Thermal [3+2] Cycloaddition of Aromatic Azomethine Imines with Allenoates

Abstract

The thermal [3+2] cycloadditions of two classes of aromatic azomethine imines with allenoates have been investigated. The reactions are operationally simple and proceed smoothly under mild reaction conditions to provide a variety of dinitrogen-fused heterocycles in moderate to excellent yields.

Key words

cycloaddition - azomethine imine - allenoate - quinoline - isoquinoline

Quinoline, isoquinoline and structurally related heterocycles occur widely in nature and some have a broad range of clinical applications, exhibiting a wide range of biological activities such as antitumor, anti-HIV, antibiotic, antifungal, antivirus, anti-inflammatory, anticoagulation, and bronchodilation, and can also act on the central nervous system.[ ¹ ] For example, Ecteinascidin 743 (Yondelis, trabectedin; Figure [1]) is a new antitumor agent of marine origin discovered in the Caribbean tunicate Ecteinascidia turbinate for the treatment of soft tissue sarcoma and ovarian cancer.[ ² ] Phase II trials with Yondelis are also being carried out for breast cancer, lung cancer, prostate cancer, and for paediatric tumors. Higenamine[ ³ ] and RESPIR 4-95[ ⁴ ] (Figure [1]) display anticoagulation and bronchodilation activities, respectively. Compounds I (Figure [1]) are potent nonnucleoside, allosteric inhibitors of reverse transcriptase, and could interact with retroviral targets relevant to anti-HIV therapy.[ ⁵ ] The tetrahydroquinoline derivative II shows activity against antibacterial targets such as DNA gyrase.[ ⁶ ] Accordingly, the synthesis of quinoline and isoquinoline derivatives has attracted much attention.[ ⁷ ] However, although many synthetic methods have been developed,[ ⁷ ] new procedures for their synthesis would still be highly desirable.

Azomethine imines have emerged as a versatile 1,3-dipole for various thermal, metal-catalyzed, and organocatalytic 1,3-dipolar cycloaddition reactions and have been extensively applied in organic synthesis because of their easy accessibility, stability and the potential applications of the corresponding cycloadducts.[8] [9] The range of azomethine imines available for the cycloaddition reactions has been expanded to include various imines such as 3-oxopyrazolidin-1-ium-2-ide derivatives and benzoyl(3,4-dihydroisoquinolin-2-ium-2-yl)amides, but research on aromatic azomethine imines is somewhat limited.[ ^9z,10 ] Recently, we successfully developed [3+2], [3+3], [4+3], and [3+2+3] annulation reactions of azomethine imines with allenoates, affording facile access to dinitrogen-fused bicyclic or tricyclic heterocycles,[ ¹¹ ] which are key units in or building blocks of many pharmaceuticals, agrochemicals, biologically active compounds, and other useful chemicals.[ ¹² ] As part of our continuing efforts to develop the annulation reaction of azomethine imines,[ ¹¹ ] we recently investigated the reactions of aromatic azo­methine imines with allenoates. Herein, we present our results on the thermal [3+2] cycloaddition of aromatic azomethine imines with allenoates to furnish functionalized dinitrogen-fused tricyclic heterocycles.

Figure 1 Pharmaceutically active quinoline and isoquinoline-related derivatives

The azomethine imines 1, 8 and 13 were easily prepared according to reported procedures.[ ¹³ ] In initial attempts, azomethine imine 1 was treated with the allenoate 2a in dichloromethane at room temperature for 96 hours (Scheme [1]). The reaction worked sluggishly, and two new products were isolated in total 20% yield. When the reaction was carried out in toluene at room temperature for 96 hours, the same two products were obtained in poor yield (5%) due to the poor solubility of azomethine imine 1 in toluene. To increase the yield, the reaction was carried out in refluxing toluene. Under these conditions the azo­methine imine was completely converted in 72 hours to give the product in 70% yield. However, several side-products were observed in small amounts. Decreasing the reaction temperature to 90 °C resulted in a clean reaction and improved yield (89%). The two products could be separated by silica gel chromatography, and were determined to be [3+2] cycloaddition products 3a and 4a (Scheme [1]), on the basis of 2D NMR spectroscopic and X-ray crystallographic[ ¹⁴ ] analyses (Figure [2]). In principle, since both active double bonds in allenoate could undergo the cycloaddition reaction with azomethine imine, three kinds of cycloadducts could be produced in the reaction, but the reaction was highly regioselective and produced the 2-exo methylene isomer as the sole regioisomer, which possessed two chiral carbons (Scheme [1]). It is noteworthy that an interesting quaternary carbon center was incorporated into the molecular skeleton of the products 3a and 4a.

Scheme 1 The thermal cycloaddition of azomethine imine 1 with ethyl α-substituted allenoate 2a

Figure 2 The X-ray crystal structure of 4a

Table 1 Thermal Cycloaddition of Azomethine Imine 1 with α-Substituted Allenoates 2 ^a

Entry	R	Product	Yield (%)b	Ratio 3/4 c
1	Ph (2a)	3a + 4a	89	53:47
2	2-MeC6H4 (2b)	3b + 4b	96	41:59
3	3-MeC6H4 (2c)	3c + 4c	81	52:48
4	4-MeC6H4 (2d)	3d + 4d	79	57:43
5	2-FC6H4 (2e)	3e + 4e	94	49:51
6	3-FC6H4 (2f)	3f + 4f	86	57:43
7	4-FC6H4 (2g)	3g + 4g	82	52:48
8	2-ClC6H4 (2h)	3h + 4h	91	40:60
9	3-ClC6H4 (2i)	3i + 4i	68	40:60
10	4-ClC6H4 (2j)	3j + 4j	65	60:40
11	2-BrC6H4 (2k)	3k + 4k	73	45:55
12	3-BrC6H4 (2l)	3l + 4l	70	53:47
13	CO2Et (2m)	3m + 4m	86	74:26d

^a 1.2 equivalent of allenoate was used.

^b Isolated yields.

^c Based on isolated yield unless otherwise stated.

^d Based on integration of signals in the ¹H NMR spectrum.

With the optimal reaction conditions in hand (toluene, 90 °C), azomethine imine 1 was treated with various substituted allenoates 2 in toluene for 72 hours, giving the functionalized dinitrogen-fused tricyclic heterocycles 3 and 4 in moderate to excellent yields, albeit with poor dia­stereoselectivity (Table 1, entries 1–13). Although poor diastereoselectivities were obtained, both diastereomers could be separated, providing diverse heterocycles for medicinal chemistry. The allenoates with electron-withdrawing substituents in the aryl group worked as well as those allenoates with electron-donating substituents in the aryl group under otherwise identical conditions (entries 1–12), and the derivatives of ethyl 1-benzoyl-2-methyl­ene-1,2,3,3a-tetrahydropyrazolo[1,5-a]quinoline-3-carbox­ylate could be obtained in 65–96% yield. The highest yield (96%) was achieved in the cycloaddition of β′-2-MeC₆H₄ substituted allenoate (entry 2). Although the R substituent in allenoate is some distance away from the active double bond, it seems that the position of R relative to the β′-position of allenoate has an influence on the yield. In general, in comparison with allenoates with meta- and para-substituents in the aryl group, allenoates with ortho-substituents in the aryl group underwent the reaction in higher yields (entries 2, 5, 8, and 11). The β′-ethoxycarbonyl­ allenoate was active and smoothly participated in the cycloaddition to give the expected cycloadduct in 86% yield (entry 13), and ethyl buta-2,3-dienoate (5a) also worked efficiently to give the cycloadducts in 85% yield (Scheme [2]). Unfortunately, the reaction with γ-substituted allenoate 5b was more sluggish and afforded the cycloadduct in moderate yield (Scheme [2]).

Scheme 2 Thermal cycloaddition of azomethine imine 1 with ethyl buta-2,3-dienoate (5a) and γ-substituted allenoate (5b)

Table 2 Thermal Cycloaddition of Azomethine Imine 8 with α-Substituted Allenoates 2 ^a

Entry	R	Product	Yield (%)b	Ratio 9/10 c
1	Ph (2a)	9a + 10a	71	41:59
2	2-MeC6H4 (2b)	9b + 10b	50	72:28d
3	3-MeC6H4 (2c)	9c + 10c	75	40:60d
4	2-FC6H4 (2e)	9e + 10e	98	52:48
5	3-FC6H4 (2f)	9f + 10f	61	23:77
6	4-FC6H4 (2g)	9g + 10g	71	32:68
7	2-ClC6H4 (2h)	9h + 10h	72	51:49
8	3-ClC6H4 (2i)	9i + 10i	66	35:65
9	3-BrC6H4 (2l)	9l + 10l	76	41:59
10	CO2Et (2m)	9m + 10m	86	37:63

^a 1.2 equivalent of allenoate was used.

^b Isolated yield.

^c Based on isolated yield unless otherwise stated.

^d Based on integration of signals in the ¹H NMR spectrum.

Having investigated the reactions of aromatic azomethine imine 1, based on the dihydroquinoline structure, with allenoates, we then explored the reaction of aromatic azomethine imine 8, based on dihydroisoquinoline structure, with allenoates (Table 2). We were pleased to find that imine 8 was also active. A wide range of aryl groups with electron-donating or withdrawing substituents at the β′-position of the allenoate could be tolerated in the cycloaddition. The reactions were carried out in toluene at 90 °C for 72 hours to afford derivatives of ethyl 3-benzoyl-2-methylene-1,2,3,10b-tetrahydropyrazolo[5,1-a]isoquinoline-1-carboxylate in 50–98% yields with moderate diastereoselectivities (entries 1–10). Fortunately, most diastereomeric mixtures could be separated by using flash column chromatography. However, the diastereomeric mixtures obtained from the reaction of imine 8 with either allenoate 2b or 2c could not be separated by flash column chromatography, and the diastereomeric ratios were determined by NMR spectroscopic analysis. In contrast to reactions with azomethine imine 1, the influence of the position of the R substituent relative to the β′-position of the allenoate on the yields were not clear (entries 2, 3 vs 4–8). Ethyl buta-2,3-dienoate (5a) also smoothly underwent the cycloaddition reactions, affording the corresponding cycloadduct in good yield (Scheme [3]). Azomethine imine 13, which is an analogue of 8, underwent the reaction to produce the desired product in 68% yield with a diastereomeric ratio of around 2:1 (Scheme [4]).

Scheme 3 Thermal cycloaddition of azomethine imine 8 with ethyl buta-2,3-dienoate (5a)

Scheme 4 Thermal cycloaddition of azomethine imine 13 with ethyl 2-benzylbuta-2,3-dienoate (2a)

In summary, thermal [3+2] cycloaddition reactions of aromatic­ azomethine imines with allenoates have been developed; the reactions were performed in toluene at 90 °C to give the functionalized dinitrogen-fused tricyclic heterocycles, which are pharmaceutically important compounds. The desired products were obtained in moderate to excellent yields. The reaction is operationally simple and works efficiently, thus it is a potentially useful protocol for the synthesis of biologically active molecules.

Unless otherwise stated, all reagents were purchased from commercial suppliers and used without further purification. Organic solutions were concentrated under reduced pressure using a rotary evaporator or oil pump. Reactions were monitored by 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 with Qingdao Haiyang flash silica gel (200–300 mesh). Infrared spectra were recorded with a Bruker Optics TENSOR 27 instrument. ¹H and ¹³C NMR spectra were recorded with a Bruker-300 spectrometer. Accurate mass measurements were performed with an Agilent instrument using the ESI-MS technique. X-ray crystallographic data were collected with a Bruker SMART CCD-based diffractometer equipped with a low-temperature apparatus operated at 100 K.

