Metal-free, ionic liquid-mediated synthesis of functionalized quinolines

Article abstract of DOI:10.1021/co500047w

An expedient and metal-free synthetic protocol for construction of substituted quinolines has been developed from anilines and phenylacetaldehydes using imidazolium cation-based ionic liquids as the reaction medium. Mechanistic analysis indicated that the reaction occurs through C-C and C-N bond formation to produce isolable 2,3-disubstituted quinoline intermediates, which undergo C-C bond cleavage to produce 3-substituted quinolines. The reaction proceeds smoothly with a range of functionalities in good to excellent yields. Advantages of this protocol include metal-free, environmentally friendly, recyclable reaction media, higher yields and shorter reaction times, and thus is promising for the efficient combinatorial synthesis of structurally diverse 2,3-disubstituted and 3-substituted quinolines.

Full text of DOI:10.1021/co500047w

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Article
Metal-free, ionic liquid-mediated synthesis of functionalized quinolines
Jaideep B Bharate, Sandip Bibishan Bharate, and Ram A. Vishwakarma
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co500047w • Publication Date (Web): 14 Oct 2014
Downloaded from http://pubs.acs.org on October 17, 2014
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Metal-free, ionic liquid-mediated synthesis of functionalized
quinolines
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Jaideep B. Bharate, †,‡ Sandip B. Bharate†,‡,* and Ram A. Vishwakarma†,‡,*
†Medicinal Chemistry Division, CSIR-Indian Institute of Integrative Medicine, Canal Road, Jammu-
180001, India
‡Academy of Scientific & Innovative Research (AcSIR), CSIR-Indian Institute of Integrative Medicine,
Canal Road, Jammu-180001, India
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TOC Graphic.
H
C
H
C
N
BF4
R
R
3
3
N
R1
R1
R1
2C
R
CH
1
N
150 oC, 4 h
NH2
N
+
C-C bond
cleavage
or
Isolable intermediate
20 examples
60-80% yield
MW, 100 W, 15 min
R
CHO
9 examples
C-C/ C-N bond
formation
ꢀMetal-free
ꢀRecyclablereaction media
ꢀShort reaction times
ꢀGreen protocol
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ABSTRACT:
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An expedient and metalꢀfree synthetic protocol for construction of substituted quinolines has been
developed from anilines and phenylacetaldehydes using imidazolium cationꢀbased ionic liquids as the
reaction medium. Mechanistic analysis indicated that the reaction occurs through CꢀC and CꢀN bond
formation to produce isolable 2,3ꢀdisubstituted quinoline intermediates, which undergo CꢀC bond
cleavage to produce 3ꢀsubstituted quinolines. The reaction proceeds smoothly with a range of
functionalities in good to excellent yields. Advantages of this protocol include metalꢀfree,
environmentally friendly, recyclable reaction media, higher yields and shorter reaction times, and thus is
promising for the efficient combinatorial synthesis of structurally diverse 2,3ꢀdisubstituted and 3ꢀ
substituted quinolines.
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KEYWORDS.
