Fischer indolisation of N-(α-ketoacyl)anthranilic acids into 2-(indol-2-carboxamido)benzoic acids and 2-indolyl-3,1-benzoxazin-4-ones and their NMR study

Abstract

N-(α-ketoacyl)anthranilic acids reacted with phenylhydrazinium chloride in boiling acetic acid to afford 2-(indol-2-carboxamido)benzoic acids in good to excellent yields and 2-indolyl-3,1-benzoxazin-4-ones as by-products. The formation of the latter products could easily be suppressed by a hydrolytic workup. Alternatively, by increasing the reaction temperature and/or time, 2-indolyl-3,1-benzoxazin-4-ones can be obtained exclusively. Optimisations of the reaction conditions as well as the scope and the course of the transformations were investigated. The products were characterized by ¹H, ¹³C and ¹⁵N NMR spectroscopy. The corresponding resonances were assigned on the basis of the standard 1D and gradient selected 2D NMR experiments (¹H–¹H gs-COSY, ¹H–¹³C gs-HSQC, ¹H–¹³C gs-HMBC) with ¹H–¹⁵N gs-HMBC as a practical tool to determine ¹⁵N NMR chemical shifts at the natural abundance level of ¹⁵N isotope.

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Introduction

Molecules containing indole¹ and anthranilic acid² scaffolds are ubiquitous in many natural products with diverse biological activities. Thus, it is not surprising that the compounds featuring both the indole and the anthranilic acid fragments are encountered in nature. Alkaloids cephalandole C and cephalinone B, isolated from the native orchid plant Cephalanceropsis gracilis,³ and the alkaloids secofascaplysins, isolated from the sponge Fascaplysinopsis reticulate,⁴ consist of the 2-(indol-2-carboxamido)benzoic acid 1 substructures, for example (Fig. 1). Derivatives of 2-(indol-2-carboxamido)benzoic acid 1 are receiving attention because of their antibacterial activities.⁵ In materials sciences, the 2-(indol-2-carboxamido)benzoic acid derivatives are used as UV absorbers.⁶ Compounds with indol-2-carboxamide scaffold are potent inhibitors of HIV-1 replication (Delavirdine, Rescriptor®)⁷ and the androgen receptor binding function 3 (BF3),⁸ and were identified as hydrogen-bonding organocatalysts for the ring-opening polymerization of cyclic esters.⁹

Fig. 1 Naturally occurring compounds containing 2-(indol-2-carboxamido)benzoic acid and 3,1-benzoxazin-4-one substructures (blue).

3,1-Benzoxazin-4-ones serve as valuable precursors for the preparation of fused heterocycles including an important pharmacophore, quinazolin-4-one.¹⁰ It is also noteworthy that 3,1-benzoxazin-4-ones are potent inhibitors of the human leukocyte elastase,¹¹ human chymase,¹² chymotrypsin¹³ and proteases of herpes simplex type 1,¹⁴ human cathepsin G¹⁵ and serine,¹⁶ for example. Avenalumin I, phytoalexin of the 3,1-benzoxazin-4-one structure that is inhibitory to the growth of rust fungi, was isolated from oat leaves (Fig. 1).¹⁷

Surprisingly, despite the biological relevance and synthetic potential of 2-(indol-2-carboxamido)benzoic acids 1, to our knowledge, the only published approach to access these compounds makes use of N-acylation of anthranilic acids with 1H-indol-2-carboxylic acid derivatives.¹⁸ As an alternative to this, herein we report the protocol that is based on the Fischer indolisation of N-(α-ketoacyl)anthranilic acids 2 (Scheme 1). Optimization of the reaction conditions and the scope as well as multinuclear NMR spectral analysis of the products is reported.

Scheme 1 Two retrosynthetic approaches to 2-(indol-2-carboxamido)benzoic acids 1.

Results and discussion

Synthesis

Out of the available methods to access indoles, the Fischer indole synthesis remains one of the most important and versatile methods.¹⁹ It is generally conducted by reacting an aryl hydrazine with a carbonyl compound.^19,20 Thus, for the construction of 2-(indol-2-carboxamido)benzoic acid 1 through this pathway N-(α-ketoacyl)anthranilic acid 2 appears to be the most suitable carbonyl substrate. Based on our recent report,²¹ the latter is easily accessible through the consecutive oxidation protocol from 4-hydroxyquinolin-2-one as shown in Scheme 2.

Scheme 2 The preparation of the starting N-(α-ketoacyl)anthranilic acids 2 and the key of substituents R¹–R⁶.

The Fischer indolisation is known to proceed through an intermediately formed hydrazone, which then undergoes several consecutive transformations. It isomerises to an enamine, which after protonation rearranges to an imine and then a cyclic aminal. Acid catalysed elimination of ammonia from the latter finally gives rise to the indole ring. The above mentioned hydrazone can in principle be pre-assembled by condensation of aryl hydrazine with an appropriate carbonyl compound. Herein, we decided to compare the stepwise protocol that proceeds through the isolated phenylhydrazone 3 (Route A, Scheme 3) with the direct-one in which N-(α-ketoacyl)anthranilic acids 2 are treated with phenylhydrazine directly into the 2-(indol-2-carboxamido)benzoic acid 1 (Route B).

Scheme 3 The stepwise (Route A) and direct (Route B) routes to the 2-(indol-2-carboxamido)benzoic acids 1 by the Fischer indolisation of N-(α-ketoacyl)anthranilic acids 2.

To examine the stepwise protocol, Route A, phenylhydrazones 3a,c–e were initially prepared by the condensation of N-(α-ketoacyl)anthranilic acids 2a,c–e with phenylhydrazine. The isolated phenylhydrazones were in the subsequent step subjected to the thermally induced rearrangement into 2-(indol-2-carboxamido)benzoic acids 1a,c–e. The results are collected in Table 1. Although the preparation of the phenylhydrazones 3a,c–e proceeded in high 78–88% yields, the subsequent indolisation step into the target 2-(indol-2-carboxamido)benzoic acids 1a,c–e returned low 17–33% yields.

Table 1 Results of the stepwise protocol to indoles 1 (Scheme 3, Route A)

Step 1		Step 2
Reaction conditions	3, yield^a	Reaction conditions	1, yield^a
a Percent yields of isolated pure products are given.
AcOH, 60 °C, 2 h	3a, 88	235 °C, 20 min	1a, 27
AcOH, 60 °C, 3 h	3c, 80	180 °C, 10 min	1c, 17
AcOH, 60 °C, 3 h	3d, 79	245 °C, 15 min	1d, 28
AcOH, 60 °C, 1.25 h	3e, 78	180 °C, 15 min	1e, 33

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The disappointing overall results of the stepwise procedure prompted us to test the direct approach, outlined as Route B in Scheme 3. In screening for the optimal reaction conditions, a mixture of selected N-(α-ketoacyl)anthranilic acid 2 and phenylhydrazinium chloride was heated under reflux in different solvents including acetonitrile, acetic acid, methanol and water. Since Lewis²² and Brønsted acids²³ are well known to promote the Fischer indolisation, we selected to test hydrochloric acid, sulphuric acid, acetic acid, zinc(II) chloride and bismuth(III) nitrate pentahydrate (Bi(NO₃)₃·5H₂O)²⁴ as acid catalysts (Table 2). Good results in terms of the reaction time and the product yields were obtained for the reactions in boiling acetonitrile either in the presence of Bi(NO₃)₃·5H₂O (entries 3, 4, 9–13) or acetic acid (entry 8). However, the highest yields of the products 1 were seen by conducting the reaction in boiling acetic acid in the absence of the additives (entry 1). As expected, the heating of N-(α-ketoacyl)anthranilic acid 2a in aqueous hydrochloric or sulphuric acid resulted in an amide bond hydrolysis to produce anthranilic acid (entries 6 and 7).

Table 2 Solvent and catalyst screening for the Fischer indolisation of 2 into 1 following the Route B (Scheme 3)

Entry	2	Solvent^a	Additive, reaction time in h	1	Yield^b
a All reactions were conducted under reflux. b Percent yields of isolated pure products are given. c Anthranilic acid was isolated as the main product in 35% (entry 6) and 26% (entry 7) yield (Experimental).
1	2a	AcOH	None, 9	1a	78
2	2a	MeOH	20 mol% Bi(NO3)3·5H2O, 8	1a	26
3	2a	MeCN	20 mol% Bi(NO3)3·5H2O, 5	1a	65
4	2a	MeCN	10 mol% Bi(NO3)3·5H2O, 12	1a	55
5	2a	MeCN	20 mol% ZnCl2, 28	1a	49
6	2a	H2O	130 mol% HCl, 3	1a	7^c
7	2a	H2O	120 mol% H2SO4, 2	1a	8^c
8	2a	MeCN	2000 mol% AcOH, 22	1a	70
9	2b	MeCN	20 mol% Bi(NO3)3·5H2O, 12	1b	53
10	2b	MeCN	10 mol% Bi(NO3)3·5H2O, 19	1b	52
11	2c	MeCN	20 mol% Bi(NO3)3·5H2O, 16	1c	71
12	2d	MeCN	20 mol% Bi(NO3)3·5H2O, 11	1d	75
13	2e	MeCN	20 mol% Bi(NO3)3·5H2O, 11	1e	69

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Having identified the optimal reaction conditions we turned to examine the scope of the reaction. Several N-(α-ketoacyl)anthranilic acids (2a–l) were allowed to react with phenylhydrazinium chloride in boiling acetic acid, which afforded the target 2-(indol-2-carboxamido)benzoic acids (1a–l) in good to excellent yields of the isolated products (Table 3). In few instances, the reactions were accompanied by the formation of small amounts of by-products, which were isolated and identified as 3,1-benzoxazin-4-ones 4 and phenylhydrazides 5. The only exception to this was compound 2m, which afforded naphthoxazinone 4m as the sole product, with the anthranilic acid 1m being undetected in the reaction mixture (entry 13).

Table 3 The Fischer indolisation of N-(α-ketoacyl)anthranilic acids 2 in boiling acetic acid

Entry	2	Substituents						Reaction time (h)	Product, yield^a
		R^1	R^2	R^3	R^4	R^5	R^6		1	4	5
a Percent yields of isolated pure products are given.
1	a	H	Me	H	H	H	H	9	78
2	b	H	Me	H	OMe	H	H	14	83	5	2
3	c	H	Me	H	H	OMe	H	15	89
4	d	H	Me	H	H	H	OMe	9	81	5
5	e	Me	Me	H	H	H	H	8	91
6	f	H	n-Pr	H	H	H	H	10	91	2	1
7	g	H	Me	H	H	H	Me	14	55	14
8	h	H	Me	H	Me	H	H	14	76
9	i	H	Me	Cl	H	H	Me	17	78	4
10	j	H	n-Pr	H	Me	H	Me	12	51	12
11	k	H	n-Pr	H	OMe	H	OMe	13	56	10
12	l	H	Ph	H	H	H	H	19	62
13	m	H	n-Pr	H	H	–(CH)4–		9	0	87

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In principle, the formation of 2-indolyl-3,1-benzoxazin-4-ones 4 could be realised by two different pathways as shown in Scheme 4. An initial formation of 2-acyl-3,1-benzoxazin-4-one 4′ through the Path a could be followed by the Fischer indolisation with phenylhydrazinium chloride. This pathway was, however, ruled out on the basis of the 3,1-benzoxazin-4-ones reactivity considerations. In the presence of nucleophiles these compounds are prone to undergo rapid ring opening into the anthranilic acid derivatives (vide infra) suggesting that somehow higher amounts of the phenylhydrazides 5 should have been formed in the reactions shown in Table 3. The Path a was also ruled out experimentally by heating compound 2a in neat acetic acid under the reflux conditions in the absence of phenylhydrazinium chloride, which resulted in no detectable formation of 2-acyl-3,1-benzoxazin-4-one 4′. This left the Path b, i.e. the initial Fischer indolisation of the N-(α-ketoacyl)anthranilic acid 2 with phenylhydrazinium chloride into 2-(indol-2-carboxamido)benzoic acid 1 and subsequent cyclodehydration into 2-indolyl-3,1-benzoxazin-4-one 4, as the most plausible.

Scheme 4 The proposed formation of 3,1-benzoxazin-4-ones 4.

