Copper-Catalyzed Asymmetric Hydroboration of 2 H-Chromenes Using a Chiral Diphosphine Ligand

Article abstract of DOI:10.1021/acs.joc.9b01109

A highly regioselective asymmetric hydroboration of 2H-chromenes catalyzed by the complex of CuCl and diphosphine ligand (S,R)-DuanPhos has been realized under mild conditions to produce 3-boryl chromans, achieving good yields and excellent enantioselectivities up to 96% ee. This work provides an efficient approach to the synthesis of chiral 3-boryl chromans and derivatives.

Full text of DOI:10.1021/acs.joc.9b01109

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Article
Copper-Catalyzed Asymmetric Hydroboration of
H-Chromenes Using Chiral Diphosphine Ligand
2
Xiufen Li, Chaoqiong Wang, Jianqiao Song, Zhihong Yang, Guofu Zi, and Guohua Hou
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b01109 • Publication Date (Web): 14 Jun 2019
Downloaded from http://pubs.acs.org on June 14, 2019
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Copper-Catalyzed Asymmetric Hydroboration of 2H-Chromenes
Using Chiral Diphosphine Ligand
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Xiufen Li, Chaoqiong Wang, Jianqiao Song, Zhihong Yang, Guofu Zi, and Guohua Hou*
Key Laboratory of Radiopharmaceuticals, College of Chemistry, Beijing Normal University,
Beijing 100875, China
E-mail: ghhou@bnu.edu.cn
ABSTRACT: A highly regioselective asymmetric hydroboration of 2H-chromenes catalyzed by
the complex of CuCl and diphosphine ligand (S,R)-DuanPhos has been realized under mild
conditions to produce 3-boryl chromans achieving good yields and excellent enantioselectivities,
up to 96% ee. This work provides an efficient approach to synthesis of chiral 3-boryl chromans
and derivatives.
INTRODUCTION
The chiral chroman is a pervasive structural motif found in numerous bioactive molecules and
1
pharmaceuticals. Chiral oxygen heterocycles are widely used as therapeutically important drugs
such as Equol for treating cardiovascular disease and breast cancer, Mucroquinone, Myristinin B
and Chromanol 293B (Figure 1).2, 3 Due to the significance in pharmaceutical synthesis,
considerable effort has been dedicated to the enantioselective synthesis of chromans.4
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Figure 1. Selected bioactive compounds bearing chiral chroman.
In addition, chiral borylated chromans are versatile intermediates in pharmaceutical and
synthetic chemistry, and can be used for construction of various important molecules via
5
convenient transformations of C-B bond to C-O, C-N, C-C, and C-halogen bonds. Therefore, to
develop efficient catalysts and approaches for enantioselective synthesis of chiral borylated
chromans is highly desirable. Although highly chemo- and regioselective catalytic asymmetric
hydroboration of various substrates, such as olefins 6 and N-heterocyclic substrates including
7
indoles, 1,2-dihydropyridines and 1,2-dihydroquinolines, has emerged substantially for the
synthesis of optically active boron-containing compounds and significant progress has also been
8
achieved, the catalyzed enantioselective hydroboration of 2H-chromenes still remains a challenge.
This is possibly attributed to the high energy barrier encountered during the conjugation of the
C=C double bond with phenyl ring, as well as the interaction of the oxygen atom with the borated
reagent which maybe has a negative effect on the hydroboration. To the best of our knowledge,
there is scarce example on the enantioselective hydroboration of 2H-chromenes reported.
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Hoveyda’s group reported the hydroboration of aryl substituted alkenes including an example of
2
H-chromene promoted by NHC-based catalysts achieving high yield and 89% ee (Scheme 1a).9
Thus far, the investigation on asymmetric hydroboration of 2H-chromenes is still in its infancy.
Both the efficient catalyst and substrate scope is limited. Herein we report a highly regioselective
copper catalyzed asymmetric hydroboration of 2H-chromenes using a chiral diphosphine ligand
(S,R)-DuanPhos to afford chiral chromans with high yields and enantioselectivities, up to 96% ee
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(Scheme 1b).
Scheme 1. Cu-catalyzed Asymmetric Hydroboration of 2H-Chromenes.
RESULTS AND DISCUSSION
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We initially chose 2H-chromene 1a as the model substrate to investigate the hydroboration
reaction using the complex of (S)-Binap (L1) and CuCl as the catalyst. In the presence of 20
2 2
mmol % of MeOK and MeOH (2.0 equiv) the reaction of 1a with bis(pinacolato)diboron (B pin )
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o
in THF proceeded at 0 C for 1 h and then was allowed to warm to room temperature and
remained for 4 h providing the desired product 2a without any regio-isomer in 59% yield and 80%
ee (Table 1, entry 1). Based on the promising result, the effect of the reaction temperature was
further evaluated. It was revealed that the higher enantioselectivity could be achieved with
o
comparable yield at the lower initial temperature of -20 C (Table 1, entry 2). However, the further
o
lower temperature, -78 C, resulted in decreased reactivity and the lower yield was observed
t
t
t
(
Table 1, entry 3). Subsequently, some other bases, such as BuONa, BuOLi, and BuOK, were
also screened. But lower yields or enantioselectivities were obtained (Table 1, entries 4 – 6). In the
absence of base the reaction could not proceed (Table 1, entry 7). Using MeOK as the base, the
effect of solvents was also investigated. Dichloromethane or toluene could only give much lower
yield (Table 1, entries 8 and 9). Despite a higher yield achieved in 1,2-dimethoxylethane, the
enantioselectivity was slightly decreased (Table 1, entry 10). On the basis of the pioneering work,
some diphosphine ligands (Figrue 2) were capable of promoting the hydroboration reaction of
various substrates.6-8 These ligands including (R)-SegPhos (L2), (R)-DM-SegPhos (L3),
p
(R,S )-JosiPhos-1 (L4) and (R,R)-Me-DuPhos (L5), which exhibited good performance were
evaluated in this transformation. However, most of them could only give poor yields or
enantioselectivities (Table 1, entries 11–14). Remarkably, (S,R)-DuanPhos (L6) provided the
desired product 2a achieving much higher yield and excellent enantioselectivity, 87% and 94% ee,
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respectively (Table 1, entry 15). Finally, the optimal reaction conditions were established as
gradient temperature/CuCl/(S,R)-DuanPhos/MeOK/THF.
Table 1. Cu-Catalyzed Asymmetric Hydroboration of 1a, Optimizing Reaction Conditions.a
1
1
1
1
1
1
1
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1
1
2
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2
2
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yield (%)b
ee (%)c
entry
1d
2
ligand
L1
L1
L1
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
base
solvent
THF
THF
THF
THF
THF
THF
THF
DCM
toluene
DME
THF
THF
THF
THF
THF
MeOK
MeOK
MeOK
tBuONa
tBuOK
tBuOLi
-
59
57
50
60
50
40
-
80
86
80
81
80
80
-
3e
4
5
6
7
8
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
MeOK
40
50
67
32
32
47
45
87
9
9
82
82
60
83
45
73
94
1
0
11
1
1
1
1
2
3
4
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a
2 2
Reaction conditions: CuCl (0.025 mmol), ligand (0.025 mmol), 1a (0.5 mmol), B pin (0.6
o
o
mmol), base (0.1 mmol), solvent (1.5 mL), MeOH (1.0 mmol), -20 C for 1 h, 0 C for 1 h, rt for 4
b
c
h. Isolated yield. Determined by chiral HPLC or SFC analysis of the corresponding derived
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alcohol. 0 C for 1 h, rt for 4 h. -78 C for 1 h, -20 C for 1 h, 0 C for 1 h, rt for 4 h.
Figure 2. Structures of the bidentate phosphine ligands screened.
