Visible Light-Induced Regioselective Cycloaddition of Benzoyl Azides and Alkenes to Yield Oxazolines

Article abstract of DOI:10.1021/acs.joc.9b00568

Visible light catalysis allows the regioselective synthesis of oxazolines in high yields. The mild photosensitized manifold leverages the intermolecular formation of oxazolines with a wide functional group tolerance on both benzoyl azides and alkenes part

Full text of DOI:10.1021/acs.joc.9b00568

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Article
Visible-Light Induced Regioselective Cycloaddition
of Benzoyl Azides and Alkenes to Oxazolines
Peter Bellotti, Julien Brocus, Fatima El Orf, Mohamed Selkti,
Burkhard König, Philippe Belmont, and Etienne BRACHET
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 16 Apr 2019
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Page 1 of 9
The Journal of Organic Chemistry
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Visible-Light Induced Regioselective Cycloaddition of Benzoyl
Azides and Alkenes to Yield Oxazolines
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§ ‡ ,
†
Peter Bellotti,
Julien Brocus, ¥ ‡ Fatima El Orf, ¥ ‡ Mohamed Selkti, Burkhard König, § Philippe
Belmont, ¥ and Etienne Brachet ¥ *
§
.
University of Regensburg Faculty of Chemistry and Pharmacy, Institute of Organic
Chemistry, Universitätsstraße 31, 93053 Regensburg, Germany.
¥
.
Université Paris Descartes, Université Sorbonne Paris Cité (USPC), Faculté de Pharmacie de
Paris, UMR CNRS 8638 (COMETE), 4 avenue de l’Observatoire, 75006 Paris, France.
†
.
Université Paris Descartes, Université Sorbonne Paris Cité (USPC), Faculté de Pharmacie de Paris, UMR CNRS
8015 (LCRB), 4 avenue de l'Observatoire, 75006 Paris, France
‡ Contributed equally to this work
Supporting Information Placeholder
R4
R3
R2
R4
N2
O
O
R3
2+
R2
Ru(bpy)3
N
N3
+
R1
R1
het
het
Visible Light Reaction
Easy Access to Oxazoline Derivatives
- Mild reaction conditions
C-N
C-O
bond
- One step formation of a
and a
R1 R2 R3 R4
- Various
,
,
,
ABSTRACT: Visible-light catalysis allows the regioselective synthesis of oxazolines in high yields. The mild photosensitized
manifold leverages the intermolecular formation of oxazolines with a wide functional group tolerance on both partners,
benzoyl azides and alkenes. Mechanistic investigations suggest the sensitization of the azide moiety as the key activation step.
Introduction
efforts should be made in order to expand the scope of this
tool and better understand the involved mechanisms. In
particular visible-light sensitization mechanisms have
remained relatively underdeveloped compared to
photoredox ones. In this direction, we report the first
visible-light sensitized reaction to build oxazolines. We
aimed at avoiding highly pre-functionalized substrates as
precursors by envisioning the use of easily accessible
benzoyl azides derivatives to generate reactive nitrogen
species. Under visible-light irradiation, dinitrogen was
released as the only by-product. In particular, we wondered
whether the in-situ generated acyl nitrene could cyclize on
alkenyl partners to yield oxazolines. In this respect, only
two UV-promoted examples, limited to fullerene or enolate
derivatives as alkenyl partners have been reported.7 In the
former case − restricted to C60 systems − a two-steps
Five-membered ring heterocycles represent one of the
most prevalent subclasses of heterocycles.1 Among them,
the oxazoline core is an attractive target, because of its
presence in many valuable synthetic and natural
derivatives (e.g. patelamide A2, useful in polymer material
sciences3 and as chiral ligands4). Despite the development
of a plethora of strategies to build oxazolines, harsh
conditions, intramolecular strategies and expensive
catalysts are often required, thus limiting their
applicability.5 Consequently, innovative approaches to
build the oxazoline core are to be sought.
Over the last decade, visible-light photocatalysis has
emerged into a powerful tool for the formation of C-C, C-N
or C-O bonds under mild conditions, using low energy light
6
sources at room temperature. Nevertheless, substantial
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Page 2 of 9
procedure involving an intermediate aziridine was used
(Entry 4). The ruthenium catalyst proved to be the only one
able to perform the efficient sensitization of benzoyl azide
1a. Decreasing the amount of catalyst from 2.5 mol% to 1
mol% caused a reduction of the yield to 58% (Entry 5).
under high dilution conditions (11% yield),7b while in the
latter synthetically useful yields were obtained on a
severely limited selection of ortho-substituted aroyl-azides
in the presence of cyclic enol-ethers.7a
1
2
3
4
5
6
7
8
Table 1: Optimization of the reaction conditions.
O
O
O
R1
Ir
Ru
X
N
N
Troc
N3
R
R1
H
2.5 mol % Ru(bpy)3Cl2
O
ref (8)
ref (9)
O
2 equiv H3PO4
DMSO [0.1M]
R2
N3
+
N
9
Ru
24 h, 455 nm @ rt
1a
2a
3a
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entry
1
variation from standard conditions a
-
yield b
78%
0%
R3
N
R4
O
R2
R1
9
2
[Ir(ppy)2(dtbbpy)]+, Blue LED, CH2Cl2
Ir(ppy)3 instead of Ru(bpy)3Cl2
Eosin Y instead of Ru(bpy)3Cl2
1 mol % of Ru(bpy)3Cl2
PTSA instead of H3PO4
25 mol % of H3PO4
X
This work : Regioselective oxazoline formation
3
traces
traces
58%
25%
10%
65%c
0%
4
Scheme 1: Visible-light activation of acyl azides.
5
Analogously, reactions of acyl azides under visible-light
catalysis are rare: to the best of our knowledge, only a
photo-induced amidation reaction using benzoyl azides and
electron-rich arenes (Scheme 1, top left), 8 the aziridination
of alkenes using Troc-N3 reagent from Yoon et al. (Scheme
1, top right)9a and a cascade cyclization towards oxindoles9b
have been reported.
6
7
8
Sunlight instead of Blue LED
No light
9
10
11
12
No catalyst
0%
No H3PO4
0%
Herein, we disclose a distinctly new reactive pathway of
benzoyl azides to selectively form oxazolines (Scheme 1,
bottom). In contrast to the previous report by Nicewicz et
al.,10 this work represents the first general method to build
the oxazoline nucleus via an intermolecular process under
visible-light irradiation. The convergent nature of the
strategy − as well as the straightforward synthesis of
benzoyl azides from the corresponding benzoyl chloride or
anhydride in the presence of sodium azide − make the
process particularly appealing for the synthesis of highly-
decorated structures. During the screening process of our
previously reported C-H amidation reaction, the low-
yielding cyclization of a putative carbenium ion was
observed in two selected cases.8 In this work, we
systematically exploited the intermolecular cyclization to
afford both carbocyclic and heterocyclic-decorated
oxazolines.
