Synthesis 2017; 49(07): 1538-1546
DOI: 10.1055/s-0036-1588113
paper
© Georg Thieme Verlag Stuttgart · New York

Enantioselective Catalytic One-Pot Synthesis of Functionalized Methyleneindanes and Methylindenes via a Michael/Conia-Ene Sequence

Arne R. Philipps
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Email: enders@rwth-aachen.de
,
Marcus Blümel
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Email: enders@rwth-aachen.de
,
Simon Dochain
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Email: enders@rwth-aachen.de
,
Daniel Hack
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Email: enders@rwth-aachen.de
,
Dieter Enders*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany   Email: enders@rwth-aachen.de
› Author Affiliations
Further Information

Publication History

Received: 09 November 2016

Accepted after revision: 11 November 2016

Publication Date:
06 December 2016 (online)

 


Abstract

An enantioselective one-pot Michael addition/Conia-ene reaction sequence catalyzed by the combination of a squaramide and indium(III) triflate has been developed. Employing 2-ethynyl-β-nitrostyrenes and 1,3-dicarbonyl compounds as substrates, the functionalized methyleneindanes and methylindenes are obtained in good to excellent enantiomeric excesses. For the indane/indene conversion a concerted fragmentation is proposed.


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The importance of the indane and indene scaffolds in pharmaceutical chemistry cannot be overstated.[1] There are numerous examples of successfully implemented molecules and the scope of their bioactivity is far reaching and broad.[2] [3] In Figure [1] the structures of indinavir (I), an HIV-1 protease inhibitor,[4] indantadol (II), an antiepileptic agent,[5] the nonsteroidal anti-inflammatory drug sulindac (III),[6] the amine uptake inhibitor indatraline (IV),[7] and the anti-inflammatory drug clidanac (V)[8] are given as typical examples of bioactive indanes and indenes. At the same time, these scaffolds have gained enormous importance in materials science.[9] [10]

Zoom Image
Figure 1 Examples of indane and indene pharmaceuticals

Recently, there has been a lot of growth in the research field of organocatalysis in combination with transition-metal catalysis,[11] enabling a large number of new accessible transformations. Our group showed the possibility of exploiting the versatile reactivity of 2-ethynyl-β-nitrostyrenes 1 to form tetracyclic indole derivatives[12] and spiropyrazolones[13] using either gold or silver salts as the metal catalyst. In particular, the Conia-ene reaction is an efficient tool which offers an easy, straightforward, and atom-economical­ approach towards cyclopentanes and cyclohexanes, as well as their heterocyclic counterparts.[14] Due to its great synthetic potential, the combination of organocatalysis with the Conia-ene reaction has been the topic of several investigations. There are novel opportunities for the introduction of stereoinformation into various important target molecules.[13] [15] In addition to the mentioned Conia-ene reactions, there have been further reports on the combination of organocatalysis and indium catalysis for various transformations, such as the α-alkylation of aldehydes,[16] allylation reactions,[17] 1,2/1,4-additions to enones,[18] and hetero-Diels–Alder reactions.[19]

To the best of our knowledge, there is only one example of an asymmetric organocatalysis/Conia-ene sequence, employing an indium salt as the metal catalyst, precedent in the literature.[15c] In contrast to our envisioned protocol, which leads to compounds bearing a stereocenter at the β-position to the dicarbonyl moiety, the reported procedure gives rise to cyclopentanes that feature the stereocenter at the α-position. Herein, we present a novel catalytic sequence utilizing an enantioselective organocatalytic Michael­ addition of dicarbonyl compounds 2 to 2-ethynyl-β-nitrostyrenes 1 and a subsequent cyclization via a Conia-ene reaction with an indium catalyst. This protocol allows for a direct one-pot access to methyleneindanes or methylindenes, depending on the nature of the dicarbonyl compound 2.[20]

Initially, we focused on the enantioselective Michael addition and thus treated 2-ethynyl-β-nitrostyrene (1a) with acetylacetone (2a) in the presence of different squaramide and thiourea catalysts in dichloromethane (Scheme [1]).[21] While the thiourea catalyst E did not show any catalytic activity in this reaction, all of the tested squaramide catalysts showed very satisfying results. This might be due to the tertiary amine moiety, which the tested thiourea catalyst does not bear, assisting in deprotonation of the nucleophile. Catalyst A derived from quinine showed the best asymmetric induction with 98% ee and an excellent yield of 92%.

Zoom Image
Scheme 1 Catalyst screening for the Michael reaction

In the next step, the choice of solvent was investigated using a reduced amount of catalyst A of only 0.5 mol% (Table [1]). The results in dichloromethane and chloroform were quite similar but, surprisingly, the lower catalyst loading had a beneficial effect on the stereoselectivity of this reaction. This may be due to a competing side reaction with higher catalyst loading. In toluene and in diethyl ether the reaction did not proceed as smoothly as in the chlorinated solvents and gave only mediocre yields. Overall, the choice of solvent did not have a stark influence on the asymmetric induction, as all isolated products had an enantiomeric excess of at least 98% ee.

Table 1 Optimization of the Reaction Conditions for the Michael Additiona

Entry

Solvent

Time (h)

Yield (%)b

ee (%)c

1d

CH2Cl2

3

92

 98

2

CH2Cl2

2

90

≥99

3

CHCl3

3

93

≥99

4

toluene

3

44

 99

5

Et2O

3

52

≥99

a Reaction conditions: 1a (0.3 mmol), 2a (0.33 mmol), A (0.5 mol%), solvent (1.5 mL).

b Yield of the isolated product 3.

c Determined by HPLC on a chiral stationary phase.

d 2 mol% of A was used.

In order to optimize the conditions for the Conia-ene cyclization of the Michael adduct 3 to form the methyleneindane 4a, several metal salts were investigated (Table [2]). The selection of metal sources was based on prior reports in the literature of their successful application in similar Conia-ene reactions.[22] While 10 mol% of AgNTf2 in toluene showed no catalytic activity, all of the tested gold sources led to decomposition of the starting material (entries 1–4). Irrespective of the phosphine ligand and the solvent, the reaction was very torpid and gave no isolable product but a complex mixture of compounds. When copper(I) chloride in chloroform was used no reaction was observed, even when the temperature was raised to 50 °C (entry 5). Zinc(II) chloride showed some reactivity, but after 24 hours at 80 °C only a trace amount of 4a could be isolated (entry 6). Increasing the temperature to 100 °C for an hour did not improve the results.

Table 2 Optimization of the Cyclization Reactiona

Entry

Catalyst

Time (h)

Temp

Yield (%)b

4a/5a

1

AgNTf2

120

r.t. to 40 °C

no reaction

2

AgNTf2/AuL1

120

r.t. to 40 °C

decomposition

3

AgNTf2/AuL2

120

r.t. to 40 °C

decomposition

4c

AgNTf2/AuL1

120

r.t. to 40 °C

decomposition

5c

CuCl

120

r.t. to 50 °C

no reaction

6

ZnCl2

 24

80–100 °C

traces

7

In(OTf)3

  3

80 °C

99

1.4:1

8c

FeCl3

  5

r.t.

98

1:15

a Reaction conditions: 3 (0.1 mmol), catalyst (10 mol%), solvent (1.0 mL).

b Yield of the isolated products.

c CHCl3 as solvent.

With indium(III) triflate in toluene at 80 °C, complete conversion was achieved after 3 hours with a surprising result. In addition to the expected methyleneindane 4a, a second product was isolated and identified as methylindene 5a (Table [2], entry 7). When iron(III) chloride in chloroform was employed at room temperature, full conversion with a strong preference towards methylindene 5a was observed after 5 hours and methyleneindane 4a was only isolated in a small amount (entry 8).