Ionic liquids,
metalꢀfree,
quinolines,
heterocycle synthesis,
green chemistry
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INTRODUCTION
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Metalꢀfree synthetic protocols can diminish adverse environmental consequences of many organic
reactions.1ꢀ4 Many efforts to establish metalꢀfree reaction conditions uses polar solvents and ionic liquids
(ILs), the latter area focusing largely on waterꢀsoluble imidazolium cationꢀbased systems.5ꢀ8 ILs have
been considered as green solvents due to their properties of high thermal stability, nonꢀflammable
nature, immiscibility with a number of organic solvents, negligible vapor pressure, and recyclability.9, 10
Furthermore, ILs are known to play roles both as solvent and catalyst.11 For example, 1ꢀbutylꢀ3ꢀ
methylimidazolium tetrafluoroborate ([Bmim]BF4) has been used in a wide variety of reactions,
including synthesis of vicꢀdiamines,12 Michael reaction,13 synthesis of 1,4ꢀ dihydropyridines,14 cleavage
of ethers,15 Stille coupling,16 halogenation of alkenes,17 olefin metathesis,18 and SuzukiꢀMiyaura crossꢀ
coupling.19 The ILs are also widely used in the synthesis of heterocyclic compounds5, 20, 21 and inorganic
materials.22
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Quinoline is one of the most widely occurring heterocyclic scaffolds in drugs and natural products,
possessing a diverse range of pharmacological activities and therefore attracting the continued attention
of medicinal and synthetic chemists. Apart from conventional approaches,23ꢀ28 several new methods
have been discovered for quinoline synthesis.29ꢀ32 Among these, the condensation of anilines and
phenylacetaldehydes provides an elegant approach to substituted quinolines, for which two methods are
reported in the literature (Table 1): (a) sulfamic acid catalyzed synthesis of 2,3ꢀdisubstituted quinolines
(3)33 and (b) CuBr/CF3SO3H catalyzed synthesis of 3ꢀsubstituted quinolines (4).34 In addition to these
two reports, there exists another similar approach for synthesis of 3ꢀsubstituted quinolines 4, which
involves FeCl3ꢀcatalyzed condensation of anilines and styrene oxides.35
In the present paper, we report a green, facile and efficient metalꢀfree synthesis of 2,3ꢀdisubstituted 3
and 3ꢀsubstituted quinolines 4 through sequential oneꢀpot CꢀC/CꢀN bond formation and CꢀC bond
cleavage (entries 3ꢀ5, Table 1). The advantages of present protocol include: (a) both 2,3ꢀdisubstituted 3
as well as 3ꢀsubstituted quinolines 4 can be prepared using this reaction; (b) metalꢀfree reaction
condition; and (c) recyclable and ecoꢀfriendly ionic liquid reaction media.
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Table 1. Methods for quinoline synthesis from aniline and phenylacetaldehyde
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2
3
4
5
Ph
Ph
C-C/ C-N bond
formation
C-C bond
cleavage
R
+
NH2
R
R
R
CHO
N
N
1
2
4
3
6
Ph
7
8
9
Sr No
1.
Group
Condition
% yield of 3/4
63ꢀ86/ 0a
0b/45ꢀ93
8/78c
Zhang et al. (2012)33
Yan et al. (2013)34
This work
NH2SO3H, 80 °C, 3ꢀ5 h
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2.
CuBr/ CF3SO3H, DMSO, 110 °C
[Bmim]BF4, 150 °C, 4 h
3.
4.
This work
[Bmim]BF4, 120 °C, MW, 100 W, 15 min
8/ 80c
5.
This work
[Bmim]BF4, 110 °C/ 0.5 h
35/50c
a only product 3 was formed; only product 4 was formed; yields are mentioned for products obtained from 2,3ꢀdimethyl
b
c
aniline.
RESULTS AND DISCUSSION
To establish a metalꢀfree protocol for the synthesis of substituted quinolines, we explored the reaction
of 2,3ꢀdimethylaniline (1a) with phenylacetaldehyde (2a) in presence of CuBr and 1ꢀbutylꢀ3ꢀ
methylimidazolium tetrafluoroborate ionic liquid (as a replacement for CF3SO3H and DMSO in the
published protocol34) at 110 °C (Table 2, entry 1). Gratifyingly, the desired 3ꢀsubstituted quinoline 4a
was obtained in good yield (entry 1), which was comparable to the Yan method (entry 2).34 Control
reactions without addition of CF3SO3H (entry 3) or CuBr (entry 4) established the essential nature of
these reagents in the absence of IL. The Lewis acid FeCl3 was an effective replacement for CuBr (giving
4a in 70% yield, entry 5), and the addition of ionic liquid gave a slightly better result (78% yield, entry
6). Most encouraging, however, was the formation of quinolines 3a and 4a in 12% and 70% yields,
respectively in the presence of ionic liquid [Bmim]BF4, without the addition of any catalyst or additive
(entry 7). Exploration of reaction temperature (entries 7ꢀ11) indicated 150 °C as optimal, with no
reaction occurring at room temperature. When the reaction time was reduced from 4 h to 30 min, the
2,3ꢀdisubstituted quinoline 3a could be isolated in 35% yield (entry 10). A different ionic liquid, 1ꢀethylꢀ
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3ꢀmethylimidazolium 1,1,2,2ꢀtetrafluoroethane sulfonate ([emim][CHF2CF2SO3]), was not successful
(entry 12).
