Intramolecular N-aza-amidoalkylation in association with Witkop-Winterfeldt oxidation as the key step to synthesize Luotonin-A analogues

Article abstract of DOI:10.1016/j.tet.2011.05.120

An expedient four-step approach for the synthesis of a short library of original analogues of the Topo-I Luotonin-A inhibitor, substituted at their C₈- and N₁₅-positions, was investigated. This consists of Rutaecarpines formation, their Witkop-Winterfeldt oxidation followed ultimately with functional adjustment of the pyrroloquinolone intermediates. In the first step of these investigations, Rutaecarpines including the Topo-I poison Evodiamine were obtained via the new tandem N-acylation/aza-amidoalkylation using a nitrogen atom as an internal nucleophile with or without association with a decarboxylation.

Full text of DOI:10.1016/j.tet.2011.05.120

Tetrahedron 67 (2011) 5564e5571
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular N-aza-amidoalkylation in association with WitkopeWinterfeldt
oxidation as the key step to synthesize Luotonin-A analogues
*
ꢀ ꢀ
ꢀ
Frederic Pin, Sebastien Comesse, Adam Daïch
ꢀ
URCOM, EA 3221, INC3M, FR-CNRS 3038, UFR des Sciences & Techniques de l’Universite du Havre, BP: 540, 25 rue Philippe Lebon, F-76058 Le Havre Cedex, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2011
Received in revised form 27 May 2011
Accepted 30 May 2011
Available online 2 June 2011
An expedient four-step approach for the synthesis of a short library of original analogues of the Topo-I
Luotonin-A inhibitor, substituted at their C8- and N15-positions, was investigated. This consists of Ru-
taecarpines formation, their WitkopeWinterfeldt oxidation followed ultimately with functional adjust-
ment of the pyrroloquinolone intermediates. In the first step of these investigations, Rutaecarpines
including the Topo-I poison Evodiamine were obtained via the new tandem N-acylation/aza-ami-
doalkylation using a nitrogen atom as an internal nucleophile with or without association with
a decarboxylation.
Keywords:
N-Acyliminium species
N-Aza-amidoalkylation
WitkopeWinterfeldt oxidation
Pentacyclic alkaloids
Topoisomerase-I
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
Rutaecarpine (2) and isolated along with it from Evodia rutaecarpa,
seems to stabilize the topoisomerase-I (Topo-I)/DNA cleavable
The quinazolinone skeleton is frequently encountered in nu-
merous alkaloids1 and synthetic structures all exhibiting biological
properties.1,2 Aromatic quinazolines have been shown to possess
tyrosine kinase inhibiting effects,3 inhibit tumour growth and dis-
play other biological profiles including anticonvulsant and antiep-
ileptic activities.4 They were used, for example, in the treatment of
tuberculosis5 as well as benign prostatic hyperplasia.6 In addition,
this skeleton fused to tetrahydro-b-carboline or pyrrolo[3,4-b]
quinoline nuclei constitutes an important class of heterocycles
belonging to quinazoline-type alkaloids both from an organic
synthetic and pharmaceutical point of view. Both Luotonin-A (1)
and Rutaecarpine (2) are members of this family whose extracts
have long been used as remedies in Chinese traditional medicine
for the treatment of various diseases.7
Despite the large spectra of activities of 2 and its derivatives, 2
has been reported as having a lower antitumour activity8 than
Camptothecin (CPT),9 Luotonin-A (1) and their analogues.10 In these
cases, 10-bromo-, 11-methoxy- and 10,11-methylene-dioxyr-
utaecarpines are the most active derivatives in the series and nu-
merous thiophene analogues have shown good anticancer activity
in vitro but no activity in vivo.8c Importantly, the alkaloid Evodi-
amine (3, Scheme 1),11 which could be considered as a reduced
complex12 effectively to inhibit the Topo-I activity with comparable
level as Luotonin-A, CPT and other aromathecins (in which the
chiral lactone as in CPT is replaced with an aryl group), such as
Rosettacin and 22-hydroxyacuminatine.13 Since the mode of action
of CPTs is now well known via the X-ray crystal structure of the CPT/
DNA/Topo-I ternary cleavage complex, outlining the pivotal role of
the hydrogen bonds between C20eOH function and quinoline-N1 of
CPT and Asp533 and Arg364 residues of Topo-I, respectively,14 the
possible similar mode of action of other compounds cited above is
intriguing.
During the last two decades, the synthetic development of
Luotonin 1 derivatives with different substituents on either A, B, C
ring and/or E ring have outlined the importance of this class of
products in the field of oncology (Scheme 1).15,16 From these con-
siderations, the development of new approaches into original
Luotonins is still of interest in the search for other new lead
compounds.
2. Results and discussion
We are interested in the development of short and effective
methods towards aza-heterocyclic systems with promising phar-
maceutical activities. Among these systems are pentacyclic Rutae-
carpines,17 aromathecins18 and finally Luotonins substituted at the
C2-, C7-, C10- and/or C11-positions.19
* Corresponding author. Tel.: þ33 02 32 74 44 03; fax: þ33 02 32 74 43 91;
e-mail address: adam.daich@univ-lehavre.fr (A. Daïch).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.05.120

F. Pin et al. / Tetrahedron 67 (2011) 5564e5571
5565
9a-phenyltetrahydroisoindolo[2,1-a]quinazoline-5,11-dione with-
out isolation of the N-acyliminium precursor23a and then later for the
production23b of diethyl dioxolo[4,5-g]pyrrolo[2,1-b]quinazoline-
8,8-dicarboxylate. Its power was also illustrated in the total synthesis
of (þ/ꢀ)- and (ꢀ)-physostigmine, namely eserine, as the principal
alkaloid
of
Calabar
bean,24
(þ/ꢀ)-glochidine
and
(þ/ꢀ)-glochidicine,25 imidazoloindoline alkaloids,26 oroidin-derived
alkaloids27 and more recentlychiral (ꢀ)-decarbamoyloxysaxitoxin as
a neurotoxin that blocks voltage-gated sodium channels, which are
critical for depolarization and conduction in most excitable cells.28
The reports of this process concern also its use: (1) in medicinal
chemistry to access aldose reductase inhibitors,29 (2) in solid-phase
parallel synthesis of D2-2-oxopiperazines,30 (3) in asymmetric syn-
thesis of Reissert compounds,31 (4) in synthesis of lactam-based
peptide-mimetics,32 and finally (5) in sterically hindered
N-substituted and fused g-lactams.33
In the context outlined above, we present herein our first find-
ings from a related study dealing with the examination of the im-
pact, during the cyclization process, of the nitrogen atom as internal
nucleophile on the reactivity of N-acyliminium species I. Also for
comparative reasons, a nitrogen atom bearing different R2 groups is
also considered (Schemes 2 and 3). The choice of R2 group was
based on two considerations: first, NHTs and NHBoc groups were
rarely engaged in the intramolecular cationic cyclization, and we
expected that both groups could be removed easily during or after
the oxidative transposition of Rutaecarpines 3 and 7. Second, both
tosyl and Boc are electron-withdrawing groups, which could render
the amino group less nucleophilic. This could consequently lead,
after hydrolysis of cations Ia,b, to corresponding hydroxy lactams as
isolable intermediates (not presented in the Schemes 2 and 4).
Complementarily, the use of Ph, Me and Bn groups could lead to
Rutaecarpines 7c,3 and 7e with another stereoelectronic profile
different from those, which could be obtained when R2¼Ts (7a) and
R2¼Boc (7b).
Scheme 1. Representative quinazoline-type alkaloids 1e3 with anticancer activity and
the structure of our target compounds 4.
