Synthesis of benzobicyclo[2.2.1] heptylimidazoles as conformationally constrained adrenergic receptor antagonists

Article abstract of DOI:10.3987/COM-05-10535

A facile method for the preparation of conformationally rigid analogues of the adrenergic α-2 receptor antagonist atipamezole and the adrenergic α-2 receptor agonist medetomidine has been developed. The efficient benzyne [4+2] cycloaddition reaction was used to give the core 7-acetylbenzonorbornadiene structure, which was subsequently elaborated to the corresponding imidazole-based syn and anti isomers by means of the classical Bredereck's method.

Full text of DOI:10.3987/COM-05-10535

HETEROCYCLES, Vol. 65, No. 11, 2005
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HETEROCYCLES, Vol. 65, No. 11, 2005, pp. 2783 - 2790
Received, 1st August, 2005, Accepted, 5th September, 2005, Published online, 6th September, 2005
SYNTHESIS OF BENZOBICYCLO[2.2.1]HEPTYLIMIDAZOLES AS
CONFORMATIONALLY CONSTRAINED ADRENERGIC RECEPTOR
ANTAGONISTS
*
,a
a
b
b
Jari Yli-Kauhaluoma , Aki Laine , Jari Ratilainen , and Arto Karjalainen
a
Technical Research Centre of Finland, VTT Processes, P. O. Box 1602, FI-02044
VTT, Finland
b
Orion Pharma, Department of Medicinal Chemistry, P. O. Box 65, FI-02101
Espoo, Finland
Abstract – A facile method for the preparation of conformationally rigid
analogues of the adrenergic α-2 receptor antagonist atipamezole and the
adrenergic α-2 receptor agonist medetomidine has been developed. The efficient
benzyne [4+2] cycloaddition reaction was used to give the core
7
-acetylbenzonorbornadiene structure, which was subsequently elaborated to the
corresponding imidazole-based syn and anti isomers by means of the classical
Bredereck’s method.
INTRODUCTION
Atipamezole (1, 4-(2,3-dihydro-2-ethyl-1H-inden-2-yl)-1H-imidazole) is a potent and selective α-2
1
adrenergic receptor antagonist. It is currently used for reversing the sedation and other effects produced
by the veterinary sedative medetomidine (2, 4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole
2
hydrochloride) that is, in turn, a highly potent and selective adrenergic α-2 receptor agonist (Figure 1).
There are few reports in the literature that describe the synthetic procedures for preparing
conformationally restricted analogues of medetomidine focusing on the preparation of naphthyl and
3
,4
tetralin and 3,4-dihydronaphthalene analogues of medetomidine. We studied the synthesis of even more
*
Corresponding Author. Current Address: Drug Discovery and Development Technology Center, Faculty of Pharmacy, P. O.
Box 56 (Viikinkaari 5 E), FI-00014 University of Helsinki, Finland. Phone +358 9 19159170. Fax +358 9 19159556. E-mail
Jari.Yli-Kauhaluoma@helsinki.fi

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HETEROCYCLES, Vol. 65, No. 11, 2005
rigid analogues of atipamezole and medetomidine. We now describe a concise synthesis of syn-3 and
anti-4 isomers of conformationally constrained imidazolyl-substituted benzobicyclo[2.2.1]heptane.
Me Me
Me
Et N
H N
N
N
H
1
2
Figure 1. Chemical structures of atipamezole (1) and medetomidine (2).
RESULTS AND DISCUSSION
The bridged enamino benzobicyclo[2.2.1]heptene cycloadduct (5) was synthesized as a key intermediate
by a straightforward benzyne-Diels−Alder reaction. The in situ generated benzyne acted as a dienophile
and an enamino-6-dimethylamino-6-methylfulvene (6) as a diene in the [4+2] cycloaddition reaction.
First, fulvene (6) was prepared by allowing cyclopentadiene (7) to react with N,N-dimethylacetamide
5
,6
dimethyl acetal (8) (Scheme 1).
N
rt, 22 h
6%
N
OMe
OMe
+
7
7
8
6
Scheme 1.
Second, the Diels−Alder reaction between the enaminofulvene (6) and benzyne, generated in situ from
phenyl)[2-(trimethylsilyl)phenyl]iodonium triflate −9 (9) in the presence of tetra-n-butylammonium
7
(
fluoride in dichloromethane, gave the bridged enamine cycloadduct (5) (Scheme 2). The recently reported
7
hypervalent iodine triflate (9) proved to be a superb and highly efficient benzyne precursor in the
Diels−Alder reaction in comparison with the other benzyne precursors studied in the early phase of this
investigation. For example, the enaminofulvene (6) failed to give the desired cycloadduct when
dienophilic benzyne was generated from benzenediazonium-2-carboxylate and 2-bromofluorotoluene in
the presence of isoamyl nitrite and methylmagnesium bromide, respectively.

