Asymmetric hydrogenation of quinazolinium salts catalysed by halide-bridged dinuclear iridium complexes bearing chiral diphosphine ligands

Article abstract of DOI:10.1039/c5cc00258c

Asymmetric hydrogenation of quinazolinium salts was catalysed by halogen-bridged dinuclear iridium complexes bearing chiral diphosphine ligands, yielding tetrahydroquinazoline and 3,4-dihydroquinazoline with high enantioselectivity. A derivative of chiral dihydroquinazoline was used as a chiral NHC ligand. This journal is

Full text of DOI:10.1039/c5cc00258c

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Asymmetric hydrogenation of quinazolinium salts
catalysed by halide-bridged dinuclear iridium
complexes bearing chiral diphosphine ligands†
Cite this: Chem. Commun., 2015,
51, 4380
Received 11th January 2015,
Accepted 3rd February 2015
Yusuke Kita, Kosuke Higashida, Kenta Yamaji, Atsuhiro Iimuro and
Kazushi Mashima*
DOI: 10.1039/c5cc00258c
www.rsc.org/chemcomm
Asymmetric hydrogenation of quinazolinium salts was catalysed by asymmetric hydrogenation of quinazoline derivatives that
halogen-bridged dinuclear iridium complexes bearing chiral diphosphine afforded not only optically pure tetrahydroquinazolines as potential
ligands, yielding tetrahydroquinazoline and 3,4-dihydroquinazoline with a-adrenergic blockers that possess antiplatelet activity,8 but also
high enantioselectivity. A derivative of chiral dihydroquinazoline was dihydroquinazolines as potent T-type Ca2+ channel blockers.9
used as a chiral NHC ligand.
Here we report the first example of asymmetric hydrogenation of
quinazoline derivatives catalysed by dinuclear iridium complexes.
Asymmetric hydrogenation of N-heteroaromatics is a straight- Optically pure 3,4-dihydroquinazolines were used as potential
forward method of synthesizing enantiomerically pure substituted precursors of chiral NHC ligands.
N-heterocycles, which are synthetic skeletons abundant in many
We began by screening of solvents and catalysts for the asym-
biologically active compounds.1–3 Many efficient catalysts based on metric hydrogenation of 4-phenylquinozolinium chloride (2a-HCl)
ruthenium, iridium, rhodium, and palladium for the asymmetric under hydrogen pressure (30 bar) at 50 1C for 16 h (Table 1). Using
hydrogenation of N-hereroaromatics have been studied by designing (S)-1a as a catalyst, the reaction in toluene proceeded to give the
supporting chiral ligands4 and utilizing appropriate additives.1d,5 We desired 4-phenyl-1,2,3,4-tetrahydroquinazoline (3a) in 75% yield
developed our synthetic protocol using halogen-bridged dinuclear with 92% ee, along with 4-phenyl-3,4-dihydroquinazoline (4a) in
iridium complexes bearing chiral diphosphine ligands (Scheme 1) 22% yield (entry 1). When 1,4-dioxane, THF, isopropyl alcohol, and
for asymmetric hydrogenation of HCl salts of quinolines, isoquino- dichloromethane were used as solvents, almost the same high
lines, and pyridines to produce the corresponding optically active enantioselectivity (95–97% ee) with full conversion was observed
cyclic amines with excellent enantioselectivity.6 As a continuation of (entries 2–5). We selected dichloromethane as the solvent for
our studies of the asymmetric hydrogenation of N-heteroaromatic
compounds,7 here we focused our attention on developing the
Table 1 Optimisation studies of the asymmetric hydrogenation of 2a-HCla
Yield of
ee of
Yield of
Entry
Catalyst
Solvent
3ab (%)
3ac (%)
4ab (%)
1
2
3
4
5
6
7d
8
9
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1a
(S)-1b
(S)-1b
(S)-1c
(S)-1d
Toluene
1,4-Dioxane
THF
75
82
84
89
89
89
4
92
95
97
95
96
99
—
99
98
22
14
14
10
10
11
Trace
12
16
iPrOH
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Scheme 1 Halogen-bridged dinuclear iridium complexes bearing chiral
diphosphine ligands.
