Revision of the Structure and Total Synthesis of Topsentin C

Abstract

An efficient synthetic approach to access (indol-3-yl)ethane-1,2-diamines with a protecting group at the indole N atom from readily available 3-(2-nitrovinyl)indoles is reported. This approach includes solvent-free conjugate addition of O-pivaloylhydroxylamines to 1-Boc-3-(2-nitrovinyl)indoles followed by mild reduction of the adducts. The obtained (indol-3-yl)ethane-1,2-diamines are convenient synthetic precursors for several classes of marine alkaloids. The first total synthesis of racemic topsentin C, a secondary metabolite from Hexadella sp., based on this approach is reported. The initially proposed structure for topsentin C has been revised.

Key words

bisindole alkaloid - topsentin - hamacanthin - spongotine - diamine - hydroxylamine

Secondary metabolites from marine invertebrates continue to be an attractive research topic because new structures and compounds with useful biological activity can be discovered.[1] A whole series of alkaloids containing the (indol-3-yl)ethane-1,2-diamine moiety in their structures and their aromatized derivatives were isolated from deep-water sponges in the last 30 years.[2] In particular, spongotines (1) and topsentins (2) contain two indoles connected through imidazoline or imidazole linker. Two indole substituents in the structures of hamacanthins (3) and dragmacidins (4) are bonded to dihydropyrazinone and piperazine rings, respectively (Figure [1]). The (indol-3-yl)ethane-1,2-diamine moiety in several alkaloids of the examined group contains one or two methyl groups; for example, dragmacidins A and B (4) and topsentin C. The latter compound was isolated from Hexadella sp., and its structure was assigned to imidazoline derivative 5a (Figure [2]).[3] Furthermore, the alkaloids could contain one or more Br atoms, which in general is characteristic of marine secondary metabolites.[4] Notably, the 1,2-diaminoethyl group in the indole 3-position, in contrast to 2-aminoethyl, is uncharacteristic for terrestrial indole alkaloids.

Figure 1 Several marine alkaloids containing an (indol-3-yl)ethanediamine fragment and their aromatized derivatives

Total syntheses of many of the natural products from this group have been reported;[2] [5] [6] however, no synthesis of topsentin C has been reported. Compounds exhibiting antibacterial, cytotoxic, antiviral, and fungicidal properties were discovered among these alkaloids and their synthetic analogues.[2,7]

Figure 2 Proposed structure of topsentin C

(Indol-3-yl)ethane-1,2-diamines could be convenient synthetic precursors of topsentins, spongotines, and hamacanthins.[5a] [b] [c] Furthermore, these diamines are of independent interest because their simple derivatives were recently shown to be capable of preventing the development of resistance to fluoroquinolone antibiotics in Staphylococcus aureus.[8]

Only two synthetic approaches to (indol-3-yl)ethane-1,2-diamines have been published and neither of them allows the corresponding N ¹-methyl derivatives to be produced.[5a] [b] [c] It was also reported that diamines of this type with an unsubstituted indole N atom are relatively stable only as the salts.[5a] We propose a convenient preparative synthetic approach to (indol-3-yl)ethane-1,2-diamines (6) with a protected indole N atom that is based on mild reduction of 7, the addition product of O-pivaloylhydroxylamines (8) and 3-nitrovinylindoles (9) (Scheme [1]). The proposed method has been used for the total synthesis of topsentin C, the previously proposed structure of which has been revised by us.

Scheme 1 Our Synthetic approach to (indol-3-yl)ethanediamine 6

Starting nitrovinylindoles 9, with tert-butoxycarbonyl-protected indole N atoms, were synthesized from the corresponding indoles by formylation using N,N-dimethylform­amide (DMF) and SOCl₂ followed by condensation of the obtained aldehydes with nitromethane and addition of the protecting group in the presence of 4-(N,N-dimethylamino)pyridine (DMAP) (Scheme [2]). We also prepared 1-acetyl-3-[(E)-2-nitrovinyl]-1H-indole (9f) and 1-methyl-3-[(E)-2-nitrovinyl]-1H-indole (9g) according to described procedures.[9] [10]

Scheme 2 Synthesis of 3-nitrovinylindoles 9; yields of three stages are shown

Scheme 3 Attempts to convert nitrovinylindole 9b into the corresponding indolic diamines by using aliphatic amines or O-benzylhydroxylamine

Reduction of the adducts of α,β-unsaturated nitrocompounds with amines, O-alkylhydroxylamines or azide anion was proposed earlier for the synthesis of vicinal diamines.[11] [12] [13] The first type of adduct was unstable, although they could be isolated as the more stable salts.[11] Adducts with O-alkylhydroxylamines or azide anion were more stable.[12] [13] However, catalytic hydrogenation or heating with Zn dust in HOAc was required to cleave the hydroxylamine N–O bond.[12] Catalytic hydrogenation was also used to reduce the azido group.[13] The proposed methods turned out to be ineffective for the synthesis of Br-containing (indol-3-yl)ethane-1,2-diamines 6. Thus, the products 10 from the reaction of methylamine or benzylamine with nitrovinylindole 9b could not be isolated; starting 9b was recovered and the reaction mixture formed a resin. Stable adduct 11 with O-benzylhydroxylamine was reduced as expected by H₂ over Pd/C with hydrogenolysis of the C–Br bond to form diamine 6a (Scheme [3]).

Indolic adduct 11 decomposed upon heating with Zn in HOAc, and reduction with Zn under milder conditions was not complete. The yield of diamine 6b was <15% even when the amount of Zn and the reaction time were increased; the main product was 12 (Scheme [3]).

Table 1 Synthesis of Adducts 7

Entry	Substrate	Product	R1	R2	R3	PG	Yield (%)
1	9a	7a	H	H	H	Boc	94
2	9b	7b	Br	H	H	Boc	96
3	9a	7c	H	H	Me	Boc	97
4	9b	7d	Br	H	Me	Boc	89
5	9c	7e	H	Br	Me	Boc	98
6	9d	7f	OMe	H	Me	Boc	91
7	9e	7g	H	Cl	Me	Boc	97
8	9f	7h	H	H	Me	Ac	88
9	9g	–[a]	H	H	Me	Me	0

^a Nitrovinylindole 9g, with a methyl on the indole N atom, did not react.

O-Acylhydroxylamines have highly labile N–O bonds and have recently been used in synthetic procedures based on sigmatropic shifts with cleavage of N–O bonds[14] in addition to amination reaction.[15] Conjugate addition of O-acylhydroxylamines to electron-deficient alkenes has not yet been described, in contrast to O-alkylhydroxylamines. We decided to study the possibility of adding O-pivaloylhydroxylamine and its N-methyl derivative to nitrovinylindoles 9 followed by reduction of the resulting adducts. Derivatives of sterically hindered pivalic acid were chosen because they isomerize rather slowly into the corresponding hydroxamic acids, in contrast to the simpler O-acylhydroxylamines.[16]

Hydrochlorides of O-pivaloylhydroxylamine and N-methyl-O-pivaloylhydroxylamine were synthesized by using the previously reported methods.[14a] [16] [17] The corresponding free bases were isolated immediately before performing the next step.

As it turned out, the reaction of nitrovinylindoles 9a with O-pivaloylhydroxylamine (8a, 1.5 equiv) in CH₂Cl₂ was complete in 96 hours and gave target adduct 7a. We also found that the solvent-free reaction was much faster. The reagents could be mixed and left overnight in a closed vessel. The nitrovinylindoles dissolved gradually, then crystals of the product formed. The solvent-free reaction was clearly advantageous from a green chemistry point of view. In this manner, we obtained the series of adducts 7a–h in high yields (Table [1]).

Table 2 Reduction of Adducts 7a,c

Entry	R	Equiv. Zn	Acid (equiv)	Solvent	t (h)	T (°C)	Yield (%)
1	H	10	AcOH (150)	MeOH	2	0–20	34
2	H	10	AcOH (150)	MeOH	6	0–20	31
3	H	10	AcOH (150)	MeOH/H2O/EtOAc	2	0–20	48
4	H	20	AcOH (150)	MeOH/H2O/EtOAc	2	0–20	57
5	H	15	HCl (30)	MeOH/EtOAc	2	–10 to 5	65
6	H	15	HBr (30)	MeOH/EtOAc	2	–10 to 5	84
7	H	15	NH4Br (15)	EtOH/H2O/EtOAc	2	20	62
8	Me	15	HBr (30)	MeOH/EtOAc	2	–10 to 5	68
9	Me	20	HBr (40)	MeOH/EtOAc	6	–10 to 5	93

The next step was the reduction of adducts 7. We decided to use Zn and acid, anticipating that their hydroxylamine N–O bond would undergo reductive cleavage at room or reduced temperature. Thus, the reduction of 7a using Zn (10 equiv) and HOAc in MeOH afforded target diamine 6a in 34% yield (Table [2], entry 1).

The reaction proceeded rather quickly. However, it was accompanied by the formation of several unidentified side products. Increasing the reaction time did not lead to an increase in the yield of 6a. We found that the yield could be increased by adding H₂O and EtOAc to the reaction mixture (keeping the solution homogeneous) and by doubling the amount of Zn (cf. Table [2], entries 3 and 4). Replacing HOAc with concentrated HCl at reduced temperature led to a further increase in the yield (entry 5). Finally, the use of HBr (40%) allowed target diamine 6a to be obtained with a very good yield (entry 6). It was also possible to conduct the reduction of adduct 7a in the presence of NH₄Br (entry 7). The reduction of adduct 7c, with a methyl group on the hydroxylamine N atom, was more difficult. However, increasing the reaction time and amount of Zn provided a high yield of diamine 6c (entry 9). The developed method was extended to adducts 7b and 7d–f (Table [3]). Boc derivatives gave the corresponding diamines 6b and 6d–g in good and high yields, whereas diamine 6h, with an acetyl on the indole N atom, was unstable and decomposed even in solution.

Table 3 Synthesis of Diamines 6

Entry	Substrate	Product	R1	R2	R3	PG	Yield (%)
1a	7a	6a	H	H	H	Boc	84
2a	7b	6b	Br	H	H	Boc	95
3b	7c	6c	H	H	Me	Boc	93
4b	7d	6d	Br	H	Me	Boc	86
5b	7e	6e	H	Br	Me	Boc	92
6b	7f	6f	OMe	H	Me	Boc	75
7b	7g	6g	H	Cl	Me	Boc	90
8b	7h	6h	H	H	Me	Ac	–c

^a Reaction conditions: Zn (15 equiv), HBr (30 equiv), 2 h.

