1-Ethyl-3-(3'-dimethylaminopropyl)carbodiimide → (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile

HRID 1807572Notes

Reaction equation

HRID 1807572 reaction equation
[C:1]([C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH:13]([CH3:15])[CH3:14])[C:6]([OH:8])=O)#[N:2].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.O[NH:38][C:39]([C:41]1[C:50]2[CH2:49][CH2:48][CH2:47][C@@H:46]([OH:51])[C:45]=2[CH:44]=[CH:43][CH:42]=1)=[NH:40]>CN(C=O)C.CC(=O)OCC>[OH:51][C@@H:46]1[CH2:47][CH2:48][CH2:49][C:50]2[C:41]([C:39]3[N:38]=[C:6]([C:5]4[CH:9]=[CH:10][C:11]([O:12][CH:13]([CH3:15])[CH3:14])=[C:3]([CH:4]=4)[C:1]#[N:2])[O:8][N:40]=3)=[CH:42][CH:43]=[CH:44][C:45]1=2

Participants

7

Reactant 4

HCID 159081-Ethyl-3-(3'-dimethylaminopropyl)carbodiimideHCID 757711-HydroxybenzotriazoleHCID 21956832RP-101124HCID 178513252HCID 178513252, compound

Product 1

HCID 52939525(R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrileYield 42.4%

Reagents, catalysts & solvents 2

HCID 6228DimethylformamideSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
90 °C

Procedure

Prepared using General Procedure 2. To a stirring solution of 3-cyano-4-isopropoxybenzoic acid (16.7 mg, 0.08 mmol) in DMF (1 mL) were added HOBt (14.3 mg, 0.11 mmol) and EDCI (20.3 mg, 0.11 mmol). After stirring for 30 min, (R)-N,5-dihydroxy-5,6,7,8-tetrahydronaphthalene-1-carboximidamide INT-4 (27.3 mg, 0.09 mmol) was added as a solution in DMF (1.5 mL). After stirring at room temperature for an additional 60 min, the mixture was heated to 90° C. for 15 h. The mixture was diluted with EA and washed with NaHCO3. The combined organic layers were dried, concentrated, chromatographed (EA/hexanes) to provide 12.72 mg (42.4%) (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile 1 as a white solid. LCMS-ESI (m/z) calculated for C22H21N3O3: 375.4; found 376.1 [M+H]+, tR=3.73 min. 1H NMR (400 MHz, CDCl3) δ 8.42 (d, J=2.2 Hz, 1H), 8.33 (dd, J=8.9, 2.2 Hz, 1H), 7.97 (dd, J=7.7, 1.3 Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.38 (t, J=7.7 Hz, 1H), 7.12 (d, J=9.0 Hz, 1H), 4.91-4.83 (m, 1H), 4.79 (dq, J=12.0, 6.0 Hz, 1H), 3.20 (dt, J=17.8, 5.4 Hz, 1H), 3.01 (dt, J=13.3, 6.4 Hz, 1H), 2.13-1.81 (m, 4H), 1.79 (d, J=7.2 Hz, 1H), 1.47 (d, J=5.6 Hz, 6H). 13C NMR (101 MHz, CDCl3) δ 172.70, 169.48, 162.75, 140.10, 137.4, 134.13, 133.88, 131.68, 129.96, 126.18, 125.97, 116.82, 115.26, 113.54, 103.95, 72.73, 68.47, 31.62, 28.50, 21.73, 18.57. Chiral HPLC: (R)-5-(3-(5-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl)-1,2,4-oxadiazol-5-yl)-2-isopropoxybenzonitrile was eluted with 10% IPA/hexane: 99.4% ee, tR=40.85 min.

Workup

  1. customPrepared
  2. stirringAfter stirring at room temperature for an additional 60 min
  3. washwashed with NaHCO3
  4. customThe combined organic layers were dried
  5. concentrationconcentrated
  6. customchromatographed (EA/hexanes)

Sources & evidence

ORD record
ord-dfc7cf591ac34c839edf9841f35bd447
Source dataset
uspto-grants-2013_01
Patent number
US08357706B2

Reaction notes

Loading…