In association with our recent reports dealing with intra-
molecular
a
a a
-thio-amidoalkylation,20 -oxo-amidoalkylation21 and
-seleno-amidoalkylation,20e we reasoned that
a
suitably
substituted N-acyliminium precursor of type I (see Scheme 2) could
allow a facile approach to the reduced Rutaecarpine derivatives
3 and 7. Their subjection further to the WitkopeWinterfeldt oxi-
dation would lead to the pentacyclic cores 8 of the title targets
14e16, which could be reached ultimately after rapid functional
adjustments. To the best of our knowledge, the use of the present
application in an intramolecular N-acyliminium mediated aza-
cyclization reaction,22 as depicted in Scheme 2, to form a six
membered ring as a cyclic N,N-acetal structure, represents a novel
illustration of this chemistry.
R1
O
9
8
7
O
O
6
O
O
O
Adjustment
N
N
5
4
OH
OH
Cl
NHR2
6a (R2=Ts)
N
13
14
N
H
Conditions
i
Conditions
15
12
N
N
NH2
NHR2
R2
R2
O
1
8
N
14-16: Luotonins
iii
>99%
9
9
10 (R2=Ts)
Witkop-
Winterfeldt
oxidation
63%
HN
iii
X
ii
85
11 (R2=Boc)
12 (R2=Ph)
6b (R2=Boc)
6c (R2=Ph)
R2
I
%
iv
>99%
N
Aza-cyclization
N
H
N
O
N
H
Y
O
O
O
N
X
O
+
5
N
X--Y = -CO-O-
X = H, Y = OH
X = H, Y = Cl
N
R2
R2
K2CO3, R2X
DMF, r.t, 5 h
O
6d (R2=Me), 56%
6e (R2=Bn), 77%
N
O
O
3,7: Rutaecarpines
6,11
R2
H
R2X=MeI or BnBr
6d,e
13
Scheme 3. Synthesis of substrates 11, 6a,c and 6d,e. Reaction conditions: (i) (Na2CO3,
TsCl, H2O, 70 ꢁC, 50 min. (ii) Boc2O, EtOH, 50 ꢁC, 72 h. (iii) (COCl)2, DCM, rt, 2 h. (iv)
SOCl2, Toluene, reflux, 30 min.
Witkop-Winterfeldt
Transposition
N
O
N
O
N
H
N
H
N
H2C
R2
Our initial work concerns the preparation of three kinds of re-
agents 6a,c, 6d,e and 11, partners of the known dihydro-b-carboline
(5)34 in the cyclocondensation reaction. These substrates are well
described in the literature starting from anthranilic acid (9) and
isatoic anhydride (13) by N-alkylation process using modified
published procedures. The protection of 9 with tosyl and Boc
groups afforded carboxylic acids 1035 and 11,36 respectively, which
upon treatment with slight excess of oxalyl chloride in dry DCM
provided acid chloride 6a37 in nearly quantitative yield and 6b,
which turned out to be unstable. By the same chlorination reaction
but using harsher conditions (2 equiv of SOCl2, toluene, reflux,
O
O
Z=CH2
Z=N-R2
N
N
H
Z
Known
This work
Scheme 2. Retrosynthetic scheme leading to N-substituted Luotonin-A analogues as
the targets.
The cationic cyclization using a nitrogen atom as internal
nucleophile has first been mentioned during the synthesis of

5566
F. Pin et al. / Tetrahedron 67 (2011) 5564e5571
reaction of 5 with N-alkylated isatoic anhydride could lead to the
expected N-alkylrutaecarpines. Indeed, reaction of 5 with 6d in
CHCl3 at reflux for 8 h provided N-methyldihydrorutaecarpine (3)
in good yield (79%), which is commonly known as Evodiamine (3,
Schemes 1 and 4). In the same manner, 5 and 6e provided
N-benzyldihydrorutaecarpine (7e) in 77% yield. Interestingly, here
the tandem N-acylation/aza-cyclization via the N-acyliminium
cation Id,e is also associated with the decarboxylation process
(Scheme 4).
Furthermore, we next planned to investigate the reactivity of
the reduced Rutaecarpines 3 and 7, particularly by examining their
behaviour in the WitkopeWinterfeldt oxidation.43 These are of
interest since their transformation could lead to the pentacyclic
pyrroloquinolones 8 (Scheme 5), as the key intermediates in route
to the Luotonins 14e16 as the targets (Scheme 1).
N
N
H
5
Et3N, DCM
0°C to r.t
CHCl3
Reflux
6d,e
6a,c
DCC, DMAP
DCM, r.t
11
Cl
DCU
N
O
N
O
N
O
N
H
N
H
N
H
R2
H
N
H
N
N
R2
Ib
O
R2
O
Id,e
Ia,c
7b: R2=Boc, 72%
- DCU
- CO2
-HCl
3: R2=Me, 79%
7e: R2=Bn, 77%
7a: R2 = Ts, 72%
7c: R2 = Ph, 83%
N
O
N
H
N
R2
N
O
N
H
R2=Ts, Boc
R2=Ph, Me, Bn
3,7: Rutaecarpines
N
R2
A, B
A, B
Scheme 4. Scheme leading to Rutaecarpines 7aec, 3 and 7e including the Topo-I
poison Evodiamine 3 (3 correspond to the initial number 7d).
O
7a-c,3,7e
O
N
O
N
N
H
N
30 min), the 2-(phenylamino)benzoyl chloride (6c) was isolated in
quantitative yield starting from the commercially available
2-(phenylamino)benzoic acid (12).38 Because it was difficult to
prepare 2-(alkylamino)benzoyl chloride using the same protocol as
for reagent 6a,b, another approach using isatoic anhydride (13) as
starting material was investigated to prepare 6d,e. Thus, N-meth-
ylation and N-benzylation of the anhydride isatoic 13 using
a modified known procedure afforded N-methylated and N-ben-
zylated anhydride isatoic derivatives 6d,e in acceptable yields of
56% for 6d and 77% for 6e, respectively.39
The operability of the crucial cyclocondensation leading to
Rutaecarpines 3,7 was first tested by treatment of cyclic imine 5
with acid chloride 6a (generated in situ) in DCM at 0 ꢁC up to room
temperature in the presence of NEt3 as HCl scavenger. After 1.5 h of
reaction, the resulting sole reaction product was identified to be 7a
in 72% yield (Scheme 4) after flash chromatography purification
(i.e., SiO2, cyclohexane/AcOEt: 7/3). This is the consequence of the
cyclization of the presumed N-acyliminium cation Ia being formed
as intermediate with a nitrogen atom as internal nucleophile. Un-
der the same conditions, reaction of imine 5 with acid chloride 6c
proved successful and the N-phenyldihydrorutaecarpine (7c) was
isolated in 83% yield in a similar manner. So far, these cyclization
conditions were never used, but in the literature the reaction of
N
H
N
R2
8c-e: R2=Ph, Me, Bn
Rutaecarpine (2)
Scheme 5. Oxidative transposition conditions of Rutaecarpines 7aec, 3, 7e.
Two kinds of substrates 7a,b and 7c,3 and three conditions A, B
and C for the WitkopeWinterfeldt oxidation were chosen. For this
purpose, conditions A (O2, t-BuOK, DMF, room temperature) and C
(NaIO4, THF/MeOH/H2O (1/1/1), reflux), which are classically used
for this transformation43 and conditions B (KO2, 18-C-6, DMF, room
temperature), introduced by Speier and Balogh-Hergovich in
198244 and extended by Sui et al.,45 were tested.