With these optimized conditions in hand, the reaction sequence was combined for a one-pot protocol and the scope of the reaction was explored (Table [3]). When the diketone acetylacetone (2a) was employed in the reaction with the unsubstituted 2-ethynyl-β-nitrostyrene (1a), the yield of methyleneindane 4a was very good (76%) and a virtually complete stereoselectivity was observed. At the same time, the methylindene 5a was obtained in 23% yield with an excellent enantioselectivity of 98% ee. In an additional attempt to influence the selectivity of this reaction, the temperature during the indium-catalyzed step was increased to 100 °C, but this gave exactly the same result concerning both yield and enantiomeric excess of 4a and 5a. For 2-ethynyl-β-nitrostyrenes bearing a halide at the para-position to the triple bond, only small amounts of the methyleneindanes 4b and 4c were isolated; however, both still exhibited excellent enantiomeric excesses. When chlorine was replaced by fluorine, the yield for the methylindene 5c was slighthly better. Electron-rich arene substrates bearing a methoxy or methylenedioxy moiety gave no methyleneindane; however, the corresponding methylindenes 5d and 5e were isolated in good to excellent yields. While the asymmetric induction for 5d was virtually complete, the stereoselectivity for 5e was still very good with 95% ee. With heptane-3,5-dione (2, R2 = Et) as the diketone compound, only the methylindene 5f was obtained in a good yield of 60% and an excellent enantiomeric excess of 97%.

Table 3 Substrate Scope of the Michael/Conia-Ene One-Pot Reaction Sequencea

4/5

R1

R2

Cat. (mol%)

Yield 4 (%)b

ee 4 (%)c

Yield 5 (%)b

ee 5 (%)c

a

H

Me

0.5

76

99

23

98

b

4-Cld

Me

0.5

 3

96

34

98

c

4-Fd

Me

0.5

 7

99

54

98

d

4-OMed

Me

0.5

 –

 –

99

≥99

e

4,5-OCH2Od

Me

0.5

 –

 –

69

95

f

H

Et

0.5

 –

 –

60

97

g

H

OMe

5

61

95

h

H

OEt

5

61

96

i

4-OMed

OMe

5

57

95

j

4-Cld

OMe

5

54

94

k

4-Fd

OMe

5

65

82

l

H

o-ClC6H4O

5

14

80

m

H

m-ClC6H4O

5

25

76

n

H

p-ClC6H4O

5

98

86

a Reaction conditions: 0.3-mmol scale using 1 (1.0 equiv), 2 (1.1 equiv), A (0.5–5 mol%), CH2Cl2 (1.5 mL); In(OTf)3 (10 mol%), toluene (1.5 mL).

b Yield of isolated products.

c Determined by HPLC on a chiral stationary phase.

d Numbering refers to the starting material 1, with the ethynyl substituent as position 1.

In the next step, different malonates were subjected to these reaction conditions. Unfortunately, the catalyst loading of the first step had to be increased to 5 mol% as no reaction with diesters occurred using a lower amount. With all the tested malonates, only the expected methyleneindane 4 was formed (Table [3]). The combination of the unsubstituted 2-ethynyl-β-nitrostyrene (1a) and dimethyl malonate gave the corresponding indane 4g in 61% yield and with an excellent enantioselectivity of 95% ee. Changing dimethyl malonate to diethyl malonate gave almost identical results with a good yield and excellent ee value of 4h. In addition, several substituents R1 at the aromatic ring of the nitroolefin, such as chlorine, fluorine, and methoxy, as well as bis(chlorophenyl) malonates, were tolerated and very good enantioselectivities of 76–95% ee were reached (4in).

However, the one-pot Michael/Conia-ene protocol also showed its limitations. Several diketones, such as hexafluoroacetylacetone, dimedone, and indandione, as well as substituted phenylmalonates, sterically demanding malonates (R2 = Ot-Bu), and Meldrum’s acid, showed no reactivity. When an internal alkyne instead of a terminal alkyne moiety was used, the Michael addition occurred but there was no subsequent cyclization reaction.

To further explore the formation of the unexpected methylindenes­ and to pursue the presumption of a subsequent process, instead of a competing side reaction, the isolated methyleneindane 4a was resubjected to the cyclization conditions with iron(III) chloride in chloroform at room temperature. After 5 hours, the methylindene 5a was obtained in 96% yield (Scheme [2]). Based on this result showing a subsequent, and not a competing, reaction pathway, we postulate a fragmentation mechanism (Scheme [3]). After enolization of the methyleneindane ketones 4ae, a concerted fragmentation reaction occurs with the loss of ketene and the formation of methylindenes 5ae. This reaction pathway is in agreement with the product selectivity of the malonates, since the corresponding methylene­indanedicarboxylates 4gn cannot undergo an enolization. Additionally, the product selectivity for the electron-rich arenes with the donor methoxy or methylenedioxy R1 group at the para-position and conjugation with the reacting double bond can be explained, resulting only in the methylindenes­ 5d and 5e.

Zoom Image
Scheme 2 Formation of methylindene 5a starting from methylene­indane 4a
Zoom Image
Scheme 3 Postulated reaction mechanism for the concerted ketene fragmentation

The proposed fragmentation is supported by HRMS measurements, which showed that in the conversion of 4a into 5a the exact mass of ketene was lost. This type of concerted fragmentation has been described previously under basic conditions,[23] and was used by Mander and Woolias on cyclic derivatives.[24]

In conclusion, we have developed a novel one-pot enantioselective synthesis of methyleneindanes and methylindenes in good to excellent enantiomeric excesses (76–99% ee) based on a catalytic Michael/Conia-ene sequence employing 2-ethynyl-β-nitrostyrenes and 1,3-dicarbonyl compounds as substrates. The formation of the methylindenes can be explained by a subsequent concerted fragmentation and loss of ketene.

All commercially available compounds were used without further purification. Analytical TLC was performed using Macherey & Nagel SIL G-25 UV254 silica gel, particle size 0.040–0.063 mm (230–240 mesh, flash). UV irradiation (254 nm) was used to visualize the developed TLC plates. Optical rotations were measured on a Perkin-Elmer 241 polarimeter. Mass spectra were recorded on a Finnigan SSQ7000 spectrometer (EI, 70 eV) and HRMS on a Thermo Fisher Scientific Orbitrap XL spectrometer. IR spectra were recorded on a Perkin-Elmer FT-IR Spectrum 100 spectrometer using an ATR unit. 1H and 13C NMR spectra were recorded on Varian Mercury 600 or Inova 400 instruments with TMS as internal standard. Analytical HPLC was performed on an Agilent 1100 or 1260 Series instrument using chiral stationary phases (Chiralpak IC, Chiralpak IA, Chiralpak IB, Chiralpak AS, Chiralcel OD). The nitroalkenes 1 were prepared as described previously,[13] and the phenyl malonates 2ln according to the reported procedure.[25] The catalysts AD were synthesized as described earlier.[21c] The absolute configuration of compounds 3, 4, and 5 was assigned by comparison with the products obtained in previous work.[21]


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(S)-3-(1-(2-Ethynylphenyl)-2-nitroethyl)pentane-2,4-dione (3)

A solution of nitroalkene 1a (52.0 mg, 0.3 mmol), acetylacetone (2a; 33.0 mg, 0.33 mmol), and squaramide A (1 mg, 0.5 mol%) in CHCl3 (1.5 mL) was stirred at r.t. for 3 h. The crude mixture was directly purified by column chromatography (silica gel, n-pentane/Et2O, 3:1) to afford 3 as a colorless solid; yield: 76 mg (93%); mp 132–134 °C; [α]D 23 +285.1 (c 1.0, CHCl3); 99% ee [HPLC: Chiralpak IC]; Rf  = 0.25 (n-pentane/Et2O, 1:1).

IR (ATR): 3240, 1709, 1546, 1483, 1446, 1358, 1253, 1143, 955, 774, 715, 676 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.54 (dd, J = 7.6, 1.2 Hz, 1 H, CH Ar ), 7.30 (td, J = 7.6, 1.4 Hz, 1 H, CH Ar ), 7.25 (td, J = 7.6, 1.2 Hz, 1 H, CH Ar ), 7.14 (d, J = 7.8 Hz, 1 H, CH Ar ), 4.88 (dd, J = 12.5, 7.2 Hz, 1 H, CHHNO2), 4.80–4.72 (m, 1 H, CHCH2), 4.67 (dd, J = 12.5, 4.2 Hz, 1 H, CHHNO2), 4.64 (d, J = 10.1 Hz, 1 H, CHCO), 3.49 (s, 1 H, C≡CH), 2.25 (s, 3 H, CH3), 2.01 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 202.0, 201.1, 138.0, 134.2, 129.6, 128.2, 127.9, 121.6, 83.7, 80.9, 76.6, 69.2, 40.3, 30.7, 28.6.

MS (EI, 70 eV): m/z (%) = 273.1 (7) [M]+, 227.2 (11), 183.1 (59), 169.1 (26), 155.2 (29), 141.1 (83), 128.1 (86), 115.1 (100), 102.2 (21), 89.2 (19).

