Abstract
Phosphine-catalyzed [3+2] and [4+3]annulation reactions of C,N-cyclic azomethine imines with allenoates have been developed to give a variety of pharmaceutically attractive tetrahydroisoquinoline derivatives in moderate to excellent yields. The two distinct reaction pathways, [3+2] and [4+3]cyclization, depend on the nature of the nucleophilic phosphine and the allenoate. Generally, for α-alkylallenoates, the reactions always proceed with [3 +2]cyclization as the major pathway no matter what phosphine was used; for α-ArCH2-substituted allenoates, the reaction pathway was controlled by the phosphine catalyst used.
Keywords: allenoates, annulation, azomethine imines, catalysis, phosphines
Introduction
Tetrahydroisoquinoline derivatives are structural motifs often occurring in natural products and pharmacologically important agents exhibiting a wide range of biological activities such as antitumor, antibiotic, antivirus, anti-inflammatory, anticoagulation, and bronchodilation.[1] Therefore, the synthesis of tetrahydroisoquinoline derivatives has attracted much attention.[2] Although some synthetic methods have been developed,[2] novel procedures applicable for their synthesis would still be highly desirable.
The nucleophilic phosphine-catalyzed intermolecular cycloaddition reaction has been developed as one of the most powerful tools for the convergent synthesis of a variety of carbo- and heterocycles from simpler precursors.[3] In these cycloaddition reactions, activated allenes have been used as a versatile reaction substrate and exhibited super diverse reactivity towards electrophilic reagents. These allenes act as one, two-, three- or four-carbon synthons to react with various electrophilic coupling partners including aldehydes, activated alkenes, imines or aziridines to render all kinds of annulation reactions.[4–11] Such a diverse pattern of reactivity of the allene as one of the reaction substrates is often induced by its electrophilic coupling partners. Consequently, searching for a new electrophilic substrate with a proper reactivity that can effectively be utilized in the synthesis of heterocycles with new skeletons or structural features constitutes a major challenge for the formation of diverse cycloaddition products from the nucleophilic phosphine catalysis of allenes. Recently, a new type of electrophilic coupling reagent, N,N′-cyclic azomethine imines (1), has been used as an N′N′C trio-of-atoms synthon in the phosphine-catalyzed [3+2]annulation with α-substituted allenoates to produce biologically active tetrahydropyrazolopyrazolones (Scheme 1).[12] This work prompted us to investigate whether the catalytic process can be used in the reactions of another noteworthy class of azomethine imines, C,N-cyclic imines, to synthesize pharmaceutically attractive tetrahydroisoquinoline derivatives. In addition, while the [4+2] and [3+2]cycloadditions are widely explored in phosphine-catalyzed annulation reactions of allenoates, only two examples of the phosphine-catalyzed [4+3]annulation reactions of allenes were reported so far.[8,12] Thus, we conceived to use an α-substituted allenoate as a 1,4-dipole to develop a novel [4+3]cycloaddition.
Scheme 1.
Phosphine-catalyzed annulations of azomethine imines with allenoates.
N,N′-Cyclic azomethine imines 1 have recently been employed as efficient 1,3-dipoles in various metal-catalyzed or organocatalytic cycloadditions.[13] However, catalytic cycloaddition reactions of C,N-cyclic azomethine imines have rarely been studied. Only three examples involving C,N-cyclic substrates have been reported so far.[14] In 2008, Charette and co-workers reported an Ni(ClO 4)2-catalyzed [3 + 3] cycloaddition of C,N-cyclic aromatic azomethine imines with 1,1-cyclopropane diesters, giving access to unique tricyclic dihydroquinoline derivatives.[14a] In 2010, Maruoka and co-workers developed the BINOL-Ti-catalyzed enantioselective [3+2]cycloaddition of C,N-cyclic azomethine imines with α,β-unsaturated aldehydes, providing derivatives of 1,2,3,5,6,10b-hexahydropyrazolo[5,1-a]isoquinoline;[14b] in 2011, Maruoka’s group further developed an axially chiral dicarboxylic acid-catalyzed asymmetric inverse-electron-demand 1,3-dipolar cycloaddition of the above azomethine imines with vinyl ether or vinylogous aza-enamines, affording 1,2,3,5,6,10b-hexahydropyrazolo[5,1-a]isoquinoline derivatives.[14c] Herein, we report the first example of phosphine-catalyzed cycloaddition of C,N-cyclic azomethine imines with allenoates. The novel [3+2] and [4+3]annulation reactions were achieved depending on the number of carbon atoms that the allenoates contribute to the final cyclic products, furnishing 1,2,3,5,6,10b-hexahydropyrazolo[5,1-a]isoquinoline derivatives and 1,4,5,7,8,12b-hexahydro-[1,2]diazepino-[7,1-a]isoquinoline derivatives, respectively (Scheme 1).
Results and Discussion
We initiated our study and screened the reaction conditions by evaluating the reactions of azomethine imine 2a and allenoate 3f (Table 1). Considering that the direct cycloadditions of azomethine imines with allenoates often occur,[15] the reaction of 2a with 3f was first carried out in dichloromethane at room temperature in the absence of phosphines, no new spot was observed on the TLC (entry 1), therefore, the background reaction resulting from possible direct [3+2]cycloaddition of azomethine imine and allenoate in dichloromethane at room temperature could be excluded. However, once the temperature is above 30°C, the thermal cycloaddition product would be observed. In order to avoid the background reaction, when the following reactions were performed, the reaction temperature was strictly controlled at room temperature (25°C). Since the efficiency of nucleophilic phosphine catalysis often depends on the nature of the tertiary phosphine catalyst, several phosphines with different nucleophilicity have been screened (entries 2–6). When PMe3 was used, a 66% yield of [3+2]cyclization product and <5%yield of [4+3]cyclization product were achieved (entry 2). In contrast, with PBu3 as the catalyst, < 5%yield of [3 + 2]cyclization product and 90%yield of [4+3]product were obtained (entry 3). The structures of the new [3+2]annulation product (4) and [4+3]product (5) were confirmed by NMR spectra and subsequently by the X-ray crystallography of 4ef and 5df (see Table 3 below). Notably, a single diastereomer (5af) of [4+ 3]cyclization product was obtained, and other diastereomer was not observed. When phosphines Me2PPh, EtPPh2 and PPh3 were utilized as catalysts, the reactions were somewhat sluggish and both overall yield and chemoselectivity were unsatisfactory (entries 4–6). On the basis of these results, PBu3 and PMe3 were established as the optimal catalysts in terms of both yield and chemoselectivity.
Table 1.
Screening of phosphine catalysts for annulations of azomethine imines with allenoates.[a]
| |||
|---|---|---|---|
| Entry | PR3 | 4af, Yield [%][b] | 5af, Yield [%][b] |
| 1 | – | 0[c] | 0[c] |
| 2 | PMe3 | 66 | <5 |
| 3 | PBu3 | <5 | 90 |
| 4 | Me2PPh | 23 | 15 |
| 5 | EtPPh2 | 18 | 33 |
| 6 | PPh3 | 20 | <5 |
1.2 equiv. of allenoate was used.
Isolated yields, unless otherwise indicated.
Without phosphine catalyst.
Table 3.
Phosphine-catalyzed cycloaddition of azomethine imines (2) with allenoates.[a]
| |||||
|---|---|---|---|---|---|
| Entry | R1 | R2 | PR3 | 4, Yield [%][b] | 5, Yield [%][b] |
| 1 | 5-Me (2b) | Ph (3f) | PBu3 | 4bf, 24 | 5bf, 73 |
| 2 | 7-Me (2c) | Ph (3f) | PBu3 | 4cf, 23 | 5cf, 68 |
| 3 | 6-Br (2d) | Ph (3f) | PBu3 | 4df, 34 | 5df, 61 |
| 4 | 7-Br (2e) | Ph (3f) | PBu3 | 4ef, 23 | 5ef, 62 |
| 5 | 7-Cl (2f) | Ph (3f) | PBu3 | 4ff, 27 | 5ff, 62 |
| 6 | 5-Me (2b) | Ph (3f) | PMe3 | 4bf, 40 | 5bf, <1 |
| 7 | 7-Me (2c) | Ph (3f) | PMe3 | 4cf, 46 | 5cf, <1 |
| 8 | 6-Br (2d) | Ph (3f) | PMe3 | 4df, 73 | 5df, <1 |
| 9 | 7-Br (2e) | Ph (3f) | PMe3 | 4ef, 92 | 5ef, <1 |
| 10 | 7-Cl (2f) | Ph (3f) | PMe3 | 4ff, 80 | 5ff, <1 |
| 11 | 5-Me (2b) | Et (3c) | PBu3 | 4bc, 95 | 5bc, <1 |
| 12 | 7-Me (2c) | Et (3c) | PBu3 | 4cc, 97 | 5cc, <1 |
| 13 | 6-Br (2d) | Et (3c) | PBu3 | 4dc, 87 | 5dc, <1 |
| 14 | 7-Br (2e) | Et (3c) | PBu3 | 4ec, 96 | 5ec, <1 |
| 15 | 7-Cl (2f) | Et (3c) | PBu3 | 4fc, 95 | 5fc, <1 |
1.2 equiv. of allenoate was used.
Isolated yields, unless otherwise indicated.
With 20 mol% of PBu3 or PMe3 as catalyst, the annulation reactions of C,N-cyclic azomethine imine 2a with various allenoates were performed in dichloromethane at room temperature for 24 h to provide the corresponding products in moderate to excellent yields (Table 2).[16] Especially, with either PBu3 or PMe3 as the catalyst, α-alkylallenoates (3a–3e) underwent the reactions to afford the [3+2]products, 1,2,3,5,6,10b-hexahydropyrazolo-[5,1-a]isoquinoline derivatives, as the major products (entries 1–5, 14–18). Those reactions demonstrated excellent chemoselectivity towards the [3+2]products in most cases, giving only very small amounts (<1%) of the [4+ 3]products (entries 2–5, 14–18), except that the reaction of α-methylallenoate (3a) exhibited a moderate chemoselectivity to deliver [3+2] and [4+3]products in 62% and 7% yields, respectively (entry 1).
Table 2.
