Martjuga et al.
JOCArticle
126.3, 126.3, 121.8, 117.8, 61.3, 58.7, 34.1, 30.7, 23.3. Anal. Calcd
for C23H27ClN2OS: C, 66.57; H, 6.56; N, 6.75. Found: C, 66.37; H,
6.60; N, 6.57. Optical rotation [R]20D -35.6 (c 1.36, EtOH).
(RS)-N-[(R)-[5-Chloro-2-(methylamino)phenyl](1-naphthyl)met-
hyl]-N,2-dimethyl-2-propanesulfinamide (6c). Following the gen-
eral procedure for the alkylation, sulfinylamide 5c (640 mg,
1.60 mmol was converted into 6c. Purification of the crude
product by column chromatography using gradient elution
from 6% EtOAc/petroleum ether to 20% EtOAc/petroleum
ether afforded 6c as a white solid (533 mg, 80% yield); analytical
TLC on silica gel, 2:5 EtOAc/petroleum ether, Rf = 0.20. Pure
material was obtained by crystallization from EtOAc/petroleum
ether: mp 168-170 °C; IR (film, cm-1) 3392 (NH), 1040 (SdO);
1H NMR (400 MHz, CDCl3 ppm) δ 7.86 (2H, dd, J = 8.6, 8.6
Hz), 7.76 (1H, d, J = 7.4 Hz), 7.60 (1H, d, J = 8.6 Hz), 7.54 (1H,
dd, J = 7.4 Hz), 7.48-7.38 (2H, m), 7.16 (1H, dd, J = 8.5, 2.4
Hz), 6.68 (1H, d, J = 6.6 Hz), 6.67 (1H, s), 6.31 (1H, s), 4.41 (1H,
q, J = 5.0 Hz), 2.91 (3H, d, J = 5.0 Hz), 2.68 (3H, s), 1.18 (9H,
s); 13C NMR (100 MHz, CDCl3 ppm) δ 145.8, 135.1, 133.9,
131.0, 129.9, 128.9, 128.8, 128.6, 126.6, 125.9, 125.8, 125.1,
123.3, 121.9, 112.1, 64.7, 58.8, 30.9, 30.5, 24.1. Anal. Calcd for
C23H27ClN2OS: C, 66.57; H, 6.56; N, 6.75. Found: C, 66.48; H,
6.54; N, 6.70. Optical rotation [R]20D þ97.9 (c 1.89, EtOH).
(RS)-N-[(R)-(2-Amino-5-chlorophenyl)(phenyl)methyl]-N,2-dim-
ethyl-2-propanesulfinamide (6d). Following the general proce-
dure for the alkylation, sulfinylamide 5d (206 mg, 0.61 mmol)
was converted into 6d. Purification of the crude product by
column chromatography using gradient elution from 6%
EtOAc/petroleum ether to 58% EtOAc/petroleum ether af-
forded 6d as a white solid (180 mg, 80% yield); analytical TLC
on silica gel, 1:1 EtOAc/petroleum ether, Rf = 0.30. Pure
material was obtained by crystallization from Et2O/petroleum
ether: mp 88-90 °C; IR (film, cm-1) 3341 (NH2), 1056 (SdO);
1H NMR (400 MHz, CDCl3, ppm) δ 7.39-7.27 (5H, m), 7.13
(1H, d, J = 2.4 Hz), 7.09 (1H, dd, J = 8.4, 2.4 Hz), 6.61 (1H, d,
J = 8.4 Hz), 5.75 (1H, s), 3.61 (2H, s), 2.63 (3H, s), 1.15 (9H, s);
13C NMR (100 MHz, CDCl3 ppm) δ 142.9, 137.9, 129.4, 128.8,
128.7, 128.2, 128.0, 127.0, 123.3, 117.9, 61.8, 58.7, 33.6, 23.3;
HRMS-ESI (m/z) calcd for C18H24N2OS35Cl [M þ H]þ
over Na2SO4, and concentrated (rotary evaporator) to afford the
1,3-diamine.
