Iron-catalyzed C(sp3)-H functionalization of methyl azaarenes: A green approach to azaarene-substituted α- Or β-hydroxy carboxylic derivatives and 2-alkenylazaarenes

Article abstract of DOI:10.1039/c4ra10939b

Bioactive azaarene-substituted lactic acids, β-hydroxy esters, 3-hydroxy-2H-indol-2-ones, and 2-alkenylazaarenes were prepared in moderate-to-excellent yields via C(sp³)-H functionalization of methyl azaarenes with carbonyl compounds in the presence of iron(ii) acetate as an inexpensive, nontoxic, efficient catalyst. The application of this atom-, step-economic, and environmentally friendly method was demonstrated by a gram-scale synthesis of 3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]benzaldehyde, a key intermediate of leukotriene receptor antagonist (Montelukast).

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Entry for the Table of Contents
Iron-Catalyzed C(sp3)–H Functionalization of Methyl Azaarenes: A Green Approach to Azaarene-substituted α- or β-Hydroxy Carboxylic
Derivatives and 2-Alkenylazaarenes
Danwei Pi, Kun Jiang, Haifeng Zhou, Yuebo Sui, Yasuhiro Uozumi and Kun Zou …….. Page No. – Page No.
R2
O
O
O
OH
R1
R3
R3
R2
X
N
X
n
n
20 examples
up to 90% yield
X= C, O, N
n = 0, 1
Iron Catalysis
O
R1
H2O
+
R4
H
R4
N
R1
35 examples
up to 99% yield
N
O
R1
R5
OH
R5
O
N
N
R6
N
R6
O
19 examples
up to 90% yield
An iron-catalyzed C(sp3)–H functionalization of methyl azaarenes with carbonyls to access the title compounds have been described

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Iron-Catalyzed C(sp3)–H Functionalization of Methyl Azaarenes: A
Green Approach to Azaarene-substituted α- or β-Hydroxy Carboxylic
Derivatives and 2-Alkenylazaarenes
Danwei Pi,a,‡ Kun Jiang,a, ‡ Haifeng Zhou,*a,b Yuebo Sui,a Yasuhiro Uozumi*a,b, Kun Zoua
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
Bioactive azaarene-substituted lactic acids, β-hydroxy esters, 3-hydroxy-2H-indol-2-ones, and 2-
alkenylazaarenes were prepared in moderate-to-excellent yields via C(sp3)–H functionalization of methyl
azaarenes with carbonyl compounds in the presence of iron(II) acetate as an inexpensive, nontoxic,
efficient catalyst. The application of this atom-, step-economic, and environmentally friendly method was
demonstrated by a gram-scale synthesis of 3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]benzaldehyde, a key
intermediate of leukotriene receptor antagonist (Montelukast).
Introduction
Darzen’s condensation of an aromatic aldehyde with ethyl
chloroacetate followed by catalytic hydrogenation is a typical
approach to access these compounds.[8a] They also can be prepared
by the addition of 2-methyl azaarenes to α-oxoesters catalyzed by
Yb(OTf)3,[3g] or Cu(OTf)2/1,10-phennanthroline.[3f]
Modern sustainable organic synthesis requires the development of
novel, efficient, atom-, and step-economic functional-group
transformations.[1] The direct C(sp3)–H bond functionalization of
2-alkyl azaarenes is such a transformation. Consequently, some
efforts have been expended on this type of reactions. Recently, the
C(sp3)–H bond functionalization of 2-alkyl azaarenes catalyzed by
palladium,[2] Lewis acids,[3] BrØnsted acids[4] or under catalyst-free
conditions,[5] have appeared. For example, Huang and co-workers
reported the addition of 2-alkyl azaarenes to the C=N double bonds
of N-sulfonyl aldimines.[3a-c] Kanai reported the direct addition of
alkyl-substituted azaarenes to the C=C double bonds of enones
promoted by Sc(OTf)3.[3e] Xiao and Li reported the TfOH-
catalyzed addition of 2-methyl pyridines to C=O double bonds of
isatins.[4a] Guo and co-workers realized the direct addition of 2-
alkyl azaarenes to ethyl azodicarboxylates.[3i] Very recently, the
C(sp3)–H bond functionalization of 2-alkyl azaarenes via oxidative
cross dehydrogenative coupling was reported.[6] The derivatives of
2-alkyl azaarenes are biologically important compounds.[7]
Although some elegant methods have emerged, the development of
mild, high efficient, environmentally friendly, and practical
methods for the direct C(sp3)–H bond functionalization of 2-alkyl
azaarenes are still highly desirable.
3-Substituted-3-hydroxy-2H-indol-2-ones are structural moiety
of natural products and biologically active compounds (Figure 1).[9]
The biological properties of such compounds are affected by the
nature of substituents at the C3 position.[9d] Several methods have
emerged for the synthesis of aryl- or alkyl-substituted
derivatives.[10] However, very few methods were disclosed for
preparing 3-azaarene-substituted 3-hydroxy-2H-indol-2-ones.[11]
For example, these compounds were synthesized by the addition of
2-alkyl azaarenes to isatins in the presence of TfOH,[4a] Iodine,[3k]
Yb(OTf)3,[3j] or under catalyst-free conditions[4b, 5b, 5c]
.
2-alkenylazaarenes are bioactive compounds,[12] as well as the
precursors of 2-alkylheterocycles (Figure 1).[13] These compounds
were originally synthesized from 2-methylazaarenes and aldehydes
promoted by stoichiometric amount of acetic anhydride or aqueous
alkali.[14] The Pd-, Ru-, Ni-, and Cu-catalyzed direct alkenylation
of activated pyridines or quinolines to give 2-alkenylazaarenes
have also been realized.[15] Recently, Huang and co-workers
developed an iron-catalyzed synthesis of trans-2-alkenylazaarenes
through the addition of 2-methyl azaarenes to N-sulfonylaldimines,
with subsequent C–N bond cleavage.[3c] Wang and co-workers
improved the same reaction under catalyst-free condition.[5a]
We have developed a facile approach to prepare azaarene-
substituted lactic acid derivatives via iron-catalyzed C(sp3)-H
functionalization of methyl azaarenes with α-oxoesters.[16] Here,
we reported the systematic study of C(sp3)–H functionalization of
methyl azaarenes with carbonyl or dicarbonyl compounds in the
presence of iron(II) acetate. The practical potential of this method
was demonstrated by a gram-scale synthesis of 3-[(E)-2-(7-
chloroquinolin-2-yl)vinyl]benzaldehyde, a key intermediate of the
leukotriene receptor antagonist (Montelukast).
