Next Article in Journal
Polyethylenimine as a Non-Innocent Ligand for Hexacyanoferrates Immobilization
Next Article in Special Issue
Alkyl 4-Aryl-6-amino-7- phenyl-3-(phenylimino)-4,7-dihydro- 3H-[1,2]dithiolo[3,4-b]pyridine-5-carboxylates: Synthesis and Agrochemical Studies
Previous Article in Journal
Recent Update on the Anti-Inflammatory Activities of Propolis
Previous Article in Special Issue
Synthesis of 1,5-Substituted Pyrrolidin-2-ones from Donor–Acceptor Cyclopropanes and Anilines/Benzylamines
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Molecules
Volume 27
Issue 23
10.3390/molecules27238488
molecules-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Synthesis of Functionalized Isoquinolone Derivatives via Rh(III)-Catalyzed [4+2]-Annulation of Benzamides with Internal Acetylene-Containing α-CF3-α-Amino Carboxylates

by
Daria V. Vorobyeva
1,
Dmitry A. Petropavlovskikh
1,
Ivan A. Godovikov
1,
Fedor M. Dolgushin
2,3 and
Sergey N. Osipov
1,*
1
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 28/1 Vavilova Str., 119334 Moscow, Russia
2
N. S. Kurnakov Institute of General and Inorganic Chemistry, Russian Academy of Sciences, Leninsky pr. 31, 119071 Moscow, Russia
3
Plekhanov Russian University of Economics, 36, Stremyanny Per., 117997 Moscow, Russia
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(23), 8488; https://doi.org/10.3390/molecules27238488
Submission received: 3 November 2022 / Revised: 22 November 2022 / Accepted: 24 November 2022 / Published: 2 December 2022
(This article belongs to the Special Issue Recent Developments in the Synthesis and Functionalization of Nitrogen Heterocycles)
Browse Figures
Versions Notes

Abstract

:
A convenient pathway to a new series of α-CF3-substituted α-amino acid derivatives bearing pharmacophore isoquinolone core in their backbone has been developed. The method is based on [4+2]-annulation of N-(pivaloyloxy) aryl amides with orthogonally protected internal acetylene-containing α-amino carboxylates under Rh(III)-catalysis. The target annulation products can be easily transformed into valuable isoquinoline derivatives via a successive aromatization/cross-coupling operation.

Graphical Abstract

1. Introduction

Isoquinolin-1(2H)-ones and analogues are important nitrogen heterocycles possessing diverse bioactivities and presented in many candidates, including antitumor, anti-diabetic, anti-inflammatory and cardiovascular drugs [1,2,3,4,5,6,7] (Figure 1). They are also widely used as key intermediates in variety of organic transformations to access more potent bioactive molecules [8,9,10,11,12,13,14].
Transition-metal-catalyzed annulation reactions via C-H activation have gained great importance as a powerful step- and atom-economical strategy for the preparation of complex molecules from simple starting materials [15,16,17,18]. In particular, [Cp*RhIII]-catalyzed annulation of the akynes with (hetero)arenes bearing different directing groups has become one of the most efficient and robust synthetic methodologies for the construction of various functionalized heterocycles [19,20,21,22,23,24,25]. In 2010, Fagnou and co-workers discovered that the N-pivaloyloxy group can act both as a directing group and as an internal oxidant through N-O bond cleavage during the synthesis of isoquinolones [26,27]. Mechanistically, this redox-neutral [4+2]-annulation process between alkynes and N-pivaloyloxy aryl amides has shown to proceed via the formation of a seven-membered rhodacycle intermediate, which undergoes a C-N bond forming/N-O bond cleaving event to yield the free NH isoquinolones suitable for further useful transformations [28,29,30,31,32,33,34]. Despite significant advances made in the field, the development of effective strategies employing new coupling partners to construct functionally substituted quinolin-2(1H)-ones remains of great demand.
On the other hand, modern peptide-based drug design very often aims on selective derivatizing of the peptide backbone through the introduction of additional functional groups or proven heterocyclic pharmacophores in order to modulate the required properties [35,36,37,38,39,40,41]. In this respect, α-fluoroalkyl-containing α-amino acids are of particular interest since they find widespread bio-organic applications as biological tracers, mechanistic probes, and enzyme inhibitors as well as medical applications including blood pressure control, allergies, and tumor growth [42,43,44,45,46]. The incorporation of fluorinated α-amino acids into key positions of bioactive peptides is one of the most common strategies to improve their pharmacokinetic profiles, conformational and proteolytic stability, and membrane permeability [43,44,45,46,47,48,49,50]. Therefore, the development of new representatives of α-fluoromethyl-α-amino acids, including those decorated with pharmacophore heterocycle rings, is of high interest.
Recently, we have elaborated an efficient strategy for the preparation of novel α-CF3-α-amino acid derivatives and their phosphorus counterparts with isoquinolone moiety in their backbone based on [Cp*RhIII]-catalyzed [4+2]-annulation of terminal propargyl-containing α-CF3-substituted α-amino carboxylates and α-propargyl-α-amino phosphonates with N-pivaloyloxy aryl amides [51] (Scheme 1).
In continuation of our current research on metal-catalyzed C-H bond activation [52,53,54,55], here we want to disclose a convenient regio-selective approach to new isoquinolone-containing α-amino acid derivatives derived from internal aryl acetylenes bearing protected α-CF3-α-amino carboxylate framework under rhodium(III)-catalysis, and their further synthetic transformations into highly functionalized isoquinolines (Scheme 1).

2. Results and Discussion

We commenced our study by examining a model reaction between phenyl hydroxamate 1a and the readily available internal phenyl acetylene 2a [56] bearing an N-Boc-protected α-CF3-α-amino ester group for the screening of optimal conditions for the annulation. The rhodium catalytic system [Cp*RhCl2]2/CsOAc, as the most competent catalyst for such type of transformation, was initially tested to activate the process. As a result, the reaction was found to smoothly proceed in the presence of 5 mol% [Cp*RhCl2]2 and 2.0 equiv. of cesium acetate in methanol at room temperature for 4 h to give the corresponding isoquinolone derivative 3a in 70% NMR yield (Table 1, entry 1), along with noticeable amounts of starting materials. Encouraged by this result, we screened some solvents and bases for the reaction (entries 2–5). The best conversion of the starting materials and isolated yield of 3a (measured by 19F NMR spectroscopy) were achieved by the usage of 2,2,2-trifluoroethanol (TFE) and CsOAc (entry 2). Subsequent reduction of catalyst and additive loading (entries 2–6) has revealed the optimal reaction conditions: [Cp*RhCl2]2 (3 mol%) and CsOAc (1 equiv.), r.t., 2 h in MeOH (entry 8). Iridium-, cobalt- and ruthenium-based complexes have proved to be absolutely inactive in the process (entries 10–12). The reaction does not take place in the absence of any catalyst or base, expectedly (entries 13, 14).
With these found conditions in hand, different aryl hydroxamates were involved in [4+2]-annulation with different internal acetylene-containing amino ester 2a–e (Scheme 2). The latter were easily synthesized via an addition of Grignard reagent (CH2=C=CH-MgBr), generated from propargyl bromide, to orthogonally protected α-CF3-α-imino carboxylates followed by Sonogashira coupling with aryl halogenides according to the previously described protocol [56]. As a result, a series of the corresponding isoquinolinone-containing α-CF3-amino carboxylates 3a–r were obtained in good yields and high degree of regio-selectivity. The observed selectivity of the [4+2]-annulation process of 1 with α-(arylpropargyl)-α-amino esters 2a–e bearing donor substituents in aryl group could be probably explained by alkyne insertion into initially formed 5-membered rhodacycle intermediate [26,27], according to its inherent polarity (for proposed mechanism see Supplementary Materials, Scheme S1). The nature of the substituents in hydroxamate component did not significantly affect the outcome of the reaction in all investigated cases (Scheme 2).
However, the presence of an electron-withdrawing nitro group in para-position of aryl substituent of acetylene component leads to a mixture of the corresponding regioisomers 3s and 3t in a ratio of 3:2 respectively, which were easily separated by column chromatography on silica gel. The absence of selectivity in this case can be likely addressed to a change in the polarity of the triple bond due to the influence of strong acceptor group. The structure of each regio-isomer was assigned by 2D NOESY experiments (see Supplementary Materials). Thus, an intensive cross peak between proton of CH2 group of amino acid residue and ortho-proton of phenyl ring was found in the spectrum of isomer 3t that has not been observed for compound 3s; instead, a cross peak between the ortho-protons of close located phenyl moieties appeared (Scheme 3).
All synthesized compounds were fully characterized by physicochemical methods. In addition, the structure of isoquinolone 3a was confirmed by X-ray crystallographic analysis (Figure 2).
Considering the fact that isoquinolines are key structural elements of many bioactive compounds including drugs [57,58,59] (see Figure 1), we were interested in further investigation of synthetic potential of obtained isoquinolones as universal precursors of the corresponding isoquinoline derivatives decorated with amino acid residues. Thus, we found that the isoquinolones 3 could easily undergo an aromatization into the isoquinolines under treatment with triflic anhydride in the presence of pyridine. The reactions proceed in CH2Cl2 under mild conditions and go to completion within 15 min at ambient temperature furnishing the corresponding 1-OTf-substituted isoquinolines 4a–o in good to high yields (Scheme 4).
The well-known pseudo-halogen nature of the TfO group pushed us to explore some further useful transformations of the synthesized isoquinoline derivatives 4, such as Pd-catalysed cross-coupling reactions. As a result, it turned out that the compounds 4 could serve as suitable cross-coupling partners in Suzuki reaction with various aryl boronic acids. It was revealed that the reactions of 4d,f,l with 4-metoxy phenyl boronic acid readily proceeded in dioxane-water mixture under catalysis with Pd(PPh3)2Cl2/NaHCO3 system at 100 °C, leading to the formation of the expected cross-coupling products 5a–c in high yields (Scheme 5a).
The same isoquinoline-containing α-amino acid derivatives 4d,f,m were included in coupling with phenyl acetylene under the classical Sonogashira reaction conditions to afford the corresponding products 6a–c in good yields (Scheme 5b). Finally, we found that the OTf group could be successfully removed in the presence of catalytic amounts of PdCl2(dppf) complex and excess of formic acid to give isoquinolines 7a,b in acceptable yields (Scheme 5c).
In addition, in order to demonstrate a feasibility for the further synthetic applications of the compounds obtained, e.g., in peptide synthesis or other useful derivatizations, we have performed selective deprotections of the N-PG-α-amino esters. Thus, the ester 3a was saponified using 5% solution of potassium hydroxide in methanol to get free carboxylic acid 8 in high yield. The Boc-protective group of compound 3q was selectively removed by the treatment of its solution in methylene chloride with excess of trifluoroacetic acid at room temperature furnishing free amino ester 9 in 85% yield (Scheme 6).

3. Materials and Methods

3.1. General Information

All solvents used in the reactions were freshly distilled from appropriate drying agents before use. All other reagents were distilled as necessary. The corresponding starting acetylenes were easily synthesized via the previously described protocol [56]. Analytical TLC was performed with Merck silica gel 60 F254 plates; visualization was accomplished with UV light or spraying with Ce(SO4)2 solution in 5% H2SO4. Chromatography was carried out using Merck silica gel (Kieselgel 60, 0.063–0.200 mm) and petroleum ether/ethyl acetate as an eluent. The NMR spectra were obtained with Bruker AV-300, AV-400, AV-500 and Inova-400 spectrometers operating at 300, 400, and 500 MHz, respectively, for 1H (TMS reference), at 101 and 126 for 13C {1H}, and at 282 and 376 MHz for 19F (CCl3F reference). Analytical data (C, H, N content) were obtained with a Carlo Erba model 1106 microanalyzer.

3.1.1. General Procedure for C-H Activation/Annulation of Aryl Hydroxamate with Acetylenes. Synthesis of the Compounds 3a–r

A dried 10 mL Shlenk tube equipped with a magnetic stirring bar was subsequently charged with a corresponding acetylene (0.1 g, 0.27 mmol, 1.0 equiv.), TFE (2 mL), corresponding aryl hydroxamate (0.06 g, 0.27 mmol, 1.0 equiv.), [Cp*RhCl2]2 (4.9 mg, 8.0 µmol, 3 mol%) and CsOAc (0.05 g, 0.27 mmol, 1.0 equiv.) under Ar. The reaction mixture was stirred at room temperature for 4 h until the completion of the reaction, monitored by TLC and 19F NMR. By this time, the product precipitate had been formed and then was isolated from the reaction mixture by filtration.

3.1.2. General Procedure for the Synthesis of TfO-Derivatives 4a–o

To a solution of the corresponding isoquinolone (0.1 g, 0.2 mmol, 1 equiv.) in dry dichloromethane (15 mL), pyridine (1.5 equiv.) and Tf2O (1.5 equiv.) were added at 0 °C. After having been stirred at 0 °C for 30 min, the reaction mixture was treated with water and extracted with dichloromethane. The organic layer was washed with saturated NaHCO3 (aq.), dried over anhydrous MgSO4, filtered, and evaporated to dryness. The residue was purified by column chromatography on silica gel (eluent petroleum ether/ethyl acetate = 15/1) to give the desired product.

3.1.3. General Procedure for the Suzuki Reaction. Synthesis of the Compounds 5a–c

A 25 mL round-bottom flask equipped with a magnetic stir bar and a reflux condenser was charged with corresponding triflate-derivative (0.1 g, 0.16 mmol, 1 equiv.), corresponding boronic acid (0.02 g, 0.16 mmol, 1 equiv.), 1,4-dioxane—water mixture (3:1, 4 mL), NaHCO3 (0.04 g, 0.5 mmol, 3 equiv.), and Pd(PPh3)2Cl2 (1.1 mg, 1.6 µmol, 1 mol %). The resulting mixture was deaerated with argon and refluxed at 100 °C under argon for 1 h until the completion (monitored by TLC). On completion, the mixture was poured into water (7 mL) and extracted with dichloromethane (3 × 5 mL). The combined organic phases were washed with brine, dried over anhydrous MgSO4, filtered, and and evaporated to dryness. The crude product was purified by column chromatography (eluent petroleum ether/ethyl acetate = 10/1) to give the desired product.