UV (254 nm) in MeCN @ 0°C
traces
a Standard conditions: reactions were performed with 1a (0.31
mmol), 2a (1.55 mmol), Ru(bpy)3Cl2·6H2O (2.5 mol %, 78
μmol), and H3PO4 (2 equiv, 0.62 mmol) in 3 mL of DMSO was
irradiated with blue LED for 24 h. isolated yields. Sunlight
irradiation without ruthenium catalyst led to a complex
mixture.
b
c
Switching H3PO4 to other acids such as p-toluene sulfonic
acid (PTSA) or diminishing the amount of H3PO4 (25 mol%)
had a dramatic effect on the yield of the reaction (25% and
10%, respectively, Entries 6 and 7). Different control
experiments confirmed that light, ruthenium catalysis and
acid additive were crucial for the formation of the oxazoline
3a (Entries 9, 10 and 11). Moreover, residual starting
material was detected after reduced reaction times (12 h),
while irradiation of 48 hours caused a slight decrease in the
yields. Interestingly, the replacement of the LED irradiation
with sunlight afforded the desired product in a good 65%
yield (Entry 8), but only in the presence of the Ru-catalyst
(Entry 8). Finally, a control experiment under the
previously reported UV irradiation conditions (254 nm)
was performed, but only traces of product can be detected,
thus confirming the specific reactivity under visible-light
conditions (Entry 12).
Results and Discussion
We started our investigation using the following
conditions: Ru(bpy)3Cl2·6H2O (2.5 mol %) as photocatalyst,
H3PO4 (2 equiv) as an additive and 5 equivalents of the
alkene in DMSO (0.1 M) under blue light irradiation (455
nm) at room temperature.8 As a model reaction p-
methylbenzoyl azide 1a was reacted with α-methylstyrene
2a in order to form the corresponding oxazoline derivative
(5-methyl-5-phenyl-2-(p-tolyl)-4,5-dihydrooxazole 3a). We
were pleased to observe the total consumption of 1a giving
3a as the product in 78% yield (Table 1, entry 1).
Intriguingly, no conversion of the starting material was
observed under Yoon’s aziridination conditions9. The same
results were obtained using several different
photocatalysts, such as fac-Ir(ppy)3 (Entry 3) and Eosin Y
With these optimized conditions in hand (2.5 mol% of
Ru(bpy)3Cl2·6H2O, 2 equivalents of H3PO4 and 5 equivalents
of alkene in DMSO (0.1 M) under blue light irradiation
(~455 nm) at room temperature), we then investigated the
scope of the synthetic manifold. At first, the substitution
pattern on the benzoyl moiety was screened with both
electron-donating and withdrawing groups (Scheme 2).
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The Journal of Organic Chemistry
The parent benzoyl azide showed good conversion (Scheme
corresponding furyl-oxazoline 3i or pyrido-oxazoline 3j in
64 % and 49 % yield, respectively. This demonstrates that
the reaction allows the synthesis of highly-decorated poly-
heterocyclic scaffolds, which are highly prevalent in
1
2
3
4
5
6
7
8
2, 3b, 73%) and electron-donating groups, such as in p-
methyl and 3,4,5-trimethoxy-derivatives 3a and 3c were
tolerated (78% and 69% yield, respectively). Gratifyingly,
compound 3a was obtained in a good 69% yield when the
reaction was performed on millimolar scale.
pharmaceutically-active
compounds.1
Finally,
the
terephthaloyl diazide 1k reagent afforded compound 3k in
62 % yield. Next, the alkenyl scope was investigated: mono-,
di- and even tri-substituted alkenes bearing both electron-
withdrawing and donating groups were found to be suitable
coupling partners (Scheme 3).
2a
9
O
O
2.5 mol % Ru(bpy)3Cl2
2 equiv H3PO4, DMSO
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N3
N
R
R
R2
24 h, 455 nm @ rt
1a-1k
3a-3k
X
X
R1
R3
R1
N
R4
R2
R3
R4
2a-m
O
O
2.5 mol % Ru(bpy)3Cl2
2 equiv H3PO4, DMSO
O
O
O
N
N3
O
R
R
N
1a-1n
4a-4n
N
24 h, 455 nm @ rt
X
X
3c
, 69%
3a
, 78%
3b
, 73%
O
1mmol, 69%
O
O
O
O
O
O
O
O
O
O
O
O
O
O
N
O
O
N
N
N
3e
N
N
3f
, 0%
3d
, 47%
, 53%
4a
4b
4c
, 55%
O
, 47%
S
, 56%
Cl
Cl
F3C
F3C
NO2
O
O
O
O
Cl
O
O
N
O
N
N
N
N
N
O
3g
, 58%
3h
3i
, 64%
, 0%
4e
, 48%
4d
4f
, 56%
, 30%
Cl
Br
O
N
O
O
N
O
N
Cl
O
O
N
N
3j
, 49%
3k
, 62%
N
4g
, 45%
X-ray
structure
4h
, 62%
Scheme 2: Benzoyl azide scope of the photocatalyzed
oxazoline formation. Reaction conditions: 1a–k (0.34
mmol, 1 equiv), alkene (1.7 mmol, 5 equiv), H3PO4 (0.68 mmol,
2 equiv) and Ru(bpy)3Cl2.6H2O (8.5 µmol, 2.5 mol %) in dry
DMSO (0.1 M) were irradiated with blue light under N2. Isolated
yield. All the compounds were obtained as racemic mixtures.
O
S
O
N
O
O
R
O
N
N
4i
R'
O
4j, 55%
, 56%
R = R' = OMe, 4k
R = H, R' = Me 4l
, 38%
, 32%
R
(only cis isomer)
O
However, reaction of o-methylbenzoyl azide met with
frustration, probably due to the steric hindrance of the
methyl group. Electron-withdrawing groups on the benzoyl
azides caused a decrease in reactivity towards α-
methylstyrene, as observed for derivatives bearing a p-
trifluoromethyl group 3d (47%) or a p-chloro group 3e
(53%). 3-Bromobenzoyl azide provided product 3g in 58%,
which could be further functionalized using metal-catalyzed
cross-coupling reactions. In the case of the m-nitro
derivative, no formation of the desired product 3f was
observed. Also, pivaloyl azide did not react to provide 3h,
most likely due to a non-favourable energy transfer
between the π-π systems. In particular, the available energy
of the long-lived [Ru(bpy)32+]* triplet state (46 kcal mol-1) is
presumably sufficient for energy transfer to aryl-acyl azides
(Etr = 41 kcal mol-1), but not for alkyl-acyl azides.8
Remarkably, heterobenzoyl azides were also efficient
partners under the reaction conditions, providing the
(only cis isomer)
O
O
O
O
O
N
N
O
O
Cl
4m
, 68%
(only cis isomer)
4n
, 0%
Scheme 3: Scope of the alkenyl partner. Reaction
conditions: 1a–n (0.34 mmol, 1 equiv), alkene (1.7 mmol, 5
equiv), H3PO4 (0.68 mmol, 2 equiv) and Ru(bpy)3Cl2.6H2O (8.5
µmol, 2.5 mol %) in dry DMSO (0.1 M) were irradiated with
blue light under N2. Isolated yield. All the compounds were
obtained as racemic mixtures.
