Synthesis of novel fused azecine ring systems through application of the tert-amino effect

Article abstract of DOI:10.1016/j.tet.2010.02.014

Novel fused azecine ring systems were synthesized via the microwave-assisted thermal isomerization of terphenyl or biphenyl-pyridazine compounds possessing a vinyl and a tert-amino group, through application of a new extension of the tert-amino effect. Substrates for the ring closure were prepared from ortho-dihalobenzene or pyridazinone by consecutive Suzuki couplings with ortho-sec-amino- and formylphenylboronic acids, followed by Knoevenagel condensation of the aldehydes obtained.

Full text of DOI:10.1016/j.tet.2010.02.014

Tetrahedron 66 (2010) 2331–2339
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Synthesis of novel fused azecine ring systems through application
of the tert-amino effect
a
a
b
c
a,
*
´ ´
´
´
´
´
Petra Dunkel , Gyo¨rgy Turos , Attila Benyei , Krisztina Ludanyi , Peter Matyus
a
}
Department of Organic Chemistry, Semmelweis University, Hogyes Endre u. 7., H-1092 Budapest, Hungary
b Institute of Physical Chemistry, University of Debrecen, Egyetem te´r 1., H-4010 Debrecen, Hungary
c
}
Department of Pharmacy, Semmelweis University, Hogyes Endre u. 7., H-1092 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel fused azecine ring systems were synthesized via the microwave-assisted thermal isomerization of
terphenyl or biphenyl-pyridazine compounds possessing a vinyl and a tert-amino group, through ap-
plication of a new extension of the tert-amino effect. Substrates for the ring closure were prepared from
ortho-dihalobenzene or pyridazinone by consecutive Suzuki couplings with ortho-sec-amino- and for-
mylphenylboronic acids, followed by Knoevenagel condensation of the aldehydes obtained.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 25 August 2009
Received in revised form
28 December 2009
Accepted 1 February 2010
Available online 4 February 2010
Keywords:
tert-Amino effect
Regioselective Suzuki coupling
Microwave
Fused azecine ring systems
1. Introduction
abiogeneticprecursorofSchelhammeraandCephalotaxusalkaloids,2–4
such as cephalotaxine, the esters of which exhibit antitumour activ-
Fused ring systems containing the benzazecine skeleton may be of
considerable chemical and biological value. Although the number of
such compounds reported in the literature is limited, some members
of the class have interesting biological functions. Dysazecine (1), the
first alkaloid containing a dibenz[d,f]azecine skeleton to be isolated
from plants, was suggested to be a biosynthetic intermediate to
homoerythrina alkaloids.1 Dibenz[d,f]azecine 2 could possibly be
ity.5 Dyshomoerythrine derivative 3 was prepared as an insecticide,6
the benzazecine alkaloid protopine (4) as a potential antimalarial
lead compound.7a Furthermore, other interesting pharmacological
properties of protopine alkaloids have also been reported (e.g., neu-
roprotective,7b anti-inflammatory7c effects). Compound 5 was pre-
pared as an analgetic8 while LE300 (6) and its derivatives are novel
types of nanomolar dopamine receptor antagonists (Fig. 1).9a,b
R1
CH3
H
R2
R6
R3
OCH2O
R4
R5
R3
1
2
H
H
OCH3
OCH3
OCH3
OH
R4
R2
R1
R2
OH
OCH3
N
N
N
H
3
4
5
CH3
OCH3
R3
OCH2O
H
H
-
N
R4
R5
R1
OCH2O
OCH2O
OCH3
O
-
R5
1, 2, 3
4, 5
6
R6
OH
H
OCH3
-
Figure 1. Some representatives of fused azecine ring systems with interesting biological effects.
The pathway reported in this communication, involving the
‘tert-amino effect’, could serve as a simple, straightforward syn-
thesis of tribenzo[b,d,f]- or pyridazino[d]dibenzo[b,f]azecines.
The term tert-amino effect was first used by Meth-Cohn and
Suschitzky in 1972 to describe unusual cyclizations of ortho-
* Corresponding author. Tel./fax: þ36 1 2170851.
´
E-mail address: peter.matyus@szerves.sote.hu (P. Matyus).
0040-4020/$ – see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.02.014

2332
P. Dunkel et al. / Tetrahedron 66 (2010) 2331–2339
N+
Ha
N
N+
C-
N
Hb
Hb
Hb
Hb
Ha
H
Ha
CN
CN
H
C- CN
Ha
H
H
NC
CN
NC
CN
CN
Figure 2. tert-Amino effect type 2 ring closure.
substituted tert-anilines.10 Of the seven types of tert-amino effect
described so far,11 which differ in the size of the ring formed and the
mode of its formation, in a special version of type 2 reactions, a new
2. Results and discussion
For this study of the tert-amino effect thermal isomerization,
two series of ortho-vinyl tert-aniline compounds were synthesized
(Scheme 1). A benzene (12a–c) and a pyridazinone (19a–d) series
were prepared, via two consecutive Suzuki reactions: firstly re-
action with boronic acids having an ortho-sec-amino substituent
(9a–c) (leading to 10a16a,b–c and 17a–d), followed by coupling with
2-formylphenylboronic acid (leading to 11a–c and 18a–d).
The synthesis of the benzene series (12a–c) started from 2-bro-
moiodobenzene; for the pyridazinone series (19a–d), 4-chloro-5-
iodo-2-methyl- (15a)17a and 4-chloro-5-iodo-2-phenylpyridazin-
3(2H)-one (15b) were selected as starting materials to carry out
regioselective Suzuki couplings. 5(4)-Chloro-4(5)-iodopyridazin-
3(2H)-ones have been rarely used for such applications (coupling
reactions with 5-chloro-4-iodo isomers have been described by
Haider and Wobus,18 Stevenson et al.;19 whereas couplings with 4-
chloro-5-iodo isomers are reported herein), although such com-
pounds are easily accessible via chloro displacement reactions of
4,5-dichloropyridazin-3(2H)-one17a or its mucochoric acid
precursor.17b
C–C bond is formed between the
a carbon of a tert-aniline group
and the atom of an ortho-vinyl substituent, resulting in the for-
b
mation of a tetrahydropyridine ring (Fig. 2).12 Type 2 ring closures
have been widely used for the synthesis of fused ring systems,13 but
only rarely for the synthesis of medium-sized rings or macrocycles.
As part of our ongoing researches on this topic, our present goal
was to study possible extensions of the tert-amino effect to biaryl14
(Fig. 3) or triaryl systems in which the ortho-positioned tert-amino
and vinyl groups are situated on aryl rings that are connected di-
rectly or linked by a third aryl ring, and to fused systems15 having
the interacting groups in peri positions. Such possible extensions
were expected to lead to fused medium-sized or macrocyclic aza
ring systems that are otherwise difficult to access. We describe
here the synthesis of 2-[(2-vinylphenyl)phenyl]-tert-anilines and
their pyridazinone analogues and our studies on their thermal
isomerizations.
GWE
Of the boronic acids used for the first series of Suzuki couplings,
2-dimethylaminophenylboronic acid (9a) was prepared by a litera-
ture procedure,20 while boronic acids 9b and 9c were obtained in
good yields from the corresponding ortho-haloarylamines by ortho-
lithiation and reaction with triisopropyl borate in THF (in a method
analogous to that used for the synthesis of 2-(4-methylpiperazin-1-
yl)-21 and 4-pyrrolidinophenylboronic22 acids) (Scheme 1). For the
preparation of the ortho-haloarylamines needed, the method de-
scribed by Verboom et al. was used.23
EWG
R1
EWG
EWG
R1
N
R2
N
R2
7
8
EWG=CN, R1+R2=(CH2)3
Figure 3. Extension of the tert-amino effect to biaryl systems.
R1
R2
N
NC
CN
CHO
B(OH)2
B(OH)2
OHC
X
X
CH2(CN)2
ethanol
RT
I
Pd(PPh3)4
Pd(PPh3)4
DME
DME
2 M Na2CO3
2 M Na2CO3
R1
R1
N
R2
R1
N
R2
N
R2
reflux
reflux
R1=H R2=CH3
R1+R2=(CH2)3
R1+R2=(CH2)4
10a (65%)
10b (54%)
10c (61%)
11a (70%)
11b (53%)
11c (74%)
12a (92%)
12b (90%)
12c (91%)
O
R1=H R2=CH3 R=CH3
R1=H R2=CH3 R=Ph
19a (88%)
19b (85%)
19c (90%)
19d (89%)
18a (73%)
18b (68%)
18c (73%)
18d (70%)
17a (75%) + 16a (14%)
17b (70%) + 16b (20%)
17c (76%)
R
N
N
R1+R2=(CH2)3
R1+R2=(CH2)4
R=CH3
R=CH3 17d (65%)
R1
R1
R2
N
R2
O
O
N
R
Cl
Cl
R
Cl
I
1. THF / n-BuLi / -78 °C
2. B(OiPr)3 / -78 °C
B(OH)2
N
NaI / DMF
N
N
N
25 h
3. aq. HCl
150 °C
15a R=CH3 (46%)17
15b R=Ph (65%)
9b R1+R2=(CH2)3 (65%)
9c R1+R2=(CH2)4 (65%)
Scheme 1. Synthesis of ortho-vinyl-terphenyl and pyridazine-biphenyl-tert-anilines.

P. Dunkel et al. / Tetrahedron 66 (2010) 2331–2339
2333
With these boronic acids in hand, Suzuki reactions could be
carried out smoothly in the presence of Pd(PPh3)4 as catalyst, in
a DME/2 M aq Na2CO3 system, affording 10a–c, 17a–d, 11a–c and
18a–d as products in good yields (Scheme 1).
In the Suzuki coupling of 15a,b with 9a, formation of an indole
derivative (16a,b) as by-product was observed, presumably via
intramolecular substitution of the coupled product. When 17a,b
were subjected to Suzuki coupling conditions (for 48 h reflux in
DME/2 M aq Na2CO3), the 2-substituent of the pyridazinone ring
greatly influenced the formation of 16a,b. The presence of a 2-CH3
group led to a starting material/product ratio of 3.5:1 (as compared
with 5:1 in the Suzuki reaction), while a 2-phenyl group resulted in
a ratio of 1.56:1 (3.5:1 in the Suzuki reaction) (Scheme 2).
representing a novel type of the tert-amino effect. Kaval et al. de-
scribed microwave-assisted tert-amino effect cyclizations.25,26 Use
of this methodology seemed feasible with regard to the rate en-
hancements and yields observed. On irradiation of 12a under
solvent-free microwave (MW) conditions (160 ꢀC, 45 min), 66% of
azecine product 20a was obtained, while 21% of the starting ma-
terial was recovered. Longer reaction times or higher temperatures
resulted in an increased rate of decomposition, and hence a lower
isolated yield of the azecine product (Scheme 4).
