2002
R. B. Strand et al. / Tetrahedron: Asymmetry 22 (2011) 1994–2006
crude product was purified by Versa flash chromatography (11%
EtOAc/n-pentane) to provide 8c (14.2 g, 98%) as a white solid. Rf
(11% EtOAc/n-pentane) 0.18. 1H NMR (400 MHz, CDCl3) d 8.36
(1H, s, NH), 7.37–7.31 (1H, m, Harom.), 7.22–7.19 (2H m, Harom.),
4.45 (2H, q, J 7.1 Hz, OCH2CH3), 3.01 (2H, J 6.8 Hz, 2 ꢃ CH(CH3)2),
1.46 (3H, J 7.1 Hz, OCH2CH3), 1.21 (12H, J 6.8, 2 ꢃ CH(CH3)2).
with DCM (3 ꢃ 20 mL). After drying (Na2SO4) the solvent was re-
moved in vacuo and the crude product was purified by flash chro-
matography (20% EtOAc/n-pentane) affording 10b (72 mg, 74%) as
a pale orange oil. Rf (25% EtOAc/n-pentane) 0.6; ½a D20
¼ þ20 (c 0.64,
ꢂ
MeOH); mmax (neat) 3372 (br), 2871 (br), 1596, 1506, 1263 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.10–7.07 (1H, m, Harom.), 7.02–6.98
(1H, m, Harom.), 6.68–6.63 (2H, m, Harom.), 6.36 (1H, s, Harom.),
6.26 (2H, s, Harom.), 3.50–3.44 (1H, m, CH), 3.38–3.28 (5H, m,
HNCH2CH2NH + NCHaHbCH2), 3.24 (1H, dd, J 9.4, 4.6 Hz, CHaH-
bOCH3), 3.22 (3H, s, OCH3) 3.10 (1H, dd, J 9.3, 6.5 Hz, CHaHbOCH3),
2.76 (1H, dt, J 9.5, 7.6 Hz, NCHaHbCH2), 2.22 (6H, s, ArCH3), 2.14–
2.04 (1H, m, CHCHaHbCH2), 1.91–1.83 (2H, m, CH2CH2CH2) 1.78–
1.70 (1H, m, CHCHaHbCH2); 13C NMR (100 MHz, CDCl3) d 148.2
(Carom.), 145.2 (Carom.), 138.7 (2 ꢃ Carom.), 136.6 (Carom.), 125.2
(CHarom.), 121.7 (CHarom.), 119.3 (CHarom.), 116.8 (CHarom.), 110.8
(2 ꢃ CHarom.), 110.2 (CHarom.), 74.9 (CH2OCH3), 62.0 (CH), 58.8
(OCH3), 53.8 (NCH2CH2), 43.1 (NCH2CH2N), 43.0 (NCH2CH2N),
28.4 (CHCH2CH2), 23.8 (CH2CH2CH2), 21.6 (ArCH3); HRMS (ESI):
MH+, found 354.2550. C22H32N3O (M+H+) requires 354.2540.
4.2.15. (S)-N1-(2-(2-((tert-Butyldimethylsilyloxy)methyl)
pyrrolidin-1-yl)phenyl)-N2-(3,5-dimethylphenyl)oxalamide 9c
At first, DCC (130 mg, 0.630 mmol) dissolved in DCM (1 mL) was
added on ice cooling to a suspension of 8a (100 mg, 0.517 mmol) and
HOBt (160 mg, 1.18 mmol) in THF (2 mL) containing molecular
sieves (4 Å). After stirring for 1 h at 0 °C, the chiral aniline derivative
4c (154 mg, 0.502 mmol) was added and the reaction mixture was
allowed to warm to room temperature overnight. The solvent was
removed under reduced pressure, and the solid residue was sus-
pended in EtOAc and filtered. The filtrate was washed with an aque-
ous citric acid solution (25 mL, 10% w/w), NaHCO3 (25 mL, 5% w/w)
and brine (25 mL). The organic layers were dried (Na2SO4), and evap-
orated to dryness. Purification by flash chromatography (0.5% Et2O/
toluene) yielded bisamide 9c (111 mg, 46%) as pale green crystals.
