External oxidant-free alkylation of quinoline and pyridine derivatives

Article abstract of DOI:10.1039/c9ob02653c

A novel and efficient method for the generation of alkyl radicals and the alkylation of quinoline and pyridine derivatives under mild conditions has been developed. This strategy allows the direct alkylation of heteroaromatics in the absence of an external oxidant. A preliminary mechanistic study suggests that the present reaction probably proceeds via an intermolecular HAT process.

Full text of DOI:10.1039/c9ob02653c

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DOI: 10.1039/C9OB02653C
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External oxidant-free alkylation of quinoline and pyridine
derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
Linhua Shen,a Xianying Gaoa, Nannan Luana, Zhenwei Liua, Jingya Lib, Dapeng Zou*a, Yangjie Wu*a
and Yusheng Wu *a,b, c
DOI: 10.1039/x0xx00000x
A novel and efficient method for the generation of alkyl
radicals and the alkylation of quinoline and pyridine
derivatives at mild conditions has been developed. This
strategy allows the direct alkylation of heteroaromatics in the
absence of external oxidant. Preliminary mechanistic study
suggests that the present reaction probably undergo an
intermolecular HAT process.
INTRODUCTION
Nitrogen-containing heteroaromatics (such as quinoline and
pyridine), especially those with cyclic and acyclic ether units,
widely exist in natural products and synthetic pharmaceuticals
with
a
wide range of biological activities (scheme 1).[1]
Therefore, the efficient introduction of ether groups into
nitrogen-containing heteroaromatics has become a significant
research field in organic chemistry. Indisputably, novel
methodologies for the efficient synthesis of this kind of
compounds have been witnessed recent years, with an intensive
emergence of numerous elegant protocols (Scheme 2).
Scheme 2. Dehydrogenative C-C cross-coupling reactions
between heteroaromatics and ethers.
Because of the electron deficient property of heteroaromatics
and the resulting low reactivity toward electrophiles, radical
alkylation of heteroaromatics seems to be an attractive protocol
to introduce ether groups to heteroaromatic nucleus. At the very
start, transition metals, such as Ag, Fe and Ti, were used as
catalysts by Minisci and co-workers in the presence of peroxides
to initiate alkyl radicals and accomplish the alkylation of
heteroaromatics.[2] Later, more transition metal catalysts like
Scheme 1. Examples illustrating the importance of compounds
alkylated pyridine and quinoline motifs.
[3]
[4]
[5]
[6]
[7]
[7]
Pd(OAc)2, Sc(OTf)3, Cu(OTf)2, FeF2, Ni(acac)2, NiF2,
[8]
and CoCO3 were also studied to undergo this conversion.
However, all these reactions were performed under harsh
conditions in the presence of peroxides, which may cause
considerable safety issues. Recently, photocatalytic system was
investigated by MacMillan to carry out the process under mild
conditions, where {Ir[dF(CF3)ppy]2-(dtbbpy)}PF6 (cat.) and
Na2S2O8 were used in a mixture of water and acetonitrile at 23 °C
under photoirradiation.[9] Very recently, due to the
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environmentally-benign property, metal-free Minisci reaction
has received increasing attention and significant progress has
been made towards this goal.[10] Typically, explosive NaN3 was
developed by Burgmann[10a] and a N-hydroxysuccinimide (NHS)
mediated process was attempted by Wang and co-workers.[10b]
6
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
H2O
2.0
2.0
2.0
2.0
1.0
3.0
5.0
3.0
3.0
3.0
3.0
3.0
3.0
5
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7
Acetone
DMSO
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DOI: 1108.1039/C9OB02653C
8
61
9
67
Among the above mentioned methods, oxidants such as
(NH4)2S2O8, K2S2O8, butyl peroxybenzoate (DTBP), t-butyl
hydroperoxide (TBHP) and benzoyl peroxide (BPO) were
inevitably used to initiate the processes. To the best of our
knowledge, such protocol, which resembles the Minisci reaction,
conducted in the absence of external oxidants is still rarely
10
11
12
13
14
15
16
17
46
82
72
53[c]
72[d]
81[e]
71[f]
55[g]
75[h]
investigated. Herein, based on the works have done by our
[11]
laboratory,
we reported a successful direct alkylation of
quinoline and pyridine derivatives without any external oxidant
under mild and neutral conditions.