[3+2] Annulation of Azomethine Imines with Allenoates; General Procedure

A mixture of azomethine imine (0.125 mmol) and allenoate (0.15 mmol) in toluene (5 mL) was stirred at 90 °C for 72 h and then concentrated. The residue was purified by flash column chromatography (EtOAc–hexane) to afford the corresponding product. Some annulation products (3m and 4m in Table 1; 9b and 10b, 9c and 10c in Table 2) were obtained as diastereomeric mixtures that could not be separated by flash silica gel column chromatography; in these cases the NMR spectra, the IR data, and HRMS data were collected for the diastereomeric mixture. Melting points are reported for crystalline solids but were not measured for amorphous solids.

Compound 3a

Yield: 26.7 mg (47%); white crystalline solid; mp 132.6–134.5 °C.

IR (film): 2979, 1722, 1666, 1599, 1484, 1454, 1339, 1292, 1261, 1222, 1187, 1095, 1079, 1043, 1009, 861, 773, 756, 738, 699, 653, 628 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.39–7.26 (m, 8 H), 7.20–7.18 (m, 2 H), 7.00–6.90 (m, 1 H), 6.78–6.70 (m, 1 H), 6.68–6.62 (m, 2 H), 6.32 (d, J = 9.8 Hz, 1 H), 6.06 (d, J = 1.4 Hz, 1 H), 5.42–5.40 (m, 1 H), 5.01 (d, J = 1.5 Hz, 1 H), 4.45–4.43 (m, 1 H), 3.88–3.83 (m, 1 H), 3.57–3.35 (m, 2 H), 3.24 (d, J = 14.3 Hz, 1 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.3, 169.7, 143.8, 143.7, 135.8, 134.6, 130.8, 130.6, 129.5, 128.5, 127.7, 127.6, 127.40, 127.36, 126.8, 121.2, 120.9, 118.7, 111.8, 100.6, 64.6, 62.6, 61.3, 40.3, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₇N₂O₃ ⁺: 451.2016; found: 451.2017.

Compound 3b

Yield: 22.83 mg (39%); white crystalline solid; mp 164.2–165.6 °C.

IR (film): 3122, 3031, 2963, 2934, 1720, 1673, 1645, 1599, 1578, 1485, 1456, 1447, 1403, 1368, 1335, 1294, 1263, 1233, 1217, 1191, 1179, 1159, 1109, 1088, 1074, 1018, 956, 931, 914, 883, 863, 835, 795, 779, 758, 726, 702, 661, 631, 601, 562, 531, 520, 462 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.55–7.43 (m, 1 H), 7.36–6.97 (m, 9 H), 6.79–6.77 (m, 1 H), 6.76–6.58 (m, 2 H), 6.33 (d, J = 10.0 Hz, 1 H), 6.05 (d, J = 1.4 Hz, 1 H), 5.56–5.53 (m, 1 H), 5.03 (d, J = 1.5 Hz, 1 H), 4.29–4.27 (m, 1 H), 3.91–3.86 (m, 1 H), 3.68 (d, J = 14.7 Hz, 1 H), 3.49–3.46 (m, 1 H), 3.22 (d, J = 14.7 Hz, 1 H), 2.39 (s, 3 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.6, 169.6, 144.1, 143.8, 137.4, 134.6, 134.3, 130.54, 130.51, 130.3, 129.6, 127.7, 127.6, 127.3, 127.2, 126.8, 126.4, 121.2, 120.9, 119.2, 111.8, 101.2, 65.2, 62.7, 61.3, 35.9, 20.5, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃ ⁺: 465.2173; found: 465.2184.

Compound 3c

Yield: 24.2 mg (42%); white solid.

IR (film): 3025, 2978, 2924, 1727, 1671, 1647, 1600, 1578, 1485, 1455, 1446, 1403, 1368, 1344, 1294, 1262, 1224, 1188, 1160, 1096, 1049, 1026, 1016, 862, 794, 785, 771, 751 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.37–7.26 (m, 3 H), 7.19–7.13 (m, 5 H), 7.12–6.93 (m, 2 H), 6.78–6.75 (m, 1 H), 6.74–6.57 (m, 2 H), 6.32 (d, J = 10.0 Hz, 1 H), 6.03 (d, J = 11.9 Hz, 1 H), 5.45–5.42 (m, 1 H), 5.03 (d, J = 1.5 Hz, 1 H), 4.45–4.43 (m, 1 H), 3.89–3.85 (m, 1 H), 3.56–3.35 (m, 2 H), 3.21 (d, J = 14.3 Hz, 1 H), 2.30 (s, 3 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.3, 169.7, 143.8, 138.2, 135.7, 134.7, 131.3, 130.5, 129.5, 128.4, 128.1, 127.8, 127.7, 127.6, 127.3, 126.7, 121.2, 120.8, 118.8, 111.8, 100.5, 64.5, 62.5, 61.3, 40.2, 21.3, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃ ⁺: 465.2173; found: 465.2174.

Compound 3d

Yield: 26 mg (45%); white crystalline solid; mp 163.4–165.4 °C.

IR (film): 3064, 3029, 2960, 2923, 1721, 1671, 1645, 1601, 1516, 1484, 1448, 1405, 1374, 1348, 1293, 1263, 1228, 1187, 1112, 1093, 1048, 1025, 1009, 874, 790, 772, 753, 694 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.39–7.15 (m, 7 H), 7.10 (d, J = 7.9 Hz, 2 H), 7.00 (m, 1 H), 6.78–6.76 (m, 1 H), 6.67–6.63 (m, 2 H), 6.31 (d, J = 10.0 Hz, 1 H), 6.13–5.95 (m, 1 H), 5.42–5.39 (m, 1 H), 5.01 (d, J = 4.2 Hz, 1 H), 4.46–4.45 (m, 1 H), 3.88–3.82 (m, 1 H), 3.59–3.34 (m, 2 H), 3.20 (d, J = 14.2 Hz, 1 H), 2.30 (s, 3 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.3, 169.7, 143.8, 143.8, 136.9, 134.7, 132.6, 130.62, 130.57, 129.5, 129.1, 127.7, 127.6, 127.4, 126.7, 121.2, 120.8, 118.8, 111.8, 100.4, 64.6, 62.6, 61.2, 39.9, 21.0, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃ ⁺: 465.2173; found: 465.2165.

Compound 3e

Yield: 27.3 mg (46%); white crystalline solid; mp 156.8–158.6 °C.

IR (film): 3070, 3029, 2980, 2936, 2902, 1726, 1674, 1644, 1601, 1484, 1453, 1401, 1351, 1315, 1291, 1263, 1227, 1186, 1176, 1168, 1152, 1110, 1092, 1046, 1020, 1006, 875, 793, 773, 753, 736, 697, 658, 527 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.48–7.46 (m, 1 H), 7.36–7.14 (m, 6 H), 7.14–6.94 (m, 3 H), 6.79–6.77 (m, 1 H), 6.68–6.62 (m, 2 H), 6.34 (d, J = 10.0 Hz, 1 H), 6.07 (d, J = 1.1 Hz, 1 H), 5.62–5.59 (m, 1 H), 5.09 (d, J = 1.5 Hz, 1 H), 4.35 (d, J = 4.9 Hz, 1 H), 3.90–3.85 (m, 1 H), 3.77 (d, J = 14.3 Hz, 1 H), 3.46–3.41 (m, 1 H), 3.03–3.01 (m, 1 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.2, 169.7, 161.7 (d, J = 244.3 Hz), 143.8, 143.5, 134.6, 132.7 (d, J = 3.7 Hz), 130.6, 129.5, 129.2 (d, J = 8.3 Hz), 127.71, 127.66, 127.2, 126.8, 124.4 (d, J = 3.5 Hz), 122.7 (d, J = 14.5 Hz), 121.2, 120.9, 119.0, 115.1 (d, J = 23.0 Hz), 111.7, 100.3, 64.5, 62.5, 61.4, 31.7, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1929.

Compound 3f

Yield: 28.8 mg (49%); white solid.

IR (film): 3065, 2964, 2927, 1726, 1671, 1646, 1600, 1577, 1485, 1471, 1455, 1446, 1401, 1367, 1345, 1310, 1292, 1261, 1225, 1187, 1092, 1027, 928, 876, 795, 757, 732, 699, 664, 655, 633, 527, 488, 463 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.64–7.50 (m, 2 H), 7.35–7.14 (m, 6 H), 7.10–7.09 (m, 1 H), 7.05–6.94 (m, 1 H), 6.79–6.77 (m, 1 H), 6.68–6.62 (m, 2 H), 6.31 (d, J = 10.0 Hz, 1 H), 6.09 (d, J = 1.3 Hz, 1 H), 5.73–5.70 (m, 1 H), 5.12 (d, J = 1.5 Hz, 1 H), 4.39–4.38 (m, 1 H), 4.04 (d, J = 14.5 Hz, 1 H), 3.93–3.70 (m, 1 H), 3.51–3.48 (m, 1 H), 3.26 (d, J = 14.6 Hz, 1 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.2, 169.5, 144.1, 143.8, 135.5, 134.5, 132.9, 132.1, 130.6, 129.5, 129.0, 127.8, 127.7, 127.5, 127.2, 126.8, 121.3, 120.9, 119.7, 111.7, 101.0, 65.1, 62.1, 61.4, 38.8, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1914.

Compound 3g

Yield: 25.3 mg (43%); white crystalline solid; mp 134.0–135.5 °C.

IR (film): 2963, 2925, 1727, 1669, 1601, 1578, 1510, 1485, 1455, 1446, 1403, 1368, 1346, 1261, 1222, 1188, 1160, 1103, 1050, 1017, 862, 839, 828, 794, 751 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.47–7.38 (m, 2 H), 7.38–7.28 (m, 3 H), 7.28–7.16 (m, 2 H), 7.08–6.92 (m, 3 H), 6.86–6.59 (m, 3 H), 6.33 (d, J = 10.0 Hz, 1 H), 6.04 (d, J = 1.4 Hz, 1 H), 5.40–5.38 (m, 1 H), 4.95 (d, J = 1.5 Hz, 1 H), 4.41–4.40 (m, 1 H), 3.88–3.85 (m, 1 H), 3.54–3.35 (m, 2 H), 3.21 (d, J = 14.3 Hz, 1 H), 0.59 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.1, 169.6, 162.2 (d, J = 246.3 Hz), 143.7, 143.6, 134.4, 132.3 (d, J = 7.9 Hz), 131.5 (d, J = 3.3 Hz), 130.8, 129.6, 127.8, 127.6, 126.8, 121.2, 121.0, 118.6, 115.3 (d, J = 21.0 Hz), 111.9, 101.0, 64.6, 63.1, 61.3, 39.7, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1915.

Compound 3h

Yield: 22.1 mg (36%); white crystalline solid; mp 185.7–187.1 °C.

IR (film): 3071, 3030, 2964, 2928, 2899, 1725, 1670, 1643, 1601, 1483, 1473, 1447, 1401, 1373, 1351, 1311, 1291, 1263, 1225, 1186, 1155, 1110, 1094, 1081, 1046, 1018, 877, 827, 793, 775, 757, 733, 695, 657, 631, 463 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.63–7.61 (m, 1 H), 7.48–7.38 (m, 1 H), 7.35–7.24 (m, 1 H), 7.24–7.14 (m, 6 H), 7.07–6.94 (m, 1 H), 6.86–6.56 (m, 3 H), 6.32 (d, J = 10.0 Hz, 1 H), 6.09 (d, J = 1.2 Hz, 1 H), 5.70–5.68 (m, 1 H), 5.13 (d, J = 1.5 Hz, 1 H), 4.34–4.32 (m, 1 H), 4.03 (d, J = 14.5 Hz, 1 H), 3.92–3.89 (m, 1 H), 3.50–3.47 (m, 1 H), 3.18 (d, J = 14.5 Hz, 1 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.2, 169.6, 143.9, 143.8, 135.8, 134.5, 133.6, 132.2, 130.5, 129.5, 129.4, 128.8, 127.7, 127.5, 127.2, 127.1, 126.7, 121.2, 120.9, 119.4, 111.7, 100.9, 65.0, 62.0, 61.4, 35.9, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1621.

