Intramolecular [4+2] cycloaddition reactions of indolylalkylpyridazines: Synthesis of annulated carbazoles

Article abstract of DOI:10.1016/j.tet.2004.06.008

Mono- and bicyclic 1,2-diazines tethered to indole dienophiles by alkylene chains were found to undergo thermally induced intramolecular Diels-Alder reactions with inverse electron demand, affording tetra- and pentacyclic condensed carbazoles.

Full text of DOI:10.1016/j.tet.2004.06.008

Tetrahedron 60 (2004) 6495–6507
Intramolecular [412] cycloaddition reactions of
indolylalkylpyridazines: synthesis of annulated carbazoles
*
Norbert Haider and Johann Kaferbock
¨
¨
Department of Pharmaceutical Chemistry, University of Vienna, Althanstrabe 14, A-1090 Vienna, Austria
Received 19 April 2004; revised 24 May 2004; accepted 3 June 2004
Dedicated with best wishes to Professor Peter Stanetty on the occasion of his 60th birthday
Available online 19 June 2004
Abstract—Mono- and bicyclic 1,2-diazines tethered to indole dienophiles by alkylene chains were found to undergo thermally induced
intramolecular Diels–Alder reactions with inverse electron demand, affording tetra- and pentacyclic condensed carbazoles.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
In the course of our investigations on the synthesis and
antitumour activity of polycyclic hetarenes, especially
condensed carbazoles of the ellipticine/olivacine type
(Fig. 1),18–22 we became interested in the intramolecular
IDA reaction of indoles with pyridazines as a promising tool
for the construction of novel fused carbazoles with an
alkylene bridge between the carbazole nitrogen in ring B
and the adjacent carbon in ring C. Such compounds would
combine some of the structural features of the b-fused
carbazole antitumour agents like ellipticine as well as of the
canthine alkaloids which are also known to possess
cytotoxic activity.23 Here, we report on the concise
synthesis of suitable indol-1-ylalkyl-substituted pyridazines
and fused pyridazines and on their intramolecular [4þ2]
cycloaddition reactions, affording annulated carbazoles.
The electron-rich C(2)–C(3) bond of indole has been
known to participate as a dienophile in inverse-electron-
demand Diels–Alder (IDA) reactions with electron-
deficient azines as dienes, such as 1,2,4,5-tetrazines1–9
and 1,2,4-triazines,6,9–13 affording pyridazino[4,5-b]indoles
or carbolines, respectively.14 In the case of the 1,2,4-triazine
ring system, various intramolecular IDA reactions with an
indole as the dienophile component have been studied by
Snyder,6,9,11 – 13 and these reactions lead to bridged
carbolines, e.g. 5,6-dihydro-4H-pyrido[1,2,3-lm]-b-carbo-
lines featuring the skeleton of the canthine alkaloids.11 Also
for indole-tethered 1,2,4,5-tetrazines, some applications of
such intramolecular [4þ2] cycloaddition processes have
been reported.6,9
So far, very few examples of pyridazines participating in
IDA reactions with indole dienophiles have been described.
The highly reactive tetramethyl pyridazine-3,4,5,6-tetra-
carboxylate was found to react with indole to afford a
phenanthridone instead of the expected carbazole,10
whereas 4,5-dicyanopyridazine on heating with indole or
N-methylindole gives dicyanocarbazoles along with minor
amounts of 3-(4-cyanopyridazin-5-yl)indole derivatives,15
the latter resulting from nucleophilic substitution of one
cyano group by the electron-rich indole C(3). Recently, the
intramolecular IDA reaction of cyclophanes containing an
indole and a pyridazine unit has been shown to yield
pentacyclic compounds featuring a reduced carbazole
skeleton very elegantly.16,17
Figure 1.
2. Results and discussion
2.1. Synthesis of tethered cycloaddition educts
For the preparation of the requisite 3-(indol-1-yl)propyl-
substituted pyridazines, two alternative pathways were
developed. Starting from a N-propargylindole of type 1,
Sonogashira coupling with 3-iodopyridazine24,25 (2) or
Keywords: Cycloaddition; Indoles; Pyridazines; Carbazoles.
*
Corresponding author. Tel.: þ43-1-4277-55124; fax: þ43-1-4277-9551;
e-mail address: norbert.haider@univie.ac.at
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.06.008

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N. Haider, J. Kaferbock / Tetrahedron 60 (2004) 6495–6507
6496
Scheme 1.
1-iodophthalazine26 (3), respectively, gives the intermediate
alkynes 4, 5 which are hydrogenated to afford the desired
compounds 6, 7. Alternatively, addition of a Grignard
reagent generated from 1-(3-chloropropyl)indoles27 (8)
across the C(1)–N(2) bond of phthalazine, followed by
dehydrogenation of the intermediate dihydrophthalazines 9
with K3Fe(CN)6 also leads to 7 in satisfactory yields.
proved to be very inert and all attempts failed to elaborate
on the allenic structure by hydrogenation. Obviously, the
alkyne/allene rearrangement is favored in this case by the
increased CH acidity of the methylene group, as compared
to the stable alkynes 4, 5 which are lacking the electron-
withdrawing ester functions at the diazine unit (Scheme 1).
In order to circumvent this problem, we sought to increase
the electron density of the propyne synthon (thus decreasing
the methylene CH acidity) by employing the corresponding
indoline derivatives (12a, 12b28) instead of the indoles
(1a,b) as the cross-coupling partners with the iodopyrida-
zine diester (1024 or 13,24 respectively; Scheme 3). Indeed,
here the Sonogashira reaction smoothly affords the desired
alkyne-type coupling products 14, 15 without any trace of
an allenic rearrangement product. Catalytic hydrogenation
of the triple bond in 14, 15 was found to result in
concomitant reduction of the highly electron-poor pyrida-
zine ring, giving the corresponding dihydropyridazine
In contrast to the smooth formation of compounds 4a and
5a,b, the palladium-catalyzed cross-coupling reaction of
5-methoxy-N-propargylindole (1a) with diethyl 3-iodo-
pyridazine-4,5-dicarboxylate (10) (Scheme 2), which is
easily accessible by free-radical ethoxycarbonylation of
3-iodopyridazine,24 did not afford the desired
indolylpropynylpyridazine derivative, but led to a red-
colored compound which, according to its mass spectrum, is
an isomer of the target propyne. Based on its spectral data
(1H NMR including DNOE, IR, MS, HRMS), the structure
of the allene 11 was established for this compound. It
Scheme 2.

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N. Haider, J. Kaferbock / Tetrahedron 60 (2004) 6495–6507
6497
Scheme 3.
derivatives: in the case of the 3,4,5-trisubstituted pyrida-
zines, the structure of the 1,4-dihydropyridazines 16 was
established by their H NMR spectra (coupling of the NH
parts of the molecules can be generated conveniently from
the precursors 16 or 17, respectively, in a single step
(Scheme 3).
1
proton with pyridazine 6-H, J¼4.2 Hz), whereas the
tetrasubstituted pyridazines afforded unseparable mixtures
of 1,4-dihydropyridazines (17) and their 2,5-dihydro-
pyridazine isomers. Heating these compounds in xylene in
the presence of air oxygen with palladium/carbon as the
catalyst effects the required dehydrogenation/aromatization
of the indole as well as of the pyridazine subunits to give
compounds 18, 19. Thus, both the dienophile and the diene
In an analogous fashion, a cycloaddition candidate with a
four-carbon tether chain (compound 23, see Scheme 4) was
prepared, starting from 1-(but-3-yn-1-yl)indole (20) and the
iodopyridazine 10. Catalytic hydrogenation, like in the
transformation of 14 into 18 via 16, results in the formation
of a 1,4-dihydropyridazine intermediate (22) which is then
dehydrogenated to give 23. Moreover, refluxing of the
Scheme 4.

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6498
diesters 18b, 19b with hydrazine hydrate in 1-propanol
smoothly affords the corresponding pyridazino[4,5-d]-
pyridazinedione derivatives 24, 25 (Scheme 4) as another
type of candidates for the envisaged intramolecular
cycloaddition step.
times as compared to the 5-unsubstituted indoles (18b and
19b), the trisubstituted pyridazines 18 react considerably
faster and give higher yields of carbazole products than the
tetrasubstituted cyclization educts 19, obviously as a
consequence of the different degree of steric hindrance
around the diazadiene structures. Expectedly, elongation of
the tether chain by one methylene unit as in compound 23
leads to a marked decrease in reactivity, which is reflected
by a longer reaction time and lower yield (product 34; entry
9), as a result of the lower degree of ‘entropic assistance’.
Application of the Grignard pathway (as described for the
preparation of 7 from 8, see above) to the pyrido[3,4-
d]pyridazine ring system gave the desired compound only in
low yield, together with other isomers. However, using the
Sonogashira coupling route, starting from 1-chloro-
pyrido[3,4-d]pyridazine29 (26) and 1-prop-2-yn-1-ylindo-
line28 (12b) provides a convenient access also to a
cycloaddition educt with a pyrido[3,4-d]pyridazine system
(compound 28) as the diene unit (Scheme 5).
In all cases where pyridazinedicarboxylic acid diesters
(compounds of type 18, 19, and 23) were employed in the
IDA reaction, we observed the formation of small amounts
of side products in which one of the two ester groups is
replaced by hydrogen, as exemplified by the isolation and
characterization of ethyl 10-methoxy-5,6-dihydro-4H-
pyrido[3,2,1-jk]carbazole-3-carboxylate30 from the
cycloaddition of compound 18a. As a possible explanation
for this side reaction, one may assume partial hydrolysis of
the diester by traces of water, followed by thermally induced
decarboxylation.31 Moreover, we investigated the
possibility of performing the sequence starting from
the indoline-tethered dihydropyridazines 16, 17 via the
aromatic pyridazines 18, 19 into the carbazoles 32, 33 as a
one-pot reaction by refluxing the starting material in TIPB
in the presence of air oxygen with palladium/carbon as a
catalyst. Indeed, the expected domino reaction (double
dehydrogenation–cycloaddition–cycloreversion–dehydro-
genation) takes place under these conditions, as the
formation of the corresponding carbazoles could be detected
by GLC–MS and TLC. However, yields are very low and
large amounts of decomposition products are formed, so
that this one-pot variant is of no preparative use.
2.2. Intramolecular [412] cycloaddition reactions
Thermally induced intramolecular IDA reactions of the
indolylalkylpyridazines could be anticipated to require
drastic conditions, taking into account the lower degree of
electron deficiency of these 1,2-diazine compounds as
compared to structurally related 1,2,4-triazines.11 Thus,
1,3,5-triisopropylbenzene (TIPB; bp¼232 8C) was chosen
as the solvent for all cycloaddition attempts to ensure
sufficiently high reaction temperatures. All reactions were
run under argon atmosphere in order to minimize formation
of decomposition products.
Surprisingly, even the unactivated monocyclic pyridazine
(compound 6a; cf. Table 1, entry 1) was found to undergo an
IDA reaction, albeit very slowly (2 weeks of refluxing) and
giving a very low yield (8%) of the corresponding carbazole
(29) besides substantial amounts of polymeric material.
Obviously, compound 29 results from air oxidation/
dehydrogenation of the initially formed dihydrocarbazole
product (see Scheme 6) during work-up. With a phthalazine
system as the diazadiene (compounds 7a,b, entries 2 and 3),
reactions are complete after 4 days at 232 8C, but the yields
of the pentacyclic products 30a,b are still rather low (mainly
because of decomposition). Introduction of an additional
nitrogen atom into the bicyclic diazadiene (i.e., replacement
of the phthalazine by a pyrido[3,4-d]pyridazine structure,
compound 28) markedly increases the reaction rate (reac-
tion time: 15 h; entry 4), however with no improvement of
product yield (compound 31). Substantially better yields are
obtained with the very electron-poor pyridazinediesters
18a,b and 19a,b, respectively (products of type 32, 33;
entries 5–8). Whereas the presence of an electron-donating
methoxy group at the dienophilic indole subunit (18a and
19a) does not significantly influence yields and reaction
The highest yields of cycloaddition products (75 and 64%
for compounds 35 and 36, respectively) were obtained on
employment of the pyridazine-fused pyridazinediones 24
and 25 as diazadienes (entries 10 and 11), and also the
observed conversion rates were higher with these educts.
Even with compound 25, in which the diazadiene structure
is sterically more crowded than in 24, the transformation is
complete within 24 h of refluxing, as compared to 50 h for
the esters 19. Inspection of the energy gaps between the
involved frontier molecular orbitals (calculated with the
PM3 method32) indicates a slight advantage for the bicyclic
pyridazines 24 (DE: 6.89 eV) and 25 (DE: 6.93 eV) towards
their monocyclic counterparts 18b (DE: 7.11 eV) and 19b
(DE: 7.16 eV).33 Moreover, a beneficial effect on reaction
rates may be assumed to arise from the forced coplanarity of
the CO groups with the pyridazine ring in 24 and 25,
Scheme 5.

