Methods for the Synthesis of Piperazine Derivatives Containing a Chiral Bi-2-naphthyl Moiety

Abstract

Piperazine derivatives containing 1,1′-bi-2-naphthyl moiety were synthesized starting from 2,2′-dimethoxy-1,1′-bi-naphthalene via acylation using ethyl chlorooxoacetate and subsequent condensation with 1,2-diamines followed by reduction of the corresponding dihydro-2-piperazinone intermediate using the NaBH₄/I₂ reagent system. The corresponding chiral piperazine derivatives containing bi-2-napthyl moiety was synthesized by asymmetric reduction of ethyl dimethoxy-bi-2-naphthyloxoacetate by chiral oxazoborolidine catalyst prepared in situ using S-diphenylprolinol (S-DPP), B(OCH₃)₃ and H₃B·THF. The resulting diols were mesylated and cyclized using 1,2-diamines to obtain the corresponding chiral piperazine derivatives.

N-Heterocycles are widely present in biologically active molecules. Recently, methods for the synthesis of a variety of chiral N-heterocycles have been reviewed.[1] Among the N-heterocycles, the piperazine derivatives are widely present in life saving drug molecules.[2] Recent reports show that piperazine derivatives are the most commonly used N-hetero­cycles in pharmaceuticals.[3] Presumably, piperazine moieties enhance the hydrophilic surface area, have additional hydrogen bond accepting and donating nature due to piperazine nitrogen atoms, which improve water solubility, oral bioavailability, absorption in intestine, and smooth excretion properties.[4a] [b] Accordingly, efficient synthetic methods with high regio-, stereo-, and enantioselectivity to access piperazine derivatives will be of interest to synthetic and medicinal chemists.

In recent years, methods were reported for the synthesis of several 2,3-diarylpiperazine derivatives (Scheme [1]).[5] [6] The trans-2,3-diphenylpiperazine derivatives were readily accessed via a diastereoselective coupling method using Ti(III) prepared in situ followed by resolution using optically active tartaric acid.[5a] Methods were also reported for the synthesis of meso- 2,3-diphenylpiperazine derivatives.[7] Also, the chiral camphorylpiperazine derivatives were prepared by condensation of ethylenediamine with optically active camphorquinone.[8] A similar condensation process with 1,2 diaminocyclohexane was also reported.[9]

Herein, we report methods for synthesis of piperazine derivatives containing chiral bi-2-napthyl moiety. Initially, the product (R)-3 was prepared in 80% yield by Friedel–Crafts acylation using bi-2-naphthyl derivative (R)-1, ethyl chlorooxoacetate (2; 1.2 equiv), and anhydrous AlCl₃ (Scheme [2]). Subsequent condensation of this keto ester (R)-3 with ethylenediamine (4) in anhydrous methanol gave the product (R)-5 in 90% yield. We have observed that similar condensation reactions of (R)-3 with 1,2-diaminobenzene (6) and (2R,3R)-1,2-diaminocyclohexane (8) under reflux conditions furnished cyclic products (R)-7 and (R)-9 in 90% and 88% yield, respectively.

The mechanism and intermediates shown in Scheme [3] may be considered to rationalize these condensation and cyclization processes. Initial reaction of the more reactive keto group with the ethylenediamine (4) followed by formation of ketimine and reaction of the amino group with the ester moiety would give the cyclic product (R)-5. Similar reactions in the case of the diamines 6 and 8 would give the corresponding condensation products (R)-7 and (R)-9, respectively.

We then carried out the reduction of the compound (R)-5 using H₃B·THF prepared in situ with the NaBH₄ and I₂ reagent­ combination.[10] We observed that the reaction at reflux­ conditions for 12 hours gave the product 3-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]piperzin-2-one [(R)-15] in 78% yield and further reduction using the NaBH₄/I₂ reagent system under reflux conditions for 24 hours gave the corresponding piperazine product R-16 in 73% yield (Scheme [4]). Unfortunately, the highly sterically hindered (4aR,8aR)-3-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]-4a,5,6,7,8,8a-hydroquinoxalin-2(1H)-one [(R)-7] failed to undergo reduction under the same conditions. However, the (4aR,8aR)-3-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]-4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one [(R)-9] gave the corresponding reduction products (4aR,8aR)-3-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]-octahydroquinoxalin-2(1H)-one [(R)-17] and (4aR,8aR)-3-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]decahydroquinoxaline [(R)-18] in 73% and 72% yield, respectively, under the same conditions. Unfortunately, there was no selectivity at the newly formed stereogenic centers in the corresponding piperazine products (R)-15 and (R)-17. The absence of stereoselectivity in the reduction of piperazenones may be due to remoteness of the atropochiral stereogenic bi-2-naphthyl system.

