Diversity-oriented synthesis of polycyclic indoles: Bronsted or lewis acid catalyzed three-component reaction for the synthesis of α-carbolines and pyrimidoindoles

Article abstract of DOI:10.1002/ejoc.201402633

We report the diversity-oriented synthesis of pyrido- and pyrimido-indoles from an acid-catalyzed three component (3C) reaction involving ethyl 2-amino-1H-indole-3-carboxylates, arylaldehydes, and terminal alkynes. In the presence of a Bronsted acid such as trifluoroacetic acid (TFA), the 3C reaction furnished a mixture of pyrido- and pyrimido-indoles, whereas when catalyzed by Yb(OTf)₃ as a Lewis acid, pyrimidoindoles were obtained as the single product. The findings demonstrate the ability to control reaction products through change in the acid catalyst. The salient feature during TFA-catalyzed 3C reaction is that two different pathways are followed in one pot after propargylamine formation. The two cascade cyclizations comprise in situ decarboxylation-carbocyclization and an intramolecular hydroamination to afford products with different connectivity.

Full text of DOI:10.1002/ejoc.201402633

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DOI: 10.1002/ejoc.201402633
Diversity-Oriented Synthesis of Polycyclic Indoles: Brønsted or Lewis Acid
Catalyzed Three-Component Reaction for the Synthesis of α-Carbolines and
Pyrimidoindoles[‡]
Rajesh K. Arigela,[a] Ravi Kumar,[a,b] Srinivas Samala,[a] Sahaj Gupta,[a] and
Bijoy Kundu*[a,b]
Keywords: Multicomponent reactions / Hydroamination / Nitrogen heterocycles / Alkynes / Ytterbium
We report the diversity-oriented synthesis of pyrido- and pyr- demonstrate the ability to control reaction products through
imido-indoles from an acid-catalyzed three component (3C)
reaction involving ethyl 2-amino-1H-indole-3-carboxylates,
arylaldehydes, and terminal alkynes. In the presence of a
Brønsted acid such as trifluoroacetic acid (TFA), the 3C reac-
tion furnished a mixture of pyrido- and pyrimido-indoles,
whereas when catalyzed by Yb(OTf)3 as a Lewis acid, pyrim-
idoindoles were obtained as the single product. The findings
change in the acid catalyst. The salient feature during TFA-
catalyzed 3C reaction is that two different pathways are fol-
lowed in one pot after propargylamine formation. The two
cascade cyclizations comprise in situ decarboxylation-car-
bocyclization and an intramolecular hydroamination to afford
products with different connectivity.
In our laboratory,[5] we have been regioselectively manip-
ulating the nucleophilicities of the N-1, C-2, and C-3 posi-
Introduction
The ubiquitous presence of N-polyheterocycles in the tions in indole by treating suitably functionalized indole de-
vast majority of drugs and natural products has led to many rivatives with alkyne-based reactants.[6] These one-pot reac-
efforts for their synthesis and functionalization with a view tions, performed in the presence of an appropriate catalyst
to generating molecules with diverse physical and chemical (metals/acids/halides), led to the formation of structurally
properties for drug discovery. Among such synthetic efforts, diverse polyheterocycles through different annulation path-
Schreiber laid down the concept of diversity-oriented syn- ways. Recently, in one such effort, alkynones were reacted
thesis (DOS),[1,2] in which one-pot reactions lead to the gen- with ethyl 2-amino-1H-indole-3-carboxylates and 2-amino
eration of structurally diverse skeletal arrays as a collection indole hydrochloride, which led to the synthesis of pyrimi-
of pure compounds that are suitable for new lead genera- doindoles[5h] and α-carbolines[5i] (Scheme 1). However,
tion against disease targets. Such a format requires the se- drawbacks associated with both methods included poor sta-
lection of substrates with multiple bond-forming sites bility of the 2-aminoindole hydrochloride and the need to
(atoms) that can be selectively exploited in one-pot[3] to af- synthesize the starting alkynones in an additional step. In
ford structurally diverse molecular architectures. The ap- view of this, we then examined the efficacy of 2-aminoindole-
proach also requires the identification of highly efficient 3-carboxyl ester 1 as a substrate for the generation of two
catalytic processes for these annulation reactions that are distinct skeletal arrays: pyrimidoindoles and α-carbolines[7]
not only efficient, selective, and high-yielding but are also through two different pathways in a one-pot fashion. We en-
rapid and eco-friendly. A detailed survey of the literature visioned that, owing to the availability of the three N1-H,
revealed few reports[4] dealing with branching pathways in C2-NH2, and C3-COOEt nucleophilic functionalities in ind-
a one-pot fashion affording annulated heterocycles with dis- ole substrate 1, coupled with the ease of decarboxylation in-
tinct connectivity in isolable yields.
duced by Brønsted acid,[8] it may be possible to trigger
differential acid-catalyzed annulation reactions, which, in
turn, may afford products with distinct atom connectivity. To
achieve this, we set out to annulate ethyl 2-amino-1H-indole-
3-carboxylates 1 with arylaldehydes 2 and terminal alkynes
3 in the presence of an acid in a one-pot reaction. Herein,
we disclose our results on a DOS involving a 3C reaction
affording two distinct indole-based heterocycles: α-carbolines
and/or pyrimidoindoles through different annulation strate-
gies that depend on the selection of acid type.
[‡] CDRI Communication No. 8725
[a] Medicinal & Process Chemistry Division, CSIR – Central Drug
Research Institute, B.S. 10/1, Sector 10,
Jankipuram Extension, Sitapur Road, Lucknow, 226031, India
E-mail: bijoy_kundu@yahoo.com
http://www.cdriindia.org/home.asp
[b] Academy of Scientific and Innovative Research,
New Delhi, 110001, India
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402633.
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Scheme 1. Synthesis of α-carbolines and pyrimidoindoles from 2-aminoindoles.
Lewis acid driven transformations because their application
in the synthesis of structurally diverse heterocycles has been
Results and Discussion
Our studies commenced with the treatment of ethyl 2- well documented.[9,10] Among the variety of Lewis acids
amino-1H-indole-3-carboxylate (1a) with 4-methylbenzal- screened, Yb(OTf)3 in toluene under microwave conditions
dehyde (2a) and 4-ethynyl toluene (3a) in the presence of for 1.5 h furnished pyrimidoindole 4aaa as a single product
various transition-metal catalysts (Pd/Ag/Cu) in a one-pot in 48% isolated yield (entry 5). Switching solvent from tolu-
fashion. Unfortunately, none of the above catalytic systems ene to N,N-dimethylformamide (DMF) or dimethyl sulfox-
facilitated the required transformation (Table 1, entries 1– ide (DMSO) failed to produce the final products (entries 6
4). This prompted us to explore the abilities of various and 7). On the other hand, a moderate increase in the iso-
Table 1. Optimization of the synthesis of pyrimidoindole 4aaa and α-carboline 5aaa.[a]
Entry
Catalyst (mol-%)
Solvent
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
–
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMF
DMSO
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
2
2
2
2
n.r.
n.r.
n.r.
n.r.
48/–
n.r.
n.r.
68/–
Cu(OTf)2 (10)
Ag(OTf) (10)
Pd(OAC)2 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (10)
Yb(OTf)3 (50)
Sc(OTf)3 (10)
Zn(OTf)2 (10)
pTsOH (10)
TFA (10)
1.5
2
2
40 min
40 min
1.5
2
9
60/Ͻ10
58/–
52/–
10
11
12
13
14
15
16
3
25/–
0.5
0.5
0.5
0.5
40/38[c]
37/44[c]
23/53[c]
27/48[c]
TFA (50)
TFA[d]
TfOH[d]
[a] Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), 3a (0.5 mmol), catalyst, solvent (5 mL), 100 °C in microwave. [b] Isolated yield;
n.r.: no reaction. [c] The crude products exhibited polar impurities on TLC. [d] Acid (1.0 equiv.) was used.
