Temperature-Controlled Diastereoselective Doebner/Ugi Tandem Reaction

Abstract

Novel peptidomimetics containing a pyrrolone fragment were synthesized by a tandem combination of Doebner and Ugi type multicomponent reactions with controlled diastereoselectivity. This approach represents a convenient synthesis in the temperature range from 25 to 45 °C. In most cases, the new method allowed each diastereomer to be isolated separately.

Keywords

multicomponent reactions - Doebner reaction - Ugi reaction - peptidomimetics - pyrrolones - diastereoselectivity

Multicomponent reactions (MCRs) play an important role in the synthesis of organic molecules and they can be used to create new highly potent bioactive structures. MCRs involve the transformation of three or more starting materials into the final product in an atom- and step-economical manner in modern organic synthesis, especially in areas of drug discovery and combinatorial chemistry, allowing large libraries of organic heterocyclic compounds to be generated. In addition, MCRs are often characterized by high yields, low waste formation, and high efficiency.[1] [2] [3] [4] [5]

The combination of Doebner and Ugi type MCRs is a way to increase the diversity of organic compounds and to obtain peptidomimetics containing a pyrrolone moiety as a biologically privileged heterocyclic structure. The pyrrolidinone scaffold is present in numerous bioactive agents, such as the endothelin receptor antagonist oteromicyn,[6] antibiotics,[7] antimicrobials,[8] antipyretics,[9] analgesics,[10] novel tyrosinase inhibitors,[11] and molecules for the treatment of Alzheimer’s disease[12] and tumors.[13] [14]

Substituted pyrrolones as heterocyclic enols (acid component) containing a conjugated ester group can be functionalized via the OH group of the 3-position by an Ugi-type condensation to produce biologically relevant heterocyclic enamines (Scheme [1]). Moreover, the presence of a stereogenic center in the pyrrolone ring would lead to the formation of two diastereomeric products in the Ugi reaction.[15]

Scheme 1 Pyrrolones as acid component in the Ugi reaction

Stereoselective control of Ugi reactions remains a difficult task, and many scientific groups have sought to address this issue.[16] [17] Good diastereoselectivity of MCRs is very useful to avoid the need to separate diastereomers, and to control the relative configuration of the final product.[18–20]

In our previous work,[21] the combination of two multicomponent reactions was studied: the pyrazolopyridine carboxylic acids obtained in the Doebner type condensation were involved in the Ugi reaction with aromatic aldehydes, amines, and tert-butyl isocyanide, which allowed the synthesis of new compounds containing a peptide bond and an azoloazine fragment (Scheme [2]). The Ugi product, possessing two pharmacophores, namely pyrazolopyridine and peptidomimetic moieties, showed antibacterial activity.[21]

Scheme 2 Synthesis of substituted 1H-pyrazolo[3,4-b]pyridine-4- and 1H-pyrazolo[3,4-b]pyridine-6-carboxamides via Doebner and Ugi type reaction

Substituted pyrrolidinones with a carboxyl-containing substituent at the 4-position, have been shown to be a privileged unit for increasing molecular diversity, and they can be introduced into subsequent MCRs. Therefore, we studied the tandem combination of three-component Doebner type reaction and four-component Ugi reaction.

Scheme 3 Diastereoselective tandem Ugi/Doebner type reaction

Pyrrolones 4a–c were synthesized via a three-component condensation of 3-amino-5-methylisoxazole (1) with aromatic aldehydes 2′a–c and α-ketoglutaric acid (3) in refluxing AcOH for 4 h in 44–62% yield (Scheme [3]).[22] Subsequently, heterocycles 4 were introduced as the acidic component in the four-component Ugi reaction with aromatic aldehydes 2a–c, aromatic amines 5a–c, and tert-butyl isocyanide (6) in trifluoroethanol in an oil bath for 24 h at 45 °C (Scheme [3]). As a result, N-(tert-butyl)-2-(2-(2-aryl-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H)-pyrrol-3-yl)-N-(arylacetamido)-2-arylacetamides 7a–o were isolated from the reaction.

It should be noted that under the above conditions, this Ugi reaction gave a mixture of two possible diastereomers (A and B) (Scheme [3]) in a different ratio. The progress of the reaction was monitored by TLC [R_f = 0.55 (n-hexane/ethyl acetate, 1:2), the location and appearance of the spots of both diastereomers were practically the same]. Separation of the diastereomers by fractional crystallization or column chromatography was unsuccessful. To avoid the separation procedure for the diastereomers, we decided to develop a synthetic method that would allow the selective (or practically selective) formation of both diastereomers.

It was found that treatment of aromatic aldehyde 2 and amine 5 in methanol at 25 °C followed by the addition of acid 4 and tert-butyl isocyanide 6 in the temperature range from 25 to 45 °C and stirring of the resulting mixture at 45 °C for 24 h (see Experimental Section) gave only diastereomer A of compound 7 in yields of 24–65% (Scheme [3], Table [1]). In turn, the precipitate formed from the mother liquor within a day at 20 °C was diastereomer B of compound 7 (20–35% yield according to the ¹H NMR spectroscopy data). It should be noted that the Ugi reaction in methanol at temperatures as low as 20 °C resulted in the formation of product 7 as a mixture of diastereomers A and B.

Table 1 Synthesis of Ugi Products 7a–o (Diastereomers A and B)

Entry	Starting materials						Product	Yield (%)
	R	Pyrrolone	R1	Amine	R2	Aldehyde		Diastereomer
								A	B
1	4-Cl	4a	4-OCH3	5a	4-Cl	2a	7a	49	29
2	4-Cl	4a	4-Cl	5b	4-Cl	2a	7b	41a
3	4-Cl	4a	4-CH3	5c	4-Cl	2a	7c	41	–
4	4-Cl	4a	4-OCH3	5a	4-OCH3	2b	7d	65	20
5	4-Cl	4a	4-Cl	5b	4-OCH3	2b	7e	89a
6	4-Cl	4a	4-CH3	5c	4-OCH3	2b	7f	45	23
7	4-Cl	4a	4-OCH3	5a	4-CO-OCH3	2c	7g	42	35
8	4-Cl	4a	4-Cl	5b	4-CO-OCH3	2c	7h	45	35
9	4-Cl	4a	4-CH3	5c	4-CO-OCH3	2c	7i	34a	24
10	4-OCH3	4b	4-OCH3	5a	4-OCH3	2b	7j	41	33
11	4-OCH3	4b	4-Cl	5b	4-Cl	2a	7k	45	–
12	4-OCH3	4b	4-CH3	5c	4-Cl	2a	7l	49	–
13	4-CO-OCH3	4c	4-OCH3	5a	4-OCH3	2b	7m	40	21
14	4-CO-OCH3	4c	4-Cl	5b	4-OCH3	2b	7n	73a
15	4-CO-OCH3	4c	4-CH3	5c	4-OCH3	2b	7o	64	–

^a Mixture of two diastereomers.