Compound 3i

Yield: 16.2 mg (27%); white solid.

IR (film): 3058, 3024, 2978, 2964, 2933, 2902, 1726, 1669, 1599, 1575, 1485, 1455, 1446, 1402, 1368, 1344, 1312, 1295, 1262, 1225, 1188, 1095, 1049, 1017, 883, 863, 786, 751, 725, 695, 671, 662, 650, 638, 629, 617, 605 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.48–7.40 (m, 2 H), 7.40–7.17 (m, 7 H), 7.08–6.95 (m, 1 H), 6.81–6.79 (m, 1 H), 6.70–6.66 (m, 2 H), 6.35 (d, J = 10.0 Hz, 1 H), 6.03 (d, J = 1.5 Hz, 1 H), 5.41–5.38 (m, 1 H), 4.96 (d, J = 1.6 Hz, 1 H), 4.42–4.40 (m, 1 H), 3.89–3.86 (m, 1 H), 3.57–3.34 (m, 2 H), 3.21 (d, J = 14.2 Hz, 1 H), 0.61 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.0, 169.6, 143.7, 143.5, 137.9, 134.4, 134.3, 130.85, 130.79, 129.7, 129.6, 128.9, 127.9, 127.8, 127.6, 126.8, 121.2, 121.0, 118.5, 111.9, 101.1, 64.4, 63.2, 61.4, 40.2, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1624.

Compound 3j

Yield: 23.5 mg (39%); white crystalline solid; mp 155.9–157.2 °C.

IR (film): 2980, 2347, 1726, 1670, 1600, 1578, 1486, 1455, 1446, 1403, 1368, 1344, 1294, 1261, 1224, 1183, 1094, 1046, 1016, 909, 866, 840, 753, 697, 650, 528, 464 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.49–7.39 (m, 2 H), 7.39–7.18 (m, 7 H), 7.09–6.96 (m, 1 H), 6.80–6.77 (m, 1 H), 6.76–6.63 (m, 2 H), 6.34 (d, J = 10.0 Hz, 1 H), 6.04 (d, J = 1.5 Hz, 1 H), 5.40–5.38 (m, 1 H), 4.95 (d, J = 1.5 Hz, 1 H), 4.39–4.38 (m, 1 H), 3.88–3.85 (m, 1 H), 3.52–3.42 (m, 1 H), 3.38 (d, J = 14.2 Hz, 1 H), 3.21 (d, J = 14.2 Hz, 1 H), 0.59 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.0, 169.7, 143.7, 143.5, 134.33, 134.29, 133.4, 132.2, 130.8, 129.6, 128.6, 127.85, 127.81, 127.6, 126.8, 121.2, 121.0, 118.5, 111.9, 101.2, 64.5, 63.2, 61.4, 39.9, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1605.

Compound 3k

Yield: 21.72 mg (33%); white crystalline solid; mp 192.4–193.9 °C.

IR (film): 3064, 2984, 2936, 2902, 1727, 1673, 1645, 1600, 1578, 1485, 1471, 1455, 1446, 1401, 1368, 1345, 1310, 1292, 1261, 1224, 1187, 1110, 1090, 1044, 1027, 1010, 929, 909, 866, 827, 756, 732, 698, 655, 634 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.64–7.50 (m, 2 H), 7.34–7.15 (m, 6 H), 7.10–7.05 (m, 1 H), 7.01–7.00 (m, 1 H), 6.79–6.70 (m, 1 H), 6.68–6.62 (m, 2 H), 6.31 (d, J = 10.0 Hz, 1 H), 6.09 (d, J = 1.3 Hz, 1 H), 5.73–5.70 (m, 1 H), 5.12 (d, J = 1.5 Hz, 1 H), 4.39–4.37 (m, 1 H), 4.04 (d, J = 14.5 Hz, 1 H), 3.93–3.89 (m, 1 H), 3.51–3.48 (m, 1 H), 3.26 (d, J = 14.6 Hz, 1 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.2, 169.5, 144.1, 143.8, 135.5, 134.5, 132.8, 132.1, 130.6, 129.5, 129.0, 127.8, 127.7, 127.5, 127.2, 126.8, 121.3, 120.9, 119.6, 111.7, 100.9, 65.1, 62.0, 61.4, 38.8, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂O₃ ⁺: 529.1121; found: 529.1125.

Compound 3l

Yield: 24.8 mg (37%); white solid.

IR (film): 2979, 1726, 1669, 1600, 1567, 1485, 1455, 1446, 1426, 1402, 1368, 1343, 1294, 1261, 1224, 1188, 1074, 1045, 1011, 863, 753, 698, 671 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.52 (t, J = 1.7 Hz, 1 H), 7.48–7.37 (m, 3 H), 7.37–7.29 (m, 2 H), 7.29–7.20 (m, 2 H), 7.16 (t, J = 7.8 Hz, 1 H), 7.07–6.97 (m, 1 H), 6.80–6.75 (m, 1 H), 6.77–6.61 (m, 2 H), 6.34 (d, J = 10.0 Hz, 1 H), 6.03 (d, J = 1.5 Hz, 1 H), 5.41–5.39 (m, 1 H), 4.96 (d, J = 1.6 Hz, 1 H), 4.41–4.40 (m, 1 H), 3.88–3.86 (m, 1 H), 3.54–3.42 (m, 1 H), 3.43–3.33 (m, 1 H), 3.20 (d, J = 14.2 Hz, 1 H), 0.60 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 172.0, 169.6, 143.7, 143.5, 138.2, 134.4, 133.7, 130.8, 130.5, 130.0, 129.6, 129.4, 127.88, 127.82, 127.6, 126.8, 122.4, 121.2, 121.0, 118.5, 111.9, 101.2, 64.5, 63.2, 61.4, 40.1, 12.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂O₃ ⁺: 529.1121; found: 529.1121.

Compounds 3m and 4m

Yield: 47.9 mg (86%); white solid.

IR (film): 3058, 2982, 2936, 1732, 1669, 1600, 1578, 1485, 1455, 1403, 1371, 1347, 1293, 1265, 1191, 1098, 1045, 1025, 981, 931, 871, 755, 698, 665, 529, 463 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.84–7.68 (m, 4 H), 7.44–7.27 (m, 6 H), 7.13–6.97 (m, 2 H), 6.94–6.64 (m, 6 H), 6.39 (t, J = 9.6 Hz, 2 H), 6.03–5.75 (m, 4 H), 5.33 (d, J = 1.5 Hz, 1 H), 5.17 (d, J = 5.5 Hz, 1 H), 5.08–4.91 (m, 2 H), 4.37–3.98 (m, 6 H), 3.98–3.76 (m, 1 H), 3.46–3.43 (m, 1 H), 3.09–2.79 (m, 3 H), 2.51 (d, J = 17.9 Hz, 1 H), 1.37–1.14 (m, 9 H), 0.62 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.2, 170.7, 170.1, 169.8, 169.7, 169.2, 143.7, 143.5, 143.33, 143.27, 134.4, 133.9, 130.9, 130.8, 129.6, 129.4, 128.0, 127.8, 127.7, 127.6, 127.1, 126.9, 126.7, 122.1, 121.7, 121.4, 121.2, 120.9, 119.0, 112.3, 111.8, 101.2, 99.9, 64.5, 62.1, 61.8, 61.7, 61.3, 60.8, 60.5, 58.9, 40.1, 39.9, 14.0, 14.0, 13.8, 12.7.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₇N₂O₅ ⁺: 447.1914; found: 447.1915.

Compound 4a

Yield: 23.4 mg (42%); white crystalline solid; mp 152.3–153.6 °C.

IR (film): 2957, 2928, 2855, 2347, 1728, 1668, 1600, 1578, 1527, 1484, 1454, 1386, 1339, 1277, 1215, 1184, 1117, 1074, 820, 772, 751, 699, 660 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.79–7.67 (m, 2 H), 7.33–7.25 (m, 3 H), 7.21–7.04 (m, 4 H), 7.00–6.71 (m, 5 H), 6.54 (d, J = 10.0 Hz, 1 H), 6.04–5.94 (m, 1 H), 5.90–5.87 (m, 1 H), 4.78 (d, J = 5.2 Hz, 1 H), 4.35 (s, 1 H), 4.22–4.18 (m, 2 H), 3.43 (d, J = 13.9 Hz, 1 H), 2.72 (d, J = 13.9 Hz, 1 H), 1.27 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.9, 169.4, 143.6, 140.6, 136.0, 134.6, 130.74, 130.71, 129.6, 128.7, 128.0, 127.7, 127.4, 127.2, 126.6, 121.9, 121.8, 120.2, 111.8, 103.9, 65.0, 62.1, 61.6, 38.5, 13.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₇N₂O₃ ⁺: 451.2016; found: 451.2008.

Compound 4b

Yield: 32.85 mg (57%); white crystalline solid; mp 147.3–148.2 °C.

IR (film): 3058, 2964, 1739, 1665, 1600, 1578, 1484, 1455, 1401, 1349, 1278, 1221, 1181, 1113, 1058, 1044, 912, 879, 796, 754, 696, 662 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.79–7.68 (m, 2 H), 7.42–7.26 (m, 3 H), 7.15–6.86 (m, 6 H), 6.86–6.73 (m, 2 H), 6.58 (d, J = 10.0 Hz, 1 H), 6.04–5.92 (m, 1 H), 5.85 (s, 1 H), 4.72–4.70 (m, 1 H), 4.44–4.13 (m, 3 H), 3.37 (d, J = 14.3 Hz, 1 H), 2.94 (d, J = 14.3 Hz, 1 H), 1.69 (s, 3 H), 1.29 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.4, 169.5, 143.6, 140.2, 138.0, 134.7, 134.6, 130.8, 130.1, 129.8, 129.5, 128.7, 128.0, 127.8, 127.2, 126.7, 125.4, 121.94, 121.87, 120.4, 112.4, 103.8, 65.3, 62.0, 61.7, 34.5, 20.0, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃ ⁺: 465.2173; found: 465.2166.

Compound 4c

Yield: 22.9 mg (39%); white crystalline solid; mp 141.1–142.3 °C.

IR (film): 3026, 2979, 2924, 1717, 1664, 1599, 1577, 1483, 1454, 1446, 1401, 1367, 1349, 1276, 1230, 1208, 1187, 1164, 1096, 1051, 1018, 796, 783, 771, 751, 696 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.73 (d, J = 6.9 Hz, 2 H), 7.32–7.25 (m, 3 H), 7.18–6.85 (m, 4 H), 6.80 (t, J = 7.4 Hz, 2 H), 6.68 (s, 2 H), 6.53 (d, J = 10.0 Hz, 1 H), 5.99 (s, 1 H), 5.90–5.87 (m, 1 H), 4.77 (d, J = 5.2 Hz, 1 H), 4.41 (s, 1 H), 4.35–4.09 (m, 2 H), 3.39 (d, J = 13.9 Hz, 1 H), 2.69 (d, J = 13.9 Hz, 1 H), 2.24 (s, 3 H), 1.27 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.1, 169.5, 143.7, 140.6, 136.9, 135.9, 134.6, 131.5, 130.8, 129.6, 128.7, 128.0, 127.8, 127.4, 127.2, 122.0, 121.8, 120.4, 111.9, 104.0, 65.0, 62.2, 61.6, 38.7, 21.3, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃ ⁺: 465.2173; found: 465.2168.