3.1.4. General Procedure for the Sonogashira Reaction. Synthesis of the Compounds 6a–c

A dried 10 mL Shlenk tube was charged with a magnetic stir bar, DMF (5.5 mL) and corresponding triflate derivative (0.1 g, 0.15 mmol, 1.0 equiv.), and the solution was degassed three times. Then, (Ph3P)2PdCl2 (5.2 mg, 7.5 µmol, 5 mol%) was added and the degassing procedure repeated. After that, Et3N (0.28 mL) and phenyl acetylene (0.02 g, 0.22 mmol, 1.5 equiv.) was added and the mixture was degassed. Then, copper iodide (2.8 mg, 0.01 mmol, 10 mol%) was added and the reaction was stirred at room temperature overnight. After the completion (monitored by TLC) the reaction mixture was poured into 1M HCl (20 mL) and extracted with ethyl acetate (3 × 10 mL). The organic layers were dried over anhydrous MgSO4, filtered and evaporated to dryness. The crude product was purified by column chromatography (eluent petroleum ether/ethyl acetate = 10/1) to give the desired product.

3.1.5. General Procedure for the Reduction of Triflate-Group. Synthesis of the Compounds 7a,b

To a dried 10 mL Shlenk tube equipped with a magnetic stir bar corresponding triflate (0.1 g, 0.16 mmol, 1.0 equiv.), (dppf)PdCl2 (5.8 mg, 8.0 µmol, 5 mol%), TEA (0.05 mL, 0.48 mmol, 3.0 equiv.), DMF (2.5 mL) and HCOOH (0.01 mL, 0.38 mmol, 2.4 equiv.) were added. The mixture was stirred at room temperature for 3 h. After the completion of the reaction (monitored by TLC), the solution was poured into 1M HCl (10 mL) and extracted with Et2O (3 × 10 mL). The organic layers were washed with water and dried over anhydrous MgSO4, filtered and evaporated to dryness. The crude product was purified by column chromatography (eluent petroleum ether/ethyl acetate = 8/1) to give the desired product.

3.1.6. General Procedure for Ester Hydrolysis. Synthesis of the Compound 8

The corresponding isoquinolone 3a (0.3 g, 0.6 mmol) was dissolved in 5% KOH/MeOH-H2O (1:1) (13 mL) and stirred at room temperature for 2 h. After evaporation of solvents under reduced pressure, water (15 mL) was added to a residue, and the suspension was washed with diethyl ester (3 × 10 mL) before being acidified with HCl conc. until pH 3–4 and extracted with ethyl acetate (3 × 7 mL). The ethyl acetate extracts were combined and dried over anhydrous MgSO4, filtered, and evaporated to dryness.

3.1.7. General Procedure for the Removing of the Boc-Protecting Group. Synthesis of the Compound 9

A solution of Boc-protected isoquinolone 3q (0.25 g, 0.42 mmol) in a biphasic mixture of trifluoroacetic acid/dichlormethane (4 mL/10 mL) was stirred at room temperature for 1.5 h. After evaporation of solvents under reduced pressure, water (15 mL) was added to the residue and the resulting water solution was neutralized with saturated solution of sodium bicarbonate until pH 7. Then the mixture was extracted with diethyl ether (3 × 10 mL). The organic layer was dried over anhydrous MgSO4 and evaporated to dryness.

