Tandem CH-activation-imine-formation reaction: A new route to imidazo[2,1-a]phthalazines

Article abstract of DOI:10.1055/s-0028-1088057

A general and efficient synthesis of imidazo[2,1-a]phthalazines by palladium- and copper-mediated coupling of N-aminoimidazoles with 2-haloaryl aldehydes with concurrent imine formation is described. This new synthesis of the imidazo[2,1-a]phthalazine rin

Full text of DOI:10.1055/s-0028-1088057

PAPER
1715
Tandem CH-Activation–Imine-Formation Reaction: A New Route to
Imidazo[2,1-a]phthalazines
New
R
oute to Imid
l
azo[2,
e
a
]
phthala
x
zines ander Heim-Riether,* Kevin R. Gipson
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA
Fax +1(203)7916072; E-mail: alexander.heim-riether@boehringer-ingelheim.com
Received 14 December 2008
NH2
N
H
O
EtO
O
Abstract: A general and efficient synthesis of imidazo[2,1-a]ph-
thalazines by palladium- and copper-mediated coupling of N-ami-
noimidazoles with 2-haloaryl aldehydes with concurrent imine
formation is described. This new synthesis of the imidazo[2,1-a]ph-
thalazine ring system allows for facile introduction of different sub-
stituents around the entire core.
Pd(OAc)2 (cat.), CuI (2 equiv)
Ph3P, Cs2CO3
Br
+
N
1
2
O
Key words: imidazo[2,1-a]phthalazine, imine formation, CH acti-
vation, N-aminoimidazoles, 2-bromoaryl aldehydes
H
N
N
N
NH2
N
EtO
N
EtO
EtO
and/or
Br
O
O
N
O
N
N
Imidazo[2,1-a]phthalazines have not been extensively ex-
plored as templates for drug discovery despite reported
antihypertensive and anti-inflammatory activity.1 One ex-
planation could be that no efficient synthesis allowing fac-
ile SAR explorations around this heterocycle has been
reported.1,2 Most published procedures start from or re-
quire construction of the pththalazine core and are there-
fore limited by the commercial availability or synthetic
accessibility of suitable precursors. The most versatile
synthesis, allowing for various substituents at the imida-
zole and pyridazine rings, involves direct cyclization of 1-
aminophthalazines with a-halocarbonyl compounds.1c
The yields for substrates having nonaromatic substituents
on the imidazole moiety similar to the ones described in
this paper vary from 6–33%. No substitution around the
phenyl moiety is reported.
3a
3b
4
Scheme 1 Palladium-catalyzed and copper-mediated arylation and
imine formation
After reviewing several published procedures, we subject-
ed a mixture of N-aminoimidazole 1 and 1.1 equivalents
of 2-bromobenzaldehyde (2) to typical conditions for di-
rect arylations of azoles [10 mol% Pd(OAc)2, 20 mol%
PPh3, 2 equiv CuI, 1 equiv Cs2CO3, DMF, 140 °C, 12 h]4
and isolated 4 in around 30% yield. We increased the
yield to 40–46% by shortening the reaction time to one
hour. Regardless of the reaction time, we did not observe
either of the two anticipated intermediates 3a or 3b by
LC–MS during the course of the reaction. However, imine
3a was formed quantitatively (LC–MS) in reactions hav-
ing only one of the metals present (Table 1, entries 6 and
7).6 We subjected imine 3a to the standard conditions with
palladium and copper(I) iodide. We observed conversion
to 4 and isolated it in the same yield as in the original re-
action between 1 and 2. This demonstrated that imine 3a
is a competent substrate under these arylation conditions
and may be an intermediate in the reaction of 1 and 2. It
can be hypothesized that once formed, 3a generates a pal-
ladacycle after oxidative insertion of the palladium into
the aryl bromide bond and therefore acts as its own
ligand.7 This hypothesis is supported by the fact that re-
ducing the phosphine ligand ratio (Table 1, entry 3),
changing the ligand (entry 2),8 or removing it altogether
(entry 4)9 does not significantly influence the outcome of
the reaction. However, since the yield was consistently
slightly better in the presence of triphenylphosphine, it
was included in the reaction conditions.
Interested in a route that would allow facile introduction
of different substitutions on the imidazo as well as the
phenyl portions of the imidazo[2,1-a]phthalazine core, we
investigated a reaction sequence between N-aminoimida-
zoles and 2-haloaryl aldehydes (Scheme 1).