HRMS (ESI): m/z [M + Na]+ calcd for C15H15NO4Na+: 296.0893; found: 296.0898.


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Methyleneindanes/Methylindenes 4/5 by Sequential Catalysis; General Procedure

A solution of nitroalkene 1 (0.3 mmol), dicarbonyl compound 2 (0.33 mmol), and squaramide A (0.5–5 mol%) in CH2Cl2 (1.5 mL) was stirred at r.t. for 2 h. The solvent was evaporated by heating at 50 °C and changed to toluene (1.5 mL). Then In(OTf)3 (10 mol%) was added and the reaction mixture was heated at 80 °C for 3 h before being directly purified by flash column chromatography (silica gel, n-pentane/Et2O, 3:1).


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(R)-1,1′-(1-Methylene-3-(nitromethyl)-2,3-dihydro-1H-indene-2,2-diyl)bis(ethan-1-one) (4a)

Compound 4a was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 62 mg (76%); colorless solid; mp 135–137 °C; [α]D 23 +255.9 (c 1.0, CHCl3); 99% ee [HPLC: Chiralcel OD]; Rf  = 0.23 (n-pentane/Et2O, 1:1).

IR (ATR): 3399, 2924, 2323, 2090, 1816, 1702, 1553, 1429, 1359, 1183, 1035, 908, 760, 676 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.51 (dd, J = 6.3, 2.2 Hz, 1 H, CH Ar ), 7.38–7.29 (m, 2 H, CH Ar ), 7.24–7.18 (m, 1 H, CH Ar ), 5.96 (d, J = 1.0 Hz, 1 H, CH ol ), 5.44 (d, J = 1.0 Hz, 1 H, CH ol ), 4.90 (dd, J = 14.4, 7.8 Hz, 1 H, CHHNO2), 4.65 (dd, J = 14.4, 4.3 Hz, 1 H, CHHNO2), 4.59 (dd, J = 7.8, 4.3 Hz, 1 H, CHCH2), 2.37 (s, 3 H, CH3), 2.25 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 203.9, 203.4, 145.6, 141.7, 137.6, 130.3, 128.6, 123.6, 121.3, 110.2, 80.8, 75.8, 46.4, 28.2, 27.1.

MS (EI, 70 eV): m/z (%) = 274.1 (10) [M + H]+, 230.1 (100), 184.1 (76), 169.1 (60).

HRMS (ESI): m/z [M + Na]+ calcd for C15H15NO4Na+: 296.0893; found: 296.0893.


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(R)-1,1′-(5-Chloro-1-methylene-3-(nitromethyl)-2,3-dihydro-1H-indene-2,2-diyl)bis(ethan-1-one) (4b)

Compound 4b was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 3 mg (3%, the major product was 5b); brownish oil; [α]D 23 –122.0 (c 0.1, CHCl3); 96% ee [HPLC: Chiralpak IC]; Rf  = 0.33 (n-pentane/Et2O, 1:1).

IR (ATR): 3408, 3283, 2943, 2667, 2325, 2094, 1912, 1705, 1556, 1364, 1188, 1086, 850, 672 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.43 (d, J = 8.3 Hz, 1 H, CH Ar ), 7.29 (ddd, J = 8.2, 1.8, 0.8 Hz, 1 H, CH Ar ), 7.23–7.19 (m, 1 H, CH Ar ), 5.93 (d, J = 1.4 Hz, 1 H, CH ol ), 5.47 (d, J = 1.4 Hz, 1 H, CH ol ), 4.89 (dd, J = 14.7, 7.8 Hz, 1 H, CHHNO2), 4.62 (dd, J = 14.7, 4.1 Hz, 1 H, CHHNO2), 4.54 (dd, J = 7.8, 4.1 Hz, 1 H, CHCH2), 2.37 (s, 3 H, CH3), 2.25 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 203.4, 203.0, 144.4, 143.4, 136.2, 136.2, 129.1, 124.0, 122.4, 110.8, 80.9, 75.3, 46.0, 28.0, 27.1.

MS (EI, 70 eV): m/z (%) = 264.1 (99), 218.0 (67), 203.0 (65), 139.0 (100).

HRMS (ESI): m/z [M + Na]+ calcd for C15H14NO4ClNa+: 330.0504; found: 330.0503.


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(R)-1,1′-(5-Fluoro-1-methylene-3-(nitromethyl)-2,3-dihydro-1H-indene-2,2-diyl)bis(ethan-1-one) (4c)

Compound 4c was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 6 mg (7%, the major product was 5c); colorless oil; [α]D 23 –33.0 (c 0.1, CHCl3); 99% ee [HPLC: Chiralpak IC]; Rf  = 0.36 (n-pentane/Et2O, 1:1).

IR (ATR): 2936, 2324, 2095, 1910, 1706, 1555, 1481, 1358, 1189, 889, 677 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.47 (dd, J = 8.5, 5.0 Hz, 1 H, CH Ar ), 7.02 (tdd, J = 8.6, 2.4, 0.8 Hz, 1 H, CH Ar ), 6.94 (ddd, J = 8.4, 2.3, 1.0 Hz, 1 H, CH Ar ), 5.88 (d, J = 0.9 Hz, 1 H, CH ol ), 5.42 (d, J = 0.4 Hz, 1 H, CH ol ), 4.89 (dd, J = 14.6, 8.0 Hz, 1 H, CHHNO2), 4.63 (dd, J = 14.6, 4.1 Hz, 1 H, CHHNO2), 4.57–4.48 (m, 1 H, CHCH2), 2.38 (s, 3 H, CH3), 2.25 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 203.6, 203.1, 164.1 (d), 144.4, 144.0 (d), 133.6, 122.9 (d), 116.2 (d), 111.1 (d), 109.8, 81.1, 75.4, 46.1, 28.0, 27.1.

19F NMR (564 MHz, CDCl3): δ = –109.43 (dd, J = 13.5, 8.4 Hz).

MS (EI, 70 eV): m/z (%) = 292.1 (26) [M + H]+, 248.1 (100), 202.1 (73), 187.0 (64).

HRMS (ESI): m/z [M + Na]+ calcd for C15H14NO4FNa+: 314.0799; found: 314.0798.


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Dimethyl (R)-1-Methylene-3-(nitromethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate (4g)

Compound 4g was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 56 mg (61%); colorless solid; mp 88–91 °C; [α]D 23 –114.8 (c 0.8, CHCl3); 95% ee [HPLC: Chiralpak IC]; Rf  = 0.50 (n-pentane/Et2O, 1:1).

IR (ATR): 3024, 2944, 2642, 2301, 2182, 2006, 1715, 1557, 1435, 1377, 1256, 1039, 909, 781 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.56–7.41 (m, 1 H, CH Ar ), 7.39–7.24 (m, 2 H, CH Ar ), 7.24–7.11 (m, 1 H, CH Ar ), 5.91 (s, 1 H, CH ol ), 5.61 (s, 1 H, CH ol ), 4.86 (t, J = 6.6 Hz, 1 H, CHCH2), 4.77 (dd, J = 14.2, 6.4 Hz, 1 H, CHHNO2), 4.68 (dd, J = 14.2, 6.8 Hz, 1 H, CHHNO2), 3.79 (s, 3 H, CH3), 3.73 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 169.0, 168.7, 144.2, 140.5, 138.2, 129.8, 128.8, 123.8, 121.2, 111.1, 76.4, 66.8, 53.5, 53.1, 47.4.

MS (EI, 70 eV): m/z (%) = 306.2 (9) [M + H]+, 258.1 (78), 230.1 (52), 199.1 (100), 141.2 (81).

HRMS (ESI): m/z [M + Na]+ calcd for C15H15NO6Na+: 328.0792; found: 328.0790.


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Diethyl (R)-1-Methylene-3-(nitromethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate (4h)

Compound 4h was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 61 mg (61%); colorless solid; mp 84–86 °C; [α]D 23 –195.5 (c 0.5, CHCl3); 96% ee [HPLC: Chiralpak IC]; Rf  = 0.48 (n-pentane/Et2O, 1:1).

