Versatile Photochemical Reactivity of Diverse Substituted 2-, 4- and 5-(o-Vinylstyryl)oxazoles

Article abstract of DOI:10.1002/ejoc.201701551

To study the effects of the position of the hexatrienyl moiety on the oxazole ring, novel substituted cis/trans-2/4/5-(2-vinylstyryl)oxazoles have been synthesized. These novel compounds were prepared by Wittig reaction from the diphosphonium salt of α,α′-o-xylenedibromide, formaldehyde and the corresponding 2-methyl-4-, 4-methyl-2-, 2-pheny-5- and 4-methyl-5-oxazolecarbaldehyde, respectively. Aldehydes were synthesized by using several synthetic approaches. By applying intramolecular photocycloaddition, 2-methyl-4-(2-vinylstyryl)oxazole afforded, as major product, fused oxazoline-benzobicyclo[3.2.1]octene with small quantities of 4-(1,2-dihydronaphthalen-2-yl)-2-methyloxazole, as electrocyclization product. Upon irradiation of 4-methyl-5-(2-vinylstyryl)oxazole, endo- and exo-benzobicyclo[2.1.1]hexene products were formed by [2+2] cycloaddition; this was the first instance of the 1,4-closure to the bicyclo[2.1.1]hexene skeleton in the 2-, 4-, and 5-oxazole-stilbene derivatives studied so far. Derivatives 2-phenyl-5- and 4-methyl-2-(2-vinylstyryl)oxazole did not react and gave only high-weight molecular products but were crucial as a comparison in the overall mechanistic study. We have found that, depending on the position of the hexatrienyl moiety in the oxazole ring, as well as on the position of the methyl/phenyl substituents, these new vinylstyryl-2/4/5-oxazole derivatives show diverse photochemical behavior.

Full text of DOI:10.1002/ejoc.201701551

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
A Journal of
Accepted Article
Title: Versatile photochemical reactivity of diverse substituted 2-, 4-
and 5-(o-vinylstyryl)oxazoles
Authors: Ivana Šagud, Marija Šindler-Kulyk, Dragana Vojnović-Jandrić,
and Željko Marinić
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701551
Link to VoR: http://dx.doi.org/10.1002/ejoc.201701551
Supported by