Compound 4d

Yield: 20.1 mg (34%); white solid.

IR (film): 3054, 3023, 2981, 2924, 2414, 2379, 2358, 2344, 2324, 1727, 1667, 1600, 1578, 1515, 1484, 1455, 1447, 1402, 1368, 1349, 1276, 1230, 1209, 1186, 1165, 1113, 1096, 1072, 1050, 1017, 984, 972, 951, 939, 928, 907, 883, 861, 851, 838, 826, 817, 795, 771, 760, 727, 715, 695, 683 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.83–7.62 (m, 2 H), 7.44–7.22 (m, 3 H), 7.09–7.04 (m, 1 H), 7.03–6.86 (m, 3 H), 6.85–6.70 (m, 4 H), 6.53 (d, J = 10.1 Hz, 1 H), 5.98 (s, 1 H), 5.89–5.87 (m, 1 H), 4.76–4.75 (m, 1 H), 4.40 (d, J = 1.0 Hz, 1 H), 4.32–4.10 (m, 2 H), 3.39 (d, J = 13.9 Hz, 1 H), 2.68 (d, J = 13.9 Hz, 1 H), 2.27 (s, 3 H), 1.28 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.1, 169.5, 143.7, 140.6, 136.2, 134.6, 132.8, 130.8, 130.6, 129.6, 128.7, 128.2, 128.0, 127.8, 127.2, 122.0, 121.8, 120.4, 111.9, 104.0, 65.0, 62.2, 61.6, 38.3, 21.0, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃ ⁺: 465.2173; found: 465.2163.

Compound 4e

Yield: 28 mg (48%); white crystalline solid; mp 143.9–145.6 °C.

IR (film): 2965, 2935, 1721, 1665, 1600, 1585, 1492, 1484, 1455, 1402, 1367, 1349, 1290, 1275, 1233, 1211, 1181, 1106, 1074, 1049, 1026, 930, 912, 884, 800, 755, 697, 662, 613, 526, 462 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.78–7.68 (m, 2 H), 7.41–7.26 (m, 3 H), 7.21–7.02 (m, 2 H), 7.00–6.84 (m, 4 H), 6.84–6.74 (m, 2 H), 6.59 (d, J = 10.0 Hz, 1 H), 5.97–5.93 (m, 2 H), 4.84–4.83 (m, 1 H), 4.37 (d, J = 1.1 Hz, 1 H), 4.28–4.15 (m, 2 H), 3.50–3.33 (m, 1 H), 2.90–2.73 (m, 1 H), 1.26 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.8, 169.6, 161.7 (d, J = 246.2 Hz), 143.6, 140.1, 134.7, 132.9 (d, J = 4.2 Hz), 130.8, 129.7, 129.0, 128.6 (d, J = 8.2 Hz), 128.0, 127.8, 127.2, 123.2, 123.0 (d, J = 3.7 Hz), 121.7 (d, J = 1.2 Hz), 120.1, 114.8 (d, J = 22.4 Hz), 112.0, 103.4, 100.0, 64.9, 61.8, 61.1, 31.3, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1902.

Compound 4f

Yield: 21.9 mg (37%); white crystalline solid; mp 141.3–142.4 °C.

IR (film): 3058, 2964, 2929, 1720, 1666, 1600, 1577, 1484, 1472, 1455, 1446, 1401, 1349, 1264, 1210, 1050, 1022, 912, 880, 800, 752, 697, 663, 549, 458 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.80–7.66 (m, 2 H), 7.48–7.21 (m, 4 H), 7.21–6.96 (m, 4 H), 6.91–6.89 (m, 1 H), 6.85–6.71 (m, 2 H), 6.60 (d, J = 10.0 Hz, 1 H), 6.04–5.89 (m, 2 H), 4.82–4.80 (m, 1 H), 4.39 (d, J = 1.0 Hz, 1 H), 4.33–4.12 (m, 2 H), 3.60 (t, J = 14.3 Hz, 1 H), 3.10 (d, J = 14.2 Hz, 1 H), 1.25 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.0, 169.6, 143.5, 140.0, 135.9, 134.7, 132.6, 131.9, 130.8, 129.5, 129.0, 128.3, 128.0, 127.8, 127.3, 126.8, 126.5, 121.8, 121.7, 120.0, 112.7, 103.8, 65.1, 62.0, 61.3, 37.2, 13.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1926.

Compound 4g

Yield: 22.8 mg (39%); white crystalline solid; mp 169.7–170.7 °C.

IR (film): 2964, 2346, 1736, 1661, 1600, 1509, 1483, 1454, 1351, 1221, 1192, 1160, 1098, 1051, 1017, 928, 881, 862, 838, 804, 759, 695, 683, 672, 660, 640, 628 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.83–7.62 (m, 2 H), 7.44–7.20 (m, 3 H), 7.10–7.07 (m, 1 H), 6.97–6.70 (m, 7 H), 6.55 (d, J = 10.0 Hz, 1 H), 5.98 (d, J = 5.2 Hz, 1 H), 5.88–5.86 (m, 1 H), 4.79–4.78 (m, 1 H), 4.31 (d, J = 1.1 Hz, 1 H), 4.22–4.19 (m, 2 H), 3.41 (d, J = 14.0 Hz, 1 H), 2.68 (d, J = 14.0 Hz, 1 H), 1.27 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.9, 169.5, 161.8 (d, J = 245.5 Hz), 143.6, 140.6, 134.6, 132.4 (d, J = 8.0 Hz), 131.7 (d, J = 3.3 Hz), 130.8, 129.8, 128.9, 128.0, 127.8, 127.3, 121.9, 121.8, 120.0, 114.3 (d, J = 21.2 Hz), 111.8, 103.8, 65.1, 62.2, 61.8, 37.5, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1916.

Compound 4h

Yield: 33.05 mg (55%); white solid.

IR (film): 3059, 2982, 2936, 1720, 1666, 1600, 1577, 1484, 1455, 1446, 1402, 1367, 1349, 1272, 1231, 1210, 1189, 1167, 1112, 1058, 1025, 972, 930, 912, 882, 786, 753, 697, 661, 621 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.79–7.66 (m, 2 H), 7.44–7.17 (m, 4 H), 7.18–6.97 (m, 4 H), 6.98–6.85 (m, 1 H), 6.79 (t, J = 7.4 Hz, 2 H), 6.61 (d, J = 10.0 Hz, 1 H), 6.06–5.87 (m, 2 H), 4.82–4.80 (m, 1 H), 4.37 (d, J = 1.0 Hz, 1 H), 4.30–4.13 (m, 2 H), 3.54 (d, J = 14.1 Hz, 1 H), 3.05 (d, J = 14.1 Hz, 1 H), 1.25 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.9, 169.6, 143.5, 139.9, 135.8, 134.6, 134.0, 132.1, 130.7, 129.5, 129.1, 129.0, 128.1, 127.9, 127.7, 127.2, 125.8, 121.7, 121.6, 120.0, 112.4, 103.6, 65.1, 61.9, 61.2, 34.6, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1630.

Compound 4i

Yield: 25 mg (41%); white solid.

IR (film): 3059, 3023, 2981, 2935, 2903, 1725, 1666, 1599, 1575, 1483, 1455, 1446, 1433, 1402, 1368, 1349, 1310, 1268, 1231, 1211, 1187, 1166, 1096, 1081, 1049, 1018, 882, 793, 752, 728, 695, 671, 661, 650, 639, 626, 616, 606 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.78–7.67 (m, 2 H), 7.42–7.22 (m, 3 H), 7.11–7.08 (m, 3 H), 6.95–6.87 (m, 2 H), 6.86–6.71 (m, 3 H), 6.54 (d, J = 10.0 Hz, 1 H), 6.04–5.96 (m, 1 H), 5.87–5.84 (m, 1 H), 4.81–4.80 (m, 1 H), 4.38 (d, J = 1.3 Hz, 1 H), 4.33–4.11 (m, 2 H), 3.38 (d, J = 14.0 Hz, 1 H), 2.70 (d, J = 14.0 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.8, 169.5, 143.6, 140.7, 138.2, 134.5, 133.3, 130.9, 129.8, 129.1, 129.0, 128.7, 128.0, 127.8, 127.3, 126.9, 121.9, 121.8, 121.0, 111.9, 103.7, 65.0, 62.1, 61.9, 38.1, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1634.

Compound 4j

Yield: 15.8 mg (26%); white crystalline solid; mp 177.8–179.0 °C.

IR (film): 2982, 2935, 2361, 2342, 1725, 1664, 1599, 1577, 1483, 1454, 1402, 1349, 1291, 1268, 1231, 1211, 1187, 1107, 1092, 1049, 1016, 928, 911, 881, 827, 785, 755, 697, 662, 521, 462 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.86–7.54 (m, 2 H), 7.49–7.19 (m, 3 H), 7.19–6.98 (m, 3 H), 6.90–6.87 (m, 1 H), 6.86–6.66 (m, 4 H), 6.54 (d, J = 10.0 Hz, 1 H), 6.07–5.93 (m, 1 H), 5.87–5.84 (m, 1 H), 4.81–4.80 (m, 1 H), 4.32 (d, J = 4.2 Hz, 1 H), 4.29–4.11 (m, 2 H), 3.40 (d, J = 14.0 Hz, 1 H), 2.68 (d, J = 14.0 Hz, 1 H), 1.28 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.8, 169.5, 143.6, 140.6, 134.6, 134.5, 132.6, 132.2, 130.9, 129.8, 129.0, 128.0, 127.8, 127.6, 127.3, 121.9, 120.0, 111.8, 103.8, 65.1, 62.2, 61.8, 37.7, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1622.

Compound 4k

Yield: 26.55 mg (40%); white crystalline solid; mp 136.3–138.2 °C.

IR (film): 2982, 1719, 1665, 1600, 1577, 1484, 1472, 1455, 1446, 1401, 1349, 1270, 1230, 1210, 1120, 1049, 1022, 912, 881, 784, 752, 697, 662 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.80–7.63 (m, 2 H), 7.44–7.21 (m, 3 H), 7.20–7.03 (m, 2 H), 6.98–6.72 (m, 4 H), 6.71–6.45 (m, 3 H), 5.98 (d, J = 4.0 Hz, 1 H), 5.87–5.84 (m, 1 H), 4.81–4.79 (m, 1 H), 4.36 (d, J = 1.3 Hz, 1 H), 4.34–4.13 (m, 2 H), 3.42 (d, J = 13.9 Hz, 1 H), 2.72 (d, J = 14.0 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.9, 169.5, 143.6, 140.7, 134.5, 130.8, 129.8, 129.0, 128.9, 128.8, 128.0, 127.8, 127.3, 126.64, 126.61, 121.91, 121.88, 120.0, 117.8, 117.5, 113.7, 113.4, 111.9, 103.7, 65.1, 62.2, 61.8, 38.2, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂O₃ ⁺: 529.1121; found: 529.1123.

Compound 4l

Yield: 21.7 mg (33%); white crystalline solid; mp 153.1–154.0 °C.

