U. Heinelt et al. / Tetrahedron 60 (2004) 9883–9888
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the aqueous layer was extracted three times with DCM
(10 mL). The combined organic layers were dried (MgSO4),
filtered, and evaporated to yield clonidine (104 mg, 60%) as
a white product.
1.00 min; MS (ESI) m/z 299.0 (100%, MCHC); H NMR
(CDCl3, 400 MHz): d 7.24 (d, 8.0 Hz, 2H), 6.82 (t, 8.0 Hz,
1H), 5.7 (bs, 1H), 4.11 (dd, 11.0, 4.5 Hz, 1H), 3.84 (t,
11.0 Hz, 1H), 3.01 (td, 10.5, 4.0 Hz, 1H), 1.61–1.86 (m,
5H), 1.20–1.41 (m, 3H), 0.89–1.06 (m, 1H); 13C NMR
(CDCl3, 100 MHz) d 150.6, 143.3, 129.7, 127.8, 122.5,
71.5, 54.7, 38.2, 31.9, 25.5, 25.0, 23.9; HRMS calcd for
C14H17Cl2N2O (MCHC): 299.0712, found: 299.0719.
4.2.2. (1H-Benzoimidazol-2-yl)-cyclohexyl-amine 4c.10
1-(2-Amino-phenyl)-3-cyclohexyl-thiourea 3c: after stirring
for 2 h at rt stirring was continued for 2 h at 50 8C. After
completion of the reaction the crude was purified by revers
phase HPLC. (1H-Benzoimidazol-2-yl)-cyclohexyl-amine
4c: (3c: 100 mg, 0.401 mmol) no additional ps-TsCl was
added to avoid product tosylation. After work up the desired
product was separated from the starting material by revers
phase HPLC. 26 mg white solid (31%) besides 16 mg (16%)
of starting material were obtained after lyophilisation.
4.2.7. (2,6-Dichloro-phenyl)-(octahydro-benzo[e][1,3]ox-
azin-2-ylidene)-amine 4h. (3h: 0.900 mmol, chromato-
graphy ethyl acetate/DCM 1/1). Yield: 137 mg (51%);
LCMS: rt 1.07 min; MS (ESI) m/z 299.4 (100%, MCHC);
1H NMR (CDCl3, 400 MHz): d 7.23 (d, 8.0 Hz, 2H), 6.80
(t, 8.0 Hz, 1H), 6.10 (sb, w1H), 3.85 (td, 10.5, 4.5 Hz, 1H),
3.31 (dd, 11.0, 5.5 Hz, 1H), 2.94 (t, 11.0 Hz, 1H), 1.95–2.09
(m, 1H), 1.63–1.88 (m, 4H), 1.18–1.44 (m, 3H), 0.94–1.11
(m, 1H); 13C NMR (CDCl3, 100 MHz) d 151.7, 143.4,
129.7, 127.8, 122.3, 79.1, 45.0, 36.6, 31.2, 28.4, 24.6, 23.9;
HRMS calcd for C14H17Cl2N2O (MCHC): 299.0712,
found: 299.0717.
4.2.3. Phenyl-thiazolidin-2-ylidene-amine ! HCl 4d.11
1-(2-Mercapto-ethyl)-3-phenyl-thiourea 3d: 1 equiv of
triethylamine was added to deprotonate cysteamine hydro-
chloride. The crude was treated with a mixture of ether/
DMF and the insoluble residue separated by filtration. After
removal of the ether in vaccuo the DMF solution was used
directly for purification by reverse phase HPLC. Phenyl-
thiazolidin-2-ylidene-amine!HCl 4d: (3d: 1,12 mmol,
reverse phase HPLC, lyophylisation in presence of HCl).
Yield: 76 mg, (32%).
4.2.8. (S)-(5-Methyl-oxazolidin-2-ylidene)-phenyl-amine
4i. (3i: 3.72 mmol, chromatography on reverse phase).
Yield: 417 mg (64%) of a white solid; LCMS: rt 0.71 min;
MS (ESI) m/z 177.1 (100%, MCHC); 1H NMR (DMSO-d6,
400 MHz): d 8.76 (bs, w1H), 7.46 (m, 1H), 7.20 (m, 1H),
6.86 (m, 1H), 4.66 (m, 1H), 3.83 (dd, JZ12.0, 8.5 Hz, 1H),
3.28 (dd, JZ12.0, 7.0 Hz, 1H), 1.30 (d, JZ6.5 Hz, 3H); 13C
NMR (DMSO-d6, 100 MHz) d 155.5, 141.6, 128,4, 120,7,
118.0, 74.1, 57.6, 20.4; HRMS calcd for C10H13N2O: (MC
HC) 177.1022, found: 177.1024.
