Improving the synthesis of spiropyran derivatives using microwave irradiation method

Article abstract of DOI:10.3987/COM-13-12920

A solvent free synthesis of spiropyran derivatives has been developed from the condensation of indoline and salicylaldehyde using a microwave irradiation method. This method starts from readily available starting materials and provides biologically interesting products. The microwave irradiation method was remarkably successful and gave spiropyran derivatives in higher yield (72-99%) with a much shorter reaction time (10-15 min) compared to the conventional heating method. The chemical structures of the compounds prepared were characterized through IR, ₁H NMR and ₁₃C NMR spectral data.

Full text of DOI:10.3987/COM-13-12920

HETEROCYCLES, Vol. 89, No. 4, 2014
1017
HETEROCYCLES, Vol. 89, No. 4, 2014, pp. 1017 - 1024. © 2014 The Japan Institute of Heterocyclic Chemistry
Received, 20th December, 2013, Accepted, 7th February, 2014, Published online, 18th February, 2014
DOI: 10.3987/COM-13-12920
IMPROVING THE SYNTHESIS OF SPIROPYRAN DERIVATIVES
USING MICROWAVE IRRADIATION METHOD
Atisya Rohadi, Siti Aishah Hasbullah,* Azwan Mat Lazim, and Rumaisa
Nordin
School of Chemical Sciences and Food Technology, Universiti Kebangsaan
Malaysia, 43600 UKM Bangi, Selangor, Malaysia. Email: aishah80@ukm.my
Abstract – A solvent free synthesis of spiropyran derivatives has been developed
from the condensation of indoline and salicylaldehyde using a microwave
irradiation method. This method starts from readily available starting materials and
provides biologically interesting products. The microwave irradiation method was
remarkably successful and gave spiropyran derivatives in higher yield (72–99%)
with a much shorter reaction time (10–15 min) compared to the conventional
heating method. The chemical structures of the compounds prepared were
characterized through IR, 1H NMR and 13C NMR spectral data.
Among the structurally diverse photochromic compounds, spiro compounds have attracted much interest
due to their remarkable properties. Spiropyrans were first synthesized and studied in early 1950’s, by
Hirschberg and Fisher.1 Particular attention has been given to spiropyran due to their potential applications
in optical devices and sensors2 as well as biomedical applications.3 Interestingly, spiropyran compound is
reversible when it undergoes photo-transformation with changes in solvent polarity.4 Scheme 1 shows the
photochromism of typical spiropyran when exposes to UV light, producing an open form compound known
as merocyanine.
R
UV
N
N
O
O
VIS
R
SPIROPYRAN
MEROCYANINE
Scheme 1. Photochromism of typical spiropyran

1018
HETEROCYCLES, Vol. 89, No. 4, 2014
Many techniques have been employed to synthesize spiropyran and their derivatives.5-8 One of the most
popular conventional methods was developed by the Wizinger and Wenning in 1940. It involves the
condensation of 2-alkyl heterocyclic quaternary salt with the substituted salicylaldehyde in refluxing
solvent such as ethanol, acetonitrile and tetrahydrofuran.9
In recent years, microwave irradiation has been widely used in organic chemistry synthesis.10 Gedye and
Majetich were the earliest researchers to report on the microwave irradiation especially in the preparation of
various heterocyclic compounds.11,12 This “non-conventional” synthetic method offers numerous benefits
such as accelerating the synthesis of inorganic13 and organic compounds,14,15 shorter reaction time,16,17
produce higher yields18 and enhance product purities.19 Moreover, microwave irradiation is also considered
as a “green” alternative since many organic reactions can be carried out in solvent-free conditions.20,21
Microwave irradiation method offers an efficient alternative approach although it is not extensively
explored in synthesizing spiropyran and their derivatives.
Among the synthetic conditions for preparation of spiropyran derivatives, the normal heating method
(reflux) is the well known method.6,8,22-25 In this reaction, the derivatives of spiropyrans 3a–3e were
prepared by the reaction of indole 1 and salicylaldehyde derivatives 2a–2e under microwave irradiation
technique in solvent free condition for 10–15 min at 300 W. Scheme 2 shows the synthesis of spiropyran
3a–3e using a microwave irradiation method.
CHO
OH
MW 300W, 10-15 min
N
N
O
R
R
R (2/3a-2/3d) = OH
R (2/3e) = OMe
2a - 2e
3a - 3e
1
Scheme 2. Preparation of spiropyran 3a–3e using microwave irradiation
The yields of the products 3a–3e were improved under the microwave irradiation compared to normal
approaches (Table 1).

