Iridium-catalyzed asymmetric hydrogenation of 2-substituted 1,4-benzodioxines

Article abstract of DOI:10.1016/j.tet.2017.12.015

An Ir-catalyzed asymmetric hydrogenation of 2-substituted 1,4-benzodioxines was developed for the preparation of chiral 1,4-benzodioxanes, which are present in numerous biologically active compounds and natural products. Our tropos biphenyl phosphine-oxazoline ligand is essential for obtaining good ee. A broad range of substrates were tolerable to the reaction conditions and gave the corresponding hydrogenation products in excellent yields and with moderate to good enantioselectivities using the Ir-complex of our tropos phosphine-oxazoline ligand.

Full text of DOI:10.1016/j.tet.2017.12.015

Tetrahedron xxx (2017) 1e6
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Iridium-catalyzed asymmetric hydrogenation of 2-substituted 1,4-
benzodioxines
,
, b, *
Yanzhao Wang a, Jingzhao Xia b, Guoqiang Yang a **, Wanbin Zhang a
a Shanghai Key Laboratory for Molecular Engineering of Chiral Drugs, School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, 800
Dongchuan Road, Shanghai, 200240, China
b School of Pharmacy, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An Ir-catalyzed asymmetric hydrogenation of 2-substituted 1,4-benzodioxines was developed for the
preparation of chiral 1,4-benzodioxanes, which are present in numerous biologically active compounds
and natural products. Our tropos biphenyl phosphine-oxazoline ligand is essential for obtaining good ee.
A broad range of substrates were tolerable to the reaction conditions and gave the corresponding
hydrogenation products in excellent yields and with moderate to good enantioselectivities using the
Ir-complex of our tropos phosphine-oxazoline ligand.
Received 18 October 2017
Received in revised form
2 December 2017
Accepted 8 December 2017
Available online xxx
© 2017 Elsevier Ltd. All rights reserved.
Keywords:
Asymmetric hydrogenation
Iridium
Tropos phosphine-oxazoline ligand
2-Substituted 1,4-benzodioxines
Chiral 1,4-benzodioxanes
1. Introduction
amounts of chirality inducing reagents which are not efficient with
regards to atom economy.2
The 1,4-benzodioxane framework has attracted considerable
interest because it is a core structural motif in a variety of biologi-
cally active compounds and natural products (Fig. 1).1 For example,
It is well-known that the asymmetric catalysis of suitable
substrates is an efficient approach towards the synthesis of chiral
1,4-benzodioxanes, with clear advantages with regards to struc-
tural diversity and the ability to use only amounts of a chiral
source. Asymmetric allylic substitution has been utilized for the
preparation of chiral 2-vinyl-1,4-benzodioxanes by several
groups.3 Recently, two newly developed enantioselective reactions
for the construction of this chiral skeleton have been reported
(Scheme 1).4,5 The Cai group reported a Pd-catalyzed asymmetric
desymmetrization of diols to form chiral 1,4-benzodioxanes
bearing a hydroxymethyl group at the 2-position.4 Tang et al.
developed an asymmetric alkene aryloxyarylation catalyzed by a
Pd/Antphos catalyst system, yielding chiral 1,4-benzodioxanes
possessing tetrasubstituted carbon stereocenters.5 However, the
preparation of chiral 2-aryl-1,4-benzodioxanes using these two
methodologies has not been reported using asymmetric catalysis.
Asymmetric hydrogenation has attracted considerable attention
since the advent of asymmetric catalysis.6 Although Ir-catalyzed
asymmetric hydrogenation was developed later than Rh and Ru-
catalysis, such catalyst systems have gained popularity due to
their ability to catalyze the asymmetric hydrogenation of
unfunctionalized olefins.7 Ir-catalyzed asymmetric hydrogenation
Piperoxan is an
a-adrenergic blocking agent with considerable
stimulating activity and is used to diagnose pheochromocytoma and
also acts as an antihypertension agent.1a 2-Aryl-1,4-benzodioxanes
are subunits of this structure and exhibit important bioactivity.
Skeleton 4 belongs to a class of leuketriiene A4 hydrolase inhibitor
compounds.1b Isovanillyl sweetening agents,1c which are 500 times
sweeter than sucrose, also contain the 1,4-benzodioxine moiety.
Numerous lignans also containing the 2-aryl-1,4-benzodioxane
nucleus represent a class of natural products with cytotoxic and
hepatoprotective activities.1d-f Therefore, reliable and efficient syn-
thetic methodologies for the preparation of these chiral skeletons
are highly desired. However, most of the present synthetic meth-
odologies rely on the use of chiral starting materials or large
* Corresponding author. School of Chemistry and Chemical Engineering,
Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai, 200240, China.
** Corresponding author.
E-mail addresses: gqyang@sjtu.edu.cn (G. Yang), wanbin@sjtu.edu.cn
(W. Zhang).
https://doi.org/10.1016/j.tet.2017.12.015
0040-4020/© 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Wang Y, et al., Iridium-catalyzed asymmetric hydrogenation of 2-substituted 1,4-benzodioxines, Tetrahedron
(2017), https://doi.org/10.1016/j.tet.2017.12.015

2
Y. Wang et al. / Tetrahedron xxx (2017) 1e6
Table 1
Reaction optimization.a
Entry
Solvent
Ligand
Yield (%)b
ee (%)c
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCE
L1
L2
L3
L4
L5
L6
L7
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
L8
trace
>99
17
>99
>99
91
>99
>99
>99
NDk
NRk
NRk
>99
>99
91
e
ꢀ82
ꢀ10
ꢀ83
5
81
70
90
88
e
Fig. 1. Example compounds containing the 1,4-benzodioxane fragment.
9
10
11
12
13d
14e
15f
16g
17h
18i
19j
Toluene
THF
e
MeOH
DCM
DCM
DCM
DCM
DCM
DCM
DCM
e
90
90
88
90
e
87
NDk
66
88
e
NDk
a
Reaction conditions: ratio of substrate/catalyst (S/C) ¼ 100, 2 mL solvent, H2
(50 bar).
b
c
d
e
f
Determined by 1H NMR spectroscopy.
Enantioselectivity was determined by HPLC using a chiral column.
H2 (20 bar).
H2 (10 bar).
H2 (5 bar).
4Å MS (50 mg) as an additive.
HOAc (0.1 equiv.) as an additive.
Na2CO3 (0.1 equiv.) as an additive.
I2 (0.1 equiv.) as an additive.
