Regioselective alkynylation followed by Suzuki coupling of 2,4-dichloroquinoline: Synthesis of 2-alkynyl-4-arylquinolines

Article abstract of DOI:10.3762/bjoc.5.32

A two step synthesis of 2-alkynyl-4-arylquinolines has been accomplished via Pd/C-mediated regioselective C-2 alkynylation of 2,4-dichloroquinoline in water followed by Suzuki coupling at C-4 of the resulting 4-chloro derivative.

Full text of DOI:10.3762/bjoc.5.32

Regioselective alkynylation followed by Suzuki
coupling of 2,4-dichloroquinoline: Synthesis of
2-alkynyl-4-arylquinolines
Ellanki A. Reddy1,2, Aminul Islam1, K. Mukkanti2, Venkanna Bandameedi1,
Dipal R. Bhowmik1 and Manojit Pal*,3
Preliminary Communication
Open Access
Address:
Beilstein Journal of Organic Chemistry 2009, 5, No. 32.
1Dr. Reddy’s Laboratories Limited, Bollaram Road, Miyapur,
Hyderabad 500049, Andhra Pradesh, India, 2Chemistry Division,
Institute of Science and Technology, JNT University, Kukutpally,
Hyderabad 500072, Andhra Pradesh, India and 3New Drug
Discovery, R&D Center, Matrix Laboratories Ltd., Anrich Industrial
Estate, Bollaram, Jinnaram Mandal, Medak District, Andra Pradesh
502 325, India (present address: Institute of Life Science, University
of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra
Pradesh, India)
doi:10.3762/bjoc.5.32
Received: 16 April 2009
Accepted: 19 June 2009
Published: 01 July 2009
Associate Editor: I. Marek
© 2009 Reddy et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
Manojit Pal* - manojitpal@rediffmail.com
* Corresponding author
Keywords:
alkyne; boronic acid; catalysis; 2,4-dichloroquinoline; palladium; water
Abstract
A two step synthesis of 2-alkynyl-4-arylquinolines has been accomplished via Pd/C-mediated regioselective C-2 alkynylation of
2,4-dichloroquinoline in water followed by Suzuki coupling at C-4 of the resulting 4-chloro derivative.
Introduction
2-Alkynyl pyridine and its benzo (i.e. quinoline) derivative 2-Alkenyl/alkynylquinolines, have been reported to possess
possessing an aryl group at the C-4 position (A, Figure 1) have anti-retroviral properties [4]. Only few methods are known for
attracted considerable interest due to their utility in the develop- the synthesis of A. Considering the possible C–C bond forming
ment of compounds of potential pharmacological interest [1-3].
reactions on a pyridine/quinoline ring (Figure 1), the synthesis
of A can be carried out following two main strategies e.g. (a)
arylation at C-4 followed by alkynylation at C-2 or (b)
alkynylation at C-2 followed by arylation at C-4. Methodolo-
gies based on strategy ‘a’ have been reported earlier. For
example, Sonogashira coupling of a terminal alkyne with
2-chloro-4-aryl substituted quinoline [3] in the presence of
(PPh3)2PdCl2-CuI or treatment of 4-aryl pyridine-N-oxide with
alkynyl Grignard [5] provided the required quinoline or
Figure 1: 2-Alkynyl-4-aryl pyridine and its benzo derivative.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 32.
Scheme 1: Sequential synthesis of 2-alkynyl-4-arylquinolines from 2,4-dichloroquinoline under palladium catalysis.
pyridine derivatives, respectively. Notably, synthesis of A compound 3a. Irradiation of protons of the benzene ring
following the strategy ‘b’ has not been explored. In our effort attached to the alkynyl group resulted in enhancement of the
towards the synthesis of quinoline derivatives of potential biolo- singlet at δ 8.03 assigned to the C-3 hydrogen of the quinoline
gical significance we have reported Pd/C-mediated regiose- ring. If the alkyne was at C-4, NOE enhancement at C-5 is
lective C-2 alkynylation of 2,4-dichloroquinoline in water [6]. expected in addition to C-3. It is note worthy that the use of the
However, only one example of regioselective C-2 alkynylation Sonogashira coupling or its modified form has been employed
was reported and no detailed study has been carried out previ- for the preparation of 2-alkynylquinolines or related derivatives
ously. Herein we report the preparation of a series of 2-alkynyl- earlier [7-17].
