Microwave assisted water mediated benzylic C-H functionalization of methyl aza-arenes and nucleophilic addition to aromatic aldehydes

Article abstract of DOI:10.1016/j.tetlet.2013.07.053

A highly efficient method is described for the sp³ C-H bond functionalization of methyl aza-arenes in the presence of water under microwave irradiation and subsequent addition to aromatic aldehydes. This transformation represents an efficient way to synthesize 2-alkyl aza-arene derivatives from simple starting materials.

Full text of DOI:10.1016/j.tetlet.2013.07.053

Tetrahedron Letters 54 (2013) 5087–5090
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Tetrahedron Letters
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Microwave assisted water mediated benzylic C–H functionalization
of methyl aza-arenes and nucleophilic addition to aromatic
aldehydes
⇑
N. Nageswara Rao, H. M. Meshram
Medicinal Chemistry and Pharmacology Division, CSIR-Indian Institute of Chemical Technology, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
A highly efficient method is described for the sp3 C–H bond functionalization of methyl aza-arenes in the
presence of water under microwave irradiation and subsequent addition to aromatic aldehydes. This
transformation represents an efficient way to synthesize 2-alkyl aza-arene derivatives from simple
starting materials.
Article history:
Received 24 April 2013
Revised 5 July 2013
Accepted 8 July 2013
Available online 13 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Aldehyde
Catalyst-free conditions
Methyl quinoline
Microwave and water
Formation of carbon–carbon bond by sp3 C–H functionalization
is an important transformation in organic chemistry.1 In particular,
the benzylic sp3 C–H functionalization of 2-alkyl aza-arenes is a
challenging task due to less reactivity of alkyl groups. This type
of reaction is particularly important because, alkyl aza-arene deriv-
atives are known to possess a wide range of pharmaceutical activ-
ities, such as anti-inflammatory agents, anti cancer, anti-HIV
agents, and usage as molecular probes.2 Consequently, many ap-
proaches have been developed for the activation of sp3 CÀH bond
of alkyl aza-arenes catalyzed by transition metals,3 Lewis acids4
and Bronsted acids.5 In addition, different protocols have been re-
ported for the sp3 C–H activation of methyl aza-arenes involving
highly reactive carbonyl compounds.6 It was reported that Lewis
acid catalyzed reaction of methyl aza-arenes with aldehydes at ele-
vated temperatures produced dehydrated products.7 To the best of
our knowledge only one method is known for the benzylic C–H
bond functionalization of aza-arenes promoted by Bronsted acid.5b
Indeed, this protocol is limited only to aromatic aldehydes bearing
electron withdrawing groups. Though the reported methods are
satisfactory, they suffer from certain drawbacks like the use of
expensive catalysts, toxic metals, extended reaction times, and
environmentally hazardous organic solvents. In view of this, the
development of a mild and highly efficient method for the direct
sp3 C–H functionalization of alkyl aza-arenes is desirable.
CHO
R4
R1
R1
H2O, MWI
105 0C, 18-40 min
OH
R3
R4
N
R3
N
R2
R2
R1 = H, Br, NO2, OMe
R2 = H, NO2
R3 = H, OMe, NO2
R4 = H, OMe, F, Cl, Br, CN, NO2
Scheme 1. sp3 C–H activation of methyl aza-arene and nucleophilic addition to
aromatic aldehydes.
Table 1
Screening of solvents and temperaturea
Entry
Solvent
Temperature (°C)
Yieldb (%)
1
2
3
4
5
6
7
8
9
THF
90
90
NRc
NRc
NRc
30
40
60
60
70
50
85
CH3CN
DCE
110
110
110
110
110
105
80
DMF
DMSO
Ionic liquid
PEG-400
D2O
H2O
H2O
H2O
10
11
105
120
60
a
Reaction conditions: methylquinoline (1.8 mmol) and 4-nitrobenzaldehyde
(1 mmol) in 2 mL of the solvent for 20 min under MW irradiation.
b
Isolated yield.
No reaction.
c
⇑
Corresponding author. Tel.: +91 402719630.
E-mail address: hmmeshram@yahoo.com (H.M. Meshram).
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.053

