Versatility of substituted 1-formyl-9H-β-carbolines for the synthesis of new fused β-carbolines via intramolecular 1, 3-dipolar cycloaddition

Article abstract of DOI:10.1002/ejoc.200901166

Substituted 1-formyl-9H-β-carbolines are demonstrated to be viable precursors for the synthesis of a library of new β-carboline-based polycyclic systems via 1,3-dipolar cycloaddition strategy.

Full text of DOI:10.1002/ejoc.200901166

FULL PAPER
DOI: 10.1002/ejoc.200901166
Versatility of Substituted 1-Formyl-9H-β-carbolines for the Synthesis of New
Fused β-Carbolines via Intramolecular 1,3-Dipolar Cycloaddition[‡]
Virender Singh,[a] Samiran Hutait,[a] Subhasish Biswas,[a] and Sanjay Batra*[a]
Dedicated to Professor Mitchell A. Avery
Keywords: Nitrogen heterocycles / β-Carbolines / Cycloaddition / Alkylation / Microwave chemistry
Substituted 1-formyl-9H-β-carbolines are demonstrated to be
boline-based polycyclic systems via 1,3-dipolar cycloaddition
viable precursors for the synthesis of a library of new β-car- strategy.
Introduction
Alkaloids comprising of the β-carboline core are ubiqui-
tously present in Nature including plants, marine organ-
isms, insects, mammalian as well as human tissues (Fig-
ure 1).[1] Such alkaloids are constitutionally a large group
of indole alkaloids with different scale of aromaticity. Re-
cently an array of pharmacological applications of alkaloids
belonging to the β-carboline class were reviewed by Cao et
al.[2] Especially they have been demonstrated to intercalate
with DNA and display activities against CNS and infec-
tious disorders. We have recently reported the synthesis of
unnatural canthin-6-ones and canthines via Baylis–Hillman
reaction of substituted 1-formyl-9H-β-carbolines.[3] During
the course of this study we engineered a facile route to gen-
erate these aldehydes in good yields using readily available
reagents. It occurred to us that these aldehydes may serve
as viable precursors to a library of β-carboline-based com-
pounds containing a D-ring utilizing intramolecular 1,3-cy-
cloaddition as the key step.[4] The presence of free NH
group of the indole subunit and the formyl group at 1-posi-
tion in close proximity provides opportunity to place the
dipole and the alkene or alkyne dipolariphile within the
same molecule. The resulting species can be further manip-
ulated using established strategies leading to a variety of
bicyclic or polycyclic products. These considerations guided
us to explore the utility of these aldehydes to obtain new β-
carboline derivatives. This paper incorporates the results of
our endeavour in this direction.
Figure 1. A few examples of β-carboline alkaloids containing D-
ring.
Results and Discussion
For initiating study, in the first instance masked substi-
tuted β-carboline aldehydes 7–9 were synthesized in high
yields following the recently reported procedure
(Scheme 1).[3]
In their efforts to develop new route to canthines, Condie
and Bergman have earlier reported the alkylation of methyl
1-formyl-9H-β-carboline carboxylate via allyl bromide in
the presence of NaH in DMSO in high yields.[5] However in
our hands the experiment did not work well and the desired
compound was obtained in minor yields only. Consequently
we decided to first install the allyl chain on NH of the β-
[‡] CDRI Communication No. 7893
[a] Medicinal and Process Chemistry Division, Central Drug
Research Institute, CSIR,
P. O. Box 173, Lucknow 226001, UP, India
Fax: +91-522-2623405
E-mail: batra_san@yahoo.co.uk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.200901166.
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V. Singh, S. Hutait, S. Biswas, S. Batra
FULL PAPER
tained in sufficiently pure form. It is significant to note that
the reaction was unsuccessful when K2CO3 was used as a
base in dry DMF at room temperature or under heating at
100 °C. Like 7, substrates 8 and 9 reacted with allyl bromide
to furnish the corresponding products 12 and 13. In the
next step the acetal group in 10,12–13 was deprotected by
heating in the presence of AcOH/water (2:3, v/v) at 120 °C
to afford respective aldehydes 14–16. More importantly this
route works well to afford higher amount (ca. 5.0 g) of N-
alkylated aldehyde. Aldehydes 14–16 reacted with
NH2OH·HCl in the presence of NaOAc to furnish the sub-
stituted oximes 17–19, respectively in good yields. Treat-
ment of 17–19 with NaOCl in the presence of Et3N at room
temperature for three days resulted in the formation of the
desired 9a,10-dihydro-9H-indolo[3,2,1-ij]isoxazolo[4,3-c]-
[1,5]naphthyridines 20–22.
Scheme 1. Reagents and conditions: i) 2–5% TFA in CH2Cl2, 4 h–
3 d. ii) KMnO4, dry THF, room temp., 6 h–5 d.
carboline in 7–9 through allyl bromide and then deprotect
the acetal functionality. Following, the nitrile oxide could
be generated from the formyl group which should partici-
pate in intramolecular 1,3-dipolar cycloaddition to afford
new β-carbolines. With the aim to optimize the reaction,
studies were initiated with 7 by alkylating it with allyl bro-
mide in the presence of NaH in dry DMF at room tempera-
ture. The reaction of 7 with 1.2 equiv. of allyl bromide re-
sulted in only 70% conversion (TLC analysis) in 2 h to yield
10. Increasing the amount of allyl bromide to 1.5 equiv. was
also found to be insufficient to take the reaction to comple-
tion. Subsequently, reaction was investigated with 2.0 equiv.
of allyl bromide. Fortunately this ratio of bromide resulted
in completion of reaction but a mixture of two products
was formed which could be separated only after a careful
chromatography (Scheme 2). On the basis of spectroscopic
data, the structure of the less polar product that was iso-
lated in minor quantity (10%) was established as 11
whereas the major product (50%) was the required product
10. The formation of 11 is attributed to hydrolysis of the
methyl ester followed by substitution with allyl bromide in
the presence of base in 7. To avoid the tedious separation
of 10 and 11, we continued seeking a reaction condition
wherein only the required product 10 is formed.
Scheme 3. Reagents and conditions: i) allyl bromide, Cs2CO3, dry
DMF, room temp., 2–3 h. ii) AcOH/H2O (2:3, v/v), reflux, 45 min.
iii) NH2OH·HCl, AcONa, MeOH, reflux, 1 h. iv) NaOCl, Et3N,
CH2Cl2, room temp., 3 d.
In our attempt to increase the diversity of products
which could be generated via this strategy, the substituted
allyl bromides prepared from the Baylis–Hillman chemistry
using known protocol were utilized to alkylate the NH to
produce highly substituted alkenes. Accordingly the reac-
tion of 7 with several substituted allyl bromides (labelled a–
d) in the presence of Cs2CO3 in dry DMF were performed
to smoothly afford the required products 23–26 in 2–3 h
(Scheme 4). The spectroscopic analysis of these products re-
vealed them to be the E-isomer exclusively. Deprotection of
the acetal group in 23–26 was carried out as described ear-
lier to obtain the aldehydes 27–30 in high yields and good
purity. Reaction of aldehydes 27–30 with NH2OH·HCl re-
sulted in the corresponding oximes 31–34 which upon treat-
ment with NaOCl in the presence of Et3N afforded the sub-
stituted isoxazoline derivatives 35–38, respectively. Al-
Scheme 2. Reagents and conditions: i) allyl bromide, NaH, dry
DMF, 0 °C–room temp., 2 h.
It was pleasing to discover that the reaction with Cs2CO3 though these products were obtained as a mixture of dia-
as base in dry DMF in 2 h furnished 10 as the sole product stereomers, based on the literature precedence of the chemi-
in 92% yields (Scheme 3). Additionally this procedure did cal shift of the CH proton it was found that the dia-
not require chromatographic purification as 10 was ob- stereomers where the phenyl and the ester groups were
532
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Eur. J. Org. Chem. 2010, 531–539

Fused β-Carbolines via Intramolecular 1,3-Dipolar Cycloaddition
placed syn to each other were formed in major quantity.[6]
Unfortunately these diastereomers could not be separated
via column chromatography.
Scheme 5. Reagents and conditions: i) propargyl bromide, Cs2CO3,
dry DMF, room temp., 2–3 h. ii) AcOH/H2O (2:3, v/v), reflux,
45 min. iii) NH2OH·HCl, AcONa, MeOH, reflux, 1–1.5 h. iv) Na-
OCl, Et3N, CH2Cl2, room temp., 3 d.