With the optimal reaction conditions in hand, a variety of 2H-chromenes with various
substituents were prepared and applied to this Cu-catalyzed asymmetric hydroboration. As shown
in Scheme 2, most of the boronated products could be afforded with excellent enantioselectivities
(
up to 96% ee) in high yields (up to 92%) by the asymmetric hydroboration of the corresponding
substrates without any regio-isomers observed. It was revealed that the electronic property of the
substituents on the phenyl ring had a significant influence on the enantioselectivity in this
transformation. For example, the 8-Cl or 6-Br substituted substrates 1b and 1c bearing an
electron-withdrawing group could only provide moderate enantioselectivities, 62% and 64% ee,
respectively. On the contrary, the substrates 1d – 1j with an electron-donating substituent, such as
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t
methyl, methoxyl, isopropyl and Butyl, could be hydroborated to produce the corresponding 2d –
2
j in good yields and higher enantioselectivities of up to 94% ee regardless of the position of the
substituents on the phenyl ring. Inspired by these optimistic results, we attempted to evaluate
larger sterically hindered substrates with multi substituents in this hydroboration. Notably, the
disubstituted substrates 1k – 1m could be efficiently converted to the desired products 2k – 2m
achieving good yields and high enantioselectivities. Especially, the product 2m was obtained with
the highest enantioselectivity, 96% ee. Even if the 5, 7, 8-trimethyl substituted substrate 1n, it
could also be converted to the product 2n with 90% ee value albeit with a lower yield, which was
perhaps attributed to the much bulkier sterically hindrance. In addition, the hydroboration of the
substrates 1o – 1q proceeded smoothly with comparable yields, but slightly decreased
enantioselectivities were observed. The larger conjugated system probably had a similarly
negative effect on the enantioselectivity like the electron-withdrawing substituent on the phenyl
ring.
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Scheme 2. Substrate Scope.a, b
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a
Unless otherwise mentioned, all reactions were carried out with CuCl (0.025 mmol),
(S,R)-DuanPhos (0.025 mmol), 1 (0.5 mmol), B
2
pin
2
(0.6 mmol), MeOK (0.1 mmol), THF (1.5
o
o
b
mL), MeOH (1.0 mmol), -20 C for 1 h, 0 C for 1 h, rt for 4 h. Enantiomeric excess values were
determined by chiral HPLC or SFC analysis of the corresponding derived alcohols.
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The resulting products 2 are versatile synthetic intermediates that can be easily converted to
numerous other useful derivatives (Scheme 3). For example, by construction of C-O bond the
product 2h could be converted into the chiral 8-isopropylchroman-3-ol 3 in 93% yield without any
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loss of enantioselectivity.7a, 10 The product 2h could also be used for the synthesis of primary
alcohol 4 by construction of C−C bond in 80% yield with maintained enantioselectivity, 92% ee.11
Besides, the chiral boronate 2n could also be successfully transformed into the corresponding
boronic acid 5 in the presence of NaIO
4
and HCl (aq).12
Scheme 3. Representative Transformations of Products 2.
8
According to previous reports, a possible catalytic cycle for the asymmetric hydroboration of
chromenes was proposed as illustrated in Scheme 4. In the presence of CuCl, the diphosphine
ligand (S, R)-DuanPhos, and MeOK, a diphosphine ligated Cu-OMe complex A was initially
2 2
formed. The borylcopper species B was then generated by reaction with B pin . Subsequently, the
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coordination of the species B with the double bonds and addition to substrate 1 provided the
intermediate D, which could be protonated by Methanol to yield the borylated product 2 and
regenerate the copper methoxide A.
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Scheme 4. Proposed Catalytic Cycle for the Hydroboration.
CONCLUSIONS
In summary, an efficient asymmetric hydroboration of 2H-chromenes catalyzed by the complex
of CuCl and chiral diphosphine ligand (S,R)-DuanPhos to afford chiral chromans with high yields
and enantioselectivities, up to 96% ee, has been realized. This strategy provides a straightforward
approach to important chiral 3-boryl chromans, which can be readily converted to various useful
compounds including chiral alcohols.
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EXPERIMENTAL SECTION
General Information: All of the air- or moisture-sensitive reactions and manipulations were
performed using standard Schlenk techniques and in a nitrogen-filled glovebox. DME, THF,
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2 2
dioxane and toluene were distilled from sodium benzophenone ketyl. CH Cl was distilled from
1
13
1
calcium hydride. Anhydrous MeOH was distilled from magnesium. H NMR and C{ H}NMR
spectra were recorded on Bruker AV (400 MHz) spectrometers and JEOL JNM-ECX600P and
JNM-ECS600 (600 MHz) spectrometers (CDC13 was the solvent used for the NMR analysis, with
tetramethylsilane (TMS) as the internal standard). Chemical shifts were reported upfield to TMS
1
(0.00 ppm) for H NMR. Data is represented as follows: chemical shift, integration, multiplicity (s
=
singlet, d = doublet, dd = double of doublets, t = triplet, q = quartet, m = multiplet), and
coupling constants (J) in Hertz (Hz). Optical rotation was determined using an automatic
polarimeter (Rudolph research Analytical). HPLC analysis was conducted on Agilent 1260 series
instrument. SFC analysis was conducted on Agilent 1260 series instrument. HRMS was carried
out on a Waters LCT Premier XE mass spectrometer with APCI or ESI.
Procedure for the preparation of substrate 1a: Chroman-4-one (0.74 g, 5.00 mmol, 1 equiv)
4
was suspended in methanol (50 mL) and treated with an excess of NaBH (0.28 g, 7.50 mmol, 1.5
o
equiv) at 0 C. The resulting mixture was stirred for 30 minutes at room temperature, then
2 2 2
concentrated in vacuo. The residue was partitioned between CH Cl and H O. The organic layer
2 2
was separated, and the aqueous layer was extracted with CH Cl . The organic layers was then
combined, washed with H
desired compound.13
2 2 4
O, dried over anhydrous Na SO , filtered and concentrated to yield the
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p-Toluenesulfonic acid (3.00 mg, 0.02 mmol) and hydroquinone (5.0 mg, 0.05 mmol) were
added to a solution of chroman-4-ol (0.75 g, 5.00 mmol) in toluene (20 mL). The reaction mixture
was heated under reflux using a Dean–Stark trap (2 h), washed with water, dried over anhydrous
0
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0
2 4
Na SO , filtered and concentrated under reduced pressure. The residue was purified by silica gel
chromatography (petroleum ether).14
Procedure for the preparation of substrates 1b-1e, 1j and 1l：Equimolar quantities of
chloropropionic acid (5.43g, 50.00 mmol, 1 equiv) and appropriate phenol (50 mmol) were placed
in a conical flask, to which aqueous solution of NaOH (11.52 g, 0.12 mol in 25 mL water) was
o
slowly added with constant stirring and then heating to 75 – 80 C, reacting for 12 h. After the
reaction, with sufficient cooling and acidified by adding con. HCl, extracted with ethyl acetate,
followed by saturated brine. It was dried over anhydrous Na
The crude product was purified by silica gel chromatography (petroleum ether: EtOAc = 5:1).15
-Phenoxypropanoic acids were placed in a conical flask, to which sulfoxide chloride (5 mL)
was quickly added with constant stirring. The reaction mixture was heated under reflux for 2 h,
2 4
SO and then solvent was removed.
3
then concentrated in vacuo and CH
2
Cl
2
was added to the mixture. The anhydrous aluminum
o
chloride (2.67g, 20.00 mmol, 2 equiv) was added in batches at 0 C and the reaction stirred for 1 h
o
at 0 C, then the reaction mixture was allowed to warm to rt. The reaction was quenched with H
2
O
o
slowly at 0 C, extracted with CH
2
Cl
2
, followed by saturated brine. It was dried over anhydrous
2 4
Na SO and then solvent was removed. The crude product was purified by silica gel
chromatography (petroleum ether: EtOAc = 7:1).