Generally, the 3,1-benzoxazin-4-one skeleton is formed by the reaction of anthranilic acids with an appropriate acid anhydride at the elevated temperatures.²⁵ Mechanistically, the amino group of the anthranilic acid is N-acylated and the carboxylic group is transformed into a mixed anhydride intermediate. This intermediate then undergoes an intramolecular nucleophilic displacement of the carboxylate ion from the anhydride moiety by the amide in its iminol form.²⁶ In turn, heating the 2-(indol-2-carboxamido)benzoic acid 1 in acetic acid is unlikely to produce mixed anhydride. Since an intramolecular nucleophilic attack of the carboxylic group to the amide is also unlikely because of the low electrophilicity of the amide, the formation of 3,1-benzoxazin-4-ones 4 could best be rationalized through the intramolecular nucleophilic attack of the iminol 1′ to the protonated carboxylic group as shown in Scheme 4. The formation of naphthoxazinone 4m as the sole product from 2m (Table 3, entry 13) could be accounted for by an enhanced resonance stabilisation of iminol 1m′, the result of an extended conjugation through the naphthalene ring.

If the mechanism shown in Scheme 4 is operating, it can be expected that a prolonged reaction time and/or an elevated reaction temperature would work beneficially to the formation of 3,1-benzoxazin-4-one 4. Indeed, by prolonging the heating of compound 1j with phenylhydrazinium chloride in acetic acid (bp_AcOH = 118 °C) from 12 h to 40 h increased the yield of the expected product 4j from 15% to 65% (compare entries 1 and 2 in Table 4). The use of the higher boiling propanoic acid (bp = 141 °C) in place of acetic acid afforded the 3,1-benzoxazin-4-one 4j in 72% yield already within 17 h (entry 3). It is noteworthy that these reaction conditions can potentially be utilized as a convenient one-pot protocol for the preparation of 3,1-benzoxazin-4-ones 4 from N-(α-ketoacyl)anthranilic acids 2 and aryl hydrazines. The synthetic methodologies toward 3,1-benzoxazin-4-ones, other than those utilizing anthranilic acids, have been reviewed.²⁷

Table 4 The influence of the reaction time and temperature on transformation of 2-(indol-2-carboxamido)benzoic acid 1j into 3,1-benzoxazin-4-one 4j

Entry	Reaction conditions	Reaction time (h)	Yield of 4j^a
a Percent yields of isolated pure products are given. b For comparison reasons the result is taken from Table 3, entry 10.
1	AcOH, reflux	12	12^b
2	AcOH, reflux	40	65
3	CH3CH2COOH, reflux	17	72

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Minute amounts of the hydrazides 5 also accompanied the formation of 2-(indol-2-carboxamido)benzoic acids 1 (Table 3). As it is less likely that under the applied reaction conditions phenylhydrazinium chloride reacts with the carboxyl group of either the starting N-(α-ketoacyl)anthranilic acids 2 or the product 2-(indol-2-carboxamido)benzoic acids 1, it is reasonable to assume that the formation of hydrazides 5 proceeds through the ring-opening at the 3,1-benzoxazin-4-ones 4. Smooth reactivity of the 3,1-benzoxazin-4-ones towards different nucleophiles is well documented.^26,28 In our case the reactivity of compound 4f towards phenylhydrazine to form 5f was independently confirmed in boiling toluene as the reaction solvent (Table 5). Analogously, treatment with n-butylamine gave the appropriate amide 6f.

Table 5 Reaction of 3,1-benzoxazin-4-ones 4 with some nucleophiles

Entry	4	NuH	Reaction conditions, reaction time in h	Product, yield^a
a Percent yields of isolated pure products are given.
1	4f	PhNHNH2	Toluene, reflux, 2	5f, 86
2	4f	n-BuNH2	Toluene, reflux, 2	6f, 84%
3	4f	H2O	DMSO, H2O, NaOH, rt, 1	1f, 91%
4	4f	H2O	dioxane, 0.1 M H2SO4, rt, 2	1f, 70%
5	4j	H2O	DMSO, H2O, NaOH, rt, 3	1j, 98%
6	4m	H2O	DMSO, H2O, NaOH, rt, 12	1m, 95%

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Aqueous sodium hydroxide in DMSO mediated complete hydrolysis of 3,1-benzoxazin-4-ones 4f,j,m to the corresponding 2-(indol-2-carboxamido)benzoic acids 1f,j,m (Table 5). High tendency of related 3,1-benzoxazin-4-ones for hydrolysis into the corresponding anthranilic acids has been documented.^29,30 With these results in mind it can be assumed that higher quantities of the 3,1-benzoxazin-4-one products 4 are actually formed during the Fischer indolisation of N-(α-ketoacyl)anthranilic acids 2 shown in Table 3 as they were actually isolated. During the isolation workup the latter most probably partly hydrolyse back into the 2-(indol-2-carboxamido)benzoic acids 1.

The elemental composition of all the compounds under investigation was confirmed by combustion analysis and high-resolution mass spectrometry with electrospray ionization. In addition, low resolution mass spectra with electron impact ionization and the infrared spectra were provided. In the latter, the characteristic absorption bands belonging to the indole N–H, C=O and C=N bonds were identified, where appropriate.

NMR study

The compounds 1, 3–6 were fully characterized by ¹H, ¹³C and ¹⁵N NMR spectroscopy. The corresponding resonances were assigned on the basis of gradient-selected 2D NMR experiments including ¹H–¹H gs-COSY, ¹H–¹³C gs-HSQC, ¹H–¹³C gs-HMBC and ¹H–¹⁵N gs-HMBC. The spectra of compounds 1, 3, 5 and 6 were recorded in DMSO-d₆. For 3,1-benzoxazin-4-ones 4, which proved to rapidly hydrolyse in DMSO-d₆ into the 2-(indol-2-carboxamido)benzoic acids 1, less polar CDCl₃ was identified as a suitable solvent. Acetone-d₆ was used as an alternative for dissolving compound 4k due to its sparing solubility in CDCl₃. Some characteristic spectral features are discussed below. For the atom numbering scheme, see Fig. 2.

Fig. 2 Atom numbering scheme for compounds 1 and 4. Curved arrows denote long-range ¹H–¹⁵N gs-HMBC connectivities.

There is a wealth of ¹H and ¹³C data³¹ as well as ¹⁵N NMR data³² on indoles reported in the literature. The relatively unsubstituted indole ring in the compounds 1 and 4 enabled us to unequivocally assign all proton, carbon and nitrogen resonances via long-range ¹H–¹³C and ¹H–¹⁵N heteronuclear coupling pathways, which we found in agreement to those discussed in the literature.³³ For the indole ring in 2-(indol-2-carboxamido)benzoic acids 1 the order of shielding in the ¹³C NMR spectra is C7′ > C3′ > C5′ > C4′ > C6′ > C2′ ≅ C3a′ > C7a′ (Table 6). By changing the indole C-2′ substituent from the carbamoyl group in compounds 1 into the 3,1-benzoxazin-4-one ring in 4, the most dramatic changes in the chemical shift are seen for the carbon atoms of the fused 5-membered ring. In comparison with compounds 1, the C2′ atoms of the indole ring in 4 are shielded by ca. 4 ppm, whereas the C3′ and C3a′ atoms are deshielded by ca. 6 ppm and ca. 1 ppm, respectively. By changing the R² = Me to the R² = n-Pr in either 1 or 4, the carbon atom C3′ becomes more shielded for ca. 5–6 ppm (Tables 6 and 7).

Table 6 ¹³C and ¹⁵N NMR chemical shifts for 2-(indol-2-carboxamido)benzoic acids 1 in ppm^a

Atom^b	1a	1b	1c	1d	1f	1g	1h	1i	1j	1k	1l	1m
a In DMSO-d6. b For atom numbering scheme, see Fig. 2. c Resonances for the C3′ phenyl ring: 132.9 ppm (C1′′), 130.2 ppm (C2′′, C6′′), 128.7 ppm (C3′′, C5′′), 127.2 ppm (C4′′). d For the complete set of resonances, see the Experimental section. e Could not be assigned unequivocally; for the complete list of resonances, see the Experimental section. f Not observed.
C1	116.5	118.0	108.6	—^e	116.4	126.8	116.4	—^e	—^e	—^e	116.4
C2	141.0	134.3	143.0	—^e	140.8	136.3	138.6	—^e	133.7	118.8	140.4
C3	120.6	122.4	105.3	153.7	120.5	135.8	120.6	—^e	—^e	155.1	120.4
C4	134.2	120.3	163.6	115.0	134.1	134.4	134.7	131.6	134.8	102.4	134.0
C5	122.8	154.3	108.6	126.1	122.8	125.7	132.0	—^e	—^e	157.5	122.9
C6	131.3	114.8	133.2	121.5	131.2	128.1	131.3	—^e	128.3	105.1	131.1
C3(CH3)						18.7		17.5	18.4
C5(CH3)							20.2		20.2
C3(OCH3)				56.1						56.2
C4(OCH3)			55.5
C5(OCH3)		55.4								55.6
C2′	128.2	128.2	128.1	127.2	127.7	127.3	128.1	126.8	126.8	—^e	128.0	—^e
C3′	113.3	112.9	113.4	115.2	119.3	114.6	113.1	114.6	120.2	120.6	118.5	121.2
C3a′	128.0	128.1	128.1	128.0	127.5	128.1	128.1	127.8	127.6	127.7	126.7	127.7
C4′	120.1	120.0	120.2	119.9	120.1	120.0	120.1	119.8	119.9	120.0	120.2	120.2
C5′	119.4	119.3	119.4	119.2	119.4	119.3	119.4	119.1	119.2	119.2	120.6	119.4
C6′	124.4	124.2	124.4	124.2	124.2	124.2	124.3	124.0	124.0	124.0	124.5	124.3
C7′	112.2	112.2	112.2	112.0	112.2	112.1	112.2	111.9	112.0	112.0	112.6	112.2
C7a′	136.0	135.9	136.1	135.6	136.0	135.7	136.0	135.4	135.5	135.5	136.0	135.7
C3′CH2					25.7				26.0	26.1
C3′CH2CH2					24.0				23.9	23.9
C3′(CH2)2CH3					13.9				14.0	14.1
C3′CH3	9.7	9.7	9.7	9.8		9.8	9.7	9.6
CONH	160.5	160.2	160.7	160.2	160.5	160.4	160.4	160.8	160.2	160.2	160.2	161.6
COOH	169.7	169.3	169.6	167.9	169.6	168.4	169.7	166.5	168.3	167.7	168.7	168.3
N1′	132.7	132.7	132.7	130.3	132.2	131.3	132.7	130.9	130.8	130.2	136.9	130.5
CONH	126.9	125.1	127.7	116.1	126.6	122.8	126.3	120.7	121.4	113.9	129.5	—^f

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Table 7 ¹³C and ¹⁵N NMR chemical shifts for 3,1-benzoxazin-4-ones 4 in ppm^a

Atom^b	4b	4c	4d	4f	4g	4i	4j	4k
a In CDCl3, unless otherwise stated. b For atom numbering scheme, see Fig. 2. c In acetone-d6. d Could not be unequivocally assigned. e Not observed.
C2	151.8	154.3	153.1	153.3	152.1	152.6	151.0	151.4
C4	159.3	158.7	158.9	159.0	159.6	156.2	159.7	159.6
C4a	117.1	—^d	117.4	116.6	116.4	113.8	116.1	—^d
C5	108.7	—^d	120.0	128.7	126.3	133.1	125.9	100.6
C6	158.9	130.4	127.8	127.6	127.1	129.3	137.4	160.6
C7	126.1	166.3	117.1	136.6	137.4	136.8	138.7	108.0
C8	128.1	—^d	153.8	126.6	135.5	134.5	135.3	156.7
C8a	141.4	—^d	137.4	147.3	145.6	147.8	143.6	133.1
C6(CH3)							17.2
C8(CH3)					17.3	17.7	21.2
C6(OCH3)	56.0							56.4
C7(OCH3)		56.0
C8(OCH3)			56.4					57.0
C2′	123.4	123.3	123.5	123.0	123.4	122.9	123.2	—^d
C3′	119.4	120.5	120.3	125.6	120.3	121.2	125.0	124.2
C3a′	129.3	129.2	129.2	128.9	129.2	129.2	128.9	129.6
C4′	120.5	120.6	120.6	120.8	120.5	120.6	120.6	121.0
C5′	120.1	120.2	120.1	120.1	120.2	120.3	120.1	120.6
C6′	125.6	125.9	125.9	125.8	125.8	126.1	125.5	125.7
C7′	111.3	111.4	111.5	111.5	111.5	111.6	111.5	113.0
C7a′	136.5	136.6	136.8	136.7	136.5	136.6	136.4	138.0
C3′CH2				26.9			27.0	27.6
C3′CH2CH2				24.2			23.8	25.0
C3′(CH2)2CH3				14.2			14.3	14.7
C3′CH3	10.4	10.5	10.5		10.6	10.7
N1	222.4	222.6	212.0	222.8		—^e	—^e	216.4
N1′	120.5	120.9	121.4	121.1	120.5	120.3	120.9	—^e

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The three-bond long-range couplings were observed in the ¹H–¹⁵N gs-HMBC spectra from H7′ to the indole N1′ resonance in both 1 and 4 (Fig. 2). In addition, a one-bond direct NH doublet response corroborated the assignment of N1′ (Fig. 3). The chemical shifts of the N1′ atoms in indoles 1 appear at δ 130.2–136.9 ppm and are in good agreement with the literature values reported for Delavirdine.³⁴ In compounds 4, the indole nitrogen atoms N1′ resonate in the narrow range of δ 120.3–121.4 ppm (Tables 6 and 7).

