KOTBu-promoted oxidative dimerizations of 2-methylquinolines to 2-alkenyl bisquinolines with molecular oxygen

Article abstract of DOI:10.1039/c9ra06465f

KO^tBu-promoted oxidative dimerizations of 2-methylquinolines with molecular oxygen as the oxidant have been developed for the first time. The mild reaction conditions allow the homo- and cross-dimerizations of 2-methylquinolines to give functionalized 2-alkenyl bisquinolines in highly trans-selective manners.

Full text of DOI:10.1039/c9ra06465f

RSC Advances
View Article Online
View Journal | View Issue
PAPER
KOtBu-promoted oxidative dimerizations of 2-
methylquinolines to 2-alkenyl bisquinolines with
Cite this: RSC Adv., 2019, 9, 30139
molecular oxygen†
a
Zhen Wang,‡b Jinjin Zhang,‡a Jianxue Shia and Huiqiao Wang
*
Received 18th August 2019
Accepted 18th September 2019
KOtBu-promoted oxidative dimerizations of 2-methylquinolines with molecular oxygen as the oxidant have
been developed for the first time. The mild reaction conditions allow the homo- and cross-dimerizations of
2-methylquinolines to give functionalized 2-alkenyl bisquinolines in highly trans-selective manners.
DOI: 10.1039/c9ra06465f
rsc.li/rsc-advances
associated with 2-alkenyl bisquinolines syntheses. Even
though many methodologies for quinoline-2-carboxaldehydes
syntheses from 2-methylquinolines have been developed,9 the
Introduction
2-Alkenylquinolines are widely present in many medicinally
active compounds and natural products of biological signi-
cance, such as VUF 5017 (CysLT1 antagonist),1 Chimanine B
(antileishmanial activity),2 and Montelukast (drug for asthma).3
As such, the construction of 2-alkenylquinolines remains
a signicant research area in organic synthesis.4 In particular, 2-
alkenyl bisquinolines exhibit signicant activity against the
replication of HIV-1, and also against intracellular amastigote
forms of L. amazonensis and L. infantum.5 However, in
comparison with the well-established synthetic methodologies
for 2-alkenylquinolines syntheses, the construction of 2-alkenyl
bisquinolines is still less explored. The classical synthetic
approach to 2-alkenyl bisquinolines relies on the Perkin reac-
tion of 2-methylquinoline with quinoline-2-carboxaldehyde in
the presence of excess amount of Ac2O (Scheme 1a).6 Despite
the synthetic utility to obtain 2-alkenyl bisquinolines, this
methodology suffers from the harsh conditions for condensa-
tion. More problematic is that quinoline-2-carboxaldehydes
should be synthesized rst, mainly based on the oxidation of
2-methylquinolines by using large amounts of toxic SeO2.7 From
an economic and synthetic point of view, the development of
new strategies to obtain 2-alkenyl bisquinolines in a green
manner is highly desirable.
compatibility of two distinct reaction conditions between
quinoline-2-carboxaldehyde synthesis and the following
condensation reaction with 2-methylquinoline remains an
unsolved problem. Our group recently reported a KOtBu-
promoted (hetero)benzylic C–H oxidation with molecular
oxygen as the oxidant (Scheme 1b).10 A variety of (hetero)aryl
ketones were obtained in good to excellent yields under basic
reaction conditions. We envisioned that 2-methylquinolines
could also undergo this KOtBu-promoted oxidation reaction
to give quinoline-2-carboxaldehydes in an effective
manner.11,12 The subsequent condensation reaction under
basic reaction conditions could realize one-pot synthesis of 2-
alkenyl bisquinolines (Scheme 1c). Herein, we report that
symmetric and unsymmetric 2-alkenyl bisquinolines could be
obtained in one-pot via a KOtBu-promoted oxidative dimer-
ization of 2-methylquinolines with molecular oxygen as the
oxidant.
Retrosynthetic analysis showed that 2-alkenyl bisquino-
lines arise via the condensation reactions of 2-methylquino-
lines
with
quinoline-2-carboxaldehydes
would
be
a straightforward, and efficient way.8 In this context, the
development of an efficient method for the in situ generation
of quinoline-2-carboxaldehydes would solve the problems
aCollege of Chemistry and Pharmaceutical Engineering, Nanyang Normal University,
Nanyang, Henan, 473061, China. E-mail: huiqiaowang@163.com
bDepartment of Pharmacy, Nanyang Medical College, Nanyang, 473061, China
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c9ra06465f
Scheme 1 The classical synthetic approach to 2-alkenyl bisquinolines
and the present reaction proposal.