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Diversity-Oriented Synthesis of Polycyclic Indoles
lated yield of 4aaa to 68% was observed in acetonitrile (en- in all cases. Employing a stronger acid such as TfOH
try 8). In an attempt to further increase the yield of 4aaa, (1.0 equiv.) under microwave conditions in acetonitrile for
we enhanced the catalyst loading from 10 to 50 mol-% (en- 0.5 h afforded 5aaa in 48% isolated yield, 4aaa in 27% yield
try 9) and notably, the altered conditions furnished a mix- and the rest comprised of polar impurities (entry 16). The
ture of two products (60 and Ͻ10% isolated yield) compris- formation of polar impurities in the presence of Brønsted
ing 4aaa and a new product that was characterized as α- acids may be attributed to degradation products arising
carboline 5aaa (1H NMR characteristic singlet at δ = from the poorly stable[11] 2-aminoindole derivative being
11.0 Hz).
generated in situ following the decarboxylation. Thus, the
Our findings thus suggest that by manipulating the reac- optimum reaction conditions for the synthesis of 5aaa in-
tion conditions it may be possible to obtain two distinct volved the use of TFA (1.0 equiv.) as catalyst in acetonitrile
annulated products. This led us to screen variety of Lewis under microwave irradiation at 100 °C for 30 min, whereas
and Brønsted acids for the 3C reaction with a view to in- the optimized synthesis of 4aaa involved the use of Yb(OTf)3
creasing the yields of reaction products 4aaa and 5aaa. as catalyst in acetonitrile under microwave irradiation at
Attempts to replace Yb(OTf)3 with Sc(OTf)3 and Zn(OTf)3 100 °C for 40 min. Attempts to treat N-methyl (ethyl 2-
furnished 4aaa in diminished yield (Table 1, entries 10 and amino-5-fluoro-1-methyl-1H-indole-3-carboxylate)
(1d)
11), whereas addition of p-toluenesulfonic acid (pTsOH) as with an aldehyde and the alkyne in the presence of either
a catalyst afforded 4aaa in poor yield (entry 12). Use of TFA or Yb(OTf)3 failed to yield the corresponding pyrido-
Brønsted acids, however, led to the formation of a mixture indole, because the indole derivative itself was found to be
of 4aaa and 5aaa in isolable yields. Employing trifluoro- highly unstable under both acidic conditions.
acetic acid (TFA) under microwave conditions in aceto-
A plausible mechanism for the formation of 4aaa and
nitrile for 0.5 h furnished a mixture of 4aaa and 5aaa in 40 5aaa is depicted in Figure 1. Initially, aldehyde 2a, in the
and 38% isolated yields, respectively (entry 13) along with presence of Lewis/Brønsted acid, may react with amine 1a
polar impurities as evident by TLC. Increasing the concen- to afford imine I, which may then be followed by nucleo-
tration of TFA from 10 to 100 mol-% resulted in a gradual philic addition of the terminal alkyne 3a to furnish propar-
decrease in the isolated yields of 4aaa from 40 to 23% and gylamine[12] II. Following activation of the alkyne moiety
simultaneous enhancement in the isolated yield of 5aaa by Yb,[13] III may then undergo concomitant intramolecu-
from 38 to 53% (entries 13–15). Indeed, the prevalence of lar nucleophilic attack from the indolic Na-H to afford di-
polar impurities under Brønsted acid catalysis was observed hydro intermediate IV. This is followed by aerial oxidation
Figure 1. Plausible mechanism for the formation of pyrimidoindole 4aaa and pyridoindole 5aaa.
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to produce the final product 4aaa along with regeneration aerial oxidation to afford 5aaa. It is interesting to note that
of catalyst. For the formation of 5aaa, the reaction may although both products are formed under acidic conditions,
commence by H+-mediated alkyne[14] activation toward in- orthogonal selectivity leading to the formation of 4 could
tramolecular nucleophilic attack by the C-3 of the indole to be observed only in the presence of a mild Lewis acid.
furnish cyclic intermediate VI via intermediate V. In the
The scope and limitations of the reaction under the opti-
next step, the ester group in VI may undergo acid hydrolysis mized conditions for the selective synthesis of 4 was estab-
followed by decarboxylation, which, in turn, provides resid- lished by introducing diversity in substrates 1, 2, and 3
ual electrons to achieve aromaticity in the indole to afford (Table 2). The efficacy of the reaction for the selective syn-
dihydro intermediate VII. The latter may finally undergo thesis of 4 was demonstrated by synthesizing 12 com-
Table 2. Substrate scope of the reaction to generate pyrimidoindole 4.[a]
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol), Yb(OTf)3 (10 mol-%), CH3CN, 100 °C in microwave, 40 min.
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Diversity-Oriented Synthesis of Polycyclic Indoles
Table 3. Substrate scope for the reaction to generate pyridoindole 5 and 4.[a]
[a] Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), 3a (1.0 mmol), TFA (1.0 equiv.), CH3CN, 100 °C in microwave, 30 min. [b] Isolated
yield.
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10 mL glass vessels. Column chromatography was performed using
silica gel (100–200 mesh) as the stationary phase. All reactions were
monitored by thin-layer chromatography (TLC). The purity and
identification of the compounds were further established by using
HRMS (ESI). Melting points were measured with a capillary melt-
ing-point apparatus and are uncorrected.
pounds, which were isolated in moderate to good yields
(58–70%). The substituents on the indole played an impor-
tant role in determining the yields of final products. Sub-
strates with R1 as electron-donating groups or unsubsti-
tuted (methyl/H) produced better yields than those with
electron-withdrawing groups (7-fluoro). Similarly, replacing
Ar in aldehydes with an electron-donating group (4-Me)
furnished products in better isolated yields when compared
with those containing electron-withdrawing groups (Ar =
4-F, 4-Cl, 4-Br, or 4-NO2). Unfortunately, substrates with
R2 as aliphatic substituents such as 1-octyne, 1-hexyne, and
1-ethynyltrimethylsilane failed to furnish any cyclized prod-
ucts; however, when replaced with 1-ethynylcyclohexene, the
corresponding products 4bad and 4bcd were obtained in
58% isolated yield.
II. General Procedure for the Preparation of Ethyl 2-Amino-1H-ind-
ole-3-carboxylate 1a–d: Prepared according to the reported pro-
cedure.[15,16] All aryl aldehydes 2a–f and alkynes 3a–d were com-
mercially available. Compounds 4bba, 4cbc, and 4aab are known[5h]
and the spectroscopic and physical data obtained here matches well
with reported data.
