3942 J ournal of Medicinal Chemistry, 2001, Vol. 44, No. 23
Zhang et al.
1.5 equiv of K2CO3 in toluene (10 mmol of N-methyl compound
in 100 mL of solvent) was heated at reflux overnight. The
solution was washed with water, extracted once with 15%
aqueous citric acid solution, then washed with water and brine,
dried over Na2SO4, and evaporated to give a light yellow
colored oil. The obtained oil was then dissolved in HOAc (10
mmol of carbamate in 100 mL of 99.7% HOAc), and Zn powder
was added. The suspension was vigorously stirred at room
temperature until TLC showed the disappearance of the
carbamate. The solvent was removed in vacuo with an equal
volume of toluene, and the residue was dissolved in CH2Cl2.
The CH2Cl2 solution containing a small amount of Zn powder
was extracted three times with a 15% aqueous citric acid
solution. The combined aqueous layer was washed once with
CH2Cl2, basified with concentrated NH4OH, and extracted 3
times with CH2Cl2. The organic extracts were combined and
washed with water and brine, dried over Na2SO4, and evapo-
rated to give the N-demethylated product as a colorless oil.
The product was usually pure enough by TLC for the next step.
Meth od F . N-Alk yla tion . A solution of the amine, alkyl
iodide, and K2CO3 in THF was heated at reflux overnight,
when TLC showed the completion of the reaction. The molar
ratio of amine to alkyl iodide to K2CO3 was 1:1.5:2. THF was
then evaporated, and the mixture was suspended in CH2Cl2.
The organic suspension was washed with water and brine and
dried over Na2SO4, and solvent was removed to give the crude
product which was purified by salt formation or column
chromatography prior to salt formation.
(MH+); 1H NMR (CDCl3) δ (ppm) 1.44 (t, J ) 8.8 Hz, 1H,
H
6endo), 1.58 (t, J ) 8.8 Hz, 1H, H7endo), 1.96 (m, 3H, H6,7exo +
H2ax), 2.14 (brd, J ) 14.7 Hz, 1H, H4ax), 2.32 (brd, J ) 14.7
Hz, 1H, H2eq), 2.39 (s, 3H, NCH3), 2.70 (brd, J ) 13.7 Hz, 1H,
H4eq), 3.26 (m, 2H, H1,5), 3.97 (m, 2H, CH2O), 5.35 (s, 1H,
ArCHAr), 5.51 (t, J ) 6.4 Hz, 1H, olefinic H), 7.02 (t, J ) 9.3
Hz, 4H, ArH), 7.28 (dd, J ) 8.3 Hz, J ) 2.9 Hz, 4H, ArH).
Anal. (C23H25NOF2•HCl) C, H, N.
(8-Meth yl-8-a za bicyclo[3.2.1]oct-3-yl)a cetic Acid Eth yl
Ester (9). This compound was synthesized from 5 according
1
to general method C. CI-MS (NH3) m/z 212 (MH+); H NMR
(CDCl3) δ (ppm) 1.25 (t, J ) 7.1 Hz, 3H, CH3), 1.32 (brs, 1H,
H3), 1.63 (m, 2H, H6,7endo), 2.04-2.31 (m, 6H, H2,4 + H6,7exo),
2.26 (s, 3H, NCH3), 2.46 (d, J ) 8.0 Hz, 2H, CH2CO), 3.10 (brs,
2H, H1,5), 4.12 (q, J ) 7.2 Hz, 2H, OCH2).
2-(8-Meth yl-8-azabicyclo[3.2.1]oct-3-yl)eth an ol (10). This
compound was synthesized from 9 according to general method
A. CI-MS (NH3) m/z 170 (MH+); 1H NMR (CDCl3) δ (ppm) 1.31
(m, 2H, H6,7endo), 1.66 (m, 2H, H6,7exo), 1.75 (t + m, J ) 6.5 Hz,
3H), 2.00-2.18 (m, 4H, H2,4), 2.24 (s, 3H, NCH3), 3.09 (m, 2H,
H1,5), 3.64 (t, J ) 6.6 Hz, 2H, CH2OH).