Azaarene-substituted lactic acid derivatives are potential
components of various biologically active compounds. However,
very limited methods were available for their preparation.[3f-g,8] The
[a] Hubei Key Laboratory of Natural Products Research and Development,
College of Biological and Pharmaceutical Sciences, China Three
Gorges University, Yichang 443002, People’s Republic of China.
Fax: +86-717-6395580
E-mail: haifeng-zhou@hotmail.com
[b] Institute for Molecular Science, Myodaiji, Okazaki 444-8787, Japan
Fax: +81-564-595574
E-mail: uo@ims.ac.jp
† Electronic Supplementary Information (ESI) available: Experimental
procedures, compound chracterizations, and copies of 1H NMR and 13C
NMR spectra. See DOI: 10.1039/b000000x/
‡ These authors contributed equally to this work.
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Figure 1. Representative biologically active compounds containing the title structures
Results and Discussion
C(sp3)–H Functionalization of Methyl Azaarenes with α- or β-Ketoesters
Initially, the reaction of 2-methyl quinoline 1a and ethyl
glyoxylate 2a catalyzed by iron (II) acetate in toluene at 120 °C for
24 h was selected as a model reaction. As shown in table 1, the
contrast, the yield of 3aa reached to 89% when an excess amount
of 2-methylquinoline 1a was used (entries 2 and 9–13). The yield
of 3aa remained unchanged with decreased catalyst loading (entry
ethyl 2-hydroxy-3-quinolin-2-ylpropanoate 3aa was obtained in 32% 14), but no reaction occurred in the absence of iron salts (entry 15).
yield (entry 1). A survey of solvents showed that 1,4-dioxane is an
optimal candidate comparing to toluene, tetrahydrofuran, methyl
tert-butyl ether, 1,2-dichloroethane, acetonitrile, N,N-dimethyl
formide, 1,2-dimethoxyethane (entries 1-8). It was found that the
yields of 3aa varied with the ratios of the two starting materials, an
excess amount of ethyl glyoxylate 2a resulted in low reactivity. In
Under the identical reaction conditions to those shown in entry 14,
other iron salts, such as FeCl3, Fe(OTf)2, Fe(BF4)2.6H2O,
Fe(ClO4)3.6H2O, Fe(acac)3, copper salts Cu(OAc)2, Cu(OTf)2, and
Sc(OTf)3 were examined. Fe(OAc)2 was proved to be the most
effective catalyst in this transformation (entries 14, 16-23).
Table 1. Optimization of the reaction conditions [a]
Entry
1
Catalyst (mol%)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (5)
–
1a (mmol)
0.4
2a (mmol)
0.6
Solvent
Yield [%][b]
toluene
32
50
48
35
23
32
10
44
31
5
2
0.4
0.6
1,4-dioxane
THF
3
0.4
0.6
4
0.4
0.6
MTBE
5
0.4
0.6
Cl(CH2)2Cl
MeCN
6
0.4
0.6
7
0.4
0.6
DMF
8
0.4
0.6
MeO(CH2)2OMe
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
9
0.4
0.8
10
11
12
13
14
15
0.4
1.0
0.6
0.4
77
85
89
90
nd
0.8
0.4
1.0
0.4
1.0
0.4
1.0
0.4
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16
17
18
19
20
21
22
23
FeCl3 (5)
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
22
60
21
37
55
57
65
nd
Fe(OTf)2 (5)
Fe(BF4)2.6H2O (5)
Fe(ClO4)3.6H2O (5)
Fe(acac)3 (5)
Cu(OAc)2 (5)
Cu(OTf)2 (5)
Sc(OTf)3 (5)
[a] Reaction conditions: 2-methylquinoline 1a, ethyl glyoxylate 2a, solvent (1 mL), 120 °C, 24 h. [b] Isolated yield. [c] nd = not detected.
Under the optimal conditions, the scope of various methyl
azaarenes 1 and α- or β-ketoesters 2 was investigated. As shown in
Scheme 1, the reactions of ethyl glyoxylate 2a and 2-methyl
azaarenes bearing electron-rich or electron-deficient substituents
proceeded smoothly to give the azaarene-substituted ethyl lactates
3ab–3af in 72–88% yield. In comparison with electron-rich 2-
methylazaarenes, electron-deficient 2-methyl-8-nitroquinoline 1f
gave hydroxy ester 3af in a relatively low yield of 72%. The
reactions of 2-methylquinoxaline 1g or 1-methylisoquinoline 1h
with 2a also gave the desired products 3ag and 3ah in 88% and
90% yield, respectively. Furthermore, the reactions of 2a with 2,6-
dimethylpyridine 1i or 2-methylpyridine 1j also proceeded to give
moderate yields of products 3ai and 3aj, respectively. Except for
ethyl glyoxylate, the ethyl 3,3,3-trifluoropyruvate, ethyl pyruvate
were also subjected to this transformation. The reaction of 2-
methyl quinoline 1a and ethyl 3,3,3-trifluoropyruvate proceeded
successfully to give the product 3ba in 86% yield. However, when
ethyl pyruvate was used instead of ethyl 3,3,3-trifluoropyruvate,
only 26% yield of 3bb was obtained even if increasing the catalyst
loading and temperature. It revealed that the electron-withdrawing
group of ketoester 2 enhanced the reactivity of carbonyl. The β-
ketoester ethyl 4,4,4-trifluoroacetoacetate was also applicable to
this reaction, and the products 3ca–3cc were obtained in relatively
moderate yield (44-51%).
Scheme 1. Substrate scope of methyl azaarenes and α- or β-ketoesters. Reaction conditions: methylazarene 1 (1.0 mmol), α- or β-ketoester 2 (0.4 mmol),
Fe(OAc)2 (0.02 mmol), 1,4-dioxane (1 mL), 120 °C, 24h, isolated yield. [a] Fe(OAc)2 (10 mol%), 130 °C, 24 h.
