New route to the synthesis of the isocryptolepine alkaloid and its related skeletons using a modified Pictet-Spengler reaction

Article abstract of DOI:10.1002/ejoc.200800929

A new route to the synthesis of the isocryptolepine alkaloid with antimalarial activity using a modified Pictet-Spengler reaction has been devised. The strategy was then used to generate libraries based on three structural variants of the alkaloid. Compounds based on these three variants in general were accessed in three steps through a modified Pictet-Spengler cyclization reaction as the key step. The C-2-, C-3-, or N-1-linked (aminoaryl)indoles (8, 12, 13) required for cyclization were obtained by treating the corresponding indoles with o-halonitrobenzene using either nucleophilic re-placement or Pd-based chemistry (Heck/Suzuki reaction) followed by reduction of the nitroaryl functionality. The substrates 8, 12, and 13 were then subjected to the Pictet-Spengler reaction to furnish polycyclic structures, indolo-quinolines 4 and 19 and indolo-quinoxalines 20 with three-point diversity in high yields and purities. One of the indolo-quinolines 4a after treatment with CH3I furnished the isocryptolepine alkaloid in excellent yield. Wiley-VCH Verlag GmbH & Co. KGaA, 2009.

Full text of DOI:10.1002/ejoc.200800929

FULL PAPER
DOI: 10.1002/ejoc.200800929
New Route to the Synthesis of the Isocryptolepine Alkaloid and Its Related
Skeletons Using a Modified Pictet–Spengler Reaction[‡]
Piyush K. Agarwal,[a] Devesh Sawant,[a] Sunil Sharma,[a] and Bijoy Kundu*[a]
Keywords: Cyclization / Natural products / Polycycles / Nitrogen heterocycles
A new route to the synthesis of the isocryptolepine alkaloid
with antimalarial activity using a modified Pictet–Spengler
reaction has been devised. The strategy was then used to
generate libraries based on three structural variants of the
placement or Pd-based chemistry (Heck/Suzuki reaction) fol-
lowed by reduction of the nitroaryl functionality. The sub-
strates 8, 12, and 13 were then subjected to the Pictet–Speng-
ler reaction to furnish polycyclic structures, indolo-quinolines
alkaloid. Compounds based on these three variants in gene- 4 and 19 and indolo-quinoxalines 20 with three-point diver-
ral were accessed in three steps through a modified Pictet–
Spengler cyclization reaction as the key step. The C-2-, C-
3-, or N-1-linked (aminoaryl)indoles (8, 12, 13) required for
cyclization were obtained by treating the corresponding in-
sity in high yields and purities. One of the indolo-quinolines
4a after treatment with CH3I furnished the isocryptolepine
alkaloid in excellent yield.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
doles with o-halonitrobenzene using either nucleophilic re- Germany, 2009)
Introduction
The indole ring system is an important structural compo-
nent in many clinically used therapeutic drugs[1] and in sev-
eral thousand indole alkaloids[2] with important physiologi-
cal activity. It has been estimated that more than one quar-
ter of all known alkaloids are indole derivatives.[3] Numer-
ous methods have been developed for the synthesis of sub-
stituted indoles[4] and indole-containing polycyclic ring sys-
tems.[5] Of the polycyclic alkaloids based on indoles, β-car-
bolines (1),[6] γ-carbolines (2),[7] and isocryptolepine (3)
(Figure 1) have remained interesting synthetic targets owing
to their various biological activities,[8] including antimalar-
ial activity.[9] Isocryptolepine (Figure 1) has been isolated
from the roots of the plant Cryptolepis sanguinolenta, which
displays antimalarial properties[10] and bears a strong struc-
tural resemblance to γ-carboline. However, despite exhibit-
ing promising activity, few attempts have been made to op-
timize its antimalarial activity by synthesizing its ana-
logues.[11] Although there are several reports in the litera-
ture dealing with the synthesis of isocryptolepine,[12] a gene-
ral strategy for generating a library based on this alkaloid
with both structural and chemical diversity has not yet been
described.
Figure 1. Polycyclic structures based on indoles.
Recently, we reported a modified strategy of the Pictet–
Spengler reaction using substrates with an arylamine linked
to an activated heterocyclic ring leading to the formation of
either six-membered quinolines and quinoxalines or seven-
membered diazepines fused to the heterocyclic ring.[13] In
contrast, the substrates used in the traditional Pictet–
Spengler reaction are based on an aliphatic amine linked to
an activated heterocyclic ring, which results in pyridines
fused to the heterocyclic ring. Following the disclosure of
our methodology, several groups[14] have successfully dem-
onstrated the application of our modified Pictet–Spengler
strategy using novel substrates derived from arylamines for
the synthesis of fused six-, seven-, and eight-membered
rings.
[‡] CDRI communication No. 7582.
[a] Medicinal and Process Chemistry Division, Central Drug Re-
search Institute,
As the isocryptolepine alkaloid is based on the in-
dolo[3,2-c]quinoline framework, we decided to apply our
modified Pictet–Spengler reaction[13] to its synthesis. In this
paper we report a new route to the synthesis of the isocryp-
tolepine alkaloid and a library based on three structural
variants of the alkaloid. These studies represent a continua-
Lucknow 226001, India
Fax: +91-522-2623405
E-mail: bijoy_kundu@yahoo.com
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
292
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Synthesis of Isocryptolepine Alkaloid and its Related Skeletons
tion of our interest in the search for novel natural-product- ported the synthesis of isocryptolepine by the intramolecu-
inspired nitrogen-rich polycyclic structures with antimalar- lar decarboxylative Heck-type reaction of indolecarboxylic
ial activity.[15]
acids. Molina et al.[12m] reported the synthesis of the iso-
cryptolepine by cyclization of a 4-(1H-benzotriazol-1-yl)-
quinoline using the Grabe–Ullmann reaction. Surprisingly,
despite being a compound of great biological significance,
the reported strategies are not amenable to the generation
of a library based on isocryptolepine with the exception of
the procedures designed by Cheng[11a] and Maes[11b] and
their co-workers. Cheng and co-workers described two syn-
thetic approaches to the preparation of 11H-indolo[3,2-c]-
quinoline derivatives using the Fischer indole synthesis,
whereas Maes and co-workers applied their palladium-
driven strategy published earlier[12j] to generate a library.
However, both these methods were restricted exclusively to
arene rings with no structural diversity in the pyridyl ring
of the quinoline moiety.
Results and Discussion
A retrosynthetic analysis of isocryptolepine suggests
three possible routes for its synthesis, as depicted in Fig-
ures 2 and 3. Out of the three routes, routes A and B are
based on strategies reported in the literature[12] (Figure 2)
and involve the formation of the indole ring in the final
step, whereas route C (Figure 3) is based on our modified
Pictet–Spengler strategy and leads to the formation of the
quinoline ring in the final step.
Unlike the strategies reported in the literature for the
synthesis of isocryptolepine, which rely predominantly on
the formation of the indole by ring closure in the final step,
we focused our attention on the formation of the quinoline
ring in the final step. Retrosynthetic analysis by route C
suggests that the isocryptolepine could be derived by meth-
ylation of 4a (Figure 3). Cleavage of the C-6–C-6a bond in
the quinoline ring (indicated by line “c”) in 4a suggests that
it can be derived by 6-endo cyclization (π cyclization) from
the corresponding Schiff base 7, which in turn could be
obtained by condensation of the arylamine substrate 8a and
formaldehyde. The key intermediate, arylamine derivative
8a, can be obtained by the Fischer indole synthesis involv-
ing o-aminoacetophenone (9) and phenyl hydrazine (10).
Note that although π cyclization of 7 is expected to proceed
via the formation of a dihydro derivative of 4a in the first
instance, subsequent oxidation[13,14] can then be affected to
furnish 4a.
Figure 2. Retrosynthetic analysis of isocryptolepine based on re-
ported strategies involving indolization.
The synthetic strategy for the preparation of the isocryp-
tolepine is depicted in Scheme 1. Our synthesis commenced
with the Fischer indole synthesis of the indole intermediate
8a by reacting phenylhydrazine (10) with o-aminoacete-
phenone (9) in two steps following the procedure reported
in the literature.[16] The resulting key intermediate 8a was
subjected to the Pictet–Spengler reaction by treating it with
paraformaldehyde in the presence of TFA as Brønsted acid
to furnish the indolo-quinoline 4a. As reported earlier by
us[13c–13e] and others,[14] indolo-quinoline 4a was formed by
Pictet–Spengler cyclization of the imine 7 to form 11 fol-
lowed by spontaneous aerial oxidation. The latter was then
subjected to N-methylation[11b] by treatment with methyl
Figure 3. Retrosynthetic analysis of isocryptolepine involving for-
mation of the quinoline ring.
The strategies reported for the synthesis of isocryptolep- iodide to furnish the desired isocryptolepine alkaloid 3.
ine as the target structure generally involved indolization by After successfully establishing the synthetic protocol for
insertion of the nitrene,[12a–12c] photocyclization of anilino- isocryptolepine we then decided to generate a library
quinoline[12d] or a Schiff base,[12h] modified Fischer indole around it for our ongoing antimalarial program. As the key
synthesis,[12i] or Pd-catalyzed Buchwald–Hartwig amination intermediate involved in the synthesis of the isocryptolepine
of 4-chloroquinoline with 2-chloroaniline followed by Pd- alkaloid is substrate 8, with an arylamine linked to C-2 of
catalyzed intramolecular arylation.[12j] An alternate strategy the indole, we envisaged that by taking into account the
involved the application of the Vilsmeier methodology to susceptibility of both C-3 and C-2 of the indole moiety to
an intramolecular reaction to produce the 3-aminoalkylid- electrophilic attack, novel structural variants of 8 as ad-
ene-3H-indole unit of the alkaloid.[12k] Miki et al.[12l] re- ditional substrates could be designed. We proposed to
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P. K. Agarwal, D. Sawant, S. Sharma, B. Kundu
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12a–c, and 13a–d all offer scope for introducing diversity
into both the indole ring as well as the aminoarene moiety
attached to it (Scheme 2).