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6499
Table 1. Intramolecular [4þ2] cycloaddition reactions of indolylalkylpyridazines
Entry
Educt
Product
Structure
Time
14 d
Yield
(%)
1
6a
29
8
2
3
4
5
7a
30a
30b
31
4 d
8
7b
28
4 d
25
21
51
15 h
17 h
18a
32a
6
7
18b
19a
32b
33a
17 h
55
41
50 h
8
19b
33b
50 h
43
9
23
24
34
35
67 h
36
75
10
17 h
11
25
36
24 h
64

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6500
Scheme 6. General pathway of the cycloaddition reactions (for individual structures, see Table 1).
minimizing steric hindrance at this part of the diene
structure, again in comparison to the esters 18, 19.
carried out on Merck LiChroprep Si 60 (0.040–
0.063 mm) with UV detection at 280 nm. Analytical grade
solvents (Merck) were used, petroleum ether (PE) refers to
the fraction of bp 50–70 8C. 1,3,5-Triisopropylbenzene
(TIPB) was stored over Linde molecular sieves (0.4 nm). IR
spectra were measured for KBr pellets on a Perkin–Elmer
Cycloaddition products 29–34 were isolated by column
chromatography whereas compounds 35 and 36 precipitated
from the reaction mixtures. In all cases, the structures of the
polycyclic products follow unambiguously from their
elemental compositions and spectral data. In particular,
the marked downfield shift of the carbazole proton which
initially was 4-H in the indole precursor proved to be a
convenient diagnostic tool in combination with significant
NOE’s which can be observed between this particular
carbazole H at ring A and the neighbouring substituent R2
(either H or CH3) at ring C.
1
1605 FT-IR spectrometer. H NMR spectra were recorded
on a Varian Unity-Plus 300 spectrometer at 300 MHz. Mass
spectra were obtained on a Hewlett–Packard 5890A/5970B
GC-MSD or on a Shimadzu QP5050A DI 50 instrument.
High-resolution mass spectra were measured on a Finnigan
MAT 8230 at the Department of Organic Chemistry,
University of Vienna. Microanalyses were performed at
the Department of Physical Chemistry (Microanalytical
Laboratory), University of Vienna. For semiempirical MO
calculations, the MOPAC program as contained in the
SYBYL 6.9 software package (Tripos Inc.) was used.
3. Conclusion
It can be stated that, despite its relatively high LUMO
energy (as compared to 1,2,4-triazine and 1,2,4,5-tetrazine),
the 1,2-diazine system is able to act as a diazadiene in
intramolecular inverse-electron-demand Diels–Alder
reactions with appropriately tethered indole dienophiles.
Whereas unactivated pyridazines undergo these thermally
induced [4þ2] cycloaddition reactions only very sluggishly,
the examples with more electron-deficient pyridazines,
especially pyridazinediesters and pyridazino[4,5-d]pyri-
dazinediones clearly demonstrate the synthetic usefulness
of the intramolecular IDA strategy for the construction of
polycyclic carbazoles. The target ring systems, which are of
interest as core structures of new antitumour agents, are
difficult to prepare via other routes34 or (as in the case of
compounds 30, 35/36) represent previously unknown ring
systems.
4.2. Preparation of cycloaddition educts
4.2.1. 5-Methoxy-1-prop-2-yn-1-yl-1H-indole (1a). To a
solution of 5-methoxyindole (1.47 g, 10 mmol) and pro-
pargyl bromide (2.23 g of a 80% solution in toluene,
15 mmol) in toluene (30 mL) were added tetrabutyl-
ammonium bromide (0.161 g, 0.5 mmol) and 50% aqueous
NaOH (6 mL). The two-phase mixture was vigorously
stirred at rt for 1 h. Toluene (10 mL) was added and the
layers were separated. The organic layer was washed with
water, dried over Na2SO4, and the solvent was removed in
vacuo to give an oil which slowly solidified. Recrystalliza-
tion from ether/PE gave 1a as yellow crystals (1.40 g, 74%):
mp 65–69 8C. IR 3246, 2958, 2833, 2122, 1618, 1575,
1487, 1432, 1240, 1154, 1027, 840, 798, 725, 697 cm21; 1H
NMR (CDCl3) d 7.32 (d, J6–7¼8.9 Hz, 1H, 7-H), 7.19 (d,
J2–3¼3.2 Hz, 1H, 2-H), 7.13 (d, J4–6¼2.4 Hz, 1H, 4-H),
6.94 (dd, J6–7¼8.9 Hz, J4–6¼2.4 Hz, 1H, 6-H), 6.48 (d,
J2–3¼3.2 Hz, 1H, 3-H), 4.85 (d, J¼2.4 Hz, 2H, NCH2-
CCH), 3.88 (s, 3H, OCH3), 2.41 (t, J¼2.4 Hz, 1H,
NCH2CCH); MS (EI, 70 eV) m/z 185 (Mþ, 100%), 170
(86), 146 (19), 142 (22), 115 (25), 103 (23), 89 (11), 76 (26),
63 (18), 51 (24). Anal. Calcd for C12H11NO: C, 77.81; H,
5.99; N, 7.56. Found: C, 77.56; H, 6.16; N, 7.48.
4. Experimental
4.1. General
Melting points were determined on a Kofler hot-stage
microscope (Reichert) and are uncorrected. Silica gel plates
(Merck, KGF254) and silica gel 60 (Merck, 0.063–
0.200 mm) were used for TLC and column chromatography.
Medium-pressure liquid chromatography (MPLC) was
4.2.2. 5-Methoxy-1-(3-pyridazin-3-ylprop-2-yn-1-yl)-
1H-indole (4a). To a solution of 1a (0.601 g, 3.25 mmol)