^b Reaction conditions: Zn (20 equiv), HBr (40 equiv), 6 h.

^c Decomposition of the product occurred.

Having established a convenient preparative method for N ¹-methyl(indol-3-yl)ethane-1,2-diamines, we focused on the total synthesis of the proposed structure for topsentin C (5a), which is related to spongotines 1 and other previously isolated topsentines. The imidazoline fragment of 5a and its analogue 5b, without a Br atom, was constructed by using the previously reported synthetic method for imidazolines that involved condensation of the vicinal diamines with aldehydes (including α-keto aldehydes) followed by oxidation of the resulting cyclic aminal.[5c] [18] The required indolylglyoxals 14a and 14b were prepared from corresponding 3-acetylindoles 15a and 15b through iodination followed by Kornblum oxidation (Scheme [4]).[19]

Scheme 4 Synthesis of spongotine analogues 5a and 5b

The aforementioned syntheses of indolylglyoxals 14a and 14b, condensations with diamines 6c and 6e, and subsequent oxidations to imidazolines 16a and 16b were carried out in one pot. This made the developed procedure attractive for preparative reactions. The protecting group could be removed to afford 5a and 5b. As it turned out, the spectral characteristics of 5a synthesized by us and the characteristics of topsentin C that was isolated from the natural source, differed dramatically. Therefore, the initially proposed structure of topsentin C had to be revised. Thus, the synthesized 5a was a methylated spongotine C derivative that has not yet been observed in nature. The developed method enables analogues of spongotines and top­sentins to be synthesized to study their biological properties, which are known to change abruptly if even a single methyl is added to the molecule.[17]

We assumed that natural topsentin C was structurally related to hamacanthins A (3) but not spongotines (1), and was the 1-methyl derivative of hamacanthin A 17a (Figure [3]),[20] which should have a set of NMR signals similar to that of 5a.

Figure 3 Revised structure of topsentin C

Scheme 5 Synthesis of topsentin C and its analogue

Scheme 6 Mechanism of dihydropyrazinone ring formation

We synthesized bis(indolyl)dihydropyrazinones 17a and 17b through cyclization of diamines 6e and 6c with indoleglyoxylic acid chlorides 18a and 18b to confirm this hypothesis (Scheme [5]).

Table 4 ¹H NMR Data for Natural Topsentin C and for Compounds 17a and 5a ^a

1H	17a	Topsentin C3	5a
N(1)CH3	3.04 (s)	3.05 (s)	2.82 (s)
CHCHa Hb	4.26 (dd, J = 16.5, 5.5)	4.27 (dd, J = 16.5, 5.3)	3.91 (dd, J = 15.3, 10.3)
CHCHa H b	4.41 (dd, J = 16.5, 5.2)	4.41 (dd, J = 16.5, 5.2)	4.31 (dd, J = 15.3, 11.3)
CHCHaHb	5.15 (dd, J = 5.5, 5.2)	5.16 (ddd, J = 5.3, 5.2, <1)	4.89 (dd, J = 11.3, 10.3)
Indolic H
1′	10.70 (br s)	10.71 (br s)	11.37 (br s)
2′	8.62 (d, J = 2.75)	8.62 (d, J = 2.7)	8.68 (s)
4′	8.37 (d, J = 8.6)	8.37 (d, J = 8.7)	8.32 (d, J = 8.5)
5′	7.17–7.23 (m)b	7.20 (dd, J = 8.7, 1.8)	7.41 (dd, J = 8.5, 1.7)
7′	7.66 (d, J = 1.8)	7.66 (d, J = 1.8)	7.76 (d, J = 1.6)
1′′	10.34 (br s)	10.34 (br s)	10.42 (br s)
2′′	7.17–7.23 (m)b	7.22 (dd, J = 2.5, <1)	7.45 (d, J = 2.1)
4′′	7.69 (d, J = 8.6)	7.69 (d, J = 8.5)	7.63 (d, J = 8.5)
5′′	7.17–7.23 (m)b	7.20 (dd, J = 8.5, 1.7)	7.17 (dd, J = 8.5, 1.7)
7′′	7.63 (d, J = 1.7)	7.63 (d, J = 1.7)	7.65 (d, J = 1.6)

^a Recorded in acetone-d ₆; shift in ppm, coupling in Hz.

^b Double resonance experiments and COSY gave the same interpretation of these signals as shown for natural topsentin C (see the Supporting Information).

Acid chlorides 18a and 18b were obtained through acylation of the corresponding indoles by using oxalylchloride according to published methods.[6k] The reaction first gave a mixture of amides 19 and 20, which were further cyclized without isolation (Scheme [6]). As noted earlier during the development of synthetic methods for hamacanthins, these amides can undergo reversible transformations under the cyclization conditions via intermediate 21, and can form a mixture of isomeric bis(indolyl)dihydropyrazinones.[6b] In this case, the cyclization was unidirectional because of the methyl group, so that 22a and 22b were isolated only.[21] These compounds were converted into target 17a and 17b by removing the protecting group. The structure of compound 17a was established by X-ray crystallographic analysis (Figure [4]).

Figure 4 Molecular structure of 17a presented as ADP ellipsoids at 50% probability

The spectral characteristics of bis(indolyl)dihydropyrazinone 17a were consistent with those of natural topsentin C,[3] [22] in contrast to imidazoline 5a (Table [4]). This data confirmed our hypothesis regarding the structure of the natural topsentin C.

Thus, we have developed a convenient preparative synthetic method to prepare (indol-3-yl)ethane-1,2-diamines and found that the natural topsentin C has the structure 17a. The total synthesis of racemic 17a was carried out in seven steps from 6-bromoindole 9c in 55% overall yield.

Starting reagents were either purchased from commercial sources and used without additional purification or were prepared according to reported procedures. ¹H and ¹³C NMR spectra were acquired with 400, 500, or 600 MHz spectrometers at r.t. and referenced to the residual signals of the solvent (for ¹H and ¹³C). The solvents for NMR samples were DMSO-d ₆, CDCl₃, and acetone-d ₆. Chemical shifts are reported in parts per million (δ, ppm). Coupling constants are reported in Hertz (J, Hz). The peak patterns are indicated as: s, singlet; d, doublet; t, triplet; q, quadruplet; m, multiplet; dd, doublet of doublets; br s, broad singlet. Signal assignment was based on COSY, HSQC, HMBC and NOESY experiments. Infrared spectra were measured with an Infralum FT-801 FT/IR instrument. The wavelengths are reported in reciprocal centimeters (ν_max, cm^–1). Mass spectra were recorded with LCMS-8040 triple quadrupole liquid chromatograph mass-spectrometer from Shimadzu (ESI) and Kratos MS-30 mass spectrometer (EI, 70 eV). Elemental analysis was performed with an Euro Vector EA-3000 elemental analyzer. The X-ray data collection of 17a was performed with a Bruker APEX-II CCD diffractometer at 120 K. Details of the X-ray structure determination are given in the Supporting Information. The progress of the reaction was monitored by TLC and the spots were visualized under UV light (254 or 365 nm). Column chromatography was performed using silica gel (230–400 mesh). Melting points were determined with a SMP-10 apparatus and are uncorrected. Solvents were distilled and dried according to standard procedures.

tert-Butyl 3-[(E)-2-Nitrovinyl]-1H-indole-1-carboxylate (9a)[23]

SOCl₂ (13.7 mL, 0.188 mol) at 0–5 °C was added dropwise to anhydrous DMF (14.6 mL, 0.188 mol) and the solution was stirred at r.t. for 30 min. The resulting mixture was degassed under vacuum and the residue was diluted with anhydrous DMF (26 mL) and treated with a solution of indole (20.0 g, 0.171 mol) in DMF (10 mL) dropwise at 0–5 °C over 10 min. The mixture was stirred at r.t. for 40 min, then treated with ice (100 g) and NaOH solution (30%) was added until pH ca. 8. The mixture was heated to reflux, and cooled. The resulting precipitate was filtered off, rinsed with H₂O (5×), dried in air, heated at reflux in EtOH (40 mL), cooled, filtered off again, and dried in air to afford 1H-indole-3-carbaldehyde (22.5 g, 91%).

A solution of 1H-indole-3-carbaldehyde (12.5 g, 0.086 mol) and NH₄OAc (6.6 g, 0.086 mmol) in CH₃NO₂ (46 mL, 0.861 mol) was heated at reflux for 45 min, cooled to r.t., and diluted with H₂O (150 mL). The resulting precipitate was filtered off, washed with H₂O (5×), dried on air, heated at reflux in EtOH (60 mL), cooled, filtered off again and dried on air to afford 3-[(E)-2-nitrovinyl]-1H-indole (11.3 g, 70%).

To a solution of 3-[(E)-2-nitrovinyl]-1H-indole (5.6 g, 30 mmol) and DMAP (0.37 g, 3.0 mmol) in anhydrous THF (30 mL) was added dropwise a solution of Boc₂O (9.9 g, 45.4 mmol) in anhydrous THF (30 mL) at 0–5 °C over a period of 15 min. The reaction mixture was stirred at r.t. for 3 h, and concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (100 mL), washed with citric acid solution (10%, 30 mL), H₂O (30 mL), and concd NaCl solution (20 mL), then dried over anhydrous Na₂SO₄. The CH₂Cl₂ was evaporated in vacuo and the residue was heated at reflux in MeOH (30 mL) and cooled. The resulting precipitate was filtered off, washed twice with cold hexane, and dried on air to afford tert-butyl 3-[(E)-2-nitrovinyl]-1H-indole-1-carboxylate.

Yield: 7.6 g (55% from indole); yellow solid; mp 144–145 °C (MeOH).

¹H NMR (600 MHz, DMSO-d ₆): δ = 8.55 (s, 1 H), 8.36 (d, J = 13.7 Hz, 1 H, CH=CHNO₂), 8.19 (d, J = 13.7 Hz, 1 H, CH=CHNO₂), 8.11 (d, J = 8.1 Hz, 1 H), 8.02 (d, J = 7.1 Hz, 1 H), 7.40–7.46 (m, 1 H), 7.33–7.39 (m, 1 H), 1.64 (s, 9 H, C(CH₃)₃).