5088
N. Nageswara Rao, H. M. Meshram / Tetrahedron Letters 54 (2013) 5087–5090
Microwave irradiation has become a complementary tool in the
Reaction of 2-methyl quinoline (1a) with p-nitro benzalde-
hyde (2k) in the presence of water under microwave irradiation
proceeded smoothly to give the expected product in excellent
yield (3k). To check the efficiency of water as a solvent under
similar conditions, a study has been made by varying the solvent
system of the reaction. As seen in Table 1, a variety of reaction
conditions were employed to find out the optimal reaction
conditions.
The result of which revealed that solvents such as tetrahydrofu-
ran, acetonitrile, and 1,2-dichloroethane are not suitable for this
reaction as there is no formation of the desired product even in a
trace quantity (Table 1, entries 1–3). When N,N-dimethylformam-
ide and dimethylsulfoxide were employed as reaction media, the
desired product was obtained in lower yields (Table 1, entries 4
and 5). However, moving on to check some alternative greener
development of green chemistry.8 Microwave irradiation with
water as reaction medium is a highly reliable and sustainable
chemical approach. Water is a clean and safe solvent which is
cheap, non-toxic, non-combustible, non-explosive, and the most
benign environmentally.9 However, water has been rarely used
as a solvent for organic reactions due to the poor solubility of most
of the organic compounds in water. But at elevated temperatures
under microwave irradiation, the physical and chemical properties
of water are altered in such a way that it behaves both as a pseudo-
organic solvent and a phase transfer catalyst too.10
In continuation of our research on sp3 C–H functionalization,11
herein we wish to report a novel, efficient, and catalyst-free meth-
od for the sp3 C–H bond activation of methyl aza-arene and nucle-
ophilic addition to aromatic aldehydes (Scheme 1).
Table 2
sp3 C–H activation of methyl quinoline and nucleophilic addition to various aromatic aldehydes
CHO
OH
R3
R4
H2O
MWI, 1050C
N
R3
N
R4
2
3
1a
Entry
1
Methyl quinoline
Aldehyde (2)
Producta (3)
Time (min)
45
Yieldb,c (%)
O
O
OH
OH
OH
O
O
N
N
40
2a
3a
1a
CHO
OMe
N
N
2
1a
2b
40
55
3b
3c
OMe
CHO
OMe
OMe
2c
2d
3
4
1a
1a
30
30
65
65
CHO
OH
OH
N
N
CHO
F
3d
3e
5
6
7
8
1a
1a
1a
1a
25
25
25
25
70
70
70
75
2e
F
CHO
Cl
OH
OH
OH
N
N
N
2f
3f
3g
3h
Cl
Br
CHO
Br
2g
CHO
CN
2h
CN
CHO
NO2
OH
OH
NO2
2i
2j
9
1a
1a
18
20
85
70
N
N
3i
3j
CHO
CHO
S
S
10
a
b
c
All the products were characterized by 1H NMR, IR,13C NMR, mass, HRMS.
Yield refers to isolated products after purification.
Starting materials were recovered.