Phosphine-catalyzed cycloaddition of azomethine imine (2a) with allenoates.[a]
| ||||
|---|---|---|---|---|
| Entry | R1 | PR3 | 4, Yield [%][b] | 5, Yield [%][b] |
| 1 | H (3a) | PBu3 | 4aa, 62 | 5aa, 7 |
| 2 | Me (3b) | PBu3 | 4ab, 89 | 5ab, <1 |
| 3 | Et (3c) | PBu3 | 4ac, 87 | 5ac, <1 |
| 4 | i-Pr (3d) | PBu3 | 4ad, 79 | 5ad, <1 |
| 5 | t-Bu (3e) | PBu3 | 4ae, 74 | 5ae, <1 |
| 6 | Ph (3f) | PBu3 | 4af, <5 | 5af, 90 |
| 7 | 2-MeC6H4 (3g) | PBu3 | 4ag, <2 | 5ag, 42 |
| 8 | 3-MeC6H4 (3h) | PBu3 | 4ah, <5 | 5ah, 55 |
| 9 | 4-MeC6H4 (3i) | PBu3 | 4ai, 16 | 5ai, 71 |
| 10 | 4-FC6H4 (3j) | PBu3 | 4aj, <5 | 5aj, 92 |
| 11 | 3-ClC6H4 (3k) | PBu3 | 4ak, <5 | 5ak, 75 |
| 12 | 4-ClC6H4 (3l) | PBu3 | 4al, <5 | 5al, 84 |
| 13 | 4-BrC6H4 (3m) | PBu3 | 4am, <5 | 5am, 93 |
| 14 | H (3a) | PMe3 | 4aa, 79 | 5aa, <1 |
| 15 | Me (3b) | PMe3 | 4ab, 91 | 5ab, <1 |
| 16 | Et (3c) | PMe3 | 4ac, 93 | 5ac, <1 |
| 17 | i-Pr (3d) | PMe3 | 4ad, 92 | 5ad, <1 |
| 18 | t-Bu (3e) | PMe3 | 4ae, 60 | 5ae, <1 |
| 19 | Ph (3f) | PMe3 | 4af, 66 | 5af, <1 |
| 20 | 2-MeC6H4 (3g) | PMe3 | 4ag, 18 | 5ag, <5 |
| 21 | 3-MeC6H4 (3h) | PMe3 | 4ah, 55 | 5ah, 11 |
| 22 | 4-MeC6H4 (3i) | PMe3 | 4ai, 92 | 5ai, <5 |
| 23 | 4-FC6H4 (3j) | PMe3 | 4aj, 18 | 5aj, 27 |
| 24 | 3-ClC6H4 (3k) | PMe3 | 4ak, 28 | 5ak, 36 |
| 25 | 4-ClC6H4 (3l) | PMe3 | 4al, 40 | 5al, <5 |
| 26 | 4-BrC6H4 (3m) | PMe3 | 4am, 30 | 5am, 35 |
1.2 equiv. of allenoate was used.
Isolated yields, unless otherwise indicated.
When β′-arylallenoate was used as substrate, PBu3 and Me3P displayed quite different catalytic behaviors. Using PBu3 as the catalyst, contrary to chemoselectivity of α-alkylallenoates (3a–3e), all β′-arylallenoates examined (3f–3m) preferably gave a single diasteoreomer of the [4+3]cyclization product, 1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline derivatives, as the major product in moderate to excellent yields, together with small amounts of [3+ 2]product (entries 6–13). A broad range of aryl groups with electron-donating or electron-withdrawing substituents on the benzene ring could be tolerated in the process. In general, allenoates bearing electron-withdrawing groups on the benzene ring provided somewhat higher yields of the [4+3]cyclization products than did those bearing electron-donating groups (entries 10–13 and 7–9). Particularly, with β′-(4-BrC6H4)-substituted allenoate (3m) as substrate, the desired [4+3]product was produced in up to 93% yield (entry 13). With PMe3 as the catalyst, however, the [4+3]products were obtained as the major product in only three cases (entries 23, 24, 26). In another five cases (entries 19—22, 25), the [3+2]products were produced as the major products.
The generality of this reaction was explored with several azomethine imines bearing different substituents on the benzene rings. α-Benzylallenoate (3f) and α-ethylallenoate (3b) were used as the standard allenoates. The reaction is tolerant of a wide range of azomethine imines (2b–2f), providing a series of the corresponding products in moderate to excellent yields with moderate to excellent chemoselectivity (Table 3). In the presence of 20 mol% of PBu3, the reactions of azomethine imines (2b–2f) with α-benzylallenoate (3f) afforded the [4+3]products as the major products in 61–73% yield, and the [3+2]products as the minor products in 23–34% yield (entries 1–5). In contrast, using 20 mol% of PMe3 as the catalyst, the reactions of azomethine imines with α-benzylallenoate (3f) demonstrated excellent chemoselectivity, giving the [3+2]products as major product in 40–92% yield and [4+3]product in <1% yield (entries 6–10). In these cases, a significant electronic effect was observed. Electron-donating alkyl-substituted azomethine imines provided lower yields than those with electron-withdrawing groups (entries 6, 7 vs. entries 8–10). When α-ethylallenoate (3b) was employed as the substrate, under the catalysis of 20 mol% PBu3, the [3 + 2]cycloaddition products were acquired in uniformly high yields with excellent chemoselectivity (entries 11–15). The X-ray crystallographic structures of 4ef and 5df are shown in the Figure 1 and Figure 2.[17]
Figure 1.
ORTEP view of compound 4ef. The hydrogen atoms have been omitted for clarity.
Figure 2.
ORTEP view of compound 5df. The hydrogen atoms have been omitted for clarity.
Asymmetric variants of these cyclizations had been investigated too. Unfortunately, a variety of commercial available chiral phosphines such as DiPAMP, BINAP, Me-DuPhos, TangPhos, Et-BINEPINE, t-Bu-BINEPINE, FerroPHANE, SITCP and Et-BPE were not active in the reactions and afforded very small amounts of [3+2]cyclization products (<10% yield and <10% ee) and no [4+3]cyclization product.
The transformations of [3+2] and [4+3]cyclization products have been demonstrated in several reports for the synthesis of tetrahydroisoquinoline derivatives and other useful compounds. For example, the 1,2,3,5,6,10b-hexahydropyrazolo[5,1-a]isoquinoline derivatives 4 could further be transformed to 1,3-diamine derivatives via N′N bond cleavage with samarium iodide (SmI2),[14b,18] reduced with SmI2[12] and oxidation[12] to give biologically important compounds or building blocks for bioactive compounds.
On the basis of the reported mechanistic studies of nucleophilic phosphine-catalyzed reactions,[3] as shown in Scheme 2, a plausible mechanism has been outlined. The zwitterionic intermediate A, which was formed from the addition of PBu3 to the β-carbon of allenoate, attacks the azomethine imine 2a via γ-carbon atom of A to provide the intermediate B. The intramolecular conjugate addition of B accomplishes the [3+2]cyclization to form β-phosphonium enoate C, which undergoes facile β-elimination to regenerate the catalyst, affording the final [3+2]product 4. When R is a hydrogen atom or aryl, the intermediate B isomerizes into another amide species F due to the more acidic nature of the γ-proton. The ylide G formed from the 7-endo cyclization of F, expels the catalyst PBu3 through the ylide-to-enoate conversion to furnish the [4+3]product 5. Compared with PBu3, when PMe3 is used as the catalyst, conjugate addition of the amide to the β-phosphonium enoates in B is the major reaction pathway in most cases, resulting in the [3+2]product due to decreased steric congestion at the β-carbon atom.
Scheme 2.
A plausible reaction mechanism for the phosphine-catalyzed cycloaddtion of azomethine imines with allenoates.
Conclusions
In summary, phosphine-catalyzed [3+2] and [4+ 3]cycloaddition reactions of C,N-cyclic azomethine imines with allenoates have successfully been developed, providing the 1,2,3,5,6,10b-hexahydropyrazolo-[5,1-a]isoquinoline derivatives and 1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline derivatives, respectively, in high yields. Particularly, the novel [4+3]cycloaddition represents one of the few examples of phosphine-catalyzed [4+3]cycloaddition of the allenoates.
Experimental Section
General Procedures
All reactions were performed under an argon atmosphere in oven-dried glassware with magnetic stirring. Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Dichloromethane employed in the reactions was freshly distilled from CaH2. Organic solutions were concentrated under reduced pressure using a rotary evaporator or oil pump. Reactions were monitored through thin-layer chromatography (TLC) on silica gel-precoated glass plates. Chromatograms were visualized by fluorescence quenching under UV light at 254 nm. Flash column chromatography was performed using Qingdao Haiyang flash silica gel (200–300 mesh). Infrared spectra were recorded using a Bruker Optics TENSOR 27 instrument. 1H and 13C NMR spectra were recorded in CDCl3 using a Bruker 300M spectrometer, as indicated. Accurate mass measurements were performed using an Agilent instrument with the ESI-MS technique. X-ray crystallographic data were collected using a Bruker SMART CCD-based diffractometer equipped with a low-temperature apparatus operated at 100 K.
