An improved preparation of 2-azabicyclo[2.2.2]octane

Article abstract of DOI:10.1081/SCC-120004848

An improved preparative four-step synthesis to isoquinuclidine tosylate salt 4 has been demonstrated in 70% overall yield from p-aminobenzoic acid (PABA) 1. Hydrogenation of PABA 1 affords 4-aminocyclohexane carboxylic acid 2 as an 80 : 20 mixture of cis- and trans-isomers. Heating the mixture at 250°C effected epimerization and cyclization to provide the bicyclic lactam 3. Subsequent Red-A1 reduction and treatment with tosic acid furnished the desired bicyclic amine, tosylate salt 4.

Full text of DOI:10.1081/SCC-120004848

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AN IMPROVED PREPARATION OF 2-
AZABICYCLO[2.2.2]OCTANE
a
a
John Y. L. Chung & Guo-Jie Ho
a
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, R800-C369,
Rahway, NJ, 07065, U.S.A.
Version of record first published: 16 Aug 2006.
To cite this article: John Y. L. Chung & Guo-Jie Ho (2002): AN IMPROVED PREPARATION OF 2-AZABICYCLO[2.2.2]OCTANE,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 32:13,
1985-1995
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SYNTHETIC COMMUNICATIONS, 32(13), 1985–1995 (2002)
AN IMPROVED PREPARATION OF
2
-AZABICYCLO[2.2.2]OCTANE
John Y. L. Chung* and Guo-Jie Ho
Department of Process Research,
Merck Research Laboratories, P.O. Box 2000,
R800-C369, Rahway, NJ 07065, USA
ABSTRACT
An improved preparative four-step synthesis to isoquinuclid-
ine tosylate salt 4 has been demonstrated in 70% overall yield
from p-aminobenzoic acid (PABA) 1. Hydrogenation of
PABA 1 affords 4-aminocyclohexane carboxylic acid 2 as an
8
0 : 20 mixture of cis- and trans-isomers. Heating the mixture
ꢀ
at 250 C effected epimerization and cyclization to provide the
bicyclic lactam 3. Subsequent Red-Al reduction and treatment
with tosic acid furnished the desired bicyclic amine, tosylate
salt 4.
Key Words: Bicyclic aza compounds; Hydrogenation; Lacta-
misation; Reduction
Recently, we had need of multi-kilogram quantities of 2-azabi-
A
cyclo[2.2.2]octane.
literature survey revealed very few proce-
dures suitable for large scale preparation of this deceptively simple
compound, most resulting in low yields. Imino Diels-Alder approaches,
*
Corresponding author. E-mail: john_chung@merck.com
985
1
Copyright & 2002 by Marcel Dekker, Inc.
www.dekker.com

1
986
CHUNG AND HO
[
1]
such as Grieco’s aqueous method
(
employing 1,3-cyclohexadiene
[
2]
CHD)/benzylamine/formaldehyde, and Cava’s approach
employing
CHD and CH ¼NCO Et are low yielding (30–35%) and require
2
2
chromatographic purification. Addition of water-soluble lanthanide Lewis
[3]
acids did not improve the yield in our hands. Malpass’s Diels-Alder type
reaction
[4]
between CHD and chlorosulfonylisocyanate followed by
de-chlorosulfonylation was also a low yielding sequence (ꢁ10%) in our
[
5]
hands. Similarly, Diels-Alder reactions of dihydropyridine
gave
[
6]
low yields (ꢁ40%). The approach via an intramolecular cyclization of
cis-4-aminocyclohexanecarboxylic acid (ACHA) is attractive, but lacks
an efficient method to prepare pure cis-ACHA, since hydrogenation of
p-aminobenzoic acid gave a mixture of cis- and trans-ACHA. However,
[
7]
an Org. Syn. preparation of bicyclic lactam 3 from a mixture of
ꢀ
cis- and trans-ACHA via
a
high temperature (250 C) induced
epimerization-cyclization protocol, avoids the need for separating the
cis- and trans-isomers. Although there is one known method that
avoids the high temperature reaction, it suffers from having two additional
[8]
steps.
We therefore focused on this high temperature route based on its
simplicity, and addressed several issues before this route could be useful
[
7]
for large scale preparation: 1) the hydrogenation conditions for the pre-
paration of ACHA, 2, require long reaction time and is difficult to
reproduce; 2) the bicyclic lactam 3 is obtained by concentrating the aqueous
solution; 3) the reduction of lactam 3 to amine 4 is generally carried out
[
9]
using highly hazardous lithium aluminum hydride, which is not safe for
large scale preparation; and finally, 4) the development of a suitable salt
form of the amine, possessing well-behaved physical properties and provid-
ing good impurity rejection, is preferred. Here we report that we have
addressed these issues and developed an improved preparative procedure
to the title compound as the tosylate salt and have successfully demon-
strated the procedure on multi-kilogram scale. The synthetic route to 4 is
depicted in Scheme 1.

