Microwave-enhanced synthesis of 2,3,6-trisubstituted pyridazines: Application to four-step synthesis of gabazine (SR-95531)

Article abstract of DOI:10.1039/c0ob00004c

Microwave-enhanced, highly efficient protocols for the synthesis of synthetically and biologically important 2,3,6-trisubstituted pyridazine architectures have been developed by sequential amination/Suzuki coupling/alkylation reactions. This powerful strategy is an economical and highly chemoselective protocol for the synthesis of diversified pyridazines. The total synthesis of gabazine (SR-95531) has been achieved using a versatile strategy in four steps and 73% overall yield.

Full text of DOI:10.1039/c0ob00004c

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Microwave-enhanced synthesis of 2,3,6-trisubstituted pyridazines: application
to four-step synthesis of gabazine (SR-95531)†
Navnath Gavande,a Graham A. R. Johnston,b Jane R. Hanrahan*a and Mary Chebib*a
Received 15th April 2010, Accepted 17th June 2010
First published as an Advance Article on the web 26th July 2010
DOI: 10.1039/c0ob00004c
Microwave-enhanced, highly efficient protocols for the synthesis of synthetically and biologically
important 2,3,6-trisubstituted pyridazine architectures have been developed by sequential
amination/Suzuki coupling/alkylation reactions. This powerful strategy is an economical and highly
chemoselective protocol for the synthesis of diversified pyridazines. The total synthesis of gabazine
(SR-95531) has been achieved using a versatile strategy in four steps and 73% overall yield.
prepared by microwave-promoted sequential selective amina-
tion/Suzuki coupling/selective N(2)-alkylation reactions.
Microwave-assisted organic synthesis has demonstrated itself
of derivatives continue to attract significant attention in the
to be superior in many instances as compared to conven-
Introduction
The nitrogen containing heterocycle pyridazine1 and its myriad
tional heating reactions.14 We were interested in developing a
general, efficient and an inexpensive approach to unsymmet-
rical 2,3,6-trisubstituted pyridazines. The synthesis of diver-
sified 2,3,6-trisubstituted pyridazines were achieved from 3,6-
dichloropyridazine through a sequence of reactions: selective
amination of the 3,6-dichloropyridazine using aq. ammonium hy-
droxide, Suzuki coupling reaction of 3-amino-6-chloropyridazine
with various boronic acids, followed by a selective N-alkylation
at N(2) to introduce the third diversity point to furnish the
corresponding 2,3,6-trisubstituted pyridazines (Fig. 1).
pharmaceutical industry in the quest for new drugs. The 3-
aminopyridazine pharmacophore has proven particularly inter-
esting from a pharmacological point of view.2–7 For example,
Minaprine (Cantor) is an antidepressant drug which acts as a
short-acting monoamine oxidase (MAO) inhibitor.2 The various
Minaprine analogues and their metabolites act as choliner-
gic, dopaminergic, and serotoninergic ligands as well as MAO
and acetylcholinesterase inhibitors.2,3 Various 3-aminopyridazine
derivatives which are extended analogues of g-aminobutyric
acid (GABA) act as competitive GABAA receptor antagonists.4
Specifically, gabazine (SR-95531)5 has shows high specificity and
potency towards both GABAA and GABAC receptors.6
There are few approaches for the construction of 3-amino-
6-arylpyridazines.3b,5b,7a,8,9,13 Generally, the construction of 3-
amino-6-arylpyridazines involves synthesis of the pyridazinone
core based on the condensation of acetophenones with 1,4-
dicarbonyl compounds in the presence of hydrazine,10 chlorina-
tion of pyridazinones with POCl3,2e,3b,3e,11 followed by amination
using ammonia or hydrazine.5b,8a Moreover, there are also a few
reports of palladium-catalyzed Suzuki cross-coupling reactions12
on 3-amino-6-chloropyridazine moieties.7a,9 Recently, Favi et al.
described a novel synthesis of diversely functionalized pyridazines
from 4-chloro-1,2-diaza-1,3-butadienes by the Michael-type addi-
tion of active methylene compounds.13 Most approaches to the
synthesis of diversified pyridazines have several disadvantages,
including limited availability of suitable substrates, harsh reaction
conditions, a high number of steps, inconvenient operations, time-
consuming experimental procedures, use of toxic chemicals, lack of
atom economy and poor yields. During the course of our ongoing
research on the development of bioactive 3-aminopyridazine
analogues, we found that diversified pyridazines can be efficiently
Fig. 1 Potential pharmaceutically important 3-aminopyridazine deriva-
tives: minaprine 1 and gabazine 2.
