Efficient one-pot synthesis of indol-3-yl-glycines via uncatalyzed friedel-crafts reaction in water

Article abstract of DOI:10.3390/molecules14031056

The three component reaction of primary aliphatic amines, glyoxalic acid and indole or N-methylindole in water at ambient temperature affords indol-3-yl or Nmethylindol-3-yl-glycine in almost quantitative yields.

Full text of DOI:10.3390/molecules14031056

Molecules 2009, 14, 1056-1061; doi:10.3390/molecules14031056
OPEN ACCESS
molecules
ISSN 1420-3049
www.mdpi.com/journal/molecules
Article
Efficient One-Pot Synthesis of Indol-3-yl-Glycines via
Uncatalyzed Friedel-Crafts Reaction in Water
Mehdi Ghandi * and Abuzar Taheri
School of Chemistry, University College of Science, University of Tehran, Tehran, Iran
* Author to whom correspondence should be addressed; E-mail: ghandi@khayam.ut.ac.ir; Tel.: +98-
21-61112250; Fax: +98-21-66495291.
Received: 11 February 2009; in revised form: 25 February 2009 / Accepted: 3 March 2009 /
Published: 5 March 2009
Abstract: The three component reaction of primary aliphatic amines, glyoxalic acid and
indole or N-methylindole in water at ambient temperature affords indol-3-yl or N-
methylindol-3-yl-glycine in almost quantitative yields.
Keywords: Amino acid; Indol-3-yl-glycine; Glyoxalic acid; Friedel-Crafts reaction.
Introduction
The use of water as an environmentally benign solvent for organic synthesis has become an
important research area from both the economical and synthetic point of view. The indole ring system
is probably the most ubiquitous heterocycle in Nature [1]. Substituted indoles have been referred to as
“privileged structures” since they are able to bind with high affinity to many receptors [2]. Indol-3-yl-
glycine derivatives are one of the important non-proteinogenic amino acids for the synthesis of many
biologically active compounds such as dragmacdins, hamacanthin and pemedolac [3-7]. Therefore, the
development of new strategies to the synthesis of indol-3-yl-glycine derivatives has been the subject of
considerable interest.
Owing to the importance of this class of amino acids, several procedures such as the Friedel-Crafts
reaction of indole either with glyoxylate imine/iminium species or glyoxalate and amines are
convenient methods for the synthesis of indol-3-yl-glycines. However, these methods in general
require utilization of catalysts such as TFA, Yb(OTf)3, 1H-benzotriazole and TiCl4 [8-11]. Recent
reports on the reaction of glyoxalic esters, amines and indole under solvent and catalyst free conditions

Molecules 2009, 14
1057
are of fundamental interest [12-13]. Utilization of glyoxalic acid as aldehyde has been reported by
Jiang et al., but indolyl boronic acid has been used in their approach, which does not seem to be a
convenient reagent [14].
In this paper, we report the one-pot synthesis of several indol-3-yl-glycines at ambient temperature
using water as solvent. The procedure is based on the uncatalyzed Friedel-Crafts condensation
between indole or N-methylindole and various iminoacids formed in situ from glyoxalic acid and
primary aliphatic amines.
Results and Discussion
The model three-component reaction was carried out by stirring the mixture of indole (10 mmol),
glyoxalic acid (10 mmol) and butylamine (10 mmol) in water (30 mL). It was found that at least 1 h is
needed for the reaction to go to completion at ambient temperature. Thus, the three-component
reactions of indole or N-methylindole with glyoxalic acid and primary aliphatic amines 1a-e in water
for 1 h afforded the indol-3-yl (2a-e) or N-methylindol-3-yl-glycines (3a-e), respectively. The reaction
is depicted in Scheme 1 and the results are presented in Table 1.
Scheme 1. Synthesis of indol-3-yl and N-methylindol-3-yl-glycine.
NHR2
CH
CO2H
H2O
+ HCOCO2H + R2NH2
N
N
R1
R1
2a-e , R1:H
3a-e , R1:CH3
R1: H or CH3
1a-e
Table 1. Yield and melting points for 2a-e and 3a-e.
Yield
M. P.
R1
R2
Product
(%)
95
96
95
94
95
93
92
93
95
96
( 0C)
H
H
CH3
2a
2b
2c
2d
2e
3a
3b
3c
3d
3e
198-200
190-191
123-125
214-216
200-201
187-188
196-197
197-198
189-190
174-176
CH3CH2
CH3(CH2)2
CH3(CH2)3
PhCH2
H
H
H
CH3
CH3
CH3
CH3
CH3
CH3
CH3CH2
CH3(CH2)2
CH3(CH2)3
PhCH2