III. General Procedure for the Synthesis of Pyrimido[1,2-a]indole (4):
A mixture of substituted ethyl 2-amino-1H-indole-3-carboxylate 1
(1.0 mmol), substituted benzaldehyde 2 (1.0 mmol), substituted
alkyne 3 (1.0 mmol), and Yb(OTf)3 (10 mol-%) in acetonitrile
The versatility of the TFA-catalyzed 3C reaction for the (5 mL) was stirred at 100 °C for 30 min under microwave irradia-
tion. The progress of the reaction was monitored by TLC. Upon
completion, the reaction was quenched with saturated sodium
hydrogen carbonate solution and extracted with ethyl acetate. The
organic layer was washed with water and brine, dried with anhy-
drous sodium sulfate and concentrated in vacuo. The crude product
was purified by column chromatography (ethyl acetate/hexane,
10%) to give 4.
synthesis of 5 was demonstrated by synthesizing 10 different
compounds in 44–53% isolated yield (Table 3). In all cases
the corresponding product 4 was obtained as a minor com-
ponent in 19–25% isolated yield. The diminished yields of
5 may be attributed to poor stability of the 2-amino indole
derivative generated in situ following decarboxylation under
acidic conditions, thereby resulting in the formation of po-
lar impurities. Thus, as depicted in Figure 1, during the for-
mation of 5 it appears that a part of intermediate II, before
undergoing conversion into VII following decarboxylation,
undergoes H+ mediated intramolecular hydroamination to
afford 4 as a minor product, whereas the decarboxylated
IV. General Procedure for the Synthesis of Pyrido[2,3-b]indole (5/
4 mixture): A mixture of substituted ethyl 2-amino-1H-indole-3-
carboxylate 1 (1.0 mmol), substituted benzaldehyde 2 (1.0 mmol),
substituted alkyne 3 (1.0 mmol), and TFA (1.0 equiv.) in aceto-
nitrile (5 mL) was stirred at 100 °C under microwave irradiation.
The progress of the reaction was monitored by TLC. Upon comple-
intermediate VII undergoes either predominant carbocy- tion, the reaction was then quenched with saturated sodium
hydrogen carbonate solution and extracted with ethyl acetate. The
organic layer was washed with water and brine, dried with anhy-
drous sodium sulfate and concentrated in vacuo. The crude product
was purified by column chromatography (ethyl acetate/hexane, 5–
10%) to give 5 and 4.
clization to afford 5 or decomposition to yield polar impuri-
ties.
Conclusions
Ethyl 2-(4-Methylphenyl)-4-[4-(methylphenyl)]pyrimido[1,2-a]indole-
10-carboxylate (4aaa): Yield 350 mg (68%); orange solid; m.p. 188–
We have described a diversity-oriented synthesis of poly-
cyclic indoles through a 3C reaction involving ethyl 2-ami-
noindole-3-carboxylates, arylaldehydes, and terminal alk-
ynes catalyzed by either Brønsted or Lewis acids. The 3C
reaction allows selective control of the formation of reac-
tion products by changing the nature of the acid catalyst to
furnish α-carbolines and/or pyrimidoindoles in a one-pot
fashion through two different reaction pathways.
190 °C; R = 0.50 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
3429, 2931, 1662, 1409, 1215 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.44 (d, J = 8.0 Hz, 1 H), 8.15 (d, J = 7.5 Hz, 2 H), 7.39–7.31
(m, 5 H), 7.38 (m, 2 H), 7.02 (s, 1 H), 6.92–6.88 (m, 1 H), 6.57 (d,
J = 8.2 Hz, 1 H), 4.50 (m, 2 H), 2.48 (s, 3 H), 2.36 (s, 3 H), 1.51
(m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.3, 158.0,
148.9, 147.1, 141.6, 141.1, 134.1, 130.9, 130.5, 130.1, 129.7, 125.2,
128.0, 127.6, 125.1, 121.8, 121.1, 115.0, 105.5, 94.9, 59.6, 21.7, 21.6,
14.8 ppm. HRMS (ESI): m/z calcd. for C28H25N2O2 [M + H]
421.1916; found 421.1901.
Experimental Section
Ethyl
4-[4-(tert-Butyl)phenyl]-2-(4-chlorophenyl)pyrimido[1,2-a]-
indole-10-carboxylate (4acc): Yield 366 mg (62%); orange solid;
m.p. 200–202 °C; Rf = 0.56 (ethyl acetate/hexane, 10%). FTIR
I. General Information and Methods: All reagents and solvents were
purchased from commercial sources and used without purification.
NMR spectra were recorded with 300 or 400 MHz spectrometers
for 1H NMR and 75 or 100 MHz for 13C NMR spectroscopy.
Chemical shifts δ are given in ppm relative to the residual signals
of tetramethylsilane in CDCl3 or deuterated solvent CDCl3/[D6]
DMSO for 1H and 13C NMR spectroscopy. Multiplicities are re-
ported as: singlet (s), doublet (d), doublet of doublets (dd), doublet
of triplets (dt), triplet (t), quartet (q), multiplet (m), broad singlet
(br. s). HRMS were obtained by using the electrospray ionization
(ESI) technique and a time-of-flight (TOF) analyzer. Microwave
irradiation was carried out with Initiator 2.5 Microwave Synthe-
sizers from Biotage. All the reactions were performed in special
(KBr): ν = 3446, 2932, 1550, 1382, 1223 cm–1. 1H NMR (400 MHz,
˜
CDCl3): δ = 8.44 (d, J = 8.0 Hz, 1 H), 8.19–8.17 (m, 2 H), 7.57 (d,
J = 8.4 Hz, 2 H), 7.44–7.38 (m, 4 H), 7.35–7.31 (m, 1 H), 6.99 (s,
1 H), 6.91–6.88 (m, 1 H), 6.56 (d, J = 8.7 Hz, 1 H), 4.49 (q, J =
7.2 Hz, 2 H), 1.49 (t, J = 7.2 Hz, 3 H), 1.38 (s, 9 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 160.4, 151.9, 149.8, 144.5, 142.1, 132.6,
130.5, 125.9, 125.7, 124.4, 124.2, 123.3, 121.6, 120.6, 117.2, 116.6,
110.3, 100.5, 90.7, 54.9, 30.4, 26.6, 10.0 ppm. HRMS (ESI): m/z
calcd. for C30H28N2O2Cl [M + H] 483.1839; found 483.1824.
Ethyl
2-(4-Bromophenyl)-4-[4-(tert-butyl)phenyl]pyrimido[1,2-a]-
indole-10-carboxylate (4adc): Yield 386 mg (60%); orange solid;
6
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m.p. 192–194 °C; Rf = 0.48 (ethyl acetate/hexane, 10%). FTIR
Ethyl
4-Cyclohex-1-en-1-yl-8-methyl-2-(4-methylpheny)pyrimido-
(KBr): ν = 3446, 2942, 2130, 1653, 1396, 1212 cm–1. 1H NMR [1,2-a]indole-10-carboxylate (4bad): Yield 281 mg (58%); orange so-
˜
(400 MHz, CDCl3): δ = 8.46 (d, J = 8.0 Hz, 1 H), 8.14–8.07 (m, 2
H), 8.57–7.59 (m, 4 H), 7.45–7.43 (m, 2 H), 7.37–7.33 (m, 1 H),
lid; m.p. 186–188 °C; Rf = 0.55 (ethyl acetate/hexane, 10%). FTIR
(KBr): ν = 3450, 2920, 1661, 1393, 1223 cm–1. 1H NMR (400 MHz,
˜
7.01 (s, 1 H), 6.93–6.91 (m, 1 H), 6.57 (d, J = 4.0 Hz, 1 H), 4.49 CDCl3): δ = 8.28–8.27 (m, 1 H), 8.14 (d, J = 8.0 Hz, 2 H), 7.74 (d,
(q, J = 7.2 Hz, 2 H), 1.50 (t, J = 6.8 Hz, 3 H), 1.39 (s, 9 H) ppm. J = 8.0 Hz, 1 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.07–7.05 (m, 1 H),
13C NMR (100 MHz, CDCl3): δ = 165.2, 156.7, 154.6, 149.3, 146.8, 6.93 (s, 1 H), 6.20 (s, 1 H), 4.48 (q, J = 8.0 Hz, 2 H), 2.49 (s, 3 H),
135.8, 132.1, 130.7, 129.2, 128.1, 128.0, 126.4, 125.9, 122.0, 121.5,
115.1, 105.3, 95.5, 59.7, 35.2, 31.4, 14.8 ppm. HRMS (ESI): m/z
calcd. for C30H28N2O2Br [M + H] 527.1334; found 527.1327.
