Modern friedel-crafts chemistry. part 37. efficient syntheses of some new julolidines via cyclialkylations of heteroaryl carbinols

Article abstract of DOI:10.1002/jhet.1797

A simple and convenient procedure for the synthesis of some novel alkyl-substituted and aryl-substituted julolidines is reported. Julolidines were smoothly synthesized in excellent isolated yields via Friedel-Crafts intramolecular alkylations of heteroarylalkanols in the presence of both Bronsted (PPA) and Lewis (AlCl₃/CH₃NO₂) acid catalysts. The precursors alkanols, 1a, 1b, 1c, 1d, 1e, 1f, 1g, 1h, 1i, were readily prepared both by reaction of selectively synthesized carboxylic acid esters and ketones with different Grignard reagents and also by reduction of the synthesized ketones with LAH. A plausible carbocation mechanism is proposed to account for the results. The structures of the compounds are established using both spectral and analytical data.

Full text of DOI:10.1002/jhet.1797

Month 2013
Modern Friedel–Crafts Chemistry. Part 37. Efficient Syntheses of Some
New Julolidines via Cyclialkylations of Heteroaryl Carbinols
*
Hassan A. K. Abd El-Aal, Ali A. Khalaf, and Ahmed M. A. El-Khawaga
Chemistry Department, Faculty of Science, Assiut University, Assiut, 71516, Egypt
*
E-mail: Hassankotb33@yahoo.com
Received April 16, 2012
DOI 10.1002/jhet.1797
Published online 00 Month 2013 in Wiley Online Library (wileyonlinelibrary.com).
Cat.
H+, -H2O
N
N
R1
OH
N
R1
R2
H
R2
2
1 a-i
8a-i
a: R1 = Me, R2 = Me; b: R1 = Et, R2 = Et; c: R1 = Ph, R2 = Ph;
d: R1 = Me, R2 = Et; e: R1 = Et, R2 = Ph; f: R1 = Ph, R2 = Me;
g: R1 = Me, R2 = H; h: R1 = Et, R2 = H; i: R1 = Ph, R2 = H
A simple and convenient procedure for the synthesis of some novel alkyl-substituted and aryl-substituted
julolidines is reported. Julolidines were smoothly synthesized in excellent isolated yields via Friedel–Crafts
intramolecular alkylations of heteroarylalkanols in the presence of both Brønsted (PPA) and Lewis
(AlCl3/CH3NO2) acid catalysts. The precursors alkanols, 1a–i, were readily prepared both by reaction of
selectively synthesized carboxylic acid esters and ketones with different Grignard reagents and also by
reduction of the synthesized ketones with LAH. A plausible carbocation mechanism is proposed to account
for the results. The structures of the compounds are established using both spectral and analytical data.
J Heterocyclic Chem., 00, 00 (2013).
INTRODUCTION
Friedel–Crafts cyclialkylations [22–27] promoted by both
Brønsted and Lewis acid catalysts is promising as an efficient
method to prepare substituted julolidines.
The chemistry of julolidine (2,3,6,7-tetrahydro-1H,
5H-pyrido[3,2,1-ij]quinoline) as well as lilolidine has been
the focus of interest of many investigations during recent years.
This growing interest can be explained because of their
importance as synthetic intermediates [1–6] and as the key
structural element exhibit interesting biological activities
[7–9] in several natural products and fluorescent dyes
[10–13]. Moreover, julolidines are the core structures of many
pharmacological agents and drug molecules such as anticancer
drugs [14], antidiabetic or cardiovascular agents [15], pesti-
cides [16], and potential antidepressants [17]. Consequently,
synthetic methodologies for preparing julolidine derivatives
have attracted considerable interest; however, few methods
offering good results have been reported for the synthesis of
julolidines [18] and julolidinones [19] and to generate bicyclic
systems with one ring junction nitrogen atom [20,21] (Fig. 1).
Despite numerous advances in the field of synthetic organic
chemistry, the developments of valuable and efficient strate-
gies for the construction of these ring systems remain as a sig-
nificant challenge. Among these methods, intramolecular
In our previous work, we developed a synthetic pathway
for the construction of seven nitrogen and nitrogen–sulfur
polycycles [28] containing quinoline, tetrahydroquinoline,
acridine, phenothiazine, and indole moieties via Friedel–
Crafts cyclialkylations of suitable synthesized alcohols.
The results showed that a number of difficult substituted
heterocycles can be easily obtained with the advantages of
short reaction time and high yield.
This prompted us to apply these procedures in developing
the synthesis of nine julolidines substituted from tetrahydro-
quinoline via Friedel–Crafts cyclialkylation of suitable
synthesized heteroarylalkanols 1a–i (Scheme 1).
RESULTS AND DISCUSSION
Synthesis of heteroarylalkanols 1a–i.
The required
3-(3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanenitrile (4)
Scheme 1. Heteroarylalkanols 1a–i.
R1 R2
Me Me
R1 R2
Ph Me
a
b
c
d
e
f
N
N
N
N
Et
Ph Ph
Me Et
Et
Me
Et
Ph
H
H
H
g
h
i
R1
OH
O
R2
julolidine
lilolidine
1-oxojulolidine
1 a-i
Et
Ph
Figure 1. Heterocycles containing tetrahydroquinoline scaffold.
© 2013 HeteroCorporation

H. A. K. Abd El-Aal, A. A. Khalaf, and A. M. A. El-Khawaga
Vol 000
Scheme 2. Reagents and conditions: (a) BnMe3NOH, dioxane, 90ꢀC, 4 h,
86%; (b) H2SO4, EtOH, reflux 7 h, 82%; (c) 2RMgX, Et2O, NH4Cl soln,
Table 1.