18
[a]
RESULTS AND DISCUSSION
Reaction conditions: 1a (0.2 mmol), base (3.0 equiv), 4 h
[b]
[c]
[d]
under Ar atmosphere; GC yield; DCM (1.0 mL); DCM (3.0
mL); [e] 6 h; [f] 2.0 equiv k3PO4; [g] 40 °C . [H] under dark condition.
Recently, we developed a facile and efficient approach for the
construction of N-methoxyquinolin-2(1H)-ones and 2-
arylquinoline using easily available N-methoxyquinoline-1-ium
tetrtafluoroborate as starting material.[11c] In these studies,
alkylation byproducts were observed when tetrahydrofuran and
1,4-dioxane were used as solvents. This interesting phenomenon
triggered our study. Initially, N-methoxy-4-methylquinolin-1-
ium tetrafluoroborate and Na2CO3 were treated in 1, 4-dioxane
(2.0 mL) at 30 °C for 4 hours under argon atmosphere, to get the
desired product with 25% yield (Table 1, entry 1). When the
base was changed to NaOH, CsF and K3PO4, the yield improved to
51%. Whereas, NaOCH3 was found to be less effective for the
reaction (Table 1, entries 2-5). When the solvent system
switched to the mixture of 1,4-dioxane with acetone, DMSO, H2O
and DCM, the yield of the desired product varied from 5% to 67%
(Table 1, entries 6-9). Then the volume of DCM and 1, 4-dioxane
was also screened and the best results were obtained when 1, 4-
dioxane (3.0 mL)/DCM (2.0 mL) were used as solvents (Table 1,
entries 10-14). Prolonging the reaction time didn’t give any
advantage to this process (Table 1, entry 15). Decreasing the
amount of the K3PO4 (Table 1, entry 16) led to a declined yield
(71%). Increasing the reaction temperature to 40 °C , the yield
was also decreased (Table 1, entry 17). Thus, the optimum
reaction conditions were obtained as 0.2 mmol compound 1a
and 3.0 equiv of K3PO4 stirring in the mixture of 1, 4-dioxane (3.0
mL) and DCM (2.0 mL) under argon atmosphere at 30 °C for 4
hours.
Table 2. Substrate scope of various heteroaromatics.[a,b]
Table 1. Optimization of the reaction conditions.[a]
Entry Base
Solvent
X(ml)
2.0
Yield (%)[b]
1
2
3
4
5
Na2CO3
-
-
-
-
-
25
49
26
7
NaOH
CsF
2.0
2.0
NaOCH3
K3PO4
2.0
2.0
51
2 | J. Name., 2012, 00, 1-3
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[a]
Standard reaction conditions: 1a (0.2 mmol), 2a (3.0 mL),
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DOI: 10.1039/C9OB02653C
DCM (2.0 mL), K3PO4 (3.0 equiv), under Ar atmosphere at 30 °C Table 3. Substrate scope of various ethers.[a,b,c]
for 4 hours; [b] Isolated yield; [c] using 10% 1a as a initiator.
Under the discovered optimal reaction conditions, a series of
N-methoxy-4-methylquinolin-1-ium
tetrafluoroborate
derivatives (1a) were investigated in the presence of 3.0 equiv of
K3PO4 in a mixture of 1, 4-dioxane (3.0 mL)/DCM (2.0 mL) at 30
ºC . The results were summarized in Table 2. Almost all the
substrates converted to the corresponding products smoothly
with moderate to good yields. Substrates with various
substituent groups (such as methyl, bromo, fluoro and
trifluoromethyl) at the C6 or C7-position reacted with 2a to
generate the desired products (3ba, 3ca and 3da) in 66-86%
yields. Substrates with benzyl and ethyl substitution at C4-
position also worked well to give the respective products (3ea
and 3fa) in 62% and 78% yields. It should be noted that N-
methoxy-4-methylpyridin-1-ium tetrafluoroborate (1g) and 4-
benzyl-1-methoxypyridin-1-ium tetrafluoroborate (1h) reacted
with 2a smoothly, giving the desired product (3ga, 3ha) in 75%
and 63% yield. As we expected, N-methoxy-4-methylpyridin-1-
ium tetrafluoroborate with phenyl and methoxyl group
substituted at 2-position worked well to give the corresponding
product (3ia, 3ja) in 42% yield. However, when the substituent
group at 2-position was switched to the cyano group, no target
product (3ka) was found. The phenomenon might be caused by
the electron-withdrawing property of the nitrile group. The
substrates without C4 substituted group or with C4 chloro group
could not work under the optimal reaction conditions (3la-3oa).