2.45 (s, 1 H), 2.37 (s, 3 H), 2.33 (s, 2 H), 2.10–2.04 (m, 1 H), 1.89–
1.85 (m, 3 H), 1.71–1.68 (m, 1 H), 1.50–1.49 (m, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 165.5, 158.3, 150.7, 147.1, 141.5,
135.2, 134.3, 133.5, 131.9, 130.8, 129.7, 127.6, 126.1, 123.3, 121.4,
114.5, 103.8, 94.3, 59.6, 29.8, 27.1, 25.3, 22.1, 22.0, 21.6, 14.8 ppm.
HRMS (ESI): m/z calcd. for C28H29N2O2 [M + H] 425.2229; found
425.2228.
Ethyl
4-[4-(tert-Butyl)phenyl]-2-(4-methylphenyl)pyrimido[1,2-a]-
indole-10-carboxylate. (4aac): Yield 356 mg (63%); orange solid;
m.p. 196–198 °C; Rf = 0.50 (ethyl acetate/hexane, 10%). FTIR
(KBr): ν = 3442, 2967, 1673, 1452, 1317, 1216 cm–1. 1H NMR
˜
(400 MHz, CDCl3): δ = 8.45 (d, J = 8.0 Hz, 1 H), 8.15 (d, J =
Ethyl
2-(4-Chlorophenyl)-4-cyclohex-1-en-1-yl-8-methylpyrimido-
8.0 Hz, 2 H), 7.57 (d, J = 8.0 Hz, 2 H), 7.44 (d, J = 8.0 Hz, 2 H), [1,2-a]indole-10-carboxylate (4bcd): Yield 295 mg (58%); orange so-
7.35–7.31 (m, 1 H), 7.25 (d, J = 8.0 Hz, 2 H), 7.04 (s, 1 H), 6.91–
6.87 (m, 1 H), 6.55 (d, J = 4.0 Hz, 1 H), 4.52 (q, J = 8.0 Hz, 2 H),
lid; m.p. 188–190 °C; Rf = 0.39 (ethyl acetate/hexanes, 10%). FTIR
(KBr): ν = 3450, 2927, 1653, 1400, 1237 cm–1. 1H NMR (400 MHz,
˜
2.36 (s, 3 H), 1.51 (m, 3 H), 1.39 (s, 9 H) ppm. 13C NMR CDCl3): δ = 8.28 (s, 1 H), 8.20–8.18 (m, 2 H), 7.75 (d, J = 8.0 Hz,
(100 MHz, CDCl3): δ = 165.3, 158.0, 154.3, 148.8, 147.2, 141.6, 1 H), 7.41 (d, J = 8.0 Hz, 2 H), 7.10–7.07 (m, 1 H), 6.91 (s, 1 H),
134.1, 130.9, 160.5, 129.6, 128.1, 128.0, 127.6, 126.3, 125.1, 121.8,
6.21 (s, 1 H), 4.48 (q, J = 8.0 Hz, 2 H), 2.49 (s, 3 H), 2.33–2.32 (m,
121.1, 114.9, 105.6, 94.9, 59.6, 35.1, 31.3, 21.5, 14.8 ppm. HRMS 2 H), 2.07–2.04 (m, 1 H), 1.91–1.83 (m, 4 H), 1.75–1.70 (m, 1 H),
(ESI): m/z calcd. for C31H31N2O2 [M + H] 463.2386; found
463.2387.
1.51 (m, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.4, 156.9,
150.9, 146.8, 137.2, 135.5, 135.4, 133.3, 132.1, 130.7, 129.1, 128.9,
128.3, 126.1, 123.6, 121.5, 114.6, 103.5, 94.7, 59.7, 27.0, 25.3, 22.0,
21.5, 14.8 ppm. HRMS (ESI): m/z calcd. for C27H26N2O2Cl [M +
H] 445.1683; found 445.1682.
Ethyl
4-[4-(tert-Butyl)phenyl]-2-(4-nitrophenyl)pyrimido[1,2-a]-
indole-10-carboxylate (4aec): Yield 380 mg (63%); crimson red so-
lid; m.p. 200–202 °C; Rf = 0.52 (ethyl acetate/hexane, 10%). FTIR
(KBr): ν = 3448, 2934, 1643, 1360, 1104 cm–1. 1H NMR (400 MHz,
Ethyl 2-(4-Methoxyphenyl)-8-methyl-4-(4-methylphenyl)pyrimido-
˜
CDCl3): δ = 8.48 (d, J = 8.0 Hz, 1 H), 8.42 (d, J = 8.0 Hz, 2 H),
[1,2-a]indole-10-carboxylate (4bba): Yield 309 mg (60%); orange so-
8.29 (d, J = 8.0 Hz, 2 H), 7.60 (d, J = 8.0 Hz, 2 H), 7.46 (d, J = lid; m.p. 198–200 °C; Rf = 0.39 (ethyl acetate/hexanes, 10%). FTIR
8.0 Hz, 2 H), 7.40–7.37 (m, 1 H), 7.08 (s, 1 H), 6.98–6.94 (m, 1 H),
(KBr): ν = 3033, 2970, 1662, 1457, 1253 cm–1. 1H NMR (300 MHz,
6.62 (d, J = 8.0 Hz, 1 H), 4.53 (q, J = 8.0 Hz, 2 H), 1.53–1.51 (m, CDCl3): δ = 8.32–8.27 (m, 3 H), 7.47–7.41 (m, 4 H), 7.04–7.01 (m,
˜
3 H), 1.39 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.0,
155.0, 154.9, 149.7, 149.2, 146.4, 142.6, 130.5, 130.4, 128.5, 128.0,
126.5, 125.7, 124.1, 122.2, 122.0, 115.3, 105.5, 59.9, 35.3, 31.4,
14.9 ppm. HRMS (ESI): m/z calcd. for C30H28N3O4 [M + H]
494.2080; found 494.2072.
3 H), 6.79 (d, J = 8.6 Hz, 1 H), 6.49 (d, J = 8.7 Hz, 1 H), 4.57 (q,
J = 7.1 Hz, 2 H), 3.89 (s, 3 H), 2.55 (s, 3 H), 2.48 (s, 3 H), 1.60 (t,
J = 7.1 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.6,
162.3, 157.4, 148.7, 147.4, 141.1, 135.1, 131.1, 130.9, 130.1, 129.5,
129.4, 128.4, 126.4, 122.8, 121.4, 114.7, 114.3, 105.1, 94.3, 59.7,
55.5, 21.9, 21.7, 14.9 ppm. HRMS (ESI): m/z calcd. for
C29H27N2O3 [M + H] 451.2022; found 451.2026.
