[3 + 2] Cycloaddition with photogenerated azomethine ylides in β-cyclodextrin

Article abstract of DOI:10.3762/bjoc.16.110

Stability constants for the inclusion complexes of cyclohexylphthalimide 2 and adamantylphthalimide 3 with β-cyclodextrin (β-CD) were determined by ¹H NMR titration, K = 190 ± 50 M^?1, and K = 2600 ± 600 M^?1, respectively. Photochemical reactivity of the inclusion complexes 2&at;β-CD and 3&at;β-CD was investigated, and we found out that β-CD does not affect the decarboxylation efficiency, while it affects the subsequent photochemical H-abstraction, resulting in different product distribution upon irradiation in the presence of β-CD. The formation of ternary complexes with acrylonitrile (AN) and 2&at;β-CD or 3&at;β-CD was also essayed by ¹H NMR. Although the formation of such complexes was suggested, stability constants could not be determined. Irradiation of 2&at;β-CD in the presence of AN in aqueous solution where cycloadduct 7 was formed highly suggests that decarboxylation and [3 + 2] cycloaddition take place in the ternary complex, whereas such a reactivity from bulky adamantane 3 is less likely. This proof of principle that decarboxylation and cycloaddition can be performed in the β-CD cavity has a significant importance for the design of new supramolecular systems for the control of photoreactivity.

Full text of DOI:10.3762/bjoc.16.110

[3 + 2] Cycloaddition with photogenerated azomethine ylides
in β-cyclodextrin
Margareta Sohora‡1, Leo Mandić‡1,2 and Nikola Basarić*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2020, 16, 1296–1304.
1Department of Organic Chemistry and Biochemistry, Ruđer Bošković
Institute, Bijenička cesta 54, 10 000 Zagreb, Croatia. Fax: +385 1
4680 195; Tel: +385 12 4561 141 and 2Department of Material
Chemistry, Ruđer Bošković Institute, Bijenička cesta 54, 10 000
Zagreb, Croatia
doi:10.3762/bjoc.16.110
Received: 03 April 2020
Accepted: 28 May 2020
Published: 12 June 2020
Email:
This article is part of the thematic issue "Molecular recognition".
Guest Editor: I. Piantanida
Nikola Basarić* - nbasaric@irb.hr
* Corresponding author ‡ Equal contributors
© 2020 Sohora et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
[3 + 2] cycloadditions; β-cyclodextrin; inclusion complexes;
photochemistry; phthalimides
Abstract
Stability constants for the inclusion complexes of cyclohexylphthalimide 2 and adamantylphthalimide 3 with β-cyclodextrin (β-CD)
were determined by 1H NMR titration, K = 190 ± 50 M−1, and K = 2600 ± 600 M−1, respectively. Photochemical reactivity of the
inclusion complexes 2@β-CD and 3@β-CD was investigated, and we found out that β-CD does not affect the decarboxylation effi-
ciency, while it affects the subsequent photochemical H-abstraction, resulting in different product distribution upon irradiation in
the presence of β-CD. The formation of ternary complexes with acrylonitrile (AN) and 2@β-CD or 3@β-CD was also essayed by
1H NMR. Although the formation of such complexes was suggested, stability constants could not be determined. Irradiation of
2@β-CD in the presence of AN in aqueous solution where cycloadduct 7 was formed highly suggests that decarboxylation and
[3 + 2] cycloaddition take place in the ternary complex, whereas such a reactivity from bulky adamantane 3 is less likely. This proof
of principle that decarboxylation and cycloaddition can be performed in the β-CD cavity has a significant importance for the design
of new supramolecular systems for the control of photoreactivity.
Introduction
Cycloadditions are highly useful reactions in organic synthesis lecular reactions [8]. Azomethine ylides can be formed by
providing complex cyclic structures from easily available pre- several photochemical or thermal catalytic methods [5-7], in-
cursors [1,2]. Among different reactions, [3 + 2] cycloadditions cluding photodecarboxylation of phthalimide derivatives of
showed applicability in the synthesis of heterocyclic 5-ring α-amino acids such as N-phthaloylglycine (1) [9,10].
compounds [3], as well as in the green synthesis of a number of
natural products [4]. One of the useful synthons in [3 + 2] Phthalimide is a versatile chromophore that has been used in the
cycloadditions is azomethine ylide [5-7], also used in intramo- synthesis of complex molecules and natural products [11] since
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the pioneering work of Kanaoka et al. [12]. Photochemical reac- turally modified CDs [42-47]. Since β-CD is often used in phar-
tions of phthalimides include H-abstractions, cycloadditions and maceutical applications for solubilization of drugs or drug
photoinduced electron transfer (PET)[13]. We became inter- delivery [48], it would be interesting to investigate its effects to
ested in the application of photochemical H-abstraction reac- the photodecarboxylation reaction. Therefore, we investigated
tions initiated by phthalimides in organic synthesis [14,15]. photochemical reactivity of phthalimide derivatives 1–3
Furthermore, H-abstractions were investigated in inclusion (Figure 1) in solution without β-CD and in the β-CD inclusion
complexes, in the cavity of β-cyclodextrins (β-CD) [16]. We complexes. Phthalimides 1–3 yield azomethine ylides 1AMY-
found out that H-abstraction reactions were about ten times 3AMY that are anticipated to react with acrylonitrile (AN) in
more efficient in the β-CD complexes than in the isotropic solu- [3 + 2] cycloadditions, which should be affected by β-CD.
tion, and the macrocyclic host affected the stereochemistry of
the reaction. Moreover, we studied photodecarboxylation reac- Results and Discussion
tions initiated by the phthalimide chromophore [17-19] and Phthalimide derivatives 1–3 were prepared according to proce-
applied them in cyclizations with memory of chirality [20] and dures published in precedent literature [17]. The synthesis
diastereoselective peptide cyclizations [21]. Photodecarboxyla- involves condensation of phthalic anhydride with unprotected
tions were also intensively investigated in a series of nons- amino acid. The synthetic procedures and characterization of
teroidal anti-inflammatory drugs [22-24] such as ketoprofen compounds are reported in Supporting Information File 1. Irra-
[25-34], due to photoallergic responses initiated by photodecar- diation of 1 was conducted first in CH3CN in the presence of
boxylation of these drugs [35].