IR (film): 3059, 2980, 2935, 1724, 1666, 1598, 1569, 1483, 1455, 1446, 1402, 1348, 1309, 1267, 1233, 1211, 1186, 1095, 1074, 1048, 1019, 972, 867, 788, 753, 697, 662, 612 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.83–7.64 (m, 2 H), 7.43–7.23 (m, 4 H), 7.17–6.96 (m, 3 H), 6.91–6.82 (m, 1 H), 6.80–6.77 (m, 3 H), 6.53 (d, J = 10.0 Hz, 1 H), 6.05–5.94 (m, 1 H), 5.86–5.84 (m, 1 H), 4.91–4.71 (m, 1 H), 4.40 (d, J = 1.3 Hz, 1 H), 4.35–4.09 (m, 2 H), 3.37 (d, J = 14.0 Hz, 1 H), 2.70 (d, J = 14.0 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.8, 169.5, 143.6, 140.7, 138.5, 134.5, 133.8, 130.9, 129.8, 129.6, 129.0, 128.0, 127.8, 127.3, 121.9, 121.8, 121.5, 120.0, 111.9, 103.7, 65.0, 62.1, 61.9, 38.1, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂O₃ ⁺: 529.1121; found: 529.1099.

Compound 6a

Yield: 24.6 mg (55%); white solid.

IR (film): 3057, 2983, 2924, 1732, 1668, 1600, 1578, 1484, 1447, 1402, 1368, 1342, 1291, 1261, 1205, 1160, 1096, 1017, 900, 881, 862, 817, 793, 772, 759, 737, 716, 694, 683, 671 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.84–7.71 (m, 2 H), 7.48–7.27 (m, 3 H), 7.19–7.02 (m, 1 H), 7.00–6.70 (m, 3 H), 6.41 (d, J = 9.8 Hz, 1 H), 6.06–5.84 (m, 2 H), 5.19 (s, 1 H), 4.53–4.50 (m, 1 H), 4.40–4.12 (m, 2 H), 3.90–3.88 (m, 1 H), 1.32 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 169.2, 168.8, 143.1, 139.1, 134.3, 130.9, 129.6, 128.3, 127.8, 127.2, 126.9, 122.7, 122.5, 121.7, 114.2, 99.8, 61.6, 60.6, 54.1, 14.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₁N₂O₃ ⁺: 361.1547; found: 361.1533.

Compound 6b

Yield: 12.1 mg (26%); white solid.

IR (film): 3058, 2963, 2925, 2859, 1732, 1651, 1600, 1577, 1485, 1453, 1404, 1378, 1337, 1308, 1259, 1211, 1156, 1115, 1044, 1015, 967, 891, 794, 760, 696, 663, 606 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.79–7.69 (m, 2 H), 7.45–7.28 (m, 3 H), 7.15 (td, J = 7.8, 1.7 Hz, 1 H), 7.02–6.93 (m, 1 H), 6.89–6.86 (m, 2 H), 6.42 (d, J = 9.9 Hz, 1 H), 6.15 (s, 1 H), 5.90–5.88 (m, 1 H), 4.41–4.38 (m, 1 H), 4.34–4.15 (m, 2 H), 3.82–3.80 (m, 1 H), 1.65–1.63 (m, 3 H), 1.31 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.2, 169.5, 142.8, 134.4, 133.9, 130.7, 129.8, 128.2, 127.7, 127.3, 126.6, 122.53, 122.49, 121.5, 115.9, 114.4, 63.2, 61.5, 54.3, 14.2, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₃N₂O₃ ⁺: 375.1703; found: 375.1711.

Compound 7a

Yield: 13.3 mg (30%); white solid.

IR (film): 3059, 3027, 2962, 2933, 2902, 1727, 1665, 1600, 1578, 1485, 1455, 1447, 1403, 1370, 1346, 1292, 1261, 1223, 1176, 1158, 1102, 1071, 1020, 896, 872, 862, 802, 775, 752, 727, 697, 671, 652, 638, 628, 617, 606, 593 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.82–7.73 (m, 2 H), 7.44–7.26 (m, 3 H), 7.11–6.96 (m, 1 H), 6.83–6.78 (m, 1 H), 6.74–6.70 (m, 2 H), 6.43 (d, J = 10.0 Hz, 1 H), 6.09–5.98 (m, 1 H), 5.80–5.78 (m, 1 H), 5.09–4.94 (m, 1 H), 4.70–4.68 (m, 1 H), 3.89–3.84 (m, 2 H), 3.65–3.62 (m, 1 H), 0.76 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.0, 169.6, 143.4, 139.7, 134.4, 131.0, 129.6, 128.1, 127.9, 127.8, 126.8, 121.50, 121.47, 119.2, 112.6, 100.4, 61.1, 60.4, 57.2, 13.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₁N₂O₃ ⁺: 361.1547; found: 361.1530.

Compound 7b

Yield: 11.9 mg (25%); white solid.

IR (film): 2979, 1725, 1648, 1600, 1577, 1484, 1455, 1404, 1376, 1322, 1291, 1260, 1216, 1176, 1156, 1114, 1071, 1047, 1022, 966, 888, 829, 796, 754, 706, 652 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.73–7.70 (m, 2 H), 7.46–7.20 (m, 3 H), 7.11–7.06 (m, 1 H), 6.95–6.67 (m, 3 H), 6.52–6.50 (m, 1 H), 6.43 (d, J = 10.0 Hz, 1 H), 5.81–5.78 (m, 1 H), 4.59–4.56 (m, 1 H), 4.00–3.81 (m, 2 H), 3.65–3.59 (m, 1 H), 1.71–1.68 (m, 3 H), 0.80 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.2, 169.9, 143.6, 134.7, 133.8, 130.7, 129.7, 128.0, 127.9, 127.8, 126.8, 121.7, 121.5, 119.5, 113.9, 112.9, 61.0, 60.6, 54.5, 14.6, 13.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₃H₂₃N₂O₃ ⁺: 375.1703; found: 375.1713.

Compound 9a

Yield: 16 mg (29%); white crystalline solid; mp 128.3–130.1 °C.

IR (film): 3029, 2964, 1725, 1661, 1631, 1494, 1454, 1409, 1368, 1340, 1262, 1237, 1200, 1084, 1042, 941, 872, 753, 700, 675, 655 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.71 (d, J = 6.4 Hz, 2 H), 7.51–7.30 (m, 3 H), 7.31–6.96 (m, 8 H), 6.93 (d, J = 7.4 Hz, 1 H), 6.10 (d, J = 7.7 Hz, 1 H), 5.96 (s, 1 H), 5.37 (d, J = 7.8 Hz, 1 H), 5.32 (s, 1 H), 4.47–4.21 (m, 2 H), 4.19 (s, 1 H), 3.16 (s, 2 H), 1.32 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.5, 167.7, 141.6, 137.2, 136.2, 134.9, 131.4, 131.3, 130.6, 129.0, 128.3, 128.00, 127.97, 127.4, 126.9, 126.8, 126.4, 125.2, 104.9, 102.0, 66.7, 64.5, 61.8, 38.0, 14.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₇N₂O₃ ⁺: 451.2016; found: 451.2017.

Compound 9b and 10b

Yield: 29 mg (50%); white crystalline solid; mp 152.1–153.7 °C.

IR (film): 3061, 3023, 2979, 1726, 1662, 1631, 1601, 1577, 1492, 1447, 1408, 1368, 1340, 1278, 1221, 1200, 1098, 1059, 1037, 940, 904, 872, 750, 699, 673, 567 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.75–7.65 (m, 2 H), 7.55–7.46 (m, 1 H), 7.46–7.27 (m, 5 H), 7.27–6.83 (m, 13 H), 6.13 (d, J = 7.8 Hz, 1 H), 5.98–5.97 (m, 1 H), 5.92 (d, J = 7.8 Hz, 1 H), 5.80 (d, J = 1.0 Hz, 1 H), 5.44 (d, J = 7.8 Hz, 1 H), 5.31 (d, J = 7.8 Hz, 1 H), 5.22 (s, 1 H), 4.82 (d, J = 10.4 Hz, 1 H), 4.61 (d, J = 1.3 Hz, 1 H), 4.40–4.19 (m, 2 H), 4.01 (d, J = 1.2 Hz, 1 H), 3.83–3.67 (m, 1 H), 3.58 (d, J = 14.7 Hz, 1 H), 3.34–3.33 (m, 1 H), 3.02 (d, J = 14.2 Hz, 1 H), 2.43 (s, 1 H), 2.14 (s, 3 H), 1.31 (t, J = 9.2, 5.1 Hz, 3 H), 0.92 (t, J = 7.1 Hz, 1 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.8, 171.6, 167.62, 167.57, 142.2, 141.1, 138.6, 137.8, 137.4, 137.1, 135.0, 134.8, 134.4, 131.3, 130.8, 130.59, 130.56, 130.51, 130.47, 130.0, 129.3, 129.0, 128.8, 128.2, 128.00, 127.95, 127.9, 127.6, 127.1, 127.0, 126.8, 126.5, 126.3, 126.1, 125.3, 125.2, 124.9, 104.8, 104.6, 101.8, 101.6, 67.3, 67.2, 64.8, 64.6, 61.8, 61.4, 37.7, 33.7, 21.1, 20.8, 14.0, 13.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃ ⁺: 465.2173; found: 465.2175.

Compound 9c and 10c

Yield: 43.4 mg (75%); white solid.

IR (film): 2963, 2926, 1727, 1667, 1634, 1603, 1491, 1447, 1408, 1368, 1340, 1260, 1227, 1203, 1097, 1047, 1026, 939, 905, 862, 755, 700, 667, 635, 561 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.71 (dd, J = 7.9, 1.6 Hz, 1 H), 7.52–7.31 (m, 3 H), 7.31–6.97 (m, 13 H), 6.93 (d, J = 7.3 Hz, 1 H), 6.87 (dd, J = 5.6, 2.1 Hz, 1 H), 6.76 (s, 1 H), 6.11 (t, J = 4.7 Hz, 1 H), 5.98 (s, 1 H), 5.89 (d, J = 7.8 Hz, 1 H), 5.44–5.18 (m, 2 H), 5.00 (d, J = 1.4 Hz, 1 H), 4.86 (s, 1 H), 4.42–4.19 (m, 1 H), 3.90–3.60 (m, 2 H), 3.51 (d, J = 14.4 Hz, 1 H), 3.34 (d, J = 14.4 Hz, 1 H), 3.14 (s, 1 H), 2.30 (s, 3 H), 2.23 (s, 1 H), 1.34 (t, J = 7.1 Hz, 2 H), 0.94 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.8, 171.6, 167.7, 143.1, 141.8, 138.2, 137.2, 136.9, 136.7, 136.0, 135.5, 134.9, 132.0, 131.5, 130.7, 130.6, 130.2, 128.9, 128.7, 128.4, 128.2, 128.1, 128.04, 127.97, 127.8, 127.7, 127.4, 127.2, 127.1, 126.9, 126.8, 126.7, 126.3, 125.1, 124.9, 105.0, 104.2, 102.0, 101.1, 66.5, 65.6, 64.4, 63.3, 61.8, 61.3, 41.4, 38.3, 21.3, 14.0, 13.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₃₀H₂₉N₂O₃ ⁺: 465.2173; found: 465.2167.

Compound 9e

Yield: 29.9 mg (51%); white crystalline solid; mp 140.3–141.6 °C.

IR (film): 3432, 2963, 1725, 1662, 1630, 1584, 1492, 1455, 1409, 1369, 1341, 1262, 1235, 1202, 1182, 1104, 1047, 942, 904, 861, 798, 758, 699, 674 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.72–7.69 (m, 2 H), 7.47–7.32 (m, 3 H), 7.33–7.06 (m, 5 H), 7.05–6.81 (m, 3 H), 6.14 (d, J = 7.8 Hz, 1 H), 5.88 (d, J = 1.3 Hz, 1 H), 5.48–5.28 (m, 2 H), 4.42–4.15 (m, 2 H), 4.04 (d, J = 1.3 Hz, 1 H), 3.45 (d, J = 14.1 Hz, 1 H), 2.91 (d, J = 14.1 Hz, 1 H), 1.31 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.4, 167.6, 162.3 (d, J = 245.7 Hz), 141.5, 137.4, 135.0, 132.7 (d, J = 4.1 Hz), 131.5, 130.6, 129.0, 128.4 (d, J = 8.4 Hz), 128.2, 128.0, 127.5, 126.8 (d, J = 2.4 Hz), 125.3, 123.9, 123.7, 123.1 (d, J = 3.4 Hz), 114.7 (d, J = 22.6 Hz), 104.3, 100.4, 66.6, 64.0, 61.9, 30.3, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1921.

