Abstract
The reactivity of azomethines based on trifluoroacetaldehyde hydrate in the Castagnoli–Cushman reaction (CCR) was researched. The impact of the nature of anhydrides explored on the reaction route was determined. The preparative procedures for the synthesis of N-substituted (3R*,4R*)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic and (1R*,2R*)-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-carboxylic acids in gram scales were elaborated. It was shown that the trifluoromethyl group remarkably decreased the reactivity of azomethines in CCR. The mechanism for the formation of different products depending on the anhydride’s nature was proposed.
Introduction
The expansion of the medicinal chemistry-relevant chemical space requires cost- and time-effective synthetic methods for producing diverse molecules from readily available starting materials (commonly called building blocks).1 Recently, synthetic chemists more often considered multicomponent reactions (MCRs) for this purpose.2 The reason is the elaboration of new methodologies and expansion of the scope and limitations of MCR, which lead to the products bearing functional groups. The Castagnoli–Cushman reaction (CCR), i.e., the reaction of imines (I) with cyclic anhydrides (II, IV), is one of the most popular in this view (Scheme 1).3
Scheme 1. Castagnoli–Cushman Reaction.
This reaction is an efficient tool for the synthesis of various lactams, which have the carboxyl function, and is widely used in the preparation of combinatorial libraries4 as well as the synthesis of building blocks.4a,5 In recent years, a significant number of papers devoted to the problem of the use of different anhydrides in CCR were published,6 and only a few ones dealt with the expansion of the scope of carbonyl and amino components.7 On the other hand, the fluorine atom is one of the most prominent in drugs and agrochemicals.8 The trifluoromethyl group is one of the most represented among the fluorine-containing compounds. This popular structural motif occurs in more than seventy approved drugs.9 Therefore, the expansion of the scope of CCR to trifluoroacetaldehyde, which could lead to the formation of new 2-trifluoromethyl-substituted 5-oxo-pyrrolidine, 6-oxo-piperidine, and 7-oxo-azepine3-carboxylic acids, was an exciting task.
In our ongoing research on the scope of CCR,4a,5a as well as the methods for the efficient synthesis of trifluoromethyl-containing building blocks,10 we examined azomethines based on trifluoroacetaldehyde as a substrate.
Results and Discussion
In this work, we describe the possibility of using azomethines based on trifluoroacetaldehyde in CCR for the production of diverse 2-trifluoromethyl-substituted 3-pyrrolidine- and 3-piperidine carboxylic acids. The previously described anhydrides were used as starting materials.4a We successfully scaled up the known methodology for obtaining Schiff bases from fluoral hydrate to gram quantities. In the first step, we used molecular sieves as a dehydrating agent for the reaction of fluoral hydrate 1 with amines 2. Then, the final Schiff base 4 was formed from hemiaminal intermediate 3 in boiling toluene using a catalytic amount of PTSA and a Dean–Stark trap (Scheme 2).11 The crude products were purified by vacuum distillation.
Scheme 2. Synthesis of Schiff Bases.
In the first step of our research, azomethine 4a (R = p-methoxybenzyl (PMB)) and succinic (5a), glutaric (6a), and homophthalic (7a) anhydrides were selected as model compounds. These substrates were examined in our standard conditions for CCR, elaborated earlier. The mixture of Schiff base and anhydride was boiled in xylenes (140 °C, 5–24 h) (Scheme 3 and Table 1). Unfortunately, only for homophthalic anhydride 7a, the desired product 10a was formed with good conversion (73%). The structure and trans stereochemistry of the derivative 10a were proven by X-ray single-crystal diffraction studies (Figure 1).12
Scheme 3. 4-Methoxy-N-(2,2,2-trifluoroethylidene)benzylamine in CCR with Model Anhydrides in Standard Conditions.
Table 1. Optimization of Reaction Conditions of 4a + 5a and 4a + 6a(13).
| no. | anhydride | solvent | conditions | result (18a by LCMS, %) |
|---|---|---|---|---|
| 2 | 5a | NMP | 160 °C, 6 h | 7 (24 h) |
| 3 | 5a | Ph2O | 160 °C, 6 h | 12 |
| 6 | 5a | Ph2O | 200 °C, 6 h | 12 |
| 8 | 5a | xylenes | MW (200 °C), 1 h | 3 |
| no. | anhydride | solvent | conditions | result (17a by LCMS, %) |
|---|---|---|---|---|
| 9 | 6a | DMA | 140 °C, 6 h | |
| 12 | 6a | Ph2O | 180 °C, 6 h | 21 (24 h) |
| 15 | 6a | sulfolane | 200 °C, 6 h | |
| 16 | 6a | xylenes | MW (200 °C), 1 h | |
| 17 | 6a | Ph2O | MW (300 °C), 1 h | 11 |
| 20 | 6a | NMP | MW (225 °C), 1 h | 15 |
| 21 | 6a | Ph2O | 225 °C, 6 h | 52 |
| 22 | 6a | NMP | 200 °C, 6 h | 12 |
| 24 | 6a | Ph2O | MW (250 °C), 1 h | 52 |
| 28 | 6a | Ph2O | 275 °C, 6 h | |
| 30 | 6a | Ph2O, 1.0 M | 225 °C, 6 h | 57 |
| 32 | 6a | Ph2O, 4.0 M | 225 °C, 6 h | 55 |
Figure 1.
X-ray diffraction patterns of (3R*,4R*)-2-(4-methoxybenzyl)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid 10a.
In the cases of 5a and 6a, only monoamides 12a and 14a were detected, respectively, after 24 h of heating as major products. These results are consistent with our previous ones5a and with the research of Bakulina and co-workers4f and could be explained by lower reactivity of the zwitterion intermediate in the cases of 5a and 6a compared to that in 7a (Scheme 4).
Scheme 4. Side Products in CCR with Succinic (5a) and Glutaric (6a) Anhydrides.
Therefore, the optimization of reaction conditions was needed. Temperature, solvent, heating type, and reaction time were varied, and the conversion was measured by liquid chromatography–mass spectrometry (LCMS); the data are summarized in Table 1.
As can be seen from the table, the product with appropriate molecular weight for anhydride 5a did not form in any reaction condition. In most cases, the product 18a was the main compound detected, which formed as a result of CCR between anhydride 5a and intermediate 16a (the result of imine metathesis between 11a and 15a). On the other hand, for anhydride 6a, we detected a product with a relevant peak in LCMS. However, a more detailed analysis of its structure showed that the isomeric product 17a formed as a result of [1,3]-H shift of the starting azomethine. The structure of this product was proven by NMR spectra (4.65 (dq, J = 15.3, 10.0 Hz, 1H) and 3.08 (dq, J = 15.2, 9.0 Hz, 1H) signals were observed that corresponded to diastereotopic protons of the CH2CF3 group) and by the counter synthesis (Scheme 5). All our attempts for reaction condition optimization to form 8a and 9a led only to 18a and 17a, respectively.
