(ortho-Chloromethyl)aryl Amides - ACS Publications

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Self [3 + 4] Cycloadditions of Isatin N,N# -Cyclic Azomethine Imine 1,3 -Dipole with N-(ortho-Chloromethyl)aryl Amides Qiaomei Jin, Jian Zhang, Cuihua Jiang, Dongjian Zhang, Meng Gao, and Shihe Hu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01055 • Publication Date (Web): 30 May 2018 Downloaded from http://pubs.acs.org on May 30, 2018

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The Journal of Organic Chemistry

Self [3 + 4] Cycloadditions of Isatin N,N′ -Cyclic Azomethine

Imine

1,3

-Dipole

with

N--(ortho-Chloromethyl)aryl Amides Qiaomei Jin *, †, ‡ Jian Zhang,

†, ‡

Cuihua Jiang,

†, ‡

Dongjian Zhang,

†, ‡

Meng Gao,

†, ‡

Shihe Hu *, †, ‡ †

Affiliated Hospital of Integrated Traditional Chinese and Western Medicine, Nanjing

University of Chinese Medicine, Nanjing 210028, Jiangsu, China ‡

Laboratories of Translational Medicine, Jiangsu Province Academy of Traditional

Chinese Medicine, Nanjing 210028, Jiangsu, China E-mail: [email protected]; [email protected] ORCID Qiaomei Jin: 0000-0002-8559-9125

ABSTRACT: A [3 + 4] annulation of isatin N,N′ -cyclic azomethine imine 1,3 -dipole 1 with in situ generated aza-oQMs has been established for the synthesis of spirooxindole seven-membered scaffolds. These highly functionalized scaffolds were assembled in moderate to good yields (up to 96% yield). The novel spirooxindole scaffolds displayed moderate antitumor activities, which represented promising lead compounds for antitumor drug discovery.

INTRODUCTION Spirooxindole alkaloids with a spiro ring fusion at the 3-position of the oxindole backbone have pronounced and diverse bioactivity.1 C3-modified spirooxindoles with a rigid nitrogen heterocyclic system are effective at inhibiting cancer cell proliferation, such as spirooxindole derivatives bearing five-membered2 and six-membered3

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N-heterocycle moieties. Thus, the development of efficient synthetic approaches to diverse spirooxindole five-membered and six-membered heterocycles is of great importance for drug discovery. Several groups have achieved synthesis of these C3-modified spirooxindoles using the organo- or organometallic-catalytic asymmetric cascade strategies.4 Nevertheless, to the best of our knowledge, methods toward the construction of spirooxindole seven-membered heterocycles are still challenging and rare. And maybe these nitrogen-containing seven-membered heterocyclic compounds possess anticancer activities like spirooxindole five-membered and six-membered heterocycles (Figure 1).

Figure 1. Representative biologically active compounds containing the 3heterocyclic system substituted oxindole skeleton. In 2003, Fu’s group5 reported the first example of catalytic asymmetric 1,3-dipolar cycloaddition of azomethine imines with alkynes, the azomethine imine molecules are among the most powerful 1,3-dipole for the construction of carbon-carbon and heterocycles over the past decade.6 Among such uses, both transition metal catalysts7 and organocatalysts8 have been introduced to promote

1,3-dipolar [3+2]

cycloadditions between azomethine imines and various alkynes/ alkenes to build a variety of five-membered heterocyclic frameworks (Scheme 1a). In addition to the common [3+2] reaction pathway, 1,3-dipolar [3+3] cycloadditions of azomethine imines, which are complement to the concerted Diels–Alder cycloaddition reaction, offer an advantage for the synthesis of diverse six-membered heterocyclic compounds (Scheme 1a).9 However, the related [3+4] cycloadditions of azomethine imines that can form seven-membered heterocyclic derivatives are much less studied.