Preparation of C,N-Cyclic Azomethine Imines (2)
All C,N-cyclic azomethine imines (2) were prepared by the reported procedure.[14b,19]
General Procedure for the [3+2] and [4+3]Cyclo-addition Reactions of Azomethine Imines and Allenoate
An oven-dried, 15-mL Schlenk tube was charged with azomethine imine (0.125 mmol), 5 mL of CH2Cl2 and allenoate (0.15 mmol) at room temperature. Then, phosphine (0.025 mmol) was added to the above solution and the mixture was stirred at room temperature for 24 h. The reaction mixture was concentrated and the residue was purified by flash column (ethyl acetate/petroleum ether) to afford the corresponding cycloaddition product.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-propanoate (4aa)
Yield: 79% (Table 2, entry 14); a yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.52; IR (film): νmax = 2965, 2929, 2849, 1703, 1644, 1600, 1580, 1493, 1446, 1368, 1281, 1222, 1104, 1041, 911, 866, 789, 762, 730, 677, 647 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.31 (t, J = 7.1 Hz, 3H), 1.94 (t, J = 1.9 Hz, 3H), 2.77 (dd, J=15.5, 2.4 Hz, 1H), 2.94–3.10 (m, 2H), 3.14–3.23 (m, 1H), 3.37–3.41 (m, 1H), 3.71 (ddd, J=18.7, 8.4, 1.9 Hz, 1H), 4.21 (q, J=7.1 Hz, 2H), 4.31 (apparent t, 1H), 7.02–7.17 (m, 4H), 7.37–7.49 (m, 3H), 7.71–7.74 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 14.4, 16.7, 29.1, 40.2, 47.8, 60.5, 61.6, 117.9, 118.1, 126.4, 126.8, 127.1, 127.7, 128.3, 128.5, 131.1, 132.3, 135.22, 135.24, 148.5, 167.6, 170.7; HR-MS (ESI): m/z=377.1858, calcd. for C23H25N2O3+ [M+H]+: 377.1860.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-butanoate (4ab)
Yield: 91% (Table 2, entry 15); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.56; IR (film): νmax = 2926, 2853, 1704, 1638, 1581, 1493, 1455, 1368, 1299, 1240, 1220, 1142, 1106, 1062, 1028, 973, 909, 865, 786, 736, 695, 678, 648 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.12 (t, J = 7.4 Hz, 3H), 1.30 (t, J = 7.1 Hz, 3H), 2.34–2.47 (m, 2H), 2.73–2.79 (m, 1H), 2.91–3.16 (m, 3H), 3.35–3.40 (m, 1H), 3.68 (dd, J=18.6, 8.5 Hz, 1H), 4.18–4.28 (m, 3H), 7.00–7.16 (m, 4H), 7.35–7.48 (m, 3H), 7.70–7.74 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 12.7, 14.3, 23.8, 29.1, 40.0, 47.6, 60.3, 61.2, 124.6, 126.3, 126.7, 127.1, 127.6, 128.2, 128.5, 131.0, 132.3, 135.25, 135.31, 147.1, 167.4, 171.5; HR-MS (ESI): m/z=391.2016, calcd. for C24H27N2O3+ [M+H]+: 391.2016.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo-[5,1-a]isoquinolin-2(3H)-ylidene]-pentanoate (4ac)
Yield: 93% (Table 2, entry 16); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.58; IR (film): νmax = 2925, 2853, 1704, 1637, 1541, 1491, 1456, 1291, 1141, 1110, 1033, 910, 863, 789, 747, 695, 677 cm−1; 1H NMR (300 MHz, CDCl3): δ = 0.91 (t, J = 7.4 Hz, 3H) 1.30 (t, J=7.1 Hz, 3H), 1.39–1.73 (m, 2H), 2.23–2.33 (m, 1H), 2.45 (ddd, J=14.0, 9.2, 5.0 Hz, 1H), 2.69–2.81 (m, 1H), 2.93–3.22 (m, 3H), 3.33–3.44 (m, 1H), 3.65 (dd, J=18.7, 8.5 Hz, 1H), 4.16–4.28 (m, 3H), 6.99–7.15 (m, 4H), 7.36–7.49 (m, 3H), 7.70–7.73 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 14.2, 21.4, 29.1, 29.6, 32.4, 40.0, 47.6, 60.3, 61.2, 123.1, 126.3, 126.7, 127.1, 127.6, 128.2, 128.4, 131.0, 132.3, 135.3, 147.5, 167.6, 171.4; HR-MS (ESI): m/z=405.2177, calcd. for C25H29N2O3+ [M+H]+: 405.2173.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-4-methylpentanoate (4ad)
Yield: 92% (Table 2, entry 17); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.58; IR (film): νmax = 2957, 2867, 1704, 1644, 1600, 1581, 1493, 1456, 1367, 1297, 1217, 1115, 1063, 1028, 973, 910, 863, 790, 763, 730, 696, 677, 647 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.85 (d, J=6.5 Hz, 3H), 0.93 (d, J=6.6 Hz, 3H), 1.30 (t, J=7.1 Hz, 3H), 1.83–1.96 (m, 1H), 2.04 (dd, J=13.9, 9.5 Hz, 1H), 2.51–2.57 (m, 1H), 2.71–2.82 (m, 1H), 2.97–3.09 (m, 2H), 3.23–3.41 (m, 2H), 3.60 (ddd, J=18.7, 8.3, 1.4 Hz, 1H), 4.12–4.29 (m, 3H), 6.99–7.16 (m, 4H), 7.36–7.49 (m, 3H), 7.69–7.73 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 14.2, 22.0, 23.4, 27.6, 29.2, 39.3, 40.0, 47.7, 60.2, 61.3, 122.1, 126.3, 126.7, 127.1, 127.6, 128.2, 128.4, 131.1, 132.3, 135.3, 135.4, 147.9, 167.7, 171.3; HR-MS (ESI): m/z=419.2319, calcd. for C26H31N2O3+ [M+ H]+: 419.2329.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-4,4-dimethylpentanoate (4ae)
Yield: 74% (Table 2, entry 5); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.60; IR (film): νmax = 2953, 1705, 1682, 1541, 1508, 1456, 1364, 1294, 1165, 1094, 1067, 1026, 789, 762, 695, 677 cm−1; 1H NMR (300 MHz, CDCl3): δ = 0.92 (s, 9H), 1.31 (t, J=7.1 Hz, 3H), 2.27 (d, J=14.1 Hz, 1H), 2.64 (d, J=14.1 Hz, 1H), 2.77 (d, J=15.5 Hz, 1H), 3.06 (dtd, J=17.0, 12.4, 4.0 Hz, 2H), 3.38–3.45 (m, 3H), 4.16–4.23 (m, 3H), 6.98–7.14 (m, 4H), 7.36–7.49 (m, 3H), 7.67–7.70 (m, 2H); 13C NMR (75 MHz, CDCl3): δ=14.2, 29.3, 29.9, 32.9, 40.3, 42.3, 47.6, 60.3, 61.4, 120.9, 126.3, 126.8, 127.1, 127.7, 128.25, 128.32, 131.1, 132.4, 135.3, 135.7, 147.6, 168.9, 171.7; HR-MS (ESI): m/z=433.2495, calcd. for C27H33N2O3+ [M+H]+: 433.2486.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-phenylpropanoate (4af)
Yield: 66% (Table 2, entry 19); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.51; IR (film): νmax = 2929, 1703, 1541, 1508, 1493, 1455, 1368, 1298, 1219, 1095, 1030. 770, 699, 677 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.20 (t, J = 7.1 Hz, 3H), 2.62–2.78 (m, 2H), 2.84–2.97 (m, 2H), 3.25 (dd, J=18.9, 10.1 Hz, 1H), 3.58–3.76 (m, 2H), 3.98 (d, J= 15.8 Hz, 1H), 4.08–4.27 (m, 3H), 6.99–7.04 (m, 2H), 7.07–7.13 (m, 2H), 7.16–7.23 (m, 5H), 7.27–7.39 (m, 2H), 7.41–7.47 (m, 1H), 7.51–7.56 (m, 2H); 13C NMR (75 MHz, CDCl3): δ=14.1, 29.1, 35.4, 40.5, 47.4, 60.6, 61.0, 122.0, 125.8, 126.3, 126.8, 127.1, 127.6, 128.1, 128.2, 128.4, 128.6, 131.0, 132.3, 135.1, 135.2, 140.7, 149.3, 167.4, 170.8; HRMS (ESI): m/z=453.2165, calcd. for C29H29N2O3+ [M+H]+: 453.2173.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-(o-tolyl)propanoate (4ag)
Yield: 18% (Table 2, entry 20); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.50; IR (film): νmax = 3062, 3023, 2976, 2932, 2848, 1706, 1682, 1601, 1581, 1493, 1447, 1368, 1299,1272, 1219, 1095, 968, 909, 788, 761, 740, 716, 699, 678, 648 cm−1; 1H NMR (300 MHz, CDCl3): δ=1.17 (t, J= 7.1 Hz, 3H), 2.27 (s, 3H), 2.66–2.98 (m, 4H), 3.34 (dd, J= 18.8, 10.0 Hz, 1H), 3.61–3.74 (m, 2H), 3.99 (d, J=16.3 Hz, 1H), 4.08–4.18 (m, 2H), 4.22–4.28 (m, 1H), 7.00–7.17 (m, 8H), 7.33–7.38 (m, 2H), 7.42–7.47 (m, 1H), 7.53–7.56 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 19.8, 29.1, 33.4, 40.3, 47.4, 60.5, 61.1, 121.3, 125.5, 125.9, 126.3, 126.8, 127.1, 127.6, 128.2, 128.4, 128.9, 130.0, 131.0, 132.4, 135.1, 136.2, 138.6, 148.9, 162.3, 167.3, 171.1; HR-MS (ESI): m/z= 467.2335, calcd. for C30H31N2O3 [M + H]+: 467.2329.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-(m-tolyl)propanoate (4ah)
Yield: 55% (Table 2, entry 21); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.48; IR (film): νmax = 2927, 2851, 1697, 1493, 1447, 1369, 1298, 1199, 1097, 1031, 969, 866, 766, 703, 678 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.22 (t, J = 7.1 Hz, 3H), 2.25 (s, 3H), 2.62–2.93 (m, 4H), 3.24 (dd, J= 18.8, 10.1 Hz, 1H), 3.60–3.76 (m, 2H), 3.97 (d, J=15.9 Hz, 1H), 4.12–4.27(m, 3H), 6.94–7.04 (m, 5H), 7.07–7.14 (m, 3H), 7.31–7.37 (m, 2H), 7.40–7.46 (m, 1H), δ 7.47–7.51 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 14.2, 21.3, 29.1, 35.2, 40.5, 47.4, 60.6, 61.0, 77.2, 122.1, 125.6, 126.3, 126.5, 126.8, 127.1, 127.6, 128.0, 128.2, 128.4, 129.6, 131.0, 132.4, 135.1, 135.2, 137.5, 140.6, 149.2, 167.5, 170.7; HR-MS (ESI): m/z= 467.2328, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-(p-tolyl)propanoate (4ai)
