Pd/C-mediated dual C-C bond forming reaction in water: Synthesis of 2,4-dialkynylquinoline

Article abstract of DOI:10.1590/S0103-50532010000900012

Pd/C facilitated dual C-C bond forming reaction between 2,4-diiodoquinoline and terminal alkynes in water providing a practical and one-step synthesis of 2,4-dialkynylquinolines. A number of related quinoline derivatives were prepared in good to excellent yields using this water-based methodology. The use of other palladium catalysts and solvents was examined and the mechanism of the reaction has been discussed.

Full text of DOI:10.1590/S0103-50532010000900012

J. Braz. Chem. Soc., Vol. 21, No. 9, 1681-1687, 2010.
Printed in Brazil - ©2010 Sociedade Brasileira de Química
0103 - 5053 $6.00+0.00
Pd/C-Mediated Dual C-C Bond Forming Reaction in Water: Synthesis of
2,4-Dialkynylquinoline
Ellanki A. Reddy,a,b Aminul Islam,a K. Mukkanti,b Bolla K. Venua and Manojit Pal*,c
aDr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur, Hyderabad,
500049 Andhra Pradesh, India
bChemistry Division, Institute of Science and Technology, JNT University, Kukutpally, Hyderabad,
500072 Andhra Pradesh, India
cNew Drug Discovery, R&D Center, Matrix Laboratories Ltd., Anrich Industrial Estate, Bollaram,
Jinnaram Mandal, Medak District, 502 325 Andra Pradesh, India
Pd/C catalisa a reação de acoplamento entre 2,4-diiodoquinolina e alquinos terminais em
água, proporcionando uma síntese prática, de uma etapa, de 2,4-dialquinilquinolinas. Uma série de
derivados de quinolinas relacionadas foi preparada em bons a excelentes rendimentos, usando esta
metodologia baseada em água. O uso de outros catalisadores de paládio e solventes foi examinado
e o mecanismo de reação discutido.
Pd/C facilitated dual C-C bond forming reaction between 2,4-diiodoquinoline and terminal
alkynes in water providing a practical and one-step synthesis of 2,4-dialkynylquinolines.A number
of related quinoline derivatives were prepared in good to excellent yields using this water-based
methodology. The use of other palladium catalysts and solvents was examined and the mechanism
of the reaction has been discussed.
Keywords: quinoline, palladium, charcoal, copper, C-C bond, alkyne
Introduction
Sonogashira or modified conditions has been studied
earlier (Scheme 1). For example 2,4-dibromoquinoline
derivative provided the 2-alkynylated product A
(Scheme 1) selectively when treated with a terminal
alkyne.7 Similarly, 2,4-dichloroquinoline afforded a
2-alkynyl derivative when coupled with a terminal alkyne
under Pd/C-Cu catalysis in water.8 Coupling of 2-bromo-
4-iodoquinoline derivative with a terminal alkyne in
the presence of (PPh3)2PdCl2-CuI though provided a
2,4-dialkynylated product B in 17% yield (Scheme 1)
the 4-alkynyl derivative however was isolated as a major
product in this case.7 Nevertheless, to the best of our
knowledge this is the only example known so far for the
preparation of 2,4-dialkynylquinoline (B) and no detailed
study on this reaction has been reported. Therefore, the
development of a general method leading to compound
B (Z = H) exclusively was required. Herein, we report
a direct and practical method for the preparation of
2,4-dialkynylquinoline under Pd/C-Cu catalysis in water.
To the best of our knowledge this is the first example of
Pd/C-mediated dual C-C bond forming reaction in water.
The quinoline core (p-electron deficient heterocycle)
being one of the privileged structures for the design and
development of potential new drugs have found wide
applications in pharmaceutical research.1-4 Though a
wide variety of quinoline derivatives have been reported
earlier a thorough literature search however revealed that
2,4-dialkynylquinolines surprisingly remained unexplored
so far. As part of our ongoing program on building of
quinoline-based library of small molecules we were in need
of a wide range of 2,4-dialkynylquinolines and a convenient
synthetic methodology to access these derivatives.
