoxazole (3h). Following the
general procedure using 4-(trifluoromethyl)benzaldehyde (8.32 mmol, 1.14
mL, 1.00 eq.) and phenylacetylene (8.74 mmol, 0.96 mL, 1.05 eq.) after
column chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 97:5
→ 80:20) afforded the title compound (644 mg, 2.22 mmol, 27%) as a
colorless solid. Rf = 0.41 (4:1 cyclohexane/ethyl acetate). Mp: 186 - 187 °C.
IR (ATR): 2924, 1450, 1390, 1158, 950, 818, 768, 693. 1H NMR (300 MHz,
CDCl3): δ 8.03 – 7.97 (m, 2H), 7.89 – 7.81 (m, 2H), 7.80 – 7.70 (m, 2H),
7.50 (m, 3H), 6.87 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 171.2, 162.0,
3-(3-Methylphenyl)-5-phenylisoxazole (3c). Following the general
procedure using 3-tolualdehyde (8.32 mmol, 0.98 mL, 1.00 eq.) and
phenylacetylene (8.74 mmol, 0.96 mL, 1.05 eq.) after column
2
132.7, 132.0 (middle signals of q, JCF = 32.7 Hz), 130.7, 129.3, 127.3,
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10.1002/ejoc.201901176
European Journal of Organic Chemistry
FULL PAPER
1
126.2, 126.1 (3JCF = 3.8 Hz), 124.0 (middle signals of q, JCF = 272 Hz),
122.2, 97.6. 19F NMR (282 MHz, CDCl3) δ − 63.99. MS (ESI): m/z = 290.2
[M + H]+. The spectroscopic data are in accordance to the literature.[9b]
(C-4’), 129.4 (C-1’), 128.8 (C-3’ + C-5’), 126.7 (C-2’ + C-6’), 98.8 (C-4),
31.2 (C-4’’), 27.2 (C-2’’), 26.8 (C-1’’), 22.3 (C-3’’), 13.9 (C-5’’). MS (ESI):
m/z = 236.1 [M + H]+. HRMS (ESI) calcd for [C14H18NO]+ 216.1383, found
216.1388.
3-Phenyl-5-(4-(tert-butyl)phenyl)isoxazole (3n). Following the general
procedure using benzaldehyde (8.32 mmol, 0.78 mL, 1.00 eq.) and
4-(tert-butyl)phenylacetylene (8.74 mmol, 1.58 mL, 1.05 eq.) after column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 97:3 → 60:40)
afforded the title compound (837 mg, 3.02 mmol, 36%) as a colorless solid.
Rf = 0.52 (4:1 cyclohexane/ethyl acetate). Mp: 95 – 96 °C. IR (ATR): 2963,
Azirine and 15N labeled azirine. 15N-3,5-Diphenylisoxazole (3s). The
labeled isoxazole was synthesized using the method of Griesbeck and
coworkers[23]: A mixture of dibenzoylmethane (6.81 mmol, 1.53 g, 1.00 eq.),
15N-hydroxylamine hydrochloride (7.15 mmol, 0.50 g, 1.05 eq.), water (12
mL) and ethanol (6 mL) was stirred at 90 °C for 18 h. The mixture was
poured into water (50 mL) and extracted with dichloromethane (3 × 50 mL).
The combined organic extracts were dried over sodium sulfate and the
solvent removed in vacuo to afford the 15N labeled isoxazole (1.24 g, 5.58
mmol, 82%) as a colourless solid. Rf = 0.44 (4:1 cyclohexane/ethyl
acetate). Mp: 141 – 142 °C. IR (ATR): 3114, 1593, 1459, 1398, 820, 762,
691. 1H NMR, COSY (400 MHz, CDCl3): δ 7.98 – 7.83 (m, 4H,
H-2‘ + H-6‘ + H-2‘‘ + H-6‘‘), 7.61 – 7.44 (m, 6H, H-3‘-5‘ + H-3‘‘‘-5‘‘‘), 6.87
1
1618, 2499, 1464, 1399, 950, 840, 765, 691. H NMR, COSY (300 MHz,
CDCl3): δ 7.92 – 7.88 (m, 2H, H-2‘ + H-6‘), 7.85 – 7.76 (m, 2H, H-2‘‘ + H-6‘‘),
7.60 – 7.46 (m, 5H, H-3‘-5‘ + H-3‘‘ + H-5‘‘), 6.82 (s, 1H, H-4), 1.39 (s, 9H,
C(CH3)3). 13C NMR, HSQC, HMBC (75 MHz, CDCl3) δ 170.7 (C-5), 163.1
(C-3), 153.8 (C-4‘‘), 130.1 (C-4‘), 129.4 (C-1‘), 129.0 (C-3‘ + C-5‘), 127.0
(C-2‘ + C-6‘), 126.1 (C-3‘‘ + C-5‘‘), 125.8 (C-2‘‘ + C-6‘‘), 124.9 (C-1‘‘), 97.1
(C-4), 35.1 (C(CH3)3), 31.3 (C(CH3)3). MS (ESI): m/z = 278.2 [M + H]+.
HRMS (ESI) calcd for [C19H20NO]+ 278.1539, found 278.1539.
3
(d, JNH = 1.3 Hz, 1H, H-4). 13C NMR, HSQC, HMBC (101 MHz, CDCl3)
2
1
δ 170.4 (d, JCN = 1.1 Hz), 163.0 (d, JCN = 2.1 Hz), 130.3 (C-4‘‘), 130.1
2
(C-4‘), 129.2 (d, JCN = 7.3 Hz, C-1‘), 129.0 (C-3‘ + C-5‘ + C-3‘‘ + C-5‘‘),
3-Phenyl-5-(4-fluorophenyl)isoxazole (3o). Following the general
procedure using benzaldehyde (7.00 mmol, 0.66 mL, 1.00 eq.) and
4-fluorophenylacetylene (7.35 mmol, 0.98 g, 1.05 eq.) a after column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 95:5 → 60:40)
afforded the title compound (670 mg, 2.80 mmol, 40%) as a colorless solid.
Rf = 0.43 (4:1 cyclohexane/ethyl acetate). Mp: 126 – 128 °C. IR (ATR):
3115, 1616, 1518, 1500, 1235, 844, 814, 768, 697. 1H NMR (300 MHz,
CDCl3): δ 7.92 – 7.77 (m, 4H), 7.53 – 7.44 (m, 3H), 7.24 – 7.14 (m, 2H),
3
127.5 (C-1‘‘) 126.8 (d, JCN = 2.3 Hz, C-2‘ + C-6‘), 125.9 (C-2‘‘ + C-6‘‘),
97.5 (C-4). 15N NMR (41 MHz, CDCl3) δ = 366.93. MS (ESI): m/z = 223.1
[M + H]+. HRMS (ESI) calcd for [C15H12[15N]O]+ 223.0886, found 223.0884.
The azirines 1a, 1l and 1m were prepared according to the procedure of
Singh et al.[6a] and using the modification of Griesbeck and coworkers[23]
:
In an oven-dried quartz tube, the isoxazole 3 (1.00 eq.) and freshly distilled
propionaldehyde (10 eq.) were dissolved in dry acetonitrile (c = 0.1 M).
The solution was degassed and irradiated for 6 h (λmax = 300 nm). The
solvent was removed in vacuo and the crude mixture purified by flash
column chromatography (eluent: cyclohexane/ethyl acetate) to afford
azirine 1.
1
6.78 (s, 1H). 13C NMR (75 MHz, CDCl3) δ 169.4, 163.8 (d, JCF = 251.2
Hz), 163.1, 130.1, 129.0, 127.9 (d, 3JCF = 8.7 Hz), 126.8, 123.8 (d, 4JCF
=
2
3.3 Hz), 116.3 (d, JCF = 22.2 Hz), 97.3. 19F NMR (282 MHz, CDCl3)
δ − (111.51 – 111.90) (m). MS (ESI): m/z = 240.1 [M + H]+. The
spectroscopic data are in accordance to the literature.[22]
3-Phenyl-5-(4-methoxyphenyl)isoxazole (3p). Following the general
procedure using benzaldehyde (8.32 mmol, 0.78 mL, 1.00 eq.) and
4-methoxyphenylacetylene (8.74 mmol, 1.13 mL, 1.05 eq.) after column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 95:5 → 60:40)
afforded the title compound (860 mg, 3.42 mmol, 41%) as a colorless solid.