Procedure for the preparation of substrates 1f-1i, 1k and 1m-1q: To a solution of
2 3
phenols (50.00 mmol) in acetone (200 mL) was added K CO (27.64 g, 0.2 mol) and
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3-bromoprop-1-yne (7.14 g, 60.00 mmol). The resulting mixture was stirred at reflux temperature
during overnight and the reaction stopped by filtration and evaporation under vacuum. The crude
2 2
product was extracted with CH Cl , followed by saturated brine. It was dried over anhydrous
1
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9
0
2 4
Na SO and then solvent was removed. The crude product was purified by silica gel
chromatography (PE/EA = 5:1).16
A mixture of (prop-2-yn-1-yloxy) benzene (10.00 mmol) and N, N-diethylaniline (1.6 mL) was
refluxed for 8-12 h. After cooling to room temperature, the reaction mixture was diluted with ethyl
acetate. The resulting mixture was washed with hydrochloric acid (2M), water and brine, and then
2 4
dried over anhydrous Na SO . The solvent was evaporated and the crude product was purified by
silica gel chromatography using petroleum ether/EtOAc as an eluent (PE/EA = 150:1–100:1) to
give the corresponding compounds.16
1
2
H-chromene (1a): Colorless oil; 0.50 g, yield: 75%; H NMR (600 MHz, CDCl
3
): δ (ppm) 6.67
(t, J = 6.2 Hz, 1H), 6.56 (d, J = 6.0 Hz, 1H), 6.50 – 6.47 (m, 1H), 6.41 (d, J = 6.3 Hz, 1H), 6.13
1
3
1
(
dd, J = 7.8, 0.9 Hz, 1H), 5.63 – 5.59 (m, 1H), 4.85 (dt, J = 2.6, 1.2 Hz, 2H); C{ H}NMR (100
): δ (ppm) 143.3, 123.4, 121.3, 119.7, 118.0, 117.6, 117.1, 112.6, 72.5. The analytical
data are consistent with the literature.17
-chloro-2H-chromene (1b): Colorless oil; 0.58 g, yield: 70%; H NMR (400 MHz, CDCl
ppm) 7.13 (dd, J = 7.9, 1.7 Hz, 1H), 6.82 (dd, J = 7.5, 1.7 Hz, 1H), 6.78 – 6.73 (m, 1H), 6.37 (dt,
MHz, CDCl
3
1
8
3
): δ
(
13
1
J = 9.9, 1.9 Hz, 1H), 5.77 (dt, J = 9.9, 3.5 Hz, 1H), 4.92 (dd, J = 3.5, 1.9 Hz, 2H); C{ H}NMR
100 MHz, CDCl ): δ (ppm) 149.8, 129.8, 125.1, 124.1, 123.7, 122.6, 121.6, 120.8, 66.4. The
analytical data are consistent with the literature.18
3
-bromo-2H-chromene (1c): Colorless oil; 0.92 g, yield: 87%; H NMR (400 MHz, CDCl ): δ
(
3
1
6
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(ppm) 7.16 (dd, J = 8.5, 2.4 Hz, 1H), 7.05 (d, J = 2.4 Hz, 1H), 6.63 (d, J = 8.5 Hz, 1H), 6.33 (dt, J
1
=
9.9, 1.9 Hz, 1H), 5.79 (dt, J = 9.9, 3.5 Hz, 1H), 4.81 (dd, J = 3.5, 1.9 Hz, 2H); 13C{ H}NMR
(
100 MHz, CDCl
analytical data are consistent with the literature.18
3
-methyl-2H-chromene (1d): Colorless oil; 0.62 g, yield: 85%; H NMR (400 MHz, CDCl ): δ
3
): δ (ppm) 153.0, 131.9, 129.1, 124.2, 123.6, 123.4, 117.5, 113.3, 65.7. The
0
1
2
3
4
5
6
7
8
9
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2
3
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
8
(ppm) 6.87 (d, J = 7.2 Hz, 1H), 6.75 – 6.60 (m, 2H), 6.31 (dt, J = 9.8, 1.7 Hz, 1H), 5.66 (dt, J =
1
9
.8, 3.5 Hz, 1H), 4.74 (dd, J = 3.5, 1.8 Hz, 2H), 2.07 (s, 3H); 13C{ H}NMR (100 MHz, CDCl
3
):
δ(ppm) 152.0, 130.7, 125.0, 124.9, 124.3, 121.9, 121.6, 120.6, 65.4. The analytical data are
consistent with the literature.18
1
7
-methyl-2H-chromene (1e): Colorless oil; 0.44 g, yield: 60%; H NMR (400 MHz, CDCl
3
): δ
(ppm) 6.84 (d, J = 7.6 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.60 (s, 1H), 6.39 (d, J = 9.8 Hz, 1H),
1
3
1
5
3
.70 (dt, J = 9.7, 3.6 Hz, 1H), 4.84 – 4.74 (m, 2H), 2.28 (s, 3H); C{ H}NMR (100 MHz, CDCl ):
δ (ppm) 143.3, 131.6, 121.1, 119.7, 117.7, 116.7, 115.9, 113.1, 72.5, 37.2. The analytical data are
consistent with the literature.19
1
8
-methoxy-2H-chromene (1f): Colorless oil; 1.12 g, yield: 69%; H NMR (400 MHz, CDCl
3
): δ
(ppm) 6.88 – 6.68 (m, 2H), 6.59 (dd, J = 7.1, 1.4 Hz, 1H), 6.39 (d, J = 9.8 Hz, 1H), 5.76 (dt, J =
1
3
1
9
.7, 3.5 Hz, 1H), 4.86 (dd, J = 3.4, 1.8 Hz, 2H), 3.84 (s, 3H); C{ H}NMR (100 MHz, CDCl
ppm) 147.6, 142.7, 124.5, 123.0, 122.0, 120.8, 118.9, 112.0, 65.7, 55.9. The analytical data are
consistent with the literature.18
-methoxy-2H-chromene (1g): Colorless oil; 0.86 g, yield: 53%; H NMR (400 MHz, CDCl
(ppm) 6.95 (t, J = 8.2 Hz, 1H), 6.67 (d, J = 9.9 Hz, 1H), 6.41 – 6.20 (m, 2H), 5.63 (dt, J = 9.7, 3.5
3
): δ
(
1
7
3
): δ
1
3
1
3
Hz, 1H), 4.66 (d, J = 1.6 Hz, 2H), 3.72 (s, 3H); C{ H}NMR (100 MHz, CDCl ): δ (ppm) 155.2,
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154.9, 129.0, 119.8, 119.4, 111.8, 108.8, 103.6, 65.0, 55.6. The analytical data are consistent with
the literature.19
1
8
-isopropyl-2H-chromene (1h): Red oil; 1.24 g, yield: 71%; H NMR (400 MHz, CDCl
3
): δ
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(ppm) 7.03 (dd, J = 7.1, 2.1 Hz, 1H), 6.83 – 6.75 (m, 2H), 6.39 (dt, J = 9.8, 1.7 Hz, 1H), 5.73 (dt,
J = 9.7, 3.6 Hz, 1H), 4.75 (dd, J = 3.6, 1.7 Hz, 2H), 3.27 – 3.12 (m, 1H), 1.19 (s, 1H), 1.18 (s, 6H);
1
3
1
C{ H}NMR (100MHz,CDCl
3
): δ(ppm) 151.1, 135.8, 126.1, 125.3, 124.2, 122.3, 121.8, 121.0,
+
6
5.3, 26.7, 22.6. TOF-HRMS calcd for C12
H
15O [M+H ]:175.1017, found 175.1013.