HETEROCYCLES, Vol. 65, No. 11, 2005
2785
TMS
O
1
.0 M TBAF in
N
i. 2 M NaOH aq,
100 C, 4 h
ii. 6 M HCl aq, 4 C
+
-
N
THF, CH Cl ,
4 οC to rt, 2 h
ο
CF SO
3 3
2
2
I
ο
+
73%
1
0
9
6
5
H
N
O
O
N
i. HCONH2
Br
H , 5% Pd/C,
EtOAc, rt, 2.5 h
Br , MeOH,
2
2
ο
1
80 C, 4 h
o
0 C to rt, 2 h
ii. HCl (g), EtOAc
92%
93% syn
2
2
7% syn
5% anti
96% anti
3-HCl
-HCl
11
12
4
Scheme 2.
The bicyclic enamine cycloadduct (5) was subsequently hydrolysed by means of aqueous sodium
hydroxide to give a moderate yield of 7-acetylbenzonorbornadiene (10) as a 55:45 syn/anti mixture. The
2
isomers were chromatographically (SiO ) separable but were carried as a mixture to the next step. An
isomeric mixture of 7-acetylbenzonorbornadienes (10) was catalytically (5% Pd/C) hydrogenated in ethyl
acetate to give benzonorbornene (11) with a 55:45 syn/anti ratio in a good yield of 92%. The isomers of
7
-acetylbenzobicyclo[2.2.1]heptane (11) were chromatographically (SiO
characterization of the syn and anti isomers of 11 was carried out by means of NOE experiments
NOESY). A strong NOE was observed between the protons H1-a and H3 in the syn isomer (11a). No
2
) separable. The structural
(
such effect was observed in the anti isomer (11b) (Figure 2). A mild regioselective bromination of
isomers (11a) and (11b) with bromine in methanol afforded the 7-bromoacetylbenzonorbornanes (12a)
1
0
and (12b) in a good yield of 93 and 96%, respectively. No isomerisation was found to take place during
the regioselective bromination.
O
O
NOE
H-3
H
H-1a
H-1b
H-1a
H-1b
11a
11b
Figure 2. NOE was observed in syn-11a but not in anti-11b.
Finally, the combined isomeric mixture of bromobenzonorbornanes (12a) and (12b) was cyclised to
1
1
imidazoles (3) and (4) in formamide at 180 °C by means of Bredereck's method (Scheme 2). The

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HETEROCYCLES, Vol. 65, No. 11, 2005
Bredereck reaction was carried out using the mixture of α-bromo ketones, because it was observed that
isomerisation takes place during the cyclisation reaction. The syn and anti 7-imidazolylbenzonorbornanes
(
3) and (4) were isolated as hydrochlorides and recrystallized in good yields from mixtures of ethyl
acetate and isopropanol or acetonitrile and isopropanol, respectively. A strong NOE was observed
between the protons H-1a and H-3 in the syn isomer (3). No such effect was observed in the anti isomer
(
4).
In conclusion, a facile method for the preparation of conformationally rigid analogues of atipamezole and
medetomidine has been developed. The efficient benzyne [4+2] cycloaddition reaction was used to give
the core 7-acetylbenzonorbornadiene structure, which was subsequently elaborated to the corresponding
imidazole-based syn and anti isomers by means of the classical Bredereck’s method.
EXPERIMENTAL
General Procedures. Unless otherwise stated, reactions were carried out in oven-dried glassware under a
positive atmosphere of argon or nitrogen. Reagents were transferred with plastic syringes and oven-dried
or disposable needles. Dichloromethane was continuously distilled from calcium hydride. All reagents
were purchased from Aldrich Chemical Company and Fluka Chemie Ag. All chromatography solvents
f
were obtained commercially and used without further purification. The R values refer to the TLC
developed using 0.25 mm Merck silica gel F-254 aluminum foil-supported plates visualised with either
1
2
ethanolic phosphomolybdic acid (5%), Pauly's reagent specific for unsubstituted imidazole ring systems
or ultraviolet lamp. Yields are for unoptimised procedures and refer to chromatographically and
1
1
spectroscopically ( H NMR) homogeneous materials, unless otherwise noted. All H NMR spectra (300
MHz) were obtained in CD OD, CDCl , DMSO-d or D O at ambient temperature on a Varian Mercury
3
3
6
2
3
00 instrument. Chemical shifts (δ) are reported in parts per million relative to the internal reference
tetramethylsilane and coupling constants (J) are given in Hz. FTIR spectra were recorded as potassium
bromide tablets with the Bruker Equinox 55 instrument. High and low resolution MS spectra were
provided by the mass spectrometry facilities of VTT Processes, Espoo, Finland.
6
1
2
6
-Dimethylamino-6-methylfulvene (6). A mixture of freshly distilled cyclopentadiene (7) (12.10 g,
83.0 mmol) and N,N-dimethylacetamide dimethyl acetal (8) (24.37 g, 183.0 mmol) was stirred at rt for
2 h. The resulting brownish orange crystals were filtered and washed with cold ether (3×10 mL) to give
as light orange crystals (18.71 g, 76%). TLC (EtOAc/n-hexane 1:1) R 0.48; mp 87−88 °C,
f
6
recrystallized from ether/n-hexane (lit., 88−89 °C).