PREPARATION OF 2-AZABICYCLO[2.2.2]OCTANE
1987
Scheme 1.
Step 1—Hydrogenation
Hydrogenation conditions for the conversion of PABA 1 to ACHA 2
were investigated, and 5% Rh/Al O was found to be an excellent hydro-
2
3
[
10]
genation catalyst in terms of reactivity. As in Windhorst et al’s procedure
the solvent is 30% ethanol in water plus 3% AcOH, which provides solu-
bility for both the starting material and the product. Hydrogenation of
ꢀ
PABA 1 at 700 psi and 65 C for 2 h afforded ACHA 2 in 90–95% yield as
a mixture of 80 : 20 cis- and trans-isomers (Table 1). The hydrogenation
ꢀ
could also be carried out at 40 psi/65 C with 5 wt% catalyst, but it required
24 h to reach completion. The rate of reaction was also significantly slower
ꢀ
in the absence of acetic acid. For scale up, we chose to run at 300 psi/65 C
with 10 wt% catalyst for speed and reliability. Under these conditions the
reaction consistently gave >99.7% completion within 2 h on 1.5 kg scale in
ꢀ
5
-gal. vessels. Hydrogenation with PtO (10 wt%) at 50 psi/22 C in water for
2
15 h also afforded the product in 90–95% yield, but the ratio of cis- and
trans-isomers is 60 : 40.
Table 1. Hydrogenation of 4-Aminobenzoic Acid to 4-Aminocyclohexane-
carboxylic Acid
Yield* of 2
(cis : trans)
Entry
1
Catalyst
Solvent(s)
Hydrogenation Time
ꢀ
5% Rh/Al O 30% EtOH/H O 700 psi, 65 C
2
2 h 90–95% (80 : 20)
2
3
(
10% wt)
’’
þ 3% AcOH
ꢀ
ꢀ
2
’’
100 psi, 65
300 psi, 65 C 2–5 h 90–95% (80 : 20)
3
4
5
6
7
’’
’’
C
40 psi, 65 C
5 h 90–95% (83: 17)
15 h 90–95% (82 : 18)
24 h 90–95% (80 : 20)
24 h 25% (84 : 16)
15 h 90–95% (60 : 40)
ꢀ
ꢀ
’’
’’
^
^
’’(5 wt%)
’’(3wt%)
PtO (10 wt%)
’’
’’(no AcOH)
100 psi, 65 C
100 psi, 65 C
ꢀ
ꢀ
H O
2
50 psi, 22 C
2
*
^
Uncorrected isolated yield, starting from 10–40 g of 4-aminobenzoic acid.
2
00 g scale.