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8
Since ILs have ability to absorb microwave energy and convert it into heat, microwave irradiation is
an attractive alternative for thermallyꢀdriven reactions in these media. Accordingly, the above model
reaction was subjected to microwave irradiation (100 W) at 120 °C for 5ꢀ15 min (entries 13 and 14),
which produced desired product 4a in 80% yield (entry 14). Thus, the entries 8 and 14 are considered as
optimized reaction conditions under conventional heating and microwave irradiation, respectively.
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Table 2. Optimization of reaction conditionsa
Ph
Ph
+
+
NH2
Ph
CHO
Ph
N
N
1a
Catalyst
2a
3a
4a
Entry
1
Additive
None
Reaction medium
[Bmim]BF4
DMSO
Temp. (°C)/ time
110/ 4 h
Yieldb (%) 3a/4a
5/80
CuBr
CuBr
CuBr
None
FeCl3
FeCl3
None
None
None
None
None
None
None
None
2
CF3SO3H
None
110/ 4 h
5/74
3
DMSO
110/ 4 h
0/0
4
CF3SO3H
None
DMSO
110/ 4 h
0/0
5
CH3CN
110/ 4 h
8/70
6
None
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
[Bmim]BF4
110/ 4 h
5/78
7
None
110/ 4 h
12/70
8/78
8c
9
None
150/ 4 h
None
180/ 4 h
8/80
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11
12
13
14c
None
110/ 30 min
25/ 4 h
35/50
0/0
None
None
[Emim][CHF2CF2SO3] 110/ 4 h
0/0
None
[Bmim]BF4
120, MW, 100 W, 5 min
18/ 48
8/ 80
None
[Bmim]BF4
120, MW, 100 W, 15 min
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MW, microwave irradiation; a 1a (1.0 mmol), 2a (2.0 mmol) and catalyst and/ or additive (wherever mentioned) and solvent;
b Isolated yields after silica gel column chromatography; c bold entries indicates optimized reaction conditions for synthesis of
3ꢀsubstituted quinolines 4.
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An exploration of aniline and phenylacetaldehyde scope using the conventional optimized reaction
conditions (entry 8, Table 2) gave the results shown in Figure 1. Anilines substituted with electronꢀ
donating groups (4a-4e, 4g-4l) and electronꢀwithdrawing groups (4m-4o and 4s) each participated well
in this reaction. Similarly, nonꢀsubstituted (4a-4o) as well as substituted (4p-4s) phenylacetaldehydes
produced corresponding quinoline products in good yields. For the latter examples, the corresponding
phenylacetaldehydes were prepared from phenyl epoxides by treatment with Zeolite in methylene
chloride.36 The phenylacetaldehydes obtained by evaporation of the solvent were treated directly with
anilines and ionic liquid in the same pot to produce the desired quinolines 4p-4s (Figure 1). In contrast
to anilines, cyclohexylamine did not produce the desired product.
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N
N
1
2
BF4
R2
3
4
5
6
CHO
[Bmim]BF4
150 oC, 4 h
R1
+
R2
R1
NH2
N
4
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N
N
N
N
4c (75%)
4d (77%)
4b (72%)
4a (78%)
O
O
O
O
N
N
N
N
4h (76%)
4e (78%)
4g (80%)
4f (79%)
OMe
F3CO
MeO
MeO
MeO
MeO
N
MeO
N
N
N
4l (80%)
4k (78%)
4j (78%)
4i (78%)
Br
Cl
Br
N
N
N
N
Br
4o (70%)
4p (60%)
4n (70%)
4m (73%)
F
F
Cl
Cl
N
N
N
4q (62%)
4r (65%)
4s (65%)
Figure 1. Metalꢀfree synthesis of 3ꢀsubstituted quinolines in ionic liquid under conventional heating.
