2-(1H-INDOL-3-YL)-N-PHENYLACETAMIDE

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2-(1H-INDOL-3-YL)-N-PHENYLACETAMIDE
 


 



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(2R, 3S)-3-Hydroxy-2-methyl-1-morpholino-5-phenylpentan-1-one

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 (2R, 3S)-3-Hydroxy-2-methyl-1-morpholino-5-phenylpentan-1-one (4), 97% ee , as white solid, mp 76-78 °C










 (S)-MTPA ester of (-)-4:  

¹⁹F (CDCl₃) δ: -70.88; ¹H (400 MHz, CDCl₃) δ: 1.14 (d, J = 6.9 Hz, 3H), 1.96 (m, 2H), 2.49 (t, J = 8.0 Hz, 2H), 2.91 (quint, J = 6.8 Hz, 1H), 3.32 (m, 2H), 5.42 (m, 1H).

Partial data for the (R)-MTPA ester of (-)-4: ¹⁹F (CDCl₃) δ: -70.81; ¹H (400 MHz, CDCl₃) δ: 1.06 (d, J = 6.9 Hz, 3 H), 2.00 (m, 2 H), 2.61 (m, 2 H), 2.89 (quint, J = 6.9 Hz, 1 H), 3.29 (m, 2H), 5.46 (m, 1 H).



  Syn-4 exhibits the following properties: white solid; mp 76-78 °C; [∝]_D^22.8 = -10.7 (c = 0.25, CHCl₃);  

¹H NMR pdf(400 MHz, CDCl₃) δ: 1.15 (d, J = 7.2 Hz, 3 H), 1.51-1.62 (m, 1 H), 1.92 (dtd, J = 5.4, 9.3, 13.6 Hz, 1 H), 2.52 (dq, J = 2.1, 7.2 Hz, 1 H), 2.68 (ddd, J = 7.1, 9.2, 13.8 Hz, 1 H), 2.88 (ddd, J = 5.2, 9.4, 14.3 Hz, 1 H), 3.43 (br t, J = 4.8 Hz, 2 H), 3.51-3.71 (m, 6 H), 3.93 (ddd, J = 2.1, 3.8, 9.4 Hz, 1 H), 4.39 (s, 1 H), 7.16-7.24 (m, 3 H), 7.26-7.31 (m, 2 H);  

¹³C NMR pdf(100 MHz, CDCl₃) δ: 10.2, 32.5, 35.7, 39.0, 41.9, 46.2, 66.8, 66.9, 70.5, 126.0, 128.5 (2C), 128.7 (2C), 142.2, 176.3; IR (neat) 3428, 2921, 2857, 1616, 1454, 1434, 1224, 1114, 1025 cm^-1;

HRMS (ESI) calcd for C₁₆H₂₃NNaO₃ [M+Na]⁺ 300.1570. Found 300.1572; Anal. calcd for C₁₆H₂₃NO₃: C, 69.29; H, 8.36; N, 5.05. Found: C, 69.15; H, 8.41; N, 5.07.

The diastereomer ratio (syn-4/anti-4) was determined to be >20:1 from the ratio of resonance integrations at 1.13-1.17 ppm (methyl substituent of syn isomer) and 1.17-1.21 ppm (methyl substituent of anti isomer-see Note 11). Both isomers co-elute by TLC analysis.

The anti-4 diastereomer was prepared in low yield (with d.r. ca. 8:1 ) from syn-4 by Mitsunobu reaction and exhibits the following properties: colorless oil; [∝]_D^26.4 = -9.4 (c = 0.54, CHCl₃);

¹H NMR (400 MHz, CDCl₃) δ: 1.20 (d, J = 7.1 Hz, 3 H), 1.70-1.85 (m, 2 H), 2.59-2.73 (m, 2 H), 2.92 (ddd, J = 5.4, 9.4, 13.7 Hz, 1 H), 3.44-3.49 (m, 2 H), 3.56-3.71 (m, 7 H), 3.94 (d, J = 6.4 Hz, 1 H), 7.16-7.23 (m, 3 H), 7.26-7.31 (m, 2 H);

¹³C NMR (100 MHz, CDCl₃) δ: 15.3, 32.3, 37.2, 40.2, 41.8, 46.1, 66.7, 66.9, 73.4, 125.8, 128.4 (2C), 128.5 (2C), 142.2, 175.1;


 IR (neat) 3426, 3026, 2922, 2857, 1614, 1496, 1454, 1435, 1361, 1301, 1268, 1220, 1113, 1069, 1026, 934, 846 cm^-1.

