Journal of Medicinal Chemistry
Article
solution was cooled to room temperature, the solvent was removed in
vacuo, and the residue was redissolved in EtOAc. Water (20 mL) was
added and the organic product extracted with EtOAc (3 × 30 mL).
30.0, 41.0, 44.9, 45.0, 56.4, 62.4, 80.3, 116.4, 121.8 (d, J = 58.2 Hz),
128.1, 130.1 (d, J = 13.2 Hz), 139.7, 140.0, 140.4, 146.5 (d, J = 58.8
Hz), 155.4, 157.7, 160.9.
7-(tert-Butoxycarbonyl)-2-exo-[2′-fluoro-3′-(4-sulfamoyl-
phenyl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane (12). A solu-
tion of 8 (488 mg, 1.32 mmol), 4-boronobenzenesulfonamide (318
The combined organic layers were dried (MgSO ), filtered through
4
Celite, and concentrated in vacuo. The crude residue was purified on
silica gel (CHCl −MeOH) by flash chromatography to provide 160
3
1
mg (78% yield) of 5g as a colorless oil: H NMR (CDCl ) δ 1.53−
mg, 1.58 mmol), PdCl
mg, 3.96 mmol) in 1,4-dioxane (3 mL) and H
2
2
(dppf) (48 mg, 0.066 mmol), and K
2 3
CO (547
3
1
3
8
4
1
.72 (m, 5H), 1.91−1.98 (m, 3H), 2.82−2.86 (m, 1H), 3.61(s, 1H),
O (1 mL) was placed in
.80 (s, 1H), 6.58 (br s, 2H), 7.62−7.65 (m, 2H), 7.89−7.92 (m, 2H),
a microwave vial and degassed through bubbling nitrogen for 20 min.
The reaction mixture was then irradiated in a CEM Corp. microwave
reactor for 20 min at 140 °C. After being cooled to room temperature,
13
.01 (dd, J = 2.4, 9.6 Hz, 1H), 8.10 (s, 1H); C NMR (CDCl ) δ 30.2,
3
0.5, 44.4, 56.4, 62.8, 122.2, 127.1, 129.0, 133.1, 137.8, 139.8, 140.8,
45.6, 160.5, 169.1; MS (ESI) m/z 312.6 (M + H) .
+
the mixture was diluted with a 10 mL CHCl
and decanted into a 10 mL aqueous solution of NaHCO
product was extracted with chloroform (3 × 20 mL), and the
combined organic layers were dried (Na SO ), filtered through Celite,
−MeOH (10:1) solution
3
A solution of 5g in chloroform in a vial was treated with a solution
3
. The organic
of HCl in diethyl ether. The excess solvent was removed in vacuo to
1
give 5g·HCl: mp 202−206 °C; H NMR (CD OD) δ 1.91−2.20
2
4
3
(
m, 5H), 2.46−2.54 (dd, J = 3.8, 9.6 Hz, 1H), 3.51−3.56 (m, 1H),
and concentrated in vacuo. The resultant residue was purified by flash
4
7
.35, (d, J = 3.5 Hz, 1H), 4.60 (d, J = 2.5 Hz, 1H), 7.77−7.74 (m, 2H),
chromatography through an ISCO column to furnish 245 mg (41%) of
1
13
1
1
1
5
1
2 as a foamy solid: H NMR (CDCl ) δ (ppm) 1.41 (s, 9H), 1.53−
.99−8.02 (m, 2H), 8.10 (dd, J = 2.4, 9.2 Hz, 1H), 8.20 (s, 1H); C NMR
3
.66 (m, 2H), 1.81−1.93 (m, 3H), 1.98−2.09 (dd, J = 9.0, 12.4 Hz,
H), 2.95−3.00 (dd, J = 4.8, 8.9 Hz, 1H), 4.24 (s, 1H), 4.40 (s, 1H),
.47 (s, 2H), 7.67 (dd, J = 1.4, 8.5 Hz, 2H), 7.91 (dd, J = 9.6, 2.4 Hz,
(
CD OD) δ 26.8, 28.9, 37.6, 43.3, 60.5, 64.3, 123.8, 129.1, 130.2,
3
1
3
35.0, 137.2, 138.3, 141.4, 146.4, 159.1, 162.3, 171.6; MS (ESI) m/z
+
12.4 (M + H) . Anal. (C H ClFN O·1.75H O): C, H, N.