Unlike substituted 1-aminophthalazines, a variety of sub-
stituted 2-haloaryl aldehydes are commercially available.
N-Amination of readily available substituted imidazoles
furnishes N-aminoimidazoles such as 13 which contain the
nitrogen of the future pyridazine ring. Palladium-cata-
lyzed arylation of azole CH bonds with aryl halides has
developed into a powerful synthetic methodology4 and in
situ benzaldehyde imine formation under cross-coupling
conditions is precedented.5 Thus, we anticipated that a
mixture of N-aminoimidazole 1 and 2-bromobenzalde-
hyde (2) would undergo coupling and imine formation to
give the desired imidazo[2,1-a]phthalazine 4.
The overall yield of 46% seems modest, but one has to
keep in mind that this is a two-step process without the use
of any protecting groups. We already applied the opti-
SYNTHESIS 2009, No. 10, pp 1715–1719
Advanced online publication: 20.04.2009
x
x.
x
x
.
2
0
0
9
DOI: 10.1055/s-0028-1088057; Art ID: M07708SS
© Georg Thieme Verlag Stuttgart · New York

1716
A. Heim-Riether, K. R. Gipson
PAPER
Table 1 Screened Conditionsa
Table 2 2-Bromobenzaldehyde Variations
Pd(OAc)2 (10 mol%)
Ph3P (20 mol%)
Entry
Pd
(OAc)2
CuI
Ligand
Yield of 4
(%)b
CuI (2 equiv)
Cs2CO3 (1 equiv)
DMF, 140 °C, 1 h
NH2
N
H
O
EtO
O
N
N
EtO
O
R3
1
2
3
4
6
7
0.1
0.1
0.1
0.1
–
2.0
2.0
2.0
2.0
2.0
–
0.2 PPh3
46
35
42
35
0
Br
+
N
0.2 MeP(t-Bu)2·HBF4
0.1 PPh3
N
R3
Entry Aldehyde
Product
Yield
(%)b
–
0.2 PPh3
O
N
EtO
O
0.1
0.2 PPh3
0
1a
4
46
N
H
a All reactions were performed with 1 equiv of Cs2CO3 in DMF at
N
Br
O
140 °C for 1 h.
b Isolated yields.
OMe
N
N
EtO
O
OMe
mized conditions for azole arylations published by the ex-
perts in the field.4 Thus, we concentrated on exploring
substituents around the ring after unsatisfying results from
the most commonly applied changes in screening condi-
tions such as using Pd2(dba)3 instead of Pd(OAc)2, ex-
changing the alternative base CsF for Cs2CO3, increasing
or decreasing the reaction temperature and lowering the
amount of copper to one equivalent. Therefore, our best
conditions giving consistently moderate yields between
40–46% proved to be the original conditions with a short-
ened reaction time of one hour.
2
39
20
5
6
H
N
Br
O
O
O
N
EtO
O
N
3
O
O
H
N
N
Br
O
CF3
N
N
EtO
O
CF3
4
43
44
7
8
H
No significant amount of isolable by-product(s) was ob-
served. However, decomposed starting materials, possi-
bly deaminated aminoimidazole or debrominated
benzaldehyde, would be difficult to observe by LC–MS
and may be lost during the workup. Minor NMR signals
characteristic of aldehyde and additional ethyl ester pro-
Br
O
F
N
N
EtO
O
F
5
H
N
N
1
Br
O
tons were observed in the H NMR of the crude after
workup.
N
N
EtO
O
With our optimized conditions in hand, we investigated
the scope of the reaction by varying substitutions around
the benzaldehyde (Table 2) and the 1-aminoimidazole
precursor (Table 3).
6
28
27
9
H
F
Br
O
F
N
Both electron donating and electron withdrawing groups
appear equally tolerated (Table 2, entries 1–7). We be-
lieve the aldehyde/imine functional groups dominate the
electronics of the ring and that additional substituents
have only minor effects on yield.
EtO
O
N
7
10
H
N
N
Br
N
O
We also investigated the reaction using 2-bromoacetophe-
none as a model to install substituents on the pyridazine
ring (Table 2, entry 8). The fact that ketones are in general
less reactive than aldehydes in intermolecular imine for-
mations may explain the very low yield.
N
EtO
O
8
7
11
N
Br
N
a 2-Iodobenzaldehyde did not influence the yield.
b Isolated yields.
