Bronsted acid promoted benzylic C-H bond functionalization of azaarenes: Nucleophilic addition to aldehydes

Article abstract of DOI:10.1039/c2ob26604k

A practical Bronsted acid promoted benzylic C-H functionalization of 2-methylazaarenes and nucleophilic addition to aldehydes was developed in good to excellent yields. A six-membered hydrogen-bonding transition state is proposed to be crucial for the reaction. Ready availability of the two starting materials, the use of acetic acid as the catalyst and the facile reaction conditions will guarantee this synthetic method attractive to the synthesis of bioactive pyridine and quinoline derivatives.

Full text of DOI:10.1039/c2ob26604k

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Brønsted acid promoted benzylic C–H bond functionalization of azaarenes:
nucleophilic addition to aldehydes†
Fang-Fang Wang, Cui-Ping Luo, Yi Wang, Guojun Deng and Luo Yang*
Received 14th August 2012, Accepted 11th September 2012
DOI: 10.1039/c2ob26604k
(−78 °C).12 Alternatively, the benzylic C–H addition to alde-
A practical Brønsted acid promoted benzylic C–H functiona-
hydes can also be catalyzed by strong Lewis acid under robust
conditions (T > 140 °C) to produce the dehydrated products.13,14
During our research, a facile synthesis of azaarene-substituted
3-hydroxy-2-oxindoles was discovered by Xiao and Li, however
this method relied on highly reactive isatins with strong ring
strain as the raw materials and consequently other acyclic 1,2-
dicarbonyls failed under the same conditions.13g A direct and
convenient benzylic C–H functionalization and nucleophilic
addition to aldehydes or 1,2-dicarbonyls under mild conditions
would be highly expected.
In line with our interest in the nucleophilic addition of enam-
ides to epoxides, ketones and aldehydes,15 we hypothesized that
the equilibrium between imine and enamine form of 2-methyl-
pyridine (Scheme 1, eqn (c)) can be accelerated by the addition
of proper Brønsted acids, and the subsequent nucleophilic
addition of enamine would be spontaneous under mild
conditions.16
To test the viability of our hypothesis, we first examined the
reaction of 2,6-lutidine (1a) and p-nitro-benzaldehyde (2a) cata-
lyzed by different Brønsted acids based on our early work based
on rhodiumIII catalyzed C–H activation and nucleophilic
addition to aldehydes (Table 1).17 To our delight, the desired
nucleophilic addition product 3a was obtained when the benzylic
C–H functionalization and nucleophilic addition was catalyzed
by p-toluenesulfonic acid, albeit the yield was rather low
lization of 2-methylazaarenes and nucleophilic addition to
aldehydes was developed in good to excellent yields. A six-
membered hydrogen-bonding transition state is proposed to
be crucial for the reaction. Ready availability of the two
starting materials, the use of acetic acid as the catalyst and
the facile reaction conditions will guarantee this synthetic
method attractive to the synthesis of bioactive pyridine and
quinoline derivatives.
Transition-metal catalyzed sp3 C–H bonds activation and sub-
sequent C–C bonds formation represent major research interests
in synthetic chemistry because of efficiency, economy and
environmental sustainability considerations.1 Although great pro-
gresses have been made on these subjects, the functionalizations
of methyl groups directly attached to an aromatic ring are rather
limited.2–10 Successful examples include palladium catalyzed
benzylic C–H arylation of 8-methylquinoline,2 azaarene N-oxides3
and N-iminopyridinium ylides4 reported by Sanford, Daugulis,
Fagnou, Charette and others.5 The N-oxides precursors can
be replaced by zincate complexes generated in situ revealed
by Knochel and co-workers recently (Scheme 1, eqn (a)).6
Besides arylation, the palladium7 or copper8 catalyzed benzylic
C–H addition of 2-methylazaarenes to N-sulfonyl aldimines was
reported by Huang and Rueping separately (Scheme 1, eqn (b)).
Later, a similar reaction was realized under catalyst-free con-
ditions9 and benzylic C–H conjugate additions10 have also been
established in the presence of transition-metal catalysts.
Pyridine and quinoline derivatives are among the most preva-
lent heterocycles in bioactive compounds and have been claimed
to be the most prevalent heterocycles in pharmaceutically active
compounds.11 The functionalization of 2-methylpyridines or
quinolines via deprotonation of the weakly acidic benzylic C–H
protons and nucleophilic addition to aldehydes traditionally
requires strong base such as BuLi or LDA at low temperature
Key Laboratory for Environmentally Friendly Chemistry and
Application of the Ministry of Education, Department of Chemistry,
Xiangtan University, Hunan, 411105, P. R. China.
E-mail: yangluo@xtu.edu.cn; Fax: +86-731-58292251;
Tel: +86-731-58298351
†Electronic supplementary information (ESI) available: Experi-
mental details, synthesis and characterisation of products. See DOI:
10.1039/c2ob26604k
Scheme 1 Benzylic C–H functionalization of azaarenes.
