A formal synthesis of lavendamycin methyl ester, nitramarine, and their analogues: A povarov approach

Article abstract of DOI:10.1021/jo302389s

A convergent formal synthesis of lavendamycin methyl ester and synthesis of its analogues have been delineated through the Povarov approach. This protocol is also applied to the formal synthesis of nitramarine (3) in good yield.

Full text of DOI:10.1021/jo302389s

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Article
A Formal Synthesis of Lavendamycin Methyl Ester,
Nitramarine and their Analogues: A Povarov Approach
S. Ramesh, and Rajagopal Nagarajan
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302389s • Publication Date (Web): 10 Dec 2012
Downloaded from http://pubs.acs.org on December 16, 2012
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A Formal Synthesis of Lavendamycin Methyl Ester, Nitramarine and their Analogues: A
Povarov Approach
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Subburethinam Ramesh and Rajagopal Nagarajan*
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School of Chemistry, University of Hyderabad, Hyderabadꢀ500 046, INDIA
rnsc@uohyd.ernet.in
This manuscript is dedicated to Dr. P. T. Perumal, Organic Chemistry Division, Central Leather Research
Institute, Chennai, India for his contributions for imino DielsꢀAlder reaction
CO2R2
R1
N
CO2R2
N
NH2
R1
i) MgSO4, DCM
reflux, 1 h
ii) I2 (10 mol %)
THF, reflux
7ꢀ10 h
R3
R4
R3
OR7
N
N
H
+
+
R4
R6
CHO
N
H
R5
R5
R6
83ꢀ94%
CO2H
H3C
N
N
O
N
N
N
N
H
H
NH2
O
Nitramarine
Lavendamycin
Abstract
A convergent formal synthesis of lavendamycin methyl ester and synthesis of its
analogues have been delineated through the Povarov approach. This protocol is also applied to
the formal synthesis of nitramarine (3) in good yield.
Introduction
For the past several years, Povarov reaction (imino DielsꢀAlder reaction) has played a
central and crucial role to produce quinoline and tetrahydroquinoline molecules.1ꢀ3 These
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nitrogen containing heterocycles have significantly attracted the synthetic community due to
their prevalence in many natural products3 and synthetic compounds with a wide spectrum of
biological activities.4 In 1981, Doyle and coꢀworkers from Bristol Laboratories reported the
isolation of naturally occurring antitumourꢀantibiotic lavendamycin (1, Figure 1) from the
fermentation broth of streptomyces lavendulae strain C22030 as a dark red solid.5 Subsequently,
its structure was elucidated as a pentacyclic quinone by Balitz and coꢀworkers by means of
analytical and spectroscopic studies.5 In 1984, first total synthesis of lavendamycin was achieved
by Kende’s et al, via BischlerꢀNapieralski reaction.6 Structurally and biosynthetically,
lavendamycin is related to wellꢀknown antitumor antibiotic streptonigrin alkaloid (2) (Figure 1).7
Lavendamycin and its analogues exhibit promising biological properties such as inhibition of
HIV reverse transcriptase,8a,8b MKN45 gastric carcinoma and WiDr colon carcinoma cells8c as
well as antiproliferative8c and cytotoxicitic9a activities. Lavendamycin exhibits antitumor activity
against topoisomerase I cell with Minimum Inhibitory Concentration (MIC) of 0.1 ꢁg/mL.9bꢀc
Produced in a challenging atmosphere and importantly for its biological significance,
lavendamycin and its analogues have stimulated the interest of synthetic community. They have
been the target of various groups with extensive synthetic efforts.6,10
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H3C
COOH
N
COOH
H3C
E
HO
C
D
N
N
N
O
N
MeO
H
N
H
N
NH2
NH2
N
A
O
MeO
OMe
B
O
NH2
O
2
3
1
Figure 1. Lavendamycin (1), Streptonigrin (2) and Nitramarine (3)
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Some of the other basic methods for the synthesis of lavendamycin methyl ester include
BischlerꢀNapieralski reaction,6,10a PictetꢀSpengler cyclization,10bꢀe Friedlander condensation,10f
azaꢀwittig/electrocyclic ring closure,10g modified Knoevenagel–Stobbe condensation10h and
transition metal catalyzed crossꢀcoupling.10iꢀl The most recent synthetic study by Nissen et al.11 is
rutheniumꢀcatalyzed [2+2+2] cycloaddition of an electronꢀdeficient nitrile to an alkynylꢀ
ynamide. Continuing with our ongoing interest in Povarov reactions,12 we have opted this
strategy as a novel and flexible synthetic route to generate lavendamycin and its analogues with
diverse substitution patterns.
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Results and discussion
Scheme 1. Retrosynthetic analysis for lavendamycin methyl ester.
Our prime target molecule would be a substituted αꢀquinolinylꢀβꢀcarboline 4 as mentioned in
scheme 1, because compound 4 had already been converted into lavendamycin methyl ester.10a
We envisioned that the compound 4 would derive from αꢀformylꢀβꢀcarboline 5 (CDE ring) and
aniline 6 (A ring) via Povarov reaction with nꢀbutylvinyl ether (7) to construct ring B.
The compound 5 & 13 (CDE ring) were prepared from racꢀthreoꢀβꢀmethyltryptophan esters (8
& 8a) (Scheme 2) that, in turn, is known to be derived from indole in a three steps sequence.13
PictetꢀSpengler cyclization of tryptophan esters 8 & 8a with dimethoxy acetaledehyde in
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DCM/TFA (rt, 5 h) led to the desired diasteromeric mixtures 9 & 10. Without further
5
6
purification, when the diastereomeric mixtures were subjected to KMnO4 oxidation (DMF, rt), αꢀ
7
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9
Me
CHO
CO2R2
NH2
Me
CO2R2
NH
OMe
MeO
OMe
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DCM, TFA
rt, 5 h
N
N
H
H
rac-threo
MeO
9, R2 = Me
10, R2 = Et
KMnO4
8, R2 = Me
8a, R2 = Et
DMF, rt
2.5 h
Me
Me
N
CO2R2
CO2R2
N
H2O/AcOH (3:2)
70 oC, 0.5 h
N
N
H
H
CHO
OMe
MeO
11, R2 = Me, 81 %
12, R2 = Et, 77 %
5, R2 = Me, 95 %
13, R2 = Et, 95 %
Yields: overall for 2 steps
Scheme 2. Synthesis of compound 5 and 13.
dimethoxymethylꢀβꢀcarbolines (11 & 12) were obtained in good yields and then deprotection of
11 & 12 afforded αꢀformylꢀβꢀcarbolines (5 & 13) in excellent yields. The requisite aniline 6 was
prepared in a four steps sequence which commenced with commercially available 4ꢀ
methoxyphenol (14) (Scheme 3).
OH
OH
OH
KBr, Br2 (1:1)
H2O/AcOH
rt, 1 h
NO2
Br
NO2
HNO3, AcOH
1 h, 70%
95%
OMe
14
OMe
15
OMe
16
CH3I
KOH, Acetone
reflux, 5 h
90%
OMe
OMe
Br
NH2
Fe/AcOH
Br
NO2
reflux, 20 min
93%
OMe
OMe
6
17
Scheme 3. Synthesis of 3ꢀbromoꢀ2,5ꢀdimethoxyaniline (6)
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We started the preliminary investigation using αꢀformylꢀβꢀcarboline (18),14 anline (19)
and nꢀbutylvinyl ether (7) so as to test the feasibility of this approach (Table 1). The first
experiment was performed in refluxing ethanol and in presence of BF3.OEt2 affording the
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Table 1. Optimization of reaction conditions.