However, when 1a was used as an initiator and N-
methoxyquinolinium (1l) was explored under the standard
conditions, a couple of isomers (C2 alkylated and C4 alkylated
product) were detected by GC-MS in a ratio of 7:3. When 1-
methoxy-2-methylquinolinium (1m) was explored in optimal
reaction conditions using 10% 1a as an initiator, only a trace
mount of alkylated product was detected.
[a]
Standard reaction conditions: 1a (0.2 mmol), 2a (3.0 mL),
To establish the scope of the developed methods, we
subsequently studied a wide range of cyclic and acyclic ethers
(Table 3). When cyclic ethers such as tetrahydrofuran (2b) and
tetrahydropyran (2c) were used, the desired single regio-
isomeric products (3ab and 3ac) were obtained in 83% and 67%
DCM (2.0 mL), K3PO4 (3.0 equiv), under Ar atmosphere at 30 °C
for 4 hours; [b] Isolated yield; [c] At 45 °C
Regarding to whether the methoxyl group was indispensable
yields, respectively. The acyclic ethers such as diethylether (2d), for this transformation, we replaced the substrate (1a) with the
methyl tert-butyl ether (2e), ethyl acetate (2f) worked well in
the conditions to give the corresponding single regio-isomeric
products (3ad, 3ae and 3af) in 40-80% yields. When 1a reacted
with ethyl acetate (2f), the reaction need to be conducted at
45 °C to ensure the process running smoothly. Unfortunately,
only trace mount of product (3ag) was detected when isopropyl
ether was used. When glycol dimethyl ether was employed, a
total 90% yield of isomers (3ah and 3ah’) were achieved in a
27:15 ratio. As we expected, when N-methoxy-4-methylpyridin-
1-ium tetrafluoroborate (1g) was employed to undergo the
process with tetrahydrofuran (2b) or diethylether (2d),
1-ethoxy-4-methylquinolin-1-ium tetrafluoroborate (1l). To our
delight, cyclic, acyclic ethers and even cycloalkanes could
convert to desired products in moderate to good yields. For
instance, when cyclic ethers like 1, 4-dioxane (2a),
tetrahydrofurane (2b), tetrahydropyrane (2c) were employed,
the desired products (3la, 3lb, 3lc) were obtained in 72%, 73%
and 56% yield, respectively. Acyclic ether like methyl tert-butyl
ether (3e) underwent this process smoothly too, giving the
desired product (3le) in 42% yield. Additionally, cyclopetane (3j)
showed partial reactivity and the corresponding product (3lj)
monoalkylated products were obtained in 73% and 80%, was isolated in 42% yield.
respectively (3gb and 3gd). What deserved to mention was that
cyclohexane (2i), cyclopetane (2j) and toluene (2k) showed
partial reactivity and the corresponding products (3ai, 3aj, 3ak)
were isolated in 49%, 46% and 33% yield, respectively.
However, when 1, 4-dimethylpiperazine (2l) was employed, no
target product (3al) was found.
Table 4. Explorations on N-ethoxy-4-methylquinolin-1-ium
tetrafluoroborate.[a,b]
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DOI: 10.1039/C9OB02653C
[a]
Standard reaction conditions: 1a (0.2 mmol), 2a (3.0 mL),
DCM (2.0 mL), K3PO4 (3.0 equiv), under Ar atmosphere at 30 °C
for 4 hours; [b] Isolated yield;
To investigate the further synthetic utility of this method, a
gram-scale reaction of N-methoxy-4-methylquinolin-1-ium
tetrafluoroborate (1a, 2.00 g, 7.62 mmol), 1, 4-dioxane (2a,
13.41 g, 152mmol) and DCM (8.5 g, 100 mmol) was performed
under the optimal reaction conditions (Scheme 3). As a result,
alkylation reaction proceeded smoothly to afford 2-(1, 4-dioxan-
2-yl)-4-methylquinoline (3aa) in 62% yield.
Scheme 4. Control Experiments.