3.2. Characterization Data for the Products

Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-phenyl-1,2-dihydroiso quinolin-3-yl)methyl)propanoate (3a).
Yield 71% as a white solid. M.p. 213–215 °C. 1H NMR (400 MHz, DMSO-d6): δ 10.87 (s, 1H, NH), 8.26 (d, J = 7.9 Hz, 1H, Ar), 8.15 (s, 1H, NH), 7.62 (t, J = 7.6 Hz, 1H, Ar), 7.54–7.43 (m, 4H, Ar), 7.26 (d, J = 7.3 Hz, 1H, Ar), 7.10 (d, J = 7.5 Hz, 1H, Ar), 6.97 (d, J = 8.2 Hz, 1H, Ar), 3.48 (s, 3H, OCH3), 3.18 (d, J = 14.8 Hz, 1H, CH2), 2.91 (d, J = 14.7 Hz, 1H, CH2), 1.37 (s, 9H 3 CH3). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.8, 161.9, 159.2, 138.3 and 137.1, 137.1, 135.3 and 135.0, 133.5 and 133.1, 132.2 and 132.1, 131.3, 130.6 and 130.5, 129.8 and 129.5, 128.9 and 128.8, 128.4 and 128.2, 127.1 and 127.0, 125.6 and 125.5, 125.3 and 125.2, 124.6 (q, J = 285.6 Hz, CF3), 118.9, 115.8, 81.2 and 80.7, 62.7 (q, J = 29.1 Hz, >C<), 53.0, 31.8 and 31.5, 28.3. 19F NMR (376 MHz, DMSO-d6): δ −74.13 (s, 3F, CF3). Elemental analysis calcd (%) for C25H25F3N2O5: C, 61.22; H, 5.14; N, 5.71; found: C, 61.18; H, 5.01; N, 5.65.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-phenyl-1,2-dihydroiso quinolin-3-yl)methyl)propanoate (3b).
Yield 73% as a white solid. M.p. 168–170 °C. 1H NMR (400 MHz, acetone-d6): δ 10.45 (s, 1H, NH), 8.37 (d, J = 7.9 Hz, 1H, Ar), 7.65–7.47 (m, 6H, Ar), 7.29–7.21 (m, 6H, Ar, 1H, NH), 7.04 (d, J = 8.1 Hz, 1H, Ar), 4.96 (s, 2H, OCH2), 3.67 (s, 3H, OCH3), 3.47 (d, J = 15.2 Hz, 1H, CH2), 3.33 (d, J = 15.3 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.0, 161.4, 154.4, 137.8, 136.0, 134.5, 132.6, 131.6, 131.5, 130.8, 129.0, 128.5, 128.4, 128.2, 128.0, 127.9, 126.7, 126.6, 126.3 (q, J = 289.5 Hz, CF3), 125.2, 124.8, 118.6, 66.5, 64.0 (q, J = 27.0 Hz, >C<), 52.7. 19F NMR (376 MHz, acetone-d6): δ −75.08 (s, 3F, CF3). Elemental analysis calcd (%) for C28H23F3N2O5: C, 64.12; H, 4.42; N, 5.34; found: C, 64.44; H, 4.66; N, 5.71.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-p-tolyl-1,2-dihydroiso quinolin-3-yl)methyl)propanoate (3c).
Yield 81% as a white solid. M.p. 224–226 °C. 1H NMR (500 MHz, DMSO-d6): δ 10.83 (s, 1H, NH), 8.25 (d, J = 7.9 Hz, 1H, Ar), 8.13 (s, 1H, NH), 7.61–7.59 (m, 1H, Ar), 7.52–7.49 (m, 1H, Ar), 7.32 (d, J = 7.8 Hz, 1H, Ar), 7.29 (d, J = 7.8 Hz, 1H, Ar), 7.13 (d, J = 7.7 Hz, 1H, Ar), 6.99–6.96 (m, 2H, Ar), 3.48 (s, 3H, OCH3), 3.20 (d, J = 15.0 Hz, 1H, CH2), 2.92 (d, J = 15.0 Hz, 1H, CH2), 2.38 (s, 3H, CH3), 1.37 (s, 9H 3 CH3). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.4, 161.4, 153.9, 138.1, 137.1, 132.6, 131.6, 131.5, 131.4, 130.7, 129.6, 129.0, 126.6, 126.5, 125.2, 124.8, 124.1 (q, J = 288.0 Hz, CF3), 118.4, 80.2, 63.9 (q, J = 23.3 Hz, >C<), 52.5, 31.1, 27.8, 20.9. 19F NMR (376 MHz, CDCl3): δ −75.21 (s, 3F, CF3). Elemental analysis calcd (%) for C26H27F3N2O5: C, 61.90; H, 5.39; N, 5.55; found: C, 62.04; H, 5.55; N, 5.63.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-p-tolyl-1,2-dihydroiso quinolin-3-yl)methyl)propanoate (3d).
Yield 69% as a white solid. M.p. 184–185 °C. 1H NMR (500 MHz, CDCl3): δ 12.45 (s, 1H, NH), 8.46 (d, J = 7.9 Hz, 1H, Ar), 7.57 (t, J = 7.7 Hz, 1H, Ar), 7.47 (t, J = 7.2 Hz, 2H, Ar), 7.32–7.28 (m, 2H, Ar), 7.15 (d, J = 8.0 Hz, 2H, Ar), 7.08–7.05 (m, 3H, Ar), 7.01 (d, J = 7.7 Hz, 1H, Ar), 6.93 (s, 1H, Ar, 1H, NH), 4.82 (s, 2H, OCH2), 3.59 (s, 3H, OCH3), 3.47 (d, J = 15.1 Hz, 1H, CH2), 3.28 (d, J = 15.2 Hz, 1H, CH2), 2.45 (s, 3H, CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 165.0, 164.0, 155.1, 138.9, 138.2, 135.8, 133.0, 131.6, 131.4, 130.9, 130.8, 129.9, 129.6, 128.3, 127.9, 127.6, 127.4, 127.1, 126.0, 124.4, 124.1 (q, J = 287.5 Hz, CF3), 121.9, 67.1, 64.9 (q, J = 27.6 Hz, >C<), 53.3, 31.9, 21.5. 19F NMR (282 MHz, CDCl3): δ −75.48 (s, 3F, CF3). Elemental analysis calcd (%) for C29H25F3N2O5: C, 64.68; H, 4.68; N, 5.20; found: C, 64.79; H, 4.85; N, 5.51.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3e).
Yield 79%. M.p. 220–221 °C. 1H NMR (500 MHz, DMSO-d6): δ 10.84 (s, 1H, NH), 8.25 (d, J = 7.9 Hz, 1H, Ar), 8.13 (s, 1H, NH), 7.61 (t, J = 7.6 Hz, 1H, Ar), 7.50 (t, J = 7.5 Hz, 1H, Ar), 7.17 (d, J = 7.8 Hz, 1H, Ar), 7.09–6.99 (m, 4H, Ar), 3.82 (s, 3H, OCH3), 3.49 (s, 3H, OCH3), 3.22 (d, J = 14.9 Hz, 1H, CH2), 2.91 (d, J = 15.0 Hz, 1H, CH2), 1.37 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.4, 161.4, 158.7, 153.9, 138.3, 132.8, 132.5, 132.0, 131.8, 126.6, 126.5, 126.4, 125.2, 124.8, 124.1 (q, J = 286.9 Hz, CF3) 118.2, 114.4, 113.9, 80.2, 63.9 (q, J = 23.9 Hz, >C<), 55.1, 52.5, 31.1, 27.8. 19F NMR (376 MHz, CDCl3): δ −75.07 (s, 3F, CF3). Elemental analysis calcd (%) for C26H27F3N2O6: C, 60.00; H, 5.23; N, 5.38; found: C, 60.27; H, 5.55; N, 5.53.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3f).
Yield 88% as a white solid. M.p. 200–201 °C. 1H NMR (500 MHz, DMSO-d6): δ 10.83 (s, 1H, NH), 8.61 (s, 1H, NH), 8.25 (d, J = 8.0 Hz, 1H, Ar), 7.61 (t, J = 7.6 Hz, 1H, Ar), 7.51 (t, J = 7.5 Hz, 1H, Ar), 7.37 (s, 5H, Ar), 7.17 (d, J = 8.4 Hz, 1H, Ar), 7.07 (d, J = 7.1 Hz, 1H, Ar), 7.04–6.99 (m, 3H, Ar), 5.09 (d, J = 12.2 Hz, 1H, OCH2), 5.02 (d, J = 12.2 Hz, 1H, OCH2), 3.82 (s, 3H, OCH3), 3.49 (s, 3H, OCH3), 3.25 (d, J = 15.0 Hz, 1H, CH2), 2.95 (d, J = 14.9 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.1, 161.4, 158.7, 154.5, 138.2, 136.0, 132.7, 132.6, 132.0, 131.6, 128.5, 128.2, 128.0, 126.7, 126.5, 126.4, 125.2, 125.0 (q, J = 290.1 Hz, CF3), 124.8, 118.3, 114.3, 113.9, 66.5, 64.0 (q, J = 25.8 Hz, >C<), 55.1, 52.7, 31.2. 19F NMR (376 MHz, DMSO-d6): δ −73.99 (s, 3F, CF3). Elemental analysis calcd (%) for C29H25F3N2O6: C, 62.81; H, 4.54; N, 5.05; found: C, 63.07; H, 4.78; N, 5.28.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((6-nitro-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3g).
Yield 84% as a white solid. M.p. 173–175 °C. 1H NMR (400 MHz, DMSO-d6): δ 11.33 (s, 1H, NH), 8.49 (d, J = 8.8 Hz, 1H, Ar), 8.24 (d, J = 9.0 Hz, 1H, Ar), 8.17 (br. s, 1H, NH), 7.75 (s, 1H, Ar), 7.60–7.50 (m, 3H, Ar), 7.33 (d, J = 7.1 Hz, 1H, Ar), 7.17 (d, J = 7.4 Hz, 1H, Ar), 3.50 (s, 3H, OCH3), 3.21 (d, J = 14.9 Hz, 1H, CH2), 2.96 (d, J = 14.9 Hz, 1H, CH2), 1.37 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.4, 160.6, 153.9, 149.9, 138.5, 133.5, 131.6, 131.0, 130.2, 129.7, 129.4, 129.3, 128.8, 128.6, 128.3, 124.1 (q, J = 288.3 Hz, CF3), 121.4, 120.2, 118.3, 80.4, 63.8 (q, J = 26.9 Hz, >C<), 52.7, 27.9. 19F NMR (376 MHz, DMSO-d6): δ −74.30 (s, 3F, CF3). Elemental analysis calcd (%) for C25H24F3N3O7: C, 56.08; H, 4.52; N, 7.85; found: C, 56.04; H, 4.55; N, 7.81.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((6-nitro-1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3h).
Yield 79% as a yellow solid. M.p. 206–208 °C. 1H NMR (300 MHz, DMSO-d6): δ 11.30 (s, 1H, NH), 8.63 (s, 1H, NH), 8.49 (d, J = 8.8 Hz, 1H, Ar), 8.25 (d, J = 8.8 Hz, 1H, Ar), 7.74 (s, 1H, Ar), 7.61–7.53 (m, 3H, Ar), 7.37 (s, 6H, Ar), 7.17 (d, J = 7.4 Hz, 1H, Ar), 5.08 (d, J = 12.2 Hz, 1H, OCH2), 5.01 (d, J = 12.2 Hz, 1H, OCH2), 3.50 (s, 3H, OCH3), 3.20 (d, J = 15.9 Hz, 1H, CH2), 3.00 (d, J = 15.2 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.4, 160.6, 153.9, 149.9, 138.5, 133.5, 131.6, 131.0, 130.2, 129.7, 129.4, 129.3, 129.1, 129.0, 128.8, 128.6, 128.3, 124.1 (q, J = 288.9 Hz, CF3), 120.2, 118.3, 114.8, 80.4, 63.8 (q, J = 23.6 Hz, >C<), 52.7, 31.3, 27.9. 19F NMR (282 MHz, DMSO-d6): δ −74.17 (s, 3F, CF3). Elemental analysis calcd (%) for C28H22F3N3O7: C, 59.05; H, 3.89; N, 7.38; found: C, 59.31; H, 4.08; N, 7.52.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((6-nitro-1-oxo-4-p-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3i).
Yield 86% as a white solid. M.p. 211–212 °C. 1H NMR (400 MHz, CDCl3): δ 11.56 (s, 1H, NH), 8.60 (d, J = 8.8 Hz, 1H, Ar), 8.22 (d, J = 8.8 Hz, 1H, Ar), 7.97 (s, 1H, Ar), 7.36 (d, J = 7.7 Hz, 2H, Ar), 7.15 (d, J = 7.9 Hz, 1H, Ar), 7.09 (d, J = 7.8 Hz, 1H), 6.15 (s, 1H, NH), 3.68 (s, 3H, OCH3), 3.49 (d, J = 14.9 Hz, 1H, CH2), 3.33 (d, J = 15.0 Hz, 1H, CH2), 2.47 (s, 3H, CH3), 1.18 (s, 9H, 3 CH3). 13C{1H} NMR (101 MHz, CDCl3): δ 165.8, 161.9, 154.3, 150.5, 139.6, 138.9, 133.8, 131.1, 130.7, 130.5, 130.4, 130.2, 129.6, 128.6, 123.7 (q, J = 288.3 Hz, CF3), 121.3, 120.8, 120.4, 81.8, 64.9 (q, J = 28.1 Hz, >C<), 53.8, 31.9, 27.9, 21.4. 19F NMR (376 MHz, CDCl3) δ −74.97 (s, 3F, CF3). Elemental analysis calcd (%) for C26H26F3N3O7: C, 56.83; H, 4.77; N, 7.65; found: C, 56.71; H, 4.57; N, 7.63.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((6-nitro-1-oxo-4-p-tolyl-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3j).
Yield 82% as a yellow solid. M.p. 215–216 °C. 1H NMR (500 MHz, DMSO-d6): δ 11.26 (s, 1H, NH), 8.61 (s, 1H, NH), 8.48 (d, J = 8.8 Hz, 1H, Ar), 8.24 (d, J = 8.8 Hz, 1H, Ar), 7.76 (s, 1H, Ar), 7.39 (m, 7H, Ar), 7.19 (d, J = 7.8 Hz, 1H, Ar), 7.05 (d, J = 7.7 Hz, 1H, Ar), 5.08 (d, J = 12.3 Hz, 1H, OCH2), 5.02 (d, J = 12.3 Hz, 1H, OCH2), 3.49 (s, 3H, OCH3), 3.27 (d, J = 15.3 Hz, 1H, CH2), 3.00 (d, J = 15.1 Hz, 1H, CH2), 2.42 (s, 3H, CH3). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.1, 160.4, 154.4, 149.9, 138.6, 137.8, 135.9, 134.4, 131.3, 130.8, 130.4, 129.9, 129.3, 129.2, 128.5, 128.3, 128.2, 128.0, 123.9 (q, J = 287.4 Hz, CF3), 120.3, 120.2, 118.3, 66.5, 64.0 (q, J = 26.7 Hz, >C<), 54.9, 52.8, 31.3. 19F NMR (282 MHz, CDCl3): δ −73.84 (s, 3F, CF3). Elemental analysis calcd (%) for C29H24F3N3O7: C, 59.69; H, 4.15; N, 7.20; found: C, 59.93; H, 4.43; N, 7.35.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-6-nitro-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3k).
Yield 89% as a white solid. M.p. 198–200 °C. 1H NMR (500 MHz, acetone-d6): δ 10.16 (s, 1H, NH), 8.54 (d, J = 8.7 Hz, 1H, Ar), 8.24 (d, J = 7.7 Hz, 1H, Ar), 7.92 (s, 1H, Ar), 7.38 (d, J = 7.8 Hz, 1H, Ar), 7.28 (d, J = 7.9 Hz, 1H, Ar), 7.16 (t, J = 6.7 Hz, 2H, Ar), 7.08 (s, 1H, NH), 3.91 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.50 (d, J = 14.9 Hz, 1H, CH2), 3.37 (d, J = 14.9 Hz, 1H, CH2), 1.27 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, acetone-d6): δ 167.7, 161.1, 160.9, 155.4, 151.4, 140.8, 139.9, 135.9, 133.7, 133.6, 130.2, 127.0, 124.8 (q, J = 287.0 Hz, CF3), 121.7, 120.9, 119.7, 115.8, 115.5, 114.8, 81.8, 66.2 (q, J = 27.0 Hz, >C<) 55.8, 54.2, 28.3. 19F NMR (376 MHz, CDCl3): δ −75.08 (s, 3F, CF3). Elemental analysis calcd (%) for C26H26F3N3O8: C, 55.22; H, 4.63; N, 7.43; found: C, 55.31; H, 4.57; N, 7.27.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-6-nitro-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3l).
Yield 83% as a yellow solid. M.p.207–209 °C. 1H NMR (500 MHz, DMSO-d6): δ 11.25 (s, 1H, NH), 8.60 (s, 1H, NH), 8.48 (d, J = 8.7 Hz, 1H, Ar), 8.23 (d, J = 8.8 Hz, 1H, Ar), 7.78 (s, 1H, Ar), 7.37 (s, 5H, Ar), 7.24 (s, 1H, Ar), 7.14–7.07 (m, 3H, Ar), 5.08 (d, J = 12.2 Hz, 1H, OCH2), 5.02 (d, J = 12.4 Hz, 1H, OCH2), 3.84 (s, 3H, OCH3), 3.50 (s, 3H, OCH3), 3.28 (d, J = 15.7 Hz, 1H, CH2), 3.00 (d, J = 15.1 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.0, 160.4, 159.1, 154.5, 149.9, 138.9, 136.0, 134.6, 132.7, 132.2, 129.2, 128.5, 128.4, 128.3, 128.1, 125.2, 123.9 (q, J = 287.9 Hz, CF3), 120.3, 120.2, 118.1, 114.7, 114.2, 66.6, 64.0 (q, J = 26.5 Hz, >C<), 55.2, 52.9, 31.3. 19F NMR (282 MHz, DMSO-d6): δ −74.07 (s, 3F, CF3). Elemental analysis calcd (%) for C29H24F3N3O8: C, 58.10; H, 4.04; N, 7.01; found: C, 58.49; H, 4.30; N, 7.32.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-phenyl-6-(trifluoromethyl)-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3m).
