Convenient one-pot preparation of dimethyl bicyclo[2.2.2]octane-1,4- dicarbolylate, a key intermediate for a novel adenosine A1 receptor antagonist

Article abstract of DOI:10.1080/00397910701216120

Dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (4), a key starting material for a novel adenosine A1 receptor antagonist, was prepared in a one-pot reaction with convenient workup and improved yield. Copyright Taylor & Francis Group, LLC.

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Convenient One‐Pot Preparation of Dimethyl
Bicyclo[2.2.2]octane‐1,4‐dicarbolylate, a
Key Intermediate for a Novel Adenosine A1
Receptor Antagonist
a
a
a
HeXi Chang , William F. Kiesman & Russell C. Petter
a
Department of Process Chemistry , Biogen Idec Inc. , Cambridge,
Massachusetts, USA
Published online: 12 Apr 2007.
To cite this article: HeXi Chang , William F. Kiesman & Russell C. Petter (2007) Convenient One‐Pot
Preparation of Dimethyl Bicyclo[2.2.2]octane‐1,4‐dicarbolylate, a Key Intermediate for a Novel Adenosine
A1 Receptor Antagonist, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 37:8, 1267-1272, DOI: 10.1080/00397910701216120
To link to this article: http://dx.doi.org/10.1080/00397910701216120
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Synthetic Communications , 37: 1267–1272, 2007
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701216120
Convenient One-Pot Preparation of
Dimethyl Bicyclo[2.2.2]octane-1,4-
dicarbolylate, a Key Intermediate for a
Novel Adenosine A Receptor Antagonist
1
HeXi Chang, William F. Kiesman, and Russell C. Petter
Department of Process Chemistry, Biogen Idec Inc., Cambridge,
Massachusetts, USA
Abstract: Dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate (4), a key starting material
for a novel adenosine A receptor antagonist, was prepared in a one-pot reaction with
convenient workup and improved yield.
1
Keywords: dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate, one-pot preparation,
stoichiometry
INTRODUCTION
Since the discovery that adenosine receptors modulate a number of important
[
1]
physiologic functions, variety of xanthine derivatives have been prepared
[2]
as potent, selective adenosine antagonists. One such xanthine deriva-
tive is 3-[4-(2,6,-dioxo-1,3-dipropyl-2,3,6,7-tertrahydro-1H-purin-8-yl)-bicy-
clo[2.2.2]octan-1-yl]-propionic acid BG9928 (1), a potential drug candidate
for congestive heart failure, currently in clinical development, possesses
[3]
high affinity and selectivity for the adenosine A receptor.
1
As indicated in Fig. 1, dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate
4) is one of the starting materials used to assemble BG9928. In addition,
(
1
,4-disubstituted bicyclo[2.2.2]octanes possess interesting physical properties
Received in the USA October 2, 2006
Address correspondence to HeXi Chang, Department of Process Chemistry, Biogen
Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA. E-mail: hexi.chang@
biogenidec.com
1
267

1
268
H. Chang, W. F. Kiesman, and R. C. Petter
Figure 1. Derivation of starting materials for BG9928.
and have been used in the synthesis of liquid-crystalline (rod-like)
[
molecules. They are also components of constrained glutamate analogues,
4]
[5]
intended for the treatment of neurological disorders.
Three distinct methods for the preparation of bicyclo[2.2.2]octane-1,4-
dicarboxylates were reported. The first, a self-condensation reaction with
diethyl succinate and subsequent ring closure with 1,2-dibromoethane,
gave diethyl bicyclo[2.2.2]octane-1,4-dicarboxylate in low yield (23%)
[
6]
after a four-step sequence.
reaction between diethyl cyclohexa-1,3-diene-1,4-dicarboxylate and
The second, based on a Diels–Alder
[
7]
[8,9]
ethylene, proceeded under pressures of 1000 atm.
sequential alkylation and intramolecular ring closure of dimethyl cyclo-
The third route, a
[10]
hexane-1,4-dicarboxylate, was developed by Della and Tsanaktsidis
Scheme 1). Methods one and two suffer from long reaction sequences or
(
low yields. Of the available synthetic routes to obtain the bicyclo[2.2.2]oc-
tane core structure, the third appeared to be the most promising for further
development because it had relatively few steps, had an opportunity to
telescope the alkylation and cyclization reactions, and utilized inexpensive,
commercially available starting materials.
As shown in Scheme 1, the chloroethyl chain was installed by treatment of
with an excess of lithium diisopropylamide (LDA) and 1.2 equiv of 1-bromo-
2
2-chloroethane; then the mixture was worked up by evaporative concentration,
dilution with water, extraction with pentane, washing, drying, and evaporation.
The chloride 3 was obtained in 62% yield after column chromatography
Scheme 1. Two-stage alkylation synthesis of bicyclo[2.2.2]octane.