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(3aα,4α.7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-lH-isoindole- l,3(2H)-dione (27D)

 


Example 27 (3aα,4α.7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-lH-isoindole- l,3(2H)-dione (27D)

A. (endo, endo)-7-Oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid (27A)

Compounds 27A, 27B and 27C were synthesized in accordance with the approaches described in Sprague et al, J. Med. Chem. 28, 1580-1590 (1985). A mixture of furan (100 mL, 1.38 mol, 1 eq) and maleic acid (159.6 g, 1.38 mol, 1 eq) in H₂O (340 mL) was stiπed at room temperature for 5 days. The mixture was placed in a separatory funnel and the aqueous layer was separated from the layer containing the unreacted furan. The aqueous layer was treated with charcoal, filtered tlirough celite and placed in the refrigerator. The desired product crystallized from solution upon seeding, was filtered, washed with cold water and dried over P₂O₅ to give 70 g (0.38 mol, 28%) of compound 27A as a white solid. B. (endo, endo)-7-Oxabicyclo[2.2.1]heptane-2,3-dicarboxylic acid (27B)

To a solution of compound 27A (69 g, 0.375 mol, 1 eq) in EtOH (700 mL) was added 10% Pd/C (4.5 g, cat.) and the mixture was shaken under a hydrogen atmosphere at 55 psi until gas uptake ceased. The mixture was filtered through celite and concentrated in vacuo to give 66 g (0.355 mol, 95%) of compound 27B as a white solid.
C. (3aα,4α,7α,7aα)-Hexahydro-4,7-epoxyisobenzofuran-l,3-dione (27C)

A solution of compound 27B (66 g, 355 mol) in acetyl chloride (300 mL) was refluxed for 1 h. The reaction solution was concentrated in vacuo and the resulting residue was recrystallized from benzene to give 49.2 g (0.292 mol, 82%o) of compound 27C as a white solid (>99% endo by 'H NMR). D. (3aα,4α,7α,7aα)-Hexahydro-2-(2-naphthalenyl)-4,7-epoxy-lH-isoindole- l,3(2H)-dione (27D)
Compound 27C (45 mg, 0.30 mmol, 1 eq) was combined with 2- naphthalenamine (47 mg, 0.33 mmol, 1.1 eq) in acetic acid (1 mL) and heated at 115°C overnight. After the reaction was cooled to rt, a drop of water was added, and the resulting precipitate was filtered. The material was washed with methanol and dried to provide 65.7 mg (74.5%) of compound 27D as a white crystalline solid. HPLC: 99% at 2.68 min (retention time) (YMC S5 ODS column 4.6 x 50 mm, 10- 90% aqueous methanol over 4 minutes containing 0.2%> phosphoric acid, 4 mL/min, monitoring at 220 nm), MS (ESI): m/z 294.0 [M+H]⁺.








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(3aα-4α α,7a )-2-(4-Bromo-3-methvIphenyl)tetrahvdro-4.7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione

 




Example 1
(3aα-4α α,7a )-2-(4-Bromo-3-methvIphenyl)tetrahvdro-4.7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione (lC)

A. 4-(tert-Butyldimethylsiloxy)-2H-thiopyran (1A)

2,3-Dihydro-4H-thiopyran-4-one (1.50 g, 13.14 mol, synthesized as described in Richards et al, J. Org. Chem. 46, 4836-4842 (1981)) was dissolved in CH₂C1₂ (130 mL) and triethylamine (5.47 mL, 39.41 mmol) was added. tert-Butyldimethylsilyl trifluoromethanesulfonate (3.62 mL, 15.77 mmol) was then added. After 10 minutes, the volatiles were removed by rotary evaporator at 25°C. The resulting yellow oil was passed through a short column of SiO₂ eluting with 3% TEA in hexanes to yield 1.82 g of compound 1A as an orange oil.
B. l-[4-bromo-3-methylphenyl]-lH-pyrrole-2,5-dione (IB)

