A convenient and mild synthesis of new 2-aryl-3-hydroxy-6,7-dihydro-1H- indol-4(5H)-ones via a one-pot, three-component reaction in water

Article abstract of DOI:10.1016/j.tetlet.2014.05.073

A simple and convenient synthesis of 2-aryl-3-hydroxy-6,7-dihydro-1H-indol- 4(5H)-ones is achieved in high yields via the one-pot, three-component reaction of arylglyoxals, 1,3-cyclohexanedione, and ammonium acetate in water under reflux conditions.

Full text of DOI:10.1016/j.tetlet.2014.05.073

Accepted Manuscript
A convenient and mild synthesis of new 2-aryl-3-hydroxy-6,7-dihydro-1H-in-
dol-4(5H)-ones via a one-pot, three-component reaction in water
Jabbar Khalafy, Nasser Etivand, Shadi Dilmaghani, Mahnaz Ezzati, Ahmad
Poursattar Marjani
PII:
S0040-4039(14)00874-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.05.073
TETL 44664
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
16 March 2014
24 April 2014
15 May 2014
Please cite this article as: Khalafy, J., Etivand, N., Dilmaghani, S., Ezzati, M., Marjani, A.P., A convenient and mild
synthesis of new 2-aryl-3-hydroxy-6,7-dihydro-1H-indol-4(5H)-ones via a one-pot, three-component reaction in
water, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.05.073
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.

Tetrahedron Letters
journal homepage: www.els evier.com
A convenient and mild synthesis of new 2-aryl-3-hydroxy-6,7-dihydro-1H-indol-
4(5H)-ones via a one-pot, three-component reaction in water
Jabbar Khalafy*, Nasser Etivand, Shadi Dilmaghani, Mahnaz Ezzati, Ahmad Poursattar Marjani
Departement of Chemistry, Faculty of Science, Urmia University, Urmia 57154, Iran
*Email: jkhalafi@yahoo.com; j.khalafi@urmia.ac.ir
ARTICLE INFO
ABSTRACT
Article history:
Received
A simple and convenient synthesis of 2-aryl-3-hydroxy-6,7-dihydro-1H-indol-4(5H)-ones is
achieved in high yields via the one-pot, three-component reaction of aryglyoxals, 1,3-
cyclohexanedione and ammonium acetate in water under reflux conditions.
Received in revised form
Accepted
2014 Elsevier Ltd. All rights reserved.
Available online
Keywords:
Arylglyoxals
1,3-Cyclohexanedione
Three-component reaction
1H-indol-4(5H)-ones
Indoles are one of the most widely distributed heterocyclic
compounds in Nature. In many natural alkaloids, the indole
nucleus is an important structural unit.1,2 Among the various
classes of nitrogen-containing heterocycles, indoles have
significant synthetic potential. They are applied in many aspects
of pharmaceutical and medicinal chemistry, for example,
GABAA receptor ligands,3 antipsychotic,4 and antiproliferative
agents,5 and as soluble guanylate cyclase inhibitors.6,7
by reaction of arylglyoxals with acyclic 1,3-diketones in aqueous
ammonium acetate.15
The use of water as the sole medium for organic reactions
contributes to the development of environmentally friendly
processes. Carrying out organic reactions in water has become
highly desirable to meet environmental considerations.8-10
Scheme 1. Retrosynthesis of 2-aryl-3-hydroxy-6,7-dihydro-1H-
indol-4(5H)-ones
The arylglyoxals 2a–h were prepared from commercially
available acetophenones 1a–h by oxidation with selenium
dioxide as outlined in Scheme 2.16
The synthesis of substituted 4-oxo-4,5,6,7-tetrahydroindoles,
reported by Stetter and Lauterbach, involved treatment of 1,3-
cyclohexanediones and α-haloketones with ammonia or primary
amines leading to triones.11 Heravi et al. have reported that a
potassium hydrogen sulfate catalyzed Ugi reaction between
cyclohexylisocyanide, an aldehyde, a cyclic 1,3-dicarbonyl
compound and ammonium acetate in acetonitrile gave 2,3-
disubstituted 6,7-dihydro-1H-indol-4(5H)-ones.12 Li’s group have
reported a microwave-promoted reaction between substituted
enamines, phenylglyoxal monohydrate and acetic acid for the
preparation of polyfunctionalized indoles via multi-component
domino reaction.13,14
a; Ar = C6H5
e; Ar = 4-O2NC6H4
f; Ar = 4-MeOC6H4
g; Ar = 3,4-(MeO)2C6H3
h; Ar = 4-PhC6H4
b; Ar = 4-BrC6H4
c; Ar = 3-MeOC6H4
d; Ar = 4-FC6H4
Scheme 2. Synthesis of arylglyoxals 2a–h
Herein, we report a convenient and mild one-pot, three-
component procedure for the synthesis of 2-aryl-3-hydroxy-6,7-
dihydro-1H-indol-4(5H)-ones 4a-h via the condensation reaction
of arylglyoxals 2 with 1,3-cyclohexanedione (3) in the presence
of ammonium acetate in water (Scheme 1) Structurally
comparable 3-acyl-4-hydroxy-5-arylpyrroles have been prepared
The reaction of arylglyoxals 2a–h with 1,3-cyclohexanedione
(3) in presence of ammonium acetate in water under reflux gave
the
4(5H)-ones 4a–h (Scheme 3).
corresponding
2-aryl-3-hydroxy-6,7-dihydro-1H-indol-

