Direct Alkenylation of 2-Methylquinolines with Aldehydes through Synergistic Catalysis of 1,3-Dimethylbarbituric Acid and HOAc

Article abstract of DOI:10.1002/adsc.201900351

An efficient and practical direct alkenylation of 2-methylquinolines with aldehydes has been achieved through a novel synergistic organocatalysis. The HOAc- activated 2-methylquiolines undergo a Michael addition to 1,3-dimethylbarbituric acid-activated aldehydes, followed by a retro-Michael addition to release 1,3-dimethylbarbituric acid and the target products. The transformation produced various 2-alkenylquinolines with good to excellent yields and featured mild reaction conditions, atom- and step-economy, good functional group tolerance, and operational simplicity. (Figure presented.).

Full text of DOI:10.1002/adsc.201900351

Title: Direct Alkenylation of 2-Methylquinolines with Aldehydes through
Synergistic Catalysis of 1,3-Dimethylbarbituric Acid and HOAc
Authors: Xiaodong Tang, En Liang, Junqi Wang, Yinrong Wu, Liangbin
Huang, and Xingang Yao
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201900351
Link to VoR: http://dx.doi.org/10.1002/adsc.201900351

10.1002/adsc.201900351
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Direct Alkenylation of 2-Methylquinolines with Aldehydes
through Synergistic Catalysis of 1,3-Dimethylbarbituric Acid
and HOAc
En Liang,a Junqi Wang,a Yinrong Wu,a Liangbin Huang,b* Xingang Yaoa and
Xiaodong Tanga*
a
Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical
University, 1023 South Shatai Road, Baiyun District, Guangzhou 510515, P. R. China.
E-mail: tangxdong@smu.edu.cn
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical
b
Engineering, South China University of Technology, 381 Wushan Road, Guangzhou, 510640 (China)
E-mail: Huanglb@scut.edu. cn
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######.
Specifically,
2-alkenylquinoline,
containing
triphenylamine moiety, has good electrochromic
properties.[6] Due to the great importance of 2-
alkenylquinolines, various methods have been
developed to construct this motif, such as the Wittig
Abstract: An efficient and practical direct alkenylation of
2-methylquinolines with aldehydes has been achieved
through a novel synergistic organocatalysis. The HOAc-
activated 2-methylquiolines undergo a Michael addition to
1,3-dimethylbarbituric acid-activated aldehydes, followed
reactions
with
expensive
2-
quinolinecarboxaldehydes,[7] condensation reactions
of 2-methylquinolines with aldehydes or imines,[8]
reductive olefinations of quinoline N-oxides with
olefins,[9] and dehydrogenative olefinations of 2-
methylquinolines with alcohols,[10]etc. Along these
lines, condensation reactions of 2-methylquinolines
with aldehydes were the most available method due to
the easy accecebility of both substrates. The
nucleophilic enamine, catalytically isomerized from
2-methylquioine,[11] proceeds the Knoevenagel
condensation with unactivated aldehyde slowly. Thus,
all reported transformations required high reaction
temperature and/or large excess of aldehydes (Scheme
1a). With the development of organocatalysis and
synergistic catalysis, we have recently suspected that
by
a
retro-Michael addition to release 1,3-
dimethylbarbituric acid and the target products. The
transformation produced various 2-alkenylquinolines with
good to excellent yields and featured mild reaction
conditions, atom- and step-economy, good functional group
tolerance, and operational simplicity.
Keywords: synergistic catalysis; organocatalysis;
alkenylation; 2-methylquinolines;
Organocatalysis has many advantages, including easy
accessibility, insensitivity towards to oxygen and
moisture, economy and non-toxicity.[1] Moreover,
transformations with organocatalysis usually proceed
in mild reaction conditions with broad substrate scope
and excellent functional group tolerance. Synergistic
catalysis combinating two distinct catalytic systems in
one reaction has received intensive attention in recent
years.[2] The typically synergistic system was
constituted by the metal catalysis and organocatalysis
or bimetallic system.[3] Although there were a few
successive synergistic organocatalysis systems,[4] it is
still of great importance to develop new and simple
synergistic small organic molecular catalysis.
the
synergistic
catalysis