Results and discussion
The initial step of the synthesis involved the monoamination
of 3,6-dichlorpyridazine using 28–30% aq. ammonium hydrox-
ide as the source for the amine functionality of 3-amino-6-
chloropyridazine under microwave irradiation (Scheme 1). The
amination proceeded rapidly and in good yield compared to
traditional procedures,7a,15 providing an efficient synthesis of 3-
amino-6-chloropyridazine.
There have been a few reports on the synthesis of 3-amino-6-
arylpyridazines using Suzuki coupling reactions7a,9 but the major
drawbacks to this procedure are poor yields and/or long reaction
times. For the purpose of optimization of the Suzuki coupling, we
chose as a model reaction coupling between unprotected 3-amino-
6-chloropyridazine with 4-methoxy phenylboronic acid (Table 1).
aFaculty of Pharmacy. The University of Sydney, Sydney, NSW, Australia.
E-mail: janeh@pharm.usyd.edu.au, maryc@pharm.usyd.edu.au; Fax: +61
2 93514391; Tel: +61 2 93518584
bAdrien Albert Laboratory of Medicinal Chemistry, Department of Pharma-
cology, The University of Sydney, Sydney, NSW, Australia
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for reaction products. See DOI:
10.1039/c0ob00004c
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Table 1 Optimization of microwave-enhanced Suzuki coupling of 3-amino-6-chloropyridazine with 4-methoxy phenylboronic acida
Entry
Catalyst
Mol (%)
Base
PTCb
Solvent
Time/min
T/◦C
Conversion (%)c
1
2
3
4
5
6
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
5
5
5
5
5
5
5
5
5
5
3
5
5
5
5
5
5
5
5
5
10
5
5
5
5
5
5
5
5
5
5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
KF
Water
Water
Water
Water
EtOH
EtOH
toluene
10
10
10
10
10
10
10
10
10
5
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
150
150
150
150
100
120
120
120
120
120
120
100
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
5
TBAB (100 mol%)
SLS (20 mol%)
SLS (100 mol%)
69
36
74
70
98
77
80
100 (94)d
92
82
80
87
85
83
90
89
12
2
EtOH–water (1 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
Toluene–water (4 : 1)
DME–water (4 : 1)
ACN–water (4 : 1)
Dioxane–water (4 : 1)
DMF–water (4 : 1)
[BMIM]BF4
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
EtOH–water (4 : 1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
PdCl2
10% Pd/C
Pd2(dba)3
4
0
0
76
98
5
Pd(OAc)2/dppp (1 : 1)
PdCl2/PPh3 (1 : 1)
Pd2(dba)3/tfp (1 : 1)
NiCl2(dppp)
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
0
90
86
73
88
93
KOH
K3PO4
Cs2CO3
a General reaction conditions: 3-amino-6-chloropyridazine 4 (0.5 mmol), 4-methoxy phenylboronic acid 5 (1.2 equiv), catalyst (3–10 mol%), base
(1.5 equiv), solvents (2 mL) and microwave irradiation at the given time, temperature using power 300 W. b Phase transfer catalyst. c GC-MS conversion
based on comparison of starting material and product peak intensities. d The figure in parentheses is the isolated yield based upon an average of three
reactions.
the reaction, with the ratio of solvent to co-solvent determining
the progress of the reaction. For example, the cross-coupling yield
increased to 100% (GC-MS conversion yield) in ethanol and water
(4 : 1) (entry 9) as compared to other solvent systems. Meanwhile,
a one to one volumetric ratio of ethanol–water made the cross-
coupling reaction sluggish (entry 8). Although ionic liquids have
been used for cross-coupling reactions, surprisingly, [BMIM]BF4
did not work in this reaction (entry 18). Among the catalysts
Scheme 1 Selective mono-amination of 3,6-dichlorpyridazine under
microwave irradiation.