Scheme 5. Proposed Pathway for the Formation of 17a and 18a.
To explain these data, we proposed the pathway shown in Scheme 5. Schiff base 4a undergoes a [1,3]-hydride shift under thermal conditions and forms another azomethine 15a. The latter reacts with a 6-membered anhydride and forms 17a but does not do the same with a 5-membered one. Meanwhile, 15a could react with the intermediate 11a and transform it into another acylated imine 16a as a result of imine exchange. We determined that azomethine 4a could transform to 15a under reaction conditions without anhydride added.14
However, the imine exchange was not observed in the absence of anhydride in the reaction mixture (RM), and imine metathesis occurred only in the presence of acid.15
The formation of 17a and 18a also has been proven by the counter synthesis based on azomethines 15a and 15b and appropriate anhydrides in the reaction conditions (Scheme 6).
Scheme 6. Counter Synthesis of Derivatives 17a and 18a.
Such behavior was general for 5- and 6-membered cyclic anhydrides. Compounds 5b and 6b with different acidity of α-methylene groups (Scheme 7) were examined in the reaction at optimized conditions. The same results, the formation of acids 18b and 17b, respectively, were observed.
Scheme 7. Formation of Derivatives 17b and 18b.
Next, we carried out the reaction of succinic (5a) or glutaric (6a) anhydrides with trifluoroethylidene methanamines 4b and 4c to finalize our attempts to direct CCR to the formation of targeted 2-trifluoromethyl-substituted 5-oxo-pyrrolidine or 6-oxo-piperidine-3-carboxylic acids. Their selection was governed by the impossibility to have the [1,3]-H shift in these substrates. Unfortunately, in such cases, no target or side products were observed. A complex mixture of the decomposition and polymerization products was formed (Figure 2).
Figure 2.
Schiff bases 4a–h, which were explored in CCR.
After such unsuccessful attempts to obtain CCR products from aliphatic 5- and 6-membered cyclic anhydrides, we focused our attention on homophthalic anhydride (7a) and its homologue adipic anhydride with an annelated benzene ring (19a). Similarly to aliphatic 5- and 6-membered cyclic anhydrides, we tried different conditions of CCR with these substrates. It was found that boiling in toluene for 6 h was the best condition for 7a (entry 7), whereas for 19a, it was boiling in xylene for 8 h (entry 9). The protocol of optimization is shown in Table 2.
Table 2. Optimization of Conditions for the Formation of 10a and 20a(13).
| no. | anhydride | solvent | conditions | result (10a by LCMS, %) |
|---|---|---|---|---|
| 1 | 7a | DMA | 140 °C, 6 h | |
| 2 | 7a | xylene | 140 °C, 6 h | 73 |
| 3 | 7a | CHCl3 | RT, 6 h | 67 |
| 4 | 7a | MeCN | RT, 6 h | 68 |
| 5 | 7a | DCE | 80 °C, 6 h | 77 |
| 6 | 7a | MeCN | 80 °C, 6 h | 54 |
| 7 | 7a | toluene | 110 °C, 6 h | 92 |
| 8 | 7a | DMA | 110 °C, 6 h |
| no. | anhydride | solvent | conditions | result (20a by LCMS, %) |
|---|---|---|---|---|
| 9 | 19a | xylene | 140 °C, 8 h | 49 |
| 10 | 19a | toluene | 110 °C, 8 h | 30 |
Once the optimal conditions were chosen, we studied CCR of 7a and 19a with a series of Schiff bases 4a, 4c–h. All of the target products 10a, 10c–h, and 20a, 20c–h were obtained in moderate to good yields (Table 3). Afterward, we made an attempt to remove the PMB protecting group from amides 10a and 20a. Unfortunately, only trace amounts of the desired products 21 and 22 were detected in the reaction mixture using different standard procedures for the debenzylation of the PMB group, even after 70 h of stirring at room temperature (rt). Increasing the temperature to 80 °C for 16 h led to higher conversion (23% for 21 and 53% for 22 by LCMS data).
Table 3. Structures and Yields of Compounds 10a,c–h and 20a,c–h.
However, at the same time, it led to the partial destruction of the products and to increase in the number and quantity of impurities. Thus, unprotected amide was obtained messy enough and the method looked unsuitable for multigram-scale synthesis. In contrast to PMB, the DMB protecting group could be deprotected in such conditions more clearly. The appropriate conditions for the deprotection of compounds 10h (trifluoroacetic acid, TFA, 16 h, reflux) and 20h (TFA, 70 h, rt), which led to target acids, were found. The acids 21 and 22 were obtained on 10 gram scales (Scheme 8).
Scheme 8. Synthetic Potential of CCR Based on Fluoral Hydrate.
The structure and trans stereochemistry of the derivative 20a were proven by X-ray single-crystal diffraction studies (Figure 3).16
Figure 3.
X-ray diffraction patterns of (1R*,2R*)-3-(4-methoxybenzyl)-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-carboxylic acid 20a.
Conclusions
In conclusion, the reactivity of azomethines based on trifluoroacetaldehyde hydrate in a Castagnoli–Cushman reaction was investigated. It was shown that an acceptor substituent such as the trifluoromethyl group remarkably decreased the reactivity of azomethines in CCR. Nevertheless, the procedures for using trifluoroethylidene methanamines in the reaction with the most active anhydrides of homophthalic and benzannelated adipic acids were elaborated. These procedures became suitable for the multigram synthesis of building blocks, as demonstrated in the synthesis of (3R*,4R*)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid and (1R*,2R*)-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine-1-carboxylic acid with preparative yields (54–55%) and good trans diastereoselectivity in 10 gram scales. Unexpected results were obtained after using succinic and glutaric anhydrides in CCR. These results allowed us to arrange anhydrides by the activity (Figure 4). Therefore, the reaction with fluoral hydrate can be used for the determination of the activity of anhydrides in CCR. The reasons for such results and possible pathways of their formation have been discussed. It was shown that the unusual products formed as a result of the [1,3]-H shift and imine metathesis, which could happen in the reaction conditions. It is very important for the understanding of possible mechanisms of CCR and can open the door for their more detailed investigation.
Figure 4.
Relative activity of anhydrides in CCR.