Next, we turned our attention towards a new protocol involving asymmetric reduction of the carbonyl group in the bi-2-naphthyl derivative (R)-3 involving the CBS-catalyzed process. There have been several reports on the asymmetric reduction of prochiral ketone to corresponding chiral alcohol with 95% ee using (S)-DPP and H₃B-Lewis base complexes.[11] In recent years, several borane reagent systems in combination with I₂, benzyl chloride, and (S)-diphenylprolinol [(S-DPP) 19] were used in chiral reduction of aryl alkyl ketones to obtain the corresponding secondary alcohol with R-configuration with >95% ee.[12] Also, aryl alkyl ketones containing a chiral biaryl moiety were reduced to the corresponding secondary alcohols with >95% ee with the S-DPP/B(OCH₃)₃/H₃B·THF with R-configuration at the new stereogenic center.[13a] [b] Previously, we have also observed that asymmetric reduction of several 6-acyl derivatives prepared using 2,2′-dimethoxy-1,1′-binaphthalene (R)-1 with the S-DPP/B(OCH₃)₃/H₃B·THF reagent combination gave the corresponding alcohols with R-configuration with >95% ee.[13c] Accordingly, we have carried out the asymmetric reduction of the 2-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]-2-oxoacetate with S-DPP (30 mol%) and B(OCH₃)₃ using H₃B·THF (2 M, 3 equiv) at 0 °C to obtain the corresponding 1,2-diol product (aR,R)-20 in 90% yield and with >95% dr. In this reaction, alignment of smaller R group with phenyl group in the oxazaborolidine intermediate over the larger bi-2-naphthyl group is expected to result in highly specific transfer of chirality while hydride is transferred to afford the chiral 1,2-diol 20 (Scheme [5]).[11]

Subsequently, we have carried out the preparation of the dimesylate 21 and its reaction with the diamines 4 and 8 (Scheme [6]). Whereas, the (2S)-2-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]piperazine [(aR,S)-22] was obtained in 76% yield, the (2R,4aS,8aR)-2-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]decahydroquinoxalin [(R)-23] was obtained in 75% yield. In this reaction, the compounds (R)-22 and (R)-23 were obtained in diastereomerically pure forms and other diastereomer was not detected by ¹H and ¹³C NMR spectral data.

A tentative S_N2 type mechanism may be considered for these transformations as outlined in Scheme [7]. Accordingly, the stereochemistry of the new stereogenic centers added in the products 22 and 23 are assigned the S-configuration.

In summary, convenient methods have been developed for the synthesis of piperazine derivatives containing the bi-2-naphthyl moiety. Since these procedures utilize readily accessible reagent systems, the methods described here open new prospects for the synthesis and study of chiral piperazine derivatives.

Melting points are uncorrected and were determined using a Super fit capillary point apparatus. IR (KBr) spectra were recorded on JASCO FT-IR spectrophotometer model 5300 and the neat IR spectra were recorded on SHIMADZU FT-IR spectrophotometer model 8300 with polystyrene as reference. ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on Bruker Avance-400 spectrometer in CDCl₃ as solvent and TMS as reference (δ = 0). The chemical shifts are expressed in δ downfield from the signal of internal TMS. Elemental analyses were carried out using a PerkinElmer elemental analyzer model-240C and Thermo Finnegan analyzer series Flash EA 1112. Mass spectral analyses were carried out on VG 7070H mass spectrometer using EI technique at 70 eV. Optical rotations were measured with an AUTOPOL-II automatic polarimeter (readability ± 0.01°). Analytical TLC chromatographic tests were carried out on glass plates (3 × 10 cm) coated with 250 mμ Acme’s silica gel-G and GF-254 containing 13% CaSO₄. The spots were visualized by short exposure to I₂ vapor or UV light. Column chromatography was carried out using Acme silica gel (100–200 mesh) or neutral alumina. All anhydrous solvents and reagents (liquids) used were distilled from appropriate drying agents.

As a routine practice, all organic extracts were washed with brine (brine), dried over anhyd Na₂SO₄, and concentrated on Heidolph-rotary evaporator. All yields reported are of isolated materials judged homogeneous by TLC, IR spectroscopy, and NMR spectrometry. CH₂Cl₂ and CHCl₃ were distilled over CaH₂ and dried over molecular sieves. (S)-DPP was supplied by Gerchem Labs, India and (S)-proline was supplied by Lancaster Synthesis Ltd., UK.

Ethyl 2-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]-2-oxoacetate [(R)-3]

To a mixture of 2,2′-dimethoxy-1,1′-binaphthalene [(R)-1; 314 mg, 1 mmol] and anhyd AlCl₃ (200 mg, 1.5 mmol) was added ethyl chloro­oxoacetate (2; 164 mg, 1.2 mmol) in CH₂Cl₂ (10 mL) at rt and the reaction mixture was stirred for 3 h. Then, the mixture was poured into ice-cold H₂O, and CH₂Cl₂ (10 mL) was added. The organic layer was extracted with CH₂Cl₂ (2 × 10 mL) and the combined organic layers were washed with brine (10 mL) and dried (anhyd Na₂SO₄). The solvent was removed and the residue was subjected to column chromatography (silica gel, hexane–EtOAc 80:20); yield: 0.332 g (80%); white solid; mp 92–94 °C; [α]_D ²⁵ +6.15 (c 0.052, CHCl₃).