Scheme 3. Reagents and conditions: (a) RMgX, PhH/Et2O, HCl; (b) RMgX,
Et2O, NH4Cl soln; (c) LAH, E2O, rt, Table 1.
a
N
CN
+
R1
OH
b
N
N
H
R2
CN
a
4
2
3
1d-f
N
b
4
COR
c
c
6a-c
N
N
R1
a: R =H
COOEt
N
OH
R2
b: R =Me
c: R = Ph
OH
R1
5
1a-c
1g-i
was readily synthesized in one step by the reaction of
tetrahydroquinoline (2) with 3-methylcrotononitrile (3) in
the presence of a catalytic amount of Triton B; 4
was successively converted to its ethyl ester 5. The ethyl
3-(3,4-dihydroquinolin-1(2H)-yl)-3-methylbutanoate (5)
was finally reacted with two equivalents of Grignard
reagents to afford alcohols 1a–c. The results are presented
in Scheme 2 and Table 1 (Entries 1–3).
Scheme 4. Cyclialkylations of heteroarylalkanols 1a–i.
Cat.
H+, -H2O
N
N
R1
OH
R1
+
R2
R2
-H+
7a-i
1a-i
N
Two-step syntheses of alcohols 1–f and 1g–i are outlined
in Scheme 3 and Table 1 (Entries 4–6 and 7–9). These alco-
hols were prepared separately via two routes starting with
nitrile 4. The nitrile 4 was allowed to react with Grignard
reagents affording the corresponding ketones 6a–c. The
resulting ketones were further reacted by two different
routes, (i) addition of Grignard reagents to yield alcohols
1d–f and (ii) reduction with LAH to afford alcohols 1g–i.
The structures of all new alcohols were appropriately estab-
lished by the usual spectroscopic methods.
R1
R2
8a-i
displayed eight signals for compound 1a, the four aromatic
protons at d 6.8–7.4. The aliphatic acyclic protons of the
methylenes and four methyl groups of the new alcohol
appeared as three singlets: thus, the gem-dimethyls at C-2
and C-4 appear at d 1.1 and d 1.3, respectively. A third singlet
at d 1.6 was assigned to the up-field proton CH2. A broad
singlet at d 2.2 was assigned to OH. In all IR spectra of the
synthesized carbinols, the characteristic peak of carbonyl
groups was absent.
The structural elucidation of alcohols 1a–c was mainly
based on IR, 1H NMR, MS, and elemental analyses. The IR
spectra of alcohols 1a–c showed absorption bands for an
OH groups as broad bands in the range 3780–3250 cmÀ1
.
Cyclialkylations of heteroaryl alcohols to substituted
The cyclialkylations of alcohols 1a–i were
carried out in the presence of both AlCl3/CH3NO2
The 1H NMR data allowed an unambiguous statement of the
heterocyclic alkanols formation. Thus, the 1H NMR spectrum
julolidine.
Table 1
Synthesis of heteroarylalkanols (1a–i).
Entry
Substrate
R1
R2
Conditionsa
mp (ꢀC)
Product (%)b
1
2
3
4
5
6
7
8
9
5
5
5
6a
6b
6c
6a
6b
6c
Me
Et
Ph
Me
Et
Ph
Me
Et
Me
Et
Ph
Et
Ph
Me
H
MeMgI, Et2O, rt, 10 h
EtMgBr, Et2O, rt, 12 h
PhMgBr, Et2O, rt, 10 h
EtMgBr, Et2O, rt, 5 h
PhMgBr, Et2O, rt, 8 h
MeMgI, Et2O, rt, 6 h
LAH, Et2O, rt, 2 h
112
90
153
75
1a (91)
1b (89)
1c (84)
1 (85)
1e (90)
1f (88)
1g (82)
1h (87)
1i (93)
89
122
136
105
132
H
H
LAH, Et2O, rt, 2 h
LAH, Et2O, rt, 3 h
Ph
aAll reactions were performed using (0.1 equiv) excess of RMgX and LAH than calculated.
bIsolated yield refers to substrate.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 Friedel–Crafts Cyclialkylations, Ring Closure, Carbocation Chemistry, Grignard Reagents
Table 2
Cyclialkylation conditions and results of heteroarylalkanols 1a–f.
Entry
Substrate
Catalyst type
Solvent
Temperature (ꢀC)
Time (h)
Product (%)a
b
1
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
AlCl3/CH3NO2
PPAd
DCMc
—
RT
160
RT
160
RT
250
RT
160
RT
160
RT
160
2
1
2
8a (84)
8a (75)
8b (86)
8b (73)
8c (81)
8c (75)
8d (82)
8d (74)
8e (78)
8e (76)
8f (79)
8f (76)
2
3c
4
AlCl3/CH3NO2
PPA
AlCl3/CH3NO2
PPA
AlCl3/CH3NO2
PPA
AlCl3/CH3NO2
PPA
PEe
—
1
5
DCM
—
PE
—
DCM
—
50
14
2
2
2
4
4
4
6
7e
8
9
10
11
12
AlCl3/CH3NO2
PPA
PE
—
1f
aIsolated yield refers to substrate.
bWith AlCl3/CH3NO2 catalyst, reactant proportions were as follows: carbinol (0.002 mole), AlCl3 (0.0024 mole), CH3NO2 (0.024 mole), and solvent
(10 mL).
cDichloromethane.
dWith PPA catalyst, reactant proportions were as follows: carbinol (0.5 g) and PPA (3 g).
ePetroleum ether (60–80ꢀ).
and PPA catalysts (Scheme 4). Under mild conditions,
cyclialkylations of carbinols 1a,b,d–i proceeded smoothly
in the presence of AlCl3/CH3NO2 and PPA catalysts
under different reaction conditions gave substituted 2,3,6,
7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolines, 8a,b,d–i in
good overall yields (Table 2).
Cyclialkylations of 3-(3,4-dihydroquinolin-1(2H)-yl)-
3-methyl-1,1-diphenylbutan-1-ol (1c) required more severe
reaction conditions compared with their methyl substituted
analog 1a (Scheme 5; Table 2, Entry 6). Accordingly, the
best results were obtained by promoted cyclialkylation under
more strenuous conditions in the presence of PPA for 14 h at
250ꢀC and with AlCl3/CH3NO2 for 50 h in DCM at room tem-
perature to yield 3,3-dimethyl-1,1-diphenyl-2,3,6,7-tetrahy-
dro-1H,5H-pyrido[3,2,1-ij]quinoline (8c) as the sole product.
