CC BY-NC-ND 4.0 · SynOpen 2021; 05(01): 1-16
DOI: 10.1055/s-0040-1706005
paper

Diversity-Oriented Synthesis of Novel Trihalomethyl-Containing Spirochromeno[3,4-a](thia)pyrrolizidines and Spirochromeno-[3,4-a]indolizidines by One-Pot, Three-Component [3+2]-Cyclo­addition Reaction

Igor B. Kutyashev
,
Maxim S. Sannikov
,
Ivan A. Kochnev
,
Alexey Y. Barkov
,
,
,
Vyacheslav Y. Sosnovskikh
The work was financially supported by the Russian Foundation for Basic Research (grant 20-03-00716) and by the Ministry of Science and Higher Education of the Russian Federation (project FEUZ-2020-0052).
 


Abstract

Regio- and stereoselective methods for the synthesis of 6′-trifluoro(trichloro)methyl substituted spiro[acenaphthylene-1,11′-chromeno[3,4-a](thia)pyrrolizidin]-2-ones and spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizidin]-2-ones have been developed based on the three-component reaction of 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes with azomethine ylides generated in situ from acenaphthenequinone and cyclic α-amino acids. The cycloaddition proceeds under mild conditions in ethanol or DMSO, and only endo-isomers of the products with cis-arrangement of nitro and trifluoromethyl groups are formed. The relative configuration of cycloadducts is reliably confirmed by X-ray diffraction analysis and by 2D NOESY spectroscopy.


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Diversity-oriented synthesis (DOS) of small molecules followed by screening of these molecules for their ability to modulate a biological pathway in cells or organisms is one of the most effective and dynamically developing approaches to modern drug discovery. In the last decade, special attention has been paid to increasing the structural and functional diversity in the construction of collections of small molecules.[1]

Zoom Image
Figure 1 Representatives of synthetic and natural bioactive chromene and chromane derivatives

One DOS approach involves the creation of compound libraries based on privileged molecular scaffolds, ubiquitous in clinically significant bioactive natural products, followed by an increase in the scaffold diversity about the privileged skeleton. From this point of view, 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes[2] are suitable starting compounds for privileged-substructure-based DOS. The molecular cores of chromenes and chromanes are present in the skeleta of numerous natural and synthetic bioactive compounds.[2] [3] For example, 3-nitro-2-trifluoromethyl-2H-chromene (TIM-38) has been shown to be a P2Y6 receptor inhibitor and a promising anti-inflammatory agent (Figure [1]).[4a] 6-Bromo-8-ethoxy-3-nitro-2H-chromene (BENC-511) exhibits antitumor activity against various cancer cell lines due to the inhibition of phosphoinositide 3-kinase.[4b] It was recently found that 6-CF3-spiro[chromenopyrrolidine-1,3′-oxindoles] (A) have a pronounced cytotoxic activity against HeLa human cervical cancer cells.[4c] Glabridin, an isoflavane, isolated from the roots of Glycyrrhiza glabra, is a drug candidate for memory improvement.[4d]

Due to the presence of the β-nitrostyrene fragment, 3-nitro-2H-chromenes actively react with nucleophiles and 1,3-dipoles. The replacement of the hydrogen atom in the 2-position with a more bulky trifluoro(trichloro)methyl group with a pronounced negative inductive effect leads to an increase in the stereoselectivity of nucleophilic addition and cycloaddition at the C=C bond.[2] It should be noted that nitrochromenes 1 (see Scheme [1]) are readily available and can be obtained from 1-nitro-3,3,3-trifluoro(trichloro)-1-nitroprop-1-enes and the corresponding salicylaldehydes in good yield.[5]

On the other hand, the trifluoromethyl group is a pharmacophore fragment that is present in a wide variety of drugs due to its increased lipophilicity and greater strength of the C–F bond compared to the C–H bond.[6] Among CCl3-containing organic molecules, compounds with GLI1-inhibitory, anthelmintic, antiplasmodial and 5-HT-inhibitory affects are known.[7]

1,3-Dipolar cycloaddition (1,3-DC) of stabilized azomethine ylides to activated alkenes is the shortest and the most efficient route to construction of the spiropyrroli(zi)dine and spiroindolizidine ring systems in a single reaction step.[8] This procedural-, atom-, and stage-economic (PASE)[9] strategy allows the creation of large libraries of such spiro-heterocycles from available reagents using a simple methodology based on intermolecular three-component reactions.[10] Intensive developments in this direction have led to the production of new representatives of spiropyrrolizidines with anticancer[11a] (B), antimicrobial[11b] (C), and AChE-inhibitory[11c] (D) activities, as depicted in Figure [2]. Pyrrolizidine and indolizidine scaffolds are ubiquitous in natural compounds. In particular, pteropodine is an alkaloid isolated from Uncaria tomentosa that acts as a positive modulator of muscarinic M1 and 5-HT2 receptors and may be involved in the improvement of impaired higher cognitive processes.[11d] Moreover, pteropodine has shown a pronounced enhancement effect on phagozytosis,[11e] as well as cytostatic[11f] and antimutagenic[11g] properties and is used in traditional medicine to cure a number of diseases (Figure [2]).

Zoom Image
Figure 2 Representatives of synthetic and natural bioactive spiro(thia)pyrrolizidines and spiroindolizidines

The cycloaddition of stabilized azomethine ylides based on acenaphthenequinone and α-amino acids to activated alkenes is being intensively studied.[8d] [e] [12] This is largely due to the fact that the spiroacenaphthylenone fragment is present in a number of synthetic compounds that have biological properties, including antimycobacterial[13a,b] (D, E) and antimalarial (F) activities.[13c] As was recently found, the spiroindolizidine derivative G is capable of enhancing osteoblast differentiation of human stem cells (Figure [3]).[13d]

Zoom Image
Figure 3 Representatives of bioactive spiroacenaphthylene-2-ones

Continuing our research aimed at studying the regio- and stereoselectivity of reaction of 1,3-DC of azomethine ylides with 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes,[14] in this work we report the regioselective and diastereoselective synthesis of chromene-spiro(thia)pyrrolizidine and chromene-spiroindolizidine hybrids 4, 6 and 7 from nitrochromenes 1, acenaphthenequinone 2 and cyclic α-amino acids 3 and 5 by a one-pot, three-component [3+2]-cycloaddition approach (Scheme [1]).

Zoom Image
Scheme 1 Strategy for the diversity-oriented synthesis of spiro(thia)pyrrolizidines and spiroindolizidines based on 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes

Diversity of substrates and reagents was provided by varying the substituents R1 and R2 in the benzene ring of the starting nitrochromenes, as well as the use of four cyclic α-amino acids (l-proline, l-thiaproline, l-pipecolic acid, (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) in the 1,3-DC reaction. Diversity of pharmacophores was ensured by the presence of chromane, spiro(thia)pyrrolizidine, spiroindolizidine and spiroacenaphthylenone scaffolds in the target products along with the trifluoro(trichloro)methyl group at the 6′ position.

First, the three-component reaction between nitrochromenes 1, acenaphthenequinone 2 and (thia)proline 3 was studied. To obtain spirochromeno[3,4-a](thia)pyrrolizidines 4, conditions optimization for a model reaction of nitrochromene 1a with azomethine ylide generated in situ from acenaphthenequinone 2 and l-proline 3a was performed (Table [1]). When the reaction was carried out in methanol or ethanol at reflux, the target product 4a was obtained as a single endo isomer in moderate yield after 2 h, but a notable darkening of the reaction mixture was observed (entries 1 and 3). Lowering the temperature to 55 °C led to an increase in product yield (entries 2 and 4). At the same temperature in isopropanol the product yield was lower (entry 5). In acetonitrile and DMSO, the target pro­duct was obtained even at room temperature within 24 h in 46% and 68% yield, respectively (entries 6 and 7). When THF was used as a solvent at room temperature over 2.5 h, a complex mixture of products was observed (entry 9). When benzene or toluene were used as solvents, the yields of the target product were noticeably lower (entries 10 and 11).

The best results were achieved when the reaction was carried out in ethanol or DMSO at 55 °C (Table [1], entries 4 and 8). In both cases, the reaction was complete after 3 h and product 4a was obtained in 77 and 75% yields, respectively. Considering the ease of removal of the solvent and its cost, we chose ethanol as the preferred solvent for the synthesis of compounds 4. No other regio- or stereoisomers were detected in the crude products by 1H NMR spectroscopic analysis.

Table 1 Conditions Optimizationa

Entry

Solvent

Temp (°C)

Time (h)

Yield (%)b

1

MeOH

reflux

2

55c

2

MeOH

55

2.5

67

3

EtOH

reflux

2

54c

4

EtOH

55

3

77

5

i-PrOH

55

3

43

6

MeCN

25

24

46

7

DMSO

25

24

68

8

DMSO

55

3

75

9

THF

25

2.5

d

10

PhH

55

3

57

11

PhMe

55

3

57

a Reaction conditions: 1a (0.1 mmol), 2 (0.1 mmol), 3a (0.13 mmol), solvent (2 mL).

b Isolated yield.

c Noticeable resinification.

d A complex mixture of products was formed.

Under the optimized conditions, the spirochromeno[3,4-a]pyrrolizidines 4aq and spirochromeno[3,4-a]thiapyrrolizidines 4ry were obtained in 36–89% yields in ethanol at 55 °C for 1–3.5 h using acenaphthenequinone 2, l-proline 3a or l-thiaproline 3b and 2-CX3 substituted (X = F, Cl) 3-nitro-2H-nitrochromenes 1 containing electron-donating or electron-withdrawing groups in the benzene ring (Table [2]). Note that due to their low solubility, the target products were isolated from the reaction mixture by filtration and purified by washing with ethanol and water.

In general, the nature of halogen and substituents R1, R2 in the starting chromene 1 has little effect on the yield of products 4. However, introduction of electron-deficient substituents such as Cl, Br or NO2 into the benzene ring of the chromene reduced the reaction time to 1–2 h, while reactions with chromenes containing electron-donating groups (R1, R2 = Me, OMe, OEt) under the same conditions were complete after 3–3.5 h. 1,3-DC involving the ylide from thiaproline was accompanied by lower yields (36–72%). In this case, the lowest yields (39 and 36%, respectively) were obtained for adducts 4v and 4w from 2-trichloromethyl substituted chromenes 1j and 1l.

Table 2 Synthesis of Spirochromeno[3,4-a](thia)pyrrolizidines 4

Entry

Chromene

X

R1

R2

Product

Y

Time (h)

Yield (%)a

Entry

Chromene

X

R1

R2

Product

Y

Time (h)

Yield (%)a

1

1a

F

H

H

4a

CH2

3

77

14

1n

Cl

Cl

H

4n

CH2

2

82

2

1b

F

Me

H

4b

CH2

3

78

15

1o

Cl

Cl

Cl

4o

CH2

2

78

3

1c

F

OMe

H

4c

CH2

3.5

78

16

1p

Cl

NO2

H

4p

CH2

1

79

4

1d

F

H

OEt

4d

CH2

3.5

80

17

1q

Cl

NO2

NO2

4q

CH2

1

82

5

1e

F

Cl

H

4e

CH2

2

81

18

1a

F

H

H

4r

S

3

56

6

1f

F

Cl

Cl

4f

CH2

2

67

19

1c

F

OMe

H

4s

S

3

61

7

1g

F

Br

OEt

4g

CH2

2

81

20

1f

F

Cl

Cl

4t

S

2

72

8

1h

F

NO2

H

4h

CH2

1

89

21

1h

F

NO2

H

4u

S

1

66

9

1i

F

NO2

NO2

4i

CH2

1

81

22

1j

Cl

H

H

4v

S

3

39

10

1j

Cl

H

H

4j

CH2

3

76

23

1l

Cl

OMe

H

4w

S

3

36

11

1k

Cl

Me

H

4k

CH2

3

71

24

1o

Cl

Cl

Cl

4x

S

2

65

12

1l

Cl

OMe

H

4l

CH2

3.5

75

25

1q

Cl

NO2

NO2

4y

S

1

69

13

1m

Cl

H

OEt

4m

CH2

3.5

63

a Isolated yield.

In contrast to α,β-unsaturated ketones and carboxylic acid derivatives, the reactions of strongly polar nitrostyrenes and 3-nitro-2H-chromenes with stabilized azomethine ylides based on cyclic carbonyl compounds and amino acids were accompanied by the binding of a more electrophilic β-C atom of the dipolarophile with the more substituted atom of the 1,3-dipole,[8] apparently due to the charge-controlled cycloaddition. A possible reaction mechanism involves the endo-addition of the S-shaped azomethine ylide to nitrochromene 1 through TS-1 (see Table [2]). In addition, the ylide attacks the C=C bond from the side of the small H-2 atom, rather than from the side of the trifluoromethyl group. In the exo-transition state TS-2 the pyran ring of the chromene and the (thia)proline moiety of ylide are located one under the other, making it less favorable due to unfavorable steric interactions (Table [2]).

Next, to obtain spirochromeno[3,4-a]indolizidines 6 and 7, reactions of chromenes 1 with azomethine ylides based on acenaphthenequinone 2 and l-pipecolic acid 5a or (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 5b were studied. Due to the low solubility of both amino acids in ethanol, DMSO was used as a solvent and a little water was added when l-pipecolic acid was used as reagent. It was found that these three-component reactions proceeded at 60–70 °C within 7 or 12 h and led to the corresponding products 6 or 7 as single isomers in 42–71% yields (Table [3]).

Table 3 Synthesis of Spirochromeno[3,4-a]indolizidines 6 and 7

Entry

Chromene

X

R1

R2

Product

Yield (%)a

Entry

Chromene

X

R1

R2

Product

Yield (%)a

1

1a

F

H

H

6a

58

12

1m

Cl

H

OEt

6l

49

2

1b

F

Me

H

6b

62

13

1n

Cl

Cl

H

6m

50

3

1c

F

OMe

H

6c

58

14

1o

Cl

Cl

Cl

6n

55

4

1d

F

H

OEt

6d

56

15

1a

F

H

H

7a

52

5

1e

F

Cl

H

6e

62

16

1b

F

Me

H

7b

71

6

1f

F

Cl

Cl

6f

64

17

1c

F

OMe

H

7c

63

7

1g

F

Br

OEt

6g

60

18

1d

F

H

OEt

7d

64

8

1h

F

NO2

H

6h

67

19

1e

F

H

Cl

7e

62

9

1j

Cl

H

H

6i

43

20

1f

F

Cl

Cl

7f

68

10

1k

Cl

Me

H

6j

44

21

1g

F

Br

OEt

7g

58

11

1l

Cl

OMe

H

6k

42

22

1h

F

NO2

H

7h

48

a Isolated yield.

As shown in Table [3], the donor-acceptor properties of substituents on the chromene have little effect on the target product yield. At the same time, the yields of 6′-trichloromethyl substituted spirochromeno[3,4-a]indoli­zidines 6 were always 7–18% lower than the yields of the corresponding CF3-substituted products.