IR (KBr): 3055, 2937, 2839, 1732, 1676, 1614, 1508, 1479, 1265, 1222, 1045, 910, 808, 740 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.61 (s, 1 H), 8.60–8.14 (d, J = 4.0 Hz, 1 H), 8.12–8.02 (d, J = 8.0 Hz, 1 H), 8.0–7.90 (d, J = 4.0 Hz, 1 H), 7.88–7.78 (d, J = 94.4 Hz, 1 H), 7.78–7.76 (d, J = 8.0 Hz, 1 H), 7.76–7.76 (d, J = 8.3 Hz, 1 H), 7.55–7.53 (d, J = 8.6 Hz, 1 H), 7.48–7.45 (d, J = 8.4 Hz, 1 H), 7.34–7.23 (m, 2 H), 7.06–7.06 (d, J = 8.0 Hz, 1 H), 4.51–4.41 (q, J = 4.0 Hz, 2 H), 3.80 (s, 3 H), 3.70 (s, 3 H), 1.52–1.43 (t, J = 8.0 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 186.4, 164.5, 158.3, 155.1, 137.5, 134.3, 133.9, 132.2, 130.1, 129.3, 128.3, 127.9, 127.8, 126.8, 126.4, 124.8, 124.5, 123.8, 119.9, 118.2, 114.7, 113.9, 62.4, 56.4, 56.2, 14.2.

MS (EI): m/z = 415 (M + 1)⁺.

Anal. Calcd for C₂₆H₂₂O₅: C, 75.35; H, 5.35; O, 19.30. Found: C, 75.25; H, 5.20; O, 19.28.

3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]-5,6-dihydropiperzin-2(1H)-ones (R)-5

and (R)-7; General Procedure

To a stirred solution of (R)-3 (414 mg, 1 mmol) in CH₃OH (10 mL) was added the respective 1,2-diamine 4 or 6 (1 mmol) and the contents were refluxed at 70 °C for 3 h. The mixture was brought to 25 °C and the solid precipitate was collected by suction filtration. The precipitate was washed thoroughly with sat. aq NH₄Cl (15 mL), H₂O (2 × 10 mL), and brine (10 mL). The products (R)-5 and (R)-7 were dried under vacuum.

3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]-5,6-dihydropiperzin-2(1H)-one [(R)-5]

Yield: 0.370 g (90%); yellow solid; mp 238–240 °C.

IR (KBr): 3270, 3042, 2928, 1682, 1630, 1598, 1460, 1342, 1084, 906, 802 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.61–8.60 (t, J = 8.4 Hz, 1 H), 8.07–8.04 (d, J = 8.2 Hz, 1 H), 7.99–7.97 (d, J = 8.1 Hz, 2 H), 7.87–7.85 (d, J = 6.8 Hz, 1 H), 7.75–7.72 (d, J = 8.5Hz, 1 H), 7.47–7.44 (m, 2 H), 7.43–7.29 (m, 1 H), 7.22–7.20 (t, J = 6.9 Hz, 2 H), 7.18–7.10 (m, 2 H), 7.09–6.23 (m, 2 H), 3.97–3.97 (m, 2 H), 3.85 (br s, 3 H), 3.75 (br s, 3 H), 3.54–3.52 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 161.9, 158, 156.1, 154.9, 135.1, 133.9, 132, 130, 129.4, 127.9, 126, 125, 123.5, 119.5, 114.5, 56.8, 56.6, 48.2, 39.0.

MS (EI): m/z = 412 (M + 1)⁺.

Anal. Calcd for C₂₆H₂₂N₂O₃: C, 76.08; H, 5.40; N, 6.82; O, 11.69. Found: C, 76.02; H, 5.28; N, 6.81; O, 11.53.

3-[2,3-Dimethoxy-(1,1′-binaphthlen)-6-yl]quinoxalin-2(1H)-one [(R)-7]

Yield: 0.412 g (90%); brown solid; mp 258–260 °C.