Varying the 1-aminoimidazole precursor furnished the
desired imidazo[2,1-a]phthalazines 12–14 (Table 3) in
comparable yields to the ones obtained by using different
aldehydes.
zoles with 2-bromoaryl aldehydes with preceding or
concurrent imine formation. This method allows the syn-
thesis of diversely substituted derivatives on the imidazo
and benzene part of the core structure. Overall, the yields
In summary, we have developed a general and efficient
one-step synthesis for imidazo[2,1-a]phthalazines via pal-
ladium- and copper-mediated coupling of N-aminoimida-
Synthesis 2009, No. 10, 1715–1719 © Thieme Stuttgart · New York

PAPER
New Route to Imidazo[2,1-a]phthalazines
1717
13C NMR (100 MHz, CDCl3): d = 158.9 (C=O), 147.7, 144.8 (CH),
137.1, 132.3 (CH), 129.1 (CH), 126.5 (CH), 123.4, 122.1, 121.9
(CH), 116.3, 59.7 (CH2), 15.4 (CH3), 13.4 (CH3).
HRMS (APCI+): m/z [M + H]+ calcd for C14H14N3O2: 256.1080;
found: 256.1078.
Table 3 1-Aminoimidazole Variations
Pd(OAc)2 (10 mol%)
Ph3P (20 mol%)
CuI (2 equiv)
Cs2CO3 (1 equiv)
DMF, 140 °C, 1 h
H
O
N
N
NH2
N
R2
Br
R2
+
N
N
Ethyl 8-Methoxy-2-methylimidazo[2,1-a]phthalazine-3-car-
boxylate (5)
R1
R1
Starting from 1 (100 mg, 0.59 mmol) and 2-bromo-5-methoxy-
benzaldehyde (140 mg, 0.65 mmol), compound 5 was obtained as a
white solid (66 mg, 39%).
1H NMR (400 MHz, CDCl3): d = 8.75 (s, 1 H), 8.49 (d, J = 8.9 Hz,
1 H), 7.24 (d, J = 2.3 Hz, 1 H), 4.47 (q, J = 7.2 Hz, 2 H), 3.96 (s, 3
H), 2.74 (s, 3 H), 1.44 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 160.9, 160.2 (C=O), 149.2, 145.0
(CH), 138.7, 124.9, 124.7 (CH), 123.6 (CH), 118.8, 116.7, 107.5
(CH), 60.5 (CH2), 55.8 (CH3), 16.6 (CH3), 14.5 (CH3).
Entry Imidazole
Product
Yield (%)a
25
NH2
N
N
MeO
MeO
1
12
N
O
O
N
N
NH2
N
N
N
2
45
31
HRMS (APCI+): m/z [M + H]+ calcd for C15H16N3O3: 286.1186;
found: 286.1184.
13
N
N
EtO
O
EtO
O
Ethyl 2-Methyl-7,9-dioxa-1,3a,4-triazadicyclopenta[a,g]naph-
thalene-3-carboxylate (6)
Starting from 1 (100 mg, 0.59 mmol) and 6-bromobenzo[1,3]di-
oxole-5-carbaldehyde (149 mg, 0.65 mmol), compound 6 was ob-
tained as a white solid (36 mg, 20%).
1H NMR (400 MHz, DMSO-d6): d = 8.91 (s, 1 H), 7.78 (s, 1 H),
7.62 (s, 1 H), 6.31 (s, 2 H), 4.35 (q, J = 7.2 Hz, 2 H), 2.62 (s, 3 H),
1.34 (t, J = 7.2 Hz, 3 H).
NH2
N
N
N
3
14
N
N
a Isolated yields.
13C NMR (100 MHz, DMSO-d6): d = 159.1 (C=O), 152.4, 149.9,
148.4, 144.5 (CH), 137.9, 121.1, 119.6, 115.9, 105.2 (CH), 102.9
(CH), 99.8 (CH2), 59.9 (CH2), 16.1 (CH3), 14.3 (CH3).
are low to moderate, but acceptable taking into account
the ease of this reaction and the lack of efficient alterna-
tive one-step procedures.
HRMS (APCI+): m/z [M + H]+ calcd for C15H14N3O4: 300.0978;
found: 300.0977.