Dimethyl Bicyclo[2.2.2]Octane-1,4-dicarbolylate
1269
(silica). Compound 3 was subsequently treated again with excess LDA to
induce cyclization to the bicyclo[2.2.2]octane ring system. The same extrac-
tive workup procedure and column chromatography were applied as with
the chloride, and the final dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate
(4) was obtained in 57% yield. Overall, 4 was obtained in 35% yield in the
two-step process from the saturated diester 2.
The reaction to prepare compound 4 went smoothly as the aforemen-
[10]
tioned two-stage process, but all attempts to telescope the reaction failed.
RESULTS AND DISCUSSION
To obtain an easy scale-up procedure, we studied the possibility of a one-pot
reaction leading to compound 4, and it turns out that the stoichiometry of
1
-bromo-2-chloroethane is the key for success.
In our initial attempt at a one-pot preparation of 4, we eliminated the
isolation of the intermediate chloride 3 and simply added a second molar
equivalent of LDA after the alkylation step. None of the expected diester
could be detected, and a brown to black oil was noticed. Similar results
were observed when the starting material was treated with more than 2
equiv of LDA and excess 1-bromo-2-chloroethane. Further work explored
controlled addition rates and reversal of the order of addition, all of which
met with little success.
We then focused on the ratio of diesters to 1-bromo-2-chloroethane. In all
the attempted reactions, at least 1.2 equiv of 1-bromo-2-chloroethane was
added. The unreacted halide, if not removed, could be deprotonated by
LDA and then reacted with other 1-bromo-2-chloroethane to generate
polymeric by-products. Such by-products could dominate the reaction while
the expected intramolecular cyclization proceeded slower than the intermole-
cular alkylation that leads to side products.
We then tried the one-pot alkylation-cyclization on diester 2 with 1.1 equiv
of LDA, and 1.0 equiv of 1-bromo-2-chloroethane to generate the chloroethyl
intermediate 3. Then another molar equivalent of LDA was added, and the
reaction was allowed to warm gradually to 258C (Scheme 2). With almost
Scheme 2. One-pot conversion to bicyclo[2.2.2]octane diester.