Due to the low solubility of adducts 6 in the DMSO/H2O mixture, most of them were isolated from the reaction mixture by filtration and purified by recrystallization. Spiroadducts 7, soluble in DMSO, were precipitated from the reaction mixture by adding water and purified by column chromatography.

The IR spectra of products 4, 6 and 7 show the stretching vibrations of the carbonyl group (ν = 1697–1728 cm–1) and the NO2 group (ν = 1547–1566 cm–1, 1327–1345 cm–1). In the 1H NMR spectra of spirochromeno[3,4-a](thia)pyrrolizidines 4 and spirochromeno[3,4-a]indolizidines 6 and 7 in CDCl3, the characteristic singlet of the benzylic H-11a′ proton (H-12a′ proton and H-14a′ proton in compounds 6 and 7, respectively) at δ = 4.58–5.39 ppm was observed. The signal of the H-6′ proton was manifest as quartet at δ = 5.43–6.56 ppm with coupling constants 3 J HF = 5.5–6.8 Hz in the 6′-CF3 substituted compounds 4, 6, and 7 or as a singlet at δ = 5.67–6.93 ppm in the 6′-CCl3 substituted compounds 4 and 6. The H-1′ aromatic proton was shielded in all adducts by the benzene ring of acenaphthene moiety, such that its signal is shifted upfield relative to other aromatic protons of the chromane ring and resonates at δ = 5.04–6.88 ppm. The 19F NMR spectra of 6′-CF3 substituted compounds 4, 6, and 7 contain a doublet or broad singlet due to the trifluoromethyl group at δ = 90.4–95.9 ppm. The 13C NMR spectra of products 4, 6, and 7 exhibit a carbonyl carbon signal at δ = 202.9–208.9 ppm and quartets due the CF3 group and the C-6′ atom are observed in the range of 121.1–123.4 and 76.8–77.7 ppm, respectively, with coupling constants 1 J CF = 280.9–284.4 Hz and 2 J CF = 32.2–34.8 Hz.

The reaction of 3,6-dinitro-2-trichloromethyl-2H-chromene 1p with the azomethine ylide based on 2 and pipecolic acid 5a was accompanied by the elimination of HCl and led to a mixture of the target product 6o and 2-dichloromethylidene derivative 8 in a 76:24 ratio (Scheme [2]). It was not possible to isolate compounds 6o and 8 in their pure form.

Zoom Image
Scheme 2 Target and side products in the reaction of nitrochromene 1p with the azomethine ylide derived from acenaphthenequinone and l-pipecolic acid

In the 1H NMR spectrum of compound 8 there was no signal for the H-6 proton, while in its 13C NMR spectrum, 21 signals of sp2-carbon atoms were observed. Moreover, the mass spectrum of the crude product obtained in the positive ion mode ESI-HRMS showed a peak at m/z 552.0727 that corresponded to the molecular ion [8+H]+ along with the molecular ion [6o+H]+ at m/z 588.0494. A similar outcome has been previously observed in reactions of 2-trichloromethyl substituted nitrochromenes 1 with sodium azide[15a] and in the interaction of (E)-3,3,3-trichloro-1-nit­roprop-1-ene with diaryldiazomethanes.[15b] The elimination of HCl is probably the main reason for the lower yields of 6′-CCl3 products 6 compared to their 6′-CF3 analogues.

It was not possible to obtain spirocycloadducts 7 in the reaction of 2-CCl3 substituted nitrochromenes 1 with azomethine ylide from 2 and tetrahydroisoquinoline-3-carboxylic acid 5b. The reaction did not proceed at 60 °C and extensive decomposition was observed at higher temperatures. This may be due to the formation of unstable 2-(dichloromethylidene)nitrochromenes at 70 °C.[15a]

The structures and relative configurations of compounds 4, 6, and 7 were unambiguously confirmed by X-ray diffraction studies of products 4a and 6g (Figures [4] and 5) and by a 2D 1H–1H NOESY experiment for product 7g (Fi­gure [6]).

Zoom Image
Figure 4 Molecular structure of compound 4a (thermal vibration ellipsoids of 50% probability)

As seen in Figure [4] and Figure [5], in both molecules the carbonyl group of the acenaphthylenone moiety and the nitro group are located on opposite sides of the plane of the condensed heterocycle, while the nitro group, CF3 group, and hydrogen atoms H-12a′ (H-14a′ in compound 6g) and H-6b′ are on the same side of this plane.

Zoom Image
Figure 5 Molecular structure of compound 6g (thermal vibration ellipsoids of 50% probability)

The 2D 1H–1H NOESY spectrum of compound 7g shows a NOE cross-peak H-6′↔H-6b′ and no cross-peak H-6′↔H-14a′, indicating the cis-arrangement of the H-6′ and H-6b′ protons and a trans-arrangement of the H-6′ and H-14a′ protons relative to the plane of the heterocyclic system (Fi­gure [6]). Along with this, the cross-peaks H-14a′↔H-1′ and H-8↔H-1′ indicate the endo-configuration of adduct 7g.

Zoom Image
Figure 6 Main correlations in the 1H–1H NOESY NMR spectrum of compound 7g

In summary, a simple and effective method for the synthesis of novel 6′-trifluoro(trichloro)methyl substituted spiro[acenaphthylene-1,11′-chromeno[3,4-a](thia)pyrrolizidin]-2-ones and spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizidin]-2-ones has been developed based on a multicomponent regio- and stereoselective PASE-strategy. Diversity of pharmacophores in the target products was ensured by the hybridization of biologically active scaffolds. This approach allows libraries of hybrid heterocycles to be obtained rapidly based on readily available 3-nitro-2-trihalomethyl-2H-chromenes in quantities sufficient for primary bioscreening. Further studies of the biological properties of the obtained spirocycloadducts are planned.

IR spectra were recorded with a Shimadzu IRSpirit-T spectrometer equipped with an ATR accessory. NMR spectra were recorded with Bruker DRX-400 (1H, 400 MHz; 19F, 376 MHz) and Bruker Avance III-500 (1H, 500 MHz; 19F, 471 MHz; 13C, 126 MHz) spectrometers in CDCl­3. The 2D 1H–1H NOESY spectrum of compound 7g was acquired on a Bruker Avance NEO (600 MHz) spectrometer with 0.3 s mixing time. Chemical shifts (δ) are reported in ppm relative to the internal standard TMS (1H NMR), C6F6 (19F NMR) and to residual signals of the solvents (δ = 77.16 ppm, 13C NMR). HRMS spectra were obtained with a Bruker maXis Impact HD (qTOF MS) instrument. Elemental analyses were performed with a Perkin Elmer PE 2400 automatic analyser. Melting points were determined with an SMP40 apparatus. The starting 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes 1aq were prepared according to described procedures.[5]


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Synthesis of Spirochromeno[3,4-a](thia)pyrrolizidines 4; General Procedure

A suspension of the corresponding nitrochromene 1 (0.25 mmol), acenaphthenequinone (46 mg, 0.25 mmol) and l-proline (38 mg, 0.33 mmol) or l-thiaproline (44 mg, 0.33 mmol) in EtOH (2 mL) was stirred at 55 °C for the time indicated in the Table [2]. Then the mixture was cooled to r.t., the precipitate was filtered off, washed successively with EtOH (5 × 1 mL), H2O (5 × 1 mL) and dried at 60 °C. In some cases, additional recrystallization from CH2Cl2–hexane (1:3) was necessary.


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(1S*,6′S*,6a′S*,6b′S*,11a′R*)-6a′-Nitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4a)

Obtained according to the general procedure from 1a (61 mg) and l-proline.

Yield: 92 mg (77%); cream powder; mp 177–178 °C (decomp.).

IR (ATR): 1714, 1581, 1553, 1497, 1340 cm–1.

1H NMR (400 MHz): δ = 8.19 (d, J = 8.1 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.90 (d, J = 6.8 Hz, 1 H), 7.84 (t, J = 7.5 Hz, 1 H), 7.79 (d, J = 6.8 Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.03–6.97 (m, 2 H), 6.42–6.34 (m, 1 H), 5.90 (q, J = 6.7 Hz, 1 H), 5.83 (d, J = 7.7 Hz, 1 H), 5.28 (s, 1 H), 4.61 (t, J = 6.9 Hz, 1 H), 3.17–1.67 (m, 6 H).

19F NMR (376 MHz): δ = 94.4 (d, J = 6.7 Hz, CF3).

13C NMR (126 MHz): δ = 203.2, 152.6, 142.8, 137.4, 132.2, 131.9, 131.0, 128.9, 128.8, 128.7, 126.6, 126.0, 123.2 (q, J = 281.8 Hz, CF3), 123.0, 122.7, 122.1, 118.7, 117.6, 96.3, 77.2, 77.1 (q, J = 33.5 Hz, C-6′), 69.6 (q, J = 2.3 Hz, C-6b′), 51.8, 49.3, 28.4, 25.1.

HRMS (ESI): m/z [M + H]+ calcd for C26H20F3N2O4: 481.1370; found: 481.1368.


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(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′-Methyl-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4b)

Obtained according to the general procedure from 1b (65 mg) and l-proline.

Yield 97 mg (78%); grey powder; mp 172–173 °C (decomp.).

IR (ATR): 1726, 1605, 1554, 1497, 1497, 1338 cm–1.

1H NMR (400 MHz): δ = 8.19 (d, J = 8.0 Hz, 1 H), 8.06 (d, J = 8.0 Hz, 1 H), 7.89 (d, J = 6.9 Hz, 1 H), 7.85 (t, J = 7.5 Hz, 1 H), 7.78 (d, J = 6.9 Hz, 1 H), 7.73 (t, J = 7.5 Hz, 1 H), 6.86 (d, J = 8.0 Hz, 1 H), 6.78 (br d, J = 8.0 Hz, 1 H), 5.83 (q, J = 6.6 Hz, 1 H), 5.52 (s, 1 H), 5.21 (s, 1 H), 4.62 (t, J = 6.8 Hz, 1 H), 3.19–1.64 (m, 6 H), 1.59 (s, 3 H).

19F NMR (376 MHz): δ = 94.4 (d, J = 6.6 Hz, CF3).

13C NMR (126 MHz): δ = 203.5 (C=O), 150.4, 142.8, 137.7, 132.2, 132.0 (2С), 130.9, 129.4, 128.9, 128.8, 126.5, 126.3, 123.3 (q, J = 281.8 Hz, CF3), 122.5, 122.1, 118.3, 117.3, 96.0, 69.7 (q, J = 2.0 Hz, C-6b′), 52.2, 49.1, 28.4, 25.1, 20.4 (the signals of two carbon atoms overlap with the signal of CDCl3).

HRMS (ESI): m/z [M + H]+ calcd for C27H22F3N2O4: 495.1526; found: 495.1522.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′-Methoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4c)

Obtained according to the general procedure from 1c (69 mg) and l-proline.

Yield: 100 mg (78%); pale-yellow powder; mp 158–159 °C (decomp.).

IR (ATR): 1717, 1606, 1557, 1498, 1338 cm–1.

1H NMR (400 MHz): δ = 8.19 (d, J = 8.0 Hz, 1 H), 8.05 (d, J = 8.1 Hz, 1 H), 7.93 (d, J = 7.0 Hz, 1 H), 7.85 (t, J = 7.5 Hz, 1 H), 7.81 (d, J = 7.0 Hz, 1 H), 7.75 (t, J = 7.5 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 1 H), 6.54 (br d, J = 8.8 Hz, 1 H), 5.74 (q, J = 6.2 Hz, 1 H), 5.27 (s, 1 H), 5.24 (s, 1 H), 4.65 (t, J = 6.2 Hz, 1 H), 3.24–1.65 (m, 9 H).

19F NMR (376 MHz): δ = 94.5 (d, J = 6.2 Hz, CF3).

13C NMR (126 MHz): δ = 203.3 (C=O), 154.8, 146.6, 142.8, 137.6, 132.1, 132.0, 130.9, 129.0 (2C), 128.8, 126.5, 123.2 (q, J = 280.9 Hz, CF3), 122.7, 122.3, 118.6, 115.8, 109.2, 96.6, 69.8 (q, J = 2.0 Hz, C-6b′), 54.7, 52.7, 49.2, 28.2, 25.1 (the signals of two carbon atoms overlap with the signal of CDCl3).

HRMS (ESI): m/z [M + H]+ calcd for C27H22F3N2O5: 511.1475; found: 511.1471.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-4′-Ethoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4d)

Obtained according to the general procedure from 1d (72 mg) and l-proline.

Yield: 105 mg (80%); cream powder; mp 189–190 °C (decomp.).

IR (ATR): 1720, 1589, 1549, 1489, 1475, 1332 cm–1.

1H NMR (400 MHz): δ = 8.18 (d, J = 8.0 Hz, 1 H), 8.04 (d, J = 8.1 Hz, 1 H), 7.91 (d, J = 6.9 Hz, 1 H), 7.83 (t, J = 7.5 Hz, 1 H), 7.78 (d, J = 7.0 Hz, 1 H), 7.73 (t, J = 7.5 Hz, 1 H), 6.59 (d, J = 8.0 Hz, 1 H), 6.29 (t, J = 8.0 Hz, 1 H), 5.83 (q, J = 6.3 Hz, 1 H), 5.42 (d, J = 8.0 Hz, 1 H), 5.32 (s, 1 H), 4.64 (t, J = 7.5 Hz, 1 H), 4.01 (q, J = 6.8 Hz, 2 H), 3.15–1.64 (m, 6 H), 1.39 (t, J = 6.8 Hz, 3 H).

19F NMR (376 MHz): δ = 94.8 (br s, CF3).

13C NMR (126 MHz): δ = 203.1 (C=O), 148.3, 143.1, 142.8, 137.6, 132.0 (2C), 131.0, 128.9, 128.8, 126.5, 123.3 (q, J = 282.0 Hz, CF3), 122.8, 122.6, 122.1, 120.1, 117.6, 113.5, 96.4, 69.7 (q, J = 2.0 Hz, C-6b′), 65.3, 52.1, 48.9, 28.0, 25.1, 14.9 (the signals of two carbon atoms overlap with the signal of CDCl3).

HRMS (ESI): m/z [M + H]+ calcd for C28H24F3N2O5: 525.1632; found: 525.1636.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′-Chloro-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4e)

Obtained according to the general procedure from 1e (70 mg) and l-proline.

Yield: 104 mg (81%); beige powder; mp 183–184 °C (decomp.).

IR (ATR): 1722, 1605, 1557, 1481, 1468, 1336 cm–1.