Experimental Section
General Information
The solvents were purified according to the standard procedures. All starting materials were obtained from Enamine Ltd. Melting points were measured on an automated melting point system. 1H, 13C, and 19F NMR spectra were recorded on a Bruker 170 Avance 500 spectrometer (at 500 MHz for protons and 126 MHz for carbon-13) and a Varian Unity Plus 400 spectrometer (at 400 MHz for protons, 101 MHz for carbon-13, and 376 MHz for fluorine-19). Tetramethylsilane (1H, 13C) or C6F6 (19F) were used as standards. Elemental analyses were performed at the Laboratory of Organic Analysis, Institute of Organic Chemistry, National Academy of Sciences of Ukraine, and their results were found to be in good agreement (±0.4%) with the calculated values. Preparative high-performance liquid chromatography (HPLC) analyses were done on an Agilent 1200 system. Mass spectra were recorded on an Agilent 1100 LCMSD SL instrument (chemical ionization (APCI)). CCDC-1986046 (10a) and CCDC-1986047 (20a) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Experimental Data and Analytical Data for Synthesized Compounds
General Procedure A
A solution of amine (0.1 mol) in dichloromethane (DCM) (300 mL) was added to fluoral hydrate 75% in H2O (23.15 g; 0.15 mol). Then, 3A molecular sieves (50 g) were added. After 24 h, molecular sieves were filtered off and washed two times with DCM. The filtrate was evaporated. The residue was dissolved in toluene (300 mL). p-Toluenesulfonic acid monohydrate (344 mg; 1.8 mmol) was added. The reaction mixture was refluxed with a Dean–Stark trap for 16 h. Then, the reaction mixture was cooled to room temperature and the precipitate was filtered off. The filtrate was evaporated, and the residue was purified by distillation.
4-Methoxy-N-(2,2,2-trifluoroethylidene)benzylamine (4a)
Scaled to 0.108 mol; colorless liquid; yield 87% (20.3 g). 1H NMR (400 MHz, chloroform-d) δ 7.53–7.63 (m, 1H), 7.17 (d, J = 8.4 Hz, 2H), 6.90 (d, J = 8.5 Hz, 2H), 4.75 (s, 2H), 3.79 (s, 3H). 13C NMR (126 MHz, chloroform-d) δ 159.3, 149.7 (q, J = 38.1 Hz), 129.7, 128.0, 119.0 (q, J = 274.6 Hz), 114.3, 62.8, 55.3. 19F NMR (376 MHz, chloroform-d) δ −72.0. EIMS, 70 eV, m/z (rel. int.): 217 [M]+ (14); 122 (9); 121 (100); 78 (11); 77 (10). Anal. calcd for C10H10F3NO: C, 55.30; H, 4.64; N, 6.45. Found: C, 55.47; H, 4.25; N, 6.74.
2-Phenyl-N-2,2,2-trifluoroethylidenepropan-2-amine (4b)
Scaled to 14.4 mmol; colorless liquid; yield 73% (2.27 g); bp = 67–69 °C (P = 7.8 mbar). 1H NMR (500 MHz, chloroform-d) δ 7.45 (q, J = 3.2 Hz, 1H), 7.43–7.35 (m, 4H), 7.31 (tt, J = 6.4, 1.8 Hz, 1H), 1.67 (s, 6H). 13C NMR (126 MHz, chloroform-d) δ 146.4 (q, J = 38.1 Hz), 144.8, 128.6, 127.2, 126.0, 119.6 (q, J = 275.0 Hz), 64.0, 28.9. 19F NMR (376 MHz, chloroform-d) δ −71.8. EIMS, 70 eV, m/z (rel. int.): 215 [M] + (1); 159 (27); 120 (10); 119 (100); 109 (17); 91 (46); 77 (12). Anal. calcd for C11H12F3N: C, 61.39; H, 5.62; N, 6.51. Found: C, 61.04; H, 5.80; N, 6.74.
4-Methoxy-N-2,2,2-trifluoroethylideneaniline (4c)
Scaled to 43.1 mmol; colorless liquid; yield 71% (6.18 g); bp = 92–93 °C (P = 7.8 mbar). 1H NMR (500 MHz, chloroform-d) δ 7.82 (q, J = 3.6 Hz, 1H), 7.28 (d, J = 8.8 Hz, 2H), 6.93 (d, J = 8.9 Hz, 2H), 3.83 (d, 3H). 13C NMR (126 MHz, chloroform-d) δ 160.5, 144.0 (q, J = 38.5 Hz), 139.9, 123.2, 119.6 (q, J = 273.7 Hz), 114.6, 55.4. 19F NMR (376 MHz, chloroform-d) δ −71.2. EIMS, 70 eV, m/z (rel. int.): 203 [M]+ (71); 134 (100); 107 (25); 92 (19); 77 (26); 64 (13); 63 (11). Anal. calcd for C9H8F3NO: C, 53.21; H, 3.97; N, 6.89. Found: C, 53.44; H, 3.97; N, 7.17.
1-Phenyl-N-2,2,2-trifluoroethylidenemethanamine (4d)
Scaled to 0.108 mol; colorless liquid; yield 82% (16.6 g). 1H NMR (500 MHz, chloroform-d) δ 7.70–7.63 (m, 1H), 7.42 (t, J = 7.2 Hz, 2H), 7.36 (t, J = 7.2 Hz, 1H), 7.31 (d, J = 7.2 Hz, 2H), 4.84 (s, 2H). 13C NMR (126 MHz, chloroform-d) δ 150.1 (q, J = 38.2 Hz), 136.2, 128.9, 128.3, 127.9, 119.0 (q, J = 274.7 Hz), 63.5. 19F NMR (376 MHz, chloroform-d) δ −72.0. EIMS, 70 eV, m/z (rel. int.): 187 [M]+ (12); 106 (10); 91 (100); 65 (10). Anal. calcd for C9H8F3N: C, 57.76; H, 4.31; N, 7.48. Found: C, 57.45; H, 4.10; N, 7.22.
1-Thiophen-2-yl-N-2,2,2-trifluoroethylidenemethanamine (4e)
Scaled to 21.5 mmol; pale yellow liquid; yield 32% (1.33 g); bp = 68–69 °C (P = 13 mbar). 1H NMR (500 MHz, chloroform-d) δ 7.63–7.57 (m, 1H), 7.32 (d, J = 5.1 Hz, 1H), 7.04 (dd, J = 5.1, 3.4 Hz, 1H), 6.99 (d, J = 3.4 Hz, 1H), 5.02 (s, 2H). 13C NMR (126 MHz, chloroform-d) δ 150.4 (q, J = 38.4 Hz), 137.5, 127.3, 127.1, 126.1, 119.0 (q, J = 274.7 Hz), 57.0. 19F NMR (376 MHz, chloroform-d) δ −72.0. EIMS, 70 eV, m/z (rel. int.): 193 [M]+ (18); 97 (100). Anal. calcd for C7H6F3NS: C, 43.52; H, 3.13; N, 7.25; S, 16.6. Found: C, 43.85; H, 3.27; N, 7.28; S, 16.98.
