Transition-Metal-Free Stereoselective and Regioselective Hydroamination of 2-Benzoylethynyl-4,5,6,7-tetrahydroindoles with Amino Acids

Abstract

A new family of unnatural amino acids possessing a tetrahydroindole moiety is obtained by nucleophilic addition of various amino acids to the triple bond of 2-benzoylethynyl-4,5,6,7-tetrahydroindoles. The reaction proceeds chemo-, regio- and stereospecifically in the presence of sodium hydroxide to give the Z-isomeric products in 35–72% yields.

The synthesis of unnatural amino acids has attracted significant attention in recent years.[ ¹ ] They represent a growing group of compounds required for a number of biotechnological applications in pharmaceutical, cosmetics and agrochemical fields. When modified with different pharmacophore substituents, unnatural amino acids can also be used as building blocks for the synthesis of molecules with specific desired biological activity.[ ² ] Hence, research on various derivatives of amino acids and the development of new synthetic strategies for amino acid modification is very important. The chemo- and regioselective transformations of amino acids are considered to be a major challenge and remain the subject of further investigations. It is envisaged that the synthesis of new amino acid derivatives containing highly reactive pyrrole or indole moieties would represent a promising approach in this field.

Examples of unnatural optically active amino acids containing a pyrrole moiety have been synthesized by condensation of 1-vinylpyrrole- and 1-vinylindole-2-carbaldehydes with l-lysine.[ ³ ]

Following the development of transition metal and solvent-free ethynylations of the pyrrole nucleus with electrophilic haloacetylenes on alumina,[ ⁴ ] or other active surfaces,[ ⁵ ] 2-ethynylpyrroles and 3-ethynylindoles possessing electron-withdrawing substituents, including an example with an acyl group on the triple bond, became readily available. This methodology has made 3-(4,5,6,7-tetrahydroindol-2-yl)-2-propynones 1–3 particularly accessible using large-scale manufactured 4,5,6,7-tetrahydroindole[ ⁶ ] as the starting material. Consequently, reactions of these compounds with amino acids can be considered as a short-cut route to amino acids containing a tetrahydroindole moiety.

These compounds, due to their easy aromatization, might be suitable intermediates for the synthesis of amino acids containing an indole function, for example, α-analogues of tryptophan. Herein, we disclose an expedient method for the synthesis of amino acid derivatives possessing a tetrahydroindole moiety

The method involves the nucleophilic addition of the natural amino acids glycine (4), β-alanine (5), γ-aminobutyric acid (6), phenylalanine (7) and tryptophan (8) to the C≡C bond of 2-benzoylethynyl-4,5,6,7-tetrahydroindoles 1–3. The reaction was carried out in the presence of sodium hydroxide (reflux, 40 h, EtOH–H₂O), followed by subsequent treatment of the mixture with aqueous hydrochloric acid to afford amino acid derivatives 10a–k and 11a–c in 35–72% yields (Table [1] and Table [2]).

In the absence of sodium hydroxide, addition of amino acids­ 4–8 to the acetylenic moiety of indoles 1–3 did not take place. The role of the base would seem to involve transformation of the zwitterionic form of the amino acid into the corresponding sodium salt and thus releasing the free amino group. The free amino group of the salt serves as a nucleophile undergoing addition to the triple bond of indoles 1–3 to deliver the sodium salt adducts 9a–k. The latter, after treatment of the reaction mixture with aqueous hydrochloric acid, furnishes free amino acids 10a–k (Table [1]). In the case of l-tryptophan (Table [2]), the corresponding products 11a–c were isolated without the need for acidification of the reaction mixture.

The reaction proved to be regio- and stereoselective with only Z-isomers of the adducts being formed in all cases. Evidence for the Z-configuration of adducts 10a–k was obtained from the 2D NOESY spectrum of compound 10f. Cross-peaks were apparent between the alkene proton (5.65 ppm) and those at the ortho-positions of the phenyl (7.45 ppm) and the CH₂ of the benzyl fragment (5.19 ppm), and also between the pyrrolic proton (6.23 ppm) and those of the NCH₂ group (3.71 ppm) in conformer A. In the 2D NOESY spectrum of conformer B, cross-peaks were observed between the pyrrole and alkene protons, and also between the CH₂ protons of the benzyl and alanine fragments (Figure [1]). It is noteworthy that the N-vinyl-substituted tetrahydroindole 3 tolerated the reaction conditions retaining the vinyl double bond intact (Table [1] and Table [2]).

As exemplified by the reaction with tryptophan (8), the elaborated method can be employed for the synthesis of amino acids containing both tetrahydroindolyl and indolyl substituents.

Table 1 Synthesis of Amino Acid Derivatives 10a–k

Entry	Substrate	R	Amino acid	X	Product	Yield (%)
1	1	Me	4	CH2	10a	55
2	1	Me	5	(CH2)2	10b	48
3	1	Me	6	(CH2)3	10c	57
4	1	Me	7	CH(CH2Ph)	10d	35
5	2	Bn	4	CH2	10e	42
6	2	Bn	5	(CH2)2	10f	71
7	2	Bn	6	(CH2)3	10g	51
8	3	CH=CH2	4	CH2	10h	72
9	3	CH=CH2	5	(CH2)2	10i	64
10	3	CH=CH2	6	(CH2)3	10j	63
11	3	CH=CH2	7	CH(CH2Ph)	10k	49

Table 2 Synthesis of Amino Acid Derivatives 11a–c

Entry	Substrate	R	Product	Yield (%)
1	1	Me	11a	71
2	2	Bn	11b	70
3	3	CH=CH2	11c	67

The reactions of 2-benzoylethynyl-4,5,6,7-tetrahydroindoles 1–3 with amino acids were accompanied by the formation of minor amounts of 2-acetyl-4,5,6,7-tetrahydroindoles. This might be the result of nucleophilic addition of water to adducts 10a–k and subsequent decomposition of the intermediates 12 to give diketones 13. Addition of a second molecule of water gives intermediates 14, which decompose to 2-acetyl-4,5,6,7-tetrahydroindoles 15a–c and benzoic acid (Scheme [1]). Both these compounds were present in the reaction mixtures in approximately 1:1 molar ratio. Also, the direct nucleophilic addition of water to the triple bond of indoles 1–3 to generate diketones 13 cannot be ruled out.

Among the common proteinogenic amino acids, only proline exists as a secondary amine, and accordingly plays a distinct role in protein chemistry and biology. In addition, proline is of significant importance in organic chemistry as a chiral starting material for the synthesis of peptide mimetics,[ ⁷ ] alkaloids,[ ⁸ ] certain peptoid natural products,[ ⁹ ] and chiral molecules, which are used in asymmetric synthesis and catalysis.