Yield 85% as a white solid. M.p. 181–183 °C. 1H NMR (400 MHz, DMSO-d6): δ 11.21 (s, 1H, NH), 8.47 (d, J = 8.3 Hz, 1H, Ar), 8.17 (br. s, 1H, NH), 7.84 (d, J = 8.4 Hz, 1H, Ar), 7.58–7.47 (m, 3H, Ar), 7.31 (d, J = 7.2 Hz, 1H, Ar), 7.21 (s, 1H, Ar), 7.14 (d, J = 7.4 Hz, 1H, Ar), 3.50 (s, 3H, OCH3), 3.19 (d, J = 15.0 Hz, 1H, CH2), 2.95 (d, J = 15.0 Hz, 1H, CH2), 1.37 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.4, 160.7, 153.9, 138.1, 134.0, 133.6, 132.4 (q, J = 31.9 Hz, CAr-CF3), 131.5, 130.9, 130.1, 129.4, 128.8, 128.6, 128.5, 127.3, 124.1 (q, J = 288.1 Hz, CF3), 123.7 (q, J = 273.0 Hz, CF3), 122.5, 121.8, 118.2, 80.4, 63.8 (q, J = 26.6 Hz, >C<), 52.7, 27.9. 19F NMR (376 MHz, CDCl3) δ −63.08 (s, 3F, CF3), −75.05 (s, 3F, CF3). Elemental analysis calcd (%) for C26H24F6N2O5: C, 55.92; H, 4.33; N, 5.02; found: C, 55.71; H, 4.57; N, 5.27.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-phenyl-6-(trifluoromethyl)-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3n).
Yield 73% as a white solid. M.p. 195–196 °C. 1H NMR (500 MHz, DMSO-d6): δ 11.18 (s, 1H, NH), 8.63 (s, 1H, NH), 8.47 (d, J = 8.3 Hz, 1H, Ar), 7.84 (d, J = 8.3 Hz, 1H, Ar), 7.57–7.48 (m, 3H, Ar), 7.37–7.33 (m, 5H, Ar), 7.30 (d, J = 7.2 Hz, 1H, Ar), 7.20 (s, 1H, Ar), 7.14 (d, J = 7.6 Hz, 1H, Ar), 5.08 (d, J = 12.3 Hz, 1H, OCH2), 5.02 (d, J = 12.2 Hz, 1H, OCH2), 3.51 (s, 3H, OCH3), 3.22 (d, J = 15.1 Hz, 1H, CH2), 2.99 (d, J = 15.1 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.0, 160.6, 154.4, 138.0, 136.0, 133.8, 133.6, 132.3 (q, J = 31.8 Hz, CAr-CF3), 131.4, 130.9, 129.3, 128.7, 128.6, 128.5, 128.2, 128.1, 127.2, 123.9 (q, J = 288.0 Hz, CF3), 123.9 (q, J = 273.1 Hz, CF3), 122.5, 121.8, 118.2, 66.5, 64.0 (q, J = 26.6 Hz, >C<), 52.9, 31.3. 19F NMR (282 MHz, CDCl3): δ −62.98 (s, 3F, CF3), −75.16 (s, 3F, CF3). Elemental analysis calcd (%) for C29H22F6N2O5: C, 58.79; H, 3.74; N, 4.73; found: C, 59.01; H, 3.81; N, 4.95.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-p-tolyl-6-(trifluoromethyl)-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3o).
Yield 89% as a white solid. M.p. 201–203 °C. 1H NMR (400 MHz, CDCl3) δ 11.99 (s, 1H, NH), 8.58 (d, J = 8.4 Hz, 1H, Ar), 7.70 (d, J = 8.4 Hz, 1H, Ar), 7.40–7.33 (m, 3H, Ar), 7.14–7.08 (m, 2H, Ar), 6.49 (s, 1H, NH), 3.65 (s, 3H, OCH3), 3.49 (d, J = 15.1 Hz, 1H, CH2), 3.32 (d, J = 15.1 Hz, 1H, CH2), 2.46 (s, 3H, CH3), 1.14 (s, 9H, CH3). 13C{1H} NMR (101 MHz, CDCl3): δ 165.6, 162.9, 154.4, 139.0, 138.7, 134.4 (q, J = 32.2 Hz, CAr-CF3), 132.9, 131.2, 130.8, 130.7, 130.3, 130.0, 128.6, 127.1, 123.9 (q, J = 288.2 Hz, CF3), 123.7 (q, J = 273.0 Hz, CF3), 123.1, 122.9, 121.0, 81.5, 64.9 (q, J = 27.2 Hz, >C<), 53.5, 31.9, 27.9, 21.5. 19F NMR (376 MHz, CDCl3) δ −63.03 (s, 3F, CF3), −75.05 (s, 3F, CF3). Elemental analysis calcd (%) for C27H26F6N2O5: C, 56.64; H, 4.58; N, 4.89; found: C, 56.71; H, 4.57; N, 4.77.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-p-tolyl-6-(trifluoromethyl)-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3p).
Yield 70% as a white solid. M.p. 213–214 °C. 1H NMR (500 MHz, DMSO-d6): δ 11.16 (s, 1H, NH), 8.62 (s, 1H, NH), 8.47 (s, 1H, Ar), 7.83 (s, 1H, Ar), 7.36–7.17 (m, 9H, Ar), 7.02 (s, 1H, Ar), 5.08 (d, J = 12.4 Hz, 1H, OCH2), 5.02 (d, J = 12.5 Hz, 1H, OCH2), 3.50 (s, 3H, OCH3), 3.24 (d, J = 15.5 Hz, 1H, CH2), 2.98 (d, J = 15.2 Hz, 1H, CH2), 2.39 (s, 3H, CH3). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.1, 160.6, 154.5, 138.2, 137.7, 136.0, 133.8, 132.3 (q, J = 31.6 Hz, CAr-CF3), 131.2, 130.8, 130.5, 129.9, 129.3, 128.6, 128.5, 128.2, 128.1, 127.3, 123.9 (q, J = 286.1 Hz, CF3), 123.7 (q, J = 272.8 Hz, CF3), 122.4, 121.8, 118.1, 66.5, 64.0 (q, J = 28.3 Hz, >C<), 52.8, 31.3, 20.9. 19F NMR (376 MHz, CDCl3): δ −62.98 (s, 3F, CF3), −75.20 (s, 3F, CF3). Elemental analysis calcd (%) for C30H24F6N2O5: C, 59.41; H, 3.99; N, 4.62; found: C, 59.67; H, 4.15; N, 4.89.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-1-oxo-6-(trifluoromethyl)-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3q).
Yield 90% as a white solid. M.p. 206–207 °C. 1H NMR (300 MHz, CDCl3): δ 11.30 (s, 1H, NH), 8.57 (d, J = 8.3 Hz, 1H, Ar), 7.69 (d, J = 8.4 Hz, 1H, Ar), 7.38 (s, 1H, Ar), 7.19–7.05 (m, 4H, Ar), 6.09 (s, 1H, NH), 3.91 (s, 3H, OCH3), 3.70 (s, 3H, OCH3), 3.48 (d, J = 15.0 Hz, 1H, CH2), 3.36 (d, J = 14.9 Hz, 1H, CH2), 1.19 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 166.0, 162.3, 159.8, 154.4, 139.2, 134.3 (q, J = 32.5 Hz, CAr-CF3), 133.1, 132.5, 132.1, 128.7, 127.3, 126.0, 123.8 (q, J = 287.8 Hz, CF3), 123.7 (q, J = 273.3 Hz, CF3), 123.0, 122.9, 120.4, 114.9, 114.8, 81.9, 65.1 (q, J = 27.4 Hz, >C<), 55.5, 53.9, 27.9. 19F NMR (282 MHz, CDCl3): δ −62.98 (s, 3F, CF3), −75.03 (s, 3F, CF3). Elemental analysis calcd (%) for C27H26F6N2O6: C, 55.10; H, 4.45; N, 4.76; found: C, 55.21; H, 4,57; N, 4.73.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-1-oxo-6-(trifluoromethyl)-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3r).
Yield 82% as a white solid. M.p. 199–200 °C. 1H NMR (500 MHz, DMSO-d6): δ 11.15 (s, 1H, NH), 8.61 (s, 1H, NH), 8.46 (d, J = 8.3 Hz, 1H, Ar), 7.82 (d, J = 8.4 Hz, 1H, Ar), 7.36 (s, 5H, Ar), 7.25 (s, 1H, Ar), 7.21 (d, J = 7.9 Hz, 1H, Ar), 7.11–7.04 (m, 3H, Ar), 5.08 (d, J = 12.3 Hz, 1H, OCH2), 5.02 (d, J = 12.4 Hz, 1H, OCH2), 3.83 (s, 3H, OCH3), 3.51 (s, 3H, OCH3), 3.26 (d, J = 15.5 Hz, 1H, CH2), 2.98 (d, J = 15.1 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.1, 160.7, 159.0, 154.5, 138.4, 136.0, 133.9, 132.6, 132.5 (q, J = 31.7 Hz, CAr-CF3), 132.2, 128.5, 128.3, 128.1, 127.3, 125.4, 124.0 (q, J = 288.5 Hz, CF3), 123.7 (q, J = 272.8 Hz, CF3), 122.4, 121.9, 117.9, 114.6, 114.1, 66.5, 64.0 (q, J = 27.7 Hz, >C<), 55.2, 52.9, 31.3. 19F NMR (282 MHz, DMSO-d6): δ −61.70 (s, 3F, CF3), −74.06 (s, 3F, CF3). Elemental analysis calcd (%) for C30H24F6N2O6: C, 57.88; H, 3.89; N, 4.50; found: C, 57.79; H, 4.05; N, 4.61.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3s).
Yield 30% as a yellow solid (eluent petroleum ether/ethyl acetate = 5/1). 1H NMR (500 MHz, DMSO-d6): δ 10.98 (s, 1H, NH), 8.62 (s, 1H, NH), 8.39 (d, J = 8.6 Hz, 1H, Ar), 8.34 (d, J = 8.4 Hz, 1H, Ar), 8.29 (d, J = 8.0 Hz, 1H, Ar), 7.65–7.60 (m, 2H, Ar), 7.55 (t, J = 7.6 Hz, 1H, Ar), 7.42 (d, J = 8.5 Hz, 1H, Ar), 7.36 (s, 5H, Ar), 6.94 (d, J = 8.1 Hz, 1H, Ar), 5.07 (d, J = 12.4 Hz, 1H, OCH2), 5.01 (d, J = 12.2 Hz, 1H, OCH2), 3.50 (s, 3H, OCH3), 3.19 (d, J = 15.4 Hz, 1H, CH2), 3.03 (d, J = 15.2 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, DMSO-d6): δ 164.8, 161.9, 154.9, 147.5, 142.5, 137.4, 136.4, 133.9, 133.4, 133.1, 132.5, 128.9, 128.7, 128.5, 127.5, 127.3, 125.3, 125.2, 124.5, 124.3 (q, J = 287.3, CF3), 123.9, 117.2, 66.9, 64.5 (q, J = 26.2 Hz, >C<), 53.4, 31.9. 19F NMR (282 MHz, DMSO-d6): δ −73.83 (s, 3F, CF3). Elemental analysis calcd (%) for C28H22F3N3O7: C, 59.05; H, 3.89; N, 7.38; found: C, 59.31; H, 4.07; N, 7.61.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-nitrophenyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)methyl)propanoate (3t).
Yield 25% as a yellow solid (eluent petroleum ether/ethyl acetate = 4/1). 1H NMR (400 MHz, acetone-d6): δ 10.46 (s, 1H, NH), 8.36 (d, J = 8.0 Hz, 1H, Ar), 8.31 (d, J = 8.2 Hz, 2H, Ar), 7.88 (d, J = 7.9 Hz, 3H, Ar), 7.78 (t, J = 7.8 Hz, 1H, Ar), 7.58 (t, J = 7.6 Hz, 1H, Ar), 7.41–7.30 (m, 5H, Ar), 6.49 (s, 1H, NH), 4.99 (d, J = 12.4 Hz, 1H, OCH2), 4.91 (d, J = 12.4 Hz, 1H, OCH2), 3.84 (d, J = 16.0 Hz, 1H, CH2), 3.59 (d, J = 16.0 Hz, 1H, CH2), 3.27 (s, 3H, OCH3). 13C{1H} NMR (151 MHz, DMSO-d6): δ 165.3, 161.3, 154.5, 147.6, 140.7, 139.8, 137.7, 136.3, 132.2, 132.0, 131.3, 128.4, 128.3, 128.1, 127.9, 127.5, 126.9, 126.7, 126.2 (q, J = 288.2 Hz, CF3), 125.4, 123.3, 106.3, 66.0, 64.3 (q, J = 26.6 Hz, >C<), 52.3, 28.9. 19F NMR (376 MHz, acetone-d6): δ −73.99 (s, 3F, CF3). Elemental analysis calcd (%) for C28H22F3N3O7: C, 59.05; H, 3.89; N, 7.38; found: C, 59.27; H, 4.11; N, 7.40.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-phenyl-1-(trifluoromethyl-sulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4a).
Yield 77% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 152–154 °C. 1H NMR (400 MHz, CDCl3): δ 8.12 (d, J = 8.2 Hz, 1H, Ar), 7.73–7.66 (m, 2H, Ar), 7.60–7.56 (m, 1H, Ar), 7.55–7.50 (m, 2H, Ar), 7.41 (t, J = 8.8 Hz, 2H, Ar), 7.23–7.20 (m, 1H, Ar), 6.85 (s, 1H, NH), 3.87–3.84 (m, 3H, OCH3, 1H, CH2), 3.53 (d, J = 15.9 Hz, 1H, CH2), 1.28 (s, 9H 3 CH3). 13C{1H} NMR (101 MHz, CDCl3): δ 166.9, 153.7, 150.8, 143.4, 139.9, 134.7, 134.5, 132.2, 130.3, 130.0, 129.3, 128.8, 128.7, 126.6, 126.3, 124.2 (q, J = 288.7 Hz, CF3), 122.7, 118.7 (q, J = 320.2 Hz, CF3), 118.5, 80.2, 64.4 (q, J = 28.2 Hz, >C<), 53.7, 33.8, 28.0. 19F NMR (282 MHz, CDCl3): δ −73.69 (s, 3F, CF3), −73.95 (s, 3F, CF3). Elemental analysis calcd (%) for C26H24F6N2O7S: C, 50.16; H, 3.89; N, 4.50; found: C, 50.07; H, 4.01; N, 4.58.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-phenyl-1-(trifluoromethyl-sulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4b).
Yield 92% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 140–142 °C. 1H NMR (400 MHz, CDCl3): δ 8.09 (d, J = 8.0 Hz, 1H, Ar), 7.74–7.67 (m, 2H, Ar), 7.57–7.51 (m, 3H, Ar), 7.38 (d, J = 8.1 Hz, 1H, Ar), 7.21–7.17 (m, 2H, Ar), 7.07–7.06 (m, 2H, Ar), 6.95–6.93 (m, 3H, Ar), 6.85 (s, 1H, NH), 5.05 (d, J = 12.3 Hz, 1H, OCH2), 4.84 (d, J = 12.2 Hz, 1H, OCH2), 4.08 (d, J = 16.1 Hz, 1H, CH2), 3.92 (s, 3H, OCH3), 3.62 (d, J = 16.4 Hz, 1H, CH2). 13C{1H} NMR (101 MHz, CDCl3): δ 166.6, 153.9, 150.6, 142.9, 139.9, 136.5, 134.7, 134.3, 132.0, 130.3, 129.9, 129.2, 128.7, 128.6, 127.9, 127.7, 127.4, 126.3, 124.1 (q, J = 289.0 Hz, CF3), 122.6, 118.6 (q, J = 320.2 Hz, CF3), 118.2, 66.7, 64.4 (q, J = 27.0 Hz, >C<), 54.2, 32.9, 29.8. 19F NMR (376 MHz, CDCl3): δ −74.11 (s, 3F, CF3), −74.67 (s, 3F, CF3). Elemental analysis calcd (%) for C29H22F6N2O7S: C, 53.05; H, 3.38; N, 4.27; found: C, 53.37; H, 3.49; N, 4.52.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-p-tolyl-1-(trifluoromethyl-sulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4c).
Yield 89% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 145–146 °C. 1H NMR (500 MHz, CDCl3): δ 8.12 (d, J = 7.4 Hz, 1H, Ar), 7.71–7.66 (m, 2H, Ar), 7.46 (d, J = 7.6 Hz, 1H, Ar), 7.38 (d, J = 7.5 Hz, 1H, Ar), 7.33 (d, J = 7.4 Hz, 1H, Ar), 7.28 (s, 1H, Ar), 7.09 (d, J = 7.3 Hz, 1H, Ar), 6.85 (s, 1H, NH), 3.87–3.84 (s, 3H, OCH3, 1H, CH2), 3.52 (d, J = 15.9 Hz, 1H, CH2), 2.48 (s, 3H, CH3), 1.28 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.0, 153.7, 150.7, 143.5, 140.1, 138.6, 134.7, 132.1, 131.7, 130.2, 129.9, 129.8, 129.6, 128.8, 126.5, 124.3 (q, J = 288.4 Hz, CF3), 122.7, 119.1 (q, J = 320.2 Hz, CF3), 118.5, 80.2, 64.4 (q, J = 27.9 Hz, >C<), 53.7, 33.8, 28.0, 21.5. 19F NMR (282 MHz, CDCl3): δ −73.67 (s, 3F, CF3), −73.83 (s, 3F, CF3). Elemental analysis calcd (%) for C27H26F6N2O7S: C, 50.94; H, 4.12; N, 4.40; found: C, 51.04; H, 4.25; N, 4.43.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-p-tolyl-1-(trifluoromethyl-sulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4d).