1H NMR (400 MHz): δ = 8.22 (d, J = 8.0 Hz, 1 H), 8.12–8.05 (m, 1 H), 7.89–7.84 (m, 2 H), 7.82 (d, J = 7.0 Hz, 1 H), 7.76 (t, J = 7.5 Hz, 1 H), 6.54 (dd, J = 8.8, 2.0 Hz, 1 H), 6.93 (d, J = 8.8 Hz, 1 H), 5.91 (q, J = 6.6 Hz, 1 H), 5.73 (d, J = 2.0 Hz, 1 H), 5.17 (s, 1 H), 4.60 (t, J = 7.1 Hz, 1 H), 3.11–1.66 (m, 6 H).

19F NMR (376 MHz): δ = 94.2 (d, J = 6.6 Hz, CF3).

13C NMR (126 MHz): δ = 203.2 (C=O), 151.0, 142.8, 136.8, 132.4, 131.6, 130.9, 129.1, 128.9 (2С), 127.9, 126.9, 125.9, 123.0 (q, J = 281.6 Hz, CF3), 122.9, 122.0, 120.2, 119.0, 96.3, 77.1, 76.9 (q, J = 33.6 Hz, C-6′), 69.5 (q, J = 2.4 Hz, C-6b′), 51.5, 49.3, 28.5, 25.1.

HRMS (ESI): m/z [M + H]+ calcd for C26H19ClF3N2O4: 515.0980; found: 515.0977.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′,4′-Dichloro-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4f)

Obtained according to the general procedure from 1f (79 mg) and l-proline.

Yield 90 mg (67%); cream powder; mp 179–180 °C (decomp.).

IR (ATR): 1719, 1605, 1557, 1461, 1432, 1411, 1338 cm–1.

1H NMR (400 MHz): δ = 8.22 (d, J = 7.9 Hz, 1 H), 8.14–8.05 (m, 1 H), 7.91–7.81 (m, 3 H), 7.78 (t, J = 7.5 Hz, 1 H), 7.09 (s, 1 H), 5.95 (q, J = 5.8 Hz, 1 H), 5.66 (s, 1 H), 5.18 (s, 1 H), 4.60 (t, J = 6.7 Hz, 1 H), 3.10–1.66 (m, 6 H).

19F NMR (376 MHz): δ = 94.2 (d, J = 5.8 Hz, CF3).

13C NMR (126 MHz): δ = 203.0 (C=O), 147.2, 142.7, 136.6, 132.5, 131.5, 131.0, 129.4, 129.1, 129.0, 127.7, 127.0, 124.3, 124.0, 123.1, 122.8 (q, J = 281.7 Hz, CF3), 122.0, 121.7, 95.0, 77.3 (q, J = 33.9 Hz, C-6′), 77.0, 69.5 (q, J = 2.0 Hz, C-6b′), 51.7, 49.1, 28.5, 25.1.

HRMS (ESI): m/z [M + H]+ calcd for C26H18Cl2F3N2O4: 549.0590; found: 549.0582.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′-Bromo-4′-ehtoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4g)

Obtained according to the general procedure from 1g (92 mg) and l-proline.

Yield: 123 mg (81%); cream powder; mp 205–206 °C (decomp.).

IR (ATR): 1709, 1603, 1557, 1484, 1469, 1339 cm–1.

1H NMR (400 MHz): δ = 8.21 (d, J = 8.0 Hz, 1 H), 8.07 (d, J = 8.0 Hz, 1 H), 7.88 (d, J = 6.9 Hz, 1 H), 7.84 (t, J = 7.5 Hz, 1 H), 7.81 (d, J = 6.9 Hz, 1 H), 7.76 (t, J = 7.5 Hz, 1 H), 6.69 (s, 1 H), 5.82 (q, J = 6.5 Hz, 1 H), 5.46 (s, 1 H), 5.19 (s, 1 H), 4.63 (t, J = 7.1 Hz, 1 H), 3.98 (q, J = 6.9 Hz, 2 H), 3.08–1.65 (m, 6 H), 1.40 (t, J = 6.9 Hz, 3 H).

19F NMR (376 MHz): δ = 94.6 (br s, CF3).

13C NMR (126 MHz): δ = 203.3 (C=O), 149.0, 142.7, 141.8, 137.1, 132.3, 131.8, 130.9, 129.0, 128.9, 126.7, 123.0 (q, J = 282.1 Hz, CF3), 122.7, 122.0, 121.4, 120.2, 116.3, 115.0, 95.4, 77.0 (q, J = 34.4 Hz, C-6′), 69.7 (q, J = 1.8 Hz, C-6b′), 65.4, 51.9, 48.8, 28.1, 25.1, 14.7 (the signal of one carbon atom overlaps with the signal of CDCl3).

HRMS (ESI): m/z [M + H]+ calcd for C28H23BrF3N2O5: 603.0737; found: 603.0726.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′,6a′-Dinitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4h)

Obtained according to the general procedure from 1h (73 mg) and l-proline.

Yield: 117 mg (89%); beige powder; mp 190–191 °C (decomp.).

IR (ATR): 1706, 1582, 1562, 1524, 1482, 1339, 1329 cm–1.

1H NMR (400 MHz): δ = 8.24 (d, J = 7.8 Hz, 1 H), 8.14 (d, J = 8.0 Hz, 1 H), 7.94–7.85 (m, 4 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.12 (d, J = 9.0 Hz, 1 H), 6.67 (d, J = 2.1 Hz, 1 H), 6.12 (q, J = 6.2 Hz, 1 H), 5.14 (s, 1 H), 4.61 (t, J = 7.4 Hz, 1 H), 3.09–1.70 (m, 6 H).

19F NMR (376 MHz): δ = 93.6 (d, J = 6.2 Hz, CF3).

13C NMR (126 MHz): δ = 203.5 (C=O), 156.8, 142.9, 142.7, 136.3, 132.9, 131.3, 131.1, 129.2, 129.1, 127.3, 124.6, 123.1, 122.7 (q, J = 281.5 Hz, CF3), 122.4, 122.1, 119.2, 118.4, 93.7, 76.8 (q, J = 33.8 Hz, C-6′), 69.5 (q, J = 2.0 Hz, C-6b′), 51.4, 49.4, 29.0, 25.1 (the signal of one carbon atom overlaps with the signal of CDCl3).

HRMS (ESI): m/z [M + H]+ calcd for C26H19F3N3O6: 526.1220; found: 526.1212.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′,4′,6a′-Trinitro-6′-(trifluoromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4i)

Obtained according to the general procedure from 1i (84 mg) and l-proline.

Yield: 115 mg (81%); cream powder; mp 178–179 °C (decomp.).

IR (ATR): 1709, 1599, 1557, 1548, 1467, 1363, 1339 cm–1.

1H NMR (400 MHz): δ = 8.55 (d, J = 2.4 Hz, 1 H), 8.27 (dd, J = 7.8, 1.0 Hz, 1 H), 8.17 (d, J = 8.2 Hz, 1 H), 7.93 (dd, J = 8.2, 7.2 Hz, 1 H), 7.86 (d, J = 7.0 Hz, 1 H), 7.82–7.74 (m, 2 H), 6.88 (d, J = 2.4 Hz, 1 H), 6.31 (q, J = 5.9 Hz, 1 H), 5.13 (s, 1 H), 4.59 (t, J = 7.5 Hz, 1 H), 3.00–1.71 (m, 6 H).

19F NMR (376 MHz): δ = 93.3 (d, J = 5.9 Hz, CF3).

13C NMR (126 MHz): δ = 203.2 (C=O), 150.2, 142.9, 141.1, 138.6, 135.7, 133.2, 131.2, 131.0, 129.4, 129.2, 127.6, 125.5, 123.5, 123.3, 122.1 (q, J = 282.1 Hz, CF3), 122.0, 121.0, 92.1, 77.5, 77.2 (q, J = 34.8 Hz, C-6′), 69.4 (q, J = 2.5 Hz, C-6b′), 51.1, 49.2, 29.1, 25.1.

HRMS (ESI): m/z [M + H]+ calcd for C26H18F3N4O8: 571.1071; found: 571.1068.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-6a′-Nitro-6′-(trichloromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4j)

Obtained according to the general procedure from 1j (74 mg) and l-proline.

Yield: 100 mg (76%); beige powder; mp 169–170 °C (decomp.).

IR (ATR): 1713, 1602, 1587, 1549, 1492, 1457, 1436, 1344, 1331 cm–1.

1H NMR (400 MHz): δ = 8.12 (d, J =7.9 Hz, 1 H), 8.05 (d, J = 8.0 Hz, 1 H), 7.84 (t, J = 7.5 Hz, 1 H), 7.81–7.69 (m, 3 H), 7.06–6.97 (m, 2 H), 6.40–6.33 (m, 1 H), 6.16 (s, 1 H), 5.81 (d, J = 7.0 Hz, 1 H), 5.17 (s, 1 H), 5.10 (t, J = 6.6 Hz, 1 H), 2.81–1.76 (m, 6 H).

13C NMR (126 MHz): δ = 204.3 (C=O), 152.5, 142.8, 137.7, 132.2, 131.8, 130.9, 129.0, 128.9, 128.7, 126.5, 125.6, 122.7, 122.4, 121.6, 118.7, 117.3, 96.8, 95.1, 84.9, 76.4, 70.0, 52.9, 47.8, 29.7, 24.7.

HRMS (ESI): m/z [M + H]+ calcd for C26H20Cl3N2O4: 529.0483; found: 529.0474.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′-Methyl-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4k)

Obtained according to the general procedure from 1k (77 mg) and l-proline.

Yield: 97 mg (71%); cream powder; mp 165–166 °C (decomp.).

IR (ATR): 1720, 1605, 1549, 1502, 1496, 1467, 1340, 1329 cm–1.

1H NMR (400 MHz): δ = 8.18 (d, J = 7.8 Hz, 1 H), 8.05 (d, J = 8.2 Hz, 1 H), 7.84 (t, J = 7.5 Hz, 1 H), 7.81–7.69 (m, 3 H), 6.91 (d, J = 8.3 Hz, 1 H), 6.79 (br d, J = 8.3 Hz, 1 H), 6.07 (s, 1 H), 5.50 (s, 1 H), 5.17–5.06 (m, 2 H), 2.83–1.81 (m, 6 H), 1.58 (s, 1 H).

13C NMR (126 MHz): δ = 204.5, 150.3, 142.8, 138.0, 132.03, 131.97, 130.9, 130.7, 129.4, 129.0, 128.8, 126.3, 126.0, 122.2, 121.6, 117.0, 116.2, 96.9, 95.0, 85.0, 76.3, 70.1, 53.4, 47.6, 29.6, 24.8, 20.4.

HRMS (ESI): m/z [M + H]+ calcd for C27H22Cl3N2O4: 545.0610; found: 545.0615.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′-Methoxy-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4l)

Obtained according to the general procedure from 1l (81 mg) and l-proline.

Yield: 105 mg (75%); pale-yellow powder; mp 170–171 °C (decomp.).

IR (ATR): 1714, 1607, 1547, 1494, 1429, 1351, 1338 cm–1.

1H NMR (400 MHz): δ = 8.18 (d, J = 8.0 Hz, 1 H), 8.06–8.01 (m, 1 H), 7.86–7.81 (m, 2 H), 7.78 (d, J = 6.9 Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 6.94 (d, J = 8.9 Hz, 1 H), 6.79 (dd, J = 8.9, 2.6 Hz, 1 H), 5.96 (s, 1 H), 5.25 (d, J = 2.6 Hz, 1 H), 5.20 (s, 1 H), 5.09 (t, J = 6.8 Hz, 1 H), 2.86–1.80 (m, 9 H).

13C NMR (126 MHz): δ = 204.4 (C=O), 154.8, 146.6, 142.8, 137.9, 132.1, 132.0, 130.9, 129.1, 128.9, 126.4, 122.4, 121.8, 119.4, 118.3, 115.8, 109.0, 96.8, 95.6, 85.6, 76.1, 70.2, 54.7, 53.9, 47.4, 29.4, 24.7.

Anal. Calcd for C27H21Cl3N2O5: C, 57.93; H, 3.78; N, 5.00. Found: C, 57.79; H, 3.83; N, 4.87.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-4′-Ethoxy-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4m)

Obtained according to the general procedure from 1m (85 mg) and l-proline.

Yield: 90 mg (62%); cream powder; mp 143–144 °C (decomp.).

IR (ATR): 1715, 1602, 1586, 1548, 1478, 1334 cm–1.

1H NMR (400 MHz): δ = 8.17 (d, J = 7.8 Hz, 1 H), 8.05–7.99 (m, 1 H), 7.85–7.79 (m, 2 H), 7.75 (d, J = 6.8 Hz, 1 H), 7.72 (t, J = 7.5 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.28 (t, J = 7.9 Hz, 1 H), 6.06 (s, 1 H), 5.42 (d, J = 7.8 Hz, 1 H), 5.26 (s, 1 H), 5.09 (t, J = 6.9 Hz, 1 H), 4.09–3.98 (m, 2 H), 2.78–1.77 (m, 6 H), 1.39 (t, J = 6.9 Hz, 3 H).

13C NMR (126 MHz): δ = 204.1 (C=O), 148.2, 142.9, 142.8, 137.9, 132.1, 132.0, 130.9, 129.0, 128.8, 126.3, 122.6, 122.2, 121.6, 120.0, 117.5, 114.1, 96.9, 95.6, 85.5, 76.0, 70.2, 65.6, 53.3, 47.3, 29.1, 24.7, 15.1.

Anal. Calcd for C28H23Cl3N2O5: С, 58.61; Н, 4.04; N, 4.88. Found: С, 58.45; Н, 3.93; N, 5.08.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′-Chloro-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4n)

Obtained according to the general procedure from 1n (82 mg) and l-proline.

Yield: 116 mg (82%); white powder; mp 175–176 °C (decomp.).

IR (ATR): 1715, 1600, 1551, 1481, 1467, 1435, 1339 cm–1.

1H NMR (400 MHz): δ = 8.21 (d, J = 7.9 Hz, 1 H), 8.07 (d, J = 7.9 Hz, 1 H), 7.85 (t, J = 7.5 Hz, 1 H), 7.81–7.73 (m, 3 H), 7.01–6.94 (m, 2 H), 6.16 (s, 1 H), 5.71 (s, 1 H), 5.10 (t, J = 6.6 Hz, 1 H), 5.06 (s, 1 H), 2.78–1.80 (m, 6 H).

13C NMR (126 MHz): δ = 204.2 (C=O), 150.9, 142.8, 137.2, 132.4, 131.6, 130.9, 129.1, 129.0, 128.9, 127.6, 126.7, 125.5, 122.6, 121.6, 120.3, 118.7, 96.6, 94.2, 84.7, 76.3, 70.0, 52.8, 47.8, 29.7, 24.8.

Anal. Calcd for C26H18Cl4N2O4: С, 55.35; Н, 3.22; N, 4.96. Found: С, 55.39; Н, 3.15; N, 4.78.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′,4′-Dichloro-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4o)

Obtained according to the general procedure from 1o (91 mg) and l-proline.