Yield: 92% (Table 2, entry 22); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.48; IR (film): νmax = 2924, 2853, 1704, 1580, 1514, 1494, 1455, 1369, 1293, 1198, 1095, 1030, 968, 909, 866, 787, 763, 677, 647 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.21 (t, J = 7.1 Hz, 3H), 2.33 (s, 3H), 2.66–3.00 (m, 4H), 3.26 (dd, J=18.8, 10.0 Hz, 1H), 3.62–3.76 (m, 2H), 3.91 (d, J=15.8 Hz, 1H), 4.08–4.34 (m, 3H), 7.00–7.15 (m, 8H), 7.34–7.59 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 21.0, 29.1, 35.1, 40.4, 47.4, 60.5, 61.1, 122.1, 126.3, 126.8, 127.1, 127.6, 128.2, 128.4, 128.5, 128.7, 131.1, 132.4, 135.20, 135.21, 137.5, 148.9, 167.4, 170.9; HR-MS (ESI): m/z= 467.2323, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-(4-fluorophenyl)propanoate (4aj)
Yield: 18% (Table 2, entry 23); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.48; IR (film): νmax = 2930, 1714, 1650, 1602, 1507, 1455, 1369, 1310, 1240, 1158, 1097, 1059, 1026, 912, 958, 825, 733, 700, 672 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.20 (t, J = 7.1 Hz, 3H), 2.72 (ddd, J=18.7, 13.2, 3.5 Hz, 2H), 2.89–3.00 (m, 2H), 3.23 (dd, J= 18.7, 10.2 Hz, 1H), 3.62–3.77 (m, 2H), 3.92 (d, J=15.8 Hz, 1H), 4.07–4.33 (m, 3H), 6.86–7.18 (m, 8H), 7.33–7.58 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 14.2, 29.1, 34.7, 40.5, 47.5, 60.6, 61.1, 114.9, 121.9, 126.4, 126.8, 127.1, 127.7, 128.3, 128.4, 129.9, 130.0, 131.1, 132.3, 135.0, 136.28, 136.32, 149.4, 159.7, 162.9, 167.3, 170.9; HR-MS (ESI): m/z=471.2068, calcd. for C29H28FN2O3+ [M+H]+: 471.2078.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-(3-chlorophenyl)propanoate (4ak)
Yield: 28% (Table 2, entry 24); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.52; IR (film): νmax = 2979, 1701, 1598, 1474, 1429, 1368, 1297, 1200, 1096, 1030, 865, 767, 697 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.21 (d, J=7.1 Hz, 3H), 2.66–2.79 (m, 2H), 2.86–2.96 (m, 2H), 3.24 (dd, J=18.8, 10.1 Hz, 1H), 3.62–3.78 (m, 2H), 3.96 (d, J= 15.7 Hz, 1H), 4.10–4.33 (m, 3H), 7.01–7.08 (m, 3H), 7.10–7.18 (m, 5H), 7.33–7.38 (m, 2H), 7.42–7.47 (m, 1H), 7.50– 7.53 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 14.2, 29.1, 35.1, 40,6, 47.5, 60.7, 61.0, 121.3, 126.0, 126.4, 126.8, 126.9, 127.1, 127.7, 128.2, 128.3, 128.7, 129.3, 131.1, 132.3, 133.9, 135.0, 142.8, 150.0, 167.2, 170.9; HR-MS (ESI): m/z= 487.1772, calcd. for C29H28ClN2O3+ [M+H]+: 487.1783.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-(4-chlorophenyl)propanoate (4al)
Yield: 40% (Table 2, entry 25); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.50; IR (film) νmax = 2927, 2853, 1697, 1600, 1541, 1490, 1455, 1368, 1276, 1199, 1095, 1015, 910, 866, 804, 763, 740, 696, 678 cm−1; 1H NMR (300 MHz, CDCl3): δ=1.21 (t, J=7.1 Hz, 3H), 2.67–2.84 (m, 2H), 2.91–3.00 (m, 2H), 3.25 (dd, J=18.8, 10.1 Hz, 1H), 3.48–3.78 (m, 2H), 3.93 (d, J=15.8 Hz, 1H), 4.11–4.34 (m, 3H), 7.00–7.25 (m, 8H), 7.32–7.58 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 29.1, 35.0, 40.5, 47.5, 60.7, 61.1, 67.1, 119.5, 121.4, 126.4, 126.9, 127.1, 127.4, 127.7, 127.8, 128.3, 128.4, 130.3, 131.1, 131.2, 131.5, 132.3, 132.7, 135.0, 139.7, 149.7, 167.2, 171.0; HR-MS (ESI): m/z=487.1776, calcd. for C29H28ClN2O3+ [M+H]+: 487.1783.
(E)-Ethyl 2-[3-benzoyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-(4-bromophenyl)propanoate (4am)
Yield: 30% (Table 2, entry 26); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.48; IR (film): νmax = 2926, 2850, 1704, 1541, 1487, 1446, 1301, 1241, 1200, 1099, 1011, 909, 788, 762, 736, 696, 677 cm−1; 1H NMR (300 MHz, CDCl3): δ=1.20 (t, J=7.1 Hz, 3H), 2.53–3.00 (m, 4H), 3.13–3.29 (m, 1H), 3.57–3.77 (m, 2H), 3.90 (d, J=15.8 Hz, 1H), 4.00–4.33 (m, 3H), 7.00–7.24 (m, 6H), 7.30–7.56 (m, 7H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 29.1, 35.0, 40.5, 47.5, 60.7, 61.1, 119.5, 121.4, 126.4, 126.9, 127.1, 127.4, 127.7, 127.8, 128.3, 128.4, 130.3, 131.1, 131.2, 131.5, 132.3, 132.7, 135.0, 139.7, 149.7, 167.2, 171.0; HR-MS (ESI): m/z= 531.1254, calcd. for C29H28BrN2O3+ [M+H]+: 531.1278.
(E)-Ethyl 2-[3-benzoyl-7-methyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]butanoate (4bb)
Yield: 95% (Table 3, entry 11); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.52; IR (film): νmax = 3059, 2974, 2934, 1941, 1704, 1639, 1599, 1447, 1369, 1299, 1252, 1234, 1211, 1175, 1143, 1110, 1046, 1027, 935, 921, 866, 785, 758, 713, 696, 678, 648, 617, 545, 517 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.13 (t, J = 7.4 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.20 (s, 3H), 2.40–2.44 (m, 2H), 2.78–2.83 (m, 1H), 2.92–3.01 (m, 2H), 3.15 (dd, J=18.7, 10.0 Hz, 1H), 3.41–3.45 (m, 1H), 3.69 (dd, J=18.6, 8.5 Hz, 1H), 4.19–4.26 (m, 3H), 6.86 (s, 1H), 6.90–7.09 (m, 2H), 7.39–7.46 (m, 3H), 7.71–7.74 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 12.7, 14.3, 19.2, 23.8, 26.6, 39.9, 47.4, 60.3, 61.3, 124.7, 124.9, 126.2, 127.6, 128.0, 128.4, 130.9, 131.0, 135.1, 135.3, 135.8, 147.0, 167.4, 171.5; HR-MS (ESI): m/z=405.2138, calcd. for C25H29N2O3+ [M+ H]+: 405.2173.
(E)-Ethyl 2-[3-benzoyl-9-methyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]butanoate (4cb)
Yield: 97% (Table 3, entry 12); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.53; IR (film): νmax = 3055, 2975, 2933, 1895, 1765, 1679, 1638, 1600, 1581, 1505, 1463, 1446, 1429, 1365, 1299, 1276, 1239, 1214, 1195, 1175, 1142, 1107, 1063, 1028, 977, 921, 880, 866, 843, 785, 734, 711, 695, 677, 641, 617, 550, 517, 460 cm−1; 1H NMR (300 MHz, CDCl3): δ=1.13 (t, J=7.4 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H), 2.25 (s, 3H), 2.37–2.47 (m, 2H), 2.66–2.77 (m, 1H), 2.89–3.01 (m, 2H), 3.11 (dd, J=18.6, 9.9 Hz, 1H), 3.35–3.38 (m, 1H), 3.67 (dd, J=18.6, 8.5 Hz, 1H), 4.18–4.26 (m, 3H), 6.83 (s, 1H), 6.91–6.97 (m, 2H), 7.36–7.46 (m, 3H), 7.70–7.73 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 12.7, 14.3, 20.9, 23.7, 28.6, 40.0, 47.7, 60.3, 61.1, 124.5, 127.51, 127.58, 127.60, 128.0, 128.4, 129.1, 131.0, 135.1, 135.3, 135.8, 147.2, 167.4, 171.5; HR-MS (ESI): m/z=405.2164, calcd. for C25H29N2O3+ [M+H]+: 405.2173.
(E)-Ethyl 2-[3-benzoyl-8-bromo-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]butanoate (4db)
Yield: 87% (Table 3, entry 13); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.47; IR (film): νmax = 3058, 2974, 2934, 1891, 1704, 1638, 1599, 1580, 1466, 1446, 1425, 1369, 1299, 1252, 1211, 1175, 1143, 1110, 1046, 1027, 935, 921, 866, 784, 758, 713, 696, 678, 649, 617, 522 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.12 (t, J = 7.4 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 2.20 (s, 3H), 2.35–2.43 (m, 2H), 2.69–2.74 (m, 1H), 2.87–3.11 (m, 3H), 3.35–3.39 (m, 1H), 3.66 (dd, J= 18.6, 8.5 Hz, 1H), 4.15–4.25 (m, 3H), 6.87 (d, J=8.2 Hz, 1H), 7.21–7.26 (m, 2H), 7.37–7.47 (m, 3H),7.69–7.72 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 12.7, 14.2, 23.7, 28.8, 39.8, 47.2, 60.3, 60.8, 120.4, 124.8, 127.7, 128.4, 128.6, 129.4, 131.0, 131.1, 134.3, 134.6, 135.1, 146.6, 167.3, 171.4; HR-MS (ESI): m/z=469.1113, calcd. for C24H26BrN2O3+ [M+H]+: 469.1121.