1-(3-Fluorophenyl)-N-2,2,2-trifluoroethylidenemethanamine (4f)
Scaled to 21.5 mmol; colorless liquid; yield 44% (1.94 g); bp = 65–70 °C (P = 7.6 mbar). 1H NMR (500 MHz, chloroform-d) δ 7.74–7.65(m, 1H), 7.38–7.31 (m, 1H), 7.10–7.05 (m, 1H), 7.04–6.97 (m, 2H), 4.80 (s, 2H). 13C NMR (126 MHz, chloroform-d) δ 163.0 (d, J = 246.5 Hz), 150.6 (q, J = 38.3 Hz), 138.8 (d, J = 7.4 Hz), 130.3 (d, J = 8.3 Hz), 123.7 (d, J = 2.9 Hz), 118.8 (q, J = 274.7 Hz), 115.1 (d, J = 21.9 Hz), 114.7 (d, J = 21.0 Hz), 62.8 (d, J = 1.9 Hz). 19F NMR (376 MHz, chloroform-d) δ −72.2, -113.2. EIMS, 70 eV, m/z (rel. int.): 205 [M]+ (14); 124 (15); 109 (100); 83 (14). Anal. calcd for C9H7F4N: C, 52.69; H, 3.44; N, 6.83. Found: C, 53.07; H, 3.41; N, 6.84.
N-2,2,2-Trifluoroethylidenecyclohexanamine (4g)
Scaled to 21.5 mmol; colorless liquid; yield 32% (1.24 g). 1H NMR (500 MHz, chloroform-d) δ 7.61 (q, J = 3.5 Hz, 1H), 3.25 (t, J = 10.5 Hz, 1H), 1.88–1.75 (m, 2H), 1.74–1.62 (m, 3H), 1.51 (qd, J = 12.4, 3.4 Hz, 2H), 1.39–1.27 (m, 2H), 1.29–1.17 (m, 1H). 13C NMR (126 MHz, chloroform-d) δ 147.0 (q, J = 37.9 Hz), 118.9 (q, J = 274.7 Hz), 68.6, 33.3, 25.2, 24.2. 19F NMR (376 MHz, chloroform-d) δ −72.3. EIMS, 70 eV, m/z (rel. int.): 178 [M–H] (3); 160 (12); 151 (12); 150 (100); 136 (48); 110 (55); 83 (83); 82 (15); 67 (17); 55 (76); 54 (25); 53 (10); 41 (35); 39 (18). Anal. calcd for C8H12F3N: C, 53.62; H, 6.75; N, 7.82. Found: C, 54.02; H, 7.00; N, 7.86.
1-(2,4-Dimethoxyphenyl)-N-2,2,2-trifluoroethylidenemethanamine (4h)
Scaled to 500 mmol; colorless liquid; yield 80% (98.4 g); bp = 85–87 °C (P = 0.6 mbar). 1H NMR (500 MHz, chloroform-d) δ 7.51 (s, 1H), 7.12 (d, J = 7.9 Hz, 1H), 6.52–6.46(m, 2H), 4.78 (s, 2H), 3.81 (s, 3H), 3.79 (s, 3H). 13C NMR (126 MHz, chloroform-d) δ 161.0, 158.7, 149.6 (q, J = 37.8 Hz), 131.1, 119.2 (q, J = 274.5 Hz), 116.4, 104.4, 98.6, 57.8, 55.3, 55.2. 19F NMR (376 MHz, chloroform-d) δ −72.0. EIMS, 70 eV, m/z (rel. int.): 247 [M]+ (16); 152 (10); 151 (100); 121 (38); 91 (12); 77 (10). Anal. calcd for C11H12F3NO2: C, 53.44; H, 4.89; N, 5.67. Found: C, 53.49; H, 4.51; N, 5.68.
Synthesis of 2,2,2-Trifluoro-N-(4-methoxyphenyl)methylideneethanamine (15a)
4-Methoxybenzaldehyde (3.134 g; 23.0 mmol) was mixed with 2,2,2-trifluoroethan-1-amine hydrochloride (6.193 g; 46.0 mmol) in toluene (65 mL). Then, triethylamine (4.66 g; 46.0 mmol) and p-toluenesulfonic acid monohydrate (79 mg; 0.42 mmol) were added. The reaction mixture was refluxed with the Dean–Stark trap for 16 h. Then, more 2,2,2-trifluoroethan-1-amine hydrochloride (3.1 g; 23.0 mmol) and triethylamine (2.33 g; 23.0 mmol) were added. The reaction mixture (RM) was refluxed with the Dean–Stark trap for additional 16 h. Then, the RM was cooled to RT. The precipitate was filtered off and washed with toluene. The filtrate was evaporated. The residue was distilled in vacuo to give 3.22 g of the product as a colorless liquid. Yield = 64%. 1H NMR (500 MHz, chloroform-d) δ 8.27 (s, 1H), 7.74 (d, J = 8.2, 2H), 6.95 (d, J = 8.1 Hz, 2H), 4.09 (q, J = 9.4, 2H), 3.86 (s, 3H). 13C NMR (126 MHz, chloroform-d) δ 166.0, 162.5, 130.3, 128.2, 124.8 (q, J = 277.2 Hz), 114.1, 61.4 (q, J = 30.5 Hz), 55.2. 19F NMR (376 MHz, chloroform-d) δ −71.5. EIMS, 70 eV, m/z (rel. int.): 217 [M]+ (12); 217 [M]+ (100); 216 (35); 148 (50); 133 (21); 121 (84); 91 (14); 77 (13). Anal. calcd for C10H10F3NO: C, 55.30; H, 4.64; N, 6.45. Found: C, 55.16; H, 4.36; N, 6.72.
Synthesis of Side Products
General Procedure B
4-Methoxy-N-(2,2,2-trifluoroethylidene)benzylamine (for 17a,b and 18a,b) or 2,2,2-trifluoro-N-(4-methoxyphenyl)methylideneethanamine (for 2-(4-methoxyphenyl)-5-oxo-1-(2,2,2-trifluoroethyl)pyrrolidine-3-carboxylic acid) (1.50 mmol) was dissolved in diphenyl ether (375 mcl), and anhydride (1.50 mmol) was added. The reaction mixture was heated to 225 °C (oil bath) in an argon atmosphere for 6 h. Then, it was cooled to room temperature and was purified by preparative HPLC (MeCN/H2O mobile phase).
(2R*,3R*)-1-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-5-oxopyrrolidine-3-carboxylic Acid (18a)
White crystals; yield 16% (44 mg); mp = 120–121 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.64 (br, 1H), 7.12 (d, J = 8.6 Hz, 2H), 6.95 (d, J = 8.9 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 6.84 (d, J = 8.6 Hz, 2H),4.75 (d, J = 14.9 Hz, 1H), 4.44 (d, J = 5.9 Hz, 1H), 3.76 (s, 3H), 3.72 (s, 3H), 3.33 (d, J = 14.9 Hz, 1H), 3.01 (dt, J = 9.7, 6.7 Hz, 1H), 2.80 (dd, J = 17.0, 9.7 Hz, 1H), 2.58 (dd, J = 16.9, 7.2 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 174.3, 172.5, 159.6, 158.9, 131.7, 129.5, 128.9, 128.5, 114.7, 114.3, 63.3, 55.6, 55.5, 46.0, 43.3, 33.8. LCMS, positive mode, m/z: 356 [M + H]+. Anal. calcd for C20H21NO5: C, 67.59; H, 5.96; N, 3.94. Found: C, 67.77; H, 5.94; N, 4.18.
