Modern Friedel-Crafts chemistry. Part 36. Facile synthesis of some new pyrido[3,2,1-jk]carbazoles via Friedel-Crafts cyclialkylations

Article abstract of DOI:10.2298/JSC120520098A

An efficient methodology for the synthesis of novel substituted pyrido[ 3,2,1-jk]carbazoles via Friedel-Crafts cyclialkylations is reported. The methodology was realized by a three-step protocol involving the addition of carbazole to 3-methylcrotononitril

Full text of DOI:10.2298/JSC120520098A

J. Serb. Chem. Soc. 78 (5) 611–619 (2013)
JSCS–4442
UDC 547.821+547.759.32+542.913+
547.631.1.05:66.095.253.095.252
Original scientific paper
Modern Friedel–Crafts chemistry. Part 36. Facile synthesis of
some new pyrido[3,2,1-jk]carbazoles via
Friedel–Crafts cyclialkylations
*
HASSAN ABDOU KOTB ABD EL-AAL and ALI ALI KHALAF
Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516, Egypt
(Received 20 May 2011, revised 8 July 2012)
Abstract: An efficient methodology for the synthesis of novel substituted py-
rido[3,2,1-jk]carbazoles via Friedel–Crafts cyclialkylations is reported. The
methodology was realized by a three-step protocol involving the addition of
carbazole to 3-methylcrotononitrile. The resulting nitrile was subjected to
alcoholysis to the desired ester, followed by addition of Grignard reagents to
afford tertiary alcohols and/or reacted directly with different Grignard reagents
to form the desired ketones. The latter ketones were converted to both second-
ary and tertiary alcohols by reduction with lithium aluminum hydride (LAH)
and addition of Grignard reagents, respectively. These alcohols were cyclial-
kylated under Friedel–Crafts conditions catalyzed by AlCl3/CH3NO2, p-tolue-
nesulfonic acid (PTSA) or polyphosphoric acid (PPA) to give tri- and tetra-
substituted pyrido[3,2,1-jk]carbazoles.
Keywords: Friedel–Crafts cyclialkylation; pyrido[3,2,1-jk]carbazole; heteropo-
lycycles; heteroarylalkanols; carbocations.
INTRODUCTION
Synthesis of heteropolycycles containing pyrido[3,2,1-jk]carbazole scaffold
is of interest because they are the core subunit often found in the heterocyclic
1
2
skeleton of many natural products, optoelectronics applications, dye-sensitized
3
4
solar cells (DSCs), photochromic dyes and were designed as vital precursors in
the synthesis of many biologically active carbazole alkaloids. Moreover, some
derivatives are of interest in biomedical and pharmacological applications.
5
6
A limited number of synthetic methodologies have been developed for the
synthesis of pyrido[3,2,1-jk]carbazole derivatives. Among these synthetic ap-
proaches described in literature are the thermal condensations of malonates with
7
8
carbazole, Diels–Alder reaction of vinylindoles, photolysis of N-aryltetrahyd-
9
10
roquinolines, dimerization of N-vinylcarbazole, Fisher reaction of tetrahydro-
*Corresponding author. E-mail: hassankotb33@yahoo.com
doi: 10.2298/JSC120520098A
611
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EL-AAL and KHALAF
11
quinolines and via intermolecular [4+2] cycloaddition of benzotriazoles with
12
alkenes.
Despite the numerous advances in the field of synthetic organic chemistry,
the development of direct, concise and economic methods is currently a popular
research area and has always been an attractive and challenging area for both
medicinal and synthetic chemists. Among these methods, intramolecular Friedel–
13–19
Crafts reaction (called cyclialkylations)
promoted by both Brönsted and
Lewis acid catalysts is promising as a powerful tool offering considerable oppor-
tunities for synthetic manipulations.
In recent years, a part of our Friedel–Crafts research was devoted to the
development of facile routes to approach the construction of novel bi- and higher
19
heterocyclic systems. The previous paper of this series described the synthesis
of seven substituted nitrogen and nitrogen–sulfur polycycles containing fused
carbazole, tetrahydrocarbazole, quinoline, tetrahydroquinoline, acridine, pheno-
thiazine and indole moieties via Friedel–Crafts cyclialkylations of the corres-
ponding heteroarylalkanols.
In connection with previous studies, herein the facile synthesis of nine un-
recorded 5,6-dihydro-4H-pyrido[3,2,1-jk]carbazole derivatives via intramolecular
cyclialkylations of suitable synthesized alcohols 1a–i (Scheme 1) is described.
Scheme 1. Heteroarylalkanols 1a–i.