The results reflect that the steric interaction exerted by
two phenyl groups encountered in ring closure of tertiary
benzylic carbocation [29,30].
On the other hand, cyclialkylations of secondary alcohols
1g–i required less strenuous reaction conditions in the ring
Scheme 5. Cyclialkylations of heteroarylalkanol 1c.
Scheme 6. Cyclialkylation of heteroarylalkanols 1g–i.
Cat.
H+, -H2O
Cat.
H+, -H2O
N
N
N
N
Ph
Ph
Ph
OH
Ph
OH
+
+
R1
R1
-H+
-H+
1c
7c
1g-i
7g-i
N
N
Ph
Ph
R1
8g-i
8c
Table 3
Cyclialkylation conditions and results of heteroarylalkanols 1g–i.
Entry
Substrate
Catalyst type
Solvent
Temperature (ꢀC)
Time (h)
Product (%)
1
2
3
4
5
6
1g
1g
1h
1h
1i
AlCl3/CH3NO2
PPA
AlCl3/CH3NO2
PPA
AlCl3/CH3NO2
PPA
DCM
—
DCM
—
DCM
—
RT
160
RT
160
RT
6
4
6
4
6
8
8g (82)
8g (76)
8h (82)
8h (76)
8i (77)
8i (75)
1i
160
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. A. K. Abd El-Aal, A. A. Khalaf, and A. M. A. El-Khawaga
Vol 000
C14H18N2 (214); C, 78.5; H, 8.14; N, 13.08. Found; C, 78.9; H,
8.62; N, 12.75.
closure step than alcohol 1c. Thus, upon treatment of 1g–i
with acidic catalysts, the products were solely the julolidines
8g–i (Table 3). The results can be explained in terms of less
stability of the secondary than tertiary carbocation intermedi-
ates (Scheme 6).
Synthesis of ethyl 3-(3,4-dihydroquinolin-1(2H)-yl)-3-
methylbutanoate (5). A mixture of 3-(9H-carbazol-9-yl)-3-
methylbutanenitrile 4 (5 g, 20 mmol), absolute ethanol (40 mL),
and concentrated sulfuric acid (5 mL) was refluxed for 7 h. The
excess alcohol is removed by distillation, and the residue was
diluted with water (50 mL), basified with Na2CO3 solution
(20 mL, 30%), and extracted with ether. The ethereal layer was
separated, washed, and dried to give 5 (5 g, 85.7%). The crude
yellow oil was subjected to flash column chromatography by
using light petroleum and DCM as eluents to yield ethyl 3-(9H-
carbazol-9-yl)-3-methylbutanoate 5 (4.8 g, 82.3%) in the form
of a pale yellowish oil: n2D5 1.572; IR (film) nmax 3070, 2985,
CONCLUSIONS
In summary, we have developed a concise and catalytic
protocol for the synthesis of alkyl-substituted and aryl-
substituted julolidines that had not been reported before,
via direct intramolecular Friedel–Crafts cyclization reaction
of heteroaryl alkanols 1a–i catalyzed by AlCl3/CH3NO2
and PPA. The simplicity of the processes, moderate cost,
and the results of this study proved that the development of
Friedel–Crafts cyclialkylation reactions in heterocyclic
chemistry can be considered as one of the most useful
pathways to the synthesis of heteropolycycles.
1750, 1610, 1570, 1485, 1450, 1320, 1170, 745 cmÀ1
;
1H NMR (90 MHz, CDCl3, ppm), d 1.2 (6H, s, 2CH3), 1.22–1.45
(3H, t, J = 7.5 Hz, CH3), 1.75 (2H, m, J = 7.5Hz, C3H2), 2.4
(2H, s, J =9 Hz, CH2), 2.5 (2H, t, J = 7.5Hz, C4H2), 3.25 (2H, t,
J = 7.5 Hz, C2H2), 3.9 (2H, m, J = 7.5 Hz, CH2), and 6.8–7.6
(4H, m, Ar–H). Anal. Calcd for C16H23NO2 (261); C, 73.56; H,
8.81; N, 5.36. Found; C, 73.22; H, 8.85; N, 5.42.
General procedures for synthesis of heteroaryl ketones 6a–c.
A solution of nitrile 4 (2.5 g, 10 mmol) in benzene (20 mL) was
added rapidly with stirring to an ice-cold Grignard reagent
obtained as usual [27] from Mg turnings (15mmol) and alkyl or
aryl halide (15mmol) in ether (40mL). After refluxing for 12h,
the reaction mixture was stirred into ice-cold hydrochloric acid
(100mL, 30%) followed by removal of the solvents in vacuo. The
crude ketimine was hydrolyzed by refluxing with a mixture of
(benzene, 20 mL; HCl, 10mL; AcOH, 10mL) until the ketimine
disappeared (6–8 h) as monitored by TLC. The solution was
cooled, and benzene layer was separated, whereas the aqueous
layer was basified by addition of solid Na2CO3 with stirring and
finally extracted with benzene (3 Â 20 mL). The combined organic
phases were washed with water, dried over MgSO4, and the
solvent was evaporated in vacuo. The crude mixture was purified
by flash column chromatography (ethyl acetate–hexane 3:7) to
afford the pure products 6a–c.
EXPERIMENTAL
General.
All reagents were purchased from Merck (Merck
KGaA, Darmstadt, Germany), Sigma, or Aldrich Chemical Co.