1
8
-(tert-butyl)-2H-chromene (1i): Colorless oil; 1.47 g, yield: 78%; H NMR (400 MHz, CDCl
3
):
δ (ppm) 7.14 – 6.90 (m, 1H), 6.90 – 6.67 (m, 2H), 6.37 (d, J = 9.7 Hz, 1H), 5.75 (dt, J = 9.4, 3.5
13
1
3
Hz, 1H), 4.84 – 4.29 (m, 2H), 1.30 (s, 9H); C{ H}NMR (100MHz,CDCl ): δ(ppm) 150.4, 132.0,
126.0, 125.2, 124.4, 122.5, 121.4, 119.0, 64.3, 34.4, 29.7. TOF-HRMS calcd for C13
H
17
O
+
[
M+H ]:189.1271, found 189.1273.
1
7
-(tert-butyl)-2H-chromene (1j): Colorless oil; 0.78 g, yield: 82%; H NMR (400 MHz, CDCl
3
):
δ (ppm) 6.89 (s, 2H), 6.82 (s, 1H), 6.40 (d, J = 9.7 Hz, 1H), 5.72 (dt, J = 9.6, 3.4 Hz, 1H), 5.03 –
13
1
4
.68 (m, 2H), 1.29 (s, 9H); C{ H}NMR (100 MHz, CDCl
3
): δ (ppm) 153.8, 153.0, 126.2, 124.4,
+
121.2, 119.8, 118.3, 113.0, 65.7, 34.8, 31.3. TOF-HRMS calcd for C13
H
17O [M+H ]:189.1271,
found 189.1273.
1
7
, 8-dimethyl-2H-chromene (1k): Colorless oil; 1.09 g, yield: 68%; H NMR (400 MHz, CDCl
3
):
δ (ppm) 6.61 (dd, J = 18.8, 7.6 Hz, 2H), 6.31 (d, J = 9.7 Hz, 1H), 5.63 (dt, J = 9.5, 3.5 Hz, 1H),
13
1
4
3
.71 (d, J = 1.5 Hz, 2H), 2.14 (s, 3H), 2.01 (s, 3H); C{ H}NMR (100 MHz, CDCl ): δ (ppm)
151.8, 138.1, 125.1, 123.7, 123.4, 122.1, 120.6, 119.9, 65.5, 20.1, 11.2. The analytical data are
consistent with the literature.20
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6, 8-dimethyl-2H-chromene (1l): Colorless oil; 0.48 g, yield: 59%; H NMR (400 MHz, CDCl
3
):
δ (ppm) 6.69 (s, 1H), 6.53 (s, 1H), 6.28 (d, J = 9.8 Hz, 1H), 5.65 (dt, J = 9.5, 3.5 Hz, 1H), 4.69 (s,
13
1
2
1
1
3
H), 2.12 (s, 3H), 2.05 (s, 3H); C{ H}NMR (100 MHz, CDCl ): δ (ppm) 150.4, 131.4, 129.9,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
25.1, 124.8, 124.7, 121.9, 121.8, 65.5, 20.5, 15.5. TOF-HRMS calcd for C11H
13O [M+H+]:
61.0800, found 161.0804.
1
5, 8-dimethyl-2H-chromene (1m): Colorless oil; 1.21 g, yield: 76%; H NMR (400 MHz,
3
CDCl ): δ (ppm) 6.90 (d, J = 7.6 Hz, 1H), 6.68 – 6.62 (m, 2H), 5.84 (dt, J = 9.9, 3.7 Hz, 1H), 4.78
13
1
(
dd, J = 3.7, 1.7 Hz, 2H), 2.29 (s, 3H), 2.18 (s, 3H); C{ H}NMR (100 MHz, CDCl
3
): δ (ppm)
1
52.4, 131.6, 130.1, 122.8, 122.4, 122.3, 121.4, 120.7, 64.8, 18.3, 15.5. The analytical data are
consistent with the literature.20
1
5, 7, 8-trimethyl-2H-chromene (1n): Colorless oil; 1.48 g, yield: 85%; H NMR (400 MHz,
CDCl ): δ (ppm) 6.51 (d, J = 9.9 Hz, 1H), 6.46 (s, 1H), 5.69 (dt, J = 9.8, 3.7 Hz, 1H), 4.63 (dd, J =
3
13
1
3
1
.5, 1.4 Hz, 2H), 2.14 (s, 3H), 2.10 (s,3H), 1.98 (s, 3H); C{ H}NMR (100 MHz, CDCl
3
): δ (ppm)
51.8, 137.1, 130.3, 123.8, 122.2, 121.1, 119.9, 118.4, 64.6, 19.8, 17.7, 11.1. The analytical data
are consistent with the literature.20
1
8-phenyl-2H-chromene (1o): Colorless oil; 1.58 g, yield: 76%; H NMR (400 MHz, CDCl
3
): δ
(
ppm) 7.57 – 7.51 (m, 2H), 7.46 – 7.38 (m, 2H), 7.36 – 7.30 (m, 1H), 7.18 (dd, J = 7.1, 2.2 Hz,
1
3
1
H), 7.01 – 6.90 (m, 2H), 6.49 (dt, J = 9.8, 1.8 Hz, 1H), 5.82 (dt, J = 9.8,3.6 Hz, 1H), 4.80 (dd, J =
.6, 1.8 Hz, 2H); 13C{ H}NMR (100MHz, CDCl
1
): δ (ppm) 150.8, 137.9, 130.5, 129.3, 128.0,
3
27.0, 126.0, 124.9, 122.9, 122.1, 121.2, 65.4. The analytical data are consistent with the
literature.21
3
H-benzo[g]chromene (1p): Colorless oil; 1.47 g, yield: 81%; H NMR (400 MHz, CDCl ): δ
1
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(ppm) 7.93 (dd, J = 8.5, 0.6 Hz, 1H), 7.77 – 7.72 (m, 1H), 7.65 (d, J = 8.8 Hz, 1H), 7.48 (m, 1H),
7
4
1
.34 (m, 1H), 7.15 – 7.10 (m, 1H), 7.07 (dd, J = 8.8, 0.5 Hz, 1H), 5.91 (dt, J = 9.9, 3.9 Hz, 1H),
.87 (dd, J = 3.9, 1.7 Hz, 2H); 13C{ H}NMR (100 MHz, CDCl
1
): δ (ppm) 152.4, 129.9, 129.5,
3
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
28.6, 126.7, 123.7, 121.5, 121.1, 120.4, 117.8, 115.5, 65.3. The analytical data are consistent with
the literature.22
1
2H-benzo[h]chromene (1q): Colorless oil; 1.49 g, yield: 82%; H NMR (400 MHz, CDCl
3
): δ
(ppm) 8.17 – 8.10 (m, 1H), 7.76 – 7.70 (m, 1H), 7.43 (m, 2H), 7.36 (d, J = 8.3 Hz, 1H), 7.13 (d, J
=
8.3 Hz, 1H), 6.54 (dt, J = 9.7, 1.7 Hz, 1H), 5.80 (dt, J = 9.7, 3.7 Hz, 1H), 5.00 (dd, J = 3.7, 1.8
1
3
1
Hz, 2H); C{ H}NMR (100 MHz, CDCl
24.8, 124.5, 121.9, 120.6, 120.4, 117.0, 66.0. The analytical data are consistent with the
literature.17
General procedure for the asymmetric hydroboration of substrates 1: In a N
an oven-dried Schlenk reaction tube with magnetic stir bar was charged with (S, R) - DuanPhos
9.6 mg, 0.025 mmol), CuCl (2.5 mg, 0.025 mmol), MeOK (7.0 mg, 0.10 mmol) and THF (0.6
3
): δ (ppm) 149.7, 134.5, 127.7, 126.3, 125.5, 125.4,
1
2
-filled glovebox,
(
mL). The mixture was sealed with cap and allowed to stir for 15 mins. Bis(pinacolato)diboron
(152 mg, 0.60 mmol) was added to the solution and THF (0.4 mL). The tube was sealed with cap
and removed from glovebox. After stirring for 20 mins at -20 °C, the solution of 2H-chromenes
(0.500 mmol) in THF (0.5 mL) and MeOH (40.6 µL, 1.00 mmol) were added by syringes
dropwise. The resulting solution was stirred at -20 °C for 1 h. The solution was allowed to warm
to 0 °C for 1 h, followed by stirring for 4 h at room temperature. Upon completion of the reaction,
2
the reaction mixture was passed through a short silica gel column eluting with Et O. The crude
mixture was purified by chromatography on silica gel to give the corresponding borylation
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product as colorless oil or white solid (petroleum ether: EtOAc=100:1).
