Flow-photochemical synthesis of the functionalized benzobicyclo[3.2.1]octadiene skeleton

Article abstract of DOI:10.1016/j.molstruc.2018.05.027

A convenient practical home-made continuous flow-photochemistry setup was evaluated with the aim to enable a more efficient protocol for the synthesis of functionalized benzobicyclo[3.2.l]octadiene skeleton by intramolecular [2+2]-photocycloaddition react

Full text of DOI:10.1016/j.molstruc.2018.05.027

Accepted Manuscript
Flow-photochemical synthesis of the functionalized Benzobicyclo[3.2.1]octadiene
skeleton
Ana Ratković, Željko Marinić, Irena Škorić
PII:
S0022-2860(18)30587-8
10.1016/j.molstruc.2018.05.027
MOLSTR 25199
DOI:
Reference:
To appear in: Journal of Molecular Structure
Received Date: 28 March 2018
Revised Date: 7 May 2018
Accepted Date: 8 May 2018
Please cite this article as: A. Ratković, Ž. Marinić, I. Škorić, Flow-photochemical synthesis of the
functionalized Benzobicyclo[3.2.1]octadiene skeleton, Journal of Molecular Structure (2018), doi:
10.1016/j.molstruc.2018.05.027.
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to
our customers we are providing this early version of the manuscript. The manuscript will undergo
copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please
note that during the production process errors may be discovered which could affect the content, and all
legal disclaimers that apply to the journal pertain.

ACCEPTED MANUSCRIPT
Flow-photochemical Synthesis of the Functionalized
Benzobicyclo[3.2.1]octadiene Skeleton
Ana Ratković,a Željko Marinićb and Irena Škorića*
aDepartment of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb,
Marulićev trg 19, 10000 Zagreb, Croatia
bNMR Center, Rudjer Bošković Institute, Bijenička cesta 54, 10000 Zagreb, Croatia
Graphical abstract
Abstract
A convenient practical home-made continuous flow-photochemistry setup was evaluated with the
aim to enable
a
more efficient protocol for the synthesis of functionalized
benzobicyclo[3.2.l]octadiene skeleton by intramolecular [2+2]-photocycloaddition reaction.
Numerous compounds with the bicyclo[3.2.l]-skeleton are proven as potent inhibitors of dopamine
and serotonin transporters and also play a crucial role in treatment of central nervous system and
Alzheimer’s disorders. The yields, reaction times and conversions gained from the flow setup were
compared to those obtained from the conventional photoreactor. In comparison to the batch
reaction, the flow reaction showed better results, both in increasing the isolated yield and
productivity and in lowering the reaction time. This first application of the flow-photochemistry on
β
-heteroaryl-o-divinylbenzenes and o-vinylphenyl substituted butadienes proved to be more
efficient and less sensitive to oxygen enabling us to scale-up the intramolecular cycloaddition
without scaling-up the equipment. Additionally, for all the obtained, potentially bioactive,
1

ACCEPTED MANUSCRIPT
derivatives promising calculated physico-chemical and absorption, distribution, metabolism, and
elimination (ADME) properties were also given.
KEYWORDS: benzobicyclo[3.2.1]octadienes, continuous flow photochemistry, functionalized
polycyclic skeleton, intramolecular photocycloaddition, physico-chemical and ADME properties.
1.
Introduction
The bicyclo[3.2.l]octane system is a common subunit in many natural products. It is present
in diterpene families of compounds such as the kaurenes and the gibberellins and also in many
sesquiterpenes [1]. One of the interesting properties of the bicyclo[3.2.1]octane skeleton is that it is
fairly rigid and can therefore coordinate two or more ligands and this is of great value to medicinal
chemists, particularly in the search for bioactivity [2-5]. This structural moiety is the basic
framework of numerous important biologically active natural compounds or their metabolites [6-8].
More importantly, compounds with the bicyclo[3.2.1]-skeleton are proving as potent inhibitors of
dopamine and serotonin transporters and play a crucial role in treatment of central nervous system
(CNS) and Alzheimer’s disorders (Figure 1) [9,10].
Synthesis of compounds containing the bicyclo[3.2.l]octane and bicyclo[3.2.l]octadiene core
are well documented in literature [11-15]. Bicyclo[3.2.l]-skeleton can be constructed using different
synthetic pathways, one of which is the photochemical approach that has been developed by our
group in batch photochemical reactor [16-20]. Photochemically induced organic reactions provide
an important path to complex products from simple starting materials. The unsaturated
bicyclo[3.2.l]octane structure can be even more useful than the saturated bicyclo[3.2.l]octane
skeleton, as it can easily be transformed further by adding various functional groups to the isolated
double bond. In our group, a whole library of polycylic compounds was obtained by utilization of
the photochemical synthesis in the traditional photoreactor.
Figure 1. Examples of compounds with benzobicyclo[3.2.1]-skeleton displaying expressed CNS
activities [10].
2

ACCEPTED MANUSCRIPT
In recent years, research groups are adopting more technological solutions to enable highly
automated syntheses which can help the discovery of compounds from early phases of discovery to
preclinical investigations and drug production. Continuous flow systems are emerging as powerful
tools in the organic synthetic community enabling highly automated synthesis. These systems have
many advantages in comparison to the conventional batch methods. They are more favoured when
applied in reaction screening and optimization. Continuous flow reactors have shown remarkable
efficiency during screening on reaction parameters such as temperature, pressure, residence time,
catalysts used, solvents [21-25]. A key advantage of such technology is the possibility to scale-up a
reaction without scaling-up the equipment by exploiting the continuous flow of the reagents through
the system [26-30].
Flow techniques have also been applied to synthetic organic photochemistry on a variety of
important platforms [31-37]. In this work, for the first time, flow photochemistry was utilized for
the synthesis of the benzobicyclo[3.2.l]octadiene skeleton. New benzobicyclo[3.2.l]octadienes were
prepared using the traditional (batch) method and also in the flow reactor to explore the benefits. In
comparison to the batch reaction, the flow reaction showed better results, both in increasing the
yield and productivity and lowering the reaction time. We were able to perform the reactions in
shorter residence times and scale-up the intramolecular [2+2]-photocycloaddition reaction obtaining
the desired products without scaling-up the equipment.
2.
Results and discussion
The intramolecular [2+2]-photocycloaddition reaction toward some already known (2, 4, 6
and 7) [16-19] and several novel (1, 3 and 5) benzobicyclo[3.2.1]octadienes from β-heteroaryl-o-
divinylbenzenes and o-vinylphenyl substituted butadienes (1a-7a) (Scheme 1) was performed on
the traditional batch way using the Rayonet reactor with 16 lamps (300 or 350 nm, 8W lamps). The
synthesis was also performed in the flow system using a convenient practical home-made flow-
photochemistry setup (Figure 2) with 19 m reactor system consisting of UV transparent tubing (for
leaking through the reaction mixture), wraped around the pyrex cuvette and placed in a Rayonet
reactor. The flow setup was evaluated with the aim to enable a more efficient protocol for the rapid
synthesis of 1-7, as valuable substrates for further functionalization of their isolated double bond
and/or the functionalization of the alkyl or aryl substituents on the benzobicyclo[3.2.1[octadiene
core (in the case of 1-6). Additionally, the targeted photoproduct 7 has two reactive double bonds
incorporated into the furan ring, making it as a substrate also synthetically very interesting.
3

ACCEPTED MANUSCRIPT
The starting materials 1a-7a for the photochemical experiments were prepared by the Wittig
reaction from
α,α’-o-xylyl(ditriphenylphosphonium)dibromide and corresponding aldehydes
according to the general procedure developed for the whole library of analogue [38-42]. Upon
irradiation the primary photoisomerization of the mixtures of the isomers of the starting compounds
1a-7a is followed by competitive stereoselective intramolecular [2+2]-photocycloaddition giving
differently substituted benzobicyclo[3.2.1]octadienes 1-7.
Scheme 1. Synthesis of benzobicyclo[3.2.1]octadiene derivatives 1-7 in a batch and flow
photochemical setup.
4-substituted benzobicyclo[3.2.1]octadienes 1-6, as endo-stereoisomers, and compound 7 were
obtained as the main products, with traces of exo-4-substituted photoproduct (in the case of 5) and
besides high-molecular-weight material in all cases (Scheme 1). The stereoselectivity of the
reaction and the preferable ring closure to endo-isomer of 1-6 have been ascribed to the stabilization
of the transition state in endo-orientation by the attractive intramolecular interactions of the benzo-
methyl/aryl groups [19]. We have chosen the derivatives 1-7 with diversified targeted alkyl-,
phenyl- and different aryl-substituents (p-dimethylaminophenyl-, p-chlorophenyl, p-fluorophenyl,
p-methoxyphenyl-) to compare their synthesis, yields, quantum yields, reaction times, residence
times and productivity in batch and flow system. Also, we performed the flow photoreaction to
obtain fused furan structure 7 suitable for further functionalization through oxidative cleavage of
the furan ring [43].
4