1
988
CHUNG AND HO
After removal of catalyst from the reaction mixture, the filtrate is
concentrated and ACHA 2 is precipitated from acetone/water as a 80 : 20
mixture of cis- and trans-isomers in 90–95% yield with ꢁ5% loss to the
mother liquor. The purity of the solid is 90–95 wt%.
Step 2—Epimerization–Cyclization
Conversion ACHA 2 to isoquinuclidone 3 is accomplished by heating
ꢀ
Õ
a slurry of the substrate in Dowtherm A at 250–260 C for 20–30 min with
[
7]
simultaneous removal of water. The product is directly crystallized out of
the reaction mixture by heptane (5 Â vol) addition, thereby avoiding the
water extractions and concentration as described in the original Org. Syn.
[7]
preparation. Initially, the reaction was carried out at a concentration of 5–
6
mL/g, followed by dilution with heptane (5 Â vol) to provide a slurry of
product for filtration/isolation. Under this protocol, the typical isolated
yield is 80–85% with loss to mother liquor at 6–10% due to high solubility
Õ
of the lactam in Dowtherm A. In order to minimize product loss to mother
ꢀ
liquor, the reaction mixture was concentrated (170 C/24 in) to half original
volume before heptane dilution. Unfortunately, lactam 3 co-distilled with
Õ
Dowtherm A during the concentration resulting in 26% loss to the distillate
and an isolated yield is only 66%. Fortunately, the distillate could be
recycled in the subsequent run without any problem. Finally, by conducting
Õ
the lactamization at a concentration of 3mL Dowtherm A per gram of
substrate with a Dean–Stark trap, the reaction afforded the bicyclic
lactam in 89% isolated yield with 91 wt% purity containing 9 wt%
Õ
Dowtherm A with 4% product loss to mother liquor. The reaction is air
sensitive and should be kept under nitrogen at all time to prevent the reac-
tion from turning into a dark brown mixture. This high temperature-
induced-epimerization results in the same yield whether starting from an
80 : 20 or a 60 : 40 mixture of cis/trans-ACHA.
Steps 3 and 4—Red-Al Reduction and Tosylate Formation
BH reduction of the bicyclic lactam 3 was met with difficulty in break-
3
ing the amine borane complex, even with refluxing 0.5 M aqueous sulfuric
acid. We therefore investigated the thermally stable bis-(2-methoxyethox-
Õ
Õ [11–14]
y)aluminum hydride (Red-Al or Vitride ).
lactam to the bicyclic amine was carried out with 2.5 eq of Red-Al (3.4 M in
. Reduction of the bicyclic
ꢀ
toluene, KF <500 mg/mL) at 80 C. The reaction is quenched with 1.4 M
NaOH solution (1.02 eq relative to Red-Al ) to furnish a slightly cloudy
Õ

PREPARATION OF 2-AZABICYCLO[2.2.2]OCTANE
1989
organic phase and a heterogeneous aqueous phase. The aqueous phase was
extracted with toluene, which gave an emulsion, but most of the aqueous
Õ
phase could be separated. Celite was added to the mixture and filtered to
remove the gummy aluminum salts. The filtrate now separated into two
clear layers. After drying the organic phase with sodium sulfate, the free
base solution is used directly in the tosylate salt formation without concen-
tration because of the volatility of the product. The concentration of the
product in each of the three organic extracts were: ꢁ90 g/L, ꢁ19 g/L and
ꢁ
3g/L, which translates to about 84%, 12% and 3% of product recovered
Õ
respectively. It is noteworthy to mention that the Celite treatment not only
made the cuts easier, but also removed some colored impurities and mini-
mized product loss to the mother liquor.
The average assay yield of the bicyclic amine in toluene for the three
7 mol batches was 95% as determined by titration. Treatment of the sol-
2
ution with one equivalent of toluenesulfonic acid monohydrate, followed by
azeotropic removal of water afforded the crystalline tosylate salt. A total of
20.5 kg of the material was isolated with an average wt% purity of 90.6%.
The corrected yield for the salt formation is 85% and the overall yield for
the two steps was 80%.
Further Optimization
In theory, the reduction of the bicyclic lactam requires only three
Õ
hydrides. The above preparation used 2.5 mole of Red-Al per mole of 3,
which corresponds to five hydride equivalents. The employment of excess
hydride is not only unnecessary but also unsafe due to large hydrogen
release during quenching of these reactions as observed in the multi-kilo-
Õ
gram runs. Therefore employment of ꢂ2 mole of Red-Al per mole of 3 or 4
hydride equivalent was investigated. Laboratory scale reaction using 36 g of
the lactam and 1.84 eq of Red-Al (3.7 hydride equivalents) gave an excel-
Õ
lent yield of 96.6% of the amine. The subsequent tosylate salt formation
step was also improved to 92.8% yield by reducing the crystallization
volume. These changes are detailed in the experimental section.
In summary, an improved procedure to provide preparative quantities
of bicyclic amine isoquinuclidine has been successfully demonstrated. The
described procedures have been used for the preparation of 20 þ kg
(
66 mol) of the bicyclic amine as the tosylate salt in 62% overall yield from
p-aminobenzoic acid (PABA, 1). The four-step synthesis begins with the
hydrogenation of PABA using Rh/Al O to furnish a 92% yield of
2
3
4-aminocyclohexane carboxylic acid, 2, as an 80 : 20 cis and trans mixture.
Subsequent heating at 250 C in Dowtherm A to effect epimerization and
ꢀ
Õ