The palladium mediated alkynylation of aryl/
heteroaryl halides under Sonogashira condition5 has
become a highly effective tool for the introduction of an
alkynyl moiety to aryl or heteroaryl ring.6 The reactivity of
2,4-dihaloquinolines towards alkynylation reaction under
*e-mail: manojitpal@rediffmail.com

1682
Pd/C-Mediated Dual C-C Bond Forming Reaction in Water
J. Braz. Chem. Soc.
R
N
X
Z
X
N
Z
Ref. 7
Ref. 7, 8
N
+
Y
Z
X= I; Y = Br
Z = CHO
X= Y =
Br or Cl
R
R
17% (minor)
R
A
B
Scheme 1. Alkynylation of 2,4-dihaloquinolines under Sonogashira or modified conditions.
Results and Discussion
product 3a albeit in inferior yield (Entries 4-6, Table 1).
While the use of other solvents, e.g. 1,4-dioxane, DMF
and EtOH provided 3a in good yield (Entries 7-9, Table 1),
water was however the solvent of our choice.
Initially, we attempted to prepare the 2,4-dialkynyl-
quinoline from its 2,4-dichloro precursor via a two-step
method. Thus 2-alkynyl quinoline prepared via earlier
method8,9 was treated with a terminal alkyne in the presence
of a number of palladium catalysts e.g. (PPh3)2PdCl2,
Pd(OAc)2 or Pd/C. However, none of these reactions
provided the desired product in good yields. It is well
known that the chloro group is less reactive than iodo group
towards palladium catalysts under normal Sonogashira
conditions. Hence we decided to use a 2,4-diiodoquinoline
(2) for our synthesis which could be readily obtained from
the corresponding 2,4-dichloro analogue (1) as shown in
Scheme 2.10
Having prepared the 2,4-diiodoquinoline (2) we
initially coupled it with 1-octyne in the presence of various
palladium catalysts (Table 1). Because of our earlier success
in the use of 10% Pd/C-PPh3-CuI as a catalyst system8 in
water we decided to conduct the reaction of 2 (1.0 equiv.)
with 1-octyne (3.0 equiv.) in the presence of same catalysts
in water using Et3N as a base. The reaction proceeded
smoothly affording the desired product 3a in 85% yield
(Entry 1, Table 1) and no monoalkynylated or other side
product was detected in the reaction mixture. The reaction
was carried out for 10 h and an increase of reaction time
did not improve the product yield (Entry 2, Table 1). The
product formation was almost suppressed in the absence
of PPh3 (Entry 3, Table 1). The use of other catalysts, e.g.
PdCl2(PPh3)2, Pd(PPh3)4 or Pd(OAc)2-PPh3 afforded the
We then decided to explore the scope and generality of
this Pd/C mediated dual C-C bond forming reaction on a
quinoline ring in water. Thus a variety of terminal alkynes
were reacted with 2 in the presence of 10% Pd/C, PPh3
and CuI in water (Scheme 2). The results of this study
are summarized in Table 2. Terminal alkynes containing a
range of groups in their side chain such as alkyl (Entries
1-3, Table 2), aryl (Entries 4-6, Table 2), cyano (Entry 7,
Table 2) or hydroxyl alkyl moieties (Entries 8-10, Table 2)
were reacted with the diiodo compound 2 and all these
groups were well tolerated under the condition employed.
The reaction proceeded well in water in all these cases
affording the corresponding 2,4-dialkynylquinolines (3a-j)
in good to excellent yields. All the products isolated
were well characterized by spectral (NMR, IR and MS)
and analytical data. The presence of alkyne moieties was
indicatedbyasharpIRabsorptionshownbyallthequinoline
derivatives synthesized in the region 2200-2230 cm-1.
This was further supported by the appearance of signals
corresponding to the sp-carbons at d 70-96 in 13C NMR
spectra of compounds 3a-j.
Mechanistically, the reaction may appeared to proceed
via a simultaneous C-C bond forming reaction at C-2 and
C-4 of the quinoline ring as neither C-2 nor C-4 mono
alkynyl derivative was isolated as a side product from
the reaction mixture. However, such a reaction would
R
I
Cl
N
NaI,
R
acetyl chloride
Pd/C, Et3N
N
CH3CN
reflux
N
I
PPh3, CuI
Water
Cl
R
2
3
80-85 °C
1
Scheme 2. Preparation of 2,4-diiodoquinoline (2) and its coupling with terminal alkynes under Pd/C-Cu catalysis in water.

Vol. 21, No. 9, 2010
Reddy et al.
