Synthesis of novel 1,2,3,4-tetrahydrocarbazole derivatives of biological interest

Article abstract of DOI:10.1080/10426500902839863

2-Cyano-N-(tetrahydrocarbazole)acetamide (1) was utilized for the synthesis of several new arylazocarbazole derivatives (2a-e). Compound (1) reacted with phenyl isothiocyanate to yield the corresponding non-isolable intermediate (3), which gave, upon trea

Full text of DOI:10.1080/10426500902839863

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Phosphorus, Sulfur, and Silicon and the
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Synthesis of Novel 1,2,3,4-
Tetrahydrocarbazole Derivatives of
Biological Interest
A. A. Fadda a , H. A. Etman a , A. A. Sarhan a & Sherihan A. El-
Hadidy a
a Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
Version of record first published: 24 Feb 2010.
To cite this article: A. A. Fadda , H. A. Etman , A. A. Sarhan & Sherihan A. El-Hadidy (2010):
Synthesis of Novel 1,2,3,4-Tetrahydrocarbazole Derivatives of Biological Interest, Phosphorus, Sulfur,
and Silicon and the Related Elements, 185:3, 526-536
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Phosphorus, Sulfur, and Silicon, 185:526–536, 2010
Copyright ꢀC Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902839863
SYNTHESIS OF NOVEL 1,2,3,4-TETRAHYDROCARBAZOLE
DERIVATIVES OF BIOLOGICAL INTEREST
A. A. Fadda, H. A. Etman, A. A. Sarhan,
and Sherihan A. El-Hadidy
Chemistry Department, Faculty of Science, Mansoura University, Mansoura, Egypt
2-Cyano-N-(tetrahydrocarbazole)acetamide (1) was utilized for the synthesis of several new
arylazocarbazole derivatives (2a–e). Compound (1) reacted with phenyl isothiocyanate to
yield the corresponding non-isolable intermediate (3), which gave, upon treatment with di-
lute hydrochloric acid, thiocarbamoyl derivative (4). Compound (3) reacted with chloroace-
tone, chloroacetic acid, chloroacetyl chloride, ethyl bromoacetate, and phenacyl bromide to
afford thiazolone derivatives (6), (8), and (10), respectively. Compound (1) was heated in
the presence of pyridine and/or hydrazine hydrate and/or isatine to give the corresponding
tetrahydrocarbazole derivatives (13), (14), and (18), respectively.
Supplemental materials are available for this article. Go to the publisher’s online edition of
Phosphorus, Sulfur, and Silicon and the Related Elements to view the free supplemental
file.
Keywords Aromatic amines; ethyl bromoacetate; phenacyl bromide; phenylisothiocyanate;
1,2,3,4-tetrahydrocarbazole
INTRODUCTION
The clinical need for therapeutic agents that restore or enhance an immune response
in immunocompromised patients, such as that which occurs in viral infections, cancer,
autoimmune diseases, and acquired immune deficiency syndrome (AIDS), has led to the
search for novel immunostimulants.1 Interferon-γ (IFN-γ ) is a potent activator of the
immune system and has been used in the treatment of infections in humans. A fused
pyrrolo[2,3-c]carbazole-6-one (Figure 1) potentiates the INF-γ induction of MHC-class
π molecules.2 Other carbazole derivatives such as ellipticin, vincristine, and vinblastine
alkaloids have a well established role in the treatment of cancer.3–5 The present work is a
part of our program aimed at developing new approaches for synthesis of fused heterocyclic
systems containing carbazole moiety and evaluating their anticancer activity.
In addition, cyanoacetamides are highly reactive compounds. They are extensively
utilized as reactants or reaction intermediates since the carbonyl and the cyano functions of
these compounds are suitably situated to enable reactions with common bidentate reagents
Received 18 October 2008; accepted 22 February 2009.
Address correspondence to A. A. Fadda, Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt. E-mail: afadda2@yahoo.com
526

NOVEL 1,2,3,4-TETRAHYDROCARBAZOLE DERIVATIVES
527
O
NH
N
X
H
X= NH, O, S, CH2
Figure 1
to form a variety of heterocyclic compounds. Moreover, the active hydrogen on the C-2 of
these compounds can take part in a variety of condensation and substitution reactions.
On the other hand, the diverse biological activities reported for many derivatives
of cyanoacetamide have also drawn the attention of biochemists in the last decade. The
literature covering the chemistry of cyanoacetamide derivatives has been limited. The main
objective of the present work is to provide a comprehensive account of the synthetic utility
of N-heteryl cyanoacetamides in building various organic heterocycles and to highlight
their potential in evolving better chemotherapeutic agents.