For compounds 7a, 7d, 7f–h, 7j, and 7m, each of the diastereomers (A and B) was isolated individually. In some cases, in addition to one diastereomer, the second diastereomer was found in amounts up to 15%. Some of the peptidomimetics 7 (7c, 7i, 7k, 7l, and 7o) spontaneously precipitated from the reaction mixture, yielding only one diastereomer (A or B). The corresponding mother liquors were examined and the reaction solution was found to contain a mixture of both diastereomers and unreacted starting materials with some intermediates. Compounds 7b, 7e and 7n were formed as a mixture of two diastereomers (diastereomer ratio was close to 1:1) irrespective of the solvent and reaction temperature. The purity of the obtained compounds 7 of both diastereomers (A and B) was determined by HPLC analysis and/or LCMS.

Diastereomers A and B have similar solubility: they are soluble in dimethyl sulfoxide, dimethyl formamide, ethanol, and dichloromethane and insoluble in toluene, ether, hexane, and water.

The purity and structures of the synthesized compounds were established by elemental analysis, mass spectrometry, ¹H and ¹³C NMR spectroscopy, and by X-ray diffraction studies. For example, the ¹H NMR spectra of compounds 7a–o exhibited the following signals: two signals for diastereotopic protons of CH₂ group at 2.14–2.24 and 3.15–3.27 ppm, protons of the t-butyl group at 1.22–1.25 ppm (diastereomer A) and 1.28–1.29 ppm (diastereomer B), a singlet for the CH group of pyrrolone at 5.53–5.59 ppm, a singlet for the CH group at the aldehyde moiety (5.93–5.99 ppm), a singlet for CH group of the isoxazole fragment (6.68–6.75 ppm), singlet protons for the NH group in the 7.58–7.93 ppm, peaks for aromatic protons in the range of 5.90–7.98 ppm, a singlet for the enol OH group in pyrrolone at 9.88–10.04 ppm and signals for terminal functional groups in appropriate regions of the spectra. Broad and double signals of some aromatic protons may indicate the presence of rotamerism. Indeed, temperature NMR experiments for compound 7j confirmed the presence of rotamers in solution due to the hindered rotation around the amide C–N bond.[23] [24] [25] [26]

The structure of compounds 7a–o for each diastereomer A and B was additionally proven by X-ray analysis of compound 7d (Figure [1] and Figure [2]).

Figure 1 Molecular structure of N-(tert-butyl)-2-(2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(4-methoxyphenyl)acetamido)-2-(4-methoxyphenyl)acetamide (7d). R,R (S,S)-Diastereomer A obtained from X-ray diffraction data.

X-ray diffraction analysis of diastereomer B (compound 7d) (Figure [2]) was described in our previous work.[27] Diastereomer A of compound 7d was crystallized as a non-solvated structure in contrast to the diastereomer B, which was found to be a methanol solvate in the crystal structure. Comparison of the molecular structures of these diastereomers revealed only one significant difference related to the conformation of the substituent on the C7 atom. The C16(=O4)–N3 carbamide group in diastereomer B is located in the –ac position with respect to the C6–C7 endocyclic bond [C6–C7–C15–C16 = –107.2 (3)°] due to rotation around the C7–C15 bond. The hydroxyl group forms an intermolecular hydrogen bond with the methanol solvent molecule. In diastereomer A, the carbamide group is in an intermediate position between sp and +sc in relation to the C6–C7 endocyclic bond [C6–C7–C15–C16 = 33.1 (6)°]. This orientation is stabilized by the intramolecular hydrogen bond O3–H3···O4 [the H3···O4 distance is 1.78 Å, the O3–H3···O4 angle is 159°].

Figure 2 Molecular structure of N-(tert-butyl)-2-(2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(4-methoxyphenyl)acetamido)-2-(4-methoxyphenyl)acetamide (7d). R,S (S,R)-Diastereomer B obtained from X-ray diffraction data.

In summary, a procedure based on the tandem combination of Doebner and Ugi reactions has been developed in which the formation of pyrrolone-containing peptidomimetics selectively generates both possible diastereomers of the target compounds in most cases. This treatment is carried out by regulating the solvent and temperature to control selectivity. The optimal conditions are methanol as solvent and heating temperature between 25 and 45 °C.

The starting pyrrolones 4a–c were synthesized according to a described procedure.[22] The aromatic aldehydes 2a–c, aromatic amines 5a–c, and tert-butyl isocyanide (6) are commercially available. All solvents were obtained from commercial suppliers and used without additional purification. Melting points of all synthesized compounds were determined with a Stuart SMP10 electronic melting-point apparatus and are uncorrected. The ¹H and ¹³C NMR spectra were performed in DMSO-d ₆ at 400 MHz (100 MHz for ¹³C) with a Varian MR-400 spectrometer. Mass spectra were measured with a Shimadzu LCMS-2020, Waters Quatro Micro API mass spectrometer, mass spectrometer VG 70-70EQ with primary FAB ion source and LC /MSD Agilent 1100 with ESI. Elemental analysis was performed with a Euro Vector EA-3000. Thin-layer chromatography was performed on pre-coated TLC films Alugram (layer 0.20 mm silica gel). HPLC analysis was performed with a Shimadzu LC -2030 3D Plus.

X-ray Crystallography

The colorless crystals of diastereomer A (C₃₆H₃₇ClN₄O₇) are triclinic. At 293 K, a = 10.3733(17), b = 12.0572(13), c = 16.474(2) Å, α = 73.728(10)°, β = 74.040(13)°, γ = 82.795(11)°, V = 1899.1(5) ų, M _r = 673.14, Z = 2, space group P-1, d _calc = 1.177 g/сm³, μ(MoK_α) = 0.150 mm^–1, F(000) = 708. Intensities of 13448 reflections (6674 independent, R_int = 0.087) were measured with an «Xcalibur-3» diffractometer (graphite monochromated MoKα radiation, CCD detector, ω-scaning, 2Θ_max = 50°). The structure was solved by direct methods using the SHELXTL package.[28] Positions of the hydrogen atoms were located from electron density difference maps and refined by the ‘riding’ model with U_iso = nU_eq (n = 1.5 for methyl groups and n = 1.2 for other hydrogen atoms) of the carrier atom. Full-matrix least-squares refinement against F² in anisotropic approximation for non-hydrogen atoms using 6674 reflections was converged to wR ₂ = 0.216 (R ₁ = 0.073 for 2969 reflections with F>4σ(F), S = 0.971).