¹³C NMR (150 MHz, DMSO-d ₆): δ = 148.79, 136.50, 136.06, 134.27, 132.37, 127.15, 126.14, 124.54, 121.40, 115.67, 112.76, 85.72, 28.08 (3С).

tert-Butyl 5-Bromo-3-[(E)-2-nitrovinyl]-1H-indole-1-carboxylate (9b); Typical Procedure

5-Bromoindole (1.35 g, 6.9 mmol) was formylated as described for 1H-indole-3-carbaldehyde to produce 6-bromo-1H-indole-3-carbaldehyde (1.50 g, 97%) with the exception that the obtained product was not purified by refluxing in EtOH.

5-Bromo-1H-indole-3-carbaldehyde (1.50 g, 6.7 mmol) and NH₄OAc (0.52 g, 6.7 mmol) were heated at reflux in CH₃NO₂ (18 mL, 335 mmol) for 45 min, cooled to r.t., and treated with H₂O (70 mL). The product was extracted with EtOAc (70 mL), washed with H₂O (5 × 50 mL) and NaCl solution (20 mL), and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo to afford 6-bromo-3-[(E)-2-nitrovinyl]-1H-indole (1.72 g, 96%, brownish crystals), which was dried in vacuo and used without further purification.

A suspension of 5-bromo-3-[(E)-2-nitrovinyl]-1H-indole (1.72 g, 6.4 mmol) and DMAP (0.08 g, 0.64 mmol) in anhydrous THF (7 mL) was treated with a solution of Boc₂O (2.1 g, 9.7 mmol) in anhydrous THF (7 mL) dropwise at 0–5 °C over a period of 15 min, stirred at r.t. for 3 h, and concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (50 mL), washed with citric acid solution (10%, 20 mL), H₂O (20 mL), and concd NaCl solution (15 mL), and dried over anhydrous Na₂SO₄. The CH₂Cl₂ was evaporated in vacuo and the residue was purified by chromatography on a column of silica gel (EtOAc–hexane, 6:1) to provide tert-butyl 5-bromo-3-[(E)-2-nitrovinyl]-1H-indole-1-carboxylate.

Yield: 2.11 g (83% from 5-bromoindole); pale-yellow solid; mp 156–157 °C (MeOH); R_f = 0.55 (EtOAc–hexane, 1:8).

IR (film): 3130, 2983, 2300 w, 1741 s (CO), 1639, 1509, 1452, 1368, 1344, 1240, 1153, 1107, 956, 853, 803, 764, 649, 613, 579 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.57 (s, 1 H), 8.33 (d, J = 13.7 Hz, 1 H, CH=CHNO₂), 8.27 (d, J = 1.9 Hz, 1 H), 8.26 (d, J = 13.7 Hz, 1 H, CH=CHNO₂), 8.02 (d, J = 8.8 Hz, 1 H), 7.56 (dd, J = 8.8, 1.9 Hz, 1 H), 1.65 (s, 9 H, C(CH₃)₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 147.89, 136.57, 134.27, 133.94, 130.89, 128.52, 128.16, 123.08, 116.83, 116.76, 111.47, 85.53, 27.48 (3С).

MS (EI, 70 eV): m/z (%) = 368/366 (4) [M]⁺, 312/310 (7) [M – C₄H₈]⁺, 268/266 (31) [M – C₄H₈ – CO₂]⁺, 219 (21), 140 (30), 57 (100).

Anal. Calcd for C₁₅H₁₅BrN₂O₄: C, 49.06; H, 4.12; N, 7.63. Found: C, 49.19; H, 4.15; N, 7.55.

tert-Butyl 6-Bromo-3-[(E)-2-nitrovinyl]-1H-indole-1-carboxylate (9c)

Yield: 2.15 g (85% from 6-bromoindole); pale-yellow solid; mp 124–126 °C (MeOH; R_f = 0.62 (EtOAc–hexane, 1:8).

IR (film): 3129, 2985, 2300 w, 1740 s (CO), 1635, 1505, 1427, 1341, 1299, 1238, 1144, 1106, 965, 842, 808, 764, 726, 650, 591 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.43 (s, 1 H), 8.12 (d, J = 13.6 Hz, 1 H, CH=CHNO₂), 7.98 (s, 1 H), 7.71 (d, J = 13.6 Hz, 1 H, CH=CHNO₂), 7.54 (d, J = 8.3 Hz, 1 H), 7.48 (dd, J = 8.3, 1.7 Hz, 1 H), 1.71 (s, 9 H, C(CH₃)₃).

¹³C NMR (150 MHz, CDCl₃): δ = 148.29, 137.09, 136.22, 132.14, 130.97, 127.58, 125.79, 121.20, 119.87, 119.27, 112.37, 86.27, 28.15 (3С).

MS (EI, 70 eV): m/z (%) = 368/366 (7) [M]⁺, 312/310 (11) [M – C₄H₈]⁺, 268/266 (40) [M – C₄H₈ – CO₂]⁺, 221 (18), 140 (21), 57 (100).

Anal. Calcd for C₁₅H₁₅BrN₂O₄: C, 49.06; H, 4.12; N, 7.63. Found: C, 49.24; H, 4.19; N, 7.60.

tert-Butyl 5-Methoxy-3-[(E)-2-nitrovinyl]-1H-indole-1-carboxylate (9d)

Yield: 1.73 g (79% from 5-methoxyindole); yellow solid; mp 153–154 °C (MeOH); R_f = 0.52 (EtOAc–hexane, 1:8).

IR (film): 3139, 2982, 2945, 2296 w, 1732 s (CO), 1633, 1544, 1500, 1374, 1325, 1251, 1161, 1097, 1024, 969, 834, 800, 765, 640, 592 cm^–1.

¹H NMR (600 MHz, DMSO-d ₆): δ = 8.52 (s, 1 H), 8.37 (d, J = 13.6 Hz, 1 H, CH=CHNO₂), 8.24 (d, J = 13.6 Hz, 1 H, CH=CHNO₂), 7.98 (d, J = 9.0 Hz, 1 H), 7.45 (d, J = 2.6 Hz, 1 H), 7.01 (dd, J = 9.0, 2.6 Hz, 1 H), 3.86 (s, 3 H, OCH₃), 1.64 (s, 9 H, C(CH₃)₃).

¹³C NMR (150 MHz, DMSO-d ₆): δ = 156.54, 148.24, 135.93, 133.46, 131.80, 129.90, 127.84, 115.87, 114.40, 112.13, 103.33, 85.04, 55.73, 27.56 (3С).

MS (EI, 70 eV): m/z (%) = 319 (8), 318 (41) [M]⁺, 263 (17), 262 (81) [M – C₄H₈]⁺, 219 (23), 218 (28) [M – C₄H₈ – CO₂]⁺, 186 (31), 175 (69), 156 (29), 57 (100).

Anal. Calcd for C₁₆H₁₈N₂O₅: C, 60.37; H, 5.70; N, 8.80. Found: C, 60.28; H, 5.76; N, 8.79.

tert-Butyl 6-Chloro-3-[(E)-2-nitrovinyl]-1H-indole-1-carboxylate (9e)

Yield: 1.71 g (77% from 6-chloroindole); mp 130–132 °C (MeOH); R_f = 0.62 (EtOAc–hexane, 1:8).

IR (film): 3131, 2983, 2294 w, 1741 s (CO), 1634, 1508, 1431, 1340, 1299, 1240, 1145, 1103, 968, 845, 810, 762, 732, 660, 599 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 8.54 (s, 1 H), 8.32 (d, J = 13.7 Hz, 1 H, CH=CHNO₂), 8.17 (d, J = 13.7 Hz, 1 H, CH=CHNO₂), 8.08 (d, J = 1.7 Hz, 1 H), 8.04 (d, J = 8.6 Hz, 1 H), 7.36 (dd, J = 8.6, 1.7 Hz, 1 H), 1.65 (s, 9 H, C(CH₃)₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 147.85, 136.40, 135.86, 133.93, 131.10, 130.14, 125.40, 123.99, 122.14, 114.88, 111.96, 85.68, 27.45 (3С).

MS (EI, 70 eV): m/z (%) = 324 (14)/322 (42) [M]⁺, 268 (9)/266 (27) [M – C₄H₈]⁺, 224 (16)/222 (55) [M – C₄H₈ – CO₂]⁺, 179 (26), 174 (26), 113 (97), 57 (100).

Anal. Calcd for C₁₅H₁₅ClN₂O₄: C, 55.82; H, 4.68; N, 8.68. Found: C, 55.70; H, 4.73; N, 8.63.

tert-Butyl 3-{1-[(Benzyloxy)amino]-2-nitroethyl}-5-bromo-1H-indole-1-carboxylate (11)

To a solution of 5-bromo-3-[(E)-2-nitrovinyl]-1H-indole (0.55 g, 1.5 mmol) in anhydrous THF (3 mL), O-benzylhydroxylamine (0.19 g, 1.6 mmol) was added. The mixture was stirred at r.t. for 1 h and allowed to stand overnight. After removing the volatile components in vacuo, the adduct 11 was obtained.

Yield: 0.74 g (ca. 100%); viscous amber oil; R_f = 0.53 (EtOAc–hexane, 1:8).

IR (film): 3253, 2980, 2931, 1738 s (CO), 1554, 1451, 1373, 1278, 1154, 1057, 843, 805, 750, 699, 609 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.03 (d, J = 8.9 Hz, 1 H), 7.75 (d, J = 1.9 Hz, 1 H), 7.58 (s, 1 H), 7.44 (dd, J = 8.9, 1.9 Hz, 1 H), 7.30–7.40 (m, 5 H, Ph), 5.84 (br s, 1 H, NH), 4.93–5.05 (m, 2 H, CHCH_aH_b + CHCH_a H _b), 4.67–4.74 (m, 2 H, CH ₂Ph), 4.65 (dd, J = 11.2, 4.2 Hz, 1 H, CHCH _aH_b), 1.67 (s, 9 H, OC(CH₃)₃).

¹³C NMR (125 MHz, CDCl₃): δ = 148.88, 136.92, 134.18, 130.03, 128.75, 128.48, 128.20, 127.94, 125.45, 122.16, 116.90, 116.36, 114.49, 84.78, 77.08, 76.40, 55.70, 28.09.