3-(2-Ben zh yd r yloxyeth yl)-8-m eth yl-8-a za bicyclo[3.2.1]-
octa n e (11). This compound was prepared from an ether
formation between 10 and benzhydrol according to general
1
method B. CI-MS (NH3) m/z 336 (MH+); H NMR (CDCl3) δ
(ppm) 1.34 (m, 2H, H6,7endo), 1.65 (m, 2H, H6,7exo), 1.83 (m, 3H),
2.01-2.15 (m, 4H, H2,4), 2.26 (s, 3H, NCH3), 3.08 (brs, 2H, H1,5),
3.45 (t, J ) 6.3 Hz, 2H, OCH2), 5.31 (s, 1H, ArCHAr), 7.33 (m,
10H, ArH). Anal. (C23H29NO•HCl) C, H, N.
8-Meth yl-8-a za bicyclo[3.2.1]oct-3-ylid en e)a cetic Acid
Eth yl Ester (5). To a slurry of 6.4 g (0.16 mole) of NaH (60%
in mineral oil, washed twice with petroleum ether) in 50 mL
of anhydrous THF cooled in an ice water bath was added
slowly a solution of 35.8 g (0.16 mol) of triethyl phosphono-
acetate in 10 mL of anhydrous THF via addition funnel. The
mixture was allowed to stir at room temperature for 1 h during
which time the light yellow solution gradually turned into a
thick gellike mixture. A solution of 11.1 g (0.08 mol) of
3-tropinone in 20 mL of anhydrous THF was then added slowly
through an addition funnel, and the reaction mixture was
stirred vigorously overnight. Water was added and the layers
were separated. The aqueous layer was then extracted with
CH2Cl2. The combined organic layer was washed with water
twice before being extracted with 15% aqueous citric acid
solution. The aqueous extracts were combined and washed
once with CH2Cl2, basified with concentrated NH4OH, and
then extracted with CH2Cl2. The organic solution was dried
over Na2SO4 and evaporated to give 16.6 g of the R,â-
unsaturated ester 5 as a light beige colored oil. CI-MS (NH3)
3-{2-[Bis-(4-flu or op h en yl)m eth oxy]eth yl}-8-m eth yl-8-
a za bicyclo[3.2.1]octa n e (12). This compound was prepared
from an ether formation between 10 and 4,4′-difluorobenzhy-
drol according to general method B. CI-MS (NH3) m/z 372
1
(MH+); H NMR (CDCl3) δ (ppm) 1.33 (m, 2H, H6,7endo), 1.65
(m, 2H, H6,7exo), 1.82 (m, 3H), 2.02-2.27 (m, 4H, H2,4), 2.30 (s,
3H, NCH3), 3.14 (brs, 2H, H1,5), 3.42 (t, J ) 6.3 Hz, 2H, OCH2),
5.27 (s, 1H, ArCHAr), 7.00 (t, J ) 8.8 Hz, 4H, ArH), 7.26 (dd,
J ) 8.4 Hz, J ) 2.5 Hz, 4H, ArH). Anal. (C23H27NOF2•C4H4O4)
C, H, N.
3-(2-Ben zh yd r yloxyet h yl)-8-(3-p h en ylp r op yl)-8-a za -
bicyclo[3.2.1]octa n e (13). This compound was synthesized
from an N-demethylation of 11 according to general method
E, followed by an N-alkylation with 1-iodo-3-phenylpropane
according to general method F. CI-MS (NH3) m/z 440 (MH+);
1H NMR (CDCl3) δ (ppm) 1.28 (d, J ) 13.8 Hz, 2H, H6,7endo),
1.63 (dd, J ) 13.8 Hz, J ) 7.8 Hz, 2H, H6,7exo), 1.75-2.12 (m,
9H), 2.37 (t, J ) 7.3 Hz, 2H, NCH2), 2.64 (t, J ) 7.8 Hz, 2H,
ArCH2), 3.17 (brs, 2H, H1,5), 3.45 (t, J ) 6.3 Hz, 2H, OCH2),
1
m/z 210 (MH+); H NMR (CDCl3) δ (ppm) 1.28 (t, J ) 6.9 Hz,
5.31 (s, 1H, ArCHAr), 7.32 (m, 15H, ArH). Anal. (C31H37
-
3H, CH3), 1.51 (m, 2H, H6,7endo), 1.97 (m, 3H, H6,7exo + H2ax),
2.38 (s + m, 4H, NCH3 + H4ax), 2.69 (brd, J ) 13.7 Hz, 1H,
NO•HCl•0.75H2O) C, H, N.