1683
Table 1. Effect of reaction conditions on the Pd-catalyzed coupling of
2,4-diiodoquinoline (2) with 1-octynea
Pd(0) generated11 in situ towards Csp2-I bond the organo-
palladium intermediate (X) formed as a result of oxidative
addition of Pd(0) to 2,4-diiodoquinoline would contain one
Csp2-Pd-I moiety initially (Scheme 3). It is likely that the
oxidative addition of Pd(0) would take place initially at C-2
of the quinoline ring8,9 due to the higher reactivity of iodo
group at this position. The copper acetylide generated from
the terminal alkyne and CuI would undergo trans metalation
with the organo-palladium species and subsequent reductive
elimination of Pd(0) would produce the monoalkynyl
quinoline intermediate (Y). A further alkynylation of this
intermediate provided the dialkynyl product 3. Though the
nature of catalytic species generated in situ is not known
when the reaction was performed in the absence of PPh3
affording the desired product in 15% yield (Entry 3, Table 1),
Pd/C-mediated Sonogashira coupling of aryl iodides with
terminal alkynes in the absence of ligand has been reported
earlier.12 Nevertheless, a similar dialkynylation reaction
was observed when 2,4-dichloroquinazoline was reacted
with a terminal alkyne in the presence of (PPh3)2PdCl2, CuI
and Et3N for 20 h.13 Notably, 2,4-dichloroquinoline did not
participate in a dual dialkynylation reaction due to the lack
of reactivity of C-4 chloro group.8,9 We overcame this issue
in the present reaction by opting for a more reactive iodo
group over chloro on the quinoline ring. Thus judicious
selection of quinoline halide can help in affording a product
of particular choice.
R
I
R
Pd cat, CuI
N
N
I
solvent, heat
R
2
3a
(R = n-hexyl)
Entry
Catalyst
Solvent; time
Yield/(%)b
85c
1
2
3
4
5
6
7
8
9
10% Pd/C-PPh3
10% Pd/C-PPh3
10% Pd/C
H2O; 10 h
H2O; 15 h
80c
H2O; 10 h
15
PdCl2(PPh3)2
Pd(PPh3)4
H2O; 10 h
62
H2O; 10 h
55
Pd(OAc)2-PPh3
10% Pd/C-PPh3
10% Pd/C-PPh3
10% Pd/C-PPh3
H2O; 10 h
58c
1,4-Dioxane; 15 h
DMF; 15 h
EtOH; 15 h
79c
81c
84c
aReaction conditions: 2 (1.0 equiv.), terminal alkyne (3.0 equiv.), Pd-
catalyst (0.05 equiv.) or Pd/C (0.26 equiv.), CuI (0.05 equiv.), Et3N (3.0
b
c
equiv.) in a solvent at 80-85 °C under N2. Isolated yield. PPh3 used:
0.20 equiv.
mechanistically be difficult as it would involve third-order
kinetics in the Pd-mediated C-I oxidative addition and/or
transmetallation process. Moreover, because of the use of
elevated reaction temperatures and the fact that theoretically,
the second alkynylation could be kinetically more facile
than the first one; the real step-by-step process was
practically not observed during the reaction. Nevertheless,
because of high reactivity of the actual catalytic species
Conclusions
In conclusion, we have described a practical and one-step
synthesisof2,4-dialkynylquinolinefrom2,4-diiodoquinoline
and commercially available terminal alkynes under Pd/C-Cu
R
Pd/C
CuI
Et3N
PPh3
CuI
Et3N
I
R
I
I
Cu
PdII
R
Pdo
2
N
N
PdII
N
I
Pd0
R
Y
CuI
X
Pdo
R
Pd0
I
PdII
N
PdII
N
R
R
Cu
R
3
R
CuI
Scheme 3. Proposed mechanism of Pd/C-Cu mediated dual C-C bond forming reaction between 2,4-diiodoquinoline (2) and terminal alkynes in water.

1684
Pd/C-Mediated Dual C-C Bond Forming Reaction in Water
J. Braz. Chem. Soc.
Table 2. Preparation of 2,4-dialkynylquinoline (3) under Pd/C-Cu catalysis in watera
Entry
1.
Alkynes time/h
Products (3)
Yieldb/(%)
Entry
6.
Alkynes time/h
Products (3)
Yieldb/(%)
10
85
8
87
N
N
3a
3f
NC
CN
2.
10
82
NC
7.
8.
9.
12
10
12
80
N
N
3b
3g
OH
HO
OH
N
92
3.
4.
5.
10
88
85
90
N
3h
3c
HO
OH
OH
80
7
N
N
3i
3d
OH
OH
10.