CO Me
2
CO Me
2
NH
N
2
OBu
N
N
+
+
N
catalyst
solvent
H
CHO
N
H
18
19
7
20
Yield (%)a
Entry
Condition
Time(h)
trace
28
22
12
72
65
68
55
51
75
61
45
89
89
82
1
2
BF3. OEt2 (10 mol %) /ethanol
BF3. OEt2 (10 mol %) /ethanol
Cu(OTf)2 (10 mol %) / CH3CN
Ag(OTf) (10 mol %) / CH3CN
La(OTf)3 (10 mol %) / CH3CN
La(OTf)3 (10 mol %) / dioxane
La(OTf)3 (10 mol %) / toluene
Sc(OTf )3 (10 mol %) / CH3CN
Yb(OTf)3 (10 mol %)/ CH3CN
I2 (10 mol %) / CH3CN
24
24
24
24
20
20
32
20
18
12
15
20
12
24
24
3
4
5
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7
8
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10
11
12
13
14
15
I2 (10 mol %) / CH3OH
I2 (10 mol %)/ toluene
I2 (10 mol %) / THF
I2 (20 mol %) / THF
I2 (5 mol %)/ THF
General conditions. Aldehyde (18) 0.25 mmol, aniline (19) 0.25 mmol and vinyl ether (7)(0.30 mmol ). a Yield refers to column purified product.
For entry 1, the Povarov reaction between aldehyde (18), aniline (19) and vinyl ether (7) was performed. For entry 2ꢀ15, the Povarov reaction
between isolated aldimine and vinyl ether (7) was performed. The aldimine was prepared by refluxing the aniline and aldehyde in DCM solvent
in the presence of MgSO4 for 1 h. For all entries, reflux temperature of corresponding solvents was maintained.
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desired product 20 in trace amount (Table 1, entry 1). We suspected that the formation of water
during shiff base formation would be deleterious to the reaction. As anticipated, the reaction
between isolated aldimine and nꢀbutylvinyl ether (7) in the same above mentioned conditions
(Table 1, entry 2), afforded the desired product in better yield (Table 1, entry 7). Consequently,
we decided to optimize the reaction conditions only with aldimine and vinyl ether. Soft metal
triflates such as Cu(OTf)2 and Ag(OTf) triggered the reaction with poor yields (Table 1, entries
3&4). In addition, lanthanide triflates such as La(OTf)3, Sc(OTf)3 and Yb(OTf)3 also catalyzed
the reaction with moderate yields (Table 1, entries 5ꢀ9). A satisfactory result was obtained with
10 mol % of I2 in refluxing CH3CN (Table 1, entry 10). With molecular iodine as a good
catalyst, we next proceeded with solvents screening and catalytic loading (Table 1, entries 11ꢀ
15). As shown in the table 1, the best result was obtained using THF as a solvent and 10 mol %
of I2 as a catalyst (Table 1, entry 13).
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Scheme 4. Synthesis of nitramarine alkaloid (3)
Nitramarine (3) (Figure 1) is a αꢀquinolinylꢀβꢀcarboline alkaloid which was isolated from
nitraria komarovii plant by Tulyaganov et al. in 1984.15 It exhibits sleeping time pronging
effect,16a hypotensive and spasmolytic activities.16b However, only few literature reports were
available.16a, 17aꢀc The compound 20 was deꢀesterified using LiOH in MeOH/H2O (3:1) at room
temperature to furnish a 92% yield of compound 45 which was deꢀcarboxylated using the
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reported procedure17b in moderate yield (Scheme 4). The spectroscopic data of synthetic 3 (1H
3
4
5
6
and 13C NMR, LCMS, CHN analysis) were in full accordance with those reported.17c
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CO2Me
Me
CO2Me
Me
N
NH2
i) MgSO4, DCM
reflux, 1 h
OMe
Br
OMe
Br
N
N
N
+
H
ii) nꢀbutylvinyl ether (7)
I2 (10 mol %)
THF, reflux
MeO
CHO
N
H
5
6
4
MeO
6 h, 92%
CO2Et
Me
CO2Et
N
Me
N
NH2
i) MgSO4, DCM
reflux, 1 h
OMe
Br
OMe
Br
N
+
N
H
CHO
ii) nꢀbutylvinyl ether (7)
I2 (10 mol %)
THF, reflux
MeO
N
H
13
6
21
MeO
6 h, 78%
CO2Me
CO2Me
Me
Me
N
N
ref 10a
5 steps
OMe
O
N
N
N
N
H
H
Br
NH2
MeO
O
Lavendamycin methyl ester
4
Scheme 5. Synthesis of compounds 4 & 21: A formal synthesis of lavendmycin methyl
ester.
With the optimized conditions in hand, αꢀformylꢀβꢀcarbolines 5 & 13 and nꢀbutylvinyl
ether (7) were subjected to the Povarov reaction with aniline 6 to give the corresponding
compounds 4 & 21 in excellent yields (Scheme 5). The compound 4 is identical to the Rao’s
intermediate which would be converted into lavendamycin methyl ester from their literature
report.10a
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CO2H
N
CO2Me
CO2Me
Me
Me
Me
N
N
3 steps
2 steps
O
OMe
Br
O
N
N
N
N
N
N
H
H
H
NH2
Br
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Lavendamycin (1)
22
4
O
MeO
O
Rao et al strategy
Oxidation
one step
Detosylation
one step
CO2Et
Me
CO2Et
Me
CO2Me
N
Me
Oxidation
one step
N
N
O
N
N
OMe
NHTs
N
OH
N
N
H
N
H
NHTs
H
Br
Our strategy
O
Our strategy
23
24
25
MeO
MeO
Scheme 6. Synthetic plan to reduce the steps reported in the literature.10a
However, the conversion of the compound 4 to lavendamycin methyl ester was tedious
and not in good yields. At this juncture, our endeavor was to modify the synthetic route
attempted in the literature10a (Scheme 6). We envisioned that replacing the Br group at Cꢀ7
position of compound 4 with amino group (Scheme 6) could perhaps favor the oxidation step.
Such a strategy, if successful, would be able to provide an intermediate 23, which in turn, could
easily be converted into lavendamycin ester (1), thereby reducing the 3 steps10a (Scheme 6).
Intermediate 24 was envisaged to be derived from αꢀformylꢀβꢀcarboline (5 or 13) and 3ꢀ
aminoꢀ2,5ꢀdimethoxyꢀ1ꢀ(4ꢀmethylphenylsulfonamido)benzene (28). To examine this hypothesis,
attempts were initiated to synthesize the aniline 28 which was constructed via a three steps
sequence starting with 4ꢀmethoxyꢀ2,6ꢀdinitrophenol (Scheme 7).
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Scheme 7. Synthesis of 3ꢀaminoꢀ2,5ꢀdimethoxyꢀ1ꢀ(4ꢀmethylphenylsulfonamido)benzene (28).
CO2Et
Me
OMe
CO2Et
N
Me
i) MgSO4, DCM
reflux, 1 h
N
TsHN
NH2
+
OMe
NHTs
N
N
ii) nꢀbutylvinyl ether
I2 (10 mol %)
THF, reflux
H
CHO
N
OMe
H
28
13
24
14 h, 72%
MeO
CO2Me
OMe
CO2Me
N
i) MgSO4, DCM
reflux, 1 h
N
TsHN
NH2
+
OMe
N
ii) nꢀbutylvinyl ether
I2 (10 mol %)
THF, reflux
N
H
CHO
N
H
NHTs
OMe
18
28
14 h, 78%
MeO
29
CO2Et
CO2Et
Me
Me
N
N
O
OMe
NHTs
N
N
N
N
H
H
NHTs
O
MeO
23
24
Scheme 8. Synthesis of compounds 24 & 29 and oxidation of 24.
