Efficient synthesis of maxonine analogues from N-substituted benzyl-1-formyl-9H-β-carbolines

Article abstract of DOI:10.1002/ejoc.201200068

Acid-catalyzed Pomeranz-Fritsch-type reaction between the acetal group at C-1 and the arene unit of the benzyl group at N-9 in 9-substituted benzyl-1-(dimethoxymethyl)-9H-β-carboline affords fused-β-carbolines that can be readily oxidized to furnish a maxonine-type framework. Mechanistically, the reaction proceeds via a protonated aldehyde as the intermediate, which undergoes attack by the activated arene subunit of the benzyl moiety. On the other hand, the Morita-Baylis-Hillman adducts of 1-formyl-N-substituted benzyl-9H-β-carbolines undergo an efficient P ₂O₅-mediated intramolecular Friedel-Crafts reaction between the secondary hydroxy group and the activated phenyl group of the benzyl subunit to yield fused-β-carbolines. Investigations into the scope of the substrates reveal that the success of the methodology relies on the degree of activation of the phenyl ring. For substrates having less-activated phenyl groups, indolizinoindole derivatives were isolated in moderate yields only. A simple and efficient synthesis of maxonine analogues from N-substituted benzyl 1-formyl-9H-β-carbolines through sequential Pomeranz-Fritsch reaction and oxidation is demonstrated. In an extension of the study, synthesis of new fused β-carbolines has been accomplished by P₂O₅-mediated Friedel-Crafts reaction of the Morita-Baylis-Hillman adducts of these aldehydes.

Full text of DOI:10.1002/ejoc.201200068

FULL PAPER
DOI: 10.1002/ejoc.201200068
Efficient Synthesis of Maxonine Analogues from N-Substituted Benzyl-1-
formyl-9H-β-carbolines[‡]
Samiran Hutait,[a] Subhasish Biswas,[a] and Sanjay Batra*[a]
Keywords: Nitrogen heterocycles / Fused-ring systems / Natural products / Alkylation
Acid-catalyzed Pomeranz–Fritsch-type reaction between the
acetal group at C-1 and the arene unit of the benzyl group
at N-9 in 9-substituted benzyl-1-(dimethoxymethyl)-9H-β-
9H-β-carbolines undergo an efficient P2O5-mediated intra-
molecular Friedel–Crafts reaction between the secondary hy-
droxy group and the activated phenyl group of the benzyl
carboline affords fused-β-carbolines that can be readily oxid- subunit to yield fused-β-carbolines. Investigations into the
ized to furnish a maxonine-type framework. Mechanistically,
the reaction proceeds via a protonated aldehyde as the inter-
mediate, which undergoes attack by the activated arene sub-
unit of the benzyl moiety. On the other hand, the Morita–
Baylis–Hillman adducts of 1-formyl-N-substituted benzyl-
scope of the substrates reveal that the success of the method-
ology relies on the degree of activation of the phenyl ring.
For substrates having less-activated phenyl groups, indoliz-
inoindole derivatives were isolated in moderate yields only.
synthesis of the maxonine-type framework by using the
MBH derivatives of N-substituted benzyl-1-formyl-9H-β-
carboline. As illustrated in the retrosynthetic plan, genera-
tion of a carbocation at the benzylic position in the pres-
ence of acid followed by intramolecular Friedel–Crafts (FC)
alkylation (route A) would afford desired product I
(Scheme 1). Alternatively, Lewis acid catalyzed generation
of the carbocation at the allylic position followed by intra-
molecular FC alkylation (route B) would result in new
fused-β-carboline system II. Intramolecular FC reactions in
MBH adducts by both routes are widely reported.[9,10]
Introduction
Fused-β-carbolines are well represented in naturally oc-
curring alkaloids[1] and are endowed with a variety of bio-
logical properties.[2] Given such importance, the synthesis
of fused-β-carbolines has been and continues to be of sig-
nificant interest to synthetic chemists.[3] In a project di-
rected towards the formulation of strategies for the con-
struction of fused-β-carbolines, we are engaged in the syn-
thesis of mimics of fused-β-carboline-based natural prod-
ucts employing substituted 1-formyl-9H-β-carboline as the
starting material.[4] Fortunately, we were able to harness this
template for the synthesis of canthin-6-one, canthine, harm-
icine, and fascaplysin skeletons by using Morita–Baylis–
Hillman (MBH) chemistry.[5] Additionally, from this alde-
hyde we could realize successfully the synthesis of a variety
of fused-β-carboline-based heterocycles through cycload-
dition, ene–carbonyl, and multicomponent reactions.[6]
Maxonine, a pentacyclic alkaloid, is a fused-β-carboline de-
rivative that was isolated from Simira maxonii and first re-
ported in 1989 (Figure 1).[7] Kelly et al. in 1993 disclosed
the correct structure of this alkaloid and successfully
achieved its total synthesis.[8] Since then there has been a
lack of literature pertaining to maxonine. Continuing with
our efforts to prepare mimics of fused-β-carboline-based
natural products, it occurred to us that we can achieve the
Figure 1. Maxonine, the pentacyclic β carboline-based alkaloid.
In addition, there are reports of several other cycliza-
tions, wherein the benzylic alcohols served as substrates in
intramolecular FC alkylation reactions under the influence
of Lewis acids.[11] Even during the course of this work, Lau-
tens et al. reported a novel Lewis acid mediated intramolec-
ular FC alkylation involving the benzylic hydroxy group
and phenyl group in tetralins.[12] Interestingly, during our
study we discovered that treatment of N-substituted benzyl-
9H-1-(dimethoxymethyl)-β-carbolines with acid for the
preparation of N-substituted aldehydes for the MBH reac-
[‡] CDRI Communication No. 8205
[a] Medicinal and Process Chemistry Division,
CSIR-Central Drug Research Institute,
P. O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405
E-mail: batra_san@yahoo.co.uk
s_batra@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200068.
Eur. J. Org. Chem. 2012, 2453–2462
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Hutait, S. Biswas, S. Batra
FULL PAPER
that were different from expected aldehydes 9a and 9b.
Spectroscopic analysis of products led us to establish them
as fused β-carbolines 14a and 14b. This result may be ra-
tionalized on the basis of a Pomeranz–Fritsch-type reaction
between the acetal group and the activated arene in the
presence of acid.[13] However, in order to explain the syn-
thesis of fused system 14a and 14b only in case of 4a and
4b, it is presumed that the reactive site in the phenyl ring of
4a and 4b is highly activated due to the +R effect of the
two methoxy groups present at the ortho and para positions.
Essentially, this facilitates attack of the arene ring to the
oxonium ion generated in the presence of AcOH. Com-
pared to this, amongst other analogues investigated, al-
though 2a and 2b have similar effects, the presence of an-
other methoxy group in the phenyl ring that is meta to the
reactive site deactivates the arene unit because of its –I ef-
fect. Henceforth, we considered exploring stronger acids to
achieve intramolecular cyclization in other substrates.
Therefore, in a model study 2a was treated with several ac-
ids under different conditions. We were delighted to note
that treatment of 2a with TFA/H2O (100:1) at room tem-
perature for 48 h resulted in product 12a. Mechanistically,
the Pomeranz–Fritsch-type intramolecular reaction was an-
ticipated to proceed either through sequential partial hy-
drolysis of the acetal group and attack of the arene on the
generated activated carbon, or through complete hydrolysis
Scheme 1. Retrosynthetic scheme illustrating the two possibilities
for the formation of fused β-carbolines from MBH derivatives by
an intramolecular FC reaction.
tion results in the formation of fused-β-carbolines through
a Pomeranz–Fritsch-type reaction in one pot. Further, we
found that in our hands the Brønsted or Lewis acids were
unsuccessful in executing the intramolecular FC alkylation,
but P2O5 worked efficiently to promote the desired reaction
to furnish the fused β-carbolines. The interesting results of
this study are disclosed herein.
Results and Discussion
For performing the MBH reaction, the first objective was
to prepare the required N-substituted benzyl-1-formyl-9H-
β-carbolines. The present study therefore commenced with
installing of the benzyl group containing an activated
phenyl ring at the N-9 of C-1-(dimethoxymethyl)-9H-β-
carbolines 1a and 1b, which in turn were prepared following
the reported procedure.[5a,5b] Considering the fact that elec-
tronically rich arene units are more suited for the FC reac-
tion, we decided to install benzyl groups at the N-9 posi-
tion, wherein the phenyl ring bears methoxy or methyl-
enedioxy groups as substituents. For the purpose of optimi-
zation, initially 3,4,5-trimethoxybenzyl bromide was pre-
pared and treated with 1a in the presence of Cs2CO3 in
DMF at room temperature. The reaction was complete in
1 h and smoothly yielded 1-(dimethoxymethyl)-9-(3,4,5-tri-
methoxybenzyl)-9H-β-carboline (2a). In the next step, the
acetal group of 2a was hydrolyzed in the presence of AcOH/
H2O (2:3) as per the reported protocol.[5a] As expected, the
reaction furnished required aldehyde 7a in 90% yield
(Scheme 2). With the optimized conditions in hand, we pro-
ceeded with the preparation of different starting materials.
Several benzyl bromides containing electron-donating sub-
stituents in the phenyl ring were prepared and treated with
1a and 1b in the presence of Cs2CO3 in DMF to afford
respective products 2a–6a and 2b–6b in excellent yields.
Subsequently, compounds 2a–6a and 2b–6b were depro-
tected with AcOH/H2O. Whereas compounds 2a, 2b, 3a, 3b,
5a, 5b, 6a, and 6b afforded the corresponding N-substituted
benzyl-1-formyl-9H-β-carbolines 7a, 7b, 8a, 8b, 10a, 10b,
Scheme 2. Reagents and conditions: (a) Substituted benzyl brom-
ide, Cs2CO3, DMF, r.t., 1 h; (b) AcOH/H2O (2:3), 90 °C, 45 min;
11a, and 11b, compounds 4a and 4b resulted in products (c) TFA/H2O (100:1), r.t., 48–96 h.