Representative aliphatic aldehydes (nꢀbutyraldehyde and phenylpropanal) also proved to be interesting
(Figure 2). The 3ꢀsubstituted quinoline product 4t was obtained from the reaction of 2ꢀbromoaniline
with nꢀbutyraldehyde, which was not possible using Yan and coworkers34 protocol. However in other
cases, 2,3ꢀdisubstituted quinolines 3u-x were obtained. As with CuBr/CF3SO3H,34 the reaction of 3ꢀ
phenylpropanal 2w with aniline 1b using our optimized reaction conditions led to formation of only 2,3ꢀ
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disubstituted product 3ꢀbenzylꢀ2ꢀphenethylquinoline 3w (Figure 2). Performing the reaction at 110 °C
for 30 min gave both 2,3ꢀdisubstituted and 3ꢀmonoꢀsubstituted products (Table 3). The 2,3ꢀdisubstituted
quinolines 3a, 3g-3k were obtained in 18ꢀ45% yields, along with 3ꢀsubstituted quinolines 4a, 4g-k (38ꢀ
50%).
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Figure 2. Metalꢀfree synthesis of 3ꢀsubstituted and 3,4ꢀdisubstituted quinolines in ionic liquid
Table 3. Synthesis of monoꢀ and disubstituted quinolinesa
R1
[Bmim]BF4
NH2
R1
+
110 oC, 30 min
1
2
R1
N
N
CHO
+
3
4
Entry
1
Product 3
Product 4
Structure
Structure
%Yield b
35
%Yield b
50
N
N
4a
3a
O
O
2
28
42
O
O
N
N
4g
3g
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O
O
1
2
3
4
5
6
7
8
3
4
30
O
O
45
38
N
N
4h
3h
MeO
MeO
MeO
MeO
18
26
N
9
N
10
11
12
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4j
3j
5
40
MeO
N
MeO
N
4k
3k
a aniline 1 (1.0 mmol), phenylacetaldehyde 2 (2.0 mmol) and ionic liquid was heated to reflux at 110 °C for 30 min; b Isolated
yields after silica gel column chromatography.
The repeated reuse of the ionic liquid reaction medium was investigated using the model reaction
between 2,3ꢀdimethyl aniline 1a and phenylacetaldehyde 2a. After completion of the reaction, products
were extracted with diethyl ether and remaining ionic liquid after drying under reduced pressure was
reused for next reaction. The desired product 4a was obtained in 70, 68, 65 and 62% yield over four
cycles, indicating good recyclability of the ionic liquid over several cycles.
Since ILs are known to activate carbonyl groups through hydrogen – bonding, we suggest that
[Bmim]BF4 activates the aldehyde electrophile by interaction with the carbonyl oxygen as illustrated in
Figure 3 for the representative reaction of 1a+2a. The ionic liquid [Bmim]BF4 may also enhance the
nucleophilicity of the amine through interaction of tetrafluoroborate with NꢀH bond. The resulting imine
intermediate undergoes selfꢀcondensation to generate 3a1 as a key intermediate. This is supported by
monitoring of the reaction by LCꢀESIꢀMS at intermittent reaction time (30 min). As shown in Figure 4,
2,3ꢀdisubstituted quinoline intermediates 3a1 and 3a2 were observed along with product 4a. At 4 h
reaction time, the ratio of 4a: 3a2 changed from 37:35 to 70:0, suggesting that 3a2 is a key intermediate
in the formation of 4a (S3 of Supporting Information).
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Ph
H
Ph
1
2
3
4
5
6
7
8
H
H
N
-H2O
O
N
H
N
NH
O
H
Ph
Ph
H
H
nBu
2a
1a
III
I
II
H
N
N
nBu
BF4
Ph
N
Dimerization
N
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Radical
formation
Ph
NH
Ph
Ph
H
Cyclization
[O]
Ph
N
IL
N
N
Ph
H
Ph
N
Ph
H
V
3a1
m/z 325
O=O +
OOH
3a2
m/z 323
H
IV
NH2
OH
Ph
Ph
OOH
Ph
PhCHO
N
N
4a
m/z 233
VII
Figure 3. Plausible reaction mechanism showing formation of 3a1 and 3a2 as key intermediates during synthesis of 3ꢀ
substituted quinoline 4a.
