Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctionalized Exocyclic C=C Bonds

Article abstract of DOI:10.1002/chem.201604298

An iridium-catalyzed asymmetric hydrogenation of unfunctionalized exocyclic C=C bonds was performed by using an axially flexible chiral phosphine–oxazoline ligand, providing the desired chiral 1-benzyl-2,3-dihydro-1H-indene products with up to 98 % ee (enantiomeric excess). This represents the first general hydrogenation of unfunctionalized exocyclic olefins with high selectivity reported thus far. The additive acetate ion plays an important role in the reaction's high enantioselectivity. The chiral product can be further transformed into key intermediates required for the synthesis of an important insecticide and a drug compound.

Full text of DOI:10.1002/chem.201604298

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Accepted Article
Title: Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctionalized
Exocyclic C=C Bonds
Authors: Jingzhao Xia, Guoqiang Yang, Ruijing Zhuge, Yangang Liu,
and Wanbin Zhang
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To be cited as: Chem. Eur. J. 10.1002/chem.201604298
Link to VoR: http://dx.doi.org/10.1002/chem.201604298
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Iridium-Catalyzed Asymmetric Hydrogenation of Unfunctionalized
Exocyclic C=C Bonds
Jingzhao Xia, Guoqiang Yang, Ruijing Zhuge, Yangang Liu, and Wanbin Zhang*
Abstract: An iridium-catalyzed asymmetric hydrogenation of
unfunctionalized exocyclic C=C bonds was achieved using an axially
flexible chiral phosphine-oxazoline ligand, providing the desired chiral
1-benzyl-2,3-dihydro-1H-indene products with up to 98% ee. This
represents the first general hydrogenation of unfunctionalized
exocyclic olefins with the highest selectivity reported thus far. The
additive acetate ion plays an important role in the reaction’s high
enantioselectivity. The chiral product can be further transformed to
key intermediates required for the synthesis of an important
insecticide and a drug compound.
iridium-catalyzed asymmetric hydrogenation of unfunctionalized
exocyclic benzofused five-membered olefins. Additionally, the
preparation of key intermediates required for the synthesis of an
insecticide and a drug compound from our chiral product is also
reported.
T
he enantioselective hydrogenation of unfunctionalized olefins
has been established as a direct and efficient method for the
preparation of optically active compounds.[1] Early successful
examples were reported by Buchwald and co-workers using chiral
metallocene complexes.[2] However, high catalyst loadings, long
reaction times and high catalyst sensitivity have limited
widespread application of this method. In 1997, Pfaltz discovered
that using a phosphine-oxazoline ligand (PHOX)[3] as a chiral
mimic of Crabtree’s catalyst[4] could enantioselectively reduce
unfunctionalized olefins, challenging substrates for ruthenium-
and rhodium-catalytic systems because of the absence of a
chelating group.[5,6] Iridium complexes bearing P,N-ligands,[7]
have attracted much attention due to their high activity and good
enantioselective control. Prompted by these groundbreaking
discoveries, hundreds of chiral iridium-based catalysts have been
developed and applied to the reduction of numerous
unfunctionalized alkenes.[1,7] However, although a considerable
number of reports have been published pertaining to the reduction
of unfunctionalized acyclic di-, tri-, and tetrasubstituted olefins, as
well as endocyclic olefins,[1,7,8] no general and efficient catalyst
system has been developed for the asymmetric hydrogenation of
unfunctionalized exocyclic olefins.[9]
Scheme 1. Important drugs possessing chiral 2,3-dihydro-1H-indene skeleton
and our method to prepare it.
Hydrogenation reaction conditions were conducted as listed
in Table 1. We commenced our investigations using 1a as the
model substrate and with 1.0 mol% of the (aS)-Ir/iPr-BiphPHOX
([Ir(L1)cod]BArF)[11] in different solvents under 40 bar of hydrogen.
The reactions were carried out at room temperature for 24 hours
(entries 1-6). Some common solvents often used in iridium-
catalyzed asymmetric hydrogenations gave the desired product
with full conversions and 37%-70% ees (entries 1-3). Conversions
decreased dramatically when the solvent was changed to 1,4-
dioxane or THF. We assumed that coordinating effects of the
solvents with the iridium deactivated the catalyst (entries 4-5).
