R. G. Sherrill / Tetrahedron Letters 48 (2007) 7053–7056
7055
and a two-step further elaboration to a differentially
protected 1,5-diazacyclooctane 11 has been disclosed.
These mono- and dibasic ring systems should allow
further investigations as novel pharmacophores in
medicinal chemistry applications which, prior to this
disclosure, were not readily accessible.
and evaporated in vacuo. Purification by flash chroma-
tography eluting with 40% ethyl acetate in hexane
provided the title compound as an oil (10.15 g, 86%).
1
H NMR (300 MHz, CDCl ) d 7.40 (m, 5H), 5.24 (m,
3
2H), 4.18 (m, 2H), 3.79 (m, 2H), 3.20 (m, 2H), 2.92
(m, 2H), 2.12 (m, 2H). APCI MS: (M+H) = 297.
Preparation of 1,1-dimethylethyl phenylmethyl 1,2-
pyrazolidinedicarboxylate (6): A suspension of sodium
hydride (60% dispersion in mineral oil, 3.75 g,
Preparation of tetrahydro-1H,5H-pyrazolo[1,2-a]pyr-
azol-1-one (9): A solution of phenylmethyl 2-(3-chloro-
propanoyl)-1-pyrazolidinecarboxylate (8, 10.1 g, 33.9
mmol) in absolute ethanol (200 mL) was combined with
10% Pd on carbon (10 wt %, 1.0 g) and hydrogenated
9
3.8 mmol) in anhydrous DMF (150 mL) was cooled
under nitrogen to 0–5 °C with an ice/water bath. 1,1-
Dimethylethyl phenylmethyl 1,2-hydrazinedicarboxy-
under a balloon of H gas. After stirring overnight, an
2
4
late (4, 12.5 g, 46.9 mmol) was added in portions and
additional 0.75 g of catalyst was added and the reaction
was maintained until the starting material was con-
sumed. The reaction mixture was filtered, evaporated
in vacuo, and dried under high vacuum to provide the
the mixture was stirred for 20 min. 1,3-Dibromopropane
(
4.75 mL, 46.9 mmol) was added via pipette and the
mixture was allowed to stir to ambient temperature
overnight. Glacial acetic acid (ꢀ0.5 mL) was added
and the solvent was removed in vacuo. The residue
was partitioned between diethyl ether and 50% saturated
aqueous brine. After separation of the layers, the aque-
ous phase was back-extracted with diethyl ether and the
combined organic layers were washed with brine, dried
1
compound as an HCl salt (5.34 g, 97%). H NMR
(300 MHz, CD OD at 50 °C) d 3.49–3.35 (m, 4H),
3
2.86 (m, 2H), 2.79 (t, J = 8.2 Hz, 2H), 2.36 (m, 2H).
ESI MS: (M+H) = 127.
Preparation of hexahydro-1,5-diazocin-2(1H)-one (3a):
A solution of tetrahydro-1H,5H-pyrazolo[1,2-a]pyra-
zol-1-one (9, 5.14 g, 31.6 mmol) in absolute ethanol
(25 mL) was combined with Raney Nickel (ꢀ4 g, wet
over anhydrous MgSO , filtered and evaporated in
4
vacuo to a viscous oil, which contained residual mineral
1
oil (15.37 g, 96% corrected for mineral oil). H NMR
(
300 MHz, CDCl ) d 7.44–7.34 (m, 5H), 5.24 (m, 2H),
weight). The mixture was reduced under 50 psi of H
3
2
3
.98 (br, 2H), 3.30 (m, 2H), 2.09 (m, 2H), 1.47 (s, 9H).
overnight. An additional 30 mL of solvent and catalyst
(ꢀ8 g) were added and the reaction was maintained
for an additional 24 h. Filtration and evaporation in
APCI MS: (M+H) = 307.