2
Tetrahedron Letters
The products 4a–h were obtained in high yields after
recrystallization from ethanol.
The structures of all the products were established from their
1H-NMR, 13C-NMR and FT-IR spectral data and microanalyses.
In summary, we have reported a convenient and simple
synthesis of 2-aryl-3-hydroxy-6,7-dihydro-1H-indol-4(5H)-ones
via the reactions of arylglyoxals with 1,3-cyclohexanedione and
ammonium acetate in water. The advantageous features of this
procedure are mild reaction conditions, high yields, operational
simplicity, ready availability of starting materials and the use of
water as an environmentally friendly solvent.
General Procedure for the synthesis of 2-aryl-3-hydroxy-
6,7-dihydro-1H-indol-4(5H)-ones (4a-h):
a; Ar = C6H5
e; Ar = 4-O2NC6H4
f; Ar = 4-MeOC6H4
g; Ar = 3,4-(MeO)2C6H3
h; Ar = 4-PhC6H4
b; Ar = 4-BrC6H4
c; Ar = 3-MeOC6H4
d; Ar = 4-FC6H4
To a mixture of 1,3-cyclohexanedione (1 mmol) and
arylglyoxal16 2a-h (1 mmol) in H2O (10 mL), NH4OAc (5 mmol)
was added. The mixture was stirred and maintained at reflux
temperature for the appropriate amount of time (2-6 h). When the
reaction was complete, as monitored by TLC, the mixture was
left to cool to room temperature. The generated yellow
precipitate was filtered, washed with H2O and dried. The crude
product was recrystallized from EtOH to give pure compound
4a-h in 80-95% yield.
Scheme 3. Synthesis of 2-aryl-3-hydroxy-6,7-dihydro-1H-
indol-4(5H)-ones
Eight examples of the conversion of arylglyoxals 2a-h into the
corresponding substituted 6,7-dihydro-1H-indol-4(5H)-ones 4a-
h, along with the reaction conditions are listed in Table 1.
3-Hydroxy-2-phenyl-6,7-dihydro-1H-indol-4(5H)-one (4a)
Yellow solid. Mp: 295-296 oC. FT-IR (KBr) (νmax, cm-1):
3439, 3243, 2944, 1611, 1470, 1378, 1338, 983, 695. H NMR
Table 1. Synthesis of 2-aryl-3-hydroxy-6,7-dihydro-1H-indol-
4(5H)-ones 4a-h
1
Entry
Substrate
Product
Ar
Time (h)
Mp (oC)
Yield
(%)a
(400 MHz, DMSO-d6) δH (ppm): 11.46 (1H, s, OH, exchanged on
D2O addition), 9.81 (1H, br s, NH, exchanged on D2O addition),
7.41 (2H, d, J = 7.2 Hz, arom), 7.30 (2H, t, J = 7.2 Hz, arom),
7.16 (1H, t, J = 7.2 Hz, arom), 2.22 (2H, br t, J = 6 Hz, CH2),
2.02 (2H, br t, J = 6 Hz, CH2), 1.87-1.95 (2H, m, CH2). 13C NMR
(100 MHz, DMSO-d6) δC (ppm): 192.12, 143.52, 143.36, 133.11,
132.90, 128.65, 125.83, 119.64, 111.06, 23.43, 22.38, 20.43.
GC–MS: m/z = 227 (M+). Anal. Calcd for C14H13NO2: C, 73.99;
H, 5.77; N, 6.16. Found: C, 73.81; H, 5.92; N, 6.01.
1
2
3
4
5
6
7
8
C6H5
2
295-296
210-212
248-249
288-289
213-215
268-269
191-193
200-202
87
91
83
93
80
85
95
94
2a
2b
2c
2d
2e
2f
4a
4b
4c
4d
4e
4f
4-BrC6H4
5
3-MeOC6H4
4-FC6H4
2.5
3
4-O2NC6H4
4-MeOC6H4
3,4-(MeO)2C6H3
4-PhC6H4
2
6
3
2g
2h
4g
4h
5
aIsolated yield after recrystallization from ethanol.
3-([1,1-Biphenyl-4-yl)-3-hydroxy-2-phenyl-6,7-dihydro-
1H-indol-4(5H)-one (4h)
The proposed mechanism for this reaction is shown in
Scheme 4. The first step involves attack of the enol form of 1,3-
cyclohexanedione on the arylglyoxal 2a-h to form the
corresponding intermediate, which is converted into the desired
product through intermediate 5, by loss of two molecules of
water.
Yellow solid. Mp 200-202 oC. FT-IR (KBr) (νmax, cm-1): 3411,
3269, 2937, 1602, 1458, 1374, 1214, 1155, 983, 765. H NMR
1
(400 MHz, DMSO-d6) δH (ppm): 11.54 (1H, s, exchanged on
D2O addition, OH), 9.87 (1H, br s, exchanged on D2O addition,
NH), 7.68 (2H, d, J = 7.2 Hz, arom), 7.64 (2H, d, J = 8.8 Hz,
arom), 7.53 (2H, d, J = 8.8 Hz, arom), 7.46 (2H, d, J = 7.2 Hz,
arom), 7.35 (1H, t, J = 7.2 Hz, arom), 2.24 (2H, t, J = 6 Hz, CH2),
2.04 (2H, t, J = 6 Hz, CH2), 1.95 (2H, m, CH2). 13C NMR (100
MHz, DMSO-d6) δC (ppm): 192.13, 143.73, 143.57, 139.63,
137.28, 132.18, 128.89, 128.28, 127.23, 126.41, 125.63, 119.77,
111.13, 23.43, 22.46, 20.44. GC–MS: m/z = 303 (M+). Anal.
Calcd for C20H17NO2: C, 79.19; H, 5.65; N, 4.62. Found: C,
79.27; H, 5.79; N, 4.61.
Acknowledgments
The authors gratefully acknowledge the financial assistance from
the University of Urmia.
References and notes
1. Sundberg, R. J. Indoles; Academic Press: London, 1996.
2. Joule, J. A. In Science of Synthesis; Thomas, E. J., Ed.; Thieme:
Stuttgart, 2001; Vol. 10, p 361.
Scheme 4. The proposed mechanism for the formation of
2-aryl-3-hydroxy-6,7-dihydro-1H-indol-4(5H)-ones.
3. Broughton, H. B.; Bryant, H. J.; Chambers, M. S.; Curtis, N. R.
WO 9962, 899, 1999; Chem. Abstr. 1999, 132: 12259y.