AN, with or without addition of H2O (Table 1). Phthalimide 1
most probably undergoes decarboxylation delivering 1AMY
Stereoselectivity in photochemical reactions can be achieved by from the S1 state [49]. In CH3CN, 1AMY decays with a rate
use of supramolecular chemistry [36,37]. For example, stereose- constant of 2.9 × 106 M−1 s−1, and reacts with methyl acrylate
lectivity has been reported for photochemical reactions taking in [3 + 2] cycloaddition with the rate constant 2.7 × 107 M−1 s−1
place in the inclusion complexes with CD [38-41] or struc- [49]. Protic solvents such as CH3OH or H2O quench
Figure 1: Phthalimide derivatives 1–3 and the corresponding azomethine ylides 1AMY-3AMY.
Table 1: Irradiation conditions, conversions and product ratio for photolysis of 1.a
irradiation conditions
solvent/ irradiation time
conversion (%) product ratiob
300 nm; c(1) = 10 mM, c(AN) = 0.25 M
300 nm, c(1) = 10 mM, c(AN) = 0.25 M
Hg-HP, c(1) = 10 mM, c(AN) = 0.10 M
300 nm, c(1) = 0.8 mM, c(AN) = 0.64 M
CH3CN 18 h
4
100
42
4/5a/5b = 1:1:1
4/5a/5b = 1:0:0
4/5a/5b = 2:1:1
4/5a/5b = 1:0:0
4/5a/5b = 1:0:0
CH3CN/H2O (1:3) 18 h
CH3CN 18 h
CH3CN/H2O (1:3) 1 h
97
300 nm, c(1) = 0.8 mM, c(AN) = 0.25 M, c(β-CD) = 0.08 mM CH3CN/H2O (1:3) 1 h
96
aIrradiations were conducted in CH3CN, or CH3CN-H2O (3:1 v/v) in the presence of a base K2CO3 to deprotonate the acid. Irradiated in a Rayonet
reactor using 12 lamps (1 lamp – 8 W) with the output at 300 nm, or by use of a high pressure mercury lamp (400 W Hg-HP). bThe product ratio deter-
mined by NMR.
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azomethyine ylides, giving formal 1,4 H-shifted products. Thus, an amino instead of the carboxylic functional group, forms an
in the presence of H2O, no cycloaddition products are anticipat- almost 35 times more stable complex with β-CD (4-amino-N-
ed. However, it should be probed if the [3 + 2] cycloaddition cyclohexylphthalimide, K = 6200 M−1) [50].
can compete with the 1,4 H-shift upon irradiation of an inclu-
sion complex.
Under our conditions, photodecarboxylation of 1 was very inef-
ficient in aprotic solvents, and it gave a mixture of simple
decarboxylation product 4, formed from 1AMY by 1,4-H shift,
in addition to the cycloadducts 5a and 5b (Scheme 1). Only use
of a strong irradiation source such as a high pressure Hg lamp
(400 W) provided higher yields of the cycloadducts. On the
other hand, upon photolysis in the presence of H2O and a base,
the photoreaction is about twenty times more efficient, but it
delivers simple decarboxylation product 4 only. Attempts to use
β-CD to complex both reactants and enhance the efficiency for
the cycloaddition failed. In the photolysis of 1, β-CD had no
effect (Table 1), which may be ascribed to a small size of 1 that
cannot fit well in the large cavity of β-CD and form a stable
complex.
Figure 2: Dependence of the chemical shift of the H-atom at the cyclo-
hexane 2 position in compound 2 on the β-CD concentration. Dots are
Molecules 2 and 3 are larger, and anticipated to form more
stable inclusion complexes with β-CD. Therefore, we per-
formed 1H NMR titrations to determine stability constants for
the inclusion complexes 2@β-CD and 3@β-CD. The NMR
experimental values and the red line corresponds to the calculated
values by the WINEQNMR program [51] according to the model for the
formation of 1:1 stoichiometry of the inclusion complex 2@β-CD.
titration for 2 with β-CD was carried out in CD3CN/D2O (3:7 An analogous titration in CD3CN/D2O (3:7 v/v) was also con-
v/v). The addition of β-CD to the solution of 2 induced down- ducted for 3 with β-CD. The addition of β-CD to the solution of
field shifts of the H-signals corresponding to the cyclohexane 2 3 induced downfield shifts of the signal corresponding to the
and 6 positions, as well as H-signals of the phthalimide, which adamantane 6 position and the phthalimide signals, which
changed from a singlet to a multiplet (Figure S1 in Supporting changed from singlet to a multiplet (Figure S4 in Supporting
Information File 1). The spectral changes are in accordance Information File 1). Nonlinear regression analysis of the chemi-
with the formation of an inclusion complex 2@β-CD, with the cal shifts to the β-CD concentration did not provide a good
dynamics for the complexation faster than the NMR time-scale quality of the fit to the model involving 1:1 complex formation
(millisecond). Nonlinear regression analysis of the chemical (Figure S5 in Supporting Information File 1). However, the ap-
shifts depending on the β-CD concentration, to a complexation proximated association constant for 3@β-CD, K = 2600 ±
model with 1:1 stoichiometry, showed good correlation 600 M−1, is similar to the known association constants for dif-
(Figure 2 and Figure S2 in Supporting Information File 1), with ferent adamantane derivatives with β-CD (K = 103–105 M−1)
the stability constant for 2@β-CD K = 190 ± 50 M−1. Forma- [52], in agreement with the anticipated good fit of the adaman-
tion of the inclusion complex was also confirmed by a NOESY tane moiety in 3 to the β-CD cavity.