‡ These two authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 30139–30143 | 30139

View Article Online
RSC Advances
Paper
Increasing or decreasing the reaction temperature failed to
improve the isolated yield of 2a (entries 16 and 17).
Results and discussions
With the optimized reaction conditions in hand, the
substrate scope of the homo-dimerization reaction was inves-
tigated (Scheme 2). It was found that the electronic nature of the
substituents on the aromatic ring had a signicant effect on the
yield. When the substrates bearing electron-donating groups,
such as 2,6-dimethylquinoline, 6-methoxyquinaldine, and 8-
methoxyquinaldine, were employed as the substrates under the
optimized conditions, the dimerization reactions proceeded
smoothly to afford the corresponding products 2b–2d in 64–
71% yields. However, when 6-nitroquinaldine or 6-chlor-
oquinaldine were examined under the optimized conditions,
the reaction mixtures were complex. Some uncharacterized
byproducts were obtained, however, no desired 2-alkenyl bis-
quinolines (2k–2l) were observed by GC-MS. 2-Methylbenzo[h]
quinoline was also a suitable substrate to give the desired
product 2e in 49% yield. Then, pyridine derivatives were tested
under the optimized conditions. However, pyridine derivatives
showed low reactivity. By increasing the reaction temperature to
100 ꢀC, the desired products 2f–2h were obtained in good yields.
It is noteworthy that 4-methylpyrimidine and 2-methylpyrazine
were also well tolerated under this reaction conditions, giving
the desired products 2i and 2j in 53% and 52% yields,
respectively.
Initially, the oxidative dimerization of 2-methylquinoline (1a)
was chosen as the model reaction to optimize the reaction
conditions (Table 1). When the reaction was carried out in N,N-
dimethylformamide (DMF) with KOtBu as the base and 18-
ꢀ
crown-6 (18-C-6) as the additive under oxygen balloon at 50 C
for 20 h, the desired 2-alkenyl bisquinoline (2a) was obtained in
72% yield (entry 1). Replacement of KOtBu with NaOtBu, LiOtBu,
or KOH led to lower yields (entries 2, 3 and 5). GC-MS analysis of
the reaction mixtures showed that quinoline-2-carboxaldehyde
was existed. However, when Cs2CO3 was employed as the
base, no desired product was detected, and the conversion of 1a
was less than 5% (entry 4). Next, tetramethylethylenediamine
(TMEDA), or 1,10-phenanthroline (1,10-phen) as the additive
were examined, and lower yields were observed (entries 6 and
7). The solvent optimizations showed that no desired product
was obtained when using DMSO, toluene, or CH3CN as the
solvent (entries 8–10). Then, a series of chemical oxidants such
as TBHP, K2S2O8, and m-CPBA were screened, however, no
desired product was observed (entries 11–13). When the reac-
tion was carried out under air atmosphere, only trace amount of
desired product was observed (entry 14); while no desired
product was observed in the absence of KOtBu (entry 15). These
two control experiments demonstrated that KOtBu and oxygen
atmosphere are essential for this dimerization reaction.
Table 1 Optimization studiesa
Entry
Base
Oxidant
Additive
Solvent
Yieldb,c (%)
1
2
3
4
5
6
7
8
KOtBu
NaOtBu
LiOtBu
Cs2CO3
KOH
O2 balloon
O2 balloon
O2 balloon
O2 balloon
O2 balloon
O2 balloon
O2 balloon
O2 balloon
O2 balloon
O2 balloon
TBHP
K2S2O8
m-CPBA
Air
O2 balloon
O2 balloon
O2 balloon
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
TMEDA
1,10-Phen
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
18-C-6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
Tol
CH3CN
DMF
DMF
DMF
DMF
DMF
DMF
DMF
72 (94)
61 (88)
55 (71)
0 (<5)
41 (70)
57 (74)
55 (79)
0 (<5)
0 (<5)
0 (<5)
0 (15)
0 (11)
0 (<5)
Trace (16)
0 (0)
62 (95)
29 (57)
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
none
9
10
11d
12d
13d
14
15
16e
17f
KOtBu
KOtBu
a
Reaction conditions: 1a (0.2 mmol), base (0.22 mmol), oxidant,
additive (0.22 mol), and solvent (1.5 mL) were stirred at 50 ꢀC for
20 h. Isolated yield. The conversion of 1a determined by GC-MS
Scheme 2 The substrate scope of homo-dimerization reactionsa.
a Reaction conditions: substrates (0.2 mmol), KOtBu (0.22 mmol), and
18-Crown-6 (0.22 mmol) were stirred in 1.5 mL DMF at 50 ꢀC for 20 h
under O2 balloon. b 100 ꢀC, 24 h. c 36 h.
b
c
d
was shown in the parentheses. 0.2 mmol of oxidant was used.
e
80 ꢀC. f 30 ꢀC.
