Iridium-catalyzed Asymmetric Hydrogenation of Polycyclic Pyrrolo/Indolo[1,2-a]quinoxalines and Phenanthridines

Article abstract of DOI:10.1002/adsc.201701450

Owing to the dehydrogenative rearomatization of hydrogenation product and poisoning effect of nitrogen atom, asymmetric hydrogenation of polycyclic nitrogen-containing heteroaromatics is still a great challenge. Herein, through in situ protection of hydro

Full text of DOI:10.1002/adsc.201701450

Title: Iridium-catalyzed Asymmetric Hydrogenation of Polycyclic
Heteroaromatics, Pyrrolo/Indolo[1,2-a]quinoxalines and
Phenanthridines
Authors: Shu-Bo Hu, Xiao-Yong Zhai, Hong-Qiang Shen, and Yong-
Gui Zhou
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10.1002/adsc.201701450
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iridium-catalyzed Asymmetric Hydrogenation of Polycyclic
Pyrrolo/Indolo[1,2-a]quinoxalines and Phenanthridines
Shu-Bo Hu,a,b Xiao-Yong Zhai,a Hong-Qiang Shena and Yong-Gui Zhoua*
a
State Key Laboratory of Catalysis, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023,
P. R. China. E-mail: ygzhou@dicp.ac.cn.
University of Chinese Academy of Sciences, Beijing 100049, P. R. China
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Owing to the dehydrogenative rearomatization of Phenanthridines--has
hydrogenation product and poisoning effect of nitrogen providing
been
facile
successfully
access
developed,
to chiral
a
atom, asymmetric hydrogenation of polycyclic nitrogen- dihydropyrrolo/indolo[1,2-a]quinoxalines
and
containing heteroaromatics is still a great challenge. Herein, dihydrophenanthridines with up to 98% ee. The strategy
through in situ protection of hydrogenation products with features broad substrate scope, easy operation and potential
acetic anhydride to inhibit rearomatization and poisoning medicinal application.
effect,
hydrogenation
a
novel iridium- catalyzed enantioselective
of polycyclic nitrogen-containing
Keywords: Iridium; asymmetric hydrogenation; polycyclic
heteroaromatics; dehydrogenation rearomatization
heteroaromatics--pyrrolo/indolo[1,2-a] quinoxalines and
Despite these advances, exploring novel strategies to
synthesize optically pure DHPQ derivatives remains
highly desirable considering the demand for
constructing the absolute configuration of the
pharmacological active molecules grows rapidly to
maximize treatment effects or mitigate drug
toxicity.[6]
Asymmetric hydrogenation is one of the most
practical and straightforward methods to access chiral
cyclic molecules.[7] Recently, considerable progress
has been made in asymmetric hydrogenation of
unsaturated heterocycles containing a fused tri- or
tetracyclic skeleton.[8-11] Zhou and coworkers have
Introduction
Dihydropyrrolo[1,2-a]quinoxaline (DHPQ)[1] and
dihydrophenanthridine (DHPD)[2] skeletons possess
diverse biological and medicinal activities and have
proved to be effective regenerable biomimetic
hydrogen sources.[3] Thus, the syntheses of them are
very important although that would be full of
challenge due to its easy dehydrogenation. Racemic
DHPQ derivatives could serve as potent Nogo
receptor modulator (Scheme 1, A),[1f] promising
agricultural fungicide (B),[1d] potent cannsabinoid
type 1 receptor (CB1R) antagonist[1b] and have
exhibited anti-HIV[1e] as well as anticancer activities.
successfully hydrogenated
a
series of seven-
membered cyclic imines using chiral iridium
[1c]
For the DHPD units, they have demonstrated
catalyst.[8a-d] Then, the catalytic systems based on Pd,
[8e]
important biological activities[2] and could act as
immunosuppressant (C). To the best of our
knowledge, most of the synthetic methods to the
substituted 4,5-dihydropyrrolo[1,2-a]quinoxalines are
racemic[4] and the asymmetric methods are mainly
focused on the Pictet–Spengler-type (PS) reactions.[5]
Tian group[5a] synthesized 4-substituted DHPQ
derivatives for the first time in good
enantioselectivities utilizing chiral boron Lewis acid
catalyst; the subsequent syntheses of quaternary
stereocentered DHPQs were realized by using
Brønsted acid catalyst, whose substrate scope,
however, was limited to the activated ketones,
pyruvates[5b] and α-ketoamides,[5c] respectively; for
chiral phosphoramidate catalyzed PS reaction, the
enantioselective control was not satisfactory.[5d]
Rh,[8g] Ru[8h] catalyst were also described.