IR (KBr): 3272, 3057, 2935, 1680, 1628, 1598, 1467, 1340, 1084, 1068, 908, 810 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 12.60–12.52 (br s, 1 H), 9.19–9.19 (d, J = 8.16 Hz, 1 H), 9.18–9.18 (d, J = 16 Hz, 1 H), 8.70–8.70 (d, J = 16.1 Hz, 1 H), 8.40–8.24 (t, J = 8.0 Hz, 1 H), 8.42–8.11 (t, J = 12.0 Hz, 1 H), 7.82–7.80 (t, J = 4.0 Hz, 1 H), 7.98 (m, 2 H), 7.69–7.65 (m, 2 H), 7.52–7.50 (t, J = 12.0 Hz, 1 H), 7.73–7.30 (m, 2 H), 7.08–7.00 (m, 1 H), 6.39–6.37 (t, J = 12.0 Hz, 1 H), 4.48–4.67 (m, 1 H), 3.99–3.82 (q, J = 4.6 Hz, 1 H), 3.30 (br s, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 186.9, 164.6, 158.5, 156.4, 155.2, 154, 153, 137, 135.4, 134.4, 132.3, 131.1, 130.5, 129.1, 128.3, 127.2, 124.2, 123.8, 118.5, 117.7, 115.5, 114.7, 56.7.

MS (EI): m/z = 459 (M + 1)⁺.

Anal. Calcd for C₃₀H₂₂N₂O₃: C, 78.59; H, 4.84; N, 6.11; O, 10.47. Found: C, 78.47; H, 4.79; N, 6.09; O, 10.20.

(4aR,8aR)-3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]-4a,5,6,7,8,8a-hexahydroquinoxalin-2(1H)-one [(R)-9]

To a stirred solution of (R)-3 (414 mg, 1 mmol) in anhyd CH₃OH (10 mL) was added (R,R)-cyclohexyldiamine (8; 114 mg, 1 mmol) at rt and the reaction mixture was refluxed at 70 °C for 3 h. CH₃OH was removed under rotor evaporator. To the residue was added sat. aq NH₄Cl (5 mL). The contents were extracted with EtOAc (2 × 10 mL) and the combined organic layers were washed with brine (10 mL) and dried (anhyd Na₂SO₄). After removal of the solvent, the residue was subjected to column chromatography (silica gel, hexane–EtOAc 20:80); yield: 0.400 g (88%); brown gum.

IR (Neat): 3272, 3057, 2935, 1680, 1628, 1598, 1467, 1340, 1268, 1084, 1068, 908, 810 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.61–8.60 (d, J = 8.2 Hz, 1 H), 8.11–8.08 (d, J = Hz, 1 H), 7.91–7.82 (m, J = 9.1 Hz, 3 H), 7.43–7.29 (m, J = 9.1 Hz, 4 H), 7.25–7.20 (m, J = 9.0 Hz, 1 H), 7.04–7.02 (d, J = 8.0 Hz, 1 H), 5.03 (br s, 1 H), 3.79 (s, 3 H), 3.10–3.09 (d, J = 8.8 Hz, 2 H), 2.40 (d, J = 8.8 Hz, 1 H), 1.88–1.77 (m, 2 H), 1.74–1.70 (m, 1 H), 1.48–1.28 (m, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 160.8, 158.6, 156.9, 151.5, 135.1, 133.8, 129.7, 128.6, 126.7, 124.8, 117, 115, 113.9, 62.7, 60.4, 56.4, 53.9, 31.8, 30.8, 25.1, 23.7.

MS (EI): m/z = 465 (M + 1)⁺.

Anal. Calcd for C₃₀H₂₈N₂O₃: C, 77.56; H, 6.08; N, 6.03; O, 10.33. Found: C, 77.47; H, 6.05; N, 6.01; O, 10.21.

3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperzin-2-ones (R)-15 and (R)-17; General Procedure

NaBH₄ (76 mg, 2 mmol) was suspended in anhyd THF (10 mL) under an inert atmosphere in a two-necked septum capped round-bottomed flask. I₂ (127 mg, 1 mmol) dissolved in anhyd THF (5 mL) was taken in an liquid additional funnel and was added dropwise slowly at 0 °C during 1 h to prepare the H₃B·THF complex. Then, the compound (R)-5 or (R)-9 (1 mmol) dissolved in anhyd THF was added dropwise slowly. The mixture was stirred at 0 °C for 1 h and brought to rt and refluxed for 12 h. The contents were brought to rt and carefully quenched by the dropwise addition of 3 N aq HCl (2 mL) and extracted with EtOAc (2 × 5 mL). The combined organic layers were washed with aq NaHCO₃ (5 mL), H₂O (5 mL), and brine (5 mL) and dried (anhyd Na₂SO₄). After removal of the solvent, the product was purified by column chromatography (silica gel 100–200 mesh, hexane–EtOAc 20:80).

3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperzin-2-one [(R)-15]

Yield: 0.320 g (78%); yellow solid; mp 237–239 °C; [α]_D ²⁵ –72.0 (c 0.030, CHCl₃).