Keeping the electrophilic substitution pattern of the in-
dole moiety[17] in mind, we envisioned that an arylamine
at C-3 in substrates 12 would undergo the Pictet–Spengler
cyclization at C-2 to furnish indolo-quinolines 19, whereas
substrates 13 with an arylamine at N-1 would undergo the
Pictet–Spengler cyclization at C-2 to furnish indolo-quinox-
alines 20 (Scheme 3).
A literature search for the synthesis of 7H-indolo[2,3-c]-
quinolines 19 revealed few papers[18] dealing with the prepa-
ration of the target structure and those that did gave prod-
ucts of limited diversity. A search for reports on the synthe-
sis of indolo[1,2-a]quinoxalines 20 revealed only two papers.
The first paper reported a condensation of 2-arylindoles
with α-bromocyclohexanone dimethyl ketal to give 1,2,3,4-
tetrahydroindolo[1,2-a]quinoxaline followed by dehydroge-
nation over a Raney nickel catalyst.[18] However, the diffi-
culty in obtaining substituted 2-halocyclohexanones re-
Scheme 1. Synthesis of isocryptolepine alkaloid 3. Reagents and
conditions: (i) (a) AcOH (5 mol-%), EtOH, 6 h; (b) PPA, 100 °C,
10 min; (ii) (CH2O)n, TFA, CH3CN, 80 °C, sealed tube, 2 h; (iii)
MeI, toluene, reflux, 2 h.
achieve this by shifting the arylamine from C-2 in 8 to stricts the generality of this procedure. The second paper
either C-3 or N-1 of the indole ring thereby furnishing two reported the preparation of 5-substituted indole-2-carbox-
new substrates 12 and 13, respectively, as structural variants ylates by Fischer indolization of the appropriate phenylhy-
of the substrate 8. Interestingly, the three substrates 8b,c, drazones followed by N-arylation with 2-bromonitroben-
Scheme 2. Synthetic strategy for substrates 8, 12, and 13.
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Synthesis of Isocryptolepine Alkaloid and its Related Skeletons
Scheme 3. Pictet–Spengler reaction of substrates 8, 12, and 13 to furnish 4, 19, and 20, respectively.
zene using Ullman chemistry.[19] Thus, the literature survey
The synthetic strategies for the key intermediates 8, 12,
for all three prototypes revealed that although target struc- and 13 are depicted in Scheme 2. For the synthesis of 8b,c,
tures based on 4, 19, and 20 have been synthesized, none N-(tert-butoxycarbonyl)-5-methoxyindole-2-boronic acid
of the methods deal with the generation of libraries with (14) was treated with 2-iodonitrobenzene following the Su-
chemical diversity for medicinal chemistry purposes.
zuki procedure reported in the literature.[20] The resulting
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P. K. Agarwal, D. Sawant, S. Sharma, B. Kundu
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coupled derivative was first deprotected by using 25% TFA cally in excess of 90% based on HPLC analysis and substit-
in DCM to furnish the nitroarene derivative 16, which was uents on either 12a–c or the aldehydes had no affect on the
then subjected to reduction using Fe/HCl to give 8b,c. The rates and yields of the endo-cyclized products. Aldehydes
substrate 12 was synthesized by treating indole 15 with 2- with an electron-donating group had no adverse effect on
iodonitrobenzene following the Heck procedure reported in the rate of cyclization.
the literature.[21] The resulting nitroarene derivative 17 was
After successfully establishing the Pictet–Spengler reac-
subjected to reduction with Fe/HCl to give 12. Finally, the tion for substrates 12, we shifted our attention to substrate
substrate 13 was synthesized by treating indole 15 with 2- 8c (Scheme 3). The substrate was initially treated with p-
fluoronitrobenzene in the presence of NaH by the pro- (dimethylamino)benzaldehyde with 2% TFA/DCM at 0 °C.
cedure reported in the literature.[22] The resulting nitroarene The progress of the reaction was monitored by TLC and
derivative 18 was subjected to reduction by catalytic hydro- HPLC. As expected, cyclization of the substrate 8c to give
genation to give 13.
4e was found to be complete within 15 min.
For the Pictet–Spengler cyclization, 12a was initially
Next we subjected 13a to the Pictet–Spengler cyclization
treated with salicylaldehyde under a variety of traditional reaction by treating it with p-(dimethylamino)benzaldehyde
Pictet–Spengler protocols involving pTsOH in toluene at re- (Scheme 3). Surprisingly, unlike substrates 8 and 12, the re-
flux, 2% TFA in DCM at 0 °C, AcOH in ethanol at reflux, action with 13a took 8 h to reach completion and furnished
neat toluene at 80 °C and Yb(OTf)3. Interestingly, endo cy- two products with similar Rf values on TLC and similar
clization resulting in indolo-quinoline 19c occurred under retention times on HPLC. ESMS of the crude product
all conditions, but the best results were obtained with 2% showed signals at 340.4 and 338.4 Da, which corresponded
TFA in DCM at 0 °C and it took 10 min for completion of to the desired product 20b. We attributed the component
the reaction (Scheme 3). The crude product obtained after with the higher mass to the dihydro product 21. Of these
work-up was purified by silica gel column chromatography two compounds, the dihydro product 21 had moderate sta-
using EtOAc/hexane as eluent and was isolated in 91% bility because, even after purification, it had a tendency to
yield. Note that although 12a successfully underwent the undergo slow oxidation to 20b. Such an oxidation has been
Pictet–Spengler reaction, its aliphatic amine analogue trypt- reported earlier by us[13a,13c,13d] and others.[25] We envi-
amine (generally used as a substrate in the traditional sioned that by using oxidizing agents in the final step, 20b
Pictet–Spengler reaction) failed to undergo endo cyclization could be synthesized in quantitative yields. Accordingly,
under a similar protocol. Cook and co-workers[23] circum- compound 13a, after the Pictet–Spengler reaction with an
vented this problem by using N-benzyltryptamine, which aldehyde, was further treated with KMnO4 for 15 min at
furnished an iminium ion intermediate with enhanced elec- room temperature to furnish 20b as the only product in
trophilicity compared with the imine obtained from trypt- excellent yield. Based on our previous reports[13] and pres-
amine and in turn facilitated endo cyclization. Based on this ent observation, we hypothesize that when an arylamine is
information it can be inferred that for the substrate 12a, linked to the carbon atom of an activated heterocyclic skel-
the imine intermediate derived from the aldehyde with an eton, it results in the formation of the oxidized product by
electron-donating group is relatively more electrophilic than spontaneous aerial oxidation. However, when an arylamine
the imine derived from tryptamine using the same aldehyde. is attached to the nitrogen atom, it results in a mixture of
This is supported by the observation of Cook and co- oxidized and dihydro derivatives. In contrast, condensation
workers that it is the electrophilicity of the imine double of traditionally used indole-based substrates, tryptamine
bond resulting from the condensation of amines with alde- with an aliphatic amine at C-3 of the indole, with aldehydes
hydes that acts as the limiting factor for the Pictet–Spengler invariably furnished tetrahydro-β-carbolines (THBC).[26]
cyclization and the pKa values of amines could be used to Indeed, spontaneous oxidation of THBC to β-carbolines
compare the electrophilicities of the “imines”.[24] Thus, the has been reported both on prolonged heating and by the
pKa values of tryptamine (10.2) and aniline (in the absence addition of an oxidizing agent.[27]
of a pKa value for 12a, the pKa value for aniline was taken
The scope and limitation of our strategy with substrates
into account; 4.2) clearly suggest that the carbon–nitrogen based on 8b,c and 13a–d were established by synthesizing
double bond derived from substrate 12a is highly electro- 12 compounds based on indolo-quinolines 4b–d,f,g and in-
philic because the nitrogen has a smaller electron density dolo-quinoxalines 20a,c–h using eight aromatic aldehydes
than that of the imines derived from tryptamine. These fin- (Scheme 3). For the substrates 8b,c, the Pictet–Spengler cy-
dings support our earlier observations[13] that arylamine- clization was found to be complete within 30 min, however,
derived substrates undergo the Pictet–Spengler reaction for 13a–d, it ranged from 180 to 600 min. The purities of
faster than the substrates derived from aliphatic amines. the crude products were typically in excess of 90% based
The scope and limitation of our strategy with substrates on HPLC analysis and substituents on either the substrates
based on 12a–c was established by synthesizing six com- or the aldehydes had no affect on the rates and yields of
pounds based on indolo-quinolines 19a,b,d–g using six aro- the endo-cyclized products.
matic aldehydes (Scheme 3). For the Pictet–Spengler cycli-
Although the three substrates 8, 12, and 13 successfully
zation, the protocol involving 2% TFA/DCM at 0 °C was underwent Pictet–Spengler cyclization, we observed that the
used and in all cases cyclization was found to be complete rate of the reaction with the N-linked arylamine substrate
within 30 min. The purities of the crude products were typi- 13 was significantly slower (15–20 times) than the rates of
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Synthesis of Isocryptolepine Alkaloid and its Related Skeletons
tonitrile (6 mL) in a sealed tube. The suspension was stirred at
80 °C for 2 h. After cooling to room temperature, the solvent was
removed by evaporation in vacuo. The reaction mixture was dis-
solved in EtOAc (30 mL) and washed with aq. NaHCO3
(2ϫ20 mL), water (2ϫ20 mL), and brine (20 mL). The combined
organic layer was dried with MgSO4. The solvent was removed in
vacuo and then purified by column chromatography on silica gel
(EtOAc/hexane, 1:9 to 2:3) to give the desired compound 4a (0.18 g,
86%) as a white solid; m.p. Ͼ250 °C (ref.[28] 339–341 °C); Rf = 0.42
the reaction with the C-linked arylamine substrates 8 and
12. This may be attributed to the fact that because the in-
dole is an activated heterocyclic ring, C-2 and C-3 in sub-
strates 8 and 12 act as powerful nucleophiles in the absence
of N-substitution, whereas in substrate 13, the nucleophilic-
ity of C-2 decreases because of the presence of an aryl ring
at the N-1 position.
(2:3 EtOAc/hexane). IR (KBr): νmax = 3421, 3021, 1595, 1427 cm–1.
