One-pot three-component synthesis of indole-3-glyoxyl derivatives and indole-3-glyoxyl triazoles

Article abstract of DOI:10.1016/j.tetlet.2013.08.064

A general and efficient reaction of indole with oxalyl chloride and nucleophiles providing indole-3-glyoxyl derivatives has been developed in mild conditions. In the same fashion, the other reaction involved the addition of organic azides leading to the synthesis of indole-3-glyoxyl-1,2,3-triazoles, which proceeds smoothly generating the products in moderate to high yields.

Full text of DOI:10.1016/j.tetlet.2013.08.064

Accepted Manuscript
One-Pot Three-component Synthesis of Indole-3-glyoxyl Derivatives and In‐
dole-3-glyoxyl Triazoles
Hélio A. Stefani, Stanley N.S. Vasconcelos, FredericoB. Souza, FláviaManarin,
Julio Zukerman-Schpector
PII:
S0040-4039(13)01437-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.08.064
TETL 43427
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
22 July 2013
9 August 2013
19 August 2013
Please cite this article as: Stefani, H.A., Vasconcelos, S.N.S., Souza, F.B., Manarin, F., Zukerman-Schpector, J.,
One-Pot Three-component Synthesis of Indole-3-glyoxyl Derivatives and Indole-3-glyoxyl Triazoles, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.08.064
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One-Pot Three-component Synthesis of Indole-
3-glyoxyl Derivatives and Indole-3-glyoxyl
Triazoles
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Hélio A. Stefani*, Stanley N. S. Vasconcelos, Frederico B. Souza, Flávia Manarin, Julio Zukerman-Schpector

1
Tetrahedron Letters
journal hom epage: www.elsevier.com
One-Pot Three-component Synthesis of Indole-3-glyoxyl Derivatives and Indole-3-
glyoxyl Triazoles
Hélio A. Stefania,*, Stanley N. S. Vasconcelosa, Frederico B. Souzaa, Flávia Manarina, Julio Zukerman-
Schpectorb
aDepartamento de Farmácia, Faculdade de Ciências Farmacêuticas, Universidade de São Paulo, São Paulo, SP – Brazil.
bDepartamento de Química, Universidade Federal de São Carlos, SP – Brazil.
ARTICLE INFO
ABSTRACT
Article history:
Received
A general and efficient reaction of indole with oxalyl chloride and nucleophiles providing
indole-3-glyoxyl derivatives has been developed in mild conditions. In the same fashion, the
other reaction involved the addition of organic azides leading to the synthesis of indole-3-
glyoxyl-1,2,3-triazoles, which proceeds smoothly generating the products in moderate to high
yields.
Received in revised form
Accepted
Available online
©2009 Elsevier Ltd. All rights reserved.
Keywords:
Indole
Oxalyl chloride
Nucleophiles
Triazole
Multicomponent reactions (MCRs)
Introduction
On the other hand, a vast number of natural and synthetic core
indoles have found applications as pharmaceuticals and
agricultural chemicals.7 The functionalization of indoles has been
intensively studied via multicomponent processes8 in recent years.
In recent years, advances in multicomponent processes
(MCPs) including multicomponent reactions (MCRs) and one-
pot multicomponent reactions have played an important role and
allowed tremendous developments in organic chemistry. A
variation of MCPs involves the sequential addition of three or
more different compounds in two or more steps in the same
reaction vessel, entitled one-pot multicomponent reactions.1
The synthesis of indole-3-glyoxyl derivatives was also explored
by Primofiore9 and Chen10 who, in both cases, developed libraries
to study the activity of this kind of compound in a cell line model
of prion disease and as a benzodiazepine receptor.
Due to the therapeutic potential of this class of compound, we
felt stimulated to develop a more efficient approach comprising a
novel structural frame, by including 1,2,3-triazoles in the
molecules.
This allows rapid access to structural variation and complexity
within single-step conversions. The potential of multiple bond
formations among more than two building blocks in a one-step
procedure has been widely exploited in combinatorial and
medicinal chemistry.2,3 In this sense, many complex molecules
were synthesized using these methodologies such bile acids,4
chimeric peptide-steroids5 and anticancer peptides,6 to mention a
few (Fig. 1).
Results and Discussion
We report here an easy and mild approach for the synthesis of
indole-3-glyoxyl derivatives and indole-3-glyoxyl-1,2,3-triazoles.
Typically, the reactions were carried out in dry tetrahydrofuran (4
mL) with indole (0.5 mmol), oxalyl chloride (0.6 mmol), a
nucleophile (0.6 mmol) and DIPEA (2 equiv) at room
temperature. The products were extracted from the reaction
mixture using ethyl acetate with a reaction time that is indicated
in Table 1. As shown below, the scope and limitation of this
reaction was evaluated.
Table 1. Synthesis of indole derivatives using different nucleophiles
Figure 1. Structures of polyfunctionalized molecules.