O
Encouraged by the success of the reaction of methyl azaarenes
H
OH
OH
with α- or β-ketoesters, we extended the carbonyls to other 1,2-
dicarbonyl compounds. As shown in Scheme 2, N-Benzyl-2-
oxoacetamide 2d and methylglyoxal 2e were compatible to this
transformation, giving the products 3da and 3ea in 79% and 76%
yield, respectively, whereas phenylglyoxal 2f decomposed under
the reaction conditions. The cyclic diketones acenaphthoquinone
2g and ninhydrin [2h: 2,2-dihydroxy-1H-indene-1,3(2H)-dione]
were also compatible to this reaction, giving the products 3ga and
3ha in 68% and 87% yield, respectively.
H
N
O
N
Bn
N
O
O
2f [a]
3da
: 79%
3ea: 76%
O
O
OH
N
N
O
HO
3ga: 68%
3ha
: 87%
Scheme 2. Reactions of 1a with other 1,2-dicarbonyl compounds. Reaction
conditions: 2-methyl quinoline 1a (1.0 mmol), 1,2-dicarbonyl 2 (0.4 mmol),
Fe(OAc)2 (10 mol%), 1,4-dioxane (1 mL), 120 °C, 24 h (isolated yield).
[a]
Decomposed under the reaction conditions.
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C(sp3)–H Functionalization of Methyl Azaarenes with Isatins
shown in Table 2, Li et al. tried the reaction of 2-methylquinoline
1a and N-methyl isatin 4b catalyzed by TfOH, but the desired
product 3-hydroxy-3-(quinolin-2-ylmethyl)indolin-2-one 6b was
not observed. Instead, the double addition product 7b was isolated
in 34% yield.[11a] Xiao et al. also tried the same reaction catalyzed
by Yb(OTf)3 and got the same result, only double addition product
6b was isolated in 21% yield.[3j] Thus in situ generated product 6b
is proposed to undergo a subsequent dehydrative coupling reaction
to furnish product 7b. Encouraged by the success of iron-catalyzed
addition reaction of methyl pyridines to isatins, we extended the
scope of azaarenes to quinolines, and attempted the reaction of 2-
methylquinoline 1a with N-methyl isatin 4b using iron (II) acetate
Although some methods for preparing 3-azaarenylmethyl-3-
hydroxy-2-oxindole derivatives from isatins and methyl azaarenes
have appeared,[3,5] they suffered from some drawbacks: 1) the
reaction partners of isatins were limited to methyl pyridines; 2) the
N-protected isatins were essential for good yield. Inspired by the
success of the reaction of methyl azaarenes with glyoxylate, α- or
β-ketoesters, and 1,2-dicarbonyl compounds, as shown in Scheme
3, we examined the reaction of isatin (4a; 1H-indole-2,3-dione)
with 2,6-dimethylpyridine in the presence of 10 mol% Fe(OAc)2 at
120 °C for 24 h. The desired product 5a was obtained in 68% yield.
To explore the scope of this reaction for the synthesis of 3-
azaarene-substituted 3-hydroxy-2H-indol-2-ones, we screened the
reactions of 2, 6-dimethylpyridine with various N-unprotected
isatins bearing electron-withdrawing or electron-donating groups.
In general, all the reactions proceeded smoothly to give the
corresponding desired products in moderate-to-excellent yields.
There was an apparent correlation between the efficiency of the
reaction and the electronic property of the substituent. Isatins
o
as catalyst in 1,4-dioxane at 120 C for 24 h. To our delight, the
desired product 6b was isolated in 49% yield, and the double
addition product 7b was not observed (entry 1), to the best of our
knowledge, this is the first example to prepare 3-azaarenylmethyl-
3-hydroxy-2-oxindoles from isatins and methyl quinolines. To
improve the productivity, other iron salts of FeCl3, FeBr3, Fe(OTf)2
and Fe(acac)3 were screened. The results indicated that only
Fe(acac)3 was effective and gave the desired product 6b in 44%
yield (entries 2-5). Other metal salts, such as Cu(OTf)2, Sc(OTf)3,
Table 2 Catalyst screening for the reaction of 2-methylquinoline and N-
methyl isatin [a]
Entry
Catalyst
Fe(OAc)2
FeBr3
6b (%)
1
49
0
2
3
Fe(OTf)2
Fe(acac)3
FeCl3
0
4
44
0
5
6
Cu(OTf)2
Sc(OTf)3
In(OTf)3
Fe(OAc)2
Fe(OAc)2
0
7
0
8
0
9[b]
10[c]
40
38
[a] Reaction conditions: 2-methylquinoline 1a (1.0 mmol), N-methyl isatin
o
4b (0.40 mmol), catalyst (10 mol%), 1,4-dioxane (1.0 mL), 120 C, 24 h,
Scheme 3. Reaction conditions: 2, 6-dimethylpyridine 1i (1.0 mmol), isatin
4 (0.4 mmol), Fe(OAc)2 (10 mol%), 1,4-dioxane (1 mL), 120 oC, 24 h,
isolated yield. [a] reaction time: 48 h.
o
N2, isolated yield of 6b, the product 7b was not detected. [b]100 C, 24 h;
[c] 5 mol% Fe(OAc)2, 120 oC, 24 h.
bearing electron-withdrawing groups exhibited relatively higher
productivity than did those with electron-donating substituents. For
example, 7-trifluoromethyl derivative 4i gave the product 5i in 90%
yield, whereas the electron-rich 5-methoxy derivative 4d and 5-
methyl derivative 4e gave the corresponding products 5d and 5e in
59% and 64% yields, respectively, even if doubling the reaction
time. This phenomenon might be ascribe to the enhancement of the
electrophilicity of the carbonyl group of the isatin by electron-
withdrawing groups. When the N-protected isatins 4b and 4c were
subjected to this transformation, the protecting groups were found
have no significant effect on the productivity of the reactions.
In the previous work about the synthesis of 3-azaarenylmethyl-
3-hydroxy-2-oxindoles, the azaarenes were limited to pyridines. As
In(OTf)3 were also subjected to this reaction, but no reaction
occurred (entries 6-8). Lowering the reaction temperature and
reducing the catalyst loading resulted in decreased yield (entries 9-
10).