Procedure for the synthesis of 3-5: In a round bottom flask, the product 2h (75.55 mg, 0.25
2 3 2
mmol) was dissolved in THF/H O (1:1, 4 mL). NaBO •4H O (0.19 g, 1.25 mmol) was added at
0
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9
0
room temperature. After stirred for 2 h, the reaction mixture was extracted with EtOAc, dried over
Na SO , filtered and concentrated under reduced pressure. The residue was purified by silica gel
2
4
chromatography (petroleum ether: EtOAc = 5:1) to afford 3.10
In an argon-filled glovebox, an oven-dried flask was charged with 2h (60.44 mg, 0.20 mmol),
dibromomethane (35 µL, 2.5 equiv) and THF (2 mL). The flask was capped, removed from the
o
n
glovebox, and cooled to -78 C. A solution of BuLi (200 µL, 2.5 M in hexanes, 2.5 equiv) was
added dropwise. After 10 mins, the resulting mixture was allowed to warm to rt and stirred for an
o
additional 2 h. The reaction mixture was cooled to 0 C, and a premixed solution of NaOH (2
M)/30% H
to rt and stir for 3 h. After quenched with water, the mixture was extracted with ethyl acetate twice.
The organic layers were combined, dried over Na SO , filtered and concentrated in vacuo. The
2 2
O (2:1, 3 mL) was added dropwise. The resulting solution was then allowed to warm
2
4
crude material was purified by flash column chromatography (petroleum ether: EtOAc=100:1).
Compound 4 was obtained as a colorless oil in 80% yield.11
In a round bottom flask, 2n (0.15 g, 0.5 mmol) was dissolved in a mixture solvent of THF and
H
2
O (4:1, 2 mL). NaIO
4
(0.16 g, 0.75 mmol) was then added at rt, and the suspension was stirred
for 15 mins. HCl (aq, 1.0 M, 0.50 mL) was added. After the completion of the reaction, the
reaction mixture was extracted with EtOAc. The combined organic layers were washed with H
and brine, dried over Na SO
2
O
=
, filtered and concentrated under vacuum to give 5 as a white solid.12
2
4
2
0
(S)-2-(chroman-3-yl)-carboxylate (2a): Colorless oil; 56.7 mg, yield: 87%; 94% ee; [α]
D
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+29.4 (c = 0.2, EtOH); H NMR (400 MHz, CDCl
3
): δ (ppm) 7.09 – 6.99 (m, 2H), 6.78 (dd, J =
1
2
1
4.1, 8.2 Hz, 2H), 4.37 (dd, J = 10.9, 3.4 Hz, 1H), 4.01 (t, J = 11.0 Hz, 1H), 2.80 (d, J = 8.4 Hz,
13
1
H), 1.70 (m, 1H), 1.24 (s, 12H); C{ H}NMR (100 MHz, CDCl
3
): δ (ppm) 155.00, 129.5, 127.3,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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0
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2
3
4
5
6
7
8
9
0
+
23.0, 119.800, 116.7, 83.8, 67.7, 26.7, 24.7; TOF-HRMS calcd for C15
H22BO
3
[M+H ]: 261.1661,
found 261.1659; HPLC conditions for the corresponding derived alcohol: Lux 5u Cellulose-4 (250
mm × 4.60 mm), ipa/hex = 5:95, 1.0 mL/min, 254 nm; t = 12.4 min (minor), t = 13.8 min
A
B
2
0
(
major). The optical rotation of the corresponding alcohol product after oxidation from 2a: [α]
D
=
+ 30.6 (c = 0.82, EtOH); The absolute configuration of 2a was assigned by comparison with the
optical rotation of the corresponding alcohol product after oxidation from 2a reported in literature
20
= + 28.8 (c = 0.82, EtOH)).9
(lit. [α]
D
20
2-(8-chlorochroman-3-yl)-carboxylate (2b): Colorless oil; 59.0 mg, yield: 81%; 62% ee; [α]
D
=
1
+
18.6 (c = 0.3, EtOH); H NMR (400 MHz, CDCl
3
): δ(ppm) 7.19 – 7.02 (m, 1H), 6.91 (m, 1H),
6
1
1
.71 (t, J = 7.7 Hz, 1H), 4.66 – 4.38 (m, 1H), 4.07 (t, J = 11.0 Hz, 1H), 2.80 (d, J = 8.8 Hz, 2H),
13
1
3
.88 – 1.53 (m, 1H), 1.23 (s, 12H); C{ H}NMR (100 MHz, CDCl ): δ (ppm) 150.6, 127.9, 127.7,
[M+H+]:
24.6, 121.5, 119.9, 83.6, 68.1, 29.2, 26.4, 24.8; TOF-HRMS calcd for C15H21BClO
3
295.1275, found 295.1270; SFC conditions for the corresponding derived alcohol: Lux 5u
Cellulose-4 (250 × 4.60 mm), CO
2
: MeOH = 90:10, 3 mL/min, 210 nm; t
A
= 3.7 min (minor), t
B
=
4
.5 min (major).
20
2
-(6-bromochroman-3-yl)-carboxylate (2c): Colorless oil; 55.0 mg, yield: 65%; 64% ee; [α]
D
1
=
– 2.2 (c = 0.4, EtOH); H NMR (400 MHz, CDCl
3
): δ (ppm) 7.04 (d, J = 6.5 Hz, 2H), 6.55 (d, J
= 9.4 Hz, 1H), 4.25 (dd, J = 11.0, 3.3 Hz, 1H), 3.90 (t, J = 10.8 Hz, 1H), 2.67 (d, J = 8.2 Hz, 2H),
1
3
1
1
3
.56 (m, 1H), 1.14 (s, 12H); C{ H}NMR (100 MHz, CDCl ): δ (ppm) 154.0, 132.0, 130.0, 124.9,
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118.3, 112.0, 83.6, 67.7, 29.6, 26.3, 24.8; SFC conditions for the corresponding derived alcohol:
Lux 5u Cellulose-4 (250 × 4.60 mm), CO
2
: MeOH = 90:10, 3 mL/min, 210 nm; t
A
= 3.5 min
(
minor), t
B
= 3.7 min (major).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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0
1
2
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6
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8
9
0
1
2
3
4
5
6
7
8
9
0
2
=
-(8-methylchroman-3-yl)-carboxylate (2d): Colorless oil; 58.0 mg, yield: 85%; 94% ee; [α] 2
D
0
1
3
+27.4 (c = 0.3, EtOH); H NMR (400 MHz, CDCl ): δ(ppm) 6.83 (d, J = 7.3 Hz, 1H), 6.77 (d, J
= 7.4 Hz, 1H), 6.60 (t, J = 7.4 Hz, 1H), 4.33 (dd, J = 10.9, 3.4 Hz, 1H), 3.91 (t, J = 10.9 Hz, 1H),
13
1
2
.70 (d, J = 8.6 Hz, 2H), 2.06 (s, 3H), 1.59 (td, J = 11.2, 3.3 Hz, 1H), 1.15 (s, 12H); C{ H}NMR
(100 MHz, CDCl
3
): δ (ppm) 153.1, 128.3, 127.2, 125.9, 122.1, 119.2, 83.6, 67.8, 30.4, 26.7, 24.9,
+
1
6.3; TOF-HRMS calcd for C16
H24BO
3
[M+H ]: 275.1818, found 275.1816; SFC conditions for
the corresponding derived alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO
2
: MeOH = 90:10, 3
mL/min, 210 nm; t
A
= 2.9 min (minor), t
B
= 3.1 min (major).