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and 3-iodopyridazine24,25 (2) (0.536 g, 2.6 mmol) in THF
(6 mL) were added triethylamine (1.0 mL, 7.2 mmol), CuI
(0.015 g, 0.08 mmol) and Pd(PPh3)2Cl2 (0.055 g,
0.08 mmol). The mixture was flushed with argon, then it
was stirred under argon at rt for 5 h. The solid material was
removed by filtration and carefully rinsed with THF. The
combined filtrate and washings were concentrated under
reduced pressure, and the residue was subjected to column
chromatography (EtOAc/PE, 4:1) to afford 4a (0.320 g,
46%) as brownish crystals: mp 95–98 8C (from EtOAc). IR
3050, 2914, 2837, 2234, 1620, 1571, 1488, 1438, 1242,
1151, 1132, 1025, 803, 720, 596 cm21; 1H NMR (CDCl3) d
9.13 (dd, J5–6¼5.1 Hz, J4–6¼1.7 Hz, 1H, pyridazine 6-H),
7.50 (dd, J4–5¼8.4 Hz, J4–6¼1.7 Hz, 1H, pyridazine 4-H),
7.45–7.35 (m, 2H, pyridazine 5-H, indole 7-H), 7.23 (d,
J2–3¼3.0 Hz, 1H, indole 2-H), 7.12 (d, J4–6¼2.6 Hz, 1H,
indole 4-H), 6.94 (dd, J6–7¼8.7 Hz, J4–6¼2.6 Hz, 1H,
indole 6-H), 6.49 (d, J2–3¼3.0 Hz, 1H, indole 3-H), 5.17 (s,
2H, NCH2), 3.87 (s, 3H, OCH3); MS (EI, 70 eV) m/z 263
(Mþ, 100%), 248 (15), 220 (76), 192 (22), 166 (9), 140 (9),
110 (7), 89 (8), 76 (10), 63 (15), 51 (8); HRMS (EI, 70 eV)
m/z 263.1070 (Mþ calcd for C16H13N3O: 263.1059). Anal.
Calcd for C16H13N3O. 0.3H2O: C, 71.52; H, 5.10; N, 15.64.
Found: C, 71.59; H, 5.08; N, 15.51.
4.2.5. 5-Methoxy-1-(3-pyridazin-3-ylpropyl)-1H-indole
(6a). A solution of 4a (0.200 g, 0.76 mmol) in EtOAc
(100 mL), containing Pd/C catalyst (10%, 0.065 g), was
hydrogenated in a Parr apparatus at a pressure of 50 psi until
TLC (EtOAc) indicated the end of the reaction (65 h). The
catalyst was filtered off and washed with EtOAc and EtOH.
The combined filtrate and washings were concentrated
under reduced pressure and the residue was purified by
MPLC (EtOAc) to give 6a (0.118 g, 58%) as a pale yellow
oil. IR 2936, 2830, 1621, 1576, 1488, 1449, 1437, 1239,
1
1151, 1031, 801, 722 cm21; H NMR (CDCl3) d 9.05 (dd,
J5–6¼4.9 Hz, J4–6¼1.8 Hz, 1H, pyridazine 6-H), 7.35 (dd,
J4–5¼8.4 Hz, J5–6¼4.9 Hz, 1H, pyridazine 5-H), 7.24–
7.16 (m, 2H, pyridazine 4-H, indole 7-H), 7.12–7.06 (m,
2H, indole 2-H, 4-H), 6.87 (dd, J6–7¼9.0 Hz, J4–6¼2.4 Hz,
1H, indole 6-H), 6.40 (d, J2–3¼3.0 Hz, 1H, indole 3-H),
4.24 (t, J¼6.6 Hz, 2H, NCH2CH2CH2), 3.86 (s, 3H, OCH3),
2.98 (t, J¼7.5 Hz, 2H, NCH2CH2CH2), 2.48–2.35 (m, 2H,
NCH2CH2CH2); MS (EI, 70 eV) m/z 267 (Mþ, 25%), 173
(100), 158 (39), 130 (13), 121 (17), 117 (25), 103 (12), 94
(49), 77 (11); HRMS (EI, 70 eV) m/z 267.1383 (Mþ calcd
for C16H17N3O: 267.1372).
4.2.6. 1-(3-Chloropropyl)-5-methoxy-1H-indole (8a). A
mixture of 5-methoxyindole (2.94 g, 20 mmol) and finely
powdered KOH (85%; 1.72 g, 26 mmol) in DMSO (47 mL)
was sonicated in an ultrasound cleaning bath for 10 min. It
was cooled to 0 8C, and 1-bromo-3-chloropropane (9.42 g,
60 mmol) was added dropwise. The mixture was stirred at rt
for 4 h, then it was poured into ice-water (100 mL) and
extracted with EtOAc. The organic layer was washed with
water and brine, and dried over Na2SO4. The volatile
components were removed in vacuo (first 10 mbar, then
1022 mbar) and the residue was subjected to column
chromatography (EtOAc/PE, 1:9) to afford 8a (4.26 g,
96%) as a colorless oil. IR 2994, 2945, 2830, 1622, 1488,
1449, 1239, 1151, 1031, 802, 720 cm21; 1H NMR (CDCl3)
d 7.27 (d, J6–7¼9.0 Hz, 1H, 7-H), 7.15–7.09 (m, 2H, 2-H,
4-H), 6.90 (dd, J6–7¼9.0 Hz, J4–6¼2.4 Hz, 1H, 6-H), 6.44
(d, J2–3¼3.3 Hz, 1H, 3-H), 4.31 (t, J¼6.3 Hz, 2H, NCH2-
CH2CH2), 3.87 (s, 3H, OCH3), 3.46 (t, J¼6.1 Hz, 2H,
NCH2CH2CH2), 2.32–2.20 (m, 2H, NCH2CH2CH2); MS
(EI, 70 eV) m/z 225 (Mþ, 11%), 223 (Mþ, 35), 208 (12), 160
(100), 145 (16), 130 (7), 117 (49), 103 (14), 89 (15), 76 (15),
63 (12), 51 (16); HRMS (EI, 70 eV) m/z 223.0768 (Mþ
calcd for C12H14ClNO: 223.0764).
4.2.3. 1-[3-(5-Methoxy-1H-indol-1-yl)prop-1-yn-1-
yl]phthalazine (5a). This compound was prepared as
described for 4a, starting from 1-iodophthalazine26 (3)
(0.666 g, 2.6 mmol) instead of 2. Chromatographic work-up
(EtOAc) afforded 5a (0.400 g, 49%) as brownish crystals:
mp 143–145 8C (from EtOAc). IR 3091, 2954, 2831, 2242,
1
1621, 1485, 1396, 1239, 1150, 1028, 758, 593 cm21; H
NMR (CDCl3) d 9.46 (s, 1H, phthalazine 4-H), 8.12–8.04
(m, 1H, phthalazine 8-H), 7.98–7.80 (m, 3H, phthalazine
5-H, 6-H, 7-H), 7.46 (d, J6–7¼8.8 Hz, 1H, indole 7-H), 7.30
(d, J2–3¼3.1 Hz, 1H, indole 2-H), 7.15 (d, J4–6¼2.4 Hz,
1H, indole 4-H), 6.96 (dd, J6–7¼8.8 Hz, J4–6¼2.4 Hz, 1H,
indole 6-H), 6.52 (d, J2–3¼3.1 Hz, 1H, indole 3-H), 5.29 (s,
2H, NCH2), 3.87 (s, 3H, OCH3); MS (EI, 70 eV) m/z 313
(Mþ, 4%), 170 (100), 156 (12), 115 (11), 102 (12), 76
(12), 69 (37), 63 (10), 51 (14). Anal. Calcd for C20H15N3O:
C, 76.66; H, 4.82; N, 13.41. Found: C, 76.43; H, 5.05; N,
13.12.
4.2.4. 1-[3-(1H-Indol-1-yl)prop-1-yn-1-yl]phthalazine
(5b). This compound was prepared as described for 4a,
starting from 1-iodophthalazine26 (3) (0.666 g, 2.6 mmol)
instead of
2
and 1-prop-2-yn-1-yl-1H-indole35 (1b)
4.2.7. 1-[3-(5-Methoxy-1H-indol-1-yl)propyl]phthala-
zine (7a). Method A. A solution of 5a (0.160 g,
(0.504 g, 3.25 mmol) instead of 1a. Chromatographic
work-up (EtOAc) afforded 5b (0.400 g, 54%) as brownish
crystals: mp 145–148 8C (from EtOAc). IR 3053, 2952,
0.51 mmol) in EtOAc (100 mL), containing Pd/C catalyst
(10%, 0.040 g), was hydrogenated in a Parr apparatus at a
pressure of 50 psi until TLC (EtOAc) indicated the end of
the reaction (65 h). The catalyst was filtered off and washed
with EtOAc and EtOH. The combined filtrate and washings
were concentrated under reduced pressure and the residue
was purified by MPLC (EtOAc) to give 7a (0.065 g, 40%) as
a pale yellow oil.
1
2238, 1483, 1463, 1353, 1187, 749, 731, 594 cm21; H
NMR (CDCl3) d 9.45 (s, 1H, phthalazine 4-H), 8.10–8.04
(m, 1H, phthalazine 8-H), 7.97–7.80 (m, 3H, phthalazine
5-H, 6-H, 7-H), 7.68 (d, J4–5¼7.8 Hz, 1H, indole 4-H), 7.56
(d, J6–7¼8.1 Hz, 1H, indole 7-H), 7.35–7.26 (m, 2H, indole
2-H, 6-H), 7.22–7.14 (m, 1H, indole 5-H), 6.60 (d,
J2–3¼3.3 Hz, 1H, indole 3-H), 5.32 (s, 2H, NCH2); MS
(EI, 70 eV) m/z 283 (Mþ, 88%), 282 (100), 266 (6), 255
(39), 228 (6), 154 (23), 139 (63), 128 (20), 116 (22), 113
(27), 101 (7), 89 (47), 75 (11), 63 (41), 50 (13), 43 (32).
Anal. Calcd for C19H13N3. 0.2H2O: C, 79.53; H, 4.71; N,
14.64. Found: C, 79.52; H, 4.77; N, 14.59.
Method B. Magnesium turnings (0.60 g, 25 mmol) were
suspended in dry THF (5 mL) and the reaction was initiated
by addition of 1,2-dibromoethane (0.26 mL, 3 mmol). Then,
a solution of 8a (3.00 g, 13.5 mmol) in dry THF (10 mL)
was added dropwise, and the mixture was refluxed for 0.5 h.

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N. Haider, J. Kaferbock / Tetrahedron 60 (2004) 6495–6507
6502
A solution of phthalazine (1.17 g, 9 mmol) in dry THF
(10 mL) was added dropwise, and refluxing was continued
for 5 h. After cooling, the mixture was poured into a
solution of NH4Cl (3.4 g) in ice-water (100 mL), and it was
exhaustively extracted with CH2Cl2. The combined extracts
were dried over Na2SO4 and evaporated in vacuo to afford
an oily residue (containing the dihydrophthalazine 9a)
which was immediately used for the following step without
purification: the residue was dissolved in toluene (10 mL)
and a solution of K3Fe(CN)6 (13.5 g, 41 mmol) in water
(63 mL) as well as a solution of KOH (6.75 g, 120 mmol) in
water (32 mL) were added. The mixture was vigorously
stirred at rt for 2 h, then it was neutralized with AcOH and
exhaustively extracted with CH2Cl2. The combined extracts
were dried over Na2SO4 and evaporated in vacuo. The
residue was subjected to MPLC (EtOAc) to give 7a (1.64 g,
57%) as a pale yellow oil. IR 2935, 2830, 1620, 1488, 1449,
washings were concentrated under reduced pressure, and the
residue was taken up in warm toluene (100 mL, 50 8C) and
filtered again. Removal of the solvent in vacuo gave an oil
which was subjected to column chromatography (toluene/
EtOAc, 39:1) to afford the allene 11 (1.63 g, 52%) as a dark-
red oil. IR 2981, 2934, 1739, 1715, 1548, 1473, 1263, 1187,
1032, 765 cm21
;
1H NMR (CDCl3) d 8.62 (s, 1H,
pyridazine 6-H, shows positive NOE on irradiation of the
quartet at 4.40 ppm), 7.45 (d, J2–3¼3.5 Hz, 1H, indole
2-H), 7.20–7.10 (m, 3H, NCHCCH, indole 4-H, 7-H),
6.94–6.86 (m, 2H, NCHCCH, indole 6-H, shows positive
NOE on irradiation of the quartet at 4.59 ppm), 6.72 (d,
J2–3¼3.5 Hz, 1H, indole 3-H), 4.59 (q, J¼7.1 Hz, 2H,
pyridazine 4-CO2CH2CH3, 4.40 (q, J¼7.1 Hz, 2H, pyrida-
zine 5-CO2CH2CH3, 3.88 (s, 3H, OCH3), 1.49 (t, J¼7.1 Hz,
3H, pyridazine 4-CO2CH2CH3), 1.40 (t, J¼7.1 Hz, 3H,
pyridazine 5-CO2CH2CH3, shows positive NOE on
irradiation of the quartet at 4.40 ppm); MS (EI, 70 eV)
m/z 407 (Mþ, 100%), 379 (15), 351 (10), 307 (20), 292 (7),
264 (19), 246 (8), 218 (12), 192 (18), 164 (8), 132 (7), 103
(6), 88 (6); HRMS (EI, 70 eV) m/z 407.1488 (Mþ calcd for
C22H21N3O5: 407.1481).
1
1238, 1151, 1031, 756 cm21; H NMR (CDCl3) d 9.41 (s,
1H, phthalazine 4-H), 7.97–7.90 (m, 1H, phthalazine 5-H),
7.89–7.70 (m, 3H, phthalazine 6-H, 7-H, 8-H), 7.23 (d,
J6–7¼8.8 Hz, 1H, indole 7-H), 7.14 (d, J2–3¼3.0 Hz, 1H,
indole 2-H), 7.11 (d, J4–6¼2.5 Hz, 1H, indole 4-H), 6.84
(dd, J6–7¼8.8 Hz, J4–6¼2.5 Hz, 1H, indole 6-H), 6.43 (d,
J2–3¼3.0 Hz, 1H, indole 3-H), 4.34 (t, J¼6.7 Hz, 2H,
NCH2CH2CH2), 3.86 (s, 3H, OCH3), 3.29 (t, J¼7.5 Hz, 2H,
NCH2CH2CH2), 2.60–2.46 (m, 2H, NCH2CH2CH2); MS
(EI, 70 eV) m/z 317 (Mþ, 6%), 173 (34), 158 (15), 144
(100), 130 (6), 117 (12), 103 (5); HRMS (EI, 70 eV) m/z
317.1533 (Mþ calcd for C20H19N3O: 317.1528).
4.2.10. 5-Methoxy-1-prop-2-yn-1-ylindoline (12a). To a
solution of 5-methoxyindoline36 (1.50 g, 10.8 mmol) in
toluene (20 mL) were added Na2CO3 (2.42 g, 22.8 mmol)
and propargyl bromide (2.64 g of a 80% solution in toluene,
17.1 mmol), and the mixture was stirred under argon at rt for
20 h. The inorganic material was removed by filtration and
the filtrate was evaporated in vacuo. Column chromato-
graphy (neutral Al2O3; EtOAc/PE, 1:19) of the residue gave
12a (1.44 g, 68%) as a pale yellow oil which slowly
solidified: mp 46–48 8C. IR 3262, 2930, 2844, 2105, 1593,
4.2.8.
1-[3-(1H-Indol-1-yl)propyl]phthalazine
(7b).
Method A. Catalytic hydrogenation of 5b (0.200 g,
0.71 mmol) as described for the preparation of 7a from 5a
gave 7b (0.110 g, 54%) as a pale yellow oil.
1490, 1433, 1288, 1238, 1137, 1026, 868, 801, 655 cm21
;
1H NMR (CDCl3) d 6.79–6.75 (m, 1H, 4-H), 6.71–6.64 (m,
1H, 6-H), 6.53 (d, J6–7¼8.4 Hz, 1H, 7-H), 3.89 (d,
J¼2.4 Hz, 2H, NCH2CCH), 3.76 (s, 3H, OCH3), 3.39 (t,
J2–3¼8.0 Hz, 2H, 2-H), 2.95 (t, J2–3¼8.0 Hz, 2H, 3-H),
2.15 (t, J¼2.4 Hz, 1H, NCH2CCH); MS (EI, 70 eV) m/z 187
(Mþ, 66%), 172 (69), 148 (100), 133 (71), 117 (36), 104
(39), 91 (23), 77 (28), 63 (17), 51 (18). Anal. Calcd for
C12H13NO: C, 76.98; H, 7.00; N, 7.48. Found: C, 76.94; H,
7.11; N, 7.47.
Method B. Grignard reaction and subsequent oxidation, as
described for the preparation of 7a from 8a, starting from
1-(3-chloropropyl)-1H-indole27 (8b) (2.60 g, 13.5 mmol)
afforded 7b (1.32 g, 51%) as a pale yellow oil. IR 3095,
2951, 2927, 1509, 1454, 1444, 1309, 1224, 756, 743 cm21
;
1H NMR (CDCl3) d 9.44 (s, 1H, phthalazine 4-H), 7.99–
7.92 (m, 1H, phthalazine 5-H), 7.91–7.73 (m, 3H,
phthalazine 6-H, 7-H, 8-H), 7.67 (d, J4–5¼7.6 Hz, 1H,
indole 4-H), 7.37 (d, J6–7¼8.4 Hz, 1H, indole 7-H), 7.26–
7.17 (m, 2H, indole 2-H, 6-H), 7.17–7.08 (m, 1H, indole
5-H), 6.54 (d, J2–3¼3.0 Hz, 1H, indole 3-H), 4.41 (t,
J¼6.6 Hz, 2H, NCH2CH2CH2), 3.33 (t, J¼7.3 Hz, 2H,
NCH2CH2CH2), 2.66–2.51 (m, 2H, NCH2CH2CH2); MS
(EI, 70 eV) m/z 287 (Mþ, 3%), 144 (100), 130 (6), 117 (7),
103 (6), 89 (8), 77 (10), 63 (5), 51 (4); HRMS (EI, 70 eV)
m/z 287.1427 (Mþ calcd for C19H17N3: 287.1422).
4.2.11. Diethyl 3-[3-(5-methoxy-2,3-dihydro-1H-indol-1-
yl)prop-1-yn-1-yl]pyridazine-4,5-dicarboxylate
To a solution of 12a (0.608 g, 3.25 mmol) and diethyl
3-iodopyridazine-4,5-dicarboxylate24
(10) (0.910 g,
(14a).
2.6 mmol) in THF (6 mL) were added triethylamine
(1.0 mL, 7.2 mmol), CuI (0.015 g, 0.08 mmol) and
Pd(PPh3)2Cl2 (0.055 g, 0.08 mmol). The mixture was
flushed with argon, then it was stirred under argon at rt
for 7 h. The solid material was removed by filtration and
carefully rinsed with THF. The combined filtrate and
washings were concentrated under reduced pressure, and the
residue was subjected to column chromatography (EtOAc/
PE, 2:3) to afford 14a (0.734 g, 69%) as a brownish oil. IR
2982, 2937, 2832, 2235, 1735, 1491, 1337, 1291, 1237,
4.2.9. Diethyl 3-[3-(5-methoxy-1H-indol-1-yl)propa-1,2-
dien-1-yl]pyridazine-4,5-dicarboxylate (11). To a solution
of diethyl 3-iodopyridazine-4,5-dicarboxylate24 (10)
(2.70 g, 7.71 mmol) and 1a (1.78 g, 9.64 mmol) in THF
(16 mL) were added triethylamine (3.0 mL, 21.6 mmol),
CuI (0.044 g, 0.23 mmol) and Pd(PPh3)2Cl2 (0.162 g,
0.23 mmol). The mixture was flushed with argon, then it
was refluxed under argon for 3 h. Another portion of 1a
(0.71 g, 3.86 mmol) was added and refluxing was continued
for 3 h. The solid material was removed by filtration and
carefully rinsed with THF. The combined filtrate and
1026, 804 cm21
;
1H NMR (CDCl3) d 9.53 (s, 1H,
pyridazine 6-H), 6.79–6.40 (m, 1H, indoline 4-H), 6.67
(dd, J6–7¼8.4 Hz, J4–6¼2.7 Hz, 1H, indoline 6-H), 6.54 (d,
J6–7¼8.4 Hz, 1H, indoline 7-H), 4.43 (q, J¼7.2 Hz, 2H,
CH2CH3), 4.21 (s, 2H, propargyl CH2), 4.18 (q, J¼7.2 Hz,