(E)-Ethyl 2-[3-benzoyl-9-bromo-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]butanoate (4eb)
Yield: 96% (Table 3, entry 14); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.50; IR (film): νmax = 3057, 2975, 2934, 2850, 1891, 1704, 1680, 1597, 1579, 1486, 1464, 1446, 1427, 1412, 1365, 1330, 1299, 1268, 1254, 1240, 1217, 1189, 1177, 1142, 1107, 1077, 1063, 1027, 974, 924, 867, 800, 785, 769, 725, 710, 696, 677, 656, 639, 611, 533 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.12 (t, J = 7.4 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H), 2.35–2.44 (m, 2H), 2.68–2.73 (m, 1H), 2.90–2.97 (m, 2H), 3.10 (dd, J=18.6, 9.9 Hz, 1H), 3.35–3.39 (m, 1H), 3.65 (dd, J=18.6, 8.6 Hz, 1H), 4.16–4.26 (m, 3H), 6.92 (d, J=8.2 Hz, 1H), 7.14–7.24 (m, 2H), 7.39–7.41 (m, 3H), 7.69–7.72 (m, 2H); 13C NMR (75 MHz, CDCl3): δ=12.7, 14.3, 23.7, 28.6, 39.8, 47.4, 60.4, 60.7, 119.9, 124.8, 127.7, 128.4, 129.85, 129.88, 129.89, 131.1, 131.3, 135.1, 137.5, 146.5, 167.4, 171.4; HR-MS (ESI): m/z=469.1123, calcd. for C24H26BrN2O3+ [M+H]+: 469.1121.
(E)-Ethyl 2-[3-benzoyl-9-chloro-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]butanoate (4fd)
Yield: 95% (Table 3, entry 15); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.51; IR (film): νmax = 3057, 2975, 2934, 2850, 1891, 1704, 1681, 1640, 1600, 1579, 1489, 1464, 1446, 1427, 1365, 1299, 1268, 1254, 1239, 1216, 1192, 1176, 1142, 1107, 1063, 1027, 975, 867, 801, 785, 725, 711, 695, 677, 630, 539 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.12 (t, J = 7.4 Hz, 3H), 1.32 (t, J=7.1 Hz, 3H), 2.35–2.44 (m, 2H), 2.70–2.75 (m, 1H), 2.92–3.15 (m, 3H), 3.37–3.39 (m, 1H), 3.66 (dd, J=18.6, 8.6 Hz, 1H), 4.16–4.26 (m, 3H), 6.97–7.10 (m, 3H), 7.39–7.47 (m, 3H),7.69–7.72 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 12.7, 14.3, 23.7, 28.6, 39.8, 47.4, 60.4, 60.8, 124.9, 126.9, 127.0, 127.7, 128.4, 129.6, 130.8, 131.1, 132.0, 135.1, 137.1, 146.5, 167.4, 171.4; HR-MS (ESI): m/z= 425.1599, calcd. for C24H26ClN2O3+ [M+H]+: 425.1626.
(E)-Ethyl 2-[3-benzoyl-7-methyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-phenylpropanoate (4bf)
Yield: 40% (Table 3, entry 6); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.51; IR (film): νmax = 3060, 3026, 2926, 2852, 1705, 1674, 1600, 1494, 1469, 1446, 1369, 1299, 1236, 1210, 1140, 1093, 1052, 1029, 979, 921, 885, 866, 845, 812, 783, 699, 677, 552 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.21 (t, J = 7.1 Hz, 3H), 2.17 (s, 3H), 2.66–2.89 (m, 4H), 3.28 (dd, J=18.9, 10.1 Hz, 1H), 3.66–3.77 (m, 2H), 3.99 (d, J=15.8 Hz, 1H), 4.12–4.25 (m, 3H), 6.85–7.24 (m, 8H), 7.33–7.55 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 19.2, 26.6, 35.4, 40.4, 47.2, 60.6, 61.2, 122.1, 124.9, 125.8, 126.2, 127.6, 128.04, 128.08, 128.4, 128.6, 131.0, 134.9, 135.2, 135.9, 140.7, 149.3, 167.4, 170.8; HR-MS (ESI): m/z=467.2322, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
(E)-Ethyl 2-[3-benzoyl-9-methyl-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-phenylpropanoate (4cf)
Yield: 46% (Table 3, entry 7); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.53; IR (film): νmax = 3059, 3026, 2925, 2851, 1766, 1601, 1581, 1505, 1494, 1447, 1428, 1365, 1298, 1274, 1251, 1216, 1136, 1095, 1077, 1030, 975, 867, 814, 788, 734, 699, 678, 561, 465 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.21 (t, J = 7.1 Hz, 3H), 2.26 (s, 3H), 2.59–2.88 (m, 4H), 4.13–4.24 (m, 3H), 3.26 (dd, J=18.9, 10.1 Hz, 1H), 3.67–3.77 (m, 2H), 3.99 (d, J=15.7 Hz, 1H), 6.82 (s, 1H), 6.93 (d, J=1.0 Hz, 2H), 7.16–7.25 (m, 5H), 7.33–7.56 (m, 5H); 13C NMR (75 MHz, CDCl3): δ=14.1, 20.9, 28.6, 35.4, 40.5, 47.5, 60.5, 61.0, 121.9, 125.8, 127.51, 127.55, 127.64, 128.0, 128.3, 128.5, 128.6, 129.2, 130.9, 134.9, 135.2, 135.9, 140.7, 149.4, 167.4, 170.84; HR-MS (ESI): m/z=467.2326, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
(E)-Ethyl 2-[3-benzoyl-8-bromo-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-phenylpropanoate (4df)
Yield: 73% (Table 3, entry 8); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.46; IR (film): νmax = 3057, 3018, 2981, 2928, 2849, 1703, 1676, 1599, 1580, 1493, 1483, 1447, 1426, 1368, 1300, 1266, 1241, 1204, 1188, 1138, 1075, 1029, 998, 969, 908, 889, 866, 854, 839, 817, 781, 738, 702, 679, 650, 545 cm−1; 1H NMR (300 MHz, CDCl3): δ=1.21 (t, J=7.1 Hz, 3H), 2.60–2.73 (m, 2H), 2.83–2.87 (m, 2H), 3.21 (dd, J=18.8, 10.1 Hz, 1H), 3.63–3.75 (m, 2H), 3.98 (d, J=15.7 Hz, 1H), 4.12–4.22 (m, 3H), 6.88 (d, J= 8.2 Hz, 1H), 7.14–7.23 (m, 7H), 7.33–7.52 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 28.9, 35.4, 40.3, 46.9, 60.6, 60.7, 120.5, 122.2, 125.9, 127.7, 128.1, 128.4, 128.6, 128.7, 129.5, 131.08, 131.12, 134.15, 134.7, 135.0, 140.6, 148.9, 167.4, 170.7; HR-MS (ESI): m/z=531.1261, calcd. for C29H28BrN2O3+ [M+H]+: 531.1278.
(E)-Ethyl 2-[3-benzoyl-9-bromo-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-phenylpropanoate (4ef)
Yield: 92% (Table 3, entry 9); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.52; IR (film): νmax = 3059, 3026, 2977, 2930, 2849, 1705, 1677, 1599, 1578, 1485, 1446, 1426, 1365, 1298, 1270, 1240, 1201, 1131, 1096, 1077, 1030, 968, 917, 867, 810, 785, 736, 700, 678, 610, 558 cm−1; 1H NMR (300 MHz, CDCl3): δ=1.22 (t, J= 7.1 Hz, 3H), 2.58–2.88 (m, 4H), 3.24 (dd, J=18.8, 10.1 Hz, 1H), 3.64–3.74 (m, 2H), 3.99 (d, J=15.9 Hz, 1H), 4.13–4.23 (m, 3H), 6.90 (d, J=8.2 Hz, 1H), 7.14–7.25 (m, 7H), 7.33–7.53 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 14.2, 28.6, 35.4, 40.3, 47.1, 60.58, 60.65, 119.9, 122.3, 125.9, 127.6, 128.1, 128.3, 128.6, 129.9, 131.1, 131.4, 135.0, 137.3, 140.6, 148.7, 167.4, 170.7; HR-MS (ESI): m/z=531.1253, calcd. for C29H28BrN2O3+ [M+H]+: 531.1278.
(E)-Ethyl 2-[3-benzoyl-9-chloro-1,5,6,10b-tetrahydropyrazolo[5,1-a]isoquinolin-2(3H)-ylidene]-3-phenylpropanoate (4ff)
Yield: 80% (Table 3, entry 10); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.52; IR (film): νmax = 3060, 3027, 2929, 2852, 1706, 1681, 1601, 1578, 1489, 1447, 1426, 1366, 1296, 1269, 1240, 1201, 1130, 1094, 1030, 969, 932, 868, 839, 813, 785, 699, 678, 630, 563 cm−1; 1H NMR (300 MHz, CDCl3): δ=1.21 (t, J=7.1 Hz, 3H), 2.60–2.72 (m, 2H), 2.80–2.88 (m, 2H), 3.23 (dd, J=18.8, 10.1 Hz, 1H), 3.63–3.75 (m, 2H), 3.98 (d, J=15.8 Hz, 1H), 4.13–4.22 (m, 3H), 6.94–7.23 (m, 8H), 7.33–7.52 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 14.1, 28.6, 35.4, 40.3, 47.2, 60.6, 60.7, 122.3, 125.9, 126.95, 127.03, 127.6, 128.1, 128.4, 128.6, 129.6, 130.9, 131.1, 132.0, 135.0, 136.9, 140.6, 148.7, 167.4, 170.7; HR-MS (ESI): m/z=487.1766, calcd. for C29H28ClN2O3+ [M+H]+: 487.1783.
Ethyl 5-benzoyl-4-phenyl-1,4,5,7,8,12b-hexahydro[1,2]diazepino[7,1-a]isoquinoline-3-carboxylate (5af)
Yield: 90% (Table 2, entry 6); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.38; IR (film): νmax = 2929, 1708, 1649, 1541, 1491, 1454, 1368, 1311, 1240, 1058, 1028, 912, 744, 699 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.95 (t, J=7.1 Hz, 3H), 2.31–2.46 (m, 2H), 2.63–2.84 (m, 2H), 3.05–3.14 (m, 1H), 3.88–3.96 (m, 3H), 4.08–4.33 (m, 1H), 5.13 (dd, J=7.7, 4.9 Hz, 1H), 6.00 (s, 1H), 7.03–7.05 (m, 1H), 7.10–7.19 (m, 3H), 7.22–7.25 (m, 3H), 7.32–7.37 (m, 2H), 7.47–7.72 (m, 5H); 13C NMR (75 MHz, CDCl3): δ = 13.8, 30.6, 38.0, 49.1, 59.5, 60.7, 65.2, 125.9, 126.0, 126.06, 126.09, 127.7, 128.0, 128.4, 128.6, 128.7, 129.6, 133.9, 134.8, 136.9, 138.0, 138.2, 141.5, 165.9, 170.7; HR-MS (ESI): m/z=453.2166, calcd. for C29H29N2O3+ [M+H]+: 453.2173.