IR (KBr): 3233, 3049, 2932, 1686, 1620, 1589, 1332, 1261, 1080, 910, 816 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.84 (m, 1 H), 7.83–7.77 (m, 3 H), 7.43–7.37 (m, 2 H), 7.34–7.30 (m, 2 H), 7.24–7.20 (m, 1 H), 7.18–7.01 (m, 1 H), 6.99–6.91 (m, 1 H), 4.96–4.63 (m, 2 H), 3.78 (s, 3 H), 3.7 (s, 3 H), 2.72 (br s, 1 H), 1.63 (br s, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 167.8, 155.8, 154.9, 133.9, 133.8, 130, 129.9, 129.2, 128.6, 128.1, 126.5, 126.3, 125.9, 125.7, 125, 123.7, 119.3, 119.1, 118.9, 114.8, 114.3, 67.7, 67.5, 57, 56.8, 56.6, 44.7, 44.3, 37.6, 29.7.

LCMS: m/z = 413 (M + 1)⁺.

Anal. Calcd for C₂₆H₂₄N₂O₃:C, 76.08; H, 5.40; N, 6.82; O, 11.69. Found: C, 76.02; H, 5.39; N, 6.81; O, 11.63.

(4aR,8aR)-3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]octahydroquinoxalin-2(1H)-one [(R)-17]

Yield: 0.350 g (76%); brown gum; [α]_D ²⁵ –420.1 (c 0.212, CHCl₃).

IR (Neat): 3273, 3059, 2937, 2841, 1680, 1593, 1508, 1469, 1342, 1267, 1091, 1066, 908, 810 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.92–7.90 (d, J = 8.6 Hz, 2 H), 7.87–7.75 (m, 4 H), 7.38–7.31 (m, 2 H), 7.29–7.23 (m, 1 H), 7.21–7.20 (m, 9 H), 7.19–7.12 (m, 2 H), 6.90–6.87 (m, 2 H), 4.63 (s, 1 H), 4.16–4.123 (m, 3 H), 3.95 (s, 3 H), 3.7 (s, 3 H), 2.92 (m, 2 H), 2.50 (m, 2 H), 1.67–1.6 5 (m, 8 H).

¹³C NMR (100 MHz, CDCl₃): δ = 171, 156, 151.6, 135.1, 133.9, 133.7, 130.6, 129.5, 129.2, 128.3, 128, 127.4, 126.2, 25.5, 124.8, 123, 118, 116.5, 115.3, 114.1, 64.7, 58.4, 58.4, 58, 56.6, 30.8, 30.3, 29.7, 29.3, 24.5 23.7.

MS (EI): m/z = 467 (M + 1)⁺.

Anal. Calcd for C₃₀H₃₀N₂O₃: C, 77.23; H, 6.48; N, 6.00; O, 10.26. Found: C, 77.22; H, 6.37; N, 5.57; O, 10.20.

3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperzines (R)-16 and (R)-18; General Procedure

NaBH₄ (76 mg, 2 mmol) was suspended in anhyd THF (10 mL) under N₂ atmosphere in a two-necked septum capped round-bottomed flask. I₂ (1 mmol) dissolved in anhyd THF (5 mL) was taken in liquid additional funnel and was added dropwise slowly at 0 °C during 1 h to prepare the H₃B·THF complex. Then, the compound (R)-15 or (R)-17 (1 mmol) dissolved in anhyd THF was added dropwise slowly. The mixture was stirred at 0 °C for 1 h and brought to rt and refluxed for 24 h. The mixture was brought to rt and carefully quenched by slowly adding with 3 N aq HCl (2 mL). The contents were extracted with EtOAc­ (2 × 5 mL). The combined organic layers were washed with aq NaHCO₃ (5 mL), H₂O (5 mL), and brine (5 mL) and dried (anhyd Na₂SO₄­). After removal of the solvent, the product was purified by column chromatography (silica gel 100–200 mesh, hexane–EtOAc 20:80).

3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperzine [(R)-16]

Yield: 0.290 g (73%); yellow solid; mp 248–250 °C; [α]_D ²⁵ –40.0 (c 0.140, CHCl₃).

IR (KBr): 3320, 3042, 3010, 2952, 2898, 1590, 1332, 1268, 1042, 889, 802 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.87 (d, J = 8.3 Hz, 2 H), 7.85–7.84 (d, J = 8.8 Hz, 1 H), 7.45–7.43 (m, 2 H), 7.33–7.31 (m, 1 H), 7.29–7.20 (m, 2 H), 7.29–7.07 (m, 2 H), 6.90–6.88 (m, 1 H), 4.67 (s, 1 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 3.50–3.40 (m, 1 H), 3.33–3.30 (m, 1 H), 3.130–3.110 (m, 1 H), 3.09–3.00 (m, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 155.2, 155, 134.8, 134.1, 133.7, 129.6, 129.5, 129.2, 129.1, 128, 127.8, 127.6, 127.0, 126.9, 126.4, 125.8, 125.3, 123.6, 119.5, 114.3, 114.2, 63.8, 63.6, 56.7, 42.9, 41, 40.8.