12
78
N
6
OH
N
3j
3e
aAll the reactions were carried out using 2,4-diiodoquinoline (1.0 equiv.), alkyne (3.0 equiv.), 10% Pd/C (0.26 equiv.), CuI (0.05 equiv.), PPh3 (0.20 equiv.)
and Et3N (3.0 equiv.) in water (5.0 mL). bIsolated yield.
catalysis in water. The reaction proceeds via dual C-C bond
forming reaction without generating any side products. All
the desired products were isolated in excellent yields. The
reaction does not involve the use of expensive catalysts or
solvents. Sincetheproductnaturecanbealteredconveniently
by changing the halide moiety of the quinoline ring hence
overall, the present process would be complimentary to the
methods previously reported for alkynylation of quinolines.
Due to the operational simplicity and easy availability of
starting materials we believe that this process would find
wide usage in the preparation of quinoline-based libraries
of pharmaceutical interest.
(60 F254), visualizing with ultraviolet light or iodine
spray. Flash chromatography was performed on silica gel
(60-120 mesh) using distilled petroleum ether and ethyl
acetate. 1H and 13C NMR spectra were determined in CDCl3
solution using 400 and 50 MHz spectrometers, respectively.
Proton chemical shifts (d) are relative to tetramethylsilane
(TMS, d 0.0) as internal standard and expressed in parts
per million. Spin multiplicities are given as s (singlet), d
(doublet), t (triplet), and m (multiplet) as well as b (broad).
Coupling constants (J) are given in hertz. Infrared spectra
were recorded on a FTIR spectrometer. Melting points
were determined by using thermal analysis and differential
scanning calorimetry (DSC) was generated with the help
of DSC-60A detector. MS spectra were obtained on a
mass spectrometer. Chromatographic (HPLC) purity was
determined by using area normalization method and the
condition specified in each case: column, mobile phase
(range used), flow rate, detection wavelength, and retention
times. Elemental analyses were performed using C,H,N
Experimental
General methods
Unless stated otherwise, reactions were monitored
by thin layer chromatography (TLC) on silica gel plates

Vol. 21, No. 9, 2010
Reddy et al.
1685
elemental analyzer.All the reagents used are commercially
available.
125.7 (C arom), 92.3 (2C, Csp), 80.7 (Csp), 77.6 (Csp), 37.0
(CH2), 36.6 (CH2), 34.3 (CH2), 32.7 (CH2), 31.9 (CH2), 30.3
(CH2), 29.3 (CH2), 28.4 (CH2), 27.9 (CH2), 22.6 (CH2),
19.5 (CH3), 14.3 (CH3); HRMS (ESI): Calc. for C25H32N
(M+H)+ 346.2535; found 346.2542; Elemental analysis
found: C, 86.85; H, 9.07; N, 4.14 C25H31N; Requires C,
86.90, H, 9.04, N, 4.05.
Preparation of 2,4-diiodoquinoline, 214
To a cold solution (5-10 °C) of 2,4-dichloroquinoline
(5.0 g, 25.3 mmol, 1.0 equiv.) in acetonitrile (50 mL) was
added acetyl chloride (6.0 g, 76.4 mmol, 3.0 equiv.) and
sodium iodide (30.0 g, 200.1 mmol, 8.0 equiv.). The mixture
was stirred at 5-10 °C for 30 min and slowly heated to
reflux. The mixture was stirred at refluxing temperature for
6 h under nitrogen atmosphere and the progress of reaction
was monitored by TLC. After completion of the reaction
the mixture was cooled to room temperature and diluted
with 10% Na2S2O3 to adjust the pH to 8.0-8.5. The solid
precipitated out was filtered and was purified by column
chromatography to give the desired product as a light brown
solid (7.2 g, yield 75%); mp 89-90 °C (lit14 90 °C);1H NMR
(CDCl3, 400 MHz) d 8.30 (s, 1H,Ar-H), 7.98-7.95 (m, 2H,
Ar-H), 7.75-7.71 (m, 1H, Ar-H), 7.65-7.61 (m, 1H,Ar-H);
m/z (ES Mass) 382 (M+1, 100%).