HETEROCYCLES, Vol. 65, No. 11, 2005
2787
7
-(Dimethylaminoethylidene)benzonorbornadiene
(5).
To
a
solution
of
(phenyl)[2-
(
(
trimethylsilyl)phenyl]iodonium triflate (9) (5.92 g, 11.78 mmol) and 6-dimethylamino-6-methylfulvene
6) (7.95 g, 58.80 mmol, 5 equiv.) in dichloromethane (70 mL) was added dropwise a 1.0 M solution of
tetra-n-butylammonium fluoride in tetrahydrofuran (14.5 mL, 14.5 mmol) at 4 °C, and the reaction
mixture was stirred at room temperature for 2 h. Then, water (50 mL) was added to the reaction mixture,
and the resulting mixture was extracted with dichloromethane (1×100 mL and 2×50 mL). The combined
organic layers were washed with brine (50 mL), dried over anhydrous Na
give crude 5 as a dark oil (23.03 g), which was used without further purification in the next step. TLC
PhMe/CH Cl /TEA (20:2:1) R 0.42.
2 4
SO and evaporated in vacuo to
(
2
2
f
7
-Acetylbenzonorbornadiene (10). A mixture of crude 5 (23.03 g) and aqueous 2 M sodium hydroxide
solution (300 mL, 600 mmol) was refluxed for 4 h. The reaction mixture was cooled to 4 °C. 6 M
Hydrochloric acid (70 mL) was added to the solution until pH was 1-2. The resulting mixture was
extracted with ether (3×100 mL). The combined organic layers were washed with brine (50 mL), dried
with anhydrous Na
2 4
SO , filtered and evaporated in vacuo to give crude 10 as a red oil (7.73 g). The
crude product was chromatographed on silica (EtOAc/n-hexanes 1:5) to give 7-acetylbenzonorbornadiene
(
f
10) as a mixture of syn and anti isomers (1.14 g, 73%, syn:anti 55:45). anti isomer: R 0.68
1
(
EtOAc−hexane 1:1); H NMR (CDCl
3
, 300 MHz) δ 1.95 (s, 3 H), 3.41 (br s, 1 H), 4.21 (br s, 1 H), 6.87
+
+
(
obsc., 1 H), 6.95−7.05 (m, 2 H), 7.28−7.30 (m, 2 H); GC−MS tret 25.5 min, m/z 184 [M ], 169 [M-CH
3
] ,
+
1
1
41[M-CH
3
CO] , 115, 89, 63, 43. syn isomer: R
f
0.66 (EtOAc−hexane 1:1); H NMR (CDCl
3
, 300
MHz) δ 2.16 (s, 3 H), 3.35 (br s, 1 H), 4.29 (br s, 1 H), 6.77 (obsc., 1 H), 6.97−7.03 (m, 2 H), 7.25−7.33
+
+
+
(
m, 2 H); GC−MS tret 26.5 min, m/z 184 [M ], 169 [M-CH
3
] , 141[M-CH
3
CO] , 115, 89, 63, 43. Anal.
Calcd for C13
a mixture to the next step.
-Acetylbenzonorbornene (11). To a mixture of 10 (0.530 g, 2.88 mmol) in ethyl acetate (30 mL) was
H12O: C, 84.75; H 6.57. Found: C, 83.06; H, 6.52. The syn and anti isomers were carried as
7
added 5% palladium on activated carbon (0.100 g). A hydrogen balloon was attached to the reaction
vessel, and the reaction mixture was stirred at rt for 2.5 h. The reaction mixture was filtered through
Celite and evaporated to dryness. The crude product was purified by flash chromatography
(EtOAc/n-hexane 1:50) providing the separable syn isomer (11a) (0.263 g) and anti isomer (11b) (0.228
1
g) as yellow oils, the total yield being 92%. syn isomer (11a): Rf 0.50 (EtOAc−hexane 1:2); H NMR
(CDCl
3
, 300 MHz) δ 1.14−1.23 (m, 2 H), 1.86 (s, 3 H), 1.96−2.00 (m, 2 H), 2.66 (t, J 1.5, 1 H), 3.58 (m,
+
2
H), 7.00−7.04 (m, 2 H), 7.09−7.13 (m, 2 H); NOESY cross peak at δ (2.66, 1.98); m/z 186 [M ]; FTIR
−
1
1
(
KBr/cm ) 2956, 1697, 1469, 1180, 1110, 756; anti isomer (11b): R
f
0.64 (EtOAc−hexane 1:2); H