spectrum where an interaction between the phthalimide
H-atoms and the β-CD was observed (Figure S3 in Supporting After demonstrating the formation of inclusion complexes
Information File 1). Note that a compound similar to 2, but with 2@β-CD and 3@β-CD, we investigated the possibility for the
Scheme 1: Irradiation of 1 in the presence of acrylonitrile (AN).
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formation of ternary complexes with AN. Therefore, we titrated solution of 3@β-CD in CD3CN/D2O (3:7 v/v) with AN, where-
solutions of 2 or 3 with AN. The solutions of 2 or 3 contained a upon spectral changes were observed (Figure S8 in Supporting
high concentration of β-CD to assure that the phthalimide deriv- Information File 1). The signal of the adamantane H-atom at the
ative was in the inclusion complex 2@β-CD or 3@β-CD, re- adamantane position 6 experienced a downfield shift, whereas
spectively. The addition of AN to the CD3CN/D2O (3:7 v/v) the phthalimide signals experienced an upfield shifts. Although
solution of 2@β-CD induced changes in the spectra, opposite to the changes were small, we tried to process them using non-
those observed upon formation of 2@β-CD (compare Figures linear regression analysis and model for the complex formation
S1 and S6 in Supporting Information File 1). The spectral with 1:1:1 stoichiometry. The fit was of poor quality, but it pro-
changes are in accordance with the formation of a ternary com- vided an estimation of the constant with the value of K2 =
plex AN@2@β-CD (Scheme 2). However, they may also indi- 0–7 M−1 (Figure S9 in Supporting Information File 1).
cate that excess of AN added to the solution competitively binds
to β-CD forming a complex AN@β-CD and inducing dissocia- The NMR titrations did not provide a clear evidence that ternary
tion of the 2@β-CD. If we assume a model for the complex for- complexes were formed. However, formation of ternary com-
mation in the stoichiometry 1:1:1, the nonlinear regression anal- plexes should affect the photochemical reactivity of 2 and 3 and
ysis of the chemical shift changes depending on the AN concen- cycloadditions of the corresponding azomethine ylides with
tration and provided a poor fit with the estimated K2 value of AN. Therefore, we performed irradiation of solutions contain-
0–6 M−1 (Figure S7 in Supporting Information File 1).
ing 2 and AN, 3 and AN, or the corresponding complexes 2@β-
CD and 3@β-CD with AN. Scheme 3 and Scheme 4 show
We investigated also the possibility for the formation of the products formed in the photochemical reactions, whereas ratio
ternary complex AN@3@β-CD. Therefore, we titrated the of photoproducts obtained is given in Table 2.
Scheme 2: Complexation of 2 with β-CD, and formation of a ternary complex AN@2@β-CD.
Scheme 3: Photochemistry of 2 in the presence of AN, with or without β-CD.
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Scheme 4: Photochemistry of 3 in the presence of AN, with or without β-CD.
Table 2: Irradiation conditions, conversions and product ratio after photolysis of 2 or 3.a
irradiation conditions
solvent
conversion (%)
/unidentified products (%)
product ratiob
2
CH3CN
99/46
99/70
45/40
99/61
99/69
58/36
10/7
6/7/8/9 = 25:0:1:0
2
CH3CN/H2O (1:1)
CH3CN
6/7/8/9 = 2.6:0:1:0
2, c(AN) = 0.78 M
2, c(AN) = 0.78 M
2, c(β-CD) = 22 mM
2, c(AN) = 0.78 M, c(β-CD) = 22 mM
3
6/7/8/9 = 2:1:2:0
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN
6/7/8/9 = 1.5:0:1:0
6/7/8/9 = 4:0:1:0
6/7/8/9 = 4.5:1:3:2.5
10/11/12/13/14 = 1:0:0:0:0
10/11/12/13/14 = 1:0:0:0:0
10/11/12/13/14 = 1:0:0:0:0
10/11/12/13/14 = 1:5:9:8:3
10/11/12/13/14 = 1:5:5:2:1
10/11/12/13/14 = 1:0:5:1:0
10/11/12/13/14 = 1:1:5:2:1
3
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN
52/50
55/5
3, c(K2CO3) = 0.7 mM
3, c(AN) = 0.74 M,
3, c(AN) = 0.74 M,
3, c(β-CD) = 15 mM
3, c(AN) = 0.74 M, c(β-CD) = 15 mM
33/2
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
75/56
58/40
45/21
aIrradiations of 2 (c = 2.0 mM) or 3 (c = 1.4 mM) were conducted in CH3CN, or CH3CN/H2O (1:1 v/v), with or without acrylonitrile (AN) and β-CD. All
samples were irradiated in a Luzchem reactor using 8 lamps (1 lamp – 8 W) with the output at 300 nm for 30 min (compound 2) or 35 min (compound
3). The detailed procedure can be found in the experimental part. bThe product ratio was determined by HPLC–MS and NMR.