2,4-di(Hept-1-ynyl)quinoline, 3b
Light brown liquid; Rf (20% ethyl acetate/n-hexane)
0.26; 1H NMR (CDCl3, 400 MHz) d 8.2 (d, J 8.1 Hz, 1H,
CH arom), 8.03 (d, J 8.5 Hz, 1H, CH arom), 7.71-7.67 (m,
1H, CH arom), 7.56-7.52 (m, 1H, CH arom), 7.50 (s, 1H,
CH arom), 2.57 (t, J 7.0 Hz, 2H, CH2), 2.48 (t, J 7.3 Hz,
2H, CH2), 1.75-1.65 (m, 4H, CH2), 1.50-1.42 (m, 8H, CH2),
0.97-0.86 (m, 6H, CH3); IR (neat) νmax/cm-1: 2929, 2227
(-C≡ C-), 1581, 1357; m/z (ES Mass) 318 (M+1,100%);
13C NMR (CDCl3, 50 MHz), 147.8 (C arom), 143.4 (C
arom), 130.7 (C arom), 129.8 (2C, C arom), 126.8 (3C, C
arom), 125.5 (C arom), 92.1 (2C, Csp), 80.6 (Csp), 77.6
(Csp), 31.8 (2C, CH2), 29.6 (2C, CH2), 28.1 (CH2), 27.9
(CH2), 22.6 (2C, CH3), 19.6, 14.0; HRMS (ESI): Calc. for
C23H28N (M+H)+ 318.2222; found 318.2231; Elemental
analysis found: C, 87.11; H, 8.29; N, 4.24 C23H27N;
Requires C, 87.02, H, 8.57, N, 4.41.
General procedure for the preparation of dialkynyl
quinolines, 3
A mixture of 2,4-diiodoquinoline (2), 10% Pd/C
(0.26 equiv.), CuI (0.05 equiv.), PPh3 (0.20 equiv.) and
triethylamine (3.0 equiv.) in water (5.0 mL) was stirred
at room temperature for 30 min. To this mixture was
added terminal alkyne (3.0 equiv.) with stirring. The
mixture was then stirred at 80-85 °C for time mentioned
in Table 1. After completion of the reaction (indicate by
TLC) the reaction mass was cooled to room temperature,
filtered through celite and extracted with ethyl acetate
(2 × 30 mL). The organic layers were collected, washed
with water (3 × 30 mL), dried over anhydrous Na2SO4, and
concentrated. The crude residue obtained was purified by
column chromatography on silica gel, using light petroleum
(60-80 °C)-ethyl acetate to afford the desired product 3.
2,4-di(Hex-1-ynyl)quinoline, 3c
Light brown liquid; Rf (20% ethyl acetate/n-hexane)
0.22; 1H NMR (CDCl3, 400 MHz) d 8.20 (d, J 8.1 Hz, 1H,
CH arom), 8.05 (d, J 8.5 Hz, 1H, CH arom), 7.71-7.67 (m,
1H, CH arom), 7.57-7.52 (m, 1H, CH arom), 7.50 (s, 1H,
CH arom), 2.58 (t, J 7.1 Hz, 2H, CH2), 2.49 (t, J 7.1 Hz,
2H, CH2), 1.69-1.48 (m, 8H, CH2), 0.99-0.89 (m, 6H, CH3);
IR (neat) νmax/cm-1: 2927, 2227 (-C≡ C-), 1581, 1357; m/z
(ES Mass) 290 (M+1, 100%); 13C NMR (CDCl3, 50 MHz)
147.8 (C arom), 143.5 (C arom), 130.7 (C arom), 129.8
(C arom), 129.5 (C arom), 126.9 (3C, C arom), 125.6 (C
arom), 92.1 (2C, Csp), 80.7 (Csp), 77.6 (Csp), 34.1 (CH2),
33.9 (CH2), 31.8 (CH2), 30.5 (CH2), 29.4 (CH2), 27.1 (CH2),
19.4 (CH3), 14.0 (CH3); HRMS (ESI): Calc. for C21H24N
(M+H)+ 290.1909; found 290.1895; Elemental analysis
found: C, 87.30; H, 8.00; N, 4.74 C21H23N; Requires C,
87.15, H, 8.01, N, 4.84.
