Reaction #216725

Reaction equation

2-chloro-4'-fluoroacetophenone

NaI

amine

3-Isopropyl-3,7-diazabicyclo[3.3.1]nonane

→

amine

Yield 86.1%

7-Isopropyl-3-(4-fluorophenacyl)-3,7-diazabicyclo[3.3.1]nonane

Yield 86.1%

Solvents

H3CCN

Conditions

Workup

1. 1
   Temperaturewas then heated for 30 minutes with stirrring
2. 2
   Otherto give a light yellow mixture which
3. 3
   FiltrationFiltration (suction)
4. 4
   Otherremoved excess NaI
5. 5
   workup.ADDITIONthe filtrate was diluted with H2O
6. 6
   Othertransferred to a separatory funnel
7. 7
   ExtractionThe resulting homogenous solution (pH~5) was extracted (ether, 3×75 ml) with the
8. 8
   ExtractionExtraction (ether, 3×75 ml) of the aqueous layer
9. 9
   Extractionwas followed by another extraction (H2CCl2, 3×75 ml)
10. 10
    DryingThe organic layer (H2CCl2) was dried (Na2SO4, 2 h)
11. 11
    Filtrationfiltered
12. 12
    Concentrationconcentrated
13. 13
    Other(rotary evaporator)

Procedure

To a standard setup was added 2-chloro-4'-fluoroacetophenone (7.55 g, 43.8 mmol) and NaI (9.85 g, 65.7 mmol) in H3CCN (30 ml) which was then heated for 30 minutes with stirrring. The solution was allowed to cool to room temperature (30 min) which was followed by dropwise addition of amine 105 (6.7 g, 39.8 mmol) to give a light yellow mixture which was stirred overnight. Filtration (suction) removed excess NaI and the filtrate was diluted with H2O and transferred to a separatory funnel. The resulting homogenous solution (pH~5) was extracted (ether, 3×75 ml) with the latter being discarded, and the pH of the aqueous layer was adjusted to 12 using 10% NaOH. Extraction (ether, 3×75 ml) of the aqueous layer was followed by another extraction (H2CCl2, 3×75 ml) and the ether extracts were discarded. The organic layer (H2CCl2) was dried (Na2SO4, 2 h), filtered, and concentrated (rotary evaporator) to give 2.9 g (86.1%) of amine 55 as a light yellow solid; mp 193°-194° C. IR (KBr) 3060, 3040 (Ar-H), 2940, 2805 (C-H), 1700 (C=O) cm-1 ; 1H NMR (DCCl3) d 1.45 (d, 6 H, CH3 isopropyl), 1.81 [d, 1 H, H(9)ax ], 2.11 [d, 1 H, H(9)eq ], 2.32 lbs, 2 H, H(1,5)], 2.85 (d, 2 H, ring protons), 3.37 (d, 2 H, ring protons), 3.49 (d, 2 H, ring protons), 3.86 (m, 3 H, ring protons, C-H isopropyl), 4.18 (s, 2 H, ArC(O)CH2), 7.15 (t, 2 H, Ar-H), 8.02 (m, 2 H, Ar-H); 13C NMR (DCCl3) ppm 17.01 (CH3 isopropyl), 28.04 [C(1,5)], 30.05 [C(9)], 53.74, 57.2257.34 (ring carbons, C-H isopropyl), 62.22 [ArC(O)CH2 ], 115.58, 115.88, 130.57, 130.70, 131.22, 131.26 (Ar-C), 164.10, 167.49 (J=265.8 Hz, ArC-F), 194.99 (C=O). Ketone 55 was slightly unstable, and thus was reduced to the corresponding alcohol 110.

Source