Molecules 2009, 14
1058
Attempts to carry out the reaction with secondary aliphatic amines such as pyrrolidine, piperidine
and diallylamine were unsuccessful, probably due to instability of the corresponding iminium salts in
water. Moreover, using aromatic amines such as aniline, and 2-aminopyridine in most of the cases,
messy and sticky mixtures were formed. The high efficiency of reaction might be rationalized on the
basis of Brønsted acid catalysis of the carboxylic acid, as indicated in Figure 1.
Figure 1. Intramolecular acid catalysis of the Friedel-Crafts reaction of indole with an iminoacid.
O
O
H
N
N
R2
H
The inefficiency of aromatic amine in achieving hydrogen bonding to the acid site may be due to
the weaker basic strength of the nitrogen, which is in direct conjugation with aromatic ring.
Identification of the products were carried out on the basis of their spectroscopic information. For
example, compound 2d exhibited a molecular ion peak at m/z 246. The IR spectrum showed the
1
correct stretching vibrations at 2,630 (CO2H) and 1,650-1,550 (C=O, C=C) cm-1. Its H-NMR
spectrum in DMSO-d6 showed a triplet at 0.80 (3H, J = 7.2 Hz), a multiplet at 1.21 (2H), a multiplet
at 1.56 (2H), two multiplets at 2.65 and 2.73 for diestereotopic CH2NH, a singlet at 4.55 (1H), a
doublet of doublets that appears as a triplet at 6.99 ( J = 7.4 Hz, 1H), a doublet of doublets that appears
as a triplet at 7.09 (J = 7.5 Hz,1H), a doublet at 7.38 (J = 8.7 Hz, 1H), a singlet at 7.39 (1H), a doublet
at 7.74 (J = 7.8 Hz, 1H), and a singlet at 11.33 (1H, disappeared upon addition of D2O). The 13C-NMR
in DMSO-d6 exhibited five peaks at 14.4 to 59.25 (aliphatic carbons), eight peaks at 109.8 to 136.9
(aromatic carbons) and a peak at 169.5 (carboxylic acid C=O).
Conclusions
In summary, a one-pot three component reaction of indole or N-methylindole, glyoxalic acid and
primary aliphatic amines at ambient temperature in water provides an efficient and green method for
the synthesis of indol-3-yl and N-methylindol-3-yl-glycine.
Experimental
General
All commercially available chemicals and reagents were purchased from the Merck Company and
used without further purification. Melting points were determined with an Electrothermal model 9100
apparatus and are uncorrected. IR spectra were recorded on a Shimadzu 4300 spectrophotometer. The
1H- and 13C-NMR spectra were recorded on a Bruker DRX-500 AVANCE spectrometer. Unless
otherwise specified DMSO-d6 was used as solvent. Chemical shifts (δ) were reported in ppm and