The combination of a pharmacophoric indole ring and proline in the same molecule might result in synergism of the properties of these important chemical structures, and could expand substantially the fields of application of such a new class of amino acids. Unfortunately, the reaction of indole 1 with l-proline using the above-described conditions gave, almost quantitatively, 2-acetyl-4,5,6,7-tetrahydroindole (15a) and benzoic acid (Scheme [2]).

This may be rationalized as follows: the addition of l-proline to the triple bond of the indole substrate is sterically hindered, hence the competitive addition of water, catalyzed by proline acting as an active organic catalyst,[ ¹⁰ ] is the only possible outcome for the reaction.

Surprisingly, the reaction of N-unsubstituted 2-benzoyl­ethynyl-4,5,6,7-tetrahydroindole (16) with glycine (4) under the same conditions did not form the expected adduct. Instead, almost quantitative cleavage into 2-acetyl-4,5,6,7-tetrahydroindole (17) and benzoic acid took place (Scheme [3]).

Of particular interest is the fact that, unlike 2-benzoyl­ethynyl-4,5,6,7-tetrahydroindoles 1–3, ethyl 3-(4,5,6,7-tetrahydro-1H-indol-2-yl)propynoate (18) did not form the expected adduct on reaction with amino acid 5 (reflux, 40 h, EtOH–H₂O). Surprisingly, a rather peculiar cleavage of the triple bond occurred to produce, almost quantitatively, 2-acetyl-4,5,6,7-tetrahydroindole (15a). Apparently, in this case, alkaline hydrolysis of the ester function occurred first, thereby consuming the sodium hydroxide. Consequently, the amino acid remained in zwitterionic form and was unable to take part in nucleophilic addition at the triple bond. Therefore, indole 18 underwent nucleophilic attack by hydroxide to give intermediate 19, which decomposed to acetylindole 15a and sodium carbonate (Scheme [4]).

It should be emphasized that the formal one-pot cleavage of the triple bond under mild conditions, as described herein, is important since there are only a few examples of such reactions reported in the literature.[ ¹¹ ]

In conclusion, a general method for the synthesis of a new family of unnatural amino acids, containing a tetrahydroindole moiety, has been developed. The procedure involves the regio- and stereoselective addition of amino acids to the triple bond of 2-benzoylethynyl-4,5,6,7-tetrahydroindoles. The synthesized products represent a combination of pharmacophoric indole and amino acid moieties, and may serve as novel building blocks for drug design. The method was also shown to be applicable for the synthesis of amino acids containing N-vinyl-4,5,6,7-tetrahydroindole moieties. These compounds represent promising monomers which might take part in various addition reactions across the double bond.

Commercially available amino acids and sodium hydroxide were used. 2-Ethynyl-4,5,6,7-tetrahydroindoles 1–3, 16 and 18 were obtained from 4,5,6,7-tetrahydroindoles and haloacetylenes using the reported method.[ ⁵ ] Column chromatography was performed using Sigma-Aldrich neutral Al₂O₃ (150 mesh). TLC was carried out using silica gel 60 F254 plates. Melting points were recorded on a Stuart melting point apparatus and are uncorrected. IR spectra were obtained using a Bruker IFS 25 spectrometer. ¹H (400.13 MHz) and ¹³C (100.6 MHz) NMR spectra were recorded on Bruker DPX 400 or AV-400 spectrometers with HMDS as the internal standard. The ¹H and ¹³C NMR resonances were assigned with the aid of 2D homonuclear COSY and NOESY, and 2D heteronuclear HSQC and HMBC experiments. Elemental analyses were recorded using an EA FLASH 1112 Series (CHN Analyzer) instrument.

1-Phenyl-3-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)prop-2-yn-1-one (3)

An equimolar mixture of 1-vinyl-4,5,6,7-tetrahydroindole (0.5 g, 3.4 mmol) and 1-benzoyl-2-bromoacetylene (0.711 g, 3.4 mmol) containing K₂CO₃ (12 g, 10 equiv by wt) was ground in a china mortar using a pestle at r.t. for 1–2 min. After 60 min, the products were extracted with Et₂O (5 × 20 mL). Evaporation of the solvent and purification of the residue by column chromatography on alumina (n-hexane) gave tetrahydroindole 3.

Yield: 0.702 g (75%); yellow needles; mp 73–74 °C.

IR (KBr): 1645 (NCH=CH₂), 1596 (CO) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 7.39–7.37 (m, 3 H, m,p-H_Ph), 7.14–7.12 (m, 2 H, o-H_Ph), 7.00 (dd, J = 16.0, 9.2 Hz, 1 H, H_N=CH), 6.71 (s, 1 H, H-3), 5.46 (d, J = 16.0 Hz, 1 H, H _trans ), 5.05 (d, J = 9.2 Hz, 1 H, H _cis ), 2.63–2.61 (m, 2 H, CH₂-7), 2.49–2.47 (m, 2 H, CH₂-4), 1.84–1.82 (m, 2 H, CH₂-5), 1.75–1.73 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 177.3, 137.4, 135.2, 133.5, 130.0, 129.3, 128.5, 122.1, 121.3, 110.4, 105.1, 96.0, 89.1, 24.1, 23.0, 22.9, 22.8.

Anal. Calcd for C₁₉H₁₇NO: C, 82.88; H, 6.22; N, 5.09. Found: C, 82.64; H, 6.01; N, 4.74.

Amino Acids 10a–k; General Procedure

A soln of 2-benzoylethynyl-4,5,6,7-tetrahydroindole 1–3 (2.5 mmol), amino acid 4–7 (2.5 mmol) and NaOH (2.5 mmol) in EtOH–H₂O (1:1, 16 mL) was heated at reflux temperature for 40 h. After cooling to r.t., the mixture was diluted with H₂O (50 mL) and extracted with Et₂O (3 × 20 mL) to isolate the by-products. The aqueous layer was neutralized with 10% HCl and extracted with Et₂O (5 × 20 mL). The combined organic layer was washed with H₂O (5 × 20 mL), dried over MgSO₄ and evaporated. The residue was purified by flash chromatography on alumina (Et₂O) to give the pure product as a yellow solid. The structures of the products were confirmed by NMR and IR techniques.

(Z)-2-{[1-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}acetic Acid (10a)

Yield: 0.465 g (55%); yellow solid; mp 186–188 °C.