2
Tetrahedron
1, entry 7). Propargylamine and propargyl alcohol both gave very
Entry
1
Product
Time (h) Yield (%)
similar yields, 78% and 80%, respectively (Table 1, entries 1 and
5). In the case of benzylalcohol pyridin-2-ylmethanamine, the
yields were also good: 87% and 79%, respectively (Table 1,
entries 2 and 6). However, terc-butyl amine resulted in only 44%
yield (Table 1, entry 4). The allyl group afforded the highest
yield of all other nucleophiles, with a yield of 98% (Table 1,
entry 3). The product 4j, containing the ester group, was obtained
in a moderate 48% yield.
2
78
2
2
87
Inspired by the first results, the next step was to study the one-
pot multicomponent reaction involving the reactants used in the
first reaction, whilst introducing organic azides in the system to
obtain the product of click chemistry, 1,2,3-triazoles. To perform
this reaction, the products 4a and 4e were employed, as shown in
Table 1.
3
4
5
2
3
2
98
44
80
Initially, the reaction conditions were screened as catalyst and
base using indole, oxalyl chloride, propargyl alcohol and
benzylazide as model reagents, as shown in Table 2.
Table 2. Screening of the indole-3-glyoxyl-1,2,3-triazoles via click
chemistry
b
Entry Catalyst
Base
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
9
CuI (1 eq)
CuI (0.5 eq)
CuI (0.1 eq)
CuCl (1 eq)
CuSO4 (1 eq)
CuI (1 eq)
CuI (1 eq)
CuI (1 eq)
CuI (1 eq)
PMDETA (1 eq)
PMDETA (1 eq)
PMDETA (1 eq)
PMDETA (1 eq)
PMDETA (1 eq)
PMDETA (2 eq)
TEA (1 eq)
0.5
1
85
33
13
73
nr
24
1
6
3
79
24
1
81
75
70
45
24
24
24
DIPEA
7
8
9
2
2
3
72
78
72
DIPA
a The first step of reactions was conducted at room temperature; indole (0.5
mmol), oxalyl chloride (0.6 mmol), DIPEA (1.2 mmol) and propargyl
alcohol (0.6 mmol) in THF (4 mL) for 2 hours. b Time for cycloaddition
with benzyl azide.
After evaluations of Cu catalysts, bases, temperatures, and
catalyst loadings, a combination of CuI 1.0 equiv and 1.0 equiv
of PMDETA (N,N,N′,N′′,N′′-pentamethyldiethylenetriamine) in
THF (4 mL) at room temperature was found to be the optimal
reaction condition, and the triazole 6a was isolated in 85% yield
within 3 h (Table 2, entry 1). Next, with the optimized reaction
condition11 established, the scope of the substrates for this
reaction was investigated (Table 3).
Table 3. Synthesis of indole-triazole derivatives via click chemistry
10
3
48
Various aromatic- and alkyl amines were used as
nucleophiles; it was observed that the electronic effect of the
electron-rich aromatic ring favored high yield (Table 1, entry 8),
electron-poor aromatics showed a moderate 72% yield (Table 1,
entry 9), while neutral aromatic rings gave a similar yield (Table