Thus, the oxidation of the quinazolino-b-carbolines 7a,b under
conditions A or B led only to the deprotection of both electron-
withdrawing groups followed spontaneously by the classical oxi-
dation into the alkaloid Rutaecarpine (2). In both cases, no products
8a,b as precursors of Luotonin-A (1) were detected (Scheme 5) but
compound 2 was isolated as the sole reaction product in yields
ranging from 37% up to 67%. The yield is better for N-Boc derivative
7b in comparison to one for derivate 7a (See entries 1e4 in Table 1).
It is worth mentioning that when classical conditions C were used
only traces of Rutaecarpine (2) were detected with the recovered
starting material.
isoquinoline and different chiral a-Cbz-amino acyl fluorides was
reported.31a,40 In the presence of Lewis acid, such as AlCl3, that
reaction sometimes provided the tricyclic imidazoisoquinolines as
a consequence of the intramolecular N-acyliminium trapping of
a nitrogen atom.
Table 1
By the way, because it was difficult to isolate the acid chloride
6b in pure form, the reaction of imine 5 with its carboxylic acid
congener 11 was explored. Interestingly, under the peptide cou-
pling conditions using DCC/DMAP (1.1 equiv peer 0.1 equiv) in
DCM at room temperature for 4 h, the N-Boc-dihydrorutaecarpine
(7b) was isolated in 72% yield. Mechanistically speaking, this
Results of the oxidation of Rutaecarpines 7aec, 3 and 7ea,b
a,b
Entry Substrate number Conditions
R2 group Product number Yield (%)c
1
2
3
4
5
6
7
8
9
10
7a
7a
7b
7b
7c
7c
3
3
7e
7e
A
B
A
B
A
B
A
B
A
B
Ts
Ts
Boc
Boc
Ph
2
2
2
2
8c
8c
8d
8d
8e
8e
48
37
67
53
52
20
48
42
58
55
process involves
a tandem N-acylation/intramolecular aza-
Ph
cyclization via the N-acyliminium cation Ib (Scheme 4). Herein
the imine function of 5 is nucleophilic enough for the displace-
ment of the reactive O-acyl-urea intermediate being obtained by
the reaction of DCC with N-Boc-carboxylic acid 11. This resulted
also in the generation of the above species Ib and the dicyclohexyl-
urea (DCU) carbanion as the counter-ion. Moreover, based on the
few reports on reaction of isatoic anhydride (13) with linear41 and
cyclic42 imines under neutral conditions, we anticipated that the
Me
Me
Bn
Bn
a
Conditions A: O2, t-BuOK, DMF, rt, 1 h; Conditions B: KO2, 18-C-6, DMF, rt, 12 h.
No reaction occurred or only traces of product were detected when conditions C
(NaIO4, THF/MeOH/H2O (1/1/1), reflux, 12 h) were used.
b
c
Isolated yield after silica gel chromatography purification.

F. Pin et al. / Tetrahedron 67 (2011) 5564e5571
5567
Elsewhere, quinazolino-
b
-carbolines 7c, 3 and 7e, in which the
N-acyliminium intermediates in association, in certain cases, with
the decarboxylation process.
Ewg group (Ts, Boc) was replaced, respectively, with the phenyl,
methyl and benzyl substituent, were submitted to react under the
oxidation conditions as above. To our satisfaction, the reaction
provided products 8cee in yields ranging from 20% up to 61% (see
Experimental section), better when conditions A were used (entries
5, 7, 9; Table 1). This is probably due to the balance between the
high reactivity of KO2 and its stability with regard to the reaction
time (12 h) in comparison to O2, which needed only 1 h of reaction.
Having in hand fused pyrroloquinolones 8c,d as the oxidative
transposition products of compounds 7c and 3, we then envisioned
their diversification by substituting them at their C8-position (the
C4-position of the quinolone nucleus). The principal objective here
is to enhance the hydro-solubility of the ultimate Luotonin-A de-
rivatives 14e16 as an important parameter in their further possible
biological screening.
Rutaecarpines 7 obtained with this protocol were then used as
valuable templates for the WitkopeWinterfeldt oxidation to pro-
vide successfully, and in the first time for these types of substrates,
the oxidative transposition products 8 and the Topo-I Rutaecarpine
poison 2 via the simple deprotection of Ts and Boc groups under the
oxidative conditions of 7. Further functionalisation of the obtained
pyrroloquinolones using standard chemistry ultimately allow ac-
cess to a small library of Luotonins 4 substituted at two points in-
cluding the nitrogen atom at N15-position for the first time.
Finally, we anticipate that the transformations developed in this
project, particularly the access to new Luotonins, will find further
applications in production of a large library for biological issues.
These systems are currently under investigation in our laboratory
and the results will be reported soon in full account.
In this context, the esterification of condensed quinolin-4-ones
8c,d was accomplished, via the presumed tautomer hydroxyl in-
termediates L in equilibrium with their congeners 8c,d (Scheme 6).
For this purpose, we have used the O-acylation conditions used
earlier by us and others (i.e., Ac2O, Et3N, DMAP, DCM, 12 h).46 Under
these conditions, the expected acetate products 14a and 14b were
isolated in 51% and 61% yields, respectively, after purification by
flash chromatography on silica gel column using the mixture of
cyclohexane/AcOEt (2/3) as the eluent.
4. Experimental section
4.1. General remarks
All melting points were measured on a Boetius micro-hotstage
and are uncorrected. The infrared spectra of solids (potassium
bromide) and liquids (neat) were recorded on a PerkineElmer FT-IR
paragon 1000 spectrometer and are reported in terms of frequency
of absorption (n, cmꢀ1). The 1H and 13C NMR spectra were recorded
on a Bruker 300 MHz instrument in deuteriochloroform unless
other indicated solvent and chemical shifts (d) are expressed in
parts per million (ppm) relative to TMS (Tetramethylsilane) as in-
ternal standard and/or referenced to residual chloroform
O
Cl
O
O
SOCl2, DMF
0°C, 2 h
N
N
N
H
N
R2 = Ph 67%
R2 = Me 72%
(
d
¼7.27 ppm). Ascending thin layer chromatography was per-
N
N
R2
8c,d
R2
15a,b
formed on precoated plates of silica gel 60 F254 (Merck) and the
spots visualized using an ultraviolet lamp or iodine vapour. The
solvents used were purified by standard protocols. The elemental
analyses were carried out by the microanalysis of COBRA labora-
tory, CNRS UMR-6014, F-76130 Mont Saint-Aignan, France.
Morpholine,
Toluene, reflux
24 h
Ac2O, Et3N,
DMAP, DCM
12 h
R2=Ph, 42%
R2=Me, 44%
R2=Ph, 51%
R2=Me, 61%
OH
O
N
4.1.1. 2-(Tosylamino)benzoyl chloride (6a). To a solution of a freshly
prepared known carboxylic acid 1035 (2.91 g, 10 mmol) in dry
dichloromethane (30 mL) was added oxalyl chloride (1.875 g,
1.275 mL, 15 mmol) at 0e5 ꢁC. The mixture was stirred at room
temperature for 2 h and then evaporated under reduced pressure.
The crude product identified as acid chloride 6a37 was obtained in
quantitative yield (3.09 g) and was used in the next without other
purification.