Org. Biomol. Chem., 2012, 10, 8605–8608 | 8605
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Table 1 Optimization of the Brønsted acid promoted benzylic C–H
Table 2 Substrate scope for the Brønsted acid promoted benzylic C–H
nucleophilic additiona
nucleophilic addition of 2,6-lutidinea
Entry
1
Aldehyde
Product
Yieldb (%)
96
2a
3a
Entry
Cat. (equiv.)
T (°C)
Solvent
Yieldb (%)
1
2
3
4
5
6
p-TSA (1.0)
HCl aq. (1.0)
AcOH (1.0)
PivOH (1.0)
PhCO2H (1.0)
Cu(OTf)2 (0.05)
Sm(OTf)3 (0.05)
AcOH (1.0)
AcOH (0.5)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
AcOH (1.0)
100
100
100
100
100
100
100
100
100
100
80
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
Toluene
Dioxane
DMF
20
26
96
64
50
44
29
70
67
74
57
70
94
89
81
2
3
2b
2c
3b
3c
91
74
7
8c
9
4
5
2d
2e
3d
3e
95
76
10d
11
12
13
14
15
120
100
100
100
a Reaction conditions: 1a (0.8 mmol), 2a (0.2 mmol), AcOH (1.0 equiv.,
0.2 mmol), DCE (0.2 mL), reacted at 100 °C for 36 h under argon,
unless otherwise noted. b The yield of isolated product is reported. c 1a
(0.4 mmol) was added. d Reacted for 24 h.
6
7
2f
3f
80
71
2g
3g
8
9
2h
2i
3h
3i
87
57
(Table 1, entry 1). To examine the influence of acidity to the
reaction, different Brønsted acids such as aqueous HCl, acetic
acid, pivalic acid (PivOH) and benzoic acid were tested (entries
1–5), and the cheap and abundant acetic acid was found out to
be the best choice. Although the reaction could be realized under
the assistance of Lewis acid (entries 6–7), the yields were much
lower. An excess of 2,6-lutidine (1a) was required to promote
the complete consumption of p-nitro-benzaldehyde (2a) and the
yield of 3a dropped after decreasing the amount of acetic acid
(entries 8 and 9), which maybe due to the transfer of proton
from the protonated product to the reactant was not fast enough.
Reacting at 100 °C for 36 h was essential for the high yields,
and shortening the reaction time, increasing or decreasing the
reaction temperature led to poorer yields (entries 10–12). Next,
the effect of solvents on this reaction was also investigated.
Besides 1,2-dichloroethane (DCE), excellent yield was obtained
when the reaction proceeded in toluene and slightly lower yields
in dioxane and DMF (entries 13–15).
Under the optimized conditions (Method A: Table 1, entry 3),
the substrate scope of this benzylic C–H functionalization and
nucleophilic addition of azaarenes to aldehydes was explored.
As the results show in Table 2, all the electron-deficient aromatic
aldehydes tested (2a–2i) reacted with 2,6-lutidine (1a) smoothly
to produce the corresponding alcohols efficiently in moderate to
excellent yields (Table 2, entries 1–9).18 It is worth noting that
when terephthalaldehyde (2g) was used, only one formyl group
took part in this reaction and the other remained intact, which
renders the product for further functionalizations readily (entry
7). Aldehyde with an unprotected hydroxyl group such as 2h or
heteroaromatic aldehyde such as 2-pyridinecarboxaldehyde (2i)
10
11
2j
3j
83
49
2k
3k
a Reaction conditions (Method A): 1a (0.8 mmol), 2 (0.2 mmol), AcOH
(1.0 equiv., 0.2 mmol), DCE (0.2 mL), reacted at 100 °C for 36 h under
argon, unless otherwise noted. b The yield of isolated product is
reported.
reacted well and slightly lower yields were realized (entries 8
and 9). Furthermore, activated aliphatic aldehydes such as ethyl
glyoxylate (2j) reacted with 2,6-lutidine (1a) smoothly and good
yields were obtained (entry 10) and the reaction of 2,3-butane-
dione (2k) was reluctant maybe due to its greater steric hindrance
after the methyl group was introduced into the substrate
(entry 11).