˜
1H NMR (300 MHz, [D6]DMSO): δ = 12.75 (br. s, 1 H, NH), 9.60
(s, 1 H, ArH), 8.53 (dd, J = 1.0, 7.5 Hz, 1 H, ArH), 8.32 (d, J =
7.7 Hz, 1 H, ArH), 8.14 (d, J = 8.4 Hz, 1 H, ArH), 7.77–7.67 (m,
3 H, ArH), 7.50 (d, J = 8.2 Hz, 1 H, ArH), 7.34 (d, J = 7.1 Hz, 1
H, ArH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 145.7, 145.2,
140.2, 139.2, 129.9, 128.5, 126.2, 126.0, 122.5, 122.3, 121.1, 120.5,
117.5, 114.7, 112.3 ppm. MS (ES+): m/z = 219.5 [M + 1]+. HRMS
(EI): calcd. for [M]+ 218.0844; found 218.0842. C15H10N2 (218.08):
calcd. C 82.55, H 4.62, N 12.84; found C 82.63, H 4.55, N 12.86.
Conclusions
We have developed a mild and efficient protocol for the
synthesis of the isocryptolepine alkaloid using our modified
Pictet–Spengler strategy. The efficacy of the strategy was
further established by generating a library with three-point
diversity based on three structural variants of the alkaloid.
The broad substrate scope and reactivity of our strategy
suggest wider application of this powerful reaction to the
synthesis of novel polycyclic skeletons based on privileged
structures. Work is in progress in our laboratory on several
second-generation substrates for the application of the
Pictet–Spengler reaction and will be reported soon.
Synthesis of Isocryptolepine (3): Compound 4a was methylated by
treating it with methyl iodide in toluene at reflux for 2 h according
to the procedure published in the literature.[11b] The crude thus ob-
tained was purified by silica gel chromatography using MeOH/
CHCl3 (1:4, v/v) as eluent to afford 3.
Yield 91%, yellow solid, m.p. 192–193 °C (ref.[29] 194–195 °C); Rf
= 0.28 (1:19 MeOH/CHCl ). IR (KBr): ν
= 3032, 2984
˜
3
max
Experimental Section
1605 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 9.27 (s, 1 H,
ArH), 8.78 (dd, J = 1.2, 7.9 Hz, 1 H, ArH), 8.09 (d, J = 7.6 Hz, 1
H, ArH), 7.99 (d, J = 8.5 Hz, 1 H, ArH), 7.82–7.77 (m, 2 H, ArH),
7.67 (d, J = 7.2 Hz, 1 H, ArH), 7.43 (t, J = 8.0 Hz, 1 H, ArH),
7.24 (t, J = 7.1 Hz, 1 H, ArH), 4.22 (s, 3 H, NCH3) ppm. 1H NMR
(75 MHz, CD3OD): δ = 152.5, 151.8, 136.5, 134.8, 128.8, 125.5,
124.6, 123.3, 120.0, 119.6, 118.9, 116.9, 116.2, 115.7, 41.1 ppm. MS
(ES+): m/z = 233.1 [M + 1]+. C16H12N2 (232.10): calcd. C 82.73, H
5.21, N 12.06; found C 82.83, H 5.31, N 12.16.
General: All solvents were commercially available and used without
purification. All products were characterized by 1H and 13C NMR,
ESMS, IR, and HPLC. Analytical TLC was performed using
2.5ϫ5 cm plates coated with a 0.25 mm thickness of silica gel (60F-
254 Merck) and visualization was accomplished with UV light and
iodine. Column chromatography was performed by using Thomas
Baker silica gel 60 (100–200 mesh). 1H NMR spectra (200,
300 MHz) are reported as follows: chemical shifts in ppm down-
field from TMS as internal standard (δ scale), multiplicity [br. =
broad, s = singlet, d = doublet, t = triplet, q = quartet, m = mul-
tiplet, o = overlapped, coupling constant (Hz), integration, and as-
signment]. All 13C NMR spectra (50, 75 MHz) were recorded at
25 °C with complete proton decoupling and are reported in ppm
except for compounds 4b, 4c, 12a, and 14c, which are insoluble
at higher concentrations. The purity and characterization of these
compounds were further established by HR/EI mass spectroscopy.
Elemental analyses were performed with a Carlo–Erba 1108 micro-
analyzer or an Elementar Vario EL III microanalyzer. The micro-
analyses were performed at the Sophisticated Analytical Instru-
ment Facility Division, CDRI. Analytical HPLC was performed
with a C-18 reversed-phase column (250 mmϫ4.6 mm). Mass
spectra were recorded with a Merck MS-8000 spectrometer and
HR/EI mass spectra were with a JEOL-600H spectrometer at 70 eV.
Melting points are uncorrected.
General Procedure for the Synthesis of 5-Methoxy-2-(2-nitrophenyl)-
1H-indole 16: A solution of o-iodonitrobenzene (4.4 mmol) in
DMF (50 mL) was degassed with nitrogen for 15 min and then
Na2CO3 (10.5 mL, 2 ) was added under the continuous flow of
nitrogen. After 10 min, N-(tert-butoxycarbonyl)-5-methoxyindole-
2-boronic acid (14) (1 g, 4.0 mmol) and [Pd(Ph3)4] (0.46 g,
0.4 mmol) were added to the reaction mixture under nitrogen. The
reaction mixture was stirred at 80 °C for 3 h. The solution was
diluted with H2O (5 mL) and then the product was extracted three
times with EtOAc (20 mL). The combined organic layer was dried
with MgSO4 and the solvent was removed in vacuo. The crude
product was purified on a silica gel column using hexane/ethyl ace-
tate (95:5, v/v) as eluent to afford tert-butyl 5-methoxy-2-(2-ni-
trophenyl)indole-1-carboxylate, which was subsequently treated
with a 25% solution of trifluoroacetic acid in DCM (25 mL) at
0 °C. The mixture was stirred further for 20 min. After completion
of the reaction, the DCM was evaporated in vacuo, and the crude
was extracted with ethyl acetate (30 mL) and subsequently washed
with aq. NaHCO3 (20 mL). The combined organic layer was dried
with MgSO4 and the solvent was removed in vacuo. The crude
product was purified on a silica gel column using hexane/ethyl ace-
tate (9:1, v/v) as eluent to afford 16.
Synthesis of 2-(2Ј-Aminophenyl)indole (8a): This was synthesized
according to the procedure published in the literature[22] by treating
phenylhydrazine (10) with o-aminoacetophenone (9) followed by
heating the resulting phenylhydrazone with polyphosphoric acid to
about 100 °C in an oil bath. The crude thus obtained was purified
by silica gel chromatography using hexane/EtOAc (20:80, v/v) as
eluent to afford 8a with a melting point of 146–148 °C (ref.[22a] 148–
150 °C).
5-Methoxy-2-(2-nitrophenyl)-1H-indole (16a): Yield 65%, yellow so-
lid, m.p. 105–107 °C; R = 0.64 (1:9 EtOAc/hexane). IR (KBr): ν
˜
f
max
Synthesis of 11H-Indolo[3,2-c]quinoline (4a): TFA (100 µL) was = 3411, 2930, 1728, 1610, 1533, 1345, 1216 cm–1. 1H NMR
added in one portion to a suspension of paraformaldehyde (36 mg,
1.2 mmol), 2-(2Ј-aminophenyl)indole (8a; 0.21 g, 1 mmol), and ace-
(300 MHz, [D6]DMSO): δ = 11.38 (br. s, 1 H, NH), 7.95 (d, J =
7.9 Hz, 1 H, ArH), 7.78 (d, J = 3.7 Hz, 2 H, ArH), 7.63–7.58 (m,
Eur. J. Org. Chem. 2009, 292–303
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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297

P. K. Agarwal, D. Sawant, S. Sharma, B. Kundu
FULL PAPER
1 H, ArH), 7.30 (d, J = 8.7 Hz, 1 H, ArH), 7.07 (d, J = 2.3 Hz, 1
8.5 Hz, 2 H, ArH), 7.18 (d, J = 8.6 Hz, 1 H, ArH), 7.10 (t, J =
H, ArH), 7.80 (dd, J = 2.4, 8.8 Hz, 1 H, ArH), 6.45 (d, J = 1.5 Hz, 7.7 Hz, 1 H, ArH), 7.03 (br. s, 1 H, NH), 6.89 (d, J = 9.0 Hz, 1 H,
1 H, ArH), 3.75 (s, 3 H, OCH3) ppm. MS (ES+): m/z 269.2 [M +
1]+. C15H12N2O3 (268.08): calcd. C 67.16, H 4.51, N 10.44; found
C 67.28, H 4.46, N 10.29.
ArH), 6.81 (t, J = 7.8 Hz, 3 H, ArH), 3.90 (q, J = 6.8 Hz, 2 H,
OCH2CH3), 3.79 (s, 3 H, OCH3), 1.38 (t, J = 6.9 Hz, 3 H,
OCH2CH3) ppm. MS (ES+): m/z = 369.3 [M + 1]+. HRMS (EI):
calcd. for [M]+ 368.1525; found 368.1528. C24H20N2O2 (368.15):
calcd. C 78.24, H 5.47, N 7.60; found C 78.18, H 5.55, N 7.61.
5-Methoxy-2-(5-methyl-2-nitrophenyl)-1H-indole (16b): Yield 70%,
brown oil; R = 0.69 (1:9 EtOAc/hexane). IR (neat): ν
= 3420,
˜
f
max
3021, 2923, 1721, 1588, 1518 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 8.14–8.09 (m, 2 H, ArH), 7.36 (d, J = 7.3 Hz, 2 H, ArH), 7.32
(br. s, 1 H, NH), 7.04 (d, J = 2.3 Hz, 1 H, ArH), 6.98 (dd, J = 2.5,
9.0 Hz, 1 H, ArH), 6.46 (s, 1 H, ArH), 3.87 (s, 3 H, OCH3), 2.50
(s, 3 H, CH3) ppm. MS (ES+): m/z 283.3 [M + 1]+. C16H14N2O3
(282.10): calcd. C 68.07, H 5.00, N 9.92; found C 68.29, H 4.89, N
10.02.
