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Y. Chu et al. / Tetrahedron 62 (2006) 5536–5548
(v/v¼1/1). The reaction tube was tightly capped and heated
at 65 ꢀC for 24 h with stirring. The reaction mixture was
cooled down to 0 ꢀC using an ice bath. Approximately half
of the solvent was removed by vacuum evaporation and
the solid was isolated by vacuum filtration. The filtrate was
treated with mixed ion exchange resin (AGÒ 501-X8 (D)
Resin, 20–50 mesh, BIO-RAD) to extract the remaining
KCN. The solid product was rinsed with dichloromethane
and dried in vacuo (2.21 g, 98%): 1H NMR (300 MHz,
DMSO-d6): d 10.55 (br s, 1H, (C]O)NH(C]O)), 8.44 (s,
1H, C]ONH–C), 3.86 (s, 4H, O(CH2)2O), 1.87–1.54 (m,
8H, central ring); 13C NMR (75.5 MHz, DMSO-d6):
d 178.2 (C40), 156.3 (C20), 106.8 (C1), 63.7 and 63.6 (OCH2-
CH2O), 61.0 (C4), 31.3 (C2 and C6), 29.8 (C3 and C5);
HRMS-CI calcd for C10H15N2O4 [M+H]+: 227.1032, found
227.1028.
DMSO-d6): d 8.86 (s, 1H, NH, 14), 8.78 (s, 1H, NH, 15),
7.32–7.10 (m, 8H, aromatic, 14 and 15), 4.51 (s, 2H,
CH2Ph, 14), 4.48 (s, 2H, CH2Ph, 15), 2.68 (br s, 2H, NH2,
14), 2.54 (br s, 2H, NH2, 15), 2.01–1.68 (m, 16H, central
ring, 14 and 15); 13C NMR (75.5 MHz, DMSO-d6):
d 176.1 (C10), 163.0 and 159.8 (d, C–F, J¼243 Hz), 155.4
(C30 of 14), 155.3 (C30 of 15), 133.0 and 132.9 (aromatic),
129.3 and 129.2 (aromatic of 14), 128.4 and 128.3 (aromatic
of 15), 125.2 (CN of 15), 124.0 (CN of 14), 115.9 and 115.2
(aromatic of 14, J¼21.0 Hz), 114.9 and 114.6 (aromatic of
15, J¼20.9 Hz), 62.1 (C1 of 15), 59.7 (C1 of 14), 50.2 (C4
of 14), 47.9 (C4 of 15), 40.3 (CH2Ph), 32.2 (C2 and C6 of
14), 31.0 (C2 and C6 of 15), 30.1 (C3 and C5 of 14), 27.8
(C3 and C5 of 15); HRMS-CI calcd for C16H18N4O2F
[M+H]+: 317.1414, found 317.1415.
4.1.12. trans-3-(4-Fluoro-benzyl)-1,3,9,11-tetraaza-dis-
piro[4.2.4.2]tetradecane-2,4,10,12-tetraone (16 and 17).
To a mixture of 14 and 15 (100 mg, 0.316 mmol) in 4 mL
of CH2Cl2 was added chlorosulfonyl isocyanate (48 mg,
0.34 mmol). After being stirred for 10 min at room temper-
ature, the clear solution was concentrated in vacuo into
a pale yellow form. Following addition of 3 mL of 1 N
HCl the suspension was stirred for 10 min at room tempera-
ture, then heated in an oil bath at 100 ꢀC for 1 h. After
approximately 15 min of heating, the reaction mixture
became homogeneous, and then a precipitate formed. The
reaction mixture was cooled to room temperature; the solid
was filtered, washed with water, and dried to give 0.08 g of
4.1.10. 3-(4-Fluoro-benzyl)-1,3-diaza-spiro[4.5]decane-
2,4,8-trione (13). Hydantoin 11 (1.13 g, 0.005 mol) was sus-
pended in 1.0 M NaOH solution (5 mL) and ethanol (5 mL)
and the mixture was heated at reflux for 15 min. To this
solution was added 4-fluorobenzyl bromide (0.59 mL,
0.0048 mol) dropwise through the top of a reflux condenser.
The mixture was heated at reflux for 24 h and allowed to cool
in ice bath. The resulting precipitate was washed with water
and recrystallized from ethanol to give pure product 12.
Compound 12 was then dissolved in 3 M HCl (10 mL) and
ethanol (10 mL). The clear solution was stirred at room tem-
perature for 16 h. The reaction was terminated by adding
3 M NaOH to adjust the pH of the solution to 7.5. CH2Cl2
(4ꢂ40 mL) was used to extract the product from the mixture.