Yield: 117 mg (82%); cream powder; mp 165–166 °C (decomp.).

IR (ATR): 1722, 1599, 1546, 1464, 1339 cm–1.

1H NMR (400 MHz): δ = 8.22 (d, J = 7.8 Hz, 1 H), 8.08 (d, J = 8.3 Hz, 1 H), 7.85 (dd, J = 8.3, 7.2 Hz, 1 H), 7.82–6.74 (m, 3 H), 7.10 (d, J = 2.3 Hz, 1 H), 6.20 (s, 1 H), 5.63 (d, J = 2.3 Hz, 1 H), 5.08 (dd, J = 7.8, 6.7 Hz, 1 H), 5.07 (s, 1 H), 2.75–1.81 (m, 6 H).

13C NMR (126 MHz): δ = 204.0 (C=O), 147.1, 142.8, 136.9, 132.6, 131.5, 130.9, 129.3, 129.1, 129.0, 127.3, 126.9, 123.9, 123.7, 122.8, 121.6, 121.5, 96.1, 94.1, 85.0, 76.2, 69.9, 52.9, 47.7, 29.7, 24.7.

Anal. Calcd for C26H17Cl5N2O4: С, 52.16; Н, 2.86; N, 4.68. Found: С, 52.35; Н, 2.84; N, 4.59.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′,6a′-Dinitro-6′-(trichloromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4p)

Obtained according to the general procedure from 1p (85 mg) and l-proline.

Yield: 114 mg (79%); beige powder; mp 163–164 °C (decomp.).

IR (ATR): 1720, 1591, 1546, 1524, 1492, 1343, 1329 cm–1.

1H NMR (400 MHz): δ = 8.25–8.20 (m, 1 H), 8.12 (d, J = 8.4 Hz, 1 H), 7.95–7.87 (m, 2 H), 7.76 (d, J = 7.0 Hz, 1 H), 7.74–7.71 (m, 2 H), 7.15 (d, J = 9.0 Hz, 1 H), 6.66 (d, J = 2.2 Hz, 1 H), 6.41 (s, 1 H), 5.15 (dd, J = 8.0, 6.8 Hz, 1 H), 4.99 (s, 1 H), 2.79–1.82 (m, 6 H).

13C NMR (126 MHz): δ = 204.4 (C=O), 156.9, 142.9, 142.3, 136.5, 132.9, 131.1, 131.0, 129.2, 129.1, 127.2, 124.7, 122.8, 122.1, 121.6, 119.0, 117.9, 96.0, 92.5, 84.3, 76.7, 70.0, 52.4, 48.2, 30.2, 24.8.

HRMS (ESI): m/z [M + H]+ calcd for C26H19Cl3N3O6: 574.0334; found: 574.0328.


#

(1S*,6′S*,6a′S*,6b′S*,11a′R*)-2′,4′,6a′-Trinitro-6′-(trichloromethyl)-6a′,6b′,7′,8′,9′,11a′-hexahydro-2H,6′H-spiro[acenaphthylene-1,11′-chromeno[3,4-a]pyrrolizin]-2-one (4q)

Obtained according to the general procedure from 1q (96 mg) and l-proline.

Yield: 127 mg (82%); pale-yellow powder; mp 162–163 °C (decomp.).

IR (ATR): 1713, 1606, 1553, 1544, 1474, 1345 cm–1.

1H NMR (400 MHz): δ = 8.56 (d, J = 2.7 Hz, 1 H), 8.26 (dd, J = 7.3, 1.6 Hz, 1 H), 8.15 (d, J = 8.3 Hz, 1 H), 7.78–7.74 (m, 3 H), 6.87 (dd, J = 2.7, 0.6 Hz, 1 H), 6.62 (s, 1 H), 5.16 (dd, J = 8.8, 6.1 Hz, 1 H), 4.97 (s, 1 H), 2.79–1.85 (m, 6 H).

13C NMR (126 MHz): δ = 203.9 (C=O), 150.2, 142.9, 140.5, 138.0, 135.8, 133.2, 131.1, 130.7, 129.4, 129.2, 127.5, 125.1, 123.3, 122.6, 121.6, 121.1, 95.0, 91.0, 84.7, 76.9, 69.9, 51.8, 48.3, 30.3, 24.8.

Anal. Calcd for C26H17Cl3N4O8: C, 50.39; H, 2.76; N, 9.04. Found: C, 50.45; H, 2.66; N, 8.86.


#

(1S*,6′S*,6a′S*,6b′R*,11a′R*)-6a′-Nitro-6′-(trifluoromethyl)-6a′,6b′,7′,11a′-tetrahydro-2H,6′H,9′H-spiro[acenaphthylene-1,11′-chromeno[3′,4′:3,4]pyrrolo[1,2-c]thiazol]-2-one (4r)

Obtained according to the general procedure from 1a (61 mg) and l-thiaproline.

Yield: 70 mg (56%); cream powder; mp 248–249 °C (decomp.).

IR (ATR): 1728, 1603, 1590, 1549, 1492, 1459, 1447, 1404, 1366, 1337 cm–1.

1H NMR (400 MHz): δ = 8.20 (dd, J = 7.2, 1.5 Hz, 1 H), 8.07 (d, J = 8.1 Hz, 1 H), 7.89 (d, J = 7.2 Hz, 1 H), 7.84 (t, J = 6.8 Hz, 1 H), 7.75–7.67 (m, 2 H), 6.96–7.08 (m, 2 H), 6.44 (q, J = 5.7 Hz, 1 H), 6.36 (t, J = 7.8 Hz, 1 H), 5.64 (d, J = 7.8 Hz, 1 H), 4.68 (s, 1 H), 4.65 (dd, J = 10.3, 5.8 Hz, 1 H), 4.14 (d, J = 9.9 Hz, 1 H), 3.64 (dd, J = 10.3, 5.8 Hz, 1 H), 3.34 (d, J = 9.9 Hz, 1 H), 2.83 (t, J = 10.3 Hz, 1 H).

19F NMR (376 MHz): δ = 90.7 (d, J = 5.7 Hz, CF3).

13C NMR (126 MHz): δ = 203.3 (C=O), 151.3, 143.1, 135.0, 132.5, 130.62, 130.60, 129.4, 129.3, 128.9, 127.0, 126.3, 122.8, 122.7 (q, J = 282.1 Hz, CF3), 122.6, 122.4, 117.3, 116.6, 88.6, 77.5, 74.2 (q, J = 32.6 Hz, C-6′), 70.7 (q, J = 3.8 Hz, C-6b′), 54.9, 49.6, 36.8.

HRMS (ESI): m/z [M + H]+ calcd for C25H18F3N2O4S: 499.0934; found: 499.0940.


#

(1S*,6′S*,6a′S*,6b′R*,11a′R*)-2′-Metoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,11a′-tetrahydro-2H,6′H,9′H-spiro[acenaphthylene-1,11′-chromeno[3′,4′:3,4]pyrrolo[1,2-c]thiazol]-2-one (4s)

Obtained according to the general procedure from 1c (69 mg) and l-thiaproline.

Yield: 80 mg (92%); cream powder; mp 224–225 °C (decomp.).

IR (ATR): 1723, 1617, 1603, 1555, 1496, 1467, 1442, 1427, 1365, 1334 cm–1.

1H NMR (400 MHz): δ = 8.24–8.17 (m, 1 H), 8.06 (d, J = 7.9 Hz, 1 H), 7.92–7.83 (m, 2 H), 7.77–7.70 (m, 2 H), 6.91 (d, J = 9.0 Hz, 1 H), 6.60 (dd, J = 9.0, 2.3 Hz, 1 H), 6.32 (q, J = 5.5 Hz, 1 H), 5.05 (d, J = 2.3 Hz, 1 H), 4.66 (dd, J = 10.4, 5.8 Hz, 1 H), 4.64 (s, 1 H), 4.15 (d, J = 9.8 Hz, 1 H), 3.63 (dd, J = 10.4, 5.8 Hz, 1 H), 3.39 (d, J = 9.8 Hz, 1 H), 2.86 (s, 3 H), 2.81 (t, J = 10.4 Hz, 1 H).

19F NMR (376 MHz): δ = 90.8 (d, J = 5.5 Hz, CF3).

13C NMR (126 MHz): δ = 203.2 (C=O), 154.5, 145.4, 142.9, 135.2, 132.4, 130.9, 130.6, 129.4, 128.9, 126.9, 122.8 (2C), 122.7 (q, J = 281.8 Hz, CF3), 118.3, 117.1, 116.4, 109.9, 88.9, 77.6, 74.4 (q, J = 32.8 Hz, C-6′), 70.6 (q, J = 3.8 Hz, C-6b′), 54.9, 54.8, 50.3, 36.8.

HRMS (ESI): m/z [M + H]+ calcd for C26H20F3N2O5S: 529.1040; found: 529.1045.


#

(1S*,6′S*,6a′S*,6b′R*,11a′R*)-2′,4′-Dichloro-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,11a′-tetrahydro-2H,6′H,9′H-spiro[acenaphthylene-1,11′-chromeno[3′,4′:3,4]pyrrolo[1,2-c]thiazol]-2-one (4t)

Obtained according to the general procedure from 1f (79 mg) and l-thiaproline.

Yield: 102 mg (72%); grey powder; mp 229–230 °C (decomp.).

IR (ATR): 1721, 1600, 1557, 1467, 1390, 1364, 1345, 1329 cm–1.

1H NMR (400 MHz): δ = 8.27–8.21 (m, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.89 (t, J = 7.7 Hz, 1 H), 7.82 (d, J = 7.0 Hz, 1 H), 7.80–7.74 (m, 2 H), 7.14 (d, J = 2.2 Hz, 1 H), 6.45 (q, J = 5.5 Hz, 1 H), 5.49 (d, J = 2.2 Hz, 1 H), 4.64 (dd, J = 10.4, 5.8 Hz, 1 H), 4.59 (s, 1 H), 4.15 (d, J = 9.9 Hz, 1 H), 3.65 (dd, J = 10.4, 5.8 Hz, 1 H), 3.34 (d, J = 9.9 Hz, 1 H), 2.79 (t, J = 10.4 Hz, 1 H).

19F NMR (376 MHz): δ = 90.7 (d, J = 5.5 Hz, CF3).

13C NMR (126 MHz): δ = 202.9 (C=O), 146.2, 143.0, 134.2, 133.0, 130.6, 130.2, 130.0, 129.3, 129.1, 127.4, 127.2, 124.5, 123.6, 123.2, 122.7, 122.3 (q, J = 282.0 Hz, CF3), 119.7, 88.1, 77.3, 74.7 (q, J = 33.3 Hz, C-6′), 70.4 (q, J = 3.6 Hz, C-6b′), 54.8, 49.5, 36.8.

HRMS (ESI): m/z [M + H]+ calcd for C25H16Cl2F3N2O4S: 567.0154; found: 567.0162.


#

(1S*,6′S*,6a′S*,6b′R*,11a′R*)-2′,6a′-Dinitro-6′-(trifluoromethyl)-6a′,6b′,7′,11a′-tetrahydro-2H,6′H,9′H-spiro[acenaphthylene-1,11′-chromeno[3′,4′:3,4]pyrrolo[1,2-c]thiazol]-2-one (4u)

Obtained according to the general procedure from 1h (73 mg) and l-thiaproline.

Yield: 90 mg (66%); beige powder; mp 244–245 °C (decomp.).

IR (ATR): 1718, 1590, 1557, 1519, 1488, 1362, 1340, 1330 cm–1.

1H NMR (400 MHz): δ = 8.25 (d, J = 7.9 Hz, 1 H, Ar), 8.14 (d, J = 7.9 Hz, 1 H), 7.97 (dd, J = 9.0, 2.0 Hz, 1 H), 7.96–7.84 (m, 2 H), 7.75–7.65 (m, 2 H), 7.13 (d, J = 9.0 Hz, 1 H), 6.56 (q, J = 5.6 Hz, 1 H), 6.54 (d, J = 2.0 Hz, 1 H), 4.70–4.59 (m, 2 H), 4.18 (d, J = 10.0 Hz, 1 H), 3.70 (dd, J = 10.4, 5.7 Hz, 1 H), 3.40 (d, J = 10.0 Hz, 1 H), 2.84 (t, J = 10.4 Hz, 1 H).

19F NMR (376 MHz): δ = 90.4 (d, J = 5.6 Hz, CF3).

13C{1H} NMR (126 MHz): δ = 203.2 (C=O), 155.9, 143.1, 142.3, 133.9, 133.3, 130.8, 130.0, 129.5, 129.1, 127.6, 125.3, 123.4, 122.8, 122.6, 122.3 (q, J = 282.0 Hz, CF3), 118.1, 117.7, 87.5, 77.5, 74.8 (q, J = 33.3 Hz, C-6′), 70.6 (q, J = 3.8 Hz, C-6b′), 54.8, 49.4, 36.8.

HRMS (ESI), m/z: [M + H]+ calcd for C25H17F3N3O6S: 544.0785; found: 544.0782.


#

(1S*,6′S*,6a′S*,6b′R*,11a′R*)-6a′-Nitro-6′-(trichloromethyl)-6a′,6b′,7′,11a′-tetrahydro-2H,6′H,9′H-spiro[acenaphthylene-1,11′-chromeno[3′,4′:3,4]pyrrolo[1,2-c]thiazol]-2-one (4v)

Obtained according to the general procedure from 1j (74 mg) and l-thiaproline.

Yield: 53 mg (39%); beige powder; mp 204–205 °C (decomp.).

IR (ATR): 1723, 1596, 1547, 1493, 1456, 1436, 1364, 1345, 1327 cm–1.

1H NMR (400 MHz): δ = 8.22–8.16 (m, 1 H), 8.07 (d, J = 7.8 Hz, 1 H), 7.92–7.81 (m, 2 H), 7.74–7.64 (m, 2 H), 7.09–6.97 (m, 2 H), 6.67 (s, 1 H), 6.33 (t, J = 7.3 Hz, 1 H), 5.62 (d, J = 7.3 Hz, 1 H), 5.48 (dd, J = 10.4, 5.7 Hz, 1 H), 4.66 (s, 1 H), 4.17 (d, J = 9.9 Hz, 1 H), 3.72 (dd, J = 10.4, 5.7 Hz, 1 H), 3.36 (d, J = 9.9 Hz, 1 H), 2.84 (t, J = 10.4 Hz, 1 H).

13C{1H} NMR (126 MHz): δ = 203.4 (C=O), 151.8, 143.2, 134.9, 132.5, 130.63, 130.57, 129.4, 129.2, 128.9, 126.9, 125.8, 122.8, 122.7, 122.1, 116.9, 116.4, 96.5, 90.2, 81.8, 77.5, 71.8, 55.1, 51.0, 37.4.

