814
J. Lewkowski et al. / Tetrahedron 70 (2014) 810e816
portions with care to temperature not rise above 0 ꢁC. The system
was kept mixed on ice-salt bath for 30 min and then the bath was
removed. Reaction mixture was allowed to warm to ambient
temperature and mixed for further 30 min. If imine substrate was
still observed on the TLC plates additional portions of phosphite
were added. After disappearance of the substrate the mixture was
again cooled on ice-salt bath and the reaction was quenched by
slow addition of ice pieces. When no more hydrogen was releasing,
a thermometer, drying tube and gas inlet were removed and 20 ml
of water was added.
Layers were separated. Organic layer was two times extracted by
10% aqueous NaOH (2ꢂ15 mL). Pale-yellow or colourless water
layers were merged and washed two times with diethyl ether to
remove traces of unreacted phosphite. Then the aqueous solution
was neutralized up to pH 7 by slow addition of 15% hydrochloric
acid (excess of acid must be avoided!) and mixture became milky.
Then it was three times extracted with ethyl acetate, organic layer
dried and solvent evaporated in vacuo yielding crude amino-
phosphonate as light-yellow or colourless dense oil, which was
further purified by column chromatography on silica gel.
isomer: (0.94 g, 72%), eluent: hexane/ethyl acetate (2:1). Elem
anal. calcd for C32H52N2O8P2: C, 58.70; H, 8.01; N, 4.28. Found: C,
58.69; H, 8.10; N, 4.33. [
a
]
20 ꢀ50.8 (c 0.83, CH2Cl2). IR (KBr): 3422
D
(
nOH); 2979 (nCH); 1603, 1456 (CeCarom); 1224 (P]O); 1054
(CeO); 1037 (PeO), 993, 754 (CeHortho), 572. 1H NMR (CDCl3,
3
600 MHz):
H
d
10.59 (br s, OH, 2H); 7.17 (dd, JHH¼8.0 and 7.4 Hz,
3
ortho, 2H); 7.02e7.01 (m, Hortho, 2H); 6.84 (d, JHH¼8.0 Hz, Hortho
,
3
2H); 6.81 (dd, JHH¼7.3 and 7.4 Hz, Hortho, 2H); 4.61e4.53 (m,
2
PeOeCH, 4H); 3.92 (d, JPH¼22.4 Hz, CHP, 2H); 2.75 (br s, NH,
2H); 2.58 (m, CHeN, 2H); 1.79e1.77 (m, CH2, 2H); 1.47e1.45 (m,
3
3
CH2, 2H); 1.31 (d, JHH¼6.1 Hz, CH3, 6H); 1.30 (d, JHH¼6.1 Hz,
3
CH3, 6H); 1.24 (d, JHH¼6.1 Hz, CH3, 6H); 1.18e1.19 (m, CH2, 2H);
1.13e1.12 (m, CH2, 2H); 1.08 (d, JHH¼6.1 Hz, CH3, 6H). 13C NMR
3
3
(CDCl3, 150 MHz):
d
157.88 (CeOH); 130.58 (d, JCP¼6.6 Hz,
C
arom); 129.61 (Carom); 121.26 (Carom); 119.97, 118.67 (Carom);
72.94 (d, 2JCP¼7.6 Hz, OCH); 72.54 (d, 2JCP¼6.8 Hz, OCH); 60.55 (d,
1JCP¼151.4 Hz, CHeP); 30.28 (Chex); 24.62 (d, JCP¼3.0 Hz, Chex);
4
3
3
24.48 (d, JCP¼3.1 Hz, Chex); 24.11 (d, JCP¼5.5 Hz, POCHCH3);
23.84 (d, JCP¼5.3 Hz, POCHCH3); 23.42 (Chex). 31P NMR (CDCl3,
3
243 MHz):
d
21.98. ESI-MS: m/z¼702 [Mþ2Hþþ2Naþ]; 672
[Mþ2Naꢀ2CH3]þ.
4.3.1. Tetramethyl (R,R)-1,2-cyclohexylenediamino-di-(R,R)-[(2-
hydroxyphenyl)methylphosphonate] (2a). Predominant diastereo
isomer: (0.80 g, 74%), eluent: methanol/ethyl acetate (1:12). Elem
anal. calcd for C24H36N2O82P02: C, 53.14; H, 6.69; N, 5.16. Found: C,
4.3.4. Tetraethyl (R,R)-1,2-cyclohexylenediamino-di-(R,R)-[(2-
hydroxy-5-methoxyphenyl)methylphosphonate] (2d). Predominant
diastereoisomer: (1.05 g, 80%), eluent: diethyl ether. Elem anal.