However, fused tricyclic and tetracyclic nitrogen-
containing heteroaromatics are more challenging
substrates than fused polycyclic imines. The key
obstacles might lie in control of stereoselectivity and
chemoselectivity, aromaticity, coordination of
nitrogen atom in substrates as well as in products and
the lability of the hydrogenation products (Scheme
1).[7c,g,k] To the best of our knowledge, among the
fused polycyclic heteroaromatics, only substituted
1,10-phenanthroline and phenanthridine derivatives
have been successfully hydrogenated.[9-11] To a
certain extent the bidentate coordination of 1,10-
phenanthroline substrates to transition-metal might
aggravate the poisoning effects. In 2008, Metallinos
group reported asymmetric reduction of 2- and 2,9-
1
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10.1002/adsc.201701450
Advanced Synthesis & Catalysis
substituted 1,10-phenanthrolines using the chiral
BINOL-derived phosphoric acid as catalyst.[9]
However, the chemoselectivity, enantioselectivity,
diastereoselectivity or reactivity is not ideal.
Subsequently, Fan and co-workers developed the
chiral cationic ruthenium diamine catalyzed enantio-
and diastereoselective hydrogenation of substituted
1,10-phenanthrolines, providing the chiral tetrahydro-
1,10-phenanthrolines and octahydrophenanthrolines
with high stereoselectivities.[10] Very recently, Chen,
Yang and Fan realized asymmetric hydrogenation of
phenanthridines with the same ruthenium catalytic
system with up to 92% ee.[11] However, the
asymmetric hydrogenation of aryl-substituted
phenanthridines did not happen. Thus, development
of a general efficient method is still desirable. Herein,
through in situ protection of hydrogenation products
with acetic anhydride to inhibit rearomatization, a
highly enantioselective iridium-catalyzed asymmetric
hydrogenation of pyrrolo/indolo[1,2-a]quinoxalines
and phenanthridines was developed, giving the chiral
DHPQs, dihydroindolo[1,2-a]quinoxalines (DHIQs)
and DHPDs with up to 98% ee.
disappointment, there was no further increase in
enantioselectivity by screening other common
solvents and ligands (entries 6-11). When we
increased the catalyst loading and reduced reaction
temperature, no obvious improvement in conversion
and enantioselectivity was observed (entries 12-13).
Table 1. Condition optimizationa)
Conv.
(%)b)
Ee
Entry Additive Solvent
Ligand
(%)c)
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L1
L1
25
65
64
67
82
32
42
71
87
77
69
80
82
90
96
90
86
94
92
93
90
80
90
85
94
95
1
2
3
4
5
6
7
8
--
I2
THF
THF
THF
THF
NBS
NCS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
THF
toluene
CH2Cl2
dioxane
THF
THF
THF
9
10
11
12d) NIS
THF
THF
13e) NIS
a)
Reaction conditions: 1a (0.20 mmol), [Ir(COD)Cl]2 (1.0
mol %), L (2.2 mol %), additive (3.0 mol %), solvent (3.0
b)
mL), H2 (600 psi), 40 °C, 24 h. Determined by 1H NMR
c)
d)
o
e)
spectroscopy. Determined by chiral HPLC. 30 C.
[Ir(COD)Cl]2 (1.5 mol %), L1 (3.3 mol %), NIS (4.5
mol %), 30 oC.
Scheme 1. Some examples of bioactive compounds and
challenges in asymmetric hydrogenation of pyrrolo[1,2-a]-
quinoxalines.
Considering the easy dehydrogenation property of
hydrogenation product DHPQ,[3j] we imagined that an
equilibrium between hydrogenation of 1a and
rearomatization of 2 may exist. Then, a control
experiment was performed. We got 25% of 1a in the
above standard hydrogenation condition and the ee
value of the recovered 2 was 14% (Scheme 2, Eq 1).