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6503
2H, CH2CH3), 3.75 (s, 3H, OCH3), 3.46 (t, J2–3¼8.0 Hz,
2H, indoline 2-H), 2.98 (t, J2–3¼8.0 Hz, 2H, indoline 3-H),
1.40 (t, J¼7.2 Hz, 3H, CH2CH3), 1.27 (t, J¼7.2 Hz, 3H,
CH2CH3); MS (EI, 70 eV) m/z 409 (Mþ, 8%), 262 (11), 233
(12), 148 (28), 133 (18), 77 (12), 58 (100); HRMS (EI,
70 eV) m/z 409.1656 (Mþ calcd for C22H23N3O5:
409.1638).
m/z 393 (Mþ, 11%), 347 (7), 318 (14), 276 (70), 247 (100),
219 (21), 203 (50), 174 (17), 147 (14), 132 (27), 118 (50), 91
(52), 65 (16); HRMS (EI, 70 eV) m/z 393.1682 (Mþ calcd
for C22H23N3O4: 393.1689).
4.2.15. Diethyl 3-[3-(5-methoxy-1H-indol-1-yl)propyl]-
pyridazine-4,5-dicarboxylate (18a). A solution of 14a
(0.630 g, 1.54 mmol) in EtOH (200 mL) containing Pd/C
catalyst (10%, 0.130 g), was hydrogenated in a Parr
apparatus at a pressure of 60 psi for 45 h. The catalyst was
filtered off and washed with EtOH and EtOAc. The
combined filtrate and washings were concentrated under
reduced pressure to afford a brown oil (0.625 g) containing
the dihydropyridazine 16a.37 This material was dissolved in
xylene (61 mL), Pd/C catalyst (10%, 0.260 g) was added,
and the mixture was refluxed with vigorous stirring for 62 h
(reaction monitoring by GLC–MS). The catalyst was
filtered off and washed with hot EtOH and hot EtOAc.
The combined filtrate and washings were concentrated
under reduced pressure and the residue was subjected to
column chromatography (EtOAc/PE, 1:2) to afford 18a
(0.225 g, 35%) as a brownish oil. IR 2981, 2937, 1734,
1489, 1298, 1239, 1152, 1032, 802 cm–1; 1H NMR (CDCl3)
d 9.54 (s, 1H, pyridazine 6-H), 7.24 (d, J6–7¼8.9 Hz, 1H,
indole 7-H), 7.11 (d, J2–3¼3.0 Hz, 1H, indole 2-H), 7.09 (d,
J4–6¼2.6 Hz, 1H, indole 4-H), 6.88 (dd, J6–7¼8.9 Hz,
J4–6¼2.6 Hz, 1H, indole 6-H), 6.42 (d, J2–3¼3.0 Hz, 1H,
indole 3-H), 4.43 (q, J¼7.2 Hz, 2H, CH2CH3), 4.32–4.19
(m, 4H, CH2CH3, NCH2CH2CH2), 3.85 (s, 3H, OCH3), 2.98
(t, J¼7.6 Hz, 2H, NCH2CH2CH2), 2.50–2.35 (m, 2H,
NCH2CH2CH2), 1.40 (t, J¼7.2 Hz, 3H, CH2CH3), 1.24 (t,
J¼7.2 Hz, 3H, CH2CH3); MS (EI, 70 eV) m/z 411 (Mþ,
8%), 238 (11), 209 (10), 173 (100), 165 (15), 158 (27), 130
(9), 117 (21), 65 (7); HRMS (EI, 70 eV) m/z 411.1811 (Mþ
calcd for C22H25N3O5: 411.1794).
4.2.12. Diethyl 3-[3-(2,3-dihydro-1H-indol-1-yl)prop-1-
yn-1-yl]pyridazine-4,5-dicarboxylate (14b). This com-
pound was prepared as described for 14a, starting from
1-prop-2-yn-1-ylindoline28 (12b) (0.510 g, 3.25 mmol)
instead of 12a. Column chromatography (EtOAc/PE, 1:3)
gave 14b (0.757 g, 77%) as a brownish oil. IR 2981, 2849,
2236, 1734, 1487, 1286, 1024, 750 cm21; 1H NMR (CDCl3)
d 9.53 (s, 1H, pyridazine 6-H), 7.16–7.07 (m, 2H, indoline
4-H, 6-H), 6.79–6.71 (m, 1H, indoline 5-H), 6.61 (d,
J6–7¼7.8 Hz, 1H, indoline 7-H), 4.42 (q, J¼7.2 Hz, 2H,
CH2CH3), 4.27 (s, 2H, propargyl CH2), 4.14 (q, J¼7.2 Hz,
2H, CH2CH3), 3.51 (t, J2–3¼8.0 Hz, 2H, indoline 2-H), 3.02
(t, J2–3¼8.0 Hz, 2H, indoline 3-H), 1.39 (t, J¼7.2 Hz, 3H,
CH2CH3), 1.25 (t, J¼7.2 Hz, 3H, CH2CH3); MS (EI, 70 eV)
m/z 379 (Mþ, 11%), 304 (9), 262 (53), 233 (100), 205 (20),
188 (30), 160 (19), 118 (72), 91 (43), 65 (14); HRMS (EI,
70 eV) m/z 379.1517 (Mþ calcd for C21H21N3O4:
379.1532).
4.2.13. Diethyl 3-[3-(5-methoxy-2,3-dihydro-1H-indol-1-
yl)prop-1-yn-1-yl]-6-methylpyridazine-4,5-dicarboxyl-
ate (15a). This compound was prepared as described for
14a, starting from diethyl 3-iodo-6-methylpyridazine-4,5-
dicarboxylate24 (13) (0.946 g, 2.6 mmol) instead of 10.
Column chromatography (EtOAc/PE, 2:3) gave 15b
(0.970 g, 88%) as a brownish oil. IR 2982, 2936, 2832,
1
2236, 1739, 1491, 1242, 1037 cm21; H NMR (CDCl3) d
6.78–6.73 (m, 1H, indoline 4-H), 6.66 (dd, J6–7¼8.5 Hz,
J4–6¼2.5 Hz, 1H, indoline 6-H), 6.55 (d, J6–7¼8.5 Hz, 1H,
indoline 7-H), 4.40 (q, J¼7.2 Hz, 2H, CH2CH3), 4.20 (s,
2H, propargyl CH2), 4.16 (q, J¼7.2 Hz, 2H, CH2CH3), 3.75
(s, 3H, OCH3), 3.47 (t, J2–3¼8.0 Hz, 2H, indoline 2-H),
2.97 (t, J2–3¼8.0 Hz, 2H, indoline 3-H), 2.85 (s, 3H, CH3),
1.37 (t, J¼7.2 Hz, 3H, CH2CH3), 1.27 (t, J¼7.2 Hz, 3H,
CH2CH3); MS (EI, 70 eV) m/z 423 (Mþ, 7%), 276 (10), 247
(15), 203 (11), 148 (100), 133 (77), 117 (27), 101 (19), 77
(13); HRMS (EI, 70 eV) m/z 423.1810 (Mþ calcd for
C23H25N3O5: 423.1794).
4.2.16. Diethyl 3-[3-(1H-indol-1-yl)propyl]pyridazine-
4,5-dicarboxylate (18b). This compound was prepared as
described for 18a, starting from 14b (0.710 g, 1.87 mmol).
Column chromatography (EtOAc/PE, 1:3) gave 18b
(0.250 g, 35%) as a pale yellow oil. IR 2980, 2936, 1733,
1464, 1369, 1297, 1201, 1013, 742 cm21; 1H NMR (CDCl3)
d 9.54 (s, 1H, pyridazine 6-H), 7.63 (d, J4–5¼7.8 Hz, 1H,
indole 4-H), 7.35 (d, J6–7¼8.1 Hz, 1H, indole 7-H), 7.26–
7.17 (m, 1H, indole 6-H), 7.14 (d, J2–3¼3.2 Hz, 1H, indole
2-H), 7.13–7.06 (m, 1H, indole 5-H), 6.51 (d, J2–3¼3.2 Hz,
1H, indole 3-H), 4.42 (q, J¼7.2 Hz, 2H, CH2CH3), 4.30 (t,
J¼6.6 Hz, 2H, NCH2CH2CH2), 4.21 (q, J¼7.2 Hz, 2H,
CH2CH3), 2.99 (t, J¼7.6 Hz, 2H, NCH2CH2CH2), 2.52–
2.37 (m, 2H, NCH2CH2CH2), 1.40 (t, J¼7.2 Hz, 3H,
CH2CH3), 1.22 (t, J¼7.2 Hz, 3H, CH2CH3); MS (EI,
70 eV) m/z 381 (Mþ, 16%), 335 (4), 290 (7), 264 (7), 238
(100), 209 (72), 164 (63), 143 (62), 130 (57), 94 (17), 77
(20), 63 (8); HRMS (EI, 70 eV) m/z 381.1679 (Mþ calcd for
C21H23N3O4: 381.1689).
4.2.14. Diethyl 3-[3-(2,3-dihydro-1H-indol-1-yl)prop-1-
yn-1-yl]-6-methylpyridazine-4,5-dicarboxylate
This compound was prepared as described for 14a, starting
from (12b) (0.510 g,
1-prop-2-yn-1-ylindoline28
(15b).
3.25 mmol) instead of 12a and diethyl 3-iodo-6-methyl-
pyridazine-4,5-dicarboxylate24 (13) (0.946 g, 2.6 mmol)
instead of 10. Column chromatography (EtOAc/PE, 1:2)
gave 15b (0.980 g, 96%) as a brownish oil. IR 2981, 2936,
1
2846, 2235, 1739, 1488, 1386, 1244, 1036, 750 cm21; H
NMR (CDCl3) d 7.16–7.06 (m, 2H, indoline 4-H, 6-H),
6.78–6.69 (m, 1H, indoline 5-H), 6.62 (d, J6–7¼7.8 Hz, 1H,
indoline 7-H), 4.39 (q, J¼7.2 Hz, 2H, CH2CH3), 4.25 (s,
2H, propargyl CH2), 4.12 (q, J¼7.2 Hz, 2H, CH2CH3), 3.51
(t, J2–3¼8.0 Hz, 2H, indoline 2-H), 3.00 (t, J2–3¼8.2 Hz,
2H, indoline 3-H), 2.85 (s, 3H, CH3), 1.37 (t, J¼7.2 Hz, 3H,
CH2CH3), 1.24 (t, J¼7.2 Hz, 3H, CH2CH3); MS (EI, 70 eV)
4.2.17. Diethyl 3-[3-(5-methoxy-1H-indol-1-yl)propyl]-6-
methylpyridazine-4,5-dicarboxylate (19a). This com-
pound was prepared as described for 18a, starting from
15a (0.916 g, 2.17 mmol). Column chromatography
(EtOAc/PE, 1:2) gave 19a (0.300 g, 33%) as a brownish
oil. IR 2982, 2937, 1737, 1489, 1238, 1031, 802, 718 cm21
;
1H NMR (CDCl3) d 7.23 (d, J6–7¼8.7 Hz, 1H, indole 7-H),

