Bromamine-B/PdCl2 is an efficient system for the synthesis of anthranilic acids from indoles and indigos

Article abstract of DOI:10.1080/00397910903457274

A convenient method has been developed for the conversion of indoles and indigos into anthranilic acids in good to excellent yields using a bromamine-B/PdCl2 system. The general process utilizes our efficient method for the oxidation of indoles and indigos in alkaline (pH 12) acetonitrile/water (1:1) at 60°C. Copyright Taylor & Francis Group, LLC.

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Bromamine-B/PdCl2 is an Efficient
System for the Synthesis of Anthranilic
Acids from Indoles and Indigos
C. H. Vinod Kumar a , K. N. Shivananda b , C. Nagu Raju a & R. V.
Jagadeesh c
a Department of Chemistry, Sri Venkateswara University, Tirupati,
India
b Schulich Faculty of Chemistry, Technion – Israel Institute of
Technology, Technion City, Haifa, Israel
c Leibniz-Institut für Katalyse e.V. an der Universität Rostock,
Rostock, Germany
Published online: 05 Nov 2010.
To cite this article: C. H. Vinod Kumar , K. N. Shivananda , C. Nagu Raju & R. V. Jagadeesh (2010)
Bromamine-B/PdCl2 is an Efficient System for the Synthesis of Anthranilic Acids from Indoles and
Indigos, Synthetic Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 40:23, 3480-3487, DOI: 10.1080/00397910903457274
To link to this article: http://dx.doi.org/10.1080/00397910903457274
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Synthetic Communications1, 40: 3480–3487, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903457274
BROMAMINE-B/PdCl2 IS AN EFFICIENT SYSTEM
FOR THE SYNTHESIS OF ANTHRANILIC ACIDS
FROM INDOLES AND INDIGOS
C. H. Vinod Kumar,1 K. N. Shivananda,2 C. Nagu Raju,1 and
R. V. Jagadeesh3
1Department of Chemistry, Sri Venkateswara University, Tirupati, India
2Schulich Faculty of Chemistry, Technion – Israel Institute of Technology,
Technion City, Haifa, Israel
3Leibniz-Institut fu¨r Katalyse e.V. an der Universita¨t Rostock, Rostock,
Germany
A convenient method has been developed for the conversion of indoles and indigos into
anthranilic acids in good to excellent yields using a bromamine-B/PdCl2 system. The general
process utilizes our efficient method for the oxidation of indoles and indigos in alkaline
(pH 12) acetonitrile/water (1:1) at 60 ꢀC.
Keywords: Antranilic acid; bromamine-B; indigos; indoles; palladium catalyst
INTRODUCTION
The economic importance of anthranilic acids resides in their well-established
anti-inflammatory activity and use as an intermediate for production of dyes, pig-
ments, and saccharin. It and its esters are used in preparing perfumes, pharmaceuti-
cals, and ultraviolet absorbers as well as corrosion inhibitors for metals and mold
inhibitors in soy sauce. Thus, many derivatives of anthranilic acids have been synthe-
sized with the objective of discovering new pharmacological agents.[1–4] Because of
the versatile properties and pharmaceutical applications of anthranilic acids, syn-
thesis of anthranilic acids is an important task. There are several reports available
in the literature about the synthesis of anthranilic acids with different approaches.[4,5]
However, still needed are safer and efficient reagents including favorable methods
for the synthesis of anthranilic acids.
N-Halo-N-metallosulfonamides, because of their ability to act as sources of
halonium cations, hypohalite species, and N-anions, which act both as bases and
nucleophiles, have proved to be valuable intermediates for a variety of functional
group transformations.[6,7] Bromamine-B and other related N-halo reagents act as
Received August 11, 2009.
Address correspondence to R. V. Jagadeesh, Leibniz-Institut fur Katalyse e.V. an der Universita¨t
¨
Rostock, Albert-Einstein-Str. 29a, D-18059, Rostock, Germany. E-mail: rvjdeesh@yahoo.com
3480