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(a) O [3+2] annulations X Y (a)

O

N X Y R' R O

[3+3] annulations Y X Z (b)

N N

N R'

R R' azomethine imine

[3+4] annulations Y X (c)

well explored

N

N X well explored Y Z

R O unexplored

N X Y

N R' R

O

(b)

O

N N 1

O

R

R3 N N

R3

N R2

N H

Cl PG

[3+4] annulations catalyst-free this work

New 1,3-dipole

N PG O N R2

3

2

1

R1

spirooxindole seven-membered

Scheme 1. (a) Different reaction models of azomethine imines. (b) Design of the new [3+4] cycloaddition. Since the first example of [4 + 2] cycloaddition reported by Corey and Steinhagen, aza-o-quinone methides (aza-oQMs), in situ generated through the base-mediated elimination of N-(ortho-chloromethyl)aryl amides, have been widely applied as useful synthons in [4 + m] cycloaddition reactions.10 Recently, Xiao’s group established [4 + 1] cycloadditions of sulfur ylides and aza-oQMs.11 And Scheidt’s group developed an efficient approache to dihydroquinolones via an organocatalytic [4 + 1] cycloaddition by combining aza-oQMs with acyl anion.12a They also reported [4 + 2] cycloadditions of enolate equivalents with aza-oQMs in the presence of N-heterocyclic carbenes in 2014.12b Very recently, the Shi’s group reported a [4+3] cycloaddition of ortho-hydroxybenzyl alcohols with of N,N′ -cyclic azomethine imines under Brønsted acid catalysis.

12c

Despite those elegant contributions, [4+3] cycloadditions of



aza-oQMs are still appealing and highly desirable. Given our ongoing interest in 1,3-dipolar cycloaddition and spirooxindole alkaloids, we envisioned a direct pathway to access spirooxindole seven-membered heterocycles via a [3 + 4] annulation of a new 1,3-dipole (isatin N,N′ -cyclic azomethine imine 1,3 -dipole 1) with the in situ-formed aza-oQMs (Scheme 1b). RESULTS AND DISCUSSION Results of our initial studies and condition optimizations with isatin N,N′ -cyclic azomethine imine 1,3 -dipole 1a and methyl (2-(chloromethyl)phenyl)carbamate 2a as the model substrates are shown in Table 1. At the outset, the reaction of 1a and 2a in the presence of K2CO3 (1.0 equiv.) in CH3CN at 55 °C for 10 h afforded 3a in 35% yield (entry 2, Table 1). A moderate yield of the target product was formed when the amount of K2CO3 was increased to 2.0 equiv. However, the yield increased slightly with more loading of base (entry 2, Table 1). The use of Na2CO3 in in CH3CN also afforded the desired product 3a in 35% yield. The structure and stereochemistry of 3a was established by analysis of its NMR data, high-resolution mass spectrometry (HRMS), and single-crystal X-ray diffraction.13Subsequently, a series of bases were explored. Organic bases, such as Et3N and DIPEA, were found ineffective for this reaction (entries 8-9, Table 1). While the use of inorganic bases like t-BuOK, KOH, NaOH failed to produce the expected product (entries 5-7, Table 1), the other bases exhibited comparable activity, and Cs2CO3 was shown to be the most effective in this reaction (entry 4, Table 1). And solvent effects were further investigated (entries 11-15, Table 1), but we did not obtain positive results when we tried to improve the reaction yield by using different solvents. The temperature has a great effect on the reaction. For example, lowering the reaction temperature to room temperature slightly affected the yields but obviously lengthened the reaction time (entry 16, Table 1). Further investigation toward the influence of the amount of Cs2CO3 revealed that we obtain almost the same results when the base loading was increased to 4.0 equiv. Thus, we established the optimal reaction conditions: 1a: 2a: Cs2CO3 = 1:1.25: 2 molar ratio, in 2 mL CH3CN under Ar at 55 °C (entry 4, Table 1).


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Table 1. Optimization of the reaction conditions a

entry

base (equiv)

Solvent

Temp (°C)

Time (h)

Yield of 3a (%) b

1

0

CH3CN

reflux

24

0

2

K2CO3 (2.0)

CH3CN

55

10

42(35)c

3

Na2CO3 (2.0)

CH3CN

55

10

35

4

Cs2CO3 (2.0)

CH3CN

55

2

73

5

t-BuOK (2.0)

CH3CN

55

10

trace

6

NaOH (2.0)

CH3CN

55

15

trace

7

KOH (2.0)

CH3CN

55

15

trace

8

NEt3 (2.0)

CH3CN

55

1

29

9

DIPEA (2.0)

CH3CN

55

2

23

10

DMAP (2.0)

CH3CN

55

5

0

11

Cs2CO3 (2.0)

DMF

55

2

62

12

Cs2CO3 (2.0)