30140 | RSC Adv., 2019, 9, 30139–30143
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
To make this methodology more appealing, the substrate
RSC Advances
scope of cross-dimerization reactions was also examined. As
shown in Scheme 3, with a minor modication of the optimized
reaction conditions, the cross-dimerization reactions were
realized. Even though the unexpected self-dimerizations of 2-
methylquinoline and substituted 2-methylquinolines make the
reaction mixture difficult for purication, the desired unsym-
metrical 2-alkenyl bisquinolines 3–7 were obtained in accept-
able yields.
To get a mechanistic insight into the oxidative dimerization
reactions, the condensation reaction of 2-methylquinoline (1a)
with 2-quinolinecarboxaldehyde (8) was carried out. As shown
in Scheme 4a, 2-alkenyl bisquinoline (2a) was obtained in 79%
yield under N2 atmosphere. This result suggests that 2-qui-
nolinecarboxaldehyde (8) is a key intermediate for this reac-
tion. Besides, the successful transformation of this
condensation reaction under N2 atmosphere also indicates
that O2 atmosphere is essential for the oxidation of 2-methyl-
quionline (1a) into 2-quinolinecarboxaldehyde (8), not for the
condensation reaction sequence. Besides, the adding of
2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) to the standard
conditions led to the decrease of the yield of 2a to 37%
(Scheme 4b), which indicates that this oxidative dimerization
involved the radical intermediate, however, reaction pathway
involving anion species could not be ruled out. The competi-
tion reactions suggest that the electronic nature of substitu-
ents on the aromatic rings has much inuence on the reaction
of methylquinolines with 2-quinolinecarboxaldehyde (8)
(Scheme 4c and d), and the electron-donating group slowed the
reaction rate.
Scheme 4 Control experiments.
to give carbamoyl radical 11.14 Intermediate 11 then abstracts
a hydrogen from 1a to generate benzylic type radical 12, which is
quenched by molecular oxygen to give the hydroperoxide inter-
mediate 14. Finally, intermediate 14 eliminated one molecule of
water to generate 2-quinolinecarboxaldehyde 8, which has
a
Knoevenagel-type condensation reaction with another
Based on the previous reports and control experiments,
a plausible reaction mechanism for the formation of 2-alkenyl
bisquinoline 2a and 7 was shown in Scheme 5. First, t-BuOꢁ
abstracts a proton from DMF to give carbamoyl anion 9.13 The
intermolecular interaction between DMF and the complex of 18-
C-6 with KOtBu was demonstrated in our previous report.10
Subsequently, intermediate 9 has an electron transfer with DMF
Scheme 3 The substrate scope of cross-dimerization reactionsa.
a
Reaction conditions: 2-methylquinoline (0.6 mmol), substituted 2-
methylquinoline (0.2 mmol), KOtBu (0.4 mmol), and 18-Crown-6 (0.4
mmol) were stirred in 3.0 mL DMF at 50 ꢀC for 20 h under O2 balloon. Scheme 5 Plausible mechanism for the formation of 2a and 7.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 30139–30143 | 30141

View Article Online
RSC Advances
Paper
molecule of methylquionline to give symmetric 2-alkenyl bis-
quinoline 2a or unsymmetric 2-alkenyl bisquinoline 7.
Conflicts of interest
There are no conicts to declare.
Conclusions
Acknowledgements
We have developed the rst example of oxidative dimerization
of 2-methylquinolines for the highly trans-selective synthesis of
2-alkenyl bisquinolines with molecular oxygen as the oxidant.
The current method is superior to the previously reported 2-
alkenyl bisquinoline synthetic strategies because mild reaction
conditions and readily accessible starting materials are used,
and toxic reagents are avoided.
We are grateful to the nancial support from the Foundation of
He'nan Educational Committee (16A150057) and the Science
and Technology Bureau of Nanyang (2016KJGG39).
References
1 M. E. Zwaagstra, S. H. H. F. Schoenmakers,
P. H. J. Nederkoorn, E. Gelens, H. Timmerman and
M.-Q. Zhang, J. Med. Chem., 1998, 41, 1439.