The CH2Cl2 layer was dried (Na2SO4), followed by vacuum
evaporation to yield the crude product. Flash silica gel chro-
matography (1/19 CH3OH/CH2Cl2) gave the product 13
1
a mixture (70%) of 16 and 17 (7/3): H NMR (300 MHz,
DMSO-d6): d 10.63 (s, 1H, NH, 17), 10.60 (s, 1H, NH,
16), 8.98 (s, 1H, NH, 17), 8.66 (s, 1H, NH, 16), 8.61 (s,
1H, NH, 17), 8.25 (s, 1H, NH, 16), 7.28–7.24 (m, aromatic,
16 and 17), 7.17–7.13 (m, aromatic, 16 and 17), 4.50 (s, 2H,
CH2Ph, 17), 4.49 (s, 2H, CH2Ph, 16), 2.12–2.07 (m, 4H, cen-
tral ring, 16), 2.00–1.97 (m, 4H, central ring, 17), 1.70–1.60
(m, 8H, central ring, 16 and 17); 13C NMR (75.5 MHz,
DMSO-d6): d 178.0 (C10 of 16), 177.8 (C10 of 17), 176.1
(C100 of 16), 176.0 (C100 of 17), 161.0 (d, C–F, JCF¼239 Hz,
16 and 17), 156.4 (C30 of 16 and 17), 155.6 (C300 of 16),
155.5 (C300 of 17), 133.0 (aromatic, 16 and 17), 129.2 (d,
1
(1.14 g, 79%, Rf¼0.33 in 1/19 CH3OH/CH2Cl2): H NMR
(300 MHz, DMSO-d6): d 9.07 (s, 1H, NH), 7.31–7.26 (m,
2H, aromatic), 7.18–7.12 (m, 2H, aromatic), 4.54 (s, 2H,
CH2Ph), 2.55–2.48 (m, 2H, axial on C2 and C6), 2.38–
2.32 (m, 2H, equatorial on C2 and C6), 2.17–2.08 (m, 2H,
axial on C3 and C5), 1.95–1.89 (m, 2H, equatorial on C3
and C5); 13C NMR (75.5 MHz, DMSO-d6): d 208.0 (CO),
1
3
175.8 (C10), 161.0 (d, aromatic C–F, JCF¼242 Hz), 155.5
C–(C–C–F), JCF¼8 Hz, 16), 129.1 (d, C–(C–C–F),
2
(C30), 132.9 (aromatic), 129.3 (d, aromatic C–(C–C–F),
3JCF¼8.8 Hz), 115.3 (d, aromatic C–(C–F), 2JCF¼21.5 Hz),
59.8 (C4), 40.4 (CH2Ph), 36.3 (C2 and C6), 32.9 (C3 and
C5); HRMS-CI calcd for C15H16N2O3F [M+H]+:
291.1145, found 291.1141.
3JCF¼8 Hz, 17), 115.3 (d, C–(C–F), JCF¼21.9 Hz, 16 and
17), 60.8 (C1 of central ring of 17), 60.0 (C4 of central
ring of 17), 59.6 (C1 of central ring of 16), 58.9 (C4 of cen-
tral ring of 16), 40.2 (CH2Ph of 17), 40.1 (CH2Ph of 16), 29.1
(C2 and C6 of central ring of 16), 29.0 (C3 and C5 of central
ring of 16), 28.6 (C2 and C6 of central ring of 17), 28.5 (C3
and C5 of central ring of 17); HRMS-CI calcd for
C17H18N4O4F [M+H]+: 361.1312, found 361.1297.
4.1.11. 8-Amino-3-(4-fluoro-benzyl)-2,4-dioxo-1,3-diaza-
spiro[4.5]decane-8-carbonitriles (14 and 15). To a
100 mL round bottom flask were added 4-fluorobenzyl
hydantoin cyclohexanone 13 (0.6 g, 2.06 mmol), potassium
cyanide (0.28 g, 4.3 mmol), ammonium chloride (0.24 g,
4.4 mmol), ammonium hydroxide (15 mL), and ethanol
(30 mL). The flask was stirred at room temperature for
16 h. The clear reaction solution was then transferred to
a separatory funnel and extracted with CH2Cl2 (4ꢂ
50 mL). The aqueous layer was treated with mixed ion ex-
change resin (AGÒ 501-X8 (D) Resin, 20–50 mesh, BIO-
RAD) to absorb KCN. The organic layer was dried over
Na2SO4, followed by vacuum evaporation to give the desired
product (0.64 g, 98%, 14—77%, 15—23%, Rf (14)¼0.16, Rf
4.1.13. (4-Hydroxymethyl-cyclohexa-1,3-dienyl)-metha-
nol (19). Starting material 18 (1.8 g, 9.25 mmol) was dis-
solved in anhydrous THF (20 mL) at 0 ꢀC, which was then
subject to ultra-pure Ar flushing for 10 min. DIBAL-H
(37 mL) in THF (1.0 M, 37 mmol) was added to the above
solution slowly via a double-ended needle. The clear solu-
tion was stirred rigorously at 0 ꢀC for 30 min then quenched
with MeOH (3 mL), followed by adding powdered
Na2SO4$10H2O (25 g). The mixture was stirred at room
temperature for 1 h and then filtered through Celite, and the
filter cake was washed by copious EtOAc. The solution was
evaporated in vacuo yielding a light orange oil. The oil was
1
(15)¼0.22 in 1/19 CH3OH/CH2Cl2); H NMR (300 MHz,