2,4-di(Oct-1-ynyl)quinoline, 3a
Light brown liquid; Rf (20% ethyl acetate/n-hexane)
0.18; 1H NMR (CDCl3, 400 MHz) d 8.19 (d, J 8.3 Hz, 1H,
CH arom), 8.04 (d, J 8.2 Hz, 1H, CH arom), 7.71-7.67 (m,
1H, CH arom), 7.56-7.52 (m, 1H, CH arom), 7.50 (s, 1H),
2.57 (t, J 7.0 Hz, 2H, CH2), 2.48 (t, J 7.3 Hz, 2H, CH2), 1.74-
1.28 (m, 4H, CH2), 1.25-1.12 (m, 12H, CH2), 0.99-0.82 (m,
6H, CH3); IR (neat) νmax/cm-1: 2926, 2227 (-C≡ C-), 1581,
1463; m/z (ES Mass) 346 (M+1, 100%); 13CNMR (CDCl3,
50 MHz) 147.8 (C arom), 143.5 (C arom), 130.8 (C arom),
129.9 (2C, C arom), 128.3 (2C, C arom), 126.9 (C arom),
2,4-bis(Phenylethynyl)quinoline, 3d
Pale yellow solid; mp 89-95 °C; Rf (20% ethyl acetate/n-
1
hexane) 0.20; H NMR (CDCl3, 400 MHz) d 8.35 (d, J
8.5 Hz, 1H, CH arom), 8.16 (d, J 8.3 Hz, 1H, CH arom),
7.79-7.74 (m, 2H, CH arom), 7.69-7.61 (m, 5H, CH arom),
7.45-7.35 (m, 6H, CH arom); IR (neat) νmax/cm-1: 2926,
2214 (-C≡ C-), 1579, 1369; m/z (ES Mass) 330 (M+1,

1686
Pd/C-Mediated Dual C-C Bond Forming Reaction in Water
J. Braz. Chem. Soc.
100%); 13C NMR (CDCl3, 50 MHz) 147.9 (C arom), 142.9
(C arom), 132.1 (4C, (C arom), 131.8 (2C, C arom), 130.3
(2C, C arom), 129.5 (3C, C arom), 128.4 (2C, C arom),
127.5 (2C, C arom), 126.6 (2C, C arom), 125.6 (C arom),
121.9 (C arom), 90.3 (2C, Csp), 88.8 (2C, Csp); HRMS
(ESI): calc. for C25H16N (M+H)+ 330.1439; found 330.1459;
Elemental analysis found: C, 91.30; H, 4.55; N, 4.21
C25H15N; Requires C, 91.16, H, 4.59, N, 4.25.
ν
max/cm-1: 2927, 2247, 2229 (-C≡ C-), 1581, 1359; m/z (ES
Mass) 312 (M+1, 100%); 13C NMR (CDCl3, 50 MHz) 147.6
(C arom), 142.5 (C arom), 130.1 (C arom), 129.9 (2C,
C arom), 128.5 (C arom), 127.4 (C arom), 126.3 (C arom),
125.3 (C arom), 118.6 (2C, C arom), 88.6 (2C, Csp), 81.9
(2C, Csp), 38.4 (CH2), 33.8 (CH2), 31.7 (CH2), 30.1 (CH2),
28.7 (CH2), 24.6 (CH2); HRMS (ESI): Calc. for C21H18N3
(M+H)+ 312.1501; found 312.1493; Elemental analysis
found: C, 81.21; H, 5.49; N, 13.28 C21H17N3; Requires C,
81.00, H, 5.50, N, 13.49.
2,4-bis(p-Tolylethynyl)quinoline, 3e
Pale yellow solid; mp 150-153 °C; Rf (20% ethyl
acetate/n-hexane) 0.24 1H NMR (CDCl3, 400 MHz) d 8.34
(d, J 8.07 Hz, 1H, CH arom) 8.14 (d, J 8.5 Hz, 1H, CH
arom), 7.77 (s, 1H, CH arom), 7.75 (d, J 6.5 Hz, 1H, CH
arom), 7.63-7.55 (m, 4H, CH arom), 7.25-7.18 (m, 5H,
CH arom), 2.41 (s, 3H, CH3), 2.39 (s, 3H, CH3); IR (neat)
1,1’-(Quinoline-2,4-diylbis(ethyne-2,1-diyl)dicyclo-
hexanol, 3h
Yellow solid, mp 154-163°C, Rf (20% ethyl acetate/n-
1
hexane); 0.19 H NMR (CDCl3, 400 MHz) d 8.19 (d, J
8.1 Hz, 1H, CH arom), 8.09 (d, J 8.1 Hz, 1H, CH arom),
7.74-7.70 (m, 1H, CH arom), 7.61-7.59 (m, 1H, CH arom),
7.58 (s, 1H, CH arom), 2.36-2.31 (bs, 2H, OH), 2.14-2.04
(m, 4H), 1.84-1.62 (m, 16H); IR (neat) νmax/cm-1: 3375 (C