ACCEPTED MANUSCRIPT
Figure 2. Home-made flow-photochemistry setup.
All irradiation experiments were performed in toluene solutions under anaerobic conditions at
300 nm (for the synthesis of 1 and 7) and 350 nm (for the synthesis of 2-6), depending on the
absorption spectra of the starting conjugated substrates 1a-7a (Figure 3). The preparative batch
irradiation experiments of starting compounds 1a-7a (Scheme 1) were performed at low
concentrations in the order of 0.001 mmol/mL. At the same time, flow irradiation experiments were
performed on the same substrates in toluene solutions using plunger pump (Flash Master Personal
Argonaut) for the applied slowest possible flow rate of 0.4 mL/min to achieve the full conversion
and concentration of the solutions of 0.093 mmol/mL.
methyl (1a)
phenyl (2a)
p
-NMe2-phenyl (3a)
-Cl-phenyl (4a)
-F-phenyl (5a)
-OMe-phenyl (6a)
furyl (7a)
1,0
0,8
0,6
0,4
0,2
0,0
p
p
p
A
250
300
350
400
450
λ
/ nm
Figure 3. Normalized absorption spectra of the mixtures of isomers of starting compounds 1a-7a
used in the photochemical synthesis of 1-7
The comparison of yields of the batch and flow [2+2]-photocycloaddition is given in Table 1.
Utilizing the experimental conditions for this stereoselective intramolecular cycloaddition in the
5

ACCEPTED MANUSCRIPT
continuous flow reactor, we obtained the desired structures 1-7 after the residence time of only 6-12
minutes in moderate to very high yields 48-95% (with complete consumption of starting material),
except for the p-dimethylamino derivative 3 (60% of consumption). Obviously, the tertiary amino
group in the photoproduct 3 (in comparison to other molecules with two aryl groups 2, 4-6)
contributes to the lower stability possibly through the lowering of the intensity of π-π interactions
by competitive electronic effects. Evidently, the strong electronic effects of the p-dimethylamino in
the starting substrate 3a during the photocycloaddition reaction also bring to the incomplete
consumption of the starting material. Besides the increase in the yields, we also achieved the
significant increase of the productivity of 1-7 in comparison to the batch photoreaction (Table 1),
especially on the photoproduct 1.
The improvement of the productivity of 1-7 during the flow photochemical reaction can be
explained by considering the different physical reaction parameters in two applied reactors. In
addition to the benefits of flow systems derived from the fluidics approach such as enhanced heat
and mass transfer, it is known that the relatively low reactor volume and especially the high surface
area to volume ratio of flow reactors have proven to be key advantages for light-initiated reactions,
as intense and uniform irradiation of the reaction mixture is assured. Because of the short path
length of the light, higher substrate concentrations were used, and therefore, the reaction throughput
was significantly increased. The light exposure is very precisely controlled by the pump flow rate,
which minimizes over irradiation of the mixture, avoiding undesired side products, which were very
common in our batch experiments. Due to the use of minimal solvents it is ensured that reactions
are sustainable, environmentally friendly and conducted in a safe manner. Continuous flow setup
(Figure 2) allowed us easy scale-up as no change in reactor size was required. It is very important to
emphasize that the application of the continuous flow-photochemistry on different β-heteroaryl-o-
divinylbenzenes and o-vinylphenyl substituted butadienes 1a-7a proved to be less sensitive to the
oxygen present in the solution compared to the traditional batch reaction due to the very short
residence times and rapid reaction. Additionally, we were able to use higher concentrations in the
flow system that are not usual for intramolecular reactions. The optimization of the reaction
conditions with higher flow rates could enable further decrease in the residence time required for
the full conversion of starting compounds 1a-7a and further increase of the productivity.
Regarding the mechanistic considerations, the formation of benzobicyclic structures 1-7 could
be explained by initial intramolecular cycloaddition and formation of resonance-stabilized
intermediate followed by 1,6-ring closure (Scheme 2), as proposed in the photochemical reactions
6

ACCEPTED MANUSCRIPT
of some β-heteroaryl substituted o-divinylbenzenes [16,20,38,39] and o-vinylphenyl substituted
butadienes [17,19].
Scheme 2. Proposed mechanism of the intramolecular photocycloaddition giving the
benzobicyclo[3.2.1]octadienes 1-7.
A study of efficiency was also conducted for the batch photoreaction where the efficiency of
intramolecular cycloaddition of starting compounds 1a-7a was investigated by the use of the
ferrioxalate actinometer. As it is shown in Table 1, the quantum yields of the intramolecular
cycloaddition of starting conjugated systems 1a-7a are relatively high toward the
benzobicyclo[3.2.1]-skeleton. These results add even more importance to the synthesis of 1-7 by
photocycloaddition. The quantum yields for the flow system is technically impossible to measure so
the benefits of the continuous flow system above the batch could not be analyzed according to that
base but through the improvement of the productivity.
Table 1. Photocycloaddition reaction[a] to photoproducts 1-7.
Photo-
Quantum
Yield for
batch [%]b
Time in
Yield for
Residence Conversiond Productivity
product yield in batchc
batch [h] flow [%]b time [min]
[%]
[µmol/min]e
1
2
0.02
0.22
25
15
5
48
95
6
6
100
100
0.18/39.2
0.65/33.0
9019
3
4
0.22
0.23
12
10
5
24
83
12
6
60
0.06/3.6
7717
100
0.48/25.0
5
6
7
0.24
0.12
0.22
80
5
87
70
92
6
100
100
100
0.53/29.0
0.13/11.0
0.24/14.8
5018
9016
15
15
12
12
7

ACCEPTED MANUSCRIPT
a
Reaction conditions: The irradiation experiments in batch photoreactor and flow system were performed in toluene solutions at
300 nm (for the synthesis of compounds 1 and 7) and 350 nm (for the synthesis of compounds 2-6), depending on the absorption
b
spectra of the starting substrates; Isolated yield; Concentration of the toluene solution in the batch was in the order of 0.001
mmol/mL and for the flow 0.093 mmol/mL; Flow rate was 0.4 mL/min; cFor calculation see Supporting Information; dConversion
is the same for the batch and flow system; eComparison of productivity in batch/flow systems.
In this study, the structure-property relationships [44-46] with predictive models (see Supporting
Information) for photoproducts 1-7 bearing the crucial benzobicyclo[3.2.1]-skeleton has been
analyzed for the first time (Table 2). Physico-chemical and ADME (absorption, distribution,
metabolism, and elimination) properties have been calculated specially logP, solubility,
permeability across biological membranes, plasma protein binding, metabolic stability and CNS
penetration. Generally, the absorption parameter shows the bioavailability, the distribution predicts
where the drug is distributed, how fast and how extensive, metabolism parameter shows how fast,
what mechanism, what metabolite is formed, and whether it is active or toxic, and the elimination
value predicts the route to the target. It is known that fundamental physico-chemical features of
CNS drugs are related to their ability to penetrate the blood-brain barrier affinity and exhibit their
CNS activity. Promising structural and physico-chemical parameters identified in the current study
will serve us as a useful tool, to design, filter and prioritize compounds to be synthesized further. As
a more detailed investigation of acetylcholinesterase (enzyme important at early stages of
Alzheimer's disease) inhibitory activity as well as the butyrylcholinesterase (enzyme important at
later stages of Alzheimer's disease) inhibitory activity is underway, the CNS penetration is one of
the most interesting parameters.
Table 2. Calculated physico-chemical and ADME properties44 for compounds 1-7.
Photo-
logP
Solubility
Permeability
PPB
[%]
82
CNS
Metabolic
stability
product
1
2
4.04
0.005
0.008
245e-6
-1.77
0.53
0.51
5.22
2196e-6
95
-2.52
3
4
5
6
7
5.15
5.53
5.03
4.89
3.77
0.003
0.001
0.007
0.003
0.020
221e-6
195e-6
228e-6
232e-6
245e-6
96
98
96
96
95
-2.48
-2.76
-2.39
-2.44
-2.31
0.53
0.53
0.51
0.53
0.52
As was mentioned before, some compounds having the same bicyclo[3.2.1]-core as structures 1-
7 have proved to be potent inhibitors of dopamine and serotonin transporters and also play a crucial
8