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N. Haider, J. Kaferbock / Tetrahedron 60 (2004) 6495–6507
6504
7.12 (d, J2–3¼3.0 Hz, 1H, indole 2-H), 7.09 (d, J4–6
2.4 Hz, 1H, indole 4-H), 6.87 (dd, J6–7¼8.7 Hz, J4–6
¼
¼
4H, indoline 2-H, NCH2CH2CC), 3.03 (t, J2–3¼8.2 Hz, 2H,
indoline 3-H), 2.83 (t, J¼7.3 Hz, 2H, NCH2CH2CC), 1.50–
1.35 (m, 6H, CH2CH3); MS (EI, 70 eV) m/z 393 (Mþ, 2%),
347 (4), 318 (5), 132 (100), 130 (15), 117 (16), 77 (6);
HRMS (EI, 70 eV) m/z 393.1674 (Mþ calcd for
C22H23N3O4: 393.1689).
2.4 Hz, 1H, indole 6-H), 6.41 (d, J2–3¼3.0 Hz, 1H, indole
3-H), 4.40 (q, J¼7.2 Hz, 2H, CH2CH3), 4.24 (t, J¼6.6 Hz,
2H, NCH2CH2CH2), 4.19 (q, J¼7.2 Hz, 2H, CH2CH3), 3.85
(s, 3H, OCH3), 3.05 (t, J¼7.6 Hz, 2H, NCH2CH2CH2), 2.83
(s, 3H, CH3), 2.45–2.30 (m, 2H, NCH2CH2CH2), 1.38 (t,
J¼7.2 Hz, 3H, CH2CH3), 1.22 (t, J¼7.2 Hz, 3H, CH2CH3);
MS (EI, 70 eV) m/z 425 (Mþ, 42%), 334 (8), 278 (11), 252
(100), 223 (57), 179 (68), 173 (52), 158 (27), 117 (28), 108
(22), 77 (14), 51 (11); HRMS (EI, 70 eV) m/z 425.1966 (Mþ
calcd for C23H27N3O5: 425.1951).
4.2.21. Diethyl 3-[4-(1H-indol-1-yl)butyl]pyridazine-4,5-
dicarboxylate (23). This compound was prepared as
described for 18a, starting from 21 (0.815 g, 2.07 mmol);
the hydrogenation time was 7 d. Column chromatography
(EtOAc/PE, 1:2) gave 23 (0.410 g, 50%) as a brownish oil.
IR 2936, 2870, 1733, 1464, 1297, 1193, 1019, 743 cm21; 1H
NMR (CDCl3) d 9.55 (s, 1H, pyridazine 6-H), 7.65 (d,
J4–5¼7.8 Hz, 1H, indole 4-H), 7.36 (d, J6–7¼8.4 Hz, 1H,
indole 7-H), 7.29–7.18 (m, 1H, indole 6-H), 7.17–7.06 (m,
2H, indole 2-H, 5-H), 6.50 (d, J2–3¼3.1 Hz, 1H, indole
3-H), 4.46 (q, J¼7.2 Hz, 2H, CH2CH3), 4.40 (q, J¼7.2 Hz,
2H, CH2CH3), 4.20 (t, J¼6.4 Hz, 2H, NCH2CH2CH2CH2),
3.10 (t, J¼7.2 Hz, 2H, NCH2CH2CH2CH2), 2.05–1.83 (m,
4H, NCH2CH2CH2CH2), 1.43 (t, J¼7.2 Hz, 3H, CH2CH3),
1.34 (t, J¼7.2 Hz, 3H, CH2CH3); MS (EI, 70 eV) m/z 395
(Mþ, 13%), 322 (10), 278 (60), 233 (49), 205 (23), 156 (63),
130 (100), 117 (27), 103 (22), 77 (23); HRMS (EI, 70 eV)
m/z 395.1857 (Mþ calcd for C22H25N3O4: 395.1845).
4.2.18. Diethyl 3-[3-(1H-indol-1-yl)propyl]-6-methyl-
pyridazine-4,5-dicarboxylate (19b). This compound was
prepared as described for 18a, starting from 15b (0.900 g,
2.29 mmol). Column chromatography (EtOAc/PE, 1:2)
gave 19b (0.384 g, 42%) as a brownish oil. IR 2981,
1
2936, 1734, 1464, 1394, 1257, 1217, 1030, 743 cm21; H
NMR (CDCl3) d 7.63 (d, J4–5¼7.8 Hz, 1H, indole 4-H),
7.35 (d, J6–7¼8.4 Hz, 1H, indole 7-H), 7.24–7.16 (m, 1H,
indole 6-H), 7.15 (d, J2–3¼3.3 Hz, 1H, indole 2-H), 7.13–
7.06 (m, 1H, indole 5-H), 6.50 (d, J2–3¼3.3 Hz, 1H, indole
3-H), 4.40 (q, J¼7.2 Hz, 2H, CH2CH3), 4.29 (t, J¼6.7 Hz,
2H, NCH2CH2CH2), 4.16 (q, J¼7.2 Hz, 2H, CH2CH3), 3.06
(t, J¼7.6 Hz, 2H, NCH2CH2CH2), 2.83 (s, 3H, CH3), 2.48–
2.32 (m, 2H, NCH2CH2CH2), 1.38 (t, J¼7.2 Hz, 3H,
CH2CH3), 1.20 (t, J¼7.2 Hz, 3H, CH2CH3); MS (EI,
70 eV) m/z 395 (Mþ, 8%), 304 (6), 252 (100), 223 (70),
179 (81), 143 (26), 130 (45), 108 (29), 77 (20); HRMS (EI,
70 eV) m/z 395.1849 (Mþ calcd for C22H25N3O4:
395.1845).
4.2.22. 5-[3-(1H-Indol-1-yl)propyl]-2,3-dihydropyrida-
zino[4,5-d]pyridazine-1,4-dione (24). A solution of 18b
(0.191 g, 0.5 mmol) and hydrazine hydrate (100%;
0.24 mL, 5 mmol) in 1-PrOH (5 mL) was refluxed under
argon for 24 h. The volatile components were removed in
vacuo and the yellow residue was taken up in water (5 mL)
and acidified (pH 2) with 2 N HCl. The mixture was cooled
and the precipitate was collected by filtration, washed with
water and EtOH, and dried in vacuo to afford 24 (0.100 g,
61%) as pale yellow crystals: mp 259–262 8C. IR 3426,
3165, 3048, 2922, 2572, 1666, 1603, 1570, 1464, 1315,
740 cm21; 1H NMR (DMSO-d6) d 12.2 (br s, 2H, NH), 9.54
(s, 1H, pyridazinopyridazine 8-H), 7.61 (d, J4–5¼7.6 Hz,
1H, indole 4-H), 7.45 (d, J6–7¼8.2 Hz, 1H, indole 7-H),
7.38 (d, J2–3¼3.0 Hz, 1H, indole 2-H), 7.14–7.05 (m, 1H,
indole 6-H), 7.02–6.93 (m, 1H, indole 5-H), 6.38 (d,
J2–3¼3.0 Hz, 1H, indole 3-H), 4.29 (t, J¼7.0 Hz, 2H,
NCH2CH2CH2), 3.54 (t, J¼7.5 Hz, 2H, NCH2CH2CH2),
2.34–2.20 (m, 2H, NCH2CH2CH2); MS (EI, 70 eV) m/z 321
(Mþ, 4%), 178 (15), 143 (100), 130 (33), 117 (16), 103 (12),
89 (13), 77 (14), 63 (10), 51 (8); HRMS (EI, 70 eV) m/z
321.1236 (Mþ calcd for C17H15N5O2: 321.1226). Anal.
Calcd for C17H15N5O2·0.3H2O: C, 62.49; H, 4.81; N, 21.43.
Found: C, 62.51; H, 4.73; N, 21.37.
4.2.19. 1-(But-3-yn-1-yl)indoline (20). A mixture of indo-
line (1.43 g, 12 mmol), Na2CO3 (2.54 g, 24 mmol) and but-
3-yn-1-yl methanesulfonate38 (2.66 g, 18 mmol) in toluene
(20 mL) was refluxed under argon for 48 h. The inorganic
material was filtered off and washed with EtOAc. The
combined filtrate and washings were evaporated in vacuo
and the residue was purified by column chromatography
(EtOAc/PE, 1:29) to give 20 (1.83 g, 89%) as a colorless oil
which slowly solidified: mp , 30 8C. IR 3292, 2920, 2843,
1
2117, 1607, 1489, 1458, 1267, 1022, 747, 643 cm21; H
NMR (CDCl3) d 7.15–7.06 (m, 2H, 4-H, 6-H), 6.74–6.65
(m, 1H, 5-H), 6.52 (d, J6–7¼8.1 Hz, 1H, 7-H), 3.46 (t,
J2–3¼8.4 Hz, 2H, 2-H), 3.35 (t, 3J¼7.4 Hz, 2H, NCH2CH2-
CCH), 3.02 (t, J2–3¼8.4 Hz, 2H, 3-H), 2.51 (dt, 3J¼7.4 Hz,
4
4J¼2.6 Hz, 2H, NCH2CH2CCH), 2.05 (t, J¼2.6 Hz, 1H,
NCH2CH2CCH); MS (EI, 70 eV) m/z 171 (Mþ, 14%), 133
(11), 132 (100), 130 (13), 117 (20), 115 (6), 103 (5), 77 (10),
51 (4); HRMS (EI, 70 eV) m/z 171.1047 (Mþ calcd for
C12H13N: 171.1048).
4.2.23. 5-[3-(1H-Indol-1-yl)propyl]-8-methyl-2,3-di-
hydropyridazino[4,5-d]pyridazine-1,4-dione (25). This
compound was prepared as described for 24, starting from
the diester 19b (0.200 g, 0.51 mmol). The product 25
(0.115 g, 67%) was obtained as pale yellow crystals: mp
259–263 8C. IR 3428, 3164, 3027, 2926, 2607, 1663, 1595,
4.2.20. Diethyl 3-[4-(2,3-dihydro-1H-indol-1-yl)but-1-yn-
1-yl]pyridazine-4,5-dicarboxylate (21). This compound
was prepared as described for 14a, using the alkyne 20
(0.556 g, 3.25 mmol) instead of 12a. Column chromato-
graphy (EtOAc/PE, 1:2) afforded 21 (0.873 g, 85%) as a
brownish oil. IR 2981, 2844, 2236, 1735, 1607, 1490, 1276,
1
1464, 1313, 741 cm–1; H NMR (DMSO-d6) d 12.2 (br s,
2H, NH), 7.53 (d, J4–5¼7.8 Hz, 1H, indole 4-H), 7.46 (d,
J6–7¼8.1 Hz, 1H, indole 7-H), 7.38 (d, J2–3¼3.2 Hz, 1H,
indole 2-H), 7.16–7.06 (m, 1H, indole 6-H), 7.04–6.96 (m,
1H, indole 5-H), 6.40 (d, J2–3¼3.2 Hz, 1H, indole 3-H),
4.29 (t, J¼7.0 Hz, 2H, NCH2CH2CH2), 3.50 (br t,
1
1209, 1029, 747 cm21; H NMR (CDCl3) d 9.57 (s, 1H,
pyridazine 6-H), 7.15–7.06 (m, 2H, indoline 4-H, 6-H),
6.74–6.66 (m, 1H, indoline 5-H), 6.52 (d, J6–7¼8.1 Hz, 1H,
indoline 7-H), 4.55–4.40 (m, 4H, CH2CH3), 3.55–3.40 (m,