CCDC 2250972 (molecule 7) contains the supplementary crystallographic data for this paper. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/structures.

Ugi Products 7a–o; General Procedure

A mixture of aldehyde 2 (0.29 mmol) and amine 5 (0.29 mmol) in MeOH (2 mL) was stirred at 25 °C for 50 min. Then pyrrolone 4 (0.29 mmol) and tert-butyl isocyanide 6 (0.29 mmol) were added at 25 °C, successively, and the temperature was increased to 45 °C. The resulting mixture was stirred at 45 °C for 24 h. The reaction was monitored by TLC (R_f = 0.55; n-hexane/EtOAc 1:2). The formed white precipitate was immediately filtered off from the warm reaction mixture and dried in vacuum (diastereomer A). The mother liquor was allowed to stand at 20 °C for 1 day, and the resulting precipitate was filtered and dried in vacuum (diastereomer B).

N-(tert-Butyl)-2-(4-chlorophenyl)-2-(2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(4-methoxyphenyl)acetamido)acetamide (7a)

DiastereomerA

Yield 96 mg (49%); white solid; mp 249–251 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.04 (s, 1 H, ОН), 7.72 (s, 1 Н, NН), 6.10–7.56 (m, 12 Н, ArH), 6.73 (s, 1 Н, СН isoxazole), 5.98 (s, 1 Н, СН), 5.58 (s, 1 Н, СН pyrrolone), 3.62 (s, 3 Н, ОСН₃), 3.28 (d, J = 17.6 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.18 (d, J = 17.6 Hz, 1 H, СН₂), 1.23 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 168.7, 168.5, 165.1, 158.2, 156.1, 142.5, 135.2, 134.6, 132.7, 132.3, 131.9, 131.8, 131.5, 129.1, 128.7, 127.8, 122.8, 113.4, 94.9, 63.1, 60.6, 55.1, 50.4, 30.4, 28.4, 12.1.

MS (ESI): m/z = 677 (100) [M + H]⁺, 604 (50).

Anal. Calcd for C₃₅H₃₄Cl₂N₄O₆: C, 62.04; H, 5.06; N, 8.27. Found: C, 62.0; H, 5.09; N, 8.22.

DiastereomerB

Yield 57 mg (29%); light-yellow solid; mp 217–219 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.02 (s, 1 H, ОН), 7.80 (s, 1 Н, NН), 6.40–7.46 (m, 12 Н, ArH), 6.75 (s, 1 Н, СН isoxazole), 5.94 (s, 1 Н, СН), 5.54 (s, 1 Н, СН pyrrolone), 3.62 (s, 3 Н, ОСН₃), 3.19 (d, J = 17.3 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.22 (d, J = 17.3 Hz, 1 H, СН₂), 1.28 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 168.8, 168.6, 165.2, 158.2, 156.1, 142.4, 135.2, 134.5, 132.5, 132.2, 131.8, 131.7, 131.6, 128.7, 128.6, 127.8, 123.5, 113.4, 94.9, 63.1, 60.8, 55.1, 50.4, 30.2, 28.4, 12.0.

MS (ESI): m/z = 677 [M + H]⁺, 604 (40).

Anal. Calcd for C₃₅H₃₄Cl₂N₄O₆: C, 62.04; H, 5.06; N, 8.27. Found: C, 62.07; H, 5.11; N, 8.24.

N-(tert-Butyl)-2-(4-chlorophenyl)-2-(N-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)acetamido)acetamide (7b)

Mixture of diastereomers A/B (diastereomeric ratio 50:50).

Yield 81 mg (41%); white solid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.02 (s, 0.5 H-B, ОН), 9.98 (s, 0.5 H-A, ОН), 7.87 (s, 0.5 H-B, NН), 7.80 (s, 0.5 H-A, NН), 6.33–7.60 (m, 12 Н, ArH), 6.75 (s, 0.5 H-B, СН isoxazole), 6.73 (s, 0.5 H-A, СН isoxazole), 6.02 (s, 0.5 H-A, СН), 5.98 (s, 0.5 H-B, СН), 5.61 (s, 0.5 H-A, СН pyrrolone), 5.54 (s, 0.5 H-B, СН pyrrolone), 3.19–3.25 (m, 1 H, СН₂), 2.33 (s, 3 Н, СН₃), 2.20–2.26 (m, 1 H, СН₂), 1.29 (s, 4.5 Н-B, t-Bu), 1.25 (s, 4.5 H-A, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 170, 168.7, 168.0, 167.9, 165.2, 164.9, 156.1, 156.0, 142.5, 138.1, 137.9, 135.2, 135.1, 134.2, 132.7, 132.5, 132.4, 132.3, 131.9, 131.8, 129.1, 128.7, 128.6, 128.4, 127.9, 123.0, 123.1, 122.2, 94.9, 63.1, 63.0, 60.8, 60.6, 50.5, 50.4, 30.5, 30.4, 28.4, 12.1.

MS (ESI): m/z (%) = 683 (100) [M + H]⁺.

Anal. Calcd for C₃₄H₃₁Cl₃N₄O₅: C, 59.88; H, 4.58; N, 8.22. Found: C, 59.84; H, 4.54; N, 8.27.

N-(tert-Butyl)-2-(4-chlorophenyl)-2-(2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(p-tolyl)acetamido)acetamide (7c)

Diastereomer A

Yield 78 mg (41%); white solid; mp 228–230 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.0 (s, 1 H, ОН), 7.73 (s, 1 Н, NН), 6.58–7.60 (m, 12 Н, ArH), 6.73 (s, 1 Н, СН isoxazole), 6.0 (s, 1 Н, СН), 5.58 (s, 1 Н, СН pyrrolone), 3.27 (d, J = 17.8 Hz¸ СН₂), 2.32 (s, 3 Н, СН₃), 2.19 (d, J = 17.8 Hz, СН₂), 1.23 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 168.6, 168.3, 165.0, 156.0, 142.5, 137.1, 136.4, 135.2, 134.5, 132.7, 132.3, 131.8, 130.2, 129.0, 128.9, 128.6, 127.8, 122.8, 94.9, 63.1, 60.6, 50.4, 30.4, 28.4, 20.5, 12.0.

MS (ESI): m/z (%) = 661 (100) [M + H]⁺.