Rf = 0.50 (2:1 cyclohexane/ethyl acetate). Mp: 128 – 129 °C. IR (ATR):
1616, 1519, 1467, 1402, 1262, 1179, 1034, 769, 691. 1H NMR (300 MHz,
CDCl3): δ 7.90 – 7.83 (m, 2H), 7.82 – 7.75 (m, 2H), 7.54 – 7.42 (m, 3H),
7.05 – 6.97 (m, 2H), 6.71 (s, 1H), 3.87 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ 170.5, 163.1, 161.3, 130.1, 129.4, 129.0, 127.6, 127.0, 120.5, 114.6,
96.3, 55.6. MS (ESI): m/z = 252.2 [M + H]+. The spectroscopic data are in
accordance to the literature.[6b]
Phenyl(3-phenyl-2H-aziren-2-yl)methanone (1a). Following the general
procedure using 3,5-diphenylisoxazole 3a (4.0 mmol, 885 mg, 1.00 eq.)
after flash column chromatography (SiO2, eluent: cyclohexane/ethyl
acetate, 95:5 → 65:35 ) afforded the title compound (430 mg, 1.94 mmol,
48%) as a yellow oil. Rf = 0.37 (4:1 cyclohexane/ethyl acetate). IR (ATR):
1
1775, 1672, 1449, 1352, 1230, 1024, 762, 721, 688, 653. H NMR (400
MHz, CDCl3): δ 8.33 – 8.06 (m, 2H), 8.00 – 7.78 (m, 2H), 7.67 – 7.60 (m,
2H), 7,58 – 7.52 (m, 4H), 3.86 (s, 1H). 13C NMR (101 MHz, CDCl3) δ 197.8,
157.4, 137.6, 134.3, 133.9, 131.0, 129.8, 129.2, 128.8, 122.8, 34.0. MS
(ESI): m/z = 222.0 [M + H]+. The spectroscopic data are in accordance to
the literature.[9b]
Phenyl(3-methyl-2H-aziren-2-yl)methanone (1m). Following the general
procedure using 3-methyl-5-phenylisoxazole 3l (5.0 mmol, 796 mg, 1.00
eq.) after flash column chromatography (SiO2, eluent: cyclohexane/ethyl
acetate, 97:3 → 70:30 ) afforded the title compound (241 mg, 1.51 mmol,
30%) as yellow oil. Rf = 0.23 (2:1 cyclohexane/ethyl acetate). IR (ATR):
3064, 1699, 1449, 1355, 1231, 1211, 720, 689. 1H NMR (300 MHz, CDCl3):
δ 8.14 – 7.94 (m, 2H), 7.64 – 7.56 (m, 1H), 7.53 – 7.46 (m, 2H), 3.47 (s,
1H), 2.54 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 198.1, 157.2, 137.3,
133.4, 128.8, 128.3, 32.6, 12.7. MS (ESI): m/z = 160.1 [M + H]+. The
spectroscopic data are in accordance to the literature.[24]
3-Phenyl-5-(4-methoxycarbonylphenyl)isoxazole (3q). Following the
general procedure using benzaldehyde (5.50 mmol, 0.52 mL, 1.00 eq.) and
4-(methoxycarbonyl)phenylacetylene (5.78 mmol, 1.03 g, 1.05 eq.) after
column chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 95:5
→ 60:40) afforded the title compound (472 mg, 1.69 mmol, 31%) as a
colorless solid. Rf = 0.23 (4:1 cyclohexane/ethyl acetate). Mp:
200 – 202 °C. IR (ATR): 1712, 1441, 1415, 1279, 1112, 825, 771, 706, 697.
1H NMR, COSY (300 MHz, CDCl3): δ 8.20 – 8.11 (m, 2H, H-3‘‘ + H-5‘‘),
7.94 – 7.90 (m, 2H, H-2‘‘ + H-6‘‘), 7.90 – 7.85 (m, 2H, H-2‘ + H-6‘),
7.55 – 7.45 (m, 3H, H-3‘-5‘), 6.94 (s, 1H, H-4), 3.96 (s, 3H, C-4‘‘-COCH3).
13C NMR, HSQC, HMBC (75 MHz, CDCl3) δ 169.2 (C-5), 166.3
(C-4‘‘-COCH3), 163.2 (C-3), 131.4 (C-4‘‘), 131.2 (C-1‘‘), 130.3
(C-3‘‘ + C-5‘‘), 130.2 (C-4‘), 129.0 (C-3‘ + C-5‘), 128.8 (C-1‘), 126.8
(C-2‘ + C-6‘), 125.7 (C-2‘‘ + C-6‘‘), 99.0 (C-4), 52.4 (C-4‘‘-COCH3). MS
(ESI): m/z = 280.2 [M + H]+. HRMS (ESI) calcd for [C17H14NO3]+ 280.0968,
found 280.0968.
15N-Phenyl(3-phenyl-2H-aziren-2-yl)methanone (1s). Following the
general procedure using 15N-3,5-diphenylisoxazole 3s (2.5 mmol, 555 mg,
1.00 eq.) after flash column chromatography (SiO2, eluent:
cyclohexane/ethyl acetate, 95:5 → 65:35) afforded the title compound (178
mg, 0.80 mmol, 33%) as yellow oil. Rf = 0.37 (4:1 cyclohexane/ethyl
acetate). IR (ATR): 3062, 1671, 1597, 1449, 1230, 971, 761, 721, 688, 649.
1H NMR (400 MHz, CDCl3): δ 8.18 – 8.10 (m, 2H, H-2‘ + H-6‘), 7.92 – 7.85
(m, 2H, H-2‘‘‘ + H-6‘‘‘), 7.68 – 7.60 (m, 2H, H-4‘ + H-4‘‘‘), 7.60 – 7.51 (m,
3-Phenyl-5-pentylisoxazole (3r). Following the general procedure using
benzaldehyde (8.32 mmol, 0.84 mL, 1.00 eq.) and 1-heptyne (8.74 mmol,
1.15 mL, 1.05 eq.) after column chromatography (SiO2, eluent:
cyclohexane/ethyl acetate, 98:2 → 85:15) afforded the title compound (472
mg, 1.69 mmol, 31%) as a colorless oil. Rf = 0.54 (4:1 cyclohexane/ethyl
acetate). IR (ATR): 2956, 1602, 1580, 1471, 1443, 1408, 950, 767, 693.
1H NMR, COSY (300 MHz, CDCl3): δ 7.92 – 7.72 (m, 2H, H-2‘ + H-6‘), 7.53
– 7.41 (m, 3H, H-3‘-5‘), 6.29 (s, 1H, H-4), 2.91 – 2.70 (m, 2H, H-1‘‘), 1.89
2
4H, H-3‘ + H-5‘ + H-3‘‘‘ + H-5‘‘‘), 3.86 (d, JNH = 3.0 Hz, 1H). 13C NMR
1
(101 MHz, CDCl3) δ 197.5 (CO), 157.0 (d, JCN = 6.6 Hz, C-3’’), 137.3
(C-1‘), 134.0 (C-4‘‘‘), 133.5 (C-4‘), 130.7 C-2‘ + C-6‘), 129.5 (C-3‘‘‘ + C-5‘‘‘),
128.9 (C-3‘ + C-5‘), 128.5 (C-2‘ + C-6‘), 122.5 (C-1‘‘‘), 33.6 (d, 1JCN = 10.4
Hz, C-2‘‘). 15N NMR (41 MHz, CDCl3) δ 261.58. MS (ESI): m/z = 223.1 [M
+ H]+. HRMS (ESI) calcd for [C15H12[15N]O]+ 223.0886, found 223.0889.
– 1.67 (m, 2H, H-2‘‘), 1.38 (m, 4H, H-3‘‘-4‘‘), 1.02 – 0.83 (m, 3H, H-5‘‘). 13
NMR, HSQC, HMBC (75 MHz, CDCl3) δ 174.3 (C-5), 162.3 (C-3), 129.8
C
General protocol for the synthesis of pyrroles 2a-r: In an oven-dried
quartz tube under nitrogen atmosphere, isoxazoles 3 (1.0 mmol, 1.00 eq.)
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10.1002/ejoc.201901176
European Journal of Organic Chemistry
FULL PAPER
and Cu(II)-2-ethylhexanoate (0.1 mmol, 35 mg, 0.10 eq.) were dissolved
or suspended in dry acetonitrile (10 mL, c = 0.1 M (method A) or 20 mL,
c = 0.05 M (method B). The reaction tube was degassed and placed into
the photoreactor. A cold finger connected to a circulator was placed into
the solution and the reaction mixture was preheated to 70 °C. The vessel
was irradiated (λmax = 300 nm, 16 × 8 W) at that temperature until TLC or
LC/MS indicated full consumption of the starting material (20 – 48 h). The
solvent was removed in vacuo and the residue purified by flash
chromatography. Some of the pyrroles were further purified using
preparative HPLC with mixtures of water and acetonitrile as eluent.
C-6‘‘), 7.53 – 7.40 (m, 6H, C-3‘–5‘, C-3‘‘–5‘‘), 6.16 (s, 1H, C-2), 5.45 (s, 1H,
NH). 13C NMR, HSQC, HMBC (75 MHz, CDCl3) δ 190.3 (C-1), 163.0 (C-3),
140.5 (C-1‘), 137.8 (C-1‘‘), 131.2 (C-4‘), 130.9 (C-4‘‘), 129.2 (C-3‘ + C-5‘),
128.4 (C-3‘‘ + C-5‘‘), 127.4 (C-2‘+ C-6‘), 126.5 (C-2‘‘ + C-6‘‘), 92.1 (C-2).
MS (ESI): m/z = 224.1 [M + H]+. The spectroscopic data are in accordance
to the literature.[25]
(3,5-Di-(4-methylphenyl)-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2b).
Following
general
procedure
A,
3-(4-methylphenyl)-5-
phenylisoxazole (1.0 mmol, 235 mg, 1.00 eq.) was irradiated for 20 h at
70 °C. After column chromatography (SiO2, eluent: cyclohexane/ethyl
acetate, 94:6 → 70:30) the title compound (116 mg, 0.26 mmol, 52%) was
afforded as a yellow solid. Rf = 0.13 (4:1 cyclohexane/ethyl acetate). Mp:
230 – 232 °C. IR (ATR): 3263, 1597, 1535, 1448, 1296, 904, 819, 727, 693.
1H NMR, COSY, NOESY (400 MHz, CDCl3): δ 10.32 (s, 1H, NH), 7.68
(3,5-Diphenyl-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2a).