Yield 90% as a thick oil (eluent petroleum ether/ethyl acetate = 15/1). 1H NMR (500 MHz, CDCl3): δ 8.07 (d, J = 8.0 Hz, 1H, Ar), 7.72–7.66 (m, 2H, Ar), 7.40 (d, J = 8.2 Hz, 1H, Ar), 7.35 (d, J = 7.8 Hz, 1H, Ar), 7.31 (d, J = 7.7 Hz, 1H, Ar), 7.08–7.03 (m, 4H, Ar), 6.98–6.92 (m, 3H, Ar), 6.83 (s, 1H, NH), 5.03 (d, J = 12.5 Hz, 1H, OCH2), 4.84 (d, J = 12.6 Hz, 1H, OCH2), 4.06 (d, J = 16.6 Hz, 1H, CH2), 3.90 (s, 3H, OCH3), 3.59 (d, J = 16.5 Hz, 1H, CH2), 2.47 (s, 3H, CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 166.7, 153.9, 150.5, 143.0, 140.1, 138.5, 136.6, 134.5, 131.9, 131.6, 130.1, 129.9, 129.8, 129.5, 128.6, 128.0, 127.7, 127.4, 126.5, 124.1 (q, J = 288.8 Hz, CF3), 122.6, 118.7 (q, J = 320.2 Hz, CF3), 118.3, 66.7, 64.5 (q, J = 28.1 Hz, >C<), 54.1, 33.0, 21.5. 19F NMR (282 MHz, CDCl3): δ −74.01 (s, 3F, CF3), −74.52 (s, 3F, CF3). Elemental analysis calcd (%) for C30H24F6N2O7S: C, 53.73; H, 3.61; N, 4.18; found: C, 53.98; H, 3.90; N, 4.25.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-1-(trifluoro-methylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4e).
Yield 70% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 112–114 °C. 1H NMR (300 MHz, CDCl3): δ 8.11–8.09 (m, 1H, Ar), 7.71–7.68 (m, 2H, Ar), 7.48–7.47 (m, 1H, Ar), 7.32–7.29 (m, 1H, Ar), 7.11–7.03 (m, 3H, Ar), 6.84 (s, 1H, NH), 3.91 (s, 3H, OCH3, 0.5 CH2), 3.84 (s, 3H, OCH3, 0.5 CH2), 3.52 (d, J = 16.0 Hz, 1H, CH2), 1.27 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.0, 159.9, 153.7, 150.7, 143.7, 140.3, 134.4, 132.1, 131.6, 131.2, 128.8, 126.7, 126.4, 124.3 (q, J = 288.4 Hz, CF3), 122.7, 118.7 (q, J = 320.2 Hz, CF3), 118.5, 114.6, 114.5, 80.1, 64.4 (q, J = 27.5 Hz, >C<), 55.5, 53.7, 33.8, 28.0. 19F NMR (282 MHz, CDCl3): δ −73.70 (s, 3F, CF3), −73.89 (s, 3F, CF3). Elemental analysis calcd (%) for C27H26F6N2O8S: C, 49.69; H, 4.02; N, 4.29; found: C, 49.64; H, 4.05; N, 4.23.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((6-nitro-4-phenyl-1-(trifluoro methylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4f).
Yield 79% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 162–164 °C. 1H NMR (400 MHz, CDCl3): δ 8.49 (d, J = 9.2 Hz, 1H, Ar), 8.39 (s, 1H, Ar), 8.34 (d, J = 9.2 Hz, 1H, Ar), 7.73–7.66 (m, 3H, Ar), 7.53 (s, 1H, Ar), 7.31 (s, 1H, Ar), 6.56 (s, 1H, NH), 4.14 (d, J = 16.5 Hz, 1H, CH2), 3.95 (s, 3H, OCH3), 3.69 (d, J = 16.5 Hz, 1H, CH2), 1.28 (s, 9H, 3 CH3). 13C{1H} NMR (101 MHz, CDCl3): δ 166.7, 153.4, 150.4, 149.6, 146.6, 139.5, 135.9, 133.2, 130.1, 129.9, 129.8, 129.7, 129.3, 125.2, 124.1 (q, J = 288.3 Hz, CF3), 122.4, 122.2, 120.2, 118.7 (q, J = 320.0 Hz, S-CF3),80.2, 64.2 (q, J = 26.6 Hz. >C<), 54.0, 33.5, 27.9. 19F NMR (376 MHz, CDCl3): δ −73.63 (s, 3F, CF3), −74.85 (s, 3F, CF3). Elemental analysis calcd (%) for C26H23F6N3O9S: C, 46.78; H, 3.47; N, 6.29; found: C, 46.71; H, 3.49; N, 6.09.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((6-nitro-4-phenyl-1-(trifluoro methylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4g).
Yield 89% as a yellow solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 123–125 °C. 1H NMR (400 MHz, CDCl3): δ 8.40 (s, 1H, Ar), 8.21 (s, 2H, Ar), 7.57 (s, 3H, Ar), 7.20 (s, 2H, Ar), 7.03 (s, 2H, Ar), 6.88 (s, 3H, Ar), 6.58 (s, 1H, NH), 4.97 (d, J = 12.4 Hz, 1H, OCH2), 4.76 (d, J = 12.6 Hz, 1H, OCH2), 4.18 (d, J = 16.9 Hz, 1H CH2), 3.91 (s, 3H, OCH3), 3.66 (d, J = 17.0 Hz, 1H, CH2). 13C{1H} NMR (101 MHz, CDCl3): δ 166.4, 153.6, 150.2, 149.5, 146.0, 139.4, 136.5, 135.7, 133.1, 130.0, 129.8, 129.7, 129.6, 129.2, 127.9, 127.7, 127.6, 125.1, 124.0 (q, J = 290.0 Hz, CF3), 122.3, 121.9, 119.9, 118.6 (q, J = 320.0 Hz, CF3), 66.7, 64.3 (q, J = 28.5 Hz, CF3), 54.4, 32.9. 19F NMR (282 MHz, CDCl3): δ −73.84 (s, 3F, CF3), −75.29 (s, 3F, CF3). Elemental analysis calcd (%) for C29H21F6N3O9S: C, 49.65; H, 3.02; N, 5.99; found: C, 49.52; H, 3.01; N, 5.87.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((6-nitro-4-p-tolyl-1-(trifluoromethylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4h).
Yield 82% as a white solid (eluent petroleum ether/ethyl acetate = 9/1). M.p. 154–155 °C. 1H NMR (500 MHz, CDCl3): δ 8.41 (d, J = 9.3 Hz, 1H, Ar), 8.37 (s, 1H, Ar), 8.26 (d, J = 9.2 Hz, 1H, Ar), 7.45 (d, J = 7.8 Hz, 1H, Ar), 7.38 (d, J = 7.8 Hz, 1H, Ar), 7.32 (d, J = 7.9 Hz, 1H, Ar), 7.12 (d, J = 6.9 Hz, 1H, Ar), 6.49 (s, 1H, NH), 4.08 (d, J = 16.4 Hz, 1H, CH2), 3.88 (s, 3H, OCH3), 3.62 (d, J = 16.4 Hz, 1H, CH2), 2.51 (s, 3H, CH3), 1.22 (s, 9H, CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 166.7, 153.4, 150.3, 149.6, 146.7, 139.6, 136.2, 130.5, 130.1, 130.0, 129.9, 129.8, 125.1, 124.1 (q, J = 288.6 Hz, CF3), 122.5, 122.1, 120.2, 118.7 (q, J = 320.3 Hz, CF3), 114.2, 80.2, 64.2 (q, J = 28.1 Hz, >C<), 54.0, 33.5, 27.9, 21.6. 19F NMR (282 MHz, CDCl3): δ −73.56 (s, 3F, CF3), −74.68 (s, 3F, CF3). Elemental analysis calcd (%) for C27H25F6N3O9S: C, 47.58; H, 3.70; N, 6.17; found: C, 47.61; H, 3.77; N, 6.15.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-6-nitro-1-(trifluoromethylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4i).
Yield 88% as a white solid (eluent petroleum ether/ethyl acetate = 9/1). M.p. 149–150 °C. 1H NMR (500 MHz, CDCl3): δ 8.41 (d, J = 9.1 Hz, 1H, Ar), 8.38 (s, 1H, Ar), 8.26 (d, J = 9.1 Hz, 1H, Ar), 7.37 (d, J = 8.4 Hz, 1H, Ar), 7.18–7.14 (m, 2H, Ar), 7.10 (d, J = 8.5 Hz, 1H, Ar), 6.48 (s, 1H, NH), 4.10 (d, J = 16.3 Hz, 1H, CH2), 3.95 (s, 3H, OCH3), 3.88 (s, 3H, OCH3), 3.63 (d, J = 16.4 Hz, 1H, CH2), 1.21 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 166.7, 160.4, 153.4, 150.2, 149.6, 146.9, 139.8, 135.9, 131.4, 131.2, 125.1, 125.0, 124.1 (q, J = 288.5 Hz, CF3), 122.5, 122.0, 120.2, 118.7 (q, J = 320.2 Hz, CF3) 115.1, 115.0, 80.2, 64.2 (q, J = 28.6 Hz, >C<), 55.5, 54.0, 33.5, 27.9. 19F NMR (282 MHz, CDCl3): δ −73.54 (s, 3F, CF3), −74.72 (s, 3F, CF3). Elemental analysis calcd (%) for C27H25F6N3O10S: C, 46.49; H, 3.61; N, 6.02; found: C, 46.62; H, 3.64; N, 6.12.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-6-nitro-1-(trifluoromethylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4j).
Yield 94% as a yellow solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 152–154 °C. 1H NMR (400 MHz, CDCl3): δ 8.41 (d, J = 9.2 Hz, 1H, Ar), 8.28 (s, 1H, Ar), 8.19 (d, J = 9.1 Hz, 1H, Ar), 7.14–7.02 (m, 6H, Ar), 6.89 (s, 3H, Ar), 6.58 (s, 1H, NH), 4.97 (d, J = 12.3 Hz, 1H, OCH2), 4.77 (d, J = 12.1 Hz, 1H, OCH2), 4.21 (d, J = 16.4 Hz, 1H CH2), 3.95 (s, 3H, OCH3), 3.93 (s, 3H, OCH3), 3.66 (d, J = 16.8 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 166.4, 160.4, 153.7, 150.0, 149.5, 146.4, 139.7, 136.5, 135.7, 131.4, 131.0, 127.9, 127.6, 127.5, 125.1, 124.9, 124.0 (q, J = 285.8 Hz, CF3), 122.5, 121.8, 119.9, 118.6 (q, J = 320.4 Hz, CF3), 115.0, 114.9, 66.7, 64.3 (q, J = 28.5 Hz, >C<), 55.5, 54.5, 32.9. 19F NMR (282 MHz, CDCl3): δ −73.83 (s, 3F, CF3), −75.22 (s, 3F, CF3). Elemental analysis calcd (%) for C30H23F6N3O10S: C, 49.25; H, 3.17; N, 5.74; found: C, 49.29; H, 3.08; N, 5.84.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-phenyl-6-(trifluoromethyl)-1-(trifluoromethylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4k).
Yield 81% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 146–148 °C. 1H NMR (500 MHz, CDCl3): δ 8.25 (d, J = 8.8 Hz, 1H, Ar), 7.87 (d, J = 8.8 Hz, 1H, Ar), 7.72 (s, 1H, Ar), 7.63 (s, 1H, Ar), 7.57 (s, 2H, Ar), 7.44 (s, 1H, Ar), 7.24 (s, 1H, Ar), 6.59 (s, 1H, NH), 4.01 (d, J = 16.1 Hz, 1H, CH2), 3.87 (s, 3H, OCH3), 3.60 (d, J = 16.3 Hz, 1H, CH2), 1.24 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 166.8, 153.5, 150.5, 145.6, 139.2, 135.1, 133.8 (q, J = 33.5 Hz, CAr-CF3), 133.7, 130.1, 129.9, 129.6, 129.4, 129.2, 124.6, 124.2 (q, J = 288.4 Hz, CF3), 124.2, 123.9–123.8 (m), 123.3 (q, J = 273.2 Hz, CF3), 119.5, 118.7 (q, J = 320.2 Hz, CF3), 80.2, 64.3 (q, J = 28.4 Hz, >C<), 53.9, 33.5, 27.9. 19F NMR (282 MHz, CDCl3): δ −73.69 (s, 3F, CF3), −73.89 (s, 3F, CF3). Elemental analysis calcd (%) for C27H23F9N2O7S: C, 46.96; H, 3.36; N, 4.06; found: C, 46.87; H, 3.32; N, 4.05.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-phenyl-6-(trifluoromethyl)-1-(trifluoromethylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4l).
Yield 80% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 109–111 °C. 1H NMR (300 MHz, CDCl3): δ 8.18 (d, J = 8.8 Hz, 1H, Ar), 7.87 (d, J = 8.8 Hz, 1H, Ar), 7.60–7.53 (m, 4H, Ar), 7.18–7.12 (m, 2H, Ar), 7.01 (s, 2H, Ar), 6.87 (s, 3H, Ar), 6.62 (s, 1H, NH), 4.99 (d, J = 12.5 Hz, 1H, OCH2), 4.76 (d, J = 12.5 Hz, 1H, OCH2), 4.12 (d, J = 16.9 Hz, 1H, CH2), 3.92 (s, 3H, OCH3), 3.63 (d, J = 16.8 Hz, 1H, CH2). 13C{1H} NMR (101 MHz, CDCl3): δ 166.5, 153.7, 150.3, 145.0, 139.1, 136.6, 134.9, 133.6 (q, J = 33.1 Hz, CAr-CF3), 133.5, 130.1, 129.8, 129.5, 129.2, 129.0, 127.8, 127.6, 127.4, 124.3, 124.2, 124.0 (q, J = 289.1 Hz, CF3), 123.9, 123.4 (q, J = 274.3 Hz, CF3), 119.2, 118.6 (q, J = 320.4 Hz, CF3), 66.7, 64.3 (q, J = 28.8 Hz, >C<), 54.4, 32.8. 19F NMR (282 MHz, CDCl3): δ −63.22 (s, 3F, CF3), −73.92 (s, 3F, CF3), −75.08 (s, 3F, CF3). Elemental analysis calcd (%) for C30H21F9N2O7S: C, 49.73; H, 2.92; N, 3.87; found: C, 49.75; H, 2.96; N, 3.83.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-p-tolyl-6-(trifluoromethyl)-1-(trifluoromethylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4m).
Yield 70% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 134–136 °C. 1H NMR (500 MHz, CDCl3): δ 8.24 (d, J = 8.8 Hz, 1H, Ar), 7.86 (d, J = 8.9 Hz, 1H, Ar), 7.77 (s, 1H, Ar), 7.42 (d, J = 7.8 Hz, 1H, Ar), 7.36 (d, J = 7.7 Hz, 1H, Ar), 7.30 (d, J = 7.8 Hz, 1H, Ar), 7.11 (d, J = 7.8 Hz, 1H, Ar), 6.61 (s, 1H, NH), 4.01 (d, J = 16.2 Hz, 1H, CH2), 3.86 (s, 3H, OCH3), 3.59 (d, J = 16.3 Hz, 1H, CH2), 2.50 (s, 3H, CH3), 1.24 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3) δ 166.8, 153.5, 150.4, 145.7, 139.3, 139.2, 135.4, 133.7 (q, J = 32.9 Hz, CAr-CF3), 130.5, 130.3, 130.0, 129.9, 129.8, 124.5, 124.2 (q, J = 288.4 Hz, CF3), 124.1, 123.9–123.9 (m), 123.3 (q, J = 274.2 Hz, CF3), 120.1, 118.7 (q, J = 320.2 Hz, CF3), 80.2, 64.3 (q, J = 28.0 Hz, >C<), 53.9, 33.6, 27.9, 21.5. 19F NMR (282 MHz, CDCl3) δ −63.17 (s, 3F, CF3), −73.58 (s, 3F, CF3), −74.38 (s, 3F, CF3). Elemental analysis calcd (%) for C28H25F9N2O7S: C, 47.73; H, 3.58; N, 3.98; found: C, 47.71; H, 3,57; N, 3.94.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-p-tolyl-6-(trifluoromethyl)-1-(trifluoromethylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4n).
Yield 92% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 101–103 °C. 1H NMR (300 MHz, CDCl3): δ 8.17 (d, J = 8.8 Hz, 1H, Ar), 7.86 (d, J = 8.8 Hz, 1H, Ar), 7.65 (s, 1H, Ar), 7.38 (d, J = 7.8 Hz, 1H, Ar), 7.33 (d, J = 7.8 Hz, 1H, Ar), 7.06–6.98 (m, 4H, Ar), 6.88 (s, 3H, Ar), 6.63 (s, 1H, NH), 4.99 (d, J = 12.5 Hz, 1H, OCH2), 4.77 (d, J = 12.5 Hz, 1H, OCH2), 4.14 (d, J = 16.8 Hz, 1H, CH2), 3.92 (s, 3H, OCH3), 3.63 (d, J = 16.8 Hz, 1H, CH2), 2.49 (s, 3H, CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 166.6, 153.7, 150.2, 145.1, 139.3, 139.0, 136.6, 135.2, 133.5 (q, J = 32.7 Hz, CAr-CF3), 130.4, 130.2, 129.9, 129.7, 129.6, 127.8, 127.6, 127.4, 124.2, 124.1, 124.0, 123.4 (q, J = 273.2 Hz, CF3), 124.1 (q, J = 288.4 Hz, CF3), 119.2, 118.6 (q, J = 319.9 Hz, CF3), 66.7, 64.4 (q, J = 28.6 Hz, >C<), 54.4, 32.9. 19F NMR (282 MHz, CDCl3): δ = −63.17 (s, 3F, CF3), −73.91 (s, 3F, CF3), −74.98 (s, 3F, CF3). Elemental analysis calcd (%) for C31H23F9N2O7S: C, 50.41; H, 3.14; N, 3.79; found: C, 50.63; H, 3.32; N, 4.01.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-(4-methoxyphenyl)-6-(trifluoromethyl)-1-(trifluoromethylsulfonyloxy)isoquinolin-3-yl)methyl)propanoate (4o).