Compound 9f

Yield: 8.4 mg (14%); white solid.

IR (film): 3066, 2981, 2935, 1726, 1662, 1630, 1616, 1588, 1524, 1489, 1448, 1409, 1368, 1340, 1254, 1201, 1144, 1122, 1099, 1080, 1047, 941, 904, 877, 753, 700, 674, 629 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.75–7.64 (m, 2 H), 7.47–7.31 (m, 3 H), 7.21–7.20 (m, 1 H), 7.09–7.07 (m, 3 H), 6.97–6.88 (m, 1 H), 6.87–6.69 (m, 3 H), 6.09 (d, J = 7.8 Hz, 1 H), 5.98 (d, J = 1.4 Hz, 1 H), 5.37 (d, J = 8.0 Hz, 2 H), 4.47–4.10 (m, 3 H), 3.16 (s, 2 H), 1.35 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.3, 167.9, 162.0 (d, J = 244.5 Hz), 141.7, 138.8 (d, J = 7.6 Hz), 137.0, 134.8, 131.3, 130.7, 129.1, 128.6 (d, J = 8.2 Hz), 128.2, 128.0, 127.8, 126.9 (d, J = 2.7 Hz), 126.83, 126.7, 125.3, 117.9 (d, J = 21.4 Hz), 113.3 (d, J = 20.9 Hz), 104.9, 101.6, 66.5, 64.4, 62.0, 37.8, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1931.

Compound 9g

Yield: 13.6 mg (23%); white solid.

IR (film): 3430, 2963, 1721, 1663, 1629, 1601, 1509, 1446, 1368, 1341, 1262, 1222, 1159, 1098, 1045, 798, 757, 699, 670 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.77–7.63 (m, 2 H), 7.50–7.30 (m, 3 H), 7.25–6.89 (m, 6 H), 6.87–6.73 (m, 2 H), 6.08 (d, J = 7.8 Hz, 1 H), 5.98 (d, J = 1.8 Hz, 1 H), 5.36 (d, J = 7.1 Hz, 2 H), 4.40–4.19 (m, 2 H), 4.15 (d, J = 9.7 Hz, 1 H), 3.13 (s, 2 H), 1.33 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.4, 167.7, 161.7 (d, J = 244.9 Hz), 141.6, 137.1, 134.8, 132.8 (d, J = 7.9 Hz), 131.8 (d, J = 3.1 Hz), 131.4, 130.7, 129.0, 128.3, 128.0, 127.8, 126.8 (d, J = 5.7 Hz), 125.3, 114.3, 114.0, 104.8, 101.7, 66.6, 64.5, 61.9, 37.0, 14.1.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1920.

Compound 9h

Yield: 22.4 mg (37%); white solid.

IR (film): 3066, 2964, 1724, 1662, 1630, 1572, 1493, 1475, 1446, 1409, 1369, 1341, 1263, 1238, 1201, 1099, 1056, 1028, 941, 904, 860, 756, 698, 668, 623, 564 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.71–7.69 (m, 2 H), 7.40–7.35 (m, 4 H), 7.31–7.02 (m, 6 H), 6.96 (d, J = 7.3 Hz, 1 H), 6.15 (d, J = 7.8 Hz, 1 H), 5.88 (s, 1 H), 5.50–5.16 (m, 2 H), 4.47–4.15 (m, 2 H), 4.02 (s, 1 H), 3.56 (d, J = 14.0 Hz, 1 H), 3.08 (d, J = 14.0 Hz, 1 H), 1.29 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.4, 167.5, 141.0, 137.6, 137.0, 135.0, 134.6, 132.5, 131.5, 130.6, 129.10, 129.04, 128.2, 128.0, 127.9, 127.6, 126.7, 126.6, 126.0, 125.3, 104.0, 100.8, 66.8, 64.5, 61.9, 34.0, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1614.

Compound 9i

Yield: 14.1 mg (23%); white solid.

IR (film): 3064, 2980, 1724, 1662, 1630, 1599, 1573, 1477, 1447, 1368, 1341, 1262, 1201, 1081, 1046, 940, 880, 771, 700, 671 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.77–7.63 (m, 2 H), 7.51–7.31 (m, 3 H), 7.21–7.20 (m, 1 H), 7.16–7.00 (m, 4 H), 7.00–6.88 (m, 3 H), 6.08 (d, J = 7.8 Hz, 1 H), 6.00 (d, J = 1.4 Hz, 1 H), 5.37 (s, 1 H), 5.35 (s, 1 H), 4.51–4.12 (m, 3 H), 3.14 (s, 2 H), 1.35 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.3, 167.7, 141.8, 138.3, 137.0, 134.8, 133.1, 131.33, 131.25, 130.7, 129.3, 129.1, 128.5, 128.3, 128.0, 127.8, 126.8, 126.7, 126.6, 125.3, 104.9, 101.6, 66.3, 64.4, 62.0, 37.9, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1604.

Compound 9l

Yield: 20.7 mg (31%); white solid.

IR (film): 3063, 2980, 1725, 1662, 1630, 1597, 1569, 1492, 1475, 1447, 1368, 1340, 1239, 1201, 1096, 1073, 1046, 941, 878, 769, 699, 664 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.73–7.66 (m, 2 H), 7.47–7.33 (m, 3 H), 7.28–7.17 (m, 2 H), 7.14–7.03 (m, 3 H), 7.03–6.89 (m, 3 H), 6.08 (d, J = 7.8 Hz, 1 H), 6.01 (d, J = 1.4 Hz, 1 H), 5.46–5.25 (m, 2 H), 4.46–4.15 (m, 3 H), 3.14 (s, 2 H), 1.35 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.3, 167.7, 141.8, 138.6, 137.0, 134.8, 134.1, 131.3, 130.7, 129.7, 129.5, 129.1, 128.8, 128.2, 128.0, 127.8, 126.8, 126.6, 125.3, 121.4, 104.9, 101.6, 66.3, 64.3, 62.0, 37.9, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂O₃ ⁺: 529.1121; found: 529.1117.

Compound 9m

Yield: 18.2 mg (32%); white solid.

IR (film): 3064, 2982, 2936, 1732, 1667, 1631, 1601, 1579, 1492, 1447, 1408, 1370, 1344, 1261, 1226, 1182, 1093, 1059, 1028, 935, 907, 878, 755, 701, 649 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.69–7.50 (m, 2 H), 7.47–7.31 (m, 3 H), 7.30–7.23 (m, 1 H), 7.23–7.04 (m, 2 H), 6.90 (d, J = 7.4 Hz, 1 H), 6.04 (d, J = 7.8 Hz, 2 H), 5.50 (s, 1 H), 5.46 (d, J = 7.8 Hz, 1 H), 5.39 (d, J = 1.0 Hz, 1 H), 4.48–4.11 (m, 2 H), 3.75–3.41 (m, 2 H), 3.12–2.90 (m, 2 H), 1.35 (t, J = 7.1 Hz, 3 H), 0.98 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.2, 169.3, 167.7, 143.8, 137.7, 134.5, 130.9, 130.8, 130.2, 129.0, 128.3, 128.0, 126.4, 126.2, 124.8, 106.3, 100.0, 63.4, 61.9, 60.5, 60.3, 40.4, 14.0, 13.8.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₇N₂O₅ ⁺: 447.1914; found: 447.1916.

Compound 10a

Yield: 23.8 mg (42%); white crystalline solid; mp 173.5–174.8 °C.

IR (film): 3062, 3026, 2963, 1728, 1666, 1634, 1601, 1572, 1494, 1453, 1408, 1368, 1340, 1286, 1260, 1226, 1200, 1096, 1017, 939, 906, 862, 769, 700, 664, 635 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.47–7.38 (m, 2 H), 7.38–7.20 (m, 8 H), 7.20–7.11 (m, 3 H), 6.91–6.80 (m, 1 H), 6.12 (d, J = 1.4 Hz, 1 H), 5.89 (d, J = 7.8 Hz, 1 H), 5.27 (d, J = 7.8 Hz, 1 H), 4.97 (d, J = 1.4 Hz, 1 H), 4.84 (s, 1 H), 3.90–3.61 (m, 2 H), 3.53 (d, J = 14.3 Hz, 1 H), 3.36 (d, J = 14.4 Hz, 1 H), 0.93 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.8, 167.7, 142.9, 136.9, 135.6, 134.8, 130.9, 130.7, 130.3, 128.8, 128.5, 127.8, 127.6, 127.5, 127.4, 126.8, 126.3, 125.0, 104.3, 101.2, 65.5, 63.5, 61.4, 41.4, 13.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₇N₂O₃ ⁺: 451.2016; found: 451.2025.

Compound 10e

Yield: 28 mg (47%); white crystalline solid; mp 176.0–177.9 °C.

IR (film): 3064, 2963, 1729, 1668, 1636, 1601, 1581, 1491, 1453, 1407, 1368, 1339, 1288, 1260, 1227, 1179, 1097, 1046, 1016, 938, 907, 871, 792, 759, 699, 663, 634 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.54–7.40 (m, 1 H), 7.33–7.31 (m, 2 H), 7.28–7.18 (m, 3 H), 7.18–7.00 (m, 6 H), 6.86–6.85 (m, 1 H), 6.10 (d, J = 1.3 Hz, 1 H), 5.85 (d, J = 7.8 Hz, 1 H), 5.27 (d, J = 7.8 Hz, 1 H), 5.07 (d, J = 1.5 Hz, 1 H), 4.81 (s, 1 H), 3.91–3.57 (m, 3 H), 3.17 (d, J = 15.8 Hz, 1 H), 0.92 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.7, 167.3, 161.6 (d, J = 243.9 Hz), 143.2, 136.4, 134.7, 132.3 (d, J = 3.6 Hz), 130.6, 130.3, 129.2 (d, J = 8.4 Hz), 128.7, 127.8, 127.4, 127.0, 126.9 (d, J = 5.9 Hz), 124.9, 124.5 (d, J = 3.5 Hz), 122.5, 122.3, 115.3 (d, J = 23.4 Hz), 104.4, 100.8, 65.9, 63.38, 63.35, 61.4, 33.29, 33.26, 13.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1931.

Compound 10f

Yield: 27.5 mg (47%); white crystalline solid; mp 155.1–156.7 °C.

IR (film): 3023, 2963, 2925, 1728, 1667, 1634, 1601, 1573, 1515, 1493, 1446, 1408, 1368, 1340, 1286, 1260, 1225, 1202, 1096, 1045, 1023, 939, 906, 863, 802, 769, 699, 665, 634 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.41–7.19 (m, 7 H), 7.20–7.05 (m, 5 H), 6.90–6.77 (m, 1 H), 6.11 (d, J = 1.3 Hz, 1 H), 5.88 (d, J = 7.8 Hz, 1 H), 5.26 (d, J = 7.8 Hz, 1 H), 4.96 (d, J = 1.4 Hz, 1 H), 4.84 (s, 1 H), 3.91–3.57 (m, 2 H), 3.49 (d, J = 14.4 Hz, 1 H), 3.31 (d, J = 14.4 Hz, 1 H), 0.92 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.8, 167.7, 142.9, 137.0, 136.9, 134.9, 132.4, 130.8, 130.7, 130.3, 129.2, 128.8, 127.8, 127.7, 127.6, 126.8, 126.3, 125.0, 104.3, 101.0, 65.5, 63.4, 61.4, 40.9, 20.9, 13.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1917.