(2R*,3R*)-5-(4-Methoxybenzyl)-4-oxo-6-(4-methoxyphenyl)-5-azaspiro[2.4]heptane-7-carboxylic Acid (18b)
Pale yellow crystals; yield 28% (82 mg); mp = 160–161 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.73 (s, 1H), 7.15 (d, J = 8.6 Hz, 2H), 6.99 (d, J = 8.6 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 6.85 (d, J = 8.6 Hz, 2H), 4.80 (d, J = 15.0 Hz, 1H), 4.62 (d, J = 4.9 Hz, 1H), 3.76 (s, 3H), 3.73 (s, 3H), 3.43 (d, J = 15.1 Hz, 1H), 2.91 (d, J = 4.8 Hz, 1H), 1.22–1.11 (m, 1H), 1.06–0.96 (m, 1H), 0.96–0.82 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 174.3, 172.9, 159.6, 158.9, 131.7, 129.5, 128.8, 128.5, 114.9, 114.3, 61.2, 55.6, 55.5, 52.1, 43.9, 25.3, 13.9, 11.0. LCMS, positive mode, m/z: 382 [M + H]+. Anal. calcd for C22H23NO5: C, 69.28; H, 6.08; N, 3.67. Found: C, 68.92; H, 6.40; N, 4.03.
(2R*,3R*)-2-(4-Methoxyphenyl)-6-oxo-1-(2,2,2-trifluoroethyl)piperidine-3-carboxylic Acid (17a)
White crystals; yield 20% (100 mg); mp = 155–156 °C. 1H NMR (500 MHz, DMSO-d6) δ 12.76 (s, 1H), 7.15 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.6 Hz, 2H), 5.00 (d, J = 5.4 Hz, 1H), 4.65 (dq, J = 15.3, 10.0 Hz, 1H), 3.76 (s, 3H), 3.08 (dq, J = 15.2, 9.0 Hz, 1H), 2.91–2.80 (m, 1H), 2.68–2.52 (m, 2H), 1.98–1.75 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 173.6, 170.4, 159.4, 131.5, 128.6, 125.1 (q, J = 281.3 Hz), 114.7, 63.0, 55.6, 46.8, 44.7 (q, J = 32.9 Hz), 30.0, 20.4. 19F NMR (376 MHz, DMSO-d6) δ −67.8. LCMS, positive mode, m/z: 332 [M + H]+. Anal. calcd for C15H16F3NO4: C, 54.38; H, 4.87; N, 4.23. Found: C, 54.04; H, 4.89; N, 4.01.
(2R*,3R*)-5,5-Difluoro-2-(4-methoxyphenyl)-6-oxo-1-(2,2,2-trifluoroethyl)piperidine-3-carboxylic Acid (17b)
Pale brownish crystals; yield 36% (196 mg); mp = 155–156 °C. 1H NMR (500 MHz, DMSO-d6) δ 13.07 (s, 1H), 7.17 (d, J = 8.6 Hz, 2H), 7.00 (d, J = 8.6 Hz, 2H), 5.23–5.05 (m, 1H), 4.65–4.40 (m, 1H), 3.76 (s, 3H), 3.62–3.47 (m, 1H), 3.44–3.28 (m, 1H), 3.13–3.03 (m, 1H), 2.83–2.66 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 171.7, 162.3 (t, J = 30.4 Hz), 159.8, 129.2, 128.9, 124.6 (q, J = 281.4 Hz), 115.0, 112.1 (t, J = 243.5 Hz), 63.0, 55.6, 45.5 (q, J = 33.6 Hz), 44.1, 31.5 (t, J = 23.4 Hz). 19F NMR (376 MHz, DMSO-d6) δ −67.3, −97.7. LCMS, positive mode, m/z: 368 [M + H]+. Anal. calcd for C15H14F5NO4: C, 49.05; H, 3.84; N, 3.81. Found: C, 49.37; H, 3.91; N, 3.47.
Synthesis of (3R*,4R*)-3-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acids
General Procedure C
The Schiff base (2.00 mmol) and homophthalic anhydride (324 mg; 2.00 mmol) were mixed in toluene (6 mL), and the reaction mixture was heated to 110 °C in an argon atmosphere. It was refluxed for 6 h and then cooled to room temperature.
(3R*,4R*)-2-(4-Methoxybenzyl)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (10a)
The product was obtained by filtration and recrystallized from (i-Pr)2O/MeOH; white crystals; yield 65% (494 mg); mp = 203–204 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.31 (s, 1H), 7.92 (d, J = 7.7 Hz, 1H), 7.55 (t, J = 7.3 Hz, 1H), 7.50–7.40 (m, 2H), 7.27 (d, J = 8.3 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 5.20 (d, J = 14.8 Hz, 1H), 5.00 (q, J = 7.6 Hz, 1H), 4.37 (s, 1H), 4.24 (d, J = 14.7 Hz, 1H), 3.73 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 170.8, 163.2, 159.0, 133.8, 132.7, 130.2, 129.7, 129.1, 128.5, 128.2, 125.7 (q, J = 286.7 Hz), 127.5, 114.0, 58.7 (q, J = 29.1 Hz), 55.4, 50.5, 42.7. 19F NMR (376 MHz, DMSO-d6) δ −71.9. LCMS, positive mode, m/z: 380 [M + H]+. Anal. calcd for C19H16F3NO4: C, 60.16; H, 4.25; N, 3.69. Found: C, 60.17; H, 3.91; N, 3.66.
(3R*,4R*)-2-(4-Methoxyphenyl)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (10c)
Purified by prep. HPLC (MeCN/H2O mobile phase); pale brownish crystals; yield 53% (387 mg); mp = 108–109 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.60 (br, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.68–7.55 (m, 2H), 7.49 (td, J = 7.5, 1.6 Hz, 1H), 7.35 (d, J = 8.8 Hz, 2H), 7.02 (d, J = 8.8 Hz, 2H), 5.30 (q, J = 7.5 Hz, 1H), 4.48 (s, 1H), 3.79 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 171.1, 162.6, 158.6, 134.8, 133.9, 133.1, 129.7, 129.0, 128.8, 128.2, 128.0, 125.5 (q, J = 286.5 Hz), 114.6, 61.6 (q, J = 28.2 Hz), 55.8, 42.9. 19F NMR (376 MHz, DMSO-d6) δ −71.3. LCMS, positive mode, m/z: 366 [M + H]+. Anal. calcd for C18H14F3NO4: C, 59.18; H, 3.86; N, 3.83. Found: C, 59.44; H, 3.56; N, 3.58.