OAc
N
N
O
O
L
N
N
N
N
a: R2=Ph
b: R2=Me
N
N
R2
14a,b
Scheme 6. Diversification of the quinazolino-
R2
16a,b
-carboline scaffold of 8c,d.
b
The chlorination of dihydroquinolinones 8c,d via also the in-
termediacy of 4-hydroxyquinolines L was accomplished under mild
conditions using SOCl2 (10 equiv) in the presence of DMF as the
solvent at 0 ꢁC up to room temperature for 2 h.47 The expected
halide derivatives 15a and 15b, were isolated in yields of 67% and
72%, respectively. These derivatives were also purified by flash
chromatography (i.e., SiO2, cyclohexane/AcOEt (7/3 up to 4/1 ra-
tio)). Ultimately, the chlorine atom of derivatives 15a and 15b was
displaced easily with large excess of freshly distilled morpholine
(10 equiv) in toluene at reflux for 24 h. Analytical pure compounds
16a and 16b were finally isolated by chromatography purification
on silica gel column by using the mixture of cyclohexane/AcOEt in
1/1 up to 3/2 ratio in yields of 42% and 44%, respectively.
4.1.2. 2-(Phenylamino)benzoyl chloride (6c). To
a solution of
a commercially available 2-(phenylamino)-benzoic acid 12 (2.13 g,
10 mmol) in dry toluene (25 mL) was added dropwise thionyl
chloride (2 equiv, 2.36 g, 1.44 mL, 20 mmol) at 0e5 ꢁC. The mixture
was stirred at reflux for 30 min and then evaporated under reduced
pressure. The crude product identified as acid chloride 6c38 was
obtained in quantitative yield (2.30 g) and was used in the next
without other purification.
4.2. General procedure for the synthesis of N-substituted
tetrahydroindolo[20,30:3,4]pyrido[2,1-b]quinazolin-5-ones
(7a,c)
To a stirred solution of 3,4-dihydro-
2.00 mmol) in 16 mL of dry dichloromethane containing triethyl-
amine (560
L, 4 mmol, 2 equiv) was added at 0 ꢁC a solution of
b-carboline (5, 340 mg,
3. Conclusion
m
In this paper, we have successfully introduced an expedient
synthetic entry to Rutaecarpines N-substituted of type 7 including
the Topo-I inhibitor Evodiamine (3). This approach consists in using
of the scarcely known tandem N-acylation/aza-cyclization of the
freshly prepared acid chloride 6a (640 mg, 2.20 mmol, 1.1 equiv) or
6c (510 mg, 2.20 mmol, 1.1 equiv) dissolved in 16 mL of dichloro-
methane. The reaction mixture was stirred at 0 ꢁC for 30 min then
an additional 1 h at room temperature, after which saturated

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F. Pin et al. / Tetrahedron 67 (2011) 5564e5571
aqueous solution of NaHCO3 was added. The organic phase after
separation was washed with brine, dried over anhydrous MgSO4,
filtered, and evaporated under reduced pressure. The resulting
crude product was purified by flash chromatography on silica gel
column using the mixture of cyclohexane/AcOEt as the eluent to
provide the title following compounds 7a and 7c.
113.1 (Cq/aro),118.8 (CHaro),120.1 (CHaro),121.8 (Cq/aro),122.8 (CHaro);
124.2 (CHaro), 125.3 (CHaro); 127.4 (Cq/aro), 128.5 (CHaro); 131.2 (Cq/
aro), 132.5 (CHaro); 135.9 (Cq/aro), 137.6 (Cq/aro), 153.4 (C]Ocarbamate),
164.8 (C]Olactam); Anal. Calcd for C23H23N3O3 (389.45): C, 70.93; H,
5.95; N, 10.79. Found: C, 70.78; H, 5.69; N, 10.54.
4.3. General procedure for the synthesis of N-substituted
tetrahydroindolo[20,30:3,4]pyrido[2,1-b]quinazolin-5-ones
(3 and 7e)
4.2.1. N14-Tosyl-7,8,13,13b-tetrahydroindolo-[20,30:3,4]pyrido[2,1-b]
quinazolin-5-one (7a). This product was isolated as a white solid
after chromatography purification (i.e., SiO2, cyclohexane/AcOEt (7/
3)) in 72% yield: mp 242 ꢁC; Rf 0.50 (cyclohexane/AcOEt: 1/1); IR
The solution of 3,4-dihydro-b-carboline (5, 340 mg, 2 mmol)
(KBr, cmꢀ1
)
n
: 3460 (NH), 1665 (C]O), 1604 (NH), 1466 (CH), 1410
(ppm) 2.34 (s, 3H, CH3), 2.59 (d,
and N-methyl isatoic anhydride (6d, 355 mg, 2 mmol) (or N-benzyl
isatoic anhydride 6e, 506.5 mg, 2 mmol), prepared by N-alkylation
of isatoic anhydride, in 10 mL of chloroform was refluxed for 8 h.
After cooling of the reaction solution at room temperature then
ꢀ10 ꢁC, the precipitated formed was filtered off, dried and recrys-
tallized from diethyl ether/ethyl acetate (3/2).
(CH); 1H NMR (300 MHz, CDCl3):
d
1H, 1CH2b, J¼12.5 Hz), 3.00e3.29 (m, 2H, 1CH2aeNCO and 1CH2b),
4.67e4.77 (m, 1H, 1CH2aeNCO), 7.00e1.18 (m, 6H, 5Haro and CH),
7.24e7.32 (m, 1H, Haro), 7.39 (d, 3H, Haro, J¼8.6 Hz), 7.49 (dd, 1H,
Haro, J¼8.6 and 7.0 Hz), 7.83 (d, 2H, Haro, J¼7.8 Hz), 8.30 (br s, 1H,
NH); 13C NMR (75 MHz, CDCl3):
d (ppm) 19.7 (CH2), 21.9 (CH3), 44.8
(CH2), 69.2 (CH), 111.7 (CHaro), 113.2 (Cq/aro), 118.8 (CHaro), 120.2
(CHaro), 123.1 (CHaro), 123.8 (Cq/aro), 126.5 (CHaro), 127.3 (Cq/aro),
127.8 (3CHaro), 128.8 (CHaro), 130.0 (2CHaro and Cq/aro), 133.4 (CHaro),
134.0 (Cq/aro), 135.8 (Cq/aro), 135.9 (Cq/aro), 145.4 (Cq/aro), 163.4 (C]
O); Anal. Calcd for C25H21N3O3S (443.13): C, 67.70; H, 4.77; N, 9.47.
Found: C, 67.59; H, 4.65; N, 9.37.
4.3.1. N14-Methyl-7,8,13,13b-tetrahydroindolo-[20,30:3,4]pyrido[2,1-
b]quinazolin-5-one (3). This product was isolated as a rose solid in
79% yield: mp 268 ꢁC (lit.11b 268e270 ꢁC); Rf 0.50 (cyclohexane/
AcOEt: 1/1); IR (KBr, cmꢀ1
)
n
: 3222 (NH), 1645 (C]O), 1628 (NH),
1509 (C]C), 1494 (C]C), 1449 (C]C), 1408 (CH), 1390 (CH); 1H
NMR (300 MHz, CDCl3): (ppm) 2.79e3.03 (m, 2H, CH2b), 2.92 (s,
d
3H, CH3), 3.17e3.29 (m, 1H, 1CH2aeNCO), 4.67 (dd, 1H, 1CH2aeNCO,
J¼13.2 and 3.5 Hz), 6.17 (s, 1H, CH), 6.96e7.19 (m, 4H, Haro), 7.40 (d,
4.2.2. N14-Phenyl-7,8,13,13b-tetrahydroindolo-[20,30:3,4]pyrido[2,1-
b]quinazolin-5-one (7c). This product was isolated as a white solid
after chromatography purification (i.e., SiO2, cyclohexane/AcOEt (4/
1)) in 83% yield: mp 211 ꢁC; Rf 0.50 (cyclohexane/AcOEt: 7/3); IR
1H, Haro, J¼7.9 Hz), 7.48e7.55 (m, 2H, Haro), 7.83 (d, 1H, Haro
,
J¼7.9 Hz), 11.12 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3):
d (ppm)
19.5 (CH2), 36.4 (CH3), 40.8 (CH2), 69.7 (CH), 111.5 (Cq/aro), 111.6
(CHaro), 117.5 (CHaro), 118.2 (CHaro), 118.9 (CHaro), 119.3 (Cq/aro), 120.3
(CHaro), 121.8 (CHaro), 125.9 (Cq/aro), 128.0 (CHaro), 130.6 (Cq/aro),
133.4 (CHaro), 136.5 (Cq/aro), 148.8 (Cq/aro), 164.2 (C]O); Anal. Calcd
for C19H17N3O (303.36): C, 75.23; H, 5.65; N, 13.85. Found: C, 75.09;
H, 5.42; N, 13.66.
