DABCO-catalyzed multicomponent reaction for synthesis of Benzo[a]carbazoles

Article abstract of DOI:10.1080/00397911.2013.871561

DABCO (1,4-diazabicyclo[2.2.2]octane) catalyzed a multicomponent reaction using the starting precursor 2,3,4,9-tetrahydro-1H-carbazol-1-one, malononitrile, and aromatic/heteroaromatic aldehyde.

Full text of DOI:10.1080/00397911.2013.871561

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DABCO-Catalyzed Multicomponent
Reaction for Synthesis of
Benzo[a]carbazoles
Thangavel Indumathi a , Frank R. Fronczek b & K. J. Rajendra Prasad
a
a Department of Chemistry , Bharathiar University , Coimbatore ,
Tamil Nadu , India
b Department of Chemistry , Louisiana State University , Baton
Rouge , Louisiana , USA
Published online: 14 May 2014.
To cite this article: Thangavel Indumathi , Frank R. Fronczek & K. J. Rajendra Prasad (2014) DABCO-
Catalyzed Multicomponent Reaction for Synthesis of Benzo[a]carbazoles, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 44:12, 1760-1770,
DOI: 10.1080/00397911.2013.871561
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Synthetic Communications1, 44: 1760–1770, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.871561
DABCO-CATALYZED MULTICOMPONENT REACTION
FOR SYNTHESIS OF BENZO[a]CARBAZOLES
Thangavel Indumathi,1 Frank R. Fronczek,2 and
K. J. Rajendra Prasad1
1Department of Chemistry, Bharathiar University, Coimbatore,
Tamil Nadu, India
2Department of Chemistry, Louisiana State University, Baton Rouge,
Louisiana, USA
GRAPHICAL ABSTRACT
Abstract DABCO (1,4-diazabicyclo[2.2.2]octane) catalyzed a multicomponent reaction
using the starting precursor 2,3,4,9-tetrahydro-1H-carbazol-1-one, malononitrile, and
aromatic/heteroaromatic aldehyde.
Keywords Aromatic=heteroaromatic aldehydes; crystal structure; DABCO; malononi-
trile; 2,3,4,9-tetrahydro-1H-carbazol-1-one
INTRODUCTION
Benzo-annulated carbazole ring systems are found rarely in natural products.
Benzo[a]carbazole ring systems are of considerable interest because they can exhibit
antifungal and pronounced antitumor activity against leukemia, renal tumor, colon
cancer, and malignant melanoma tumor cell lines[1–5] and demonstrate kinase inhibi-
tory activities.[6–9] The benzo[a]carbazoles, which contain an aromatic ring fused to
the a face of the carbazole nucleus, are potential candidates for cancer treatment as a
result of DNA intercelative binding properties.[10] A series of simple benzo[a]-
carbazoles have been shown to bind to estrogen receptors and inhibit the growth
of mammary tumors of rats.[11] Benzo[a]carbazole derivatives have also found exten-
sive application as photographic materials.[12] Very recently, several benzocarbazole
Received October 18, 2013.
Address correspondence to K. J. Rajendra Prasad, Department of Chemistry, Bharathiar
University, Coimbatore, Tamil Nadu, India. E-mail: Prasad_125@yahoo.com
Color versions of one or more of the figures in the article can be found online at www.tandfonline.
com/lsyc.
1760

SYNTHESIS OF BENZO[a]CARBAZOLES
1761
Figure 1. Bioactive compounds with a benzo[a]carbazole core structure.
analogs have also been explored as functional building blocks in the construction of
organic materials for optoelectronic devices.[13,14] Examples of bioactive benzo[a]-
carbazoles are shown in Fig. 1.
Numerous synthetic methodologies for the construction of benzo[a]carbazoles
have been developed in past decades including thermal and photochemical cycliza-
tion, Fisher indolization, and pericyclic reaction.[15] In addition to these more classi-
cal synthetic strategies, various transition-metal-mediated reactions have been
applied as well.[16,17] Most of these procedures have involved several steps, and the
overall yields were, in general, not very good. The most serious drawbacks of the
established methods, however, are a lack of flexibility and tolerance of functional
groups, and regiochemical ambiguities originating from orienting effects of the sub-
stituents. There is thus still a considerable need for the development of more versatile
and regioselective synthetic routes towards highly substituted benzocarbazoles,
especially with respect to tolerance of a wider variety of functional groups. One sim-
ple, efficient, and reliable synthetic method for this class of compounds in a direct
and atom-economical manner is strongly required. We adopted the method for
the construcution of benzo[a]carbazoles by multicomponent reaction using precursor
2,3,4,9-tetrahydro-1H-carbazol-1-one, malononitrile, and aromatic=heteroaromatic
aldehyde using bases. There are few reports for the synthesis of dicyanoanilines using
various bases by solvent-free conditions,[17] microwave irradiation,[18] and various
other methods.[19] Construction of novel benzo[a]carbazole ring systems would also
lead to the development of promising templates for drug discovery.
Pertinent to this fact, benzo[a]carbazole was constructed in the present study
by an efficient and versatile method. 1,4-Diazabicyclo[2.2.2]octane (DABCO)–
catalyzed multicomponent reaction using the starting precursor 2,3,4,9-tetrahydro-
1H-carbazol-1-one, malononitrile, and aromatic=heteroaromatic aldehyde was
carried out.
RESULTS AND DISCUSSION
Synthesis of Benzo[a]carbazoles
2,3,4,9-Tetrahydro-1H-carbazol-1-one[20] (1) was reacted with malononitrile
(2) and aromatic=heteroaromatic aldehydes (3) in ethanol medium. The reaction
condition was optimized using various bases shown in Table 1. When NaOH and