(3R*,4R*)-2-Benzyl-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (10d)
Scaled to 20 mmol; the product was obtained by filtration; yellow crystals; yield 53% (3.71 g); mp = 189–190 °C. 1H NMR (500 MHz, DMSO-d6) δ 13.34 (br, 1H), 7.91 (d, J = 7.7 Hz, 1H), 7.57 (t, J = 7.5 Hz, 1H), 7.48 (d, 8.3 Hz), 7.45 (t, 7.5 Hz), 7.36–7.22 (m, 5H), 5.16 (d, J = 15.1 Hz, 1H), 5.06 (q, J = 7.7 Hz, 1H), 4.46–4.33 (m, 2H). 13C NMR (126 MHz, DMSO-d6) δ 170.9, 163.3, 137.4, 134.0, 132.8, 129.7, 128.6, 128.5, 128.4, 128.0, 127.6, 127.5, 125.7 (q, J = 286.4 Hz), 59.3 (q, J = 28.8 Hz), 51.6, 42.8. 19F NMR (376 MHz, DMSO-d6) δ −72.0. LCMS, positive mode, m/z: 350 [M + H]+. Anal. calcd for C18H14F3NO3: C, 61.89; H, 4.04; N, 4.01. Found: C, 62.25; H, 3.77; N, 3.65.
(3R*,4R*)-1-oxo-2-(Thiophen-2-ylmethyl)-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (10e)
The product was obtained by filtration; yellow crystals; yield 52% (370 mg); mp = 196–197 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.33 (br, 1H), 7.93 (d, J = 7.7 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.49–7.44 (m, 2H), 7.44–7.40 (m, 1H), 7.15 (d, J = 3.5 Hz, 1H), 6.94 (t, J = 4.3 Hz, 1H), 5.31 (d, J = 15.2 Hz, 1H), 5.13 (q, J = 7.6 Hz, 1H), 4.59 (d, J = 15.2 Hz, 1H), 4.38 (s, 1H). 13C NMR (126 MHz, DMSO-d6) δ 170.7, 163.0, 139.2, 134.0, 132.8, 129.7, 128.5, 128.1, 128.0, 127.5, 126.8, 126.7, 125.6 (q, J = 286.2 Hz), 58.7 (q, J = 29.4 Hz), 46.14, 42.8. 19F NMR (376 MHz, DMSO-d6) δ −72.2. LCMS, positive mode, m/z: 356 [M + H]+. Anal. calcd for C16H12F3NO3S: C, 54.08; H, 3.40; N, 3.94; S, 9.02. Found: C, 54.39; H, 3.53; N, 3.96; S, 9.21.
(3R*,4R*)-2-(3-Fluorobenzyl)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (10f)
Purified by prep. HPLC (MeCN/H2O mobile phase); pale brownish crystals; yield 63% (463 mg); mp = 149–150 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.46 (br, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.57 (t, J = 7.1 Hz, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.33 (q, J = 7.0 Hz, 1H), 7.23–7.12 (m, 2H), 7.06 (td, J = 8.6, 2.6 Hz, 1H), 5.19 (q, J = 7.5 Hz, 1H), 5.13 (d, J = 15.2 Hz, 1H), 4.47 (d, J = 15.3 Hz, 1H), 4.41 (s, 1H). 13C NMR (126 MHz, chloroform-d) δ 171.0, 163.4, 162.6 (d, J = 242.8 Hz), 140.6 (d, J = 7.3 Hz), 134.1, 132.9, 130.4 (d, J = 8.2 Hz), 129.8, 128.6, 127.9, 127.5, 125.7 (q, J = 287.2 Hz), 124.5, 115.1 (d, J = 21.7 Hz), 114.3 (d, J = 20.8 Hz), 59.5 (q, J = 29.1 Hz), 51.4, 42.9. 19F NMR (376 MHz, DMSO-d6) δ −72.1, −114.1. LCMS, positive mode, m/z: 368 [M + H]+. Anal. calcd for C18H13F4NO3: C, 58.86; H, 3.57; N, 3.81. Found: C, 58.88; H, 3.84; N, 3.79.
(3R*,4R*)-2-Cyclohexyl-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (10g)
Purified by prep. HPLC (MeCN/H2O mobile phase); white crystals; yield 52% (355 mg); mp = 139–140 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.37 (br, 1H), 7.83 (d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.48–7.34 (m, 2H), 4.99 (q, J = 7.7 Hz, 1H), 4.32 (s, 1H), 3.77 (tt, J = 11.8, 3.6 Hz, 1H), 2.08–1.92 (m, 1H), 1.88–1.66(m, 5H), 1.66–1.54 (m, 1H), 1.40–1.20 (m, 2H), 1.19–1.03 (m, 1H). 13C NMR (126 MHz, DMSO-d6) δ 171.0, 163.2, 133.4, 132.4, 129.5, 129.1, 128.4, 127.4, 125.4 (q, J = 285.9 Hz), 60.2, 58.0 (q, J = 29.3 Hz), 43.6, 29.9, 29.7, 26.3, 26.1, 25.6. 19F NMR (376 MHz, DMSO-d6) δ −71.1. LCMS, positive mode, m/z: 342 [M + H]+. Anal. calcd for C17H18F3NO3: C, 59.82; H, 5.32; N, 4.10. Found: C, 59.59; H, 5.10; N, 3.92.
(3R*,4R*)-2-(2,4-Dimethoxybenzyl)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (10h)
Scaled to 150 mmol; the product was obtained by filtration; white crystals; yield 62% (37.95 g); mp = 224–225 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.16 (s, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.54 (t, J = 7.5, 1H), 7.47–7.40 (m, 2H), 7.11 (d, J = 8.3 Hz, 1H), 6.53 (d, J = 2.4 Hz, 1H), 6.44 (dd, J = 8.3, 2.4 Hz, 1H), 5.21 (d, J = 14.7 Hz, 1H), 4.90 (q, J = 7.7 Hz, 1H), 4.33 (s, 1H), 4.16 (d, J = 14.7 Hz, 1H), 3.75 (s, 3H), 3.74 (s, 3H). 13C NMR (126 MHz, DMSO-d6) δ 170.7, 162.9, 160.7, 158.9 133.8, 132.6, 131.4, 128.5, 128.2, 127.5, 125.9 (q, J = 286.7 Hz), 116.5, 104.9, 98.7, 58.2 (q, J = 29.2 Hz), 55.8, 55.6, 45.3, 42.6. 19F NMR (376 MHz, DMSO-d6) δ −72.1. LCMS, negative mode, m/z: 408 [M–H]−. Anal. calcd for C20H18F3NO5: C, 58.68; H, 4.43; N, 3.42. Found: C, 58.78; H, 4.12; N, 3.26.
Synthesis of (1R*,2R*)-2-(Trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acids
General Procedure D
The Schiff base (2.00 mmol) and 1,5-dihydro-3-benzoxepine-2,4-dione (352 mg; 2.00 mmol) were mixed in xylene (6 mL), and the reaction mixture was heated to 140 °C in an argon atmosphere. It was refluxed for 8 h and then cooled to room temperature.