(cmꢀ1
(C]C), 1416 (CH); 1H NMR (300 MHz, CDCl3):
)
n
: 1652 (C]O), 1605 (C]C), 1591 (C]C), 1495 (C]C), 1471
(ppm) 2.65e2.78
d
(m, 1H, 1CH2b), 2.68e3.29 (m, 2H, 1CH2 and 1CH2aeNCO),
b
4.85e4.95 (m, 1H, 1CH2aeNCO), 6.37 (s, 1H, CH), 6.94e7.36 (m, 11H,
Haro), 7.45 (d, 1H, Haro, J¼7.8 Hz), 8.03 (dd, 1H, Haro, J¼7.8 and
1.6 Hz), 8.09 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3):
d (ppm) 20.0
(CH2), 43.2 (CH2), 72.9 (CH), 111.5 (CHaro), 113.8 (Cq/aro), 119.0
(CHaro), 120.2 (CHaro), 120.6 (CHaro), 121.3 (Cq/aro), 122.8 (CHaro),
123.0 (CHaro), 124.7 (2CHaro), 125.7 (CHaro), 127.2 (Cq/aro), 129.2
(CHaro), 129.8 (2CHaro), 131.2 (Cq/aro), 133.3 (CHaro), 136.2 (Cq/aro),
145.2 (Cq/aro), 146.7 (Cq/aro), 165.3 (C]O); Anal. Calcd for C24H19N3O
(365.15): C, 78.88; H, 5.24; N, 11.50. Found: C, 78.65; H, 5.09; N,
11.41.
4.3.2. N14-Benzyl-7,8,13,13b-tetrahydroindolo-[20,30:3,4]pyrido[2,1-b]
quinazolin-5-one (7e). This product was isolated as a white solid in
77% yield: mp 224 ꢁC (Decomposition); Rf 0.57 (cyclohexane/AcOEt:
3/2); IR (cmꢀ1
)
n
: 3209 (NH), 1658 (C]O), 1619 (NH), 1512(C]C),
1489 (C]C), 1451 (C]C), 1412 (CH), 1395 (CH); 1H NMR (300 MHz,
CDCl3): (ppm) 2.20e2.97 (m, 2H, CH2b), 3.20e3.30 (m, 1H,
d
1CH2aeNCO), 4.04 (d, 1H, 1PhCH2eN, J¼14.8 Hz), 4.27 (d, 1H,
1PhCH2eN, J¼14.8 Hz), 4.81e4.88 (m, 1H, 1CH2aeNCO), 6.06 (s, 1H,
CH), 6.82 (d, 1H, Haro, J¼7.8 Hz), 7.02e7.45 (m, 9H, Haro), 7.48 (t, 1H,
Haro, J¼7.9 Hz), 7.55 (d, 1H, Haro, J¼7.8 Hz), 8.01 (br s, 1H, NH), 8.11
4.2.3. N14-Tertiobutoxycarbonyl-7,8,13,13b-tetrahydroindolo-
[20,30:3,4]pyrido[2,1-b]quinazolin-5-one (7b). To a solution of 3,4-
dihydro-
b-carboline (5, 340 mg, 2.00 mmol) and N-Boc-anthralinic
(dd, 1H, Haro, J¼7.8 and 1.9 Hz); 13C NMR (75 MHz, CDCl3):
d (ppm)
acid (11,36 512 mg, 2 mmol, 1 equiv) in dry dichloromethane
(20 mL), was added under stirring 4-dimethylaminopyridine
(DMAP, 24.0 mg, 0.20 mmol, 0.1 equiv) and N,N-dicyclohex-
ylcarbodiimide (DCC, 454 mg, 2.20 mmol, 1.1 equiv) at room
temperature. After 4 h of the reaction, the mixture was filtered on
Celite-545 with washing twice by dichloromethane. The combined
organic filtrate was treated with saturated solution of NaHCO3,
separated, dried over anhydrous MgSO4, filtered again and evapo-
rated under reduced pressure. The ultimate residue was purified by
flash column chromatography (silica gel, eluted with the mixture
cyclohexane/AcOEt (3/2)) to provide the N-Boc-dihydro-rutae-
carpine (7b) in 72% yield as a white solid. Mp 221 ꢁC; Rf 0.30 (cy-
19.2 (CH2), 41.7 (CH2eNCO), 52.7 (CH2Ph), 70.1 (CH), 111.4 (Cq/aro),
111.6 (CHaro), 117.1 (CHaro), 118.1 (CHaro), 118.8 (CHaro), 119.7 (CHaro),
121.8 (CHaro), 126.2 (Cq/aro), 127.1 (CHaro and Cq/aro), 127.5 (2CHaro),
128.1 (CHaro), 128.3 (2CHaro), 131.5 (Cq/aro), 133.1 (CHaro), 136.2 (Cq/
aro), 138.2 (Cq/aro), 146.7 (Cq/aro), 164.7 (C]O); Anal. Calcd for
C25H21N3O (379.45): C, 79.13; H, 5.58; N, 11.07. Found: C, 79.01; H,
5.38; N, 10.88.
4.4. The procedures for the oxidation reaction of N-
substituted dihydrorutaecarpines 7aec, 3 and 7e
Method A (O2, t-BuOK, DMF). A mixture of N-substituted dihy-
drorutaecarpines (7aec,3 and 7e, 1 mmol) and potassium tert-
butanoate (KOt-Bu, 2.50 mmol, 2.5 equiv) in 5 mL of dry DMF at
room temperature was stirred slowly under constant oxygen bub-
ble for 2 h. After an additional stirring for 5 h, the reaction mixture
was diluted with ethyl acetate (30 mL) and water (30 mL). The
collected organic layers were washed with aqueous HCl (1 N) so-
lution (50 mL) and brine (50 mL) and, then dried and concentrated
under reduced pressure. Ultimately, the crude product 8 was
clohexane/AcOEt: 3/2); IR (KBr, cmꢀ1
(C]O), 1643 (C]O), 1606 (NH), 1488 (C]C), 1470 (CH); 1H NMR
(300 MHz, CDCl3): (ppm) 1.58 (s, 9H, N-Boc), 2.66 (d, 1H, 1CH2
) n: 3319 (NH), 2989 (CH), 1702
d
,
b
J¼13.3 Hz), 3.12e3.46 (m, 2H, 1CH2b and 1CH2aeNCO), 4.91e5.1 (m,
1H,1CH2aeNCO), 7.02e7.17 (m, 4H, 3Haro and CH), 7.22e7.28 (m,1H,
Haro), 7.35e7.46 (m, 2H, Haro), 7.53 (d,1H, Haro, J¼8.6 Hz), 7.98 (d,1H,
Haro, J¼7.8 Hz), 8.15 (br s,1H, NH); 13C NMR (75 MHz, CDCl3):
d (ppm)
20.0 (CH2), 28.4 (3CH3), 45.1 (CH2), 67.0 (CH), 84.0 (Cq),111.4 (CHaro),

F. Pin et al. / Tetrahedron 67 (2011) 5564e5571
5569
purified by silica gel column chromatography by using the mixture
of EtOAc/cyclohexane as the eluent (See Table 1 for yields).