Ethyl 8-Methyl-2-(4-bromophenyl)-4-phenylpyrimido[1,2-a]indole-
10-carboxylate (4bdb): Yield 338 mg (61%); orange solid; m.p. 198–
200 °C; R = 0.53 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
Ethyl 4-[4-(tert-Butyl)phenyl]-7-fluoropyrimido-2-(4-methoxyphen-
yl)pyrimido[1,2-a]indole-10-carboxylate (4cbc): Yield 255 mg (58%);
orange solid; m.p. 204–206 °C; Rf = 0.40 (ethyl acetate/hexanes,
˜
f
3434, 2400, 1638, 1405, 1215 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.36 (s, 1 H), 8.23–8.21 (m, 2 H), 7.72–7.64 (m, 5 H), 7.60–7.58
(m, 2 H), 7.09 (s, 1 H), 6.84–6.81 (m, 1 H), 6.46 (d, J = 8.0 Hz, 1
10%). FTIR (KBr): ν = 3068, 2972, 1664, 1486, 1224 cm–1. 1H
˜
H), 4.60 (q, J = 8.0 Hz, 2 H), 2.51 (s, 3 H), 1.61 (t, J = 7.2 Hz, 3 NMR (300 MHz, CDCl3): δ = 8.48–8.43 (m, 1 H), 8.2 (d, J =
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.4, 156.4, 148.8,
146.8, 135.9, 135.5, 133.7, 132.2, 131.0, 130.9, 129.6, 129.1, 128.4,
126.4, 125.9, 123.4, 121.5, 114.7, 104.9, 95.2, 59.8, 21.9, 14.9 ppm.
HRMS (ESI): m/z calcd. for C27H22N2O2Br [M + H] 485.0865;
found 485.0860.
8.8 Hz, 2 H), 7.66 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 8.2 Hz, 2 H),
7.19–7.13 (m, 1 H), 7.07–7.01 (m, 3 H), 6.21–6.17 (m, 1 H), 4.56
(q, J = 7.1 Hz, 2 H), 3.89 (s, 3 H), 1.59 (t, J = 7.1 Hz, 3 H), 1.46
(s, 9 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 165.2, 162.4, 160.3,
157.5, 154.7, 148.4, 147.5, 130.4, 129.5, 129.4, 128.2, 127.6, 127.4,
126.8, 126.5, 122.9, 122.7, 114.4, 114.1, 113.7, 105.3, 101.9, 101.4,
94.7, 59.7, 55.5, 35.2, 31.4, 14.9 ppm. HRMS (ESI): m/z calcd. for
C31H30FN2O3 [M + H] 497.2240; found 497.2242.
Ethyl 8-Methyl-2-(4-methylphenyl)-4-phenylpyrimido[1,2-a]indole-
10-carboxylate (4bab): Yield 360 mg (75%); orange solid; m.p. 200–
202 °C; R = 0.55 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
3449, 2927, 1655, 1393, 1223, 1107 cm–1. 1H NMR (400 MHz, Ethyl 2-(4-Bromophenyl)-7-fluoro-4-phenylpyrimido[1,2-a]indole-10-
CDCl3): δ = 8.36 (s, 1 H), 8.25 (d, J = 8.0 Hz, 2 H), 7.71–7.64 (m,
3 H), 7.60–7.59 (m, 2 H), 7.35 (d, J = 8.0 Hz, 2 H), 7.13 (s, 1 H),
carboxylate (4cdb): Yield 222 mg (65%); orange solid; m.p. 196–
198 °C; R = 0.58 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
6.81 (d, J = 9.0 Hz, 1 H), 6.44 (d, J = 9.0 Hz, 1 H), 4.60 (q, J = 3433, 2400, 1636, 1488, 1215 cm–1. 1H NMR (400 MHz, CDCl3):
4.0 Hz, 2 H), 2.50 (s, 3 H), 2.46 (s, 3 H), 1.62 (t, J = 7.2 Hz, 3 δ = 8.43–8.39 (m, 1 H), 8.12–8.10 (m, 2 H), 7.66–7.64 (m, 1 H),
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.6, 157.9, 148.5,
7.61–7.57 (m, 3 H), 7.51–7.49 (m, 2 H), 7.18 (s, 1 H), 7.15–7.10 (m,
141.7, 135.3, 134.3, 134.0, 131.0, 130.8, 129.8, 129.5, 128.5, 127.7,
1 H), 7.00 (s, 1 H), 6.15–6.12 (m, 1 H), 4.49 (q, J = 6.0 Hz, 2 H),
126.4, 123.1, 121.5, 114.6, 105.3, 59.8, 22.0, 21.6, 14.9 ppm. HRMS 1.50 (t, J = 4.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
(ESI): m/z calcd. for C28H25N2O2 [M + H] 421.1916; found
164.9, 159.3, 156.6, 148.6, 146.9, 135.6, 133.0, 131.3, 129.4, 127.4
421.1906.
(d, J = 10.0 Hz), 126.8, 126.1, 123.2 (d, J = 96.0 Hz), 114.4 (d, J
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

Job/Unit: O42633
/KAP1
Date: 04-08-14 18:42:48
Pages: 11
R. K. Arigela, R. Kumar, S. Samala, S. Gupta, B. Kundu
FULL PAPER
= 24.0 Hz), 105.2, 101.6 (d, J = 28.0 Hz), 95.6, 59.9, 14.8 ppm.
HRMS (ESI): m/z calcd. for C26H19N2O2FBr [M + H] 489.0614;
found 489.0612.
59.7, 14.8 ppm. HRMS (ESI): m/z calcd. for C26H20N2O2Cl [M +
H] 427.1213; found 427.1211.
4-[4-(tert-Butyl)phenyl]-2-(4-methylphenyl)-9H-pyrido[2,3-b]indole
(5aac): Yield 238 mg (50%); white solid; m.p. Ͼ250 °C; Rf = 0.44
Ethyl 2-Amino-5-fluoro-1-methyl-1H-indole-3-carboxylate (1d):
Yield 159 mg (75%); red solid; m.p. 178–180 °C; Rf = 0.58 (ethyl
(ethyl acetate/hexane, 10%). FTIR (KBr): ν = 3433, 3019, 1636,
˜
1403, 1215, 1109 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 11.43
(s, 1 H), 8.29 (d, J = 7.8 Hz, 1 H), 8.18 (d, J = 8.2 Hz, 2 H), 7.95
(s, 1 H), 7.87–7.85 (m, 2 H), 7.68 (d, J = 8.4 Hz, 2 H), 7.61 (d, J
= 8.0 Hz, 1 H), 7.54–7.49 (m, 1 H), 7.33 (d, J = 8.0 Hz, 2 H), 7.30–
7.26 (m, 1 H), 2.39 (s, 3 H), 1.40 (s, 9 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 155.0, 151.2, 149.0, 141.2, 141.6,
137.2, 137.0, 133.6, 131.8, 129.6, 129.5, 129.2, 128.3, 127.4, 126.4,
126.0, 121.8, 120.2, 119.5, 116.1, 115.0, 112.2, 34.5, 31.1, 20.8 ppm.
HRMS (ESI): m/z calcd. for C28H27N2 [M + H] 391.2174; found
391.2169.
1
acetate/hexane, 20%). H NMR (400 MHz, CDCl3): δ = 7.74–7.70
(m, 1 H), 6.92–6.90 (m, 1 H), 6.87–6.80 (m, 1 H), 5.70 (br. s, 2 H),
4.38 (q, J = 8.0 Hz, 2 H), 3.47 (s, 3 H), 1.45 (t, J = 8.0 Hz, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 160.0, 157.7, 129.4,
129.3, 120.3, 120.2, 109.7, 109.5, 94.8, 94.5, 81.9, 64.4, 59.4,
14.8 ppm. HRMS (ESI): m/z calcd. for C12H14FN2O2 [M + H]
237.1039; found 237.1040.