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
10.1002/ejoc.201701551
European Journal of Organic Chemistry
FULL PAPER
Versatile photochemical reactivity of diverse substituted 2-, 4-
and 5-(o-vinylstyryl)oxazoles
Ivana Šagud,*[a] Marija Šindler-Kulyk,[a] Dragana Vojnović-Jandrić,[a] and Željko Marinić[b]
Abstract: To study the effects of the position of the hexatrienyl
moiety on the oxazole ring, novel substituted cis/trans-2/4/5-(2-
vinylstyryl)oxazoles have been synthesized. These novel
compounds were prepared by Wittig reaction from diphosphonium
salt of ,’-o-xylenedibromide, formaldehyde and the corresponding
2-methyl-4-,
4-methyl-2-,
2-pheny-5-
and
4-methyl-5-
oxazolecarbaldehyde, respectively. Aldehydes were synthesized by
several synthetic approaches. By intramolecular photocycloaddition
2-methyl-4-(2-vinylstyryl)oxazole afforded, as major product, fused
oxazoline-benzobicyclo[3.2.1]octene with small quantities of 4-(1,2-
dihydronaphthalen-2-yl)-2-methyloxazole,
as
electrocyclization
product. Upon irradiation of 4-methyl-5-(2-vinylstyryl)oxazole endo-
and exo-benzobicyclo[2.1.1]hexene products were formed by [2+2]
cycloaddition and this was the first instance of the 1,4-closure to the
bicyclo[2.1.1]hexene skeleton in the 2-, 4-, and 5-oxazole-stilbene
derivatives studied so far. Derivatives, 2-phenyl-5- and 4-methyl-2-
(2-vinylstyryl)oxazole do not react and give only high weight
molecular products but are crucial as a comparison in the overall
mechanistic study. We have found that depending on the position
of the hexatrienyl moiety in the oxazole ring, as well as the position
of the methyl/phenyl substituents these new vinylstyryl-2/4/5-oxazole
derivatives show diverse photochemical behavior.
Scheme 1. Photoproducts of 2-, 4- and 5-(2-vinylstyryl)oxazoles. 1,2
Only those derivatives that have a phenyl substituent in the
position 4 on the ring react by 10 followed by 6ring closure to
products E. These experimental findings were confirmed by TD-
DFT calculations. The oxo-bridged photoproducts
E could
further be easily converted to benzo[f]qouinolines (scheme 1).
We have also described unsubstituted 4- and 5-(2-
vinylstyryl)oxazoles which by intramolecular photocycloaddition
gave fused tetracyclic oxazoline compounds (A, C, scheme 1).2
New routes to oxazoline derivatives are more than welcome due
to the presence of the oxazoline ring in ligand scaffolds, natural
products3,4 and potential pharmaceuticals.5,6 In our case the
obtained tetracyclic oxazoline compounds further hydrolyzed,
either spontaneously, or during work up, and gave functionalized
benzobicyclo[3.2.1]octenone derivatives. On the other side, this
ring opening gave a new route for the synthesis of functionalized
Introduction
In our previous paper we have described the synthesis of 2-(2-
vinylstyryl)oxazoles1 which upon irradiation gave quinolines via
oxo-bridged derivatives. The study of the 5-tolyl-, 4,5-diphenyl-
and 4-phenyl-5-methyl-2-(2-vinylstyryl)oxazole showed that the
phenyl substituent on the position 4 in the oxazole ring has a
high impact on the overall electron density distribution in the
molecule and the photocyclization process (scheme 1).1
benzobicyclo[3.2.1]octenes
which
are
useful
reactive
intermediates found in stereoselective transformations7 as the
bicyclo[3.2.1]octane skeleton appears in numerous biologically
active natural compounds and their metabolites.8 There are
various methodologies and synthetic approaches for the
synthesis of the oxazole ring incorporated into diverse
skeletons9 as the oxazole structure is commonly found in a vast
number of natural products and pharmaceuticals.10-13
The examples of photochemical intermolecular cycloadditions
that include oxazoles are numerous14-20 but as for the
intramolecular photocycloaddition, to the best of our knowledge,
the only examples are the ones published by us for various
substituted 2-(2-vinylstyryl)oxazoles1 and the unsubstituted 4-
and 5-(2-vinylstyryl)oxazoles.2
In this work, in order to study further the photochemical reactivity
of oxazole derivatives, the hexatrienyl and alkyl or aryl
substituents were placed in various positions on the oxazole ring.
We synthesized new 4-methyl-2-(2-vinylstyryl)oxazole (1), 4-
[a]
[b]
I. Šagud, M. Šindler-Kulyk, D. Vojnović-Jandrić,
Department of Organic Chemistry
Faculty of Chemical Engineering and Technology, University of
Zagreb
Marulićev trg 19, 10000 Zagreb, Croatia
E-mail: isagud@fkit.hr
Ž. Marinić
NMR Center
Rudjer Bošković Institute,
Bijenička cesta 54, 10000 Zagreb, Croatia
methyl-5-(2-vinylstyryl)oxazole
(2),
2-methyl-4-(2-
vinylstyryl)oxazole (3) and 2-phenyl-5-(2-vinylstyryl)oxazole (4).
Supporting information for this article is given via a link at the end of
the document
This article is protected by copyright. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
10.1002/ejoc.201701551
European Journal of Organic Chemistry
FULL PAPER
Excited state behavior of all of the new derivatives was
investigated.
vinylstyryl)oxazole (4) Wittig reaction was utilized. The starting
compounds were synthesized from the diphosphonium salt of
,’-o-xylenedibromide, formaldehyde and the corresponding
substituted oxazole-2/4/5-carbaldehydes (5-8) with the reaction
taking place in absolute ethanol and sodium ethoxide as base
(scheme 2).
Results and Discussion
.
For the synthesis of cis/trans-isomers of 4-methyl-2-(2-
vinylstyryl)oxazole (1), 4-methyl-5-(2-vinylstyryl)oxazole (2), 2-
methyl-4-(2-vinylstyryl)oxazole
(3)
and
2-phenyl-5-(2-
Scheme 2. Synthesis of substituted 2-, 4- and 5-(2-vinylstyryl)oxazoles (1-4).
In order to maximize the yields the described procedure for the
multi-component Wittig reaction21 was modified. The yield of the
Wittig reaction for all of the three derivatives 1-4 was moderately
good, ranging from 57 - 67%. Both cis- and trans-isomers of all
of the new compounds 1-4, were isolated by column
chromatography on silica gel and characterized by
spectroscopic methods (see Supporting information file). The
synthesis of the required oxazole-2/4/5-carbaldehydes (5-8),
needed for the Wittig reactions, proved to be challenging. The 4-
methyl-oxazole-2-carbaldehyde22 (5) was synthesized by n-
BuLi/DMF formylation from the corresponding oxazole 923. To
synthesize 4-methyl-oxazole-5-carbaldehyde22 (6), from the
parent oxazole, Villsmeyer formylation reaction was utilized. This
Derivative 14 was synthesized in a multiple step synthesis by a
series of well-known reactions28, 29 that included ring closure of
2-bromoethan-1-aminium bromide (16) with benzoyl chloride to
2-phenyloxazoline 15 followed by a reaction with NBS to form 14.
Preliminary irradiations of 1-4 were conducted in UV tubes, in
ethanol (c ≈ 3 x 10-5 mol/L) at 300 nm, and the process was
followed by UV spectrophotometry. At the beginning of
irradiation in the UV tubes the trans-cis isomerization is recorded
and is shifted towards the cis-isomer. There is also a drop of the
absorption maxima, indicating that the species that are formed
have less, or no chromophores. One of the examined
compounds, cis-2-methyl-4-(2-vinylstyryl)oxazole (3) was
additionally irradiated in a sealed NMR tube in degassed
deuterated benzene solution and the progress was followed by
1H NMR measurements. By this combination of methods a more
detailed analysis of the irradiation progress was obtained (figure
1).
reaction gave
a
mixture of oxazole-2- and oxazole-5-
carbaldehyde,22 where the 5-carbaldehyde 6 was the major
product, but was impossible to purify due to its extreme volatility.
The approach was changed and compound 6 was synthesized
by a two-step reaction pathway from the corresponding ester
1023, via alcohol 11,24 (scheme 2) in a good overall yield of 60%.
Compound 2-methyl-oxazole-4-carbaldehyde25 (7) was prepared
from the commercially available ester 12 by DIBAL-H reduction
following the described procedure for the oxazole-4-
carbaldehyde.26 2-phenyl-oxazole-4-carbaldehyde27 (8) was
prepared from 5-bromo-2-phenyloxazole27 (14) in two steps.
This article is protected by copyright. All rights reserved.

