Acid ionic liquid promoted addition of C(sp3)-H bond to aldehyde

Article abstract of DOI:10.1016/j.tetlet.2014.08.034

A novel protocol for acid ionic liquid promoted C(sp³)-H bond functionalization of alkyl azaarenes and nucleophilic addition to aldehydes was developed in good to excellent yields, which provides an efficient approach for the synthesis of alkyl-substituted azaarene derivatives. It is worthwhile to note that acid ionic liquid used for this reaction can be recycled and reused six times without a significant decrease in activity.

Full text of DOI:10.1016/j.tetlet.2014.08.034

Tetrahedron Letters 55 (2014) 5462–5464
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Tetrahedron Letters
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Acid ionic liquid promoted addition of C(sp3)–H bond to aldehyde
Xue-Yan Zhang a, Dao-Qing Dong a, Tao Yue b, Shuang-Hong Hao a, Zu-Li Wang a,
⇑
a College of Chemistry and Pharmaceutical Sciences, Qingdao Agricultural University, Qingdao 266109, PR China
b Chemical Technology Academy of Shandong Province, Jinan, Shandong 250014, PR China
a r t i c l e i n f o
a b s t r a c t
A novel protocol for acid ionic liquid promoted C(sp3)–H bond functionalization of alkyl azaarenes and
nucleophilic addition to aldehydes was developed in good to excellent yields, which provides an efficient
approach for the synthesis of alkyl-substituted azaarene derivatives. It is worthwhile to note that acid
ionic liquid used for this reaction can be recycled and reused six times without a significant decrease
in activity.
Article history:
Received 20 May 2014
Revised 27 July 2014
Accepted 9 August 2014
Available online 14 August 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
2-Methyl pyridine
C–H functionalization
Azaarenes
Acid ionic liquids
Aldehyde
Introduction
Letter we described that acid ionic liquids were also a good catalyst
for C(sp3)–H bond functionalization of alkyl-substituted azaarenes.
Since alkyl-substituted azaarenes such as pyridine and quino-
line derivatives are known to exhibit extremely potent biological,
chemical, and pharmaceutical activities,1 tremendous efforts have
been paid to access these compounds.2 One of the most efficient
methods for obtaining pyridine and quinoline derivatives is the
direct C(sp3)–H functionalization of alkyl-substituted azaarene.
The direct addition of C(sp3)–H bond of alkyl-substituted azaa-
renes to unsaturated chemical bonds was first independently real-
ized in 2010 by Huang and co-workers.3f Then lots of efforts were
made on this area. At present, examples catalyzed by transition
metal,3 Bronsted acids,4 and microwave5 have been reported. Even
in some cases, these reactions could also be realized without any
catalyst.5d,3j Although these methods could meet the demand of
C(sp3)–H bond activation, the discovery of a new, less expensive,
less toxic, and more environmental method is urgently needed.
As we all know, ionic liquids have very low vapor pressure and
high dissolvabilities toward many organic and inorganic sub-
stances. In view of the stable physicochemical properties of ionic
liquids, it can be used as a catalyst or solvent in many reactions
and recycled many times without loss of activity.6 In some cases,
acid ionic liquids can show similar acidity with Bronsted acids.
Acid ionic liquid catalyzed Pechmann reaction,7 esterification reac-
tion,8 Mannich reaction,9 and so on10 have been disclosed. In this
At the outset of our experiment, a series of acid ionic liquids
such as [C3SO3Hnhm][HSO4],11 [Hnhm][HSO4],11 [Hmim][H2PO4],12
PyAcCl,13 [Et3NH][HSO4],14 and MAcImCl13 were synthesized
according to the literature (Scheme 1). Then they were subjected
to the model reaction of 2,6-lutidine and p-nitrobenzaldehyde
in H2O at 100 °C. As can be seen from Table 1, a moderate
yield (61%) of the desired products was isolated when acid ionic
liquids [Hmim][H2PO4] were used (Table 1, entry 3). Although
[C3SO3Hnhm][HSO4], [Hnhm][HSO4], and [Et3NH][HSO4] have the
strong acidity, the lower yields were obtained when they were
used (Table 1, entries 1–2, 5). On the other hand, PyAcCl and MAc-
ImCl which show weak acidity also afforded low yields (Table 1,
entries 4, 6). The reason that [Hmim][H2PO4] showed the highest
efficiency maybe that [Hmim][H2PO4] have the most suitable
acidity for this reaction. We further investigated other reaction
conditions in the presence of acid ionic liquids [Hmim][H2PO4].
When the amount of [Hmim][H2PO4] was increased to two equiv-
alent, there was still no significant increase in the yield (Table 1,
entry 7). We thought that the lower yields of this reaction may
somewhat be attributed to the low solubility of 2,6-lutidine and
p-nitrobenzaldehyde in H2O. To our delight, when 1,4-dioxane
was added as a co-solvent, high yield of 90% was observed (Table 1,
entry 8). If we increase the reaction temperature from 100 °C to
110 °C, the yield of the reaction still did not increase (Table 1, entry
9). However, the yield slightly decreased if the reaction tempera-
ture was changed to 90 °C (Table 1, entry 10). Finally, we tried to
extend the reaction time to 36 h (Table 1, entry 11) and 48 h
⇑
Corresponding author.
E-mail address: wangzulichem@163.com (Z.-L. Wang).
http://dx.doi.org/10.1016/j.tetlet.2014.08.034
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