Mono-substituted
alkenes
−
such
as
3,4,5-
trimethoxystyrene − reacted with various benzoyl azides
(p-Cl, p-CF3, p-Me) yielding compounds 4a, 4b and 4c in
43%, 47% and 56% yield, respectively. p-Methylbenzoyl
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azide gave 4d in 56% yield, as well as the derivative 4e in
Page 4 of 9
experiments corroborate this hypothesis.8 We therefore
suggest the following mechanistic manifold: benzoyl azide I
is excited by the photocatalyst, providing the triplet benzoyl
azide II, which loses dinitrogen to give the corresponding
benzoyl nitrene III. This intermediate could then follow two
pathways: without acid, III is readily converted into the
isocyanate IV via Curtius rearrangement, whereas in the
presence of acid the protonated benzoyl nitrene V is most
likely formed.13 Computational studies suggest that a triplet
acyl-nitrenium is less prone towards the rearrangement
than its singlet counterpart.13b
1
2
3
4
5
6
7
8
48% yield when coupled with 4,5-dimethoxystyrene and 3-
vinylthiophene. Additionally, p-methylbenzoyl azide and
3,4,5-trimethoxybenzoyl azide produced respectively 4i
and 4j in 56% and 55% yield. Moreover − electron-
withdrawing groups were tolerated − as shown by using o-
chlorostyrene, which was coupled with p-chloro benzoyl
azide and p-methylbenzoyl azide giving products 4f and 4g
in 30% and 45% yield. To our delight, the regiochemistry of
the oxazoline formation was confirmed by the crystal
structure of compound 4g (highlighted in Scheme 3),
allowing us to correct our previous report.8 Then we
focused our attention on αα’ and in αβ disubstituted
alkenes. First, we evaluated the reaction of a sterically-
congested 1,1’-diarylethene with p-methylbenzoyl azide,
which afforded the corresponding product 4h (62% yield).
α,β-disubstituted alkenes, such as anethole and indene,
were also found to be compatible: p-methylbenzoyl azide 1a
afforded compound 4i (56%) and indene gave products 4k
and 4l, albeit in moderate yields. Cyclohex-1-en-1-yl
acetate, a trisubstituted enol-ester, gave the corresponding
product 4m (68% yield), proving that aliphatic alkenes
could also act as reaction partners. Notably, all α,β
disubstituted alkenes coupled diastereoselectively with
benzoyl azides, yielding exclusively the cis addition
products (See S.I.). Finally, tetraphenyl ethene was tested in
this reaction, but did not provide the desired product 4n.
Our reaction conditions have also been tested with alkynes
(i.e. phenylacetylene, octyne, pentyne or propargyl alcohol)
in order to reach oxazole derivatives. Unfortunately, alkynyl
substrates were not reactive under the reaction conditions.
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O
Optimized conditions
O
O
N3
O
O
2 eq. TEMPO
eq. A
eq. B
N
O
1c
2a
6
(68%)
O
O
O
O
O
N
Optimized conditions
or Acid
No oxazoline formation
7
O
Curtius rearrangement
O
[Ru(bpy)3]2+
O
*
2+
•
[Ru(bpy)3
]
N
N2
*
O
IV
N3
N3
Triplet
photo-
Without acid
Dinitrogen
extrusion
II
I
sensitization
O
N
III
H3PO4
Nitrene
protonation
O
Proposed
Sensitized
Mechanism
N
O
VIII
N
H
V
O
O
Proton
loss
-H+
Nucleophilic attack
on the nitrenium
O
O
O


O
2a
O
O
O
2.5 mol % Ru(bpy)3Cl2
2 equiv H3PO4, DMSO
O
Ring
closure
N
H
O
O
O
O
N
H
N3
N
VII
VI
24 h, 455 nm @ rt
1c
5
, 65%
0.34 mmol scale
O
O
Scheme 5: Mechanistic investigations (upper) and
proposed mechanism (lower).
Scheme 4: Application to the synthesis of a bioactive
compound
The electron-rich alkene reacts regioselectively with the
protonated intermediate V to give the carbocation
intermediate VI. The formation of a stabilized benzylic
carbenium intermediate − which spontaneously cyclizes to
form the protonated oxazoline VII − could explain the
observed regiochemistry. The intermediate VII − after loss
of a proton − liberates the desired product VIII. Despite the
fact that a catalytic amount of phosphoric acid was in
principle needed, a sub-stoichiometric amount of acid
caused the yield to drop from 78% to 10%. This may suggest
that the excess of acid can inhibit the formation of side
products, such as the isocyanate IV. Under Yoon’s
conditions (Scheme 1), the selective aziridine formation
from troc-N3 was observed for almost all alkenes; only a few
electron-rich alkenes gave mixtures of aziridines and
oxazolines, which may result from the acidic ring opening
To demonstrate the synthetic applicability of the
reported method, an anti-aggregant platelet agent was
synthesized.11 Trimethoxybenzoyl azide 1c and the
corresponding
3,4,5-trimethoxystyrene
converted
regioselectively under the reaction conditions to the
desired product 5 in 65% yield (Scheme 4).
6-11
Based on literature data
and experiments, we propose
the following mechanism. The presence of an acid additive
was found to be crucial to obtain the desired products.
Without acid, the slow conversion of the benzoyl azide into
an isocyanate derivative was observed.8 A sensitization
pathway − rather than a radical mechanism − is supported
by the absence of reaction inhibition upon addition of two
equivalents of TEMPO (Scheme 5, upper, eq. A).
Additionally, cyclic voltammetry and Stern-Volmer
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reaction from aziridine to oxazoline.14 Therefore − to
exclude the involvement of an aziridine intermediate − our
conditions were applied to an acyl-aziridine derivative 7
(Scheme 5, upper, eq. B). Interestingly − no oxazoline
formation could be detected, while the starting aziridine
was recovered − thus hinting against its involvement in the
catalytic process.
The blue light irradiation was performed using high-power
1
2
3
4
5
6
7
8
LEDs Philips LUXEON® Rebel (1W, λmax = 450±10 nm, 145 lm
@700mA). Irradiation occurred from the bottom of each vials
at a distance of 2 cm. Each vial was cooled to 20°C by a cryostat
plug connected to to a custom-made aluminum cooling block
(see S.I.), equipped with a magnetic stirrer.
General procedure for the synthesis of benzoyl azides
In conclusion − a new synthetic access to the oxazoline
skeleton via a regioselective visible-light photoinduced
cyclization − yielding a wide range of polysubstituted
oxazolines was reported. A protonated triplet nitrene −
which reacts with the alkene via a formal 1,3-cycloaddition
process − was proposed as an intermediate. Overall, our
The appropriate benzoyl chloride (5 mmol, 1.0 equiv) was
dissolved in 7 mL of acetone. After cooling the reaction mixture
to 0°C using ice bath, sodium azide (358 mg, 5.5 mmol, 1.1
equiv) in 7 mL of water is added dropwise at 0°C. The resulting
mixture was stirred for 2 hours at 0°C, then transferred to a
separating funnel. The organic layer was collected, dried on
magnesium sulfate and evaporated under reduced pressure
(temperature of the bath should not exceed 30°C) to give the
corresponding acyl azide. Caution: It is known that these
reagents are potentially explosive and must be handle
with care and store in the fridge. It is also recommended to
prepare acyl azides at maximum 10 mmol scale to limit
risks.
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mechanistic investigations suggested
a sensitization
mechanism rather than a radical pathway via electron
transfer. While we observed that electron-rich alkenes and
benzoyl azide derivatives converted best in this reaction, a
wide range of functional groups such as acetals, esters or
halogen substituents, as well as heterocyclic scaffolds,
proved to be compatible with our reaction conditions. We
successfully applied our procedure to the synthesis of a
biologically active compound and its wider use in synthetic
chemistry may be easily envisaged.