The addition of H2O to the solution of 2 or 3 in CH3CN gener- by the bulky cyclohexane or adamantine moiety. Thus, irradia-
ally increase the efficiency of the decarboxylation reaction, as tion of 2 gave cycloadducts 7 in ≈9% yield, and 3 gave cyclo-
well as the efficiency of the secondary photochemical adducts 11 in ≈6% yield. Furthermore, it is anticipated that the
H-abstraction from primarily formed products 6 or 10, giving 8, addition of H2O quenches the cycloaddition reaction due to a
or 12–14, respectively. Upon addition of AN to the solution of 2 faster reaction of AMY with H2O then with AN, giving formal
or 3 in CH3CN, in aprotic conditions, 2AMY and 3AMY 1,4-H-shifted products. Indeed, H2O quenched the cycloaddi-
should be formed and intercepted with AN to yield cyclo- tion of 2AMY with AN, but it did not quench the cycloaddition
adducts 7 or 11, respectively. However, the formation of cyclo- of 3AMY with AN. Thus, cycloadduct 11 was detected after ir-
adducts is very inefficient, which may be ascribed to a smaller radiation of 3 with AN in CH3CN/H2O, but not when a base
rate constant for the quenching due to steric hindrance imposed was added to the solution.
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Addition of β-CD did not affect the decarboxylation reaction, 600 MHz spectrometer. CD3OD or CD3CN-D2O were used as
since the same conversion to photoproducts was observed in the deuterated solvent. TMS (1H NMR) or deuterated solvent itself
presence and absence of β-CD. However, for the adamantane (13C NMR) was used as internal reference. Chemical shifts
derivative in the presence of β-CD, the secondary photochemi- were reported in ppm. Irradiation experiments were performed
cal H-abstraction became more efficient, resulting in a different in a Rayonet RPR-100 photoreactor equipped with 12 lamps or
product distribution. More efficient H-abstraction reaction in a Luzchem reactor equipped with 8 lamps with the maximum
the presence of β-CD have been reported [16].
output at ≈300 nm (1 lamp – 8 W). During the irradiations in
the Rayonet reactor, the irradiated solutions were continuously
β-CD affected the cycloaddition reaction of photogenerated purged with Ar and cooled by a tap water finger condenser. Sol-
AMY with AN. Upon irradiation of 2 with AN in the presence vents for the irradiations were of HPLC purity. Chemicals were
of β-CD, the cycloadduct was formed in ≈5% yield, even purchased from the usual commercial sources and used as
though the irradiation was conducted in aqueous solution. The received. Solvents for chromatographic separations were used
finding suggests that formation of a ternary complex from the supplier (p.a. or HPLC grade) as is or were purified by
AN@2@β-CD is possible and that photolysis of 2 in such a distillation (CH2Cl2). Semipreparative HPLC separations were
complex yields 2AMY, which is then readily intercepted with performed on a Varian Pro Star instrument equipped with a
AN in the same complex. Note that cycloadduct 11 was also Phenomenex Jupiter C18 5μ 300A column, using CH3OH/H2O
detected (≈4%), upon irradiation of 3 with AN in the presence + TFA as eluent. HPLC–MS analyses were conducted on an
of β-CD, suggesting that the photodecarboxylation reaction and Agilent 1200 Series machine equipped with a DAD detector
subsequent [3 + 2] cycloaddition take place in the ternary com- and a mass spectrometer with a triple quadrupole Agilent 6420
plex AN@3@β-CD. However, cycloadduct 11 was formed in a device.
higher yield (≈20%) when 3 was photolyzed with AN in the
aqueous solution without β-CD. Although a reason for the dif- Photochemistry of 2 and 3 under different conditions
ferent effect of β-CD is not clear, it may be due to a lower A solution of 2 (30 mg, 0.11 mmol) in CH3CN (27.5 mL) was
stability of the ternary complex AN@3@β-CD, compared to prepared and transferred to 7 quartz cuvettes (3.9 mL into each).
AN@2@β-CD. Namely, the adamantane is a bulky moiety that Then, CH3CN (3.9 mL) or H2O (3.9 mL) was added to each of
occupies most of the space in the inclusion complex 3@β-CD, the cuvettes, followed by the addition of β-CD (200 mg,
making formation of the ternary complex less likely. Further- 0.176 mmol), acrylonitrile (AN, 0.4 mL, 6.1 mmol) or nothing
more, if AN@3@β-CD was formed, photogenerated (see Table 2). Solutions were purged with N2 for 15 min, sealed
3AMY@β-CD may not be in the right orientation for the cyclo- and irradiated at the same time in a Luzchem reactor at 300 nm
addition to take place, leading predominantly to the reaction of (8 lamps) for 30 min. After the irradiation, solutions were
3AMY with H2O.
extracted with EtOAc (3 × 3 mL), the extracts were dried over
MgSO4, filtered and the solvent was removed on a rotary evap-
orator. The crude reaction mixtures were filtered through a plug
Conclusion
Herein we have demonstrated a proof of principle that β-CD can of silica gel by use of CH2Cl2/EtOAc as eluent and were
be used as a molecular container in which two molecules can be analyzed by 1H NMR and HPLC–MS (Table 2).
complexed, a phthalimide derivative and acrylonitrile, forming
a ternary complex. Irradiation of such a complex leads to Alternatively, a solution of 3 (44 mg, 0.135 mmol) in CH3CN
decarboxylation and formation of the reactive intermediate, azo- (50 mL) was prepared and transferred to 7 quartz cuvettes
methine ylide, within the supramolecular host. The subsequent (7.0 mL into each). Then, CH3CN (7.0 mL) or H2O (7.0 mL)
[3 + 2] cycloaddition within the inclusion complex gives hetero- was added to each of the cuvettes, followed by the addition of
cyclic cycloadducts, even though it is conducted in aqueous sol- β-CD (240 mg, 0.21 mmol), AN (0.7 mL, 10.7 mmol), K2CO3
vent in which ylides have short lifetimes. The reaction needs to (1.3 mg, 0.009 mmol), or nothing (see Table 2). Solutions were
be optimized for different substrates with the right choice of purged with N2 for 15 min, sealed and irradiated at the same
host size. However, the proof of principle provides a new idea time in a Luzchem reactor at 300 nm (8 lamps) for 35 min.
for the development of supramolecular systems for the tuning of After the above described work up, the composition of the irra-
photochemical reactivity.
diated solutions was analyzed by 1H NMR and HPLC–MS (Ta-
ble 2).