Scheme 4. Reagents and conditions: i) methyl 2-bromomethyl-3- evaluate this reaction under microwave heating. It was
phenylacrylate, methyl 2-bromomethyl-3-(4-chlorophenyl)acrylate,
pleasing to note that the reaction of 40 in the presence of
methyl 2-bromomethyl-3-(4-fluorophenyl)acrylate, methyl 2-bro-
In(OTf)3 in DCE at 150 °C was completed in 15 min to af-
momethyl-3-pTol-acrylate, Cs2CO3, dry DMF, room temp., 3 h. ii)
ford the desired product 52 in 83% yield (Scheme 6). En-
AcOH/H2O (2:3, v/v), reflux, 45 min. iii) NH2OH·HCl, AcONa,
couraged by these results we repeated the reaction with sub-
strate 39 and 41 under microwave heating and in both cases
the reaction was complete in 10 min to yield the β-carbol-
ine-containing triazoles 51 and 53 in 72% and 55% yield,
respectively. Similar reaction with the alkene 23 under mi-
crowave heating, however, yielded the diazido derivative 54
in 54% yield (Scheme 7). An analogous derivative was ob-
tained as side product also by Taguchi et al.
MeOH, reflux, 1 h. iv) NaOCl, Et3N, CH2Cl2, room temp., 3 d.
Having established the protocol with allyl bromides, we
next shifted our investigations to substrates afforded from
the reaction of 7–9 with propargyl bromide. For this pur-
pose, initially substrates 7–9 were treated with propargyl
bromide in dry DMF using Cs2CO3 as the base to smoothly
furnish the desired product 39–41, respectively in good
yields (Scheme 5). Deprotection of the acetal moiety in the
presence of AcOH/H2O resulted in the formation of alde-
hydes 42–44. Transformation of 42–44 to oximes 45–47 was
achieved by their reaction with NH2OH·HCl. Treating ox-
imes 45–47 with NaOCl produced the required isoxazole
derivatives 48–50.
Recently Taguchi and co-workers reported an In(OTf)3-
catalysed efficient azidation reaction of ω,ω-dialkoxy alkyne
with TMSN3 and its further application in 1,3-dipolar cy-
cloaddition reaction to yield the annulated six and five
membered ring system under heating condition.[7] Inspired
by their results, we envisaged that the ε,ε-dimethoxy alkyne
derivatives 39–41 generated during the present study may
undergo similar reaction to afford β-carboline-based system
containing seven-member -ring found in natural com-
Scheme 6. Reagents and conditions: i) TMSN3, DCE, MW, 150 °C,
10–15 min.
The triazoles 51–53 generated via the above-reported se-
pounds such as maxomine, arborescidine-B, C and D. With quence invariably carried the methoxy group originating
the aim to optimize the conditions, in the first instance ace- from the acetal moiety of the precursor. Hence it was de-
tal 39 was treated with TMSN3 in the presence of In- cided to formulate another simple route for generating such
(OTf)3 in dry DCE under heating at 50 °C. The reaction triazole derivative devoid of the methoxy substitution. Con-
was observed to be sluggish and took 3 d to go to comple- sequently, in a model study 42 was subjected to reduction
tion to yield the desired product in 67% yield. However, with NaBH4 to yield the alcohol 55 as a solid in 96% yield
when the same conditions were applied to reaction of acetal (Scheme 8). Reacting 55 with mesyl chloride in the presence
40, even after 5 d only 30% (HPLC analysis) conversion of Et3N in dichloromethane led to the mesyl derivative 56
was observed. To facilitate the reaction it was decided to (85%). Treatment of 56 with NaN3 in DMF under heating
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533

V. Singh, S. Hutait, S. Biswas, S. Batra
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of a library of β-carboline fused systems containing D-ring
via intramolecular 1,3-dipolar cycloaddition reactions. This
approach is attractive because all reagents utilized in the
study are cheap and readily available and reaction condi-
tions are simple. Although we have showcased 1,3-dipolar
cycloaddition only for building up new β-carbolines, we en-
visage that this aldehyde could provide intermediates for
RCM, Diels–Alder and other established reactions for con-
structing a large library of β-carboline-based derivatives.
Work toward these objectives is underway in our laboratory.
Scheme 7. i) TMSN3, DCE, MW, 150 °C, 15 min.
for 3 h gave the product in 95% yield which was spectro-
scopically analysed to be the desired compound 57. Fortu-
nately in this sequence of reactions at no stage purification
protocols were required.
Experimental Section
General: Melting points are uncorrected and were determined in
capillary tubes on a Precision melting point apparatus containing
silicon oil. IR spectra were recorded using a Perkin–Elmer’s RX I
FTIR spectrophotometer. 1H NMR and 13C NMR spectra were
recorded either on a Bruker DPX-200 FT or Bruker Avance DRX-
300 spectrometer, using TMS as an internal standard (chemical
shifts are given as δ values). The ESMS were recorded on
MICROMASS Quadro-II LCMS system. The HRMS spectra were
recorded as EI-HRMS on a JEOL system or as DART-HRMS
(recorded as ES+) on a JEOL-AccuTOF JMS-T100LC Mass spec-
trometer having DART (Direct Analysis in Real Time) source. Ele-
mental analyses were performed on a Carlo–Erba’s 108 or an Ele-
mentar’s Vario EL III microanalyzer. Microwave-mediated reac-
tions were performed in Biotage initiator 2.5 microwave system.
The room temperature varied between 21 °C and 35 °C. 13C NMR
could not be recorded for a few derivatives (fluoro-analogs) due to
poor solubility even in [D6]DMSO.
Scheme 8. Reagents and conditions: i) NaBH4, MeOH, room
temp., 20 min. ii) MsCl, Et3N, CH2Cl2, 0 °C, 45 min. iii) NaN3,
DMF, 90 °C, 3 h.
In order to further diversify the range of the products
which could be generated by applying intramolecular 1,3-
dipolar cycloaddition reaction, we decided to generate un-
stable azomethane ylide which may have the potential to
react with alkyne. Towards this objective aldehyde 42 was
treated with sarcosine in dry toluene under refluxing condi-
tion. This reaction resulted in compound 61 (Scheme 9).
Repeating the reaction with 43 and 44 with sarcosine
yielded the β-carboline-fused pyrroles 62–63, albeit in low
yield. The final product may have formed via oxidation of
the intermediate 58–60.
General Procedure for the Synthesis of Compounds 10, 12–13, 23–
26, 39–41, as Exemplified for Compound 10: To a stirred solution
of 7 (6.0 g, 20.0 mmol) in dry DMF (30 mL), Cs2CO3 (9.8 g,
30.0 mmol) was added and stirred the reaction at room temperature
for 30 min. Thereafter allyl bromide (2.6 mL, 30.0 mmol) in 5 mL
dry DMF was added drop wise and the reaction was stirred for
additional 1.5 h at room temperature. On completion of the reac-
tion as monitored by TLC, the contents were poured into water
(150 mL) whilst stirring with a glass rod. Thereafter the aqueous
layer was extracted with EtOAc (4ϫ60 mL). The organic layers
were combined and washed with water (40 mL), subsequently with
brine (80 mL), dried with anhydrous Na2SO4 and concentrated to
yield the product (6.25 g from 6.00 g, 92%) which was utilized for
the next step without any purification. For analytical grade, purifi-
cation via short silica gel (60–120 mesh) column chromatography
[EtOAc/hexane, 30:70, Rf = 0.50 (EtOAc/hexane, 20:80, v/v)] af-
forded 10 as a white solid.
Methyl 9-Allyl-1-(dimethoxymethyl)-9H-β-carboline-3-carboxylate
(10): M.p. 106–108 °C. IR (KBr): νmax = 1721 (CO2CH3) cm–1. 1H
˜
NMR (300 MHz, CDCl3): δ = 3.51 (s, 6 H, 2ϫOCH3), 4.05 (s, 3
H, CO2CH3), 4.97 (dd, J1 = 1.2, J2 = 10.4 Hz, 1 H, =CHH), 5.15
(dd, J1 = 1.2, J2 = 10.4 Hz, 1 H, =CHH), 4.49 (q, J = 1.7 Hz, 2 H,
CH2N), 5.76 (s, 1 H, CHOCH3), 5.96–6.07 (m, 1 H, =CH), 7.36 (t,
J = 7.4 Hz, 1 H, ArH), 7.51 (d, J = 8.3 Hz, 1 H, ArH), 7.59–7.65
(m, 1 H, ArH), 8.20 (d, J = 7.8 Hz, 1 H, ArH), 8.90 (s, 1 H, ArH)
ppm. 13C NMR (50 MHz, CDCl3): δ = 48.9, 52.8, 55.8, 109.7,
111.5, 116.0, 118.4, 120.9, 121.3, 121.7, 128.9, 131.2, 134.1, 135.5,
135.7, 141.0, 142.6, 166.6 ppm. MS (ES): m/z (%) = 341.0 (100) [M
+ 1]+, 363.2 (30) [M + 23]+. C19H20N2O4 (340.1423): calcd. C 67.05,
Scheme 9. Reagents and conditions: 1) Sarcosine, dry PhMe, reflux,
24–36 h.