Ethyl 5-benzoyl-4-(o-tolyl)-1,4,5,7,8,12b-hexahydro[1,2]diazepino[7,1-a]isoquinoline-3-carboxylate (5ag)
Yield: 42% (Table 2, entry 7); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.33; IR (film): νmax = 2920, 1716, 1647, 1541, 1488, 1456, 1410, 1362, 1339, 1260, 735 cm−1; 1H NMR (300 MHz, CDCl3): δ = 1.00 (t, J = 7.1 Hz, 3H), 2.01 (s, 3H), 2.19–2.39 (m, 2H), 2.56–2.90 (m, 2H), 3.16 (dt, J=18.1, 5.2 Hz, 1H), 3.86–4.05 (m, 3H), 4.11–4.33 (m, 1H), 5.08 (dd, J=8.1, 5.0 Hz, 1H), 6.11 (s, 1H), 7.02–7.10 (m, 3H), 7.12–7.22 (m, 4H), 7.41–7.47 (m, 4H), 7.49–7.73 (m, 2H); 13C NMR (75 MHz, CDCl3): δ = 13.8, 19.3, 30.5, 38.7, 49.1, 59.3, 60.7, 62.4, 125.2, 125.9, 126.1, 126.3, 126.5, 127.8, 128.3, 128.6, 129.6, 130.0, 130.1, 134.7, 134.8, 135.4, 136.3, 136.6, 138.4, 141.7, 165.9, 170.6; HR-MS (ESI): m/z=467.2338, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
Ethyl 5-benzoyl-4-(m-tolyl)-1,4,5,7,8,12b-hexahydro[1,2]-diazepino[7,1-a]isoquinoline-3-carboxylate (5ah)
Yield: 55% (Table 2, entry 8); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.34; IR (film): νmax = 2930, 1714, 1651, 1491, 1446, 1368, 1313, 1243, 1157, 1096, 1059, 1038, 778, 734, 701, 677 cm−1; 1H NMR (300 MHz, CDCl3): δ = 0.98 (t, J=7.1 Hz, 3H), 2.31 (s, 3H), 2.44–2.49 (m, 2H), 2.67–2.85 (m, 2H),3.05–3.15 (m, 1H), 3.92–3.97 (m, 3H), 4.17–4.34 (m, 1H), 5.11–5.15 (m, 1H), 5.97 (s, 1H), 7.04–7.09 (m, 4H), 7.12–7.20 (m, 4H), 7.30–7.39 (m, 1H), δ 7.48–7.53 (m, 4H); 13C NMR (75 MHz, CDCl3): δ = 13.8, 21.4, 30.6, 38.0, 49.1, 59.5, 60.7, 65.2, 125.6, 125.9, 126.1, 127.8, 128.4, 128.6, 128.7, 129.1, 129.6, 133.9, 134.8, 137.0, 137.4, 137.9, 138.3, 141.3, 166.0, 170.7; HR-MS (ESI): m/z=467.2425, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
Ethyl 5-benzoyl-1-(p-tolyl)-1,4,5,7,8,12b-hexahydro[1,2]-diazepino[7,1-a]isoquinoline-2-carboxylate (5ai)
Yield: 71% (Table 2, entry 9); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.34; IR (film): νmax = 2927, 1714, 1650, 1541, 1509, 1491, 1370, 1311, 1240, 1096, 1025, 911, 855, 788, 732, 700, 674 cm−1; 1H NMR (300 MHz, CDCl3): δ = 0.98 (t, J = 7.1 Hz, 3H), 2.34 (s, 3H), 2.47 (d, J=13.7 Hz, 2H), 2.69–2.85 (m, 2H), 2.99–3.24 (m, 1H), 3.86–4.01 (m, 3H), 4.25 (d, J=45.9 Hz, 1H), 5.07–5.26 (m, 1H), 5.97 (s, 1H), 7.05–7.20 (m, 8H), 7.31–7.39 (m, 2H), 7.48–7.53 (m, 3H); 13C NMR (75 MHz, CDCl3): δ = 13.8, 21.1, 30.6, 38.1, 49.0, 59.5, 60.7, 64.9, 125.9, 126.0, 126.1, 128.4, 128.6, 128.7, 129.6, 134.1, 134.8, 135.0, 137.0, 137.3, 138.3, 141.1, 166.0, 170.7; HR-MS (ESI): m/z=467.2320, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
Ethyl 5-benzoyl-4-(4-fluorophenyl)-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-3-carboxylate (5aj)
Yield: 92 (Table 2, entry 10); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.34; IR (film): νmax = 2924, 2853, 1714, 1650, 1602, 1541, 1507, 1456, 1369, 1310, 1239, 1157, 1097, 1026, 911, 825, 735, 700, 670 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.98 (t, J=7.0 Hz, 3H), 2.39–2.51 (m, 2H), 2.66–2.84 (m, 2H), 3.06–3.15 (m, 1H), 3.90–3.98 (m, 3H), 4.15–4.33 (m, 1H), 5.11–5.16 (m, 1H), 5.96 (s, 1H), 6.94–7.07 (m, 4H), 7.13–7.23 (m, 5H), 7.31–7.39 (m, 1H), 7.47–7.60 (m, 3H); 13C NMR (75 MHz, CDCl3): δ = 13.9, 30.6, 37.8, 49.1, 59.6, 60.8, 64.5, 114.8, 115.1, 125.97, 126.03, 126.2, 128.7, 128.8, 129.8, 130.1, 130.2, 133.7, 134.0, 134.6, 136.8, 138.2, 141.5, 165.8, 170.6; HR-MS (ESI): m/z=471.2070, calcd. for C29H28FN2O3+ [M+H]+: 471.2078.
Ethyl 5-benzoyl-4-(3-chlorophenyl)-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-3-carboxylate (5ak)
Yield: 75% (Table 2, entry 11); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.36; IR (film): νmax = 3062, 2980, 1714, 1651, 1596, 1575, 1493, 1475, 1446, 1429, 1368, 1311, 1242, 1189, 1059, 1026, 787, 752, 701 cm−1; 1H NMR (300 MHz, CDCl3): δ=1.00 (t, J=7.1 Hz, 3H), 2.45–2.53 (m, 2H), 2.71–2.85 (m, 2H), 3.06–3.16 (m, 1H), 3.91–4.00 (m, 3H), 4.17–4.34 (m, 1H), 5.12–5.16 (m, 1H), 5.97 (m, 1H), 7.07–7.22 (m, 7H), 7.36–7.48 (m, 6H); 13C NMR (75 MHz, CDCl3): δ = 13.8, 30.5, 38.0, 49.2, 59.6, 60.8, 64.7, 126.0, 126.2, 126.7, 127.9, 128.5, 128.7, 128.8, 129.3, 129.8, 133.2, 133.8, 134.6, 136.7, 138.1, 140.2, 165.6, 170.7; HR-MS (ESI): m/z=487.1819, calcd. for C29H28ClN2O3+ [M+H]+: 487.1783.
Ethyl 5-benzoyl-4-(4-chlorophenyl)-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-3-carboxylate (5al)
Yield: 84% (Table 2, entry 12); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.36; IR (film): νmax = 2924, 2854, 1714, 1650, 1541, 1489, 1456, 1368, 1309, 1241, 1091, 1015, 912, 852, 748, 709, 670 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.99 (t, J=7.1 Hz, 3H), 2.43–2.52 (m, 2H), 2.68–2.84 (m, 2H), 3.05–3.15 (m, 1H), 3.89–3.98 (m, 3H), 4.16–4.33 (m, 1H), 5.11–5.15 (m, 1H), 5.95 (s, 1H), 7.05–7.19 (m, 6H), 7.24–7.25 (m, 1H), 7.27 (s, 1H), 7.33–7.36 (m, 1H), 7.47 (s, 4H); 13C NMR (75 MHz, CDCl3): δ = 13.9, 30.6, 37.8, 49.2, 59.6, 60.8, 64.6, 125.9, 126.0, 126.2, 128.2, 128.7, 128.8, 129.8, 133.5, 133.6, 134.6, 136.7, 138.1, 141.8, 165.7, 170.7; HR-MS (ESI): m/z=487.1775, calcd. for C29H28ClN2O3+ [M+H]+: 487.1783.
Ethyl 5-benzoyl-4-(4-bromophenyl)-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-3-carboxylate (5am)
Yield: 93% (Table 2, entry 13); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.33; IR (film): νmax = 2930, 1713, 1650, 1540, 1487, 1445, 1368, 1308, 1241, 1158, 1071, 910, 851, 803, 734, 704, 647, 503 cm−1; 1H NMR (300 MHz, CDCl3): δ=0.99 (t, J=7.1 Hz, 3H), 2.44–2.53 (m, 2H), 2.68–2.84 (m, 2H), 3.05–3.13 (m, 1H), 3.89–3.98 (m, 3H), 4.16–4.33 (m, 1H), 5.11–5.15 (m, 1H), 5.93 (s, 1H), 7.05–7.20 (m, 6H), 7.33–7.42 (m, 4H), 7.47 (s, 3H); 13C NMR (75 MHz, CDCl3): δ = 13.9, 30.6, 37.8, 49.2, 59.7, 60.8, 64.6, 121.8, 125.96, 126.03, 126.3, 128.7, 128.8, 129.8, 130.2, 131.2, 133.4, 134.6, 136.7, 137.3, 138.1, 141.8, 165.7, 170.7; HR-MS (ESI): m/z=531.1258, calcd. for C29H28BrN2O3+ [M+H]+: 531.1278.