HRMS (ESI): m/z [M + H]+ calcd for C25H18Cl3N2O4S: 547.0047; found: 547.0052.


#

(1S*,6′S*,6a′S*,6b′R*,11a′R*)-2′-Metoxy-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,11a′-tetrahydro-2H,6′H,9′H-spiro[acenaphthylene-1,11′-chromeno[3′,4′:3,4]pyrrolo[1,2-c]thiazol]-2-one (4w)

Obtained according to the general procedure from 1l (81 mg) and l-thiaproline.

Yield: 52 mg (36%); brown powder; mp 192–193 °C (decomp.).

IR (ATR): 1716, 1602, 1545, 1502, 1462, 1434, 1344 cm–1.

1H NMR (400 MHz): δ = 8.24–8.15 (m, 1 H), 8.06 (d, J = 7.5 Hz, 1 H), 7.92–7.83 (m, 2 H), 7.76–7.68 (m, 2 H), 6.95 (d, J = 8.9 Hz, 1 H), 6.60 (dd, J = 8.9, 2.2 Hz, 1 H), 6.55 (s, 1 H), 5.49 (dd, J = 10.4, 5.8 Hz, 1 H), 5.04 (d, J = 2.2 Hz, 1 H), 4.62 (s, 1 H), 4.18 (d, J = 9.8 Hz, 1 H), 3.72 (dd, J = 10.4, 5.7 Hz, 1 H), 3.41 (d, J = 9.8 Hz, 1 H), 2.85 (s, 3 H), 2.83 (t, J = 10.4 Hz, 1 H).

13C NMR (126 MHz): δ = 203.3 (C=O), 154.3, 145.9, 143.1, 135.1, 132.3, 130.9, 130.5, 129.4, 128.9, 126.9, 122.9, 122.7, 118.0, 116.9, 116.4, 109.4, 96.5, 90.5, 82.0, 77.5, 71.7, 55.0, 54.9, 51.7, 37.4.

HRMS (ESI): m/z [M + H]+ calcd for C26H20Cl3N2O5S: 577.0153; found: 577.0149.


#

(1S*,6′S*,6a′S*,6b′R*,11a′R*)-2′,4′-Dichloro-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,11a′-tetrahydro-2H,6′H,9′H-spiro[acenaphthylene-1,11′-chromeno[3′,4′:3,4]pyrrolo[1,2-c]thiazol]-2-one (4x)

Obtained according to the general procedure from 1o (91 mg) and l-thiaproline.

Yield: 95 mg (65%); beige powder; mp 224–255 °C (decomp.).

IR (ATR): 1716, 1599, 1553, 1453, 1432, 1364, 1327 cm–1.

1H NMR (400 MHz): δ = 8.27–8.20 (m, 1 H), 8.10 (d, J = 8.1 Hz, 1 H), 7.94–7.70 (m, 4 H), 7.13 (d, J = 2.2 Hz, 1 H), 6.67 (s, 1 H), 5.52–5.40 (m, 2 H), 4.58 (s, 1 H), 4.17 (d, J = 9.9 Hz, 1 H), 3.72 (dd, J = 10.3, 5.8 Hz, 1 H), 3.36 (d, J = 9.9 Hz, 1 H), 2.81 (t, J = 10.3 Hz, 1 H).

13C NMR (126 MHz): δ = 203.0 (C=O), 146.7, 143.1, 134.1, 132.9, 130.6, 130.3, 129.8, 129.3, 129.1, 127.4, 126.8, 124.0, 123.3, 123.2, 122.8, 119.3, 95.9, 89.7, 82.2, 77.3, 71.6, 55.0, 50.9, 37.4.

HRMS (ESI): m/z [M + H]+ calcd for C25H16Cl5N2O4S: 614.9268; found: 614.9270.


#

(1S*,6′S*,6a′S*,6b′R*,11a′R*)-2′,4′,6a′-Trinitro-6′-(trichloromethyl)-6a′,6b′,7′,11a′-tetrahydro-2H,6′H,9′H-spiro[acenaphthylene-1,11′-chromeno[3′,4′:3,4]pyrrolo[1,2-c]thiazol]-2-one (4y)

Obtained according to the general procedure from 1q (96 mg) and l-thiaproline.

Yield: 110 mg (69%); beige powder; mp 214–215 °C (decomp.).

IR (ATR): 1708, 1602, 1557, 1547, 1535, 1479, 1340 cm–1.

1H NMR (400 MHz): δ = 8.62 (d, J = 1.8 Hz, 1 H), 8.30–8.24 (m, 1 H), 8.17 (d, J = 8.0 Hz, 1 H), 7.95 (t, J = 7.6 Hz, 1 H), 7.91 (d, J = 6.9 Hz, 1 H), 7.78–7.70 (m, 2 H), 6.93 (s, 1 H), 6.75 (d, J = 1.8 Hz, 1 H), 5.47 (dd, J = 10.4, 5.8 Hz, 1 H), 4.69 (s, 1 H), 4.21 (d, J = 10.2 Hz, 1 H), 3.79 (dd, J = 10.4, 5.8 Hz, 1 H), 3.39 (d, J = 10.2 Hz, 1 H), 2.85 (t, J = 10.4 Hz, 1 H).

13C NMR (126 MHz): δ = 202.9 (C=O), 149.9, 143.3, 140.2, 137.6, 133.6, 133.0, 130.7, 129.6, 129.5, 129.3, 128.0, 125.2, 123.7, 123.1, 121.7, 121.1, 94.7, 88.0, 83.2, 77.3, 71.8, 54.9, 50.2, 37.2.

HRMS (ESI): m/z [M + H]+ calcd for C25H17Cl3N3O6S: 636.9749; found: 636.9744.


#

Synthesis of Spirochromeno[3,4-a]indolizidines 6 and 7; General Procedure

A suspension of the requisite nitrochromene 1 (0.25 mmol), acenaphthenequinone (46 mg, 0.25 mmol) and l-pipecolic acid (43 mg, 0.33 mmol) or (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (58 mg, 0.33 mmol) in DMSO (2 mL, 100 μL of H2O was added to the reaction mixture in order to dissolve the pipecolic acid) was stirred at 60 °C for 7 h (compounds 6) or at 70 °C for 12 h (compounds 7). Then the mixture was cooled to r.t., water (4 mL) was added, the precipitate was filtered off, washed with H2O (5 × 1 mL) and dried at 60 °C. After drying, compounds 7 were purified by column chromatography on silica gel, elution with chloroform.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-6a′-Nitro-6′-(trifluoromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6a)

Obtained according to the general procedure from 1a (61 mg) and l-pipecolic acid.

Yield: 72 mg (58%); pale-yellow powder; mp 231–232 °C (decomp.).

IR (ATR): 1703, 1605, 1585, 1562, 1487, 1457, 1409, 1354, 1342, 1338 cm–1.

1H NMR (500 MHz): δ = 8.18 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 8.2 Hz, 1 H), 7.98 (d, J = 6.9 Hz, 1 H), 7.87 (t, J = 7.6 Hz, 1 H), 7.71 (t, J = 7.5 Hz, 1 H), 7.66 (d, J = 6.9 Hz, 1 H), 7.04–6.90 (m, 1 H), 6.36 (t, J = 7.6 Hz, 1 H), 5.80 (d, J = 7.6 Hz, 1 H), 5.55 (q, J = 6.3 Hz, 1 H), 5.23 (s, 1 H), 4.02 (d, J = 10.2 Hz, 1 H), 2.43–1.10 (m, 8 H).

19F NMR (471 MHz): δ = 95.0 (br s, CF3).

13C NMR (126 MHz): δ = 207.6 (C=O), 153.0, 143.2, 138.6, 132.4, 132.3, 130.6, 129.6, 128.8, 128.7, 126.6, 126.1, 123.3 (q, J = 282.1 Hz, CF3), 123.2, 121.3, 121.1, 118.7, 117.7, 96.1, 78.4, 77.4 (q, J = 33.8 Hz, C-6′), 65.0, 50.8, 46.3, 28.9, 25.1, 24.3.

HRMS (ESI): m/z [M + H]+ calcd for C27H22F3N2O4: 495.1526; found: 495.1529.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′-Methyl-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6b)

Obtained according to the general procedure from 1b (65 mg) and l-pipecolic acid.

Yield: 79 mg (62%); yellow powder; mp 221–222 °C (decomp.).

IR (ATR): 1706, 1606, 1557, 1502, 1464, 1439, 1403, 1336 cm–1.

1H NMR (400 MHz): δ = 8.18 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 8.3 Hz, 1 H), 7.98 (d, J = 6.9 Hz, 1 H), 7.87 (dd, J = 8.3, 6.9 Hz, 1 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.65 (d, J = 6.9 Hz, 1 H), 6.84 (d, J = 8.4 Hz, 1 H), 6.77 (dd, J = 8.4, 1.4 Hz, 1 H), 5.49 (d, J = 1.4 Hz, 1 H), 5.46 (q, J = 6.8 Hz, 1 H), 5.14 (s, 1 H), 4.05 (d, J = 10.5 Hz, 1 H), 2.42–1.11 (m, 11 H).

19F NMR (376 MHz): δ = 95.3 (br s, CF3).

13C NMR (126 MHz): δ = 207.5 (C=O), 150.7, 143.2, 138.9, 132.5, 132.4, 132.2, 130.6, 129.7, 129.5, 128.6, 127.1, 125.9, 123.4 (q, J = 283.0 Hz, CF3), 121.3, 120.9, 118.5, 117.3, 96.1, 78.5, 65.1, 51.0, 46.4, 28.9, 25.2, 24.2, 20.3 (the signal of the C-6′ atom overlaps with the signal of CDCl3).

HRMS (ESI): m/z [M + H]+ calcd for C28H24F3N2O4: 509.1683; found: 509.1682.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′-Methoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6c)

Obtained according to the general procedure from 1c (69 mg) and l-pipecolic acid.

Yield: 76 mg (58%); pale-yellow powder; mp 210–211 °C (decomp.).

IR (ATR): 1705, 1604, 1566, 1499, 1466, 1423, 1409, 1357, 1335 cm–1.

1H NMR (400 MHz): δ = 8.18 (d, J = 8.0 Hz, 1 H), 8.05–7.95 (m, 2 H), 7.87 (t, J = 7.6 Hz, 1 H), 7.76–7.65 (m, 2 H), 6.86 (d, J = 8.9 Hz, 1 H), 6.52 (dd, J = 8.9, 2.0 Hz, 1 H), 5.43 (q, J = 6.6 Hz, 1 H), 5.20 (d, J = 2.0 Hz, 1 H), 5.18 (s, 1 H), 4.04 (d, J = 10.3 Hz, 1 H), 2.73 (s, 3 H), 2.46–1.11 (m, 8 H).

19F NMR (376 MHz): δ = 94.9 (br s, CF3).

13C{1H} NMR (126 MHz): δ = 207.5 (C=O), 154.9, 146.9, 143.2, 138.8, 132.5, 132.2, 130.6, 129.7, 128.7, 126.0, 123.3 (q, J = 282.4 Hz, CF3), 121.4, 121.2, 119.0, 118.6, 116.3, 109.5, 96.0, 78.4, 77.7 (q, J = 33.3 Hz, C-6′), 65.1, 54.6, 51.4, 46.4, 28.9, 25.1, 24.3.

HRMS (ESI): m/z [M + H]+ calcd for C28H23F3N2O5: 525.1632; found: 525.1630.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-4′-Ethoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6d)

Obtained according to the general procedure from 1d (72 mg) and l-pipecolic acid.

Yield: 75 mg (56%); pale-yellow powder; mp 235–236 °C (decomp.).

IR (ATR): 1703, 1607, 1586, 1557, 1487, 1475, 1452, 1444, 1438, 1377, 1345, 1334 cm–1.

1H NMR (400 MHz): δ = 8.16 (d, J = 8.0 Hz, 1 H), 8.01 (d, J = 7.0 Hz, 1 H), 8.00 (d, J = 8.3 Hz, 1 H), 7.85 (dd, J = 8.3, 7.0 Hz, 1 H), 7.69 (dd, J = 8.0, 7.0 Hz, 1 H), 7.63 (d, J = 7.0 Hz, 1 H), 6.59 (d, J = 8.0 Hz, 1 H), 6.29 (t, J = 8.0 Hz, 1 H), 5.52 (q, J = 6.8 Hz, 1 H), 5.41 (d, J = 8.0 Hz, 1 H), 5.19 (s, 1 H), 4.11 (dd, J = 10.7, 1.5 Hz, 1 H), 4.04 (dq, J = 9.5, 7.0 Hz, 1 H), 4.00 (dq, J = 9.5, 7.0 Hz, 1 H), 2.34–1.07 (m, 11 H).

19F NMR (376 MHz): δ = 95.9 (br s, CF3).

13C NMR (126 MHz): δ = 206.9 (C=O), 148.4, 143.1, 142.9, 139.0, 132.4, 132.1, 130.6, 129.6, 128.6, 125.9, 123.4 (q, J = 284.0 Hz, CF3), 123.0, 121.5, 120.9, 120.6, 118.2, 113.2, 96.2, 78.5, 77.1 (q, J = 32.2 Hz, C-6′), 65.1, 65.0, 50.7, 46.3, 28.8, 25.1, 24.1, 14.9.

HRMS (ESI): m/z [M + H]+ calcd for C29H26F3N2O5: 539.1788; found: 539.1784.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′-Chloro-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6e)

Obtained according to the general procedure from 1e (70 mg) and l-pipecolic acid.

Yield: 87 mg (62%); beige powder; mp 214–215 °C (decomp.).

IR (ATR): 1705, 1605, 1557, 1481, 1402, 1336 cm–1.

1H NMR (400 MHz): δ = 8.21 (d, J = 7.7 Hz, 1 H), 8.06 (d, J = 8.2 Hz, 1 H), 8.01–7.64 (m, 4 H), 6.99–6.85 (m, 2 H), 5.69 (s, 1 H), 5.52 (q, J = 6.4 Hz, 1 H), 5.14 (s, 1 H), 4.03 (d, J = 10.2 Hz, 1 H), 2.43–1.10 (m, 8 H).

19F NMR (376 MHz): δ = 95.1 (br s, CF3).

13C NMR (126 MHz): δ = 207.4 (C=O), 151.4, 143.2, 138.0, 132.6, 132.1, 130.7, 129.7, 129.0, 128.8, 128.2, 126.6, 126.3, 123.1 (q, J = 282.7 Hz, CF3), 121.34, 121.31, 120.5, 119.0, 95.5, 78.3, 77.3 (q, J = 34.0 Hz, C-6′), 65.1, 50.6, 46.4, 28.9, 25.1, 24.2.

HRMS (ESI): m/z [M + H]+ calcd for C27H21ClF3N2O4: 529.1136; found: 529.1129.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′,4′-Dichloro-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6f)

Obtained according to the general procedure from 1f (79 mg) and l-pipecolic acid.

