Reduction of Nitroarenes to Anilines with a Benzothiazoline: Application to Enantioselective Synthesis of 2-Arylquinoline Derivatives

Article abstract of DOI:10.1055/s-0037-1611639

The metal-free reduction of nitroarenes to aniline derivatives was accomplished in a short time by using a benzothiazoline as the hydrogen donor in combination with a Bronsted acid. An enantioselective synthesis of 2-arylquinolines was achieved by using 1-aryl-3-(2-nitrophenyl)propan-1-ones as starting materials and a combination of a benzothiazoline and a chiral phosphoric acid.

Full text of DOI:10.1055/s-0037-1611639

SYNLETT
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Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
M. Miyagawa et al.
Letter
Synlett
Reduction of Nitroarenes to Anilines with a Benzothiazoline:
Application to Enantioselective Synthesis of 2-Arylquinoline
Derivatives
Masamichi Miyagawa
Ryota Yamamoto
0
0
0
0-0
0
0
2-0
8
7
4-
6
7
2
6
NO2
NH2
Short time
Metal-free
benzothiazoline
X
X
Nanako Kobayashi
X = halogen, cyano,
carbonyl, ether…
Takahiko Akiyama*
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0
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0-0
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3-4
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14 examples
up to 98%
Ar3
O
Department of Chemistry, Faculty of Science, Gakushuin
University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan
takahiko.akiyama@gakushuin.co.jp
(R)-CPA
H
N
O
O
benzothiazoline
O
Ar1
Ar2
P
N
H
Ar1
S
OH
NO2
Published as part of the 30 Years SYNLETT – Pearl Anniversary
Issue
up to 66% yield
up to 96% ee
benzothiazoline
Ar3
(R)-CPA
Received: 09.10.2018
Accepted after revision: 19.11.2018
Published online: 17.12.2018
combination with a chiral phosphoric acid.8,9 Benzothiazo-
lines proved to be effective for the transfer hydrogenation
of C=N bonds in a range of ketimines. To expand the utility
of benzothiazolines, we set our sights on the reduction of
nitroarenes. Here we describe a rapid metal-free reduction
of nitroarenes that uses a combination of a benzothiazoline
and a Brønsted acid. Furthermore, we applied this reaction
to the enantioselective synthesis of 2-arylquinolines, starting
from 1-aryl-3-(2-nitrophenyl)propan-1-ones (Scheme 1).
DOI: 10.1055/s-0037-1611639; Art ID: st-2018-b0650-l
License terms:
Abstract The metal-free reduction of nitroarenes to aniline derivatives
was accomplished in a short time by using a benzothiazoline as the hy-
drogen donor in combination with a Brønsted acid. An enantioselective
synthesis of 2-arylquinolines was achieved by using 1-aryl-3-(2-nitro-
phenyl)propan-1-ones as starting materials and a combination of a
benzothiazoline and a chiral phosphoric acid.
A) Bechamp reduction (ref. 3)
metal
Key words benzothiazolines, phosphoric acids, isoquinolines, nitro-
arenes, anilines, reduction
Ar NO2
Ar NH2
Brønsted acid
B) Metal-free reduction
HSiCl3
ref. 5
Aniline is a fundamental motif, frequently found in
pharmaceuticals, natural compounds, and building blocks.
It is also an important building block for organic synthesis.1
A conventional method for the synthesis of aniline involves
the reduction of aryl nitroarenes by using metals.2 The Bé-
champ reduction, which uses tin or zinc in the presence of a
Brønsted acid at high temperature, is extensively em-
ployed.3 Alternatively, transition-metal-catalyzed reduc-
tions of nitroarenes with hydrogen gas are used under rela-
tively mild reaction conditions. Palladium on carbon is a
widely used catalyst in reductions performed in the labora-
tory and industry because it presents benefits with regards
to cost and handling.4 However, the reduction using palladi-
um is sometimes hampered by such issues as residuals,
flammability, and chemoselectivity. The reduction of ni-
troarenes by using such organic reductants as trichlorosi-
lane5 or phenyl(2-pyridyl)methanol6 has been developed.