combined
two
organocatalysts could enable the condensation
reaction under a much milder conditions. Herein, we
reported
a
HOAc/1,3-DMBBA
(1,3-
dimethylbarbituric acid) -catalyzed dehydration
reaction system which allows efficent synthesis of
various 2-alkenylquinolines from 2-methylquinolines
and aldehydes (Scheme 1b). This protocol involving
cascade Knoevenagel condensation followed by
Micheal addition and retra-Micheal addition gave the
desired product in good to excellent yield with water
as the sole byproduct.
Quinoline motif widely exists in pharmaceutical,
Scheme 1. Synthesis of 2-alkenylquinolines from 2-
methylquinolines and aldehydes
agrochemical,
and
advanced
material.
2-
Alkenylquinoline is one of typical scaffolds such as
]
Montelukast,[5a Chimanine B,[5b] and so on.[5c-f]
1
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10.1002/adsc.201900351
Advanced Synthesis & Catalysis
7
8
A1 (20)
A1 (20)
A1 (20)
A1 (20)
A2 (20)
A3 (20)
A4 (20)
A5 (20)
A1 (10)
A1 (20)
A1 (20)
A1 (20)
TFA (20)
76
74
68
84
13
10
20
39
65
81
25
84
HCl (20)
HClO4 (20)
TsOH (20)
HOAc (20)
HOAc (20)
HOAc (20)
HOAc (20)
HOAc (20)
HOAc (10)
HOAc (20)
HOAc (20)
9
10
11
12
13
14
15
16
17[b]
18[c]
[a] Reaction conditions: unless otherwise noted, all reactions
were performed with 1a (0.5 mmol), 2a (0.5 mmol),
catalyst (0-20 mol %), acid (0-20 mol %) in H2O (3.0
2-Methylquinoline (1a) and benzaldehyde (2a)
o
mL) and dioxane (0.3 mL) at 60 C for 24 h. Isolated
were chosen as the model substrates for this
investigation, and the results were shown in Table 1.
In our initial studies, we found the reaction proceeded
in low efficiency under one organocatalyst or without
catalyst (Table 1, entries 1-5). To our delight, the
reaction yield improved dramatically to 95% in the
presence of 20 mol % HOAc and 1,3-DMBBA (Table
1, entry 6). Encouraged by this result, we screened
various Bronsted acids (TFA, HCl, HClO4, TsOH),
and found that the yields ranged from 68% to 84%
(Table 1, entries 7-10). Then, other active methylene
compounds (A2-A5) were used together with HOAc
to catalyze this transformation. The results showed
that 1,3-DMBBA was the most active catalyst for this
reaction (Table 1, entries 11-14). Moreover, the yields
decreased with the reduction of the catalyst or acid
loading (Table 1, entries 15-16). When we used water
as the single solvent, the yield was reduced to 25%
(Table 1, entry 17). A gram-scale reaction was
performed, and the yield was also satisfactory (Table
1, entry 18).
[b]
[c]
yield.
Water was used as the single solvent.
A
gram-scale reaction was performed with 1a (10 mmol),
2a (10 mmol), 1,3-DMBBA (20 mol%), HOAc (20
o
mol%), H2O (40.0 mL), dioxane (4.0 mL), at 60 C for
24 h.
With the optimized reaction conditions in hand, we
firstly studied the scope of methylazaarenes and the
results were summarized in Scheme 2. Various 2-
methylquinolines bearing different substituents on the
aromatic ring such as methyl, methoxyl, fluoro,
chloro and bromo were transformed into the 2-
alkenylated quinolines in good to excellent yields
(Scheme 2, 3aa-3ja). When 1-methylisoquinoline was
employed in the reaction, the corresponding product
was obtained in 62% yield (Scheme 2, 3ka). In
addition, 2-methylquinoxaline was
a
suitable
substrate for this transformation, albeit in a low yield
of desired product 3la. However, the method was not
suitable for 2-methylquinoline with strong electron-
withdrawing groups (CF3, NO2). 2-Methyl pyridine
derivatives were not compatible with the present
system.
Table 1. Optimization of the reaction conditions [a]
Scheme 2. Substrate scope of various methylazaarenes [a]
Entry
Catalyst
Acid
--
Yield [%]
1
2
3
4
5
6
A1 (20)
19
14
--
HOAc (20)
TFA (20)
TsOH (20)
--
--
--
16
12
trace
95
--
A1 (20)
HOAc (20)
2
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10.1002/adsc.201900351
Advanced Synthesis & Catalysis
[a]
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), 1,3-
DMBBA (20 mol %), HOAc (20 mol %), H2O (3.0 mL),
[a] Reaction conditions: 1a (0.5 mmol), 2 (0.5 mmol), 1,3-
dioxane (0.3 mL), at 60 oC for 24 h. Isolated yields.
DMBBA (20 mol %), HOAc (20 mol %), H2O (3.0 mL),
o
dioxane (0.3 mL), at 60 C for 24 h. Isolated yields. [b]1
mmol aldehyde was used.
The reaction scope with respect to aldehydes was
To gain some mechanistic information, we