General procedure for the reaction of benzoyl azide with
alkenes
In a 5 mL snap vial, sealed with a PTFE septum and equipped
with PTFE-coated magnetic stirring bar, Ru(bpy)3Cl2·6H2O,
(6.4 mg, 8.5 µmol, 2.5 mol%), benzoyl azide 1a-m (0.34 mmol,
1 equiv), H3PO4 (67 mg, 0.68 mmol, 2 equiv) and alkene (1.7
mmol, 5 equiv) were dissolved in dry DMSO (0.09 mmol/mL)
and the resulting mixture was degassed by “freeze-pump-
thaw” cycles (×2) via a syringe needle. The vial was irradiated
through the flat bottom-side of the snap vial using blue LEDs.
After 24 hours of irradiation (the consumption of starting
material was checked by TLC, using cyclohexane:AcOEt 8:2 as
eluant), the pressure in the vial is released by a needle and the
reaction mixture was transferred to separating funnel, diluted
with ethyl acetate (15 ml) and washed with 15 mL of water. The
aqueous layer was extracted three times with ethyl acetate (15
ml each time). The combined organic layers were dried over
MgSO4, filtered and concentrated under reduced pressure.
Purification of the crude product was achieved by flash column
chromatography on silica using cyclohexane/ethyl acetate as
eluent.
EXPERIMENTAL SECTION
General Information
1H NMR spectra were recorded on a Bruker Avance 300 or 400
MHz spectrometer in CDCl3 or acetone-d6. The residual non-
deuterated solvent signal was used as reference, relative to the
tetramethylsilane signal. 13C NMR were recorded on a Bruker
Avance 300 or 400 MHz (respective resonance frequency: 75
MHz and 101 MHz) under broadband 1H decoupling in CDCl3 or
acetone-d6. The residual non-deuterated solvent signal was
used as reference, relative to the tetramethylsilane signal. In
the case of 19F spectra, the absolute referencing to the 1H
spectrum was used, as suggested by IUPAC. High resolution
mass spectrometry (HRMS) analyses were performed at the
mass spectrometry laboratory of UMR 8638 of the Faculty of
Pharmacy, Université Paris Descartes. 1H NMR data are
reported as follows: chemical shift (ppm), multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, quint = quintet, dd =
doublet of doublets, ddd = doublet of doublet of doublets, td =
triplet of doublets, qd = quartet of doublets, m = multiplet, br.
s. = broad singlet), coupling constants (Hz) and number of
protons.
Compound
3a:
5-methyl-5-phenyl-2-(p-tolyl)-4,5-
dihydrooxazole. Yield: 78% (0.23 mmol, 56 mg), (69% on
1mmol scale of starting material giving 173mg of 3a) Rf = 0.30
(cyclohexane:AcOEt 8:2). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, acetone-d6) δ 7.92 (d, J = 7.9 Hz, 2H),
7.48 (d, J = 8.5 Hz, 2H), 7.38 (t, J = 7.5 Hz, 2H), 7.34-7.24 (m, 3H),
4.13 (d, J = 14.9 Hz, 1H), 4.04 (d, J = 14.8 Hz, 1H), 2.40 (s, 3H),
1.77 (s, 3H). 13C{1H} NMR (75 MHz, acetone-d6) δ 163.1, 147.2,
142.6, 130.1, 129.9, 129.5, 129.4, 129.0, 128.2, 125.3, 87.4, 70.0,
28.7, 21.7. HRMS (TOF ESI+) m/z: [M+H+] Calcd. for C17H18NO
252.1388; Found 252.1386.
All reactions were monitored by thin-layer chromatography
using Merck silica gel plates 60 F254; visualization was
accomplished with short wavelength UV light (254 nm) and/or
staining
with
appropriate
stains
(anisaldehyde,
orthophosphomolybdic acid). Standard flash-chromatography
was performed using Macherey-Naghel silica gel of particle size
40−63 μm according Still et al. Ru(bpy)3Cl2·6H2O was
purchased from Sigma Aldrich. All other commercially
available reagents and solvents were used without further
purification. Dry DMSO was stored in septum-sealed bottles in
presence of 4Å MS as withdrawn using a syringe under a
positive argon pressure.
Compound 3b: 5-methyl-2,5-diphenyl-4,5-dihydrooxazole,
Yield: 73% (0.20 mmol, 51 mg). Rf = 0.30 (cyclohexane:AcOEt
1
8:2). Physical aspect: yellow oil. Spectral data: H NMR (300
MHz, acetone-d6) δ 8.04 (d, J = 7.4 Hz, 2H), 7.54 – 7.46 (m, 5H),
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7.39 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.2 Hz, 1H), 4.15 (d, J = 14.7
Hz, 1H), 4.06 (d, J = 14.7 Hz, 1H), 1.78 (s, 3H). Spectral data are
in agreement with the literature. 15
MHz, acetone-d6) δ 161.3, 153.1, 150.0, 146.7, 136.1, 129.6,
129.1, 128.3, 125.3, 124.4, 88.0, 69.8, 28.6. HRMS (TOF ESI-)
m/z: [M-H-] Calcd. for C15H13N2O 237.1028; Found 237.1018.
Compound 3k: 1,4-bis(5-methyl-5-phenyl-4,5-dihydrooxazol-
2-yl)benzene. Yield: 62% (0.20 mmol, 51 mg). Rf = 0.15
(cyclohexane:AcOEt 8:2). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, acetone-d6) δ 8.15 (s, 4H), 7.53 – 7.47
(m, 4H), 7.40 (t, J = 7.5 Hz, 4H), 7.30 (t, J = 7.2 Hz, 2H), 4.20 (d, J
= 15.1 Hz, 2H), 4.11 (d, J = 15.1 Hz, 2H), 1.81 (s, 6H). 13C{1H}
NMR (75 MHz, acetone-d6) δ 162.4, 146.8, 131.8, 129.4, 129.0,
128.2, 125.1, 87.8, 69.8, 28.5. HRMS (TOF ESI+) m/z: [M+H+]
Calcd. for C26H25N2O2 397.1916; Found 397.1913.
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Compound
3c:
5-methyl-5-phenyl-2-(3,4,5-
trimethoxyphenyl)-4,5-dihydrooxazole, Yield: 69% (0.21
mmol, 70 mg). Rf = 0.11 (cyclohexane:AcOEt 8:2). Physical
aspect: yellow oil. Spectral data: 1H NMR (300 MHz, acetone-d6)
δ 7.55-7.45 (m, 2H), 7.39 (t, J = 7.4 Hz, 2H), 7.32 (s, 2H), 7.30 –
7.22 (m, 1H), 4.13 (d, J = 14.7 Hz, 1H), 4.04 (d, J = 14.7 Hz, 1H)
3.89 (s, 6H), 3.87 – 3.74 (m, 3H), 1.78 (s, 3H). 13C{1H} NMR (75
MHz, acetone-d6) δ 162.9, 154.4, 147.1, 142.2, 129.5, 128.2,
127.0, 125.3, 106.5, 87.7, 70.0, 60.8, 56.7, 28.5. HRMS (TOF
ESI+) m/z: [M+Na+] Calcd. for C19H21NO4Na 350.1368; Found
350.1364.