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HETEROCYCLES, Vol. 65, No. 11, 2005
NMR (CDCl
3
, 300 MHz) δ 1.09−1.12 (m, 2 H), 1.84−1.91 (m, 2 H), 2.10 (s, 3 H), 2.68 (app. quintet, J
1
.5, 1 H), 3.53 (app. dd, J 1.6, 2 H), 7.00−7.06 (m, 2 H), 7.07−7.12 (m, 2 H); NOESY no cross peak at δ
+
−1
(
2.68, 1.86); m/z 186 [M ]; FTIR (KBr/cm ) 2975, 2875, 1707, 1471, 1361, 1112, 751. Anal. Calcd for
13
C H14O: C, 83.83; H 7.58. Found: C, 83.69; H, 7.60.
syn-7-Bromoacetylbenzonorbornene (12a). syn-7-Acetylbenzonorbornene (11a) (0.217 g, 1.17 mmol)
was dissolved in methanol (10 mL), and the resulting solution was cooled to 0 °C. Then, a solution of
bromine (65.0 µL, 1.26 mmol) in methanol (0.50 mL) was added, and the reaction mixture was stirred at
rt for 2 h. The reaction mixture was diluted with an equimixture of n-hexane and ether (50 mL). The
3
resulting solution was washed with distilled water (10 mL), a saturated solution of NaHCO (10 mL) and
10% solution of Na
2
SO
3
(15 mL), dried with anhydrous Na
2
SO
4
, filtered and evaporated in vacuo to give
1
syn-12a (0.290 g; 93%) as a yellowish oil. R
f
0.77 (EtOAc−hexane 1:2); H NMR (CDCl
3
, 300 MHz) δ
1
2
1
.25−1.29 (m, 2 H), 2.06−2.09 (m, 2 H), 3.04 (t, J 1.5, 1 H), 3.68 (s, 2 H), 3.64−3.68 (app. quintet, J 1.5,
+
−1
H), 7.08−7.11 (m, 2 H), 7.17−7.20 (m, 2 H). m/z 265 [M ]; FTIR (KBr/cm ) 2947, 1721, 1707, 1468,
392, 1060, 754, 645. Anal. Calcd for C13 13OBr: C, 58.89; H, 4.94; Br, 30.14. Found: C, 58.81; H, 4.97;
H
Br, 30.10. The product was carried to the next step without additional purification.
anti-7-Bromoacetylbenzonorbornene (12b). anti-7-acetylbenzonorbornene (11b) (0.250 g, 1.34 mmol)
was dissolved in methanol (10 mL), and the resulting solution was cooled to 0 °C. Then, a solution of
bromine (75.0 µL, 1.46 mmol) in methanol (0.50 mL) was added, and the reaction mixture was stirred at
rt for 2 h. The reaction mixture was diluted with an equimixture of n-hexane and ether (50 mL). The
3
resulting solution was washed with distilled water (10 mL), a saturated solution of NaHCO (10 mL) and
10% solution of Na
2
SO
3
(15 mL), dried with anhydrous Na
2
SO
4
, filtered and evaporated in vacuo to give
1
anti-12b (0.342 g; 96%) as a yellowish oil. R
f
0.72 (EtOAc−hexane 1:2); H NMR (CDCl
3
, 300 MHz) δ
1
7
1
.18−1.24 (m, 2 H), 1.96−2.00 (m, 2 H), 3.07 (t, J 1.5, 1 H), 3.63 (app dd, J 1.6, 2 H), 3.96 (s, 2 H),
+
−1
.08−7.12 (m, 2 H), 7.15−7.18 (m, 2 H). m/z 265 [M ]; FTIR (KBr/cm ) 2975, 2875, 1709, 1460, 1392,
068, 754. Anal. Calcd for C13 13OBr: C, 58.89; H, 4.94; Br, 30.14. Found: C, 58.83; H, 4.89; Br, 30.09.
H
7
-Imidazolylbenzonorbornenes (3 and 4). A mixture of syn and anti bromides (12) (0.603 g, 2.27
mmol) in formamide (25 mL) was heated at 180 °C for 4 h. The reaction mixture was cooled to rt and
diluted with distilled water (60 mL). The resulting mixture was acidified with 6 M hydrochloric acid (5
mL) and washed with ethyl acetate (2×20 mL). The aqueous layer was made alkaline with a concentrated
solution of ammonia (20 mL) and extracted with ethyl acetate (1×40 mL, 2×20 mL). The combined