Yield 93% as a thick oil (eluent petroleum ether/ethyl acetate = 15/1). 1H NMR (500 MHz, CDCl3): δ 8.17 (d, J = 8.8 Hz, 1H, Ar), 7.86 (d, J = 8.8 Hz, 1H, Ar), 7.67 (s, 1H, Ar), 7.12–7.01 (m, 6H, Ar), 6.87 (s, 3H, Ar), 6.62 (s, 1H, NH), 4.99 (d, J = 12.5 Hz, 1H, OCH2), 4.77 (d, J = 12.5 Hz, 1H, OCH2), 4.16 (d, J = 16.7 Hz, 1H, CH2), 3.93 (s, 6H, 2 CH3), 3.64 (d, J = 16.7 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 166.6, 160.1, 153.7, 150.1, 145.4, 139.5, 136.6, 134.9, 133.5 (q, J = 33.0 Hz, CAr-CF3), 131.4, 131.0, 127.9, 127.6, 127.4, 125.4, 124.2, 124.1, 124.0 (q, J = 288.7 Hz, CF3), 124.0, 123.4 (q, J = 273.2 Hz, CF3), 119.2, 118.6 (q, J = 320.4 Hz, S-CF3), 114.8, 114.7, 66.7, 64.4 (q, J = 28.5 Hz, >C<), 55.5, 54.4, 32.9. 19F NMR (282 MHz, CDCl3): δ −63.16 (s, 3F, CF3), −73.93 (s, 3F, CF3), −75.01 (s, 3F, CF3). Elemental analysis calcd (%) for C31H23F9N2O8S: C, 49.34; H, 3.07; N, 3.71; found: C, 49.44; H, 3.02; N, 3.85.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((1-(4-methoxyphenyl)-4-p-tolyl-isoquinolin-3-yl)methyl)propanoate (5a).
Yield 92% as a white solid (eluent petroleum ether/ethyl acetate = 10/1). M.p. 214–215 °C. 1H NMR (500 MHz, CDCl3): δ 8.57 (s, 1H, NH), 8.22 (d, J = 8.2 Hz, 1H, Ar), 7.77 (d, J = 8.1 Hz, 2H, Ar), 7.56–7.52 (m, 2H, Ar), 7.46 (d, J = 8.3 Hz, 1H, Ar), 7.35 (d, J = 7.7 Hz, 1H, Ar), 7.31 (d, J = 7.8 Hz, 1H, Ar), 7.24 (d, J = 7.8 Hz, 1H, Ar), 7.10 (d, J = 8.0 Hz, 3H, Ar), 3.92 (s, 3H, OCH3), 3.71–3.67 (m, 3H, OCH3, 1H, CH2), 3.49 (d, J = 14.7 Hz, 1H, CH2), 2.48 (s, 3H, CH3), 1.37 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.4, 160.4, 158.2, 154.2, 144.7, 137.9, 137.7, 132.9, 131.9, 131.7, 131.6, 130.5, 130.3, 130.2, 129.7, 129.3, 127.7, 126.9, 126.4, 125.2, 124.5 (q, J = 288.0 Hz, CF3), 115.3, 114.0, 80.0, 67.2, 64.8 (q, J = 25.4 Hz, >C<), 55.6, 53.0, 34.2, 28.3, 21.5. 19F NMR (282 MHz, CDCl3): δ −72.96 (s, 3F, CF3). Elemental analysis calcd (%) for C33H33F3N2O5: C, 66.66; H, 5.59; N, 4.71; found: C, 66.35; H, 5.21; N, 4.43.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((1-(4-methoxyphenyl)-6-nitro-4-phenylisoquinolin-3-yl)methyl)propanoate (5b).
Yield 88% as a yellow solid (eluent petroleum ether/ethyl acetate = 10/1). M.p. 180–181 °C. 1H NMR (500 MHz, CDCl3): δ 8.38 (d, J = 9.2 Hz, 1H, Ar), 8.33 (d, J = 1.7 Hz, 1H, Ar), 8.23 (dв, J = 9.2, 2.3 Hz, 1H, Ar), 7.73 (d, J = 8.3 Hz, 2H, Ar), 7.67 (br. s, 1H, NH), 7.64–7.61 (m, 1H, Ar), 7.58–7.56 (m, 2H, Ar), 7.42 (d, J = 7.0 Hz, 1H, Ar), 7.26–7.25 (m, 1H, Ar), 7.13 (d, J = 8.3 Hz, 2H, Ar), 3.94 (s, 3H, OCH3), 3.82 (d, J = 15.3 Hz, 1H, CH2), 3.66 (s, 3H, OCH3), 3.59 (d, J = 15.5 Hz, 1H, CH2), 1.29 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.3, 160.9, 158.6, 153.7, 148.3, 147.2, 137.1, 134.6, 132.8, 131.7, 130.5, 130.2, 130.0–129.9 (m), 129.5, 129.1, 129.0, 126.7, 124.4 (q, J = 287.3 Hz, CF3), 122.4, 120.0, 114.2, 100.1, 80.2, 64.7 (q, J = 27.7 Hz, >C<), 55.6, 53.4, 34.1, 28.2. 19F NMR (282 MHz, CDCl3): δ −73.71 (s, 3F, CF3). Elemental analysis calcd (%) for C32H30F3N3O7: C, 61.44; H, 4.83; N, 6.72; found: C, 61.18; H, 4.61; N, 6.56.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((1-(4-methoxyphenyl)-4-phenyl-6-(trifluoromethyl)isoquinolin-3-yl)methyl)propanoate (5c).
Yield 87% as a white solid (eluent petroleum ether/ethyl acetate = 10/1). M.p. 107–108 °C. 1H NMR (400 MHz, CDCl3): δ 8.30 (d, J = 7.8 Hz, 1H, Ar), 7.92 (s, 1H, NH), 7.68–7.66 (m, 2H, Ar), 7.62–7.50 (m, 5H, Ar), 7.22–7.20 (m, 2H, Ar), 7.14–7.05 (m, 5H, Ar), 6.95–6.94 (m, 2H, Ar), 5.07 (d, J = 11.9 Hz, 1H, OCH2), 4.88 (d, J = 12.0 Hz, 1H, OCH2), 3.88 (s, 3H, OCH3, 1H, CH2), 3.65 (s, 3H, OCH3), 3.59 (d, J = 16.1 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 167.2, 160.6, 158.5, 154.2, 145.8, 136.7, 136.5, 134.9, 132.2, 131.8 (q, J = 32.3 Hz, CAr-CF3), 131.7, 130.6, 130.5, 130.1, 129.3, 129.1, 128.9, 128.7, 128.3, 127.9, 127.8, 126.0, 125.5, 124.3 (q, J = 287.9 Hz, CF3), 123.9 (q, J = 273.0 Hz, CF3), 123.8–123.7 (m), 122.4, 114.0, 66.9, 64.8 (q, J = 28.5 Hz, >C<), 55.6, 53.6, 33.8. 19F NMR (376 MHz, CDCl3): δ −62.99 (s, 3F, CF3), −73.68 (s, 3F, CF3). Elemental analysis calcd (%) for C36H28F6N2O5: C, 63.34; H, 4.13; N, 4.10; found: C, 63.18; H, 4.01; N, 4.25.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-(phenylethynyl)-1-p-tolylnaphthalen-2-yl)methyl)propanoate (6a).
Yield 58% as a white solid (eluent petroleum ether/ethyl acetate = 10/1). M.p. 180–182 °C. 1H NMR (400 MHz, CDCl3): δ 8.52 (d, J = 8.4 Hz, 1H, Ar), 8.03 (s, 1H, NH), 7.70–7.61 (m, 4H, Ar), 7.44–7.40 (m, 4H, Ar), 7.33–7.29 (m, 2H, Ar), 7.16–7.12 (m, 2H, Ar), 7.08–7.02 (m, 5H, Ar), 5.07 (d, J = 12.5 Hz, 1H, OCH2), 4.96 (d, J = 12.8 Hz, 1H, OCH2), 3.85 (s, 3H, OCH3, 1H, CH2,), 3.56 (d, J = 15.5 Hz, 1H, CH2), 2.47 (s, 3H, CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.4, 154.3, 145.5, 141.9, 138.1, 136.6, 136.5, 133.1, 132.5, 132.3, 130.7, 130.4, 129.9, 129.6, 129.5, 129.3, 128.7, 128.3, 127.9, 127.8, 127.7, 127.4, 126.9, 126.3, 124.4 (q, J = 287.2 Hz, CF3), 122.3, 94.0, 86.8, 66.7, 64.9 (q, J = 27.8 Hz, >C<), 53.6, 33.9, 21.5. 19F NMR (282 MHz, CDCl3): δ −73.59 (s, 3F, CF3). Elemental analysis calcd (%) for C37H29F3N2O4: C, 71.37; H, 4.69; N, 4.50; found: C, 71.14; H, 4.48; N, 4.27.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((7-nitro-1-phenyl-4-(phenyl-ethynyl)naphthalen-2-yl)methyl)propanoate (6b).
Yield 60% as a white solid (eluent petroleum ether/ethyl acetate = 10/1). M.p. 98–99 °C. 1H NMR (500 MHz, CDCl3): δ 8.68 (d, J = 8.0 Hz, 1H, Ar), 8.37 (d, J = 7.8 Hz, 1H, Ar), 8.32 (s, 1H, Ar), 7.75 (s, 2H, Ar), 7.62 (s, 2H, Ar), 7.58 (s, 2H, Ar), 7.48 (s, 3H, Ar), 7.41 (s, 1H, Ar), 7.26 (br. s, 1H, NH), 3.89 (m, 3H, OCH3, 1H, CH2), 3.59 (d, J = 14.8 Hz, 1H, CH2), 1.30 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.4, 153.6, 148.9, 148.2, 145.3, 144.9, 134.3, 134.0, 132.5, 130.5, 130.1, 129.5, 129.4, 129.3, 129.1, 128.9, 128.3, 124.4 (q, J = 290.4 Hz, CF3), 122.6, 121.7, 121.0, 90.4, 85.9, 66.6, 64.7 (q, J = 27.2 Hz, >C<), 60.6, 53.6, 29.8, 28.2. 19F NMR (282 MHz, CDCl3): δ −73.71 (s, 3F, CF3). Elemental analysis calcd (%) for C33H28F3N3O6: C, 63.97; H, 4.56; N, 6.78; found: C, 63.83; H, 4.41; N, 6.54.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-(phenylethynyl)-1-p-tolyl-7-(trifluoromethyl)naphthalen-2-yl)methyl)propanoate (6c).
Yield 67% as a white solid (eluent petroleum ether/ethyl acetate = 15/1). M.p. 198–200 °C. 1H NMR (400 MHz, CDCl3): δ 8.65 (d, J = 8.7 Hz, 1H, Ar), 7.82 (d, J = 8.8 Hz, 1H, Ar), 7.77–7.74 (m, 3H, Ar), 7.61 (s, 1H, NH), 7.47–7.46 (m, 3H, Ar), 7.38 (d, J = 7.7 Hz, 1H, Ar), 7.33 (d, J = 7.6 Hz, 1H, Ar), 7.23 (d, J = 8.0 Hz, 1H, Ar), 7.08 (d, J = 7.7 Hz, 1H, Ar), 3.84 (s, 3H, OCH3, 1H, CH2), 3.54 (d, J = 15.3 Hz, 1H, CH2), 2.49 (s, 3H, CH3), 1.32 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, CDCl3): δ 167.5, 153.8, 147.6, 142.1, 138.7, 135.8, 133.7, 132.4, 132.3 (q, J = 32.3 Hz, CAr-CF3), 131.4, 130.3, 130.0, 129.9, 129.8, 129.6, 128.8, 128.6, 128.4, 124.3 (q, J = 288.3 Hz, CF3), 123.9–123.9 (m), 123.7 (q, J = 273.0 Hz, CF3), 123.3, 121.9, 94.9, 86.3, 80.1, 64.7 (q, J = 27.3 Hz, >C<), 53.4, 34.2, 28.2, 21.5. 19F NMR (282 MHz, CDCl3): δ −62.99 (s, 3F, CF3), −73.60 (s, 3F, CF3). Elemental analysis calcd (%) for C35H30F6N2O4: C, 64.02; H, 4.61; N, 4.27; found: C, 64.29; H, 4.41; N, 4.25.
Methyl 2-(tert-butoxycarbonylamino)-3,3,3-trifluoro-2-((4-phenylisoquinolin-3-yl)methyl)-propanoate (7a).
Yield 50% as a white solid (eluent petroleum ether/ethyl acetate = 5/1). M.p. 124–126 °C. 1H NMR (400 MHz, CDCl3): δ 9.19 (s, 1H, Ar), 8.01–7.99 (m, 1H, Ar), 7.94 (br. s, 1H, NH), 7.59–7.48 (m, 5H, Ar), 7.31 (s, 2H, Ar), 7.19 (m, 1H, Ar), 3.78 (s, 3H, OCH3), 3.66 (d, J = 15.9 Hz, 1H, CH2), 3.47 (d, J = 15.2 Hz, 1H, CH2), 1.35 (s, 9H, 3 CH3). 13C{1H} NMR (101 MHz, CDCl3): δ 167.8, 153.9, 150.6, 145.7, 136.2, 135.9, 132.8, 130.8, 130.5, 130.1, 128.9, 128.6, 128.3, 127.6, 127.1, 125.7, 124.5 (q, J = 288.4 Hz, CF3), 80.1, 66.5, 64.6 (q, J = 24.0 Hz, >C<), 53.2, 34.5, 28.2. 19F NMR (376 MHz, CDCl3): δ −72.99 (s, 3F, CF3). Elemental analysis calcd (%) for C25H25F3N2O4: C, 63.28; H, 5.31; N, 5.90; found: C, 63.08; H, 5.01; N, 5.75.
Methyl 2-(benzyloxycarbonylamino)-3,3,3-trifluoro-2-((4-phenylisoquinolin-3-yl)methyl)-propanoate (7b).
Yield 61% as a white solid (eluent petroleum ether/ethyl acetate = 8/1). M.p. 136–137 °C. 1H NMR (400 MHz, CDCl3): δ 9.13 (s, 1H, Ar), 7.98 (s, 1H, Ar, 1H, NH), 7.2–7.58 (m, 2H, Ar), 7.53–7.48 (m, 3H, Ar), 7.35 (d, J = 7.8 Hz, 1H, Ar), 7.23 (d, J = 7.6 Hz, 1H, Ar), 7.20–7.10 (m, 6H, Ar), 5.09 (d, J = 12.5 Hz, 1H, OCH2), 4.94 (d, J = 12.5 Hz, 1H, OCH2), 3.81 (s, 3H, OCH3, 1H, CH2), 3.55 (d, J = 15.6 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 167.6, 154.3, 150.4, 145.3, 136.6, 136.2, 135.8, 132.8, 130.7, 130.5, 130.1, 128.9, 128.6, 128.4, 128.2, 127.9, 127.7, 127.2, 127.1, 125.7, 124.4 (q, J = 286.9 Hz, CF3), 66.7, 64.8 (q, J = 28.2 Hz, >C<), 53.5, 34.0. 19F NMR (282 MHz, CDCl3): δ −73.27 (s, 3F, CF3). Elemental analysis calcd (%) for C28H23F3N2O4: C, 66.14; H, 4.56; N, 5.51; found: C, 66.31; H, 4.89; N, 5.76.
2-(tert-Butoxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)methyl)propanoic acid (8).
Yield 83% as a white solid. M.p. 176–177 °C. 1H NMR (300 MHz, DMSO-d6): δ 10.84 (s, 1H, NH), 8.26 (d, J = 7.7 Hz, 1H, Ar), 8.00 (s, 1H, Ar), 7.60 (t, J = 7.5 Hz, 1H, Ar), 7.51–7.42 (m, 4H, Ar), 7.25–7.23 (m, 2H, Ar), 6.92 (d, J = 8.2 Hz, 1H, Ar), 3.36 (br. s, 1H, OH), 3.10 (d, J = 14.8 Hz, 1H, CH2), 2.87 (d, J = 14.8 Hz, 1H, CH2), 1.37 (s, 9H, 3 CH3). 13C{1H} NMR (126 MHz, DMSO-d6): δ 165.3, 161.4, 153.7, 138.2, 134.6, 132.5, 132.2, 132.0, 130.8, 128.7, 128.5, 127.8, 126.6, 126.3, 125.2, 124.7, 124.4 (q, J = 287.6 Hz, CF3), 118.6, 79.8, 64.0 (q. J = 30.8 Hz, >C<), 31.2, 27.9. 19F NMR (282 MHz, acetone-d6): δ −74.93 (s, 3F, CF3). Elemental analysis calcd (%) for C24H23F3N2O5: C, 60.50; H, 4.87; N, 5.88; found: C, 63.38; H, 5.03; N, 5.77.
2-(tert-Butoxycarbonylamino)-3,3,3-trifluoro-2-((1-oxo-4-phenyl-1,2-dihydroisoquinolin-3-yl)methyl)propanoic acid (9).
Yield 85% as a white solid. M.p. 184–185 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.43 (d, J = 8.3 Hz, 1H, Ar), 7.79 (d, J = 8.4 Hz, 1H, Ar), 7.25 (s, 1H, Ar), 7.20 (d, J = 7.8 Hz, 2H, Ar), 7.16–7.09 (m, 2H, Ar, 1H, NH), 3.85 (s, 3H, OCH3), 3.61 (s, 3H, OCH3), 3.31 (s, 2H, NH2), 3.06 (d, J = 15.0 Hz, 1H, CH2), 2.93 (d, J = 14.9 Hz, 1H, CH2). 13C{1H} NMR (126 MHz, CDCl3): δ 166.6, 161.4, 159.7, 139.2, 134.3, 134.1 (q. J = 32.4 Hz, CAr-CF3), 132.2, 131.9, 128.7, 127.5, 126.2, 124.0 (q. J = 286.9 Hz, CF3), 123.8 (q. J = 273.0 Hz, CF3), 122.9–122.9 (m), 122.5–122.5 (m), 118.0, 114.8, 114.6, 64.6 (q. J = 27.8 Hz, >C<), 55.5, 54.1, 31.2. 19F NMR (282 MHz, CDCl3): δ −62.95 (s, 3F, CF3), −79.00 (s, 3F, CF3). Elemental analysis calcd (%) for C22H18F6N2O4: C, 54.10; H, 3.71; N, 5.74; found: C, 54.22; H, 3.99; N, 5.82.

