Metal-Free One-Pot Synthesis of (Tetrahydro)Quinolines through Three-Component Assembly of Arenediazonium Salts, Nitriles, and Styrenes

Article abstract of DOI:10.1002/adsc.201701451

A highly efficient and convenient metal-free, one-pot synthesis of diversely substituted (tetrahydro)quinolines has been achieved through a three-component assembly reaction of arenediazonium salts, nitriles, and styrenes. In sharp contrast to the prior works with the same reagent blend, the formation of N-arylnitrilium intermediates from arenediazonium salts and nitriles was followed by reaction with styrenes, leading to 3,4-dihydroquinolinium salts as a common intermediate. These could be further transformed to quinolines and tetrahydroquinolines depending on the reaction conditions. The advantages of this protocol include its simplicity, metal-free and mild conditions, readily available starting materials, and good functional group tolerance. (Figure presented.).

Full text of DOI:10.1002/adsc.201701451

Title: Metal-Free One-Pot Synthesis of (Tetrahydro)Quinolines through
Three-Component Assembly of Arenediazonium Salts, Nitriles,
and Styrenes
Authors: So Won Youn, Huen Ji Yoo, Eun Mi Lee, and Seo Young Lee
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701451
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10.1002/adsc.201701451
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Metal-Free One-Pot Synthesis of (Tetrahydro)Quinolines
through Three-Component Assembly of Arenediazonium Salts,
Nitriles, and Styrenes
So Won Youn,a,* Huen Ji Yoo,a Eun Mi Lee,a and Seo Young Leea
a
Center for New Directions in Organic Synthesis, Department of Chemistry and Institute for Material Design, Hanyang
University, Seoul 04763, Korea
Fax: (+82)-2-2298-0319; e-mail: sowony73@hanyang.ac.kr
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
nucleophile to afford N,N′-diarylamidines. Therefore,
we reasoned that other second nucleophiles (instead of
anilines) could be used to construct other heterocyclic
scaffolds with this strategy. Given the low cost,
diversity, and wide availability of styrenes, we were
interested in utilizing these reagents to develop a new
one-pot, three-component reaction for the facile
formation of quinoline derivatives (Scheme 1d).
Abstract. A highly efficient and convenient metal-free,
one-pot synthesis of diversely substituted
(tetrahydro)quinolines has been achieved through a three-
component assembly reaction of arenediazonium salts,
nitriles, and styrenes. In sharp contrast to the prior works
with the same reagent blend, the formation of N-
arylnitrilium intermediates from arenediazonium salts and
nitriles was followed by reaction with styrenes, leading to
3,4-dihydroquinolinium salts as a common intermediate.
These could be further transformed to quinolines and
tetrahydroquinolines depending on the reaction conditions.
The advantages of this protocol include its simplicity,
metal-free and mild conditions, readily available starting
materials, and good functional group tolerance.
Keywords: multicomponent reactions; nitrogen
heterocycles; one-pot reaction; quinolines;
tetrahydroquinolines
Arenediazonium salts can be easily prepared from
inexpensive and readily available anilines, and thus
they have been used as useful and versatile precursors
in a variety of organic transformations.[1] For instance,
they have been employed as the most convenient and
cost-effective aryl radical source for intermolecular
alkene functionalization, namely, the Meerwein
arylation reaction.[2] Kꢀnig’s group reported the
intermolecular amino-arylation of styrenes through a
photoredox-catalyzed Meerwein arylation under the
Ritter reaction conditions (Scheme 1a).[3a] In addition,
Heinrich and co-workers demonstrated a base- or
thermally-induced amino- and hydroxy-arylation of
alkenes (Scheme 1b-c).[3b-c]
Scheme 1. (a)-(d) Various outcomes of the reaction of
arenediazonium salts with alkenes in nitrile solvents and (e)
our previous work.
Quinolines and tetrahydroquinolines are an
important class of N-heterocycles due to their wide
range of biological activities and multiple applications.