4-chloroquinoline (3) followed by successful Suzuki coupling at
C-4 of compound 3 leading to the corresponding 4-arylated Next, in order to prepare 2-alkynyl-4-arylquinolines (5) we
derivatives (5) in good yields (Scheme 1). To the best of our planned to exploit the reactivity of chloro group of 3 towards
knowledge this is the first synthesis of 2-alkynyl-4- Suzuki arylation reaction. Accordingly, a variety of arylboronic
arylquinolines following such a strategy.
acids were coupled with 3 and results of this study are summar-
ized in Table 2. The Suzuki reaction was carried out using aryl-
boronic acids in the presence of (PPh3)2PdCl2 as a catalyst,
Results and Discussion
A number of 2-alkynyl-4-chloroquinolines (3) were prepared CsCO3 as a base, tricyclohexyl phophine, (PCy3) as a ligand in
via coupling of 2,4-dichloroquinoline (1) in the presence of dioxane–water at 80 °C. The arylboronic acids used in this reac-
10% Pd/C (10 mol%), PPh3 (20 mol%) and CuI (5 mol%) as a tion include phenylboronic acid (entries 1–6, Table 2), 3-meth-
catalyst system in water. The results are presented in Table 1. oxyphenylboronic acid (entry 7, Table 2) and 4-fluorophenyl
Both aryl and alkyl substituted terminal alkynes participated boronic acid (entry 8, Table 2), all of which participated well in
well in this C–C bond forming reaction to afford the desired the coupling reaction with 3. A number of 2-alkynyl-4-
product in good yields. The reaction was found to be highly arylquinolines (5) were prepared in good to excellent yields
selective for mono-substituted product and no dialkynylated without affecting the alkynyl substituents present in
product was isolated from the reaction mixture. Moreover, the compound 3.
reaction displayed good regioselectivity for C-2 alkynylation
though the formation of C-4 alkynylated product cannot be The reaction mechanism of the present stepwise C–C bond
ruled out completely. Regioselectivity for C-2 alkynylation was forming reactions consisting of alkynylation followed by aryla-
confirmed by NOE (Nuclear Overhauser Effect) studies using tion is shown in Scheme 2. The Pd/C–Cu mediated coupling of
Scheme 2: The reaction mechanism of stepwise C–C bond forming reactions.
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Beilstein Journal of Organic Chemistry 2009, 5, No. 32.
Table 1: Pd/C-mediated [Pd/C (10 mol%)–CuI (5 mol%)–PPh3 (20 mol%)] synthesis of 2-alkynyl-4-chloroquinolines (3).a
Entry
Terminal alkynes (2)
Time (h)
Products (3)b
Yield (%)c
1.
10
88
2a
3a
2.
3.
8
85
90
2b
3b
10
2c
2d
2e
2f
3c
3d
3e
3f
4.
5.
6.
12
12
8
92
90
87
aAll the reactions were carried out by using compound 1 (1.0 equiv), terminal alkyne 2 (1.5 equiv), 10% Pd/C (0.026 equiv), PPh3 (0.20 equiv), CuI
(0.05 equiv), and Et3N (3.0 equiv) at 80 °C.
bIdentified by 1H NMR, IR, and MS.
cIsolated yields.
2,4 dichloroquinoline (1) with terminal alkynes (2) in water compound 3 followed by trans-organometallation of the
proceeds via normal Sonogashira pathway [6]. Due to the pres- resultant aryl-palladium complex formed with arylboronic acids
ence of electronegative nitrogen atom the chloro group at the provides the desired compound 5.
azomethine carbon is more susceptible to undergo oxidative
addition with Pd(0) than chloro group at C-4. Moreover, the Conclusions
coordination of quinoline nitrogen to the palladium [18,19] In conclusion, a two-step method consisting of alkynylation
controls the regioselectivity in alkynylation of 2,4- followed by arylation has been developed for the synthesis of
dichloroquinoline at C-2 position. The 2-alkynyl-4- 2-alkynyl-4-arylquinolines. The alkynylation step involved Pd/
chloroquinolines 3 thus formed then undergo Suzuki reaction in C–Cu mediated regioselective C-2 alkynylation of 2,4-
the next step. Oxidative addition of Pd0 generated in situ to dichloroquinoline in water to afford 2-alkynyl-4-
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Beilstein Journal of Organic Chemistry 2009, 5, No. 32.
chloroquinoline. The arylation step is a Pd-mediated (Suzuki) quinoline derivatives of potential pharmacological significance
coupling of 2-alkynyl-4-chloro derivative with arylboronic and may therefore find wide usage in organic/medicinal chem-
acids in aqueous media to give the target compounds. The istry.
process is amenable to the diversity-oriented synthesis of
Table 2: Synthesis of 2-alkynyl-4-arylquinolines (5).