Recently, Uozumi and co-workers reported a reduction that
used diboronic acid and water.7
phenyl(2-pyridyl)methanol
ref. 6
NO2
NH2
R
R
H
N
B2(OH)4
H2O
Ar2
ref. 7
S
C) This work
R
benzothiazoline
NO2
NH2
benzothiazoline
R
Brønsted acid
R
O
O
O
P
Ar1
OH
(R)-CPA
O
R
benzothiazoline
NO2
N
Ar1
H
(R)-CPA
Scheme 1 Reduction of nitroarenes
We have reported an enantioselective transfer hydroge-
nation of ketimines, in which we used a benzothiazoline
(2,3-dihydro-1,3-benzothiazole) as the hydrogen donor in
At the outset, we examined the reduction of methyl 4-
nitrobenzoate (1a) with 2-phenylbenzothiazoline (2a) in
the presence of a catalytic amount of 10-camphorsulfonic
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
M. Miyagawa et al.
Letter
Synlett
2a (4.0 equiv)
H
N
NO2
NH2
Ar
CSA (10 mol%)
+
toluene, reflux, 24 h
MeO2C
MeO2C
MeO2C
44%
19%
N
1a
3a
4aa
5aa
H
N
NH2
SH
Ar
O
+ H2O
– H2O
+
Ar
Ar
S
H
MeO2C
2a
Ar = 4-NCC6H4
Scheme 2 Reduction of nitroarenes and the formation of N-benzylamine 4aa
acid (CSA) as a Brønsted acid (Scheme 2). Gratifyingly, ani-
line 3a was obtained in 44% yield, accompanied by the cor-
responding N-benzylamine 4aa in 19% yield. We already
knew that the hydrolysis and condensation of benzothiazo-
lines and benzaldehydes occur under these reaction condi-
tions. We therefore believed that 4aa was formed by the re-
duction of imine 5aa, derived from 3a and 4-cyanobenzal-
dehyde.
In order to suppress the hydrolysis of the benzothiazo-
line 2a and to increase the yield of 3a, we added molecular
sieves (MS), which had a pronounced effect; the addition of
MS 4Å suppressed the formation of the benzylamine 4aa
and gave aniline 3a in high yield (Table 1, entries 1–3). Next,
we explored the effects of the Brønsted acid and of various
2-substituents on the benzothiazoline. A long reaction time
was required in the absence of a Brønsted acid (entry 4).
The 2-substituent on the benzothiazoline did not affect the
yield (entries 5–7). During the investigations, we had diffi-
culties purifying the aniline after the reaction, because an
excess of benzothiazole 6 (Ar = Ph) was generated and the
separation of the desired product 3a from 6 (Ar = Ph) was
not a trivial issue. We surmised that the introduction of a
carboxy group onto the benzothiazoline 2 might increase
its polarity and facilitate separation. In addition, we expect-
Table 1 Effects of Molecular Sieves and Various Substituents on the Benzothiazolinea
hydrogen donor (4.0 equiv)
CSA (10 mol%)
molecular sieves
toluene, reflux, time
H
N
NO2
NH2
Ar
+
MeO2C
MeO2C
3a
MeO2C
1a
4aa–ad
H
N
EtO2C
CO2Et
N
Ar
Ar
S
S
N
H
Ar = 4-NC-C6H4
Ph
2a
2b
2c
2d
2e
6
7
4-(F3C)-C6H4
4-MeOC6H4
4-HO2CC6H4
Entry
H donor
MS
Time (h)
Yield (%) of 3a
Yield (%) of 4
1
2a
2a
2a
2a
2b
2c
2d
2e
2e
7
MS 3Å
MS 4Å
MS 5Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
MS 4Å
24
43
86
52
88
84
87
75
98
97
23
0
2
24
5
3
24
27
<8
15
10
<38
-
4b
5
48
19
6
24
7
10.5
0.5
0.5
20
8b
9
-
10
-
a Reaction conditions: 1a (0.080 mmol), H donor (0.32 mmol), CSA (0.008 mmol), MS (100 mg), toluene (0.80 mL).