MS (EI): m/z = 399 (M + 1)⁺.

Anal. Calcd for C₂₆H₂₆N₂O₂: C, 78.36; H, 6.58; O, 8.03; S, 7.03. Found: C, 78.22; H, 6.51; O, 8.01; S, 7.05.

(4aS,8aR)-3-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]decahydroquinoxalin [(R)-18]

Yield: 0.320 g (72%); brown gum; [α]_D ²⁵ –782.8 (c 0.211, CHCl₃).

IR (Neat): 3273, 3059, 2937, 2841, 1680, 1593, 1508, 1469, 1342, 1267, 1091, 1066, 908, 810 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.03–8.01 (m, 1 H), 7.99–7.90 (d, J = 8.1 Hz, 1 H), 7.88–7.83 (m, 2 H), 7.76–7.75 (d, J = 6.8 Hz, 1 H), 7.47–7.45 (d, J =8.2 Hz, 1 H), 7.38–7.31 (m, 1 H), 7.38–7.31 (m, 1 H), 7.29–7.21 (m, 1 H), 7.19–7.10 (m, 1 H), 7.09–7.02 (m, 1 H), 3.92 (br s, 1 H), 3.78 (s, 4 H), 3.52–3.43 (m, 1 H), 3.25–3.24 (m, 1 H), 2.39–3.33 (m, 2 H), 2.16–2.15 (s, 1 H), 1.95–1.63 (m, 3 H), 1.30–1.25 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 155.0, 151.7, 135.6, 133.7, 129.2, 128.3, 127.1, 125.5, 124.3, 122.0, 118.0, 117.0, 114.0, 113.1, 60.8, 60.6, 58.8, 55.8, 51.7, 48.7, 30.8, 30.49, 24.3, 24.09.

MS (EI): m/z = 453 (M + 1)⁺.

Anal. Calcd for C₃₀H₃₂N₂O₂: C, 79.61; H, 7.09; N, 6.19; O, 7.07. Found: C, 79.41; H, 7.09; N, 6.13; O, 7.05.

Chiral (R)-1-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]ethane-1,2-diol [(R)-20]

NaBH₄ (76 mg, 2 mmol) was suspened in anhyd THF (10 mL) under N₂ atmosphere in a two-necked septum capped round-bottome flask. I₂ (127 mg, 1 mmol) dissolved in anhyd THF (5 mL) was taken in liquid additional funnel and was added dropwise slowly at 0 °C during 1 h to prepare the H₃B·THF complex. To this, a solution of (S)-DPP (19; 76 mg, 0.3 mmol) and B(OCH₃)₃ (31 mg, 0.3 mmol) in anhyd THF (5 mL) was added and the contents were stirred for 20 min. Then, the compound (R)-3 (414 mg, 1 mmol) dissolved in anhyd THF (5 mL) was added slowly during 1 h at 10 °C and the contents were further stirred at rt for 1 h. The mixture was carefully quenched with 1 N aq HCl (2 mL) and extracted with Et₂O (2 × 5 mL). The combined organic extracts were washed with brine (5 mL) and dried (anhyd Na₂SO₄). The solvent was removed under reduced pressure and the product was purified by column chromatography (silica gel, 100–200 mesh, hexane–EtOAc 20:80); yield: 0.330 g (90%); white solid; mp 112–114 °C; [α]_D ²⁵ +28.4 (c 0.100, CHCl₃);.

IR (KBr): 3402, 2935, 2837, 1622, 1593, 1506, 1462, 1263, 1064, 895, 808 cm^–1.

¹H NMR (400 MHz, CHCl₃): δ = 7.99–7.97 (d, J = 8.0 Hz, 1 H), 7.89–7.87 (d, J = 8.1 Hz, 2 H), 7.45–7.49 (d, J = 7.8 Hz, 2 H), 7.20–7.18 (d, J = 8.0 Hz, 2 H), 6.97–6.95 (d, J = 4.4 Hz, 2 H), 4.80–4.77 (t, J = 12.0 Hz, 2 H), 3.79–3.76 (s, 8 H), 2.57 (br s, 1 H), 2.09 (br s, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 157.3, 155.1, 154.9, 135.5, 133.9, 133.7, 129.5, 129.2, 128.9, 128, 126.4, 125.6, 125.2, 124.7, 123.6, 119.4, 114.5, 114.1, 74.6, 67.8, 56.8.

MS (EI): m/z = 375 (M + 1)⁺.

Anal. Calcd for C₂₄H₂₂O₄: C, 76.99; H, 5.92; O, 17.09. Found: C, 76.02; H, 5.62; O, 16.86.