IR (ATR): 2982, 1729, 1555, 1455, 1377, 1234, 1042, 886, 763 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.52–7.48 (m, 1 H, CH Ar ), 7.33–7.27 (m, 2 H, CH Ar ), 7.22–7.19 (m, 1 H, CH Ar ), 5.92 (s, 1 H, CH ol ), 5.63 (s, 1 H, CH ol ), 4.85–4.79 (m, 2 H, CH2NO2), 4.71 (td, J = 9.9, 5.2 Hz, 1 H, CHCH2), 4.29–4.12 (m, 4 H, 2 × OCH2), 1.28 (t, J = 7.2 Hz, 3 H, CH3), 1.25 (d, J = 7.1 Hz, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 168.5, 168.2, 144.2, 140.6, 138.3, 129.8, 128.7, 123.8, 121.2, 111.0, 76.6, 66.8, 62.4, 62.3, 47.3, 13.9, 13.8.

MS (EI, 70 eV): m/z (%) = 334.1 (16) [M + H]+, 286.1 (100), 258.1 (11), 214.1 (59), 169.1 (63), 141.1 (58).

HRMS (ESI): m/z [M + Na]+ calcd for C17H19NO6Na+: 356.1105; found: 356.1104.


#

Dimethyl (R)-5-Methoxy-1-methylene-3-(nitromethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate (4i)

Compound 4i was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 57 mg (57%); colorless oil; [α]D 23 –54.0 (c 0.1, CHCl3); 95% ee [HPLC: Chiralpak IA]; Rf  = 0.63 (n-pentane/Et2O, 1:1).

IR (ATR): 2955, 1731, 1559, 1440, 1374, 1237, 1081, 904, 827, 726 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.40 (d, J = 8.6 Hz, 1 H, CH Ar ), 6.85 (ddd, J = 8.4, 2.3, 0.5 Hz, 1 H, CH Ar ), 6.69 (d, J = 2.2 Hz, 1 H, CH Ar ), 5.73 (d, J = 0.7 Hz, 1 H, CH ol ), 5.45 (d, J = 0.7 Hz, 1 H, CH ol ), 4.81 (t, J = 6.5 Hz, 1 H, CHCH2), 4.75 (dd, J = 14.2, 6.4 Hz, 1 H, CHHNO2), 4.67 (dd, J = 14.2, 6.7 Hz, 1 H, CHHNO2), 3.79 (s, 3 H, CH3), 3.79 (s, 3 H, CH3), 3.73 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 169.1, 168.7, 161.3, 143.6, 142.2, 131.0, 122.4, 115.7, 108.7, 108.2, 76.4, 67.1, 55.5, 53.5, 53.1, 47.4.

MS (EI, 70 eV): m/z (%) = 335.6 (3) [M]+, 288.6 (19), 229.5 (36), 185.4 (46), 171.4 (59), 128.3 (100), 115.3 (38), 98.3 (53).

HRMS (ESI): m/z [M + Na]+ calcd for C16H17NO7Na+: 358.0897; found: 358.0895.


#

Dimethyl (R)-5-Chloro-1-methylene-3-(nitromethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate (4j)

Compound 4j was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 55 mg (54%); colorless solid; mp 100–101 °C; [α]D 23 +3.5 (c 0.6, CHCl3); 94% ee [HPLC: Chiralpak IC]; Rf  = 0.58 (n-pentane/Et2O, 1:1).

IR (ATR): 2294, 2093, 1724, 1556, 1436, 1376, 1252, 1070, 899, 826, 716 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.42 (d, J = 8.3 Hz, 1 H, CH Ar ), 7.31–7.25 (m, 1 H, CH Ar ), 7.19 (s, 1 H, CH Ar ), 5.88 (d, J = 0.8 Hz, 1 H, CH ol ), 5.64 (d, J = 0.8 Hz, 1 H, CH ol ), 4.81 (t, J = 6.3 Hz, 1 H, CHCH2), 4.77 (dd, J = 14.2, 6.0 Hz, 1 H, CHHNO2), 4.68 (dd, J = 14.2, 6.6 Hz, 1 H, CHHNO2), 3.80 (s, 3 H, CH3), 3.74 (s, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 168.7, 168.4, 143.0, 142.1, 136.9, 135.5, 129.2, 124.2, 122.4, 111.8, 76.0, 66.8, 53.6, 53.2, 47.0.

MS (EI, 70 eV): m/z (%) = 339.0 (33) [M]+, 292.1 (100), 264.0 (51), 233.0 (66).

HRMS (ESI): m/z [M + Na]+ calcd for C15H14NO6ClNa+: 362.0402; found: 362.0393.


#

Dimethyl (R)-5-Fluoro-1-methylene-3-(nitromethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate (4k)

Compound 4k was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 63 mg (65%); colorless oil; [α]D 23 –4.3 (c 0.9, CHCl3); 82% ee [HPLC: Chiralpak IC]; Rf  = 0.52 (n-pentane/Et2O, 1:1).

IR (ATR): 3464, 3283, 2955, 2324, 2097, 1730, 1551, 1436, 1371, 1218, 1071, 916, 832, 690 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.44 (dd, J = 8.5, 5.0 Hz, 1 H, CH Ar ), 6.99 (td, J = 8.6, 2.3 Hz, 1 H, CH Ar ), 6.89 (dd, J = 8.5, 2.3 Hz, 1 H, CH Ar ), 5.81 (s, 1 H, CH ol ), 5.57 (s, 1 H, CH ol ), 4.80 (dd, J = 12.4, 6.1 Hz, 1 H, CHCH2), 4.76 (dd, J = 18.5, 5.6 Hz, 1 H, CHHNO2), 4.66 (dd, J = 13.1, 5.9 Hz, 1 H, CHHNO2), 3.78 (s, 3 H, CH3), 3.72 (s, 3 H, CH3).

13C NMR (101 MHz, CDCl3): δ = 168.8, 168.4, 163.8, 142.9, 142.6, 134.3, 122.8, 116.4, 111.1, 110.7, 76.0, 67.0, 53.5, 53.2, 47.1.

19F NMR (376 MHz, CDCl3): δ = –110.47 (s).

MS (EI, 70 eV): m/z (%) = 323.1 (24) [M]+, 276.1 (100), 248.1 (56), 217.1 (90), 159.1 (53).

HRMS (ESI): m/z [M + Na]+ calcd for C15H14NO6FNa+: 346.0697; found: 346.0699.


#

Bis(2-chlorophenyl) (R)-1-Methylene-3-(nitromethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate (4l)

Compound 4l was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 21 mg (14%); yellowish oil; [α]D 23 –18.0 (c 0.1, CHCl3); 80% ee [HPLC: Chiralpak IA]; Rf  = 0.32 (n-pentane/Et2O, 4:1).

IR (ATR): 3288, 3072, 2925, 2087, 1924, 1756, 1641, 1555, 1474, 1375, 1202, 1056, 1002, 945, 906, 832, 744, 682 cm–1.

1H NMR (400 MHz, CDCl3): δ = 7.61–7.57 (m, 1 H, CH Ar ), 7.44 (dt, J = 7.8, 1.8 Hz, 2 H, CH Ar ), 7.38–7.32 (m, 2 H, CH Ar ), 7.29–7.18 (m, 7 H, CH Ar ), 6.13 (d, J = 1.1 Hz, 1 H, CH ol ), 6.00 (d, J = 1.0 Hz, 1 H, CH ol ), 5.25 (dd, J = 14.0, 4.5 Hz, 1 H, CHHNO2), 5.10 (dd, J = 7.7, 4.5 Hz, 1 H, CHCH2), 5.02 (dd, J = 14.0, 7.7 Hz, 1 H, CHHNO2).

13C NMR (101 MHz, CDCl3): δ = 165.9, 165.6, 146.5, 146.3, 143.3, 140.3, 138.0, 130.6, 130.5, 130.1, 129.0, 128.0, 127.9, 127.8, 127.7, 126.8, 126.5, 123.9, 123.3, 123.1, 121.4, 112.5, 76.3, 66.9, 47.7.

MS (EI, 70 eV): m/z (%) = 450.1 (10), 295.1 (43), 231.1 (53), 214.1 (100), 168.1 (36).

HRMS (ESI): m/z [M + K]+ calcd for C25H17NO6Cl2K+: 536.0065; found: 536.0064.


#

Bis(3-chlorophenyl) (R)-1-Methylene-3-(nitromethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate (4m)

Compound 4m was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 37 mg (25%); yellowish oil; [α]D 23 –48.3 (c 1.0, CHCl3); 76% ee [HPLC: Chiralpak IA]; Rf  = 0.27 (n-pentane/Et2O, 4:1).