3
were obtained an X-ray structural analysis was undertaken (Fig.
2).
Entry
1
Product
Time (h)
Yield (%)
85
3
2
3
5
4
74
57
Figure 2. X-ray crystal structure of 6d.
Analysis of Table 3 shows that, in general, all reactions
proceeded with acceptable yields. Initially, we evaluated the
influence of 4a (Table 1, entry 1) with different azides for the
cycloaddition reaction.
Alkyl and phenyl azides gave good yields of 85% (Table 3,
entry 1) and 74% (Table 3, entry 2), respectively, but an aryl
group containing an electron-withdrawing substituent as m-Cl
gave a moderate yield of 57% (Table 3, entry 3).
4
5
4
4
65
63
We investigated the influence of 4e as the starting material.
Azides containing benzyl groups gave 65% yield (Table 3, entry
4), while phenyl azide gave 63% (Table 3, entry 5). Next, we
evaluated the influence of different substituents in the aromatic
ring of azide partner such as the position of these groups,
electron-donating and electron-withdrawing groups were
employed in the reaction. The substituent m-OMe gave a
moderate yield of 62% (Table 3, entry 6), while the o-OMe gave
the desired product in 41% yield in 6h (Table 3, entry 10).
6
4
62
Additionally, the aryl group containing the substituent o-Cl
gave a good yield: 75% (Table 3, entry 7), while the m-Cl
afforded the product in 67% (Table 3, entry 11).
7
4
75
The formation of bistriazole did not lead to the desired
product using 1,8-diazidooctane and two equivalents of alkyne
4a or 4e. We observed by 1H NMR just one triazole ring; therefore,
the compounds were obtained in moderated yields, 59% (Table 3,
entry 8) and 62% (Table 3, entry 9), respectively.
8
9
5
5
59
62
Conclusions
In conclusion, we have developed a transformation that
provided an easy, mild and efficient method for the synthesis of
3-glyoxyl indole and indole-3-glyoxyl-1,2,3-triazole derivatives
and exhibited good functional group tolerance and a remarkably
wide scope. Further investigations to gain detailed mechanistic
insight into this reaction and extension of the reaction are
currently underway in our group.
6
41
10
Acknowledgments
The authors are grateful for financial support provided by
FAPESP - São Paulo Research Foundation (grant 2012/00424-2),
CNPq – National Council for Scientific and Technological
Development (308.320/2010–7 to HAS and 306532/2009-3 to
JZS ) and CAPES – Coordination for the Improvement of Higher
Education Personnel (to SNSV and 808/2009 to JZS). Prof.
Regina H.A. Santos of IQSC-USP is gratefully acknowledged for
the crystal data collection.
3
67
11
All products were purified by column chromatography,
appropriate
recrystallized from an
1
solvent, and their structures were
confirmed by H, 13C NMR. As suitable single crystals of 6d