Scheme 1. Synthesis of chiral 1,4-benzodioxane via asymmetric catalysis.
g
h
i
of cyclic compounds has become an efficient protocol for the
synthesis of chiral cyclic compounds.6i,8 The Ir-catalyzed asym-
metric hydrogenation of 2-substituted 1,4-benzodioxines provides
an attractive route to the preparation of chiral 2-aryl-1,4-
benzodioxanes. Herein, we report such a methodology using an
Ir-complex of our chiral axially-unfixed biphenyl phosphine-
oxazoline ligand (Scheme 1).9
j
2. Results and discussion
2-Substituted 1,4-benzodioxines could be prepared easily in 3
steps from 1,4-benzodioxane.10 After a photo-induced dibromina-
tion and an elimination reaction, compound 7 could be prepared in
large quantities. Cross-coupling of 7 with a series of arylboronic
acids gave different 2-substituted 1,4-benzodioxines in moderate to
high yields (Scheme 2).
Our study began with the asymmetric hydrogenation of 2-phenyl
1,4-benzodioxines 8a (Table 1). Firstly, different Ir-complexes of
different phosphine-oxazoline ligands were screened (entries 1e8).
k
ND ¼ a complex mixture not determined; NR ¼ no reaction.
The type of ligand greatly influences this catalytic reaction (entries
2e8). When planar chiral ruthenocene-derived P-N ligands were
used,11 ligands bearing the sterically bulky tBu group on the
oxazoline ring(s) gave hydrogenated product 9a in excellent con-
version and good ee, while those bearing an iPr group exhibited poor
catalytic activity and enantio-inducing ability (entry 2 vs 1, 4 vs 3).
Ligands bearing bis-(phosphine-oxazoline) groups provided similar
behaviour to those bearing a mono-(phosphine-oxazoline) moiety
(entry 1 vs 3, 2 vs 4). This suggests that these two (phosphine-oxa-
zoline) functionalities present in L3 and L4 do not interact with each
Scheme 2. Synthesis of substrates.
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Y. Wang et al. / Tetrahedron xxx (2017) 1e6
3
other. The well-known ligand, tBu-Phox, also afforded the desired
product in high conversion but with very low ee (entry 5). These
results suggest that the planar chirality that is present in ligands L2
and L4 is important for obtaining good results in the hydrogenation
reaction. Further screening of ligands bearing a biphenyl backbone
developed by our group exhibit another interesting phenomenon;
the axially-chiral backbone also has a significant influence on this
reaction and possesses the opposite enantio-inducing ability
compared to ligands bearing a planar chiral backbone. Ligands L6-L8
gave the reduced product 9a in excellent conversions with 70e90%
ees. The effect of the substituents on the oxazoline rings of L6-L8 on
ee also differs from the planar chiral ligands L1-L4. Ligand L6 bearing
an iPr on the oxazoline gave product 9a with better ee than that of L7
bearing a tBu group (entry 6 vs 7). The best ee was obtained with the
Ir-complex of ligand L8 bearing a chiral indane-fused oxazoline
(entry 8). The above results indicate that the backbones of the
phosphine-oxazoline ligands have a dramatic effect on the configu-
ration of the hydrogenation product (L2 vs L5 vs L7). Different
solvents were also tested. Hydrogenation in the solvent DCE afforded
9a with a similar result to that of carrying out the hydrogenation in
DCM (entry 9). Other solvents, such as MeOH, EtOH, and toluene, did
not give the desired product or gave a complex mixture (entries
10e12). Different hydrogen pressures were also investigated, and the
optimal pressure was found to be 10 bar (entries 13e15). The addi-
tion of additives, including 4 Å molecular sieves, acids, bases and I2,
did not further improve the ee. Therefore, the best conditions were
found to be using [Ir(L8)COD]BArF as a catalyst precursor and
carrying out the reaction under 10 bar of hydrogen in DCM solvent at
room temperature for 12 h.
With the optimized conditions in hand, different 2-substituted
1,4-benzodioxines were examined, as shown in Scheme 3. The
results showed that substrates bearing both electron-rich and
electron-neutral mono-substituted aryl groups gave the corre-
sponding products with excellent yields and with almost identical
enantioselectivities (Scheme 3, 9a-9i). However, increasing the
electron-withdrawing ability of the substituents on the phenyl
group led to a concomitant decrease in ee (9j-9o). Substrate bearing
a OMe group at the ortho position gave its corresponding product
with lower ee (9e), while a Me group at the same position did not
affect the ee (9b). This may be due to the coordinating effect of OMe
group. It should be noted that the bromide substituent is also
tolerable to the hydrogenation conditions thus allowing for further
functionalization. Substrates bearing fused-ring aryl, heteroaryl
and disubstituted aryl groups at the C2 position also gave their
corresponding products with excellent yields and good enantio-
selectivities (9p-9r). Product 9q was obtained with the best ee. A
substrate bearing chlorine atoms on the benzene ring of the
1,4-benzodioxane was successfully hydrogenated, yielding 9s with
good results. Finally, an alkyl substituted substrate 8t was also used
for this hydrogenation; however, the desired product was obtained
with only 48% ee. The absolute configuration of 9s was determined
to be (R) by X-ray analysis.12 Since the Ir/mono-tBu-RuPHOX
complex is able to provide hydrogenation products with opposite
configuration and with relatively high ee, we decided to test this
catalyst for several substrates. Interestingly, we found that the Ir/
mono-tBu-RuPHOX catalyst exhibited better enantioinducing
ability compared to Ir/In-BiphPHOX for substrates bearing electron-
withdrawing groups (9l-9n). Compound 5, which is a sweetening
agent, was prepared via a sequence process of asymmetric hydro-
genation and hydrogenative deprotection of 8u (Scheme 4).
Scheme 3. Scope of substrates.
Scheme 4. Transformations of hydrogenation product.
of chiral 1,4-benzodioxanes. The ligand backbone is essential for
obtaining good results, and our tropos biphenyl phosphine-oxazoline
ligand and planar chiral ruthenocene-derived phosphine-oxazoline
ligand provided the hydrogenation products in good ees with
opposite configurations. A broad range of substrates were tested and
gave the corresponding hydrogenation products in excellent yields
and with moderate to good enantioselectivities using the Ir-complex
of our tropos phosphine-oxazoline ligand.
4. Experimental section
3. Conclusions
4.1. General
In summary, we have developed an Ir-catalyzed asymmetric hy-
drogenation of 2-substituted 1,4-benzodioxines for the preparation
All reactions were carried out under an atmosphere of nitrogen
using standard Schlenk techniques, unless otherwise noted.1H NMR
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Y. Wang et al. / Tetrahedron xxx (2017) 1e6
(400 MHz), 13C NMR (100 MHz) spectra were recorded on a Varian
MERCURY plus-400 spectrometer with TMS as an internal standard.