Following general procedure A, 3,5-diphenylisoxazole (1.0 mmol, 221 mg,
1.00 eq.) was irradiated for 20 h at 70 °C. After column chromatography
(SiO2, eluent: cyclohexane/ethyl acetate, 94:6 → 70:30) the title compound
(119 mg, 0.28 mmol, 56%) was obtained as yellow solid. Rf = 0.16 (4:1
cyclohexane/ethyl acetate). Mp: 220 – 222 °C. IR (ATR): 3265, 1653, 1599,
1575, 1493, 1463, 1417, 1260, 914, 736, 695. 1H NMR, COSY, NOESY
(400 MHz, CDCl3): δ 10.53 (s, 1H, NH), 7.68 – 7.62 (m, 2H, H-2‘‘‘ + H-6‘‘‘),
7.56 (m, 2H, H-2‘‘‘‘ + H-6‘‘‘‘), 7.44 – 7.37 (m, 2H, H-2‘ + H-6‘), 7.33 – 7.24
(m, 4H, H-3‘‘‘‘ + H-5‘‘‘‘), 7.20 (m, 1H, H-4‘), 7.12 (m, 2H, H-3‘‘‘ + H-5‘‘‘),
7.00 (m, 2H, H-3‘ + H-5‘), 6.95 – 6.91 (m, 2H, H-2‘‘ + H-6‘‘), 6.84 (m, 3H,
H-3‘‘-5‘‘). 13C NMR, HSQC, HMBC (101 MHz, CDCl3) δ 194.2 (C-4-CO),
187.8 (C-2-CO), 138.1 (C-5), 138.0 (C-1’’’), 137.3 (C-1’), 133.9 (C-3),
133.2 (C-1’’), 132.7 (C-4’’’), 131.4 (C-4’), 130.7 (C-2’’ + C-6’’), 130.3
(C-1’’’’), 129.8 (C-2’’’ + C-6’’’), 129.3 (C-2’ + C-6’), 128.9 (C-4’’’’), 128.8
(C-3’’’’ + C-5’’’’), 128.0 (C-2 + C-2’’’’ + C-6’’’’), 127.9 (C-3’’’ + C-5’’’), 127.4
(C-3’ + C-5’ + C-3’’ + C-5’’), 126.9 (C-4’’), 123.2 (C-4). MS (ESI):
m/z = 427.2 [M + H]+. The spectroscopic data are in accordance to the
literature.[9b]
– 7.63 (m, 2H, H-2‘‘‘
+
H-6‘‘‘), 7.44
–
7.37 (m, 4H,
H-2‘ + H-6‘ + H-2‘‘‘‘ + H-6‘‘‘‘), 7.32 – 7.24 (m, 1H, H-4‘‘‘), 7.23 – 7.17 (m,
1H, H-4‘), 7.16 – 7.11 (m, 2H, H-3‘‘‘ + H-5‘‘‘), 7.11 – 7.07 (m, 2H,
H-3‘‘‘‘ + H-5‘‘‘‘), 7.03 – 6.97 (m, 2H, H-3‘ + H-5‘), 6.84 – 6.78 (m, 2H, H-2’’
+ H-6’’), 6.63 (m, 2H, H-3’’ + H-5’’), 2.30 (s, 3H, C-4‘‘‘‘-CH3), 2.07 (s, 3H,
C-4‘‘-CH3). 13C NMR, HSQC, HMBC (101 MHz, CDCl3) δ 194.5 (C-2-CO),
187.7 (C-4-CO), 138.9 (C-4’’’’), 138.1 (C-5), 138.0 (C-1’’’), 137.5 (C-1’),
136.5 (C-4’’), 134.1 (C-3), 132.6 (C-4’’’), 131.1 (C-4’), 130.6 (C-2’’ + C-6’’),
130.2 (C-1’’), 129.9 (C-2’’’ + C-6’’’), 129.5 (C-3’’’’ + C-5’’’’), 129.3 (C-2’
+ C-6’), 128.1 (C-3’’ + C-5’’), 127.9 (C-3’’’ + C-5’’’), 127.8 (C-2 + C-2’’’’
+ C-6’’’’), 127.5 (C-1’’’’), 127.4 (C-3’ + C-5’), 122.9 (C-4), 21.3 (C-4‘‘‘‘-CH3),
21.0 (C-4‘‘-CH3). MS (ESI): m/z = 456.3 [M + H]+. HRMS (ESI) calcd for
[C32H25NO2Na]+ 478.1778, found 478.1773.
(3,5-Di-(3-methylphenyl)-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2c).
Following
general
procedure
A,
3-(3-methylphenyl)-5-
In an upscaled reaction following general procedure A,
3,5-diphenylisoxazole (3.16 mmol, 700 mg, 1.00 eq.) was irradiated for 20
h at 70 °C. Beside pyrrole 2a (373 mg, 0.87 mmol, 56%), column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 94:6 → 70:30)
and reverse phase column chromatography (SiO2-C18, eluent:
phenylisoxazole (1.0 mmol, 235 mg, 1.00 eq.) was irradiated for 20 h at
70 °C. After column chromatography (SiO2, eluent: cyclohexane/ethyl
acetate, 95:5 → 80:20) the title compound (105 mg, 0.23 mmol, 46%) was
afforded as a yellow solid. Rf = 0.25 (4:1 cyclohexane/ethyl acetate). Mp:
195 – 197 °C. IR (ATR): 3261, 1599, 1449, 1402, 1210, 944, 914, 751,
695. 1H NMR, COSY (600 MHz, CDCl3): δ 10.16 (s, 1H, NH), 7.66 – 7.62
(m, 2H, H-2‘ + H-6‘), 7.41 – 7.37 (m, 2H, H-2‘‘‘ + H-6‘‘‘), 7.34 – 7.29 (m, 2H,
H-4‘‘ + H-6‘‘), 7.30 – 7.25 (m, 1H, H-4‘), 7.22 – 7.16 (m, 2H, H-5‘‘ + H-4‘‘‘),
7.16 – 7.08 (m, 3H, H-2‘ + H-3‘ + H-5‘), 7.00 (m, 2H, H-3‘‘‘ + H-5‘‘‘), 6.80
– 6.73 (m, 2H, H-5‘‘‘‘ + H-6‘‘‘‘), 6.68 – 6.64 (m, 2H, H-2‘‘‘‘ + H-4‘‘‘‘), 2.29 (s,
3H, C-3‘‘-CH3), 1.92 (s, 3H, C-3‘‘‘‘-CH3). 13C NMR, HSQC, HMBC
(151 MHz, CDCl3) δ 194.3 (C-4-CO), 187.8 (C-2-CO), 138.5 (C-3’’’’), 138.3
(C-4), 138.2 (C-1’’’), 137.5 (C-1’), 136.8 (C-3’’), 134.2 (C-3), 132.9 (C-1’’),
132.6 (C-4’’’), 131.8 (C-4’’) , 131.3 (C-4’), 130.2 (C-1’’’’), 129.7 (C-2’’’ C-6’’’
+ C-2’’’’), 129.0 (C-2’ + C-6’), 128.7 (C-5’’’’), 128.6 (C-4’’’’), 127.9 (C-2
+ C-3’’’ +C-5’’’), 127.6 (C-2’’), 127.4 (C-5’’ + C-6’’), 127.3 (C-3’ + C-5’),
125.2 (C-6’’’’), 123.0 (C-4), 21.4 (C-3’’’’-CH3), 20.9 (C-3’’-CH3). MS (ESI):
m/z = 456.3 [M + H]+. HRMS (ESI) calcd for [C32H25NO2Na]+ 478.1778,
found 478.1775.
acetonitrile/water, 50:50
→ 90:10) afforded the following primary
byproducts:
(3,6-Diphenyl-pyrazine-2,5-diyl)bis(phenylmethanone) (8a). The title
compound (42 mg, 0.10 mmol, 6%) was obtained as a colorless solid.
Rf = 0.20 (4:1 cyclohexane/ethyl acetate). Mp: 160 – 162 °C. IR (ATR):
3060, 1669, 1526, 1492, 1218, 924, 768, 732, 694, 647. 1H NMR, COSY
(300 MHz, CDCl3): δ 8.20 – 8.13 (m, 2H, H-2‘ + H-6‘), 7.68 – 7.60 (m, 7H,
H-4‘ + H-2‘‘ + H-6‘‘ + H-2‘‘‘ + H-6‘‘‘ + H-2‘‘‘‘ + H-6‘‘‘‘), 7.56 – 7.49 (m, 2H,
H-3‘
+ H-5‘), 7.48 – 7.41 (m, 1H, H-4‘‘‘), 7.37 – 7.22 (m, 8H,
H-3‘‘ + H-5‘‘ + H-3‘‘‘ + H-5‘‘‘ + H-3‘‘‘‘ + H-5‘‘‘‘). 13C NMR, HSQC, HMBC
(75 MHz, CDCl3) δ 196.1 (C-2-CO), 191.2 (C-5-CO), 165.1 (C-3 + C-6),
162.5 (C-2 + C-5), 136.7 (2C, CAr), 134.9 (C-1‘), 134.0 (CAr), 133.9 (C-4‘),
131.0 (C-2‘ + C-6‘), 130.8 (CAr), 130.3 (CAr), 129.3 (CAr), 128.8 (CAr), 128.6
(CAr), 128.5 (C-3‘
+
C-5‘). MS (ESI): m/z = 441.2 [M + H]+. The
spectroscopic data are in accordance to the literature.[7]
(3,5-Di-(4-fluorophenyl)-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2e). Following general procedure A, 3-(4-fluorophenyl)-5-phenylisoxazole
(1.0 mmol, 239 mg, 1.00 eq.) was irradiated for 20 h at 70 °C. After column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 96:4 → 80:20)
and preparative HPLC (eluent: acetonitrile/water 60 : 40, tr = 11.5 – 13.5
min) the title compound (110 mg, 0.24 mmol, 48%) was obtained as a
colorless solid. Rf = 0.17 (4:1 cyclohexane/ethyl acetate). Mp:
223 – 225 °C. IR (ATR): 3259, 1597, 1595, 1504, 1420, 1258, 1234, 912,
838, 734. 1H NMR, COSY, NOESY (600 MHz, CDCl3): δ 10.63 (s, 1H, NH),
7.63 – 7.59 (m, 2H, H-2‘‘‘ + H-6‘‘‘), 7.57 – 7.51 (m, 2H, H-2‘‘‘‘ + H-6‘‘‘‘), 7.36
– 7.33 (m, 2H, H-2‘ + H-6‘), 7.33 – 7.29 (m, 1H, H-4‘), 7.29 – 7.23 (m, 1H,
H-4‘‘‘), 7.15 (m, 2H, H-3‘‘‘ + H-5‘‘‘), 7.04 (m, 2H, H-3‘ + H-5‘), 6.96 (m, 2H,
H-3‘‘‘‘ + H-5‘‘‘‘), 6.92 – 6.86 (m, 2H, H-2‘‘ + H-6‘‘), 6.53 (m, 2H, H-3‘‘ + H-5‘‘).