IR (KBr): 3092–2500 (NH, OH), 1727 [C(=O)OH], 1592 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.45 (br s, 1 H, NH), 9.32 (br s, 1 H, OH), 7.87–7.85 (m, 2 H, o-H_Ph), 7.38–7.36 (m, 3 H, m,p-H_Ph), 6.13 (s, 1 H, H-3), 5.83 (s, 1 H, CH=), 4.19 (s, 2 H, NCH₂), 3.48 (s, 3 H, NMe), 2.55–2.53 (m, 2 H, CH₂-7), 2.50–2.48 (m, 2 H, CH₂-4), 1.85–1.83 (m, 2 H, CH₂-5), 1.74–1.72 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 187.5, 171.9, 158.2, 139.5, 133.0, 130.5, 127.8, 126.7, 124.1, 117.9, 110.8, 94.7, 46.2, 31.0, 22.9, 22.5, 22.4, 21.8.

Anal. Calcd for C₂₀H₂₂N₂O₃: C, 70.99; H, 6.55; N, 8.28. Found: C, 70.64; H, 6.31; N, 8.42.

(Z)-3-{[1-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}propanoic Acid (10b)

Yield: 0.422 g (48%); yellow solid; mp 152–153 °C.

IR (KBr): 3092–2500 (NH, OH), 1726 [C(=O)OH], 1592 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.49 (br s, 1 H, NH), 11.07 (br s, 1 H, OH), 7.80–7.78 (m, 2 H, o-H_Ph), 7.37–7.35 (m, 3 H, m,p-H_Ph), 6.10 (s, 1 H, H-3), 5.71 (s, 1 H, CH=), 3.62 (br s, 2 H, NCH₂), 3.45 (s, 3 H, NMe), 2.65 (br s, 2 H, CH₂COO), 2.55–2.53 (m, 2 H, CH₂-7), 2.50–2.48 (m, 2 H, CH₂-4), 1.85–1.83 (m, 2 H, CH₂-5), 1.74–1.72 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 187.5, 173.9, 159.4, 140.1, 132.8, 130.7, 128.2, 127.1, 125.0, 118.1, 110.7, 94.8, 40.8, 35.1, 31.4, 23.4, 23.0, 22.9, 22.2.

Anal. Calcd for C₂₁H₂₄N₂O₃: C, 71.57; H, 6.86; N, 7.95. Found: C, 71.42; H, 6.99; N, 7.61.

(Z)-4-{[1-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}butanoic Acid (10c)

Yield: 0.522 g (57%); yellow solid; mp 153–154 °C.

IR (KBr): 3058–2500 (NH, OH), 1711 [C(=O)OH], 1596 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.31 (br s, 1 H, NH), 9.05 (br s, 1 H, OH), 7.85–7.83 (m, 2 H, o-H_Ph), 7.38–7.36 (m, 3 H, m,p-H_Ph), 6.10 (s, 1 H, H-3), 5.75 (s, 1 H, CH=), 3.46 (s, 3 H, NMe), 3.38 (br s, 2 H, NCH₂), 2.55–2.53 (m, 2 H, CH₂-7), 2.50–2.48 (m, 2 H, CH₂-4), 2.43–2.41 (m, 2 H, CH₂COO), 1.93–1.91 (m, 2 H, CH₂), 1.85–1.83 (m, 2 H, CH₂-5), 1.74–1.72 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 187.6, 177.2, 159.2, 140.3, 132.6, 130.7, 128.3, 127.1, 125.3, 118.1, 110.6, 94.4, 44.2, 31.4, 31.2, 25.8, 23.4, 23.1, 22.9, 22.2.

Anal. Calcd for C₂₂H₂₆N₂O₃: C, 72.11; H, 7.15; N, 7.64. Found: C, 71.87; H, 6.98; N, 7.71.

(Z)-2-{[1-(1-Methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}-3-phenylpropanoic Acid (10d)

Yield: 0.375 g (35%); yellow solid; mp 90–92 °C.

IR (KBr): 3060–2500 (NH, OH), 1736 [C(=O)OH], 1590 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.52 (br s, 1 H, NH), 7.78–7.76 (m, 2 H, o-H_Ph), 7.31–7.28 (m, 1 H, p-H_Ph), 7.20–7.16 (m, 2 H, m-H_Ph), 7.01–6.98 (m, 5 H, Ph), 6.46 (br s, 1 H, OH), 5.85 (s, 1 H, H-3), 5.68 (s, 1 H, CH=), 4.41–4.39 (m, 1 H, NCH), 3.27–3.23 (m, 1 H, CH₂-Ph), 3.15 (s, 3 H, NMe), 3.09–3.05 (m, 1 H, CH₂-Ph), 2.45–2.43 (m, 4 H, CH₂-4,7), 1.82–1.80 (m, 2 H, CH₂-5), 1.71–1.69 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 188.1, 174.7, 158.5, 140.2, 136.8, 132.6, 130.9, 129.7, 128.4, 128.3, 127.3, 126.8, 124.5, 118.0, 110.6, 95.5, 59.9, 40.2, 30.9, 23.5, 23.1, 22.9, 22.2.

Anal. Calcd for C₂₇H₂₈N₂O₃: C, 75.68; H, 6.59; N, 6.54. Found: C, 75.30; H, 6.84; N, 6.15.

(Z)-2-{[1-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}acetic Acid (10e)

Yield: 0.435 g (42%); yellow solid; mp 192–194 °C.

IR (KBr): 3060–2500 (NH, OH), 1726 [C(=O)OH], 1593 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.39 (br s, 1 H, NH), 9.66 (br s, 1 H, OH), 7.48–7.46 (m, 2 H, o-H_Ph), 7.30–7.25 (m, 6 H, Ph), 6.93–6.91 (m, 2 H, o-H_Bn), 6.21 (s, 1 H, H-3), 5.74 (s, 1 H, CH=), 5.16 (s, 2 H, CH₂-Ph), 4.15 (s, 2 H, NCH₂), 2.54–2.52 (m, 2 H, CH₂-7), 2.45–2.43 (m, 2 H, CH₂-4), 1.79–1.77 (m, 2 H, CH₂-5), 1.76–1.74 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, DMSO-d ₆): δ = 187.6, 172.5, 158.5, 141.1, 140.2, 134.2, 132.2, 130.2, 129.7, 128.5, 128.0, 127.1, 126.1, 119.2, 112.7, 94.6, 48.8, 47.6, 24.6, 24.1, 24.0, 23.0.

Anal. Calcd for C₂₆H₂₆N₂O₃: C, 75.34; H, 6.32; N, 6.76. Found: C, 74.97; H, 6.05; N, 6.95.

(Z)-3-{[1-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}propanoic Acid (10f)

Yield: 0.760 g (71%); yellow solid; mp 158–160 °C.