Then some isotopic labeling experiments for both the
hydrogenation of 1a and the rearomatization of 2 was
Results and Discussion
Initially,
we
chose
4-phenylpyrrolo[1,2-
a]quinoxaline (1a) as model substrate for direct
asymmetric hydrogenation and the results of
condition optimization were depicted in Table 1. To
our delight, the desired hydrogenation product 4-
phenyl-4,5-dihydropyrrolo[1,2-a]quinoxaline (2) was
obtained in 90% ee albeit with low conversion (25%,
entry 1). In view of the performance of halogen
o
carried out in D2 at 40 C for 4 days (Eq 2 vs Eq 3).
The conversion of 1a was over 95% and the
deuterium content at the C4 position was over 95%.
When racemic 2 was conducted in the same
conditions above, only 6% of 1a was obtained and
the ee value of the recovered 2 was 7%. These
results revealed that an equilibrium between
hydrogenation and rearomatization indeed happened
and iridium catalyst played dual roles as both
additives
in
iridium-catalyzed
asymmetric
hydrogenation,[12] effects of halogen additives on
reactivity and enantioselectivity were examined and
obvious improvement in reactivity was observed
(entries 2-5). Among the screened additives, N-
iodosuccinimide (NIS) was the best considering both
the reactivity and enantioselectivity with 82%
conversion and 94% ee (entry 5). To our
hydrogenation
catalyst
However,
and
the
dehydrogenation
dehydrogenative
catalyst.[13]
2
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10.1002/adsc.201701450
Advanced Synthesis & Catalysis
Yield
Ee
Yield
Ee
rearomatization of 2 proceeds slowly in the
hydrogenation conditions. Considering that 4,5-
dihydropyrrolo[1,2-a]quinoxalines are sensitive to the
atmosphere and could rearomatize to the
corresponding pyrrolo[1,2-a]quinoxalines,[5d] the
dehydrogenative rearomatization of 2 experiments in
air were carried out (Eq 4). When the tetrahydrofuran
solution of 2 was stirred in air for 2 hours, 21% of 1a
was furnished. The oxidation of 2 gets slower and
slower with time. Since 2 could be easily converted
to the acetyl protected 3a without any loss of
enantioselectivity,[5d] we attempted to introduce
acetyl in situ protection to 2 through addition of
acetic anhydride (Ac2O) to inhibit the reversible
rearomatization process and make the reaction easier
to operate.
Entry
x
(2)b)
(2)c)
(3a)b)
(3a)c)
1.1
2.0
4.0
4.0
75%
61%
52%
<5%
93%
95%
96%
--
11%
28%
37%
>95%
96%
96%
96%
96%
1
2
3
4d)
a)
Reaction conditions: 1a (0.20 mmol), [Ir(COD)Cl]2 (1.5
mol %), L1 (3.3 mol %), NIS (4.5 mol %), THF (3.0 mL),
b)
1
H2 (600 psi), 30 °C, 24 h.
Determined by H NMR
spectroscopy. c) Determined by chiral HPLC. d) 48 h.
The optimized catalytic system could be extended
to a series of pyrrolo[1,2-a]quinoxalines, affording
the corresponding 5-acetyl-4,5-dihydropyrrolo[1,2-
a]quinoxalines in up to 97% ee and 99% yield (Table
3). The asymmetric hydrogenation of pyrrolo[1,2-
a]quinoxalines containing a fluorine atom at ortho-,
meta- and para-position of 4-aryl substituent were
also conducted (entries 2-4). The reactivity was
slightly decreased when the fluorine at the ortho-
position and the enantioselectivity was slightly lower
when the fluorine at the para-position. The electron
properties of the substrates had negligible influence
on the stereocontrol in the hydrogenation reaction
(entries 4-9). No matter electron-withdrawing or
electron-donating groups at the para-position of 4-
aryl substituent, excellent enantioselectivities (95-
96%) were obtained. To our surprise, for the substrate
1j, moderate reactivity and high enantioselectivity
were observed (entry 10). The reason of low yield
mainly is the direct hydogenation product could not
be protected totally in the standard conditions and
there was about 20% of substrate 1j remained.
However, the pyrrolo[1,2-a]quinoxaline 1k bearing a
methyl at the meta-position of 4-aryl substituent was
successfully hydrogenated with high reactivity and
enantioselectivity (entry 11). Introducing a methyl or
chloride to the 7-position of pyrrolo[1,2-
a]quinoxaline, the reaction proceeded smoothly both
with 96% ee (entries 12-13). For 4-alkyl substituted
substrates, moderate to good enantioselectivities were
given and relatively large steric hindrance group
avails to the enantioselectivity (entries 14-17). In
general, the enantiocontrol of aryl substituted
substrates is better than that of substrates bearing
alkyl groups. The π-stacking interaction between the
aryl substituted substrate and the chiral catalyst might
be responsible for the phenomena. The absolute
configuration of 3a was determined to be S based on
single-crystal X-ray analysis (Figure 1).