conducted several control experiments (Scheme 4).
next
examined
(Scheme
3).
Substituted
benzaldehydes bearing alkyl substituents at the para
position provided the target products 3ab, 3ac and
3ad in 84%, 93% and 93% yields, respectively.
Halogen functional groups (F, Cl, Br, I) were well
tolerated to give the corresponding products in good
yields (Scheme 3, 3ae-3ah). Furthermore, strong
electron-donating and electron-withdrawing groups at
the para position could also be used to afford the
desired products, with the yields ranged from 70% to
89% (Scheme 3, 3ai-3am, 3ar-3as). To our delight,
some sensitive groups such as amide, ester, alkynyl
and nitrile were all compatible in the present system
(Scheme 3, 3an-3aq). In addition, this alkenylation
protocol was also applied to ortho-, meta- and multi-
substituted benzaldehydes affording the target
products in good to excellent yields (Scheme 3, 3at-
3az). Gratifyingly, other aromatic and heteromatic
aldehydes including 2-naphthaldehyde, thiophene-2-
carboxaldehyde and 4-pyridinecarboxaldehyde were
converted into corresponding products in acceptable
yields (Scheme 3, 3az-1-3az-3). Finally, when
aliphatic aldehydes were used as the substrates,
moderate yields were generally obtained even with
excessive aldehydes (Scheme 3, 3az-4-3az-6).
With the treatment of
1, 3-DMBBA and
benzaldehyde in the presence of 20 mol% HOAc, the
condensation product 4 was obtained in 79% yield.
While the yield was 80% in the absence of HOAc [Eq.
(1)]. Those results reveal that 4 may be an
intermediate and its formation is not catalyzed by
HOAc. It was found that 57% yield of 5 and 20%
yield of 3aa were obtained when the reaction was
carried with 4 and 2-methylquinolines in the present
of HOAc. While the yields of 5 and 3aa were
obviously decreased when the same reaciton occurred
in the absence of HOAc [Eq. (2)]. Those results
suggested that HOAc played a key role in the Michael
addition process. Furthermore, compound 5 could
transform to product 3aa under the standard reaction
conditions [Eq. (3)], which indicated that compound 5
could probably be the intermediate of this
transformation. On the basis of the results described
above and literatures, a plausible mechanism was
proposed. Firstly, 2-methylquinolines is isomerized
into its more nucleophilic enamine isomer A by
Brønsted acid-promoted.11 At the same time, 2a and
1,3-DMBBA undergo Knoevenagel condensation to
produce intermediate 4. The intermediate A proceeds
through a Michael addition to intermediate 4 to form
intermediate 5, which dissociates into 1,3-DMBBA
and the product 3aa by a retro-Michael addition.
Scheme 3. Substrate scope of various aldehydes [a]
Scheme 4. Control experiments and Plausible reaction
mechanism
3
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10.1002/adsc.201900351
Advanced Synthesis & Catalysis
This work was supported by Natural Science Foundation of
Guangdong Province (2017A030310546), the National Natural
Science Foundation of China (21702096), and the High-level
Talent Introduction Foundation of Southern Medical University
(C1033520) for financial support.
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Experimental Section
General Procedure for the Synthesis of Product 3
2-methylquinoline 1 (0.5 mmol), aldehyde (0.5 mmol),
HOAc (20 mol %), 1,3-DMBBA (20 mol %), H2O (3.0
mL), dioxane (0.3 mL), were added to a 25 mL tube with
magnetic stirrer bar. The reaction mixture was stirred at
60°C (oil bath temperature) for 24 h. After the reaction was
finished (monitored by TLC), the mixture was cooled to
room temperature, quenched with solution of NaHCO3 (10
mL) and extracted with EtOAc (3 × 10 mL). The combined
organic layers were dried over anhydrous MgSO4 and the
solvent was removed under vacuum. The crude product
was purified by column chromatography (EtOAc/hexanes)
on silica gel.
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Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201900351
Advanced Synthesis & Catalysis
UPDATE
Direct Alkenylation of 2-Methylquinolines with
Aldehydes through Synergistic Catalysis of 1,3-
Dimethylbarbituric Acid and HOAc
Adv. Synth. Catal. 2019, Volume, Page – Page
En Liang,a Junqi Wang,a Yinrong Wu,a Liangbin
Huang,b* Xingang Yaoa and Xiaodong Tang a*
6
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