Yield: 85 mg (60%); yellow powder; mp 219–220 °C (decomp.).

IR (ATR): 1699, 1605, 1557, 1481, 1441, 1402, 1336 cm–1.

1H NMR (400 MHz): δ = 8.21 (d, J = 8.0 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 8.00 (d, J = 6.9 Hz, 1 H), 7.88 (dd, J = 8.3, 6.9 Hz, 1 H), 7.74 (t, J = 7.5 Hz, 1 H), 7.70 (d, J = 6.9 Hz, 1 H), 7.09 (d, J = 1.8 Hz, 1 H), 5.64 (d, J = 1.8 Hz, 1 H), 5.56 (q, J = 6.7 Hz, 1 H), 5.13 (s, 1 H), 4.08 (d, J = 10.2 Hz, 1 H), 2.40–1.11 (m, 8 H).

19F NMR (376 MHz): δ = 95.5 (br s, CF3).

13C NMR (126 MHz): δ = 207.7 (C=O), 147.4, 143.1, 137.8, 132.7, 132.0, 130.6, 129.7, 129.4, 128.9, 128.1, 126.4, 125.0, 124.2, 122.9 (q, J = 283.6 Hz, CF3), 122.3, 121.5, 121.4, 95.4, 78.3, 65.0, 50.5, 46.3, 28.8, 25.0, 24.0 (the signal of the C-6′ atom overlaps with the signal of CDCl­3).

HRMS (ESI): m/z [M + H]+ calcd for C27H20Cl2F3N2O4: 563.0747; found: 563.0745.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′-Bromo-4′-ethoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6g)

Obtained according to the general procedure from 1g (92 mg) and l-pipecolic acid.

Yield: 92 mg (60%); yellow powder; mp 211–212 °C (decomp.).

IR (ATR): 1700, 1602, 1554, 1487, 1473, 1422, 1401, 1344, 1329 cm–1.

1H NMR (400 MHz): δ = 8.19 (d, J = 8.0 Hz, 1 H), 8.03 (d, J = 8.4 Hz, 1 H), 8.01 (d, J = 7.0 Hz, 1 H), 7.86 (dd, J = 8.4, 7.0 Hz, 1 H), 7.72 (dd, J = 8.0, 7.0 Hz, 1 H), 7.67 (d, J = 7.0 Hz, 1 H), 6.70 (d, J = 2.0 Hz, 1 H), 5.48 (q, J = 6.8 Hz, 1 H), 5.46 (d, J = 2.0 Hz, 1 H), 5.07 (s, 1 H), 4.13 (d, J = 10.5 Hz, 1 H), 4.01 (dq, J = 9.3, 6.9 Hz, 1 H), 3.99 (dq, J = 9.3, 6.9 Hz, 1 H), 2.38–1.07 (m, 11 H).

19F NMR (376 MHz): δ = 96.1 (br s, CF3).

13C NMR (126 MHz): δ = 206.7 (C=O), 149.1, 143.0, 141.6, 138.4, 132.3, 132.2, 130.6, 129.6, 128.7, 126.1, 123.2 (q, J = 284.4 Hz, CF3), 122.3, 121.5, 121.1, 120.9, 116.1, 115.4, 95.7, 78.4, 65.3, 65.1, 50.3, 46.3, 28.7, 25.1, 23.9, 14.7 (the signal of the C-6′ atom overlaps with the signal of CDCl3).

HRMS (ESI): m/z [M + H]+ calcd for C29H25BrF3N2O5: 617.0893; found: 617.0886.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′,6a′-Dinitro-6′-(trifluoromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6h)

Obtained according to the general procedure from 1h (73 mg) and l-pipecolic acid.

Yield: 90 mg (67%); yellow powder; mp 241–242 °C (decomp.).

IR (ATR): 1697, 1603, 1585, 1565, 1527, 1483, 1434, 1341 cm–1.

1H NMR (400 MHz): δ = 8.25 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 8.00 (d, J = 6.9 Hz, 1 H), 7.92 (dd, J = 8.3, 6.9 Hz, 1 H), 7.87 (dd, J = 9.0, 2.2 Hz, 1 H), 7.71 (t, J = 7.5 Hz, 1 H), 7.66 (d, J = 6.9 Hz, 1 H), 7.09 (d, J = 9.0 Hz, 1 H), 6.64 (d, J = 2.2 Hz, 1 H), 5.66 (q, J = 6.4 Hz, 1 H), 5.19 (s, 1 H), 4.05 (d, J = 10.7 Hz, 1 H), 2.51–1.18 (m, 8 H).

19F NMR (376 MHz): δ = 94.7 (br s, CF3).

13C NMR (126 MHz): δ = 207.7 (C=O), 157.4, 143.3, 143.0, 137.2, 133.2, 131.9, 130.9, 129.8, 128.9, 126.8, 124.6, 123.0, 122.8 (q, J = 282.3 Hz, CF3), 121.5, 121.4, 119.5, 118.6, 94.8, 78.4, 77.6 (q, J = 34.5 Hz, C-6′), 65.3, 50.7, 46.4, 29.0, 25.0, 24.3.

HRMS (ESI): m/z [M + H]+ calcd for C27H21F3N3O6: 540.1377; found: 540.1378.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-6a′-Nitro-6′-(trichloromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6i)

Obtained according to the general procedure from 1j (74 mg) and l-pipecolic acid.

Yield: 58 mg (43%); yellow powder; mp 219–220 °C (decomp.).

IR (ATR): 1701, 1606, 1554, 1489, 1455, 1443, 1329 cm–1.

1H NMR (500 MHz): δ = 8.17 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 8.2 Hz, 1 H), 7.93 (d, J = 6.9 Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.65 (d, J = 6.9 Hz, 1 H), 7.02–6.98 (m, 2 H), 6.38–6.34 (m, 1 H), 5.81 (d, J = 8.0 Hz, 1 H), 5.80 (s, 1 H), 5.18 (s, 1 H), 4.44 (d, J = 9.4 Hz, 1 H), 2.66–1.22 (m, 8 H).

13C NMR (126 MHz): δ = 207.7 (C=O), 152.4, 143.3, 138.8, 132.34, 132.29, 130.6, 129.6, 128.7 (2C), 126.2, 126.0, 123.1, 121.3, 121.1, 119.5, 117.8, 97.6, 97.5, 85.8, 78.2, 66.0, 51.7, 46.8, 30.5, 25.2, 24.6.

HRMS (ESI): m/z [M + H]+ calcd for C27H22Cl3N2O4: 543.0640; found: 543.0637.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′-Methyl-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6j)

Obtained according to the general procedure from 1k (77 mg) and l-pipecolic acid.

Yield: 62 mg (44%); yellow powder; mp 223–224 °C (decomp.).

IR (ATR): 1698, 1605, 1550, 1498, 1443, 1432, 1339, 1331 cm–1.

1H NMR (400 MHz): δ = 8.16 (d, J = 8.0 Hz, 1 H), 8.02 (d, J = 8.3 Hz, 1 H), 7.95 (d, J = 6.8 Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 7.69 (t, J = 7.5 Hz, 1 H), 7.63 (d, J = 6.9 Hz, 1 H), 6.88 (d, J = 8.2 Hz, 1 H), 6.79 (dd, J = 8.2, 1.5 Hz, 1 H), 5.70 (s, 1 H), 5.51 (d, J = 1.5 Hz, 1 H), 5.11 (s, 1 H), 4.46 (d, J = 9.6 Hz, 1 H), 2.60–1.23 (m, 8 H).

13C NMR (126 MHz): δ = 207.5 (C=O), 149.9, 143.2, 139.1, 132.5, 132.3, 132.0, 130.5, 129.6, 129.3, 128.5, 126.8, 125.8, 121.4, 120.8, 119.5, 117.6, 97.73, 97.65, 85.8, 78.3, 66.1, 51.7, 46.8, 30.3, 25.2, 24.5, 20.4.

HRMS (ESI): m/z [M + H]+ calcd for C28H24Cl3N2O4: 557.0796; found: 557.0798.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′-Methoxy-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6k)

Obtained according to the general procedure from 1l (81 mg) and l-pipecolic acid.

Yield: 75 mg (52%); yellow powder; mp 229–230 °C (decomp.).

IR (ATR): 1698, 1605, 1552, 1493, 1468, 1454, 1447, 1429, 1377, 1341 cm–1.

1H NMR (400 MHz): δ = 8.16 (d, J = 7.4 Hz, 1 H), 8.00 (d, J = 8.2 Hz, 1 H), 7.95 (d, J = 6.8 Hz, 1 H), 7.86 (t, J = 7.6 Hz, 1 H), 7.74–7.65 (m, 2 H), 6.91 (d, J = 8.9 Hz, 1 H), 6.54 (dd, J = 8.9, 2.1 Hz, 1 H), 5.67 (s, 1 H), 5.25 (d, J = 2.1 Hz, 1 H), 5.14 (s, 1 H), 4.46 (d, J = 8.7 Hz, 1 H), 2.75 (s, 3 H), 2.65–1.21 (m, 8 H).

13C NMR (126 MHz): δ = 207.5 (C=O), 154.9, 146.3, 143.2, 139.0, 132.6, 132.1, 130.6, 129.7, 128.7, 125.9, 121.4, 121.1, 119.9, 118.8, 116.2, 109.3, 97.6, 97.5, 86.2, 78.2, 66.0, 54.6, 52.1, 46.9, 30.5, 25.2, 24.6.

HRMS (ESI): m/z [M + H]+ calcd for C28H23Cl3N2O5: 573.0745; found: 573.0747.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-4′-Ethoxy-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6l)

Obtained according to the general procedure from 1m (85 mg) and l-pipecolic acid.

Yield: 87 mg (59%); yellow powder; mp 222–223 °C (decomp.).

IR (ATR): 1708, 1607, 1586, 1548, 1488, 1470, 1435, 1392, 1335 cm–1.

1H NMR (400 MHz): δ = 8.14 (d, J = 7.6 Hz, 1 H), 8.05–7.94 (m, 2 H), 7.84 (t, J = 7.5 Hz, 1 H), 7.67 (t, J = 7.4 Hz, 1 H), 7.60 (d, J = 6.7 Hz, 1 H), 6.61 (d, J = 8.0 Hz, 1 H), 6.32 (t, J = 8.0 Hz, 1 H), 5.77 (s, 1 H), 5.45 (d, J = 8.0 Hz, 1 H), 5.22 (s, 1 H), 4.48 (d, J = 9.1 Hz, 1 H), 4.17–3.93 (m, 2 H), 2.53–1.14 (m, 11 H).

13C NMR (126 MHz): δ = 206.6 (C=O), 148.5, 143.0, 141.4, 139.3, 132.5, 131.9, 130.5, 129.6, 128.5, 125.7, 123.2, 122.0, 121.6, 120.7, 118.1, 113.2, 98.2, 97.9, 85.9, 78.3, 66.2, 65.1, 51.2, 46.6, 29.8, 25.2, 24.1, 15.1.

HRMS (ESI): m/z [M + H]+ calcd for C29H26Cl3N2O5: 587.0902; found: 587.0908.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′-Chloro-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6m)

Obtained according to the general procedure from 1n (82 mg) and l-pipecolic acid.

Yield: 87 mg (60%); yellow powder; mp 222–223 °C (decomp.).

IR (ATR): 1698, 1605, 1554, 1482, 1446, 1432, 1339 cm–1.

1H NMR (400 MHz): δ = 8.20 (d, J = 8.0 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.93 (d, J = 6.8 Hz, 1 H), 7.87 (t, J = 7.6 Hz, 1 H), 7.73 (t, J = 7.5 Hz, 1 H), 7.69 (d, J = 6.9 Hz, 1 H), 6.97 (dd, J = 8.8, 1.8 Hz, 1 H), 6.94 (d, J = 8.8 Hz, 1 H), 5.76 (s, 1 H), 5.71 (br s, 1 H), 5.09 (s, 1 H), 4.44 (d, J = 9.4 Hz, 1 H), 2.66–1.21 (m, 8 H).

13C NMR (126 MHz): δ = 207.5 (C=O), 150.7, 143.2, 138.3, 132.5, 132.2, 130.6, 129.6, 128.83, 128.78, 128.1, 126.26, 126.24, 121.4, 121.3, 121.3, 111.3, 97.3, 97.0, 85.7, 78.2, 66.1, 51.4, 46.8, 30.4, 25.1, 24.6.

HRMS (ESI): m/z [M + H]+ calcd for C27H21Cl4N2O4: 579.0220; found: 579.0229.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′,4′-Dichloro-6a′-nitro-6′-(trichloromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6n)

Obtained according to the general procedure from 1o (91 mg) and l-pipecolic acid.

Yield: 100 mg (65%); pale-yellow powder; mp 199–200 °C (decomp.).

IR (ATR): 1704, 1603, 1555, 1493, 1464, 1442, 1433, 1420, 1409, 1329 cm–1.

1H NMR (400 MHz): δ = 8.20 (d, J = 8.0 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.95 (d, J = 6.8 Hz, 1 H), 7.87 (t, J = 7.6 Hz, 1 H), 7.73 (t, J = 7.5 Hz, 1 H), 7.69 (d, J = 6.9 Hz, 1 H), 7.09 (d, J = 1.8 Hz, 1 H), 5.82 (s, 1 H), 5.65 (d, J = 1.8 Hz, 1 H), 5.10 (s, 1 H), 4.42 (d, J = 9.5 Hz, 1 H), 2.61–1.24 (m, 8 H).

13C NMR (126 MHz): δ = 207.1 (C=O), 146.8, 143.1, 138.0, 132.6, 132.0, 130.6, 129.7, 129.3, 128.8, 127.9, 126.3, 124.7, 124.2, 122.9, 121.5, 121.4, 97.0, 96.7, 86.0, 78.1, 66.1, 51.4, 46.8, 30.3, 25.1, 24.4.

HRMS (ESI): m/z [M + H]+ calcd for C27H20Cl5N2O4: 612.9831; found: 612.9839.


#

(1S*,6′S*,6a′S*,6b′S*,12a′R*)-2′,6a′-Dinitro-6′-(trichloromethyl)-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (6o) and (1S*,6a′S*,6b′S*,12a′R*)-6′-(dichloromethylene)-2′,6a′-dinitro-6a′,6b′,7′,9′,10′,12a′-hexahydro-2H,6′H,8′H-spiro[acenaphthylene-1,12′-chromeno[3,4-a]indolizin]-2-one (8)

Obtained according to the general procedure from 1p (85 mg) and l-pipecolic acid.

Combined yield: 39 mg; 6o/8 = 76:24; pale-brown powder; mp 168–170 °C (decomp.).