With the requisite aniline 28 in hand, we next attempted the Povarov reactions with αꢀ
formylꢀβꢀcarboline aldehyde 13 & 18 to afford compounds 24 & 29 in good yields (Scheme 8).
Our attempts to oxidize the compound 24 under the conditions (Table 2) failed to deliver the
desired compound 23, however the compound 24 remained unaffected in some of conditions
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(Table 2, entries 1, 5ꢀ10) and recovered from the reaction mixture. Oxidation conditions such as
a higher equivalent of CAN (more than 5 equiv.), higher temperature (entry 3) and the presence
of acid (entries 2&4) led to an unidentified complex reaction mixture. On the other hand, the
Povarov reaction of aldehyde 5 and aniline 30 did not yield the expected intermediate 25
(Scheme 9).
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Table 2. Conditions attempted for the oxidation step.
Scheme 9. Povarov reaction of aldehyde 5 and aniline 30.
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Scheme 10. Revised strategy for lavendamycin ester.
Next, we directed a revised retrosynthetic analysis, as delineated in scheme 10 according
to the literature report.9c We endeavored to attain the intermediate 33 for two reasons: (i) the
Povarov reaction is not working without protection of aminophenol (Scheme 9) and (ii) the
quinolyl carboline, particularly protected with PMB ether (33), could be easily deꢀprotected as
well as oxidized by CAN in a single step to generate compound 31.
Scheme 11. Synthesis of PMBꢀaniline 34.
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The route to synthesize the compound 33 commenced with the preparation of PMB (pꢀ
methoxybenzyl)ꢀprotected aniline 34 which in turn could be accessed from 2ꢀnitrophenol (35) in
a short sequence (Scheme 11). With the aniline 34 in hand, we explored the Povarov reaction of
aldehydes 13 & 18 with aniline 34, giving rise to the compounds 33 and 38 respectively (Scheme
12). But unfortunately, all our efforts to oxidize the compound 33 were abortive under various
conditions with CAN and DDQ (Table 2, entry 1,3,5ꢀ8). Under these conditions, the PMBꢀ
protected compound 33 was stable and could be recovered from the reaction mixture.
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Scheme 12. Synthesis of compounds 33, 38 and 31.
We failed to obtain the quinolinedione 31, despite our extensive efforts in
troubleshooting the oxidation process. Hence, we resolved to synthesize an acylated quinolyl
carboline which had been accounted by Nissen et al. in their recent total synthesis of
lavendamycin methyl ester.11
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CO2Me
N
Me
CO2Me
Me
CO2Me
Me
CHO
N
H
N
N
5
N
Povarov
reaction
ref 11
+
O
OMe
10
11
12
13
14
15
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19
20
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N
N
N
H
OMe
H
NH2
NHCOCH3
H2N
NHCOCH3
1
O
MeO
39
40
OMe
Scheme 13. Revised strategy for the lavendamycin metyl ester.
OMe
OMe
OMe
OMe
Acetyl chloride
O2N
NO2
O2N
NHCOMe
O2N
NH2
Fe/AcOH
60 oC, 2 h
80%
K2CO3
DCM, 2 h
rt, 84%
OMe
OMe
26
42
41
OMe
H2N
NHCOMe
Fe/AcOH
EtOH, reflux
4 h, 92%
40
OMe
Scheme 14. Synthesis of monoacylated aniline 40.
As indicated in the revised retrosynthetic analysis (Scheme 13), for the construction of the
intermediate 39, N1ꢀ(3ꢀaminoꢀ2,5ꢀdimethoxyphenyl)acetamide (40) had to be prepared. Upon
preparation of the requisite aniline 40 (Scheme 14), we proceeded next to the Povarov reaction
between aldehydes (5 & 18) and the aniline 40 (Scheme 15) which afforded the expected βꢀ
carbolines (39 & 43) in good yields, thereby completing the formal synthesis of lavendamycin
methyl ester, as the compound 39 could easily be converted into lavendamycin methyl ester in
two steps sequence with excellent yields. The overall yield for our synthetic sequence toward the
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CO2Me
Me
OMe
CO2Me
N
Me
i) MgSO4, DCM
N
H2N
NHCOMe
reflux, 1 h
+
OMe
NHCOMe
N
ii) nꢀbutylvinyl ether (7)
I2 (10 mol %)
N
H
CHO
N
OMe
H
THF, reflux
5
39
40
10 h, 78%
MeO
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CO2Me
OMe
CO2Me
N
i) MgSO4, DCM
reflux, 1 h
N
H2N
NHCOMe
+
OMe
NHCOMe
ii) nꢀbutylvinyl ether (7)
I2 (10 mol %)
THF, reflux
N
N
H
CHO
N
H
OMe
8 h, 81%
18
40
43
MeO
CO2Me
Me
CO2Me
Me
CO2Me
N
Me
N
N
ref 11
DIB
ref 11
O
N
N
OMe
NHCOMe
N
O
N
H
N
N
H2SO4 / H2O
60 oC, 30 min
97 %
H
NH2
H
CH3CN / H2O
88%
NHCOMe
O
MeO
O
39
lavendamycin methyl ester
44
Scheme 15. Synthesis of intermediate 39: A formal synthesis of lavendamycin methyl ester.
compound 39 is 60.02% with respect to methyltryptophan ester 8. Upon completion of the two
reported steps, our synthetic strategy would be able to provide lavendamycin methyl ester at
51.2% overall yield.
Figure 2. ORTEP of compound 20c18
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Table 3. Synthesis of lavendamycin analogues (20, 20aꢀh).
CO2CH3
6
7
8
9
N
CO2 CH3
i) MgSO4, DCM
reflux, 1 h
NH2
R3
N
R3
R4
N
N
+
H
R4
ii) vinylether (7 or 7a)
I2 (10 mol %)
THF, reflux
7ꢀ10 h
R6
CHO
OR7
N
H
R5
R5
10
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12
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18
19
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60
R6
20, 20aꢀh
18
19, 19aꢀh
7 (R7 = Bu)
7a (R7 = Et)
83 ꢀ 94%
Product
Time/Yielda
Product
Time/Yield
Entry
Aniline
Entry
Aniline
a
CO2Me
CO2Me
NH2
N
N
NH2
N
1
N
H
6
H
N
N
OMe
20e, 8 h, 94 %
19
19e
20, 8 h, 89 %
OMe
CO2Me
CO2Me
N
NH2
NH2
N
OMe
N
H
N
H
N
N
OMe
2
F
19f
7
20f, 8 h, 90 %
19a
20a, 10 h, 87 %
F
CO2Me
CO2 Me
NH2
N
NH2
N
N
N
H
H
3
N
N
Cl
Cl
Cl
19g
Cl
8
19b
Cl
20b, 10 h, 85%
Cl
20g, 10 h, 86 %
CO2Me
CO2 Me
N
NH2
NH2
N
N
H
N
H
4
N
N
OMe
Br
19h
OMe
19c
20h, 7 h, 85%
20c, 10 h, 85%
Br
9
CO2 Me
CO2Me
NH2
N
N
NH2
N
H
N
H
N
N
5
10b
Me
20, 10 h, 83%
19
20d, 7 h, 92%
19d
Me
aYield refers to column purified product. For entry 1ꢀ9, nꢀbutylvinyl ether (7) was used. bFor entry 10, ethylvinyl ether (7a) was used.