Molecules 2009, 14
1059
referenced to the NMR solvent. Mass spectra of the products were obtained with a HP (Agilent
technologies) 5937 Mass Selective Detector.
General procedure for the synthesis of indol-3-yl or N-methylindol-3-yl-glycines 2a-e and 3a-e
To a solution of indole or N-methylindole (10 mmol) and glyoxalic acid (10 mmol) in water (30
mL) was added aliphatic amine (10 mmol) and the mixture was stirred for 1 h at ambient temperature.
After filtration of the precipitate formed, the solid was purified by trituration in hot methanol and then
in hot ethylacetate.
Indol-3-yl-N-methylglycine (2a): White solid; IR (KBr): 3448 (NH), 3153, 2993, 2875, 2528 (CO2H),
1645 (C=O), 1602 cm-1; 1H-NMR δ: 2.35 (s, 3H), 4.48 (s, 1H), 6.99 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 7.9
Hz, 1H), 7.36 (s, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.74 (d, J = 7.7 Hz, 1H), 11.34 (s, 1H) ppm; 13C-NMR
δ: 31.9, 60.5, 109.5, 112.3, 119.5, 120.5, 122.1, 126.7, 127.2, 137.0, 169.2 ppm; MS (EI): m/z 149
(M+-45).
Indol-3-yl-N-ethylglycine (2b): Cream solid; IR (KBr): 3514, 3186, 2877,2763, 2592 (CO2H), 1625
(C=O), 1602 cm-1; 1H-NMR δ: 1.13 (dd, 3H), 2.69 (m, 1H), 2.80 (m, 1H), 4.52 (s, 1H), 6.99 (t, J = 7.5
Hz, 1H), 7.08 (t, J = 7.7 Hz, 1H), 7.36-7.37 (bd, 2H), 7.73 (d, J = 7.5 Hz, 1H), 11.24 (s, 1H) ppm; 13C-
NMR δ: 11.9, 41.2, 58.8, 109.8, 112.3, 119.5, 120.3, 122.1, 126.4, 127.3, 136.9, 169.0 ppm; MS (EI):
m/z 218 (M+).
Indol-3-yl-N-propylglycine (2c): Cream solid; IR (KBr): 3109, 2960, 2711, 2559 (CO2H), 1645 (C=O),
1600 cm-1; 1H-NMR δ: 0.79 (t, J=7.4 Hz, 3H), 1.59 (m, 2H), 2.62 (m, 1H), 2.69 (m, 1H), 4.59 (s, 1H),
6.99 (t, J = 7.5 Hz, 1H), 7.08 (t, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.4 (s, 1H), 7.73 (d, J = 7.5
Hz, 1H), 11.42 (s, 1H) ppm; 13C-NMR δ: 11.9, 19.8, 47.9, 59.1, 109.5, 112.4, 119.5, 120.2, 122.0,
126.6, 127.3, 137.0, 169.7 ppm; MS (EI): m/z 232 (M+).
Indol-3-yl-N-butylglycine (2d): Light pink solid; IR (KBr): 3492 (NH), 3321, 3060,2933, 2759, 2630
1
(CO2H), 1650-1550 (C=O, C=C) cm-1; H-NMR δ: 0.80 (t, J = 7.2 Hz, 3H), 1.21 (m, 2H), 1.56 (m,
2H), 2.65 (m, 1H), 2.73 (m, 1H), 4.55 (s, 1H), 6.99 (t, J = 7.5 Hz, 1H), 7.09 (t, J = 7.8 Hz, 1H), 7.38
(d, J = 7.8Hz, 1H), 7.39 (s, 1H), 7.74 (d, J = 7.5 Hz), 11.33 (s, 1H) ppm; 13C-NMR δ: 14.4, 20.3, 28.4,
46.1, 59.2, 109.9, 112.3, 119.5, 120.3, 122.0, 126.5, 127.4, 136.9, 169.5 ppm; MS (EI): m/z 246 (M+).
Indol-3-yl-N-benzylglycine (2e): Dark pink solid; IR (KBr): 3373 (NH), 3213, 3109, 2991, 2493, 2629
(CO2H), 1650-1550 (C=O, C=C) cm-1; 1H-NMR δ: 3.89 (AB, J = 13.3 Hz, 2H), 4.47 (s, 1H), 6.98 (t, J
= 7.3 Hz, 1H), 7.09 (t, J = 7.6 Hz, 1H), 7.32- 7.60 (m, 7H), 7.60 (d, J = 7.6 Hz, 1H), 11.13 (s, 1H)
ppm; 13C-NMR δ: 48.8, 55.3, 112.4, 117.7, 120.5, 122.8, 124.9, 127.7, 128.9, 129.5, 129.7, 136.0,
170.1 ppm; MS (EI): m/z 280 (M+).
N-methylindol-3-yl-N-methylglycine (3a): White solid; IR (KBr): 3111, 3003, 2879, 2522 (CO2H),
1
1643 (CO), 1598 cm-1; H-NMR δ: 2.36 (s, 3H), 3.78 (s, 3H), 4.40 (s, 1H), 7.04 (t, J = 7.7 Hz, 1H),

