Organocatalytic Approach for Transfer Hydrogenation of Quinolines, Benzoxazines and Benzothiazines

Article abstract of DOI:10.1007/s10562-017-2061-1

Abstract: This study reports on the thiourea dioxide catalyzed transfer hydrogenation of diverse C=N–containing heterocyclic compounds with Hantzsch ester as the hydrogen source. With this cost effective and readily available catalyst, a wide range of 2-s

Full text of DOI:10.1007/s10562-017-2061-1

Catal Lett
DOI 10.1007/s10562-017-2061-1
Organocatalytic Approach for Transfer Hydrogenation
of Quinolines, Benzoxazines and Benzothiazines
Xiang Qiao1 · Zongbi Bao1 · Huabin Xing1 · Yiwen Yang1 · Qilong Ren1 ·
Zhiguo Zhang1
Received: 14 February 2017 / Accepted: 22 April 2017
© Springer Science+Business Media New York 2017
Abstract This study reports on the thiourea dioxide cata-
lyzed transfer hydrogenation of diverse C=N–containing
heterocyclic compounds with Hantzsch ester as the hydro-
gen source. With this cost effective and readily available
catalyst, a wide range of 2-substituted quinolines, 3-substi-
tuted-2H-1,4-benzoxazines and 3-substituted-2H-1,4-ben-
zothiazines were efficiently reduced to the corresponding
tetrahydroquinolines, dihydro-2H-benzoxazines and dihy-
dro-2H-benzothiazines under mild conditions.
Graphical Abstract This study reports on the first thio-
urea dioxide catalyzed transfer hydrogenation of 2-sub-
stituted quinolines, 3-substituted-2H-1,4-benzoxazines
and 3-substituted-2H-1,4-benzothiazines with Hantzsch
1,4-dihydropyridine as the hydrogen source.
Keywords Thiourea dioxide · Transfer hydrogenation ·
Quinoline · Benzoxazine · Benzothiazine
1 Introduction
The use of small molecule metal-free hydrogen-bond in
catalysis is an important frontier of research in recent years
[1–6]. In this context, a number of classes of compounds
have been introduced including binols [7], silanediols [8, 9],
squaramides [10–13], and α,α,α,α-tetraaryl-1,3-dioxolane-
4,5-dimethanols (TADDOLs) [14, 15], but no species have
received more attention than thioureas [16–21]. Thioureas
have two N–H bonds, which can activate substrate via
hydrogen bonding and facilitate a nucleophilic attack [22,
23]. In addition, their catalytic properties are possible to be
Electronic supplementary material The online version of this
article (doi:10.1007/s10562-017-2061-1) contains supplementary
material, which is available to authorized users.
* Zhiguo Zhang
zhiguo.zhang@zju.edu.cn
1
Key Laboratory of Biomass Chemical Engineering
of Ministry of Education, College of Chemical
and Biological Engineering, Zhejiang University, Zheda
Road 38, Hangzhou 310027, China
Vol.:(0123456789)
1 3