(New Road, Gillingham, Dorset, SP8 4XT, UK) and were used
without further purification. Melting points were measured on a
digital Gallenkamp capillary melting point apparatus (London,
England) at Assiut university, and are uncorrected. The IR spectra
were determined with a Shimadzu 470 Infrared spectrophotometer
(3. Kanda-Nishikicho 1-chome, Chiyoda-ku, Tokyo 101-8448,
Japan) at the Faculty of Science, Assiut university, Assiut, Egypt,
using KBr wafer and thin film techniques (n cmÀ1). The 1H NMR
spectra were recorded on Jeol LA 400 MHz FT-NMR (400 MHz)
(1-2, Musashino 3-chome Akishima, Tokyo 196-8558, Japan) and
Varian 90MHz NMR (Palo Alto, California USA) spectrometers
at Assiut university, using CDCl3 solvent with TMS as internal
standard. Chemical shifts (d) and J values are reported in ppm and
Hz, respectively. Elemental analyses were performed on a Perkin-
Elmer 2400 Series II analyzer (Waltham, MA 02451 USA) at the
Faculty of Science, Assiut university, Assiut, Egypt. The mass
spectra were performed by JEOL JMS 600 spectrometer at an
ionizing potential of 70 eV using the direct inlet system. Reactions
were monitored by TLC using precoated silica plates visualized
with UV light. Flash column chromatography was performed on
silica gel and basic alumina.
Synthesis of 3-(3,4-dihydroquinolin-1(2H)-yl)-3-methyl-
butanenitrile (4). A solution of tetrahydroquinoline 2 (6.9 g,
40mmol) and b-methylcrotononitrile 3 (3.4 g, 42mmol) in
dioxane (30mL) was cooled in ice bath and treated with 0.5 mL
of Triton B. The reaction mixture was then heated in water bath
for 4 h and then concentrated in vacuo. The pasty product
triturated with methanol (3Â 10mL) portions and the resulting
orange precipitate was filtered off, washed excessively with
methanol, and dried to yield the crude nitrile 4 (9.5g, 92.5%),
which was crystallized from acetone (8.9g, 86.6%) as pale yellow
crystals: mp 138ꢀC; IR (KBr) nmax 3070, 2950, 2260, 1595, 1480,
1455, 1340, 1170, 745 cmÀ1; 1H NMR (90 MHz, CDCl3, ppm), d
1.2 (6H, s, 2CH3), 1.82 (2H, m, J = 7.5 Hz, C3H2), 2.44 (2H, m,
J = 7.5 Hz, C4H2 ), 2.55 (2H, m, J = 9 Hz, CH2 ), 3.2 (2H, m,
J = 9 Hz, C2H2 ), and 6.9–7.5 (4H, m, Ar–H). Anal. Calcd for
4-(3,4-Dihydroquinolin-1(2H)-yl)-4-methylpentan-2-one (6a).
Brown viscous oil (75%); nD25 1.588; Rf 0.43 (1:3, EtOAc/hexane);
IR (film) nmax 3065, 2990, 1740, 1580, 1480, 1440, 1370, 1270,
1020, 740, 695cmÀ1 1H NMR (90 MHz, CDCl3, ppm), d 1.2
;
(6H, s, 2CH3), 1.75 (2H, m, J = 7.5 Hz, C3H2), 2.1 (3H, s, CH3),
2.45 (2H, t, J = 7.5 Hz, C4H2), 2.6 (2H, s, CH2), 3.3 (2H, t,
J = 7.5Hz, C2H2), 3.9 (2H, m, J = 9 Hz, CH2), and 7.1–7.6 (4H,
m, Ar–H). Anal. Calcd for C15H21NO (231); C, 77.92; H, 9.09;
N, 6.06. Found; C, 77.6; H, 8.85; N, 5.82.
5-(3,4-Dihydroquinolin-1(2H)-yl)-5-methylhexan-3-one (6b).
Reddish viscous oil (77%); n2D5 1.592; Rf 0.46 (1:3, EtOAc/
hexane); IR (film) nmax 3060, 2990, 2910, 1745, 1580, 1470,
1
1450, 1360, 1250, 1030, 680cmÀ1; H NMR (90MHz, CDCl3,
ppm), d 0.9 (3H, t, J = 9 Hz, CH3), 1.2 (6H, s, 2CH3), 1.8 (2H,
m, C3H2), 2.4–2.7 (4H, m, C4H2, CH2), 2.65 (2H, s, CH2), 3.2
(2H, t, J = 7.5 Hz, C2H2), and 7.0–7.6 (4H, m, Ar–H). Anal. Calcd
for C16H23NO (245); C, 78.3; H, 9.38; N, 5.71. Found; C, 78.5;
H, 9.33; N, 5.84.
3-(3,4-Dihydroquinolin-1(2H)-yl)-3-methyl-1-phenylbutan-1-
one (6c). Pale yellow viscous oil (72%); n2D5 1.605; Rf 0.34 (1:3,
EtOAc/hexane); IR (KBr) nmax 3040, 3000, 2970, 1750,
1
1580, 1480, 1450, 1375, 1275, 1060, 740, 690 cmÀ1; H NMR
(90 MHz, CDCl3, ppm), d 1.3 (6H, 2s, 2CH3), 1.75 (2H, m,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 Friedel–Crafts Cyclialkylations, Ring Closure, Carbocation Chemistry, Grignard Reagents
C3H2), 2.4 (2H, t, J = 7.5, C4H2), 2.7 (2H, s, CH2), 3.25 (2H, t,
J = 7.5 Hz, C2H2), and 7.15–7.7 (9H, m, Ar–H). Anal. Calcd for
C20H23NO (293); C, 81.9; H, 7.85; N, 4.77. Found; C, 82.3; H,
7.45; N, 4.4.
740, 690cmÀ1 1H NMR (90MHz, CDCl3, ppm), d 0.9
;
(3H, t, J = 9 Hz, CH3), 1.6 (2H, q, J = 9 Hz, CH2), 1.2 (6H, 2s,
2CH3), 1.65–1.8 (2H, m, C3H2), 1.8 (2H, d, J =6 Hz, CH2), 2.55
(2H, t, J = 7.5, C4H2), 3.32 (2H, t, J = 7.5 Hz, C2H2), 4.2 (1H, s,
OH exchangeable with D2O), and 6.8–7.7 (9H, m, Ar–H). Anal.
Calcd for C22H29NO (323): C, 81.73; H, 8.98; N, 4.33. Found:
C, 81.6; H, 8.68; N, 4.75.