Molecules 2009, 14
1060
7.17 (t, J = 7.8 Hz, 1H), 7.33 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.75 (d, J = 7.7 Hz, 1H) ppm; 13C-NMR
(D2O + HCl) δ: 30.5, 32.6, 57.2, 100.9, 110.7, 118.1, 120.7, 122.8, 125.4, 132.3, 137.1, 170.69 ppm;
MS (EI): m/z 218 (M+).
N-methylindol-3-yl-N-ethylglycine (3b): White solid; IR (KBr): 3109, 2979, 2680, 2534 (CO2H), 1650
1
(CO), 1596 cm-1; H-NMR δ: 1.14 (t, J = 7.1 Hz, 3H), 2.70 (m, 1H), 2.80 (m, 1H), 3.78 (s, 3H), 4.46
(s, 1H), 7.05 (t, J = 7.5 Hz, 1H), 7.17 (t, J = 7.8 Hz, 1H), 7.35 (s, 1H), 7.42 (d, J = 7.8 Hz, 1H), 7.75
(d, J = 7.5 Hz, 1H) ppm; 13C-NMR (D2O + HCl) δ: 10.6, 32.7, 41.0, 55.8, 101.5, 110.8, 118.2, 120.8,
122.9, 125.6, 132.0, 137.1, 170.8 ppm; MS (EI): m/z 232 (M+).
N-methylindol-3-yl-N-propylglycine (3c): White solid; IR (KBr): 3111, 2966, 2825, 2549 (CO2H),
1
1630 (CO), 1573 cm-1; H-NMR δ: 0.43 (t, J = 8 Hz, 3 H), 1.23 (m, 1 H), 1.3 (m, 1H), 2.43 (m, 1H),
2.51 (m, 1H), 3.25 (s, 1 H), 6.8 (m, 2 H), 6.91 (d, J = 7.8 Hz, 1H), 7.12 (s, 1H), 7.28 (d, J = 7.6 Hz,
13
1H) ppm; C-NMR (D2O + HCl) δ: 10.5, 19.2, 32.7, 47.2, 56.0, 101.6, 110.8, 118.3, 120.8, 122.9,
125.9, 131.9, 137.1, 170.9 ppm; MS (EI): m/z 201 (M+-45).
N-methylindol-3-yl-N-buthylglycine (3d): Light pink solid; IR (KBr): 3111, 2934, 26940, 2549(CO2H),
1620 (CO), 1596 cm-1; 1H-NMR δ: 0.83 (t, J = 6.5 Hz, 3H), 1.23 (m, 2H), 1.55 (m, 2H), 2.80 (m, 2H),
3.73 (s, 3H), 4.45 (s, 1H), 7.02 (m, 1H), 7.14 (m, 1H), 7.30 (s, 1H), 7.37 (d, J = 7.9 Hz, 1H), 7.74 (d, J
= 7.7 Hz, 1H) ppm; 13C-NMR (D2O + HCl) δ: 12.8, 19.3, 27.4, 32.8, 45.5, 56.0, 101.4, 110.9, 118.2,
120.8, 122.9, 125.7, 132.1, 137.1, 170.8 ppm; MS (EI): m/z 260 (M+).
N-methylindol-3-yl-N-benzylglycine (3e): White solid; IR (KBr): 3438, 3069, 2825, 2333 (CO2H),
1635 (CO), 1600 cm-1; 1H-NMR δ: 3.75 (s, 3H), 3.88 (AB, J= 13.4 2H), 4.48 (s, 1H), 7.02 (t, J = 7.5
Hz, 1H), 7.16 (t, J = 7.7 Hz, 1H), 7.31- 7.42 (m, 7H), 7.61 (d, J = 7.5 Hz, 1H) ppm; 13C-NMR δ: 33.3,
50.5, 58.1, 110.5, 119.7, 120.4, 122.2, 127.5, 128.6, 129.2, 129.9, 136.9, 137.4, 171.5 ppm; MS (EI):
m/z 294 (M+).
Acknowledgements
The authors wish to thank the Research Council of the University of Tehran for financial support.
References and Notes
1. Humphrey, G.R.; Kuethe, T.J. Practical Methodologies for the Synthesis of Indoles. Chem. Rev.
2006, 106, 2875-2911.
2. Horton, D.A.; Bourne, G.T.; Smythe, M.L. The Combinatorial Synthesis of Bicyclic Privileged
Structures or Privileged Substructures. Chem. Rev. 2003, 103, 893-930.
3. Kawasaki, T.; Enoki, H.; Matasumura, K.; Ohyama, M.; Inagawa, M.; Sakamato, M. First Total
Synthesis of Dragmacidin A via Indolylglycines. Org. Lett. 2000, 2, 3027-3029.
4. Blaszczak, L.C.; Turner, J.R. Indolylglycyl cephalosporin derivatives. US Patent 4492694, 1985.