ACCEPTED MANUSCRIPT
role in treatment of CNS and Alzheimer’s disorders [9,10]. Analizing the obtained calculated values
(Table 2), it is evident that all photoproducts 1-7 show significant CNS penetration properties,
especially compounds 1, 5 and 7, the alkyl, p-fluorophenyl and furyl derivative, respectively. It is
important experimental result that the fluorinated photoproduct 5 also gave 100% conversion within
6 minutes in the flow system and significant CNS penetration properties in the same time, as the
fluorinated compounds are currently trending in organic synthesis [47]. This derivative has a very
high yield in batch and flow system and good productivity in both systems. For all photoproducts 1-
7 in silico analysis were also performed showing the best CNS penetration and lipophilicity
properties for structures 1, 5 and 7, which means that they could possess good blood-brain barrier
penetration capability. Generally, the promising value of CNS penetration is between -3 and 0 (see
Supporting Information). Photoproduct 1 has better CNS and plasma protein binding (PPB, Table 2)
values than the other products 2-7, probably because of smaller molecule with only one aryl
substituent and consequently not so rigid structure (without π-π interactions between two aromatic
rings). Analizing all in silico values, it can be concluded that bicyclo[3.2.1]octadiene structures in
general show potentially good CNS activity.
The described home-made flow-photochemistry setup allowed improvement of the productivity
of photoreaction products 1-7 strengthen this way the further purpose of this work. As it was
mentioned, some compounds having the same bicyclo[3.2.1]-core as 1-7 have proved to be potent
inhibitors of dopamine and serotonin transporters and also play a crucial role in treatment of CNS
and Alzheimer’s disorders (see Supporting Information) [9,10]. On the other hand, the flow-
photochemical methodology could be a practical option also for further functionalization reactions
of these efficiently obtained and potentially bioactive structures (Scheme 3).
Scheme 3. Schematic representation of further possible applications using the evaluated flow-
photochemistry setup.
9

ACCEPTED MANUSCRIPT
3.
Conclusion
In this paper we have demonstrated a convenient practical home-made continuous flow-
photochemistry setup to enable more efficient protocol for the synthesis of functionalized
benzobicyclo[3.2.l]-skeleton by intramolecular [2+2]-photocycloaddition reaction. The yields,
residence time and conversion of these reactions were compared to those obtained in traditional
batch photoreactor. This first application of continuous flow methodology on the photochemistry of
different
β-heteroaryl-o-divinylbenzenes and o-vinylphenyl substituted butadienes proved to be
much more efficient and less sensitive to oxygen compared to the traditional batch reaction,
enabling us to scale-up the intramolecular cycloaddition reaction without scaling-up the equipment
and allowing the improvement of the productivity of photoproducts 1-7. The measurements of
experimental physico-chemical and ADME properties, biological activity and cholinesterase
inhibitory activity of the photoproducts are also currently underway proving the further purpose of
this work.
4.
Experimental section
General
1
13
The H and C NMR spectra were recorded on a Bruker AV-600 Spectrometer All NMR spectra
were measured in CDCl3 using tetramethylsilane as reference. UV spectra were measured on a
Varian Cary 50 UV/VIS Spectrophotometer. Mass spectra were obtained on a GC-MS (Varian CP-
3800 Gas Chromatograph-Varian Saturn 2200) equipped with FactorFour Capillary Column VF-
5ms. Irradiations were performed in a quartz or pyrex cuvettes in toluene solutions using RPR 3000
Å and RPR 3500 Å lamps. All irradiation experiments were carried out in deoxygenated solutions
by bubbling a stream of argon prior to irradiation. Melting points were obtained using an Original
Kofler Mikroheitztisch apparatus (Reichert, Wien) and are uncorrected. HRMS analysis were
carried out on a mass spectrometer (MALDI TOF/TOF analyzer), equipped with Nd:YAG laser
operating at 355 nm with firing rate 200 Hz in the positive (H+) or negative (H–) ion reflector
mode. Silica gel (Merck 0.063-0.2 mm) was used for chromatographic purifications. Solvents were
purified by distillation. Boiling range of petroleum ether, used for chromatographic separation, was
40-70 ºC.
10

ACCEPTED MANUSCRIPT
The starting cinnamaldehydes and furan-2-carboxaldehyde for the Wittig reaction were obtained
from a commercial source. β,β'-o-xylyl(ditriphenylphosphonium)dibromide was synthesized from
the corresponding dibromide and triphenylphosphine in benzene solution.
General procedure for synthesis of starting substrates 1a-7a used in photochemical
reactions:48 To a stirred solution of the diphosphonium salt of
α,α'-o-xylenedibromide (5.5 mmol)
in absolute ethanol (100 mL, 3 Å sieves), corresponding aldehydes (1.1 eq) were added. A solution
of sodium ethoxide (1.1 eq in 15 mL of absolute ethanol) was added dropwise and reaction mixture
stirred under nitrogen for 1h at RT. Under a stream of dry nitrogen, gaseous formaldehyde
(obtained by decomposition of paraformaldehyde used in excess, (1.0 g) was introduced together
with sodium ethoxide solution, which was added dropwise. The reaction mixture was stirred
overnight at RT. After removal of the solvent, the residue was worked up with ice-water and
extracted with toluene (5 x 30 ml). The toluene extracts were dried with anhydrous MgSO4.
Evaporation of solvent under reduced pressure afforded crude mixture of geometrical isomers of
1a-7a as starting materials for the photochemical reactions to afford compounds 1-7. The crude
reaction mixture was purified and the isomers of 1a-7a were separated by repeated column
chromatography on silica gel using petroleum ether as eluent. The first fractions yielded cis- or
cis,trans- and the last fractions trans- or trans,trans-isomer depending on the starting aldehydes.
Characterization data of the synthesized compounds 1a-7a are given below.
1-ethenyl-2-(penta-1,3-dien-1-yl)benzene (1a): Yield 35.0%, according to 1H NMR spectroscopy,
a mixture of 50% cis,trans- and 50% of trans,trans-isomer. HRMS for C13H14: M+
M+found 170.1167 (for a mixture of isomers of 1a).
170.1157;
calcd
cis,trans-1a: Rf 0.75 (petroleum ether); colourless oil; UV (EtOH) λmax (log ε
) 263 (4.09); 1H NMR
(CDCl3, 600 MHz) δ/ppm 7.47-7.44 (m, 1H), 7.20-7.16 (m, 3H), 6.81 (dd, 1H, J = 17.5; 10.5 Hz),
6.31 (d, 1H, J = 11.6 Hz), 6.25-6.16 (m, 2H), 5.81-5.74 (m, 1H), 5.59 (dd, 1H, J = 17.5; 1.3 Hz),
5.19 (dd, 1H, J = 11.3; 1.3 Hz), 1.67 (dd, 3H, J = 7.2; 1.0 Hz); 13C NMR (CDCl3, 150 MHz)
δ/ppm
136.0 (s), 135.1 (d), 132.1 (d), 131.3 (d), 130.1 (d), 128.1 (d), 127.7 (d), 127.2 (d), 127.1 (d), 126.2
(d), 125.5 (d), 125.4 (s), 115.2 (t), 18.3 (q); MS m/z (%, fragment): 170 (5, M+), 128 (100);
11