1,4-Dioxane

55

2

32

13

Cs2CO3 (2.0)

toluene

55

5

trace

14

Cs2CO3 (2.0)

THF

55

2

trace

15

Cs2CO3 (2.0)

DCE

55

2

< 10

16

Cs2CO3 (2.0)

CH3CN

rt

24

68

17

Cs2CO3 (4.0)

CH3CN

55

1

65

a

Unless noted otherwise, reaction of 1a (0.2 mmol), 2a (0.25 mmol) and base (0.4 mmol) was performed in 2.0 mL of solvent under Ar. b Isolated yield based on 1a. c Using 0.2 mmol of K2CO3.

With the optimized reaction conditions established, the generality of the catalyst-free self [3 + 4] cycloaddition of isatin N,N′ -cyclic azomethine imine 1,3 -dipole 1 with N-(ortho-chloromethyl)aryl amides 2 was explored. As shown in Scheme

2,

most

isatin

N,N′

-cyclic

azomethine

imines

1

and

N-(ortho-chloromethyl)aryl amides 2 were well tolerated. Initially, different 1,3-dipoles 1 with diverse substituents were investigated in reaction with 2a. It seems that the electronic nature of the substituents had certain impact on the reaction yields



since the desired products 3a-3h were all obtained in Scheme 2. Reaction scope a, b


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a

Typical conditions: Cs2CO3 (2.0 equiv) was added to a stirred solution of 1 (0.2 mmol) and 2 (0.25 mmol) in CH3CN (2.0 mL) at 55 °C for 2 h under Ar atmosphere. b Isolated yield based on 1.

moderate to excellent yields. In general, substrates with electron-donating groups (3g: 96%) exhibited higher reactivity than with electron-withdrawing group (3h: 48%), probably because the latter substituent would lower the nucleophilicity of the 1,3-dipoles 1. In addition, N- methyl, N- isopropyl and N- allyl could smoothly afford the desired products with good results. However, N- unprotected 1,3-dipole was found to be not suitable for this reaction, only a trace product was formed. Subsequently, the generality of a series of N-(ortho-chloromethyl)aryl amides 2 bearing different substituents were evaluated. At first, the reaction of the N-protecting group of aza-oQM precursors either resulted in decreased yields or did not work at all. For example, N- Cbz group, N-Boc group and N-COOi-Pr group afforded the corresponding products in inferior yields, while N-Ac substituted gave complex product. Nevertheless, the N-Ts group was not suitable and the expected [3 + 4] cycloadduct was formed in a trace amount. On the other hand, good tolerance for diverse electron-donating or -withdrawing groups at different positions on the phenyl ring of the N-(ortho-chloromethyl)aryl amides 2 was observed. As expected, the reactions of these aza-oQM precursors worked equally smoothly to give the desired products

3i-3m

in

moderate

yields.

However,

methyl

(3-chloro-2-(chloromethyl)phenyl)carbamate resulted in a lower yield (3k). To further explore the synthetic utility of this protocol, we then focused on the application of several substrates. As shown in Scheme 3, first, methyl (2-(bromomethyl)phenyl)carbamate was employed to react with 1a under standard conditions. Gratifyingly, this reaction works smoothly to afford the desired product 3a in 65% yield. However, 2-((methoxycarbonyl)amino)benzyl methanesulfonate was found to be inapplicable to this protocol (Scheme 3a). Subsequently, the reaction between N,N′-cyclic azomethine imine 4 and 2a was also further examined under standard conditions which produced [3 + 4] annulation product 5 in 78% yield (Scheme 3b). To demonstrate the synthetic potential of this catalytic system, the gram-scale preparation of highly functionalized 3a was investigated. The reaction of 3


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mmol of 1a proceeded smoothly, delivering the corresponding product 3a without a significant loss of efficiency (gram scale, 70%) (Scheme 3c), showing the reaction to be a practical tool for

the

synthesis

of

highly

functionalized

spirooxindole

seven-membered

heterocycles. Scheme 3. Synthetic applications

On the basis of our results and the previous studies, a plausible mechanism was proposed as illustrated in Scheme 4. First, N-(ortho-chloromethyl)aryl amides 2 reacts with Cs2CO3 to form the in situ generated aza-oQMs intermediate. Then, aza-oQMs intermediate reacts with the isatin N,N′ -cyclic azomethine imines 1 to generate the final product 3 through a thermal [3 + 4] annulation.