4.2.18. (S)-N1-(2-(2-((tert-Butyldimethylsilyloxy)methyl)
pyrrolidin-1-yl)phenyl)-N2-mesityloxalamide 11
Mp 192 °C; Rf (10% Et2O/n-pentane) 0.41; ½a D20
¼ þ53 (c 0.59,
ꢂ
MeOH); mmax (neat) 3358, 2927, 2854, 1684, 1519, 1456,
1081 cmꢁ1 1H NMR (400 MHz, CDCl3) d 10.45 (1H, s, NH), 9.29
;
The title compound 11 was prepared from DCC (438 mg,
2.12 mmol), 8b (359 mg, 1.73 mmol), HOBt (539 mg, 3.99 mmol)
and 4c (587 mg, 1.92 mmol) as described above for 9c. Purification
by flash chromatography (0.5% Et2O/toluene) yielded the bisamide
11 (622 mg, 72%) as pale green crystals. Mp 99–101 °C;
(1H, s, NH), 8.37–8.32 (1H, m, Harom.), 7.33–7.25 (3H, m, Harom.),
7.17–7.12 (2H, m, Harom.), 6.84 (1H, s, Harom.), 3.63–3.57 (1H, m,
CH), 3.55–3.50 (1H, m, CHaHbOSi), 3.48–3.41 (2H, m, CHaHbO-
Si + NCHaHbCH2), 2.85–2.79 (1H, m, NCHaHbCH2), 2.34 (6H, s,
ArCH3), 2.23–2.14 (1H, m, CHCHaHbCH2), 2.10–1.99 (1H, m,
CH2CHaHbCH2), 1.98–1.80 (2H, m, CH2CHaHbCH2 + CHCHaHbCH2),
0.79 (9H, s, C(CH3)3), ꢁ0.09 (3H, s, Si(CH3)2), ꢁ0.10 (3H, s, Si(CH3)2);
13C NMR (100 MHz, CDCl3) d 157.7 (CO), 157.4 (CO), 141.0 (Carom.),
139.0 (2 ꢃ Carom.), 136.3 (Carom.), 133.0 (Carom.), 127.1
(CHarom.), 125.3 (CHarom.), 124.5 (CHarom.), 122.0 (CHarom.), 119.5
(CHarom.), 117.5 (2 ꢃ CHarom.), 65.9 (CH2OSi), 63.9 (CH), 55.7
(NCH2CH2), 28.8 (CHCH2CH2), 25.8 (C(CH3)3), 24.1 (CH2CH2CH2),
21,3 (ArCH3), 18.1 (C(CH3)3), ꢁ5.5 (Si(CH3)2), ꢁ5.6 (Si(CH3)2); HRMS
(ESI): MH+, found 482.2844. C27H40N3O3Si requires 482.2833.
½
a 2D0
ꢂ
¼ þ54:7 (c 1.0, MeOH); mmax (neat) 3298, 3226, 2940, 2850
(br), 1659, 1510, 1451, 1102, 835,747 cmꢁ1 1H NMR (400 MHz,
;
CDCl3) d 10.52 (1H, s, NH), 8.85 (1H, s, NH), 8.39–8.34 (1H, m, Har-
om.), 7.30–7.27 (1H, m, Harom.), 7.18–7.12 (2H, m, Harom.), 6.93 (2H,
s, Harom.), 3.60–3.52 (1H, m, CH), 3.50 (1H, dd, J 9.8, 4.9 Hz, CHaH-
bOSi), 3.42 (1H, dd, J 9.8, 6.3 Hz, CHaHbOSi), 3.43–3.38 (1H, m,
NCHaHb), 2.81 (1H, dd, J 9.0, 7.3 Hz, NCHaHb), 2.28 (3H, s, p-ArCH3),
2.22 (6H, s, o-ArCH3), 2.19–2.09 (1H, m, CHCHaHbCH2), 2.02–1.94
(1H, m, NCH2CHaHb), 1.94–1.84 (1H, m, NCH2CHaHb), 1.84–1.74
(m, 1H, CHCHaHbCH2), 0.76 (9H, s, C(CH3)3), ꢁ0.11 (s, 6H, Si(CH3)2),
-0.12 (6H, s, Si(CH3)2); 13C NMR (100 MHz, CDCl3) d 158.7 (CO),
157.2 (CO), 140.9 (Carom.), 137.5 (Carom.), 134.7 (2 ꢃ Carom.), 133.3
(Carom.), 129,9 (Carom.), 129,1 (2 ꢃ CHarom.), 125.3 (CHarom.), 124.7
(CHarom.), 122.3 (CHarom.), 119.3 (CHarom.), 66.0 (CH2OSi), 63.7
(CH), 55.7 (NCH2), 28.7 (CHCH2CH2), 25.8 (C(CH3)3), 24.1
(NCH2CH2), 20.9 (p-ArCH3), 18.4 (o-ArCH3), 18.1 (C(CH3)3), -5.5
(Si(CH3)2), -5.6 (Si(CH3)2); HRMS (EI): M+, found 495.2914.
C28H41N3O3Si requires 495.2912.