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Compound
4a:
2-(4-chlorophenyl)-5-(3,4,5-
trimethoxyphenyl)-4,5-dihydrooxazole. Yield: 55% (0.17
mmol, 59 mg). Rf = 0.12 (cyclohexane:AcOEt 8:2). Physical
aspect: yellow oil. Spectral data: 1H NMR (300 MHz, acetone-d6)
δ 8.00 (d, J = 8.5 Hz, 2H), 7.52 (d, J = 8.5 Hz, 2H), 6.72 (s, 2H),
5.69 (dd, J = 9.6, 8.4 Hz, 1H), 4.43 (dd, J = 15.1, 10.1 Hz, 1H), 3.98
– 3.86 (m, 1H), 3.81 (s, 6H), 3.72 (s, 3H). 13C{1H} NMR (75 MHz,
acetone-d6) δ 163.0, 154.8, 137.8, 137.8, 130.7, 129.6, 127.9,
106.6, 104.2, 82.3, 64.0, 60.6, 56.6. HRMS (TOF ESI+) m/z:
[M+Na+] Calcd. for C18H18NO435ClNa 370.0822; Found
370.0825.
Compound
3d:
5-methyl-5-phenyl-2-(4-
(trifluoromethyl)phenyl)-4,5-dihydrooxazole, Yield: 47%
(0.15 mmol, 45 mg). Rf = 0.30 (cyclohexane:AcOEt 9:1).
1
Physical aspect: yellow oil. Spectral data: H NMR (300 MHz,
acetone-d6) δ 8.25 (d, J = 7.6 Hz, 2H), 7.86 (d, J = 8.0 Hz, 2H),
7.55 – 7.46 (m, 2H), 7.46 – 7.36 (m, 2H), 7.35-7.25 (m, 1H), 4.21
(d, J = 15.2 Hz, 1H), 4.12 (d, J = 15.2 Hz, 1H), 1.87 – 1.79 (m, 3H).
19F{1H} NMR (282 MHz, acetone-d6) δ -63.44 (s). 13C{1H} NMR
(101 MHz, acetone-d6) δ 161.9, 146.7, 133.1 (q, J = 32.3 Hz, C-
CF3), 129.6, 129.5, 128.4, 126.4 (q, J = 3.8 Hz, CH-C-CF3), 125.2,
125.1 (q, J = 271.8 Hz, CF3), 117.7, 88.2, 69.9, 28.6. HRMS (TOF
ESI+) m/z: [M+Na+] Calcd. for C17H14F3NONa 328.0925; Found
328.0916.
Compound 3e: 2-(4-chlorophenyl)-5-methyl-5-phenyl-4,5-
dihydrooxazole. Yield: 53% (0.17 mmol, 45 mg). Rf = 0.23
(cyclohexane:AcOEt 8:2). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, acetone-d6) δ 8.04 (d, J = 8.8 Hz, 2H),
7.54 (d, J = 8.4 Hz, 2H), 7.48 (d, J = 7.7 Hz, 2H), 7.39 (t, J = 7.4 Hz,
2H), 7.29 (t, J = 7.2 Hz, 1H), 4.16 (d, J = 14.9 Hz, 1H), 4.07 (d, J =
15.0 Hz, 1H), 1.78 (s, 3H). 13C{1H} NMR (101 MHz, acetone-d6)
δ 162.1, 146.9, 137.8, 130.6, 129.7, 129.5, 128.3, 128.2, 125.2,
87.9, 69.9, 28.6. HRMS (TOF ESI+) m/z: [M+H+] Calcd. for
C16H1535ClNO 272.0842; Found 272.0845.
Compound
4b:
2-(4-(trifluoromethyl)phenyl)-5-(3,4,5-
trimethoxyphenyl)-4,5-dihydrooxazole. Yield: 47% (0.15
mmol, 57 mg). Rf = 0.18 (cyclohexane:AcOEt 6:4). Physical
1
aspect: amorphous orange solid. Spectral data: H NMR (300
MHz, acetone-d6) δ 8.20 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.2 Hz,
2H), 6.74 (s, 2H), 5.74 (t, J = 9.1 Hz, 1H), 4.48 (dd, J = 15.3, 10.1
Hz, 1H), 4.10 – 3.95 (m, 1H), 3.81 (s, 6H), 3.72 (s, 3H). 19F{1H}
NMR (282 MHz, acetone-d6) δ -63.5. 13C{1H} NMR (101 MHz,
acetone-d6) δ 162.7, 154.8, 139.3, 137.6, 132.8 (d, J = 32.5 Hz,
C-CF3), 132.7, 129.7, 126.4 (q, J = 3.8 Hz, CH-C-CF3), 125.0 (q, J
= 271.8 Hz, CF3) 104.2, 82.5, 64.0, 60.6, 56.6. HRMS (TOF ESI+)
m/z: [M+Na+] Calcd. for C19H18F3NO4Na 404.1086; Found
404.1070.
Compound 4c: 2-(p-tolyl)-5-(3,4,5-trimethoxyphenyl)-4,5-
dihydrooxazole. Yield: 56% (0.18 mmol, 57 mg). Rf = 0.30
(cyclohexane:AcOEt 8:2). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, acetone-d6) δ 7.89 (d, J = 7.8 Hz, 2H),
7.29 (d, J = 7.8 Hz, 2H), 6.71 (s, 2H), 5.65 (t, J = 8.9 Hz, 1H), 4.40
(dd, J = 14.9, 9.8 Hz, 1H), 3.88 (dd, J = 15.2, 8.2 Hz, 1H), 3.80 (s,
6H), 3.72 (s, 3H), 2.39 (s, 3H). 13C{1H} NMR (101 MHz, acetone-
d6) δ 163.8, 154.8, 142.5, 139.1, 138.2, 130.0, 129.0, 126.4,
104.1, 81.8, 64.0, 60.6, 56.6, 21.6 HRMS (TOF ESI+) m/z:
[M+Na+] Calcd. for C19H21NO4Na 350.1368; Found 350.1357.
Compound 4d: 5-(3,4-dimethoxyphenyl)-2-(p-tolyl)-4,5-
dihydrooxazole. Yield: 56% (0.18 mmol, 51.5 mg). Rf = 0.40
(cyclohexane:AcOEt 1:1). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, CDCl3) δ 7.89 (d, J = 8.2 Hz, 2H), 7.23
(d, J = 8.0 Hz, 2H), 7.04 – 6.71 (m, 3H), 5.78 – 5.44 (m, 1H), 4.43
(dd, J = 14.8, 10.1 Hz, 1H), 3.98 (dd, J = 14.8, 8.2 Hz, 1H), 3.87 (s,
3H), 3.85 (s, 3H), 2.39 (s, 3H). Spectral data are in accordance
with the literature. 17
Compound 3g: 2-(3-bromophenyl)-5-methyl-5-phenyl-4,5-
dihydrooxazole. Yield: 58% (0.18 mmol, 57 mg). Rf = 0.45
(cyclohexane:AcOEt 7:3). Physical aspect: yellow oil. Spectral
1
data: H NMR (300 MHz, CDCl3) δ 8.14 (s, 1H), 7.93 (d, J = 7.7
Hz, 1H), 7.57 (d, J = 7.4 Hz, 1H), 7.44 – 7.11 (m, 6H), 4.10 (s, 2H),
1.74 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3) δ 161.8, 145.2, 134.7,
134.3, 131.2, 130.0, 128.6, 127.5, 126.8, 124.3, 122.5, 87.2, 68.9,
28.2. HRMS (TOF ESI+) m/z: [M+H+] Calcd. for C16H1679BrNO
316.0337; Found 316.0335.