Anal. Calcd for C₃₅H₃₄Cl₂N₄O₅: C, 63.54; H, 5.18; N, 8.47. Found: C, 63.60; H, 5.14; N, 8.51.

N-(tert-Butyl)-2-(2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(4-methoxyphenyl)acetamido)-2-(4-methoxyphenyl)acetamide (7d)

DiastereomerA

Yield 127 mg (65%); white solid; mp 251–253 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.99 (s, 1 H, ОН), 7.58 (s, 1 Н, NН), 5.96–7.63 (m, 12 Н, ArH), 6.70 (s, 1 Н, СН isoxazole), 5.94 (s, 1 Н, СН), 5.59 (s, 1 Н, СН pyrrolone), 3.65 (s, 3 Н, ОСН₃), 3.62 (s, 3 Н, ОСН₃), 3.27 (d, J = 17.6 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.19 (d, J = 17.6 Hz, 1 H, СН₂), 1.23 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.2, 169.4, 168.5, 165.1, 158.6, 158.1, 156.1, 142.5, 135.3, 132.8, 131.9, 131.4, 129.1, 128.7, 127.4, 123.1, 113.4, 113.3, 113.2, 95.0, 63.4, 60.8, 55.2, 55.0, 50.3, 30.6, 28.5, 12.1.

MS (ESI): m/z (%) = 673 (82) [M + H]⁺, 600 (70).

Anal. Calcd for C₃₆H₃₇ClN₄O₇: C, 64.23; H, 5.54; N, 8.32. Found: C, 64.18; H, 5.49; N, 8.37.

DiastereomerB.

Yield 40 mg (20%); white solid; mp 191–193 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.99 (s, 1 H, ОН), 7.66 (s, 1 Н, NН), 6.36–7.52 (m, 12 Н, ArH), 6.75 (s, 1 Н, СН isoxazole), 5.88 (s, 1 Н, СН), 5.54 (s, 1 Н, СН pyrrolone), 3.63 (s, 3 Н, ОСН₃), 3.61 (s, 3 Н, ОСН₃), 3.17 (d, J = 17.4 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.21 (d, J = 17.4 Hz, 1 H, СН₂), 1.28 (s, 9 H, t-Bu).

¹³C NMR spectrum (100 MHz, DMSO-d ₆): δ = 170.1, 169.4, 168.5, 158.4, 158.0, 156.1, 142.4, 135.2, 132.5, 131.9, 131.5, 131.3, 128.7, 128.6, 127.3, 123.6, 113.3, 113.2, 113.1, 94.9, 63.3, 60.8, 55.0, 54.9, 50.3, 30.3, 28.4, 12.1.

MS (ESI): m/z (%) = 673 (38) [M + H]⁺, 600 (41), 695 (100) [M + Na]⁺.

Anal. Calcd for C₃₆H₃₇ClN₄O₇: C, 64.23; H, 5.54; N, 8.32. Found: C, 64.15; H, 5.45; N, 8.4.

N-(tert-Butyl)-2-(N-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)acetamido)-2-(4-methoxyphenyl)acetamide (7e)

Mixture of diastereomers A/B (diastereomeric ratio 40:60).

Yield 175 mg (89%); white solid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.05 (s, 0.6 H-B, ОН), 10.02 (s, 0.4 H-A, ОН), 7.80 (s, 0.6 H-B, NН), 7.73 (s, 0.4 H-A, NН), 6.30–7.65 (m, 12 Н, ArH), 6.76 (s, 0.6 H-B, СН isoxazole), 6.73 (s, 0.4 H-A, СН isoxazole), 5.98 (s, 0.4 H-A, СН), 5.93 (s, 0.6 H-B, СН), 5.62 (s, 0.4 H-A, СН pyrrolone), 5.55 (s, 0.6 H-B, СН pyrrolone), 3.64 (s, 3 Н, ОСН₃), 3.10–3.32 (m, 1 H, СН₂), 2.33 (s, 3 Н, СН₃), 2.17–2.27 (m, 1 H, СН₂), 1.29 (s, 5Н-B, t-Bu), 1.25 (s, 4 H-A, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.6, 170.5, 169.8, 169.7, 168.4, 168.3, 165.7, 159.0, 156.5, 142.9, 138.8, 138.7, 135.8, 135.7, 133.2, 133.0, 132.9, 132.6, 132.5, 131.7, 129.6, 129.1, 128.8, 128.7, 127.4, 123.7, 122.9, 113.8, 95.4, 63.7, 55.4, 50.8, 30.9, 28.9, 12.6.

MS (ESI): m/z (%) = 677 (64) [M + H]⁺.

Anal. Calcd for C₃₅H₃₄Cl₂N₄O₆: C, 62.04; H, 5.06; N, 8.27. Found: C, 61.98; H, 5.01; N, 8.31.

N-(tert-Butyl)-2-(2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(p-tolyl)acetamido)-2-(4-methoxyphenyl)acetamide (7f)

DiastereomerA.

Yield 85 mg (45%); white solid; mp 245–247 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.99 (s, 1 H, ОН), 7.58 (s, 1 Н, NН), 6.48–7.47 (m, 12 Н, ArH), 6.72 (s, 1 Н, СН isoxazole), 5.94 (s, 1 Н, СН), 5.58 (s, 1 Н, СН pyrrolone), 3.64 (s, 3 Н, ОСН₃), 3.25 (d, J = 17.4 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.17 (d, J = 17.4 Hz, 1 H, СН₂), 2.12 (s, 3 Н, СН₃), 1.23 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 169.2, 168.2, 165.1, 158.5, 156.1, 142.4, 136.8, 136.6, 135.3, 132.7, 131.3, 130.2, 129.0, 128.8, 128.6, 127.3, 123.0, 113.2, 94.9, 63.3, 60.7, 55.0, 50.3, 30.5, 28.5, 20.5, 12.1.

MS (ESI): m/z (%) = 657 (100) [M + H]⁺.

Anal. Calcd for C₃₆H₃₇ClN₄O₆: C, 65.8; H, 5.68; N, 8.53. Found: C, 65.88; H, 5.62; N, 8.59.

DiastereomerB.