(2S)-2-(2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl)piperazines (R)-22 and (R)-23; General Procedure

To a stirred solution of the compound (R)-20 (374 mg, 1 mmol, 99% ee) and Et₃N (252 mg, 2.2 mmol) in CH₂Cl₂ (5 mL) was added MsCl (2.2 mmol) at –20 °C. The reaction mixture was stirred for 2 h at –20 °C and then quenched with sat. aq NH₄Cl (2 mL). The contents were brought to 25 °C. The organic layer was washed with H₂O (5 mL), sat. aq NaHCO₃ (2 mL), and brine (5 mL). The organic extract was dried (anhyd Na₂SO₄) and concentrated under reduced pressure to approximately 3 mL. This crude dimesylate (R)-21 was added to ethylenediamine 4 or 8 (0.5 mL) at 0 °C and stirred at rt for 24 h. The excess amine was removed under reduced pressure. The residue was dissolved in Et₂O (5 mL) and washed successively with sat. aq NaHCO₃ (2 mL), H₂O (5 mL), and brine (5 mL). The organic extract was dried (anhyd Na₂SO₄) and concentrated. The crude product was purified by column chromatography (silica gel 100–200 mesh, EtOAc 95:5).

(2S)-2-[2,2′-Dimethoxy-(1,1′-binaphthalen)-6-yl]piperazine [(R)-22]

Yield: 0.310 g (76%); yellow solid; mp 251–253 °C; [α]_D ²⁵ –43.4 (c 0.140, CHCl₃).

IR (KBr): 3320, 3031, 3012, 2952, 2898, 1596, 1328, 1268, 1062, 889, 810 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.88–7.87 (d, J = 8.3 Hz, 2 H), 7.85–7.84 (d, J = 8.8 Hz, 1 H), 7.45–7.43 (m, 2 H), 7.33–7.31 (m, 1 H), 7.29–7.20 (m, 2 H), 7.29–7.07 (m, 2 H), 6.90–6.88 (m, 1 H), 4.67 (s, 1 H), 3.75 (s, 3 H), 3.74 (s, 3 H), 3.50–3.40 (m, 1 H), 3.33–3.30 (m, 1 H), 3.13–3.11 (m, 1 H), 3.09–3.0 (m, 1 H).

¹³C NMR (100 MHz, CDCl₃): δ = 155.2, 155, 134.8, 134.1, 133.7, 129.6, 129.5, 129.2, 129.1, 128, 127.8, 127.6, 127.0, 126.9, 126.4, 125.8, 125.3, 123.6, 119.5, 114.3, 114.2, 63.8, 63.6, 56.7, 42.9, 41, 40.8.

MS (EI): m/z = 399 (M + 1)⁺.

Anal. Calcd for C₂₆H₂₆N₂O₂: C, 78.36; H, 6.58; O, 8.03; S, 7.03. Found: C, 78.20; H, 6.47; O, 8.01; S, 7.05.

(2S,4aR,8aR)-2-[2,2′-dimethoxy-(1,1′-binaphthalen)-6-yl]decahydroquinoxalin [(R)-23]

Yield: 0.330 g (75%); brown gum; [α]_D ²⁵ –823.05 (c 0.210, CHCl₃).

IR (Neat): 3273, 3059, 2937, 2841, 1680, 1593, 1508, 1469, 1342, 1267, 1091, 1066, 908, 810 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 8.03–8.01 (m, 1 H), 7.99–7.90 (d, J = 8.1 Hz, 1 H), 7.88–7.83 (m, 2 H), 7.76–7.75 (d, J = 6.8 Hz, 1 H), 7.47–7.45 (d, J = 8.2 Hz, 1 H), 7.38–7.31 (m, 1 H), 7.38–7.31 (m, 1 H), 7.29–7.21 (m, 1 H), 7.19–7.10 (m, 1 H), 7.09–7.02 (m, 1 H), 3.92 (br s, 1 H), 3.78 (s, 4 H), 3.52–3.43 (m, 1 H), 3.25–3.24 (m, 1 H), 2.39–3.33 (m, 2 H), 2.16–2.15 (s, 1 H), 1.95–1.63 (m, 3 H), 1.30–1.25 (m, 3 H).

¹³C NMR (100 MHz, CDCl₃ and CD₃OD): δ = 155.0, 151.7, 135.6, 133.7, 129.2, 128.3, 127.1, 125.0, 124.0, 122.0, 118.0, 117.0, 114.0, 113.1, 60.89, 60.6, 58.8, 55.89, 51.7, 30.8, 30.49, 24.3, 24.0.

MS (EI): m/z = 453 (M + 1)⁺.

Anal. Calcd for C₃₀H₃₂N₂O₂: C, 79.61; H, 7.09; N, 6.19; O, 7.07. Found: C, 79.37; H, 7.01; N, 6.11; O, 7.05.

Acknowledgment

B.V. is thankful to the CSIR (New Delhi) and DST-SERB for research fellowships.