Ethyl 5-benzoyl-9-methyl-4-phenyl-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-3-carboxylate (5bf)
Yield: 73% (Table 3, entry 1); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.36; IR (film): νmax = 3060, 3028, 2978, 2926, 2855, 1955, 1710, 1648, 1600, 1534, 1492, 1465, 1452, 1388, 1368, 1310, 1240, 1191, 1159, 1096, 1074, 1060, 1028, 1092, 977, 904, 875, 857, 844, 783, 735, 700, 674, 648, 625, 567, 505, 467 cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.56–7.34 (m, 5H), 7.32–7.11 (m, 5H), 7.09–7.00 (m, 3H), 5.98 (s, 1H), 5.17 (t, J=8.9 Hz, 1H), 4.29–4.15 (m, 1H), 3.94–3.87 (m, 3H), 3.14–3.04 (m, 1H), 2.84–2.74 (m, 1H), 2.46–2.44 (m, 3H), 2.19 (t, J=7.1 Hz, 3H), 0.95 (t, J= 8.9 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ = 170.8, 165.9, 141.4, 138.2, 137.0, 136.0, 133.8, 133.4, 129.7, 128.8, 128.4, 128.0, 127.7, 127.6, 126.0, 125.7, 123.8, 65.3, 60.6, 59.7, 49.0, 37.5, 27.6, 19.4, 13.8; HR-MS (ESI): m/z=467.2332, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
Ethyl 5-benzoyl-11-methyl-4-phenyl-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-3-carboxylate (5cf)
Yield: 68% (Table 3, entry 2); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.38; IR (film): νmax = 3058, 3028, 2979, 2927, 2866, 1891, 1710, 1649, 1601, 1578, 1536, 1504, 1493, 1452, 1393, 1368, 1311, 1240, 1186, 1158, 1097, 1075, 1039, 1059, 1027, 972, 960, 942, 909, 876, 844, 815, 736, 700, 677, 649, 678, 560, 536, 470, 457 cm−1; 1H NMR (300 MHz, CDCl3): δ = 7.57–7.49 (m, 5H), 7.38–7.27 (m, 5H), 6.99–6.96 (m, 3H), 6.01 (s, 1H), 5.12–5.08 (m, 1H), 4.31–4.17 (m, 1H), 3.96–3.88 (m, 3H), 3.13–3.03 (m, 1H), 2.85–2.77 (m, 1H), 2.75–2.77 (m, 1H), 2.41–2.39 (m, 2H), 2.34 (s, 3H), 0.97 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ = 170.7, 165.9, 141.6, 138.0, 137.0, 135.3, 133.8, 131.7, 129.6, 128.7, 128.4, 128.0, 127.6, 127.0, 126.6, 126.0, 65.2, 60.6, 59.5, 49.2, 38.0, 30.1, 21.1, 13.8; HR-MS (ESI): m/z=467.2324, calcd. for C30H31N2O3+ [M+H]+: 467.2329.
Ethyl 5-benzoyl-10-bromo-4-phenyl-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-3-carboxylate (5df)
Yield: 61 (Table 3, entry 3); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.32; IR (film): νmax = 2922, 2851, 1709, 1647, 1482, 1452, 1368, 1309, 1239, 1058, 1026, 851, 729, 699 cm−1; 1H NMR (300 MHz, CDCl3): δ=7.55–7.48 (m, 5H), 7.35–7.25 (m, 5H), 7.23–7.03 (m, 3H), 6.01 (s, 1H), 5.09 (s, 1H), 4.26–4.16 (m, 1H), 3.96–3.87 (m, 3H), 3.11–3.03 (m, 1H), 2.81–2.60 (m, 2H), 2.44–2.39 (m, 2H), 2.34 (s, 3H), 0.96 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ=170.8, 165.8, 140.9, 138.0, 137.2, 136.7, 134.0, 131.4, 129.8, 129.0, 128.8, 128.4, 128.1, 127.8, 126.0, 120.0, 65.2, 60.8, 59.3, 48.8, 37.5, 30.3, 13.8; HR-MS (ESI): m/z=531.1254, calcd. for C29H28BrN2O3+ [M+H]+: 531.1278.
Ethyl 5-benzoyl-11-bromo-4-phenyl-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-3-carboxylate (5ef)
Yield: 62% (Table 3, entry 4); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.38; IR (film): νmax = 3059, 3028, 2927, 2852, 1709, 1649, 1600, 1484, 1452, 1392, 1368, 1310, 1189, 1158, 1127, 1097, 1077, 1059, 1038, 1026, 973, 954, 912, 855, 843, 810, 735, 699, 678, 648, 531 cm−1; 1H NMR (300 MHz, CDCl3): δ=7.55–7.48 (m, 5H), 7.35–7.25 (m, 5H), 7.23–6.91 (m, 3H), 6.00 (s, 1H), 5.10–5.05 (m, 1H), 4.26–4.16 (m, 1H), 3.96–3.85 (m, 3H), 3.13–3.03 (m, 1H), 2.83–2.57 (m, 2H), 2.43–2.39 (m, 2H), 0.96 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ=170.8, 165.8, 140.8, 140.4, 138.1, 136.7, 134.0, 133.9, 130.4, 129.8, 129.3, 129.0, 128.8, 128.4, 128.1, 127.8, 126.1, 119.6, 65.3, 60.8, 59.3, 48.9, 37.3, 30.1, 13.8; HRMS (ESI): m/z=531.1255, calcd. for C29H28BrN2O3+ [M+H]+: 531.1278.
Ethyl 5-benzoyl-11-chloro-1-phenyl-1,4,5,7,8,12b-hexahydro[1,2]diazepino [7,1-a]isoquinoline-2-carboxylate (5ff)
Yield: 62% (Table 3, entry 5); yellow solid. TLC (EtOAc/petroleum ether 1/5): Rf = 0.38; IR (film): νmax = 3059, 3018, 2927, 2852, 1709, 1648, 1650, 1484, 1452, 1392, 1368, 1310, 1241, 1159, 1158, 1097, 1077, 1059, 1038, 1026, 973, 924, 912, 855, 843, 810, 735, 699, 678, 648, 531 cm−1; 1H NMR (300 MHz, CDCl3): δ=7.55–7.48 (m, 5H), 7.35–7.31 (m, 3H), 7.23–6.97 (m, 3H), 6.00 (s, 1H), 5.10–5.05 (m, 1H), 4.29–4.16 (m, 1H), 3.96–3.86 (m, 3H), 3.13–3.04 (m, 1H), 2.83–2.59 (m, 2H), 2.44–2.40 (m, 2H), 0.96 (t, J=7.1 Hz, 3H); 13C NMR (75 MHz, CDCl3): δ=170.8, 165.8, 140.8, 140.0, 138.0, 136.7, 134.0, 133.4, 131.6, 130.1, 129.8, 128.8, 128.4, 128.1, 127.8, 126.4, 126.1, 65.3, 60.8, 59.4, 49.0, 37.3, 30.0, 13.8; HR-MS (ESI): m/z=487.1763, calcd. for C29H28ClN2O3+ [M+H]+: 487.1783.
Supplementary Material
Acknowledgments
This study was supported by the National Scientific and Technology Supporting Program of China (2011BAE06B05-5), the National Natural Science Foundation of China (No. 21172253), the startup research funding from China Agricultural University, Chinese Universities Scientific Fund (Nos. 2011JS029 and 2011JS031), the Key Technologies R&D Program of China (No. 2012BAK25B03), and Nutriechem Company.
Footnotes
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100831.
Contributor Information
Jiangchun Zhong, Email: dr_zhongjiangchun@yahoo.com.cn.
Hongchao Guo, Email: hchguo@cau.edu.cn.
References
- 1.a) Liu CJ, Liu DY, Xiang L. Acta Pharm Sin. 2010;45:9–16. [PubMed] [Google Scholar]; b) Blay JY. Eur J Clin Med Oncol. 2010;2:1–8. [Google Scholar]; c) Vincenzi B, Napolitano A, Frezza AM, Schiavon G, Santini D, Tonini G. Pharmacogenomics. 2010;11:865–878. doi: 10.2217/pgs.10.69. [DOI] [PubMed] [Google Scholar]; d) Carter NJ, Keam SJ. Drugs. 2010;70:355–376. doi: 10.2165/11202860-000000000-00000. [DOI] [PubMed] [Google Scholar]
- 2.a) Scott JD, Williams RM. Chem Rev. 2002;102:1669–1730. doi: 10.1021/cr010212u. [DOI] [PubMed] [Google Scholar]; b) Chrzanowska M, Rozwadowska MD. Chem Rev. 2004;104:3341–3370. doi: 10.1021/cr030692k. [DOI] [PubMed] [Google Scholar]; c) Siengalewicz P, Rinner U, Mulzer J. Chem Soc Rev. 2008;37:2676–2690. doi: 10.1039/b804167a. [DOI] [PubMed] [Google Scholar]; d) Pulka K. Curr Opin Drug Discov Devel. 2010;13:669–684. [PubMed] [Google Scholar]
- 3.For reviews on phosphine-promoted cycloadditions, see: Lu X, Zhang C, Xu Z. Acc Chem Res. 2001;34:535–544. doi: 10.1021/ar000253x.Valentine DH, Hillhouse JH. Synthesis. 2003:317–334.Methot JL, Roush WR. Adv Synth Catal. 2004;346:1035–1050.Lu X, Du Y, Lu C. Pure Appl Chem. 2005;77:1985–1990.Nair V, Menon RS, Sreekanth AR, Abhilash N, Biju AT. Acc Chem Res. 2006;39:520–530. doi: 10.1021/ar0502026.Ye LW, Zhou J, Tang Y. Chem Soc Rev. 2008;37:1140–1152. doi: 10.1039/b717758e.Denmark SE, Beutner GL. Angew Chem. 2008;120:1584–1663.Angew Chem Int Ed. 2008;47:1560–1638. doi: 10.1002/anie.200604943.Kwong CKW, Fu MY, Lam CSL, Toy PH. Synthesis. 2008:2307–2317.Aroyan CE, Dermenci A, Miller SJ. Tetrahedron. 2009;65:4069–4084.Cowen BJ, Miller SJ. Chem Soc Rev. 2009;38:3102–3116. doi: 10.1039/b816700c.Marinetti A, Voituriez A. Synlett. 2010:174–194.Beata K. Cent Eur J Chem. 2010:1147–1171.