4.2.4. Benzoxazol-2-yl-phenyl-amine 4e.12 (One-pot, poly-
mer-bound TsCl): preparation of benzoxazol-2-yl-phenyl-
amine 3e: 2-aminophenol 2e (202 mg, 1.85 mmol) was
dissolved in THF (2 mL) and phenyl isothiocyanate 1e
(250 mg, 1.85 mmol) dissolved in THF (2 mL) was added
with stirring. After standing overnight the reaction was
complete (LC UV/MS). Sodium hydroxide solution
(242 mg/6.05 mmol NaOH in 4.8 mL water) was added
followed by ps-bound TsCl (1.245 g, 1.92 mmol, loading:
1.54 mmol/g) suspended in THF (11 mL). The mixture was
stirred for 30 min. Since there was still starting material left
(LCMS) additional ps-bound TsCl (223 mg, 0.343 mmol)
was added to achieve complete conversion. Then the resin
was filtered off and washed twice with dichloromethane
(DCM). The combined organic layers were evaporated and
the residue dissolved in a mixture of water and DCM. The
layers were separated and the aqueous layer was extracted
three times with DCM. The combined organic layers were
dried (MgSO4), filtered and evaporated to yield 278 mg
(72%) of a white solid; LCMS: rt 1.42 min; MS (ESI) m/z
4.2.9. Oxazolidin-2-ylidene-pyridin-3-yl-amine 4j. (3j:
1.16 mmol, chromatography DCM/MeOH 100/0 to 80/20,
lyophilisation from water/acetonitrile). Yield: 99 mg (52%)
of an off-white solid; LCMS: rt 0.14 min; MS (ESI) m/z
164.1 (100%, MCHC); H NMR (CDCl3, 400 MHz): d
1
8.38 (d, 2.0 Hz, 1H), 8.21 (dd, 4.5, 1.5 Hz, 1H), 7.64 (bs,
1H), 7.18 (dd, 8.0, 4.5 Hz, 1H), 4.46 (t, 8.0 Hz, 2H), 3.76 (t,
8.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) d 157.6, 143.5,
143.3, 140.7, 128.2, 123.4, 67.8, 45.8; HRMS calcd for
C8H10N3O: (MCHC) 164.0818, found: 164.0822.
4.2.10. (4,4-Dimethyl-oxazolidin-2-ylidene)-pyridin-3-yl-
amine 4k. (3k: 1.10 mmol, chromatography DCM/MeOH
100/0 to 90/10, lyophilisation from water/acetonitrile).
Yield: 194 mg (92%) of a white solid; LCMS: rt 0.23 min;
1
211.1 (100%, MCHC); H NMR (CDCl3, 400 MHz): d
1
8.06 (bs, 1H), 7.61 (m, 2H), 7.49 (m, 1H), 7.32–7.44
(m, 3H), 7.24 (m, 1H), 7.08–7.17 (m, 2H); 13C NMR
(CDCl3, 100 MHz) d 158.3, 147.9, 142.2, 137.9, 129.4,
124.3, 123.4, 121.9, 118.5, 117.1, 109.1; HRMS calcd for
C13H11N2O (MCHC): 211.0866, found: 211.0867.
MS (ESI) m/z 192.1 (100%, MCHC); H NMR (CDCl3,
400 MHz): d 8.38 (bs, 1H), 8.20 (dd, 4.5, 1.5 Hz, 1H), 7.55
(bs, 1H), 7.17 (dd, 8.0, 4.5 Hz, 1H), 4.10 (s, 2H), 1.36 (s,
6H); 13C NMR (CDCl3, 100 MHz) d 156.2, 144.1, 141.5,
143.3, 128.9, 123.4, 78.9, 58.8, 27.5; HRMS calcd for
C10H14N3O (MCHC): 192.1131, found: 191.1135.
4.2.5. [1,3]Oxazinan-2-ylidene-phenyl-amine 4f.13 1-(3-
Hydroxy-propyl)-3-phenyl-thiourea 3f: The crude was
purified by reverse phase HPLC. [1,3]Oxazinan-2-ylidene-
phenyl-amine 4f: (3f: 0.238 mmol, chromatography on silica
gel (DCM/MeOH 50/1 to 0/100). Yield: 27.4 mg (64%).
4.2.11. (3-Methyl-oxazolidin-2-ylidene)-phenyl-amine 6,
(3-methyl-thiazolidin-2-ylidene)-phenyl-amine 7, and
1-methyl-3-phenyl-imidazolidine-2-thione 8. MS and H
1
NMR data were in accordance with the literature.6,15
4.2.6. (2,6-Dichloro-phenyl)-(octahydro-benzo[d][1,3]ox-
azin-2-ylidene)-amine 4g. (3g: 0.900 mmol, no chroma-
tography). Yield: 261 mg (97%) of a white solid; LCMS: rt
4.2.12. Cyclohexyl-thiazolidin-2-ylidene-amine hydro-
chloride 10 and cyclohexyl-oxazolidin-2-ylidene-amine
11. Compound 10 was isolated as its hydrochloride salt. 1H