4084 J . Org. Chem., Vol. 67, No. 12, 2002
Athey and Kiefer
ppm. X-ray crystallographic analysis information of 4 can be
found in Supporting Information.
advantages in overall yield, number of steps, and
efficiency.4-9 Each route has its appeal and is capable of
producing 1. However, with the coupling of dibromo-
ethane and bis-imidazoline (6), we have demonstrated
that 1 can be easily liberated from the resulting imida-
zolinium intermediate 7. The generation of 7 is proposed
to be an example of an intramolecular diaminocarbene
C-H insertion.
This process is well suited to both laboratory-scale and
plant production quantities of 1. On a lab scale, it is
straightforward to produce 50 g of final product in 2 days.
On a large production scale, this process is appealing
because of the rapid nature of each reaction and the low
volume of overall waste produced. We believe this process
represents the most predictable approach to cyclen (1)
with a minimum of procedural development.
Syn th esis of 4 via Hyd r ogen P er oxid e. The cyclized
intermediate 7 (1 g, 3.6 mmol) was dissolved in 10 mL of water.
A 10% H2O2 aqueous solution was added to the mixture. The
solution was heated to reflux. After 30 min, the heat source
was removed and the solution was dried in vacuo. No further
purification of the material was performed.
Cyclen (1). The cyclized intermediate (7, 113 g, 0.41 mol)
was dissolved in water to give a total volume of 450 mL and
added dropwise to a refluxing solution of 400 mL of caustic (8
equiv, 129 g, 3.3 mol). The caustic solution was heated for an
additional 30 min after the addition of 7. The aqueous caustic
solution was gravity filtered while hot. The filtrate was then
concentrated (in vacuo) until crystalline 1 was observed in the
solution. After the mixture had cooled to ambient temperature,
1 was filtered and the precipitation process was repeated until
no further crystallization occurred. The final aqueous filtrate
was dried in vacuo, and the remaining cyclen was removed
by extractions of the solid residue with hot toluene. The overall
yield of (1) was 88% (62 g, 0.36 mol): 1H NMR (CDCl3) δ 2.54
ppm; 13C NMR (CDCl3) δ 45.9 ppm; MS m/e 174 (M + 1), 173
(2), 128 (8), 104 (45), 85 (100), 56 (80).
Syn th esis of 3 (Deca h yd r o-2a ,4a ,6a ,8a -tetr a a za cyclo-
p en t[fg]a cen a p h th ylen e) fr om 7. The cyclized intermediate
(7, 1 g, 0.0036 mol) was dissolved in a 50:50 MeOH/EtOH
solution to give a final volume of 20 mL. NaBH4 was added in
small portions to the ethanolic solution. Excess NaBH4 was
added, and the solution was refluxed for 1 h. Water was added
to the reaction mixture, and the refluxing was continued for
an additional 1 h. The solution was dried in vacuo. No further
purification of the material was performed. The overall yield
was 90% (0.63 g, 0.0032): 13C NMR (D2O) δ 78.8 (CH), 53.0
(CH2), 52.0 (CH2) ppm; MS m/e 195 (M + 1), 194 (56), 152 (43),
124 (15), 83 (100), 56 (50).
Exp er im en ta l Section
Gen er a l. Reactions were run under nitrogen with stirring.
Materials: N,N-Dimethylformamide dimethyl acetal (94%),
1,2-dibromoethane, anhydrous potassium carbonate (325 type
mesh), tetrahydrofuran, acetonitrile, and triethyletetraamine
(TETA) were purchased commercially. Instrumentation: MS
data for 7 were collected using a flow injection MS/ESI. GC
analyses were performed on a gas chromatograph with a 50
× 33µ capillary column. The temperature program employed
was 60 °C for 5 min with an increase to 270 °C at 10 °C. The
samples were prepared for GC analysis by removing a small
portion of the solution and diluting with 2-3 mL of toluene.
The resulting binary solution was rinsed with 50% (w/w)
NaOH. NMR data were collected on a 250 MHz instrument.
Chemical shifts reported are internally referenced to tetra-
methylsilane.
1,1′-Eth ylen ed i-2-im id a zolin e (6). To a stirred solution
of linear TETA (100 g, 0.68 mol) was added N,N-dimethylfor-
mamide dimethyl acetal (173.37 g, 1.36 mol). The solution was
refluxed for 30 min. The reaction mixture was dried in vacuo.
The resulting off-white solid was recrystallized from THF. The
resulting white solid was filtered under a blanket of nitrogen
and isolated in 85% yield (96.3 g, 0.58 mol): mp 107-9 °C; 1H
NMR (CDCl3) δ 6.7 (s, 2H), 3.7 (t, 4H), 3.1-3.2 (overlapping
signals, 8H) ppm; 13C NMR (CDCl3) δ 157.2 (CH), 55.0 (CH2),
48.4 (CH2), 46.4 (CH2) ppm. MS m/e 167 (M + 1, 1), 166 (6),
83 (100), 56 (89).
2,3,4,5,6,7,8,8c-Oct a h yd r o-1H -4a ,6a ,8a -t r ia za -2a -a zo-
n ia cyclop en t[fg]a cen a p h th ylen e Br om id e Sa lt (7). A 5
L three-neck round-bottom flask equipped with an overhead
mechanical stirrer, a condenser, and a nitrogen inlet was
charged with in 2.4 L of acetonitrile, 6 (50 g, 0.30 mol), 1,2-
dibromoethane (78.9 g, 0.42 mol), and K2CO3 (31.2 g, 0.23 mol).