Using the same procedure led to high rates of decomposition of
12b and 19a; further isomerizations were therefore carried out in
the solution phase (DMSO). When 12a–c and 19a–d were heated in
DMSO solution, the desired azecine-fused products 20a–c and 21a–
d were obtained, the pyridazine analogues behaving similarly to
their benzene counterparts. From the N,N-dimethylamino de-
rivatives (12a and 19a,b), the desired fused products (20a and 21a,b)
were obtained in good yields. For irradiation of the pyrrolidino and
piperidino derivatives (12b,c and 19c,d), a compromise between the
conversion of the starting material (as monitored by HPLC) and
decomposition (leading to a drop in the isolated yield) was difficult
to find, even at relatively low reaction temperatures (Table 1).
The structures of 18a, 12a, 20a, 19a and 21c were confirmed by
X-ray diffraction.27 Investigation of the geometric arrangement of
the ortho, ortho0 functionalities in the biphenyl series14 by X-ray
analysis revealed that in the biaryl analogue of compound 12a, the
tert-amino and vinyl groups were located on the same face of the
biaryl system (compound 7), their distance from each other
N
B(OH)2
O
O
O
R
Cl
I
R
Cl
R
N
N
N
N
N
N
N
+
Pd(PPh3)4
DME
2 M Na2CO3
15a
15b
N
reflux
DME, 2 M Na2CO3, reflux
17a
17b
16a R=CH3
16b
R=Ph
Scheme 2. Formation of indole by-products 16a,b.
An alternative route for the synthesis of biaryl amines 10b,c uses
Suzuki coupling first with 2-pivaloylaminophenylboronic acid,
followed by deprotection in aq H2SO4 (Scheme 3). Primary amine
14 could be converted in high yields to N-heterocyclic derivatives
via the microwave-assisted N-heterocyclization described by Ju and
Varma24 with dihaloalkanes in alkaline aqueous medium.
(2.878 Å for the tert-amino nitrogen–a-vinylic carbon) indicating
a weak interaction between them. For triphenylvinyl derivative
12a, two conformers were found in the asymmetric unit, the cor-
responding distances between the tert-amino nitrogen and the
a-vinylic carbon (located on opposite faces of the triaryl system)
R2
NHPiv
R1
N
H2N
B(OH)2 PivHN
Br(CH2)nBr
K2CO3
65% H2SO4
reflux
I
water
Pd(PPh3)4
MW
Br
Br
Br
Br
120 °C
60 min
DME
2 M Na2CO3
reflux
13 (81%)
14 (88%)
10b n=4 (88%)
10c n=5 (85%)
Scheme 3. Synthesis of 10b,c via aqueous N-heterocyclization of 14.
Aldehydes 11a–c and 18a–d, obtained in the Suzuki reactions of
amines 10a–c and 17a–d with 2-formylphenylboronic acid, were
subjected to Knoevenagel condensation (Scheme 1). Vinyl products
12a–c and 19a–d could be obtained under mild conditions (ethanol
at room temperature in the presence of piperidine), with malono-
nitrile as the active methylene agent.
being significantly longer, 4.25 and 3.98 Å, respectively. (Fig. 4)
Interestingly, two conformers were also found in the asymmetric
unit of azecine 21c.
In the azecine-fused products, the NMR signals of the methylene
hydrogens adjacent to the nitrogen and the carbon bearing the
electron-withdrawing groups are characteristic of the ring closure.
Their appearance in the NMR spectra is accompanied by the
disappearance of the signal broadening or signal duplication
In the following series of experiments, the thermal isomeriza-
tions of vinyl compounds 12a–c and 19a–d were studied,
NC
O
CN
NC
CN
O
CN
CN
R1
CN
CN
R1
R
R
N
N
MW
N
N
MW
N
N
R2
R2
R1
N
R2
R1
N
R2
12a R1=H R2=CH3
12b R1+R2=(CH2)3
12c R1+R2=(CH2)4
20a
20b
20c
19a R1=H R2=CH3 R=CH3
19b R1=H R2=CH3 R=Ph
21a
21b
21c
21d
19c R1+R2=(CH2)3
19d R1+R2=(CH2)4
R=CH3
R=CH3
Scheme 4. Microwave-assisted isomerization of vinyl compounds.

2334
P. Dunkel et al. / Tetrahedron 66 (2010) 2331–2339
CN
CN
Table 1
CN
C-
Synthesis of azecine-fused systems. Solution-phase (DMSO) reactions
CN
Compound
Temp (ꢀC)/time (min)a
200/150
Product (yield)c
Hb
Hb
[1,9]-H
Ha
Ha
12a
20a (85%)
R1
R1
H- transfer
N+
N
R2
R2
12b
12c
100/30
100/90
150/2
20b (19%), 12b (50%)
20b (11%), 12b (6%)
20b (11%), 12b (2%)
150/5
150/10
175/2
20c (32%), 12c (20%)
20c (13%), 12c (2%)
20c (34%), 12c (3%)
CN
C-
Ha
CN
CN
Hb
R1
CN
Ha
Hb
N+
19a
19b
19c
200/150
200/150
21a (83%)
21b (80%)
R1
N
R2
R2
100/180
125/10
150/1
21c (20%), 19c (11%)
21c (16%), 19c (24%)
21c (14%), 19c (21%)
Scheme 5. Proposed mechanism of the isomerization.
19d
150/5
175/5
175/10
200/1b
21d (24%), 19d (30%)
21d (44%), 19d (2%)
21d (18%), 19d (7%)
21d (51%), 19d (6%)
3. Conclusion
a
Hold time for MW-assisted experiments; reactions were carried out in open
vessels (if not indicated otherwise) on a 0.25 mmol scale, at a maximum power level
of 200 W.
This study of the extension of the tert-amino effect to ortho,
ortho00-functionalized triaryl compounds and their pyridazinone
analogues demonstrates that this novel type of isomerization offers
a straightforward synthetic pathway for the synthesis of fused
azecine ring systems.
b
Reaction was carried out in a 10 mL sealed MW process vial.
Isolated yields.
c
4. Experimental
4.1. Materials and methods
All reagents and solvents were purchased from commercial
sources and were utilized without further purification. Melting
points were determined on a Bu¨chi-540 capillary melting point
apparatus and are uncorrected. The IR spectra were recorded on
a Perkin–Elmer 1600 FTIR instrument in KBr pellets. The 1H and 13
C
NMR spectra were recorded at ambient temperature, if not in-
dicated otherwise, in the solvent indicated, with a Varian Mercury
Plus spectrometer at a frequency of 400/600 or 100/150 MHz or
a with a Bruker 400 MHz spectrometer, at a frequency of 400 or
100 MHz, and are reported in parts per million. Spectra were
recorded at 400 MHz (1H) or 100 MHz (13C), if not indicated oth-
erwise. Chemical shifts are given on the d-scale relative to tetra-
methylsilane or the residual solvent signal as an internal reference.
For structure elucidation, one-dimensional 1H, 13C, DEPT, two-
dimensional 1H, 1H-COSY, 1H, 13C-HSQC, 1H, 13C-HMBC measure-
ments were run. Mass spectra utilizing fast atom bombardment
ionization were recorded on a VG-ZAB-2SEQ spectrometer. Ele-
mental analyses were performed on a Carlo Erba 1012 apparatus.
MW irradiation experiments were carried out in a monomode
CEM-Discover MW reactor, using the standard configuration as
delivered, including proprietary software. The experiments were
executed either in 10 mL MW process vials or in open-vessel mode,
with control of the temperature by infrared detection. After com-
pletion of the reaction, the vial/flask was cooled to 50 ꢀC by air jet
cooling. For flash column chromatography purification, Kieselgel 60
(Merck, 0.040–0.063 mm) was used; for TLC analysis, Silica gel 60
F254 (Merck) plates were applied. Solvent mixtures used for chro-
matography are always given in a vol/vol ratio. The structures of all
compounds were consistent with their analytical and spectroscopic
data. Compounds 9a,20 10a16a,b and 15a17a were prepared according
to the literature procedures cited. Compounds 9a,20 10a,16a,b 15a,17a
16a,29a,b 16b30 and 1431a,b had melting points and spectral data
identical with the published values. Spectroscopic data are pro-
vided for compounds described previously but not characterized
spectroscopically.
Figure 4. X-ray structures of compounds 12a and 7; geometric arrangement of the
interacting functionalities.
phenomena observed for the vinyl (and aldehyde) compounds, due
to hindered rotation. As exemplified with vinyl compound 12a and
7 and their cyclic azecine (20a) and azocine (8) counterparts, the
characteristic NMR data14 (in ppm, CDCl3/DMSO-d6 for 12a) of the
corresponding atoms are (i) –CH]C(CN)2 (vinyl compounds)d1H:
7.31 (12a)/7.58 (7), 13C: 160.4 (12a)/162.4 (7), (ii) –CH2–C(CN)2–
CHR1– (cyclic products)d1H: 3.40 and 3.52 (20a)/3.38 and 3.64 (8);
13C: 35.9 (20a)/40.1 (8).
The formation of the azecine ring could be explained in terms of
a two-step mechanism, the first, rate-limiting step involving either
a [1,9]-hydrogen migration or, more likely, direct hydride dona-
tion28 between the interacting groups, resulting in a dipolar in-
termediate, the next step comprising bond formation between the
oppositely charged carbons (Scheme 5).