1H NMR (400 MHz): δ (6o) = 8.23 (d, J = 8.0 Hz, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 7.99–7.87 (m, 3 H), 7.70 (t, J = 7.5 Hz, 1 H), 7.65 (d, J = 6.9 Hz, 1 H), 7.12 (d, J = 9.0 Hz, 1 H), 6.66 (d, J = 2.2 Hz, 1 H), 5.92 (s, 1 H), 5.08 (s, 1 H), 4.42 (d, J = 9.5 Hz, 1 H), 2.76–1.19 (m, 8 H); δ (8) = 8.64–7.60 (m, 7 H), 7.06 (d, J = 9.0 Hz, 1 H), 6.74 (d, J = 2.2 Hz, 1 H), 5.25 (s, 1 H), 4.50 (d, J = 10.2 Hz, 1 H), 2.76–1.19 (m, 8 H).

13C NMR (126 MHz): δ (6o) = 207.9, 157.0, 143.3, 142.8, 137.5, 133.1, 131.9, 130.9, 129.7, 128.9, 126.8, 124.5, 122.7, 121.5, 121.3, 120.1, 118.5, 96.5, 95.9, 85.8, 78.2, 66.4, 51.8, 47.0, 30.7, 25.1, 24.8; δ (8) = 206.1, 154.6, 143.4, 142.6, 141.9, 135.9, 132.8, 131.6, 130.8, 129.5, 128.8, 126.9, 124.9, 122.9, 121.2 (2C), 118.5, 117.6, 116.0, 95.8, 79.0, 67.5, 51.6, 47.0, 29.8, 25.1, 24.4.

HRMS (ESI): m/z [M + H]+ calcd for C27H21Cl3N3O6: 588.0490; found: 588.0494 (6o).

HRMS (ESI): m/z [M + H]+ calcd for C27H20Cl2N3O6: 552.0724; found: 552.0727 (8).


#

(1S*,6′S*,6a′S*,6b′S*,14a′R*)-6a′-Nitro-6′-(trifluoromethyl)-6a′,6b′,7′,14a′-tetrahydro-2H,6′H,12′H-spiro[acenaphthylene-1,14′-chromeno[3′,4′:3,4]pyrrolo[1,2-b]isoquinolin]-2-one (7a)

Obtained according to the general procedure from 1a (61 mg) and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Yield: 71 mg (52%); pale-yellow powder; mp 239–240 °C (decomp.).

IR (ATR): 1702, 1607, 1556, 1490, 1442, 1436, 1403, 1346, 1333 cm–1.

1H NMR (400 MHz): δ = 8.26 (dd, J = 8.2, 1.0 Hz, 1 H), 8.08 (d, J = 8.2 Hz, 1 H), 7.95 (d, J = 6.8 Hz, 1 H), 7.87 (dd, J = 8.2, 7.2 Hz, 1 H), 7.97–7.72 (m, 2 H), 7.21–6.94 (m, 5 H), 6.72 (d, J = 7.6 Hz, 1 H), 6.38–6.32 (m, 1 H), 5.79 (q, J = 6.5 Hz, 1 H), 5.75 (d, J = 7.9 Hz, 1 H), 5.38 (s, 1 H), 4.42 (dd, J = 11.1, 2.9 Hz, 1 H), 3.67 (d, J = 14.5 Hz, 1 H), 3.47 (d, J = 14.5 Hz, 1 H), 3.29 (dd, J = 15.2, 2.9 Hz, 1 H), 2.81 (dd, J = 15.2, 11.1 Hz, 1 H).

19F NMR (376 MHz): δ = 94.2 (d, J = 6.5 Hz, CF3).

13C NMR (126 MHz): δ = 208.3 (C=O), 153.0, 143.3, 137.9, 132.8 (2C), 132.7, 132.3, 130.8, 129.7, 129.6, 128.9, 128.87, 126.8, 126.6, 126.44, 126.41, 126.3, 123.2 (q, J = 281.3 Hz, CF3), 123.1, 121.5 (2C), 117.7, 117.3, 95.8, 78.3, 77.4 (q, J = 34.0 Hz, C-6′), 61.7, 51.0, 48.5, 33.5.

HRMS (ESI): m/z [M + H]+ calcd for C31H22F3N2O4: 543.1526; found: 543.1518.


#

(1S*,6′S*,6a′S*,6b′S*,14a′R*)-2′-Methyl-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,14a′-tetrahydro-2H,6′H,12′H-spiro[acenaphthylene-1,14′-chromeno[3′,4′:3,4]pyrrolo[1,2-b]isoquinolin]-2-one (7b)

Obtained according to the general procedure from 1b (65 mg) and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Yield: 99 mg (71%); yellow powder; mp 226–227 °C (decomp.).

IR (ATR): 1700, 1603, 1587, 1559, 1488, 1438, 1421, 1403, 1336 cm–1.

1H NMR (500 MHz): δ = 8.25 (d, J = 7.8 Hz, 1 H), 8.09 (d, J = 8.3 Hz, 1 H), 7.98 (d, J = 6.9 Hz, 1 H), 7.88 (dd, J = 8.3, 7.2 Hz, 1 H), 7.78–7.71 (m, 2 H), 7.19–7.03 (m, 3 H), 6.83 (d, J = 8.3 Hz, 1 H), 6.76 (dd, J = 8.3, 1.2 Hz, 1 H), 6.73 (d, J = 7.7 Hz, 1 H), 5.70 (q, J = 6.6 Hz, 1 H), 5.44 (d, J = 1.2 Hz, 1 H), 5.31 (s, 1 H), 4.43 (dd, J = 11.2, 2.8 Hz, 1 H), 3.70 (d, J = 14.4 Hz, 1 H), 3.52 (d, J = 14.4 Hz, 1 H), 3.29 (dd, J = 15.2, 2.8 Hz, 1 H), 2.81 (dd, J = 15.2, 11.2 Hz, 1 H), 1.55 (s, 3 H, Me).

19F NMR (376 MHz): δ = 94.2 (d, J = 6.6 Hz, CF3).

13C NMR (126 MHz): δ = 208.4 (C=O), 150.9, 143.3, 138.0, 132.9, 132.8, 132.6, 132.4, 132.3, 130.7, 129.7, 129.61, 129.56, 128.8, 127.0, 126.8, 126.4, 126.28, 126.26, 123.2 (q, J = 281.4 Hz, CF3), 121.4, 121.3, 117.3, 116.9, 95.7, 78.4, 77.5 (q, J = 33.8 Hz, C-6′), 61.7, 51.2, 48.5, 33.5, 20.3.

HRMS (ESI): m/z [M + H]+ calcd for C32H24F3N2O4: 557.1683; found: 557.1677.


#

(1S*,6′S*,6a′S*,6b′S*,14a′R*)-2′-Methoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,14a′-tetrahydro-2H,6′H,12′H-spiro[acenaphthylene-1,14′-chromeno[3′,4′:3,4]pyrrolo[1,2-b]isoquinolin]-2-one (7c)

Obtained according to the general procedure from 1c (69 mg) and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Yield: 90 mg (63%); yellow powder; mp 201–202 °C (decomp.).

IR (ATR): 1704, 1607, 1556, 1431, 1408, 1337 cm–1.

1H NMR (400 MHz): δ = 8.27–8.21 (m, 1 H), 8.06 (d, J = 8.2 Hz, 1 H), 7.97 (d, J = 7.1 Hz, 1 H), 7.88 (dd, J = 8.2, 7.1 Hz, 1 H), 7.80–7.74 (m, 2 H), 7.19–7.12 (m, 2 H), 7.09–7.03 (m, 1 H), 6.87 (d, J = 9.0 Hz, 1 H), 6.73 (d, J = 7.6 Hz, 1 H), 6.53 (dd, J = 9.0, 2.9 Hz, 1 H), 5.65 (q, J = 6.6 Hz, 1 H), 5.34 (s, 1 H), 5.17 (d, J = 2.9 Hz, 1 H), 4.44 (dd, J = 11.3, 3.1 Hz, 1 H), 3.71 (d, J = 14.3 Hz, 1 H), 3.54 (d, J = 14.3 Hz, 1 H), 3.29 (dd, J = 15.4, 3.1 Hz, 1 H), 2.80 (dd, J = 15.4, 11.3 Hz, 1 H), 2.72 (s, 3 H).

19F NMR (376 MHz): δ = 94.2 (d, J = 6.6 Hz, CF3).

13C NMR (126 MHz): δ = 208.2 (C=O), 154.8, 147.0, 143.3, 138.0, 132.8, 132.7, 132.5, 132.4, 130.7, 129.8, 129.6, 129.0, 126.8, 126.4, 126.29, 126.25, 123.2 (q, J = 281.2 Hz, CF3), 121.6 (2C), 118.7, 117.6, 116.7, 109.3, 95.7, 78.3, 77.5 (q, J = 33.8 Hz, C-6′), 61.7, 54.6, 51.5, 48.5, 33.5.

HRMS (ESI): m/z [M + H]+ calcd for C32H24F3N2O5: 573.1632; found: 573.1621.


#

(1S*,6′S*,6a′S*,6b′S*,14a′R*)-4′-Ethoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,14a′-tetrahydro-2H,6′H,12′H-spiro[acenaphthylene-1,14′-chromeno[3′,4′:3,4]pyrrolo[1,2-b]isoquinolin]-2-one (7d)

Obtained according to the general procedure from 1d (72 mg) and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Yield: 94 mg (64%); pale-yellow powder; mp 226–227 °C (decomp.).

IR (ATR): 1698, 1605, 1585, 1557, 1487, 1471, 1436, 1405, 1337 cm–1.

1H NMR (400 MHz): δ = 8.27 (d, J = 7.8 Hz, 1 H), 8.07 (d, J = 8.3 Hz, 1 H), 7.95 (d, J = 6.7 Hz, 1 H), 7.86 (t, J = 7.8 Hz, 1 H), 7.79–7.70 (m, 3 H), 7.19–7.10 (m, 2 H), 7.05 (t, J = 7.2 Hz, 1 H), 6.71 (d, J = 8.0 Hz, 1 H), 6.57 (d, J = 8.0 Hz, 1 H), 6.25 (t, J = 8.0 Hz, 1 H), 5.76 (q, J = 6.6 Hz, 1 H), 5.39 (s, 1 H), 5.34 (d, J = 8.0 Hz, 1 H), 4.43 (dd, J = 11.2, 2.5 Hz, 1 H), 4.03–3.94 (m, 2 H), 3.66 (d, J = 14.4 Hz, 1 H), 3.45 (d, J = 14.4 Hz, 1 H), 3.29 (dd, J = 15.3, 2.5 Hz, 1 H), 2.79 (dd, J = 15.3, 11.2 Hz, 1 H), 1.39 (t, J = 6.9 Hz, 3 H).

19F NMR (376 MHz): δ = 94.5 (d, J = 6.6 Hz, CF3).

13C NMR (126 MHz): δ = 208.9 (C=O), 148.3, 143.5, 143.3, 138.0, 132.8, 132.7, 132.3, 130.8, 129.7, 129.6, 128.8, 128.6, 126.8, 126.38, 126.35, 126.2, 123.2 (q, J = 281.4 Hz, CF3), 122.8, 122.2, 121.5, 121.3, 118.1, 113.5, 95.9, 78.3, 77.6 (q, J = 33.8 Hz, C-6′), 65.3, 61.6, 51.0, 48.4, 33.4, 14.9.

HRMS (ESI): m/z [M + H]+ calcd for C33H26F3N2O5: 587.1788; found: 587.1792.


#

(1S*,6′S*,6a′S*,6b′S*,14a′R*)-2′-Chloro-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,14a′-tetrahydro-2H,6′H,12′H-spiro[acenaphthylene-1,14′-chromeno[3′,4′:3,4]pyrrolo[1,2-b]isoquinolin]-2-one (7e)

Obtained according to the general procedure from 1e (70 mg) and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Yield: 89 mg (62%); pale-yellow powder; mp 240–241 °C (decomp.).

IR (ATR): 1703, 1605, 1557, 1482, 1435, 1415, 1404, 1344, 1333 cm–1.

1H NMR (500 MHz): δ = 8.29 (d, J = 7.6 Hz, 1 H), 8.11 (d, J = 8.2 Hz, 1 H), 7.94 (d, J = 6.9 Hz, 1 H), 7.89 (t, J = 7.7 Hz, 1 H), 7.82–7.74 (m, 2 H), 7.19–7.12 (m, 2 H), 7.06 (t, J = 7.8 Hz, 1 H), 6.95 (dd, J = 8.8, 2.1 Hz, 1 H), 6.90 (d, J = 8.8 Hz, 1 H), 6.73 (d, J = 7.7 Hz, 1 H), 5.77 (q, J = 6.3 Hz, 1 H), 5.64 (d, J = 2.1 Hz, 1 H), 5.29 (s, 1 H), 4.43 (dd, J = 11.2, 2.6 Hz, 1 H), 3.69 (d, J = 14.5 Hz, 1 H), 3.51 (d, J = 14.5 Hz, 1 H), 3.29 (dd, J = 15.2, 2.6 Hz, 1 H), 2.81 (dd, J = 15.2, 11.2 Hz, 1 H).

19F NMR (376 MHz): δ = 94.1 (d, J = 6.3 Hz, CF3).

13C NMR (126 MHz): δ = 208.2 (C=O), 151.5, 143.3, 137.2, 133.1, 132.7, 132.6, 132.0, 130.7, 129.7, 129.6, 129.1, 129.0, 128.1, 126.8, 126.7, 126.6, 126.5, 126.3, 122.0 (q, J = 281.5 Hz, CF3), 121.7, 121.5, 119.1, 118.9, 95.1, 78.2, 77.4 (q, J = 34.0 Hz, C-6′), 61.7, 50.8, 48.5, 33.5.

HRMS (ESI): m/z [M + H]+ calcd for C31H21ClF3N2O4: 577.1136; found: 577.1135.


#

(1S*,6′S*,6a′S*,6b′S*,14a′R*)-2′,4′-Dichloro-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,14a′-tetrahydro-2H,6′H,12′H-spiro[acenaphthylene-1,14′-chromeno[3′,4′:3,4]pyrrolo[1,2-b]isoquinolin]-2-one (7f)

Obtained according to the general procedure from 1f (79 mg) and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Yield: 104 mg (68%); pale-yellow powder; mp 184–185 °C (decomp.).

IR (ATR): 1699, 1606, 1564, 1495, 1460, 1435, 1411, 1335 cm–1.

1H NMR (500 MHz): δ = 8.29 (d, J = 7.3 Hz, 1 H), 8.12 (d, J = 8.3 Hz, 1 H), 7.94 (d, J = 6.8 Hz, 1 H), 7.89 (t, J = 7.5 Hz, 1 H), 7.84–7.75 (m, 2 H), 7.20–7.03 (m, 4 H), 6.73 (d, J = 7.6 Hz, 1 H), 5.81 (q, J = 6.4 Hz, 1 H), 5.57 (s, 1 H), 5.30 (s, 1 H), 4.44 (dd, J = 11.4, 2.5 Hz, 1 H), 3.69 (d, J = 14.4 Hz, 1 H), 3.51 (d, J = 14.4 Hz, 1 H), 3.30 (dd, J = 15.2, 2.5 Hz, 1 H), 2.81 (dd, J = 15.2, 11.4 Hz, 1 H).