3.3. X-ray Structure Determination of 3a

A single-crystal X-ray diffraction experiment was carried out with a Bruker SMART APEX II diffractometer (graphite monochromated Mo-Kα radiation, λ = 0.71073 Å, ω-scan technique). The structure was solved with direct methods and refined by the full-matrix least-squares technique against F2,with the anisotropic thermal parameters for all non-hydrogen atoms using the SHELXL [60] program package. Hydrogen atoms of the NH groups were located in the different Fourier maps and freely refined without constraints. The remaining hydrogen atoms were placed in calculated positions and refined using a riding model with Uiso(H) = 1.5Ueq(C) for hydrogen atoms of methyl groups and Uiso(H) = 1.2Ueq(C) for other carbon atoms. The crystal data and structure refinement details are presented in Supplementary Materials (Table S1). Single-crystal X-ray diffraction analysis was performed using the equipment of the JRC PMR IGIC RAS.

4. Conclusions

In conclusion, we have elaborated a convenient pathway to a new series of α-CF3-substituted α-amino acid derivatives bearing a pharmacophore isoquinolone core in their backbone. The method is based on [4+2]-annulation of N-(pivaloyloxy) aryl amides with orthogonally protected internal acetylene-containing α-amino carboxylates under Rh(III)-catalysis. The reaction smoothly proceeds at an ambient temperature in trifluoroethanol in the presence of 3 mol/% of rhodium dimer complex (Cp*RhCl2)2 and 1 equiv. of cesium acetate to afford the target products in good yields. The latter compounds proved to be suitable substrates for further conversion to valuable isoquinoline derivatives via a subsequent aromatization/cross-coupling synthetic operation. The biological activity of the obtained compounds is currently being studied.

Supplementary Materials

The following supporting information can be downloaded at: https://www.mdpi.com/article/10.3390/molecules27238488/s1, Figures S1–S92. 1H and 13C NMR spectra of compounds. Figure S93. H-bonded dimer in the crystal of 3a. Scheme S1. Proposed mechanism. Table S1. Crystal data, data collection and structure refinement parameters for 3a.

Author Contributions

Conceptualization, S.N.O.; methodology, S.N.O.; investigation, D.V.V., D.A.P. (synthesis), I.A.G. (NMR spectra registering and characterization), F.M.D. (X-ray analysis); writing—original draft preparation, S.N.O., D.V.V.; writing—review and editing, D.V.V., S.N.O.; supervision, S.N.O.; project administration, S.N.O.; funding acquisition, S.N.O. All authors have read and agreed to the published version of the manuscript.

Funding

This work was financially supported by the Russian Science Foundation (grant RSF No. 21-13-00328).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data are contained within the article and Supplementary Materials.

Acknowledgments

NMR studies and spectral characterization were performed with financial support from the Ministry of Science and Higher Education of the Russian Federation using the equipment of the Center for Molecular Composition Studies of INEOS RAS.

Conflicts of Interest

The authors declare no conflict of interest.

Sample Availability

Samples of all of the compounds are available from the authors.