Entry
4-Chloro compd (3)
Arylboronic acid (4)
Producta (5)
Time (h)
Yield (%)b
1.
3e
phenylboronic acid (4a)
4
83
5a
2.
3b
4a
3
88
5b
3.
4.
5.
6.
3c
3d
3a
3f
4a
4a
4a
4a
2
4
2
3
87
82
84
5c
5d
5e
79
5f
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Beilstein Journal of Organic Chemistry 2009, 5, No. 32.
Table 2: Synthesis of 2-alkynyl-4-arylquinolines (5). (continued)
3-methoxy-phenylboronic acid
7.
3a
2
86
(4b)
5g
8.
3a
4-fluoro-phenylboronic acid (4c)
2
86
5h
aIdentified by 1H NMR, IR, and MS.
bIsolated yields.
Experimental
7.75–7.71 (m, 1H), 7.56–7.47 (m, 9H), 7.25–7.17 (m, 2H), 2.38
General Procedure for the preparation of compound 5: A (s, 3H); IR (cm−1, neat) 2924, 2216, 1583, 1541; m/z (ES Mass)
mixture of alkyne 3 (1.0 mmol) and (PPh3)2PdCl2 (0.05 mmol) 320 (M+1, 100%); 13C NMR (CDCl3, 50 MHz) 148.6, 148.5,
in dioxane (5.0 mL) was stirred for 10 min under nitrogen at 143.2 (2C), 139.3 (2C), 137.3 (2C), 134, 132, 129.5 (3C), 129.3
room temperature and then heated to 80 °C. To this mixture was (2C), 126.9 (2C), 125.6 (2C), 124.4, 118.9, 90.2, 88.8, 29.0;
added a solution of PCy3 (0.05 mmol) and CsCO3 (3.5 mmol) HRMS (ESI): calcd for C24H17N (M+H)+ 320.1439, found
dissolved in water (3.0 mL) and arylboronic acid (1.5 mmol) 320.1454.
dissolved in dioxane (3.0 mL) at the same temperature. The
mixture was stirred at 80 °C according to the time indicated in
Supporting Information
Table 2. After completion of the reaction the mixture was
cooled to room temperature, concentrated under vacuum and
Supporting Information File 1
the residue was extracted with EtOAc (3 × 30 mL). The organic
layers were collected, combined, washed with cold water (3 ×
30 mL), dried over anhydrous Na2SO4 and concentrated under
vacuum. The crude product was purified by column chromato-
graphy on silica gel, using light petroleum ether (60–80 °C)-
ethyl acetate to afford the desired product. Spectral data for
selected compounds; Compound 5a; light brown gum, Rf (20%
ethyl acetate/n-hexane) 0.21; 1H NMR (CDCl3, 400 MHz) δ
8.14 (d, J = 8.0 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.69 (t, J =
7.8 Hz, 1H), 7.50–7.41 (m, 7H), 2.49 (t, J = 7.0 Hz, 2H),
1.69–1.21 (m, 8H), 0.91–0.8 (m, 3H); IR (cm−1, neat) 2927,
2225, 1587, 1543, 1357; m/z (ES Mass) 314 (M+1, 100%); 13C
NMR (CDCl3, 50 MHz) 148.5, 143.6, 137.5 (2C), 129.6 (3C),
128.4 (2C), 126.7 (2C), 125.5 (3C), 124.3, 92.2, 81.0, 76.3,
31.3, 29.6, 28.0, 24.6, 22.5; HRMS (ESI): calcd for C23H23N
(M+H)+ 314.1909, found 314.1896. Compound 5b, low melting
solid, Rf (20% ethyl acetate/n-hexane) 0.28; 1H NMR (CDCl3,
400 MHz) δ 8.20 (d, J = 7.8 Hz, 1H), 7.87 (d, J = 7.8 Hz, 1H),
Spectral data of 2-alkynyl-4-arylquinolines 5c–h.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-5-32-S1.doc]
Acknowledgments
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.
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