4-Bromo-3-methylaniline (1.55 g, 8.33 mmol) and maleic anhydride (0.898 g, 9.16 mmol) were dissolved in acetic acid (10 mL) and heated at 115 °C for 12 h. The reaction was then cooled to 25°C and the acetic acid was removed in vacuo. The resulting residue was suspended in 5% K₂CO₃ (100 mL), stirred for 25 minutes and followed by filtering and rinsing with water. The material was then dried in vacuo to give compound IB as a light brown solid (1.65 g). HPLC: 100% at 2.96 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm).
C. (3 a ,4α,7α,7aα)-2-(4-Bromo-3-methylphenyl)tetrahydro-4,7- ethanothiopyrano[3,4-c]pyrrole-l,3,8(2H,4H)-trione (IC)
Compound 1A (0.313 g, 1.41 mmol) and compound IB (0.250 g, 0.94 mmol) were dissolved in toluene and heated to reflux for 5 h. The toluene was then removed by passing a stream of argon through the reaction flask. The residue was then purified by flash chromatography on SiO₂ eluting with 20% hexane in chloroform. This gave 0.168 g ofthe enol ether intermediate as a yellow solid. The enol ether intermediate was dissolved in dichloroethane (2.0 mL) and TFA (0.25 mL) was added. After 0.5 h, the reaction was quenched with saturated aqueous NaHCO₃ and extracted with CH₂C1₂ (2 x 30 mL). The organics were dried over anhydrous sodium sulfate and evaporated to give 0.079 g of compound IC as a white solid. HPLC: 99% at 3.010 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90%) aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS (ES): m z 396.9 [M+ NH₄]⁺.














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(3aα,4β,7β,7aα)-2-[3.5-Bis(trifluoromethyl)phenyl]hexahydro-4.7-epoxy-lH- isoindole-l,3(2H)-dione

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Example 8 (3aα,4β,7β,7aα)-2-[3.5-Bis(trifluoromethyl)phenyl]hexahydro-4.7-epoxy-lH- isoindole-l,3(2H)-dione (8)

3,5-Bis-(trifluoromethyl)-aniline (0.017 g, 0.0075 mmol) was dissolved in acetic acid (0.300 mL) and transfeπed to a 1.5 mL conical vial with a septa cap. Stock solutions of an additional 95 amines were prepared as described above. To each of the above vials was added 0.4 mL (0.12 mmol) of a stock solution of exo-7- oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride in acetic acid. The vials were then sealed and heated at 110°C for 11 h. Upon cooling to 25°C, the caps were removed from the vials and the acetic acid was removed in vacuo. To each vial was added 1 mL of 2:1 acetone/methylene chloride and the vials were heated at 40°C for 1 h. Once all products were in solution, they were transfeπed via robot to filter tubes with coarse frits pre- wetted with 0.2 mL of water. Nitrogen was blown through each tube until the volatile organics were removed. 1.5 mL of 10% aq K₂CO₃ was then added to each tube followed by vigorous shaking at 25°C for 15 min. The tubes were then drained, resealed and 1.0 mL of water was added to each tube followed by shaking. The tubes were drained again and washed with water a second time. The resulting residues in each tube was then dried in vacuo for 48 h. After drying, 1.0 mL of 20% TFA in methylene chloride was added to each tube and the racks were shaken for 30 min. The tubes were then drained into a 96-well plate with pre-tared custom micro-tubes present. Each tube was assayed for product purity (analytical LC) and identity (LC-MS). The tubes were then concentrated in vacuo and weighed for yields. The tube containing the reaction of 3,5-bistrifluoromethylaniline and exo-7- oxabicyclo[2.2.1]heptane-2,3-dicarboxylic anhydride, yielded 0.022 g of compound 8 as a white solid. HPLC: 94% at 4.03 min (retention time) (YMC S5 ODS column 4.6 x 50 mm eluting with 10-90% aqueous methanol over 4 minutes containing 0.1% TFA, 4 mL/min, monitoring at 220 nm), MS (ES): m/z 434.2 [M+Na+MeOH]⁺\ Of the remaining 95 additional reactions run, a total of 80 final compounds were obtained in >70% purity and >5 mg yield. Several samples needed further purification which was performed by short SiO₂ column eluting with methylene chloride/acetone. See Table 2 below.










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(3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2- dioxide hydrobromide

(3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2- dioxide hydrobromide; (2b)
 


Synthesis of substituent R² (3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2- dioxide hydrobromide; (2b) was carried out as shown in Scheme-4 and the stepwise procedure is depicted below:
Scheme-4:

Bz-NH

Substitued R² (2b)
Step-1 : 2,3-dimethylbuta-L3-diene (14)
To 2,3-dimethylbutane-2,3-diol (13, 85g), 48% aqueous HBr was added to get the colorless solution. Mixture was fractionally distilled, washed twice with water and dried over anhydrous CaCl₂. Mixture was redistilled and the fraction of 69-70 °C was collected to get 2,3-dimethylbuta-l,3-diene (14, 38g. 64%yield). 1H NMR: (CDCl₃, 400 MHz): δ 5.06 (2H, s), 4.97 (2H, s), 1.92 (6H, s); ESI-MS: (+ve mode) 83.3 (M+H)⁺ (70 %).