Consequently, a diverse range of synthetic methods
have been developed to synthesize these materials over
the years.[6] However, most of the known methods
have several drawbacks, such as the use of expensive
transition metal catalysts and reagents, troublesome
operation, harsh reaction conditions, and low yields,
limiting their practical utility. Thus, the development
of more efficient and economical synthetic strategies
is highly desirable. The realization of our proposed
method would provide another new and potentially
powerful route for the expedient synthesis of a diverse
Recently, our group reported a highly effective one-
pot, three-component reaction to construct a wide
range of N-arylbenzimidazoles through in situ
generation
of
N,N′-diarylamidines
from
arenediazonium salts, nitriles, and free anilines
(Scheme 1e).[4] This reaction proceeded via the
formation of N-arylnitrilium intermediates (A)[5] by an
initial attack of nitriles to arenediazonium salts,
followed by the addition of anilines as a second
1
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10.1002/adsc.201701451
Advanced Synthesis & Catalysis
range of quinoline derivatives using simple,
inexpensive, readily available chemical feedstocks
(anilines, nitriles, styrenes) via a metal-free one-pot
reaction. Considering the previously reported, related
reaction systems with the same reagent blend as shown
in Scheme 1a-c,[3] however, the challenge with this
strategy would be the competing reactions of styrenes
with the arenediazonium salts, which lead to undesired
products via intermediate I.
Herein, we report a highly effective and convenient
one-pot synthesis of diversely substituted quinoline
derivatives under metal-free conditions (Scheme 1d).
In sharp contrast to the related prior works (Scheme
1a-c),[3] this new protocol involves the initial
formation of N-arylnitrilium intermediates from
arenediazonium salts and nitriles. Then the following
reaction with styrenes leads to 3,4-dihydroquinolinium
salts as a common intermediate, which can be further
selectively transformed to quinolines and/or
tetrahydroquinolines depending on the reaction
conditions.[7]
presence of K2CO3 in MeCN solvent (Table 1, entry 1).
Much to our delight, both tetrahydroquinoline 3aaa
and quinoline 4aaa were obtained in low yields, while
the absence of base gave no desired products (Table 1,
entries 1 vs. 2). A variety of other inorganic and
organic bases were examined (Table S1), and KHCO3
appeared preferable. After scrupulous examination of
the reaction parameters (Tables S2-S3), we could find
an optimal condition as entry 5 in Table 1. In stark
contrast to the previous works under similar reaction
conditions using base promoters (Scheme 1b-c),[3b-c]
these findings suggest that arenediazonium salts
indeed initially react with nitriles more favorably
rather than styrenes under our reaction conditions,
leading to N-arylnitrilium salts (A).
Table 1. Optimization studies.
Entr Base
y
Additiv Solvent
e
t
3aaa 4aaa
[h] [%][a] [%][a]
1[b]
-
-
-
MeCN
MeCN
2
2
-
-
2[b-c] K2CO3
18
20
(16)
25
(19)
(20)
23
(75)
(73)
3[b]
4
5
KHCO3
KHCO3
KHCO3
-
-
-
MeCN
MeCN
3
3
MeCN/ 12 (15)
DCE
(2:1)
MeCN/ 12
DCE
Scheme 2.
6
KHCO3 DDQ
-
(85)
4
(2:1)
A series of control experiments were performed to
gain insight into the mechanism of this reaction. We
speculated that this reaction might proceed through a
disproportionation reaction of the initially generated
7
KHCO3 NaBH4 MeCN/
5
18
DCE
(2:1)
MeCN/ 12
DCE
(17)
8[d]
-
-
DDQ
-
(84)
-
3,4-dihydroquinolines
to
quinolines
and
tetrahydroquinolines.[8]
Gratifyingly,
3,4-
(2:1)
9[d]
NaBH4 MeCN/
4
(80)
dihydroquinolinium salt 5aaa was successfully
obtained in the absence of KHCO3 under otherwise
identical conditions (Scheme 2a). Subjecting 5aaa to
the standard reaction conditions (i.e., entry 5 in Table
1) led to the formation of 3aaa and 4aaa in 40% and
59% yields, respectively (Scheme 2b). However, no
reaction occurred with both 3aaa and 4aaa (Scheme
2c). These results suggest that 5aaa generated from the
three-component assembly reaction of 1a, 2a, and
MeCN is a likely intermediate in this process. The
reason why the formation of 3aaa was in much lower
yield than 4aaa under the standard conditions in the
one-pot reaction (Table 1, entry 5) remains unclear at
this point.
DCE
(2:1)
[a]
Yields were determined by 1H NMR using
trichloroethylene as an internal standard. Values in
parentheses indicate isolated yields. [b] Using 1 equiv 2a. [c]
Using 1 equiv base. [d] Additives were added after 2 h.