tested, Pd(PPh3)4 was the most effective (entry 9). PdCl2/PPh3 and
Pd(OAc)2/dppp were also effective; however, Pd(OAc)2, PdCl2,
Pd/C, Pd2(dba)3, Pd2(dba)3/tfp and NiCl2(dppp) were inactive as
catalysts in this case. An investigation of the influence of the base
suggested that K2CO3 was the base of choice. Other bases such
as Na2CO3, KF, KOH, K3PO4 and Cs2CO3 also led to moderate
to good yields (entries 27–31). We have screened various catalysts,
solvents, bases and microwave irradiation conditions (temperature
and time) to optimize the Suzuki coupling reaction of unprotected
3-amino-6-chloropyridazine with 4-methoxy phenylboronic acid.
Finally, we found that reaction of 3-amino-6-chloropyridazine
(1.0 equiv), arylboronic acid (1.2 equiv), K2CO3 (1.5 equiv), and
5 mol% Pd(PPh3)4 in ethanol–water (4 : 1, 2 mL) under microwave
Due to environmental, economic and safety concerns, we
screened water as a solvent for the Suzuki coupling. Unfortunately
the transformation did not proceed, most likely due to poor sub-
strate solubility in water (entry 1). In addition, we found that when
water was used as a solvent with the addition of one equivalent of
phase transfer catalyst (TBAB, tetrabutylammonium bromide or
SDS, sodium dodecyl sulfate) to the reaction mixture it moderately
facilitated the reaction but required higher temperatures and
longer times to complete the coupling reaction (entries 2–4). How-
ever, an appropriately chosen solvent and co-solvent facilitated
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Table 2 Suzuki coupling of 3-amino-6-chloropyridazine with diversified
Table 2 (Cont.)
boronic acids under microwave irradiationa
Entry
p
Ar/HetAr-B(OH)2
Product (6a–q)
Yield (%)b
79
Entry
a
Ar/HetAr-B(OH)2
Product (6a–q)
Yield (%)b
94
q
75
b
c
d
e
f
88
95
86
90
92
a Reaction conditions: 3-amino-6-chloropyridazine
aryl/heteroaryl boronic acid (1.2 equiv), Pd(PPh3)4 (5 mol%), K2CO3
(1.5 equiv), EtOH–H2O (4 : 1, 2 mL) and microwave irradiation for 10
min at 120 ◦C using power 300 W. b Yields of the isolated products.
4
(1 mmol),
irradiation (CEM Discover S-Class microwave reactor: equipped
with single mode reactor and fiber optic temperature control;
method: dynamic mode at power 300 W) at 120 C with stirring
for 10 min gave the best result (6a in 100% GC-MS conversion
and 94% isolated yield, entry 9).
◦
As shown in Table 2, we utilized different boronic acids to
synthesize the corresponding 3-amino-6-arylpyridazines under
the optimized conditions. We were pleased to observe excellent
reactivity for a variety of electron-deficient (entries b–f and p),
electron-rich (entries a, g, j, k–m and q) and sterically hindered
arylboronic acids (entries h–j), as well as heteroaromatic boronic
acids (entries m–o) with yields being uniformly good to excellent.
For more challenging electronically unactivated and deactivated
arylboronic acids, the corresponding coupling products were
obtained in good to excellent yields (For example, entries a and
h–j). Also, a good yield (75%) was obtained for the coupling
reaction with unprotected 4-amino phenylboronic acid (entry q).
Chloro and amino substituents on the boronic acid and amino
substituent on the pyridazine ring were well tolerated under the
reaction conditions, which could extend the scope for further
functionalization of the pyridazine ring. Therefore, these results
reveal the broad substrate scope and high efficiency of microwave-
assisted protocol for the Suzuki coupling of unprotected 3-amino-
6-chloropyridazine, which are better than those reported to date
with conventional heating.