18
19
3
2
H), 7.98 (dd, J = 1.9, 8.6 Hz, 2H), 8.10 (s, 1H); 13C NMR (CDCl ) δ
7
-(tert-Butoxycarbonyl)-2-exo-(2′-fluoro-3′-bromo-5′-pyri-
dinyl)-7-azabicyclo[2.2.1]heptane (8). A solution of 7 (447 mg,
.65 mmol) in CH Cl (15 mL) and Et N (350 μL) was treated with
3
(ppm) 28.3 (3C), 28.8, 29.6, 40.4, 44.7, 56.0, 61.9, 80.1, 121.4 (JCF
=
1
28.2 Hz), 126.6, 129.4, 129.4, 138.2 (JCF = 5.2 Hz), 139.5 (JCF = 3.7
Hz), 140.0 (JCF = 4.8 Hz), 142.2 145.6, (JCF = 15.0 Hz), 155.0, 157.3,
160.5.
2
2
3
(
Boc) O (540 mg, 2.47 mmol) and stirred overnight. The reaction
2
mixture was then diluted with an additional CH Cl (20 mL) and
2
2
washed with brine. The organic phase was dried over anhydrous
7-(tert-Butoxycarbonyl)-2-exo-[2′-fluoro-3′-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)-5′-pyridinyl]-7-azabicyclo-
Na SO and concentrated in vacuo. The resultant residue was purified
2
4
[
2.2.1]heptane (13). In a microwave vial were placed 8 (214 mg,
by flash chromatography, and the title compound was isolated as a
1
0.578 mmol, 1.0 equiv), bis(pinacolato)diboron (176 mg, 0.694 mmol,
.2 equiv), KOAc (170 mg, 1.73 mmol, 3.0 equiv), PdCl (dppf) (21
yellow oil (591 mg, 97%): H NMR (CDCl ) δ (ppm) 7.8−8.0 (2H,
3
1
m), 4.33 (br s, 1H), 4.11 (br s, 1H), 2.83 (dd, 1H, J = 4.8, 9.0 Hz),
.96 (dd, 1H, J = 9.0, 12.3 Hz), 1.4−1.8 (5H, m), 1.39 (9H, s); C
NMR (CDCl ) δ (ppm) 160.2, 157.1, 144.9 (d, J = 21.9 Hz), 142.7 (d,
2
13
mg, 0.0289 mmol, 5 mol %), and anhydrous 1,4-dioxane (3 mL). The
mixture was degassed through bubbling nitrogen for 20 min followed
by irradiation in a microwave at 140 °C for 20 min. After being cooled
to room temperature, the mixture was diluted with EtOAc, filtered
through a plug of Celite and anhydrous Na SO , and concentrated in
1
3
J = 6.9 Hz), 141.2 (d, J = 19.8 Hz), 62.2, 56.3, 44.8, 40.8, 30.0, 29.1,
28.6.
General Procedure for the Synthesis of Compounds 9−11.
2
4
vacuo. The resultant residue was purified by flash chromatograph
Compound 8 (0.7 mmol) was cross-coupled with the respective
boronic acid (1.4 mmol), [4-(trifluoromethyl)phenyl-, 4-cyanophenyl-,
or 4-(methylsulfonyl)phenylboronic acid] in the presence of Pd-
through a Teledyne ISCO column (EtOAc−hexanes) to provide 589
1
mg (94%) of 13 as a colorless oil: H NMR (CDCl ) δ (ppm) 1.26 (s,
3
1
2
4
2
4
1
2H), 1.44 (s, 9H), 1.60−1.53 (m, 2H), 1.75−1.92 (m, 3H), 1.96−
.03 (dd, J = 9.0, 12.4 Hz, 1H), 2.87−2.92 (dd, J = 4.8, 8.9 Hz, 1H),
.19 (s, 1H), 4.40 (s, 1H), 8.07 (dd, J = 8.4, 2.4 Hz, 1H), 8.17 (d, J =
(
OAc)2 (0.07 mmol), tris(o-tolyl)phosphine (0.14 mmol), and
Na CO (1.7 mmol) mixed in DME (2 mL) and H O (0.5 mL).
2
3
2
The mixture was purged with argon, sealed, and heated in an 85 °C oil
bath overnight. After cooling, the mixture was filtered through Celite
and washed with EtOAc. The organic phase was washed with brine,
dried (Na SO ), and concentrated in vacuo. The residue was purified
.7 Hz, 1H); 13C NMR (CDCl ) δ (ppm) 24.8, 28.3 (3C), 28.8, 29.8,
3
0.2, 44.9, 61.8, 79.7, 84.3, 138.2 (JCF = 5.0 Hz), 146.8, 149.2 (J
5.0 Hz), 154.9, 164.2, 167.4; MS (ESI) m/z 419.7 (M + H) .
=
CF
+
2
4
1-Bromo-4-[(trifluoromethyl)sulfonyl]benzene (15). A stirred
by flash chromatography on a silica gel column using EtOAc−hexanes
as the eluent.