HETEROCYCLES, Vol. 89, No. 4, 2014
1019
Table 1. Yield of spiropyran 3a – 3e
Product
Salicylaldehyde
Normal Method/
% yield
time
Microwave
% yield
t/min
10
2a–2e
O
H
3a
44a,22
4 h
93
OH
O
H
3b
3c
90a,23
5.5 h
99
10
10
OH
OH
O
H
40b,18
No reaction
OH
-
OH
O
H
3d
3e
62a,24
6 h
97
72
10
15
OH
HO
O
H
58c,20
20 min
OH
MeO
Conditions: a = reflux; b = room temperature; c = ultrasound
Comparison of the product were made for normal and microwave approach respectively. By using the
microwave method, the yields of 3a–3e products were increased in ranged of 72–99%. It is due to the low
reactivity of formyl group with additional electron donating group at 4-position of
2,4-dihydroxybenzaldehyde which led to produce 3c crude product with unidentified side product that
failed to be purified.17 Compound 3d gives a higher yield (97%) compared to compound 3e by the fact that
a hydroxyl group at para position of salicylaldehyde which is more reactive compared to a methoxy
group with respect to benzene.
The products (3a–3e) were prepared according to the described microwave method. The structures of
spiropyrans (3a–3e) were confirmed by FT-IR and NMR spectral data. The IR spectrum of spiropyran

1020
HETEROCYCLES, Vol. 89, No. 4, 2014
showed the presence of the hydroxyl group of intramolecular H-band in substituent salicylaldehydes at
3300–3200 cm-1.26 The absorption band at 1610–1600 cm-1 and 1480–1460 cm-1 are refer to the aromatic
ring C=C stretching. It is known that the presence of absorption bands at 1260–1240 cm-1 to 1070 cm-1 were
attributed to the aryl C-O stretching. Furthermore, the Cspiro-O stretching frequencies are found to be at
930–920 cm-1 that signify the indolinobenzospiropyran compounds.27
Structural elucidations of 3a–3e were also achieved by 1H NMR spectroscopy. All the spiropyrans (3a–3e)
show signals of two gem-dimethyl groups at 1.13±1.18 ppm and 1.28±1.32 ppm. The results indicate the
methyl group is not magnetically equivalent. N-Methyl peak is observed as a singlet at 2.71±2.75 ppm, due
to the orthogonal nature of the indoline and benzopyran halves.28 The olefinic protons appear as a doublet at
5.67±5.72 and 6.82±6.87 ppm respectively, with large coupling constants J = 10.1±10.2 Hz. This is a
typical value for cis configuration.29 For 3b and 3d compounds which have a hydroxyl group attached to the
aromatic ring are observed as a broad singlet peak at 5.47 ppm and 4.68 ppm. Apart from that, 3e shows a
singlet peak at 3.77 ppm which integrates for 3 protons where it indicates the methoxy group. The proton
NMR spectra of (3a–3e) show aromatic hydrogens that appeared as multiplet from 6.49 to 7.91 ppm
respectively.
All the entire signal comprising an indoline and benzopyran subunits, the common components are
accordance for all the spiropyran moieties.29 According to Natali and co-workers,30 the reaction mechanism
takes place when the Fisher base forms a carbanion caused by mesomeric effect. Thus, the nucleophiles of
Fisher base attack the carbonyl group of the substituted salicylaldehydes. This allows the internal proton
transfer of hydroxyl group within the ring.31 Then, it underwent intramolecular ring closing followed by the
elimination of water to form the spiro compound (Scheme 3).
O
OH
O
R
R
CH2
CH2
N
N
O
N
H
H
OH
HO
R
-H2O
N
O
N
N
O
O
R
R
3a - 3e
Scheme 3. Proposed mechanism of compounds 3a–3e