Fig. 3 ¹H–¹⁵N gs-HMBC spectrum of 2-(indol-2-carboxamido)benzoic acid 1b recorded in DMSO-d₆, optimized for 5 Hz long-range coupling. Direct responses for the N1′ and CONH resonances were observed as doublets at 132.7 ppm and 125.1 ppm, respectively. The spectrum also features three-bond long-range response to N1′ and CONH from H7′ and H3, respectively. Five-bond long-range correlation to CONH from C3′CH₃ is also observed.

Systematic NMR investigations of 3,1-benzoxazin-4-ones are more scarce.^29,35 As pointed out by Osborne and Goolamali some early NMR data should be taken with care because these compounds often show high tendency for hydrolysis into the corresponding anthranilic acids, especially when measured in polar solvents such as DMSO-d₆.²⁹ High susceptibility towards hydrolysis has been illustrated by 2-methyl-3,1-benzoxazin-4-one that reacts with water into 2-acetylaminobenzoic acid already in the solid state.³⁰ Osborne and Goolamali reported an unequivocal differentiation between anthranilic acids and 3,1-benzoxazin-4-ones that was achieved through determination of characteristic J_CH coupling interactions in the carbonyl region of the proton coupled ¹³C NMR spectra.²⁹

Herein, the proton, carbon and nitrogen resonances belonging to the anthranilic moiety in 1 and the 3,1-benzoxazin-4-one group in 4 were rapidly assigned using the gradient-selected 2D NMR experiments. The results are collected in Tables 6 and 7. Characteristic for the downfield regions of the ¹³C NMR spectra of the acylanthranilic acids 1 were two signals appearing at δ 160.2–161.6 ppm and δ 166.5–169.7 ppm for the amide carbonyl and for the carboxylic group, respectively. In 3,1-benzoxazin-4-one 4, the downfield region of the spectra were occupied with three signals for C8a (δ 133.1–147.8 ppm), C2 (δ 151.0–154.3 ppm) and C4 (δ 156.2–159.7 ppm). Our results are in agreement with the literature data.²⁹

Chemical shifts for the 3,1-benzoxazin-4-one nitrogen atoms in compounds 4 were in the range of δ 212.0–222.8 ppm (Table 7). Due to the lack of the ¹⁵N NMR data no comparison with the literature could be done. In C8-unsubstituted 3,1-benzoxazin-4-ones 4b,c,f,h (R⁶ = H), three-bond long-range couplings were observed in the ¹H–¹⁵N gs-HMBC spectra from H8 to the N1 resonance as illustrated in Fig. 2. The strongly electron donating C8-methoxy substituent in derivatives 4d,k (R⁶ = OMe) enabled a four-bond long-range couplings from H7 to the N1 whereas no such correlation could be observed in the C8-methyl substituent analogues 4g,i,j (R⁶ = Me).

The amide nitrogen atoms (CONH) in acylanthranilic acids 1 resonate in the range of δ 113.9–129.5 ppm (Table 6). In analogy with the above, the cross-peaks between H3 and CONH resonance were observed in ¹H–¹⁵N gs-HMBC spectra of 1a–c,h,l. In the 4-methoxy substituted acylanthranilic acid 1c there was also a four-bond long-range coupling from H6 to the CONH. With the exception of 1l and 1m, the ¹H–¹⁵N gs-HMBC spectra also featured the one-bond direct NH doublet response. Interestingly, in 3-methylindoles 1a,b,g,h, five-bond long-range couplings were observed in the ¹H–¹⁵N gs-HMBC spectra from the C3′CH₃ to the amide nitrogen (CONH) resonance. With the 2-(indol-2-carboxamido)benzoic acid 1b as a representative example, the above mentioned ¹H–¹⁵N gs-HMBC spectral features are illustrated in Fig. 3.

Conclusions

We have demonstrated that Fischer indolisation of N-(α-ketoacyl)anthranilic acids can serve as a mild and highly efficient alternative for the preparation of 2-(indol-2-carboxamido)benzoic acids. By simple changes in the reaction conditions, this protocol offers a potential to access 2-indolyl-3,1-benzoxazin-4-ones. The anthranilic acid, indol-2-carboxamide and 3,1-benzoxazin-4-one structural motifs discussed herein were fully characterized by ¹H, ¹³C and ¹⁵N NMR spectroscopy. The data presented will help in unequivocal identification of these classes of compounds.

Experimental section

General

The reagents and solvents were used as obtained from commercial sources. Compounds 2a–k,m were prepared according to the literature procedure.²¹ Column chromatography was carried out on Fluka Silica gel 60 (particle size 0.063–0.2 mm, activity acc. Brockmann and Schodder 2–3). Melting points were determined on the microscope hot stage, Kofler, PolyTherm, manufacturer Helmut Hund GmbH, Wetzlar and are uncorrected. TLC was carried out on pre-coated TLC sheets ALUGRAM® SIL G/UV₂₅₄ for TLC, MACHEREY-NAGEL. NMR spectra were recorded with a Bruker Avance III 500 MHz NMR instrument operating at 500 MHz (¹H), 126 MHz (¹³C) and 51 MHz (¹⁵N). Proton spectra were referenced to TMS as an internal standard. Carbon chemical shifts were determined relative to the ¹³C signal of DMSO-d₆ (39.5 ppm), CDCl₃ (77.0 ppm) or acetone-d₆ (high-field at 20.8 ppm). ¹⁵N chemical shifts were extracted from ¹H–¹⁵N gs-HMBC spectra (with 20 Hz digital resolution in the indirect dimension and the parameters adjusted for a long-range ¹H–¹⁵N coupling constant of 5 Hz) determined with respect to external nitromethane and are corrected to external ammonia by addition of 380.5 ppm. Nitrogen chemical shifts are reported to one decimal place as measured from the spectrum; however, the data should not be considered to be more accurate than ±0.5 ppm because of the digital resolution limits of the experiment. Chemical shifts are given on the δ scale (ppm). Coupling constants (J) are given in Hz. Multiplicities are indicated as follows: s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet) or br (broadened). Infrared spectra were recorded on a Mattson 3000 FTIR Spectrometer or a Thermo Scientific Nicolet iS10 FT-IR Spectrometer using samples in potassium bromide disks and only the strongest/structurally most important peaks are listed; absorption band intensities are indicated as follows: s (strong), m (medium), w (weak) or b (broad). Electron impact mass spectra (EI) were recorded on a Shimadzu QP–2010 instrument at 70 eV. HRMS spectra were recorded with the Agilent 6224 Accurate Mass TOF LC/MS system with electrospray ionization (ESI). Elemental analyses (C, H, N) were performed with the FlashEA1112 Automatic Elemental Analyzer (Thermo Fisher Scientific Inc.).

2-(2-Oxo-3-phenylpropanamido)benzoic acid (2l)

To a solution of 3-benzyl-3-hydroxyquinoline-2,4(1H,3H)-dione (669.4 mg, 2.50 mmol) in ethyl acetate (120 mL), a solution of sodium periodate (1.62 g, 7.55 mmol) in water (60 mL) was added. The two-phase reaction mixture was vigorously stirred for 7 hours at room temperature. The organic layer was separated, and extracted with 5% aqueous sodium thiosulphate (2 × 20 mL), 5% aqueous hydrochloric acid (2 × 20 mL) and finally with 5% aqueous potassium carbonate (7 × 10 mL). The potassium carbonate extract was washed with benzene (30 mL) and neutralised by addition of 10% aqueous hydrochloric acid. The resulting solution was extracted with ethyl acetate. The organic layer was separated, dried over sodium sulphate and concentrated in vacuo. The crude product was recrystallized from cyclohexane (85 mL) to give compound 2l (424.3 mg, 60%) as colourless microcrystals, mp 179–181 °C, R_f = 0.49 (10% ethanol in chloroform), ¹H NMR (500 MHz, DMSO-d₆) δ 4.32 (s, 2H), 7.23–7.37 (m, 6H), 7.67–7.72 (m, 1H), 8.07 (dd, 1H, J = 8.0, 1.6 Hz), 8.72 (d, 1H, J = 8.5 Hz), 12.39 (br s, 1H), 13.84 (br s, 1H); due to decomposition, no ¹³C NMR spectrum could be recorded. IR (cm⁻¹): ν 3221 w, 3063 w, 3031 w, 1697 s, 1672 s, 1603 m, 1583 s, 1531 s, 1451 m, 1420 s, 1270 s, 1055 m, 755 m, 695 m; MS (EI) m/z (%): 284 (3), 283 (17, [M⁺]), 164 (20), 146 (100), 137 (25), 118 (14), 92 (15), 91 (54), 90 (25), 65 (16); HRMS (ESI⁺): m/z calcd for C₁₆H₁₄NO₄⁺ [M + H]⁺ 284.0917, found 284.0917; HRMS (ESI⁻): m/z calcd for C₁₆H₁₂NO₄⁻ [M − H]⁻ 282.0772, found 282.0773. Found: C, 67.9; H, 4.6; N, 4.9. Calc. for C₁₆H₁₃NO₄: C, 67.8; H, 4.6; N, 4.9%.

The synthesis of phenylhydrazones (3a,c–e) (Table 1)

To a solution of an appropriate N-(α-ketoacyl)anthranilic acid 2 (3.0 mmol) in acetic acid (25 mL), phenylhydrazine (0.49 g, 4.5 mmol) was slowly added and the resulting solution was stirred at 60 °C until TLC analysis revealed complete consumption of the starting compound (Table 1). The reaction mixture was cooled and poured into crushed ice (200 g). For phenylhydrazones 3a,d,e, the precipitated solid was collected by filtration and washed with water (3 × 20 mL) and cyclohexane (2 × 10 mL). For phenylhydrazone 3c the filter cake was dried at 50 °C and recrystallized from ethyl acetate to yield 3c·AcOH. The yields of compounds 3a,c–e are collected in Table 1.

2-(2-(2-Phenylhydrazono)butanamido)benzoic acid (3a). Pale yellow solid, yield 822 mg (88%), mp 208–210 °C (benzene), R_f = 0.42 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 1.07 (t, 3H, J = 7.2 Hz, CH₃), 2.68–2.78 (m, 2H, CH₂), 6.91 (dd, 1H, J = 7.1, 7.1 Hz, H4 of phenyl), 7.14 (dd, 1H, J = 7.5, 7.5 Hz, H5), 7.30 (dd, 2H, J = 7.6, 7.6 Hz, H3 and H5 of phenyl), 7.55 (dd, 2H, J = 7.6, 7.6 Hz, H2 and H6 of phenyl), 7.59–7.64 (m, 1H, H4), 8.06 (dd, 1H, J = 1.5, 7.7 Hz, H6), 8.80 (d, 1H, J = 8.4 Hz, H3), 9.98 (s, 1H, NNH), 12.40 (s, 1H, CONH), 13.54 (br s, 1H, COOH); ¹³C NMR (75 MHz, DMSO-d₆) δ 10.2 (CH₃), 16.2 (CH₂), 113.7 (C2, C6 of phenyl), 115.9 (C1), 119.3 (C3), 120.7 (C4 of phenyl), 121.9 (C5), 129.0 (C3, C5 of phenyl), 131.4 (C6), 134.2 (C4), 139.5 (C=N), 141.2 (C2), 144.4 (C1 of phenyl), 163.2 (CONH), 169.4 (COOH); ¹⁵N NMR (51 MHz, DMSO-d₆) δ 116.4 (CONH), 144.1 (NHPh), 327.6 (C=N); IR (cm⁻¹): ν 3287 m, 2970 w, 1665 s, 1650 s, 1604 m, 1586 m, 1577 m, 1518 s, 1496 s, 1449 m, 1241 s, 1225 s, 748 m, 694 m; MS (EI) m/z (%): 312 (8), 311 (40, [M⁺]), 147 (11), 146 (91), 145 (16), 93 (19), 92 (55), 91 (100), 90 (18), 65 (46). Found: C, 65.6; H, 5.5; N, 13.25. Calc. for C₁₇H₁₇N₃O₃: C, 65.6; H, 5.5; N, 13.5%.