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Considering the biological importance of lavendamycin analogues and scope of this
methodology, we extended this reaction to different anilines (19, 19aꢀh) and alkylvinyl ethers (7
& 7a), resulting in high yields of corresponding lavendamycin methyl ester derivatives (20, 20aꢀ
h) (Table 3). Aromatic amines contain both electronꢀdonating (Table 3, entries 5ꢀ7, 9) as well as
electronꢀwithdrawing (Table 3, entries 2ꢀ4, 8) groups which tolerated the reaction in excellent
yields. The compound 20 was also synthesized in good yield (83%, Table 2, entry 10) using this
synthetic approach via ethylvinyl ether (7a) instead of nꢀbutylvinyl ether (7). The structure of
compound 20c (Figure 2) was unambiguously confirmed by Xꢀray single crystal analysis.18 The
proposed reaction mechanism is shown in scheme 16.
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Scheme 16. Proposed mechanism for the synthesis of 20.
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Conclusions
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It is noteworthy that all the synthetic steps of this sequence, involved readily available
inexpensive materials to start with and gave good to excellent yields. The formal synthesis of
lavendamycin methyl ester was accomplished using a Povarov approach that featured
inexpensive catalyst with an overall yield of 51.2% to produce the lavenamycin methyl ester.
We have also demonstrated the versatility of this approach toward the synthesis of lavendamycin
analogues (20, 20aꢀh). The synthesized lavendamycin analogue (20) was transformed into 45,
thereby completing the formal synthesis of nitramarine (3).
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Experimental section
General Information
13
1H and CꢀNMR spectra were recorded at 400 and 100 MHz, respectively, or at 500 and 125
1
MHz, respectively. Chemical shifts were calculated in ppm downfield from TMS (δ = 0) for H
13
NMR, and relative to the central CDCl3 resonance (δ =77.0) and DMSOꢀd6 (δ = 39.51) for Cꢀ
NMR. Data presented in the experimental section are as follows: chemical shift, integration,
multiplicity (s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, dd=doublet doublet),
coupling constant in Hertz (Hz). Xꢀray diffraction measurements were carried out at 298 K on an
automated diffractometer using graphiteꢀmonochromated MoꢀKa (l = 0.71073 Å) radiation with
CAD4 software or the Xꢀray intensity data were measured at 298 K on an instrument equipped
with a graphite monochromator and a MoꢀKa fineꢀfocus sealed tube (l = 0.71073 Å). TOF and
quadrupole mass analyzer types are used for the HRMS measurements.
Mass spectral data was obtained from LCꢀMS (ESI). IR spectra were recorded on a FTꢀIR
spectrometer using KBr pellets. Elemental analysis was carried out in CHN analyzer. Melting
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points were measured in open capillary tubes and are uncorrected. All the obtained products
were purified by column chromatography using silica gel (100ꢀ200 mesh). All reaction solvents
used were of GR grade and used without drying unless mentioned. All other commercial
reagents were used as received.
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Methyl 1ꢀdimethoxymethylꢀ4ꢀmethylꢀ9Hꢀβꢀcarbolineꢀ3ꢀcarboxylates (11). To a solution of βꢀ
methyltryptophan ester (8) (500 mg, 2.15 mmol) in dichloromethane (25 mL) were added 60%
wt. solution in water of dimethoxyacetaldehyde (3 mmol) and 98% of TFA (3 mmol). The
reaction mixture was allowed to stir at room temperature for a period of 5 h. The reaction
mixture was concentrated in vacuum and extracted with EtOAc. The organic layer was dried
over anhydrous Na2SO4, concentrated in vacuum and carried forward to the next step without
further purification. To the crude diastereomeric mixture (9, 685 mg, 2.1 mmol) in DMF (20 mL)
was added KMnO4 (3.1 mmol). The reaction mixture was stirred over a period of 2.5 h at room
temperature. The reaction mixture was filtered using Celiteꢀ545 bed. The filterate was
concentrated and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuum. The residue was purified by column chromotography (silicaꢀgel:
hexanes/ethyl acetate = 10:4) to give the desired product 11 as a viscous liquid in 81% yield
1
(overall two steps) (548 mg); IR(KBr): 3366, 3059, 1716, 1215, 798, 746 cmꢀ1; H NMR (400
MHz, CDCl3, TMS) δ: 9.50 (1H, s), 8.26 (1H, d, J = 8.0 Hz), 7.52 (2H, d, J = 3.2 Hz), 7.28ꢀ7.33
(1H, m), 5.71 (1H, s), 3.99 (3H, s), 3.48 (6H, s), 3.11 (3H, s); 13C NMR (100 MHz, CDCl3,
TMS) δ: 167.7, 140.4, 137.7, 136.5, 133.8, 131.5, 129.5, 128.1, 123.8, 121.9, 120.5, 111.9, 106.8
(aromatic C), 54.7, 52.5, 16.6 (aliphatic C); HRMS (ESIꢀMS) calcd. for C17H18N2O4; 315.1345
(M+H), found: 315.1349; LCMS: m/z = 315.20 (M+H), positive mode; Anal. calcd. for: C,
64.96; H, 5.77; N, 8.91 %; found: C, 64.79; H, 5.85; N, 8.96 %.
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Ethyl 1ꢀdimethoxymethylꢀ4ꢀmethylꢀ9Hꢀβꢀcarbolineꢀ3ꢀcarboxylate (12). To a solution of βꢀ
methyltryptophan ester (8a) (500 mg, 2.0 mmol) in dichloromethane (25 mL) were added 60%
wt. solution in water of dimethoxyacetaldehyde (3 mmol) and 98% of TFA (3 mmol). The
reaction mixture was allowed to stir at room temperature for a period of 5 h. The reaction
mixture was concentrated in vacuum and extracted with EtOAc. The organic layer was dried
over anhydrous Na2SO4, concentrated in vacuum and carried forward to the next step without
further purification. To the crude diastereomeric mixture (10, 607 mg 1.83 mmol) in DMF (20
mL) was added KMnO4 (3.0 mmol). The reaction mixture was stirred over a period of 2.5 h at
room temperature. The reaction mixture was filtered using Celiteꢀ545 bed. The filterate was
concentrated and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and
concentrated in vacuum. The residue was purified by column chromotography (silicaꢀgel:
hexanes/ethyl acetate = 10:4) to give the desired product 12 as a viscous liquid in 77% yield
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(overall two steps) (513 mg). IR(KBr): 3360, 2935, 1712, 1213, 1070, 746 cmꢀ1; H NMR (400
MHz, CDCl3, TMS) δ: 9.81 (1H, s), 8.16 (1H, d, J = 8.0 Hz), 7.37ꢀ7.51 (2H, m), 7.21 (1H, t, J =
6.8 Hz), 5.62 (1H, s), 4.44 (2H, q, J = 6.8 Hz), 3.37 (6H, s), 3.06 (3H, s), 1.35 (3H, t, J = 7.2
Hz); 13C NMR (100 MHz, CDCl3, TMS) δ: 167.5, 140.5, 137.8, 137.1, 133.6, 130.6, 129.3,
127.9, 123.5, 121.8, 120.3, 112.0, 106.8 (aromatic C), 61.3, 54.7, 16.6, 14.3 (aliphatic C); HRMS
(ESIꢀMS) calcd. for C18H20N2O4; 329.1501 (M+H), found: 329.1501; LCMS: m/z = 329.35
(M+H), positive mode; Anal. calcd. for: C, 65.84; H, 6.14; N, 8.53 %; found: C, 65.73; H, 6.19 ;
N, 8.45 %.
Methyl 1ꢀformylꢀ4ꢀmethylꢀ9Hꢀβꢀcarbolineꢀ3ꢀcarboxylate (5). In a 150 mL round bottom flask
equipped with a magnetic bar, compound 11 (400 mg, 1.2 mmol) was dissolved in H2O/AcOH
o
(40 mL/32 mL) solvent mixture then the solution was heated at 70 C over a period of 30 min.
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The hot solution was cooled down to room temperature and concentrated under reduced pressure.