X. Qiao et al.
CF3
CF3
transfer hydrogenation of these substrates, but also give
direct access to the biologically relevant building blocks,
1,2,3,4-tetrahydroquinolines, dihydro-2H-benzoxazines
and dihydro-2H-benzothiazines (Scheme 2).
O
O
S
S
vs
H2N
NH2
F3C
N
H
N
H
CF3
TDO
T1
Scheme 1 Schreiner thiourea (T1) and thiourea dioxide (TDO)
2 Experimental
2.1 Materials
intricately tuned through the systematic adjustment of their
structures by incorporation of various substituents or chi-
ral building blocks [24, 25]. Among thiourea-based deriva-
tives reported, N,N′-bis(trifluoromethyl)phenylthiourea
[(3,5-(CF3)2C6H3NH)2CS] (T1), also known as Schreiner’s
thiourea [26–28], has stood to be a privileged catalyst for a
plethora of chemical transformations [29]. While the past
20 years have seen many examples of H-bond activation
with T1 under remarkably mild conditions and with high
reactivity, no profitable practical applications have yet been
developed. This is mainly because of the cost of T1 and
considerably tedious separation process after the reaction
(Scheme 1).
Unless otherwise noted, all materials were obtained from
commercial suppliers and were used without further puri-
fication. Solvents for chromatography were of technical
grade and were distilled prior to use. Solvents used in the
reactions were reagent grade. For thin-layer chromatogra-
phy (TLC), silica gel plates coated glass plates (Haiyang)
were used and chromatograms were visualized by irra-
diation with UV light. Column chromatography was per-
formed using silica gel (200–300 mesh) from Haiyang.
Solvent mixtures are understood as volume/volume.
Recently, thiourea dioxide, one of the best known
reducing agents in textile, paper and other industries, has
started to serve as a new arsenal in organocatalysis, as it
shows stronger hydrogen bonding activation than thio-
urea itself owing to the presence of two extra electron-
egative oxygen atoms [30]. Sain and co-workers reported
that thiourea dioxide was an efficient organocatalyst for
the synthesis of a series of heterocyclic compounds via
one-pot multicomponent coupling reactions [31]. Jain
and co-workers demonstrated that thiourea dioxide in
combination with t-butyl hydroperoxide (TBHP) served
to be a fruitful and greener recipe for the catalytic oxi-
dation of sulfides and alcohols [32, 33]. Mansoor et al.
developed a simple and highly efficient TDO-catalyzed
one-pot synthesis of pyrano[4,3-b] pyran derivatives
in water [34]. Bhale and Patel groups reported the effi-
cient synthesis of 1,8-dioxooctahydoxanthenes and
1,4-dihydropyrano[2,3-c]-pyrazole-5-carbonitrile deriva-
tives in aqueous media, respectively [35, 36]. Although
the exact mechanisms for these transformations are
unknown at current stage, most of its catalytic activity
was attributed to H-bond interaction with the substrates.
In view of the great potential utilization of TDO as an
alternative H-bond catalyst, together with our recently
developed T1-catalyzed biomimetic reduction of quino-
lines [37], as well as other hydrogenation of quinolines
[38–41], we reasoned that it might be possible to replace
T1 with TDO in the transfer hydrogenation of quinolines
with Hantzsch ester as the hydrogen source [42–44].
Similarly, this strategy can even be further extended to
the reduction of benzoxazines and benzothiazines. This
would not only be the first example of TDO-catalyzed
2.2 Instrumentation
All NMR experiments were performed on a Bruker
Avance 400 MHz NMR spectrometer equipped with a
5 mm BBO probe at 295 K. The data were collected and
processed by TOPSPIN software (Bruker) running on a
PC with Microsoft Windows 7. Proton and 13C chemical
shifts were referred to the solvent signal (CDCl3) at 7.26
and 77.23 ppm, respectively. Data are presented as fol-
lows: chemical shift, integration, multiplicity (br = broad,
s = singlet, d = doublet, t = triplet, q = quartet, m = mul-
tiplet, cm = complex multiplet) and coupling constant
in Hertz (Hz). Infrared (IR) spectra were scanned with
thermo NICOLET 6700 in terms of frequency of absorb-
tion (cm−1). GC analyses were carried out with a SHI-
MADZU GC-2010 Plus gas chromatograph equipped
with a Agilent J&W scientific fused silica GC column
Scheme 2 Thiourea catalyzed transfer hydrogenations with HEH
1 3