Under the optimized reaction conditions, the scope of the
substrates were investigated. As shown in Scheme 4, the reaction
of 2-methylquinoline 1a with simple NH protic isatins gave the
product 6a in 60% yield. In contrast, when the N-substituted isatins
were used as reaction partners, the corresponding products 6b and
6c were obtained in relatively lower yields. Next, we focused on
the generality of the methyl quinolines, it was found that both
electron-donating and electron-withdrawing groups (including
halogen groups) at the phenyl ring of quinolines were well-
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tolerated in this reaction, and the desired products were isolated in
moderate yields (6d–6f). 1-methylisoquinoline was also applicable
to this transformation and provided the product 6g in 60% yield.
When 4-methylquinoline was subjected to the reaction with isatin,
it proceeded successfully and furnished the product 6h in 24%
yield. The electron effect of isatins was also investigated, the
results showed that electron-rich 5-methoxyisatin and electron-
deficient 5-nitroisatin were tolerated in this transformation to give
the desired products 6i and 6j in 37% and 35% yields, respectively.
Scheme 4. Reaction conditions: methyl quinoline 1 (1.0 mmol), isatin 4 (0.40 mmol), Fe(OAc)2 (10 mol%), 1,4-dioxane (1.0 mL), 120 oC, 24 h, N2, isolated
yield.
C(sp3)–H Functionalization of Methyl Azaarenes with Aldehydes
Encouraged by the successful C(sp3)–H functionalization of
methyl azaarenes with glyoxylate, α- or β-ketoesters, isatins,
and 1,2-dicarbonyls, the simple aldehydes were also subjected
to this transformation. The reaction of 2-methylquinoline 1a
with benzaldehyde 8a in the presence of various iron salts were
investigated. As shown in Table 3, our preliminary experimental
results indicated that iron(II) acetate was the best catalyst, and it
gave the desired product 2-[(E)-2-phenylvinyl]quinoline 9aa in
66% isolated yield when the reaction was performed at 120 °C
for 24 hours (entries 1–6). 1H NMR and GC/MS analyses of the
product showed that the (E)-isomer was formed exclusively.
These promising results encouraged us to optimize the reaction
conditions with Fe(OAc)2 as the catalyst. To our delight, the
yields were markedly enhanced by the addition of a catalytic
amount of a Brønsted acid such as methanesulfonic acid, triflic
acid, 4-toluenesulfonic acid, acetic acid, or trifluoroacetic acid
(TFA) as a co-catalyst (entries 7–11), and 98% yield of 9aa was
obtained in the presence of 10 mol% TFA. Next, we examined
the effect of catalyst loading, 9aa was isolated in 97% and 82%
yields in the presence of 5% and 1 mol% of Fe(OAc)2,
respectively (entries 12 and 13). To confirm the role of the iron
catalyst in this transformation, control experiments showed that
9aa was obtained in 29% yield in the absence of Fe(OAc)2
under otherwise identical conditions to entry 12, and only 18%
yield of 9aa was obtained in the absence of Fe(OAc)2 and TFA.
The results proved that iron(II) acetate was essential for high
reactivity. Solvent screening showed that, of the solvents tested,
toluene gave the best results (entries 12 and 16–18).
Comparable yields were obtained at 120 °C and 100 °C (entries
12 and 19), but slightly lower yield was available at 80°C (entry
20). No effect was observed when the amount of benzaldehyde
(8a) was reduced (entry 21).
Under the optimized reaction conditions, we examined the
scope of the reaction of various aldehydes with 2-
methylquinoline 1a. Generally, as shown in Scheme 5,
aldehydes bearing electron-donating or electron-withdrawing
group at various positions on the aromatic ring were
transformed into the desired (E)-2-alkenylazaarenes smoothly in
good-to-excellent yields. The electron-deficient aldehydes 8j–
8n gave the desired products 9aj–9an in high yields of 90–99%.
In contrast, the electron-rich aldehydes 8p and 8q gave the
corresponding products 9ap and 9aq in slightly lower yields of
89% and 85%, respectively. Interestingly, the reaction of 1a
with 4-acetylbenzaldehyde 8o proceeded selectively to give 76%
yield of product 9ao with an intact acetyl group. Note that
sterically hindered 2,6-dichlorobenzaldehyde 8f also gave the
desired product 9af in 91% yield. 1-, and 2-naphthaldehydes (8r
and 8s, respectively) and the aromatic hetero aldehydes 2-
furaldehyde 8t, thiophene-2-carbaldehyde 8u, pyridine-2-
carbaldehyde 8v, and nicotinaldehyde 8w were also suitable for
this transformation and gave the corresponding products 9ar–
9aw in 71–95% yields, which were superior to those previously
reported.[10] To our delight, linear, secondary, and tertiary
aliphatic aldehydes also underwent this transformation and gave
the desired products 9ax–9az, respectively, in moderate yields
by increasing temperature and prolonging the reaction time.
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Table 3. Optimization of the reaction conditions[a]
Entry
1
Catalyst (mol%)
FeCl3 (10)
Brønsted acid
Solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
1,4-dioxane
Cl(CH2)2Cl
MeCN
Temp. [°C]
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
Yield [%][b]
–
40
49
42
55
37
66
70
82
80
84
98
97
82
29
18
71
83
49
97
72
96
2
FeCl2 (10)
–
3
Fe(ClO4)3.6H2O (10)
Fe(BF4)2.6H2O (10)
Fe(acac)3 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (10)
Fe(OAc)2 (5)
Fe(OAc)2 (1)
–
–
4
–
5
–
6
–
7
MeSO3H
TfOH
TsOH
AcOH
TFA
TFA
TFA
TFA
-
8
9
10
11
12
13
14
15
16
17
18
19
20
21[c]
–
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
Fe(OAc)2 (5)
TFA
TFA
TFA
TFA
TFA
TFA
toluene
toluene
toluene
100
[a] Reaction conditions: 2-methylquinoline 1a (0.4 mmol), benzaldehyde 8a (0.6 mmol), Brønsted acid (0.04 mmol; entries 8–15, 17–22), solvent (1.0 mL),
24 h. [b] Isolated yield. [c] 0.48 mmol of benzaldehyde 2a was used.
Next, we examined the scope of this transformation with
regard to the 2-methylazaarene components. As shown in Scheme
5, the reactions of a series of 2-methylazaarenes 1b–1i with
benzaldehyde 8a were examined under the optimized conditions.