General procedure for the synthesis of alcohols 1a–f. To an
ice-cold Grignard reagent obtained as usual [26] from Mg turnings
(0.2g, 8 mmol) and alkyl or aryl halide (8 mmol) in ether (25 mL)
was added with ester 5 (1.0g, 3.6 mmol) and/or ketone 6a–c
(7.3mmol). The reaction mixture was stirred at required
temperature for the appointed time (Table 1) and decomposed by
sat. aq. NH4Cl soln. The product was extracted with ether
(3Â 15mL), and the 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, ethyl acetate/hexane, 2:3) to
afford the desired pure product 1a–f. The conditions and yields
are shown in Table 1 (Entries 1–6), and spectral data are given in
the following.
4-(3,4-Dihydroquinolin-1(2H)-yl)-4-methyl-2-phenylpentan-2-
ol (1f). This compound was obtained as white crystals in yield, 78%,
mp 122ꢀC (ethanol), Rf 0.41 (1:4, EtOAc/hexane); IR (KBr) nmax
3570, 3120, 2970, 1605, 1550, 1520, 1480, 1365, 1145, 950, 740
1
cmÀ1; H NMR (90MHz, CDCl3, ppm), d 1.2 (6H, 2s, 2CH3),
1.5 (3H, s, CH3), 1.6–1.8 (2H, m, C3H2), 1.85 (2H, d, J =6 Hz,
CH2), 2.6 (2H, t, J =7.5, C4H2), 2.9 (1H, s, OH exchangeable
with D2O), 3.4 (2H, t, J = 7.5 Hz, C2H2), and 6.9–7.7 (9H, m,
Ar–H). Anal. Calcd for C21H27NO (309): C, 81.55; H, 8.73; N,
4.53. Found: C, 81.3; H, 8.9; N, 4.75.
General procedure for the synthesis of heteroaryl alcohols 1g–i.
To an ice-cold (0ꢀC) stirred solution of LAH (0.1 g, 2.7 mmol) in
25 mL of ether, a solution of ketone 6a–c (2.5 mmol) in THF
(15 mL) was added dropwise over 10 min. The reduction was
complete after stirring for appointed time and temperature
(monitored by TLC, 20% ethyl acetate/hexane). The cold reaction
mixture was quenched at (0ꢀC) by the sequential addition of
distilled water (2 mL), NaOH solution (4 mL, 20%), and distilled
water (4 mL); then, it was warmed to room temperature. Suction
filtration removed the white precipitate of aluminum compounds,
which were thoroughly triturated with ethyl acetate. Evaporation of
the organic phase afforded crude alcohols 1g–i. The products were
purified by flash column chromatography (hexane/ethyl acetate, 3:2)
to afford the desired pure product. The conditions and yields
are shown in Table 1 (Entries 7–9), and spectral data are given in
the following.
4-(3,4-Dihydroquinolin-1(2H)-yl)-2,4-dimethylpentan-2-ol (1a).
This compound was obtained as white crystals in yield, 84%, mp
112ꢀC (ethanol), Rf 0.62 (1:4, EtOAc/hexane); IR (KBr) nmax 3360,
3070, 2950, 1590, 1485, 1450, 1440, 1340, 1145, 750, 670 cmÀ1
;
1H NMR (90 MHz, CDCl3, ppm), d 1.1 (6H, 2s, 2CH3), 1.3 (6H, 2s,
2CH3), 1.6 (2H, s, CH2), 1.8 (2H, m, C3H2), 2.2 (1H, s, OH
exchangeable with D2O) 2.45 (2H, t, J=7.5, C4H2), 3.1 (2H, t,
J=7.5Hz, C2H2), and 6.8–7.4 (4H, m, Ar–H). Anal. Calcd for
C16H25NO (247); C, 77.7; H, 10.1; N, 5.66. Found; C, 78.1; H,
9.85; N, 5.4.
3-Ethyl-5-(3,4-dihydroquinolin-1(2H)-yl)-5-methylhexan-
3-ol (1b).
This compound was obtained as white crystals in
yield, 80%, mp 90ꢀC (ethanol), Rf 0.58 (1:4, EtOAc/hexane); IR
(KBr) nmax 3570, 3060, 2970, 2850, 1590, 1480, 1460, 1450,
1340, 1230, 1120, 720 cmÀ1; 1H NMR (90 MHz, CDCl3, ppm), d
0.85 (6H, m, 2CH3), 1.1 (6H, 2s, 2CH3), 1.25 (6H, 2s, 2CH3), 1.4
(4H, m, 2CH2), 1.55 (2H, s, CH2), 1.75 (2H, m, C3H2), 2.35 (1H,
s, OH exchangeable with D2O) 2.6 (2H, t, J = 7.5, C4H2), 3.2 (2H,
t, J = 7.5 Hz, C2H2), and 6.8–7.7 (4H, m, Ar–H). Anal. Calcd for
C18H29NO (275); C, 78.54; H, 10.54; N, 5.09; Found; C, 78.82;
H, 10.36; N, 5.25.
4-(3,4-Dihydroquinolin-1(2H)-yl)-4-methylpentan-2-ol (1g).
This compound was obtained as white crystals in yield, 70%, mp
136ꢀC (methanol), Rf 0.63 (1:4, EtOAc/hexane); IR (KBr) nmax
3380, 3055, 2980, 1610, 1480, 1460, 1370, 1210, 740, 690 cmÀ1
;
1H NMR (90 MHz, CDCl3, ppm), d 1.1 (3H, s, J = 9 Hz, CH3),
d 1.3 (6H, s, 2CH3), 1.5 (3H, s, CH3), 1.6 (2H, d, J = 7.5 Hz,
CH2), 1.8 (2H, m, C3H2), 2.55 (2H, t, J = 7.5, C4H2), 2.8
(1H, s, OH exchangeable with D2O), 3.2–3.45 (3H, m, C2H2,
CH), and 6.8–7.5 (4H, m, Ar–H). Anal. Calcd for C15H23NO
(233): C, 77.25; H, 9.87; N, 6.0. Found: C, 77.56; H, 9.6; N, 5.85.