IR (KBr): 3061–2500 (NH, OH), 1738, 1719 [C(=O)OH], 1588 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.44 (br s, 1 H, NH), 9.90 (br s, 1 H, OH), 7.48–7.45 (m, 2 H, o-H_Ph), 7.36–7.34 (m, 3 H, m,p-H_Ph), 7.30–7.25 (m, 3 H, m,p-H_Ph), 6.95–6.93 (m, 2 H, o-H_Bn), 6.23 (s, 1 H, H-3), 5.65 (s, 1 H, CH=), 5.19 (s, 2 H, CH₂-Ph), 3.71 (s, 2 H, NCH₂), 2.66 (m, 2 H, CH₂COO), 2.54–2.52 (m, 2 H, CH₂-7), 2.45–2.43 (m, 2 H, CH₂-4), 1.79–1.77 (m, 2 H, CH₂-5), 1.77–1.75 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 187.2, 173.9, 159.2, 139.9, 138.5, 133.1, 130.6, 128.9, 128.2, 127.3, 127.1, 125.9, 125.0, 118.7, 111.8, 94.4, 47.9, 40.9, 35.1, 23.5, 23.2, 23.1, 22.4.

Anal. Calcd for C₂₇H₂₈N₂O₃: C, 75.68; H, 6.59; N, 6.54. Found: C, 75.38; H, 6.62; N, 6.53.

(Z)-4-{[1-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}butanoic Acid (10g)

Yield: 0.564 g (51%); yellow solid; mp 168 °C.

IR (KBr): 3060–2500 (NH, OH), 1710 [C(=O)OH], 1586 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.28 (br s, 1 H, NH), 10.54 (br s, 1 H, OH), 7.53–7.51 (m, 2 H, o-H_Ph), 7.28–7.25 (m, 6 H, Ph), 6.91–6.89 (m, 2 H, o-H_Bn), 6.17 (s, 1 H, H-3), 5.68 (s, 1 H, CH=), 5.15 (s, 2 H, CH₂-Ph), 3.35–3.33 (m, 2 H, NCH₂), 2.54–2.52 (m, 2 H, CH₂-7), 2.46–2.44 (m, 2 H, CH₂-4), 2.36–2.33 (m, 2 H, CH₂COO), 1.81–1.79 (m, 2 H, CH₂-5), 1.77–1.75 (m, 2 H, CH₂-6), 1.75–1.73 (m, 2 H, CH₂).

¹³C NMR (100.6 MHz, CDCl₃): δ = 187.1, 177.2, 158.8, 140.1, 138.5, 132.8, 130.5, 128.8, 128.1, 127.2, 127.0, 125.9, 125.2, 118.6, 111.7, 93.8, 47.9, 44.4, 29.7, 25.7, 23.5, 23.1, 23.0, 22.4.

Anal. Calcd for C₂₈H₃₀N₂O₃: C, 75.99; H, 6.83; N, 6.33. Found: C, 75.81; H, 6.60; N, 5.97.

(Z)-2-{[3-Oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)prop-1-en-1-yl]amino}acetic Acid (10h)

Yield: 0.630 g (72%); yellow solid; mp 114–115 °C.

IR (KBr): 3087–2500 (NH, OH), 1727 [C(=O)OH], 1643 (N-CH=CH₂), 1592 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.38 (br s, 1 H, NH), 7.87–7.85 (m, 2 H, o-H_Ph), 7.38–7.36 (m, 3 H, m,p-H_Ph), 7.23 (br s, 1 H, OH), 6.77 (dd, J = 15.9, 8.9 Hz, 1 H, H_N=CH), 6.21 (s, 1 H, H-3), 5.93 (s, 1 H, CH=), 5.06 (d, J = 15.9 Hz, 1 H, H _trans ), 4.85 (d, J = 8.9 Hz, 1 H, H _cis ), 4.07 (s, 2 H, NCH₂), 2.64–2.62 (m, 2 H, CH₂-7), 2.49–2.47 (m, 2 H, CH₂-4), 1.82–1.80 (m, 2 H, CH₂-5), 1.74–1.72 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 188.1, 172.0, 158.1, 139.5, 132.1, 130.8, 129.8, 127.9, 127.0, 124.3, 119.6, 113.5, 104.4, 95.1, 29.4, 23.5, 22.9, 22.7, 22.6.

Anal. Calcd for C₂₁H₂₂N₂O₃: C, 71.98; H, 6.33; N, 7.99. Found: C, 72.31; H, 6.67; N, 7.63.

(Z)-3-{[3-Oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)prop-1-en-1-yl]amino}propanoic Acid (10i)

Yield: 0.582 g (64%); yellow solid; mp 69–70 °C.

IR (KBr): 3056–2500 (NH, OH), 1729 [C(=O)OH], 1643 (N-CH=CH₂), 1591 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.41 (br s, 1 H, NH), 8.31 (br s, 1 H, OH), 7.79–7.77 (m, 2 H, o-H_Ph), 7.37–7.35 (m, 3 H, m,p-H_Ph), 6.77 (dd, J = 15.9, 8.9 Hz, 1 H, H_N=CH), 6.19 (1 H, s, H-3), 5.81 (s, 1 H, CH=), 5.06 (d, J = 15.9 Hz, 1 H, H _trans ), 4.86 (d, J = 8.9 Hz, 1 H, H _cis ), 3.55 (br s, 2 H, NCH₂), 2.71–2.69 (m, 2 H, CH₂-7), 2.66–2.64 (m, 2 H, CH₂-4), 2.51–2.49 (m, 2 H, CH₂COO), 1.83–1.81 (m, 2 H, CH₂-5), 1.75–1.73 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 187.7, 173.5, 159.0, 139.7, 131.6, 130.5, 129.9, 127.9, 126.9, 124.5, 119.5, 112.9, 104.1, 94.8, 40.4, 34.5, 23.5, 22.9, 22.7, 22.6.

Anal. Calcd for C₂₂H₂₄N₂O₃: C, 72.50; H, 6.64; N, 7.69. Found: C, 72.24; H, 6.43; N, 7.39.

(Z)-4-{[3-Oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)prop-1-en-1-yl]amino}butanoic Acid (10j)

Yield: 0.595 g (63%); yellow solid; mp 60 °C.

IR (KBr): 3057–2500 (NH, OH), 1728 [C(=O)OH], 1643 (N-CH=CH₂), 1592 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.22 (br s, 1 H, NH), 8.84 (br s, 1 H, OH), 7.86–7.84 (m, 2 H, o-H_Ph), 7.38–7.36 (m, 3 H, m,p-H_Ph), 6.74 (dd, J = 15.9, 9.0 Hz, 1 H, H_N=CH), 6.17 (s, 1 H, H-3), 5.85 (s, 1 H, CH=), 5.04 (d, J = 15.9 Hz, 1 H, H _trans ), 4.82 (d, J = 9.0 Hz, 1 H, H _cis ), 3.26 (br s, 2 H, NCH₂), 2.65–2.63 (m, 2 H, CH₂-7), 2.50–2.48 (m, 2 H, CH₂-4), 2.40–2.38 (m, 2 H, CH₂COO), 1.89–1.87 (m, 2 H, CH₂CH₂CH₂), 1.82–1.80 (m, 2 H, CH₂-5), 1.74–1.72 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 188.6, 177.7, 159.6, 140.8, 132.2, 131.4, 130.8, 128.9, 127.7, 125.7, 120.3, 113.6, 104.6, 95.2, 44.7, 31.8, 26.1, 24.4, 23.9, 23.6, 23.5.