Compound
3i:
2-(furan-3-yl)-5-methyl-5-phenyl-4,5-
dihydrooxazole. Yield: 64% (0.20 mmol, 46 mg). Rf = 0.50
(cyclohexane:AcOEt 6:4). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, acetone-d6) δ 8.14 (s, 1H), 7.67 (s, 1H),
7.45 (d, J = 7.8 Hz, 2H), 7.38 (t, J = 7.6 Hz, 2H), 7.28 (t, J = 7.1 Hz,
1H), 6.81 (s, 1H), 4.06 (d, J = 14.6 Hz, 1H), 3.97 (d, J = 14.6 Hz,
1H), 1.74 (s, 3H). Spectral data are in agreement with the
literature. 16
Compound
3j:
5-methyl-5-phenyl-2-(pyridin-3-yl)-4,5-
Compound 4e: 2-(4-methylphenyl)-4-(thiophen-3-yl)-4,5-
dihydro-1,3-oxazole. Yield: 48% (0.15 mmol, 36 mg). Rf = 0.36
(cyclohexane:AcOEt 8:2). Physical aspect: amorphous yellow
solid. Spectral data: 1H NMR (300 MHz, acetone-d6) δ 7.86 (d, J
= 8.1 Hz, 2H), 7.50 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.14 (dd, J =
4.7, 1.1 Hz, 1H), 5.81 (dd, J = 9.7, 7.6 Hz, 1H), 4.36 (dd, J = 14.8,
10.0 Hz, 1H), 3.93 (dd, J = 14.8, 7.4 Hz, 1H), 2.38 (s, 3H) . 13C{1H}
dihydrooxazole. Yield: 49% (0.15 mmol, 37 mg). Rf = 0.16
(cyclohexane:AcOEt 6:4). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, acetone-d6) δ 9.18 (s, 1H), 8.74 (d, J =
4.9 Hz, 1H), 8.33 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 3H), 7.40
(t, J = 7.5 Hz, 1H), 7.31 (t, J = 6.6 Hz, 1H), 4.19 (d, J = 14.9 Hz,
1H), 4.10 (d, J = 15.0 Hz, 1H), 1.81 (s, 3H). 13C{1H} NMR (75
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The Journal of Organic Chemistry
NMR (75 MHz, acetone-d6) δ163.7, 143.6, 142.5, 130.0, 129.0,
data: 1H NMR (300 MHz, CDCl3) δ 7.54 (d, J = 7.2 Hz, 1H), 7.38 –
7.22 (m, 3H), 7.17 (d, J = 1.1 Hz, 2H), 6.03 (d, J = 8.0 Hz, 1H),
5.09 (td, J = 8.0, 1.9 Hz, 1H), 3.87 (s, 6H), 3.84 (s, 3H), 3.48 (dd,
J = 17.2, 7.8 Hz, 1H), 3.29 (d, J = 17.2 Hz, 1H). 13C{1H} NMR (75
MHz, CDCl3) δ 162.9, 153.0, 142.1, 140.8, 139.5, 129.9, 127.3,
126.4, 125.7, 123.1, 105.6, 86.9, 70.0, 61.0, 56.3, 39.6. HRMS
(TOF ESI+) m/z: [M+Na+] Calcd. for C19H19NO4Na 348.1212;
Found 348.1195.
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3
4
5
6
7
8
128.2, 128.0, 126.4, 123.0, 77.96, 63.0, 21.6. HRMS (TOF ESI+)
m/z: [M+H+] Calcd. for C14H14NOS 244.0796; Found 244.0784.
Compound 4f: 5-(2-chlorophenyl)-2-(4-chlorophenyl)-4,5-
dihydrooxazole. Yield: 30% (0.10 mmol, 26 mg). Rf = 0.60
(cyclohexane:AcOEt 9:1). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, acetone-d6) δ 8.04 (d, J = 8.4 Hz, 2H),
7.55 (d, J = 8.4 Hz, 2H), 7.52 – 7.42 (m, 2H), 7.42 – 7.31 (m, 2H),
6.02 (dd, J = 9.6, 8.1 Hz, 1H), 4.60 (dd, J = 15.2, 10.3 Hz, 1H), 3.82
(dd, J = 15.1, 7.3 Hz, 1H). 13C{1H} NMR (75 MHz, acetone-d6) δ
162.9, 140.1, 138.0, 130.8, 130.7, 130.4, 129.8, 129.5, 128.5,
127.6, 127.1, 79.0, 63.5. HRMS (TOF ESI-) m/z: [M-H-] Calcd. for
C15H10NO35Cl2 290.0139; Found 290.0153.
Compound
4l:
2-(p-tolyl)-3a,8b-dihydro-4H-indeno[2,1-
d]oxazole. Yield 32% (0.10 mmol, 25 mg). Rf = 0.19
(cyclohexane:AcOEt 8:2). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 1H), 7.48-
7.63 (m, 1H), 7.28-7.41 (m, 3H), 7.22 (d, J = 8.3 Hz, 1H), 6.08 (d,
J=8.0 Hz, 1H), 5.14 (ddd, J = 8.0, 7.9, 2.1 Hz, 1H),3.53 (dd, J =
17.2, 7.9 Hz, 1H), 3.35 (dd, J = 17.2, 2.1 Hz, 1H),2.41 (s, 3H).
13C{1H} NMR (75 MHz, CDCl3) δ 163.2, 142.1, 141.7, 139.7,
129.7, 129.0, 128.3, 127.3, 126.3, 125.6, 125.0, 86.5, 70.0, 39.6,
21.3. HRMS (TOF ESI+) m/z: [M+Na+] Calcd. for C17H15NONa
272.1051; Found 272.1049.
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Compound
4g:
5-(2-chlorophenyl)-2-(p-tolyl)-4,5-
dihydrooxazole. Yield: 45% (0.14 mmol, 38 mg). Rf = 0.28
(cyclohexane). Physical aspect: Orange crystalline solid. Single
crystals suitable for X-ray analysis were obtained by slow
1
evaporation with acetone as solvent. Spectral data: H NMR
(300 MHz, acetone-d6) δ 7.93 (d, J = 8.1 Hz, 2H), 7.52 – 7.42 (m,
2H), 7.39 – 7.34 (m, 2H), 7.32 (d, J = 8.0 Hz, 2H), 5.97 (dd, J =
10.2, 7.2 Hz, 1H), 4.57 (dd, J = 14.9 Hz, 10.2 Hz, 1H), 3.78 (dd, J
= 14.9, 7.2 Hz, 1H), 2.41 (s, 3H). 13C{1H} NMR (75 MHz, acetone-
d6) δ 163.7, 142.8, 140.5, 131.8, 130.6, 130.5, 130.3, 130.1,
129.1, 128.5, 127.0, 126.1, 78.5, 63.5, 21.6. HRMS (TOF ESI+)
m/z: [M+H+] Calcd. for C16H15NOCl 272.0842; Found 272.0833.