2-[(R)-Amino(phenyl)methyl]-4-chloro-N-methylaniline (1a). Fol-
lowing the general procedure, cleavage of the chiral auxiliary in
sulfinylamide 5a (500 mg, 1.43 mmol) afforded 1,3-diamine 1a as a
white solid (353 mg, 99% yield); analytical TLC on silica gel, 1:1
EtOAc/petroleum ether, Rf = 0.48. Pure material was obtained by
crystallization from petroleum ether: mp 57-59 °C; IR (film, cm-1);
1
3374 (NH), 3307 (NH); H NMR (400 MHz, CDCl3, ppm) δ
7.39-7.24 (5H, m), 7.12 (1H, dd, J = 8.8, 2.6 Hz), 6.85 (1H, d, J =
2.6Hz), 6.52(1H, d,J=8.8Hz), 5.11(1H, s), 2.78(3H, s), 1.76(2H,
br s); 13C NMR (100 MHz, CDCl3, ppm) δ 0.8, 143.3, 129.6, 128.7,
128.0, 127.9, 127.4, 126.9, 120.9, 111.3, 57.6, 30.4. Anal. Calcd for
C14H15ClN2: C, 68.15; H, 6.13; N, 11.35. Found: C, 68.21; H, 6.09;
N, 11.36. Optical rotation (99% ee, HPLC/csp) [R]20D -31.1 (c3.30,
EtOH). HPLC/csp assay: Daicel CHIRALPAK IB, 25 cm ꢀ 4.6
mm i.d., mobile phase 1% IPA/99% Hex/0.1% DEA, flow rate 0.9
mL/min, detector UV 254 nm, retention time 13.3 min ((R)-1a)
major and 14.6 min ((S)-1a) minor.
2-[(R)-Amino(2-naphthyl)methyl]-4-chloro-N-methylaniline (1b).
Following the general procedure, cleavage of the chiral auxiliary
in sulfinylamide 5b (250 mg, 0.62 mmol) afforded 1,3-diamine 1b
as a white solid (184 mg, 99% yield); analytical TLC on silica gel,
1:1 EtOAc/petroleum ether, Rf = 0.56. Pure material was
obtained by crystallization from Et2O/petroleum ether: mp
118-120 °C; IR (film, cm-1) 3301 (NH); 1H NMR (400 MHz,
CDCl3, ppm) δ 7.89-7.81 (4H, m), 7.56-7.47 (2H, m), 7.42 (1H,
dd, J = 8.6, 1.4 Hz), 7.44-7.39 (1H, m), 7.19-7.14 (1H, m),
6.95-6.91 (1H, m), 6.57 (1H, d, J = 8.6 Hz), 5.29 (1H, s), 2.80
(3H, s), 1.91 (2H, br s); 13C NMR (100 MHz, CDCl3, ppm) δ
146.8, 140.7, 133.3, 132.8, 129.4, 128.4, 128.1, 128.0, 127.9,
127.7, 126.2, 125.9, 125.5, 125.0, 121.0, 111.4, 57.6, 30.5. Anal.
Calcd for C18H17ClN2: C, 72.84; H, 5.77; N, 9.44. Found:
C,72.55; H, 5.82; N, 9.22. Optical rotation [R]20D þ8.1 (c 1.88,
EtOH).
2-[(R)-Amino(1-naphthyl)methyl]-4-chloro-N-methylaniline (1c).
Following the general procedure, cleavage of the chiral auxiliary
in sulfinylamide 5c (226 mg, 0.56 mmol) afforded 1,3-diamine 1c
as a white solid (166 mg, 99% yield); analytical TLC on silica gel,
1:1 EtOAc/petroleum ether, Rf = 0.60. Pure material was
obtained by crystallization from petroleum ether: mp 141-
142 °C; IR (film, cm-1) 3384 (NH), 3309 (NH); 1H NMR (400
MHz, CDCl3, ppm) δ 7.93-7.89 (1H, m), 7.87-7.82 (2H, m),
7.58-7.41 (4H, m), 7.14 (1H, dd, J = 8.6, 2.4 Hz), 6.67 (1H, d,
J = 2.4 Hz), 6.64 (1H, d, J = 8.6 Hz), 5.84 (1H, s), 5.49 (1H, br
s), 2.87 (3H, s), 1.82 (2H, br s); 13C NMR (100 MHz, CDCl3) δ
146.7, 139.4, 133.8, 131.0, 129.9, 128.9, 128.2, 128.0, 127.6,
126.4, 125.8, 125.4, 123.7, 123.4, 121.4, 111.4, 52.6, 30.6. Anal.