0
2
-(7-methylchroman-3-yl)-carboxylate (2e): Colorless oil; 56.4 mg, yield 82%; 92% ee; [α] 2
D
=
1
+
27.2 (c = 0.2, EtOH); H NMR (600 MHz, CDCl
3
): δ(ppm) 6.89 (d, J = 8.1 Hz, 1H), 6.71 – 6.52
(
m, 2H), 4.35 (dd, J = 11.9, 3.9 Hz, 1H), 3.97 (t, J = 11.5 Hz, 1H), 2.75 (d, J = 9.2 Hz, 2H), 2.24 (s,
13
1
3
H), 1.67 (m, 1H), 1.23 (s, 12H); C{ H}NMR (100 MHz, CDCl
3
): δ (ppm) 154.4, 136.9, 129.1,
[M+H+]:
75.1818, found 275.1816; SFC conditions for the corresponding derived alcohol: Lux 5u
120.4, 119.4, 117.0, 83.6, 68.2, 26.0, 24.8, 24.8, 21.2; TOF-HRMS calcd for C16H24BO
3
2
Cellulose-4 (250 × 4.60 mm), CO
2
: MeOH = 95:5, 3 mL/min, 230 nm; t
A
= 2.8 min (minor), t
B
=
3
.1 min (major).
20
2
-(8-methoxychroman-3-yl)-carboxylate (2f): Colorless oil; 63.2 mg, yield: 87%; 90% ee; [α]
D
1
= +25.6 (c = 0.2, EtOH); H NMR (400 MHz, CDCl
3
): δ(ppm) 6.74 (t, J = 7.8 Hz, 1H), 6.66 (dd, J
=
15.1, 7.1 Hz, 2H), 4.51 (dd, J = 10.6, 3.5 Hz, 1H), 4.02 (t, J = 11.2 Hz, 1H), 3.84 (s, 3H), 2.79 (d,
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J = 8.7 Hz, 2H), 1.77 – 1.64 (m, 1H), 1.24 (s, 12H); 13C{ H}NMR (100 MHz, CDCl
1
): δ (ppm)
3
1
48.4, 144.4, 123.6, 121.7, 119.2, 108.9, 83.7, 68.2, 55.9, 26.5, 24.9, 24.8; TOF-HRMS calcd for
+
C
16 4
H24BO [M+H ]: 291.1760, found 291.1765; SFC conditions for the corresponding derived
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1
1
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1
1
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8
9
0
2 A
alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO : MeOH = 90:10, 3 mL/min, 230 nm; t = 5.1
min (minor), t
B
= 5.6 min (major).
2-(7-methoxychroman-3-yl)-carboxylate (2g): Colorless oil; 50.8 mg, yield: 70%; 89% ee;
20
1
[
α]
D
3
= +26.3 (c = 0.2, EtOH); H NMR (400 MHz, CDCl ): δ(ppm) 6.90 (d, J = 8.4 Hz, 1H),
6
1
.40 (dd, J = 8.3, 2.6 Hz, 1H), 6.34 (d, J = 2.6 Hz, 1H), 4.35 (dd, J = 11.5, 3.3 Hz, 1H), 3.99 (t, J =
0.9 Hz, 1H), 3.73 (s, 3H), 2.73 (d, J = 9.5 Hz, 2H), 1.72 – 1.61 (m, 1H), 1.24(s, 12H);
13
1
C{ H}NMR (100 MHz, CDCl
3
): δ (ppm) 158.7, 155.7, 129.7, 114.6, 106.9, 101.4, 83.8, 67.9,
+
55.5, 29.8, 25.6, 24.5; TOF-HRMS calcd for C16
H24BO
4
[M+H ]: 291.1760, found 291.1765; SFC
2
conditions for the corresponding derived alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO :
MeOH = 90:10, 3 mL/min, 210 nm; t
A B
= 4.2 min (minor), t = 5.0 min (major).
2
-(8-isopropylchroman-3-yl)-carboxylate (2h): Colorless oil; 70.3 mg, yield: 92%; 92% ee;
20
1
[
α]
6.87 (d, J = 7.3 Hz, 1H), 6.78 (t, J = 7.4 Hz, 1H), 4.41 (d, J = 8.2 Hz, 1H), 4.02 (t, J = 10.7 Hz,
H), 3.25 (dt, J = 13.6, 6.8 Hz, 1H), 2.82 (d, J = 8.3 Hz, 2H), 1.69 (dd, J = 15.7, 7.3 Hz, 1H), 1.24
D
3
= +28.4 (c = 0.2, EtOH); H NMR (400 MHz, CDCl ): δ(ppm) 7.01 (d, J = 7.5 Hz, 1H),
1
13
1
(
3
s, 12H), 1.19 (d, J = 6.9 Hz, 6H); C{ H}NMR (100 MHz, CDCl ): δ (ppm) 152.2, 136.4, 127.1,
1
23.6, 122.2, 119.5, 83.5, 67.7, 29.9, 26.6, 24.7, 22.8, 22.6. TOF-HRMS calcd for C18H28BO
3
+
[
M+H ]: 303.2131, found 303.2129; SFC conditions for the corresponding derived alcohol: Lux
5u Cellulose-4 (250 × 4.60 mm), CO : MeOH = 90:10, 3 mL/min, 254 nm; t = 2.4 min (minor),
2
A
B
t = 2.6 min (major).
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2-(8-(tert-butyl)chroman-3-yl)-carboxylate (2i): Colorless oil; 68.7 mg, yield: 87%; 92% ee;
20
1
[
α]
D
= +30.9 (c = 0.5, EtOH); H NMR (400 MHz, CDCl
3
): δ(ppm) 7.06 (d, J = 7.7 Hz, 1H),
6
.89 (d, J = 7.5 Hz, 1H), 6.73 (t, J = 7.6 Hz, 1H), 4.40 (dd, J = 10.7, 3.5 Hz, 1H), 4.03 (t, J = 10.5
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 1H), 2.83 (d, J = 8.4 Hz, 2H), 1.79 – 1.59 (m, 1H), 1.34 (s, 12H), 1.23 (d, J = 4.1 Hz, 9H);
13
1
C{ H}NMR (100 MHz, CDCl
3
): δ (ppm) 154.0, 137.7, 127.8, 124.2, 122.9, 119.2, 83.6, 67.0,
+
34.8, 29.8, 29.7, 27.1, 24.8; TOF-HRMS calcd for C19
H30BO
3
[M+H ]: 317.2284, found 317.2286;
2
SFC conditions for the corresponding derived alcohol: Lux 5u Cellulose-3 (250 × 4.60 mm), CO :
MeOH = 95:5, 1.5 mL/min, 254 nm; t
A B
= 4.9 min (major), t = 5.2 min (minor).
2
-(7-(tert-butyl)chroman-3-yl)-carboxylate (2j): Colorless oil; 43.5 mg, yield: 55%; 92% ee;
20
1
[
α]
D
3
= +29.3 (c = 0.2, EtOH); H NMR (400 MHz, CDCl ): δ(ppm) 7.17 – 7.10 (m, 1H), 6.94 –
6.89 (m, 1H), 6.71 (t, J = 7.7 Hz, 1H), 4.55 – 4.48 (m, 1H), 4.07 (t, J = 11.0 Hz, 1H), 2.80 (d, J =
1
3
1
9
1
3
.2 Hz, 2H), 1.75 – 1.64 (m, 1H), 1.24 (s, 12H); C{ H}NMR (100 MHz, CDCl ): δ (ppm) 154.3,
50.7, 129.1, 119.6, 116.9, 113.6, 83.6, 67.9, 34.6, 31.4, 29.6, 26.2, 24.8; TOF-HRMS calcd for
+
C
19
H30BO
3
[M+H ]: 317.2284, found 317.2286; SFC conditions for the corresponding derived
2 A
alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO : MeOH = 95:5, 3 mL/min, 210 nm; t = 4.3
min (minor), t
B
= 4.8 min (major).