13C NMR, HSQC, HMBC (151 MHz, CDCl3) δ 194.0 (C-4-CO) , 187.8
(4,6-Diphenyl-5-benzoylpyrimidine) (9a). The title compound (65 mg,
0.19 mmol, 12%) was obtained as a colorless solid. Rf = 0.13 (2:1
cyclohexane/ethyl acetate). Mp: 149 – 150 °C. IR (ATR): 3059, 1667, 1536,
1518, 1430, 1226, 926, 755, 696. 1H NMR, COSY, NOESY (400 MHz,
CDCl3): δ 9.44 (s, 1H, H-2), 7.61 – 7.57 (m, 2H, H-2‘‘ + H-6‘‘), 7.57 – 7.54
(m, 4H, H-2‘ + H-6‘ + H-2‘‘‘ + H-6‘‘‘), 7.43 – 7.38 (m, 1H, H-4‘‘), 7.36 – 7.23
(m, 9H, H-3‘-5‘ + H-3‘‘ + H-5‘‘ + H-3‘‘‘-5‘‘‘). 13C NMR, HSQC, HMBC
(101 MHz, CDCl3) δ 196.1 (C-5-CO), 164.6 (C-4 + C-6), 158.4 (C-2), 137.2
(C-1‘ + C-1‘‘‘), 137.0 (C-1‘‘), 133.8 (C-4‘‘), 130.5 (C-5), 130.0 (C-4‘ + C-4‘‘‘),
129.3 (C-2‘‘ + C-6‘‘), 129.0 (C-2‘ + C-6‘ + C-2‘‘‘ + C-6‘‘‘), 128.6
(C-3‘‘ + C-5‘‘), 128.5 (C-3‘ + C-5‘ + C-3‘‘‘ + C-5‘‘‘). MS (ESI): m/z = 337.1
[M + H]+. HRMS (ESI) calcd for [C23H17N2O]+ 337.1335, found 337.1335.
Crystals suitable for X-ray crystallography could be obtained by
recrystallization of 9a from cyclohexane/ethyl acetate (2:1).
1
1
(C-2-CO), 163.00 (d, JCF = 248.6 Hz, C-4‘‘‘‘), 161.8 (d, JCF = 248.6 Hz,
C-4‘‘), 137.8 (C-1‘‘‘), 137.5 (C-1‘), 137.2 (C-5), 133.0 (C-4‘), 132.9 (C-3),
3
3
132.3 (d, JCF = 8.4 Hz, C-2‘‘ + C-6‘‘), 131.7 (C-4‘‘‘), 130.1 (d, JCF = 8.4
Hz, C-2‘‘‘‘ + C-6‘‘‘‘), 129.7 (C-2‘‘‘ + C-6‘‘‘), 129.2 (C-1‘‘ + C-2‘ + C-6‘), 128.1
(C-2), 128.0 (C-3‘‘‘ + C-5‘‘‘), 127.6 (C-3‘ + C-5‘), 126.4 (d, 4JCF = 3.4 Hz,
C-1‘‘‘‘), 123.2 (C-4), 115.9 (d, 2JCF = 21.8 Hz, C-3‘‘‘‘ + C-5‘‘‘‘), 114.4 (d, 2JCF
= 21.8 Hz, C-3‘‘ + C-5‘‘). 19F NMR (282 MHz, CDCl3) δ - 112.65 (m),
- 116.04 (m). MS (ESI): m/z = 464.2 [M + H]+. HRMS (ESI) calcd for
[C30H20F2NO2]+ 464.1457, found 464.1455.
(3-Amino-1,3-diphenylprop-2-en-1-one) (10a). The title compound (29
mg, 0.13 mmol, 4%) was obtained as a colorless solid. Rf = 0.47 (1:1
cyclohexane/ethyl acetate). IR (ATR): 3352, 3167, 1599, 1565, 1525,
1484, 1307, 1226, 740, 694. 1H NMR, COSY (300 MHz, CDCl3): δ 10.43
(s, 1H, NH), 8.00 – 7.92 (m, 2H, C-2‘ + C-6‘), 7.68 – 7.61 (m, 2H, C-2‘‘,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901176
European Journal of Organic Chemistry
FULL PAPER
(3,5-Di-(4-chlorophenyl)-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2f). Following general procedure A, 3-(4-chlorophenyl)-5-phenylisoxazole
(1.0 mmol, 255 mg, 1.00 eq.) was irradiated for 20 h at 70 °C. After column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 97:3 → 80:20)
the title compound (110 mg, 0.22 mmol, 45%) was afforded as a colorless
solid. Rf = 0.50 (2:1 cyclohexane/ethyl acetate). Mp: 233 – 235 °C. IR
(ATR): 3259, 1599, 1490, 1419, 1277, 1255, 1094, 911, 833, 731. 1H NMR,
COSY, NOESY (600 MHz, CDCl3): δ 10.72 (s, 1H, NH), 7.64 – 7.58 (m,
2H, C-2‘‘‘ + C-6‘‘‘), 7.50 – 7.45 (m, 2H, C-2‘‘‘‘ + C-6‘‘‘‘), 7.36 – 7.32 (m, 3H,
C-2‘ + C-6‘ + C-4‘‘‘), 7.29 (m, 1H, C-4‘), 7.23 (m, 2H, C-3‘‘‘‘ + C-5‘‘‘‘), 7.19
– 7.14 (m, 2H, C-3‘‘‘ + C-5‘‘‘), 7.05 (m, 2H, C-3‘ + C-5‘), 6.82 (m, 4H,
C-2‘‘-3‘‘ + C-5‘‘-6‘‘). 13C NMR, HSQC, HMBC (151 MHz, CDCl3) δ 193.9
(C-4-CO), 187.8 (C-2-CO), 137.6 (C-1’’’), 137.1 (C-5), 137.0 (C-1’), 135.1
(C-4’’’’), 133.1 (C-4’’ + C-4’’’), 132.6 (C-3), 131.8 (C-2’’ + C-6’’ + C-4’),
131.6 (C-1’’), 129.7 (C-2’’’ + C-6’’’), 129.4 (C-2’’’’ + C-6’’’’), 129.2 (C-2’
+ C-6’), 129.0 (C-3’’’’ + C-5’’’’), 128.5 (C-1’’’’), 128.3 (C-2), 128.2 (C-3’’’
+ C-5’’’), 127.6 (C-3’ + C-5’ + C-3’’ + C-5’’), 123.3 (C-4). MS (ESI):
m/z = 496.3 [M + H]+. HRMS (ESI) calcd for [C30H20Cl2NO2]+ 496.0863,
found 496.0863.
1718, 1609, 1400, 1275, 1190, 1106, 732, 697. 1H NMR, COSY, NOESY
(600 MHz, CDCl3): δ 10.80 (s, 1H, NH), 7.96 – 7.92 (m, 2H, H-3‘‘‘‘ + H-5‘‘‘‘),
7.62 (m, 4H, H-2‘‘‘‘ + H-6‘‘‘‘), 7.53 – 7.49 (m, 2H, H-3‘‘ + H-5‘‘), 7.39 – 7.35
(m, 2H, H-2‘ + H-6‘), 7.29 (m, 1H, H-4‘‘‘), 7.21 (m, 1H, H-4‘), 7.14 (m, 2H,
H-3‘‘‘ + H-5‘‘‘), 7.03 – 6.96 (m, 4H, H-2‘‘ + H-6‘‘ + H-3‘ + H-5‘), 3.90 (s, 3H,
C-4‘‘‘‘-COOCH3), 3.80 (s, 3H, C-4‘‘-COOCH3). 13C NMR, HSQC, HMBC
(151 MHz, CDCl3) δ 193.7 (C-4-CO), 187.8 (C-2-CO), 166.7
(C-4’’-COOCH3), 166.4 (C-2’’-COOCH3), 137.9 (C-1’’), 137.5 (C-1’’’),
136.9 (C-1’), 136.7 (C-5), 134.2 (C-1’’’’), 133.3 (C-4’’’), 132.5 (C-3), 132.1
(C-4’), 130.6 (C-2’’ + C-6’’), 130.2 (C-4’’’’), 130.0 (C-3’’’’ + C-5’’’’), 129.7
(C-2’’’ + C-5’’’), 129.2 (C-2’ + C-6’), 128.7 (C-2, C-3’’ + C-5’’), 128.3 (C-4’’),
128.2 (C-3’’’ + C-5’’’), 127.9 (C-2’’’’ + C-6’’’’), 127.7 (C-3’ + C-5’), 123.9
(C-4), 52.3 (C-4’’’’-CO2CH3), 52.1 (C-4’’-CO2CH3). MS (ESI): m/z = 544.3
[M + H]+. HRMS (ESI) calcd for [C34H25NO6]+ 544.1755, found 544.1764.