8-Methoxy-6-(4-nitrophenyl)-11H-indolo[3,2-c]quinoline (4c): Yield
79%, white solid, m.p. Ͼ250 °C; Rf = 0.51 (1:4 EtOAc/hexane). IR
(KBr): ν
= 3415, 1518, 1345 cm–1. 1H NMR (300 MHz, [D6]-
˜
max
DMSO): δ = 12.85 (br. s, 1 H, NH), 8.57 (d, J = 7.6 Hz, 1 H, ArH),
8.50 (d, J = 8.7 Hz, 2 H, ArH), 8.14 (d, J = 8.4 Hz, 3 H, ArH),
7.80–7.70 (m, 2 H, ArH), 7.67 (d, J = 8.8 Hz, 1 H, ArH), 7.13 (dd,
J = 2.4, 7.7 Hz, 1 H, ArH), 6.95 (d, J = 2.2 Hz, 1 H, ArH), 3.65
(s, 3 H, OCH3) ppm. MS (ES+): m/z = 370.2 [M + 1]+. HRMS
(EI): calcd. for [M]+ 369.1113; found 369.1121. C22H15N3O3
(369.11): calcd. C 71.54, H 4.09, N 11.38; found C 71.45, H 4.06,
N 11.34.
General Procedure for the Synthesis of 2-(5-Methoxy-1H-indol-2-yl)-
phenylamines 8b,c: A solution of 5-methoxy-2-(2-nitrophenyl)-1H-
indole (16, 2.09 mmol) and Fe (2.36 g, 10.45 mmol) in acidic etha-
nol (1:4 aq. HCl/EtOH, 40 mL) was heated at reflux under nitrogen
for 1.5 h. The solution was cooled down and then poured into ice.
The pH was made slightly basic (pH 8) by the addition of 5% aque-
ous NaHCO3. EtOAc (50 mL) was added to the mixture and fil-
tered through a bed of Celite. The organic layer was finally washed
with water (50 mL) and then brine (50 mL) and dried with anhy-
drous Na2SO4. The organic layer was evaporated to dryness under
reduced pressure. The crude product was purified on a silica gel
column using hexane/ethyl acetate (9:1, v/v) as eluent to afford 8b
(or 8c).
2-(8-Methoxy-11H-indolo[3,2-c]quinolin-6-yl)phenol (4d): Yield
84%, white solid, m.p. 223–225 °C; Rf = 0.40 (1:4 EtOAc/hexane).
IR (KBr): νmax = 3413, 3020, 1590 cm–1. 1H NMR (300 MHz, [D6]-
˜
DMSO): δ = 12.67 (br. s, 1 H, NH), 8.53 (d, J = 8.4 Hz, 1 H, ArH),
8.10 (d, J = 8.0 Hz, 1 H, ArH), 7.75 (t, J = 8.0 Hz, 1 H, ArH),
7.68 (t, J = 6.8 Hz, 1 H, ArH), 7.61 (d, J = 8.8 Hz, 1 H, ArH),
7.54 (dd, J = 1.2, 7.4 Hz, 1 H, ArH), 7.43 (t, J = 8.7 Hz, 1 H,
ArH), 7.11–7.03 (m, 3 H, ArH), 6.88 (d, J = 2.2 Hz, 1 H, ArH),
3.62 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3 + 20 µL
CF3COOD): δ = 155.6, 153.3, 148.0, 143.8, 134.6, 134.4, 134.2,
132.2, 130.8, 128.2, 122.0, 121.4, 120.3, 117.7, 116.9, 116.7, 114.0,
113.5, 112.6, 105.0, 55.6 ppm. MS (ES+): m/z = 341.3 [M + 1]+.
HRMS (EI): calcd. for [M]+ 340.1212; found 340.1201.
C22H16N2O2 (340.12): calcd. C 77.63, H 4.74, N 8.23; found C
77.71, H 4.79, N 8.26.
2-(5-Methoxy-1H-indol-2-yl)phenylamine (8b): Yield 87%, white so-
lid, m.p. 196–198 °C; R = 0.50 (1:9 EtOAc/hexane). IR (KBr): ν
˜
f
max
= 3426, 2928, 1612 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ =
11.06 (br. s, 1 H, NH), 7.33 (dd, J = 1.2, 7.7 Hz, 1 H, ArH), 7.26
(d, J = 8.7 Hz, 1 H, ArH), 7.06–7.03 (m, 2 H, ArH), 6.82 (d, J =
7.3 Hz, 1 H, ArH), 6.74–6.67 (m, 2 H, ArH), 6.59 (d, J = 1.4 Hz,
1 H, ArH), 5.16 (br. s, 2 H, NH2), 3.76 (s, 3 H, OCH3) ppm. MS
(ES+): m/z = 239.2 [M + 1]+. C15H14N2O (238.11): calcd. C 75.61,
H 5.92, N 11.76; found C 70.48, H 5.88, N 11.61.
N-[4-(8-Methoxy-2-methyl-11H-indolo[3,2-c]quinolin-6-yl)phenyl]-
N,N-dimethylamine (4e): Yield 76%, white solid, m.p. 253–255 °C;
R = 0.53 (1:4 EtOAc/hexane). IR (KBr): ν
= 3021, 1483, 1427,
˜
f
max
1215 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 12.54 (br. s, 1 H,
NH), 8.26 (s, 1 H, ArH), 7.96 (d, J = 8.5 Hz, 1 H, ArH), 7.72 (d,
J = 8.7 Hz, 2 H, ArH), 7.60 (d, J = 8.7 Hz, 1 H, ArH), 7.52 (dd,
J = 1.7, 8.6 Hz, 1 H, ArH), 7.26 (d, J = 2.3 Hz, 1 H, ArH), 7.07
(dd, J = 2.4, 8.8 Hz, 1 H, ArH), 6.92 (d, J = 8.8 Hz, 2 H, ArH),
3.68 (s, 3 H, OCH3), 3.41 (s, 6 H, 2ϫCH3), 2.57 (s, 3 H, CH3) ppm.
13C NMR (75 MHz, CDCl3): δ = 155.4, 154.0, 151.2, 143.9, 141.6,
134.6, 134.3, 130.4, 129.3, 128.4, 123.0, 121.2, 116.5, 114.2, 112.7,
112.3, 111.9, 105.2, 55.7, 40.3, 21.8 ppm. MS (ES+): m/z = 382.4
[M + 1]+. C25H23N3O (381.18): calcd. C 78.71, H 6.08, N 11.02;
found C 78.78, H 6.06, N 11.09.
2-(5-Methoxy-1H-indol-2-yl)-4-methylphenylamine (8c): Yield 91%,
brown oil; R = 0.50 (1:4 EtOAc/hexane). IR (KBr): ν
= 3422,
˜
f
max
3021, 2975, 1633 cm–1. 1H NMR (300 MHz, CDCl3): δ = 11.00 (br.
s, 1 H, NH), 7.26 (d, J = 8.7 Hz, 1 H, ArH), 7.17 (s, 1 H, ArH),
7.02 (d, J = 2.2 Hz, 1 H, ArH), 6.88 (dd, J = 1.4, 8.1 Hz, 1 H,
ArH), 6.74–6.70 (m, 2 H, ArH), 6.58 (d, J = 8.1 Hz, 1 H, ArH),
4.93 (br. s, 2 H, NH2), 3.75 (s, 3 H, OCH3), 2.22 (s, 3 H, CH3) ppm.
MS (ES+): m/z = 253.1 [M + 1]+. C16H16N2O (252.12): calcd. C
76.16, H 6.39, N 11.10; found C 76.34, H 6.43, N 11.06.
General Procedure for the Synthesis of 8-Methoxy-11H-indolo-
[3,2-c]quinoline 4b–g: A mixture of 8b (or 8c) (0.39 mmol) and alde-
hyde (0.39 mmol) in DCM (2 mL) was treated with 2% TFA in
DCM (2 mL). Completion of the Pictet–Spengler cyclization was
monitored by TLC. After 30 min, the solvent was evaporated and
the residue thus obtained was triturated with aq. NaHCO3
(10 mL). It was then extracted with EtOAc (20 mL), washed with
brine (10 mL), and dried with sodium sulfate. EtOAc was evapo-
rated to dryness under reduced pressure and the crude product was
purified on a silica gel column using hexane/ethyl acetate (1:4, v/v)
as eluent to afford 4b–g.
8-Methoxy-2-methyl-6-(p-tolyl)-11H-indolo[3,2-c]quinoline
(4f):
Yield 78%, white solid, m.p. 248–250 °C; Rf = 0.56 (1:4 EtOAc/
hexane). IR (KBr): νmax = 3405, 2923, 2855, 1588, 1464, 1205 cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 9.55 (br. s, 1 H, NH), 8.16 (d, J
= 8.6 Hz, 1 H, ArH), 7.91 (s, 1 H, ArH), 7.79 (d, J = 7.9 Hz, 2 H,
ArH), 7.48 (d, J = 8.7 Hz, 2 H, ArH), 7.38 (d, J = 7.8 Hz, 2 H,
ArH), 7.13 (d, J = 2.3 Hz, 1 H, ArH), 7.06 (dd, J = 2.5, 8.8 Hz, 1
H, ArH), 3.72 (s, 3 H, OCH3), 2.57 (s, 3 H, CH3), 2.49 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.1, 154.0, 143.8,
141.5, 138.6, 138.2, 135.1, 134.4, 130.6, 129.5, 129.3, 129.2, 122.8,
121.3, 116.7, 114.3, 112.8, 112.3, 104.9, 55.68, 21.8, 21.4 ppm. MS
(ES+): m/z = 353.3 [M + 1]+. C24H20N2O (352.15): calcd. C 81.79,
H 5.72, N 7.95; found C 81.71, H 5.75, N 8.03.
6-(4-Ethoxyphenyl)-8-methoxy-11H-indolo[3,2-c]quinoline
Yield 81%, white solid, m.p. 215–217 °C; Rf = 0.46 (1:4 EtOAc/
hexane). IR (KBr): ν
= 3422, 1538, 1226 cm–1. 1H NMR
(4b):
˜
max
(300 MHz, CDCl3): δ = 7.67 (d, J = 7.5 Hz, 1 H, ArH), 7.45 (d, J 8-Methoxy-2-methyl-6-phenyl-11H-indolo[3,2-c]quinoline (4g): Yield
= 9.0 Hz, 1 H, ArH), 7.32 (d, J = 8.3 Hz, 1 H, ArH), 7.23 (d, J = 72%, white solid, m.p. 232–233 °C; Rf = 0.62 (1:4 EtOAc/hexane).