Anal. Calcd for C₂₃H₂₆N₂O₃: C, 72.99; H, 6.92; N, 7.40. Found: C, 72.64; H, 6.57; N, 7.44.

(Z)-2-{[3-Oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)prop-1-en-1-yl]amino}-3-phenylpropanoic Acid (10k)

Yield: 0.539 g (49%); yellow solid; mp 104–106 °C.

IR (KBr): 3060–2500 (NH, OH), 1735 [C(=O)OH], 1643 (N-CH=CH₂), 1593 (C=O) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.37 (br s, 1 H, NH), 7.86–7.84 (m, 2 H, o-H_Ph), 7.38–7.36 (m, 3 H, m,p-H_Ph), 7.19–7.17 (m, 3 H, m,p-H_Ph), 7.15–7.13 (m, 2 H, o-H_Ph), 6.39 (dd, J = 16.0, 8.6 Hz, 1 H, H_N=CH), 5.75 (s, 1 H, H-3), 5.73 (s, 1 H, CH=), 4.85 (d, J = 16.0 Hz, 1 H, H _trans ), 4.64 (d, J = 8.6 Hz, 1 H, H _cis ), 4.58 (br s, 1 H, OH), 4.43–4.41 (m, 1 H, CHCOO), 3.21–3.18 (m, 1 H, CH₂Ph), 3.03–2.97 (m, 1 H, CH₂Ph), 2.59–2.57 (m, 2 H, CH₂-7), 2.42–2.40 (m, 2 H, CH₂-4), 1.77–1.75 (m, 2 H, CH₂-5), 1.71–1.69 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 188.3, 174.7, 157.7, 140.2, 136.7, 131.8, 130.9, 130.1, 129.8, 128.4, 128.3, 127.3, 126.8, 124.4, 119.7, 113.4, 104.3, 95.8, 59.8, 40.3, 23.9, 23.3, 23.0, 22.9.

Anal. Calcd for C₂₈H₂₈N₂O₃: C, 76.34; H, 6.41; N, 6.36. Found: C, 76.66; H, 6.52; N, 5.99.

Amino Acids 11a–c; General Procedure

A soln of 2-benzoylethynyl-4,5,6,7-tetrahydroindole 1–3 (2.5 mmol), tryptophan (8) (2.5 mmol) and NaOH (2.5 mmol) in EtOH–H₂O (1:1, 16 mL) was heated at reflux temperature for 40 h. After cooling to r.t., the mixture was diluted with H₂O (50 mL) and extracted with Et₂O (5 × 30 mL). The combined organic layer was washed with H₂O (5 × 30 mL), dried over MgSO₄ and evaporated. The residue was purified by flash chromatography on alumina (Et₂O–n-hexane, 1:5, then Et₂O) to give the pure product as a yellow solid.

(Z)-3-(1H-Indol-3-yl)-2-{[1-(1-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}propanoic Acid (11a)

Yield: 0.829 g (71%); yellow solid; mp 128–130 °C.

IR (KBr): 3412 (NH of indole), 3084–2500 (NH, OH), 1732 [C(=O)OH], 1589 cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.53 (br s, 1 H, NH), 8.45 (br s, 1 H, NH of indole), 7.87–7.85 (m, 2 H, o-H_Ph), 7.40–7.37 (m, 2 H, m-H_Ph), 7.36–7.34 (m, 1 H, p-H_Ph), 7.33–7.30 (m, 1 H, CH-4 of indole), 7.22–7.20 (m, 1 H, CH-7 of indole), 7.08–7.06 (m, 1 H, CH-6 of indole), 7.07–7.05 (m, 1 H, CH-2 of indole), 6.95–6.93 (m, 1 H, CH-5 of indole), 6.36 (br s, 1 H, OH), 5.92 (s, 1 H, H-3 of pyrrole), 5.71 (s, 1 H, CH=), 4.82 (m, 1 H, CH), 3.34–3.32 (m, 1 H, CH₂), 3.22–3.20 (m, 1 H, CH₂), 3.02 (s, 3 H, NMe), 2.56–2.54 (m, 2 H, CH₂-7), 1.83–1.81 (m, 2 H, CH₂-4), 1.79–1.77 (m, 2 H, CH₂-5), 1.70–1.68 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 186.9, 173.4, 157.6, 140.4, 136.7, 132.3, 131.3, 128.8, 127.5, 127.4, 124.8, 124.6, 121.4, 118.8, 118.6, 117.2, 111.8, 110.1, 109.3, 94.5, 58.4, 31.0, 30.4, 23.6, 23.2, 23.1, 22.0.

Anal. Calcd for C₂₉H₂₉N₃O₃: C, 74.50; H, 6.25; N, 8.99. Found: C, 74.16; H, 6.18; N, 8.70.

(Z)-2-{[1-(1-Benzyl-4,5,6,7-tetrahydro-1H-indol-2-yl)-3-oxo-3-phenylprop-1-en-1-yl]amino}-3-(1H-indol-3-yl)propanoic Acid (11b)

Yield: 0.950 g (70%); yellow solid; mp 76–78 °C.

IR (KBr): 3421 (NH of indole), 3057–2500 (NH, OH), 1731 [C(=O)OH], 1591 cm^–1.

¹H NMR (400.13 MHz, DMSO-d ₆): δ = 11.38 (br s, 1 H, NH), 10.92 (br s, 1 H, NH of indole), 7.39–7.34 (m, 3 H, o-H_Ph, CH-4 of indole), 7.31–7.23 (m, 8 H, m,p-H_Ph, CH-7 of indole, OH), 7.13–7.11 (m, 1 H, CH-6 of indole), 7.09–7.06 (m, 1 H, CH-2 of indole), 6.92–6.88 (m, 1 H, CH-5 of indole), 6.82–6.80 (m, 2 H, o-H_Bn), 5.92 (s, 1 H, H-3 of pyrrole), 5.49 (s, 1 H, CH=), 4.63 (m, 1 H, CH), 4.52 (s, 2 H, CH₂-Ph), 3.21–3.17 (m, 1 H, CH₂), 3.07–3.01 (m, 1 H, CH₂), 2.45–2.43 (m, 2 H, CH₂-7), 2.23–2.22 (m, 2 H, CH₂-4), 1.65 (m, 4 H, CH₂-5,6).

