Synthesis of 3′-allylindoline spirobenzopyrans derived from 3-allyl-3H-indoles

Article abstract of DOI:10.1016/j.tetlet.2014.09.121

In this study, 8 new spirobenzopyrans were synthesized. A novel, three-step, facile route for the synthesis of 3′-allylindoline spirobenzopyrans via 3-allyl-3H-indoles was developed. The newly synthesized spirobenzopyrans were evaluated for their photochr

Full text of DOI:10.1016/j.tetlet.2014.09.121

Tetrahedron Letters xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of 30-allylindoline spirobenzopyrans derived
from 3-allyl-3H-indoles
a
c
Natsuko Kagawa a,b, , Hiroki Takabatake , Yoshitake Masuda
⇑
a Graduate School of Pharmaceutical Sciences, Chiba University, 1-8-1 Inohana, Chuo, Chiba 260-8675, Japan
b Center for Environment, Health and Field Sciences, Chiba University, 6-2-1 Kashiwa-no-ha, Kashiwa, Chiba 277-0882, Japan
c National Institute of Advanced Industrial Science and Technology (AIST), Nagoya 463-8560, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In this study, 8 new spirobenzopyrans were synthesized. A novel, three-step, facile route for the synthesis
of 30-allylindoline spirobenzopyrans via 3-allyl-3H-indoles was developed. The newly synthesized spiro-
benzopyrans were evaluated for their photochromic properties. The presence of an allyl moiety at the 30
position did not disturb the photochromic response. The steric effects of the diallyl groups at the 30 posi-
tion affected the interconversion between colored and colorless forms. Therefore, the allyl chain in 30-
allylindoline spirobenzopyrans can be utilized to attach these compounds to a molecular matrix. Conse-
quently, this synthetic methodology could be readily applied to the creation of new photo-switchable
materials.
Received 6 July 2014
Revised 19 September 2014
Accepted 26 September 2014
Available online xxxx
Keywords:
Indole
Spiropyran
Photochromism
Allylation
Ó 2014 Elsevier Ltd. All rights reserved.
Palladium catalyst
The photo-responsive behavior of indoline spirobenzopyrans
(ISPs) and photochromic compounds (PCCs) has attracted signifi-
cant attention from photochemists working in material sci-
ences.1–3 ISPs impart biochemical materials with attributes such
as photo-controlled color changes (photochromism),4 photo-
induced interconversion,5–7 long wavelengths of absorption max-
ima, and promising thermosolvatochromism,8–10 while PCCs are
extremely useful component parts for the synthesis of photo-
switchable functional materials.11–13 According to current syn-
thetic requirements in the biological applications of PCCs, entries
involving new UVA-reactive ISPs are particularly welcome.
available 2,3,3-trimethy-3H-indoles are easily obtained and used
as starting substrates, which ensure the quick syntheses of ISPs.
We thought, furthermore, that the lack of variation on R4,R5-sub-
stitution in ISPs was caused by the synthetic difficulties of
2-methyl-3,3-disubstituted 3H-indole derivatives, which could be
key intermediates for the synthesis of R4,R5-substituted ISPs. To
the best of our knowledge, the two major synthetic routes
to 3H-indoles are Fisher indole synthesis and the b-substitution
of indoles, although both of these methods present considerable
limitations to the production of various 3,3-disubstituted
3H-indoles.22,23
The indoline nucleus is an important substructure in ISP 1, as it
exhibits photo-induced isomerization to the indolenine (3H-
indole) nucleus in merocyanine (MC) 2 (Fig. 1).14,15 Among various
classes of ISPs, R1 and R2-substituted derivatives on aromatic rings
have been studied extensively as an effective modification in a shift
of the absorbance spectrum associated with a color change.16–18
R3-Substituted derivatives are useful molecules that combine a
photo-responsive ISP unit into polymer/nanoparticles utilized in
biomedical applications such as targeted drug delivery and sens-
ing.5,19–21 In most instances, R4,R5-dimethyl substitutions are com-
monly chosen and adopted into ISPs because commercially
Based on the photochemical interest in compounds that belong
to the ISP family, and considering that only a few examples have
been reported for the syntheses of R4 and R5-substituted (not
methylated) derivatives,22,23 we present herein a novel three-step
process for the synthesis of 30-allylindoline spirobenzopyrans via
⇑
Corresponding author. Tel.: +81 471 378 179; fax: +81 471 378 174.