Compound
4m:
2-(3,4,5-trimethoxyphenyl)-4,5,6,7-
tetrahydrobenzo[d]oxazol-7a(3aH)-yl acetate. Yield 68% (0.20
mmol, 51 mg). Rf = 0.15 (cyclohexane:AcOEt 7:3). Physical
1
aspect: yellow oil. Spectral data: H NMR (300 MHz, CDCl3) δ
7.22 (s, 1H), 4.40 (t, J = 4.2 Hz, 1H), 3.91 (s, 6H), 3.88 (s, 3H),
2.10 (s, 2H), 1.91 – 1.83 (m, 4H), 1.62 (m, 2H), 1.58 – 1.46 (m,
4H). 13C{1H} NMR (101 MHz, CDCl3) δ 184.7, 168.9, 154.7,
153.2, 151.7, 105.7, 61.0, 56.5, 27.9, 25.3, 24.0, 22.5, 21.5, 16.8,
16.1. HRMS (TOF ESI+) m/z: [M+H+] Calcd. for C18H24NO6
350.1604; Found 350.1605.
Compound 4h: 5-(4-methoxyphenyl)-5-phenyl-2-(p-tolyl)-4,5-
dihydrooxazole. Yield: 62% (0.20 mmol, 51 mg). Rf = 0.33
(cyclohexane:AcOEt 8:2). Physical aspect: yellow oil. Spectral
data: 1H NMR (300 MHz, CDCl3) δ 7.99 (d, J = 8.0 Hz, 2H), 7.48 –
7.24 (m, 9H), 6.89 (d, J = 8.7 Hz, 2H), 4.69 (d, J = 14.6 Hz, 1H),
4.60 (d, J = 15.1 Hz, 1H), 3.81 (s, 3H), 2.43 (s, 3H). 13C{1H} NMR
(75 MHz, CDCl3) δ 163.2, 159.2, 144.7, 142.0, 136.5, 129.3,
128.5, 128.4, 127.7, 127.6, 126.0, 125.2, 113.9, 90.1, 69.2, 55.4,
21.7. HRMS (TOF ESI+) m/z: [M+H+] Calcd. for C23H22NO2
344.1651; Found 344.1655.
Compound
5:
2,5-bis(3,4,5-trimethoxyphenyl)-4,5-
dihydrooxazole. Yield 65% (0.20 mmol, 81 mg). Rf = 0.16
(cyclohexane:AcOEt 6:4). Physical aspect: amorphous yellow
1
solid. Spectral data: H NMR (300 MHz, acetone-d6) δ 7.28 (s,
2H), 6.72 (s, 2H), 5.66 (dd, J = 10.0, 8.6 Hz, 1H), 4.41 (dd, J =
14.9, 10.0 Hz, 1H), 3.95-3.90 (m, 1H), 3.87 (s, 6H), 3.82 (s, 3H),
3.79 (s, 3H), 3.73 (s, 3H). 13C{1H} NMR (101 MHz, acetone-d6) δ
163.6, 154.8, 154.3, 142.1, 139.2, 138.0, 124.2, 106.4, 104.2,
82.1, 64.0, 60.7, 60.6, 56.6, 56.6. HRMS (TOF ESI+) m/z:
[M+Na+] Calcd. for C21H25NO7Na 426.1529; Found 426.1519.
Compound 4i: 5-(4-methoxyphenyl)-4-methyl-2-(p-tolyl)-4,5-
dihydrooxazole. Yield: 56% (0.19 mmol, 53 mg). Rf = 0.10
(cyclohexane:AcOEt 8:2). Physical aspect: yellow oil. Spectral
data: 1H NMR (400 MHz, CDCl3) δ 7.90 (d, J = 8.2 Hz, 2H), 7.28
(d, J = 8.7 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H), 6.91 (d, J = 8.7 Hz,
2H), 5.03 (d, J = 7.9 Hz, 1H), 4.26 – 4.14 (m, 1H), 3.80 (s, 3H),
2.39 (s, 3H), 1.46 (d, J = 6.7 Hz, 3H. 13C{1H} NMR (101 MHz,
CDCl3) δ 162.9, 159.8, 141.8, 132.6, 129.1, 128.4, 127.3, 125.2,
114.2, 88.2, 70.7, 55.4, 21.6, 21.4. HRMS (TOF ESI+) m/z:
[M+Na+] Calcd. for C18H19NO2Na 304.1313; Found 304.1299.
Compound 4j: 4-(thiophen-3-yl)-2-(3,4,5-trimethoxyphenyl)-
4,5-dihydro-1,3-oxazole. Yield: 55% (0.19 mmol, 59 mg). Rf :
0.22 (cyclohexane:AcOEt 6:4). Physical aspect: orange oil.
Spectral data: 1H NMR (300 MHz, acetone-d6) δ 7.55 – 7.47 (m,
2H), 7.26 (s, 2H), 7.19-7.12 (m, 1H), 5.83 (dd, J = 9.9, 7.5 Hz, 1H),
4.37 (dd, J = 14.8 Hz, 9.9 Hz, 1H), 3.93 (dd, J = 14.9, 7.6 Hz, 1H),
3.86 (s, 6H), 3.78 (s, 3H). 13C{1H} NMR (101 MHz, acetone-d6) δ
163.6, 154.3, 143.5, 142.1, 128.0, 126.5, 124.3, 123.2, 106.5,
78.2, 63.0, 60.7, 56.6. HRMS (TOF ESI+) m/z: [M+Na+] Calcd. for
C16H17NO4SNa 342.0776; Found 342.0778.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information, containing full spectroscopic data
for all new compounds, cyclovoltammetry data, Stern-Volmer
analysis, X-ray crystallographic data and the corresponding CIF
file is available free of charge on the ACS Publications website.
AUTHOR INFORMATION
Corresponding Author
* e-mail: etienne.brachet@parisdescartes.fr
Author Contributions
The manuscript was written through contributions of all
authors. / All authors have given approval to the final version
of the manuscript. / ‡These authors contributed equally.
Notes
The authors declare no competing financial interest.
Compound 4k: 2-(3,4,5-trimethoxyphenyl)-3a,8b-dihydro-4H-
indeno[2,1-d]oxazole. Yield 38% (0.12 mmol, 39 mg). Rf = 0.18
(cyclohexane:AcOEt 6:4). Physical aspect: yellow oil. Spectral
ACKNOWLEDGMENT
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This work was supported by a joint CNRS and INCa fellowship
reactions, Addition of photochemically generated acylnitrenes
to C60. Synthesis of fulleroaziridines and thermal
rearrangement to fullerooxazoles, Tetrahedron, 1995, 51,
2543. For examples with little synthetic utility (8% yield) see:
c) Clauss, K.-U.; Buck, K.; Abraham, W. The photochemistry of
acyl azides — IX. Direct and sensitized photolytic generation of
acylnitrenes for cycloaddition reactions, Tetrahedron, 1995,
51, 7181; d) Roeske, Y.; Abraham, W. Photochemistry of Acyl
Azides, Synthesis 2001, 1125.
(8) Brachet, E.; Ghosh, T.; Ghosh, I.; König, B. Visible light C–
H amidation of heteroarenes with benzoyl azides, Chem. Sci.,
2015, 6, 987.
(9) a) Scholz, S. O.; Farney, E. P.; Kim, S.; Bates, D. M.; Yoon, T.
P. Spin-Selective Generation of Triplet Nitrenes: Olefin
Aziridination through Visible-Light Photosensitization of
Azidoformates, Angew. Chem. Int. Ed., 2016, 55, 2239. b) Bagal,
D. B. Park, S. -W. Song, H. -J., Chang, S. Visible light sensitization of
benzoyl azides: cascade cyclization toward oxindoles via a non-
nitrene pathway. Chem. Commun. 2017, 53, 8798.