N. Nageswara Rao, H. M. Meshram / Tetrahedron Letters 54 (2013) 5087–5090
5089
Table 3
sp3 C–H activation of methyl aza-arenes and nucleophilic addition 4-nitrobenzaldehydel
CHO
OH
R1
H O
2
N
MWI
N
3
NO2
R2
1
2k
NO2
OH
Entry
1
Methyl quinoline
Producta (3)
Temperature
102
Time (min)
15
Yieldb,c (%)
N
N
N
CH3
CH3
85
75
3k
1a
NO2
NO2
OH
N
2
3
4
5
102
102
102
102
28
35
28
30
NO2
1b
O2N
NO2
O2N
3l
OH
3m
OH
N
CH3
N
65
65
70
1c
NO2
Br
Br
N
CH3
N
1d
3n
NO2
MeO
MeO
OH
3o
N
CH3
N
1e
NO2
N
N
N
N
OH
3p
OH
3q
OH
3r
6
7
8
CH3
CH3
102
110
110
25
40
45
60
55
50
1f
NO2
H3C
N
1g
N
NO2
N
CH3
N
1h
NO2
a
b
c
All the products were characterized by IR, mass, HRMS, 1H and 13C NMRS.
Yield refers to pure products after purification.
Starting materials were recovered.
media such as ionic liquid and PEG-400 produced the product in
moderate yields (Table 1, entries 6 and 7). Also, a reaction carried
out under neat condition led to an inseparable mixture of various
products. In addition, among the wide range of solvent systems
tested, the water mediated reactions were the most effective in
terms of yields. Furthermore, varying the temperature below or
above the optimal 105 °C temperature led to a decrease in yields
(Table 1, entries 9 and 11). The time duration of the reaction was
particularly important as longer reaction time, will result in the
formation of the by-products.
and provided the desired products in excellent yields (Table 2, en-
tries 8 and 9). Aromatic aldehydes bearing halogen substituents
were well tolerated and gave a good yield of the products (Table
2, entries 5–7). Furthermore, we extended the scope of aldehydes
to hetero aromatic aldehydes. Hetero aromatic aldehydes gave
the corresponding product in good yield (Table 2, entry 10). Next,
an attempt was made to examine the reactivity of aliphatic alde-
hydes and benzophenones, they however failed to give the desired
product.
Next we moved onto check the scope of 2-alkyl aza-arenes and
the results are summarized in Table 3. Various substituents on the
aromatic ring of the 2-alkyl aza-arenes were well tolerated and the
reaction was found comparable to the unsubstituted aza-arenes.
Both electron-poor (Table 3, entries 2 and 3) and electron-rich (Ta-
ble 2, entry 5) substituted 2-alkyl aza-arenes were effective to fur-
nish the desired products. It was remarkable that halide
substituent was tolerated in the quinoline ring (Table 3, entry 4).
When 2-methyl-quinoxaline was used as the substrate, the yield
of the corresponding adduct was only modest (Table 3, entry 6).
Therefore, this process was not only applicable to quinolines and
quinoxalines but also to 2, 6-lutidine and 2-picoline though with
modest yields (Table 3, entries 7 and 8). Pyrimidine and pyrazines
Having the optimized reaction conditions in hand,12 the scope
of the reaction with regard to the electronic structure of aldehydes
was screened (Table 2). It was found that all aromatic aldehydes
bearing an electron withdrawing group as well as electron-releas-
ing groups underwent smooth coupling though the latter was less
efficient compared to the former. The present protocol is found to
be advantageous over the previous report which only worked with
aromatic aldehyde bearing electron withdrawing groups.5b Reac-
tion of methyl quinoline 1a with aromatic aldehydes bearing elec-
tron neutral and electron-donating substituents led to a modest
yield of the product (Table 2, entries 1–4). Aromatic aldehydes at-
tached to electron-withdrawing substituents proceeded effectively

5090
N. Nageswara Rao, H. M. Meshram / Tetrahedron Letters 54 (2013) 5087–5090
References and notes
1. For selected reviews on sp3 C–H bonds transformations: (a) Chen, X.; Engle, K.
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H
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Scheme 2. A plausible mechanism of the reaction.
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We presume that under microwave irradiation, the acidity of
aza-allylic protons and the ligating ability of the nitrogen atom
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ine formation. The nucleophilic addition of enamine intermediate
to aromatic aldehyde (2) would afford the desired adduct. An
experiment was conducted to check the deuterium exchange dur-
ing the reaction. The reaction was performed in deuteriated water
which did not result in any deuteriated product and thereby elim-
inating any assumption of a proton exchange from the medium
during the course of the reaction (see Scheme 2).
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In summary, we have developed a mild, highly efficient, and
water mediated protocol for the sp3 C–H functionalization of
methyl quinolines with aromatic aldehydes. The method is exten-
sively applicable for the rapid preparation of a library of biologi-
cally active pyridine and quinoline derivatives.
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Acknowledgments
N.N.R. thanks UGC for the award of fellowship and Dr. A. Kamal,
HOD, MCP Division, IICT, for his support and encouragement.
12. General procedure: A sealed 10 mL glass tube containing aldhyde (1 equiv),
methyl quinoline (1.8 equiv) and water (2 mL) was placed in the cavity of a
microwave reactor and irradiated for the appropriate time, at 105 °C
(temperature monitored by a built-in infrared sensor), and power 160 W.
After cooling to room temperature by an air-flow, the tube was removed from
the rotor. The reaction mixture was diluted with water and extracted with
ethyl acetate. The combined ethyl acetate extracts were then dried over
anhydrous Na2SO4 and after removal of the solvent, the mixture was purified
by (silica gel) column chromatography (hexane/AcOEt, 70:30 as eluent) to give
pure products.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.
07.053.