E-mail address: knatsuko@faculty.chiba-u.jp (N. Kagawa).
Figure 1. Photo-induced and reversible interconversion of ISP 1 and MC 2 isomers.
http://dx.doi.org/10.1016/j.tetlet.2014.09.121
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Kagawa, N.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.121

2
N. Kagawa et al. / Tetrahedron Letters xxx (2014) xxx–xxx
salts 5a–d were treated with a solution of potassium hydroxide
to give oxazolidines 6a–d, which were purified by silica gel column
chromatography in good yields (41–76% from 4a–d) as an insepa-
rable mixture of 2 stereoisomers for 6a–c. The oxazolidines 6a–d
were condensed with 2-hydroxy-5-nitorobenzaldehyde 7a
(R2 = NO2) in refluxing ethanol to provide ISPs 1a–d (62–78%)
and treatment of 6a with salicylaldehyde 7b (R2 = H) provided 1h
in 86% yield (Table 1).26,27 When iodomethane was used for 3H-
indole 4e, the crude salt 5e was condensed with 7a in refluxing
ethanol for 1 h to provide ISP 1e (14% from 4e). In addition, ISP
1a was subjected to alkene metathesis with allyl acetate (6 equiv),
forming ISP 1c in 20% yield with 52% recovery.
In search of viable structural designs to attach the ISP with a
biomolecule, a maleimide motif was introduced in the R3 side
chain28,29 of ISPs 1f–g, as shown in Figure 2, using a Mitsunobu
reaction in the displacement of a primary alcohol of 1a to malei-
mide or furan-protected maleimide.30,31 The deprotection of 1g
by retro Diels–Alder reaction afforded 1f (41% from 1a). This
two-step method of the synthesis for 1f achieved a better yield
and successive removal of excess aldehyde 7a in the crude product
during column purification, compared with a direct transformation
of 1a to 1f by Mitsunobu reaction (11%).29,32
All new compounds were characterized by NMR and IR spec-
troscopy, as well as by mass spectrometry. Regarding the struc-
tures of products 4 and 6, their 1H NMR spectra showed signals
that could be attributed to an alkene with reasonable coupling con-
stants. In the 13C NMR spectra of 3H-indoles 4a–e, a prominent car-
bon signal appeared, which was ascribed to the imino carbon at
position 2 of the indole (4a: d 186.4, 4b: d 186.3, 4c: d 186.0, 4d:
d 184.8, and 4e: d 179.3), while during the following cyclization
the same carbon was remarkably shielded (6a: d108.8, 108.6, 6b:
d 108.8, 108.4, 6c: d 108.7, 108.4, and 6d: d 108.5). The 1H NMR
spectra of compounds 1a–h exhibited signals for the H-3 protons
of the chromene ring at 5.87–6.00 ppm as characteristic doublets
with J = 10–11 Hz, which indicated a cis conformation. The 1H
NMR and 13C NMR spectra for the 6 ISPs, 1a–c and 1f–h, revealed
that the 2 adjacent stereogenic centers in the structure caused an
inseparable mixture of diastereomers in unequal ratios. As for ISP
1e, the 1D NMR (1H, 13C, and DEPT) spectra showed that all signals
could be assigned to a single stereoisomer. The assignment of the
signals was achieved with the aid of the 2D NMR (1H–1H COSY,
HMQC, and HMBC) spectra. The stereochemistry of 1e was con-
firmed via NOEs and X-ray crystallography (Fig. 3). To assess the
relative stability of 1e for 20,30-cis-substituted stereoisomer
against 20,30-trans, optimized structures was calculated at the
Hartree–Fock/3-21G(⁄) level utilizing the Spartan program.
The 20,30-cis isomer 1e was 17.2 kJ molꢀ1 lower in energy than
the 20,30-trans isomer (see Supplementary material).