The residue was extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated in
vacuum. The title compound 5 was isolated as a pale yellow solid which was carried forward to
further reactions without further purifications. (324 mg, 95%) mp: 160 °C; IR(KBr): 3364, 2920,
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1720, 1441, 1073, 739 cmꢀ1; H NMR (400 MHz, CDCl3, TMS) δ: 10.34 (1H, s), 10.32 (1H, s),
13
8.29 (1H, d, J = 8.0 Hz), 7.63ꢀ7.64 (2H, m), 7.38ꢀ7.42 (1H, m), 4.07 (3H, s), 3.17 (3H, s); C
NMR (100 MHz, CDCl3, TMS) δ: 194.9, 166.9, 141.3, 138.5, 136.2, 135.2, 132.9, 131.1, 129.2,
124.1, 121.8, 121.4, 112.4 (aromatic C), 52.9, 17.2 (aliphatic C); HRMS (ESIꢀMS) calcd. for
C15H12N2O3; 269.0926 (M+H), found: 269.0927; LCMS: m/z = 269.15 (M+H), positive mode;
Anal. calcd. for: C, 67.16; H, 4.51; N, 10.44 %; found: C, 67.25; H, 4.61; N, 10.31 %.
Ethyl 1ꢀformylꢀ4ꢀmethylꢀ9Hꢀβꢀcarbolineꢀ3ꢀcarboxylate (13). In a 150 mL round bottom flask
equipped with a magnetic bar, compound 12 (400 mg, 1.2 mmol) was dissolved in H2O/ AcOH
o
(40 mL/ 32 mL) solvent mixture then the solution was heated at 70 C over a period of 30 min.
The hot solution was cooled down to room temperature and concentrated under reduced pressure.
The residue was extracted with EtOAc, dried over anhydrous Na2SO4 and concentrated in
vacuum. The title compound 7 was isolated as a pale yellow solid which was carried forward to
further reactions without further purifications. (326 mg, 95%). mp: 148 °C; IR(KBr): 3360,
2986, 1707, 1331, 1280, 927, 742 cmꢀ1; H NMR (400 MHz, CDCl3, TMS) δ 10.34 (1H, s),
1
10.30 (1H, s), 8.30 (1H, d, J = 8.0 Hz), 7.64ꢀ7.65 (2H, m), 7.39ꢀ7.43 (1H, m), 4.56 (2H, q, J =
7.2 Hz), 3.16 (3H, s), 1.51 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3, TMS) δ: 195.2,
166.7, 141.3, 139.3, 135.6, 135.2, 133.0, 131.0, 129.2, 124.1, 121.8, 121.5, 112.4 (aromatic C),
61.9, 17.3, 14.4 (aliphatic C); HRMS (ESIꢀMS) calcd. for C16H14N2O3; 283.1082 (M+H), found:
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283.1084; LCMS: m/z = 283.10 (M+H), positive mode; Anal. calcd. for: C, 68.07; H, 5.00; N,
5
6
9.92 %; found: C, 68.15; H, 5.12; N, 9.85 %.
7
8
9
Procedure for the synthesis of 4ꢀmethoxyꢀ2ꢀnitrophenol (15). A round bottom flask equipped
with magnetic stir bar, was charged with 4ꢀmethoxyꢀnitrophenol (14) (500 mg, 4 mmol) and
glacial AcOH (25 mL), then 67% nitric acid was added drop wise and maintaining the internal
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temperature of the flask below 20 C. Upon completion of acid addition, the reaction mixture
was stirred at room temperature for a period of 1 h. The reaction mixture was quenched by
saturated solution of NaHCO3 and extracted with EtOAc. The organic layer was dried over
anhydrous Na2SO4, filtered and concentrated under reduced pressure. The title compound (15)
was purified by column chromotography (silicaꢀgel: hexanes/EtOAc = 10:0.5) (476 mg, yield.
70%). The spectroscopic data of the compound 15 were in full accordance with those
1
reported.19a,19b mp: 80 °C; IR(KBr): 3321, 2831, 1675, 765 cmꢀ1; H NMR (400 MHz, CDCl3,
TMS) δ: 10.31 (1H, s), 7.48 (1H, d, J = 3.2 Hz), 7.20 (1H, dd, J = 3.2 & 9.2 Hz), 7.07 (1H, d, J =
13
9.2 Hz), 3.81 (3H, s); C NMR (100 MHz, CDCl3, TMS) δ: 152.6, 150.0, 132.9, 127.3, 120.9,
105.6 (aromatic C), 55.9 (aliphatic C); LCMS found for C7H7NO4: m/z = 170 (M+H), positive
mode; Anal. calcd. for: C, 49.71; H, 4.17; N, 8.28 %; found: C, 49.65; H, 4.06; N, 8.35 %.
Procedure for the synthesis of 2ꢀbromoꢀ4ꢀmethoxyꢀ6ꢀnitrophenol (16). To a solution of 4ꢀ
methoxyꢀ2ꢀnitrophenol (15) (400 mg, 2.3 mmol), KBr (1 equiv) in H2O (5 mL) and AcOH (15
mL), was added bromine (1 equiv.) in drop wise. After completion of the addition, the reaction
mixture was agitated at room temperature for a period of 1 h. Then, the reaction was quenched
with saturated solution of Na2S2O3.5H2O and extracted with EtOAc. The organic layer was dried
over anhydrous Na2SO4 and concentrated under vacuum. The residue was obtained (557 mg,
95%) as a yellow solid and carried forward to the next step without purification. The
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spectroscopic data of the compound 16 were in full accordance with those reported.20a,20b mp:
3
4
5
6
1
116 °C; IR(KBr): 3244, 3101, 2845, 1711, 1244, 1138, 858, 677 cmꢀ1; H NMR (400 MHz,
7
8
9
CDCl3, TMS) δ: 10.79 (1H, s), 7.50ꢀ7.53 (2H, m), 3.82 (3H, s); 13C NMR (100 MHz, CDCl3,
TMS) δ: 152.2, 147.1, 133.6, 129.8, 113.8, 106.3 (aromatic C), 56.2 (aliphatic C); LCMS found
for C7H6BrNO4: m/z = 246 (MꢀH), negative mode; Anal. calcd. for: C, 33.90; H, 2.44; N, 5.65
%; found: C, 33.85; H, 2.39; N, 5.57 %.
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Procedure for the synthesis of 1ꢀbromoꢀ2,5ꢀdimethoxyꢀ3ꢀnitrobenzene (17). To the solution
of compound 16 (500 mg, 2 mmol), KOH (3 equiv.) in acetone (20 mL) was added CH3I (1.5
equiv.) dropwise. The reaction mixture was heated at reflux temperature of acetone. After
completion of the reaction as indicated by TLC, the reaction mixture was cooled to room
temperature. The reaction mass was concentrated under vacuum and extracted with EtOAc. The
organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The compound 17
(475 mg, 90%) was isolated as a yellow solid and carried forward to the next step without
purification. The spectroscopic data of the compound 17 were in full accordance with those
1
reported.20b,21 mp: 106 °C; IR(KBr): 2854, 1544, 1012, 756 cmꢀ1; H NMR (500 MHz, CDCl3,
TMS) δ: 7.35 (1H, d, J = 3.0 Hz), 7.29 (1H, d, J = 3.0 Hz), 3.97 (3H, s), 3.84 (3H, s); 13C NMR
(125 MHz, CDCl3, TMS) δ: 155.5, 145.0, 144.5, 123.9, 120.2, 109.2 (aromatic C), 62.7, 56.3
(aliphatic C); LCMS found for C8H8BrNO4: m/z = 261 (M+), 262 (M+H), 263 (M+2), positive
mode; Anal. calcd. for: C, 36.67; H, 3.08; N, 5.34 %; found: C, 36.51; H, 3.13; N, 5.28 %.