2454 Eur. J. Org. Chem. 2012, 2453–2462
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Efficient Synthesis of Maxonine Analogues
of the acetal to afford the aldehyde first, which then forms ence of DABCO were performed. For the purpose of opti-
an oxonium ion that is attacked by the electron-rich arene mization, 7a was treated with acrylonitrile (A) in the pres-
system. To investigate the suggested possibilities experimen- ence of DABCO to afford MBH adduct 7aA in 88% yield.
tally, in a representative experiment 7a was treated with In order to accomplish the intramolecular FC alkylation in
TFA/H2O. After 24 h, the reaction was complete and 7aA, several reagents that have been reported in the litera-
yielded product 12a. The formation of 12a from 7a proved ture for analogous reactions were evaluated, and the results
that the reaction proceeded through formation of a proton- of the study are compiled in Table 1.[15] We failed to achieve
ated aldehyde as the intermediate. Additionally, during the desired cyclization under the influence of Brønsted or
careful monitoring of the reaction of 2a with TFA/H2O by Lewis acids. Basavaiah et al. reported the P2O5-mediated
TLC, initially the spot for aldehyde 7a was present, but it intramolecular FC alkylation in MBH adducts for prepar-
slowly disappeared to afford product 12a, which suggested ing indenes.[10a] Taking a cue from this report we evaluated
that a cascade sequence was operating.
the reaction of 7aA with P2O5 in dichloromethane at room
In view of these results we proceeded to test the scope of temperature. Fortunately, the reaction was complete in 1 h
the substrates and therefore acetals 2b, 3a, 3b, 5a, 5b, 6a, to yield a major product in 85% yield, which was delineated
and 6b were treated with TFA/H2O. It was pleasing to note to be required fused-β-carboline 19aA. Although Basavaiah
that all substrates produced respective fused-β-carbolines et al. suggested the formation of indene through electro-
12b, 13a, 13b, 15a, 15b, 16a, and 16b in 79–91% yield, cyclic ring closure, we speculate that the formation of the
though the time to reach completion of the reaction varied. product in our case proceeds through an SN2-type reaction.
We found that product 16b afforded from 6b started to dis- As reported,[16] it is assumed that in the first step the phos-
integrate when subjected to column chromatography for pu- phate ester is formed by the reaction of the N-substituted
rification, though no reason could be assigned for this un- MBH adduct with P2O5 (exists as P4O10). Subsequently,
usual behavior. In order to ascertain that the intramolecular this phosphate ester, which is a nice leaving group, can be
reaction is restricted to the phenyl ring carrying the elec- eliminated by either route I, II, or III (Figure 2). To explain
tron-donating substituents, we investigated a similar reac- the formation of 19aA, we presume that elimination by
tion of 9-benzyl-1-(dimethoxymethyl)-9H-β-carboline with route I predominates.
TFA/H2O.[14] However this substrate failed to undergo a
similar transformation and the corresponding aldehyde was
the sole product.
Table 1. Optimization of the conditions for achieving the intramo-
lecular FC alkylation in MBH adduct.[a]
To demonstrate the usefulness of compounds 12–16 for
obtaining the maxonine-type product in a model reaction,
12a was subjected to activated MnO2-mediated oxidation in
the presence of dichloromethane at room temperature. The
reaction was complete in 2 h and afforded oxidized product
17 in 92% yield (Scheme 3).
Entry
Catalyst
Solvent
Temp.
[°C]
Time
[h]
Yield
[%]
1
2
3
4
5
6
7
8
9
PPA
MeSO3H
H2SO4
silica H2SO4 CH2Cl2
Yb(OTf)3
PTSA
FeCl3·6H2O
BF3·Et2O
P2O5
–
r.t.
r.t.
r.t.
r.t.
90
r.t.
r.t.
r.t.
r.t.
12
3
2
3
3
6
10
2
1
2
–
–
–
–
–
–
85
CH2Cl2
CH2Cl2
MeCN
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Scheme 3. Reagents and conditions: (a) MnO2, CH2Cl2, r.t., 2 h.
Because the synthesis of aldehydes 9a and 9b could not
be achieved by the general route, an alternate procedure
was sought to synthesize them. Towards this goal, com-
pounds 1a and 1b were initially transformed into aldehydes
18a and 18b, which were then treated with 3,5-dimethoxy-
1
[a] All reactions were investigated by using 0.5 mmol of 7aA.
Next, we decided to test the scope of our protocol with
benzyl bromide in the presence of Cs2CO3 in DMF to af- MBH adducts 7aA–D; 7bA,C; 8aA,B; 8bB; 9aA–C; 9bA,B;
ford desired products 9a and 9b, respectively (Scheme 2). 10aA–C; and 11aA,B generated from the corresponding al-
With the required aldehydes in hand, in the next stage of dehydes and the appropriate alkenes, and the results of this
the study we focused on our original objective of accomp- study are presented in Table 2.
lishing the intramolecular FC alkylation in the MBH ad-
Substrates originating from tryptophan (a series) were
ducts. Accordingly, the MBH reactions of aldehydes 7a, 7b, fast reacting compared to those originating from trypt-
8a, 8b, 9a, 9b, 10a, and 11a with alkenes A–D in the pres- amine (b series). MBH adducts 7–9 and 11 afforded the
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2455

S. Hutait, S. Biswas, S. Batra
FULL PAPER
were moderate only. Formation of 23, however, could be
explained on the basis of a reaction proceeding through
route III (Figure 2).
Mechanistic considerations provided a basis to investi-
gate the fate of substrate 24 originating from the MBH re-
action between 7a and cyclohexene-2-one. It was found that
the reaction of 24 with P2O5 under similar conditions re-
sulted in the formation of product 25 in 91% yield
(Scheme 4). The formation of 25 can again be explained by
route III. In this case, due to the conjugation of the double
bond with the keto group, the substrate becomes highly ac-
tivated resulting in preferential attack of the lone pair of
electrons on the nitrogen at this double bond.
Figure 2. Plausible mechanism for the FC reaction in MBH deriva-
tives.
respective fused-β-carbolines 19–22. Whereas reactions of
substrates 11aA,B incorporating
a 3,4-methylenedioxy
phenyl group were sluggish to afford products 22aA,B in
more than 48 h of heating, substrates 10aA–C bearing only
a 3-methoxy group in the phenyl ring yielded products
Scheme 4. Reagents and conditions. (a) Cyclohex-2-enone,
23aA–C. The yields of compounds belonging to series 23 DABCO, r.t., 24 h; (b) P2O5, dry CH2Cl2, r.t., 5 h.
Table 2. Results of the FC reaction of several MBH adducts.
Reactant
R
R1
R2
R3
EWG
Time
[h]
Product
Yield
[%]
7aA
7aB
CO2Me
CO2Me
CO2Me
CO2Me
H
OMe
OMe
OMe
OMe
OMe
OMe
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
CN
CO2Me
CO2Et
CO2nBu
CN
CO2Et
CN
CO2Me
CO2Me
CN
CO2Me
CO2Et
CN
CO2Me
CN
CO2Me
CN
CO2Me
CO2Et
1
1
1
1
2
2
3
3
4
3
3
3
3
19aA
19aB
19aC
19aD
19bA
19bC
20aA
20aB
20bB
21aA
21aB
21aC
21bA
21bB
22aA
22aB
23aA
23aB
23aC
85
80
81
81
83
79
85
81
79
81
82
80
82
78
72
78
45
47
52
7aC
7aD
7bA
7bC
8aA
8aB
8bB
9aA
9aB
9aC
9bA
9bB
11aA
11aB
10aA
10aB
10aC
H
CO2Me
CO2Me
H
CO2Me
CO2Me
CO2Me
H
H
H
OMe
OMe
OMe
OMe
OMe
H
H
H
H
H
H
4
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
OCH2O
OCH2O
48
96
8
19
17
H
H
H
OMe
OMe
OMe
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Eur. J. Org. Chem. 2012, 2453–2462

Efficient Synthesis of Maxonine Analogues
(0.30 g, 1 mmol) in dry DMF (3 mL) was added Cs2CO3 (0.46 g,
1.4 mmol) at room temperature. After 15 min, 3,4,5-trimethoxyb-
enzyl bromide (0.36 g, 1.4 mmol) was added dropwise, and the re-
action mixture was stirred for an additional 1 h at the same tem-
perature. Upon completion of the reaction as monitored by TLC,
the contents were poured into water (25 mL) whilst stirring with a
glass rod. The resulting suspension was filtered, and the solid resi-
due was washed with hexane (10 mL) and dried in a desiccator over
P2O5 under vacuum to obtain 2a (0.45 g, 94%) as a yellowish white
solid.
At this point of the study it was considered essential to
investigate whether simple alcohols, which can be readily
generated by the reduction of the formyl group, can partici-
pate in the FC alkylation under the influence of Lewis acids
or P2O5. Accordingly, 7a was treated with NaBH4 in MeOH
to successfully afford corresponding alcohol 26 (Scheme 5).
Subsequently, FC reaction of 26 with several Lewis acids
[FeCl3, In(OTf)3, Sc(OTf)3, ZnBr2, BF3·Et2O] and P2O5 was
investigated, but unfortunately the reaction was unsuccess-
ful.
Methyl 1-(Dimethoxymethyl)-9-(3,4,5-trimethoxybenzyl)-9H-β-
carboline-3-carboxylate (2a): M.p. 101–102 °C; Rf = 0.56 (hexanes/
EtOAc, 60:40). IR (KBr): ν = 1718 (CO CH ) cm–1. 1H NMR
˜
2
3
(300 MHz, CDCl3): δ = 3.41 (s, 6 H, 2 OCH3), 3.65 (s, 6 H, 2
OCH3), 3.80 (s, 3 H, OCH3), 4.06 (s, 3 H, CO2CH3), 5.74 (s, 1 H,
CH), 6.04 (s, 2 H, NCH2), 6.25 (s, 2 H, ArH), 7.34–7.38 (m, 2 H,
ArH), 7.55 (t, J = 7.6 Hz, 1 H, ArH), 8.22 (d, J = 7.8 Hz, 1 H,
ArH), 8.95 (s, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ =
50.2, 52.7, 55.5, 56.0, 60.8, 103.2, 109.3, 111.6, 118.4, 121.1, 121.2,
121.7, 129.1, 131.2, 133.9, 135.7, 136.2, 136.8, 141.1, 142.8, 153.3,
166.4 ppm. MS (ESI+): m/z = 481.1 [M + H]+. HRMS (ESI): calcd.
for C26H29N2O7 [M + H]+ 481.1975; found 481.1978.
Scheme 5. Reagents and conditions (a) NaBH4, MeOH, r.t.,
20 min; (b) Lewis acid, CH2Cl2, reflux, 24 h.
General Procedure for the Synthesis of 12,13, 15, and 16 By Using
TFA and Water, as Exemplified by 12a: A mixture of 2a (0.48 g,
1 mmol), trifluoroacetic acid (7.5 mL), and water (0.07 mL) was
stirred at room temperature for 48 h. After completion of the reac-
tion as monitored by TLC, TFA was removed under reduced pres-
sure. After neutralization with a saturated solution of NaHCO3,
the contents were extracted with ethyl acetate (2ϫ20 mL). Then
the pooled organic layer was dried with anhydrous Na2SO4 and
concentrated under reduced pressure to obtain a yellow oil as a
crude product. The crude product was purified by column
chromatography (silica gel hexanes/EtOAc, 70:30) to afford 12a
(0.37 g, 85%) as a yellow solid.