HRMS was performed at the Analysis Center of Shanghai Jiao Tong
University. Optical rotations were measured with a SPSI SGW-1
polarimeter. Enantioselectivity was performed on a Shimadzu
LC-2010 HPLC system and using Daicel Chiralcel columns with
n-hexane/i-propyl alcohol as an eluent. Chiralpak OJ-H, Chiralpak
AD-H were purchased from Daicel Chiral Technologies (China) Co.,
Ltd.. Column chromatography was performed using 200e300 mesh
silica gel. Melting points were measured with SGW X-4 micro
melting point apparatus. All commercially available substrates
were used as received.
4.2.4. (R)-2-(p-Tolyl)-2,3-dihydrobenzo[b][1,4]dioxine (9d)
White solid; 96% yield; m. p. 33.4e34.1 ꢁC; 1H NMR (400 MHz,
CDCl3): d 7.32e7.30 (m, 2H, ArH), 7.25e7.21 (m, 2H, ArH), 6.99e6.96
(m, 1H, ArH), 6.95e6.92 (m, 1H, ArH), 6.90e6.87 (m, 2H, ArH), 5.09
(dd, J ¼ 8.8, 2.4 Hz, 1H), 4.33 (dd, J ¼ 11.6, 2.4 Hz, 1H), 4.03 (dd,
J ¼ 11.6, 9.2 Hz,1H), 2.38 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 144.1,
143.2, 138.8, 133.6, 129.6, 126.6, 121.7, 121.6, 117.7, 117.2, 75.1, 69.5,
21.4; HRMS (ESI): calcd for C15H15O2 [MþH]þ: 227.1072, found
227.1067; HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10,
210 nm,1.0 mL/min. tR1 ¼10.8 min (S), tR2 ¼ 19.1 min (R)]; ee ¼ 90%;
D
[a
]
¼ ꢀ67.36 (c ¼ 0.29, CHCl3).
25
4.2.5. (R)-2-(2-Methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxine
(9e)
4.2. General procedure for Ir-Catalyzed asymmetric hydrogenation
White solid; 95% yield; m. p. 64.6e65.6 ꢁC; 1H NMR (400 MHz,
CDCl3): d 7.50e7.48 (m, 1H, ArH), 7.35e7.11 (m, 1H, ArH), 7.06e6.99
Under nitrogen atmosphere, the catalyst ([Ir(L8)(COD)]BArF,
3.20 mg, 0.002 mmol, 0.01 equiv.) and substrate 8 (0.2 mmol, 1.0
equiv.) were placed in a 5 mL tube equipped with a magnetic stirrer
bar. This tube was then put into an argon-filled autoclave. DCM
(2.0 mL) was added to the mixture under a nitrogen atmosphere.
The autoclave was then closed, purged three times with hydrogen
(less than the pressure needed), and finally pressurized to 10 bar.
The reaction mixture was stirred at r.t. for 12 h. The hydrogen gas
was slowly released and the solvent was removed by vacuum
evaporation. The residue was purified by preparative TLC on silica
gel to give the product 9. The ee was determined by chiral HPLC.
The absolute configuration of 9s was determined by X-ray crystal-
lographic analysis.
(m, 2H, ArH), 6.95e6.90 (m, 2H, ArH), 6.89e6.86 (m, 2H, ArH), 5.52
(dd, J ¼ 8.4, 2.4 Hz, 1H), 4.45 (dd, J ¼ 11.2, 2.4 Hz, 1H), 3.91 (dd,
J ¼ 11.2, 8.8 Hz, 1H), 3.86 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
156.3, 144.3, 143.4, 129.6, 127.1, 124.9, 121.6, 121.5, 121.1, 117.7,
117.2, 110.5, 70.3, 68.4, 55.5; HRMS (ESI): calcd for C15H15O3
[MþH]þ: 243.1021, found 243.1024; HPLC [Daicel Chiralcel OJ-H,
hexane/i-PrOH ¼ 90/10, 210 nm, 1.0 mL/min. tR1 ¼ 8.1 min (S),
D
tR2 ¼ 10.6 min (R)]; ee ¼ 78%; [
a
]
¼ ꢀ61.88 (c ¼ 0.57, CHCl3).
25
4.2.6. (R)-2-(3-Methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxine
(9f)
Colorless oil; 94% yield; 1H NMR (400 MHz, CDCl3):
d 7.33 (t,
J ¼ 8.0 Hz, 1H, ArH), 7.01e6.97 (m, 3H, ArH), 6.95e6.87 (m, 4H,
ArH), 5.10 (dd, J ¼ 8.8, 2.4 Hz,1H), 4.35 (dd, J ¼ 11.6, 2.4 Hz,1H), 4.02
(dd, J ¼ 11.6, 8.8 Hz, 1H), 3.83 (s, 3H); 13C NMR (100 MHz, CDCl3):
4.2.1. (R)-2-Phenyl-2,3-dihydrobenzo[b][1,4]dioxine (9a)
White solid; 97% yield; m. p. 54.5e55.2 ꢁC; 1H NMR (400 MHz,
d 160.1, 143.9, 143.2, 138.1, 130.0, 121.73, 121.72, 118.9, 117.7, 117.3,
CDCl3):
d
7.45e7.26 (m, 5H, ArH), 7.02e7.00 (m, 1H, ArH), 6.97e6.94
114.3, 112.2, 75.1, 69.5, 55.5; HRMS (ESI): calcd for C15H15O3
(m, 1H, ArH), 6.92e6.88 (m, 2H, ArH), 5.14 (dd, J ¼ 9.2, 2.4 Hz, 1H),
[MþH]þ: 243.1021, found 243.1026; HPLC [Daicel Chiralcel OJ-H,
4.37 (dd, J ¼ 11.2, 2.4 Hz, 1H), 4.05 (dd, J ¼ 11.6, 9.2 Hz, 1H); 13C NMR
hexane/i-PrOH ¼ 90/10, 210 nm, 1.0 mL/min. tR1 ¼ 12.8 min (S),
D
(100 MHz, CDCl3):
d
144.0, 143.2, 136.6, 128.9, 126.7, 121.7, 117.7,
tR2 ¼ 16.1 min (R)]; ee ¼ 88%; [
a]
¼ ꢀ53.74 (c ¼ 0.93, CHCl3).
25
117.3, 75.2, 69.5; HRMS (ESI): calcd for C14H13O2 [MþH]þ: 213.0916,
found 213.0919; HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/
4.2.7. (R)-2-(4-Methoxyphenyl)-2,3-dihydrobenzo[b][1,4]dioxine
10, 210 nm, 1.0 mL/min. tR1 ¼ 12.0 min (S), tR2 ¼ 18.6 min (R)];
(9g)
D
ee ¼ 90%; [
a
]
¼ ꢀ64.71 (c ¼ 0.50, CHCl3).
