1570 J . Org. Chem., Vol. 63, No. 5, 1998
Chapman et al.
improved difluoramination procedure described above, 8 mL
of fuming sulfuric acid (30% SO3) was added to 75 mL of CFCl3
in a jacketed flask at -10 °C. While HNF2 (6.66 g, 126 mmol)
was being absorbed by the solvents, the temperature was
gradually raised to 10 °C to liquefy the acid layer; upon
immediate recooling to -10 °C, the acid remained liquid.
Dione 4 (1.42 g, 3.15 mmol) was added gradually via powder
addition funnel; 10 mL of CFCl3 was used to wash the solid
out of the funnel. After 3 h at -10 °C, the reaction mixture
was quenched onto ice-water. The mixture was extracted
with CH2Cl2 (3 × 500 mL). Rotary evaporation produced 1.02
g of solid, which was chromatographed on silica gel (25 mm ×
35 cm) in ethanol-free HPLC-grade CHCl3, eluting successively
with CHCl3 (250 mL), 1:9 acetone-CHCl3 (250 mL), and then
2:8 acetone-CHCl3 (250 mL); the content of 6 can be conve-
niently monitored in effluent fractions by 19F NMR. Yield:
0.61 g (38%). Mp: 182-184 °C (dec). 1H NMR (200 MHz,
acetone-d6): δ 2.46 (s, 6 H), 2.68, 3.75 (AB q, 11.1 Hz, 4 H),
2.91, 3.84 (AB q, 11.1 Hz, 4 H), 6.80 (s, 1 H), 7.49 (d, 8.0 Hz,
4 H), 7.74 (d, 8.3 Hz, 4 H). 13C NMR (50 MHz, acetone-d6): δ
21.6, 46.3 (t, 15 Hz), 52.6, 95.18, 95.32 (t, 10.0 Hz), 128.9, 131.0,
133.3, 145.4. 19F NMR (188 MHz, acetone-d6): δ 20.71.
Octa h yd r o-1,5-bis(4-n itr oben zen esu lfon yl)-1,5-d ia zo-
cin e-3,7-d iol (7). 4-Nitrobenzenesulfonamide (25.17 g, 0.125
mol; Sigma-Aldrich-Fluka Bulk) and 12.5 mL of 10 M NaOH
were mixed in 171 mL of 95% EtOH + 12.5 mL of H2O. At
reflux temperature, the nosylamide salt dissolved. A solution
(45 mL) of epichlorohydrin (11.52 g, 0.125 mol) in 95% EtOH
was added in one portion. In this, our best-quantified run,
the mixture was held at reflux for 2 days, but we have also
observed that an overnight reaction is sufficient. The EtOH
solvent was removed by rotary evaporation. Additional H2O
(300 mL) was added to the reaction residue; this was boiled,
cooled to lukewarm, and decanted off to remove salt byprod-
ucts. The organic residue was vacuum-dried overnight, redis-
solved in a minimum volume of boiling acetone, and filtered.
Concentration by rotary evaporation precipitated a first crop
(6.91 g) of diol 7. The filtrate was taken to dryness by rotary
evaporation, and the residue was boiled with 350 mL of
absolute EtOH; upon cooling to lukewarm, the supernatant
EtOH solution was decanted off and discarded. The residue
was digested with 1:1 acetone-absolute EtOH, producing a
second crop (2.28 g) of 7 for a total yield of 9.19 g (29%) [mp:
272.5-275.5 °C (dec)]. The collective light yellow product is
usably pure but can be purified further by recrystallization
from acetone (for purest product) or by digestion with 1:1
acetone-EtOH (for higher recovery). 1H NMR (200 MHz,
DMSO-d6): δ 2.88 (m, ∼3 H, cis-7), 3.19 (m, ∼2 H, trans-7),
3.69 (dm, 14.8 Hz, ∼3 H, cis-7), 3.90 (bm, 2 H), 5.29 (d, 5.7
Hz, trans-7), 5.39 (d, 4.4 Hz, cis-7), 8.09 (dm, 8.8 Hz, 4 H),
8.46 (dm, 8.8 Hz, 4 H). cis-7 13C NMR (50 MHz, DMSO-d6):
δ 52.7, 66.8, 124.8, 128.6, 142.9, 149.9. trans-7 13C NMR (50
MHz, DMSO-d6): δ 57.5, 69.4, 124.9, 128.3, 143.5, 149.9. NMR
analysis showed a ratio of ∼68:32 for cis:trans isomers by
analogy to assignments reported for 3.9 Anal. Calcd for
in most organic solvents. 1H NMR (200 MHz, DMSO-d6, 110
°C): δ 4.28 (s, 8 H), 8.16 (d, 9.0 Hz, 4 H), 8.44 (d, 9.0 Hz, 4 H).
Anal. Calcd for C18H16N4O10S2‚1.46H2O: C, 40.12; H, 3.54; N,
10.40; S, 11.90. Found: C, 40.09; H, 3.12; N, 10.09; S, 12.01.