IR (ATR): 3495, 3075, 2922, 2665, 2329, 2087, 1996, 1936, 1752, 1642, 1588, 1556, 1471, 1430, 1376, 1299, 1192, 1070, 998, 946, 874, 816, 769, 675 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.64–7.60 (m, 1 H, CH Ar ), 7.42–7.37 (m, 2 H, CH Ar ), 7.34 (t, J = 8.1 Hz, 2 H, CH Ar ), 7.31–7.25 (m, 3 H, CH Ar ), 7.18 (dt, J = 12.0, 2.1 Hz, 2 H, CH Ar ), 7.07 (ddd, J = 8.2, 2.2, 1.0 Hz, 1 H, CH Ar ), 7.05 (ddd, J = 8.2, 2.2, 1.0 Hz, 1 H, CH Ar ), 6.13 (d, J = 1.2 Hz, 1 H, CH ol ), 5.86 (d, J = 1.2 Hz, 1 H, CH ol ), 5.10–5.03 (m, 2 H, CHHNO2, CHCH2), 4.95 (dd, J = 16.8, 8.6 Hz, 1 H, CHHNO2).

13C NMR (151 MHz, CDCl3): δ = 166.6, 166.2, 150.8, 150.4, 143.9, 139.9, 137.8, 135.0, 135.0, 130.5, 130.5, 130.4, 129.2, 127.1, 127.0, 123.9, 121.7, 121.7, 121.6, 119.4, 119.4, 112.1, 76.0, 66.9, 47.8.

MS (EI, 70 eV): m/z (%) = 450.1 (11), 295.1 (26), 267.2 (18), 231.1 (26), 216.1 (100), 168.1 (27).

HRMS (ESI): m/z [M + Na]+ calcd for C25H17NO6Cl2Na+: 520.0325; found: 520.0325.


#

Bis(4-chlorophenyl) (S)-1-Methylene-3-(nitromethyl)-1,3-dihydro-2H-indene-2,2-dicarboxylate (4n)

Compound 4n was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 146 mg (98%); yellowish oil; [α]D 23 –26.0 (c 0.2, CHCl3); 86% ee [HPLC: Chiralcel OD]; Rf  = 0.32 (n-pentane/Et2O, 4:1).

IR (ATR): 3886, 3473, 3068, 2672, 2330, 2090, 1891, 1746, 1559, 1480, 1194, 1088, 820 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.63–7.59 (m, 1 H, CH Ar ), 7.41–7.35 (m, 6 H, CH Ar ), 7.30–7.27 (m, 1 H, CH Ar ), 7.12–7.06 (m, 4 H, CH Ar ), 6.12 (d, J = 1.0 Hz, 1 H, CH ol ), 5.85 (d, J = 0.8 Hz, 1 H, CH ol ), 5.08–5.03 (m, 2 H, CHHNO2, CHCH2), 4.94 (dd, J = 16.6, 8.2 Hz, 1 H, CHHNO2).

13C NMR (151 MHz, CDCl3): δ = 166.9, 166.5, 148.9, 148.5, 144.0, 139.9, 137.9, 132.2, 132.1, 130.3, 129.8 (2 C), 129.8 (2 C), 129.2, 123.9, 122.4 (2 C), 122.4 (2 C), 121.6, 112.0, 75.9, 66.9, 47.8.

MS (EI, 70 eV): m/z (%) = 450.6 (3), 370.6 (10), 295.5 (25), 216.5 (62), 168.4 (100), 155.4 (34), 141.4 (71), 128.2 (48).

HRMS (ESI): m/z [M – HNO2]+ calcd for C25H16O4Cl2 +: 450.0420; found: 450.0422.


#

(R)-1-(3-Methyl-1-(nitromethyl)-1H-inden-2-yl)ethan-1-one (5a)

Compound 5a was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 16 mg (23%); colorless solid; mp 83–84 °C; [α]D 23 –123.3 (c 0.4, CHCl3); 98% ee [HPLC: Chiralpak IC]; Rf  = 0.21 (n-pentane/Et2O, 1:1).

IR (ATR): 3438, 2924, 2337, 2092, 1921, 1710, 1639, 1545, 1430, 1358, 1245, 1163, 1002, 925, 843, 757 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.57–7.51 (m, 1 H, CH Ar ), 7.43 (dt, J = 7.7, 4.1 Hz, 1 H, CH Ar ), 7.40 (d, J = 4.0 Hz, 2 H, CH Ar ), 5.18 (dd, J = 12.3, 4.0 Hz, 1 H, CHHNO2), 4.51 (dd, J = 12.3, 8.1 Hz, 1 H, CHHNO2), 4.47–4.40 (m, 1 H, CHCH2), 2.57 (s, 3 H, COCH3), 2.55 (d, J = 2.1 Hz, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 195.9, 150.7, 144.4, 143.3, 138.9, 129.3, 128.4, 123.5, 122.3, 76.1, 47.4, 31.2, 13.7.

MS (EI, 70 eV): m/z (%) = 232.3 (31) [M + H]+, 185.3 (35), 169.2 (86), 159.2 (100), 141.2 (70), 115.2 (65).

HRMS (ESI): m/z [M]+ calcd for C13H13NO3 +: 231.0890; found: 231.0898.


#

(R)-1-(6-Chloro-3-methyl-1-(nitromethyl)-1H-inden-2-yl)ethan-1-one (5b)

Compound 5b was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 27 mg (34%); colorless solid; mp 122–124 °C; [α]D 23 –48.8 (c 0.3, CHCl3); 98% ee [HPLC: Chiralpak IC]; Rf  = 0.25 (n-pentane/Et2O, 1:1).

IR (ATR): 3263, 2928, 2315, 2096, 1912, 1740, 1628, 1550, 1353, 1252, 1159, 1070, 984, 832 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.49–7.44 (m, 1 H, CH Ar ), 7.43–7.38 (m, 2 H, CH Ar ), 5.15 (dd, J = 12.7, 3.9 Hz, 1 H, CHHNO2), 4.55 (dd, J = 12.7, 7.9 Hz, 1 H, CHHNO2), 4.42 (ddd, J = 7.8, 3.9, 2.0 Hz, 1 H, CHCH2), 2.57 (s, 3 H, COCH3), 2.53 (d, J = 2.1 Hz, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 195.6, 149.6, 144.9, 143.0, 139.0, 135.6, 128.9, 124.1, 123.3, 75.6, 47.2, 31.1, 13.7.

MS (EI, 70 eV): m/z (%) = 266.0 (39) [M + H]+, 218.0 (76), 203.0 (100).

HRMS (ESI): m/z [M]+ calcd for C13H12NO3Cl+: 265.0500; found: 265.0501.


#

(R)-1-(6-Fluoro-3-methyl-1-(nitromethyl)-1H-inden-2-yl)ethan-1-one (5c)

Compound 5c was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 40 mg (54%); colorless solid; mp 130–132 °C; [α]D 23 –163.9 (c 0.7, CHCl3); 98% ee [HPLC: Chiralpak IC]; Rf  = 0.21 (n-pentane/Et2O, 1:1).

IR (ATR): 3456, 3245, 3060, 2661, 2329, 2093, 1912, 1741, 1612, 1539, 1429, 1354, 1270, 1197, 1099, 841, 668 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.55–7.42 (m, 1 H, CH Ar ), 7.19–7.07 (m, 2 H, CH Ar ), 5.17 (dd, J = 12.6, 4.0 Hz, 1 H, CHHNO2), 4.51 (dd, J = 12.6, 8.1 Hz, 1 H, CHHNO2), 4.44–4.40 (m, 1 H, CHCH2), 2.56 (s, 3 H, COCH3), 2.53 (d, J = 2.1 Hz, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 195.4, 163.8 (d), 149.9, 145.7 (d), 140.4 (d), 138.7 (d), 123.7 (d), 115.8 (d), 111.5 (d), 75.8, 47.2 (d), 31.0, 13.8.

19F NMR (564 MHz, CDCl3): δ = –110.23 (td, J = 8.6, 5.1 Hz).

MS (EI, 70 eV): m/z (%) = 249.9 (97) [M + H]+, 202.9 (76), 186.9 (100).

HRMS (ESI): m/z [M]+ calcd for C13H12NO3F+: 249.0796; found: 249.0805.