Yield 43 mg (23%); white solid; mp 205–207 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.0 (s, 1 H, ОН), 7.68 (s, 1 Н, NН), 6.35–7.50 (m, 12 Н, ArH), 6.74 (s, 1 Н, СН isoxazole), 5.90 (s, 1 Н, СН), 5.54 (s, 1 Н, СН pyrrolone), 3.63 (s, 3 Н, ОСН₃), 3.16 (d, J = 17.6 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.19 (d, J = 17.6 Hz, 1 H, СН₂), 2.12 (s, 3 Н, СН₃), 1.28 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.2, 169.4, 168.3, 165.3, 158.4, 156.1, 142.4, 136.8, 136.8, 135.2, 132.6, 131.3, 130.3, 128.8, 128.7, 128.6, 127.3, 123.6, 113.2, 95.0, 63.4, 60.9, 55.0, 50.4, 30.4, 28.5, 20.6, 12.1.

MS (ESI): m/z (%) = 657 (100) [M + H]⁺.

Anal. Calcd for C₃₆H₃₇ClN₄O₆: C, 65.8; H, 5.68; N, 8.53. Found: C, 65.84; H, 5.61; N, 8.61.

Methyl 4-(2-(tert-Butylamino)-1-(2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(4-methoxyphenyl)acetamido)-2-oxoethyl)benzoate (7g)

DiastereomerA.

Yield 85 mg (42%); white solid; mp 240–242 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.04 (s, 1 H, ОН), 7.80 (s, 1 Н, NН), 6.12–7.77 (m, 12 Н, ArH), 6.73 (s, 1 Н, СН isoxazole), 6.06 (s, 1 Н, СН), 5.59 (s, 1 Н, СН pyrrolone), 3.79 (s, 3 Н, ОСН₃), 3.60 (s, 3 Н, ОСН₃), 3.29 (d, J = 17.1 Hz, 1 H, СН₂), 2.33 (s, 3 Н, СН₃), 2.21 (d, J = 17.1 Hz, 1 H, СН₂), 1.23 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 168.6, 168.4, 165.9, 165.1, 158.2, 156.0, 142.5, 141.0, 135.2, 132.7, 131.9, 131.5, 131.0, 130.5, 129.1, 128.7, 128.6, 122.8, 113.5, 94.9, 63.5, 60.6, 55.1, 52.1, 50.4, 30.3, 28.4, 12.1.

MS (ESI): m/z (%) = 701 (100) [M + H]⁺.

Anal. Calcd for C₃₇H₃₇ClN₄O₈: C, 63.38; H, 5.32; N, 7.99. Found: C, 63.29; H, 5.37; N, 8.02.

Diastereomer B.

Yield 71 mg (35%); white solid; mp 157–159 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.01 (s, 1 H, ОН), 7.84 (s, 1 Н, NН), 6.46–7.76 (m, 12 Н, ArH), 6.75 (s, 1 Н, СН isoxazole), 6.02 (s, 1 Н, СН), 5.54 (s, 1 Н, СН pyrrolone), 3.79 (s, 3 Н, ОСН₃), 3.60 (s, 3 Н, ОСН₃), 3.21 (d, J = 17.6 Hz, 1 H, СН₂), 2.33 (s, 3 Н, СН₃), 2.25 (d, J = 17.6 Hz, 1 H, СН₂), 1.29 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.0, 168.6, 168.4, 165.8, 165.0, 158.2, 156.0, 142.5, 141.0, 135.6, 131.6, 131.5, 131.1, 130.4, 129.4, 128.6, 128.5, 122.7, 121.2, 113.4, 94.9, 63.5, 60.7, 55.1, 52.1, 50.4, 30.3, 28.4, 12.0.

MS (ESI): m/z = 701 [M + H]⁺.

Methyl 4-(2-(tert-Butylamino)-1-(N-(4-chlorophenyl)-2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)acetamido)-2-oxoethyl)benzoate (7h)

DiastereomerA.

Yield 92 mg (45%); white solid; mp 227–229 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.0 (s, 1 H, ОН), 7.87 (s, 1 Н, NН), 6.40–7.78 (m, 12 Н, ArH), 6.73 (s, 1 Н, СН isoxazole), 6.10 (s, 1 Н, СН), 5.61 (s, 1 Н, СН pyrrolone), 3.79 (s, 3 Н, ОСН₃), 3.23 (d, J = 17.0 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.25 (d, J = 17.0 Hz, 1 H, СН₂), 1.25 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 168.4, 168.0, 165.8, 165.2, 164.9, 156.0, 142.5, 140.6, 138.0, 135.1, 132.6, 132.3, 130.4, 129.1, 128.7, 128.6, 128.4, 123.0, 122.2, 94.9, 63.4, 60.8, 52.0, 50.5, 30.3, 28.3, 12.0.

MS (ESI): m/z (%) = 705 (100) [M + H]⁺.

Anal. Calcd for C₃₆H₃₄Cl₂N₄O₇: C, 61.28; H, 4.86; N, 7.94. Found: C, 61.21; H, 4.90; N, 8.04.

DiastereomerB.

Yield 71 mg (35%); light-yellow solid; mp 170–172 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 7.93 (s, 1 Н, NН), 7.01–7.81 (m, 12 Н, ArH), 6.75 (s, 1 Н, СН isoxazole), 6.06 (s, 1 Н, СН), 5.53 (s, 1 Н, СН pyrrolone), 3.78 (s, 3 Н, ОСН₃), 3.24 (d, J = 17.3 Hz, 1 H, СН₂), 2.33 (s, 3 Н, СН₃), 2.24 (d, J = 17.3 Hz, 1 H, СН₂), 1.29 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.0, 168.4, 168.2, 165.8, 165.5, 156.1, 142.9, 140.6, 138.0, 135.3, 132.6, 132.5, 132.3, 130.4, 129.1, 128.8, 128.7, 128.6, 128.4, 122.6, 94.9, 63.4, 60.8, 52.1, 50.5, 30.3, 28.4, 12.0.

MS (ESI): m/z (%) = 705 (100) [M + H]⁺.

Anal. Calcd for C₃₆H₃₄Cl₂N₄O₇: C, 61.28; H, 4.86; N, 7.94. Found: C, 61.21; H, 4.91; N, 7.89.

Methyl 4-(2-(tert-Butylamino)-1-(2-(2-(4-chlorophenyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(p-tolyl)acetamido)-2-oxoethyl)benzoate (7i)

DiastereomerB.