X.-Y. Zhang et al. / Tetrahedron Letters 55 (2014) 5462–5464
5463
Table 2
O
N
O
N
Substrate scope of the 2-alkyl azaarenes and aldehydea
HSO4
SO3H
HSO4
H
H
H
OH
OH
NO2 OH
[C3SO3Hnhm][HSO4]
[Hnhm][HSO4]
O2N
NC
N
N
N
N
Cl
N
O2N
N
NH
H2PO4
3b, 80%
3a, 92%
3c,
83%
COOH
[Hmim][H2PO4]
PyAcCl
OH
OH
OH
N
N
NH
N
N
HSO4
CH2COOH
OHC
NC
3e, 78%
3d, 92%
3f,
86%
N
Cl
[Et3NH][HSO4]
MAcImCl
OH
OH
OH
Scheme 1. Structure of acid ionic liquids.
N
N
N
N
O2N
O2N
3g,
O2N
80%
3h,
76%
3i,
87%
Table 1
N
N
Optimization of the reaction conditionsa
F
N
OH
OH
OH
OH
N
CHO
IL, solvent
100ഒ, 24h
N
O2N
3k,
74%
O2N
O2N
3j,
3l,
73%
+
95%
O2N
N
2a
O2N
1a
3a
OH
OH
OH
O2N
N
Entry Acid ionic liquids (IL)
Solvent
T (°C) Yield 3a (%)
N
N
NO2
NO2
3m,
3p,
70%
1
[C3SO3Hnhm][HSO4]
(1.0 equiv)
H2O
100
13
69%
N
3n,
90%
O2N
2
3
4
5
6
7
8
[Hnhm][HSO4] (1.0 equiv)
[Hmim][H2PO4] (1.0 equiv)
PyAcCl (1.0 equiv)
[Et3NH][HSO4] (1.0 equiv)
MAcImCl (1.0 equiv)
[Hmim][H2PO4] (2.0 equiv)
[Hmim][H2PO4] (1.0 equiv)
H2O
H2O
H2O
H2O
H2O
H2O
H2O/
dioxane
H2O/
dioxane
H2O/
dioxane
H2O/
dioxane
H2O/
dioxane
H2O/
100
100
100
100
100
100
100
25
61
32
41
36
62
92
Br
OH
OH
OH
N
N
3r
O2N
3o,
O2N
93%
NC
HO
3q,
65%
no reaction
N
HO
HO
HO
N
CO2Et
O2N
N
9
10
11
12
13
[Hmim][H2PO4] (1.0 equiv)
[Hmim][H2PO4] (1.0 equiv)
[Hmim][H2PO4] (1.0 equiv)
[Hmim][H2PO4] (1.0 equiv)
[Hmim][H2PO4] (0.5 equiv)
110
90
91
N
N
O2N
85
3u, 76%
3t, 75%
3v, 80%
3s, 67%
100
100
100
89b
92c
82
a
Unless otherwise stated, all reactions were carried out with 1 (0.25 mmol), 2
(0.75 mmol), and [Hmim] H2PO4 (1 equiv) in H2O (0.5 ml) and dioxane (0.5 ml) at
100 °C for 24 h. Isolated yields.
dioxane
a
Unless otherwise stated, all reactions were carried out with 1a (0.25 mmol), 2a
intact, which provides a useful handle for further chemical manip-
ulations (Table 2, 3f). Furthermore, heteroaromatic aldehyde
(Table 2, 3s) and activated aliphatic aldehyde (Table 2, 3u) also
reacted well with 2,6-lutidine and moderate yields were obtained.
To further evaluate the scope of the methodology, the application
of other azaarenes to this reaction was investigated. Substituted
pyridines such as 2,4,6-trimethylpyridine reacted with p-nitro-
benzaldehyde smoothly under the optimized reaction conditions
(Table 2, 3g). When 2-methylpyridine was subjected to this reac-
tion, slightly lower yields were realized (Table 2, 3t) than those
of 2,4,6-trimethylpyridine and 2,6-lutidine. The reason may come
from the less opportunities to react with 4-nitrobenzaldehyde.
However, when 2,5-dimethyl pyrazine and 2-methylpyrazine were
used, only moderate yields were obtained (Table 2, 3k–3l). Besides
2-methylpyridine derivatives, 2-methylquinoline, 2,6-dimethyl-
quinoline, and 2-methylquinoxaline derivatives can also react with
aldehyde in moderate to high yields (Table 2, 3h–3i, 3m–3p, 3q,
3v). Substituents including nitro, halogen groups in phenyl rings
of quinoline were well tolerated under reaction conditions (Table 2,
3j, 3p–3o), which also provide a useful handle for further chemical
manipulations. 2-methyl-8-nitroquinoline afforded lower yield
than those of 6-fluoroquinaldine and 6-bromoquinaldine and the
reason may come from the hindrance of the nitro group. Generally,
substituted 2-methylquinoline with the electron-withdrawing
group attached to benzene rings afforded higher yields than the
(0.75 mmol), IL (1 equiv), H2O/dioxane (0.5 ml/0.5 ml) reacted at 100 °C for 24 h.
b
Reacted for 36 h.
Reacted for 48 h.
c
(Table 1, entry 12) to get higher yields, but the yields of the reac-
tion still remained almost unaffected. When the amount of the
ionic liquids was reduced to 0.5 equiv, the yields of the product
decreased to 82%. Thus the optimized reaction conditions for this
reaction were acid ionic liquids [Hmim][H2PO4] (1 equiv) in H2O/
dioxane at 100 °C for 24 h.
With the optimized reaction conditions in hand, we set out to
explore the substrate scope of the reaction. As shown in Table 2,
substituted benzaldehydes with the electron-withdrawing group
attached to benzene rings, such as 4-nitrobenzaldehyde, 2-nitro-
benzaldehyde, and 3-nitrobenzaldehyde could react with 2,6-luti-
dine smoothly to generate the corresponding products in good to
excellent yields. Because of the smaller hindrance of 4-nitrobenzal-
dehyde compared with its analogues 3-nitrobenzaldehyde and 2-
nitrobenzaldehyde, 4-nitrobenzaldehyde gave a higher yield than
that of 2-nitrobenzaldehyde and 3-nitrobenzaldehyde (Table 2,
3a–3c). Additionally, aldehyde with the moderate electron-with-
drawing group such as the cyanl group could also react with 2,6-
lutidine to produce the products in moderate to good yields
(Table 2, 3d–3e). When 1,4-phthalaldehyde was used, only one for-
myl group took part in this reaction and the other one remained