To characterize the photochromic properties of ISPs 1a–h, the
UV–vis absorption spectra were measured in chloroform solution
both before and after UV light irradiation (Fig. 4). The results
showed the UV–vis absorption spectra of 1a–h at a concentration
of 1 ꢁ 10ꢀ4 mol/L, in which characteristic peaks were clearly
shown at 565–569 nm for 1a–d and at 593–595 nm for 1e–g after
UV light irradiation (Table 1). The peaks appeared as a result of
366 nm UV light irradiation for 3 min, indicating the photoisomer-
ization from ISP form 1 to MC form 2, as shown in Figure 1.33 The
colored solution after UV light irradiation was stored in the dark,
and the absorption spectra were measured as a function of concur-
rent time (Fig. 5). The absorption at 560–595 nm gradually
decreased as time increased (Fig. 4c and Fig. 5). For ISPs 1a–g,
the intensity of the peaks was completely repeatable with the UV
light irradiation (Table 1). The maximum absorption at
560–595 nm of 1a–g during irradiation of 366 nm proved to be a
trans–trans–cis conformation of MC chromophores, which has
been suggested to be the thermodynamically stable version of
Scheme 1. Synthesis of 3H-indoles 4, indolenium salts 5, oxazolidines 6, and ISP 1.
3-allyl-3H-indoles using b-allylation of 2,3-disubstituted indoles
(Scheme 1).
Here, 3H-indoles 4a–b were prepared in a classic method, start-
ing from 2,3-dimethylindole 3a under basic and nucleophilic con-
ditions using a Grignard reagent and R5-halide in 91 and 80% yields
for 4a and 4b, respectively. The major drawbacks to this method
were low selectivities, excess use of reagents, functional group
incompatibility, and complex operating conditions and workups.
Grignard reagents are inexpensive, but their application to a
large-scale preparation is difficult.
Thus, we turned our attention to the use of a palladium catalyst,
in a mild, functional group tolerant method for the regioselective
introduction of an allyl group on 2,3-disubstituted indoles
3d–e.24 Reactions were carried out via the addition of indole to a
solution of Pd2(dba)3 (2.5 mol %), R5-OCO2Me (2.0 equiv), and
P(2-furyl)3 (15 mol %) in CH2Cl2 at 20 °C. After the reaction com-
pleted, the solvent was evaporated to give a crude product, which
was purified. This reaction provided the desired 3H-indoles 4d–e in
91% and 51% yields, respectively, depending on the R4-substitution
on the 2-methylindoles 3d–e. In particular, for indole 3e wherein
the nucleophilic reaction of a Grignard reagent with the substrate
(CO2Et) is faster than a substitution reaction with allyl bromide,
the palladium-catalytic method proved to be effective since indole
3e was allylated to 3H-indole 4e without affecting the ethoxy car-
bonyl group. The 3H-indole 4c was derived from 3H-indole 4a via a
cross-metathesis with allyl acetate (1 equiv) and 5 mol % of a Zhan
1B catalyst,25 in a 10% yield, with a 80% recovery. When a
Hoveyda–Grubbs catalyst 2nd generation was employed for the
metathesis, the reaction proceeded much slower, while the yield
of the product was almost the same (by 9%). These substituted
3H-indoles are useful intermediates for the synthesis of ISP 1.
Therefore, 3H-indoles 4a–e were N-alkylated with R3-halide to give
indolenium salts 5a–e, which were very polar ionic liquid com-
pounds those could be utilized for the next step without isolation.