HETEROCYCLES, Vol. 89, No. 4, 2014
1021
In summary, a series of spiropyran 3a–3e were successfully prepared using a domestic microwave as
irradiation source with improved yield (72–99%). This technique offers an alternative to synthesize organic
compounds with a high yield and short reaction time compare to the conventional method. Furthermore,
this research also demonstrated that microwave irradiation is a convenient, inexpensive and highly efficient
technique which can also contributes towards the green chemistry.
EXPERIMENTAL
Microwave irradiation was carried out using the domestic microwave oven (Electrolux, model
EMM2017X,PCR). Infrared (IR) spectra were recorded by using Perkin Elmer FT-IR at room temperature.
The test samples were prepared by using KBr disc method and analyzed over the range of 400 – 4000 cm-1.
13
1H NMR and C NMR spectra were recorded on a Bruker Advance spectrophotometer (400MHz) using
tetramethylsilane (TMS) as internal reference. Purification was performed using flash column
chromatography on grade silica gel (Merck, 70-230 mesh). Analytical thin layer chromatography (TLC)
was performed on precoated silica gel Merck DC Kieselgel 60 F254 plates and the spots were visualized with
UV light. All the chemicals were obtained from commercial sources and were used without further
purification.
Microwave method
To a mixture of spiroyrans (3a–3e (2.5 mmol)), salicylaldehyde derivatives 2a–2e (2.5 mmol) and
1,3,3-trimethyl-2-methyleneindoline 1 (2.5 mmol) were added. The reaction mixture was taken in vial and
placed in a microwave oven and irradiated at 300 W for 10–15 min. The crude product was concentrated
and purified by flash column chromatography with hexane–EtOAc (4:1) as the eluent to afford the product.
Spiro [2H-1-benzopyran-2,2’-(1’,3’,3’-trimethylindoline)] (3a)
IR υmax (KBR)/cm-1: 2941, 1605, 1444, 1250, 951; 1H NMR (600 MHz, CDCl3) δH 1.18 (3H, s, CH3), 1.33
(3H, s, CH3), 2.75 (3H, s, N-CH3), 5.69 (1H, m, J = 10.2, C=CH), 6.54 (1H, m, J = 7.8, HAr), 6.72 (1H, m,
J = 8.4, HAr), 6.83 (1H, m, J = 7.2, HAr), 6.85 (1H, m, J = 7.8, HAr), 6.87 (1H, m, J = 10.2, C=CH), 7.06 (1H,
m, J = 7.8, HAr), 7.10 (1H, m, J = 7.8, HAr), 7.11 (1H, s, HAr), 7.19 (1H, m, J = 7.8, HAr); 13C NMR (150
MHz, CDCl3) δc 20.2 (C-CH3), 25.8 (C-CH3), 28.9 (N-CH3), 51.7 (CH3-C-CH3), 104.1 (N-Cspiro-O), 106.8
(CHAr), 115.0 (CHAr), 118.8 (CAr), 119.1 (CHAr), 119.3 (CHAr), 120.0 (CHAr), 121.5 (CHAr), 126.6 (HC=),
127.6 (HC=), 129.4 (CHAr), 129.6 (CHAr), 136.8 (CAr), 148.2 (CAr) and 154.4 (CAr). All the spectral data
were in accordance to the literature.22
Spiro [2H-1-benzopyran-2,2’-(8’-hydroxy-1’,3’,3’-trimethylindoline)] (3b)