1762
T. INDUMATHI, F. R. FRONCZEK, AND K. J. R. PRASAD
Table 1. Optimization of catalyst
Entry
Solvent
Base
Time (h)
T (ꢀC)
Yield (%)
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
—
NaOH
6
6
6
5
5
5
3
3
2
1
80
80
80
80
80
80
80
80
80
80
25
40
40
50
62
60
78
75
80
82
3
KOH
K2CO3
4
5
Et3N
Piperidine
6
7
DABCO (10 mol%)
DBACO (15 mol%)
DABCO (20 mol%)
DABCO (25 mol%)
8
9
10
KOH were used as bases, the reaction times were longer and the yields were less than
40%. Using potassium carbonate as the base, the product was obtained in poor yield
and the reaction time was longer. With piperidine and triethyl amine as base, a mod-
erate yield of around 60% was achieved. The best yield of the target was obtained
using DABCO as base under refluxing condition.
With DABCO as the catalyst the reaction proceeded smoothly in an even
shorter reaction time with similar good yields, thus indicating DABCO as the most
efficient catalyst of those tested (Table 1). To optimize the reaction condition we
evaluated the most appropriate catalyst loading, using 10, 15, 20, and 25 mol% of
DABCO at 80 ꢀC. The yield steadily increased with loading until it reached a
maximum of >82% at 25 mol% of the catalyst.
6-Methyl-2,3,4,9-tetrahydro-1H-carbazol-1-one (1a) was reacted with benzal-
dehyde (2), malononitrile (3), and DABCO in dry ethanol for 1 h (Scheme 1) which
afforded compound 4a. Its IR spectrum showed absorption bands at 3462 cmꢁ1
1
(asym, NH2), 3321 cmꢁ1 (sym, NH2), and 2221 cmꢁ1 (CꢂN). In its H NMR spec-
trum a singlet at d 5.14 was due to amino protons. The indole NH proton appeared
as a broad singlet at d 8.92. The C7, C9, and C10 protons appeared as a multiplet
between d 7.56 and 7.51. The five aromatic protons appeared as a multiplet between
0
0
0
0
0
d 7.37–7.33 for C2 , C3 , C4 , C5 , and C6 protons. The four aliphatic protons of C5
and C6 appeared as a multiplet between d 2.88 and 2.82. Methyl protons appeared as
a singlet at d 2.52. The total number of protons matched perfectly with its structure.
The 13C NMR spectrum revealed the presence of 25 carbons. The molecular ion
peak in the mass spectrum at m=z 374 and the elemental analysis agree well with
Scheme 1. Synthesis of benzo[a]carbazoles.

1763

1764

1765

1766

SYNTHESIS OF BENZO[a]CARBAZOLES
1767
the molecular formula C25H18N4. All details attest to the structure of the
compound as 2-amino-4-phenyl-8-methyl-5,6-dihydro-11H-benzo[a]carbazole-1,3-
dicarbonitrile (4a). The generality of the reaction was tested with various
aromatic=heteroaromatic aldehydes to form the corresponding product, which is
represented in Table 2.
CRYSTAL STRUCTURE OF COMPOUND 8b
The structure of one of the members of the series 8b was confirmed by
single-crystal x-ray analysis (Fig. 2).
Mechanism for the Formation of Final Compounds 4–8
We proposed the following mechanism for the multicomponent reaction
(Scheme 2): DABCO-assisted Knoevenagel condensation of the aldehyde with mal-
ononitrile to yield arylidene malononitrile intermediate (I). Then the intermediate (I)
on Michael addition gives the arylidene malononitrile (II), which subsequently reacts
with another mole of malononitrile to give intermediate III and further on cycliza-
tion yields the intermediate IV. The base abstracts the proton from intermediate
IV followed by b-elimination, which leads to intermediate V. The intermediate V
on imino-amino tautomerisation afforded the final product.
CONCLUSION
We have designed and synthesized novel benzo[a]carbazoles by multicompo-
nent reaction of 2,3,4,9-tetrahydro-1H-carbazol-1-ones with malononitrile and
aromatic=heteroaromatic aldehydes in ethanol medium, and the reaction condition
was optimized using various bases. The best yield of the product was obtained using
Figure 2. X-ray crystal structure and atom numbering scheme for 8b as thermal ellipsoids at 50%
probability level. Solvent moiety is omitted for clarity.