b Without CSA.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
M. Miyagawa et al.
Letter
Synlett
ed that the benzothiazoline bearing a carboxy group 2e
might function as a Brønsted acid instead of CSA. We there-
fore attempted to perform the reaction with 2e in the ab-
sence of CSA (entries 8 and 9). As expected, benzothiazole
6e was readily removed from the crude mixture by filtra-
tion with dichloromethane. Gratifyingly, the use of 2e ac-
celerated the reaction remarkably and improved the yield of
3a to 98% in 0.5 hours. We also examined the utility of the
Hantzsch ester (7) as a hydrogen donor in place of a benzo-
thiazoline, but this gave 3a in low yield (entry 10).10 Benzo-
thiazoline 2e was therefore found to be the most suitable
hydrogen donor for the present reduction.
Having clarified the optimal reaction conditions, we in-
vestigated the substrate scope. Nitroarenes bearing elec-
tron-withdrawing groups, such as an ester, nitrile, or ketone
group, gave the desired anilines 3b–d in excellent yields
(Scheme 3). Bromo- and iodo(nitro)benzenes provided the
corresponding anilines 3e–i in good yields, except for 2-
bromo-1-nitrobenzene. 4-Methoxy and 4-(benzyloxy)-1-
nitrobenzenes gave the desired anilines 3m and 3n in mod-
erate yields, because benzylamines 4ma and 4na were also
formed. The reduction was completed in 0.5 hours for all
substrates. Aliphatic nitro compounds, nitrobenzenes bear-
ing vinyl groups, and trans--nitrostyrene were not suit-
able substrates for this reduction, and the corresponding
anilines were not obtained.
was recovered. On the other hand, amine 3a was obtained
in 85% yield when BHT was added (Scheme 4). The latter re-
sult did not agree with our hypothesis, so we are exploring
other reaction pathways.
2e (4.0 equiv)
MS (4 Å)
NO2
NH2
+ recovery of 1a
TEMPO (4.0 equiv)
toluene, reflux, 0.5 h
MeO2C
MeO2C
1a
1a
3a
0%
96%
2e (4.0 equiv)
MS (4 Å)
NO2
NH2
+ recovery of 1a
BHT (4.0 equiv)
MeO2C
MeO2C
toluene, reflux, 0.5 h
3a
85%
0%
Scheme 4 Mechanistic study
The present reduction of nitroarenes was applied in a
tandem reaction to synthesize 2-substituted chiral quino-
line derivatives (Scheme 5).11 The tandem reaction consists
of (I) reduction of a 1-aryl-3-(2-nitrophenyl)propan-1-one
9, (II) imine formation by intramolecular cyclization, and
(III) asymmetric reduction by a chiral phosphoric acid and a
benzothiazoline.12
O
O
I
Ar
Ar
2e (4.0 equiv)
MS (4 Å)
NO2
NH2
NH2
NO2
R
R
9
toluene, reflux, 0.5 h
1
3
II
III
NH2
N
Ar
NH2
N
H
Ar
NH2
10
EtO2C
NC
Scheme 5 Tandem reaction
O
3b 89%
3c 90%
NH2
3d 83%
NH2
NH2
We optimized the reaction conditions to furnish the de-
sired 2-arylquinolines 10a–c in good yields and with excel-
lent enantioselectivities by the combined use of benzothi-
azoline 2f and chiral phosphoric acid 8 (Scheme 6).13
In summary, we have developed a reduction of ni-
troarenes by using a benzothiazoline in the presence of a
Brønsted acid. The reduction with a benzothiazoline bear-
ing a carboxy group was completed in a short time. Selec-
tive reduction without use of metal reagents was achieved.