ACCEPTED MANUSCRIPT
1
trans,trans-1a: Rf 0.75 (petroleum ether); colourless oil; UV (EtOH) λmax (log ε) 275 (4.19); H
NMR (CDCl3, 600 MHz) δ/ppm 7.40-7.35 (m, 2H), 7.15-7.10 (m, 2H), 6.95 (dd, 1H, J = 17.3; 11.1
Hz), 6.65 (d, 1H, J = 15.5 Hz), 6.50 (dd, 1H, J = 15.5; 9.8 Hz), 6.19-6.15 (m, 1H), 5.81-5.74 (m,
1H), 5.55 (dd, 1H, J = 17.4; 1.4 Hz), 5.25 (dd, 1H, J = 11.1; 1.4 Hz), 1.75 (dd, 3H, J = 6.8; 1.4 Hz);
too small a quantity of the isolated isomer for the assignment of the 13C nuclei, as both geometrical
isomers have the same Rf value; MS m/z (%, fragment): 170 (100, M+), 127 (20).
1-ethenyl-2-(4-phenylbuta-1,3-dien-1-yl)benzene (2a): Yield 77.0%, lit.19 92.0%; according to 1H
NMR spectroscopy, a mixture of 53% cis,trans- and 47% of trans,trans-isomer. HRMS for C18H16:
M+calcd 232.1334; M+found 232.1323 (for a mixture of isomers of 2a).
cis,trans-2a: Rf 0.52 (petroleum ether); colourless oil; UV (EtOH) λmax (log ε) 306 (4.46, sh), 236
(4.14, sh); 1H NMR (CDCl3, 600 MHz) δ/ppm 7.57 (d, 1H, J = 7.3 Hz), 7.31-7.34 (m, 7H), 7.20 (t,
1H, J = 7.3 Hz), 7.03 (dd, 1H, J = 15.6; 11.3 Hz), 6.91 (dd, 1H, J = 17.5; 11.2 Hz), 6.69 (d, 1H, J =
15.6 Hz), 6.62 (d, 1H, J = 11.2 Hz), 6.50 (t, 1H, J = 11.2 Hz), 5.70 (dd, 1H, J = 17.5; 1.2 Hz), 5.29
13
(dd, 1H, J = 11.2; 1.2 Hz); C NMR (CDCl3, 150 MHz)
δ
/ppm 137.33 (s), 136.53 (s), 135.74 (s),
135.18 (d), 134.49 (d), 131.23 (d), 130.26 (d), 129.34 (d), 128.60 (d), 127.68 (d), 127.53 (d), 127.40
(d), 126.59 (d), 125.76 (d), 125.54 (d), 115.63 (t); MS m/z (%, fragment): 232 (2, M+), 128 (100);
trans,trans-2a: Rf 0.48 (petroleum ether); colourless crystals; mp 91-92 ºC; UV (EtOH) λmax (log
ε)
354 (4.33, sh), 336 (4.58), 262 (4.09) 234 (4.09); 1H NMR (CDCl3, 600 MHz)
δ
/ppm 7.51 (d, 1H, J
= 7.5 Hz), 7.41-7.45 (m, 3H), 7.31 (t, 1H, J = 7.5 Hz), 7.19-7.26 (m, 3H), 7.06 (dd, 1H, J = 17.4;
11.0 Hz), 6.97 (dd, 1H, J = 15.8; 10.5 Hz), 6.95 (d, 1H, J = 15.4 Hz), 6.83 (dd, J = 1H, 15.4; 10.5
Hz), 6.65 (d, 1H, J = 15.8 Hz), 5.62 (dd, 1H, J = 17.4; 1.2 Hz), 5.35 (dd, 1H, J = 11.0; 1.2 Hz); 13C
NMR (CDCl3, 150 MHz) δ/ppm 136.91 (s), 135.90 (s), 134.93 (s), 134.52 (d), 132.58 (d), 130.94
(d), 129.82 (d), 129.03 (d), 128.33 (d), 127.38 (d), 127.18 (d), 126.27 (d), 126.00 (d), 125.99 (d),
125.46 (d), 116.11 (t); MS m/z (%, fragment): 232 (100, M+).
12

ACCEPTED MANUSCRIPT
4-(4-(2-ethenylphenyl)buta-1,3-dien-1-yl)-N,N-dimethylaniline (3a): Yield 63.0%, according to
1H NMR spectroscopy, a mixture of 51% cis,trans- and 49% of trans,trans-isomer. HRMS for
C18H21N: M+calcd 275.1722; M+found 275.1713 (for a mixture of isomers of 3a).
cis,trans-3a: Rf 0.60 (petroleum ether/dichloromethane (30%)); yellow oil; UV (EtOH) λmax (logε)
1
355 (4.16); H NMR (CDCl3, 600 MHz) δ/ppm 7.50 (m, 1H), 7.27 (d, 1H, J = 7.2 Hz), 7.21-7.15
(m, 3H), 7.12 (dt, 1H, J = 7.8; 1.3 Hz), 6.86 (dd, 1H, J = 17.6; 11.3 Hz), 6.82-6.79 (m, 1H), 6.55 (d,
2H, J = 9.7 Hz), 6.53 (d, 1H, J = 15.9 Hz), 6.39 (t, 1H, J = 11.4 Hz), 6.37 (d, 1H, J = 11.4 Hz), 5.55
(dd, 1H, J = 17.4; 1.2 Hz), 5.20 (dd, 1H, J = 11.1; 1.2 Hz), 2.87 (s, 6H); too small a quantity of the
13
isolated isomer for the assignment of the C nuclei, as both geometrical isomers have the same Rf
value and due to the fast isomerization of the cis,trans-3 to trans,trans-3a; MS m/z (%, fragment):
128 (100);
trans,trans-3a: Rf 0.60 (petroleum ether/dichloromethane (30%)); yellow oil; UV (EtOH) λmax
(logε δ/ppm 7.54 (d, 1H, J = 7.8 Hz), 7.47 (d,
) 378 (4.33), 266 (4.09); 1H NMR (CDCl3, 600 MHz)
1H, J = 7.1 Hz), 7.31 (d, 2H, J = 9.0 Hz), 7.27 (dt, 1H, J = 7.7; 1.2 Hz), 7.19 (dt, 1H, J = 7.7; 1.2
Hz), 7.11 (dd, 1H, J = 17.2; 11.2 Hz), 6.91-6.81 (m, 3H), 6.71 (d, 2H, J = 9.0 Hz), 6.64 (d, 1H, J =
13
14.8 Hz), 5.65 (dd, 1H, J = 17.6; 1.5 Hz), 5.37 (d, 1H, J = 10.9; 1.5 Hz), 2.99 (s, 6H); C NMR
(CDCl3, 150 MHz) δ/ppm 150.1 (s), 136.0 (s), 135.9 (s), 135.2 (d), 133.5 (d), 132.2 (d), 127.8 (s),
127.6 (2d), 127.1 (d), 126.6 (d), 125.8 (s), 125.7 (d), 125.4 (d), 116.2 (t), 112.4 (2d), 40.4 (2q); MS
m/z (%, fragment): 275 (100, M+), 134 (50).
1-(4-(4-chlorophenyl)buta-1,3-dien-1-yl)-2-ethenylbenzene (4a): Yield 70.0%, lit.17 78.0%;
1
according to H NMR spectroscopy, a mixture of 50% cis,trans- and 50% of trans,trans-isomer.
HRMS for C18H15Cl: M+calcd 266.0857; M+found 266.0867 (for a mixture of isomers of 4a).
13