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X.-Y. Zhang et al. / Tetrahedron Letters 55 (2014) 5462–5464
Table 3
Foundation of Shandong Province Outstanding Young Scientist
Recovery and reuse of recoverable acid ionic liquidsa
Award [BS2013YY024] and the Qingdao Technology R&D Program
for Basic Research, China [No. 12-1-4-5-(9)-jch] was gratefully
acknowledged.
We thank Qing-Hui Guo for helping us to prepare the support-
ing information.
Entry
Yieldb (%)
Entry
Yieldb (%)
1
2
3
90
92
89
4
5
6
91
88
88
a
p-Nitrobenzaldehyde (0.25 mmol); 2,6-lutidine (0.75 mmol) and [Hmim]
[H2PO4] (1 equiv) in H2O (0.5 ml) and dioxane (0.5 ml) at 100 °C for 24 h.
Supplementary data
b
Isolated yields.
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
08.034.
R
[Hmim][H2PO4]
N
H
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R
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R
H
N
H
OH
R
Ar
O
N
Ar
O
P
O
H
O
O
N
NH
Scheme 2. Proposed mechanism of addition of C(sp3)–H bond to aldehyde.
substituted 2-methylquinoline with the electron-donating group
attached to benzene rings (Table 2, 3j, 3o, 3v). However, when 4-
methylpyridine was subjected to this system, no desired products
were obtained (Table 2, 3r).
Finally, the recyclability of acid ionic liquids was investigated.
After the reaction was over, dioxane was evaporated under vacuum
and the residue was extracted with ether three times. After ether
was evaporated from the residue under vacuum, the remaining
water which contains acid ionic liquids was reused for the next
trial. To our delight, the acid ionic liquids can be reused six times
without a significant decrease in activity (Table3).
Since 4-methylpyridine was not successful in this reaction
(Table 2, 3r), we presume the mechanism of this reaction maybe
as shown in Scheme 2. In the presence of [Hmim][H2PO4], 2-methyl
azaarene tends to isomerization and the enamine intermediate is
formed. Then the nucleophilic addition of the enamine intermedi-
ate to aromatic aldehyde which was activated by [Hmim][H2PO4]
would occur to afford the desired adduct.
In summary, we have developed an efficient acid ionic liquid
promoted addition of 2-alkyl azaarenes to aldehydes through
C(sp3)–H bond functionalization in good to excellent yields. The
mild reaction conditions make this method attractive for the prep-
aration of biologically active pyridine and quinoline derivatives.
Further investigation to apply this method to more useful sub-
strates and mechanistic study are ongoing in our laboratory.
Acknowledgments
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66, 1837.
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14. Tao, D.-J.; Wu, J.; Wang, Z.-Z.; Lu, Z.-H.; Yang, Z.; Chen, X.-S. RSC Adv. 2014, 4, 1.
Financial support from the research fund of Qingdao Agricul-
tural University’s high-level Person [631303], the National Natural
Science Foundation of China (21402103), the Scientific Research