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Ph
Ph
1
2
3
4
Ph
(a)
N
N
3a2
m/z 323
4a
m/z 233
5
6
7
NH2
8
9
1a
m/z 121
Ph
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30
H
N
H
Ph
3a1
m/z 325
(b)
(c)
(d)
4a
[M+H]+
3a1
3a2
[M+H]+
[M+H]+
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Figure 4. LCꢀESIꢀMS analysis of reaction mixture after 30 min. (a) LCMS chromatogram showing product 4a and
intermediates 3a1 and 3a2; (bꢀd). MS chromatograms of peaks appearing at tR 10.9, 14.9 and 16.0 min, respectively.
The cleavage process that takes 3 to 4 was found to be inhibited by a radical quencher: the reaction of
1a+2a performed in the presence of TEMPO produced 3a1 as the major product with 4a formed only in
trace amounts. In the absence of TEMPO, the cleavage event generates benzaldehyde as a byproduct
(seen in TLC). These observations are consistent with the presumed formation of a benzylic radical V
and hydroperoxide VII (Figure 3). Based on the literature precedence,37, 38 we presume that IL plays a
role in generating benzylic radical V from intermediate 3a2; however, the exact mechanism of radical
generation is not clearly understood.
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In summary, we have found that an ionic solvent allows for the direct synthesis of substituted
quinolines without metal catalyst or additive, presumably by functioning both as a Lewis acid and Lewis
base. The method is operationally simple and can be used to access both 2,3ꢀdisubstituted and 3ꢀ
substituted quinolines. The ionic liquid [Bmim]BF4 provides a recyclable and nonꢀvolatile medium,
simple workꢀup, and high product yield, and therefore a useful alternative to existing processes for
quinoline synthesis.
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EXPERIMENTAL PROCEDURES
General optimized procedure for synthesis of 3-substituted quinolines 4a-t. The ionic liquid
1ꢀbutylꢀ3ꢀmethylimidazolium tetrafluoroborate used in the present study was purchased from Sigmaꢀ
Aldrich. Although this IL is commercially available, it can be prepared starting from Nꢀ
methylimidazole.39 The mixture of aniline (1, 1.0 mmol) and phenylacetaldehyde (2, 2.0 mmol) in ionic
liquid [Bmim]BF4 (1 mL) was stirred at 150 °C in an oil bath in an openꢀair atmosphere for 4 h. After
completion of the reaction, products were extracted with diethyl ether (50 ml x 3). The remaining ionic
liquid was further washed with diethyl ether and dried at 80 °C under reduced pressure, for its reuse.
The combined organic layer was evaporated under reduced pressure to give the crude product.
Purification by silica gel column chromatography (mesh 100ꢀ200) using hexaneꢀEtOAc as eluent gave
quinolines 4a-4t as major products in 60ꢀ80% yield. The spectral data for all synthesized quinolines 4a-
4t and 3a-x is provided in the supporting information.
ACKNOWLEDGEMENT. Authors are thankful to analytical department, IIIM for NMR, MS and IR
analysis of our compounds. Authors are grateful to Dr. Ajai P. Gupta and Mr. Manoj Kushwaha for
LCMS analysis. This work was supported by CSIR 12th FYP grant # BSCꢀ0205.
AUTHOR INFORMATION
Corresponding Author
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*Tel: +91ꢀ191ꢀ2569111. Fax: +91ꢀ191ꢀ2569333. Eꢀmail: ram@iiim.ac.in. (R.A.V.).
*Tel: +91ꢀ191ꢀ2569000 (Ext. 345). Fax: +91ꢀ191ꢀ2569333. Eꢀmail: sbharate@iiim.ac.in. (S.B.B.)
Notes
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The authors declare no competing financial interest.
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IIIM Communication number. IIIM/1672/2014
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SUPPORTING INFORMATION.
Experimental procedures and NMR spectra of all compounds. This information is available free of
charge via the Internet at http://pubs.acs.org/
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