Compound 10g

Yield: 27.9 mg (48%); white crystalline solid; mp 146.0–147.0 °C.

IR (film): 3064, 2961, 2929, 1727, 1665, 1635, 1602, 1573, 1510, 1493, 1446, 1408, 1368, 1340, 1286, 1223, 1160, 1098, 1046, 1016, 939, 906, 863, 837, 756, 699, 664, 633 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.45–7.24 (m, 7 H), 7.24–7.09 (m, 3 H), 7.07–6.94 (m, 2 H), 6.88 (d, J = 6.6 Hz, 1 H), 6.11 (d, J = 1.4 Hz, 1 H), 5.91 (d, J = 7.8 Hz, 1 H), 5.30 (d, J = 7.8 Hz, 1 H), 4.90 (d, J = 1.4 Hz, 1 H), 4.77 (s, 1 H), 3.88–3.57 (m, 2 H), 3.51 (d, J = 14.4 Hz, 1 H), 3.29 (d, J = 14.4 Hz, 1 H), 0.93 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.6, 167.8, 162.2 (d, J = 246.3 Hz), 142.6, 136.9, 134.7, 132.5 (d, J = 7.8 Hz), 131.3 (d, J = 3.2 Hz), 130.6, 130.5, 128.9, 127.9, 127.7, 127.4, 126.8, 126.3, 125.1, 115.3 (d, J = 21.1 Hz), 104.6, 101.7, 65.4, 64.2, 61.4, 40.6, 13.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆FN₂O₃ ⁺: 469.1922; found: 469.1914.

Compound 10h

Yield: 21.2 mg (35%); white crystalline solid; mp 104.1–106.0 °C.

IR (film): 3065, 2963, 2930, 1729, 1668, 1636, 1601, 1572, 1494, 1475, 1446, 1407, 1368, 1338, 1287, 1260, 1226, 1096, 1045, 1016, 936, 906, 865, 757, 699, 663, 635, 562, 462 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.62–7.60 (m, 1 H), 7.47–7.41 (m, 1 H), 7.40–7.21 (m, 6 H), 7.21–7.06 (m, 4 H), 6.85–6.83 (m, 1 H), 6.08 (d, J = 1.5 Hz, 1 H), 5.82 (d, J = 7.8 Hz, 1 H), 5.27 (d, J = 7.8 Hz, 1 H), 4.94 (d, J = 1.5 Hz, 2 H), 3.97 (d, J = 14.8 Hz, 1 H), 3.81–3.73 (m, 1 H), 3.68–3.59 (m, 1 H), 3.42 (d, J = 14.8 Hz, 1 H), 0.91 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.6, 167.1, 143.4, 136.5, 135.6, 134.7, 133.5, 131.8, 130.6, 130.4, 129.8, 128.74, 128.69, 127.9, 127.6, 127.5, 127.13, 127.09, 126.4, 124.9, 104.4, 100.9, 66.1, 64.1, 61.5, 37.8, 13.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1641.

Compound 10i

Yield: 26 mg (43%); white crystalline solid; mp 152.5–153.4 °C.

IR (film): 3064, 3024, 2981, 2931, 1728, 1667, 1634, 1598, 1572, 1493, 1476, 1446, 1408, 1368, 1339, 1286, 1226, 1202, 1120, 1096, 1047, 1027, 940, 907, 865, 769, 699, 666, 645 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.46–7.08 (m, 12 H), 6.92–6.85 (m, 1 H), 6.10 (d, J = 1.2 Hz, 1 H), 5.93 (d, J = 7.8 Hz, 1 H), 5.31 (d, J = 7.8 Hz, 1 H), 4.89 (d, J = 1.3 Hz, 1 H), 4.77 (s, 1 H), 3.86–3.61 (m, 2 H), 3.52 (d, J = 14.3 Hz, 1 H), 3.27 (d, J = 14.3 Hz, 1 H), 0.94 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.4, 167.8, 142.5, 137.7, 136.9, 134.7, 134.3, 131.0, 130.6, 130.5, 129.7, 129.1, 129.0, 127.9, 127.7, 127.6, 127.3, 126.8, 126.4, 125.1, 104.6, 101.9, 65.3, 64.6, 61.5, 41.1, 13.5.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆ClN₂O₃ ⁺: 485.1626; found: 485.1613.

Compound 10l

Yield: 29.5 mg (45%); white crystalline solid; mp 162.0–164.0 °C.

IR (film): 2978, 1727, 1665, 1634, 1599, 1567, 1493, 1474, 1446, 1407, 1367, 1339, 1286, 1226, 1201, 1096, 1073, 1045, 939, 863, 783, 751, 698, 668 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.57 (s, 1 H), 7.44–7.26 (m, 7 H), 7.24–7.08 (m, 4 H), 6.91–6.84 (m, 1 H), 6.09 (d, J = 1.4 Hz, 1 H), 5.93 (d, J = 7.8 Hz, 1 H), 5.31 (d, J = 7.8 Hz, 1 H), 4.89 (d, J = 1.5 Hz, 1 H), 4.76 (s, 1 H), 3.90–3.60 (m, 2 H), 3.52 (d, J = 14.2 Hz, 1 H), 3.25 (d, J = 14.3 Hz, 1 H), 0.94 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.3, 167.8, 142.5, 138.0, 136.9, 134.7, 133.8, 130.58, 130.52, 130.46, 130.0, 129.6, 128.9, 127.9, 127.7, 127.3, 126.8, 126.4, 125.0, 122.5, 104.6, 101.9, 65.3, 64.6, 61.5, 41.1, 13.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂O₃ ⁺: 529.1121; found: 529.1126.

Compound 10m

Yield: 30.2 mg (54%); white solid.

IR (film): 3063, 2982, 2937, 2905, 1732, 1666, 1633, 1602, 1579, 1492, 1447, 1409, 1370, 1343, 1261, 1189, 1097, 1071, 1026, 940, 910, 865, 773, 754, 701, 667, 646 cm^–1.

¹H NMR (75 MHz, CDCl₃): δ = 7.70–7.68 (m, 2 H), 7.46–7.30 (m, 3 H), 7.25–7.06 (m, 3 H), 6.90 (d, J = 7.3 Hz, 1 H), 6.14 (d, J = 1.6 Hz, 1 H), 5.95 (t, J = 8.1 Hz, 1 H), 5.28 (d, J = 7.9 Hz, 1 H), 5.28 (d, J = 7.9 Hz, 1 H), 5.21 (s, 1 H), 4.24–4.06 (m, 2 H), 3.84–3.62 (m, 2 H), 3.22–2.91 (m, 2 H), 1.26 (td, J = 7.1, 2.6 Hz, 3 H), 0.91 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.8, 169.9, 167.9, 142.5, 137.3, 135.1, 130.6, 130.4, 129.1, 128.1, 127.9, 127.1, 126.9, 126.3, 125.0, 104.3, 98.8, 65.2, 61.5, 61.1, 61.0, 39.0, 14.1, 13.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₆H₂₇N₂O₅ ⁺: 447.1914; found: 447.1917.

Compound 11

Yield: 16.9 mg (38%); white solid.

IR (film): 2963, 1733, 1665, 1631, 1525, 1492, 1447, 1369, 1346, 1261, 1177, 1088, 1027, 930, 864, 798, 758, 700, 657 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.79–7.63 (m, 2 H), 7.50–7.31 (m, 3 H), 7.24–7.06 (m, 3 H), 6.96 (d, J = 7.5 Hz, 1 H), 6.00–5.95 (m, 1 H), 5.91 (d, J = 7.4 Hz, 1 H), 5.54 (d, J = 7.8 Hz, 1 H), 5.08–5.01 (m, 1 H), 4.95 (d, J = 10.5 Hz, 1 H), 4.42–4.12 (m, 3 H), 1.32 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 169.0, 167.8, 139.9, 137.4, 134.7, 130.7, 129.4, 129.0, 128.4, 127.9, 127.0, 126.9, 125.2, 107.2, 97.4, 62.5, 61.7, 54.4, 14.2.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₁N₂O₃ ⁺: 361.1547; found: 361.1539.

Compound 12

Yield: 14.1 mg (31%); white solid.

IR (film): 3064, 2962, 2929, 2870, 1734, 1703, 1664, 1631, 1601, 1577, 1524, 1492, 1452, 1408, 1371, 1336, 1276, 1261, 1210, 1195, 1178, 1162, 1087, 1028, 968, 936, 899, 866, 797, 762, 700, 665, 644, 632 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.76–7.63 (m, 2 H), 7.46–7.32 (m, 3 H), 7.23–7.08 (m, 3 H), 6.90 (d, J = 6.8 Hz, 1 H), 6.13 (s, 1 H), 5.94 (d, J = 7.9 Hz, 1 H), 5.32 (d, J = 7.9 Hz, 1 H), 5.10 (d, J = 7.8 Hz, 1 H), 5.02–4.98 (m, 1 H), 4.03–3.88 (m, 1 H), 3.86–3.56 (m, 2 H), 0.82 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 170.3, 167.7, 139.1, 136.7, 134.8, 130.7, 130.4, 128.9, 128.3, 128.0, 127.7, 127.1, 126.4, 125.1, 105.0, 99.5, 62.0, 61.1, 57.7, 13.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₂₁N₂O₃ ⁺: 361.1547; found: 361.1542.

Compound 14

Yield: 31.3 mg (47%); white solid.

IR (film): 2979, 1729, 1671, 1523, 1486, 1449, 1381, 1355, 1278, 1225, 1086, 1018, 959, 802, 758, 702 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 7.50–7.07 (m, 14 H), 6.26 (s, 1 H), 6.08 (d, J = 1.6 Hz, 1 H), 5.00 (d, J = 1.6 Hz, 1 H), 4.85 (s, 1 H), 3.85 (dq, J = 10.8, 7.2 Hz, 1 H), 3.67 (dq, J = 10.8, 7.1 Hz, 1 H), 3.52 (d, J = 14.4 Hz, 1 H), 3.36 (d, J = 14.4 Hz, 1 H), 0.98 (t, J = 7.2 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.4, 167.6, 142.8, 137.5, 135.3, 134.5, 130.9, 130.5, 129.6, 129.1, 128.6, 127.9, 127.7, 127.6, 127.53, 127.48, 126.5, 125.2, 101.3, 98.5, 65.5, 63.5, 61.7, 41.4, 13.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂O₃ ⁺: 529.1121; found: 529.1113.

Compound 15

Yield: 13.6 mg (21%); white solid.

IR (film): 3063, 2965, 1706, 1603, 1522, 1451, 1367, 1323, 1277, 1261, 1198, 1165, 1108, 1086, 1024, 861, 799, 756, 711 cm^–1.

¹H NMR (300 MHz, DMSO-d ₆): δ = 7.72–7.62 (m, 2 H), 7.50–7.24 (m, 5 H), 7.22–7.05 (m, 5 H), 7.02–6.90 (m, 2 H), 6.48 (s, 1 H), 5.90 (d, J = 1.4 Hz, 1 H), 5.35 (s, 1 H), 4.41 (d, J = 1.5 Hz, 1 H), 4.37–4.22 (m, 2 H), 3.16 (s, 2 H), 1.33 (t, J = 7.1 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 171.4, 167.8, 141.8, 137.7, 135.8, 134.5, 131.4, 130.9, 130.4, 129.3, 129.0, 128.2, 128.12, 128.09, 127.99, 127.5, 126.9, 126.6, 125.3, 102.4, 99.2, 66.6, 63.9, 62.0, 38.9, 14.0.