3,3,7,7-Tetr a k is(d iflu or a m in o)octa h yd r o-1,5-bis(4-n i-
tr oben zen esu lfon yl)-1,5-d ia zocin e (11). By the typical
difluoramination procedure described above, 22 mL of 30%
fuming sulfuric acid was added to 40 mL of CH2Cl2 cooled to
-15 °C in a jacketed flask. The system used a dry ice-cooled
Dewar condenser but no auxiliary addition funnel. Gaseous
HNF2 (0.20 mol) was absorbed into the CH2Cl2 layer. HNF2-
CH2Cl2 mixture refluxed from the dry ice condenser. Because
the oleum was initially frozen, the temperature was briefly
raised to 2 °C, which melted it; upon absorption of HNF2 and
recooling to -15 °C, it remained liquid. Solid dione 8 (3.458
g, 6.75 mmol) was added over ∼0.5 h and washed in with 15
mL of CH2Cl2. The mixture was stirred for 15 days; the
temperature gradually rose from -15 to -8 °C. The reaction
mixture was carefully poured into ice-water. The solution
was basified to pH 8 with saturated aqueous sodium carbonate.
Precipitated solids were filtered, dried, and Soxhlet-extracted
with CH2Cl2 for 6 days; 19F NMR analysis showed a 25:12:63
mole ratio of 9:10:11 among the CH2Cl2 extract. The Soxhlet
extraction solvent was changed to acetone; extraction for 1 day
yielded solute (1.28 g, 27%) which was 99% pure 11. 1H NMR
(200 MHz, DMSO-d6): δ 4.25 (s, 8 H), 8.25, 8.46 (AB q, J )
3
8.9 Hz, 8 H). 13C NMR (50 MHz, DMSO-d6): δ 48.4 (m, J CF
) 6.5 Hz), 96.1 (m), 125.0, 129.7, 141.4, 150.6. 19F NMR (188
MHz, DMSO-d6): δ 29.4. Anal. Calcd for C18H16F8N8O8S2: C,
31.40; H, 2.34; N, 16.28; F, 22.08; S, 9.31. Found: C, 31.94;
H, 2.48; N, 15.66; F, 22.30; S, 9.48.
Concentration (∼2×) of the CH2Cl2 extract yielded another
crop of solid (0.64 g); addition of an equal volume of CHCl3 to
the filtrate followed by concentration yielded another crop (0.27
g). the total yield of (difluoramino)diazocines was 3.27 mmol
(48%) in a 10:9:81 mole ratio of 9:10:11.
Mod ified (Atyp ica l) P r ep a r a tion of 3,3,7,7-Tetr a k is-
(diflu or am in o)octah ydr o-1,5-bis(4-n itr oben zen esu lfon yl)-
1,5-d ia zocin e (11). Dione 8 (13.22 g, 25.8 mmol) was added
to a mixture of ∼425 mL of fuming sulfuric acid (containing
8-10% SO3) plus 100 mL of CFCl3 in a 1-L jacketed flask, into
which was absorbed 13 g (0.25 mol) of HNF2 while a refriger-
ated circulator cooled the reaction vessel to ca. -15 °C. Over
the course of 48 h, organic solids separated out of this
suspension into a single solid mass. Warming the mixture to
∼0 °C over 6 h produced a more-fluid suspension, which was
recooled to ca. -15 °C over 6 h and then held there for 11 days.
Additional (100 mL) fuming sulfuric acid (1-3% SO3) was
added; the reaction was warmed to ∼0 °C over 6 h, cooled to
ca. -15 °C, and then held there overnight. A total of four more
cycles of warming to ∼0 °C over 6 h followed by cooling to ca.
-15 °C were conducted (a total of six cycles over six consecu-
tive days). The reaction mixture was warmed once more to
∼0 °C over 6 h and then quenched by pouring it into a mixture
of ice and saturated aqueous sodium carbonate. The quenched
solution was neutralized to pH 7 with additional solid Na2-
CO3. Upon warming, the CFCl3 evaporated. The precipitate
was filtered, washed with water, and dried to yield 10.52 g
(60%) of 11.
C
18H20N4S2O10: C, 41.86; H, 3.90; N, 10.85. Found (mean of
two): C, 41.68; H, 3.87; N, 10.70.
Tetr a h yd r o-1,5-bis(4-n itr oben zen esu lfon yl)-1,5-d ia zo-
cin e-3,7(2H,6H)-d ion e (8). Dinosyldiazocinediol 7 (4.08 g,
7.90 mmol) was dissolved in 42 mL of DMSO (Aldrich
anhydrous grade) + 9 mL of CH2Cl2. Swern reagent was made
from a solution of oxalyl chloride (3.85 g, 30.3 mmol) in 100
mL of CH2Cl2, cooled in a dry ice-acetone bath, to which was
added dropwise a solution of DMSO (3.26 g, 41.7 mmol) in 9
mL of CH2Cl2, washed in with 10 mL of CH2Cl2. The solution
of 7 was added dropwise. After 3 h with stirring, cooling being
maintained by a dry ice-acetone bath, triethylamine (7.99 g,
79.0 mmol) was added and washed in with 10 mL of CH2Cl2.
The mixture was left stirring overnight, warming adventi-
tiously to room temperature. Water (150 mL) was added to
the mixture, producing a sludge which was filtered by filter
paper, washed with water, and dried, to give a crude yield of
3.97 g (98%) of 8. The crude product was boiled in 150 mL of
acetone; the light-tan solid was filtered and oven-dried, for a
purified yield of 3.79 g (94%). Pure 8 has quite low solubility
Ack n ow led gm en t. The financial support of this
work by the Office of Naval Research and the Ballistic
Missile Defense Organization under ONR contract
N00014-93-C-0126 to TPL, Inc. and Work Order
N0001496WX20101 to NAWCWPNS, managed by Dr.
Richard S. Miller (ONR), is gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: 1H, 13C, and 19F
NMR spectra of compound 6 (2 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
J O9718399