ACCEPTED MANUSCRIPT
cis,trans-4a: 45%; Rf 0.69 (petroleum ether/dichloromethane = 9:1); colourless oil; UV (EtOH) λmax
1
(log
ε
) 317 (4.43), 237 (4.33); H NMR (CDCl3, 600 MHz)
δ
/ppm 7.56 (dd, 1H, J = 8.0; 2.3 Hz),
7.30 – 7.28 (m, 3H), 7.26–7.23 (m, 4H), 6.97 (dd, 1H, J = 15.4; 11.0 Hz), 6.90 (dd, 1H, J = 17.5;
11.1 Hz), 6.64 (d, 1H, J = 11.2 Hz), 6.61 (d, 1H, J = 15.4 Hz,), 6.47 (t, 1H, J =11.2 Hz), 5.69 (d,
13
1H, J = 17.5 Hz); 5.29 (d, 1H, J = 11.1 Hz); C NMR (CDCl3, 150 MHz)
δ
/ppm 136.5 (s), 135.8
(2s), 135.6 (s), 135.1 (d), 133.0 (d), 130.9 (d), 130.2 (d), 129.9 (d), 128.7 (2d), 127.7 (2d), 127.6
(d), 127.4 (d), 126.1 (d), 125.8 (d), 115.7 (t); MS m/z (%, fragment): 266 (5, M+), 128 (100);
trans,trans-4a: 33%; Rf 0.66 (petroleum ether/dichloromethane = 9 : 1); colourless crystals; mp
1
110–113 °C; UV (EtOH) λmax (log
MHz)
ε
) 340 (4.57), 329 (4.56, sh), 265 (4.53); H NMR (CDCl3, 600
δ
/ppm 7.51 (dd, 1H, J = 7.3; 1.7 Hz), 7.45 (dd, 1H, J = 7.3; 1.7 Hz), 7.36 (d, 2H, J = 8.5 Hz),
7.29 (d, 2H, J = 8.5 Hz), 7.27 – 7.23 (m, 2H), 7.06 (dd, 1H, J = 17.3; 11.0 Hz), 6.98 (d, 1H, J = 15.3
Hz), 6.95 (dd, 1H, J = 15.4; 10.5 Hz), 6.82 (dd, 1H, J = 15.4; 10.5 Hz), 6.61 (d, 1H, J = 15.4 Hz),
5.63 (dd, 1H, J = 17.3; 1.2 Hz), 5.36 (dd, 1H, J = 11.0; 1.2 Hz); 13C NMR (CDCl3, 150
MHz) δ/ppm 135.9 (s), 135.4 (s), 134.7 (s), 134.4 (d), 132.7 (s), 131.0 (d), 130.5 (d), 130.4 (d),
129.6 (d), 128.3 (2d) 127.3 (d), 127.2 (d), 127.0 (2d), 126.3 (d), 125.4 (d), 116.1 (t); MS m/z (%,
fragment): 266 (100, M+), 121 (40).
1
1-ethenyl-2-(4-(4-fluorophenyl)buta-1,3-dien-1-yl)benzene (5a): Yield 50.0%, according to H
NMR spectroscopy, a mixture of 48% cis,trans- and 52% of trans,trans-isomer. HRMS for
C18H15F: M+calcd 250.1265; M+found 250.1256 (for a mixture of isomers of 5a).
cis,trans-5a: Rf 0.59 (petroleum ether); bright yellow oil; UV (EtOH) λmax (logε) 319 (4.41), 224
(4.30); 1H NMR (CDCl3, 600 MHz) δ/ppm 7.40-7.35 (m, 3H), 7.31-7.28 (m, 2H), 7.06 (dd, 1H, J =
17.2; 10.9 Hz), 6.93-6.86 (m, 3H), 6.83 (dd, 1H, J = 15.7; 11.2 Hz), 6.65 (d, 1H, J = 10.6 Hz), 6.62
(d, 1H, J = 15.7 Hz), 6.61 (d, 1H, J = 15.6 Hz), 6.48 (t, 1H, J = 11.2 Hz), 5.63 (dd, 1H, J = 17.2; 1.3
Hz), 5.29 (dd, 1H, J = 10.9; 1.3 Hz); 13C NMR (CDCl3, 150 MHz)
δ/ppm 136.3 (s), 135.7 (s), 135.4
(s), 135.2 (s), 134.8 (d), 133.1 (d), 131.6 (d), 130.9 (d), 130.6 (d), 130.2 (d), 129.6 (d), 127.9 (2d),
127.8 (2d), 124.4 (d), 125.7 (d), 115.4 (t); MS m/z (%, fragment): 250 (2, M+), 128 (100);
14

ACCEPTED MANUSCRIPT
trans,trans-5a: Rf 0.59 (petroleum ether); bright yellow oil; UV (EtOH) λmax (logε) 343 (4.54), 269
(4.56); 1H NMR (CDCl3, 600 MHz)
δ/ppm 7.59-7.51 (m, 2H), 7.46 (dd, 1H, J = 7.2; 1.7 Hz), 7.27-
7.15 (m, 6H), 7.01-6.94 (m, 2H), 6.62 (d, 1H, J = 15.6 Hz), 6.61 (d, 1H, J = 15.6 Hz), 5.69 (dd, 1H,
13
J = 17.4; 1.3 Hz), 5.37 (dd, 1H, J = 11.4; 1.3 Hz); C NMR (CDCl3, 150 MHz)
δ
/ppm 136.4 (s),
135.9 (s), 135.6 (s), 135.2 (s), 135.1 (d), 133.3 (d), 131.7 (d), 131.1 (d), 130.7 (d), 130.2 (d), 129.6
(d), 128.0 (2d), 127.8 (2d), 127.5 (d), 125.8 (d), 115.6 (t); MS m/z (%, fragment): 250 (100, M+),
135 (90).
1-ethenyl-2-(4-(4-methoxyphenyl)buta-1,3-dien-1-yl)benzene (6a): Yield 65.0%, lit.18 69.0%;
1
according to H NMR spectroscopy, a mixture of 50% cis,trans- and 50% of trans,trans-isomer.
HRMS for C19H18O: M+calcd. 262.1352; M+found 262.1347 (for a mixture of isomers 6a).
cis,trans-6a: 32%; Rf 0.28 (petroleum ether/dichloromethane = 8:2); colourless oil; UV (96%
) 323 (4.73), 235 (4.56); 1H NMR (CDCl3, 600 MHz)
EtOH) λmax (log ε δ/ppm 7.56 (d, 1H, J = 9.0
Hz), 7.31 (d, 1H, J = 8.9 Hz), 7.28 (d, 2H, J = 8.7 Hz), 7.25–7.29 (m, 2H), 6.92 (dd, 1H, J = 17.4;
11.0 Hz), 6.90 (dd, 1H, J = 15.6; 11.1 Hz), 6.82 (d, 2H, J = 8.7 Hz), 6.63 (d, 1H, J = 15.6 Hz), 6.55
(d, 1H, J = 11.2 Hz), 4.46 (t, 1H, J = 11.1 Hz), 5.68 (dd, 1H, J = 17.4; 1.1 Hz), 5.28 (dd, 1H, J =
11.0; 1.1 Hz), 3.79 (s, 3H, -OCH3); 13C NMR (CDCl3, 150 MHz) δ/ppm 158.9 (s), 136.0 (s), 135.4
(s), 134.7 (d), 133.6 (d), 130.9 (d), 129.7 (d), 129.6 (s), 127.6 (d), 127.5 (d), 127.3 (2d), 126.8 (2d),
125.2 (d), 123.0 (d), 115.0 (t), 113.6 (d), 54.8 (q); MS m/z (%, fragment): 262 (2, M+), 128 (100);
trans,trans-6a: 37%; Rf 0.25 (petroleum ether/dichloromethane = 8:2); colourless crystals; mp 114-
1
116 °C; UV (96% EtOH) λmax (log ε) 344 (4.32); H NMR (CDCl3, 600 MHz)
δ
/ppm 7.51 (d, J =
7.5 Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.38 (d, J = 8.6 Hz, 2H), 7.24 (dt, J = 7.5; 0.9 Hz, 1H), 7.21
(dt, J = 7.5; 0.9 Hz, 1H), 7.07 (dd, J = 17.4; 11.0 Hz, 1H), 6.91 (d, J = 14.7 Hz, 1H), 6.88 (d, J = 8.6
Hz, 2H), 6.80 – 6.88 (m, 2H), 6.63 (d, J = 14.7 Hz, 1H), 5.62 (dd, J = 17.4; 1.1 Hz, 1H), 5.35 (dd, J
= 11.0; 1.1 Hz, 1H), 3.82 (s, 3H, -OCH3); 13C NMR (CDCl3, 150 MHz) δ 158.9 (s), 135.7 (s), 135.1
(s), 134.5 (d), 132.1 (d), 131.2 (d), 129.7 (s), 128.6 (d), 127.3 (d), 127.1 (2d), 127.0 (d), 126.9 (2d),
126.2 (d), 125.3 (d), 115.9 (t), 113.7 (d), 54.8 (q); MS m/z (%, fragment): 262 (100, M+).
15