Method B (KO2, 18-C-6, DMF). To a solution of N-substituted
dihydrorutaecarpines (7aec, 3 and 7e, 1 mmol) and 18-crown-6
(264 mg, 1 mmol) in dry DMF (6 mL) was added potassium super-
oxide (KO2, 284 mg, 4.00 mmol) in one portion at room tempera-
ture. The reaction mixture turned red and was stirred for 16 h at the
same temperature. After the end of the reaction, the excess of KO2
was consumed by adding several drops of water. The mixture was
then extracted with ethyl acetate and decanted. The aqueous phase
was extracted three times with ethyl acetate. The combined organic
layer was washed with brine, dried over anhydrous MgSO4, filtered
and concentrated under reduced pressure to provide the crude
product 8, which was purified by silica gel column chromatography
by using the mixture of EtOAc/cyclohexane as the eluent (See Table
1 for yields).
127.8 (2CHaro), 128.1 (2CHaro), 131.8 (CHaro), 132.9 (CHaro), 136.7 (Cq/
aro), 141.9 (Cq/aro), 145.2 (Cq/aro), 148.3 (Cq/aro), 160.6 (C]Olactam),
173.5 (C]Oketone); Anal. Calcd for C25H19N3O2 (393.44): C, 76.32; H,
4.87; N, 10.68. Found: C, 76.18; H, 4.64; N, 10.49.
4.5. Procedure for the esterification reaction of
N-substituted-quinolines 8c,d. formation of the pentacyclic
acetates 14a,b
To a suspension mixture of N-substituted-quinoline (8c or 8d,
1 mmol) dissolved in 15 mL of dry dichloromethane was added
successively dry triethylamine (280
mL, 2 mmol, 2 equiv), acetic
anhydride (188 L, 2 mmol, 2 equiv) and catalytic amounts of
m
4-dimethylaminopyridine (DMAP, 12 mg, 0.1 mmol, 0.1 equiv). Af-
ter stirring at room temperature for 12 h, a cold saturated solution
of NaHCO3 (15 mL) was added to the reaction mixture. The organic
layers separated were combined, washed with brine, dried over
anhydrous MgSO4 and evaporated under reduced pressure. The
residue was ultimately purified by silica gel column chromatogra-
phy by using the mixture of cyclohexane/AcOEt as the eluent to
provide the expected ester derivatives 14.
4.4.1. 14-Phenyl-1,2-dihydroquinolino[20,30:3,4]-pyrrolo[2,1-b]quina-
zoline-5,8(13H)-dione (8c). This product was isolated as a brown
solid in yields of 52% (Method A) and 20% (Method B). Mp 200 ꢁC
(Decomposition); Rf 0.11 (cyclohexane/AcOEt: 0.5/9.5); IR (KBr,
cmꢀ1
(CH); 1H NMR (300 MHz, CDCl3):
)
n
: 1662 (C]O), 1630 (C]O), 1592 (C]C), 1567 (C]C), 1410
d
(ppm) 4.48 (d, 1H, 1CH1
,
a
4.5.1. 8-Acetyloxy-14-phenyl-1,2-dihydroquinolino-[20,30:3,4]pyrrolo
[2,1-b]quinazolin-5-one (14a). This product was isolated as an or-
ange oil in 51% yield; Rf 0.48 (cyclohexane/AcOEt: 3/2); IR (neat,
J¼14.9 Hz), 4.55 (d, 1H, 1CH1b, J¼14.9 Hz), 6.74 (s, 1H, CH), 7.03e7.27
(m, 6H, Haro), 7.32e7.42 (m, 2H, Haro), 7.59 (dd, 1H, Haro, J¼7.9 and
7.0 Hz), 7.69e7.75 (m, 2H, Haro), 8.07 (d, 2H, Haro, J¼7.0 Hz), 12.8 (s,
cmꢀ1
)
n
: 1777 (C]O), 1651 (C]O), 1607 (C]N), 1491 (C]C), 1473
1H, NH); 13C NMR (75 MHz, CDCl3):
d
(ppm) 47.0 (CH2), 77.6 (CH),
(C]C), 1434 (CH); 1H NMR (300 MHz, CDCl3):
d
(ppm) 2.47 (s, 3H,
115.7 (Cq/aro), 118.6 (CHaro), 123.5 (CHaro), 124.3 (CHaro), 124.6 (CHaro),
125.0 (CHaro),125.1 (Cq/aro),126.6 (Cq/aro),126.9 (CHaro),127.7 (CHaro),
128.0 (2CHaro), 129.0 (2CHaro), 132.0 (CHaro), 133.6 (CHaro), 140.2 (Cq/
aro), 143.3 (Cq/aro), 144.4 (Cq/aro), 148.3 (Cq/aro), 160.8 (C]Olactam),
173.2 (C]Oketone); Anal. Calcd for C24H17N3O2 (379.41): C, 75.97; H,
4.52; N, 11.08. Found: C, 75.76; H, 4.43; N, 10.90.
OAc), 4.82 (d, 1H, 1CH1a, J¼16.4 Hz), 5.03 (dd, 1H, 1CH1b, J¼16,4 Hz
and 1.6 Hz), 6.53 (s,1H, CH), 6.73 (d,1H, Haro, J¼8.6 Hz), 7.09 (dd,1H,
Haro, J¼7.8 and 7.0 Hz), 7.17e7.38 (m, 6H, Haro), 7.54 (ddd, 1H, Hquino
,
J¼7.8, 7.0 and 1.6 Hz), 7.66 (ddd, 1H, Hquino, J¼8.6, 7.0 and 1.6 Hz),
7.83 (d, 1H, Hquino, J¼8.6 Hz), 7.86 (d, 1H, Haro, J¼7.8 Hz), 8.11 (dd,
1H, Hquino, J¼7.8 Hz); 13C NMR (75 MHz, CDCl3):
d (ppm) 20.8 (CH3),
46.7 (CH2), 76.7 (CH), 120.0 (CHaro), 120.8 (Cq/aro), 121.1 (CHaro),
122.1 (Cq/aro), 122.2 (Cq/aro), 122.3 (CHaro), 127.3 (CHaro), 127.8
(CHaro), 128.5 (CHaro), 129.2 (2CHaro), 129.9 (CHaro), 130.1 (2CHaro),
130.3 (CHaro), 133.8 (CHaro), 142.8 (Cq/aro), 149.5 (Cq/aro), 149.6 (Cq/
aro), 150.0 (Cq/aro), 157.7 (C]N), 162.8 (C]Olactam), 167.0 (C]Oester);
Anal. Calcd for C26H19N3O3 (421.45): C, 74.10; H, 4.54; N, 9.97.
Found: C, 74.00; H, 4.39; N, 9.80.