The reaction of benzaldehyde 8a with quinolines 1b–1f bearing
election-deficient or electron-rich substituents on the benzene ring
proceeded smoothly, to give the corresponding 2-
alkenylquinolines 9ba–9fa in 82–99% yield. 1-methylisoquinoline
1h similarly gave the alkenyl derivative 9ha in 85% yield, and 2-
methylquinoxaline 1g, gave 2-[(E)-2-phenylvinyl]quinoxaline 9ga,
albeit in slightly lower yield. In addition, 2,6-dimethylpyridine 1i
gave the desired product 9ia in 35% yield at a higher temperature
and with a longer reaction time, whereas 2-methylpyridine did not
give any product, possibly as a result of the electronic effect of the
methyl group on the pyridyl ring.
performed in the presence of a catalytic amount of acetic acid in
toluene at 110 °C for 30 h, the desired compound 11 was obtained
in 65% yield, which is comparable to the best result yet reported.
Cl
N
1e (2.0 g)
Fe(OAc)2 (5 mol%)
CH3COOH (10 mol%)
CHO
+
Cl
N
toluene,110 oC, 30 h
OHC
CHO
11
2.16 g, 65%
10 (1.2 equiv)
Scheme 6. Gram-scale synthesis of the intermediate of Montelukast
The proposed reaction pathway for the addition of 2-methyl
azaarenes to carbonyl compounds was described in Scheme 7. The
acidity of C(sp3)–H bond of 2-methyl quinoline 1a should be
significantly enhanced upon ligation to iron to form complex A.
Driven by the endogenous basic OAc- anion abstraction, C–H
cleavage is known to occur to give iron-enamide species B. On
the one hand, the active iron-enamide species B undergo
nucleophilic attack to the proton activated aldehyde 8 to form
intermediate D, in which the endogenous basic anion OAc-
abstract the proton, giving compound 9 via an E2-elimination
process in high stereoselectivity with regenerated iron catalyst. On
the other hand, when the active iron-enamide species B undergo
nucleophilic attack to 1,2-dicarbonyl compound 2, the
electrophilicity of the carbonyl group is dramatically enhanced by
Finally, we applied this attractive protocol to the synthesis of
3-[(E)-2-(7-chloroquinolin-2-yl)vinyl]benzaldehyde 11,
a key
intermediate in the synthesis of leukotriene receptor antagonist
Montelukast (Singulair). Compound 11 is usually prepared in 45–
65% yield by the reaction of 7-chloro-2-methylquinoline 1e and
isophthalaldehyde 10 promoted by a stoichiometric amount of
acetic acid or acetic anhydride.[17] The use of large amounts of
acetic acid or acetic anhydride in manufacture is very
inconvenient, making the process uneconomical. In addition,
acetic anhydride is a regulated commercial item, as it is widely
used in the production of illicit narcotics. As shown in Scheme 6,
when the gram-scale reaction of chloro compound 1e with
isophthalaldehyde 10 catalyzed by 5 mol% Fe(OAc)2 was
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the complexation of carbonyl groups with iron, to give
with regenerated iron catalyst after hydrolysis of intermediate F.
intermediate F via a transition state E. The compound 3 is formed
Scheme 5. Substrate scope of aldehydes and methyl azaarenes. Reaction conditions: methyl azaarene 1 (0.4 mmol), aldehyde 8 (0.48 mmol), Fe(OAc)2 (5
mol%), TFA (10 mol%), toluene (1.0 mL), 100 °C, 24 h, isolated yield. The E-isomer was obtained exclusively in all cases. [a] Reaction temperature: 120 °C;
[b] Reaction time: 36 h; [c] 1.0 mmol pivaldehyde 2z was used; [d] 140 °C for 48 h.
Experimental Section
Conclusions
General Remarks: All the experiments were performed under nitrogen
in standard Schlenk tubes. All chemicals and solvents were purchased
from commercial suppliers and were used without further purification.
1-Methyl- and 1-Benzyl-1H-indole-2,3-diones were prepared according
to the literature method. NMR spectra were recorded at 25 °C by using a
JEOL JNM-A500 spectrometer (500 MHz for 1H, 125 MHz for 13C).
Chemical shifts are reported in ppm relative to tetramethylsilane as
internal standard. Chemical shifts of 13C NMR are reported relative to
the solvent peak as an internal standard. Mass spectra were recorded
with a JEOL AccuTOF GC JMS-T100GC equipped with Agilent 6890N
In summary, we have developed an iron-catalyzed atom-, step-
economic green synthesis of azaarene-substituted α- or β-
hydroxy carboxylic esters, 3-azarenylmethyl-3-hydroxy-2-
oxindoles, and trans-2-alkenylazaarenes via C(sp3)–H bond
functionalization of methyl azaarenes with carbonyl compounds.
The investigation of detailed reaction mechanism of iron-
catalyzed C(sp3)–H bond functionalization and their asymmetric
variants are currently underway.
GC or
a JEOL AccuTOF JMS-T100LC. Melting points were
determined by using a Yanaco MP-J3 micro melting-point apparatus
and are uncorrected.
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Scheme 7. Proposed reaction pathway for the addition of 2-methyl azaarenes and carbonyl compounds
Typical Procedure for the Synthesis of Azaarene-Substituted
Lactate Derivatives, Exemplified by the Synthesis of Ethyl 2-
Hydroxy-3-quinolin-2-ylpropanoate (3aa): Fe(OAc)2 (3.5 mg, 0.02
mmol), 2-methylquinoline 1a (1.0 mmol), and ethyl glyoxylate 2a (0.4
mmol) were dissolved in 1,4-dioxane (1.0 mL) under N2, and the
mixture was stirred at 120 °C for 24 h. The mixture was cooled to room
temperature, and the solvent was removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel) to give
Typical Procedure for the Synthesis of (E)-2-Alkenylazaarenes,
Exemplified by the Synthesis of 2-[(E)-2-Phenylvinyl]quinoline
(9aa): Fe(OAc)2 (3.5 mg, 0.02 mmol), 2-methylquinoline 1a (58 mg,
0.4 mmol), PhCHO 8a (51 mg, 0.48 mmol), and TFA (3 ꢀL, 0.04 mmol)
were dissolved in dry toluene (1.0 mL) under N2 and the mixture was
stirred at 100 °C for 24 h. The mixture was then cooled to room
temperature and the solvent was removed under reduced pressure. The
residue was purified by flash column chromatography (silica gel) to give
9aa as a white solid; yield: 89 mg (96%). mp: 99-101oC; 1H NMR (500
MHz, CDCl3): δ = 7.32-7.52 (m, 5H, ArH), 7.64-7.73 (m, 5H, ArH),
7.79 (d, J = 8.0 Hz, 1H, CH), 8.08 (d, J = 8.0 Hz, 1H, CH), 8.14 (d, J =
8.5 Hz, 1H, ArH) ppm; 13C NMR (125 MHz, CDCl3): δ = 119.2, 126.1,
127.2, 127.3, 127.5, 128.6, 128.8, 129.0, 129.2, 129.7, 134.4, 136.3,
136.5, 148.3, 156.0 ppm; EI-HR-MS: m/z = 231.1054, calcd. for
C17H13N: 231.1048.