Conclusions
In summary, we have demonstrated a new application of
substituted 1-formyl-9H-β-carboline for the synthesis of
maxonine analogues. The pentacyclic products could be
achieved either directly from the N-substituted aldehyde by
an acid-catalyzed Pomeranz–Fritsch-type process or from
MBH adducts by using a P2O5-catalyzed FC reaction. Al-
though the process works only with activated arenes, it may
be considered to be an efficient route to maxonine variants. Methyl 3,4,5-Trimethoxy-6-hydroxy-1,6-dihydro-7,13b-diazabenzo-
[5,6]cyclohepta[1,2,3-jk]fluorene-8-carboxylate (12a): M.p. 132–
Further work on developing a library of new maxonine-
based compounds for bioevaluation is underway in our lab-
oratory.
134 °C; R = 0.47 (hexanes/EtOAc, 55:45). IR (KBr): ν = 1734
˜
f
(CO2CH3), 3286 (OH) cm–1. 1H NMR (300 MHz, CDCl3): δ =
3.83–3.90 (m, 12 H, 3 OCH3 and CO2CH3), 4.02 (br. s, 1 H, OH),
5.25 (d, J = 13.8 Hz, 1 H, NCHH), 6.36 (d, J = 13.7 Hz, 1 H,
NCHH), 6.76 (s, 1 H, CH), 6.81 (s, 1 H, ArH), 7.33–7.38 (m, 1 H,
ArH), 7.68–7.70 (m, 2 H, ArH), 8.17 (d, J = 7.8 Hz, 1 H, ArH),
8.75 (s, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3/[D6]DMSO):
δ = 46.8, 51.6, 55.6, 60.2, 61.5, 69.0, 110.0, 110.3, 117.4, 120.0,
120.2, 121.4, 126.9, 128.2, 129.9, 135.0, 135.4, 140.5, 141.4, 145.1,
150.8, 152.4, 165.7 ppm. MS (ESI+): m/z = 435.1 [M + H]+.
HRMS (ESI): calcd. for C24H23N2O6 [M + H]+ 435.1556; found
435.1561.
Experimental Section
General Methods: Melting points were determined in capillary
tubes with a Precision melting point apparatus containing silicon
oil. IR spectra were recorded by using a Perkin–Elmer’s RX I FTIR
spectrophotometer. 1H NMR and 13C NMR spectra were recorded
either with a Bruker DPX-200 or Bruker Avance DRX-300 FT
spectrometer by using TMS as an internal standard. MS (ESI) were
recorded with a Micromass Quadro-II LCMS system, whereas MS
(EI) were recorded with a JEOL JMS600H mass spectrometer.
HRMS (ESI) were recorded with an Agilent 6520 Q-TOF, LC–MS/
MS mass spectrometer. Elemental analyses were performed with a
Carlo Erba 108 or an Elementar Vario EL III microanalyzer. The
room temperature varied between 20 and 35 °C. All the solvents
and chemicals were used as procured from the suppliers. Com-
pounds 7bA, 8bB, and 9bA decomposed on standing so they were
immediately subjected to reactions without any purification.
Hence, the spectral characterization for these compounds was not
performed. The spectroscopic data for compound 16 is of the crude
product, as it disintegrated during purification.
3,4,5-Trimethoxy-1,6-dihydro-7,13b-diazabenzo[5,6]cyclohepta-
[1,2,3-jk]fluoren-6-ol (12b): Yield: 79 %; white solid; m.p. 193–
195 °C; R = 0.40 (hexanes/EtOAc, 60:40). IR (KBr): ν = 3428
˜
f
(OH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.84 (s, 3 H, OCH3),
3.87 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3), 5.24 (d, J = 13.8 Hz, 1
H, NCHH), 6.28 (d, J = 13.7 Hz, 1 H, NCHH), 6.68 (s, 1 H, CH),
6.76 (s, 1 H, ArH), 7.28–7.31 (m, 1 H, ArH), 7.64–7.66 (m, 2 H,
ArH), 7.88 (d, J = 5.2 Hz, 1 H, ArH), 8.12 (d, J = 7.8 Hz, 1 H,
ArH), 8.27 (d, J = 5.2 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3/[D6]DMSO): δ = 47.1, 55.7, 60.3, 61.6, 69.4, 108.9, 109.8,
114.3, 118.9, 120.1, 121.2, 127.2, 127.8, 128.5, 129.8, 133.5, 136.8,
140.0, 141.5, 145.1, 150.9, 152.3 ppm. MS (ESI+): m/z = 377.2 [M
+ H]+. HRMS (ESI): calcd. for C22H21N2O4 [M + H]+ 377.1501;
found 377.1496.
General Procedure for the Synthesis of Compounds 2–6, as Exem-
plified by Compound 2a: To a stirred solution of compound 1a
Eur. J. Org. Chem. 2012, 2453–2462
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2457

S. Hutait, S. Biswas, S. Batra
FULL PAPER
Methyl 3,4-Dimethoxy-6-hydroxy-1,6-dihydro-7,13b-diazabenzo-
CDCl3): δ = 3.78 (s, 3 H, OCH3), 4.02 (s, 3 H, CO2CH3), 5.50 (d,
[5,6]cyclohepta[1,2,3-jk]fluorene-8-carboxylate (13a): Yield: 88 %; J = 14.2 Hz, 1 H, NCHH), 5.67 (d, J = 14.4 Hz, 1 H, NCHH),
white solid; m.p. 205–207 °C; Rf = 0.41 (hexanes/EtOAc, 70:30). IR 6.61 (s, 1 H, CH), 6.88–7.00 (m, 2 H, ArH), 7.35–7.38 (m, 1 H,
(KBr): ν = 1717 (CO CH ), 3415 (OH) cm–1. 1H NMR (300 MHz, ArH), 7.66–7.80 (m, 3 H, ArH), 8.14 (d, J = 7.7 Hz, 1 H, ArH),
˜
2
3
CDCl3/[D6]DMSO): δ = 3.76 (s, 3 H, OCH3), 3.78 (s, 3 H, OCH3), 8.74 (s, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 47.9,
3.93 (s, 3 H, CO2CH3), 5.71 (d, J = 13.6 Hz, 1 H, NCHH), 5.98 52.6, 55.5, 74.1, 109.5, 113.3, 116.1, 118.0, 120.8, 121.0, 121.9,
(d, J = 13.8 Hz, 1 H, NCHH), 6.42 (s, 1 H, CH), 7.24 (s, 1 H, 122.2, 128.5, 129.0, 132.9, 133.5, 134.7, 141.0, 143.5, 159.3, 163.5,
ArH), 7.30 (s, 1 H, ArH), 7.36 (t, J = 7.4 Hz, 1 H, ArH), 7.72 (t,
J = 7.7 Hz, 1 H, ArH), 8.07 (d, J = 8.5 Hz, 1 H, ArH), 8.41 (d, J
= 8.0 Hz, 1 H, ArH), 8.90 (s, 1 H, ArH) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 46.3, 52.2, 55.8, 55.9, 79.2, 110.8, 114.6, 117.9,
120.3, 120.6, 122.3, 125.9, 128.2, 128.9, 133.7, 134.7, 135.2, 140.8,
145.2, 148.1, 148.2, 166.0 ppm. MS (ESI+): m/z = 405.1
[M + H]+. HRMS (ESI): calcd. for C23H21N2O5 [M + H]+
405.1450; found 405.1464.
166.2 ppm. MS (ESI+): m/z = 375.1 [M + H]+. HRMS (ESI): calcd.
for C22H19N2O4 [M + H]+ 375.1345; found 375.1357.
3-Methoxy-1,6-dihydro-7,13b-diazabenzo[5,6]cyclohepta[1,2,3-jk]-
fluoren-6-ol (15b): Yield: 81%; white solid; m.p. 182–184 °C; Rf =
0.44 (hexanes/EtOAc, 60:40). IR (KBr): ν = 3451 (OH) cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 3.77 (s, 3 H, OCH3), 5.37 (d, J =
14.4 Hz, 1 H, NCHH), 5.70 (d, J = 14.4 Hz, 1 H, NCHH), 6.66 (s,
1 H, CH), 6.88–6.93 (m, 2 H, ArH), 7.28–7.30 (m, 1 H, ArH),
7.62–7.66 (m, 2 H, ArH), 7.78–7.84 (m, 2 H, ArH), 8.09 (d, J =
7.8 Hz, 1 H, ArH), 8.27 (d, J = 5.3 Hz, 1 H, ArH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 47.8, 55.5, 70.1, 109.1, 113.2, 114.7, 115.9,
119.8, 120.8, 122.1, 126.5, 128.4, 133.0, 134.4, 136.4, 140.5, 143.4,
159.1 ppm. MS (ESI+): m/z = 317.2 [M + H]+. HRMS (ESI): calcd.
for C20H17N2O2 [M + H]+ 317.1290; found 317.1293.
3,4-Dimethoxy-1,6-dihydro-7,13b-diazabenzo[5,6]cyclohepta-
[1,2,3-jk]fluoren-6-ol (13b): Yield: 81 %; white solid; m.p. 188–
189 °C; R = 0.43 (hexanes/EtOAc, 70:30). IR (KBr): ν = 3373
˜
f
(OH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.86 (s, 3 H, OCH3),
3.92 (s, 3 H, OCH3), 5.32 (d, J = 14.6 Hz, 1 H, NCHH), 5.72 (d,
J = 14.5 Hz, 1 H, NCHH), 6.69 (s, 1 H, CH), 6.89 (s, 1 H, ArH),
7.28–7.31 (m, 1 H, ArH), 7.49 (s, 1 H, ArH), 7.63–7.65 (m, 2 H,
ArH), 7.84 (d, J = 5.1 Hz, 1 H, ArH), 8.10 (d, J = 7.9 Hz, 1 H,
ArH), 8.27 (d, J = 5.4 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ = 45.2, 54.4, 54.6, 108.3, 108.9, 111.1, 112.7, 113.2,
118.1, 118.7, 120.4, 123.8, 126.9, 128.0, 131.5, 133.3, 134.8, 138.9,
142.9, 146.4, 147.1 ppm. MS (ESI+): m/z = 347.1 [M + H]+.
HRMS (ESI): calcd. for C21H19N2O3 [M + H]+ 347.1396; found
347.1413.
Methyl 8-Hydroxy-8,14-dihydro-10,12-dioxa-7,14a-diazaindeno-
[5Ј,6Ј:5,6]cyclohepta[1,2,3-jk]fluorine-6-carboxylate (16a): Yield:
82%; white solid; m.p. Ͼ250 °C; Rf = 0.42 (hexanes/EtOAc, 60:40).
IR (KBr): ν = 1703 (CO CH ), 3472 (OH) cm–1 1H NMR
.