References

  1. Chen, H.-Y.; He, L.-J.; Li, S.-Q.; Zhang, Y.-J.; Huang, J.-H.; Qin, H.-X.; Wang, J.-L.; Li, Q.-Y.; Yang, D.-L. A derivate of benzimidazole-isoquinolinone induces SKP2 transcriptional inhibition to exert anti-tumor activity in glioblastoma cells. Molecules 2019, 24, 2722. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. He, L.-J.; Yang, D.-L.; Li, S.-Q.; Zhang, Y.-J.; Tang, Y.; Lei, J.; Frett, B.; Lin, H.-K.; Li, H.-Y.; Chen, Z.-Z.; et al. Facile construction of fused benzimidazole-isoquinolinones that induce cell-cycle arrest and apoptosis in colorectal cancer cells. Bioorg. Med. Chem. 2018, 26, 3899. [Google Scholar] [CrossRef] [PubMed]
  3. Tang, Z.; Niu, S.; Liu, F.; Lao, K.; Miao, J.; Ji, J.; Wang, X.; Yan, M.; Zhang, L.; You, Q.; et al. Synthesis and biological evaluation of 2,3-diaryl isoquinolinone derivatives as anti-breast cancer agents targeting ERα and VEGFR-2. Bioorg. Med. Chem. Lett. 2014, 24, 2129. [Google Scholar] [CrossRef] [PubMed]
  4. Scalia, M.; Satriano, C.; Greca, R.; Stella, A.M.G.; Rizzarelli, E.; Spina-Purrello, V. PARP-1 inhibitors DPQ and PJ-34 negatively modulate proinflammatory commitment of human glioblastoma cells. Neurochem. Res. 2013, 38, 50. [Google Scholar] [CrossRef] [PubMed]
  5. Zhang, Z.; You, Z.; Dobrowsky, R.T.; Rick, T.; Blagg, B.S.J. Synthesis and evaluation of a ring-constrained Hsp90 C-terminal inhibitor that exhibits neuroprotective activity. Bioorg. Med. Chem. Lett. 2018, 28, 2701. [Google Scholar] [CrossRef]
  6. Nair, J.J.; Rarova, L.; Strnad, M.; Bastida, J.; van Staden, J. Apoptosis-inducing effects of distichamine and narciprimine, rare alkaloids of the plant family Amaryllidaceae. Bioorg. Med. Chem. Lett. 2012, 22, 6195. [Google Scholar] [CrossRef]
  7. Du, J.; Xi, L.; Lei, B.; Liu, H.; Yao, X. Structural requirements of isoquinolones as novel selective c-Jun N-terminal kinase 1 inhibitors: 2D and 3D QSAR analyses. Chem. Biol. Drug Des. 2011, 77, 248. [Google Scholar] [CrossRef]
  8. Guo, S.; Wang, F.; Sun, L.; Zhang, X.; Fan, X. Palladium-catalyzed oxidative cyclocarbonylation of isoquinolones with CO via C-H/N-H bond cleavage: Easy access to isoindolo[2,1-b]isoquinoline-5,7-dione derivatives. Adv. Synth. Catal. 2018, 360, 2537. [Google Scholar] [CrossRef]
  9. Thirupataiah, B.; Reddy, G.S.; Ghule, S.S.; Kumar, J.S.; Mounika, G.; Hossain, K.A.; Mudgal, J.; Mathew, J.E.; Shenoy, G.G.; Parsa, K.V.L.; et al. Synthesis of 11,12-dihydro benzo[c]phenanthridines via a Pd-catalyzed unusual construction of isocoumarin ring/FeCl3-mediated intramolecular arene-allyl cyclization: First identification of a benzo[c]phenanthridine based PDE4 inhibitor. Bioorg. Chem. 2020, 97, 103691. [Google Scholar] [CrossRef]
  10. Guo, S.; Sun, L.; Wang, F.; Zhang, X.; Fan, X. Rh(III)-Catalyzed oxidative annulation of isoquinolones with diazoketoesters featuring an in situ deacylation: Synthesis of isoindoloisoquinolones and their transformation to Rosettacin analogues. J. Org. Chem. 2018, 83, 12034. [Google Scholar] [CrossRef]
  11. Coles-Taylor, B.L.; McCallum, S.M.; Scott Lee, J.; Michel, B.W. Accessing 4-oxy-substituted isoquinolinones via C-H activation and regioselective migratory insertion with electronically biased ynol ethers. Org. Biomol. Chem. 2018, 16, 8639. [Google Scholar] [CrossRef]
  12. Wu, J.-Q.; Zhang, S.-S.; Gao, H.; Qi, Z.; Zhou, C.-J.; Ji, W.-W.; Liu, Y.; Chen, Y.; Li, Q.; Li, X.; et al. Experimental and theoretical studies on rhodium-catalyzed coupling of benzamides with 2,2-difluorovinyl tosylate: Diverse synthesis of fluorinated heterocycles. J. Am. Chem. Soc. 2017, 139, 3537. [Google Scholar] [CrossRef]
  13. Salvati, E.; Botta, L.; Amato, J.; Saverio Di Leva, F.; Zizza, P.; Gioiello, A.; Pagano, B.; Graziani, G.; Tarsounas, M.; Randazzo, A.; et al. Lead discovery of dual G-quadruplex stabilizers and poly(ADP-ribose) polymerases (PARPs) inhibitors: A new avenue in anticancer treatment. J. Med. Chem. 2017, 60, 3626. [Google Scholar] [CrossRef]
  14. Wu, Y.; Sun, P.; Zhang, K.; Yang, T.; Yao, H.; Lin, A. Rh(III)-Catalyzed redox-neutral annulation of primary benzamides with diazo compounds: Approach to isoquinolinones. J. Org. Chem. 2016, 81, 2166. [Google Scholar] [CrossRef]
  15. Newton, C.G.; Wang, S.-G.; Oliveira, C.C.; Cramer, N. Catalytic enantioselective transformations involving C-H bond cleavage by transition-metal complexes. Chem. Rev. 2017, 117, 8908. [Google Scholar] [CrossRef]
  16. Park, Y.; Kim, Y.; Chang, S. Transition metal-catalyzed C-H amination: Scope, mechanism, and applications. Chem. Rev. 2017, 117, 9247. [Google Scholar] [CrossRef]
  17. Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Formal [4+1] annulation reactions in the synthesis of carbocyclic and heterocyclic systems. Chem. Rev. 2015, 115, 5301. [Google Scholar] [CrossRef]
  18. Ackermann, L. Carboxylate-assisted ruthenium-catalyzed alkyne annulations by C-H/Het-H bond functionalizations. Acc. Chem. Res. 2014, 47, 281. [Google Scholar] [CrossRef]
  19. Upadhyay, N.S.; Thorat, V.H.; Sato, R.; Annamalai, P.; Chuang, S.-C.; Cheng, C.-H. Synthesis of isoquinolones via Rh-catalyzed C-H activation of substituted benzamides using air as the sole oxidant in water. Green Chem. 2017, 19, 3219. [Google Scholar] [CrossRef]
  20. Reddy Chidipudi, S.; Burns, D.J.; Khan, I.; Lam, H.W. Enantioselective synthesis of spiroindenes by enol-directed rhodium(III)-catalyzed C-H functionalization and spiroannulation. Angew. Chem. Int. Ed. 2015, 54, 13975. [Google Scholar] [CrossRef]
  21. Zhang, X.; Si, W.; Bao, M.; Asao, N.; Yamamoto, Y.; Jin, T. Rh(III)-Catalyzed regioselective functionalization of C-H bonds of naphthylcarbamates for oxidative annulation with alkynes. Org. Lett. 2014, 16, 4830. [Google Scholar] [CrossRef] [PubMed]
  22. Chuang, S.-C.; Gandeepan, P.; Cheng, C.-H. Synthesis of isoquinolines via Rh(III)-catalyzed C-H activation using hydrazone as a new oxidizing directing group. Org. Lett. 2013, 15, 5750. [Google Scholar] [CrossRef] [PubMed]
  23. Pham, M.V.; Ye, B.; Cramer, N. Access to sultams by rhodium(III)-catalyzed directed C-H activation. Angew. Chem. Int. Ed. 2012, 51, 10610. [Google Scholar] [CrossRef] [PubMed]
  24. Hyster, T.K.; Rovis, T. Rhodium-catalyzed oxidative cycloaddition of benzamides and alkynes via C-H/N-H Activation. J. Am. Chem. Soc. 2010, 132, 10565. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  25. Song, G.; Chen, D.; Pan, C.-L.; Crabtree, R.H.; Li, X. Rh-Catalyzed oxidative coupling between primary and secondary benzamides and alkynes: Synthesis of polycyclic amides. J. Org. Chem. 2010, 75, 7487. [Google Scholar] [CrossRef] [PubMed]
  26. Guimond, N.; Gouliaras, C.; Fagnou, K. Rhodium(III)-Catalyzed isoquinolone synthesis: The N-O bond as a handle for C-N bond formation and catalyst turnover. J. Am. Chem. Soc. 2010, 132, 6908. [Google Scholar] [CrossRef]
  27. Guimond, N.; Gorelsky, S.I.; Fagnou, K. Rhodium(III)-Catalyzed heterocycle synthesis using an internal oxidant: Improved reactivity and mechanistic studies. J. Am. Chem. Soc. 2011, 133, 6449. [Google Scholar] [CrossRef]
  28. Mochida, S.; Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. Rhodium-catalyzed oxidative coupling/cyclization of benzamides with alkynes via C-H bond cleavage. Chem. Lett. 2010, 39, 744. [Google Scholar] [CrossRef]
  29. Xu, X.; Liu, Y.; Park, C.-M. Rhodium(III)-Catalyzed intramolecular annulation through C-H activation: Total synthesis of (±)-antofine, (±)-septicine, (±)-tylophorine, and rosettacin. Angew. Chem. Int. Ed. 2012, 51, 9372. [Google Scholar] [CrossRef]
  30. Wang, H.; Grohmann, C.; Nimphius, C.; Glorius, F. Mild Rh(III)-Catalyzed C-H activation and annulation with alkyne MIDA Boronates: Short, efficient synthesis of heterocyclic boronic acid derivatives. J. Am. Chem. Soc. 2012, 134, 19592. [Google Scholar] [CrossRef]
  31. Huckins, J.R.; Bercot, E.A.; Thiel, O.R.; Hwang, T.-L.; Bio, M.M. Rh(III)-Catalyzed C-H activation and double directing group strategy for the regioselective synthesis of naphthyridinones. J. Am. Chem. Soc. 2013, 135, 14492. [Google Scholar] [CrossRef]
  32. Yu, D.-G.; de Azambuja, F.; Glorius, F. α-MsO/TsO/Cl ketones as oxidized alkyne equivalents: Redox-neutral rhodium(III)-catalyzed C-H activation for the synthesis of N-heterocycles. Angew. Chem. Int. Ed. 2014, 53, 2754. [Google Scholar] [CrossRef]
  33. Wang, F.; Qi, Z.; Zhao, Y.; Zhai, S.; Zheng, G.; Mi, R.; Huang, Z.; Zhu, X.; He, X.; Li, X. Rhodium(III)-catalyzed atroposelective synthesis of biaryls by C-H activation and intermolecular coupling with sterically hindered alkynes. Angew. Chem. Int. Ed. 2020, 59, 13288. [Google Scholar]
  34. Chen, J.; Zhang, L.; Zheng, X.; Zhou, J.; Zhong, T.; Yu, C. Synthesis of isoquinolinone derivatives by Rh(III)-catalyzed C-H functionalization of N-ethoxybenzamides. Synthetic Commun. 2020, 50, 1799. [Google Scholar] [CrossRef]
  35. Ohata, J.; Martin, S.C.; Ball, Z.T. Metal-mediated functionalization of natural peptides and proteins: Panning for bioconjugation gold. Angew. Chem. Int. Ed. 2019, 58, 6176. [Google Scholar] [CrossRef]
  36. Zhang, C.; Vinogradova, E.V.; Spokoyny, A.M.; Buchwald, S.L.; Pentelute, B.L. Arylation chemistry for bioconjugation. Angew. Chem. Int. Ed. 2019, 58, 4810. [Google Scholar] [CrossRef] [Green Version]
  37. Rodríguez, J.; Martínez-Calvo, M. Transition-metal-mediated modification of biomolecules. Chem. Eur. J. 2020, 26, 9792. [Google Scholar] [CrossRef]
  38. Haase, C.; Seitz, O. Chemical Synthesis of Glycopeptides. Top. Curr. Chem. 2006, 267, 1. [Google Scholar]
  39. Wang, Y.; Cheetham, A.G.; Angacian, G.; Su, H.; Xie, L.; Cui, H. Peptide-drug conjugates as effective prodrug strategies for targeted delivery. Adv. Drug Deliv. Rev. 2017, 110, 112. [Google Scholar] [CrossRef] [Green Version]
  40. Sunna, A.; Care, A. Peptides and Peptide-based Biomaterials and their Biomedical Applications; Springer Nature: Cham, Switzerland, 2017. [Google Scholar]
  41. Hoppenz, P.; Els-Heindl, S.; Beck-Sickinger, A.G. Peptide-drug conjugates and their targets in advanced cancer therapies. Front. Chem. 2020, 8, 571. [Google Scholar] [CrossRef]
  42. Ojima, I. Fluorine in Medicinal Chemistry and Chemical Biology; Wiley-Blackwell: Chichester, UK, 2009. [Google Scholar]
  43. Yoder, N.C.; Kumar, K. Fluorinated amino acids in protein design and engineering. Chem. Soc. Rev. 2002, 31, 335. [Google Scholar] [CrossRef] [PubMed]
  44. Jaeckel, C.; Koksch, B. Fluorine in peptide design and protein engineering. Eur. J. Org. Chem. 2005, 2005, 4483. [Google Scholar] [CrossRef]
  45. Salwiczek, M.; Nyakatura, E.K.; Gerling, U.I.; Ye, S.; Koksch, B. Fluorinated amino acids: Compatibility with native protein structures and effects on protein–protein interactions. Chem. Soc. Rev. 2012, 41, 2135. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  46. Marsh, E.N.G. Fluorinated proteins: From design and synthesis to structure and stability. Acc. Chem. Res. 2014, 47, 2878. [Google Scholar] [CrossRef] [PubMed]
  47. Berger, A.A.; Völler, J.; Budisa, N.; Koksch, B. Deciphering the fluorine code—The many hats fluorine wears in a protein environment. Acc. Chem. Res. 2017, 50, 2093. [Google Scholar] [CrossRef] [Green Version]
  48. Huhmann, S.; Koksch, B. Fine-tuning the proteolytic stability of peptides with fluorinated amino acids. Eur. J. Org. Chem. 2018, 2018, 3667. [Google Scholar] [CrossRef]
  49. Moschner, J.; Stulberg, V.; Fernandes, R.; Huhmann, S.; Leppkes, J.; Koksch, B. Approaches to obtaining fluorinated α-amino acids. Chem. Rev. 2019, 119, 10718. [Google Scholar] [CrossRef]
  50. Smits, R.; Cadicamo, C.D.; Burger, K.; Koksch, B. Synthetic strategies to α-trifluoromethyl and α-difluoromethyl substituted α-amino acids. Chem. Soc. Rev. 2008, 37, 1727. [Google Scholar] [CrossRef]
  51. Vorobyeva, D.V.; Petropavlovskikh, D.A.; Godovikov, I.A.; Nefedov, S.E.; Osipov, S.N. Rh(III)-Catalyzed C-H activation/annulation of aryl hydroxamates with CF3-containing α-propargyl α-amino acid derivatives. Eur. J. Org. Chem. 2021, 2021, 1883. [Google Scholar] [CrossRef]
  52. Iagafarova, I.E.; Vorobyeva, D.V.; Peregudov, A.S.; Osipov, S.N. CF3-Carbenoid C-H functionalization of (hetero)arenes under chelation-controlled RhIII catalysis. Eur. J. Org. Chem. 2015, 2015, 4950. [Google Scholar] [CrossRef]
  53. Iagafarova, I.E.; Vorobyeva, D.V.; Loginov, D.A.; Peregudov, A.S.; Osipov, S.N. Rh(III)-catalyzed CF3-carbenoid C-7 functionalization of indolines. Eur. J. Org. Chem. 2017, 2017, 840. [Google Scholar] [CrossRef]
  54. Vorobyeva, D.V.; Vinogradov, M.M.; Nelyubina, Y.V.; Loginov, D.A.; Peregudov, A.S.; Osipov, S.N. Rhodium(III)-catalyzed CF3-carbenoid C-H functionalization of 6-arylpurines. Org. Biomol. Chem. 2018, 16, 2966. [Google Scholar] [CrossRef] [PubMed]
  55. Petropavlovskikh, D.A.; Vorobyeva, D.V.; Godovikov, I.A.; Nefedov, S.E.; Filippov, O.A.; Osipov, S.N. Lossen rearrangement by Rh(III)-catalyzed C-H activation/annulation of aryl hydroxamates with alkynes: Access to quinolone-containing amino acid derivatives. Org. Biomol. Chem. 2021, 19, 9421. [Google Scholar] [CrossRef] [PubMed]
  56. Shchetnikov, G.T.; Zotova, M.A.; Bruneau, C.; Dixneuf, P.H.; Osipov, S.N. Synthesis of α-Alkynyl-β,β,β-trifluoroalanine Derivatives by Sonogashira Cross-Coupling Reaction. Eur. J. Org. Chem. 2010, 2010, 1587. [Google Scholar] [CrossRef]
  57. Ullyot, G.E. Basic ether-substituted isoquinolines. US Patent 2612503, 30 September 1952. [Google Scholar]
  58. Merck, G. Vorläufige Notiz über eine neue organische Base im Opium. Liebigs Ann. Chem. 1848, 66, 125. [Google Scholar] [CrossRef]
  59. Graulich, A.; Scuvée-Moreau, J.; Seutin, V.; Liégeois, J.-F. Orthogonal Synthesis of Indolines and Isoquinolines via Aryne Annulation. J. Med. Chem. 2005, 48, 4972. [Google Scholar]
  60. Sheldrick, G.M. Crystal Structure Refinement with SHELXL. Acta Cryst. 2015, C71, 3. [Google Scholar]
Molecules 27 08488 g001 550
Figure 1. Selected bioactive isoquinolones and isoquinolines.
Figure 1. Selected bioactive isoquinolones and isoquinolines.
Molecules 27 08488 g001
Molecules 27 08488 sch001 550
Scheme 1. Previous and present work.
Scheme 1. Previous and present work.
Molecules 27 08488 sch001
Molecules 27 08488 sch002 550
Scheme 2. Synthesis of isoquinolone-containing α-amino carboxylates 3.
Scheme 2. Synthesis of isoquinolone-containing α-amino carboxylates 3.
Molecules 27 08488 sch002
Molecules 27 08488 sch003 550
Scheme 3. Reaction of 1a with para-nitrophenyl acetylene 2f.
Scheme 3. Reaction of 1a with para-nitrophenyl acetylene 2f.
Molecules 27 08488 sch003
Molecules 27 08488 g002 550
Figure 2. ORTEP representation of the molecular structure of 3a (CCDC 2217085). Thermal ellipsoids are drawn at the 30% probability level).
Figure 2. ORTEP representation of the molecular structure of 3a (CCDC 2217085). Thermal ellipsoids are drawn at the 30% probability level).
Molecules 27 08488 g002
Molecules 27 08488 sch004 550
Scheme 4. Synthesis of 1-OTf-substituted isoquinolines 4.
Scheme 4. Synthesis of 1-OTf-substituted isoquinolines 4.
Molecules 27 08488 sch004
Molecules 27 08488 sch005 550
Scheme 5. Transformations of the OTf-substituted isoquinolines 4 under Pd-catalysis: (a) Suzuki reaction; (b) Sonogashira reaction; (c) removal of OTf group.
Scheme 5. Transformations of the OTf-substituted isoquinolines 4 under Pd-catalysis: (a) Suzuki reaction; (b) Sonogashira reaction; (c) removal of OTf group.
Molecules 27 08488 sch005
Molecules 27 08488 sch006 550
Scheme 6. Removal of protective groups.
Scheme 6. Removal of protective groups.
Molecules 27 08488 sch006
Table
Table 1. Optimization of [4+2]-annulation of aryl hydroxamate 1a with acetylene 2a.
Table 1. Optimization of [4+2]-annulation of aryl hydroxamate 1a with acetylene 2a.
Molecules 27 08488 i001
EntryCatalyst (mol. %)Additive (equiv.)SolventYield b (%)
1[Cp*RhCl2]2 (5)CsOAc (2)MeOH70(60 c)
2[Cp*RhCl2]2 (5)CsOAc (2)TFE87(72 c)
3[Cp*RhCl2]2 (5)CsOAc (2)toluene65
4[Cp*RhCl2]2 (5)NaOAc (2)MeOH73
5[Cp*RhCl2]2 (5)KOAc (2)MeOH69
6[Cp*RhCl2]2 (3)CsOAc (2)MeOH73
7[Cp*RhCl2]2 (3)CsOAc (2)TFE80
8[Cp*RhCl2]2 (3)CsOAc (1)TFE84(71 c)
9[Cp*RhCl2]2 (3)CsOAc (1)MeOH68
10[Cp*IrCl2]2 (5)CsOAc (2)MeOHNR
11[Cp*CoI2]2 (5)CsOAc (2)MeOHNR
12[(p-cymene)RuCl2]2 (5)CsOAc (2)MeOHNR
13-CsOAc (2)MeOHNR
14[Cp*RhCl2]2 (5)-MeOHNR
a Reagents and conditions: aryl hydroxamate 1a (0.2 mmol), acetylene 2a (0.2 mmol), solvent (2 mL), r.t.; b Determined by 19F NMR spectroscopy; c Isolated yield.
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Vorobyeva, D.V.; Petropavlovskikh, D.A.; Godovikov, I.A.; Dolgushin, F.M.; Osipov, S.N. Synthesis of Functionalized Isoquinolone Derivatives via Rh(III)-Catalyzed [4+2]-Annulation of Benzamides with Internal Acetylene-Containing α-CF3-α-Amino Carboxylates. Molecules 2022, 27, 8488. https://doi.org/10.3390/molecules27238488

AMA Style

Vorobyeva DV, Petropavlovskikh DA, Godovikov IA, Dolgushin FM, Osipov SN. Synthesis of Functionalized Isoquinolone Derivatives via Rh(III)-Catalyzed [4+2]-Annulation of Benzamides with Internal Acetylene-Containing α-CF3-α-Amino Carboxylates. Molecules. 2022; 27(23):8488. https://doi.org/10.3390/molecules27238488

Chicago/Turabian Style

Vorobyeva, Daria V., Dmitry A. Petropavlovskikh, Ivan A. Godovikov, Fedor M. Dolgushin, and Sergey N. Osipov. 2022. "Synthesis of Functionalized Isoquinolone Derivatives via Rh(III)-Catalyzed [4+2]-Annulation of Benzamides with Internal Acetylene-Containing α-CF3-α-Amino Carboxylates" Molecules 27, no. 23: 8488. https://doi.org/10.3390/molecules27238488

Article Metrics

Back to TopTop