In light of our recent success in the one-pot
synthesis of N-arylbenzimidazoles in the presence of a
base such as K2CO3,[4] we began our studies on the
proposed reaction using styrene (1a) and
phenyldiazonium salt (2a) as the test substrates in the
2
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10.1002/adsc.201701451
Advanced Synthesis & Catalysis
Although the combined yield of 3aaa and 4aaa is
Table 2. Substrate scope: Alkenes.[a]
high under the reaction conditions as shown in entry 5
in Table 1, selective formation of either 3aaa or 4aaa
in high yields would be preferable. Therefore, to
investigate both the oxidation and reduction of 3,4-
dihydroquinolinium
salts
prior
to
the
disproportionation, various oxidants and reductants
were introduced to the reaction mixture as an additive
(Table S4).[8a-c, 9] To our delight, the use of DDQ as an
oxidant gave the desired 4aaa in good yields without
the formation of 3aaa, regardless of the presence of
KHCO3 (Table 1, entries 6 and 8). In contrast, the
absence of KHCO3 was beneficial to the selective and
high-yielding formation of 3aaa in the presence of
NaBH4 as a reductant (Table 1, entries 7 vs. 9). On the
other hand, reaction of 5aaa in the presence of NaBH4
or DDQ indeed afforded 3aaa and/or 4aaa (Scheme
with NaBH4
3 [%]
with DDQ
4 [%]
Entry Ar
1
Ph
80, 85[b] (15)
(3aaa)
84, 73[b] (73)
(4aaa)
2
3
4-AcOC6H4 52 (14) (3baa) 58 (52) (4baa)
3-MeOC6H4 73 (22) (3caa) 81 (63) (4caa)
71 (15) (3daa) 62 (69) (4daa)
4
5
6
7
8
9
10
11
12
13
14
4-MeC6H4
3-MeC6H4
2-MeC6H4
4-PhC6H4
1-naphthyl
3-BrC6H4
4-ClC6H4
3-CF3C6H4
4-CNC6H4
4-NO2C6H4
3-thienyl
72 (11) (3eaa)
72 (29) (3faa)
48 (14) (3gaa)
89 (71) (4eaa)
73 (64) (4faa)
66 (65) (4gaa)
67 (21) (3haa) 86 (63) (4haa)
2d),
which
further
supports
that
3,4-
82 (21) (3iaa)
77 (14) (3jaa)
62 (3) (3kaa)
49 (11) (3laa)
23 (21) (3maa) 36 (28) (4maa)
56 (12) (3naa) 49 (43) (4naa)
83 (53) (4iaa)
88 (69) (4jaa)
76 (46) (4kaa)
65 (40) (4laa)
dihydroquinolinium salt 5aaa is a likely intermediate
in this process.
Having determined the optimized conditions for the
synthesis of either quinolines (Table 1, entry 8) or
tetrahydroquinolines (entry 9) or both (entry 5), we set
out to explore the scope of this one-pot process. First,
we examined the reaction of various styrenes (1) with
phenyldiazonium salt (2a) and MeCN (Table 2). A
wide range of styrenes underwent a one-pot three-
component reaction to afford the corresponding
tetrahydroquinolines (3) and quinolines (4) in
moderate to good yields irrespective of their electronic
properties and the position of their substituents.
However, strongly electron-deficient styrenes resulted
in no (Ar = C6F5, not shown) or low conversion (entry
13), which suggests the involvement of a cationic
intermediate (vide infra, B in Scheme 4). Both
naphthyl and heteroaryl moieties could also be
incorporated as a substituent at the alkene terminus
(entries 8 and 14). Internal and 1,1-disubstituted
terminal alkenes proved to be suitable substrates
(entries 15-17), while the latter afforded 4oaa via 1,2-
phenyl migration (entry 15). It should be noted that the
formation of fused-tetracyclic 4paa-4qaa could be
advantageous compared to other annulation methods
using alkynes.[6, 7b-c]
In general, a KHCO3-promoted reaction afforded
both tetrahydroquinolines (3) in low yields and
quinolines (4) in moderate yields, while NaBH4- and
DDQ-mediated reactions led to the selective formation
of 3 and 4, respectively, in much higher yields. It
should be noted that any byproducts derived from the
Meerwein-type reaction of aryl radical with styrene
(via I in Scheme 1) were not observed in this protocol
at all. Both terminal and internal aryl-substituted
alkenes resulted in the regioselective formation of 4-
aryl-substituted 3 and 4, which further supports an
electrophilic process via a benzylic carbocation
intermediate (B in Scheme 4). This process can
tolerate various functional groups such as halogen,
nitro, ester, and cyano groups. In addition, the
reactions on a gram scale gave comparable yields
(entry 1), thus showing the synthetic potential of this
method. Furthermore, from a practical perspective,
15
81 (3oaa)
56 (3paa)
56 (3qaa)
26 (4oaa)
53 (4paa)
67 (4qaa)
16
17
[a]
Reaction conditions (with KHCO3): 1 (1 equiv), 2a (2
equiv), KHCO3 (1.5 equiv) in MeCN/DCE (2:1, 0.1 M) at
90 °C under air. (with NaBH4 or DDQ): 1 (1 equiv), 2a (2
equiv) in MeCN/DCE (2:1, 0.1 M) at 90 °C for 2 h under air.