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N. Haider, J. Kaferbock / Tetrahedron 60 (2004) 6495–6507
6505
J¼6.9 Hz, 2H, NCH2CH2CH2), 2.99 (s, 3H, CH3), 2.34–
4.3. Intramolecular [412] cycloaddition reactions.
General procedure
2.18 (m, 2H, NCH2CH2CH2); MS (EI, 70 eV) m/z 335 (Mþ,
21%), 218 (8), 192 (100), 163 (16), 143 (66), 130 (40), 117
(12), 103 (15), 89 (12), 77 (22), 51 (12). Anal. Calcd for
C18H17N5O2: C, 64.47; H, 5.11; N, 20.88. Found: C, 64.21;
H, 5.22; N, 20.64.
A solution (or suspension, in the case of 24, 25) of 0.5 mmol
of the cycloaddition educt (0.11 mmol in the case of 6a) in
1,3,5-triisopropylbenzene (7 mL) was heated to reflux under
argon for the time given in Table 1. Except in those cases
where the product precipitated from the mixture (com-
pounds 35, 36), the solvent was removed by Kugelrohr
distillation (1021 mbar, 80 8C) and the residue was
subjected to column chromatography.
4.2.24. 1-[3-(2,3-Dihydro-1H-indol-1-yl)prop-1-yn-1-
yl]pyrido[3,4-d]pyridazine (27). To a solution of 12b28
(1.02 g, 6.5 mmol) and 1-chloropyrido[3,4-d]pyridazine29
(26) (0.860 g, 5.2 mmol) in THF (12 mL) were added
triethylamine (2.0 mL, 14.4 mmol), CuI (0.030 g,
0.16 mmol) and Pd(PPh3)2Cl2 (0.110 g, 0.16 mmol). The
mixture was refluxed under argon for 3 h, then the solid
material was removed by filtration and carefully rinsed with
THF. The combined filtrate and washings were concentrated
under reduced pressure, and the residue was subjected to
column chromatography (EtOAc/MeOH, 19:1) to afford 27
(1.04 g, 70%) as almost colorless crystals: mp 120–122 8C
(from EtOAc/PE). IR 2920, 2835, 2224, 1606, 1484, 1359,
1242, 764, 668, 594 cm21; 1H NMR (CDCl3) d 9.54 (s, 1H,
pyridopyridazine 4-H), 9.40 (s, 1H, pyridopyridazine 5-H),
8.86 (d, J7–8¼5.8 Hz, 1H, pyridopyridazine 7-H), 7.41 (d,
J7–8¼5.8 Hz, 1H, pyridopyridazine 8-H), 7.24–7.15 (m,
2H, indoline 4-H, 6-H), 6.90–6.81 (m, 1H, indoline 5-H),
6.77 (d, J6–7¼7.7 Hz, 1H, indoline 7-H), 4.39 (s, 2H,
propargyl CH2), 3.57 (t, J2–3¼8.3 Hz, 2H, indoline 2-H),
3.05 (t, J2–3¼8.3 Hz, 2H, indoline 3-H); MS (EI, 70 eV) m/z
286 (Mþ, 100%), 271 (12), 258 (7), 169 (43), 156 (12), 143
(25), 128 (17), 117 (27), 103 (14), 89 (16), 77 (35), 63 (15),
51 (19). Anal. Calcd for C18H14N4: C, 75.51; H, 4.93; N,
19.57. Found: C, 75.65; H, 5.00; N, 19.57.
4.3.1. 10-Methoxy-5,6-dihydro-4H-pyrido[3,2,1-jk]car-
bazole (29). Elution with EtOAc/PE (1:19) gave 29
1
(0.002 g, 8%) as a brownish oil. H NMR (CDCl3) d 7.86
(d, J1–2¼7.8 Hz, 1H, 1-H), 7.60 (d, J9–11¼2.4 Hz, 1H,
11-H), 7.30 (d, J8–9¼9.0 Hz, 1H, 8-H), 7.19–7.06 (m, 3H,
2-H, 3-H, 9-H), 4.22 (t, J5–6¼5.7 Hz, 2H, 6-H), 3.94 (s, 3H,
OCH3), 3.08 (t, J4–5¼6.1 Hz, 2H, 4-H), 2.40–2.27 (m, 2H,
5-H); MS (EI, 70 eV) m/z 237 (Mþ, 71%), 222 (100), 194
(24), 166 (13), 139 (7), 119 (8); HRMS (EI, 70 eV) m/z
237.1147 (Mþ calcd for C16H15NO: 237.1154).
4.3.2. 7-Methoxy-2,3-dihydro-1H-benzo[b]pyrido[1,2,3-
lm]carbazole (30a). Elution with EtOAc/PE (1:9) gave an
oil which was triturated with PE to afford 30a (0.012 g, 8%)
as yellow crystals: mp 131–132 8C (from toluene/PE). IR
2935, 2830, 1640, 1484, 1287, 1230, 1129, 1072, 835,
742 cm21; 1H NMR (CDCl3) d 8.39 (s, 1H, 9-H), 8.09–7.99
(m, 2H, 10-H, 13-H), 7.74 (d, J6–8¼2.5 Hz, 1H, 8-H, shows
positive NOE on irradiation at 8.39 ppm or at 3.97 ppm),
7.55–7.47 (m, 1H, 12-H), 7.42–7.33 (m, 1H, 11-H), 7.26
(d, J5–6¼8.7 Hz, 1H, 5-H), 7.17 (dd, J5–6¼8.7 Hz,
J6–8¼2.5 Hz, 1H, 6-H), 4.20 (t, J2–3¼5.8 Hz, 2H, 3-H),
3.97 (s, 3H, OCH3), 3.37 (t, J1–2¼6.1 Hz, 2H, 1-H), 2.52–
2.40 (m, 2H, 2-H); MS (EI, 70 eV) m/z 287 (Mþ, 100%),
272 (91), 244 (16), 216 (13), 144 (17), 121 (14), 109 (9).
Anal. Calcd for C20H17NO: C, 83.60; H, 5.96; N, 4.87.
Found: C, 83.42; H, 6.13; N, 4.78.
4.2.25. 1-[3-(1H-Indol-1-yl)propyl]pyrido[3,4-d]pyrida-
zine (28). A solution of 27 (0.500 g, 1.75 mmol) in EtOAc
(200 mL) containing Pd/C catalyst (5%, 0.300 g), was
hydrogenated in a Parr apparatus at a pressure of 30 psi for
5 h (TLC monitoring: EtOAc/MeOH, 19:1). The catalyst
was filtered off and washed with EtOH and EtOAc. The
combined filtrate and washings were concentrated under
reduced pressure to afford a brown oil (0.500 g) containing
the intermediate. This material was dissolved in xylene
(90 mL), Pd/C catalyst (10%, 0.300 g) was added, and the
mixture was refluxed with vigorous stirring for 120 h
(reaction monitoring by GLC–MS). The catalyst was
filtered off and washed with hot EtOH and hot EtOAc.
The combined filtrate and washings were concentrated
under reduced pressure and the residue was subjected to
column chromatography (EtOAc/MeOH, 19:1) to afford 28
(0.107 g, 21%) as a brownish oil. IR 3048, 2918, 2849,
4.3.3. 2,3-Dihydro-1H-benzo[b]pyrido[1,2,3-lm]carba-
zole (30b). Elution with EtOAc/PE (1:19) gave an oil
which was triturated with PE to afford 30b (0.032 g, 25%) as
pale yellow crystals: mp 143 8C (from toluene/PE). IR 3052,
2936, 2854, 1637, 1607, 1475, 1364, 1240, 1131, 879, 736,
1
772 cm21; H NMR (CDCl3) d 8.43 (s, 1H, 9-H, shows
positive NOE on irradiation at 8.22 ppm), 8.22 (d,
J7–8¼7.8 Hz, 1H, 8-H, shows positive NOE on irradiation
at 8.43 ppm or at 7.28–7.20), 8.11–8.01 (m, 2H, 10-H,
13-H), 7.58–7.48 (m, 2H, 6-H, 12-H), 7.43–7.33 (m, 2H,
5-H, 11-H), 7.28–7.20 (m, 1H, 7-H), 4.24 (t, J2–3¼5.7 Hz,
2H, 3-H), 3.40 (t, J1–2¼6.0 Hz, 2H, 1-H), 2.53–2.41 (m,
2H, 2-H); MS (EI, 70 eV) m/z 257 (Mþ, 100%), 254 (35),
241 (9), 229 (9), 202 (6), 129 (16), 127 (18), 121 (9), 100
(8). Anal. Calcd for C19H15N: C, 88.68; H, 5.88; N, 5.44.
Found: C, 88.40; H, 5.87; N, 5.33.
1
1610, 1463, 1315, 744 cm21; H NMR (CDCl3) d 9.52 (s,
1H, pyridopyridazine 4-H), 9.40 (s, 1H, pyridopyridazine
5-H), 8.87 (d, J7–8¼5.7 Hz, 1H, pyridopyridazine 7-H),
7.63 (d, J4–5¼7.6 Hz, 1H, indole 4-H), 7.41 (d,
J7–8¼5.7 Hz, 1H, pyridopyridazine 8-H), 7.30 (d,
J6–7¼7.9 Hz, 1H, indole 7-H), 7.22–7.05 (m, 3H, indole
2-H, 5-H, 6-H), 6.50 (d, J2–3¼3.0 Hz, 1H, indole 3-H), 4.38
(t, J¼6.4 Hz, 2H, NCH2CH2CH2), 3.25 (t, J¼7.5 Hz, 2H,
NCH2CH2CH2), 2.64–2.50 (m, 2H, NCH2CH2CH2); MS
(EI, 70 eV) m/z 288 (Mþ, 11%), 145 (100), 143 (80), 130
(15), 117 (9), 103 (11), 89 (14), 77 (19), 63 (12), 51 (7);
HRMS (EI, 70 eV) m/z 288.1386 (Mþ calcd for C18H16N4:
288.1375).
4.3.4. 2,3-Dihydro-1H-indolo[3,2,1-gh][3,7]phenanthro-
line (31). Elution with EtOAc gave 31 (0.028 g, 21%) as a
yellow oil. IR 3049, 2929, 2859, 1604, 1460, 1361, 1309,
1
1243, 1132, 745 cm21; H NMR (CDCl3) d 9.36 (s, 1H,
10-H), 8.46 (d, J12–13¼6.5 Hz, 1H, 12-H), 8.43 (s, 1H, 9-H,
shows positive NOE on irradiation at 8.20 ppm), 8.20 (d,