HETEROCYCLES, Vol. 65, No. 11, 2005
2789
EtOAc layers were washed with distilled water (15 mL) and brine (15 mL), dried with Na
2
SO
4
, filtered
and evaporated in vacuo to give the dark brown oil as a crude mixture of syn-3 and anti-4 isomers
0.270 g). The crude product (0.270 g) was dissolved in EtOAc (1 mL). The resulting solution was
(
triturated with a saturated solution of hydrogen chloride in EtOAc (10 mL) to give a crude mixture of
imidazole hydrochlorides. The crystallization of the crude hydrochloride from EtOAc/i-PrOH gave the
syn imidazole (3) hydrochloride (153 mg, 27%) and the crystallization of the residual mother liquor from
MeCN/i-PrOH in the refrigerator gave the corresponding anti imidazole (4) hydrochloride (137 mg, 25%)
both as colorless crystals. syn-(3) hydrochloride: R
f
0.26 (CH
2
Cl
2
−MeOH−NH 9:1:0.05); mp 209−211
3
1
°
C, from EtOAc/i-PrOH; H NMR (D
2
O, 300 MHz) δ 1.13 (dd, J 4.9, 12, 2 H), 2.03 (d, J 7.5, 2 H), 3.12
(s, 1 H), 3.55 (app s, 2 H), 6.57 (s, 1 H), 7.02 (m, 2 H), 7.18 (m, 2 H), 8.20 (s, 1 H); NOESY cross peak at
+
−1
δ (2.03, 3.12); FABMS 211 [M+1] ; FTIR (KBr/cm ) 3093, 2806, 2613, 1617, 1404, 853, 753; Anal.
Calcd for C14
H
15
N
2
Cl: C, 68.15; H, 6.13; N, 11.35. Found: C, 67.93; H, 6.08; N, 11.38. anti-(4)
1
hydrochloride: R
f
0.28 (CH
2
Cl
2
−MeOH−NH
3
9:1:0.05); mp 193−195 °C, from MeCN/i-PrOH; H NMR
2
(D O, 300 MHz) δ 1.01 (m, 2 H), 1.72 (m, 2 H), 2.94 (s, 1 H), 3.58 (app s, 2 H), 7.08 (m, 2 H), 7.19 (m, 2
+
H), 7.22 (s, 1 H), 8.39 (s, 1 H); NOESY no cross peak at δ (1.72, 2.94); FABMS 211 [M+1] ; FTIR
−
1
(
KBr/cm ) 3096, 2772, 2674, 1616, 1460, 842, 755. Anal. Calcd for C14
1.35. Found: C, 68.99; H, 6.06; N, 11.41.
15 2
H N Cl: C, 68.15; H, 6.13; N,
1
ACKNOWLEDGEMENTS
We thank Mrs. Anja Salakari for excellent technical assistance. We are greatly indebted to Tekes - The
National Technology Agency for financial support of this research project.
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HETEROCYCLES, Vol. 65, No. 11, 2005
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8
.
.
The hypervalent iodine-benzyne precursor (phenyl)[2-(trimethylsilyl)phenyl]iodonium triflate was
readily prepared from 1,2-bis(trimethylsilyl)benzene and (diacetoxyiodo)benzene in the presence of
trifluoromethanesulfonic acid as reported in the reference 7.
9
1
1
1
P. Bourgeois and R. Calas, J. Organomet. Chem., 1975, 84, 165.
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1
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