298
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 292–303

Synthesis of Isocryptolepine Alkaloid and its Related Skeletons
IR (KBr): ν
= 3454, 2926, 1594, 1442, 1205 cm–1. 1H NMR
2-(1H-Indol-3-yl)phenylamine (12a): Yield 83%, colorless oil; Rf =
˜
max
(300 MHz, CDCl3): δ = 12.65 (br. s, 1 H, NH), 8.30 (s, 1 H, ArH), 0.40 (1:9 EtOAc/hexane). IR (neat): νmax = 3386, 2936, 1608, 1528,
˜
1
8.01 (d, J = 8.5 Hz, 1 H, ArH), 7.80 (dd, J = 1.6, 7.8 Hz, 2 H,
1350 cm–1. H NMR (300 MHz, [D6]DMSO): δ = 8.32 (br. s, 1 H,
ArH), 7.66–7.56 (m, 5 H, ArH), 7.08 (dd, J = 2.4, 8.8 Hz, 1 H, NH), 7.66 (d, J = 7.9 Hz, 1 H, ArH), 7.46 (d, J = 8.1 Hz, 1 H,
ArH), 6.94 (dd, J = 2.3, 8.8 Hz, 1 H, ArH), 3.60 (s, 3 H, OCH3), ArH), 7.35–7.14 (m, 5 H, ArH), 6.86 (t, J = 7.6 Hz, 2 H,
2.60 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.1, ArH) ppm. MS (ES+): m/z = 209.2 [M + 1]+. C14H12N2 (208.10):
154.1, 143.8, 141.5, 141.1, 135.3, 134.3, 130.6, 129.6, 129.3, 129.2,
128.7, 122.7, 121.3, 116.7, 114.6, 112.9, 112.3, 104.5, 55.5,
21.8 ppm. MS (ES+): m/z = 339.4 [M + 1]+. C23H18N2O (338.14):
calcd. C 81.63, H 5.36, N 8.28; found C 81.81, H 5.33, N 8.39.
calcd. C 80.74, H 5.81, N 13.45; found C 80.82, H 5.66, N 13.52.
2-(1H-Indol-3-yl)-4-methylphenylamine (12b): Yield 79%, brown
oil; R = 0.69 (1:9 EtOAc/hexane). IR (neat): ν
= 3420, 3021,
˜
f
max
2923, 1721, 1588, 1518 cm–1. 1H NMR (300 MHz, CDCl3): δ =
8.32 (br. s, 1 H, NH), 7.64 (d, J = 7.9 Hz, 1 H, ArH), 7.46 (d, J =
8.1 Hz, 1 H, ArH), 7.31 (dd, J = 2.4, 7.9 Hz, 1 H, ArH), 7.27–7.14
(m, 2 H, ArH), 6.85 (d, J = 7.7 Hz, 1 H, ArH), 6.70–6.69 (m, 2 H,
ArH), 2.51 (s, 3 H, CH3) ppm. MS (ES+): m/z = 223.2 [M + 1]+.
C15H14N2 (222.11): calcd. C 81.05, H 6.35, N 12.60; found C 81.25,
H 6.24, N 12.51.
General Procedure for the Synthesis of 3-(2-Nitrophenyl)-1H-indole
17: A solution of o-iodonitrobenzene (10.2 mmol) and indole 15
(8.5 mmol) in dioxane (30 mL) was degassed with nitrogen for
15 min and K2CO3 (3.27 g, 25.6 mmol) and Pd(OAc)2 (0.19 g,
0.85 mmol) were added under a continuous flow of nitrogen. The
reaction mixture was stirred at 100 °C for 16 h. The solution was
passed through Celite, which was thoroughly washed with dioxane.
The combined filtrate was evaporated to dryness and then diluted
with H2O (5 mL) followed by extraction of the product with EtOAc
(2ϫ20 mL) three times. The combined organic layer was dried with
MgSO4 and the solvent was removed in vacuo. The crude product
was purified on a silica gel column using hexane/ethyl acetate
(90:10, v/v) as eluent to afford 17.
2-(5-Bromo-1H-indol-3-yl)phenylamine (12c): Yield 90%, white
solid, m.p. 141–143 °C; Rf = 0.46 (1:9 EtOAc/hexane). IR (KBr):
ν
= 3369, 3021, 1603 cm–1. 1H NMR (300 MHz, CDCl3): δ =
˜
max
8.38 (br. s, 1 H, NH), 7.77 (s, 1 H, ArH), 7.34–7.32 (m, 3 H, ArH),
7.29–7.26 (m, 1 H, ArH), 7.29–7.26 (m, 1 H, ArH), 6.86 (t, J =
7.9 Hz, 2 H, ArH) ppm. MS (ES+): m/z = 287.3 [M + 1]+.
C14H11BrN2 (286.01): calcd. C 58.56, H 3.86, N 9.76; found C
58.68, H 3.82, N 9.59.
3-(2-Nitrophenyl)-1H-indole (17a): Yield 43%, yellow solid, m.p.
112–114 °C; R = 0.68 (1:9 EtOAc/hexane). IR (KBr): νmax = 3403,
˜
f
General Procedure for the Synthesis of 7H-Indolo[2,3-c]quinoline 19:
A mixture of 12 (0.48 mmol) and aldehyde (0.48 mmol) in DCM
(2 mL) was treated with 2% TFA in DCM (2 mL). Completion of
the Pictet–Spengler cyclization was monitored by TLC. After
30 min, the reaction mixture was evaporated and the residue thus
obtained was triturated with aq. NaHCO3 (10 mL). It was then
extracted with EtOAc (20 mL), washed with brine (10 mL), and
dried with sodium sulfate. The organic layer was concentrated to
dryness under reduced pressure and the crude obtained was puri-
fied by column chromatography to afford 19.
2926, 1610, 1533, 1350 cm–1. H NMR (300 MHz, [D6]DMSO): δ
1
= 11.51 (br. s, 1 H, NH); 7.95 (dd, J = 0.9, 8.1 Hz, 1 H, ArH),
7.76–7.67 (m, 2 H, ArH), 7.56–7.51 (m, 2 H, ArH), 7.47 (d, J =
8.1 Hz, 1 H, ArH), 7.31 (d, J = 7.9 Hz, 1 H, ArH), 7.16 (t, J =
7.0 Hz, 1 H, ArH), 7.04 (t, J = 7.0 Hz, 1 H, ArH) ppm. MS (ES+):
m/z = 239.3 [M + 1]+. C14H10N2O2 (238.07): calcd. C 70.58, H
4.23, N 11.76; found C 70.44, H 4.25, N 11.49.
3-(5-Methyl-2-nitrophenyl)-1H-indole (17b): Yield 46%, yellow so-
lid, m.p. 101–102 °C; R = 0.60 (1:9 EtOAc/hexane). IR (KBr): ν
˜
f
max
= 3472, 3021, 1594, 1527, 1352 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 8.38 (br. s, 1 H, NH), 7.68 (s, 1 H, ArH), 7.56–7.49 (m, 2 H,
ArH), 7.44 (d, J = 8.1 Hz, 1 H, ArH), 7.33 (d, J = 2.3 Hz, 1 H,
ArH), 7.25 (d, J = 8.1 Hz, 2 H, ArH), 7.16 (t, J = 7.9 Hz, 1 H,
ArH), 2.49 (s, 3 H, CH3) ppm. MS (ES+): m/z = 253.1 [M + 1]+.
C15H12N2O2 (252.08): calcd. C 71.42, H 4.79, N 11.10; found C
71.48, H 4.75, N 11.11.
6-(4-Ethoxyphenyl)-7H-indolo[2,3-c]quinoline (19a): Yield 88%,
white solid, m.p. 219–221 °C; Rf = 0.76 (1:9 EtOAc/hexane). IR
1
(KBr): ν
= 3401, 3019, 1603, 1368 cm–1. H NMR (300 MHz,
˜
max
CDCl3): δ = 8.85 (br. s, 1 H, NH), 8.74 (dd, J = 1.7, 8.2 Hz, 1 H,
ArH), 8.64 (d, J = 8.0 Hz, 1 H, ArH), 8.36 (dd, J = 7.8, 1.5 Hz, 1
H, ArH), 8.00 (d, J = 8.7 Hz, 2 H, ArH), 7.74–7.57 (m, 4 H, ArH),
7.46 (t, J = 8.0 Hz, 1 H, ArH), 7.14 (d, J = 8.7 Hz, 2 H, ArH),
4.15 (q, J = 7.0 Hz, 2 H, OCH2CH3), 1.49 (t, J = 6.9 Hz, 3 H,
OCH2CH3) ppm. MS (ES+): m/z = 339.3 [M + 1]+. HRMS (EI):
calcd. for [M]+ 338.1419; found 338.1415. C23H18N2O (338.14):
calcd. C 81.63, H 5.36, N 8.28; found C 81.80, H 5.21, N 8.11.
5-Bromo-3-(2-nitrophenyl)-1H-indole (17c): Yield 81%, yellow solid,
m.p. 118–119 °C; R = 0.54 (1:9 EtOAc/hexane). IR (KBr): ν
=
˜
f
max
3467, 3021, 1594, 1526, 1433, 761 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.43 (br. s, 1 H, NH), 7.87 (d, J = 8.4 Hz, 1 H, ArH),
7.68–7.61 (m, 3 H, ArH), 7.51–7.46 (m, 1 H, ArH), 7.36–7.30 (m,
3 H, ArH) ppm. MS (ES+): m/z = 317.1 [M + 1]+. C14H9BrN2O2
(315.98): calcd. C 53.02, H 2.86, N 8.83; found C 53.11, H 2.93, N
8.79.
