Highly enantioselective spinol-derived phosphoric acid catalyzed transfer hydrogenation of diverse C=N-containing heterocycles

Article abstract of DOI:10.1002/ejoc.201500330

A highly efficient and enantioselective hydrogenation of diversely substituted C=N-containing heterocyclic compounds such as 3-aryl-1,4-benzoxazines and 2-arylquinolines was experimentally explored by using 1,1′-spirobiindane-7,7′-diol-derived chiral phosphoric acids as the catalyst. This method provides straightforward access to the corresponding tetrahydroquinolines and dihydro-2H-1,4-benzothiazines in high yields (85-99%) with excellent enantioselectivities (91-99%). The attractive features of this procedure, which include mild reaction conditions, operational simplicity, relatively low catalyst loading (1 mol-%), and high levels of enantioselectivities, make it a useful approach for the practical synthesis of optically active nitrogen-containing aromatic heterocycles.

Full text of DOI:10.1002/ejoc.201500330

FULL PAPER
DOI: 10.1002/ejoc.201500330
Highly Enantioselective SPINOL-Derived Phosphoric Acid Catalyzed Transfer
Hydrogenation of Diverse C=N-Containing Heterocycles
Yiliang Zhang,[a] Rong Zhao,[a] Robert Li-Yuan Bao,[a] and Lei Shi*[a]
Keywords: Asymmetric catalysis / Organocatalysis / Enantioselectivity / Hydrogenation / Fused-ring systems
A highly efficient and enantioselective hydrogenation of di-
versely substituted C=N-containing heterocyclic compounds
such as 3-aryl-1,4-benzoxazines and 2-arylquinolines was
experimentally explored by using 1,1Ј-spirobiindane-7,7Ј-
diol-derived chiral phosphoric acids as the catalyst. This
method provides straightforward access to the corresponding
tetrahydroquinolines and dihydro-2H-1,4-benzothiazines in
high yields (85–99%) with excellent enantioselectivities (91–
99%). The attractive features of this procedure, which in-
clude mild reaction conditions, operational simplicity, rela-
tively low catalyst loading (1 mol-%), and high levels of
enantioselectivities, make it a useful approach for the practi-
cal synthesis of optically active nitrogen-containing aromatic
heterocycles.
active pharmaceutical ingredients.[1] More noticeably, a
great deal of effort has been devoted to the development of
Introduction
Chiral nitrogen-containing aromatic heterocycles are im- stereoselective methods for the manufacture of highly en-
portant targets in synthetic organic chemistry. One of the antioenriched tetrahydroquinolines and dihydro-2H-1,4-
effective methods for their preparation is the asymmetric benzoxazines (Figure 1).[2] Despite significant progress in
transfer hydrogenation of the corresponding C=N-contain- this field, the asymmetric hydrogenation of C=N-contain-
ing heterocyclic compounds. In the past few decades, many ing heterocyclic compounds is still a promising research di-
researchers have specifically concentrated on the hydrogen- rection in the domain of organic synthesis and methodol-
ation of C=N-containing heterocyclic compounds, the cor- ogy.
responding products of which are the substructures or
With respect to asymmetric hydrogenation of quinoline
building blocks of many naturally occurring alkaloids and and benzoxazine derivatives, although many highly enantio-
Figure 1. Natural molecules and drugs containing a chiral 1,4-benzoxazine or quinoline scaffold.
[a] Institute of Organic Chemistry, The Academy of Fundamental
selective processes catalyzed by transition-metal complexes
and Interdisciplinary Sciences, Harbin Institute of Technology,
based on Ir,[3] Rh,[4] Ru,[5] and Pd[6] have been reported,
Harbin 150080, P. R. China
E-mail: lshi@hit.edu.cn
most of the papers fail to give satisfactory results for 2-aryl-
http://homepage.hit.edu.cn/pages/shilei
or heteroaryl-substituted quinolines and 3-aryl-1,4-benz-
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500330.