3-{2-[Bis-(4-flu or op h en yl)m eth oxy]eth yl}-8-(3-p h en yl-
p r op yl)-8-a za bicyclo[3.2.1]octa n e (14). This compound was
synthesized from an N-demethylation of 12 according to
general method E, followed by an N-alkylation with 1-iodo-3-
phenylpropane according to general method F. CI-MS (NH3)
m/z 476 (MH+); 1H NMR (CDCl3) δ (ppm) 1.35 (d, J ) 13.7
Hz, 2H, H6,7endo), 1.68-2.22 (m, 11H), 2.50 (t, J ) 7.8 Hz, 2H,
NCH2), 2.66 (t, J ) 7.8 Hz, 2H, ArCH2), 3.33 (brs, 2H, H1,5),
3.42 (t, J ) 6.4 Hz, 2H, OCH2), 5.27 (s, 1H, ArCHAr), 7.01 (t,
J ) 8.8 Hz, 4H, ArH), 7.27 (m, 9H, ArH). Anal. (C31H35NOF2•-
HCl•1.75H2O) C, H, N.
Bis(4-flu or op h en yl)m eth yla m in e (15). A solution of 5.0
g (23 mmol) of 4,4′-difluorobenzophenone and 5.0 g (72 mmol)
of hydroxylamine (HCl salt) in 100 mL of ethanol was heated
at reflux overnight, when TLC showed only a trace amount of
starting ketone left. The solvent was evaporated, and the
residue was redissolved in CH2Cl2. The solution was washed
with water and saturated aqueous NaHCO3, dried over Na2-
SO4, and evaporated to give 5.26 g (99% yield) of product as
white solid. CI-MS (NH3) m/z 234 (MH+), 251 (M + 18). The
crude material (5.1 g, 22 mmol) in 30 mL of THF was then
added slowly to 50 mL of 1 M refluxing LiAlH4 in THF. The
reaction mixture turned from dark yellow to bright orange to
light yellow with a precipitate while refluxing and was allowed
H
2eq), 3.25 (brs, 2H, H1,5), 3.50 (brd, J ) 15.1 Hz, 1H, H4eq),
4.14 (q, J ) 6.6 Hz, 2H, OCH2), 5.69 (s, 1H, olefinic H). Anal.
(C12H19NO2•HCl) C, H, N.
2-(8-Meth yl-8-azabicyclo[3.2.1]oct-3-yliden e)eth an ol (6).
This compound was synthesized from 5 according to general
1
method A. CI-MS (NH3) m/z 168 (MH+); H NMR (CDCl3) δ
(ppm) 1.38-1.56 (m, 2H, H6,7endo), 1.94 (m, 3H, H2ax + H6,7exo),
2.28 (m, 2H, H2eq, H4ax), 2.32 (s, 3H, NCH3), 2.57 (brd, J )
14.4 Hz, 1H, H4eq), 3.18 (m, 2H, H1,5), 4.14 (m, 2H, CH2OH),
5.48 (t, J ) 6.7 Hz, 1H, olefinic H).
3-(2-Ben zh yd r yloxyeth ylid en e)-8-m eth yl-8-a za bicyclo-
[3.2.1]octa n e (7). This compound was prepared from an ether
formation between 6 and benzhydrol according to general
1
method B. CI-MS (NH3) m/z 334 (MH+); H NMR (CDCl3) δ
(ppm) 1.38-1.56 (m, 2H, H6,7endo), 1.91 (m, 3H, H6,7exo + H2ax),
2.15 (m, 2H, H2eq, H4ax), 2.32 (s, 3H, NCH3), 2.56 (brd, J )
13.7 Hz, 1H, H4eq), 3.16 (m, 2H, H1,5), 4.00 (m, 2H, CH2O), 5.40
(s, 1H, ArCHAr), 5.50 (t, J ) 6.8 Hz, 1H, olefinic H), 7.33 (m,
10H, ArH). Anal. (C23H27NO•HCl) C, H, N.
3-{2-[Bis-(4-flu or oph en yl)m eth oxy]eth yliden e}-8-m eth -
yl-8-a za bicyclo[3.2. 1]octa n e (8). This compound was pre-
pared from an ether formation between 6 and 4,4′-difluorobenz-
hydrol according to general method B. CI-MS (NH3) m/z 370