¹³C NMR (100.6 MHz, DMSO-d ₆): δ = 186.3, 173.8, 157.1, 140.2, 139.3, 136.8, 132.3, 131.1, 129.2, 128.6, 127.6, 127.3, 127.0, 125.9, 125.1, 124.6, 121.4, 118.8, 117.8, 111.9, 110.8, 109.7, 93.7, 65.4, 58.9, 47.0, 23.6, 23.1, 23.0, 22.1.

Anal. Calcd for C₃₅H₃₃N₃O₃: C, 77.32; H, 6.12; N, 7.73. Found: C, 76.94; H, 6.01; N, 7.38.

(Z)-3-(1H-Indol-3-yl)-2-{[3-oxo-3-phenyl-1-(1-vinyl-4,5,6,7-tetrahydro-1H-indol-2-yl)prop-1-en-1-yl]amino]propanoic Acid (11c)

Yield: 0.802 g (67%); yellow solid; mp 96–98 °C.

IR (KBr): 3425 (NH of indole), 3057–2500 (NH, OH), 1733 [C(=O)OH], 1643 (N-CH=CH₂), 1592 cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 11.44 (br s, 1 H, NH), 8.29 (br s, 1 H, NH of indole), 7.85–7.83 (m, 2 H, o-H_Ph), 7.40–7.36 (m, 5 H, m,p-H_Ph, CH-4 of indole, OH), 7.23–7.21 (m, 1 H, CH-7 of indole), 7.07–7.04 (m, 2 H, CH-2,6 of indole), 6.97–6.94 (m, 1 H, CH-5 of indole), 6.38 (dd, J = 15.6, 9.0 Hz, 1 H, H_N=CH), 5.81 (s, 1 H, H-3 of pyrrole), 5.78 (s, 1 H, CH=), 4.86 (d, J = 15.6 Hz, 1 H, H _trans ), 4.60 (d, J = 9.0 Hz, 1 H, H _cis ), 4.57 (m, 1 H, CH), 3.29–3.20 (m, 2 H, CH₂Ph), 2.54–2.52 (m, 4 H, CH₂-7,4), 1.80–1.71 (m, 4 H, CH₂-5,6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 187.2, 173.2, 157.1, 140.3, 136.7, 131.5, 131.4, 130.6, 128.8, 127.6, 127.3, 124.6, 121.4, 119.2, 118.8, 118.6, 113.1, 111.8, 111.1, 109.2, 104.9, 95.0, 58.5, 41.6, 23.5, 23.0, 22.9, 21.8.

Anal. Calcd for C₃₀H₂₉N₃O₃: C, 75.13; H, 6.10; N, 8.76. Found: C, 75.40; H, 6.39; N, 8.66.

2-Acetyl-4,5,6,7-tetrahydroindole (17)

A soln of 2-benzoylethynyl-4,5,6,7-tetrahydroindole (16) (620 mg, 2.5 mmol), glycine (4) (189 mg, 2.5 mmol) and NaOH (100 mg, 2.5 mmol) in EtOH–H₂O (1:1, 16 mL) was heated at reflux temperature for 40 h. After cooling to r.t., the mixture was diluted with H₂O (50 mL) and extracted with Et₂O (3 × 20 mL). The combined organic layer was dried over MgSO₄ and evaporated to afford the title product 17. The aqueous layer was neutralized with 10% HCl, extracted with Et₂O (5 × 20 mL) and the combined organic layer dried over MgSO₄. The solvent was evaporated to give benzoic acid (244 mg, 80%).

Yield: 375 mg (91%); yellow oil.

¹H NMR (400.13 MHz, CDCl₃): δ = 8.94 (br s, 1 H, NH), 6.62 (s, 1 H, H-3), 2.58 (m, 2 H, CH₂-7), 2.49 (m, 2 H, CH₂-4), 2.33 (s, 3 H, COMe), 1.79 (m, 2 H, CH₂-5), 1.73 (m, 2 H, CH₂-6).

2-Acetyl-1-methyl-4,5,6,7-tetrahydroindole (15a)

A soln of ethyl 3-(1-methyl-4,5,6,7-tetrahydro-1H-indol-2-yl)propynoate (18) (542 mg, 2.5 mmol), alanine (5) (228 mg, 2.5 mmol) and NaOH (100 mg, 2.5 mmol) in EtOH–H₂O (1:1, 16 mL) was heated at reflux temperature for 10 h (TLC at this point did not show any traces of the starting acetylene). After cooling to r.t., the mixture was diluted with H₂O (50 mL) and extracted with Et₂O (3 × 20 mL). The combined organic layer was dried over MgSO₄ and evaporated to afford tetrahydroindole 15a.

Yield: 398 mg (89%); yellow oil.

IR (KBr): 1704 (CO) cm^–1.

¹H NMR (400.13 MHz, CDCl₃): δ = 6.71 (s, 1 H, H-3), 3.76 (s, 3 H, NMe), 2.52–2.48 (m, 4 H, CH₂-7,4), 2.35 (s, 3 H, COMe), 1.83–1.81 (m, 2 H, CH₂-5), 1.72–1.70 (m, 2 H, CH₂-6).

¹³C NMR (100.6 MHz, CDCl₃): δ = 187.6, 138.2, 129.4, 118.4, 118.0, 32.5, 26.9, 23.3, 22.8, 22.7, 22.1.

Acknowledgment

This work was carried out under financial support from the Russian Foundation of Basic Research (Grant No. 09-03-00064a).

