The Journal of Organic Chemistry
Article
residue was washed with hexanes (4 mL) and the wash layer was
decanted to afford the desired product as a 1:1 mixture with imidazole.
This was used without further purification. The urea (47 mg, 84 μmol)
was dissolved in dichloromethane (2.0 mL), and the solution was treated
with TFA (180 μL, 3.3 mmol) and stirred at room temperature
overnight. The reaction mixture was diluted with dichloromethane,
poured into saturated aqueous NaHCO3, and extracted with dichloro-
methane. The combined organic layers were dried (MgSO4), filtered,
and concentrated to an oil. The residue was washed with hexanes, and
the wash layer was decanted to afford the desired product as a yellow
foam (40 mg, 63% over two steps) in about 20:1 dr (by 1H NMR): Rf =
0.1 (5% MeOH/CH2Cl2); IR (film) 3344, 3262, 2924, 1668 cm−1; 1H
NMR (600 MHz, CDCl3) δ 7.31 (t, J = 7.8 Hz, 1H), 7.18 (d, J = 8.4 Hz,
2H), 7.09 (d, J = 7.8 Hz, 1H), 7.04 (m, 2H), 6.90 (d, J = 8.4 Hz, 2H),
6.88 (s, 1H), 6.00 (d, J = 7.2 Hz, 1H), 5.03 (dd, J = 12.6, 1.8 Hz, 1H),
4.33 (d, J = 4.8 Hz, 1H), 4.07 (dd, J = 17.4, 12.6 Hz, 2H), 3.60 (m, 2H),
3.31 (m, 2H), 1.24 (br m, 2H); 13C NMR (150 MHz, CDCl3) ppm
167.5, 155.7, 149.1, 144.5, 136.6, 133.4, 129.8, 128.8 (2C), 128.3 (2C),
125.2, 120.1, 119.5, 59.4, 59.0, 47.5, 40.9, 39.6, 14.1; HRMS (ESI) exact
mass calcd for C20H21ClF3N4O3 [M + H]+ 457.1254, found 457.1268.
cis-Imidazoline 15. Tf2O (16 μL, 96 μmol) was added to a stirred
solution of Ph3PO (53 mg, 191 μmol) in dichloromethane (300 μL)
at 0 °C, and this mixture was stirred for 10 min and then treated with cis-
amide urea 19 (30.2 mg, 48.8 μmol) as a solution in dichloromethane
(800 μL). The mixture was stirred at 0 °C for 1 h prior to stirring at room
temperature for 4 h. The reaction mixture was quenched with NaHCO3,
the aqueous layer was extracted with dichloromethane, and the
combined organic layers were dried (MgSO4), filtered, and concen-
trated. Column chromatography (SiO2, 0−4% methanol in dichloro-
methane) of the residue provided the product as a white solid (21.0 mg,
73%): [α]D20 = −1.7° (c 0.21, CHCl3); mp 125−126 °C; Rf = 0.26 (5%
MeOH/CH2Cl2); IR (film) 3216, 2980, 2932, 1683, 1614, 1440 cm−1;
1H NMR (400 MHz, CDCl3) δ 7.60 (d, J = 8.8 Hz, 1H), 7.13 (t, J = 8.0
Hz, 1H), 7.00 (d, J = 8.4 Hz, 2H), 6.94 (t, J = 8.0 Hz, 2H), 6.87 (s, 1H),
6.84 (d, J = 8.4 Hz, 2H), 6.56 (dd, J = 8.4, 2.0 Hz, 1H), 6.49 (d, J = 2.0
Hz, 1H), 6.40 (s, 1H), 5.59 (d. J = 10.0 Hz, 1H), 5.52 (d, J = 10.0 Hz,
1H), 4.61 (qq, J = 6.0, 6.0 Hz, 1H), 3.83 (s, 3H), 3.83 (d, J = 18.0 Hz,
1H), 3.62 (d, J = 18.0 Hz, 1H), 3.42 (m, 1H), 3.18 (m, 1H), 3.00 (m,
2H), 1.38 (d, J = 6.0 Hz, 3H), 1.33 (d, J = 6.0 Hz, 3H); 13C NMR (100
61.8, 57.7, 55.6, 47.5, 41.1, 40.0, 21.8, 21.4; HRMS (ESI) exact mass
calcd for C31H33ClF3N4O6 [M + H]+ 649.2041, found 649.2023.