Step-2: 3,4-dimethyl-2,5-dihydrothiophene 1,1 -dioxide (15)
A mixture of hydroquinone (492mg) and 2,3-dimethylbuta-l ,3-diene (14, 31.96 ml) was placed in sealed tube and a solution of sulfur dioxide in MeOH (140 ml) was added. Reaction mixture was heated at 85 °C for 4 h and cooled to room temperature. Crystals obtained was filtered, washed with cold methanol and dried to get 3,4- dimethyl-2,5-dihydrothiophene 1,1 -dioxide (15) as white crystalline solid (30 gm, 72% yield).
lH NMR: (CDCl_3, 400 MHz): δ 3.73 (4H, d, J = 1.2 Hz), 1.78 (6H, t, J = 1.2 Hz); ESI- MS: (+ve mode) 147.2 (M+H)⁺ (70 %), 169.1 (M+Na)⁺ (40%).


Step-3: 3,4-bis(bromomethyl)-2,5-dihydrothiophene 1,1 -dioxide (16)
A mixture of 3,4-dimethyl-2,5-dihydrothiophene 1,1-dioxide (15, 20g), 1- bromopyrrolidine-2,5-dione (53.5g), and AIBN (400mg) in CHC1₃ was heated for 15 hr. After completion of reaction, filtrate was evaporated under reduced pressure. The residue obtained was recrystallize from methanol to get 3,4-bis(bromomethyl)-2,5- dihydrothiophene 1,1-dioxide as a white crystals (16, 19 g, 45% yield).
1H NMR: (CDC1_3> 400 MHz): δ 4.06 (4H, s), 4.01 (4H, s); ESI-MS: (+ve mode) 303.8 (M+H)⁺ (90 %), 305.7 (M+2H)⁺ (70%).


Step-4: 5-benzyl-3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2-dioxide (17)
Mixture of 3,4-bis(bromomethyl)-2,5-dihydrothiophene 1,1-dioxide (16, 12g) and phenylmethanamine (10.84ml) in acetonitrile was stirred at 25 °C for 2 hr. After completion of reaction, solvent was removed under reduced pressure, ethyl acetate and IN NaOH were added, organic layer was separated and aq layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried over anhydrous Na₂S0₄ and concentrated under reduced pressure to give 5-benzyI-3,4,5,6-tetrahydro- lH-thieno[3,4-c]pyrrole 2,2-dioxide (17) as a solid compound (3.7 g, 38% yield).
1H NMR: (CDCI_3, 400 MHz): δ 7.34-7.29 (5H, m), 3.88 (2H, s), 3.77 (4H,s), 3.61 (4H, s); ESI-MS: (+ve mode) 250.3 (M+H)⁺ (100 %).

Step-5: benzyl 4,6-dihvdro-lH-thieno[3,4-clpyrrole-5(3H^")-carboxylate 2,2-dioxide (IS) A mixture of 5-benzyl-3,4,5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2-dioxide (17, 3.6g) and CBZ-C1 (13.5 ml) in toluene was stirred for 3 hr. After completion of reaction, diethyl ether was added till solid precipitated out. Solid was filtered and dried under reduced pressure to get benzyl 4,6-dihydro-lH-thieno[3,4-c]pyrrole-5(3H)- carboxylate 2,2-dioxide (18, 2.7 g, 64% yield). ^lH NMR: (CDC1_3, 400 MHz): δ 7.38-7.35 (5H, m), 5.19 (2H, s), 4.31 (4H, s), 3.88 (4H, d, J = 13.6 Hz); ESI-MS: (+ve mode) 294.4 (M+H)⁺ (80 %).


Step-6: 3 A5,6-tetrahydro-lH-thieno[3,4-c]pyrrole 2,2-dioxide hydrobromide (2b)
To a solution of benzyl 4,6-dihydro-lH-thieno[3,4-c]pyrrole-5(3H)-carboxylate 2,2-dioxide (18, 3.7 g) in glacial acetic acid, HBr in glacial acetic acid was added and the reaction mixture was stirred at 2 °C for 3h. After completion of reaction, diethyl ether was added to afford sticky solid, solvent was decanted and added minimum amount of methanol to get the crystalline solid as 3,4,5,6-tetrahydro-lH-thieno[3,4- c]pyrrole 2,2-dioxide hydrobromide as a hydrobromide salt (2b, 1.5 g, 50% yield). 1H NMR: (CDCI₃, 400 MHz): δ 9.43 (2H, bs), 4.08 (4H, s), 4.02 (4H, s); ESI-MS: (+ve mode) 160.4 (M+H)⁺ (88 %).