P. Dunkel et al. / Tetrahedron 66 (2010) 2331–2339
2335
4.2. Synthesis of boronic acids 9b,c
(2.76 g), for 11b: 10b (3.02 g), for 11c: 10c (3.16 g), for 17a,c,d: 15a
(2.70 g), for 17b: 15b (3.33 g), for 18a: 17a (2.64 g), for 18b: 17b
(3.26 g), for 18c: 17c (2.90 g), for 18d: 17d (3.04 g)) in DME (50 mL),
Pd(PPh3)4 (578 mg, 0.50 mmol) was added at room temperature
under an argon flow. After stirring at room temperature for 10 min,
the appropriate boronic acid (12.00 mmol, for 10a,17a,b: 9a20
(1.98 g), for 10b,17c: 9b (2.29 g), for 10c,17d: 9c (2.46 g), for 13:
2-pivalamidophenylboronic acid32,33 (2.65 g), for 11a–c,18a–d:
2-formylphenylboronic acid (1.80 g)) and aq 2 M Na2CO3 solution
(10 mL) were added, and the reaction mixture was heated at reflux
at 110 ꢀC (oil temperature) until the starting material had been
consumed (24–48 h, monitored by TLC). The cooled reaction mix-
ture was poured into H2O (50 mL). After separation of the phases,
the aqueous layer was extracted with CH2Cl2 (3ꢂ50 mL). The
combined organic layers were dried (MgSO4), filtered and evapo-
rated to dryness. The crude product obtained was purified by flash
column chromatography on silica gel with the eluents indicated
below.
A four-neck, round-bottom flask was charged with 1-(2-bro-
mophenyl)pyrrolidine23 (4.97 g, 22.00 mmol; for 9b) or 1-(2-bro-
mophenyl)piperidine23 (5.28 g, 22.00 mmol; for 9c) and anhydrous
THF (75 mL) under argon. n-BuLi (2.5 M solution in hexane,
9.90 mL, 24.75 mmol) was added to the solution dropwise (over
20 min) at ꢁ78 ꢀC. The reaction mixture was stirred for 75 min
at ꢁ78 ꢀC, after which time B(OiPr)3 (10.15 mL, 44.00 mmol) was
added dropwise (over 20 min) to the suspension, followed by
a further 1 h of stirring at ꢁ78 ꢀC. Subsequently, the reaction
mixture was allowed to warm up to room temperature and stirred
overnight. The following day, the reaction mixture was cooled
to ꢁ70 ꢀC and 1 M HCl solution (44 mL) was added slowly (over
15 min). The mixture was next allowed to warm up to 0 ꢀC and
stirred for 30 min. H2O (100 mL) and EtOAc (100 mL) were added,
the phases were separated and the organic layer was extracted with
H2O (3ꢂ100 mL). The pH of the combined aqueous layers was ad-
justed to 8 with 2 M NaOH. The aqueous phase was extracted with
EtOAc (3ꢂ100 mL). The combined organic layers were dried
(MgSO4), filtered and evaporated to dryness. The crude product
obtained was used without further purification.
4.4.1. Biphenyl compounds and their pyridazine analogues
4.4.1.1. 20-Bromo-N,N-dimethylbiphenyl-2-amine (10a)16a,b. The
work-up and purification accorded to the literature procedure
cited. White crystals (1.80 g, 65%), mp 55–57 ꢀC (lit. mp
4.2.1. 2-(Pyrrolidin-1-yl)phenylboronic acid (9b). Crude product:
white crystals (3.03 g, w85% pure according to 1H NMR), Rf¼0.40
55–57 ꢀC)16b, Rf¼0.64 (toluene). 1H NMR (CDCl3)
d (ppm): 7.66 (dm,
J¼8.0 Hz, 1H), 7.37–7.29 (m, 3H), 7.19–7.11 (m, 2H), 7.06 (dm,
(toluene/EtOH 2:1). 1H NMR (DMSO-d6)
d (ppm): 8.10 (br s, 2H),
J¼8.0 Hz, 1H), 7.00 (tm, J¼7.6 Hz, 1H), 2.53 (s, 6H). 13C NMR (CDCl3)
7.22–7.11 (m, 2H), 6.71–6.67 (m, 2H), 3.23–3.17 (m, 4H), 1.92–1.85
(m, 4H). 13C NMR (CD3OD): 148.3, 135.2, 125.6, 123.6, 117.7, 56.0,
25.7 (C–B(OH)2 was not observed).
d (ppm): 151.2, 143.2, 134.4, 133.6, 132.5, 132.5, 129.4, 128.8, 127.8,
124.6, 121.5, 118.6, 43.9. IR (KBr) nmax: 2964, 2834, 1452, 1262, 1022,
802, 744 cmꢁ1. Anal. Calcd for C14H14BrN (276.17): C, 60.89; H, 5.11;
N, 5.07. Found: C, 60.85; H, 5.00; N, 5.06.
4.2.2. 2-(Piperidine-1-yl)phenylboronic acid (9c). Crude product:
white crystals (3.83 g, w70% pure according to 1H NMR), Rf¼0.37
4.4.1.2. 1-(20-Bromobiphenyl-2-yl)pyrrolidine
(10b). Column
(toluene/EtOH 2:1). 1H NMR (CDCl3)
d
(ppm): 9.34 (br s, 2H), 7.93
chromatography: n-hexane/EtOAc 9:1. Colourless oil (1.63 g, 54%),
(dm, J¼7.6 Hz, 1H), 7.45 (tm, J¼7.6 Hz, 1H), 7.31 (dm, J¼7.6 Hz, 1H),
Rf¼0.67 (hexane/EtOAc 9:1). 1H NMR (CDCl3)
d (ppm): 7.64 (dm,
7.24 (tm, J¼7.6 Hz, 1H), 2.95–2.87 (m, 4H), 1.84–1.76 (m, 4H), 1.67–
J¼8.0 Hz, 1H), 7.37 (dm, J¼7.6 Hz, 1H), 7.33–7.26 (m, 2H), 7.16 (ddd,
1.55 (br m, 2H). 13C NMR (CDCl3)
d (ppm): 160.4, 136.5, 132.4, 126.2,
J¼7.2, 1.8, 0.8 Hz, 1H), 7.08 (dm, J¼7.6 Hz, 1H), 6.86–6.79 (m, 2H),
121.7, 56.1, 27.3, 24.3 (C–B(OH)2 was not observed).
2.99–2.85 (m, 4H), 1.80–1.72 (m, 4H). 13C NMR (CDCl3)
d (ppm):
148.1, 144.7, 133.1, 133.0, 132.9, 129.1, 128.7, 128.5, 127.4, 125.3, 117.4,
114.7, 50.8, 26.4. IR (KBr) nmax: 2922, 1596, 1498, 1464, 1336, 1154,
1024, 746 cmꢁ1. HRMS: calcd for (C16H16BrNþHþ): 302.0544.
Found: 302.0535.
4.3. Synthesis of 4-chloro-5-iodo-2-phenylpyridazin-3(2H)-
one (15b) via halogen replacement
Compound 15b was prepared by applying the procedure cited
for 15a.17a To a solution of 4,5-dichloro-2-phenylpyridazin-3(2H)-
one (3.62 g, 15.00 mmol) in DMF (30 mL), NaI (4.50 g, 30.00 mmol)
was added, and the mixture was then heated at reflux for 1 h.
Following this, further NaI (2.25 g, 15.00 mmol) was added to the
mixture and it was heated at reflux again for 1 h. The latter pro-
cedure was repeated once more, and the mixture was heated at
reflux for 25 h. Then the DMF was removed in vacuo. An aqueous
solution (10%) of Na2S2O3 was added to the residue until the colour
of the iodine had disappeared. The solution was extracted with
CHCl3 (4ꢂ70 mL) and the combined organic layers were dried
(MgSO4), filtered and evaporated to dryness. Analytically pure 9b
could be obtained by recrystallization from MeOH. White crystals
(3.24 g, 65%), mp 152–153 ꢀC, Rf¼0.21 (toluene). 1H NMR (CDCl3)
4.4.1.3. 1-(20-Bromobiphenyl-2-yl)piperidine
chromatography: n-hexane. Colourless oil (1.93 g, 61%), Rf¼0.8 (n-
hexane/EtOAc 9:1). 1H NMR (CDCl3)
(10c). Column
d
(ppm): 7.64 (dm, J¼8.0 Hz,
1H), 7.38 (dm, J¼7.6 Hz, 1H), 7.34–7.29 (m, 2H), 7.18–7.11 (m, 2H),
7.08–7.01 (m, 2H), 2.82–2.70 (m, 4H), 1.42–1.23 (m, 6H). 13C NMR
(CDCl3)
d (ppm): 152.8, 142.7, 136.2, 133.4, 132.7, 131.9, 129.5, 128.7,
127.5, 124.7, 122.5, 119.8, 53.4, 26.8, 24.9. IR (KBr) nmax: 2932, 2794,
1462, 1228, 1026, 924, 748 cmꢁ1. Anal. Calcd for C17H18BrN (316.24):
C, 64.57; H, 5.74; N, 4.43. Found: C, 64.88; H, 5.83; N, 4.54.
4.4.1.4. N-(20-Bromobiphenyl-2-yl)-2,2-dimethylpropanamide
(13). Column chromatography: toluene/EtOAc 16:1. Colourless oil
(2.69 g, 81%), Rf¼0.47 (toluene/EtOAc 16:1). 1H NMR (CDCl3)
d
(ppm): 8.11 (s,1H), 7.59–7.54 (m, 2H), 7.50–7.45 (m, 2H), 7.44–7.39
d
(ppm): 8.27 (dm, J¼8.0 Hz, 1H), 7.73 (dm, J¼8.0 Hz, 1H), 7.46–7.39
(m, 1H). 13C NMR (CDCl3)
d
(ppm): 155.6, 144.3, 142.8, 141.5, 129.6,
(m, 2H), 7.33–7.28 (m, 2H), 7.21–7.14 (m, 2H), 7.11 (br s, 1H), 1.05 (s,
129.5, 125.8, 105.2. IR (KBr) nmax: 3054, 1654, 1552, 1126, 896, 754,
688 cmꢁ1. HRMS: calcd for (C10H6ClIN2OþHþ): 332.9292. Found:
332.9284.
9H). 13C NMR (CDCl3)
d
(ppm): 177.0,139.5,135.9, 133.7,132.5, 132.4,
130.6,130.0,129.8,128.7,124.7,124.7,122.0, 40.3, 28.0. IR (KBr) nmax
:
3438, 2960, 1688, 1518, 1442, 1304, 1160, 758 cmꢁ1. Anal. Calcd for
C17H18BrNO (332.23): C, 61.46; H, 5.46; N, 4.22. Found: C, 61.26; H,
5.42; N, 4.33.