1
990
CHUNG AND HO
cyclization afforded the bicyclic lactam 3 in 84% yield. Red-Al reduction
furnished the desired 2-azabicyclo[2.2.2]octane in 95% yield, which was con-
verted to the tosylate salt 4 in 85% yield. The employment of a more con-
Õ
Õ
centrated Dowtherm mixture and reduced amounts of Red-Al led to yield
improvements for the cyclization step from 84 to 89% and the
tosylate salt step from 85 to 91%. These improvements raised the overall
yield of the bicyclic amine to as high as 70%.
EXPERIMENTAL
General
All reactions were conducted under an atmosphere of dry N . As
2
˚
necessary, most of the solvents and reagents were dried over 3or 4 A mole-
cular sieves and residual water was determined by Karl Fisher titration.
1
13
Melting points were uncorrected. H and C NMR spectra were collected
at 500 and 125 MHz, respectively, from samples in the specified deuterated
solvent. Assay yields of products were determined by HPLC analysis
Õ
using the corresponding pure products as standards. Dowtherm A was
purchased from Fluka.
Cis- and Trans-4-Aminocyclohexanecarboxylic Acid (2): Prior to the
actual run, a conditioning run in the 5-gallon vessel is carried out using
2
5 g of the catalyst with 10 L of 30% EtOH/H O, and 300 mL acetic acid
2
ꢀ
at 300 psi hydrogen and 65 C for 3h. A general procedure is as follows:
A mixture of 4-aminobenzoic acid (PABA, 1) (1500 g, 10.9 mol), 30%
EtOH/H O (15 L), acetic acid (450 mL) and 5% Rh/Al O (150 g) is hydro-
2
2
4
ꢀ
genated at 300 psi and 65 C. When 3eq of hydrogen has been absorbed
1
(
in D O), the mixture is cooled to 20 C and transferred to a storage bottle.
ꢂ2 h, <0.3% starting material relative to product by H NMR analysis
ꢀ
2
The vessel is rinsed with 30% EtOH/H O (7.5 L). The mixture and the
2
Õ
rinse are filtered through Celite 545 (Aldrich; 1–2 inch pad; wet-packed
with H O), then washed with H O (3.75 L). The filtrate is concentrated
2
2
ꢀ
under reduced pressure at 30–60 C to ꢁ3.75 L. The mixture is diluted
ꢀ
with acetone (33.75 L) and aged at 20 C for 2–15 h. The resulting slurry is
filtered, washed with acetone (5.63L) and vacuum dried under a nitrogen
sweep to give 1.6 kg (91 wt%, 91% yield) of 4-aminocyclohexanecarboxylic
acid, 2, as a 80 : 20 cis- and trans-isomer mixture based on NMR. The wt%
of the material is determined based on HClO titration, thermogravimetric
4
and Karl Fisher measurements.
In one preparative campaign, 14.85 kg of PABA 1 were hydrogenated
in 11 batches using 5-gallon autoclaves (stainless steel and Hasteloy).