RESULTS AND DISCUSSION
Synthesis of the starting alcohols
The requisite precursor 3-(9H-carbazol-9-yl)-3-methylbutanenitrile (4) was
readily obtained by refluxing a solution of 3-methylcrotononitrile (3) and carba-
zole (2) in dioxane in the presence of a catalytic amount of triton B. Ethanolysis
of 4 gave ethyl 3-(9H-carbazol-9-yl)-3-methylbutanoate (5), which was con-
verted to tertiary alcohols 1a–c, by reaction with two equivalents of the corres-
20
ponding Grignard reagent.
Furthermore, reaction of 4 with one equivalent of Grignard afforded ketones
6a–c which were successively converted to the respective tertiary alcohols 1d–f
by reaction with one equivalent of the corresponding Grignard reagent and to
21
secondary alcohols 1g–i by reduction with LAH The structures of all new al-
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MODERN FRIEDEL–CRAFTS CHEMISTRY
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cohols were appropriately established by the usual spectroscopic methods. The
results are presented in Table I and Scheme 2.
TABLE I. Synthesis of heteroarylalkanols 1a–i
m.p. / °C Yieldb
Entry Substrate R1
R2
Conditionsa
Product
( nD25
)
%
1
2
3
7
8
9
5
5
5
6a
6b
6c
6a
6b
6c
Me Me
MeMgI, Et2O, rt, 10 h
EtMgBr, Et2O, rt, 12 h
1a
1b
1c
1d
1e
1f
1g
1h
1i
122
115
(1.542)
(1.558)
112
(1.538)
(1.533)
(1.536)
(1.541)
86
92
84
85
83
85
84
91
88
Et
Ph
Me
Et
Et
Ph PhMgBr, Et2O, 40 °C, 12 h
Et
Ph
EtMgBr, Et2O, rt, 5 h
PhMgBr, Et2O, rt, 8 h
MeMgI, Et2O, rt, 6 h
LAH, Et2O, rt, 3 h
LAH, Et2O, rt, 2 h
LAH, Et2O, rt, 3 h
Ph Me
10
11
12
a
Me
Et
Ph
H
H
H
b
All reactions were performed using 0.1 equivalent excess of RMgX and LAH, then calculated; isolated yield
referred to substrate
6a: R = Me; 6b: R = Et; 6c: R = Ph
Scheme 2. Synthesis of heteroarylalkanols 1a–i; reagents and conditions: i) BnMe3NOH,
dioxane, 90 °C, 4 h, yield: 92.5 %, ii) EtOH, H2SO4, reflux 10 h, yield: 85.7 %, iii) 2RMgX,
Et2O, NH4Cl solution, iv) RMgX, THF/Et2O, HCl solution, v) RMgX, Et2O, NH4Cl
solution and vi) LAH, Et2O, room temperature (Table I).
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1
The H-NMR data allowed an unambiguous confirmation of the formation
1
of the heterocyclic alkanols. Thus, the H-NMR spectrum for alcohol 1a dis-
played signals in which aromatic protons appeared at δ 7.0–7.9 ppm. The gem-di-
methyls at C-2 and C-4 appeared as two singlets at δ 1.1 and 1.6 ppm, respecti-
vely. The third singlet at δ 2.1 ppm was assigned to the downfield CH protons.
2
A broad singlet appearing at δ 2.8 ppm was assigned to OH group. In all IR spec-
tra, the characteristic peaks of carbonyl groups were absent. The characterization
data for the synthesized compounds are given in the Supplementary material to
this paper.
Cyclialkylation of heteroaryl alcohols
Cyclialkylations of alcohols 1a–i were performed in the presence of AlCl /
3
/CH NO , polyphosphoric acid (PPA) and p-toluenesulfonic acid (PTSA) catal-
3
2
ysts under varying conditions. Cyclialkylations of carbinols 1a, 1b and 1d–f pro-
ceeded smoothly in the presence of AlCl /CH NO for 2 h at room temperature
3
3
2
to give the substituted 5,6-dihydro-4H-pyrido[3,2,1-jk]carbazoles 8a, 8b and 8d–f.
The results are embedded in Table II and Scheme 3.