o
a 3aa as a white solid: yield: 97 mg (90%); mp: 112-115 C; IR (ATR,
neat) ν = 626, 763, 831, 1040, 1161, 1287, 1508, 1599, 1732, 2979,
1
3065 cm-1; H NMR (500 MHz, CDCl3): δ = 1.23 (t, J = 7.5 Hz, 3H,
CH3), 3.39-3.52 (m, 2H, CH2), 4.22 (q, J = 7.5 Hz, 2H, CH2), 4.77 (dd,
J1 = 7.5 Hz, J2 = 3.5 Hz, 1H, CH), 7.31 (d, J = 8.5 Hz, 1H, ArH), 7.51-
7.53 (m, 1H, ArH), 7.68-7.72 (m, 1H, ArH), 7.79 (d, J = 8.0 Hz, 1H,
ArH), 8.00 (d, J = 8.0 Hz, 1H, ArH), 8.11 (d, J = 9.0 Hz, 1H, ArH) ppm;
13C NMR (125 MHz, CDCl3): δ = 14.1, 40.9, 61.3, 70.4, 122.0, 126.2,
126.9, 127.5, 128.7, 129.7, 136.7, 147.1, 158.8, 173.6 ppm; EI-HR-MS:
m/z = 268.0952, calcd. for C14H15NNaO3 [M+Na]+: 268.0950.
Gram-Scale Synthesis of 3-[(E)-2-(7-Chloroquinolin-2-yl)vinyl]
benzaldehyde (11): A solution of 7-chloro-2-methylquinoline (1e; 2.0 g,
11.26 mmol), isophthalaldehyde 10 (1.80 g, 13.4 mmol), Fe(OAc)2 (98
mg, 0.56 mmol), and AcOH (65 ꢀL, 1.13 mmol) in toluene (12 mL) was
stirred at 110 °C for 30 h while the reaction was monitored by TLC. The
mixture was then allowed to cool to room temperature and the
precipitated crude solid was recovered by filtration. The wet crude solid
was added to EtOAc (60 mL) and the mixture was refluxed with stirring
for 2 h. The mixture was then filtered and the filtrate was concentrated
to 10 mL. The resultant slurry was cooled to 0 °C with stirring for 3 h.
The solid that separated was collected by filtration, washed with chilled
EtOAc, and dried under vacuum to give 11 a light-yellow solid; yield:
Typical Procedure for the Synthesis of 3-Azaarene-Substituted-3-
Hydroxy-2H-indol-2-ones, Exemplified by the Synthesis of 3-
Hydroxy-3-[(6-methyl pyridin-2-yl)methyl]-7-(trifluoromethyl)-1,3-
dihydro-2H-indol-2-one 5i: Fe(OAc)2 (7.0 mg, 0.04 mmol), 7-
(trifluoromethyl)-1H-indole-2,3-dione 4i (0.4 mmol), and 2,6-
dimethylpyridine 1i (1.0 mmol) were dissolved in 1,4-dioxane (1.0 mL)
under N2, and the mixture was stirred at 120 °C for 24 h. The mixture
was cooled to room temperature and the solvent was removed under
reduced pressure. The residue was then purified by flash column
chromatography (silica gel) to give 5i as a light-yellow solid; yield: 124
o
1
2.16 g (65%). mp: 150-152 C; H NMR (500 MHz, CDCl3): δ = 7.45-
7.49 (m, 2H, ArH), 7.59 (t, J = 8.0 Hz, 1H, ArH), 7.64 (d, J = 9.0 Hz,
1H, CH), 7.74 (d, J = 8.5 Hz, 1H, ArH), 7.81 (d, J = 16.5 Hz, 1H, CH),
7.85 (d, J = 7.5 Hz, 1H, ArH), 7.90 (d, J = 7.5 Hz, 1H, ArH), 8.10-8.15
(m, 3H, ArH), 10.08 (s, 1H, CHO) ppm; 13C NMR (125 MHz, CDCl3): δ
= 119.9, 125.8, 127.3, 128.1, 128.2, 128.7, 129.5, 129.7, 130.1, 132.9,
133.4, 135.7, 136.3, 136.9, 137.3, 148.6, 156.1,192.0 ppm; EI-HR-MS:
m/z = 293.0615, calcd. for C18H12ClNO: 293.0607.
o
mg (90%). mp: 166-168 C; IR (ATR, neat) ν = 711, 814, 1110, 1342,
1
1458, 1623, 1735, 3125, 3238 cm-1; H NMR (500 MHz, CDCl3): δ =
2.61 (s, 3H, CH3), 3.07 (d, J = 15.0 Hz, 1H, CH2), 3.28 (d, J = 15.5 Hz,
1H, CH2), 6.88 (d, J = 7.0 Hz, 1H, ArH), 6.97-7.03 (m, 2H, ArH), 7.16
(d, J = 8.0 Hz, 1H, ArH), 7.42 (d, J = 7.0 Hz, 1 H, ArH), 7.57 (t, J = 7.5
Hz, 1H, ArH) ppm; 13C NMR (125 MHz, CDCl3): δ = 24.2, 42.1, 75.4,
111.9, 112.1, 112.4, 121.5, 122.1, 122.4, 122.6, 124.8, 125.8, 125.9,
126.0, 127.6, 133.2, 137.5, 137.6, 156.2, 157.3, 178.2 ppm; ESI-HR-
MS: m/z =345.0816, calcd. for C16H13F3N2NaO2 [M+Na]+:345.0826.
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[7] a) J.-B. Behr, T. Gourlain, A. Helimi, G. Guillerm, Bioorg. Med.
Chem. Lett. 2003, 13, 1713–1716; b) B. H. Heasley, R. Jarosz, K.