˜
2
3
(300 MHz, CDCl3/[D6]DMSO): δ = 3.93 (s, 3 H, CO2CH3), 5.69
(d, J = 14.5 Hz, 1 H, CH), 5.95 (s, 2 H, NCH2), 6.01 (s, 2 H,
OCH2O), 7.23 (s, 1 H, ArH), 7.28 (s, 1 H, ArH), 7.36 (t, J = 7.1 Hz,
1 H, ArH), 7.72 (t, J = 7.5 Hz, 1 H, ArH), 8.06 (d, J = 7.6 Hz, 1
H, ArH), 8.41–8.47 (m, 1 H, ArH), 8.91 (s, 1 H, ArH) ppm. 13C
NMR (50 MHz, CDCl3): insoluble. MS (ESI+): m/z = 389.2 [M +
H]+. HRMS (ESI): calcd. for C22H17N2O5 [M + H]+ 389.1137;
found 389.1132.
Methyl 3,5-Dimethoxy-6-hydroxy-1,6-dihydro-7,13b-diazabenzo-
[5,6]cyclohepta[1,2,3-jk]fluorene-8-carboxylate (14a): Yield: 91%;
white solid; m.p. 234–236 °C; Rf = 0.41 (hexanes/EtOAc, 60:40). IR
(KBr): ν = 1722 (CO CH ), 3426 (OH) cm–1. 1H NMR (300 MHz,
˜
2
3
CDCl3): δ = 3.20 (br. s, 1 H, CHOH), 3.80 (s, 3 H, OCH3), 3.83 (s,
3 H, OCH3), 4.00 (s, 3 H, CO2CH3), 5.24 (d, J = 13.7 Hz, 1 H,
NCHH), 6.30 (d, J = 13.8 Hz, 1 H, NCHH), 6.43 (d, J = 2.2 Hz,
1 H, ArH), 6.55 (d, J = 2.3 Hz, 1 H, ArH), 6.88 (s, 1 H, CHOH),
7.32–7.37 (m, 1 H, ArH), 7.67–7.69 (m, 2 H, ArH), 8.17 (d, J =
7.9 Hz, 1 H, ArH), 8.82 (s, 1 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3/[D6]DMSO): δ = 45.3, 50.4, 53.7, 54.3, 66.2, 96.4, 106.0,
108.9, 116.0, 118.6, 118.8, 119.5, 120.4, 126.6, 127.1, 133.7, 134.8,
139.0, 143.9, 155.6, 158.4, 164.4 ppm. MS (ESI+): m/z = 405.0 [M
+ H]+. HRMS (ESI): calcd. for C23H21N2O5 [M + H]+ 405.1450;
found 405.1455.
8,14-Dihydro-10,12-dioxa-7,14a-diazaindeno[5Ј,6Ј:5,6]cyclohepta-
[1,2,3-jk]fluoren-8-ol (16b): Yield: 65%; brown solid; m.p. Ͼ250 °C;
R = 0.46 (hexanes/EtOAc, 60:40). IR (KBr): ν = 3443 (OH) cm–1.
˜
f
1H NMR (300 MHz, CDCl3/[D6]DMSO): δ = 5.54–5.63 (m, 1 H,
NHH), 5.79 (br. s, 1 H, NHH), 5.94 (s, 2 H, OCH2O), 6.23 (s, 1
H, CHOH), 6.93 (s, 1 H, CHOH), 7.13 (s, 1 H, ArH), 7.15 (s, 1 H,
ArH), 7.26 (t, J = 7.7 Hz, 1 H, ArH), 7.63 (t, J = 7.7 Hz, 1 H,
ArH), 7.86 (d, J = 8.2 Hz, 1 H, ArH), 7.94 (d, J = 2.0 Hz, 1 H,
ArH), 8.14 (d, J = 7.7 Hz, 1 H, ArH), 8.26 (d, J = 5.1 Hz, 1 H,
ArH) ppm. MS (EI+): m/z = 330 [M]+.
General Procedure for the Friedel–Crafts Reaction by using P2O5 as
a Catalyst, as Exemplified by 19aA: To a stirred solution of 7aA
(0.49 g, 1.0 mmol) in dry dichloromethane (30 mL) in a round-bot-
tomed flask was added P2O5 (0.2 g) at room temperature, and the
reaction was continued for 1 h. Upon completion (TLC) of the re-
action, the reaction mixture was poured into water and neutralized
with a saturated solution of NaHCO3. The contents were extracted
with dichloromethane (2ϫ30 mL). The combined organic layer
was dried (Na2SO4) and concentrated to obtain a yellow residue,
which was purified by column chromatography (silica gel; hexanes/
EtOAc, 82:18) to furnish 19aA (0.40 g, 85%) as a white solid.
3,5-Dimethoxy-1,6-dihydro-7,13b-diazabenzo[5,6]cyclohepta-
[1,2,3-jk]fluoren-6-ol (14b): Yield: 88 %; white solid; m.p. 200–
202 °C; R = 0.52 (hexanes/EtOAc, 55:45). IR (KBr): ν = 3321
˜
f
(OH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.80 (s, 3 H, OCH3),
3.81 (s, 3 H, OCH3), 5.22 (d, J = 13.7 Hz, 1 H, NCHH), 6.27 (d,
J = 13.7 Hz, 1 H, NCHH), 6.43 (d, J = 2.2 Hz, 1 H, ArH), 6.56
(d, J = 2.3 Hz, 1 H, ArH), 6.77 (s, 1 H, CH), 7.27–7.30 (m, 1 H,
ArH), 7.60–7.64 (m, 2 H, ArH), 7.88 (d, J = 5.3 Hz, 1 H, ArH),
8.11 (d, J = 7.8 Hz, 1 H, ArH), 8.29 (d, J = 5.3 Hz, 1 H, ArH) ppm.
13C NMR (50 MHz, CDCl3/[D6]DMSO): δ = 46.4, 54.1, 54.7, 67.4,
96.8, 106.3, 108.3, 113.4, 118.2, 119.2, 120.4, 120.8, 126.9, 127.4,
132.8, 135.4, 136.0, 139.1, 144.8, 156.3, 159.0 ppm. MS (ESI+): m/z
= 347.1 [M + H]+. HRMS (ESI): calcd. for C21H19 N2 O3
[M + H]+ 347.1396; found 347.1409.
2-(3,4,5-Trimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-diaza-
benzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylonitrile (19aA):
White solid; m.p. 204–206 °C; Rf = 0.48 (hexanes/EtOAc, 60:40).
IR (KBr): ν = 1718 (CO CH ), 2226 (CN) cm–1 1H NMR
.
˜
2
3
Methyl 6-Hydroxy-3-methoxy-1,6-dihydro-7,13b-diazabenzo[5,6]cy- (300 MHz, CDCl3): δ = 3.84 (s, 3 H, OCH3), 3.88 (s, 3 H, OCH3),
clohepta[1,2,3-jk]fluorene-8-carboxylate (15a): Yield: 83%; white
solid; m.p. 185–187 °C; Rf = 0.45 (hexanes/EtOAc, 55:45). IR
4.04 (s, 3 H, OCH3), 4.06 (s, 3 H, CO2CH3), 5.20–5.25 (m, 2 H,
NCHH and CH), 5.62 (d, J = 14.6 Hz, 1 H, NCHH), 6.11–6.18
(KBr): ν = 1709 (CO CH ), 3341 (OH) cm–1. 1H NMR (300 MHz, (m, 2 H, =CH2), 6.71 (s, 1 H, ArH), 7.35–7.41 (m, 1 H, ArH),
˜
2
3
2458
www.eurjoc.org
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2453–2462

Efficient Synthesis of Maxonine Analogues
7.64–7.73 (m, 2 H, ArH), 8.19 (d, J = 7.8 Hz, 1 H, ArH), 8.85 (s, 2.5 Hz, 1 H, =CHH), 6.10 (d, J = 2.7 Hz, 1 H, =CHH), 6.72 (s, 1
1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 47.3, 47.5, 52.9,
56.2, 60.9, 61.9, 109.5, 109.7, 117.6, 118.1, 121.0, 121.2, 122.3,
123.1, 125.6, 129.2, 129.4, 129.7, 131.8, 136.3, 137.7, 140.4, 141.0,
143.0, 152.8, 153.5, 166.6 ppm. MS (ESI+): m/z = 470.2
H, ArH), 7.26–7.33 (m, 1 H, ArH), 7.59–7.68 (m, 2 H, ArH), 7.91
(d, J = 5.2 Hz, 1 H, ArH), 8.14 (d, J = 7.8 Hz, 1 H, ArH), 8.41 (d,
J = 5.2 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 47.3,
47.4, 56.2, 60.9, 61.9, 109.1, 109.8, 114.8, 117.7, 119.9, 120.8, 122.1,
[M + H]+. HRMS (ESI): calcd. for C27H24N3O5 [M + H]+ 123.5, 125.9, 128.6, 129.5, 130.0, 131.6, 134.8, 138.9, 140.4, 140.6,
470.1716; found 470.1728.
142.8, 152.6, 153.4 ppm. MS (ESI+): m/z = 412.2 [M + H]+.
HRMS (ESI): calcd. for C25H22N3O3 [M + H]+ 412.1661; found
412.1665.
Methyl 2-(3,4,5-Trimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-
diazabenzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylate (19aB):
White solid; m.p. 215–216 °C; Rf = 0.45 (hexanes/EtOAc, 60:40).
Ethyl 2-(3,4,5-Trimethoxy-1,6-dihydro-7,13b-diazabenzo[5,6]cy-
clohepta[1,2,3-jk]fluoren-6-yl)acrylate (19bC): White solid; m.p.
IR (KBr): ν = 1722 (CO CH ) cm–1. 1H NMR (300 MHz, CDCl ):
˜
2
3
3
δ = 3.65 (s, 3 H, OCH3), 3.83 (s, 6 H, 2 OCH3), 4.01 (s, 3 H,
CO2CH3), 4.05 (s, 3 H, CO2CH3), 4.86 (d, J = 2.2 Hz, 1 H, CH),
5.12 (d, J = 14.6 Hz, 1 H, NCHH), 5.77 (d, J = 14.5 Hz, 1 H,
162–164 °C; R = 0.53 (hexanes/EtOAc, 60:40). IR (KBr): ν = 1716
˜
f
(CO2C2H5) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.17 (t, J =
7.1 Hz, 3 H, CO2CH2CH3), 3.83 (s, 3 H, OCH3), 3.85 (s, 3 H,
NCHH), 6.29–6.31 (m, 2 H, =CH2), 6.59 (s, 1 H, ArH), 7.33–7.38 OCH3), 3.96 (s, 3 H, OCH3), 4.08–4.16 (m, 2 H, CO2CH2CH3),
(m, 1 H, ArH), 7.61–7.70 (m, 2 H, ArH), 8.19 (d, J = 7.8 Hz, 1 H, 4.86 (d, J = 2.1 Hz, 1 H, CH), 5.10 (d, J = 14.5 Hz, 1 H, NCHH),
ArH), 8.83 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 5.75 (d, J = 14.4 Hz, 1 H, NCHH), 6.13 (t, J = 2.2 Hz, 1 H,
46.1, 47.4, 51.9, 52.8, 56.0, 60.8, 61.6, 109.0, 109.5, 117.7, 120.6,
121.2, 122.1, 125.6, 126.9, 128.7, 129.3, 136.5, 137.4, 140.9, 142.2,
142.7, 143.2, 152.6, 152.9, 166.6, 166.9 ppm. MS (ESI+): m/z =
503.1 [M + H]+. HRMS (ESI): calcd. for C28H27N2O7 [M + H]+
503.1818; found 503.1821.