2
-(7, 8-dimethylchroman-3-yl)-carboxylate (2k): Colorless oil; 59.0 mg, yield: 82%; 94% ee;
20
1
[
α]
D
3
= +30.3 (c = 0.4, EtOH); H NMR (400 MHz, CDCl ): δ(ppm) 6.68 (d, J = 7.7 Hz, 1H), 6.53
(d, J = 7.7 Hz, 1H), 4.33 (dd, J = 10.9, 2.8 Hz, 1H), 3.88 (t, J = 11.1 Hz, 1H), 2.68 (d, J = 8.7 Hz,
13
1
2
H), 2.12 (s, 3H), 1.99 (s, 3H), 1.56 (td, J = 11.0, 3.3 Hz, 1H), 1.15 (s, 12H); C{ H}NMR (100
MHz, CDCl
3
): δ (ppm) 152.7, 135.0, 126.0, 123.9, 121.1, 119.7, 83.3, 67.9, 29.8, 26.8, 24.7, 20.1,
+
11.6; TOF-HRMS calcd for C17
H26BO
3
[M+H ]: 289.1976, found 289.1973; SFC conditions for
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the corresponding derived alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO : MeOH = 90:10, 3
mL/min, 210 nm; t
A B
= 3.3 min (minor), t = 3.5 min (major).
2
-(6, 8-dimethylchroman-3-yl)-carboxylate (2l): Colorless oil; 57.6 mg, yield: 80%; 92% ee;
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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1
2
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4
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7
8
9
0
1
2
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8
9
0
1
2
3
4
5
6
7
8
9
0
20
1
[
α]
D
= +27.9 (c = 0.2, EtOH); H NMR (400 MHz, CDCl
3
): δ(ppm) 6.68 (s, 1H), 6.58 (s, 1H),
4
.31 (dd, J = 10.9, 2.9 Hz, 1H), 3.88 (t, J = 11.0 Hz, 1H), 2.66 (d, J = 7.9 Hz, 2H), 2.11 (s, 3H),
1
3
1
2.04 (s, 3H), 1.62 – 1.52 (m, 1H), 1.15 (s, 12H); C{ H}NMR (100 MHz, CDCl
3
): δ (ppm) 150.6,
1
28.7, 127.9, 127.1, 125.2, 121.5, 83.2, 67.5, 29.4, 26.4, 24.5, 20.1, 15.6; TOF-HRMS calcd for
+
C
17 3
H26BO [M+H ]: 289.1976, found 289.1973; SFC conditions for the corresponding derived
2 A
alcohol: Lux 5u Cellulose-1 (250 × 4.60 mm), CO : MeOH = 95:5, 3 mL/min, 230 nm; t = 5.8
min (major), t
B
= 6.2 min (minor).
2-(5, 8-dimethylchroman-3-yl)-carboxylate (2m): Colorless oil; 61.2 mg, yield: 85%; 96% ee;
20
1
[
α]
D
3
= +32.1 (c = 0.3, EtOH); H NMR (400 MHz, CDCl ): δ(ppm) 6.86 (d, J = 7.5 Hz, 1H),
6
.61 (d, J = 7.5 Hz, 1H), 4.41 (m, 1H), 3.94 (t, J = 11.0 Hz, 1H), 2.73 (m, 1H), 2.59 (dd, J = 16.8,
1
1
1.6 Hz, 1H), 2.19 (s, 3H), 2.15 (s, 3H), 1.70 (m, 1H), 1.27 (s, 12H); 13C{ H}NMR (100 MHz,
CDCl
3
): δ (ppm) 151.8, 133.4, 126.1, 122.0, 119.5, 119.1, 82.2, 65.7, 23.4, 22.9, 17.6, 14.6;
+
TOF-HRMS calcd for C17
H
26BO
3
[M+H ]: 289.1976, found 289.1973; SFC conditions for the
corresponding derived alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO
2
: MeOH = 95:5, 3
A B
mL/min, 210 nm; t = 5.4 min (minor), t = 5.7 min (major).
o
2
-(5, 7, 8-trimethylchroman-3-yl)-carboxylate (2n): White solid; MP: 87-89 C, 38.5 mg, yield:
20
1
5
1%; 90% ee; [α]
D
3
= +28.2 (c = 0.2, EtOH); H NMR (400 MHz, CDCl ): δ(ppm) 6.60 (s, 1H),
4.47 (m, 1H), 4.01 – 3.92 (m, 1H), 2.77 (dd, J = 15.3, 5.6 Hz, 1H), 2.62 (dd, J = 16.7, 11.8 Hz,
1
1
H), 2.25 (s, 3H), 2.22 (s, 3H), 2.13 (s, 3H), 1.77 – 1.66 (m, 1H), 1.32 (s, 12H); 13C{ H}NMR
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6
(100 MHz, CDCl
3
): δ (ppm) 153.3, 134.3, 133.9, 122.9, 121.8, 118.2, 83.6, 67.5, 25.0, 24.6, 19.7,
+
1
8.8, 11.7; TOF-HRMS calcd for C18
H28BO
3
[M+H ]: 303.2131, found 303.2129; SFC conditions
2
for the corresponding derived alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO : MeOH = 90:10,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
A B
mL/min, 230 nm; t = 3.9 min (major), t = 4.1 min (minor).
-(8-phenylchroman-3-yl)-carboxylate (2o): Colorless oil; 71.4 mg, yield: 85%; 86% ee; [α] 20
2
D
1
= +18.2 (c = 0.3, EtOH); H NMR (600 MHz, CDCl
3
): δ(ppm) 7.52 (dd, J = 9.4, 2.3 Hz, 2H), 7.38
(t, J = 7.1 Hz, 2H), 7.32 – 7.25 (m, 1H), 7.11 (dd, J = 7.6, 1.9 Hz, 1H), 7.02 (dd, J = 7.7, 1.8 Hz,
1
H), 6.86 (t, J = 7.6 Hz, 1H), 4.38 (dd, J = 11.1, 4.3 Hz, 1H), 4.01 (t, J = 11.0 Hz, 1H), 2.88 (d, J
9.2 Hz, 2H), 1.79 – 1.65 (m, 1H), 1.23 (s, 12H); 13C{ H}NMR (100 MHz, CDCl
1
): δ (ppm)
=
3
1
51.9, 138.8, 130.0, 129.7, 129.1, 128.6, 127.9, 126.7, 123.2, 119.7, 83.6, 67.7, 29.7, 27.2, 24.8;
+
TOF-HRMS calcd for C21
H26BO
3
[M+H ]: 337.1969, found 337.1973; SFC conditions for the
2
corresponding derived alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO : MeOH = 90:10, 3
mL/min, 254 nm; t
A
= 5.4 min (minor), t
B
= 5.9 min (major).