MS (ESI): m/z = 492/490 [M + H]⁺.

Anal. Calcd for C₂₂H₂₄BrN₃O₅: C, 53.89; H, 4.93; N, 8.57. Found: C, 54.01; H, 5.00; N, 8.58.

Addition of O-Pivaloylhydroxylamines 8a,b to Nitrovinylindoles 9a–f; General Procedure

The hydrochloride salt of the corresponding O-pivaloylhydroxylamine (6 mmol) was dissolved in CH₂Cl₂ (20 mL) and carefully shaken with saturated aqueous NaHCO₃ solution, then the organic phase was washed with concd NaCl solution and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo at 30 °C and the resulting O-pivaloylhydroxylamine (ca. 5.2 mmol) was carefully mixed with nitrovinylindole (3.5 mmol) in a round-bottom vial and allowed to stand overnight at r.t. The reaction mixture was triturated with hexane (7 mL) and the resulting crystals of adducts 7a–h were filtered, washed with cold hexane (2 × 4 mL), and dried in vacuo.

tert-Butyl 3-{1-[(Pivaloyloxy)amino]-2-nitroethyl}-1H-indole-1-carboxylate (7a)

Yield: 1.33 g (94%); light-brown solid; mp 109–111 °C (hexane); R_f = 0.46 (EtOAc–hexane, 1:8).

IR (film): 3229, 2977, 2936, 1746 s (CO), 1727 s (CO), 1555, 1452, 1371, 1278, 1235, 1154, 1085, 822, 762, 661, 594 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.19 (d, J = 8.1 Hz, 1 H), 7.89 (d, J = 3.5 Hz, 1 H, NH), 7.70 (d, J = 7.7 Hz, 1 H), 7.67 (s, 1 H), 7.39 (dd, J = 8.1, 7.3 Hz, 1 H), 7.31 (dd, J = 7.7, 7.3 Hz, 1 H), 5.14–5.26 (m, 1 H, CHCH_aH_b), 5.01 (dd, J = 12.9, 8.0 Hz, 1 H, CHCH_a H _b), 4.75 (dd, J = 12.9, 4.5 Hz, 1 H, CHCH _aH_b), 1.68 (s, 9 H, OC(CH₃)₃), 1.24 (s, 9 H, C(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 178.21, 149.15, 135.48, 127.82, 125.36, 124.60, 123.23, 118.99, 115.61, 113.38, 84.51, 78.04, 56.25, 38.44, 28.15 (3C), 26.90 (3С).

MS (ESI): m/z = 406 [M + H]⁺, 345 [M – CH₃NO₂ + H]⁺, 304 [M – (CH₃)₃CO₂H + H]⁺.

Anal. Calcd for C₂₀H₂₇N₃O₆: C, 59.25; H, 6.71; N, 10.36. Found: C, 59.31; H, 6.73; N, 10.11.

tert-Butyl 3-{1-[(Pivaloyloxy)amino]-2-nitroethyl}-5-bromo-1H-indole-1-carboxylate (7b)

Yield: 1.62 g (96%); white solid; mp 108–109 °C (hexane); R_f = 0.39 (EtOAc–hexane, 1:8).

IR (film): 3260, 2974, 2935, 1728 s (CO), 1557, 1453, 1378, 1276, 1157, 1092, 1057, 872, 805, 778, 662, 604 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.07 (d, J = 8.8 Hz, 1 H), 7.84 (d, J = 1.8 Hz, 1 H), 7.66 (s, 1 H), 7.47 (dd, J = 8.8, 1.8 Hz, 1 H), 7.89 (br s, 1 H, NH), 5.11 (dd, J = 7.7, 4.8 Hz, 1 H, CHCH_aH_b), 4.99 (dd, J = 12.8, 7.7 Hz, 1 H, CHCH_a H _b), 4.72 (dd, J = 12.8, 4.8 Hz, 1 H, CHCH _aH_b), 1.67 (s, 9 H, OC(CH₃)₃), 1.24 (s, 9 H, C(O)C(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 178.26, 148.84, 134.37, 129.59, 128.39, 125.86, 121.98, 117.14, 116.75, 112.91, 85.13, 77.87, 56.20, 38.54, 28.19 (3C), 27.00 (3C).

MS (ESI): m/z = 486/484 [M + H]⁺, 425/423 [M – CH₃NO₂ + H]⁺, 384/382 [M – (CH₃)₃CO₂H + H]⁺.

Anal. Calcd for C₂₀H₂₆BrN₃O₆: C, 49.60; H, 5.41; N, 8.68. Found: C, 49.71; H, 5.50; N, 8.53.

tert-Butyl 3-{1-[(Pivaloyloxy)(methyl)amino]-2-nitroethyl}-1H-indole-1-carboxylate (7c)

Yield: 1.42 g (97%); light-beige solid; mp 113 °C (hexane); R_f = 0.47 (EtOAc–hexane, 1:8).

IR (film): 2977, 2931, 1754 s (CO), 1737 s (CO), 1557, 1452, 1378, 1248, 1153, 1103, 1075, 1026, 845, 750, 702, 659 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.18 (d, J = 7.7 Hz, 1 H), 7.81 (d, J = 7.7 Hz, 1 H), 7.69 (s, 1 H), 7.38 (dd, J = 8.1, 7.3 Hz, 1 H), 7.31 (dd, J = 7.8, 7.7 Hz, 1 H), 5.08 (dd, J = 7.4, 5.6 Hz, 1 H, CHCH_aH_b), 5.00 (dd, J = 12.7, 7.4 Hz, 1 H, CHCH_a H _b), 4.65 (dd, J = 12.7, 5.6 Hz, 1 H, CHCH _aH_b), 2.68 (s, 3 H, NCH₃), 1.69 (s, 9 H, OC(CH₃)₃), 1.26 (s, 9 H, C(O)C(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 175.96, 149.16, 135.30, 128.65, 125.22, 124.99, 123.24, 119.51, 115.36, 113.78, 84.38, 77.17, 62.04, 43.84, 38.67, 28.10 (3C), 27.05 (3C).

MS (ESI): m/z = 420 [M + H]⁺, 318 [M – (CH₃)₃CO₂H + H]⁺.

Anal. Calcd for C₂₁H₂₉N₃O₆: C, 60.13; H, 6.97; N, 10.02. Found: C, 60.27; H, 7.03; N, 10.00.

tert-Butyl 3-{1-[(Pivaloyloxy)(methyl)amino]-2-nitroethyl}-5-bromo-1H-indole-1-carboxylate (7d)

Yield: 1.55 g (89%); amorphous amber solid; R_f = 0.53 (EtOAc–hexane, 1:8).

IR (film): 2977, 2933, 1744 s (CO), 1602, 1559, 1451, 1370, 1276, 1153, 1092, 1057, 842, 807, 767, 679, 609 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.07 (br s, 1 H), 7.93 (d, J = 1.7 Hz, 1 H), 7.68 (s, 1 H), 7.47 (dd, J = 9.0, 1.7 Hz, 1 H), 4.95–5.03 (m, 2 H, CHCH_aH_b + CHCH_a H _b), 4.63 (dd, J = 11.6, 5.0 Hz, 1 H, CHCH _aH_b), 2.67 (s, 3 H, NCH₃), 1.68 (s, 9 H, OC(CH₃)₃), 1.26 (s, 9 H, C(O)C(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 175.79, 148.76, 134.11, 130.37, 128.20, 126.17, 122.20, 116.87, 116.71, 113.16, 84.94, 77.00, 61.86, 43.83, 38.66, 28.08 (3C), 27.07 (3C).

MS (ESI): m/z = 500/498 [M + H]⁺, 398/396 [M – (CH₃)₃CO₂H + H]⁺.

Anal. Calcd for C₂₁H₂₈BrN₃O₆: C, 50.61; H, 5.66; N, 8.43. Found: C, 50.90; H, 5.81; N, 8.25.

tert-Butyl 3-{1-[(Pivaloyloxy)(methyl)amino]-2-nitroethyl}-6-bromo-1H-indole-1-carboxylate (7e)

Yield: 1.70 g (98%); light-beige solid; mp 115–116 °C (hexane); R_f = 0.39 (EtOAc–hexane, 1:8).

IR (film): 2976, 2933, 1762 s (CO), 1727 s (CO), 1561, 1433, 1370, 1255, 1152, 1097, 865, 818, 772, 679, 590 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.40 (s, 1 H), 7.70 (d, J = 8.3 Hz, 1 H), 7.64 (s, 1 H), 7.42 (dd, J = 8.3, 1.7 Hz, 1 H), 5.02 (dd, J = 7.4, 5.8 Hz, 1 H, CHCH_aH_b), 4.98 (dd, J = 12.4, 7.4 Hz, 1 H, CHCH_a H _b), 4.63 (dd, J = 12.7, 5.8 Hz, 1 H, CHCH _aH_b), 2.66 (s, 3 H, NCH₃), 1.69 (s, 9 H, OC(CH₃)₃), 1.26 (s, 9 H, C(O)C(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 175.92, 148.72, 136.02, 127.39, 126.53, 125.29, 120.84, 119.09, 118.61, 113.91, 85.01, 77.00, 62.02, 43.70, 38.64, 28.03 (3C), 27.02 (3C).

MS (ESI): m/z = 522/520 [M + Na]⁺.

Anal. Calcd for C₂₁H₂₈BrN₃O₆: C, 50.61; H, 5.66; N, 8.43. Found: C, 50.73; H, 5.72; N, 8.42.

tert-Butyl 3-{1-[(Pivaloyloxy)(methyl)amino]-2-nitroethyl}-5-methoxy­-1H-indole-1-carboxylate (7f)

Yield: 1.43 (91%); yellow solid; mp 96 °C (hexane); R_f = 0.33 (EtOAc–hexane, 1:8).