#

(R)-1-(6-Methoxy-3-methyl-1-(nitromethyl)-1H-inden-2-yl)ethan-1-one (5d)

Compound 5d was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 78 mg (99%); colorless solid; mp 107–109 °C; [α]D 23 –118.6 (c 0.5, CHCl3); ≥99% ee [HPLC: Chiralpak IA]; Rf  = 0.21 (n-pentane/Et2O, 1:1).

IR (ATR): 3413, 3088, 2921, 2846, 2606, 2291, 2113, 1998, 1894, 1706, 1620, 1574, 1475, 1421, 1368, 1343, 1278, 1225, 1178, 1137, 1089, 1026, 948, 877, 827, 772, 723, 661 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.44 (d, J = 8.4 Hz, 1 H, CH Ar ), 6.96 (dd, J = 8.5, 2.3 Hz, 1 H, CH Ar ), 6.92 (d, J = 2.2 Hz, 1 H, CH Ar ), 5.19 (dd, J = 11.0, 2.5 Hz, 1 H, CHHNO2), 4.48–4.35 (m, 2 H, CHHNO2, CHCH2), 3.83 (s, 3 H, OCH3), 2.54 (s, 3 H, COCH3), 2.52 (d, J = 1.7 Hz, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 195.2, 161.4, 151.2, 145.9, 137.2, 137.0, 123.4, 114.7, 109.2, 76.3, 55.6, 47.1, 30.9, 13.9.

MS (EI, 70 eV): m/z (%) = 260.9 (71) [M]+, 213.9 (83), 199.0 (100).

HRMS (ESI): m/z [M + H]+ calcd for C14H16NO4 +: 262.1074; found: 262.1072.


#

(R)-1-(7-Methyl-5-(nitromethyl)-5H-indeno[5,6-d][1,3]dioxol-6-yl)ethan-1-one (5e)

Compound 5e was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 57 mg (69%); colorless solid; mp 102–104 °C; [α]D 23 –126.8 (c 0.4, CHCl3); 95% ee [HPLC: Chiralpak IB]; Rf  = 0.30 (n-pentane/Et2O, 1:1).

IR (ATR): 3448, 3251, 2916, 2783, 2698, 2326, 2105, 1996, 1864, 1705, 1633, 1537, 1472, 1434, 1372, 1330, 1216, 1157, 1110, 1028, 930, 871, 834, 739, 665 cm–1.

1H NMR (600 MHz, CDCl3): δ = 6.96 (s, 1 H, CH Ar ), 6.87 (s, 1 H, CH Ar ), 6.03 (dd, J = 6.1, 1.3 Hz, 2 H, OCH2O), 5.15 (dd, J = 12.4, 4.0 Hz, 1 H, CHHNO2), 4.44 (dd, J = 12.4, 8.2 Hz, 1 H, CHHNO2), 4.33 (ddd, J = 8.0, 3.7, 1.9 Hz, 1 H, CHCH2), 2.53 (s, 3 H, COCH3), 2.48 (d, J = 2.0 Hz, 3 H, CH3).

13C NMR (151 MHz, CDCl3): δ = 194.8, 150.9, 149.6, 148.5, 138.8, 138.5, 138.0, 104.6, 102.5, 101.8, 76.3, 47.0, 30.9, 14.0.

MS (EI, 70 eV): m/z (%) = 274.9 (61) [M]+, 228.0 (64), 212.9 (100).

HRMS (ESI): m/z [M]+ calcd for C14H13NO5 +: 275.0788; found: 275.0793.


#

(R)-1-(3-Methyl-1-(nitromethyl)-1H-inden-2-yl)propan-1-one (5f)

Compound 5f was isolated after flash chromatography (n-pentane/Et2O, 3:1); yield: 44 mg (60%); colorless solid; mp 87–89 °C; [α]D 23 –97.5 (c 0.2, CHCl3); 97% ee [HPLC: Chiralpak AS]; Rf  = 0.59 (n-pentane/Et2O, 1:1).

IR (ATR): 3817, 3390, 2927, 2676, 2336, 2094, 1877, 1755, 1629, 1550, 1361, 1199, 1035, 919, 758 cm–1.

1H NMR (600 MHz, CDCl3): δ = 7.54 (d, J = 7.5 Hz, 1 H, CH Ar ), 7.46–7.37 (m, 3 H, CH Ar ), 5.17 (dd, J = 12.1, 3.8 Hz, 1 H, CHHNO2), 4.51 (dd, J = 12.1, 8.0 Hz, 1 H, CHHNO2), 4.48–4.43 (m, 1 H, CHCH2), 2.89 (tdd, J = 17.3, 10.1, 7.2 Hz, 2 H, CH 2CH3), 2.54 (d, J = 2.0 Hz, 3 H, =CCH3), 1.21 (t, J = 7.2 Hz, 3 H, CH2CH 3).

13C NMR (151 MHz, CDCl3): δ = 199.1, 149.6, 144.5, 143.3, 138.6, 129.1, 128.4, 123.4, 122.2, 76.2, 47.5, 36.3, 13.8, 8.1.

MS (EI, 70 eV): m/z (%) = 245.5 (2) [M]+, 216.4 (2), 199.4 (4), 173.3 (7), 169.3 (35), 141.3 (17), 57.3 (100).

HRMS (ESI): m/z [M]+ calcd for C14H15NO3 +: 245.1052; found: 245.1057.


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#

Acknowledgment

We thank the European Research Council (ERC Advanced Grant 320493 ‘DOMINOCAT’) for financial support.

Supporting Information

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    • 9a Sun S.-S, Zhang C, Yang Z, Dalton LR, Garner SM, Chen A, Steier WH. Polymer 1998; 39: 4977
    • 9b Yang J, Lakshmikantham MV, Cava MP, Lorcy D, Bethelot JR. J. Org. Chem. 2000; 65: 6739
    • 9c Diesendruck CE, Steinberg BD, Sugai N, Silberstein MN, Sottos NR, White SR, Braun PV, Moore JS. J. Am. Chem. Soc. 2012; 134: 12446
    • 9d Morales AR, Frazer A, Woodward AW, Ahn-White H.-Y, Fonari A, Tongwa P, Timofeeva T, Belfield KD. J. Org. Chem. 2013; 78: 1014
    • 10a Barberá J, Rakitin OA, Ros MB, Torroba T. Angew. Chem. Int. Ed. 1998; 37: 296
    • 10b Konstantinova LS, Rakitin OA, Souvorova LI, Rees CW, White AJ. P, Williams DJ, Torroba T. Chem. Commun. 1999; 73
    • 10c Basurto S, García S, Neo AG, Torroba T, Marcos CF, Miguel D, Barberá J, Ros MB, de la Fuente MR. Chem. Eur. J. 2005; 11: 5362
    • 10d Mohammady SZ, Elkholy SS, Elsabee MZ. Polym. Int. 2007; 56: 7
    • 10e He Y, Zhao G, Peng B, Li Y. Adv. Funct. Mater. 2010; 20: 3383
    • 10f Xia Z.-Y, Zhang Z.-Y, Su J.-H, Zhang Q, Fung K.-M, Lam M.-K, Li K.-F, Wong W.-Y, Cheah K.-W, Tian H, Chen CH. J. Mater. Chem. 2010; 20: 3768
    • 10g He Y, Chen H.-Y, Hou J, Li Y. J. Am. Chem. Soc. 2010; 132: 1377
    • 10h He Y, Li Y. Phys. Chem. Chem. Phys. 2011; 13: 1970
    • 10i Seyler H, Wong WW. H, Jones DJ, Holmes AB. J. Org. Chem. 2011; 76: 3551
    • 10j Matano Y, Saito A, Suzuki Y, Miyajima T, Akiyama S, Otsubo S, Nakamoto E, Aramaki S, Imahori H. Chem. Asian J. 2012; 7: 2305
    • 10k Barrera EG, Stedile FC, de Souza MO, Miranda MS. L, de Souza RF, Bernardo-Gusmão K. Appl. Catal., A 2013; 462-463: 1
    • 11a Shao Z, Zhang H. Chem. Soc. Rev. 2009; 38: 2745
    • 11b Du Z, Shao Z. Chem. Soc. Rev. 2013; 42: 1337
  • 12 Loh CC. J, Badorrek J, Raabe G, Enders D. Chem. Eur. J. 2011; 17: 13409
  • 13 Hack D, Dürr AB, Deckers K, Chauhan P, Seling N, Rübenach L, Mertens L, Raabe G, Schoenebeck F, Enders D. Angew. Chem. Int. Ed. 2016; 55: 1797
    • 14a Conia JM, Le Perchec P. Synthesis 1975; 1
    • 14b Dénès F, Pérez-Luna A, Chemla F. Chem. Rev. 2010; 110: 2366
    • 14c Hack D, Blümel M, Chauhan P, Philipps AR, Enders D. Chem. Soc. Rev. 2015; 44: 6059
    • 15a Binder JT, Crone B, Haug TT, Menz H, Kirsch SF. Org. Lett. 2008; 10: 1025
    • 15b Yang T, Ferrali A, Sladojevich F, Campbell L, Dixon DJ. J. Am. Chem. Soc. 2009; 131: 9140
    • 15c Ramachary DB, Mondal R, Venkaiah C. Eur. J. Org. Chem. 2010; 3205
    • 15d Montaignac B, Vitale MR, Ratovelomanana-Vidal V, Michelet V. J. Org. Chem. 2010; 75: 8322
    • 15e Montaignac B, Vitale MR, Michelet V, Ratovelomanana-Vidal V. Org. Lett. 2010; 12: 2582
    • 15f Praveen C, Montaignac B, Vitale MR, Ratovelomanana-Vidal V, Michelet V. ChemCatChem 2013; 5: 2395
    • 16a Capdevila MG, Benfatti F, Zoli L, Stenta M, Cozzi PG. Chem. Eur. J. 2010; 16: 11237
    • 16b Motoyama K, Ikeda M, Miyake Y, Nishibayashi Y. Eur. J. Org. Chem. 2011; 2239
    • 16c Sinisi R, Vita MV, Gualandi A, Emer E, Cozzi PG. Chem. Eur. J. 2011; 17: 7404
    • 16d Guiteras Capdevila M, Emer E, Benfatti F, Gualandi A, Wilson CM, Cozzi PG. Asian J. Org. Chem. 2012; 1: 38
    • 16e Xiao J. Org. Lett. 2012; 14: 1716
    • 16f Gualandi A, Mengozzi L, Wilson CM, Cozzi PG. Synthesis 2014; 46: 1321
    • 17a Kim S.-G, Park T.-H, Kim BJ. Tetrahedron Lett. 2006; 47: 6369
    • 17b Lim A, Choi JH, Tae J. Tetrahedron Lett. 2008; 49: 4882
  • 18 Lv J, Zhang L, Zhou Y, Nie Z, Luo S, Cheng J.-P. Angew. Chem. Int. Ed. 2011; 50: 6610
  • 19 Lv J, Zhang L, Hu S, Cheng J.-P, Luo S. Chem. Eur. J. 2012; 18: 799