6-(4-Nitrophenyl)-7H-indolo[2,3-c]quinoline (19b): Yield 75%, yel-
low solid, m.p. Ͼ250 °C; Rf = 0.74 (1:9 EtOAc/hexane). IR (KBr):
ν
= 3456, 3021, 1671, 1598 cm–1. 1H NMR (300 MHz, [D6]-
˜
max
DMSO): δ = 12.08 (br. s, 1 H, NH), 8.89 (d, J = 8.1 Hz, 1 H, ArH),
8.76 (d, J = 8.1 Hz, 1 H, ArH), 8.52 (d, J = 8.8 Hz, 2 H, ArH),
8.38 (d, J = 8.7 Hz, 2 H, ArH), 8.26 (dd, J = 0.8, 8.1 Hz, 1 H,
ArH), 7.82–7.79 (m, 2 H, ArH), 7.73 (t, J = 7.8 Hz, 1 H, ArH),
7.63 (t, J = 8.1 Hz, 1 H, ArH), 7.44 (t, J = 7.7 Hz, 1 H, ArH) ppm.
13C NMR (75 MHz, [D6]DMSO + 20 µL CF3COOD): δ = 149.1,
142.8, 142.6, 139.4, 137.3, 131.8, 130.1, 129.6, 129.1, 128.4, 125.6,
125.1, 124.4, 124.2, 124.1, 123.8, 122.0, 121.1, 117.7, 113.8 ppm.
MS (ES+): m/z = 340.3 [M + 1]+. HRMS (EI): calcd. for [M]+
339.1008; found 339.1020. C21H13N3O2 (339.10): calcd. C 74.33, H
3.86, N 12.38; found C 74.48, H 3.84, N 12.44.
General Procedure for the Synthesis of 2-(1H-Indol-3-yl)phenylam-
ine 12: A solution of 17 (4.62 mmol) and Fe (1.3 g, 23.1 mmol) in
acidic ethanol (1:4 HCl/EtOH, 20 mL) was heated at reflux under
nitrogen for 2 h. The solution was cooled down and then poured
into ice. The pH was made slightly basic (pH 8) by the addition of
5% aqueous NaHCO3 (20 mL). Subsequently, EtOAc (50 mL) was
added to the mixture and filtered through a bed of Celite. The
organic layer was finally washed with water (50 mL), brine (50 mL),
and dried with anhydrous Na2SO4. The organic layer was evapo-
rated to dryness under reduced pressure. The residue was purified
by silica gel chromatography using hexane/ethyl acetate (1:4, v/v)
as eluent to afford 12.
2-(7H-Indolo[2,3-c]quinolin-6-yl)phenol (19c): Yield 91%, yellow so-
lid, m.p. 219–220 °C; R = 0.65 (1:9 EtOAc/hexane). IR (KBr): ν
˜
f
max
Eur. J. Org. Chem. 2009, 292–303
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
299

P. K. Agarwal, D. Sawant, S. Sharma, B. Kundu
= 3407, 3020, 1609 cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = General Procedure for the Synthesis of 1-(2-Nitrophenyl)-1H-indole
FULL PAPER
12.28 (br. s, 1 H, OH), 11.90 (br. s, 1 H, NH), 8.86 (d, J = 7.4 Hz,
1 H, ArH), 8.72 (d, J = 8.1 Hz, 1 H, ArH), 8.21 (d, J = 8.0 Hz, 1
18: Indole 15 (8.5 mmol) was treated with NaH (0.38 g in 60% oil,
12.8 mmol) in DMF (10 mL) at room temp. for 15 min. Then o-
H, ArH), 7.99 (dd, J = 1.2, 7.6 Hz, 1 H, ArH), 7.86 (d, J = 8.1 Hz, fluoronitrobenzene (8.5 mmol) was added portionwise over a
1 H, ArH), 7.78 (t, J = 7.1 Hz, 1 H, ArH), 7.69 (t, J = 6.8 Hz, 1 period of 5 min. The reaction was monitored by TLC and after
H, ArH), 7.60 (t, J = 7.3 Hz, 1 H, ArH), 7.49–7.43 (m, 2 H, ArH), completion of the reaction; the mixture was poured into ice-cold
7.13 (t, J = 7.9 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz, [D6]- water (50 mL) and was extracted with EtOAc (2ϫ25 mL). The
DMSO): δ = 157.8, 146.8, 140.8, 140.6, 131.4, 130.8, 130.6, 129.7,
127.5, 127.3, 126.4, 123.5, 123.3, 122.5, 121.7, 121.0, 119.6, 117.5,
113.6 ppm. MS (ES+): m/z = 311.4 [M + 1]+. HRMS (EI): calcd.
for [M]+ 310.1106; found 310.1107. C21H14N2O (310.11): calcd. C
81.27, H 4.55, N 9.03; found C 81.33, H 4.56, N 8.97.
EtOAc layer was washed with water (2ϫ10 mL) and brine
(1ϫ10 mL). The organic layers were combined and dried with an-
hydrous Na2SO4 and evaporated to obtain a yellow residue, which
after column chromatography on silica gel with hexane/EtOAc
(20:80, v/v) as eluent afforded 18.
1-(2-Nitrophenyl)-1H-indole (18a): Yield 72%, yellow solid, m.p.
6-(4-Chlorophenyl)-2-methyl-7H-indolo[2,3-c]quinoline (19d): Yield
85%, white solid, m.p. 156–158 °C; Rf = 0.61 (1:9 EtOAc/hexane).
85–87 °C; R = 0.50 (1:19 EtOAc/hexane). IR (KBr): ν
= 3036,
˜
f
max
1612, 1530, 1313 cm–1. H NMR (300 MHz, CDCl3): δ = 8.02 (d,
J = 7.86 Hz, 1 H, ArH), 7.76–7.66 (m, 2 H, ArH), 7.59–7.53 (m, 2
H, ArH), 7.20–7.11 (m, 4 H, ArH), 6.72 (d, J = 3.7 Hz, 1 H,
ArH) ppm. MS (ES+): m/z = 239.2 [M + 1]+. C14H10N2O2 (238.07):
calcd. C 70.58, H 4.23, N 11.76; found C 70.71, H 4.28, N 11.71.
1
IR (KBr): νmax = 3417, 3020, 1586, 762 cm–1. 1H NMR (300 MHz,
˜
[D6]DMSO): δ = 11.86 (br. s, 1 H, NH), 8.74 (d, J = 8.4 Hz, 1 H,
ArH), 8.69 (d, J = 8.1 Hz, 1 H, ArH), 8.11 (d, J = 8.5 Hz, 2 H,
ArH), 8.01 (s, 1 H, ArH), 7.77 (d, J = 8.3 Hz, 1 H, ArH), 7.73 (d,
J = 8.5 Hz, 2 H, ArH), 7.59 (t, J = 8.4 Hz, 2 H, ArH), 7.39 (t, J
= 7.2 Hz, 1 H, ArH), 2.58 (s, 3 H, CH3) ppm. 13C NMR (75 MHz,
[D6]DMSO): δ = 145.6, 142.8, 141.0, 137.1, 131.1, 130.7, 130.5,
130.3, 129.4, 129.2, 127.2, 126.1, 124.1, 123.5, 123.2, 122.9, 121.8,
120.8, 119.8, 113.1, 21.6 ppm. MS (ES+): m/z = 343.4 [M + 1]+.
C22H15ClN2 (342.09): calcd. C 77.08, H 4.41, N 8.17; found C
76.99, H 4.45, N 8.10.
1-(5-Bromo-2-nitrophenyl)-1H-indole (18b): Yield 67%, yellow
solid, m.p. 101–103 °C; Rf = 0.54 (1:19 EtOAc/hexane). IR (KBr):
1
ν
= 3018, 1598, 1533, 1323 cm–1. H NMR (300 MHz, CDCl3):
˜
max
δ = 8.08 (d, J = 6.9 Hz, 1 H, ArH), 7.76–7.68 (m, 4 H, ArH), 7.56–
7.72 (m, 2 H, ArH), 7.21 (d, J = 8.1 Hz, 1 H, ArH), 6.72 (d, J =
2.8 Hz, 1 H, ArH) ppm. MS (ES+): m/z = 317.2 [M + 1]+.
C14H9BrN2O2 (317.13): calcd. C 53.02, H 2.86, N 8.83; found C
53.23, H 3.01, N 8.63.
Dimethyl[4-(2-methyl-7H-indolo[2,3-c]quinolin-6-yl)phenyl]amine
(19e): Yield 81%, yellow solid, m.p. 208–210 °C; Rf = 0.58 (1:9
EtOAc/hexane). IR (KBr): ν
= 3021, 1605 cm–1 1H NMR 5-Benzyloxy-1-(5-methyl-2-nitrophenyl)-1H-indole (18c): Yield 75%,
.
˜
max
(300 MHz, CDCl3): δ = 8.92 (br. s, 1 H, NH), 8.63–8.58 (m, 2 H, yellow solid, m.p. 98–99 °C; Rf = 0.48 (1:19 EtOAc/hexane). IR
1
ArH), 8.17 (s, 1 H, ArH), 7.96 (d, J = 8.7 Hz, 2 H, ArH), 7.69– (KBr): ν
= 3043, 1608, 1531, 1331 cm–1. H NMR (300 MHz,
˜
max
7.52 (m, 3 H, ArH), 7.43 (t, J = 8.1 Hz, 1 H, ArH), 6.89 (d, J =
CDCl3): δ = 7.50 (d, J = 6.9 Hz, 2 H, ArH), 7.43–7.28 (m, 5 H,
8.6 Hz, 2 H, ArH), 3.05 [s, 6 H, N(CH3)2], 2.56 (s, 3 H, CH3) ppm. ArH), 7.20–7.13 (m, 3 H, ArH), 7.06–6.93 (m, 2 H, ArH), 6.64 (d,
13C NMR (75 MHz, CDCl3): δ = 153.2, 143.8, 143.6, 139.3, 134.8, J = 3.2 Hz, 1 H, ArH), 5.14 (s, 2 H, CH2), 2.51 (s, 3 H, CH3) ppm.
130.0, 130.7, 130.1, 128.4, 125.7, 124.6, 124.1, 120.8, 122.2, 120.6,
120.1, 115.6, 114.0, 112.3, 40.4, 21.8 ppm. MS (ES+): m/z = 352.4
[M + 1]+. HRMS (EI): calcd. for [M]+ 351.1735; found 351.1739.
C24H21N3 (351.17): calcd. C 82.02, H 6.02, N 11.96; found C 82.19,
H 5.93, N 11.88.
MS (ES+): m/z = 359.3 [M + 1]+. C22H18N2O3 (358.13): calcd. C
73.73, H 5.06, N 7.82; found C 73.91, H 4.96, N 7.69.