19F NMR (376 MHz): δ = 94.1 (d, J = 6.4 Hz, CF3).

13C NMR (126 MHz): δ = 208.0 (C=O), 147.7, 143.3, 136.9, 133.2, 132.50, 132.45, 131.9, 130.8, 129.8, 129.61, 129.55, 129.1, 128.0, 126.90, 126.85, 126.5, 126.3, 125.0, 124.1, 122.8 (q, J = 281.7 Hz, CF3), 121.9, 121.6, 120.4, 95.0, 78.2, 77.4 (q, J = 34.6 Hz, C-6′), 61.7, 50.9, 48.5, 33.4.

HRMS (ESI): m/z [M + H]+ calcd for C31H20Cl2F3N2O4: 611.0747; found: 611.0723.


#

(1S*,6′S*,6a′S*,6b′S*,14a′R*)-2′-Bromo-4′-ethoxy-6a′-nitro-6′-(trifluoromethyl)-6a′,6b′,7′,14a′-tetrahydro-2H,6′H,12′H-spiro[acenaphthylene-1,14′-chromeno[3′,4′:3,4]pyrrolo[1,2-b]isoquinolin]-2-one (7f)

Obtained according to the general procedure from 1f (92 mg) and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Yield: 96 mg (58%); yellow powder; mp 183–184 °C (decomp.).

IR (ATR): 1705, 1607, 1562, 1482, 1473, 1429, 1396, 1336 cm–1.

1H NMR (400 MHz): δ = 8.27 (d, J = 7.6 Hz, 1 H), 8.10 (d, J = 8.3 Hz, 1 H), 7.93 (d, J = 6.8 Hz, 1 H), 7.87 (t, J = 7.5 Hz, 1 H), 7.82–7.72 (m, 2 H), 7.20–7.11 (m, 2 H), 7.06 (t, J = 7.0 Hz, 1 H), 6.72 (d, J = 7.6 Hz, 1 H), 6.67 (s, 1 H), 5.71 (q, J = 6.0 Hz, 1 H), 5.36 (s, 1 H), 5.28 (s, 1 H), 4.44 (dd, J = 11.6, 2.6 Hz, 1 H), 4.02–3.90 (m, 2 H), 3.69 (d, J = 14.4 Hz, 1 H), 3.51 (d, J = 14.4 Hz, 1 H), 3.29 (dd, J = 14.8, 2.6 Hz, 1 H), 2.79 (dd, J = 14.8, 11.6 Hz, 1 H), 1.39 (t, J = 6.9 Hz, 3 H).

19F NMR (376 MHz): δ = 94.4 (d, J = 6.0 Hz, CF3).

13C NMR (126 MHz): δ = 208.1 (C=O), 148.9, 143.2, 142.4, 137.3, 133.0, 132.63, 132.61, 132.1, 130.7, 129.7, 129.6, 128.9, 126.8, 126.6, 126.4, 126.3, 123.0 (q, J = 281.9 Hz, CF3), 121.6, 121.5, 120.8, 120.0, 116.2, 115.1, 95.3, 78.3, 65.4, 61.7, 50.7, 48.5, 33.4, 14.7 (the signal of the C-6′ carbon atom overlaps with the signal of CDCl3).

HRMS (ESI): m/z [M + H]+ calcd for C33H25BrF3N2O5: 667.0873; found: 667.0867.


#

(1S*,6′S*,6a′S*,6b′S*,14a′R*)-2′,6a′-Dinitro-6′-(trifluoromethyl)-6a′,6b′,7′,14a′-tetrahydro-2H,6′H,12′H-spiro[acenaphthylene-1,14′-chromeno[3′,4′:3,4]pyrrolo[1,2-b]isoquinolin]-2-one (7h)

Obtained according to the general procedure from 1h (73 mg) and (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid.

Yield: 70 mg (48%); yellow powder; mp 232–233 °C (decomp.).

IR (ATR): 1706, 1607, 1587, 1557, 1525, 1494, 1486, 1450, 1432, 1398, 1346, 1339 cm–1.

1H NMR (400 MHz): δ = 8.31 (d, J = 8.0 Hz, 1 H), 8.18 (d, J = 8.2 Hz, 1 H), 8.02–7.69 (m, 5 H), 7.21–7.07 (m, 4 H), 6.76 (d, J = 6.7 Hz, 1 H), 6.60 (d, J = 2.5 Hz, 1 H), 5.90 (q, J = 6.2 Hz, 1 H), 5.32 (s, 1 H), 4.47 (dd, J = 11.3, 2.9 Hz, 1 H), 3.74 (d, J = 14.5 Hz, 1 H), 3.59 (d, J = 14.5 Hz, 1 H), 3.33 (dd, J = 15.5, 2.9 Hz, 1 H), 2.86 (dd, J = 15.5, 11.3 Hz, 1 H).

19F NMR (376 MHz): δ = 93.9 (d, J = 6.2 Hz, CF3).

13C NMR (126 MHz): δ = 208.3 (C=O), 157.3, 143.4, 142.9, 136.5, 133.6, 132.50, 132.45, 131.8, 131.0, 129.8, 129.6, 129.1, 127.2, 126.9, 126.6, 126.3, 124.7, 123.1, 122.7 (q, J = 281.9 Hz, CF3), 121.9, 121.6, 118.6, 118.2, 94.4, 78.2, 77.6 (q, J = 34.4 Hz, C-6′), 61.9, 50.9, 48.5, 33.5.

HRMS (ESI): m/z [M + H]+ calcd for C31H21F3N3O6: 588.1377; found: 588.1380.


#
#

Acknowledgment

Analytical studies were carried out using equipment at the Centre for Joint Use ‘Spectroscopy and Analysis of Organic Compounds’ at the Postovsky Institute of Organic Synthesis of the Russian Academy of Sciences (Ural Branch) and Centre for Joint Use ‘Laboratory of Complex Investigations and Expert Evaluation of Organic Materials’ at the Ural Federal University.

Supporting Information

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Corresponding Author

Vladislav Y. Korotaev
Institute of Natural Sciences and Mathematics, Ural Federal University
pr. Lenina 51, 620000 Ekaterinburg
Russian Federation   

Publication History

Received: 13 November 2020

Accepted after revision: 05 December 2020

Publication Date:
04 January 2021 (online)

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  • References

    • 1a Schreiber SL. Science 2000; 287: 1964
    • 1b O’Connor CJ, Beckmann HS. G, Spring DR. Chem. Soc. Rev. 2012; 41: 4444

      For reviews, see:
    • 2a Korotaev VY, Sosnovskikh VY, Barkov AY. Russ. Chem. Rev. 2013; 82: 1081
    • 2b Vroemans R, Dehaen W. In Targets in Heterocyclic Systems, Vol. 22. Attanasi OA, Merino P, Spinelli D. Società Chimica Italiana; Roma: 2018: 318
    • 2c Korotaev VY, Kutyashev IB, Barkov AY, Sosnovskikh VY. Russ. Chem. Rev. 2019; 88: 27

      For selected reviews, see:
    • 3a Costa M, Dias TA, Brito A, Proença F. Eur. J. Med. Chem. 2016; 123: 487
    • 3b Pratap R, Ram VJ. Chem. Rev. 2014; 114: 10476
    • 3c Goel A, Kumar A, Raghuvanshi A. Chem. Rev. 2013; 113: 1614
    • 4a Ito M, Egashira S.-I, Yoshida K, Mineno T, Kumagai K, Kojima H, Okabe T, Nagano T, Ui M, Matsuoka I. Life Sci. 2017; 180: 137
    • 4b Tian H, Zhang Y, Zhang Q, Li S, Liu Y, Han X. BioSci. Trends 2019; 13: 40
    • 4c Kutyashev IB, Ulitko MV, Zimnitskiy NS, Barkov AY, Korotaev VY, Sosnovskikh VY. New J. Chem. 2019; 43: 18495
    • 4d Cui Y.-M, Ao M.-Z, Li W, Yu L.-J. Planta Med. 2008; 74: 377
  • 5 Korotaev VY, Kutyashev IB, Sosnovskikh VY. Heteroat. Chem. 2005; 16: 492
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    • 6b Meanwell NA. J. Med. Chem. 2011; 54: 2529
    • 6c Meyer F. Chem. Commun. 2016; 53: 3077
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      For reviews, see:
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    • 8b Nájera C, Sansano JM. Pure Appl. Chem. 2019; 91: 575
    • 8c Korotaev VY, Zimnitskiy NS, Barkov AY, Kutyashev IB, Sosnovskikh VY. Chem. Heterocycl. Compd. 2018; 54: 905
    • 8d Döndas HA, Retamosa MG, Sansano JM. Synthesis 2017; 49: 2819
    • 8e Arumugam N, Kumar RS, Almansour AI, Perumal S. Curr. Org. Chem. 2013; 17: 1929

      For selected papers, see:
    • 9a Kanchithalaivan S, Sumesh RV, Kumar RR. ACS Comb. Sci. 2014; 16: 566
    • 9b Rao JN. S, Raghunathan R. Tetrahedron Lett. 2015; 56: 1539
    • 9c Haddad S, Boudriga S, Porzio F, Soldera A, Askri M, Knorr M, Rousselin Y, Kubicki MM, Golz C, Strohmann C. J. Org. Chem. 2015; 80: 9064
    • 9d Kumar RS, Almansour AI, Arumugam N, Altaf M, Menéndez JC, Kumar RR, Osman H. Molecules 2016; 21: 165
    • 9e Zhou Y, Huang Y, Tang G, Li X. Chem. Heterocycl. Compd. 2019; 55: 1044
  • 10 Zhang W, Yi W.-B. Pot, Atom, and Step Economy (PASE) Synthesis . Springer; Cham (Switzerland): 2019
    • 11a Filatov AS, Knyazev NA, Ryazantsev MN, Suslonov VV, Larina AG, Molchanov AP, Kostikov RR, Boitsov VM, Stepakov AV. Org. Chem. Front. 2018; 5: 595
    • 11b Kathirvelan D, Haribabu J, Reddy BS. R, Balachandran C, Duraipandiyan V. Bioorg. Med. Chem. Lett. 2015; 25: 389
    • 11c Akondi AM, Mekala S, Kantam ML, Trivedi R, Chowhan LR, Das A. New J. Chem. 2017; 41: 873
    • 11d Kang T.-H, Matsumoto K, Tohda M, Murakami Y, Takayama H, Kitajima M, Aimi N, Watanabe H. Eur. J. Pharmacol. 2002; 444: 39
    • 11e Wagner H, Kreutzkamp B, Jurcic K. Planta Med. 1985; 51: 419
    • 11f Sheng Y, Pero RW, Amiri A, Bryngelsson C. Anticancer Res. 1998; 18: 3363
    • 11g Rizzi R, Re F, Bianchi A, De Feo V, De Simone F, Bianchi L, Stivala LA. J. Ethnopharmacol. 1993; 38: 63

      For recent selected examples, see:
    • 12a Chakraborty D, Maity A, Jain CK, Hazra A, Bharitkar YP, Jha T, Majumder HK, Roychoudhury S, Mondal NB. Med. Chem. Commun. 2015; 6: 702
    • 12b Sumesh RV, Muthu M, Almansour AI, Kumar RS, Arumugam N, Athimoolam S, Prabha EA. J. Y, Kumar RR. ACS Comb. Sci. 2016; 18: 262
    • 12c Thimmarayaperumal S, Shanmugam S. New J. Chem. 2018; 42: 4061
    • 12d Kumar RS, Almansour AI, Arumugam N, Periyasami G, Athimoolam S, Kumar RR, Asad M, Asiri AM. Tetrahedron Lett. 2018; 59: 3336
    • 12e Yavari I, Baoosi L, Halvagar MR. Synlett 2018; 29: 635
    • 12f Kumar RS, Antonisamy P, Almansour AI, Arumugam N, Al-thamili DM, Kumar RR, Kim H.-R, Kwon K.-B. Bioorg. Chem. 2019; 91: 103180
    • 13a Kumar RS, Perumal S, Manju SC, Bhatt P, Yogeeswari P, Sriram D. Bioorg. Med. Chem. Lett. 2009; 19: 3461
    • 13b Wei AC, Ali MA, Yoon YK, Ismail R, Choon TS, Kumar RS. Bioorg. Med. Chem. Lett. 2013; 23: 1383
    • 13c Dandia A, Kumari S, Soni P. Eur. Chem. Bull. 2013; 2: 1004
    • 13d Periyasami G, Arumugam N, Rahaman M, Kumar RS, Manikandan M, Alfayez MA, Premnath D, Aldalbahi A. RSC Adv. 2018; 8: 16303
    • 14a Korotaev VY, Barkov AY, Moshkin VS, Matochkina EG, Kodess MI, Sosnovskikh VY. Tetrahedron 2013; 69: 8602
    • 14b Korotaev VY, Kutyashev IB, Barkov AY, Sosnovskikh VY. Chem. Heterocycl. Compd. 2017; 53: 1192
    • 14c Kutyashev IB, Barkov AY, Korotaev VY, Sosnovskikh VY. Chem. Heterocycl. Compd. 2019; 55: 529
    • 14d Kutyashev IB, Barkov AY, Zimnitskiy NS, Korotaev VY, Sosnovskikh VY. Chem. Heterocycl. Compd. 2019; 55: 861
    • 15a Korotaev VY, Kutyashev IB, Barkov AY, Sosnovskikh VY. Chem. Heterocycl. Compd. 2017; 53: 597
    • 15b Kula K, Dobosz J, Jasinski R, Kacka-Zych A, Lapczuk-Krygier A, Miroslaw B, Demchuk OM. J. Mol. Struct. 2020; 1203: 127473

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Figure 1 Representatives of synthetic and natural bioactive chromene and chromane derivatives
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Figure 2 Representatives of synthetic and natural bioactive spiro(thia)pyrrolizidines and spiroindolizidines
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Figure 3 Representatives of bioactive spiroacenaphthylene-2-ones
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Scheme 1 Strategy for the diversity-oriented synthesis of spiro(thia)pyrrolizidines and spiroindolizidines based on 3-nitro-2-trifluoro(trichloro)methyl-2H-chromenes
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Scheme 2 Target and side products in the reaction of nitrochromene 1p with the azomethine ylide derived from acenaphthenequinone and l-pipecolic acid
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Figure 4 Molecular structure of compound 4a (thermal vibration ellipsoids of 50% probability)
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Figure 5 Molecular structure of compound 6g (thermal vibration ellipsoids of 50% probability)
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Figure 6 Main correlations in the 1H–1H NOESY NMR spectrum of compound 7g