Gratifyingly, 80% ee was achieved with toluene as a solvent, but
only 40% conversion was observed (entry 6). To drive the reaction
to completion, the hydrogen pressure was increased from 40 to
60 bar and full conversion was observed within 24 hours. Further
screening of solvents showed that o-xylene was the best solvent,
giving the desired product with 81% ee (entries 7-9). Under 60 bar
of H2, and using o-xylene as the solvent of choice, we explored
the effects of the ligands on the reaction. Firstly, the substitute on
the oxazoline ring was changed to a bulky tert-Bu group, giving
Due to the large number of chiral benzofused five-membered
rings encountered in pharmaceutical natural products and
intermediates of key bioactive drugs (Scheme 1),[10] synthetic
protocols for the straightforward and efficient construction of such
skeletons are highly desired. Herein, we report a highly efficient
[]
J. Xia, Prof. Dr. Y. Liu, Prof. Dr. W. Zhang
School of Pharmacy
Dr. G. Yang, R. Zhuge, Prof. Dr. W. Zhang
School of Chemistry and Chemical Engineering
Shanghai Jiao Tong University
800 Dongchuan Road, Shanghai 200240 (China)
E-mail: wanbin@sjtu.edu.cn
rise to
a sharp decrease in both catalytic activity and
Homepage: http://wanbin.sjtu.edu.cn
enantioselectivity (entry 10). A Bn substituent improved the
enantioselectivity slightly, but conversion decreased (entry 11).
The novel ligand L4 bearing a chiral indane-fused oxazoline gave
Supporting information for this article is given via a link at the end of
the document.
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the best result (entry 12). Other types of phosphine-oxazoline
ligands, such as tBu-PHOX (L5), planar-chiral mono-tBu-Ru-
PHOX (L6) and (aS)-tBu-BinaphPHOX (L7), were also screened.
Unfortunately, they also gave trace amounts of product (entries
13-15). To our delight, when 1 μL of AcOH was used as an
additive in the reaction, the hydrogenation also proceeded
smoothly and provided the best overall performance with full
conversion and 93% ee (entry 16). Previous studies by the Pfaltz
group have shown that the coordinating ion usually deactivates
the Ir-catalyst towards hydrogenation of unfunctionalized
olefins.[3d,3e] To detect results from the acetate ion or the proton of
AcOH, AcONa was also used as an additive (entry 17). The
results showed that the acetate ion plays a crucial role in
improving the ee with AcOH.
Table 1. Reaction optimization.[a]
With the optimized reaction conditions in hand, the
asymmetric hydrogenation of substituted (E)-1-benzylidene-2,3-
dihydro-1H-indene was conducted at room temperature using the
complex iridium-L4 ((aS)-Ir/In-BiphPHOX,1 mol%) in o-xylene (2
mL), under 60 bar of hydrogen for 24 hours (Table 2). Various
substrates 1 bearing unfunctionalized exocyclic double bonds
could be easily converted into chiral substituted 1-benzyl-2,3-
dihydro-1H-indenes 2. The R1 electron-withdrawing and electron-
donating groups had no effect on the conversion (entries 1-12).
Reduction of substrates bearing 4-Cl or 6-CH3 groups provided a
slightly lower enantioselectivity with 91% ee and 90% ee,
respectively (entries 2 and 9), whereas substrates bearing aryl
groups with 5-substituted electron-withdrawing F, Cl, Br
substituents, were all reduced with higher ees (entries 4-7). It is
worth noting that when the ratio of substrate/catalyst was 1000,
the reaction also proceeded smoothly within 48 hours with no loss
of enantioselectivity (entry 6). Di-substituted 5,6-(OMe)2 and 5,6-
Cl2 substrates[12] were also tested with our optimized conditions
affording their corresponding products with 93% ee and 98% ee,
respectively (entries 11 and 12). Substrates with substituents on
the R2 phenyl ring were also evaluated. With 2-Br as a substituent,
the enantiomeric ratio dramatically decreased with the desired
product being obtained with only 78% ee (entry 13). The
hydrogenation of other substrates in which substituents were
present on the R2 aryl ring also gave their corresponding products
with full conversion and 89%-92% ee (entries 14-19). The more
bulky substrate with a 2-naphthyl substituent was reduced with
97% ee (entry 20). Since substrates with unfunctionalized alkyl R2
groups cannot be prepared with the E-configuration in pure form,
substrates bearing hydroxymethyl or methoxymethyl R2 groups
were tested with our catalytic system. It was found that all of these
substrates could be hydrogenated with full conversions and poor
or moderate ee (entry 21 and 22). (Z)-3-Benzylidene-2,3-
dihydrobenzofuran could also be reduced with 93% ee (entry 23).
The reduction of a benzo-six membered substrate only gave its
corresponding product with 75% ee (entry 24). These results
represent the first highly asymmetric hydrogenation of cyclic
systems bearing unfunctionalized exocyclic C=C bonds to afford
benzo-five membered chiral compounds.