Scheme 2. Rearomatization experiments of 2.
As shown in Table 2, Ac2O was added to the
reaction and it possessed good compatibility with the
iridium catalytic system, which exhibited slightly
better stereocontrol. However, some substrate 1a was
still remaining and compound 2 could not be
protected completely by increasing the amounts of
Ac2O (entries 1-3). When we prolonged the reaction
time to 48 hours, the substrate 1a could be totally
converted. Thus, the optimal conditions were finally
established as: [Ir(COD)Cl]2/L1/NIS/Ac2O/THF/30
oC/48 h.
Table 3. Substrate scope: pyrrolo[1,2-a]quinoxalinesa)
Table 2. Further condition optimizationa)
Entry
R
C6H5
2-FC6H4
3-FC6H4
R’ Yield (%)b) Ee (%)c)
1
2
3
H
H
H
96 (3a)
90 (3b)
98 (3c)
96 (S)d)
97 (+)
97 (+)
3
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10.1002/adsc.201701450
Advanced Synthesis & Catalysis
4
5
6
7
8
9
10
11
12
13
14
15
16
4-FC6H4
4-ClC6H4
4-BrC6H4
4-F3CC6H4
4-MeOCOC6H4
4-MeOC6H4
4-MeC6H4
3-MeC6H4
C6H5
H
H
H
H
H
H
H
H
98 (3d)
94 (3e)
94 (3f)
98 (3g)
99 (3h)
99 (3i)
53 (3j)
97 (3k)
95 (+)
96 (+)
96 (+)
96 (+)
96 (+)
95 (+)
95 (+)
95 (+)
96 (+)
96 (+)
37 (+)
55 (+)
87 (+)
86 (+)
As given in Table 4, phenanthridines are also
suitable substrates under the above optimal
conditions. It is noteworthy that the phenanthridines
bearing aryl groups were also well hydrogenated,
providing the corresponding DHPDs with excellent
yields (98-99%) and ee values (97-98%) (entries 1-3).
These substrates could not be hydrogenated utilizing
chiral cationic ruthenium diamine catalytic system[11]
Me 97 (3l)
Cl 90 (3m)
H
H
H
H
and the catalytic system herein provides
a
C6H5
complementary strategy. In addition, the asymmetric
hydrogenation of substrates bearing alkyl groups
could also proceed smoothly in moderate
enantioselectivities (entries 4-6). The absolute
configuration of 7b was also determined to be S
based on single-crystal X-ray analysis (Figure 2).
Me
99 (3n)
97 (3o)
93 (3p)
96 (3q)
nPr
iPr
17
Cy
a)
Reaction conditions: 1 (0.30 mmol), [Ir(COD)Cl]2 (1.5
mol %), L1 (3.3 mol %), NIS (4.5 mol %), Ac2O (4.0 eq.),
Table 4. Substrate scope: phenanthridinesa)
THF (3.0 mL), H2 (600 psi), 30 oC, 48 h. b) Isolated yield. c)
d)
Determined by chiral HPLC.
The CCDC number is
1579062. These details can be obtained free of charge via
www.ccdc.com.ac.uk/ data_request/cif from the
Cambridge Crystallographic Data Centre.
Entry
R
C6H5
4-ClC6H4
4-MeOC6H4
Bn
R’
H
H
H
H
H
Yield (%)b) Ee (%)c)
1
2
3
4
5
6
98 (7a)
98 (7b)
99 (7c)
98 (7d)
93 (7e)
98 (+)
98 (S)d)
97 (+)
78 (+)
73 (+)
62 (+)
Me
Me
MeO 98 (7f)
a)
Reaction conditions: 6 (0.30 mmol), [Ir(COD)Cl]2 (1.5
mol %), L1 (3.3 mol %), NIS (4.5 mol %), Ac2O (4.0 eq.),
THF (3.0 mL), H2 (600 psi), 30 oC, 48 h. b) Isolated yield. c)
d)
Determined by chiral HPLC.