4. Fick, D. B.; Foreman, M. M.; Glasky, A J.; Helton, D. R. WO
0311, 396, 2003; Chem. Abstr. 2003, 138: 163572v.
5. Chiang, C. C.; Lin, Y. H.; Lin, S. F.; Lai, C. L.; Liu, C.; Wei, W.
Y.; Yang, S. C.; Wang, R. W.; Teng, L. W.; Chuang, S. H.;
Chang, J. M.; Yuan, T. T.; Lee, Y. S.; Chen, P.; Chi, W. K.; Yang,
J. Y.; Huang, H. J.; Liao, C. B.; Huang, J. J. J. Med. Chem. 2010,
53, 5929.
9. Demko, Z. P.; Sharpless, K. B. J. Org. Chem. 2001, 66, 7945.
10. Li, C. -J. Chem. Rev. 2005, 105, 3095.
11. Stetter, H.; Lauterbach, R. Liebigs Ann. Chem. 1962, 655, 20.
12. Heravi, M. M.; Baghernejad, B.; Oskooie, H. A.; Hekmatshoar, R.
Tetrahedron Lett. 2008, 49, 6101.
13. Jiang, B.; Yi, M. S.; Shi, F.; Tu, S. J.; Pindi, S.; McDowell, P.; Li,
G. Chem. Commun. 2012, 48, 808.
6. Zapf, C. W.; Bloom, J. D.; McBean, J. L.; Dushin, R. G.; Nittoli,
T.; Ingalls, C.; Sutherland, A. G.; Sonye, J. P.; Eid, C. N.; Golas,
J.; Liu, H.; Boschelli, F.; Hu, Y.; Vogan, E.; Levin, J. I. Bioorg.
Med. Chem. Lett. 2011, 21, 2278.
14. Jiang, B.; Li, Q. Y.; Zhang, H.; Tu, S. J.; Pindi, S.; Li, G. Org.
Lett. 2012, 14, 700.
15. Khalili, B.; Jajarmi, P.; Eftekhari-Sis, B.; Hashemi, M. M. J. Org.
Chem. 2008, 73, 2090.
7. Spyridonidou, K.; Fousteris, M.; Antonia, M.; Chatzianastasiou,
A.; Papapetropoulos, A.; Nikolaropoulos, S. Bioorg. Med. Chem.
Lett. 2009, 19, 4810.
16. Riley, H. A.; Gray, A. R. Org. Synth. Collect. Vol. II, 1943, p. 509
(Wiley & Sons: New York).
8. Grieco, P. A. Organic Synthesis in Water; Blackie Academic and
Professional: London, 1998.

Graphical Abstract
A convenient and mild synthesis of new 2-aryl-3-hydroxy-6,7-dihydro-1H-indol-4(5H)-ones via a
one-pot, three-component reaction in water
Jabbar Khalafy, Nasser Etivand, Shadi Dilmaghani, Mahnaz Ezzati, Ahmad Poursattar Marjani