Experimental
2 J. P. Michael, Nat. Prod. Rep., 2005, 22, 627.
3 M. L. Belley, S. Leger, M. Labelle, P. Roy, Y. B. Xiang and
D. Guay, US Pat. Appl., US 5565473, 1996.
All reactions were performed in oven-dried reaction tubes under
oxygen atmosphere unless otherwise mentioned. Commercial
reagents were purchased from Energy chemical, and TCI. Flash
column chromatographic purication of products was accom-
plished using forced-ow chromatography on Silica Gel (100–
200 mesh). 1H-NMR, and 13C-NMR spectra were recorded on
a Bruker Avance 300 or 400 spectrometer at ambient tempera-
ture. The chemical shis (d) and coupling constants (J) were
expressed in ppm and Hz respectively. The abbreviations used
for explaining the multiplicities were as follows: s ¼ singlet, d ¼
doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet, br ¼ broad.
High resolution mass spectra (HRMS) were measured using EI-
TOF Mass spectrometer. Melting points were uncorrected and
measured with a micro melting point apparatus.
4 For recent examples, see: (a) J. J. Mousseau, J. A. Bull and
A. B. Charette, Angew. Chem., Int. Ed., 2010, 49, 1115; (b)
B. Qian, P. Xie, Y. Xie and H. Huang, Org. Lett., 2011, 13,
2580; (c) Y.-G. Zhang, J.-K. Xu, X.-M. Li and S.-K. Tian, Eur.
J. Org. Chem., 2013, 2013, 3648; (d) P. Wen, Y. Li, K. Zhou,
C. Ma, X. Lan, C. Ma and G. Huang, Adv. Synth. Catal.,
2012, 354, 2135; (e) L. Xu, Z. Shao, L. Wang, H. Zhao and
J. Xiao, Tetrahedron Lett., 2014, 55, 6856; (f) L. Bering and
A. P. Antonchick, Org. Lett., 2015, 17, 3134; (g) H. Xia,
Y. H. Liu, P. Zhao, S. H. Gou and J. Wang, Org. Lett., 2016,
18, 1796; (h) G. E. M. Crisenza, E. M. Dauncey and
J. F. Bower, Org. Biomol. Chem., 2016, 14, 5820; (i)
Z. Zhang, C. Pi, H. Tong, X. Cui and Y. Wu, Org. Lett.,
2017, 19, 440.
General procedure for the synthesis of symmetric 2-alkenyl
bisquinolines 2a–2l
5 M. A. Fakhfakh, A. Fournet, E. Prina, J. F. Mouscadet,
X. Franck, R. Hocquemiller and B. Figadere, Bioorg. Med.
Chem., 2003, 11, 5013.
To a reaction tube (10 mL) was added 2-methylquinolines (0.2
mmol), KOtBu (25 mg, 0.22 mmol), and dry 18-Crown-6 (58 mg,
0.22 mmol). The tube was then evacuated and back-lled with
oxygen three times. Anhydrous DMF (1.5 mL) was added
subsequently. The reaction mixture was stirred at 50 ꢀC for 20 h
under oxygen balloon. Aer the reaction, DMF was removed by
vacuum distillation. The resulting crude was directly puried by
column chromatography on silica gel (elute: petroleum : ethyl
acetate ¼ 15 : 1–8 : 1) to give the desired 2-alkenyl bisquinolines
as white or yellow solids.
6 (a) M. A. Fakhfakh, X. Franck, A. Fournet, R. Hocquemiller
`
and B. Figadere, Synth. Commun., 2002, 32, 2863; (b) L. He,
J.-Q. Wang, Y. Gong, Y.-M. Liu, Y. Cao, H.-Y. He and
K.-N. Fan, Angew. Chem., Int. Ed., 2011, 50, 10216.
7 For selected examples on the oxidation of 2-methylquionline
to 2-quinolinecarboxaldehyde using SeO2, see: (a) D. Ding,
L. P. Dwoskin and P. A. Crooks, Tetrahedron Lett., 2013, 54,
5211; (b) H. Bao, B. Zhou, H. Jin and Y. Liu, Org. Biomol.
Chem., 2019, 17, 5021.
8 A pioneering work concerning the oxidative dimerization of
toluene with benzaldehyde giving stilbene has been
described, see: S. Takemoto, E. Shibata, M. Nakajima,
Y. Yumoto, M. Shimamoto and H. Matsuzaka, J. Am. Chem.
Soc., 2016, 138, 14836.