SYNTHESIS OF ANTHRANILIC ACIDS
3481
Scheme 1. Palladium-catalyzed synthesis of anthranilic acids.
good oxidants both in alkaline and acidic media and have been widely used for the
oxidation of variety of organic and bio molecules.[7–10]
Palladium has been extensively used[8,11,12] as catalyst for a number of reactions.
In recent times, the studies on the use of palladium as catalyst in many redox and
synthetic reactions have been gaining interest. In continuation of our studies with pal-
ladium catalysts and the synthetic applications of anthranilic acids, we report herein a
new and simple method for the preparation of anthranilic acids from indoles and
indigo using bromamine-B and palladium chloride as the catalyst (Scheme 1).
The present method developed for the synthesis of anthranilic acids from
indoles and indigos offers many advantages including good conversion, short reac-
tion times, and nontoxic reagents.
RESULTS AND DISCUSSION
Synthesis of anthranilic acid and substituted anthranilic acids were achieved by
using a catalytic amount of palladium chloride in acetonitrile=water (1:1) at 60 ꢀC by
bromamine-B with (1:3) substrate=bromamine-T ratio in the presence of alkali. The
products and the yields are summarized in Table 1. The indigos proceed with an
increasing rate of reaction when compared to indoles. In general, substrates contain-
ing electron-donating moieties are more reactive and required shorter reaction times
compared to substrates containing electron-withdrawing groups.
The effect of various solvents [acetonitrile, 1,2-dichloromethane, ethanol, and
acetonitrile=water (1:1) mixture] was studied using indole and indigo as substrates.
The mixture of acetonitrile=water (1:1) was found to be the best solvent system,
perhaps because of the high dielectric constant of water.
The reactions were found to be highly dependent upon the pH of the system.
To evaluate the effect of pH, oxidation of indole was carried out under similar
experimental conditions at different pH. At neutral pH, the oxidation of indole
was found to be very slow. Reaction rates increased with increasing in pH (addition
of NaOH) and were maximum at pH 12. This behavior of the reaction is attributed
to the dissociation of bromamine-B in aqueous medium by furnishing different

3482
C. H. V. KUMAR ET AL.
Table 1. Products and yields of anthranilic acids and substituted anthranilic acids.
Reaction
time
(hr. min)
Yield
(%)
Entry
1
Substrate
Product
Mp (ꢀC)
3.30
3.20
95
96
145 (146–148)
2
3
4
5
6
7
8
177 (178–179)
237 (235–236)
213 (211–216)
171 (172)
3.20
3.40
3.20
3.40
3.50
3.50
96
94
96
95
92
92
210 (210)
335 (336)
180 (183–184)
9
2.20
2.10
96
96
145 (146–148)
10
177 (178–179)
(Continued )

SYNTHESIS OF ANTHRANILIC ACIDS
3483
Table 1. Continued
Reaction
time
(hr. min)
Yield
(%)
Entry
11
Substrate
Product
Mp (ꢀC)
2.10
2.40
2.00
2.40
2.40
95
95
97
94
94
237 (235–236)
213 (211–216)
171 (172)
12
13
14
15
335 (336)
319 (317)
Note. Melting points given in parantheses refer to authentic samples.
oxidizing species[13–15] in which PhSO2NHBr was the predominant species. Further,
in the presence of alkali, the free acid, PhSO2NHBr underwent dissociation[16,17] to
furnish the species PhSO2NBrꢁ as presented in Eq. (1):
PhSO2NHBr þ OHꢁ Ð PhSO2NBrꢁ þ H2O
ð1Þ
The species PhSO2NBrꢁ furnished by bromamine-B in the presence of alkali
enhances the reaction, and thus the reactions proceed with an increasing rate.
Palladium(II) chloride catalysis has been observed during various reactions, and
it exists as different complexes in alkaline solutions.[18–20] The possible Pd(II) complex
species are [Pd(OH)Cl3]2ꢁ, [Pd(OH)2Cl2]2ꢁ, [Pd(OH)3Cl]2ꢁ, and [Pd(OH)4]2ꢁ. The
species [Pd(OH)3Cl]2ꢁ and [Pd(OH)4]2ꢁ are not commonly found as they are insolu-
ble. Further, the rate increases with increase in [OHꢁ] and there was no effect of [Clꢁ]
on the rate of reaction, which clearly rules out [Pd(OH)Cl3]2ꢁ as the reactive species.
Hence, [Pd(OH)2Cl2]2ꢁ complex ion has been assumed to be the reactive species in the
present study.
The synthesis of anthranilic acid from both indoles and indigos proceeds
with the formation of isatins as the intermediate. Both indoles and indigos first
utilize 2 mol of bromamine-B to form isatins. Isatin consumes another mole of