Yield 48 mg (24%); white solid; mp 178–180 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.02 (s, 1 H, ОН), 7.85 (s, 1 Н, NН), 6.75–7.75 (m, 12 Н, ArH), 6.75 (s, 1 Н, СН isoxazole), 6.03 (s, 1 Н, СН), 5.54 (s, 1 Н, СН pyrrolone), 3.78 (s, 3 Н, ОСН₃), 3.20 (d, J = 17.3 Hz, 1 H, СН₂), 2.33 (s, 3 Н, СН₃), 2.22 (d, J = 17.3 Hz, 1 H, СН₂), 1.28 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 168.4, 165.8, 165.2, 156.0, 142.5, 140.8, 141.0, 137.1, 136.4, 135.1, 132.5, 130.4, 130.2, 128.9, 128.7, 128.6, 128.5, 123.4, 94.9, 63.5, 60.8, 52.1, 50.5, 30.2, 28.4, 20.4, 12.0.

MS (ESI): m/z (%) = 685 (100) [M + H]⁺, 612 (50).

Anal. Calcd for C₃₇H₃₇ClN₄O₇: C, 64.86; H, 5.44; N, 8.18. Found: C, 64.8; H, 5.49; N, 8.25.

Mixture of diastereomers A/B(diastereomeric ratio 50:50).

Yield 67 mg (34%); white solid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.02 (s, 1 H, ОН), 7.86 (s, 0.5 H-B, NН), 7.78 (s, 0.5 H-A, NН), 6.69–7.77 (m, 12 Н, ArH), 6.75 (s, 0.5 H-B, СН isoxazole), 6.73 (s, 0.5 H-A, СН isoxazole), 6.07 (s, 0.5 H-A, СН), 6.03 (s, 0.5 H-B, СН), 5.58 (s, 0.5 H-A, СН pyrrolone), 5.54 (s, 0.5 H-B, СН pyrrolone), 3.79 (s, 3 Н, ОСН₃), 3.18–3.28 (m, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.18–2.24 (m, 1 H, СН₂), 2.11 (s, 3 Н, СН₃), 1.28 (s, 4.5 Н-B, t-Bu), 1.23 (s, 4.5 H-A, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 170.0, 168.4, 168.3, 168.2, 165.8, 165.2, 165.0, 156.0, 142.5, 142.4, 141.0, 140.9, 137.1, 137.0, 136.4, 136.3, 135.2, 135.1, 132.7, 132.5, 130.4, 130.2, 129.0, 128.8, 128.7, 128.6, 123.3, 122.7, 94.9, 63.5, 60.8, 60.6, 52.0, 50.4, 50.3, 30.3, 30.2, 20.4, 12.0.

MS (ESI): m/z (%) = 685 (100) [M + H]⁺.

Anal. Calcd for C₃₇H₃₇ClN₄O₇: C, 64.86; H, 5.44; N, 8.18. Found: C, 64.82; H, 5.47; N, 8.25.

N-(tert-Butyl)-2-(4-chlorophenyl)-2-(2-(4-hydroxy-2-(4-methoxyphenyl)-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(4-methoxyphenyl)acetamido)acetamide (7j)

DiastereomerA.

Yield 80 mg (41%); white solid; mp 239–241 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.90 (s, 1 H, ОН), 7.72 (s, 1 Н, NН), 5.90–7.62 (m, 12 Н, ArH), 6.70 (s, 1 Н, СН isoxazole), 5.99 (s, 1 Н, СН), 5.52 (s, 1 Н, СН pyrrolone), 3.72 (s, 3 Н, ОСН₃), 3.62 (s, 3 Н, ОСН₃), 3.25 (d, J = 17.1 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.19 (d, J = 17.1 Hz, 1 H, СН₂), 1.22 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 168.5, 165.2, 165.0, 158.2, 156.0, 142.5, 135.6, 134.6, 132.3, 132.0, 131.9, 131.6, 129.4, 127.8, 123.4, 122.8, 121.1, 113.4, 94.9, 63.1, 60.7, 55.1, 55.4, 30.4, 28.4, 12.0.

MS (ESI): m/z (%) = 673 (80) [M + H]⁺.

Anal. Calcd for C₃₆H₃₇ClN₄O₇: C, 64.23; H, 5.54; N, 8.32. Found: C, 64.31; H, 5.51; N, 8.39.

DiastereomerB.

Yield 64 mg (33%); light-yellow solid; mp 210–212 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.90 (s, 1 H, ОН), 7.78 (s, 1 Н, NН), 6.40–7.48 (m, 12 Н, ArH), 6.72 (s, 1 Н, СН isoxazole), 5.95 (s, 1 Н, СН), 5.47 (s, 1 Н, СН pyrrolone), 3.75 (s, 3 Н, ОСН₃), 3.61 (s, 3 Н, ОСН₃), 3.17 (d, J = 17.3 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.22 (d, J = 17.3 Hz, 1 H, СН₂), 1.28 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 168.8, 168.6, 165.2, 158.2, 156.1, 142.4, 135.2, 134.5, 132.5, 132.2, 131.8, 131.7, 131.6, 128.7, 128.6, 127.8, 123.5, 113.4, 94.9, 63.1, 60.8, 55.1, 50.4, 30.2, 28.4, 12.0.

MS (ESI): m/z (%) = 673 (100) [M + H]⁺.

Anal. Calcd for C₃₆H₃₇ClN₄O₇: C, 64.23; H, 5.54; N, 8.32. Found: C, 64.29; H, 5.50; N, 8.37.

N-(tert-Butyl)-2-(4-chlorophenyl)-2-(N-(4-chlorophenyl)-2-(4-hydroxy-2-(4-methoxyphenyl)-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)acetamido)acetamide (7k)

DiastereomerA.

Yield 88 mg (45%); white solid; mp 253–255 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.94 (s, 1 H, ОН), 7.85 (s, 1 Н, NН), 6.08–7.75 (m, 12 Н, ArH), 6.70 (s, 1 Н, СН isoxazole), 6.02 (s, 1 Н, СН), 5.53 (s, 1 Н, СН pyrrolone), 3.72 (s, 3 Н, ОСН₃), 3.29 (d, J = 17.1 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.19 (d, J = 17.1 Hz, 1 H, СН₂), 1.23 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.8, 168.5, 168.1, 165.1, 159.1, 156.1, 142.2, 138.0, 134.2, 132.5, 132.4, 132.2, 131.8, 128.5, 128.4, 128.0, 127.6, 123.1, 114.0, 95.1, 63.0, 60.8, 55.1, 50.4, 30.5, 28.4, 12.0.

MS (ESI): m/z (%) = 677 (100) [M + H]⁺.

Anal. Calcd for C₃₅H₃₄Cl₂N₄O₆: C, 62.04; H, 5.06; N, 8.27. Found: C, 62.11; H, 5.01; N, 8.31.

N-(tert-Butyl)-2-(4-chlorophenyl)-2-(2-(4-hydroxy-2-(4-methoxyphenyl)-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-3-yl)-N-(p-tolyl)acetamido)acetamide (7l)

DiastereomerA.