All chemicals used, including anhydrous solvents, were of reagent
grade and used as supplied. Chromatography was carried out on sil-
ica gel, TLC on silica plates (Merck, Art. 5554). In general, the
course of reactions was followed by TLC and/or LC–MS. NMR
spectra were obtained on a Bruker DPX-400 spectrometer at 400
MHz. LC–MS data was recorded utilizing the electrospray (ESI)
technique. HRMS data was acquired using a Thermo LTQFT Ultra
Mass Spectrometer in APCI+ mode. This instrument achieved a
mass resolution of greater than 100 000.
Ethyl 2-Methyl-8-trifluoromethylimidazo[2,1-a]phthalazine-3-
carboxylate (7)
Starting from 1 (100 mg, 0.59 mmol) and 2-bromo-5-trifluorometh-
ylbenzaldehyde (165 mg, 0.65 mmol), compound 7 was obtained as
a white solid (83 mg, 43%).
1H NMR (400 MHz, CDCl3): d = 8.92 (s, 1 H), 8.73 (d, J = 8.4 Hz,
1 H), 8.24 (s, 1 H), 8.11 (dd, J = 8.4, 1.5 Hz, 1 H), 4.50 (q, J = 7.2
Hz, 2 H), 2.79 (s, 3 H), 1.47 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.8 (C=O), 149.6, 145.1 (CH),
136.9, 131.7 (q, J = 33.3 Hz, CCF3), 129.2 (d, J = 3.0 Hz, CH),
126.7, 124.9 (d, J = 4.0 Hz, CH), 124.1 (CH), 123.4 (d, J = 273.0
Hz, CF3), 122.4, 118.0, 60.9 (CH2), 16.6 (CH3), 14.4 (CH3).
HRMS (APCI+): m/z [M + H]+ calcd for C15H13F3N3O2: 324.0954;
found: 324.0951.
Imidazo[2,1-a]phthalazines; General Procedure
In a sealed tube, 1-aminoimidazole10 (0.59 mmol), bromobenzalde-
hyde (0.65 mmol, 1.1 equiv), PPh3 (31 mg, 0.12 mmol, 0.2 equiv),
Pd(OAc)2 (13.3 mg, 0.06 mmol, 0.1 equiv), Cs2CO3 (192.2 mg, 0.59
mmol, 1.0 equiv), and CuI (224.9 mg, 1.18 mmol, 2.0 equiv) were
dissolved in anhyd DMF (2 mL). The tube was evacuated and
flushed with argon before it was heated at 140 °C for 1 h. After
cooling to r.t., EtOAc (20 mL) was added and the mixture was ex-
tracted with NH4OH (6 M, 20 mL). The aqueous layer was re-ex-
tracted with EtOAc (20 mL) and the combined organic layers were
washed with brine (10 mL) and dried (MgSO4). After removal of the
solvent, the crude residue was purified on silica gel (gradients: 0–
75% EtOAc in hexane).
Ethyl 8-Fluoro-2-methylimidazo[2,1-a]phthalazine-3-carboxy-
late (8)
Starting from 1 (100 mg, 0.59 mmol) and 2-bromo-5-fluorobenzal-
dehyde (132 mg, 0.65 mmol), compound 8 was obtained as a white
solid (65 mg, 40%).
1H NMR (400 MHz, CDCl3): d = 8.79 (s, 1 H), 8.62 (dd, J = 9.0, 5.1
Hz, 1 H), 7.64 (m, 1 H), 7.58 (dd, J = 8.2, 2.4 Hz, 1 H), 4.48 (q,
J = 7.2 Hz, 2 H), 2.76 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 162.9 (d, J = 253 Hz, CF), 159.9
(C=O), 149.3, 144.5 (d, J = 3.4 Hz, CH), 137.8, 125.9 (d, J = 8.6
Hz, CH), 124.5 (d, J = 8.6 Hz, C), 122.4 (d, J = 24 Hz, CH), 121.4,
117.3, 112.3 (d, J = 22 Hz, CH), 60.1 (CH2), 16.5 (CH3), 14.5
(CH3).
Ethyl 2-Methylimidazo[2,1-a]phthalazine-3-carboxylate (4)
Starting from ethyl 3-amino-5-methyl-3H-imidazole-4-carboxylate
(1; 100 mg, 0.59 mmol) and 2-bromobenzaldehyde (2; 120 mg, 0.65
mmol), compound 4 was obtained as a white solid (69 mg, 46%).
1H NMR (400 MHz, CDCl3): d = 8.85 (s, 1H), 8.61 (dd, J = 8.0, 0.5
Hz, 1 H), 7.94 (d, J = 8.0 Hz, 1 H), 7.92 (m, 1 H), 7.78 (m, 1 H),
4.48 (q, J = 7.2 Hz, 2 H), 2.78 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).