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N. Haider, J. Kaferbock / Tetrahedron 60 (2004) 6495–6507
6506
J7–8¼8.0 Hz, 1H, 8-H), 7.74 (d, J12–13¼6.5 Hz, 1H, 13-H),
7.62–7.52 (m, 1H, 6-H), 7.37 (d, J5–6¼8.3 Hz, 1H, 5-H),
7.33–7.25 (m, 1H, 7-H), 4.19 (t, J2–3¼6.0 Hz, 2H, 3-H),
3.28 (t, J1–2¼6.3 Hz, 2H, 1-H), 2.48–2.35 (m, 2H, 2-H);
MS (EI, 70 eV) m/z 258 (Mþ, 100%), 255 (25), 230 (16),
202 (7), 176 (5), 128 (24), 114 (16), 101 (8), 88 (9), 75 (7),
63 (4); HRMS (EI, 70 eV) m/z 258.1163 (Mþ calcd for
C18H14N2: 258.1157).
4.22 (t, J5–6¼5.8 Hz, 2H, 6-H), 3.22 (t, J4–5¼6.1 Hz, 2H,
4-H), 2.92 (s, 3H, CH3), 2.37–2.24 (m, 2H, 5-H), 1.41 (t,
J¼7.0 Hz, 6H, CH2CH3); MS (EI, 70 eV) m/z 365 (Mþ,
24%), 319 (12), 290 (100), 247 (12), 218 (30), 204 (13), 180
(7), 109 (7); HRMS (EI, 70 eV) m/z 365.1639 (Mþ calcd for
C22H23NO4: 365.1627).
4.3.9. Diethyl 4,5,6,7-tetrahydroazepino[3,2,1-jk]carba-
zole-2,3-dicarboxylate (34). Elution with EtOAc/toluene
(1:19) gave 34 (0.066 g, 36%) as a brownish oil. IR 2977,
2932, 2865, 1728, 1711, 1592, 1474, 1367, 1336, 1261,
4.3.5. Diethyl 10-methoxy-5,6-dihydro-4H-pyrido[3,2,1-
jk]carbazole-2,3-dicarboxylate (32a). Elution with
EtOAc/toluene (1:14) afforded 32a (0.097 g, 51%) as a
brownish oil.30 IR 2979, 2937, 1725, 1707, 1485, 1300,
1265, 1209, 1120, 1048, 1031, 785 cm21; 1H NMR (CDCl3)
d 8.58 (s, 1H, 1-H), 7.62 (d, J9–11¼2.4 Hz, 1H, 11-H), 7.34
1
1144, 1040, 1022, 748 cm21; H NMR (CDCl3) d 8.66 (s,
1H, 1-H), 8.15 (d, J11–12¼7.8 Hz, 1H, 12-H, shows positive
NOE on irradiation at 8.66 ppm), 7.59–7.50 (m, 1H, 10-H),
7.45 (d, J9–10¼8.4 Hz, 1H, 9-H), 7.37–7.27 (m, 1H, 11-H),
4.51 (q, J¼7.2 Hz, 2H, CH2CH3), 4.50–4.38 (m, 4H, 7-H,
CH2CH3), 3.22 (t, J4–5¼5.8 Hz, 2H, 4-H), 2.34–2.13 (m,
4H, 5-H, 6-H), 1.52–1.40 (m, 6H, CH2CH3); MS (EI,
70 eV) m/z 365 (Mþ, 15%), 319 (20), 290 (100), 246 (7),
218 (24), 204 (17), 191 (11); HRMS (EI, 70 eV) m/z
365.1634 (Mþ calcd for C22H23NO4: 365.1627).
(d, J8–9¼9.0 Hz, 1H, 8-H), 7.17 (dd, J8–9¼9.0 Hz, J9–11
¼
2.4 Hz, 1H, 9-H), 4.47 (q, J¼7.2 Hz, 2H, CH2CH3), 4.41 (q,
J¼7.2 Hz, 2H, CH2CH3), 4.21 (t, J5–6¼5.8 Hz, 2H, 6-H),
3.95 (s, 3H, OCH3), 3.08 (t, J4–5¼6.1 Hz, 2H, 4-H), 2.40–
2.27 (m, 2H, 5-H), 1.49–1.38 (m, 6H, CH2CH3); MS (EI,
70 eV) m/z 381 (Mþ, 51%), 336 (10), 306 (100), 292 (17),
281 (7), 264 (7), 235 (21), 221 (22), 207 (20), 191 (14), 154
(15), 135 (6), 96 (5), 73 (10); HRMS (EI, 70 eV) m/z
381.1583 (Mþ calcd for C22H23NO5: 381.1576).
4.3.10. 2,3,11,12-Tetrahydro-1H-pyridazino[4,5-b]-
pyrido[1,2,3-lm]carbazole-10,13-dione (35). The material
which precipitated from the reaction mixture was collected
by filtration and washed with EtOAc. It was then suspended in
MeOH (10 mL) and refluxed for 0.5 h. After cooling, the solid
was collected by filtration and dried to afford 35 (0.111 g,
75%)asalmost colorless crystals: mp .330 8C(dec). IR3404,
3154, 3018, 2937, 1645, 1625, 1474, 1328, 1246, 819,
745 cm21; 1H NMR (DMSO-d6) d 11.18 (s, 2H, NH), 8.73 (s,
4.3.6. Diethyl 5,6-dihydro-4H-pyrido[3,2,1-jk]carbazole-
2,3-dicarboxylate (32b). Elution with EtOAc/toluene
(1:19) gave 32b (0.097 g, 55%) as a brownish oil. IR
2978, 2935, 1727, 1709, 1476, 1329, 1264, 1224, 1144,
1078, 1048, 1023, 785, 747, 734 cm21; 1H NMR (CDCl3) d
8.59 (s, 1H, 1-H), 8.14 (d, J10–11¼8.1 Hz, 1H, 11-H), 7.58–
7.48 (m, 1H, 9-H), 7.42 (d, J8–9¼8.1 Hz, 1H, 8-H), 7.36–
7.24 (m, 1H, 10-H), 4.48 (q, J¼7.2 Hz, 2H, CH2CH3), 4.41
(q, J¼7.2 Hz, 2H, CH2CH3), 4.23 (t, J5–6¼5.7 Hz, 2H,
6-H), 3.09 (t, J4–5¼6.3 Hz, 2H, 4-H), 2.41–2.27 (m, 2H,
5-H), 1.51–1.47 (m, 6H, CH2CH3); MS (EI, 70 eV) m/z 351
(Mþ, 29%), 305 (21), 276 (100), 204 (45), 177 (8), 151 (6);
HRMS (EI, 70 eV) m/z 351.1467 (Mþ calcd for C21H21NO4:
351.1471).
1H, 9-H), 8.38 (d, J7–8¼7.8 Hz, 1H, 8-H), 7.65 (d, J5–6
¼
8.1 Hz, 1H, 5-H), 7.64–7.53 (m, 1H, 6-H), 7.36–7.25 (m, 1H,
7-H), 4.30 (t, J2–3¼5.5 Hz, 2H, 3-H), 3.76 (t, J1–2¼6.0 Hz,
2H, 1-H), 2.40–2.15 (m, 2H, 2-H); MS (EI, 70 eV) m/z 291
(Mþ, 100%), 246 (9), 204 (24), 177 (8), 146 (9), 102 (20), 51
(9), 44 (13). Anal. Calcd for C17H13N3O2·0.25H2O: C, 69.03;
H, 4.60; N, 14.20. Found: C, 68.95; H, 4.62; N, 14.08.
4.3.11. 9-Methyl-2,3,11,12-tetrahydro-1H-pyridazino-
[4,5-b]pyrido[1,2,3-lm]carbazole-10,13-dione (36). The
material which precipitated from the reaction mixture was
collected by filtration and washed with EtOAc. It was then
suspended in MeOH (10 mL) and refluxed for 0.5 h. After
cooling, the solid was collected by filtration and dried to
afford 36 (0.098 g, 64%) as beige crystals: mp .350 8C
(dec). IR 3405, 3149, 3041, 2934, 1632, 1579, 1475, 1414,
4.3.7. Diethyl 10-methoxy-1-methyl-5,6-dihydro-4H-
pyrido[3,2,1-jk]carbazole-2,3-dicarboxylate (33a).
Elution with EtOAc/toluene (1:14) afforded 33a (0.081 g,
41%) as a brownish oil. IR 2955, 1721, 1489, 1299, 1175,
1038, 801 cm21
;
1H NMR (CDCl3) d 7.75 (d, J9–11
¼
2.5 Hz, 1H, 11-H), 7.36 (d, J8–9¼8.9 Hz, 1H, 8-H), 7.19
(dd, J8–9¼8.9 Hz, J9–11¼2.5 Hz, 1H, 9-H), 4.43 (q,
J¼7.2 Hz, 4H, CH2CH3), 4.20 (t, J5–6¼5.7 Hz, 2H, 6-H),
3.95 (s, 3H, OCH3), 3.21 (t, J4–5¼6.3 Hz, 2H, 4-H), 2.91 (s,
3H, CH3), 2.35–2.22 (m, 2H, 5-H), 1.46–1.35 (m, 6H,
CH2CH3); MS (EI, 70 eV) m/z 395 (Mþ, 44%), 350 (11),
320 (100), 306 (18), 277 (9), 249 (20), 234 (19), 207 (16),
178 (8), 161 (12), 102 (7); HRMS (EI, 70 eV) m/z 395.1721
(Mþ calcd for C23H25NO5: 395.1733).
1
1321, 1249, 744 cm21; H NMR (DMSO-d6) d 11.1 (br s,
2H, NH), 8.43 (d, J7–8¼7.8 Hz, 1H, 8-H), 7.70 (d, J5–6
¼
8.1 Hz, 1H, 5-H), 7.67–7.58 (m, 1H, 6-H), 7.40–7.30 (m,
1H, 7-H), 4.31 (t, J2–3¼5.7 Hz, 2H, 3-H), 3.73 (t, not
resolved, 2H, 1-H), 3.44 (s, 3H, CH3), 2.32–2.18 (m, 2H,
2-H); MS (EI, 70 eV) m/z 305 (Mþ, 100%), 289 (17), 260
(20), 244 (9), 232 (12), 217 (21), 204 (14), 191 (11), 152
(14), 109 (12), 95 (11), 57 (10), 43 (20); HRMS (EI, 70 eV)
m/z 305.1172 (Mþ calcd for C18H15N3O2: 305.1164).
4.3.8. Diethyl 1-methyl-5,6-dihydro-4H-pyrido[3,2,1-
jk]carbazole-2,3-dicarboxylate (33b). Elution with
EtOAc/toluene (1:19) gave 33b (0.079 g, 43%) as a
brownish oil. IR 2979, 2938, 2902, 2869, 1722, 1484,
1375, 1316, 1260, 1203, 1162, 1055, 1029, 745, 730 cm21
;
References and notes
1H NMR (CDCl3) d 8.25 (d, J10–11¼8.1 Hz, 1H, 11-H),
7.58–7.48 (m, 1H, 9-H), 7.44 (d, J8–9¼8.1 Hz, 1H, 8-H),
7.34–7.25 (m, 1H, 10-H), 4.47–4.33 (m, 4H, CH2CH3),
¨
1. Seitz, G.; Kampchen, T. Arch. Pharm. (Weinheim) 1976, 309,
679–681.