86
84
Department of Materials Engineering, Graduate School of Engineering Science,
Osaka University, Toyonaka, Osaka 560-8531, Japan.
a
Reaction conditions: a mixture of 2a-HCl (0.24 mmol), Ir catalyst
(2.4 mmol), and solvent (3 mL) under H2 pressure (30 bar) was heated at
E-mail: mashima@chem.es.osaka-u.ac.jp
50 1C for 16 h. Determined by 1H NMR analysis with phenanthrene as
b
† Electronic supplementary information (ESI) available: Experimental details and
characterization data. CCDC 1042856 and 1042857. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c5cc00258c
c
d
an internal standard. Determined by HPLC analysis. 2a was used as
a substrate.
4380 | Chem. Commun., 2015, 51, 4380--4382
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subsequent ligand screening. The iridium catalyst (S)-1b bearing
(S)-SEGPHOS furnished excellent enantioselectivity (99% ee) (entry 6).
In sharp contrast to the successful asymmetric hydrogenation
of 2a-HCl, asymmetric hydrogenation of 4-phenylquinazoline
(2a) under the best reaction conditions resulted in a low yield of
3a (4%) (entry 7), clearly indicating the advantages of the HCl
salt. Iridium catalysts (S)-1c and (S)-1d served as catalysts for the
hydrogenation with the same high performance as (S)-1b (entries 8
and 9). Thus, we selected (S)-1b as the optimal catalyst.
Having determined the optimized conditions using (S)-1b,
we next examined the effects of the counter anions of substrate
salts 2a-HX (Table 2). In sharp contrast to 2a-HCl (entry 1),
hydrogenation of 2a-HBr gave 4-phenyl-1,2-dihydroquinazoline
(5a) in 97% yield (entry 2). Even with a longer reaction time,
5a-HBr was not converted to 3a.10 The same tendency was
observed in the reaction of 2a-HI, which afforded a lower yield
Fig. 1 Time-course of conversion and yields in asymmetric hydrogena-
tion of 2a-HCl catalysed by (S)-1b.E: conversion of 2a-HCl, m: yield of 3a,
’: yield of 4a, K: yield of 5a.
of 5a (78%) (entry 3). The use of 2a-HNO3 resulted in low 4th position of the aryl group affected the distribution among
conversion (entry 4). These results indicated that the counter hydrogenated products. The reactions of 4-phenylquinazolinium
anions of the substrate salt clearly affected product distribu- salts substituted with trifluoromethyl and chloro groups were
tion. We previously demonstrated remarkable effects of the efficiently promoted by (S)-1b to give 3b and 3c in 82% and 87%
ClÀ of the substrate, which facilitated the reaction rate and enantio- yields, respectively, with excellent ee (entries 1 and 2). In these
selectivity for the asymmetric hydrogenation of isoquinolinium salts, cases, 5b and 5c were generated in 10% and 5% yields, respec-
and revealed that these ClÀ effects were due to the 6-membered tively, whereas no 5a was formed in the reaction of 2a-HCl. The
transition state including chloride coordination to an iridium center effects of the methoxy group were more noticeable; the yield of
and hydrogen bond between the chloride ligand and N–H proton of 3e decreased to 66% together with a significant increase in 4e
the substrate on the hydride attack of the iridium hydride complex to and 5e (entry 4). The reaction of the 4-phenylquinazolinium salt
the substrate salt.6c Thus, the HCl salt was selected as the optimal with meta- and ortho-methyl groups provided predominantly
salt substrate.