Synthesis 2009, No. 10, 1715–1719 © Thieme Stuttgart · New York

1718
A. Heim-Riether, K. R. Gipson
PAPER
Ethyl 3-Methylimidazo[2,1-a]phthalazine-2-carboxylate (13)
HRMS (APCI+): m/z [M + H]+ calcd for C14H13FN3O2: 274.0986;
found: 274.0984.
Starting from ethyl 1-amino-5-methyl-1H-imidazole-4-carboxylate
(100 mg, 0.59 mmol) and 2 (120 mg, 0.65 mmol), compound 13 was
obtained as a white solid (67 mg, 45%).
1H NMR (400 MHz, CDCl3): d = 8.69 (d, J = 8.0 Hz, 1 H), 8.68 (s,
1 H), 7.90–7.85 (m, 2 H), 7.73–7.69 (m, 1 H), 4.50 (q, J = 7.2 Hz,
2 H), 2.89 (s, 3 H), 1.48 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 158.9 (C=O), 147.7, 144.8 (CH),
137.1, 132.3 (CH), 129.1 (CH), 126.5 (CH), 123.4, 122.1, 121.9
(CH), 116.3, 59.7 (CH2), 15.4 (CH3), 13.4 (CH3).
Ethyl 9-Fluoro-2-methylimidazo[2,1-a]phthalazine-3-carboxy-
late (9)
Starting from 1 (100 mg, 0.59 mmol) and 2-bromo-4-fluorobenzal-
dehyde (132 mg, 0.65 mmol), compound 9 was obtained as a white
solid (47 mg, 29%).
1H NMR (400 MHz, CDCl3): d = 8.80 (s, 1 H), 8.22 (dd, J = 8.8, 2.5
Hz, 1 H), 7.96 (dd, J = 8.8, 5.1 Hz, 1 H), 7.48 (m, 1 H), 4.48 (q,
J = 7.2 Hz, 2 H), 2.76 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): d = 165.1 (d, J = 256 Hz, CF), 159.9
(C=O), 149.2, 144.7 (CH), 137.5 (d, J = 3.9 Hz, C), 130.6 (d,
J = 9.5 Hz, CH), 126.8 (d, J = 11.0 Hz, C), 119.9, 119.2 (d, J = 24.0
Hz, CH), 117.6, 108.4 (d, J = 24.0 Hz, CH), 60.8 (CH2), 16.6 (CH3),
14.5 (CH3).
HRMS (APCI+): m/z [M + H]+ calcd for C14H14N3O2: 256.1080;
found: 256.1078.
Benzimidazo[2,1-a]phthalazine (14)
Starting from benzimidazol-1-ylamine (100 mg, 0.75 mmol, new
reference for calculation of all additional reagents) and 2 (153 mg,
0.83 mmol), compound 14 was obtained as a beige solid (51 mg,
31%).
HRMS (APCI+): m/z [M + H]+ calcd for C14H13FN3O2: 274.0986;
found: 274.0984.
1H NMR (400 MHz, CDCl3): d = 8.72 (d, J = 7.4 Hz, 1 H), 8.61 (s,
1 H), 8.08 (d, J = 7.4 Hz, 1 H), 7.99 (d, J = 8.1 Hz, 1 H), 7.91–7.87
(m, 2 H), 7.79–7.74 (m, 1 H), 7.55–7.45 (m, 2 H).
13C NMR (100 MHz, CDCl3): d = 143.5 (CH), 142.1, 141.4, 133.0
(CH), 131.5, 130.7 (CH), 127.8 (CH), 125.5, 125.1 (CH), 124.6,
123.9 (CH), 123.1 (CH), 120.0 (CH), 111.2 (CH).
Ethyl 2-Methyl-1,3a,4,9-tetraazabenz[e]indene-3-carboxylate
(10)
Starting from 1 (100 mg, 0.59 mmol) and 2-bromopyridine-3-
carbaldehyde (121 mg, 0.65 mmol), compound 10 was obtained as
a white solid (40 mg, 26%).