1
2
3
4
5
6
7
8
(ATIP) to PhB. PeB thanks the Elitenetzwerk Bayern (SynCat)
for financial support and Dr. Stefano Crespi for the helpful
discussion.
REFERENCES
(1) a) Heterocycles in Natural Product Synthesis, ed.
Majumdar K. C.; Chattopadhyay S. K. Wiley, Hoboken, NJ, 2012;
b) Horton, D. A.; Bourne, G. T.; Smythe, M. L.; The Combinatorial
Synthesis of Bicyclic Privileged Structures or Privileged
Substructures, Chem. Rev., 2003, 103, 893; c) Deiters, A.;
Martin, S. F.; Synthesis of Oxygen- and Nitrogen-Containing
Heterocycles by Ring-Closing Metathesis, Chem. Rev., 2004,
104, 2199; d) de Sà Alves, F. R.; Barreiro, E. J.; Fraga, C. A. From
nature to drug discovery: the indole scaffold as a 'privileged
structure' Mini-Rev. Med. Chem., 2009, 9, 782; e) Brancale, A.;
Silvestri, R. Indole, a core nucleus for potent inhibitors of
tubulin polymerization Med. Res. Rev., 2007, 27, 209;
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(2) Ireland, C. M.; Durso, A. R.; Newman, R. A.; Hacker, M. P.;
Antineoplastic cyclic peptides from the marine tunicate
Lissoclinum patella J. Org. Chem. 1982, 47, 1807.
(10) Morse, P. D.; Nicewicz, D. A. Divergent regioselectivity
in photoredox-catalyzed hydrofunctionalization reactions of
unsaturated amides and thioamides, Chem. Sci. 2015, 6, 270.
(11) Peet; N.P.; Burkhart; J. P.; Broersma, R. J.; Heminger, E.
(3) de la Rosa, V. R.; Van Den Bulcke, A.; Hoogenboom, R.
POLY(2-OXAZOLINE)S:
THE
VERSATILE
POLYMER
F.; Synthesis of
a 2,5-diaryloxazoline as a potential
PLATFORM FOR BIOMEDICINE Material Matters, 2016, 11, 75.
(4) Hargaden G. C.; Guiry P. J. Recent Applications of
Oxazoline-Containing Ligands in Asymmetric Catalysis, Chem.
Rev., 2009, 109, 2505.
platelet-activating factor antagonist, J. Het. Chem., 1994, 31,
419.
(12) a) Gritsan, N.; Platz, M. Photochemistry of Azides: The
Azide/Nitrene Interface, in Organic Azides: Syntheses and
Applications, ed. Bräse, S. and Banert, K. Wiley, Chichester,
2010. b) Kubicki, J.; Zhang, Y.; Wang, J.; Luk, H. L.; Peng, H.-L.;
Vyas, S.; Platz, M. S.; Direct Observation of Acyl Azide Excited
States and Their Decay Processes by Ultrafast Time Resolved
Infrared Spectroscopy, J. Am. Chem. Soc., 2009, 131, 4212;
(13) For a computational report on triplet acyl-nitrenium
ions as energy minima see: Falvey, D. E. Discrete Existence of
Singlet Nitrenium Ions Revisited: Computational Studies of
Non-Aryl Nitrenium Ions and Their Rearrangements, ACS
Omega, 2018, 3, 10418
(14) Hua, Y. -G.; Yang, Q. -Q.; Yang, Y.; Wang, M. -J.; Chu, W. -
C.; Bai, P. -Y.; Cui, D. -Y.; Zhang, E.; Liu, H. -M. Metal-free
synthesis of 1,2-amino alcohols by one-pot olefin aziridination
and acid ring-opening, Tetrahedron lett. 2018, 59, 2748.
(15) Kawato, Y.; Kubota, A.; Ono, H.; Egami, H.; Hamashima,
Y. Enantioselective Bromocyclization of Allylic Amides
Catalyzed by BINAP Derivatives, Org. Lett. 2015, 17, 1244.
(16) Wang, Y. -F.; Chen, H.; Zhu, X.; Chiba, S. Copper-
Catalyzed Aerobic Aliphatic C–H Oxygenation Directed by an
Amidine Moiety,J. Am. Chem. Soc. 2012, 134, 11980.
(17) Gwaltney, S. L., II; Jae, H.-S.; Kalvin, D. M.; Liu, G.; Sham,
H. L.; Li, Q.; Claiborne, A. K.; Wang, L.; Barr, K. J.; Woods, K. W.
Preparation of oxazoline antiproliferative agents U.S. Pat.,
6228868, 08 May 2001.
(5) For examples see: a) Rajaram S.; Sigman, M. S. Modular
Synthesis of Amine-Functionalized Oxazolines, Org. Lett., 2002,
4, 3399.; b) Ohshima, T.; Iwasaki, T.; Mashima, K. Direct
conversion of esters, lactones, and carboxylic acids to
oxazolines catalyzed by a tetranuclear zinc cluster, Chem.
Commun., 2006, 2711.; c) Nishimura, M.; Minakata, S.;
Takahashi, T.; Oderaotoshi Y.; Komatsu, M. Asymmetric N1 Unit
Transfer to Olefins with a Chiral Nitridomanganese Complex:ꢀ
Novel Stereoselective Pathways to Aziridines or Oxazolines, J.
Org. Chem., 2002, 67, 2101.
(6) Selected reviews on photocatalysis: a) Prier, C. K.; Rankic
D. A.; MacMillan, D. W. C. Visible Light Photoredox Catalysis
with Transition Metal Complexes: Applications in Organic
Synthesis, Chem. Rev., 2013, 113, 5322; b) Hopkinson, M. N.;
Sahoo, B.; Li, J.-L.; Glorius, F. Dual Catalysis Sees the Light:
Combining
Photoredox
with
Organo-,
Acid,
and
Transition-Metal Catalysis, Chem. - Eur. J., 2014, 20, 3874; c)
Nicewicz, D. A.; Nguyen, T. M. Recent Applications of Organic
Dyes as Photoredox Catalysts in Organic Synthesis, ACS Catal.,
2014, 4, 355; d) Hari, D. P.; König, B. The Photocatalyzed
Meerwein Arylation: Classic Reaction of Aryl Diazonium Salts
in a New Light, Angew. Chem., Int. Ed., 2013, 52, 4734; e) Chen,
J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Visible light photoredox-
controlled reactions of N-radicals and radical ions, Chem. Soc.
Rev., 2016, 45, 2044.; f) Menigaux, D.; Belmont, P.; Brachet, E.
Light
on
Unsaturated
Hydrocarbons
-
“Gotta
Heterofunctionalize Them All”, Eur. J. Org. Chem. 2017, 15,
2008.
(7) a) Buck, K.; Jacobi, D.; Ploegert, Y.; Abraham W.
Photochemie von Acylaziden. VIII [1]. Reagieren Acylnitrene
wie 1, 3-Dipole??, J. Prakt. Chem.j Chem.-Ztg., 1994, 336, 678;
b) Averdung, J.; Mattay, J.; Jacobi, D.; Abraham, W. The
photochemistry of acyl azides — IX. Direct and sensitized
photolytic generation of acylnitrenes for cycloaddition
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