Entry
1
Solvent
CH2Cl2
Ligand[b]
L1
H2 (bar)
40
Conv.[%][c]
>99
>99
>99
28
ee [%][d]
37
55
70
73
--
2
ClCH2CH2Cl
benzene
1,4-dioxane
THF
L1
40
3
L1
40
4
L1
40
N.R.
40
5
L1
40
80
76
79
81
45
83
84
--
6
toluene
L1
40
>99
>99
>99
39
7
toluene
L1
60
8
m-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
L1
60
9
L1
60
10
11
12
13
14
15
16[e]
17[f]
L2
60
87
L3
60
>99
<5
L4
60
L5
60
<5
--
L6
60
<5
--
L7
60
>99
>99
93
91
L4
60
L4
60
[a] Reaction conditions: ratio of substrate/catalyst (S/C) = 100, 2 mL solvent.
[b] When L1~L4 are used, the axial chirality of catalysts is aS. [c] Determined
by 1H NMR spectroscopy. [d] Enantioselectivity was determined by HPLC
using a chiral Daicel column. [e] AcOH (1 μL, 0.34 equiv.) as an additive. [f]
AcONa (0.3 equiv.) as an additive.
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Table 2. Substrate scope.[a]
Entry
1
R1; R2
H; Ph
Product [2]
2a
Yield [%][b]
99
ee [%][c]
93
98
91
2
4-Cl; Ph
2b
2c
98
95
3
4-Br; Ph
99
96
4
5-F; Ph
2d
2e
98
96
5
5-Cl; Ph
6[d]
7
5-Cl; Ph
2e
98
96
97
98
5-Br; Ph
2f
96
92
8
6-Br; Ph
2g
2h
2i
97
90
9
6-CH3; Ph
6-OCH3; Ph
5,6-(OCH3)2; Ph
5,6-Cl2; Ph
H; 2-BrC6H4
H; 3-FC6H4
H; 3-ClC6H4
H; 3-CH3C6H4
H; 4-FC6H4
H; 4-ClC6H4
H; 4-CH3C6H4
H; 2-naphthyl
98
92
10
11
12[e]
13
14
15
16
17
18
19
20
21
96
93
2j
Scheme 2. Deuterium labelling study and asymmetric hydrogenation of
unfunctionalized (Z)-1a and endocyclic olefin.
97
98
2k
96
78
2l
It has been reported that the double bond of cyclic systems
with exocyclic-olefins can isomerize to the more stable internal
double bond in iridium-catalyzed hydrogenation reactions.[9a,13] To
determine if this occurred in our catalytic system (Scheme 2, a),
we conducted three experiments. The deuterium labelling study
showed that isomerization of the olefin did occur under our
hydrogenation conditions (Scheme 2, b), but that the α and α’
positions were the main deuterated sites. A control experiment
showed that hydrogenation of (Z)-1a gave 2a with very low ee and
with the opposite optical selectivity (Scheme 2, c). Deuterium
labelling D0.15 at the α’ position suggests that E-Z isomerization
may occur but that the high ee is not the result of hydrogenation
of the (Z)-isomer generated from (E)-1a. When endocyclic olefin
substrate 3 was hydrogenated under the standard asymmetric
catalytic conditions (Scheme 2, d), product 2a was also obtained
with very low ee and with the opposite optical selectivity. All of
these experiments suggest that the high enantioselectivities
observed in these reactions are a result of the hydrogenation of
the (E)-exocyclic olefin (For more mechanistic study, see SI file).
96
94
2m
2n
2o
2p
2q
2r
97
89
97
91
98
90
99
92
97
90
96
97
2s
98
96
22
78
2t
22
23
2u
96
99
93
75
2v
24
2w
To demonstrate the potential application of this simple and
highly efficient catalytic asymmetric hydrogenation, we prepared
a key intermediate required for the the synthesis of an
insectide.[10g] Our hydrogenated product was oxidatied with CrO3
under AcOH/H2O[14] with 58% yield and 93% ee, then reduced to
(1S,3R)-3-benzyl-2,3-dihydro-1H-inden-1-ol. Enantioselectivity
was retained with >20:1 d.r.. According to a patent,[10g] this
intermediate can be further transformed into a series of
insecticides (Scheme 3, a). An additional transformation was
[a] Reaction conditions: (aS)-Ir/In-BiphPHOX (1 mol%), 2 mL o-xylene,
AcOH (1 μL), 60 bar H2, r.t., 24 hours. [b] Isolated yields obtained by column
chromatography. [c] Enantioselectivity was determined by HPLC using a
chiral Daicel column. [d] The ratio of substrate/catalyst was 1000, 48 hours,
AcOH (10 μL, 5 μL/mL). [e] The absolute configuration of 2k was determined
by X-ray crystallographic analysis.[12]
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