Subsequently, NaBH4 or DDQ (1 equiv) was added to the
reaction mixture and stirred at 90 °C under air. Isolated
yields of 3 (using NaBH4) and 4 (using DDQ) are given.
Values in parentheses indicate isolated yields of 3 and 4
from the reactions using KHCO3. [b] Using 1.0 mL of styrene
1a.
this newly developed method offers user-friendly
access to
a
diverse array of valuable
(tetrahydro)quinolines from the readily available,
simple starting materials under air without the need for
anhydrous solvents and an inert atmosphere.
Comparable or even better product yields were
obtained using reagent grade, undistilled solvents
under an ambient atmosphere, thereby eliminating the
need for precautionary measures to rigorously exclude
air and moisture from the reaction mixture. This
protocol could be a potentially powerful and effective
alternative to the methods known for the synthesis of
quinoline derivatives.
3
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10.1002/adsc.201701451
Advanced Synthesis & Catalysis
Next, we proceeded to explore the scope of
Table 4. Substrate scope: Nitriles.[a]
arenediazonium salts (2) (Table 3). A variety of
substituted arenediazonium salts were well tolerated
regardless of the position of their substituents, leading
to the assembly of diversely substituted 3 and 4.
Table 3. Reaction of various arenediazonium salts and
styrenes.[a]
with NaBH4
3 [%]
with DDQ
4 [%]
Entry
R
1
2
3
4
5
6
7
Et
nPr
CH2CH2OMe
iPr
cHex
tBu
Ph
78 (3ebb)[b]
60 (3ebc)[b]
-
83 (4ebb)
82 (4ebc)
49 (4ebd)
80 (4ebe)
62 (4ebf)
56 (4ebg)
47 (4ebh)[e]
61 (3ebe)[b]
[c]
-
[c]
-
trace[d]
[a]
Reaction conditions: 1 (1 equiv), 2b (2 equiv) in
RCN/DCE (2:1, 0.1 M) at 90 °C for 2 h under air.
Subsequently, NaBH4 or DDQ (1 equiv) was added to the
reaction mixture and stirred at 90 °C under air. Isolated
yields of 3 (using NaBH4) and 4 (using DDQ) are given. [b]
4ebb, 4ebc, and 4ebe were also obtained in 13%, 19%, and
20%, respectively. [c] Only 4ebf and 4ebg were obtained in
59% and 55%, respectively. [d] 4ebh and 6bh were obtained
[e]
in 21% and 40% yield, respectively.
obtained in 51% yield.
6bh was also
salts reacted faster than their electron-deficient
counterparts. The former (Scheme 3a) is consistent
with the observed electronic dependence in Table 2,
where substituents that cannot stabilize positive charge
resulted in relatively low yields. The latter (Scheme
3b) may be attributed to the involvement of aryl
cations generated from arenediazonium salts along
with the loss of N2.
[a]
Reaction conditions: 1 (1 equiv), 2 (2 equiv) in
MeCN/DCE (2:1, 0.1 M) at 90 °C for 2 h under air.
Subsequently, NaBH4 or DDQ (1 equiv) was added to the
reaction mixture and stirred at 90 °C under air. Isolated
yields of 3 (using NaBH4) and 4 (using DDQ) are given. [b]
3aaa was obtained in 66% yield. [c] In the reaction using
NaBH4, 4afa, 4aha, and 4fha were also obtained at 5%,
13%, and 15%, respectively.