Conclusions
In summary, we have disclosed the potential of substi-
tuted 1-formyl-9H-β-carbolines for achieving the synthesis H 5.92, N 8.23; found C 67.23, H 6.05, N 8.02.
534 Eur. J. Org. Chem. 2010, 531–539
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Fused β-Carbolines via Intramolecular 1,3-Dipolar Cycloaddition
(9-Allyl-9H-β-carbolin-1-yl)(methoxy)methyl Methyl Ether (12):
The title compound was prepared following the above described
general procedure and after purification by column chromatog-
raphy [EtOAC/hexane, 08:92, v/v, Rf = 0.60 (EtOAC/hexane, 80:20,
ArH), 7.45–7.50 (m, 1 H, ArH), 7.70 (s, 1 H, ArH), 7.99 (d, J =
7.8 Hz, 1 H, ArH), 8.72 (d, J = 2.8 Hz, 1 H, ArH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 44.9, 52.3, 52.8, 55.9, 109.9, 111.4, 118.1,
120.3, 120.8, 121.1, 127.5, 128.6, 128.9, 129.0, 129.5, 131.1, 132.1,
139.6, 140.9, 166.5, 167.3 ppm. MS (ES): m/z (%) = 509.1 (100) [M
v/v)] was obtained as yellow oil (3.00 g from 3.20 g); yield 80%. IR
1
(neat): ν
= 3020 (NH) cm–1. H NMR (300 MHz, CDCl3): δ = + 1]+. C27H25ClN2O6 (508.1461): calcd. C 63.72, H 4.95, N 5.50;
˜
max
3.48 (s, 6 H, 2ϫOCH3), 4.89 (d, J = 17.3 Hz, 1 H, =CHH), 5.12 found C 63.68, H 5.08, N 5.59.
(d, J = 17.3 Hz, 1 H, =CHH), 5.41 (t, J = 2.2 Hz, 2 H, CH2N),
(E)-Methyl 1-(Dimethoxymethyl)-9-[3-(4-fluorophenyl)-2-(methoxy-
5.78 (s, 1 H, CHOCH3), 6.01–6.10 (m, 1 H, =CH), 7.30 (t, J =
7.5 Hz, 1 H, ArH), 7.45 (d, J = 8.3 Hz, 1 H, ArH), 7.59 (t, J =
7.7 Hz, 1 H, ArH), 8.02 (d, J = 5.1 Hz, 1 H, ArH), 8.15 (d, J =
7.8 Hz, 1 H, ArH), 8.43 (d, J = 5.1 Hz, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 48.2, 54.7, 107.1, 110.7, 115.3, 115.7, 120.0,
121.2, 121.3, 128.6, 131.0, 134.2, 134.3, 137.2, 140.4, 142.2 ppm.
MS (ES): m/z (%) = 283.0 (100) [M + 1]+. C17H18N2O2 (282.1368):
calcd. C 72.32, H 6.43, N 9.92; found C 72.57, H 6.56, N 9.85.
carbonyl)allyl]-9H-pyrido[3,4-b]indole-3-carboxylate (25): The title
compound was prepared following the above described general pro-
cedure and after purification by column chromatography [EtOAC/
hexane, 25:75, v/v, Rf = 0.38 (EtOAC/hexane, 30:70, v/v)] was ob-
tained as white solid (1.13 g from 1.00 g); yield 69%; m.p. 203–
205 °C. IR (KBr): ν
= 1718 (CO2CH3) cm–1. 1H NMR
˜
max
(300 MHz, CDCl3): δ = 3.55 (s, 6 H, 2ϫOCH3), 3.57 (s, 3 H,
=CO2CH3), 4.06 (d, J = 2.7 Hz, 3 H, CO2CH3), 5.84 (d, J = 5.0 Hz,
1 H, CHOCH3), 6.00 (s, 2 H, CH2N), 6.55 (t, J = 8.5 Hz, 2 H,
ArH), 6.88 (t, J = 6.6 Hz, 2 H, ArH), 7.11 (d, J = 8.3 Hz, 1 H,
ArH), 7.24 (q, J = 6.2 Hz, 1 H, ArH), 7.46 (t, J = 7.7 Hz, 1 H,
ArH), 7.73 (s, 1 H, ArCH), 7.99 (d, J = 7.7 Hz, 1 H, ArH), 8.74
(d, J = 4.9 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ =
44.8, 52.2, 52.8, 55.8, 109.8, 111.4, 114.3, 114.7, 118.1, 120.8, 121.1,
121.7, 128.6, 128.8, 129.7, 129.8, 129.9, 131.0, 135.4, 136.8, 139.9,
Methyl
9-Allyl-1-(dimethoxymethyl)-6-fluoro-9H-β-carboline-3-
carboxylate (13): The title compound was prepared following the
above described general procedure and after purification by tritu-
rating with hexane [Rf = 0.55 (EtOAC/hexane, 30:70, v/v)] was ob-
tained as white solid (0.766 g from 0.800 g); yield 85%; m.p. 114–
116 °C. IR (KBr): ν
= 1712 (CO2CH3) cm–1. 1H NMR
˜
max
(300 MHz, CDCl3): δ = 3.52 (s, 6 H, 2ϫOCH3), 4.05 (s, 3 H,
CO2CH3), 4.97 (dd, J1 = 1.1, J2 = 17.3 Hz, 1 H, =CHH), 5.15 (dd,
J1 = 1.1, J2 = 10.4 Hz, 1 H, =CHH), 4.48 (q, J = 1.7 Hz, 2 H,
CH2N), 5.75 (s, 1 H, CHOCH3), 5.95–6.07 (m, 1 H, =CH), 7.32–
7.39 (s, 1 H, ArH), 7.45 (q, J = 4.2 Hz, 1 H, ArH), 7.84 (dd, J1 =
2.4, J2 = 8.3 Hz, 1 H, ArH), 8.84 (s, 1 H, ArH) ppm. 13C NMR
(50 MHz, CDCl3): δ = 49.2, 52.8, 55.8, 106.5, 106.9, 109.9, 112.5,
112.7, 116.2, 117.0, 117.5, 118.6, 122.1, 122.3, 130.5, 130.6, 134.0,
135.3, 136.4, 138.9, 141.4, 155.7, 160.5, 166.4 ppm. MS (ES): m/z
(%) = 359.0 (100) [M + 1]+. C19H19FN2O4 (358.1329): calcd. C
63.68, H 5.34, N 7.82; found C 63.83, H 5.53, N 7.91.
140.8, 141.9, 166.5, 167.4 ppm. MS (ES): m/z (%) = 493.1 (M+
+
1, 30%), 515.2 (100) [M + 23]+. C27H25FN2O6 (492.1697): calcd. C
65.85, H 5.12, N 5.69; found C 65.97, H 5.34, N 5.77.
(E)-Methyl 1-(Dimethoxymethyl)-9-[2-(methoxycarbonyl)-3-p-tolyl-
allyl]-9H-pyrido[3,4-b]indole-3-carboxylate (26): The title com-
pound was prepared following the above described general pro-
cedure and after purification by column chromatography [EtOAC/
hexane, 25:75, v/v, Rf = 0.52 (EtOAC/hexane, 30:70, v/v)] was ob-
tained as a white solid (1.93 g from 1.50 g); yield 79%; m.p. 162–
164 °C. IR (KBr): ν
= 1720 (CO2CH3) cm–1. 1H NMR
˜
max
(300 MHz, CDCl3): δ = 2.27 (s, 3 H, ArCH3), 3.39 (s, 3 H,
=CO2CH3), 3.54 (s, 6 H, 2ϫOCH3), 4.06 (s, 3 H, ArCO2CH3),
5.89 (s, 1 H, CHOCH3), 6.02 (d, J = 8.0 Hz, 2 H, CH2N), 6.94 (t,
J = 8.0 Hz, 2 H, ArH), 7.03–7.08 (m, 3 H, ArH), 7.22–7.27 (m, 1
H, ArH), 7.41–7.46 (m, 1 H, ArH), 7.78 (s, 1 H, ArCH), 8.03 (d,
J = 7.7 Hz, 1 H, ArH), 8.77 (s, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.3, 44.4, 51.9, 52.7, 55.5, 109.0, 111.6,
118.1, 120.7, 121.1, 121.8, 128.2, 128.5, 128.8, 131.0, 131.3, 135.3,
137.2, 138.7, 140.8, 141.5, 142.0, 166.7, 167.4 ppm. MS (ES): m/z
(%) = 489.1 (100) [M + 1]+. C28H28N2O6 (488.1947): calcd. C 68.84,
H 5.78, N 5.73; found C 68.99, H 5.65, N 5.86.