(3,5-Di-(2-naphthyl)-1H-pyrrole-2,4-diyl)bis(phenylmethanone) (2j).
Following general procedure B, 3-(2-naphthyl)-5-phenylisoxazole (1.0
mmol, 271 mg, 1.00 eq.) was irradiated for 48 h at 70 °C. After column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 95:5 → 80:20)
and preparative HPLC (eluent: acetonitrile/water 65:35, tr = 14 – 16 min)
the title compound (128 mg, 0.24 mmol, 48%) was obtained as a colorless
solid. Rf = 0.22 (4:1 cyclohexane/ethyl acetate). Mp: 203 – 206 °C. IR
(ATR): 3255, 3056, 1598, 1450, 1262, 907, 819, 728, 695, 645. 1H NMR,
COSY, NOESY (600 MHz, CDCl3): δ 10.41 (s, 1H, NH), 8.09 (d, 4JHH = 1.8
Hz, 1H, H-1‘‘‘‘), 7.83 – 7.78 (m, 2H, H-5‘‘‘‘ + H-8‘‘‘‘), 7.77 (d, 3JHH = 8.5 Hz,
(3,5-Di-(4-bromophenyl)-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2g).
Following
general
procedure
A,
3-(4-bromophenyl)-5-
phenylisoxazole (1.0 mmol, 298 mg, 1.00 eq.) was irradiated for 20 h at
70 °C. After column chromatography (SiO2, eluent: cyclohexane/ethyl
acetate, 96:4 → 80:20) the title compound (102 mg, 0.18 mmol, 35%) was
obtained as a yellow solid. Rf = 0.25 (4:1 cyclohexane/ethyl acetate). Mp:
244 – 245 °C. IR (ATR): 3257, 1598, 1450, 1253, 1042, 1009, 907, 828,
730, 696. 1H NMR, COSY, NOESY (600 MHz, CDCl3): δ 10.80 (s, 1H, NH),
3
1H, H-4‘‘‘‘), 7.72 – 7.68 (m, 2H, H-2‘‘‘ + H-6‘‘‘), 7.61 (dd, JHH = 8.5 Hz,
4JHH = 1.8 Hz, 1H, H-3‘‘‘‘), 7.57 – 7.54 (m, 1H, H Naph(C-3)), 7.52 – 7.46 (m,
2H, H-6‘‘‘‘ + H-7‘‘‘‘), 7.45 – 7.42 (m, 2H, H-1‘‘ + HNaph(C-3)), 7.41 – 7.37 (m,
2H, H-2‘ + H-6‘), 7.34 – 7.27 (m, 4H, H-4‘‘ + HNaph(C-3)), 7.18 – 7.12 (m, 1H,
H-4‘‘‘), 7.05 (m, 3H, H-3‘‘‘ + H-5‘‘‘ + H-3‘‘‘‘), 6.95 – 6.90 (m, 1H, H-4‘), 6.78
(m, 2H, H-3‘ + H-5‘). 13C NMR, HSQC, HMBC (151 MHz, CDCl3) δ 194.4
(C-4-CO), 187.8 (C-2-CO), 138.0 (C-1‘‘‘), 137.9 (C-5), 137.3 (C-1‘), 133.8
(C-3), 133.1 (C-4a‘‘‘‘ + C-8a‘‘‘‘), 132.8 (C-4‘‘‘), 132.5 (CNaph(C-3)), 131.9
(C-4a‘‘), 131.3 (C-4‘), 130.6 (C-2‘‘), 130.3 (C-1‘‘), 129.7 (C-2‘‘‘ + C-6‘‘‘),
129.0 (C-2‘ + C-6‘), 128.7 (C-4‘‘‘‘), 128.4 (C-2, C-8‘‘‘‘), 128.3 (C-3‘‘‘), 128.0
(C-3‘‘‘ + C-5‘‘‘), 127.7 (C-5‘‘‘‘ + CNaph(C-3)), 127.6 (C-2‘‘‘‘), 127.4 (C-1‘‘‘‘),
127.3 (C-3‘ + C-5‘), 127.2 (CNaph(C-3)), 127.0 + 126.7 (C-6‘‘‘‘ + C-7‘‘‘‘), 126.9
(CNaph(C-3)), 125.8 (CNaph(C-3)), 125.6 (CNaph(C-3)), 125.6 (CNaph(C-3)), 123.7
(C-4). MS (ESI): m/z = 528.3 [M + H]+. HRMS (ESI) calcd for [C38H26NO2]+
528.1958, found 528.1952.
7.65
–
7.59 (m, 2H, H-2‘‘‘
+
H-6‘‘‘), 7.44 – 7.36 (m, 4H,
7.28 (m, 4H,
H-2‘‘‘‘ + H-3‘‘‘‘ + H-5‘‘‘‘
+
H-6‘‘‘‘), 7.36
–
H-2‘ + H-4‘ + H-6‘ + H-4‘‘‘), 7.16 (m, 2H, H-3‘‘‘ + H-5‘‘‘), 7.06 (m, 2H,
H-3‘ + H-5‘), 6.96 (m, 2H, H-2‘‘ + H-6‘‘), 6.77 (m, 2H, H-3‘‘ + H-5‘‘). 13C
NMR, HSQC, HMBC (151 MHz, CDCl3) δ 193.8 (C-4-CO), 187.8 (C-2-CO),
137.6 (C-1’’’), 137.1 (C-5), 137.0 (C-1’), 133.2 (C-4’’’), 132.7 (C-1’’), 132.1
(C-3’’ + C-5’’), 132.0 (C-3 + C-3’’’’ + C-5’’’’), 131.8 (C-4’), 130.6 (C-2’’
+ C-6’’), 129.7 (C-2’’’ + C-6’’’), 129.6 (C-2’’’’ + C-6’’’’), 129.2 (C-2’ + C-6’),
129.0 (C-1’’’’), 128.3 (C-2), 128.2 (C-3’’’ + C-5’’’), 127.7 (C-3’ + C-5’), 123.4
(C-4’’’’), 123.2 (C-4), 121.4 (C-4’’). MS (ESI): m/z = 584.3 [M(2 × 79Br)
+ H]+, 586.1 [M(79Br + 81Br) + H]+, 588.0 [M(2 × 81Br) + H]+. HRMS (ESI)
calcd for [C30H20[79Br]2NO2]+ 583.9855, found 583.9850.
(3,5-Di-(4-(trifluoromethyl)phenyl)-1H-pyrrole-2,4-
(3,5-Di-(4-methoxyphenyl)-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2k). Following general procedure B, 3-(2-naphthyl)-5-phenylisoxazole
(1.0 mmol, 251 mg, 1.00 eq.) was irradiated for 40 h at 70 °C. After column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 94:6 → 70:30)
the title compound (29 mg, 0.10 mmol, 19%) was obtained as a colorless
solid. Rf = 0.08 (4:1 cyclohexane/ethyl acetate). Mp: 207 – 209 °C. IR
(ATR): 3263, 1608, 1574, 1505, 1420, 1248, 1177, 913, 834, 697. 1H NMR,
COSY, NOESY (600 MHz, CDCl3): δ 10.15 (s, 1H, NH), 7.67 – 7.61 (m,
2H, H-2‘‘‘ + H-6‘‘‘), 7.48 – 7.45 (m, 2H, H-2‘‘‘‘ + H-6‘‘‘‘), 7.41 – 7.39 (m, 2H,
H-2‘ + H-6‘), 7.30 – 7.26 (m, 1H, H-4‘‘‘), 7.21 (m, 1H, H-4‘), 7.16 – 7.11 (m,
2H, H-3‘‘‘ + H-5‘‘‘), 7.05 – 6.99 (m, 2H, H-3‘ + H-5‘), 6.86 – 6.83 (m, 2H,
H-2‘‘ + H-4‘‘), 6.82 – 6.79 (m, 2H, H-2‘‘‘‘ + H-6‘‘‘‘), 6.39 – 6.35 (m, 2H,
H-3‘‘ + H-5‘‘), 3.77 (s, 3H, C-4‘‘‘‘-OCH3), 3.59 (s, 3H, C-4‘‘-OCH3). 13C NMR,
HSQC, HMBC (151 MHz, CDCl3) δ 194.5 (C-4-CO), 187.6 (C-2-CO),
160.1 (C-4’’’’), 158.5 (C-4’’), 138.1 (C-5), 138.0 (C-1’’’), 137.5 (C-1’), 133.9
(C-3), 132.7 (C-4’’’), 131.9 (C-2’’ + C-6’’), 131.2 (C-4’), 129.8 (C-2’’’
+ C-6’’’), 129.3 (C-2’’’’ + C-6’’’’), 129.2 (C-2’ + C-6’), 127.9 (C-3’’’ + C-5’’’),
127.6 (C-2), 127.4 (C-3’ + C-5’), 125.6 (C-1’’), 122.8 (C-1’’’’), 122.6 (C-4),
114.2 (C-3’’’’ + C-5’’’’), 112.9 (C-3’’ + C-5’’), 55.3 (C-4’’’’-OCH3), 55.1
(C-4’’-OCH3). MS (ESI): m/z = 488.3 [M + H]+. HRMS (ESI) calcd for
[C32H26NO4]+ 488.1856, found 488.1855. Crystals suitable for X-ray
crystallography could be obtained by recrystallization of 2k from
dichloromethane/diethyl ether (1:4).