1022
HETEROCYCLES, Vol. 89, No. 4, 2014
IR υmax (KBR)/cm-1: 3513, 2962, 1650, 1466, 1248, 931; 1H NMR (400 MHz, CDCl3) δH 1.17 (3H, s, CH3),
1.29 (3H, s, CH3), 2.74 (3H, s, N-CH3), 5.47 (1H, s, OH), 5.67 (1H, m, J = 10.2, C=CH), 6.53 (1H, m, J =
8.0, HAr), 6.63 (1H, m, J = 8.0, HAr), 6.73 (1H, m, J = 8.0, J = 7.5, HAr), 6.76 (1H, m, J = 8.0, HAr), 6.78
(1H,m, J 8.0, HAr), 6.85 (1H, m, J = 10.2, C=CH), 7.07 (1H, m, J = 8.0, HAr), 7.18 (1H, m, J = 8.0, HAr); 13C
NMR (100 MHz, CDCl3) δc 19.9 (C-CH3), 25.9 (C-CH3), 28.9 (N-CH3), 51.8 (CH3-C-CH3), 105.4
(N-Cspiro-O), 107.0 (CHAr), 115.6 (CHAr), 118.1 (CHAr), 119.0 (CAr), 119.3 (CHAr), 119.5 (CHAr), 120.4
(CHAr), 121.7 (CHAr), 127.7 (HC=), 129.5 (HC=), 136.5 (CAr), 140.8 (CAr), 143.2 (CAr) and 147.9 (CAr). All
the spectral data were in accordance to the literature.23
Spiro [2H-1-benzopyran-2,2’-(7’-hydroxy-1’,3’,3’-trimethylindoline)] (3c)
All the spectral data were in accordance to the literature.18
Spiro [2H-1-benzopyran-2,2’-(6’-hydroxy-1’,3’,3’-trimethylindoline)] (3d)
IR υmax (KBR)/cm-1: 3296, 2959, 1606, 1466, 1249, 938; 1H NMR (400 MHz, CDCl3) δH 1.14 (3H, s, CH3),
1.28 (3H, s, CH3), 2.71 (3H, s, N-CH3), 4.68 (1H, s, OH), 5.68 (1H, m, J = 10.2, C=CH), 6.49 (1H, m, J =
8.0, HAr), 6.51 (1H, m, J = 9.5, HAr), 6.54 (1H, m, J = 8.0, HAr), 6.57 (1H, m, J = 8.0, HAr), 6.59 (1H, m, J
= 8.0, HAr), 6.75 (1H, m, J = 10.2, C=CH), 7.07 (1H, m, J = 7.0, HAr), 7.18 (1H, m, J = 8.0, HAr); 13C NMR
(400 MHz, CDCl3) δc 20.3 (C-CH3), 25.9 (C-CH3) ,29.0 (N-CH3), 51.7 (CH3-C-CH3), 106.8 (N-Cspiro-O),
112.9 (CHAr), 115.6 (2 x CHAr), 116.4 (CHAr), 119.0 (CHAr), 119.3 (CAr), 120.5 (CHAr), 121.5 (CHAr),
127.6 (HC=), 129.1 (HC=), 136.8 (CAr), 148.2 (CAr), 148.6 (CAr) and 148.7 (CAr). All the spectral data were
in accordance to the literature.24
Spiro [2H-1-benzopyran-2,2’-(7’-methoxy-1’,3’,3’-trimethylindoline)] (3e)
IR υmax (KBR)/cm-1: 2833, 1644, 1468, 1240, 922; 1H NMR (600 MHz, CDCl3) δH 1.17 (3H, s, CH3), 1.32
(3H, s, CH3), 2.74 (3H, s, N-CH3), 3.77 (3H, s, OCH3), 5.72 (1H, m, J = 10.2, C=CH), 6.53 (1H, m, J = 7.8,
HAr), 6.62 (1H, s, HAr), 6.66 (1H, s, HAr), 6.68 (1H, m, J = 8.4, HAr), 6.82 (1H, m, J = 10.2, C=CH), 6.85
(1H, m, J = 7.8, HAr), 7.09 (1H, m, J = 7.2, HAr), 7.19 (1H, m, J = 7.8, HAr); 13C NMR 150 MHz, CDCl3) δc
20.2 (C-CH3), 25.8 (C-CH3), 28.9 (N-CH3), 51.6 (CH3-C-CH3), 55.8 (OCH3), 103.8 (CAr), 106.7
(N-Cspiro-O), 111.4 (CHAr), 115.2 (CHAr), 115.5 (CHAr), 119.0 (CHAr), 119.1 (CHAr), 120.3 (CHAr), 121.5
(CHAr), 127.5 (2 x HC=), 129.3 (CHAr), 136.6 (CAr), 148.2 (CAr), 148.6 (CAr) and 153.1 (CAr). All the
spectral data were in accordance to the literature.20
ACKNOWLEDGEMENTS
The authors thank the School of Chemical Sciences and Food Technology, Faculty of Science and