5-(3,4-Dihydroquinolin-1(2H)-yl)-5-methylhexan-3-ol (1h).
This compound was obtained as white plates in yield, 74%,
mp 105ꢀC (ethanol), Rf 0.67 (1:4, EtOAc/hexane); IR (KBr)
nmax 3640, 3070, 2980, 1595, 1460, 1450, 1370, 1220, 1175,
3-(3,4-Dihydroquinolin-1(2H)-yl)-3-methyl-1,1-diphenylbutan-1-
ol (1c). This compound was obtained as pale yellow crystals in yield,
75%, mp 153 ꢀC (methanol), Rf 0.28 (1:4, EtOAc/hexane); IR (KBr)
nmax 3380, 3060, 2990, 1580, 1555, 1445, 1370, 1220, 1120,
730 cmÀ1; 1H NMR (90 MHz, CDCl3, ppm), d 1.2 (6H, 2s, 2CH3),
1.85 (2H, m, C3H2), 2.1 (2H, s, CH2), 2.55 (2H, t, J=7.5, C4H2),
3.3 (2H, t, C2H2), 4.2 (1H, s, OH exchangeable with D2O), and 7.1–
7.9 (14H, m, Ar–H). Anal. Calcd for C26H29NO (371); C, 84.09; H,
7.81; N, 3.77. Found; C, 84.4; H, 7.45; N, 3.9.
;
740, 695 cmÀ1 1H NMR (90 MHz, CDCl3, ppm), d 0.9
5-(3,4-Dihydroquinolin-1(2H)-yl)-3,5-dimethylhexan-3-ol (1d).
This compound was obtained as white crystals in yield, 77%, mp
75ꢀC (ethanol), Rf 0.4 (1:4, EtOAc/hexane); IR (KBr) nmax 3530,
(3H, t, J = 9 Hz, CH3), 1.2 (6H, s, 2CH3), 1.4 (2H, q, J = 9 Hz,
CH2), ), 1.55 (2H, d, J = 9 Hz, CH2), 1.8 (2H, m, C3H2), 2.3
(1H, s, OH exchangeable with D2O), 2.5 (2H, t, J = 7.5, C4H2),
3.4 (2H, t, J = 7.5, C2H2), and 6.8–7.7 (4H, m, Ar–H). Anal.
Calcd for C16H25NO (247): C, 77.73; H, 10.1; N, 5.66. Found:
C, 77.8; H, 9.84; N, 5.7.
3050, 2990, 1740, 1600, 1465, 1445, 1340, 1190, 740, 695cmÀ1
;
1H NMR (90MHz, CDCl3, ppm), d 0.9 (3H, t, J = 9 Hz, CH3),
1.15 (6H, 2s, 2CH3), 1.3 (3H, s, CH3), 1.5 (2H, q, J = 9 Hz, CH2),
1.6 (2H, s, CH2), 1.8 (2H, m, C3H2), 2.5 (2H, t, J = 7.5, C4H2), 3.3
(2H, t, J = 7.5Hz, C2H2), 4.5 (1H, s, OH exchangeable with D2O),
and 7.0–7.6 (4H, m, Ar–H). Anal. Calcd for C17H27NO (261): C,
78.16; H, 10.34; N, 5.36. Found: C, 78.5; H, 10.25; N, 5.6.
3-(3,4-Dihydroquinolin-1(2H)-yl)-3-methyl-1-phenylbutan-1-
ol (1i). This compound was obtained as faintly yellow crystals in
yield, 80%, mp 132ꢀC (benzene), Rf 0.36 (1:4, EtOAc/hexane); IR
(KBr) nmax 3440, 3085, 2975, 1600, 1475, 1450, 1375, 1210,
5-(3,4-Dihydroquinolin-1(2H)-yl)-5-methyl-3-phenylhexan-3-
ol (1e). This compound was obtained as creamy plates in yield,
79%, mp 89ꢀC (ethanol), Rf 0.45 (1:4, EtOAc/hexane); IR (KBr)
nmax 3450, 3055, 2985, 1600, 1486, 1440, 1370, 1210, 1180,
1180, 740, 695cmÀ1 1H NMR (90MHz, CDCl3, ppm), d 1.2
;
(6H, s, 2CH3), 1.85 (2H, m, C3H2), 2.0 (2H, d, J = 7.5 Hz, CH2),
2.5 (2H, t, J = 7.5, C4H2), 3.4 (2H, t, J = 7.5, C2H2), 4.2 (1H, s,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

H. A. K. Abd El-Aal, A. A. Khalaf, and A. M. A. El-Khawaga
Vol 000
OH exchangeable with D2O), 4.5 (H, m, CH), and 6.9–7.6 (9H, m,
Ar–H). Anal. Calcd for C20H25NO (295): C, 81.35; H, 8.47; N,
4.74. Found: C, 81.7; H, 8.3; N, 4.38.
1-Ethyl-3,3-dimethyl-1-phenyl-2,3,6,7-tetrahydro-1H,5H-
pyrido[3,2,1-ij]quinoline (8e). This product was isolated as
white solid in yields indicated earlier, mp 76ꢀC (benzene/PE
60–80ꢀC); IR (KBr) nmax 3070, 2980, 1600, 1550, 1455,
Cyclialkylation procedures.
The procedures described
1
1442, 1320, 743 cmÀ1; H NMR (400 MHz, CDCl3, ppm), d 0.9
earlier for cyclialkylations of arylalkanols with AlCl3/CH3NO2
[23] and PPA [26] were essentially followed. The conditions and
yields are shown in Tables 2 and 3, whereas the physical constants
and spectral data of the products 8a–i are given in the following.