In view of the above-mentioned findings, and as continuation of our efforts6,7 to iden-
tify new candidates that may be of value in designing new, potent, selective, and less toxic
antimicrobial agents, we report in this article the synthesis of some new heterocycles incor-
porating tetrahydrocarbazole moiety starting from N-tetrahydrocarbazolyl cyanoacetamide
in order to investigate their antimicrobial activity.
RESULTS AND DISCUSSION
The synthetic procedures that were adopted to obtain the target compounds are
depicted in Schemes 1–5 and the Supplemental Materials (available online). The starting
compound 2-cyano-N-(tetrahydrocarbazole)acetamide (1) was prepared according to the
previously reported procedure.8 In continuation of our interest in the synthesis of a bridge-
head nitrogen heterocyclic system,9 we have found that diazotized aromatic amine is
an excellent building block for the synthesis of the target compound. Thus, coupling of
compound 1 with amine diazonium salts, mainly benzene diazonium salt, p-tolyl diazonium
salt, p-anisyl diazonium salt, p-chlorophenyl diazonium salt, and p-nitrophenyl diazonium
salt in pyridine at 0–5◦C afforded the corresponding hydrazono compounds 2a–e. The
1
analytical and spectral data are in agreement with the proposed structure. Thus, the H
NMR spectrum of the reaction product 2b showed signals at δ 1.77 (m, 4H, 2CH2-cyclo),
a 1.91 singlet signal due to CH3 protons, 2.49 (t, J = 6.8 Hz, 2H, CH2-cyclo), 3.32 (t, J =
6.8 Hz, 2H, CH2-cyclo), 6.87–7.66 ppm corresponding to aromatic protons, and finally
1
a singlet signal at δ 12.30 ppm due to NH proton. Similarly, the H NMR of compound
1
2c showed the same H NMR picture as for 2b, except the OCH3 protons appeared at
δ 3.73 ppm. The IR spectrum of compounds 2a–e in general showed the presence of a
strong and broad band in the region 3100–3225 cm−1, assigned to NH stretching of the
hydrazone moiety, but a weak band at 1550–1580 cm−1, also indicating their presence in
the azo form and in a tautomeric mixture as well. The large shift and broadening of the
NH band, as reported by Ramirez and Kerby,10 for simple hydrazones can result only from

528
A. A. FADDA ET AL.
intramolecular hydrogen bonding as in A. The fact that the compounds 2a–e show evidence
for intramolecular hydrogen bonding is in favor of the hydrazone structure. Compounds
2a–e exhibited bands in the region 1665–1669 cm−1 due to stretching vibration of the CO
groups (Scheme 1).
ArN2+Cl-
pyridine
N
N
CN
CN
O
O
1
N
NH
Ar
2a-e
2a, Ar = C6H5; 2b, Ar = C6H4- CH3-p; 2c, Ar = C6H4-OCH3-p;
2d, Ar = C6H4- Cl-p; 2e, Ar = C6H4- NO2-p
Scheme 1
Among the structural factors that lead to the lowering of the stretching vibration
of the CO group are conjugation and hydrogen bonding. However, even if allowance is
made for conjugation, the CO frequencies of the compounds studied are still much lower
than those encountered in α,β-unsaturated ketones. This significant difference suggests that
the CO group of these compounds should be involved in hydrogen bonding in the solid
state, as shown in the proposed structure A. The UV spectra of the diazonium coupling
products provided additional evidence that such compounds have the tautomeric relation
with monohydrazones. Most of the dyes show four absorption bands in the region 196–438
nm. The relatively small difference in λmax may be due to the polarity change of the
absorption system caused by solvent interactions due to the general solvent effect.11 It
has been reported that the UV spectra of monophenylazo compounds differ from those
of monophenylhydrazones. The azo compounds generally show two absorption bands at
400–410 and 290–300 nm corresponding to n–π∗ and π–π∗ transitions, respectively.12
On the other hand, monophenylhydrazones show three intense bands in 220–230,
250–280, and 330–390 nm regions.11 The UV spectra of compounds 2a–e can be interpreted
in terms of the tautomeric mixture as well. It is clear that these dyes exhibit four bands;
of these, the medium and high wavelength bands seem to be affected by the nature of the
polar substituent in the arylazo group, and the low wavelength bands are unaffected. Table I
shows that both electron-withdrawing and electron-donating groups cause the absorption to
occur at higher wavelengths. Also from Table I, we can show that the presence of electron-
donating or electron-withdrawing groups has not brought about any marked increase or
decrease in λmax in the visible region, and log ε has nearly remained constant. This does
point towards the presence of the hydrazone structure where the resonance interactions with
the substituents in the diazo component are minimal due to steric factors. Moreover, the
structure of compounds 2a–e was further confirmed by mass spectroscopic measurements,
which showed the molecular ion peak at m/z for 2a (342, 64%), 2b (356, 80%), 2c (372,
100%), 2d (376, 75%), and 2e (387, 76%), and in general showed the fragment at m/z 250
corresponding to C15H12N3O+.
