Efficient dehydrogenation of 1,2,3,4-tetrahydroquinolines mediated by dialkyl azodicarboxylates

Article abstract of DOI:10.1080/00397911.2018.1445866

Various dialkyl azodicarboxylates were investigated for the dehydrogenation of 1,2,3,4-tetrahydroquinolines to quinolines. The dehydrogenation rates varied according to the electronic and steric nature of the used dialkyl azodicarboxylates. Among solvents screened with diethyl azodicarboxylate, chloroform exhibited superior results to others. A variety of 1,2,3,4-tetrahydroquinolines underwent the present dehydrogenation to produce the corresponding quinolines. Diethyl hydrazodicarboxylate, which is a reduced species of diethyl azodicarboxylate, was easily separated for recycle.

Full text of DOI:10.1080/00397911.2018.1445866

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Efficient dehydrogenation of 1,2,3,4-
tetrahydroquinolines mediated by dialkyl
azodicarboxylates
Saet Byeol Bang & Jinho Kim
To cite this article: Saet Byeol Bang & Jinho Kim (2018): Efficient dehydrogenation of 1,2,3,4-
tetrahydroquinolines mediated by dialkyl azodicarboxylates, Synthetic Communications, DOI:
10.1080/00397911.2018.1445866
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https://doi.org/10.1080/00397911.2018.1445866
Efficient dehydrogenation of 1,2,3,4-tetrahydroquinolines
mediated by dialkyl azodicarboxylates
Saet Byeol Bang and Jinho Kim
Department of Chemistry, and Research Institute of Basic Sciences, Incheon National University, Incheon,
Republic of Korea
ABSTRACT
ARTICLE HISTORY
Received 27 December 2017
Various dialkyl azodicarboxylates were investigated for the dehydro-
genation of 1,2,3,4-tetrahydroquinolines to quinolines. The dehydro-
genation rates varied according to the electronic and steric nature of
the used dialkyl azodicarboxylates. Among solvents screened with
diethyl azodicarboxylate, chloroform exhibited superior results to
KEYWORDS
Dehydrogenation; diethyl
azodicarboxylate; organic
synthesis; quinolines; 1,2,3,4-
tetrahydroquinolines
others.
A variety of 1,2,3,4-tetrahydroquinolines underwent the
present dehydrogenation to produce the corresponding quinolines.
Diethyl hydrazodicarboxylate, which is a reduced species of diethyl
azodicarboxylate, was easily separated for recycle.
GRAPHICAL ABSTRACT
Introduction
Dialkyl azodicarboxylates including diethyl azodicarboxylate (DEAD), diisopropyl azodi-
carboxylate (DIAD), and di-tert-butyl azodicarboxylate (DBAD) are of importance in
organic synthesis due to their interesting reactivity.[1] The most representative utilization
of dialkyl azodicarboxylates, especially DEAD, is Mitsunobu reaction.[2] The Mitsunobu
reaction has been widely used in the preparation of chiral alcohol due to clean inversion
of the stereogenic center.[3] In addition to Mitsunobu reaction, dialkyl azodicarboxylates
were used in electrophilic amination,[4] [4þ2] cycloaddition,[5] hydroacylation,[6] alcohol
oxidation,[7] amine oxidation,[8] and oxidative coupling of tertiary amines.[9]
Quinolines are common pharmacophores in numerous pharmaceuticals and bioactive
compounds.[10] For the synthesis of quinolines, Friedländer reaction is a traditional
method using a condensation of 2-amino benzaldehydes with carbonyl derivatives contain-
ing α -methylene group.[11] Similarly, various quinolines synthesis using aniline derivatives
have been developed by virtue of appropriate coupling partners and catalysts.[12] Recently,
CONTACT Jinho Kim
jinho@inu.ac.kr
Department of Chemistry, Incheon National University, 119 Academy-ro,
Yeonsu-gu, Incheon 22012, Republic of Korea.
Supplemental data for this article can be accessed on the publisher’s website.
© 2018 Taylor & Francis