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Scheme 4. Plausible reaction mechanism

Table 2. In vitro antitumor activities of the seven-membered N-heterocycle-fused spirooxindoles (IC50, µM)

IC50 (µM) Compounds

a

Previously,

the

MCF-7

MDA-MB-231

3a

N.D.a

N.D.

3b

7.26

15.50

3c

2.74

N.D.

3d

>100

5.141

3f

7.03

20.61

3g

N.D.

N.D.

3h

4.47

N.D.

3i

>100

N.D.

3j

5.12

N.D.

3l

>100

N.D.

3m

>100

N.D.

3n

>100

N.D.

3p

>100

N.D.

Withaferin A

1.08

1.15

Not determined. five-membered

and

six-membered

N-heterocycle-fused

spirooxindoles displayed good in vitro antitumor activity. Therefore, the target seven-membered compounds were assayed for in vitro antitumor activity against two breast cancer lines (MCF-7 and MDA-MB-231) using the standard MTT method. As summarized in Table 2, most compounds exhibited moderate to good antitumor


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activities against MCF-7 breast cancer cells at low micromolar concentrations. However, these compounds showed little bioactivity against MDA-MB-231 cells. Among all the compounds, 3b (7.26 µM, 15.50 µM) and 3f (7.03 µM, 20.61 µM) showed the best antitumor activities against these two breast cancer lines. These results suggest that seven-membered N-heterocycle-fused spirooxindoles framework could be a new template for the design of novel anticancer molecules. CONCLUSION In summary, we have established an efficient method for the [3 + 4] annulation of isatin N,N′ -cyclic azomethine imine 1,3 -dipole 1 with in situ generated aza-oQMs, which constructed biologically important spirooxindole seven-membered scaffolds in considerable yields (up to 96% yield). The present methodology is mild, practical and one-pot method. The in vitro antitumor activity assay indicated that these scaffolds displayed moderate antitumor activities. Further chemical modification and biological exploration of these compounds are underway in our laboratory. EXPERIMENTAL SECTION General information All reactions were performed in anhydrous solvents under an argon atmosphere and were monitored by thin-layer chromatography carried out on silica gel aluminum sheets (60F-254) and spots were visualized with UV light. All solvents were purchased from commercial suppliers and were purified according to standard procedures. 1,3 -dipoles 114 and N-(ortho-chloromethyl)aryl amides 215 can be prepared according to known procedures. 1H NMR and

13

C NMR spectra were

recorded at room temperature on BRUKER Avance 400 spectrometers. Chemical shifts were reported in parts per million (ppm, δ units), and tetramethylsilane (TMS) was used as an internal reference. Coupling constants (J) were expressed in hertz. High-resolution mass spectra (HRMS) were recorded on TOF perimer for ESI+. General procedure for the [3 + 4] annulation of satin N,N′ -cyclic azomethine imine 1,3 -dipole 1 with the N-(ortho-chloromethyl)aryl amides 2 To the solution of isatin N,N′ -cyclic azomethine imine 1,3 -dipole 1 (0.2 mmol) and N-(ortho-chloromethyl)aryl amides 2 (0.25 mmol) in CH3CN (2 mL), Cs2CO3 ACS Paragon Plus Environment