M. Carter, S. Jenny Van, K. R. Lynch, T. L. Macdonald, Bioorg.
Med. Chem. Lett. 2004, 14, 4069–4074; c) V. R. Solomon, H. Lee,
Curr. Med. Chem. 2011, 18, 1488–1508.
Acknowledgments
We are grateful for the financial support from the National Natural
Science Foundation of China (21202092), Startup Foundation from
China Three Gorges University (KJ2012B080).
[8] a) B. A. Lefker, W. A. Hada, P. J. McGarry, Tetrahedron Lett.
1994, 35, 5205–5208; b) S. Ye, K. Gao, J. Wu, Adv. Synth. Catal.
2010, 352, 1746–1751.
Notes and references
[1] For a recent review, see: P. A. Wender, Tetrahedron 2013, 69,
7529–7550.
[9] For selected reviews, see: a) C. Marti, E. M. Carreira, Eur. J. Org.
Chem. 2003, 2009–2119; b) H. Lin, S. J. Danishefsky, Angew.
Chem. Int. Ed. 2003, 42, 36–51; c) C. V. Gallifor, K. A. Scheidt,
Angew. Chem. Int. Ed. 2007, 46, 8748–8758. d) S. Peddibhota,
Curr. Bioact. Compd. 2009, 5, 20–38; e) F. Zhou, Y. L. Liu, J.
Zhou, Adv. Synth. Catal. 2010, 352, 1381–1407.
[2] For the Pd-catalyzed C(sp3)–H bond functionalisation of pyridines,
see: a) D. Shabashov and O. Daugulis, Org. Lett. 2005, 7, 3657–
3659; b) T. Niwa, H. Yorimitsu and K. Oshima, Org. Lett. 2007, 9,
2373–2375; c) P. M. Burton, J. A. Morris, Org. Lett. 2010, 12,
5359–5361; d) H. F. Jiang, H. J. Chen, A. Wang, X. H. Liu, Chem.
Commun. 2010, 46, 7259–7261; e) D. Shabashov and O. Daugulis, J.
Am. Chem. Soc. 2010, 132, 3965–3972; f) G. Y. Song, Y. Su, X.
Gong, K. L. Han, X. W. Li, Org. Lett. 2011, 13, 1968–1971; g) S.
Duez, A. K. Steib, S .M. Manolikakes, P.Knochel, Angew. Chem.,
Int. Ed. 2011, 50, 7686–7690; h) K. J. Stowers, K. C. Fortner, M. S.
Sanford, J. Am. Chem. Soc. 2011, 133, 6541–6544.
[10] For selected recent examples, see: a) D. Tomita, K. Yamatsugu, M.
Kanai, M. Shibasaki, J. Am. Chem. Soc. 2009, 131, 6946–6948; b)
N. V. Hanhan, A. H. Sahin, T. W. Chang, J. C. Fettinger, A. K.
Franz, Angew. Chem. Int. Ed. 2010, 49, 744–747; c) J. Itoh, S. B.
Han, M. J. Krische, Angew. Chem. Int. Ed. 2009, 48, 6313–6316;
d) C. D. Grant, M. J. Krische, Org. Lett. 2009, 11, 4485–4487; e)
J. Deng, S. Zhang, P. Ding, H. Jiang, W. Wang, J. Li, Adv. Synth.
Catal. 2010, 352, 833–838; f) P. Chauhan, S. S. Chimni, Chem.–
Eur. J. 2010, 16, 7709–7713; g) Q. Guo, M. Bhanushai, C. G.
Zhou, Angew. Chem. Int. Ed. 2010, 49, 9460–9464; h) N. Hara, S.
Nakamura, N. Shibata, T. Toru, Chem.–Eur. J. 2009, 15, 6790–
6793; h) Y. L. Liu, B. L. Wang, J. J. Cao, L. Chen, Y. X. Zhang,
C. Wang, J. Zhou, J. Am. Chem. Soc. 2010, 132, 15176–15178; i)
F. Zhong, G. Y. Chen, Y. Lu, Org. Lett. 2011, 13, 82–85.
[3] For Lewis acid catalyzed reactions, see: a) B. Qian, S. Guo, J. Shao,
Q. Zhu, L. Yang, C. Xia, H. Huang, J. Am. Chem. Soc. 2010, 132,
3650–3651; b) B. Qian, S. Guo, C. Xia, H. Huang, Adv. Synth. Catal.
2010, 352, 3195–3200; c) B. Qian, P. Xie, Y. Xie, H. Huang, Org.
Lett., 2011, 13, 2580–2583; d) M. Rueping, N. Tolstoluzhsky, Org.
Lett. 2011, 13, 1095–1097; e) H. Komai, T. Yoshino, S. Matsunaga,
M. Kanai, Org. Lett. 2011, 13, 1706–1709; f) J. J. Jin, H. Y. Niu, G.
R. Qu, H. M. Guo, J. S. Fossey, RSc Adv. 2012, 2, 5968–5971; g) V.
B. Graves, A. Shaikh, Tetrahedron Lett. 2013, 54, 695–698; h) B.
Qian, L. Yang, H. M. Huang. Tetrahedron Lett. 2013, 54, 711–714;
i) J. Y. Liu, H. Y. Niu, S. Wu, G. R. Qu, H. M. Guo, Chem.
Commun. 2012, 48, 9723–9725; j) R. Niu, S.Yang, J. Xiao, T. Liang,
X. Li, Chin. J. Catal. 2012, 33, 1636–1641; k) S. V. N.Vuppalapati,
Y. R. Lee, Tetrahedron 2012, 68, 8286–8292.
[11] a) R. Niu, J. Xiao, T. Liang, X. Li, Org. Lett. 2012, 14, 676–679; b)
H. M. Meshram, N. N. Rao, L. C. Rao, N. S. Kumar, Tetrahedron
Lett. 2012, 53, 3963–3966; c) M. Raghu, M. Rajasekhar, B.
Chandra Obula Reddy, C. Suresh Reddy, B. V. Subba Reddy,
Tetrahedron Lett. 2013, 54, 3503–3506; d) S. V. Nuppalapati, Y.
R. Lee, Tetrahedron 2012, 68, 8268–8292.
[4] For BrØnsted acid catalyzed reactions, see: a) R. Niu, J. Xiao, T.