Colorless oil; 95% yield; 1H NMR (400 MHz, CDCl3):
d 7.36e7.33
25
(m, 2H, ArH), 6.99e6.92 (m, 4H, ArH), 6.90e6.86 (m, 2H, ArH), 5.07
(dd, J ¼ 8.8, 2.4 Hz, 1H), 4.31 (dd, J ¼ 11.6, 2.4 Hz, 1H), 4.03 (dd,
4.2.2. (R)-2-(o-Tolyl)-2,3-dihydrobenzo[b][1,4]dioxine (9b)
J ¼ 11.2, 8.8 Hz,1H), 3.82 (s, 3H); 13C NMR (100 MHz, CDCl3):
d 160.1,
White solid; 95% yield; m. p. 31.3e32.0 ꢁC; 1H NMR (400 MHz,
144.1, 143.2, 128.7, 128.1, 121.7, 121.6, 117.7, 117.2, 114.3, 74.9, 69.5,
55.5; HRMS (ESI): calcd for C15H15O3 [MþH]þ: 243.1021, found
243.1019; HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10,
CDCl3): d 7.48e7.46 (m, 1H, ArH), 7.31e7.20 (m, 3H, ArH), 7.01e6.93
(m, 2H, ArH), 6.91e6.87 (m, 2H, ArH), 5.32 (dd, J ¼ 9.2, 2.4 Hz, 1H),
4.34 (dd, J ¼ 11.6, 2.4 Hz, 1H), 3.99 (dd, J ¼ 11.6, 9.2 Hz, 1H), 2.41 (s,
210 nm, 1.0 mL/min. tR1 ¼17.6 min (S), tR2 ¼ 27.0 min (R)]; ee ¼ 90%;
3H); 13C NMR (100 MHz, CDCl3):
d 144.3, 143.2, 135.3, 134.5, 130.8,
D
[a
]
¼ ꢀ37.63 (c ¼ 0.62, CHCl3).
25
128.7, 126.8, 126.5, 121.71, 121.69, 117.8, 117.2, 72.3, 68.5, 19.2; HRMS
(ESI): calcd for C15H15O2 [MþH]þ: 227.1072, found 227.1079; HPLC
4.2.8. (R)-2-(4-(tert-Butyl)phenyl)-2,3-dihydrobenzo[b][1,4]dioxine
(9h)
[Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10, 210 nm, 1.0 mL/min.
D
tR1 ¼ 7.3 min (S), tR2 ¼ 11.2 min (R)]; ee ¼ 89%; [
(c ¼ 0.74, CHCl3).
a
]
¼ ꢀ56.52
25
White solid; 95% yield; m. p. 56.0e57.0 ꢁC; 1H NMR (400 MHz,
CDCl3):
d
7.44 (t, J ¼ 8.4 Hz, 2H, ArH), 7.35 (t, J ¼ 8.8 Hz, 2H, ArH),
6.99e6.85 (m, 4H, ArH), 5.10 (dd, J ¼ 8.8, 2.4 Hz, 1H), 4.35 (dd,
4.2.3. (R)-2-(m-Tolyl)-2,3-dihydrobenzo[b][1,4]dioxine (9c)
J ¼ 11.6, 2.4 Hz, 1H), 4.05 (dd, J ¼ 11.6, 8.8 Hz, 1H), 1.33 (s, 9H); 13
C
Colorless oil; 95% yield; 1H NMR (400 MHz, CDCl3):
d
7.31 (t,
NMR (100 MHz, CDCl3): d 152.1, 144.2, 143.2, 133.5, 126.5, 125.9,
J ¼ 7.6 Hz, 1H, ArH), 7.25e7.18 (m, 3H, ArH), 7.01e6.97 (m, 1H, ArH),
6.96e6.92 (m, 1H, ArH), 6.91e6.86 (m, 2H, ArH), 5.09 (dd, J ¼ 8.8,
2.4 Hz, 1H), 4.34 (dd, J ¼ 11.2, 2.4 Hz, 1H), 4.03 (dd, J ¼ 11.6, 8.8 Hz,
121.7, 121.6, 117.7, 117.2, 75.1, 69.4, 34.8, 31.4; HRMS (ESI): calcd for
C
18H21O3 [MþH]þ: 269.1542, found 269.1541; HPLC [Daicel Chir-
alcel OJ-H, hexane/i-PrOH
¼
95/5, 210 nm, 0.5 mL/min.
D
1H), 2.39 (s, 3H); 13C NMR (100 MHz, CDCl3):
d
144.1, 143.2, 138.7,
tR1 ¼ 13.6 min (S), tR2 ¼ 14.3 min (R)]; ee ¼ 90%; [
a]
¼ ꢀ36.67
25
136.5, 129.7, 128.8, 127.3, 123.8, 121.7, 117.7, 117.2, 75.3, 69.5, 21.6;
HRMS (ESI): calcd for C15H15O2 [MþH]þ: 227.1072, found 227.1066;
HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10, 210 nm, 1.0
(c ¼ 0.72, CHCl3).
4.2.9. (R)-2-([1,10-Biphenyl]-4-yl)-2,3-dihydrobenzo[b][1,4]dioxine
(9i)
mL/min. tR1 ¼ 9.7 min (S), tR2 ¼ 14.4 min (R)]; ee ¼ 90%;
D
[
a]
¼ ꢀ45.94 (c ¼ 0.58, CHCl3).
White solid; 94% yield, m. p. 71.5e72.3 ꢁC; 1H NMR (400 MHz,
25
Please cite this article in press as: Wang Y, et al., Iridium-catalyzed asymmetric hydrogenation of 2-substituted 1,4-benzodioxines, Tetrahedron
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5
D
CDCl3):
d
7.65e7.57 (m, 4H, ArH), 7.50e7.43 (m, 4H, ArH), 7.38e7.34
tR2 ¼ 14.4 min (R)]; ee ¼ 78%; [
a
]
¼ ꢀ43.41 (c ¼ 0.53, CHCl3);
25
(m, 1H, ArH), 7.02e6.87 (m, 4H, ArH), 5.17 (dd, J ¼ 9.2, 2.4 Hz, 1H),
(S)-9m: HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10,
4.39 (dd, J ¼ 11.6, 2.4 Hz,1H), 4.08 (dd, J ¼ 11.6, 8.8 Hz, 1H); 13C NMR
210 nm, 1.0 mL/min. tR1 ¼ 8.8 min (S), tR2 ¼ 12.5 min (R)];
D
(100 MHz, CDCl3):
d
144.0, 143.2, 141.9, 140.7, 135.5, 129.0, 127.70,
ee ¼ ꢀ85%; [
a
]
¼ 52.36 (c ¼ 0.60, CHCl3).
25
127.67, 127.3, 127.1, 121.8, 117.7, 117.3, 75.0, 69.4; HRMS (ESI): calcd
for C20H17O2 [MþH]þ: 289.1229, found 289.1224; HPLC [Daicel
4.2.14. (R)-2-(4-Bromophenyl)-2,3-dihydrobenzo[b][1,4]dioxine
Chiralcel AD-H, hexane/i-PrOH ¼ 99/1, 210 nm, 0.5 mL/min.