PREPARATION OF 2-AZABICYCLO[2.2.2]OCTANE
1991
Isolation was performed in four batches with a total of 15.66 kg of crystal-
line solid isolated. The material had an average wt% purity of 91.1%, which
was 14.27 kg of pure product. The overall yield for the step was 92%. 2: m.p.
ꢀ
1
2
34–236 C; H NMR (D O) d 3.32 (m, cis NH –CH), 3.17 (m, trans NH –
2
2
2
CH), 2.42 (m, cis CO H–CH), 2.14 (m, trans CO H–CH), 2.09 (m, trans
H3,5 eq), 1.90–2.00 (m, H2,6 eq), 1.87 (m, cis H3,5 eq), 1.56–1.70 (m, H2,6
2
2
1
3
ax, cis H3,5 ax), 1.43 (m, trans H3,5 ax); C NMR (D O) d 185.5 (trans
2
CO H), 184.3( cis CO H), 50.7 (trans C4), 49.9 (cis C4), 46.0 (trans C1), 42.2
(cis C1), 30.5 (trans C3,5), 28.5 (trans C2,6), 28.1 (cis C3,5), 25.7 (cis C2,6).
2
2
Anal. Calcd for C H NO Á 0:5 H O: C, 55.24; H, 9.27; N, 9.20. Found: C,
7
13
2
2
55.09; H, 9.21; N, 8.81.
3-Isoquinuclidinone (3). Method A: In a 72-L round bottomed flask
equipped with a mechanical stir, and a distillation apparatus, a mixture of
cis- and trans-4-aminocyclohexanecarboxylic acid 2 (3.83 kg, 92.6 wt%,
Õ
2
4.8 mol) and Dowtherm A (23.5 L) is heated as a slurry to reflux tempera-
ꢀ
ture (250–260 C) under a slight nitrogen sweep using two 220-volt heating
mantles. Heating is continued for 30 min during which time water formed is
Õ
allowed to distill away (ꢁ3–4 L of Dowtherm A and water is collected). A
homogeneous solution is formed by the end of the reaction. The solution is
allowed to cool to 22 C. The mixture is concentrated under reduced pressure
ꢀ
ꢀ
(
b.p. 165–175 C/25–27 Hg in) to about half volume (ꢁ12 L). The mixture is
ꢀ
cooled to 20 C and then diluted with heptane (55 L). After aging at À5 to
ꢀ
0
C for 1–2 h, the mixture is filtered and washed with cold heptane
ꢀ
(3 Â 6.3L). The wet cake is dried under vacuum/nitrogen sweep at 20 C,
yielding 2.55 kg of 3-isoquinuclidone 3 as a beige solid. The product is
8
Õ
0 wt% pure along with ꢁ19 wt% Dowtherm A based on LC assay. This
corresponds to a yield of 2.05 kg (66%) pure. Product loss to the mother
liquor is ꢁ150 g (5%). About 800 g (26%) of product is lost to the distillate
(
14.4 L), which is recycled the subsequent runs as follows.
The distillate (ꢁ800 g lactam/14.4 L) is combined with 24.8 mol of
a mixture of cis- and trans-4-aminocyclohexanecarboxylic acid 2 and
Õ
ꢀ
Dowtherm A (10 L) and heated to reflux temperature (250–260 C)
under a slight nitrogen sweep as before and processed as described
above to provide 3.38 kg of 3-isoquinuclidone 3 as a light beige solid.
Õ
The product is 76.4 wt% along with ꢁ20 wt% Dowtherm A based on
LC assay. This gives a yield of 2.58 kg (83%) pure. Product loss to the
mother liquor is ꢁ100 g (3%). About 920 g (30%) of product is lost to the
distillate (17.7 L).
The distillate (ꢁ920 g lactam/17.7 L) is again combined with 24.8 mol
of a mixture of cis- and trans-4-aminocyclohexanecarboxylic acid and
Dowtherm A (7 L) and processed as before to provide 3.06 kg of 3-isoqui-
nuclidone 3 as an off-white solid. The product is 87.6 wt% along with
Õ