(2.0 equiv) was added. The resulting mixture was stirred and heated at 55 °C under argon atmosphere for the required period of time. After completion of the reaction as monitored by TLC, the solvents were evaporated under reduced pressure and the residue was purified by silica gel chromatography (PE/EtOAc, 2:1) to afford the product 3. Methyl (S)-1'-benzyl-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triaz epine-5,3'-indoline]-6(11H)-carboxylate (3a) White solid (68 mg, 73%), MP: 199-200 °C. 1H NMR (400 MHz, CDCl3) δ 7.49-7.44(m, 3H), 7.41 (s, 2H), 7.38-7.28 (m, 5H), 7.17 (d, J = 7.1 Hz, 1H), 7.04 (t, J = 7.3 Hz, 1H), 6.89 (dd, J = 21.1, 7.7 Hz, 1H), 5.15-4.87 (m, 4H), 3.59 (s, 3H), 2.96-2.89 (m, 1H), 2.69-2.62 (m, 1H), 2.40-2.31 (m, 1H), 2.17-2.11 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.8, 169.8, 153.8, 143.7, 138.6, 135.9, 131.7, 130.8, 129.01, 128.9, 128.7, 128.4, 128.4, 127.8, 125.8, 123.7, 123.2, 109.5, 79.2, 53.4, 46.7, 44.6, 44.0, 30.7. HRMS calcd for C27H24N4O4Na [M+Na]+ 491.1695, found 491.1689. Methyl (S)-1'-methyl-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]tria zepine-5,3'-indoline]-6(11H)-carboxylate (3b) White solid (37 mg, 48%), MP: 239-240 °C. 1H NMR (400 MHz, CDCl3) δ 7.49-7.36 (m, 4H), 7.32 (t, J = 7.3 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 7.07 (t, J = 7.4 Hz, 1H), 6.92-6.85 (m, 1H), 5.03-4.94 (m, 2H), 3.55(s, 3H), 3.34 (s, 3H), 2.98-2.91 (m, 1H), 2.71-2.64 (m, 1H), 2.50-2.46(m, 1H), 2.29-2.13 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.9, 169.7, 153.8, 144.4, 138.4, 131.6, 130.9, 130.4, 129.4, 128.9, 128.6, 128.3, 128.3, 125.8, 123.5, 123.1, 108.5, 79.2, 53.2, 46.6, 44.0, 30.8, 26.6. HRMS calcd for C21H20N4O4Na [M+Na]+ 415.1382, found 415.1375. Methyl (S)-1'-isopropyl-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]tr iazepine-5,3'-indoline]-6(11H)-carboxylate (3c) White solid (64 mg, 76%), MP: 251-252 °C. 1H NMR (400 MHz, CDCl3) δ 7.45-7.42 (m, 1H), 7.42-7.33 (m, 3H), 7.30-7.27 (m, 1H), 7.17-7.13 (m, 1H), 7.13-7.02 (m, 2H), ACS Paragon Plus Environment

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5.06-4.90 (m, 2H), 4.79-4.62 (m, 1H), 3.54 (s, 3H), 3.00-2.92 (m, 1H), 2.75-2.65 (m, 1H), 2.55-2.51 (m, 1H), 2.29-2.14 (m, 1H), 1.59 (d, J = 7.1 Hz, 3H) , 1.56 (d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ170.4, 169.8, 153.7, 138.6, 131.7, 130.6, 129.3, 128.9, 128.6, 128.4, 128.2, 126.2, 123.8, 122.5, 110.0, 78.7, 53.1, 46.6, 44.3, 43.8, 30.9, 19.4, 18.9. HRMS calcd for C23H24N4O4Na [M+Na]+ 443.1695, found 443.1699. Methyl (S)-1'-allyl-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triazep ine-5,3'-indoline]-6(11H)-carboxylate (3d) White solid (74 mg, 89%), MP: 248-249 °C. 1H NMR (400 MHz, CDCl3) δ 7.49-7.43 (m, 1H), 7.41-7.35 (m, 3H), 7.31 (d, J = 7.7 Hz, 1H), 7.17 (d, J = 7.1 Hz, 1H), 7.06 (t, J = 7.4 Hz, 1H), 6.94 (d, J = 7.8 Hz, 1H), 5.98-5.84 (m, 1H), 5.43 (d, J = 17.2 Hz, 1H), 5.30 (d, J = 10.2 Hz, 1H), 5.08-4.90 (m, 2H), 4.54-4.37 (m, 2H), 3.55 (s, 3H), 3.01-2.94 (m, 1H), 2.75-2.69 (m, 1H), 2.60-2.47 (m, 1H), 2.27-2.14 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.5, 169.7, 153.7, 143.5, 138.5, 131.6, 131.3, 130.7, 128.9, 128.6, 128.4, 128.2, 125.8, 123.5, 123.0, 118.7, 118.3, 109.4, 79.1, 53.2, 46.6, 43.9, 42.9, 30.8. HRMS calcd for C23H22N4O4Na [M+Na]+ 441.1539, found 441.1543. Methyl (S)-1'-benzyl-5'-methyl-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][ 1,2,4]triazepine-5,3'-indoline]-6(11H)-carboxylate (3f) White solid (49 mg, 51%), MP: 225-226 °C. 1H NMR (400 MHz, CDCl3) δ 7.50-7.42 (m, 3H), 7.43-7.37 (m, 2H), 7.36-7.27 (m, 4H), 7.10 (t, J = 9.2 Hz, 1H), 6.98 (s, 1H), 6.79-6.72 (m, 1H), 5.10-4.89 (m, 4H), 3.59 (s, 3H), 2.95-2.88 (m, 1H), 2.71-2.59 (m, 1H), 2.39-2.32 (m, 1H), 2.29 (s, 3H), 2.19-2.06 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.7, 169.7, 153.8, 136.0, 132.9, 131.7, 131.1, 129.0, 128.9, 128.6, 128.4, 128.3, 127.8, 124.4, 109.3, 79.4, 53.3, 46.6, 44.6, 44.0, 307, 21.1. HRMS calcd for C28H26N4O4Na [M+Na]+ 505.1852, found 505.1858. Methyl (S)-1'-benzyl-5'-methoxy-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a ][1,2,4]triazepine-5,3'-indoline]-6(11H)-carboxylate (3g) ACS Paragon Plus Environment