(E)-Methyl 1-(Dimethoxymethyl)-9-[2-(methoxycarbonyl)-3-phen-
ylallyl]-9H-pyrido[3,4-b]indole-3-carboxylate (23): The title com-
pound was prepared following the above described general pro-
cedure and after purification by column chromatography [EtOAC/
hexane, 20:80, v/v, Rf = 0.45 (EtOAC/hexane, 30:70, v/v)] was ob-
tained as a white solid (1.80 g from 1.50 g); yield 76%; m.p. 159–
161 °C. IR (KBr): ν
= 1716 (CO2CH3) cm–1. 1H NMR
˜
max
(300 MHz, CDCl3): δ = 3.46 (s, 3 H, =CO2CH3), 3.55 (s, 6 H,
2ϫOCH3), 4.05 (s, 3 H, ArCO2CH3), 5.87 (d, J = 3.2 Hz, 1 H,
CHOCH3), 6.02 (s, 2 H, CH2N), 7.05–7.10 (m, 6 H, ArH), 7.24 (t,
J = 7.7 Hz, 1 H, ArH), 7.45 (t, J = 7.7 Hz, 1 H, ArH), 7.80 (s, 1
H, ArCH), 8.00 (d, J = 7.7 Hz, 1 H, ArH), 8.74 (d, J = 3.2 Hz, 1
H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 44.6, 52.0, 52.7,
55.6, 109.4, 111.5, 118.1, 120.7, 121.1, 121.7, 127.8, 128.2, 128.3,
128.5, 128.8, 131.0, 134.1, 135.3, 137.0, 140.8, 141.1, 142.0, 166.6,
167.3 ppm. MS (ES): m/z (%) = 475.1 (100) [M + 1]+. C27H26N2O6
(474.1791): calcd. C 68.34, H 5.52, N 5.90; found C 68.44, H 5.46,
N 6.13.
Methyl 1-(Dimethoxymethyl)-9-prop-2-ynyl-9H-β-carboline-3-carb-
oxylate (39): The title compound was prepared following the above
described general procedure and purified crystallization by triturat-
ing with EtOAC/hexane, 05:95, v/v, (Rf = 0.48) (EtOAC/hexane,
30:70, v/v) was obtained as a white solid (1.87 g from 2.00 g); yield
83%; m.p. 114–118 °C. IR (KBr): ν
= 2106 (CCH) cm–1. 1H
˜
max
NMR (300 MHz, CDCl3): δ = 2.27 (t, J = 2.9 Hz, 1 H, CCH), 3.56
(s, 6 H, 2ϫOCH3), 4.04 (s, 3 H, CO2CH3), 5.64 (d, J = 2.3 Hz, 2
H, CH2N), 5.77 (s, 1 H, CHOCH3), 7.35–7.40 (m, 1 H, ArH), 7.66–
7.69 (m, 2 H, ArH), 8.17 (d, J = 7.9 Hz, 1 H, ArH), 8.88 (s, 1 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 29.8, 36.5, 52.8, 56.0,
71.9, 79.1, 109.8, 111.1, 118.5, 121.4, 121.5, 121.8, 129.3, 131.5,
135.0, 135.9, 141.1, 142.1, 166.4 ppm. MS (ES): m/z (%) = 338.1
(100) [M + 1]+. EI-HRMS: calcd. for C19H18N2O4 338.1267; found
338.1394.
(E)-Methyl 9-[3-(4-Chlorophenyl)-2-(methoxycarbonyl)allyl]-1-(di-
methoxymethyl)-9H-pyrido[3,4-b]indole-3-carboxylate (24): The title
compound was prepared following the above described general pro-
cedure and after purification by column chromatography [EtOAC/
hexane, 25:75, v/v, Rf = 0.40 (EtOAC/hexane, 30:70, v/v)] was ob-
tained as colorless oil (1.10 g from 1.00 g); yield 65%. IR (neat):
ν
˜
= 1718 (CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ =
max
3.54 (s, 6 H, 2ϫOCH3), 3.62 (d, J = 2.7 Hz, 3 H, =CO2CH3), 4.11
(d, J = 2.7 Hz, 3 H, ArCO2CH3), 5.81 (d, J = 2.7 Hz, 1 H, Methoxy(9-prop-2-ynyl-9H-β-carbolin-1-yl)methyl Methyl Ether
CHOCH3), 5.99 (s, 2 H, CH2N), 6.77 (t, J = 8.0 Hz, 3 H, ArH),
7.62 (dd, J1 = 2.4, J2 = 8.3 Hz, 1 H, ArH), 7.23–7.27 (m, 2 H,
(40): The title compound was prepared following the above de-
scribed general procedure and after purification by column
Eur. J. Org. Chem. 2010, 531–539
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
535

V. Singh, S. Hutait, S. Biswas, S. Batra
FULL PAPER
chromatography (EtOAC/hexane, 20:80, v/v), (Rf = 0.50) (EtOAC/
1 H, ArH), 8.31 (d, J = 7.9 Hz, 1 H, ArH), 8.44 (d, J = 5.2 Hz, 1
hexane, 20:80, v/v) was obtained as a white solid (0.74 g from H, ArH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 44.0, 46.7,
0.87 g); yield 73%; m.p. 115–117 °C. IR (KBr): νmax = 2106 (CCH)
72.1, 110.4, 116.6, 120.2, 121.1, 122.8, 126.7, 128.9, 130.2, 136.1,
139.7, 140.4, 152.8 ppm. MS (ES): m/z (%) = 250.1 (100) [M + 1]
+. C15H11N3O (249.0902): calcd. C 72.28, H 4.45, N 16.86; found
˜
1
cm–1. H NMR (300 MHz, CDCl3): δ = 2.25 (s, 1 H, CCH), 3.54
(s, 6 H, 2ϫOCH3), 5.58 (d, J = 2.4 Hz, 2 H, CH2N), 5.76 (s, 1 H,
CHOCH3), 7.31–7.36 (m, 1 H, ArH), 7.64 (t, J = 2.1 Hz, 2 H, C 72.22, H 4.63, N 16.97.
ArH), 8.00 (t, J = 2.6 Hz, 1 H, ArH), 8.13 (d, J = 7.9 Hz, 1 H,
Methyl 5-Fluoro-9a,10-dihydro-9H-indolo[3,2,1-ij]isoxazolo[4,3-c]-
ArH), 8.41 (d, J = 2.6 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 36.0, 55.4, 71.8, 79.6, 108.9, 110.6, 115.4, 120.5, 121.3,
121.6, 128.8, 131.4, 133.6, 137.6, 140.9, 141.8 ppm. MS (ES): m/z
(%) = 281.0 (100) [M + 1]+. C17H16N2O2 (280.1212): calcd. C 72.84,
H 5.75, N 9.99; found C 73.02, H 5.83, N 10.06.
[1,5]naphthyridine-2-carboxylate (22): The title compound was pre-
pared following the above described general procedure and after
purification by triturating [EtOAc/hexane, 10:90, Rf = 0.35 (CHCl3/
MeOH, 95:05, v/v)] was obtained as yellow solid (0.10 g from
0.20 g); yield 50%; m.p. 211–213 °C. IR (KBr): ν
= 1718
˜
max
1
Methyl 1-(Dimethoxymethyl)-6-fluoro-9-prop-2-ynyl-9H-β-carbol-
ine-3-carboxylate (41): The title compound was prepared following
the above described general procedure and after purification by
triturating with hexane (Rf = 0.46, EtOAC/hexane, 30:70, v/v) was
obtained as white solid (1.33 g from 1.70 g); yield 70%; m.p. 163–
(CO2CH3), 2229 (CNOH), 3450 (OH) cm–1. H NMR (300 MHz,
CDCl3): δ = 4.10 (s, 3 H, CO2CH3), 5.00 (d, J = 10.2 Hz, 1 H,
CHH), 5.29 (d, J = 10.2 Hz, 1 H, CHH), 5.44–5.47 (m, 2 H, CH
and CHH), 6.07–6.17 (m, 1 H, CHH), 7.53 (t, J = 5.0 Hz, 2 H,
ArH), 7.92 (d, J = 7.6 Hz, 1 H, ArH), 9.00 (s, 1 H, ArH) ppm. 13
C
165 °C. IR (KBr): ν
= 1720 (CO2CH3), 2108 (CCH) cm–1. 1H
NMR: not recorded due to poor solubility. MS (ES): m/z (%) = 326.1
˜
max
NMR (300 MHz, [D6]DMSO): δ = 3.21 (s, 1 H, CCH), 3.50 (d, J
(100) [M + 1]+. C17H12FN3O3 (325.0863): calcd. C 62.77, H 3.72,
= 1.0 Hz, 6 H, 2ϫOCH3), 3.94 (s, 3 H, CO2CH3), 5.66 (d, J = N 12.92; found C 62.83, H 3.90, N 12.87.