3484
C. H. V. KUMAR ET AL.
bromamine-B to yield the ultimate and desired compound, anhtranilic acid. The
reaction is shown in Scheme 2.
UV-visible spectroscopic studies indicate that the intermediate complex forms
between Pd catalyst and bromamine-B. Absorption maxima in alkaline medium
appear at 350 nm for PdCl2, 230 nm for bromamine-B, and 340 nm for a mixture
of both. A hypsochromic shift of 10 nm from 350 nm to 340 nm of PdCl2 suggests
that the complexation occurs between PdCl2 and bromamine-B. The detailed reac-
tions for the synthesis of anthranilic acids from indoles and indigoes are depicted
in Scheme 2.
The synthetic reactions were also performed with other N-haloamines, namely
bromamine-T and chloramine-B. Reactions with bromamine-B are faster when com-
pared to both bromamine-T and chloramine-B. This is attributable to the difference
in electrophilicities of the halo cations Brþ and Clþ involved in the oxidation process
Scheme 2.

SYNTHESIS OF ANTHRANILIC ACIDS
3485
and is also related to the ease with which these species are generated in reactions. In
these reactions, the electronegativity values of Brþ and Clþ play a vital role. Bromine
has the electronegativity of 2.7, while chlorine has a greater value of 3.0. As the elec-
tronegativity increases, the electropositive nature decreases, since the halo cations are
the reactive species in these oxidation reactions and the electropositive nature is
Br > Cl. Hence, it can be generalized that bromamines are stronger oxidants com-
pared to chloramines. The oxidizing power of bromamine-B is more than
bromamine-T. This is due the participation of the –CH3 group in bromamine-T,
which exerts a strong inductive effect in enriching the electron density at the polar
=
N-X (X Cl or Br) bond, thereby reducing the electrophilicity of the X atom. A simi-
lar behavior has been reported[9] in the N-haloamine reactions.
Synthesis of anthranalic acids from indigos have shorter reaction times than
that of indoles. This can be explained by the fact that indigos contain electron-rich
olefinic double bonds, and the complex intermediate of Pd-bromamine-B can easily
attack the double bond and there by increase the reaction rate.
CONCLUSION
Bromamine-B=palladium chloride system was found to be an efficient system
for the facile conversion of indoles and indigos into anthranilic acids in alkaline
medium in good to excellent yields. Indigos proceed with faster conversion compared
to indoles. The present method developed for the synthesis of anthranilic acids from
indoles and indigos offers many advantages including high conversion, short
reaction times, and the involvement of nontoxic reagents.
EXPERIMENTAL
Melting points were determined on an X-4 apparatus and are uncorrected. Infra-
red (IR) spectra were obtained using a Shimadzu Fourier transform (FT)–IR-8900
spectrometer. Mass spectral (MS) data were obtained on a 17A Shimadzu gas chroma-
tograph with a QP-5050A Shimadzu mass spectrometer. The MS data were obtained
using the electron-impact ionization technique.
Preparation of Bromamine-B
Bromamine-B was prepared[21] by the partial debromination of dibromamine-B
(DBB), which was obtained as follows. Pure chlorine was bubbled through an aque-
ous solution of chloramine-B (30 g in 560 mL of water), and liquid bromine (6 mL)
was added dropwise with constant stirring. The resulting yellow precipitate of DBB
was thoroughly washed with water, filtered under suction, and dried in a desiccator.
DBB (31.5 g) was digested in batches with constant stirring in 50 mL of 4 mol dmꢁ3
NaOH. The mass obtained was cooled in ice and filtered under suction, and the pro-
duct (BAB) was dried over anhydrous calcium chloride. The purity of bromamine-B
was assayed iodometrically to determine the active halogen content. Aqueous
solutions of the oxidant were standardized by iodometric procedure and preserved
in brown bottles to prevent photochemical deterioration. Bromamine-B was con-
firmed by MS analysis.