=CHH), 6.27 (d, J = 2.1 Hz, 1 H, =CHH), 6.60 (s, 1 H, ArH),
7.26–7.30 (m, 1 H, ArH), 7.56–7.65 (m, 2 H, ArH), 7.87 (d, J =
5.3 Hz, 1 H, ArH), 8.13 (d, J = 7.8 Hz, 1 H, ArH), 8.38 (d, J =
5.3 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.0,
46.0, 47.2, 53.5, 56.0, 60.8, 61.6, 109.0, 109.1, 114.1, 119.5, 120.8,
121.9, 126.1, 126.2, 128.2, 128.7, 129.5, 134.8, 138.6, 140.4, 142.5,
142.9, 143.4, 152.4, 152.6, 166.4 ppm. MS (ESI+): m/z = 459.2 [M
+ H]+. HRMS (ESI): calcd. for C27H27N2O5 [M + H]+ 459.1920;
found 459.1930.
Ethyl 2-(3,4,5-Trimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-di-
azabenzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylate (19aC): White
solid; m.p. 170–171 °C; Rf = 0.51 (hexanes/EtOAc, 60:40). IR
(KBr): ν = 1715 (CO CH and CO2C2H5) cm–1 1H NMR
.
˜
2
3
(300 MHz, CDCl3): δ = 1.65 (t, J = 7.1 Hz, 3 H, CO2CH2CH3), 2-(3,4-Dimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-diaza-
3.83 (s, 3 H, OCH3), 3.84 (s, 3 H, OCH3), 3.98 (s, 3 H, OCH3), benzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylonitrile (20aA):
4.09–4.14 (m, 5 H, CO2CH3 and CO2CH2CH3), 4.83 (d, J = 1.9 Hz, White solid; m.p. 213-215 °C; Rf = 0.46 (hexanes/EtOAc, 60:40). IR
1 H, CH), 5.12 (d, J = 14.6 Hz, 1 H, NCHH), 5.79 (d, J = 14.5 Hz, (KBr): ν = 1726 (CO CH ), 2216 (CN) cm–1. 1H NMR (300 MHz,
˜
2
3
1 H, NCHH), 6.28 (s, 2 H, =CH2), 6.59 (s, 1 H, ArH), 7.36 (t, J =
6.6 Hz, 1 H, ArH), 7.61–7.70 (m, 2 H, ArH), 8.18 (d, J = 7.7 Hz,
CDCl3): δ = 3.89 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), 4.07 (s, 3
H, CO2CH3), 5.23–5.34 (m, 3 H, CH, =CHH and NCHH), 5.60
1 H, ArH), 8.83 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): (d, J = 14.8 Hz, 1 H, NCHH), 6.11 (d, J = 2.5 Hz, 1 H, =CHH),
δ = 14.2, 46.2, 47.5, 52.8, 56.1, 60.8, 61.7, 109.1, 109.5, 117.7, 120.7,
121.3, 122.2, 126.0, 126.5, 128.8, 129.4, 136.6, 137.5, 141.0, 142.7,
142.8, 143.4, 152.7, 152.9, 166.4, 167.0 ppm. MS (ESI+): m/z =
517.2 [M + H]+. HRMS (ESI): calcd. for C29H29F6N2O7
[M + H]+ 517.1975; found 517.1971.
6.90 (s, 1 H, ArH), 7.07 (s, 1 H, ArH), 7.39 (t, J = 6.4 Hz, 1 H,
ArH), 7.66–7.74 (m, 2 H, ArH), 8.21 (d, J = 7.8 Hz, 1 H, ArH),
8.86 (s, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 47.2,
53.0, 56.19, 56.24, 56.8, 109.6, 114.0, 115.0, 117.3, 118.2, 121.0,
122.3, 125.0, 126.0, 129.0, 129.2, 129.6, 132.0, 136.1, 137.2, 140.2,
141.1, 149.0, 149.5, 166.5 ppm. MS (ESI+): m/z = 440.1
[M + H]+. HRMS (ESI): calcd. for C26H22N3O4 [M + H]+
440.1610; found 440.1601.
Butyl 2-(3,4,5-Trimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-di-
azabenzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylate (19aD):
White solid; m.p. 155–156 °C; Rf = 0.53 (hexanes/EtOAc, 55:45).
IR (KBr): ν = 1718 (CO CH and CO2C4H9) cm–1
( 3 0 0 M H z , C D C l 3 ) : δ = 0 . 8 8 ( t , J = 7 . 3 H z , 3 H ,
.
1H NMR Methyl 2-(3,4-Dimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-di-
azabenzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylate (20aB): White
˜
2
3
CO2CH2CH2CH2CH3), 1.26–1.34 (m, 2 H, CO2CH2CH2CH2CH3), solid; m.p. 198–200 °C; Rf = 0.46 (hexanes/EtOAc, 60:40). IR
1
1.48–1.55 (m, 2 H, CO2CH2CH2CH2CH3), 3.82 (s, 3 H, OCH3), (KBr): ν = 1719 (CO CH ) cm–1. H NMR (300 MHz, CDCl ): δ
˜
2
3
3
3.84 (s, 3 H, OCH3), 3.99 (s, 3 H, OCH3), 4.03–4.07 (m, 5 H, = 3.69 (s, 3 H, OCH3), 3.85 (s, 3 H, OCH3), 3.91 (s, 3 H, CO2CH3),
CO2CH2CH2CH2CH3 and CO2CH3), 4.83 (s, 1 H, CH), 5.12 (d, J 4.06 (s, 3 H, CO2CH3), 4.92 (d, J = 1.6 Hz, 1 H, CH), 5.18 (d, J =
= 14.5 Hz, 1 H, NCHH), 5.79 (d, J = 14.6 Hz, 1 H, NCHH), 6.27
14.6 Hz, 1 H, NCHH), 5.66–5.73 (m, 2 H, =CHH and NCHH),
(s, 2 H, =CH2), 6.59 (s, 1 H, ArH), 7.35 (t, J = 6.5 Hz, 1 H, ArH), 6.30 (d, J = 1.3 Hz, 1 H, =CHH), 6.78 (s, 1 H, ArH), 7.21 (s, 1 H,
7.61–7.70 (m, 2 H, ArH), 8.19 (d, J = 7.8 Hz, 1 H, ArH), 8.83 (s, ArH), 7.33–7.38 (m, 1 H, ArH), 7.66 (br. s, 2 H, ArH), 8.19 (d, J
1 H, ArH) ppm. 13C NMR (50 MHz, CDCl ): δ = 13.8, 19.2, 29.8
= 7.8 Hz, 1 H, ArH), 8.84 (s, 1 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 46.8, 51.9, 52.8, 55.3, 56.1, 109.6, 113.2, 116.3, 117.7,
120.7, 121.1, 122.1, 126.1, 128.8, 130.6, 136.6, 137.2, 141.0, 141.6,
142.7, 148.1, 148.8, 166.4, 166.7 ppm. MS (ESI+): m/z = 473.2 [M
+ H]+. HRMS (ESI): calcd. for C27H25N2O6 [M + H]+ 473.1713;
found 473.1716.
¸
3
52.9, 56.1, 60.8, 61.7, 64.9, 109.0, 109.6, 117.7, 120.7, 121.3, 122.2,
125.7, 126.0, 126.6, 128.8, 129.3, 136.6, 137.4, 141.0, 142.6, 142.8,
143.5, 152.7, 152.9, 166.4, 167.0 ppm. MS (ESI+): m/z = 545.2 [M
+ H]+. HRMS (ESI): calcd. for C31H33N2O7 [M + H]+ 545.2288;
found 545.2293.
2-(3,4,5-Trimethyl-1,6-dihydro-7,13b-diazabenzo[5,6]cyclohepta-
Methyl 2-(3,4-Dimethoxy-1,6-dihydro-7,13b-diazabenzo[5,6]cy-
[1,2,3-jk]fluoren-6-yl)acrylonitrile (19bA): White solid; m.p. 134–
clohepta[1,2,3-jk]fluoren-6-yl)acrylate (20bB): White solid; m.p.
136 °C; R = 0.52 (hexanes/EtOAc, 60:40). IR (KBr): ν = 2225 185–187 °C; R = 0.54 (hexanes/EtOAc, 60:40). IR (KBr): ν = 1714
˜
˜
f
f
(CN) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.86 (s, 3 H, OCH3), (CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.71 (s, 3 H,
3.88 (s, 3 H, OCH3), 4.01 (s, 3 H, OCH3), 5.17–5.26 (m, 2 H, CH
and NCHH), 5.59 (d, J = 14.6 Hz, 1 H, NCHH), 6.00 (d, J =
OCH3), 3.85 (s, 3 H, OCH3), 3.91 (s, 3 H, CO2CH3), 4.98 (d, J =
1.6 Hz, 1 H, CH), 5.14 (d, J = 14.5 Hz, 1 H, NCHH), 5.51 (s, 1 H,
Eur. J. Org. Chem. 2012, 2453–2462
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2459

S. Hutait, S. Biswas, S. Batra
=CHH), 5.67 (d, J = 14.5 Hz, 1 H, NCHH), 6.30 (d, J = 1.1 Hz, 7.26–7.32 (m, 1 H, ArH), 7.58–7.67 (m, 2 H, ArH), 7.90 (d, J =
FULL PAPER
1 H, =CHH), 6.78 (s, 1 H, ArH), 7.16 (s, 1 H, ArH), 7.29–7.32 (m,
1 H, ArH), 7.60–7.67 (m, 2 H, ArH), 7.90 (d, J = 5.3 Hz, 1 H,
ArH), 8.14 (d, J = 7.8 Hz, 1 H, ArH), 8.38 (d, J = 5.3 Hz, 1 H,
ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 46.7, 52.0, 55.7, 56.2,
109.1, 113.4, 114.3, 116.3, 119.7, 120.9, 122.0, 126.0, 126.5, 128.4,
5.2 Hz, 1 H, ArH), 8.13 (d, J = 7.8 Hz, 1 H, ArH), 8.41 (d, J =
5.2 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 46.0,
47.6, 55.5, 56.3, 98.7, 107.4, 109.1, 114.7, 117.7, 117.9, 119.8, 120.8,
122.1, 126.3, 128.6, 129.4, 131.1, 135.0, 136.3, 138.8, 140.5, 140.8,
158.8, 160.6 ppm. MS (ESI+): m/z = 382.2 [M + H]+. HRMS
129.1, 131.0, 135.1, 138.7, 140.5, 142.2, 142.7, 148.2, 148.8, (ESI): calcd. for C24H20N3O2 [M + H]+ 382.1556; found 382.1557.