cis-Imidazoline 21.44 In a microwave vial under an inert atmo-
sphere was placed Pd(PPh3)4 (4.7 mg, 4.1 μmol). The vial was charged
with K2CO3 (13.3 mg, 96.0 μmol), boronic ester 20 (10.0 mg,
48.0 μmol), and cis-imidazoline 11 (20.0 mg, 32.0 μmol). The vial was
sealed, evacuated, and back-filled with argon. This process was repeated
three times. A 5/1 mixture of dioxanes in water (865 μL) was then added
via syringe under argon. The mixture was stirred for 20 h at 80 °C
(conventional heating), and the solvent was then evaporated after
cooling. Column chromatography (SiO2, 0−5% methanol in dichloro-
methane) of the residue afforded the adduct as an off-white foam
(13 mg, 62%): [α]D20 = −37° (c 0.27, CHCl3); Rf = 0.68 (10% MeOH/
CH2Cl2); IR (film) 3259, 2923, 2852, 1674, 1607, 1423 cm−1; 1H NMR
(400 MHz, CDCl3) δ 7.65 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 1.6 Hz, 1H),
7.14 (d, J = 8.0 Hz, 2H), 7.06 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.4 Hz,
2H), 6.89 (d, J = 8.4 Hz, 2H), 6.57 (dd, J = 8.4, 2.0 Hz, 1H), 6.49 (d, J =
2.0 Hz, 1H), 6.24 (d, J = 2.0 Hz, 1H), 5.86 (br s, 1H), 5.62 (d, J = 9.6 Hz,
1H), 5.58 (d, J = 9.6 Hz, 1H), 4.61 (qq, J = 6.0, 6.0 Hz, 1H), 3.85 (s, 3H),
3.76 (s, 3H), 3.73 (m, 2H), 3.38 (m, 1H), 3.28 (m, 1H), 3.04 (m, 2H),
1.40 (d, J = 6.0 Hz, 3H), 1.62 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz,
CDCl3) ppm 166.5, 163.0, 160.3, 157.1, 154.9, 143.2, 138.4, 138.0,
135.3, 133.1, 132.2, 129.5, 128.4, 128.2 (2C), 127.9, 105.8, 104.6, 100.2,
72.2, 71.1, 69.3, 68.4, 63.7, 55.6, 49.8, 41.7, 40.5, 37.3, 29.7, 22.1; HRMS
(ESI) exact mass calcd for C34H36ClN6O4 [M + H]+ 627.2487, found
627.2466.
tert-Butyl ((1S,2R)-2-Amino-2-(4-chlorophenyl)-1-(4-
fluorophenyl)ethyl)carbamate (S19). β-Nitro Boc-amine 4ad
(301 mg, 760 μmol), methanol (2.9 mL), and cobalt(II) chloride
(49.3 mg, 379 μmol) were combined and stirred. The solution was
cooled to 0 °C, and sodium borohydride (431 mg, 11.2 mmol) was
added in five portions over 1 h. The reaction mixture was stirred at 0 °C
for an additional 30 min before the mixture was quenched with saturated
aqueous NH4Cl. The reaction mixture was adjusted to pH 10 with
concentrated aqueous NH4OH. The mixture was placed on a glass frit
and washed with water, and the aqueous layer was collected. The
remaining solid was thoroughly washed with CH2Cl2 and collected in a
separate flask. The organic layers were dried (MgSO4), filtered, and
concentrated to afford a white solid (221 mg, 75%): [α]D20 = −45° (c
0.84, CHCl3); mp 144−146 °C; Rf = 0.36 (50% EtOAc in hexanes); IR
(film) 3371, 2970, 2922, 2355, 1692, 1602, 1512 cm−1; 1H NMR (400
MHz, CD3OD) δ7.58 (d, J = 8.4 Hz, 2H), 7.02−6.92 (m, 6H), 4.81
(br m, 1H), 4.24 (br d, 1H), 1.48−1.38 (m, 12H); 13C NMR (100 MHz,
MHz, CDCl3) ppm 166.8, 163.0, 160.6, 157.1, 154.7, 148.9, 134.8,
1
133.3, 132.1, 129.2, 128.2, 128.1, 126.4, 121.6, 120.6, 120.4 (q, JCF
=
256 Hz), 119.9, 133.4, 104.6, 104.1, 100.2, 71.8, 71.1, 69.1, 63.9, 55.5,
49.3, 42.0, 40.5, 22.0 (2C), 18.0, 15.3; HRMS (ESI) exact mass calcd for
C31H31ClF3N4O5 [M + H]+ 631.1935, found 631.1917.