IR (film): 2971, 2935, 1755 s (CO), 1731 s (CO), 1557, 1480, 1382, 1286, 1157, 1098, 1070, 849, 807, 767, 677, 626 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.04 (br s, 1 H), 7.64 (s, 1 H), 7.28 (d, J = 1.7 Hz, 1 H), 6.97 (dd, J = 9.0, 1.7 Hz, 1 H), 5.02 (dd, J = 7.4, 5.0 Hz, 1 H, CHCH_aH_b), 4.98 (dd, J = 12.4, 7.4 Hz, 1 H, CHCH_a H _b), 4.63 (dd, J = 12.4, 5.0 Hz, 1 H, CHCH _aH_b), 3.90 (s, 3 H, OCH₃), 2.68 (s, 3 H, NCH₃), 1.67 (s, 9 H, OC(CH₃)₃), 1.25 (s, 9 H, C(O)C(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 175.89, 156.27, 149.14, 130.00, 129.53, 125.39, 116.13, 114.07, 113.70, 102.11, 84.21, 77.00, 62.13, 55.78, 43.71, 38.66, 28.12 (3C), 27.06 (3C).

MS (ESI): m/z = 450 [M + H]⁺, 348 [M – (CH₃)₃CO₂H + H]⁺.

Anal. Calcd for C₂₂H₃₁N₃O₇: C, 58.78; H, 6.95; N, 9.35. Found: C, 58.89; H, 7.00; N, 9.23.

tert-Butyl 3-{1-[(Pivaloyloxy)(methyl)amino]-2-nitroethyl}-6-chloro-1H-indole-1-carboxylate (7g)

Yield: 1.54 (97%); light-brown solid; mp 108–109 °C (hexane); R_f = 0.39 (EtOAc–hexane, 1:8).

IR (film): 2976, 2906, 1754 s (CO), 1744 s (CO), 1562, 1439, 1368, 1256, 1157, 1100, 866, 817, 761, 661, 600 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.21 (s, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.65 (s, 1 H), 7.27 (dd, J = 8.5, 1.7 Hz, 1 H), 4.92–5.02 (m, 2 H, CHCH_aH_b + CHCH_a H _b), 4.63 (dd, J = 12.1, 5.3 Hz, 1 H, CHCH _aH_b), 2.66 (s, 3 H, NCH₃), 1.68 (s, 9 H, OC(CH₃)₃), 1.25 (s, 9 H, C(O)C(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 175.91, 148.75, 135.75, 131.35, 127.04, 125.38, 123.86, 120.53, 115.70, 113.92, 84.98, 77.00, 62.09, 43.68, 38.65, 28.04 (3C), 27.02 (3C).

MS (ESI): m/z = 456/454 [M + H]⁺, 354/352 [M – (CH₃)₃CO₂H + H]⁺.

Anal. Calcd for C₂₁H₂₈ClN₃O₆: C, 55.57; H, 6.22; N, 9.26. Found: C, 55.69; H, 6.28; N, 9.21.

1-Acetyl-3-{1-[(pivaloyloxy)(methyl)amino]-2-nitroethyl}-1H-indole (7h)

Yield: 1.11 g (88%); light-orange solid; mp 84–85 °C (hexane); R_f = 0.15 (EtOAc–hexane, 1:8).

IR (film): 2973, 2937, 2910, 2874, 1753 s (CO), 1715 s (CO), 1553, 1451, 1386, 1313, 1225, 1125, 1077, 1023, 939, 755, 672, 641, 564 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.44 (br d, J = 8.3 Hz, 1 H), 7.83 (d, J = 7.4 Hz, 1 H), 7.55 (s, 1 H), 7.38–7.43 (m, 1 H), 7.32–7.37 (m, 1 H), 5.07 (dd, J = 7.4, 5.8 Hz, 1 H, CHCH_aH_b), 4.98 (dd, J = 12.8, 7.4 Hz, 1 H, CHCH_a H _b), 4.66 (dd, J = 12.8, 5.8 Hz, 1 H, CHCH _aH_b), 2.70 (s, 3 H, C(O)CH₃ or NCH₃), 2.66 (s, 3 H, C(O)CH₃ or NCH₃), 1.25 (s, 9 H, C(O)C(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 175.98, 168.27, 135.76, 128.36, 126.16, 124.28, 124.22, 119.58, 116.69, 116.11, 77.14, 62.39, 44.09, 38.68, 27.00 (3C), 23.92.

MS (ESI): m/z = 362 [M + H]⁺, 260 [M – (CH₃)₃CO₂H + H]⁺.

Anal. Calcd for C₁₈H₂₃N₃O₅: C, 59.82; H, 6.41; N, 11.63. Found: C, 60.00; H, 6.48; N, 11.58.

Catalytic Hydrogenation of Adduct 11

To a solution of adduct 11 (0.54 g, 1.1 mmol) in MeOH (10 mL) was added AcOH (9.5 mL, 1.165 mol) and 5% Pd on charcoal (0.05 g) and the mixture was purged with hydrogen. The mixture was vigorously stirred under a hydrogen atmosphere (1 atm) for 18 h, filtered, and concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (50 mL), treated with cold NaOH solution (10%, 40 mL) and concd NaCl solutions (20 mL), and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the residue was purified by chromatography on a column of silica gel (CHCl₃–MeOH–NH_3(aq), 100:10:0.2) to afford diamine 7b (0.206 g, 68 %). Its characteristics correspond to the sample obtained from adduct 9a (see below).

Reduction of Adduct 11 with Zn Dust

To a solution of adduct 11 (0.54 g, 1.1 mmol) in MeOH (10 mL) was added AcOH (9.5 mL, 1.165 mol) and Zn dust (1.44 g, 22 mmol). The mixture was vigorously stirred at r.t. for 2 h, and then another portion of Zn dust (1.43 g, 22 mmol) was added. The resulting mixture was vigorously stirred further for 12 h, filtered, and concentrated in vacuo. The residue was dissolved in CH₂Cl₂ (100 mL), treated with chipped ice (10 g), and carefully shaken with cold NaOH solution (10%, 90 mL). The organic layer was separated and washed with cold NaOH (10%, 30 mL) and concd NaCl solutions (20 mL), and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the residue was purified by chromatography on a column of silica gel with gradient of MeOH in CHCl₃ to afford compound 12.

Yield: 0.27 g (53%); pale-yellow oil.

IR (film): 3378 br, 2978, 2931, 2866, 1736 s, (CO), 1603, 1451, 1371, 1256, 1155, 1054, 842, 803, 750, 698, 611 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.03 (m, 1 H), 7.81 (d, J = 1.8 Hz, 1 H), 7.55 (s, 1 H), 7.41 (dd, J = 8.8, 1.8 Hz, 1 H), 7.28–7.36 (m, 5 H, Ph), 6.02 (br s, 1 H, NH), 4.64–4.70 (m, 2 H, CH ₂Ph), 4.19–4.24 (m, 1 H, CHCH₂), 3.07–3.13 (m, 2 H, CHCH ₂), 1.67 (s, 9 H, OC(CH₃)₃), 1.47 (br s, 2 H, NH₂).

¹³C NMR (150 MHz, CDCl₃): δ = 149.20, 137.62, 134.28, 131.10, 128.54, 128.31, 127.85, 127.33, 124.77, 122.60, 118.24, 116.70, 115.90, 84.18, 76.73, 59.96, 43.26, 28.12 (3C).

MS (ESI): m/z = 462/460 [M + H]⁺.

Anal. Calcd for C₂₂H₂₆BrN₃O₃: C, 57.40; H, 5.69; N, 9.13. Found: C, 57.37; H, 5.61; N, 9.04.

After the chromatography, diamine 7b (5.8 mg, 15%) was also isolated. The analytical data was in accordance with the characteristics of the sample obtained from adduct 9b (see below).

Synthesis of (Indol-3-yl)ethane-1,2-diamines 6; General Procedure A

A solution of adduct 7 (2.2 mmol) in EtOAc (8.3 mL) was added to a cooled (–10 °C) mixture of MeOH (16.5 mL) and HBr (40%, 5.5 mL, 37.8 mmol) under vigorous stirring and treated with Zn dust (2.2 g, 33 mmol). The reaction mixture was allowed to warm to 0–5 °C (1 h), stirred at that temperature for 1 h, and filtered. The precipitate was filtered off and rinsed with a small amount of MeOH. The filtrate was diluted with CH₂Cl₂ (100 mL), treated with crushed ice (10 g), and carefully shaken with cold NaOH solution (10%, 90 mL). The organic layer was separated and the aqueous layer was washed with CH₂Cl₂ (20 mL). The combined organic extracts were washed with cold NaOH (10%, 30 mL) and concd NaCl solutions (20 mL), and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo to afford target diamine 6 as a yellowish oil. The product was pure enough for further syntheses. Chromatographic purification on a column with silica gel (CHCl₃–MeOH–NH_3(aq), 100:10:0.2) was performed, if necessary.

Synthesis of (Indol-3-yl)ethane-1,2-diamines 6; General Procedure B

A solution of adduct 7 (2.2 mmol) in EtOAc (13 mL) was added to a cooled (–10 °C) mixture of MeOH (26 mL) and HBr (40%, 13 mL, 89.0 mmol) under vigorous stirring and treated with Zn dust (1.44 g, 22 mmol). The mixture was allowed to warm to 0 °C (1 h), then another portion of Zn dust (1.44 g, 22 mmol) was added. The reaction mixture was stirred further at 0–5 °C for 5 h, and filtered. The precipitate was rinsed with a small amount of MeOH and the filtrate was diluted with CH₂Cl₂ (100 mL), treated with crushed ice (10 g), and shaken carefully with cold NaOH solution (10%, 120 mL). General Procedure A was then followed.

1-[(1-tert-Butoxycarbonyl)-1H-indol-3-yl]ethane-1,2-diamine (6a)

Obtained by following General Procedure A.

Yield: 0.51 g (84%); pale-yellow viscous oil; R_f = 0.30 (CHCl₃–MeOH–NH_3(aq), 10:1:0.02).

IR (film): 3365 br, 2978, 2932, 2868, 1729 s (CO), 1606, 1555, 1453, 1375, 1256, 1158, 1079, 856, 747, 591 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.16 (d, J = 8.2 Hz, 1 H, 7-H), 7.61 (d, J = 7.8 Hz, 1 H, 4-H), 7.54 (s, 1 H, 2-H), 7.32 (dd, J = 8.2, 7.1 Hz, 1 H, 6-H), 7.23 (dd, J = 7.8, 7.1 Hz, 1 H, 5-H), 4.23 (dd J = 6.6, 4.5 Hz, 1 H, CHCH_aH_b), 3.10 (dd, J = 12.7, 4.5 Hz, 1 H, CHCH_a H _b), 2.94 (dd, J = 12.7, 6.6 Hz, 1 H, CHCH _aH_b), 1.67 (s, 9 H, OC(CH₃)₃), 1.58 (br s, 4 H, 2NH₂).