arom), 3062, 2929, 2222 (-C≡ C-), 1583; m/z (ES Mass)
374 (M+1, 100%); 13C NMR (CDCl3, 50 MHz) 147.8 (C
arom), 142.6 (C arom), 130.3 (C arom), 129.7 (2C, C arom),
127.6 (2C, C arom), 126.6 (C arom), 125.5 (C arom), 94.3
(2C, Csp), 83.7 (2C, Csp), 39.8 (C-OH), 39.6 (C-OH), 29.7
(3C, CH2), 25.1 (3C, CH2), 23.4 (3C, CH2), 23.2 (CH2);
HRMS (ESI): Calc. for C25H28NO2 (M+H)+ 374.2120; found
374.2115; Elemental analysis found: C, 80.56; H, 7.30;
N, 3.67 C25H27NO2; Requires C, 80.40, H, 7.29, N, 3.75.-
ν
max/cm-1: 2918, 2206 (-C≡ C-), 1577, 1363; m/z (ES Mass)
358 (M+1, 100%); 13C NMR (CDCl3, 50 MHz) 148.13 (C
arom), 143.27 (C arom), 139.4 (2C, C arom), 132.1 (2C,
C arom), 131.8 (2C, C arom), 130.2 (C arom), 129.4 (4C,
C arom), 127.39 (3C, C arom), 126.6 (2C, C arom), 125.7
(C arom), 118.9 (2C, C arom), 90.6 (2C, Csp), 88.5 (2C,
Csp), 21.6 (2C, CH3); HRMS (ESI): calc. for C27H20N
(M+H)+ 358.1596; found 358.1600; Elemental analysis
found: C, 90.83; H, 5.40; N, 3.84 C27H19N; Requires C,
90.72, H, 5.36, N, 3.92.
2,4-bis(4-Phenylbut-1-ynyl)quinoline, 3f
Low melting solid; Rf (20% ethyl acetate/n-hexane)
1
0.25; H NMR (CDCl3, 400 MHz) d 8.04 (d, J 8.2 Hz,
1,1’-(Quinoline-2,4-diyl)dipent-1-yn-3-ol, 3i
1H, CH arom), 7.9 (d, J 8.1 Hz, 1H, CH arom), 7.7-7.68
(m, 1H, CH arom), 7.50-7.48 (m, 1H, CH arom), 7.42 (s,
1H, CH arom), 7.37-7.23 (m, 10H, CH arom), 3.04-2.99
(m, 4H, CH2), 2.91-2.87 (m, 2H, CH2), 2.80-2.76 (m, 2H,
CH2); IR (neat) νmax/cm-1: 2927, 2227 (-C≡ C-), 1581, 1359;
m/z (ES Mass) 386 (M+1, 100%); 13C NMR (CDCl3, 50
MHz) 147.7 (C arom), 143.1 (C arom), 140.2 (2C) (C
arom), 130.0 (4C, C arom), 128.4 (3C, C arom), 127.0
(4C, C arom), 126.4 (4C, (C arom), 125.7 (2C, C arom),
91.2 (2C, Csp), 81.2 (2C, Csp), 34.6 (2C, CH2), 21.5 (2C,
CH2); HRMS (ESI): Calc. for C29H24N (M+H)+ 386.1909;
found 386.1907; Elemental analysis found: C, 90.19; H,
6.00; N, 3.94 C29H23N; Requires C, 90.35, H, 6.01, N, 3.63.
Light brown oil; Rf (30% ethyl acetate/n-hexane) 0.19;
1H NMR (CDCl3, 400 MHz) d 8.16 (d, J 7.6 Hz, 1H, CH
arom), 8.07 (d, J 8.6 Hz, 1H, CH arom), 7.72-7.68 (m, 1H,
CH arom), 7.58-7.56 (m, 1H, CH arom), 7.50 (s, 1H, CH
arom), 3.98-3.90 (m, 4H, CH2), 2.70-2.65 (m, 2H, CH2),
2.65-2.69 (m, 2H, CH2), 2.30-2.05 (bs, 2H, OH), 1.95-
1.85 (m, 4H, CH2); IR (neat) νmax/cm-1: 3352, 3091, 2964,
2225 (-C≡ C-), 1583; m/z (ES Mass) 294 (M+1, 100%); 13C
NMR (CDCl3, 50 MHz) 147.5 (C arom), 142.3 (C arom),
130.6 (2C, C arom), 129.8 (C arom), 127.6 (2C, C arom),
126.6 (C arom), 125.5 (C arom), 91.9 (2C, Csp), 84.0 (2C,
Csp), 64.4 (2C, CH2), 31.9 (CH2), 30.5 (CH2), 29.3 (CH2),
24.8 (CH2); HRMS (ESI): calc. for C19H20NO2 (M+H)+
294.1494; found 294.1480; Elemental analysis found: C,
77.82; H, 6.51; N, 4.70 C19H19NO2; Requires C, 77.79, H,
6.53, N, 4.77.