(1R*,2R*)-3-(4-Methoxybenzyl)-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acid (20a)
The product was obtained by filtration and recrystallized from (i-Pr)2O/MeOH; pale brownish crystals; yield 43% (338 mg); mp = 225–226 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.58 (s, 1H), 7.34 (s, 3H), 6.99–6.87 (m, 1H), 6.53 (d, J = 8.1 Hz, 2H), 6.34 (d, J = 8.1 Hz, 2H), 5.12 (d, J = 15.4 Hz, 1H), 4.81–4.69 (m, 1H), 4.64 (d, J = 9.5 Hz, 1H), 4.19 (d, J = 14.3 Hz, 1H), 3.85 (d, J = 15.5 Hz, 1H), 3.64 (s, 3H), 3.49 (d, J = 14.4 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 172.3, 171.9, 158.6, 136.8, 132.3, 128.8, 128.4, 128.4, 128.4, 128.1, 126.9, 126.4 (q, J = 286.6 Hz), 113.9, 60.0 (q, J = 27.6 Hz), 55.4, 50.8, 47.5, 42.1. 19F NMR (376 MHz, DMSO-d6) δ −72.8. LCMS, positive mode, m/z: 394 [M + H]+. Anal. calcd for C20H18F3NO4: C, 61.07; H, 4.61; N, 3.56. Found: C, 60.95; H, 4.52; N, 3.31.
(1R*,2R*)-3-(4-Methoxyphenyl)-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acid (20c)
Purified by prep. HPLC (MeCN/H2O mobile phase); pale brownish
crystals; yield 4% (31 mg); mp = 188–189 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.64 (br, 1H), 7.41–7.29 (m, 3H), 7.25
(d, J = 7.4 Hz, 1H), 6.88 (d, J =
8.5 Hz, 2H), 6.79 (d, J = 8.5 Hz, 2H), 5.15 (p, J = 7.7 Hz, 1H), 4.72 (d, J = 8.6 Hz, 1H),
4.12 (d, J = 15.1 Hz, 1H), 3.75 (d, J = 15.1 Hz, 1H), 3.71 (s, 3H). 13C
NMR (126 MHz, chloroform-d) δ 172.4,
171.0, 158.5, 136.9, 136.0, 132.8, 129.2, 129.0, 128.8, 128.4, 128.3,
125.6 (
, J = 285.2 Hz), 114.6, 64.7 (q, J = 28.4
Hz), 55.8, 48.7, 42.8. 19F NMR (376 MHz, DMSO-d6) δ −70.8.
LCMS, positive mode, m/z: 380 [M
+ H]+. Anal. calcd for C19H16F3NO4: C, 60.16; H, 4.25; N, 3.69. Found: C, 60.27;
H, 4.31; N, 3.45.
(1R*,2R*)-3-Benzyl-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acid (20d)
Scaled to 20 mmol; the product was obtained by filtration; white crystals; yield 32% (2.34 g); mp = 211–212 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.63 (s, 1H), 7.36 (s, 3H), 7.08 (t, J = 7.5 Hz, 1H), 7.04–6.91 (m, 3H), 6.39 (d, J = 7.5 Hz, 2H), 5.17 (d, J = 15.8 Hz, 1H), 4.80 (p, J = 8.0 Hz, 1H), 4.68 (d, J = 9.4 Hz, 1H), 4.22 (d, J = 14.4 Hz, 1H), 3.99 (d, J = 15.8 Hz, 1H), 3.50 (d, J = 14.4 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 172.3, 172.0, 136.9, 136.9, 132.4, 128.8, 128.5, 128.5, 128.2, 127.4, 126.9, 126.9, 126.3 (q, J = 286.2 Hz), 60.6 (q, J = 27.3 Hz), 51.5, 47.5, 42.1. 19F NMR (376 MHz, DMSO-d6) δ −72.9. LCMS, positive mode, m/z: 364 [M + H]+. Anal. calcd for C19H16F3NO3: C, 62.81; H, 4.44; N, 3.86. Found: C, 62.57; H, 4.56; N, 3.85.
(1R*,2R*)-4-oxo-3-(Thiophen-2-ylmethyl)-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acid (20e)
The product was obtained by filtration and recrystallized from (i-Pr)2O/MeOH; pale brownish crystals; yield 30% (222 mg); mp = 217–218 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.60 (br, 1H), 7.35–7.25 (m, 3H), 7.20 (d, J = 5.1 Hz, 1H), 6.93 (d, J = 6.9 Hz, 1H), 6.74 (t, J = 4.3 Hz, 1H), 6.54 (d, J = 3.5 Hz, 1H), 5.24 (d, J = 15.6 Hz, 1H), 4.91 (p, J = 7.5 Hz, 1H), 4.61 (d, J = 9.4 Hz, 1H), 4.22 (d, J = 15.6 Hz, 1H), 4.15 (d, J = 14.4 Hz, 1H), 3.49 (d, J = 14.4 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 172.2, 171.4, 139.0, 136.4, 132.1, 128.6, 128.5, 128.0, 127.0, 126.6, 126.5, 126.3, 126.2 (q, J = 286.2 Hz), 60.1 (q, J = 27.4 Hz), 47.5, 47.1, 42.0. 19F NMR (376 MHz, DMSO-d6) δ −72.9. LCMS, positive mode, m/z: 370 [M + H]+. Anal. calcd for C17H14F3NO3S: C, 55.28; H, 3.82; N, 3.79; S, 8.68. Found: C, 55.46; H, 3.68; N, 4.07; S, 8.45.
(1R*,2R*)-3-(3-Fluorobenzyl)-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acid (20f)
The product was obtained by filtration and recrystallized from (i-Pr)2O/MeOH; white crystals; yield 24% (183 mg); mp = 226–227 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.67 (s, 1H), 7.45–7.29 (m, 3H), 7.12–6.99(m, 2H), 6.89 (td, J = 8.5, 2.6 Hz, 1H), 6.36 (d, J = 7.6 Hz, 1H), 6.03 (d, J = 10.3 Hz, 1H), 5.12 (d, J = 16.0 Hz, 1H), 4.85 (p, J = 8.0 Hz, 1H), 4.70 (d, J = 9.4 Hz, 1H), 4.22 (d, J = 14.4 Hz, 1H), 4.08 (d, J = 16.0 Hz, 1H), 3.50 (d, J = 14.4 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 172.3, 172.0, 163.4, 162.4 (d, J = 243.4 Hz), 140.2 (d, J = 7.2 Hz), 136.8, 132.3, 130.3 (d, J = 8.2 Hz), 128.8, 128.6, 128.3, 126.9, 126.3 (q, J = 285.8 Hz), 122.9 (d, J = 2.7 Hz), 114.1 (d, J = 20.9 Hz), 113.2 (d, J = 22.1 Hz), 61.0 (q, J = 27.4 Hz), 51.3, 47.5, 42.0. 19F NMR (376 MHz, DMSO-d6) δ −73.1, −113.9. LCMS, positive mode, m/z: 382 [M + H]+. Anal. calcd for C19H15F4NO3: C, 59.85; H, 3.97; N, 3.67. Found: C, 59.99; H, 3.84; N, 3.54.