• References

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• 12a Periasamy M, Seenivasaperumal M, Dharma Rao V. Synthesis 2003; 2507
  Thieme Connect
• 12b Periasamy M, Gurubrahamam R, Muthukumargopal GP. Synthesis 2009; 1739
  Thieme Connect
• 12c Anwar S, Periasamy M. Tetrahedron: Asymmetry 2006; 17: 3244
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• 13a Delogu G, Fabbri D, de Candia C, Patti A, Pedotti S. Tetrahedron: Asymmetry 2002; 13: 891
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• 13b Delogu G, Dettori MA, Patti A, Pedotti SA, Casalone G. Tetrahedron: Asymmetry 2003; 14: 2467
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• 13c Nagaraju M. Ph. D. Thesis . University of Hyderabad; Hyderabad: 2012
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• References

• 1 Vol CV. T, Bode TW. J. Org. Chem. 2014; 79: 2809
  CrossrefPubMedSearch in Google Scholar
• 2a Taylor RD, Macloss M, Lawon AD. G. J. Med. Chem. 2014; 57: 5845
  CrossrefPubMedSearch in Google Scholar
• 2b Zhang TY. Adv. Heterocycl. Chem. 2017; 121: 1
  Search in Google Scholar
• 3 Vitarin E, Smith DT, Njardarson JT. J. Med. Chem. 2014; 57: 10257
  CrossrefPubMedSearch in Google Scholar
• 4a Walker MA. Expert Opin. Drug Discovery 2014; 9: 1421
  CrossrefPubMedSearch in Google Scholar
• 4b Gettys KE, Ye Z, Dai M. Synthesis 2017; 49: 2589
  Thieme ConnectSearch in Google Scholar
• 5a Viraprakash P, Periasamy M. J. Org. Chem. 2006; 71: 3636
  CrossrefPubMedSearch in Google Scholar
• 5b Viraprakash P, Periasamy M. J. Chem. Sci. 2008; 120: 175
  CrossrefSearch in Google Scholar
• 5c Viraprakash P, Periasamy M. Tetrahedron Lett. 2008; 49: 1233
  CrossrefSearch in Google Scholar
• 6a Periasamy M, Sanjeevkumar N, Dalai M, Gurubrahmam R, Reddy PO. Org. Lett. 2012; 14: 2932
  CrossrefPubMedSearch in Google Scholar
• 6b Periasamy M, Reddy PO, Edukondalu A, Dalai M, Alakanda LM, Udaykumar B. Eur. J. Org. Chem. 2014; 6067
• 7 Periasamy M, Edukondalu A, Ramesh E. ChemistrySelect 2017; 2: 7615
  CrossrefSearch in Google Scholar
• 8 Periasamy M, Sanjeevkumar N, Reddy PO. Synthesis 2012; 44: 3185
  Thieme ConnectSearch in Google Scholar
• 9 Elsevier CJ, Vermeer PJ. J. Org. Chem. 1989; 54: 3726
  CrossrefSearch in Google Scholar
• 10a Narayana C, Periasamy M. J. Organomet. Chem. 1987; 323: 145
  CrossrefSearch in Google Scholar
• 10b Kanth JV. B, Periasamy M. J. Org. Chem. 1991; 56: 5964
  CrossrefSearch in Google Scholar
• 10c Prasad AS. B, Kanth JV. B, Periasamy M. Tetrahedron 1992; 48: 462
  Search in Google Scholar
• 10d Periasamy M, Muthukumaragopal GP, Sanjeevakumar N. Tetrahedron Lett. 2007; 48: 6966
  CrossrefSearch in Google Scholar
• 11a Corey EJ, Bakshi RK, Shibata S. J. Am Chem. Soc. 1987; 109: 5551
  CrossrefSearch in Google Scholar
• 11b Corey EJ, GuzmanPerez A, Lazerwith SE. J. Am Chem. Soc. 1997; 119: 11769
  CrossrefSearch in Google Scholar
• 12a Periasamy M, Seenivasaperumal M, Dharma Rao V. Synthesis 2003; 2507
  Thieme Connect
• 12b Periasamy M, Gurubrahamam R, Muthukumargopal GP. Synthesis 2009; 1739
  Thieme Connect
• 12c Anwar S, Periasamy M. Tetrahedron: Asymmetry 2006; 17: 3244
  CrossrefSearch in Google Scholar
• 13a Delogu G, Fabbri D, de Candia C, Patti A, Pedotti S. Tetrahedron: Asymmetry 2002; 13: 891
  CrossrefSearch in Google Scholar
• 13b Delogu G, Dettori MA, Patti A, Pedotti SA, Casalone G. Tetrahedron: Asymmetry 2003; 14: 2467
  CrossrefSearch in Google Scholar
• 13c Nagaraju M. Ph. D. Thesis . University of Hyderabad; Hyderabad: 2012
  Search in Google Scholar

• Supplementary Material