Experimental
General
Preparative irradiation of 2 with AN and with β-CD
1H and 13C NMR spectroscopic data were recorded at room Phthalimide 2 (110 mg, 0.403 mmol) was dissolved in CH3CN
temperature on a Bruker Avance 300 MHz or Bruker Avance (50 mL) and this solution was added slowly to the solution of
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Beilstein J. Org. Chem. 2020, 16, 1296–1304.
β-CD (4.0 g, 3.52 mmol) in H2O (250 mL). The solution was 28.0 (t, 1C), 26.5 (t, 1C), 21.7 (t, 1C), 11.7 (t, 1C), signals for 2
sonicated for 15 min and then AN (10 mL, 152.6 mmol) was quaternary C-atoms were not observed; MS m/z (% relative in-
added. After sonicating for additional 15 min, the solution was tensity): 282 (100), 283 (18.4), 284 (1.6).
transferred to fifteen quartz test tubes (each containing 20 mL),
purged with N2 for 20 min and sealed. The solutions were irra- Preparative irradiation of phthalimide 3 with AN and
diated for 1 h in a Luzchem reactor using 8 lamps with the with β-CD
output at 300 nm. When the irradiation was completed, the irra- Phthalimide 3 (150 mg, 0.461 mmol) was dissolved in CH3CN
diated solutions were combined and extracted with pentane (3 × (100 mL) and this solution was added slowly to the solution of
50 mL), and then with CH2Cl2 (2 × 50 mL) and EtOAc (2 × β-CD (5.23 g, 4.61 mmol) in H2O (370 mL). The solution was
50 mL). The organic extracts were dried over anhydrous sonicated for 15 min and then AN (10 mL, 152.6 mmol) was
Na2SO4, and CH2Cl2 and EtOAc were combined. The solu- added. After sonicating for additional 15 min, the solution was
tions were filtered and the solvent was removed on a rotary transferred to twenty quartz test tubes (each containing ≈20
evaporator. The photoproducts were separated by chromatogra- mL), purged with N2 for 20 min and sealed. The solutions were
phy on semipreparative HPLC followed by preparative TLC irradiated for 4 h in a Luzchem reactor using 8 lamps with the
using 5% MeOH/10% Et2O/85% CH2Cl2 and 40% EtOAc/ output at 300 nm. When the irradiation was completed, the irra-
CH2Cl2 as eluent. Compound 6 (11 mg, 10%) was identified by diated solutions were combined and extracted with pentane (3 ×
comparison of the spectra with those from precedent literature 50 mL), and then with CH2Cl2 (2 × 50 mL) and EtOAc (2 ×
[53].
50 mL). The organic extracts were dried over anhydrous
Na2SO4, and CH2Cl2 and EtOAc were combined. The solu-
HPLC method: 0–10 min (25% H2O/MeOH), 10–30 min tions were filtered and the solvent was removed on a rotary
(25–0% H2O/MeOH), 30–40 min (MeOH), 40-45 min (0–25% evaporator. The photoproducts were separated by chromatogra-
H2O/MeOH).
phy on a column of silica gel using 2–10% MeOH/CH2Cl2 fol-
lowed by preparative TLC with 5% MeOH/DCM and 5%
9b'-Hydroxy-5'-oxo-1',2',5',9b'-tetrahydrospiro[cyclo- MeOH/10% Et2O/DCM. The separation afforded only products
hexane-1,3'-pyrrolo[2,1-a]isoindole]-1'-carbonitrile (7): 2 10, 12, 13, and 14, which were identified by comparison of the
mg (2%), oily crystals; 1H NMR (CD3OD, 600 MHz) δ 7.81 spectra with literature precedent [54].
(dd, J = 1.0, 7.6 Hz, 1H), 7.70 (dt, J = 1.3, 7.6 Hz, 1H), 7.65 (dt,
J = 1.3, 7.6 Hz, 1H), 7.48 (dd, J = 1.0, 7.6 Hz, 1H), 4.55 (br s, Preparative irradiation of phthalimide 3 with AN and
3H), 3.48–3.42 (m, 1H), 2.65–2.59 (m, 1H), 2.06–2.00 (m, 2H), without β-CD
1.86–1.78 (m, 2H), 1.53–1.27 (m, 7H); MS m/z (% relative in- A solution of phthalimide 3 (142 mg, 0.450 mmol) and AN
tensity): 282 (100), 283 (18.4), 284 (1.6).