A tandem reaction with a chiral phosphoric acid and a ben-
zothiazoline gave 2-aryltetrahydroquinoline derivatives
with excellent enantioselectivities.
Br
Br
Br
3g
3e 64%
3f 60%
27%
NH2
NH2
NH2
I
I
3h 60%
3i 83%
3k 91%
NH2
NH2
NH2
Ph
NH2
MeO
BnO
Ph
55%
3n
3j
74%
3l 74%
3m 46%
Scheme 3 Substrate scope of nitroarenes
Funding Information
We hypothesized that the reduction proceeds by a radi-
cal pathway. 2,2,6,6-Tetramethylpiperidine 1-oxyl (TEMPO)
and 2,6-di-tert-butyl-4-methylphenol (BHT) were added to
the reaction mixture as radical scavengers. The addition of
TEMPO suppressed the reduction completely, and 96% of 1a
This work was partially supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas “Advanced Transformation Organocatalysis”
from MEXT, Japan, and JSPS KAKENHI Grant Number JP17H03060.
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Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
M. Miyagawa et al.
Letter
Synlett
O
OMe
OMe
OMe
2f (6.0 equiv)
8 (10 mol%)
H
N
Ar1
N
Ar1
MS (3 Å)
toluene, reflux, 2 d
S
NO2
H
9
10
2f
N
H
Ar2
O
N
H
Cl
O
10a
60%, 92% ee
10b
60%, 96% ee
P
OH
O
Ar2
N
H
Ar2 = 2,4,6-(i-Pr)3C6H2
8
10c
66%, 84% ee
Scheme 6 Asymmetric synthesis of 2-substituted quinolines
Supporting Information
2014, 114, 9047. (f) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M.
Chem. Rev. 2017, 117, 10608. (g) Merad, J.; Lalli, G.; Bernadat, G.;
Maur, J.; Masson, G. Chem. Eur. J. 2018, 24, 3925.
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611639.
S
u
p
p
orti
n
gInformati
o
n
S
u
p
p
orit
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gInformati
o
n
(10) For pioneering works on chiral phosphoric acid-catalyzed
transfer hydrogenation of ketimines by using the Hantzsch ester
as a hydrogen donor, see: (a) Rueping, M.; Sugiono, E.; Azap, C.;
Theissmann, T.; Bolte, M. Org. Lett. 2005, 7, 3781. (b) Hoffmann,
S.; Seayad, A.; List, B. Angew. Chem. Int. Ed. 2005, 44, 7424.
(c) Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2006, 128, 84; For selected reviews, see. (d) Rueping,
M.; Sugiono, E.; Schoepke, F. R. Synlett 2010, 852. (e) Zheng, C.;
You, S.-L. Chem. Soc. Rev. 2012, 41, 2498.
(11) For an enantioselective metal-free cascade reaction with
a chiral phosphoric acid, see: Rueping, M.; Antonchick, A. P.;
Theissmann, T. Angew. Chem. Int. Ed. 2006, 45, 3683.
(12) Shibata, Y.; Yamanaka, M. J. Org. Chem. 2013, For a theoretical
study on chiral phosphoric acid-catalyzed transfer hydrogena-
tion using a benzothiazoline, see: 78, 3731.
References and Notes
(1) (a) Downing, R. S.; Kunkeler, P. J.; van Bekkum, H. Catal. Today
1997, 37, 121. (b) Lawrence, S. A. Amines: Synthesis, Properties
and Applications; Cambridge University Press: Cambridge,
2004. (c) MacDiarmid, A. G. Synth. Met. 1997, 84, 27.
(2) For reviews, see: (a) Kadam, H. K.; Tilve, S. G. RSC Adv. 2015, 5,
83391. (b) Blaser, H.-U.; Steiner, H.; Studer, M. ChemCatChem
2009, 1, 210. (c) Orlandi, M.; Brenna, D.; Harms, R.; Jost, S.;
Benaglia, M. Org. Process Res. Dev. 2018, 22, 430. (d) Aditya, T.;
Pal, A.; Pal, T. Chem. Commun. 2015, 51, 9410.