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Hexahydro-lH-furo[3,4-c]pyrrole

 

 

 

hexahydro-lH-furo[3,4-c]pyrrole; (2a)

 

 

Synthesis of substituent R (hexahydro-lH-furo[3,4-c]pyrrole; 2a) was out as shown in Scheme-3 and the stepwise procedure is depicted below:
Schem -3:

Substituted R² (2a)


Step-1 : 1 -Benzyl -pyrrolidine-3,4-dicarbQxylic acid dimethyl ester (10
N-benzyl-l-methoxy-N-((trimethylsilyl)methyl)methanamine (8, 21.4g) and dimethyl maleate (9, lOg) were dissolved in DCM (200 ml). To the reaction mixture TFA (0.54ml, 6.94mmol) was added and stirred for 3h. After completion of reaction, reaction mixture was neutralized with saturated NaHC0₃ solution (100 ml). Organic layer was washed with water, brine solution, dried over anhydrous Na₂S0₄ and evaporated under reduced pressure to get l-Benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (10) as a light yellow color oil (16.7g, 87% yield).
lH NMR: (CDC1₃, 400 MHz): 6 7.25-7.13 (m, 5H), 3.72 (s, 2H), 3.58 (s, 6H), 3.26- 3.20 (m, 2H), 3.08-3.04 (m, 2H), 3.04-2.63 (m, 2H); ESI-MS: (+ve mode) 277.9 (M+H)⁺ (60 %), 299.9 (M+Na) (80 %).; HPLC: 90 %.


Step-2: (l-Benzylpyn:olidine-3,4-divOdimethanol (11)
l-Benzyl-pyrrolidine-3,4-dicarboxylic acid dimethyl ester (10, 15g), dissolved in THF (30 ml) was added to a suspension of LiAlH₄ (4.3g) and stirred for 2h at 25 °C. Reaction mixture was quenched with water (2 ml) and 2N NaOH solution (2 ml). The reaction mixture was filtered, dried over anhydrous Na₂S0₄ and evaporated under reduced pressure to get (l-Benzylpyrrolidine-3,4-diyl)dimethanol (11) as a yellow color oil (1 1.6 g, 97% yield).
1H NMR: (CDCI3, 400 MHz): δ 7.25-7.13 (m, 5H), 3.67 (s, 2H), 3.64-3.47 (m, 4H), 2.70-2.65 (m, 2H), 2.44-2.39 (m, 2H), 2.15-2.1 l(m, 2H); ESI-MS: (+ve mode) 222.1 (M+H)⁺ (85%); HPLC: 94 %.


Step-3: 5-Benzyl-hexahvdro-furo[^"3,4-c pyrrole (12) A mixture of l-Benzylpyrrolidine-3,4-diyl)dimethanol (11, lOg) and PTSA
(1.94g) in dry toluene (100 ml) was refluxed at 140 °C for 16h. The reaction mixture was cooled and basified with IN NaOH solution (100 ml), organic layer was separated off, washed with water, brine solution and dried to yield 5-Benzyl-hexahydro-furo[3,4- cjpyrrole (12) as an oil (5.9 g, 64% yield).
1H NMR: (CDCI3_, 400 MHz): δ 7.05-7.23 (m, 5H), 3.77-3.67 (s, 4H), 3.49 (s, 2H), 2.27-2.25 (m, 4H) 2.26-2.25 (m, 2H); ESI-MS: (+ve mode) 204.2 (M+H)⁺ (89%); HPLC: 84 %.


Step-4: hexahydro-lH-furo|^"3,4-c|pyrrole (2a)
5-Benzyl-hexahydro-furo[3,4-c]pyrrole (12, 5g) was dissolved in EtOH (50 ml) and hydrogenated in presence of 10 % Pd/C (0.5 g) at 60 psi. Filtered the reaction mixture was filtered, evaporated to dryness to get hexahydro-lH-furo[3,4-c]pyrrole (2a) as a colorless oil (2.56g, 92% yield). 1H NMR: (CDCI3_, 400 MHz): δ 3.67-3.58 (m, 4H) 3.43-3.33 (m, 2H), 2.97-2.88 (m, 4H); ESI-MS: (+ve mode) 1 13.8 (M+H)⁺ (55%); GC: 92 %.

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