Calcd for C18H17ClN2: C, 72.84; H, 5.77; N, 9.44. Found: C,
351.1298, found 351.1277. Optical rotation [R]20 -44.9
D
(c 1.33, EtOH).
(RS)-N-[(S)-[5-Chloro-2-(dimethylamino)phenyl](phenyl)methyl]-
N,2-dimethyl-2-propanesulfinamide (6e). Following the general
procedure for the alkylation, sulfinylamide 5e (300 mg, 0.82 mmol
was converted into 6e. Purification of the crude product by column
chromatography using gradient elution from 6% EtOAc/petro-
leum ether to 36% EtOAc/petroleum ether afforded 6e as a white
solid (249 mg, 80% yield); analytical TLC on silica gel, 1:1 EtOAc/
petroleum ether, Rf = 0.48. Pure material was obtained by crystal-
lization from Et2O/petroleum ether: mp 116-117 °C; IR (film,
cm-1) 1073 (SdO); 1HNMR(400MHz, CDCl3 ppm) δ7.35-7.17
(7H, m), 7.12 (1H, d, J = 8.6 Hz), 6.32 (1H, s), 2.55 (6H, s), 2.52
(3H, s), 1.09 (9H, s); 13C NMR (100 MHz, CDCl3 ppm) δ 151.6,
139.7, 137.9, 129.6, 129.2, 128.5, 128.5, 128.3, 127.3, 122.2, 65.7,
65.7, 58.6, 45.6, 28.2, 23.9. Anal. Calcd for C20H27ClN2OS: C,
63.39; H, 7.18; N, 7.39. Found: C, 63.37; H, 7.18; N, 7.26. Optical
rotation [R]20D þ41.8 (c 2.79, EtOH).
72.88; H, 5.78; N, 9.38. Optical rotation [R]20 -28.7 (c 1.86,
D
EtOH).
2-[(R)-Amino(phenyl)methyl]-4-chloroaniline (1d). Following
the general procedure, cleavage of the chiral auxiliary in sulfi-
nylamide 5d (376 mg, 1.09 mmol) afforded 1,3-diamine 1d as a
yellow oil (253 mg, 99% yield); analytical TLC on silica gel, 1:1
EtOAc/petroleum ether, Rf = 0.40: IR (film, cm-1) 3436 (NH),
3309 (NH); 1H NMR (400 MHz, CDCl3, ppm) δ 7.41-7.27 (5H,
m), 7.03 (1H, dd, J = 8.4, 2.4 Hz), 7.01 (1H, d, J = 2.4 Hz), 6.58
(1H, d, J = 8.4 Hz), 5.16 (1H, s), 4.35 (2H, br s), 1.86 (2H, br s);
13C NMR (100 MHz, CDCl3, ppm) δ 143.7, 142.2, 129.7, 128.8,
128.0, 127.6, 126.9, 123.1, 118.0, 57.1; HRMS-ESI (m/z) calcd
for C13H14N235Cl [M þ H]þ 233.0846, found 233.0785. Optical
rotation [R]20D -15.6 (c 2.35, EtOH).
2-[(S)-Amino(phenyl)methyl]-4-chloro-N,N-dimethylaniline (1e).
Following the general procedure, cleavage of the chiral auxi-
liary in sulfinylamide 5e (159 mg, 0.44 mmol) afforded 1,
3-diamine 1e as a yellow oil (115 mg, 99% yield); analytical
TLC on silica gel, 1:1 EtOAc/petroleum ether, Rf = 0.48: IR
General Procedure for Cleavage of N-tert-Butanesulfinyl Chir-
al Auxiliary. Sulfinylamide 6 (1.0 equiv) was dissolved in a 1:1
mixture of anhydrous 1,4-dioxane and anhydrous MeOH (6 mL/
mmol of amide 6), and anhydrous HCl in dioxane (4 M solution in
dioxane, 4.0 equiv) was added. After stirring at room temperature
for 1 h, all volatiles were removed in vacuo, and the residue was
dissolved in water (20 mL/mmol of amide 6) and extracted with
EtOAc (10 mL/mmol of amide 6). Water layer was basified to
pH = 8 with aqueous concentrated NH4OH and extracted with
EtOAc. Combined organic extracts were washed with brine, dried
J. Org. Chem. Vol. 75, No. 7, 2010 2367