diyl)bis(phenylmethanone) (2h). Following general procedure A, 3-(4-
(trifluoromethyl)phenyl)-5-phenylisoxazole (1.0 mmol, 289 mg, 1.00 eq.)
was irradiated for 20 h at 70 °C. After column chromatography (SiO2,
eluent: cyclohexane/ethyl acetate, 96:4 → 80:20) and preparative HPLC
(eluent: acetonitrile/water 70:30, tr = 11 – 13 min) the title compound (109
mg, 0.19 mmol, 40%) was obtained as a colorless solid. Rf = 0.22
(4:1 cyclohexane/ethyl acetate). Mp: 213 – 215 °C. IR (ATR): 3256, 1652,
1607, 1321, 1166, 1123, 1067, 905, 731, 697. 1H NMR, COSY, NOESY
3
(600 MHz, CDCl3): δ 11.10 (s, 1H, NH), 7.68 (d, JHH = 8.1 Hz, 2H,
H-2‘‘‘‘ + H-6‘‘‘‘), 7.63 – 7.60 (m, 2H, H-2‘‘‘ + H-6‘‘‘), 7.50 (d, 3JHH = 8.1 Hz,
2H, H-3‘‘‘‘ + H-5‘‘‘‘), 7.32 (m, 1H, H-4‘‘‘), 7.29 – 7.27 (m, 2H, H-2‘ + H-6‘),
7.24 (m, 1H, H-4‘), 7.18 – 7.13 (m, 2H, H-3‘‘‘ + H-5‘‘‘), 7.09 (d, 3JHH = 8.1
3
Hz, 2H, H-3‘‘ + H-6‘‘), 7.03 (d, JHH = 8.1 Hz, 2H, H-2‘‘ + H-6‘‘), 7.00 (m,
2H, H-3‘ + H-5‘). 13C NMR, HSQC, HMBC (151 MHz, CDCl3) δ 193.5
(C-4-CO), 187.9 (C-2-CO), 137.5 (C-1‘‘‘), 136.9 (C-5 + C-1‘), 136.8 (C-1‘‘),
133.4 (C-1‘‘‘‘), 133.3 (C-4‘‘‘), 132.5 (C-3), 132.0 (C-4‘), 130.9 (C-2‘‘ + C-6‘‘),
130.7 (q, 2JCF = 32.7 Hz, C-4‘‘‘‘), 129.7 (C-2‘‘‘ + C-6‘‘‘), 129.0 (C-2‘ + C-6‘),
129.0 (q, 2JCF = 32.7 Hz, C-4‘‘), 128.0 (C-2) 128.6 (C-2‘‘‘‘ + C-6‘‘‘‘), 128.2
(C-3‘‘‘ + C-5‘‘‘), 127.6 (C-3‘ + C-5‘), 125.7 (q, 3JCF = 3.7 Hz, C-3‘‘‘‘ + C-5‘‘‘‘),
3
1
124.3 (q, JCF = 3.7 Hz, C-3‘‘ + C-5‘‘), 123.8 (2 × q, JCF = 272.1 Hz,
C-4‘‘-CF3 + C-4‘‘‘‘-CF3). 19F NMR (282 MHz, CDCl3) δ – 64.01 (s), – 64.19
(s). MS (ESI): m/z = 564.2 [M + H]+. HRMS (ESI) calcd for [C32H20F6NO2]+
564.1393, found 564.1394.
(3,5-Di-(2-furanyl)-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2l).
(3,5-Di-(4-(methoxylcarbonyl)phenyl)-1H-pyrrole-2,4-
Following general procedure B, 3-(2-furanyl)-5-phenylisoxazole (1.0 mmol,
211 mg, 1.00 eq.) was irradiated for 30 h at 70 °C. After column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 94:6 → 70:30)
and preparative HPLC (eluent: acetonitrile/water 55:45, tr = 11 – 13 min)
the title compound (88 mg, 0.22 mmol, 43%) was obtained as a colorless
solid. Rf = 0.22 (4:1 cyclohexane/ethyl acetate). Mp: 188 – 191 °C. IR
(ATR): 3247, 3061, 1611, 1598, 1494, 1431, 1267, 943, 920, 729, 697. 1H
NMR, COSY, NOESY (600 MHz, CDCl3): δ 10.15 (s, 1H, NH), 7.69 (m, 2H,
diyl)bis(phenylmethanone) (2i). Following general procedure A, 3-(4-
(methoxycarbonyl)phenyl)-5-phenylisoxazole (1.0 mmol, 279 mg, 1.00
eq.) was irradiated for 30 h at 70 °C. After column chromatography (SiO2,
eluent: cyclohexane/ethyl acetate, 85:15 → 60:40) and preparative HPLC
(eluent: acetonitrile/water 55:45, tr = 12 – 14 min) the title compound (90
mg, 0.17 mmol, 34%) was obtained as a colorless solid. Rf = 0.17
(4:1 cyclohexane/ethyl acetate). Mp: 250 – 253 °C. IR (ATR): 3327, 3000,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901176
European Journal of Organic Chemistry
FULL PAPER
H-2‘‘‘ + H-6‘‘‘), 7.58 (m, 2H, H-2‘ + H-6‘), 7.44 (m, 1H, H-5‘‘‘‘), 7.37 (m, 2H,
H-4‘ + H-4‘‘‘), 7.23 (m, 4H, H-3‘ + H-5‘ + H-3‘‘‘ + H-5‘‘‘ ), 6.84 (m, 1H, H-
3‘‘‘‘), 6.73 (m, 1H, H-5‘‘), 6.41 (m, 1H, H-4‘‘‘‘), 6.00 (m, 1H, H-3‘‘), 5.90 (m,
1H, H-4‘‘). 13C NMR, HSQC, HMBC (151 MHz, CDCl3) δ 193.0 (C-4-CO),
186.8 (C-2-CO), 145.3 (C-2’’), 144.3 (C-2’’’’), 143.1 (C-5’’’’), 142.2 (C-5’’),
137.9 + 137.8 (C-1’ + C-1’’’), 132.7 (C-4’’’), 131.7 (C-4’), 129.3 (C-2’’’ + C-
6’’’), 128.6 (C-5), 128.5 (C-2’ + C-5’), 128.1 + 128.0 (C-3’ +C-5’ + C-3’’’ +
C-5’’’), 127.2 (C-2), 121.9 (C-3), 120.3 (C-4), 112.3 (C-4’’’’), 111.9 (C-3’’),
111.1 (C-3’’’’), 111.0 (C-4’’). MS (ESI): m/z = 408.2 [M + H]+. HRMS (ESI)
calcd for [C26H18NO4]+ 408.1230, found 408.1238.
7.68 – 7.63 (m, 2H, H-2‘‘‘ + H-6‘‘‘), 7.56 – 7.50 (m, 2H, H-2‘‘‘‘ + H-6‘‘‘‘), 7.42
– 7.38 (m, 2H, H-2‘ + H-6‘), 7.35 – 7.31 (m, 3H, H-3‘‘‘‘-5‘‘‘‘), 6.97 – 6.93 (m,
1H, H-4‘‘), 6.93 – 6.87 (m, 4H, H-2‘‘-3‘‘ + H-5‘‘-6‘‘), 6.79 (m, 2H,
H-3‘‘‘ + H-5‘‘‘), 6.70 – 6.64 (m, 2H, H-3‘ + H-5‘). 13C NMR, HSQC, HMBC
(151 MHz, CDCl3) δ 192.6 (C-4-CO), 186.3 (C-2-CO), 165.47 (d,
1JCF = 254.0 Hz, C-4‘‘‘), 164.7 (d, 1JCF = 254.0 Hz, C-4‘), 138.2 (C-5), 134.3
(d, 4JCF = 2.9 Hz, C-1‘‘‘), 133.6 (C-3), 133.4 (d, 4JCF = 2.9 Hz, C-1‘), 132.9
(C-1‘‘), 132.4 (d, JCF = 9.3 Hz, C-2‘‘‘ + C-6‘‘‘), 131.7 (d, JCF = 9.3 Hz,
C-2‘ + C-6‘), 130.7 (C-2‘‘ + C-6‘‘), 130.1 (C-1‘‘‘‘), 129.1 (C-4‘‘‘‘), 128.9
(C-3‘‘‘‘ + C-5‘‘‘‘), 128.0 (C-2‘‘‘‘ + C-6‘‘‘‘), 127.8 (C-2), 127.6 (C-3‘‘ + C-5‘‘),
127.3 (C-4‘‘), 122.9 (C-4), 115.1 (d, 2JCF = 22.0 Hz, C-3‘‘‘ + C-5‘‘‘), 114.6
(d, 2JCF = 22.0 Hz, C-3‘ + C-5‘). 19F NMR (282 MHz, CDCl3) δ = – 106.49
(tt, J = 8.4, 5.5 Hz), – 108.14 (tt, J = 8.4, 5.5 Hz). MS (ESI): m/z = 464.2
[M + H]+. HRMS (ESI) calcd for [C30H20F2NO2]+ 464.1457, found 464.1455.
3
3
(3,5-Dimethyl-1H-pyrrole-2,4-diyl)bis(phenylmethanone)
(2m).