1
CD3OD) ppm 163.7 (d, JCF = 244 Hz), 157.2, 142.2, 137.6, 134.2,
130.7 (d, 3JCF = 8.0 Hz), 130.4, 129.3, 116.2 (d, 2JCF = 22.0 Hz), 80.2,
61.5, 60.9, 28.6; LRMS (ESI) exact mass calcd for C19H22ClFN2O2
[M + H]+ 365.135, found 365.57,
N-((1S,2R)-1-(4-Chlorophenyl)-2-(2-isopropoxy-4-methoxy-
benzamido)-2-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopiper-
azine-1-carboxamide (19). N-((1R,2S)-2-Amino-1-(4-chlorophenyl)-
2-(3-(trifluoromethoxy)phenyl)ethyl)-3-oxopiperazine-1-carboxamide
(35 mg, 76 μmol) and carboxylic acid 18 (16 mg, 77 μmol) were
dissolved in dichloromethane (385 μL), and the solution was chilled to
0 °C and treated with EDC·HCl (19 mg, 99 μmol) and DMAP (1 mg,
7.7 μmol). The reaction mixture was stirred and gradually warmed to
room temperature over 2 h. After 17 h, the mixture was diluted with
water and extracted with dichloromethane. The combined organic layers
were washed with water, saturated aqueous NaHCO3, and once more
with water. The organic layer was dried (MgSO4), filtered, and con-
centrated. Column chromatography (SiO2, 0−4% methanol in
dichloromethane) afforded a single diastereomer of the amide as a
yellow oil (42 mg, 87%): [α]D20 = +84° (c 1.01, CHCl3); Rf = 0.2 (5%
MeOH/CH2Cl2); IR (film) 3368, 3257, 2980, 2931, 1676, 1641, 1537,
1503 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.38 (d, J = 8.0 Hz, 1H), 8.24
(d, J = 8.8 Hz, 1H), 7.66 (d, J = 5.2 Hz, 1H), 7.37 (t, J = 8.0 Hz, 1H), 7.17
(m, 1H), 7.16 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.88 (d, J =
8.0 Hz, 2H), 6.87 (m, 1H), 6.83 (br d, 1H), 6.60 (dd, J = 8.8, 2.0 Hz,
1H), 6.45 (d, J = 2.0 Hz, 1H), 5.85 (dd, J = 8.0, 2.4 Hz, 1H), 5.14 (dd, J =
2.4, 2.4 Hz, 1H), (qq, J = 6.0, 6.0 Hz, 1H), 4.12 (br m, 2H), 3.85 (s, 3H),
3.70 (m, 1H), 3.58 (m, 1H), 3.38 (br m, 2H), 1.19 (d, J = 6.0 Hz, 3H),
1.16 (d, J = 6.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) ppm 167.9,
167.2, 157.3, 155.9, 149.2, 140.5, 136.3, 134.5, 133.4, 130.0, 129.2, 128.1,
125.8, 121.0 (q, 1JCF = 254 Hz), 120.5, 119.8, 113.4, 105.4, 100.3, 71.6,
tert-Butyl ((1S,2R)-2-(4-Chlorophenyl)-1-(4-fluorophenyl)-2-
(3-oxopiperazine-1-carboxamido)ethyl)carbamate (S20).
Amine S19 (210 mg, 575 μmol), dichloromethane (2.9 mL), and
carbonyl diimidazole (112 mg, 689 μmol) were combined, and the
mixture was stirred at room temperature for 1 h before adding oxo-
piperazine (115 mg, 1.15 mmol). The resulting mixture was stirred for
5 h before quenching with water and extracting with dichloromethane.
The organic layers were combined, dried (MgSO4), filtered, and
concentrated to afford a white solid (166 mg, 54%): [α]D20 = +16° (c
0.09, CH3COCH3); Mp: 216−218 °C; Rf = 0.54 (10% MeOH in
CH2Cl2); IR (film) 3379 (br), 2981, 1505, 1682, 1608 cm−1; 1H NMR
(400 MHz, CD3OD) δ 7.68 (s, 1H), 7.45−7.40 (m, 4H), 7.32 (d, J = 8.4
Hz, 2H), 7.05 (dd, J = 8.8 Hz, 8.0 Hz, 4H), 5.06 (d, J = 10.8 Hz, 1H),
4.97 (d, J = 10.8 Hz, 1H), 3.90 (d, J = 17.6 Hz, 1H), 3.72 (d, J = 17.6 Hz,
1H), 3.62−3.42 (m, 1H), 3.37−3.36 (m, 1H), 3.10 (m, 2H), 1.25 (s,
9H); 13C NMR (100 MHz, CD3OD) ppm 169.9, 163.5 (d, 1JCF = 243
Hz), 157.9, 157.3, 140.9, 138.2, 136.2, 134.2, 130.7, 130.6 (d, 3JCF = 8.0
Hz), 129.2, 116.0 (d, 2JCF = 21 Hz), 80.3, 59.5, 58.5, 48.2, 41.33, 41.26,
28.6; HRMS (ESI) exact mass cald for C24H28ClFN4NaO4 [M + Na]+
513.1681, found 513.1704.
N-((1R,2S)-2-Amino-1-(4-chlorophenyl)-2-(4-fluorophenyl)-
ethyl)-3-oxopiperazine-1-carboxamide (S21). Boc-protected urea
S20 (150 mg, 306 μmol) was dissolved in dichloromethane (3.0 mL),
6931
dx.doi.org/10.1021/jo501003r | J. Org. Chem. 2014, 79, 6913−6938