When 2-bromoethanol was used as a R3-halide, the indolenium
Please cite this article in press as: Kagawa, N.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.121

N. Kagawa et al. / Tetrahedron Letters xxx (2014) xxx–xxx
3
Table 1
Indoline spirobenzopyrans 1a–h and merocyanine 2i produced via Scheme 1, and their photochromic properties
Product
R2
R3
R4
R5
Photochromism [stectra]a
k (nm)b
1a
1b
1c
1d
1e
1f
1g
1h
2i
6-NO2
6-NO2
6-NO2
6-NO2
6-NO2
6-NO2
6-NO2
H
CH2CH2OH
CH2CH2OH
CH2CH2OH
CH2CH2OH
CH3
CH2CH2NR2
CH2CH2NR2
CH2CH2OH
CH3
CH3
CH3
CH3
CH2CH@CH2
CO2Et
CH3
CH3
CH3
CH2CH@CH2
CH2CH@CHAPh
CH2CH@CHCH2OAc
CH2CH@CH2
CH2CH@CH2
CH2CH@CH2
CH2CH@CH2
CH2CH@CH2
CH2CH@CH2
Yes [Fig. 5a]
Yes [Fig. 5b]
Yes [Fig. 5c]
Yes [Fig. 5d]
Yes [Fig. 5e]
Yes [Fig. 5f]
Yes [Fig. 5g]
Noe
565
566
569
568
595
593
594
—
c
d
6-NO2
CH2CH@CH2
Nof
429
a
b
c
d
e
f
Irradiation with 366 nm was carried out in a chloroform solution of each substrates.
Wavelengths at a maximum peak for the corresponding MC 2 forms.
A unit of maleimide was attached (Fig. 2).
A unit of protected maleimide was attached (Fig. 2).
Color change was not observed.
Conversion from MC to ISP was observed, but it was not reversible.
and closing.37 It should be noted that ISP 1h was distinct from
1a–g for its lack of a nitro group. The photoconversion of 1h into
colored forms did not occur with light at 366 nm since no absorp-
tion for excitation was observed in the spectrum of 1h, as shown in
Figure 4a (brown). In the case of 30,30-diallyl ISP, some interesting
observations were made. Left in the dark after irradiation of ISP 1d,
the lifetime of 30,30-diallyl MC 2d was the longest based on the fact
that the absorption of a maximum peak (568 nm for 2d) decreased
into a pre-irradiation levels at a much slower rate compared with
other examples of MC 2 (Fig. 4c, Fig. 5d). Furthermore, a 30,30-dial-
lyl derivative with R3 = CH3 was isolated dominantly as the MC
form 2i, which was confirmed by NMR.38 The chloroform solution
of this compound was gradually changed to the ISP form 1i by the
irradiation of light at 365 nm. The NMR measurement revealed
that a negative type of photoisomerization, from the MC to the
Figure 2. Structure of ISPs 1f and 1g.
MC-isomers.34–36 It also showed that the hydroxyethyl group on N
did not form an oxazolidine intramolecularly in a ring-opened iso-
mer. There was, however, the possibility that the hydroxyethyl
group contributed something to the processes of ring opening
Figure 3. ORTEP diagram of 1e, assigned as a 20,30-cis diastereomer.
Figure 4. UV–vis spectra of ISP 1a–h in solutions [a], after irradiation of 1a–h. [b] Time dependence of the absorption at a maximum peak of 1a–g. [c] The concentration of
1a–h was 1 ꢁ 10ꢀ4 M in chloroform at 293 K. The solutions were stored in the dark after irradiation at 366 nm for 3 min.
Please cite this article in press as: Kagawa, N.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.121

4
N. Kagawa et al. / Tetrahedron Letters xxx (2014) xxx–xxx
Figure 5. Evolution of UV–vis absorption spectrum of 1a [a], 1b [b], 1c [c], 1d [d], 1e [e], 1f [f], and 1g [g] in solutions after removing the UV light irradiation (366 nm, 3 min).
The concentration of 1a–g was 1 ꢁ 10ꢀ4 M in chloroform at 293 K.
ISP with UV irradiation, had occurred.19 However, the phenomenon
was not reversible, and complete conversion required more than
1 h of irradiation. These results implied that diallyl substitution
at the 30 position led to a steric effect during the process of inter-
conversion between the colored and colorless forms. The ratios
between two isomers were determined by 1H NMR in favor of col-
orless-form ISPs and corresponded to the equilibrium constants
(K1) of 9.8 ꢁ 10ꢀ3 (for 1a) and 5.0 ꢁ 10ꢀ2 (for 1d) at 298 K (see Sup-
plementary material). From the concentration dependence of the
absorbance and the K1, the molar extinction coefficients of MC 2a
attachable templates in the structural design of new photo-switch-
able materials.