Procedure for the synthesis of 3ꢀbromoꢀ2,5ꢀdimethoxyaniline (6). To compound 17 (400 mg,
1.5 mmol) in AcOH (20 mL) was added Feꢀpowder (3 equiv.). The reaction mixture was heated
o
at 80 C for a period of 20 min. then cooled to room temperature. The mixture was filtered to
remove iron powder using Celiteꢀ545 bed. The filtrate was concentrated and extracted with
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EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuum. The
compound 3ꢀBromoꢀ2,5ꢀdimethoxyaniline (6) was obtained as a brown viscous oil in 93% yield
and used for further reactions without any purification. The spectroscopic data of the compound
6 were in full accordance with those reported.20b,21,22a,22b IR(KBr): 3463, 3369, 2832, 1616, 1227,
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997, 838 cmꢀ1; H NMR (400 MHz, CDCl3, TMS) δ: 6.31 (1H, d, J = 2.4 Hz), 6.08 (1H, d, J =
13
2.8 Hz), 3.88 (2H, s), 3.63 (3H, s), 3.54 (3H, s); C NMR (100 MHz, CDCl3, TMS) δ: 156.8,
141.5, 138.6, 116.9, 106.9, 101.2 (aromatic C), 59.8, 55.6 (aliphatic C); LCMS found for
C8H10BrNO2: m/z = 231 (M+), 232 (M+H), 233 (M+2), positive mode; Anal. calcd. for: C, 41.40;
H, 4.34; N, 6.04 %; found: C, 41.52; H, 4.31; N, 6.15 %.
A typical procedure for the preparation of methyl 1ꢀ(quinolinꢀ2ꢀyl)ꢀ9Hꢀβꢀcarbolineꢀ3ꢀ
carboxylate 20: In a round bottom flask equipped with a magnetic stirring bar, mixture of 0.3
mmol of αꢀformylꢀβꢀcarboline (18), 0.3 mmol of aniline (19) and 0.5 mmol of anhydrous MgSO4
in 10 mL of dichloromethane was refluxed for 1 h under stirring. The yellow solution was
filtered and the filtrate was concentrated under vacuum. Without purification, the isolated imine
in 10 mL of THF solvent were added 0.32 mmol of nꢀbutylvinyl ether and 10 mol% of I2. The
mixture was refluxed for 8 h. After completion of the reaction, as indicated by the TLC, the
reaction mixture was quenched by saturated solution of Na2S2O3.5H2O, extracted with ethyl
acetate and dried over anhydrous Na2SO4. The solvent was concentrated under the reduced
pressure. Product was purified by column chromatography (silicaꢀgel: hexanes/ethyl acetate =
10:2) to afford 20 (Yield. 89%). mp: 202ꢀ204 °C; IR(KBr): 3364, 3061, 2854, 1712, 1564, 1259,
750 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS) δ: 11.96 (1H, s), 9.04 (1H, d, J = 8.8 Hz), 8.98 (1H,
s), 8.38 (1H, d, J = 8.8 Hz), 8.31 (1H, d, J = 8.4 Hz), 8.26 (1H, d, J = 8.0 Hz), 7.92 (1H, d, J =
8.0 Hz), 7.83 (1H, t, J = 8.0 Hz), 7.75 (1H, d, J = 8.4 Hz), 7.63ꢀ7.69 (2H, m), 7.40 (1H, t, J = 7.6
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Hz), 4.13 (3H, s); 13C NMR (100 MHz, CDCl3, TMS) δ: 166.8, 157.5, 147.2, 141.0, 137.5,
136.9, 136.7, 130.7, 129.8, 129.2, 129.1, 128.1, 128.0, 127.1, 122.0, 121.6, 121.0, 119.7, 118.7,
112.4 (aromatic C), 52.7 (aliphatic C); HRMS (ESIꢀMS) calcd. for C22H15N3O2; 354.1242
(M+H), found: 354.1242; LCMS: m/z = 354.15 (M+H), positive mode; Anal. calcd. for: C,
74.78; H, 4.28; N, 11.89 %; found: C, 74.65; H, 4.21; N, 12.07 %.
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Methylꢀ1ꢀ(7ꢀbromoꢀ5,8ꢀdimethoxyꢀ2ꢀquinolyl)ꢀ4ꢀmethylꢀ9Hꢀβꢀcarbolineꢀ3ꢀcarboxylate (4).
1
mp: 284ꢀ286 °C; IR(KBr): 3346, 1714, 1456, 1082, 1016 cmꢀ1; H NMR (500 MHz, CDCl3,
TMS) δ: 12.42 (1H, s), 8.90 (1H, d, J = 9.0 Hz), 8.67 (1H, d, J = 9.0 Hz), 8.40 (1H, d, J = 8.0
Hz), 7.74 (1H, d, J = 8.5 Hz), 7.66 (1H, dt, J = 0.5 & 7.5 Hz), 7.41 (1H, dt, J = 0.5 & 8.0 Hz),
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7.01 (1H, s), 4.27 (3H, s), 4.11 (3H, s), 4.05 (3H, s), 3.24 (3H, s); C NMR (100 MHz, CDCl3,
TMS) δ: 167.9, 157.8, 151.8, 146.7, 142.0, 141.0, 137.0, 135.9, 134.8, 132.6, 132.1, 130.1,
128.2, 124.1, 122.3, 120.7, 120.5, 118.7, 116.6, 112.2, 108.7 (aromatic C), 61.5, 56.1, 52.5, 16.9
(aliphatic C); HRMS (ESIꢀMS) calcd. for C25H20BrN3O4; 506.0715 (M+H), found: 506.0716;
LCMS: m/z = 507.90 (M+2), positive mode; Anal. calcd. for: C, 59.30; H, 3.98; N, 8.30 %;
found: C, 59.42; H, 3.93; N, 8.45 %.
Ethylꢀ1ꢀ(7ꢀbromoꢀ5,8ꢀdimethoxyꢀ2ꢀquinolyl)ꢀ4ꢀmethylꢀ9Hꢀβꢀcarbolineꢀ3ꢀcarboxylate (21).
mp: 276ꢀ278 °C; IR(KBr): 3342, 2843, 1764, 1034, 754 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS)
δ: 12.34 (1H, s), 8.86 (1H, d, J = 8.8 Hz), 8.63 (1H, d, J = 8.8 Hz), 8.36 (1H, d, J = 8.0 Hz), 7.71
(1H, d, J = 8.0 Hz), 7.63 (1H, t, J = 7.2 Hz), 7.38 (1H, t, J = 7.2 Hz), 6.97 (1H, s), 4.57 (2H, q, J
= 7.2 Hz), 4.25 (3H, s), 4.02 (3H, s), 3.20 (3H, s), 1.56 (3H, t, J = 7.2 Hz); 13C NMR (100 MHz,
CDCl3, TMS) δ: 167.6, 157.8, 151.8, 146.6, 141.9, 141.0, 137.6, 135.8, 134.7, 132.0, 130.0,
128.2, 124.0, 122.3, 120.6, 120.5, 118.6, 116.6, 112.2, 108.6 (aromatic C), 61.5, 61.4, 56.1, 16.9,
14.5 (aliphatic C); HRMS (ESIꢀMS) calcd. for C26H22BrN3O4; 520.0872 (M+H), found:
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520.0870; LCMS: m/z = 520.00 (M+H), positive mode; Anal. calcd. for: C, 60.01; H, 4.26; N,
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8.07 %; found: C, 60.15; H, 4.21; N, 7.96 %.