52.93; H, 6.89; N, 5.42. [
a
]
ꢀ47.5 (c 0.91, CH2Cl2); IR (KBr): 3424
calcd for C30H48N2O10P2: C, 54.71; H, 7.35; N, 4.25. Found: C,
D
20
(
nOH); 2951 (nCH); 1601, 1451 (CeCarom); 1227 (P]O); 1054 (CeO);
54.89; H, 7.53; N, 4.45. [
a
]
ꢀ42.5 (c 1.045, CH2Cl2). IR (KBr):
D
1037 (PeO), 828, 755 (CeHortho), 569. 1H NMR (CDCl3, 600 MHz):
3412 (nOH); 2983 (nCH); 1617, 1499, 1449 (CeCarom); 1213 (P]O);
d
10.43 (br s, OH, 2H); 7.19e7.17 (m, Hortho, 2H); 7.09 (d, 3JHH¼7.6 Hz,
1026 (CeO); 969. 1H NMR (CDCl3, 600 MHz):
d
10.00 (br s, OH,
3
3
H
ortho, 2H); 6.88 (d, 3JHH¼8.1 Hz, Hortho, 2H); 6.84 (dd, 3JHH¼7.4 and
2H); 6.80 (d, JHH¼8.8 Hz, Harom, 2H); 6.74 (ddd, JHH¼8.8 Hz and
2
6
4
7.6 Hz, Hortho, 2H); 4.15 (d, JPH¼21.2 Hz, CHP, 2H); 3.76 (d,
4JHH¼2.1 Hz and JPH¼2.9 Hz, Harom, 2H); 6.64 (dd, JHH¼2.1 Hz
3JPH¼10.6 Hz, OCH3, 6H); 3.64 (d, JPH¼10.4 Hz, OCH3, 6H); 2.90
and JPH¼2.3 Hz, Harom, 2H); 4.14e4.02 (m, PeOeCH2, 6H); 3.96
3
4
(br s, NH, 2H); 2.46e2.44 (m, CHeN, 2H); 1.75e1.73 (m, CH2, 2H);
(d, 2JPH¼21.8 Hz, CHP, 2H); 3.95e3.90 (m, PeOeCH2, 2H); 3.75 (s,
OCH3, 6H); 2.87 (br s, NH, 2H); 2.46e2.45 (m, CHeN, 2H);
1.77e1.74 (m, CH2, 2H); 1.49e1.48 (m, CH2, 2H); 1.30 (t,
1.49e1.48 (m, CH2, 2H); 1.10e1.07 (m, CH2, 2H); 1.02e1.00 (m, CH2,
3
2H). 13C NMR (CDCl3, 150 MHz):
d
157.23 (d, JCP¼5.0 Hz, CeOH);
129.56 (d, 3JCP¼6.9 Hz, Carom); 120.91 (d, 2JCP¼3.5 Hz, Carom); 119.90,
118.11,118.09 (Carom); 63.10 (ChexeN); 58.77 (d, 1JCP¼152.3 Hz, CeP);
53.88 (d, 2JCP¼7.0 Hz, POC); 53.70 (d, 2JCP¼7.3 Hz, POC); 31.23 (Chex);
3JHH¼7.1 Hz, CH3, 6H); 1.22 (t, JHH¼7.1 Hz, CH3, 6H); 1.10e1.07
3
(m, CH2, 2H); 1.00e0.97 (m, CH2, 2H). 13C NMR (CDCl3, 150 MHz):
4
3
d
152.94 (d, JCP¼1.3 Hz, CaromeOCH3); 151.04 (d, JCP¼4.7 Hz,
24.14 (Chex). 31P NMR (CDCl3, 243 MHz):
d
26.35. ESI-MS: m/z¼592
CeOH); 122.12 (Carom); 119.21 (Ca2rom); 114.90 (Carom); 114.84 (d,
[Mþ4Hþþ2Naþ]; 569 [Mþ4HþþNaþ]; 560 [Mþ2Hþþ2Naꢀ2CH3]þ;
2JCP¼3.2 Hz, Carom); 63.77 (d, JCP¼7.2 Hz, POC); 63.31 (d,
546 [Mþ4Hþ]; 552 [Mþ].
2JCP¼7.2 Hz, POC); 59.96 (d, JCP¼151.2 Hz, CeP); 55.73 (OCH3);
1
2
31.08 (Chex); 23.98 (Chex); 16.52 (d, JCP¼5.2 Hz, POCC); 16.31 (d,
4.3.2. Tetraethyl (R,R)-1,2-cyclohexylenediamino-di-(R,R)-[(2-
hydroxyphenyl)methylphosphonate] (2b). Predominant diastereo
isomer: (1.14 g, 95%), eluent: hexane/ethyl acetate (4:1). Elem
2JCP¼5.3 Hz, POCC). 31P NMR (CDCl3, 243 MHz):
m/z¼674 [Mþ2Naꢀ2CH3]þ.