1.1 Hz, 2 H, CH2N), 5.69 (s, 1 H, CHOCH3), 7.62 (d, J = 9.2 Hz,
Dimethyl
10-Phenyl-9a,10-dihydro-9H-indolo[3,2,1-ij]isoxazolo-
1 H, ArH), 7.82 (dd, J1 = 4.1, J2 = 8.9 Hz, 1 H, ArH), 8.40 (d, J
= 8.9 Hz, 1 H, ArH), 9.06 (d, J = 1.6 Hz, 1 H, ArH) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 36.1, 52.2, 55.7, 74.6, 79.3, 107.5,
107.8, 109.2, 113.0, 113.1, 117.2, 117.6, 118.9, 121.7, 121.9, 130.2,
130.3, 135.0, 135.2, 137.9, 141.1, 156.1, 159.3, 165.4 ppm. MS (ES):
[4,3-c][1,5]naphthyridine-2,9a-dicarboxylate (35): The title com-
pound was prepared following the above described general pro-
cedure and after purification by column chromatography [CHCl3/
MeOH, 95:05, Rf = 0.50 (CHCl3/MeOH, 99:01, v/v)] was obtained
as a light yellow solid (0.113 g from 018 g); yield 63%; m.p. 137–
m/z (%)
= 357.1 (100) [M + +
1]+, 379.2 (30) [M 23]+.
139 °C. IR (KBr): ν
= 1720 (CO2CH3) cm–1. 1H NMR
˜
max
C19H17FN2O4 (356.1172): calcd. C 64.04, H 4.81, N 7.86; found C
64.32, H 4.61, N 7.93.
(300 MHz, CDCl3): δ = 3.31 (d, J = 12.1 Hz, 2 H, 2ϫCHHN),
3.54 (s, 3 H, CO2CH3), 3.65 (s, 3 H, CO2CH3), 4.08 (s, 6 H, 2ϫAr-
CO2CH3), 4.84 (d, J = 12.1 Hz, 2 H, 2ϫCHHN), 6.00 (s, 1 H,
ArCH), 6.15 (s, 1 H, ArCH), 7.35–7.42 (m, 14 H, 2ϫArH), 7.61
(t, J = 7.8 Hz, 2 H, 2ϫArH), 8.10 (d, J = 7.9 Hz, 1 H, ArH), 8.16
(d, J = 7.9 Hz, 1 H, ArH), 8.90 (s, 1 H, ArH), 8.94 (s, 1 H, ArH)
ppm. 13C NMR (50 MHz, CDCl3): δ = 29.8, 45.7, 53.0, 54.2, 64.8,
88.9, 110.5, 119.3, 121.9, 122.6, 123.1, 125.8, 128.2, 129.0, 129.4,
129.5, 129.8, 135.1, 136.5, 139.7, 141.4, 148.6, 166.5, 171.3 ppm.
MS (ES): m/z (%) = 442.2 (100) [M + 1]+. DART-HRMS [ES+]:
calcd. for C25H20N3O5 442.1403; found 442.1391.
General Procedure for the Synthesis of Compounds 20, 21–22, 35–
38, 48–50 as Exemplified for Compound 20: To a solution/suspen-
sion of 17 (0.5 g, 1.29 mmol) in CH2Cl2 (10 mL), NaOCl (10 mL,
4% aq. sol. in water) was added drop wise and stirred the reaction
at room temperature for 3 d. After completion of the reaction as
monitored by TLC, the content was extracted with CHCl3
(3ϫ30 mL). The organic layers were combined and washed with
brine (40 mL), dried with anhydrous Na2SO4 and concentrated to
yield the yellow solid (0.324 g from 0.423 g, 81%) which was puri-
fied via short silica gel (60–120 mesh) column chromatography
[CHCl3/MeOH, 99.5:0.5, Rf = 0.50 (CHCl3/MeOH, 95:05, v/v)] to
obtained 20 as a yellow solid.
Dimethyl
10-(4-Chlorophenyl)-9a,10-dihydro-9H-indolo[3,2,1-ij]-
isoxazolo[4,3-c][1,5]naphthyridine-2,9a-dicarboxylate (36): The title
compound was prepared following the above described general pro-
cedure and after purification by column chromatography [CHCl3/
hexane, 70:30, Rf = 0.48 (CHCl3/MeOH, 99:01, v/v)] was obtained
Methyl 9a,10-Dihydro-9H-indolo[3,2,1-ij]isoxazolo[4,3-c][1,5]naph-
thyridine-2-carboxylate (20): M.p. 243–245 °C. IR (neat): ν
=
˜
max
1712 (CO2CH3), 2110 (CNOH), 3353 (OH) cm–1. 1H NMR as pale yellow solid (0.073 g from 0.15 g); yield 49%; m.p. 154–
(300 MHz, [D6]DMSO): δ = 3.94 (s, 3 H, CO2CH3), 3.94–4.25 (m, 156 °C. IR (KBr): ν
= 1723 (CO2CH3) cm–1. 1H NMR
˜
max
2 H, CH2N), 4.48–4.62 (m, 1 H, CH), 4.93 (t, J = 9.1 Hz, 1 H,
OCHH), 5.13 (q, J = 5.1 Hz, 1 H, OCHH), 7.42 (t, J = 7.1 Hz, 1
(300 MHz, CDCl3): δ = 3.32 (d, J = 12.0 Hz, 2 H, 2ϫCHHN),
3.56 (s, 3 H, CO2CH3), 3.65 (s, 3 H, CO2CH3), 4.08 (s, 6 H, 2ϫAr-
H, ArH), 7.70–7.80 (m, 2 H, ArH), 8.48 (t, J = 7.9 Hz, 1 H, ArH), CO2CH3), 4.84 (d, J = 12.0 Hz, 2 H, 2ϫCHHN), 5.95 (s, 1 H,
8.98 (s, 1 H, ArH) ppm. 13C NMR: not recorded due to poor solubil-
ArCH), 6.12 (s, 1 H, ArCH), 7.25 (d, J = 5.8 Hz, 2 H, 2ϫArH),
ity. MS (ES): m/z (%) = 308.2 (100) [M + 1]+. C17H13N3O3 7.35 (t, J = 6.1 Hz, 4 H, 2ϫArH), 7.41 (d, J = 7.7 Hz, 6 H,
(307.0957): calcd. C 66.44, H 4.26, N 13.67; found C 66.62, H 4.34,
N 13.81.
2ϫArH), 7.63 (t, J = 7.9 Hz, 2 H, 2ϫArH), 8.16 (t, J = 7.9 Hz,
2 H, 2ϫArH), 8.90 (s, 1 H, ArH), 8.93 (s, 1 H, ArH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 45.8, 53.0, 54.2, 64.8, 88.2, 110.5,
119.4, 122.0, 122.6, 123.1, 127.2, 128.4, 129.2, 129.7, 129.9, 130.1,
130.4, 133.6, 135.6, 136.5, 139.8, 141.4, 148.7, 166.5, 171.1 ppm.
MS (ES): m/z (%) = 476.1 (100) [M + 1]+. C25H18ClN3O5
(475.0935): calcd. C 63.10, H 3.81, N 8.83; found C 63.17, H 3.97,
N 8.99.
9a,10-Dihydro-9H-indolo[3,2,1-ij]isoxazolo[4,3-c][1,5]naphthyridine
(21): The title compound was prepared following the above de-
scribed general procedure and after purification by triturating
[EtOAc/hexane, 10:90, Rf = 0.50 (CHCl3/MeOH, 95:05, v/v)] was
obtained as a light brown solid (0.124 g from 0.15 g); yield 83%;
m.p. 218–220 °C. IR (KBr): νmax = 1712 (CO2CH3), 2110 (CNOH),
˜
1
3353 (OH) cm–1. H NMR (300 MHz, [D6]DMSO): δ = 4.06–4.20 Dimethyl 10-(4-Fluorophenyl)-9a,10-dihydro-9H-indolo[3,2,1-ij]isox-
(m, 2 H, CH2), 4.45–4.59 (m, 1 H, CH), 4.90 (dd, J1 = 2.1, J2 =
8.1 Hz, 1 H, OCHH), 5.08 (q, J = 6.9 Hz, 1 H, OCHH), 7.32–7.37
(m, 1 H, ArH), 7.68 (q, J = 7.6 Hz, 2 H, ArH), 8.17 (d, J = 5.2 Hz,
azolo[4,3-c][1,5]naphthyridine-2,9a-dicarboxylate (37): The title
compound was prepared following the above described general pro-
cedure and after purification by triturating [EtOAc/hexane, 20:80,
536
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 531–539

Fused β-Carbolines via Intramolecular 1,3-Dipolar Cycloaddition
Rf = 0.50 (CHCl3/MeOH, 98:02, v/v)] was obtained as a white solid
the above described general procedure and after purification by
triturating with [EtOAC/hexane, 20:80, v/v, Rf = 0.25 (EtOAC/hex-
ane, 50:50, v/v)] was obtained as a light yellow solid (0.127 g from
(0.102 g from 0.16 g); yield 64%; m.p. 156–158 °C. IR (KBr): ν
˜
max
= 1723 (CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.32 (d,
J = 12.1 Hz, 2 H, 2ϫCHHN), 3.64 (s, 6 H, 2ϫCO2CH3), 4.08 (s, 0.20 g); yield 63%; m.p. Ͼ250 °C. IR (KBr): νmax = 1708 (CO2CH3)
˜
6 H, 2ϫArCO2CH3), 4.83 (d, J = 12.0 Hz, 2 H, 2ϫCHHN), 6.13
(s, 2 H, 2ϫArCH), 7.12 (t, J = 7.7 Hz, 4 H, 2ϫArH), 7.39 (s, 8 H,
cm–1. 1H NMR (600 MHz, [D6]DMSO): δ = 3.93 (s, 3 H,
CO2CH3), 5.63 (s, 2 H, CH2N), 7.60–7.63 (m, 1 H, ArH), 7.73 (d,
2ϫArH), 7.61 (d, J = 7.5 Hz, 2 H, 2ϫArH), 8.17 (d, J = 7.1 Hz, 2 J = 4.5 Hz, 1 H, ArH), 8.36 (d, J = 9.7 Hz, 1 H, ArH), 8.99 (s, 1
H, 2ϫArH), 8.90 (s, 2 H, 2ϫArH) ppm. 13C NMR (50 MHz,
CDCl3): δ = 45.8, 53.0, 54.2, 64.8, 88.3, 110.5, 116.4, 116.8, 119.4,
122.0, 122.6, 123.2, 127.7, 127.9, 128.4, 129.8, 130.9, 131.0, 136.5,
139.9, 141.5, 148.7, 160.8, 165.8, 166.5, 171.2 ppm. MS (ES): m/z
(%) = 460.1 (100) [M + 1]+. C25H18FN3O5 (459.1230): calcd. C
65.36, H 3.95, N 9.15; found C 65.43, H 4.13, N 8.99.