¹³C NMR (100 MHz, CDCl₃): δ = 149.59, 135.74, 128.83, 124.43, 123.34, 122.39, 122.31, 119.17, 115.34, 83.57, 50.51, 47.94, 28.09.

MS (ESI): m/z = 276 [M + H]⁺, 259 [M – NH₃ +H]⁺.

Anal. Calcd for C₁₅H₂₁N₃O₂: C, 65.43; H, 7.69; N, 15.26. Found: C, 65.33; H, 7.73; N, 15.15.

1-[5-Bromo-(1-tert-Butoxycarbonyl)-1H-indol-3-yl]ethane-1,2-diamine (6b)

Obtained by following General Procedure A.

Yield: 0.75 g (95%); pale-yellow viscous oil; R_f = 0.35 (CHCl₃–MeOH–NH_3(aq), 10:1:0.02).

IR (film): 3368 br, 2979, 2933, 2867, 1733 s (CO), 1601, 1450, 1372, 1276, 1255, 1157, 1055, 842, 801, 765, 636 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.02 (d, J = 8.8 Hz, 1 H, 7-H), 7.76 (d, J = 2.0 Hz, 1 H, 4-H), 7.54 (s, 1 H, 2-H), 7.39 (dd, J = 8.8, 2.0 Hz, 1 H, 6-H), 4.18 (dd J = 7.0, 4.7 Hz, 1 H, CHCH_aH_b), 3.09 (dd, J = 12.7, 4.7 Hz, 1 H, CHCH_a H _b), 2.91 (dd, J = 12.7, 7.0 Hz, 1 H, CHCH _aH_b), 1.67 (br s, 4 H, 2NH₂), 1.66 (s, 9 H, OC(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 149.29, 134.60, 130.69, 127.29, 123.54, 122.82, 122.11, 116.83, 115.84, 84.08, 50.55, 48.13, 28.14 (3C).

MS (ESI): m/z = 356/354 [M + H]⁺, 339/337 [M – NH₃ + H]⁺.

Anal. Calcd for C₁₅H₂₀BrN₃O₂: C, 50.86; H, 5.69; N, 11.86. Found: C, 50.80; H, 5.75; N, 11.79.

1-[(1-tert-Butoxycarbonyl)-1H-indol-3-yl]-N ¹-methylethane-1,2-diamine (6c)

Obtained by following General Procedure B.

Yield: 0.59 g (93%); pale-yellow viscous oil; R_f = 0.34 (CHCl₃–MeOH–NH_3(aq), 10:1:0.02).

IR (film): 3366 br, 2976, 2932, 2794, 1728 s (CO), 1607, 1450, 1367, 1250, 1152, 1078, 1017, 854, 743, 665 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.17 (d, J = 8.0 Hz, 1 H, 7-H), 7.66 (d, J = 7.7 Hz, 1 H, 4-H), 7.53 (s, 1 H, 2-H), 7.33 (dd, J = 8.0, 7.4 Hz, 1 H, 6-H), 7.23 (dd, J = 7.7, 7.4 Hz, 1 H, 5-H), 3.83 (dd J = 6.4, 5.4 Hz, 1 H, CHCH_aH_b), 3.10 (dd, J = 12.7, 5.4 Hz, 1 H, CHCH_a H _b), 2.98 (dd, J = 12.7, 6.4 Hz, 1 H, CHCH _aH_b), 2.43 (s, 3 H, NCH₃), 1.68 (s, 9 H, OC(CH₃)₃), 1.43 (br s, 3 H, NH + NH₂).

¹³C NMR (100 MHz, CDCl₃): δ = 149.48, 135.68, 129.27, 124.25, 123.12, 122.23, 120.92, 119.33, 115.19, 83.39, 59.72, 46.04, 34.45, 28.00 (3C).

MS (ESI): m/z = 290 [M + H]⁺.

Anal. Calcd for C₁₆H₂₃N₃O₂: C, 66.41; H, 8.01; N, 14.52. Found: C, 66.33; H, 8.06; N, 14.45.

1-[5-Bromo-(1-tert-butoxycarbonyl)-1H-indol-3-yl]-N ¹-methyl­ethane-1,2-diamine (6d)

Obtained by following General Procedure B.

Yield: 0.70 g (86%); pale-yellow viscous oil; R_f = 0.46 (CHCl₃–MeOH–NH_3(aq), 10:1:0.02).

IR (film): 3326 br, 2934, 2791, 1733 s (CO), 1602, 1449, 1373, 1275, 1256, 1156, 1055, 802, 732, 640, 611 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.7 Hz, 1 H, 7-H), 7.81 (d, J = 1.9 Hz, 1 H, 4-H), 7.52 (s, 1 H, 2-H), 7.37 (dd, J = 8.7, 1.9 Hz, 1 H, 6-H), 3.76 (dd J = 6.7, 5.3 Hz, 1 H, CHCH_aH_b), 3.06 (dd, J = 12.8, 5.3 Hz, 1 H, CHCH_a H _b), 2.93 (dd, J = 12.8, 6.7 Hz, 1 H, CHCH _aH_b), 2.39 (s, 3 H, NCH₃), 1.69 (br s, 3 H, NH + NH₂), 1.64 (s, 9 H, OC(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 149.19, 134.55, 131.07, 127.18, 124.42, 122.24, 120.28, 116.71, 115.77, 84.01, 59.62, 46.05, 34.42, 28.07 (3C).

MS (ESI): m/z = 370/368 [M + H]⁺.

Anal. Calcd for C₁₆H₂₂BrN₃O₂: C, 52.18; H, 6.02; N, 11.41. Found: C, 52.20; H, 6.06; N, 11.34.

1-[6-Bromo-(1-tert-butoxycarbonyl)-1H-indol-3-yl]-N ¹-methyl­ethane-1,2-diamine (6e)

Obtained by following General Procedure B.

Yield: 0.74 g (92%); pale-yellow viscous oil; R_f = 0.31 (CHCl₃–MeOH–NH_3(aq), 10:1:0.02).

IR (film): 3320 br, 2977, 2935, 2792, 1736 s (CO), 1602, 1453, 1432, 1370, 1251, 1156, 1082, 810, 766, 590 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.37 (br s, 1 H, 7-H), 7.55 (d, J = 8.4 Hz, 1 H, 4-H), 7.50 (s, 1 H, 2-H), 7.33 (dd, J = 8.4, 1.7 Hz, 1 H, 5-H), 3.81 (dd J = 6.8, 5.3 Hz, 1 H, CHCH_aH_b), 3.08 (dd, J = 12.8, 5.3 Hz, 1 H, CHCH_a H _b), 2.96 (dd, J = 12.8, 6.8 Hz, 1 H, CHCH _aH_b), 2.41 (s, 3 H, NCH₃), 1.76 (br s, 3 H, NH + NH₂), 1.67 (s, 9 H, OC(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 149.23, 136.56, 128.20, 125.69, 123.79, 120.75, 120.69, 118.59, 118.25, 84.23, 59.65, 46.11, 34.43, 28.12 (3C).

MS (ESI): m/z = 370/368 [M + H]⁺.

Anal. Calcd for C₁₆H₂₂BrN₃O₂: C, 52.18; H, 6.02; N, 11.41. Found: C, 52.27; H, 6.07; N, 11.30.

1-[5-Methoxy-(1-tert-butoxycarbonyl)-1H-indol-3-yl]-N ¹-methyl­ethane-1,2-diamine (6f)

Obtained by following General Procedure B.

Yield: 0.53 g (75%); pale-yellow viscous oil; R_f = 0.34 (CHCl₃–MeOH–NH_3(aq), 10:1:0.02).

IR (film): 3325 br, 2976, 2836, 2794, 1730 s (CO), 1612, 1477, 1449, 1385, 1256, 1159, 1074, 855, 803, 732, 656 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.02 (d, J = 9.0 Hz, 1 H, 7-H), 7.51 (s, 1 H, 2-H), 7.12 (d, J = 2.5 Hz, 1 H, 4-H), 6.92 (dd, J = 9.0, 2.5 Hz, 1 H, 6-H), 3.84 (s, 3 H, OCH₃), 3.81 (dd J = 6.5, 5.5 Hz, 1 H, CHCH_aH_b), 3.09 (dd, J = 12.9, 5.5 Hz, 1 H, CHCH_a H _b), 2.97 (dd, J = 12.9, 6.5 Hz, 1 H, CHCH _aH_b), 2.42 (s, 3 H, NCH₃), 1.91 (br s, 3 H, NH + NH₂), 1.65 (s, 9 H, OC(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 155.68, 149.53, 130.52, 130.17, 123.99, 120.33, 115.99, 112.89, 102.46, 83.42, 59.54, 55.73, 45.85, 34.32, 28.13 (3C).

MS (ESI): m/z = 320 [M + H]⁺.

Anal. Calcd for C₁₇H₂₅N₃O₃: C, 63.93; H, 7.89; N, 13.16. Found: C, 63.81; H, 7.96; N, 13.10.

1-[6-Chloro-(1-tert-butoxycarbonyl)-1H-indol-3-yl]-N ¹-methyl­ethane-1,2-diamine (6g)

Obtained by following General Procedure B.

Yield: 0.655 g (92%); pale-yellow viscous oil; R_f = 0.32 (CHCl₃–MeOH–NH_3(aq), 10:1:0.02).

IR (film): 3366 br, 2978, 2937, 2796, 1737 s (CO), 1606, 1435, 1455, 1371, 1252, 11576, 1087, 812, 767, 733, 595 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.18 (br s, 1 H, 7-H), 7.57 (d, J = 8.3 Hz, 1 H, 4-H), 7.50 (s, 1 H, 2-H), 7.16 (dd, J = 8.3, 2.0 Hz, 1 H, 5-H), 3.80 (dd J = 6.7, 5.3 Hz, 1 H, CHCH_aH_b), 3.06 (dd, J = 12.8, 5.3 Hz, 1 H, CHCH_a H _b), 2.94 (dd, J = 12.8, 6.7 Hz, 1 H, CHCH _aH_b), 2.38 (s, 3 H, NCH₃), 2.01 (br s, 3 H, NH + NH₂), 1.64 (s, 9 H, OC(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 149.24, 136.24, 130.48, 127.83, 123.91, 123.01, 120.61, 120.33, 115.67, 84.21, 59.46, 45.99, 34.37, 28.12 (3C).