1H NMR (400 MHz, CDCl3): d = 9.22 (dd, J = 4.6, 1.5 Hz, 1 H),
8.87 (s, 1 H), 8.28 (dd, J = 8.2, 1.5 Hz, 1 H), 7.72 (dd, J = 8.2, 4.6
Hz, 1 H), 4.50 (q, J = 7.2 Hz, 2 H), 2.82 (s, 3 H), 1.47 (t, J = 7.2 Hz,
3 H).
HRMS (APCI+): m/z [M + H]+ calcd for C14H10N3: 220.0869;
found: 220.0867.
13C NMR (100 MHz, CDCl3): d = 159.9 (C=O), 155.9 (CH), 150.1,
144.8 (CH), 140.9, 137.9, 135.1 (CH), 124.8 (CH), 118.8, 118.1,
60.9 (CH2), 16.7 (CH3), 14.4 (CH3).
HRMS (APCI+): m/z [M + H]+ calcd for C13H13N4O2: 257.1033;
found: 257.1031.
Acknowledgment
We thank Chris Robak for HRMS experimentation. Additional
thanks go to Dr. Matthew Netherton and Dr. Neil Moss for
proofreading the manuscript.
Ethyl 2,6-Dimethylimidazo[2,1-a]phthalazine-3-carboxylate
(11)
Starting from 1 (100 mg, 0.59 mmol) and 1-(2-bromophenyl)eth-
anone (130 mg, 0.65 mmol), compound 11 was obtained as a white
solid (11 mg, 7%).
1H NMR (300 MHz, CDCl3): d = 8.61 (d, J = 8.0 Hz, 1 H), 8.01 (d,
J = 8.0 Hz, 1 H), 7.88–7.86 (m, 1 H), 7.78–7.74 (m, 1 H), 4.47 (q,
J = 7.2 Hz, 2 H), 2.92 (s, 3 H), 2.76 (s, 3 H), 1.45 (t, J = 7.2 Hz, 3
H).
13C NMR (100 MHz, CDCl3): d = 160.2 (C=O), 152.2, 148.6, 138.4,
132.7 (CH), 129.9 (CH), 125.8 (CH), 124.5, 123.3 (CH), 117.1,
60.5 (CH2), 20.1 (CH3), 16.5 (CH3), 14.4 (CH3).
References
(1) (a) Hardtmann, G. E. US Patent 3 711 481, Chem. Abstr.
1973, 78, 84430. (b) Razvi, M.; Ramalingam, T. Indian J.
Chem., Sect. B: Org. Chem. Incl. Med. Chem. 1992, 31, 788.
(c) Catarzi, D.; Cecchi, L.; Colotta, V.; Conti, G.; Melani, F.;
Filacchioni, G.; Martini, C.; Giusti, L.; Lucacchini, A.
Farmaco 1993, 48, 447.
(2) (a) Castle, R. N.; Takano, S. J. Heterocycl. Chem. 1966, 3,
381. (b) Barlin, G. B. Aust. J. Chem. 1986, 39, 1803.
(c) Mavel, S.; Thery, I.; Gueiffier, A. Arch. Pharm. Pharm.
Med. Chem. 2002, 335, 7. (d) Solyom, S.; Hamori, T.;
Borosy, A. P.; Tarnawa, I.; Berzsenyi, P.; Pallagi, I. Med.
Chem. Res. 2002, 11, 39. (e) Shubin, K. M.; Kuznetsov, V.
A.; Galishev, V. A. Tetrahedron Lett. 2004, 45, 1407.
(f) Kuznetsov, V. A.; Shubin, K. M.; Schipalkin, A. A.;
Petrov, M. L. Tetrahedron 2006, 62, 10018. (g) Parenty, A.
D. C.; Song, Y.-F.; Richmond, C. J.; Cronin, L. Org. Lett.
2007, 9, 2253.
(3) (a) Heim-Riether, A.; Healy, J. J. Org. Chem. 2005, 70,
7331. (b) N-Amination of imidazoles leads to separable
regioisomers.
(4) (a) For a review, see: Miura, M.; Nomura, M. Top. Curr.
Chem. 2002, 219, 211. For most recent examples of direct
intermolecular Pd-catalyzed arylation of azoles, see:
(b) Yokooji, A.; Okazawa, T.; Satoh, T.; Miura, M.;
Nomura, M. Tetrahedron 2003, 59, 5685. (c) Mori, A.;
Sekiguchi, A.; Masui, K.; Shimada, T.; Horie, M.; Osakada,
HRMS (APCI+): m/z [M + H]+ calcd for C15H16N3O2: 270.1237;
found: 270.1235.