166.7 ppm. MS (ESI+): m/z = 415.2 [M + H]+. HRMS (ESI): calcd.
Methyl 2-(3,5-Dimethoxy-1,6-dihydro-7,13b-diazabenzo[5,6]cy-
for C25H23N2O4 [M + H]+ 415.1658; found 415.1653.
clohepta[1,2,3-jk]fluoren-6-yl)acrylate (21bB): White solid; m.p.
2-(3,5-Dimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-diaza-
benzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylonitrile (21aA):
White solid; m.p. 140–142 °C; Rf = 0.42 (hexanes/EtOAc, 60:40).
187–189 °C; R = 0.42 (hexanes/EtOAc, 70:30). IR (KBr): ν = 1710
˜
f
(CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.64 (s, 3 H,
OCH3), 3.77 (s, 3 H, OCH3), 3.91 (s, 3 H, CO2CH3), 4.88 (d, J =
IR (KBr): ν = 1721 (CO CH ), 2223 (CN) cm–1 1H NMR 1.7 Hz, 1 H, CHOH), 5.10 (d, J = 14.5 Hz, 1 H, NCHH), 5.74 (d,
.
˜
2
3
(300 MHz, CDCl3): δ = 3.83 (s, 3 H, OCH3), 3.92 (s, 3 H, OCH3), J = 14.2 Hz, 1 H, NCHH), 6.26 (br. s, 2 H, =CH2), 6.43 (s, 1 H,
4.08 (s, 3 H, CO2CH3), 5.22–5.27 (m, 2 H, NCHH and CHOH),
5.63 (d, J = 14.7 Hz, 1 H, NCHH), 6.08 (d, J = 2.8 Hz, 1 H,
ArH), 6.49 (d, J = 2.3 Hz, 1 H, ArH), 7.26–7.29 (m, 1 H, ArH),
7.56–7.62 (m, 2 H, ArH), 7.86 (d, J = 5.3 Hz, 1 H, ArH), 8.12 (d,
=CHH), 6.30 (t, J = 2.6 Hz, 1 H, =CHH), 6.56 (d, J = 1.2 Hz, 2 J = 7.9 Hz, 1 H, ArH), 8.38 (d, J = 5.3 Hz, 1 H, ArH) ppm. 13C
H, ArH), 7.36–7.42 (m, 1 H, ArH), 7.66–7.74 (m, 2 H, ArH), 8.21
NMR (75 MHz, CDCl3): δ = 44.9, 47.5, 51.9, 55.4, 56.4, 98.9,
106.7, 109.1, 114.1, 119.6, 120.6, 121.0, 126.2, 128.2, 128.8, 135.2,
(d, J = 7.8 Hz, 1 H, ArH), 8.86 (s, 1 H, ArH) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ = 45.3, 46.2, 52.1, 55.3, 56.3, 98.8, 107.9, 135.9, 138.7, 140.5, 143.2, 143.5, 159.0, 159.7, 167.0 ppm. MS
110.7, 116.5, 117.4, 117.8, 120.2, 120.7, 122.4, 123.9, 128.6, 128.9,
132.8, 135.8, 136.5, 139.9, 140.7, 158.1, 160.2, 165.7 ppm. MS
(ESI+): m/z = 440.1 [M + H]+ . HRMS (ESI): calcd. for
C26H22N3O4 [M + H]+ 440.1610; found 440.1599.
(ESI+): m/z = 415.3 [M + H]+ . HRMS (ESI): calcd. for
C25H23N2O4 [M + H]+ 415.1658; found 415.1661.
2-(6-Carboxymethyl-8,14-dihydro-10,12-dioxa-7,14a-diazaindeno-
[5Ј,6Ј:5,6]cyclohepta[1,2,3-jk]fluorine-8-yl)acrylonitrile (22aA):
White solid; m.p. 203–205 °C; Rf = 0.43 (hexanes/EtOAc, 60:40).
Methyl 2-(3,5-Dimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-di-
azabenzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylate (21aB): White
IR (KBr): ν = 1713 (CO CH ), 2225 (CN) cm–1 1H NMR
.
˜
2 3
solid; m.p. 209–211 °C; Rf = 0.42 (hexanes/EtOAc, 55:45). IR
(300 MHz, CDCl3): δ = 4.07 (s, 3 H, CO2CH3), 5.18–5.23 (m, 2 H,
1
(KBr): ν = 1719 (CO CH ) cm–1. H NMR (300 MHz, CDCl ): δ CH and NCHH), 5.32 (s, 1 H, =CHH), 5.56 (d, J = 14.8 Hz, 1 H,
˜
2
3
3
= 3.62 (s, 3 H, OCH3), 3.77 (s, 3 H, OCH3), 3.91 (s, 3 H, CO2CH3),
4.05 (s, 3 H, CO2CH3), 4.84 (d, J = 2.2 Hz, 1 H, CHOH), 5.13 (d,
J = 14.5 Hz, 1 H, NCHH), 5.77 (d, J = 14.4 Hz, 1 H, NCHH),
6.27 (d, J = 2.2 Hz, 1 H, =CHH), 6.39–6.42 (m, 2 H, =CHH and
ArH), 6.48 (d, J = 2.3 Hz, 1 H, ArH), 7.32–7.37 (m, 1 H, ArH),
NCHH), 5.95 (s, 1 H, =CHH), 6.01 (d, J = 1.0 Hz, 1 H, OCHHO),
6.12 (d, J = 2.5 Hz, 1 H, OCHHO), 6.89 (s, 1 H ArH), 7.04 (s, 1
H, ArH), 7.38 (t, J = 6.9 Hz, 1 H, ArH), 7.62–7.73 (m, 2 H, ArH),
8.20 (d, J = 7.9 Hz, 1 H, ArH), 8.86 (s, 1 H, ArH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 47.0, 53.1, 56.9, 101.8, 109.5, 110.9, 112.1,
7.61–7.69 (m, 2 H, ArH), 8.18 (d, J = 7.8 Hz, 1 H, ArH), 8.82 (s, 117.2, 118.3, 121.2, 122.3, 125.1, 127.4, 129.3, 130.4, 132.1, 136.1,
1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 44.9, 47.5, 51.8,
52.7, 55.3, 56.3, 98.9, 106.6, 109.5, 117.6, 120.2, 120.6, 121.2, 122.1,
126.4, 128. 7, 135.6, 136.8, 137.3, 140.9, 142.7, 143.3, 159.1, 159.7,
166.7, 166.9 ppm. MS (ESI+): m/z = 473.2 [M + H]+. HRMS
(ESI): calcd. for C27H25N2O6 [M + H]+ 473.1713; found 473.1716.
137.5, 140.0, 141.0, 148.5, 166.6 ppm. MS (ESI+): m/z = 424.1 [M
+ H]+. HRMS (ESI): calcd. for C25H18N3O4 [M + H]+ 424.1297;
found 424.1294.
Methyl 2-(6-Carboxymethyl-8,14-dihydro-10,12-dioxa-7,14a-di-
azaindeno[5Ј,6Ј:5,6]cyclohepta[1,2,3-jk]fluorine-8-yl)acrylate (22aB):
Ethyl 2-(3,5-Dimethoxy-8-methoxycarbonyl-1,6-dihydro-7,13b-di- White solid; m.p. 164–165 °C; Rf = 0.49 (hexanes/EtOAc, 70:30).
azabenzo[5,6]cyclohepta[1,2,3-jk]fluoren-6-yl)acrylate (21aC): White
solid; m.p. 229–231 °C; Rf = 0.44 (hexanes/EtOAc, 70:30). IR
IR (KBr): ν = 1717 (CO CH ) cm–1. 1H NMR (300 MHz, CDCl ):
˜
2 3 3
δ = 3.45 (d, J = 14.8 Hz, 1 H, NCHH), 3.75 (s, 1 H, CH), 3.79 (s,
(KBr): ν = 1716 (CO CH and CO2C2H5) cm–1 1H NMR 3 H, CO2CH3), 4.07 (s, 3 H, CO2CH3), 4.76 (d, J = 16.0 Hz, 1 H,
.
˜
2
3
(300 MHz, CDCl3): δ = 1.14 (t, J = 7.1 Hz, 3 H, COCH2CH3), NCHH), 5.99 (s, 2 H, OCH2O), 6.41 (d, J = 15.4 Hz, 1 H, =CHH),
3.77 (s, 3 H, OCH3), 3.89 (s, 3 H, OCH3), 4.05–4.10 (m, 5 H, 6.80 (s, 1 H, =CHH), 7.02 (s, 1 H, ArH), 7.38 (t, J = 7.0 Hz, 1 H,
CO2CH3 and CO2CH2CH3), 4.79 (d, J = 2.1 Hz, 1 H, CH), 5.13 ArH), 7.51 (d, J = 8.4 Hz, 1 H, ArH), 7.61 (t, J = 7.5 Hz, 1 H,
(d, J = 14.5 Hz, 1 H, NCHH), 5.79 (d, J = 14.5 Hz, 1 H, NCHH), ArH), 8.20 (d, J = 7.6 Hz, 1 H, ArH), 8.28 (s, 1 H, ArH), 8.82 (s,
6.27 (d, J = 2.1 Hz, 1 H, =CHH), 6.37–6.46 (m, 3 H, =CHH and
ArH), 7.32–7.37 (m, 1 H, ArH), 7.61–7.69 (m, 2 H, ArH), 8.18 (d, J
1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 46.8, 52.1, 52.9,
55.5, 101.5, 109.5, 110.2, 113.5, 117.8, 120.8, 121.2, 122.2, 126.6,
= 7.8 Hz, 1 H, ArH), 8.82 (s, 1 H, ArH) ppm. 13C NMR (50 MHz, 127.3, 129.0, 132.1, 136.6, 137.4, 141.0, 141.6, 142.5, 147.1, 147.8,
CDCl3): δ = 14.0, 44.8, 47.6, 52.7, 55.3, 56.0, 60.7, 98.7, 106.4,
109.5, 117.6, 120.2, 120.6, 121.2, 122.0, 126.2, 128.6, 135.6, 137.2,
140.9, 143.0, 143.5, 159.1, 159.8, 166.5 ppm. MS (ESI+): m/z =
487.2 [M + H]+. HRMS (ESI): calcd. for C28H27N2O6 [M + H]+
487.1869; found 487.1875.
166.4, 166.8 ppm. MS (ESI+): m/z = 457.1 [M + H]+. HRMS
(ESI): calcd. for C26H21N2O6 [M + H]+ 457.1400; found 457.1397.