4.4. General procedure for Suzuki cross-coupling reactions
(syntheses of 10a16a–c, 11a–c, 13, 17a–d and 18a–d)
4.4.1.5. 4-Chloro-5-[2-(dimethylamino)phenyl]-2-methylpyr-
idazin-3(2H)-one (17a). Column chromatography: n-hexane/EtOAc
2:1. Yellow crystals (1.98 g, 75%), mp 104–105 ꢀC, Rf¼0.36
To a solution of the appropriate halo compound (10.00 mmol,
for 10a–c,13: 1-bromo-2-iodobenzene (1.25 mL), for 11a: 10a

2336
P. Dunkel et al. / Tetrahedron 66 (2010) 2331–2339
(n-hexane/EtOAc 2:1). 1H NMR (CDCl3)
d
(ppm): 7.74 (s, 1H), 7.40
(11a–c, 18a–d) and vinyl (12a–c, 19a–d) compounds, broad signals
or two separate signal sets with different population ratios were
observed, due to hindered rotation around the C–C bonds con-
necting the phenyl (and pyridazine) rings. For unambiguous
structure elucidation, NMR spectra were also recorded at elevated
temperatures (100/120 ꢀC).
(ddd, J¼8.2, 7.5, 1.7 Hz, 1H), 7.27 (dm, J¼7.5 Hz, 1H), 7.13 (dm,
J¼8.2 Hz, 1H), 7.08 (tm, J¼7.5 Hz, 1H), 3.88 (s, 3H), 2.63 (s, 6H). 13C
NMR (CDCl3)
d (ppm): 158.9, 152.3, 143.2, 138.7, 133.6, 131.7, 131.4,
126.5, 122.6, 119.3, 44.4, 41.5. IR (KBr) nmax: 2922, 1652, 1266, 868,
740 cmꢁ1. Anal. Calcd for C13H14ClN3O (263.72): C, 59.21; H, 5.35; N,
15.93. Found: C, 58.95; H, 5.18; N, 15.64.
4.4.2.1. 200-Dimethylamino-1,10:20,100-terphenyl-2-carbaldehyde
(11a). Column chromatography: toluene/hexane 1:1. Yellow crys-
tals (2.11 g, 70%), mp 119–120 ꢀC, Rf¼0.35 (toluene/hexane 1:1). 1H
4.4.1.6. 3,5-Dimethyl-3,5-dihydro-4H-pyridazino[4,5-b]indol-4-
one (16a)29a,b. White crystals (recrystallized from MeOH, 299 mg,
14%), mp 214–215 ꢀC (lit. mp 214–215 ꢀC)29b, Rf¼0.23 (n-hexane/
NMR (DMSO-d6) d
(ppm) (major rotamer at 25 ꢀC): 9.72 (s, 1H), 7.83
EtOAc 2:1). 1H NMR (CDCl3)
d
(ppm): 8.42 (s, 1H), 7.97 (d, J¼8.0 Hz,
(dm, J¼7.6 Hz, 1H), 7.57 (td, J¼7.4, 1.4 Hz, 1H), 7.53–7.38 (m, 2H),
1H), 7.58–7.52 (m, 1H), 7.48 (d, J¼8.0 Hz, 1H), 7.39–7.35 (m, 1H),
7.35–7.25 (m, 3H), 7.21–7.10 (m, 2H), 7.03 (tm, J¼7.3 Hz, 1H), 6.70–
4.32 (s, 3H), 3.91 (s, 3H). 13C NMR (CDCl3)
d
(ppm): 156.7, 141.2,
6.63 (m, 2H), 1.97 (s, 6H). 13C NMR (DMSO-d6)
d (ppm) (major
132.9, 131.3, 127.9, 122.5, 121.7, 120.9, 118.2, 111.2, 39.9, 32.2. IR (KBr)
nmax: 3054, 2940, 1644, 1522, 1476, 1340, 952, 740 cmꢁ1. Anal. Calcd
for C12H11N3O (213.23): C, 67.59; H, 5.20; N, 19.71. Found: C, 67.23;
H, 5.03; N, 19.56.
rotamer at 25 ꢀC): 191.5, 150.3, 145.6, 140.6, 136.9, 134.6, 133.8,
131.6, 131.5, 131.2, 130.6, 130.4, 128.6, 128.5, 126.8, 126.5, 125.0,
122.2, 118.0, 42.6. IR (KBr) nmax: 2940, 2862, 1686, 1594, 1258, 1096,
940, 754 cmꢁ1. Anal. Calcd for C21H19NO (301.38): C, 83.69; H, 6.35;
N, 4.65. Found: C, 83.33; H, 6.21; N, 4.54.
4.4.1.7. 4-Chloro-5-[2-(dimethylamino)phenyl]-2-phenyl-
pyridazin-3(2H)-one (17b). Column chromatography: n-hexane/
EtOAc 3:1. Yellow crystals (2.28 g, 70%), mp 90–92 ꢀC, Rf¼0.33 (n-
4.4.2.2. 200-Pyrrolidin-1-yl-1,10:20,100-terphenyl-2-carbaldehyde
(11b). Column chromatography: toluene. Yellow crystals (1.74 g,
53%), mp 104–105 ꢀC, Rf¼0.40 (toluene). 1H NMR (DMSO-d6,
hexane/EtOAc 4:1). 1H NMR (CDCl3)
d (ppm): 7.88 (s, 1H), 7.72–7.67
(m, 2H), 7.53–7.47 (m, 2H), 7.46–7.36 (m, 3H), 7.17 (dm, J¼8.0 Hz,
120 ꢀC)
d
(ppm): 9.65 (br s, 1H), 7.64 (br d, J¼8.0 Hz, 1H), 7.56–
1H), 7.12 (tm, J¼7.6 Hz, 1H), 2.68 (s, 6H). 13C NMR (CDCl3)
d
(ppm):
7.48 (m, 2H), 7.47–7.35 (br m, 2H), 7.33–7.27 (m, 2H), 7.09 (br s,
158.2, 152.5, 143.0, 142.2, 139.5, 134.7, 131.8, 131.6, 129.5, 129.0,
1H), 7.05 (dm, J¼7.2 Hz, 1H), 7.01 (tm, J¼7.4 Hz, 1H), 6.73 (t,
126.4, 125.9, 122.7, 119.4, 44.6. IR (KBr) nmax: 2930, 2782, 1656, 1486,
J¼7.2 Hz, 1H), 6.50 (dm, J¼8.0 Hz, 1H), 2.53–2.00 (br m, 4H), 1.54–
1320, 1146, 756 cmꢁ1
.
Anal. Calcd for C18H16ClN3O (325.79):
1.51 (m, 4H). C NMR (DMSO-d6, 120 ꢀC)
d (ppm): 189.6, 147.0,
13
C, 66.36; H, 4.95; N, 12.90. Found: C, 65.98; H, 4.83; N, 12.56.
144.0, 141.5, 136.6, 132.6, 131.5, 131.2, 130.4, 130.4, 129.7, 129.6,
127.6, 127.2, 126.3, 126.0, 125.0, 117.8, 114.2, 49.3, 23.7. IR (KBr)
nmax: 2918, 2850, 1692, 1596, 1468, 1334, 754 cmꢁ1. Anal. Calcd for
C23H21NO (327.42): C, 84.37; H, 6.46; N, 4.28. Found: C, 84.05; H,
6.24; N, 4.28.
4.4.1.8. 5-Methyl-3-phenyl-3,5-dihydro-4H-pyridazino[4,5-b]in-
dol-4-one (16b)30. White crystals (recrystallized from MeOH,
551 mg, 20%), mp 171–172 ꢀC (lit. mp 169 ꢀC)30, Rf¼0.17 (n-hexane/
EtOAc 3:1). 1H NMR (CDCl3)
d (ppm): 8.62 (s, 1H), 8.05 (dm,
J¼8.0 Hz, 1H), 7.67–7.48 (m, 6H), 7.45–7.39 (m, 2H), 4.38 (s, 3H). 13C
4.4.2.3. 200-Piperidin-1-yl-1,10:20,100-terphenyl-2-carbaldehyde
(11c). Column chromatography: toluene. White crystals (2.53 g,
74%), mp 131–133 ꢀC, Rf¼0.30 (toluene). 1H NMR (DMSO-d6, 100 ꢀC)
NMR (CDCl3)
d (ppm): 142.6, 141.6, 133.9, 131.7, 129.5, 129.2, 128.6,
128.1, 126.9, 122.8, 121.8, 121.0, 118.0, 111.4, 32.4. IR (KBr) nmax: 3054,
2928, 1658, 1530, 1300, 956, 738 cmꢁ1. Anal. Calcd for C17H13N3O
(275.30): C, 74.17; H, 4.76; N, 15.26. Found: C, 73.81; H, 4.50; N,
15.22.
d
(ppm): 9.77 (br s, 1H), 7.66 (br d, J¼7.6 Hz, 1H), 7.56–7.50 (m, 1H),
7.49–7.38 (br m, 3H), 7.35–7.29 (m, 2H), 7.21 (br m, 1H), 7.13 (tm,
J¼7.8 Hz, 1H), 7.09 (dm, J¼7.8 Hz, 1H), 6.93 (t, J¼7.6 Hz, 1H), 6.79
(dm, J¼8.0 Hz, 1H), 2.52–2.38 (br m, 4H), 1.45–1.20 (m, 6H). 13C
4.4.1.9. 4-Chloro-2-methyl-5-(2-pyrrolidin-1-ylphenyl)pyridazin-
3(2H)-one (17c). Column chromatography: n-hexane/EtOAc 4:1.
Yellow crystals (2.20 g, 76%), mp 91–92 ꢀC, Rf¼0.24 (n-hexane/
NMR (DMSO-d6, 100 ꢀC)
d (ppm): 190.6, 150.9, 144.3, 140.3, 135.9,
134.2, 132.6, 131.6, 131.4, 131.0, 130.3, 129.9, 127.9, 127.6, 126.4,
126.4, 125.3, 121.4, 118.1, 51.8, 24.5, 22.9. IR (KBr) nmax: 2936, 2852,
1690, 1594, 1440, 1196, 756 cmꢁ1. HRMS calcd for (C24H23NOþHþ):
342.1858. Found: 342.1845.
EtOAc 4:1). 1H NMR (CDCl3)
d
(ppm): 7.75 (s, 1H), 7.31 (ddd, J¼8.5,
7.2, 1.7 Hz, 1H), 7.14 (dd, J¼7.7, 1.7 Hz, 1H), 6.91 (dd, J¼8.5, 1.1 Hz,
1H), 6.86 (ddd, J¼7.7, 7.2, 1.1 Hz, 1H), 3.87 (s, 3H), 3.04–2.98 (m, 4H),
1.89–1.81 (m, 4H). 13C NMR (CDCl3)
d
(ppm): 158.6, 148.4, 144.6,
4.4.2.4. 2-{5-[2-(Dimethylamino)phenyl]-2-methyl-3-oxo-2,3-di-
hydropyridazin-4-yl}benzaldehyde (18a). Column chromatography:
toluene/EtOAc 4:1. Yellow crystals (2.43 g, 73%), mp 156–158 ꢀC,
138.5, 132.9, 131.7, 131.0, 120.3, 118.4, 115.3, 51.7, 41.6, 26.4. IR (KBr)
nmax: 2920, 2854, 1656, 1446, 1358, 1022, 868, 746 cmꢁ1. Anal. Calcd
for C15H16ClN3O (289.76): C, 62.18; H, 5.57; N, 14.50. Found: C,
61.91; H, 5.16; N, 14.31.