3344
oxazines. In particular, the groups of Zhou,[7] Beller,[8] Pa-
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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SPINOL-Based Catalytic Transfer Hydrogenation
til,[9] and Gong[10] successfully utilized metal/Brønsted acid asymmetric transfer hydrogenation of 2-aryl- and het-
binary catalytic systems[11] in asymmetric hydrogenation re- eroaryl-substituted quinolines and 3-aryl-1,4-benzoxazines.
actions to afford 2-aryltetrahydroquinolines and 3-aryl-di- To the best of our knowledge, there have been no reports
hydro-2H-1,4-benzo-xazines in good yields with good concerning the use of chiral SPINOL-derived phosphoric
enantioselectivities.
acid catalysts in asymmetric transfer hydrogenation of quin-
Small organic molecules have recently been shown to be olines and 1,4-benzoxazines.[29]
highly efficient and selective chiral catalysts for the enantio-
selective reduction of C=N bonds by using an organic
hydride source.[12] On the one hand, for asymmetric re-
duction of 1,4-benzoxazine derivatives, the combined re-
search groups of Wang and Sun[13] and Zhang[14] indepen-
dently implemented the targeted transformations by using
trichlorosilane as the reducing agent and a Lewis base as
the catalyst; this afforded good levels of enantioselectivities.
Figure 2. Chiral SPINOL-derived phosphoric acids.
Significant contributions to this topic have been disclosed
by the groups of Rueping,[15] Antilla,[16] Thomas,[17] Blech-
ert,[17,18] and Schmidt,[18] who found the combination of
chiral phosphoric acids based on the 1,1Ј-binaphthalene-
2,2Ј-diol (BINOL) skeleton and Hantzsch ester proved
useful for the highly enantioselective reduction of 1,4-benz-
oxazines. On the other hand, for the enantioselective
hydrogenation of quinoline derivatives, the first asymmetric
organocatalytic transfer hydrogenation of 2-substituted
quinolines was described by Rueping in 2006 in a system
with a Hantzsch ester as the hydride donor and 3,3Ј-disub-
stituted binaphthyl–phosphoric acids.[19] Later on, Du[20]
demonstrated the use of chiral phosphoric acid catalysts
based on the bis-BINOL scaffold for the reduction of 2-
substituted quinolines, in which high enantioselectivities up
to 98%ee were achieved with a practical catalyst loading
as low as 0.2 mol-%. Subsequently, the groups of Toste,[21]
Zhou,[22] Bousquet,[23] and Pélinski[23] reported the use of
BINOL-based phosphoric acids as catalysts in the asym-
metric organocatalytic hydrogenation of a range of quinol-
ine derivatives with good enantioselectivities. Almost at the
same time, the groups of Betzer and Marinetti,[24] Guinch-
ard and Voituriez,[25] and Zhang[26] individually investigated
the potential and efficiency of other organocatalysts to pro-
mote the analogous reactions with Hantzsch ester as the
stoichiometric hydride source, and in some cases,[24,25] mod-
erate enantioselectivities were observed. Clearly, each of
these aforementioned approaches has its own virtues, but
each suffers from a limited substrate scope, especially if 2-
aryl or heteroaryl-substituted quinolines and 3-aryl-1,4-
benzoxazines are employed as the reactants in the asymmet-
ric hydrogenation (see Schemes S1 and S2, Supporting In-
formation).
Results and Discussion
We started our research by analyzing the reactivity and
selectivity in the asymmetric hydrogenation of 1,4-benzox-
azine (2a) by using Hantzsch ester as the stoichiometric
hydride source in the presence of a catalytic amount of
SPINOL-derived phosphoric acid catalyst 1 (10 mol-%) at
60 °C. As can be seen in Table 1, 9-anthracenyl-substituted
SPINOL-derived phosphoric acid catalyst 1d performed ex-
ceptionally well in the model reaction; it provided expected
Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Solvent[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
(S)-1a
(S)-1b
(S)-1c
(S)-1d
(S)-1e
(S)-1f
(S)-1g
(S)-1d
(S)-1d
(S)-1d
(S)-1d
(S)-1d
(S)-1d
(S)-1d
(S)-1d
(S)-1d
(S)-1d
THF
THF
THF
THF
THF
THF
THF
THF
57
98
97
97
86
67
92
98
97
95
94
65
95
89
90
0
8
93
70
97
37
45
69
97
97
98
95
97
98
96
95
–
7
8[e]
9[f]
THF
10[f,g]
11[f,g]
12[f,g]
13[f]
14[f]
15[f,g]
16[f–h]
17[f,g,i]
CH2Cl2
CHCl3
CCl4
benzene
toluene
MTBE
CH2Cl2
CH2Cl2
Despite the fact that a number of chiral BINOL-based
phosphoric acids are known and have been used in the field
of organocatalysis over the past decade,[27] the search for
novel and efficient chiral phosphoric acids is still required
to satisfy the new needs of mankind for chiral compounds.