2,4-Bis(4-methylphenyl)-9H-pyrido[2,3-b]indole
(5aaa):
Yield
225 mg (53%); white solid; m.p. 238–240 °C; Rf = 0.46 (ethyl acet-
ate/hexane, 10%). FTIR (KBr): ν = 3452, 3021, 1631, 1405, 1215,
˜
1113 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 11.39 (s, 1 H),
8.28 (m, 1 H), 8.17 (d, J = 8.1 Hz, 2 H), 7.93 (s, 1 H), 7.81 (d, J =
8.0 Hz, 2 H), 7.60 (m, 1 H), 7.53–7.49 (m, 1 H), 7.46 (m, 2 H), 7.32
(m, 2 H), 7.29–7.23 (m, 1 H), 2.45 (s, 3 H), 2.38 (s, 3 H) ppm. 13C
NMR (100 MHz, [D6]DMSO): δ = 149.0, 142.0, 141.5, 138.1,
137.1, 137.0, 133.5, 131.8, 129.6, 129.5, 129.1, 128.4, 127.3, 126.4,
121.7, 120.1, 119.4, 115.9, 112.1, 20.8, 20.7 ppm. HRMS (ESI): m/z
calcd. for C25H21N2 [M + H] 349.1705; found 349.1699.
Ethyl 4-[4-(tert-Butyl)phenyl]-2-(4-methylphenyl)pyrimido[1,2-a]-
indole-10-carboxylate (4aac); Method IV: Yield 130 mg (23%); see
above for data.
2-(4-Chlorophenyl)-6-methyl-4-phenyl-9H-pyrido[2,3-b]indole
(5bcb): Yield 222 mg (53%); white solid; m.p. 222–224 °C; Rf = 0.48
(ethyl acetate/hexane, 10%). FTIR (KBr): ν = 3448, 2949, 1643,
˜
1
1393, 1093 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 11.38 (s, 1
H), 8.33 (d, J = 8.7 Hz, 2 H), 8.10 (s, 1 H), 8.00 (s, 1 H), 7.93–7.91
(m, 2 H), 7.62–7.64 (m, 2 H), 7.58–7.53 (m, 3 H), 7.52–7.37 (m, 1
H), 7.35 (s, 1 H), 2.53–2.43 (m, 3 H) ppm. 13C NMR (100 MHz,
[D6]DMSO): δ = 147.7, 142.5, 140.5, 139.1, 136.8, 133.1, 132.3,
132.1, 130.5, 129.6, 129.1, 129.0, 128.7, 126.3, 122.3, 120.4, 116.7,
112.5, 21.5 ppm. HRMS (ESI): m/z calcd. for C24H18N2Cl [M +
H] 369.1158; found 369.1154.
Ethyl 2-(4-Methylphenyl)-4-(4-methylphenyl)pyrimido[1,2-a]indole-
10-carboxylate (4aaa); Method IV: The corresponding isomer data
were disclosed above, yield 118 mg (23%).
2-(4-Methylphenyl)-4-phenyl-9H-pyrido[2,3-b]indole (5aab): Yield
195 mg (48%); white solid; Rf = 0.48 (ethyl acetate/hexane, 10%);
m.p. 240–242 °C. FTIR (KBr): ν = 3462, 3024, 1631, 1405,
˜
Ethyl 2-(4-Chlorophenyl)-8-methyl-4-phenylpyrimido[1,2-a]indole-
10-carboxylate (4bcb): Yield 110 mg (22%); orange solid; m.p. 182–
1250 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 11.44 (s, 1 H),
8.30 (d, J = 8.0 Hz, 1 H), 8.19 (d, J = 8.0 Hz, 2 H), 7.96–7.91 (m,
1 H), 7.68–7.63 (m, 2 H), 7.61–7.51 (m, 5 H), 7.34–7.27 (m, 3 H),
2.34 (s, 3 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 149.0,
142.0, 141.6, 137.2, 137.0, 136.4, 131.8, 129.5, 129.1, 128.6, 127.5,
126.4, 121.7, 120.2, 119.5, 116.1, 112.2, 20.8 ppm. HRMS (ESI):
m/z calcd. for C24H19N2 [M + H] 335.1548; found 335.1553.
184 °C; R = 0.48 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
3430, 2401, 1632, 1409, 1215, 1110 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 8.33 (s, 1 H), 8.28–8.26 (m, 2 H), 7.70–7.62 (m, 3 H),
7.58–7.56 (m, 2 H), 7.50–7.48 (m, 2 H), 7.07 (s, 1 H), 6.82–6.79 (m,
1 H), 6.43 (d, J = 8.7 Hz, 1 H), 4.57 (q, J = 8.0 Hz, 2 H), 2.48 (s,
3 H), 1.58 (t, J = 8.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 165.3, 156.3, 148.7, 146.8, 137.3, 135.3 (d, J = 8.0 Hz), 133.6,
130.8 (d, J = 8.0 Hz), 129.5, 129.1, 128.6 (d, J = 51.0 Hz), 126.3,
123.3, 121.4, 114.6, 104.9, 95.1, 59.7, 21.9, 14.8 ppm. HRMS (ESI):
m/z calcd. for C27H22N2O2Cl [M + H] 441.1370; found 441.1364.
Ethyl
2-(4-Methylphenyl)-4-phenylpyrimido[1,2-a]indole-10-carb-
oxylate (4aab): Yield 109 mg (22%); orange solid; Rf = 0.50 (ethyl
acetate/hexane, 10%); m.p. 188–190 °C [ref.[5h] 190–192 °C]. 1H,
13C, HRMS matches well with the data reported above.
2-(4-Chlorophenyl)-4-phenyl-9H-pyrido[2,3-b]indole (5acb): Yield
207 mg (48%); white solid; Rf = 0.42 (ethyl acetate/hexane, 10%);
4-[4-(tert-Butyl)phenyl]-2-(4-fluorophenyl)-6-methyl-9H-pyrido-
[2,3-b]indole (5bfc): Yield 232 mg (50 %); white solid; m.p. 238–
m.p. 238–240 °C. FTIR (KBr): ν = 3456, 2432, 1650, 1473,
˜
240 °C; R = 0.60 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
1215 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 11.51 (s, 1 H),
8.35 (d, J = 8.6 Hz, 1 H), 8.30 (d, J = 7.5 Hz, 1 H), 8.04 (s, 1 H),
7.93 (d, J = 7.0 Hz, 2 H), 7.69–7.53 (m, 8 H), 7.30 (t, J = 7.2 Hz,
1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 148.0, 142.7,
142.2, 139.1, 136.7, 133.2, 132.5, 130.3, 129.7, 129.2, 129.1, 129.0,
128.8, 128.2, 122.2, 120.8, 120.2, 116.9, 112.8, ppm. HRMS (ESI):
m/z calcd. for C23H16N2Cl [M + H] 355.1002; found 355.0998.
3445, 2949, 1624, 1382, 1213, 1150 cm–1. 1H NMR (400 MHz, [D6]-
DMSO): δ = 11.33 (s, 1 H), 8.35–8.31 (m, 2 H), 8.10 (s, 1 H), 7.95
(s, 1 H), 7.84–7.82 (m, 2 H), 7.66–7.64 (m, 2 H), 7.52–7.45 (m, 1
H), 7.36–7.33 (m, 3 H), 2.52 (s, 3 H), 1.39 (s, 9 H) ppm. 13C NMR
(100 MHz, [D6]DMSO): δ = 163.9, 161.5, 151.6, 148.1, 142.4,
140.1, 136.9, 134.1, 132.2, 130.8, 129.5, 129.0, 128.9 (d, J = 5.0 Hz),
128.77, 126.4, 122.4, 120.3, 116.5, 115.8 (d, J = 21.0 Hz), 112.5,
34.9, 31.5, 21.5 ppm. HRMS (ESI): m/z calcd. for C28H26N2F [M
+ H] 409.2080; found 409.2072.