Rf¼0.26 (toluene/EtOAc 4:1). 1H NMR (DMSO-d6, 100 ꢀC)
d (ppm):
9.79 (s, 1H), 8.01 (s, 1H), 7.82 (dm, J¼7.2 Hz, 1H), 7.41–7.33 (m, 2H),
7.20 (tm, J¼7.2 Hz, 1H), 7.13 (br d, J¼7.2 Hz, 1H), 6.94 (t, J¼7.2 Hz,
4.4.1.10. 4-Chloro-2-methyl-5-(2-piperidin-1-ylphenyl)pyridazin-
3(2H)-one (17d). Column chromatography: CH2Cl2. Yellow crystals
(1.97 g, 65%), mp 96–97 ꢀC, Rf¼0.38 (CH2Cl2/EtOAc 95:5). 1H NMR
1H), 6.89 (br d, J¼7.2 Hz, 1H), 6.84 (dm, J¼8.0 Hz, 1H), 3.77 (s, 3H),
13
2.34 (s, 6H). C NMR (DMSO-d6, 100 ꢀC)
d (ppm): 190.4, 159.0,
150.5, 141.3,137.6,135.9,134.6,134.5,131.9,130.1,129.4, 129.3, 127.6,
126.9, 126.6, 121.1, 118.0, 42.6, 39.3. IR (KBr) nmax: 2920, 2850, 1696,
1642, 1594, 1494, 1268, 736 cmꢁ1. Anal. Calcd for C20H19N3O2
(333.38): C, 72.05; H, 5.74; N, 12.60. Found: C, 72.15; H, 5.72; N,
12.64.
(CDCl3)
d
(ppm): 7.80 (s, 1H), 7.41 (ddd, J¼8.4, 7.2, 1.6 Hz, 1H), 7.31
(dm, J¼7.6 Hz, 1H), 7.15–7.09 (m, 2H), 3.88 (s, 3H), 2.81 (br m, 4H),
1.48 (br m, 6H). 13C NMR (CDCl3)
d
(ppm): 159.0, 152.6, 142.9, 139.2,
133.7, 131.6, 131.5, 127.8, 123.3, 120.3, 54.1, 41.5, 26.7, 24.6. IR (KBr)
nmax: 2918, 1654, 1448, 1228, 1022, 866, 750 cmꢁ1. Anal. Calcd for
C16H18ClN3O (303.79): C, 63.26; H, 5.97; N, 13.83. Found: C, 62.90;
H, 5.62; N, 13.49.
4.4.2.5. 2-{5-[2-(Dimethylamino)phenyl]-2-phenyl-3-oxo-2,3-di-
hydropyridazin-4-yl}benzaldehyde (18b). Column chromatography:
toluene/EtOAc 3:1. Yellow crystals (2.69 g, 68%), mp 191–192 ꢀC,
4.4.2. Triphenyl compounds and their pyridazine analogues. At room
Rf¼0.51 (toluene/EtOAc 3:1). 1H NMR (DMSO-d6, 100 ꢀC)
d (ppm):
temperature, in the 1H and 13C NMR spectra of some aldehydes
9.92 (s, 1H), 8.18 (s, 1H), 7.86 (dm, J¼7.2 Hz, 1H), 7.72–7.68 (m, 2H),

P. Dunkel et al. / Tetrahedron 66 (2010) 2331–2339
2337
7.55–7.49 (m, 2H), 7.45–7.37 (m, 3H), 7.24 (tm, J¼7.8 Hz,1H), 7.19 (br
d, J¼7.2 Hz, 1H), 7.00–6.93 (m, 2H), 6.89 (dm, J¼8.0 Hz, 1H), 2.43 (s,
organic layers were dried (Na2SO4), filtered and evaporated to
dryness. The crude product obtained was purified by column
chromatography (n-hexane/EtOAc 9:1). Compound 10b: 266 mg,
88%, compound 10c: 269 mg, 85%.
6H). 13C NMR (DMSO-d6, 100 ꢀC)
d (ppm): 190.5, 158.6, 150.6, 141.4,
140.9, 138.6, 136.1, 135.4,134.7,132.0, 130.1, 129.5, 129.3, 127.9,127.7,
127.4, 127.2, 126.6, 124.8, 121.0, 118.0, 42.7. IR (KBr) nmax: 2918, 1702,
1646, 1492, 1302, 1140, 764 cmꢁ1. Anal. Calcd for C25H21N3O2
(395.45): C, 75.93; H, 5.35; N, 10.63. Found: C, 75.73; H, 5.11; N,
10.56.
4.7. General procedure for the synthesis of vinyl compounds
12a–c and 19a–d via Knoevenagel condensation
To a solution of the aldehyde (11a–c and 18a–d) (2.00 mmol) in
EtOH (10 mL), malononitrile (132 mg, 2.00 mmol) and a few drops
of piperidine were added. The mixture was stirred at room tem-
perature until the starting material had been consumed (monitored
by TLC, reaction time: 1–2 h). The mixture was then evaporated to
dryness, and EtOH (2 mL) was added to the crude product. The
precipitated crystals were filtered off and washed with EtOH to
afford the analytically pure product.
4.4.2.6. 2-[2-Methyl-3-oxo-5-(2-pyrrolidin-1-ylphenyl)-2,3-dihy-
dropyridazin-4-yl]benzaldehyde (18c). Column chromatography: n-
hexane/EtOAc 1:1. Yellow crystals (2.62 g, 73%), mp 185–187 ꢀC,
Rf¼0.37 (n-hexane/EtOAc 1:1). 1H NMR (DMSO-d6, 100 ꢀC)
d (ppm):
9.78 (s, 1H), 8.01 (s, 1H), 7.79–7.75 (m, 1H), 7.42–7.37 (m, 2H), 7.10
(tm, J¼7.8 Hz, 1H), 7.03–6.95 (br m, 2H), 6.73 (br t, J¼7.8 Hz, 1H),
6.66 (dm, J¼8.0 Hz, 1H), 3.76 (s, 3H), 3.00–2.80 (br m, 4H), 1.85–1.70
(br m, 4H). 13C NMR (DMSO-d6, 100 ꢀC)
d (ppm): 190.3, 158.8, 147.1,
142.5, 137.6, 135.3, 134.2, 134.1, 132.0, 130.3, 129.6, 128.9, 127.6,
127.0, 122.7, 118.0, 114.9, 50.0, 39.2, 24.1. IR (KBr) nmax: 2960, 1690,
1640, 1592, 1442, 1324, 760 cmꢁ1. Anal. Calcd for C22H21N3O2
(359.42): C, 73.52; H, 5.89; N, 11.69. Found: C, 73.17; H, 5.77; N,
11.29.
4.7.1. {[200-(Dimethylamino)-1,10:20,100-terphenyl-2-yl]methylidene}-
malononitrile (12a). Orange crystals (643 mg, 92%), mp 157–158 ꢀC,
Rf¼0.57 (toluene). 1H NMR (DMSO-d6)
d (ppm) (major rotamer at
25 ꢀC): 7.74 (tm, J¼7.2 Hz, 1H), 7.69–7.64 (m, 1H), 7.60 (td, J¼7.6,
1.2 Hz, 1H), 7.56–7.47 (m, 3H), 7.45–7.28 (m, 3H), 7.25–7.19 (m, 2H),
7.03 (tm, J¼7.6 Hz, 1H), 6.57 (dd, J¼7.7, 1.3 Hz, 1H), 1.95 (s, 6H). 13C
4.4.2.7. 2-[2-Methyl-3-oxo-5-(2-piperidine-1-ylphenyl)-2,3-dihy-
dropyridazin-4-yl]benzaldehyde (18d). Column chromatography:
toluene/EtOAc 1:1. Yellow crystals (2.61 g, 70%), mp 171–172 ꢀC,
NMR (DMSO-d6) d
(ppm) (major rotamer at 25 ꢀC): 160.4, 149.4,
144.4, 141.5, 136.6, 133.0, 132.9, 131.4, 131.0, 130.9, 130.0, 129.6,
129.3, 127.5, 127.2, 127.1, 126.0, 122.0, 117.2, 114.4, 112.6, 79.8, 41.1. IR
(KBr) nmax: 2772, 2224, 1582, 1494, 1430, 1336, 948, 758 cmꢁ1. Anal.
Calcd for C24H19N3 (349.43): C, 82.49; H, 5.48; N, 12.03. Found: C,
82.48; H, 5.30; N, 11.91.
Rf¼0.57 (toluene/EtOAc 1:1). 1H NMR (DMSO-d6, 100 ꢀC)
d (ppm):
9.92 (s, 1H), 8.02 (s, 1H), 7.87–7.82 (m, 1H), 7.47–7.40 (m, 2H),
7.23 (tm, J¼7.8 Hz, 1H), 7.05–7.00 (m, 2H), 6.97 (dm, J¼7.2 Hz, 1H),
6.89 (t, J¼7.2 Hz, 1H), 3.76 (s, 3H), 2.90–2.60 (br m, 4H), 1.60–1.40
13
(m, 6H). C NMR (DMSO-d6, 100 ꢀC)
d
(ppm): 190.7, 159.1, 151.0,
4.7.2. {[200-(Pyrrolidin-1-yl)-1,10:20,100-terphenyl-2-yl]methylidene}-
malononitrile (12b). Red crystals (676 mg, 90%), mp 152–153 ꢀC,
140.9, 137.9, 135.1, 134.7, 134.3, 132.2, 130.4, 129.6, 129.4, 128.0,
127.8, 127.7, 121.8, 119.3, 52.3, 39.1, 24.8, 22.9. IR (KBr) nmax: 2942,
Rf¼0.52 (toluene). 1H NMR (DMSO-d6)
d (ppm) (major rotamer at
1692, 1640, 1592, 1442, 1226, 764 cmꢁ1
.