Liang, X. W. Li, Org. Lett. 2012, 14, 676–679; b) J. J. Jian, D. C.
Wang, H. Y. Niu, S. Wu, G. R. Qu, Z. B. Zhang, H. M. Guo,
Tetrahedron. 2013, 69, 6579–6584; c) F. F. Wang, C. P. Luo, Y.
Wang, G. J. Deng, L. Yang, Org. Biolmol. Chem. 2012, 10, 8605–
8608; d) X. Gao, F. Zhang, G. J. Deng, L. Yang, Org. Lett. 2014,
16, 3664–3667.
[12] a) K. Mekouar, J. F. Mouscadet, D. Desmaële, F. Subra, H. Leh,
D. Savouré, C. Auclair, J. d’Angelo, J. Med. Chem. 1998, 41,
2846–2857; b) A. Fournet, R. Mahieux, M. A. Fakhfakh, X.
Franck, R. Hocquemiller, B. Figadère, Bioorg. Med. Chem. Lett.
2003, 13, 891–894; c) M. A. Fakhfakh, A. Fournet, E. Prina, J. -F.
Mouscadet, X. Franck, R. Hocquemiller, B. Figadère, Bioorg. Med.
Chem. 2003, 11, 5013–5023; d) X. Franck, A. Fournet, E. Prina, R.
Mahieux, R. Hocquemiller, B. Figadère, Bioorg. Med. Chem. Lett.
2004, 14, 3635–3638; e) F. S. Chang, W. C. Chen, C. H. Wang, C.
C. Tzeng, Y. L. Chen, Bioorg. Med. Chem. 2010, 18, 124–133.
[5] For catalyst-free reactions, see: a) Y. Yan, K. Xu, Y. Fang, Z.
Wang, J. Org. Chem. 2011, 76, 6849–6859; b) H. M. Meshram, N.
Nageswara Rao, L. Chandrasekhara Rao, N. Satish Kumar,
Tetrahedron Lett. 2012, 53, 3963–3966; c) M. Raghu, M.
Rajasekhar, B. Chandra Obula Reddy, C. Suresh Reddy, B. V.
Subba Reddy, Tetrahedron Lett. 2013, 54, 3503–3506; d) H. Y. Li,
L. J. Xing, T. Xu, P. Wang, R. H. Liu, B. Wang, Tetrahedron Lett.
2013, 54, 858–860; e) N. Rao Nageswara, H. M. Meshram,
Tetrahedron Lett. 2013, 54, 5087–5090; f) N. Nageswara, H. M.
Meshram, Tetrahedron Lett. 2013, 54, 1315–1317; g) L. Xu, Z.
Shao, L. Wang, J. Xiao, Org. Lett. 2014, 16, 796–799; h) J. Xiao,
H. Zhao, L. Wang, L. Xu, Z. Shao, RSC Adv. 2014,
DOI:10.1039/C4RA09338K.
[13] a) F.-X. Felpin, J. Lebreton, Eur. J. Org. Chem. 2003, 3693–3712;
b) J. S. Carey, L. Laffan, C. Thompson, M. T. Williams, Org.
Biomol. Chem. 2006, 4, 2337–2347.
[14] a) C. E. Kalsow, R. D. Stayner, J. Am. Chem. Soc. 1945, 67, 1716–
1717; b) C. Compton, W. Bergmann, J. Org. Chem. 1947, 12, 363–
368.
[15]
a) J. Wu, X. Cui, L. Chen, G. Jiang, Y. Wu, J. Am. Chem. Soc.
2009, 131, 13888–13889; b) S. H. Cho, S. J. Hwang, S. Chang, J.
Am. Chem. Soc. 2008, 130, 9254–9256; c) M. Murakami, S. Hori,
J. Am. Chem. Soc. 2003, 125, 4720–4721; d) K. S. Kanyiva, Y.
Nakao, T. Hiyama, Angew. Chem. Int. Ed. 2007, 46, 8872–8874;
e) Y. Nakao, K. S. Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2008,
130, 2448–2449; f) J. J. Mousseau, J. A. Bull, A. B. Charette,
[6] a) Z. Q. Zhu, P. Bai, Z. Z. Huang, Org. Lett. 2014, 16, 4881–4883;
b) F. F. wang, C. P. Luo, G. Deng, L. Yang, Green Chem. 2014, 16,
2428–2431; c) D. Liu, C. Liu, H. Li, A. Lei, Angew. Chem. Int. Ed.
2013, 52, 4453–4456; d) L. Zhou, S. Tang, X. Qi, C. Lin, K. Liu, C.
Liu, Y. Lan, A. Lei, Org. Lett. 2014, 16, 3404–3407.
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Angew. Chem. Int. Ed. 2010, 49, 1115–1118; g) R. Rossi, F.
Rushikesh, Canadian Patent 2666208, 2006; c) N. K. Namurthy,
C. Sekhar, T. Kashyap, J. Singh, World Patent 2010/064109,
2010.
Bellina, M. Lessi, Synthesis, 2010, 4131–4153.
[16] K. Jiang, D. Pi, H. Zhou, S. Liu, K. Zou, Tetrahedron 2014, 70,
3056–3060.
Received: ((will be filled in by the editorial staff))
Published online: ((will be filled in by the editorial staff))
[17] a) S. Suri, G. S. Sarin, M. Mahendru, World Patent 2006/021974,
2006; b) C. Sugatar, R. A. Singh, K. Neeraj, C. Mukesh, K.
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Iron-Catalyzed C(sp3)–H Functionalization of Methyl Azaarenes: A Green Approach to Azaarene-substituted α- or β-Hydroxy Carboxylic
Derivatives and 2-Alkenylazaarenes
Danwei Pi, Kun Jiang, Haifeng Zhou, Yuebo Sui, Yasuhiro Uozumi and Kun Zou …….. Page No. – Page No.
R2
O
O
O
OH
R1
R3
R3
R2
X
N
X
n
n
20 examples
up to 90% yield
X= C, O, N
n = 0, 1
Iron Catalysis
O
R1
H2O
+
R4
H
R4
N
R1
35 examples
up to 99% yield
N
O
R1
R5
OH
R5
O
N
N
R6
N
O
19 examples
up to 90% yield
R6
An iron-catalyzed C(sp3)–H functionalization of methyl azaarenes with carbonyls to access the title compounds have been described.
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