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S. B. BANG AND J. KIM
Scheme 1. Previously reported dehydrogenation of 1,2,3,4-tetrahydroquinolines using dialkyl
azodicarboxylates.
dehydrogenative approaches from 1,2,3,4-tetrahydroquinoline have received much atten-
tion from organic chemists.[13] However, the reported dehydrogenation of 1,2,3,4-tetrahy-
droquinolines usually required transition metals and harsh conditions.
In 2011, Stone revealed that DIAD increased the yield of quinoline products in the Pd-
catalyzed Heck reaction between 2-bromoanilines and allylic alcohols through the DIAD-
mediated dehydrogenation of 1,2,3,4-tetrahydroquinolines (Scheme 1A).[14] Recently, our
group developed CuI/DBAD-catalyzed aerobic dehydrogenation of 1,2,3,4-tetrahydroqui-
nolines under mild conditions.[15] The developed method consisted of DBAD-mediated
dehydrogenation of 1,2,3,4-tetrahydroquinolines and CuI-catalyzed aerobic regeneration
of DBAD from di-tert-butyl hydrazodicarboxylate (DBAD-H2) (Scheme 1B). Although it
was already reported that dialkyl azodicarboxylates could be used in the dehydrogenation
of 1,2,3,4-tetrahydroquinolines, the reaction parameter and the substrate scope for the
dehydrogenation of 1,2,3,4-tetrahydroquinolines were not investigated sufficiently. Herein,
we describe our efforts and findings for dialkyl azodicarboxylate-mediated dehydrogena-
tion of 1,2,3,4-tetrahydroquinolines (Scheme 1C).
Results and discussion
Initially, we measured reaction rates of the dehydrogenation of 6-methyl-1,2,3,4-tetrahy-
droquinoline 1a in CDCl3 at room temperature using aliquot method with various dialkyl
azodicarboxylates (Fig. 1). It was observed that bis(2,2,2-trichloroethyl) azodicarboxylate
(BTAD), which has electron-withdrawing trichloroethyl groups, showed the fastest dehy-
drogenation rate. In addition, the significant reaction rate drop with DBAD was observed
compare to other dialkyl azodicarboxylates. These observations indicated that electron-
deficient as well as less sterically hindered dialkyl azodicarboxylates were required for
the successful dehydrogenation of 1,2,3,4-tetrahydroquinolines. We also examined the
dehydrogenation of 1a with other azo compounds such as 1,10-(azodicarbonyl)dipiperidine
(ADDP), N,N,N0,N0-tetramethylazodicarboxamide, azobenzene, and ethyl 2-phenylazocar-
boxylate, however, these azo compounds showed no reactivity. Although BTAD displayed

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Figure 1. Reaction rates of the dehydrogenation of 1a with various dialkyl azodicarboxylates.
slightly better performance than DEAD, the lower cost of DEAD relative to BTAD
prompted us to proceed with DEAD.
Next, we tried to investigate the effect of solvent on the dehydrogenation of 1a (Fig. 2)
with DEAD. The dehydrogenation of 1a in CDCl3 showed a superior reaction rate to other
deuterated solvents such as CD3CN, THF-d8, DMSO-d6, and toluene-d8. Gratifyingly, no
decrease of reaction rate was observed in the dehydrogenation of 1a, when we used com-
mercially available DEAD solution in toluene (40 wt%). For safety issue, we decided to use
Figure 2. Reaction rates of the dehydrogenation of 1a in various solvents.

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S. B. BANG AND J. KIM
DEAD solution in toluene for further study. Although the dehydrogenation of 1a in CHCl3
with DEAD solution showed an acceptable result in 3 h, prolonged reaction time (12 h) was
required for full conversion of 1a.
With the optimized conditions in hand (2.2eq DEAD, CHCl3, and 12 h), we investigated
the substrate scope of 1,2,3,4-tetrahydroquinolines (Table 1). In general, the developed
dehydrogenation protocol produced various quinolines in high to excellent yields. Simple
1,2,3,4-tetrahydroquinolines underwent dehydrogenation to produce quinoline in 90%
yield (2b). Although a variety of methyl substituted quinolines were efficiently synthesized
in high yields from the corresponding tetrahydroquinolines (2c–2f), the dehydrogenation
of 2-methyl 1,2,3,4-tetrahydroquinoline 1c showed a lower yield in the optimized con-
ditions presumably due to steric effect. When the dehydrogenation of 1c was performed
at reflux, however, we could obtain 2-methyl quinoline 2c in 84% yield. Several 1,2,3,4-tet-
rahydroquinolines having other substituents were also tested in the developed protocol.
While electron rich 1,2,3,4-tetrahydroquinolines such as 6-methoxy 1,2,3,4-tetrahydroqui-
noline underwent the present dehydrogenation efficiently (2g), the dehydrogenation of
1,2,3,4-tetrahydroquinolines having electron withdrawing substituents gave poor yields
(2i–2l). Similar to the dehydrogenation of 1c, these substrates required the increase of
Table 1. Substrate scope of DEAD-mediated dehydrogenation of 1,2,3,4-tetrahydroquinolines.a,b
aReaction conditions: 1 (0.5 mmol) and DEAD solution 40 wt% in toluene (2.2 eq, 1.1 mmol, 0.5 mL) in CHCl3 (1.0 mL) at room
temperature for 12 h.
bAt reflux.