TABLE II. Cyclialkylation conditions and results for the heteroarylalkanols 1a–f
Entry Substrate
Catalyst
Product Solvent
t / °C
Time, h Yielda, %
b
1
2
3
4
5
6
7
9
10
11
12
13
14
1a
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1e
1f
AlCl3/CH3NO2
PPAd
8a
8a
8a
8b
8b
8c
8c
8d
8d
8e
8e
8e
8f
DCMc
–
PhH
PEf
–
DCM
–
DCM
–
PE
–
PhH
DCM
–
RT
160
reflux
RT
160
RT
250
RT
160
RT
2
1
10
2
82
75
88
81
73
81
76
79
74
84
74
78
80
76
PTSAe
AlCl3/CH3NO2
PPA
AlCl3/CH3NO2
PPA
AlCl3/CH3NO2
PPA
AlCl3/CH3NO2
PPA
1
48
12
2
2
2
2
10
4
160
reflux
RT
PTSA
AlCl3/CH3NO2
15
1f
PPA
8f
160
4
a
b
Isolated yield referred to substrate; with AlCl /CH NO catalyst reactant proportions were: alcohol (0.002
3
3
2
c
d
mol), AlCl (0.0024 mol), CH NO (0.024 mol), solvent (10 mL); dichloromethane; with PPA catalyst, the
3
3
2
e
reactant proportions were: alcohol (0.5 g) and PPA (3 g); with PTSA catalyst, the reactant proportions were:
alcohol (0.5 g), PTSA (3 g) and solvent (10 mL); petroleum ether (60–80 °C)
f
Intramolecular cyclization of alcohol 1c, required more severe reaction con-
ditions compared to its methyl-substituted analogs 1a. Accordingly, the best re-
sults were via cyclialkylations of alcohol 1c under more strenuous conditions in
the presence of PPA for 12 h at 250 °C and with AlCl /CH NO for 48 h in
3
3
2
dichloromethane (DCM) solution at room temperature to yield 5,6-dihydro-
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MODERN FRIEDEL–CRAFTS CHEMISTRY
615
-6,6-dimethyl-4,4-diphenyl-4H-pyrido[3,2,1-jk]carbazole (8c) as the sole product
(Scheme 3; Table II, Entries 6 and 7).
Scheme 3. Cyclialkylation of heteroarylalkanols 1a–i.
Cyclialkylations of alcohols 1g–i were performed in the presence of AlCl /
3
/CH NO , PPA and PTSA catalysts under different reaction conditions (Table
3
2
III, Scheme 3). The closure step of the secondary alcohols required less strenuous
reaction conditions than alcohol 1c. Thus, upon treatment of such alcohols with
acidic catalysts, the products were shown to be the tetracyclic amines 8g–i.
TABLE III. Cyclialkylation conditions and results for heteroarylalkanols 1g–i
Entry
Substrate
Catalyst
Product Solvent t / °C Time, h Yield, %
1
2
3
4
5
6
7
8
9
1g
1g
1g
1h
1h
1h
1i
AlCl3/CH3NO2
PPA
PTSA
AlCl3/CH3NO2
PTSA
PPA
AlCl3/CH3NO2
PPA
8g
8g
8g
8h
8h
8h
8i
PE
–
PhH
DCM
PhH
–
PE
–
PhH
RT
160
reflux
RT
reflux
160
RT
5
8
15
6
15
8
4
80
74
83
82
80
75
79
76
77
1i
1i
8i
8i
160
reflux
6
10
PTSA
Examination of the data depicted in Tables II and III revealed the following
significant points: i) most cyclialkylations could be easily achieved by AlCl /
3
/CH NO in DCM and petroleum ether (60–80 °C) (PE) at room temperature, by
3
2
PPA at 160 °C and by PTSA in benzene under reflux, ii) the only exception lies
in the cyclialkylations of 1c in which both R and R are phenyl groups. This
1
2
reaction required much longer times with AlCl /CH NO and much higher tem-
3
3
2
peratures with PPA. Certainly, this is due to the development steric interactions
exerted by both phenyls at the closure step. Similar steric observations were also
13
noted in other reported cases.
EXPERIMENTAL
Instrumentation
All reagents were purchased from Merck, Sigma or Aldrich Chemical Co. and were used
without further purification. Melting points were measured on a digital Gallenkamp capillary
melting point apparatus and are uncorrected. The IR spectra were recorded on a Shimadzu 470
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616
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1
infrared spectrophotometer using KBr wafer and thin film techniques. The H-NMR spectra
were recorded on Jeol LA 400 MHz FT-NMR (400 MHz) and Varian 90 MHz NMR spectro-
meters using CDCl3 as the solvent with TMS as the internal standard. Elemental analyses
were performed on a Perkin-Elmer 2400 Series II analyzer. The mass spectra were obtained
using a JEOL JMS 600 spectrometer at an ionizing potential of 70 eV using the direct inlet
system. Reactions were monitored by thin layer chromatography (TLC) using pre-coated
silica plates and visualized with UV light. Flash column chromatography was performed on
silica gel and basic alumina.