MS (ESI): m/z = 326/324 [M + H]⁺.

Anal. Calcd for C₁₆H₂₂ClN₃O₂: C, 59.35; H, 6.85; N, 12.98. Found: C, 59.27; H, 6.90; N, 12.91.

tert-Butyl 6-Bromo-3-{2-[(6-bromo-1H-indol-3-yl)carbonyl]-1-methyl-4,5-dihydro-1H-imidazol-5-yl}-1H-indole-1-carboxylate (16a)

A solution of 3-acetyl-6-bromoindole (0.2 g, 0.84 mmol) and I₂ (0.23 g, 0.92 mmol) in DMSO (1.7 mL) was heated for 2 h at 100 °C. The reaction mixture was cooled to 0–5 °C then treated with NaHCO₃ (0.08 g, 0.92 mmol) and a solution of diamine 6e (0.32 g, 0.86 mmol) in MeCN (8.5 mL). After stirring for 0.5 h the reaction mixture was treated with NCS (0.11 g, 0.86 mmol) under cooling (0–5 °C), stirred for 20 min, and left to stand overnight. The reaction mixture was diluted with CHCl₃ (50 mL), washed with saturated NaHCO₃ (30 mL) and Na₂S₂O₃ (30 mL) solutions, H₂O (5 × 30 mL), and concd NaCl solution (30 mL), and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the solid was purified by chromatography on a column with silica gel (СHCl₃–MeOH, 100:1) to provide the title compound.

Yield: 0.388 g (77%); brownish amorphous solid; R_f = 0.53 (СHCl₃–MeOH, 40:1).

IR (film): 3119, 2978, 2869, 1742 s (CO), 1630, 1574, 1434, 1369, 1249, 1155, 1086, 980, 810, 689, 591 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 12.14 (br s, 1 H, NH), 8.41 (br s, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 7.98 (s, 1 H), 7.62 (s, 1 H), 7.44 (s, 1 H), 7.29–7.41 (m, 3 H), 4.91 (dd J = 12.2, 10.4 Hz, 1 H, CHCH_aH_b), 4.17 (dd, J = 14.4, 12.2 Hz, 1 H, CHCH_a H _b), 3.80 (dd, J = 14.4, 10.4 Hz, 1 H, CHCH _aH_b), 2.81 (s, 3 H, NCH₃), 1.70 (s, 9 H, OC(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 180.54, 163.28, 149.06, 137.87, 137.63, 136.93, 126.62, 126.42 (2C), 124.88, 124.57, 123.46, 120.55, 118.96, 118.93, 118.39, 117.63, 115.60, 115.24, 84.82, 61.00, 58.76, 31.86, 28.16 (3C).

MS (ESI): m/z = 602/601/600 [M + H]⁺.

Anal. Calcd for C₂₆H₂₄Br₂N₄O₃: C, 52.02; H, 4.03; N, 9.33. Found: C, 52.21; H, 4.11; N, 9.21.

tert-Butyl 3-[2-(1H-Indol-3-ylcarbonyl)-1-methyl-4,5-dihydro-1H-imidazol-5-yl]-1H-indole-1-carboxylate (16b)

The compound was prepared as described above for 16a.

Yield: 0.290 (79%); light-brown amorphous solid; R_f = 0.46 (СHCl₃–MeOH, 40:1).

IR (film): 3105 br, 2979, 2932, 1737 s (CO), 1640, 1607, 1514, 1451, 1369, 1240, 1154, 1091, 749, 589 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 12.40 (br s, 1 H, NH), 8.42 (d, J = 7.9 Hz, 1 H), 8.21 (d, J = 8.3 Hz, 1 H), 7.88 (s, 1 H), 7.58–7.67 (m, 2 H), 7.34–7.41 (m, 1 H), 7.20–7.29 (m, 3 H), 7.13–7.19 (m, 1 H), 4.82 (dd J = 11.6, 10.6 Hz, 1 H, CHCH_aH_b), 4.15 (dd, J = 14.5, 11.6 Hz, 1 H, CHCH_a H _b), 3.88 (dd, J = 14.5, 10.6 Hz, 1 H, CHCH _aH_b), 2.83 (s, 3 H, NCH₃), 1.72 (s, 9 H, OC(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 180.93, 163.58, 149.51, 137.72, 137.20, 136.18, 127.99, 125.79, 124.95, 124.30, 123.97, 123.08, 123.05, 122.16, 119.58, 118.71, 115.69, 115.58, 112.29, 84.13, 61.08, 58.78, 31.86, 28.19 (3C).

MS (ESI): m/z = 443 [M + H]⁺.

Anal. Calcd for C₂₆H₂₆N₄O₃: C, 70.57; H, 5.92; N, 12.66. Found: C, 70.41; H, 5.84; N, 12.55.

tert-Butyl 6-Bromo-3-[5-(6-bromo-1H-indol-3-yl)-1-methyl-6-oxo-1,2,3,6-tetrahydropyrazin-2-yl]-1H-indole-1-carboxylate (22a)

A solution of diamine 6e (0.26 g, 0.70 mmol) in EtOH (2.6 mL) at 0–5 °C was treated portionwise with acid chloride 18a (0.20 g, 0.7 mmol) over a period of 10 min and stirred for 15 min at r.t. Anhydrous AcONa (57.4 mg, 0.7 mmol) and AcOH (0.26 mL) were then added and the reaction mixture was heated at reflux for 1.5 h. After cooling, the mixture was diluted with EtOAc (25 mL), washed with saturated NaHCO₃ (20 mL) and concd NaCl (10 mL) solutions, and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the residue was purified by chromatography on a column with silica gel (toluene–EtOAc, 3:1) to provide the title compound.

Yield: 0.302 g (72%); pale-yellow amorphous solid; R_f = 0.49 (toluene–EtOAc, 2:1).

IR (film): 3151 br, 2976, 2932, 1740 s (CO), 1650, 1590, 1434, 1369, 1252, 1154, 1088, 809, 766, 731, 589 cm^–1.

¹H NMR (600 MHz, CDCl₃): δ = 8.89 (br s, 1 H, NH), 8.47 (d, J = 2.6 Hz, 1 H), 8.35 (br s, 1 H), 8.27 (d, J = 8.8 Hz, 1 H), 7.54 (d, J = 1.8 Hz, 1 H), 7.45 (d, J = 8.4 Hz, 1 H), 7.42 (br s, 1 H), 7.40 (dd, J = 8.4, 1.8 Hz, 1 H), 7.28 (dd, J = 8.8, 1.8 Hz, 1 H), 4.96 (dd J = 5.9, 5.5 Hz, 1 H, CHCH_aH_b), 4.38 (dd, J = 16.5, 5.9 Hz, 1 H, CHCH_a H _b), 4.31 (dd, J = 16.5, 5.5 Hz, 1 H, CHCH _aH_b), 3.10 (s, 3 H, NCH₃), 1.60 (s, 9 H, OC(CH₃)₃).

¹³C NMR (125 MHz, CDCl₃): δ = 157.84, 157.21, 148.91, 136.90, 136.52, 131.99, 127.18, 126.25, 125.22, 124.65, 124.54, 124.10, 119.98, 118.94, 118.79, 117.00, 116.40, 114.11, 112.13, 84.90, 53.31, 51.87, 33.00, 28.00 (3C).

MS (ESI): m/z = 602/601/600 [M + H]⁺.

Anal. Calcd for C₂₆H₂₄Br₂N₄O₃: C, 52.02; H, 4.03; N, 9.33. Found: C, 52.24; H, 4.11; N, 9.24.

tert-Butyl 3-[5-(1H-Indol-3-yl)-1-methyl-6-oxo-1,2,3,6-tetrahydropyrazin-2-yl]-1H-indole-1-carboxylate (22b)

The compound was prepared as described for 22a.

Yield: 0.214 g (69 %); light-brown amorphous solid; R_f = 0.45 (toluene–EtOAc, 2:1).

IR (film): 3270 br, 2976, 2931, 1736 s (CO), 1650, 1590, 1453, 1371, 1310, 1256, 1155, 1088, 852, 746, 591 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.88 (br s, 1 H, NH), 8.54 (d, J = 2.6 Hz, 1 H), 8.43 (d, J = 8.7 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 7.7 Hz, 1 H), 7.45 (s, 1 H), 7.33–7.42 (m, 2 H), 7.25–7.31 (m, 1 H), 7.17–7.25 (m, 2 H), 4.98 (dd, J = 5.9, 5.4 Hz, 1 H, CHCH_aH_b), 4.46 (dd, J = 16.5, 5.9 Hz, 1 H, CHCH_a H _b), 4.31 (dd, J = 16.5, 5.4 Hz, 1 H, CHCH _aH_b), 3.13 (s, 3 H, NCH₃), 1.60 (s, 9 H, OC(CH₃)₃).

¹³C NMR (100 MHz, CDCl₃): δ = 158.07, 157.29, 149.36, 136.09, 135.87, 132.13, 128.44, 126.23, 124.93, 124.18, 122.94 (2C), 122.70, 121.57, 118.93, 117.00, 115.67, 111.94, 111.19, 84.20, 53.45, 51.63, 32.96, 28.06 (3C).

MS (ESI): m/z = 443 [M + H]⁺.

Anal. Calcd for C₂₆H₂₆N₄O₃: C, 70.57; H, 5.92; N, 12.66. Found: C, 70.71; H, 5.99; N, 12.60.

Removal of the Boc Protecting Group; General Procedure

A suspension of the substrate (0.43 mmol) in CH₂Cl₂ (2 mL) at 0–5 °C was treated with TFA (0.4 mL, 5.2 mmol) in four portions, stirred at the same temperature for 20 min, left overnight, and evaporated in vacuo. The residue was dissolved in EtOAc (40 mL), washed with saturated NaHCO₃ (2 × 20 mL) and concd NaCl (20 mL) solutions, and dried over anhydrous Na₂SO₄. The solvent was removed in vacuo and the residue was purified by chromatography on a column with silica gel.