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Scheme 2. Proposed mechanism.
Scheme 3. Disproportionation of intermediate B.
temperature to obtain acceptable yields (2i–2l).1 This may be attributed to the facilitation
of nucleophilic attack of electron poor 1,2,3,4-tetrahydroquinolines to DEAD for the
formation of triazane at higher temperature (vide infra). The dehydrogenation of 2-phenyl
1,2,3,4-tetrahydroquinolines, which could be synthesized Suzuki coupling of 2-chloro-
quinoline with the corresponding phenyl boronic acid followed by reduction with
NaBH3CN,[13h] gave 2-phenylquinolines in quantitative product yields, regardless of
electronic environments in phenyl groups (2m–2o). In addition to 2-phenylquinolines,
4-phenylquinolines were produced in high yields by dehydrogenation of 4-phenyl 1,2,3,4-
tetrahydroquinolines synthesized from anilines and cinnamaldehyde (2p and 2q).[16]
The use of 9,10-dihydroacridine in the present dehydrogenation conditions produced the
acridine in quantitative yield (2r).
On the basis of previous references and our observations, a possible mechanism for
DEAD-mediated dehydrogenation of 1,2,3,4-tetrahydroquinolines is illustrated in
Scheme 2. We propose that the present dehydrogenation is initiated by the formation
of a triazane intermediate A which is generated by a Micheal-type addition of 1,2,3,4-
tetrahydroquinolines to DEAD.[8a,17] The generated triazane A then undergoes an
elimination and a proton transfer to produce an imine intermediate B as well as diethyl
hydrazodicarboxylate (DEAD-H2), which is the reduced form of DEAD. The tauto-
merization of the resulting imine B and the following second dehydrogenation give
the desired quinolines,[13e] however, the disproportionation of B cannot be ruled out
at this stage (Scheme 3).[14]
1Instead of CHCl3, the use of other solvents such as CH3CN and dichloroethane (DCE) at 70 °C also gave high product yields.
For example, the yields of 2i were 97% in CH3CN and 96% in DCE at 70 °C.

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S. B. BANG AND J. KIM
The used oxidant, DEAD, was able to be recycled by the simple process.[8b] After
the present protocol, DEAD-H2 was generated as a byproduct. Because DEAD-H2
has poor solubility in nonpolar organic solvents, we could simply isolate the generated
DEAD-H2 from the reaction mixture through the recrystallization with hexane (87%).
The isolated DEAD-H2 could be transformed to DEAD by the known oxidation
process.[18]
Conclusion
In summary, we have developed dehydrogenation of 1,2,3,4-tetrahydroquinolines mediated
by dialkyl azodicarboxylate. The measurement of reaction rates revealed that electronic and
steric nature of dialkyl azodicarboxylates affected on the developed dehydrogenation.
A variety of quinolines could be synthesized by the DEAD-mediated dehydrogenation of
the corresponding 1,2,3,4-tetrahydroquinolines. Although several 1,2,3,4-tetrahydroquino-
lines showed poor yields in the optimized conditions, slightly modified conditions
including temperature increase produced quinolines in acceptable yields. The generated
DEAD-H2, which was the byproduct in the present protocol, could be isolated by simple
recrystallization after the reaction and used for the recycle of DEAD.
Experimental details
All commercially available compounds and solvents were purchased and used
as received, unless otherwise noted. Analytical thin layer chromatography (TLC) was
performed on precoated silica gel 60 F254 plates. Visualization on TLC was achieved
by the use of UV light (254 nm) and treatment with phosphomolybdic acid stain
followed by heating. Flash chromatography was performed using silica gel (particle size
1
40–63 µm, 230–400 mesh). H and 13C NMR spectra were recorded on 400 MHz NMR
(400 MHz for 1H, 101 MHz for 13C). Chemical shift values are given in parts per million
relative to internal TMS (0.00 ppm for 1H) or CDCl3 (77.06 ppm for 13C). The following
abbreviations were used to describe peak splitting patterns when appropriate: br ¼ broad,
s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, p ¼ pentet, m ¼ multiplet, dd ¼ double
of doublet, dt ¼ double of triplet, td ¼ triple of doublet. Coupling constants, J, were
reported in hertz unit (Hz).
General procedure of the DEAD-mediated dehydrogenation
of 1,2,3,4-tetrahydroquinolines
To a 10 mL round bottom flask equipped with a magnetic stir bar, 1,2,3,4-tetrahydroquino-
line (0.5 mmol), DEAD solution 40 wt% in toluene (2.2 eq, 1.1 mmol, 0.5 mL), and CHCl3
(1.0 mL) was added. The reaction mixture was stirred at room temperature for 12 h. The
mixture was concentrated on rotary evaporator. The residue was purified by column
chromatography with EtOAc:hexane (1:5) to give quinolines.
In case of 2f and 2m, the product spot was close to the spot of the remained DEAD. To
eliminate the remained DEAD, 1 equivalent of PPh3 was added after the reaction and the
reaction mixture was stirred.[19] After 10 min, the reaction mixture was concentrated on
rotary evaporator. The residue was purified by column chromatography with CHCl3:
hexane (1:1) to give quinolines.

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Selected product
1
6-Methylquinoline (2a)[13h]; 95% (68 mg), yellow oil, EtOAc/hexane ¼ 1:5, H NMR
(400 MHz, CDCl3) δ 8.83 (d, J ¼ 4.0 Hz, 1H), 8.14–7.75 (m, 2H), 7.55–7.49 (m, 2H),
7.35–7.27 (m, 1H), 2.50 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 149.5, 146.8, 136.3,
135.3, 131.7, 129.0, 128.2, 126.5, 121.0, 21.5.
Funding
This research was supported by the Basic Science Research Program through the National Research
Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning
(NRF-2015R1C1A1A02037185).
ORCID
Jinho Kim
http://orcid.org/0000-0002-3592-9026
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