(5 mL, 76.33 mmol) in CH3CN (100 mL) was poured to a
quartz Erlenmayer flask. The solution was purged with N2 for
1,3,4,4a,5,11a-Hexahydro-6H-dibenzo[b,e]azepine-6,11(2H)- 30 min and then irradiated for 20 h with continuous stirring.
dione (8): 4 mg (4%), oily crystals; 1H NMR (CD3OD, 300 After the irradiation, the solvent was removed on a rotary evap-
MHz) δ 7.83–7.77 (m, 1H), 7.71–7.61 (m, 2H), 7.55–7.49 (m, orator and the crude reaction mixture was chromatographed on
1H), 4.18 (d, J =2.4 Hz, 1H), 2.74–2.64 (m, 1H), 2.31–2.20 (m, a column of SiO2 with 0–10% MeOH/CH2Cl2 as eluent, fol-
1H), 1.97–1.84 (m, 5H), 1.47–1.34 (m, 1H); 13C NMR lowed by chromatography on a semipreparative HPLC with
(CD3OD, 75 MHz) δ 207.1 (s, 1C), 172.2 (s, 1C), 139.1 (s, 1C), 0–50% H2O/MeOH, 0.1% TFA as eluent, and finally by prepar-
133.3 (s, 1C), 133.2 (d, 1C), 133.1 (d, 1C), 130.0 (d, 1C), 128.8 ative TLC with 3% MeOH/CH2Cl2 as eluent.
(d, 1C), 57.3 (d, 1C), 49.7 (d, 1C), 30.1 (t, 1C), 26.2 (t, 1C),
23.7 (t, 1C), 21.3 (t, 1C); MS m/z (% relative intensity): 229 HPLC method: 0–5 min (35% H2O/MeOH, 0.1% TFA),
(100), 230 (15.1), 231 (1.1).
5–20 min (35–0% H2O/MeOH, 0.1% TFA), 20–25 min
(MeOH), 25–30 min (0−35% H2O/MeOH, 0.1% TFA).
1,6-Dioxo-1,4,5,6-tetrahydro-2H-spiro[benzo[c]azocine-3,1'-
cyclohexane]-5-carbonitrile (9): 3 mg (3%), oily crystals; 1H 9b'-Methyl-5'-oxo-1',2',5',9b'-tetrahydrospiro[adamantane-
NMR (CD3OD, 300 MHz) δ 8.19-8.15 (m, 1H), 8.04–8.00 (m, 2,3'-pyrrolo[2,1-a]isoindole]-1'-carbonitrile (11): 2 mg (2%),
1H), 7.80–7.66 (m, 2H), 2.84 (dd, J = 3.3, 12.0 Hz, 1H), oily crystals; 1H NMR (CD3OD, 300 MHz) δ 7.70–7.65 (m,
2.50–2.30 (m, 2H), 2.10–1.70 (m, 8H), 1.55–1.35 (m, 2H); 13C 2H), 7.59 (d, J = 7.6 Hz, 1H), 7.53 (dt, J = 0.6, 7.4 Hz, 1H),
NMR (CD3OD, 75 MHz) δ 202.5 (s, 1C), 134.9 (s, 1C), 134.7 4.03 (d, J = 7.9 Hz, 1H), 2.30–2.26 (m, 1H), 2.04–2.00 (m, 1H),
(d, 1C), 133.4 (d, 1C), 132.9 (d, 1C), 130.6 (d, 1C), 120.7 (s, 1.97–1.91 (m, 5H), 1.89–1.85 (m, 3H), 1.80–1.76 (m, 1H); 13C
1C, CN), 62.0 (d, 1C), 36.1 (t, 1C), 35.7 (t, 1C), 30.7 (s, 1C), NMR (CD3OD, 75 MHz) δ 208.6 (s, 1C), 135.4 (s, 1C), 134.7
1302

Beilstein J. Org. Chem. 2020, 16, 1296–1304.
(d, 1C), 132.9 (s, 1C), 130.8 (d, 1C), 124.2 (d, 1C), 123.3 (d,
1C), 98.1 (s, 1C), 71.6 (s, 1C), 39.0 (t, 1C), 37.9 (t, 1C), 35.5 (t,
1C), 35.3 (d, 1C), 34.3 (d, 1C), 33.5 (t, 1C), 33.2 (t, 1C), 30.7
(d, 1C), 28.6 (d, 1C), 28.3 (d, 1C), 27.3 (t, 1C), the singlet cor-
responding to the CN was not observed; MS m/z (% relative in-
tensity): 334 (100), 335 (22.7), 336 (2.5).
References
1. Kobayashi, S.; Jørgensen, K. A., Eds. Cycloaddition Reactions in
Organic Synthesis; WILEY-VCH: Weinheim, 2002.
doi:10.1002/3527600256
2. Chiacchio, U.; Padwa, A.; Romeo, G. Curr. Org. Chem. 2009, 13,
422–447. doi:10.2174/138527209787582268
3. Hashimoto, T.; Maruoka, K. Chem. Rev. 2015, 115, 5366–5412.
doi:10.1021/cr5007182
4. Martina, K.; Tagliapietra, S.; Veselov, V. V.; Cravotto, G.
Front. Chem. (Lausanne, Switz.) 2019, 7, No. 95.
doi:10.3389/fchem.2019.00095
NMR titrations with β-CD
A solution of 2 (c = 7.21 mM), or 3 (c = 2.83 mM) in CD3CN/
D2O (3:7 v/v, 1.0 or 0.5 mL, respectively) in NMR tube was
titrated with a solution of β-CD (c = 20.5 mM). After each addi-
tion of β-CD, an 1H NMR spectrum was recorded. The changes
of chemical shifts depending on the β-CD concentration were
processed by nonlinear regression analysis using WinEQNMR
software [51]. The titration was performed at 25 °C.