(9n)
D
tR1 ¼ 38.6 min (R), tR2 ¼ 43.7 min (S)]; ee ¼ 87%; [
(c ¼ 0.78, CHCl3).
a]
¼ ꢀ47.17
Colorless oil; 93% yield; 1H NMR (400 MHz, CDCl3):
d 7.57e7.54
25
(m, 2H, ArH), 7.32e7.29 (m, 2H, ArH), 6.99e6.87 (m, 4H, ArH), 5.10
(dd, J ¼ 8.4, 2.4 Hz, 1H), 4.33 (dd, J ¼ 11.6, 2.4 Hz, 1H), 3.98 (dd,
4.2.10. (R)-2-(2-Fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine
(9j)
J ¼ 11.6, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 143.7, 143.1,
135.6, 132.1, 128.3, 122.9, 121.9, 121.8, 117.6, 117.3, 74.6, 69.2; HRMS
(ESI): calcd for C14H12BrO2 [MþH]þ: 291.0021, found 291.0023;
HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10, 210 nm, 1.0
White solid; 93% yield; m. p. 34.5e35.2 ꢁC; 1H NMR (400 MHz,
CDCl3): d 7.55e7.51 (m, 1H, ArH), 7.38e7.33 (m, 1H, ArH), 7.25e7.20
(m, 1H, ArH), 7.13e7.08 (m, 1H, ArH), 7.01e6.98 (m, 1H, ArH),
6.96e6.93 (m, 1H, ArH), 6.92e6.88 (m, 2H, ArH), 5.47 (dd, J ¼ 8.4,
2.4 Hz, 1H), 4.43 (ddd, J ¼ 11.2, 2.4, 0.8 Hz, 1H), 4.02 (ddd, J ¼ 11.2,
mL/min. tR1 ¼ 10.9 min (S), tR2 ¼ 14.6 min (R)]; ee ¼ 76%;
D
[
a
]
¼ ꢀ36.59 (c ¼ 0.63, CHCl3); (S)-9n: HPLC [Daicel Chiralcel
25
OJ-H, hexane/i-PrOH ¼ 90/10, 210 nm, 1.0 mL/min. tR1 ¼ 10.1 min
8.6, 0.6 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d
159.9 (d,
(S), tR2 ¼ 13.2 min (R)]; ee ¼ ꢀ86%; [
a
]
¼ 44.21 (c ¼ 0.65,
D
25
J ¼ 246.0 Hz), 143.8, 143.2, 130.3 (d, J ¼ 9.0 Hz), 128.1 (d, J ¼ 4.0 Hz),
124.8 (d, J ¼ 3.0 Hz), 124.0, 123.9, 121.8 (d, J ¼ 5.0 Hz), 117.6, 117.4,
115.5 (d, J ¼ 22.0 Hz), 69.5 (d, J ¼ 3.0 Hz), 68.2 (d, J ¼ 2.0 Hz); HRMS
(ESI): calcd for C14H12FO2 [MþH]þ: 231.0821, found 231.0823; HPLC
CHCl3).
4.2.15. (R)-2-(4-(Trifluoromethyl)phenyl)-2,3-dihydrobenzo[b][1,4]
dioxine (9o)
[Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10, 210 nm, 1.0 mL/min.
White solid; 92% yield; m. p. 59.6e60.5 ꢁC; 1H NMR (400 MHz,
D
tR1 ¼ 6.4 min (S), tR2 ¼ 9.3 min (R)]; ee ¼ 71%; [
(c ¼ 0.48, CHCl3).
a
]
¼ ꢀ63.58
CDCl3):
d
7.69 (d, J ¼ 8.0 Hz, 2H, ArH), 7.56 (d, J ¼ 8.4 Hz, 2H, ArH),
25
7.02e6.89 (m, 4H, ArH), 5.21 (dd, J ¼ 8.8, 2.4 Hz, 1H), 4.38 (dd,
J ¼ 11.6, 2.4 Hz, 1H), 4.02 (dd, J ¼ 11.6, 8.8 Hz, 1H); 13C NMR
4.2.11. (R)-2-(4-Fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine
(9k)
(100 MHz, CDCl3):
d
143.5, 143.1, 140.6, 131.1 (q, J ¼ 32.0 Hz), 126.9,
125.9 (q, J ¼ 4.0 Hz), 124.1 (q, J ¼ 271.0 Hz), 122.02, 121.96, 117.7,
117.4, 74.5, 69.2; HRMS (ESI): calcd for C15H12F3O2 [MþH]þ:
281.0789, found 281.0797; HPLC [Daicel Chiralcel OJ-H, hexane/i-
White solid; 94% yield; m. p. 56.7e57.3 ꢁC; 1H NMR (400 MHz,
CDCl3): d 7.43e7.39 (m, 2H, ArH), 7.14e7.09 (m, 2H, ArH), 7.00e6.88
(m, 4H, ArH), 5.11 (dd, J ¼ 8.8, 2.4 Hz, 1H), 4.33 (dd, J ¼ 11.6, 2.4 Hz,
PrOH ¼ 90/10, 210 nm, 1.0 mL/min. tR1 ¼ 7.6 min (S), tR2 ¼ 8.7 min
D
1H), 4.00 (dd, J ¼ 11.6, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
(R)]; ee ¼ 57%; [
a]
¼ ꢀ40.11 (c ¼ 0.50, CHCl3).
25
d
163.1 (d, J ¼ 246.0 Hz), 143.9, 143.1, 132.4 (d, J ¼ 3.0 Hz), 128.5 (d,
J ¼ 8.0 Hz), 121.84, 121.80, 117.7, 117.3, 115.9 (d, J ¼ 21.0 Hz), 74.6,
69.4; HRMS (ESI): calcd for C14H12FO2 [MþH]þ: 231.0821, found
231.0824; HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10,
4.2.16. (R)-2-(Naphthalen-2-yl)-2,3-dihydrobenzo[b][1,4]dioxine
(9p)
White solid; 93% yield; m. p. 47.1e47.9 ꢁC; 1H NMR (400 MHz,
210 nm,1.0 mL/min. tR1 ¼10.3 min (S), tR2 ¼ 17.6 min (R)]; ee ¼ 83%;
CDCl3): d 7.93e7.85 (m, 4H, ArH), 7.53e7.49 (m, 3H, ArH), 7.06e7.03
D
[
a
]
¼ ꢀ46.72 (c ¼ 0.46, CHCl3).