Anal. Calcd for
25 ꢀC): 7.73–7.66 (m, 2H), 7.60–7.46 (m, 4H), 7.44 (tm, J¼7.8 Hz, 1H),
7.33 (dm, J¼7.6 Hz, 1H), 7.20–7.14 (m, 2H), 7.11 (tm, J¼7.6 Hz, 1H),
6.86 (tm, J¼7.6 Hz, 1H), 6.40 (dm, J¼8.0 Hz, 1H), 2.65–2.55 (m, 2H),
2.10–2.00 (m, 2H), 1.70–1.60 (m, 2H), 1.50–1.35 (m, 2H). 13C NMR
C23H23N3O2 (373.45): C, 73.97; H, 6.21; N, 11.25. Found: C, 73.59;
H, 5.82; N, 11.15.
4.5. 20-Bromobiphenyl-2-amine (14)31a,b
(DMSO-d6) d
(ppm) (major rotamer at 25 ꢀC): 159.4, 146.9, 143.6,
142.5, 137.1, 133.1, 133.0, 131.5, 130.4, 129.8, 129.3, 128.9, 127.7, 127.6,
127.5, 126.9, 125.7, 119.1, 114.6, 113.8, 112.8, 79.6, 49.5, 24.8. IR (KBr)
nmax: 2920, 2226, 1640, 1440, 1342, 1160, 954, 752 cmꢁ1. Anal. Calcd
for C26H21N3 (375.47): C, 83.17; H, 5.64; N, 11.19. Found: C, 82.80; H,
5.47; N, 11.02.
H2SO4 (65% aq, 30 mL) was added to 13 (1.99 g, 5.98 mmol) and
the reaction mixture was heated at reflux for 15 h. After cooling to
room temperature, the mixture was poured into H2O (30 mL). The
pH was adjusted to 8 with concentrated aq NH3 and the aqueous
phase was extracted with CH2Cl2 (4ꢂ30 mL). The combined or-
ganic layers were dried (Na2SO4), filtered and evaporated to dry-
ness. To the oil obtained, n-hexane was added to afford white
crystals, which were filtered off and washed with n-hexane. White
crystals (1.31 g, 88%), mp 48–50 ꢀC (lit. mp 46–50 ꢀC),31b Rf¼0.63
4.7.3. {[200-(Piperidin-1-yl)-1,10:20,100-terphenyl-2-yl]methylidene}-
malononitrile (12c). Orange crystals (709 mg, 91%), mp 156–158 ꢀC,
Rf¼0.54 (toluene). 1H NMR (DMSO-d6)
d (ppm) (major rotamer at
25 ꢀC): 7.73–7.66 (m, 2H), 7.65–7.57 (m, 2H), 7.54–7.36 (m, 5H),
7.28–7.17 (m, 2H), 7.06 (tm, J¼7.6 Hz, 1H), 6.71 (dm, J¼8.0 Hz, 1H),
2.55–2.45 (br m, 2H), 2.05–1.95 (br m, 2H), 1.37–1.11 (br m, 6H). 13C
(toluene/EtOAc 5:1). 1H NMR (CDCl3)
d
(ppm): 7.69 (dm, J¼8.0,
1H), 7.38 (tm, J¼7.6 Hz, 1H), 7.32 (dm, J¼7.6 Hz, 1H), 7.27–7.20 (m,
2H), 7.03 (dm, J¼7.6 Hz, 1H), 6.84 (tm, J¼7.2 Hz, 1H), 6.79 (dm,
NMR (DMSO-d6)
d
(ppm) (major rotamer at 25 ꢀC): 160.7, 150.7,
J¼8.0 Hz, 1H), 3.53 (br s, 2H). 13C NMR (CDCl3)
d
(ppm): 144.2,
144.2, 141.2, 136.9, 133.3, 133.2, 133.1, 132.9, 131.0, 130.5, 129.5,
129.4, 128.0, 127.5, 127.4, 126.2, 122.8, 118.2, 114.4, 112.7, 80.5, 51.6,
24.8, 23.6. IR (KBr) nmax: 2930, 2222, 1656, 1580, 1438, 1272, 1026,
752 cmꢁ1. HRMS: calcd for (C27H23N3þHþ): 390.1970. Found:
390.1958.
140.6, 133.8, 132.4, 130.9, 129.9, 129.8, 128.5, 127.8, 125.0, 119.0,
116.2. IR (KBr) nmax: 3374, 2920, 1616, 1466, 1254, 1026, 752 cmꢁ1
.
Anal. Calcd for C12H10BrN (248.12): C, 58.09; H, 4.06; N, 5.65.
Found: C, 58.28; H, 3.78; N, 5.60.
4.6. Synthesis of 10b,c via aqueous N-heterocyclization24 of 14
4.7.4. (2-{5-[2-(Dimethylamino)phenyl]-2-methyl-3-oxo-2,3-dihy-
dropyridazin-4-yl}benzylidene)malononitrile (19a). Orange crystals
(671 mg, 88%), mp 161–162 ꢀC, Rf¼0.33 (n-hexane/EtOAc 1:1). 1H
A 10 mL MW process vial was charged with 14 (248 mg,
1.00 mmol), dihaloalkane (1.10 mmol) (for 10b: 1,4-dibromobutane
(0.13 mL), for 10c: 1,5-dibromopentane (0.15 mL)), K2CO3 (162 mg,
1.10 mmol) and water (2 mL). The mixture was irradiated in
a closed vessel with pressure control at 120 ꢀC for 60 min (hold
time) at 70 W maximum power. After completion of the reaction,
the mixture was extracted with EtOAc (4ꢂ5 mL). The combined
NMR (DMSO-d6, 100 ꢀC)
d (ppm): 8.02 (s, 1H), 7.97–7.90 (m, 2H),
7.53–7.40 (m, 2H), 7.28–7.15 (m, 3H), 6.98 (tm, J¼7.8 Hz, 1H), 6.81
(dm, J¼8.0 Hz, 1H), 3.79 (s, 3H), 2.32 (s, 6H). 13C NMR (DMSO-d6,
100 ꢀC)
d (ppm): 159.7, 158.5, 150.1, 142.4, 137.5, 136.3, 132.6, 131.6,
130.5, 130.4, 129.8, 129.4, 127.8, 126.2, 125.8, 121.0, 117.7, 113.4, 112.1,
81.6, 42.3, 39.5. IR (KBr) nmax: 2920, 2232, 1750, 1634, 1380, 1170,

2338
P. Dunkel et al. / Tetrahedron 66 (2010) 2331–2339
732 cmꢁ1. Anal. Calcd for C23H19N5O (381.43): C, 72.42; H, 5.02; N,
18.36. Found: C, 72.03; H, 4.78; N, 18.23.
2858, 2244, 1444, 1258, 1072, 954, 756 cmꢁ1. Anal. Calcd for
C24H19N3 (349.43): C, 82.49; H, 5.48; N, 12.03. Found: C, 82.65; H,
5.69; N, 11.96.
4.7.5. (2-{5-[2-(Dimethylamino)phenyl]-3-oxo-2-phenyl-2,3-dihy-
dropyridazin-4-yl}benzylidene)malononitrile (19b). Orange crystals
(754 mg, 85%), mp 145–147 ꢀC, Rf¼0.70 (n-hexane/EtOAc 1:1). 1H
4.8.2. 6,7,8,8a-Tetrahydrotribenzo[e,g,i]pyrrolo[1,2-a]azecine-
9,9(10H)-dicarbonitrile (20b). Column chromatography: n-hexane/
EtOAc 7:1. White crystals, mp 137–140 ꢀC, Rf¼0.43 (n-hexane/EtOAc
NMR (DMSO-d6, 100 ꢀC)
d (ppm): 8.22 (s, 1H), 8.09 (s, 1H), 7.95 (dm,
J¼7.6 Hz,1H), 7.76–7.70 (m, 2H), 7.57–7.40 (m, 5H), 7.35–7.20 (m, 3H),
7:1). 1H NMR (CDCl3)
d
(ppm): 7.65 (dm, J¼8.0 Hz, 1H), 7.50–7.45
7.00 (t, J¼7.2 Hz, 1H), 6.85 (dm, J¼7.6 Hz, 1H), 2.40 (s, 6H). 13C NMR
(m, 1H), 7.42–7.36 (m, 2H), 7.29–7.25 (m, 1H), 7.16–7.05 (m, 4H),
6.93 (tm, J¼7.6 Hz, 1H), 6.66 (dd, J¼7.6, 1.4 Hz, 1H), 6.49 (dm,
J¼7.6 Hz, 1H), 3.55 (d, J¼14.0 Hz, 1H), 3.47 (dd, J¼8.4, 2.0 Hz, 1H),
3.35 (d, J¼14.0 Hz, 1H), 3.08–2.99 (m, 1H), 2.69–2.61 (m, 1H), 2.52–
2.41 (m, 1H), 2.32–2.23 (m, 1H), 2.11–1.94 (m, 2H). 13C NMR (CDCl3)
(DMSO-d6, 100 ꢀC)
d (ppm): 159.8, 158.2, 150.2, 142.2, 141.4, 138.5,
136.1, 133.9, 131.6, 130.5, 130.4, 129.9, 129.4, 127.8, 127.8, 127.2, 126.2,
125.4, 124.8, 121.0, 117.7, 113.4, 112.1, 81.8, 42.3. IR (KBr) nmax: 2918,
2228,1646,1496,1142, 756 cmꢁ1. Anal. Calcd for C28H21N5O (443.50):
C, 75.83; H, 4.77; N, 15.79. Found: C, 75.59; H, 4.56; N, 15.74.
d
(ppm): 152.7, 144.1, 141.5, 141.5, 140.2, 132.1, 131.8, 131.1, 129.8,
129.4, 129.3, 128.7, 128.5, 127.9, 127.4, 127.4, 125.9, 122.7, 117.6, 117.3,
70.1, 56.2, 45.0, 37.1, 31.3, 24.2. IR (KBr) nmax: 2954, 2242,1690,1640,
1440, 1264, 1092, 756 cmꢁ1. HRMS: calcd for (C26H21N3þHþ):
376.1814. Found: 376.1804.
4.7.6. (2-{2-Methyl-3-oxo-5-[2-(pyrrolidin-1-yl)phenyl]-2,3-dihy-
dropyridazin-4-yl}benzylidene)malononitrile (19c). Orange crystals
(733 mg, 90%), mp 112–115 ꢀC (dec), Rf¼0.60 (toluene/EtOAc 1:1).