Based on the control experiments and the literature
precedent,[11c,12] a plausible mechanism was proposed for this
process as shown in Scheme 5. Firstly, an intermediate I and
methoxy radical II were generated from a homolytic cleavage of
N-O bond in N-methoxyquinoline-1-ium tetrtafluoroborate. Then
1,4-dioxane underwent a hydrogen deprivation from the C-H
bond border on the oxygen atom in the presence of I and/or II to
get the corresponding α-alkoxy radical III. Further, the
intermediate IV was formed through a radical addition of the α-
alkoxy radical III with the substrate 1a. Finally, the desired
product (3aa) was obtained in the presence of base.
Scheme 3. Scalability of the alkylation reaction of 1a
Some control experiments were conducted under the
optimized conditions to verify the mechanism (Scheme 4).
When 2, 2, 6, 6-tetramethylpiperidyl-1-oxyl (TEMPO) and 1,1-
diphenylethylene were added to the system respectively. The
formation of the 3aa was suppressed and only trace amount of
3aa was detected (Scheme 4, eq, 1). Further, the dioxane radical
was catched by the TEMPO and the product (b) was detected by
the GC-MS. At the same time, 1H NMR analysis showed that
compound (c) was produced. What’s more, the discovery of
compound (d) showed that the alkoxyl radical might exist in the
process. These control experiments strongly revealed that the
reaction involved a radical process. Then a couple of control
experiments were designed to investigate the role of bases
(Scheme 4, eqs, 3, 4). When quinolinium and TEMPO were
treated at 80 °C in the presence of K3PO4 for 4h, the intermediate
c was obtained in a 17% yield (Scheme 4, eq, 3). In the contrast,
only a trace mount of intermediate c was detected in the absence
of base (Scheme 4, eq, 4). We suspected that the base was
necessary for the homolytic cleavage.
Scheme 5. Proposed reaction mechanism.
Conclusions
In summary, we have developed a novel and efficient protocol
for the generation of α-alkoxy or alkyl radicals and alkylation of
quinoline and pyridine derivatives.
substituted quinolines and pyridines were constructed without
the addition of any transition-metal catalyst and oxidant. This
method exhibits a good functional group tolerance and mild
A series of 2-alkyl
4 | J. Name., 2012, 00, 1-3
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L. K. Jin, L. Wan, J. Feng, C. Cai, Org. Lett., 201V5iew1Ar7ti,cl4e 7On2li6ne-
7
8
9
,
reaction conditions. We believe that this method will be practical
in synthetic applications.
4729.
Y. R. Li, M. S. Wang, W. Fan, F. Qian, DGO. IG: 1.0L.1i0, 3H9./CJ.9LOuB,0J2.6O5r3gC.
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EXPERIMENTAL SECTION
.
A dried glass reaction tube equipped with a magnetic stir bar
was charged with 1a (0.2 mmol, 1.0 equiv), 2a (3.0 mL), K3PO4
(0.6 mmol, 3.0 equiv), and DCM (2.0 mL). The resulting mixture
was then stirred at 30 °C under argon for 4h. The crude
production was extracted with ethyl acetate (3 × 10 mL). The
combined organic layers dried over anhydrous Na2SO4,
concentrated in vacuo, and purified by flash column
chromatograph to give the pure products. The products were
,
,
, 8
,
Xie, J. Liu, L. Wang, Org. Biomol. Chem., 2015, 13, 4596-
4604; e) S. Ambala T. Thatikonda, S. Sharma, G. Munagala,
K. R. Yempalla, A. Vishwakarma, P. P. Singh, Org. Biomol.
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,
13
,
11341-11350; f) N. Okugawa, K.
4973–4981. g)
37, 1704. h)
,
.
,
characterized by H NMR, 13C NMR, MS. Quinoline (pyridine) N-
oxides were prepared according to the literature.11a
1
,
,
General procedure for the synthesis of substrates (1a−1l).
All N-methoxyquinoline (pyridine)-1-ium tetrafluoroborate salts
were prepared according to the reported procedure.11a,b,13.
,
Han, X. Y. Gao, J. Y. Li, D. P. Zou, Y. J. Wu, Y. S. Wu,
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,
Conflicts of interest
There are no conflicts to declare.
,
.
,
,
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21172200, 21702191) for financial support.
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