4-Methoxy-2-(2-(2-phenylhydrazono)butanamido)benzoic acid, acetic acid salt (3c·AcOH). Pale yellow microcrystals, yield 795 mg (66%), mp 223–226 °C (ethyl acetate), R_f = 0.66 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 1.06 (t, 3H, J = 7.5 Hz), 1.92 (s, 3H, CH₃CO₂H), 2.72 (q, 2H, J = 7.5 Hz), 3.84 (s, 3H), 6.70 (dd, 1H, J = 8.9, 2.6 Hz), 6.90 (dd, 1H, J = 7.3, 7.3 Hz), 7.28 (dd, 2H, J = 7.9, 7.9 Hz), 7.56 (d, 2H, J = 7.7 Hz), 7.99 (d, 1H, J = 8.9 Hz), 8.47 (d, 1H, J = 2.6 Hz), 9.99 (s, 1H), 12.54 (br s, 1H), 12.57 (br s, 2H); ¹³C NMR (75 MHz, DMSO-d₆) δ 10.2, 16.2, 21.1 (CH₃CO₂H), 55.4, 103.9, 108.1, 108.4, 113.8, 120.7, 129.0, 133.2, 139.5, 143.2, 144.4, 163.4, 163.6, 169.3, 172.0 (CH₃CO₂H); IR (cm⁻¹): ν 2971 w, 2937 w, 1694 m, 1603 s, 1585 s, 1494 s, 1462 m, 1231 s, 1059 m, 751 m, 751 m, 692 w. Found: C, 59.6; H 5.7; N, 10.8. Calc. for C₂₀H₂₃N₃O₆: C, 59.8; H, 5.8; N, 10.5%.

3-Methoxy-2-(2-(2-phenylhydrazono)butanamido)benzoic acid (3d). Colourless crystals, yield 809 mg (79%), mp 210–212 °C (ethyl acetate), R_f = 0.52 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 1.02 (t, 3H, J = 7.5 Hz), 2.65 (q, 2H, J = 7.5 Hz), 3.85 (s, 3H), 6.86–6.91 (m, 1H), 7.22–7.40 (m, 7H), 9.69 (br s, 1H), 9.97 (br s, 1H), 12.82 (br s, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ 10.2, 16.4, 56.2, 113.5, 114.8, 120.5, 121.3, 125.0, 126.1, 127.3, 129.1, 139.3, 144.5, 153.0, 162.0, 168.2; IR (cm⁻¹): ν 3334 w, 3303 m, 3249 m, 2967 m, 1695 s, 1650 s, 1603 s, 1583 s, 1493 s, 1461 s, 1277 s, 1261 s, 1232 s, 1056 s, 748 m, 691 m; MS (EI) m/z (%): 341 (1, [M]⁺), 167 (78), 134 (54), 121 (73), 119 (59), 106 (59), 93 (76), 92 (64), 91 (100), 77 (73), 43 (74); HRMS (ESI⁺): m/z calcd for C₁₈H₂₀N₃O₄⁺ [M + H]⁺ 342.1448, found 342.1450; HRMS (ESI⁻): m/z calcd for C₁₈H₁₈N₃O₄⁻ [M − H]⁻ 340.1303, found 340.1303. Found: C, 63.15; H, 5.6; N, 12.15. Calc. for C₁₈H₁₉N₃O₄: C, 63.3; H, 5.6; N, 12.3%.

2-(N-Methyl-2-(2-phenylhydrazono)butanamido)benzoic acid (3e). Pale yellow microneedles, yield 761 mg (78%), mp 173–178 °C (ethyl acetate–benzene), R_f = 0.73 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 1.02 (t, 3H, J = 5 Hz), 2.37–2.52 (m, 2H, CH₂), 3.23 (s, 3H), 6.49 (d, 2H, J = 10 Hz), 6.67 (dd, 1H, J = 7.5, 7.5 Hz), 7.01 (dd, 2H, J = 7.5, 7.5 Hz), 7.28 (dd, 1H, J = 7.5, 7.5 Hz), 7.45 (d, 1H, J = 7.5 Hz), 7.63 (ddd, 1H, J = 7.7, 7.7, 1.6 Hz), 7.76 (d, 1H, J = 10 Hz), 9.15 (br s, 1H), 12.94 (br s, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ 10.0, 18.8, 38.4, 112.9, 119.5, 126.3, 127.8, 128.4, 129.3, 131.0, 132.8, 139.9, 144.5, 146.0, 166.5, 166.8; IR (cm⁻¹): ν 3326 m, 1707 s, 1619 s, 1598 s, 1577 s, 1454 m, 1392 m, 1256 s, 1203 m, 760 m, 747 m, 694 m; MS (EI) m/z (%): 325 (1, [M]⁺), 174 (100), 151 (24), 146 (24), 145 (34), 105 (28), 104 (26), 91 (34), 77 (37), 43 (25). Found: C, 66.2; H, 5.9; N, 12.7. Calc. for C₁₈H₁₉N₃O₃: C, 66.45; H, 5.9; N, 12.9%.

General procedure for the Fischer indolisation of phenylhydrazones 3a,c–e into 2-(indol-2-carboxamido)benzoic acids 1a,c–e (Table 1)

Phenylhydrazones 3a,d,e or 3c· AcOH (2.0 mmol) were heated under a nitrogen atmosphere on a metal bath at the temperature and for the time given in Table 1. The course of reaction was monitored by a moistened pH test strip (alkaline reaction of released ammonia gas). After cooling the reaction mixture, the corresponding product was isolated as follows.

Compound 1a was obtained from the solidified reaction mixture by two subsequent recrystallizations from ethanol and isopropyl alcohol.

Compound 1c was obtained from the oily reaction mixture by trituration with toluene (10 mL). The precipitate that formed was collected by filtration, recrystallized from isopropyl alcohol and additionally purified by column chromatography on silica gel using successive mixtures of ethyl acetate and ethanol as eluents.

Compound 1d was obtained by triturating the solidified reaction mixture with toluene for 1 hour at ambient temperature followed by filtration. Pure 1d was obtained after recrystallization of the filter cake from isopropyl alcohol.

Compound 1e was obtained by washing the solidified reaction mixture with toluene (10 mL) and cyclohexane (10 mL). The solid was subjected to column chromatography on silica gel using successive mixtures of ethyl acetate and ethanol as eluents. Recrystallisation from the benzene–ethyl acetate mixture afforded pure 1e.

Solvent and catalyst screening for the Fischer indolisation of 2 into 1 (Table 2)

A stirred mixture of N-(α-ketoacyl)anthranilic acid 2 (2.00 mmol), phenylhydrazinium chloride (310 mg, 2.15 mmol) and the catalyst in the solvent (entry 1: 7.5 mL; entries 2–13: 13 mL) was heated under reflux until TLC analysis indicated complete consumption of the starting material. The progress of the reaction was accompanied by the colour change of the reaction mixture from pale yellow to green and finally to dark red. The products were isolated as follows.

Entries 1 and 5: the cooled reaction mixture was poured into ice water (35–60 mL). The solid was collected by filtration, washed with water (20–60 mL) and recrystallized from ethanol affording pure compound 1a.

Entries 2–4, 9–13: the cooled reaction mixture was poured into ice water (35 mL). If an oily organic phase was formed (entry 13), the resulting mixture was stirred overnight. The resulting solid was collected by filtration, washed with 10% HCl (16 mL) and water (25 mL), and recrystallized from ethanol affording the appropriate pure compound 1.

Entries 6 and 7: the cooled reaction mixture was filtered. The filter cake was washed with water (10 mL) and recrystallized from ethanol affording a pure compound 1a. The filtrate was evaporated to dryness and the residue was dissolved in a minimal amount of water (ca. 25 mL). The solution was made alkaline with 0.5 M NaOH, washed with benzene (3 × 5 mL) and carefully neutralised with 5% HCl. The precipitated anthranilic acid was filtered off as colourless crystals.

Entry 8: the reaction mixture was concentrated in vacuo and the oily residue was triturated with water (10 mL) to give white precipitate of pure 1a, which was collected by filtration and washed with water (2 × 3 mL).

General procedure for the Fischer indolisation of N-(α-ketoacyl)anthranilic acids 2 into 2-(indol-2-carboxamido)benzoic acids 1 (Table 3)

A mixture of N-(α-ketoacyl)anthranilic acid 2 (2.00 mmol) and phenylhydrazinium chloride (310 mg, 2.15 mmol) in acetic acid (7.5 mL) was heated under reflux until TLC indicated complete consumption of the starting material 2. In the case of 2m (entry 13), at the onset of the reaction the formation of solid prevented an efficient stirring of the reaction mixture. Thus an additional amount of acetic acid (5 mL) was added. The reaction mixture was cooled and diluted with ice water (60 mL). After stirring the resulting mixture for several hours, the Precipitate A was collected by filtration and washed with water (20 mL). The filtrates were combined into the Filtrate A. The Precipitate A and the Filtrate A were treated as follows.

Entries 1–6, 8, 10–12: recrystallization of the Precipitate A from ethanol gave pure products 1a–f,h,j–l.

Entries 2, 4, 6, 11: the Filtrate A was concentrated in vacuo and the residue was subjected to column chromatography on silica gel using 30% ethyl acetate in chloroform as an eluent to isolate benzoxazinones 4d,f,k and phenylhydrazides 5b,f as indicated in Table 3.

Entry 7: recrystallisation of the Precipitate A from ethanol afforded the appropriate benzoxazinones 4g. The mother liquor was concentrated in vacuo. From the residue the second crop of 1g crystallized, which was collected by filtration and washed with a small amount of benzene and recrystallized from ethanol. The yield of the combined crops of 1g is given in Table 3, entry 7.

Entry 13: recrystallisation of the Precipitate A from ethanol afforded benzoxazinone 4m.

Entry 9: the Precipitate A was washed with boiling benzene (15 mL) and recrystallized from ethanol affording a pure compound 1i. The benzene extract was concentrated to the oily residue and subjected to column chromatography on silica gel using 10% ethyl acetate in chloroform as an eluent, to give benzoxazinone 4i.

Entry 10: the Filtrate A was evaporated to dryness and subjected to column chromatography on silica gel with chloroform as an eluent, affording benzoxazinone 4j.

2-{[(3-Methyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1a). Colourless solid, mp 276–284 °C (ethanol), R_f = 0.48 (20% methanol in ethyl acetate), R_f = 0.18 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 2.66 (s, 3H, CH₃), 7.09 (dd, 1H, J = 7.5, 7.4 Hz, H5′), 7.22 (dd, 1H, J = 7.6, 7.6 Hz, H5), 7.26 (dd, 1H, J = 7.6, 7.6 Hz, H6′), 7.44 (d, 1H, J = 8.2 Hz, H7′), 7.66–7.71 (m, 2H, H4 and H4′), 8.07 (dd, 1H, J = 7.9, 1.1 Hz, H6), 8.69 (d, 1H, J = 8.4 Hz, H3), 11.53 (s, 1H, H1′), 11.69 (s, 1H, CONH), 13.82 (br s, 1H, COOH); IR (cm⁻¹): ν 3328 s, 3061 w, 1682 s, 1664 s, 1581 w, 1524 s, 1450 m, 1412 m, 1338 m, 1261 s, 727 m, 662 w; MS (EI) m/z (%): 295 (12), 294 (63, [M]⁺), 158 (95), 157 (100), 130 (56), 129 (48), 128 (26), 120 (78), 103 (36), 77 (36) m/z (%). Found: C, 69.1; H 4.8; N, 9.7. Calc. for C₁₇H₁₄N₂O₃: C, 69.4; H, 4.8; N, 9.5%.