Synthesis of 3-(9H-carbazol-9-yl)-3-methylbutanenitrile (4)
An ice-cold solution of carbazole 2 (6.9 g, 40 mmol) and 3-methylcrotononitrile (3) (3.4
g, 42 mmol) in dioxane (30 mL) was treated with 0.7 ml of triton B. The reaction mixture was
heated in a water bath for 5 h and then concentrated in vacuo. The pasty product was triturated
with methanol (3×5 mL) and the resulting precipitate was filtered off, washed excessively
with methanol and dried to yield 9.5 g (92.5 %) of the crude product. Crystallization from
acetone gave (8.9 g, 86.6 %) of pure nitrile 4 in the form of white crystals.
Synthesis of ethyl 3-(9H-carbazol-9-yl)-3-methylbutanoate (5)
A mixture of 3-(9H-carbazol-9-yl)-3-methylbutanenitrile (4) (5 g, 20 mmol), absolute
ethanol (40 mL) and 7 ml of concentrated sulfuric acid was refluxed for 10 h. Excess alcohol
was then removed by distillation and the residue was diluted with cold water (50 mL), basified
with Na2CO3 solution (20 mL, 30%) and extracted with ether (3×30 mL). The combined
ethereal extracts were washed with water, dried over MgSO4, filtered and finally concentrated
to give 5 g (85.7 %) of crude oily ester. Purification by flash column chromatography (basic
alumina, EtOAc/n-hexane, 2/3) gave 4.8 g (82.3 %) of pure 5 in the form of pale yellow oil.
General procedure for the synthesis of heteroaryl ketones 6a–c
A solution of nitrile 4 (2.5g, 10 mmol) in THF (20 mL) was added rapidly under stirring
to an ice-cold Grignard reagent obtained as usual20 from Mg turnings (0.3 g, 12 mmol) and
alkyl or aryl halide (12 mmol) in diethyl ether (30 mL). After refluxing for 15 h, the mixture
was poured into ice-cold hydrochloric acid (100 mL, 30 %) when the ketimine hydrochloride
separated. The organic solvent was removed in vacuo and the cold aqueous mixture was fil-
tered under suction. The resulting ketimine was then hydrolyzed by refluxing with a mixture
of benzene, 20 mL; HCl, 10 mL; AcOH, 10 mL until the ketimine disappeared (7–9 h). The
solution was cooled and the benzene layer was separated, while the aqueous layer was
basified by addition of solid Na2CO3 under stirring and finally extracted with benzene (2×30
mL). The combined organic phases were washed with water, dried over anhydrous Na2SO4
and the solvent was evaporated in vacuo to afford the crude product that was purified by
crystallization.
General procedure for the synthesis of heteroaryl alcohols 1a–f
To an ice-cold Grignard reagent solution obtained as usual20 from Mg turnings (0.2 g, 8
mmol) and alkyl or aryl halide (8 mmol) in ether (25 mL), a solution of ester 5 (1.0 g, 3.6
mmol) and/or ketone 6a–c (7.3 mmol) in ether (30 mL)was added. The reaction mixture was
stirred at required temperature for appointed time (Table I) followed by decomposition with
saturated NH4Cl aqueous solution. The product was extracted with ether (3×20 mL) and
combined organic phases were washed with water, dried over anhydrous Na2SO4 and the
solvent was evaporated in vacuo. The residue was purified by flash column chromatography
(basic alumina, EtOAc/n-hexane, 2/3), which gave the pure products 1a–f.
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MODERN FRIEDEL–CRAFTS CHEMISTRY
617
General procedure for the synthesis of heteroaryl alcohols 1g–i
A solution of ketone 6a–c (2.5 mmol) in anhydrous ether (15 mL) was added in 30 min
to an ice-cold (0 °C) solution of LAH (0.10 g, 2.7 mmol)21 in ether (15 mL). The reduction
was complete after stirring for appointed time at defined temperature (Table I, TLC, 20%
ethyl acetate/hexane). The cold reaction mixture was quenched at 0 °C by the sequential
addition of water (2 mL), NaOH solution (10 mL, 20%) and water (10 mL). Then it was
warmed to room temperature. Suction filtration removed the white precipitate of aluminum
compounds, which were thoroughly triturated with ethyl acetate. The organic layer was
separated, washed with water, dried over anhydrous Mg2SO4 and the solvent was evaporated
in vacuo to afford crude alcohols 1g–i. Purification of the crude products with flash column
chromatography (basic alumina, EtOAc/n-hexane, 2/3) gave the pure products 1g–i.