1
992
CHUNG AND HO
ꢁ
15 wt% DowthermÕ A based on LC assay. This gives a yield of 2.68 kg
86%) pure. Product loss to the mother liquor is ꢁ120 g (4%). About 1 kg
(
(
32%) of product is loss to the distillate (18.1 L).
Again, the distillate (ꢁ1 kg lactam/18.1 L) is combined with 24.8 mol
of a mixture of cis- and trans-4-aminocyclohexanecarboxylic acid 2, but no
Õ
additional Dowtherm A is added and processed the same way as before but
without concentration to provide 4.1 kg of 3-isoquinuclidone 3 as a white
Õ
solid. The product is 78 wt% along with ꢁ15 wt% Dowtherm A based on
LC assay. This gives a yield of 3.2 kg (103%) pure. Product loss to the
mother liquor is ꢁ200 g (6%). About 7 g (0.2%) of product is lost to the
distillate (2 L).
All four batches of product (ꢁ10.5 kg pure) from above are combined
ꢀ
and stirred in heptane (50 L) at þ50 C for 10 min under nitrogen. After
ꢀ
ꢀ
cooling to 20 C, and aging at À5 to 0 C for 1–2 h, it is filtered and
washed with cold heptane (3 Â 9 L). The wet cake is dried under vacuum/ni-
ꢀ
trogen at 22 C, to afford 12.3kg of 3-isoquinuclidone 3 as a light tan solid.
The product is 84 wt% pure and contains ꢁ15 wt% Dowtherm A based on
Õ
LC assay. This give a yield of 10.33 kg (98%) pure. Product loss to the
mother liquor is ꢁ12 g (0.1%).
Method B: In a round bottom flask equipped with a mechanical stirrer,
and a Dean–Stark trap, a mixture of cis- and trans-4-aminocyclohexanecar-
Õ
boxylic acid 2 (50 g, 94.8 wt%, 0.331 mol), and Dowtherm A (142 mL) is
ꢀ
heated to reflux temperature (250–260 C) under a slight nitrogen sweep.
Heating is continued for 30 min during which time a total of ꢁ15 mL of a
Õ
water/Dowtherm A mixture is collected. The mixture becomes a homoge-
ꢀ
neous solution at the end of reaction. The solution is allowed to cool to 20 C
ꢀ
and then diluted with heptane (635 mL). After stirring at À5 to 0 C for
1
–2 h, it is filtered and washed with cold heptane (2 Â 100 mL). The wet
ꢀ
cake is dried under vacuum/nitrogen sweep at 22 C overnight, yielding
40.7 g of 3-isoquinuclidone 3 as an off-white solid. The product is 91 wt%
Õ
containing 9 wt% Dowtherm A based on LC assay. This corresponds to a
yield of 37 g (89%) pure. Product loss to the mother liquor is ꢁ1.7 g (4%).
An analytical sample is obtained by recrystallization from cyclohexane: m.p.
68–170 C; H NMR (D O) d 3.72 (br s, 1H), 2.50 (br s, 1H), 1.85–1.65
m, 8H); C NMR (D O) d 182.5, 48.3, 37.8, 27.2, 24.0. Anal. Calcd for
ꢀ
1
1
(
2
13
2
C H NO Á 0:25 H O: C, 64.84; H, 8.94; N, 10.80. Found: C, 64.85; H, 8.82;
7
11
2
N, 10.41.
Isoquinuclidine Tosylate (4). Method A: To a 100-L round bottomed
flask equipped with a mechanical stir, and a condenser, is charged 3-isoqui-
nuclidone 3 (4.02 kg, 84%, 26.97 mol) and toluene (19 L, KF 6 mg/mL) under
a nitrogen atmosphere. The resulting suspension (KF 470 mg/mL) is cooled