5-Methoxy-2-{[(3-methyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1b). Yellowish solid, mp 265–269 °C (ethanol), R_f = 0.41 (20% methanol in ethyl acetate), R_f = 0.16 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 2.64 (s, 3H, C3′CH₃), 3.81 (s, 3H, OCH₃), 7.09 (dd, 1H, J = 7.3, 7.3 Hz, H5′), 7.25 (ddd, 1H, J = 7.6, 7.6, 0.8 Hz, H6′), 7.30 (dd, 1H, J = 9.2, 3.1 Hz, H4), 7.43 (d, 1H, J = 8.2 Hz, H7′), 7.53 (d, 1H, J = 3.2 Hz, H6), 7.67 (d, 1H, J = 8.0 Hz, H4′), 8.59 (d, 1H, J = 9.2 Hz, H3), 11.37 (s, 1H, CONH), 11.49 (s, 1H, H1′), 13.88 (br s, 1H, COOH); IR (cm⁻¹): ν 3321 s, 1638 s, 1521 s, 1337 m, 1289 m, 1245 s, 1218 m, 1036 w, 744 s; MS (EI) m/z (%): 325 (19), 324 (90, [M]⁺), 307 (16), 306 (71), 158 (97), 157 (40), 150 (57), 130 (65), 129 (41), 77 (41); HRMS (ESI⁺): m/z calcd for C₁₈H₁₇N₂O₄⁺ [M + H]⁺ 325.1183, found 325.1184. Found: C, 66.5; H, 5.0; N, 8.6. Calc. for C₁₈H₁₆N₂O₄: C, 66.7; H, 5.0; N, 8.6%.

4-Methoxy-2-{[(3-methyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1c). Colourless solid, mp 264–267 °C (iPrOH), R_f = 0.61 (20% methanol in ethyl acetate), R_f = 0.23 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 2.65 (s, 3H, C3′CH₃), 3.87 (s, 3H, OCH₃), 6.79 (dd, 1H, J = 8.9, 2.6 Hz, H5), 7.09 (ddd, 1H, J = 7.2, 7.2, 0.6 Hz, H5′), 7.26 (ddd, 1H, J = 7.6, 7.6, 0.8 Hz, H6′), 7.43 (d, 1H, J = 8.3 Hz, H7′), 7.68 (d, 1H, J = 8.0 Hz, H4′), 8.02 (d, 1H, J = 8.9 Hz, H6), 8.38 (d, 1H, J = 2.6 Hz, H3), 11.53 (s, 1H, H1′), 11.91 (s, 1H, CONH), 13.47 (br s, 1H, COOH); IR (cm⁻¹): ν 3320 m, 3054 w, 2975 w, 1671 s, 1640 m, 1613 s, 1577 m, 1524 m, 1407 m, 1337 m, 1269 s, 1243 s, 1235 s, 1151 m, 740 m; MS (EI) m/z (%): 325 (2), 324 (8, [M]⁺), 306 (42), 158 (35), 157 (26), 150 (28), 130 (33), 129 (23), 45 (30), 44 (100); HRMS (ESI⁺): m/z calcd for C₁₈H₁₇N₂O₄⁺ [M + H]⁺ 325.1183, found 325.1187. Found: C, 66.6; H, 5.0; N, 8.45. Calc. for C₁₈H₁₆N₂O₄: C, 66.7; H, 5.0; N, 8.6%.

3-Methoxy-2-{[(3-methyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1d). Colourless solid, mp 265–267 °C (ethyl acetate), R_f = 0.39 (20% methanol in ethyl acetate), R_f = 0.24 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 2.58 (s, 3H, C3′CH₃), 3.85 (s, 3H, OCH₃), 7.08 (dd, 1H, J = 7.4, 7.4 Hz, H5′), 7.25 (ddd, 1H, J = 7.6, 7.6, 0.7 Hz, H6′), 7.30–7.34 (m, 2H, H4 and H5), 7.39–7.46 (m, 2H, H6 and H7′), 7.65 (d, 1H, J = 8.1 Hz, H4′), 9.31 (br s, 1H, CONH), 11.47 (br s, 1H, H1′), 12.91 (br s, 1H, COOH); ¹³C NMR (126 MHz, DMSO-d₆): δ 9.8, 56.1, 112.0, 115.0, 115.2, 119.2, 119.9, 121.4, 124.2, 125.7, 126.1, 127.2, 128.0, 128.5, 135.6, 153.7, 160.2, 167.9; IR (cm⁻¹): ν 3387 w, 3292 s, 2837 m, 1690 s, 1619 s, 1538 m, 1506 s, 1478 s, 1459 m, 1280 s, 1257 s, 1056 m, 747 m, 510 w; MS (EI) m/z (%): 324 (3, [M]⁺), 323 (26), 322 (100), 250 (13), 149 (48), 111 (6), 97 (8), 85 (8), 71 (10), 57 (24), 43 (8), 41 (13); HRMS (ESI⁻): m/z calcd for C₁₈H₁₅N₂O₄⁻ [M − H]⁻ 323.1037, found 323.1039. Found: C, 66.5; H, 5.0; N, 8.5. Calc. for C₁₈H₁₆N₂O₄: C, 66.7; H, 5.0; N, 8.6%.

2-{Methyl[(3-methyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1e). White solid, mp 216–219 °C (EtOAc–benzene), R_f = 0.54 (20% methanol in EtOAc), R_f = 0.36 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 1.95 (br s, 3H), 3.35 (s, 3H), 6.88–7.72 (m, 8H), 10.56 (br s, 1H), 13.07 (br s, 1H); ¹³C NMR (126 MHz, DMSO-d₆) δ 9.0, 38.0, 111.3, 111.6, 118.6, 119.2, 122.7, 127.1, 127.3, 128.3, 129.7, 130.9, 132.7, 135.5, 143.5, 164.3, 166.5; IR (cm⁻¹): ν 3233 s, 2913 m, 1704 s, 1614 s, 1590 s, 1545 m, 1445 m, 1421 m, 1395 m, 1349 m, 1287 m, 1256 s, 759 m, 752 m, 741 m; MS (EI): m/z (%) 309 (14), 308 (67, [M]⁺), 290 (100), 250 (89), 234 (37), 233 (80), 232 (63), 204 (52), 158 (48), 102 (37), 77 (42), 44 (53); HRMS (ESI⁺): m/z calcd for C₁₈H₁₇N₂O₃⁺ [M + H]⁺ 309.1234, found 309.1237.

2-{[(3-Propyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1f). Colourless solid, mp 239–246 °C (ethanol), R_f = 0.23 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 0.94 (t, 3H, J = 7.3 Hz, C3′(CH₂)₂CH₃), 1.67–1.74 (m, 2H, C3′CH₂CH₂), 3.08–3.14 (m, 2H, C3′CH₂), 7.08 (dd, 1H, J = 7.7, 7.7 Hz, H5′), 7.22 (dd, 1H, J = 8.0, 8.0 Hz, H5), 7.26 (dd, 1H, J = 7.8, 7.8 Hz, H6′), 7.44 (d, 1H, J = 8.2 Hz, H7′), 7.65–7.70 (m, 2H, H4, H4′), 8.07 (dd, 1H, J = 1.4, 8.0 Hz, H6′), 8.66 (d, 1H, J = 8.4 Hz, H3), 11.52 (br s, 1H, H1′), 11.64 (br s, 1H, CONH), 13.79 (br s, 1H, COOH); IR (cm⁻¹): ν 3311 s, 2956 m, 2870 w, 1673 s, 1655 s, 1580 m, 1540 m, 1521 m, 1511 m, br, 1449 m, 1407 m, 1262 s, 1166 m, 752 m, 730 m; MS (EI) m/z (%): 324 (4), 323 (11), 322 (56, [M]⁺), 304 (11), 275 (39), 186 (40), 185 (100), 170 (21), 168 (15), 156 (48), 130 (21), 129 (22), 128 (47), 120 (50), 77 (13); HRMS (ESI⁺): m/z calcd for C₁₉H₁₉N₂O₃⁺ [M + H]⁺ 323.1390, found 323.1390. Found: C, 70.8; H, 5.75; N, 8.6. Calc. for C₁₉H₁₈N₂O₃: C, 70.8; H, 5.6; N, 8.7%.

3-Methyl-2-{[(3-methyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1g). Colourless solid, mp 234–241 °C (benzene), R_f = 0.26 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 2.29 (s, 3H, C3CH₃), 2.62 (s, 3H, C3′CH₃), 7.08 (dd, 1H, J = 7.4, 7.4 Hz, H5′), 7.25 (dd, 1H, J = 7.5, 7.5 Hz, H6), 7.30 (dd, 1H, J = 7.7, 7.7 Hz, H5), 7.44 (d, 1H, J = 8.2 Hz, H7′), 7.53 (d, 1H, J = 7.4 Hz, H4), 7.66 (d, 1H, J = 8.0 Hz, H4′), 7.77 (d, 1H, J = 7.1 Hz, H6), 9.83 (s, 1H, CONH), 11.45 (s, 1H, H1′), 13.14 (br s, 1H, COOH); IR (cm⁻¹): ν 3460 w, 3303 s, 3059 w, 2966 w, 1673 s, 1647 s, 1622 s, 1505 s, 1463 s, 1447 s, 1335 s, 1243 s, 744 s, 739 m; HRMS (ESI⁺): m/z calcd for C₁₈H₁₇N₂O₃⁺ [M + H]⁺ 309.1234; found 309.1236.

5-Methyl-2-{[(3-methyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1h). Pale yellow crystals, mp 268–274 °C (ethanol), R_f = 0.63 (20% methanol in ethyl acetate), R_f = 0.30 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 2.34 (s, 3H, C5CH₃), 2.65 (s, 3H, C3′CH₃), 7.09 (ddd, 1H, J = 7.5, 7.5, 0.7 Hz, H5′), 7.25 (ddd, 1H, J = 7.6, 7.6, 0.9 Hz, H6′), 7.44 (d, 1H, J = 8.2 Hz, H7′), 7.49 (dd, 1H, J = 8.6, 2.0 Hz, H4), 7.67 (d, 1H, J = 8.0 Hz, H4′), 7.88 (d, 1H, J = 1.8 Hz, H6), 8.58 (d, 1H, J = 8.5 Hz, H3), 11.51 (s, 1H, H1′), 11.58 (s, 1H, CONH), 13.76 (br s, 1H, COOH); IR (cm⁻¹): ν 3316 m, 2919 w, 2863 w, 1672 m, 1648 m, 1586 m, 1520 s, 1418 m, 1398 m, 1336 m, 1296 m, 1259 s, 1217 m, 736 m, 671 w; MS (EI) m/z (%): 310 (1), 309 (8), 308 (36, [M]⁺), 290 (53), 158 (65), 157 (49), 134 (100), 130 (60), 129 (42), 103 (40), 77 (57); HRMS (ESI⁺): m/z calcd for C₁₈H₁₇N₂O₃⁺ [M + H]⁺ 309.1234, found 309.1234. Found: C, 70.2; H, 5.4; N, 9.1. Calc. for C₁₈H₁₆N₂O₃: C, 70.1; H, 5.2; N, 9.1%.

6-Chloro-3-methyl-2-{[(3-methyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1i). Colourless solid, mp 256–264 °C (ethanol), R_f = 0.38 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 2.23 (s, 3H, C3CH₃), 2.57 (s, 3H, C3′CH₃), 7.07 (ddd, 1H, J = 7.8, 7.2, 0.7 Hz, H5′), 7.24 (ddd, 1H, J = 8.1, 7.1, 0.9 Hz, H6′), 7.40–7.45 (m, 3H, H4, H5 and H7′), 7.64 (d, 1H, J = 8.0 Hz, H4′), 9.43 (br s, 1H, CONH), 11.35 (br s, 1H, H1′), 13.59 (br s, 1H, COOH); ¹³C NMR (126 MHz, DMSO-d₆) δ 9.6, 17.5, 111.8, 114.6, 119.1, 119.8, 124.0, 126.3, 126.8, 127.75, 127.83, 131.6, 134.1, 134.2, 135.4, 136.3, 160.8, 166.5; IR (cm⁻¹): ν 3820 m, 3057 w, 2927 m, 1734 s, 1686 s, 1624 s, 1617 s, 1583 s, 1556 s, 1509 s, 1335 s, 1296 s, 743 s; MS (EI) m/z (%): 327 (7), 326 (35), 325 (22), 324 (100, [M − H₂O]⁺), 295 (48), 130 (76), 129 (56), 128 (50), 103 (40), 102 (57), 77 (60), 44 (70); HRMS (ESI⁺): m/z calcd for C₁₈H₁₆ClN₂O₃⁺ [M + H]⁺ 343.0844, found 343.0849. Found: C, 62.8; H, 4.5; N, 7.9. Calc. for C₁₈H₁₅ClN₂O₃: C, 63.1; H, 4.4; N, 8.2%.