The CCDC number is
1579064. These details can be obtained free of charge via
www.ccdc.com.ac.uk/data_request/cif from the Cambridge
Crystallographic Data Centre.
Figure 1. X-ray crystal structure of compound (S)-3a.
To further define the substrate scope, the fused
tetracyclic indolo[1,2-a]quinoxalines were also
investigated,
98-99%
yields
and
96-97%
enantioselectivities could be obtained under the
optimal conditions (Scheme 3). The indolo[1,2-
a]quinoxaline 4 with an electron-deficient or an
electron-donating group could be hydrogenated
smoothly in a high enantioselective performance
manner.
Figure 2. X-ray crystal structure of compound (S)-7b.
To further exhibit the practicality of this
methodology, a 4.2 mmol reaction of 1a was
conducted to provide 1.101 g of 3a in 91% yield and
96% ee without loss of enantioselectivity using 1
mol% of [Ir(COD)Cl]2 (28.2 mg) and 2.2 mol% of
(S)-SynPhos (59.0 mg) (Scheme 4, Eq. 3). Besides,
Scheme 3. Substrate scope: indolo[1,2-a]quinoxalines.
4
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10.1002/adsc.201701450
Advanced Synthesis & Catalysis
Experimental Section
when the chiral 3a was dealt with different amounts
of
N-bromosuccinimide
(NBS),
both
General Procedure: Asymmetric Hydrogenation of
Pyrrolo[1,2-a]quinoxalines 1
monobrominated product 8 and dibrominated product
9 were furnished (Eq. 4). The introduction of bromine
offered opportunities for further diversification.
Notably, amides 8 and 9 could not be synthesized by
asymmetric hydrogenation of the corresponding
pyrrolo[1,2-a]quinoxalines due to the lability of 8 and
9. Meanwhile, the acetyl group can be effectively
removed using Schwartz reagent without any
epimerization (Eq. 5).[14] According to the known
methods, formal synthesis of CB1R antagonist 11
could be realized after deacetylation of 3e, which
provides an alternative method to prepare chiral
potent cannabinoid 1 receptor antagonists (Eq. 6).[1b]
A mixture of [Ir(COD)Cl]2 (3.0 mg, 0.0045 mmol) and
(S)-SynPhos (L1, 6.3 mg, 0.0099 mmol) was stirred in
tetrahydrofuran (1.0 mL) at room temperature for 5 min in
the glove box. Then the catalyst solution together with
tetrahydrofuran (1.0 mL) was transferred to the vial
containing N-iodosucciniodimide (NIS) (3.0 mg, 0.0135
mmol). After stirring for 5 min, the mixture was
transferred to the vial containing the substrate 1 (0.3 mmol)
together with tetrahydrofuran (1.0 mL) and then acetic
anhydride (112 μL, 1.2 mmol) was added. The vial was
taken to an autoclave and the hydrogenation was
o
conducted at 30 C as well as at a hydrogen pressure of
600 psi for 48 h. After carefully releasing the hydrogen,
the autoclave was opened. The solution was made alkaline
with saturated aqueous sodium carbonate and then
extracted with dichloromethane (10 mL3). The organic
layer was dried over anhydrous sodium sulfate, filtered and
evaporated under reduced pressure. The residue was
purified by column chromatography using hexanes/ethyl
acetate to afford the corresponding product 3.
Acknowledgements
Financial support from National Natural Science Foundation of
China (21532006, 21690074) and Dalian Institute of Chemical
Physics (DMTO201501) is acknowledged.
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In summary, we have developed an efficient
strategy for syntheses of fused tricyclic and
tetracyclic dihydropyrrolo/-indolo[1,2-a]quinoxalines
via asymmetric hydrogenation of pyrrolo- and
indolo[1,2-a]quinoxalines with up to 97% ee. Besides,
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products. Furthermore, by demonstrating the
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physiological and biological skeletons, we have
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10.1002/adsc.201701450
Advanced Synthesis & Catalysis
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10.1002/adsc.201701450
Advanced Synthesis & Catalysis
FULL PAPER
Iridium-catalyzed Asymmetric Hydrogenation of
Polycyclic Pyrrolo/Indolo[1,2-a]quinoxalines and
Phenanthridines
TOC Graphic
Adv. Synth. Catal. Year, Volume, Page – Page
Shu-Bo Hu, Xiao-Yong Zhai, Hong-Qiang Shen
and Yong-Gui Zhou*
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