Aryl isothiocyanates are versatile reagents, which have been used as synthetic inter-
mediates to prepare biologically active heterocyclic compounds.13 As a part of our program

NOVEL 1,2,3,4-TETRAHYDROCARBAZOLE DERIVATIVES
529
Table I Spectral data of the newly prepared compounds
Spectral data
Compound
2a
IR (KBr)νmax.cm−1: 3225 (NH), 2220 (CN), 1665 (CO), 1600 (C N), 1550 (N N).
1H NMR (DMSO) (δ, ppm), 1.77 (m, 4H, 2CH2-cyclo), 2.49 (t, J = 6.8 Hz, 2H, CH2-cyclo), 3.31
(t, J = 6.8 Hz, 2H, CH2-cyclo), 6.87–7.66 (m, 9H, Ar H), 12.32 (s, 1H, NH).
MS: m/z (%), 342 (M+, 64).
UV: λmax(nm)(log ε): 200 (2.32), 250 (2.86), 290 (3.3), 424 (4.03).
IR (KBr)νmax.cm−1: 3200 (NH), 2220 (CN), 1665 (CO), 1600 (C N), 1560 (N N).
1H NMR (DMSO) (δ, ppm), 1.77 (m, 4H, 2CH2-cyclo), 1.91 (s, 3H, CH3), 2.49 (t, J = 6.8 Hz,
2H, CH2-cyclo), 3.32 (t, J = 6.8 Hz, 2H, CH2-cyclo), 6.87–7.66 (m, 8H, Ar H), 12.30 (s, 1H,
NH).
2b
2c
MS: m/z (%), 356 (M+, 80).
UV: λmax(nm)(log ε): 196 (2.30), 260 (2.91), 305 (3.95), 438 (4.10).
IR (KBr)νmax.cm−1: 3220 (NH), 2220 (CN), 1665 (CO), 1600 (C N), 1565 (N N).
1H NMR (DMSO) (δ, ppm), 1.77 (m, 4H, 2CH2-cyclo), 2.49 (t, J = 6.8 Hz, 2H, CH2-cyclo), 3.30
(t, J = 6.8 Hz, 2H, CH2-cyclo), 3.73 (s, 3H, OCH3), 6.87–7.66 (m, 8H, Ar H), 12.35
(s, 1H, NH).
MS: m/z (%), 372 (M+, 100).
UV: λmax(nm)(log ε): 203 (2.38), 250 (2.86), 295 (3.41), 424 (4.03).
IR (KBr)νmax.cm−1: 3100 (NH), 2220 (CN), 1665 (CO), 1610 (C N), 1580 (N N).
1H NMR (DMSO) (δ, ppm), 1.77 (m, 4H, 2CH2-cyclo), 2.49 (t, J = 6.8 Hz, 2H, CH2-cyclo), 3.32
(t, J = 6.8 Hz, 2H, CH2-cyclo), 6.87–7.66 (m, 8H, Ar H), 12.31 (s, 1H, NH).
MS: m/z (%), 376 (M+, 75).
UV: λmax(nm)(log ε): 198 (2.31), 250 (2.86), 290 (3.31), 428 (4.08).
IR (KBr)νmax.cm−1: 3150 (NH), 2219 (CN), 1669 (CO), 1610 (C N), 1580 (N N), 1530, 1350
(NO2).
1H NMR (DMSO) (δ, ppm), 1.77 (m, 4H, 2CH2-cyclo), 2.49 (t, J = 6.8 Hz, 2H, CH2-cyclo), 3.31
(t, J = 6.8 Hz, 2H, CH2-cyclo), 6.87–7.66 (m, 8H, Ar H), 12.30 (s, 1H, NH).
MS: m/z (%), 387 (M+, 76).
2d
2e
UV: λmax(nm)(log ε): 198 (2.31), 248 (2.62), 280 (3.25), 420 (4.02).
IR (KBr)νmax.cm−1: 3205 (NH), 2200 (CN), 1625 (CO), 1305 (C S).
1H NMR (DMSO) (δ, ppm), 1.84 (m, 4H, 2CH2-cyclo), 2.49 (t, J = 6.8 Hz, 2H, CH2-cyclo), 3.41
(t, J = 6.8 Hz, 2H, CH2-cyclo), 7.12–7.50 (m, 9H, Ar H), 11.93 (s, 1H, NH).