ACCEPTED MANUSCRIPT
1
2-(2-(2-ethenylphenyl)ethenyl]furan (7a): Yield 71.0%, lit.48 85.0%; according to H NMR
spectroscopy, a mixture of 30% cis- and 70% of trans-isomer. HRMS for C14H12O: M+
calcd
196.0957; M+found 196.0969 (for a mixture of isomers of 7a).
cis-7a: Rf 0.50 (petroleum ether); colourless oil; UV (EtOH) λmax (logε) 305 (3.96), 280 (3.99), 255
1
(4.13); H NMR (CDCl3, 600 MHz) δ/ppm 7.60-7.10 (m, 5H), 6.89 (dd, 1H, J = 17.5; 10.9 Hz),
6.54 (d, 1H, J = 12.2 Hz), 6.50 (d, 1H, J = 12.2 Hz), 6.21 (dd, 1H, J = 3.4; 2.0 Hz), 5.90 (dd, 1H, J
= 3.4; 0.5 Hz), 5.61 (dd, 1H, J = 17.5; 1.4 Hz), 5.22 (dd, 1H, J = 10.9; 1.4 Hz); 13C NMR (CDCl3,
150 MHz) δ/ppm 152.1 (s), 141.5 (s), 136.4 (s), 135.9 (s), 134.9 (d), 129.2 (d), 127.6 (d), 126.7 (d),
125.3 (d), 119.8 (d), 118.2 (d), 115.2 (t), 111.2 (d), 109.5 (d); MS m/z (%, fragment): 196 (100,
M+);
trans-7a: Rf 0.40 (petroleum ether); colourless oil; UV (EtOH) λmax (logε) 340 (4.00), 322 (4.29),
1
310 (4.30), 256 (4.15); H NMR (CDCl3, 600 MHz)
δ
/ppm 7.60-7.12 (m, 6H), 7.10 (dd, 1H, J =
17.5; 10.9 Hz), 6.76 (d, 1H, J = 16.1 Hz), 6.41 (dd, 1H, J = 3.4; 2.0 Hz), 6.33 (dd, 1H, J = 3.4; 0.5
Hz), 5.63 (dd, 1H, J = 17.5; 1.4 Hz), 5.35 (dd, 1H, J = 10.9; 1.4 Hz); 13C NMR (CDCl3, 150 MHz)
δ
/ppm 153.4 (s), 142.2 (s), 136.5 (s), 135.2 (s), 135.0 (d), 127.8 (d), 127.6 (d), 126.7 (d), 125.8 (d),
124.8 (d), 118.6 (d), 116.5 (t), 111.6 (d), 108.6 (d); MS m/z (%, fragment): 196 (100, M+);
General procedure for synthesis of benzobicyclo[3.2.1]octadiene structures 1-7 by batch
photoreaction: A mixture of isomers of the corresponding starting compounds 1a-7a (50 mg) were
dissolved in toluene (50 mL) and transferred to a quartz or pyrex vessel, purged with argon for 20
minutes, and irradiated with 16 UV lamps at 300 or 350 nm for 5 or 16 h. After removal of the
solvent, GC-MS and NMR measurements showed unreacted starting material and the photoproduct
1-7. The crude product was purified by column chromatography using petroleum ether/diethylether
(0-50%) as eluent. In the first fractions the starting compounds 1a-7a were isolated according to
NMR analyses followed by the photoproducts 1-7. High-molecular-weight products remained on
the column.
General procedure for synthesis of benzobicyclo[3.2.1]octadiene structures 1-7 by continuous
flow photoreaction: a) A 2 mL of 0.093 mmol/mL solution in toluene of mixture of isomers of
16

ACCEPTED MANUSCRIPT
starting compound, obtained by Wittig reaction as the starting substrate for the synthesis of
photoproducts 1, 2 and 4-7, were purged with argon for 5 minutes, placed in injection loop and
passed through a 19 m reactor system consisting of fluorinated ethylene–propylene copolymer
(FEP) tubing (IDEX Health and Science, natural color, 1.57 mm outer diameter, 0.76 mm inner
diameter), wraped around the pyrex cuvettes and placed in a Rayonet reactor, using plunger pump
(piston pump; Flash Master Personal Argonaut). Reaction loop was irradiated with 16 UV lamps at
300 or 350 nm. Residence times were 6 or 12 mim, and after the removal of the solvent, full
conversion to photoproducts 1, 2 and 4-7 was detected by GC-MS system and 1H NMR spectra also
show no unreacted starting material. Solvent was removed and crude product was purified by
column chromatography using petroleum ether/diethylether (0-10%) as eluent to afford the products
in 48-95% of the desired benzobicyclo[3.2.1]-derivatives 1, 2 and 4-7 as white crystals (1, 5 and 7),
or as colourless oil (2, 4 and 6). High-molecular-weight products remained on the column.
b) A 2 mL of 0.093 mmol/mL solution in toluene of mixture of isomers of starting compound,
obtained by Wittig reaction as the starting substrate for the synthesis of dimethylamino derivative 3,
was purged with argon for 5 minutes, placed in injection loop and pumped through a 19 m reactor
system consisting of fluorinated ethylene–propylene copolymer (FEP) tubing (IDEX Health and
Science, natural color, 1.57 mm outer diameter, 0.76 mm inner diameter). Reaction loop was
irradiated with 16 UV lamps at 350 nm. Residence time was 12 min, 60% conversion was observed
by GC-MS system and NMR measurements. Solvent was removed and crude product was obtained
as dark yellow oil that was purified by column chromatography using petroleum ether/diethylether
(0-50%) as eluent. In the first fractions 20% of the mixture of the starting isomerrs 3a was isolated
according to NMR analyses followed by the photoproduct endo-3. High-molecular-weight products
remained on the column.
17

ACCEPTED MANUSCRIPT
11-methyltricyclo[6.3.1.0²,⁷]dodeca-2,4,6,9-tetraene (endo-1): Yield 48.0%; High-molecular-
weight products remained on the column. HRMS for C13H14: M+calcd 170.1157; M+found 170.1148.
1
endo-1: Rf 0.60 (petroleum ether); colourless crystals; mp 49 ºC; H NMR (CDCl3, 600 MHz)
δ
/ppm 7.21-6.92 (m, 4H), 6.14 (m, 1H), 5.03 (m, 1H), 3.15 (m, 2H), 2.64 (m, 1H), 2.41 (m, 1H),
2.18 (d, 1H, J = 9.2 Hz), 0.82 (d, J = 10.1 Hz, 3H); 13C NMR (CDCl3, 150 MHz)
δ
/ppm 143.3 (s),
142.1 (s), 125.9 (d), 125.8 (d), 125.3 (d), 125.2 (d), 123.3 (d), 120.1 (d), 42.5 (t), 39.4 (d), 37.5 (d),
29.2 (d), 10.8 (q); MS m/z (%, fragment): 170 (100, M+), 115 (20).
11-phenyltricyclo[6.3.1.0²,⁷]dodeca-2,4,6,9-tetraene (endo-2): Yield 95.0%, lit.19 90.0%; High-
molecular-weight products remained on the column. HRMS for C18H16: M+
232.1334; M+
calcd
found
232.1341.
1
endo-2: Rf 0.44 (petroleum ether); colourless crystals; mp 51 ºC; H NMR (CDCl3, 600 MHz)
δ
/ppm 7.17-7.18 (m, 3H), 7.12 (d, 1H, J = 7.3 Hz), 7.03 (t, 1H, J = 7.4 Hz), 6.81 (t, 1H, J = 7.4 Hz),
6.73-6.76 (m, 2H), 6.37 (ddd, 1H, J = 9.5 Hz; J = 6.0 Hz; J = 2.5 Hz), 6.18 (d, 1H, J = 7.3 Hz), 5.33
(dt, 1H, J = 9.5 Hz; J = 2.5 Hz), 3.98 (m, 1H), 3.38 (t, 1H, J = 4.7 Hz), 3.29 (dd, 1H, J = 6.0; 4.7
Hz), 2.52 (dt, 1H, J = 9.9; 4.7 Hz), 2.38 (d, 1H, J = 9.9 Hz,); 13C NMR (CDCl3, 150 MHz)
δ
/ppm 152.27 (s), 142.44 (s), 141.93 (s), 132.71 (d), 128.21 (d), 127.60 (d), 126.34 (d), 126.10 (d),
126.05 (d), 125.97 (d), 124.89 (d), 120.03 (d), 48.59 (d), 46.29 (d), 44.13 (t), 40.37 (d); MS m/z (%,
fragment): 232 (100, M+), 117 (25), 115 (10).
18