d 24.11. ESI-MS:
anal. calcd for C28H44N2O8P2: C, 56.18; H, 7.41; N, 4.68. Found: C,
4.3.5. Tetraisopropyl (R,R)-1,2-cyclohexylenediamino-di-(R,R)-[(2-
hydroxy-5-methoxyphenyl)-methylphosphonate] (2e). Predominant
diastereoisomer: (1.06 g, 74%), eluent: diethyl ether, mp
162e163 ꢁC. Elem anal. calcd for C34H56N2O10P2: C, 57.14; H, 7.90; N,
20
55.93; H, 7.64; N, 4.75. [
a
]
ꢀ57.4 (c 1.045, CH2Cl2). IR (KBr):
D
3385 (nOH); 2981 (nCH); 1601, 1457 (CeCarom); 1223 (P]O); 1054
(CeO); 1027 (PeO), 969, 754 (CeHortho). 1H NMR (CDCl3,
3
600 MHz):
d
10.51 (br s, OH, 2H); 7.18 (dd, JHH¼7.8 and 7.6 Hz,
3.92. Found: C, 57.26; H, 8.08; N, 4.13. [
a]
20 ꢀ34.0 (c 1.06, CH2Cl2). IR
D
3
3
H
H
ortho, 2H); 7.09 (d, JHH¼7.6 Hz, Hortho, 2H); 6.88 (d, JHH¼8.1 Hz,
(KBr): 3420 (nOH); 2979 (nCH); 1617, 1498, 1466 (CeCarom); 1209 (P]
ortho, 2H); 6.84e6.81 (m, Hortho, 2H); 4.11e4.01 (m, CHP, OCH2,
O); 1023 (CeO); 992, 584. 1H NMR (CDCl3, 600 MHz):
d 10.09 (br s,
8H); 3.94e3.90 (m, OCH2, 2H); 2.84 (br s, NH, 2H); 2.54e2.46 (m,
CHeN, 2H); 1.77e1.75 (m, CH2, 2H); 1.49e1.47 (m, CH2, 2H); 1.30
(t, J¼7.0 Hz, CH2CH3, 6H); 1.22 (t, J¼7.0 Hz, CH2CH3, 6H);
OH, 2H); 6.78 (d, 3JHH¼8.8 Hz, Harom, 2H); 6.75e6.72 (m, Harom, 2H);
6.64 (s, Harom
, 2H); 4.61e4.55 (m, PeOeCH, 4H); 3.87 (d,
2JPH¼22.7 Hz, CHP, 2H); 3.74 (s, OCH3, 6H); 2.80 (br s, NH, 2H); 2.52
(m, CHeN, 2H); 1.79e1.77 (m, CH2, 2H); 1.47e1.45 (m, CH2, 2H);
1.13e1.11 (m, CH2, 2H); 1.08e1.04 (m, CH2, 2H). 13C NMR (CDCl3,
3
3
150 MHz):
d
157.39 (d, JCP¼4.5 Hz, CeOH); 129.82 (Carom);
1.32 (d, 3JHH¼7.1 Hz, CH3, 6H); 1.30 (d, JHH¼6.4 Hz, CH3, 6H); 1.25
3
129.39 (Carom); 121.02, 119.79, 118.27 (Carom); 63.65 (d,
(d, JHH¼6.4 Hz, CH3, 6H); 1.13e1.12 (m, CH2, 2H); 1.10 (d,
2JCP¼7.0 Hz, POC); 63.32 (d, JCP¼7.1 Hz, POC); 61.88 (ChexeN);
3JHH¼6.4 Hz, CH3, 6H); 1.06e1.03 (m, CH2, 2H). 13C NMR (CDCl3,
2
59.51 (d, 1JCP¼154.0 Hz, CeP); 30.73 (Chex); 23.73 (Chex); 16.45 (d,
150 MHz):
d
152.76 (d, JCP¼0.9 Hz, CaromeOCH3); 151.15 (d,
4
2JCP¼5.2 Hz, POC); 16.26 (d, JCP¼5.2 Hz, POC). 31P NMR (CDCl3,
3JCP¼4.0 Hz, CeOH); 122.15 (Carom); 119.13 (Carom); 115.05 (d,
2
3
243 MHz):
d
24.02. ESI-MS: m/z¼646 [Mþ2Hþþ2Naþ]; 615
2JCP¼7.0 Hz, Carom); 114.83 (d, JCP¼2.8 Hz, Carom); 72.69 (d,
[Mþ2NaꢀCH2CH3]; 602 [Mþ4Hþ].
2JCP¼7.6 Hz, POC); 72.14 (d, JCP¼7.4 Hz, OCH); 60.45 (d,
2
1JCP¼153.6 Hz, CHeP); 55.74 (OCH3); 30.46 (Chex); 24.36 (d,
4JCP¼2.9 Hz, Chex); 24.48 (d, 3JCP¼3.0 Hz, Chex); 23.79 (d, 3JCP¼5.7 Hz,
POCHCH3); 23.53 (d, 2JCP¼5.7 Hz, POCHCH3); 23.46 (Chex). 31P NMR
4.3.3. Tetraisopropyl (R,R)-1,2-cyclohexylenediamino-di-(R,R)-[(2-
hydroxyphenyl)methylphosphonate] (2c). Predominant diastereo