Recently, a relatively new class of chiral phosphoric acids
with a 1,1Ј-spirobiindane-7,7Ј-diol (SPINOL) scaffold was
developed and investigated by different research groups
with remarkable results.[28] To overcome the limited sub-
strate scope, we decided to apply the chiral SPINOL-de-
70
47
[a] Reaction conditions: 2a (0.1 mmol), 6 (1.3 equiv.), and 1
(10 mol-%) at 60 °C. [b] MTBE = methyl tert-butyl ether. [c] Yield
of isolated product after column chromatography. [d] Determined
by HPLC analysis by using a Chiralcel OD-H column. [e] Catalyst:
5 mol-%. [f] Catalyst: 1 mol-%. [g] At room temperature. [h] Tri-
chlorosilane was used as the hydride donor. [i] 2-Naphthylbenzothi-
rived phosphoric acid catalyst system (Figure 2) in the azoline was used as the hydride donor.
Eur. J. Org. Chem. 2015, 3344–3351
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Y. Zhang, R. Zhao, R. L.-Y. Bao, L. Shi
FULL PAPER
3-phenyl-dihydro-2H-benzoxazine 4a in 97% yield with solvent at room temperature for the asymmetric hydrogen-
97%ee (Table 1, entry 4). Notably, the catalyst loading was ation of 1,4-benzoxazine derivatives instead of benzene at
reduced from 10 to 1 mol-% without any loss in the yield 60 °C. Other organohydride donors such as trichlorosilane
or enantioselectivity (Table 1, entries 8 and 9). Having iden- and 2-naphthylbenzothiazoline were also examined to re-
tified catalyst 1d as our optimal catalyst, an extensive screen place Hantzsch ester; however, unsatisfactory result were
of the solvent was undertaken (Table 1, entries 10–15). The obtained, in that no product was formed (Table 1, entry 16)
enantioselectivity of the reaction sometimes depended on or only a moderate yield and low enantioselectivity were
the solvent polarity, and excellent enantioselectivities up to obtained (Table 1, entry 17).
98% were achieved in both dichloromethane and benzene.
With the optimized reaction conditions established, sub-
It would be more convenient to use dichloromethane as the stituted 1,4-benzoxazines 2a–t were used to investigate the
reaction scope; the results are summarized in Table 2. Vari-
ous substituents on the phenyl ring of 3-substituted 1,4-
benzoxazines did not have any detrimental effect on either
the yields or the enantioselectivities. Both electron-donating
groups (e.g., Me and OMe; see 2b, 2e, and 2f) and electron-
withdrawing groups (e.g., F, Cl, and Br; see 2c, 2d, 2g, 2h,
and 2k) on the phenyl ring of the 3-substituted 1,4-benzox-
azines were tolerated in this protocol. The corresponding
dihydro-2H-1,4-benzoxazines were furnished in good yields
with excellent enantioselectivities. Next, we examined the
influence of different substituents in the 6-position of the
1,4-benzoxazines towards the enantioselectivity. The intro-
duction of electron-donating or electron-withdrawing sub-
Table 2. Substrate scope of the transfer hydrogenation of 1,4-benz-
oxazines.[a]
Table 3. Substrate scope of the transfer hydrogenation of quinol-
ines.[a]
[a] Unless indicated otherwise, the reaction was performed on a
0.1 mmol scale under a nitrogen atmosphere in benzene at 60 °C
for 24 h; the ratio of 3:6 was 1:2.5, yields of the isolated product
are given, and the ee values were determined by HPLC. [b] Reac-
tions of 3b and 3d were catalyzed by 1 mol-% 1b.
[a] The reaction was performed on a 0.1 mmol scale under a nitro-
gen atmosphere in CH2Cl2 at r.t. for 24 h; the ratio of 2/6 was
1:1.25, yields of the isolated products are given, and the ee values
were determined by HPLC.
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SPINOL-Based Catalytic Transfer Hydrogenation
stituents in the 6-position had no definite effect on the ee cal structures of 2-arylquinolines 3 and 3-aryl-1,4-benzox-
values.
azines 2, catalyst 1d (1 mol-%) was used as the preferred
Asymmetric transfer hydrogenation of 2-arylquinolines 3 organocatalyst in the enantioselective reduction of 2-ar-
was subsequently explored, and the results are listed in ylquinolines 3. However, the corresponding hydrogenation
Table 3. Considering the significant similarity in the chemi- reactions were conducted in the nonpolar solvent benzene
Scheme 1. Substrate scope of other transfer hydrogenation reactions.