Following general procedure A, 3-methyl-5-phenylisoxazole (1.0 mmol,
159 mg, 1.00 eq.) was irradiated for 20 h at 70 °C. After column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 90:10 → 75:25)
the title compound (100 mg, 0.20 mmol, 41%) was obtained as a colorless
solid. Rf = 0.13 (4:1 cyclohexane/ethyl acetate). Mp: 193 – 195 °C. IR
(ATR): 3269, 1597, 1550, 1500, 1420, 1284, 952, 911, 734, 700. 1H NMR,
COSY (400 MHz, CDCl3): δ 9.69 (s, 1H, NH), 7.79 – 7.72 (m, 2H,
H-2‘‘‘ + H-6‘‘‘), 7.72 – 7.65 (m, 2H, H-2‘ + H-6‘), 7.58 – 7.51 (m, 2H,
H-4‘ + H-4‘‘‘), 7.50 – 7.42 (m, 4H, H-3‘ + H-5‘ H-3‘‘‘ + H-5‘‘‘), 2.25 (s, 3H,
C-5-CH3), 1.90 (s, 3H, C-3-CH3). 13C NMR, HSQC, HMBC (101 MHz,
CDCl3) δ 194.1 (C-4-CO), 187.2 (C-2-CO), 140.3 (C-1‘), 139.5 (C-1‘‘‘),
139.0 (C-5), 132.5 (C-4‘‘‘), 131.9 (C-4‘), 130.3 (C-2), 129.3 (C-2‘‘‘ + C-6‘‘‘),
128.6 (C-2‘ + C-3‘ + C-5‘ + C-6‘ + C-3‘‘‘ + C-5‘‘‘), 128.1 (C-3), 124.2 (C-4),
13.9 (C-5-CH3), 13.7 (C-3-CH3). MS (ESI): m/z = 304.2 [M + H]+. The
spectroscopic data is in accordance to the literature.[26]
3,5-Diphenyl-1H-pyrrole-2,4-diyl)bis((4-methoxyphenyl)methanone)
(2p).
Following
general
procedure
A,
3-phenyl-5-(4-
methoxyphenyl)isoxazole (1.0 mmol, 251 mg, 1.00 eq.) was irradiated for
30 h at 70 °C. After automatic column chromatography (SiO2, eluent:
cyclohexane/ethyl acetate, 85:15 → 70:30) and reverse phase column
chromatography (SiO2-C18, eluent: acetonitrile/water, 50:50 → 90:10) the
title compound (179 mg, 0.37 mmol, 73%) was obtained as a colorless
solid. Rf = 0.16 (4:1 cyclohexane/ethyl acetate). Mp: 223 – 225 °C. IR
(ATR): 3251, 1592, 1572, 1422, 1249, 1112, 1024, 842, 726, 697. 1H NMR,
COSY, NOESY (600 MHz, CDCl3): δ 10.71 (s, 1H, NH), 7.64 (d, 3JHH = 8.4
Hz, 2H, H-2‘‘‘ + H-6‘‘‘), 7.57 – 7.52 (m, 2H, H-2‘‘‘‘ + H-6‘‘‘‘), 7.43 (d, 3JHH
=
8.4 Hz, 2H, H-2‘ + H-6‘), 7.32 – 7.27 (m, 3H, H-3‘‘‘‘-5‘‘‘‘), 6.96 – 6.91 (m,
2H, H-2‘‘ + H-6‘‘), 6.91 – 6.85 (m, 3H, H-3‘‘-5‘‘), 6.59 (d, 3JHH = 8.4 Hz, 2H,
H-3‘‘‘ + H-5‘‘‘), 6.49 (d, 3JHH = 8.4 Hz, 2H, H-3‘ + H-5‘), 3.68 + 3.69 (2  s,
6H, C-4‘-OCH3 + C-4‘‘‘-OCH3). 13C NMR, HSQC, HMBC (151 MHz, CDCl3)
δ 193.3 (C-4-CO), 186.7 (C-2-CO), 163.2 (C-4’’’), 162.4 (C-4’), 136.7 (C-5),
133.5 (C-1’’’’), 132.7 (C-3), 132.2 (C-2’’’ + C-6’’’), 131.9 (C-2’ + C-6’), 131.1
(C-1’’’), 130.7 (C-2’’ + C-6’’), 130.5 (C-1’’), 129.8 (C-1’), 128.8 (C-3’’’’
+ C-5’’’’), 128.6 (C-4’’’’), 128.1 (C-2), 127.7 (C-2’’’’ + C-6’’’’), 127.5 (C-3’’
+ C-5’’), 126.7 (C-4’’), 123.1 (C-4), 113.2 (C-3’’’ + C-5’’’), 112.8 (C-3’
+ C-5’), 55.3 (C-4‘-OCH3 + C-4‘‘‘-OCH3). MS (ESI): m/z = 488.3 [M + H]+.
HRMS (ESI) calcd for [C32H26NO4]+ 488.1856, found 488.1860.
Additionally
(3,6-Dimethylpyrazine-2,5-diyl)bis(phenylmethanone)
(8m) (57 mg, 0,18 mmol, 36%) was obtained as yellow solid. Rf = 0.22
(4:1 cyclohexane/ethyl acetate). Mp: 170 – 172 °C. IR (ATR): 2978, 1670,
1596, 1548, 1449, 1220, 921, 697. 1H NMR, COSY (400 MHz, CDCl3):
δ 9.69 (s, 1H, NH), 7.79 – 7.72 (m, 2H, H-2‘‘‘ + H-6‘‘‘), 7.72 – 7.65 (m, 2H,
H-2‘ + H-6‘), 7.58 – 7.51 (m, 2H, H-4‘ + H-4‘‘‘), 7.50 – 7.42 (m, 4H,
H-3‘ + H-5‘ H-3‘‘‘ + H-5‘‘‘), 2.25 (s, 3H, C-5-CH3), 1.90 (s, 3H, C-3-CH3).
13C NMR, HSQC, HMBC (101 MHz, CDCl3) δ 196.1 (C-5-CO), 191.5
(C-2-CO), 164.0 (C-2 + C-5), 162.1 (C-3 + C-6), 135.8 (C-1‘‘‘), 135.1
(C-4‘‘‘), 135.0 (C-1‘), 133.9 (C-4‘), 131.1 (C-2‘ + C-6‘), 129.5 (C-3‘‘‘ + C-5‘‘‘),
129.4 (C-2‘‘‘ + C-6‘‘‘), 128.5 (C-3‘ + C-5‘), 22.8 (C-2-CH3 + C-5-CH3). MS
(ESI): m/z = 317.2 [M + H]+. The spectroscopic data are in accordance to
the literature.[27]
(3,5-Diphenyl-1H-pyrrole-2,4-diyl)bis((4-methoxycarbonylphenyl)
methanone) (2q). Following general procedure A, 3-phenyl-5-(4-
methoxycarbonylphenyl)isoxazole (1.0 mmol, 279 mg, 1.00 eq.) was
irradiated for 20 h at 70 °C. After column chromatography (SiO2, eluent:
cyclohexane/ethyl acetate, 90:10 → 70:30) and and preparative HPLC
(eluent: acetonitrile/water 55:45, tr = 14 – 17 min) the title compound (126
mg, 0.23 mmol, 46%) was obtained as a colorless solid. Rf = 0.23
(4:1 cyclohexane/ethyl acetate). Mp: 253 – 256 °C. IR (ATR): 3273, 2952,
1723, 1604, 1421, 1278, 1107, 917, 743, 650. 1H NMR, COSY, NOESY
(600 MHz, CDCl3): δ 10.31 (s, 1H, NH), 7.79 – 7.74 (m, 2H, H-3‘‘‘ + H-5‘‘‘),
7.68 – 7.63 (m, 4H, H-3‘ + H-5‘ + H-2‘‘‘ + H-6‘‘‘), 7.55 – 7.50 (m, 2H, H-
2‘‘‘‘ + H-6‘‘‘‘), 7.43 – 7.37 (m, 2H, H-2‘ + H-6‘), 7.32 (m, 3H, H-3‘‘‘‘-5‘‘‘‘),
6.91 – 6.88 (m, 2H, H-2‘‘ + H-6‘‘), 6.87 – 6.85 (m, 1H, H-4‘‘), 6.81 (m, 2H,
H-3‘‘ + H-5‘‘), 3.87 (s, 3H, C-4‘-COOCH3), 3.84 (s, 3H, C-4‘‘‘-COOCH3).
13C NMR, HSQC, HMBC (151 MHz, CDCl3) δ 193.1 (C-4-CO), 186.8 (C-
2-CO), 166.2 (C-4‘-COOCH3), 166.2 (C-4‘’’-COOCH3), 141.3 (C-1’’’),
141.1 (C-1’), 139.2 (C-5), 134.5 (C-3), 133.2 (C-4’’’), 132.5 (C-1’’), 132.1
(C-4’), 130.6 (C-2’’ + C-6’’), 129.9 (C-1’’’’), 129.5 (C-2’’’ + C-6’’’), 129.4 (C-
4’’’’), 129.1 (C-3’’’ + C-5’’’), 128.9 (C-3’ + C-5’), 128.6 (C-2’ + C-6’ + C-3’’’’
+ C-5’’’’), 128.2 (C-2’’’’ + C-6’’’’), 127.9 (C-2), 127.6 (C-3’’ + C-5’’), 127.5
(C-4’’), 122.9 (C-4), 52.4 + 52.3 (C-4‘-COOCH3, C-4‘‘‘-COOCH3). MS
(ESI): m/z = 544.3 [M + H]+. HRMS (ESI) calcd for [C3H25NO6Na]+
566.1574, found 566.1561.