IR (KBr)νmax.cm−1: 3405 (NH), 2191 (CN), 1697 (CO), 1615 (N CO).
1H NMR (DMSO) (δ, ppm), 1.85 (m, 4H, 2CH2-cyclo), 1.95 (s, 3H, COCH3), 2.83 (t, J = 6.8
Hz, 2H, CH2-cyclo), 2.95 (t, J = 6.8 Hz, 2H, CH2-cyclo), 4.75 (s, 2H, COCH2), 7.24–7.65 (m,
9H, Ar H).
4
5
6
IR (KBr)νmax.cm−1: 2190 (CN), 1615 (N CO), 1597 (C C).
1H NMR (CDCl3) (δ, ppm), 1.85 (m, 4H, 2CH2-cyclo), 1.97 (s, 3H, CH3), 2.83 (t, J = 6.8 Hz,
2H, CH2-cyclo), 2.95 (t, J = 6.8 Hz, CH2-cyclo), 6.61–7.65 (m, CH+9-Ar H).
MS: m/z (%), 411 (M+, 12.8).
7
IR (KBr)νmax.cm−1: 3404 (NH), 2200 (CN), 1715 (CO), 1615 (N CO).
1H NMR (DMSO) (δ, ppm), 1.33 (t, 3H, CH3), 1.86 (m, 4H, 2CH2-cyclo), 2.81 (t, J = 6.8 Hz,
2H, CH2-cyclo), 2.95 (t, J = 6.8 Hz, 2H, CH2-cyclo), 4.34 (q, 2H, CH2), 4.70 (s, 2H, COCH2),
6.82–7.71 (m, 9H, Ar H), 12.94 (s, 1H, NH).
8
IR (KBr)νmax.cm−1: 2210–2202 (CN), 1700 (CO), 1650 (N CO).
1H NMR (DMSO) (δ, ppm), 1.85 (m, 4H, 2CH2-cyclo), 2.82 (t, J = 6.8 Hz, 2H, CH2-cyclo), 2.95
(t, J = 6.8 Hz, 2H, CH2-cyclo), 3.10 (s, 2H, SCH2), 7.11–7.53 (m, 9H, Ar H).
MS: m/z (%), 413 (M+, 45.0).
10
13
IR (KBr)νmax.cm−1: 2929 (CH), 2201 (CN), 1644 (CO), 1604 (C C).
1H NMR (CDCl3) (δ, ppm), 1.83 (m, 4H, 2CH2-cyclo), 2.65 (t, J = 6.8 Hz, 2H, CH2-cyclo), 2.85
(t, J = 6.8 Hz, 2H, CH2-cyclo), 4.85 (s, 1H, CH), 7.26–7.61 (m, 14H, Ar H).
MS (70 ev): m/z (%), 473 (M+, 25).
IR (KBr)νmax.cm−1: 2930 (CH), 1600 (C C).
(Continued on next page)

530
A. A. FADDA ET AL.
Table I Spectral data of the newly prepared compounds (Continued)
Compound
Spectral data
1H NMR (200 MHZ, DMSO) (δ, ppm), 1.73 (m, 8H, 4CH2), 2.64 (m, 4H, 2CH2), 2.76 (m, 4H,
2CH2), 6.93–7.51 (m, 8H, Ar H).
MS: m/z (%), 341 (M++1, 10.8), 340 (M+, 29.6), 338 (15.1), 312 (5.4), 283 (12.4), 269 (10.8),
189 (6.5), 187 (20.4), 186 (11.3), 185 (15.6), 184 (23.7), 171 (30.1), 170 (100.0), 169 (39.2),
168 (45.7), 167 (31.2), 166 (18.3), 154 (14.5).
14
18
IR (KBr)νmax.cm−1: 3400–3350 (NH2, NH), 2925 (aliphatic CH2), 1681 (amidic carbonyl), 1617
(C N).
1H NMR (CDCl3) (δ, ppm), 1.43, 1.72 (m, 2H, CH2-cyclo), 1.72, 1.82 (m, 2H, CH2-cyclo, J =
6.8 Hz), 2.67, 2.74 (m, 2H, CH2-cyclo, J = 6.8 Hz), 2.81 (t, 1H, CH-pyridine ring), 6.91–7.70
(m, 4H, Ar H), 8.58, 8.68 (d.d, 2H, CH2-pyridine ring).
MS: m/z (%), 242 (M++4, 55).
IR (KBr)νmax.cm−1: 3365 (NH), 1721 (CO).
1H NMR (CDCl3) (δ, ppm), 1.84 (m, 2H, CH2-cyclo), 1.98 (t, 2H, CH2-cyclo, J = 6.8 Hz), 3.01
(t, 2H, CH2-cyclo, J = 6.8 Hz), 6.89–7.97 (m, 8H, Ar H), 8.63 (s, 1H, NH).