ice-cold solution of 4-bromophenyl trifluoromethyl sulfide (14) (1.5 g,
5
.83 mmol) in CH Cl (40 mL) was treated with mCPBA (5.03 g,
2 2
Data for 7-(tert-butoxycarbonyl)-2-exo-[2′-fluoro-3′-[4-
2
9.2 mmol), and the reaction mixture was allowed to warm to room
(
(
(
trifluoromethyl)phenyl]-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane
1
9): H NMR (CDCl ) δ (ppm) 1.43 (s, 9H), 1.5−1.9 (m, 5H), 2.02
temperature. Stirring was continued overnight, after which the reaction
3
m, 1H), 2.98 (dd, 1H, J = 4.8, 9.0 Hz), 4.25 (br s, 1H), 4.41 (br s,
mixture was diluted with additional CH Cl (60 mL) and washed
2
2
H), 7.70 (s, 4H), 7.91 (dd, 1H, J = 2.4, 6.3 Hz), 8.10 (m, 1H); 13
NMR (CDCl ) δ (ppm) 28.3, 28.9, 29.7, 40.7, 44.8, 56.1, 62.1, 80.0,
C
sequentially with an aqueous saturated NaHCO solution (50 mL) and
1
3
brine (50 mL). The organic layer was dried over anhydrous MgSO4,
filtered through Celite, and concentrated in vacuo to provide 1.12 g
3
125.6 (q, J = 15 Hz), 129.3 (d, J = 12.6 Hz), 137.9 (d, J = 18.6 Hz),
139.4 (d, J = 15.3 Hz), 140.0 (d, J = 19.5 Hz), 145.7 (d, J = 58.2 Hz),
155.0, 157.5, 160.7.
(67%) of 15 as a white crystalline solid that was used without further
purification.
7
-(tert-Butoxycarbonyl)-2-exo-[2′-fluoro-3′-[4-[(trifluoromethyl)-
Data for 7-(tert-butoxycarbonyl)-2-exo-[2′-fluoro-3′-(4-cyano-
1
sulfonyl]phenyl]-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane (16). A
phenyl)-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane (10): H NMR
solution of the boronic ester 13 (480 mg, 1.15 mmol), 15 (431 mg,
(
2
CDCl ) δ (ppm) 1.43 (s, 9H), 1.5−1.9 (m, 5H), 2.02 (m, 1H),
3
1
3
.49 mmol), Pd(PPh ) (133 mg, 0.115 mmol), and K CO (462 mg,
3 4 2 3
.99 (dd, 1H, J = 4.8, 9.0 Hz), 4.25 (br s, 1H), 4.41 (br s, 1H), 7.6−7.8
13
.34 mmol) in DME−EtOH−H O (3.2 mL/0.8 mL/1 mL) was
(
m, 4H), 7.92 (dd, 1H, J = 2.4, 9.6 Hz), 8.12 (m, 1H); C NMR
2
placed in a microwave vial and degassed through bubbling nitrogen for
(
CDCl ) δ (ppm) 28.6, 29.2, 30.0, 41.0, 45.0, 56.3, 62.3, 80.3, 112.4,
3
2
0 min. The mixture was irradiated in a CEM Corp. microwave reactor
1
1
16.7, 118.8, 121.7 (d, J = 112.5 Hz), 129.8 (d, J = 12.9 Hz), 132.7,
39.1, 139.5, 140.4, 146.5 (d, J = 58.2 Hz), 155.3, 157.6, 160.8.
Data for 7-(tert-butoxycarbonyl)-2-exo-[2′-fluoro-3′-[4-
for 20 min at 140 °C. After the mixture was cooled to room
temperature, the solvent was removed under reduced pressure, the
(
(
(
methylsulfonyl)phenyl]-5′-pyridinyl]-7-azabicyclo[2.2.1]heptane
residue was redissolved in CH
Cl (10 mL), and H O (10 mL) was
2 2 2
1
11): H NMR (CDCl ) δ (ppm) 1.58 (s, 9H), 1.5−1.9 (m, 5H), 2.02
added. The organic product was extracted with CH Cl (3 × 20 mL),
3
2
2
m, 1H), 3.00 (dd, 1H, J = 4.8, 9.0 Hz), 3.12 (s, 3H), 4.25 (br s, 1H),
the combined organic layers were dried (Na SO ) and filtered through
2 4
4
8
.41 (br s, 1H), 7.7−7.8 (m, 2H), 7.93 (dd, 1H, J = 2.4, 9.6 Hz), 8.0−
Celite, and the solvent was removed in vacuo. The resultant residue
was purified by flash chromatography through a Teledyne ISCO
.1 (m, 2H), 8.13 (m, 1H); 13C NMR (CDCl ) δ (ppm) 28.6, 29.2,
3
6
519
dx.doi.org/10.1021/jm300575y | J. Med. Chem. 2012, 55, 6512−6522