• References

• 1a Magrioti V, Antonopoulou G, Pantoleon E, Kokotos G. ARKIVOC 2002; (xiii): 55
  Search in Google Scholar
• 1b Nájera C. Synlett 2002; 1388
  Thieme Connect
• 1c Trofimov BA, Mal’kina AG, Shemyakina OA, Borisova AP, Nosyreva VV, Dyachenko OA, Kazheva ON, Alexandrov GG. Synthesis 2007; 2641
  Thieme Connect
• 1d Caligiuri A, Arrigo PD, Rosini E, Pedrocchi-Fantoni G, Tessaro D, Molla G, Servi S, Pollegioni L. J. Mol. Catal. B: Enzym. 2008; 50: 93
  CrossrefSearch in Google Scholar
• 1e Trofimov BA, Mal’kina AG, Shemyakina OA, Nosyreva VV, Borisova AP, Albanov AI, Kazheva ON, Alexandrov GG, Chekhlov AN, Dyachenko OA. Tetrahedron 2009; 65: 2472
  CrossrefSearch in Google Scholar
• 1f Trofimov BA, Mal’kina AG, Shemyakina OA, Nosyreva VV, Borisova AP, Khutsishvili SS, Krivdin LB. Synthesis 2009; 3136
  Thieme Connect
• 1g Glotova TE, Dvorko MYu, Ushakov IA, Chipanina NN, Kazheva ON, Chekhlov AN, Dyachenko OA, Gusarova NK, Trofimov BA. Tetrahedron 2009; 65: 9814
  CrossrefSearch in Google Scholar
• 1h Trofimov BA, Mal’kina AG, Borisova AP, Shemyakina OA, Nosyreva VV, Albanov AI. Synthesis 2010; 3174
  Thieme Connect
• 1i Mal’kina AG, Borisova AP, Nosyreva VV, Shemyakina OA, Albanov AI, Trofimov BA. ARKIVOC 2011; (ix): 281
  Search in Google Scholar
• 2a Caujolle R, Payard M, Loiseau PR, Amarouch H, Linas MD, Séguéla JP, Bories C, Loiseau PM, Gayral P. Eur. J. Med. Chem. 1991; 26: 723
  CrossrefSearch in Google Scholar
• 2b Kurchan AN, Kutateladze AG. Org. Lett. 2002; 4: 4129
  CrossrefSearch in Google Scholar
• 2c Jsselstijn MI, Kaiser J, Van Delft FL, Schoemaker HE, Rutjes FP. J. T. Amino Acids 2003; 24: 263
  Search in Google Scholar
• 2d Ma JS. Chim. Oggi 2003; 21: 65
  Search in Google Scholar
• 2e Burger EC, Tunge JA. J. Am. Chem. Soc. 2006; 128: 10002
  CrossrefSearch in Google Scholar
• 2f Fülöp F, Martinek TA, Tόth GK. Chem. Soc. Rev. 2006; 35: 323
  CrossrefSearch in Google Scholar
• 2g Che Y, Marshall GR. J. Med. Chem. 2006; 49: 111
  CrossrefSearch in Google Scholar
• 3 Ivanov AV, Ushakov IA, Petrushenko KB, Mikhaleva AI, Trofimov BA. Eur. J. Org. Chem. 2010; 24: 4554
  Search in Google Scholar
• 4a Trofimov BA, Stepanova ZV, Sobenina LN, Mikhaleva AI, Ushakov IA. Tetrahedron Lett. 2004; 45: 6513
  CrossrefSearch in Google Scholar
• 4b Stepanova ZV, Sobenina LN, Mikhaleva AI, Ushakov IA, Elokhina VN, Voronov VK, Trofimov BA. Synthesis 2004; 2736
  Thieme Connect
• 4c Sobenina LN, Demenev AP, Mikhaleva AI, Ushakov IA, Vasil’tsov AM, Ivanov AV, Trofimov BA. Tetrahedron Lett. 2006; 47: 7139
  CrossrefSearch in Google Scholar
• 4d Trofimov BA, Sobenina LN, Stepanova ZV, Demenev AP, Mikhaleva AI, Ushakov IA, Vakul’skaya TI, Petrova OV. Russ. J. Org. Chem. 2006; 42: 1348
  CrossrefSearch in Google Scholar
• 4e Trofimov BA, Sobenina LN, Stepanova ZV, Ushakov IA, Petrova OV, Tarasova OA, Volkova KA, Mikhaleva AI. Synthesis 2007; 447
  Thieme Connect
• 4f Trofimov BA, Sobenina LN, Demenev AP, Stepanova ZV, Petrova OV, Ushakov IA, Mikhaleva AI. Tetrahedron Lett. 2007; 48: 4661
  CrossrefSearch in Google Scholar
• 5a Trofimov BA, Sobenina LN, Stepanova ZV, Vakul’skaya TI, Kazheva ON, Aleksandrov GG, Dyachenko OA, Mikhaleva AI. Tetrahedron 2008; 64: 5541
  CrossrefSearch in Google Scholar
• 5b Trofimov BA, Sobenina LN, Stepanova ZV, Petrova OV, Ushakov IA, Mikhaleva AI. Tetrahedron Lett. 2008; 49: 3946
  CrossrefSearch in Google Scholar
• 6a Trofimov BA, Mikhaleva АI. N-Vinylpyrroles . Nauka; Novosibirsk: 1984
  Search in Google Scholar
• 6b Trofimov BA. Advances in Heterocyclic Chemistry . Vol. 51. Academic Press; New York: 1990: 177
  Search in Google Scholar
• 6c Trofimov BA, Mikhaleva АI, Schmidt EYu, Ryapolov OA, Platonov VB. Patent RF RU 2297410, 2006 ; Chem. Abstr. 2007, 146, 462130
• 7a Sun H, Martin C, Kesselring D, Keller R, Moeller KD. J. Am. Chem. Soc. 2006; 128: 13761
  CrossrefSearch in Google Scholar
• 7b Dai N, Etzkorn FA. J. Am. Chem. Soc. 2009; 131: 13728
  CrossrefSearch in Google Scholar
• 7c Gentilucci L, Cerisoli L, De Marco R, Tolomelli A. Tetrahedron Lett. 2010; 51: 2576
  CrossrefSearch in Google Scholar
• 8a Ni Y, Zhao G, Ding Y. J. Chem. Soc., Perkin Trans. 1 2000; 3264
• 8b Woodin KS, Jamison TF. J. Org. Chem. 2007; 72: 7451
  CrossrefSearch in Google Scholar
• 9 Chen Z, Ye T. New J. Chem. 2006; 30: 518
  CrossrefSearch in Google Scholar
• 10a Enders D, Lenzen A, Müller M. Synthesis 2004; 1486
  Thieme Connect
• 10b Källström S, Erkkilä A, Pihko PM, Sjöholm R, Sillanpää R, Leino R. Synlett 2005; 751
• 10c Balalaie S, Bararjanian M, Amani AM, Movassagh B. Synlett 2006; 263
  Thieme Connect
• 11a Davydova MP, Vasilevskii SF, Tolstikov GA. Izv. Akad. Nauk. Ser. Khim. 2011; 180
• 11b Roy S, Davydova MP, Pal R, Gilmore K, Tolstikov GA, Vasilevsky SF, Alabugin IV. J. Org. Chem. 2011; 76: 7482
  CrossrefSearch in Google Scholar