5-Benzyloxy-1-(2-nitrophenyl)-1H-indole (18d): Yield 81%, yellow
solid, m.p. 102–104 °C; Rf = 0.42 (1:19 EtOAc/hexane). IR (KBr):
ν
= 3056, 2986, 1608, 1530, 1313 cm–1. 1H NMR (300 MHz,
˜
max
CDCl3): δ = 8.02 (dd, J = 2.0, 8.2 Hz, 1 H, ArH), 7.72 (dd, J =
2.3, 9.2 Hz, 1 H, ArH), 7.60–7.55 (m, 2 H, ArH), 7.52–7.31 (m, 4
H, ArH), 7.20 (d, J = 3.2 Hz, 1 H, ArH), 7.13 (d, J = 4.9 Hz, 2 H,
ArH), 7.03 (s, 1 H, ArH), 6.95 (d, J = 3.5 Hz, 1 H, ArH), 6.64 (dd,
J = 1.0, 4.9 Hz, 1 H, ArH), 5.11 (s, 2 H, CH2) ppm. MS (ES+): m/z
= 345.3 [M + 1]+. C21H16N2O3 (344.16): calcd. C 73.24, H 4.68, N
8.13; found C 73.36, H 4.71, N 8.23.
6-(4-Methoxyphenyl)-2-methyl-7H-indolo[2,3-c]quinoline (19f):
Yield 89%, white solid, m.p. 156–158 °C; Rf = 0.52 (1:9 EtOAc/
hexane). IR (KBr): ν
= 3417, 3020, 1586, 762 cm–1. 1H NMR
˜
max
(300 MHz, [D6]DMSO): δ = 8.70 (d, J = 8.5 Hz, 1 H, ArH), 8.06
(d, J = 8.6 Hz, 2 H, ArH), 7.99 (br. s, 1 H, NH), 7.78 (d, J =
8.3 Hz, 1 H, ArH), 7.57 (t, J = 5.8 Hz, 2 H, ArH), 7.38 (t, J =
7.8 Hz, 2 H, ArH), 7.23 (d, J = 8.7 Hz, 3 H, ArH), 3.90 (s, 3 H,
OCH3), 2.57 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
146.6, 143.0, 140.4, 136.7, 135.2, 131.1, 130.6, 129.4, 128.9, 126.9,
123.4, 123.1, 122.8, 121.9, 121.8, 121.4, 120.7, 114.6, 113.5, 55.8,
21.6 ppm. MS (ES+): m/z = 339.4 [M + 1]+. C23H18N2O (338.14):
calcd. C 81.63, H 5.36, N 8.28; found C 81.81, H 5.45, N 8.19.
General Procedure for the Synthesis of 2-(Indol-1-yl)phenylamine 13:
A mixture of compound 18 (5.8 mmol) and Pd/C (100 mg) in meth-
anol (10 mL) was subjected to hydrogenation for 2 h in a Parr ap-
paratus at 35 psi at room temperature. Thereafter, the catalyst was
removed by vacuum filtration of the reaction mixture through a
Celite bed with methanol. The filtrate was evaporated to obtain an
oily residue, which was taken up in EtOAc (2ϫ20 mL) and washed
with water (20 mL). The organic layers were evaporated in vacuo
to obtain the crude oil, which was purified by column chromatog-
raphy using EtOAc/hexane (1:4) as eluent to obtain 13.
N-[4-(10-Bromo-7H-indolo[2,3-c]quinolin-6-yl)phenyl]dimethylamine
(19g): Yield 84%, white solid, m.p. 220–222 °C; Rf = 0.62 (1:9
1
EtOAc/hexane). IR (KBr): ν
= 3233, 1632, 1217, 757 cm–1. H
˜
max
NMR (300 MHz, CDCl3): δ = 9.77 (br. s, 1 H, NH), 8.20 (d, J =
8.5 Hz, 1 H, ArH), 7.98 (dd, J = 1.2, 7.7 Hz, 3 H, ArH), 7.56–7.51
(m, 4 H, ArH), 7.46 (d, J = 8.5 Hz, 1 H, ArH), 7.07–7.03 (m, 2 H, 2-(Indol-1-yl)phenylamine (13a): Yield 86%, colorless oil; Rf = 0.48
ArH), 3.68 (s, 3 H, CH3), 2.57 (s, 3 H, CH3) ppm. 13C NMR (1:9 EtOAc/hexane). IR (neat): ν = 3372, 1616, 1508 cm–1. 1H
˜
max
(75 MHz, CDCl3): δ = 147.3, 142.7, 139.0, 138.2, 131.4, 130.3, NMR (300 MHz, CDCl3): δ = 7.74 (d, J = 7.86 Hz, 1 H, ArH),
129.8, 129.7, 129.3, 127.6, 126.4, 125.2, 123.8, 123.6, 123.5, 120.6,
115.5, 113.2, 40.6 ppm. MS (ES+): m/z = 416.2 [M + 1]+.
C23H18BrN3 (415.06): calcd. C 66.36, H 4.36, N 10.09; found C
66.24, H 4.39, N 10.21.
7.31–7.17 (m, 6 H, ArH), 6.92–6.86 (m, 2 H, ArH), 6.73 (d, J =
3.2 Hz, 1 H, ArH), 3.60 (br. s, 2 H, NH2) ppm. MS (ES+): m/z =
209.3 [M + 1]+. C14H12N2 (208.25): calcd. C 80.74, H 5.81, N 13.45;
found C 80.69, H 5.79, N 13.52.
300
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 292–303

Synthesis of Isocryptolepine Alkaloid and its Related Skeletons
4-Bromo-2-(indol-1-yl)phenylamine (13b): Yield 91%, yellow oil; Rf
ν
˜
= 3016, 1595, 1350 cm–1. 1H NMR (300 MHz, CDCl3): δ =
max
=
0.53 (1:9 EtOAc/hexane). IR (neat):
ν
=
3412, 1596,
8.62 (t, J = 8.5 Hz, 1 H, ArH), 8.46 (d, J = 10.8 Hz, 2 H, ArH),
˜
max
1512 cm–1. H NMR (300 MHz, CDCl3): δ = 7.72 (d, J = 4.9 Hz, 8.24 (d, J = 9.0 Hz, 2 H, ArH), 8.10 (dd, J = 1.5, 6 Hz, 1 H, ArH),
1
1 H, ArH), 7.24–7.13 (m, 4 H, ArH), 7.06–7.04 (m, 2 H, ArH), 7.98 (d, J = 9.0 Hz, 1 H, ArH) 7.73–7.60 (m, 2 H, ArH), 7.54–7.48
6.97 (dd, J = 0.9, 8.2 Hz, 1 H, ArH), 6.72 (d, J = 3.1 Hz, 1 H,
ArH) ppm. MS (ES+): m/z = 287.2 [M + 1]+. C14H11BrN2 (286.01):
calcd. C 58.56, H 3.86, N 9.76; found C 58.68, H 3.81, N 9.87.
(m, 2 H, ArH), 7.25 (d, J = 9.0 Hz, 2 H, ArH) ppm. MS (ES+): m/z
= 340.2. HRMS (EI): calcd. for [M]+ 339.1008; found 339.1012.
C21H13N3O2 (339.10): calcd. C 74.33, H 3.86, N 12.38; found C
74.24, H 3.76, N 12.30.
2-(5-Benzyloxyindol-1-yl)-4-(methylphenyl)amine (13c): Yield 72%,
brown oil; R = 0.48 (1:9 EtOAc/hexane). IR (KBr): ν
= 3412,
˜
6-(4-Bromophenyl)indolo[1,2-a]quinoxaline (20d): Yield 76%, yellow
solid, m.p. 219–221 °C; Rf = 0.60 (1:19 EtOAc/hexane). IR (KBr):
f
max
1596, 1512 cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.76 (d, J =
7.1 Hz, 2 H, ArH), 7.56–7.46 (m, 5 H, ArH), 7.35–7.02 (m, 5 H,
ArH), 6.66 (d, J = 3.1 Hz, 1 H, ArH), 5.14 (s, 2 H, CH2), 3.42 (s,
2 H, NH2), 2.53 (s, 3 H, CH3) ppm. MS (ES+): m/z = 329.3 [M +
1]+. C22H20N2O (328.15): calcd. C 80.46, H 6.14, N 8.53; found C
80.64, H 6.08, N 8.68.
ν
= 3021, 2965, 1597 cm–1. 1H NMR (300 MHz, CDCl3): δ =
˜
max
8.54 (t, J = 8.3 Hz, 2 H, ArH), 8.09 (dd, J = 1.2, 7.9 Hz, 1 H,
ArH), 7.95–7.93 (m, 3 H, ArH), 7.74 (d, J = 7.9 Hz, 2 H, ArH),
7.68–7.57 (m, 2 H, ArH), 7.48 (t, J = 7.9 Hz, 2 H, ArH), 7.23 (s,
1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.0, 135.8,
133.0, 131.6, 130.9, 130.2, 130.1, 129.5, 129.4, 127.5, 126.5, 125.9,
125.1, 124.4, 123.1, 117.2, 115.8, 114.9, 114.7 ppm. MS (ES+): m/z
= 375.4. HRMS (EI): calcd. for [M]+ 373.03404; found 373.03046.
C21H13BrN2 (372.02): calcd. C 67.58, H 3.51, N 7.51; found C
67.66, H 3.58, N 7.54.
2-(5-Benzyloxyindol-1-yl)phenylamine (13d): Yield 78%, yellow oil;
Rf = 0.46 (1:9 EtOAc/hexane). IR (neat): ν
= 3396, 1608,
˜
max
1523 cm–1. H NMR (300 MHz, CDCl3): δ = 7.51 (d, J = 6.8 Hz,
1 H, ArH), 7.44–7.34 (m, 3 H, ArH), 7.25–7.19 (m, 5 H, ArH),
7.07 (d, J = 8.8 Hz, 1 H, ArH), 6.97–6.83 (m, 3 H, ArH), 6.63 (d,
J = 3.0 Hz, 1 H, ArH), 5.15 (s, 2 H, CH2) ppm. MS (ES+): m/z =
315.2 [M + 1]+. C21H18N2O (314.14): calcd. C 80.23, H 5.77, N
8.91; found C 80.15, H 5.82, N 8.88.