Molecules 2009, 14
1061
5. Katz, A. H.; Demerson, C.A.; Shaw, C.C.; Asselin, A.A.; Humber, L.G.; Conway, K.M.; Gavin,
G.; Guinosso, C.; Jensen, N.P.; Mobilio, D.; Noureldin, R.; Schmid, J.; Shah, U.V.; Engen, D.;
Chau, T.T.; Weichman, B.M. Synthesis and Analgesic Activity of Pemedolac [cis- l-Ethyl-
1,3,4,9-tetrahydro-4-(phenylmethyl)pyrano[3,4-b]indole-l-acetic acid]. J. Med. Chem. 1981, 31,
1244-1250.
6. Kawasaki, T.; Kouko, T.; Totsuka, H.; Hiramatsu, H. Synthesis of marine bisindole alkaloids,
hamacanthins A and B through intramolecular transamidation–cyclization. Tetrahedron Lett.
2003, 44, 8849-8852.
7. Jiang, B.; Gu, X.H. Syntheses of bis(3- indolyl) 2-(1H)- pyrazinones. Heterocycles 2000, 53,
1559-1568
8. Nakata, H.; Imai, T.; Yokoshima, S.; Fukuyama, T. A Simple Chiral Template for the Synthesis of
Fuctionalized α-Arylglycine Derivatives. Heterocycles 2008, 76, 747-757.
9. Fan, R.; Li, W.; Wang, B. A one-pot oxidative decarboxylation–Friedel-Crafts reaction of acyclic
α -amino acid derivatives activated by the combination of iodobenzene diacetate/iodine and iron
dust. Org. Biomol. Chem. 2008, 6, 4615-4621.
10. Grumbach, H.J.; Merla, B.; Rischo, N. Efficient synthesis of racemic α- aryl- α-amino acid esters
via amino alkylation with in situ generated glycine cation equivalents. Synthesis 1999, 1027-1033.
11. Clark, B.; Harris, J. Syntheses of 7-carboxyindolylglycines utilizing glycine cation equivalents.
Syn. Commun. 1991, 27, 4223-4234.
12. Jiang, B.; Huang, Z.G. Synthesis of α-(3-Indolyl) glycine Derivatives via Spontaneous Friedel-
Crafts Reaction between Indoles and Glyoxylate Imines. Synthesis 2005, 2198-2204.
13. Zhao, J.L.; Liu, L.; Zhang, H.B.; Wu, Y.C.; Wang, D.; Chen, Y.J. Three-Component Friedel-
Crafts Reaction of Indoles, Glyoxylate, and Amine under Solvent-Free and Catalyst-Free
Conditions- Synthesis of (3-Indolyl) glycine Derivatives. Synlett 2006, 96-100.
14. Jiang, B.; Yang, C.G.; Gu, X.H. A highly stereoselective synthesis of indolyl N- substituted
glycines. Tetrahedron Lett. 2001, 42, 2545-2547.
Sample Availability: Samples of the compounds 2 and 3 are available from the authors.
© 2009 by the authors; licensee Molecular Diversity Preservation International, Basel, Switzerland.
This article is an open-access article distributed under the terms and conditions of the Creative
Commons Attribution license (http://creativecommons.org/licenses/by/3.0/).