Scheme 2. Proposed catalytic cycle for the SPINOL-derived chiral phosphoric acid catalyzed hydrogenation of 3-aryl-1,4-benzoxazines 2.
Eur. J. Org. Chem. 2015, 3344–3351
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Y. Zhang, R. Zhao, R. L.-Y. Bao, L. Shi
FULL PAPER
at 60 °C, owing to poor solubility of quinolines in chlorin- 3d), modification of the substituents in the SPINOL-de-
ated solvents. Pleasingly, the reduction of 2-arylquinolines rived phosphoric acid catalyst from 9-anthracenyl groups
3 proceeded with similar enantiocontrol, and differently to less bulky 1-naphthyl groups significantly improved the
substituted 2-aryltetrahydroquinolines 5 bearing either elec- enantioselectivities to 99%ee, and this occurred together
tron-donating groups (e.g., tBu and OMe; see 5b, 5f, and with a clear increase in reactivity. Notably, the hydrogen-
5g) or electron-withdrawing groups (e.g., NO2 and F; see ation reaction of 2-(2-pyridine)quinoline (3k) did not occur
5h and 5i) on the phenyl ring were isolated in good yields under our optimized reaction conditions.
with excellent enantioselectivities. For the cases in which
With the successful achievement of the asymmetric
relatively low enantioselectivities were obtained (i.e., 3b and hydrogenation of 2-arylquinolines and 3-aryl-1,4-benzox-
Scheme 3. Proposed catalytic cycle for the SPINOL-derived chiral phosphoric acid catalyzed hydrogenation of 2-arylquinolines 3.
3348 Eur. J. Org. Chem. 2015, 3344–3351
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SPINOL-Based Catalytic Transfer Hydrogenation
azines, we further examined the performance of chiral the present study is by far the best in the asymmetric
SPINOL-derived phosphoric acid catalysts in the enantio- hydrogenation of 2-arylquinolines and 3-aryl-1,4-benzox
selective reduction of other analogous C=N-containing het- azines reported to date. The mild reaction conditions of this
erocyclic compounds, and the results are presented in asymmetric transfer hydrogenation of C=N-containing het-
Scheme 1. The reduction of 3-(4-methoxyphenyl)-2H-1,4- erocycles, its operational simplicity, and the relatively low
benzthiazine (2u) and 3-phenyl-2H-1,4-benzoxazin-2-one catalyst loading (1 mol-%) make this transformation one of
(2v) proceeded with similar enantiocontrol, and good the most convenient and general methods for the prepara-
enantioselectivities of 95 and 98% were obtained, respec- tion of optically active tetrahydroquinolines and dihydro-
tively. Moreover, upon using 2-(naphthalen-2-yl) quinoline 2H-1,4-benzothiazines, which are important structural units
1-oxide (3l) as the starting material, a slightly diminished present in many biologically active alkaloids and pharma-
enantioselectivity of 90% was observed. Last, but not least, ceutical intermediates.
we attempted to apply our SPINOL-derived phosphoric
acid catalyst system to the synthesis of the biologically
active tetrahydroquinoline alkaloid galipinine. Unfortu-
Experimental Section
General Method: All reactions were monitored by TLC and visual-
nately, the asymmetric transfer hydrogenation of corre-
sponding quinoline 3m only gave rise to moderate enantio-
selectivity by using Hantzsch ester as the hydride donor and
a loading as high as 10 mol-% of the 1-naphthyl-substituted
SPINOL-derived phosphoric acid as the catalyst. Further-
more, some Lewis acids[30] and Brønsted acids[31] were em-
ployed as additives (see Table S1, Supporting Information),
but they did not help to enhance the enantioselectivities.