HETEROCYCLES, Vol. 89, No. 4, 2014
1023
Technology, Universiti Kebangsaan Malaysia, Bangi and Centre for Research and Instrumentation
Management UKM for instrumental facilities as well as grants GGPM-2011-054 and
FRGS/1/2013/ST01/UKM/03/4 for funding the project.
REFERENCES (AND NOTES)
1. E. Fischer and Y. Hirshberg, J. Chem. Soc., 1952, 4522.
2. N. Shao, Y. Zhang, S. M. Cheung, R. H. Yang, W. H. Chan, T. Mo, K. A. Li, and F. Liu, J. Anal.
Chem., 2005, 77, 7294.
3. M. Alonso, V. Reboto, L. Guiscardo, V. Mate, and J. C. Rodríguez-Cabello, Macromolecules, 2001,
34, 8072.
4. H. R. Allcock and C. Kim, Macromolecules, 1991, 24, 2846.
5. Y. J. Cho, S. H. Lee, J. W. Bae, S. H. Kim, S. R. Keum, and C. M. Yoon, Synth. Commun., 2000, 30,
2205.
6. S. Han and Y. Chen, Dyes Pigments, 2011, 88, 235.
7. L. E. Elizalde and G. de los Santos, Dyes Pigments, 2008, 78, 111.
8. T. R. Silvia, V. S. L. Ana, and E. A. S. González, Synth. Commun., 1995, 25, 105.
9. B. Lukyanov and M. Lukyanova, Chem. Heterocycl. Compd., 2005, 41, 281.
10. R. Gedye, F. Smith, K. Westaway, H. Ali, L. Baldisera, L. Laberge, and J. Rousell, Tetrahedron Lett.,
1986, 27, 279.
11. O. O. Ajani, C. A. Obafemi, C. O. Ikpo, K. O. Ajanaku, K. O. Ogunniran, and O. O. James, Int. J. Phys.
Sci., 2009, 4, 156.
12. M. A. Surati, S. Jauhari, and K. R. Desai, Arch. Appl. Sci. Res., 2012, 4, 645.
13. A. S. Vanetsev, E. V. Makshina, N. N. Oleynikov, Y. D. Tret’yakov, and B. V. Romanovskii, Dokl.
Chem., 2005, 405, 226.
14. K. L. Tan, A. Vasudevan, R. G. Bergman, J. A. Ellman, and A. J. Souers, Org. Lett., 2003, 5, 2131.
15. W. Dai, D. Guo, L. Sun, and X. Huang, Org. Lett., 2003, 5, 2919.
16. P. Parasuraman, Sci. Rep., 2013, 2, 1.
17. B. L. Hayes, Aldrichimica. Acta, 2004, 37, 66.
18. R. Martínez-Palou, J. Mex. Chem. Soc., 2007, 51, 252.
19. D. Nasrin, N. Islam, F. Hoque, T. Ferdous, and F. Z. Farhana, Int. J. Basic Appl. Sci., 2012, 12, 50.
20. B. A. Roberts and C. R. Strauss, Acc. Chem. Res., 2005, 38, 653.
21. R. Sarma, D. Prajapati, and R. C. Boruah, Sci. Cult., 2011, 77, 461.
22. A. E. Garcia, L. E. Elizalde, L. Guillén, G. de los Santos, and D. I. Medellín, Rev. Soc. Quim. Mex.,
2004, 48, 269.

1024
HETEROCYCLES, Vol. 89, No. 4, 2014
23. S. Yagi, S. Nakamura, D. Watanabe, and H. Nakazumi, Dyes Pigments, 2009, 80, 98.
24. B.-I. Tan, M. Yoshio, T. Ichikawa, T. Mukai, H. Ohno, and T. Kato, Chem. Commun., 2006, 4703.
25. Y. M. Chuneav, N. M. Przhiyalgovskaya, L. N. Kurkovskaya, and M. A. Gal’bershtam, Khim.
Geterotsikl. Soed., 1982, 11, 1501.
26. S.-R. Keum, Y.-K. Choi, M.-J. Lee, and S.-H. Kim, Dyes Pigments, 2001, 50, 171.
27. S.-R. Keum, Y.-K. Choi S.-H. Kim, and C.-M. Yoon, Dyes Pigments, 1999, 41, 41.
28. M. J. Preigh, M. T. Stauffer, F. T. Lin, and S. G. Weber, J. Chem. Soc., Faraday Trans., 1996, 92,
3991.
29. D. L. Pavia, G. M. Lampman, G. S. Kriz, and J. A. Vyvyan, ‘Introduction to Spectroscopy,’
Brooks/Cole: Belmont, USA, 2009, p. 144.
30. M. Natali, C. Aakeröy, J. Desper, and S. Giordani, Dalton Trans., 2010, 39, 8269.
31. S. Hencht, ‘Introduction to the Synthesis of Photochromes: Spiropyran and Diarylethenes,’ SFB
Colluquium. Humboldt-Universitat zu Berlin, 2011.