¨ ¨
N. Haider, J. Kaferbock / Tetrahedron 60 (2004) 6495–6507
6507
2. Takahashi, M.; Ishida, H.; Kohmoto, M. Bull. Chem. Soc. Jpn
1976, 49, 1725–1726.
J1–2¼8.2 Hz, 1H, 1-H, shows positive NOE on irradiation at
6.60 ppm), 7.81 (d, J1–2¼8.2 Hz, 1H, 2-H), 6.60 (d, J9–11
¼
3. Seitz, G.; Mohr, R. Chem.-Ztg. 1987, 111, 81–82.
4. Benson, S. C.; Palabrica, C. A.; Snyder, J. K. J. Org. Chem.
1987, 52, 4610–4614.
2.5 Hz, 1H, 11-H), 7.33 (d, J8–9¼8.8 Hz, 1H, H-8), 7.18 (dd,
J8–9¼8.8 Hz, J9–11¼2.5 Hz, 1H, 9-H), 4.42 (q, J¼7.1 Hz, 2H,
CH2CH3), 4.22 (t, J5–6¼5.7 Hz, 2H, 6-H), 3.95 (s, 3H, OCH3,
shows positive NOE on irradiation at 6.60 ppm), 3.51 (t,
J4–5¼6.3 Hz, 2H, 4-H), 2.40-2.27 (m, 2H, 5-H), 1.45 (t,
J¼7.1 Hz, 3H, CH2CH3); MS (EI, 70 eV) m/z 309 (Mp, 100%),
294 (38), 280 (22), 266 (33), 236 (15), 221 (19), 207 (12), 191
(21), 165 (9), 125 (11), 111 (10), 96 (12), 84 (10), 73 (6);
HRMS (EI, 70 eV) m/z 309.1378 (Mp calcd for C19H19NO3:
309.1365).
5. Haider, N.; Wanko, R. Heterocycles 1994, 38, 1805.
6. Benson, S. C.; Lee, L.; Snyder, J. K. Tetrahedron Lett. 1996,
37, 5061–5064.
7. Daly, K.; Nomak, R.; Snyder, J. K. Tetrahedron Lett. 1997, 38,
8611–8614.
8. Girardot, M.; Nomak, R.; Snyder, J. K. J. Org. Chem. 1998,
63, 10063–10068.
9. Benson, S. C.; Lee, L.; Yang, L.; Snyder, J. K. Tetrahedron
2000, 56, 1165–1180.
10. Benson, S. C.; Gross, J. L.; Snyder, J. K. J. Org. Chem. 1990,
55, 3257–3269.
11. Benson, S. C.; Li, J. H.; Snyder, J. K. J. Org. Chem. 1992, 57,
5285–5287.
31. This assumption is supported by the observation that only one
of the two possible monoesters is formed from pyridazines
18a,b and 23, in which one ester group is sterically more
shielded than the other one, whereas from the tetrasubstituted
pyridazines 19a,b mixtures of both mono-decarboxylation
products are formed. This is in agreement with the
regioselective hydrolysis of 1-methylcarbazole-2,3-dicar-
boxylic acid dimethyl ester into 2-(methoxycarbonyl)-1-
methyl-9H-carbazole-3-carboxylic acid, which was described
recently20.
12. Fan, W.-H.; Parikh, M.; Snyder, J. K. Tetrahedron Lett. 1995,
36, 6591–6594.
13. Wan, Z.-K.; Snyder, J. K. Tetrahedron Lett. 1998, 39,
2487–2490.
14. For a review on indole as a dienophile in IDA and related
reactions, cf. Lee, L.; Snyder, J. K. Advances in Cyclo-
additions; Harmata, M., Ed.; JAI: Stamford, CT, 1999; Vol. 6,
pp 119–171.
15. Giomi, D.; Cecchi, M. Tetrahedron 2002, 58, 8067–8071.
16. Bodwell, G. J.; Li, J. Org. Lett. 2002, 4, 127–130.
17. Bodwell, G. J.; Li, J. Angew. Chem. Int. Ed. Engl. 2002, 41,
3261–3262.
32. Stewart, J. J. P. J. Comp. Chem. 1989, 10, 209–220.
33. It should be noted that in most of the cycloaddition educts
studied (with the exception of 7a, 7b, and 26), the molecular
orbital of the diazadiene which participates in the reaction is
the LUMOþ1 orbital rather than the LUMO, as follows from
analysis of the respective pz orbital coefficients at the involved
pyridazine carbon atoms.
18. Haider, N.; Jbara, R.; Khadami, F.; Wanko, R. Heterocycles
1998, 48, 1609–1622.
´
19. Haider, N.; Kaferbock, J.; Matyus, P. Heterocycles 1999, 51,
2703–2710.
¨
¨
20. Fidesser, E.; Haider, N.; Jbara, R. ARKIVOC 2001, 2,
133–139.
34. Ratcliffe, A. J.; Sainsbury, M.; Smith, A. D.; Scopes, D. I. C.
J. Chem. Soc., Perkin Trans. 1 1988, 2933–2943.
´
35. Broggini, G.; Bruche, L.; Zecchi, G. J. Chem. Soc., Perkin
Trans. 1 1990, 533–539.
21. Haider, N. J. Heterocycl. Chem. 2002, 39, 511–521.
22. Haider, N.; Sotelo, E. Chem. Pharm. Bull. 2002, 50,
1479–1483.
36. Gangjee, A.; Vasudevan, A.; Queener, S. F. J. Med. Chem.
1997, 40, 479–485.
23. For a review of the canthine alkaloids, cf. Ohmoto, T.; Koike,
K. The Alkaloids; Brossi, A., Ed.; Academic: New York, 1989;
Vol. 36, pp 135–170.
37. A sample of the intermediate 16a was isolated by column
chromatography (EtOAc/PE, 1:2) as a brownish oil. IR 3376,
¨
¨
24. Haider, N.; Kaferbock, J. Heterocycles 2000, 53, 2527–2534.
25. Barlin, G. B.; Yap, C. Y. Aust. J. Chem. 1977, 30, 2319–2322.
26. Hirsch, A.; Orphanos, D. G. Can. J. Chem. 1966, 44,
1551–1554.
2935, 2830, 1734, 1685, 1623, 1493, 1238, 1194, 1030 cm21
;
1H NMR (CDCl3) d 7.64 (br d, J1–6¼4.2 Hz, 1H, NH), 7.52 (d,
J1–6¼4.2 Hz, 1H, pyridazine 6-H), 6.76–6.71 (m, 1H, indo-
line 4-H), 6.62 (dd, J6–7¼8.5 Hz, J4–6¼2.5 Hz, 1H, indoline
6-H, shows positive NOE on irradiation at 6.40 ppm), 6.40 (d,
J6–7¼8.5 Hz, 1H, indoline 7-H), 4.34 (s, 1H, pyridazine 4-H),
4.25–4.10 (m, 4H, CH2CH3), 3.74 (s, 3H, OCH3), 3.28 (t,
J2–3¼8.1 Hz, 2H, indoline 2-H), 3.03 (t, J¼7.2 Hz, 2H,
NCH2CH2CH2), 2.92 (t, J2–3¼8.1 Hz, 2H, indoline 3-H),
2.70–2.40 (m, 2H, NCH2CH2CH2), 2.06–1.80 (m, 2H,
NCH2CH2CH2), 1.32–1.20 (m, 6H, CH2CH3); MS (EI,
70 eV) m/z 415 (Mp, 13%), 193 (25), 175 (47), 162 (100),
148 (10), 130 (9), 57 (7); HRMS (EI, 70 eV) m/z 415.2118 (Mp
calcd for C22H29N3O5: 415.2107).
27. Artis, D. R.; Cho, I.-S.; Jaime-Figueroa, S.; Muchowski, J. M.
J. Org. Chem. 1994, 59, 2456–2466.
28. Torregrosa, J.-L.; Baboulene, M.; Speziale, V.; Lattes, A.
J. Organomet. Chem. 1983, 244, 311–317.
29. Morita, T.; Naitou, H.; Oishi, E. Biol. Pharm. Bull. 1995, 18,
363–367.
30. From the column fraction preceding the main product (32a), a
side product was isolated. Purification of this material by
MPLC (EtOAc/toluene, 1:14) gave ethyl 10-methoxy-5,6-
dihydro-4H-pyrido[3,2,1-jk]carbazole-3-carboxylate (0.016 g,
10%) as a yellow oil. IR 2927, 2855, 1704, 1490, 1243, 1213,
1138, 1076, 1040, 815, 749 cm21; 1H NMR (CDCl3) ( 7.88 (d,
38. Reich, H. J.; Shah, S. K.; Chow, F. J. Am. Chem. Soc. 1979,
101, 6648–6656.