4.2.16. (S)-(1-(2-(2-(3,5-Dimethylphenylamino) ethylamino)
phenyl)pyrrolidin-2-yl) methanol 10a
The title compound 10a was prepared from bisamide 9c (150 mg,
0.311 mmol) and LiAlH4 (82 mg, 2.2 mmol) in THF (6 mL) as described
above for 6b. Purification by flash chromatography (2% iPrOH/toluene)
yielded 10a (93 mg, 88%) as a slightly orange oil. Rf (2% iPrOH/toluene)
0.16; ½a 2D0
ꢂ
¼ þ10 (c 1.2, MeOH);
mmax (neat) 3353 (br), 2917 (br), 1597,
1506, 1264 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d 7.20–7.15 (1H, m,
H
arom.), 7.14–7.09 (1H, m, Harom.), 6.81–6.73 (2H, m, Harom.), 6.46
4.2.19. (S)-(1-(2-(2-(Mesitylamino)ethylamino)phenyl)
pyrrolidin-2-yl)methanol 12a
(1H, s, Harom.), 6.37 (2H, s, Harom.), 3.50–3.39 (7H, m, CH + NCH2
CH2N + CH2OH), 3.39–3.32 (1H, m, NCHaHbCH2), 2.91–2.83 (1H, m,
NCHaHbCH2), 2.31 (6H, s, ArCH3), 2.14–2.04 (1H, m, CHCHaHbCH2),
1.99–1.82 (3H, m, CH2CH2CH2 + CHCHaHbCH2); 13C NMR (100 MHz,
CDCl3) d 148.1 (Carom.), 145.0 (Carom.), 138.8 (2 ꢃ Carom.), 136.5 (Carom.),
125.6 (CHarom.), 122.3 (CHarom.), 119.6 (CHarom.), 117.4 (CHarom.), 110.9
(2 ꢃ CHarom.), 110.6 (CHarom.), 64.6 (CH2OH), 63.3 (CH), 54.6
(NCH2CH2), 43.1 (NCH2CH2N) 42.9 (NCH2CH2N), 27.3 (CHCH2CH2),
23.9 (CH2CH2CH2), 21.4 (ArCH3); HRMS (ESI): MH+, found 340.2375.
C21H30N3O requires 340.2383.
The title compound 12a was prepared from bisamide 11
(591 mg, 1.19 mmol) and LiAlH4 (337 mg, 8.89 mmol) in THF
(16 mL) as described above for 6a. No purification was required
to provide the desired diamine 12a (386 mg, 91%) as an orange
oil. ½a 2D0
ꢂ
¼ þ19:2 (c 1.0, MeOH); mmax (neat) 3354 (br), 2950–
2800 (br), 1506, 1037, 740 cmꢁ1
;
1H NMR (400 MHz, CDCl3) d
7.13 (1H, dd, J 7.8, 1.4 Hz, Harom.), 7.05 (1H, dt, J 7.5, 1.5 Hz, Harom.),
6.82 (2H, s, Harom.), 6.71 (1H, dt, J 7.6. 1.4 Hz, Harom.), 6.68 (1H, dd, J
8.0, 1.4 Hz,
Harom.), 5.37 (1H, br, NH), 3.47–3.27 (6H, m,
4.2.17. (S)-N1-(3,5-Dimethylphenyl)-N2-(2-(2-(methoxymethyl)
pyrrolidin-1-yl)phenyl)ethane-1,2-diamine 10b
Diamine alcohol 10a (93 mg, 0.27 mmol) dissolved in THF
(1 mL) was added to a solution of tBuOK (42 mg, 0.37 mmol) in
CH + CH2OH + NCHaHb + ArNHCH2), 3.22–3.16 (2H, m, MesNHCH2),
2.82 (1H, dt, J 9.3, 7.6 Hz, NCHaHbCH2), 2.26 (6H, s, o-ArCH3), 2.22
(3H, s, p-ArCH3), 2.10–1.98 (1H, m, CHCHaHbCH2), 1.94–1.84 (3H,
m, CHCHaHbCH2 + NCH2CH2); 13C NMR (100 MHz, CDCl3) d 145.6
(Carom.), 142.9 (Carom.), 136.4 (Carom.), 132.1 (Carom.), 130.4
(2 ꢃ Carom.), 129.5 (2 ꢃ CHarom.), 125.8 (CHarom.), 122.2 (CHarom.),
117.6 (CHarom.), 110.8 (CHarom.), 64.5 (CH), 63.3 (CH2OH), 54.8
(NCH2CH2), 47.8 (MesNHCH2), 44.7 (ArNHCH2), 27.1 (CHCH2CH2),
THF (1 mL) at 0 °C and stirred for 1 h. Next, MeI (46 mg, 20 lL,
0.32 mmol) was added and the reaction mixture was allowed to
warm to room temperature overnight. The reaction mixture was
poured into water (20 mL) and the aqueous layer was extracted