- 4.For examples of [3+2]annulations, see: Zhang C, Lu X. J Org Chem. 1995;60:2906–2908.Zhu G, Chen Z, Jiang Q, Xiao D, Cao P, Zhang X. J Am Chem Soc. 1997;119:3836–3837.Wilson JE, Fu GC. Angew Chem. 2006;118:1454–1457.Angew Chem Int Ed. 2006;45:1426–1429. doi: 10.1002/anie.200503312.Tang X, Zhang B, He Z, Gao R, He Z. Adv Synth Catal. 2007;349:2007–2017.Cowen BJ, Miller SJ. J Am Chem Soc. 2007;129:10988–10989. doi: 10.1021/ja0734243.Xia Y, Liang Y, Chen Y, Wang M, Jiao L, Huang F, Liu S, Li Y, Yu Z. J Am Chem Soc. 2007;129:3470–3471. doi: 10.1021/ja068215h.Fang YQ, Jacobsen EN. J Am Chem Soc. 2008;130:5660–5661. doi: 10.1021/ja801344w.Voituriez A, Panossian A, Fleury-Bregeot N, Retailleau P, Marinetti A. J Am Chem Soc. 2008;130:14030–14031. doi: 10.1021/ja806060a.Lu Z, Zheng S, Zhang X, Lu X. Org Lett. 2008;10:3267–3270. doi: 10.1021/ol8011452.Jones RA, Krische MJ. Org Lett. 2009;11:1849–1851. doi: 10.1021/ol900360h.Xu S, Zhou L, Ma R, Song H, He Z. Chem Eur J. 2009;15:8698–8702. doi: 10.1002/chem.200901276.Xiao H, Chai Z, Zheng C, Yang Y, Liu W, Zhang J, Zhao G. Angew Chem. 2010;122:4569–4572. doi: 10.1002/anie.201000446.Angew Chem Int Ed. 2010;49:4467–4470. doi: 10.1002/anie.201000446.Voituriez A, Pinto N, Neel M, Retailleau P, Marinetti A. Chem Eur J. 2010;16:12541–12544. doi: 10.1002/chem.201001791.Guan X, Wei Y, Shi M. Org Lett. 2010;12:5024–5027. doi: 10.1021/ol102191p.Zhang X, Cao S, Wei Y, Shi M. Org Lett. 2011;13:1142–1145. doi: 10.1021/ol1031798.Han X, Wang Y, Zhong F, Lu Y. J Am Chem Soc. 2011;133:1726–1729. doi: 10.1021/ja1106282.Han X, Wang S, Zhong F, Lu Y. Synthesis. 2011:1859–1864.Pinto N, Retailleau P, Voituriez A, Marinetti A. Chem Commun. 2011:1015–1017. doi: 10.1039/c0cc03164j.
- 5.For an example of [3+3]annulation, see: Guo H, Xu Q, Kwon O. J Am Chem Soc. 2009;131:6318–6319. doi: 10.1021/ja8097349.
- 6.For examples of [4+1]annulations, see: Meng X, Huang Y, Chen R. Org Lett. 2009;11:137–140. doi: 10.1021/ol802453c.Zhang Q, Yang L, Tong X. J Am Chem Soc. 2010;132:2550–2551. doi: 10.1021/ja100432m.
- 7.For examples of [4+2]annulations, see: Zhu XF, Lan J, Kwon O. J Am Chem Soc. 2003;125:4716–4717. doi: 10.1021/ja0344009.Wurz RP, Fu GC. J Am Chem Soc. 2005;127:12234–12235. doi: 10.1021/ja053277d.Zhu XF, Schaffner AP, Li RC, Kwon O. Org Lett. 2005;7:2977–2980. doi: 10.1021/ol050946j.Tran YS, Kwon O. J Am Chem Soc. 2007;129:12632–12633. doi: 10.1021/ja0752181.Castellano S, Fiji HDG, Kinderman SS, Watanabe M, de Leon P, Tamanoi F, Kwon O. J Am Chem Soc. 2007;129:5843–5845. doi: 10.1021/ja070274n.Meng X, Huang Y, Zhao H, Xie P, Ma J, Chen R. Org Lett. 2009;11:991–994. doi: 10.1021/ol802917d.Sun Y, Guan X, Shi M. Org Lett. 2010;12:5664–5667. doi: 10.1021/ol102461c.Tran YS, Martin TJ, Kwon O. Chem Asian J. 2011;6:2101–2106. doi: 10.1002/asia.201100190.Ma R, Xu S, Tang X, Wu G, He Z. Tetrahedron. 2011;67:1053–1061.
- 8.For an example of [4+3]annulation of allene, see: Kumar K, Kapoor R, Kapur A, Ishar MPS. Org Lett. 2000;2:2023–2025. doi: 10.1021/ol0000713.. For a phosphine-catalyzed [4+ 3]annulation of allylic carbonates with coumalate, see: Zheng S, Lu X. Org Lett. 2009;11:3978–3981. doi: 10.1021/ol901618h.
- 9.For an example of [8+2]annulation, see: Kumar K, Kapur A, Ishar MPS. Org Lett. 2000;2:787–789. doi: 10.1021/ol000007l.
- 10.For an example of [2+2+2]annulation, see: Zhu XF, Henry CE, Wang J, Dudding T, Kwon O. Org Lett. 2005;7:1387–1390. doi: 10.1021/ol050203y.
- 11.For other examples of phosphine-catalyzed annulations of allenes, see: Creech GS, Kwon O. Org Lett. 2008;10:429–432. doi: 10.1021/ol702462w.Xu S, Zhou L, Ma R, Song H, He Z. Org Lett. 2010;12:544–547. doi: 10.1021/ol902747c.
- 12.Na R, Jing C, Xu Q, Jiang H, Wu X, Shi J, Zhong J, Wang M, Benitez D, Tkatchouk E, Goddard WA, III, Guo H, Kwon O. J Am Chem Soc. 2011;133:13337–13348. doi: 10.1021/ja200231v. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.For recent examples of the cycloadditions of N,N′-azomethine imines, see: Shintani R, Fu GC. J Am Chem Soc. 2003;125:10778–10779. doi: 10.1021/ja036922u.SuQrez A, Downey CW, Fu GC. J Am Chem Soc. 2005;127:11244–11245. doi: 10.1021/ja052876h.Shintani R, Hayashi T. J Am Chem Soc. 2006;128:6330–6331. doi: 10.1021/ja061662c.Chen W, Yuan X, Li R, Du W, Wu Y, Ding L, Chen Y. Adv Synth Catal. 2006;348:1818–1822.Chan A, Scheidt KA. J Am Chem Soc. 2007;129:5334–5335. doi: 10.1021/ja0709167.Suga H, Funyu A, Kakehi A. Org Lett. 2007;9:97–100. doi: 10.1021/ol062675y.Shintani R, Murakami M, Hayashi T. J Am Chem Soc. 2007;129:12356–12357. doi: 10.1021/ja073997f.Chen W, Du W, Duan Y, Wu Y, Yang S, Chen Y. Angew Chem. 2007;119:7811–7814.Angew Chem Int Ed. 2007;46:7667–7670. doi: 10.1002/anie.200702618.Sibi MP, Rane D, Stanley LM, Soeta T. Org Lett. 2008;10:2971–2974. doi: 10.1021/ol800904t.Kato T, Fujinami S, Ukaji Y, Inomata K. Chem Lett. 2008;37:342–343.Shapiro ND, Shi Y, Toste FD. J Am Chem Soc. 2009;131:11654–11655. doi: 10.1021/ja903863b.Keller M, Sido ASS, Pale P, Sommer J. Chem Eur J. 2009;15:2810–2817. doi: 10.1002/chem.200802191.
- 14.For recent examples of the cycloadditions of C,N-azomethine imines, see: Perreault C, Goudreau SR, Zimmer LE, Charette AB. Org Lett. 2008;10:689–692. doi: 10.1021/ol702414e.Hashimoto T, Maeda Y, Omote M, Nakatsu H, Maruoka K. J Am Chem Soc. 2010;132:4076–4077. doi: 10.1021/ja100787a.Hashimoto T, Omote M, Maruoka K. Angew Chem. 2011;123:3551–3554. doi: 10.1002/anie.201100331.Angew Chem Int Ed. 2011;50:3489–3492. doi: 10.1002/anie.201100331.. For a CuI/chiral Brønsted acid-catalyzed alkynylation of C,N-cyclic azomethine imines, see: Hashimoto T, Omote M, Maruoka K. Angew Chem. 2011;123:9114–9117. doi: 10.1002/anie.201100331.Angew Chem Int Ed. 2011;50:8952–8955. doi: 10.1002/anie.201104017.
- 15.About direct [3+2]cycloaddition of allenes with various 1,3-dipoles in the absence of catalyst, for a review, see: Pinho e Melo TMVD. Curr Org Chem. 2009;13:1406–1431.
- 16.An unknown side-product in each case was observed in < 5% yield.
- 17.Crystallographic data for 4ef and 5df have been deposited with the Cambridge Crystallographic Data Centre under the numbers CCDC 838502 and CCDC 838503. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: (+44)-1223-336033.
- 18.a) Burk MJ, Feaster JE. J Am Chem Soc. 1992;114:6266–6267. [Google Scholar]; b) Burk MJ, Martinez JP, Feaster JE, Cosford N. Tetrahedron. 1994;50:4399–4428. [Google Scholar]; c) Kobayashi S, Shimizu H, Yamashita Y, Ishitani H, Kobayashi J. J Am Chem Soc. 2002;124:13678–13679. doi: 10.1021/ja027681d. [DOI] [PubMed] [Google Scholar]; d) Yamashita Y, Kobayashi S. J Am Chem Soc. 2004;126:11279–11282. doi: 10.1021/ja049498l. [DOI] [PubMed] [Google Scholar]; e) Shirakawa S, Lombardi PJ, Leighton JL. J Am Chem Soc. 2005;127:9974–9975. doi: 10.1021/ja052307+. [DOI] [PubMed] [Google Scholar]
- 19.Reisman SE, Doyle AG, Jacobsen EN. J Am Chem Soc. 2008;130:7198–7199. doi: 10.1021/ja801514m. [DOI] [PMC free article] [PubMed] [Google Scholar]
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