1
270
H. Chang, W. F. Kiesman, and R. C. Petter
Figure 2. Crystal structure of dimethyl bicyclo[2.2.2]octane-1,4-dicarboxylate(4)
[10]
the same final extractive workup as previously reported,
the desired
bicyclo[2.2.2]octane 4 was isolated in 63% yield, almost double that of the
original two-step procedure.
Some effort was then put into simplification of the extractive workup
method. The reaction mixture was diluted with water, and the precipitated
product was collected by filtration; this eliminated the extraction, washing,
drying, and concentration. Because the diester was slightly soluble in water,
the yield from this procedure diminished to 53%; however the use of
saturated brine solution restored the overall yield of the final product.
In conclusion, a convenient one-pot reaction to prepare bicyclo[2.2.2]oc-
tane 4 was developed. The diester 4 was produced in yields 18% to 28% higher
than the original two-step literature method. In addition, precipitation of the
product with water avoided extraction with hexanes or pentane, which
increased the safety and minimized waste. Future work will be focused on
the replacement of hexamethylphosphoramide (HMPA) with more environ-
mentally friendly and less toxic substitutes.
Figure 2 shows the crystal structure of dimethyl bicyclo[2.2.2]octane-1,4-
dicarboxylate (4).
EXPERIMENTAL
Starting materials and reagents were used as purchased from Sigma-Aldrich.
Melting points were measured on a Mettler Toledo FP62 digital melting-point
1 13
apparatus and are not corrected. H and C NMR spectra were recorded on a
Bruker spectrometer (400 MHz) in CDCl , Chemical shifts are expressed as d
3
(
ppm) values. The X-ray structure for dimethyl bicyclo[2.2.2]octane-1,4-
dicarboxylate (4) was determined on a Bruker Smart CCD diffractometer.
The crystal used for the diffraction study showed no decomposition during
data collection. The crystal showed signs of twin for the mixture, and the
percentage of twin was 29%. The full structural information is available as
electronic supporting information (hexi.chang@biogenidec.com).

Dimethyl Bicyclo[2.2.2]Octane-1,4-dicarbolylate
1271
Dimethyl Bicyclo[2.2.2]octane-1,4-dicarboxylate (4)
To a stirred solutin of N,N-diisopropylamine (84.5 mL, 600 mmol) in
THF(700 ml) cooled to 2308C under N2, n-BuLi (220 mL, 2.5 M in
hexane, 550 mmol) was added by a syringe. The mixture was stirred for
3
0 min at 2308C and then cooled to 2788C. HMPA (360 mL, 2000 mmol)
was added, and a solution of dimethyl cyclohexane-1,4-dicarboxylate
100 g, 500 mmol) in THF (100 mL) was charged subsequently over
0 min. The mixture was stirred further for 40 min, and then 1-bromo-2-
(
3
chloroethane (41.5 mL, 499 mmol) was added dropwise. After the mixture
was stirred at 2788C for 1 h, a solution of HMPA (360 ml, 2000 mmol) in
THF (600 mL) was added slowly. By cannula, freshly prepared LDA
[200 mL of n-BuLi (2.5 M in hexane, 500 mmol) added to N,N-diisopropyla-
mine (78 mL, 556 mmol) in THF (700 mL) at 2788C]was transferred to the
reaction mixture at 2788C over a period of 1 h. The resultant mixture was
stirred at 2788C for 1.5 h. The cold bath was removed, and the mixture
was stripped further for 4–6 h. The clear brown solution was then quenched
with saturated aqueous NH Cl(400 mL) and concentrated in vacuo (bath
4
temperature 30–358C) to remove THF.
Workup Method A
The residue was diluted with 800 mL of water and extracted with hexane
(
3 Â 600 mL). The combined extracts were washed with brine (700 mL),
dried with Na SO , and concentrated in vacuo (bath temperature 358C) to
2
4
give a yellow sticky solid. The solid was stirred with 60 mL of hexane at rt
for 30 min. The resulting suspension was cooled to 08C for 2 h and filtered
1
to give light yellow crystalline solid (71.6 g, 63% yield), mp 92.88C, H
1
NMR (CDCl ) d 3.61 (s, 3H, -OCH ), 1.75(s, 6H, -CH ); C NMR
3
3
3
2
(
CDCl ) d 177.72, 51.65, 38.56, 27.68. Anal. calcd. for C H18 O : C,
3
12
4
6
3.70; H, 8.02. Found: C, 63.47; H, 8.10.
Workup Method B
While stirring, the residue was diluted slowly with 800 mL of water, and the
resulting suspension was stirred for approximately 3 h at rt. The yellow solid
was collected by suction filtration, washed with water, and dried under
vacuum (60 g, 53% yield).
ACKNOWLEDGMENT
The authors thank Richard J. Staples (X-ray Crystallographic Laboratory,
Harvard University) for performing single-crystal X-ray diffraction.

1
272
H. Chang, W. F. Kiesman, and R. C. Petter
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