1,1,3,3-Tetramethyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]
quinoline (8a). This product was isolated as white-yellow crystals
in yields indicated earlier, mp 82ꢀC (benzene); IR (KBr) nmax
(3H, t, J = 9 Hz, CH3), 1.21 (6H, s, 2CH3), 1.8 (2H, m, C3H2), 2.0
(2H, m, CH2), 1.9–2.2 (2H, m, CH2), 2.5 (2H, t, J = 7.5, C4H2),
3.35 (2H, t, J = 7.5 Hz, C2H2), and 7.0–7.6 (8H, m, Ar–H);
MS (EI, 70 eV) m/z (%), 305 (M+, 12.4), 304 80.2), 290
(M+ÀCH3, 75.2), 276 (M+ÀCH3CH2,100), 275 (45.3), 246
(M+À2CH3ÀC2H5, 38.4), 228 (18.3), 213 (15.3), 198 (26.2),
199 (5.7), 169 (14.3), 151 (2.6), 132 (14.2), 90 (2.8), 77 (4.2), 66
(1.8). Anal. Calcd for C22H27N (305): C, 86.55; H, 8.85; N, 4.6.
Found: C, 86.75; H, 8.55; N, 4.82.
1
3060, 2980, 1600, 1560, 1480, 1450, 1420, 1330, 1060 cmÀ1; H
NMR (400 MHz, CDCl3, ppm), d 1.25 (6H, s, 2CH3), 1.5
(6H, 2s, 2CH3), 1.6 (2H, s, CH2), 1.8 (2H, m, C3H2), 2.4 (2H, t,
J = 7.5, C4H2), 3.3 (2H, t, J = 7.5 Hz, C2H2), and 6.7–7.5
(3H, m, Ar–H); MS (EI, 70 eV) m/z (%), 229 (M+, 8.5), 214
(M+ÀCH3, 100), 199 (65.8), 184 (M+À2CH3, 22.8), 165 (25.3),
168 (44.3), 151 (5.4), 132 (9.5), 109 (6.5), 90 (3.3), 78 (5.4), 77
(6.5), 66 (2.2). Anal. Calcd for C16H23N (229): C, 83.8; H, 10.0;
N, 6.1. Found: C, 84.2; H, 9.75; N, 5.88.
1,3,3-Trimethyl-1-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido
[3,2,1-ij]quinoline (8f).
This product was isolated as pale
yellow crystals in yields indicated earlier, mp 64ꢀC (benzene/
PE 60–80ꢀC); IR (KBr) nmax 3085, 2990, 1605, 1560, 1455,
1440, 1330, 745 cmÀ1 1H NMR (400 MHz, CDCl3, ppm),
;
d 1.21 (6H, s, 2CH3), 1.65 (3H, s, CH3), 1.8 (2H, m, C3H2),
1.9–2.1 (2H, m, CH2), 2.5 (2H, t, J = 7.5, C4H2), 3.35 (2H, t,
J = 7.5 Hz, C2H2), and 6.9–7.4 (8H, m, Ar–H); MS (EI, 70 eV)
m/z (%), 291 (M+, 13.5), 290 (66.8), 276 (M+ÀCH3, 72.3), 261
(M+À2CH3, 100), 245 (M+À3CH3ÀH, 49.0), 214 (11.3), 199
(12.6), 169 (24.4), 151 (4.6), 132 (15.4), 91 (4.3), 78 (5.3).
Anal. Calcd for C21H25N (291): C, 86.59; H, 8.59; N, 4.8.
Found: C, 86.82; H, 8.38; N, 5.2.
1,1-Diethyl-3,3-dimethyl-2,3,6,7-tetrahydro-1H,5H-pyrido
[3,2,1-ij]quinoline (8b). This product was isolated as brownish
viscous oil in yields indicated earlier, n2D5 1.615; IR (film) nmax
1
3070, 2995, 1615, 1550, 1450, 1410, 1330, 745 cmÀ1; H NMR
(400MHz, CDCl3, ppm), d 0.95 (6H, t, J = 9 Hz, 2CH3), 1.2
(6H, s, 2CH3), 1.5 (4H, t, J = 9 Hz, 2CH2), 1.7 (2H, s, CH2), 1.8
(2H, m, C3H2), 2.5 (2H, t, J = 7.5, C4H2), 3.4 (2H, t, J = 7.5 Hz,
C2H2), and 6.9–7.6 (3H, m, Ar–H); MS (EI, 70eV) m/z (%),
257 (M+, 6.8), 241 (34), 242 (M+ÀCH3, 77.4), 228
(M+ÀCH3CH2,100), 213 (M+ÀCH3ÀCH3CH2, 83.8), 199 (46.5),
185 (25.5), 173 (26.4), 169 (15.3), 151 (25.5), 132 (13.6), 109
(10.3), 91 (3.4), 78 (2.4), 78 (6.1), 77 (3.7), 67 (2.2). Anal. Calcd
for C18H27N (257): C, 84.0; H, 10.5; N, 5.44. Found: C, 84.32; H,
9.82; N, 5.5.
1,3,3-Trimethyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]
quinoline (8g). This product was isolated as white solid in yields
indicated earlier, mp 52ꢀC (PE 60–80ꢀC); IR (KBr) nmax 3080,
2983, 1600, 1553, 1450, 1440, 1325, 740 cmÀ1 1H NMR
;
(400 MHz, CDCl3, ppm), d 1.21 (6H, s, 2CH3), 1.32 (3H, m,
J = 6 Hz, CH3), 1.6–1.8 (2H, m, CH2), 1.86 (2H, m, C3H2), 2.5
(2H, t, J = 7.5, C4H2), 2.86 (1H, m, CH), 3.4 (2H, t, J = 7.5 Hz,
C2H2), and 6.8–7.4 (3H, m, Ar–H); MS (EI, 70 eV) m/z (%),
215 (M+, 100), 214 (82), 200 (M+ÀCH3, 75.4),185 (66.2), 170
(M+À3CH3, 35.8), 169 (21.3), 158 (14.3), 132 (21.3), 91 (3.3),
77 (3.6). Anal. Calcd for C15H21N (215): C, 83.7; H, 9.76; N,
6.5. Found: C, 83.5; H, 10.12; N, 6.47.
3,3-Dimethyl-1,1-diphenyl-2,3,6,7-tetrahydro-1H,5H-pyrido
[3,2,1-ij]quinoline (8c).