(m, 1H, ArH), 6.98e6.95 (m, 1H, ArH), 6.93e6.90 (m, 2H, ArH), 5.30
(dd, J ¼ 9.2, 2.4 Hz, 1H), 4.44 (dd, J ¼ 11.2, 2.4 Hz, 1H), 4.12 (dd,
25
4.2.12. (R)-2-(3-Fluorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine
(9l)
J ¼ 11.6, 9.2 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 144.0, 143.2,
133.9, 133.6, 133.3, 128.8, 128.2, 127.9, 126.63, 126.61, 126.0, 124.0,
121.8, 117.7, 117.3, 75.3, 69.5; HRMS (ESI): calcd for C18H15O2
[MþH]þ: 263.1072, found 263.1075; HPLC [Daicel Chiralcel OJ-H,
White solid; 93% yield; m. p. 80.7e81.1 ꢁC; 1H NMR (400 MHz,
CDCl3):
d 7.41e7.36 (m, 1H, ArH), 7.21e7.15 (m, 2H, ArH), 7.09e7.04
(m, 1H, ArH), 7.01e6.98 (m, 1H, ArH), 6.95e6.88 (m, 3H, ArH), 5.13
(dd, J ¼ 8.8, 2.4 Hz, 1H), 4.36 (dd, J ¼ 11.6, 2.4 Hz, 1H), 4.00 (dd,
hexane/i-PrOH ¼ 90/10, 210 nm, 1.0 mL/min. tR1 ¼ 18.6 min (S),
D
tR2 ¼ 22.9 min (R)]; ee ¼ 83%; [
a]
¼ ꢀ45.10 (c ¼ 0.76, CHCl3).
25
J ¼ 11.2, 8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 163.2 (d,
J ¼ 245.0 Hz), 143.7, 143.1, 139.3 (d, J ¼ 7.0 Hz), 130.5 (d, J ¼ 8.0 Hz),
122.2 (d, J ¼ 3.0 Hz), 121.91, 121.87, 117.7, 117.3, 115.8 (d, J ¼ 21.0 Hz),
113.7 (d, J ¼ 23.0 Hz), 74.5 (d, J ¼ 2.0 Hz), 69.3; HRMS (ESI): calcd for
4.2.17. (R)-2-(3,5-Dimethylphenyl)-2,3-dihydrobenzo[b][1,4]
dioxine (9q)
Colorless oil; 95% yield; 1H NMR (400 MHz, CDCl3):
d 7.04e6.87
C
14H12FO2 [MþH]þ: 231.0821, found 231.0825; HPLC [Daicel Chir-
(m, 7H, ArH), 5.04 (dd, J ¼ 9.2, 2.4 Hz, 1H), 4.33 (dd, J ¼ 11.2, 2.4 Hz,
alcel OJ-H, hexane/i-PrOH
¼
90/10, 210 nm, 1.0 mL/min.
1H), 4.02 (dd, J ¼ 11.6, 9.2 Hz, 1H), 2.35 (s, 6H); 13C NMR (100 MHz,
D
tR1 ¼ 9.2 min (S), tR2 ¼ 11.2 min (R)]; ee ¼ 77%; [
a
]
¼ ꢀ54.33
CDCl3): d 144.1, 143.2, 138.6, 136.4, 130.6, 124.5, 121.7, 117.7, 117.2,
25
(c ¼ 0.50, CHCl3); (S)-9l: HPLC [Daicel Chiralcel OJ-H, hexane/i-
75.4, 69.6, 21.5; HRMS (ESI): calcd for C16H17O2 [MþH]þ: 241.1229,
found 241.1224; HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/
PrOH ¼ 90/10, 210 nm, 1.0 mL/min. tR1 ¼ 8.1 min (S), tR2 ¼ 9.3 min
D
(R)]; ee ¼ ꢀ84%; [
a
]
¼ 64.28 (c ¼ 0.58, CHCl3).
10, 210 nm, 1.0 mL/min. tR1 ¼ 6.6 min (S), tR2 ¼ 8.0 min (R)];
25
D
ee ¼ 92%; [
a]
¼ ꢀ51.93 (c ¼ 0.56, CHCl3).
25
4.2.13. (R)-2-(4-Chlorophenyl)-2,3-dihydrobenzo[b][1,4]dioxine
(9m)
4.2.18. (R)-2-(Thiophen-3-yl)-2,3-dihydrobenzo[b][1,4]dioxine (9r)
Colorless oil; 93% yield; 1H NMR (400 MHz, CDCl3):
7.40e7.39
Colorless oil; 95% yield; 1H NMR (400 MHz, CDCl3):
d
7.41e7.35
d
(m, 4H, ArH), 7.00e6.88 (m, 4H, ArH), 5.11 (dd, J ¼ 8.8, 2.4 Hz, 1H),
(m,1H, ArH), 7.38 (t, J ¼ 2.8 Hz,1H, ArH), 7.14 (dd, J ¼ 5.2,1.6 Hz,1H),
6.98e6.86 (m, 4H, ArH), 5.26 (dd, J ¼ 8.8, 2.4 Hz, 1H), 4.39 (dd,
J ¼ 11.2, 2.4 Hz, 1H), 4.11 (dd, J ¼ 11.6, 8.8 Hz, 1H); 13C NMR
4.33 (dd, J ¼ 11.6, 2.4 Hz,1H), 3.99 (dd, J ¼ 11.2, 8.8 Hz, 1H); 13C NMR
(100 MHz, CDCl3):
d 143.7, 143.1, 135.1, 134.8, 129.1, 128.0, 121.9,
121.8, 117.7, 117.3, 74.5, 69.3; HRMS (ESI): calcd for C14H12ClO2
[MþH]þ: 247.0526, found 247.0527; HPLC [Daicel Chiralcel OJ-H,
hexane/i-PrOH ¼ 90/10, 210 nm, 1.0 mL/min. tR1 ¼ 9.8 min (S),
(100 MHz, CDCl3): d 143.7, 143.2, 137.7, 126.8, 125.8, 123.3, 121.77,
121.75, 117.6, 117.3, 71.8, 68.7; HRMS (ESI): calcd for C12H11SO2
[MþH]þ: 219.0480, found 219.0474; HPLC [Daicel Chiralcel OJ-H,
Please cite this article in press as: Wang Y, et al., Iridium-catalyzed asymmetric hydrogenation of 2-substituted 1,4-benzodioxines, Tetrahedron
(2017), https://doi.org/10.1016/j.tet.2017.12.015

6
Y. Wang et al. / Tetrahedron xxx (2017) 1e6
(e) Rouf A, Gupta P, Aga MA, et al. Tetrahedron Asymmetry. 2012;23:1615. for
synthesis from the chiral pool, see;
(f) Valoti E, Pallavicini M, Villa L, Pezzetta D. J Org Chem. 2001;66:1018;
(g) Rouf A, Aga MA, Kumar B, Taneja SC. Tetrahedron Lett. 2013;54:6420. for
Mitsunobu coupling, see;
(h) Pilkington LI, Barker D. J Org Chem. 2012;77:8156;
(i) Pilkington LI, Barker D. Eur J Org Chem. 2014;2014:1037. for a palladium-
catalyzed etherification of arylhalides, see;
hexane/i-PrOH ¼ 90/10, 210 nm, 1.0 mL/min. tR1 ¼ 20.3 min (R),
D
tR2 ¼ 22.7 min (S)]; ee ¼ 88%; [
a
]
¼ ꢀ22.11 (c ¼ 0.58, CHCl3).