HRMS (ESI): m/z [M + H]⁺ calcd for C₂₉H₂₆BrN₂O₃ ⁺: 529.1121; found: 529.1099.

Acknowledgment

This study was supported by the National Natural Science Foundation of China (No. 21172253), the Program for New Century Excellent Talents in University (No. NCET-11-0481), the National Scientific and Technology Supporting Program of China (No. 2011BAE06B05-5), the National S&T Pillar Program of China (2012BAK25B03), the Scientific Research Foundation for the Returned Overseas Chinese Scholars, State Education Ministry, Chinese Universities Scientific Fund (No. 2012RC004), and Nutrichem Company.

• References

• 1a Kartsev VG. Med. Chem. Res. 2004; 13: 325
• 1b Madapa S, Tusi Z, Batra S. Curr. Org. Chem. 2008; 12: 1116
• 1c Kumar S, Bawa S, Gupta H. Mini-Rev. Med. Chem. 2009; 9: 1648
• 1d Musiol R, Serda M, Hensel-Bielowka S, Polanski J. Curr. Med. Chem. 2010; 17: 1960
• 1e Kaur K, Jain M, Reddy RP, Jain R. Eur. J. Med. Chem. 2010; 45: 3245
• 1f Liu CJ, Liu DY, Xiang L. Acta Pharmacol. Sin. 2010; 45: 9
• 1g Solomon VR, Lee H. Curr. Med. Chem. 2011; 18: 1488

For recent reviews on Et743, see:
• 2a Blay J.-Y. Eur. J. Clin. Med. Oncol. 2010; 2: 1
• 2b Vincenzi B, Napolitano A, Frezza AM, Schiavon G, Santini D, Tonini G. Pharmacogenomics J. 2010; 11: 865
• 2c Carter NJ, Keam SJ. Drugs 2010; 70: 355
• 2d Ganjoo KN, Patel SR. Expert Opin. Pharmacother. 2009; 10: 2735
• 2e Boudou L, Baconnier M, Blay J.-Y, Lombard-Bohas C, Cassier PA. Expert Rev. Anticancer Ther. 2009; 9: 727
• 2f Cuevas C, Francesch A. Nat. Prod. Rep. 2009; 26: 322

Hisamine:
• 3a Pyo MK, Lee DH, Kim DH, Lee JH, Moon JC, Chang KC, Yun-Choi HS. Bioorg. Med. Chem. Lett. 2008; 18: 4110
• 3b Pyo MK, Kim JM, Jin JL, Chang KC, Lee DH, Yun-Choi HS. Thromb. Res. 2007; 120: 81

RIR-4-95:
• 4a Skogvall S, Dalence-Guzman MF, Berglund M, Svensson K, Mesic A, Jonsson P, Persson CG. A, Sterner O. Pulm. Pharmacol. Ther. 2008; 21: 125
• 4b Berglund M, Dalence-Guzman MF, Skogvall S, Sterner O. Bioorg. Med. Chem. 2008; 16: 2513
• 4c Berglund M, Dalence-Guzman MF, Skogvall S, Sterner O. Bioorg. Med. Chem. 2008; 16: 2529
• 4d Dalence-Guzman MF, Berglund M, Skogvall S, Sterner O. Bioorg. Med. Chem. 2008; 16: 2499
• 5 Su D.-S, Lim JJ, Tinney E, Wan B.-L, Young MB, Anderson KD, Rudd D, Munshi V, Bahnck C, Felock PJ, Lu M, Lai M.-T, Touch S, Moyer G, DiStefano DJ, Flynn JA, Liang Y, Sanchez R, Prasad S, Yan Y, Perlow-Poehnelt R, Torrent M, Miller M, Vacca JP, Williams TM, Anthony NJ. Bioorg. Med. Chem. Lett. 2009; 19: 5119
• 6 Ramesh E, Manian RD. R. S, Raghunathan R, Sainath S, Raghunathan M. Bioorg. Med. Chem. 2009; 17: 660

Synthesis:
• 7a Scott JD, Williams RM. Chem. Rev. 2002; 102: 1669
• 7b Chrzanowska M, Rozwadowska MD. Chem. Rev. 2004; 104: 3341
• 7c Siengalewicz P, Rinner U, Mulzer J. Chem. Soc. Rev. 2008; 37: 2676
• 7d Pulka K. Curr. Opin. Drug Discovery Dev. 2010; 13: 669
• 7e Sridharan V, Suryavanshi PA, Menéndez JC. Chem. Rev. 2011; 111: 7157
• 7f Montalban AG In Heterocycles in Natural Product Synthesis . Majumdar KC, Chattopadhyay SK. Wiley-VCH; Weinheim: 2011: 299-339
• 7g Alajarin R, Burgos C In Modern Heterocyclic Chemistry . Vol. 3. Alvarez-Builla J, Vaquero JJ, Barluenga J. Wiley-VCH; Weinheim: 2011: 1527-1629
• 7h Mekheimer RA, Ahmed EA, Sadek KU. Tetrahedron 2012; 68: 1637
• 8 For a review, see: Schantl JG. In Science of Synthesis . Vol. 27. Padwa A. Georg Thieme Verlag; Stuttgart, New York: 2004: 731-824

For examples of the cycloaddition of azomethine imines, see:
• 9a Stanovnik B. Tetrahedron 1991; 47: 2925
• 9b Žličar M, Stanovnik B, Tišler M. Tetrahedron 1992; 48: 7965
• 9c Svete J, Prešeren A, Stanovnik B, Golič L, Golič-Grdadolnik S. J. Heterocycl. Chem. 1997; 34: 1323
• 9d Roussi F, Bonin M, Chiaroni A, Micouin L, Riche C, Husson H.-P. Tetrahedron Lett. 1999; 40: 3727
• 9e Roussi F, Chauveau A, Bonin M, Micouin L, Husson H.-P. Synthesis 2000; 1170
• 9f Chuang T.-H, Sharpless KB. Helv. Chim. Acta 2000; 83: 1734
• 9g Chauveau A, Martens T, Bonin M, Micouin L, Husson H.-P. Synthesis 2002; 1885
• 9h Panfil I, Urbanczyk-Lipkowska Z, Suwinska K, Solecka J, Chmielewski M. Tetrahedron 2002; 58: 1199
• 9i Belanger G, Hong F.-T, Overman LE, Rogers BN, Tellew JE, Trenkle WC. J. Org. Chem. 2002; 67: 7880
• 9j Shintani R, Fu GC. J. Am. Chem. Soc. 2003; 125: 10778
• 9k Chung F, Chauveau A, Seltki M, Bonin M, Micouin L. Tetrahedron Lett. 2004; 45: 3127
• 9l Pezdirc L, Jovanovski V, Bevk D, Jakše R, Pirc S, Meden A, Stanovnik B, Svete J. Tetrahedron 2005; 61: 3977
• 9m Suárez A, Downey CW, Fu GC. J. Am. Chem. Soc. 2005; 127: 11244
• 9n Shintani R, Hayashi T. J. Am. Chem. Soc. 2006; 128: 6330
• 9o Chen W, Yuan X.-H, Li R, Du W, Wu Y, Ding L.-S, Chen Y.-C. Adv. Synth. Catal. 2006; 348: 1818
• 9p Gergely J, Morgan JB, Overman LE. J. Org. Chem. 2006; 71: 9144
• 9q Chan A, Scheidt KA. J. Am. Chem. Soc. 2007; 129: 5334
• 9r Suga H, Funyu A, Kakehi A. Org. Lett. 2007; 9: 97
• 9s Pezdirc L, Cerkovnik J, Pirc S, Stanovnik B, Svete J. Tetrahedron 2007; 63: 991
• 9t Svete J. ARKIVOC 2006; (vii): 35
• 9u Pezdirc L, Grošelj U, Meden A, Stanovnik B, Svete J. J. Comb. Chem. 2007; 9: 717
• 9v Shintani R, Murakami M, Hayashi T. J. Am. Chem. Soc. 2007; 129: 12356
• 9w Chen W, Du W, Duan Y.-Z, Wu Y, Yang S.-Y, Chen Y.-C. Angew. Chem. Int. Ed. 2007; 46: 7667
• 9x Sibi MP, Rane D, Stanley LM, Soeta T. Org. Lett. 2008; 10: 2971
• 9y Kato T, Fujinami S, Ukaji Y, Inomata K. Chem. Lett. 2008; 37: 342
• 9z Perreault C, Goudreau SR, Zimmer LE, Charette AB. Org. Lett. 2008; 10: 689
• 9aa Shapiro ND, Shi Y, Toste FD. J. Am. Chem. Soc. 2009; 131: 11654
• 9ab Keller M, Sido AS. S, Pale P, Sommer J. Chem.–Eur. J. 2009; 15: 2810
• 9ac Hashimoto T, Maeda Y, Omote M, Nakatsu H, Maruoka K. J. Am. Chem. Soc. 2010; 132: 4076
• 9ad Ogawa S, Nishimine T, Tokunaga E, Shibata N. Synthesis 2010; 3274
• 9ae Hashimoto T, Omote M, Maruoka K. Angew. Chem. Int. Ed. 2011; 50: 3489
• 9af Hashimoto T, Omote M, Maruoka K. Angew. Chem. Int. Ed. 2011; 50: 8952
• 9ag Novak A, Bezenšek J, Pezdirc L, Grošelj U, Kasunič M, Podlipnik Č, Stanovnik B, Šimůnek P, Svete J. Tetrahedron 2011; 67: 9729
• 10 Tamura Y, Miki Y, Nishikawa Y, Ikeda M. J. Heterocycl. Chem. 1976; 13: 317
• 11a Na R, Jing C, Xu Q, Jiang H, Wu X, Shi J, Zhong J, Wang M, Benitez D, Tkatchouk E, Goddard III WA, Guo H, Kwon O. J. Am. Chem. Soc. 2011; 133: 13337
• 11b Jing C, Na R, Wang B, Liu H, Zhang L, Liu J, Wang M, Zhong J, Kwon O, Guo H. Adv. Synth. Catal. 2012; 354: 1023
• 11c Na R, Liu H, Li Z, Wang B, Liu J, Wang M.-A, Wang M, Zhong J, Guo H. Tetrahedron 2012; 68: 2349
• 11d Liu J, Liu H, Na R, Wang G, Wang M, Zhong J, Guo H. Chem. Lett. 2012; 41: 218

For reviews, see:
• 12a Eicher T, Hauptmann S. The Chemistry of Heterocycles . 2nd ed. Wiley-VCH; Weinheim: 2003
• 12b Varvounis G, Fiamegos Y, Pilidis G. Adv. Heterocycl. Chem. 2001; 80: 75
• 12c Elguero J. Pyrazoles: Comprehensive Heterocyclic Chemistry II . Vol. 3. Katritzky AR, Rees CW, Scriven EF. V. Elsevier; Oxford: 1996: 1-75, and references cited therein
• 12d Marchand-Brynaert J, Ghosez L In Recent Progress in the Chemical Synthesis of Antibiotics . Lukacs G, Ohno M. Springer; Berlin: 1990
• 12e Hanessian S, McNaughton-Smith G, Lombart H.-G, Lubell WD. Tetrahedron 1997; 53: 12789
• 12f Konaklieva MI, Plotkin BJ. Curr. Med. Chem. Anti-infect. Agents 2003; 2: 287
• 13 Legault C, Charette AB. J. Org. Chem. 2003; 68: 7119
• 14 Crystallographic data for 6a have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication number CCDC 899345. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing [e-mail], or by contacting The Cambridge Crystallographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK; fax: [phone].