ACCEPTED MANUSCRIPT
N,N-dimethyl-4-{tricyclo[6.3.1.0²,⁷]dodeca-2,4,6,10-tetraen-9-yl}aniline (endo-3): Yield 24.0%;
High-molecular-weight products remained on the column. HRMS for C18H21N: M+
275.1722;
calcd
M+found 275.1733.
1
endo-3: Rf 0.57 (petroleum ether/dichloromethane (30%)); dark yellow oil; H NMR (CDCl3, 600
MHz) δ/ppm 7.20-7.18 (m, 3H), 7.10 (d, 1H, J = 7.2 Hz), 7.05 (t, 1H, J = 7.2 Hz), 6.83-6.76 (m,
2H), 6.35 (dt, 1H, J = 9.0; 2.5 Hz), 6.20 (d, 1H, J = 7.3 Hz), 5.30 (m, 1H), 3.89 (ddd, 1H, J = 9.8;
4.7; 2.5 Hz), 3.30 (t, 1H, J = 4.7 Hz), 3.21 (d.d., 1H, J = 6.8; 4.7 Hz), 2.86 (s, 6H), 2.44 (dt, 1H, J =
13
9.9; 4.7 Hz), 2.30 (d, 1H, J = 9.9 Hz); C NMR (CDCl3, 150 MHz)
δ
/ppm 152.6 (s), 152.4 (s),
142.1 (s), 138.3 (s), 135.4 (d), 127.9 (2d), 127.8 (2d), 126.8 (d), 125.5 (d), 125.2 (d), 124.8 (d),
121.7 (d), 53.9 (d), 49.2 (d), 46.9 (d), 46.5 (t), 45.7 (2q); MS m/z (EI) 275 (M+, 100%), 121 (50).
11-(4-chlorophenyl)tricyclo[6.3.1.0²,⁷]dodeca-2,4,6,9-tetraene (endo-4): Yield 83.0%, lit.17
77.0%; High-molecular-weight products remained on the column. HRMS (-H+) for C18H15Cl:
M+calcd. 265.0789; M+found 265.0786.
1
endo-4: Rf 0.66 (petroleum ether/dichloromethane = 9 : 1); colourless oil; H NMR (CDCl3, 600
MHz) δ/ppm 7.14 (d, 2H, J = 8.4 Hz), 7.12 (d, 1H, J = 7.3 Hz), 7.03 (dt, 1H, J = 7.4; 1.0 Hz), 6.84
(dt, 1H, J = 7.4; 1.0 Hz), 6.65 (d, 2H, J = 8.3 Hz), 6.40–6.35 (m, 1H), 6.23 (d, 1H, J = 7.3 Hz), 5.25
(ddd, 1H, J = 9.6; 4.0; 1.9 Hz), 3.96–3.92 (m, 1H), 3.34 (t, 1H, J = 9.4; 4.7 Hz), 3.29 (dd, 1H, J =
6.1; 4.7 Hz), 2.54–2.50 (m, 1H), 2.37 (d, 1H, J = 10.0 Hz); 13C NMR (CDCl3, 150 MHz)
δ/ppm
140.6 (s), 137.3 (s), 132.9 (s), 130.9 (s), 134.7 (d), 129.2 (2d), 127.3 (d), 125.7 (d), 125.6 (d), 125.4
(2d), 124.7 (d), 119.7 (d), 48.0 (d), 45.3 (d), 43.7 (t), 39.9 (d).
11-(4-fluorophenyl)tricyclo[6.3.1.0²,⁷]dodeca-2,4,6,9-tetraene (endo-5): Yield 87.0%; High-
molecular-weight products remained on the column. HRMS for C18H15F: M+
250.1265; M+
calcd
found
250.1256.
1
endo-5: Rf 0.60 (petroleum ether); colourless crystals; mp 53-54 ºC; H NMR (CDCl3, 600 MHz)
δ
/ppm 7.11 (d, 1H, J = 6.9 Hz), 7.04-6.99 (m, 2H), 6.87-6.81 (m, 2H), 6.66 (m, 2H), 6.37-6.33 (m,
1H), 6.20 (d, 1H, J = 7.9 Hz), 5.27-5.26 (m, 1H), 3.95-3.93 (m, 1H), 3.33 (t, 1H, J = 4.8 Hz), 3.27
(dd, 1H, J = 6.4; 4.8 Hz), 2.50 (dt, 1H, J = 9.8; 4.7 Hz), 2.35 (d, 1H, J = 9.8 Hz); 13C NMR (CDCl3,
150 MHz) δ/ppm 141.8 (s), 138.2 (s), 135.8 (s), 135.5 (s), 135.0 (d), 129.7 (2d), 129.6 (d), 126.2
(2d), 126.1 (d), 125.1 (d), 120.2 (2), 48.6 (d), 45.5 (d), 44.1 (t), 40.3 (d); MS m/z (%, fragment): 250
(100, M+), 135 (25).
19

ACCEPTED MANUSCRIPT
²,7
11-(4-methoxyphenyl)tricyclo[6.3.1.0 ]dodeca-2,4,6,9-tetraene (endo-6): Yield 70.0%, lit.18
55.0%; High-molecular-weight products remained on the column. HRMS for HRMS for C19H18O:
M+calcd. 262.1352; M+found 262.1351.
1
endo-6: Rf 0.27 (petroleum ether/dichloromethane = 8:2); colourless crystals; mp 45-47 °C; H
NMR (CDCl3, 600 MHz) δ/ppm: 7.11 (d, 1H, J = 7.3 Hz), 7.03 (dt, 1H, J = 7.3; 1.0 Hz), 6.82 (dt,
1H, J = 7.3; 1.0 Hz), 6.72 (d, 2H, J = 8.6 Hz), 6.64 (d, 2H, J = 8.6 Hz), 6.32-6.36 (m, 1H), 6.25 (d,
1H, J = 7.3 Hz), 5.28 (dt, 1H, J = 9.6; 2.6 Hz), 3.91-3.94 (m, 1H), 3.77 (s, 3H), 3.35 (t, 1H, J = 4.5
Hz), 3.27 (dd, 1H, J = 6.3; 4.7 Hz), 2.49-2.53 (m, 1H), 2.37 (d, 1H, J = 9.9 Hz); 13C NMR (CDCl3,
75 MHz) δ/ppm: 157.6 (s), 152.0 (s), 141.7 (s), 134.2 (s), 134.1 (d), 128.8 (2d), 126.3 (d), 125.8 (d),
125.5 (d), 124.5 (d), 119.6 (d), 112.6 (2d), 52.4 (q), 48.2 (d), 45.0 (d), 43.7 (t), 40.3 (d); MS m/z (%,
fragment): 262 (100, M+), 154 (75), 115 (50).
5-oxatetracyclo[6.6.1.0²,⁶.0⁹,¹⁴]pentadeca-2(6),3,9(14),10,12-pentaene (7): Yield 92.0%, lit.16
90.0%; High-molecular-weight products remained on the column. HRMS for C14H12O: M+
calcd
196.0957; M+found 196.0950.
1
endo-7: Rf 0.41 (petroleum ether); colourless crystals; mp 58-59 ºC; H NMR (CDCl3, 300 MHz)
δ
/ppm 7.30-6.90 (m, 5H), 6.30 (d, 1H, J = 2.0 Hz), 3.78 (d, 1H, J = 4.5 Hz), 3.57 (dt, 1H, J = 5.0;
1.0 Hz), 3.11 (dd, 1H, J = 16.0; 5.0 Hz), 2.58 (dd, 1H, J = 16.0; 1.0 Hz), 2.39 (dt, 1H, J = 10.0; 5.0;
4.5 Hz), 2.01 (d, 1H, J = 10 Hz); 13C NMR (CDCl3, 150 MHz)
/ppm 151.9 (s), 146.7 (s), 144.8 (s),
δ
140.1 (d), 126.4 (d), 126.1 (d), 124.3 (s), 123.8 (d), 120.5 (d), 108.7 (d), 43.0 (t), 40.4 (d), 39.3 (d),
30.9 (t); MS m/z (EI) 196 (M+, 100%), 167 (25).
5. Acknowledgments
The authors thank I. Grgičević for his technical assistance in the initial part of this work.
6. References
[1] Abad, A.; Agulló, C.; Cuñat, A. C.; de Alfonso, I.; Navarro, I.; Vera, N. Molecules 2004, 9,
287-299.
[2] Miller, J. A.; Harris, J.; Miller, A. A.; Ullaha, G. M.; Welsh, G. M. Tetrahedron Letters
2004, 45, 4323-4327.
20