9 For selected examples on the oxidation of 2-methylquionline
into 2-quinolinecarboxaldehyde using other oxidants, see:
(a) Y. Nagasawa, Y. Tachikawa, E. Yamaguchi, N. Tada,
T. Miura and A. Itoh, Adv. Synth. Catal., 2016, 358, 178; (b)
M. Liu, X. Chen, T. Chen, Q. Xu and S.-F. Yin, Org. Biomol.
Chem., 2017, 15, 9845; (c) A. Rahim, S. P. Shaik, M. F. Baig,
A. Alari and A. Kamal, Org. Biomol. Chem., 2018, 16, 635;
(d) Z. C. Yan, C. F. Wan, Y. Yang, Z. G. Zha and Z. Y. Wang,
General procedure for the synthesis of unsymmetric 2-alkenyl
bisquinolines 3–7
To a reaction tube (10 mL) was added 2-methylquinoline
(86 mg, 0.6 mmol), substituted 2-methylquinoline (0.2 mmol),
KOtBu (45 mg, 0.4 mmol), and 18-Crown-6 (106 mg, 0.4 mmol).
The tube was then evacuated and back-lled with oxygen three
times. Anhydrous DMF (3.0 mL) was added subsequently. The
reaction mixture was stirred at 50 ꢀC for 20 h under oxygen
balloon. Aer the reaction, DMF was removed by vacuum
distillation. The resulting crude was directly puried by column
chromatography on silica gel (elute: petroleum : ethyl acetate ¼
15 : 1–8 : 1) to give the desired 2-alkenyl bisquinolines as white
or pale yellow solids.
30142 | RSC Adv., 2019, 9, 30139–30143
This journal is © The Royal Society of Chemistry 2019

View Article Online
Paper
RSC Adv., 2018, 8, 23058; (e) R. Ye, Y. Cao, X. Xi, L. Liu and
T. Chen, Org. Biomol. Chem., 2019, 17, 4220.
10 H. Q. Wang, Z. Wang, H. C. Huang, J. J. Tan and K. Xu, Org.
Lett., 2016, 18, 5680.
11 Recent examples on the t-BuOK-mediated oxidative
reactions, see: (a) H. Yang, D.-Z. Chu and L. Jiao, Chem.
Sci., 2018, 9, 1534; (b) L. Wu, V. T. Annibale, H. Jiao,
RSC Advances
Sci., 2018, 9, 935; (f) H. Wang, J. Zhang, J. Tan, L. Xin,
Y. Li, S. Zhang and K. Xu, Org. Lett., 2018, 20, 2505; (g)
T. Zheng, J. Tan, R. Fan, S. Su, B. Liu, C. Tan and K. Xu,
Chem. Commun., 2018, 54, 1303; (h) X. Tian, X. Cheng,
X. Yang, Y.-L. Ren, K. Yao, H. Wang and J. Wang, Org.
Chem. Front., 2019, 6, 952; (i) S. Haldar and C. K. Jana, Org.
Biomol. Chem., 2019, 17, 1800.
A. Brookeld, D. Collision and I. Manners, Nat. Commun., 13 M. P. Drapeau, I. Fabre, L. Grimaud, I. Cioni, T. Ollevier
2019, 10, 2786. and M. Taillefer, Angew. Chem., Int. Ed., 2015, 54, 10587.
12 For selected recent examples on metal-free activated C(sp3)– 14 (a) W.-T. Wei, X.-J. Dong, S.-Z. Nie, Y.-Y. Chen, X.-J. Zhang
H functionalization, see: (a) C. J. Evoniuk, G. P. Gomes,
S. P. Hill, S. Fujita, K. Hanson and I. V. Alabugin, J. Am.
Chem. Soc., 2017, 139, 16210; (b) J. Tan, T. Zheng, Y. Yu
and K. Xu, RSC Adv., 2017, 7, 15176; (c) A. Gini,
and M. Yan, Org. Lett., 2013, 15, 6018; (b) W.-T. Wei,
Y.-J. Cheng, Y. Hu, Y.-Y. Chen, X.-J. Zhang, Y. Zou and
M. Yan, Adv. Synth. Catal., 2015, 357, 3474; (c)
J. P. Barham, G. Coulthard, K. J. Emery, E. Doni,
F. Cumine, G. Nocera, M. P. John, L. E. A. Berlouis,
T. McGuire, T. Tuttle and J. A. Murphy, J. Am. Chem. Soc.,
2016, 138, 7402.
˜
T. Brandhofer and O. G. Mancheno, Org. Biomol. Chem.,
2017, 15, 1294; (d) S. Zhang, F. Lian, M. Xue, T. Qin, L. Li,
X. Zhang and K. Xu, Org. Lett., 2017, 19, 6622; (e)
L. A. Combee, B. Raya, D. Wang and M. K. Hilinski, Chem.
This journal is © The Royal Society of Chemistry 2019
RSC Adv., 2019, 9, 30139–30143 | 30143