Organocatalytic Approach for Transfer Hydrogenation of Quinolines, Benzoxazines and…
Table 1 Optimization of transfer hydrogenation of 2-phenylquinoline
(30 m × 0.250 mm, 0.25 micron HP-5 stationary phase:
(5%-Phenyl)-methylpolysiloxane) using nitrogen as car-
rier gas; T-program standard 60–250 °C (15 °C/min heat-
ing rate), injector and transfer line 250 °C.
2.3 General Procedure for Transfer Hydrogenation
of 2‑Substituted Quinolines
Entrya
Catalyst (mol%)
Solvent
Conver-
sionb
(%)
An oven-dried flask was fitted with magnetic stirring bar
and charged with 2-substituted quinoline (0.10 mmol),
thiourea dioxide (1 mol%), Hantzsch dihydropyridine
(2.5 equiv.) and chloroform (1 mL). The resulting mix-
ture was stirred at 60°C for 24–48 h. The solvent was
removed under reduced pressure and the residue was puri-
fied by column chromatography on silica gel using hex-
ane/EtOAc (20:1) as eluent to yield the corresponding
1,2,3,4-tetrahydroquinolines.
1
2
3
4
5
6
7
8
20
20
20
20
20
20
20
20
20
20
20
20
10
5
Toluene
CHCl3
EtOAc
CH3CN
DMF
MeOH
THF
77
98
52
97
34
53
86
84
39c
74d
44c
8e
92
91
90
88
40f
6
EtOH
9
CH2Cl2
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
10
11
12
13
14
15
16
17
18
2.4 General Procedure for Transfer Hydrogenation
of 3‑Substituted‑2H‑1,4‑Benzoxazines
An oven-dried flask was fitted with magnetic stirring
bar and charged with 3-substituted-2H-1,4-benzoxazine
(0.10 mmol), thiourea dioxide (1 mol%), Hantzsch dihy-
dropyridine (1.3 equiv.) and chloroform (1 mL). The result-
ing mixture was stirred at 60°C for 16 h. The solvent was
removed under reduced pressure and the residue was puri-
fied by column chromatography on silica gel using hexane/
EtOAc (15:1) as eluent to yield the corresponding products.
3
1
0.1
0
aThe reactions were performed with 2-phenylquinoline (0.10 mmol)
and HEH (0.25 mmol) in 1 mL of solvent at 60°C for 24 h
bConversion is determined by GC analysis with tridecane as the inter-
nal standard.
2.5 General Procedure for Transfer Hydrogenation
of 3‑Substituted‑2H‑1,4‑Benzothiazines
cAt 40°C
dAt 50°C
eAt r.t.
An oven-dried flask was fitted with magnetic stirring bar
and charged with 3-substituted-2H-1,4-benzothiazine
(0.10 mmol), thiourea dioxide (10 mol%), Hantzsch dihy-
dropyridine (1.3 equiv.) and chloroform (1 mL). The result-
ing mixture was stirred at 60°C for 48 h. The solvent was
removed under reduced pressure and the residue was puri-
fied by column chromatography on silica gel using hexane/
EtOAc (15:1) as eluent to yield the corresponding products.
f48 h
(Table 1, entry 1). It should be noted that TDO, sparingly
soluble in toluene, has been able to promote this transfor-
mation. Encouraged by this result, we further investigated
solvent effects on reaction outcomes (Table 1, entries
2–9). Without regard to the solubilities of TDO in com-
mon organic solvents, when the reaction was carried out
in polar solvents such as EtOAc, DMF, MeOH, THF, and
EtOH, it gives the conversions in the range of 34–86%,
presumably due to competitive H-bond interaction in
these solvents. CHCl3 and CH3CN proved to be optimal
solvents for this transformation, furnishing the product
in excellent conversions (entries 2 and 4). Using CHCl3
as the solvent, we evaluated other reaction parameters
including temperature and catalyst loadings. The reaction
proceeds slowly as the temperature decreases (entries
10–12). Notably, the catalyst loading could be reduced to
1 mol% without obvious compromise of the conversion
3 Results and Discussion
3.1 Optimization of TDO Catalyzed Transfer
Hydrogenation of 2‑Phenylquinoline
To test our hypothesis, we first examined the reduction
of 2-phenyl quinoline with TDO as a catalyst. To our
delight, in the presence of 20 mol% of TDO and 2.5
equiv. of HEH, the reaction proceeded smoothly in tolu-
ene at 60 °C, giving a 77% conversion of substrate at 24 h
1 3