(1R*,2R*)-3-Cyclohexyl-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acid (20g)
Purified by prep. HPLC (MeCN/H2O mobile phase); gray crystals; yield 15% (109 mg); mp = 217–218 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.75 (br, 1H), 7.39–7.19 (m, 3H), 7.10–6.96 (m, 1H), 4.87 (p, J = 7.9 Hz, 1H), 4.58 (d, J = 8.1 Hz, 1H), 4.06 (d, J = 14.2 Hz, 1H), 3.78 (tt, J = 11.9, 3.5 Hz, 1H), 3.39 (d, J = 14.2 Hz, 1H), 1.77–1.61 (m, 1H), 1.61–1.42 (m, 3H), 1.40–1.25 (m, 1H), 1.28–1.09 (m, 2H), 1.10–0.86 (m, 2H), 0.60 (d, J = 12.0 Hz, 1H). 13C NMR (126 MHz, chloroform-d) δ 173.1, 172.6, 136.8, 132.3, 128.7, 128.4, 128.1, 126.9, 125.8 (q, J = 284.6 Hz), 59.0, 57.2 (q, J = 28.3 Hz), 48.4, 43.1, 30.8, 30.1, 25.9, 25.8, 25.3. 19F NMR (376 MHz, DMSO-d6) δ −71.9. LCMS, positive mode, m/z: 356 [M + H]+. Anal. calcd for C18H20F3NO3: C, 60.84; H, 5.67; N, 3.94. Found: C, 60.50; H, 5.41; N, 3.96.
(1R*,2R*)-3-(2,4-Dimethoxybenzyl)-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acid (20h)
Scaled to 200 mmol; the product was obtained by filtration and recrystallized from (i-Pr)2O; white crystals; yield 37% (31.6 g); mp = 245–246 °C. 1H NMR (400 MHz, DMSO-d6) δ 13.55 (s, 1H), 7.33–7.17 (m, 3H), 6.95 (d, J = 6.0 Hz, 1H), 6.35–6.23 (m, 2H), 6.10 (dd, J = 8.4, 2.3 Hz, 1H), 4.99–4.85 (m, 2H), 4.59 (d, J = 9.5 Hz, 1H), 4.13 (d, J = 14.4 Hz, 1H), 3.82 (d, J = 15.3 Hz, 1H), 3.65 (s, 3H), 3.46 (s, 3H), 3.39 (d, J = 14.4 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 172.4, 171.5, 160.4, 158.5, 136.9, 132.2, 130.2, 128.5, 128.3, 127.8, 126.6, 126.5 (q, J = 286.4 Hz), 116.3, 104.1, 98.3, 60.2 (q, J = 27.1 Hz), 55.5, 55.4, 47.7, 47.5, 42.1. 19F NMR (376 MHz, DMSO-d6) δ −73.1. LCMS, negative mode, m/z: 422 [M–H]−. Anal. calcd for C21H20F3NO5: C, 59.57; H, 4.76; N, 3.31. Found: C, 59.61; H, 4.40; N, 3.55.
Preparation of (3R*,4R*)-1-oxo-3-(Trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic Acid (21)
(3R*,4R*)-2-(2,4-Dimethoxybenzyl)-1-oxo-3-(trifluoromethyl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid (10h) (30.00 g; 73.2 mmol) was dissolved in trifluoroacetic acid (300 mL; 3.93 mol). The reaction mixture was heated to 80 °C (oil bath) and was refluxed for 16 h. Then, the solvent was removed in vacuo. The residue was evaporated with toluene (2 × 300 mL). Then, it was purified by column chromatography (CombiFlash MeCN/H2O mobile phase C18) to give 10.47 g of product as pale yellow crystals (mp = 166–167 °C). Yield = 55%. 1H NMR (400 MHz, DMSO-d6) δ 13.39 (s, 1H), 8.76 (d, J = 5.5 Hz, 1H), 7.86 (d, J = 7.5 Hz, 1H), 7.56 (t, J = 7.4 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.5 Hz, 1H), 4.71–4.59 (m, 1H), 4.32 (s, 1H). 13C NMR (126 MHz, chloroform-d) δ 171.1, 163.6, 134.3, 132.8, 129.9, 128.5, 127.9, 127.2, 125.4 (q, J = 284.2 Hz), 53.3 (q, J = 30.5 Hz), 42.0. 19F NMR (376 MHz, DMSO-d6) δ −75.0. LCMS, positive mode, m/z: 260 [M + H]+. Anal. calcd for C11H8F3NO3: C, 50.98; H, 3.11; N, 5.40. Found: C, 51.33; H, 3.06; N, 5.64.
Preparation of (1R*,2R*)-4-oxo-2-(Trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic Acid (22)
(1R*,2R*)-3-(2,4-Dimethoxybenzyl)-4-oxo-2-(trifluoromethyl)-2,3,4,5-tetrahydro-1H-3-benzazepine-1-carboxylic acid (20h) (30.00 g; 70.8 mmol) was dissolved in trifluoroacetic acid (300 mL; 3.93 mol). The reaction mixture was stirred for 70 h at room temperature. Then, the solvent was removed in vacuo. The residue was evaporated with toluene (2 × 300 mL). Then, it was purified by column chromatography (CombiFlash MeCN/H2O mobile phase C18) to give 10.5 g of product as white crystals (mp= 246–247 °C). Yield = 54%. 1H NMR (400 MHz, DMSO-d6) δ 13.45 (s, 1H), 7.99 (d, J = 5.4 Hz, 1H), 7.33–7.25 (m, 3H), 7.25–7.20 (m, 1H), 4.79–4.67(m, 1H), 4.44 (d, J = 9.1 Hz, 1H), 3.74 (d, J = 15.1 Hz, 1H), 3.68 (d, J = 15.1 Hz, 1H). 13C NMR (126 MHz, DMSO-d6) δ 172.3, 172.2, 135.5, 132.8, 129.7, 129.3, 128.6, 128.0, 125.4 (q, J = 283.5 Hz), 55.5 (q, J = 28.5 Hz), 47.9, 42.3. 19F NMR (376 MHz, DMSO-d6) δ −74.3. LCMS, positive mode, m/z: 274 [M + H]+. Anal. calcd for C12H10F3NO3: C, 52.75; H, 3.69; N, 5.13. Found: C, 52.72; H, 3.48; N, 5.30.
Acknowledgments
The work was supported by Enamine Ltd. Chromatographic separation and purification were performed at the Preparative Chromatography Department of Enamine Ltd. under supervision of Olga Maksymenko. X-ray diffraction studies were performed by Dr. Eduard Rusanov. The authors thank Prof. Andrey A. Tolmachev for his encouragement and support and Dr. Halyna Buvailo for her help with manuscript preparation.
Supporting Information Available
The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.0c02394.
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.
The authors declare no competing financial interest.
Supplementary Material
References
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