25
4.2.19. (R)-6,7-Dichloro-2-phenyl-2,3-dihydrobenzo[b][1,4]dioxine
(9s)
White solid; 94% yield; m. p. 69.0e69.6 ꢁC; 1H NMR (400 MHz,
(j) Kuwabe S, Torraca KE, Buchwald SL. J Am Chem Soc. 2001;123:12202.
3. (a) Massacret M, Goux C, Lhoste P, Sinou D. Tetrahedron Lett. 1994;35:6093;
(b) Massacret M, Lakhmiri R, Lhoste P, et al. Tetrahedron Asymmetry. 2000;11:
3561;
(c) Ito K, Imahayashi Y, Kuroda T, Eno S, Saito B, Katsuki T. Tetrahedron Lett.
2004;45:7277;
(d) Cannon JS, Olson AC, Overman LE, Solomon NS. J Org Chem. 2012;77:1961.
4. Shi J, Wang T, Huang Y, Zhang X, Wu Y-D, Cai Q. Org Lett. 2015;17:840.
5. Hu N, Li K, Wang Z, Tang W. Angew Chem Int Ed. 2016;55:5044.
6. (a) Noyori R, Takaya H. Acc Chem Res. 1990;23:345;
(b) Tang W, Zhang X. Chem Rev. 2003;103:3029;
CDCl3): d 7.46e7.38 (m, 5H, ArH), 7.09 (s, 1H, ArH), 7.04 (s, 1H, ArH),
5.11 (dd, J ¼ 8.8, 2.4 Hz, 1H), 4.36 (dd, J ¼ 11.6, 2.4 Hz, 1H), 4.01 (dd,
J ¼ 11.6, 8.8 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d 143.2, 142.4,
135.6, 129.2, 129.0, 126.6, 124.38, 124.35, 118.9, 118.5, 75.3, 69.3;
HRMS (ESI): calcd for C14H11Cl2O2 [MþH]þ: 281.0136, found
281.0132; HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 90/10,
210 nm, 1.0 mL/min. tR1 ¼ 8.2 min (S), tR2 ¼ 10.2 min (R)]; ee ¼ 87%;
D
[
a]
¼ ꢀ24.42 (c ¼ 0.80, CHCl3).
25
(c) Cui X, Burgess K. Chem Rev. 2005;105:3272;
4.2.20. (R)-2-Ethyl-2,3-dihydrobenzo[b][1,4]dioxine (9t)
(d) Church TL, Andersson PG. Coord Chem Rev. 2008;252:513;
(e) Xie J-H, Zhu S-F, Zhou Q-L. Chem Rev. 2011;111:1713;
(f) Xie J-H, Zhu S-F, Zhou Q-L. Chem Soc Rev. 2012;41:4126;
(g) Chen Q-A, Ye Z-S, Duan Y, Zhou Y-G. Chem Soc Rev. 2013;42:497;
Colorless oil; 91% yield; 1H NMR (400 MHz, CDCl3):
d 6.89e6.81
(m, 4H, ArH), 4.24 (dd, J ¼ 11.2, 2.0 Hz, 1H), 4.07e4.01 (m, 1H), 3.88
(dd, J ¼ 11.2, 8.0 Hz, 1H), 1.78e1.57 (m, 2H), 1.07 (t, J ¼ 7.6 Hz, 3H);
ꢀ
ꢁ
(h) Verendel JJ, Pamies O, Dieguez M, Andersson PG. Chem Rev. 2014;114:2130;
(i) Zhang Z, Butt NA, Zhang W. Chem Rev. 2016;116:14769.
13C NMR (100 MHz, CDCl3):
d 143.6, 143.4, 121.5, 121.2, 117.4, 117.1,
ꢁ ^
74.4, 67.9, 24.3, 9.6; HRMS (ESI): calcd for C10H13O2 [MþH]þ:
7. (a) Schnider P, Koch G, Pretot R, et al. Chem Eur J. 1997;3:887;
(b) Lightfoot A, Schnider P, Pfaltz A. Angew Chem Int Ed. 1998;37:2897;
(c) Tang W, Wang W, Zhang X. Angew Chem Int Ed. 2003;42:943;
(d) Liu D, Tang W, Zhang X. Org Lett. 2004;6:513;
165.0916, found 165.0912; HPLC [Daicel Chiralcel OJ-H, hexane/i-
PrOH ¼ 95/5, 210 nm, 1.0 mL/min. tR1 ¼ 5.7 min (S), tR2 ¼ 5.9 min
D
(e) Zhu S-F, Xie J-B, Zhang Y-Z, Li S, Zhou Q-L. J Am Chem Soc. 2006;128:12886;
(f) Lu W, Chen Y, Hou X. Angew Chem Int Ed. 2008;47:10133;
(g) Roseblade SJ, Pfaltz A. Acc Chem Res. 2007;40:1402;
(h) Schrems MG, Neumann E, Pfaltz A. Angew Chem Int Ed. 2007;46:8274;
(i) Tolstoy P, Engman M, Paptchikhine A, et al. J Am Chem Soc. 2009;131:8855;
(j) Paptchikhine A, Itto K, Andersson PG. Chem Commun. 2011;47:3989;
(k) Zhou T, Peters B, Maldonado MF, Govender T, Andersson PG. J Am Chem Soc.
2012;134:13592;
(l) Cadu A, Andersson PG. J Organomet Chem. 2012;714:3;
(m) Zhu Y, Burgess K. Acc Chem Res. 2012;45:1623;
(n) Zhu S-F, Yu Y-B, Li S, Wang L-X, Zhou Q-L. Angew Chem Int Ed. 2012;51:
8872;
(o) Wang X, Han Z, Wang Z, Ding K. Angew Chem Int Ed. 2012;51:936;
(p) Spahn E, Albright A, Shevlin M, Pauli L, Pfaltz A, Gawley RE. J Org Chem.
2013;78:2731;
(q) Schumacher A, Bernasconi M, Pfaltz A. Angew Chem Int Ed. 2013;52:7422;
(r) Qu B, Samankumara LP, Ma S, et al. Angew Chem Int Ed. 2014;53:14428;
(s) Peters BK, Liu J, Margarita C, et al. J Am Chem Soc. 2016;138:11930;
(t) Xia J, Yang G, Zhuge R, Liu Y, Zhang W. Chem Eur J. 2016;22:18354;
(u) Friedfeld MR, Shevlin M, Margulieux GW, Campeau L-C, Chirik PJ. J Am Chem
Soc. 2016;138:3314;
(R)]; ee ¼ 48%; [
a
]
¼ 20.29 (c ¼ 0.50, CHCl3).