MS: m/z (%), 349 (M+, 2.4), 243 (19.2), 242 (93.8), 214 (10.9), 198 (13.3), 171 (15.7), 170
(100.0), 169 (50.9), 168 (13.8), 145 (5.0), 144 (14.7), 143 (24.6), 142 (66.8), 141 (67.2), 140
(11.2), 115 (45.0), 114 (74.1), 113 (12.9), 100 (14.2), 88 (28.9), 62 (13.3).
to develop a new, simple, and efficient procedure for the synthesis of new aromatic com-
pounds using readily available aryl isothiocyanates, we have recently affected recyclization
of thiocarbamoyl in thiophenes, pyrazoles, and thiazoles.14 Thus, the base-prompted reac-
tion of the acidic methylene compound 1 with phenyl isothiocyanate in dry DMF at room
temperature in basic medium led to the formation of the non-isolable intermediate 3, which
gave thiocarbamoyl derivative 4 upon treatment with dilute HCl (Scheme 2). Assignment
of the product 4 was based on elemental analysis, IR, and 1H NMR spectral data. The IR
spectrum showed absorption bands at 3205, 2200, 1625, and 1305 cm−1 attributable to the
1
NH, CN, CO, and C = S functions, respectively. The H NMR spectrum of 4 displayed
multiplet signals at δ 1.84, 2.49, and 3.41 ppm for CH2 protons and multiplet signals at δ
7.12–7.50 ppm for aromatic protons besides an exchangeable proton at δ 11.93 ppm for
NH proton.
O
CN
DMF
KOH
+
PhNCS
Ar
N
PhHN
S-K+
CN
3
O
1
dil. HCl
O
O
CN
S
CN
SH
Ar
Ar
PhHN
Ar=
PhHN
N
4
Scheme 2

NOVEL 1,2,3,4-TETRAHYDROCARBAZOLE DERIVATIVES
531
On the other hand, it has been found that stirring of the intermediate 3 with chloroace-
tone in DMF for 2 h yielded a product 5, which analyzed correctly for C25H23N3O2S. The
structure 5 was inferred from its spectral data. Thus, the IR showed absorption bands at
3405, 2191, 1697, and 1615 cm−1 corresponding to NH, CN, CO, and N CO functions.
1
Its H NMR spectrum showed signals at δ 1.85 (m, 4H, 2CH2-cyclo), 2.83 (t, J 6.8
=
Hz, 2H, CH2-cyclo), 2.95 (t, J = 6.8 Hz, 2H, CH2-cyclo), and two singlet signals at δ
1.95 and 4.75 ppm corresponding to COCH3 and COCH2 protons, respectively, besides
multiplet signals at δ 7.24–7.65 ppm due to aromatic protons and singlet signal at δ 8.25
ppm for NH proton. Upon shaking the compound with D2O, the band signal at δ 8.22 ppm
disappeared.
However, if the reaction was stirred overnight, it afforded a product 6. The structure
of 6 was inferred from its spectral data. Thus, the IR spectrum showed absorption bands
1
at 2190, 1615, and 1597 cm−1 characteristic for CN, N CO, and C C functions. Its H
NMR spectrum showed, besides the normal and expected tetrahydrocarbazole protons, the
presence of CH3 protons at δ 1.97 ppm and CH proton at δ 6.61 ppm and the disappearance
of the NH proton, indicating that the NH group was involved in the cyclization process,
which lost one molecule of water. Moreover, the mass spectrum gave additional evidence for
the structure 6, which showed its molecular ion peak at m/z 411 (12.8%) and the base peak
at m/z 241 corresponding to C14H9NOS+ fragment. Based on the foregoing data, structure
6 was assigned to this product. The structure of 6 was further confirmed by alternative
synthesis. Thus, it was found that refluxing of 5 in ethanol with a few drops of TEA led to
the formation of a product identical in all respects (mp, mixed mp, IR) to 6. (See Scheme
S2, available online in the Supplemental Materials.)
Similarly, when the intermediate potassium salt 3 is stirred with an equimolar amount
of chloroacetyl chloride or with chloroacetic acid in ethanol, a product that was analyzed
for C26H25N3O3S was isolated in each case in good yield. The acyclic structure of 7
was established on the basis of its IR spectrum, which shows bands related to NH and
1
CO functions. Its H NMR spectrum reveals multiplet signals at δ 6.82–7.71 ppm (9H,
aromatic), a triplet signal at δ 1.33 (3H, CH3), a singlet at δ 4.70 (2H, CH2CO), a quartet
at δ 4.34 (2H, CH2), and a D2O exchangeable NH at δ 12.92 ppm besides the normal
tetrahydrocarbazol protons. Alternatively, treatment of the intermediate salt 3 with ethyl
bromoacetate in ethanol gives a single product, which is identical in all respects to 7
(mp, mixed mp, and IR spectrum). The mass spectrum of 7 showed a molecular formula
C26H25N3O3S (M+ = 459). Refluxing of 7 in ethanol with a catalytic amount of TEA or
leaving it in DMF containing potassium carbonate at room temperature overnight afforded
the corresponding thiazole derivative 8.