4.4.2. 14-Methyl-1,2-dihydroquinolino[20,30:3,4]-pyrrolo[2,1-b]qui-
nazoline-5,8(13H)-dione (8d). This product was isolated as a white
solid in yields of 48% (Method A) and 42% (Method B). Mp 240 ꢁC
(Decomposition); Rf 0.21 (cyclohexane/AcOEt: 0.5/9.5); IR (cmꢀ1
) n:
3100 (CH), 2924 (CH), 1649 (C]O), 1607 (NH), 1575 (C]C); 1H NMR
(300 MHz, CDCl3): (ppm) 2.64 (s, 3H, CH3), 4.56 (d, 1H, 1CH1
d
,
a
J¼14.4 Hz), 4.73 (d, 1H, 1CH1b, J¼14.4 Hz), 6.32 (s, 1H, CH),
7.29e7.48 (m, 3H, Haro), 7.64 (dd, 1H, Haro, J¼7.4 and 7.1 Hz),
4.5.2. 8-Acetyloxy-14-methyl-1,2-dihydroquinolino-[20,30:3,4]pyrrolo
[2,1-b]quinazolin-5-one (14b). This product was isolated as an or-
ange solid in 61% yield; Mp 182 ꢁC (Decomposition); Rf 0.50 (cy-
7.73e7.80 (m, 2H, Haro), 7.95 (d, 1H, Haro, J¼7.4 Hz), 8.22 (d, 1H, Haro
,
J¼7.9 Hz), 12.78 (br s, 1H, NH); 13C NMR (75 MHz, CDCl3):
d (ppm)
37.3 (CH3), 47.0 (CH2), 76.7 (CH), 115.8 (Cq/aro), 118.9 (CHaro), 123.5
(CHaro), 124.4 (CHaro), 124.7 (CHaro), 125.1 (Cq aro), 127.5 (2CHaro),
131.9 (CHaro), 133.3 (CHaro), 140.7 (Cq/aro), 144.0 (Cq/aro), 150.4 (2Cq/
aro), 160.3 (C]Olactam), 173.3 (C]Oketone); Anal. Calcd for
C19H15N3O2 (317.34): C, 71.91; H, 4.76; N, 13.24. Found: C, 71.77; H,
4.59; N, 13.05.
clohexane/AcOEt: 2/3); IR (KBr, cmꢀ1
)
n
: 1778 (C]O), 1653 (C]O),
1608 (C]N), 1480 (C]C), 1442 (CH); 1H NMR (300 MHz, CDCl3):
(ppm) 2.50 (s, 3H, OAc), 3.21 (s, 3H, NMe), 4.79 (d, 1H, 1CH1
d
,
a
J¼16.4 Hz), 5.10 (d, 1H, 1CH1b, J¼16.4 Hz), 5.97 (s, 1H, CH), 7.02e7.10
(m,1H, Haro), 7.07 (d, 1H, Haro, J¼7.8 Hz), 7.44e7.53 (m, 1H, Haro), 7.62
(dd, 1H, Hquino, J¼7.8 Hz and 7.0 Hz), 7.82 (dd, 1H, Hquino, J¼7.8 and
7.0 Hz), 7.95 (d, 1H, Hquino, J¼7.8 Hz), 8.04 (dd, 1H, Hquino, J¼7.8 and
1.6 Hz), 8.21 (d, 1H, Haro, J¼8.6 Hz); 13C NMR (75 MHz, CDCl3):
4.4.3. 14-Benzyl-1,2-dihydroquinolino[20,30:3,4]-pyrrolo[2,1-b]quina-
zoline-5,8(13H)-dione (8e). This product was isolated as a white-
yellow solid in yields of 58% (Method A) and 55% (Method B): mp
d
(ppm) 20.8 (CH3), 34.2 (NCH3), 46.5 (CH2), 75.9 (CH), 116.8 (CHaro),
120.6 (Cq/aro), 121.0 (Cq/aro), 121.3 (CHaro), 121.4 (CHaro), 122.4 (Cq/aro),
128.0 (CHaro), 128.5 (CHaro), 130.0 (CHaro), 130.6 (CHaro), 134.0
(CHaro), 149.9 (Cq/aro), 150.2 (Cq/aro), 150.6 (Cq/aro), 159.0 (C]N), 162.5
(C]Olactam),167.1 (C]Oester); Anal. Calcd for C21H17N3O3 (359.38): C,
70.18; H, 4.77; N, 11.69. Found: C, 70.03; H, 4.49; N, 11.52.
202 ꢁC (Decomposition); Rf 0.27 (cyclohexane/AcOEt: 1/9); IR (cmꢀ1
n
)
: 3089 (CH), 2936 (CH), 16,454 (C]O), 1600 (NH), 1566 (C]C); 1H
NMR (300 MHz, DMSO-d6):
d (ppm) 3.41 (br s, 1H, NH), 3.92 (d, 1H,
1CH2aePh, J¼14.1 Hz), 4.18 (dd, 1H, 1CH1aeN, J¼14.4 and 3.3 Hz),
4.32 (d, 1H, 1CH1beN, J¼14.4 Hz), 4.43 (d, 1H, 1CH2aePh, J¼14.1 Hz),
6.38 (d, 1H, CH, J¼3.3 Hz), 6.71e6.75 (m, 2H, Haro), 7.01e7.15 (m, 3H,
Haro), 7.23 (d, 1H, Haro, J¼7.2 Hz), 7.30 (t, 1H, Haro, J¼6.8 Hz),
7.37e7.42 (m, 1H, Haro), 7.51 (t, 1H, Haro, J¼8.6 Hz), 7.65e7.76 (m, 2H,
Haro), 7.87 (d,1H, Haro, J¼7.8 Hz), 8.18 (d,1H, Haro, J¼8.1 Hz); 13C NMR
4.6. Procedure for the chlorination reaction of N-substituted-
quinolines 8c,d. Formation of the pentacyclic halides 15a,b
To a suspension mixture of N-substituted-quinoline (8c or 8d,
1 mmol) dissolved in 10 mL of dry N,N-dimethylformamide was
added at 0 ꢁC, was added under stirring dropwise thionyl chloride
(75 MHz, CDCl3): d (ppm) 46.6 (CH2eNCO), 53.9 (CH2Ph), 76.3 (CH),
115.7 (Cq/aro),119.6 (CHaro), 122.9 (CHaro), 123.7 (CHaro), 124.0 (CHaro),
124.6 (CHaro), 125.0 (Cq/aro), 125.5 (Cq/aro), 127.0 (CHaro), 127.5 (CHaro),
(725
mL, 10.0 mmol, 10 equiv). The reaction mixture was then

5570
F. Pin et al. / Tetrahedron 67 (2011) 5564e5571
stirred for an additional 2 h at room temperature and hydrolyzed
by adding slowly a saturated solution of NaHCO3. The reaction
mixture was extracted twice with ethyl acetate and the combined
organic layers were washed with water, brine and decanted. The
organic phase was dried over MgSO4 and evaporated under re-
duced pressure. The residue was purified by silica gel column
chromatography by using the mixture of cyclohexane/AcOEt as the
eluent to provide the expected halides 15.
2NCHa beCH2O), 5.04 (d, 1H, 1CH1aeN, J¼15.4 Hz), 5.25 (dd, 1H,
,
1CH1beN, J¼15.4 and 1.6 Hz), 6.40 (s, 1H, CH), 6.77 (d, 1H, Haro
,
J¼8.3 Hz), 7.09e7.18 (m, 6H, Haro), 7.32e7.38 (m, 1H, Haro), 7.47 (dd,
1H, Haro, J¼7.2 and 6.8 Hz), 7.60 (t, 1H, Haro, J¼7.2 Hz), 7.79 (d, 1H,
Haro, J¼8.3 Hz), 8.02 (d, 1H, Haro, J¼7.9 Hz), 8.12 (dd, 1H, Haro, J¼7.9
and 1.6 Hz); 13C NMR (75 MHz, CDCl3):
d (ppm) 48.2 (CH2N), 51.9
(2NCH2eCH2O), 67.5 (2NCH2eCH2O), 76.2 (CH), 119.3 (Cq/aro), 120.6
(CHaro), 122.5 (CHaro), 122.8 (Cq/aro), 124.1 (Cq/aro), 124.2 (CHaro),
124.3 (Cq/aro), 126.6 (CHaro), 127.0 (CHaro), 128.4 (CHaro), 129.1
(2CHaro), 129.6 (CHaro), 130.0 (2CHaro), 130.2 (CHaro), 133.7 (CHaro),
143.3 (2Cq/aro), 149.7 (Cq/aro), 157.3 (C]N), 162.6 (C]O); Anal. Calcd
for C28H24N4O2 (448.62): C, 74.98; H, 5.39; N,12.49. Found: C, 74.69;
H, 5.10; N, 12.25.