(3) Béchamp, A. Ann. Chim. Phys. 1854, 42[3], 186.
(4) Blaser, H.-U. Chimia 2015, 69, 393.
(13) 2-Aryl-1,2,3,4-tetrahydroquinolines 10a–c; General Proce-
dure
(5) (a) Porta, R.; Puglisi, A.; Colombo, G.; Rossi, S.; Benaglia, M. Beil-
stein J. Org. Chem. 2016, 12, 2614. (b) Orlandi, M.; Tosi, F.;
Bonsignore, M.; Benaglia, M. Org. Lett. 2015, 17, 3941.
(c) Orlandi, M.; Benaglia, M.; Tosi, F.; Annunziata, R.; Cozzi, F.
J. Org. Chem. 2016, 81, 3037.
(6) Giomi, D.; Alfini, R.; Brandi, A. Tetrahedron 2011, 67, 167.
(7) Chen, D.; Zhou, Y.; Zhou, H.; Liu, S.; Liu, Q.; Zhang, K.; Uozumi,
Y. Synlett 2018, 29, 1765.
(8) (a) Zhu, C.; Akiyama, T. Org. Lett. 2009, 11, 4180. (b) Zhu, C.;
Saito, K.; Yamanaka, M.; Akiyama, T. Acc. Chem. Res. 2015, 48,
388. (c) Zhu, C.; Akiyama, T. Synlett 2011, 1251.
(9) For seminal papers on chiral phosphoric acid catalysis, see:
(a) Akiyama, T.; Itoh, J.; Yokota, K.; Fuchibe, K. Angew. Chem. Int.
Ed. 2004, 43, 1566. (b) Uraguchi, D.; Terada, M. J. Am. Chem. Soc.
2004, 126, 5356. For selected reviews, see: (c) Akiyama, T. Chem.
Rev. 2007, 107, 5744. (d) Terada, M. Synthesis 2010, 1929.
(e) Parmar, D.; Sugiono, E.; Raja, S.; Rueping, M. Chem. Rev.
Under a N2 atmosphere, a mixture of the appropriate ketone 9
(0.10 mmol), benzothiazoline 2f (0.60 mmol), chiral phosphoric
acid 8 (0.010 mmol), and MS 3Å (600 wt%, activated) in toluene
(1.0 mL) was refluxed for 2 days. When the reaction was com-
plete (TLC), it was quenched by adding sat. aq NaHCO3. The
crude mixture was filtered through a Celite pad and extracted
with EtOAc (×3). The organic extracts were combined, washed
with brine, dried (Na2SO4), and concentrated in vacuo. The
residue was purified by preparative TLC.
2-Phenyl-1,2,3,4-tetrahydroquinoline (10a)
White solid; yield: 13 mg (60%, 92% ee); mp 52–54 °C; []D24 –42
(c 0.75, CHCl3). 1H NMR (400 MHz, CDCl3):  = 1.94–2.05 (m, 1
H), 2.09–2.15 (m, 1 H), 2.74 (dt, J = 4.8, 16.4 Hz, 1 H), 2.93 (ddd,
J = 5.6, 10.8, 16.4 Hz, 1 H), 4.04 (br s, 1 H), 4.43 (dd, J = 3.4, 9.2
Hz, 1 H), 6.53 (d, J = 8.4 Hz, 1 H), 6.65 (t, J = 7.6 Hz, 1 H), 6.99–
7.02 (m, 2 H), 7.24–7.40 (m, 5 H). 13C NMR (100 MHz, CDCl3):
 = 26.4, 31.0, 56.3, 114.0, 117.2, 120.9, 126.6, 126.9, 127.5,
128.6, 129.3, 144.7, 144.8.
Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D