Friedel–Crafts cyclialkylations procedures
The procedures described earlier for cyclialkylation of heteroarylalkanols with AlCl3/
/CH3NO2,14 PTSA,16 and PPA19 were essentially followed and are mentioned below. In all
reactions, the crude oily or solid products were purified by flash column chromatography
(basic alumina, EtOAc/n-hexane, 1/1) giving the pure products 8a–i. The conditions and
yields for the products 8a–i are presented in Tables II and III while the characterization data
for the products are given in the Supplementary material to this paper.
Method A. Cyclialkylations using AlCl3/CH3NO2 catalyst. To a solution of AlCl3 (2.4
mmol) in CH3NO2 (24 mmol) was added a solution of alcohols 1a–i (2.0 mmol) in DCM or
PE (60–80 °C) (10 mL) dropwise under stirring over 10–15 min. The reaction mixture was
further stirred for a certain time at room temperature and decomposed by careful addition of
10 % ice-cold hydrochloric acid solution (20 mL). The residue was extracted with diethyl
ether (3×20 mL) and the combined organic phases were washed with 10 % Na2CO3, water and
dried over anhydrous MgSO4. The solvent was evaporated under reduced pressure to afford
the crude products 8a–i.
Method B. Cyclialkylations using PTSA catalyst. A solution of the carbinols 1a, 1e and
1g–i (0.5 g) and PTSA (3 g) in dry benzene (10 ml) was refluxed for 10 h. After cooling to
room temperature, the reaction mixture was diluted with ether (30 mL). The organic layer was
separated, washed successively with a saturated solution of NaHCO3, water and dried over
MgSO4. The solvent was evaporated under reduced pressure to afford the crude products 8a,
8e and 8g–i.
Method C. Cyclialkylations using PPA catalyst. A stirred mixture of alcohols 1a–i (0.5
g) and the PPA (3 g) was heated on an oil bath and kept at the required temperature for a
certain time. Afterwards, the flask was cooled to room temperature and basified by addition of
NaHCO3 solution (25 ml, 30 %). The residue was extracted with diethyl ether (3×20 mL) and
the combined organic phases were washed with water, dried over anhydrous Na2SO4 and the
solvent was evaporated in vacuo to give the crude products 8a–i.
CONCLUSIONS
In summary, a facile protocol was developed for the synthesis of nine new
pyrido[3,2,1-jk]carbazole derivatives via the direct intramolecular Friedel–Crafts
cyclization reaction of heteroarylalkanols (1a–i) catalyzed by AlCl /CH NO ,
3
3
2
PTSA or PPA. The simplicity of the processes, accessibility and moderate cost of
the required substrates proved that Friedel–Crafts cyclialkylation could be con-
sidered as one of the most useful pathways to the synthesis of heteropolycycles.
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618
EL-AAL and KHALAF
SUPPLEMENTARY MATERIAL
Characterization data for the synthesized compounds are available electronically from
http://www.shd.org.rs/JSCS/, or from the corresponding author on request.
И З В О Д
УНАПРЕЂЕНА ФРИДЕЛ–КРАФТСОВА РЕАКЦИЈА. ДЕО 36. ЛАКА СИНТЕЗА НОВИХ
ПИРИДО[3,2,1-jk]КАРБАЗОЛА ФРИДЕЛ–КРАФТСОВИМ ЦИКЛИАЛКИЛОВАЊЕМ
HASSAN ABDOU KOTB ABD EL-AAL И ALI ALI KHALAF
Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516, Egypt
Приказана је ефикасна методологија синтезе нових супституисаних пиридо[3,2,1-
-jk]карбазола Фридел–Крафтсовим циклиалкиловањем. Поступак је реализован прото-
колом од три корака који укључују адицију карбазола на 3-метилкротононитрил. Ново-
добијени нитрил је подвргнут алкохолизи до жељеног естра, након чека су употребом
Грињаревог реагенса добијени терцијарни алкохоли. Другим Грињаревим реагенсима
нитрил је трансформисан у жељене кетоне који су редукцијом помоћу LAH или другим
Грињаревим реагенсима преведени у одговарајуће секундарне или терцијарне алкохоле.
Алкохоли су подвргнути реакцији циклиалкиловања под Фридел–Крафтсовим условима
у присуству AlCl3/CH3NO2, PTSA и PPA чиме су добијени три- и тетра-субституисани
пиридо[3,2,1-jk]карбазоли.
(Примљено 20. маја, ревидирано 8. јула 2012)
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619
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