1H NMR (DMSO-d6)
d
(ppm) (major rotamer at 25 ꢀC): 8.12 (s, 1H),
7.87 (s, 1H), 7.73 (dm, J¼8.0 Hz, 1H), 7.64 (tm, J¼7.6 Hz, 1H), 7.57
(dm, J¼7.6 Hz, 1H), 7.45 (tm, J¼7.6 Hz, 1H), 7.19–7.11 (m, 2H), 6.84
(tm, J¼7.6 Hz, 1H), 6.49 (dm, J¼8.4 Hz, 1H), 3.75 (s, 3H), 2.95–2.88
(m, 2H), 2.24–2.18 (m, 2H), 1.85–1.75 (br m, 2H), 1.58–1.50 (m, 2H).
4.8.3. 7,8,9,9a-Tetrahydro-6H-tribenzo[e,g,i]pyrido[1,2-a]azecine-
10,10(11H)-dicarbonitrile (20c). Column chromatography: toluene.
White crystals, mp 141–143 ꢀC, Rf¼0.61 (toluene). 1H NMR (CDCl3)
d
(ppm): 7.72 (dm, J¼8.0 Hz, 1H), 7.51–7.36 (m, 3H), 7.28–7.23 (m,
13C NMR (DMSO-d6)
d
(ppm) (major rotamer at 25 ꢀC): 159.6, 158.9,
1H), 7.16–7.03 (m, 4H), 6.91 (tm, J¼7.6 Hz, 1H), 6.81–6.76 (m, 1H),
6.62 (dd, J¼8.0,1.3 Hz,1H), 3.46 (d, J¼13.6 Hz,1H), 3.37 (d, J¼13.6 Hz,
1H), 3.23–3.19 (m, 1H), 2.86–2.77 (m, 1H), 2.64–2.57 (m, 1H), 2.38–
2.15 (m, 3H), 1.84–1.75 (m, 1H), 1.47–1.34 (m, 1H), 1.24–1.16 (m, 1H).
13C NMR (CDCl3): 151.4, 143.9, 141.4, 141.2, 138.8, 132.1, 131.7, 131.4,
130.0, 129.6, 128.7, 128.7, 128.5, 127.8, 127.5, 127.2, 124.8, 123.2, 118.7,
118.1, 59.4, 48.7, 43.4, 37.8, 25.3, 19.8, 19.8. IR (KBr) nmax: 2928, 2244,
1634, 1442, 1228, 1054, 754 cmꢁ1. Anal. Calcd for C27H23N3 (389.49):
C, 83.26; H, 5.95; N, 10.79. Found: C, 82.95; H, 5.68; N, 10.58.
146.9, 144.1, 137.9, 136.1, 132.2, 131.4, 131.3, 131.2, 130.2, 128.7, 128.6,
126.3, 120.1, 118.5, 114.3, 114.0, 112.8, 80.9, 50.2, 40.3, 25.1. IR (KBr)
nmax: 2952, 2226, 1636, 1442, 1352, 1014, 752 cmꢁ1. Anal. Calcd for
C25H21N5O (407.47): C, 73.69; H, 5.19; N, 17.19. Found: C, 73.35; H,
4.88; N, 16.91.
4.7.7. (2-{2-Methyl-3-oxo-5-[2-(piperidin-1-yl)phenyl]-2,3-dihy-
dropyridazin-4-yl}benzylidene)malononitrile (19d). Yellow crystals
(750 mg, 89%), mp 186–187 ꢀC, Rf¼0.76 (toluene/EtOAc 1:1). 1H
NMR (DMSO-d6, 100 ꢀC)
d
(ppm): 8.08 (s, 1H), 8.04 (s, 1H), 7.95 (dm,
4.8.4. 5,14-Dimethyl-13-oxo-5,8,13,14-tetrahydrodibenzo[b,f]pyr-
idazino[4,5-d]azecine-7,7(6H)-dicarbonitrile (21a). Column chro-
matography: n-hexane/EtOAc 4:1. White crystals, mp 289–294 ꢀC
(dec), Rf¼0.39 (n-hexane/EtOAc 1:1). 1H NMR (600 MHz, CDCl3)
J¼7.6 Hz, 1H), 7.52–7.42 (m, 2H), 7.30–7.24 (m, 2H), 7.03–6.91 (m,
3H), 3.78 (s, 3H), 2.74–2.65 (br m, 4H), 1.66–1.43 (m, 6H). 13C NMR
(DMSO-d6, 100 ꢀC)
d (ppm): 160.1, 158.6, 150.8, 142.2, 137.8, 135.8,
132.8, 131.7, 130.9, 130.5, 129.9, 129.8, 127.9, 127.3, 126.5, 121.8, 119.1,
113.2, 112.0, 82.3, 52.2, 39.3, 24.7, 22.9. IR (KBr) nmax: 2934, 2230,
1640, 1586, 1442, 1228, 1016, 762 cmꢁ1. Anal. Calcd for C26H23N5O
(421.49): C, 74.09; H, 5.50; N, 16.62. Found: C, 73.73; H, 5.19; N,
16.29.
d
(ppm): 7.86 (s, 1H), 7.66 (dm, J¼7.8 Hz, 1H), 7.31–7.20 (m, 4H), 7.05
(tm, J¼7.8 Hz, 1H), 6.85 (dm, J¼8.0 Hz, 1H), 6.63 (dm, J¼7.8 Hz, 1H),
3.93 (s, 3H), 3.58 (d, J¼13.8 Hz, 2H), 3.24 (d, J¼13.8 Hz, 1H), 2.79 (d,
J¼13.2 Hz, 1H), 2.62 (s, 3H). 13C NMR (150 MHz, CDCl3)
d (ppm):
160.4, 152.8, 142.1, 140.6, 137.4, 135.9, 133.1, 132.6, 131.5, 131.0, 129.6,
129.3, 129.3, 128.9, 126.8, 124.4, 117.3, 116.2, 59.2, 45.4, 41.4, 38.1,
4.8. MW-assisted isomerization of vinyl compounds in DMSO
(synthesis of 20a–c and 21a–d)
36.9. IR (KBr) nmax: 2920, 2242, 1644, 1448, 1260, 1014, 764 cmꢁ1
.
Anal. Calcd for C23H19N5O (381.43): C, 72.42; H, 5.02; N, 18.36.
Found: C, 72.22; H, 4.84; N, 18.22.
A solution of the vinyl precursor (12a–c and 19a–d) (0.25 mmol)
in 1 mL dry DMSO was irradiated in an open vessel or in a 10 mL
MW process vial at the temperature and for the reaction time
shown in Table 1. The reaction mixture was subsequently cooled to
ambient temperature and poured into CH2Cl2 (15 mL). The organic
layer was washed with H2O (3ꢂ15 mL), dried (MgSO4), filtered and
evaporated to dryness. The residue obtained was purified by flash
column chromatography on silica gel with the eluents indicated
below.
4. 8. 5. 5-Methyl-13-oxo-14-phenyl-5, 8,13,14-tetrahy-
drodibenzo[b,f]pyridazino[4,5-d]azecine-7,7(6H)-dicarbonitrile
(21b). Column chromatography: n-hexane/EtOAc 4:1. White crys-
tals, mp 195–198 ꢀC, Rf¼0.70 (n-hexane/EtOAc 1:1). 1H NMR
(600 MHz, CDCl3) d (ppm): 8.03 (s, 1H), 7.82–7.75 (m, 2H), 7.67 (dm,
J¼7.8 Hz, 1H), 7.52–7.48 (m, 2H), 7.43–7.39 (m, 1H), 7.38 (dm,
J¼7.2 Hz, 1H), 7.32–7.22 (m, 3H), 7.08 (tm, J¼7.8 Hz, 1H), 6.89 (dm,
J¼7.8 Hz, 1H), 6.72 (dm, J¼7.8 Hz, 1H), 3.61 (d, J¼13.8 Hz, 1H), 3.58
(d, J¼13.8 Hz, 1H), 3.31 (d, J¼13.8 Hz, 1H), 2.80 (d, J¼13.8 Hz, 1H),
4.8.1. 5-Methyl-5,8-dihydrotribenzo[b,d,f]azecine-7,7(6H)-dicarboni-
trile (20a). Column chromatography: n-hexane/EtOAc 97:3. White
crystals, mp 149–152 ꢀC, Rf¼0.36 (n-hexane/EtOAc 9:1). 1H NMR
2.69 (s, 3H). 13C NMR (150 MHz, CDCl3)
d (ppm): 159.9, 152.9, 142.2,
142.2,141.9,138.5,135.9,133.0,132.9,131.7,131.0,129.7,129.4,129.3,
129.3, 129.0, 129.0, 126.9, 125.9, 124.5, 117.2, 116.2, 59.3, 45.6, 38.1,
(CDCl3)
d
(ppm): 7.65 (dm, J¼8.0 Hz, 1H), 7.51–7.46 (m, 1H), 7.42–
37.0. IR (KBr) nmax: 2922, 2242, 1652, 1490, 1294, 1126, 758 cmꢁ1
.
7.38 (m, 2H), 7.35–7.31 (m, 1H), 7.19–7.09 (m, 4H), 6.96 (tm,
J¼7.6 Hz, 1H), 6.73–6.67 (m, 2H), 3.55 (d, J¼13.1 Hz, 1H), 3.52 (d,
J¼13.8 Hz, 1H), 3.40 (d, J¼13.8 Hz, 1H), 2.85 (d, J¼13.1 Hz, 1H), 2.41
Anal. Calcd for C28H21N5O (443.50): C, 75.83; H, 4.77; N, 15.79.
Found: C, 75.62; H, 4.54; N, 15.41.