H, ArH), 9.15 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, [D6]-
DMSO): not recorded due to poor solubility. MS (ES): m/z (%) =
324.1 (100) [M + 1]+. C17H10FN3O3 (323.0706): calcd. C 63.16, H
3.12, N 13.00; found C 63.34, H 3.04, N 13.29.
General Procedure for the Synthesis of Compounds 51–53 as Exem-
plified for Compound 51: To a solution of 39 (0.162 g, 0.48 mmol)
in dichloroethane (5 mL) in a vial (10–20 mL size), TMSN3
(0.075 mL, 0.57 mmol) and In(OTf)3 (0.028 g, 0.05 mmol) were
added and irradiated with microwave under low absorption at
150 °C for 15 min. with pre-stirring of 30 sec. After completion of
the reaction as monitored by TLC, the content was poured into
10% aqueous NaHCO3 (25 mL) solution and extracted with
CHCl3 (3ϫ30 mL). The organic layers were combined and washed
Dimethyl
10-p-Tolyl-9a,10-dihydro-9H-indolo[3,2,1-ij]isoxazolo-
[4,3-c][1,5]naphthyridine-2,9a-dicarboxylate (38): The title com-
pound was prepared following the above described general pro-
cedure and after purification by triturating [EtOAc/hexane, 10:90,
Rf = 0.50 (CHCl3/MeOH, 99:01, v/v)] was obtained as yellow solid
(0.44 g from 0.53 g); yield 83%; m.p. 148–150 °C. IR (KBr): ν
˜
max
= 1724 (CO2CH3) cm–1. H NMR (300 MHz, CDCl3): δ = 2.34 (s,
1
3 H, ArCH3), 2.40 (s, 3 H, ArCH3), 3.32 (d, J = 12.0 Hz, 2 H, with brine (30 mL), dried with anhydrous Na2SO4 and concen-
2ϫCHHN), 3.56 (s, 3 H, CO2CH3), 3.65 (s, 3 H, CO2CH3), 4.08 trated to yield the off white solid which was further purified via
(s, 6 H, 2ϫArCO2CH3), 4.84 (d, J = 12.0 Hz, 2 H, 2ϫCHHN), short silica gel (60–120 mesh) column chromatography [EtOAC/
6.01 (s, 1 H, ArCH), 6.12 (s, 1 H, ArCH), 7.16–7.26 (m, 8 H,
2ϫArH), 7.34–7.42 (t, 4 H, 2ϫArH), 7.61 (t, J = 7.4 Hz, 2 H,
2ϫArH), 8.02 (t, J = 7.9 Hz, 1 H, ArH), 8.16 (t, J = 7.9 Hz, 1 H,
ArH), 8.89 (s, 1 H, ArH), 8.95 (s, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 21.3, 45.7, 52.9, 54.1, 64.7, 89.0, 110.5,
119.3, 121.8, 122.6, 123.1, 125.7, 128.2, 129.7, 129.9, 130.1, 132.1,
136.5, 139.5, 139.7, 141.5, 148.6, 166.6, 171.3 ppm. MS (ES): m/z
(%) = 456.1 (100) [M + 1]+. DART-HRMS [ES+]: calcd. for
C25H20N3O5 455.1481; found 455.1493.
hexane, 90:10, v/v, Rf = 0.50 (CHCl3/MeOH, 90:10, v/v)] to ob-
tained (0.162 g from 0.22 g, 72%) 51 as a white solid.
Methyl 5-Methoxy-1H,5H-3,4,4a,6,12b-pentaazaazuleno[5,6,7-jk]-
fluorene-7-carboxylate (51): M.p. 243–245 °C. IR (KBr): ν
=
˜
max
1712 (CO2CH3) cm–1. H NMR (300 MHz, CDCl3): δ = 3.55 (s, 3
H, OCH3), 4.09 (s, 3 H, CO2CH3), 5.62 (d, J = 14.9 Hz, 1 H,
CHHN), 5.80 (d, J = 14.9 Hz, 1 H, CHHN), 7.23 (s, 1 H,
CHOCH3), 7.43 (t, J = 7.2 Hz, 1 H, ArH), 7.62 (d, J = 8.4 Hz, 1
H, ArH), 7.71–7.76 (m, 1 H, ArH), 7.82 (s, 1 H, ArHtriazole), 8.22
(d, J = 7.9 Hz, 1 H, ArH), 8.93 (s, 1 H, ArH) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ = 36.3, 52.3, 56.3, 91.8, 110.8, 119.0,
120.1, 121.3, 122.5, 129.6, 130.4, 130.7, 133.9, 134.0, 136.3, 136.6,
140.7, 165.2 ppm. MS (ES): m/z (%) = 350.1 (100) [M + 1]+.
C18H15N5O3 (349.1175): calcd. C 61.89, H 4.33, N 20.05; found C
1
Methyl 9H-Indolo[3,2,1-ij]isoxazolo[4,3-c][1,5]naphthyridine-2-carb-
oxylate (48): The title compound was prepared following the above
described general procedure and after purification by triturating
with [EtOAC/hexane, 20:80, v/v, Rf = 0.25 (EtOAC/hexane, 40:60,
v/v)] was obtained as a light yellow solid (0.127 g from 0.20 g); yield
64%; m.p. Ͼ250 °C. IR (KBr): ν
= 1716 (CO2CH3) cm–1. 1H 62.04, H 4.20, N 20.33.
˜
max
NMR (300 MHz, [D6]DMSO): δ = 3.96 (s, 3 H, CO2CH3), 5.65 (s,
2 H, CH2N), 7.42–7.48 (m, 1 H, ArH), 7.75 (d, J = 3.8 Hz, 2 H,
ArH), 8.49 (d, J = 7.8 Hz, 1 H, ArH), 8.97 (s, 1 H, ArH), 9.17 (s,
1 H, ArH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 53.0, 56.5,
111.8, 113.8, 120.3, 121.6, 122.2, 122.3, 123.9, 126.9, 130.1, 137.0,
138.2, 141.5, 156.9, 166.5 ppm. MS (ES): m/z (%) = 306.1 (100) [M
+ 1]+. C17H11N3O3 (305.0800): calcd. C 66.88, H 3.63, N 13.76;
found C 66.72, H 3.75, N 13.97.
1H,5H-3,4,4a,6,12b-Pentaazaazuleno[5,6,7-jk]fluoren-5-yl Methyl
Ether (52): The title compound was prepared following the above-
described general procedure and after purification by column
chromatography [EtOAC/hexane, 70:30, v/v, Rf = 0.50 (CHCl3/
MeOH, 95:05, v/v)] was obtained as a white solid (0.65 g from
0.75 g); yield 81%; m.p. 173–175 °C. IR (KBr): ν
= 1074, 1448,
˜
max
1621, 2829, 2928, 3423 cm–1. 1H NMR (300 MHz, CDCl3): δ =
3.56 (s, 3 H, OCH3), 5.56 (d, J = 14.8 Hz, 1 H, CHHN), 5.76 (d,
J = 14.8 Hz, 1 H, CHHN), 7.07 (s, 1 H, CHOCH3), 7.36 (t, J =
7.8 Hz, 1 H, ArH), 7.58 (d, J = 8.3 Hz, 1 H, ArH), 7.66–7.72 (m,
1 H, ArH), 7.81 (m, 1 H, ArH), 8.03 (d, J = 5.2 Hz, 1 H, ArH),
8.16 (d, J = 7.8 Hz, 1 H, ArH), 8.49 (d, J = 5.2 Hz, 1 H, ArH)
ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 36.8, 57.1, 93.4, 109.1,
9H-Indolo[3,2,1-ij]isoxazolo[4,3-c][1,5]naphthyridine (49): The title
compound was prepared following the above described general pro-
cedure and after purification by column chromatography [CHCl3/
MeOH, 95:05, Rf = 0.50 (CHCl3/MeOH, 95:05, v/v)] was obtained
as a brown solid (0.124 g from 0.20 g); yield 63%; m.p. 246–248 °C.