(6-Bromo-1H-indol-3-yl)[5-(6-bromo-1H-indol-3-yl)-1-methyl-4,5-dihydro-1H-imidazol-2-yl]methanone (5a)

Yield: 0.210 g (98%); light-beige solid; mp 247–249 °C (dec.) (EtOAc); R_f = 0.36 (CHCl₃–MeOH, 20:1).

IR (film): 3426, 3119, 3012, 2850, 1637, 1569, 1513, 1450, 1265, 1085, 986, 822, 793, 692, 600 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.30 (br s, 1 H, 1′-NH), 11.20 (br s, 1 H, 1′′-NH), 8.51 (s, 1 H, 2′-H), 8.17 (d, J = 8.4 Hz, 1 H, 4′-H), 7.74 (d, J = 1.6 Hz, 1 H, 7′-H), 7.59 (d, J = 1.6 Hz, 1 H, 7′′-H), 7.53 (d, J = 8.4 Hz, 1 H, 4′′-H), 7.45 (d, J = 2.4 Hz, 1 H, 2′′-H), 7.40 (dd, J = 8.4, 1.6 Hz, 1 H, 5′-H), 7.14 (dd, J = 8.4, 1.6 Hz, 1 H, 5′′-H), 4.86 (dd J = 11.2, 10.3 Hz, 1 H, CHCH_aH_b), 4.26 (dd, J = 15.1, 11.2 Hz, 1 H, CHCH_a H _b), 3.80 (dd, J = 15.1, 10.3 Hz, 1 H, CHCH _aH_b), 2.67 (s, 3 H, NCH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 182.24, 162.09, 139.09, 137.80, 137.60, 125.27 (2C), 124.65, 124.43, 122.90, 121.67, 120.56, 115.82, 115.23, 114.80, 114.40, 114.13, 113.88, 60.54 (2C), 31.69.

¹H NMR (400 MHz, acetone-d ₆): δ = 11.37 (br s, 1 H, 1′-NH), 10.42 (br s, 1 H, 1′′-NH), 8.68 (s, 1 H, 2′-H), 8.32 (d, J = 8.5 Hz, 1 H, 4′-H), 7.76 (d, J = 1.6 Hz, 1 H, 7′-H), 7.65 (d, J = 1.6 Hz, 1 H, 7′′-H), 7.63 (d, J = 8.5 Hz, 1 H, 4′′-H), 7.45 (d, J = 2.1 Hz, 1 H, 2′′-H), 7.41 (dd, J = 8.5, 1.7 Hz, 1 H, 5′-H), 7.17 (dd, J = 8.5, 1.7 Hz, 1 H, 5′′-H), 4.90 (dd J = 11.3, 10.3 Hz, 1 H, CHCH_aH_b), 4.31 (dd, J = 15.3, 11.3 Hz, 1 H, CHCH_a H _b), 3.91 (dd, J = 15.3, 10.3 Hz, 1 H, CHCH _aH_b), 2.82 (s, 3 H, NCH₃).

¹³C NMR (100 MHz, acetone-d ₆): δ = 183.28, 163.42, 139.61, 139.36, 138.78, 126.40, 126.31, 125.93, 125.78, 124.34, 123.13, 121.83, 117.27, 116.72, 116.13, 115.88, 115.83, 115.59, 62.40, 61.88, 32.51.

MS (ESI): m/z = 502/501/500 [M + H]⁺.

Anal. Calcd for C₂₁H₁₆Br₂N₄O: C, 50.43; H, 3.22; N, 11.20. Found: C, 50.49; H, 3.26; N, 11.18.

1H-Indol-3-yl[5-(1H-indol-3-yl)-1-methyl-4,5-dihydro-1H-imidazol-2-yl]methanone (5b)

Yield: 0.139 g (94%); light-brown amorphous solid; R_f = 0.33 (CHCl₃–MeOH, 20:1).

IR (film): 3360 br, 3059, 2919, 1620, 1580, 1518, 1442, 1241, 1085, 977, 858, 743, 642 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 12.22 (br s, 1 H, 1′-NH), 11.08 (br s, 1 H, 1′′-NH), 8.50 (s, 1 H), 8.24–8.29 (m, 1 H), 7.61 (d, J = 8.0 Hz, 1 H), 7.52–7.58 (m, 1 H), 7.37–7.44 (m, 2 H), 7.22–7.32 (m, 2 H), 7.08–7.15 (m, 1 H), 6.97–7.04 (m, 1 H), 4.88 (dd J = 11.3, 10.2 Hz, 1 H, CHCH_aH_b), 4.26 (dd, J = 14.8, 11.3 Hz, 1 H, CHCH_a H _b), 3.86 (dd, J = 14.8, 10.2 Hz, 1 H, CHCH _aH_b), 2.68 (s, 3 H, NCH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 182.32, 162.48, 138.42, 137.02, 137.79, 125.62, 125.50, 124.34, 123.46, 122.52, 121.36 (2C), 118.94, 118.83, 115.01, 113.41, 112.60, 111.92, 60.83, 60.36, 31.73.

MS (ESI): m/z = 343 [M + H]⁺.

Anal. Calcd for C₂₁H₁₈N₄O: C, 73.67; H, 5.30; N, 16.36. Found: C, 73.48; H, 5.23; N, 16.28.

Topsentin C (17a)

Yield: 0.214 g (99%); pale-yellow solid; mp 179–181 °C (dec.) (i-PrOH); R_f = 0.18 (CHCl₃).

IR (film): 3404, 3208, 2924, 2853, 1647, 1592, 1524, 1440, 1397, 1340, 1290, 1231, 1111, 1049, 947, 895, 852, 793, 734, 647, 570 cm^–1.

¹H NMR (400 MHz, DMSO-d ₆): δ = 11.62 (br s, 1 H, 1′-NH), 11.14 (br s, 1 H, 1′′-NH), 8.46 (d, J = 2.4 Hz, 1 H, 2′-H), 8.22 (d, J = 8.6 Hz, 1 H, 4′-H), 7.49–7.71 (m, 3 H, 7′-H + 7′′-H + 4′′-H), 7.03–7.25 (m, 3 H, 2′′-H + 5′-H + 5′′-H), 5.11 (dd, J = 5.3, 4.8 Hz, 1 H, CHCH_aH_b), 4.29 (dd, J = 16.5, 4.8 Hz, 1 H, CHCH_a H _b), 4.18 (dd, J = 16.5, 5.3 Hz, 1 H, CHCH _aH_b), 2.97 (s, 3 H, NCH₃).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 157.08, 156.69, 137.42, 137.04, 132.77, 125.09, 124.64, 124.52, 124.10, 123.21, 121.83, 120.33, 114.70, 114.35, 114.20 (2C), 112.12, 111.02, 52.46, 52.28, 32.36.

¹H NMR (400 MHz, acetone-d ₆): δ = 10.70 (br s, 1 H, 1′-NH), 10.34 (br s, 1 H, 1′′-NH), 8.62 (d, J = 2.75 Hz, 1 H, 2′-H), 8.37 (d, J = 8.6 Hz, 1 H, 4′-H), 7.69 (d, J = 8.6 Hz, 1 H, 4′′-H), 7.66 (d, J = 1.8 Hz, 1 H, 7′-H), 7.63 (d, J = 1.7 Hz, 1 H, 7′′-H), 7.17–7.23 (m, 3 H, 2′′-H + 5′-H + 5′′-H), 5.15 (dd J = 5.5, 5.2 Hz, 1 H, CHCH_aH_b), 4.41 (dd, J = 16.5, 5.2 Hz, 1 H, CHCH_a H _b), 4.26 (dd, J = 16.5, 5.5 Hz, 1 H, CHCH _aH_b), 3.04 (s, 3 H, NCH₃).

¹³C NMR (100 MHz, acetone-d ₆): δ = 158.47, 158.06, 138.86, 138.34, 133.67, 126.67, 126.07, 125.49, 125.39, 124.40, 123.30, 121.19, 116.17, 115.82, 115.53, 115.09, 113.93, 113.05, 54.07, 53.54, 32.77.

MS (ESI): m/z = 502/501/500 [M + H]⁺.

Anal. Calcd for C₂₁H₁₆Br₂N₄O: C, 50.43; H, 3.22; N, 11.20. Found: C, 50.55; H, 3.25; N, 11.16.

3,6-Di-1H-Indol-3-yl-1-methyl-5,6-dihydropyrazin-2(1H)-one (17b)

Yield: 0.141 g (96%); R_f = 0.60 (CHCl₃–MeOH, 15:1).

IR (film): 3400, 3271, 3055, 2926, 1644, 1589, 1422, 1339, 1239, 1172, 1100, 1011, 851, 744 cm^–1.

¹H NMR (600 MHz, DMSO-d ₆): δ = 11.53 (br s, 1 H, NH), 11.01 (br s, 1 H, NH), 8.44 (d, J = 3.3 Hz, 1 H), 8.29 (d, J = 8.3 Hz, 1 H), 7.64 (d, J = 8.3 Hz, 1 H), 7.42 (d, J = 8.3 Hz, 1 H), 7.36 (d, J = 8.3 Hz, 1 H), 7.08–7.17 (m, 2 H), 7.07 (d, J = 2.5 Hz, 1 H), 6.98–7.05 (m, 2 H), 5.11 (dd, J = 5.8, 4.9 Hz, 1 H, CHCH_aH_b), 4.30 (dd, J = 16.5, 4.9 Hz, 1 H, CHCH_a H _b), 4.19 (dd, J = 16.5, 5.8 Hz, 1 H, CHCH _aH_b), 2.99 (s, 3 H, NCH₃).

¹³C NMR (125 MHz, DMSO-d ₆): δ = 157.43, 157.02, 136.63, 136.17, 132.06, 126.14, 125.73, 123.46, 122.54, 122.07, 121.46, 120.44, 119.09, 118.59, 111.85 (2C), 111.61, 111.06, 52.78, 52.40, 32.47.

MS (ESI): m/z = 343 [M + H]⁺.

Anal. Calcd for C₂₁H₁₈N₄O: C, 73.67; H, 5.30; N, 16.36. Found: C, 73.79; H, 5.34; N, 16.31.

No conflict of interest has been declared by the author(s).

Acknowledgment

This work was supported by the Ministry of Education and Science of the Russian Federation (Agreement number 02.a03.21.0008) and by RFBR (research project No. 16-03-00190 a).

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