    • For recent indane syntheses undertaken by our group, see:
    • 20a Loh CC. J, Hack D, Enders D. Chem. Commun. 2013; 49: 10230
    • 20b Loh CC. J, Atodiresei I, Enders D. Chem. Eur. J. 2013; 19: 10822
    • 20c Loh CC. J, Chauhan P, Hack D, Lehmann C, Enders D. Adv. Synth. Catal. 2014; 356: 3181
    • 21a Okino T, Hoashi Y, Takemoto Y. J. Am. Chem. Soc. 2003; 125: 12672
    • 21b Okino T, Hoashi Y, Furukawa T, Xu X, Takemoto Y. J. Am. Chem. Soc. 2005; 127: 119
    • 21c Malerich JP, Hagihara K, Rawal VH. J. Am. Chem. Soc. 2008; 130: 14416
    • 22a Nakamura M, Liang C, Nakamura E. Org. Lett. 2004; 6: 2015
    • 22b Kennedy-Smith JJ, Staben ST, Toste FD. J. Am. Chem. Soc. 2004; 126: 4526
    • 22c Itoh Y, Tsuji H, Yamagata K.-i, Endo K, Tanaka I, Nakamura M, Nakamura E. J. Am. Chem. Soc. 2008; 130: 17161
    • 22d Montel S, Bouyssi D, Balme G. Adv. Synth. Catal. 2010; 352: 2315
    • 22e Chan LY, Kim S, Park Y, Lee PH. J. Org. Chem. 2012; 77: 5239
    • 22f Boominathan SS. K, Hu W.-P, Senadi GC, Wang J.-J. Adv. Synth. Catal. 2013; 355: 3570
  • 23 Kochetkov NK, Kudryashov LJ, Gottich BP. Tetrahedron 1961; 12: 63
  • 24 Mander LN, Woolias M. Synthesis 1979; 185
  • 25 Jabin I, Revial G, Monnier-Benoit N, Netchitaïlo P. J. Org. Chem. 2001; 66: 256

  • References

    • 1a Vilums M, Heuberger J, Heitman LH, Ijzerman AP. Med. Res. Rev. 2015; 35: 1097
    • 1b Gabriele B, Mancuso R, Veltri L. Chem. Eur. J. 2016; 22: 5056

      For selected indane examples, see:
    • 2a Daum S, Erdmann F, Fischer G, Féaux de Lacroix B, Hessamian-Alinejad A, Houben S, Frank W, Braun M. Angew. Chem. Int. Ed. 2006; 45: 7454
    • 2b Gross MF, Beaudoin S, McNaughton-Smith G, Amato GS, Castle NA, Huang C, Zou A, Yu W. Bioorg. Med. Chem. Lett. 2007; 17: 2849
    • 2c Sharma M, Ray SM. Eur. J. Med. Chem. 2008; 43: 2092
    • 2d Shiohara H, Nakamura T, Kikuchi N, Ozawa T, Nagano R, Matsuzawa A, Ohnota H, Miyamoto T, Ichikawa K, Hashizume K. Bioorg. Med. Chem. 2012; 20: 3622
    • 2e Ugliarolo EA, Gagey D, Lantaño B, Moltrasio GY, Campos RH, Cavallaro LV, Moglioni AG. Bioorg. Med. Chem. 2012; 20: 5986
    • 2f Kumar S, Dwivedi AP, Kashyap VK, Saxena AK, Dwivedi AK, Srivastava R, Sahu DP. Bioorg. Med. Chem. Lett. 2013; 23: 2404
    • 2g Dutt R, Madan AK. Med. Chem. Res. 2013; 22: 3213
    • 2h Singh A, Fatima K, Singh A, Behl A, Mintoo MJ, Hasanain M, Ashraf R, Luqman S, Shanker K, Mondhe DM, Sarkar J, Chanda D, Negi AS. Eur. J. Pharm. Sci. 2015; 76: 57