IR (KBr): νmax = 1716 (CO2CH3) cm–1. 1H NMR (300 MHz, [D6]- 116.3, 120.7, 120.8, 122.1, 129.3, 130.2, 131.0, 133.3, 133.6, 137.2,
˜
DMSO): δ = 5.59 (d, J = 1.0 Hz, 2 H, CH2N), 7.36–7.41 (m, 1 H,
ArH), 7.69 (d, J = 3.7 Hz, 2 H, ArH), 8.16 (d, J = 5.3 Hz, 1 H,
ArH), 8.32 (d, J = 7.9 Hz, 1 H, ArH), 8.42 (d, J = 5.3 Hz, 1 H,
ArH), 9.11 (s, 1 H, ArH) ppm. 13C NMR (50 MHz, [D6]DMSO):
δ = 38.7, 110.5, 112.7, 116.8, 120.4, 121.2, 122.7, 126.2, 128.8,
129.7, 134.9, 139.3, 140.3, 154.1, 155.6 ppm. MS (ES): m/z (%) =
248.1 (100) [M + 1]+. C15H9N3O (247.0746): calcd. C 72.87, H 3.67,
N 16.99; found C 72.96, H 3.87, N 17.02.
138.8, 140.4 ppm. MS (ES): m/z (%) = 292.1 (100) [M + 1]+.
DART-HRMS [ES+]: calcd. for C16H14N5O 292.1198; found
292.1181.
Methyl
5-Fluoro-12-methoxy-8H,12H-1,7b,10,11,11a-pentaaza-
azuleno[5,6,7-jk]fluorene-2-carboxylate (53): The title compound
was prepared following the above described general procedure and
after purification by column chromatography [EtOAC/hexane,
90:10, v/v, Rf = 0.50 (CHCl3/MeOH, 90:10, v/v)] was obtained as
a white solid (0.189 g from 0.28 g); yield 66%; m.p. Ͼ245 °C. IR
Methyl 5-Fluoro-9H-indolo[3,2,1-ij]isoxazolo[4,3-c][1,5]naphthyrid-
ine-2-carboxylate (50): The title compound was prepared following
(KBr): ν
= 1709 (CO2CH3) cm–1. 1H NMR (300 MHz, [D6]-
˜
max
Eur. J. Org. Chem. 2010, 531–539
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
537

V. Singh, S. Hutait, S. Biswas, S. Batra
FULL PAPER
DMSO): δ = 3.46 (s, 3 H, OCH3), 3.95 (s, 3 H, CO2CH3), 5.50 (d,
J = 15.2 Hz, 1 H, CHHN), 6.40 (d, J = 15.2 Hz, 1 H, CHHN),
Typical Procedure for the Synthesis of Compounds 57: To a solution
of 56 (0.40 g, 1.08 mmol) in dry DMF (8 mL), NaN3 (0.14 g,
7.05 (s, 1 H, CHOCH3), 7.64–7.71 (m, 1 H, ArH), 8.00 (s, 1 H, 2.16 mmol) was added and heated at 90 °C for 3 h. After comple-
ArHtriazole), 8.04 (q, J = 4.5 Hz, 1 H, ArH), 8.41 (dd, J1 = 2.5, J2 tion of the reaction as monitored by TLC, the content was poured
= 8.9 Hz, 1 H, ArH), 9.12 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, into water (100 mL) and extracted with EtOAc (3ϫ30 mL). The
[D6]DMSO): δ = 36.6, 52.3, 56.3, 91.7, 107.9, 108.2, 112.3, 112.4,
117.6, 117.9, 119.5, 120.7, 120.8, 129.8, 129.9, 130.6, 134.1, 134.7,
136.1, 137.0, 137.2, 155.9, 159.0, 165.2 ppm. MS (ES): m/z (%) =
368.1 (100) [M + 1]+. C18H14FN5O3 (367.1081): calcd. C 58.85, H
3.84, N 19.07; found C 58.76, H 3.96, N 19.23.
organic layers were combined and washed with water (50 mL) and
brine (30 mL), dried with anhydrous Na2SO4 and concentrated to
yield the crude product which was further purified by triturating
with EtOAC/hexane, 05:95, v/v, (Rf = 0.35) (CHCl3/MeOH, 95:05,
v/v) to yield 57 as a white solid (0.33 g from 0.40 g, 95%).
Methyl
1H,5H-3,4,4a,6,12b-Pentaazaazuleno[5,6,7-jk]fluorene-7-
Typical Procedure for the Synthesis of Compound 55: To a stirred
suspension of 42 (1.50 g, 5.12 mmol) in dry methanol (60 mL),
NaBH4 (0.28 g, 7.68 mmol) was added in small portions at 0 °C.
After the addition was complete, the reaction was continued for
20 min at room temperature. On completion of the reaction as
monitored by TLC, the precipitated solid was filtered and dried in
air. The filtrate was evaporated in vacuo and the residue was dis-
solved in EtOAc (50 mL). Thereafter water (50 mL) was added and
the organic layer partitioned in a separating funnel. The aqueous
layer was further extracted with EtOAc (2ϫ30 mL). The organic
layers were combined and washed with brine (30 mL), dried with
anhydrous Na2SO4 and concentrated to yield a yellowish product
which was pooled with the solid isolated earlier. The crude product
was further purified by triturating with EtOAC/hexane, 05:95, v/v,
[Rf = 0.50 (EtOAC/hexane, 40:60, v/v)] to afford 55 as a yellowish
brown solid (1.45 g from 1.50 g, 96%).
carboxylate (57): M.p. Ͼ250 °C. IR (KBr): νmax = 1712 (CO2CH3)
˜
cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.08 (s, 3 H, CO2CH3),
5.71 (s, 2 H, CH2), 6.37 (s, 2 H, CH2), 7.42 (t, J = 7.5 Hz, 1 H,
ArH), 7.61 (d, J = 8.4 Hz, 1 H, ArH), 7.74 (t, J = 7.5 Hz, 1 H,
ArH), 7.82 (s, 1 H, ArHtriazole), 8.21 (d, J = 7.9 Hz, 1 H, ArH),
8.86 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
36.3, 52.2, 53.3, 110.6, 118.0, 120.1, 122.5, 128.9, 129.3, 132.7,
133.1, 135.4, 136.2, 137.3, 140.5, 165.5 ppm. MS (ES): m/z (%) =
320.1 (100) [M + 1]+. C17H13N5O2 (319.1069): calcd. C 63.94, H
4.10, N 21.93; found C 64.12, H 4.11, N 22.04.
General Procedure for the Synthesis of Compounds 61–63 as Exem-
plified for Compound 61: To a suspension of 42 (0.12 g, 0.41 mmol)
in dry toluene (8 mL), sarcosine (0.30 g, 3.37 mmol) was added and
heated at reflux for 24 h. After completion of the reaction as moni-
tored by TLC, the content was poured into 10% aqueous NaHCO3
(25 mL) solution and extracted with EtOAc (3ϫ30 mL). The or-
ganic layers were combined and washed with brine (30 mL), dried
with anhydrous Na2SO4 and concentrated to yield the crude prod-
uct which was further purified via short silica gel (60–120 mesh)
column chromatography [EtOAc/hexane, 20:80, Rf = 0.50 (EtOAc/
hexane, 20:80, v:v)] to obtained (0.046 g from 0.12 g, 35%) 61 as a
white solid.
Methyl
1-(Hydroxymethyl)-9-prop-2-ynyl-9H-β-carboline-3-carb-
= 1712 (CO2CH3)
oxylate (55): M.p. 215–217 °C. IR (KBr): ν
˜
max
1
cm–1. H NMR (300 MHz, CDCl3): δ = 2.38 (d, J = 2.2 Hz, 1 H,
CCH), 4.05 (s, 3 H, CO2CH3), 5.34 (d, J = 2.2 Hz, 2 H, CH2N),
5.43 (s, 2 H, CH2O), 7.42 (t, J = 7.5 Hz, 1 H, ArH), 7.60 (d, J =
8.6 Hz, 1 H, ArH), 7.70 (t, J = 7.7 Hz, 1 H, ArH), 8.22 (d, J =
7.8 Hz, 1 H, ArH), 8.84 (s, 1 H, ArH) ppm. 13C NMR (50 MHz,
[D6]DMSO): δ = 33.7, 52.0, 64.1, 75.6, 79.7, 110.8, 117.4, 121.1,
121.2, 122.0, 129.1, 129.6, 135.7, 136.0, 141.1, 143.6, 165.6 ppm.