In a similar manner, 8 was prepared by stirring ethyl bromoacetate with the interme-
diate 3 in the presence of DMF. The structure of 8 was proven on the basis of both spectral
and analytical data. The IR spectrum showed absorption bands at 2210–2202 cm−1 due to
CN, and 1650 and 1700 for two carbonyl groups. 1H NMR spectrum showed signals at δ
1.85 as a multiplet for two CH2 groups, 2.82 and 2.95 as triplet for two CH2 groups, and δ
3.10 as a singlet for SCH2. The mass spectroscopic measurements gave additional evidence
for the correct structure of compound 8, which showed the molecular ion peak at m/z 413
(45%). In addition, stirring of 3 with phenacyl bromide in DMF overnight yielded a product
10, which analyzed correctly for C30H23N3OS. The structure of 10 was inferred from its
spectral data. See Scheme 3. Thus, the IR spectrum showed absorption bands at 2929, 2201,
1
1644, and 1604 cm−1 corresponding to CH, CN, CO, and C C functions. Its H NMR
spectrum showed signals at δ 1.83, 2.65, and 2.85 ppm for 8H of 4CH2 protons, δ 4.85

532
A. A. FADDA ET AL.
O
ClCH2COCl
CN
or ClCH2COOH
Ar
DMF
R.T.
PhHN
SCH2COOCH2CH3
or DMF
7
EtOH / TEA
Reflux
K2CO3/R.T.
O
Ar=
CN
BrCH2COOEt
N
Ar
3
DMF
R.T.
Ph
N
S
O
8
O
O
CN
S
Ar
Ph
CN
PhCOCH2Br
Ar
PhHN
N
DMF,
R.T
SCH2COPh
Ph
10
9
Scheme 3
(CH cyclic), and multiplet at δ 7.26–7.61 for (14H, aromatic). All attempts to synthesize
the acyclic intermediate 9 failed.
Moreover, by refluxing compound 1 in pyridine, we could isolate a dark yellow
compound. Elgemeie et al.15 claimed that refluxing phenacyl cyanide in pyridine afforded
the so-called trimmer and assigned structure of 11. However, our isolated product may be
also the trimmer of compound 1 structure 12, but the IR spectrum of this product did not
show any absorption bands that can be attributed to amino or carbonyl or cyano functions
(see the Experimental section). Furthermore, the 1H NMR spectrum of this product showed
only an aliphatic CH2 proton and an aromatic multiplet. Mass spectrum measurements
showed that this compound has a molecular weight of 341 (M++1, 10.8%), which is
consistent with two molecules of 1 losing 2H atom (see Figure S1 in the Supplemental
Materials available online).
On the basis of these data, it was assumed that two molecules of 1 underwent
dimerization with each other, maybe via a free radical reaction, to afford 13. If the structure
was 12, a carbonyl signal would have appeared in the IR spectrum at 1700–1720 cm−1 (see
Scheme S3 in the Supplemental Materials).
In continuation of our work, the pyridocarbazole derivative 14 was synthesized by
refluxing an equimolar amount of compound 1 and hydrazine hydrate in ethanol in the
presence of TEA. The formation of compound 14 was provided by the 1H NMR spectrum,
1
in particular the chemical shift of the H-2 proton. The H NMR spectrum of compound
14 showed signals at δ 1.43, 1.72 (m, CH2), 1.72, 1.82 (m, CH2), 2.67, 2.74 (m, CH2),
2.81 (t, CH-pyridine ring), 6.91–7.70 (m, Ar-ring), 8.85–8.68 (d.d, CH2-pyridine ring).