Yield 93 mg (49%); white solid; mp 223–225 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 9.88 (s, 1 H, ОН), 7.71 (s, 1 Н, NН), 6.68–7.20 (m, 12 Н, ArH), 6.70 (s, 1 Н, СН isoxazole), 6.01 (s, 1 Н, СН), 5.51 (s, 1 Н, СН pyrrolone), 3.73 (s, 3 Н, ОСН₃), 3.24 (d, J = 17.8 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.18 (d, J = 17.8 Hz, 1 H, СН₂), 2.13 (s, 3 Н, СН₃), 1.22 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 169.9, 168.6, 168.5, 165.2, 159.2, 156.1, 142.2, 137.1, 136.4, 134.6, 132.3, 131.9, 130.2, 128.8, 128.4, 127.8, 127.7, 123.6, 114.1, 95.1, 63.0, 60.8, 55.2, 50.4, 30.4, 28.4, 20.5, 12.1.

MS (ESI): m/z (%) = 657 (100) [M + H]⁺.

Anal. Calcd for C₃₆H₃₇ClN₄O₆: C, 65.8; H, 5.68; N, 8.53. Found: C, 65.83; H, 5.61; N, 8.59.

Methyl 4-(3-(2-((2-(tert-Butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)(4-methoxyphenyl)amino)-2-oxoethyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (7m)

DiastereomerA.

Yield 80 mg (40%); white solid; mp 215–217 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.1 (s, 1 H, ОН), 7.60 (s, 1 Н, NН), 6.02–7.94 (m, 12 Н, ArH), 6.75 (s, 1 Н, СН isoxazole), 5.95 (s, 1 Н, СН), 5.68 (s, 1 Н, СН pyrrolone), 3.83 (s, 3 Н, ОСН₃), 3.64 (s, 3 Н, ОСН₃), 3.59 (s, 3 Н, ОСН₃), 3.27 (d, J = 17.6 Hz, 1 H, СН₂), 2.31 (s, 3 Н, СН₃), 2.16 (d, J = 17.6 Hz, 1 H, СН₂), 1.23 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 169.3, 168.4, 165.9, 165.1, 158.5, 158.1, 156.1, 142.5, 141.8, 131.8, 131.6, 131.3, 131.1, 129.6, 129.5, 127.4, 122.8, 113.3, 113.2, 94.9, 63.3, 61.0, 55.1, 55.0, 52.2, 50.3, 30.5, 28.5, 12.1.

MS (ESI): m/z (%) = 697 (82) [M + H]⁺.

Anal. Calcd for C₃₈H₄₀N₄O₉: C, 65.51; H, 5.79; N, 8.04. Found: C, 65.58; H, 5.73; N, 8.10.

DiastereomerB.

Yield 42 mg (21%); light-yellow solid; mp 163–165 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.1 (s, 1 H, ОН), 7.70 (s, 1 Н, NН), 6.38–7.94 (m, 12 Н, ArH), 6.77 (s, 1 Н, СН isoxazole), 5.89 (s, 1 Н, СН), 5.67 (s, 1 Н, СН pyrrolone), 3.87 (s, 3 Н, ОСН₃), 3.63 (s, 3 Н, ОСН₃), 3.59 (s, 3 Н, ОСН₃), 3.18 (d, J = 17.8 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.19 (d, J = 17.8 Hz, 1 H, СН₂), 1.29 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.2, 169.5, 168.5, 166.0, 165.3, 158.4, 158.0, 156.1, 142.4, 141.8, 131.9, 131.6, 131.3, 129.5, 129.3, 127.3, 127.1, 123.4, 113.3, 113.1, 94.9, 63.3, 61.2, 55.0, 54.9, 52.2, 50.3, 30.4, 28.5, 12.1.

MS (ESI): m/z (%) = 697 (100) [M + H]⁺.

Anal. Calcd for C₃₈H₄₀N₄O₉: C, 65.51; H, 5.79; N, 8.04. Found: C, 65.54; H, 5.71; N, 8.11.

Methyl 4-(3-(2-((2-(tert-Butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)(4-chlorophenyl)amino)-2-oxoethyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (7n)

Mixture of diastereomers A/B (diastereomeric ratio 50:50).

Yield 148 mg (73%); white solid.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.1 (s, 0.5 H-B, ОН), 10.0 (s, 0.5 H-A, ОН), 7.81 (s, 0.5 H-B, NН), 7.74 (s, 0.5 H-A, NН), 6.20–7.94 (m, 12 Н, ArH), 6.79 (s, 0.5 H-B, СН isoxazole), 6.76 (s, 0.5 H-A, СН isoxazole), 5.99 (s, 0.5 H-A, СН), 5.93 (s, 0.5 H-B, СН), 5.71 (s, 0.5 H-A, СН pyrrolone), 5.69 (s, 0.5 H-B, СН pyrrolone), 3.87 (s, 1.5 Н-B, ОСН₃), 3.83 (s, 1.5 Н-A, ОСН₃), 3.64 (s, 1.5 Н-A, ОСН₃), 3.63 (s, 1.5 Н-B, ОСН₃), 3.17–3.34 (m, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.14–2.26 (m, 1 H, СН₂), 1.30 (s, 4.5Н-B, t-Bu), 1.25 (s, 4.5 H-A, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.2; 170.1; 169.3; 169.2; 167.8; 165.9; 165.8; 165.2; 165.0; 158.6; 158.5; 156.1; 142.5; 141.7; 138.3; 138.1; 132.4; 132.1; 131.3; 131.2; 129.5; 129.3; 128.2; 127.4; 127.0; 126.9; 123.0; 122.3; 113.3; 94.9; 63.3; 63.2; 61.2; 61.0; 54.9; 52.2; 50.4; 50.3; 30.7; 30.5; 28.4; 12.0.

MS (FAB): m/z (%) = 701 (12) [M + H]⁺, 723 (48) [M + Na]⁺.

Anal. Calcd for C₃₇H₃₇ClN₄O₈: C, 63.38; H, 5.32; N, 7.99. Found: C, 63.44; H, 5.29; N, 8.04.

Methyl 4-(3-(2-((2-(tert-Butylamino)-1-(4-methoxyphenyl)-2-oxoethyl)(p-tolyl)amino)-2-oxoethyl)-4-hydroxy-1-(5-methylisoxazol-3-yl)-5-oxo-2,5-dihydro-1H-pyrrol-2-yl)benzoate (7o)

DiastereomerA.