Acknowledgments
This work was supported in part by JSPS KAKENHI Grant Num-
bers 26870101 and 20890129. We thank Dr. Masato Takahashi for
assistance with the FAB mass spectral analyses.
and 2d were estimated to be 3.3 ꢁ 104 and 1.7 ꢁ 104 Mꢀ1 cmꢀ1
,
Supplementary data
respectively.27 Moreover, the time dependence of the absorbance
Supplementary data (experimental details, characterization
data, NMR spectra for 4a–e, 6a–d, and 1a–h) associated with this
article can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.09.121. (CCDC n.-1012225–1012226, contain
the crystallographic data for this article. These data can be
obtained, free of charge, from the Cambridge Crystallographic Data
Centre via: www.ccdc.cam.ac.uk/data_request/cif) These data
include MOL files and InChiKeys of the most important compounds
described in this article.
in Figure 5a indicated that estimates for the rate constant (k1) for
the thermal interconversion of ISP 1a into MC 2a and that (k
)
,
ꢀ1
for the opposite process should be 3.9 ꢁ 10ꢀ5 and 4.0 ꢁ 10ꢀ3 sꢀ1
respectively. Similarly, the k1 and kꢀ1 between 1d and 2d were esti-
mated to be 4.7 ꢁ 10ꢀ5 and 9.5 ꢁ 10ꢀ4 sꢀ1 (Fig. 5d), respectively.37
In summary, a novel, three-step, facile synthesis of 30-allylindo-
line spirobenzopyrans enhanced by palladium-catalyzed b-allyla-
tion was accomplished via their 3-allyl-3H-indoles. The reactions
occurred selectively under mild conditions using accessible 2-
methylindoles, and 5 types of 3-allyl-3H-indoles were isolated.
These 5 types were transformed into 8 ISPs, which contained allyl
moieties at the 30 position. Most of the compounds proved to have
photochromic properties, indicating that the presence of an allyl
moiety at the 30 position did not disturb the photochromic
response. This result allowed us to propose these compounds as
References and notes
1. Minkin, V. I. Chem. Rev. 2004, 104, 2751.
2. Tamai, N.; Miyasaka, H. Chem. Rev. 2000, 1875, 100.
3. Swaminathan, S.; Garcia-Amorós, J.; Fraix, A.; Kandoth, N.; Sortino, S.; Raymo,
F. M. Chem. Soc. Rev. 2014, 43, 4167.
Please cite this article in press as: Kagawa, N.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.121

N. Kagawa et al. / Tetrahedron Letters xxx (2014) xxx–xxx
5
4. Hammarson, M.; Andersson, J.; Li, S.; Lincoln, P.; Andréasson, J. Chem. Commun.
2010, 46, 7130.
21. Tong, R.; Hemmati, H. D.; Langer, R.; Kohane, D. S. J. Am. Chem. Soc. 2012, 134,
8848.
5. Ipe, B. I.; Mahima, S.; Thomas, K. G. J. Am. Chem. Soc. 2003, 125, 7174.
6. Shao, N.; Jin, J.; Wang, H.; Zheng, J.; Yang, R.; Chan, W.; Abliz, Z. J. Am. Chem. Soc.
2010, 132, 725.
22. Inouye, M.; Akamatsu, K.; Nakazumi, H. J. Am. Chem. Soc. 1997, 119, 9160.
23. Gruda, I.; Leblanc, R. M. Can. J. Chem. 1976, 54, 576.
24. Kagawa, N.; Malerich, J. P.; Rawal, V. H. Org. Lett. 2008, 10, 2381.
25. Arsianti, A.; Tanimoto, H.; Morimoto, T.; Bahtiar, A.; Takeya, T.; Kakiuchi, K.
Tetrahedron 2012, 68, 2884.
7. Czugala, M.; O0Connell, C.; Blin, C.; Fisher, P.; Fraser, K. J.; Benito-Lopez, F.;
Diamond, D. Sens. Actuators B-Chem. 2014, 194, 105.