Alternatively, when structure 15 was the reaction product, it revealed the pyrazol ring CH2

NOVEL 1,2,3,4-TETRAHYDROCARBAZOLE DERIVATIVES
533
path way
N
N
A
O
O
NH2
NH
14
NH2NH2
N
CN
O
N
path way
B
1
N
HN
NH
15
Scheme 4
Ar
O
CN
O
EtOH, TEA
+
O
O
N
H
N
N
H
CN
O
16
1
N
N
-H2O
O
O
NH2
NH
Ar=
N
O
N
N
H
18
17
Scheme 5
and the carbazol 2-H protons at δ 1.40 and 2.74 ppm, respectively, but they disappeared.16
The formation of 14 is assumed to proceed via the nucleophilic attack of C2 of carbazol to
the cyano group, in which the hydrazine hydrate acts as base medium and is not involved
in the cyclization process. The structure of 14 could be established for the reaction product
based on its elemental and spectral data. The IR spectrum showed absorption frequencies at
3400–3350, 2925, 1681 and 1617 cm−1 corresponding to NH2 NH, aliphatic CH2, amidic
carbonyl, and C N functions.
Moreover, the mass spectroscopic measurements of the product 14 gave more confir-
mation for its correct structure, which showed the molecular ion peak at m/z 242 (M++4,
55%) and the base peak at m/z 143 due to the loss of CH2 CH2 fragment. On the basis of
these results, the structure of 15 for the reaction product 14 can be discarded (Scheme 4).
Interestingly, isatine reacts with 1 to give a single product that analyzed correctly for
C23H15N3O. This product was formulated as poly cyclic compound 18. The structure of 18

534
A. A. FADDA ET AL.
Table II Characterization data of the newly prepared compounds
Calcd (Found)%
H
Compound
No.
Melting
point, ◦C
Yield
(%)
Mol. Formula
(M. Wt.)
C
N
1
181
182
193
170
203
180
85
164
259
264
112
153
118
115
206
73
68
70
78
56
66
70
68
74
69
66
72
73
69
68
C15H14N2O (238.28)
C21H18N4O (342.39)
75.61 (75.31)
73.67 (73.45)
74.14 (74.43)
70.95 (70.72)
66.93 (66.72)
65.11 (65.42)
70.75 (70.53)
69.91 (69.78)
72.97 (72.75)
67.95 (67.72)
69.71 (69.91)
76.08 (76.26)
84.67 (84.43)
75.61 (75.82)
79.07 (79.26)
5.92 (5.59)
5.30 (5.21)
5.66 (5.56)
5.41 (5.21)
4.55 (4.74)
4.42 (4.42)
5.13 (5.33)
5.40 (5.64)
5.14 (5.34)
5.48 (5.17)
4.63 (4.43)
4.90 (4.90)
7.11 (7.32)
5.92 (5.71)
4.33 (4.12)
11.76 (11.96)
16.36 (16.15)
15.72 (16.02)
15.04 (15.25)
14.87 (14.56)
18.08 (18.12)
11.25 (11.33)
9.78 (9.74)
10.21 (10.31)
9.14 (9.11)
10.16 (10.46)
8.87 (8.67)
2a
2b
2c
2d
2e
4
5
6
7
8
C
C
C
C
C
C
C
C
C
C
C
C
C
22H20N4O (356.42)
22H20N4O2 (372.42)
21H17ClN4O (376.84)
21H17N5O3 (387.39)
22H19N3OS (373.47)
25H23N3O2S (429.53)
25H21N3OS (411.52)
26H25N3O3S (459.56)
24H19N3O2S (413.49)
30H23N3OS (473.59)
24H24N2 (340.46)
10
13
14
18
8.23 (8.51)
11.76 (11.52)
12.03 (12.03)
15H14N2O (238.28)
23H15N3O (349.38)
was proven by IR, 1H NMR, and mass spectra. Its mass spectrum showed the molecular ion
peak at m/z 349 (2.4%) and the base peak at m/z 170. The IR spectrum showed absorption
1
bands at 3365 cm−1 and 1721 cm−1 due to the NH and CO functions. For the H NMR
spectrum, see the Experimental section and Table II). The reaction gave the condensation
product intermediate 16, which was followed by nucleophilic attack of the active methylene
group to the cyano group to afford the second intermediate 17, which lost a water molecule
to give the final product 18 (Scheme 5).
EXPERIMENTAL
All melting points were recorded on Gallenkamp electric melting point apparatus
and are uncorrected. The IR spectra υ cm−1 (KBr) were recorded on a Perkin Elmer
1
Infrared Spectrophotometer Model 157, Grating. The H NMR spectra were run on a
Varian Spectrophotometer at 200 MHz using TMS as an internal reference and DMSO-d6
as solvent. The mass spectra (EI) were recorded on 70 eV with Kratos MS equipment and/or
a Varian MAT 311 A Spectrometer. Elemental analyses (C, H, and N) were carried out at
the Microanalytical Center of Cairo University, Giza, Egypt. The results were found to be
in good agreement ( 0.3%) with the calculated values.