3486
C. H. V. KUMAR ET AL.
Synthesis of Anthranilic Acids
To a stirred solution of indole=indigo (10 mmol) and bromamine-T (30 mmol)
in alkaline (pH 12) acetonitrile=water (1:1) mixture (20 mL), PdCl2 (1 mol%) was
added, and the mixture was heated at 60 ꢀC for 2–4 h. The reaction progress was mon-
itored by thin-layer chromatography (TLC). After completion of the reaction, the
reduction product of bromamine-B, PhSO2NH2, was extracted with ethyl acetate,
identified by TLC, and confirmed by MS analysis. The aqueous part of the reaction
mixture was neutralized with acid, and the solvent was evaporated under reduced
pressure. The residue was dissolved in dichloromethane. The dichloromethane layer
was washed twice with water and dried over sodium sulfate. The solvent was evapo-
rated under reduced pressure, and the residue thus obtained was purified by passing
through a short silica-gel column using dichloromethane as eluent. Evaporation of
the solvent yielded anthranilic acids in around 95% yield. Alternatively, after extract-
ing out p-toluenesulfonamide, the aqueous layer was neutralized with acid and the
anthranilic acids were estimated as their zinc anthranilates. The procedure for the esti-
mation is as follows: anthranilate was precipitated as its zinc salt.[22] To the reaction
mixture, a calculated volume of 1 mol dmꢁ3 HCl was added, followed by 10 mL of pH
5.0 buffer and 10 mL of 1% zinc sulfate. The precipitate formed was filtered, dried at
105–110 ꢀC, and weighed, and the recovery of (C7H6O2N)2Zn was around 95%. The
reaction times and yields are given in Table 1. The products were identified by TLC
and mp by comparing with authentic samples. Further, they were subjected to MS
analysis, which showed a molecular ion peak of 137 amu, confirming anthranilic acid.
Other peaks observed in the mass spectrum can be interpreted in accordance with the
observed structure.
REFERENCES
1. Joshi, J. K.; Patel, V. R.; Patel, K.; Rana, D.; Shah, K.; Patel, R. Synthesis and
antiinflammatory activity of n-aryl anthranilic acid and its derivatives. Indian J. Chem.
Pharm. Sci. 2007, 69, 697–699.
2. Thorarensen, A.; Li, J.; Wakefield, B. D.; Romero, D. L.; Marotti, K. R.; Sweeney, M. T.;
Zurenko, G. E.; Sarver, R. W. Preparation of novel anthranilic acids as antibacterial
agents: Extensive evaluation of structural and physical properties on antibacterial activity
and human serum albumin affinity. Bioorg. Med. Chem. Lett. 2007, 17(11), 3113–3116.
3. Jan, H.; Jan, S. Synthesis of 3-(6-azauracil-5-yl)anthranilic acid and its application to the
preparation of other 1,2,4-triazine derivatives. Collect. Czech. Chem. Commun. 1996, 61,
941–945.
4. Silva da, J. F. M.; Garden, S. J.; Pinto, A. C. The chemistry of isatins: A review from
1975–1999. J. Braz. Chem. Soc. 2001, 12, 273–324.
5. Chapman, E.; Stephen, H. J. The preparation of phthalamic acids and their conversion
into anthranilic acids. Chem. Soc. Trans. 1925, 127, 1791–1797.
6. Campbell, M. M.; Johnson, G. Chloramine-T and related N-halogeno-N-metallo
reagents. Chem. Rev. 1978, 78, 65.
7. Kolvari, E.; Choghamarani, A. G.; Salehi, P.; Shirini, F.; Zolfigol, M. A. Application of
N-halo reagents in organic synthesis. J. Iran. Chem. Soc. 2007, 4, 126–174.
8. Jagadeesh, R. V.; Puttaswamy. Ru(III), Os(VIII), Pd(II) and Pt(IV) catalysed oxidation of
glycyl–glycine by sodium N-chloro-p-toluenesulfonamide: Comparative mechanistic
aspects and kinetic modeling. J. Phys. Org. Chem. 2008, 21, 844–858.