Subsequently, we investigated this reaction with
various nitriles (Table 4). In the case of the DDQ-
mediated reaction, various 1º, 2º, and 3º alkyl nitriles
as well as aryl nitriles were all well tolerated to afford
the desired quinolines 4 in moderate to good yields. It
should be noted that the reaction with PhCN gave
quinazoline 6bh as a byproduct as a result of the
sequential reaction of 2b and two equivalents of
PhCN,[10] along with the desired quinoline 4ebh (entry
7). In contrast, both steric and electronic properties of
nitriles seemed to have a great influence on the
NaBH4-mediated reaction. Only simple 1º and 2º alkyl
nitriles could afford 3 in good yields along with a small
amount of 4 (entries 1-2 and 4), while the reaction with
sterically bulky alkyl and aryl nitriles failed to afford
the desired 3, leading to only the corresponding 4
instead (entries 5-7).
Scheme 3. Competition experiments.
Based on our experimental findings, we proposed a
plausible mechanism outlined in Scheme 4. N-
Arylnitrilium salt
A
generated from an
To gain further mechanistic insight into this reaction,
we performed competition experiments (Scheme 3).
This study revealed an electronic dependence, in
which the electron-rich styrenes and arenediazonium
arenediazonium salt and a nitrile undergoes an
electrophilic addition to a styrene to afford a benzylic
carbocation intermediate B. Subsequent electrophilic
cyclization of B to produce C followed by the
4
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10.1002/adsc.201701451
Advanced Synthesis & Catalysis
cooled to 25 °C and then NaBH4 (0.12~0.15 mmol, 1.0
equiv) was added. After being stirred at 90 °C for additional
1~22 h (the reported time = initial 2 h + additional time after
adding NaBH4) under air (closed flask), the reaction mixture
was concentrated in vacuo. The residue was purified by
column chromatography on silica gel to afford the
corresponding product 3 (In some cases, along with a small
amount of 4, or only 4 instead of 3 was obtained. See Tables
S6-S8 for details).
deprotonation gives a 3,4-dihydroquinolinium salt D.
Under basic conditions, a disproportionation reaction
of the free bases, 3,4-dihydroquinoline E and its
enamine tautomer E', leads to the formation of
tetrahydroquinoline 3 and quinoline 4. On the other
hand, D reacts with either NaBH4 or DDQ to afford
either 3 or 4, respectively.
General Procedure for the DDQ-Mediated Reaction. To
a
solution of 1 (0.12~0.15 mmol, 1.0 equiv) in
R'CN/ClCH2CH2Cl (1.2~1.5 mL, 2:1, 0.1 M) was added 2
(0.24~0.30 mmol, 2.0 equiv). After being stirred at 90 °C
for 2 h under air (closed flask), the reaction mixture was
cooled to 25 °C and then DDQ (0.12~0.15 mmol, 1.0 equiv)
was added. After being stirred at 90 °C for additional 10~22
h (the reported time = initial 2 h + additional time after
adding DDQ) under air (closed flask), the reaction mixture
was concentrated in vacuo. The residue was purified by
column chromatography on silica gel to afford the
corresponding product 4.
Acknowledgements
This work was supported by both Basic Science Research Program
and Nano∙Material Technology Department Program through the
National Research Foundation of Korea (NRF) funded by the
Korea government (MSIP) (Nos. 2012M3A7B4049644, 2014-
011165, and 2015R1A2A2A01002559).
Scheme 4. Proposed mechanism.
References
In summary, we developed a highly efficient and
convenient one-pot reaction for the three-component
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of
diversely
substituted
(tetrahydro)quinolines under metal-free mild
conditions. The formation of 3,4-dihydroquinolinium
salts as a common intermediate for the synthesis of
quinolines and tetrahydroquinolines is involved as a
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arylnitrilium
intermediates
generated
from
arenediazonium salts and nitriles. To the best of our
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To a solution of 1 (0.12~0.15 mmol, 1.0 equiv) and KHCO3
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equiv). After being stirred at 90 °C for the reported time
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chromatography on silica gel to afford the corresponding
products 3 and 4.
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(0.24~0.30 mmol, 2.0 equiv). After being stirred at 90 °C
for 2 h under air (closed flask), the reaction mixture was
5
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10.1002/adsc.201701451
Advanced Synthesis & Catalysis
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10.1002/adsc.201701451
Advanced Synthesis & Catalysis
COMMUNICATION
Metal-Free One-Pot Synthesis of
(Tetrahydro)Quinolines through Three-Component
Assembly of Arenediazonium Salts, Nitriles, and
Styrenes
Adv. Synth. Catal. Year, Volume, Page – Page
So Won Youn,* Huen Ji Yoo, Eun Mi Lee, and Seo
Young Lee
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