Ethyl
oxylate (4acb): Yield 99 mg (19%); orange solid; m.p. 188–190 °C;
R = 0.52 (ethyl acetate/hexane, 10%). FTIR (KBr): ν = 3435, 1673,
2-(4-Chlorophenyl)-4-phenylpyrimido[1,2-a]indole-10-carb-
Ethyl 4-[4-(tert-Butyl)phenyl]-8-methyl-2-(4-fluorophenyl)pyr-
˜
f
1482, 1216, 1101 cm–1. H NMR (400 MHz, CDCl3): δ = 8.45 (d, imido[1,2-a]indole-10-carboxylate (4bfc): Yield 137 mg (25 %);
1
J = 8.0 Hz, 1 H), 8.21–8.20 (m, 2 H), 7.64–7.56 (m, 3 H), 7.52–
orange solid; m.p. 178–180 °C; Rf = 0.46 (ethyl acetate/hexane,
7.50 (m, 2 H), 7.49–7.41 (m, 2 H), 7.36–7.33 (m, 1 H), 7.01 (s, 1
10%). FTIR (KBr): ν = 3452, 2949, 1656, 1396, 1234, 1168 cm–1.
˜
H), 6.92–6.88 (m, 1 H), 6.51 (d, J = 8.0 Hz, 1 H), 4.50 (q, J = 1H NMR (400 MHz, CDCl3): δ = 8.36–8.33 (m, 2 H), 7.68–7.66
8.0 Hz, 2 H), 1.52–1.48 (m, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.1, 156.6, 148.9, 146.7, 137.4, 135.2, 133.6, 130.9,
129.5, 129.2, 128.9, 128.3, 127.9, 125.3, 122.0, 121.5, 114.9, 105.1,
(m, 2 H), 7.53 (d, J = 8.5 Hz, 2 H), 7.28 (s, 1 H), 7.22 (t, J =
8.8 Hz, 2 H), 7.08 (s, 1 H), 6.84 (dd, J1 = 1.4, J2 = 8.8 Hz, 1 H),
6.52 (d, J = 8.7 Hz, 1 H), 4.60 (q, J = 8.0 Hz, 2 H), 2.51 (s, 3 H),
8
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© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42633
/KAP1
Date: 04-08-14 18:42:48
Pages: 11
Diversity-Oriented Synthesis of Polycyclic Indoles
1.61–1.59 (m, 3 H), 1.48 (s, 9 H) ppm. 13C NMR (100 MHz, 129.9, 129.2, 128.6 (d, J = 20.0 Hz), 126.4, 121.8 (d, J = 10.0 Hz),
CDCl3): δ = 165.9, 165.3, 163.5, 156.5, 154.4, 148.9, 146.9, 135.2, 118.0, 116.0, 108.0, 107.8, 98.5, 98.2, 20.7 ppm. HRMS (ESI): m/z
133.1, 130.7, 129.7 (d, J = 9.0 Hz), 128.0, 126.3, 123.1, 121.3, 115.9 calcd. for C24H18N2F [M + H] 353.1454; found 353.1449.
(d, J = 22.0 Hz), 114.7, 105.1, 94.7, 59.6, 35.1, 31.3, 21.8, 14.8 ppm.
Ethyl 7-Fluoro-2-(4-methylphenyl)-4-phenylpyrimido[1,2-a]indole-
HRMS (ESI): m/z calcd. for C31H30N2O2F [M + H] 481.2291;
10-carboxylate (4cab): Yield 114 mg (24%); orange solid; m.p. 168–
found 481.2286.
170 °C; R = 0.49 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
3432, 1625, 1486, 1216, 1104 cm–1. 1H NMR (400 MHz, CDCl3):
δ = 8.46–8.42 (m, 1 H), 8.18 (d, J = 8.0 Hz, 2 H), 7.70–7.65 (m, 3
H), 7.62–7.53 (m, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 7.17–7.12 (m, 1
H), 7.07 (s, 1 H), 6.17–6.14 (m, 1 H), 4.53 (q, J = 8.0 Hz, 2 H),
2.40 (s, 3 H), 1.55 (t, J = 8.0 Hz, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 165.1, 159.2, 158.0, 148.3, 147.3, 141.9, 134.0, 133.2,
131.1, 129.7 (d, J = 13.0 Hz), 128.5, 127.7, 127.4 (d, J = 12.0 Hz),
126.8, 123.0, 123.0, 114.1 (d, J = 24.0 Hz), 105.6, 101.5 (d, J =
30.0 Hz), 95.1, 59.8, 21.6, 14.8 ppm. HRMS (ESI): m/z calcd. for
C27H22N2O2F [M + H] 425.1665; found 425.1664.
2-(4-Chlorophenyl)-6-methyl-4-(4-methylphenyl)-9H-pyrido-
[2,3-b]indole (5bca): Yield 231 mg (53 %); white solid; m.p. 240–
242 °C; R = 0.48 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
3432, 1630, 1402, 1216, 1111 cm–1
.
1H NMR (400 MHz, [D6]
DMSO): δ = 11.33 (s, 1 H), 8.32 (d, J = 8.0 Hz, 2 H), 8.10 (s, 1
H), 7.97 (s, 1 H), 7.81 (d, J = 7.0 Hz, 2 H), 7.57–7.34 (m, 6 H),
2.52–2.45 (m, 6 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ =
147.7, 142.5, 140.5, 139.2, 138.7, 133.9, 133.1, 132.3, 130.5, 129.6,
129.0, 128.9, 128.7, 122.4, 120.4, 116.5, 112.5, 21.5, 21.4, ppm.
HRMS (ESI): m/z calcd. for C25H20N2Cl [M + H] 383.1315; found
383.1306.
4-Cyclohex-1-en-1-yl-7-fluoro-2-(4-fluorophenyl)-9H-pyrido-
[2,3-b]indole (5cfd): Yield 117 mg (44 %); white solid; m.p. 229–
Ethyl 2-(4-Chlorophenyl)-8-methyl-4-(4-methylphenyl)pyrimido-
[1,2-a]indole-10-carboxylate (4bca): Yield 120 mg (23%); orange so-
lid; m.p. 190–192 °C; Rf = 0.42 (ethyl acetate/hexane, 10%). FTIR
231 °C; R = 0.52 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
3425, 1629, 1513, 1472, 1216 cm–1 1H NMR (400 MHz, [D6]
.
(KBr): ν = 3450, 1652, 1403, 1235, 1168 cm–1. 1H NMR (400 MHz,
˜
DMSO): δ = 11.33 (s, 1 H), 8.28–8.22 (m, 3 H), 7.78 (s, 1 H), 7.34–
7.29 (m, 3 H), 7.12–7.09 (m, 1 H), 6.39 (s, 1 H), 2.59–2.35 (m, 4
H), 1.85–1.75 (m, 4 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ
= 163.9 (d, J = 15.0 Hz), 161.5 (d, J = 11.0 Hz), 148.5, 142.3 (d, J
= 13.0 Hz), 141.8, 136.7, 134.8, 133.7, 130.2 (d, J = 26.0 Hz), 129.0,
128.9, 122.2 (d, J = 10.0 Hz), 119.1, 115.8 (d, J = 21.0 Hz), 108.3
(d, J = 24.0 Hz), 98.7 (d, J = 26.0 Hz), 27.8, 25.8, 22.9, 22.0 ppm.