4.6.1. 8-Chloro-14-phenyl-1,2-dihydroquinolino-[20,30:3,4]pyrrolo
[2,1-b]quinazolin-5-one (15a). This product was isolated as a yellow
solid in 67% yield; mp 190 ꢁC (Decomposition); Rf 0.67 (cyclohex-
ane/AcOEt: 7/3); IR (KBr, cmꢀ1
)
n
: 1654 (C]O), 1607 (C]N), 1562
(C]C), 1488 (C]C), 1434 (CH), 1385 (CH); 1H NMR (300 MHz,
CDCl3):
d
(ppm) 4.97 (d, 1H, 1CH1a, J¼17.2 Hz), 5.16 (d, 1H, 1CH1
,
4.7.2. 8-Morpholino-14-methyl-1,2-dihydroquinol-ino[20,30:3,4]pyr-
rolo[2,1-b]quinazolin-5-one (16b). This product was isolated as
a yellow solid in 44% yield; mp 170 ꢁC (Decomposition); Rf 0.37
b
J¼17.2 Hz), 6.55 (s, 1H, CH), 6.74 (d, 1H, Haro, J¼8.6 Hz), 7.08e7.28
(m, 6H, Haro), 7.32e7.41 (m, 1H, Haro), 7.59e7.75 (m, 2H, Hquino), 7.85
(d, 1H, Haro, J¼7.8 Hz), 8.13 (d, 1H, Hquino, J¼7.8 Hz), 8.17 (d, 1H,
(cyclohexane/AcOEt: 1/1); IR (KBr, cmꢀ1
)
n
: 2971 (CH), 2894 (CH),
2859 (CH), 1651 (C]O), 1607 (C]N), 1571 (C]C), 1479 (CH), 1378,
1364 (CH); 1H NMR (300 MHz, CDCl3):
(ppm) 3.16 (s, 3H, NMe),
Hquino, J¼7.8 Hz); 13C NMR (75 MHz, CDCl3):
d (ppm) 48.1 (C1), 77.4
(C2), 120.2 (CHaro), 122.4 (Cq/aro), 122.5 (CHaro), 123.7 (CHaro), 125.9
(Cq/aro), 127.3 (CHaro), 128.0 (Cq/aro), 128.4 (CHaro), 128.5 (CHaro),
129.3 (2CHaro), 130.1 (2CHaro), 130.2 (CHaro), 130.5 (CHaro), 133.8
(CHaro), 137.9 (Cq/aro), 142.9 (Cq/aro), 149.0 (Cq/aro), 149.6 (Cq/aro),
156.1 (C]N), 162.8 (C]O); Anal. Calcd for C24H16ClN3O (397.86): C,
72.45; H, 4.05; N, 10.56. Found: C, 72.18; H, 3.86; N, 10.37.
d
3.32e3.39 (m, 4H, 2NCH2eCH2O), 3.92e4.01 (m, 4H,
2NCH2eCH2O), 5.01 (d, 1H, 1CH1aeN, J¼15.7 Hz), 5.37 (d, 1H,
1CH1beN, J¼15.7 Hz), 5.84 (s, 1H, CH), 7.03e7.11 (m, 2H, Haro), 7.48
(td, 1H, Haro, J¼7.3 and 1.1 Hz), 7.55 (t, 1H, Haro, J¼7.8 Hz), 7.70 (dd,
1H, Haro, J¼8.1 and 7.3 Hz), 8.04 (dd, 1H, Haro, J¼7.7 Hz), 8.13 (d, 2H,
Haro, J¼8.7 Hz); 13C NMR (75 MHz, CDCl3):
d (ppm) 34.3 (CH3), 48.0
4.6.2. 8-Chloro-14-methyl-1,2-dihydroquinolino-[20,30:3,4]pyrrolo
[2,1-b]quinazolin-5-one (15b). This product was isolated as a yellow
solid in 72% yield; mp 189 ꢁC (Decomposition); Rf 0.31 (cyclohex-
(CH2N), 51.9 (2NCH2eCH2O), 67.5 (2NCH2eCH2O), 74.1 (CH), 117.2
(CHaro), 119.4 (Cq/aro),121.0 (Cq/aro), 121.5 (CHaro),124.2 (Cq/aro), 124.3
(CHaro), 126.8 (CHaro), 128.5 (CHaro), 129.9 (CHaro), 130.2 (CHaro),
134.0 (CHaro), 149.8 (Cq/aro), 150.8 (Cq/aro), 151.9 (Cq/aro), 158.6 (C]
N), 162.6 (C]O); Anal. Calcd for C23H22N4O2 (486.45): C, 71.48; H,
5.74; N, 14.50. Found: C, 71.422; H, 5.59; N, 14.17.
ane/AcOEt: 4/1); IR (KBr, cmꢀ1
)
n
: 1654 (C]O), 1608 (C]N), 1561
(C]C), 1479 (C]C), 1441 (CH), 1370 and 1387 (CH); 1H NMR
(300 MHz, CDCl3): (ppm) 3.20 (s, 3H, CH3), 4.92 (d, 1H, 1CH1
d
,
a
J¼17.2 Hz), 5.25 (d, 1H, 1CH1b, J¼17.2 Hz), 5.98 (s, 1H, CH), 7.03e7.11
(m, 1H, Haro), 7.08 (d, 1H, Haro, J¼7.8 Hz), 7.50 (ddd, 1H, Haro, J¼8.6,
7.0 and 1.6 Hz), 7.71 (ddd, 1H, Hquino, J¼7.8, 7.0 and 1.6 Hz), 7.81 (dd,
1H, Hquino, J¼8.6 and 7.0 Hz), 8.07 (dd, 1H, Haro, J¼7.0 and 1.6 Hz),
8.19e8.24 (m, 1H, Hquino), 8.26 (d, 1H, Hquino, J¼8.6 Hz); 13C NMR
Acknowledgements
The authors are grateful to Region of ‘Haute Normandie’ for the
Graduate Fellowship (2006e2009) attributed to one of us, F.P. We
wish also to thank our colleague Dawn Hallidy for proofreading
the text.
(75 MHz, CDCl3):
d (ppm) 34.2 (CH3), 48.0 (CH2), 76.5 (CH), 116.8
(CHaro), 120.7 (Cq/aro), 121.6 (CHaro), 123.8 (CHaro), 126.1 (Cq/aro),
128.2 (Cq/aro), 128.6 (2CHaro), 130.3 (CHaro), 130.8 (CHaro), 134.1
(CHaro), 138.4 (Cq/aro), 149.2 (Cq/aro), 150.6 (Cq/aro), 157.4 (C]N),
162.5 (C]O); Anal. Calcd for C19H14ClN3O (335.79): C, 67.96; H,
4.20; N, 12.51. Found: C, 67.79; H, 4.06; N, 12.35.
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the mixture of cyclohexane/AcOEt as the eluent to afford the
expected pentacyclic tertiary amines 16a,b.
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IR (neat, cmꢀ1
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3.31e3.38 (m, 2H, 2NCHa beCH2O), 3.87e3.95 (m, 4H,
d
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