6,6’-(Quinoline-2,4-diyl)dihex-5-ynenitrile, 3g
Light brown oil; Rf (20% ethyl acetate/n-hexane) 0.19;
1H NMR (CDCl3, 400 MHz) d 8.19 (d, J 7.1 Hz, 1H, CH
arom), 8.05 (d, J 8.1 Hz, 1H, CH arom), 7.75-7.72 (m, 1H,
CH arom), 7.61-7.58 (m, 1H, CH arom), 7.53 (s, 1H, CH
arom), 2.82-2.78 (m, 2H, CH2), 2.71-2.64 (m, 2H, CH2),
2.62-2.59 (m, 4H, CH2), 2.14-2.0 (m, 4H, CH2); IR (neat)
5,5’-(Quinoline-2,4-diyl)dipent-4-yn-1-ol, 3j
Light brown liquid; Rf (30% ethyl acetate/n-hexane)
0.19; 1H NMR (CDCl3, 400 MHz) d 8.17 (d, J 8.1 Hz, 1H,
CH arom), 8.05 (d, J 8.2 Hz, 1H, CH arom), 7.7-7.67 (m,

Vol. 21, No. 9, 2010
Reddy et al.
1687
1H, CH arom), 7.55-7.52 (m, 1H, CH arom), 7.47 (s, 1H,
CH arom), 4.89-4.65 (m, 1H, CH(OH)), 4.65-4.60 (m, 1H,
CH(OH)), 1.98-1.88 (m, 4H, CH2), 1.65-1.60 (bs, 2H, OH),
1.20-1.05 (m, 6H, CH3); IR (neat) νmax/cm-1: 3319 (broad),
2927, 2229 (-C≡ C-), 1583, 1361; m/z (ES Mass) 294 (M+1,
100%); 13C NMR (CDCl3, 50 MHz) 147.5 (C arom), 143.0
(C arom), 130.8 (2C, C arom), 128.7 (C arom), 127.1
(C arom), 126.6 (2C, C arom), 125.6 (C arom), 91.8 (2C,
Csp), 80.8 (2C, Csp), 61.0 (CH), 60.9 (CH), 31.8 (CH2),
30.8 (CH2), 28.8 (CH3), 24.7 (CH3); HRMS (ESI): Calc. for
C19H20NO2 (M+H)+ 294.1494; found 294.1480; Elemental
analysis found: C, 77.53; H, 6.52; N, 4.79 C19H19NO2;
Requires C, 77.79, H, 6.53, N, 4.77.
3. Daines, R. A.; Kingsbury, W. D.; Pendrak, I.; Mallamo, J. P.;
U.S. Patent Application U.S. 6,100,267, 2000.
4. Martínez-Grueiro, M.; Giménez-Pardo, C.; Gómez-Barrio,
A.; Franck, X.; Fournet, A.; Hocquemiller, R.; Figadère, B.;
Casado-Escribano, N.; IL Farmaco 2005, 60, 219 and references
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6. Chinchilla, R.; Nájera, C.; Chem. Rev. 2007, 107, 874; Singh,
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Acknowledgments
7. Comins, D. L.; Nolan, J. M.; Bori, I. D.; Tetrahedron Lett. 2005,
46, 6697.
The authors thank Dr. V. Dahanukar and Mr. A.
Mukherjee for their encouragement and the analytical group
for spectral data. Mr. E.A.R. thanks CPS-DRL, Hyderabad,
India for allowing him to pursue this work as a part of his
Ph.D. program.
8. Reddy, E.A.; Islam, A.; Mukkanti, K.; Bandameedi, V.;
Bhowmik, D. R.; Pal, M.; Beilstein; J. Org. Chem. 2009, 5, 32.
9. Reddy, E.A.; Barange, D. K.; Islam,A.; Mukkanti, K.; Pal, M.;
Tetrahedron 2008, 64, 7143.
10. Chessa, G.; Canovese, L.; Visentin, F.; Santo, C.; Seragila, R.;
Tetrahedron 2005, 61, 1755.
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Submitted: March 12, 2010
Published online: May 20, 2010