3,5-Dimethyl-2-{[(3-propyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1j). Colourless solid, mp 240–244 °C (benzene), R_f = 0.51 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 0.92 (t, 3H, J = 7.4 Hz, C3′(CH₂)₂CH₃), 1.67 (tq, 2H, J = 7.4, 7.4 Hz, C3′CH₂CH₂), 2.23 (s, 3H, C3CH₃), 2.34 (s, 3H, C5CH₃), 3.07 (t, 1H, J = 7.6 Hz, C3′CH₂), 7.07 (ddd, 1H, J = 7.9, 7.2, 0.7 Hz, H5′), 7.24 (ddd, 1H, J = 8.1, 7.1, 0.9 Hz, H6′), 7.34, (d, 1H, J = 1.3 Hz, H4), 7.44 (d, 1H, J = 8.2 Hz, H7′), 7.58 (d, 1H, J = 1.7 Hz, H6), 7.66 (d, 1H, J = 8.1 Hz, H4′), 9.71 (br s, 1H, CONH), 11.41 (br s, 1H, H1′), 13.06 (br s, 1H, COOH); ¹³C NMR (126 MHz, DMSO-d₆): δ 14.0, 18.4, 20.2, 23.9, 26.0, 112.0, 119.2, 119.9, 120.2, 124.0, 126.4, 126.8, 127.6, 128.3, 133.7, 134.8, 134.9, 135.5, 160.2, 168.3; IR (cm⁻¹): ν 3368 w, 3301 m, 3263 m, 3052 m, 2956 m, 1663 s, 1618 w, 1603 w, 1547 m, 1527 w, 1477 w, 1444 m, 1405 m, 1336 w, 1300 m, 1231 m, 742 w; MS (EI) m/z (%): 351 (11), 350 (46, [M]⁺), 332 (5, [M − H₂O]⁺), 186 (44), 185 (70), 156 (33), 148 (100), 130 (30), 129 (25), 128 (39); HRMS (ESI⁺): m/z calcd for C₂₁H₂₃N₂O₃⁺ [M + H]⁺ 351.1703, found, 351.1702. Found: C, 71.7; H, 6.3; N, 7.9. Calc. for C₂₁H₂₂N₂O₃: C, 72.0; H, 6.3; N, 8.0%.

3,5-Dimethoxy-2-{[(3-propyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1k). Pale yellow solid, mp 227–230 °C (ethanol), R_f = 0.33 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 0.92 (t, 3H, J = 7.3 Hz, C3′(CH₂)₂CH₃), 1.64 (tq, 2H, J = 7.4 Hz, C3′CH₂CH₂), 3.05 (t, 3H, J = 7.6 Hz, C3′CH₂), 3.82 (s, 3H, C3OCH₃), 3.83 (s, 3H, C5OCH₃), 6.88 (d, 1H, J = 2.7 Hz, H4), 6.92 (d, 1H, J = 2.7 Hz, H6), 7.06 (dd, 1H, J = 7.4 Hz, H5′), 7.23 (ddd, 1H, J = 7.9, 7.2, 0.7 Hz, H6′), 7.43 (d, 1H, J = 8.2 Hz, H7′), 7.64 (d, 1H, J = 8.0 Hz, H4′), 9.06 (br s, 1H, CONH), 11.40 (br s, 1H, H1′), 12.92 (br s, 1H, COOH); ¹³C NMR (126 MHz, DMSO-d₆) δ 14.1, 23.9, 26.1, 55.6, 56.2, 102.4, 105.1, 112.0, 118.8, 119.2, 120.0, 121.0, 124.0, 126.8, 127.7, 129.6, 135.5, 155.1, 157.5, 160.2, 167.7; IR (cm⁻¹): ν 3409 w, 3288 m, 2957 m, 1694 s, 1657 s, 1597 m, 1502 s, 1471 m, 1454 m, 1334 s, 1309 m, 1215 m, 1067 m, 1043 m, 752 m; MS (EI) m/z (%): 382 (6, [M]⁺), 365 (25), 364 (100), 335 (82), 221 (35), 179 (50), 156 (32), 129 (38), 128 (56), 73 (51); HRMS (ESI⁺): m/z calcd for C₂₁H₂₃N₂O₅⁺ [M + H]⁺ 383.1601, found 383.1601. Found: C, 65.9; H, 5.8; N, 7.1. Calc. for C₂₁H₂₂N₂O₅: C, 66.0; H, 5.8; N, 7.3%.

2-{[(3-Phenyl-1H-indol-2-yl)carbonyl]amino}benzoic acid (1l). Colourless crystals, mp 237–246 °C (ethanol), R_f = 0.36 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 7.11–7.17 (m, 2H, H5, H5′), 7.29–7.36 (m, 2H, H6′, H4′′), 7.44 (dd, 2H, J = 7.7, 7.7 Hz, H3′′, H5′′), 7.53–7.55 (m, 3H, H7′, H2′′, H6′′), 7.59 (d, 1H, J = 8.1 Hz, H4′), 7.64 (ddd, 1H, J = 8.6, 7.1, 1.6 Hz, H4), 7.91 (dd, 1H, J = 7.9, 1.5 Hz, H6), 8.60 (dd, 1H, J = 8.4, 0.6 Hz, H3), 11.28 (br s, 1H, CONH), 12.03 (br s, 1H, H1′), 13.36 (br s, 1H, COOH); IR (cm⁻¹): ν 3309 s, 3057 w, 1671 s, 1655 s, 1605 m, 1580 m, 1519 s, 1449 m, 1405 m, 1332 m, 1296 m, 1262 s, 1230 m, 754 m, 700 m; MS (EI) m/z (%): 357 (3), 356 (13, [M]⁺), 339 (24), 338 (100), 337 (44), 293 (17), 220 (29), 219 (31), 207 (20), 191 (27), 190 (47), 165 (31), 164 (18), 90 (21), 44 (54); HRMS (ESI⁺): m/z calcd for C₂₂H₁₇N₂O₃⁺ [M + H]⁺ 357.1234; found 357.1228. Found: C, 74.1; H, 4.6; N, 7.8. Calc. for C₂₂H₁₆N₂O₃: C, 74.2; H, 4.5; N, 7.9%.

6-Methoxy-2-(3-methyl-1H-indol-2-yl)-4H-benzo[d][1,3]oxazin-4-one (4b). Pale-yellow microcrystals, mp 220–225 °C, R_f = 0.44 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, CDCl₃) δ 2.78 (s, 3H, C3′CH₃), 3.92 (s, 3H, OCH₃), 7.15 (ddd, 1H, J = 7.8, 7.0, 0.9 Hz, H5′), 7.32 (ddd, 1H, J = 7.5, 7.5, 0.9 Hz, H6′), 7.36–7.39 (m, 2H, H7 and H7′), 7.55 (d, 1H, J = 9.0 Hz, H8), 7.59 (d, 1H, J = 2.9 Hz, H5), 7.67 (d, 1H, J = 8.1 Hz, H4′), 8.94 (br s, 1H, H1′); IR (cm⁻¹): ν 3399 m, 3047 w, 2836 w, 1747 s, 1624 s, 1603 m, 1492 s, 1354 m, 1335 m, 1326 m, 1240 s, 1035 m, 838, 743 m; MS (EI) m/z (%): 307 (8), 306 (35, [M]⁺), 181 (100), 158 (30), 157 (18), 130 (28), 129 (17), 103 (18), 77 (16); HRMS (ESI⁺): m/z calcd for C₁₈H₁₅N₂O₃⁺ [M + H]⁺ 307.1077, found 307.1080.

7-Methoxy-2-(3-methyl-1H-indol-2-yl)-4H-benzo[d][1,3]oxazin-4-one (4c). Pale-yellow crystals, mp 234–236 °C (benzene), R_f = 0.52 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, CDCl₃) δ 2.79 (s, 1H, C3′CH₃), 3.95 (s, 1H, OCH₃), 6.99–7.02 (m, 2H, H5 and H8), 7.16 (ddd, 1H, J = 7.8, 7.1, 0.8 Hz, H5′), 7.34 (ddd, 1H, J = 7.9, 7.2, 0.7 Hz, H6′), 7.39 (d, 1H, J = 8.2 Hz, H7′), 7.69 (d, 1H, J = 8.0 Hz, H4′), 8.11 (d, 1H, J = 9.0 Hz, H6), 8.98 (br s, 1H, H1′); ¹³C NMR (126 MHz, CDCl₃) δ 10.5, 55.8, 108.4, 109.3, 111.4, 116.6, 120.2, 120.5, 120.6, 123.3, 125.9, 129.2, 130.4, 136.6, 149.7, 154.3, 158.7, 166.3; IR (cm⁻¹): ν 3376 m, 2946 w, 1736 s, 1622 s, 1599 s, 1565 s, 1548 s, 1493 m, 1444 m, 1439 m, 1287 m, 1203 m, 1043 m, 744 m; MS (EI) m/z (%): 308 (2), 307 (19), 306 (100, [M]⁺), 277 (27), 249 (25), 157 (14), 150 (23), 130 (17), 129 (20), 128 (17), 120 (10), 103 (12), 102 (13), 77 (18); HRMS (ESI⁺): m/z calcd for C₁₈H₁₅N₂O₃⁺ [M + H]⁺ 307.1077, found 307.1081; found: C, 70.2; H, 4.6; N, 9.0. Calc. for C₁₈H₁₄N₂O₃: C, 70.6; H, 4.6; N, 9.15%.

8-Methoxy-2-(3-methyl-1H-indol-2-yl)-4H-benzo[d][1,3]oxazin-4-one (4d). Yellow microcrystals, mp 238–240 °C (benzene), R_f = 0.54 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, CDCl₃) δ 2.79 (s, 3H, C3′CH₃) 4.03 (s, 3H, OCH₃), 7.15 (ddd, 1H, J = 7.4, 7.0, 0.5 Hz, H5′), 7.27 (dd, 1H, J = 8.2, 0.7 Hz, H7), 7.32 (ddd, 1H, J = 7.5, 7.0, 0.6 Hz, H6′), 7.38 (d, 1H, J = 8.8 Hz, H7′), 7.40 (dd, 1H, J = 8.1, 8.1 Hz, H6), 7.68 (d, 1H, J = 8.1 Hz, H4′), 7.81 (dd, 1H, J = 7.9 Hz, 1.0 Hz, H5), 9.23 (br s, 1H, H1′); IR (cm⁻¹): ν 3379 m, 2838 w, 1755 s, 1612 s, 1597 s, 1574 s, 1488 m, 1445 m, 1335 s, 1274 s, 1046 m, 1023 m, 754 m, 738 m, 720 m; MS (EI) m/z (%): 308 (2), 307 (19), 306 (100, [M]⁺), 305 (9, [M − H]⁺], 260 (12), 130 (27), 129 (16), 128 (18), 103 (17), 102 (14), 77 (23); HRMS (ESI⁺): m/z calcd for C₁₈H₁₅N₂O₃⁺ [M + H]⁺ 307.1077, found 307.1075. Found: C, 70.5; H, 4.6; N, 9.2. Calc. for C₁₈H₁₄N₂O₃: C, 70.6; H, 4.6; N, 9.15%.

2-(3-Propyl-1H-indol-2-yl)-4H-benzo[d][1,3]oxazin-4-one (4f). Pale-yellow microcrystals, mp 160–165 °C (cyclohexane), R_f = 0.60 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, CDCl₃) δ 1.05 (t, 3H, J = 7.4 Hz, C3′(CH₂)₂CH₃), 1.81 (tq, 2H, J = 7.4, 7.4 Hz, C3′CH₂CH₂), 3.27 (t, 2H, J = 7.5 Hz, C3′CH₂), 7.15 (ddd, 1H, J = 7.8, 7.1, 0.8 Hz, H5′), 7.31 (ddd, 1H, J = 8.0, 7.1, 0.9 Hz, H6′), 7.39 (d, 1H, J = 8.2 Hz, H7′), 7.46 (ddd, 1H, J = 8.0, 7.1, 1.0 Hz, H6), 7.60 (d, 1H, J = 7.9 Hz, H8), 7.70 (d, 1H, J = 8.0 Hz, H4′), 7.79 (ddd, 1H, J = 8.4, 7.0, 1.5 Hz, H7), 8.21 (dd, 1H, J = 7.9, 1.2 Hz, H5), 9.01 (br s, 1H, H1′); IR (cm⁻¹): ν 3372 s, 2957 w, 1754 s, 1621 s, 1603 s, 1571 m, 1472 m, 1261 m, 1240 w, 1055 m, 766 w, 741 m, 684 w; MS (EI) m/z (%): 305 (14), 304 (66, [M]⁺), 289 (10, [M − CH₃]⁺), 276 (24), 275 (100, [M − CH₂CH₃]⁺), 257 (12), 247 (19), 146 (15), 128 (26), 90 (14); HRMS (ESI⁺): m/z calcd for C₁₉H₁₇N₂O₂⁺ [M + H]⁺ 305.1285, found 305.1283. Found: C, 75.25; H, 5.45; N, 9.3. Calc. for C₁₉H₁₆N₂O₂: C, 75.0; H, 5.3; N, 9.2%.

8-Methyl-2-(3-methyl-1H-indol-2-yl)-4H-benzo[d][1,3]oxazin-4-one (4g). Yellow microcrystals, mp 251–254 °C (benzene), R_f = 0.62 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, CDCl₃) δ 2.64 (s, 3H, C8CH₃), 2.80 (s, 3H, C3′CH₃), 7.15 (ddd, 1H, J = 7.9, 7.1, 0.8 Hz, H5′), 7.34 (ddd, 1H, J = 8.1, 8.1, 1.0 Hz, H6′), 7.35 (dd, 1H, J = 7.5, 7.5 Hz, H6), 7.41 (d, 1H, J = 8.2 Hz, H7′), 7.66 (d, 1H, J = 7.4 Hz, H7), 7.69 (d, 1H, J = 8.0 Hz, H4′), 8.06 (dd, 1H, J = 7.6, 0.6 Hz, H5), 8.93 (br s, 1H, H1′); IR (cm⁻¹): ν 3365 s, 2918 w, 1746 s, 1623 s, 1597 m, 1548 m, 1446 m, 1322 m, 1322(m), 1234 m, 1062 m, 1029 m, 764 m, 740 m; MS (EI) m/z (%): 291 (23), 290 (100, [M]⁺), 289 (17), 261 (21), 233 (20), 165 (22), 158 (99), 157 (86), 145 (18), 130 (68), 129 (55), 128 (27), 104 (17), 103 (37), 102 (24), 77 (46); HRMS (ESI⁺): m/z calcd for C₁₈H₁₅N₂O₂⁺ [M + H]⁺ 291.1128, found 291.1127. Found: C, 74.4; H, 4.9; N, 9.4. Calc. for C₁₈H₁₄N₂O₂: C, 74.5; H, 4.9; N, 9.65%.

5-Chloro-8-Methyl-2-(3-methyl-1H-indol-2-yl)-4H-benzo[d][1,3]oxazin-4-one (4i). Pale-yellow microcrystals, mp 251–256 °C (cyclohexane), R_f = 0.82 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, CDCl₃) δ 2.59 (s, 3H, C8CH₃), 2.79 (s, 3H, C3′CH₃), 7.17 (ddd, 1H, J = 7.9, 7.0, 0.9 Hz, H5′), 7.35 (ddd, 1H, J = 8.6, 7.7, 1.0 Hz, H6′), 7.36 (d, 1H, J = 8.1 Hz, H6), 7.42 (d, 1H, J = 8.3 Hz, H7′), 7.53 (dd, 1H, J = 8.1, 0.6 Hz, H7), 7.69 (dd, 1H, J = 7.5, 0.5 Hz, H4′), 8.92 (br s, 1H, H1′); IR (cm⁻¹): ν 3384 m, 3351 m, 3057 w, 2917 w, 1739 s, 1629 s, 1576 m, 1328 m, 1262 m, 1232 w, 1028 w, 914 m, 744 m, 730 m; MS (EI) m/z (%): 327 (7), 326 (34), 325 (22), 324 (100, [M]⁺), 323 (4), 295 (49), 130 (53), 129 (46), 128 (44), 102 (50), 77 (51); HRMS (ESI⁺): m/z calcd for C₁₈H₁₄ClN₂O₂⁺ [M + H]⁺ 325.0738, found 325.0740. Found: C, 66.4; H, 4.0; N, 8.8. Calc. for C₁₈H₁₃ClN₂O₂: C, 66.6; H, 4.0; N, 8.6%.

6,8-Dimethyl-2-(3-propyl-1H-indol-2-yl)-4H-benzo[d][1,3]oxazin-4-one (4j). Pale-yellow microcrystals, mp 201–202 °C (benzene), R_f = 0.93 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, CDCl₃) δ 1.04 (t, 3H, J = 7.4 Hz, C3′(CH₂)₂CH₃), 1.81 (tq, 2H, J = 7.4, 7.4 Hz, C3′CH₂CH₂), 2.41 (s, 3H, C6CH₃), 2.59 (s, 3H, C8CH₃), 3.27 (t, 2H, J = 7.6 Hz, C3′CH₂), 7.14 (ddd, 1H, J = 7.8, 7.2, 0.7 Hz, H5′), 7.32 (ddd, 1H, J = 8.0, 7.2, 0.8 Hz, H6′), 7.40 (d, 1H, J = 8.2 Hz, H7′), 7.46 (s, 1H, H7), 7.69 (d, 1H, J = 8.0 Hz, H4′), 7.84 (s, 1H, H5), 8.93 (br s, 1H, H1′); IR (cm⁻¹): ν 3363 s, 2953 w, 1740 s, 1623 s, 1603 s, 1477 m, 1249 m, 1054 m, 789 m, 729 m; MS (EI) m/z (%): 334 (3), 333 (18), 332 (77, [M]⁺), 303 (100), 288 (33), 128 (37), 85 (31), 71 (36), 57 (65); HRMS (ESI⁺): m/z calcd for C₂₁H₂₁N₂O₂⁺ [M + H]⁺ 333.1598, found 333.1597. Found: C, 75.9; H, 6.1; N, 8.35. Calc. for C₂₁H₂₀N₂O₂: C, 75.9; H, 6.1; N, 8.4%.

6,8-Dimethoxy-2-(3-propyl-1H-indol-2-yl)-4H-benzo[d][1,3]oxazin-4-one (4k). Yellow crystals, mp 202–204 °C (cyclohexane), R_f = 0.69 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, (CD₃)₂CO) δ 0.97 (t, 1H, J = 7.4 Hz, C3′(CH₂)₂CH₃), 1.71 (tq, 2H, J = 7.7, 7.4 Hz, C3′CH₂CH₂), 3.19 (t, 2H, J = 7.7 Hz, C3′CH₂), 3.85 (s, 3H, C6OCH₃), 3.93 (s, 3H, C8OCH₃), 6.93 (d, 1H, J = 2.6 Hz, H7), 7.01 (ddd, 1H, J = 7.9, 7.2, 0.7 Hz, H5′), 7.05 (d, 1H, J = 2.6 Hz, H5), 7.18 (ddd, 1H, J = 8.1, 7.1, 0.9 Hz, H6′), 7.46 (d, 1H, J = 8.2 Hz, H7′), 7.62 (d, 1H, J = 8.0 Hz, H4′), 10.80 (br s, 1H, H1′); ¹³C NMR (126 MHz, (CD₃)₂CO) δ 14.6, 25.0, 27.6, 56.4, 57.0, 100.6, 108.0, 113.0, 118.9, 120.6, 121.0, 124.2, 125.7, 129.6, 133.1, 138.0, 151.4, 156.7, 159.6, 160.6; IR (cm⁻¹): ν 3368 m, 2963 w, 1736 s, 1619 s, 1491 m, 1437 m, 1373 s, 1325 m, 1300 m, 1219 m, 1036 m, 782 m, 739 m; MS (EI) m/z (%): 366 (4), 365 (24), 364 (100, [M]⁺), 349 (18), 336 (22), 335 (82), 179 (48), 156 (24), 129 (29), 128 (44); HRMS (ESI⁺): m/z calcd for C₂₁H₂₁N₂O₂⁺ [M + H]⁺ 365.1496, found 365.1494. Found: C, 69.1; H, 5.5; N, 7.6. Calc. for C₂₁H₂₀N₂O₄: C, 69.2; H, 5.5; N, 7.7%.

2-(3-Propyl-1H-indol-2-yl)-4H-naphtho[1,2-d][1,3]oxazin-4-one (4m). Bright yellow crystals, mp 273–274 °C (ethanol), R_f = 0.73 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, CDCl₃) δ 1.12 (t, 3H, J = 7.4 Hz), 1.92 (tq, 2H, J = 7.6, 7.4 Hz), 3.42 (t, 2H, J = 7.6 Hz), 7.19 (dd, 1H, J = 7.4, 7.4 Hz), 7.38 (dd, 1H, J = 7.2, 7.2 Hz), 7.46 (d, 1H, J = 8.2 Hz), 7.72–7.80 (m, 3H), 7.86 (d, 1H, J = 8.6 Hz), 7.94 (dd, 1H, J = 8.1, 1.6 Hz), 8.13 (d, 1H, J = 8.6 Hz), 8.98 (dd, 1H, J = 8.2, 1.6 Hz), 9.10 (br s, 1H); ¹³C NMR (126 MHz, CDCl₃) δ 14.4, 24.0, 27.2, 111.6, 112.3, 120.3, 120.9, 122.7, 123.2, 125.3, 126.1, 126.4, 127.4, 127.7, 128.1, 128.9, 129.0, 130.2, 136.7, 137.3, 146.6, 159.4 (one resonance could not be determined due to low solubility of the compound and thus the low signal/noise ratio); IR (cm⁻¹): ν 3360 m, 3057 w, 2951 w, 1744 s, 1602 s, 1564 s, 1542 w, 1509 w, 1444 w, 1394 w, 1272 m, 780 w, 765 m, 736 m, 626 w; MS (EI) m/z (%): 355 (22), 354 (86), 326 (27), 325 (100), 297 (23), 283 (18), 269 (18), 170 (23), 169 (18), 156 (17), 140 (46), 129 (15), 128 (49), 115 (18), 101 (17), 77 (12); HRMS (ESI⁺): m/z calcd for C₂₃H₁₉N₂O₂⁺ [M + H]⁺ 355.1441; found 355.1438. Found: C, 78.1; H, 5.1; N, 8.0. Calc. for C₂₃H₁₈N₂O₂: C, 78.0; H, 5.1; N, 7.9%.

N′-Phenyl-5-methoxy-2-{[(3-methyl-1H-indol-2-yl)carbonyl]amino}benzohydrazide (5b). White solid mp 243–253 °C (benzene), R_f = 0.47 (20% benzene in ethyl acetate). ¹H NMR (500 MHz, DMSO-d₆) δ 2.52 (s, 3H, C3′CH₃), 3.87 (s, 3H, OCH₃), 6.72 (t, 1H, J = 7.3 Hz, H4′′), 6.82 (d, 2H, J = 7.7 Hz, H2 and H6 of phenyl), 7.05 (ddd, 1H, J = 7.5, 7.5, 0.6 Hz, H5′), 7.14 (dd, 2H, J = 8.2, 7.6 Hz, H3 and H5 of phenyl), 7.20–7.25 (m, 2H, H4 and H6′), 7.40 (d, 1H, J = 8.2 Hz, H7′), 7.48 (d, 1H, J = 3.0 Hz, H6), 7.62 (d, 1H, J = 8.1 Hz, H4′), 8.00 (d, 1H, J = 1.0 Hz, NHPh), 8.35 (d, 1H, J = 9.1 Hz, H3), 10.65 (d, 1H, J = 1.0 Hz, NHNHPh), 11.00 (br s, 1H, C2NH), 11.45 (br s, 1H, H1′); ¹³C NMR (126 MHz, DMSO-d₆): δ 9.7 (C3′CH₃), 55.6 (OCH₃), 112.1 (C7′), 112.4 (C2 and C6 of phenyl), 112.8 (C6), 113.0 (C3′), 117.9 (C4), 118.9 (C4 of phenyl), 119.3 (C5′), 120.0 (C4′), 121.9 (C1), 123.6 (C3), 124.1 (C6′), 127.9 (C3a′), 128.1 (C2′), 128.8 (C3 and C5 of phenyl), 131.6 (C2), 135.9 (C7a′), 149.1 (C1 of phenyl), 154.7 (C5), 160.1 (C2′CO), 168.0 (COOH); ¹⁵N NMR (51 MHz, DMSO-d₆) δ 89.0 (NPh), 123.2 (C2N); 132.3 (N1′), 137.6 (C1CON); IR (cm⁻¹): ν 3374 m, 3302 m, 3053 w, 1655 s, 1609 m, 1541 s, 1524 s, 1494 m, 1419 m, 1335 m, 1283 m, 1234 m, 1223 m, 740 m; MS (EI) m/z (%): 338 (43), 181 (100), 158 (38), 130 (32), 129 (25), 77 (25), 60 (23), 45 (35), 44 (39), 43 (40); HRMS (ESI⁺): m/z calcd for C₂₄H₂₃N₄O₃⁺ [M + H]⁺ 415.1765; found 415.1760; Found: C, 69.6; H, 5.3; N, 13.35. Calc. for C₂₄H₂₂N₄O₃: C, 69.6; H, 5.35; N, 13.5%.