5. Nájera, C.; Sansano, J. M. Curr. Org. Chem. 2003, 7, 1105–1150.
doi:10.2174/1385272033486594
6. Hladíková, V.; Váňa, J.; Hanusek, J. Beilstein J. Org. Chem. 2018, 14,
1317–1348. doi:10.3762/bjoc.14.113
7. Ryan, J. H. ARKIVOC 2015, No. i, 160–183.
doi:10.3998/ark.5550190.p008.928
8. Coldham, I.; Hufton, R. Chem. Rev. 2005, 105, 2765–2809.
doi:10.1021/cr040004c
NMR titrations with AN
9. Yoon, U. C.; Kim, D. U.; Lee, C. W.; Choi, Y. S.; Lee, Y.-J.;
Ammon, H. L.; Mariano, P. S. J. Am. Chem. Soc. 1995, 117,
2698–2710. doi:10.1021/ja00115a004
A solution of 2@β-CD (prepared by mixing 2 in the concentra-
tion of 2.71 mM with β-CD in the concentration of 8.20 mM),
or 3@β-CD (prepared by mixing 3 in the concentration of
1.54 mM with β-CD in the concentration of 20.5 mM) in
CD3CN/D2O (3:7 v/v, 1.0 mL) was titrated with acrylonitrile
(AN). After each addition of AN, an 1H NMR spectrum was re-
corded. The changes of chemical shifts depending on the AN
concentration were processed by nonlinear regression analysis
using WinEQNMR software [51]. The titration was performed
at 25 °C.
10.Yoon, U. C.; Cho, S. J.; Lee, Y.-J.; Mancheno, M. J.; Mariano, P. S.
J. Org. Chem. 1995, 60, 2353–2360. doi:10.1021/jo00113a012
11.Griesbeck, A. G.; Hoffmann, N.; Warzecha, K.-D. Acc. Chem. Res.
2007, 40, 128–140. doi:10.1021/ar068148w
12.Kanaoka, Y. Acc. Chem. Res. 1978, 11, 407–413.
doi:10.1021/ar50131a002
13.Horvat, M.; Mlinarić-Majerski, K.; Basarić, N. Croat. Chem. Acta 2010,
83, 179–188.
14.Basarić, N.; Horvat, M.; Mlinarić-Majerski, K.; Zimmermann, E.;
Neudörfl, J.; Griesbeck, A. G. Org. Lett. 2008, 10, 3965–3968.
doi:10.1021/ol801362x
15.Horvat, M.; Görner, H.; Warzecha, K.-D.; Neudörfl, J.; Griesbeck, A. G.;
Mlinarić-Majerski, K.; Basarić, N. J. Org. Chem. 2009, 74, 8219–8231.
doi:10.1021/jo901753z
Supporting Information
16.Cindro, N.; Halasz, I.; Mlinarić-Majerski, K.; Basarić, N.
Eur. J. Org. Chem. 2013, 929–938. doi:10.1002/ejoc.201201332
17.Mandić, L.; Mlinarić-Majerski, K.; Griesbeck, A. G.; Basarić, N.
Eur. J. Org. Chem. 2016, 4404–4414. doi:10.1002/ejoc.201600491
18.Sohora, M.; Šumanovac Ramljak, T.; Mlinarić-Majerski, K.; Basarić, N.
Croat. Chem. Acta 2014, 87, 431–446. doi:10.5562/cca2482
19.Horvat, M.; Mlinarić-Majerski, K.; Griesbeck, A. G.; Basarić, N.
Photochem. Photobiol. Sci. 2011, 10, 610–617.
Supporting Information File 1
Experimental procedures, characterization of the known
compounds, NMR spectra from the titration experiments
and copies of 1H and 13C NMR spectra of all compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-16-110-S1.pdf]
doi:10.1039/c0pp00357c
20.Šumanovac Ramljak, T.; Sohora, M.; Antol, I.; Kontrec, D.; Basarić, N.;
Mlinarić-Majerski, K. Tetrahedron Lett. 2014, 55, 4078–4081.
doi:10.1016/j.tetlet.2014.05.118
Acknowledgements
MS and LM are both first authors who contributed equally. This
21.Sohora, M.; Vazdar, M.; Sović, I.; Mlinarić-Majerski, K.; Basarić, N.
J. Org. Chem. 2018, 83, 14905–14922. doi:10.1021/acs.joc.8b01785
22.Boscá, F.; Miranda, M. A. J. Photochem. Photobiol., B 1998, 43, 1–26.
doi:10.1016/s1011-1344(98)00062-1
manuscript is dedicated to Professor Carsten Schmuck.
Funding
These materials are based on work financed by the Croatian
23.Boscá, F.; Marín, M.-L.; Miranda, M. A. Photochem. Photobiol. 2001,
74, 637–655. doi:10.1562/0031-8655(2001)074<0637:potnai>2.0.co;2
24.Boscá, F.; Marín, M.-L.; Miranda, M. A. In Handbook of Organic
Photochemistry and Photobiology, 2nd ed.; Horspool, W.; Lenci, F.,
Eds.; CRC Press: Boca Raton, 2004.
Science Foundation (HRZZ IP-2014-09-6312 for NB).
ORCID® iDs
Nikola Basarić - https://orcid.org/0000-0001-9412-9734
1303

Beilstein J. Org. Chem. 2020, 16, 1296–1304.
25.Monti, S.; Sortino, S.; De Guidi, G.; Marconi, G.
J. Chem. Soc., Faraday Trans. 1997, 93, 2269–2275.
doi:10.1039/a700367f
51.Hynes, M. J. J. Chem. Soc., Dalton Trans. 1993, 311–312.
doi:10.1039/dt9930000311
52.Rekharsky, M. V.; Inoue, Y. Chem. Rev. 1998, 98, 1875–1918.
doi:10.1021/cr970015o
26.Martínez, L. J.; Scaiano, J. C. J. Am. Chem. Soc. 1997, 119,
11066–11070. doi:10.1021/ja970818t
53.Worlikar, S. A.; Larock, R. C. J. Org. Chem. 2008, 73, 7175–7180.
doi:10.1021/jo800936h
27.Cosa, G.; Martínez, L. J.; Scaiano, J. C. Phys. Chem. Chem. Phys.