SYNTHESIS OF ANTHRANILIC ACIDS
3487
9. Puttaswamy; Jagadeesh, R. V. Ruthenium (III)-catalyzed mechanistic investigation of
oxidation of an azo dye by sodium N-haloarenesulfonamidates in acid medium: A
comparative spectrophotometric kinetic study. Applied Catal. A 2005, 292, 259–271.
10. Mahadevappa, D. S.; Ananda, S.; Murthy, A. S. A.; Rangappa, K. S. Oxidation of
dimethylsulphoxide by sodium m-bromobenzene-sulphonamide: A kinetic and mechan-
istic study. Tetrahedron 1984, 40, 1673–1683.
11. (a) Shannon, S. S. Palladium-catalyzed oxidation of organic chemicals with O2. Science
2005, 309, 1824; (b) Peterson, K. P.; Larock, R. C. Palladium catalyzed oxidation of
primary and secondary allylic and benzylic alcohols. J. Org. Chem. 1998, 63, 3185–3189.
12. Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Palladium catalyzed cross coupling reactions in
total synthesis. Angwdt. Chem. Int Ed. 2005, 44, 4442–4489.
13. Bishop, E.; Jennings, V. J. Titrimetric analysis with chloramine-T: The status of chlora-
mine-T as a titrimetric reagent. Talanta 1958, 1, 197–199.
14. Hardy, F. F.; Johnston, J. P. The interactions of N-bromo-N-sodiobenzesulfonamide
(bromamine-B) with p-nitrophenoxide ion. J. Chem Soc. Perkin Trans. II 1973, 742–746.
15. Pryde, B. G.; Soper, F. G. The direct interchange of chlorine in the interaction of
p-toluenesulfonamide and N-chloroacetalinide. J. Chem Soc. 1962, 1582; ibid 1931,
1510–1512.
16. Puttaswamy; Jagadeesh, R. V. Kinetics of oxidation of pantothenic acid by chloramine-T
in perchloric acid and in alkaline medium catalyzed by OsO4: A mechanistic approach.
Int. J. Chem. Kinet. 2005, 37, 201–210.
17. Puttaswamy; Jagadeesh, R. V. Mechanistic studies of oxidation of thiols to disulfides by
sodium n-chloro-p-toluenesulfonamide in an alkaline medium: A kinetic approach. Ind.
Eng. Chem. Res. 2006, 45, 1563–1570.
18. Cotton, F. A.; Wilkinson, G.; Murillo, C. A.; Bochmann, M. Advanced Inorganic Chem-
istry, 6th ed.; John Wiley and Sons Inc.: New York, 1999.
19. Wan, W. K.; Zaw, K.; Henry, P. M. Oxidation of olefins by palladium(II). 11. Kinetics
and mechanism of the oxidation of allyl alcohol by PdCl42- in aqueous solution. Organo-
metallics 1998, 7(8), 1677–1683.
20. Kondarasaiah, M. H.; Ananda, S.; Puttaswamy; Made Gowda, N. M. Palladium(II)-
catalyzed oxidation of primary amines by bromamine-T in alkaline medium: A kinetic
and mechanistic study. Synth. React. Inorg. Met. Org. Chem. 2003, 33, 1145–1156.
21. Ahmed, M. S.; Mahadevappa, D. S. Bromamine-B as a new oxidimetric titrant. Talanta
1980, 27, 669–670.
22. Vogel, A. I. Text Book of Quantitative Inorganic Analysis, 4th ed.; ELBS-Longman:
London, 1978, p. 427.