X. Qiao et al.
Table 2 Transfer hydrogenation of 2-substituted quinolines
3.2 Scope of TDO Catalyzed Transfer Hydrogenation
of 2‑Phenylquinoline
Subsequently, the optimized conditions were used for
further evaluation of the substrate scope (Table 2). Vari-
ous 2-substituted quinolines were subjected to this trans-
fer hydrogenation reactions and smoothly converted into
1,2,3,4-tetrahydroquinolines in high to excellent yields
(entries 1–12). Substrates with electron-donating sub-
stituents on 2-phenyl ring need longer time to give a sat-
isfactory yield (Table 2, entries 2–6). The halogen sub-
stituents (F, Cl, Br) at 2-phenyl ring slightly improved the
reactivity and afforded the desired product in high yields
within 24 h (Table 2, entries 7–9). In addition, 2-butyl and
2-methyl quinolines also proceeds smoothly, affording
the product with 77% yield (Table 2, entries 10–11). This
new methodology is also applicable to the production of
biologically active alkaloid galipinine (Table 2, entry 12).
Notably, when 2-vinylquinoline was employed as the sub-
strate, a product of 2-ethyl-1,2,3,4-tetrahydroquinoline was
afforded (Table 2, entry 13). From a practical point of view,
a gram-scale experiment with 2-phenylquinolines (1.025 g)
has also been performed, giving the product in 85% yield
(Table 2, entry 1).
Entrya
R
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
Phenyl
24
48
48
48
48
48
24
24
24
24
24
24
87 (85)c
90
83
84
80
88
89
87
86
4-Methylphenyl
4-Isopropylphenyl
4-Methoxyphenyl
1,1′-Biphenyl-4-yl
2,4-Dimethylphenyl
4-Chlorophenyl
4-Bromophenyl
2-Fluorophenyl
n-Butyl
9
10
11
12
77
80
84
Methyl
2-(3,4-Methylenedioxy-
phenyl)ethyl
13
Vinyl
24
69 d
aAll reactions were performed with quinoline (0.10 mmol) and HEH
(0.25 mmol) in the presence of 1 mol% of thiourea dioxide at 60°C in
1 mL of CHCl3
bYield of isolated product after column chromatography
cWith 1.025 g of 2-phenylquinoline
3.3 TDO Catalyzed Transfer Hydrogenation
of 3‑Substituted‑2H‑1,4‑Benzoxazines
dAffording 2-ethyl-1,2,3,4-tetrahydroquinoline as product
In view of the structural similarities of quinolines with
benzoxazines and benzothiazines, we further extended this
protocol to these two types of substrates, as the reduced
products dihydro-2H-benzoxazines and dihydro-2H-benzo-
thiazines are of great interest in pharmaceuticals [45–47].
Benzoxazine 3a was initially tested as a benchmark for
comparison to quinolines. Gratifyingly, in the presence of
1 mol% of TDO and 1.3 equiv. of HEH, benzoxazine 3a
was successfully converted to 3-phenyl-substituted product
4a with 98% yield, which exhibited higher reactivity than
quinoline derivatives, since the reaction can be completed
in less reaction time (16 vs. 24–48 h). Substitutions with
either electron-donationg or -withdrawing groups at 3-sub-
stituted phenyl ring showed marginal effect on reactivities
and all the corresponding products 4b–e were obtained in
high to excellent yields (Table 3).
Table 3 Transfer hydrogenation of 3-substituted-2H-1,4-benzoxa-
zines
Entrya
R
Time (h)
Yieldb (%)
1
2
3
4
5
Phenyl
16
16
16
16
16
98
96
92
89
89
4-Methylphenyl
4-Methoxyphenyl
4-Bromophenyl
4-Chlorophenyl
aAll reactions were performed with 2 H-1,4-benzoxazine (0.10 mmol)
and HEH (0.13 mmol) in the presence of 1 mol% of thiourea dioxide
at 60°C in 1 mL of CHCl3
bYield of isolated product after column chromatography
3.4 TDO Catalyzed Transfer Hydrogenation
of 3‑Substituted‑2H‑1,4‑Benzothiazines
(entries 13–16), suggesting that TDO is even more effi-
cient than T1 in accelerating this transformation. A con-
trol experiment showed that no reaction took place in the
absence of TDO, indicating the crucial role of TDO in
substrate activation (Table 1, entry 18).
After transfer hydrogenation of quinolines and benzoxa-
zines were established with this organocatalytic protocol,
we next turned our attention to the reduction of benzo-
thiazines, which was generally considered to be challeng-
ing substrates for transition metal catalysts because of the
1 3

Organocatalytic Approach for Transfer Hydrogenation of Quinolines, Benzoxazines and…
Table 4 Transfer hydrogenation of 3-substituted-2H-1,4-benzothia-
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