• References

• 1a Magrioti V, Antonopoulou G, Pantoleon E, Kokotos G. ARKIVOC 2002; (xiii): 55
  Search in Google Scholar
• 1b Nájera C. Synlett 2002; 1388
  Thieme Connect
• 1c Trofimov BA, Mal’kina AG, Shemyakina OA, Borisova AP, Nosyreva VV, Dyachenko OA, Kazheva ON, Alexandrov GG. Synthesis 2007; 2641
  Thieme Connect
• 1d Caligiuri A, Arrigo PD, Rosini E, Pedrocchi-Fantoni G, Tessaro D, Molla G, Servi S, Pollegioni L. J. Mol. Catal. B: Enzym. 2008; 50: 93
  CrossrefSearch in Google Scholar
• 1e Trofimov BA, Mal’kina AG, Shemyakina OA, Nosyreva VV, Borisova AP, Albanov AI, Kazheva ON, Alexandrov GG, Chekhlov AN, Dyachenko OA. Tetrahedron 2009; 65: 2472
  CrossrefSearch in Google Scholar
• 1f Trofimov BA, Mal’kina AG, Shemyakina OA, Nosyreva VV, Borisova AP, Khutsishvili SS, Krivdin LB. Synthesis 2009; 3136
  Thieme Connect
• 1g Glotova TE, Dvorko MYu, Ushakov IA, Chipanina NN, Kazheva ON, Chekhlov AN, Dyachenko OA, Gusarova NK, Trofimov BA. Tetrahedron 2009; 65: 9814
  CrossrefSearch in Google Scholar
• 1h Trofimov BA, Mal’kina AG, Borisova AP, Shemyakina OA, Nosyreva VV, Albanov AI. Synthesis 2010; 3174
  Thieme Connect
• 1i Mal’kina AG, Borisova AP, Nosyreva VV, Shemyakina OA, Albanov AI, Trofimov BA. ARKIVOC 2011; (ix): 281
  Search in Google Scholar
• 2a Caujolle R, Payard M, Loiseau PR, Amarouch H, Linas MD, Séguéla JP, Bories C, Loiseau PM, Gayral P. Eur. J. Med. Chem. 1991; 26: 723
  CrossrefSearch in Google Scholar
• 2b Kurchan AN, Kutateladze AG. Org. Lett. 2002; 4: 4129
  CrossrefSearch in Google Scholar
• 2c Jsselstijn MI, Kaiser J, Van Delft FL, Schoemaker HE, Rutjes FP. J. T. Amino Acids 2003; 24: 263
  Search in Google Scholar
• 2d Ma JS. Chim. Oggi 2003; 21: 65
  Search in Google Scholar
• 2e Burger EC, Tunge JA. J. Am. Chem. Soc. 2006; 128: 10002
  CrossrefSearch in Google Scholar
• 2f Fülöp F, Martinek TA, Tόth GK. Chem. Soc. Rev. 2006; 35: 323
  CrossrefSearch in Google Scholar
• 2g Che Y, Marshall GR. J. Med. Chem. 2006; 49: 111
  CrossrefSearch in Google Scholar
• 3 Ivanov AV, Ushakov IA, Petrushenko KB, Mikhaleva AI, Trofimov BA. Eur. J. Org. Chem. 2010; 24: 4554
  Search in Google Scholar
• 4a Trofimov BA, Stepanova ZV, Sobenina LN, Mikhaleva AI, Ushakov IA. Tetrahedron Lett. 2004; 45: 6513
  CrossrefSearch in Google Scholar
• 4b Stepanova ZV, Sobenina LN, Mikhaleva AI, Ushakov IA, Elokhina VN, Voronov VK, Trofimov BA. Synthesis 2004; 2736
  Thieme Connect
• 4c Sobenina LN, Demenev AP, Mikhaleva AI, Ushakov IA, Vasil’tsov AM, Ivanov AV, Trofimov BA. Tetrahedron Lett. 2006; 47: 7139
  CrossrefSearch in Google Scholar
• 4d Trofimov BA, Sobenina LN, Stepanova ZV, Demenev AP, Mikhaleva AI, Ushakov IA, Vakul’skaya TI, Petrova OV. Russ. J. Org. Chem. 2006; 42: 1348
  CrossrefSearch in Google Scholar
• 4e Trofimov BA, Sobenina LN, Stepanova ZV, Ushakov IA, Petrova OV, Tarasova OA, Volkova KA, Mikhaleva AI. Synthesis 2007; 447
  Thieme Connect
• 4f Trofimov BA, Sobenina LN, Demenev AP, Stepanova ZV, Petrova OV, Ushakov IA, Mikhaleva AI. Tetrahedron Lett. 2007; 48: 4661
  CrossrefSearch in Google Scholar
• 5a Trofimov BA, Sobenina LN, Stepanova ZV, Vakul’skaya TI, Kazheva ON, Aleksandrov GG, Dyachenko OA, Mikhaleva AI. Tetrahedron 2008; 64: 5541
  CrossrefSearch in Google Scholar
• 5b Trofimov BA, Sobenina LN, Stepanova ZV, Petrova OV, Ushakov IA, Mikhaleva AI. Tetrahedron Lett. 2008; 49: 3946
  CrossrefSearch in Google Scholar
• 6a Trofimov BA, Mikhaleva АI. N-Vinylpyrroles . Nauka; Novosibirsk: 1984
  Search in Google Scholar
• 6b Trofimov BA. Advances in Heterocyclic Chemistry . Vol. 51. Academic Press; New York: 1990: 177
  Search in Google Scholar
• 6c Trofimov BA, Mikhaleva АI, Schmidt EYu, Ryapolov OA, Platonov VB. Patent RF RU 2297410, 2006 ; Chem. Abstr. 2007, 146, 462130
• 7a Sun H, Martin C, Kesselring D, Keller R, Moeller KD. J. Am. Chem. Soc. 2006; 128: 13761
  CrossrefSearch in Google Scholar
• 7b Dai N, Etzkorn FA. J. Am. Chem. Soc. 2009; 131: 13728
  CrossrefSearch in Google Scholar
• 7c Gentilucci L, Cerisoli L, De Marco R, Tolomelli A. Tetrahedron Lett. 2010; 51: 2576
  CrossrefSearch in Google Scholar
• 8a Ni Y, Zhao G, Ding Y. J. Chem. Soc., Perkin Trans. 1 2000; 3264
• 8b Woodin KS, Jamison TF. J. Org. Chem. 2007; 72: 7451
  CrossrefSearch in Google Scholar
• 9 Chen Z, Ye T. New J. Chem. 2006; 30: 518
  CrossrefSearch in Google Scholar
• 10a Enders D, Lenzen A, Müller M. Synthesis 2004; 1486
  Thieme Connect
• 10b Källström S, Erkkilä A, Pihko PM, Sjöholm R, Sillanpää R, Leino R. Synlett 2005; 751
• 10c Balalaie S, Bararjanian M, Amani AM, Movassagh B. Synlett 2006; 263
  Thieme Connect
• 11a Davydova MP, Vasilevskii SF, Tolstikov GA. Izv. Akad. Nauk. Ser. Khim. 2011; 180
• 11b Roy S, Davydova MP, Pal R, Gilmore K, Tolstikov GA, Vasilevsky SF, Alabugin IV. J. Org. Chem. 2011; 76: 7482
  CrossrefSearch in Google Scholar