25
4.2.21. (R)-5-(2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)-2-
methoxyphenol (5)
White solid; 92% yield; m. p. 88.7e89.6 ꢁC; 1H NMR (400 MHz,
CDCl3):
2.4 Hz, 1H), 4.31 (dd, J ¼ 11.2, 2.4 Hz, 1H), 4.01 (dd, J ¼ 11.6, 8.8 Hz,
1H), 3.91 (s, 3H); 13C NMR (100 MHz, CDCl3):
147.0, 146.0, 144.1,
d
7.00e6.86 (m, 7H, ArH), 5.69 (s, 1H), 5.03 (dd, J ¼ 9.2,
d
143.2, 129.8, 121.7, 121.6, 118.5, 117.7, 117.2, 113.0, 110.9, 74.9, 69.5,
56.2; HRMS (ESI): calcd for C15H15O4 [MþH]þ: 259.0970, found
259.0971; HPLC [Daicel Chiralcel OJ-H, hexane/i-PrOH ¼ 80/20,
210 nm, 1.0 mL/min. tR1 ¼ 23.9 min (S), tR2 ¼ 33.5 min (R)];
D
ee ¼ 75%; [
a
]
¼ ꢀ37.07 (c ¼ 0.50, CHCl3).
25
Acknowledgments
(v) Yuan Q, Zhang W. Chin J Org Chem. 2016;36:274;
The National Natural Science Foundation of China (No.
21620102003), Science and Technology Commission of Shanghai
Municipality (No. 15JC1402200), and Shanghai Municipal Educa-
tion Commission (No. 201701070002E00030).
(w) Margarita C, Andersson PG. J Am Chem Soc. 2017;139:1346.
8. For selected examples, see: (a) Cheruku P, Church TL, Trifonova A, Wartmann T,
Andersson PG. Tetrahedron Lett. 2008;49:7290;
(b) Yan P-C, Xie J-H, Hou G-H, Wang L-X, Zhou Q-L. Adv Synth Catal. 2009;351:
3243;
(c) Hou G-H, Xie J-H, Yan P-C, Zhou Q-L. J Am Chem Soc. 2009;131:1366;
(d) Ye Z-S, Guo R-N, Cai X-F, Chen M-W, Shi L, Zhou Y-G. Angew Chem Int Ed.
2013;52:3685;
Appendix A. Supplementary data
(e) Xia J, Nie Y, Yang G, Liu Y, Zhang W. Org Lett. 2017;19:4884.
9. (a) Tian F, Yao D, Zhang Y, Zhang W. Tetrahedron. 2009;65:9609;
(b) Tian F, Yao D, Liu Y, Zhang W. Adv Synth Catal. 2010;352:1841;
(c) Liu Y, Yao D, Li K, Tian F, Xie F, Zhang W. Tetrahedron. 2011;67:8445;
(d) Liu Y, Yang G, Yao D, Tian F, Zhang W. Sci China Chem. 2011;54:87;
(e) Liu Y, Zhang W. Angew Chem Int Ed. 2013;52:2203;
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2017.12.015.
References
(f) Liu Y, Gridnev ID, Zhang W. Angew Chem Int Ed. 2014;53:1901;
(g) Quan M, Tang L, Shen J, Yang G, Zhang W. Chem Commun. 2017;53:609.
10. (a) Valerie T, Gerard C, Gerald G. Tetrahedron. 1997;53:2061;
(b) Harrak Y, Rosell G, Daidone G, Plescia S, Pujol MD. Bioorg Med Chem.
2007;15:4876.
1. (a) Zhou R, Luo G, Ewing AG. J Neurosci. 1994;14:2402;
(b) Asitha, A.; Michael, B. J.; Martin, K. T. Jr; Russell, N. M.; Kumar, P. A.; Louise,
S. K. L.; Hidenori, T.; Robert, T. M.; Zhang, Q.; Zhang, Q. WO 2012125598 A1,
2012; (c) Arnoldi A, Bassoli A, Merlini L, Ragg E. J Chem Soc Perkin Trans. 1993;1:
1359;
(d) Pilkington LI, Barker D. Nat Prod Rep. 2015;32:1369;
(e) Zhuang L-G, Seligmann O, Jurcic K, Wagner H. Planta Med. 1982;45:172;
(f) Hikino H, Kiso Y, Wagner H, Fiebig M. Planta Med. 1984;50:248.
2. For a synthetic route via a chiral epoxide, see: (a) Arnoldi A, Merlini L. J Chem
Soc Perkin Trans. 1985;1:2555;
(b) Gu W, Jing X, Chen X, Pan X. Chin Chem Lett. 2001;12:189. for an aldol
condensation, see;
(c) Nakamura Y, Hirata M, Kuwano E, Taniguchi E. Biosci Biotechnol Biochem.
1998;62:1550. for symmetric dihydroxylation, see;
(d) Ito K, Imahayashi Y, Kuroda T, Eno S, Saito B, Katsuki T. Tetrahedron Lett.
2004;45:7277;
ꢁ
ꢁ
ꢁ
11. (a) Zhao X, Liu D, Xie F, Liu Y, Zhang W. Org Biomol Chem. 2011;9:1871;
(b) Butt NA, Liu D, Zhang W. Synlett. 2014;25:615;
(c) Wang Y, Wang J, Liu D, Zhang W. Chin J Org Chem. 2014;34:1766;
(d) Wang J, Wang Y, Liu D, Zhang W. Adv Synth Catal. 2015;357:3262;
(e) Li J, Shen J, Xia C, Wang Y, Liu D, Zhang W. Org Lett. 2016;18:2122;
(f) An Q, Liu D, Shen J, Liu Y, Zhang W. Org Lett. 2017;19:238;
(g) Huo X, He R, Fu J, Zhang J, Yang G, Zhang W. J Am Chem Soc. 2017;139:9819;
(h) Wang Y, Liu Y, Li K, Yang G, Zhang W. Adv Synth Catal. 2017;359:1933.
12. CCDC 1578630 [(R)-6,7-Dichloro-2-phenyl-2,3-dihydrobenzo[b][1,4]dioxine]
contains the supplementary crystallographic data for this paper. Data are
provided free of charge by The Cambridge Crystallographic Data Centre.
Please cite this article in press as: Wang Y, et al., Iridium-catalyzed asymmetric hydrogenation of 2-substituted 1,4-benzodioxines, Tetrahedron
(2017), https://doi.org/10.1016/j.tet.2017.12.015