      For selected indene examples, see:
    • 3a Voets M, Antes I, Scherer C, Müller-Vieira U, Biemel K, Marchais-Oberwinkler S, Hartmann RW. J. Med. Chem. 2006; 49: 2222
    • 3b Ahn JH, Shin MS, Jung SH, Kim JA, Kim HM, Kim SH, Kang SK, Kim KR, Rhee SD, Park SD, Lee JM, Lee JH, Cheon HG, Kim SS. Bioorg. Med. Chem. Lett. 2007; 17: 5239
    • 3c Tu S, Xu L.-H, Ye L.-Y, Wang X, Sha Y, Xiao Z.-Y. J. Agric. Food Chem. 2008; 56: 5247
    • 3d Norrgård MA, Mannervik B. J. Mol. Biol. 2011; 412: 111
    • 3e Kahlon AK, Negi AS, Kumari R, Srivastava KK, Kumar S, Darokar MP, Sharma A. Appl. Microbiol. Biotechnol. 2014; 98: 2041
    • 3f Banothu J, Basavoju S, Bavantula R. J. Heterocycl. Chem. 2015; 52: 853
  • 4 Dorsey BD, Levin RB, McDaniel SL, Vacca JP, Guare JP, Darke PL, Zugay JA, Emini EA, Schleif WA, Quintero JC, Lin JH, Chen IW, Holloway MK, Fitzgerald PM. D, Axel MG, Ostovic D, Anderson PS, Huff JR. J. Med. Chem. 1994; 37: 3443
  • 5 Villetti G, Bregola G, Bassani F, Bergamaschi M, Rondelli I, Pietra C, Simonato M. Neuropharmacology 2001; 40: 866
  • 6 Jung M, Wahl AF, Neupert W, Geisslinger G, Senter PD. Pharm. Pharmacol. Commun. 2000; 6: 217
  • 7 Yu H, Kim IJ, Folk JE, Tian X, Rothman RB, Baumann MH, Dersch CM, Flippen-Anderson JL, Parrish D, Jacobson AE, Rice KC. J. Med. Chem. 2004; 47: 2624
  • 8 Juby PF, Partyka RA, Hudyma TW. US Patent 3565943, 1971
    • 9a Sun S.-S, Zhang C, Yang Z, Dalton LR, Garner SM, Chen A, Steier WH. Polymer 1998; 39: 4977
    • 9b Yang J, Lakshmikantham MV, Cava MP, Lorcy D, Bethelot JR. J. Org. Chem. 2000; 65: 6739
    • 9c Diesendruck CE, Steinberg BD, Sugai N, Silberstein MN, Sottos NR, White SR, Braun PV, Moore JS. J. Am. Chem. Soc. 2012; 134: 12446
    • 9d Morales AR, Frazer A, Woodward AW, Ahn-White H.-Y, Fonari A, Tongwa P, Timofeeva T, Belfield KD. J. Org. Chem. 2013; 78: 1014
    • 10a Barberá J, Rakitin OA, Ros MB, Torroba T. Angew. Chem. Int. Ed. 1998; 37: 296
    • 10b Konstantinova LS, Rakitin OA, Souvorova LI, Rees CW, White AJ. P, Williams DJ, Torroba T. Chem. Commun. 1999; 73
    • 10c Basurto S, García S, Neo AG, Torroba T, Marcos CF, Miguel D, Barberá J, Ros MB, de la Fuente MR. Chem. Eur. J. 2005; 11: 5362
    • 10d Mohammady SZ, Elkholy SS, Elsabee MZ. Polym. Int. 2007; 56: 7
    • 10e He Y, Zhao G, Peng B, Li Y. Adv. Funct. Mater. 2010; 20: 3383
    • 10f Xia Z.-Y, Zhang Z.-Y, Su J.-H, Zhang Q, Fung K.-M, Lam M.-K, Li K.-F, Wong W.-Y, Cheah K.-W, Tian H, Chen CH. J. Mater. Chem. 2010; 20: 3768
    • 10g He Y, Chen H.-Y, Hou J, Li Y. J. Am. Chem. Soc. 2010; 132: 1377
    • 10h He Y, Li Y. Phys. Chem. Chem. Phys. 2011; 13: 1970
    • 10i Seyler H, Wong WW. H, Jones DJ, Holmes AB. J. Org. Chem. 2011; 76: 3551
    • 10j Matano Y, Saito A, Suzuki Y, Miyajima T, Akiyama S, Otsubo S, Nakamoto E, Aramaki S, Imahori H. Chem. Asian J. 2012; 7: 2305
    • 10k Barrera EG, Stedile FC, de Souza MO, Miranda MS. L, de Souza RF, Bernardo-Gusmão K. Appl. Catal., A 2013; 462-463: 1
    • 11a Shao Z, Zhang H. Chem. Soc. Rev. 2009; 38: 2745
    • 11b Du Z, Shao Z. Chem. Soc. Rev. 2013; 42: 1337
  • 12 Loh CC. J, Badorrek J, Raabe G, Enders D. Chem. Eur. J. 2011; 17: 13409
  • 13 Hack D, Dürr AB, Deckers K, Chauhan P, Seling N, Rübenach L, Mertens L, Raabe G, Schoenebeck F, Enders D. Angew. Chem. Int. Ed. 2016; 55: 1797
    • 14a Conia JM, Le Perchec P. Synthesis 1975; 1
    • 14b Dénès F, Pérez-Luna A, Chemla F. Chem. Rev. 2010; 110: 2366
    • 14c Hack D, Blümel M, Chauhan P, Philipps AR, Enders D. Chem. Soc. Rev. 2015; 44: 6059
    • 15a Binder JT, Crone B, Haug TT, Menz H, Kirsch SF. Org. Lett. 2008; 10: 1025
    • 15b Yang T, Ferrali A, Sladojevich F, Campbell L, Dixon DJ. J. Am. Chem. Soc. 2009; 131: 9140
    • 15c Ramachary DB, Mondal R, Venkaiah C. Eur. J. Org. Chem. 2010; 3205
    • 15d Montaignac B, Vitale MR, Ratovelomanana-Vidal V, Michelet V. J. Org. Chem. 2010; 75: 8322
    • 15e Montaignac B, Vitale MR, Michelet V, Ratovelomanana-Vidal V. Org. Lett. 2010; 12: 2582
    • 15f Praveen C, Montaignac B, Vitale MR, Ratovelomanana-Vidal V, Michelet V. ChemCatChem 2013; 5: 2395
    • 16a Capdevila MG, Benfatti F, Zoli L, Stenta M, Cozzi PG. Chem. Eur. J. 2010; 16: 11237
    • 16b Motoyama K, Ikeda M, Miyake Y, Nishibayashi Y. Eur. J. Org. Chem. 2011; 2239
    • 16c Sinisi R, Vita MV, Gualandi A, Emer E, Cozzi PG. Chem. Eur. J. 2011; 17: 7404
    • 16d Guiteras Capdevila M, Emer E, Benfatti F, Gualandi A, Wilson CM, Cozzi PG. Asian J. Org. Chem. 2012; 1: 38
    • 16e Xiao J. Org. Lett. 2012; 14: 1716
    • 16f Gualandi A, Mengozzi L, Wilson CM, Cozzi PG. Synthesis 2014; 46: 1321
    • 17a Kim S.-G, Park T.-H, Kim BJ. Tetrahedron Lett. 2006; 47: 6369
    • 17b Lim A, Choi JH, Tae J. Tetrahedron Lett. 2008; 49: 4882
  • 18 Lv J, Zhang L, Zhou Y, Nie Z, Luo S, Cheng J.-P. Angew. Chem. Int. Ed. 2011; 50: 6610
  • 19 Lv J, Zhang L, Hu S, Cheng J.-P, Luo S. Chem. Eur. J. 2012; 18: 799

    • For recent indane syntheses undertaken by our group, see:
    • 20a Loh CC. J, Hack D, Enders D. Chem. Commun. 2013; 49: 10230
    • 20b Loh CC. J, Atodiresei I, Enders D. Chem. Eur. J. 2013; 19: 10822
    • 20c Loh CC. J, Chauhan P, Hack D, Lehmann C, Enders D. Adv. Synth. Catal. 2014; 356: 3181
    • 21a Okino T, Hoashi Y, Takemoto Y. J. Am. Chem. Soc. 2003; 125: 12672
    • 21b Okino T, Hoashi Y, Furukawa T, Xu X, Takemoto Y. J. Am. Chem. Soc. 2005; 127: 119
    • 21c Malerich JP, Hagihara K, Rawal VH. J. Am. Chem. Soc. 2008; 130: 14416
    • 22a Nakamura M, Liang C, Nakamura E. Org. Lett. 2004; 6: 2015
    • 22b Kennedy-Smith JJ, Staben ST, Toste FD. J. Am. Chem. Soc. 2004; 126: 4526
    • 22c Itoh Y, Tsuji H, Yamagata K.-i, Endo K, Tanaka I, Nakamura M, Nakamura E. J. Am. Chem. Soc. 2008; 130: 17161
    • 22d Montel S, Bouyssi D, Balme G. Adv. Synth. Catal. 2010; 352: 2315
    • 22e Chan LY, Kim S, Park Y, Lee PH. J. Org. Chem. 2012; 77: 5239
    • 22f Boominathan SS. K, Hu W.-P, Senadi GC, Wang J.-J. Adv. Synth. Catal. 2013; 355: 3570
  • 23 Kochetkov NK, Kudryashov LJ, Gottich BP. Tetrahedron 1961; 12: 63
  • 24 Mander LN, Woolias M. Synthesis 1979; 185
  • 25 Jabin I, Revial G, Monnier-Benoit N, Netchitaïlo P. J. Org. Chem. 2001; 66: 256

Zoom Image
Figure 1 Examples of indane and indene pharmaceuticals
Zoom Image
Scheme 1 Catalyst screening for the Michael reaction
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Scheme 2 Formation of methylindene 5a starting from methylene­indane 4a
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Scheme 3 Postulated reaction mechanism for the concerted ketene fragmentation