This product was isolated as white-
yellow solid in yields indicated earlier, mp 92ꢀC (benzene); IR
(KBr) nmax 3055, 2974, 1605, 1570, 1465, 1440, 1420, 1335,
1060 cmÀ1 1H NMR (400 MHz, CDCl3, ppm), d 1.2 (6H, s,
;
1-Ethyl-3,3-dimethyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]
quinoline (8h). This product was isolated as reddish viscous oil in
2CH3), 1.8 (2H, m, C3H2), 2.2 (2H, s, CH2), 2.6 (2H, t, J = 7.5,
C4H2), 3.45 (2H, t, J = 7.5 Hz, C2H2), and 6.8–7.4 (3H, m, Ar–
H); MS (EI, 70 eV) m/z (%), 353 (M+, 17.2), 352 (M+ÀH,
82.5), 338 (M+ÀCH3, 100), 323 (13.8), 246 (M+À2CH3ÀPh,
45.8), 245 (19.3), 184 (14.7), 178 (11.2), 169 (62.5), 155 (7.6),
132 (18.0), 90 (14.3), 78 (7.5), 77 (6.3), 66 (2.3). Anal. Calcd
for C26H27N (353): C, 88.38; H, 7.64; N, 3.96. Found: C, 88.5;
H, 7.33; N, 4.2.
yields indicated earlier, n2D5 1.592; IR (film) IR (film) nmax 3055,
2986, 1600, 1550, 1445, 1450, 1330, 744 cmÀ1 1H NMR
;
(400 MHz, CDCl3, ppm), d 0.85 (3H, t, J=9Hz, CH3), 1.2
(6H, s, 2CH3), 1.56 (2H, m, CH2), 1.62–1.82 (2H, m, CH2), 1.86
(2H, m, C3H2), 2.5 (2H, t, J=7.5, C4H2), 2.72 (1H, m, CH),
3.32 (2H, t, J=7.5Hz, C2H2), and 7.2–7.5 (3H, m, Ar–H); MS
(EI, 70 eV) m/z (%), 229 (M+, 16.2), 228 (M+ÀH, 100), 214
((M+ÀCH3, 74.6), 200 (M+ÀCH3ÀC2H5, 32.2), 199 (18.4), 185
(36.4), 190 (3.7), 170 (4.7), 169 (12.4), 166 (11.3), 155 (5.7), 132
(10.2), 90 (4.3), 77 (2.3). Anal. Calcd for C16H23N (229): C, 83.84;
H, 10.0; N, 6.1. Found: C, 83.85; H, 10.2; N, 5.82.
1-Ethyl-1,3,3-trimethyl-2,3,6,7-tetrahydro-1H,5H-pyrido
[3,2,1-ij]quinoline (8d).
This product was isolated as
white crystals in yields indicated earlier, mp 68ꢀC (benzene/PE
60–80ꢀC); IR (KBr) nmax 3060, 2985, 1615, 1580, 1460, 1440,
1335, 1050 cmÀ1 1H NMR (400MHz, CDCl3, ppm), d 0.95
;
(3H, t, J =9 Hz, CH3), 1.2 (6H, s, 2CH3), 1.4 (3H, s, CH3), 1.57
(2H, m, CH2), 1.61–1.83 (2H, m, CH2), 1.85 (2H, m, C3H2),
2.59 (2H, t, J = 7.5, C4H2), 3.43 (2H, t, J = 7.5 Hz, C2H2), and
7.1–7.5 (3H, m, Ar–H); MS (EI, 70 eV) m/z (%), 243 (M+,
14.2), 242 (M+-H, 100), 228 (M+ÀCH3, 92.5), 214 (38.5), 213
(66.8), 191 (4.7), 184 (22.5), 178 (5.4), 168 (13.3), 150 (2.6),
132 (11.8), 109 (4.3), 91 (4.3), 78 (3.1). Anal. Calcd for
C17H25N (243): C, 83.95; H, 10.28; N, 5.76. Found: C, 83.9; H,
10.6; N, 5.95.
3,3-Dimethyl-1-phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido
[3,2,1-ij]quinoline (8i). This product was isolated as white
needless in yields indicated earlier, mp 56ꢀC (hexane); IR (KBr)
1
nmax 3074, 2970, 1615, 1470, 1450, 1335, 745 cmÀ1; H NMR
(400 MHz, CDCl3, ppm), d 1.2 (6H, s, 2CH3), 1.82 (2H, m,
C3H2), 1.96–2.2 (2H, m, CH2), 2.52 (2H, t, J = 7.5, C4H2),
3.35 (2H, t, J = 7.5 Hz, C2H2), 3.9 (1H, m, CH), and 7.2–7.6
(8H, m, Ar–H); MS (EI, 70 eV) m/z (%), 277 (M+, 9.3), 261
(M+ÀCH3ÀH, 100), 247 (55.8), 246 (M+À2CH3ÀH, 34.5), 200
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2013 Friedel–Crafts Cyclialkylations, Ring Closure, Carbocation Chemistry, Grignard Reagents
(12.3), 185 (26.4), 190 (4.7), 170 (13.2), 167 (6.1), 158 (6.6), 131
(2.6), 90 (4.1), 78 (3.5). Anal. Calcd for C20H23N (277): C, 86.64;
H, 8.3; N, 5.05. Found: C, 86.7; H, 8.1; N, 5.2.
Chem. 2009, 5162; [b] Koerner, T. A. W. Jr.; Prestegard, J. H.; Demou,
P. C.; Yu, R. K. Biochemistry 1983, 22, 2676; [c] Poupot, M.; Griffe, L.;
Marchand, P.; Maraval, A.; Rolland, O.; Martinet, L.; L’Faqihi-Olive, F.
E.; Turrin, C. O.; Caminade, A. M.; Fournié, J. J.; Majoral, J. P.; Poupot,
R. FASEB J 2006, 20, 2339.
Acknowledgments. The authors are grateful for the financial
support and all the facilities received while performing and writing
this work by the Chemistry Department, Faculty of Science, Assiut
University, Egypt.
[17] Vejdelek, Z.; Protiva, M. Collect. Czech. Chem. Commun.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet