Oxidant-Controlled C-sp2/sp3-H Cross-Dehydrogenative Coupling of N-Heterocycles with Benzylamines

Article abstract of DOI:10.1021/acs.joc.7b00856

Oxidant controlled ionic liquid mediated cross-dehydrogenative coupling (CDC) of benzylamines with N-heterocycles having sp² or sp³ carbon resulted in the formation of C-benzoylated or alkenylated products. Benzoylation of N-heterocycles occurs via (NH₄)₂S₂O₈ catalyzed benzoyl radical formation. An oxidative alkenylation of N-heterocycles having C-sp³ carbon (2-methylaza-arenes) occurs via deamination of benzylamine followed by C-sp³-H bond activation in high stereoselectivity. Both benzoylation and alkenylation protocols are metal-free, green, simple, efficient, and tolerate a wide variety of functional groups.

Full text of DOI:10.1021/acs.joc.7b00856

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Note
Oxidant-Controlled C-sp2/sp3 – H Cross-dehydrogenative
Coupling of N-Heterocycles with Benzylamines
Rohit Sharma, Mohd Abdullaha, and Sandip B. Bharate
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b00856 • Publication Date (Web): 18 Aug 2017
Downloaded from http://pubs.acs.org on August 18, 2017
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The Journal of Organic Chemistry
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OxidantꢀControlled Cꢀsp2/sp3 – H Crossꢀ
dehydrogenative Coupling of NꢀHeterocycles with
Benzylamines
Rohit Sharma,†‡ Mohd Abdullaha,†‡ Sandip B. Bharate†‡*
†Medicinal Chemistry Division, CSIRꢀIndian Institute of Integrative Medicine, Canal Road, Jammuꢀ
180001, India
‡
Academy of Scientific & Innovative Research, CSIRꢀIndian Institute of Integrative Medicine, Canal
Road, Jammuꢀ180001, India
TOC
o New method for CDC coupling of Nꢀ
N
N
N
N
heterocycles
IL
(NH4)2S2O
8/IL
O
CDC of C-sp3
CDC of C-sp2
o No use of metal or ligand
o Use of ionic liquid
O
OH
NH2 TBHP
IL
O
CDC of C-sp2
CDC of C-sp3
o
CDC coupling with Nꢀheterocycles having Cꢀ
sp2 and sp3 carbon
N
(NH4)2S2O
8 /IL
I2/HCl/DMSO
N
N
N
N
N
ABSTRACT. Oxidant controlled ionic liquid mediated crossꢀdehydrogenative coupling (CDC) of
benzylamines with Nꢀheterocycles having sp2 or sp3 carbon resulted in the formation of Cꢀbenzoylated
or alkenylated products. Benzoylation of Nꢀheterocycles occurs via (NH4)2S2O8 catalyzed benzoyl
radical formation. An oxidative alkenylation of Nꢀheterocycles having Cꢀsp3 carbon (2ꢀmethylazaꢀ
arenes) occurs via deamination of benzylamine followed by Csp3ꢀH bond activation in high
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stereoselectivity. Both benzoylation and alkenylation protocols are metalꢀfree, green, simple, efficient
and tolerates wide variety of functional groups.
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KEYWORDS. Crossꢀdehydrogenative coupling, Nꢀheterocycles, sp3 CꢀH bond functionalization, ionic
8
liquid, oxidative coupling, oxidative alkenylation
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In recent years, oxidative cross coupling reaction has gained tremendous importance in synthetic
organic chemistry.1,2 Organic transformations for direct conversion of CꢀH bonds to CꢀC bonds is a hot
area in organic chemistry because they are atom economical and provide short route for construction of
CꢀC bonds.3ꢀ7 Formation of CꢀC bonds from two different CꢀH bonds is known as ‘cross
dehydrogenative coupling (CDC)’ reaction and it does not require preꢀfunctionalized starting
materials.4,8 9 In this context, the activation of CꢀH bonds (sp2, sp3) remains a challenging task for
synthetic organic chemists.10,11
The CDC reaction of Nꢀheterocycles with wide range of substrates has emerged as a powerful tool in
organic chemistry.12,13 Direct CꢀH bond functionalization of Nꢀheterocycles requires metal catalyst to
precede the reaction. The benzoyl derivatives of Nꢀheterocycles possess various biological activities and
are also present among various natural products.14ꢀ17 There are few reports available in literature where
CꢀH functionalizations of electron deficient arenes are described.18ꢀ21 Formation of benzoylated product
in electron deficient arenes is done in Minisci type fashion by generation of acyl radical in situ from
aldehydes19,21ꢀ23 and toluene,20 but these methods suffers from various drawbacks such as harsh reaction
conditions and involves the use of additives/ oxidants.11 In last few decades, lot of work has been done
on transition metal catalyzed or metalꢀfree aerobic C–X (X = C, N, O etc) bond activation,24 C–C bond
cleavage and functionalization.25 However, to the best of our knowledge, direct C–N bond cleavage26 of
benzyl amines utilizing an ionic liquid (IL) oxidation strategy under metalꢀfree conditions has not yet
been established. Furthermore, benzoylation of Nꢀheterocycles from benzylamine has never been
reported.
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The Journal of Organic Chemistry
ILs have received considerable attention in organic synthesis,27,28 because of their fascinating
1
2
physiochemical properties such as nonꢀvolatility, nonꢀflammability and recyclability.28 1ꢀButylꢀ3ꢀ
methylimidazolium tetrafluoroborate ([Bmim]BF4)27 has been utilized in various reactions such as
Michael reaction,29 cleavage of ethers,30 halogenations of alkenes,31 and in olefin metathesis.32 Based on
these reports we explored the use of [Bmim]BF4 as a solvent for our proposed CꢀH functionalization. In
continuation to our interest in using benzylamine for Nꢀheterocycle synthesis,33,34 herein we report
ammonium persulfate catalyzed ILꢀmediated CDC reaction of Nꢀheterocycles with benzylamine. Here,
the benzylamine gets oxidized to aldehyde and then in presence of IL, it gets coupled with Nꢀ
heterocycles having Cꢀsp2 and Cꢀsp3 carbon.
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The benzoylation of isoquinoline/ quinoxaline is reported via AlCl3 catalyzed Minisci type reaction
21
with toluene,20 or TBHP/TFA19 or PhI(OCOCF3)2/TMSN3 catalyzed coupling with benzaldehydes
(Figure 1). The palladium acetate catalyzed coupling of isoquinoline Nꢀoxides with nitroalkenes also
produces benzoylated isoquinolines.35 Furthermore, there are only three reports on the alkenylation of 2ꢀ
substituted azaarenes.36ꢀ38 Amongst these, only Qian et al37 reported alkyenylation of both 2ꢀmethyl
pyridines and 2ꢀmethyl quinolines, which is an ironꢀcatalyzed reaction. These methods requires either
use of metal catalyst37 or an external oxidant36,38 and longer reaction times.36 The present work describes
metalꢀfree IL or iodineꢀmediated alkenylation of 2ꢀsubstituted azaarenes.
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Literature reports
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2
3
4
Matcha and Antonchick (2013)/ Liu (2015)
O
H
N
N
(a) PhI(OCOCF3)2, TMSN3, rt, 2 h
(b) TBHP, TFA, DCE, 110 oC, 10 h
R
R
N
N
O
+
5
6
7
8
C-sp2-CDC
Pan et al (2016)
AlCl3
NO2
Pd(OAc)2
tBuOOH
N
N
DMSO, 110 o
12-16 h
C
95 o
C
N
O
18 h
Patel et al (2015)
O
9
Qian (2011)/ Yaragorla (2015)/ Wang (2014)
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Ts
C-sp3-CDC
+
Ph
N
O
Fe(OAc)2, 120 oC, 24 h
Ca(OTf)2, Bu4NPF6, 130 oC, 4-5 h
N
N
+
+
Ph
Ph
TBHP, NBS, ACN, 100 oC, 48 h
NH2
Our approaches
NH2
NH2
N
N
N
R
N
(NH4)2S2O8 (3 equiv)
O
C-sp2-CDC
[Bmim] [BF4]
120 oC, 12 h
N
N
O
C-sp3-CDC
N
NH2
N
N
N
[Bmim] [BF4]
120 oC, 5 h
I2/HCl/DMSO
120 oC, 12 h
Figure 1. Literature reports and current approaches
for Cꢀsp2/Cꢀsp3 CDC coupling of Nꢀheterocycles
The study was initiated with preliminary reaction of quinoxaline 2 with benzylamine 3a in presence of
K2S2O8 and ionic liquid (1ꢀnꢀbutylꢀ3ꢀmethyl imidazolium tetrafluroborate) (Table 1). The benzoylated
product 1a was obtained but only in 10% yield (entry 1). Then, we screened various oxidants including
TBHP, DTBP, (NH4)2S2O8, TBAI, iodine (entries 2ꢀ18), solvents (ionic liquid, DMSO, DCE), out of
which (NH4)2S2O8 (ammonium persulfate) was found to be the best oxidant in combination with IL as a
reaction medium for this coupling reaction yielding the product 1a in 80% yield (entry 6).
Table 1. Optimization of reaction conditions for CDC coupling of quinoxaline 2 with benzylamine 3a
NH2
N
N
N
N
O
2
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1a, % yielda
Entry
Oxidant(equiv.)
K2S2O8 (3)
K2S2O8 (4)
TBHP (3)
Solvent
Temp(°C)
100
120
120
120
120
120
100
140
120
120
120
120
120
120
120
120
120
120
Time (h)
10
1
2
3
4
5
6
7
8
1
Bmim[BF4]
Bmim[BF4]
Bmim[BF4]
Bmim[BF4]
Bmim[BF4]
Bmim[BF4]
Bmim[BF4]
Bmim[BF4]
Bmim[BF4]
DMSO
10
2
12
15
3a
4
12
traces
0
9
DTBP (3)
12
10
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5
O2
24
0
6b
7
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
TBAI (0.5)
Iodine (0.8)
K2S2O8 (3)
K2S2O8 (3)
TBHP (3)
12
80
12
70
8
12
80
9
12
0
10
11
12
13
14
15
16
17
18
12
0
DMSO
12
traces
traces
traces
traces
traces
10
DCE
12
DCE
12
DTBP (3)
DCE
12
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
TBAI (0.5)
Iodine (0.8)
DMSO
12
DCE
12
DCE
12
0
DCE
12
0
b
aThe benzoic acid was obtained as the only product (~90% yield) in this reaction. For 100 mg of
reaction: 2 (1 equiv.), 3a (2 equiv.), (NH4)2S2O8 (3 equiv.) and 1 ml of ionic liquid.
During the course of oxidant optimization studies, we surprisingly obtained benzoic acid 3aa from
benzylamine 3a under TBHP/IL condition (entry 3 of Table 1). After conducting literature search, it was
observed that conversion of benzyl amine 3a to benzoic acid 3aa requires metal catalyst,39ꢀ41 dual
oxidant,42 or bioꢀoxidation.43 Therefore, we explored the scope of this transformation for various
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substituted benzylamines. The reaction of electronꢀwithdrawing (3ac, 3ad, 3af, 3ag, 3aj) as well as
electronꢀdonating (3ab, 3ae, 3ai, 3ak) groups containing benzyl amines participated well in this
transformation giving corresponding benzoic acids 3aa-ak in good yields (Figure 2).
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Figure 2. TBHP catalyzed conversion of
benzylamines to benzoic acids (all reactions were
carried out at 50 mg scale).
Next, we moved towards our primary goal of performing a CDC reaction of Nꢀheterocycles with
benzylamines. Under optimized reaction conditions, the scope of the reaction was explored for CDC
reaction of various Nꢀheterocycles such as quinoxalines, isoquinolines and quinolines with substituted
benzylamines. Reaction works well with all three Nꢀheterocycles resulting in regioselective
benzoylation. Various substituted benzylamines participated well in this reaction. Reaction works well
with benzylamines substituted with electron withdrawing as well as electron donating groups. No
particular electronic effect was seen but in case of electron donating groups (example 1g), the yields are
slightly less in comparison to electron withdrawing groups (examples 1b, 1c, 1d, 1e, 1f). In case of
isoquinoline heterocycle, C1ꢀbenzoylated products 5a-d were obtained but in comparatively lower yields
than quinoxalines (Figure 3). In case of quinoline heterocycle, benzoylation occurred specifically at C4ꢀ
position (examples 7a, 7b). In order to get C1ꢀacylated product for quinoline, we conducted a CDC
reaction of 4ꢀchloroquinoline (where C4ꢀposition is blocked) with benzyl amine, but the reaction does
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not proceed at all. This indicated that benzoylation reaction is regiospecific. For benzoylation of
quinoline, the optimized condition for this reaction of 2 equivalents of benzylamine, where generally
only a C4ꢀacylated product gets formed, without formation of C2ꢀbenzoylation product, even in traces.
Further in order to understand whether this reaction takes place to some extent at C2 position, we used
excess of benzylamine. In this case also, only C4ꢀbenzoylation product was formed, and there was no
formation of C2ꢀbenzoylated product (not even in traces). This observation is indicative of the fact that
this reaction is highly regiospecific. Further, we also performed the reaction of isoquinoline 5b (where
the C1ꢀposition is already blocked by benzoyl group) with benzyl amine 3 under optimized reaction
condition, in order to check whether further benzoylation occurs at C4 or any other position. Reaction
does not proceed at all, and starting material 5b was recovered as such.
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N
N
N
1a: R = H (80%)
1e: R = 3-F (75%)
1f: R = 4-CF3 (78%)
1g: R = 4-Me (77%)
1h: R = 3-CF3 (70%)
R
1b: R = 4-Cl (82%)
1c: R = 4-F (81%)
1d: R = 3-Cl (78%)
N
O
1a-h
2
R
NH2
N
3
(NH4)2S2O8 (3 equiv)
N
O
5a: R = H (50%)
5b: R = 4-F (45%)
5c: R = 3-Cl (48%)
5d: R = 3-Br (47%)
R
R
[Bmim] [BF4]
120 oC, 12 h
4
5a-d
O
N
N
7a: R = H (60%)
7b: R = 4-Me (65%)
6
7a-b
Figure 3. Substrate scope for oxidative CDC reaction of Nꢀheterocycles having sp2 carbon.
The proposed mechanism of the reaction is depicted in Figure 4. When the reaction was monitored at
intermediate stage, the formation of benzaldehyde I was noticed, indicating that benzylamine 3a first
gets converted to benzaldehyde. Here, the aerial oxygen may be playing role for conversion of
benzylamine to benzaldehyde. Ammonium persulfate generates the benzoyl radical II which attacks C2
position of III resulting in formation of intermediate IV. The [Bmim]BF4 helps in radical formation.
Finally, aromatization of IV leads to formation of 1a.
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Figure 4. Proposed reaction mechanism for
direct metalꢀfree benzoylation of Nꢀheterocycle
Next, we thought to conduct a CDC reaction for Nꢀheterocycles having Cꢀsp3 carbon. In case of cyclic
carbon containing Cꢀsp3 carbon (for example: 1,2,3,4ꢀtetrahydroquinoline) reaction does not proceed.
Then, we conducted the reaction of 2ꢀmethylquinoline 8 (which contain Cꢀsp3 carbon outside the ring)
with benzylamine 3a under optimized reaction condition (entry 6 of Table 1), where reaction worked
well giving 2ꢀstyrylquinoline 9a as a major product (Figure 5). The alkenylation of quinoline occurred
via deamination of benzylamine. The Cꢀsp3ꢀH proton of 2ꢀmethylquinoline 8 is more acidic as the
resulting carbanion is stabilized by resonance. Therefore, next we performed reaction only in IL, without
using any oxidant. To our surprise, the 2ꢀstyrylquinoline 9a was still obtained in good yield. Further, the
substrate scope of the reaction for substituted benzylamines was explored. Reaction works well with all
type of groups on benzylamines. Also electronic substituents at otho, meta and para position are well
tolerated in this alkenylation reaction. The recyclability of IL was also investigated using a model
reaction between 8 and benzylamine 3a. After completion of reaction, reaction mixture was extracted
with diethyl ether and remaining ionic liquid was dried under reduced pressure for its reuse. Ionic liquid
was reused up to five times yielding 60, 58, 58, 56, 54% yield of 9a. There is no appreciable loss of
activity of ionic liquid. Small decrease in yields might be due to loss of ionic liquid during work up.
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NH2
Bmim[BF4]
120 oC, 5 h
R
1
2
3
4
5
6
7
8
9
N
N
R
3a
9a-i
8
N
N
N
9c (56%)
OMe
Cl
9a (60%)
9b (55%)
Cl
Br
N
N
N
F
F
10
11
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9d (58%)
9e (62%)
9f (60%)
N
N
N
9g (61%)
9i (63%)
9h (64%)
Cl
F
N
11a (traces)
Figure 5. Substrate scope for oxidative CDC reaction
of 2ꢀmethyl quinoline having sp3 carbon
Next, we investigated another Cꢀsp3 carbon containing azaarene (i.e. 2ꢀmethyl pyridine) for this CDC
reaction. When reaction of 2ꢀmethylpyridine (10) was performed with benzylamine 3a under optimized
reaction condition (entry 6 of Table 1), the 2ꢀstyryl pyridine 11a was formed, but only in traces. Further,
on performing this reaction only in Bmim[BF4], the 2ꢀstyryl pyridine 11a was not formed at all. All
further optimization efforts in IL does not led to improvement in the product yield. This might be due to
the difference in reactivity of 2ꢀmethyl pyridine 10 and 2ꢀmethyl quinoline 8 which is also reported in
the literature.44 Further, we explored variation in the reaction conditions, other than IL, and it was
observed that in presence of iodine (80 mol%), HCl (20 µl) in DMSO solvent under reflux conditions,
2ꢀstyryl pyridine 11a was formed in 40% yield. Using these reaction conditions, substrate scope of the
reaction was explored. Reaction works well with electron withdrawing groups (11d, 11e, 11f) and
neutral groups (11a, 11b, 11c) substituted benzylamines. Also in case of substituted 2ꢀmethyl pyridines,
reaction works better than simple 2ꢀmethyl pyridines, giving better yields (Figure 6).
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1
2
NH2
I2/ HCl, DMSO
120 oC, 12 h
N
N
R
3
10
3a
11a-f
4
5
6
7
8
N
N
N
11a (50%)
11b (54%)
11c (55%)
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Cl
N
N
N
11d (40%)
11e (45%)
11f (52%)
Cl
Cl
Figure 6. Substrate scope for oxidative CDC reaction
of 2ꢀmethyl pyridine having sp3 carbon
In conclusion, we have developed oxidant controlled ionic liquid mediated conversion of benzylamine
to carboxylic acid followed by application towards CDC reaction of Nꢀheterocycles having Cꢀsp2/sp3
carbon atom producing C1ꢀacylated/ alkenylated products.
EXPERIMENTAL SECTION
General information. H, 13C and DEPT NMR spectra were recorded on FTꢀNMR 500 and 400
1
MHz instruments. Chemical data for protons are reported in parts per million (ppm) downfield from
tetramethylsilane and are referenced to the residual proton in the NMR solvent (CDCl3: 7.26, CD3OD:
3.28 and DMSOꢀd6: 2.5 ppm). Carbon nuclear magnetic resonance spectra (13C NMR) were recorded at
125 MHz or 100 MHz. The chemical shift values for carbons are reported in parts per million (ppm, δ
scale) downfield from tetramethylsilane and are referenced to the carbon resonance of the solvent
(CDCl3: 77, CD3OD: 49 and DMSOꢀd6: 39.5 ppm). IR spectra were recorded on IR spectrophotometer.
Melting points were recorded on digital melting point apparatus.
General procedure for synthesis of benzoic acid 3aa-ak from benzylamines. To the solution
of benzyl amine 3a-k (50 mg, 1 equiv.) in 1 mL of ionic liquid was added 5 equiv. of TBHP and the
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reaction mixture was heated at 120 C for 5 h. After completion of the reaction, the resultant reaction
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mixture was extracted with ethyl acetate and diethyl ether. Ether layer was collected and dried over
rotavapor so as to recover ionic liquid for further use. Ethyl acetate layer was separated and concentrated
on rotavapor to get crude product. Purification of crude products using silica gel chromatography
(hexane: EtOAc ꢀ 10: 1) gave benzoic acids 3aa-ak.
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Benzoic acid (3aa).45 Figure 2; white solid (52 mg, 92%); m.p. 120ꢀ125 C; H NMR (400 MHz,
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CDCl3): δ 8.14 (d, J = 8.0 Hz, 1H), 7.63 (t, J = 8.0 Hz, 1H), 7.50 (t, J = 12.0 Hz, 2H); C NMR (100
MHz, CDCl3): δ 172.3, 133.8, 130.2, 129.5, 128.5; IR (CHCl3): νmax 3342, 2922, 2322, 1645, 1253,
1254 cmꢀ1; ESIꢀMS: m/z 121.10 [MꢀH]ꢀ.
4-Methylbenzoic acid (3ab).46 Figure 2; white solid (57.5 mg, 90%); m.p. 175ꢀ180 C; 1H NMR (400
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MHz, CDCl3): δ 7.68 (d, J = 8.0 Hz, 1H), 7.25ꢀ7.20 (m, 2H), 7.16 (d, J = 8.0 Hz, 1H) 2.38 (s, 3H); IR
(CHCl3): νmax 3314, 2924, 2354, 1639, 1454, 1254 cmꢀ1; ESIꢀMS: m/z 135.10 [MꢀH]ꢀ.
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4-Chlorobenzoic acid (3ac).46 Figure 2; white solid (77 mg, 90%); m.p. 240ꢀ245 C; H NMR (400
MHz, acetoneꢀd6): δ 8.05 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H); IR (CHCl3): νmax 3093, 2917,
2845, 2678, 1932, 1683, 1594, 1425, 1295, 1282, 1129, 1016.18 cmꢀ1; ESIꢀMS: m/z 155.10 [MꢀH]ꢀ.
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4-Bromobenzoic acid (3ad).46 Figure 2; white solid (77 mg, 84%); m.p. 140ꢀ145 C; H NMR (400
MHz, acetoneꢀd6): δ 7.97 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 2H); ESIꢀMS: m/z 199.10 [MꢀH]ꢀ.
3,5-Dimethoxybenzoic acid (3ae).47 Figure 2; white solid (73 mg, 86%); m.p. 182ꢀ186 C; H NMR
(400 MHz, acetoneꢀd6): δ 7.17 (d, J = 4.0 Hz, 2H), 6.73 (t, J = 4.0 Hz, 1H), 3.84 (s, 3H); IR (CHCl3):
νmax 3418, 2957, 2645, 1762, 1599, 1348, 1212, 1070 cmꢀ1; ESIꢀMS: m/z 181.20 [MꢀH]ꢀ.
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3-Chlorobenzoic acid (3af).46 Figure 2; yellow solid (63 mg, 88%); m.p. 155ꢀ158 C; H NMR (400
MHz, CDCl3): δ 8.10 (s, 1H), 8.02ꢀ7.99 (m, 1H), 7.61ꢀ7.58 (m, 1H), 7.45 (t, J = 8.0 Hz, 1H); ESIꢀMS:
m/z 155.10 [MꢀH]ꢀ.
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3-Bromobenzoic acid (3ag).46 Figure 2; yellow solid (78 mg, 85%); m.p. 150ꢀ155 C; H NMR (400
MHz, acetoneꢀd6): δ 8.15 (s, 1H), 8.03 (d, J = 8.0 Hz, 1H), 7.82ꢀ7.79 (m, 1H), 7.50 (t, J = 8.0 Hz, 1H);
IR (CHCl3): νmax 2842, 2657, 2552, 1682, 1568, 1437, 1313, 1261, 1083 cmꢀ1; ESIꢀMS: m/z 199.10 [Mꢀ
H]ꢀ.
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[1,1'-Biphenyl]-4-carboxylic acid (3ah).46 Figure 2; yellow solid (76 mg, 82%); m.p. 150ꢀ155 C; 1H
NMR (400 MHz, acetoneꢀd6): δ 8.14 (d, J = 8.0 Hz, 2H), 7.81 (d, J = 4.0 Hz, 2H), 7.55 (d, J = 8.0 Hz,
2H) 7.53 (d, J = 8.0 Hz, 2H), 7.44 (t, J = 8.0 Hz, 1H); IR (CHCl3): νmax 2846, 2557, 2552, 2442, 2362,
1680, 15580 1437, 1261, 1261, 1040 cmꢀ1; ESIꢀMS: m/z 197.10 [MꢀH]ꢀ.
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3-Methoxybenzoic acid (3ai).48 Figure 2; white solid (64 mg, 89%); m.p. 100ꢀ102 C; H NMR (400
MHz, CDCl3): δ 7.73 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 1H),
3.85 (s, 3H); IR (CHCl3): νmax 3392, 2922, 2850, 1681, 1584, 1456, 1439, 1414, 1281, 1233, 1193, 1047
cmꢀ1; ESIꢀMS: m/z 151.20 [MꢀH]ꢀ.
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4-Nitrobenzoic acid (3aj).46 Figure 2; yellow solid (64 mg, 89%); H NMR (400 MHz, acetoneꢀd6): δ
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8.37ꢀ8.35 (m, 2H), 8.29ꢀ8.27 (m, 2H); IR (CHCl3): νmax 3113, 2918, 1959, 1691, 1605, 1520, 1495,
1430, 1293, 1128, 1109, 1014 cmꢀ1; ESIꢀMS: m/z 166.1000 [MꢀH]ꢀ.
3,4,5-Trimethoxybenzoic acid (3ak).49 Figure 2; white solid (87 mg, 86%); m.p. 170ꢀ175 oC; 1H NMR
(400 MHz, acetoneꢀd6): δ 7.32 (s, 2H), 3.88 (s, 6H), 3.80 (s, 3H); IR (CHCl3): νmax3419, 3018, 2836,
2645, 1682, 1586, 1416, 1325, 1269, 1224, 1123, 1001 cmꢀ1; ESIꢀMS: m/z 211.2000 [MꢀH]ꢀ.
General procedure for synthesis of C-1 acylated products 1a-h, 5a-d and 7a-b by coupling of N-
heterocycles and benzylamine. To the solution of Nꢀheterocycles 2, 4 or 6 (100 mg, 1 equiv.) in 1 mL
of ionic liquid was added 2 equiv of benzylamine 3 followed by addition of (NH4)2S2O8 (3 equiv.).
Reaction mixture was then heated at 120 oC for 12 h. After completion of the reaction, resulting reaction
mixture was extracted with ethyl acetate and diethyl ether. Ether layer was collected and dried over
rotary evaporator so as to recover ionic liquid for further use. Ethyl acetate layer was separated and
concentrated on rotavapor to get crude product. Purification by using silica gel chromatography (hexane:
EtOAc ꢀ 10:1) yielded pure products 1a-h, 5a-d and 7a-b.
Phenyl(quinoxalin-2-yl)methanone (1a).20 Figure 3; yellow solid (143 mg, 80%); m.p. 80ꢀ85 C; H
NMR (400 MHz, CDCl3): δ 9.50 (s, 1H), 8.26ꢀ8.20 (m, 4H), 7.91ꢀ7.86 (m, 2H), 7.67ꢀ7.65 (m, 1H),
7.57ꢀ5.53 (m, 2H); IR (CHCl3): νmax 3399, 2923, 2955, 2852, 1730, 1659, 1597, 1491, 1464, 1447,
1322, 1310, 1207, 1184, 1163, 1126, 1080 cmꢀ1; ESIꢀMS: m/z 235.1057 [M+H]+.
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(4-Chlorophenyl)(quinoxalin-2-yl)methanone (1b).20 Figure 3; yellow solid (168 mg, 82%); m.p. 110ꢀ
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115 C; H NMR (400 MHz, CDCl3): δ 9.51 (s, 1H), 8.27ꢀ8.19 (m, 4H), 7.94ꢀ7.87 (m, 2H), 7.54ꢀ7.50
(m, 2H); ); IR (CHCl3):νmax 3444, 2918, 2346, 1668, 1590, 1463, 1317, 1167, 1127, 1090, 1014 cmꢀ1;
ESIꢀMS: m/z 269.0715 [M+H]+.
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(4-Fluorophenyl)(quinoxalin-2-yl)methanone (1c). Figure 3; yellow oil (155 mg, 81%); 1H NMR (400
MHz, CDCl3): δ 9.48 (s, 1H), 8.35ꢀ8.31 (m, 2H), 8.21ꢀ8.17 (m, 2H), 7.92ꢀ7.83 (m, 2H), 7.22 (t, J = 8
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Hz, 2H); C NMR (100 MHz, CDCl3) δ 194.3, 171.2, 168.7, 152.2, 149.1, 147, 144.1, 137.9, 137.8,
135.9, 135.7, 134.7, 134.2, 133.2, 119.5, 119.3; IR (CHCl3): νmax 3428, 1957, 2923, 2852, 1643, 1598,
1505, 1414, 1294, 1233, 1159, 1133 cmꢀ1; ESIꢀMS: m/z 253.0640 [M+H]+; TOFꢀHRMS calcd for
C15H10FN2O [M+H]+ 253.0772, found 253.0770.
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(3-Chlorophenyl)(quinoxalin-2-yl)methanone (1d).50 Figure 3; yellow oil (160 mg, 78%); H NMR
(400 MHz, CDCl3): δ 9.52 (s, 1H), 8.28ꢀ8.15 (m, 4H), 7.93ꢀ7.88 (m, 2H), 7.65ꢀ7.64 (m, 1H), 7.63ꢀ7.47
(m, 1H); IR (CHCl3): νmax 3584, 3419, 3068, 2924, 2957, 2853, 1725, 1666, 1568, 1493, 1465, 1422,
1363, 1312, 1207, 1166, 1081 cmꢀ1; ESIꢀMS: m/z 269.03 [M+H]+.
(3-Fluorophenyl)(quinoxalin-2-yl)methanone (1e). Figure 3; yellow oil (145 mg, 75%); 1H NMR (400
MHz, CDCl3): δ 9.50 (s, 1H), 8.21 (d, J = 8.0 Hz, 2H), 8.07ꢀ8.04 (m, 1H), 8.01ꢀ7.98 (m, 1H), 7.93ꢀ7.86
(m, 2H), 7.54ꢀ7.48 (m, 1H), 7.38ꢀ7.33 (m, 1H); 13C NMR (100 MHz, CDCl3) δ 194.7, 167.5, 151.8,
149.1, 147.1, 144.2, 136.1, 134.8, 134.3, 133.9, 133.3, 130.9, 128.2, 127.8, 124.5, 122.0; IR (CHCl3):
νmax 3386, 2923, 2852, 1738, 1674, 1585, 1435, 1363, 1240, 1209, 1184, 1080 cmꢀ1; ESIꢀMS: m/z
253.09 [M+H]+; TOFꢀHRMS calcd for C15H10FN2O [M+H]+ 253.0772, found 253.0772.
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Quinoxalin-2-yl(4-(trifluoromethyl)phenyl)methanone (1f). Figure 3; yellow oil (180 mg, 78%); H
NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 8.39 (d, J = 8 Hz, 2H), 8.25ꢀ8.19 (m, 2H), 7.97ꢀ7.88 (m, 2H),
7.83 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 191.4, 147.6, 147.1, 145.1, 143.4, 140.4,
138.5, 132.5, 131.5, 130.5, 129.5, 125.4, 125.3, 124.5, 123.9, 119.1; IR (CHCl3): νmax 3444, 2099, 1658,
1650, 1644, 1633, 1318 cmꢀ1; ESIꢀMS: m/z 303.1067 [M+H]+; TOFꢀHRMS calcd for C16H10F3N2O
[M+H]+ 303.0740, found 303.0735.
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Quinoxalin-2-yl(p-tolyl)methanone (1g).21 Figure 3; yellow solid (134 mg, 77%); m.p. 102ꢀ105 oC; 1H
NMR (400 MHz, CDCl3): δ 9.45 (s, 1H), 8.20 (d, J = 8 Hz, 2H), 8.15 (d, J = 8 Hz, 2H), 7.89ꢀ7.84 (m,
2H), 7.34 (d, J = 8.0 Hz, 2H), 2.46 (s, 3H); 13C NMR (100 MHz, CDCl3): δ 195.4, 152.6, 148.9, 148.2,
146.7, 144, 136.5, 135.4, 134.9, 134.2, 133.9, 132.9, 132.7, 25.4; IR (CHCl3): νmax 3421, 2954, 2928,
2851, 1731, 1658, 1606, 1571, 1464, 1491, 1319, 1233, 1209, 1185, 1161 cmꢀ1; ESIꢀMS: m/z 249.11
[M+H]+.
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Quinoxalin-2-yl(3-(trifluoromethyl)phenyl)methanone (1h). Figure 3; yellow oil (163 mg, 70%); H
NMR (400 MHz, CDCl3): δ 9.58 (s, 1H), 8.62 (s, 1H), 8.49 (d, J = 8 Hz, 1H), 8.25ꢀ8.19 (m, 2H), 7.97ꢀ
7.89 (m, 3H), 7.72 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 194.6, 151.5, 149, 147.3, 144.2,
140, 138.2, 136.3, 134.9, 134.3, 133.6, 133.3, 132.8, 132.1, 132.0; IR (CHCl3): νmax 3398, 2923, 2851,
1730, 1666, 1611, 1339, 1304, 1283, 1228, 1161, 1128, 1073, 1013 cmꢀ1; ESIꢀMS: m/z 303.10 [M+H]+;
TOFꢀHRMS calcd for C16H9F3N2OH [M+H]+ 303.0740, found 303.0736.
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Isoquinolin-1-yl(phenyl)methanone (5a).20 Figure 3; white solid (90 mg, 50%); m.p. 72ꢀ75 C; H
NMR (400 MHz, CDCl3): δ 8.64 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H),
7.97ꢀ7.95 (m, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.74ꢀ7.73 (m, 1H), 7.62ꢀ7.58 (m,
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1H), 7.48ꢀ7.43 (m, 3H); C NMR (100 MHz, CDCl3): δ 198, 160.2, 144.8, 140.6, 140.4, 137.6, 137.5,
137.2, 134.7, 134.5, 133.9, 133.6, 132.3, 132.2, 132, 130.9, 130.2, 130, 126.6, 126.5; IR (CHCl3): νmax
3058, 2924, 2623, 1918, 1672, 1622, 1597, 1418, 1389, 1214, 1278, 1249, 1227, 1156 cmꢀ1; ESIꢀMS:
m/z 234.11 [M+H]+.
(4-Fluorophenyl)(isoquinolin-1-yl)methanone (5b).35 Figure 3; yellow solid (88 mg, 45%); m.p. 92ꢀ95
oC; 1H NMR (400 MHz, CDCl3): δ 8.61 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0 Hz, 1H), 8.03ꢀ7.98 (m, 2H),
7.91 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.73ꢀ7.70 (m, 1H), 7.61ꢀ7.59 (m, 1H), 7.15 (t, J = 8.0
Hz, 2H); 13C NMR (100 MHz, CDCl3): δ 196.6, 171.2, 159.7, 144.7, 140.6, 137.4, 137.3, 136.5, 134.7,
132.3, 131, 130.2, 129.9, 126.2, 119.6, 119.3, 119.1; IR (CHCl3): νmax 3421, 3057, 2928, 2609, 1922,
1668, 1597, 1504, 1412, 1387, 1279, 148, 1231, 1151, 1049 cmꢀ1; ESIꢀMS: m/z 252.11 [M+H]+.
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(3-Chlorophenyl)(isoquinolin-1-yl)methanone (5c).35 Figure 3; yellow oil (100 mg, 48%); H NMR
(400 MHz, CDCl3): δ 8.61 (d, J = 4.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 7.96 (s, 1H), 7.94 (d, J = 8.0
Hz, 1H), 7.85ꢀ7.82 (m, 2H), 7.77ꢀ7.73 (m, 1H), 7.66ꢀ7.64 (m, 1H), 7.58ꢀ7.56 (m, 1H), 7.43 (t, J = 8.0
Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 197.6, 159.1, 144.9, 142.2, 140.7, 138.5, 137.3, 134.7, 134.5,
133.6, 132.8, 132.4, 131, 130.3, 129.8, 126.9; IR (CHCl3): νmax 3585, 3056, 2925, 2853, 1667, 1570,
1425, 1245, 1157, 1018, 1050 cmꢀ1; ESIꢀMS: m/z 268.08 [M+H]+.
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(3-Bromophenyl)(isoquinolin-1-yl)methanone (5d).35 Figure 3; yellow oil (145 mg, 47%); H NMR
(400 MHz, CDCl3): δ 8.61 (d, J = 4.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 8.11 (s, 1H), 7.94 (d, J = 8.0
Hz, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.78ꢀ7.72 (m, 2H), 7.65 (t, J = 8.0 Hz, 1H),
7.37 (t, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): δ 196.6, 159.1, 144.9, 142.4, 140.7, 140.1,
137.4, 134.7, 133.8, 133.2, 132.4, 131.0, 130.3, 129.9, 126.9, 126.5; IR (CHCl3): νmax3419, 3057, 2922,
2850, 1672, 1563, 1423, 1278, 1244, 1155, 1070, 1017 cmꢀ1; ESIꢀMS: m/z 312.04 [M+H]+.
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Phenyl(quinolin-4-yl)methanone (7a).51 Figure 3; yellow oil (108 mg, 80%); H NMR (400 MHz,
CDCl3): δ 9.04 (d, J = 4.0 Hz, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.88ꢀ7.85 (m, 3H), 7.79 (t, J = 8.0 Hz, 1H),
7.66 (t, J = 8.0 Hz, 1H), 7.56ꢀ7.53 (m, 1H), 7.52 (t, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 1H); ESIꢀMS:
m/z 234.08 [M+H]+.
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Quinolin-4-yl(p-tolyl)methanone (7b). Figure 3; yellow oil (125 mg, 65%); H NMR (400 MHz,
CDCl3): δ 9.01 (d, J = 4.0 Hz, 1H), 8.20 (d, J = 8.0 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0
Hz, 3H), 7.53 (t, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 3H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3): δ
195, 149.5, 148.5, 145.4, 144.9, 134.2, 130.4, 130, 129.9, 129.5, 129.2, 127.6, 125.5, 119.4, 21.8; IR
(CHCl3): νmax 3583, 3283, 2923, 3054, 2345, 1730, 1651, 1604, 1505, 1463, 1312, 1276, 1178, 1155
cmꢀ1; ESIꢀMS: m/z 248.08 [M+H]+; TOFꢀHRMS calcd for C17H14NO [M+H]+ 248.1070, found
248.1077.
General procedure for synthesis of (E)-2-styrylquinolines 9a-i. To the solution of 2ꢀ
methylquinoline (8, 100 mg, 1 equiv.) in 1 mL of ionic liquid was added 2 equiv of benzylamine 3 and
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mixture was extracted with ethyl acetate and diethyl ether. Ether layer was collected and dried over
rotavapor so as to recover ionic liquid for further use. Ethyl acetate layer was separated and concentrated
on rotavapor to get crude product. The crude products were purified by using silica gel chromatography
(hexane: EtOAc ꢀ 10:1) to get pure products 9a-i.
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(E)-2-Styrylquinoline (9a).52 Figure 5; offꢀwhite solid (96 mg, 60%); m.p. 95ꢀ100 C; H NMR (400
MHz, CDCl3): δ 8.09 (d, J = 8.0 Hz, 2H), 7.76 (d, J = 8.0 Hz, 1H), 7.69ꢀ7.62 (m, 5H), 7.49ꢀ7.37 (m,
4H), 7.33ꢀ7.29 (m, 1H); 13C NMR (125 MHz, CDCl3): δ 157.4, 149.7, 137.8, 131.2, 130.6, 130.4, 130.3,
130.1, 128.9, 128.7, 127.6, 120.7; IR (CHCl3): νmax 3387, 3057, 2919, 2849, 1633, 1611, 1593, 1551,
1502, 1446, 1426, 1345, 1316, 1203, 1181, 1140, 1013 cmꢀ1; ESIꢀMS: m/z 232.00 [M+H]+.
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(E)-2-(4-Methoxystyryl)quinoline (9b).52 Figure 5; offꢀwhite solid (100 mg, 55%); m.p. 120ꢀ123 C;
o
1H NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.8 Hz, 1H), 8.07 (d, J = 8.8 Hz, 1H), 7.80 (d, J = 8.0 Hz,
1H), 7.70ꢀ7.58 (m, 5H), 7.50ꢀ7.48 (m, 1H), 7.30 (d, J = 16.8 Hz, 1H), 6.95ꢀ6.93 (m, 2H), 3.85 (s, 3H);
13C NMR (125 MHz, CDCl3): δ 160.2, 156.4, 148.3, 136.2, 134.1, 129.7, 129.4, 129.1, 128.7, 127.5,
127.2, 126.9, 125.9, 119.2, 114.3, 55.4; IR (CHCl3): νmax 3745, 3416, 2917, 2849, 1632, 1596, 1554,
1455, 1429, 1328, 1303, 1258, 1175, 1111, 1027 cmꢀ1; ESIꢀMS: m/z 262.20 [M+H]+.
(E)-2-(4-Methylstyryl)quinoline (9c).53 Figure 5; offꢀwhite solid (95 mg, 56%); m.p. 140ꢀ143 C; H
o
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NMR (400 MHz, CDCl3): δ 8.13ꢀ8.07 (m, 2H), 7.79 (d, J = 6.4 Hz, 1H), 7.71ꢀ7.65 (m,3H), 7.56 (d, J =
13
6.4 Hz, 2H), 7.50ꢀ7.48 (m, 1H), 7.39 (d, J = 13.2 Hz, 1H), 7.23 (d, J = 6.4 Hz, 2H), 2.39 (s, 3H); C
NMR (125 MHz, CDCl3): δ 136.2, 134.5, 129.7, 129.6, 129.1, 128, 127.5, 127.2, 126, 119.2, 21.4; IR
(CHCl3): νmax 3587, 3420, 2919, 2354, 2346, 1637, 1591, 1502, 1425, 1177, 1118, 1016 cmꢀ1; ESIꢀMS:
m/z 245.80 [M+H]+.
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(E)-2-(2-Chloro-4-fluorostyryl)quinoline (9d). Figure 5; yellow oil (115 mg, 58%); H NMR (400
MHz, CDCl3): δ 8.17 (d, J = 7.2 Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.99 (d, J = 13.2 Hz, 1H), 7.81ꢀ7.71
(m, 4H), 7.54ꢀ7.51 (m, 1H), 7.36 (d, J = 13.2, 1H), 7.20ꢀ7.18 (m, 1H), 7.07ꢀ7.03 (m, 1H); 13C NMR
(125 MHz, CDCl3): δ 164.7, 157.0, 149.6, 137.9, 132.9, 131.3, 130.7, 130.6, 129.5, 128.9, 127.9, 120.4,
118.5, 116.0; IR (CHCl3): νmax 3393, 3061, 3031, 2922, 2851, 1593, 1490, 1504, 1428, 1407, 1272,
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1247, 1229, 1120, 1044 cmꢀ1: ESIꢀMS: m/z 284.70 [M+H]+; TOFꢀHRMS calcd for C17H12ClFN [M+H]+
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284.0637, found 284.0622.
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(E)-2-(3-Chlorostyryl)quinoline (9e).52 Figure 5; offꢀwhite solid (115 mg, 62%); m.p. 95ꢀ100 C;1H
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NMR (400 MHz, CDCl3): δ 8.16 (d, J = 6.8 Hz, 1H), 8.10 (d, J = 6.8 Hz, 1H), 7.81 (d, J = 6.4, 1H),
7.73 (m, 1H), 7.67ꢀ7.63 (m, 3H), 7.53ꢀ7.50 (m, 2H), 7.42ꢀ7.27 (m, 3H); 13C NMR (125 MHz, CDCl3): δ
155.4, 148.2, 136.5, 130, 129.9, 129.2, 128.5, 127.5, 127.1, 126.4, 125.4, 119.5; IR (CHCl3): νmax 3392,
3058, 2955, 2924, 2853, 1931, 1732, 1613, 1562, 1594, 1504, 1465, 1376, 1311, 1202, 1118, 1096,
1077 cmꢀ1; ESIꢀMS: m/z 265.90 [M+H]+.
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(E)-2-(2-Bromostyryl)quinoline (9f).52 Figure 5; offꢀwhite solid (130 mg, 60%); m.p. 58ꢀ60 C; H
NMR (500 MHz, CDCl3): δ 8.16 (d, J = 9.0 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H), 8.01 (d, J = 16 Hz, 1H),
7.82ꢀ7.70 (m, 4H), 7.64 (d, J = 8.0 Hz, 1H), 7.53ꢀ7.50 (m, 1H), 7.40ꢀ7.34 (m, 2H), 7.19ꢀ7.17 (m, 1H);
13C NMR (125 MHz, CDCl3): δ 155.7, 148.2, 133.2, 132.9, 129.8, 129.7, 129.3, 127.7, 127.5, 127.1,
126.4, 118.8; IR (CHCl3): νmax 3585, 3381, 3056, 2955, 2923, 2851, 1952, 1726, 1614, 1555, 1595,
1504, 1467, 1437, 1427, 1376, 1347, 1312, 1182, 1118, 1080 cmꢀ1; ESIꢀMS: m/z 311.80 [M+H]+.
(E)-2-(3-Fluorostyryl)quinoline (9g).44 Figure 5; offꢀwhite solid (107 mg, 61%); m.p. 245ꢀ248 oC; 1H
NMR (400 MHz, CDCl3): δ 8.16 (d, J = 8.8 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.81 (d, J = 8.0 Hz, 1H),
7.74ꢀ7.65 (m, 3H), 7.54ꢀ7.50 (m, 1H), 7.42ꢀ7.34 (m, 4H), 7.05ꢀ7.00 (m, 1H); 13C NMR (125 MHz,
CDCl3): δ 163.6, 156.9, 149.7, 140.2, 137.9, 134.5, 134.5, 131.7, 131.6, 131.3, 130.7, 128.9, 128.8,
127.8, 124.6, 120.9, 116.8, 114.9; IR (CHCl3): νmax 3585, 3299, 3059, 3034, 2920, 2850, 1731, 1637,
1606, 1593, 1582, 1504, 1446, 1428, 1350, 1313, 1268, 1142, 1122, 1018 cmꢀ1; ESIꢀMS: m/z 250.20
[M+H]+.
o
(E)-2-(4-Chlorostyryl)quinoline (9h).52 Figure 5; offꢀwhite solid (120 mg, 64%); m.p. 140ꢀ145 C; 1H
NMR (400 MHz, CDCl3): δ 8.12ꢀ8.07 (m, 2H), 7.82 (d, J = 6.4 Hz, 1H), 7.72ꢀ7.70 (m, 1H), 7.64ꢀ7.60
(m, 2H), 7.55ꢀ7.49 (m, 3H), 7.37ꢀ7.34 (m, 3H); 13C NMR (125 MHz, CDCl3): δ 155.6, 148.2, 136.5,
133, 129.9, 129.5, 129.2, 129, 128.4, 127.5, 126.3, 119.3; IR (CHCl3): νmax 3585, 3363, 3045, 3028,
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2918, 2850, 1903, 1613, 1591, 1504, 1492, 1428, 1404, 1315, 1106, 1096, 1079, 1009 cmꢀ1; ESIꢀMS:
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m/z 265.80 [M+H]+.
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(E)-2-(4-Fluorostyryl)quinoline (9i).52 Figure 5; offꢀwhite solid (110 mg, 63%); m.p. 121ꢀ125 C; H
NMR (400 MHz, CDCl3): δ 8.14 (d, J = 6.8 Hz, 1H), 8.09 (d, J = 6.8 Hz, 1H), 7.79 (d, J = 6.4 Hz, 1H),
7.71ꢀ7.60 (m, 5H), 7.52 (t, J = 5.6 Hz, 1H), 7.34 (d, J = 12.8 Hz, 1H), 7.11 (t, J = 7.2 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 163.9, 161.9, 155.8, 148.2, 136.4, 133.1, 132.7, 129.8, 129.1, 128.9, 128.8, 128.6,
127.5, 126.2, 119.2, 115.9, 115.7; IR (CHCl3): νmax 3421, 3035, 2920, 1613, 1555, 1509, 1429, 1413,
1316, 1297, 1220, 1165, 1102, 1121, 1015 cmꢀ1; ESIꢀMS: m/z 250.00 [M+H]+.
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General procedure for synthesis of (E)-2-styrylpyridines 11a-f. To the solution of 2ꢀ
methylpyridine (10, 100 mg, 1 equiv.) in 2 mL of DMSO was added 2 equiv of benzylamine 3, 80 mol%
o
of iodine and 20 µl of HCl. Reaction mixture was then heated at 120 C for 12 h. After completion of
the reaction, resultant reaction mixture was extracted with ethyl acetate and water. Ethyl acetate layer
was separated and concentrated on rotavapor to get crude product. The crude products were purified by
using silica gel chromatography (hexane: EtOAc ꢀ 10: 1) to get pure products 11a-f.
(E)-2-Styrylpyridine (11a).54 Figure 6; yellow oil (97 mg, 50%); H NMR (400 MHz, CDCl3): δ 8.62
1
(d, J = 4.0 Hz, 1H), 7.69ꢀ7.65 (m, 1H), 7.61ꢀ7.58 (m, 3H), 7.41ꢀ7.36 (m, 3H), 7.32ꢀ7.28 (m, 1H), 7.17ꢀ
13
7.14 (m, 2H); C NMR (125 MHz, CDCl3) δ 157, 151, 138.1, 138, 134.2, 130.2, 129.8, 128.2, 128.6,
123.6, 123.5; IR (CHCl3): νmax 3361, 2921, 2850, 1734, 1638, 1584, 1562, 1494, 1468, 1429, 1186,
1149, 1080, 1019 cmꢀ1; ESIꢀMS: m/z 181.90 [M+H]+.
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(E)-5-Ethyl-2-styrylpyridine (11b). Figure 6; yellow oil (105 mg, 54%); H NMR (400 MHz, CDCl3):
δ 8.45 (s, 1H), 7.58ꢀ7.54 (m, 3H), 7.46ꢀ7.44 (m, 1H), 7.37ꢀ7.26 (m, 4H), 7.18 (d, J = 16.0 Hz, 1H), 2.65
(dd, J = 8.0, 16.0 Hz, 2H), 1.25 (t, J = 8.0 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ 153.2, 149.3, 137.9,
136.9, 135.9, 131.8, 128.7, 128.1, 127.9, 127, 121.7, 25.9, 15.3; IR (CHCl3): νmax 3380, 3036, 2966,
2929, 2874, 1608, 1583, 1487, 1445, 1395, 1324, 1270, 1242, 1188, 1076, 1024 cmꢀ1; ESIꢀMS: m/z
209.90 [M+H]+; TOFꢀHRMS calcd for C15H16N [M+H]+ 210.1277, found 210.1259.
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(E)-2-Methyl-6-styrylpyridine (11c).55 Figure 6; yellow oil (100 mg, 55%); H NMR (400 MHz,
CDCl3): δ 7.64ꢀ7.55 (m, 3H), 7.39 (t, J = 6.0 Hz, 2H), 7.31ꢀ7.17 (m, 4H), 7.04 (d, J = 6.0 Hz, 1H), 2.60
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(s, 3H); C NMR (125 MHz, CDCl3): δ 159.7, 156.5, 138.1, 133.8, 130.6, 130.1, 129.6, 128.5, 128.2,
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123.2, 120.2, 24.4; IR (CHCl3): νmax 3335, 3060, 3027, 2958, 2924, 2852, 1725, 1638, 1583, 1567,
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1537, 1453, 1326, 1188, 1157, 1074, 1028 cmꢀ1; ESIꢀMS: m/z 195.90 [M+H]+.
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(E)-2-(4-Chlorostyryl)pyridine (11d).56 Figure 6; yellow oil (93 mg, 40%); H NMR (400 MHz,
CDCl3): δ 8.62ꢀ8.60 (m, 1H), 7.69ꢀ7.64 (m, 1H), 7.60 (d, J = 16.0 Hz, 1H), 7.51ꢀ7.48 (m, 2H), 7.39ꢀ
7.26 (m, 3H), 7.18ꢀ7.12 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 156.6, 151.1, 138.2, 136.6, 135.4,
132.9, 130.4, 129.8, 129.7, 123.8, 123.7; IR (CHCl3): νmax 3416, 3045, 3001, 2956, 2924, 2852, 2359,
1714, 1636, 1560, 1582, 1491, 1469, 1326, 1274, 1186, 1148, 1090, 1046 cmꢀ1; ESIꢀMS: m/z 215.90
[M+H]+.
(E)-2-(3-Chlorostyryl)pyridine (11e).57 Figure 6; offꢀwhite solid (105 mg, 45%); Yield, 45%; 105 mg;
o
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m.p. >300 C; H NMR (400 MHz, CDCl3): δ 8.63ꢀ8.62 (m, 1H), 7.69ꢀ7.67 (m, 1H), 7.60 (d, J = 12.8
Hz, 2H), 7.45ꢀ7.37 (m, 2H), 7.32ꢀ7.27 (m, 2H), 7.19ꢀ7.15 (m, 2H); 13C NMR (125 MHz, CDCl3): δ
156.5, 151.2, 139.9, 138.1, 136.1, 132.7, 131.4, 130.6, 129.7, 128.2, 126.9, 123.9; IR (CHCl3): νmax
3385, 3057, 2919, 2850, 1954, 1690, 1663, 1729, 1635, 1611, 1551, 1593, 1502, 1446, 1426, 1345,
1316, 1182, 1117, 1140, 1071 cmꢀ1; ESIꢀMS: m/z 215.90 [M+H]+.
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(E)-2-(4-Chlorostyryl)-6-methylpyridine (11f). Figure 6; yellow oil (112 mg, 52%); H NMR (400
MHz, CDCl3): δ 7.58ꢀ7.49 (m, 4H), 7.34 (d, J = 8.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 1H), 7.15 (d, J = 16.4
13
Hz, 1H), 7.04 (d, J = 7.6 Hz, 1H), 2.59 (s, 3H); C NMR (125 MHz, CDCl3): δ 158.4, 154.7, 136.8,
135.3, 133.8, 131, 130.9, 128.9, 128.2, 122, 119, 24.7; IR (CHCl3): νmax 3417, 2958, 2924, 2851, 2346,
1725, 1639, 1582, 1491, 1451, 1404, 1375, 1286, 1121, 1089, 1074, 1012 cmꢀ1; ESIꢀMS: m/z 229.80
[M+H]+; TOFꢀHRMS calcd for C14H13ClN [M+H]+ 230.0731, found 230.0721.
ACKNOWLEDGEMENT. R.S is thankful to DST for award of INSPIRE fellowship. Authors thank
analytical department, IIIM for NMR and MS analysis of our compounds. This work was supported by
SERB project (grant no SR/FT/CSꢀ168/2011).
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AUTHOR INFORMATION.
Corresponding Author
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*Tel: +91ꢀ191ꢀ2586333; Tel: +91ꢀ191ꢀ2585006 (Extn. 345). Eꢀmail: sbharate@iiim.ac.in,
sandipbharate@gmail.com (S.B.B.)
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ORCID: 0000ꢀ0001ꢀ6081ꢀ5787
Notes
The authors declare no competing financial interest.
SUPPORTING INFORMATION AVAILABLE: NMR spectra scans. This material is available
free of charge via the Internet at http://pubs.acs.org.
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