1999, 1, 3533–3537. doi:10.1039/a903268a
54.Basarić, N.; Horvat, M.; Franković, O.; Mlinarić-Majerski, K.;
Neudörfl, J.; Griesbeck, A. G. Tetrahedron 2009, 65, 1438–1443.
doi:10.1016/j.tet.2008.12.010
28.Laferrière, M.; Sanramé, C. N.; Scaiano, J. C. Org. Lett. 2004, 6,
873–875. doi:10.1021/ol036313r
29.Blake, J. A.; Gagnon, E.; Lukeman, M.; Scaiano, J. C. Org. Lett. 2006,
8, 1057–1060. doi:10.1021/ol052953d
30.Chuang, Y. P.; Xue, J.; Du, Y.; Li, M.; An, H.-Y.; Phillips, D. L.
J. Phys. Chem. B 2009, 113, 10530–10539. doi:10.1021/jp903234m
31.Li, M.-D.; Du, Y.; Chuang, Y. P.; Xue, J.; Phillips, D. L.
Phys. Chem. Chem. Phys. 2010, 12, 4800–4808.
License and Terms
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Creative Commons Attribution License
doi:10.1039/b919330h
(http://creativecommons.org/licenses/by/4.0). Please note
that the reuse, redistribution and reproduction in particular
requires that the authors and source are credited.
32.Xu, Y.; Chen, X.; Fang, W.-H.; Phillips, D. L. Org. Lett. 2011, 13,
5472–5475. doi:10.1021/ol202182k
33.Li, M.-D.; Yeung, C. S.; Guan, X.; Ma, J.; Li, W.; Ma, C.; Phillips, D. L.
Chem. – Eur. J. 2011, 17, 10935–10950. doi:10.1002/chem.201003297
34.Li, M.-D.; Su, T.; Ma, J.; Liu, M.; Liu, H.; Li, X.; Phillips, D. L.
Chem. – Eur. J. 2013, 19, 11241–11250. doi:10.1002/chem.201300285
35.Boscá, F.; Miranda, M. A.; Carganico, G.; Mauleón, D.
Photochem. Photobiol. 1994, 60, 96–101.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(https://www.beilstein-journals.org/bjoc)
doi:10.1111/j.1751-1097.1994.tb05073.x
36.Ramamurthy, V.; Inoue,, Y., Eds. Supramolecular Photochemistry;
Wiley: Hoboken, 2011. doi:10.1002/9781118095300
37.Ramamurthy, V.; Sivaguru, J. Chem. Rev. 2016, 116, 9914–9993.
doi:10.1021/acs.chemrev.6b00040
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.16.110
38.Aoyama, H.; Miyazaki, K.-I.; Sakamoto, M.; Omote, Y. Tetrahedron
1987, 43, 1513–1518. doi:10.1016/s0040-4020(01)90267-4
39.Koodanjeri, S.; Joy, A.; Ramamurthy, V. Tetrahedron 2000, 56,
7003–7009. doi:10.1016/s0040-4020(00)00523-8
40.Shailaja, J.; Karthikeyan, S.; Ramamurthy, V. Tetrahedron Lett. 2002,
43, 9335–9339. doi:10.1016/s0040-4039(02)02338-9
41.Vízvárdi, K.; Desmet, K.; Luyten, I.; Sandra, P.; Hoornaert, G.;
Van der Eycken, E. Org. Lett. 2001, 3, 1173–1175.
doi:10.1021/ol0156345
42.Inoue, Y.; Dong, F.; Yamamoto, K.; Tong, L.-H.; Tsuneishi, H.;
Hakushi, T.; Tai, A. J. Am. Chem. Soc. 1995, 117, 11033–11034.
doi:10.1021/ja00149a037
43.Inoue, Y.; Wada, T.; Sugahara, N.; Yamamoto, K.; Kimura, K.;
Tong, L.-H.; Gao, X.-M.; Hou, Z.-J.; Liu, Y. J. Org. Chem. 2000, 65,
8041–8050. doi:10.1021/jo001262m
44.Fukuhara, G.; Mori, T.; Wada, T.; Inoue, Y. Chem. Commun. 2005,
4199–4201. doi:10.1039/b504948b
45.Fukuhara, G.; Mori, T.; Wada, T.; Inoue, Y. J. Org. Chem. 2006, 71,
8233–8243. doi:10.1021/jo061389x
46.Lu, R.; Yang, C.; Cao, Y.; Wang, Z.; Wada, T.; Jiao, W.; Mori, T.;
Inoue, Y. Chem. Commun. 2008, 374–376. doi:10.1039/b714300a
47.Lu, R.; Yang, C.; Cao, Y.; Tong, L.; Jiao, W.; Wada, T.; Wang, Z.;
Mori, T.; Inoue, Y. J. Org. Chem. 2008, 73, 7695–7701.
doi:10.1021/jo801439n
48.Uekama, K.; Hirayama, F.; Irie, T. Chem. Rev. 1998, 98, 2045–2076.
doi:10.1021/cr970025p
49.Takahashi, Y.; Miyashi, T.; Yoon, U. C.; Oh, S. W.; Mancheno, M.;
Su, Z.; Falvey, D. F.; Mariano, P. S. J. Am. Chem. Soc. 1999, 121,
3926–3932. doi:10.1021/ja9841862
50.Wintgens, V.; Amiel, C. J. Photochem. Photobiol., A 2004, 168,
217–226. doi:10.1016/j.jphotochem.2004.06.002
1304