Synthesis of 3-(5,6,7,8-Tetrahydrocarbazol-9-yl)-3-oxopropanenitrile (1)
It has been prepared according to the previously reported work.8
Coupling of (1) with Aromatic Diazonium Salts: Synthesis of Aryl
Hydrazono Tetrahydrocarbazolyl Propionitrile (2a–e)
A well-stirred solution of aromatic amines (20 mmol) in concentrated HCl (6 mL)
and water (4 mL) was cooled in an ice bath and diazotized with a solution of sodium nitrite
(1.39 g, 20 mmol) in water (5 mL).

NOVEL 1,2,3,4-TETRAHYDROCARBAZOLE DERIVATIVES
535
The cooled diazonium solution was added dropwise to a well-stirred cooled solution
of 1 in ethanol (10 mL) containing sodium acetate (1.75 g, 20 mmol). The reaction mixture
was stirred for 1–2 h until it reached complete coupling reaction. The crude product was
filtered off, dried well, and recrystallized from ethanol. The results are given in Table II.
Synthesis of 3-Mercapto-3-phenylamino-2-(1,2,3,4-tetrahydro-
carbazole-9-carbonyl)-acrylonitrile (4)
To a cold suspension of potassium hydroxide (1.4 g, 25 mmol) in DMF (30 mL),
cyanotetrahydro-carbazoloacetamide (6.0 g, 25 mmol) was added followed by phenyl isoth-
iocyanate (2.99 mL, 25 mmol). The mixture was stirred overnight at room temperature and
then poured onto ice-cold water. Acidification using dilute HCl until the medium became
acidic gave solid product 4, which was filtered off, washed with water, dried, and crystallized
from aqueous ethanol to give compound 4 (see Tables I and II).
Synthesis of the Acyclic Intermediate (5)
Equimolar quantities of 4 (3.37 g, 10 mmol) in ethanol containing potassium car-
bonate (1.39 g, 10 mmol) and chloroacetone (0.798 mL, 10 mmol) were stirred for 2 h at
room temperature, then left to stand at the same temperature for 24 h. The separated solid
product was washed with water, dried, and crystallized from ethanol to give 5 (see Tables I
and II).
Synthesis of 2-(4-Methyl-3-phenyl-3H-thiazol-2-ylidene)-3-oxo-3-
(1,2,3,4-tetrahydro-carbazol-9-yl)-propionitrile (6), 3-Oxo-2-(4-oxo-3-
phenyl-thiazolidin-2-ylidene)-3-(1,2,3,4-tetrahydro-carbazol-9-yl)-
propionitrile (8), and 2-(3,4-Diphenyl-3H-thiazol-2-ylidene)-3-oxo-3-
(1,2,3,4-tetrahydro-carbazol-9-yl)-propionitrile (10)
Pathway 1. A mixture of equimolar amounts of 3 and α-halo compounds (10 mmol)
was stirred in DMF (20 mL) containing potassium carbonate (1.39 g, 10 mmol) overnight.
The reaction mixture was poured onto ice-cold water, acidified by dilute HCl, filtered off,
and recrystallized from ethanol to give the corresponding thiazole derivatives (see Tables I
and II).
Pathway 2. Refluxing the acyclic intermediates 5 and 7 in ethanol (20 mL) con-
taining a catalytic amount of TEA for 3 h afforded the corresponding thiazole derivatives
6 and 8.
Synthesis of 6,7,8,9-Tetrahydro-9-(5,6,7,8-tetrahydrocarbazol-9-yl)-5H-
carbazole (13)
Compound 1 (2.38 g, 10 mmol) was refluxed in dry pyridine for 2 h and then left
to cool at room temperature, where a yellow crystalline product appeared. This prod-
uct was collected by filtration, washed thoroughly with ethanol, and recrystallized from
ethanol/DMF to afford compound 13 (see Tables I and II).

536
A. A. FADDA ET AL.
Synthesis of 4-Amino-2,3-dihydro-1H-pyrido[3,2,1-jk]carbazol-
6(5H)-one (14)
A mixture of 1 (2.38 g, 10 mmol) and hydrazine hydrate (0.49 mL, 10 mmol) in
ethanol (25 mL) in the presence of TEA (4 drops) was refluxed for 3 h. The reaction
mixture was then cooled to room temperature, and the obtainable solid material was filtered
off, dried, and recrystallized from ethanol to give compound 14 (see Tables I and II).
Synthesis of Pyrrolopyridocarbazol Derivative (18)
Equimolar amounts of 1 (2.38 g, 10 mmol) and isatine (1.47 g, 10 mmol) in ethanol
(25 mL) in presence of few drops of pyridine were refluxed for 4 h. The reaction mixture
was left to cool at room temperature overnight. The formed precipitate was filtered off,
dried, and recrystallized from ethanol to give compound 18 (see Tables I and II).
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