PREPARATION OF 2-AZABICYCLO[2.2.2]OCTANE
1993
ꢀ
Õ
to 10–15 C and 3.4 M Red-Al /toluene (20.13L, 68.45 mol) was slowly
ꢀ
added, while keeping the internal temperature ꢂ50 C (Caution: vigorous
ꢀ
hydrogen gas evolution). The resulting mixture is heated at 80–90 C for
2 h and then cooled to 20 C. After cooling to 10–15 C, it is carefully
quenched with a 1.4 M NaOH (50 L, 70 mol) over 2 h, while maintaining
ꢀ
ꢀ
ꢀ
the internal temperature ꢂ60 C. The quenched mixture is gradually heated
ꢀ
ꢀ
Õ
to 70 C, aged for 10 min, then cooled to 22 C. Celite 545 (Aldrich, 3kg) is
added and the emulsified mixture is filtered via a centrifuge through a 5 mm
bag coated with 0.5 kg of wet Celite in order to remove the pasty aluminum
salts. The filter cake is washed with toluene (2 L). The filtrate was allowed to
settle and the layers were separated. The aqueous layer is extracted with
toluene (2 Â 19 L). The combined organic phases are dried with Na SO
2
4
(
2 kg), filtered, and washed with toluene (6 L). The bicyclic amine in the
filtered organic phase (ꢁ71.5 L 0.3wt% H O) is assayed by titration to
2
have a concentration of 39.6 mg/mL. This corresponds to 25.46 mol or
94% yield. To the filtrate is added p-toluenesulfonic acid monohydrate
ꢀ
(
(
4.9 kg, 25.46 mol) at 20 C over 20 min. A slight exotherm is observed
ꢀ
ꢀ
19!32 C). The mixture is heated to 70–75 C and then distilled under
ꢀ
reduced pressure (65–75 C/15–20 in) to remove ꢁ15 L (ꢁ20 vol%) of tolue-
ꢀ
ne/water (until KF <0.4 mg/mL). The solution is seeded (ꢁ0.1 g) at ꢁ50 C,
ꢀ
ꢀ
and allow to cool to 20 C under nitrogen. After stirring at 20 C overnight,
the product is filtered and washed with toluene (2 Â 5 L) and heptane
ꢀ
(
2 Â 5 L). The wet cake is dried under vacuum/nitrogen at 20 C to furnish
6.9 kg of 2-azabicyclo[2.2.2]octane tosylate, 4, as a light brown clumpy solid.
The wt% is 89.83wt% based on GC, TG, and KF. This corresponds to
6.20 kg pure or 86% yield from the free base.
Method B (Recommended Procedure): To a 1-L round bottomed flask
equipped with a mechanical stir, and a condenser, is charged 3-isoquinucli-
done 3 (36 g, 91 wt%, 0.26 mol) and toluene (171 mL, KF 50 mg/mL) under a
ꢀ
nitrogen atmosphere. The suspension (KF 380 mg/mL) was cooled to 0–5 C
and then slowly added 3.4 M Red-Al/toluene (153 mL, 0.52 mol), while
ꢀ
keeping the internal temperature ꢂ40 C (Caution: vigorous hydrogen gas
ꢀ
evolution). The resulting mixture is heated at 80–90 C for 2 h, cooled to
20 C and stirred overnight. After cooling to 10–15 C, it is carefully
quenched with a 1.1 M NaOH (480 mL, 0.525 mol) over 2 h, while maintain-
ꢀ
ꢀ
ꢀ
ing the internal temperature ꢂ60 C. The quenched mixture is gradually
ꢀ
ꢀ
Õ
heated to 70 C, aged for 10 min, then cooled to 22 C. Celite 545
(
Aldrich, 36 g) is added to the emulsified mixture and then filtered through
a pad of Celite (20 g) to remove the pasty aluminum salts. The filtrate is now
in two clear layers. After separating the layers, the aqueous layer is extracted
with toluene (2 Â 171 mL). The combined organic phases are dried with
Na SO (20 g), filtered and washed with toluene (90 mL). The filtrate is
2
4

1
994
CHUNG AND HO
assayed by titration to contain 27.93g (0.251 mol) of the bicyclic amine free
base (96.6%).
To the filtrate is added p-toluenesulfonic acid monohydrate
ꢀ
(
(
48.8 g, 0.251 mol) at 20 C over 20 min. A slight exotherm is observed
ꢀ
ꢀ
20!32 C). The mixture is heated to 70–75 C and then distilled under
ꢀ
reduced pressure (65–75 C/15–20 in) to remove ꢁ170 mL (ꢁ25 vol%) of
toluene/water (until KF <0.4 mg/mL). The solution is allowed to cool to
20 C under nitrogen during which time solid crystallized. After stirring at
ꢀ
ꢀ
2
0 C overnight, the product is filtered and washed with toluene (2 Â 50 mL)
ꢀ
and heptane (100 mL). The wet cake is dried under vacuum/nitrogen at 20 C
to furnish 68.4 g of 2-azabicyclo[2.2.2]octane tosylate, 4, as an off-white
solid. The purity is 96.55 wt% based on GC, TG, and KF measurements.
This corresponds to 66 g pure or 94.3% yield from the free base. The overall
yield is 91% from lactam 3. Product loss to the mother liquor is 0.1 g
ꢀ
1
(
0.2%). 4: m.p. 131–133 C; H NMR (D O) d 7.70 (d, J ¼ 8.3Hz, 2H),
2
7
2
1
.38 (d, J ¼ 8.3 Hz, 2H), 3.42 (br s, 1H), 3.20 (br s, 2H), 2.40 (s, 3H),
1
3
.00–1.90 (m, 3H), 1.82–1.68 (m, 6H); C NMR (D O) d 143.3, 140.3,
2
30.3, 126.2, 45.9, 45.7, 22.8, 22.62, 22.58, 21.3. Anal. Calcd for
C H NO S: C, 59.34; H, 7.47; N, 4.94; S, 11.32. Found: C, 59.32; H,
3
1
4
21
7.42; N, 4.83; S, 11.29.
ACKNOWLEDGMENTS
We thank Drs. Li Li, Thomas Dowling, and Ms. Lisa DiMichele for
their help with the analytical assays and NMR studies.
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Received in the USA June 23, 2001