On the basis of previous reports,[3c,7a,15a,19a,22] possible
mechanisms for the asymmetric hydrogenation of 2-aryl-
quinolines and 3-aryl-1,4-benzoxazines are depicted in
Schemes 2 and 3. The asymmetric hydrogenation of 1,4-
benzoxazines (Scheme 2) begins with the protonation of
cyclic imine 2 by SPINOL-derived chiral phosphoric acid
1, which results in the formation of chiral iminium/phos-
phate ion pair A. Subsequently, hydride transfer from
Hantzsch 1,4-dihydropyridines gives rise to corresponding
dihydro-2H-1,4-benzothiazines 4 and pyridinium salts B,
which further undergoes proton transfer to regenerate
SPINOL-derived chiral phosphoric acid 1 for the catalytic
cycle and affords Hantzsch pyridine 7. In this sequence,
SPINOL-derived chiral phosphoric acid 1 might behave as
a Lewis base/Brønsted acid bifunctional catalyst by engag-
ing in a hydrogen bond with cyclic imine 2 and in another
hydrogen bond with the N–H bond of Hantzsch ester 6.
Similarly, enantioselective reduction of 2-arylquinolines
(Scheme 3) involves a cascade transfer hydrogenation, in-
cluding 1,4-hydride addition to form enamine intermediate
8, enamine–imine isomerization by protonation, subsequent
1,2-hydride addition to furnish expected tetrahydroquinol-
ines 5, and final proton transfer to regenerate chiral catalyst
1.
ized by UV lamp (254/365 nm). Column chromatography was per-
1
formed by using 230–400 mesh silica gel. H NMR and 13C NMR
spectra were recorded with a Bruker AV-400 or Bruker AV-600
spectrometer in CDCl3 or [D6]DMSO. HRMS (ESI) was recorded
by using an Agilent 6520 accurate-Mass Q-TOF LC–MS system
(1200–6520/Agilent). Optical rotations were measured with an An-
ton Paar MCP 500 Polarimeter in a 1 dm cell. Melting points were
measured in open capillaries. The enantiomeric excesses were deter-
mined by HPLC analysis by using a Waters 2695 Series instrument
(column Daicel Co. CHIRALCEL OD-H; eluent: hexane/2-prop-
anol). The chiral HPLC methods were calibrated with the corre-
sponding racemic mixtures. Chemical yields refer to pure isolated
substances. Unless otherwise noted, commercially available com-
pounds were used as provided without further purification. Sol-
vents for chromatography were technical grade. The reaction sol-
vents, CH2Cl2 and benzene, were used without purification.
General Procedure for the Transfer Hydrogenation of Benzoxazines:
A 10 mL Schlenk tube was charged with the 3-aryl-1,4-benzoxazine
(0.1 mmol, 1 equiv.), Hantzsch ester (32 mg, 0.125 mmol,
1.25 equiv.), catalyst (1 mol-%), and CH2Cl2 (1 mL). The resulting
mixture was stirred at room temperature for 24 h. The solvent was
removed under reduced pressure, and purification of the crude
product by column chromatography on silica gel (petroleum ether/
ethyl acetate) afforded the pure product.
General Procedure for the Transfer Hydrogenation of Quinolines: A
10 mL Schlenk tube was charged with the 2-arylquinoline
(0.1 mmol, 1 equiv.), Hantzsch ester (64 mg, 0.25 mmol, 2.5 equiv.),
catalyst (1 mol-%), and benzene (1 mL). The resulting mixture was
stirred at 60 °C for 24 h. The solvent was removed under reduced
pressure, and purification of the crude product by column
chromatography on silica gel (petroleum ether/ethyl acetate) af-
forded the pure product.
Acknowledgments
The authors are grateful to the Harbin Institute of Technology
(HIT) (Hundred Talents Program), the National Natural Science
Foundation of China (NSFC) (grant number 21202027), the Pro-
gram for New Century Excellent Talents in University (NCET)
(NCET-12-0145), and the Ministry of Human Resources and So-
cial Security of China (MOHRSS) (Technology Foundation for Se-
lected Overseas Chinese Scholars) for providing financial support
for this research.
Conclusions
In summary, we successfully developed a highly efficient
SPINOL-derived chiral phosphoric acid catalyzed transfer
hydrogenation of various aryl-substituted 1,4-benzoxazines
and quinolines. The chiral phosphoric acids based on the
1,1Ј-spirobiindane-7,7Ј-diol framework were found to be
highly effective to access the corresponding dihydro-2H-1,4-
benzoxazines and tetrahydroquinolines in good yields with
excellent enantioselectivities. To the best of our knowledge,
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Received: March 11, 2015
Published Online: April 17, 2015
Eur. J. Org. Chem. 2015, 3344–3351
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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