1768
T. INDUMATHI, F. R. FRONCZEK, AND K. J. R. PRASAD
Scheme 2. Mechanism for the formation of compounds 4–8.
DABCO as base under refluxing condition. All the synthesized compounds were
characterized by infrared (IR), 1H NMR, 13C NMR, and mass spectroscopic techni-
ques. One of the synthesized compounds, 2-amino-4-(50-bromothiophen-20-yl)-
8-chloro-5,6-dihydro-11H-benzo[a]carbazole-1,3-dicarbonitrile (8b), was solved by
x-ray crystallography.
EXPERIMENTAL
Melting points (mp) were determined on a Mettler FP 51 apparatus (Mettler
Instruments, Switzerland) and are uncorrected. They are expressed in degrees centi-
grade (ꢀC). A Nicolet Avatar model FT-IR spectrophotometer was used to record
1
the IR spectra (4000–400 cmꢁ1). H NMR and 13C NMR spectra were recorded
1
on Bruker AV 500 (500 MHz, H, and 125 MHz, 13C) spectrometer using tetra-
methylsilane (TMS) as an internal reference. The chemical shifts are expressed in
parts per million (ppm). Mass spectra (MS) were recorded on an Auto Spec EI þ
Shimadzu QP 2010 Plus gas chromatography–mass spectrometry (GC-MS) instru-
ment. Microanalyses were performed on a Vario EL III model CHNS analyzer
(Vario, Germany) at the Department of Chemistry, Bharathiar University. X-ray
diffraction measurements were performed on a Bruker Kappa Apex-II diffract-
ometer equipped with an Oxford Cryostream chiller and graphite monochromatized
CuK alpha radiation. The purity of the products was tested by thin-layer chromato-
graphy (TLC) with plates coated with silica gel G; petroleum ether and ethyl acetate
were used as developing solvents.

SYNTHESIS OF BENZO[a]CARBAZOLES
1769
General Procedure for the Synthesis of 2-Amino-5,6-dihydro-11H-
benzo[a]carbazole-1,3-dicarbonitrile 4–8
A mixture of 2,3,4,9-tetrahydro-1H-carbazol-1-one (1, 0.001 mol), aromatic=
hetero aromatic aldehyde (2, 0.01 mol), malononitrile (3, 0.002 mol), and DABCO
(25 mol%) in dry ethanol (15 mL) was heated under reflux for 1 h. After completion
of the reaction, the excess solvent was evaporated. The residue was poured in ice
water and extracted with ethyl acetate. Combined organic layers were dried over
anhydrous sodium sulfate. It was then purified on a silica-gel column (eluent: pet-
roleum ether=ethyl acetate, 95:5). The pure product was recrystallized from ethanol.
2-Amino-4-phenyl-8-methyl-5,6-dihydro-11H-
benzo[a]carbazole-1,3-dicarbonitrile (4a)
Yellow solid; yield: 82%; mp 220–222 ꢀC; IR (KBr, cmꢁ1) nmax: 3462 (asym,
NH2), 3321 (sym, NH2), 2221 (CꢂN); 1H NMR (500 MHz, CDCl3) (ppm) dH:
0
8.92 (b0s, 1H, N11-H), 7.56–7.51 (m, 3H, C7, C9 & C10-H), 7.37–7.33 (m, 5H, C2 ,
0
0
0
C3 , C4 , C5 & C6 -H), 5.14 (s, 2H, NH2), 2.88–2.82 (m, 4H, C5-2H & C6-2H),
2.52 (s, 3H, C8-CH3); 13C NMR (125 MHz, CDCl3) (ppm) dC: 159.5 (C2), 147.9
0
0
0
(C11b), 143.4 (C4), 136.2 (C10a), 1300.0 (C1 ), 129.2 (C3 & C5 ), 128.0 (C4a), 127.2
0
0
(C8), 126.9 (C2 & C6 ), 126.4 (C4 ), 125.5 (C6b), 122.8 (C11a), 120.0 (C9), 119.1
(C7), 116.4 (C6a), 115.4 (CꢂN), 114.3 (CꢂN), 110.2 (C10), 95.0 (C3), 93.3 (C1),
29.7 (C5), 24.2 (C6), 21.7 (C8-CH3); MS: m=z (%) 374 (Mþ 100). Anal. calcd. for
C25H18N4: C, 80.19; H, 4.85; N, 19.6. Found: C, 80.21; H, 4.88; N, 19.3%.
The supplementary data includes the experimental details of all the newly
synthesized compounds and x-ray single-crystal structure details of compound 8b.
1
13
The IR spectrum of compound 4a and H NMR and C NMR spectra of 4a–8a,
4b–8b, and 4c–8c have also been provided. The crystallographic data of 8b is given
in Table 3.
ACKNOWLEDGMENTS
The authors thank the Indian Institute of Technology Madras, Chennai, for
NMR data and the Indian Institute of Chemical Technology, Hyderabad, for mass
spectral data.
FUNDING
This research was supported by the Council of Scientific and Industrial
Research, New Delhi. The award of senior research fellow to T. Indumathi is
gratefully acknowledged.
SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.

1770
T. INDUMATHI, F. R. FRONCZEK, AND K. J. R. PRASAD
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