Encouraged by the good results obtained between the reaction
of 2,6-lutidine and different aldehydes, the application of this
reaction to other azaarenes was investigated. Substituted pyri-
dines such as 2,4,6-trimethylpyridine (1b), 2-methyl-6-phenyl-
pyridine (1c) and 2-picoline (1d) reacted with p-nitro-
benzaldehyde (2a) smoothly under the optimized reaction con-
ditions (entries 1–3, Method A). However, under the same con-
ditions, the reaction of 2-methylquinoline (1e) and p-nitro-
8606 | Org. Biomol. Chem., 2012, 10, 8605–8608
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Table 3 Substrate scope for the Brønsted acid promoted benzylic C–H nucleophilic addition of azaarenes to p-nitro-benzaldehydea
Entry
1
Azaarene
Product
t (h)
Method
A
Yieldb (%)
89
1b
3l
36
2
3
4
5
1c
1d
1e
1f
3m
3n
3o
36
36
5
A
A
B
B
62
59
95
75
3p
6
6
7
8
9
1g
1h
1i
3q
3r
3s
3t
6
15
5
B
B
B
B
84
88
79
71
1j
6
a Reaction conditions, Method A: 1 (0.8 mmol), 2a (0.2 mmol), AcOH (1.0 equiv., 0.2 mmol), DCE (0.2 mL), reacted at 100 °C for 36 h under argon.
Method B: 1 (0.4 mmol), 2a (0.2 mmol), AcOH (1.0 equiv., 0.2 mmol), dioxane (0.2 mL), H2O (0.02 mL) reacted at 80 °C under argon, unless
otherwise noted. b The yield of isolated product is reported.
benzaldehyde (2a) afforded the dehydrated 2-(p-nitrostyryl)-
quinoline as the main product. By switching the solvent to a
dioxane–H2O (10 : 1) mixture and decreasing the reaction temp-
erature at the same time (Method B), the dehydration was sup-
pressed and good yield was obtained for the desired product (3o)
(Table 3, entry 1). Other 2-methylquinolines substituted by
methyl, methoxy, fluoro, chloro and bromo groups can also take
part in this benzylic C–H functionalization in moderate to excel-
lent yields, and the electron-deficient substituents resulted in
higher yields than the electron-donating substituents (entries
5–9).
To gain insight into the mechanism of this benzylic C–H func-
tionalization, the reaction of 4-picoline (1k) with p-nitro-benz-
aldehyde (2a) was carried out (Scheme 2). As expected, while
the reaction between 2-picoline and p-nitro-benzaldehyde
afforded the corresponding nucleophilic addition product 3n in
59% yield, the counterpart 4-picoline failed in this reaction.
Scheme 2 Brønsted acid promoted benzylic C–H nucleophilic addition
of 4-picoline to p-nitro-benzaldehyde.
These results seem to suggest that six-membered hydrogen-
bonding transition state is crucial for this benzylic C–H functio-
nalization of azaarenes.
C–H functionalization to other nucleophilic additions are
ongoing.
In summary, we have demonstrated a practical Brønsted acid
promoted benzylic C–H functionalization of 2-methylazaarene
and nucleophilic addition to aldehydes in good to excellent
yields. The cheapness and abundance of the two starting
materials, the usage of acetic acid as the catalyst and the facile
reaction conditions should make this synthetic method attractive
for the synthesis of bioactive pyridine and quinoline derivatives.
Further studies to expand this Brønsted acid promoted benzylic
Experimental section
A general experimental procedure is described as following:
Method A: An oven-dried reaction vessel was charged with
2,6-lutidine (1a, 85.8 mg, 0.8 mmol, 4 equiv.), 1,2-dichloro-
ethane (DCE, 0.2 mL), p-nitro-benzaldehyde (2a, 30.2 mg,
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4 J. J. Mousseau and A. B. Charette, Org. Lett., 2008, 10, 1641.
0.2 mmol) and acetic acid (12 μL, 0.2 mmol, 1 equiv.) under
argon. The vessel was sealed and heated at 100 °C (oil bath
temperature) for 36 h. After the resulting mixture was cooled to
room temperature, aqueous Na2CO3 solution (5%, 10 mL) was
added and the mixture was extracted with dichloromethane (3 ×
10 mL), and washed with brine (2 × 10 mL). The organic layer
was dried with anhydrous Na2SO4, and concentrated under
vacuum. The residue was chromatographed on a silica gel
column eluted with a mixture of petroleum ether and ethyl
acetate (1 : 1) to give pure products 3a (49.6 mg, 96% yield).
Method B: An oven-dried reaction vessel was charged with
2-methylquinoline (1b, 57.3 mg, 0.4 mmol, 2 equiv.), 1,4-
dioxane (0.2 mL), H2O (20 μL), p-nitro-benzaldehyde (2a,
30.2 mg, 0.2 mmol) and acetic acid (12 μL, 0.2 mmol, 1 equiv.)
under argon. The vessel was sealed and heated at 80 °C (oil bath
temperature) for 5 h. The workup was the same as Method A.
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Acknowledgements
This work was supported by the National Natural Science Foun-
dation of China (21202138), Xiangtan University “Academic
Leader Program” (11QDZ20), and Project of Hunan Provincial
Natural Science Foundation of China (12JJ7002). We are also
grateful to Prof. Mei-Xiang Wang and De-Xian Wang in the
Institute of Chemistry, Chinese Academy of Sciences for con-
structive suggestions.
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8608 | Org. Biomol. Chem., 2012, 10, 8605–8608
This journal is © The Royal Society of Chemistry 2012