1
2-Bromo-6-(4-methoxyphenyl)indolo[1,2-a]quinoxaline (20e): Yield
77%, yellow solid, m.p. 234–236 °C; Rf = 0.48 (1:19 EtOAc/hex-
ane). IR (KBr): ν
= 3413, 2921, 1094, 1389 cm–1. 1H NMR
˜
max
(300 MHz, CDCl3): δ = 8.43 (d, J = 8.6 Hz, 1 H, ArH), 8.38 (d, J
= 8.8 Hz, 1 H, ArH), 8.23 (d, J = 2.2 Hz, 1 H, ArH), 8.03 (d, J =
8.8 Hz, 2 H, ArH), 7.96 (d, J = 7.9 Hz, 1 H, ArH), 7.69 (dd, J =
2.3, 8.8 Hz, 1 H, ArH), 7.59 (t, J = 7.0 Hz, 1 H, ArH), 7.47 (t, J
= 7.5 Hz, 1 H, ArH), 7.32 (s, 1 H, ArH), 7.12 (d, J = 8.8 Hz, 2 H,
ArH) 3.94 (s, 3 H, OCH3) ppm. 13C NMR (75 MHz, CDCl3): δ =
165.3, 155.3, 135.8, 133.7, 132.0, 130.5, 130.2, 127.9, 125.9, 125.8,
125.2, 124.8, 124.6, 120.3, 118.9, 117.0, 116.1, 115.5, 114.6,
55.8 ppm. MS (ES+): m/z = 405.3 [M + 1]+. C22H15BrN2O (402.03):
calcd. C 65.52, H 3.75, N 6.95; found C 65.48, H 3.81, N 6.89.
General Procedure for the Synthesis of Indolo[1,2-a]quinoxaline 20:
A mixture of 13 (0.36 mmol) and benzaldehyde (0.36 mmol) in
DCM (2 mL) was treated with 2% TFA in DCM. Completion of
the Pictet–Spengler cyclization was monitored by TLC. After com-
plete consumption of the amine (by TLC) the mixture was treated
with KMnO4 (50 mg) for 15 min, the reaction mixture was then
evaporated, and the residue thus obtained was triturated with aq.
NaHCO3. It was then extracted with EtOAc, washed with brine
(10 mL), and dried with sodium sulfate. EtOAc was evaporated to
dryness under reduced pressure and the crude obtained was puri-
fied by column chromatography using EtOAc/hexane (1:9) to afford
20.
2-(2-Bromoindolo[1,2-a]quinoxalin-6-yl)phenol (20f): Yield 75%,
yellow solid, m.p. 159–161 °C; Rf = 0.59 (1:19 EtOAc/hexane). IR
(KBr): ν
= 3428, 2928, 1669, 1595, 1478 cm–1. 1H NMR
˜
6-Phenylindolo[1,2-a]quinoxaline (20a): Yield 81%, white solid, m.p.
max
(300 MHz, CDCl3): δ = 8.38 (d, J = 8.7 Hz, 1 H, ArH), 8.34 (d, J
= 8.9 Hz, 1 H, ArH), 8.23 (dd, J = 1.5, 7.9 Hz, 1 H, ArH), 8.04
(d, J = 2.3 Hz, 1 H, ArH), 7.98 (d, J = 8.0 Hz, 1 H, ArH), 7.69
(dd, J = 2.3, 8.9 Hz, 1 H, ArH), 7.62–7.57 (m, 2 H, ArH), 7.51–
7.44 (m, 2 H, ArH), 7.17 (d, J = 8.3 Hz, 1 H, ArH), 7.06 (t, J =
8.0 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 155.7,
153.2, 136.4, 135.8, 134.0, 131.1, 127.9, 128.9, 125.9, 125.3, 125.1,
124.74, 124.7, 121.1, 118.9, 118.1, 117.0, 116.6, 114.7, 114.5 ppm.
MS (ES+): m/z = 389.3 [M + 1]+. C21H13BrN2O (388.02): calcd. C
64.80, H 3.37, N 7.20; found C 64.60, H 3.17, N 7.30.
169–172 °C; Rf = 0.65 (1:19 EtOAc/hexane). IR (KBr): ν
=
˜
max
3021, 2965, 1597 cm–1. H NMR (300 MHz, CDCl3): δ = 8.54 (t,
J = 8.3 Hz, 2 H, ArH), 8.11 (dd, J = 1.2, 7.9 Hz, 1 H, ArH), 8.06–
8.03 (m, 2 H, ArH), 7.96 (d, J = 7.9 Hz, 1 H, ArH), 7.67–7.56 (m,
5 H, ArH), 7.50–7.44 (m, 2 H, ArH), 7.28 (s, 1 H, ArH) ppm. 13C
NMR (75 MHz, CDCl3, 25 °C): δ = 156.1, 138.3, 136.3, 133.0,
130.5, 130.1, 130.0, 129.0, 129.1, 128.6, 128.2, 124.3, 124.1, 122.7,
122.6, 114.6, 114.5, 102.4 ppm. MS (ES+): m/z = 295.4 [M + 1]+.
HRMS (EI): calcd. for [M]+ 294.1157; found 294.1165. C21H14N2
(294.11): calcd. C 85.69, H 4.79, N 9.52; found C 85.78, H 4.72, N
9.50.
1
9-Benzyloxy-2-methyl-6-phenylindolo[1,2-a]quinoxaline (20g): Yield
70%, yellow solid, m.p. 172–173 °C; Rf = 0.62 (1:19 EtOAc/hex-
N-(4-Indolo[1,2-a]quinoxalin-6-ylphenyl)dimethylamine (20b): Yield
80%, yellow solid, m.p. 145–147 °C; Rf = 0.38 (1:9 EtOAc/hexane).
ane). IR (KBr): νmax = 3020, 1597, 1381 cm–1. 1H NMR (300 MHz,
˜
IR (KBr): ν
= 3020, 2924, 1599 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 8.42 (d, J = 9.0 Hz, 1 H, ArH), 8.26 (s, 1 H, ArH),
8.04–7.97 (m, 3 H, ArH), 7.59–7.51 (m, 5 H, ArH), 7.46–7.26 (m,
6 H, ArH), 7.15 (s, 1 H, ArH), 5.20 (s, 2 H, CH3), 2.65 (s, 3 H,
CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 154.9, 138.9, 138.6,
137.2, 134.3, 130.0, 129.9, 128.8, 128.7, 128.5, 128.1, 127.7, 125.2,
115.9, 115.7, 114.6, 103.9, 101.6, 70.5, 22.3 ppm. MS (ES+): m/z =
415.2 [M + 1]+. C29H22N2O (414.17): calcd. C 84.03, H 5.35, N
6.76; found C 84.18, H 5.25, N 6.56.
˜
max
CDCl3): δ = 8.52 (d, J = 8.2 Hz, 1 H, ArH), 8.07 (dd, J = 1.2,
7.9 Hz, 1 H, ArH), 8.03 (d, J = 8.8 Hz, 2 H, ArH), 7.96 (d, J =
7.8 Hz, 1 H, ArH), 7.75 (d, J = 8.9 Hz, 1 H, ArH), 7.61–7.54 (m,
2 H, ArH), 7.45 (t, J = 7.4 Hz, 1 H, ArH), 7.36 (s, 1 H, ArH), 6.90
(d, J = 8.8 Hz, 2 H, ArH), 6.72 (d, J = 8.8 Hz, 1 H, ArH), 3.10 (s,
6 H, 2ϫCH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 136.6, 133.0,
131.9, 130.1, 129.9, 129.8, 129.4, 129.3, 127.6, 126.1, 124.0, 122.6,
122.4, 114.6, 114.5, 111.8, 110.9, 102.3, 40.5 ppm. MS (ES+): m/z
= 338.4 [M + 1]+. C23H19N3 (337.15): calcd. C 81.87, H 5.68, N
12.45; found C 81.78, H 5.69, N 12.53.
9-Benzyloxy-6-(p-tolyl)indolo[1,2-a]quinoxaline (20h): Yield 69%,
yellow solid, m.p. 153–155 °C; Rf = 0.58 (1:9 EtOAc/hexane). IR
1
(KBr): ν
= 3021, 1600, 1441, 1382 cm–1. H NMR (300 MHz,
˜
max
6-(4-Nitrophenyl)indolo[1,2-a]quinoxaline (20c): Yield 70%, red CDCl3): δ = 8.48 (d, J = 8.2 Hz, 1 H, ArH), 8.42 (d, J = 9.2 Hz, 1
solid, m.p. 213–214 °C; Rf = 0.56 (1:19 EtOAc/hexane). IR (KBr): H, ArH), 8.09 (dd, J = 1.4, 7.9 Hz, 1 H, ArH), 7.94 (d, J = 8.0 Hz,
Eur. J. Org. Chem. 2009, 292–303
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P. K. Agarwal, D. Sawant, S. Sharma, B. Kundu
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2 H, ArH), 7.62 (t, J = 8.5 Hz, 1 H, ArH), 7.52 (d, J = 6.9 Hz, 2
H, ArH), 7.48–7.28 (m, 8 H, ArH), 7.18 (s, 1 H, ArH), 5.20 (s, 2
H, CH2), 2.50 (s, 3 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ
= 155.6, 154.7, 140.0, 137.0, 136.2, 135.5, 130.4, 130.1, 129.6, 129.1,
129.3, 128.6, 128.5, 128.4, 128.1, 128.0, 127.5, 123.9, 116.0, 115.5,
114.2, 103.7, 101.8, 70.4, 21.5 ppm. MS (ES+): m/z = 415.2 [M +
1]+. C29H22N2O (414.17): calcd. C 84.03, H 5.35, N 6.76; found C
84.23, H 5.41, N 6.82.
Supporting Information (see also the footnote on the first page of
this article): The NMR and MS spectroscopic data for the repre-
sentative compounds is provided.
Acknowledgments
P. K. A., D. S. and S. S. are thankful to the Council of Scientific
and Industrial Research (CSIR), New Delhi for providing fellow-
ships.
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Received: September 23, 2008
Published Online: November 28, 2008
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