N′-Phenyl-2-{[(3-propyl-1H-indol-2-yl)carbonyl]amino}benzohydrazide (5f). Colourless needles, mp 214–216 °C (benzene), R_f = 0.61 (20% methanol in ethyl acetate), R_f = 0.28 (20% ethyl acetate in petroleum ether). ¹H NMR (500 MHz, DMSO-d₆) δ 0.83 (t, 3H, J = 7.4, Hz, CH₃), 1.58 (tq, 2H, J = 7.4, 7.4 Hz, CH₂CH₃), 3.02 (t, 2H, J = 7.4 Hz, C3′CH₂), 6.72 (t, 1H, J = 7.3 Hz, H4 of phenyl), 6.82 (d, 2H, J = 7.8 Hz, H2 and H6 of phenyl), 7.05 (dd, 1H, J = 7.4, 7.4, Hz, H5′), 7.14 (dd, 2H, J = 7.8, 7.8 Hz, H3 and H5 of phenyl), 7.22 (dd, 1H, J = 7.5, 7.5 Hz, H6′), 7.27 (ddd, 1H, J = 7.6, 7.6, 0.7 Hz, H5), 7.41 (d, 1H, J = 8.2 Hz, H7′), 7.60–7.65 (m, 2H, H4 and H4′), 7.96 (dd, 1H, J = 7.9, 1.1 Hz, H6), 7.98 (br d, 1H, J = 2.3 Hz, CONHNH), 8.45 (d, 1H, J = 8.1 Hz, H3), 10.66 (br d, 1H, J = 2.3 Hz, CONHNH), 11.33 (br s, 1H, C2NH), 11.49 (br s, 1H, H1′); ¹³C NMR (126 MHz, DMSO-d₆): δ 13.7 (CH₃), 24.0 (CH₂CH₃), 25.6 (C3′CH₂), 112.1 (C7′), 112.2 (C2 and C6 of phenyl), 118.8 (C4 of phenyl), 119.26 (C3′), 119.29 (C5′), 120.0 (C4′), 120.3 (C1), 121.8 (C3), 123.1 (C5), 124.1 (C6′), 127.3 (C2′), 127.7 (C3a′), 128.0 (C6), 128.7 (C3 and C5 of phenyl), 132.2 (C4), 135.9 (C7a′), 138.5 (C2), 149.0 (C1 of phenyl), 160.3 (C2′CO), 168.2 (COOH); ¹⁵N NMR (51 MHz, DMSO-d₆) δ 88.9 (NPh), 124.6 (C2N), 131.9 (N1′), 137.6 (C1CON); IR (cm⁻¹): ν 3319 s, 2953 w, 2869 w, 1655 s, 1631 s, 1593 s, 1540 m, 1515 s, 1493 m, 1446 m, 1281 m, 1244 m, 740 s; MS (EI) m/z (%): 413 (3), 412 (12, [M]⁺), 306 (21), 305 (100), 186 (67), 146 (28), 130 (22), 128 (22), 120 (68), 108 (37), 77 (21); HRMS (ESI⁺): m/z calcd for C₂₅H₂₅N₄O₂⁺ [M + H]⁺ 413.1972, found 413.1971. Found: C, 72.7; H, 5.9; N, 13.6. Calc. for C₂₅H₂₄N₄O₂: C, 72.8; H, 5.9; N, 13.6%.

Reaction of 4f with phenylhydrazine into hydrazide 5f (Table 5, entry 1)

A mixture of benzoxazinone 4f (332 mg, 1.09 mmol) and phenylhydrazine (143 mg, 1.32 mmol) in toluene (15 mL) was heated under reflux for 2 hours. After cooling, the precipitated solid was filtered off with suction and crystallized from benzene to give hydrazide 5f (382 mg, 86%). The spectral and analytical data were in agreement with those for the authentic sample, as prepared above.

Reaction of 4f with n-butylamine into amide 6f (Table 5, entry 2). A mixture of benzoxazinone 4f (305 mg, 1.00 mmol) and n-butylamine (90 mg, 1.23 mmol) in toluene (15 mL) was stirred at room temperature for 2 hours. The precipitated solid was filtered off with suction and crystallized from benzene to give amide 6f (316 mg, 84%) as a white crystalline solid, mp 187–188 °C (benzene), R_f = 0.41 (20% methanol in ethyl acetate). ¹H NMR (500 MHz, DMSO-d₆) δ 0.89 (t, 3H, J = 7.4 Hz, NH(CH₂)₃CH₃), 0.95 (t, 3H, J = 7.3 Hz, C3′(CH₂)₂CH₃), 1.29–1.38 (m, 2H, NH(CH₂)₂CH₂), 1.49–1.57 (m, 2H, NHCH₂CH₂), 1.62–1.72 (m, 2H, C3′CH₂CH₂), 3.08–3.14 (m, 2H, C3′CH₂), 3.26–3.32 (m, 2H, NHCH₂), 7.07 (ddd, 1H, J = 7.8, 7.2, 0.6 Hz, H5′), 7.21 (ddd, 1H, J = 8.4, 7.4, 1.0 Hz, H5), 7.24 (ddd, 1H, J = 7.9, 7.2, 0.8 Hz, H6′), 7.44 (d, 1H, J = 8.2 Hz, H7′), 7.56 (ddd, 1H, J = 7.4, 7.4, 1.3 Hz, H4), 7.67 (d, 1H, J = 8.0 Hz, H4′), 7.78 (dd, 1H, J = 7.8, 1.3 Hz, H6), 8.53 (dd, 1H, J = 8.3, 0.5 Hz, H3), 8.83 (br t, 1H, J = 5.4 Hz, C1′CONH), 11.48 (br s, 1H, H1′), 11.71 (br s, 1H, C2NH); ¹³C NMR (126 MHz, DMSO-d₆) δ 13.6 (NH(CH₂)₃CH₃), 13.8 (C3′(CH₂)₂CH₃), 19.6 (NHCH₂CH₂), 24.1 (C3′CH₂CH₂), 25.7 (C3′CH₂), 30.9 (NHCH₂CH₂), 38.8 (NHCH₂), 112.2 (C7′), 118.6 (C3′), 119.2 (C5′), 120.0 (C4′), 121.2 (C3), 121.5 (C1), 122.7 (C5), 124.0 (C6′), 127.6 (C2′), 127.7 (C3a′), 128.0 (C6), 131.6 (C4), 135.9 (C7a′), 138.6 (C2), 160.3 (C2′CO), 168.1 (C1CO); ¹⁵N NMR (51 MHz, DMSO-d₆) δ 120.33 (Cα-NH), 125.0 (C2-NH), 132.6 (N1′); IR (cm⁻¹): ν 3320 s, 2956 m, 2932 w, 2869 w, 1653 s, 1626 s, 1595 s, 1538 m, 1518 s, 1465 w, 1446 m, 1432 w, 1338 w, 1325 w, 1281 s, 1241 m, 762 w, 736 s, 677 m; MS (EI) m/z (%): 378 (19), 377 (70), 305 (20), 304 (76), 276 (22), 275 (88), 247 (15), 219 (20), 186 (29), 185 (100), 170 (62), 168 (39), 167 (20), 159 (20), 158 (33), 157 (31), 156 (56), 146 (23), 130 (46), 129 (36), 128 (58), 120 (66), 119 (30), 77 (15); HRMS (ESI⁺): m/z calcd for C₂₃H₂₈N₃O₂⁺ [M + H]⁺ 378.2176, found 378.2168. Found: C, 73.0; H, 7.3; N, 11.1. Calc. for C₂₃H₂₇N₃O₂: C, 73.2; H, 7.2; N, 11.1%.

General procedure for the hydrolysis of benzoxazinones 4f,j,m into 2-(indol-2-carboxamido)benzoic acids 1f,j,m (Table 5, entries 3–6)

A mixture of benzoxazinone 4 (343 mg, 0.968 mmol), dimethyl sulfoxide (10 mL) and aqueous sodium hydroxide (0.5 M, 1 mL) was stirred at room temperature for the time indicated in Table 5 (for the reaction in entry 4, dioxane (3 mL) and aqueous sulphuric acid (0.1 M, 2 mL) were used). The reaction mixture was diluted with water (50 mL) and acidified with 10% hydrochloric acid to Congo red (for the reaction from entry 4, no additional acid was added). After stirring for 1 h, the precipitate was filtered off, washed with water and dried to afford 2-(indol-2-carboxamido)benzoic acid 1. Yields of the products are indicated in Table 5. The spectral and analytical data for 1f,j were in agreement with those for the authentic samples, prepared above.

1m: Colourless solid, mp 227–230 °C (ethanol), R_f = 0.39 (10% ethanol in chloroform). ¹H NMR (500 MHz, DMSO-d₆) δ 0.94 (t, 3H, J = 7.1 Hz, C3′(CH₂)₂CH₃), 1.69 (tq, 2H, J = 7.1, 7.1 Hz, C3′CH₂CH₂), 3.11 (t, 2H, J = 7.1 Hz, C3′CH₂), 7.10 (dd, 1H, J = 7.5, 7.5 Hz, H5′), 7.28 (dd, 1H, J = 7.5, 7.5 Hz, H6′), 7.50 (d, 1H, J = 8.2 Hz, H7′), 7.61 (dd, 1H, J = 7.5, 7.5 Hz, H7), 7.67 (dd, 1H, J = 7.5, 7.5 Hz, H6), 7.70 (d, 1H, J = 8.0 Hz, H4′), 7.95 (d, 1H, J = 8.7 Hz, H4), 7.98 (d, 1H, J = 8.6 Hz, H3), 8.03 (d, 1H, J = 8.1 Hz, H5), 8.09 (d, 1H, J = 8.4 Hz, H8), 10.27 (br s, 1H, CONH), 11.54 (br s, 1H, H1′), 13.30 (br s, 1H, COOH); ¹³C NMR (126 MHz, DMSO-d₆) δ 14.2 (C3′(CH₂)₂CH₃), 24.1 (C3′CH₂CH₂), 26.2 (C3′CH₂), 112.2 (C7′), 119.4 (C5′), 120.2 (C4′), 121.2 (C3′), 123.8 (C2), 124.3 (C6′), 125.5 (C8), 126.0 (C3), 126.2 (C4), 126.6 (C7), 126.7 (C2′), 127.7 (C3a′), 128.0 (C5), 128.1 (C6), 129.5 (C8a), 135.2 (C4a), 135.7 (C7a′), 135.8 (C1), 161.6 (CONH), 168.3 (COOH); IR (cm⁻¹): ν 3311 s, 3051 w, 2957 m, 2927 m, 2865 w, 1675 s, 1641 s, 1604 w, 1571 m, 1530 w, 1482 m, 1465 w, 1451 w, 1416 m, 1335 m, 1285 m, 1259 m, 1238 s, 1224 w, 1204 w, 1178 w, 767 m, 749 s; MS (EI) m/z (%): 373 (2), 372 (7), 355 (23), 354 (87), 326 (28), 325 (100), 297 (23), 283 (19), 269 (19), 170 (46), 169 (26), 156 (27), 140 (48), 129 (20), 128 (58), 115 (25), 77 (16); HRMS (ESI⁺): m/z calcd for C₂₃H₂₁N₂O₃⁺ [M + H]⁺ 373.1547, found 373.1544. Found: C, 74.4; H, 5.5; N, 7.7. Calc. for C₂₃H₂₀N₂O₃: C, 74.2; H, 5.4; N, 7.5%.

Acknowledgements

This study was supported by the internal grant of the TBU in Zlin (no. IGA/FT/2014/010) funded from the resources of specific university research and The Ministry of Education, Science and Sport, Republic of Slovenia, the Slovenian Research Agency (P1-0230 and Post-doctoral Grant to M. G. (430-168/2013/114). This work was also partly supported through the infrastructure of the EN-FIST Centre of Excellence, Ljubljana.

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Footnotes

† Dedicated to Professor Marijan Kočevar on his 65th birthday.

‡ Electronic supplementary information (ESI) available: ¹H NMR and ¹³C NMR spectra. See DOI: 10.1039/c4ob01714e

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