ACCEPTED MANUSCRIPT
[3] Kavitha, C. V.; Nambiar, M.; Narayanaswamy, P. B.; Thomas, E.; Rathore, U., Kumar, C. S.
A.; Choudhary, B.; Rangappa, K. S.; Raghavan, S. C. PlosOne 2013, 8.
[4] Mascitti, V.; Preville, C. Org. Lett. 2010, 12, 2940-2943.
[5] Thomson, C. G.; Carlson, E.; Chicchi, G. G.; Kulagowski, J. J.; Kurtz, M. M.; Swain, C. J.;
Tsaoc, K. L. C.; Wheeldon, A. Bioorg. Med. Chem. Lett. 2006, 16, 811-814.
[6] Presset, M.; Coquerel, Y.; Rodriguez, J. Chem.Rev. 2013, 113, 525-595.
[7] Filippini, M. H.; Rodriguez, J. Chem. Rev. 1999, 99, 27-76.
[8] Kraus, G. A.; Hon, Y. S.; Sy, J. J. Org. Chem. 1986, 51, 2625-2627.
[9] Mandzhulo, A. Yu.; Mel’nichuk, N. A.; Fetyukhin, V. N.; Vovka, M. V. Russian Journal of
OrganicChemistry 2016, 52, 87-91.
[10] Meltzer, P. C.; Blundell, P.; Yong, Y. F.; Chen, Z.; George, C.; Gonzalez, M. D.; Madras,
B. K. J. Med. Chem. 2000, 43, 2982-2991.
[11] Su, X.; Sun, Y.; Yao, J.; Chen, H.; Chen, C. Chem. Commun. 2016, 52, 4537-4540.
[12] Sakata, J.; Ando, Y.; Ohmori, K.; Suzuki, K. Org. Lett. 2015, 17, 3746-3749.
[13] Jones, P. S.; Smith, P. W.; Hardy, G. W.; Howes, P. D.; Upton, R. J.; Bethell, R. C.
Bioorganic & Medicinal Chemistry Letters 1999, 9, 605-610.
[14] Nitta, M.; Okada, S.; Kato, M. Bull. Chem. Soc. Jpn. 1984, 57, 2463-2467.
[15] Klumpp, G. W.; Barnick, J. W. F. K.; Veefkind, A. H.; Bickelhaupt, F. Recueil 1969, 88,
766-778.
[16] Šindler-Kulyk, M.; Špoljarić, L.; Marinić, Ž. Heterocycles 1989, 29, 679-682.
[17] Vuk, D.; Potroško, D.; Šindler-Kulyk, M.; Marinić, Ž.; Molčanov, K.; Kojić-Prodić, B.;
Škorić, I. J. Mol. Structure 2013, 1051, 1-14.
[18] Vuk, D.; Marinić, Ž.; Škorić, I. Croat. Chem. Acta 2014, 87, 465-473.
[19] Škorić, I.; Šmehil, M.; Marinić, Ž.; Molčanov, K.; Kojić-Prodić, B.; Šindler-Kulyk, M. J.
Photochem. Photobiol. 2009, 207, 190-196.
[20] Šagud, I.; Levačić, M.; Marinić, Ž.; Škorić, I. Eur. J. Org. Chem. 2017, 3787-3794.
[21] Plutschack, M. B.; Pieber, B.; Gilmore, K.; Seeberger, P. H. Chem. Rev. 2017, 117, 11796-
11893.
[22] Koenig, S. G.; Sneddon, H. F. Green Chem. 2017, 19, 1418-1419.
[23] Mohamed, D. K. B.; Yu, X.; Li, J.; Wu, J. Tetrahedron Letters 2016, 57, 3965-3977.
[24] Cambié, D.; Bottecchia, C.; Straathof, N. J. W.; Hessel, V.; Noël, T. Chem. Rev. 2016, 116,
10276-10341.
21

ACCEPTED MANUSCRIPT
[25] Gioiello, A.; Mancino, V.; Filipponi, P.; Mostarda, S.; Cerra, B. J. Flow Chem. 2016, 6,
167-180.
[26] Calleri, E.; Cattaneo, G.; Rabuffetti, M.; Serra, I.; Bavaro, T.; Massolini, G.; Speranza, G.;
Ubiali, D. Adv. Synth. Catal. 2015, 357, 2520-2528.
[27] Elliott, L. D.; Knowles, J. P.; Koovits, P. J.; Maskill, K. G.; Ralph M. J.; Lejeune, G.;
Edwards, L. J.; Robinson, R. I.; Clemens, I. R.; Cox, B.; Pascoe, D. D.; Koch, G.; Eberle, M.;
Berry, M. B.; Booker- Milburn, K. I. Chem. Eur. J. 2014, 20, 15226-15232.
[28] Kopetzki, D.; Lēvesque, F.; Seeberger, P. H. Chem. Eur. J. 2013, 19, 5450-5456.
[29] Nettekoven, M.; Püllmann, B.; Martin, R. E.; Wechsler, D. Tetrahedron Letters 2012, 53,
1363-1366.
[30] Wegner, J.; Ceylan, S.; Kirschninga, A. Adv. Synth. Catal. 2012, 354, 17-57.
[31] DeLaney, E. N.; Lee, D. S.; Elliott, L. D.; Jin, J.; Booker-Milburn, K. I.; Poliakoff, M.;
George, M. W. Green Chem. 2017, 19, 1431-1438.
[32] Loubièrea, K.; Oelgemöllerc, M.; Ailleta, T.; Dechy-Cabareta, O.; Prata, L. Chemical
Engineering and Processing 2016, 104, 120-132.
[33] Gilmore, K.; Seeberger, P. H.; Chem. Rec. 2014, 14, 410-418.
[34] Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I. Beilstein J. Org. Chem. 2012, 8, 2025–
2052.
[35] Wendell, Ch. I.; Boyd, M. J. Tetrahedron Letters 2015, 56, 897-899.
[36] Lēvesque, F.; Seeberger, P. H. Org. Lett. 2011, 13, 5008-5011.
[37] Bach, T.; Hehn, J. P. Angew. Chem. Int. Ed. 2011, 50, 1000-1045.
[38] Škorić, I.; Basarić, N.; Marinić, Ž.; Višnjevac, A.; Kojić-Prodić, B.; Šindler-Kulyk, M.
Chem. Eur. J. 2005, 11, 543-551.
[39] Vidaković, D.; Škorić, I.; Horvat, M.; Marinić, Ž.; Šindler-Kulyk, M. Tetrahedron 2008,
64, 3928-3934.
[40] Basarić, N.; Marinić, Ž.; Šindler-Kulyk, M. J. Org. Chem. 2006, 71, 9382-9392.
[41] Butković, K.; Marinić, Ž.; Molčanov, K.; Kojić-Prodić, B.; Šindler-Kulyk, M. Beilstein J.
Org. Chem. 2011, 7, 1663-1670.
[42] Šagud, I.; Antol, I.; Marinić, Ž.; Šindler-Kulyk, M. J. Org. Chem. 2015, 80, 9535-9541.
[43] Kikaš, I.; Horváth, O.; Škorić, I. Tetrahedron Letters 2011, 52, 6255-6259.
[44] Pajouhesh, H.; Lenz, G. R. NeuroRx 2005, 2, 541-553.
[45] Alavijeh, M. S.; Chishty, M.; Qaiser, M. Z.; Palmer, A. M. NeuroRx 2005, 2, 554-571.
22

ACCEPTED MANUSCRIPT
[46] Testa, B.; Crivori, P.; Reist, M.; Carrupt, P. A. Perspectives in Drug Discovery and Design
2000, 19,179–211.
[47] Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Aceña, J. L.; Soloshonok, V. A.; Izaw, K.;
Liu, H. Chem. Rev. 2016, 116, 422–518.
[48] Šindler-Kulyk, M.; Stiplošek, Z.; Vojnović, D.; Metelko, B.; Marinić, Ž. Heterocycles
1991, 32, 2357-2363.
5.
Supporting Information
Supporting information consists of actinometry experiments, mass spectra of the photoproducts 1-7,
table of biological targets and effects predicted by Pass (in silico) for structures 1-7 and table with
general values for prediction of physico-chemical and ADME properties.
23

ACCEPTED MANUSCRIPT
Flow-photochemical Synthesis of the Functionalized
Benzobicyclo[3.2.1]octadiene Skeleton
Ana Ratkovića, Željko Marinićb and Irena Škorića,
aDepartment of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb,
Marulićev trg 19, 10 000 Zagreb, Croatia
bNMR Center, Rudjer Bošković Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia
Highlights
ꢀ
ꢀ
ꢀ
ꢀ
A convenient practical home-made continuous flow-photochemistry setup enables efficient
intramolecular photocycloaddition.
The first application of continuous flow methodology in the synthesis of functionalized
benzobicyclo[3.2.l]-skeleton.
Higher yields and shorter reaction times in comparison to those obtained in traditional batch
photoreactor.
Promising calculated physico-chemical and ADME properties of the obtained potentially
bioactive photoproducts.
Corresponding author. Tel.: +385 1 4597 241; fax: ++385 1 4597 250; e-mail: iskoric@fkit.hr.