Methyl 2-Cyano-11-(3-methoxybenzyl)-11H-indolizino[8,7-b]indole-
5-carboxylate (23aA): Yellow solid; m.p. 207–208 °C; Rf = 0.39
(hexanes/EtOAc, 90:10). IR (KBr): ν = 1709 (CO CH ), 2230
˜
2
3
2-(3,5-Dimethyl-1,6-dihydro-7,13b-diazabenzo[5,6]cyclohepta- (CN) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.71 (s, 3 H, OCH3),
[1,2,3-jk]fluoren-6-yl)acrylonitrile (21bA): White solid; m.p. 183– 4.03 (s, 3 H, CO2CH3), 5.68 (s, 2 H, NCH2), 6.60 (s, 1 H, ArH),
185 °C; R = 0.41 (hexanes/EtOAc, 60:40). IR (KBr): ν = 2224 6.67 (d, J = 7.2 Hz, 1 H, ArH), 6.80 (d, J = 6.7 Hz, 1 H, ArH),
˜
f
(CN) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.81 (s, 3 H, OCH3), 6.92 (s, 1 H, ArH), 7.20–7.26 (m, 1 H, ArH), 7.38–7.43 (m, 3 H,
3.90 (s, 3 H, OCH3), 5.17–5.25 (m, 2 H, NCHH and CHOH), 5.58 ArH), 8.00 (d, J = 7.4 Hz, 1 H, ArH), 8.45 (s, 1 H, ArH), 9.33 (s,
(d, J = 14.6 Hz, 1 H, NCHH), 6.06 (d, J = 2.6 Hz, 1 H, =CHH),
6.12 (d, J = 2.4 Hz, 1 H, =CHH), 6.54 (d, J = 3.0 Hz, 2 H, ArH),
1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 48.2, 52.6, 55.9,
97.0, 102.2, 110.0, 110.1, 116.4, 116.6, 117.8, 119.5, 122.0, 123.3,
2460
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© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2012, 2453–2462

Efficient Synthesis of Maxonine Analogues
125.4, 125.9, 129.3, 135.8, 140.0, 160.2, 162.9 ppm. MS (ESI+): m/z
= 410.2 [M + H]+. HRMS (ESI): calcd. for C25H20 N3 O3
[M + H]+ 410.1505; found 410.1511.
HRMS (ESI): calcd. for C24H21N2O6 [M + H]+ 433.1400; found
433.1404.
Procedure for the Synthesis of Compound 26: To a stirred suspen-
sion of 7a (0.43 g, 1 mmol) in dry methanol (25 mL) was added
NaBH4 (0.04 g, 1 mmol) at room temperature. The reaction mix-
ture was stirred for 20 min, and upon completion of the reaction,
methanol was removed under reduced pressure. The reaction was
neutralized with 5% aq. HCl and extracted with chloroform
Dimethyl 11-(3-Methoxybenzyl)-11H-indolizino[8,7-b]indole-2,5-di-
carboxylate (23aB): Yellow solid; m.p. 211–212 °C; Rf = 0.41 (hex-
anes/EtOAc, 90:10). IR (KBr): ν = 1717 (CO CH ) cm–1. 1H NMR
˜
2
3
(300 MHz, CDCl3): δ = 3.70 (s, 3 H, OCH3), 3.88 (s, 3 H,
CO2CH3), 4.03 (s, 3 H, CO2CH3), 5.75 (s, 2 H, NCH2), 6.67–6.78
(m, 3 H, ArH), 7.16–7.21 (m, 2 H, ArH), 7.26–7.39 (m, 3 H, ArH), (2ϫ20 mL). The organic layers were pooled, washed with brine,
7.98 (d, J = 7.0 Hz, 1 H, ArH), 8.42 (s, 1 H, ArH), 9.40 (s, 1 H, dried (Na2SO4), and concentrated to afford 26 (0.41 g, 94%) as a
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 48.3, 51.6, 52.3, 55.3,
100.7, 109.3, 110.1, 112.4, 112.8, 116.5, 118.1, 118.5, 119.1, 119.3,
121.6, 121.7, 123.7, 124.2, 124.8, 130.3, 134.1, 137.9, 139.9, 160.3,
163.2, 165.5 ppm. MS (ESI+): m/z = 443.1 [M + H]+. HRMS
(ESI): calcd. for C26H23N2O5 [M + H]+ 443.1607; found 443.1603.
yellow solid.
Supporting Information (see footnote on the first page of this arti-
cle): Remaining spectroscopic data and copies of the 1H NMR and
13C NMR spectra of all compounds.
2-Ethyl 5-Methyl-11-(3-methoxybenzyl)-11H-indolizino[8,7-b]-
indole-2,5-dicarboxylate (23aC): Yellow solid; m.p. 171–173 °C; Rf
Acknowledgments
= 0.42 (hexanes/EtOAc, 90:10). IR (KBr): ν = 1718 (CO CH and
˜
2
3
S. H. and S. B. gratefully acknowledge financial support in the
form of fellowships from the Council of Scientific and Industrial
Research, New Delhi. All authors acknowledge the Sophisticated
Analytical Instruments Facility of CDRI for providing the spectro-
scopic and analytical data. This work was supported by a grant
from the Department of Science and Technology, New Delhi. We
acknowledge the comments of the anonymous reviewers for im-
proving the quality of the manuscript.
CO2C2H5) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.41 (t, J =
7.1 Hz, 3 H, CO2CH2CH3), 3.71 (s, 3 H, OCH3), 4.05 (s, 3 H,
CO2CH3), 4.37 (q, J = 7.1 Hz, 2 H, CO2CH2CH3), 5.77 (s, 2 H,
NCH2), 6.70–6.81 (m, 3 H, ArH), 7.19–7.24 (m, 2 H, ArH), 7.32–
7.41 (m, 3 H, ArH), 7.99 (d, J = 6.8 Hz, 1 H, ArH), 8.43 (s, 1 H,
ArH), 9.41 (s, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ =
14.6, 48.3, 52.3, 55.3, 60.4, 100.8, 109.2, 110.1, 112.4, 112.8, 116.5,
118.1, 118.5, 119.3, 119.5, 121.5, 121.6, 123.8, 124.1, 124.8, 130.2,
134.1, 137.9, 140.0, 160.2, 163.2, 165.1 ppm. MS (ESI+): m/z =
457.4 [M + H]+. HRMS (ESI): calcd. for C27H25N2O5 [M + H]+
457.1763; found 457.1758.
[1] a) M. M. Airaksinen, I. Kari, Med. Biol. 1981, 59, 190–211; b)
L. A. Anderson, A. Harris, J. D. Phillipson, J. Nat. Prod. 1983,
46, 374–378; c) C. S. L. Karin, S. L. Yang, M. F. Roberts, J. D.
Phillipson, Phytochemistry 1990, 29, 141–143; d) J. E. Saxton
(Ed.: G. A. Cordell), Academic Press, San Diego, CA, 1998,
vol. 51, pp. 2–197; e) G. M. Carbrera, A. M. Seldes, J. Nat.
Prod. 1999, 62, 759–760; f) P. C. Kuo, L. S. Shi, A. G. Damu,
C. R. Su, C. H. Huang, C. H. Ke, J. B. Wu, A. J. Lin, K. F.
Bastow, K. H. Lee, T. S. Wu, J. Nat. Prod. 2003, 66, 1324–1327;
g) T. Kawasaki, K. Higuchi, Nat. Prod. Rep. 2005, 22, 761–
793; h) F. Soriano-Agaton, D. Lagoutte, E. Poupon, F. Roblot,
A. Fournet, J. C. Gantier, R. Hocquemiller, J. Nat. Prod. 2005,
68, 1581–1587; i) K. Higuchi, T. Kawasaki, Nat. Prod. Rep.
2007, 24, 843–868; j) T. A. Mansoor, C. Ramalhete, J. Molnar,
S. Mulhovo, M. J. U. Ferreira, J. Nat. Prod. 2009, 72, 1147–
1150; k) W. H. Jiao, H. Gao, C. Y. Li, F. Zhao, R. W. Jiang, Y.
Wang, G. X. Zhou, X. S. Yao, J. Nat. Prod. 2010, 73, 167–171;
l) W. D. Inman, W. M. Bray, N. C. Gassner, R. S. Lokey, K.
Tenney, Y. Y. Shen, K. TenDyke, T. Suh, P. Crews, J. Nat. Prod.
2010, 73, 255–257; m) S. F. Li, Y. T. Di, H. P. He, Y. Zhang,
Y. H. Wang, J. L. Yin, C. J. Tan, S. L. Li, X. J. Hao, Tetrahe-
dron Lett. 2011, 52, 3186–3188; n) S. T. S. Chan, A. N. Pearce,
M. J. Page, M. Kaiser, B. R. Copp, J. Nat. Prod. 2011, 74,
1972–1979; o) H. Huang, Y. Yao, Z. He, T. Yang, J. Ma, X.
Tian, Y. Li, C. Huang, X. Chen, W. Li, S. Zhang, C. Zhang, J.
Ju, J. Nat. Prod 2011, 74, 2122–2127.
[2] a) R. Cao, W. Peng, Z. Wang, A. Xu, Curr. Med. Chem. 2007,
14, 479–500 and the references cited therein; b) Q. Wu, R. Cao,
M. Feng, X. Guan, C. Ma, J. Liu, H. Song, W. Peng, Eur. J.
Med. Chem. 2009, 44, 533–540; c) J. Wu, M. Zhao, K. Qian,
K. H. Lee, S. Morris-Natschke, S. Peng, Eur. J. Med. Chem.
2009, 44, 4153–4161; d) Y. Rook, K. U. Schmidtke, F. Gaube,
D. Schepmann, B. Wunsch, J. Heilmann, J. Lehmann, T.
Winckler, J. Med. Chem. 2010, 53, 3611–3617; e) C. Ma, R.
Cao, B. Shi, S. Li, Z. Chen, W. Yi, W. Peng, Z. Ren, H. Song,
Eur. J. Med. Chem. 2010, 45, 1515–1523; f) R. Kumar, L.
Gupta, P. Pal, S. Khan, N. Singh, S. B. Katiyar, S. Meena, J.
Sarkar, S. Sinha, J. K. Kanaujiya, S. Lochab, A. K. Trivedi,
P. M. S. Chauhan, Eur. J. Med. Chem. 2010, 45, 2265–2276; g)
R. Cao, X. Guan, B. Shi, Z. Chen, Z. Ren, W. Peng, H. Song,
Methyl 12-(3,4,5-Trimethoxybenzyl)-1-oxo-2,3,4,12-tetrahydro-1H-
benzo[2,3]indolizino[8,7-b]indole-6-carboxylate (25): Yield: 91%;
yellow solid; m.p. 174–176 °C; Rf = 0.47 (hexanes/EtOAc, 90:10).
IR (KBr): ν = 1673 (CO), 1710 (CO CH ) cm–1 1H NMR
.