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Procedure for the synthesis of 1,4ꢀdimethoxyꢀ3,5ꢀdinitrobenzene (26). To a solution of 4ꢀ
methoxyꢀ2,6ꢀdinitrophenol23 (1.00 g, 4.6 mmol) in DMF (20 mL) were added methyliodide (0.99
g, 6.99 mmol), and K2CO3 (1.49 g, 14.03 mmol). The resultant mixture was stirred at room
temperature for 12 h. The reaction mixture was poured into iceꢀcooled water. The solid
precipitate was filtered off and dissolved in EtOAc. The organic layer was dried over Na2SO4
and concentrated under reduced pressure. The compound 26 was obtained as a colorless solid in
92% yield (0.965 g) and used for further reactions without any purification. The spectroscopic
data of the compound 26 were in full accordance with those reported.23,11 mp: 111ꢀ112 °C;
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IR(KBr): 3094, 1416, 1037, 787 cmꢀ1; H NMR (400 MHz, CDCl3, TMS) δ: 7.57 (2H, s), 4.02
(3H, s), 3.92 (3H, s); 13C NMR (125 MHz, CDCl3, TMS) δ: 154.7, 145.7, 141.0, 114.7 (aromatic
C), 65.0, 56.7 (aliphatic C); HRMS (ESIꢀMS) calcd. for C8H8N2O6; 251.0280 (M+Na), found:
251.0280; LCMS: m/z = 229.15 (M+H), positive mode; Anal. calcd. for: C, 42.11; H, 3.53; N,
12.28 %; found: C, 41.25; H, 3.43; N, 12.15 %.
Procedure for the synthesis of 2,5ꢀdimethoxyꢀ1,3ꢀbenzenediamine (27). The dimethoxynitro
compound 26 (0.5 g, 2.19 mmol) was dissolved in AcOH (15 mL) and heated to 80 oC. After 10
min stirring, Fe powder (0.611 g, 10.95 mmol) was added in the reaction mixture. The reaction
mixture was then allowed to 80 oC over 1 h with stirring. After disappearance of starting material
monitored by TLC, the residue was filtered off and extracted with EtOAc. The organic layer was
dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by column
chromatography (silicaꢀgel, hexanes/EtOAc = 100:30) to give the desired product 27 as a viscous
liquid in 86% yield (0.965 g). The spectroscopic data of the compound 27 were in full
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accordance with those reported.24 IR(KBr): 3345, 2876, 1675, 1544, 776 cmꢀ1; H NMR (400
MHz, CDCl3, TMS) δ: 5.77 (2H, s), 3.73 (3H, s), 3.69 (3H, s); 13C NMR (100 MHz, CDCl3,
TMS) δ: 157.0, 140.4, 129.1, 92.1 (aromatic C), 58.8, 55.2 (aliphatic C); LCMS found for
C8H12N2O2: m/z = 169.10 (M+H), positive mode; Anal. calcd. for: C, 57.13; H, 7.19; N, 16.66
%; found: C, 57.26; H, 7.23; N, 16.43 %.
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Procedure
for
the
synthesis
of
3ꢀAminoꢀ2,5ꢀdimethoxyꢀ1ꢀ(4ꢀ
methylphenylsulfonamido)benzene (28). To a solution of compound 27 (0.2 g, 1.19 mmol) in
CH3CN was added tosyl chloride (0.181 g, 0.951 mmol). The reaction mixture was stirred at
room temperature for 30 min and then quenched with water. The aqueous layer was extracted
with EtOAc and dried over Na2SO4. The organic layer was concentrated in vacuo and was
purified by column chromatography (silica gel, hexanes/EtOAc = 10:3) to give the desired
compound 28 (0.203 g, 53%) as a viscous liquid. IR(KBr): 3211, 2425, 1433, 1221, 1024, 744
cmꢀ1; H NMR (400 MHz, CDCl3, TMS) δ: 7.74 (2H, d, J = 7.5 Hz), 7.21 (2H, d, J = 7.3 Hz),
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6.56 (1H, s), 5.98 (1H, s), 3.76 (2H, s), 3.69 (3H, s), 3.42 (3H, s), 2.35 (3H, s); C NMR (100
MHz, CDCl3, TMS) δ: 156.8, 143.9, 140.3, 136.4, 130.9, 130.8, 129.6, 127.2, 97.6, 94.7
(aromatic C), 59.7, 55.4, 21.5 (aliphatic C); LCMS found for C15H18N2O4S: m/z = 323.20
(M+H), positive mode; Anal. calcd. for: C, 55.88; H, 5.63; N, 8.69 %; found: C, 55.68; H, 5.59;
N, 8.81 %.
Ethyl
1ꢀ[5,8ꢀdimethoxyꢀ7ꢀ(4ꢀmethylphenylsulfonamido)ꢀ2ꢀquinolyl]ꢀ4ꢀmethylꢀ9Hꢀβꢀ
carbolineꢀ3ꢀcarboxylate (24). mp: 267ꢀ269 °C; IR(KBr): 3423, 3034, 2834, 2234, 1897, 1327,
867 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS) δ: 12.08 (1H, s), 8.76 (1H, d, J = 8.8 Hz), 8.59 (1H,
d, J = 8.8 Hz), 8.34 (1H, d, J = 7.9 Hz), 7.80 (2H, d, J = 8.1 Hz), 7.62ꢀ7.64 (2H, m), 7.52 (1H, s),
7.34ꢀ7.39 (2H, m), 7.24ꢀ7.27 (1H, m), 4.56 (2H, q, J = 7.0 Hz), 4.05 (3H, s), 3.86 (3H, s), 3.17
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(3H, s), 2.30 (3H, s), 1.55 (3H, t, J = 7.1 Hz); 13C NMR (100 MHz, CDCl3, TMS) δ: 167.6,
157.7, 152.1, 144.4, 141.1, 140.8, 137.7, 136.9, 136.2, 135.6, 134.7, 131.9, 131.8, 130.3, 129.97,
129.9, 128.1, 127.2, 124.0, 122.3, 120.7, 118.1, 117.6, 111.9, 98.1 (aromatic C), 61.9, 61.4, 56.1,
21.5, 16.8, 14.5 (aliphatic C); HRMS (ESIꢀMS) calcd. for C33H30N4O6S; 633.1784 (M+Na),
found: 633.1786; Anal. calcd. for: C, 64.90; H, 4.95; N, 9.17 %; found: C, 64.71; H, 4.86; N,
9.25 %.
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Ethyl
1ꢀ[5,8ꢀdimethoxyꢀ7ꢀ(4ꢀmethylphenylsulfonamido)ꢀ2ꢀquinolyl]ꢀ9Hꢀβꢀcarbolineꢀ3ꢀ
1
carboxylate (29). mp: 284ꢀ286 °C; IR(KBr): 3423, 2639, 1123, 1102, 732 cmꢀ1; H NMR (400
MHz, DMSOꢀd6, TMS) δ: 12.11 (1H, s), 10.29 (1H, s), 9.06 (1H, s), 8.65 (2H, s), 8.50 (1H, d, J
= 7.7 Hz), 7.80ꢀ7.82 (3H, m), 7.69 (1H, t, J = 7.5 Hz), 7.36ꢀ7.42 (3H, m), 7.21 (1H, s), 3.97 (3H,
s), 3.94 (3H, s), 3.86 (3H, s), 2.29 (3H, s); Due to limited solubitity of the compound 29 both in
13
CDCl3 as well as in DMSOꢀd6, we were unable to record C NMR spectrum. HRMS (ESIꢀMS)
calcd. for C31H26N4O6S; 583.1651 (M+H), found: 583.1656; Anal. calcd. for: C, 63.91; H, 4.50;
N, 9.62 %; found: C, 63.85; H, 4.45; N, 9.56 %.