4
Tetrahedron
2H); 5.04 (d, J = 2.4 Hz, 2H); 3.70 (t, J = 2.4 Hz, 1H). 13C NMR
(Methyl sulfoxide-d6, 75 MHz) δ (ppm): 177.7; 162.4; 138.3;
136.7; 125.4; 123.9; 122.9; 121.1; 112.7; 112.4; 78.5; 77.6; 53.1.
12. General procedure for one pot reaction with nucleophiles and
cycloaddition 6a-k: To a two-necked 50 mL round-bottomed
flask under a nitrogen atmosphere containing indole (58.5 mg, 0.5
mmol), in dry THF (5 mL). Oxalyl chloride (52 µL, 76.2 mg, 0.6
mmol) was added at room temperature. After 15 min. N,N-
diisopropylethylamine (196 µL, 155 mg, 1.2 mmol) was
introduced to the mixture, followed by the relevant propargyl
amine or propargyl alcohol (0.6 mmol) and stirred vigorously at
room temperature for 2 h. The CuI (95 mg, 0.5 mmol), organic
azide (0.6 mmol), and PMDETA (100 µL,86 mg, 0.5 mmol) was
added and the reaction mixture was stirred at room temperature.
The reaction time was determined by monitoring TLC (see table
3). Then, the reaction mixture was diluted with ethyl acetate and
washed with aqueous NH4Cl; the organic phase was collected,
dried with MgSO4, filtered and the solvent was removed under
vacuum. Purification was performed using silica gel
chromatography (eluting with ethyl acetate / hexane 1:1). (1-
References and notes
1.
a) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168-
3210. b) Humphrey, G. R.; Kuethe, J. T. Chem. Rev. 2006, 106,
2875-2911.
2.
3.
Multicomponent Reactions; Zhu, J., Bienyam_e, H., Eds.; Wiley-
VCH: Weinheim, Germany, 2005.
For reviews, see: a) Dömling, A. Chem. Rev. 2006, 106, 17. b)
Lesanko-Ulaczyk, A.; Hall, D. G. Curr. Opin. Chem. Biol. 2005,
9, 266. c) Nair, V.; Rajesh, C.; Vinod, A. U.; Bindu, S.; Sreekanth,
A. R.; Mathen, J. S.; Balagopal, L. Acc. Chem. Res. 2003, 36, 899.
Rivera, D. G.; Pando, O.; Bosch, R.; Wessjohann, L. A. J. Org.
Chem. 2008, 73, 6229-6238.
4.
5.
6.
7.
8.
Rivera, D. G.; León, F.; Concepción, O.; Morales, F. E.;
Wessjohann, L. A. Chem. Eur. J. 2013, 19, 6417-6428.
Pando, O.; Stark, S.; Denkert, A.; Porzel, A.; Preusentanz, R.;
Wessjohann, L. A. J. Am. Chem. Soc. 2011, 133, 7692-7695.
a) Bandini, M.; Eichholzer, A. Angew. Chem. Int. Ed. 2009, 48,
9608-9644. b) S.; Morteza Chem. Rev. 2012, 112, 3508-3549.
a) Shaabani, A.; Maleki, A.; Rezayan, A.; Sarvary, A. Mol.
Diversity 2011, 15, 41. b) Sadjadi, S.; Heravi, M. M. Tetrahedron
2011, 67, 2707. c) Ivachtchenko, A. V.; Ivanenkov, Y. A.; Kysil,
V. M.; Krasavin, M. Y.; Ilyin, A. P. Russ. Chem. Rev. 2011, 79,
787.
benzyl-1H-1,2,3-triazol-4-yl)methyl
2-(1H-indol-3-yl)-2-
oxoacetate (6a). Yield 153 mg (85%), yellow crystal. mp 176-
178°C. 1H NMR (Methyl sulfoxide-d6, 300 MHz) δ (ppm): 12.41
(s, 1H); 8.42 (d, J = 3.3 Hz, 1H); 8.32 (s, 1H); 8.15-8.12 (m, 1H);
7.56-7.53 (m, 1H); 7.37-7.24 (m, 7H); 5.63 (s, 2H); 5.44 (s, 2H).
13C NMR (Methyl sulfoxide-d6, 75 MHz) δ (ppm): 178.4; 163.0;
141.4; 138.2; 136.6; 135.8; 128.7; 128.1; 128.0; 127.99; 127.90;
125.4; 125.2; 123.8; 122.8; 121.0; 112.7; 112.4; 58.4; 52.8.
9.
Settimo, A.; Primofiore, G.; Settimo, F.; Marini, A. M.;
Novellino, E.; Greco, G.; Martini, C.; GIannaccini, G.;
Lucacchini, A. J. Med. Chem. 1996, 39, 5083-5091
10. Thompson, M. J.; Borsenberger, V.; Louth, J. C.; Judd, K. E.;
Chen, B. J. Med. Chem. 2009, 52, 7503-7511.
11. General procedure for one pot reaction with nucleophiles 4a-
j: To a two-necked 25 mL round-bottomed flask under a nitrogen
atmosphere containing indole (58.5 mg, 0.5 mmol), in dry THF (4
mL). Oxalyl chloride (52 µL, 76.2 mg, 0.6 mmol) was added at
room temperature. After 15 min. N,N-diisopropylethylamine (196
µL, 155 mg, 1.2 mmol) was introduced to the mixture, followed
by the nucleophile (0.6 mmol) and stirred vigorously at room
temperature for 2 h. Then the reaction mixture was diluted with
ethyl acetate and washed with aqueous NH4Cl; the organic phase
was collected, dried with MgSO4, filtered and the solvent was
removed under vacuum. Purification was performed using silica
gel chromatography (eluting with ethyl acetate / hexane 1:2).
prop-2-ynyl 2-(1H-indol-3-yl)-2-oxoacetate (4a). Yield 98.7 mg
(78%), yellow crystal. mp 184-186°C. 1H NMR (Methyl
sulfoxide-d6, 300 MHz) δ (ppm): 12.45 (s, 1H); 8.46 (d, J = 3.3
Hz, 1H); 8.21-8.18 (m, 1H); 7.60-7.59 (m, 1H); 7.33-7.29 (m,
Supplementary data
Crystallographic data (excluding structure factors) for the structure in this
paper has been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 951530. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union Road, Cambridge
CB2 1EZ, UK, (fax: +44(0)1223336033 or e-mail: deposit@ccdc.cam.ac.uk).
Supplementary data associated with this article can be found
in the online version.
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