Yield 126 mg (64%); white solid; mp 224–226 °C.

¹H NMR (400 MHz, DMSO-d ₆): δ = 10.04 (s, 1 H, ОН), 7.62 (s, 1 Н, NН), 6.04–7.92 (m, 12 Н, ArH), 6.75 (s, 1 Н, СН isoxazole), 5.98 (s, 1 Н, СН), 5.67 (s, 1 Н, СН pyrrolone), 3.85 (s, 3 Н, ОСН₃), 3.64 (s, 3 Н, ОСН₃), 3.25 (d, J = 17.7 Hz, 1 H, СН₂), 2.32 (s, 3 Н, СН₃), 2.18 (d, J = 17.7 Hz, СН₂), 2.11 (s, 3 Н, СН₃), 1.23 (s, 9 H, t-Bu).

¹³C NMR (100 MHz, DMSO-d ₆): δ = 170.1, 169.2, 168.1, 165.8, 165.0, 158.4, 156.1, 142.9, 142.4, 141.8, 136.8, 131.3, 129.5, 129.4, 128.7, 127.3, 127.2, 122.7, 113.1, 94.8, 63.3, 61.0, 54.9, 52.2, 50.2, 30.5, 28.4, 20.5, 12.0.

MS (Mass-FAB): m/z (%) = 681 (13) [M + H]⁺.

Anal. Calcd for C₃₈H₄₀CN₄O₈: C, 67.05; H, 5.92; N, 8.23. Found: C, 67.09; H, 5.88; N, 8.27.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

Authors thank National Research Foundation of Ukraine for financial support and the Royal Society of Chemistry for the possibility of purchasing uninterruptible power sources for scientific equipment operating in conditions of unstable power grids due to constant missile shelling of Ukraine. The authors also thank all the brave defenders of Ukraine who allow us to continue our scientific work and complete this research.

• References

• 1 Graebin CS, Ribeiro FV, Rogério KR, Kümmerle AE. Curr. Org. Synth. 2019; 16: 855
• 2 John SE, Gulati S, Shankaraiah N. Org. Chem. Front. 2021; 8: 4237
• 3 Murlykina MV, Morozova AD, Zviagin IM, Sakhno YI, Desenko SM, Chebanov VA. Front. Chem. 2018; 527
• 4 Multicomponent Reactions towards Heterocycles . Van der Eycken E, Sharma UK. Wiley; Weinheim: 2022
• 5 Younus HA, Al-Rashida M, Hameed A, Uroos M, Salar U, Rana S, Khan KM. Expert Opin. Ther. Pat. 2021; 31: 267
• 6 Uchiro H, Shionozaki N, Tanaka R, Kitano H, Iwamura N, Makino K. Tetrahedron Lett. 2013; 54: 506
• 7 Tanaka R, Ohishi K, Takanashi N, Nagano T, Suizu H, Suzuki T, Kobayashi S. Org. Lett. 2012; 14: 4886
• 8 Khalaf AI, Waigh RD, Drummond AJ, Pringle B, McGroarty I, Skellern GG, Suckling CJ. J. Med. Chem. 2004; 47: 2133
• 9 Gein VL, Popov AV, Kolla V, Popova NA, Potemkin KD. Pharm. Chem. J. 1993; 27: 343
• 10 Gein VL, Popov AV, Kolla WE, Popova NA. Pharmazie 1993; 48: 107
• 11 Alizadeh N, Hossein Sayahi M, Iraji A, Yazzaf R, Moazzam A, Mobaraki K, Adib M, Attarroshan M, Larijani B, Rastegar H, Khoshneviszadeh M, Mahdavi M. Bioorg. Chem. 2022; 126: 105876
• 12 Bhajammanavar V, Mallik S, Baidya M. Org. Biomol. Chem. 2019; 17: 1740
• 13 Joksimović N, Petronijević J, Milović E, Janković N, Baskić D, Popović S, Todorović D, Matić S, Vraneš M, Tot A. Med. Chem. 2022; 18: 337
• 14 del Corte X, López-Francés A, Villate-Beitia I, Sainz-Ramos M, Martínez de Marigorta E, Palacios F, Alonso C, de los Santos JM, Pedraz JL, Vicario J. Pharmaceuticals 2022; 15: 511
• 15 Castellano TG, Neo AG, Marcaccini S, Marcos CF. Org. Lett. 2012; 14: 6218
• 16 Nunes PS. G, Vidal HD. A, Corrêa AG. Org. Biomol. Chem. 2020; 18: 7751
• 17 Zhu D, Xia L, Pan L, Li S, Chen R, Mou Y, Chen X. J. Org. Chem. 2012; 77: 1386
• 18 Lambruschini C, Moni L, Banfi L. Eur. J. Org. Chem. 2020; 3766
• 19 Riva R. Science 2018; 361: 1072
• 20 Zhang J, Yu P, Li S.-Y, Sun H, Xiang S.-H, Wang J, Houk KN, Tan B. Science 2018; 361: eaas8707 ; DOI: 10.1126/science.aas8707
• 21 Murlykina MV, Kolomiets OV, Kornet MM, Sakhno YI, Desenko SM, Dyakonenko VV, Shishkina SV, Brazhko OA, Musatov VI, Tsygankov AV, van der Eycken EV, Chebanov VA. Beilstein J. Org. Chem. 2019; 15: 1281
• 22 Sakhno YI, Radchenko OV, Muravyova EA, Sirko SM, Shishkina SV, Musatov VI, Desenko SM, Chebanov VA. Chem. Heterocycl. Compd. 2021; 57: 261
• 23 de Koning CB, van Otterlo WA, Michael JP. Tetrahedron 2003; 59: 8337
• 24 Kessler H. Angew. Chem., Int. Ed. Engl. 1970; 9: 219
• 25 Ōki M. The Chemistry of Rotational Isomers. In Reactivity and Structure Concepts in Organic Chemistry, Vol. 30. Springer; Berlin: 1993
• 26 Akkit JW. NMR and Chemistry: An Introduction to Modern NMR Spectroscopy, Third Edition. Akitt JW. Chapman & Hall; London: 1993
• 27 Shyshkina MO, Sakhno YI, Radchenko OV, Shishkina SV, Desenko SM, Chebanov VA. Acta Crystallogr., Sect. E: Crystallogr. Commun. 2021; 77: 1208
• 28 Sheldrick GM. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008; 64: 112

Publication History

Received: 19 April 2023

Accepted after revision: 10 May 2023

Accepted Manuscript online:
11 May 2023

Article published online:
31 May 2023