Procedure for the synthesis of 2,4ꢀDibromoꢀ6ꢀnitrophenol (36). A mixture of oꢀnitrophenol
(35) (1.0 g, 7.18 mmol), KBr (0.846 g, 7.18 mmol) in acetic acid/water (10 mL/ 5 mL) was
stirred for 10 min and cooled on ice. Then, 1 mL of con. H2SO4 was added dropwise over a
period of 10 min. Into the ice cooled solution, was added bromine (1.133 g, 7.18 mmol)
dropwise. After the addition, the reaction was left stirring at room temperature for a further 1 h.
After completion of the reaction as indicated by TLC, the reaction was then quenched with
saturated solution of Na2S2O3.5H2O and extracted with EtOAc. The combined organic layers
were dried over Na2SO4 and concentrated in vacuo to yield the desired compound 36 (1.97 g,
93%) as a bright yellow solid. The spectroscopic data of the compound 36 were in full
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accordance with those reported.25a,25b mp: 108ꢀ110 °C; IR(KBr): 3387, 3088, 1704, 1453, 1022,
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675 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS) δ: 11.05 (1H, s), 8.25 (1H, d, J = 2.2 Hz), 7.99 (1H,
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d, J = 2.1 Hz); C NMR (100 MHz, CDCl3, TMS) δ: 151.4, 142.9, 134.4, 126.8, 114.5, 111.5
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(aromatic C); LCMS found for C6H3Br2NO3: 296.05 (M+2), positive mode; Anal. calcd. for: C,
24.27; H, 1.02; N, 4.72 %; found: C, 24.36; H, 1.12; N, 4.85 %.
Procedure for the synthesis of 1,5ꢀDibromoꢀ2ꢀ(4ꢀmethoxybenzyloxy)ꢀ3ꢀnitrobenzene (37).
A solution of compound 36 (1.0 g, 3.39 mmol) and K2CO3 (1.41 g, 10.17 mmol) in 20 mL of
acetone was vigorously stirred whilst adding pꢀmethoxybenzyl bromide (0.812 g, 4.06 mmol).
The reaction mixture was heated at reflux temperature of acetone. Upon completion
(disappearance of starting materials as indicated by TLC), the mixture was quenched with water
and extracted with EtOAc. The combined organic layers were concentrated under reduced
pressure and purified by column chromatography (silicaꢀgel, hexanes/ethylacetate = 10:1) to give
the desired product 37 as a colorless solid (1.48 g, 92%). mp: 105ꢀ107 °C; IR(KBr): 3299, 3099,
1654, 1455, 1287, 876, 653 cmꢀ1; 1H NMR (400 MHz, CDCl3, TMS) δ: 7.90ꢀ7.96 (2H, m), 7.45
13
(2H, d, J = 7.9 Hz), 6.93 (2H, d, J = 7.9 Hz), 5.11 (2H, s), 3.83 (3H, s); C NMR (100 MHz,
CDCl3, TMS) δ: 160.2, 148.5, 145.9, 140.1, 130.8, 127.4, 127.1, 121.3, 116.9, 114.0 (aromatic
C), 76.7, 55.3 (aliphatic C); LCMS found for C14H11Br2NO4: 415.25 (M+1), positive mode;
Anal. calcd. for: C, 40.32; H, 2.66; N, 3.36 %; found: C, 40.38; H, 2.62; N, 3.31 %.
Procedure for the synthesis of 3,5ꢀDibromoꢀ2ꢀ(4ꢀmethoxybenzyloxy)aniline (34). Into a
solution of compound 37 (1.0 g, 2.41 mmol) in 20 mL of acetic acid was added Fe powder
o
(0.672 g, 12.05 mmol) and heated around 65ꢀ70 C. After the completion of the reaction as
indicated by TLC, the reaction mixture was filtered off. The filtrate was quenched with water
and extracted with EtOAc. The combined organic layer was concentrated under reduced pressure
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and purified using column chromatography (silicaꢀgel: hexanes/EtOAc = 10:3) as a colourless
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solid 34 (0.798 g, 86%). mp: 88ꢀ90 °C; IR(KBr): 3455, 2976, 1527, 1235, 987 cmꢀ1; H NMR
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(400 MHz, CDCl3, TMS) δ: 7.42 (2H, d, 8.6 Hz), 7.06 (1H, d, J = 2.2 Hz), 6.93 (2H, d, J = 8.6
Hz), 6.79 (1H, d, J = 2.2 Hz), 4.89 (2H, s), 3.83ꢀ3.85 (5H, m); 13C NMR (100 MHz, CDCl3,
TMS) δ: 159.9, 142.8, 142.3, 130.2, 128.8, 124.3, 118.0, 117.6, 114.1 (aromatic C), 74.1, 55.3
(aliphatic C); HRMS (ESIꢀMS) calcd. for C14H13Br2NO2; 385.9391 (M+H), found: 385.9393;
LCMS: m/z = 385.35 (M+), positive mode; Anal. calcd. for: C, 43.44; H, 3.39; N, 3.62 %; found:
C, 43.52; H, 3.32; N, 3.51 %.
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Methyl 1ꢀ[5,7ꢀdibromoꢀ8(4ꢀmethoxybenzyloxy)ꢀ2ꢀquinolyl]ꢀ9Hꢀβꢀcarbolineꢀ3ꢀcarboxylate
1
(38) mp: 320ꢀ322 °C; IR(KBr): 3432, 3133, 2298, 1723, 1673, 739 cmꢀ1; H NMR (400 MHz,
CDCl3, TMS) δ: 11.64 (1H, s), 8.96 (1H, d, J = 8.5 Hz), 8.89 (1H, s), 8.54 (1H, d, J = 8.5 Hz),
8.14 (1H, d, J = 7.3 Hz), 8.00 (1H, s), 7.49 (2H, d, J = 7.6 Hz), 7.40 (1H, t, J = 6.96 Hz), 7.29ꢀ
7.31 (1H, m), 6.86 (2H, d, J = 7.8 Hz), 6.55 (1H, d, J = 7.8 Hz), 5.20 (2H, s), 4.11 (3H, s), 3.81
13
(3H, s); C NMR (100 MHz, CDCl3, TMS) δ: 166.5, 159.9, 157.9, 151.8, 142.8, 140.9, 136.8,
136.5, 136.4, 133.7, 130.9, 129.8, 128.7, 128.6, 127.5, 121.5, 121.2, 120.9, 119.0, 117.3, 114.2,
113.1 (aromatic C), 75.9, 55.4, 52.7 (aliphatic C); LCMS found for C30H21Br2N3O4: m/z =
647.30 (M+2), positive mode; Anal. calcd. for: C, 55.66; H, 3.27; N, 6.49 %; found: C, 55.76; H,
3.21; N, 6.43 %.
Ethyl
1ꢀ[5,7ꢀdibromoꢀ8(4ꢀmethoxybenzyloxy)ꢀ2ꢀquinolyl]ꢀ4ꢀmethylꢀ9Hꢀβꢀcarbolineꢀ3ꢀ
1
carboxylate (33). mp: 298ꢀ300 °C; IR(KBr): 3011, 2109, 1543, 1109, 621 cmꢀ1; H NMR (500
MHz, CDCl3, TMS) δ: 11.75 (1H, s), 8.97 (1H, d, J = 8.9 Hz), 8.59 (1H, d, J = 8.9 Hz), 8.30
(1H, d, J = 7.9 Hz), 8.03 (1H, s), 7.52 (2H, d, J = 8.7 Hz), 7.40 (1H, dt, J1 = 1.0 & J2 = 7.2 Hz),
7.32 (1H, dt, J1 = 1.0 & J2 = 7.2 Hz), 6.86ꢀ6.89 (2H, m), 6.62 (1H, d, J = 8.2 Hz), 5.24 (2H, s),
29
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