White solid (96 mg, 96%), MP: 198-199 °C. 1H NMR (400 MHz, CDCl3) δ 7.48-7.43 (m, 3H), 7.42-7.27 (m, 6H), 6.89-6.70 (m, 3H), 5.09-4.89 (m, 4H), 3.73 (s, 3H), 3.59 (s, 3H), 2.98-2.90(m, 1H), 2.74-2.56 (m, 1H), 2.42-2.34 (m, 1H), 2.22-2.06 (m, 1H). 13

C NMR (100 MHz, CDCl3) δ170.6, 169.7, 156.2, 153.8, 138.6, 137.0, 136.0, 131.7,

129.0, 128.9, 128.7, 128.3, 127.8, 114.8, 111.1, 110.0, 79.4, 55.7, 53.3, 46.7, 44.7, 44.0, 30.7. HRMS calcd for C28H26N4O5Na [M+Na]+ 521.1801, found 521.1803. Methyl (S)-1'-benzyl-5'-chloro-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][ 1,2,4]triazepine-5,3'-indoline]-6(11H)-carboxylate (3h) White solid (48 mg, 48%), MP: 250-251 °C. 1H NMR (400 MHz, CDCl3) δ 7.51-7.43 (m, 3H), 7.40 (d, J = 4.3 Hz, 2H), 7.38-7.26 (m, 5H), 7.14 (d, J = 1.2 Hz, 1H), 6.79 (dd, J = 16.5, 8.3 Hz, 1H), 5.13-4.89 (m, 4H), 3.61 (s, 3H), 3.01-2.93 (m, 1H), 2.71-2.57 (m, 1H), 2.40-2.31 (m, 1H), 2.22-2.07 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.4, 169.6, 153.9, 142.2, 138.2, 135.4, 131.5, 130.7, 129.2, 129.0, 128.7, 128.5, 128.3, 128.0, 127.7, 127.4, 124.1, 110.5, 79.0, 53.4, 46.6, 44.7, 44.0, 30.5. HRMS calcd for C27H23N4O4ClNa [M+Na]+ 525.1306, found 525.1312. Methyl (S)-1'-benzyl-8-chloro-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1 ,2,4]triazepine-5,3'-indoline]-6(11H)-carboxylate (3i) White solid (51 mg, 51%), MP: 166-167 °C. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.4 Hz, 2H), 7.41-7.30 (m, 7H), 7.20 (d, J = 7.2 Hz, 1H), 7.13-7.08(m, 1H), 6.97-6.82 (m, 1H), 5.15-4.89 (m, 4H), 3.63 (s, 3H), 3.00-2.83 (m, 1H), 2.66-2.57 (mz, 1H), 2.31-2.19 (m, 1H), 2.18-2.09 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.4, 169.7, 135.8, 134.2, 131.0, 130.2, 129.5, 128.9, 128.6, 128.4, 127.9, 127.8, 123.6, 123.3, 109.6, 79.4, 53.5, 46.0, 44.6, 44.00, 30.6. HRMS calcd for C27H23N4O4ClNa [M+Na]+ 525.1306, found 525.1315. Methyl (S)-1'-benzyl-8-fluoro-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1 ,2,4]triazepine-5,3'-indoline]-6(11H)-carboxylate (3j) White solid (38 mg, 39%), MP: 175-176 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J ACS Paragon Plus Environment