˜
2
3
(300 MHz, CDCl3): δ = 2.15–2.19 (m, 2 H, CH2), 2.66 (t, J =
6.7 Hz, 2 H, CH2), 2.87 (t, J = 6.0 Hz, 2 H, CH2) 3.68 (s, 6 H, 2
OCH3), 3.79 (s, 3 H, OCH3), 4.05 (s, 3 H, CO2CH3), 5.73 (s, 2 H,
NCH2), 6.36 (s, 2 H, ArH), 7.30–7.44 (m, 4 H, ArH), 7.96 (d, J =
7.3 Hz, 1 H, ArH), 8.12 (s, 1 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 25.0, 26.7, 38.4, 46.9, 52.6, 56.2, 60.9, 97.0, 108.8,
109.9, 117.0, 117.3, 119.2, 119.8, 121.5, 123.6, 123.7, 124.6, 124.8,
133.7, 138.4, 139.5, 153.5, 163.5, 196.5 ppm. MS (ESI+): m/z =
513.2 [M + H]+. HRMS (ESI): calcd. for C30H29N2O6 [M + H]+
513.2026; found 513.2033.
Typical Procedure for the Synthesis of Compound 17 By Using
MnO2: To a stirred solution of 12a (0.22 g, 0.5 mmol) in dichloro-
methane (15 mL) was added activated MnO2 (0.4 g, 5 mmol), and
the mixture was stirred for 2 h. Upon completion of the reaction,
the reaction mixture was filtered through a bed of Celite, and the
filtrate was concentrated to afford a residue. Triturating the residue
with hexanes/EtOAc (80:20) [Rf = 0.44 (hexanes/EtOAc, 55:45)] af-
forded pure 17 (0.20 g, 92%) as a white solid.
Methyl 6-Oxo-3,4,5-trimethoxy-1,6-dihydro-7,13b-diazabenzo[5,6]-
cyclohepta[1,2,3-jk]fluorene-8-carboxylate (17): M.p. Ͼ250 °C; Rf =
0.44 (hexanes/EtOAc, 55:45). IR (KBr): ν = 1708 (CO and
˜
CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.83 (s, 3 H,
OCH3), 3.97 (s, 3 H, OCH3), 4.01 (s, 3 H, OCH3), 4.05 (s, 3 H,
CO2CH3), 5.39 (s, 2 H, NCH2), 6.78 (s, 1 H, ArH), 7.41 (t, J =
6.0 Hz, 1 H, ArH), 7.71 (s, 2 H, ArH), 8.22 (d, J = 7.8 Hz, 1 H,
ArH), 8.96 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ =
48.7, 52.8, 56.4, 61.0, 62.8, 108.0, 109.7, 120.0, 121.2, 121.6, 122.6,
129.0, 129.4, 129.8, 131.7, 137.0, 138.9, 139.0, 141.2, 143.2, 153.5,
155.8, 166.5, 190.8 ppm. MS (ESI+): m/z = 433.1 [M + H]+.
Eur. J. Org. Chem. 2012, 2453–2462
© 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2461

S. Hutait, S. Biswas, S. Batra
FULL PAPER
Eur. J. Med. Chem. 2010, 45, 2503–2515; h) Z. Chen, R. Cao,
L. Yu, B. Shi, J. Sun, L. Guo, Q. Ma, W. Yi, X. Song, H. Song,
Eur. J. Med. Chem. 2010, 45, 4740–4745; i) Z. Chen, R. Cao,
B. Shi, W. Yi, L. Yu, H. Song, Z. Ren, W. Peng, Bioorg. Med.
Chem. Lett. 2010, 20, 3876–3879; j) H. A. Mohamed, N. M. R.
Girgis, R. Wilcken, M. R. Bauer, H. N. Tinsley, B. D. Gary,
G. A. Piazza, F. M. Boeckler, A. H. Abadi, J. Med. Chem.
2011, 54, 495–509; k) T. Suzuki, T. Kubota, J. Kobayashi, Bi-
oorg. Med. Chem. Lett. 2011, 21, 4220–4223; l) R. Ikeda, T.
Iwaki, T. Iida, T. Okabayashi, E. Nishi, M. Kurosawa, N.
Sakai, T. Konakahara, Eur. J. Med. Chem. 2011, 46, 636–646;
m) W. Bi, Y. Bi, P. Xue, Y. Zhang, X. Gao, Z. Wang, M. Li,
M. Baudy-Floch, N. Ngerebara, X. Li, K. M. Gibson, L. Bi,
Eur. J. Med. Chem. 2011, 46, 2441–2452; n) J. Reniers, S. Rob-
ert, R. Frederick, B. Masereel, S. Vincent, J. Wouters, Bioorg.
Med. Chem. 2011, 19, 134–144; o) V. A. Barbosa, A. S. N.
Formagio, F. C. Savariz, M. A. Foglio, H. M. Spindola, J. E. D.
Carvalho, E. Meyer, M. H. Sarragiotto, Bioorg. Med. Chem.
2011, 19, 6400–6408.
a) G. Dominguez, J. Perez-Castells, Eur. J. Org. Chem. 2011,
7243–7253; b) F. Pin, S. Comesse, A. Daich, Tetrahedron 2011,
67, 5564–5571; c) S. Saha, C. V. R. Reddy, B. Patro, Tetrahe-
dron Lett. 2011, 52, 4014–4016; d) L. Jung-Deyon, B. Giethlen,
A. Mann, Eur. J. Org. Chem. 2011, 6409–6412; e) X. Wu, L.
Nie, H. Fang, J. Chen, W. Cao, G. Zhao, Eur. J. Org. Chem.
2011, 6755–6763; f) T. Mizuno, Y. Oonishi, M. Takimoto, Y.
Sato, Eur. J. Org. Chem. 2011, 2606–2609.
2001, 42, 3025–3027; c) H. J. Lee, T. H. Kim, J. N. Kim, Bull.
Korean Chem. Soc. 2001, 22, 1063–1064; d) D. Basavaiah, D. S.
Sharada, A. Veerendhar, Tetrahedron Lett. 2004, 45, 3081–
3083.
[11] a) N. Philippe, F. Denivet, J. L. Vasse, J. S. D. O. Santos, V. Lev-
acher, G. Dupas, Tetrahedron 2003, 59, 8049–8056; b) V. A.
Mahajan, H. B. Borate, R. D. Wakharkar, Tetrahedron 2006,
62, 1258–1272; c) S. Guo, Y. Liu, Org. Biomol. Chem. 2008, 6,
2064–2070; d) M. Bandini, A. Eichholzer, P. Kotrusz, M.
Tragni, S. Troisi, A. U. Ronchi, Adv. Synth. Catal. 2009, 351,
319–324; e) J. Wang, L. Zhang, Y. Jing, W. Huang, X. Zhou,
Tetrahedron Lett. 2009, 50, 4978–4982; f) W. Ying, C. L.
Barnes, M. Harmata, Tetrahedron Lett. 2011, 52, 177–180.
[12] C. Liebert, M. K. Brinks, A. G. Capacci, M. J. Fleming, M.
Lautens, Org. Lett. 2011, 13, 3000–3003.
[13] a) C. Pomeranz, Monatsh. Chem. 1893, 14, 116; b) P. Fritsch,
Justus Liebigs Ann. Chem. 1895, 386, 1; c) J. M. Bobbitt, D. N.
Roy, A. Marchand, C. W. Allen, J. Org. Chem. 1967, 32, 2225–
2227; d) J. M. Bobbitt, J. C. Sib, J. Org. Chem. 1968, 33, 856–
858; e) M. Schlosser, G. Simig, H. Gencste, Tetrahedron 1998,
54, 9023–9032; f) C. Chan, R. Heid, S. Zheng, J. Guo, B. Zhou,
T. Furuuchi, S. J. Danishefsky, J. Am. Chem. Soc. 2005, 127,
4596–4598; g) A. J. Jimenez, C. Jeandon, J. P. Gisselbrecht, R.
Ruppert, Eur. J. Org. Chem. 2009, 5725–5730.
[3]
[14]
[4]
[5]
V. Singh, S. Batra, Curr. Org. Synth. 2012, DOI: BSP/COS/E-
Pub/00007.
a) V. Singh, S. Hutait, S. Batra, Eur. J. Org. Chem. 2009, 6211–
6216; b) V. Singh, S. Hutait, S. Batra, Eur. J. Org. Chem. 2010,
3684–3691.
[6]
a) V. Singh, S. Hutait, S. Biswas, S. Batra, Eur. J. Org. Chem.
2010, 531–539; b) S. Hutait, V. Singh, S. Batra, Eur. J. Org.
Chem. 2010, 6269–6276; c) S. Hutait, M. Nayak, P. Ashok, S.
Batra, Synthesis 2011, 419–430.
[15] a) Y. Shen, H. Liu, M. Wu, W. Du, Y. Chen, N. Li, J. Org.
Chem. 1991, 56, 7160–7162; b) A. Alizadeh, M. M. Khodaei,
E. Nazari, Bull. Korean Chem. Soc. 2007, 28, 1854–1856; c) M.
Noji, T. Ohno, K. Fuji, N. Futaba, H. Tajima, K. Ishii, J. Org.
Chem. 2003, 68, 9340–9347; d) K. Mertins, I. Iovel, J. Kischel,
A. Zapf, M. Beller, Angew. Chem. 2005, 117, 242; Angew.
Chem. Int. Ed. 2005, 44, 238–242.
[16] a) D. J. Tracy, R. L. Reierson, J. Surfactants Deterg. 2002, 5,
169–172; b) A. Whitehead, M. D. McReynolds, J. D. Moore,
P. R. Hanson, Org. Lett. 2005, 7, 3375–3378; c) A. Whitehead,
J. D. Waetzig, C. D. Thomas, P. R. Hanson, Org. Lett. 2008,
10, 1421–1424; d) F. Robertson, J. Wu, Org. Lett. 2010, 12,
2668–2671.
[7] C. P. Hasbun, M. Calderon, O. Castro, E. Gacs-Baitz, G. D.
Monache, F. D. Monache, Tetrahedron Lett. 1989, 30, 6199–
6202.
[8] T. R. Kelly, X. Wei, J. Sundaresan, Tetrahedron Lett. 1993, 34,
6173–6176.
[9] a) W. Zhong, W. Ma, Y. Liu, Tetrahedron 2011, 67, 3509–3518;
b) K. H. Kim, H. S. Lee, J. N. Kim, Tetrahedron Lett. 2009, 50,
1249–1251; c) H. N. Lim, S. H. Ji, K. J. Lee, Synthesis 2007,
16, 2454–2460.
[10] a) D. Basavaiah, M. Bakthadoss, J. G. Reddy, Synthesis 2001,
Received: January 19, 2012
Published Online: March 7, 2012
919–923; b) D. Basavaiah, R. M. Reddy, Tetrahedron Lett.
2462
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Eur. J. Org. Chem. 2012, 2453–2462