2
-(3, 4-dihydro-2H-benzo[g]chromen-3-yl)-carboxylate (2p): Colorless oil; 54.3 mg, yield:
20
1
7
0%; 76% ee; [α]
D
3
= -2.6 (c = 0.3, EtOH); H NMR (400 MHz, CDCl ): δ(ppm) 7.86 (d, J = 8.4
Hz, 1H), 7.73 (d, J = 9.3 Hz, 1H), 7.58 (d, J = 8.9 Hz, 1H), 7.46 (m, 1H), 7.31 (m, 1H), 7.03 (d, J
8.9 Hz, 1H), 4.45 (m, 1H), 4.07 (t, J = 10.9 Hz, 1H), 3.18 (m, 1H), 2.98 (dd, J = 16.7, 11.2 Hz,
=
13
1
1
1
3
H), 1.89 – 1.78 (m, 1H), 1.28 (s, 12H); C{ H}NMR (100 MHz, CDCl ): δ (ppm) 152.7, 133.4,
29.0, 128.5, 127.6, 126.3, 123.2, 122.1, 119.3, 114.5, 83.7, 67.6, 24.9, 23.0; TOF-HRMS calcd
+
for C19
H24BO
3
[M+H ]: 311.1820, found 311.1817; HPLC conditions for the corresponding
derived alcohol: Lux 5u Cellulose-4 (250 mm × 4.60 mm), ipa/hex = 10:90, 1.0 mL/min, 254 nm;
= 9.5 min (minor), t = 12.7 min (major).
t
A
B
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2-(2, 3-dihydro-1H-benzo[f]chromen-2-yl)-carboxylate (2q): Colorless oil; 64.2 mg, yield: 83%;
1
8
1
6% ee; [α] 20
D
= +18.9 (c = 0.3, EtOH); H NMR (400 MHz, CDCl
3
): δ(ppm) 8.15 (d, J = 5.4 Hz,
H), 7.72 (d, J = 4.2 Hz, 1H), 7.40 (d, J = 4.8 Hz, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 8.4
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Hz, 1H), 4.59 (d, J = 10.9 Hz, 1H), 4.16 (t, J = 12.0 Hz, 1H), 2.91 (t, J = 14.0 Hz, 2H), 1.81 (dd, J
1
=
15.3, 12.5 Hz, 1H), 1.25 (s, 12H); 13C{ H}NMR (100 MHz, CDCl
3
): δ (ppm) 149.9, 133.2,
128.0, 127.4, 125.5, 125.1, 121.5, 119.2, 116.4, 99.9, 83.7, 68.1, 29.8, 26.7, 24.8; TOF-HRMS
+
calcd for C19
H
24BO
3
[M+H ]: 311.1820, found 311.1817; HPLC conditions for the corresponding
derived alcohol: Lux 5u Cellulose-4 (250 mm × 4.60 mm), ipa/hex =10:90, 1.0 mL/min, 254 nm;
= 7.1 min (minor), t = 7.8 min (major).
t
A
B
-isopropylchroman-3-ol (3): Colorless oil; 44.7 mg, yield 93%; 92% ee; [α] 20
8
D
= +28.4 (c = 0.2,
1
EtOH); H NMR (600 MHz, CDCl
3
): δ (ppm) 7.06 (dd, J = 7.8, 2.2 Hz, 1H), 7.01 – 6.57 (m, 2H),
4
2
.24 (m, 1H), 4.23 – 4.02 (m, 2H), 3.29 (dq, J = 14.3, 7.2 Hz, 1H), 3.11 (dd, J = 17.1, 5.6 Hz, 1H),
.80 (dd, J = 17.1, 6.7 Hz, 1H), 2.02 (s, 1H), 1.21 (dd, J = 7.1, 1.7 Hz, 6H); 13C{ H}NMR (100
1
3
MHz, CDCl ): δ (ppm) 151.0, 136.5, 127.7, 124.2, 121.0, 118.9, 69.9, 63.5, 33.9, 26.6, 22.8, 22.6;
2
SFC conditions for the corresponding derived alcohol: Lux 5u Cellulose-4 (250 × 4.60 mm), CO :
A B
MeOH = 90:10, 3 mL/min, 254 nm; t = 2.4 min (minor), t = 2.6 min (major).
20
(8-isopropylchroman-3-yl) methanol (4): Colorless oil; 33.0 mg, yield: 80%; 92% ee; [α]
D
=
1
+
3
49.6 (c = 0.2, EtOH); H NMR (600 MHz, CDCl ): δ (ppm) 7.03 (d, J = 8.5 Hz, 1H), 6.89 (d, J =
9
2
.4 Hz, 1H), 6.82 (t, J = 7.8 Hz, 1H), 4.54 – 4.21 (m, 1H), 3.99 (dd, J = 11.3, 8.0 Hz, 1H), 3.68 (m,
H), 3.26 (dt, J = 14.3, 7.2 Hz, 1H), 2.88 (dd, J = 17.1, 6.6 Hz, 1H), 2.59 (dd, J = 16.7, 8.2 Hz,1H),
2.39 – 2.11 (m,1H), 1.19 (dd, J = 7.3, 2.6 Hz, 6H); 13C{ H}NMR (100 MHz, CDCl
1
): δ (ppm)
3
1
52.0, 136.2, 127.5, 123.7 120.7, 120.2, 67.5, 63.7, 34.8, 27.6, 26.4, 22.8, 22.7; TOF-HRMS calcd
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1
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2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
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4
4
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5
5
5
5
5
5
5
5
5
6
+
19 2
for C13H O [M+H ]: 207.1379, found 207.1384; SFC conditions for the corresponding derived
alcohol: Lux 5 μm Amylose-1 (250 × 4.60 mm), CO
2
A
: MeOH = 90:10, 3 mL/min, 210 nm; t =
2
B
.6 min (minor), t = 2.9 min (major).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
(
5,7,8-trimethylchroman-3-yl) boronic acid (5): White solid; MP: 111-113 C, 81.4 mg, yield:
20
1
7
4%; [α]
D
3
= +9.4 (c = 0.4, EtOH); H NMR (400 MHz, CDCl ): δ (ppm) 6.62 (s, 1H), 4.36 –
4.17 (m, 1H), 4.16 – 3.93 (m, 2H), 2.91 (dd, J = 17.2, 5.8 Hz, 1H), 2.65 (dd, J = 17.2, 5.4 Hz, 1H),
1
2
1
.20 (s, 3H), 2.14 (s, 3H), 2.10 (s, 3H); 13C{ H}NMR (100 MHz, CDCl
3
): δ (ppm) 135.4, 134.2,
24.0, 121.8, 115.4, 100.1, 69.3, 63.8, 31.8, 19.8, 18.9, 11.6; TOF-HRMS calcd for C12H18BO
3
+
[
M+H ]: 220.1346, found 220.1347.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (Grant Nos. 21672024, 21272026,
and 21871029), Beijing Natural Science Foundation (2182025), and Beijing Municipal
Commission of Education for generous financial support.
SUPPORTING INFORMATION
NMR, HPLC and SFC spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
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M. S. Advances in Transition Metal (Pd, Ni, Fe)-Catalyzed Cross-Coupling Reactions Using
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0
[
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X.; Cheng, Z. Y.; Guo, J.; Lu, Z. Asymmetric Remote C-H Borylation of Internal Alkenes via
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Cobalt-Catalyzed Asymmetric Markovnikov Hydroboration of Styrenes. ACS Catal. 2019, 9, 4025;
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, 260. (h) Chen, J.; Guo, J.; Lu, Z. Recent Advances in Hydrometallation of Alkenes and Alkynes
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(
b) Kubota, K.; Watanabe, Y.; Hayama, K.; Ito, H. Enantioselective Synthesis of Chiral Piperidines
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1
1
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2
2
2
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7
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5
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7
8
9
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6
7
8
9
0
via the Stepwise Dearomatization/Borylation of Pyridines. J. Am. Chem. Soc. 2016, 138, 4338. (c)
Kubota, K.; Watanabe, Y.; Ito, H. Synthesis of Enantiomerically Enriched Chiral
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,2-Dihydroquinolines via Asymmetric Cu-catalyzed Borylation. Chem. Sci. 2017, 8, 4558.
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Asymmetric Pinacolboryl Addition of N-Boc-imines Using a Chiral Sulfoxide–Phosphine Ligand.
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