(3,5-Diphenyl-1H-pyrrole-2,4-diyl)bis((4-(tert-
butyl)phenyl)methanone) (2n). Following general procedure A,
3-phenyl-5-((4-tert-butyl)phenyl)isoxazole (1.0 mmol, 277 mg, 1.00 eq.)
was irradiated for 20 h at 70 °C. After column chromatography (SiO2,
eluent: cyclohexane/ethyl acetate, 97:3 → 85:15) the title compound (146
mg, 0.28 mmol, 57%) was obtained as
a yellow solid. Rf = 0.34
(4:1 cyclohexane/ethyl acetate). Mp: 224 – 227 °C. IR (ATR): 3258, 2963,
1601, 1445, 1419, 1262, 1108, 907, 732, 696. 1H NMR, COSY, NOESY
(600 MHz, CDCl3): δ 10.33 (s, 1H, NH), , 7.56 – 7.55 (m, 2H, H-2‘‘‘ + H-6‘‘‘),
7.55 – 7.53 (m, 2H, H-2‘‘‘‘ + H-6‘‘‘‘), 7.31 (m, 2H, H-2‘ + H-6‘), 7.30 – 7.27
(m, 3H, H-3‘‘‘‘-5‘‘‘‘), 7.14 – 7.11 (m, 2H, H-3‘‘‘ + H-5‘‘‘), 7.00 – 6.96 (m, 2H,
H-3‘ + H-5‘), 6.90 – 6.87 (m, 2H, H-2‘‘ + H-6‘‘), 6.83 – 6.77 (m, 3H, H-3‘‘-5‘‘),
1.18 (s, 9H, C-4‘-C(CH3)3), 1.17 (s, 9H, C-4‘‘‘-C(CH3)3). 13C NMR, HSQC,
HMBC (151 MHz, CDCl3) δ 194.1 (C-4-CO), 187.7 (C-2-CO), 156.3 (C-4’’’),
154.7 (C-4’), 137.5 (C-5), 135.4 (C-1’’’), 134.5 (C-1’), 133.9 (C-3), 133.8
(C-1’’), 130.7 (C-2’’ + C-6’’), 130.4 (C-1’’’’), 129.8 (C-2’’’ + C-6’’’), 129.0
(C-2’ + C-6’), 128.8 (C-3’’’’ + C-5’’’’), 128.7 (C-4’’’’), 128.2 (C-2), 127.9
(C-2’’’’ + C-6’’’’), 127.2 (C-3’’ + C-5’’), 126.5 (C-4’’), 124.8 (C-3’’’ + C-5’’’),
124.3 (C-3’ + C-5’), 123.4 (C-4), 34.9 (C-4‘‘‘-C(CH3)3), 34.8 (C-4‘-C(CH3)3),
30.9 ((C-4‘-C(CH3)3 + C-4‘‘‘-C(CH3)3). MS (ESI): m/z = 540.4 [M + H]+.
HRMS (ESI) calcd for [C38H38NO2]+ 540.2897, found 540.2896.
(1,1’-(3,5-diphenyl-1H-pyrrole-2,4-diyl)dihexan-1-one) (2t). Following
general procedure A, 3-phenyl-5-pentylisoxazole (1.0 mmol, 215 mg, 1.00
eq.) was irradiated for 96 h at 70 °C. After column chromatography (SiO2,
eluent: cyclohexane/ethyl acetate, 96:4 → 75:25) and the title compound
(57 mg, 0.14 mmol, 46%) was obtained as a yellow oil. Rf = 0.54
(4:1 cyclohexane/ethyl acetate). IR (ATR): 3270, 1597, 1576, 1550, 1420,
1284, 952, 911, 734, 700. 1H NMR, COSY, NOESY (600 MHz, CDCl3):
δ 9.60 (s, 1H, NH), 7.55 – 7.51 (m, 2H, H-2‘‘‘‘ + H-6‘‘‘‘), 7.48 – 7.40 (m, 6H,
H-3‘‘-5‘‘ + H-3‘‘‘‘-5‘‘‘‘), 7.39 (m, 2H, H-2‘‘ + H-6‘‘), 2.16 – 2.07 (m, 4H,
H-2‘ + H-2‘‘‘), 1.46 – 1.31 (m, 4H, H-3‘ + H-5‘), 1.15 – 1.03 (m, 4H,
H-4‘ + H-4‘‘‘), 1.01 – 0.90 (m, 4H, H-3‘ + H-3‘‘‘), 0.81 – 0.72 (m, 6H,
(3,5-Diphenyl-1H-pyrrole-2,4-diyl)bis((4-fluorophenyl)methanone)
(2o). Following general procedure A, 3-phenyl-5-(4-fluorophenyl)isoxazole
(1.0 mmol, 239 mg, 1.00 eq.) was irradiated for 25 h at 70 °C. After column
chromatography (SiO2, eluent: cyclohexane/ethyl acetate, 95:5 → 80:20)
and preparative HPLC (eluent: acetonitrile/water 60 : 40, tr = 10.5 – 13.5
min) the title compound (126 mg, 0.27 mmol, 54%) was afforded as
colorless solid. Rf = 0.22 (4:1 cyclohexane/ethyl acetate). Mp:
204 – 208 °C. IR (ATR): 3262, 3066, 1597, 1420, 1260, 1230, 1186, 905,
731, 697. 1H NMR, COSY, NOESY (600 MHz, CDCl3): δ 10.38 (s, 1H, NH),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901176
European Journal of Organic Chemistry
FULL PAPER
H-5‘ + H-5‘‘‘). 13C NMR, HSQC, HMBC (151 MHz, CDCl3) δ 200.4
(C-4-CO), 192.5 (C-2-CO), 137.8 (C-5), 134.9 + 131.1 (C-1‘‘ + C-1‘‘‘‘),
131.2 (C-3), 130.1 (C-2‘‘ + C-6‘‘), 129.2 (C-4‘‘‘‘), 128.9 (C-2), 128.7
(C-2‘‘‘‘ + C-6‘‘‘‘), 128.6 + 128.3 (C-3‘‘ + C-5‘‘ + C-3‘‘‘‘ + C-5‘‘‘‘), 128.2 (C-4‘‘),
125.2 (C-4), 43.3 (C-1‘‘‘), 39.4 (C-1‘), 31.3 (C-3‘), 31.1 (C-3‘‘‘), 24.4 (C-2‘),
24.0 (C-2‘‘‘), 22.2 (C-4‘ + C-4‘‘‘), 13.9 (C-5‘ + C-5‘‘‘). MS (ESI): m/z = 416.4
[M + H]+. HRMS (ESI) calcd for [C34H25NO6Na]+ 416.2584, found 416.2594.
Additionally 3-phenyl-5-pentylisoxazole (75 mg, 0.35 mmol, 35%) was
recovered.
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A
mixture of 15N-labeled azirine 1s (0.3 mmol, 67 mg, 1.0 eq), unlabeled
azirine 1m (0,6 mmol, 96 mg, 2.0 eq.) and copper(2-ethylhexanoate)2 (0.1
mmol, 31 mmol, 0.1 eq.) in anhydrous acetonitrile (9 mL, c = 0.1 M) was
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purified using automatic flash column chromatography (SiO2, eluent:
cyclohexane/ethyl acetate, 86:4 → 75:25) and preparative HPLC (eluent:
acetonitrile/water 45 : 55, tr = 27 – 28 min) to afford the title compound
(8.9 mg, 0.02 mmol, 3%) as colorless lyophilizate. Rf = 0.33
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130.1 (C-2‘‘ + C-6‘‘), 129.2 (C-4‘‘‘‘), 128.9 (C-2), 128.7 (C-2‘‘‘‘ + C-6‘‘‘‘),
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22.2 (C-4‘ + C-4‘‘‘), 13.9 (C-5‘ + C-5‘‘‘). MS (ESI): m/z = 366.2 [M + H]+.
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20 – 22 min) afforded an impure sample of 15N-(3-phenyl-5-methyl-1H-
pyrrol-2,4-diyl)bis(phenylmethanone) (2u) as a colorless lyophilizate
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Acknowledgments
Financial support of the DFG (Grant Op90/12-1) is gratefully
acknowledged. The authors would like to thank Dr. Johannes C.
Liermann (Mainz) for NMR spectroscopy, Dr. Christopher Kampf
(Mainz) for mass spectrometry and Dr. Dieter Schollmeyer for
X-ray crystallography. CCDC-1946259 and CCDC-1946260 are
containing the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/data_request/cif
Keywords: Photochemistry • Small ring systems • Nitrogen
heterocycles • Copper • Reaction mechanisms
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This article is protected by copyright. All rights reserved.

10.1002/ejoc.201901176
European Journal of Organic Chemistry
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Strain and Release*
Jan Paternoga and Till Opatz*
Page No. – Page No.
A Copper-Catalyzed Synthesis of
Pyrroles through Photochemically
Generated Acylazirines
A protocol for the synthesis of highly substituted 2,4-Diacypryrroles via an copper-
catalyzed ring strain releasing dimerization reaction was developed. The pyrroles are
synthesized combing UV-photochemistry and metal-catalyzed follow up reaction in
an one-pot system. To match the rates of the thermal and the photoinduced step, an
internal temperature control was established.
*one or two words that highlight the emphasis of the paper or the field of the study
[a]
Institute of Organic Chemistry, Johannes Gutenberg Unive
Duesbergweg 10-14, 55128 Mainz, Germany
E-mail: opatz@uni-mainz.de
https://ak-opatz.chemie.uni-mainz.de/prof-dr-till-opatz/
This article is protected by copyright. All rights reserved.
Supporting information for this article is given via a link at t
the document.