(s, 3H). 13C NMR (CDCl3)
d
(ppm): 153.0, 144.1, 141.6, 140.4, 139.2,
4.8.6. 3-Methyl-4-oxo-3,9,10a,11,12,13-hexahydrodibenzo[e,i]pyr-
idazino[4,5-g]pyrrolo[1,2-a]azecine-10,10(4H)-dicarbonitrile
(21c). Column chromatography: n-hexane/EtOAc 1:1. White
132.5, 131.1, 131.0, 130.2, 130.0, 129.6, 129.1, 128.6, 128.0, 127.6, 127.5,
126.1, 123.0, 117.6, 116.7, 59.0, 44.2, 38.5, 35.9. IR (KBr) nmax: 2952,

P. Dunkel et al. / Tetrahedron 66 (2010) 2331–2339
2339
crystals, mp 184–188 ꢀC, Rf¼0.35 (n-hexane/EtOAc 1:1). 1H NMR
6. Hart, J. B.; Mason, J. M.; Gerard, P. J. Tetrahedron 2001, 57, 10033–10038.
7. (a) Kulkarni, B. K.; Dhar, R. K.; de Souza, N. J. J. Heterocycl. Chem. 1990, 27, 623–
626; (b) Xiao, X.; Liu, J.; Hu, J.; Zhu, X.; Yang, H.; Wang, C.; Zhang, Y. Eur. J.
Pharmacol. 2008, 591, 21–27; (c) Saeed, S. A.; Gilani, A. H.; Majoo, R. U.; Shah, B.
H. Pharmacol. Res. 1997, 36, 1–7.
8. Sawa, Y.; Hirose, K.; Maeda, S.; Hamada, Y. U.S. Patent 3,932,384, 1976; Chem.
Abstr. 1976, 80, 146050.
(600 MHz, CDCl3)
d
(ppm): 7.87 (s, 1H), 7.68 (dm, J¼7.8 Hz, 1H),
7.26–7.18 (m, 4H), 7.02 (tm, J¼7.2 Hz,1H), 6.64–6.58 (m, 2H), 3.94 (s,
3H), 3.56 (d, J¼14.4 Hz, 1H), 3.42–3.35 (m, 2H), 3.27 (d, J¼14.4 Hz,
1H), 2.75–2.68 (m, 1H), 2.55–2.48 (m, 1H), 2.38–2.30 (m, 1H), 2.22–
2.15 (m, 1H), 2.12–2.04 (m, 1H). 13C NMR (150 MHz, CDCl3)
d (ppm):
9. (a) Kassack, M. U.; Ho¨fgen, B.; Decker, M.; Eckstein, N.; Lehmann, J. Naunyn-
Schmiedeberg’s Arch. Pharmacol 2002, 366, 543–550; (b) Mohr, P.; Decker, M.;
Enzensperger, C.; Lehmann, J. J. Med. Chem. 2006, 49, 2110–2116.
10. Meth-Cohn, O.; Suschitzky, H. Adv. Heterocycl. Chem. 1972, 14, 211–278.
11. Quintela, J. M. Recent Res. Dev. Org. Chem. 2003, 7, 259–278.
12. Verboom, W.; Reinhoudt, D. N. Recl. Trav. Chim. Pays-Bas 1990, 109, 311–324.
160.6, 152.5, 143.5, 140.5, 137.3, 136.0, 134.2, 132.8, 131.3, 130.6,
129.4, 129.3, 129.1, 128.8, 126.7, 124.4, 117.1, 117.0, 70.7, 56.9, 44.8,
41.7, 37.9, 31.2, 24.3. IR (KBr) nmax: 2918, 2246, 1644, 1444, 1266,
1016, 758 cmꢁ1. HRMS: calcd for (C25H21N5OþHþ): 408.1824.
Found: 408.1811.
´
´
´
´
´
´
´
13. Matyus, P.; Elias, O.; Tapolcsanyi, P.; Polonka-Balint, A.; Halasz-Dajka, B.
Synthesis 2006, 16, 2625–2639.
´
´
´
´
´
14. Polonka-Balint, A.; Saraceno, C.; Ludanyi, K.; Benyei, A.; Matyus, P. Synlett 2008,
4.8.7. 3-Methyl-4-oxo-3,9,11,12,13,14-hexahydro-4H-dibenzo[e,i]pyr-
idazino[4,5-g]pyrido[1,2-a]azecine-10,10(10aH)-dicarbonitrile
(21d). Column chromatography: toluene/EtOAc 2:1. Yellow crys-
tals, mp 140–144 ꢀC, Rf¼0.38 (toluene/EtOAc 2:1). 1H NMR (DMSO-
2846–2850.
´
15. Fo¨ldi, A. A.; Ma´tyus, P., unpublished results.
16. (a) Buchwald, S. L.; Huang, X.; Zim, D. WO 2004052939; Chem. Abstr. 2004, 141,
71718; (b) Bonnaventure, I.; Charette, A. B. J. Org. Chem. 2008, 73, 6330–6340.
17. (a) Krajsovszky, G.; Karolyhazy, L.; Riedl, Zs.; Csampai, A.; Dunkel, P.; Lernyei, A.;
´
´
´
´
Dajka-Hala´sz, B.; Hajo´ s, Gy.; Ma´tyus, P. J. Mol. Struct. (THEOCHEM) 2005, 713,
d6)
d
(ppm): 8.16 (s, 1H), 7.59 (dm, J¼8.0 Hz, 1H), 7.33 (dd, J¼7.2,
ˇ
ˇ
235–243; (b) Beska, E.; Rapos, P. J. Chem. Soc., Perkin Trans. 1 1976, 2470–2471.
18. Haider, N.; Wobus, A. Heterocycles 2006, 68, 2549–2561.
19. Stevenson, T. M.; Crouse, B. A.; Thieu, T. V.; Gebreysus, C.; Finkelstein, B. L.;
Sethuraman, M. R.; Dubas-Cordery, C. M.; Piotrowski, D. L. J. Heterocycl. Chem.
2005, 42, 427–435.
20. Lauer, M.; Wulff, G. J. Organomet. Chem. 1983, 256, 1–9.
21. Howard, H. R. EP 0957099; Chem. Abstr. 1999, 131, 351348.
22. Biadatti, T.; Dumais, L.; Soulet, C.; Talano, S.; Daver, S. WO 2006066978; Chem.
Abstr. 2006, 145, 103438.
23. Verboom, W.; Reinhoudt, D. N.; Visser, R.; Harkema, S. J. Org. Chem. 1984, 49,
269–276.
24. Ju, Y.; Varma, R. S. J. Org. Chem. 2006, 71, 135–141.
25. Kaval, N.; Dehaen, W.; Ma´tyus, P.; Van der Eycken, E. Green Chem. 2004, 6,
125–127.
1.8 Hz, 1H), 7.22 (tm, J¼8.0 Hz, 1H), 7.19–7.10 (m, 2H), 7.06 (dm,
J¼8.0 Hz, 1H), 7.00 (tm, J¼8.0 Hz, 1H), 6.62 (dm, J¼7.6 Hz, 1H), 3.79
(s, 3H), 3.72 (d, J¼14.0 Hz, 1H), 3.14 (dm, J¼13.6 Hz, 1H), 3.04 (tm,
J¼14.5 Hz, 1H), 3.01 (d, J¼14.0 Hz, 1H), 2.56 (dm, J¼14.5 Hz, 1H),
2.41–2.31 (m, 1H), 2.28–2.15 (m, 1H), 2.00–1.94 (m, 1H), 1.80–1.73
(m, 1H), 1.35–1.22 (m, 2H). 13C NMR (DMSO-d6)
d (ppm): 159.1,
150.0, 142.2, 138.3, 137.2, 135.8, 132.5, 131.7, 130.1, 129.6, 129.5,
129.3, 128.0, 127.6, 124.3, 123.6, 117.9, 117.1, 58.5, 48.8, 42.2, 40.3,
36.2, 23.9, 18.8, 18.7. IR (KBr) nmax: 2932, 2240, 1648, 1444, 1228,
1014, 764 cmꢁ1. Anal. Calcd for C26H23N5O (421.49): C, 74.09; H,
5.50; N, 16.62. Found: C, 73.77; H, 5.38; N, 16.36.
26. Kaval, N.; Hala´ sz-Dajka, B.; Vo-Thanh, G.; Dehaen, W.; Van der Eycken, J.;
´
Matyus, P.; Loupy, A.; Van der Eycken, E. Tetrahedron 2005, 61,
9052–9057.
Acknowledgements
27. The X-ray data are available from the Cambridge Crystallographic Data Centre
CCDC under the numbers 731714–731718 for 12a, 18a, 19a, 20a and 21c, re-
spectively. Copies of the data can be obtained free of charge on application to
CCDC, 12 Union Road, Cambridge CB2 1EZ, UK; fax: þ44(1223)336033 or
e-mail: deposit@ccdc.cam.ac.uk. The details of the X-ray structures will be
published elsewhere.
The authors thank the Hungarian Scientific Research Fund for
´
´
financial support (K73389), Dr. Tamas Gati for his contribution to
´
´ ´
the assignment of NMR spectra, and Dr. Peter Tetenyi for recording
IR spectra.
28. O’Leary, J.; Formosa, X.; Skranc, W.; Wallis, J. D. Org. Biomol. Chem. 2005, 3,
3273–3283.
29. (a) Guven, A.; Jones, R. A. J. Chem. Res., Miniprint 1993, 9, 2411–2428; (b)
Mongevega, A.; Palop, J. A.; Martinez, M. T.; Fernandez-Alvarez, E. An. Quim.
1979, 75, 889.
References and notes
30. Ali, M. I.; El-Sayed, A. A.; Abdel-Fattah, A. M.; El-Reedy, A. M. Indian J. Chem. B
1977, 15, 64–66.
31. (a) Gait, S. F.; Peek, M. E.; Rees, C. W.; Storr, R. C. J. Chem. Soc., Perkin Trans. 1
1974, 1248–1260; (b) Mascarelli, G. Gazz. Chim. Ital. 1931, 61, 782–788.
32. Fuhrer, W.; Gschwend, H. W. J. Org. Chem. 1979, 44, 1133–1136.
33. Rocca, P.; Marsais, F.; Godard, A.; Queguiner, G. Tetrahedron 1993, 49, 49–64.
1. Aladesanmi, A. J.; Kelley, C. J.; Leary, J. D. J. Nat. Prod. 1983, 46, 127–131.
2. McDonald, E.; Suksamrarn, A. Tetrahedron Lett. 1975, 49, 4425–4428.
3. Marino, J. P.; Samanen, J. M. J. Org. Chem. 1976, 41, 179–180.
4. McDonald, E.; Suksamrarn, A. J. Chem. Soc., Perkin Trans. 1 1978, 5, 434–440.
5. Efferth, T.; Sauerbrey, A.; Halatsch, M.-E.; Ross, D. D.; Gebhart, E. Naunyn-
Schmiedeberg’s Arch. Pharmacol. 2003, 367, 56–67.