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= 7.3 Hz, 2H), 7.38-7.29 (m, 5H), 7.18 (d, J = 7.0 Hz, 1H), 7.13-7.04 (m, 3H), 6.93-6.85 (m, 1H), 5.13-4.87 (m, 4H), 3.60 (s, 3H), 2.94-2.87(m, 1H), 2.65-2.54 (m, 1H), 2.38-2.90 (m, 1H), 2.21-2.07 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.5, 169.6, 163.8, 161.3, 153.4, 135.8, 130.9, 129.6 (d, J = 36.0 Hz), 128.9, 127.9, 127.9, 127.8, 127.7, 123.6, 123.3, 116.1, 115.9, 115.3, 115.1, 109.6, 79.4, 53.5, 45.9, 44.6, 44.0, 30.6. HRMS calcd for C27H23N4O4FNa [M+Na]+ 509.1601, found 509.1607. Methyl (S)-1'-benzyl-7-methyl-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][ 1,2,4]triazepine-5,3'-indoline]-6(11H)-carboxylate (3l) White solid (37 mg, 38%), MP: 201-202 °C. 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.4 Hz, 2H), 7.37-7.28(m, 5H), 7.23-7.13 (m, 3H), 7.03 (t, J = 7.4 Hz, 1H), 6.93-6.84 (m, 1H), 5.09 (d, J = 15.4 Hz, 1H), 5.01-4.89 (m, 3H), 3.58 (s, 3H), 3.01-2.85 (m, 1H), 2.72-2.58 (m, 1H), 2.42 (s, 3H), 2.40-2.30 (m, 1H), 2.17-.08 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.9, 169.7, 153.9, 143.7, 138.4, 135.9, 131.4, 130.8, 129.6, 129.4, 128.9, 128.1, 127.8, 123.7, 123.1, 109.5, 79.1, 53.3, 46.7, 44.6, 43.9, 30.7, 21.2. HRMS calcd for C28H26N4O4Na [M+Na]+ 505.1852, found 505.1855. Methyl (S)-1'-benzyl-9-bromo-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][ 1,2,4]triazepine-5,3'-indoline]-6(11H)-carboxylate (3m) White solid (48 mg, 44%), MP: 199-200 °C. 1H NMR (400 MHz, CDCl3) δ 7.62-7.51 (m, 2H), 7.47 (d, J = 7.3 Hz, 2H), 7.39-7.28 (m, 4H), 7.19-7.12 (m, 2H), 7.04 (t, J = 7.4 Hz, 1H), 6.95-6.80 (m, 1H), 5.15-4.88 (m, 4H), 3.58(s, 3H), 2.92-2.87 (m, 1H), 2.72-2.55 (m, 1H), 2.46-2.28 (m, 1H), 2.16-2.07 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.5, 169.8, 153.5, 135.8, 133.6, 132.1, 131.6, 130.9, 130.0, 128.9, 127.9, 127.7, 123.5, 123.3, 121.6, 109.6, 79.2, 53.4, 46.2, 44.6, 44.0, 30.6. HRMS calcd for C27H23N4O4BrNa [M+Na]+ 569.0800, found 569.0810. Benzyl (S)-1'-benzyl-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triaz epine-5,3'-indoline]-6(11H)-carboxylate (3n) White solid (25 mg, 23%), MP: 169-170 °C. 1H NMR (400 MHz, CDCl3) δ 7.52-7.48 ACS Paragon Plus Environment