Preparation of phenylmethyl 1-pyrazolidinecarboxylate
7): 1,1-Dimethylethyl phenylmethyl 1,2-pyrazolidinedi-
vacuo provided the title compound as a white HCl salt
1
(
(4.98 g, 96%). H NMR (300 MHz, CD OD) d 3.44
3
carboxylate (5, 15.4 g, 45.3 mmol) was combined with
trifluoroacetic acid (25 mL) under nitrogen with vigor-
ous agitation at ambient temperature. After 10 min,
the reaction mixture was evaporated in vacuo and parti-
tioned between water and 1:1 ethyl acetate–hexane.
After separating the layers, the organic phase was
back-extracted with 1 N hydrochloric acid and the com-
bined aqueous phases were combined with dichloro-
methane and carefully brought to basic pH with 50%
aq NaOH. The layers were separated the aqueous phase
was back-extracted with dichloromethane. The com-
bined organic layers were dried over anhydrous Na SO ,
(app t, J = 6.0 Hz, 2H), 3.06 (m, 2H), 2.80 (app t,
J = 5.9 Hz, 2H), 2.54 (m, 2H), 1.72 (m, 2H). ESI MS:
(M+H) = 129.
Preparation of 5-(phenylmethyl)hexahydro-1,5-diazocin-
7
2(1H)-one (10): A mixture of hexahydro-1,5-diazocin-
2(1H)-one (3a, 4.84 g, 29.5 mmol), benzaldehyde
(3.0 mL, 29.5 mmol), diisoproylethylamine (5.14 mL,
29.5 mmol) in THF (300 mL) was treated with
Na(OAc) BH (9.38 g, 44.3 mmol) and allowed to stir
3
at ambient temperature under nitrogen for 16 h. The sol-
vent was removed in vacuo and the residue was parti-
tioned between dichloromethane and 5% aq K CO .
2
4
filtered, evaporated in vacuo and dried under high vac-
2
3
uum to provide the title compound as an oil (8.31 g,
The layers were separated and the aqueous phase was
back-extracted with dichloromethane. The combined
organic phases were dried over anhydrous Na SO ,
1
8
5
6
9%). H NMR (300 MHz, CDCl ) d 7.46–7.30 (m,
H), 5.23 (s, 2H), 3.56 (t, J = 7.5 Hz, 2H), 3.09 (t, J =
.6 Hz, 2H), 2.10 (m, 2H). APCI MS: (M+H) = 207.
3
2
4
filtered and evaporated in vacuo to provide the title
1
compound as
a
solid (5.66 g, 88%).
H NMR
Preparation of phenylmethyl 2-(3-chloropropanoyl)-1-
pyrazolidinecarboxylate (8): A solution of phenylmethyl
(400 MHz, CD OD) d 7.33 (m, 2H), 7.27 (m, 2H),
3
7.20 (m, 1H), 3.70 (s, 2H), 3.38 (app t, J = 5.7 Hz,
2H), 2.86 (m, 2H), 2.62 (app t, J = 5.6 Hz, 2H), 2.52
(m, 2H), 1.45 (m, 2H). ESI MS: (M+H) = 219.
1
-pyrazolidinecarboxylate (7, 8.24 g, 39.9 mmol) and
diisoproylethylamine (7.10 mL, 40.7 mmol) in dichloro-
methane (70 mL) was cooled under nitrogen to 0–5 °C
with an ice/water bath. 3-Chloropropionyl chloride
Preparation of 1-(phenylmethyl)octahydro-1,5-diazocine
7
(
3.89 mL, 40.74 mmol) in dichloromethane (30 mL)
(11): A solution of 5-(phenylmethyl)hexahydro-1,5-di-
was added dropwise over 45 min. The reaction was stir-
red for an additional 1 h and then quenched by addition
of 1 N hydrochloric acid. The phases were separated and
the aqueous layer was back-extracted with dichloro-
methane. The combined organic layers were washed
azocin-2(1H)-one (10, 6.33 g, 29.3 mmol) in anhydrous
tetrahydrofuran (125 mL) was treated with LiAlH4
(2.20 g, 58.0 mmol) and stirred at ambient temperature
under nitrogen for 16 h. The reaction mixture was
quenched by dropwise addition of 2.2 mL H O, then
2
with 1 N HCl, dried over anhydrous MgSO , filtered
2.2 mL of 3 N NaOH, and finally 6.6 mL of H O. The
4
2