Evaluation Only. Created with Aspose.PDF. Copyright 2002-2021 Aspose Pty Ltd.
10.1002/ejoc.201701551
European Journal of Organic Chemistry
FULL PAPER
cis-3
trans-3
MP
rel-(2R)-17) is seen. At the end of irradiation almost all of the
isomers are consumed and two new products are present in 5:2
ratio.
The preparative irradiation experiments were conducted in a
Rayonet reactor equipped with 300 nm lamps, in petroleumether
and benzene, respectively. All of the irradiation mixtures were
purged with argon for 20 minutes. The four newly synthesized,
substituted 2-, 4- and 5-(o-vinylstyryl)oxazoles reacted differently
upon irradiation. The 1H NMR spectra of the crude photo-
mixtures of compounds 2-methyl-4-(2-vinylstyryl)oxazole (3) and
100
mp
80
60
%
40
4-methyl-5-(2-vinylstyryl)oxazole
(2)
showed
complete
20
0
conversion after 5 and 15 hours of irradiation, respectively.
Compound 4-methyl-2-(2-vinylstyryl)oxazole (1) and 2-phenyl-5-
(2-vinylstyryl)oxazole (4) gave no product, only starting material
was present after 5 and 10 h of irradiation and high molecular
weight products after 24 h of irradiation.
t/min
0
50
100
150
200
250
300
-20
In the case of 2-methyl-4-(2-vinylstyryl)oxazole (3) the crude
reaction mixture consisted of rel-(2S)- and rel-(2R)-4-methyl-3-
oxa-5-azatetracyclo[6.6.1.02,6.09,14]pentadeca-4,6,11,13-
pentaene (17) as well as 5-(1,2-dihydronaphtalene-2-yl)-2-
methyloxazole (18) (scheme 3).
Figure 1. Graphical interpretation of irradiation of cis-2-methyl-4-(2-
vinylstyryl)oxazole (3).
The trans-cis isomerization was confirmed. After 32 minutes of
irradiation one major product (MP), later identified as rel-(2S)-17
is detected and on continuing irradiation one other product (mp,
Scheme 3. Irradiation of 2-methyl-4(2-vinylstyryl)oxazole (3).
The methyl substituent at the position 2 of the oxazole moiety
does not influence the excited state reaction course and the
products are analogue to the ones that were obtained upon
irradiation of the unsubstituted derivative.2 Compounds rel-(2S)-
17 (63%) and cyclization product 18 (7%) were isolated and their
structures were determined using COSY, NOESY and HSQC
techniques (See Supporting Information).
chemistry31 the presence of the nonaromatic intermediate was
only seen in H NMR spectra, in the case of irradiation of 2-(2-
1
(vinylstyryl)furan/benzofuran derivatives in NMR tubes. The 1,6-
ring closure of the biradical F stereoselectively gives the major
product rel-(2S)-17 in which the hydrogen on C-2 is oriented
toward the methano-bridge. The formation of the
dihydronaphthalene derivative 18, is explained by 6
electrocyclization of the benzo-divinyl moiety to intermediate G.
The second step is the [1,5]-H shift and rearomatization of the
The formation of the photoproduct 17 is explained by
intramolecular cycloaddition and formation of the resonance
stabilized biradical F followed by the 1,6-ring closure (scheme 3). benzene ring. Analogue electrocyclization was not detected in
An [1,3]-H shift that would result in aromatization of the
oxazoline ring, that happens in furan and thiophene derivatives
by default,30 does not take place in the structure 17. In the furan
the, so far studied, phenyl- or furyl-substituted o-divinylbenzenes.
In the case of the phenyl- or furyl-substituted o-divinylbenzenes,
stilbene-like, 6 electrocyclization and formation of 1-
This article is protected by copyright. All rights reserved.