(m, 2H), 7.40-7.27 (m, 9H), 7.25-7.14 (m, 3H), 7.10-7.04 (m, 3H), 6.87-6.80(m, 1H), 5.14-4.90 (m, 5H), 4.89-4.61 (m, 1H), 2.98-2.74 (m, 1H), 2.70-2.45 (m, 1H), 2.42-2.26 (m, 1H), 2.23-2.04 (m, 1H). 13C NMR (100 MHz, CDCl3) δ170.9, 169.7, 135.9, 131.6, 131.5, 130.8, 128.9, 128.6, 128.5, 128.4, 128.4, 128.3, 127.8, 127.2, 123.7, 123.2, 109.5, 100.0, 79.2, 46.7, 44.0, 30.7, 14.2. HRMS calcd for C33H28N4O4Na [M+Na]+ 567.2008, found 567.2012. Tert-butyl (S)-1'-benzyl-1,2'-dioxo-2,3-dihydro-1H-spiro[benzo[e]pyrazolo[1,2-a][1,2,4]triaz epine-5,3'-indoline]-6(11H)-carboxylate (3p) White solid (58 mg, 57%), MP: 199-201 °C. 1H NMR (400 MHz, CDCl3) δ 7.52-7.43 (m, 3H), 7.38-7.27 (m, 7H), 7.136-7.10 (m, 1H), 7.05-6.96 (m, 1H), 6.98-6.81 (m, 1H), 5.16-4.72 (m, 4H), 2.90-2.71(m, 1H), 2.68-2.48 (m, 1H), 2.44-2.13 (m, 1H), 2.05-1.91 (m, 1H), 1.26 (s, 9H).

13

C NMR (100 MHz, CDCl3) δ171.0, 170.8, 153.2,

140.6, 139.5, 136.1, 135.5, 131.5, 130.4, 129.0, 128.7, 128.4, 128.2, 127.7, 127.3, 123.5, 109.4, 81.2, 47.9, 46.7, 44.5, 43.8, 30.8, 28.1, 27.8. HRMS calcd for C30H30N4O4Na [M+Na]+ 533.2165, found 533.2168. Methyl 1-oxo-5-phenyl-2,3-dihydro-1H,5H-benzo[e]pyrazolo[1,2-a][1,2,4]triazepine-6(11 H)-carboxylate (5) White solid (53 mg, 78%), MP: 193-194 °C. 1H NMR (400 MHz, CDCl3) δ 7.41-7.30 (m, 5H), 7.21 (s, 2H), 6.73 (d, J = 7.6 Hz, 1H), 6.14 (s, 1H), 4.92 (d, J = 14.5 Hz, 1H), 4.70-4.50 (m, 1H), 3.90-3.75 (m, 1H), 3.63 (s, 3H), 3.33 (d, J = 8.5 Hz, 1H), 3.10-2.90 (m, 2H), 2.39-2.21 (m, 1H).13C NMR (100 MHz, CDCl3) δ171.4, 155.5, 133.1, 130.5, 129.0, 128.5, 128.3, 128.3, 128.2, 128.1, 78.8, 53.2, 48.5, 47.3, 30.0. HRMS calcd for C19H19N3O3Na [M+Na]+ 360.1324, found 360.1329. ASSOCIATED CONTENT

Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: X-ray data of 3a (CIF); 1H and 13C NMR spectra of final products.


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ACKNOWLEDGMENT We sincerely thank the China Pharmaceutical University for providing spectra.

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imines. Chem. Commun. 2017, 53, 2768-2771. (13) CCDC 1818995 contains the supplementary crystallographic data for compound 3a. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. (14) For selected examples, see: (a) Wang, X.; Yang, P.; Zhang, Y.; Tang, C.Z.; Tian, F.; Peng, L.; Wang, L.X. Isatin N,N'-cyclic azomethine imine 1,3-Dipole and abnormal

[3

+

2]-cycloaddition

with

maleimide

in

the

presence

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1,4-Diazabicyclo[2.2.2]octane. Org. Lett., 2017, 19, 646-649. (b) Wang, X.; Wu, L.; Yang, P.; Song, X. J.; Ren, H. X.; Peng, L.; Wang, L.X. Isatin N,N'-cyclic azomethine imine 1,3-Dipole and base catalyzed Michael addition with β-Nitrostyrene via C3 umpolung of oxindole. Org. Lett., 2017, 19, 3051-3054. (15) For selected examples, see: (a) Lee, A.; Younai, A.; Price, C. K.; Izquierdo, J.; Mishra, R. K.; Scheidt, K. A. Enantioselective annulations for dihydroquinolones by in situ generation of azolium enolates. J. Am. Chem. Soc. 2014, 136, 10589-10592. (b) Kim, S.; Kang, K. T.; Kim, S. G. Asymmetric domino aza-Michael–Michael reaction of o-N-protected aminophenyl α,β-unsaturated ketones: construction of chiral functionalized tetrahydroquinolines. Tetrahedron 2014, 70, 5114-5121.


(ortho-Chloromethyl)aryl Amides - ACS Publications

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