The mixture was heated to reflux while being stirred. After 3
h at reflux, the K2CO3 was filtered and the filtrate was dried
in vacuo. Typically, the salt was taken up in water without
purification and carried on to the hydrolysis step. However,
the pure salt form of 7 may be isolated by rinsing the crude
solid with a minimal amount of cold acetonitrile, followed by
filtration under nitrogen, which yielded a pale yellow solid
weighing 35.3 g (0.21 mmol) for a yield of 70%: mp 130 °C
dec; 1H NMR (D2O) δ 4.6 (s, 1H), 3.7-3.9 (m, 4H), 3.3-3.5 (m,
6H), 2.5-3.2 (m, 6H) ppm; 13C NMR (CDCl3) δ 162.0 (C), 72.7
(CH), 54.2 (CH2), 52.4 (CH2), 45.5 (CH2), 44.3 (CH2) ppm. Anal.
Calcd for C10H18N4Br: C, 43.96; H, 6.23; N, 20.5; Br, 29.3.
Found: C, 43.24; H, 6.38; N, 20; Br, 32.8.
Syn th esis of 3 fr om 4. The cyclized intermediate (4, 0.2
g, 1 mmol) was dissolved in 5 mL of EtOH. NaBH4 was added
in small portions to the ethanolic solution. The solution was
refluxed for 2 h. The solution was dried in vacuo. No further
purification of the material was performed. The yield of (3)
was quantitative: 13C NMR (D2O) δ 78.8 (CH), 53.0 (CH2), 52.0
(CH2) ppm; MS m/e 195 (M + 1), 194 (56), 152 (43), 124 (15),
83 (100), 56 (50).15
2,3,5,6,8,9-Hexa h yd r o-d iim id a zo[1,2-a :2′,1′-c]p yr a zin e-
1(10bH)-eth a n ol (15). Bis-imidazoline (6) (2 g, 12 mmol) and
ethylene carbonate (1.06 g, 12 mmol) were dissolved in 100
mL of anhydrous DMF. The resulting solution was heated to
140 °C for 5 h while under nitrogen. The solution was dried
in vacuo, leaving a yellow, golden-colored oil. The oil was taken
up in CH2Cl2 and then rinsed with 2 × 50 mL of 1 N HCl. The
pH of the aqueous layer was raised to 13.5-14 with the
addition of aqueous NaOH. The basic solution was rinsed with
CH2Cl2 (3 × 100 mL). The combined CH2Cl2 layers were dried
over Na2SO4. Removal of the solvent left 240 mg of colorless
oil. Crystal growth of 15 was accomplished by taking the oil
up in diethyl ether and allowing the solvent to slowly evapo-
rate: 1H NMR (CDCl3) δ 2.3-3.7 (m, 17H), 4.4 (s, 1H) ppm;
13C NMR (CDCl3) δ 43.19 (CH2), 45.59 (CH2), 48.83 (CH2),
51.31 (CH2), 52.37 (CH2), 54.01 (CH2), 59.64 (CH2), 61.1 (CH2),
75.55 (CH), 166.71 (C) ppm; MS m/e 211 (M + 1) (3), 210 (21),
180 (32), 138 (100), 124 (26), 97 (25), 83 (12), 56 (31). X-ray
crystallographic analysis information of 15 can be found in
Supporting Information.
1,4,7,10-Tetr a a za bicyclo[8.2.1]tr id eca n -13-on e (20). The
cyclized intermediate (6, 1 g, 5.2 mmol) was dissolved in 15
mL of water. The aqueous solution was added dropwise to a
solution of 50% NaOH (10 equiv, 2.04 g, 50 mmol). The solution
was stirred for 16 h at ambient temperature and then heated
to a reflux for 1 h. When the solution was cooled, 1 precipitated
and was filtered. The filtrate was extracted with chloroform
(4 × 20 mL). The resulting chloroform solution was dried over
K2CO3, filtered, and dried in vacuo: 1H NMR (CDCl3) δ 2.4
(br s, 2NH), 2.6 (m, 2H), 2.9 (m, 6H), 3.1 (m, 2H), 3.6 (m, 4H),
4.0 (m, 2H) ppm: 13C NMR (CDCl3) δ 42.0 (CH2), 44.9 (CH2),
45.8 (CH2), 49.6 (CH2), 165.9 (C) ppm; IR (CHCl3) 2998, 2932,
Syn th esis of Oxa m id in iu m 4 fr om 7. The procedure used
for the synthesis of 7 was followed with the exception that the
DMF solution was heated for 12-14 h at 100 °C (1.14 g, 6.8
mmol of 6; 1.8 g, 9.58 mmol of 1,2-dibromoethane; 0.71 g, 5.24
mmol of K2CO3). The cooled solution was dried in vacuo leaving
an amber-colored solid. No further purification of the material
1
was performed: mp 295 °C dec; H NMR (D2O) δ 4.3 (s), 4.0
(s) ppm; 13C NMR (D2O) δ 46.3 (CH2), 54.3 (CH2), 150.6 (C)