Methyl Imidazo[2,1-a]phthalazine-3-carboxylate (12)
Starting from methyl 3-amino-3H-imidazole-4-carboxylate (100
mg, 0.71 mmol, new reference for calculation of all additional re-
agents) and 2-bromobenzaldehyde (2; 144 mg, 0.78 mmol), com-
pound 12 was obtained as a white solid (40 mg, 25%).
1H NMR (400 MHz, CDCl3): d = 8.91 (s, 1 H), 8.64 (dd, J = 8.1, 0.8
Hz, 1 H), 8.29 (s, 1 H), 7.99–7.93 (m, 2 H), 7.84–7.79 (m, 1 H), 3.99
(s, 3 H).
13C NMR (100 MHz, CDCl3): d = 159.5 (C=O), 146.7 (CH), 140.1,
138.6 (CH), 133.6 (CH), 130.3 (CH), 127.7 (CH), 125.3, 123.1
(CH), 120.5, 51.9 (CH3).
HRMS (APCI+): m/z [M + H]+ calcd for C12H10N3O2: 228.0767;
found: 228.0766.
Synthesis 2009, No. 10, 1715–1719 © Thieme Stuttgart · New York

PAPER
K.; Kawamoto, M.; Ikeda, T. J. Am. Chem. Soc. 2003, 125,
New Route to Imidazo[2,1-a]phthalazines
1719
(5) Caron, S.; Massett, S. S.; Bogle, D. E.; Castaldi, M. J.;
Braish, T. F. Org. Process Res. Dev. 2001, 5, 254.
(6) No imine formation was observed under standard coupling
conditions without one of the two metals (Pd, Cu) present.
(7) (a) Ohff, M.; Ohff, A.; Milstein, D. Chem. Commun. 1999,
357. (b) For a review on palladacyles, see: Ghedini, M.;
Aiello, I.; Crispini, A.; Golemme, A.; La Deda, M.; Pucci,
D. Coord. Chem. Rev. 2006, 250, 1373.
1700. (d) Li, W.; Nelson, D. P.; Jensen, M. S.; Hoerrner, R.
S.; Javadi, G. J.; Cai, D.; Larsen, R. D. Org. Lett. 2003, 5,
4835. (e) Zificsak, C. A.; Hlasta, D. J. Tetrahedron 2004, 60,
8991. (f) Park, C.-H.; Ryabova, V.; Seregin, I. V.; Sromek,
A. W.; Gevorgyan, V. Org. Lett. 2004, 6, 1159.
(g) Alagille, D.; Baldwin, R. M.; Tamagnan, G. D.
Tetrahedron Lett. 2005, 46, 1349. (h) Bellina, F.;
Cauteruccio, S.; Mannina, L.; Rossi, R.; Veil, S. J. Org.
Chem. 2005, 70, 3997. (i) Gracias, V.; Gasiecki, A. F.;
Pagano, T. G.; Djuric, S. W. Tetrahedron Lett. 2006, 47,
8873. (j) Bellina, F.; Cauteruccio, S.; Mannina, L.; Rossi, R.;
Viel, S. Eur. J. Org. Chem. 2006, 693. (k) Cerna, I.; Pohl,
R.; Klepetarova, B.; Hocek, M. Org. Lett. 2006, 8, 5389.
(l) Bellina, F.; Cauteruccio, S.; Rossi, R. J. Org. Chem.
2007, 72, 8543. (m) Hien-Quang, D.; Daugulis, O. J. Am.
Chem. Soc. 2007, 129, 12404. (n) Yoshizumi, T.; Tsurugi,
H.; Satoh, T.; Miura, M. Tetrahedron Lett. 2008, 49, 1598.
(8) MeP(t-Bu)2·HBF4 has been reported to significantly increase
yield in CH activation reaction: Wang, J. X.; McCubbin, A.;
Meizhong, J.; Laufer, R. S.; Mao, Y.; Crew, A. P.; Mulvihill,
M. J.; Snieckus, V. Org. Lett. 2008, 10, 2923.
(9) Direct arylations of azoles were performed under ligandless
conditions; see reference 4j and: Bellina, F.; Cauteruccio, S.;
Rossi, R. Eur. J. Org. Chem. 2006, 1379.
(10) Starting 1-aminoimidazoles, except commercially available
benzimidazol-1-ylamine, were prepared according to
reference 3.
Synthesis 2009, No. 10, 1715–1719 © Thieme Stuttgart · New York