5f and 5g (entries 5 and 6). Substituents at the 6th and 7th
To gain further insight into the product distribution among positions markedly affected the distribution of these products:
3a, 4a, and 5a, we performed a time-course study of the asym- the 6,7-dimethoxy substrate was predominantly converted to 5k
metric hydrogenation of 2a-HCl under the optimized conditions (entry 10).
using (S)-1b. The conversion of 2a-HCl together with the yields of
When 4-isopropylquinazoline was transformed to the corres-
3a, 4a, and 5a plotted over the reaction time indicated that 5a ponding HCl salt by treatment with HCl, the aromaticity of the
was initially formed in conjunction with the conversion of pyrimidine ring was completely broken to form the salt of an
2a-HCl, and 3a formed immediately after 5 h. The initial enamine 2l-HCl, which was hydrogenated and underwent a
formation of 5a indicated that the 1,2-reduction occurred pre- basic work-up to give 4l selectively in 52% yield with 94% ee
ferentially as the first step, and then 5a was gradually consumed. (eqn (1)). Notably, the half-reduced product 4l was a precursor
The content of 4a simultaneously increased, reaching 11% after for the chiral NHC ligands. In fact, exposure of 4l to excess
40 h, presumably due to the stability of the HCl salt of 4a. The amounts of benzyl bromide to supply a conjugate acid of
isolated HCl salt of 4a was not readily hydrogenated (Fig. 1).
amidine, which was further treated with KOtBu/[IrCl(cod)2],
We investigated the scope and limitations of different 4- gave an Ir–NHC complex 6 in 20% yield.11
arylquinazolinium chlorides (Table 3). The substituent at the
Table 2 Screening of the counter anion of the quinazolinium salta
(1)
Entry Substrate Yield of 3ab (%) Yield of 4ab (%) Yield of 5ab (%)
In summary, we developed the asymmetric hydrogena-
tion of quinazolines using [{Ir(H)[(S)-segphos]}2(m-Cl)3]Cl
[(S)-1b] as the optimal catalyst and their HCl salts as sub-
strates to afford the corresponding 1,2,3,4-tetrahydroquin-
azolines in high enantiomeric excess along with dihydroquinazolines.
Time-course studies revealed that this reaction proceeded pre-
ferentially through the initial 1,2-reduction. 4-Isopropylquin-
azolinium chloride was selectively hydrogenated to give an
1
2
3
4
2a-HCl
2a-HBr
2a-HI
89
10
—
97
78
3
Trace
Trace
2
Trace
Trace
Trace
2a-HNO3
a
Reaction conditions: a mixture of 2a-HX (0.24 mmol), (S)-1b (2.4 mmol),
and CH2Cl2 (3 mL) under H2 pressure (30 bar) was heated at 50 1C for
b
16 h. Determined by 1H NMR analysis with phenanthrene as an
internal standard.
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Table 3 Ir-catalysed asymmetric hydrogenation of 2-HCla
Entry
R1
R2
R3
Yield of 3b (%)
ee of 3c (%)
Yield of 4d (%)
Yield of 5d (%)
1
2
3
4
H
H
H
H
H
H
H
H
2b-HCl
2c-HCl
2d-HCl
2e-HCl
82
87
81
66
99 (À)
499 (À)
97 (À)
6
7
10
5
8
2
98 (À)
14
20
5
H
H
2f-HCl
Trace
—
2
89
6
7
H
H
H
H
2g-HCl
2g-HCl
35
97 (À)
63
2
Not detected
94
Trace
—
8
9
10
Ph
Ph
Ph
Br
Cl
OMe
H
H
OMe
2i-HCl
2j-HCl
2k-HCl
89
78
96 (S)
97 (À)
—
6
2
Not detected
1
36
Not detected
Not detected
a
Reaction conditions: a mixture of 2-HCl (0.24 mmol), (S)-1b (2.4 mmol), and CH2Cl2 (3 mL) under H2 pressure (30 bar) was heated at 50 1C for 16 h.
b
c
d
Isolated yield. Determined by HPLC analysis. Determined by 1H NMR analysis with phenanthrene as an internal standard.
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This work was financially supported by The Core Research for
Evolutionary Science and Technology (CREST), program of the Japan
Science and Technology Agency (JST), a Grant-in Aid for Scientific
Research on Innovative Areas ‘‘Molecular Activation Directed toward
Straightforward Synthesis’’ from the Ministry of Education, Culture,
Sports, Science, and Technology (MEXT), Japan.
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4382 | Chem. Commun., 2015, 51, 4380--4382
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