g
88
92
h
i
j
84
82
k
l
92
90
The alkylation of the endo amidinic system of 3-amino-6-
arylpyridazines with alkyl halides4f ,5a,b (Table 3) using microwave
irradiation was also explored. Under solvent and catalyst free
conditions, we obtained exclusively N(2)-alkylated 3-amino-6-(4¢-
methoxyphenyl)pyridazine. We found excellent reactivity for alkyl
halides bearing esters, phosphinates and nitriles with reactions
proceeding rapidly in uniformly good to excellent yields. Inter-
estingly, we also observed selective N(2) alkylation of 3-amino-6-
(4¢-methoxyphenyl)pyridazine with 3-bromo-1-propanol without
protecting hydroxy group (entry h). The selective N(2) alkylations
were confirmed by IR and NMR. Selective N(2) alkylation of
3-amino-6-(4¢-methoxyphenyl)pyridazine is thought to be due to
both steric effects of the phenyl ring and the electron-attracting
effect of the phenyl ring at the 6-position which makes the N(l)
m
n
86
91
o
87
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Table 3 Selective N(2)-alkylation of 3-amino-6-(4¢-methoxyphenyl) pyridazine under microwave irradiationa
Entry
a
R1–X
Product (7a–h)
Yield (%)b
84
R1 = (CH2)3COOEt; X Cl, (7a)
b
c
R1 = (CH2)3COOEt; X Br, (7b)
R1 = (CH2)2COOEt; X Br, (7c)
95
93
d
e
R1 = (CH2)4COOEt; X Br, (7d)
R1 = (CH2)3PO(OEt)2; X Br, (7e)
96
90
f
R1 = (CH2)3CN; X Br, (7f)
R1 = (CH2)4; X Br, (7g)
R1 = (CH2)3OH; X Br, (7h)
84 (92)c
93
g
h
52d
a Reaction conditions: 3-amino-6-(4¢-methoxyphenyl)pyridazine 6a (1 mmol), alkyl halide (1.2 equiv) and microwave irradiation for 15 min at 80 ◦C using
power 300 W. b Yields of the isolated products. c The reaction was carried out in the presence of 0.1 mL DMF. d The reaction was carried out for 1 h in
the presence of 0.1 mL DMF.
nitrogen less nucleophilic.5b The solvent-free, metal-free, non-
hazardous experimental condition, short reaction times, ease of
product isolation/purification and high yields fulfilled the triple
bottom-line philosophy of green chemistry and made the present
methodology environmentally benign.
useful scaffold for the synthesis of novel gabazine analogues with
demonstrated biological activity at GABA receptors.
Experimental section
We demonstrated the synthetic utility of the powerful strategy
for the four-step synthesis of neuroactive gabazine (SR-95531)
2. An efficient and inexpensive total synthesis of gabazine 2 was
achieved using the versatile strategy in four steps and 73% overall
yield (Scheme 2). To date, there is only one report by Wermuth
et al. (1987),5b which describes a seven-step conventional strategy
for the preparation of gabazine 2 which involves the synthesis of
the pyridazinone intermediate.
General details
All glass apparatus were oven dried prior to use. All chemicals
used were purchased from Aldrich Chemical Co. Ltd. (St Louis,
MO), Boron Molecular Inc. (NC, USA) and were of highest
commercially available purity. All solvents were distilled by
standard techniques prior to use. Where stated, reactions were
performed under an inert atmosphere of nitrogen. Melting points
were measured on a Stuart SMP10 (UK) melting point apparatus.
1H NMR spectra were recorded at 400 MHz using a Varian
(Palo Alto, CA) Gemini 400 spectrometer. Chemical shifts (d)
are quoted in parts per million (ppm), referenced externally to
tetramethylsilane at 0 ppm. 13C NMR spectra were recorded at
100 MHz using a Varian (USA) 400 MI spectrometer. Chemical
shifts (d) are quoted in ppm, referenced internally to CDCl3
at 77.0 ppm. All coupling constants (J) are given in Hertz.
Low Resolution Mass Spectra (LRMS) was carried out using a
Bruker (USA) Daltronics BioApexII with a 7T superconducting
magnet and an analytical ESI source. High Resolution Mass
Spectra (HRMS) were obtained by the Mass Spectrometry Unit
at the School of Chemistry, The University of Sydney, on a
Conclusions
In conclusion, we have successfully developed an efficient and ver-
satile protocol for the synthesis of diversified 2,3,6-trisubstituted
pyridazines under microwave irradiation. The synthesis of syn-
thetically and biologically important 2,3,6-trisubstituted pyri-
dazine architectures have been developed by sequential selective
amination/Suzuki coupling/selective N(2) alkylation reactions.