HRMS (ESI): m/z calcd. for C23H19N2F2 [M + H] 361.1516; found
361.1508.
CDCl3): δ = 8.36 (s, 1 H), 8.28 (d, J = 8.5 Hz, 2 H), 7.52–7.47 (m,
6 H), 7.07 (s, 1 H), 6.85 (d, J = 8.7 Hz, 1 H), 6.55 (d, J = 8.7 Hz,
1 H), 4.60 (q, J = 8.0 Hz, 2 H), 2.58 (s, 3 H), 2.51 (s, 3 H), 1.61 (t,
J = 4.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 165.4,
156.3, 149.0, 146.9, 141.2, 137.3, 135.4, 130.8, 130.1, 129.9, 129.2,
128.9, 128.3, 126.4, 123.3, 121.5, 114.8, 105.0, 95.0, 59.8, 21.9, 21.7,
14.9 ppm. HRMS (ESI): m/z calcd. for C28H24N2O2Cl [M + H]
455.1526; found 455.1526.
2-(4-Chlorophenyl)-7-fluoro-4-phenyl-9H-pyrido[2,3-b]indole (5ccb):
Yield 217 mg (52%); white solid; m.p. 248–250 °C; Rf = 0.46 (ethyl
Ethyl 4-Cyclohex-1-en-1-yl-7-fluoro-2-(4-fluorophenyl)pyrimido-
[1,2-a]indole-10-carboxylate (4cfd): Yield 97 mg (20%); orange so-
lid; m.p. 158–160 °C; Rf = 0.54 (ethyl acetate/hexane, 10%). FTIR
acetate/hexane, 10%). FTIR (KBr): ν = 3437, 2401, 1630, 1409,
˜
1
1215, 1102 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 11.64 (s, 1
(KBr): ν = 3432, 2930, 1642, 1250 cm–1 1H NMR (400 MHz,
.
˜
H), 8.35–8.29 (m, 3 H), 8.03 (s, 1 H), 7.92 (d, J = 4.0 Hz, 2 H),
7.72–7.65 (m, 2 H), 7.60–7.57 (m, 3 H), 7.34–7.32 (m, 1 H), 7.17–
7.12 (m, 1 H) ppm. 13C NMR (100 MHz, [D6]DMSO): δ = 163.9,
161.6, 148.5, 142.8 (d, J = 13.0 Hz), 142.2, 138.9, 136.5, 133.4,
132.5, 130.8, 129.7, 129.2 (d, J = 23.0 Hz), 128.8, 122.4 (d, J =
11.0 Hz), 118.9, 116.7, 108.7 (d, J = 25.0 Hz), 98.9 (d, J =
26.0 Hz) ppm. HRMS (ESI): m/z calcd. for C23H15N2FCl [M + H]
373.0908; found 373.0902.
CDCl3): δ = 8.54–8.50 (m, 1 H), 8.36–8.33 (m, 2 H), 7.67 (dd, J =
2.0, 10.0 Hz, 1 H), 7.32–7.31 (m, 1 H), 7.25–7.20 (m, 2 H), 6.99 (s,
1 H), 6.33 (s, 1 H), 4.57 (q, J = 8.0 Hz, 2 H), 2.56–2.52 (m, 1 H),
2.44 (s, 2 H), 2.21–2.17 (m, 1 H), 2.00 (s, 3 H), 1.82–1.79 (m, 1 H),
1.58 (t, J = 8.0 Hz, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
164.9, 157.3, 150.7, 146.9, 133.1, 132.7, 132.6, 129.0 (d, J = 8.0 Hz),
128.7 (d, 8.0 Hz), 126.9, 126.5, 123.0 (d, J = 22.0 Hz), 115.5 (d, J
= 21.0 Hz), 114.4 (d, J = 24.0 Hz), 101.4 (d, J = 14.0 Hz), 94.9,
59.7, 27.3, 25.2, 22.1, 21.4, 14.7 ppm. HRMS (ESI): m/z calcd. for
C26H23N2O2F2 [M + H] 432.1649; found 432.1652.
Ethyl 2-(4-Chlorophenyl)-7-fluoro-4-phenylpyrimido[1,2-a]indole-10-
carboxylate (4ccb): Yield 104 mg (21%); orange solid; m.p. 178–
180 °C; R = 0.58 (ethyl acetate/hexane, 10%). FTIR (KBr): ν =
˜
f
Supporting Information (see footnote on the first page of this arti-
3445, 2948, 2150, 1643 cm–1. 1H NMR (400 MHz, CDCl3): δ =
8.38 (s, 1 H), 8.16 (d, J = 7.0 Hz, 2 H), 7.63–7.58 (m, 3 H), 7.50
(s, 2 H), 7.39 (d, J = 7.4 Hz, 2 H), 7.10 (s, 1 H), 6.98 (s, 1 H), 6.11
(d, J = 9.4 Hz, 1 H), 4.47–4.46 (m, 2 H), 1.48 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 164.8, 159.2, 156.8, 156.5, 148.5,
146.8, 137.5, 135.0, 132.9, 131.2, 129.6, 129.2, 128.9, 128.3, 127.3
(d, J = 12.0 Hz), 126.7, 123.1 (d, J = 9.0 Hz), 114.3 (d, J =
24.0 Hz), 105.2, 101.5 (d, J = 29.0 Hz), 95.5, 59.9, 14.7 ppm.
HRMS (ESI): m/z calcd. for C26H19N2O2FCl [M + H] 445.1119;
found 445.1125.
1
cle): H and 13C NMR spectroscopic data for representative com-
pounds.
Acknowledgments
R. K. A., R. K., S. S., and S. G. thank the Council of Scientific and
Industrial Research (CSIR), New Delhi and the University Grants
Commission (UGC), New Delhi for fellowships. The authors
would like to thank SAIF, CDRI, India for providing NMR spec-
troscopic data.
7-Fluoro-2-(4-methylphenyl)-4-phenyl-9H-pyrido[2,3-b]indole (5cab):
Yield 185 mg (47%); white solid; m.p. 228–230 °C; Rf = 0.48 (ethyl
acetate/hexane, 10%). FTIR (KBr): ν = 3433, 2400, 1629, 1473,
˜
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1215, 1105 cm–1. H NMR (400 MHz, [D6]DMSO): δ = 11.57 (s, 1
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
9

Job/Unit: O42633
/KAP1
Date: 04-08-14 18:42:48
Pages: 11
R. K. Arigela, R. Kumar, S. Samala, S. Gupta, B. Kundu
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Received: May 26, 2014
Published Online: ᭿
10
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42633
/KAP1
Date: 04-08-14 18:42:48
Pages: 11
Diversity-Oriented Synthesis of Polycyclic Indoles
Multicomponent Reactions
R. K. Arigela, R. Kumar, S. Samala,
S. Gupta, B. Kundu* ....................... 1–11
Diversity-Oriented Synthesis of Polycyclic
Indoles: Brønsted or Lewis Acid Catalyzed
Three-Component Reaction for the Syn-
thesis of α-Carbolines and Pyrimidoindoles
Keywords: Multicomponent reactions / Hy-
droamination / Nitrogen heterocycles / Al-
kynes / Ytterbium
We report the diversity-oriented synthesis
of pyrido- and pyrimido-indoles from an
acid-catalyzed three-component (3C) reac-
tion involving ethyl 2-amino-1H-indole-3-
carboxylates, arylaldehydes, and terminal
alkynes. With a Brønsted acid, the 3C reac-
tion furnished a mixture of pyrido- and py-
rimido-indoles, whereas when a Lewis acid
was used, pyrimidoindoles were obtained
as the single product.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
11