MS (ES): m/z (%) = 295.1 (100) [M + 1]+. C17H14N2O3 (294.1004):
calcd. C 69.38, H 4.79, N 9.52; found C 69.51, H 4.93, N 9.69.
Methyl
12-Methyl-9,12-dihydroindolo[3,2,1-ij]pyrrolo[3,2-c][1,5]-
naphthyridine-2-carboxylate (61): M.p. 153–155 °C. IR (KBr): ν
˜
max
= 1724 (CO2CH3) cm–1. H NMR (300 MHz, CDCl3): δ = 4.01 (s,
3 H, CO2CH3), 4.34 (s, 3 H, NCH3), 5.57 (s, 2 H, CH2N), 6.15 (d,
J = 2.6 Hz, 1 H, ArHpyrrole), 6.81 (d, J = 2.6 Hz, 1 H, ArHpyrrole),
7.36 (d, J = 7.9 Hz, 1 H, ArH), 7.44 (d, J = 8.2 Hz, 1 H, ArH),
7.57–7.62 (m, 1 H, ArH), 8.12 (d, J = 7.9 Hz, 1 H, ArH), 8.52 (s,
1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 36.5, 43.4, 52.4,
106.0, 109.8, 116.1, 119.4, 120.7, 122.2, 122.7, 123.2, 127.4, 127.6,
134.2, 136.0, 136.3, 140.5, 167.2 ppm. MS (ES): m/z (%) = 318.1
(100) [M + 1]+. C19H15N3O2 (317.1164): calcd. C 71.91, H 4.76, N
13.24; found C 72.26, H 4.96, N 13.43.
1
Typical Procedure for the Synthesis of Compounds 56: To a suspen-
sion of 55 (0.70 g, 2.37 mmol) in dry dichloromethane (30 mL),
Et3N (0.49 mL, 3.56 mmol) was added and stirred at 0 °C for
10 min. Thereafter MsCl (0.23 mL, 2.85 mmol) in dichloromethane
(5 mL) was added drop wise at 0 °C and continued stirring for ad-
ditional 45 min. After completion of the reaction as monitored by
TLC, the content was poured into water and extracted with CHCl3
(3ϫ30 mL). The organic layers were combined and washed with
brine (30 mL), dried with anhydrous Na2SO4 and concentrated to
yield the crude product which was further purified by triturating
with EtOAc/hexane, 05:95, v/v, Rf = 0.60 (EtOAC/hexane, 40:60,
v/v) to obtain 56 as a brown solid (0.75 g from 0.70 g, 85%); m.p.
188–190 °C.
12-Methyl-9,12-dihydroindolo[3,2,1-ij]pyrrolo[3,2-c][1,5]naphthyrid-
ine (62): The title compound was prepared following the above de-
scribed general procedure and after purification by short silica gel
(60–120) column chromatography [EtOAC/hexane, 10:90, v/v, Rf =
0.60 (EtOAC/hexane, 10:90, v/v)] was obtained as white solid
(0.08 g from 0.20 g); yield 38%; m.p. 145–147 °C. IR (KBr): ν
˜
max
Methyl 1-[(Methylsulfonyloxy)methyl]-9-(prop-2-ynyl)-9H-pyrido-
= 1216, 2145, 2928, 3021, 3451 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 4.27 (s, 3 H, NCH3), 5.58 (s, 2 H, CH2N), 6.15 (s, 1 H,
ArHpyrrole), 6.78 (s, 1 H, ArHpyrrole), 7.26–7.33 (m, 1 H, ArH), 7.42
(d, J = 7.8 Hz, 1 H, ArH), 7.57 (t, J = 5.8 Hz, 2 H, ArH), 8.09 (d,
J = 7.8 Hz, 1 H, ArH), 8.16 (dt, J = 5.8 Hz, 1 H, ArH) ppm. 13C
NMR (50 MHz, CDCl3): δ = 36.7, 43.2, 105.8, 109.4, 112.1, 118.9,
119.7, 122.1, 122.5, 123.8, 124.0, 126.7, 127.1, 136.7, 137.7,
140.2 ppm. MS (ES): m/z (%) = 260.1 (100) [M + 1]+. DART-
HRMS calcd. For C17H14N3 (260.1188); found (260.1183).
[3,4-b]indole-3-carboxylate (56): M.p. 188–190 °C. IR (KBr): ν
˜
max
1
= 1712 (CO2CH3) cm–1. H NMR (300 MHz, CDCl3): δ = 2.40 (t,
J = 2.4 Hz, 1 H, CCH), 3.15 (s, 3 H, SO2CH3), 4.06 (s, 3 H,
CO2CH3), 5.36 (d, J = 2.4 Hz, 2 H, CH2N), 6.01 (s, 2 H, CH2O),
7.45 (t, J = 7.5 Hz, 1 H, ArH), 7.62 (d, J = 8.3 Hz, 1 H, ArH),
7.74 (t, J = 7.3 Hz, 1 H, ArH), 8.22 (d, J = 7.9 Hz, 1 H, ArH),
8.93 (s, 1 H, ArH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ =
34.8, 52.3, 72.6, 76.9, 78.9, 110.9, 117.8, 120.6, 120.7, 121.6, 122.2,
129.6, 130.2, 133.8, 135.8, 137.6, 141.4, 165.2 ppm. MS (ES): m/z
(%) = 373.1 (100) [M + 1]+. C18H16N2O5S (372.0780): calcd. C
58.05, H 4.33, N 7.52; found C 58.21, H 4.46, N 7.50.
Methyl 5-Fluoro-12-methyl-9,12-dihydroindolo[3,2,1-ij]pyrrolo[3,2-c]-
[1,5]naphthyridine-2-carboxylate (63): The title compound was pre-
538
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 531–539

Fused β-Carbolines via Intramolecular 1,3-Dipolar Cycloaddition
ences cited therein; b) T. Hudlicky, J. W. Reed, The Way of
Synthesis, Wiley-VCH, Weinheim, 2007; Introduction to Alka-
loids: A Biosynthetic Approach (Ed.: G. A. Cordell), Wiley,
New York, NY, 1981; c) J. E. Saxton, in: The Alkaloids: Chem-
istry and Biology (Ed.: G. A. Cordell), Academic Press, San
Diego, CA, 1998, vol. 51, pp. 1–197; d) T. A. Mansoor, C. Ra-
malhete, J. Molnar, S. Mulhovo, M. J. U. Ferreira, J. Nat. Prod.
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Trans. R. Soc. Trop. Med. Hyg. 2008, 102, 1089–1094; f) K.
Higuchi, T. Kawasaki, Nat. Prod. Rep. 2007, 24, 843–868; g) T.
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R. Cao, W. Peng, Z. Wang, A. Xung, Curr. Med. Chem. 2007,
14, 479–500 and references cited therein.
pared following the above described general procedure and after
purification by column chromatography [EtOAC/hexane, 20:80,
v/v, Rf = 0.50 (EtOAC/hexane, 20:80, v/v)] was obtained as white
solid (0.07 g from 0.20 g); yield 32%; m.p. 159–161 °C. IR (KBr):
ν
= 1719 (CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ =
˜
max
4.00 (s, 3 H, CO2CH3), 4.31 (s, 3 H, NCH3), 5.51 (s, 2 H, CH2N),
6.13 (d, J = 2.6 Hz, 1 H, ArHpyrrole), 6.79 (d, J = 2.6 Hz, 1 H,
ArHpyrrole), 7.31–7.34 (m, 2 H, ArH), 7.73 (t, J = 8.1 Hz, 1 H,
ArH), 8.41 (s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3 or [D6]-
DMSO): not recorded due to poor solubility. MS (ES): m/z (%) =
336.1 (100) [M + 1]+. C19H14FN3O2 (335.1070): calcd. C 68.05, H
4.21, N 12.53; found C 67.83, H 4.35, N 12.78.
[2]
[3]
[4]
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6216.
Supporting Information (see also the footnote on the first page of
this article): Experimental details, spectroscopic data for remaining
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1
compounds and copies of H and 13C NMR spectra for all com-
pounds are provided.
Acknowledgments
Three of the authors (V. S., S. H. and S. B.) gratefully acknowledge
the financial support from Council of Scientific and Industrial Re-
search, New Delhi. This work was partially supported by a grant
from Department of Science and Technology, New Delhi.
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Received: October 15, 2009
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Published Online: December 4, 2009
Eur. J. Org. Chem. 2010, 531–539
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
539