Furthermore, The significance of the approach is demonstrated
by synthesizing neuroactive gabazine 2 in four steps and in high
yield. Finally, these aminopyridazine frameworks can provide a
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Representative procedure for the synthesis of 6a–q:
3-amino-6-(4¢-methoxyphenyl)pyridazine (6a)9c
To a thick-wall borosilicate glass vial (10 mL) were added 3-
amino-6-chloropyridazine 4 (129 mg, 1 equiv.), K2CO3 (206 mg,
1.5 equiv.), 4-methoxy phenylboronic acid 5 (181 mg, 1.2 equiv.),
Pd(PPh3)4 (57 mg, 5 mol%) and ethanol–water (4 : 1, 2 mL). The
mixture was degassed with nitrogen for 5 min and then vial was
sealed with a lid. The reaction mixture was pre-stirred for 1 min
to ensure sufficient mixing of the reagents. The reaction mixture
was irradiated at 120 ◦C for 10 min at the maximum power of 300
W. The reaction mixture is filtered and extracted with ethyl acetate
(the product can also purified without extraction by flash chro-
matography: the reaction mixture is dried under reduced pressure
and crude mixture is directly loaded on flash chromatography for
purification). The collected organic extracts were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The crude was
purified by flash chromatography [EtOAc–MeOH (98 : 2)/TFA
2%] to furnish 3-amino-6◦-(4¢-methoxyphenyl)pyridazine 6a (white
solid, 94%). mp 195–198 C. 1H NMR (400 MHz, DMSO): d 7.88
(d, 2H, J = 8.8 Hz), 7.73 (d, 1H, J = 9.2 Hz), 7.00 (d, 2H, J = 8.8
Hz), 6.81 (d, 1H, J = 9.2 Hz), 6.34 (s, 2H), 3.78 (s, 3H). MS (ESI)
m/z = 202.33 [M + 1]. HRMS (ESI) calcd for C11H11N3O [M+]
201.0902, found 201.0904.
Scheme 2 Total synthesis of gabazine (SR-95531) 2.
Bruker 7T Fourier Transform Ion Cyclotron Resonance Mass
Spectrometer. GCMS was performed on a PolarisQ GC-MS-
MS ion trap mass spectrometer coupled to a Trace GC and
automated injections were performed on an AS2000 Autosampler.
Thin layer chromatography was performed on Merck aluminium
backed plates, precoated with silica (0.2 mm, 60F254), which were
developed using one of the following techniques: UV fluorescence
(254 nm), alkaline potassium permanganate solution (0.5% w/v)
or ninhydrin (0.2% w/v) and Iodine vapors. Flash chromatography
was performed on silica gel (Merck silica gel 60H, particle size 5–
40 mm).
Representative procedure for the synthesis of 7a–h: ethyl-4-[6-
imino-3-(4-methoxyphenyl)pyridazin-1-yl]butanoic acid
hydrobromide (7b)
To a thick-wall borosilicate glass vial (10 mL) were added 3-
amino-6-(4-methoxyphenyl)pyridazine 6a (200 mg, 1 equiv.), ethyl
4-bromobutyrate (0.17 mL, 1.2 equiv.). The vial was sealed with
a lid and then reaction mixture was pre-stirred for 1 min to
ensure sufficient mixing of the reagents. The reaction mixture was
irradiated at 80 ◦C for 15 min at the maximum power of 300 W. The
hot solution was poured with stirring into ethyl acetate (30 mL),
affording a crystalline compound to give ethyl-4-[6-imino-3-(4-
methoxyphenyl)pyri-dazin-1-yl]butanoic◦ acid hydrobromide 7b
(off-white solid, 95% yield). mp 239–242 C. 1H NMR (400 MHz,
DMSO): d 9.00 (brs, 2H), 8.38 (d, 1H, J = 9.2 Hz), 7.93 (d, 2H,
J = 9.2 Hz), 7.62 (d, 1H, J = 9.6 Hz), 7.11 (d, 2H, J = 9.2 Hz),
4.35–4.31 (t, 2H, J = 6.8 Hz), 3.96–3.91 (q, 2H), 3.82 (s, 3H), 2.12-
2.03 (m, 2H), 1.09–1.05 (t, 3H, J = 6.8 Hz).). 13C NMR (100 MHz,
DMSO): d 172.64, 161.90, 152.48, 149.66, 131.47, 128.45, 126.22,
125.46, 115.10, 60.49, 55.94, 55.54, 30.57, 21.97, 14.42. MS (ESI)
m/z = 317.27 [M + 1]; HRMS (ESI) calcd for C17H22N3O3 [M+ -
Br] 316.1661, found 316.1655.