8. Burke, K.; Riccardi, C.; Buthelezi, T. J. Phys. Chem. B 2012, 116, 2483.
9. Shiraishi, Y.; Miyamoto, R.; Hirai, T. Org. Lett. 2009, 11, 1571.
10. Zanoni, M.; Coleman, S.; Fraser, K. J.; Byrne, R.; Wagner, K.; Gambhir, S.; Officer,
D. L.; Wallace, G. G.; Diamond, D. Phys. Chem. Chem. Phys. 2012, 14, 9112.
11. Liu, D.; Chen, W.; Sun, K.; Deng, K.; Zhang, W.; Wang, Z.; Jiang, X. Angew. Chem.,
Int. Ed. 2011, 50, 4103.
12. Ventura, C.; Byrne, R.; Audouin, F.; Heise, A. J. Polym. Sci., Part A: Polym. Chem.
2011, 49, 3455.
13. Wagner, K.; Byrne, R.; Zanoni, M.; Gambhir, S.; Dennany, L.; Breukers, R.;
Higgins, M.; Wagner, P.; Diamond, D.; Wallace, G. G.; Officer, D. L. J. Am. Chem.
Soc. 2011, 133, 5453.
26. Bergmann, E. D.; Weizmann, A.; Fischer, E. J. Am. Chem. Soc. 1950, 72, 5009.
27. Raymo, F. M.; Giordani, S.; White, A. J. P.; Williams, D. J. J. Org. Chem. 2003, 68,
4158.
28. Biswas, S.; Kinbara, K.; Oya, N.; Ishii, N.; Taguchi, H.; Aida, T. J. Am. Chem. Soc.
2009, 131, 7556.
29. Sakata, T.; Yan, Y.; Marriott, G. J. Org. Chem. 2005, 70, 2009.
30. Lu, Z.; Weber, R.; Twieg, R. J. Tetrahedron Lett. 2006, 47, 7213.
31. Bailey, G. C.; Swager, T. M. Macromolecules 2006, 39, 2815.
32. Walker, M. A. Tetrahedron Lett. 1994, 35, 665.
33. The solution was irradiated with
a Mineralight UVGL-58 lamp. A
photostationary state was reached in ca. 3 min.
14. Fischer, E.; Hirshberg, Y. J. Chem. Soc. 1952, 4522.
15. Flannery, J. B. J. J. Am. Chem. Soc. 1968, 90, 5660.
34. Sheng, Y.; Leszczynski, J.; Garcia, A. A.; Rosario, R.; Gust, D.; Springer, J. J. Phys.
Chem. B 2004, 108, 16233.
16. Champagne, B.; Plaquet, A.; Pozzo, J. L.; Rodriguez, V.; Castet, F. J. Am. Chem. Soc.
2012, 134, 8101.
35. Wohl, C. J.; Kuciauskas, D. J. Phys. Chem. B 2005, 109, 22186.
36. Futami, Y.; Chin, M. L. S.; Kudoh, S.; Takayanagi, M.; Nakata, M. Chem. Phys. Lett.
2003, 370, 460.
17. Sakata, T.; Jackson, D. K.; Mao, S.; Marriott, G. J. Org. Chem. 2008, 73, 227.
18. Voloshin, N. A.; Chernyshev, A. V.; Solov0eva, E. V.; Shepelenko, K. E.; Metelitsa,
A. V.; Minkin, V. I. Chem. Heterocycl. Compd. 2014, 49, 1815.
19. Han, J.; Wang, J.; Shen, K.; Wang, G.; Li, Y.; Zhao, D. J. Appl. Polym. Soc. 2012,
126, 30.
37. This discussion is based on a suggestion made by one of the referees, which is
gratefully acknowledged by the authors.
38. In the 1H NMR spectrum for 2i, the doublets of signal for a proton appeared at
8.48 ppm with J = 16 Hz, which confirmed the trans-configuration of the
associated double bond.
20. Brun, M. A.; Tan, K. T.; Griss, R.; Kielkowska, A.; Reymond, L.; Johnsson, K. J. Am.
Chem. Soc. 2012, 134, 7676.
Please cite this article in press as: Kagawa, N.; et al. Tetrahedron Lett. (2014), http://dx.doi.org/10.1016/j.tetlet.2014.09.121