Microwave details
All microwave irradiation reactions were conducted by using
CEM Discover S-Class microwave reactor (single mode reactor,
method: dynamic mode at power 300 W). The microwave reactor
is equipped with fiber optic temperature control.
Synthesis of 3-amino-6-chloropyridazine (4)
To a thick-wall borosilicate glass vial (30 mL) were added 3,6-
dichloropyridazine 3 (1.5 g) and NH4OH solution (5 mL; NH3
content: 28 to 30%). The vial was sealed with a lid and placed
in the microwave reactor for 30 min at 120 ◦C (power: 300 W).
After cooling down, the precipitate that deposited was filtered
off, washed with ethyl acetate–hexane (3 : 7), dried to give as a
light yellowish-white solid of 3-amino-6-chloropyridazine 4 (87%
yield, require no further purification). mp 229–232 ◦C. 1H NMR
(400 MHz, DMSO): d 7.35 (d, 1H, J = 9.2 Hz), 6.83 (d, 1H, J =
9.2 Hz), 6.59 (s, 2H). 13C NMR (100 MHz, DMSO): d 160.76,
145.45, 129.43, 117.99. MS (ESI) m/z = 130.46 [M + 1]. HRMS
(ESI) calcd for C4H4N3Cl [M+] 129.5477, found 129.5662.
Synthesis of gabazine (SR-95531) 2
To a solution of ethyl-4-[6-imino-3-(4-methoxyphenyl)pyri-dazin-
1-yl] butanoic acid hydrobromide 7b (500 mg) in water (1.5 mL)
was added NaOH (208 mg) at room temperature. The resulting
mixture was stirred for 2 h, maintaining 40–45 ◦C using conven-
tional heating. After cooling to 10 ◦C, to the reaction mixture was
added water (5 mL) and ethyl acetate (10 mL). The aqueous layer
was separated, washed with ethyl acetate (2.5 mL) and treated
with 17.5% hydrogen chloride in water to adjust the pH to 0.5–1.0
◦
◦
at 20–25 C. The resulting mixture was further stirred at 0–5 C
for 1 h, and the precipitate was filtered off and washed with water
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(1 mL). Drying under reduced pressure afforded crude gabazine 2
(375 mg, 90% yield) of 95% purity as a light yellowish solid. The
crude gabazine 2 (375 mg) was treated with carbon (15 mg) in a
mixture of 2-propanol (2 mL) and water (1 mL) at 80 ◦C. The
filtrate was cooled to 0 ◦C, and the precipitate was filtered off and
washed with a mixture of 2-propanol (0.5 mL) and water (0.3 mL),
and successively water (0.5 mL). Drying under reduced pressure
afforded purified gabazine 2 (347 mg, 85% yield) of 100% purity
as a white solid. mp 219–222 C. H NMR (400 MHz, DMSO):
d 12.25 (brs, 1H), 8.95 (brs, 2H), 8.37 (d, 1H, J = 9.6 Hz), 7.93
(d, 2H, J = 9.2 Hz), 7.58 (d, 1H, J = 9.6 Hz), 7.11 (d, 2H, J = 9.2
Hz), 4.33–4.29 (t, 2H, J = 6.8 Hz), 3.82 (s, 3H), 2.42–2.38 (t, 2H,
J = 14.4 Hz), 2.09–2.02 (m, 2H). 13C NMR (100 MHz, DMSO):
d 174.18, 161.88, 152.48, 149.73, 131.51, 128.51, 126.18, 125.54,
115.10, 55.92, 55.54, 30.65, 22.14. MS (ESI) m/z = 288.07 [M+];
HRMS (ESI) calcd for C15H18N3O3 [M+ - Cl] 288.1348, found
288.1337.
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◦
1
Acknowledgements
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We are thankful to Bruce Tattam and Dr Keith Fischer for techni-
cal assistance with GC-MS and mass spectrometry measurements.
N.G. acknowledges support from an Endevour International Post-
graduate Research Scholarship [EIPRS] and the John Lamberton
Scholarship.
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